PMID- 28892021 TI - Near-Infrared-Triggered Photodynamic Therapy toward Breast Cancer Cells Using Dendrimer-Functionalized Upconversion Nanoparticles. AB - Water-soluble upconversion nanoparticles (UCNPs) that exhibit significant ultraviolet, blue, and red emissions under 980-nm laser excitation were successfully synthesized for performing near infrared (NIR)-triggered photodynamic therapy (PDT). The lanthanide-doped UCNPs bearing oleate ligands were first exchanged by citrates to generate polyanionic surfaces and then sequentially encapsulated with NH2-terminated poly(amido amine) (PAMAM) dendrimers (G4) and chlorine6 (Ce6) using a layer-by-layer (LBL) absorption strategy. Transmission electron microscopy and X-ray diffraction analysis confirm that the hybrid UCNPs possess a polygonal morphology with an average dimension of 16.0 +/- 2.1 nm and alpha-phase crystallinity. A simple calculation derived through thermogravimetric analysis revealed that one polycationic G4 dendrimer could be firmly accommodated by approximately 150 polyanionic citrates through multivalent interactions. Moreover, zeta potential measurements indicated that the LBL fabrication results in the hybrid nanoparticles with positively charged surfaces originated from these dendrimers, which assist the cellular uptake in biological specimens. The cytotoxic singlet oxygen based on the photosensitization of the adsorbed Ce6 through the upconversion emissions can be readily accumulated by increasing the irradiation time of the incident lasers. Compared with that of 660-nm lasers, NIR-laser excitation exhibits optimized in vitro PDT effects toward human breast cancer MCF-7 cells cultured in the tumorspheres, and less than 40% of cells survived under a low Ce6 dosage of 2.5 * 10-7 M. Fluorescence microscopy analysis indicated that the NIR-driven PDT causes more effective destruction of the cells located inside spheres that exhibit significant cancer stem cell or progenitor cell properties. Moreover, an in vivo assessment based on immunohistochemical analysis for a 4T1 tumor-bearing mouse model confirmed the effective inhibition of cancer cell proliferation through cellular DNA damage by the expression of Ki67 and gammaH2AXser139 protein markers. Thus, the hybrid UCNPs are a promising NIR-triggered PDT module for cancer treatment. PMID- 28892022 TI - Preparation of Authigenic Pyrite from Methane-bearing Sediments for In Situ Sulfur Isotope Analysis Using SIMS. AB - Different sulfur isotope compositions of authigenic pyrite typically result from the sulfate-driven anaerobic oxidation of methane (SO4-AOM) and organiclastic sulfate reduction (OSR) in marine sediments. However, unravelling the complex pyritization sequence is a challenge because of the coexistence of different sequentially formed pyrite phases. This manuscript describes a sample preparation procedure that enables the use of secondary ion mass spectroscopy (SIMS) to obtain in situ delta34S values of various pyrite generations. This allows researchers to constrain how SO4-AOM affects pyritization in methane-bearing sediments. SIMS analysis revealed an extreme range in delta34S values, spanning from -41.6 to +114.80/00, which is much wider than the range of delta34S values obtained by the traditional bulk sulfur isotope analysis of the same samples. Pyrite in the shallow sediment mainly consists of 34S-depleted framboids, suggesting early diagenetic formation by OSR. Deeper in the sediment, more pyrite occurs as overgrowths and euhedral crystals, which display much higher SIMS delta34S values than the framboids. Such 34S-enriched pyrite is related to enhanced SO4-AOM at the sulfate-methane transition zone, postdating OSR. High resolution in situ SIMS sulfur isotope analyses allow for the reconstruction of the pyritization processes, which cannot be resolved by bulk sulfur isotope analysis. PMID- 28892023 TI - Experimental Protocol to Determine the Chloride Threshold Value for Corrosion in Samples Taken from Reinforced Concrete Structures. AB - The aging of reinforced concrete infrastructure in developed countries imposes an urgent need for methods to reliably assess the condition of these structures. Corrosion of the embedded reinforcing steel is the most frequent cause for degradation. While it is well known that the ability of a structure to withstand corrosion depends strongly on factors such as the materials used or the age, it is common practice to rely on threshold values stipulated in standards or textbooks. These threshold values for corrosion initiation (Ccrit) are independent of the actual properties of a certain structure, which clearly limits the accuracy of condition assessments and service life predictions. The practice of using tabulated values can be traced to the lack of reliable methods to determine Ccrit on-site and in the laboratory. Here, an experimental protocol to determine Ccrit for individual engineering structures or structural members is presented. A number of reinforced concrete samples are taken from structures and laboratory corrosion testing is performed. The main advantage of this method is that it ensures real conditions concerning parameters that are well known to greatly influence Ccrit, such as the steel-concrete interface, which cannot be representatively mimicked in laboratory-produced samples. At the same time, the accelerated corrosion test in the laboratory permits the reliable determination of Ccrit prior to corrosion initiation on the tested structure; this is a major advantage over all common condition assessment methods that only permit estimating the conditions for corrosion after initiation, i.e., when the structure is already damaged. The protocol yields the statistical distribution of Ccrit for the tested structure. This serves as a basis for probabilistic prediction models for the remaining time to corrosion, which is needed for maintenance planning. This method can potentially be used in material testing of civil infrastructures, similar to established methods used for mechanical testing. PMID- 28892024 TI - Stereological Estimation of Dopaminergic Neuron Number in the Mouse Substantia Nigra Using the Optical Fractionator and Standard Microscopy Equipment. AB - In pre-clinical Parkinson's disease research, analysis of the nigrostriatal tract, including quantification of dopaminergic neuron loss within the substantia nigra, is essential. To estimate the total dopaminergic neuron number, unbiased stereology using the optical fractionator method is currently considered the gold standard. Because the theory behind the optical fractionator method is complex and because stereology is difficult to achieve without specialized equipment, several commercially available complete stereology systems that include the necessary software do exist, purely for cell counting reasons. Since purchasing a specialized stereology setup is not always feasible, for many reasons, this report describes a method for the stereological estimation of dopaminergic neuronal cell counts using standard microscopy equipment, including a light microscope, a motorized object table (x, y, z plane) with imaging software, and a computer for analysis. A step-by-step explanation is given on how to perform stereological quantification using the optical fractionator method, and pre programmed files for the calculation of estimated cell counts are provided. To assess the accuracy of this method, a comparison to data obtained from a commercially available stereology apparatus was performed. Comparable cell numbers were found using this protocol and the stereology device, thus demonstrating the precision of this protocol for unbiased stereology. PMID- 28892025 TI - A Novel Approach to Overcome Movement Artifact When Using a Laser Speckle Contrast Imaging System for Alternating Speeds of Blood Microcirculation. AB - The laser speckle contrast imager (LSCI) provides a powerful yet simple technique for measuring microcirculatory blood flow. Ideal for blood dynamic responses, the LSCI is used in the same way as a conventional Laser Doppler Imager (LDI). However, with a maximum skin depth of approximately 1 mm, the LSCI is designed to focus on mainly superficial blood flow. It is used to measure skin surface areas of up to 15 cm x 20 cm. The new technique introduced in this paper accounts for alternating speeds of microcirculations; i.e. both slow and fast flow flux measurement using the LSCI. The novel technique also overcomes LSCI's biggest shortcoming, which is high sensitivity to artifact movement. An adhesive opaque patch (AOP) is introduced for satisfactory recording of microcirculatory blood flow, by subtracting the LSCI signal from the AOP from the laser speckle skin signal. The optimal setting is also defined because the LSCI is most powerful when flux changes are measured relative to a reference baseline, with blood microcirculatory flux expressed as a percentage change from the baseline. These changes may be used for analyzing the status of the blood flow system. PMID- 28892026 TI - Purification of Viral DNA for the Identification of Associated Viral and Cellular Proteins. AB - The goal of this protocol is to isolate herpes simplex virus type 1 (HSV-1) DNA from infected cells for the identification of associated viral and cellular proteins by mass spectrometry. Although proteins that interact with viral genomes play major roles in determining the outcome of infection, a comprehensive analysis of viral genome associated proteins was not previously feasible. Here we demonstrate a method that enables the direct purification of HSV-1 genomes from infected cells. Replicating viral DNA is selectively labeled with modified nucleotides that contain an alkyne functional group. Labeled DNA is then specifically and irreversibly tagged via the covalent attachment of biotin azide via a copper(I)-catalyzed azide-alkyne cycloaddition or click reaction. Biotin tagged DNA is purified on streptavidin-coated beads and associated proteins are eluted and identified by mass spectrometry. This method enables the selective targeting and isolation of HSV-1 replication forks or whole genomes from complex biological environments. Furthermore, adaptation of this approach will allow for the investigation of various aspects of herpesviral infection, as well as the examination of the genomes of other DNA viruses. PMID- 28892027 TI - Novel Object Recognition Test for the Investigation of Learning and Memory in Mice. AB - The object recognition test (ORT) is a commonly used behavioral assay for the investigation of various aspects of learning and memory in mice. The ORT is fairly simple and can be completed over 3 days: habituation day, training day, and testing day. During training, the mouse is allowed to explore 2 identical objects. On test day, one of the training objects is replaced with a novel object. Because mice have an innate preference for novelty, if the mouse recognizes the familiar object, it will spend most of its time at the novel object. Due to this innate preference, there is no need for positive or negative reinforcement or long training schedules. Additionally, the ORT can also be modified for numerous applications. The retention interval can be shortened to examine short-term memory, or lengthened to probe long-term memory. Pharmacological intervention can be used at various times prior to training, after training, or prior to recall to investigate different phases of learning (i.e., acquisition, early or late consolidation, or recall). Overall, the ORT is a relatively low-stress, efficient test for memory in mice, and is appropriate for the detection of neuropsychological changes following pharmacological, biological, or genetic manipulations. PMID- 28892028 TI - Microfluidic Dry-spinning and Characterization of Regenerated Silk Fibroin Fibers. AB - The protocol demonstrates a method for mimicking the spinning process of silkworm. In the native spinning process, the contracting spinning duct enables the silk proteins to be compact and ordered by shearing and elongation forces. Here, a biomimetic microfluidic channel was designed to mimic the specific geometry of the spinning duct of the silkworm. Regenerated silk fibroin (RSF) spinning doped with high concentration, was extruded through the microchannel to dry-spin fibers at ambient temperature and pressure. In the post-treated process, the as-spun fibers were drawn and stored in ethanol aqueous solution. Synchrotron radiation wide-angle X-ray diffraction (SR-WAXD) technology was used to investigate the microstructure of single RSF fibers, which were fixed to a sample holder with the RSF fiber axis normal to the microbeam of the X-ray. The crystallinity, crystallite size, and crystalline orientation of the fiber were calculated from the WAXD data. The diffraction arcs near the equator of the two dimensional WAXD pattern indicate that the post-treated RSF fiber has a high orientation degree. PMID- 28892029 TI - Fabrication of Periodic Gold Nanocup Arrays Using Colloidal Lithography. AB - Within recent years, the field of plasmonics has exploded as researchers have demonstrated exciting applications related to chemical and optical sensing in combination with new nanofabrication techniques. A plasmon is a quantum of charge density oscillation that lends nanoscale metals such as gold and silver unique optical properties. In particular, gold and silver nanoparticles exhibit localized surface plasmon resonances-collective charge density oscillations on the surface of the nanoparticle-in the visible spectrum. Here, we focus on the fabrication of periodic arrays of anisotropic plasmonic nanostructures. These half-shell (or nanocup) structures can exhibit additional unique light-bending and polarization-dependent optical properties that simple isotropic nanostructures cannot. Researchers are interested in the fabrication of periodic arrays of nanocups for a wide variety of applications such as low-cost optical devices, surface-enhanced Raman scattering, and tamper indication. We present a scalable technique based on colloidal lithography in which it is possible to easily fabricate large periodic arrays of nanocups using spin-coating and self assembled commercially available polymeric nanospheres. Electron microscopy and optical spectroscopy from the visible to near-infrared (near-IR) was performed to confirm successful nanocup fabrication. We conclude with a demonstration of the transfer of nanocups to a flexible, conformal adhesive film. PMID- 28892030 TI - Expedited Radiation Biodosimetry by Automated Dicentric Chromosome Identification (ADCI) and Dose Estimation. AB - Biological radiation dose can be estimated from dicentric chromosome frequencies in metaphase cells. Performing these cytogenetic dicentric chromosome assays is traditionally a manual, labor-intensive process not well suited to handle the volume of samples which may require examination in the wake of a mass casualty event. Automated Dicentric Chromosome Identifier and Dose Estimator (ADCI) software automates this process by examining sets of metaphase images using machine learning-based image processing techniques. The software selects appropriate images for analysis by removing unsuitable images, classifies each object as either a centromere-containing chromosome or non-chromosome, further distinguishes chromosomes as monocentric chromosomes (MCs) or dicentric chromosomes (DCs), determines DC frequency within a sample, and estimates biological radiation dose by comparing sample DC frequency with calibration curves computed using calibration samples. This protocol describes the usage of ADCI software. Typically, both calibration (known dose) and test (unknown dose) sets of metaphase images are imported to perform accurate dose estimation. Optimal images for analysis can be found automatically using preset image filters or can also be filtered through manual inspection. The software processes images within each sample and DC frequencies are computed at different levels of stringency for calling DCs, using a machine learning approach. Linear-quadratic calibration curves are generated based on DC frequencies in calibration samples exposed to known physical doses. Doses of test samples exposed to uncertain radiation levels are estimated from their DC frequencies using these calibration curves. Reports can be generated upon request and provide summary of results of one or more samples, of one or more calibration curves, or of dose estimation. PMID- 28892031 TI - Simple Elimination of Background Fluorescence in Formalin-Fixed Human Brain Tissue for Immunofluorescence Microscopy. AB - Immunofluorescence is a common method used to visualize subcellular compartments and to determine the localization of specific proteins within a tissue sample. A great hindrance to the acquisition of high quality immunofluorescence images is endogenous autofluorescence of the tissue caused by aging pigments such as lipofuscin or by common sample preparation processes such as aldehyde fixation. This protocol describes how background fluorescence can be greatly reduced through photobleaching using white phosphor light emitting diode (LED) arrays prior to treatment with fluorescent probes. The broad-spectrum emission of white phosphor LEDs allow for bleaching of fluorophores across a range of emission peaks. The photobleaching apparatus can be constructed from off-the-shelf components at very low cost and offers an accessible alternative to commercially available chemical quenchers. A photobleaching pre-treatment of the tissue followed by conventional immunofluorescence staining generates images free of background autofluorescence. Compared to established chemical quenchers which reduced probe as well as background signals, photobleaching treatment had no effect on probe fluorescence intensity while it effectively reduced background and lipofuscin fluorescence. Although photobleaching requires more time for pre treatment, higher intensity LED arrays may be used to reduce photobleaching time. This simple method can potentially be applied to a variety of tissues, particularly postmitotic tissues that accumulate lipofuscin such as the brain and cardiac or skeletal muscles. PMID- 28892032 TI - Semi-automated Analysis of Mouse Skeletal Muscle Morphology and Fiber-type Composition. AB - For years, distinctions between skeletal muscle fiber types were best visualized by myosin-ATPase staining. More recently, immunohistochemical staining of myosin heavy chain (MyHC) isoforms has emerged as a finer discriminator of fiber-type. Type I, type IIA, type IIX and type IIB fibers can now be identified with precision based on their MyHC profile; however, manual analysis of these data can be slow and down-right tedious. In this regard, rapid, accurate assessment of fiber-type composition and morphology is a very desirable tool. Here, we present a protocol for state-of-the-art immunohistochemical staining of MyHCs in frozen sections obtained from mouse hindlimb muscle in concert with a novel semi automated algorithm that accelerates analysis of fiber-type and fiber morphology. As expected, the soleus muscle displayed staining for type I and type IIA fibers, but not for type IIX or type IIB fibers. On the other hand, the tibialis anterior muscle was composed predominantly of type IIX and type IIB fibers, a small fraction of type IIA fibers and little or no type I fibers. Several image transformations were used to generate probability maps for the purpose of measuring different aspects of fiber morphology (i.e., cross-sectional area (CSA), maximal and minimal Feret diameter). The values obtained for these parameters were then compared with manually-obtained values. No significant differences were observed between either mode of analysis with regards to CSA, maximal or minimal Feret diameter (all p > 0.05), indicating the accuracy of our method. Thus, our immunostaining analysis protocol may be applied to the investigation of effects on muscle composition in many models of aging and myopathy. PMID- 28892033 TI - Ultrasound-guided Intracardiac Injection of Human Mesenchymal Stem Cells to Increase Homing to the Intestine for Use in Murine Models of Experimental Inflammatory Bowel Diseases. AB - Crohn's disease (CD) is a common chronic inflammatory disease of the small and large intestines. Murine and human mesenchymal stem cells (MSCs) have immunosuppressive potential and have been shown to suppress inflammation in mouse models of intestinal inflammation, even though the route of administration can limit their homing and effectiveness 1,3,4,5. Local application of MSCs to colonic injury models has shown greater efficacy at ameliorating inflammation in the colon. However, there is paucity of data on techniques to enhance the localization of human bone marrow-derived MSCs (hMSCs) to the small intestine, the site of inflammation in the SAMP-1/YitFc (SAMP) model of experimental Crohn's disease. This work describes a novel technique for the ultrasound-guided intracardiac injection of hMSCs in SAMP mice, a well-characterized spontaneous model of chronic intestinal inflammation. Sex- and age-matched, inflammation-free AKR/J (AKR) mice were used as controls. To analyze the biodistribution and the localization, hMSCs were transduced with a lentivirus containing a triple reporter. The triple reporter consisted of firefly luciferase (fl), for bioluminescent imaging; monomeric red fluorescent protein (mrfp), for cell sorting; and truncated herpes simplex virus thymidine kinase (ttk), for positron emission tomography (PET) imaging. The results of this study show that 24 h after the intracardiac administration, hMSCs localize in the small intestine of SAMP mice as opposed to inflammation-free AKR mice. This novel, ultrasound-guided injection of hMSCs in the left ventricle of SAMP mice ensures a high success rate of cell delivery, allowing for the rapid recovery of mice with minimal morbidity and mortality. This technique could be a useful method for the enhanced localization of MSCs in other models of small-intestinal inflammation, such as TNFDeltaRE6. Future studies will determine if the increased localization of hMSCs by intra-arterial delivery can lead to increased therapeutic efficacy. PMID- 28892034 TI - Shifting Zebrafish Lethal Skeletal Mutant Penetrance by Progeny Testing. AB - Zebrafish mutant phenotypes are often incompletely penetrant, only manifesting in some mutants. Interesting phenotypes that inconsistently appear can be difficult to study, and can lead to confounding results. The protocol described here is a straightforward breeding paradigm to increase and decrease penetrance in lethal zebrafish skeletal mutants. Because lethal mutants cannot be selectively bred directly, the classic selective breeding strategy of progeny testing is employed. This method also includes protocols for Kompetitive Allele Specific PCR (KASP) genotyping zebrafish and staining larval zebrafish cartilage and bone. Applying the husbandry strategy described here can increase the penetrance of an interesting skeletal phenotype enabling more reproducible results in downstream applications. In addition, decreasing the mutant penetrance through this selective breeding strategy can reveal the developmental processes that most crucially require the function of the mutated gene. While the skeleton is specifically considered here, we propose that this methodology will be useful for all zebrafish mutant lines. PMID- 28892035 TI - Determination of Inorganic Arsenic in a Wide Range of Food Matrices using Hydride Generation - Atomic Absorption Spectrometry. AB - The European Food Safety Authority (EFSA) underlined in its Scientific Opinion on Arsenic in Food that in order to support a sound exposure assessment to inorganic arsenic through diet, information about distribution of arsenic species in various food types must be generated. A method, previously validated in a collaborative trial, has been applied to determine inorganic arsenic in a wide variety of food matrices, covering grains, mushrooms and food of marine origin (31 samples in total). The method is based on detection by flow injection-hydride generation-atomic absorption spectrometry of the iAs selectively extracted into chloroform after digestion of the proteins with concentrated HCl. The method is characterized by a limit of quantification of 10 ug/kg dry weight, which allowed quantification of inorganic arsenic in a large amount of food matrices. Information is provided about performance scores given to results obtained with this method and which were reported by different laboratories in several proficiency tests. The percentage of satisfactory results obtained with the discussed method is higher than that of the results obtained with other analytical approaches. PMID- 28892036 TI - An Integrated System to Remotely Trigger Intracellular Signal Transduction by Upconversion Nanoparticle-mediated Kinase Photoactivation. AB - Upconversion nanoparticle (UCNP)-mediated photoactivation is a new approach to remotely control bioeffectors with much less phototoxicity and with deeper tissue penetration. However, the existing instrumentation on the market is not readily compatible with upconversion application. Therefore, modifying the commercially available instrument is essential for this research. In this paper, we first illustrate the modifications of a conventional fluorimeter and fluorescence microscope to make them compatible for photon upconversion experiments. We then describe the synthesis of a near-infrared (NIR)-triggered caged protein kinase A catalytic subunit (PKA) immobilized on a UCNP complex. Parameters for microinjection and NIR photoactivation procedures are also reported. After the caged PKA-UCNP is microinjected into REF52 fibroblast cells, the NIR irradiation, which is significantly superior to conventional UV irradiation, efficiently triggers the PKA signal transduction pathway in living cells. In addition, positive and negative control experiments confirm that the PKA-induced pathway leading to the disintegration of stress fibers is specifically triggered by NIR irradiation. Thus, the use of protein-modified UCNP provides an innovative approach to remotely control light-modulated cellular experiments, in which direct exposure to UV light must be avoided. PMID- 28892037 TI - Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model. AB - Mutations in the CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation (CCM) in humans. Mouse models of CCM disease have been established by tamoxifen induced deletion of Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. An accurate and quantitative method to assess lesion burden and progression is essential to harness the full value of these animal models. Here, we demonstrate the induction of CCM disease in a mouse model and the use of the contrast enhanced X-ray micro computed tomography (micro CT) method to measure CCM lesion burden in mouse brains. At postnatal day 1 (P1), we used 4-hydroxytamoxifen (4HT) to activate Cre recombinase activity from the Cdh5-CreErt2 transgene to cleave the floxed allele of Ccm2. CCM lesions in mouse brains were analyzed at P8. For micro-CT, iodine based Lugol's solution was used to enhance contrast in brain tissue. We have optimized the scan parameters and utilized a voxel dimension of 9.5 um, which lead to a minimum feature size of approximately 25 um. This resolution is sufficient to measure CCM lesion volume and number globally and accurately, and provide high-quality 3-D mapping of CCM lesions in mouse brains. This method enhances the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases. PMID- 28892038 TI - Measuring Synaptic Vesicle Endocytosis in Cultured Hippocampal Neurons. AB - During endocytosis, fused synaptic vesicles are retrieved at nerve terminals, allowing for vesicle recycling and thus the maintenance of synaptic transmission during repetitive nerve firing. Impaired endocytosis in pathological conditions leads to decreases in synaptic strength and brain functions. Here, we describe methods used to measure synaptic vesicle endocytosis at the mammalian hippocampal synapse in neuronal culture. We monitored synaptic vesicle protein endocytosis by fusing a synaptic vesicular membrane protein, including synaptophysin and VAMP2/synaptobrevin, at the vesicular lumenal side, with pHluorin, a pH-sensitive green fluorescent protein that increases its fluorescence intensity as the pH increases. During exocytosis, vesicular lumen pH increases, whereas during endocytosis vesicular lumen pH is re-acidified. Thus, an increase of pHluorin fluorescence intensity indicates fusion, whereas a decrease indicates endocytosis of the labelled synaptic vesicle protein. In addition to using the pHluorin imaging method to record endocytosis, we monitored vesicular membrane endocytosis by electron microscopy (EM) measurements of Horseradish peroxidase (HRP) uptake by vesicles. Finally, we monitored the formation of nerve terminal membrane pits at various times after high potassium-induced depolarization. The time course of HRP uptake and membrane pit formation indicates the time course of endocytosis. PMID- 28892039 TI - Metabolites of flavonoid compounds preserve indices of endothelial cell nitric oxide bioavailability under glucotoxic conditions. AB - We hypothesized that metabolites of dietary flavonoids attenuate impairments in nitric oxide (NO) bioavailability evoked by glucotoxic conditions mimicking Type 1 or 2 diabetes. To test this, human aortic endothelial cells were treated with either vehicle control, quercetin-3-O-glucoronide, piceatannol or 3-(3 hydroxyphenyl)propionoic acid for 24 h. These are metabolites of quercetin, resveratrol and proanthocyanidin, respectively. Next, cells were exposed to control (5 mM) or high (25 mM) glucose conditions for 48 h, followed by insulin treatment (100 nM, 10 min) to stimulate NO production. In control glucose conditions NO production, phosphorylated to total endothelial nitric oxide synthase (p-eNOSser1177: eNOS), and phosphorylated to total Akt (p-AktSer473: Akt) were all increased by insulin stimulation. This response was abolished during high glucose conditions. Pretreatment of cells with flavonoid metabolites prior to high glucose challenge preserved insulin stimulated increases in NO production, p-AktSer473: Akt and p-eNOSSer1177: eNOS. These effects may be secondary to oxidative stress as pretreatment with all flavonoid metabolites prevented elevations in reactive oxygen and nitrogen species in response to high glucose. These data support the hypothesis that beneficial effects of flavonoids on endothelial cell function in the context of glucotoxicity, at least in part, are secondary to their metabolites. PMID- 28892040 TI - Structure of a transcribing RNA polymerase II-DSIF complex reveals a multidentate DNA-RNA clamp. AB - During transcription, RNA polymerase II (Pol II) associates with the conserved elongation factor DSIF. DSIF renders the elongation complex stable and functions during Pol II pausing and RNA processing. We combined cryo-EM and X-ray crystallography to determine the structure of the mammalian Pol II-DSIF elongation complex at a nominal resolution of 3.4 A. Human DSIF has a modular structure with two domains forming a DNA clamp, two domains forming an RNA clamp, and one domain buttressing the RNA clamp. The clamps maintain the transcription bubble, position upstream DNA, and retain the RNA transcript in the exit tunnel. The mobile C-terminal region of DSIF is located near exiting RNA, where it can recruit factors for RNA processing. The structure provides insight into the roles of DSIF during mRNA synthesis. PMID- 28892041 TI - Guide-bound structures of an RNA-targeting A-cleaving CRISPR-Cas13a enzyme. AB - CRISPR adaptive immune systems protect bacteria from infections by deploying CRISPR RNA (crRNA)-guided enzymes to recognize and cut foreign nucleic acids. Type VI-A CRISPR-Cas systems include the Cas13a enzyme, an RNA-activated RNase capable of crRNA processing and single-stranded RNA degradation upon target transcript binding. Here we present the 2.0-A resolution crystal structure of a crRNA-bound Lachnospiraceae bacterium Cas13a (LbaCas13a), representing a recently discovered Cas13a enzyme subtype. This structure and accompanying biochemical experiments define the Cas13a catalytic residues that are directly responsible for crRNA maturation. In addition, the orientation of the foreign-derived target RNA-specifying sequence in the protein interior explains the conformational gating of Cas13a nuclease activation. These results describe how Cas13a enzymes generate functional crRNAs and how catalytic activity is blocked before target RNA recognition, with implications for both bacterial immunity and diagnostic applications. PMID- 28892042 TI - Structures of the human mitochondrial ribosome in native states of assembly. AB - Mammalian mitochondrial ribosomes (mitoribosomes) have less rRNA content and 36 additional proteins compared with the evolutionarily related bacterial ribosome. These differences make the assembly of mitoribosomes more complex than the assembly of bacterial ribosomes, but the molecular details of mitoribosomal biogenesis remain elusive. Here, we report the structures of two late-stage assembly intermediates of the human mitoribosomal large subunit (mt-LSU) isolated from a native pool within a human cell line and solved by cryo-EM to ~3-A resolution. Comparison of the structures reveals insights into the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and the evolutionary adaptations that are required to preserve biogenesis after the structural diversification of mitoribosomes. Furthermore, the structures redefine the ribosome silencing factor (RsfS) family as multifunctional biogenesis factors and identify two new assembly factors (L0R8F8 and mt-ACP) not previously implicated in mitoribosomal biogenesis. PMID- 28892043 TI - Loss of PRP4K drives anoikis resistance in part by dysregulation of epidermal growth factor receptor endosomal trafficking. AB - Anoikis acts as a critical barrier to metastasis by inducing cell death upon cancer cell detachment from the extracellular matrix (ECM), thereby preventing tumor cell dissemination to secondary sites. The induction of anoikis requires the lysosomal-mediated downregulation of epidermal growth factor receptors (EGFRs) leading to termination of pro-survival signaling. In this study, we demonstrate that depletion of pre-mRNA splicing factor 4 kinase (PRP4K; also known as PRPF4B) causes dysregulation of EGFR trafficking and anoikis resistance. We also report a novel cytoplasmic localization of PRP4K at the late endosome, and demonstrate both nuclear and cytoplasmic localization in breast, lung and ovarian cancer tissue. Mechanistically, depletion of PRP4K leads to reduced EGFR degradation following cell detachment from the ECM and correlates with increased TrkB, vimentin and Zeb1 expression. As a result, PRP4K loss promotes sustained growth factor signaling and increased cellular resistance to anoikis in vitro and in a novel zebrafish xenotransplantation model of anoikis sensitivity, as well as increased metastasis in a mouse model of ovarian cancer. Thus, PRP4K may serve as a potential biomarker of anoikis sensitivity in ovarian and other epithelial cancers. PMID- 28892044 TI - A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo. AB - Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype. Therefore, we generated a transgenic MDM2-ALT1 mouse model that would allow us to investigate the effects of this splice variant on the progression of tumorigenesis. Here we show that when MDM2 ALT1 is ubiquitously expressed in p53 null mice it leads to increased incidence of spindle cell sarcomas, including RMS. Our data provide evidence that constitutive MDM2-ALT1 expression is itself an oncogenic lesion that aggravates the tumorigenesis induced by p53 loss. On the contrary, when MDM2-ALT1 is expressed solely in B-cells in the presence of homozygous wild-type p53 it leads to significantly increased lymphomagenesis (56%) when compared with control mice (27%). However, this phenotype is observable only at later stages in life (?18 months). Moreover, flow cytometric analyses for B-cell markers revealed an MDM2 ALT1-associated decrease in the B-cell population of the spleens of these animals. Our data suggest that the B-cell loss is p53 dependent and is a response mounted to persistent MDM2-ALT1 expression in a wild-type p53 background. Overall, our findings highlight the importance of an MDM2 splice variant as a critical modifier of both p53-dependent and -independent tumorigenesis, underscoring the complexity of MDM2 posttranscriptional regulation in cancer. Furthermore, MDM2-ALT1-expressing p53 null mice represent a novel mouse model of fusion-negative RMS. PMID- 28892045 TI - MN1 overexpression is driven by loss of DNMT3B methylation activity in inv(16) pediatric AML. AB - In acute myeloid leukemia (AML), specific genomic aberrations induce aberrant methylation, thus directly influencing the transcriptional programing of leukemic cells. Therefore, therapies targeting epigenetic processes are advocated as a promising therapeutic tool for AML treatment. However, to develop new therapies, a comprehensive understanding of the mechanism(s) driving the epigenetic changes as a result of acquired genetic abnormalities is necessary. This understanding is still lacking. In this study, we performed genome-wide CpG-island methylation profiling on pediatric AML samples. Six differentially methylated genomic regions within two genes, discriminating inv(16)(p13;q22) from non-inv(16) pediatric AML samples, were identified. All six regions had a hypomethylated phenotype in inv(16) AML samples, and this was most prominent at the regions encompassing the meningioma (disrupted in balanced translocation) 1 (MN1) oncogene. MN1 expression primarily correlated with the methylation level of the 3' end of the MN1 exon-1 locus. Decitabine treatment of different cell lines showed that induced loss of methylation at the MN1 locus can result in an increase of MN1 expression, indicating that MN1 expression is coregulated by DNA methylation. To investigate this methylation-associated mechanism, we determined the expression of DNA methyltransferases in inv(16) AML. We found that DNMT3B expression was significantly lower in inv(16) samples. Furthermore, DNMT3B expression correlated negatively with MN1 expression in pediatric AML samples. Importantly, depletion of DNMT3B impaired remethylation efficiency of the MN1 exon-1 locus in AML cells after decitabine exposure. These findings identify DNMT3B as an important coregulator of MN1 methylation. Taken together, this study shows that the methylation level of the MN1 exon-1 locus regulates MN1 expression levels in inv(16) pediatric AML. This methylation level is dependent on DNMT3B, thus suggesting a role for DNMT3B in leukemogenesis in inv(16) AML, through MN1 methylation regulation. PMID- 28892046 TI - Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors. AB - Most anticancer therapies to date focus on druggable features of tumor epithelia. Despite the increasing repertoire of treatment options, patient responses remain varied. Moreover, tumor resistance and relapse remain persistent clinical challenges. These observations imply an incomplete understanding of tumor heterogeneity. The tumor microenvironment is a major determinant of disease progression and therapy outcome. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive stroma of tumors. They orchestrate paracrine pro-tumorigenic signaling with adjacent tumor cells, thus exacerbating the hallmarks of cancer and accelerating tumor malignancy. Although CAF-derived soluble factors have been investigated for tumor stroma-directed therapy, the underlying transcriptional programs that enable the oncogenic functions of CAFs remain poorly understood. Nuclear receptors (NRs), a large family of ligand responsive transcription factors, are pharmacologically viable targets for the suppression of CAF-facilitated oncogenesis. In this study, we defined the expression profiles of NRs in CAFs from clinical cutaneous squamous cell carcinoma (SCC) biopsies. We further identified a cluster of driver NRs in CAFs as important modifiers of CAF function with profound influence on cancer cell invasiveness, proliferation, drug resistance, energy metabolism and oxidative stress status. Importantly, guided by the NR profile of CAFs, retinoic acid receptor beta and androgen receptor antagonists were identified for concurrent therapy with cisplatin, resulting in the inhibition of chemoresistance in recurred SCC:CAF xenografts. Our work demonstrates that treatments targeting both the tumor epithelia and the surrounding CAFs can extend the efficacy of conventional chemotherapy. PMID- 28892047 TI - A system for detecting high impact-low frequency mutations in primary tumors and metastases. AB - Tumor complexity and intratumor heterogeneity contribute to subclonal diversity. Despite advances in next-generation sequencing (NGS) and bioinformatics, detecting rare mutations in primary tumors and metastases contributing to subclonal diversity is a challenge for precision genomics. Here, in order to identify rare mutations, we adapted a recently described epithelial reprograming assay for short-term propagation of epithelial cells from primary and metastatic tumors. Using this approach, we expanded minor clones and obtained epithelial cell-specific DNA/RNA for quantitative NGS analysis. Comparative Ampliseq Comprehensive Cancer Panel sequence analyses were performed on DNA from unprocessed breast tumor and tumor cells propagated from the same tumor. We identified previously uncharacterized mutations present only in the cultured tumor cells, a subset of which has been reported in brain metastatic but not primary breast tumors. In addition, whole-genome sequencing identified mutations enriched in liver metastases of various cancers, including Notch pathway mutations/chromosomal inversions in 5/5 liver metastases, irrespective of cancer types. Mutations/rearrangements in FHIT, involved in purine metabolism, were detected in 4/5 liver metastases, and the same four liver metastases shared mutations in 32 genes, including mutations of different HLA-DR family members affecting OX40 signaling pathway, which could impact the immune response to metastatic cells. Pathway analyses of all mutated genes in liver metastases showed aberrant tumor necrosis factor and transforming growth factor signaling in metastatic cells. Epigenetic regulators including KMT2C/MLL3 and ARID1B, which are mutated in >50% of hepatocellular carcinomas, were also mutated in liver metastases. Thus, irrespective of cancer types, organ-specific metastases may share common genomic aberrations. Since recent studies show independent evolution of primary tumors and metastases and in most cases mutation burden is higher in metastases than primary tumors, the method described here may allow early detection of subclonal somatic alterations associated with metastatic progression and potentially identify therapeutically actionable, metastasis-specific genomic aberrations. PMID- 28892048 TI - CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A. AB - Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRASG12D expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRASG12D overexpression in these cells activated transforming growth factor-beta signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery. PMID- 28892049 TI - Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. AB - Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. Although it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL (Neu DeLetion mutant) model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with platelets and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation. PMID- 28892051 TI - A map of high-mobility molecular semiconductors. AB - The charge mobility of molecular semiconductors is limited by the large fluctuation of intermolecular transfer integrals, often referred to as off diagonal dynamic disorder, which causes transient localization of the carriers' eigenstates. Using a recently developed theoretical framework, we show here that the electronic structure of the molecular crystals determines its sensitivity to intermolecular fluctuations. We build a map of the transient localization lengths of high-mobility molecular semiconductors to identify what patterns of nearest neighbour transfer integrals in the two-dimensional (2D) high-mobility plane protect the semiconductor from the effect of dynamic disorder and yield larger mobility. Such a map helps rationalizing the transport properties of the whole family of molecular semiconductors and is also used to demonstrate why common textbook approaches fail in describing this important class of materials. These results can be used to rapidly screen many compounds and design new ones with optimal transport characteristics. PMID- 28892050 TI - Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N glycosylation. AB - Aberrant protein glycosylation could be a distinct surface-marker of cancer cells that influences cancer progression and metastasis because glycosylation can regulate membrane protein folding which alters receptor activation and changes epitope exposure for antibody (Ab) recognition. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol-anchored protein, is a heavily glycosylated tumor antigen. However, the clinical significance and biological effect of CEACAM6 glycosylation has not been addressed in cancers. We recently developed an anti-CEACAM6 Ab (TMU) from an immune llama library which can be engineered to a single-domain (sd)Ab or a heavy-chain (HC)Ab. The TMU HCAb specifically recognized glycosylated CEACAM6 compared to the conventional antibodies. Using the TMU HCAb, we found that glycosylated CEACAM6 was a tumor marker associated with recurrence in early-stage OSCC (oral squamous cell carcinoma) patients. CEACAM6 promoted OSCC cell invasion, migration, cytoskeletal rearrangement, and metastasis via interaction with epidermal growth factor (EGF) receptor (EGFR) and enhancing EGFR activation, clustering and intracellular signaling cascades. These functions were modulated by N acetylglucosaminyltransferase 5 (MGAT5) which mediated N-glycosylation at Asn256 (N256) of CEACAM6. Finally, the TMU sdAb and HCAb treatment inhibited the migration, invasion and EGF-induced signaling in CEACAM6-overexpressing cells. In conclusion, the complex N-glycosylation of CEACAM6 is critical for EGFR signaling of OSCC invasion and metastasis. Targeting glycosylated CEACAM6 with the TMU sdAb or TMU HCAb could be a feasible therapy for OSCC. PMID- 28892052 TI - Cell mechanics: When tissues collide. PMID- 28892053 TI - Organic semiconductors: A map to find winners. PMID- 28892055 TI - Electrotunable nanoplasmonic liquid mirror. AB - Recently, there has been a drive to design and develop fully tunable metamaterials for applications ranging from new classes of sensors to superlenses among others. Although advances have been made, tuning and modulating the optical properties in real time remains a challenge. We report on the first realization of a reversible electrotunable liquid mirror based on voltage-controlled self assembly/disassembly of 16 nm plasmonic nanoparticles at the interface between two immiscible electrolyte solutions. We show that optical properties such as reflectivity and spectral position of the absorption band can be varied in situ within +/-0.5 V. This observed effect is in excellent agreement with theoretical calculations corresponding to the change in average interparticle spacing. This electrochemical fully tunable nanoplasmonic platform can be switched from a highly reflective 'mirror' to a transmissive 'window' and back again. This study opens a route towards realization of such platforms in future micro/nanoscale electrochemical cells, enabling the creation of tunable plasmonic metamaterials. PMID- 28892054 TI - Long-lived force patterns and deformation waves at repulsive epithelial boundaries. AB - For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries are commonly attributed to mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical events. Following contact between two epithelial monolayers expressing, respectively, EphB2 and its ligand ephrinB1, both monolayers exhibit oscillatory patterns of traction forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. With time, monolayers jam, accompanied by the emergence of deformation waves that propagate away from the boundary. This phenomenon is not specific to EphB2/ephrinB1 repulsion but is also present during the formation of boundaries with an inert interface and during fusion of homotypic epithelial layers. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary. PMID- 28892056 TI - Observation of the spin Nernst effect. AB - The observation of the spin Hall effect triggered intense research on pure spin current transport. With the spin Hall effect, the spin Seebeck effect and the spin Peltier effect already observed, our picture of pure spin current transport is almost complete. The only missing piece is the spin Nernst (-Ettingshausen) effect, which so far has been discussed only on theoretical grounds. Here, we report the observation of the spin Nernst effect. By applying a longitudinal temperature gradient, we generate a pure transverse spin current in a Pt thin film. For readout, we exploit the magnetization-orientation-dependent spin transfer to an adjacent yttrium iron garnet layer, converting the spin Nernst current in Pt into a controlled change of the longitudinal and transverse thermopower voltage. Our experiments show that the spin Nernst and the spin Hall effect in Pt are of comparable magnitude, but differ in sign, as corroborated by first-principles calculations. PMID- 28892057 TI - Reactivations of emotional memory in the hippocampus-amygdala system during sleep. AB - The consolidation of context-dependent emotional memory requires communication between the hippocampus and the basolateral amygdala (BLA), but the mechanisms of this process are unknown. We recorded neuronal ensembles in the hippocampus and BLA while rats learned the location of an aversive air puff on a linear track, as well as during sleep before and after training. We found coordinated reactivations between the hippocampus and the BLA during non-REM sleep following training. These reactivations peaked during hippocampal sharp wave-ripples (SPW Rs) and involved a subgroup of BLA cells positively modulated during hippocampal SPW-Rs. Notably, reactivation was stronger for the hippocampus-BLA correlation patterns representing the run direction that involved the air puff than for the 'safe' direction. These findings suggest that consolidation of contextual emotional memory occurs during ripple-reactivation of hippocampus-amygdala circuits. PMID- 28892058 TI - Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis. AB - Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9-Brn2 and Isl1 Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS. PMID- 28892059 TI - A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. AB - Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 * 10-6) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 * 10-8) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis-expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD. PMID- 28892060 TI - A functional genomics predictive network model identifies regulators of inflammatory bowel disease. AB - A major challenge in inflammatory bowel disease (IBD) is the integration of diverse IBD data sets to construct predictive models of IBD. We present a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through genome-wide association studies (GWAS) using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD. Our model consists of individual networks constructed using molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease. We performed key driver analysis to identify genes predicted to modulate network regulatory states associated with IBD, prioritizing and prospectively validating 12 of the top key drivers experimentally. This validated key driver set not only introduces new regulators of processes central to IBD but also provides the integrated circuits of genetic, molecular, and clinical traits that can be directly queried to interrogate and refine the regulatory framework defining IBD. PMID- 28892061 TI - Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection. AB - Recent work has hinted at the linkage disequilibrium (LD)-dependent architecture of human complex traits, where SNPs with low levels of LD (LLD) have larger per SNP heritability. Here we analyzed summary statistics from 56 complex traits (average N = 101,401) by extending stratified LD score regression to continuous annotations. We determined that SNPs with low LLD have significantly larger per SNP heritability and that roughly half of this effect can be explained by functional annotations negatively correlated with LLD, such as DNase I hypersensitivity sites (DHSs). The remaining signal is largely driven by our finding that more recent common variants tend to have lower LLD and to explain more heritability (P = 2.38 * 10-104); the youngest 20% of common SNPs explain 3.9 times more heritability than the oldest 20%, consistent with the action of negative selection. We also inferred jointly significant effects of other LD related annotations and confirmed via forward simulations that they jointly predict deleterious effects. PMID- 28892062 TI - Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. AB - Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people (n = 173,430), we found 85 loci significantly associated with obesity (P < 5.0 * 10 8), of which 51 were previously unknown. We conducted trans-ancestral meta analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19+ cells. We also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 * 10-5, rg = 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity. PMID- 28892063 TI - Interpreting short tandem repeat variations in humans using mutational constraint. AB - Identifying regions of the genome that are depleted of mutations can distinguish potentially deleterious variants. Short tandem repeats (STRs), also known as microsatellites, are among the largest contributors of de novo mutations in humans. However, per-locus studies of STR mutations have been limited to highly ascertained panels of several dozen loci. Here we harnessed bioinformatics tools and a novel analytical framework to estimate mutation parameters for each STR in the human genome by correlating STR genotypes with local sequence heterozygosity. We applied our method to obtain robust estimates of the impact of local sequence features on mutation parameters and used these estimates to create a framework for measuring constraint at STRs by comparing observed versus expected mutation rates. Constraint scores identified known pathogenic variants with early-onset effects. Our metric will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies. PMID- 28892064 TI - A mouse model for embryonal tumors with multilayered rosettes uncovers the therapeutic potential of Sonic-hedgehog inhibitors. AB - Embryonal tumors with multilayered rosettes (ETMRs) have recently been described as a new entity of rare pediatric brain tumors with a fatal outcome. We show here that ETMRs are characterized by a parallel activation of Shh and Wnt signaling. Co-activation of these pathways in mouse neural precursors is sufficient to induce ETMR-like tumors in vivo that resemble their human counterparts on the basis of histology and global gene-expression analyses, and that point to apical radial glia cells as the possible tumor cell of origin. Overexpression of LIN28A, which is a hallmark of human ETMRs, augments Sonic-hedgehog (Shh) and Wnt signaling in these precursor cells through the downregulation of let7-miRNA, and LIN28A/let7a interaction with the Shh pathway was detected at the level of Gli mRNA. Finally, human ETMR cells that were transplanted into immunocompromised host mice were responsive to the SHH inhibitor arsenic trioxide (ATO). Our work provides a novel mouse model in which to study this tumor type, demonstrates the driving role of Wnt and Shh activation in the growth of ETMRs and proposes downstream inhibition of Shh signaling as a therapeutic option for patients with ETMRs. PMID- 28892065 TI - Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4. AB - Malaria, caused by the protozoan Plasmodium, is a devastating mosquito-borne disease with the potential to affect nearly half the world's population. Despite mounting substantial T and B cell responses, humans fail to efficiently control blood-stage malaria or develop sterilizing immunity to reinfections. Although forkhead box P3 (FOXP3)+CD4+ regulatory T (Treg) cells form a part of these responses, their influence remains disputed and their mode of action is unknown. Here we show that Treg cells expand in both humans and mice in blood-stage malaria and interfere with conventional T helper cell responses and follicular T helper (TFH)-B cell interactions in germinal centers. Mechanistically, Treg cells function in a critical temporal window to impede protective immunity through cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Targeting Treg cells or CTLA-4 in this precise window accelerated parasite clearance and generated species-transcending immunity to blood-stage malaria in mice. Our study uncovers a critical mechanism of immunosuppression associated with blood-stage malaria that delays parasite clearance and prevents development of potent adaptive immunity to reinfection. These data also reveal a temporally discrete and potentially therapeutically amenable functional role for Treg cells and CTLA-4 in limiting antimalarial immunity. PMID- 28892066 TI - Effects of vagus nerve stimulation on extinction of conditioned fear and post traumatic stress disorder symptoms in rats. AB - Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD. PMID- 28892067 TI - Association of the serotonin transporter-linked polymorphic region genotype with lower bone mineral density. AB - The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) S allele is linked to pathogenesis of depression and slower response to selective serotonin reuptake inhibitors (SSRIs); depression and SSRIs are independently associated with bone loss. We aimed to determine whether 5-HTTLPR was associated with bone loss. This cross-sectional study included psychiatric patients with both 5-HTTLPR analysis and bone mineral density (BMD) assessment (hip and spine Z-scores if age <50 years and T-scores if ?50 years). BMD association with 5-HTTLPR was evaluated under models with additive allele effects and dominant S allele effects using linear regression models. Patients were stratified by age (<50 and ?50 years) and sex. Of 3016 patients with 5-HTTLPR genotyping, 239 had BMD assessments. Among the younger patients, the S allele was associated with lower Z-scores at the hip (P=0.002, dominant S allele effects; P=0.004, additive allele effects) and spine (P=0.0006, dominant S allele effects; P=0.01, additive allele effects). In sex-stratified analyses, the association of the S allele with lower BMD in the younger patients was also significant in the subset of women (P?0.003 for both hip and spine BMD under the additive allele effect model). In the small group of men younger than 50 years, the S allele was marginally associated with higher spine BMD (P=0.05). BMD T-scores were not associated with 5-HTTLPR genotypes in patients 50 years or older. The 5-HTTLPR variants may modify serotonin effects on bone with sex specific effects. PMID- 28892068 TI - Dysregulation of objectively assessed 24-hour motor activity patterns as a potential marker for bipolar I disorder: results of a community-based family study. AB - There has been a growing number of studies that have employed actigraphy to investigate differences in motor activity in mood disorders. In general, these studies have shown that people with bipolar disorders (BPDs) tend to exhibit greater variability and less daytime motor activity than controls. The goal of this study was to examine whether patterns of motor activity differ in euthymic individuals across the full range of mood disorder subtypes (Bipolar I (BPI), Bipolar II (BPII) and major depression (MDD)) compared with unaffected controls in a community-based family study of mood spectrum disorders. Minute-to-minute activity counts derived from actigraphy were collected over a 2-week period for each participant. Prospective assessments of the level, timing and day-to-day variability of physical activity measures were compared across diagnostic groups after controlling for a comprehensive list of potential confounding factors. After adjusting for the effects of age, sex, body mass index (BMI) and medication use, the BPI group had lower median activity intensity levels across the second half of the day and greater variability in the afternoon compared with controls. Those with a history of BPII had increased variability during the night time compared with controls, indicating poorer sleep quality. No differences were found in the average intensity, variability or timing of activity in comparisons between other mood disorder subgroups and controls. Findings confirm evidence from previous studies that BPI may be a manifestation of a rhythm disturbance that is most prominent during the second half of the day. The present study is the largest study to date that included the full range of mood disorder subgroups in a nonclinical sample that increases the generalizability of our findings to the general community. The manifestations of activity patterns outside of acute episodes add to the accumulating evidence that dysregulation of patterns of activity may constitute a potential biomarker for BPD. PMID- 28892069 TI - Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. AB - The establishment of mechanism-driven peripheral markers is important for translational psychiatry. Many groups, including ours, have addressed molecular alterations in peripheral tissues in association with symptomatic changes in major illnesses. Oxidative stress is implicated in the pathophysiology of schizophrenia (SZ) and bipolar disorder (BP) through studies of patient peripheral tissues and animal models. Although the relationship between peripheral changes and brain pathology remain elusive, oxidative stress may bridge such translational efforts. Nonetheless, the molecular substrates of oxidative stress are not well defined in mental conditions. Glutathione (GSH) is a non-enzymatic antioxidant that eliminates free radicals, and has been suggested to have a role in SZ. We performed a cross-sectional study of 48 healthy controls (CON), 52 SZ patients and 62 BP patients to compare the levels of peripheral GSH by a biochemical enzyme assay. We show a significant reduction of plasma GSH in both SZ and BP patients compared with CON. We evaluated possible influences of clinical characteristics on the level of GSH in SZ and BP. A decrease in GSH level correlated with Positive and Negative Syndrome Scale (PANSS) total and positive scores for SZ and correlated with the PANSS general for BP. Taken together, we provide evidence that SZ and BP display a common molecular signature in the reduction of peripheral GSH in the psychosis dimension. PMID- 28892070 TI - Anterior cingulate cortex gamma-aminobutyric acid deficits in youth with depression. AB - Abnormally low gamma-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12-21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder. PMID- 28892071 TI - A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility. AB - Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P=0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder. PMID- 28892072 TI - Neuregulin signaling pathway in smoking behavior. AB - Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine dependence and nicotine withdrawal. We comprehensively annotated the associated variants using expression (eQTL) and methylation quantitative trait loci (meQTL) analyses in a Finnish population sample. Among the 66 variants, we identified 25 eQTLs (in NRG1 and ERBB4), 22 meQTLs (in NRG3, ERBB4 and PSENEN), a missense variant in NRG1 (rs113317778) and a splicing disruption variant in ERBB4 (rs13385826). Majority of the QTLs in blood were replicated in silico using publicly available databases, with additional QTLs observed in brain. In conclusion, our results support the involvement of NSP in smoking behavior but not in alcohol use and abuse, and disclose functional potential for 56 of the 66 associated single nucleotide polymorphism. PMID- 28892074 TI - Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries. AB - The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) is usually achieved by exogenous induction of transcription by factors acting in the nucleus. In contrast, during development, signaling pathways initiated at the membrane induce differentiation. The central idea of this study is to identify antibodies that can catalyze cellular de-differentiation and nuclear reprogramming by acting at the cell surface. We screen a lentiviral library encoding ~100 million secreted and membrane-bound single-chain antibodies and identify antibodies that can replace either Sox2 and Myc (c-Myc) or Oct4 during reprogramming of mouse embryonic fibroblasts into iPSCs. We show that one Sox2-replacing antibody antagonizes the membrane-associated protein Basp1, thereby de-repressing nuclear factors WT1, Esrrb and Lin28a (Lin28) independent of Sox2. By manipulating this pathway, we identify three methods to generate iPSCs. Our results establish unbiased selection from autocrine combinatorial antibody libraries as a robust method to discover new biologics and uncover membrane-to-nucleus signaling pathways that regulate pluripotency and cell fate. PMID- 28892073 TI - Progress and roadblocks in the search for brain-based biomarkers of autism and attention-deficit/hyperactivity disorder. AB - Children with neurodevelopmental disorders benefit most from early interventions and treatments. The development and validation of brain-based biomarkers to aid in objective diagnosis can facilitate this important clinical aim. The objective of this review is to provide an overview of current progress in the use of neuroimaging to identify brain-based biomarkers for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), two prevalent neurodevelopmental disorders. We summarize empirical work that has laid the foundation for using neuroimaging to objectively quantify brain structure and function in ways that are beginning to be used in biomarker development, noting limitations of the data currently available. The most successful machine learning methods that have been developed and applied to date are discussed. Overall, there is increasing evidence that specific features (for example, functional connectivity, gray matter volume) of brain regions comprising the salience and default mode networks can be used to discriminate ASD from typical development. Brain regions contributing to successful discrimination of ADHD from typical development appear to be more widespread, however there is initial evidence that features derived from frontal and cerebellar regions are most informative for classification. The identification of brain-based biomarkers for ASD and ADHD could potentially assist in objective diagnosis, monitoring of treatment response and prediction of outcomes for children with these neurodevelopmental disorders. At present, however, the field has yet to identify reliable and reproducible biomarkers for these disorders, and must address issues related to clinical heterogeneity, methodological standardization and cross-site validation before further progress can be achieved. PMID- 28892075 TI - Analysis of somatic microsatellite indels identifies driver events in human tumors. AB - Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3). PMID- 28892076 TI - Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring. AB - Studies of the dynamics of the antibody-mediated immune response have been hampered by the absence of quantitative, high-throughput systems to analyze individual antibody-secreting cells. Here we describe a simple microfluidic system, DropMap, in which single cells are compartmentalized in tens of thousands of 40-pL droplets and analyzed in two-dimensional droplet arrays using a fluorescence relocation-based immunoassay. Using DropMap, we characterized antibody-secreting cells in mice immunized with tetanus toxoid (TT) over a 7-week protocol, simultaneously analyzing the secretion rate and affinity of IgG from over 0.5 million individual cells enriched from spleen and bone marrow. Immunization resulted in dramatic increases in the range of both single-cell secretion rates and affinities, which spanned at maximum 3 and 4 logs, respectively. We observed differences over time in dynamics of secretion rate and affinity within and between anatomical compartments. This system will not only enable immune monitoring and optimization of immunization and vaccination protocols but also potentiate antibody screening. PMID- 28892077 TI - Mapping the secrets of the antibody pool. PMID- 28892078 TI - Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities. AB - The formation of protein complexes and the co-regulation of the cellular concentrations of proteins are essential mechanisms for cellular signaling and for maintaining homeostasis. Here we use isobaric-labeling multiplexed proteomics to analyze protein co-regulation and show that this allows the identification of protein-protein associations with high accuracy. We apply this 'interactome mapping by high-throughput quantitative proteome analysis' (IMAHP) method to a panel of 41 breast cancer cell lines and show that deviations of the observed protein co-regulations in specific cell lines from the consensus network affects cellular fitness. Furthermore, these aberrant interactions serve as biomarkers that predict the drug sensitivity of cell lines in screens across 195 drugs. We expect that IMAHP can be broadly used to gain insight into how changing landscapes of protein-protein associations affect the phenotype of biological systems. PMID- 28892079 TI - Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. AB - Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of alpha5beta1 integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway. PMID- 28892080 TI - Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. AB - Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+ CaMKII-NF-kappaB signalling and suppresses LTBP1-mediated TGF-beta secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-beta signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches. PMID- 28892081 TI - A20 promotes metastasis of aggressive basal-like breast cancers through multi monoubiquitylation of Snail1. AB - Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF beta1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3beta (GSK3beta), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-beta1-induced EMT and metastasis of basal-like breast cancers. PMID- 28892082 TI - Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle. AB - Nuclear movements are important for multiple cellular functions, and are driven by polarized forces generated by motor proteins and the cytoskeleton. During skeletal myofibre formation or regeneration, nuclei move from the centre to the periphery of the myofibre for proper muscle function. Centrally located nuclei are also found in different muscle disorders. Using theoretical and experimental approaches, we demonstrate that nuclear movement to the periphery of myofibres is mediated by centripetal forces around the nucleus. These forces arise from myofibril contraction and crosslinking that 'zip' around the nucleus in combination with tight regulation of nuclear stiffness by lamin A/C. In addition, an Arp2/3 complex containing Arpc5L together with gamma-actin is required to organize desmin to crosslink myofibrils for nuclear movement. Our work reveals that centripetal forces exerted by myofibrils squeeze the nucleus to the periphery of myofibres. PMID- 28892083 TI - Depression and anxiety following hematopoietic stem cell transplantation: a prospective population-based study in Germany. AB - In this prospective multicenter study, we investigated the course of depression and anxiety during hematopoietic stem cell transplantation (HSCT) until 5 years after transplantation adjusting for medical information. Patients were consulted before HSCT (n=239), at 3 months (n=150), 12 months (n=102) and 5 years (n=45) after HSCT. Depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS). Detailed medical and demographic information was collected. Prevalence rates were compared with an age- and gender-matched control group drawn from a large representative sample (n=4110). The risk of depression before HSCT was lower for patients than for the control group (risk ratio (RR), 0.56; 95% confidence interval (CI), 0.39/0.81). Prevalence rates of depression increased from 12 to 30% until 5 years post HSCT. Anxiety rates were most frequently increased before HSCT (29%, RR, 1.31; 95% CI, 1.02/1.68) and then reached a stable level comparable to the background population (RR 0.83, 95% CI, 0.56/1.22). This study confirms the low levels of depression in the short term after HSCT and identifies depression as a long-term effect. Furthermore, it confirms previous results of heightened anxiety before HSCT. Surveillance of symptoms of anxiety during the short-term phase of HSCT and of depression during the following years is crucial. PMID- 28892084 TI - Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation: a retrospective analysis of the EBMT chronic malignancies working party. AB - The International Prognostic Scoring System has been revised (IPSS-R) to predict prognosis of patients with myelodysplastic syndromes at diagnosis. To validate the use of the IPSS-R assessed before transplant rather than at diagnosis we performed a retrospective analysis of the EBMT database. A total of 579 patients had sufficient information available to calculate IPSS-R at transplant. Median overall survival (OS) from transplant was significantly different according to IPSS-R: very low 23.6 months, low 55.0 months, intermediate 19.7 months, high 13.5 months, very high 7.8 months (P<0.001). In a multivariate Cox model the following parameters were significant risk factors for OS: IPSS-R, graft source, age and prior treatment. Median relapse free survival also showed significant differences according to IPSS-R: very low: 23.6 months, low: 24.8 months, intermediate 10.6 months, high 7.9 months, very high 5.5 months (P<0.001). Multivariate risk factors for relapse-free survival (RFS) were: IPSS-R, reduced intensity conditioning, graft source and prior treatment. A trend for an increased relapse incidence was noted for very high risk IPSS-R. We conclude that the IPSS-R at transplant is a useful prognostic score for predicting OS and RFS after transplantation, capturing both disease evolution and response to prior treatment before transplant. PMID- 28892085 TI - Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation. AB - The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity 'endothelial GvHD' as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an 'on demand' evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972). PMID- 28892086 TI - Allogeneic stem cell transplantation and subsequent treatments as a comprehensive strategy for long-term survival of multiple myeloma patients. AB - We evaluated 71 patients treated with allogeneic hematopoietic cell transplantation (allo-HCT) for multiple myeloma (MM). Forty-three patients (61%) received allo-HCT after the first line of therapy. Fifty-eight patients (82%) had chemosensitive disease at the time of allo-HCT. A HLA-matched related or unrelated donor was available for 68 patients (96%). Non-myeloablative or reduced intensity conditioning regimen and peripheral blood hematopoietic cells as a graft source were used in most patients. The cumulative incidence of grade II-IV acute GVHD at day +100 and chronic GVHD at 5 years was 13% (95% CI 7-23%) and 35% (95% CI 24-46), respectively. Non-relapse mortality and relapse/progression incidence at 5 years were 12% (95% CI 5-23) and 65% (95% CI 49-76), respectively. With a median follow-up in survivors of 100 months (range 16-186), the 5-year PFS and OS were 39% (95% CI 27-52) and 60% (95% CI 55-77), respectively. On multivariate analysis: age >55 years was associated with both a reduced PFS (RR 2.11, 95% CI 1.15-3.87) and OS (RR 5.53, 95% CI 2.22-13.76); chemorefractory disease at allo-HCT was associated with both reduced PFS (RR 3.09, 95% CI 1.37 7.00) and OS (RR 3.19, 95% CI 1.23-8.22). At relapse, 24 patients (56%) received bortezomib, 28 (65%) lenalidomide, 11 (26%) pomalidomide, 16 (37%) donor lymphocytes infusion as part of salvage therapy after allo-HCT relapse. Median PFS from time of salvage treatment was 7 months (range 0-113 months) for bortezomib-based therapy, 14 months (range 0-79 months) for lenalidomide and 10 months (range 1-28) for pomalidomide. Allo-HCT is a feasible and effective strategy in selected patients with MM and could be an effective platform for subsequent therapies. PMID- 28892087 TI - Durable remission with salvage decitabine and donor lymphocyte infusion (DLI) for relapsed early T-cell precursor ALL. PMID- 28892088 TI - Pan-neuronal calcium imaging with cellular resolution in freely swimming zebrafish. AB - Calcium imaging with cellular resolution typically requires an animal to be tethered under a microscope, which substantially restricts the range of behaviors that can be studied. To expand the behavioral repertoire amenable to imaging, we have developed a tracking microscope that enables whole-brain calcium imaging with cellular resolution in freely swimming larval zebrafish. This microscope uses infrared imaging to track a target animal in a behavior arena. On the basis of the predicted trajectory of the animal, we applied optimal control theory to a motorized stage system to cancel brain motion in three dimensions. We combined this motion-cancellation system with differential illumination focal filtering, a variant of HiLo microscopy, which enabled us to image the brain of a freely swimming larval zebrafish for more than an hour. This work expands the repertoire of natural behaviors that can be studied with cellular-resolution calcium imaging to potentially include spatial navigation, social behavior, feeding and reward. PMID- 28892089 TI - CRISPR-Cas9-based photoactivatable transcription systems to induce neuronal differentiation. AB - Our improved CRISPR-Cas9-based photoactivatable transcription systems, CPTS2.0 and Split-CPTS2.0, enable high blue-light-inducible activation of endogenous target genes in various human cell lines. We achieved reversible activation of target genes with CPTS2.0 and induced neuronal differentiation in induced pluripotent stem cells (iPSCs) by upregulating NEUROD1 with Split-CPTS2.0. PMID- 28892090 TI - Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor. AB - Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML 792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology. PMID- 28892091 TI - Oxidative cyclization of prodigiosin by an alkylglycerol monooxygenase-like enzyme. AB - Prodiginines, which are tripyrrole alkaloids displaying a wide array of bioactivities, occur as linear and cyclic congeners. Identification of an unclustered biosynthetic gene led to the discovery of the enzyme responsible for catalyzing the regiospecific C-H activation and cyclization of prodigiosin to cycloprodigiosin in Pseudoalteromonas rubra. This enzyme is related to alkylglycerol monooxygenase and unrelated to RedG, the Rieske oxygenase that produces cyclized prodiginines in Streptomyces, implying convergent evolution. PMID- 28892092 TI - High concordance of a closed-system, RT-qPCR breast cancer assay for HER2 mRNA, compared to clinically determined immunohistochemistry, fluorescence in situ hybridization, and quantitative immunofluorescence. AB - Historically, mRNA measurements have been tested on several commercially available platforms, but none have gained broad acceptance for assessment of HER2. An mRNA measurement, as a continuous value, has the potential for use in adjudication of the equivocal category. Here we use a real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay in a closed, single-use cartridge, automated system. Multiple cores (1 mm in diameter) were retrospectively collected from 80 formalin-fixed paraffin-embedded (FFPE) tissue blocks with invasive breast cancer seen by Yale Pathology Labs between 1998 and 2011. Tissue cores were processed with a FFPE lysis kit to create lysates that were tested with the automated RT-qPCR assay. Results for IHC and FISH were extracted from the pathology reports and quantitative immunofluorescence (QIF) for each case was measured as previously described. Quality control testing showed that the GX platform RT-qPCR shows no case to case cross contamination on material from routine histology practices. Concordance between RT-qPCR and IHC/FISH was 91.25% (sensitivity=0.87; specificity=0.94; PPV=0.89; NPV=0.92) using a pre-defined delta Ct cut-off (dCt>=-1) for HER2. Concordance (OPA) between RT-qPCR and QIF was 94% (sensitivity=0.90; specificity=0.96; PPV=0.93; NPV=0.94) using dCt>=-1 and a previously defined cut-point for positivity by QIF. In conclusion, the closed system RT-qPCR assay shows >90% concordance with the ASCO/CAP HER2 IHC/FISH scoring. Additionally, the RT-qPCR assay is highly concordant (94%) with the continuous variable HER2 QIF assay, and may better reflect the true continuum of HER2 receptor status in invasive breast cancer. These initial results suggest that fast, closed system molecular assays may have future value for the adjudication of the ASCO/CAP HER2 equivocal category or possibly routine usage in time constrained or low resource settings. PMID- 28892093 TI - Rapid generation of Col7a1-/- mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating and ultimately lethal blistering disease caused by mutations to the Col7a1 gene. Development of novel cell therapies for the treatment of RDEB would be fostered by having immunodeficient mouse models able to accept human cell grafts; however, immunodeficient models of many genodermatoses such as RDEB are lacking. To overcome this limitation, we combined the clustered regularly interspaced short palindromic repeats and associated nuclease (CRISPR/Cas9) system with microinjection into NOD/SCID IL2rgammacnull (NSG) embryos to rapidly develop an immunodeficient Col7a1-/- mouse model of RDEB. Through dose optimization, we achieve F0 biallelic knockout efficiencies exceeding 80%, allowing us to quickly generate large numbers of RDEB NSG mice for experimental use. Using this strategy, we clearly demonstrate important strain-specific differences in RDEB pathology that could underlie discordant results observed between independent studies and establish the utility of this system in proof-of-concept human cellular transplantation experiments. Importantly, we uncover the ability of a recently identified skin resident immunomodulatory dermal mesenchymal stem cell marked by ABCB5 to reduce RDEB pathology and markedly extend the lifespan of RDEB NSG mice via reduced skin infiltration of inflammatory myeloid derivatives. PMID- 28892095 TI - Cholecystectomy as a risk factor of metabolic syndrome: from epidemiologic clues to biochemical mechanisms. AB - Cholecystectomy has long been regarded as a safe procedure with no deleterious influence on the body. However, recent studies provide clues that link cholecystectomy to a high risk for metabolic syndrome (MetS). In the present review, we describe the epidemiologic evidence that links cholecystectomy to MetS. Various components of MetS are investigated, including visceral obesity, dyslipidemia, elevated blood pressure, impaired fasting glucose, and insulin resistance. The possible mechanisms that associate cholecystectomy with MetS are discussed on the basis of experimental studies. PMID- 28892094 TI - Deletion of Pkd1 in renal stromal cells causes defects in the renal stromal compartment and progressive cystogenesis in the kidney. AB - Autosomal dominant polycystic kidney disease (ADPKD), caused by PKD1 and PKD2 gene mutations, is one of the most common genetic diseases, affecting up to 1 in 500 people. Mutations of PKD1 account for over 85% of ADPKD cases. However, mechanisms of disease progression and explanations for the wide range in disease phenotype remain to be elucidated. Moreover, functional roles of PKD1 in the renal stromal compartment are poorly understood. In this work, we tested if Pkd1 is essential for development and maintenance of the renal stromal compartment and if this role contributes to pathogenesis of polycystic kidney disease using a novel tissue-specific knockout mouse model. We demonstrate that deletion of Pkd1 from renal stromal cells using Foxd1-driven Cre causes a spectrum of defects in the stromal compartment, including excessive apoptosis/proliferation and extracellular matrix deficiency. Renal vasculature was also defective. Further, mutant mice showed epithelial changes and progressive cystogenesis in adulthood modeling human ADPKD. Altogether, we provide robust evidence to support indispensable roles for Pkd1 in development and maintenance of stromal cell derivatives by using a novel ADPKD model. Moreover, stromal compartment defects caused by Pkd1 deletion might serve as an important mechanism for pathogenesis of ADPKD. PMID- 28892096 TI - Development and characterization of cholangioids from normal and diseased human cholangiocytes as an in vitro model to study primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is an incurable, fibroinflammatory biliary disease for which there is no effective pharmacotherapy. We recently reported cholangiocyte senescence as an important phenotype in PSC while others showed that portal macrophages accumulate in PSC. Unfortunately, our ability to explore cholangiocyte senescence and macrophage accumulation has been hampered by limited in vitro models. Thus, our aim was to develop and characterize a three dimensional (3D) model of normal and diseased bile ducts (cholangioids) starting with normal human cholangiocytes (NHC), senescent NHC (NHC-sen), and cholangiocytes from PSC patients. In 3D culture, NHCs formed spheroids of ~5000 cells with a central lumen of ~150 MUm. By confocal microscopy and western blot, cholangioids retained expression of cholangiocyte proteins (cytokeratin 7/19) and markers of epithelial polarity (secretin receptor and GM130). Cholangioids are functionally active, and upon secretin stimulation, luminal size increased by ~80%. Cholangioids exposed to hydrogen peroxide exhibited cellular senescence and the senescence-associated secretory phenotype (SASP; increased IL-6, p21, SA-beta Gal, yH2A.x and p16 expression). Furthermore, cholangioids derived from NHC-sen or PSC patients were smaller and had slower growth than the controls. When co cultured with THP-1 macrophages, the number of macrophages associated with NHC sen or PSC cholangioids was five- to seven-fold greater compared to co-culture with non-senescent NHC. We observed that NHC-sen and PSC cholangioids release greater number of extracellular vesicles (EVs) compared to controls. Moreover, conditioned media from NHC-sen cholangioids resulted in an ~2-fold increase in macrophage migration. In summary, we developed a method to generate normal and diseased cholangioids, characterized them morphologically and functionally, showed that they can be induced to senescence and SASP, and demonstrated both EV release and macrophage attraction. This novel model mimics several features of PSC, and thus will be useful for studying the pathogenesis of PSC and potentially identifying new therapeutic targets. PMID- 28892097 TI - Ligand-mediated cytoplasmic retention of the Ah receptor inhibits macrophage mediated acute inflammatory responses. AB - The Ah receptor (AHR) has been shown to exhibit both inflammatory and anti inflammatory activity in a context-specific manner. In vivo macrophage-driven acute inflammation models were utilized here to test whether the selective Ah receptor modulator 1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce inflammation. Exposure to SGA360 was capable of significantly inhibiting lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms of lethality and attenuating inflammatory signaling in tissues. Topical exposure to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU) crystal gout mouse model. Inhibition was dependent on the expression of the high-affinity allelic AHR variant in both acute inflammation models. Upon peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360 attenuated the expression of numerous inflammatory genes and genes known to be directly regulated by AHR in thioglycolate-elicited primary peritoneal macrophages treated with LPS. In addition, expression of the high affinity allelic AHR variant in cultured macrophages was necessary for SGA360 mediated repression of inflammatory gene expression. Mechanistic studies revealed that SGA360 failed to induce nuclear translocation of the AHR and actually enhanced cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR ligand activity was detected in peritoneal exudates isolated from MSU-treated mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated at least in part through AHR antagonism of endogenous agonist activity. These results underscore an important role of the AHR in participating in acute inflammatory signaling and warrants further investigations into possible clinical applications. PMID- 28892098 TI - Correlation between E-cadherin interactions, survivin expression, and apoptosis in MDCK and ts-Src MDCK cell culture models. AB - Survivin, a member of inhibitor of apoptosis (IAP) protein family, is a multifunctional protein expressed in most cancers. In addition to inhibition of apoptosis, it regulates proliferation and promotes migration. Its presence and function in cells is strongly regulated via transcription factors, intracellular localization, and degradation. We analyzed the presence of survivin at protein level in various culture environments and under activation of Src tyrosine kinase in epithelial canine kidney MDCK cells in order to elucidate factors controlling survivin 'lifespan'. We used untransformed and temperature sensitive ts-Src MDCK cells as a model and forced them to grow in suspension (1D), in 2D on hard and soft surfaces and in soft 3D Matrigel environment with or without EGTA. In addition, we tested the effect of stressful conditions by cultivating the cells in the presence of an anti-cancer drug and a generator of reactive oxygen species (ROS), piperlongumine (PL) with or without an antioxidant, N-acetylcysteine (NAC). We could confirm that inhibition of apoptosis and simultaneous downregulation of survivin in MDCK cells required both intact cell-cell junctions, trans-interactions of E-cadherin and soft 3D matrix environment. In ts Src-transformed MDCK cells, survivin was upregulated as soon as the cell-cell junctions were disintegrated. ROS generation with PL-induced cell death of ts-Src MDCK cells concomitantly with survivin downregulation. NAC rescued the ts-Src MDCK cells from ROS-induced apoptosis without upregulation of survivin resulting in a situation resembling untransformed MDCK cells in 3D environment and E cadherin delineating the lateral cell walls. PMID- 28892099 TI - Glomerular barrier behaves as an atomically precise bandpass filter in a sub nanometre regime. AB - The glomerular filtration barrier is known as a 'size cutoff' slit, which retains nanoparticles or proteins larger than 6-8 nm in the body and rapidly excretes smaller ones through the kidneys. However, in the sub-nanometre size regime, we have found that this barrier behaves as an atomically precise 'bandpass' filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10-11). Compared to Au25 (~1.0 nm), just few-atom decreases in size result in four- to ninefold reductions in renal clearance efficiency in the early elimination stage, because the smaller AuNCs are more readily trapped by the glomerular glycocalyx than larger ones. This unique in vivo nano-bio interaction in the sub-nanometre regime also slows down the extravasation of sub-nanometre AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through an enhanced permeability and retention effect. This discovery highlights the size precision in the body's response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases associated with glycocalyx dysfunction. PMID- 28892100 TI - Kidney physiology: A size bandpass filter. PMID- 28892101 TI - Zero-power infrared digitizers based on plasmonically enhanced micromechanical photoswitches. AB - State-of-the-art sensors use active electronics to detect and discriminate light, sound, vibration and other signals. They consume power constantly, even when there is no relevant data to be detected, which limits their lifetime and results in high costs of deployment and maintenance for unattended sensor networks. Here we propose a device concept that fundamentally breaks this paradigm-the sensors remain dormant with near-zero power consumption until awakened by a specific physical signature associated with an event of interest. In particular, we demonstrate infrared digitizing sensors that consist of plasmonically enhanced micromechanical photoswitches (PMPs) that selectively harvest the impinging electromagnetic energy in design-defined spectral bands of interest, and use it to create mechanically a conducting channel between two electrical contacts, without the need for any additional power source. Our zero-power digitizing sensor prototypes produce a digitized output bit (that is, a large and sharp off to-on state transition with an on/off conductance ratio >1012 and subthreshold slope >9 dec nW-1) when exposed to infrared radiation in a specific narrow spectral band (~900 nm bandwidth in the mid-infrared) with the intensity above a power threshold of only ~500 nW, which is not achievable with any existing photoswitch technologies. PMID- 28892102 TI - Length-independent DNA packing into nanopore zero-mode waveguides for low-input DNA sequencing. AB - Compared with conventional methods, single-molecule real-time (SMRT) DNA sequencing exhibits longer read lengths than conventional methods, less GC bias, and the ability to read DNA base modifications. However, reading DNA sequence from sub-nanogram quantities is impractical owing to inefficient delivery of DNA molecules into the confines of zero-mode waveguides-zeptolitre optical cavities in which DNA sequencing proceeds. Here, we show that the efficiency of voltage induced DNA loading into waveguides equipped with nanopores at their floors is five orders of magnitude greater than existing methods. In addition, we find that DNA loading is nearly length-independent, unlike diffusive loading, which is biased towards shorter fragments. We demonstrate here loading and proof-of principle four-colour sequence readout of a polymerase-bound 20,000-base-pair long DNA template within seconds from a sub-nanogram input quantity, a step towards low-input DNA sequencing and mammalian epigenomic mapping of native DNA samples. PMID- 28892103 TI - Internet of things: Sensing without power. PMID- 28892104 TI - Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8 activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication. AB - Lysine-specific demethylase 1A (LSD1, KDM1A) specifically demethylates di- and monomethylated histones H3K4 and K9, resulting in context-dependent transcriptional repression or activation. We previously identified an irreversible LSD1 inhibitor T-3775440, which exerts antileukemic activities in a subset of acute myeloid leukemia (AML) cell lines by inducing cell transdifferentiation. The NEDD8-activating enzyme inhibitor pevonedistat (MLN4924, TAK-924) is an investigational drug with antiproliferative activities in AML, and is also reported to induce cell differentiation. We therefore tested the combination of these two agents in AML models. The combination treatment resulted in synergistic growth inhibition of AML cells, accompanied by enhanced transdifferentiation of an erythroid leukemia lineage into granulomonocytic-like lineage cells. In addition, pevonedistat-induced rereplication stress during the S phase was greatly augmented by concomitant treatment with T-3775440, as reflected by the increased induction of apoptosis. We further demonstrated that the combination treatment was markedly effective in subcutaneous tumor xenograft models as well as in a disseminated model of AML, leading to tumor eradication or prolonged survival in T-3775440/pevonedistat cotreated mice. Our findings indicate the therapeutic potential of the combination of LSD1 inhibitors and pevonedistat for the treatment of AML. PMID- 28892105 TI - Letter to the Editor (May 17, 2017) concerning the paper "Impact of road traffic noise on sleep disturbances and attention disorders amongst school children living in Upper Silesian Industrial Zone, Poland". PMID- 28892107 TI - The effect of bisphenol A on growth, pigment composition and photosystem II activity of Arabidopsis thaliana. AB - Bisphenol A (BPA) is a widely used chemical, that can potentially be toxic to plants. In this study we examined the toxicity of 5-50 mg/l of BPA on Arabidopsis thaliana. Additionally, the effects of 0.5-5 mg/l of BPA were examined after four weeks of development. BPA had no effect on the germination rate and the chlorophyll a/b ratio. The chlorophyll a and carotenoid content was significantly elevated in seedlings treated with 5 mg/l of BPA. In 4-week-old plants there was no change in the chlorophyll and carotenoid content and photosynthetic parameters (Fv/Fm, Fv/F0 and PI) were unaffected, which suggests no photoinhibition. No oxidative stress symptoms were observed. BPA significantly decreased leaf protein content. A low concentration of BPA seems to have no significant effect on A. thaliana flowering, but further investigation is needed. The results obtained indicate that a low concentration of BPA has no negative effect on the growth and development of A. thaliana. PMID- 28892106 TI - Biochemical characterization of a catalase from Vibrio vulnificus, a pathogen that causes gastroenteritis. AB - Vibrio vulnificus is a virulent human pathogen causing gastroenteritis and possibly life threatening septicemia in patients. Most V. vulnificus are catalase positive and can deactivate peroxides, thus allowing them to survive within the host. In the study presented here, a catalase from V. vulnificus (CAT-Vv) was purified to homogeneity after expression in Escherichia coli. The kinetics and function of CAT-Vv were examined. CAT-Vv catalyzed the reduction of H2O2 at an optimal pH of 7.5 and temperature of 35 degrees C. The Vmax and Km values were 65.8+/-1.2 U/mg and 10.5+/-0.7 mM for H2O2, respectively. Mutational analysis suggests that amino acids involved in heme binding play a key role in the catalysis. Quantitative reverse transcription-PCR revealed that in V. vulnificus, transcription of CAT-Vv was upregulated by low salinity, heat, and oxidative stresses. This research gives new clues to help inhibit the growth of, and infection by V. vulnificus. PMID- 28892108 TI - Solvation of apolar compounds in protic ionic liquids: the non-synergistic effect of electrostatic interactions and hydrogen bonds. AB - The solvation properties of protic ionic liquids such as alkylammonium salts are still virtually uncharacterized. Both electrostatic interactions between charged particles and hydrogen bond networks in a solvent are known to hinder the solubility of apolar species. Protic ionic liquids can be a priori expected to dissolve hydrocarbons worse than aprotic ionic liquids which do not form hydrogen bonds between the ions. We measured the limiting activity coefficients of several alkanes and alkylbenzenes in propylammonium and butylammonium nitrates at 298 K. Surprisingly, we observed the tendency of higher solubility than for the same compounds in aprotic ionic liquids with a similar molar volume. The calculations of the excess Gibbs free energies using test particle insertions into the snapshots of molecular dynamics trajectories reproduced lower values in protic rather than in aprotic ionic liquids for both methane molecules and hard sphere solutes. This can be explained by the favorable solvation of apolar species in the apolar domain of nanostructured PILs. For the first time, we point out at the essential difference between the solvation properties of two types of ionic liquids and prove that it arises from the cavity formation term. PMID- 28892109 TI - The effect of STM parameters on tip-enhanced Raman spectra. AB - In this work, we evaluate the dependence of tip-enhanced Raman (TER) spectra of a monolayer of thiophenol at a Au(111) electrode on the scanning tunneling microscope's tunneling current set-point and bias voltage parameters. We find an increase of the TER intensity upon set-point increase or bias decrease as expected from a gap-distance reduction. The relations obtained follow a theoretical model considering a simple gap-distance change when tuning the mentioned parameters. We find that the value of the bias voltage affects the TER intensity to a larger extent than the current set-point. Therefore it is advisable to work in a low-bias regime when aiming for ultrasensitive TER measurements. PMID- 28892110 TI - Hexabromocyclododecane and tetrabromobisphenol A in tree bark from different functional areas of Shanghai, China: levels and spatial distributions. AB - The concentrations and spatial distributions of hexabromocyclododecane (HBCDD) and tetrabromobisphenol A (TBBPA) were measured in tree bark from different functional areas of Shanghai. SigmaHBCDD (sum of alpha-, beta-, and gamma-HBCDD) concentrations ranged from 1.2 * 102 to 6.6 * 103 ng g-1 lw (median 5.7 * 102 ng g-1 lw) and TBBPA concentrations ranged from 48 to 7.2 * 104 ng g-1 lw (median 2.8 * 102 ng g-1 lw). The concentrations of SigmaHBCDD and TBBPA all followed the order of industrial areas > commercial areas > residential areas. The mean percentage of alpha-HBCDD in bark samples (44%) from Shanghai was higher than that in technical HBCDD products, but comparable with that in air. The concentrations of TBBPA and individual HBCDD diastereoisomers between industrial areas and commercial areas were correlated. Based on the concentrations of HBCDD in the bark, the corresponding atmospheric HBCDD concentrations were estimated. Compared with the published data for HBCDD in urban air, the estimated atmospheric HBCDD concentrations in Shanghai had a relatively high level, and more attention should be paid to the pollution status of HBCDD in Shanghai. PMID- 28892113 TI - Significantly improved charge collection and interface injection in 3D BiVO4 based multilayered core-shell nanowire photocatalysts. AB - It is challenging to design a photocatalyst with high-efficiency light absorption, charge separation and even high-efficiency charge transfer. Here, we report a demonstration by utilizing a three-dimensional multilayered core-shell nanowire array (rGO-ITO@BiVO4) as the composite photocatalyst. The core-shell structure can shorten the length of charge transfer and enhance light absorption through multireflection. RGO with defects can work as the charge transfer medium to improve the hole injection from semiconductor to electrolyte. Associated with the above effects, the Co-pi electrocatalyst modified rGO-ITO@BiVO4 photocatalyst yields a photocurrent of about 6.0 mA cm-2 at 0.6 V vs. Ag/AgCl. Transient-state surface photovoltage measurement shows that the rGO layer can prolong the lifetime of the photogenerated holes through pi-pi interactions, so that more holes can participate in the water oxidation reaction. PMID- 28892116 TI - Magnetism of the hypo-oxide state at the diffuse interface between the ferromagnet and antiferromagnet phases. AB - At the interface between ferromagnetic and antiferromagnetic phases, various spin configurations with a higher degrees of complexity than in the bulk states can be derived due to the diverse possible interface atomic structures, where coupling interactions among the constituting atoms can form in consistence with altered atomic configurations. The interface magnetic properties then depend on the collective behavior of such spin structures. In the present work, an extended interfacial configuration of a hypo-oxide state was prepared by establishing the gradient of oxygen concentration across the spatially diffuse interface region between ferromagnetic metallic and antiferromagnetic oxide phases at the nanometer scale. With these mixed ferromagnetic and antiferromagnetic couplings among the atoms in the interfacial hypo- or sub-oxide state, novel magnetic behavior can be induced. We report here, for the first time, a significant increase of saturation magnetization with temperature over a broad temperature range, which is against the conventional expectation for any generally known magnetic materials. And the unusual temperature dependent behavior can be understood as the combined effects of competing ferromagnetic and antiferromagnetic couplings acting on atoms in and near the interface region. PMID- 28892117 TI - Cell Motility as Contrast Agent in Retinal Explant Imaging With Full-Field Optical Coherence Tomography. AB - Purpose: To use cell motility as a contrast agent in retinal explants. Methods: Macaque and mouse retinal explants were imaged with high resolution full field optical coherence tomography (FFOCT) and dynamic FFOCT, coupled with fluorescence imaging. Results: Static and dynamic FFOCT create complementary contrast from different structures within a cell. When imaging in vitro samples, static FFOCT detects steep refractive index gradients to reveal stationary structures including fibers, vessels, collagen, and cell contours, while dynamic FFOCT emphasizes metabolic activity of moving structures that are mainly intracellular, thus creating or enhancing contrast in cells that were previously hidden in noise. Dynamic FFOCT enables detection of most of the retinal cell types in the ganglion cell, inner and outer nuclear layers, where static FFOCT contrast is too low in relation to the noise background. Conclusions: Composite static and dynamic FFOCT provides a new kind of FFOCT image containing valuable information for imaging of retinal explants. It provides label-free en face images of living retinas, with a subcellular resolution. Dynamic FFOCT adds information about cell activity, which is of interest in longitudinal explant studies. PMID- 28892118 TI - Association of Trial Registration With Reporting of Primary Outcomes in Protocols and Publications. PMID- 28892119 TI - Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia. AB - BACKGROUND: This is an update of the original Cochrane Review published in Cochrane Library, Issue 10, 2012.Hydatidiform mole (HM), also called a molar pregnancy, is characterised by an overgrowth of foetal chorionic tissue within the uterus. HMs may be partial (PM) or complete (CM) depending on their gross appearance, histopathology and karyotype. PMs usually have a triploid karyotype, derived from maternal and paternal origins, whereas CMs are diploid and have paternal origins only. Most women with HM can be cured by evacuation of retained products of conception (ERPC) and their fertility preserved. However, in some women the growth persists and develops into gestational trophoblastic neoplasia (GTN), a malignant form of the disease that requires treatment with chemotherapy. CMs have a higher rate of malignant transformation than PMs. It may be possible to reduce the risk of GTN in women with HM by administering prophylactic chemotherapy (P-Chem). However, P-Chem given before or after evacuation of HM to prevent malignant sequelae remains controversial, as the risks and benefits of this practice are unclear. OBJECTIVES: To evaluate the effectiveness and safety of P-Chem to prevent GTN in women with a molar pregnancy. To investigate whether any subgroup of women with HM may benefit more from P-Chem than others. SEARCH METHODS: For the original review we performed electronic searches in the Cochrane Gynaecological Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 2, 2012), MEDLINE (1946 to February week 4, 2012) and Embase (1980 to 2012, week 9). We developed the search strategy using free text and MeSH. For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 5, 2017), MEDLINE (February 2012 to June week 1, 2017) and Embase (February 2012 to 2017, week 23). We also handsearched reference lists of relevant literature to identify additional studies and searched trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of P-Chem for HM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and extracted data using a specifically designed data collection form. Meta-analyses were performed by pooling data from individual trials using Review Manager 5 (RevMan 5) software in line with standard methodological procedures expected by Cochrane methodology. MAIN RESULTS: The searches identified 161 records; after de-duplication and title and abstract screening 90 full-text articles were retrieved. From these we included three RCTs with a combined total of 613 participants. One study compared prophylactic dactinomycin to no prophylaxis (60 participants); the other two studies compared prophylactic methotrexate to no prophylaxis (420 and 133 participants). All participants were diagnosed with CMs. We considered the latter two studies to be of poor methodological quality.P-Chem reduced the risk of GTN occurring in women following a CM (3 studies, 550 participants; risk ratio (RR) 0.37, 95% confidence interval (CI) 0.24 to 0.57; I2 = 0%; P < 0.00001; low quality evidence). However, owing to the poor quality (high risk of bias) of two of the included studies, we performed sensitivity analyses excluding these two studies. This left only one small study of high-risk women to contribute data for this primary outcome (59 participants; RR 0.28, 95% CI 0.10 to 0.73; P = 0.01); therefore we consider this evidence to be of low quality.The time to diagnosis was longer in the P-Chem group than the control group (2 studies, 33 participants; mean difference (MD) 28.72, 95% CI 13.19 to 44.24; P = 0.0003; low quality evidence); and the P-Chem group required more courses to cure subsequent GTN (1 poor-quality study, 14 participants; MD 1.10, 95% CI 0.52 to 1.68; P = 0.0002; very low quality evidence).There were insufficient data to perform meta analyses for toxicity, overall survival, drug resistance and reproductive outcomes. AUTHORS' CONCLUSIONS: P-Chem may reduce the risk of progression to GTN in women with CMs who are at a high risk of malignant transformation; however, current evidence in favour of P-Chem is limited by the poor methodological quality and small size of the included studies. As P-Chem may increase drug resistance, delays treatment of GTN and may expose women toxic side effects, this practice cannot currently be recommended. PMID- 28892120 TI - Reply to: Proton Pump Inhibitors and Risk of Pneumonia in Individuals with Dementia. PMID- 28892121 TI - Statins for Primary Prevention of Cardiovascular Events and Mortality in Older Men. AB - BACKGROUND/OBJECTIVES: We sought to determine whether statin use for primary prevention is associated with a lower risk of cardiovascular events or mortality in older men. DESIGN: Prospective cohort study. SETTING: Physicians' Health Study participants. PARTICIPANTS: 7,213 male physicians >=70 years without a history of cardiovascular disease (CVD). MEASUREMENTS: Multivariable propensity score for statin use with greedy matching (1:1) to minimize confounding by indication. RESULTS: Median baseline age was 77 (70-102), median follow-up was 7 years. Non users were matched to 1,130 statin users. Statin use was associated with an 18% lower risk of all-cause mortality, HR 0.82 (95% CI 0.69-0.98) and non-significant lower risk of CVD events, HR 0.86 (95% CI 0.70-1.06) and stroke, HR 0.70 (95% CI 0.45-1.09). In subgroup analyses, results did not change according to age group at baseline (70-76 or >76 years) or functional status. There was a suggestion that those >76 at baseline did not benefit from statins for mortality, HR 1.14 (95% CI 0.89-1.47), compared to those 70-76 at baseline, HR 0.83 (95% CI 0.61 1.11); however the CIs overlap between the two groups, suggesting no difference. Statin users with elevated total cholesterol had fewer major CVD events than non users, HR 0.68 (95% CI 0.50-0.94) and HR 1.43 (95% CI 0.99-2.07)), respectively. CONCLUSIONS: Statin use was associated with a significant lower risk of mortality in older male physicians >=70 and a nonsignificant lower risk of CVD events. Results did not change in those who were >76 years at baseline or according to functional status. There was a suggestion that those with elevated total cholesterol may benefit. Further work is needed to determine which older individuals will benefit from statins as primary prevention. PMID- 28892122 TI - Effects of prenatal alcohol consumption on cognitive development and ADHD-related behaviour in primary-school age: a multilevel study based on meconium ethyl glucuronide. AB - BACKGROUND: Alcohol intake during pregnancy is considered to be a risk factor for child development. Child biomarkers of intrauterine alcohol exposure have been rarely studied. We investigated whether a meconium alcohol metabolite (ethyl glucuronide, EtG) was associated with cognitive development, ADHD-related behaviour and neurophysiological markers of attention and executive control of children at primary-school age. METHODS: Mothers provided self-report on prenatal alcohol consumption during their 3rd trimester. Meconium samples were collected at birth. A total of 44 children with a meconium EtG above the detection limit (>=10 ng/g) and 44 nonexposed matched controls were compared. A second threshold (>=154 ng/g) was applied to study the dose effects. When children reached primary school age, mothers rated ADHD-related behaviour, child cognitive development was measured using an IQ test battery, and event-related potentials were recorded during a cued go/nogo task. RESULTS: Children in both EtG-positive groups allocated fewer attentional resources than controls to the go/nogo task (reduced P3 component in go-trials). Children with a meconium EtG above 154 ng/g were also found to have an IQ that was six points lower than the other groups. Within the EtG >= 154 ng/g group, there was a positive correlation between EtG value and ADHD-related behaviour. These significant effects were not observed in relation to the maternal self-report data. CONCLUSIONS: Associations between EtG and cognitive deficits, attentional resource capacity and ADHD-related behaviour could be documented with effects that were partially dose-dependent. In addition to maternal self-reports, this biomarker of intrauterine alcohol exposure may be considered as a predictor of child development. PMID- 28892123 TI - Proton Pump Inhibitors and Risk of Pneumonia in Individuals with Dementia. PMID- 28892124 TI - Systematic optimization of L-tryptophan riboswitches for efficient monitoring of the metabolite in Escherichia coli. AB - Riboswitches form a class of genetically encoded sensor-regulators and are considered as promising tools for monitoring various metabolites. Functional parameters of a riboswitch, like dynamic or operational range, should be optimized before the riboswitch is implemented in a specific application for monitoring the target molecule efficiently. However, optimization of a riboswitch was not straightforward and required detailed studies owing to its complex sequence-function relationship. Here, we present three approaches for tuning and optimization of functional parameters of a riboswitch using an artificial L tryptophan riboswitch as an example. First, the constitutive expression level was adjusted to control the dynamic range of an L-tryptophan riboswitch. The dynamic range increased as the constitutive expression level increased. Then, the function of a riboswitch-encoded protein was utilized to connect the regulatory response of the riboswitch to another outcome for amplifying the dynamic range. Riboswitch-mediated control of the host cell growth enabled the amplification of the riboswitch response. Finally, L-tryptophan aptamers with different dissociation constants were employed to alter the operational range of the riboswitch. The dose-response curve was shifted towards higher L-tryptophan concentrations when an aptamer with higher dissociation constant was employed. All strategies were effective in modifying the distinct functional parameters of the L-tryptophan riboswitch, and they could be easily applied to optimization of other riboswitches owing to their simplicity. PMID- 28892125 TI - Novel spondyloepimetaphyseal dysplasia due to UFSP2 gene mutation. AB - Beukes hip dysplasia is an autosomal dominant disease which has to date been described only in a large South African family of Dutch origin. The patients presented with progressive epiphyseal dysplasia limited to femoral capital epiphysis and their height was not significantly reduced. A unique variant of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 (UFSP2) gene (c.868T>C) has been reported in all individuals from Beukes family with clinical and radiological diagnosis of Beukes hip dysplasia. Three individuals, propositus, mother, and grandmother, presented with short stature, joint pain, genu vara and a novel spondyloepimetaphyseal dysplasia involving epiphyses predominantly at hips, but also at knees, ankles, wrists and hands, associated with variable degrees of metaphysis and spine involvement. Exome sequencing allowed us to identify the heterozygous variant c.1277A>C of the UFSP2 gene, leading to the missense change p.D426A, in all 3 patients. This mutation is predicted as damaging and, similarly to the mutation originally described in the Beukes family (p. Y290H), directly affects one of the catalytic residues participating in the active site of the protein. This supports the novel notion that loss of catalytic UFSP2 activity, observed in association with different mutants and already experimentally proven in vitro, may have different clinical outcomes. PMID- 28892126 TI - Peer victimization predicts heightened inflammatory reactivity to social stress in cognitively vulnerable adolescents. AB - BACKGROUND: During adolescence, peer victimization is a potent type of social stressor that can confer enduring risk for poor mental and physical health. Given recent research implicating inflammation in promoting a variety of serious mental and physical health problems, this study examined the role that peer victimization and cognitive vulnerability (i.e. negative cognitive styles and hopelessness) play in shaping adolescents' pro-inflammatory cytokine responses to an acute social stressor. METHODS: Adolescent girls at risk for psychopathology (n = 157; Mage = 14.73 years; SD = 1.38) were exposed to a laboratory-based social stressor before and after which we assessed salivary levels of three key pro-inflammatory cytokines - interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). RESULTS: As hypothesized, adolescents with greater peer victimization exposure exhibited greater increases in IL-6 and IL1-beta in response to the laboratory-based social stressor. Moreover, for all three cytokines individually, as well as for a combined latent factor of inflammation, peer victimization predicted enhanced inflammatory responding most strongly for adolescents with high levels of hopelessness. CONCLUSIONS: The findings reveal a biological pathway by which peer victimization may interact with cognitive vulnerability to influence health in adolescence. PMID- 28892127 TI - Parental Co-Construction of 5- to 13-Year-Olds' Global Self-Esteem Through Reminiscing About Past Events. AB - The current study explored parental processes associated with children's global self-esteem development. Eighty 5- to 13-year-olds and one of their parents provided qualitative and quantitative data through questionnaires, open-ended questions, and a laboratory-based reminiscing task. Parents who included more explanations of emotions when writing about the lowest points in their lives were more likely to discuss explanations of emotions experienced in negative past events with their child, which was associated with child attachment security. Attachment was associated with concurrent self-esteem, which predicted relative increases in self-esteem 16 months later, on average. Finally, parent support also predicted residual increases in self-esteem. Findings extend prior research by including younger ages and uncovering a process by which two theoretically relevant parenting behaviors impact self-esteem development. PMID- 28892128 TI - Nursing Home Use Across The Spectrum of Cognitive Decline: Merging Mayo Clinic Study of Aging With CMS MDS Assessments. AB - BACKGROUND/OBJECTIVES: Objective, complete estimates of nursing home (NH) use across the spectrum of cognitive decline are needed to help predict future care needs and inform economic models constructed to assess interventions to reduce care needs. DESIGN: Retrospective longitudinal study. SETTING: Olmsted County, MN. PARTICIPANTS: Mayo Clinic Study of Aging participants assessed as cognitively normal (CN), mild cognitive impairment (MCI), previously unrecognized dementia, or prevalent dementia (age = 70-89 years; N = 3,545). MEASUREMENTS: Participants were followed in Centers for Medicare and Medicaid Services (CMS) Minimum Data Set (MDS) NH records and in Rochester Epidemiology Project provider-linked medical records for 1-year after assessment of cognition for days of observation, NH use (yes/no), NH days, NH days/days of observation, and mortality. RESULTS: In the year after cognition was assessed, for persons categorized as CN, MCI, previously unrecognized dementia, and prevalent dementia respectively, the percentages who died were 1.0%, 2.6%, 4.2%, 21%; the percentages with any NH use were 3.8%, 8.7%, 19%, 40%; for persons with any NH use, median NH days were 27, 38, 120, 305, and median percentages of NH days/days of observation were 7.8%, 12%, 33%, 100%. The year after assessment, among persons with prevalent dementia and any NH use, >50% were a NH resident all days of observation. Pairwise comparisons revealed that each increase in cognitive impairment category exhibited significantly higher proportions with any NH use. One-year mortality was especially high for persons with prevalent dementia and any NH use (30% vs 13% for those with no NH use); 58% of all deaths among persons with prevalent dementia occurred while a NH resident. CONCLUSIONS: Findings suggest reductions in NH use could result from quality alternatives to NH admission, both among persons with MCI and persons with dementia, together with suitable options for end-of-life care among persons with prevalent dementia. PMID- 28892129 TI - Invariant natural killer T-cell development and function with loss of microRNA 155. AB - Invariant natural killer T (iNKT) cells are adaptive T cells with innate-like characteristics including rapid cytokine production and a proliferative response to stimulation. Development of these cells in the thymus is dependent on expression of the microRNA (miRNA) processing enzyme Dicer, indicating that iNKT cells probably have distinct miRNA requirements for gene regulation during development. The miRNA miR-155 has previously been shown to have numerous roles in T cells, including regulation of proliferation and differentiation, and positive modulation of interferon-gamma expression. We examined the role of miR 155 in the development and function of iNKT cells. Using germline-deficient miR 155 mice, we showed that loss of miR-155 resulted in unchanged iNKT cell frequency and cell number. Although miR-155 was up-regulated in iNKT cells upon activation with alpha-galactosylceramide, loss of miR-155 did not affect cytokine production or proliferation by iNKT cells. Hence, cytokine production occurs in iNKT cells independently of miR-155 expression. PMID- 28892130 TI - Fibrinogen-like protein-2 causes deterioration in cardiac function in experimental autoimmune myocarditis rats through regulation of programmed death-1 and inflammatory cytokines. AB - Programmed death-1 (PD-1) plays an important role in protecting against inflammation and myocyte damage in T-cell-mediated myocarditis. To understand whether fibrinogen-like protein-2 (FGL2) can affect the role of the PD-1/PD-L1 pathway in experimental autoimmune myocarditis (EAM), we investigated cardiac function in EAM rats over-expressing FGL2. Over-expression of FGL2 significantly decreased PD-1 and deteriorated cardiac function in rats with autoimmune myocarditis. Histopathology revealed increased inflammatory cell infiltrate in EAM-FGL2 rats compared with the control groups (EAM, EAM-GFP and NC). Notably, transcription factor forkhead box P3 (Foxp3) and retinoic acid-related orphan receptor gammat (RORgammat) protein and mRNA levels were statistically (P < 0.05) increased in EAM rats. We also found that interferon-gamma, interleukin-6, interleukin-17 and brain natriuretic peptide levels were profoundly increased in serum of FGL2 over-expressing EAM rats. Hence, FGL2 plays an important role in the pathogenesis of autoimmune myocarditis that also involves the PD-1/PD-L1 pathway. Our findings may provide novel therapeutic targets for the treatment of immune-induced heart injury. PMID- 28892131 TI - Use of endoscopy to determine the resection margin during laparoscopic gastrectomy for cancer. AB - BACKGROUND: It can be difficult to determine the transection line during totally laparoscopic surgery for early gastric cancer owing to lack of tactile feedback. This retrospective cohort study aimed to assess the role of intraoperative endoscopy in determining the resection margin in totally laparoscopic gastrectomy. METHODS: Consecutive patients with histologically confirmed gastric cancer who underwent laparoscopic gastrectomy between March 2012 and July 2015 were eligible. Preoperative placement of marking clips and intraoperative endoscopy were performed to determine the resection margin. Frozen-section analyses were also performed to confirm the absence of cancer cells at the surgical margin. Success was defined as the proportion of specimens with all clips present and by the proportion of resections with a negative surgical margin following initial transection. RESULTS: Total laparoscopic gastrectomy with intraoperative endoscopy was performed in 522 patients; a total of 662 surgical margins were analysed. The overall success rate was 99.8 per cent (661 of 662 margins). The success rate of achieving a negative surgical margin during the initial transection was 98.9 per cent (550 of 556 margins). CONCLUSION: Preoperative placement of marking clips and intraoperative endoscopy is helpful in the determination of a safe surgical margin in patients with gastric cancer who undergo laparoscopic gastrectomy. PMID- 28892132 TI - Nutritional and Nutraceutical Properties of Triticum dicoccum Wheat and Its Health Benefits: An Overview. AB - Triticum dicoccum wheat is one of the ancient wheat species and is gaining popularity due to its suggested health benefits as well as its suitability for organic farming. In some parts of the world, certain traditional foods prepared with dicoccum wheat are preferred due to their better taste, texture, and flavor. It is rich in bioactive compounds and its starch has been reported to have slow digestibility. However, content and composition of bioactive compounds is reported to vary depending on the geographical location, seasonal variations, varieties used, and the analytical methods followed. Therefore, in the present study, we report the food uses, digestibility of starch, nutritional and nutraceutical compositions of dicoccum wheat grown in different parts of the world, and also its health benefits in ameliorating diabetes and celiac disease. PMID- 28892133 TI - Statins for Primary Prevention in Older Adults: An Unresolved Conundrum. PMID- 28892134 TI - Inhibition analysis of inhibitors derived from lignocellulose pretreatment on the metabolic activity of Zymomonas mobilis biofilm and planktonic cells and the proteomic responses. AB - Lignocellulose pretreatment produces various toxic inhibitors that affect microbial growth, metabolism, and fermentation. Zymomonas mobilis is an ethanologenic microbe that has been demonstrated to have potential to be used in lignocellulose biorefineries for bioethanol production. Z. mobilis biofilm has previously exhibited high potential to enhance ethanol production by presenting a higher viable cell number and higher metabolic activity than planktonic cells or free cells when exposed to lignocellulosic hydrolysate containing toxic inhibitors. However, there has not yet been a systematic study on the tolerance level of Z. mobilis biofilm compared to planktonic cells against model toxic inhibitors derived from lignocellulosic material. We took the first insight into the concentration of toxic compound (formic acid, acetic acid, furfural, and 5 HMF) required to reduce the metabolic activity of Z. mobilis biofilm and planktonic cells by 25% (IC25 ), 50% (IC50 ), 75% (IC75 ), and 100% (IC100 ). Z. mobilis strains ZM4 and TISTR 551 biofilm were two- to three fold more resistant to model toxic inhibitors than planktonic cells. Synergetic effects were found in the presence of formic acid, acetic acid, furfural, and 5-HMF. The IC25 of Z. mobilis ZM4 biofilm and TISTR 551 biofilm were 57 mm formic acid, 155 mm acetic acid, 37.5 mm furfural and 6.4 mm 5-HMF, and 225 mm formic acid, 291 mm acetic acid, 51 mm furfural and 41 mm 5-HMF, respectively. There was no significant difference found between proteomic analysis of the stress response to toxic inhibitors of Z. mobilis biofilm and planktonic cells on ZM4. However, TISTR 551 biofilms exhibited two proteins (molecular chaperone DnaK and 50S ribosomal protein L2) that were up-regulated in the presence of toxic inhibitors. TISTR 551 planktonic cells possessed two types of protein in the group of 30S ribosomal proteins and motility proteins that were up-regulated. PMID- 28892136 TI - Identification and measurement of dystonia in cerebral palsy. PMID- 28892135 TI - Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection. AB - High glucose transporter 1 (Glut1) surface expression is associated with increased glycolytic activity in activated CD4+ T cells. Phosphatidylinositide 3 kinases (PI3K) activation measured by p-Akt and OX40 is elevated in CD4+Glut1+ T cells from HIV+ subjects. TCR engagement of CD4+Glut1+ T cells from HIV+ subjects demonstrates hyperresponsive PI3K-mammalian target of rapamycin signaling. High basal Glut1 and OX40 on CD4+ T cells from combination antiretroviral therapy (cART)-treated HIV+ patients represent a sufficiently metabolically active state permissive for HIV infection in vitro without external stimuli. The majority of CD4+OX40+ T cells express Glut1, thus OX40 rather than Glut1 itself may facilitate HIV infection. Furthermore, infection of CD4+ T cells is limited by p110gamma PI3K inhibition. Modulating glucose metabolism may limit cellular activation and prevent residual HIV replication in 'virologically suppressed' cART-treated HIV+ persons. PMID- 28892137 TI - Medical treatment of dyskinetic cerebral palsy: translation into practice. PMID- 28892138 TI - Towards a geography of omnivory: Omnivores increase carnivory when sodium is limiting. AB - Towards understanding the geography of omnivory, we tested three hypotheses that predict the proportion of animal tissue consumed: the sodium limitation hypothesis predicts that omnivores increase animal consumption in Na-poor environments because Na bioaccumulates from plants to predators; thus, heterotrophs are Na-rich sources. The nitrogen limitation and habitat productivity hypotheses use the same logic to predict more animal consumption in N-poor and productive environments respectively. Omnivory is a common trophic strategy, but what determines the balance of plant and animal tissue omnivores consume is relatively unexplored. Most of what we know comes from single populations at local scales. Here we quantitatively test these three hypotheses at a large geographic scale and across 20 species of omnivorous ants. We tested each hypothesis using N stable isotopes (delta15 N) to quantify the degree of carnivory in ant populations in 20 forests that span 12 degrees latitude from Georgia to Maine, USA. We used the difference in delta15 N between 20 ant conspecifics in 10 genera between two paired forests (10 pairs of 20 forests) that consisted of a coastal and inland forests on the same latitude to determine if the proportion of animal tissue consumed could be predicted based on Na, N or net primary productivity. Sodium gradients accounted for 18% of the variation in delta15 N, 45% if one outlier ant species was omitted. In contrast, the nitrogen limitation and habitat productivity hypotheses, which predict more animal consumption in N-poor and more productive environments respectively, failed to vary with delta15 N. Our results reveal a geography of omnivory driven in part by access to Na. PMID- 28892139 TI - Influence of Technological Treatments on the Functionality of Bifidobacterium lactis INL1, a Breast Milk-Derived Probiotic. AB - : The aim of this study is to evaluate the influence of the technological processing on the functionality of the human breast milk probiotic strain Bifidobacterium lactis INL1. In vitro antagonistic activity of B. lactis INL1 was detected for Gram-positive and Gram-negative pathogens. B. lactis INL1 was administered to mice as fresh (F), frozen (Z), spray-dried (S), or lyophilized (L) culture. Immune parameters (IgA, IL-10, and IFN-gamma) were determined and histological analysis was performed to assess functionality and protection capacity against Salmonella. In BALB/c mice, F and S cultures induced an increase in the number of IgA-producing cells in the small intestine and IL-10 levels were increased for L culture in the large intestine. In Swiss mice, B. lactis INL1 increased secretory-IgA levels in the small intestine before and after Salmonella infection, both as F or dehydrated culture. Also, an attenuation of damage in the intestinal epithelium and less inflammatory infiltrates were observed in animals that received F and S cultures, whereas in liver only F showed some effect. The anti-inflammatory effect was confirmed in both tissues by myeloperoxidase activity and by IFN-gamma levels in the intestinal content. B. lactis INL1 showed inhibitory activity against pathogens and confirmed its probiotic potential in animal models. Technological processing of the probiotic strain affected its functionality. PRACTICAL APPLICATION: This work provides evidence about the influence of technology on the functionality of probiotics, which may help probiotics and functional food manufacturers to take processing into consideration when assessing the functionality of new strains. PMID- 28892140 TI - Biofilm Formation and Its Relationship with the Molecular Characteristics of Food Related Methicillin-Resistant Staphylococcus aureus (MRSA). AB - : The capability to produce biofilm is an important persistence and dissemination mechanism of some foodborne bacteria. This paper investigates the relationship between some molecular characteristics (SCCmec, ST, spa-type, agr-type, cna, sarA, icaA, icaD, clfA, fnbA, fnbB, hla, hlb) of 22 food-related methicillin resistant Staphylococcus aureus (MRSA) strains and their ability to form biofilm on stainless steel and polystyrene. Five (22.7%, 5/22) strains were able to synthesize biofilm on polystyrene, and one of these (4.5%, 1/22) strains was also able to synthesize biofilm on stainless steel. The largest amount of biofilm was formed on polystyrene by 2 MRSA strains isolated from cows' milk, thus raising concern about the dairy industry. The majority of MRSA biofilm producers carried SCCmec type IVa, suggesting that the presence of SCCmecIVa and/or agr type III could be related to the ability to form biofilm. In conclusion, in order to achieve an acceptable level of food safety, Good Hygiene Practices should be strictly implemented along the food chain to reduce the risk of colonization and dissemination of MRSA biofilm-producing strains in the food industry. PRACTICAL APPLICATION: In this study, some assayed isolates of food-related MRSA demonstrated the capacity to form biofilm. Biofilm formation differed according to surface characteristics and MRSA strains. A relationship was observed between some molecular characteristics and the ability to form biofilms. Few studies have investigated the ability of MRSA to form biofilms, and the majority of these studies have investigated clinical aspects. This work was performed to investigate whether or not there is a difference between MRSA food isolates and MRSA clinical isolates in their ability to form biofilm. These initial findings could provide information that will contribute to a better understanding of these aspects. PMID- 28892141 TI - Novel insights on population and range edge dynamics using an unparalleled spatiotemporal record of species invasion. AB - Quantifying the complex spatial dynamics taking place at range edges is critical for understanding future distributions of species, yet very few systems have sufficient data or the spatial resolution to empirically test these dynamics. This paper reviews how data from a large-scale pest management programme have provided important contributions to the fields of population dynamics and invasion biology. The invasion of gypsy moth (Lymantria dispar) is well documented from its introduction near Boston, Massachusetts USA in 1869 to its current extent of over 900,000 km2 in Eastern North America. Over the past two decades, the USDA Forest Service Slow the Spread (STS) programme for managing the future spread of gypsy moth has produced unrivalled spatiotemporal data across the invasion front. The STS programme annually deploys a grid of 60,000-100,000 pheromone-baited traps, currently extending from Minnesota to North Carolina. The data from this programme have provided the foundation for investigations of complex population dynamics and the ability to examine ecological hypotheses previously untestable outside of theoretical venues, particularly regarding invasive spread and Allee effects. This system provides empirical data on the importance of long-distance dispersal and time-lags on population establishment and spatial spread. Studies showing high rates of spatiotemporal variation of the range edge, from rapid spread to border stasis and even retraction, highlight future opportunities to test mechanisms that influence both invasive and native species ranges. The STS trap data have also created a unique opportunity to study low-density population dynamics and quantify Allee effects with empirical data. Notable contributions include evidence for spatiotemporal variation in Allee effects, demonstrating empirical links between Allee effects and spatial spread, and testing mechanisms of population persistence and growth rates at range edges. There remain several outstanding questions in spatial ecology and population biology that can be tested within this system, such as the scaling of local ecological processes to large-scale dynamics across landscapes. The gypsy moth is an ideal model of how important ecological questions can be answered by thinking more broadly about monitoring data. PMID- 28892142 TI - Loneliness and friendships among eight-year-old children: time-trends over a 24 year period. AB - BACKGROUND: Loneliness in childhood has a wide range of negative consequences for well-being and mental health later in life. This study reports time-trends in children's loneliness and the association between children's loneliness and psychiatric symptoms over a 24-year period. METHODS: Information on 3,749 eight year-old Finnish-speaking children born in 1981, 1991, 1997, and 2004 was gathered at four time points from the area covered by Turku University Hospital in southwest Finland. The actual numbers of participants at these time points were 986 (1989), 891 (1999), 930 (2005), and 942 (2013), with participation rates of 86%-95%. The study design and methods were similar at every time point. Information on children's loneliness and friendships was obtained from the children and also parents and teachers evaluated how many friends children had and their psychiatric symptoms. RESULTS: Approximately 20% of the children reported loneliness at each time point, 5% always felt lonely, and 25% wished they had more friends. Conduct and emotional problems, and hyperactivity were independently associated with loneliness in the multiple-regression analysis. The strength of these associations remained at similar levels over the 24-year study period. Living in a nonnuclear family, parents with a lower level of vocational education, and negative life events among the girls in the study were all associated with loneliness. CONCLUSIONS: Loneliness was a common phenomenon in childhood, and no notable changes were found during the 24-year study period. Psychiatric symptoms were strongly associated with loneliness. It is important to pay attention to children's loneliness and make it an integral part of school health care. Further epidemiological research is needed. PMID- 28892143 TI - Rodent Test of Attention and Impulsivity: The 5-Choice Serial Reaction Time Task. AB - The 5-choice serial reaction time task (5-CSRTT) is employed extensively to measure attention in rodents. The assay involves animals trained to respond to a brief, unpredictable visual stimulus presented in one of five locations. The effects of experimental manipulations on response speed and choice accuracy are measured, and each related to attentional performance. The 5-CSRTT is also used to measure motor impulsivity. Adapted from a human task, the 5-CSRTT can be employed with rodents or primates, highlighting its translational value. Another strength of this procedure is its adaptability to task modification. An example is the 5-choice continuous performance task, which has both target and non-target trial types. Overall, the 5-CSRTT has proven to be valuable for drug discovery efforts aimed at identifying new agents for the treatment of central nervous system disorders and for further understanding the neurobiological processes of attention and impulsivity. Its flexibility offers considerable scope to the experimenter, and in this respect the task continues to evolve. (c) 2017 by John Wiley & Sons, Inc. PMID- 28892144 TI - Development and Applications of Patient-Derived Xenograft Models in Humanized Mice for Oncology and Immune-Oncology Drug Discovery. AB - With the recent approval of four novel immune oncology agents for the treatment of various cancers, the emerging power of this drug class has been substantiated. However, the full potential of such agents is yet to be realized, with only a fraction of the patient population responding to these drugs. A more advanced pre clinical and translational research platform may increase our understanding of the mechanisms associated with immune-mediated cancer cell death, thereby facilitating the design and development of more generally efficacious agents and drug regimens. Described in this report are the nuances, advantages, and limitations of such a research approach. (c) 2017 by John Wiley & Sons, Inc. PMID- 28892145 TI - All-Optical Electrophysiology for Disease Modeling and Pharmacological Characterization of Neurons. AB - A key challenge for establishing a phenotypic screen for neuronal excitability is measurement of membrane potential changes with high throughput and accuracy. Most approaches for probing excitability rely on low-throughput, invasive methods or lack cell-specific information. These limitations stimulated the development of novel strategies for characterizing the electrical properties of cultured neurons. Among these was the development of optogenetic technologies (Optopatch) that allow for stimulation and recording of membrane voltage signals from cultured neurons with single-cell sensitivity and millisecond temporal resolution. Neuronal activity is elicited using blue light activation of the channelrhodopsin variant 'CheRiff'. Action potentials and synaptic signals are measured with 'QuasAr', a rapid and sensitive voltage-indicating protein with near-infrared fluorescence that scales proportionately with transmembrane potential. This integrated technology of optical stimulation and recording of electrical signals enables investigation of neuronal electrical function with unprecedented scale and precision. (c) 2017 by John Wiley & Sons, Inc. PMID- 28892146 TI - Murine Retrovirally-Transduced Bone Marrow Engraftment Models of MLL-Fusion Driven Acute Myelogenous Leukemias (AML). AB - MLL-rearranged leukemia represents approximately 5% to 10% of adult acute myelogenous leukemia (AML) and nearly half of all infant/pediatric acute leukemia cases. These leukemias have a poor prognosis, and there are no approved therapeutic options. The rearrangement in the MLL gene leads to aberrant expression of MLL-fusion proteins. These are transforming in murine bone marrow and, in particular, on stem cells and myeloid progenitors derived from bone marrow or fetal liver. The commonality of the MLL fusions is the in-frame fusion of 8 to 11 N-terminal exons of MLL1 (KMT2a) with the C-terminus of a partner fusion gene. Currently, over 80 different fusion partners are known. The protocols detailed in this unit focus on bone marrow-derived models only, using one particular MLL fusion, MLL-AF9. These models have proven effective for drug screening to predict clinical response. (c) 2017 by John Wiley & Sons, Inc. PMID- 28892147 TI - Carpal tunnel syndrome in mucopolysaccharidosis I: a registry-based cohort study. AB - AIM: To characterize carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). METHOD: Data were included for patients with MPS I who had either nerve conduction examination that included a diagnosis of CTS or who had CTS release surgery. Although this represented a subset of patients with CTS in the MPS I Registry, the criteria were considered the most objective for data analysis. RESULTS: As of March 2016, 994 patients were categorized with either severe (Hurler syndrome) or attenuated (Hurler-Scheie or Scheie syndromes) MPS I. Among these, 291 had a CTS diagnosis based on abnormal nerve conduction (n=54) or release surgery (n=237). Median ages (minimum, maximum) at first CTS diagnosis were 5 years 2 months (10mo, 16y 2mo) and 9y 11mo (1y 8mo, 44y 1mo) for patients with severe and attenuated MPS I respectively. Most patients had their first CTS diagnosis after MPS I diagnosis (94%) and treatment (hematopoietic stem cell transplant and/or enzyme replacement therapy) (74%). For 11% of patients with attenuated disease, CTS diagnosis preceded MPS I diagnosis by a mean of 7 years 6 months. INTERPRETATION: CTS is a rare complication in pediatric patients and should alert medical care providers to the potential diagnosis of MPS I. Significant delays exist between diagnosis of CTS and MPS I for patients with attenuated disease. WHAT THIS PAPER ADDS: There are significant delays in diagnosing carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). Enzyme replacement therapy or hematopoietic stem cell transplant do not prevent the development of CTS. Testing for CTS in patients with MPS I is recommended to prevent irreparable damage. CTS in pediatric patients should alert physicians to potential diagnosis of MPS I. PMID- 28892148 TI - mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. AB - Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations. PMID- 28892149 TI - Raisins and Currants as Conventional Nutraceuticals in Italian Market: Natural Occurrence of Ochratoxin A. AB - The healthy consumers make a strong pressure to natural products that can prevent the chronic diseases and improve the general health status, and therefore an important aspect that have to be considered is the safe level of the nutraceuticals. This study reports the occurrence of Ochratoxin A (OTA) and associated fungal contamination in 35 samples of dried vine fruits imported in the European community potentially used for the development of new nutraceutical supplements. High pressure liquid chromatography analysis identified 18 samples as contaminated by OTA with an average level of 2.6 MUg/kg. OTA was measured in 4 samples of currants (mean value of 6.6 MUg/kg) and 13 samples of raisins (mean value of 1.4 MUg/kg). In one sample of currants and one of raisins from Turkey OTA exceeded the limits set by European Commission of 10 MUg/kg, being contaminated with 12.61 and 15.99 MUg/kg, respectively. All the positive samples were confirmed by Orbitrap Q Exactive through their molecular weight and the corresponding fragmentation. The worldwide consumption of dried vine fruits contributed to OTA exposure in several group of consumers. In particular, considering the potential nutraceutical approach, this consumption may be represent a severe risk for healthy consumers that consider these products like healthy and salutistic for their contents in antioxidants, flavonoids, and polyphenols. Data reported in this study confirmed the need to regularly monitor mycotoxin levels in these food products and optimize the process of fruits drying in order to reduce the development of toxigenic molds. PMID- 28892150 TI - Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation. AB - Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic beta-muricholic acid (beta MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic beta-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic beta-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28892151 TI - The genetic breakdown of sporophytic self-incompatibility in Tolpis coronopifolia (Asteraceae). AB - Angiosperm diversity has been shaped by mating system evolution, with the most common transition from outcrossing to self-fertilizing. To investigate the genetic basis of this transition, we performed crosses between two species endemic to the Canary Islands, the self-compatible (SC) species Tolpis coronopifolia and its self-incompatible (SI) relative Tolpis santosii. We scored self-compatibility as self-seed set of recombinant plants within two F2 populations. To map and genetically characterize the breakdown of SI, we built a draft genome sequence of T. coronopifolia, genotyped F2 plants using multiplexed shotgun genotyping (MSG), and located MSG markers to the genome sequence. We identified a single quantitative trait locus (QTL) that explains nearly all variation in self-seed set in both F2 populations. To identify putative causal genetic variants within the QTL, we performed transcriptome sequencing on mature floral tissue from both SI and SC species, constructed a transcriptome for each species, and then located each predicted transcript to the T. coronopifolia genome sequence. We annotated each predicted gene within the QTL and found two strong candidates for SI breakdown. Each gene has a coding sequence insertion/deletion mutation within the SC species that produces a truncated protein. Homologs of each gene have been implicated in pollen development, pollen germination, and pollen tube growth in other species. PMID- 28892152 TI - Pharmacokinetics of chlortetracycline in maternal plasma and in fetal tissues following oral administration to pregnant ewes. AB - The purpose of this study was to determine if concentrations of chlortetracycline could be detected in fetal plasma or tissues after administering an oral dose of chlortetracycline (CTC; 500 mg/head/day) reported to be effective in controlling Campylobacter spp. abortions. Five pregnant ewes were administered 250 mg/head twice a day (total dose 500 mg/hd/d) for 7 days. On the beginning of day 7, intravenous catheters were surgically implanted or inserted into the fetus and dam. Plasma samples were collected from the ewe and fetus at various time points before and up to 36 hr after the last dose of CTC. All ewes were then sacrificed, and tissues were harvested from the fetus for drug analysis. Concentrations of CTC in maternal plasma were consistent with our previous study and below the minimum inhibitory concentration of Campylobacter abortion isolates. Concentrations of CTC were below the limit of detection in three of five fetal plasma samples and all of the placenta, amniotic fluid, and fetal stomach contents. Low concentrations were detectable in fetal kidney and liver, suggesting that CTC reaches the fetus, although at a variable and low ratio when compared to maternal concentrations. PMID- 28892153 TI - Effects of Ultra-High Pressure Homogenization and Hydrocolloids on Physicochemical and Storage Properties of Soymilk. AB - : This study investigated the efficacy of ultra-high pressure homogenization (UHPH) in the presence or absence of added hydrocolloids for enhancing a range of physic-chemical properties of soymilk-which are important for extending shelf life. Soymilk preparations containing different concentrations (0.01%, 0.02%, and 0.05%, w/v) of 2 different hydrocolloids (kappa-carrageenan, kappa-C, and gum Arabic, GA) were subjected to 3 different levels of UHPH (70, 140, and 210 MPa) and stored in sterilized containers at 4 degrees C. Emulsion properties of the soymilk preparations were analyzed over a period of 5 weeks. The results showed that soymilk with 0.05% kappa-C had markedly improved storage properties, evident by significantly (P < 0.05) enhanced surface energy and absolute zeta potential values compared to the unhomogenized soymilk with no hydrocolloid (16% and 39% augmentations, respectively) at the 1st week of storage. This trend continued throughout the entire period of study. The soymilk containing 0.05% kappa-C also exhibited significantly (P < 0.05) lower (60%) mean globular particle size at the initial week compared to the latter ones and maintained the trend throughout the 3rd week of storage. The study can potentially lead to a considerable economic benefit to the soymilk industry by providing valuable information to extend shelf life of soymilk. PRACTICAL APPLICATION: Soymilk is one of the most important soy products, and as a beverage, it is rapidly gaining popularity in the Western markets. However, it tends to form precipitates during storage to affect quality of the product. This study used a 2-prong approach of ultra-high pressure homogenization and addition of hydrocolloids to prevent aggregation of soymilk particles and the retention of antioxidant capacity. The results showed enhancement of the quality of soymilk during storage. The techniques developed can be adopted by the food industry. PMID- 28892154 TI - Pharmacogenetics of opioid analgesics in dogs. AB - Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs. PMID- 28892155 TI - Pharmacokinetics of tildipirosin in beagle dogs. AB - The objective of this study was to investigate the pharmacokinetic profile of tildipirosin (TD) in 24 beagle dogs following intravenous (i.v.) and intramuscular (i.m.) administration, respectively, at 2, 4, and 6 mg/kg. Plasma samples at certain time points (0-14 days) were collected, and the concentrations of drug were quantified by UPLC-MS/MS. Plasma concentration-time data and relevant parameters were described by noncompartmental through WinNonlin 6.4 software. After single i.m. injection at 2, 4, and 6 mg/kg body weight, mean maximum concentration (Cmax ) was 412.73 +/- 76.01, 1,051 +/- 323, and 1,061 +/- 352 ng/ml, respectively. Mean time to reach Cmax was 0.36 +/- 0.2, 0.08 +/- 0.00, and 0.13 +/- 0.07 hr after i.m. injection at 2, 4, and 6 mg/kg, respectively. The mean value of T1/2lambdaz for i.m. administration at doses of 2, 4, and 6 mg/kg was 71.39 +/- 28.42, 91 .33 +/- 50.02, and 96.43 +/- 45.02 hr, respectively. The mean residence times were 63.81 +/- 10.96, 35.83 +/- 15.13, and 38.18 +/- 16.77 hr for doses of 2, 4, and 6 mg/kg, respectively. These pharmacokinetic characteristics after i.m. administration indicated that TD could be rapidly distributed into tissues on account of the high lipid solubility and then released into plasma. In addition, the absolute bioavailability of 2 mg/kg after i.m. injection was 112%. No adverse effects were observed after i.v. and i.m. administration. PMID- 28892157 TI - Adaptability and specificity of inhibition processes in distractor-induced blindness. AB - In a rapid serial visual presentation task, inhibition processes cumulatively impair processing of a target possessing distractor properties. This phenomenon known as distractor-induced blindness-has thus far only been elicited using dynamic visual features, such as motion and orientation changes. In three ERP experiments, we used a visual object feature-color-to test for the adaptability and specificity of the effect. In Experiment I, participants responded to a color change (target) in the periphery whose onset was signaled by a central cue. Presentation of irrelevant color changes prior to the cue (distractors) led to reduced target detection, accompanied by a frontal ERP negativity that increased with increasing number of distractors, similar to the effects previously found for dynamic targets. This suggests that distractor-induced blindness is adaptable to color features. In Experiment II, the target consisted of coherent motion contrasting the color distractors. Correlates of distractor-induced blindness were found neither in the behavioral nor in the ERP data, indicating a feature specificity of the process. Experiment III confirmed the strict distinction between congruent and incongruent distractors: A single color distractor was embedded in a stream of motion distractors with the target consisting of a coherent motion. While behavioral performance was affected by the distractors, the color distractor did not elicit a frontal negativity. The experiments show that distractor-induced blindness is also triggered by visual stimuli predominantly processed in the ventral stream. The strict specificity of the central inhibition process also applies to these stimulus features. PMID- 28892156 TI - A Randomized, Controlled Trial Evaluating Polydextrose as a Fiber in a Wet and Dry Matrix on Glycemic Control. AB - Functional fibers can help Americans increase their fiber intake by incorporating extracted or synthesized fibers into food products. The United States Food and Drug Administration has recently proposed that "added" fibers must demonstrate a physiological health benefit, such as glucose control, to be included on the Nutrition Facts label as a dietary fiber. The objective of this study was to assess the effects of polydextrose (PDX), a water-soluble glucose polymer resistant to mammalian digestion, on postprandial glucose concentrations when added to relatively high moisture (beverage) versus low moisture (bar) food products. The study was designed as 2 parts with each being controlled, randomized, singe-blinded, cross-over trials. A total of 34 and 19 healthy subjects were asked to consume PDX in a beverage and bar, respectively. PDX was investigated at 0, 8, 12, and 16 g in the beverage and 0 and 12 g in the bar. Blood samples were collected before beverage/bar consumption and for 3 h thereafter to evaluate changes in plasma glucose and insulin concentrations. The 12 g PDX condition had significant impact on both outcomes as glucose was significantly increased in both matrices (P > 0.05) and insulin was increased in bar form only (P > 0.05). PDX was well tolerated at all dosages and matrices investigated. PDX did not lower postprandial glucose or insulin in either matrix at the doses provided; therefore, data do not support reporting PDX as a dietary fiber on the Nutrition Facts label under the current proposed rule using glycemic control as the endpoint for physiological benefit. PMID- 28892158 TI - Reduction of 4(5)-Methylimidazole Using Cookie Model Systems. AB - : The objective of this study was to determine the reduction of 4(5) methylimidazole (4-MI) under various baking conditions. For 4-MI analysis, an analytical method using gas chromatography-mass spectrometry was developed. The developed method was validated with linearity (r2 > 0.999), recovery (101% to 103%, 3 levels), and precision (1.5% to 4.3%, 3 levels). Limits of detection and quantification were 18.5 and 56.0 MUg/kg, respectively. This method was used to monitor the level of 4-MI in 11 commercial cookies, which ranged from 71.5 to 1254.8 MUg/kg. Time and temperature were modified in the cookie model system to reduce 4-MI. The largest reduction in 4-MI (56%) was achieved by baking at 140 degrees C for 8 min; however the cookies baked at this condition were not well accepted by consumers. With combination of consumer liking test result, baking cookies at 140 degrees C for 16 min is optimal for 4-MI reduction (28% reduction), while it has minimal impact on consumer acceptance. A strong correlation (r2 = 0.9981) was found between caramel colorant and 4-MI in the cookie model system. PRACTICAL APPLICATION: A consumer awareness toward toxicity of 4-MI has been arising, and method to reduce the levels of 4-MI in food products are being developed in many studies. Yet, these reduction studies in food model systems only focused on use of food additives for 4-MI reduction. Current study investigated the use of process modification on 4-MI reduction in cookie, and suggested that baking cookies longer at lower temperature, in turn, reduces the levels of 4-MI in cookies without compromising consumer acceptance. Finding from current study can practically aid bakery industry to ensure safety of bakery products without affecting consumer likings. PMID- 28892159 TI - Integrative models for joint analysis of shoot growth and branching patterns. AB - Plants exhibit dependences between shoot growth and branching that generate highly structured patterns. The characterization of the patterning mechanism is still an open issue because of the developmental processes involved with both succession of events (e.g. internode elongation, axillary shoot initiation and elongation) and complex dependences among neighbouring positions along the parent shoot. Statistical models called semi-Markov switching partitioned conditional generalized linear models were built on the basis of apple and pear tree datasets. In these models, the semi-Markov chain represents both the succession and lengths of branching zones, whereas the partitioned conditional generalized linear models represent the influence of parent shoot growth variables on axillary productions within each branching zone. Parent shoot growth variables were shown to influence specific developmental events. On this basis, the growth and branching patterns of two apple tree (Malus domestica) cultivars, as well as of pear trees (Pyrus spinosa) between two successive growing cycles, were compared. The proposed integrative statistical models were able to decipher the roles of successive developmental events in the growth and branching patterning mechanisms. These models could incorporate other parent shoot explanatory variables, such as the local curvature or the maximum growth rate of the leaf. PMID- 28892160 TI - Are litter decomposition and fire linked through plant species traits? AB - Contents 653 I. 654 II. 657 III. 659 IV. 661 V. 662 VI. 663 VII. 665 665 References 665 SUMMARY: Biological decomposition and wildfire are connected carbon release pathways for dead plant material: slower litter decomposition leads to fuel accumulation. Are decomposition and surface fires also connected through plant community composition, via the species' traits? Our central concept involves two axes of trait variation related to decomposition and fire. The 'plant economics spectrum' (PES) links biochemistry traits to the litter decomposability of different fine organs. The 'size and shape spectrum' (SSS) includes litter particle size and shape and their consequent effect on fuel bed structure, ventilation and flammability. Our literature synthesis revealed that PES-driven decomposability is largely decoupled from predominantly SSS-driven surface litter flammability across species; this finding needs empirical testing in various environmental settings. Under certain conditions, carbon release will be dominated by decomposition, while under other conditions litter fuel will accumulate and fire may dominate carbon release. Ecosystem-level feedbacks between decomposition and fire, for example via litter amounts, litter decomposition stage, community-level biotic interactions and altered environment, will influence the trait-driven effects on decomposition and fire. Yet, our conceptual framework, explicitly comparing the effects of two plant trait spectra on litter decomposition vs fire, provides a promising new research direction for better understanding and predicting Earth surface carbon dynamics. PMID- 28892161 TI - A gene is known by the company it keeps: enrichment of TNFAIP3 gene aberrations in MALT lymphomas expressing IGHV4-34 antigen receptors. AB - Associations between immunoglobulin (IG) receptors with distinctive immunogenetic features and particular gene mutations are a recurring theme in mature B-cell lymphomas. Relevant observations have been made in chronic lymphocytic leukemia (CLL), where gene mutations are distributed asymmetrically in cases bearing or not somatic hypermutations within the clonotypic immunoglobulin heavy chain variable region (IGHV) genes (e.g. TP53 mutations predominate in IG-unmutated CLL, whereas the opposite is seen for MYD88 mutations, enriched in IG-mutated CLL) and in subsets of cases with stereotyped IG (enrichment for SF3B1 mutations in CLL subset #2). Moreover, similar findings have been reported in splenic marginal-zone lymphoma, where KLF2 mutations are biased to cases expressing IGHV1 2*04 IG receptors, and in hairy cell leukemia, where IGHV4-34-expressing cases display a low frequency of BRAF mutations but a high frequency of MAP2K1 mutations. The list is now growing with the report of increased frequency of inactivating mutations in the TNFAIP3 gene in MALT lymphomas expressing IG receptors encoded by the IGHV4-34 gene, particularly of the ocular adnexa. Considering that TNFAIP3 encodes a negative regulator of NF-kappaB, this finding further highlights the importance of NF-kappaB pathway activation in the natural history of MALT lymphomas. Altogether, these findings allude to selection of genomic aberrations in lymphoma cases with distinctive immune signaling profiles linked to the expression of particular IG receptors. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28892162 TI - When does it pay off to prime for defense? A modeling analysis. AB - Plants can prepare for future herbivore attack through a process called priming. Primed plants respond more strongly and/or faster to insect attack succeeding the priming event than nonprimed plants, while the energetic costs of priming are relatively low. To better understand the evolution of priming, we developed a simulation model, partly parameterized for Brassica nigra plants, to explore how the fitness benefits of priming change when plants are grown in different biotic environments. Model simulations showed that herbivore dynamics (arrival probability, arrival time, and feeding rate) affect the optimal duration, the optimal investment and the fitness benefits of priming. Competition for light increases the indirect costs of priming, but may also result in a larger payoff when the nonprimed plant experiences substantial leaf losses. This modeling approach identified some important knowledge gaps: herbivore arrival rates on individual plants are rarely reported but they shape the optimal duration of priming, and it would pay off if the likelihood, severity and timing of the attack could be discerned from the priming cue, but it is unknown if plants can do so. In addition, the model generated some testable predictions, for example that the sensitivity to the priming cue decreases with plant age. PMID- 28892163 TI - Disparity, diversity, and duplications in the Caryophyllales. AB - The role played by whole genome duplication (WGD) in plant evolution is actively debated. WGDs have been associated with advantages such as superior colonization, various adaptations, and increased effective population size. However, the lack of a comprehensive mapping of WGDs within a major plant clade has led to uncertainty regarding the potential association of WGDs and higher diversification rates. Using seven chloroplast and nuclear ribosomal genes, we constructed a phylogeny of 5036 species of Caryophyllales, representing nearly half of the extant species. We phylogenetically mapped putative WGDs as identified from analyses on transcriptomic and genomic data and analyzed these in conjunction with shifts in climatic occupancy and lineage diversification rate. Thirteen putative WGDs and 27 diversification shifts could be mapped onto the phylogeny. Of these, four WGDs were concurrent with diversification shifts, with other diversification shifts occurring at more recent nodes than WGDs. Five WGDs were associated with shifts to colder climatic occupancy. While we find that many diversification shifts occur after WGDs, it is difficult to consider diversification and duplication to be tightly correlated. Our findings suggest that duplications may often occur along with shifts in either diversification rate, climatic occupancy, or rate of evolution. PMID- 28892164 TI - MCPIP1 attenuates the innate immune response to influenza A virus by suppressing RIG-I expression in lung epithelial cells. AB - The pattern recognition receptor retinoic acid-inducible gene I (RIG-I) reportedly plays a key role in sensing influenza A virus (IAV) infection and activating type I interferon (IFN) response. MCP-1-induced protein 1 (MCPIP1) can directly degrade cytokine mRNAs, such as IL-6, IL-12, IL-1beta, and IL-2, by functioning as an RNase. Here, we initially observed that MCPIP1 exhibited virus supportive functions later in the course of IAV infection in A549 cells, and negatively regulated IAV-induced RIG-I-dependent innate antiviral response. Exogenous overexpression of MCPIP1 suppressed the expression of RIG-I, whereas shRNA-mediated inhibition of endogenous MCPIP1 enhanced RIG-I expression. The results of experiments with actinomycin D and luciferase assay demonstrated that MCPIP1 reduced RIG-I expression through destabilizing its mRNA. Various mutants of functional domains of MCPIP1 further confirmed that the inhibitory effect of MCPIP1 on RIG-I expression required RNase activity but not deubiquitinase activity. Finally, the overexpression of several IAV proteins, which have the ability to inhibit the host IFN response at different levels, induced MCPIP1 expression, especially non-structural protein 1 (NS1). Conclusively, these data demonstrate the MCPIP1 contributes to attenuate IAV-induced host antiviral response by suppressing RIG-I expression. PMID- 28892165 TI - Environment and host identity structure communities of green algal symbionts in lichens. AB - An understanding of how biotic interactions shape species' distributions is central to predicting host-symbiont responses under climate change. Switches to locally adapted algae have been proposed to be an adaptive strategy of lichen forming fungi to cope with environmental change. However, it is unclear how lichen photobionts respond to environmental gradients, and whether they play a role in determining the fungal host's upper and lower elevational limits. Deep coverage Illumina DNA metabarcoding was used to track changes in the community composition of Trebouxia algae associated with two phylogenetically closely related, but ecologically divergent fungal hosts along a steep altitudinal gradient in the Mediterranean region. We detected the presence of multiple Trebouxia species in the majority of thalli. Both altitude and host genetic identity were strong predictors of photobiont community assembly in these two species. The predominantly clonally dispersing fungus showed stronger altitudinal structuring of photobiont communities than the sexually reproducing host. Elevation ranges of the host were not limited by the lack of compatible photobionts. Our study sheds light on the processes guiding the formation and distribution of specific fungal-algal combinations in the lichen symbiosis. The effect of environmental filtering acting on both symbiotic partners appears to shape the distribution of lichens. PMID- 28892166 TI - Clinical patterns associated with the concurrent detection of anti-HBs and HBV DNA. AB - Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average >1 for the SHB region and <1 for the RT region. The Ka/Ks ratio (>1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing. PMID- 28892167 TI - Effect of cadmium on kitl pre-mRNA alternative splicing in murine ovarian granulosa cells and its associated regulation by miRNAs. AB - In this study, we established an in vitro exposure model of murine ovarian granulosa cells to observe the effect of Cd on alternative splicing of the kitl pre-mRNA and subsequently to explore the role of kitl gene expression regulation related miRNAs through miRNA prediction, miRNA chip, bioinformatics and real-time quantitative polymerase chain reaction analyses. Our results showed that the kitl1/kitl2 mRNA ratio was significantly different (P < 0.05) at different dosages and times. The miRNA chip analysis showed that the miRNA expression profiles for the Cd treatment were significantly changed, and the expression of 29 miRNAs involved in alternative splicing of the kitl pre-mRNA was changed. The gene ontology analysis showed that the target gene functions of these 29 miRNAs were mainly enriched in the biological processes of cell metabolism regulation, post-transcriptional regulation of mRNA, interleukin-6-mediated signal transduction, cell cycle, cell proliferation, differentiation and migration. The pathway enrichment analysis showed that the target genes of the differentially expressed miRNAs were mainly enriched in the Ras signaling pathway, the Rap1 signaling pathway, the Foxo signaling pathway, the Hippo signaling pathway, the MAPK signaling pathway and the carcinogenic pathway. Polymerase chain reaction verification results showed that compared to the control group, the variation trends in the expression of mmu-miR-27a-3p, mmu-miR-34b-5p, mmu-miR-297a-3p, mmu miR-129-5p and mmu-miR-107-3p in the 4 hour 10 MUm Cd treatment group were basically the same as that of the chip result. Our results indicate that Cd exposure can affect alternative splicing of the kitl pre-mRNA in ovarian granulosa cells, and miRNAs play regulatory roles in the alternative splicing of kitl. PMID- 28892168 TI - 'Where there is a will, there is a way': Belief in school meritocracy and the social-class achievement gap. AB - Meritocratic ideology can promote system justification and the perpetuation of inequalities. The present research tests whether priming merit in the school context enhances the effect of socioeconomic status (SES) on school achievement. French fifth graders read a text priming either school merit or a neutral content, reported their French and mathematics self-efficacy as well as their belief in school meritocracy (BSM), and then took French and mathematics tests. Compared to the neutral condition, the merit prime condition increased the SES achievement gap. Self-efficacy and BSM were tested as two potential mediators of the effect. The results support a mediated moderation model in which belief in school meritocracy is the mechanism through which the merit prime increased the SES achievement gap. PMID- 28892169 TI - A global survey of alternative splicing in allopolyploid cotton: landscape, complexity and regulation. AB - Alternative splicing (AS) is a crucial regulatory mechanism in eukaryotes, which acts by greatly increasing transcriptome diversity. The extent and complexity of AS has been revealed in model plants using high-throughput next-generation sequencing. However, this technique is less effective in accurately identifying transcript isoforms in polyploid species because of the high sequence similarity between coexisting subgenomes. Here we characterize AS in the polyploid species cotton. Using Pacific Biosciences single-molecule long-read isoform sequencing (Iso-Seq), we developed an integrated pipeline for Iso-Seq transcriptome data analysis (https://github.com/Nextomics/pipeline-for-isoseq). We identified 176 849 full-length transcript isoforms from 44 968 gene models and updated gene annotation. These data led us to identify 15 102 fibre-specific AS events and estimate that c. 51.4% of homoeologous genes produce divergent isoforms in each subgenome. We reveal that AS allows differential regulation of the same gene by miRNAs at the isoform level. We also show that nucleosome occupancy and DNA methylation play a role in defining exons at the chromatin level. This study provides new insights into the complexity and regulation of AS, and will enhance our understanding of AS in polyploid species. Our methodology for Iso-Seq data analysis will be a useful reference for the study of AS in other species. PMID- 28892170 TI - Application of Visible/Near-Infrared Spectroscopy in the Prediction of Azodicarbonamide in Wheat Flour. AB - : Azodicarbonamide is wildly used in flour industry as a flour gluten fortifier in many countries, but it was proved by some researches to be dangerous or unhealthy for people and not suitable to be added in flour. Applying a rapid, convenient, and noninvasive technique in food analytical procedure for the safety inspection has become an urgent need. This paper used Vis/NIR reflectance spectroscopy analysis technology, which is based on the physical property analysis to predict the concentration of azodicarbonamide in flour. Spectral data in range from 400 to 2498 nm were obtained by scanning 101 samples which were prepared using the stepwise dilution method. Furthermore, the combination of leave-one-out cross-validation and Mahalanobis distance method was used to eliminate abnormal spectral data, and correlation coefficient method was used to choose characteristic wavebands. Partial least squares, back propagation neural network, and radial basis function were used to establish prediction model separately. By comparing the prediction results between 3 models, the radial basis function model has the best prediction results whose correlation coefficients (R), root mean square error of prediction (RMSEP), and ratio of performance to deviation (RPD) reached 0.99996, 0.5467, and 116.5858, respectively. PRACTICAL APPLICATION: Azodicarbonamide has been banned or limited in many countries. This paper proposes a method to predict azodicarbonamide concentrate in wheat flour, which will be used for a rapid, convenient, and noninvasive detection device. PMID- 28892171 TI - Systematic review with meta-analysis: breastfeeding and the risk of Crohn's disease and ulcerative colitis. AB - BACKGROUND: Breastfeeding is a modifiable factor that may influence development of inflammatory bowel diseases. However, literature on this has been inconsistent and not accounted for heterogeneity in populations and exposure. AIM: To conduct a meta-analysis to examine the association between breastfeeding in infancy and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A systematic search of Medline/PubMed and Embase was performed for full text, English-language literature through November 2016. Studies were included if they described breastfeeding in infancy in patients with CD or UC, and healthy controls. Data were pooled using a random effects model for analysis. RESULTS: A total of 35 studies were included in the final analysis, comprising 7536 individuals with CD, 7353 with UC and 330 222 controls. Ever being breastfed was associated with a lower risk of CD (OR 0.71, 95% CI 0.59-0.85) and UC (OR 0.78, 95% CI 0.67-0.91). While this inverse association was observed in all ethnicity groups, the magnitude of protection was significantly greater among Asians (OR 0.31, 95% CI 0.20-0.48) compared to Caucasians (OR 0.78, 95% CI 0.66-0.93; P = .0001) in CD. Breastfeeding duration showed a dose-dependent association, with strongest decrease in risk when breastfed for at least 12 months for CD (OR 0.20, 95% CI 0.08-0.50) and UC (OR 0.21, 95% CI 0.10-0.43) as compared to 3 or 6 months. CONCLUSION: Breastfeeding in infancy protects against the development of CD and ulcerative colitis. PMID- 28892172 TI - Evolutionary conservation of structure and function of the UVR8 photoreceptor from the liverwort Marchantia polymorpha and the moss Physcomitrella patens. AB - The ultraviolet-B (UV-B) photoreceptor UV RESISTANCE LOCUS 8 (UVR8) mediates photomorphogenic responses to UV-B in Arabidopsis through differential gene expression, but little is known about UVR8 in other species. Bryophyte lineages were the earliest diverging embryophytes, thus being the first plants facing the UV-B regime typical of land. We therefore examined whether liverwort and moss species have functional UVR8 proteins and whether they are regulated similarly to Arabidopsis UVR8. We examined the expression, dimer/monomer status, cellular localisation and function of Marchantia polymorpha and Physcomitrella patens UVR8 in experiments with bryophyte tissue and expression of green fluorescent protein (GFP)-UVR8 fusions in Nicotiana leaves and transgenic Arabidopsis. P. patens expresses two UVR8 genes that encode functional proteins, whereas the single M. polymorpha UVR8 gene expresses two transcripts by alternative splicing that encode functional UVR8 variants. P. patens UVR8 proteins form dimers that monomerise and accumulate in the nucleus following UV-B exposure, similar to Arabidopsis UVR8, but M. polymorpha UVR8 has weaker dimers and the proteins appear more constitutively nuclear. We conclude that liverwort and moss species produce functional UVR8 proteins. Although there are differences in expression and regulation of P. patens and M. polymorpha UVR8, the mechanism of UVR8 action is strongly conserved in evolution. PMID- 28892173 TI - Prevalence and diversity of rotavirus A genotypes cirulating in Turkey during a 2 year sentinel surveillance period, 2014-2016. AB - Human rotavirus A (RVA) is the main etiological agent of watery diarrhea among children under 5 years of age worldwide. The aims of this study were to investigate the prevalence and diversity of RVA genotypes circulating in Turkey during a 2-year sentinel surveillance study. A total of 1639 rotavirus antigen positive stool samples were obtained from children younger than 5 years of age hospitalized with acute gastroenteritis. Rotavirus G and P genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) with consensus primers for the VP7 and VP4 genes, followed by semi-nested type specific multiplex PCR. Rotavirus RNA was detected in 1396 (85.3%) of the samples tested. The highest detection rate (38.2%) was obtained among children in the 0 12 months age group, followed by children in the 13-24 months age group (36.2%). The most prevalent genotype was G1P[8] (24.6%) followed by G3P[8] (19.6%), G9P[8] (12.2%), G2P[4] (9.5%), G2P[8] (6.5%), and G4P[8] (4.8%). The proportions of uncommon and mixed genotypes were 21.5% and 1.14%, respectively. The large number of genotypes observed, including common, uncommon, and mixed types, indicates a high heterogeneity of RVA strains circulating in Turkey. The current study also exhibited dramatic fluctuations on the prevalences of the common genotypes, with increases in G3 and G1 and decreases in G9 and G2 from 2014-2016. PMID- 28892174 TI - A quantitative comparison of the electrical and anatomical definition of the pulmonary vein ostium. AB - BACKGROUND: Anatomically guided pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation. However, the position where to confirm electrical isolation is ill-defined. The aim of the current study was to quantify the relationship between the anatomical and electrical definition of the pulmonary vein ostium. METHODS: We analyzed 20 patients with paroxysmal AF undergoing PVI using radiofrequency energy and an electroanatomical mapping system. The anatomical ostium was defined based on the geometry obtained from preprocedural magnetic resonance imaging and computed tomography. The electrical ostium was defined at the position with a far-field atrial signal preceding a sharp pulmonary vein (PV) signal without any isoelectric interval in between. RESULTS: The electrically defined ostia were 8.4 +/- 4.7 mm more distal in the PV compared to the anatomically defined ostia. The distances varied considerably between the four PVs and were 10.5 +/- 6.5 mm, 7.4 +/- 4.3 mm, 5.3 +/- 4.0 mm, and 8.3 +/- 3.4 mm for the left superior, left inferior, right superior, and right inferior PVs, respectively (P = 0.009). CONCLUSIONS: The position of the electrical and anatomical ostium differs markedly. The site of the electrical ostium is variable within the PV but always more distal in the PV compared to the site of the anatomical ostium. PMID- 28892175 TI - (Almost) forgetting to care: an unanticipated source of empathy loss in clerkship. AB - CONTEXT: The erosion of empathy in medical students is well documented. Both the hidden curriculum associated with poor role modelling and a sense of burnout have been proposed as key factors, but the precise mechanisms by which this loss of empathy occurs have not been elaborated. OBJECTIVES: In the context of a course designed to help students manage the hidden curriculum, we collected data that raised questions about current conceptualisations of the aspects of medical training that lead to loss of empathy. METHODS: We held nine sessions in the first year of clinical clerkship, in which we asked students to bring to the group their experiences of the hidden curriculum for reflection. Course sessions were recorded, transcribed and qualitatively analysed, and themes were generated for further exploration. RESULTS: We identified an identity developmental trajectory in early clerkship in which students started with feelings of excitement, transitioned quickly to 'shock and awe', progressed into 'survival mode' and then passed into a stage of 'recovery'. Interestingly, in the early stages, students' sense of empathic virtuosity was reinforced. It was not until later, when students were more comfortable in their clinical role, that they reported their tendency to connect with the patient only as an afterthought to the encounter, or not at all, and needed to remind themselves to care. CONCLUSIONS: We offer new data for consideration with regard to medical students' loss of empathy during early clinical training that suggest it is the process of making patient care routine that shifts the patient from the status of an individual with suffering to the object of the work of being a physician. PMID- 28892176 TI - The Role of Gesture in Supporting Mental Representations: The Case of Mental Abacus Arithmetic. AB - People frequently gesture when problem-solving, particularly on tasks that require spatial transformation. Gesture often facilitates task performance by interacting with internal mental representations, but how this process works is not well understood. We investigated this question by exploring the case of mental abacus (MA), a technique in which users not only imagine moving beads on an abacus to compute sums, but also produce movements in gestures that accompany the calculations. Because the content of MA is transparent and readily manipulated, the task offers a unique window onto how gestures interface with mental representations. We find that the size and number of MA gestures reflect the length and difficulty of math problems. Also, by selectively interfering with aspects of gesture, we find that participants perform significantly worse on MA under motor interference, but that perceptual feedback is not critical for success on the task. We conclude that premotor processes involved in the planning of gestures are critical to mental representation in MA. PMID- 28892177 TI - Lasioglossins LLIII affect the morphogenesis of Candida albicans and reduces the duration of experimental vaginal candidiasis in mice. AB - Lasioglossins are a group of peptides with identified antimicrobial activity. The inhibitory effects of two synthetic lasioglossin derivatives, LLIII and D isomeric variant LLIII-D, on morphological changes in Candida albicans in vitro and the effect of local administration of LLIII during experimental murine candidiasis were investigated. C. albicans blastoconidia were grown in the presence of lasioglossin LLIII or LLIII-D at concentrations of 11.5 MUM and 21 MUM, respectively, for 1, 2 and 3 days and their viability determined by flow cytometry using eosin Y staining. Morphological changes were examined by light and fluorescent microscopy. The Candida-inhibitory effect of daily intravaginal administration of 0.7 or 1.4 MUg of LLIII was assessed in mice with experimentally-induced vaginal candidiasis. LLIII and LLIII-D lasioglossins exhibited candidacidal activity in vitro (>76% after 24 hr and >84% after 48 hr of incubation). After 72 hr incubation of Candida with low concentration of lasioglossins, an increase in viability was detected, probably due to a Candida antimicrobial peptides evasion strategy. Furthermore, lasioglossins inhibited temperature-induced morphotype changes toward hyphae and pseudohyphae with sporadic occurrence of atypical cells with two or enlarged nuclei, suggesting interference with mitosis or cytokinesis. Local application of LLIII reduced the duration of experimental candidiasis with no evidence of adverse effects. Lasioglossin LLIII is a promising candidate for development as an antimicrobial drug for treating the vaginal candidiasis. PMID- 28892178 TI - Review article: the diagnostic approach and current management of chylous ascites. AB - BACKGROUND: Chylous ascites is rare, accounting for less than 1% of cases. An appropriate and stepwise approach to its diagnosis and management is of key importance. AIM: To review the current diagnostic approach and management of chylous ascites. METHODS: A literature search was conducted using PubMed using the key words 'chylous', 'ascites', 'cirrhosis', 'pathophysiology', 'nutritional therapy', 'paracentesis", "transjugular intrahepatic portosystemic shunt" and "TIPSS'. Only articles in English were included. RESULTS: Chylous ascites is caused by the traumatic or obstructive disruption of the lymphatic system that leads to extravasation of thoracic or intestinal lymph into the abdominal space and the accumulation of a milky fluid rich in triglycerides. The most common causes are malignancy, cirrhosis and trauma after abdominal surgery. This condition can lead to chyle depletion, which results in nutritional, immunologic and metabolic deficiencies. An ascitic triglyceride concentration above 200 mg/dL is consistent with chylous ascites. Treatment is based on management of the underlying cause and nutritional support. CONCLUSIONS: Chylous ascites is mostly due to malignancy and cirrhosis in adults, and congenital lymphatic disorders in children. Treatment with nutritional optimization and management of the underlying etiology are the cornerstones of therapy. When conservative measures fail, other interventions such as octreotide/somatostatin analogues, surgical ligation, embolization and transjugular intrahepatic portosystemic shunt in patients with cirrhosis can be considered. PMID- 28892179 TI - Behavioural and electrophysiological responses of Triatoma dimidiata nymphs to conspecific faecal volatiles. AB - The behavioural and electrophysiological (electroantennography) responses of the first two instars of Triatoma dimidiata (Hemiptera: Reduviidae) Latreille to fresh and dry faecal headspace volatile extracts from fifth instar conspecific nymphs and synthetic compounds were analysed in this study. Recently emerged nymphs (3-5 days) aggregated around filter paper impregnated with dry faeces and around filter paper impregnated with extracts from both fresh and dry faeces. Older first instars (10-15 days) and second instars aggregated around filter paper impregnated with fresh and dry faeces, and their respective headspace extracts. Dry faecal volatile extracts elicited the strongest antennal responses, followed by fresh faecal extracts. Gas chromatography-mass spectrometry analysis of dried faecal headspace volatiles demonstrated the presence of 12 compounds: 2 ethyl-1-hexanol, 1,2,4-trimethylbenzene, n-octadecane, n-nonadecane, n-eicosane, n-heneicosane, n-tricosane, n-pentaeicosane, n-hexaeicosane, n-octaeicosane, nonanal, and 4-methyl quinazoline. In fresh faecal headspace extracts, only nonanal was clearly detected, although there were other trace compounds, including several unidentified sesquiterpenes. Four of the 11 compounds tested individually elicited aggregation behaviour at concentrations of 100 ng/uL and 1 ug/uL. A blend containing these four components also mediated the aggregation of nymphs. These volatiles may be valuable for developing monitoring methods and designing sensitive strategies to detect and measure T. dimidiata infestation. PMID- 28892180 TI - Long-term exposure to bisphenol S damages the visual system and reduces the tracking capability of male zebrafish (Danio rerio). AB - Bisphenol S (BPS) is widely detected in aquatic environments and in human bodies. BPS has reproductive and thyroid disrupting effects, but its effect on the visual system remains unknown. In the present study, zebrafish embryos were exposed to BPS at concentrations of 1, 10, 100 and 1000 MUg l-1 until 120 days post fertilization in a semistatic system, and the effect of BPS on the visual behavior was examined using the optokinetic response and the optomotor response tests in male zebrafish. The retinal histology, mRNA expression of photoreceptor opsin genes (zfrho, zfblue, zfgr1, zfred and zfuv) and apoptosis-related genes (bax and bcl-2) were also assessed. Long-term BPS exposure decreased the tracking capability of male zebrafish, consistent with structural damage to the retina. BPS induced different amounts of vacuoles in the retinal pigment epithelium, and 1000 MUg l-1 BPS exposure decreased the length of the inner plexiform layer, ganglion cell layer and retina, and induced an irregular arrangement of photoreceptor cells. The expression levels of the opsin genes (zfred, zfgr1 and zfrho) were significantly elevated, indicating an enhanced spectral sensitivity to red, green and dim light to compensate for the reduction of the optomotor response. Together, the results showed for the first time that long-term exposure to BPS damaged the structure of male zebrafish retina and reduced their tracking capability. PMID- 28892181 TI - The impact of obesity and timely antiviral administration on severe influenza outcomes among hospitalized adults. AB - Obesity was identified as a risk factor for severe influenza during the 2009 influenza A(H1N1)pandemic, but evidence of this association has been mixed since. Post-pandemic antiviral treatment guidelines may have increased antiviral treatment among obese individuals. A prospective study of adults hospitalized with laboratory-confirmed influenza in Detroit, Michigan in 2011-2012 and 2012 2013 was conducted. Patient information was collected from interviews and medical chart abstraction. Obese (BMI >= 30) and non-obese (BMI < 30) participants were compared. Late antiviral treatment (>2 days from symptom onset), obesity (30 <= BMI < 40), and morbid obesity (BMI >= 40) were evaluated as predictors of lower respiratory tract disease (LRD), ICU admission, and length of stay (LOS) using logistic regression and inverse probability weighted models. Forty-eight participants were included in the study after exclusions and all patients received antiviral treatment. Participants who were obese were significantly more likely to have a cough and to take steroids than non-obese participants, and had a shorter time from hospital admission to antiviral treatment (median time from admission to treatment of 0 days for obese patients and 1 day for non-obese patients [P = 0.001]). In all models, late antiviral treatment was associated with increased odds of LRD (OR: 3.9 [1.1,15.9] in fully adjusted model). After adjustment for treatment timing, the odds of ICU admission (OR: 6.4 [0.8,58.2] to 7.9 [0.9, 87.1]) and LRD (OR: 3.3 [0.5, 23.5] to 4.0 [0.6, 35.0]) associated with morbid obesity increased. Obese individuals were treated with antivirals earlier than others. Late antiviral treatment was associated with severe influenza in the hospital. PMID- 28892182 TI - Health-related quality of life in patients with lymphoedema - a cross-sectional study. AB - INTRODUCTION: Lymphoedema may cause complex problems that can strongly influence patients' health-related quality of life (HRQoL). The main purpose of this study was to investigate the impact of lymphoedema on HRQoL in patients with varying forms of lymphoedema. METHODS: The Lymphoedema Quality of Life Inventory (LyQLI), measuring three domains, physical, psychosocial and practical, and the Short Form 36 Health Survey Questionnaire (SF-36), measuring eight health domains, were sent to 200 lymphoedema patients. Out of those who answered both questionnaires, 88 patients had lymphoedema secondary to cancer treatment and they additionally received the Functional Assessment of Cancer Therapy Scale-General (FACT-G). The relation between continuous variables and the three domains were analysed by Spearman's correlation coefficients, and Kruskal-Wallis test was used to analyse categorical variables. RESULTS: Altogether 129 patients completed the LyQLI and SF-36 and 79 of them also completed FACT-G. Twenty per cent had a high mean score (>=2.0) in at least one domain of the LyQLI, thus having a low HRQoL. Lower HRQoL was found in the practical domain of LyQLI in patients with lower limb lymphoedema compared to patient with lymphoedema in upper limb or head/neck (p = 0.002) and in patients working part-time compared to patients working full-time (p = 0.005). The impact on HRQoL tended to decrease with age, with a significant correlation in the psychosocial domain (rs = 0.194, p = 0.028). Compared with the general Swedish population, patients with lymphoedema scored significantly lower in general health (p = 0.006), vitality (p = 0.002) and social functioning (p = 0.025) assessed by the SF-36. From a cancer-specific view, HRQoL was similar to other Swedish studies using the FACT-G. CONCLUSIONS: This study indicates that about 20% of the patients with lymphoedema had major impact on their HRQoL. More effort and research is needed to identify, understand and support groups of patients with severe lymphoedema-related problems. PMID- 28892183 TI - Histopathologic features of cutaneous leishmaniasis and use of CD1a staining for amastigotes in Old World and New World leishmaniasis. AB - BACKGROUND: Positive CD1a staining of Leishmania has been reported in Old World leishmaniasis, but the sensitivity of such staining for other Leishmania species is unknown. METHODS: A retrospective review was done on skin biopsies of proven cutaneous leishmaniasis based on histology, immunohistochemistry, culture and/or polymerase chain reaction (PCR). We assessed the pattern of inflammation present and assessed for CD1a (MTB1 clone) positivity in amastigotes. Patients without a clearly documented travel history to delineate Old vs New World leishmaniasis and cases without tissue for CD1a staining were excluded. RESULTS: Various patterns of granulomatous inflammation were observed including sarcoidal (31%), diffuse (25%), suppurative and granulomatous (25%), palisaded (13%) and lichenoid (6%). CD1a staining was positive in amastigotes in 9 of 16 cases (56%). Five of 7 (71%) cases of Old World disease were CD1a positive, while 4 of 9 cases (44%) of New World cases were positive. CONCLUSIONS: Multiple patterns of granulomatous inflammation occur in cutaneous leishmaniasis. Our results confirm CD1a (MTB1 clone) can be a diagnostic adjunct to highlight amastigotes in biopsies of cutaneous leishmaniasis, with variable positivity in both Old World and New World forms of the disease. As 44% of cases were CD1a negative in our cohort, there are significant limitations to this screening approach. PMID- 28892184 TI - Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. AB - BACKGROUND: Up-to-date information regarding the recurrence rate of Helicobacter pylori (H. pylori) after eradication therapy is not available. AIM: To evaluate the global recurrence rate following H. pylori eradication therapy and confirm its association with socioeconomic and sanitary conditions. METHODS: A systematic search of PubMed, EMBASE and the Cochrane library was performed to identify potentially relevant publications using the following keywords: "Helicobacter pylori" or "H. pylori" or "Hp" and "recurrence" or "recrudescence" or "reinfection" or "recurrent" or "recurred" or "re-infect*" or "relapse*." RESULTS: A total of 132 studies (53 934 patient-years) were analysed. Each study was weighted according to the duration of patient-years. The global annual recurrence, reinfection and recrudescence rate of H. pylori were 4.3% (95% CI, 4 5), 3.1% (95% CI, 2-5) and 2.2% (95% CI, 1-3), respectively. The H. pylori recurrence rate was inversely related to the human development index (HDI) (ie, 3.1% [95% CI, 2-4], 6.2% [95% CI, 4-8] and 10.9% [95% CI, 6-18] in countries with a very high, high and medium or low HDI) (P <.01) and directly related to H. pylori prevalence (10.9% [95% CI, 7-16], 3.7% [95% CI, 3-5], 3.4% [95% CI, 2-5] and 1.6% [95% CI, 0.5-3] in countries with a very high, high, medium or low local H. pylori prevalence) (P <.01). Global recurrence rates remained relatively stable between 1990s, 2000s and 2010s but varied across different regions (P <.05). CONCLUSIONS: H. pylori recurrence remains a problem closely associated with socioeconomic and sanitary conditions. Methods to reduce recurrence in developing countries are needed. PMID- 28892185 TI - Prevalence, comorbidities and mortality of toxic shock syndrome in children and adults in the USA. AB - Toxic Shock Syndrome (TSS), a superantigen-mediated illness, is characterized by rash, hypotension and multi-organ dysfunction. Predictors of TSS and related morbidity and mortality are poorly defined. In this study, data on 61,959,084 hospitalizations from the 2003-2012 Nationwide Inpatient Sample, a 20% stratified sample of US hospitalizations, were analyzed and ICD-9-CM coding used to identify 4491 hospitalizations with a diagnosis of TSS. Incidence, in-hospital mortality rate, comorbidities, length of stay and costs of care attributable to TSS were determined. In multivariate survey logistic regression models, TSS was associated with female sex (adjusted odds ratio [95% confidence interval], 1.54 [1.48 1.60]), younger age (0-17 years, 2.17 [2.06-2.29]; 40-59: 0.53 [0.50-0.56]; 60 79: 0.28 [0.26-0.30]; 80+: 0.13 [0.11-0.14] compared with 18-39) and race/ethnicity (black, 0.63 [0.59-0.67]; Hispanic: 0.60 [0.56-0.64]; Asian, 1.11 [1.00-1.11]; and other, 0.83 [0.75-0.92] compared with white). Patients with TSS had a three-fold greater cost of care (mean: $36,656 +/- 942) and length of stay (LOS) (mean: 10.65 +/- 0.23 days) than patients without TSS. Shared predictors of increased LOS and costs in patients with TSS were male sex; age 40-79 years; Black, Hispanic, Asian and other race/ethnicity; and more than one chronic condition. Predictors of in-hospital mortality included respiratory failure (13.66 [11.37-16.43]), liver disease/failure (3.36 [2.59-4.34]), chickenpox (91.26 [27.74-300.25]), coagulopathy (2.14 [1.85-2.48]), and higher age. In conclusion, there are significant racial/ethnic, socioeconomic, and comorbid disparities in the incidence and mortality of TSS in adults and children in the USA. PMID- 28892186 TI - Investigating the impact of innate dexterity skills and visuospatial aptitude on the performance of baseline laparoscopic skills in veterinary students. AB - OBJECTIVE: To determine if manual dexterity and visuospatial skills can be used to predict baseline laparoscopic surgery skills in veterinary students. STUDY DESIGN: Pilot study. METHODS: Veterinary students (n = 45) from years 1-4 volunteered for this study. An hour-long electronic questionnaire was completed by participants. The first section was used to collect demographics and information about prior nonsurgical experiences. The second section included 3 tests of visuospatial skills, including the Purdue Visualization of Rotations Test, Mental Rotations Test, and Raven's Advanced Progressive Matrices Test. Multiple tests were administered to assess innate dexterity, including the grooved pegboard test, indirect and direct zigzag tracking tests, and the 3Dconnexion proficiency test. Each dexterity test was performed once with the left hand and once with the right hand. The order of task performance was randomized. Basic laparoscopic skills were assessed using the validated fundamentals of laparoscopic surgery (FLS) peg transfer task. RESULTS: There was an association between left-handed grooved pegboard scores (95% CI -10046.36 to 1636.53, P-value = .008) and left-handed indirect zigzag tracking task (95% CI 35.78 to -8.20, P-value = .003) with FLS peg transfer scores. Individuals who reported playing videogames achieved higher scores on the FLS peg transfer task than those without videogame experience (95% CI 583.59 to 3509.97, P-value = .007). CONCLUSION: The results of this study suggest that dexterity was a better predictor of baseline laparoscopic skills than visuospatial skills in veterinary students. PMID- 28892187 TI - Patient satisfaction with health care services at a national institute of ophthalmology. AB - Little is known about how patients in developing countries, such as Vietnam, are satisfied with eye care services. The purpose of this study was to assess the satisfaction with health services and its associated factors among patients attending a national institute of ophthalmology in Vietnam. In a cross-sectional study utilizing quantitative methods, 500 inpatients and their relatives attending a national institute of ophthalmology in Vietnam were approached for data collection. The results indicated that under 50% of the patients were satisfied with eye care services. However, when classified by level of satisfaction, only 6.8% were very satisfied with all domains of care. There was no significant difference in satisfaction by gender and income, while significant differences by department, residence, and education were found. Patients who were from rural areas, were better educated, and used the services of the glaucoma department, were more satisfied with eye care than those from urban areas, were less educated, and used the services of treatment-on-demand department. Multivariable regression detected 2 main factors, gender and location, associated with patient satisfaction. Patients who were female and came from rural and remote areas were more likely to be satisfied than patients who were male and living in urban areas. The study suggests that to continue to improve health care quality, it is important to eliminate differences in providing eye care services regardless of whether patients are male or female, and whether they come from a rural or urban area. PMID- 28892188 TI - Person-centred climate and psychometrical exploration of person-centredness and among patients not conveyed by the Ambulance Care Service. AB - BACKGROUND: What already is known is that as many as 50% of all Swedish Ambulance Care Service assignments are considered as non-emergency. Therefore, due to medical protocols and triage system, patients are refused conveyance to the Accident and Emergency Department by the Ambulance Care Service. AIM: The aim of this study was to psychometrically explore the construct validity of a possible dimension of person-centredness, developed from a previous published qualitative study in a nonemergency ambulance care context. A second aim was to explore patients' experiences of the person-centred climate and to explore possible relationship between it and person-centredness. DESIGN/METHODS: A retrospective, explorative, cross-sectional survey design with a convenience sample was employed. A total of 111 questionnaires were analysed using descriptive and comparative statistics. An explanatory factor analysis was also conducted. FINDINGS: A one-factor solution for the specific items possibly constructing person-centredness was found. The responses to the Person-centred Climate Questionnaire-Patient version (PCQ-P) revealed that the climate was received as highly person-centred. Relationships were found between the specific items possibly constructing person-centredness and PCQ-P. CONCLUSION: A highly valid construct of person-centredness exists within nonurgent Ambulance Care Service assignments comprising eight aspects of being taken seriously. The climate in which nonemergency ambulance care is provided has great potential to facilitate person-centredness by means of taking patients seriously. The psychosocial aspects of PCQ-P and person-centredness are somewhat related to each other. PMID- 28892189 TI - Sensitive community responses of microbiota to copper in sediment toxicity test. AB - Sediment contamination is widespread and can be toxic to aquatic ecosystems and impair human health. Despite their significant ecological function, meio- and microbiota in aquatic ecosystems have been poorly studied in conventional sediment ecotoxicity tests because of the difficulty in sample collecting and identification. In the present study, a novel DNA metabarcoding method was used to assess the effects of spiked copper (Cu) on benthic eukaryotic and prokaryotic communities in laboratory sediment toxicity tests with macroinvertebrates, the chironomid Chironomus tepperi and the amphipod Austrochiltonia subtenuis. In addition to the obvious toxic effects to experimental animals, microbiota (bacteria, protists, algae, and fungi) were significantly altered by spiked Cu in the sediments. The phylogenetic diversity of eukaryotic communities was decreased after spiked-Cu exposure. Even a low-spiked Cu treatment (125 mg/kg) altered structures of eukaryotic and prokaryotic communities in the amphipod experiment. The present study demonstrates that measuring microbiota communities will expand our understanding of the influences of contaminants on aquatic ecosystems. Particularly, the alterations of phylogenetic biodiversity of eukaryotic communities and the structure of sedimentary communities are sensitive indicators for sediment contamination, which can be incorporated in the monitoring and assessment of sediment quality. Environ Toxicol Chem 2018;37:599-608. (c) 2017 SETAC. PMID- 28892190 TI - Parasitemia due to Sarcocystis neurona-like infection in a clinically ill domestic cat. AB - An 8-year-old, 6-kg, male neutered Domestic Shorthair cat was presented to The Ohio State University Veterinary Medical Center (OSU-VMC) for difficulty breathing. Physical examination and thoracic radiographs indicated pneumonia, a soft-tissue mass in the left caudal lung lobe, and diffuse pleural effusion. The effusion was classified as modified transudate. Rare extracellular elongated (~5 7 MUm * 1-2 MUm) zoites with a central round to oval-shaped purple to deep purple vesicular nucleus with coarsely stippled chromatin and light blue cytoplasm were seen on a peripheral blood smear. Serum IgG and IgM were positive for Sarcocystis sp. antibodies and negative for Toxoplasma gondii antibodies, suggesting that the infection was acute rather than a recrudescence of prior infection. This organism was most consistent with either Sarcocystis neurona or Sarcocystis dasypi based on DNA sequence analysis of PCR products using COC ssRNA, ITS-1, snSAG2, and JNB25/JD396 primer sets. This is the first report to visualize by light microscopy circulating Sarcocystis sp. merozoites in the peripheral blood of a domestic cat. Therefore, Sarcocystis should be considered as a differential diagnosis in cats with suspected systemic protozoal infection. PMID- 28892191 TI - Psychometric evaluation of a motor control test battery of the craniofacial region. AB - The primary objective of this study was to determine the structural and known group validity as well as the inter-rater reliability of a test battery to evaluate the motor control of the craniofacial region. Seventy volunteers without TMD and 25 subjects with TMD (Axes I) per the DC/TMD were asked to execute a test battery consisting of eight tests. The tests were video-taped in the same sequence in a standardised manner. Two experienced physical therapists participated in this study as blinded assessors. We used exploratory factor analysis to identify the underlying component structure of the eight tests. Internal consistency (Cronbach's alpha), inter-rater reliability (intra-class correlation coefficient) and construct validity (ie, hypothesis testing-known group validity) (receiver operating curves) were also explored for the test battery. The structural validity showed the presence of one factor underlying the construct of the test battery. The internal consistency was excellent (0.90) as well as the inter-rater reliability. All values of reliability were close to 0.9 or above indicating very high inter-rater reliability. The area under the curve (AUC) was 0.93 for rater 1 and 0.94 for rater two, respectively, indicating excellent discrimination between subjects with TMD and healthy controls. The results of the present study support the psychometric properties of test battery to measure motor control of the craniofacial region when evaluated through videotaping. This test battery could be used to differentiate between healthy subjects and subjects with musculoskeletal impairments in the cervical and oro facial regions. In addition, this test battery could be used to assess the effectiveness of management strategies in the craniofacial region. PMID- 28892192 TI - Estimating activity of Japanese macaques (Macaca fuscata) using accelerometers. AB - Accelerometers have been used to study both terrestrial and aquatic wildlife, mainly for mammal and bird species. In terrestrial mammals, there is a bias toward ungulates and carnivores, with fewer studies on nonhuman primates. In this study, we tested the use of accelerometers for studying the activity of Japanese macaques (Macaca fuscata). We modeled the activity of a male and a female subject by matching continuous focal observations from video recordings to sensor parameters derived from collar-mounted accelerometers. Models achieved classification performance (AUC) of greater than 90% for both subjects, with similar results when subjects were cross-validated. Accelerometer-based estimates of activity had comparable accuracies to estimates from instantaneous sampling at 1 min and 5 min intervals. We further demonstrated the use of model estimates for analyzing circadian rhythm and night time activity of M. fuscata. Our results add support to the feasibility of using accelerometers for studying activity of nonhuman primates. We discussed the limitations, benefits and potential applications of remote-sensing technology like accelerometers for advancing primalotogical studies. PMID- 28892193 TI - Direct Observations of the Formation and Redox-Mediator-Assisted Decomposition of Li2 O2 in a Liquid-Cell Li-O2 Microbattery by Scanning Transmission Electron Microscopy. AB - Operando scanning transmission electron microscopy observations of cathodic reactions in a liquid-cell Li-O2 microbattery in the presence of the redox mediator tetrathiafulvalene (TTF) in 1.0 m LiClO4 dissolved dimethyl sulfoxide electrolyte are reported. It is found that the TTF addition does not obviously affect the discharge reaction for the formation of a solid Li2 O2 phase. The coarsening of Li2 O2 nanoparticles occurs via both conventional Ostwald ripening and nonclassical crystallization by particle attachment. During charging, the oxidation reaction at significantly reduced charge potentials mainly takes place at Li2 O2 /electrolyte interfaces and has obvious correspondence with the oxidized TTF+ distributions in the electric fields of the charged electrode. This study provides direct evidence that TTF truly plays a role in promoting the decomposition of Li2 O2 as a soluble charge-transfer agent between the electrode and the Li2 O2 . PMID- 28892195 TI - Metal-Free Carbon Materials for CO2 Electrochemical Reduction. AB - The rapid increase of the CO2 concentration in the Earth's atmosphere has resulted in numerous environmental issues, such as global warming, ocean acidification, melting of the polar ice, rising sea level, and extinction of species. To search for suitable and capable catalytic systems for CO2 conversion, electrochemical reduction of CO2 (CO2 RR) holds great promise. Emerging heterogeneous carbon materials have been considered as promising metal-free electrocatalysts for the CO2 RR, owing to their abundant natural resources, tailorable porous structures, resistance to acids and bases, high-temperature stability, and environmental friendliness. They exhibit remarkable CO2 RR properties, including catalytic activity, long durability, and high selectivity. Here, various carbon materials (e.g., carbon fibers, carbon nanotubes, graphene, diamond, nanoporous carbon, and graphene dots) with heteroatom doping (e.g., N, S, and B) that can be used as metal-free catalysts for the CO2 RR are highlighted. Recent advances regarding the identification of active sites for the CO2 RR and the pathway of reduction of CO2 to the final product are comprehensively reviewed. Additionally, the emerging challenges and some perspectives on the development of heteroatom-doped carbon materials as metal free electrocatalysts for the CO2 RR are included. PMID- 28892194 TI - Roll-to-Roll Production of Transparent Silver-Nanofiber-Network Electrodes for Flexible Electrochromic Smart Windows. AB - Electrochromic smart windows (ECSWs) are considered as the most promising alternative to traditional dimming devices. However, the electrode technology in ECSWs remains stagnant, wherein inflexible indium tin oxide and fluorine-doped tin oxide are the main materials being used. Although various complicated production methods, such as high-temperature calcination and sputtering, have been reported, the mass production of flexible and transparent electrodes remains challenging. Here, a nonheated roll-to-roll process is developed for the continuous production of flexible, extralarge, and transparent silver nanofiber (AgNF) network electrodes. The optical and mechanical properties, as well as the electrical conductivity of these products (i.e., 12 Omega sq-1 at 95% transmittance) are comparable with those AgNF networks produced via high temperature sintering. Moreover, the as-prepared AgNF network is successfully assembled into an A4-sized ECSW with short switching time, good coloration efficiency, and flexibility. PMID- 28892196 TI - Effect of biomechanical stress on endogenous antioxidant networks in bovine articular cartilage. AB - Mechanosensitve pathways in chondrocytes are essential for maintaining articular cartilage homeostasis. Traumatic loading increases cartilage oxidation and causes cell death and osteoarthritis. However, sub-lethal doses of the pro-oxidant molecule tert-Butyl hydroperoxide (tBHP) protects against loading-induced chondrocyte death. We hypothesized that compressive cyclic loading at moderate strains (<20%) causes sub-lethal cartilage oxidation that induces an adaptive increase in the endogenous antioxidant defense network. We tested this hypothesis by subjecting healthy bovine articular cartilage explants to in vitro static or cyclic (1 Hz) compressive loading at 50 kPa (15% strain, "physiologic") versus 300 kPa (40% strain, "hyper-physiologic") for 12 h per day for 2 days. We also treated unloaded explants with 100 MUM tBHP for 12 h per day for 2 days to differentiate between biomechanical and chemical pro-oxidant stimulation. All loading conditions induced glutathione oxidation relative to unloaded controls, but only the 50 kPa cyclic loading condition increased total glutathione content (twofold). This increase was associated with a greater expression of glutamate cysteine ligase, the rate-limiting step in glutathione synthesis, compared to 300 kPa cyclic loading. 50 kPa cyclic loading also increased the expression of superoxide dismutase-1 and peroxiredoxin-3. Like 50 kPa loading, tBHP treatment also increased total glutathione content. However, tBHP treatment and 50 kPa cyclic loading differed in their effect on the expression of genes regulating antioxidant defense and cartilage matrix synthesis and degradation. These findings suggest that glutathione metabolism is a mechanosensitive antioxidant defense pathway in chondrocytes and that intermittent pro-oxidant treatment alone is insufficient to account for all changes in mediators of cartilage homeostasis associated with cyclic loading. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:760-769, 2018. PMID- 28892197 TI - Aspirin is an enhancing factor for food-dependent exercise-induced anaphylaxis in children. PMID- 28892198 TI - Polyhedral Oligomeric Silsesquioxane (POSS) Bearing Glyoxylic Aldehyde as Clickable Platform Towards Multivalent Conjugates. AB - The straightforward access to octafunctional "cubic" silsesquioxane platform grafter with pendant glyoxylic aldehydes is described. This clickable hybrid platform readily reacts with oxyamine or hydrazide compounds to provide, respectively, oxime and acylhydrazone conjugates, thereby offering a new and effective access from which one can elaborate multivalent systems for the targeting of biomolecules of interest. PMID- 28892199 TI - Photoredox Catalysis with Metal Complexes Made from Earth-Abundant Elements. AB - Photoredox chemistry with metal complexes as sensitizers and catalysts frequently relies on precious elements such as ruthenium or iridium. Over the past 5 years, important progress towards the use of complexes made from earth-abundant elements in photoredox catalysis has been made. This review summarizes the advances made with photoactive CrIII , FeII , CuI , ZnII , ZrIV , Mo0 , and UVI complexes in the context of synthetic organic photoredox chemistry using visible light as an energy input. Mechanistic considerations are combined with discussions of reaction types and scopes. Perspectives for the future of the field are discussed against the background of recent significant developments of new photoactive metal complexes made from earth-abundant elements. PMID- 28892200 TI - Shorter Exciton Lifetimes via an External Heavy-Atom Effect: Alleviating the Effects of Bimolecular Processes in Organic Light-Emitting Diodes. AB - Multiexcited-state phenomena are believed to be the root cause of two exigent challenges in organic light-emitting diodes; namely, efficiency roll-off and degradation. The development of novel strategies to reduce exciton densities under heavy load is therefore highly desirable. Here, it is shown that triplet exciton lifetimes of thermally activated delayed-fluorescence-emitter molecules can be manipulated in the solid state by exploiting intermolecular interactions. The external heavy-atom effect of brominated host molecules leads to increased spin-orbit coupling, which in turn enhances intersystem crossing rates in the guest molecule. Wave function overlap between the host and the guest is confirmed by combined molecular dynamics and density functional theory calculations. Shorter triplet exciton lifetimes are observed, while high photoluminescence quantum yields and essentially unaltered emission spectra are maintained. A change in the intersystem crossing rate ratio due to increased dielectric constants leads to almost 50% lower triplet exciton densities in the emissive layer in the steady state and results in an improved onset of the photoluminescence quantum yield roll-off at high excitation densities. Efficient organic light-emitting diodes with better roll-off behavior based on these novel hosts are fabricated, demonstrating the suitability of this concept for real world applications. PMID- 28892201 TI - Two BRM promoter polymorphisms predict poor survival in patients with hepatocellular carcinoma. AB - Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89-11.54 and BRM-1321 per variant allele aHR 4.09, 95%CI 2.22-7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wild-type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants. PMID- 28892203 TI - Intraflap anastomoses for separated bone and cutaneous pedicle vascular anomaly in a chimeric medial femoral condyle flap. PMID- 28892202 TI - Syringomyelia and Craniocervical Junction Abnormalities in Chihuahuas. AB - BACKGROUND: Chiari-like malformation (CM) and syringomyelia (SM) are widely reported in Cavalier King Charles Spaniels and Griffon Bruxellois dogs. Increasing evidence indicates that CM and SM also occur in other small and toy breed dogs, such as Chihuahuas. OBJECTIVES: To describe the presence of SM and craniocervical junction (CCJ) abnormalities in Chihuahuas and to evaluate the possible association of CCJ abnormalities with SM. To describe CM/SM-related clinical signs and neurologic deficits and to investigate the association of CM/SM-related clinical signs with signalment, SM, or CCJ abnormalities. ANIMALS: Fifty-three client-owned Chihuahuas. METHODS: Prospective study. Questionnaire analyses and physical and neurologic examinations were obtained before magnetic resonance and computed tomography imaging. Images were evaluated for the presence of SM, CM, and atlantooccipital overlapping. Additionally, medullary kinking, dorsal spinal cord compression, and their sum indices were calculated. RESULTS: Scratching was the most common CM/SM-related clinical sign and decreased postural reaction the most common neurologic deficit in 73 and 87% of dogs, respectively. Chiari-like malformation and SM were present in 100 and 38% of dogs, respectively. Syringomyelia was associated with the presence of CM/SM-related clinical signs (P = 0.034), and medullary kinking and sum indices were higher in dogs with clinical signs (P = 0.016 and P = 0.007, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Syringomyelia and CCJ abnormalities are prevalent in Chihuahuas. Syringomyelia was an important factor for the presence of CM/SM related clinical signs, but many dogs suffered from similar clinical signs without being affected by SM, highlighting the clinical importance of CCJ abnormalities in Chihuahuas. PMID- 28892204 TI - Crude oil toxicity to fiddler crabs (Uca longisignalis and Uca panacea) from the northern Gulf of Mexico: Impacts on bioturbation, oxidative stress, and histology of the hepatopancreas. AB - The intensive drilling and extraction of fossil fuels in the Gulf of Mexico result in a considerable risk of oil spills impacting its coastal ecosystems. Impacts are more likely to be far-reaching if the oil affects ecosystem engineers like fiddler crabs, whose activities modify biogeochemical processes in the sediment. The present study investigated effects of oil on the fiddler crabs Uca longisignalis and Uca panacea, which are important as ecosystem engineers and as prey for a wide variety of species. The present study used mesocosms and microcosms to investigate the effects of crude oil on fiddler crab burrowing and to assess cellular and tissue damage by the oil. Fiddler crabs were exposed for periods of 5 or 10 d to oil concentrations up to 55 mg/cm2 on the sediment surface. Their burrowing was delayed, their burrows were smaller, and they transported less sediment in the presence of oil. The hepatopancreas had elevated levels of oxidative stress and a higher abundance of blister cells, which play a role in secretory processes. Interspecific differences were observed; most effects were strongest in U. panacea, though burrowing was more strongly affected in U. longisignalis. The present study demonstrates that crude oil is likely to impact fiddler crabs and many species that depend on them for their diet or for the ecological changes that result from their burrowing. Environ Toxicol Chem 2018;37:491-500. (c) 2017 SETAC. PMID- 28892205 TI - Desoxycorticosterone Pivalate Duration of Action and Individualized Dosing Intervals in Dogs with Primary Hypoadrenocorticism. AB - BACKGROUND: Clinicians alter dosing for desoxycorticosterone pivalate (DOCP) to mitigate costs, but this practice has not been critically evaluated in a prospective clinical trial. HYPOTHESIS/OBJECTIVES: The duration of action of DOCP is longer than 30 days in dogs with primary hypoadrenocorticism (PH). ANIMALS: A total of 53 client-owned dogs with PH. Twenty-four dogs with newly diagnosed PH (Group 1) and 29 dogs with treated PH (Group 2). METHODS: Prospective, multicenter, clinical trial. For phase I, DOCP was administered and plasma sodium and potassium concentrations were measured until the dog developed hyponatremia or hyperkalemia at a planned evaluation, or displayed clinical signs with plasma electrolyte concentrations outside of the reference interval independent of a planned evaluation, thus defining DOCP duration of action. Plasma electrolyte concentrations then were assessed at the end of the individualized dosing interval (IDI; i.e., DOCP duration of action minus 7 days, phase II and at least 3 months after concluding phase II, phase III). RESULTS: The duration of action of DOCP in dogs in phase I with naive PH (n = 24) ranged from 32 to 94 days (median, 62 days; 95% confidence interval [CI], 57, 65) and previously treated PH (n = 29) from 41 to 124 days (median, 67 days; CI, 56, 72). Overall, the final DOCP dosing interval for all dogs that completed phase II (n = 36) ranged from 38 days to 90 days (median, 58 days; CI, 53, 61). No dog that completed phase III (n = 15) required reduction in the IDI. The DOCP duration of action, independent of group, was not significantly associated with several baseline variables. The median drug cost reduction using IDI was approximately 57.5% per year. CONCLUSION AND CLINICAL IMPORTANCE: The duration of action of DOCP in dogs with PH is >30 days, and plasma sodium and potassium concentrations can be maintained with an IDI >30 days long term. PMID- 28892206 TI - IL-33 and IgE stimulate mast cell production of IL-2 and regulatory T cell expansion in allergic dermatitis. AB - BACKGROUND: We have previously shown that mast cells (MCs) suppress chronic allergic dermatitis in mice. The underlying mechanism involves MC-derived IL-2, which supports regulatory T cell (Treg) response at the site of inflammation. However, it is not clear what are the factors that drive MCs to produce IL-2. OBJECTIVE: To understand the mechanisms that lead to IL-2 production from MCs in chronic allergic dermatitis. METHODS: Isolated murine bone marrow-derived MCs (BMMCs) were incubated with various stimulators, and IL-2 production was assessed by RT-PCR and ELISA. The response of signalling pathways was evaluated by MAPK inhibitors and Western blot analysis. The effect of MC-IL-2 on Tregs was studied by incubation of splenic T cells with conditioned media obtained from activated BMMCs. Dermatitis was elicited by repeated exposures of mouse ears to oxazolone. MCs in mouse and human skin samples were evaluated by immunostaining. RESULTS: BMMCs released IL-2 in response to IL-33, and IL-2 production was further enhanced by concomitant FcepsilonRI activation. The effect of IL-33 was mediated by activation of the MAPK family members. IL-2 in conditioned media from IL-33 and IgE-stimulated BMMCs led to considerable expansion of Tregs in vitro. IL-33 levels were elevated in oxazolone-challenged ears along with increased numbers of IL-2-expressing MCs. Human skin with chronic inflammation also contained IL-2 expressing MCs that colocalized with IL-33 staining in the dermis. CONCLUSIONS: IL-33, in collaboration with IgE, is critical for MC-IL-2 production in allergic skin disease, thus leading to Treg stimulation and suppression of allergic dermatitis. PMID- 28892207 TI - Topological Design of Ultrastrong and Highly Conductive Graphene Films. AB - Nacre-like graphene films are prepared by evaporation-induced assembly of graphene oxide dispersions containing small amounts of cellulose nanocrystal (CNC), followed by chemical reduction with hydroiodic acid. CNC induces the formation of wrinkles on graphene sheets, greatly enhancing the mechanical properties of the resultant graphene films. The graphene films deliver an ultrahigh tensile strength of 765 +/- 43 MPa (up to 800 MPa in some cases), a large failure strain of 6.22 +/- 0.19%, and a superior toughness of 15.64 +/- 2.20 MJ m-3 , as well as a high electrical conductivity of 1105 +/- 17 S cm-1 . They have a great potential for applications in flexible electronics because of their combined excellent mechanical and electrical properties. PMID- 28892208 TI - Perspectives of oncology nurses and oncologists regarding barriers to working with patients from a minority background: Systemic issues and working with interpreters. AB - This study aimed to ascertain the systemic barriers encountered by oncology health professionals (HPs) working with patients from ethnic minorities to guide the development of a communication skills training programme. Twelve medical and five radiation oncologists and 21 oncology nurses were invited to participate in this qualitative study. Participants were interviewed individually or in a focus group about their experiences working with people from minority backgrounds. All interviews were transcribed verbatim and analysed thematically. HPs encountered language and communication barriers in their interactions with patients and their families, which were perceived to impact negatively on the quality and amount of information and support provided. There was a shortage of, and poor processes for engaging, interpreters and some HPs were concerned about the accuracy of interpretation. HPs expressed a need for training in cultural awareness and communication skills with a preference for face-to-face delivery. A lack of funding, a culture of "learning on the job", and time constraints were systemic barriers to training. Oncologists and oncology nurses encounter complex challenges in clinical interactions with minority patients and their families, including difficulties working with interpreters. Formal training programmes targeted to the development of culturally competent communication skills are required. PMID- 28892210 TI - Myoma and myomectomy: Poor evidence concern in pregnancy. AB - AIM: Summarize the results of the many, but often underpowered, studies on pregnancy complicated by myoma or myomectomy. METHODS: Survey of the electronic PubMed database for the last two decades was conducted. We selected reviews, meta analyses, case series, case reports, clinical studies only with statistical analysis, and guidelines from scientific societies. RESULTS: Delaying childbearing leads to an increased incidence of pregnancy complicated by fibroids or previous myomectomy. Approximately 10-30% of pregnant women with myomas develop complications during gestation, at delivery and in puerperium. Submucosal, retroplacental, large and multiple myomas have a greater risk of complications. Cervical myomas, although rare, need careful management. The location and size of the fibroids should be assessed from the first trimester. Despite the increased risk of cesarean section, fibroids are not a contraindication to labor, unless they obstruct the birth canal or other obstetric conditions coexist. Myomectomy during pregnancy, in selected cases, is feasible and safe. Myomectomy cannot be considered a prophylactic measure prior to conception, but has to be individualized. Uterine rupture after myomectomy generally occurs in the third trimester or during labor and some associated risk factors have been identified. There is no consensus on the optimal interval between myomectomy and conception. CONCLUSIONS: Pregnancy in patients with fibroids or previous myomectomy should be considered as high risk, requiring a maternal-fetal medicine specialist. To date available literature is inconsistent on evidence-based management. Further research is needed for definitive recommendations. PMID- 28892209 TI - Pharmacokinetics of Mycophenolic Acid after Intravenous Administration of Mycophenolate Mofetil to Healthy Cats. AB - BACKGROUND: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is becoming increasingly popular as an alternative immunosuppressant in feline medicine. Pharmacokinetic information is not available for cats. OBJECTIVE: The purpose of this study was to determine whether MMF is biotransformed into the active metabolite MPA and to evaluate the disposition of MPA after a 2-hour constant rate intravenous (IV) infusion of MMF in healthy cats. ANIMALS: Healthy cats (n = 6). METHODS: This was a prospective pilot study. All cats were administered MMF at 20 mg/kg every 12 hours over a 2-hour constant rate infusion for 1 day. The concentrations of MPA and its derivatives in blood were determined using a validated UHPLC-UV method. RESULTS: All cats biotransformed MMF into MPA. The mean AUC0-14 h ranged from 6 to 50 h*mg/L after IV dosing of MMF. Transient large bowel diarrhea was recorded in 2 of 6 cats after medication administration. CONCLUSION AND CLINICAL IMPORTANCE: The disposition of MPA in plasma was highly variable, which could result in high interindividual variability in the safety and efficacy of treatment with MMF in cats. PMID- 28892211 TI - Early menarche is associated with non-alcoholic fatty liver disease in adulthood. AB - BACKGROUND: The aim of this study was to examine the association between early menarche (<12 years) and non-alcoholic fatty liver disease (NAFLD) in premenopausal women and to explore whether it is mediated by adult obesity and insulin resistance. METHODS: We analyzed data of premenopausal women, aged >=15 years, from the Korea National Health and Nutrition Examination Survey (2007 2009). We divided the women into three groups: early menarche, reference (12.00 15.99 years), and late menarche. The presence of NAFLD was determined using hepatic steatosis index >36.0. RESULTS: Of the 4,387 women evaluated, 673 (15.4%) met the criteria for NAFLD. The prevalence of NAFLD was higher in both women with early and late menarche compared with the reference (early, 23.4%; reference, 14.0%; late, 19.9%, P < 0.001). After adjustment of confounders including age, the OR for NAFLD in early menarche compared with the reference was 3.04 (95%CI: 1.99-4.65). Further adjustment of mediators, such as central obesity or insulin resistance, attenuated the association to 1.91-2.17. There was no association, however, between late menarche and NAFLD after adjustment of confounders. CONCLUSIONS: Early menarche was associated with an increased risk of NAFLD in young and middle-aged premenopausal Korean women. PMID- 28892212 TI - Incidental appendectomy during mini incision post-partum sterilization (Chokchai technique): A prospective cross-sectional study. AB - AIM: We aimed to determine the success rate of incidental appendectomy during post-partum sterilization (PPS) using the Chokchai technique and to compare the postoperative morbidity between patients who underwent this procedure with those who underwent simple PPS. METHODS: Appendectomy during PPS was performed in 141 patients from 1 May 2012 to 30 April 2014. The control group consisted of 182 simple PPS patients. Primary outcomes were the success rate of the procedure and secondary outcomes were postoperative morbidity and complications. RESULTS: The success rate of this procedure was 98.6%. There was no statistically significant difference in intraoperative blood loss, hospital length of stay, or postoperative morbidity. Appendectomy added 7.5 min to the total procedure. Intravenous sedation requirements were 13.7% and 33.3% in the control and study groups, respectively. Pathologic evaluation of resected appendices revealed 15 abnormalities (10.8%), including two cases of periappendicitis (1.4%). CONCLUSION: When carried out by experienced surgeons and with appropriate anesthesia, incidental appendectomy during PPS is safe. The Chokchai technique (approach through a small periumbilical incision) achieved a high success rate and resulted in minimal scar. Incidental appendectomy not only prevents any future appendicitis but also helps to detect periappendicitis and treat its primary cause. However, this is an option for only selected patients who are clearly informed about the possible risks and benefits of the procedure. PMID- 28892213 TI - Evaluation of longitudinal and radial left ventricular functions on 2-D and 3-D echocardiography before and after intravenous immunoglobulin in acute Kawasaki disease. AB - BACKGROUND: The relationship between left ventricular (LV) function and longitudinal or radial contraction has not yet been elucidated in acute Kawasaki disease (KD), especially before and after treatment with intravenous immunoglobulin (IVIG). METHODS: We studied 28 KD patients without coronary aneurysms (average age, 3.2 years). The LV end-diastolic volume (LVEDV), end systolic volume (LVESV), stroke volume (LVSV), and ejection fraction (LVEF) were assessed on 3-D echocardiography before IVIG, after IVIG, and in the convalescent phase. LV fractional shortening (LVFS) and the mitral annular plane systolic excursion (MAPSE) z-score were measured as surrogates for radial and longitudinal LV wall motions, respectively. Serum brain natriuretic peptide (BNP) was also assessed as a heart failure indicator in acute KD patients. RESULTS: In all KD patients, LVEDV decreased in the acute phase with preservation of LVESV. Both LVSV and MAPSE z-score were lowest before IVIG and increased after IVIG. MAPSE z score was highly correlated with LVEF before and after IVIG treatment. Although there was a good correlation between logBNP and LVEF before IVIG, it was lost after IVIG. CONCLUSIONS: LVEDV decreased longitudinally during the acute phase of KD with preservation of LVESV, reducing both LVSV and LVEF. Serum BNP is a useful marker for evaluating LV function only prior to IVIG treatment. PMID- 28892214 TI - Parental decisions following prenatal diagnosis of sex chromosome aneuploidy in Hong Kong. AB - AIM: According to the published work, pregnancy termination rates due to prenatal diagnosis of fetal sex chromosome aneuploidies (SCA) vary widely. Some potentially modifiable and non-modifiable factors have been reported to be associated with parental decision. This study aimed to evaluate the rate of pregnancy termination for fetal SCA and the factors influencing parents' decisions in Hong Kong. METHODS: This was a 21-year retrospective cohort study of parents' decisions following prenatal diagnosis of SCA. Univariate and multivariate analyses for the association between demographic factors, prenatal factors, or counseling provided and decision-making were conducted. RESULTS: The study included 399 pregnancies with prenatal diagnosis of SCA and the overall termination rate was 55.6% (91.7%, 48.0%, 23.4%, 4.8%, and 22.7% for 45,X, 47,XXY, 47,XXX, 47,XYY, and mosaicism, respectively). Pregnancies with ultrasound abnormalities were associated with higher termination rates than pregnancies with normal ultrasound findings (91.3% vs 28.3%, P < 0.0001). From multivariate regression analysis on 226 pregnancies with normal ultrasound examination, a higher likelihood to terminate was found in pregnancies affected by 45,X and 47,XXY (adjusted odds ratio, 4.72, P < 0.0001). Increased maternal age and history of infertility were associated with lower likelihood to terminate (adjusted odds ratio, 0.9, P = 0.012; and 5.12, P = 0.038, respectively). The pregnancy termination rate declined over time. CONCLUSION: A significant correlation was found between the termination of SCA-affected pregnancy and the presence of fetal sonographic abnormalities, type of SCA, maternal age, and presence of infertility. PMID- 28892215 TI - Living with life-prolonging chemotherapy-control and meaning-making in the tension between life and death. AB - Chemotherapy, radiotherapy, hormone therapy and immune therapy have made many cancers chronic, potential curable diseases rather than inevitably fatal, but the treatments are often both mentally and physically stressful even if the side effects varies. The right use of palliative chemotherapy is a complex issue and there are many aspects to take into consideration. The aim of the study was to gain insight into the illness narratives of cancer patients, from the day they suspected that something was wrong up to the present day where they are living with incurable cancer, undergoing life-prolonging chemotherapy. Thirteen narrators were included. They were all cancer patients on chemotherapy with the intention of prolonging life (informed by their oncologist) in an outpatient's clinic in Norway. Narrative analyse of their illness stories was applied. The main findings showed that the narrators considered their lives worth living in spite of the treatment. They seemed to take control and build a new life on "what was left after the storm," and described how they found meaning living in the tension between life and death. PMID- 28892216 TI - Delayed and localized pemphigus vulgaris after breast cancer radiotherapy. AB - Breast cancer treatment involving ionizing radiation causes characteristic radiation dermatitis in the majority of patients. The DNA damaging effects of radiation can rarely predispose to primary inflammatory dermatoses, such as pemphigus vulgaris. In such cases, the disease presents with all the hallmarks of the primary dermatosis, but the eruption is limited to the field of irradiation and is often amenable to treatment. In contrast, occurrence of generalized pemphigus vulgaris in this setting may mean cancer recurrence. The mechanism by which radiotherapy induces localized disease remains unknown, but there is likely a loss of self-tolerance which maybe coupled to antigen exposure. PMID- 28892217 TI - Squamous cell carcinoma antigen as a novel candidate marker for amniotic fluid embolism. AB - AIM: We aimed to evaluate the clinical usefulness of serum squamous cell carcinoma (SCC) antigen for the diagnosis of amniotic fluid embolism (AFE). METHODS: Sera and information of 20 patients with AFE (autopsy-proven AFE, four cases; clinical AFE, 16 cases) were obtained from the Japan Amniotic Fluid Embolism Registration Center at Hamamatsu University School of Medicine. As controls, we included 74 gestational-age-matched healthy women who gave birth to healthy newborns during the period from December 2012 to January 2014. Receiver operator curves (ROC) were used to evaluate the diagnostic performance of SCC levels for prediction of AFE. RESULTS: Serum SCC antigen levels in women with autopsy-proven AFE (112.0 +/- 169.4 ng/mL, P = 0.001) and clinical AFE (9.5 +/- 10.3 ng/mL, P = 0.004) were significantly higher than those in healthy controls with normal delivery (4.4 +/- 2.2 ng/mL). On ROC analysis, the optimal cut-off value for SCC antigen levels was 7.15 ng/mL, for which the sensitivity and specificity for AFE prediction was 60.0% and 89.2%, respectively (area under the ROC, 0.785; 95% confidence interval, 0.663-0.908; P < 0.001). CONCLUSION: Serum SCC antigen may be a promising predictor of the entry of amniotic fluid into the maternal circulation, potentially serving as a candidate marker for noninvasive diagnosis of AFE. PMID- 28892218 TI - Quality of erections by age group in men with erectile dysfunction. AB - AIMS: The aim of this study was to assess erection quality with sildenafil vs placebo and adverse events (AEs) according to age (<=45, 46-55 and >=56 years) in 997 men with erectile dysfunction (ED) using pooled data from four randomized, double-blind, placebo-controlled, flexible-dose trials. METHODS: The trials included 6- to 10-week treatment periods. The starting sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with subsequent adjustment to 100 or 25 mg based on efficacy and safety. Exclusion criteria included blood pressure <90/50 or >170/110 mmHg, taking nitrate therapy or nitric oxide donors, severe cardiac failure/unstable angina or recent stroke or myocardial infarction. Changes from baseline in Quality of Erection Questionnaire (QEQ), International Index of Erectile Function (IIEF) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores were analysed. RESULTS: Improvements in QEQ scores with sildenafil vs placebo were significant (P<.0001) for the overall sample (33.7 sildenafil; 8.1 placebo) and each age group (<=45 years: 38.5 sildenafil, 13.9 placebo; 46-55 years: 34.9 sildenafil, 5.8 placebo; >=56 years: 26.9 sildenafil, 4.9 placebo). IIEF Erectile Function domain (P<.0001), question 3 (achieving erection; P<.003), and question 4 (maintaining erection; P<.001) scores also improved significantly for the overall sample and each age group. Treatment satisfaction was significantly greater (P<.0001) with sildenafil vs placebo for the overall sample and each age group. The most common AEs with sildenafil were headache, flushing and nasal congestion in all age groups. CONCLUSIONS: Sildenafil significantly improved erection quality across all age groups of men with ED. Efficacy improvements with sildenafil were consistent with the QEQ, IIEF, and EDITS. AEs were comparable across age groups. ClinicalTrials.gov ID: NCT00159900, NCT00147628, NCT00301262, NCT00343200. PMID- 28892220 TI - Annual Report of the Committee on Gynecologic Oncology, Japan Society of Obstetrics and Gynecology: Patient Annual Report for 2014 and Treatment Annual Report for 2009. AB - The Japan Society of Obstetrics and Gynecology collects and analyzes annual data on gynecologic cancers from member institutions. We present the Patient Annual Report for 2014 and the Treatment Annual Report for 2009. Data on 7436 patients with cervical cancer, 9673 with endometrial cancer, 5924 with ovarian cancer, and 1909 with ovarian borderline tumor for whom treatment was initiated in 2014 were summarized in the Patient Annual Report. Stage I accounted for 55.6%, stage II for 22.9%, stage III for 10.2%, and stage IV for 11.2% of all patients with cervical cancer. Stage I accounted for 72.3%, stage II for 6.0%, stage III for 14.1%, and stage IV for 7.7% of all patients with endometrial cancer. Stage I accounted for 43.3%, stage II for 9.1%, stage III for 27.6%, and stage IV for 7.2% of all patients with ovarian cancer. Data on the prognosis of 4126 patients with cervical cancer, 4613 with endometrial cancer, and 3205 with ovarian cancer for whom treatment was initiated in 2009 were analyzed in the Treatment Annual Report. Survival was analyzed by using the Kaplan-Meier method, the log-rank test and the Wilcoxon test. The 5-year overall survival rates for patients with cervical cancer were 92.4% for stage I, 76.7% for stage II, 54.3% for stage III, and 25.2% for stage IV. The equivalent rates for patients with endometrial cancer were 94.6%, 89.4%, 78.3%, and 25.0%, respectively; and those for patients with ovarian cancer (surface epithelial-stromal tumors) were 90.5%, 78.8%, 46.0%, and 25.1%, respectively. PMID- 28892219 TI - Offering non-invasive prenatal testing as part of routine clinical service. Can high levels of informed choice be maintained? AB - OBJECTIVES: To assess rates of informed choice among women offered non-invasive prenatal testing (NIPT) for aneuploidy as part of routine clinical care. METHODS: A cross-sectional survey was conducted across 6 antenatal clinics in England. Women with a high risk (>=1/150) Down syndrome screening result were offered NIPT, invasive testing, or no further testing. Pretest counselling was delivered as part of routine care by the local maternity team. Women were given a questionnaire containing a measure of informed choice immediately after pretest counselling. RESULTS: In total, 220 of 247 women completed the questionnaire. Seventy-six percent were judged to have made an informed choice, a significant decline from our previous study (89.0% vs 75.6%; chi2 (2) = 20.2, P < .001). Of those making an uninformed choice, 46% had insufficient knowledge, 19% had not deliberated, and 13% had made a value-inconsistent decision. Multivariate analysis showed women who were highly educated (OR, 4.33; 95% CI, 1.08-17.36) or had had screening in a previous pregnancy (OR, 0.24; 95% CI, 0.90-0.65) were significantly more likely to make an informed choice. CONCLUSIONS: The findings highlight the challenges of ensuring informed choice in routine prenatal care where NIPT is not discussed at multiple points, less time is available for counselling, and written consent is not required. PMID- 28892221 TI - A novel leadless, miniature implantable Tibial Nerve Neuromodulation System for the management of overactive bladder complaints. AB - BACKGROUND: Overactive bladder is a chronic condition affecting lower urinary tract function that has a significant negative impact on QoL. OBJECTIVE: Evaluation of the BlueWind implantable tibial nerve system performance and safety in refractory OAB. DESIGN, SETTING, AND PARTICIPANTS INTERVENTION: A 6-month multi-center prospective intervention study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Objective assessment was done by voiding diary parameters including voids/day, volume voided/day, urgency assessment, leaking episodes/day, pads used/day, leak severity, and clinical success defined as a >=50% reduction in the number of leaks/day or number of voids/day or number of episodes with degree of urgency >2 or a return to <8 voids/day on a 3 Day diary. Subjective assessment was based on OAB-q including HRQL and symptom severity score. Safety was evaluated by adverse event (AE) analysis. RESULTS AND LIMITATIONS: Thirty-four of the 36 implanted subjects completed the study. One subject withdrew voluntarily and one developed inflammation necessitating removal of the system. In the remaining subjects, 71% experienced clinical success at 6 months. Leaks/day, leak severity, and pad changes/day decreased significantly over time with 27.6% of urge incontinence subjects that became "dry." Voids/day, degree of urgency, volume/void, pads changed improved significantly. All quality of life aspects (concern, coping, sleep, and social) improved as well as symptom severity scores measured by the OAB-q. Adverse events included: implant site pain (13.9%), suspected infection (22.2%), and procedural wound complications (8.3%). CONCLUSIONS: The BlueWind implantable tibial nerve stimulator is a safe, minimally invasive system that affords OAB patients significant improvements. PATIENT SUMMARY: The performance and safety of the BlueWind RENOVATM implantable tibial nerve neuromodulator for OAB was tested. Our preliminary results demonstrate that the system has a low risk safety profile and may be considered an effective treatment option for OAB management. PMID- 28892222 TI - Oral challenge without skin tests in children with non-severe beta-lactam hypersensitivity: Time to change the paradigm? AB - Suspected allergy to penicillins and cephalosporins is very common in childhood. After a proper evaluation, allergy will be confirmed only in a small portion of them. Intradermal tests are usually part of the allergy workup, but they are painful for children and time-consuming, and their role has been debated. A systematic review found only two studies reporting a positive predictive value of skin tests in children of 36% and 33%, respectively, leading to a high rate of inaccurate diagnosis. Moreover, considering that skin tests are negative in more than 90%-95% of cases, an oral provocation test (OPT) is finally needed to confirm tolerance in most of these children. Positive OPT are rare, and even where children demonstrate reproducible signs on challenge, they rarely constitute immediate or serious symptoms. Therefore, OPT to the index antibiotic without skin tests are increasingly being considered an accepted procedure for children with a suspected mild non-immediate reaction related to a beta-lactam antibiotic. Furthermore, a recent research has taken the same approach including children with suspected mild immediate reactions, with similar safety and positive results. In light of recent evidence highlighted, it is now the time for large and multicentric studies to confirm that OPT with the index antibiotic, without skin tests, are safe and convenient for children with a history of a mild reaction with a beta-lactam antibiotic before it can be recommended in pediatric allergy guidelines. PMID- 28892223 TI - Dehydroepiandrosterone as a potential agent to slow down ovarian aging. AB - AIM: Ovarian aging, which leads to diminished ovarian reserve and decreased oocyte quality, is highly associated with poor reproductive outcomes. It has been suggested that dehydroepiandrosterone (DHEA) might be able to temporarily slow down the aging process. This study attempted to investigate the clinical benefits of DHEA in older patients and the anti-senescence effect of DHEA on cumulus cells (CC) and human ovarian granulosa cells (HO23 cell line). METHODS: This prospective study enrolled 88 patients who underwent in vitro fertilization (IVF), including 30 younger patients (aged <= 37 years) and 58 older patients (aged > 37 years). Older patients were assigned to receive DHEA treatment or not prior to the IVF cycle. CC were obtained from all patients after oocyte retrieval and the HO23 granulosa cell line was used for in vitro studies. Senescence associated beta-galactosidase (SA-beta-gal) was used as a biomarker of senescence. RESULTS: In older patients, following DHEA supplementation, a greater number of transferred embryos and a higher fertilization rate were observed compared with those in patients without DHEA supplementation. However, the clinical pregnancy rate was not significantly increased following DHEA supplementation. Additionally, treatment with DHEA resulted in significantly reduced SA-beta-gal staining in both CC and HO23 cells. CONCLUSION: DHEA supplementation ameliorated IVF outcomes but without a consequence on pregnancy rate in older patients and decreased SA-beta-gal activity in CC and HO23 cells, suggesting that DHEA might be used as a possible intervention to slow down ovarian aging. PMID- 28892224 TI - A case of metastatic lobular carcinoma with overexpression of Trop-2: Implications for the consideration of novel therapeutics. PMID- 28892225 TI - Expectant management of pregnancies complicated by fetal growth restriction without any evidence of placental dysfunction at term: Comparison with routine labor induction. AB - AIM: To assess the feasibility and practicality of expectant management for pregnancies with fetal growth restriction (FGR) at term without evidence of placental dysfunction. METHODS: We reviewed the records of pregnancies with an estimated fetal weight <= 1.5 SD below the mean at 37 weeks of gestation. We excluded elective cesarean deliveries and pregnancies that, at 37 weeks, were complicated by oligohydramnios, decreased fetal cerebroplacental ratio, or pregnancy-related hypertensive disorders. Prior to May 2013, we performed routine labor induction for FGR at term; after that time, we used routine expectant management. The rate of delivery by cesarean or instrumental assist and the rate of neonatal morbidity were compared between the groups. RESULTS: The gestational age at delivery and the neonatal birthweight were higher in the expectant management policy group (39+4 vs 38+1 weeks; 2405 vs 2205 g). The cesarean rate (7/77 vs 7/73) and the instrumental delivery rate (5/77 vs 6/73) did not differ. Neonatal hypoglycemia and hyperbilirubinemia were significantly less frequent (10/77 vs 21/73; 7/77 vs 20/73) in the expectant management policy group. Seven patients in the expectant management policy group underwent emergency cesarean delivery; five of these (71%) had required labor induction because of progression to oligohydramnios. CONCLUSIONS: Expectant management policy for FGR at term can reduce neonatal morbidity without increasing maternal risk or the cesarean rate. Caution should be used, however, during labor if oligohydramnios develops during expectant management. PMID- 28892226 TI - Letter to 'Silent uterine rupture occluded by intestinal adhesions following laparoscopic myomectomy: A case report': Do some remain permanently silent? PMID- 28892227 TI - Dynamic changes of QTc interval and prognostic significance in takotsubo (stress) cardiomyopathy. AB - BACKGROUND: Prolonged QT corrected (QTc) intervals are associated with adverse cardiovascular outcomes both in healthy and high-risk populations. Our objective was to evaluate the QTc intervals during a takotsubo cardiomyopathy (TTC) episodes and their potential prognostic role. HYPOTHESIS: Dynamic changes of QTc interval during hospitalization for TTC could be associated with outcome at follow-up. METHODS: Fifty-two consecutive patients hospitalized for TTC were enrolled. Twelve-lead electrocardiogram (ECG) was performed within 3 h after admission and repeated after 3, 5, and 7 days. Patients were classified in 2 groups: group 1 presented the maximal QTc interval length at admission and group 2 developed maximal QTc interval length after admission. RESULTS: Mean admission QTc interval was 493 +/- 71 ms and mean QTc peak interval was 550 +/- 76 ms (P < 0.001). Seventeen (33%) patients were included in group 1 and 35 (67%) patients in group 2. There were no differences for cardiovascular risk factors and in terms of ECG findings such as ST elevation, ST depression, and inverted T waves. Rates of adverse events during hospitalization among patients of group 1 and 2 were different although not significantly (20% vs 6%, P = 0.22). After 647 days follow-up, patients of group 1 presented higher risk of cardiovascular rehospitalization (31% vs 6%, P = 0.013; log-rank, P < 0.01). At multivariate analysis, including age and gender, a prolonged QTc interval at admission was significantly associated with higher risk of rehospitalization at follow-up (hazard ratio: 1.07 every 10 ms, 95% confidence interval: 1.003-1.14, P = 0.04). CONCLUSIONS: Prolonged QTc intervals at admission during a TTC episode could be associated with a higher risk of cardiovascular rehospitalization at follow-up. Dynamic increase of QTc intervals after admission are characterized by a trend toward a better prognosis. PMID- 28892228 TI - Immediate nipple reconstruction in combination with implant reconstruction using dermal sling. AB - The inferior de-epithelialized dermal flap with implant is increasingly used for immediate breast reconstruction. We have adapted the technique to provide concurrent immediate nipple reconstruction by recruiting the triangle of skin above the excised nipple as a modified C-V flap. The safety and efficacy of this technique has been assessed in 15 patients, of which eight were bilateral and seven were unilateral cases. We suggest that this is a safe, reliable, and original technique for immediate nipple reconstruction in patients undergoing immediate breast reconstruction with an inferior dermal sling and implant. PMID- 28892229 TI - Black Phosphorus Quantum Dots Used for Boosting Light Harvesting in Organic Photovoltaics. AB - Although organic photovoltaic devices (OPVs) have been investigated for more than two decades, the power conversion efficiencies of OPVs are much lower than those of inorganic or perovskite solar cells. One effective approach to improve the efficiency of OPVs is to introduce additives to enhance light harvesting as well as charge transportation in the devices. Here, black phosphorus quantum dots (BPQDs) are introduced in OPVs as an additive. By adding 0.055 wt % BPQDs relative to the polymer donors in the OPVs, the device efficiencies can be dramatically improved for more than 10 %. The weight percentage is much lower than that of any other additive used in OPVs before, which is mainly due to the two-dimentional structure as well as the strong broadband light absorption and scattering of the BPQDs. This work paves a way for using two-dimentional quantum dots in OPVs as a cost-effective approach to enhance device efficiencies. PMID- 28892230 TI - Effector-Triggered Self-Replication in Coupled Subsystems. AB - In living systems processes like genome duplication and cell division are carefully synchronized through subsystem coupling. If we are to create life de novo, similar control over essential processes such as self-replication need to be developed. Here we report that coupling two dynamic combinatorial subsystems, featuring two separate building blocks, enables effector-mediated control over self-replication. The subsystem based on the first building block shows only self replication, whereas that based on the second one is solely responsive toward a specific external effector molecule. Mixing the subsystems arrests replication until the effector molecule is added, resulting in the formation of a host effector complex and the liberation of the building block that subsequently engages in self-replication. The onset, rate and extent of self-replication is controlled by the amount of effector present. PMID- 28892232 TI - Visualization of Stereoselective Supramolecular Polymers by Chirality-Controlled Energy Transfer. AB - Chirality-driven self-sorting is envisaged to efficiently control functional properties in supramolecular materials. However, the challenge arises because of a lack of analytical methods to directly monitor the enantioselectivity of the resulting supramolecular assemblies. Presented herein are two fluorescent core substituted naphthalene-diimide-based donor and acceptor molecules with minimal structural mismatch and they comprise strong self-recognizing chiral motifs to determine the self-sorting process. As a consequence, stereoselective supramolecular polymerization with an unprecedented chirality control over energy transfer has been achieved. This chirality-controlled energy transfer has been further exploited as an efficient probe to visualize microscopically the chirality driven self-sorting. PMID- 28892231 TI - Genome-wide analysis of bacterial determinants of plant growth promotion and induced systemic resistance by Pseudomonas fluorescens. AB - Pseudomonas fluorescens strain SS101 (Pf.SS101) promotes growth of Arabidopsis thaliana, enhances greening and lateral root formation, and induces systemic resistance (ISR) against the bacterial pathogen Pseudomonas syringae pv. tomato (Pst). Here, targeted and untargeted approaches were adopted to identify bacterial determinants and underlying mechanisms involved in plant growth promotion and ISR by Pf.SS101. Based on targeted analyses, no evidence was found for volatiles, lipopeptides and siderophores in plant growth promotion by Pf.SS101. Untargeted, genome-wide analyses of 7488 random transposon mutants of Pf.SS101 led to the identification of 21 mutants defective in both plant growth promotion and ISR. Many of these mutants, however, were auxotrophic and impaired in root colonization. Genetic analysis of three mutants followed by site-directed mutagenesis, genetic complementation and plant bioassays revealed the involvement of the phosphogluconate dehydratase gene edd, the response regulator gene colR and the adenylsulfate reductase gene cysH in both plant growth promotion and ISR. Subsequent comparative plant transcriptomics analyses strongly suggest that modulation of sulfur assimilation, auxin biosynthesis and transport, steroid biosynthesis and carbohydrate metabolism in Arabidopsis are key mechanisms linked to growth promotion and ISR by Pf.SS101. PMID- 28892233 TI - Hyaluronic acid microneedle patch for the improvement of crow's feet wrinkles. AB - Hyaluronic acid (HA) has an immediate volumizing effect, due to its strong water binding potential, and stimulates fibroblasts, causing collagen synthesis, with short- and long-term effects on wrinkle improvement. We investigated the efficacy and safety of HA microneedle patches for crow's feet wrinkles. Using a randomized spilt-face design, we compared microneedle patches with a topical application containing the same active ingredients. We enrolled 34 Korean female subjects with mild to moderate crow's feet wrinkles. The wrinkle on each side of the subject's face was randomly assigned to a HA microneedle patch or HA essence application twice a week for 8 weeks. Efficacy was evaluated at weeks 2, 4, and 8. Skin wrinkles were measured as average roughness using replica and PRIMOS. Skin elasticity was assessed using a cutometer. Two independent blinded dermatologists evaluated the changes after treatment using the global visual wrinkle assessment score. Subjects assessed wrinkles using the subject global assessment score. Skin wrinkles were significantly reduced and skin elasticity significantly increased in both groups, although improvement was greater in the patch group at week 8 after treatment. In the primary and cumulative skin irritation tests, the HA microneedle patch did not induce any skin irritation. The HA microneedle patch is more effective than the HA essence for wrinkle improvement and is a safe and convenient without skin irritation. PMID- 28892234 TI - Reactivity of a Dihydrodiborene with CO: Coordination, Insertion, Cleavage, and Spontaneous Formation of a Cyclic Alkyne. AB - Under a CO atmosphere, the dihydrodiborene [(cAAC)HB=BH(cAAC)] underwent coordination of CO concomitant with reversible hydrogen migration from boron to the carbene carbon atom, as well as reversible CO insertion into the B=B bond. Heating the CO adduct resulted in two unusual cAAC ring-expansion products, one presenting a B=C bond to a six-membered 1,2-azaborinane-3-ylidene, the other an unprecedented nine-membered cyclic alkyne resulting from reductive cleavage of CO and spontaneous formation of a C=C bond. PMID- 28892235 TI - Beclabuvir in combination with asunaprevir and daclatasvir for hepatitis C virus genotype 1 infection: A systematic review and meta-analysis. AB - Daclatasvir, asunaprevir (ASV), and beclabuvir (BCV) are direct-acting antivirals (DAAs) for patients with hepatitis C virus genotype 1 infection. This systematic review and meta-analysis investigating the efficacy and safety of this three-drug combination in HCV genotype 1 infection. Eleven electronic search engines were searched for relevant publications. Studies were screened for eligibility and data was extracted. The outcomes were pooled as event rate and risk ratio (RR). The protocol was registered in PROSPERO (CRD42017054391). Among the included six studies, five studies were included for the meta-analysis (n = 1261). The three drug combination showed a high response rate in naive patients with sustained virologic response at week-12 posttreatment (SVR12 ) rate = 95.7% (95%CI [93.8 97.1]) and no difference detected by adding ribavirin (RBV) (the pooled RR = 0.98, 95%CI [0.90-1.08], P = 0.70) or comparing with interferon-experienced patients (RR = 1.02, 95%CI [0.98-1.07], P = 0.31) regardless the genotype 1 subtypes or IL28B genotype. Treatment failure was minimal and showed no difference regarding the previous comparisons. Increasing the dose or the duration did not show a significant increase in the efficacy. In conclusion, this analysis showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, ASV, and BCV irrespective of RBV use, prior interferon-based therapy, or restriction on non-cirrhotic patients, IL28B genotype, or baseline resistance-associated variants. PMID- 28892236 TI - Visualization instructions enhance preschoolers' spatial problem-solving. AB - This study explores whether verbal instructions to visualize an event can improve children's ability to make predictions about a difficult spatial problem. Three year-olds (N = 48) were introduced to two intertwined tubes, and prior to predicting how a ball would travel through a given tube, one group of children was told to imagine the ball rolling down the tube, one group was told an explicit rule about where the ball would land, and a third group was given no instructions. Children were prevented from interacting with the apparatus to investigate the effect of the different verbal instructions alone on their problem-solving. Children in the imagine condition made more correct predictions than both children who received no instructions and those who were told an explicit rule (but were not told to visualize). These results suggest that verbal instructions to imagine an event are enough to help children solve difficult spatial problems, likely by visualizing the outcome prior to making a prediction. Statement of Contribution What is already known on this subject? Preschoolers exhibit a gravity bias when predicting how objects will travel through several intertwined tubes (Hood, 1995, Cogn. Dev., 10, 577). Preschoolers can overcome this gravity bias when they are first told to look at (Bascandziev & Harris, , Cogn. Dev., 25, 233) or visualize (Joh et al., 2011, Child Dev., 82, 744) the tubes. This work emphasized the role of visualization in improving children's ability to solve this difficult spatial problem. What does this study add? Previous work typically allowed children to interact directly with the apparatus during familiarization or while making predictions. Previous work did not consider whether a synergy between physical interaction and visualization instructions improved predictions. The current study shows that visualization instructions alone can improve children's ability to overcome the gravity bias. PMID- 28892237 TI - Partners of nulliparous women with severe fear of childbirth: A longitudinal study of psychological well-being. AB - BACKGROUND: Little is known about the psychological status of partners of women with severe fear of childbirth (FOC). In this longitudinal study from Helsinki University Central Hospital, we investigated FOC, depression, and posttraumatic stress in the partners of women with severe FOC, and possible effects of group psychoeducation and mode of birth. METHODS: During pregnancy, 250 partners of nulliparous women with severe FOC participated, 93 in the intervention group and 157 in the control group. At 3 months postpartum, 52 partners in the intervention group and 93 in the control group participated. Both the partners and the childbearing women filled in the Wijma Delivery Expectancy/Experience Questionnaire and the Edinburgh Postnatal Depression Scale mid-pregnancy as well as 3 months postpartum, when they also filled in the Traumatic Event Scale. RESULTS: Partners of women with severe FOC reported less antenatal and postnatal FOC and fewer depressive symptoms than the childbearing women. No partner reached the threshold of severe FOC. No partner reported a possible posttraumatic stress disorder. Group psychoeducation with relaxation was not associated with better or worse psychological well-being of the partners. An emergency cesarean delivery was associated with a more fearful delivery experience in the partners. CONCLUSION: Partners of nulliparous women with severe FOC neither seem to suffer from severe FOC nor reported posttraumatic stress symptoms after childbirth. They reported better psychological well-being than the mothers both during pregnancy and after delivery. An unexpected cesarean may be a negative experience even for partners of childbearing women. PMID- 28892238 TI - Low-Temperature Reductive Aminolysis of Carbohydrates to Diamines and Aminoalcohols by Heterogeneous Catalysis. AB - Short amines, such as ethanolamines and ethylenediamines, are important compounds in today's bulk and fine chemicals industry. Unfortunately, current industrial manufacture of these chemicals relies on fossil resources and requires rigorous safety measures when handling explosive or toxic intermediates. Inspired by the elegant working mechanism of aldolase enzymes, a novel heterogeneously catalyzed process-reductive aminolysis-was developed for the efficient production of short amines from carbohydrates at low temperature. High-value bio-based amines containing a bio-derived C2 carbon backbone were synthesized in one step with yields up to 87 C%, in the absence of a solvent and at a temperature below 405 K. A wide variety of available primary and secondary alkyl- and alkanolamines can be reacted with the carbohydrate to form the corresponding C2-diamine. The presented reductive aminolysis is therefore a promising strategy for sustainable synthesis of short, acyclic, bio-based amines. PMID- 28892239 TI - Impact of physical activity on obesity and lipid profile of adults with intellectual disability. AB - INTRODUCTION: This study assessed overweight, obesity and lipid profiles in adults with intellectual disability and compared these metrics with their physical activity. MATERIALS AND METHOD: Basic somatic parameters, lipid profile and weekly physical activity were examined in 27 adults with moderate intellectual disability. Chi-square independence tests and Pearson's linear correlation coefficients were used. RESULTS: The participants had excess body mass, excess body fat and abdominal obesity. Very high positive correlations were shown between body mass index and both waist circumference and %fat. The lipid profiles were more favourable in the general population. Healthy levels of physical activity were observed in 8% of women and 26% of men. A high negative correlation was found between physical activity and body mass index. CONCLUSION: The study group was characterized by excess body mass and insufficient levels of physical activity. Body mass index and waist circumference are sufficient indicators for identifying obesity in adults with intellectual disability. PMID- 28892240 TI - Phylogenetic evidence for a Miocene origin of Mediterranean lineages: species diversity, reproductive traits and geographical isolation. AB - A review of 27 angiosperm clades (26 genera) of species-rich and species-poor plant groups of the Mediterranean floristic region was performed with phylogenetic and biological trait data. The emergent pattern is that a majority of Mediterranean plant clades split from their sister groups between the Miocene (23-5 Ma) and the Oligocene (34-23 Ma), far earlier than the onset of the Mediterranean climate (ca. 3.2 Ma). In addition, 12 of 14 clades of the species poor group have stem ages inferred for each clade in the Miocene or older, and six of 13 clades within the species-rich group show divergence of each stem clade within the Oligocene and/or Miocene. High levels of species diversity are related to an ancient (Paleocene-Miocene) origin and also to recent origin (Pliocene Pleistocene) followed by active speciation and even explosive radiations: some species and lineages diversified over a short period (Aquilegia, Cistus, Dianthus, Linaria sect. Supinae, Reseda). In the species-rich group, key reproductive characters were found to be significantly more important for species recognition than key vegetative characters in eight clades, but no difference was found in four clades, and vegetative characters were predominant in one clade (Saxifraga). Geographical differentiation is proposed as predominant over divergence driven by pollination ecology. We hypothesise an evolutionary process in which lineages adapted to pre-Mediterranean (pre-Pliocene) conditions in relatively small, xeric areas became strongly competitive and expanded as the Mediterranean climate became dominant (Pliocene-Quaternary) across the Mediterranean Basin. PMID- 28892241 TI - Seasonal variations in the profile of main phospholipids in Mytilus galloprovincialis mussels: A study by hydrophilic interaction liquid chromatography-electrospray ionization Fourier transform mass spectrometry. AB - A systematic characterization of phosphatidylcholines and phosphatidylethanolamines in mussels of sp Mytilus galloprovincialis was performed by high-efficiency hydrophilic interaction liquid chromatography combined with electrospray ionization and Fourier transform mass spectrometry (FTMS), based on a quadrupole-Orbitrap hybrid spectrometer. The FTMS/MS experiments under high collisional energy dissociation conditions, complemented by low-energy collisionally induced dissociation MSn (n = 2,3) experiments, performed in a linear ion trap mass spectrometer, were exploited for structural elucidation purposes. The described approach led to an unprecedented characterization of the mussel phospholipidome, with 185 phosphatidylcholines and 131 phosphatidylethanolamines species recognized, distributed among diacylic, plasmanylic, and plasmenylic forms. This was the starting point for the evaluation of the effects of season (in particular, of sea temperature) on the profile of those phospholipids. To this aim, a set of mussel samples retrieved from commercial sources in different periods of the year was considered. Principal component analysis revealed a clear separation between samples collected in periods characterized by cold, intermediate, or warm sea temperatures, respectively. In particular, an enrichment in phospholipids containing unsaturated side chains was observed in mussels collected from cold seawaters (winter-early spring), thus confirming the general model previously elaborated to explain the adaptation of marine invertebrates, including some bivalve molluscs, to low temperatures. On the other hand, relevant levels of plasma(e)nylic and acylic phospholipids bearing either saturated or non-methylene interrupted side chains were found in mussels collected in warm seawaters (typical of summer and early autumn, at Italian latitudes). This finding opened interesting perspectives towards the development of strategies able to prevent global warming-related mussel losses in aquacultural plants. PMID- 28892242 TI - Opposing Phase-Segregation and Hydrogen-Bonding Forces in Supramolecular Polymers. AB - Phase segregation between different macromolecules and specific weak interactions are the basis of molecular organization in many biological systems, which are held together by attractive hydrogen bonds (H-bonds) and dissociated by phase segregation. We report significant changes in the association behavior of covalent H-bonds by the phase of attached polymer chains. Depending on the aggregation state, we observed either intact H-bonds despite segregation of the phases, or macrophase separation with a larger amount of H-bonding dissociation. PMID- 28892243 TI - Direct Observation of Hemithioindigo-Motor Unidirectionality. AB - Hemithioindigo molecular motors undergo very fast unidirectional rotation upon irradiation with visible light, which has prevented a complete analysis of their working mechanism. In this work, we have considerably slowed down their motion by using a new synthesis for sterically hindered motor derivatives. This method allowed the first observation of all four intermediate states populated during rotation. The exact order in which each isomeric state is formed under irradiation conditions was elucidated using low temperature 1 H NMR spectroscopy in conjunction with other analytical methods. At the same time, complete unidirectionality could also be directly shown. Access to slowly rotating hemithioindigo motors opens up a plethora of new applications for visible-light induced unidirectional motions, especially in areas such as catalysis, smart materials, and supramolecular chemistry. PMID- 28892244 TI - Gold(III) Alkyne Complexes: Bonding and Reaction Pathways. AB - The synthesis and characterization of hitherto hypothetical AuIII pi-alkyne complexes is reported. Bonding and stability depend strongly on the trans effect and steric factors. Bonding characteristics shed light on the reasons for the very different stabilities between the classical alkyne complexes of PtII and their drastically more reactive AuIII congeners. Lack of back-bonding facilitates alkyne slippage, which is energetically less costly for gold than for platinum and explains the propensity of gold to facilitate C-C bond formation. Cycloaddition followed by aryl migration and reductive deprotonation is presented as a new reaction sequence in gold chemistry. PMID- 28892245 TI - Size-resolved particle measurements of polybrominated diphenyl ethers indoors: Implications for sources and human exposure. AB - Polybrominated diphenyl ethers (PBDEs) are flame retardant polymer additives that are widely detected in outdoor and indoor environments. Release of PBDEs from consumer products leads to high concentrations indoors, but mechanisms of release are poorly understood. Although ingestion of dust is a well-studied indoor PBDE exposure route, the importance of inhalation exposure is uncertain. To address these unknowns, dust was collected from household vacuum cleaners, and suspended particulate matter was collected from the same homes in St. John's, Newfoundland, Canada, using a cascade impactor. Size-fractionated particulate matter samples (0.01-18 MUm diameter) were analyzed for PBDEs. The sum of PBDEs in all particulate matter ranged from 8.7 +/- 0.5 to 15.7 +/- 0.5 pg/m3 , with >50% of PBDE mass in respirable particulate matter (<1 MUm). Mass loadings as a function of particle size suggested that both abrasion and off-gassing led to the presence of PBDEs in particulate matter. Variability in the particulate matter mass loadings indicated that emission mechanisms were both product- and location dependent. Congener profiles in colocated vacuum dust and particulate matter samples were different, indicating that vacuum dust cannot accurately predict PBDE congeners in respirable particulate matter. A calculated lower limit inhalation exposure to PBDEs (0.19 ng/d) is lower than exposure via diet or ingestion of dust, although the different biochemical pathways for inhalation compared with ingestion may have different biological effects. The present study highlights the importance of contaminant analysis in size-fractionated particulate matter to assess human exposure via inhalation compared with traditional vacuum dust methods. Environ Toxicol Chem 2018;37:481-490. (c) 2017 SETAC. PMID- 28892246 TI - Novel hyperthermia applicator system allows adaptive treatment planning: Preliminary clinical results in tumour-bearing animals. AB - Hyperthermia (HT) as an adjuvant to radiation therapy (RT) is a multimodality treatment method to enhance therapeutic efficacy in different tumours. High demands are placed on the hardware and treatment planning software to guarantee adequately planned and applied HT treatments. The aim of this prospective study was to determine the effectiveness and safety of the novel HT system in tumour bearing dogs and cats in terms of local response and toxicity as well as to compare planned with actual achieved data during heating. A novel applicator with a flexible number of elements and integrated closed-loop temperature feedback control system, and a tool for patient-specific treatment planning were used in a combined thermoradiotherapy protocol. Good agreement between predictions from planning and clinical outcome was found in 7 of 8 cases. Effective HT treatments were planned and verified with the novel system and provided improved quality of life in all but 1 patient. This individualized treatment planning and controlled heat exposure allows adaptive, flexible and safe HT treatments in palliatively treated animal patients. PMID- 28892247 TI - Short-term results of self-expanding metal stents for acute malignant large bowel obstruction. AB - AIM: Self-expanding metal stents (SEMSs) can be used as a palliative treatment or to initially decompress colon prior to definitive surgery (as a so-called 'bridge to surgery'). The purpose of this study was to investigate the efficacy and safety of SEMS used as palliation and bridge to surgery for malignant large bowel obstruction. METHOD: A multicentre retrospective study was conducted from January 2010 to December 2013 to identify patients undergoing stent placement for acute large bowel obstruction. Patients were included from four Danish colorectal centres. Outcomes identified included clinical success, 30-day mortality, stent related complications and surgery related complications. Furthermore, we analysed for predictive factors for successful stenting. Clinical success was defined as relief of obstructive symptoms, without the need of other additional surgical interventions during the hospital stay. RESULTS: SEMSs were inserted in 239 patients for whom the indication was as a bridge to surgery in 112 patients (47%) and as palliation in 127 (53%) patients. Clinical success was achieved in 90 patients (80.4%) in the bridge to surgery group and in 105 patients (82.8%) in the palliation group. The 30-day mortality rates in the two groups were 5.4% and 11.8% for bridge to surgery and palliation respectively. A total of 17.8% of the patients in the bridge to surgery group had a stent related complication and in the palliation group it was 20.4%. Multivariate analysis demonstrated that clinical failure is a predictive factor of 30-day mortality (OR 11.1, 95% CI: 4.1 30.0). CONCLUSION: The use of a SEMS to relieve a malignant large bowel obstruction is generally an effective and safe method, but complications are seen in about 20% of patients. Further investigations are required to determine the role of SEMSs in the treatment of acute, malignant, large bowel obstruction. PMID- 28892248 TI - Colloidal Supercapattery: Redox Ions in Electrode and Electrolyte. AB - Redox chemistry is the cornerstone of various electrochemical energy conversion and storage systems, associated with ion diffusion process. To actualize both high energy and power density in energy storage devices, both multiple electron transfer reaction and fast ion diffusion occurred in one electrode material are prerequisite. The existence forms of redox ions can lead to different electrochemical thermodynamic and kinetic properties. Here, we introduce novel colloid system, which includes multiple varying ion forms, multi-interaction and abundant redox active sites. Unlike redox cations in solution and crystal materials, colloid system has specific reactivity-structure relationship. In the colloidal ionic electrode, the occurrence of multiple-electron redox reactions and fast ion diffusion leaded to ultrahigh specific capacitance and fast charge rate. The colloidal ionic supercapattery coupled with redox electrolyte provides a new potential technique for the comprehensive use of redox ions including cations and anions in electrode and electrolyte and a guiding design for the development of next-generation high performance energy storage devices. PMID- 28892249 TI - Mandatory reporting by doctors of medically unsafe drivers is unpopular and poorly adhered to: a survey of sleep physicians and electro-physicians. AB - BACKGROUND: Medical fitness to drive is one way governments control the issuing and renewal of driving licences, and some jurisdictions demand mandatory reporting (MR) of unsafe drivers by doctors. AIM: To determine the views, adherence rate and experiences of sleep physicians and electro-physicians with regards to South Australia's (SA) MR law. METHODS: Self-administered surveys were delivered by post and email to all SA Medical Board-registered sleep physicians (n = 49) and electro-physicians (n = 11). Twenty-nine sleep physicians and six electro-physicians returned surveys, giving a 61% response rate. RESULTS: Of the doctors, 8 agreed with MR, 19 thought reporting should be voluntary and 6 that doctors should never report. Four doctors had reported all reportable patients, five had never reported any and the rest inconsistently applied the law. MR affected doctors' relationships with their patients as follows: 28 had experienced abuse by patients, 25 suspected patients of doctor shopping and 33 suspected patients of withholding information for fear of loss of licence. Only eight thought they were the most appropriate person to determine their patient's fitness to drive; 29 had not received any training with regards to making such determinations, yet, of these, 27 desired training. CONCLUSIONS: Widely disliked and causing deterioration of doctor-patient relationships, the MR law is ignored by some and inconsistently applied by most of the doctors surveyed. Further clinician and community education is required regardless of whether the law is abandoned, modified or left unchanged. PMID- 28892250 TI - Case report of apatinib mesylate treatment in rare advanced tracheal adenoid cystic carcinoma. AB - A 57-year-old man was admitted to our department 10 years ago, diagnosed with tracheal adenoid cystic carcinoma. After discontinuing chemotherapy and radiotherapy, the disease recurred in December 2016. Apatinib mesylate (500 mg/day) was administered and computed tomography revealed that his symptoms were significantly relieved. Treatment with apatinib mesylate represents a novel method of treatment for tracheal adenoid cystic carcinoma. PMID- 28892251 TI - Genomes of rumen bacteria encode atypical pathways for fermenting hexoses to short-chain fatty acids. AB - Bacteria have been thought to follow only a few well-recognized biochemical pathways when fermenting glucose or other hexoses. These pathways have been chiseled in the stone of textbooks for decades, with most sources rendering them as they appear in the classic 1986 text by Gottschalk. Still, it is unclear how broadly these pathways apply, given that they were established and delineated biochemically with only a few model organisms. Here, we show that well-recognized pathways often cannot explain fermentation products formed by bacteria. In the most extensive analysis of its kind, we reconstructed pathways for glucose fermentation from genomes of 48 species and subspecies of bacteria from one environment (the rumen). In total, 44% of these bacteria had atypical pathways, including several that are completely unprecedented for bacteria or any organism. In detail, 8% of bacteria had an atypical pathway for acetate formation; 21% of bacteria had an atypical pathway for propionate or succinate formation; 6% of bacteria had an atypical pathway for butyrate formation and 33% of bacteria had an atypical or incomplete Embden-Meyerhof-Parnas pathway. This study shows that reconstruction of metabolic pathways - a common goal of omics studies - could be incorrect if well-recognized pathways are used for reference. Furthermore, it calls for renewed efforts to delineate fermentation pathways biochemically. PMID- 28892252 TI - Clinical decision-making in managing changes in gastrointestinal function following cancer therapies: Is experience enough? AB - In patients with gastrointestinal (GI) disorders, identical symptoms may occur for many different reasons. This prospective study assessed whether experienced clinicians can predict accurately the underlying diagnosis or diagnoses contributing to specific symptoms based on the history and physical examination. Three clinicians assessed 47 patients referred for management of troublesome GI symptoms identified after treatment for cancer. Investigations were requested following our comprehensive, peer-reviewed algorithm. The clinicians then recorded their predictions as to the results of those investigations. After each patient had completed all their investigations, had received optimal management and had been discharged from the clinic, the predicted diagnoses were compared to those made. The clinicians predicted 92 diagnoses (1.9 per patient). After investigation, a total of 168 unique diagnoses were identified (3.5 per patient). Of the 92 predicted diagnoses, 41 (43%) matched the diagnosis. Of the 168 actual diagnoses identified, only 24% matched the prediction. None of the clinicians predicted the correct combination of diagnoses contributing to bowel symptoms. Clinical acumen alone is inadequate at determining cause for symptoms in patients with GI symptoms developing after cancer therapy. PMID- 28892254 TI - Transcriptional regulation of ectoine catabolism in response to multiple metabolic and environmental cues. AB - Ectoine and hydroxyectoine are effective microbial osmostress protectants, but can also serve as versatile nutrients for bacteria. We have studied the genetic regulation of ectoine and hydroxyectoine import and catabolism in the marine Roseobacter species Ruegeria pomeroyi and identified three transcriptional regulators involved in these processes: the GabR/MocR-type repressor EnuR, the feast and famine-type regulator AsnC and the two-component system NtrYX. The corresponding genes are widely associated with ectoine and hydroxyectoine uptake and catabolic gene clusters (enuR, asnC), and with microorganisms predicted to consume ectoines (ntrYX). EnuR contains a covalently bound pyridoxal-5'-phosphate as a co-factor and the chemistry underlying the functioning of MocR/GabR-type regulators typically requires a system-specific low molecular mass effector molecule. Through ligand binding studies with purified EnuR, we identified N (alpha)-L-acetyl-2,4-diaminobutyric acid and L-2,4-diaminobutyric acid as inducers for EnuR that are generated through ectoine catabolism. AsnC/Lrp-type proteins can wrap DNA into nucleosome-like structures, and we found that the asnC gene was essential for use of ectoines as nutrients. Furthermore, we discovered through transposon mutagenesis that the NtrYX two-component system is required for their catabolism. Database searches suggest that our findings have important ramifications for an understanding of the molecular biology of most microbial consumers of ectoines. PMID- 28892256 TI - Possibility of quantitative T2-mapping MRI of cartilage near metal in high tibial osteotomy: A human cadaver study. AB - T2-mapping is a widely used quantitative MRI technique in osteoarthritis research. An important challenge for its application in the context of high tibial osteotomy (HTO) is the presence of metallic fixation devices. In this study, we evaluated the possibility of performing T2-mapping after a HTO, by assessing the extent of magnetic susceptibility artifacts and the influence on T2 relaxation times caused by two commonly used fixation devices. T2-mapping with a 3D fast spin-echo sequence at three Tesla was performed on 11 human cadaveric knee joints before and after implantation of a titanium plate and screws (n = 5) or cobalt chrome staples (n = 6). Mean T2 relaxation times were calculated in six cartilage regions, located in the distal and posterior cartilage of femoral condyles and the cartilage of tibial plateaus, both medially and laterally. T2 relaxation times before and after the implantation were compared with paired t tests and Wilcoxon rank tests. Due to the extent of the magnetic susceptibility artifact, it was not possible to segment the knee cartilage and thus calculate T2 relaxation times in the lateral weight-bearing femoral and tibial cartilage regions only in the cobalt chrome group. In all cartilage regions of the titanium implanted knees and those unaffected by artifacts due to cobalt chrome implants, T2 relaxation times did not significantly differ between the two scans. Our results suggest that accurate T2-mapping after a HTO procedure is possible in all areas after implantation of a titanium fixation device and in most areas after implantation of a cobalt chrome fixation device. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1206-1212, 2018. PMID- 28892255 TI - Does cardiovascular risk vary according to the criteria for a diagnosis of polycystic ovary syndrome? AB - AIM: The risk of cardiovascular disease is higher in women with polycystic ovary syndrome (PCOS) compared to healthy individuals. Chronic inflammation, insulin resistance, hyperandrogenemia, hyperlipidemia and increased oxidative stress are known to have a role in the formation of atherosclerosis and cardiovascular disease. The aim of our study was to evaluate if cardiovascular risk varied according to different PCOS criteria, using carotid intima-media thickness (CIMT), which is an important marker of major cardiovascular events in the later stages of life. METHODS: The study group included 52 women aged 18-35 diagnosed with PCOS, and the control group comprised 45 age-matched healthy women. Body mass index, CIMT, fasting serum glucose and insulin levels and hormonal and lipid profiles were compared between the groups. RESULTS: There was no significant difference in CIMT levels between the groups. The CIMT levels in the PCOS group did not differ whether hyperandrogenism, polycystic ovary-like appearance on ultrasound or oligo/anovulation status were present or not. Furthermore, when all cases were divided into subgroups according to BMI values, the CIMT values were similar between the groups. CONCLUSION: Because PCOS and atherosclerosis both have a complex nature, it is likely that the evaluation of CIMT alone may not be sufficient to determine endothelial dysfunction in a reproductive age group. PMID- 28892253 TI - Host-microbe interaction in the gastrointestinal tract. AB - The gastrointestinal tract is a highly complex organ in which multiple dynamic physiological processes are tightly coordinated while interacting with a dense and extremely diverse microbial population. From establishment in early life, through to host-microbe symbiosis in adulthood, the gut microbiota plays a vital role in our development and health. The effect of the microbiota on gut development and physiology is highlighted by anatomical and functional changes in germ-free mice, affecting the gut epithelium, immune system and enteric nervous system. Microbial colonisation promotes competent innate and acquired mucosal immune systems, epithelial renewal, barrier integrity, and mucosal vascularisation and innervation. Interacting or shared signalling pathways across different physiological systems of the gut could explain how all these changes are coordinated during postnatal colonisation, or after the introduction of microbiota into germ-free models. The application of cell-based in-vitro experimental systems and mathematical modelling can shed light on the molecular and signalling pathways which regulate the development and maintenance of homeostasis in the gut and beyond. PMID- 28892257 TI - Candidate gene molecular markers as tools for analyzing genetic susceptibility to morbillivirus infection in stranded Cetaceans. AB - Morbilliviruses, such as Cetacean morbillivirus (CeMV) or Phocine distemper virus (PDV), represent a growing threat for marine mammals on both hemispheres. Because free-ranging animal populations strongly rely on natural resistance mechanisms, innate immunity-related genes and virus cell entry receptor genes may represent key factors involved in susceptibility to CeMV in Cetaceans. Using the next generation sequencing technology, we have sequenced 11 candidate genes in two model species, Stenella coeruleoalba and Phocoena phocoena. Suitable single nucleotide polymorphism markers of potential functional importance, located in genes coding for basigin (BSG, CD147), the signaling lymphocyte activating molecule (SLAMF1), the poliovirus-related receptor-4 (NECTIN4, PVRL4), toll-like receptors 3, 7, 8 (TLR3, TLR7, TLR8), natural resistance-associated macrophage protein (SLC11A1) and natural cytotoxicity triggering receptor 1 (NCR1), were identified in each model species, along with MHC-DQB haplotypes unique for each species. This set of molecular markers represents a potentially useful tool for studying host genetic variation and susceptibility to morbillivirus infection in Cetaceans as well as for studying functionally important genetic diversity of selected Cetacean populations. PMID- 28892258 TI - Sitagliptin and Roux-en-Y gastric bypass modulate insulin secretion via regulation of intra-islet PYY. AB - AIMS: The gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV) has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB. METHODS: Immunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and the effects of sitagliptin on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets. RESULTS: PYY and DPP-IV localized in different cell types in islets while NPYR expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels. CONCLUSION: Local regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery. PMID- 28892259 TI - Cellulose production is coupled to sensing of the pyrimidine biosynthetic pathway via c-di-GMP production by the DgcQ protein of Escherichia coli. AB - Production of cellulose, a stress response-mediated process in enterobacteria, is modulated in Escherichia coli by the activity of the two pyrimidine nucleotide biosynthetic pathways, namely, the de novo biosynthetic pathway and the salvage pathway, which relies on the environmental availability of pyrimidine nitrogenous bases. We had previously reported that prevalence of the salvage over the de novo pathway triggers cellulose production via synthesis of the second messenger c-di GMP by the DgcQ (YedQ) diguanylate cyclase. In this work, we show that DgcQ enzymatic activity is enhanced by UTP, whilst being inhibited by N-carbamoyl aspartate, an intermediate of the de novo pathway. Thus, direct allosteric control by these ligands allows full DgcQ activity exclusively in cells actively synthesizing pyrimidine nucleotides via the salvage pathway. Inhibition of DgcQ activity by N-carbamoyl-aspartate appears to be favoured by protein-protein interaction between DgcQ and PyrB, a subunit of aspartate transcarbamylase, which synthesizes N-carbamoyl-aspartate. Our results suggest that availability of pyrimidine bases might be sensed, somehow paradoxically, as an environmental stress by E. coli. We hypothesize that this link might have evolved since stress events, leading to extensive DNA/RNA degradation or lysis of neighbouring cells, can result in increased pyrimidine concentrations and activation of the salvage pathway. PMID- 28892260 TI - Synthetic Poly(Vinylalcohol)-Based Membranes for Cartilage Surgery and Repair. AB - Cell-based therapies for cartilage repair are continually being developed to treat osteoarthritis. The cells are either introduced directly by intra-articular injection or via a cell-seeded matrix scaffold. Here, poly(vinylalcohol)-based membranes are developed to be used for mesenchymal stem cell implantation in cartilage repair procedures, having controllable physicochemical properties such as porosity, mechanical strength, and permeability, and a unique self-sealing property. The membranes possess a bilayer structure with a less porous layer providing mechanical strength and selective permeability, exhibit an elastic modulus of between 0.3 and 0.9 MPa, and are permeable to molecules <40 kDa, which is in the range of cartilage permeability. Three different peptide ligands with the sequences Ac-GCGYGRGDSPG, Ac-GCG(OPG)4REGOFG(OPG)4, and Ac-GCG(OPG)7, respectively, are conjugated to the membranes and subject to in vitro cell adhesion and differentiation assays. Col I/Col II gene expression ratios indicated that the collagen-mimetic peptide, Ac-GCG(OPG)7, best supported mesenchymal stem cell differentiation into the chondrogenic lineage. Although low retention of the membrane is observed in vivo in a rabbit knee model, results suggest that the membrane was able to facilitate mesenchymal stem cell implantation and differentiation to chondrocytes. These PVA-based membranes provide a feasible, synthetic, off-the-shelf material for the delivery of stem cells, and can be modified for other surgical applications. PMID- 28892261 TI - Fabrication of Trabecular Bone-Templated Tissue-Engineered Constructs by 3D Inkjet Printing. AB - 3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient-specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the <100 micrometer-scale trabecular architecture essential for investigating the cellular response to the morphometric properties of bone. In this study, it is hypothesized that the architecture of trabecular bone regulates osteoblast differentiation and mineralization. To test this hypothesis, human bone-templated 3D constructs are fabricated via a new micro-CT/3D inkjet printing process. It is shown that this process reproducibly fabricates bone-templated constructs that recapitulate the anatomic site-specific morphometric properties of trabecular bone. A significant correlation is observed between the structure model index (a morphometric parameter related to surface curvature) and the degree of mineralization of human mesenchymal stem cells, with more concave surfaces promoting more extensive osteoblast differentiation and mineralization compared to predominately convex surfaces. These findings highlight the significant effects of trabecular architecture on osteoblast function. PMID- 28892262 TI - Glycan Stimulation Enables Purification of Prostate Cancer Circulating Tumor Cells on PEDOT NanoVelcro Chips for RNA Biomarker Detection. AB - A glycan-stimulated and poly(3,4-ethylene-dioxythiophene)s (PEDOT)-based nanomaterial platform is fabricated to purify circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This new platform, phenylboronic acid (PBA)-grafted PEDOT NanoVelcro, combines the 3D PEDOT nanosubstrate, which greatly enhances CTC capturing efficiency, with a poly(EDOT-PBA-co-EDOT-EG3) interfacial layer, which not only provides high specificity for CTC capture upon antibody conjugation but also enables competitive binding of sorbitol to gently release the captured cells. CTCs purified by this PEDOT NanoVelcro chip provide well-preserved RNA transcripts for the analysis of the expression level of several PCa-specific RNA biomarkers, which may provide clinical insights into the disease. PMID- 28892264 TI - Synthetic Nanosheets of Natural van der Waals Heterostructures. AB - Creation of new van der Waals heterostructures by stacking different two dimensional (2D) crystals on top of each other in a chosen sequence is the next challenge after the discovery of graphene, mono/few layer of h-BN, and transition metal dichalcogenides. However, chemical syntheses of van der Waals heterostructures are rarer than the physical preparation techniques. Herein, we demonstrate the kinetic stabilization of 2D ultrathin heterostructure (ca. 1.13 2.35 nm thick) nanosheets of layered intergrowth SnBi2 Te4 , SnBi4 Te7 , and SnBi6 Te10 , which belong to the Snm Bi2n Te3n+m homologous series, by a simple solution based synthesis. Few-layer nanosheets exhibit ultralow lattice thermal conductivity (kappalat ) of 0.3-0.5 W m-1 K-1 and semiconducting electron transport properties with high carrier mobility. PMID- 28892265 TI - Effects of preemptive analgesia with flurbiprofen ester on lymphocytes and natural killer cells in patients undergoing esophagectomy: A randomized controlled pilot study. AB - BACKGROUND: Tumors may induce systemic immune dysfunction, which can be aggravated by surgery and anesthesia/analgesia. Data on the effect of flurbiprofen preemptive analgesia on immune dysfunction is limited. The aim of this study was to investigate the effect of flurbiprofen preemptive analgesia on lymphocytes and natural killer (NK) cells in patients undergoing thoracotomy and thoracoscopy radical esophagectomy, and to explore the analgesic methods suitable for tumor patients. METHODS: This was a randomized controlled pilot study of 89 patients with esophageal cancer treated with surgery at the Henan Cancer Hospital between January 1, 2015 and December 31, 2016. The patients were divided into three groups: group 1, thoracotomy; group 2, thoracoscopy and laparoscopic surgery; and group 3, flurbiprofen, thoracoscopy, and laparoscopic surgery. CD3+, CD19+, NK, CD4+, and CD8+ cells in whole blood were measured by flow cytometry 30 minutes before surgery (T0), at the end of the thoracic section of the procedure (T1), and at the end of the operation (T2). RESULTS: There were no significant differences in CD3+, CD19+, CD8+, NK, and CD4+ cells between the three groups or regarding the time points during the procedure (all P > 0.05). Thoracotomy and thoracoscopy surgery resulted in similar immunological outcomes. CONCLUSION: Flurbiprofen ester preemptive analgesia did not suppress the immune function in patients and could be a safe analgesic method for patients with esophageal cancer undergoing surgery. PMID- 28892266 TI - Cervical dilatation patterns of 'low-risk' women with spontaneous labour and normal perinatal outcomes: a systematic review. AB - BACKGROUND: The call for women-centred approaches to reduce labour interventions, particularly primary caesarean section, has renewed an interest in gaining a better understanding of natural labour progression. OBJECTIVE: To synthesise available data on the cervical dilatation patterns during spontaneous labour of 'low-risk' women with normal perinatal outcomes. SEARCH STRATEGY: PubMed, EMBASE, CINAHL, POPLINE, Global Health Library, and reference lists of eligible studies. SELECTION CRITERIA: Observational studies and other study designs. DATA COLLECTION AND ANALYSIS: Two authors extracted data on: maternal characteristics; labour interventions; the duration of labour centimetre by centimetre; and the duration of labour from dilatation at admission through to 10 cm. We pooled data across studies using weighted medians and employed the Bootstrap-t method to generate the corresponding confidence bounds. MAIN RESULTS: Seven observational studies describing labour patterns for 99 971 women met our inclusion criteria. The median time to advance by 1 cm in nulliparous women was longer than 1 hour until a dilatation of 5 cm was reached, with markedly rapid progress after 6 cm. Similar labour progression patterns were observed in parous women. The 95th percentiles for both parity groups suggest that it was not uncommon for some women to reach 10 cm, despite dilatation rates that were much slower than the 1 cm/hour threshold for most part of their first stage of labours. CONCLUSION: An expectation of a minimum cervical dilatation threshold of 1 cm/hour throughout the first stage of labour is unrealistic for most healthy nulliparous and parous women. Our findings call into question the universal application of clinical standards that are conceptually based on an expectation of linear labour progress in all women. FUNDING: UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, and the United States Agency for International Development (USAID). TWEETABLE ABSTRACT: Cervical dilatation threshold of 1 cm/hour throughout labour is unrealistic for most women, regardless of parity. PMID- 28892267 TI - Reply to Costs of ALK, ROS1, EGFR, and KRAS testing in non-small cell lung cancer: About different strategies in France. PMID- 28892263 TI - Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle. AB - Prior to ovulation, the mammalian oocyte undergoes a process of differentiation within the ovarian follicle that confers on it the ability to give rise to an embryo. Differentiation comprises two phases-growth, during which the oocyte increases more than 100-fold in volume as it accumulates macromolecules and organelles that will sustain early embryogenesis; and meiotic maturation, during which the oocyte executes the first meiotic division and prepares for the second division. Entry of an oocyte into the growth phase appears to be triggered when the adjacent granulosa cells produce specific growth factors. As the oocyte grows, it elaborates a thick extracellular coat termed the zona pellucida. Nonetheless, cytoplasmic extensions of the adjacent granulosa cells, termed transzonal projections (TZPs), enable them to maintain contact-dependent communication with the oocyte. Through gap junctions located where the TZP tips meet the oocyte membrane, they provide the oocyte with products that sustain its metabolic activity and signals that regulate its differentiation. Conversely, the oocyte secretes diffusible growth factors that regulate proliferation and differentiation of the granulosa cells. Gap junction-permeable products of the granulosa cells prevent precocious initiation of meiotic maturation, and the gap junctions also enable oocyte maturation to begin in response to hormonal signals received by the granulosa cells. Development of the oocyte or the somatic compartment may also be regulated by extracellular vesicles newly identified in follicular fluid and at TZP tips, which could mediate intercellular transfer of macromolecules. Oocyte differentiation thus depends on continuous signaling interactions with the somatic cells of the follicle. WIREs Dev Biol 2018, 7:e294. doi: 10.1002/wdev.294 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Cell Fate Signaling Early Embryonic Development > Gametogenesis. PMID- 28892268 TI - Decoupling the Effects of High Crystallinity and Surface Area on the Photocatalytic Overall Water Splitting over beta-Ga2 O3 Nanoparticles by Chemical Vapor Synthesis. AB - Chemical vapor synthesis (CVS) is a unique method to prepare well-defined photocatalyst materials with both large specific surface area and a high degree of crystallinity. The obtained beta-Ga2 O3 nanoparticles were optimized for photocatalysis by reductive photodeposition of the Rh/CrOx co-catalyst system. The influence of the degree of crystallinity and the specific surface area on photocatalytic aqueous methanol reforming and overall water splitting (OWS) was investigated by synthesizing beta-Ga2 O3 samples in the temperature range from 1000 degrees C to 1500 degrees C. With increasing temperature, the specific surface area and the microstrain were found to decrease, whereas the degree of crystallinity and the crystallite size increased. Whereas the photocatalyst with the highest specific surface area showed the highest aqueous methanol reforming activity, the highest OWS activity was that for the sample with an optimum ratio between high degree of crystallinity and specific surface area. Thus, it was possible to show that the facile aqueous methanol reforming and the demanding OWS have different requirements for high photocatalytic activity. PMID- 28892269 TI - Bacteria utilizing plant-derived carbon in the rhizosphere of Triticum aestivum change in different depths of an arable soil. AB - Root exudates shape microbial communities at the plant-soil interface. Here we compared bacterial communities that utilize plant-derived carbon in the rhizosphere of wheat in different soil depths, including topsoil, as well as two subsoil layers up to 1 m depth. The experiment was performed in a greenhouse using soil monoliths with intact soil structure taken from an agricultural field. To identify bacteria utilizing plant-derived carbon, 13 C-CO2 labelling of plants was performed for two weeks at the EC50 stage, followed by isopycnic density gradient centrifugation of extracted DNA from the rhizosphere combined with 16S rRNA gene-based amplicon sequencing. Our findings suggest substantially different bacterial key players and interaction mechanisms between plants and bacteria utilizing plant-derived carbon in the rhizosphere of subsoils and topsoil. Among the three soil depths, clear differences were found in 13 C enrichment pattern across abundant operational taxonomic units (OTUs). Whereas, OTUs linked to Proteobacteria were enriched in 13 C mainly in the topsoil, in both subsoil layers OTUs related to Cohnella, Paenibacillus, Flavobacterium showed a clear 13 C signal, indicating an important, so far overseen role of Firmicutes and Bacteriodetes in the subsoil rhizosphere. PMID- 28892270 TI - Biomimetic Artificial Basilar Membranes for Next-Generation Cochlear Implants. AB - Patients with sensorineural hearing loss can recover their hearing using a cochlear implant (CI). However, there is a need to develop next-generation CIs to overcome the limitations of conventional CIs caused by extracorporeal devices. Recently, artificial basilar membranes (ABMs) are actively studied for next generation CIs. The ABM is an acoustic transducer that mimics the mechanical frequency selectivity of the BM and acoustic-to-electrical energy conversion of hair cells. This paper presents recent progress in biomimetic ABMs. First, the characteristics of frequency selectivity of the ABMs by the trapezoidal membrane and beam array are addressed. Second, to reflect the latest research of energy conversion technologies, ABMs using various piezoelectric materials and triboelectric-based ABMs are discussed. Third, in vivo evaluations of the ABMs in animal models are discussed according to the target position for implantation. Finally, future perspectives of ABM studies for the development of practical hearing devices are discussed. PMID- 28892271 TI - Potential drug-drug interactions and polypharmacy in institutionalized elderly patients in a public hospital in Brazil. AB - : WHAT IS KNOWN ON THE SUBJECT?: Older individuals constitute an increasing proportion of the population, and therefore, are the major consumers of drugs. The elderly, especially those with mental disabilities, frequently develop chronic diseases and start using numerous drugs. Drug-drug interactions (DDIs) are a major clinical problem in the elderly population, and previous studies have focused only on antidepressants and others types of drugs used to treat mental health conditions. WHAT THIS ARTICLE ADDS TO EXISTING KNOWLEDGE?: This study shows that in hospitalized elderly patients with mental disorders (aged 60-69 years), polypharmacy (>=5 drugs) and the use of drugs that act on the cardiovascular, respiratory and nervous systems can lead to potential drug-drug interactions. Moreover, it was reported that the prevalence of drug-drug interactions in elderly patients with mental disorders was high during their hospitalization in a public hospital in Brazil. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nurses should know the factors associated with drug-drug interactions in hospitalized elderly patients with mental disorders to choose appropriate strategies for avoiding treatment failure and adverse events in patients. ABSTRACT: Introduction Despite the impact on patient safety and the fact that prevalence is higher in older patients, previous research did not analyse drug drug interactions (DDIs) in view of nursing care of elderly psychiatric patients. Aim To identify potential drug-drug interactions and polypharmacy in prescriptions of aged inpatients with psychiatric disorders and analyse associated factors. Methods In this retrospective cross-sectional study, we analysed the medical records of institutionalized patients diagnosed with psychiatric disorders (n = 94), aged >60 years, and prescribed multiple medications. Drug prescriptions were checked at admission, midway through and the last prescription. Factors associated with DDI occurrence were assessed using multivariable logistic regression analysis. Results A DDI prevalence potential of 67.0%, 74.5% and 80.8% occurred in patients at admission, midway through hospitalization and the last prescription, respectively. Most of the prescribed drugs were nervous system agents. A high percentage of serious and contraindicated potential DDIs occurred. Age between 60 and 69 years, use of cardiovascular and respiratory system drugs, and the number of medications contributed significantly to DDI. Implications for mental health nursing Knowledge on the factors associated with DDIs in patients with mental disorders can contribute to the improvement of effectiveness and safety of nursing care. PMID- 28892272 TI - Effect of cerebrospinal fluid shunt surgery on lower urinary tract dysfunction in idiopathic normal pressure hydrocephalus. AB - AIMS: To examine the outcomes of lower urinary tract symptoms (LUTS) and urodynamic test results after cerebrospinal fluid (CSF) shunt surgery in idiopathic normal pressure hydrocephalus (iNPH). METHODS: Records of 48 patients (33 men; 15 women), who met the definite iNPH criteria and underwent CSF shunt surgery, were retrospectively analyzed. LUTS and their impact on quality of life (QOL) were evaluated using an all-or-none questionnaire targeting four symptoms, the Overactive Bladder Symptoms Score (OABSS), and the QOL index. Urodynamic investigations included filling cystometry and pressure-flow studies performed before and after surgery. RESULTS: Forty-seven (98%) patients complained of LUTS, 41 (87%) patients of whom experienced LUTS improvement after surgery. The OABSS and QOL index, which before surgery were 6.8 +/- 0.7 and 4.1 +/- 0.4, respectively, significantly decreased to 4.6 +/- 0.6 and 3.2 +/- 0.3, respectively, after surgery. The maximum cystometric capacity (174.9 +/- 13.3 mL to 222.4 +/- 14.7 mL) and bladder compliance (35.8 +/- 4.4 ml/cmH2 O to 52.1 +/- 5.4 ml/cmH2 O) significantly increased after surgery. Detrusor overactivity, which was observed in 37 (77%) patients preoperatively, became undetectable in 7 patients postoperatively. Voiding dysfunction (defined as maximum flow rate <10 mL/s or post-void residual >100 mL) was observed in 29 (60%) patients, 22 (75%) of whom had detrusor underactivity before surgery. None of the voiding urodynamic parameters significantly improved postoperatively. CONCLUSIONS: iNPH is often associated with LUTS and both storage and voiding dysfunctions. CSF shunt surgery improved LUTS and storage dysfunction, with limited effects on voiding dysfunction. PMID- 28892273 TI - Corrigendum to Hyatt (2015) "Specific default mode subnetworks support mentalizing as revealed through opposing network recruitment by social and semantic fMRI tasks". PMID- 28892274 TI - Biosynthesis and function of simple amides in Xenorhabdus doucetiae. AB - Xenorhabdus doucetiae, the bacterial symbiont of the entomopathogenic nematode Steinernema diaprepesi produces several different fatty acid amides. Their biosynthesis has been studied using a combination of analysis of gene deletions and promoter exchanges in X. doucetiae and heterologous expression of candidate genes in E. coli. While a decarboxylase is required for the formation of all observed phenylethylamides and tryptamides, the acyltransferase XrdE encoded in the xenorhabdin biosynthesis gene cluster is responsible for the formation of short chain acyl amides. Additionally, new, long-chain and cytotoxic acyl amides were identified in X. doucetiae infected insects and when X. doucetiae was grown in Galleria Instant Broth (GIB). When the bioactivity of selected amides was tested, a quorum sensing modulating activity was observed for the short chain acyl amides against the two different quorum sensing systems from Chromobacterium and Janthinobacterium. PMID- 28892275 TI - Selective Synthesis of Fluorine-Containing Cyclic beta-Amino Acid Scaffolds. AB - Fluorine-containing organic molecules have generated increasing impact in drug research over the past decade. Their preparation and development of novel synthetic methods towards new types of fluorinated molecules among them of beta amino acid derivatives has received large interest. Our research group have designed various highly selective and stereocontrolled methods for the construction of fluorine-containing cyclic beta-amino acid derivatives. The synthetic approaches developed for the synthesis of various pharmacologically interesting cyclic beta-amino acid derivatives as monomers with multiple stereogenic centers might be valuable protocols for the access of other classes of organic compounds. PMID- 28892276 TI - What makes rhizobia rhizosphere colonizers? PMID- 28892277 TI - Ungulates increase forest plant species richness to the benefit of non-forest specialists. AB - Large wild ungulates are a major biotic factor shaping plant communities. They influence species abundance and occurrence directly by herbivory and plant dispersal, or indirectly by modifying plant-plant interactions and through soil disturbance. In forest ecosystems, researchers' attention has been mainly focused on deer overabundance. Far less is known about the effects on understory plant dynamics and diversity of wild ungulates where their abundance is maintained at lower levels to mitigate impacts on tree regeneration. We used vegetation data collected over 10 years on 82 pairs of exclosure (excluding ungulates) and control plots located in a nation-wide forest monitoring network (Renecofor). We report the effects of ungulate exclusion on (i) plant species richness and ecological characteristics, (ii) and cover percentage of herbaceous and shrub layers. We also analyzed the response of these variables along gradients of ungulate abundance, based on hunting statistics, for wild boar (Sus scrofa), red deer (Cervus elaphus) and roe deer (Capreolus capreolus). Outside the exclosures, forest ungulates maintained higher species richness in the herbaceous layer (+15%), while the shrub layer was 17% less rich, and the plant communities became more light-demanding. Inside the exclosures, shrub cover increased, often to the benefit of bramble (Rubus fruticosus agg.). Ungulates tend to favour ruderal, hemerobic, epizoochorous and non-forest species. Among plots, the magnitude of vegetation changes was proportional to deer abundance. We conclude that ungulates, through the control of the shrub layer, indirectly increase herbaceous plant species richness by increasing light reaching the ground. However, this increase is detrimental to the peculiarity of forest plant communities and contributes to a landscape-level biotic homogenization. Even at population density levels considered to be harmless for overall plant species richness, ungulates remain a conservation issue for plant community composition. PMID- 28892278 TI - Reflection on stroke deaths and end-of-life stroke care. AB - BACKGROUND: The benefit of palliative care referral for severe stroke patients on end-of-life care pathway (EOLCP) is increasingly recognised. Palliative care provides assistance with symptom management and transition to end-of-life care. Advance care planning (ACP) may help accommodate patient/family expectations and guide management. METHODS: This is a retrospective study of all stroke deaths (2014-2015) at Liverpool Hospital, Sydney, Australia. Data examined included age, comorbidities, living arrangements, pre-existing ACP, palliative care referral rates and 'survival time'. RESULTS: In total, 123 patient (mean age +/- SD = 76 +/- 13 years) deaths were identified from 1067 stroke admissions (11.5% mortality); 64 (52%) patients had ischaemic stroke and 59 (48%) intracerebral haemorrhage (ICH), and 40% suffered a prior stroke, and 43% required a carer at home or were in an aged care facility. Survival time from admission was significantly longer in patients with ischaemic stroke compared to intracerebral haemorrhage (median, interquartile range [IQR]: 9.5 [18] vs 2 [4] days, P < 0.001). Only two patients had pre-existing ACP; 44% of patients were referred to palliative care and 41% were commenced on dedicated EOLCP. Palliative care referral was less likely in patients who died under neurosurgery. EOLCP were significantly less likely to be commenced in patients who underwent acute intervention or were not referred to palliative care. CONCLUSION: In this cohort, palliative care referral and EOLCP were commenced in less than 50% of patients, highlighting significant variations in clinical care. These data support the need to promote awareness of ACP, particularly in patients with prior stroke or significant comorbidities. This may help reduce potentially futile invasive investigations and treatment. PMID- 28892279 TI - The Role of Rubidium in Multiple-Cation-Based High-Efficiency Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) based on cesium (Cs)- and rubidium (Rb)-containing perovskite films show highly reproducible performance; however, a fundamental understanding of these systems is still emerging. Herein, this study has systematically investigated the role of Cs and Rb cations in complete devices by examining the transport and recombination processes using current-voltage characteristics and impedance spectroscopy in the dark. As the credibility of these measurements depends on the performance of devices, this study has chosen two different PSCs, (MAFACs)Pb(IBr)3 (MA = CH3 NH3+ , FA = CH(NH2 )2+ ) and (MAFACsRb)Pb(IBr)3 , yielding impressive performances of 19.5% and 21.1%, respectively. From detailed studies, this study surmises that the confluence of the low trap-assisted charge-carrier recombination, low resistance offered to holes at the perovskite/2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9 spirobifluorene interface with a low series resistance (Rs ), and low capacitance leads to the realization of higher performance when an extra Rb cation is incorporated into the absorber films. This study provides a thorough understanding of the impact of inorganic cations on the properties and performance of highly efficient devices, and also highlights new strategies to fabricate efficient multiple-cation-based PSCs. PMID- 28892280 TI - Costs of ALK, ROS1, EGFR, and KRAS testing in non-small cell lung cancer: About different strategies in France. PMID- 28892281 TI - Transgenerational and developmental plasticity at the molecular level: Lessons from Daphnia. AB - Listen to the news and you are bound to hear that researchers are increasingly interested in the biological manifestations of trauma that reverberate through the generations. Research in this area can be controversial in the public realm, provoking societal issues about personal responsibility (are we really born free or are we born with the burden of our ancestors' experience?). It is also a touchy subject within evolutionary biology because it provokes concerns about Lamarckianism and general scepticism about the importance of extra-genetic inheritance (Laland et al., ). Part of why the research in this area has been controversial is because it is difficult to study. For one, there is the problem of how long it takes to track changes across generations, making long-term, multi generational studies especially tricky in long-lived species. Moreover, there are presently very few (if any) known molecular mechanisms by which environmental effects can be incorporated into the genome and persist for multiple successive generations, casting doubt on their evolutionary repercussions. Fortunately, you only have to look in your local pond to find the creatures that are teaching us a great deal about how and why the experiences of parents are passed down to their offspring. In this issue of Molecular Ecology, Hales et al. (Hales et al., ) illustrate the power of Daphnia ("water fleas") for making headway in this field. PMID- 28892282 TI - Diabetic foot infection: Antibiotic therapy and good practice recommendations. AB - BACKGROUND: Healthcare events related to diabetic foot disease carry a burden of morbidity, mortality and economic cost. Prompt identification of clinical infection with appropriate tissue sampling limits use of broad spectrum empirical antibiotics and improves antibiotic stewardship. Staphylococcus aureus remains the commonest infecting organism and high-dose flucloxacillin remains the empirical antibiotic of choice for antibiotic naive patients. Barriers to microbe specific treatment include: adequate tissue sampling, delays in culture results, drug allergies and the emergence of multidrug-resistant organisms which can complicate the choice of targeted antibiotics. Even appropriate antibiotic treatment carries a risk of adverse events including the selection of resistant organisms. AIMS: Multidisciplinary clinical assessment of a diabetic foot infection is supported by the use of appropriate imaging modalities and deep tissue sampling, both of which are encouraged to enhance sampling accuracy. Narrow-spectrum, high dose, short duration antimicrobial therapy is ideal. Further clarity in these areas would be of benefit to clinicians involved in management of diabetic foot infections. METHODS: A combination of literature review with expert discussion was used to generate consensus on management of diabetic foot infection, with a specific focus on empirical antimicrobial therapy. RESULTS: Gram positive organisms represent the commonest pathogens in diabetic foot infection. However there are developing challenges in antimicrobial resistance and antibiotic availability. DISCUSSION: Recommendations for empirical therapy, including the choice of alternative oral agents and use of outpatient antibiotics would be of benefit to those involved in diabetic foot care. CONCLUSION: This paper provides advice on empirical antibiotic therapy that may be used as a framework for local guideline development to support clinicians in the management of diabetic foot infection. PMID- 28892283 TI - Kinetics of NH3 -oxidation, NO-turnover, N2 O-production and electron flow during oxygen depletion in model bacterial and archaeal ammonia oxidisers. AB - Ammonia oxidising bacteria (AOB) are thought to emit more nitrous oxide (N2 O) than ammonia oxidising archaea (AOA), due to their higher N2 O yield under oxic conditions and denitrification in response to oxygen (O2 ) limitation. We determined the kinetics of growth and turnover of nitric oxide (NO) and N2 O at low cell densities of Nitrosomonas europaea (AOB) and Nitrosopumilus maritimus (AOA) during gradual depletion of TAN (NH3 + NH4+) and O2 . Half-saturation constants for O2 and TAN were similar to those determined by others, except for the half-saturation constant for ammonium in N. maritimus (0.2 mM), which is orders of magnitudes higher than previously reported. For both strains, cell specific rates of NO turnover and N2 O production reached maxima near O2 half saturation constant concentration (2-10 MUM O2 ) and decreased to zero in response to complete O2 -depletion. Modelling of the electron flow in N. europaea demonstrated low electron flow to denitrification (<=1.2% of the total electron flow), even at sub-micromolar O2 concentrations. The results corroborate current understanding of the role of NO in the metabolism of AOA and suggest that denitrification is inconsequential for the energy metabolism of AOB, but possibly important as a route for dissipation of electrons at high ammonium concentration. PMID- 28892284 TI - Logistical Challenges and Opportunities for Conducting Peer Nomination Research in Schools. AB - Although conducting psychological research within schools has always required effort, persistence, and the careful navigation of various interests, there is a consensus among child and adolescent researchers that, over the past 2 decades, it has become increasingly difficult to collect data within schools. In this chapter, we lay out common and consistent difficulties, frustrations, and obstacles that researchers face when attempting to conduct peer nomination research in schools. Many of these difficulties are faced not only by researchers conducting peer nominations but by any investigator attempting to do school-based research, and we discuss these issues more broadly. We also focus on the specific challenges associated with sociometric methods. We present suggestions and solutions for overcoming these issues and consider ways that researchers can give back to schools and establish long-term partnerships that benefit the students, teachers, and administrators of participating schools, as well as the researchers themselves. Such partnerships have the potential to make data collection easier and to open doors to new research opportunities. PMID- 28892285 TI - Computer-Based Methods for Collecting Peer Nomination Data: Utility, Practice, and Empirical Support. AB - New technologies have led to several major advances in psychological research over the past few decades. Peer nomination research is no exception. Thanks to these technological innovations, computerized data collection is becoming more common in peer nomination research. However, computer-based assessment is more than simply programming the questionnaire and asking respondents to fill it in on computers. In this chapter the advantages and challenges of computer-based assessments are discussed. In addition, a list of practical recommendations and considerations is provided to inform researchers on how computer-based methods can be applied to their own research. Although the focus is on the collection of peer nomination data in particular, many of the requirements, considerations, and implications are also relevant for those who consider the use of other sociometric assessment methods (e.g., paired comparisons, peer ratings, peer rankings) or computer-based assessments in general. PMID- 28892286 TI - Methodological Choices in Peer Nomination Research. AB - Although peer nomination measures have been used by researchers for nearly a century, common methodological practices and rules of thumb (e.g., which variables to measure; use of limited vs. unlimited nomination methods) have continued to develop in recent decades. At the same time, other key aspects of the basic nomination procedure (e.g., whether nonparticipants should be included as nominees, the consequences of pairing code numbers with names on rosters) are underdiscussed and understudied. Beyond providing a general introduction to peer nomination methods and their utility, the current article discusses the advantages and disadvantages of various methodological choices facing researchers who wish to use peer nomination methods, in addition to other considerations that researchers must make in collecting peer nomination data (e.g., establishing reliability and validity, maximizing participation rates, computerized assessments). This article provides recommendations for researchers based on empirical findings (where possible) and the typical practices used in the recent published literature. PMID- 28892287 TI - Introduction to the Special Issue: 20th-Century Origins and 21st-Century Developments of Peer Nomination Methodology. AB - This issue of New Directions for Child and Adolescent Development looks at current practices and recent advances in peer nomination methodology. Peer nominations provide a key method for assessing relationships, social status, and interpersonal behavior. This introductory article begins with a history of peer nomination methods, with a focus on the early origins of peer informant measures and the nature of Moreno's (1934) sociometric methodology (highlighting fundamental differences from the modern sociometric procedure). Next, the article addresses major changes that have occurred in peer nomination research over the course of the past 2 decades, including the recent focus on popularity and relational aggression, statistical advances, logistical challenges and innovations, and the changing conventions of the nomination procedure itself. The final section includes a brief overview of the articles included in this issue. PMID- 28892288 TI - The Current Status of Peer Assessment Techniques and Sociometric Methods. AB - Current issues in the use of peer assessment techniques and sociometric methods are discussed. Attention is paid to the contributions of the four articles in this volume. Together these contributions point to the continual level of change and progress in these techniques. They also show that the paradigm underlying these methods has been unchanged for decades. It is argued that this domain is ripe for a paradigm change that takes advantage of recent developments in statistical techniques and technology. PMID- 28892289 TI - The need to change from a phenomenological to a target engagement approach. PMID- 28892290 TI - Is microbial terroir related to geographic distance between vineyards? AB - While there are substantial studies suggesting that characteristics of wine are related to regional microbial community composition (microbial terroir), there has been little discussion about what factors affect variation in regional microbial community composition. In this study, we compared the microbial community composition of leaves and berries of a grape variety (Carmenere) from six different Chilean vineyards within 35 km of each other. In order to determine relationships between spatial proximity and microbial compositional dissimilarity, we sequenced amplicons of the internal transcribed spacer (ITS) region for fungi and 16S rRNA gene for bacteria. Results showed that both the fungal and the bacterial community compositions of the studied vineyards differed, but this difference was much clearer in fungi than in bacteria. In addition, while bacterial community dissimilarity was not correlated with geographic distance, the leaf and berry fungal community dissimilarities between locations increased with geographic distance. This indicates that spatial processes play an important role in structuring the biogeographic pattern of grape-associated fungal communities at local scales, which might in turn contribute to the local identity of wine. PMID- 28892291 TI - Ectosymbiotic Endomicrobia - a transition stage towards intracellular symbionts? PMID- 28892292 TI - Dissemination and loss of a biofilm-related genomic island in marine Pseudoalteromonas mediated by integrative and conjugative elements. AB - Acquisition of genomic islands (GIs) plays a central role in the diversification and adaptation of bacteria. Some GIs can be mobilized in trans by integrative and conjugative elements (ICEs) or conjugative plasmids if the GIs carry specific transfer-related sequences. However, the transfer mechanism of GIs lacking such elements remains largely unexplored. Here, we investigated the transmissibility of a GI found in a coral-associated marine bacterium. This GI does not carry genes with transfer functions, but it carries four genes required for robust biofilm formation. Notably, this GI is inserted in the integration site for SXT/R391 ICEs. We demonstrated that acquisition of an SXT/R391 ICE results in either a tandem GI/ICE arrangement or the complete displacement of the GI. The GI displacement by the ICE greatly reduces biofilm formation. In contrast, the tandem integration of the ICE with the GI in cis allows the GI to hijack the transfer machinery of the ICE to excise, transfer and re-integrate into a new host. Collectively, our findings reveal that the integration of an ICE into a GI integration site enables rapid genome dynamics and a new mechanism by which SXT/R391 ICEs can augment genome plasticity. PMID- 28892293 TI - Phospholipase D and phosphatidic acid mediate heat stress induced secondary metabolism in Ganoderma lucidum. AB - Phospholipid-mediated signal transduction plays a key role in responses to environmental changes, but little is known about the role of phospholipid signalling in microorganisms. Heat stress (HS) is one of the most important environmental factors. Our previous study found that HS could induce the biosynthesis of the secondary metabolites, ganoderic acids (GA). Here, we performed a comprehensive mass spectrometry-based analysis to investigate HS induced lipid remodelling in Ganoderma lucidum. In particular, we observed a significant accumulation of phosphatidic acid (PA) on HS. Further genetic tests in which pld-silencing strains were constructed demonstrated that the accumulation of PA is dependent on HS-activated phospholipase D (PLD) hydrolysing phosphatidylethanolamine. Furthermore, we determined the role of PLD and PA in HS induced secondary metabolism in G. lucidum. Exogenous 1-butanol, which decreased PLD-mediated formation of PA, reverses the increased GA biosynthesis that was elicited by HS. The pld-silenced strains partly blocked HS-induced GA biosynthesis, and this block can be reversed by adding PA. Taken together, our results suggest that PLD and PA are involved in the regulation of HS-induced secondary metabolism in G. lucidum. Our findings provide key insights into how microorganisms respond to heat stress and then consequently accumulate secondary metabolites by phospholipid remodelling. PMID- 28892294 TI - Nuclease activity gives an edge to host-defense peptide piscidin 3 over piscidin 1, rendering it more effective against persisters and biofilms. AB - Host-defense peptides (HDPs) feature evolution-tested potency against life threatening pathogens. While piscidin 1 (p1) and piscidin 3 (p3) are homologous and potent fish HDPs, only p1 is strongly membranolytic. Here, we hypothesize that another mechanism imparts p3 strong potency. We demonstrate that the N termini of both peptides coordinate Cu2+ and p3-Cu cleaves isolated DNA at a rate on par with free Cu2+ but significantly faster than p1-Cu. On planktonic bacteria, p1 is more antimicrobial but only p3 features copper-dependent DNA cleavage. On biofilms and persister cells, p3-Cu is more active than p1-Cu, commensurate with stronger peptide-induced DNA damage. Molecular dynamics and NMR show that more DNA-peptide interactions exist with p3 than p1, and the peptides adopt conformations simultaneously poised for metal- and DNA-binding. These results generate several important conclusions. First, homologous HDPs cannot be assumed to have identical mechanisms since p1 and p3 eradicate bacteria through distinct relative contributions of membrane and DNA-disruptive effects. Second, the nuclease and membrane activities of p1 and p3 show that naturally occurring HDPs can inflict not only physicochemical but also covalent damage. Third, strong nuclease activity is essential for biofilm and persister cell eradication, as shown by p3, the homolog more specific toward bacteria and more expressed in vascularized tissues. Fourth, p3 combines several physicochemical properties (e.g., Amino Terminal Copper and Nickel binding motif; numerous arginines; moderate hydrophobicity) that confer low membranolytic effects, robust copper scavenging capability, strong interactions with DNA, and fast nuclease activity. This new knowledge could help design novel therapeutics active against hard-to treat persister cells and biofilms. PMID- 28892295 TI - Transcriptome and proteome dynamics in chemostat culture reveal how Campylobacter jejuni modulates metabolism, stress responses and virulence factors upon changes in oxygen availability. AB - Campylobacter jejuni, the most frequent cause of food-borne bacterial gastroenteritis worldwide, is a microaerophile that has to survive high environmental oxygen tensions, adapt to oxygen limitation in the intestine and resist host oxidative attack. Here, oxygen-dependent changes in C. jejuni physiology were studied at constant growth rate using carbon (serine)-limited continuous chemostat cultures. We show that a perceived aerobiosis scale can be calibrated by the acetate excretion flux, which becomes zero when metabolism is fully aerobic (100% aerobiosis). Transcriptome changes in a downshift experiment from 150% to 40% aerobiosis revealed many novel oxygen-regulated genes and highlighted re-modelling of the electron transport chains. A label-free proteomic analysis showed that at 40% aerobiosis, many proteins involved in host colonisation (e.g., PorA, CadF, FlpA, CjkT) became more abundant. PorA abundance increased steeply below 100% aerobiosis. In contrast, several citric-acid cycle enzymes, the peptide transporter CstA, PEB1 aspartate/glutamate transporter, LutABC lactate dehydrogenase and PutA proline dehydrogenase became more abundant with increasing aerobiosis. We also observed a co-ordinated response of oxidative stress protection enzymes and Fe-S cluster biogenesis proteins above 100% aerobiosis. Our approaches reveal key virulence factors that respond to restricted oxygen availability and specific transporters and catabolic pathways activated with increasing aerobiosis. PMID- 28892296 TI - Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems. AB - Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century. PMID- 28892297 TI - Urolithiasis is associated with an increased risk of stroke: a population-based 5 year follow-up study. AB - BACKGROUND: Epidemiological studies have reported an association between urolithiasis and cardiovascular disease. However, studies examining the risks of ischaemic and haemorrhagic stroke in patients with urolithiasis are limited. AIMS AND METHODS: By using a nationwide population database, we conducted a matched cohort study to investigate the association between urolithiasis and longitudinal risks of ischaemic and haemorrhagic stroke. RESULTS: The urolithiasis and non urolithiasis cohorts included 12 979 and 64 895 patients respectively. Of these, 728 (5.6%) and 2802 (4.3%) patients in the urolithiasis and non-urolithiasis cohorts, respectively, had a stroke during the 5-year follow-up period. The hazard ratio (HR) for stroke was 1.19 times higher (95% confidence interval [CI] = 1.10-1.29; P < 0.001) in the urolithiasis cohort than in the non-urolithiasis cohort after adjustment for potential confounders. The risk of both ischaemic (adjusted HR = 1.16; 95% CI = 1.05-1.29) and haemorrhagic stroke (adjusted HR = 1.30; 95% CI = 1.03-1.64) remained significant in the urolithiasis cohort. Furthermore, the risk of stroke was significant in both men (adjusted HR = 1.16; 95% CI = 1.05-1.28) and women (adjusted HR = 1.26; 95% CI = 1.10-1.45). Middle aged (40-59 years; adjusted HR = 1.26; 95% CI = 1.10-1.45) and older (>=60 years; adjusted HR = 1.14; 95% CI = 1.03-1.27) patients had a particularly high risk of stroke. CONCLUSIONS: The present study detected an increased risk of both ischaemic and haemorrhagic stroke in patients with urolithiasis, particularly in those older than 40 years. PMID- 28892298 TI - Impact of hysteroscopic surgery for isthmocele associated with cesarean scar syndrome. AB - AIM: Cesarean scar syndrome (CSS) is characterized by increased risk of postmenstrual abnormal uterine bleeding, dysmenorrhea, and infertility, due to a post-cesarean scar defect known as an isthmocele. This study aimed to assess the impact of hysteroscopic surgery on isthmocele associated with CSS. METHODS: Eighteen patients with CSS were enrolled. Surgical methods included resection of the inferior edge and superficial cauterization of the isthmocele via hysteroscopic surgery. We evaluated the residual myometrial thickness and isthmocele volume using magnetic resonance imaging, before and after hysteroscopic surgery. RESULTS: All patients underwent surgery without any complications. The residual myometrium was thicker after hysteroscopic surgery (median: 2.1 mm and 4.2 mm, before and after surgery, respectively; P = 0.0001). Isthmocele volume was significantly reduced after hysteroscopic surgery (median: 494.9 mm3 and 282.8 mm3 , before and after surgery, respectively; P = 0.0016). CONCLUSION: This study demonstrated that hysteroscopic surgery is effective in increasing the residual myometrial thickness and reducing the size of isthmocele. PMID- 28892299 TI - Research progress on the relationship between zinc deficiency, related microRNAs, and esophageal carcinoma. AB - Esophageal cancer (EC) is a common malignant tumor of the gastrointestinal tract with a high incidence in China. Zinc (Zn) deficiency is a key risk factor for the occurrence and development of EC and affects progression by regulating microRNA (miRNA, miR) expression. In addition, the dysregulation of miRNAs is accompanied by the dysregulation of their target genes in EC. In this paper, we review the potential molecular mechanisms between Zn deficiency and EC with the aim of providing new strategies and methods for early diagnosis, targeted therapy, and prognostic evaluation. PMID- 28892300 TI - Thermodynamically diverse syntrophic aromatic compound catabolism. AB - Specialized organotrophic Bacteria 'syntrophs' and methanogenic Archaea 'methanogens' form a unique metabolic interaction to accomplish cooperative mineralization of organic compounds to CH4 and CO2 . Due to challenges in cultivation of syntrophs, mechanisms for how their organotrophic catabolism circumvents thermodynamic restrictions remain unclear. In this study, we investigate two communities hosting diverse syntrophic aromatic compound metabolizers (Syntrophus, Syntrophorhabdus, Pelotomaculum and an uncultivated Syntrophorhabdacaeae member) to uncover their catabolic diversity and flexibility. Although syntrophs have been generally presumed to metabolize aromatic compounds to acetate, CO2 , H2 and formate, combined metagenomics and metatranscriptomics show that uncultured syntrophs utilize unconventional alternative metabolic pathways in situ producing butyrate, cyclohexanecarboxylate and benzoate as catabolic byproducts. In addition, we also find parallel utilization of diverse H2 and formate generating pathways to facilitate interactions with partner methanogens. Based on thermodynamic calculations, these pathways may enable syntrophs to combat thermodynamic restrictions. In addition, when fed with specific substrates (i.e., benzoate, terephthalate or trimellitate), each syntroph population expresses different pathways, suggesting ecological diversification among syntrophs. These findings suggest we may be drastically underestimating the biochemical capabilities, strategies and diversity of syntrophic bacteria thriving at the thermodynamic limit. PMID- 28892301 TI - Deep nirS amplicon sequencing of San Francisco Bay sediments enables prediction of geography and environmental conditions from denitrifying community composition. AB - Denitrification is a dominant nitrogen loss process in the sediments of San Francisco Bay. In this study, we sought to understand the ecology of denitrifying bacteria by using next-generation sequencing (NGS) to survey the diversity of a denitrification functional gene, nirS (encoding cytchrome-cd1 nitrite reductase), along the salinity gradient of San Francisco Bay over the course of a year. We compared our dataset to a library of nirS sequences obtained previously from the same samples by standard PCR cloning and Sanger sequencing, and showed that both methods similarly demonstrated geography, salinity and, to a lesser extent, nitrogen, to be strong determinants of community composition. Furthermore, the depth afforded by NGS enabled novel techniques for measuring the association between environment and community composition. We used Random Forests modelling to demonstrate that the site and salinity of a sample could be predicted from its nirS sequences, and to identify indicator taxa associated with those environmental characteristics. This work contributes significantly to our understanding of the distribution and dynamics of denitrifying communities in San Francisco Bay, and provides valuable tools for the further study of this key N cycling guild in all estuarine systems. PMID- 28892302 TI - Cancer-Targeted Selenium Nanoparticles Sensitize Cancer Cells to Continuous gamma Radiation to Achieve Synergetic Chemo-Radiotherapy. AB - Cancer radiotherapy with 125 I seeds demonstrates higher long-term efficacy and fewer side effects than traditional X-ray radiotherapy owing to its low-dose and continuous radiation but is still limited by radioresistance in clinical applications. Therefore, the design and synthesis of sensitizers that could enhance the sensitivity of cancer cells to 125 I seeds is of great importance for future radiotherapy. Selenium nanoparticles (SeNPs) have been found to exhibit high potential in cancer chemotherapy and as drug carriers. In this study, we found that, based on the Auger-electron effect and Compton effect of Se atoms, cancer-targeted SeNPs in combination with 125 I seeds achieve synergetic effects to inhibit cancer-cell growth and colony formation through the induction of cell apoptosis and cell cycle arrest. Detailed studies on the action mechanisms reveal that the combined treatments effectively activate intracellular reactive oxygen species (ROS) overproduction to regulate p53-mediated DNA damage apoptotic signaling pathways and mitogen-activated protein kinase (MAPK) phosphorylation and to prevent the self-repair of cancer cells simultaneously. Taken together, the combination of SeNPs with 125 I seeds could be further exploited as a safe and effective strategy for next-generation cancer chemo-radiotherapy in clinical applications. PMID- 28892303 TI - Association between coffee consumption and risk of renal cell carcinoma: a meta analysis. AB - BACKGROUND/OBJECTIVES: The risk of renal cell carcinoma (RCC) in individuals who regularly drink coffee is controversial. Several antioxidant compounds in coffee have been proposed to reduce the risk of RCC, while the findings from several studies raise concerns regarding a potential increased risk of RCC with coffee consumption. AIM: This meta-analysis aims to evaluate the association between coffee consumption and RCC. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception until December 2016. Studies that reported odd ratios or hazard ratios comparing the risk of RCC in individuals who consumed a significant amount of coffee (at least one cup of coffee per day) versus those who did not consume coffee were included. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using a random-effect, generic inverse variance method. RESULTS: Twenty-two observational studies (16 case-control and 6 cohort studies) were included in our analysis to assess the association between RCC and coffee consumption. The pooled RR of RCC in individuals consuming coffee was 0.99 (95% CI, 0.89-1.11). Subgroup analyses stratified by gender showed pooled RRs of RCC of 1.15 (95% CI, 0.85-1.55) in females and 0.87 (95% CI, 0.72-1.04) in males. CONCLUSIONS: Our study demonstrates no significant association between coffee consumption and RCC. Thus, coffee consumption is likely not a risk factor for RCC. Whether coffee consumption has a potential role in reduced risk of RCC, particularly in men, requires further investigations. PMID- 28892304 TI - Redefining the sponge-symbiont acquisition paradigm: sponge microbes exhibit chemotaxis towards host-derived compounds. AB - Marine sponges host stable and species-specific microbial symbionts that are thought to be acquired and maintained by the host through a combination of vertical transmission and filtration from the surrounding seawater. To assess whether the microbial symbionts also actively contribute to the establishment of these symbioses, we performed in situ experiments on Orpheus Island, Great Barrier Reef, to quantify the chemotactic responses of natural populations of seawater microorganisms towards cellular extracts of the reef sponge Rhopaloeides odorabile. Flow cytometry analysis revealed significant levels of microbial chemotaxis towards R. odorabile extracts and 16S rRNA gene amplicon sequencing showed enrichment of 'sponge-specific' microbial phylotypes, including a cluster within the Gemmatimonadetes and another within the Actinobacteria. These findings infer a potential mechanism for how sponges can acquire bacterial symbionts from the surrounding environment and suggest an active role of the symbionts in finding their host. PMID- 28892305 TI - High-level resistance of Melissococcus plutonius clonal complex 3 strains to antimicrobial activity of royal jelly. AB - Melissococcus plutonius is the causative agent of European foulbrood of honey bee larvae. Among its three genetically distinct groups (CC3, CC12 and CC13), CC3 strains have been suggested to be more virulent at the colony level. Honey bee larvae are fed royal or worker jellies by adult bees, and these jellies exhibit antimicrobial activity. Since M. plutonius orally infects larvae via brood food, we herein investigated the resistance of M. plutonius to the antimicrobial activity of royal jelly (RJ). The results obtained revealed that M. plutonius strains were more resistant to RJ and its component, 10-hydroxy-2-decenoic acid, than the other species tested. Moreover, among the M. plutonius strains examined, CC3 strains exhibited the strongest resistance to antimicrobial activity; they temporarily proliferated and survived for a long period in 50% RJ-containing broth. However, resistance was not observed when freshly cultured bacteria were used, it was only detected after a preculture on agar media for five or more days, suggesting that, under certain conditions, CC3 strains change their physiological state to that which is advantageous for survival in brood food. This high-level RJ resistance of CC3 strains may contribute to their virulence in the field. PMID- 28892306 TI - Effect of locally tailored labour management guidelines on intrahospital stillbirths and birth asphyxia at the referral hospital of Zanzibar: a quasi experimental pre-post study (The PartoMa study). AB - OBJECTIVE: To evaluate effect of locally tailored labour management guidelines (PartoMa guidelines) on intrahospital stillbirths and birth asphyxia. DESIGN: Quasi-experimental pre-post study investigating the causal pathway through changes in clinical practice. SETTING: Tanzanian low-resource referral hospital, Mnazi Mmoja Hospital. POPULATION: Facility deliveries during baseline (1 October 2014 until 31 January 2015) and the 9th to 12th intervention month (1 October 2014 until 31 January 2015). METHODS: Birth outcome was extracted from all cases of labouring women during baseline (n = 3690) and intervention months (n = 3087). Background characteristics and quality of care were assessed in quasi-randomly selected subgroups (n = 283 and n = 264, respectively). MAIN OUTCOME MEASURES: Stillbirths and neonates with 5-minute Apgar score <=5. RESULTS: Stillbirth rate fell from 59 to 39 per 1000 total births (RR 0.66, 95% CI 0.53-0.82), and subanalyses suggest that this was primarily due to reduction in intrahospital stillbirths. Apgar scores between 1 and 5 fell from 52 to 28 per 1000 live births (RR 0.53, 95% CI 0.41-0.69). Median time from last fetal heart assessment till delivery (or fetal death diagnosis) fell from 120 minutes (IQR 60-240) to 74 minutes (IQR 30-130) (Mann-Whitney test for difference, P < 0.01). Oxytocin augmentation declined from 22% to 12% (RR 0.54, 95% CI 0.37-0.81) and timely use improved. CONCLUSION: Although low human resources and substandard care remain major challenges, PartoMa guidelines were associated with improvements in care, leading to reductions in stillbirths and birth asphyxia. Findings furthermore emphasise the central role of improved fetal surveillance and restricted intrapartum oxytocin use in safety at birth. TWEETABLE ABSTRACT: #PartoMa guidelines aided in reducing stillbirths and birth asphyxia at a Tanzanian low resource hospital PLAIN LANGUAGE SUMMARY: PartoMa guidelines help birth attendants in Tanzania to save lives Every year, 3 million babies die on the day of birth. The vast majority of these deaths occur in the poorest countries. If their mothers had received better care during birth, most babies would have survived. At Mnazi Mmoja Hospital, an East African referral hospital, the PartoMa study shows that use of locally developed guidelines helps birth attendants to deliver better quality of care, which has led to improved survival at birth. At the hospital studied, resources are scarce. Each birth attendant assists four to six birthing women simultaneously, and many have less than 1 year of professional experience. International guidelines are available, but they are often unachievable and seldom applied. The PartoMa guidelines were developed in close collaboration with the birth attendants and approved by seven international experts. The result is an 8-page pocket booklet providing locally achievable and simple decision support for care during birth. Use of the PartoMa guidelines began in February 2015. As the staff group frequently changes, quarterly seminars are conducted where birth attendants are welcomed after working hours to learn about the guidelines. The guidelines have been positively received, and seminar attendance remains high. Use of the PartoMa guidelines is associated with: A decrease by one-third in stillbirths (59 to 39 per 1000 total births) A nearly halving in the number of babies born in immediate poor medical condition (52 to 28 per 1000 live births) The results presented here derive from a comparison of births before using the PartoMa guidelines and during the 9th-12th month of use. Such a 'before-after' study cannot exclude the possibility of other causes of better survival at birth. However, the improved survival is consistent with improved care during birth, which is in line with the PartoMa guidelines. PMID- 28892307 TI - Purification of polysaccharide from artificially cultivated Anoectochilus roxburghii (wall.) Lindl. by high-speed counter current chromatography and its antitumor activity. AB - To establish a systematic method for the extraction, purification, characterization and antitumor activity study of polysaccharide from artificially cultivated Anoectochilus roxburghii (wall.) Lindl. (AC-ARPS). High-speed counter current chromatography with two-phase aqueous systems was successfully applied to purify AC-ARPS after one-step separation. The purity of the AC-ARPS obtained by phenol/sulfuric acid method was 95.01%. The chemical structures of AC-ARPS were identified by a series of analytical methods including high-performance liquid chromatography and liquid chromatography with mass spectrometry. High-performance liquid chromatography and liquid chromatography with mass spectrometry indicated that AC-ARPS was mainly composed of mannose, ribose, glucose, galactose and arabinose with a molar ratio of 1.00:8.47:47.30:1.17:1.19. AC-ARPS is a homogeneous polysaccharide with a molecular weight of 25 681 Da. The antitumor effect of AC-ARPS was evaluated on lung cancer A549, osteosarcoma 143B, rat adrenal pheochromocytoma PC 12, breast cancer MCF-7, acute leukemia HL 60, chronic leukemia K562, colon cancer SW620, esophageal cancer OE 19, liver cancer HepG2, and neuroglioma U251 cells in vitro. AC-ARPS showed the best inhibitory effect on OE 19 cells, and the IC50 value was 5.67 +/- 0.831 MUmol/L. Fluorescence analysis and flow cytometry results showed that AC-ARPS induced apoptosis and G2/M phase arrest in OE 19 cells. PMID- 28892308 TI - Targeting epidermal growth factor receptor co-dependent signaling pathways in glioblastoma. AB - The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that is critical for normal development and function. EGFR is also amplified or mutated in a variety of cancers including in nearly 60% of cases of the highly lethal brain cancer glioblastoma (GBM). EGFR amplification and mutation reprogram cellular metabolism and broadly alter gene transcription to drive tumor formation and progression, rendering EGFR as a compelling drug target. To date, brain tumor patients have yet to benefit from anti-EGFR therapy due in part to an inability to achieve sufficient intratumoral drug levels in the brain, cultivating adaptive mechanisms of resistance. Here, we review an alternative set of strategies for targeting EGFR-amplified GBMs, based on identifying and targeting tumor co-dependencies shaped both by aberrant EGFR signaling and the brain's unique biochemical environment. These approaches may include highly brain-penetrant drugs from non-cancer pipelines, expanding the pharmacopeia and providing promising new treatments. We review the molecular underpinnings of EGFR-activated co-dependencies in the brain and the promising new treatments based on this strategy. WIREs Syst Biol Med 2018, 10:e1398. doi: 10.1002/wsbm.1398 This article is categorized under: Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Genetic/Genomic Methods Translational, Genomic, and Systems Medicine > Translational Medicine. PMID- 28892310 TI - Genetic diversity of marine anaerobic ammonium-oxidizing bacteria as revealed by genomic and proteomic analyses of 'Candidatus Scalindua japonica'. AB - Anaerobic ammonium-oxidizing (anammox) bacteria affiliated with the genus 'Candidatus Scalindua' are responsible for significant nitrogen loss in oceans, and thus their ecophysiology is of great interest. Here, we enriched a marine anammox bacterium, 'Ca. S. japonica' from a Hiroshima bay sediment in Japan, and comparative genomic and proteomic analyses of 'Ca. S. japonica' were conducted. Sequence of the 4.81-Mb genome containing 4019 coding regions of genes (CDSs) composed of 47 contigs was determined. In the proteome, 1762 out of 4019 CDSs in the 'Ca. S. japonica' genome were detected. Based on the genomic and proteomic data, the core anammox process and carbon fixation of 'Ca. S. japonica' were further investigated. Additionally, the present study provides the first detailed insights into the genetic background responsible for iron acquisition and menaquinone biosynthesis in anammox bacterial cells. Comparative analysis of the 'Ca. Scalindua' genomes revealed that the 1502 genes found in the 'Ca. S. japonica' genome were not present in the 'Ca. S. profunda' and 'Ca. S. rubra' genomes, showing a high genomic diversity. This result may reflect a high phylogenetic diversity of the genus 'Ca. Scalindua'. PMID- 28892309 TI - Fundamental niche prediction of the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii in Europe. AB - Fundamental niche prediction of Cryptococcus neoformans and Cryptococcus gattii in Europe is an important tool to understand where these pathogenic yeasts have a high probability to survive in the environment and therefore to identify the areas with high risk of infection. In this study, occurrence data for C. neoformans and C. gattii were compared by MaxEnt software with several bioclimatic conditions as well as with soil characteristics and land use. The results showed that C. gattii distribution can be predicted with high probability along the Mediterranean coast. The analysis of variables showed that its distribution is limited by low temperatures during the coldest season, and by heavy precipitations in the driest season. C. neoformans var. grubii is able to colonize the same areas of C. gattii but is more tolerant to cold winter temperatures and summer precipitations. In contrast, the C. neoformans var. neoformans map was completely different. The best conditions for its survival were displayed in sub-continental areas and not along the Mediterranean coasts. In conclusion, we produced for the first time detailed prediction maps of the species and varieties of the C. neoformans and C. gattii species complex in Europe and Mediterranean area. PMID- 28892311 TI - [How i treat a patient with idiopathic pulmonary fibrosis]. AB - Idiopathic pulmonary fibrosis (IPF) is a rare disorder of unknown origin, which is associated with a high mortality and whose incidence has been increasing for several years. Nowadays there are two anti-fibrotic therapies (pirfenidone - nintedanib) known to reduce significantly the decline in respiratory function tests of patients suffering from this condition. The only curative therapeutic option remains the pulmonary transplantation whose accessibility remains limited. Pulmonary rehabilitation is also central in the treatment of patients. A major challenge for patients remains early and aggressive management to reduce as early as possible the evolution towards severe pulmonary fibrosis. PMID- 28892312 TI - [Case report : Emphysematous cystitis]. AB - The emphysematous cystitis is a rare condition characterized by the presence of air in the wall and/or the bladder lumen. The clinical expression of this cystitis is variable. Some patients complain of abdominal pain or urinary symptoms. Other may present only pneumaturia or be totally asymptomatic. This condition is considered as potentially severe since it can lead to an emphysematous pyelonephritis with septicemia and septic shock. Peritonitis may also occur in case of necrosis and perforation of the bladder wall. However, this negative development can be avoided by a diagnosis and an early treatment, and the emphysematous cystitis become therefore of good prognosis. We are here stating the case of a patient with an emphysematous cystitis with symptoms of pneumaturia and lower urinary tract symptoms. PMID- 28892313 TI - [HIV cure : a realistic perspective ?] AB - More than 30 years after its discovery, human immunodeficiency virus (HIV) continues to be a major global public health issue. Antiretroviral therapy increases survival and quality of life of HIV-infected patients but is not curative. Indeed, interruption of therapy invariably leads to the re-emergence of detectable viral replication, since HIV persists in extremely long-lived viral latent reservoirs. Those viral latent reservoirs constitute the major source of viral recovery following antiretroviral treatment interruption and are considered as the most important hurdle to HIV eradication. Multiple strategies aimed at targeting the HIV latent reservoirs are intensively being explored. We discuss here the most recent innovative works that will hopefully contribute to find a cure for HIV. PMID- 28892314 TI - [Use of sFlt-1/PlGF ratio in preeclampsia : a monocentric retrospective analysis]. AB - Soluble Fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor released in higher amounts in preeclampsia and implicated in endothelial dysfunction. sFlt 1/PlGF ratio is used in the prediction of preeclampsia. An sFlt-1/PlGF ratio inferior to 38 predicts the short-term absence of preeclampsia. A ratio ? 85 (early-onset PE) or ? 110 (late-onset of PE) could diagnose preeclampsia. In this study, sFlt-1/PlGF ratio has been measured in 183 patients. Sixty-seven preeclampsia have been diagnosed preeclamptic at delivery. The median sFlt-1/PlGF ratio was 100.3. The median ratio among women with preeclampsia (N=67) versus no preeclampsia (N=116) was 212.7 versus 35.4. In accordance with this analysis, an sFlt-1/PlGF ratio ? 38 has a sensibility of 95,5 % and a specificity of 73.3 %. The positive predictive value and the negative predictive value were 67.4 % and 96.6 %, respectively. These results suggest that sFlt-1/PlGF ratio is helpful in the diagnosis of preeclampsia. PMID- 28892315 TI - [Which psychiatric symptoms must raise suspicion about a possible brain tumor ?] AB - Many case studies reported psychiatric symptoms during the months before a brain tumor (BT) is diagnosed. Unfortunately, these symptoms are rarely considered as a warning of an organic problem and patients are regularly misoriented towards psychiatric care. Knowing better what psychiatric symptoms look like in patients with a BT would help to diagnose it sooner, which would obviously benefit the patient. The present study aims to quantify the prevalence and further describe psychiatric symptoms occurring before a BT diagnosis. The presence of psychiatric manifestations was systematically investigated in 100 patients with a first diagnosis of BT. Overall, 85 % of the patients reported at least one psychiatric symptom present before the BT diagnosis, most often depressive ones. Somatic manifestations of depression (loss of energy, changes in appetite...) were more often reported than affective or cognitive ones (no negative thought content: no pessimism, no guilty feelings, no worthlessness...). The present research stresses the high prevalence of psychiatric symptoms, especially depressive-like ones, occurring before a BT is diagnosed and provides a first description of these symptoms, as a basis of practical recommendations. PMID- 28892316 TI - [Epidemic of measles in the Verviers area (Belgium) : management and precautions at the reception in the emergency department]. AB - Measles is a highly contagious viral disease. Transmission occurs from person to person through direct contact or by aerosolization of pharyngeal secretions. In the area of Verviers (Belgium), we were confronted to a group of patients with measles, a public health event with local concentration. In our hospital institution, our case index dates back to the beginning of February 2017 and the follow-up of the cases indicates an upward trajectory. Sorting measures and isolations of potential patients, extensive screening and vaccinations were undertaken and coordinated from an internal management unit. Numerous contacts have been made with the competent authorities. The limitation of a measles epidemic remains a public health problem that is difficult to manage optimally, and a limited number of nosocomial cases and infections of hospital staff could not be avoided. PMID- 28892317 TI - [Sleep bruxism : state of the art and management]. AB - Although well studied since the 50's, bruxism remains a largely unknown pathology. Its origin is complex, mixing psychological as well as neurological, odontological and hypnic aspects. However, the few analyzes performed on this topic have allowed to set convincing etiopathological hypotheses, including central dysregulation of the dopaminergic system as well as of the neuro masticatory system. To avoid harmful consequences as headaches, temporomandibular disorders and premature dental scuffs / fractures, it is mandatory to diagnose bruxism as early as possible. For this purpose, and in addition to anamnestic and clinical data, the practitioner can confirm diagnosis with polysomnography, including electromyographic study of masticatory muscles and audiovisual recording. Some orthodontic, pharmacological and psychological solutions have already proved efficient. Nevertheless, a better knowledge of causative neurobiological mechanisms would allow to foresee etiology-based treatments. PMID- 28892318 TI - [Lipertance(r) The ASCOT single-pill combination has finally arrived]. AB - The fixed association of atorvastatin, perindopril and amlodipine was recently launched by the firm SERVIER under the name of Lipertance(r). It is the first fixed association of a statin, an ACE inhibitor and a calcium blocker present on the Belgian market to handle the risk factors that are hypertension and dyslipidemia which can be used both in primary and secondary cardiovascular prevention. The interests of such a triple combined therapy are many in terms of morbimortality reduction, as observed in ASCOT trial. Besides these results, the association of these three agents gives probably a synergic effect, which would be more effective to protect both heart and vessels. Moreover, a fixed association will improve treatment compliance and adherence, which are generally quite poor in the management of cardiovascular risk factors. Lipertance(r) is available with three different doses : 20/5/5 mg, 20/10/5 mg and 40/10/10 mg, respectively for atorvastatin, perindopril and amlodipine. Contraindications and side effects are the same as each component of this association and are well known. PMID- 28892320 TI - Looking forward. PMID- 28892321 TI - Italian training program in Cameroon: A model for developing cultural competence. PMID- 28892319 TI - [Which antidiabetic agent in a patient with type 2 diabetes and heart failure ?] AB - Heart failure is raising an increasing interest in patients with type 2 diabetes. Indeed, they combine different risk factors for this complication and they have time to develop it because they survive longer due to a better prevention of atherothrombotic cardiovascular events. Beyond the classical therapy of heart failure, management should select the most suited glucose-lowering agents. Indeed, all do not have the same impact as some of them have proven their ability to reduce the risk of hospitalisation for heart failure whereas others are associated with an increased risk, either well proven or at least suspected. The aim of this clinical case is to discuss the use of glucose-lowering drugs in a patient with type 2 diabetes with or at risk to develop heart failure. PMID- 28892322 TI - Trauma care funding, scope of practice, and cancer prevention lead state legislative agendas. PMID- 28892323 TI - Health care leaders develop strategies for improving access to surgical care in Latin America. PMID- 28892324 TI - 2016 ACS Governors Survey: Will acute care surgery change the surgical landscape? PMID- 28892325 TI - American College of Surgeons 2017 statement on health care reform. PMID- 28892326 TI - Practice changes lower rates of transfusion, superficial SSI, and morbidity. PMID- 28892327 TI - Interventions to promote better conversations about initial treatment for prostate cancer. PMID- 28892328 TI - The Halifax Explosion and the unofficial birth of pediatric surgery. PMID- 28892329 TI - Leadership is crucial to establishing safety culture, reducing adverse events. PMID- 28892330 TI - I broke my neck: Femur fractures. PMID- 28892348 TI - Nitrogen and Fluorine-Codoped Porous Carbons as Efficient Metal-Free Electrocatalysts for Oxygen Reduction Reaction in Fuel Cells. AB - The severe dependence of oxygen reduction reaction (ORR) in fuel cells on platinum (Pt)-based catalysts greatly limits the process of their commercialization. Therefore, developing cost-reasonable non-precious-metal catalysts to replace Pt-based catalysts for ORR is an urgent task. Here, we use the composite of inexpensive polyaniline and superfine polytetrafluoroethylene powder as precursor to synthesize a metal-free N,F-codoped porous carbon catalyst (N,F-Carbon). Results indicate that the N,F-Carbon catalyst obtained at the optimized temperature 1000 degrees C exhibits almost the same onset (0.97 V vs RHE) and half-wave potential (0.84 V vs RHE) and better durability and higher crossover resistance in alkaline medium compared to commercial 20% Pt/C, which is attributed to the good dispersion of fluorine and nitrogen atoms in the carbon matrix, high specific surface area, and the synergistic effects of fluorine and nitrogen on the polarization of adjacent carbon atoms. This work provides a new strategy for in situ synthesis of N,F-codoped porous carbon as highly efficient metal-free electrocatalyst for ORR in fuel cells. PMID- 28892347 TI - Two Cooperative Glycosyltransferases Are Responsible for the Sugar Diversity of Saquayamycins Isolated from Streptomyces sp. KY 40-1. AB - Glycosyltransferases are key enzymes involved in the biosynthesis of valuable natural products providing an excellent drug-tailoring tool. Herein, we report the identification of two cooperative glycosyltransferases from the sqn gene cluster directing the biosynthesis of saquayamycins in Streptomyces sp. KY40-1: SqnG1 and SqnG2. Gene inactivation of sqnG1 leads to 50-fold decrease in saquayamycin production, while inactivation of sqnG2 leads to complete production loss, suggesting that SqnG2 acts as dual O- and C-glycosyltransferase. Gene inactivation of a third putative glycosyltransferase-encoding gene, sqnG3, does not affect saquayamycin production in a major way, suggesting that SqnG3 has no or a supportive role in glycosylation. The data indicate that SqnG1 and SqnG2 are solely and possibly cooperatively responsible for the sugar diversity observed in saquayamycins 1-7. This is the first evidence of a glycosyltransferase system showing codependence to achieve dual O- and C-glycosyltransferase activity, utilizing NDP-activated d-olivose, l-rhodinose, as well as an unusual amino sugar, presumably 3,6-dideoxy-l-idosamine. PMID- 28892349 TI - Proton-Conducting La-Doped Ceria-Based Internal Reforming Layer for Direct Methane Solid Oxide Fuel Cells. AB - Performance degradation caused by carbon deposition substantially restricts the development of direct methane solid oxide fuel cells (SOFCs). Here, an internal reforming layer composed of Ni supported on proton conducting La-doped ceria, such as La2Ce2O7 (LDC) and La1.95Sm0.05Ce2O7 (LSDC) is applied over conventional Ni-Ce0.8Sm0.2O2-x (SDC) anodes for direct methane SOFCs. The proton conducting layer can adsorb water for internal reforming thus significantly improving the performance of the direct methane SOFCs. In situ Raman and FTIR results confirm the water adsorption capacity of LDC and LSDC. They also exhibit excellent phase stability in wet CO2 at 650 degrees C for 10 h, which ensures that the additional catalyst layer maintains structure stability during the internal reforming. In wet methane at 650 degrees C, the peak power density of the conventional cell is only 580 +/- 20 mW cm-2, and increases to 699 +/- 20 and 639 +/- 20 mW cm-2 with the addition of Ni-LDC and -LSDC layers, respectively. For the stability test in wet methane at 650 degrees C and 0.2 A cm-2, the voltage of the conventional cell starts to drop dramatically in 10 h, while the Ni-LDC and -LSDC catalyst layers operate stably in 26 h under the identical conditions. These catalyst layers even show comparable stability in dry and wet methane in 26 h, but for longer operation, the wet methane is still preferred for maintaining the stability of the cell. PMID- 28892350 TI - Side-Chain Effects on Energy-Level Modulation and Device Performance of Organic Semiconductor Acceptors in Organic Solar Cells. AB - Two new non-fullerene acceptors, IDTC and IDTO, were designed and synthesized for the application in organic solar cells (OSCs). Compared with IDTC, the introduction of electron-donating alkoxy groups of IDTO leads to a higher LUMO level with a slightly blue-shifted absorption. Using the polymer PBDB-T as donor and the two small molecules as acceptors in the conventional device structure, the IDTC-based OSC exhibits a power conversion efficiency (PCE) of 9.35% with an open-circuit voltage (VOC) of 0.917 V, a short-circuit current density (JSC) of 16.56 mA cm-2, and a fill factor (FF) of 61.61%. For the OSC based on IDTO, a higher PCE of 10.02% with a VOC of 0.943 V, a JSC of 16.25 mA cm-2, and an FF of 65.41% are obtained. The more balanced MUe/MUh, evident aggregation, and phase separation contribute to the higher FF for the device based on IDTO. The increased JSC for the device based on PBDB-T:IDTC can be attributed to the red shifted and stronger absorption of the PBDB-T:IDTC blend film. These results indicate fine-tuning the electronic energy and absorption of non-fullerene acceptors is feasible to improve the performance of OSCs. PMID- 28892351 TI - Transparent Conducting Graphene Hybrid Films To Improve Electromagnetic Interference (EMI) Shielding Performance of Graphene. AB - Conducting graphene-based hybrids have attracted considerable attention in recent years for their scientific and technological significance in many applications. In this work, conductive graphene hybrid films, consisting of a metallic network fully encapsulated between monolayer graphene and quartz-glass substrate, were fabricated and characterized for their electromagnetic interference shielding capabilities. Experimental results show that by integration with a metallic network the sheet resistance of graphene was significantly suppressed from 813.27 to 5.53 Omega/sq with an optical transmittance at 91%. Consequently, the microwave shielding effectiveness (SE) exceeded 23.60 dB at the Ku-band and 13.48 dB at the Ka-band. The maximum SE value was 28.91 dB at 12 GHz. Compared with the SE of pristine monolayer graphene (3.46 dB), the SE of graphene hybrid film was enhanced by 25.45 dB (99.7% energy attenuation). At 94% optical transmittance, the sheet resistance was 20.67 Omega/sq and the maximum SE value was 20.86 dB at 12 GHz. Our results show that hybrid graphene films incorporate both high conductivity and superior electromagnetic shielding comparable to existing ITO shielding modalities. The combination of high conductivity and shielding along with the materials' earth-abundant nature, and facile large-scale fabrication, make these graphene hybrid films highly attractive for transparent EMI shielding. PMID- 28892352 TI - High-Efficiency InGaN/GaN Quantum Well-Based Vertical Light-Emitting Diodes Fabricated on beta-Ga2O3 Substrate. AB - We demonstrate a state-of-the-art high-efficiency GaN-based vertical light emitting diode (VLED) grown on a transparent and conductive (-201)-oriented (beta Ga2O3) substrate, obtained using a straightforward growth process that does not require a high-cost lift-off technique or complex fabrication process. The high resolution scanning transmission electron microscopy (STEM) images confirm that we produced high quality upper layers, including a multiquantum well (MQW) grown on the masked beta-Ga2O3 substrate. STEM imaging also shows a well-defined MQW without InN diffusion into the barrier. Electroluminescence (EL) measurements at room temperature indicate that we achieved a very high internal quantum efficiency (IQE) of 78%; at lower temperatures, IQE reaches ~86%. The photoluminescence (PL) and time-resolved PL analysis indicate that, at a high carrier injection density, the emission is dominated by radiative recombination with a negligible Auger effect; no quantum-confined Stark effect is observed. At low temperatures, no efficiency droop is observed at a high carrier injection density, indicating the superior VLED structure obtained without lift-off processing, which is cost-effective for large-scale devices. PMID- 28892353 TI - The Next Wave of Influenza Drugs. AB - Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with great success. There are now several candidates in late stage development which include small molecules targeting the three subunits of the viral polymerase complex and monoclonal antibodies targeting the hemagglutinin, as well as host-directed therapies. The availability of drugs with diverse mechanisms now opens the door to exploring combination therapies for influenza, and the range of administration routes presents more opportunities for treating hospitalized patients. PMID- 28892354 TI - Hydrophilic and Compressible Aerogel: A Novel Draw Agent in Forward Osmosis. AB - Forward osmosis (FO) technology is an efficient route to obtain purity water for drinking from wastewater or seawater. However, there are some challenges in draw solution to limit its application. We first introduce a novel sodium alginate graphene oxide (SA-GO) aerogel as draw agent for highly efficient FO process. The GO nanosheets covalently cross-linked to SA matrix to form a three-dimensional and highly porous aerogel to provide excellent water flux and operation stability, together with the property of compressibility served by SA-GO aerogel resulting in easy water production and regeneration process. When deionized water was used as the feed solution, the SA-GO aerogel exhibited a higher water flux (15.25 +/- 0.65 L m-2 h-1, abbreviated as LMH) than that of 1 mol L-1 NaCl (1 M), and there was no nonreverse osmosis phenomenon. The water fluxes were stabilized in the range of 5-6.5 LMH during recycle process of absorbing and releasing water as high as 100 times. It also had a great desalination capacity (water flux was 7.49 +/- 0.61 LMH) with the seawater (Huanghai coast) as the feed solution. Moreover, the water production and regeneration process of the SA-GO aerogel can be rapidly and cost-effectively accomplished with low-strength mechanical compression (merely 1 kPa). The results present that the SA-GO aerogels as a promising, innovative draw agent can make the FO process simpler, more efficient, and lower energy consumption. It can be a potential material for hydration bags to fast and repeatable product fresh water from saline water or wastewater. PMID- 28892355 TI - Photolabile Hydrogels Responsive to Broad Spectrum Visible Light for Selective Cell Release. AB - We introduce an efficient method for the preparation of photolabile polymer linkers to be used in the fabrication of bioorthogonal and photodegradable hydrogels. The versatility of this synthesis strategy allows for incorporation of a series of chromophores responsive to addressable wavelengths of UV and broad spectrum visible light. Consequently, selective release of different cell types from composite hydrogels by user-defined timing can be achieved by irradiating the materials with different wavelengths of light. PMID- 28892356 TI - Electrochemical Scanning Tunneling Microscopic Study of the Potential Dependence of Germanene Growth on Au(111) at pH 9.0. AB - Germanene is a 2D material whose structure and properties are of great interest for integration with Si technology. Preparation of germanene experimentally remains a challenge because, unlike graphene, bulk germanene does not exist. Thus, germanene cannot be directly exfoliated and is mostly grown in ultrahigh vacuum. The present report uses electrodeposition in an aqueous HGeO3- solution at pH 9. Germanene deposition has been limited to 2-3 monolayers, thus greatly restricting many applicable characterization methods. The in situ technique of electrochemical scanning tunneling microscopy was used to follow Ge deposition on Au(111) as a function of potential. Previous work by this group at pH 4.5 suggested germanene growth, but no buffer was used, resulting in change in surface pH. The addition of borate buffer to create pH 9.0 solution has reduced hydrogen formation and stabilized the surface pH, allowing systematic characterization of germanene growth versus potential. Initial germanene nucleated at defects in the Au(111) herringbone (HB) reconstruction. Subsequent growth proceeded down the face-centered cubic troughs, slowly relaxing the HB. The resulting honeycomb (HC) structure displayed an average lattice constant of 0.41 +/- 0.06 nm. Continued growth resulted in the addition of a second layer on top, formed initially by nucleating around small islands and subsequent lateral 2D growth. Near atomic resolution of the germanene layers displayed small coherent domains, 2-3 nm, of the HC structure composed of six-membered rings. Domain walls were based on defective, five- and seven-membered rings, which resulted in small rotations between adjacent HC domains. PMID- 28892358 TI - Design and Fabrication of Highly Reducible PtCo Particles Supported on Graphene Coated ZnO. AB - Cobalt particles dispersed on an oxide support form the basis of many important heterogeneous catalysts. Strong interactions between cobalt and the support may lead to irreducible cobalt oxide formation, which is detrimental for the catalytic performance. Therefore, several strategies have been proposed to enhance cobalt reducibility, such as alloying with Pt or utilization of nonoxide supports. In this work, we fabricate bimetallic PtCo supported on graphene-coated ZnO with enhanced cobalt reducibility. By employing a model/planar catalyst formulation, we show that the surface reduction of cobalt oxide is substantially enhanced by the presence of the graphene support as compared to bare ZnO. Stimulated by these findings, we synthesized a realistic powder catalyst consisting of PtCo particles grafted on graphene-coated ZnO support. We found that the addition of graphene coating enhances the surface reducibility of cobalt, fully supporting the results obtained on the model system. Our study demonstrates that realistic catalysts with designed properties can be developed on the basis of insights gained from model catalytic formulation. PMID- 28892359 TI - Microporous Nanocomposite Enabled Microfluidic Biochip for Cardiac Biomarker Detection. AB - This paper demonstrates an ultrasensitive microfluidic biochip nanoengineered with microporous manganese-reduced graphene oxide nanocomposite for detection of cardiac biomarker, namely human cardiac troponin I. In this device, the troponin sensitive microfluidic electrode consisted of a thin layer of manganese-reduced graphene oxide (Mn3O4-RGO) nanocomposite material. This nanocomposite thin layer was formed on surface of a patterned indium tin oxide substrate after modification with 3-aminopropyletriethoxysilane and was assembled with a polydimethylsiloxane-based microfluidic system. The nanoengineered microelectrode was functionalized with antibodies specific to cardiac troponin I. The uniformly distributed flower-shaped nanostructured manganese oxide (nMn3O4) onto RGO nanosheets offered large surface area for enhanced loading of antibody molecules and improved electrochemical reaction at the sensor surface. This microfluidic device showed an excellent sensitivity of log [87.58] kOmega/(ng mL-1)/cm2 for quantification of human cardiac troponin I (cTnI) molecules in a wide detection range of 0.008-20 ng/mL. This device was found to have high stability, high reproducibility, and minimal interference with other biomarkers cardiac troponin C and T, myoglobin, and B-type natriuretic peptide. These advantageous features of the Mn3O4-RGO nanocomposite, in conjunction with microfluidic integration, enabled a promising microfluidic biochip platform for point-of-care detection of cardiac troponin. PMID- 28892357 TI - Library Design-Facilitated High-Throughput Sequencing of Synthetic Peptide Libraries. AB - A methodology to achieve high-throughput de novo sequencing of synthetic peptide mixtures is reported. The approach leverages shotgun nanoliquid chromatography coupled with tandem mass spectrometry-based de novo sequencing of library mixtures (up to 2000 peptides) as well as automated data analysis protocols to filter away incorrect assignments, noise, and synthetic side-products. For increasing the confidence in the sequencing results, mass spectrometry-friendly library designs were developed that enabled unambiguous decoding of up to 600 peptide sequences per hour while maintaining greater than 85% sequence identification rates in most cases. The reliability of the reported decoding strategy was additionally confirmed by matching fragmentation spectra for select authentic peptides identified from library sequencing samples. The methods reported here are directly applicable to screening techniques that yield mixtures of active compounds, including particle sorting of one-bead one-compound libraries and affinity enrichment of synthetic library mixtures performed in solution. PMID- 28892360 TI - In Vivo Imaging-Guided Photothermal/Photoacoustic Synergistic Therapy with Bioorthogonal Metabolic Glycoengineering-Activated Tumor Targeting Nanoparticles. AB - Developing multifunctional phototheranostics with nanoplatforms offers promising potential for effective eradication of malignant solid tumors. In this study, we develop a multifunctional phototheranostic by combining photothermal therapy (PTT) and photoacoustic therapy (PAT) based on a tumor-targeting nanoagent (DBCO ZnPc-LP). The nanoagent DBCO-ZnPc-LP was facilely prepared by self-assembling of a single lipophilic near-infrared (NIR) dye zinc(II)-phthalocyanine (ZnPc) with a lipid-poly(ethylene glycol) (LP) and following modified further with dibenzyl cyclootyne (DBCO) for introducing the two-step chemical tumor-targeting strategy based on metabolic glycoengineering and click chemistry. The as-prepared DBCO ZnPc-LP could not only convert NIR light into heat for effective thermal ablation but also induce a thermal-enhanced ultrasound shockwave boost to trigger substantially localized mechanical damage, achieving synergistic antitumor effect both in vitro and in vivo. Moreover, DBCO-ZnPc-LP can be efficiently delivered into tumor cells and solid tumors after being injected intravenously via the two step tumor-targeting strategy. By integrating the targeting strategy, photoacoustic imaging, and the synergistic interaction between PTT and PAT, a solid tumor could be accurately positioned and thoroughly eradicated in vivo. Therefore, this multifunctional phototheranostic is believed to play an important role in future oncotherapy by the enhanced synergistic effect of PTT and PAT under the guidance of photoacoustic imaging. PMID- 28892362 TI - Direct, Precise Measurements of Isotopologue Abundance Ratios in CO2 Using Molecular Absorption Spectroscopy: Application to Delta17O. AB - We present an ultrasensitive absorption spectrometer based on a 30 Hz/s stability, sub-kHz line width laser source coupled to a high-stability cavity ring-down-spectroscopy setup. It provides direct and precise measurements of the isotopic ratios delta17O and delta18O in CO2. We demonstrate the first optical absorption measurements of 17O anomalies in CO2 with a precision better than 10 ppm, matching the requirements for paleo-environmental applications. This illustrates how optical absorption methods have become a competitive alternative to state-of-the-art isotopic ratio mass spectrometry techniques. PMID- 28892361 TI - Immunopurification of Acetylcholinesterase from Red Blood Cells for Detection of Nerve Agent Exposure. AB - Nerve agents and organophosphorus pesticides make a covalent bond with the active site serine of acetylcholinesterase (AChE), resulting in inhibition of AChE activity and toxic symptoms. AChE in red blood cells (RBCs) serves as a surrogate for AChE in the nervous system. Mass spectrometry analysis of adducts on RBC AChE could provide evidence of exposure. Our goal was to develop a method of immunopurifying human RBC AChE in quantities adequate for detecting exposure by mass spectrometry. For this purpose, we immobilized 3 commercially available anti human acetylcholinesterase monoclonal antibodies (AE-1, AE-2, and HR2) plus 3 new monoclonal antibodies. The monoclonal antibodies were characterized for binding affinity, epitope mapping by pairing analysis, and nucleotide and amino acid sequences. AChE was solubilized from frozen RBCs with 1% (v/v) Triton X-100. A 16 mL sample containing 5.8 MUg of RBC AChE was treated with a quantity of soman model compound that inhibited 50% of the AChE activity. Native and soman inhibited RBC AChE samples were immunopurified on antibody-Sepharose beads. The immunopurified RBC AChE was digested with pepsin and analyzed by liquid chromatography tandem mass spectrometry on a 6600 Triple-TOF mass spectrometer. The aged soman-modified PheGlyGluSerAlaGlyAlaAlaSer (FGESAGAAS) peptide was detected using a targeted analysis method. It was concluded that all 6 monoclonal antibodies could be used to immunopurify RBC AChE and that exposure to nerve agents could be detected as adducts on the active site serine of RBC AChE. PMID- 28892363 TI - Exploiting a "Beast" in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy. AB - The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented. PMID- 28892364 TI - Bulky Surface Ligands Promote Surface Reactivities of [Ag141X12(S-Adm)40]3+ (X = Cl, Br, I) Nanoclusters: Models for Multiple-Twinned Nanoparticles. AB - Surface ligands play important roles in controlling the size and shape of metal nanoparticles and their surface properties. In this work, we demonstrate that the use of bulky thiolate ligands, along with halides, as the surface capping agent promotes the formation of plasmonic multiple-twinned Ag nanoparticles with high surface reactivities. The title nanocluster [Ag141X12(S-Adm)40]3+ (where X = Cl, Br, I; S-Adm = 1-adamantanethiolate) has a multiple-shell structure with an Ag71 core protected by a shell of Ag70X12(S-Adm)40. The Ag71 core can be considered as 20 frequency-two Ag10 tetrahedra fused together with a dislocation that resembles multiple-twinning in nanoparticles. The nanocluster has a strong plasmonic absorption band at 460 nm. Because of the bulkiness of S-Adm, the nanocluster has a low surface thiolate coverage and thus unusually high surface reactivities toward exchange reactions with different ligands, including halides, phenylacetylene and thiols. The cluster can be made water-soluble by metathesis with water-soluble thiols, thereby creating new functionalities for potential bioapplications. PMID- 28892365 TI - Recent Developments in Antimicrobial-Peptide-Conjugated Gold Nanoparticles. AB - The escalation of multidrug-resistant pathogens has created a dire need to develop novel ways of addressing this global therapeutic challenge. Because of their antimicrobial activities, the combination of antimicrobial peptides (AMPs) and nanoparticles is a promising tool with which to kill drug-resistant pathogens. In recent years, several studies using AMP-nanoparticle conjugates, especially metallic nanoparticles, as potential antimicrobial agents against drug resistant pathogens have been published. Among these, antimicrobial-peptide conjugated gold nanoparticles (AMP-AuNPs) are particularly attractive because of the nontoxic nature of gold and the possibility of fine-tuning the AMP-NP conjugation chemistry. The following review discusses recent developments in the synthesis and antimicrobial activity studies of AMP-AuNPs. The classification of AMPs, their mechanisms of action, methods used for functionalizing AuNPs with AMPs, and the antimicrobial activities of the conjugates are discussed. PMID- 28892366 TI - Crystal Structure, Stability, and Physical Properties of Metastable Electron-Poor Narrow-Gap AlGe Semiconductor. AB - We report for the first time the full crystal structure, the electronic structure, the lattice dynamics, and the elastic constants of metastable monoclinic AlGe. In addition to ultrarapid cooling techniques such as melt spinning, we show the possibility of obtaining monoclinic AlGe by water-quenching in a quartz tube. Monoclinic AlGe and rhombohedral Al6Ge5 are competing phases with similar stability since they both begin to decompose above 230 degrees C. The crystal structure and electronic bonding of monoclinic AlGe are similar to those of ZnSb and comply with its 3.5 valence electrons per atom: besides classical two electron-two center Al-Ge and Ge-Ge covalent bonds, Al2Ge2 parallelogram rings are formed by uncommon multicenter bonds. Monoclinic AlGe could be used in various applications since it is found theoretically to be an electron-poor semiconductor with a narrow indirect energy bandgap of about 0.5 eV. The lattice dynamics calculations show the presence of low energy optical phonons, which should lead to a low thermal conductivity. PMID- 28892367 TI - Real-Time Food Authentication Using a Miniature Mass Spectrometer. AB - Food adulteration is a threat to public health and the economy. In order to determine food adulteration efficiently, rapid and easy-to-use on-site analytical methods are needed. In this study, a miniaturized mass spectrometer in combination with three ambient ionization methods was used for food authentication. The chemical fingerprints of three milk types, five fish species, and two coffee types were measured using electrospray ionization, desorption electrospray ionization, and low temperature plasma ionization. Minimum sample preparation was needed for the analysis of liquid and solid food samples. Mass spectrometric data was processed using the laboratory-built software MS food classifier, which allows for the definition of specific food profiles from reference data sets using multivariate statistical methods and the subsequent classification of unknown data. Applicability of the obtained mass spectrometric fingerprints for food authentication was evaluated using different data processing methods, leave-10%-out cross-validation, and real-time classification of new data. Classification accuracy of 100% was achieved for the differentiation of milk types and fish species, and a classification accuracy of 96.4% was achieved for coffee types in cross-validation experiments. Measurement of two milk mixtures yielded correct classification of >94%. For real-time classification, the accuracies were comparable. Functionality of the software program and its performance is described. Processing time for a reference data set and a newly acquired spectrum was found to be 12 s and 2 s, respectively. These proof-of-principle experiments show that the combination of a miniaturized mass spectrometer, ambient ionization, and statistical analysis is suitable for on-site real-time food authentication. PMID- 28892369 TI - Unveiling Adsorption Mechanisms of Organic Pollutants onto Carbon Nanomaterials by Density Functional Theory Computations and Linear Free Energy Relationship Modeling. AB - Predicting adsorption of organic pollutants onto carbon nanomaterials (CNMs) and understanding the adsorption mechanisms are of great importance to assess the environmental behavior and ecological risks of organic pollutants and CNMs. By means of density functional theory (DFT) computations, we investigated the adsorption of 38 organic molecules (aliphatic hydrocarbons, benzene and its derivatives, and polycyclic aromatic hydrocarbons) onto pristine graphene in both gaseous and aqueous phases. Polyparameter linear free energy relationships (pp LFERs) were developed, which can be employed to predict adsorption energies of aliphatic and aromatic hydrocarbons on graphene. Based on the pp-LFERs, contributions of different interactions to the overall adsorption were estimated. As suggested by the pp-LFERs, the gaseous adsorption energies are mainly governed by dispersion and electrostatic interactions, while the aqueous adsorption energies are mainly determined by dispersion and hydrophobic interactions. It was also revealed that curvature of single-walled carbon nanotubes (SWNTs) exhibits more significant effects than the electronic properties (metallic or semiconducting) on gaseous adsorption energies, and graphene has stronger adsorption abilities than SWNTs. The developed models may pave a promising way for predicting adsorption of environmental chemicals onto CNMs with in silico techniques. PMID- 28892368 TI - Structure-Based Design and Synthesis of Apramycin-Paromomycin Analogues: Importance of the Configuration at the 6'-Position and Differences between the 6' Amino and Hydroxy Series. AB - The preparation of a series of four analogues of the aminoglycoside antibiotics neomycin and paromomycin is described in which ring I, involved in critical binding interactions with the ribosomal target, is replaced by an apramycin-like dioxabicyclo[4.4.0]octane system. The effect of this modification is to lock the hydroxymethyl side chain of the neomycin or paromomycin ring I, as part of the dioxabicyclooctane ring, into either the gauche-gauche or the gauche-trans conformation (respectively, axial or equatorial to the bicyclic system). The antiribosomal activity of these compounds is investigated with cell-free translation assays using both bacterial ribosomes and recombinant hybrid ribosomes carrying eukaryotic decoding A site cassettes. Compounds substituted with an equatorial hydroxyl or amino group in the newly formed ring are considerably more active than their axial diastereomers, lending strong support to crystallographically derived models of aminoglycoside-ribosome interactions. One such bicyclic compound carrying an equatorial hydroxyl group has activity equal to that of the parent yet displays better ribosomal selectivity, predictive of an enhanced therapeutic index. A paromomycin analog lacking the hydroxymethyl ring I side chain is considerably less active than the parent. Antibacterial activity against model Gram negative and Gram positive bacteria is reported for selected compounds, as is activity against ESKAPE pathogens and recombinant bacteria carrying specific resistance determinants. Analogues with a bicyclic ring I carrying equatorial amino or hydroxyl groups mimicking the bound side chains of neomycin and paromomycin, respectively, show excellent activity and, by virtue of their novel structure, retain this activity in strains that are insensitive to the parent compounds. PMID- 28892370 TI - Mass Spectrometry-Based Chemical Cartography of a Cardiac Parasitic Infection. AB - Trypanosoma cruzi parasites are the causative agents of Chagas disease, a leading infectious form of heart failure whose pathogenesis is still not fully characterized. In this work, we applied untargeted liquid chromatography-tandem mass spectrometry to heart sections from T. cruzi-infected and uninfected mice. We combined molecular networking and three-dimensional modeling to generate chemical cartographical heart models. This approach revealed for the first time preferential parasite localization to the base of the heart and regiospecific distributions of nucleoside derivatives and eicosanoids, which we correlated to tissue-damaging immune responses. We further detected novel cardiac chemical signatures related to the severity and ultimate outcome of the infection. These signatures included differential representation of higher- vs lower-molecular weight carnitine and phosphatidylcholine family members in specific cardiac regions of mice infected with lethal or nonlethal T. cruzi strains and doses. Overall, this work provides new insights into Chagas disease pathogenesis and presents an analytical chemistry approach that can be broadly applied to the study of host-microbe interactions. PMID- 28892371 TI - Synthetic Graphene Oxide Leaf for Solar Desalination with Zero Liquid Discharge. AB - Water vapor generation through sunlight harvesting and heat localization by carbon-based porous thin film materials holds great promise for sustainable, energy-efficient desalination and water treatment. However, the applicability of such materials in a high-salinity environment emphasizing zero-liquid-discharge brine disposal has not been studied. This paper reports the characterization and evaporation performance of a nature-inspired synthetic leaf made of graphene oxide (GO) thin film material, which exhibited broadband light absorption and excellent stability in high-salinity water. Under 0.82-sun illumination (825 W/m2), a GO leaf floating on water generated steam at a rate of 1.1 L per m2 per hour (LMH) with a light-to-vapor energy conversion efficiency of 54%, while a GO leaf lifted above water in a tree-like configuration generated steam at a rate of 2.0 LMH with an energy efficiency of 78%. The evaporation rate increased with increasing light intensity and decreased with increasing salinity. During a long term evaporation experiment with a 15 wt % NaCl solution, the GO leaf demonstrated stable performance despite gradual and eventually severe accumulation of salt crystals on the leaf surface. Furthermore, the GO leaf can be easily restored to its pristine condition by simply scraping off salt crystals from its surface and rinsing with water. Therefore, the robust high performance and relatively low fabrication cost of the synthetic GO leaf could potentially unlock a new generation of desalination technology that can be entirely solar powered and achieve zero liquid discharge. PMID- 28892372 TI - Transcriptomic Analysis of Thalidomide Challenged Chick Embryo Suggests Possible Link between Impaired Vasculogenesis and Defective Organogenesis. AB - Since the conception of thalidomide as a teratogen, approximately 30 hypotheses have been put forward to explain the developmental toxicity of the molecule. However, no systems biology approach has been taken to understand the phenomena yet. The proposed work was aimed to explore the mechanism of thalidomide toxicity in developing chick embryo in the context of transcriptomics by using genome wide RNA sequencing data. In this study, we challenged the developing embryo at the stage of blood island formations (HH8), which is the most vulnerable stage for thalidomide-induced deformities. We observed that thalidomide affected the early vasculogenesis through interfering with the blood island formation extending the effect to organogenesis. The transcriptome analyses of the embryos collected on sixth day of incubation showed that liver, eye, and blood tissue associated genes were down regulated due to thalidomide treatment. The conserved gene coexpression module also indicated that the genes involved in lens development were heavily affected. Further, the Gene Ontology analysis explored that the pathways of eye development, retinol metabolism, and cartilage development were dampened, consistent with the observed deformities of various organs. The study concludes that thalidomide exerts its toxic teratogenic effects through interfering with early extra-embryonic vasculogenesis and ultimately gives an erroneous transcriptomic pattern to organogenesis. PMID- 28892373 TI - Time-Resolved Luminescence Spectroelectrochemistry at Screen-Printed Electrodes: Following the Redox-Dependent Fluorescence of [Ru(bpy)3]2. AB - In this work, a compact instrument for time-resolved luminescence spectroelectrochemistry using low-cost disposable electrodes is reported. This instrument can be coupled with screen-printed electrodes via a specific cell and a reflection probe, which allows one to observe changes occurring at the electrode/solution interface. This approach allowed one to follow the fluorescence variation of electrofluorochromic species such as [Ru(bpy)3]2+ at screen-printed carbon electrodes. A strong correlation between the electrochemical processes and the fluorescence was found during potentiostatic or multipulsed amperometric measurements. A decrease of the fluorescence was observed when the [Ru(bpy)3]2+ was oxidized to [Ru(bpy)3]3+ and part of this fluorescence is recovered when [Ru(bpy)3]3+ was reduced to the initial species. Moreover, a significant increment of the fluorescence was found when the oxygen reduction reaction takes place, which also confirms its quenching effect. Finally, multipulsed amperometric detection was employed in order to obtain more information about the redox-dependent luminescence of [Ru(bpy)3]2+ finding a continuous quenching over time attributed to bleaching chlorine-based species. PMID- 28892374 TI - Phase Segregation in Cs-, Rb- and K-Doped Mixed-Cation (MA)x(FA)1-xPbI3 Hybrid Perovskites from Solid-State NMR. AB - Hybrid (organic-inorganic) multication lead halide perovskites hold promise for a new generation of easily processable solar cells. Best performing compositions to date are multiple-cation solid alloys of formamidinium (FA), methylammonium (MA), cesium, and rubidium lead halides which provide power conversion efficiencies up to around 22%. Here, we elucidate the atomic-level nature of Cs and Rb incorporation into the perovskite lattice of FA-based materials. We use 133Cs, 87Rb, 39K, 13C, and 14N solid-state MAS NMR to probe microscopic composition of Cs-, Rb-, K-, MA-, and FA-containing phases in double-, triple-, and quadruple cation lead halides in bulk and in a thin film. Contrary to previous reports, we have found no proof of Rb or K incorporation into the 3D perovskite lattice in these systems. We also show that the structure of bulk mechanochemical perovskites bears close resemblance to that of thin films, making them a good benchmark for structural studies. These findings provide fundamental understanding of previously reported excellent photovoltaic parameters in these systems and their superior stability. PMID- 28892375 TI - Solvation Properties of the Actinide Ion Th(IV) in DMSO and DMSO:Water Mixtures through Polarizable Molecular Dynamics. AB - We have studied the solvation of Th4+ in water, in dimethyl sulfoxide (DMSO), and in their equimolar mixture by using molecular dynamics based on an Amoeba-derived polarizable force field. We have performed an extended structural analysis in order to provide a complete picture of the chemical-physical features of the interaction of Th4+ with the two solvents in their pure and mixed states. Through our simulations we found that, very likely, the first solvation shell in DMSO is not unlike the one found in pure water and contains 9 solvent molecules. The residence time of first shell of DMSO molecules is however much longer than the residence time of water. For the 1:1 mixture we present computational evidence that both water and DMSO participate in the solvation of Th4+ with a slight preference for the latter. PMID- 28892376 TI - Modifications to EPA Method 3060A to Improve Extraction of Cr(VI) from Chromium Ore Processing Residue-Contaminated Soils. AB - It has been shown that EPA Method 3060A does not adequately extract Cr(VI) from chromium ore processing residue (COPR). We modified various parameters of EPA 3060A toward understanding the transformation of COPR minerals in the alkaline extraction and improving extraction of Cr(VI) from NIST SRM 2701, a standard COPR contaminated soil. Aluminum and Si were the major elements dissolved from NIST 2701, and their concentrations in solution were correlated with Cr(VI). The extraction fluid leached additional Al and Si from the method-prescribed borosilicate glass vessels which appeared to suppress the release of Cr(VI). Use of polytetrafluoroethylene vessels and intensive grinding of NIST 2701 increased the amount of Cr(VI) extracted. These modifications, combined with an increased extraction fluid to sample ratio of >=900 mL g-1 and 48-h extraction time resulted in a maximum release of 1274 +/- 7 mg kg-1 Cr(VI). This is greater than the NIST 2701 certified value of 551 +/- 35 mg kg-1 but less than 3050 mg kg-1 Cr(VI) previously estimated by X-ray absorption near edge structure spectroscopy. Some of the increased Cr(VI) may have resulted from oxidation of Cr(III) released from brownmillerite which rapidly transformed during the extractions. Layered double hydroxides remained stable during extractions and represent a potential residence for unextracted Cr(VI). PMID- 28892377 TI - Bis(stibahousene). AB - Strained hydrocarbons constitute one of the most prominent classes of organic compounds. Among them, bicyclo[2.1.0]pentene ("housene") derivatives represent a highly challenging and very attractive class. Although organic housenes have been known for more than five decades, there are still very few of them containing heavier main group elements. In this paper, we report on the two housene-type structures, novel monomeric stibahousene and dimeric bis(stibahousene). The bonding natures of both compounds were approached from both experimental and computational directions to reveal their peculiar structural features. PMID- 28892378 TI - Synthesis of Defect Perovskites (He2-x?x)(CaZr)F6 by Inserting Helium into the Negative Thermal Expansion Material CaZrF6. AB - Defect perovskites (He2-x?x)(CaZr)F6 can be prepared by inserting helium into CaZrF6 at high pressure. They can be recovered to ambient pressure at low temperature. There are no prior examples of perovskites with noble gases on the A sites. The insertion of helium gas into CaZrF6 both elastically stiffens the material and reduces the magnitude of its negative thermal expansion. It also suppresses the onset of structural disorder, which is seen on compression in other media. Measurements of the gas released on warming to room temperature and Rietveld analyses of neutron diffraction data at low temperature indicate that exposure to helium gas at 500 MPa leads to a stoichiometry close to (He1?1)(CaZr)F6. Helium has a much higher solubility in CaZrF6 than silica glass or crystobalite. An analogue with composition (H2)2(CaZr)F6 would have a volumetric hydrogen storage capacity greater than current US DOE targets. We anticipate that other hybrid perovskites with small neutral molecules on the A site can also be prepared and that they will display a rich structural chemistry. PMID- 28892379 TI - Toroidal Condensates by Semiflexible Polymer Chains: Insights into Nucleation, Growth and Packing Defects. AB - Deciphering the principles of DNA condensation is important to understand problems such as genome packing and DNA compaction for delivery in gene therapy. DNA molecules condense into toroids and spindles upon the addition of multivalent ions. Nucleation of a loop in the semiflexible DNA chain is critical for both the toroid and spindle formation. To understand the structural differences in the nucleated loop, which cause bifurcation in the condensation pathways leading to toroid or spindle formation, we performed molecular dynamics simulations using a coarse-grained bead-spring polymer model. We find that the formation of a toroid or a spindle is correlated with the orientation of the chain segments close to the loop closure in the nucleated loop. Simulations show that toroids grow in size when spindles in solution interact with a pre-existing toroid and merge into it by spooling around the circumference of the toroid, forming multimolecular toroidal condensates. The merging of spindles with toroids is facile, indicating that this should be the dominant pathway through which the toroids grow in size. The Steinhardt bond order parameter analysis of the toroid cross section shows that the chains pack in a hexagonal fashion. In agreement with the experiments there are regions in the toroid with good hexagonal packing and also with considerable disorder. The disorder in packing is due to the defects, which are propagated during the growth of toroids. In addition to the well-known crossover defect, we have identified three other forms of defects, which perturb hexagonal packing. The new defects identified in the simulations are amenable to experimental verification. PMID- 28892381 TI - Low-Temperature Dynamics of Chain-Labeled Lipids in Ester- and Ether-Linked Phosphatidylcholine Membranes. AB - Continuous wave electron paramagnetic resonance spectroscopy and two-pulse echo detected spectra of chain-labeled lipids are used to study the dynamics of frozen lipid membranes over the temperature range 77-260 K. Bilayers of ester-linked dihexadecanoylphosphatidylcholine (DPPC) with noninterdigitated chains and ether linked dihexadecyl phosphatidylcholine (DHPC) with interdigitated chains are considered. Rapid stochastic librations of small angular amplitude are found in both lipid matrices. In noninterdigitated DPPC bilayers, the mean-square angular amplitude, [Formula: see text], of the motion increases with temperature and it is larger close to the chain termini than close to the polar/apolar interface. In contrast, in interdigitated DHPC lamellae, [Formula: see text] is small and temperature and label-position independent at low temperature and increases steeply at high temperature. The rotational correlation time, tauc, of librations lies in the subnanosecond range for DPPC and in the nanosecond range for DHPC. In all membrane samples, the temperature dependence of [Formula: see text] resembles that of the mean-square atomic displacement revealed by neutron scattering and a dynamical transition is detected in the range 210-240 K. The results highlight the librational oscillations and the glass-like behavior in bilayer and interdigitated lipid membranes. PMID- 28892382 TI - Indirect Intersystem Crossing (S1 -> T3/T2 -> T1) Promoted by the Jahn-Teller Effect in Cycloparaphenylenes. AB - Vibronic-coupling effects play a key role for excited-state charge- and energy transfer processes in organic molecular systems. Here, we demonstrate how the Jahn-Teller effect in triplet excited states of highly symmetric cycloparaphenylenes triggers an indirect intersystem crossing deactivation pathway. Strong Jahn-Teller distortion in the doubly degenerate second excited triplet state (T2) brings the molecular system energetically close to the lowest triplet state (T1), thereby opening the possibility for an extremely rapid internal conversion. Quantum dynamics simulations reveal an initial T2 -> T1 population decay within 50 fs. Experimental observation of size-dependent intersystem crossing rates of cycloparaphenylenes is explained based on the proposed S1 -> T3/T2 -> T1 mechanism. PMID- 28892380 TI - GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP). AB - Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100 nMU) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner. PMID- 28892383 TI - O2(b1Sigmag+) Quenching by O2, CO2, H2O, and N2 at Temperatures of 300-800 K. AB - Rate constants for the removal of O2(b1Sigmag+) by collisions with O2, N2, CO2, and H2O have been determined over the temperature range from 297 to 800 K. O2(b1Sigmag+) was excited by pulses from a tunable dye laser, and the deactivation kinetics were followed by observing the temporal behavior of the b1Sigmag+-X3Sigmag- fluorescence. The removal rate constants for CO2, N2, and H2O were not strongly dependent on temperature and could be represented by the expressions kCO2 = (1.18 +/- 0.05) * 10-17 * T1.5 * exp[Formula: see text], kN2 = (8 +/- 0.3) * 10-20 * T1.5 * exp[Formula: see text], and kH2O = (1.27 +/- 0.08) * 10-16 * T1.5 * exp[Formula: see text] cm3 molecule-1 s-1. Rate constants for O2(b1Sigmag+) removal by O2(X), being orders of magnitude lower, demonstrated a sharp increase with temperature, represented by the fitted expression kO2 = (7.4 +/- 0.8) * 10-17 * T0.5 * exp[Formula: see text] cm3 molecule-1 s-1. All of the rate constants measured at room temperature were found to be in good agreement with previously reported values. PMID- 28892384 TI - Kinetics of Trifluoromethane Clathrate Hydrate Formation from CHF3 Gas and Ice Particles. AB - We report the formation kinetics of trifluoromethane clathrate hydrate (CH) from less than 75 MUm diameter ice particles and CHF3 gas. As previously observed for difluoromethane and propane hydrate formation, the initial stages of the reaction exhibit a strong negative correlation of the reaction rate with temperature, consistent with a negative activation energy of formation. The values obtained for trifluoromethane, ca. -6 kJ/mol (H2O), are similar to those for difluoromethane, even though the two molecules have different intermolecular interactions and sizes. The activation energy is lesser per mole of H2O, but greater per mole of guest molecule, than for propane hydrate, which has a different crystal structure. We propose a possible explanation for the negative activation barrier based on the stabilization of metastable structures at low temperature. A pronounced dependence of the formation kinetics on the gas flow rate into the cell is observed. At 253 K and a flow rate of 15 mmol/h, the stage II enclathration of trifluoromethane proceeds so quickly that the overpressure, the difference between the gas cell pressure and the hydrate vapor pressure, is only 0.06 MPa. PMID- 28892385 TI - Infrared-Vacuum Ultraviolet Spectroscopic and Theoretical Study of Neutral Methylamine Dimer. AB - The methylamine dimer, (CH3NH2)2, is a model system to study the CH3 and NH2 spectral patterns in the neutral microsolvated systems relevant to chemical biology, atmospheric chemistry, and catalysis. We report infrared-vacuum ultraviolet spectroscopic measurements to probe the neutral (CH3NH2)2. Quantum chemical calculations and ab initio molecular dynamics simulations were performed to understand the observed spectral features. Experimental and theoretical results indicate the likely coexistence of both cis and trans structures. A salient feature of this work is that the peak widths are not significantly affected by the structural transformation and the fluctuation of hydrogen bond distance, allowing the stretching modes to be clearly resolved. PMID- 28892386 TI - Double-Mutated 5-Enol Pyruvylshikimate-3-phosphate Synthase Protein Expressed in MZHG0JG Corn (Zea mays L.) Has No Impact on Toxicological Safety and Nutritional Composition. AB - MZHG0JG corn will offer growers the flexibility to alternate between herbicides with two different modes of action in their weed-management programs, helping to mitigate and manage the evolution of herbicide resistance in weed populations. The proteins conferring herbicide tolerence in MZHG0JG corn, double-mutated 5 enol pyruvylshikimate-3-phosphate synthase protein (mEPSPS) and phosphinothricin acetyltransferase (PAT), as well as the MZHG0JG corn event, have been assessed by regulatory authorities globally and have been determined to be safe for humans, animals, and the environment. In addition to the safety data available for these proteins, further studies were conducted on MZHG0JG corn to assess levels of mEPSPS as compared to previously registered genetically modified (GM) corn. The results support the conclusion of no impact on toxicological safety or nutritional composition. PMID- 28892387 TI - Functionalized Poly(3,4-ethylenedioxy bithiophene) Films for Tuning Electrochromic and Thermoelectric Properties. AB - Conductive thiophene-based polymers have garnered great attention for use in organic electron materials such as electrochromic and thermoelectric materials. However, they suffer from poor electron transport properties and long-term stability, leading to limited development eventually. Here, we proposed a strategy of functionalized thiophene-based polymers with oligo(ethylene glycol) or alkyl side chains and synthesized a series of poly(3,4-ethylenedioxy bithiophene)s (PEDTs) to tune their electrochromic and thermoelectric properties. An alkyl group bearing electronic ability at the thiophene ring effectively achieved a large increase in the electrical conductivity with nearly invariable Seebeck coefficient, resulting in an enhancement by 1 order of magnitude for the thermoelectric power factor. Moreover, the electrochromic properties of functionalized PEDTs gained an effective improvement in the optical contrast and coloration efficiency as well as stability with multicolor changes between neutral and oxidized states. The functionalized PEDTs can be proposed as an alternative strategy to tune the electrochromic and thermoelectric properties for organic polymer materials. PMID- 28892388 TI - Novel Radiolabeled Vanilloid with Enhanced Specificity for Human Transient Receptor Potential Vanilloid 1 (TRPV1). AB - Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20 fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl [3H])piperidin-1-yl-4-[3H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4 dihydro-2H-benzo[b][1,4]oxazin-8-yl)urea ([3H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility. PMID- 28892389 TI - Formation of Hydroxylamine in Low-Temperature Interstellar Model Ices. AB - We irradiated binary ice mixtures of ammonia (NH3) and oxygen (O2) ices at astrophysically relevant temperatures of 5.5 K with energetic electrons to mimic the energy transfer process that occurs in the track of galactic cosmic rays. By monitoring the newly formed molecules online and in situ utilizing Fourier transform infrared spectroscopy complemented by temperature-programmed desorption studies with single-photon photoionization reflectron time-of-flight mass spectrometry, the synthesis of hydroxylamine (NH2OH), water (H2O), hydrogen peroxide (H2O2), nitrosyl hydride (HNO), and a series of nitrogen oxides (NO, N2O, NO2, N2O2, N2O3) was evident. The synthetic pathway of the newly formed species, along with their rate constants, is discussed exploiting the kinetic fitting of the coupled differential equations representing the decomposition steps in the irradiated ice mixtures. Our studies suggest the hydroxylamine is likely formed through an insertion mechanism of suprathermal oxygen into the nitrogen-hydrogen bond of ammonia at such low temperatures. An isotope-labeled experiment examining the electron-irradiated D3-ammonia-oxygen (ND3-O2) ices was also conducted, which confirmed our findings. This study provides clear, concise evidence of the formation of hydroxylamine by irradiation of interstellar analogue ices and can help explain the question how potential precursors to complex biorelevant molecules may form in the interstellar medium. PMID- 28892390 TI - Virtual Orbital Many-Body Expansions: A Possible Route towards the Full Configuration Interaction Limit. AB - It is demonstrated how full configuration interaction (FCI) results in extended basis sets may be obtained to within sub-kJ/mol accuracy by decomposing the energy in terms of many-body expansions in the virtual orbitals of the molecular system at hand. This extension of the FCI application range lends itself to two unique features of the current approach, namely, that the total energy calculation can be performed entirely within considerably reduced orbital subspaces and may be so by means of embarrassingly parallel programming. Facilitated by a rigorous and methodical screening protocol and further aided by expansion points different from the Hartree-Fock solution, all-electron numerical results are reported for H2O in polarized core-valence basis sets ranging from double-zeta (10 e, 28 o) to quadruple-zeta (10 e, 144 o) quality. PMID- 28892391 TI - Simple Enantioselective Syntheses of (2R,6R)-Hydroxynorketamine and Related Potential Rapid-Onset Antidepressants. AB - A novel strategy for accessing cyclic alpha-amino ketones enantioselectively has opened a simple synthetic route to the antidepressant (2R,6R)-hydroxynorketamine and numerous analogues. Mechanistically guided catalyst selection was essential in an initial olefin epoxidation step. In a second crucial step, the epoxide was subjected to a novel O -> N displacement that occurred with retention of configuration through the use of Al- or Ti-based azides, which promote epoxide activation and internal cis delivery of N3 to carbon. PMID- 28892392 TI - Analysis of the Nucleus-Independent Chemical Shifts of [10]Cyclophenacene: Is It an Aromatic or Antiaromatic Molecule? AB - [10]Cyclophenacene is an important synthetic target that shows a pair of nucleus independent chemical shift (NICS) values for the center of mass and six-membered rings typical of an aromatic species. This is found in contrast with the global paratropic current density induced by a magnetic field parallel to the main symmetry axis. This apparent contradiction has been analyzed by studying the tensor character of the magnetic response. It turns out that the molecule displays two characters, one paratropic (antiaromatic) and another one diatropic (aromatic), depending on the orientation of the inducing magnetic field. The paratropic response, which cannot be recognized from the NICS values, is associated with a well-defined destabilization of the belt closure, as witnessed by homodesmotic reactions. A scalar measure of magnetic aromaticity, the field independent current strength, has been introduced, which allows us to reach the conclusion that [10]cyclophenacene is indeed an aromatic molecule, although it is significantly affected by the paratropic response. PMID- 28892393 TI - Micrometer-Sized Magnesium Whitlockite Crystals in Micropetrosis of Bisphosphonate-Exposed Human Alveolar Bone. AB - Osteocytes are contained within spaces called lacunae and play a central role in bone remodelling. Administered frequently to prevent osteoporotic fractures, antiresorptive agents such as bisphosphonates suppress osteocyte apoptosis and may be localized within osteocyte lacunae. Bisphosphonates also reduce osteoclast viability and thereby hinder the repair of damaged tissue. Osteocyte lacunae contribute to toughening mechanisms. Following osteocyte apoptosis, the lacunar space undergoes mineralization, termed "micropetrosis". Hypermineralized lacunae are believed to increase bone fragility. Using nanoanalytical electron microscopy with complementary spectroscopic and crystallographic experiments, postapoptotic mineralization of osteocyte lacunae in bisphosphonate-exposed human bone was investigated. We report an unprecedented presence of ~80 nm to ~3 MUm wide, distinctly faceted, magnesium whitlockite [Ca18Mg2(HPO4)2(PO4)12] crystals and consequently altered local nanomechanical properties. These findings have broad implications on the role of therapeutic agents in driving biomineralization and shed new insights into a possible relationship between bisphosphonate exposure, availability of intracellular magnesium, and pathological calcification inside lacunae. PMID- 28892394 TI - Probing Elastic and Viscous Properties of Phospholipid Bilayers Using Neutron Spin Echo Spectroscopy. AB - The elastic and viscous properties of self-assembled amphiphilic membranes dictate the intricate hierarchy of their structure and dynamics ranging from the diffusion of individual molecules to the large-scale deformation of the membrane. We previously demonstrated that neutron spin echo spectroscopy measurements of model amphiphilic membranes can access the naturally occurring submicrosecond membrane motions, such as bending and thickness fluctuations. Here we show how the experimentally measured fluctuation parameters can be used to determine the inherent membrane properties and demonstrate how membrane viscosity and compressibility modulus are influenced by lipid composition in a series of simple phosphatidylcholine bilayers with different tail lengths as a function of temperature. This approach highlights the interdependence of the bilayer elastic and viscous properties and the collective membrane dynamics and opens new avenues to investigating the mechanical properties of more complex and biologically inspired systems. PMID- 28892395 TI - Influence of Sulfur on Acid-Mediated Enamide Formation. AB - The acid-mediated condensation of acetamide with butanal dimethylacetal and EtSCH2CH(OMe)2, followed by dehydration, was investigated by electronic structure calculations that supported the prediction that the Z-geometry would be favored in the product. The reaction was investigated experimentally using suitably functionalized cysteine building blocks. Some side reactions and optimization of reaction conditions are reported, en route to identifying a mild, inexpensive Lewis acid that achieves a reasonable yield of (Z)-thioenamide 21 with high stereoselectivity. PMID- 28892396 TI - Crystal Phase Quantum Well Emission with Digital Control. AB - One of the major challenges in the growth of quantum well and quantum dot heterostructures is the realization of atomically sharp interfaces. Nanowires provide a new opportunity to engineer the band structure as they facilitate the controlled switching of the crystal structure between the zinc-blende (ZB) and wurtzite (WZ) phases. Such a crystal phase switching results in the formation of crystal phase quantum wells (CPQWs) and quantum dots (CPQDs). For GaP CPQWs, the inherent electric fields due to the discontinuity of the spontaneous polarization at the WZ/ZB junctions lead to the confinement of both types of charge carriers at the opposite interfaces of the WZ/ZB/WZ structure. This confinement leads to a novel type of transition across a ZB flat plate barrier. Here, we show digital tuning of the visible emission of WZ/ZB/WZ CPQWs in a GaP nanowire by changing the thickness of the ZB barrier. The energy spacing between the sharp emission lines is uniform and is defined by the addition of single ZB monolayers. The controlled growth of identical quantum wells with atomically flat interfaces at predefined positions featuring digitally tunable discrete emission energies may provide a new route to further advance entangled photons in solid state quantum systems. PMID- 28892397 TI - Retraction of "Transition-Metal-Free C-CN/C-H Cross-Coupling: Effect of Cyano Group". PMID- 28892398 TI - Droplet Transport in a Nanochannel Coated by Hydrophobic Semiflexible Polymer Brushes: The Effect of Chain Stiffness. AB - We study the influence of chain stiffness on droplet flow in a nanochannel, coated with semiflexible hydrophobic polymers by means of nonequilibrium molecular dynamics simulations. The studied system is then a moving droplet in the slit channel, coexisting with its vapor and subjected to periodic boundary conditions in the flow direction. The polymer chains, grafted by the terminal bead to the confining walls, are described by a coarse-grained model that accounts for chain connectivity, excluded volume interactions and local chain stiffness. The rheological, frictional and dynamical properties of the brush are explored over a wide range of persistence lengths. We find a rich behavior of polymer conformations and concomitant changes in the friction properties over the wide range of studied polymer stiffnesses. A rapid decrease in the droplet velocity was observed as the rigidity of the chains is increased for polymers whose persistence length is smaller than their contour length. We find a strong relation between the internal dynamics of the brush and the droplet transport properties, which could be used to tailor flow properties by surface functionalization. The monomers of the brush layer, under the droplet, present a collective "treadmill belt" like dynamics which can only be present due the existence of grafted chains. We describe its changes in spatial extension upon variations of polymer stiffness, with bidimensional velocity and density profiles. The deformation of the polymer brushes due to the presence of the droplet is analyzed in detail. Lastly, the droplet-gas interaction is studied by varying the liquid to gas ratio, observing a 16% speed increase for droplets that flow close to each other, compared to a train of droplets that present a large gap between consecutive droplets. PMID- 28892399 TI - Intramolecular Electron Transfer in Frozen Solvents: Charge Transfer and Local Triplet States Population Dynamics Revealed by Dual Phosphorescence. AB - In frozen solvents at 77 K, ultrafast (<=250 fs) photoinduced intramolecular electron transfer (ET) in bichromophoric donor-acceptor ([D-A]) diarylmethane lactones produces a covalently linked radical ion pair, 1[D*+-A*-]. Steady state and time-resolved luminescence measurements reveal that 1[D*+-A*-] decays to charge-separated (3[D*+-A*-]) and donor-centered ([3D*-A]) triplets, which display dual phosphorescence. 3[D*+-A*-] and [3D*-A] are formed in parallel via two intersystem crossing mechanisms: spin orbit charge transfer (SOCT) and hyperfine coupling (HFC), with solvent dependent branching ratio. The solvent drives the D-A alignment during the freezing process to adapt to increasing solvent polarity, producing inhomogeneous ground-state population distribution with solvent-dependent D-A exchange interaction, which plays a key role in partitioning into SOCT and HFC mechanisms. In polar glasses, a third phosphorescence band appears due to dissociative back ET in 3[D*+-A*-] resulting in excited open ring biradical. PMID- 28892400 TI - Poly(vinyl methyl ether/maleic anhydride)-Doped PEG-PLA Nanoparticles for Oral Paclitaxel Delivery To Improve Bioadhesive Efficiency. AB - Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 +/ 4.0%. The nanoparticles were uniform and spherical in shape and exhibited a sustained drug release compared with Taxol. m-NPs also exhibited favorable bioadhesive efficiency at the same time. Coumarin 6 or DiR-loaded nanoparticles with/without PVMMA (C6-m-NPs/DiR-m-NPs or C6-p-NPs/DiR-p-NPs) were used for cellular uptake and intestinal adhesion experiments, respectively. C6-m-NPs were shown to enhance cellular uptake, and caveolae/lipid raft mediated endocytosis was the primary route for the uptake of the nanoparticles. Favorable bioadhesive efficiency led to prolonged retention in the intestine reflected by the fluorescence in isolated intestines ex vivo. In a ligated intestinal loops model, C6-m-NPs showed a clear advantage for transporting NPs across the mucus layer over C6-p-NPs and free C6. The apparent permeability coefficient (Papp) of PTX-m NPs through Caco-2/HT29 monolayers was 1.3- and 1.6-fold higher than PTX-p-NPs and Taxol, respectively, which was consistent with the AUC0-t of different PTX formulations after oral administration in rats. PTX-m-NPs also exhibited a more effective anticancer efficacy, with an IC50 of 0.2 +/- 1.4 MUg/mL for A549 cell lines, further demonstrating the advantage of bioadhesive nanoparticles. The bioadhesive nanoparticles m-NPs demonstrated both mucus permeation and epithelial absorption, and thus, this bioadhesive drug delivery system has the potential to improve the bioavailability of drugs that are insoluble in the gastrointestinal environment. PMID- 28892401 TI - Pulmonary Cryptococcus Presenting as a Solitary Pulmonary Nodule. PMID- 28892402 TI - Metformin: A Review of Characteristics, Properties, Analytical Methods and Impact in the Green Chemistry. AB - Diabetes mellitus (DM) is considered a public health problem. The initial treatment consists of improving the lifestyle and making changes in the diet. When these changes are not enough, the use of medication becomes necessary. The metformin aims to reduce the hepatic production of glucose and is the preferred treatment for type 2. The objective is to survey the characteristics and properties of metformin, as well as hold a discussion on the existing analytical methods to green chemistry and their impacts for both the operator and the environment. For the survey, data searches were conducted by scientific papers in the literature as well as in official compendium. The characteristics and properties are shown, also, methods using liquid chromatography techniques, titration, absorption spectrophotometry in the ultraviolet and the infrared region. Most of the methods presented are not green chemistry oriented. It is necessary the awareness of everyone involved in the optimization of the methods applied through the implementation of green chemistry to determine the metformin. PMID- 28892403 TI - Plexiform Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension. PMID- 28892404 TI - Mechanisms underlying metabolic disturbances associated with psychosis and antipsychotic drug treatment. AB - The increase in cardiovascular disease and reduced life expectancy in schizophrenia likely relate to an increased prevalence of metabolic disturbances. Such metabolic risk factors in schizophrenia may result from both symptom-related effects and aetiological factors. However, a major contributory factor is that of treatment with antipsychotic drugs. These drugs differ in effects on body weight; the underlying mechanisms are not fully understood and may vary between drugs, but may include actions at receptors associated with the hypothalamic control of food intake. Evidence supports 5-hydroxytryptamine receptor 2C and dopamine D2 receptor antagonism as well as antagonism at histamine H1 and muscarinic M3 receptors. These M3 receptors may also mediate the effects of some drugs on glucose regulation. Several antipsychotics showing little propensity for weight gain, such as aripiprazole, have protective pharmacological mechanisms, rather than just the absence of a hyperphagic effect. In addition to drug differences, there is large individual variation in antipsychotic drug-induced weight gain. This pharmacogenetic association reflects genetic variation in several drug targets, including the 5-hydroxytryptamine receptor 2C, as well as genes involved in obesity and metabolic disturbances. Thus predictive genetic testing for drug induced weight gain would represents a first step towards personalised medicine addressing this severe and problematic iatrogenic disease. PMID- 28892405 TI - To screen or not to screen? Vitamin D deficiency in chronic mental illness. AB - OBJECTIVES: The objective of the current study was to examine the pathology test utilisation of 25-hydroxyvitamin D (25(OH)D) within an Australian inpatient psychiatric setting. METHOD: A retrospective audit of 300 random hospital files of those admitted as inpatients between Nov 2014 and Nov 2015 was undertaken. Data was quantitatively analysed and described. RESULTS: The number of inpatients who had a vitamin D determination during their admission was 37/300 (12.33%). The mean vitamin D level of those tested was 51.63 nmol/l. Of those that were tested, 18/37 (48.6%) were mildly to moderately deficient. There was a statistically significant difference in age and length of stay between those that were and were not tested for vitamin D levels, p-value <0.001 and 0.017, respectively. In addition, a simple linear regression indicated a weak association between length of stay and vitamin D levels. CONCLUSION: This audit highlights vitamin D screening inadequacy. More research is recommended to establish tangible benefits of supplementation, while local practice provides valuable data for education and policy purposes. PMID- 28892407 TI - Nonparametric bootstrap technique for calibrating surgical SmartForceps: theory and application. AB - Knowledge of forces, exerted on the brain tissue during the performance of neurosurgical tasks, is critical for quality assurance, case rehearsal, and training purposes. Quantifying the interaction forces has been made possible by developing SmartForceps, a bipolar forceps retrofitted by a set of strain gauges. The forces are estimated using voltages read from strain gauges. We therefore need to quantify the force-voltage relationship to estimate the interaction forces during microsurgery. This problem has been addressed in the literature by following the physical and deterministic properties of the force-sensing strain gauges without obtaining the precision associated with each estimate. In this paper, we employ a probabilistic methodology by using a nonparametric Bootstrap approach to obtain both point and interval estimates of the applied forces at the tool tips, while the precision associated with each estimate is provided. To show proof-of-concept, the Bootstrap technique is employed to estimate unknown forces, and construct necessary confidence intervals using observed voltages in data sets that are measured from the performance of surgical tasks on a cadaveric brain. Results indicate that the Bootstrap technique is capable of estimating tool tissue interaction forces with acceptable level of accuracy compared to the linear regression technique under the normality assumption. PMID- 28892406 TI - Moving and stopping: Regulation of chromosome movement to promote meiotic chromosome pairing and synapsis. AB - Meiosis is a specialized cellular division occurring in organisms capable of sexual reproduction that leads to the formation of gametes containing half of the original chromosome number. During the earliest stage of meiosis, prophase I, pairing of homologous chromosomes is achieved in preparation for their proper distribution in the coming divisions. An important question is how do homologous chromosomes find each other and establish pairing interactions. Early studies demonstrated that chromosomes are dynamic in nature and move during this early stage of meiosis. More recently, there have been several studies across different models showing the conserved nature and importance of this chromosome movement, as well as the key components involved in chromosome movement. This review will cover these major findings and also introduce unexamined areas of regulation in meiotic prophase I chromosome movement. PMID- 28892408 TI - Variation in asthma care at hospital discharge by race/ethnicity groups. AB - OBJECTIVE: While asthma disproportionately affects minorities, little is known about racial/ethnic differences in asthma care at hospital discharge. METHODS: Secondary data analysis of multicenter retrospective study using standardized medical record review. A random sample of patients aged 2-54 years, who were hospitalized for asthma at 25 hospitals from 2012 to 2013 was analyzed. We categorized patients into three race/ethnicity groups: non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic. Multivariable logistic regression using generalized estimating equations was used to examine the relationship between race/ethnicity and the provision of guideline-concordant asthma care at hospital discharge including: the provision of asthma action plans, provision of new prescription of an inhaled corticosteroid, and referral to an asthma specialist. RESULTS: Nine hundred thirteen patients (39% children, 71% minorities) hospitalized for asthma were included. In adjusted models, NHB children were significantly less likely to receive a written asthma action plan (OR 0.48; 95% CI 0.31-0.76) than NHW children. In contrast, among adults, we found no statistically significant difference in the provision of asthma action plan. Additionally, we found no difference in the provision of a new inhaled corticosteroid prescription or referral to an asthma specialist among children or adults. CONCLUSIONS: NHB and Hispanic patients represent the majority of patients hospitalized for acute asthma in our cohort and were more likely than NHW patients to have increased markers of asthma severity. Despite this, the only significant racial/ethnic difference in asthma care at hospital discharge was among NHB children, who were less likely to receive a written asthma action plan . PMID- 28892409 TI - Changes in the Delivery of Veterans Affairs Cancer Care: Ensuring Delivery of Coordinated, Quality Cancer Care in a Time of Uncertainty. PMID- 28892411 TI - Repeated Measures Design with Generalized Linear Mixed Models for Randomized Controlled Trials, by Toshiro Tango. PMID- 28892410 TI - Ethics Never Left. PMID- 28892412 TI - Expert review on the VenaSeal(r) system for endovenous cyano-acrylate adhesive ablation of incompetent saphenous trunks in patients with varicose veins. AB - INTRODUCTION: The treatment of incompetent truncal veins has been innovated by the introduction of minimally invasive non-thermal non-tumescent (NTNT) techniques. One of these consists of the use of cyanoacrylate glue to occlude the vein lumen by means of the VenaSeal device. Areas covered: This expert-review aims to evaluate NTNT ablation of incompetent saphenous trunks using the VenaSeal device. Expert commentary: Cyanoacrylate adhesive embolization of incompetent truncal veins using the VenaSeal device is a safe and efficacious innovative technique. Further studies are needed to evaluate anatomical and clinical outcomes at long term. PMID- 28892413 TI - Enhancing the 'real world' prediction of cardiovascular events and major bleeding with the CHA2DS2-VASc and HAS-BLED scores using multiple biomarkers. AB - BACKGROUND: Atrial fibrillation (AF)-European guidelines suggest the use of biomarkers to stratify patients for stroke and bleeding risks. We investigated if a multibiomarker strategy improved the predictive performance of CHA2DS2-VASc and HAS-BLED in anticoagulated AF patients. METHODS: We included consecutive patients stabilized for six months on vitamin K antagonists (INRs 2.0-3.0). High sensitivity troponin T, NT-proBNP, interleukin-6, von Willebrand factor concentrations and glomerular filtration rate (eGFR; using MDRD-4 formula) were quantified at baseline. Time in therapeutic range (TTR) was recorded at six months after inclusion. Patients were follow-up during a median of 2375 (IQR 1564 2887) days and all adverse events were recorded. RESULTS: In 1361 patients, adding four blood biomarkers, TTR and MDRD-eGFR, the predictive value of CHA2DS2 VASc increased significantly by c-index (0.63 vs. 0.65; p = .030) and IDI (0.85%; p < .001), but not by NRI (-2.82%; p < .001). The predictive value of HAS-BLED increased up to 1.34% by IDI (p < .001). Nevertheless, the overall predictive value remains modest (c-indexes approximately 0.65) and decision curve analyses found lower net benefit compared with the originals scores. CONCLUSIONS: Addition of biomarkers enhanced the predictive value of CHA2DS2-VASc and HAS-BLED, although the overall improvement was modest and the added predictive advantage over original scores was marginal. Key Messages Recent atrial fibrillation (AF) European guidelines for the first time suggest the use of biomarkers to stratify patients for stroke and bleeding risks, but their usefulness in real world for risk stratification is still questionable. In this cohort study involving 1361 AF patients optimally anticoagulated with vitamin K antagonists, adding high sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, interleukin 6, von Willebrand factor, glomerular filtration rate (by the MDRD-4 formula) and time in therapeutic range, increased the predictive value of CHA2DS2-VASc for cardiovascular events, but not the predictive value of HAS-BLED for major bleeding. Reclassification analyses did not show improvement adding multiple biomarkers. Despite the improvement observed, the added predictive advantage is marginal and the clinical usefulness and net benefit over current clinical scores is lower. PMID- 28892414 TI - Efficacy of recombinant adenovirus expressing a fusion gene from GM-CSF and Epstein-Barr virus LMP2A in a mouse tumor model. AB - In this study, purified GM-CSF and LMP2A mRNAs were amplified by PCR. Then, the GM-CSF and LMP2A sequences were connected by the polypeptide linker (Gly4Ser)3 using gene splicing by overlap extension. The constructed fusion gene GC2A was inserted into the adenovirus vector. Then the recombinant vector was introduced into HEK 293T cells by calcium phosphate transfection to package the adenovirus. The levels of antibodies against the GM-CSF and LMP2Afusion proteins were measured by ELISA, and the CTL activity of the mouse splenic lymphocytes was determined by lactate dehydrogenase (LDH) release assay. Immunotherapy of mouse tumor (EBV-positive epithelial tumor cell line (GT39)) tissues was performed, and their morphologies were assessed. Finally, the data of each group were analyzed using SPSS 11.5 statistical software. The recombinant adenovirus could replicate in HEK 293Tcells and induce humoral and cellular immune responses in the mice. The maximum dose resulted in an antibody titer of 18500 (184.5 +/- 8.7 pg/ml). At an effector: target ratio of 40:1, maximum specific lysis was observed which was approximately three times that detected in the control immunized mice. The tumor inhibition rate was approximately 76% compared with the control groups, indicating the presence of significant differences among the groups. Tumor infiltrating lymphocytes were detected by hematoxylin-eosin (HE) staining. The recombinant adenovirus induced humoral and cellular immune responses and inhibited tumor growth in mice. It provided a theoretical basis and candidate vaccine for further preclinical trials. PMID- 28892416 TI - Roman high and low avoidance rats differ in their response to chronic olanzapine treatment at the level of body weight regulation, glucose homeostasis, and cortico-mesolimbic gene expression. AB - Olanzapine, an antipsychotic agent mainly used for treating schizophrenia, is frequently associated with body weight gain and diabetes mellitus. Nonetheless, studies have shown that not every individual is equally susceptible to olanzapine's weight-gaining effect. Therefore, Roman high and low avoidance rat strains were examined on their responsiveness to olanzapine treatment. The Roman high avoidance rat shares many behavioral and physiological characteristics with human schizophrenia, such as increased central dopaminergic sensitivity, whereas the Roman low avoidance rat has been shown to be prone to diet-induced obesity and insulin resistance. The data revealed that only the Roman high avoidance rats are susceptible to olanzapine-induced weight gain and attenuated glucose tolerance. Here it is suggested that the specific olanzapine-induced weight gain in Roman high avoidance rats could be related to augmented dopaminergic sensitivity at baseline through increased expression of prefrontal cortex dopamine receptor D1 mRNA and nucleus accumbens dopamine receptor D2 mRNA expression. Regression analyses revealed that olanzapine-induced weight gain in the Roman high avoidance rat is above all related to increased prolactin levels, whereas changes in glucose homeostasis is best explained by differences in central dopaminergic receptor expressions between strains and treatment. Our data indicates that individual differences in dopaminergic receptor expression in the cortico-mesolimbic system are related to susceptibility to olanzapine-induced weight gain. PMID- 28892415 TI - Susceptibility of Mycobacterium tuberculosis-infected host cells to phospho-MLKL driven necroptosis is dependent on cell type and presence of TNFalpha. AB - An important feature of Mycobacterium tuberculosis pathogenesis is the ability to control cell death in infected host cells, including inhibition of apoptosis and stimulation of necrosis. Recently an alternative form of programmed cell death, necroptosis, has been described where necrotic cell death is induced by apoptotic stimuli under conditions where apoptotic execution is inhibited. We show for the first time that M. tuberculosis and TNFalpha synergise to induce necroptosis in murine fibroblasts via RIPK1-dependent mechanisms and characterized by phosphorylation of Ser345 of the MLKL necroptosis death effector. However, in murine macrophages M. tuberculosis and TNFalpha induce non-necroptotic cell death that is RIPK1-dependent but independent of MLKL phosphorylation. Instead, M. tuberculosis-infected macrophages undergo RIPK3-dependent cell death which occurs both in the presence and absence of TNFalpha and involves the production of mitochondrial ROS. Immunocytochemical staining for MLKL phosphorylation further demonstrated the occurrence of necroptosis in vivo in murine M. tuberculosis granulomas. Phosphorylated-MLKL immunoreactivity was observed associated with the cytoplasm and nucleus of fusiform cells in M. tuberculosis lesions but not in proximal macrophages. Thus whereas pMLKL-driven necroptosis does not appear to be a feature of M. tuberculosis-infected macrophage cell death, it may contribute to TNFalpha-induced cytotoxicity of the lung stroma and therefore contribute to necrotic cavitation and bacterial dissemination. PMID- 28892417 TI - Green biologics: The algal chloroplast as a platform for making biopharmaceuticals. AB - Most commercial production of recombinant pharmaceutical proteins involves the use of mammalian cell lines, E. coli or yeast as the expression host. However, recent work has demonstrated the potential of eukaryotic microalgae as platforms for light-driven synthesis of such proteins. Expression in the algal chloroplast is particularly attractive since this organelle contains a minimal genome suitable for rapid engineering using synthetic biology approaches; with transgenes precisely targeted to specific genomic loci and amenable to high level, regulated and stable expression. Furthermore, proteins can be tightly contained and bio-encapsulated in the chloroplast allowing accumulation of proteins otherwise toxic to the host, and opening up possibilities for low-cost, oral delivery of biologics. In this commentary we illustrate the technology with recent examples of hormones, protein antibiotics and immunotoxins successfully produced in the algal chloroplast, and highlight possible future applications. PMID- 28892418 TI - Shared decision making and time to exacerbation in children with asthma. AB - OBJECTIVE: Although shared decision making (SDM) is a promising approach for improving outcomes for patients with chronic diseases, no evidence currently supports the use of SDM to delay asthma exacerbations. We evaluated the impact of an SDM intervention implemented by providers in a real-world setting on time to exacerbation in children with asthma. METHODS: This study used a prospective cohort observed between 2011 and 2013 at five primary care practices that serve vulnerable populations (e.g., Medicaid and uninsured patients) in Charlotte, NC. Patients aged 2 to 17 receiving SDM were matched to those receiving usual care using propensity scores. Time to asthma exacerbation (asthma hospitalization, emergency department visit or oral steroid prescription in the outpatient setting) was compared between groups using Kaplan-Meier curves and conditional Cox proportional hazards models. RESULTS: The cohort included 746 children, 60.5% male and 54.2% African American, with a mean age of 8.6 years. Of these, 625 received usual care and 121 received SDM. The final analysis included 100 matched pairs of children. Kaplan-Meier curves showed longer exacerbation-free time for patients in the SDM intervention compared to those in usual care (p = 0.005). The difference in risk of experiencing an exacerbation was marginally significant between the two groups (HR = 0.56, 95% C.I. = 0.29-1.08, p = 0.08). CONCLUSIONS: SDM was found to delay exacerbations among children with asthma. Clinicians should consider incorporating patient preferences in treatment decisions through SDM as a means for longer exacerbation-free time among children with poor asthma control. PMID- 28892419 TI - The Effect of a Backpack Hip Strap on Energy Expenditure While Walking. AB - Objective To examine the effect of backpack hip strap use on walking energy expenditure while carrying a loaded backpack. Background Previous studies have demonstrated that energy cost increases as the mass of the load carried increases. However, few investigations have focused on backpack carriage design. Methods Fifteen young, healthy, male subjects walked at a self-selected pace for 10 minutes in two backpack loading conditions: with a hip strap (strapped) and without a hip strap (nonstrapped). Oxygen consumption (VO2), rating of perceived exertion (RPE), respiratory exchange ratio (RER), and heart rate (HR) were monitored throughout each 10-minute trial. Change scores from the 4th to 10th minute were calculated for each variable. A t test was used to evaluate the difference between conditions for each variable. Results The changes in VO2 ( 0.62 +/- 0.40 vs. 0.33 +/- 0.23, p = .04) and RPE (1 +/- 0.25 vs. 2 +/- 0.21, p < .01) from the 4th to the 10th minute were different for the strapped versus nonstrapped condition. There was no difference in the change in RER (0.04 +/- 0.01 vs. 0.03 +/- 0.01, p > .05) or HR (3.53 +/- 0.93 vs. 4.07 +/- 1.39, p > .05) for the strapped versus unstrapped condition. Conclusions Wearing a hip strap reduced the energy expenditure and perceived exertion in as little as 10 minutes of walking compared to the nonstrapped condition. Future work should consider the effect of a hip strap on these variables while hiking for extended periods. Application Wearing a hip strap may increase the comfort and reduce the energy required of wearing a backpack. This is useful information for backpack designers, military personnel, and recreational hikers. PMID- 28892420 TI - Eating disorders: Insights from imaging and behavioral approaches to treatment. AB - Understanding factors that contribute to eating disorders, which affect 13% of females, is critical to developing effective prevention and treatment programs. In this paper, we summarize results from prospective studies that identified factors predicting onset and persistence of eating disorders and core symptom dimensions. Next, implications for intervention targets for prevention, and treatment interventions from the risk- and maintenance-factor findings are discussed. Third, given that evidence suggests eating disorders are highly heritable, implying biological risk and maintenance factors for eating disorders, we offer working hypotheses about biological factors that might contribute to eating disorders, based on extant risk factor findings, theory, and cross sectional studies. Finally, potentially fruitful directions for future research are presented. We suggest that it would be useful for experimental therapeutics trials to evaluate the effects of reducing the risk factors on future onset of eating pathology and on reducing maintenance factors on the risk for persistence of eating pathology, and encourage researchers to utilize prospective high-risk studies so that knowledge regarding potential intervention targets for prevention and treatment interventions for eating disorders can be advanced. Using the most rigorous research designs should help improve the efficacy of prevention and treatment interventions for eating disorders. PMID- 28892421 TI - Preliminary evaluation of a human laboratory model of impaired control over alcohol using intravenous alcohol self-administration. AB - Impaired control over alcohol is central to alcohol use disorder, but most research on impaired control is limited to self-report methods. This study applied intravenous alcohol self-administration to conduct a preliminary investigation of a novel human laboratory model of impaired control. Heavy episodic drinkers (ages 19-22 years) completed a two-hour intravenous alcohol self-administration session that involved an incentive to maintain breath alcohol concentration below 80 mg%. Impaired control was operationalized based on whether participants exceeded (impaired control positive; IC+) or adhered to (impaired control negative; IC-) the breath alcohol concentration limit, as well as the discrepancy between intended and actual peak breath alcohol concentration. Analyses of subjective processes revealed that IC+ participants tended to underestimate their peak breath alcohol concentration relative to IC- participants. Further, IC+ reported greater craving after an initial priming phase, and craving mediated the relationship between self-report impaired control and discrepancies between intended and actual breath alcohol concentration. IC+ participants also showed stronger within-person associations between state changes in stimulation and momentary alcohol self-administration throughout the session. Laboratory impaired control indices demonstrated convergent validity with an established self-report measure of impaired control. These findings provide preliminary validation of a novel human laboratory model of impaired control in a sample of young heavy episodic drinkers, and offer insight into the role of subjective responses (craving, stimulation) in impaired control. PMID- 28892423 TI - Gastric Dilatation Associated with Gastric Colonization with Sarcina-Like Bacteria in a Cat with Chronic Enteritis. AB - An 11 yr old spayed female domestic longhair cat was presented for an acute onset of vomiting. Abdominal radiographs and ultrasound revealed severe gastric dilatation (GD) without evidence of gastric outflow obstruction. On esophagogastroduodenoscopy, the duodenal mucosa was mildly erythematous, and a moderate, diffuse, chronic enteritis was found by histological examination of duodenal biopsies. Large numbers of Sarcina-like bacteria without associated inflammation were present in gastric mucosal biopsies. To the authors' knowledge, this is the first report of GD associated with colonization by Sarcina-like bacteria in a cat. Gastric colonization by Sarcina-like bacteria should be suspected when cats are presented with acute onset of GD and vomiting. PMID- 28892422 TI - Clinicopathologic and Microbiologic Findings Associated with Emphysematous Cystitis in 27 Dogs. AB - This is a retrospective case series of 27 dogs with emphysematous cystitis. Medical records from two veterinary teaching hospitals from 1992 to 2014 were reviewed. The aims of the study were to determine imaging findings, common underlying disease processes, and prevalent bacterial species and their antimicrobial susceptibility patterns in dogs with emphysematous cystitis. The most common lower urinary tract sign was hematuria. Gas was detected in the wall and lumen of the urinary bladder in 14 of 27 dogs (51.9%), in only the wall of the bladder in 9 of 27 dogs (33%), and in only the lumen of the bladder in 4 of 27 dogs (14.8%). Comorbid diseases were identified in all but one case. The most common comorbid disease processes were diabetes mellitus in 33% of dogs, neurologic disease in 26% of dogs, and adrenal disease in 19% of dogs. Bacterial isolates included Escherichia coli, Enterococcus spp., Klebsiella pneumoniae, Proteus mirabilis, Streptococcus spp., and Actinomyces spp. Enterococcus spp. were always isolated in mixed infections with gas-producing bacterial species. During the period of study, most isolates were predicted to be susceptible to beta-lactam drugs, but updated veterinary breakpoints suggest that fluoroquinolones or trimethoprim-sulfamethoxazole would be more appropriate choices for empiric therapy. PMID- 28892424 TI - An Unusual Case of Portal Hypertension Secondary to Primary Hypoplasia of the Portal Vein. AB - Primary hypoplasia of the portal vein with secondary portal hypertension and acquired portosystemic collateral circulation is infrequently reported in the veterinary literature. Diagnosis of this condition requires documentation of abnormal hepatocellular function, the lack of intrahepatic or extrahepatic macroscopic congenital portosystemic shunts, and liver histopathology demonstrating portal hypoperfusion in the absence of hepatic inflammation or nodular regeneration. Due to a perceived poor prognosis, many patients with this condition are euthanized; however, those that are spared can be medically managed, in some cases for years. This case report describes the diagnosis and management of a patient with primary hypoplasia of the portal vein and secondary portal hypertension that presented with the severe but typical clinical manifestations of ascites and hepatic encephalopathy, normal liver enzyme concentrations, and normal serum bile acid concentrations. PMID- 28892425 TI - Laparoscopic Resection of a Pancreatic beta Cell Tumor in a Dog. AB - Laparoscopic partial pancreatectomy has been performed in experimental canine studies and has been evaluated in human medicine but has not been reported in a clinical veterinary case. The authors present a 9 yr old field spaniel with weakness and hypoglycemia with insulin levels and Amended Insulin: Glucose Ratio results equivocal for a pancreatic insulinoma. Multiple abdominal ultrasounds did not detect the tumor, yet dual-phase computed tomographic angiography revealed the presence of a focal hypoattenuating nodule in the left lobe of the pancreas. A 3-port laparoscopic approach to the abdomen confirmed a 1.5-cm mass in the mid left limb of the pancreas, and resection of the mass was performed with a bipolar vessel-sealing device. The surgery was performed without complication, and the dog became normoglycemic within 4 hr following surgery. Final histopathology results revealed pancreatic neuroendocrine carcinoma of the beta cells. Recurrence of hypoglycemia was noted 18 mo postoperatively; however, repeat computed tomographic angiography did not reveal pancreatic abnormalities and fine needle aspirates of liver nodules did not suggest metastatic disease. Medical management was elected and the patient was euthanized 28 mo after surgery due to refractory hypoglycemic seizures. PMID- 28892426 TI - Agreement of Axillary and Auricular Temperature with Rectal Temperature in Systemically Healthy Dogs Undergoing Surgery. AB - Obtaining a patient's temperature is an important part of a patient's physical examination. As human medicine transitions to noninvasive temperature measurements, so does veterinary medicine. Historically, temperature measurement has been obtained from rectal readings; however, alternative methods, such as axillary and auricular temperatures, are increasing in popularity. The purpose of the study was to compare these alternative techniques to the gold standard of rectal temperature. Temperatures were obtained three ways for each patient: rectal, axillary, and auricular. Results indicated a positive linear relationship between rectal and axillary temperatures (bivariate correlation coefficient [r] = 0.65, P < .001) and axillary and auricular temperatures (r = 0.55, P < .001). Agreement was strongest between rectal and auricular temperatures (r = 0.80, P < .001). The average discrepancy between axillary and rectal temperature was 1.2 degrees C [2.1 degrees F] with the highest difference being 4.0 degrees C [7.3 degrees F]. The average discrepancy between auricular and rectal temperature was 0.6 degrees C [1.2 degrees F] with the highest difference being 2.2 degrees C [4.1 degrees F]. Despite auricular temperatures having stronger agreement, Bland Altman Limits of Agreement testing revealed that it was a poor predictor of rectal temperature. Based on these results, axillary and auricular temperatures should not be substituted for rectal temperature. PMID- 28892427 TI - Norwegian or Crusted Sarcoptic Mange in Two Leishmanial Dogs. AB - Norwegian or crusted scabies (N/CS) is a rare skin disease with very few cases reported in the dog or the cat. Two adult, stray dogs were admitted in our clinic with a generalized, multifocal to diffuse and nonpruritic dermatitis that was characterized by severe crusting, scaling, and ulceration. In both instances, leishmaniosis and N/CS were diagnosed by immunofluorescent antibody test serology, lymph node cytology, and skin scrapings in which high numbers of Sarcoptes mites were found. The combination of miticidal and antileishmanial treatment, supported by topical treatment and nutritional support, resulted in the complete resolution of the skin lesions and spectacular improvement of the body condition in both cases. Dog 1 eventually died from end-stage kidney disease attributed to leishmaniosis-associated glomerulonephritis, whereas the also proteinuric dog 2 remains clinically healthy. The manifestation of the rare type of N/CS in these dogs could be attributed to cell-mediated immunosuppression, which was most likely induced by leishmaniosis and malnutrition. The necessity of searching for leishmaniosis in those scabietic cases, especially in the endemic areas of leishmaniosis, is strongly recommended. PMID- 28892428 TI - Successful Surgical Correction of a Mesenteric Volvulus with Concurrent Foreign Body Obstruction in Two Puppies. AB - A 9 mo old female intact English mastiff (case 1) presented for anorexia and vomiting for 7 days. A 7 mo old male castrated American bulldog (case 2) presented for vomiting and anorexia for 2 days without diarrhea. Both dogs were diagnosed with mesenteric volvulus based on exploratory laparotomy, which also revealed an intestinal foreign body obstruction. Case 1 required critical care support during recovery but was ultimately discharged, whereas case 2 had an uncomplicated recovery. Both were reported to be back to normal 1 wk after surgery. Case 1 survived 3 mo and then died due to a colonic torsion diagnosed by exploratory laparotomy. Case 2 has been reported to be completely normal more than 18 mo after surgery. These two cases illustrate that mesenteric volvulus can be present with a several-day history of gastrointestinal signs and that shock may be absent on presentation. This is also the first published report of mesenteric volvulus with a concurrent foreign body obstruction. PMID- 28892429 TI - Adjuvant Doxorubicin with or without Metronomic Cyclophosphamide for Canine Splenic Hemangiosarcoma. AB - This retrospective study investigated the outcome of 33 dogs with splenic hemangiosarcoma treated with surgery followed by adjuvant dose-intensified doxorubicin (DOX) with or without low-dose metronomic cyclophosphamide (LDM-C) maintenance therapy. Among the 33 dogs, 18 dogs received LDM-C. Clinical stage was available for all dogs (5 stage I, 18 stage II, and 10 stage III). Nine dogs had macroscopic, and 24 dogs had microscopic disease at the start of DOX treatment. Median progression-free survival (PFS) and overall survival were 125 and 133 days, respectively. Clinical stage and tumor burden (microscopic versus macroscopic) at the start of chemotherapy was prognostic for PFS. No significant difference was observed in PFS or overall survival for the addition of LDM-C after a completed DOX protocol (P = .563 and P = .148, respectively). Based on the results of this retrospective study, the addition of LDM-C therapy as a maintenance regimen following a completed protocol of DOX adjuvant treatment of canine hemangiosarcoma may not improve outcome. PMID- 28892430 TI - Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children's Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children's Oncology Group. AB - Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children's Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and >= 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those < 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis. PMID- 28892431 TI - Nintedanib Plus Pemetrexed/Cisplatin in Patients With Malignant Pleural Mesothelioma: Phase II Results From the Randomized, Placebo-Controlled LUME-Meso Trial. AB - Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naive patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade >= 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing. PMID- 28892432 TI - Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline. AB - Purpose To provide guidance to oncology clinicians on how to use effective communication to optimize the patient-clinician relationship, patient and clinician well-being, and family well-being. Methods ASCO convened a multidisciplinary panel of medical oncology, psychiatry, nursing, hospice and palliative medicine, communication skills, health disparities, and advocacy experts to produce recommendations. Guideline development involved a systematic review of the literature and a formal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, and randomized controlled trials published from 2006 through October 1, 2016. Results The systematic review included 47 publications. With the exception of clinician training in communication skills, evidence for many of the clinical questions was limited. Draft recommendations underwent two rounds of consensus voting before being finalized. Recommendations In addition to providing guidance regarding core communication skills and tasks that apply across the continuum of cancer care, recommendations address specific topics, such as discussion of goals of care and prognosis, treatment selection, end-of-life care, facilitating family involvement in care, and clinician training in communication skills. Recommendations are accompanied by suggested strategies for implementation. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki . PMID- 28892433 TI - Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population Based Cohort Study. AB - Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients. PMID- 28892434 TI - Project Public Health Ready: History and Evolution of a Best Practice for Public Health Preparedness Planning. AB - We review the history and evolution of Project Public Health Ready and demonstrate why it is considered a best practice in public health preparedness planning. Previous articles on this program have described its impact on single health departments. We provide background information, review successes and challenges to date, and inform public health practitioners about a vetted tool for local public health planners to develop capacity and capability in all hazards planning and response. PMID- 28892435 TI - Community Assessment for Public Health Emergency Response (CASPER): An Innovative Emergency Management Tool in the United States. AB - OBJECTIVES: To demonstrate how inclusion of the Centers for Disease Control and Prevention's Community Assessment for Public Health Emergency Response (CASPER) as a tool in Public Health Preparedness Capabilities: National Standards for State and Local Planning can increase public health capacity for emergency response. METHODS: We reviewed all domestic CASPER activities (i.e., trainings and assessments) between fiscal years 2012 and 2016. Data from these CASPER activities were compared with respect to differences in geographic distribution, type, actions, efficacy, and usefulness of training. RESULTS: During the study period, the Centers for Disease Control and Prevention conducted 24 domestic in person CASPER trainings for 1057 staff in 38 states. On average, there was a marked increase in knowledge of CASPER. Ninety-nine CASPERs were conducted in the United States, approximately half of which (53.5%) assessed preparedness; the others were categorized as response or recovery (27.2%) or were unrelated to a disaster (19.2%). CONCLUSIONS: CASPER trainings are successful in increasing disaster epidemiology skills. CASPER can be used by Public Health Emergency Preparedness program awardees to help build and sustain preparedness and response capabilities. PMID- 28892436 TI - A Conceptual Framework for the Evaluation of Emergency Risk Communications. AB - OBJECTIVES: To articulate a conceptual framework in support of evaluation activities in emergency risk communications (ERC). METHODS: The framework proposed is based on a systematic review of the scientific literature (2001-2016) combined with data derived from a series of semistructured interviews with experts and practitioners in ERC, and it is designed to support local, national, and international public health organizations in implementing evaluation studies in ERC. RESULTS: We identified a list of ERC outcomes from the full-text review of 152 articles and categorized these into 3 groups, depending upon the level at which the outcome was measured: (1) information environment, (2) population, and (3) public health system. We analyzed interviewees' data from 18 interviews to identify practices and processes related to the effectiveness of ERC and included these as key structural components and processes in the developed evaluation framework. CONCLUSIONS: Researchers and public health practitioners interested in the evaluation of ERC can use the conceptual framework described in this article to guide the development of evaluation studies and methods for assessing communication outcomes related to public health emergencies. PMID- 28892438 TI - Evolution of Public Health Emergency Management From Preparedness to Response and Recovery: Introduction and Contents of the Volume. PMID- 28892437 TI - Public Health System Research in Public Health Emergency Preparedness in the United States (2009-2015): Actionable Knowledge Base. AB - BACKGROUND: In 2008, the Institute of Medicine released a letter report identifying 4 research priority areas for public health emergency preparedness in public health system research: (1) enhancing the usefulness of training, (2) improving timely emergency communications, (3) creating and maintaining sustainable response systems, and (4) generating effectiveness criteria and metrics. OBJECTIVES: To (1) identify and characterize public health system research in public health emergency preparedness produced in the United States from 2009 to 2015, (2) synthesize research findings and assess the level of confidence in these findings, and (3) describe the evolution of knowledge production in public health emergency preparedness system research. Search Methods and Selection Criteria. We reviewed and included the titles and abstracts of 1584 articles derived from MEDLINE, EMBASE, and gray literature databases that focused on the organizational or financial aspects of public health emergency preparedness activities and were grounded on empirical studies. DATA COLLECTION AND ANALYSIS: We included 156 articles. We appraised the quality of the studies according to the study design. We identified themes during article analysis and summarized overall findings by theme. We determined level of confidence in the findings with the GRADE-CERQual tool. MAIN RESULTS: Thirty-one studies provided evidence on how to enhance the usefulness of training. Results demonstrated the utility of drills and exercises to enhance decision-making capabilities and coordination across organizations, the benefit of cross-sector partnerships for successfully implementing training activities, and the value of integrating evaluation methods to support training improvement efforts. Thirty-six studies provided evidence on how to improve timely communications. Results supported the use of communication strategies that address differences in access to information, knowledge, attitudes, and practices across segments of the population as well as evidence on specific communication barriers experienced by public health and health care personnel. Forty-eight studies provided evidence on how to create and sustain preparedness systems. Results included how to build social capital across organizations and citizens and how to develop sustainable and useful planning efforts that maintain flexibility and rely on available medical data. Twenty-six studies provided evidence on the usefulness of measurement efforts, such as community and organizational needs assessments, and new methods to learn from the response to critical incidents. CONCLUSIONS: In the United States, the field of public health emergency preparedness system research has been supported by the US Centers for Disease Control and Prevention since the release of the 2008 Institute of Medicine letter report. The first definition of public health emergency preparedness appeared in 2007, and before 2008 there was a lack of research and empirical evidence across all 4 research areas identified by the Institute of Medicine. This field can be considered relatively new compared with other research areas in public health; for example, tobacco control research can rely on more than 70 years of knowledge production. However, this review demonstrates that, during the past 7 years, public health emergency preparedness system research has evolved from generic inquiry to the analysis of specific interventions with more empirical studies. Public Health Implications: The results of this review provide an evidence base for public health practitioners responsible for enhancing key components of preparedness and response such as communication, training, and planning efforts. PMID- 28892439 TI - A Child's Health Is the Public's Health: Progress and Gaps in Addressing Pediatric Needs in Public Health Emergencies. AB - Children are the most prevalent vulnerable population in US society and have unique needs during the response to and recovery from public health emergencies. The physiological, behavioral, developmental, social, and mental health differences of children require specific attention in preparedness efforts. Despite often being more severely affected in disasters, children's needs are historically underrepresented in preparedness. Since 2001, much progress has been made in addressing this disparity through better pediatric incorporation in preparedness planning from national to local levels. Innovative approaches, policies, and collaborations contribute to these advances. However, many gaps remain in the appropriate and proportional inclusion of children in planning for public health emergencies. Successful models of pediatric planning can be developed, evaluated, and widely disseminated to ensure that further progress can be achieved. PMID- 28892440 TI - Progress in Public Health Emergency Preparedness-United States, 2001-2016. AB - OBJECTIVES: To evaluate the Public Health Emergency Preparedness (PHEP) program's progress toward meeting public health preparedness capability standards in state, local, and territorial health departments. METHODS: All 62 PHEP awardees completed the Centers for Disease Control and Prevention's self-administered PHEP Impact Assessment as part of program review measuring public health preparedness capability before September 11, 2001 (9/11), and in 2014. We collected additional self-reported capability self-assessments from 2016. We analyzed trends in congressional funding for public health preparedness from 2001 to 2016. RESULTS: Before 9/11, most PHEP awardees reported limited preparedness capabilities, but considerable progress was reported by 2016. The number of jurisdictions reporting established capability functions within the countermeasures and mitigation domain had the largest increase, almost 200%, by 2014. However, more than 20% of jurisdictions still reported underdeveloped coordination between the health system and public health agencies in 2016. Challenges and barriers to building PHEP capabilities included lack of trained personnel, plans, and sustained resources. CONCLUSIONS: Considerable progress in public health preparedness capability was observed from before 9/11 to 2016. Support, sustainment, and advancement of public health preparedness capability is critical to ensure a strong public health infrastructure. PMID- 28892441 TI - Improvements in State and Local Planning for Mass Dispensing of Medical Countermeasures: The Technical Assistance Review Program, United States, 2007 2014. AB - OBJECTIVES: To evaluate and describe outcomes of state and local medical countermeasure preparedness planning, which is critical to ensure rapid distribution and dispensing of a broad spectrum of life-saving medical assets during a public health emergency. METHODS: We used 2007 to 2014 state and local data collected from the Centers for Disease Control and Prevention's Technical Assistance Review. We calculated descriptive statistics from 50 states and 72 local Cities Readiness Initiative jurisdictions that participated in the Technical Assistance Review annually. RESULTS: From 2007 to 2014, the average overall Technical Assistance Review score increased by 13% for states and 41% for Cities Readiness Initiative jurisdictions. In 2014, nearly half of states achieved the maximum possible overall score (100), and 94% of local Cities Readiness Initiative jurisdictions achieved a score of 90 or more. CONCLUSIONS: Despite challenges, effective and timely medical countermeasure distribution and dispensing is possible with appropriate planning, staff, and resources. However, vigilance in training, exercising, and improving plans from lessons learned in a sustained, coordinated way is critical to ensure continued public health preparedness success. PMID- 28892442 TI - From Anthrax to Zika: Fifteen Years of Public Health Emergency Preparedness. PMID- 28892443 TI - Promoting Community Preparedness and Resilience: A Latino Immigrant Community Driven Project Following Hurricane Sandy. AB - As community residents and recovery workers, Latino immigrants play important roles after disasters, yet are rarely included in preparedness planning. A community-university-labor union partnership created a demonstration project after Hurricane Sandy to strengthen connections to disaster preparedness systems to increase community resilience among Latino immigrant communities in New York and New Jersey. Building ongoing ties that connect workers and community-based organizations with local disaster preparedness systems provided mutual benefits to disaster planners and local immigrant communities, and also had an impact on national disaster-related initiatives. PMID- 28892444 TI - The Evolution of Public Health Emergency Management as a Field of Practice. AB - The health impacts of recent global infectious disease outbreaks and other disasters have demonstrated the importance of strengthening public health systems to better protect communities from naturally occurring and human-caused threats. Public health emergency management (PHEM) is an emergent field of practice that draws on specific sets of knowledge, techniques, and organizing principles necessary for the effective management of complex health events. We highlight how the nascent field of PHEM has evolved in recent years. We explore this development by first examining multiple sites of intersection between the fields of public health and emergency management. We then analyze 2 of the principal pillars on which PHEM was built: organizational and programmatic (i.e., industry) standards and the incident management system. This is followed by a sketch of the key domains, or functional areas, of PHEM and their application to the emergency management cycle. We conclude with some observations about PHEM in a global context and discuss how the field might continue to evolve. PMID- 28892445 TI - Applying the 15 Public Health Emergency Preparedness Capabilities to Support Large-Scale Tuberculosis Investigations in Complex Congregate Settings. AB - Public Health-Seattle and King County, a metropolitan health department in western Washington, experiences rates of tuberculosis (TB) that are 1.6 times higher than are state and national averages. The department's TB Control Program uses public health emergency management tools and capabilities sustained with Centers for Disease Control and Prevention grant funding to manage large-scale complex case investigations. We have described 3 contact investigations in large congregate settings that the TB Control Program conducted in 2015 and 2016. The program managed the investigations using public health emergency management tools, with support from the Preparedness Program. The 3 investigations encompassed medical evaluation of more than 1600 people, used more than 100 workers, identified nearly 30 individuals with latent TB infection, and prevented an estimated 3 cases of active disease. These incidents exemplify how investments in public health emergency preparedness can enhance health outcomes in traditional areas of public health. PMID- 28892446 TI - Funding Public Health Emergency Preparedness in the United States. AB - The historical precedents that support state and local leadership in preparedness for and response to disasters are in many ways at odds with the technical demands of preparedness and response for incidents affecting public health. New and revised laws and regulations, executive orders, policies, strategies, and plans developed in response to biological threats since 2001 address the role of the federal government in the response to public health emergencies. However, financial mechanisms for disaster response-especially those that wait for gubernatorial request before federal assistance can be provided-do not align with the need to prevent the spread of infectious agents or efficiently reduce the impact on public health. We review key US policies and funding mechanisms relevant to public health emergencies and clarify how policies, regulations, and resources affect coordinated responses. PMID- 28892447 TI - How Health Department Contextual Factors Affect Public Health Preparedness (PHP) and Perceptions of the 15 PHP Capabilities. AB - OBJECTIVES: To assess how health department contextual factors influence perceptions of the 15 Public Health Preparedness Capabilities, developed by the Centers for Disease Control and Prevention (CDC) to provide guidance on organizing preparedness activities. METHODS: We conducted an online survey and focus group between September 2015 and May 2016 with directors of preparedness programs in state, metropolitan, and territorial jurisdictions funded by CDC's Public Health Emergency Preparedness (PHEP) cooperative agreement. The survey collected demographic information and data on contextual factors including leadership, partnerships, organizational structure, resources and structural capacity, and data and evaluation. RESULTS: Seventy-seven percent (48 of 62) of PHEP directors completed the survey and 8 participated in the focus group. Respondents were experienced directors (mean = 10.6 years), and 58% led 7 or more emergency responses. Leadership, partnerships, and access to fiscal and human resources were associated with perception and use of the capabilities. CONCLUSIONS: Despite some deficiencies, PHEP awardees believe the capabilities provide useful guidance and a flexible framework for organizing their work. Contextual factors affect perceptions of the capabilities and possibly the effectiveness of their use. Public Health Implications. The capabilities can be used to address challenges in preparedness, including identifying evidence-based practices, developing performance measures, and improving responses. PMID- 28892448 TI - Primary Care Emergency Preparedness Network, New York City, 2015: Comparison of Member and Nonmember Sites. AB - OBJECTIVES: To assess whether Primary Care Emergency Preparedness Network member sites reported indicators of preparedness for public health emergencies compared with nonmember sites. The network-a collaboration between government and New York City primary care associations-offers technical assistance to primary care sites to improve disaster preparedness and response. METHODS: In 2015, we administered an online questionnaire to sites regarding facility characteristics and preparedness indicators. We estimated differences between members and nonmembers with natural logarithm-linked binomial models. Open-ended assessments identified preparedness gaps. RESULTS: One hundred seven sites completed the survey (23.3% response rate); 47 (43.9%) were nonmembers and 60 (56.1%) were members. Members were more likely to have completed hazard vulnerability analysis (risk ratio [RR] = 1.94; 95% confidence interval [CI] = 1.28, 2.93), to have identified essential services for continuity of operations (RR = 1.39; 95% CI = 1.03, 1.86), to have memoranda of understanding with external partners (RR = 2.49; 95% CI = 1.42, 4.36), and to have completed point-of-dispensing training (RR = 4.23; 95% CI = 1.76, 10.14). Identified preparedness gaps were improved communication, resource availability, and train-the-trainer programs. Public Health Implications. Primary Care Emergency Preparedness Network membership is associated with improved public health emergency preparedness among primary care sites. PMID- 28892449 TI - Emergency Preparedness in the Workplace: The Flulapalooza Model for Mass Vaccination. AB - OBJECTIVES: To explore whether an emergency preparedness structure is a feasible, efficient, and sustainable way for health care organizations to manage mass vaccination events. METHODS: We used the Hospital Incident Command System to conduct a 1-day annual mass influenza vaccination event at Vanderbilt University Medical Center over 5 successive years (2011-2015). Using continuous quality improvement principles, we assessed whether changes in layout, supply management, staffing, and documentation systems improved efficiency. RESULTS: A total of 66 591 influenza vaccines were administered at 5 annual Flulapalooza events; 13 318 vaccines per event on average. Changes to the physical layout, staffing mix, and documentation processes improved vaccination efficiency 74%, from approximately 38 to 67 vaccines per hour per vaccinator, while reducing overall staffing needs by 38%. An unexpected finding was the role of social media in facilitating active engagement. CONCLUSIONS: Health care organizations can use a closed point-of dispensing model and Hospital Incident Command System to conduct mass vaccination events, and can adopt the "Flulapalooza method" as a best practice model to enhance efficiency. PMID- 28892450 TI - 2015 Pandemic Influenza Readiness Assessment Among US Public Health Emergency Preparedness Awardees. AB - OBJECTIVES: To assess how US Public Health Emergency Preparedness (PHEP) awardees plan to respond to an influenza pandemic with vaccination. METHODS: The Centers for Disease Control and Prevention developed the Pandemic Influenza Readiness Assessment, an online survey sent to PHEP directors, to analyze, in part, the readiness of PHEP awardees to vaccinate 80% of the populations of their jurisdictions with 2 doses of pandemic influenza vaccine, separated by 21 days, within 16 weeks of vaccine availability. RESULTS: Thirty-eight of 60 (63.3%) awardees reported being able to vaccinate their populations within 16 weeks; 38 (63.3%) planned to allocate more than 20% of their pandemic vaccine supply to points of dispensing (PODs). Thirty-four of 58 (58.6%) reported staffing as a challenge to vaccinating 80% of their populations; 28 of 60 (46.7%) reported preparedness workforce decreases, and 22 (36.7%) reported immunization workforce decreases between January 2012 and July 2015. CONCLUSIONS: Awardees relied on PODs to vaccinate segments of their jurisdictions despite workforce decreases. Planners must ensure readiness for POD sites to vaccinate, but should also leverage complementary sites and providers to augment public health response. PMID- 28892451 TI - Public Health Preparedness Funding: Key Programs and Trends From 2001 to 2017. AB - OBJECTIVES: To evaluate trends in funding over the past 16 years for key federal public health preparedness and response programs at the US Department of Health and Human Services, to improve understanding of federal funding history in this area, and to provide context for future resource allocation decisions for public health preparedness. METHODS: In this 2017 analysis, we examined the funding history of key federal programs critical to public health preparedness by reviewing program budget data collected for our annual examination of federal funding for biodefense and health security programs since fiscal year (FY) 2001. RESULTS: State and local preparedness at the Centers for Disease Control and Prevention initially received $940 million in FY2002 and resulted in significant preparedness gains, but funding levels have since decreased by 31%. Similarly, the Hospital Preparedness Program within the Office of the Assistant Secretary for Preparedness and Response was funded at a high of $515 million in FY2003, but funding was reduced by 50%. Investments in medical countermeasure development and stockpiling remained relatively stable. CONCLUSIONS: The United States has made significant progress in preparing for disasters and advancing public health infrastructure. To enable continued advancement, federal funding commitments must be sustained. PMID- 28892452 TI - Science in Emergency Response at CDC: Structure and Functions. AB - Recent high-profile activations of the US Centers for Disease Control and Prevention (CDC) Emergency Operations Center (EOC) include responses to the West African Ebola and Zika virus epidemics. Within the EOC, emergency responses are organized according to the Incident Management System, which provides a standardized structure and chain of command, regardless of whether the EOC activation occurs in response to an outbreak, natural disaster, or other type of public health emergency. By embedding key scientific roles, such as the associate director for science, and functions within a Scientific Response Section, the current CDC emergency response structure ensures that both urgent and important science issues receive needed attention. Key functions during emergency responses include internal coordination of scientific work, data management, information dissemination, and scientific publication. We describe a case example involving the ongoing Zika virus response that demonstrates how the scientific response structure can be used to rapidly produce high-quality science needed to answer urgent public health questions and guide policy. Within the context of emergency response, longer-term priorities at CDC include both streamlining administrative requirements and funding mechanisms for scientific research. PMID- 28892453 TI - Public Health Disasters: Be Prepared. PMID- 28892454 TI - Disease Staging and Prognosis in Smokers Using Deep Learning in Chest Computed Tomography. AB - RATIONALE: Deep learning is a powerful tool that may allow for improved outcome prediction. OBJECTIVES: To determine if deep learning, specifically convolutional neural network (CNN) analysis, could detect and stage chronic obstructive pulmonary disease (COPD) and predict acute respiratory disease (ARD) events and mortality in smokers. METHODS: A CNN was trained using computed tomography scans from 7,983 COPDGene participants and evaluated using 1,000 nonoverlapping COPDGene participants and 1,672 ECLIPSE participants. Logistic regression (C statistic and the Hosmer-Lemeshow test) was used to assess COPD diagnosis and ARD prediction. Cox regression (C index and the Greenwood-Nam-D'Agnostino test) was used to assess mortality. MEASUREMENTS AND MAIN RESULTS: In COPDGene, the C statistic for the detection of COPD was 0.856. A total of 51.1% of participants in COPDGene were accurately staged and 74.95% were within one stage. In ECLIPSE, 29.4% were accurately staged and 74.6% were within one stage. In COPDGene and ECLIPSE, the C statistics for ARD events were 0.64 and 0.55, respectively, and the Hosmer-Lemeshow P values were 0.502 and 0.380, respectively, suggesting no evidence of poor calibration. In COPDGene and ECLIPSE, CNN predicted mortality with fair discrimination (C indices, 0.72 and 0.60, respectively), and without evidence of poor calibration (Greenwood-Nam-D'Agnostino P values, 0.307 and 0.331, respectively). CONCLUSIONS: A deep-learning approach that uses only computed tomography imaging data can identify those smokers who have COPD and predict who are most likely to have ARD events and those with the highest mortality. At a population level CNN analysis may be a powerful tool for risk assessment. PMID- 28892455 TI - Modeling specific antibody responses to natural immunization to predict a correlate of protection against infection before commencing a clinical vaccine trial. AB - BACKGROUND: Clinical trials of vaccines for children to prevent acute otitis media (AOM) infections caused by the bacteria Streptococcus pneumonia (Spn) are in Phase I. The objective of this study was to use serum antibody measurements to pneumococcal purified protein candidate antigens that occurred after natural "immunization" to predict a correlate of protection response needed following an injectable vaccine against AOM in children. METHODS: 590 nasal and serum samples were collected from 129 healthy children at 6, 9, 12, 15, 18, 24 and 30-36 months of age and when the child developed AOM. Middle ear fluid to detect Spn was collected at every episode of AOM. Quantitative ELISA was used to determine serum IgG against 7 Spn vaccine antigens: PspA clade 3, PspA clade 5, PhtD, PhtE, LytB, PcpA and Ply. A correlate of protection (COP) was estimated by regressing AOM events against age adjusted antibody levels induced by nasopharyngeal colonization and AOM infections, using logistic regression and generalized estimating equation methods. RESULTS: A significant COP was found for Spn PhtD (p = 0.0015), PhtE (p = 0.00034), LytB (p = 0.004), PcpA (p = 0.002), and Ply (p = 0.007) between higher antibody levels and reduced frequency of AOM. We estimated that a 2-fold higher antibody level in a child than the mean antibody level induced by NP colonization (after adjusting for subject age) to PhtD, LytB, PcpA, PhtE or Ply reduced the risk of AOM by 14-21%, a 4-fold higher level reduced it by 25-38% and a 10-fold higher level reduced it by 39-54%. CONCLUSION: We developed a model to predict the necessary level of serum antibody and fold higher above a threshold to PhtD, PhtE, LytB, PcpA and Ply that would correlate with a reduced likelihood of AOM in children age 6-24 months old if enrolled in a Phase III clinical efficacy trial. PMID- 28892456 TI - Nobiletin Attenuates the Inflammatory Response Through Heme Oxygenase-1 Induction in the Crosstalk Between Adipocytes and Macrophages. AB - Crosstalk between adipocytes and macrophages has been suggested to play a crucial role in metabolic disorders such as obesity, insulin resistance, and type 2 diabetes. The objective of this study was to evaluate the effect of nobiletin on the interaction between adipocytes and macrophages. The results showed that nobiletin significantly and dose-dependently inhibited the secretion of inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor (TNF alpha), and monocyte chemoattractant protein (MCP)-1, in a coculture of adipocytes and macrophages. The expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha), in differentiated 3T3-L1 cells cocultured in transwell system was blocked by nobiletin. Nobiletin also downregulated the expression of inducible NO synthase in cocultured differentiated RAW264.7 cells. Furthermore, heme oxygenase-1 (HO-1) was significantly induced by nobiletin treatment in both cell types, and small interfering (si) RNA-mediated knockdown of HO-1 significantly recovered the inhibitory effects of nobiletin on the NO production in cocultured cells. These results suggest that nobiletin exerts anti-inflammatory effects on the crosstalk between adipocytes and macrophages by inducing HO-1. Nobiletin may have potential for the prevention of obesity-related metabolic diseases. PMID- 28892457 TI - Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. AB - BACKGROUND: Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS: We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in >=330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS: Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS: In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .). PMID- 28892459 TI - Romosozumab - Promising or Practice Changing? PMID- 28892460 TI - Fatigue-related changes in technique emerge at different timescales during repetitive training. AB - Training consisting of numerous repetitions performed as closely as possible to ideal techniques is common in sports and every-day tasks. Little is known about fatigue-related technique changes that emerge at different timescales when repeating complex actions such as a karate front kick. Accordingly, 15 karatekas performed 600 kicks (1 pre-block and 9 blocks). The pre-block comprised 6 kicks (3 with each leg) at maximum intensity (K-100%). Each block comprised 60 kicks (10 with each leg) at 80% of their self-perceived maximum intensity (K-80%) plus 6 K-100%. In between blocks, the participants rested for 90 seconds. Right leg kinematics (peak joint angles, peak joint angular velocities, peak joint linear resultant velocities, and time of occurrence of peaks) and kick duration corresponding to the K-80% were measured resulting in numerous variations with fatigue. At the timescale of tens of seconds, the changes involved variables that were related to velocity of execution (slowed down), while variables related to movement form were hardly affected. At the timescale of tens of minutes, the opposite results were observed. These findings challenge the long-standing rationale underlying repetitive training, suggesting instead that such involuntary variations in technique might play a crucial role in motor skill training. PMID- 28892461 TI - Satisfaction with assistive technology device in relation to the service delivery process-A systematic review. AB - The service delivery process (SDP) of assistive technology devices (ATDs) is attracting interest, as the provision of ATDs is critical for the independence and participation in society of individuals with disabilities. The purpose of the current study was to investigate what impact the SDP has on satisfaction with ATDs in individuals with disabilities in relation to everyday activities. A systematic literature review was conducted, which resulted in 53 articles included. The results showed that there are factors in almost all the different steps of the SDP that affect the satisfaction with of the devices, which can lead to underutilization and abandonment of ATDs. Only a few studies have been conducted with a design robust enough to generalize the results; therefore, more research is needed. Therefore, the conclusion is the SDP as a whole contributes to the satisfaction with and usability of ATDs in individuals with disability in relation to achieving the desired goals of participation in everyday activities, for the articles included must be deemed as moderate. A client-centred approach in the process is advocated, and was found to be an important factor for an effective SDP and satisfied users. PMID- 28892458 TI - Linearity, Bias, and Precision of Hepatic Proton Density Fat Fraction Measurements by Using MR Imaging: A Meta-Analysis. AB - Purpose To determine the linearity, bias, and precision of hepatic proton density fat fraction (PDFF) measurements by using magnetic resonance (MR) imaging across different field strengths, imager manufacturers, and reconstruction methods. Materials and Methods This meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search identified studies that evaluated the linearity and/or bias of hepatic PDFF measurements by using MR imaging (hereafter, MR imaging-PDFF) against PDFF measurements by using colocalized MR spectroscopy (hereafter, MR spectroscopy-PDFF) or the precision of MR imaging-PDFF. The quality of each study was evaluated by using the Quality Assessment of Studies of Diagnostic Accuracy 2 tool. De-identified original data sets from the selected studies were pooled. Linearity was evaluated by using linear regression between MR imaging-PDFF and MR spectroscopy-PDFF measurements. Bias, defined as the mean difference between MR imaging-PDFF and MR spectroscopy-PDFF measurements, was evaluated by using Bland-Altman analysis. Precision, defined as the agreement between repeated MR imaging-PDFF measurements, was evaluated by using a linear mixed-effects model, with field strength, imager manufacturer, reconstruction method, and region of interest as random effects. Results Twenty-three studies (1679 participants) were selected for linearity and bias analyses and 11 studies (425 participants) were selected for precision analyses. MR imaging-PDFF was linear with MR spectroscopy-PDFF (R2 = 0.96). Regression slope (0.97; P < .001) and mean Bland-Altman bias (-0.13%; 95% limits of agreement: -3.95%, 3.40%) indicated minimal underestimation by using MR imaging-PDFF. MR imaging-PDFF was precise at the region-of-interest level, with repeatability and reproducibility coefficients of 2.99% and 4.12%, respectively. Field strength, imager manufacturer, and reconstruction method each had minimal effects on reproducibility. Conclusion MR imaging-PDFF has excellent linearity, bias, and precision across different field strengths, imager manufacturers, and reconstruction methods. (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on October 2, 2017. PMID- 28892462 TI - Cycling performance is superior for time-to-exhaustion versus time-trial in endurance laboratory tests. AB - Time-to-exhaustion (TTE) trials are used in a laboratory setting to measure endurance performance. However, there is some concern with their ecological validity compared with time-trials (TT). Consequently, we aimed to compare cycling performance in TTE and TT where the duration of the trials was matched. Seventeen trained male cyclists completed three TTE trials at 80, 100 and 105% of maximal aerobic power (MAP). On a subsequent visit they performed three TT over the same duration as the TTE. Participants were blinded to elapsed time, power output, cadence and heart rate (HR). Average TTE was 865 +/- 345 s, 165 +/- 98 s and 117 +/- 45 s for the 80, 100 and 105% trials respectively. Average power output was higher for TTE (294 +/- 44 W) compared to TT (282 +/- 43 W) at 80% MAP (P < 0.01), but not at 100 and 105% MAP (P > 0.05). There was no difference in cadence, HR, or RPE for any trial (P > 0.05). Critical power (CP) was also higher when derived from TTE compared to TT (P < 0.01). It is concluded that TTE results in a higher average power output compared to TT at 80% MAP. When determining CP, TTE rather than TT protocols appear superior. PMID- 28892463 TI - Effect of different velocity loss thresholds during a power-oriented resistance training program on the mechanical capacities of lower-body muscles. AB - This study compared the effects of two velocity loss thresholds during a power oriented resistance training program on the mechanical capacities of lower-body muscles. Twenty men were counterbalanced in two groups (VL10 and VL20) based on their maximum power capacity. Both groups used the same exercises, relative intensity and repetition volume, only differing in the velocity loss threshold of each set (VL10: 10% vs. VL20: 20%). Pre- and post-training assessments included an incremental loading test and a 15-m linear sprint to assess the force- and load-velocity relationships and athletic performance variables, respectively. No significant between-group differences (P > 0.05) were observed for the force velocity relationship parameters (ES range = 0.15-0.42), the MPV attained against different external loads (ES range = 0.02-0.18) or the 15-m sprint time (ES = 0.09). A high between-participants variability was reported for the number of repetitions completed in each training set (CV = 30.3% for VL10 and 29.4% for VL20). These results suggest that both velocity loss thresholds induce similar changes on the lower-body function. The high and variable number of repetitions completed may compromise the velocity-based approach for prescribing and monitoring the repetition volume during a power-oriented resistance training program conducted with the countermovement jump exercise. PMID- 28892465 TI - Shifting memories. AB - A region of the brain called the putamen has a central role in procedural memory consolidation during sleep. PMID- 28892464 TI - Network-wide reorganization of procedural memory during NREM sleep revealed by fMRI. AB - Sleep is necessary for the optimal consolidation of newly acquired procedural memories. However, the mechanisms by which motor memory traces develop during sleep remain controversial in humans, as this process has been mainly investigated indirectly by comparing pre- and post-sleep conditions. Here, we used functional magnetic resonance imaging and electroencephalography during sleep following motor sequence learning to investigate how newly-formed memory traces evolve dynamically over time. We provide direct evidence for transient reactivation followed by downscaling of functional connectivity in a cortically dominant pattern formed during learning, as well as gradual reorganization of this representation toward a subcortically-dominant consolidated trace during non rapid eye movement (NREM) sleep. Importantly, the putamen functional connectivity within the consolidated network during NREM sleep was related to overnight behavioral gains. Our results demonstrate that NREM sleep is necessary for two complementary processes: the restoration and reorganization of newly-learned information during sleep, which underlie human motor memory consolidation. PMID- 28892466 TI - Malignant transformation of a tailgut cyst. AB - INTRODUCTION: Tailgut cyst are congenital cystic lesion arising from remnant of the embryological postnatal gut. Tailgut cyst are multinodular, uncapsulated and usually well-circumscribed. Presacral cysts are rare in adult and most of the lesions are benign. Malignant degeneration can occur, however is extremely rare. CASE REPORT: We present the case of a 74 years old woman with slow increase in size and malignant degeneration of a tailgut cyst. Five years before, during the follow up after mastectomy for cancer, she manifested rise of CA 19-9 tumor marker and a presacral cystic collection on thoraco-abdominal CT. She was followed with CT and MRI that showed that the cyst, with a solid component of the wall, was growing larger. After a five-year evolution, the cyst was resected. The histological examination on the solid component demonstrated intestinal adenocarcinoma. CONCLUSION: MRI ant TC can play essential role in the preoperative detection and characterization for the differential diagnosis, treatment strategies and evaluate neoplastic degeneration. Due to the risk of malignancy surgical resection must be performed after the diagnosis. Surgical therapy is mandatory when the cyst grow larger and a solid component is present. KEY WORDS: Presacral cyst, Retrorectal tumors, Tailgut cyst. PMID- 28892467 TI - A new approach to umbilical hernia repair: the circular suture technique for defects less than 2 cm. AB - BACKGROUND: Umbilical hernia, unlike other abdominal wall hernias, occurs when the umbilical ring opens and expands. Its' symptoms and complications show similarities with other hernias. Although there are various repair techniques, there is not a standard technique yet. This paper investigated the outcomes of double layer circular suture technique as a new approach in the repair of umbilical hernia. MATERIAL AND METHOD: A total number of 282 patients comprised of 102 males and 180 females with an age range of 18-89 whose umbilical hernias were repaired between 2002 and 2013, retrospectively studied in two groups group 1 (circular suture technique) and group 2 (open primary suture). The subjects were investigated with regards to age, sex, body mass index (BMI), accompanying disease, anesthesia method, surgical complications, hospital stay, total costs, mortality and recurrence. RESULTS: The study participants were 282 patients with an age average of 49, 09 +/- 16, 62 including 182 patients in group 1 (male/female ratio 76/106) and 100 patients in group 2 (26/74). There was a significant difference between the groups in terms of time and recurrence. During the follow-up period, 9 patients in group 1 (4.94%) and 16 patients in group 2 (16%) had a recurrence. This result was statistically significant (p=0.014) CONCLUSION: We believe that the double layer circular suture technique is practical, inexpensive and effective in the repair of umbilical hernia defects, which are smaller than 2 cm diameter. Key words: Hernia, Repair, Umbilical hernia. PMID- 28892468 TI - Association Between Oxidative Stress and Peripheral Leukocyte Telomere Length in Patients with Premature Coronary Artery Disease. AB - BACKGROUND Leukocyte telomere length (LTL) is regarded as a potential marker of biological aging. Oxidative stress plays a major role in the rate of telomeric DNA loss. The aim of this study was to explore whether the LTL was shorter in Chinese patients with premature coronary artery disease (PCAD) than in non-CAD controls and to determine the relationship between oxidative stress and LTL shortening in this population. MATERIAL AND METHODS Patients for coronary angiography were recruited. In total, 128 patients with PCAD and 128 non-CAD controls were enrolled. Samples of circulating leukocytes and plasma were collected. The mean LTL was measured using a polymerase chain reaction-based assay and expressed as the ratio of telomere repeat copies to single-copy gene (SCG) copies (T/S ratio). Reactive oxygen species (ROS) levels and total antioxidant capacity (T-AOC) were determined in plasma. RESULTS Both the T/S ratio (0.88+/-0.86 vs. 1.10+/-0.57, P=0.015) and telomere base pairs (4.97+/-1.37 kb vs. 5.32+/-0.91 kb, P=0.015) were significantly shorter in the PCAD group than in non-CAD controls. The T-AOC levels of the PCAD group were significantly lower than those of the non-CAD controls (0.482 mM [0.279, 0.603 mM]) vs. 0.778 mM [0.421, 0.924 mM], P=0.000). The ratio of T-AOC to ROS in the PCAD patients was significantly decreased compared to that of the non-CAD controls (0.1026+/-0. 1587 [Mm*ml/ng] vs. 0.1435+/-0.1946 [Mm*ml/ng], P=0.013). CONCLUSIONS The results point to a potential link between reduced LTLs in patients with PCAD and early onset of atherosclerosis. The decline in antioxidant capacity may play an important role in accelerating the attrition of telomeres in PCAD patients. PMID- 28892469 TI - De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors. AB - The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms. PMID- 28892470 TI - Different molecular complexes that mediate transcriptional induction and repression by FoxP3. AB - FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-expressed in Treg cells. We evaluated the impact of a panel of FoxP3 mutants on its transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 existed in distinct multimolecular complexes. It was active and primarily an activator when complexed with the transcriptional factors RELA, IKZF2 and KAT5. In contrast, FoxP3 was inactive when complexed with the histone methyltransferase EZH2 and transcription factors YY1 and IKZF3. The latter complex partitioned to a peripheral region of the nucleus, as shown by super-resolution microscopy. Thus, FoxP3 acts in multimodal fashion to directly activate or repress transcription, in a context- and partner-dependent manner, to govern Treg cell phenotypes. PMID- 28892472 TI - Target product profiles for the diagnosis of Taenia solium taeniasis, neurocysticercosis and porcine cysticercosis. AB - Target Product Profiles (TPPs) are process tools providing product requirements to guide researchers, developers and manufacturers in their efforts to develop effective and useful products such as biologicals, drugs or diagnostics. During a WHO Stakeholders Meeting on Taenia solium diagnostics, several TPPs were initiated to address diagnostic needs for different stages in the parasite's transmission (taeniasis, human and porcine cysticercosis). Following the meeting, draft TPPs were completed and distributed for consultation to 100 people/organizations, including experts in parasitology, human and pig cysticercosis, diagnostic researchers and manufacturers, international organizations working with neglected or zoonotic diseases, Ministries of Health and Ministries of Livestock in some of the endemic countries, WHO regional offices and other interested parties. There were 53 respondents. All comments and feedback received were considered and discussions were held with different experts according to their area of expertise. The comments were consolidated and final TPPs are presented here. They are considered to be live documents which are likely to undergo review and updating in the future when new knowledge and technologies become available. PMID- 28892471 TI - Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. AB - Interleukin 2 (IL-2) promotes Foxp3+ regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses. PMID- 28892473 TI - A multi-center field study of two point-of-care tests for circulating Wuchereria bancrofti antigenemia in Africa. AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis uses point-of care tests for circulating filarial antigenemia (CFA) to map endemic areas and for monitoring and evaluating the success of mass drug administration (MDA) programs. We compared the performance of the reference BinaxNOW Filariasis card test (ICT, introduced in 1997) with the Alere Filariasis Test Strip (FTS, introduced in 2013) in 5 endemic study sites in Africa. METHODOLOGY: The tests were compared prior to MDA in two study sites (Congo and Cote d'Ivoire) and in three sites that had received MDA (DRC and 2 sites in Liberia). Data were analyzed with regard to % positivity, % agreement, and heterogeneity. Models evaluated potential effects of age, gender, and blood microfilaria (Mf) counts in individuals and effects of endemicity and history of MDA at the village level as potential factors linked to higher sensitivity of the FTS. Lastly, we assessed relationships between CFA scores and Mf in pre- and post-MDA settings. PRINCIPAL FINDINGS: Paired test results were available for 3,682 individuals. Antigenemia rates were 8% and 22% higher by FTS than by ICT in pre-MDA and in post-MDA sites, respectively. FTS/ICT ratios were higher in areas with low infection rates. The probability of having microfilaremia was much higher in persons with CFA scores >1 in untreated areas. However, this was not true in post-MDA settings. CONCLUSIONS/SIGNIFICANCE: This study has provided extensive new information on the performance of the FTS compared to ICT in Africa and it has confirmed the increased sensitivity of FTS reported in prior studies. Variability in FTS/ICT was related in part to endemicity level, history of MDA, and perhaps to the medications used for MDA. These results suggest that FTS should be superior to ICT for mapping, for transmission assessment surveys, and for post-MDA surveillance. PMID- 28892474 TI - Enhancing case definitions for surveillance of human monkeypox in the Democratic Republic of Congo. AB - BACKGROUND: Human monkeypox (MPX) occurs at appreciable rates in the Democratic Republic of Congo (DRC). Infection with varicella zoster virus (VZV) has a similar presentation to that of MPX, and in areas where MPX is endemic these two illnesses are commonly mistaken. This study evaluated the diagnostic utility of two surveillance case definitions for MPX and specific clinical characteristics associated with laboratory-confirmed MPX cases. METHODOLOGY/PRINCIPAL FINDINGS: Data from a cohort of suspect MPX cases (identified by surveillance over the course of a 42 month period during 2009-2014) from DRC were used; real-time PCR diagnostic test results were used to establish MPX and VZV diagnoses. A total of 333 laboratory-confirmed MPX cases, 383 laboratory-confirmed VZV cases, and 36 cases that were determined to not be either MPX or VZV were included in the analyses. Significant (p<0.05) differences between laboratory-confirmed MPX and VZV cases were noted for several signs/symptoms including key rash characteristics. Both surveillance case definitions had high sensitivity and low specificities for individuals that had suspected MPX virus infections. Using 12 signs/symptoms with high sensitivity and/or specificity values, a receiver operator characteristic analysis showed that models for MPX cases that had the presence of 'fever before rash' plus at least 7 or 8 of the 12 signs/symptoms demonstrated a more balanced performance between sensitivity and specificity. CONCLUSIONS: Laboratory-confirmed MPX and VZV cases presented with many of the same signs and symptoms, and the analysis here emphasized the utility of including 12 specific signs/symptoms when investigating MPX cases. In order to document and detect endemic human MPX cases, a surveillance case definition with more specificity is needed for accurate case detection. In the absence of a more specific case definition, continued emphasis on confirmatory laboratory-based diagnostics is warranted. PMID- 28892475 TI - Cost-effectiveness of a national enterovirus 71 vaccination program in China. AB - BACKGROUND AND AIMS: Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Vaccines against EV71 have been proved effective and safe by recent phase 3 trials and are now available in China. The purpose of this study was to evaluate the health impact and cost-effectiveness of a national EV71 vaccination program in China. METHODS: Using Microsoft Excel, a decision model was built to calculate the net clinical and economic outcomes of EV71 vaccination compared with no EV71 vaccination in a birth cohort of 1,000,000 Chinese children followed for five years. Model parameters came from published epidemiology, clinical and cost data. RESULTS: In the base-case, vaccination would annually avert 37,872 cases of hand, foot and mouth disease (HFMD), 2,629 herpangina cases, 72,900 outpatient visits, 6,363 admissions to hospital, 29 deaths, and 945 disability adjusted life years. The break-even price of the vaccine was $5.2/dose. When the price was less than $8.3 or $14.6/dose, the vaccination program would be highly cost-effective or cost-effective, respectively (incremental cost-effectiveness ratio less than or between one to three times China GDP per capita, respectively). In one-way sensitivity analyses, the HFMD incidence was the only influential parameter at the price of $5/dose. CONCLUSIONS: Within the price range of current routine vaccines paid by the government, a national EV71 vaccination program would be cost-saving or highly cost-effective to prevent EV71 related morbidity, mortality, and use of health service among children younger than five years in China. Policy makers should consider including EV71 vaccination as part of China's routine childhood immunization schedule. PMID- 28892476 TI - Induction of allopurinol resistance in Leishmania infantum isolated from dogs. AB - Resistance to allopurinol in zoonotic canine leishmaniasis has been recently shown to be associated with disease relapse in naturally-infected dogs. However, information regarding the formation of resistance and its dynamics is lacking. This study describes the successful in-vitro induction of allopurinol resistance in Leishmania infantum cultured under increasing drug pressure. Allopurinol susceptibility and growth rate of induced parasites were monitored over 23 weeks and parasite clones were tested at selected time points and compared to their parental lines, both as promastigotes and as amastigotes. Allopurinol resistance was formed in strains from two parasite stocks producing a 20-fold rise in IC50 along three distinct growth phases. In addition, characteristic differential clustering of single nucleotide polymorphisms (SNP) was found in drug sensitive and resistant parasite clones. Results confirm that genetic polymorphism, as well as clonal heterogeneity, contribute to in-vitro resistance to allopurinol, which is likely to occur in natural infection. PMID- 28892478 TI - Continuous robust sound event classification using time-frequency features and deep learning. AB - The automatic detection and recognition of sound events by computers is a requirement for a number of emerging sensing and human computer interaction technologies. Recent advances in this field have been achieved by machine learning classifiers working in conjunction with time-frequency feature representations. This combination has achieved excellent accuracy for classification of discrete sounds. The ability to recognise sounds under real world noisy conditions, called robust sound event classification, is an especially challenging task that has attracted recent research attention. Another aspect of real-word conditions is the classification of continuous, occluded or overlapping sounds, rather than classification of short isolated sound recordings. This paper addresses the classification of noise-corrupted, occluded, overlapped, continuous sound recordings. It first proposes a standard evaluation task for such sounds based upon a common existing method for evaluating isolated sound classification. It then benchmarks several high performing isolated sound classifiers to operate with continuous sound data by incorporating an energy based event detection front end. Results are reported for each tested system using the new task, to provide the first analysis of their performance for continuous sound event detection. In addition it proposes and evaluates a novel Bayesian-inspired front end for the segmentation and detection of continuous sound recordings prior to classification. PMID- 28892477 TI - Allosteric conformational change cascade in cytoplasmic dynein revealed by structure-based molecular simulations. AB - Cytoplasmic dynein is a giant ATP-driven molecular motor that proceeds to the minus end of the microtubule (MT). Dynein hydrolyzes ATP in a ring-like structure, containing 6 AAA+ (ATPases associated with diverse cellular activities) modules, which is ~15 nm away from the MT binding domain (MTBD). This architecture implies that long-distance allosteric couplings exist between the AAA+ ring and the MTBD in order for dynein to move on the MT, although little is known about the mechanisms involved. Here, we have performed comprehensive molecular simulations of the dynein motor domain based on pre- and post- power stroke structural information and in doing so we address the allosteric conformational changes that occur during the power-stroke and recovery-stroke processes. In the power-stroke process, the N-terminal linker movement was the prerequisite to the nucleotide-dependent AAA1 transition, from which a transition cascade propagated, on average, in a circular manner on the AAA+ ring until it reached the AAA6/C-terminal module. The recovery-stroke process was initiated by the transition of the AAA6/C-terminal, from which the transition cascade split into the two directions of the AAA+ ring, occurring both clockwise and anti clockwise. In both processes, the MTBD conformational change was regulated by the AAA4 module and the AAA5/Strut module. PMID- 28892479 TI - Towards Chagas disease elimination: Neonatal screening for congenital transmission in rural communities. AB - Chagas disease is a neglected tropical disease that continues to affect populations living in extreme poverty in Latin America. After successful vector control programs, congenital transmission remains as a challenge to disease elimination. We used the PRECEDE-PROCEED planning model to develop strategies for neonatal screening of congenital Chagas disease in rural communities of Guatemala. These communities have persistent high triatomine infestations and low access to healthcare. We used mixed methods with multiple stakeholders to identify and address maternal-infant health behaviors through semi-structured interviews, participatory group meetings, archival reviews and a cross-sectional survey in high risk communities. From December 2015 to April 2016, we jointly developed a strategy to illustratively advertise newborn screening at the Health Center. The strategy included socioculturally appropriate promotional and educational material, in collaboration with midwives, nurses and nongovernmental organizations. By March 2016, eight of 228 (3.9%) pregnant women had been diagnosed with T. cruzi at the Health Center. Up to this date, no neonatal screening had been performed. By August 2016, seven of eight newborns born to Chagas seropositive women had been parasitologically screened at the Health Center, according to international standards. Thus, we implemented a successful community-based neonatal screening strategy to promote congenital Chagas disease healthcare in a rural setting. The success of the health promotion strategies developed will depend on local access to maternal-infant services, integration with detection of other congenital diseases and reliance on community participation in problem and solution definition. PMID- 28892480 TI - Estimating global, regional and national rotavirus deaths in children aged <5 years: Current approaches, new analyses and proposed improvements. AB - BACKGROUND: Rotavirus is a leading cause of diarrhoeal mortality in children but there is considerable disagreement about how many deaths occur each year. METHODS AND FINDINGS: We compared CHERG, GBD and WHO/CDC estimates of age under 5 years (U5) rotavirus deaths at the global, regional and national level using a standard year (2013) and standard list of 186 countries. The global estimates were 157,398 (CHERG), 122,322 (GBD) and 215,757 (WHO/CDC). The three groups used different methods: (i) to select data points for rotavirus-positive proportions; (ii) to extrapolate data points to individual countries; (iii) to account for rotavirus vaccine coverage; (iv) to convert rotavirus-positive proportions to rotavirus attributable fractions; and (v) to calculate uncertainty ranges. We conducted new analyses to inform future estimates. We found that acute watery diarrhoea was associated with 87% (95% CI 83-90%) of U5 diarrhoea hospitalisations based on data from 84 hospital sites in 9 countries, and 65% (95% CI 57-74%) of U5 diarrhoea deaths based on verbal autopsy reports from 9 country sites. We reanalysed data from the Global Enteric Multicenter Study (GEMS) and found 44% (55% in Asia, and 32% in Africa) rotavirus-positivity among U5 acute watery diarrhoea hospitalisations, and 28% rotavirus-positivity among U5 acute watery diarrhoea deaths. 97% (95% CI 95-98%) of the U5 diarrhoea hospitalisations that tested positive for rotavirus were entirely attributable to rotavirus. For all clinical syndromes combined the rotavirus attributable fraction was 34% (95% CI 31-36%). This increased by a factor of 1.08 (95% CI 1.02-1.14) when the GEMS results were reanalysed using a more sensitive molecular test. CONCLUSIONS: We developed consensus on seven proposals for improving the quality and transparency of future rotavirus mortality estimates. PMID- 28892481 TI - Cost-efficient vaccination protocols for network epidemiology. AB - We investigate methods to vaccinate contact networks-i.e. removing nodes in such a way that disease spreading is hindered as much as possible-with respect to their cost-efficiency. Any real implementation of such protocols would come with costs related both to the vaccination itself, and gathering of information about the network. Disregarding this, we argue, would lead to erroneous evaluation of vaccination protocols. We use the susceptible-infected-recovered model-the generic model for diseases making patients immune upon recovery-as our disease spreading scenario, and analyze outbreaks on both empirical and model networks. For different relative costs, different protocols dominate. For high vaccination costs and low costs of gathering information, the so-called acquaintance vaccination is the most cost efficient. For other parameter values, protocols designed for query-efficient identification of the network's largest degrees are most efficient. PMID- 28892482 TI - 'Spin' in published biomedical literature: A methodological systematic review. AB - In the scientific literature, spin refers to reporting practices that distort the interpretation of results and mislead readers so that results are viewed in a more favourable light. The presence of spin in biomedical research can negatively impact the development of further studies, clinical practice, and health policies. This systematic review aims to explore the nature and prevalence of spin in the biomedical literature. We searched MEDLINE, PreMEDLINE, Embase, Scopus, and hand searched reference lists for all reports that included the measurement of spin in the biomedical literature for at least 1 outcome. Two independent coders extracted data on the characteristics of reports and their included studies and all spin-related outcomes. Results were grouped inductively into themes by spin-related outcome and are presented as a narrative synthesis. We used meta-analyses to analyse the association of spin with industry sponsorship of research. We included 35 reports, which investigated spin in clinical trials, observational studies, diagnostic accuracy studies, systematic reviews, and meta-analyses. The nature of spin varied according to study design. The highest (but also greatest) variability in the prevalence of spin was present in trials. Some of the common practices used to spin results included detracting from statistically nonsignificant results and inappropriately using causal language. Source of funding was hypothesised by a few authors to be a factor associated with spin; however, results were inconclusive, possibly due to the heterogeneity of the included papers. Further research is needed to assess the impact of spin on readers' decision-making. Editors and peer reviewers should be familiar with the prevalence and manifestations of spin in their area of research in order to ensure accurate interpretation and dissemination of research. PMID- 28892483 TI - Quality control methods for Aedes albopictus sterile male production. AB - The capacity of the released sterile males to survive, disperse, compete with wild males and inseminate wild females is an essential prerequisite to be evaluated in any area-wide integrated pest management (AW-IPM) programs including a sterile insect release method. Adequate quality control tests supported by standardized procedures need to be developed to measure these parameters and to identify and correct potential inappropriate rearing or handling methods affecting the overall male quality. In this study, we report results on the creation and validation of the first quality control devices designed to infer the survival and mating capacity of radio-sterilized Aedes albopictus males through the observation of their flight capacity under restricted conditions (flight organ device) and after stress treatment (aspirator device). Results obtained consistently indicate comparable flight capacity and quality parameters between untreated and 35 Gy irradiated males while a negative impact was observed with higher radiation doses at all observation time performed. The male flight capacity registered with the proposed quality control devices can be successfully employed, with different predictive capacities and response time, to infer the adult male quality. These simple and cost-effective tools provide a valuable method to detect and amend potentially sub-standard procedures in the sterile male production line and hence contribute to maintaining optimal quality and field performance of the mosquitoes being released. PMID- 28892484 TI - Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium. AB - The organ of Corti in the cochlea is a two-cell layered epithelium: one cell layer of mechanosensory hair cells that align into one row of inner and three rows of outer hair cells interdigitated with one cell layer of underlying supporting cells along the entire length of the cochlear spiral. These two types of epithelial cells are derived from common precursors in the four- to five-cell layered primordium and acquire functionally important shapes during terminal differentiation through the thinning process and convergent extension. Here, we have examined the role of Six1 in the establishment of the auditory sensory epithelium. Our data show that prior to terminal differentiation of the precursor cells, deletion of Six1 leads to formation of only a few hair cells and defective patterning of the sensory epithelium. Previous studies have suggested that downregulation of Sox2 expression in differentiating hair cells must occur after Atoh1 mRNA activation in order to allow Atoh1 protein accumulation due to antagonistic effects between Atoh1 and Sox2. Our analysis indicates that downregulation of Sox2 in the differentiating hair cells depends on Six1 activity. Furthermore, we found that Six1 is required for the maintenance of Fgf8 expression and dynamic distribution of N-cadherin and E-cadherin in the organ of Corti during differentiation. Together, our analyses uncover essential roles of Six1 in hair cell differentiation and formation of the organ of Corti in the mammalian cochlea. PMID- 28892485 TI - Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Galphai1. AB - Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled receptor signal transduction pathways, which is a well-known target for drug development. AC is regulated by activated stimulatory (Galphas) and inhibitory (Galphai) G proteins in the cytosol. Although experimental studies have shown that these Galpha subunits can stimulate or inhibit AC's function in a non competitive way, it is not well understood what the difference is in their mode of action as both Galpha subunits appear structurally very similar in a non lipidated state. However, a significant difference between Galphas and Galphai is that while Galphas does not require any lipidation in order to stimulate AC, N terminal myristoylation is crucial for Galphai's inhibitory function as AC is not inhibited by non-myristoylated Galphai. At present, only the conformation of the complex including Galphas and AC has been resolved via X-ray crystallography. Therefore, understanding the interaction between Galphai and AC is important as it will provide more insight into the unknown mechanism of AC regulation. This study demonstrates via classical molecular dynamics simulations that the myristoylated Galphai1 structure is able to interact with apo adenylyl cyclase type 5 in a way that causes inhibition of the catalytic function of the enzyme, suggesting that Galpha lipidation could play a crucial role in AC regulation and in regulating G protein function by affecting Galphai's active conformation. PMID- 28892486 TI - Misattribution of musical arousal increases sexual attraction towards opposite sex faces in females. AB - Several theories about the origins of music have emphasized its biological and social functions, including in courtship. Music may act as a courtship display due to its capacity to vary in complexity and emotional content. Support for music's reproductive function comes from the recent finding that only women in the fertile phase of the reproductive cycle prefer composers of complex melodies to composers of simple ones as short-term sexual partners, which is also in line with the ovulatory shift hypothesis. However, the precise mechanisms by which music may influence sexual attraction are unknown, specifically how music may interact with visual attractiveness cues and affect perception and behaviour in both genders. Using a crossmodal priming paradigm, we examined whether listening to music influences ratings of facial attractiveness and dating desirability of opposite-sex faces. We also tested whether misattribution of arousal or pleasantness underlies these effects, and explored whether sex differences and menstrual cycle phase may be moderators. Our sample comprised 64 women in the fertile or infertile phase (no hormonal contraception use) and 32 men, carefully matched for mood, relationship status, and musical preferences. Musical primes (25 s) varied in arousal and pleasantness, and targets were photos of faces with neutral expressions (2 s). Group-wise analyses indicated that women, but not men, gave significantly higher ratings of facial attractiveness and dating desirability after having listened to music than in the silent control condition. High-arousing, complex music yielded the largest effects, suggesting that music may affect human courtship behaviour through induced arousal, which calls for further studies on the mechanisms by which music affects sexual attraction in real-life social contexts. PMID- 28892487 TI - Transcriptome sequencing and delimitation of sympatric Oscarella species (O. carmela and O. pearsei sp. nov) from California, USA. AB - The homoscleromorph sponge Oscarella carmela, first described from central California, USA is shown to represent two superficially similar but both morphologically and phylogenetically distinct species that are co-distributed. We here describe a new species as Oscarella pearsei, sp. nov. and re-describe Oscarella carmela; the original description was based upon material from both species. Further, we correct the identification of published genomic/transcriptomic resources that were originally attributed to O. carmela, and present new Illumina-sequenced transcriptome assemblies for each of these species, and the mitochondrial genome sequence for O. pearsei sp. nov. Using SSU and LSU ribosomal DNA and the mitochondrial genome, we report the phylogenetic relationships of these species relative to other Oscarella species, and find strong support for the placement of O. pearsei sp. nov. in a distinct clade within genus Oscarella defined by the presence of spherulous cells that contain paracrystalline inclusions; O. carmela lacks this cell type. Oscarella pearsei sp. nov and O. carmela can be tentatively distinguished based upon gross morphological differences such as color, surface texture and extent of mucus production, but can be more reliably identified using mitochondrial and nuclear barcode sequencing, ultrastructural characteristics of cells in the mesohyl, and the morphology of the follicle epithelium which surrounds the developing embryo in reproductively active individuals. PMID- 28892488 TI - Self-fertility in Chromocrea spinulosa is a consequence of direct repeat-mediated loss of MAT1-2, subsequent imbalance of nuclei differing in mating type, and recognition between unlike nuclei in a common cytoplasm. AB - The filamentous fungus Chromocrea spinulosa (Trichoderma spinulosum) exhibits both self-fertile (homothallic) and self-sterile (heterothallic) sexual reproductive behavior. Self-fertile strains produce progeny cohorts that are 50% homothallic, 50% heterothallic. Heterothallic progeny can mate only with homothallic strains, and progeny also segregate 50% homothallic, 50% heterothallic. Sequencing of the mating type (MAT) region of homothallic and heterothallic strains revealed that both carry an intact MAT1-1 locus with three MAT1-1 genes (MAT1-1-1, MAT1-1-2, MAT1-1-3), as previously described for the Sordariomycete group of filamentous fungi. Homothallic strains, however, have a second version of MAT with the MAT1-2 locus genetically linked to MAT1-1. In this version, the MAT1-1-1 open reading frame is split into a large and small fragment and the truncated ends are bordered by 115bp direct repeats (DR). The MAT1-2-1 gene and additional sequences are inserted between the repeats. To understand the mechanism whereby C. spinulosa can exhibit both homothallic and heterothallic behavior, we utilized molecular manipulation to delete one of the DRs from a homothallic strain and insert MAT1-2 into a heterothallic strain. Mating assays indicated that: i) the DRs are key to homothallic behavior, ii) looping out of MAT1-2-1 via intra-molecular homologous recombination between the DRs in self fertile strains results in two nuclear types in an individual (one carrying both MAT1-1 and MAT1-2 and one carrying MAT1-1 only), iii) self-fertility is achieved by inter-nuclear recognition between these two nuclear types before meiosis, iv) the two types of nuclei are in unequal proportion, v) having both an intact MAT1 1-1 and MAT1-2-1 gene in a single nucleus is not sufficient for self-fertility, and vi) the large truncated MAT1-1-1 fragment is expressed. Comparisons with MAT regions of Trichoderma reesei and Trichoderma virens suggest that several crossovers between misaligned parental MAT chromosomes may have led to the MAT architecture of homothallic C. spinulosa. PMID- 28892489 TI - Funneled potential and flux landscapes dictate the stabilities of both the states and the flow: Fission yeast cell cycle. AB - Using fission yeast cell cycle as an example, we uncovered that the non equilibrium network dynamics and global properties are determined by two essential features: the potential landscape and the flux landscape. These two landscapes can be quantified through the decomposition of the dynamics into the detailed balance preserving part and detailed balance breaking non-equilibrium part. While the funneled potential landscape is often crucial for the stability of the single attractor networks, we have uncovered that the funneled flux landscape is crucial for the emergence and maintenance of the stable limit cycle oscillation flow. This provides a new interpretation of the origin for the limit cycle oscillations: There are many cycles and loops existed flowing through the state space and forming the flux landscapes, each cycle with a probability flux going through the loop. The limit cycle emerges when a loop stands out and carries significantly more probability flux than other loops. We explore how robustness ratio (RR) as the gap or steepness versus averaged variations or roughness of the landscape, quantifying the degrees of the funneling of the underlying potential and flux landscapes. We state that these two landscapes complement each other with one crucial for stabilities of states on the cycle and the other crucial for the stability of the flow along the cycle. The flux is directly related to the speed of the cell cycle. This allows us to identify the key factors and structure elements of the networks in determining the stability, speed and robustness of the fission yeast cell cycle oscillations. We see that the non-equilibriumness characterized by the degree of detailed balance breaking from the energy pump quantified by the flux is the cause of the energy dissipation for initiating and sustaining the replications essential for the origin and evolution of life. Regulating the cell cycle speed is crucial for designing the prevention and curing strategy of cancer. PMID- 28892490 TI - Development of risk reduction behavioral counseling for Ebola virus disease survivors enrolled in the Sierra Leone Ebola Virus Persistence Study, 2015-2016. AB - BACKGROUND: During the 2014-2016 West Africa Ebola Virus Disease (EVD) epidemic, the public health community had concerns that sexual transmission of the Ebola virus (EBOV) from EVD survivors was a risk, due to EBOV persistence in body fluids of EVD survivors, particularly semen. The Sierra Leone Ebola Virus Persistence Study was initiated to investigate this risk by assessing EBOV persistence in numerous body fluids of EVD survivors and providing risk reduction counseling based on test results for semen, vaginal fluid, menstrual blood, urine, rectal fluid, sweat, tears, saliva, and breast milk. This publication describes implementation of the counseling protocol and the key lessons learned. METHODOLOGY/PRINCIPAL FINDINGS: The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol was developed from a framework used to prevent transmission of HIV and other sexually transmitted infections. The framework helped to identify barriers to risk reduction and facilitated the development of a personalized risk-reduction plan, particularly around condom use and abstinence. Pre-test and post-test counseling sessions included risk reduction guidance, and post-test counseling was based on the participants' individual test results. The behavioral counseling protocol enabled study staff to translate the study's body fluid test results into individualized information for study participants. CONCLUSIONS/SIGNIFICANCE: The Ebola Virus Persistence Risk Reduction Behavioral Counseling Protocol provided guidance to mitigate the risk of EBOV transmission from EVD survivors. It has since been shared with and adapted by other EVD survivor body fluid testing programs and studies in Ebola affected countries. PMID- 28892491 TI - A map of protein dynamics during cell-cycle progression and cell-cycle exit. AB - The cell-cycle field has identified the core regulators that drive the cell cycle, but we do not have a clear map of the dynamics of these regulators during cell-cycle progression versus cell-cycle exit. Here we use single-cell time-lapse microscopy of Cyclin-Dependent Kinase 2 (CDK2) activity followed by endpoint immunofluorescence and computational cell synchronization to determine the temporal dynamics of key cell-cycle proteins in asynchronously cycling human cells. We identify several unexpected patterns for core cell-cycle proteins in actively proliferating (CDK2-increasing) versus spontaneously quiescent (CDK2 low) cells, including Cyclin D1, the levels of which we find to be higher in spontaneously quiescent versus proliferating cells. We also identify proteins with concentrations that steadily increase or decrease the longer cells are in quiescence, suggesting the existence of a continuum of quiescence depths. Our single-cell measurements thus provide a rich resource for the field by characterizing protein dynamics during proliferation versus quiescence. PMID- 28892493 TI - Control of multidimensional systems on complex network. AB - Multidimensional systems coupled via complex networks are widespread in nature and thus frequently invoked for a large plethora of interesting applications. From ecology to physics, individual entities in mutual interactions are grouped in families, homogeneous in kind. These latter interact selectively, through a sequence of self-consistently regulated steps, whose deeply rooted architecture is stored in the assigned matrix of connections. The asymptotic equilibrium eventually attained by the system, and its associated stability, can be assessed by employing standard nonlinear dynamics tools. For many practical applications, it is however important to externally drive the system towards a desired equilibrium, which is resilient, hence stable, to external perturbations. To this end we here consider a system made up of N interacting populations which evolve according to general rate equations, bearing attributes of universality. One species is added to the pool of interacting families and used as a dynamical controller to induce novel stable equilibria. Use can be made of the root locus method to shape the needed control, in terms of intrinsic reactivity and adopted protocol of injection. The proposed method is tested on both synthetic and real data, thus enabling to demonstrate its robustness and versatility. PMID- 28892492 TI - HIF-1alpha is a key regulator in potentiating suppressor activity and limiting the microbicidal capacity of MDSC-like cells during visceral leishmaniasis. AB - Leishmania donovani is known to induce myelopoiesis and to dramatically increase extramedullary myelopoiesis. This results in splenomegaly, which is then accompanied by disruption of the splenic microarchitecture, a chronic inflammatory environment, and immunosuppression. Chronically inflamed tissues are typically hypoxic. The role of hypoxia on myeloid cell functions during visceral leishmaniasis has not yet been studied. Here we show that L. donovani promotes the output from the bone marrow of monocytes with a regulatory phenotype that function as safe targets for the parasite. We also demonstrate that splenic myeloid cells acquire MDSC-like function in a HIF-1alpha-dependent manner. HIF 1alpha is also involved in driving the polarization towards M2-like macrophages and rendering intermediate stage monocytes more susceptible to L. donovani infection. Our results suggest that HIF-1alpha is a major player in the establishment of chronic Leishmania infection and is crucial for enhancing immunosuppressive functions and lowering leishmanicidal capacity of myeloid cells. PMID- 28892494 TI - Infections by human gastrointestinal helminths are associated with changes in faecal microbiota diversity and composition. AB - Investigations of the impact that patent infections by soil-transmitted gastrointestinal nematode parasites exert on the composition of the host gut commensal flora are attracting growing interest by the scientific community. However, information collected to date varies across experiments, and further studies are needed to identify consistent relationships between parasites and commensal microbial species. Here, we explore the qualitative and quantitative differences between the microbial community profiles of cohorts of human volunteers from Sri Lanka with patent infection by one or more parasitic nematode species (H+), as well as that of uninfected subjects (H-) and of volunteers who had been subjected to regular prophylactic anthelmintic treatment (Ht). High throughput sequencing of the bacterial 16S rRNA gene, followed by bioinformatics and biostatistical analyses of sequence data revealed no significant differences in alpha diversity (Shannon) and richness between groups (P = 0.65, P = 0.13 respectively); however, beta diversity was significantly increased in H+ and Ht when individually compared to H-volunteers (P = 0.04). Among others, bacteria of the families Verrucomicrobiaceae and Enterobacteriaceae showed a trend towards increased abundance in H+, whereas the Leuconostocaceae and Bacteroidaceae showed a relative increase in H- and Ht respectively. Our findings add valuable knowledge to the vast, and yet little explored, research field of parasite microbiota interactions and will provide a basis for the elucidation of the role such interactions play in pathogenic and immune-modulatory properties of parasitic nematodes in both human and animal hosts. PMID- 28892496 TI - Effectiveness of food supplements in increasing fat-free tissue accretion in children with moderate acute malnutrition: A randomised 2 * 2 * 3 factorial trial in Burkina Faso. AB - BACKGROUND: Children with moderate acute malnutrition (MAM) are treated with lipid-based nutrient supplement (LNS) or corn-soy blend (CSB). We assessed the effectiveness of (a) matrix, i.e., LNS or CSB, (b) soy quality, i.e., soy isolate (SI) or dehulled soy (DS), and (c) percentage of total protein from dry skimmed milk, i.e., 0%, 20%, or 50%, in increasing fat-free tissue accretion. METHODS AND FINDINGS: Between September 9, 2013, and August 29, 2014, a randomised 2 * 2 * 3 factorial trial recruited 6- to 23-month-old children with MAM in Burkina Faso. The intervention comprised 12 weeks of food supplementation providing 500 kcal/day as LNS or CSB, each containing SI or DS, and 0%, 20%, or 50% of protein from milk. Fat-free mass (FFM) was assessed by deuterium dilution technique. By dividing FFM by length squared, the primary outcome was expressed independent of length as FFM index (FFMI) accretion over 12 weeks. Other outcomes comprised recovery rate and additional anthropometric measures. Of 1,609 children, 4 died, 61 were lost to follow-up, and 119 were transferred out due to supplementation being switched to non-experimental products. No children developed allergic reaction. At inclusion, 95% were breastfed, mean (SD) weight was 6.91 kg (0.93), with 83.5% (5.5) FFM. In the whole cohort, weight increased 0.90 kg (95% CI 0.88, 0.93; p < 0.01) comprising 93.5% (95% CI 89.5, 97.3) FFM. As compared to children who received CSB, FFMI accretion was increased by 0.083 kg/m2 (95% CI 0.003, 0.163; p = 0.042) in those who received LNS. In contrast, SI did not increase FFMI compared to DS (mean difference 0.038 kg/m2; 95% CI -0.041, 0.118; p = 0.35), irrespective of matrix. Having 20% milk protein was associated with 0.097 kg/m2 (95% CI -0.002, 0.196) greater FFMI accretion than having 0% milk protein, although this difference was not significant (p = 0.055), and there was no effect of 50% milk protein (0.049 kg/m2; 95% CI -0.047, 0.146; p = 0.32). There was no effect modification by season, admission criteria, or baseline FFMI, stunting, inflammation, or breastfeeding (p > 0.05). LNS compared to CSB resulted in 128 g (95% CI 67, 190; p < 0.01) greater weight gain if both contained SI, but there was no difference between LNS and CSB if both contained DS (mean difference 22 g; 95% CI -40, 84; p = 0.49) (interaction p = 0.017). Accordingly, SI compared to DS increased weight by 89 g (95% CI 27, 150; p = 0.005) when combined with LNS, but not when combined with CSB. A limitation of this and other food supplementation trials is that it is not possible to collect reliable data on individual adherence. CONCLUSIONS: Based on this study, children with MAM mainly gain fat free tissue when rehabilitated. Nevertheless, LNS yields more fat-free tissue and higher recovery rates than CSB. Moreover, current LNSs with DS may be improved by shifting to SI. The role of milk relative to soy merits further research. TRIAL REGISTRATION: ISRCTN registry ISRCTN42569496. PMID- 28892495 TI - Chlamydomonas DYX1C1/PF23 is essential for axonemal assembly and proper morphology of inner dynein arms. AB - Cytoplasmic assembly of ciliary dyneins, a process known as preassembly, requires numerous non-dynein proteins, but the identities and functions of these proteins are not fully elucidated. Here, we show that the classical Chlamydomonas motility mutant pf23 is defective in the Chlamydomonas homolog of DYX1C1. The pf23 mutant has a 494 bp deletion in the DYX1C1 gene and expresses a shorter DYX1C1 protein in the cytoplasm. Structural analyses, using cryo-ET, reveal that pf23 axonemes lack most of the inner dynein arms. Spectral counting confirms that DYX1C1 is essential for the assembly of the majority of ciliary inner dynein arms (IDA) as well as a fraction of the outer dynein arms (ODA). A C-terminal truncation of DYX1C1 shows a reduction in a subset of these ciliary IDAs. Sucrose gradients of cytoplasmic extracts show that preassembled ciliary dyneins are reduced compared to wild-type, which suggests an important role in dynein complex stability. The role of PF23/DYX1C1 remains unknown, but we suggest that DYX1C1 could provide a scaffold for macromolecular assembly. PMID- 28892498 TI - Comment on Rohrscheib et al. 2016 "Intensity of mutualism breakdown is determined by temperature not amplification of Wolbachia genes". PMID- 28892497 TI - Improved DOP-PCR (iDOP-PCR): A robust and simple WGA method for efficient amplification of low copy number genomic DNA. AB - Whole-genome amplification (WGA) techniques are used for non-specific amplification of low-copy number DNA, and especially for single-cell genome and transcriptome amplification. There are a number of WGA methods that have been developed over the years. One example is degenerate oligonucleotide-primed PCR (DOP-PCR), which is a very simple, fast and inexpensive WGA technique. Although DOP-PCR has been regarded as one of the pioneering methods for WGA, it only provides low genome coverage and a high allele dropout rate when compared to more modern techniques. Here we describe an improved DOP-PCR (iDOP-PCR). We have modified the classic DOP-PCR by using a new thermostable DNA polymerase (SD polymerase) with a strong strand-displacement activity and by adjustments in primers design. We compared iDOP-PCR, classic DOP-PCR and the well-established PicoPlex technique for whole genome amplification of both high- and low-copy number human genomic DNA. The amplified DNA libraries were evaluated by analysis of short tandem repeat genotypes and NGS data. In summary, iDOP-PCR provided a better quality of the amplified DNA libraries compared to the other WGA methods tested, especially when low amounts of genomic DNA were used as an input material. PMID- 28892499 TI - Effectiveness and economic assessment of routine larviciding for prevention of chikungunya and dengue in temperate urban settings in Europe. AB - In the last decades, several European countries where arboviral infections are not endemic have faced outbreaks of diseases such as chikungunya and dengue, initially introduced by infectious travellers from tropical endemic areas and then spread locally via mosquito bites. To keep in check the epidemiological risk, interventions targeted to control vector abundance can be implemented by local authorities. We assessed the epidemiological effectiveness and economic costs and benefits of routine larviciding in European towns with temperate climate, using a mathematical model of Aedes albopictus populations and viral transmission, calibrated on entomological surveillance data collected from ten municipalities in Northern Italy during 2014 and 2015.We found that routine larviciding of public catch basins can limit both the risk of autochthonous transmission and the size of potential epidemics. Ideal larvicide interventions should be timed in such a way to cover the month of July. Optimally timed larviciding can reduce locally transmitted cases of chikungunya by 20% - 33% for a single application (dengue: 18-22%) and up to 43% - 65% if treatment is repeated four times throughout the season (dengue: 31-51%). In larger municipalities (>35,000 inhabitants), the cost of comprehensive larviciding over the whole urban area overcomes potential health benefits related to preventing cases of disease, suggesting the adoption of more localized interventions. Small/medium sized towns with high mosquito abundance will likely have a positive cost-benefit balance. Involvement of private citizens in routine larviciding activities further reduces transmission risks but with disproportionate costs of intervention. International travels and the incidence of mosquito-borne diseases are increasing worldwide, exposing a growing number of European citizens to higher risks of potential outbreaks. Results from this study may support the planning and timing of interventions aimed to reduce the probability of autochthonous transmission as well as the nuisance for local populations living in temperate areas of Europe. PMID- 28892500 TI - Are attitudes toward peace and war the two sides of the same coin? Evidence to the contrary from a French validation of the Attitudes Toward Peace and War Scale. AB - Bizumic et al. (2013) have recently shown that attitudes towards peace and war reflect two distinct constructs rather than two poles of a single dimension. We present an attempt at validating the French version of their 16-item Attitudes toward Peace and War Scale (APWS) on five distinct (mainly Belgian) French speaking samples (total N = 808). Confirmatory factor and criterion validity analyses confirmed that attitudes toward peace and war, although negatively related, are distinct in terms of their antecedents and consequences. On the one hand, antecedents of attitudes toward peace included egalitarian ideological beliefs and empathic concern for others, and consequences included intentions to engage in pro-peace behaviors. On the other hand, antecedents of attitudes toward war included national identification and authoritarian ideological beliefs, and consequences included intentions to engage in pro-war behaviors. Furthermore, both attitudes toward peace and war were, respectively, negatively and positively related to (a right-wing) political orientation. Unexpectedly however, attitudes toward war were positively related to nonegalitarian ideological beliefs and were not related to personal distress. Scores on the translated scale were unrelated to socially desirable responding. In terms of known-groups validity, men had, respectively, more and less positive attitudes toward war and peace than women. Finally, based on exploratory factor analyses, the inclusion of some items for the factorial structure of the measure is questioned and a shortened form of the measure is validated. Overall, these findings are in line with Bizumic et al. and suggest that attitudes toward peace and war also reflect two distinct constructs in a French-speaking population. PMID- 28892501 TI - Implementation of a study to examine the persistence of Ebola virus in the body fluids of Ebola virus disease survivors in Sierra Leone: Methodology and lessons learned. AB - BACKGROUND: The 2013-2016 West African Ebola virus disease epidemic was unprecedented in terms of the number of cases and survivors. Prior to this epidemic there was limited data available on the persistence of Ebola virus in survivors' body fluids and the potential risk of transmission, including sexual transmission. METHODOLOGY/PRINCIPAL FINDINGS: Given the urgent need to determine the persistence of Ebola virus in survivors' body fluids, an observational cohort study was designed and implemented during the epidemic response operation in Sierra Leone. This publication describes study implementation methodology and the key lessons learned. Challenges encountered during implementation included unforeseen duration of follow-up, complexity of interpreting and communicating laboratory results to survivors, and the urgency of translating research findings into public health practice. Strong community engagement helped rapidly implement the study during the epidemic. The study was conducted in two phases. The first phase was initiated within five months of initial protocol discussions and assessed persistence of Ebola virus in semen of 100 adult men. The second phase assessed the persistence of virus in multiple body fluids (semen or vaginal fluid, menstrual blood, breast milk, and urine, rectal fluid, sweat, saliva, tears), of 120 men and 120 women. CONCLUSION/SIGNIFICANCE: Data from this study informed national and global guidelines in real time and demonstrated the need to implement semen testing programs among Ebola virus disease survivors. The lessons learned and study tools developed accelerated the implementation of such programs in Ebola virus disease affected countries, and also informed studies examining persistence of Zika virus. Research is a vital component of the public health response to an epidemic of a poorly characterized disease. Adequate resources should be rapidly made available to answer critical research questions, in order to better inform response efforts. PMID- 28892502 TI - Rapid and recent diversification patterns in Anseriformes birds: Inferred from molecular phylogeny and diversification analyses. AB - The Anseriformes is a well-known and widely distributed bird order, with more than 150 species in the world. This paper aims to revise the classification, determine the phylogenetic relationships and diversification patterns in Anseriformes by exploring the Cyt b, ND2, COI genes and the complete mitochondrial genomes (mito-genomes). Molecular phylogeny and genetic distance analyses suggest that the Dendrocygna species should be considered as an independent family, Dendrocygnidae, rather than a member of Anatidae. Molecular timescale analyses suggests that the ancestral diversification occurred during the Early Eocene Climatic Optimum (58 ~ 50 Ma). Furthermore, diversification analyses showed that, after a long period of constant diversification, the median initial speciation rate was accelerated three times, and finally increased to approximately 0.3 sp/My. In the present study, both molecular phylogeny and diversification analyses results support that Anseriformes birds underwent rapid and recent diversification in their evolutionary history, especially in modern ducks, which show extreme diversification during the Plio-Pleistocene (~ 5.3 Ma). Therefore, our study support that the Plio-Pleistocene climate fluctuations are likely to have played a significant role in promoting the recent diversification for Anseriformes. PMID- 28892503 TI - Structural and functional correlates for language efficiency in auditory word processing. AB - This study aims to provide convergent understanding of the neural basis of auditory word processing efficiency using a multimodal imaging. We investigated the structural and functional correlates of word processing efficiency in healthy individuals. We acquired two structural imaging (T1-weighted imaging and diffusion tensor imaging) and functional magnetic resonance imaging (fMRI) during auditory word processing (phonological and semantic tasks). Our results showed that better phonological performance was predicted by the greater thalamus activity. In contrary, better semantic performance was associated with the less activation in the left posterior middle temporal gyrus (pMTG), supporting the neural efficiency hypothesis that better task performance requires less brain activation. Furthermore, our network analysis revealed the semantic network including the left anterior temporal lobe (ATL), dorsolateral prefrontal cortex (DLPFC) and pMTG was correlated with the semantic efficiency. Especially, this network acted as a neural efficient manner during auditory word processing. Structurally, DLPFC and cingulum contributed to the word processing efficiency. Also, the parietal cortex showed a significate association with the word processing efficiency. Our results demonstrated that two features of word processing efficiency, phonology and semantics, can be supported in different brain regions and, importantly, the way serving it in each region was different according to the feature of word processing. Our findings suggest that word processing efficiency can be achieved by in collaboration of multiple brain regions involved in language and general cognitive function structurally and functionally. PMID- 28892504 TI - Clinical impact of depression and anxiety in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Although depression and anxiety represent significant yet treatable comorbidities in patients with idiopathic pulmonary fibrosis (IPF), their impact on the clinical course and prognosis of IPF remain unclear. PURPOSE: We investigated the prevalence and clinical significance of depression and anxiety in patients with IPF. METHODS: The present study included a prospective cohort comprising 112 Korean patients with IPF who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: Symptoms of depression and anxiety were present in 25.9% and 21.4% of patients with IPF, respectively (HADS scores >=8). No significant differences in demographic data, age, sex, smoking status, Modified Medical Research Council Dyspnea Scale (MMRC) scores, pulmonary function tests, or Gender-Age-Physiology Index for IPF were observed between patients with depression or anxiety and those without. However, in patients with anxiety, St. George's Respiratory Questionnaire (SGRQ) scores were significantly higher than those of patients without anxiety (40.5 versus 23.5; p = 0.003). The survival rate and total number of hospital admissions did not significantly differ between patients with depression/anxiety and those without. CONCLUSIONS: Our findings indicate that depression and anxiety are relatively common in patients with IPF. Although no significant differences were noted with regard to survival rate and hospitalization, the present study suggests that depression and anxiety significantly influence quality of life in patients with IPF. PMID- 28892505 TI - Frailty is associated with objectively assessed sedentary behaviour patterns in older adults: Evidence from the Toledo Study for Healthy Aging (TSHA). AB - OBJECTIVE: The aim of this study was to examine the association of sedentary behaviour patterns with frailty in older people. SETTING: Clinical setting. DESIGN: Cross-sectional, observational study. PARTICIPANTS AND MEASUREMENTS: A triaxial accelerometer was used in a subsample from the Toledo Study for Healthy Aging (519 participants, 67-97 years) to assess several sedentary behaviour patterns including sedentary time per day, the number and duration (min) of breaks in sedentary time per day, and the proportion of the day spent in sedentary bouts of 10 minutes or more. Frailty was assessed using the Frailty Trait Scale (FTS). Regression analysis was used to ascertain the associations between sedentary behaviour patterns and frailty. RESULTS: Sedentary time per day and the proportion of the day spent in sedentary bouts of 10 minutes or more, were positively associated with frailty in the study sample. Conversely, the time spent in breaks in sedentary time was negatively associated with frailty. CONCLUSION: In summary, breaking up sedentary time and time spent in sedentary behaviour are associated with frailty in older people. PMID- 28892506 TI - Does progestin-only contraceptive use after pregnancy affect recovery from pelvic girdle pain? A prospective population study. AB - OBJECTIVE: To estimate associations of progestin-only contraceptives with persistent pelvic girdle pain 18 months after delivery. METHODS: Prospective population based cohort study during the years 2003-2011. We included 20,493 women enrolled in the Norwegian Mother and Child Cohort Study who reported pelvic girdle pain in pregnancy week 30. Data were obtained by 3 self-administered questionnaires and the exposure was obtained by linkage to the Prescription Database of Norway. The outcome was pelvic girdle pain 18 months after delivery. RESULTS: Pelvic girdle pain 18 months after delivery was reported by 9.7% (957/9830) of women with dispense of a progestin-only contraceptive and by 10.5% (1114/10,663) of women without dispense (adjusted odds ratio 0.93; 95% CI 0.84 1.02). In sub-analyses, long duration of exposure to a progestin intrauterine device or progestin-only oral contraceptives was associated with reduced odds of persistent pelvic girdle pain (Ptrend = 0.021 and Ptrend = 0.005). Conversely, long duration of exposure to progestin injections and/or a progestin implant was associated with modest increased odds of persistent pelvic girdle pain (Ptrend = 0.046). Early timing of progestin-only contraceptive dispense following delivery (<=3 months) was not significantly associated with persistent pelvic girdle pain. CONCLUSIONS: Our findings suggest a small beneficial effect of progestin intrauterine devices and progestin-only oral contraceptives on recovery from pelvic girdle pain. We cannot completely rule out an opposing adverse effect of exposure to progestin injections and/or progestin implants. However, the modest increased odds of persistent pelvic girdle pain among these users could be a result of unmeasured confounding. PMID- 28892509 TI - Quantitative assessment of a data-limited recreational bonefish fishery using a time-series of fishing guides reports. AB - Recreational fisheries can be prone to severe declines, yet these fisheries, particularly catch-and-release, are often data-limited, constraining our ability to conduct stock assessments. A combination of catch and effort indices derived from fisheries-dependent data (FDD) gathered from fishing logbooks could be a powerful approach to inform these data gaps. This study demonstrates the utility of using different catch metrics such as indices of abundance, species richness associated with reported catch, and the success rate of targeted trips, to assess historical shifts in the trajectory of the data-limited bonefish (Albula vulpes) fishery in Florida Bay, an economically-important recreational fishery within the Caribbean Basin. We used FDD from fishing guide reports submitted to Everglades National Park to determine temporal patterns in the bonefish population over the past 35 years. These reports indicated a decline in recreational catches in Florida Bay since the late 1980s, with an accelerated decline starting in the late 1990s-early 2000s. Analyses showed an overall 42% reduction in bonefish catches. Trends in the proportion of positive trips (i.e., the probability of catching success) followed the declining catch patterns, suggesting major population changes starting in 1999-2000. As bonefish catches declined, species richness in bonefish trips increased by 34%, suggesting a decrease in bonefish abundance and/or shift in fishing effort (e.g., giving-up time, changes in preferred species). Results provide additional resolution to a pattern of decline for bonefish in South Florida and highlight the value of reconstructing time series for the development of hypotheses about the potential driving mechanisms of species decline. Further, the data-limited nature of most recreational fisheries, and the increase in a use of catch-and-release as a fisheries management strategy point to the need to develop further data integration tools to assess population trends and the sustainability of these fishery resources. PMID- 28892508 TI - Physical, psychological, sexual, and systemic abuse of children with disabilities in East Africa: Mapping the evidence. AB - Children with disabilities (CWDs) are at a higher risk of being maltreated than are typical children. The evidence base on the abuse of children with disabilities living in low- and middle-income countries is extremely limited but the problem is particularly acute in East Africa. We don't know the types of evidence that exist on this topic. This problem is compounded by the fact that key indicators of disability, such as reliable prevalence rates, are not available currently. This paper addresses this serious problem by mapping the existing evidence-base to document the coverage, patterns, and gaps in existing research on the abuse of children with disabilities in East Africa. An evidence map, following systematic review guidelines, was conducted and included a systematic search, transparent and structured data extraction, and critical appraisal. Health and social science databases (Medline, EMBASE, PsychInfo, Taylor&Francis, Web of Science, and SAGE) were systematically searched for relevant studies. A substantive grey literature search was also conducted. All empirical research on the abuse of CWDs in East Africa was eligible for inclusion: Data on abuse was systematically extracted and the research evidence, following critical appraisal, mapped according to the type of abuse and disability condition, highlighting gaps and patterns in the evidence-base. 6005 studies were identified and screened, of which 177 received a full-text assessment. Of these, 41 studies matched the inclusion criteria. By mapping the available data and reports and systematically assessing their trustworthiness and relevance, we highlight significant gaps in the available evidence base. Clear patterns emerge that show a major data gap and lack of research on sexual abuse of children with disabilities and an identifiable lack of methodological quality in many relevant studies. These make the development of a concerted and targeted research effort to tackle the abuse of children with disabilities in East Africa extremely difficult. This needs to be addressed urgently if the abuse of children with disabilities is to be prioritised by the global health community. PMID- 28892510 TI - Structure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38alpha MAPK. AB - In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38alpha MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38alpha MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography. PMID- 28892507 TI - Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis. AB - Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%-61% median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize alpha-glucans rather than beta-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease. PMID- 28892512 TI - Grape microbiome as a reliable and persistent signature of field origin and environmental conditions in Cannonau wine production. AB - Grape berries harbor a wide range of microbes originating from the vineyard environment, many of which are recognized for their role in the must fermentation process shaping wine quality. To better clarify the contribution of the microbiome of grape fruits during wine fermentation, we used high-throughput sequencing to identify bacterial and fungi communities associated with berries and musts of Cannonau. This is the most important cultivar-wine of Sardinia (Italy) where most vineyards are cultivated without phytochemical treatments. Results suggested that microbiomes of berries collected at four different localities share a core composition characterized by Enterobacteriales, Pseudomonadales, Bacillales, and Rhodospirillales. However, any area seems to enrich berries microbiome with peculiar microbial traits. For example, berries belonging to the biodynamic vineyards of Mamoiada were rich in Bacillales typical of manure (i.e. Lysinibacillus, Bacillus, and Sporosarcina), whereas in the Santadi locality, berries showed soil bacteria such as Pasteurellales and Bacteroidales as well as Rhodospirillales and Lactobacillales which are commonly involved in wine fermentation. In the case of fungi, the most abundant taxa were Dothioraceae, Pleosporaceae, and Saccharomycodaceae, and although the proportion of these families varied among localities, they occurred ubiquitously in all vineyards. During vinification processes performed at the same wine cellar under controlled conditions and without using any yeast starter, more than 50% of bacteria groups of berries reached musts, and each locality had its own private bacteria signature, even if Saccharomyces cerevisiae represented the most abundant fungal species. This work suggests that natural berries microbiome could be influenced by pedoclimatic and anthropologic conditions (e.g., farming management), and the fruits' microorganisms persist during the fermentation process. For these reasons, a reliable wine genotyping should include the entire holobiont (plant and all its symbionts), and bioprospecting activities on grape microbiota could lead to improved viticulture yields and wine quality. PMID- 28892511 TI - The equilibrium between antagonistic signaling pathways determines the number of synapses in Drosophila. AB - The number of synapses is a major determinant of behavior and many neural diseases exhibit deviations in that number. However, how signaling pathways control this number is still poorly understood. Using the Drosophila larval neuromuscular junction, we show here a PI3K-dependent pathway for synaptogenesis which is functionally connected with other previously known elements including the Wit receptor, its ligand Gbb, and the MAPkinases cascade. Based on epistasis assays, we determined the functional hierarchy within the pathway. Wit seems to trigger signaling through PI3K, and Ras85D also contributes to the initiation of synaptogenesis. However, contrary to other signaling pathways, PI3K does not require Ras85D binding in the context of synaptogenesis. In addition to the MAPK cascade, Bsk/JNK undergoes regulation by Puc and Ras85D which results in a narrow range of activity of this kinase to determine normalcy of synapse number. The transcriptional readout of the synaptogenesis pathway involves the Fos/Jun complex and the repressor Cic. In addition, we identified an antagonistic pathway that uses the transcription factors Mad and Medea and the microRNA bantam to down regulate key elements of the pro-synaptogenesis pathway. Like its counterpart, the anti-synaptogenesis signaling uses small GTPases and MAPKs including Ras64B, Ras-like-a, p38a and Licorne. Bantam downregulates the pro-synaptogenesis factors PI3K, Hiw, Ras85D and Bsk, but not AKT. AKT, however, can suppress Mad which, in conjunction with the reported suppression of Mad by Hiw, closes the mutual regulation between both pathways. Thus, the number of synapses seems to result from the balanced output from these two pathways. PMID- 28892513 TI - Placebo can enhance creativity. AB - BACKGROUND: The placebo effect is usually studied in clinical settings for decreasing negative symptoms such as pain, depression and anxiety. There is interest in exploring the placebo effect also outside the clinic, for enhancing positive aspects of performance or cognition. Several studies indicate that placebo can enhance cognitive abilities including memory, implicit learning and general knowledge. Here, we ask whether placebo can enhance creativity, an important aspect of human cognition. METHODS: Subjects were randomly assigned to a control group who smelled and rated an odorant (n = 45), and a placebo group who were treated identically but were also told that the odorant increases creativity and reduces inhibitions (n = 45). Subjects completed a recently developed automated test for creativity, the creative foraging game (CFG), and a randomly chosen subset (n = 57) also completed two manual standardized creativity tests, the alternate uses test (AUT) and the Torrance test (TTCT). In all three tests, participants were asked to create as many original solutions and were scored for originality, flexibility and fluency. RESULTS: The placebo group showed higher originality than the control group both in the CFG (p<0.04, effect size = 0.5) and in the AUT (p<0.05, effect size = 0.4), but not in the Torrance test. The placebo group also found more shapes outside of the standard categories found by a set of 100 CFG players in a previous study, a feature termed out-of the-boxness (p<0.01, effect size = 0.6). CONCLUSIONS: The findings indicate that placebo can enhance the originality aspect of creativity. This strengthens the view that placebo can be used not only to reduce negative clinical symptoms, but also to enhance positive aspects of cognition. Furthermore, we find that the impact of placebo on creativity can be tested by CFG, which can quantify multiple aspects of creative search without need for manual coding. This approach opens the way to explore the behavioral and neural mechanisms by which placebo might amplify creativity. PMID- 28892514 TI - L-thyroxine modifies nephrotoxicity by regulating the apoptotic pathway: The possible role of CD38/ADP-ribosyl cyclase-mediated calcium mobilization. AB - Thyroid hormones are well-established as a key regulator of many cellular metabolic pathways developed in various pathogeneses. Here, we dedicated the current work to investigate the role of thyroid hormone analogue (L-thyroxine, L TH) in regulating the renal cytotoxicity using in vivo and in vitro models. Swiss mice were exposed to gamma radiation (IRR, 6Gy) or treated with cisplatin (CIS, 15 mg/kg, i.p.) for induction of nephrotoxicity. Remarkably, pretreatment with L TH (1MUg/kg) ameliorated the elevated kidney function biomarkers, oxidative stress and protected the renal tissue from the subsequent cellular damage. Likewise, L-TH inhibited the apoptotic cascade by down-regulating the extreme consumption of the cellular energy (ATP), the expression of caspase-3 and Bax, and the stimulation of cyclic ADP ribose (cADPR)/calcium mobilization. Moreover, incubation with L-TH (120nM/4h) significantly blocked the cytotoxicity of CIS on Vero cells and the depletion of NAD+ content as well as modified the ADP-ribose cyclase (CD38) enzymatic activity. High doses of L-TH (up to30 nM/4h) inversely increased the radiosensitivity of Vero cells towards IRR (up to 6Gy). On the other hand, L-TH did not interfere CIS-induced cytotoxicity of colorectal adenocarcinoma (Caco-2) cell line. In conclusion, pretreatment with L-TH could be a promising protective approach to the renal cellular damage induced during either CIS or IRR therapy by regulating the unbalanced oxidative status, the expression of pro-apoptotic biomarkers via modulation of cADPR mediated-calcium mobilization. PMID- 28892516 TI - Heterogeneity and nonlinearity in consumers' preferences: An application to the olive oil shopping behavior in Chile. AB - In relatively unknown products, consumers use prices as a quality reference. Under such circumstances, the utility function can be non-negative for a specific price range and generate an inverted U-shaped function. The extra virgin olive oil market in Chile is a good example. Although domestic production and consumption have increased significantly in the last few years, consumer knowledge of this product is still limited. The objective of this study was to analyze Chilean consumer preferences and willingness to pay for extra virgin olive oil attributes. Consumers were segmented taking into account purchasing frequency. A Random Parameter Logit model was estimated for preference heterogeneity. Results indicate that the utility function is nonlinear allowing us to differentiate between two regimes. In the first regime, olive oil behaves as a conspicuous good, that is, higher utility is assigned to higher prices and consumers prefer foreign products in smaller containers. Under the second regime, Chilean olive oil in larger containers is preferred. PMID- 28892515 TI - Strong interferon-gamma mediated cellular immunity to scrub typhus demonstrated using a novel whole cell antigen ELISpot assay in rhesus macaques and humans. AB - Scrub typhus is a febrile infection caused by the obligate intracellular bacterium Orientia tsutsugamushi, which causes significant morbidity and mortality across the Asia-Pacific region. The control of this vector-borne disease is challenging due to humans being dead-end hosts, vertical maintenance of the pathogen in the vector itself, and a potentially large rodent reservoir of unclear significance, coupled with a lack of accurate diagnostic tests. Development of an effective vaccine is highly desirable. This however requires better characterization of the natural immune response of this neglected but important disease. Here we implement a novel IFN-gamma ELISpot assay as a tool for studying O. tsutsugamushi induced cellular immune responses in an experimental scrub typhus rhesus macaque model and human populations. Whole cell antigen for O. tsutsugamushi (OT-WCA) was prepared by heat inactivation of Karp strain bacteria. Rhesus macaques were infected intradermally with O. tsutsugamushi. Freshly isolated peripheral blood mononuclear cells (PBMC) from infected (n = 10) and uninfected animals (n = 5) were stimulated with OT-WCA, and IFN-gamma secreting cells quantitated by ELISpot assay at five time points over 28 days. PBMC were then assayed from people in a scrub typhus-endemic region of Thailand (n = 105) and responses compared to those from a partially exposed population in a non-endemic region (n = 14), and to a naive population in UK (n = 12). Mean results at Day 0 prior to O. tsutsugamushi infection were 12 (95% CI 0 25) and 15 (2-27) spot-forming cells (SFC)/106 PBMC for infected and control macaques respectively. Strong O. tsutsugamushi-specific IFN-gamma responses were seen post infection, with ELISpot responses 20-fold higher than baseline at Day 7 (mean 235, 95% CI 200-270 SFC/106 PBMC), 105-fold higher at Day 14 (mean 1261, 95% CI 1,097-1,425 SFC/106 PBMC), 125-fold higher at Day 21 (mean 1,498, 95% CI 1,496-1,500 SFC/106 PBMC) and 118-fold higher at Day 28 (mean 1,416, 95% CI 1,306 1,527 SFC/106 PBMC). No significant change was found in the control group at any time point compared to baseline. Humans from a scrub typhus endemic region of Thailand had mean responses of 189 (95% CI 88-290) SFC/106 PBMC compared to mean responses of 40 (95% CI 9-71) SFC/106 PBMC in people from a non-endemic region and 3 (95% CI 0-7) SFC/106 PBMC in naive controls. In summary, this highly sensitive assay will enable field immunogenicity studies and further characterization of the host response to O. tsutsugamushi, and provides a link between human and animal models to accelerate vaccine development. PMID- 28892517 TI - Naturally acquired antibody responses to more than 300 Plasmodium vivax proteins in three geographic regions. AB - Plasmodium vivax remains an important cause of malaria in South America and the Asia-Pacific. Naturally acquired antibody responses against multiple P. vivax proteins have been described in numerous countries, however, direct comparison of these responses has been difficult with different methodologies employed. We measured antibody responses against 307 P. vivax proteins at the time of P. vivax infection, and at 2-3 later time-points in three countries. We observed that seropositivity rates at the time of infection were highest in Thailand, followed by Brazil then PNG, reflecting the level of antigenic input. The majority of sero reactive antigens in all sites induced short-lived antibody responses with estimated half-lives of less than 6 months, although there was a trend towards longer-lived responses in PNG children. Despite these differences, IgG seropositivity rates, magnitude and longevity were highly and significantly rank correlated between the different regions, suggesting such features are reflective of the individual protein. PMID- 28892518 TI - Response to: Comment on Rohrscheib et al. 2016 "Intensity of mutualism breakdown is determined by temperature not amplification of Wolbachia genes". PMID- 28892519 TI - Convergent evolution involving dimeric and trimeric dUTPases in pathogenicity island mobilization. AB - The dUTPase (Dut) enzymes, encoded by almost all free-living organisms and some viruses, prevent the misincorporation of uracil into DNA. We previously proposed that trimeric Duts are regulatory proteins involved in different cellular processes; including the phage-mediated transfer of the Staphylococcus aureus pathogenicity island SaPIbov1. Recently, it has been shown that the structurally unrelated dimeric Dut encoded by phage phiNM1 is similarly able to mobilize SaPIbov1, suggesting dimeric Duts could also be regulatory proteins. How this is accomplished remains unsolved. Here, using in vivo, biochemical and structural approaches, we provide insights into the signaling mechanism used by the dimeric Duts to induce the SaPIbov1 cycle. As reported for the trimeric Duts, dimeric Duts contain an extremely variable region, here named domain VI, which is involved in the regulatory capacity of these enzymes. Remarkably, our results also show that the dimeric Dut signaling mechanism is modulated by dUTP, as with the trimeric Duts. Overall, our results demonstrate that although unrelated both in sequence and structure, dimeric and trimeric Duts control SaPI transfer by analogous mechanisms, representing a fascinating example of convergent evolution. This conserved mode of action highlights the biological significance of Duts as regulatory molecules. PMID- 28892522 TI - White Blood Cell Count in the Evaluation of the Febrile Infant: Time to Revisit the Dogma? PMID- 28892523 TI - A Much-Needed Corrective on Drug Development Costs. PMID- 28892520 TI - Knowledge and attitude towards Ebola and Marburg virus diseases in Uganda using quantitative and participatory epidemiology techniques. AB - BACKGROUND: Uganda has reported five (5) Ebola virus disease outbreaks and three (3) Marburg virus disease outbreaks from 2000 to 2016. Peoples' knowledge and attitude towards Ebola and Marburg virus disease impact on control and prevention measures especially during outbreaks. We describe knowledge and attitude towards Ebola and Marburg virus outbreaks in two affected communities in Uganda to inform future outbreak responses and help in the design of health education and communication messages. METHODS: The study was a community survey done in Luweero, Ibanda and Kamwenge districts that have experienced outbreaks of Ebola and Marburg virus diseases. Quantitative data were collected using a structured questionnaire and triangulated with qualitative participatory epidemiology techniques to gain a communities' knowledge and attitude towards Ebola and Marburg virus disease. RESULTS: Out of 740 respondents, 48.5% (359/740) were categorized as being knowledgeable about Ebola and Marburg virus diseases, whereas 60.5% (448/740) were having a positive attitude towards control and prevention of Ebola and Marburg virus diseases. The mean knowledge and attitude percentage scores were 54.3 (SD = 23.5, 95%CI = 52.6-56.0) and 69.9 (SD = 16.9, 95%CI = 68.9-71.1) respectively. People educated beyond primary school were more likely to be knowledgeable about Ebola and Marburg virus disease than those who did not attain any formal education (OR = 3.6, 95%CI = 2.1-6.1). Qualitative data revealed that communities describe Ebola and Marburg virus diseases as very severe diseases with no cure and they believe the diseases spread so fast. Respondents reported fear and stigma suffered by survivors, their families and the broader community due to these diseases. CONCLUSION: Communities in Uganda affected by filovirus outbreaks have moderate knowledge about these diseases and have a positive attitude towards practices to prevent and control Ebola and Marburg viral diseases. The public health sector should enhance this community knowledge gap to empower them more by supplying educational materials for epidemic preparedness in future using appropriate communication channels as proposed by the communities. PMID- 28892524 TI - Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. AB - Importance: A common justification for high cancer drug prices is the sizable research and development (R&D) outlay necessary to bring a drug to the US market. A recent estimate of R&D spending is $2.7 billion (2017 US dollars). However, this analysis lacks transparency and independent replication. Objective: To provide a contemporary estimate of R&D spending to develop cancer drugs. Design, Setting, and Participants: Analysis of US Securities and Exchange Commission filings for drug companies with no drugs on the US market that received approval by the US Food and Drug Administration for a cancer drug from January 1, 2006, through December 31, 2015. Cumulative R&D spending was estimated from initiation of drug development activity to date of approval. Earnings were also identified from the time of approval to the present. The study was conducted from December 10, 2016, to March 2, 2017. Main Outcomes and Measures: Median R&D spending on cancer drug development. Results: Ten companies and drugs were included in this analysis. The 10 companies had a median time to develop a drug of 7.3 years (range, 5.8-15.2 years). Five drugs (50%) received accelerated approval from the US Food and Drug Administration, and 5 (50%) received regular approval. The median cost of drug development was $648.0 million (range, $157.3 million to $1950.8 million). The median cost was $757.4 million (range, $203.6 million to $2601.7 million) for a 7% per annum cost of capital (or opportunity costs) and $793.6 million (range, $219.1 million to $2827.1 million) for a 9% opportunity costs. With a median of 4.0 years (range, 0.8-8.8 years) since approval, the total revenue from sales of these 10 drugs since approval was $67.0 billion compared with total R&D spending of $7.2 billion ($9.1 billion, including 7% opportunity costs). Conclusions and Relevance: The cost to develop a cancer drug is $648.0 million, a figure significantly lower than prior estimates. The revenue since approval is substantial (median, $1658.4 million; range, $204.1 million to $22 275.0 million). This analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing. PMID- 28892525 TI - Trends and Characteristics of US Medicare Spending on Repository Corticotropin. PMID- 28892527 TI - Association of Insurance Gains and Losses With Access to Prescription Drugs. PMID- 28892521 TI - A systems medicine approach for finding target proteins affecting treatment outcomes in patients with non-Hodgkin lymphoma. AB - Autoantibody profiling with a systems medicine approach can help identify critical dysregulated signaling pathways (SPs) in cancers. In this way, immunoglobulins G (IgG) purified from the serum samples of 92 healthy controls, 10 pre-treated (PR) non-Hodgkin lymphoma (NHL) patients, and 20 NHL patients who underwent chemotherapy (PS) were screened with a phage-displayed random peptide library. Protein-protein interaction networks of the PR and PS groups were analyzed and visualized by Gephi. The results indicated AXIN2, SENP2, TOP2A, FZD6, NLK, HDAC2, HDAC1, and EHMT2, in addition to CAMK2A, PLCG1, PLCG2, GRM5, GRIN2B, GRIN2D, CACNA2D3, and SPTAN1 as hubs in 11 and 7 modules of PR and PS networks, respectively. PR- and PS-specific hubs were evaluated in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. The PR-specific hubs were involved in Wnt SP, signaling by Notch1 in cancer, telomere maintenance, and transcriptional misregulation. In contrast, glutamate receptor SP, Fc receptor-related pathways, growth factors-related SPs, and Wnt SP were statistically significant enriched pathways, based on the pathway analysis of PS hubs. The results revealed that the most PR-specific proteins were associated with events involved in tumor development, while chemotherapy in the PS group was associated with side effects of drugs and/or cancer recurrence. As the findings demonstrated, PR- and PS-specific proteins in this study can be promising therapeutic targets in future studies. PMID- 28892529 TI - Nonoperative Treatment of Appendicitis. PMID- 28892528 TI - Determinants of Market Exclusivity for Prescription Drugs in the United States. AB - The high prices of brand-name prescription drugs are a growing source of controversy in the United States. Manufacturers of brand-name drugs can command high prices because they are protected from generic competition by two types of government-granted monopoly rights. The first are patents on the drugs that generally define the basic period of brand-name-only sales. The second is awarded at the time of US Food and Drug Administration (FDA) approval and usually defines the minimum time until a generic can be sold. The initial patents last for 20 years and may be extended to account for time spent in clinical trials and regulatory review; other laws prevent approval of other manufacturers' versions of new drugs for about 6 to 7 years, and for new biologics for 12 years. Overall, most new drugs receive about 12 to 16 years of market exclusivity from both kinds of monopoly protection combined. We reviewed the peer-reviewed medical and health policy literature to identify studies that described the different types of patent protection and regulatory exclusivities that shield brand-name prescription drugs from competition and thus help to sustain high drug prices. We also identified potential policy reforms intended to modify exclusivity periods to address public health needs by balancing drug affordability and industry revenue. The goal of policy in this area should be to ensure that drug market exclusivity periods provide for fair return on investment but do not indefinitely block availability of lower-cost generic drugs. PMID- 28892526 TI - Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial. AB - Importance: In atrial fibrillation (AF)-related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. Objective: To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. Design, Setting, and Participants: A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. Interventions: Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. Main Outcomes and Measures: The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. Results: Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70 1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001). Conclusions and Relevance: In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02042534. PMID- 28892530 TI - Nonoperative Treatment of Appendicitis-Reply. PMID- 28892531 TI - Deception in Schools-When Crisis Preparedness Efforts Go Too Far. PMID- 28892532 TI - Nonoperative Treatment of Appendicitis. PMID- 28892534 TI - Utility of Combining a Simulation-Based Method With a Lecture-Based Method for Fundoscopy Training in Neurology Residency. AB - Importance: Fundoscopic examination is an essential component of the neurologic examination. Competence in its performance is mandated as a required clinical skill for neurology residents by the American Council of Graduate Medical Education. Government and private insurance agencies require its performance and documentation for moderate- and high-level neurologic evaluations. Traditionally, assessment and teaching of this key clinical examination technique have been difficult in neurology residency training. Objective: To evaluate the utility of a simulation-based method and the traditional lecture-based method for assessment and teaching of fundoscopy to neurology residents. Design, Setting, and Participants: This study was a prospective, single-blinded, education research study of 48 neurology residents recruited from July 1, 2015, through June 30, 2016, at a large neurology residency training program. Participants were equally divided into control and intervention groups after stratification by training year. Baseline and postintervention assessments were performed using questionnaire, survey, and fundoscopy simulators. Interventions: After baseline assessment, both groups initially received lecture-based training, which covered fundamental knowledge on the components of fundoscopy and key neurologic findings observed on fundoscopic examination. The intervention group additionally received simulation-based training, which consisted of an instructor-led, hands-on workshop that covered practical skills of performing fundoscopic examination and identifying neurologically relevant findings on another fundoscopy simulator. Main Outcomes and Measures: The primary outcome measures were the postintervention changes in fundoscopy knowledge, skills, and total scores. Results: A total of 30 men and 18 women were equally distributed between the 2 groups. The intervention group had significantly higher mean (SD) increases in skills (2.5 [2.3] vs 0.8 [1.8], P = .01) and total (9.3 [4.3] vs 5.3 [5.8], P = .02) scores compared with the control group. Knowledge scores (6.8 [3.3] vs 4.5 [4.9], P = .11) increased nonsignificantly in both groups. Conclusions and Relevance: This study supports the use of a simulation-based method as a supplementary tool to the lecture-based method in the assessment and teaching of fundoscopic examination in neurology residency. PMID- 28892535 TI - Anticoagulation Timing for Atrial Fibrillation in Acute Ischemic Stroke: Time to Reopen Pandora's Box? PMID- 28892533 TI - Association of Guideline-Adherent Antibiotic Treatment With Readmission of Children With Sickle Cell Disease Hospitalized With Acute Chest Syndrome. AB - Importance: Acute chest syndrome (ACS) is a common, serious complication of sickle cell disease (SCD) and a leading cause of hospitalization and death in both children and adults with SCD. Little is known about the effectiveness of guideline-recommended antibiotic regimens for the care of children hospitalized with ACS. Objectives: To use a large, national database to describe patterns of antibiotic use for children with SCD hospitalized for ACS and to determine whether receipt of guideline-adherent antibiotics was associated with lower readmission rates. Design, Setting, and Participants: Retrospective cohort study including 14 480 hospitalizations in 7178 children (age 0-22 years) with a discharge diagnosis of SCD and either ACS or pneumonia. Information was obtained from 41 children's hospitals submitting data to the Pediatric Health Information System from January 1, 2010, to December 31, 2016. Exposures: National Heart, Lung, and Blood Institute guideline-adherent (macrolide with parenteral cephalosporin) vs non-guideline-adherent antibiotic regimens. Main Outcomes and Measures: Acute chest syndrome-related and all-cause 7- and 30-day readmissions. Results: Of the 14 480 hospitalizations, 6562 (45.3%) were in girls; median (interquartile range) age was 9 (4-14) years. Guideline-adherent antibiotics were provided in 10 654 of 14 480 hospitalizations for ACS (73.6%). Hospitalizations were most likely to include guideline-adherent antibiotics for children aged 5 to 9 years (3230 of 4047 [79.8%]) and declined to the lowest level for children 19 to 22 years (697 of 1088 [64.1%]). Between-hospital variation in antibiotic regimens was wide, with use of guideline-adherent antibiotics ranging from 24% to 90%. Children treated with guideline-adherent antibiotics had lower 30-day ACS related (odds ratio [OR], 0.71; 95% CI, 0.50-1.00) and all-cause (OR, 0.50; 95% CI, 0.39-0.64) readmission rates vs children who received other regimens (cephalosporin and macrolide vs neither drug class). Conclusions and Relevance: Current approaches to antibiotic treatment in children with ACS vary widely, but guideline-adherent therapy appears to result in fewer readmissions compared with non-guideline-adherent therapy. Efforts to increase the dissemination and implementation of SCD treatment guidelines are warranted as is comparative effectiveness research to strengthen the underlying evidence base. PMID- 28892536 TI - Notice of Retraction and Replacement: Colla et al. Association between Medicare accountable care organization implementation and spending among clinically vulnerable beneficiaries. JAMA Internal Medicine. 2016;176(8):1167-1175. PMID- 28892540 TI - New (Very High) Prices on Old Drugs. PMID- 28892537 TI - Accuracy of Complete Blood Cell Counts to Identify Febrile Infants 60 Days or Younger With Invasive Bacterial Infections. AB - Importance: Clinicians often risk stratify young febrile infants for invasive bacterial infections (IBIs), defined as bacteremia and/or bacterial meningitis, using complete blood cell count parameters. Objective: To estimate the accuracy of individual complete blood cell count parameters to identify febrile infants with IBIs. Design, Setting, and Participants: Planned secondary analysis of a prospective observational cohort study comprising 26 emergency departments in the Pediatric Emergency Care Applied Research Network from 2008 to 2013. We included febrile (>=38 degrees C), previously healthy, full-term infants younger than 60 days for whom blood cultures were obtained. All infants had either cerebrospinal fluid cultures or 7-day follow-up. Main Outcomes and Measures: We tested the accuracy of the white blood cell count, absolute neutrophil count, and platelet count at commonly used thresholds for IBIs. We determined optimal thresholds using receiver operating characteristic curves. Results: Of 4313 enrolled infants, 1340 (31%; 95% CI, 30% to 32%) were aged 0 to 28 days, 2412 were boys (56%), and 2471 were white (57%). Ninety-seven (2.2%; 95% CI, 1.8% to 2.7%) had IBIs. Sensitivities were low for common complete blood cell count parameter thresholds: white blood cell count less than 5000/uL, 10% (95% CI, 4% to 16%) (to convert to 109 per liter, multiply by 0.001); white blood cell count >=15 000/uL, 27% (95% CI, 18% to 36%); absolute neutrophil count >=10 000/uL, 18% (95% CI, 10% to 25%) (to convert to * 109 per liter, multiply by 0.001); and platelets <100 * 103/uL, 7% (95% CI, 2% to 12%) (to convert to * 109 per liter, multiply by 1). Optimal thresholds for white blood cell count (11 600/uL), absolute neutrophil count (4100/uL), and platelet count (362 * 103/uL) were identified in models that had areas under the receiver operating characteristic curves of 0.57 (95% CI, 0.50-0.63), 0.70 (95% CI, 0.64-0.76), and 0.61 (95% CI, 0.55-0.67), respectively. Conclusions and Relevance: No complete blood cell count parameter at commonly used or optimal thresholds identified febrile infants 60 days or younger with IBIs with high accuracy. Better diagnostic tools are needed to risk stratify young febrile infants for IBIs. PMID- 28892541 TI - Possible Insufficiency of Generic Price Competition to Contain Prices for Orally Administered Anticancer Therapies. PMID- 28892543 TI - The Importance of an "Optimal" Night's Sleep for Children and "Secondhand and Thirdhand" Smoke Exposure. PMID- 28892542 TI - Nonoperative Treatment of Appendicitis-Reply. PMID- 28892544 TI - You Can Reduce Secondhand Smoke Exposure! Prescribing Nicotine Replacement in the Pediatrician's Office. AB - It is universally known that secondhand smoke is detrimental to children's health. There is emerging research about the negative effects of thirdhand smoke as well. Most pediatricians focus on the child's medical evaluation and treatment, without considering other family members as it impacts the child's health. Screening rates for secondhand smoke exposure are low to begin with, and when we find a family member who is smoking, most pediatricians feel comfortable counseling and referring, but many do not know how to prescribe nicotine replacement therapy (NRT). In offering a prescription for NRT, pediatricians can offer tangible, timely treatment to help the family get one step closer to being smoke-free. Additionally, families may see their pediatrician more frequently than their own adult physician, and pediatricians have a unique perspective on how smoking may affect the child's health, and can use this as a motivator for quitting. This article encourages pediatricians to screen for secondhand smoke exposure and prescribe NRT to their patient's family members. [Pediatr Ann. 2017;46(9):e315-e318.]. PMID- 28892545 TI - Pediatric Sleep Medicine. PMID- 28892546 TI - Insomnia in Infants and Young Children. AB - Sleep problems in infants and young children are common and often underdiagnosed. The potential negative outcomes that chronic disrupted sleep can have on a child's daytime functioning, as well as the adverse impact it can have on the family, are well known. There is considerable evidence to support the use of behavioral interventions to treat childhood insomnia. These strategies not only produce reliable and durable positive changes in sleep in most young children, but may also improve child and family well-being without negative effects on a child's social-emotional development. This article serves as a guide to help the pediatric provider identify, evaluate, and treat insomnia in infants and young children. [Pediatr Ann. 2017;46(9):e321-e326.]. PMID- 28892547 TI - Non-Rapid Eye Movement Arousal Parasomnias in Children. AB - Parasomnia is a common pediatric sleep disorder that can cause parents or caregivers distress when experienced by their children. Based on the International Classification of Sleep Disorders, parasomnias can be divided into two subgroups: non-rapid eye movement (NREM) parasomnias and rapid eye movement (REM) parasomnias. REM sleep parasomnias include nightmares, REM behavior disorder, and sleep paralysis, whereas NREM sleep parasomnias include disorders of arousal such as confusional arousals, sleepwalking, sleep talking, night terrors, and sleep-related eating disorder. This review focuses on the epidemiology, clinical presentation, diagnosis, and treatment of the most common form of parasomnias-NREM arousal parasomnias. Additionally, this review aims to help clinicians distinguish NREM parasomnias from nocturnal frontal lobe seizures, as this distinction is important to avoid diagnostic delays and inappropriate medication exposure. [Pediatr Ann. 2017;46(9):e327-e331.]. PMID- 28892548 TI - Pediatric Obstructive Sleep Apnea and Asthma: Clinical Implications. AB - Obstructive sleep apnea (OSA) and asthma are common conditions in children with preventable long-term consequences. There is significant overlap in symptomatology and pathophysiology for pediatric OSA and asthma. Recent evidence supports clear associations between the two diseases; however, causality has not been demonstrated. Regardless, it is important to recognize the overlap and evaluate for the other condition when one is present. For example, in patients with severe OSA, clinical evaluation for asthma should be considered, including history for typical asthma symptoms and spirometry. For patients with severe or poorly controlled asthma, OSA should be considered as a complicating condition. Clinical history for OSA as well as pediatric sleep questionnaires may be helpful tools in evaluation of the child with severe asthma. To decrease long-term consequences from asthma and OSA in children, clinicians should consider the relationship between these two diseases. [Pediatr Ann. 2017;46(9):e332-e335.]. PMID- 28892549 TI - Pediatric Obstructive Sleep Apnea in High-Risk Populations: Clinical Implications. AB - Certain common medical conditions are associated with a higher risk of pediatric obstructive sleep apnea (OSA). A lower threshold for screening is therefore indicated for such patient cohorts. In this article, we briefly discuss the high prevalence of OSA in children born prematurely, and in those with Down syndrome, craniofacial disorders, and neuromuscular disorders. Primary care providers should have an increased index of suspicion for OSA in these children, considering the neurocognitive disability that occurs in these high-risk groups when OSA is left untreated. [Pediatr Ann. 2017;46(9):e336-e339.]. PMID- 28892550 TI - Adolescent Sleepiness: Causes and Consequences. AB - Insufficient sleep duration and poor sleep quality are common among adolescents. The multidimensional causes of insufficient sleep duration and poor sleep quality include biological, health-related, environmental, and lifestyle factors. The most common direct consequence of insufficient and/or poor sleep quality is excessive daytime sleepiness, which may contribute to poor academic performance, behavioral health problems, substance use, and drowsy driving. Evaluation of sleepiness includes a detailed sleep history and sleep diary, with polysomnography only required for the assessment of specific sleep disorders. Management involves encouraging healthy sleep practices such as having consistent bed and wake times, limiting caffeine and electronics at night before bed, and eliminating napping, in addition to treating any existing sleep or medical disorders. [Pediatr Ann. 2017;46(9):e340-e344.]. PMID- 28892551 TI - Transforming the Pediatric Experience: The Story of Child Life. AB - During the past century, child life programming has evolved into a standard of care for children experiencing life's most challenging events. From pediatric outpatient clinics and dentists' offices to funeral homes and courtrooms, children are now being provided access to professionals that relieve the anxiety and fear associated with emotional and physical pain. Recognized by the American Academy of Pediatrics, child life specialists focus on the "strengths and sense of well-being of children while promoting their optimal development and minimizing the adverse effects of children's experiences in health care or other potentially stressful settings." Armed with a strong background in child development, child life specialists provide therapeutic play experiences and developmentally appropriate language to promote normalcy within an unknown and potentially stressful environment, procedural education and emotional support, coping and pain management techniques, and grief and bereavement support. Child life programming plays an integral role in addressing the psychosocial concerns across the health care continuum and should be included in all general pediatric provider settings as a standard of quality care for young patients. [Pediatr Ann. 2017;46(9):e345-e351.]. PMID- 28892552 TI - Effectiveness of Mental Health Simulation in Replacing Traditional Clinical Hours in Baccalaureate Nursing Education. AB - The purpose of the current study was to (a) determine whether baccalaureate nursing students receiving mental health simulation as a replacement for 25% of traditional clinical hours have equivalent or greater mental health knowledge and self-confidence compared to those who did not receive this simulation; and (b) explore students' perceptions of their mental health simulation compared to traditional clinical hours. An evidence-based practice pilot study was conducted using a mixed-methods design. Quantitative data demonstrated that students who received mental health simulation as a replacement for 25% of traditional clinical hours have equivalent mental health knowledge and self-confidence as those who did not receive the simulation. Qualitative data indicated students found the simulation helpful in learning how to manage patient behaviors. The current study provides substantial evidence that simulation can be used as a replacement for 25% of traditional clinical hours in mental health nursing. [Journal of Psychosocial Nursing and Mental Health Services, 55(11), 36-43.]. PMID- 28892553 TI - Impulsivity and Sensation-Seeking Personality Traits as Predictors of Substance Use Among University Students. AB - The purpose of the current study was to investigate the relationship between substance use and impulsivity and sensation-seeking personality traits among 655 university students using a cross-sectional, descriptive, correlational design. A significant correlation was found between students' impulsivity level scores and frequency of substance use (r = 0.11, p < 0.05). A positive correlation was found between frequency of substance use and sensation-seeking levels (r = 0.2, p < 0.05), as well as impulsivity levels (r = 0.31, p < 0.01). Multiple linear regression analysis showed that the two predictors model was able to account for 12.4% of variation in substance use. Impulsivity and sensation-seeking personality traits are significant predictors of substance use among university students. [Journal of Psychosocial Nursing and Mental Health Services, 56(1), 57 63.]. PMID- 28892554 TI - Complementary and Integrative Health Practices for Depression. AB - The current article reviews selected complementary health approaches for the treatment of depressive symptoms. Complementary and integrative health (CIH) focuses on the whole person with the goal of optimal health-body, mind, and spirit. Patient use of integrative health practices and products is increasing; therefore, providers must understand these practices and products and be able to recommend or advise for or against their use based on research and guidelines. Difficulty with the current limitations of research on CIH practices is discussed, as these studies often may not have the same rigor or scientific weight as conventional treatment research. Although some individuals may use certain treatment options alone, such as massage therapy, meditation, and supplements to diet, the article discusses ways to combine CIH with allopathic care. Nurse practitioners should be open to considering complementary practices for health care and knowledgeable to guide patients in making safe health decisions. [Journal of Psychosocial Nursing and Mental Health Services, 55(12), 22-33.]. PMID- 28892555 TI - Stigma of HIV Testing on Online HIV Forums: Self-Stigma and the Unspoken. AB - Most studies examining HIV-related content in web forums have revolved around the most frequently used terms in HIV-related messages and topics, as well as the supportive nature of those messages. The current study explored barriers that prevent individuals from seeking HIV testing (specifically stigma). The current study analyzed a total of 210 threads and 319 posts, yielding 13 threads that revealed how individuals self-stigmatize and expressed how the fear of being diagnosed prevented them from seeking HIV testing. Results suggest that forums or online communities may perpetuate subculture values that deviate from mainstream values. Another important finding is that there is a lack of HIV testing information in forums for adolescents, which may contribute to the trend of young individuals engaging in risky sexual behaviors not getting tested in a timely fashion. [Journal of Psychosocial Nursing and Mental Health Services, 55(12), 34 43.]. PMID- 28892557 TI - The basis of differences in thermodynamic efficiency among skeletal muscles. AB - Muscles convert chemical free energy into mechanical work. The energy conversion occurs in 2 steps. First, free energy obtained from oxidation of metabolic substrates (DeltaGS ) is transferred to ATP and, second, free energy from ATP hydrolysis (DeltaGATP ) is converted into work by myosin cross-bridges. The fraction of DeltaGS transferred to ATP is called mitochondrial efficiency (etaM ) and the fraction of DeltaGATP converted into work is called cross-bridge efficiency (etaCB ). Overall cross-bridge efficiency varies among muscles from ~20% and 35% and the analysis presented in the current studies shows that this variation is largely due to differences in etaCB whereas etaM is similar (~80%) in all the muscles assessed. There is an inverse, linear relationship between maximum normalised power output and etaCB ; that is, more efficient muscles tend to be less powerful than less efficient muscles. It is proposed that differences in cross-bridge efficiency reflect the extent to which cross-bridges traverse the force-length relationship for attached cross-bridges. In this framework, cross bridges from tortoise muscle (etaCB = 45%) produce close to the maximum possible work a cross-bridge can perform in a single attachment cycle. PMID- 28892556 TI - Parenteral anticoagulation in ambulatory patients with cancer. AB - BACKGROUND: Anticoagulation may improve survival in patients with cancer through a speculated anti-tumour effect, in addition to the antithrombotic effect, although may increase the risk of bleeding. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: A comprehensive search included (1) a major electronic search (February 2016) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (1946 to February 2016; accessed via OVID) and Embase (1980 to February 2016; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies in trial registries. As part of the living systematic review approach, we are running searches continually and we will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 August, 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding, and quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE handbook). MAIN RESULTS: Of 6947 identified citations, 18 RCTs fulfilled the eligibility criteria. These trials enrolled 9575 participants. Trial registries' searches identified nine registered but unpublished trials, two of which were labeled as 'ongoing trials'. In all included RCTs, the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin appears to have no effect on mortality at 12 months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.93 to 1.03; risk difference (RD) 10 fewer per 1000; 95% CI 35 fewer to 15 more; moderate certainty of evidence) and mortality at 24 months (RR 0.99; 95% CI 0.96 to 1.01; RD 8 fewer per 1000; 95% CI 31 fewer to 8 more; moderate certainty of evidence). Heparin therapy reduces the risk of symptomatic VTE (RR 0.56; 95% CI 0.47 to 0.68; RD 30 fewer per 1000; 95% CI 36 fewer to 22 fewer; high certainty of evidence), while it increases in the risks of major bleeding (RR 1.30; 95% 0.94 to 1.79; RD 4 more per 1000; 95% CI 1 fewer to 11 more; moderate certainty of evidence) and minor bleeding (RR 1.70; 95% 1.13 to 2.55; RD 17 more per 1000; 95% CI 3 more to 37 more; high certainty of evidence). Results failed to confirm or to exclude a beneficial or detrimental effect of heparin on thrombocytopenia (RR 0.69; 95% CI 0.37 to 1.27; RD 33 fewer per 1000; 95% CI 66 fewer to 28 more; moderate certainty of evidence); quality of life (moderate certainty of evidence). AUTHORS' CONCLUSIONS: Heparin appears to have no effect on mortality at 12 months and 24 months. It reduces symptomatic VTE and likely increases major and minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy should balance the benefits and downsides, and should integrate the patient's values and preferences.Editorial note:This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. PMID- 28892558 TI - The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. AB - : Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. CONCLUSION: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2017). PMID- 28892559 TI - Spirometry-adjusted fraction of exhaled nitric oxide increases accuracy for assessment of asthma control in children. AB - Spirometry and exhaled nitric oxide are two important complimentary tools to identify and assess asthma control in children. We aimed to determine the ability of a new suggested spirometry-adjusted fraction of exhaled nitric oxide (NO) index in doing that. A random sample of 1602 schoolchildren were screened by a health questionnaire, skin prick tests, spirometry with bronchodilation and exhaled NO. A total of 662 children were included with median (IQR) exhaled NO 11(14) ppb. Receiver operating characteristic (ROC) curves using exhaled NO equations from Malmberg, Kovesi and Buchvald, and spirometry-adjusted fraction of exhaled NO values were applied to identify asthmatic children and uncontrolled asthma. Receiver operating characteristic (ROC) curves failed to identify asthmatic children (all AUC < 0.700). Spirometry-adjusted fraction of exhaled NO/FEV1 (AUC = 0.712; P = .010) and NO/FEF25%-75% (AUC = 0.735 P = .004) had a fair and increased ability to identify uncontrolled disease compared with exhaled NO (AUC = 0.707; P = .011) or the Malmberg equation (AUC = 0.701; P = .014). Sensitivity and specificity identifying non-controlled asthma were 59% and 81%, respectively, for the cut-off value of 9.7 ppb/L for exhaled NO/FEV1 , and 40% and 100% for 15.7 ppb/L/s for exhaled NO/FEF25%-75% . Exhaled NO did not allow to identify childhood asthma. Spirometry-adjusted fraction of exhaled NO performed better-assessing asthma control in children. Thus, although more validation studies are needed, we suggest its use in epidemiological studies to assess asthma control. PMID- 28892561 TI - Beta-2 receptor agonist exposure in the uterus associated with subsequent risk of childhood asthma. AB - BACKGROUND: Although the beta-2 receptor agonist (B2RA) is occasionally prescribed in the prenatal period for women with preterm labor, few studies have referred to the long-term effects of intrauterine exposure to B2RA on fetus. We examined the association between intrauterine exposure to B2RA and asthma in the offspring. METHODS: We obtained data from a hospital-based birth cohort study conducted in Tokyo, Japan. The outcomes of interest were three indicators, consisting of current wheeze, current asthma, and ever asthma at 5 years of age, based on the International Study of Asthma and Allergies in Childhood questionnaire. Logistic regression analysis was used to evaluate the association between intrauterine B2RA exposure and outcomes. To evaluate dose-dependent risk, we categorized children into three groups according to both the cumulative dose and duration (days) and conducted trend analysis. RESULTS: Of 1158 children, 94 (8.1%) were exposed to B2RA in utero, and 191 (16.5%), 111 (9.6%), and 168 (14.5%) children experienced current wheeze, current asthma, and ever asthma, respectively. After adjusting for confounders, we found an increased risk of current asthma caused by B2RA exposure with an adjusted odds ratio of 2.04 (95% confidence interval: 1.02-4.05). Trend analysis showed that B2RA exposure in utero was associated with a dose-dependent increased risk of current asthma in terms of both cumulative dose and duration (P values for trend were .015 and .017, respectively). These results were similar to those for other outcome measures. CONCLUSION: Exposure to B2RA in utero could be a risk for childhood asthma. PMID- 28892560 TI - Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. AB - OBJECTIVE: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. METHODS: Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. RESULTS: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14 depleted cells. INTERPRETATION: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577. PMID- 28892562 TI - Triggering immunological memory against the tapeworm Hymenolepis diminuta to protect against colitis. AB - Infection with parasitic helminths can ameliorate the severity of concomitant inflammatory disease. To use the tapeworm, Hymenolepis diminuta, and to extend this concept by assessing whether triggering a memory response against the worm inhibits dinitrobenzene sulphonic acid (DNBS)-induced colitis in Balb/c mice. Initial studies revealed that oral infection with 1, 3 or 5 H. diminuta cysticercoids 8 days before intrarectal administration of DNBS (3 mg) resulted in less severe inflammation and that infected mice displayed an increased propensity for T helper-2 immunity. A 1 mg dose of a PBS-soluble extract of the worm (HdAg) delivered intraperitoneally concomitant with DNBS was anticolitic as determined by macroscopic and histological disease scores 72 hour post-DNBS. Mice infected 28 days previously had a memory response as determined by HdAg-evoked increases in interleukin (IL)-4 and IL-10 from in vitro stimulated splenocytes and serum anti-H. diminuta IgG. Moreover, mice infected with 5 H. diminuta 28 days previously were protected from DNBS-induced colitis by secondary infection or 100 MUg HdAg (ip.) at the time of DNBS treatment. An additional approach to managing inflammatory disease could be infection with H. diminuta followed by eliciting antiworm recall responses. PMID- 28892563 TI - Sensory evaluation and chemical analysis of exhaled and dermally emitted bioeffluents. AB - Conditions in which exhaled and dermally emitted bioeffluents could be sampled separately or together (whole-body emission) were created. Five lightly dressed males exhaled the air through a mask to another, identical chamber or without a mask to the chamber in which they were sitting; the outdoor air supply rate was the same in both chambers. The carbon dioxide concentration in the chamber with exhaled air was 2000 ppm. Chamber temperatures were 23 degrees C or 28 degrees C, and ozone was present or absent in the supply airflow. When dermally emitted bioeffluents were present, the perceived air quality (PAQ) was less acceptable, and the odor intensity was higher than when only exhaled bioeffluents were present. The presence or absence of exhaled bioeffluents in the unoccupied chamber made no significant difference to sensory assessments. At 28 degrees C and with ozone present, the odor intensity increased and the PAQ was less acceptable in the chambers with whole-body bioeffluents. The concentrations of nonanal, decanal, geranylacetone, and 6-MHO were higher when dermally emitted bioeffluents were present; they increased further when ozone was present. The concentration of squalene then decreased and increased again at 28 degrees C. Dermally emitted bioeffluents seem to play a major role in the sensory nuisance experienced when occupied volumes are inadequately ventilated. PMID- 28892564 TI - From the Editors. PMID- 28892565 TI - The yeasts of the genus Spathaspora: potential candidates for second-generation biofuel production. AB - Yeasts of the Spathaspora clade have the ability to convert d-xylose to ethanol and/or xylitol. This is an important trait, as these yeasts may be used to produce bioethanol from lignocellulosic biomass or as a source of new d-xylose metabolism genes for recombinant industrial strains of Saccharomyces cerevisiae. The core group of the genus Spathaspora has 22 species, both formally described and not yet described. Other species, such as Sp. allomyrinae, Candida alai, C. insectamans, C. lyxosophila, C. sake, Sp. boniae and C. subhashii are weakly associated with this clade, based on LSU rRNA gene D1/D2 sequence analyses. Spathaspora passalidarum, Sp. arborariae, Sp. gorwiae and Sp. hagerdaliae produce mostly ethanol from d-xylose, whereas the remaining species within the Spathaspora clade already tested for this property may be considered xylitol producers. Among the d-xylose-fermenting Spathaspora species, Sp. passalidarum is the best ethanol producer, displaying high ethanol yields and productivities when cultured in media supplemented with this pentose under oxygen-limited or anaerobic conditions. The species also exhibits rapid d-xylose consumption and the ability to ferment glucose, xylose and cellobiose simultaneously. These characteristics suggest that Sp. passalidarum is a potential candidate for domestication and use in the fermentation of lignocellulosic materials. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28892566 TI - Brain-heart interactions reveal consciousness in noncommunicating patients. AB - OBJECTIVE: We here aimed at characterizing heart-brain interactions in patients with disorders of consciousness. We tested how this information impacts data driven classification between unresponsive and minimally conscious patients. METHODS: A cohort of 127 patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS; n = 70) and minimally conscious state (MCS; n = 57) were presented with the local-global auditory oddball paradigm, which distinguishes 2 levels of processing: short-term deviation of local auditory regularities and global long-term rule violations. In addition to previously validated markers of consciousness extracted from electroencephalograms (EEG), we computed autonomic cardiac markers, such as heart rate (HR) and HR variability (HRV), and cardiac cycle phase shifts triggered by the processing of the auditory stimuli. RESULTS: HR and HRV were similar in patients across groups. The cardiac cycle was not sensitive to the processing of local regularities in either the VS/UWS or MCS patients. In contrast, global regularities induced a phase shift of the cardiac cycle exclusively in the MCS group. The interval between the auditory stimulation and the following R peak was significantly shortened in MCS when the auditory rule was violated. When the information for the cardiac cycle modulations and other consciousness-related EEG markers were combined, single patient classification performance was enhanced compared to classification with solely EEG markers. INTERPRETATION: Our work shows a link between residual cognitive processing and the modulation of autonomic somatic markers. These results open a new window to evaluate patients with disorders of consciousness via the embodied paradigm, according to which body-brain functions contribute to a holistic approach to conscious processing. Ann Neurol 2017;82:578-591. PMID- 28892567 TI - Using omics to explore complications of kidney transplantation. AB - The importance of genetic and biochemical variation in renal transplant outcomes has been clear since the discovery of the HLA in the 1950s. Since that time, there have been huge advancements in both transplantation and omics. In recent years, there has seen an increased number of genome-, proteome- and transcriptome wide studies in the field of transplantation moving away from the earlier candidate gene/protein approaches. These areas have the potential to lead to the development of personalized treatment depending on individual molecular risk profiles. Here, we discuss recent progress and the current literature surrounding omics and renal transplant complications. PMID- 28892568 TI - Quantifying fine particle emission events from time-resolved measurements: Method description and application to 18 California low-income apartments. AB - PM2.5 exposure is associated with significant health risk. Exposures in homes derive from both outdoor and indoor sources, with emissions occurring primarily in discrete events. Data on emission event magnitudes and schedules are needed to support simulation-based studies of exposures and mitigations. This study applied an identification and characterization algorithm to quantify time-resolved PM2.5 emission events from data collected during 224 days of monitoring in 18 California apartments with low-income residents. We identified and characterized 836 distinct events with median and mean values of 12 and 30 mg emitted mass, 16 and 23 minutes emission duration, 37 and 103 mg/h emission rates, and pseudo first-order decay rates of 1.3 and 2.0/h. Mean event-averaged concentrations calculated using the determined event characteristics agreed to within 6% of measured values for 14 of the apartments. There were variations in event schedules and emitted mass across homes, with few events overnight and most emissions occurring during late afternoons and evenings. Event characteristics were similar during weekdays and weekends. Emitted mass was positively correlated with number of residents (Spearman coefficient, rho=.10), bedrooms (rho=.08), house volume (rho=.29), and indoor-outdoor CO2 difference (rho=.27). The event schedules can be used in probabilistic modeling of PM2.5 in low-income apartments. PMID- 28892569 TI - Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells. AB - Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide (. NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR coding gene (Srrnull ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srrnull mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation primed WT RPEs expressed more inducible NOS, produced more. NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including. NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis. PMID- 28892570 TI - DNAJC12 and dopa-responsive nonprogressive parkinsonism. AB - Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79-2A>G;p.V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640-646. PMID- 28892571 TI - Regenerative immunology: the immunological reaction to biomaterials. AB - Regenerative medicine promises to meet two of the most urgent needs of modern organ transplantation, namely immunosuppression-free transplantation and an inexhaustible source of organs. Ideally, bioengineered organs would be manufactured from a patient's own biomaterials-both cells and the supporting scaffolding materials in which cells would be embedded and allowed to mature to eventually regenerate the organ in question. While some groups are focusing on the feasibility of this approach, few are focusing on the immunogenicity of the scaffolds that are being developed for organ bioengineering purposes. This review will succinctly discuss progress in the understanding of immunological characteristics and behavior of different scaffolds currently under development, with emphasis on the extracellular matrix scaffolds obtained decellularized animal or human organs which seem to provide the ideal template for bioengineering purposes. PMID- 28892572 TI - Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration. AB - Idiopathic normal pressure hydrocephalus (NPH) remains both oversuspected on clinical grounds and underconfirmed when based on immediate and sustained response to cerebrospinal fluid diversion. Poor long-term postshunt benefits and findings of neurodegenerative pathology in most patients with adequate follow-up suggest that hydrocephalic disorders appearing in late adulthood may often result from initially unapparent parenchymal abnormalities. We critically review the NPH literature, highlighting the near universal lack of blinding and controls, absence of specific clinical, imaging, or pathological features, and ongoing dependence for diagnostic confirmation on variable cutoffs of gait response to bedside fluid-drainage testing. We also summarize our long-term institutional experience, in which postshunt benefits in patients with initial diagnosis of idiopathic NPH persist in only 32% of patients at 36 months, with known revised diagnosis in over 25% (Alzheimer's disease, dementia with Lewy bodies, and progressive supranuclear palsy). We postulate that previously reported NPH cases with "dual" pathology (ie, developing a "second" disorder) more likely represent ventriculomegalic presentations of selected neurodegenerative disorders in which benefits from shunting may be short-lived, with a consequently unfavorable risk benefit ratio. Ann Neurol 2017;82:503-513. PMID- 28892573 TI - Bicycling suppresses abnormal beta synchrony in the Parkinsonian basal ganglia. AB - OBJECTIVE: Freezing of gait is a poorly understood symptom of Parkinson disease, and can severely disrupt the locomotion of affected patients. However, bicycling ability remains surprisingly unaffected in most patients suffering from freezing, suggesting functional differences in the motor network. The purpose of this study was to characterize and contrast the oscillatory dynamics underlying bicycling and walking in the basal ganglia. METHODS: We present the first local field potential recordings directly comparing bicycling and walking in Parkinson disease patients with electrodes implanted in the subthalamic nuclei for deep brain stimulation. Low (13-22Hz) and high (23-35Hz) beta power changes were analyzed in 22 subthalamic nuclei from 13 Parkinson disease patients (57.5 +/- 5.9 years old, 4 female). The study group consisted of 5 patients with and 8 patients without freezing of gait. RESULTS: In patients without freezing of gait, both bicycling and walking led to a suppression of subthalamic beta power (13 35Hz), and this suppression was stronger for bicycling. Freezers showed a similar pattern in general. Superimposed on this pattern, however, we observed a movement induced, narrowband power increase around 18Hz, which was evident even in the absence of freezing. INTERPRETATION: These results indicate that bicycling facilitates overall suppression of beta power. Furthermore, movement leads to exaggerated synchronization in the low beta band specifically within the basal ganglia of patients susceptible to freezing. Abnormal ~18Hz oscillations are implicated in the pathophysiology of freezing of gait, and suppressing them may form a key strategy in developing potential therapies. Ann Neurol 2017;82:592 601. PMID- 28892574 TI - Identification of a novel interspecific hybrid yeast from a metagenomic spontaneously inoculated beer sample using Hi-C. AB - Interspecific hybridization is a common mechanism enabling genetic diversification and adaptation; however, the detection of hybrid species has been quite difficult. The identification of microbial hybrids is made even more complicated, as most environmental microbes are resistant to culturing and must be studied in their native mixed communities. We have previously adapted the chromosome conformation capture method Hi-C to the assembly of genomes from mixed populations. Here, we show the method's application in assembling genomes directly from an uncultured, mixed population from a spontaneously inoculated beer sample. Our assembly method has enabled us to de-convolute four bacterial and four yeast genomes from this sample, including a putative yeast hybrid. Downstream isolation and analysis of this hybrid confirmed its genome to consist of Pichia membranifaciens and that of another related, but undescribed, yeast. Our work shows that Hi-C-based metagenomic methods can overcome the limitation of traditional sequencing methods in studying complex mixtures of genomes. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28892577 TI - Development of a prediction model for severe wheat allergy. PMID- 28892575 TI - Effects of treating helminths during pregnancy and early childhood on risk of allergy-related outcomes: Follow-up of a randomized controlled trial. AB - BACKGROUND: Helminth infections, common in low-income countries, may protect against allergy-related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. METHODS: This randomized, double-blind, placebo-controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow-up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor-diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. RESULTS: 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. CONCLUSIONS: Prenatal and early-life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting. PMID- 28892576 TI - Pregnancy modulates the allergen-induced cytokine production differently in allergic and non-allergic women. AB - BACKGROUND: The immunological environment during pregnancy may differ between allergic and non-allergic women. This study investigates the effect of maternal allergy on the allergen-induced cytokine and chemokine levels and whether pregnancy modulates these immune responses differently in allergic and non allergic women. METHODS: The birch-, cat-, phytohemagglutinin- and tetanus toxoid induced interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-5, IL-10, IL-13, the T-helper 1 (Th1)-associated chemokine CXCL10 and the Th2-associated chemokine CCL17 levels were quantified in 20 women with allergic symptoms (sensitized, n = 13) and 36 women without allergic symptoms (non-sensitized, n = 30) at gestational weeks 10-12, 15-16, 25, 35 and 2 and 12 months post-partum. RESULTS: Birch-, but not cat-induced, IL-5, IL-13 and CCL17 levels were increased during pregnancy as compared to post-partum in the sensitized women with allergic symptoms. In contrast, cat-, but not birch-induced, IL-5 and IL-13 levels were increased during pregnancy as compared to post-partum in the non-sensitized women without allergic symptoms. Furthermore, IFN-gamma secretion was increased in the first and decreased in the second and third trimesters in response to birch and decreased in the third trimester in response to cat as compared to post-partum in the non-sensitized women without allergic symptoms. Increased allergen-induced IL 4, IL-5 and IL-13 levels were associated with allergic symptoms and sensitization. CONCLUSIONS: Pregnancy had a clear effect on the allergen-induced IL-5, IL-13, CCL17, IFN-gamma and CXCL10 production, with distinct enhanced Th2 responses to birch in the allergic group and to cat in the non-allergic group. PMID- 28892578 TI - CO2 evasion from boreal lakes: Revised estimate, drivers of spatial variability, and future projections. AB - Lakes (including reservoirs) are an important component of the global carbon (C) cycle, as acknowledged by the fifth assessment report of the IPCC. In the context of lakes, the boreal region is disproportionately important contributing to 27% of the worldwide lake area, despite representing just 14% of global land surface area. In this study, we used a statistical approach to derive a prediction equation for the partial pressure of CO2 (pCO2 ) in lakes as a function of lake area, terrestrial net primary productivity (NPP), and precipitation (r2 = .56), and to create the first high-resolution, circumboreal map (0.5 degrees ) of lake pCO2 . The map of pCO2 was combined with lake area from the recently published GLOWABO database and three different estimates of the gas transfer velocity k to produce a resulting map of CO2 evasion (FCO2 ). For the boreal region, we estimate an average, lake area weighted, pCO2 of 966 (678-1,325) MUatm and a total FCO2 of 189 (74-347) Tg C year-1 , and evaluate the corresponding uncertainties based on Monte Carlo simulation. Our estimate of FCO2 is approximately twofold greater than previous estimates, as a result of methodological and data source differences. We use our results along with published estimates of the other C fluxes through inland waters to derive a C budget for the boreal region, and find that FCO2 from lakes is the most significant flux of the land-ocean aquatic continuum, and of a similar magnitude as emissions from forest fires. Using the model and applying it to spatially resolved projections of terrestrial NPP and precipitation while keeping everything else constant, we predict a 107% increase in boreal lake FCO2 under emission scenario RCP8.5 by 2100. Our projections are largely driven by increases in terrestrial NPP over the same period, showing the very close connection between the terrestrial and aquatic C cycle. PMID- 28892580 TI - Correlation of quantitative parameters of magnetic resonance perfusion-weighted imaging with vascular endothelial growth factor, microvessel density and hypoxia inducible factor-1alpha in nasopharyngeal carcinoma: Evaluation on radiosensitivity study. AB - OBJECTIVES: To investigate the correlation of parameters of magnetic resonance perfusion-weighted imaging (MR-PWI) with the expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1alpha (HIF-1alpha) and microvessel density (MVD) in nasopharyngeal carcinoma (NPC) so as to explore the value of predicting radiosensitivity. DESIGN: A prospective study. SETTING: Department of Head-and-neck radiotherapy in Hunan Cancer Hospital. PARTICIPANTS: Ninety-four patients of NPC were included between December 2013 and December 2014. MAIN OUTCOME MEASURES: The expression of VEGF, MVD and HIF-1alpha was studied by immunohistochemistry, and magnetic resonance perfusion-weighted imaging (MR-PWI) was performed before and after undergoing radiotherapy (20 Gy dose). Parameters of MR-PWI, volume of primary tumour and rate of tumour remission were measured and calculated. Patients with primary local tumour were then divided into completely response group (CR group) and partially response group (non-CR group) according to tumour regression condition. Relevant parameters were analysed by Spearman, and diagnostic efficiency of radiosensitivity was analysed by receiver operating characteristic curve (ROC). RESULTS: The expression of VEGF was positively correlated with MVD (r = .322,P < .05), but the expression of HIF-1alpha was no significant correlations with VEGF and MVD. The expression VEGF was in positive correlation with fractional plasma volume (fpv) (r = .339, P = .05) before radiotherapy. There was a significant difference in the quantitative parameters of MR-PWI between CR group and non-CR group during the course of radiotherapy and at the end of radiotherapy treatment. The change of blood reflux constant (Deltakep20) and extravascular extracellular space volume fraction (DeltaVe20) before and after treatment was positively correlated with primary local tumour remission condition after 3 month treatment; Deltakep and DeltaVe were negatively correlated with primary local tumour remission condition after 3 months. Tumour regression rate was only positively correlated with Ve and the average volume of primary tumour after 2 week treatment (V1). ROC curve showed that R20 >= 65.69%, and was considered as a threshold to predict primary local tumour remission, with a sensitivity of 0.84 and specificity of 0.69, and area under the curve was 0.819 (P = .000). CONCLUSIONS: The parameters of MR-PWI with the expression of VEGF, HIF-1alpha and MVD could be guidance for predicting radiosensitivity in NPC. PMID- 28892579 TI - Elevated expression of DeltaNp63 in advanced esophageal squamous cell carcinoma. AB - This study aims to explore the expression level of DeltaNp63 in esophageal squamous cell carcinoma (ESCC). To investigate the association between DeltaNp63 (p40) expression and ESCC biology, we compared the levels of DeltaNp63 expression in normal and tumor tissues, with a specific focus on the diagnostic value of DeltaNp63 in ESCC. We analyzed 160 consecutive patients with ESCC who underwent surgical resection without neoadjuvant chemotherapy at Gunma University Hospital (Maebashi, Japan) between September 2000 and January 2010. The clinicopathological characteristics and survival of patients were subclassified based on the expression of DeltaNp63 as determined by immunohistochemistry, indicating that DeltaNp63 was highly expressed in 75.6% (121/160) of ESCC patients. Clinicopathological analysis of DeltaNp63 expression showed that DeltaNp63-positive tumors significantly correlated with two important clinical parameters: T factor (P = 0.0316) and venous invasion (P = 0.0195). The 5-year overall survival rates of advanced ESCC patients with positive and negative expression of DeltaNp63 were 35.6% and 71.7%, respectively. Multivariate analysis revealed that the expression of DeltaNp63 was identified as an independent prognostic factor (P = 0.0049) in advanced ESCC. In line with this, DeltaNp63alpha-transduced ESCC cell lines increased tumor growth in a soft agar colony formation assay. We report here for the first time that DeltaNp63 expression increases the oncogenic potential of ESCC and is an independent marker for predicting poor outcome in advanced ESCC. Our findings suggest that DeltaNp63 could serve as a new diagnostic marker for ESCC and might be a relevant therapeutic target for the treatment of patients with this disease. PMID- 28892581 TI - Direct current stimulation modulates the excitability of the sensory and motor fibres in the human posterior tibial nerve, with a long-lasting effect on the H reflex. AB - Several studies demonstrated that transcutaneous direct current stimulation (DCS) may modulate central nervous system excitability. However, much less is known about how DC affects peripheral nerve fibres. We investigated the action of DCS on motor and sensory fibres of the human posterior tibial nerve, with supplementary analysis in acute experiments on rats. In forty human subjects, electric pulses at the popliteal fossa were used to elicit either M-waves or H reflexes in the Soleus, before (15 min), during (10 min) and after (30 min) DCS. Cathodal or anodal current (2 mA) was applied to the same nerve. Cathodal DCS significantly increased the H-reflex amplitude; the post-polarization effect lasted up to ~ 25 min after the termination of DCS. Anodal DCS instead significantly decreased the reflex amplitude for up to ~ 5 min after DCS end. DCS effects on M-wave showed the same polarity dependence but with considerably shorter after-effects, which never exceeded 5 min. DCS changed the excitability of both motor and sensory fibres. These effects and especially the long-lasting modulation of the H-reflex suggest a possible rehabilitative application of DCS that could be applied either to compensate an altered peripheral excitability or to modulate the afferent transmission to spinal and supraspinal structures. In animal experiments, DCS was applied, under anaesthesia, to either the exposed peroneus nerve or its Dorsal Root, and its effects closely resembled those found in human subjects. They validate therefore the use of the animal models for future investigations on the DCS mechanisms. PMID- 28892582 TI - Study on the tumor-induced angiogenesis using mathematical models. AB - We studied angiogenesis using mathematical models describing the dynamics of tip cells. We reviewed the basic ideas of angiogenesis models and its numerical simulation technique to produce realistic computer graphics images of sprouting angiogenesis. We examined the classical model of Anderson-Chaplain using fundamental concepts of mass transport and chemical reaction with ECM degradation included. We then constructed two types of numerical schemes, model-faithful and model-driven ones, where new techniques of numerical simulation are introduced, such as transient probability, particle velocity, and Boolean variables. PMID- 28892583 TI - Fluorescent Probe DCVJ Shows High Sensitivity for Characterization of Amyloid beta-Peptide Early in the Lag Phase. AB - The aggregation of intrinsically disordered and misfolded proteins in the form of oligomers and fibrils plays a crucial role in a number of neurological and neurodegenerative diseases. Currently, most probes and biophysical techniques that detect and characterize fibrils at high resolution fail to show sensitivity and binding for oligomers. Here, we show that 9-(dicyano-vinyl)julolidine (DCVJ), a class of molecular rotor, binds amyloid beta (Abeta) early aggregates, and we report the kinetics as well as packing of the oligomer formation. The binding of DCVJ to Abeta40 increased its emission intensity with time at 510 nm and produced a second excimer peak at 575 nm. However, DCVJ did not bind to the prefibrillar aggregates of Abeta42, which indicated that the oligomers formed by Abeta40 and Abeta42 were not the same. The F4C F19W mutant of Abeta40, which did not form fibrils, also bound DCVJ, but the emission spectral profile varied from that of the wild-type (WT). Atomic force microscopy images of WT Abeta40, the F4C F19W mutant, and Abeta42 oligomers displayed differences in size and shape, confirming the difference in their DCVJ spectra. The effect of epigallocatechin-3-gallate (EGCG) on the reduction of Abeta42 fibrils was also observed with finer detail than with other techniques. The results of this study show that DCVJ detects early aggregates and provides valuable information regarding the oligomer kinetics, packing, and mechanism of formation. PMID- 28892584 TI - Evidence of Organic Luminescent Centers in Sol-Gel-Synthesized Yttrium Aluminum Borate Matrix Leading to Bright Visible Emission. AB - Yttrium aluminum borate (YAB) powders prepared by sol-gel process have been investigated to understand their photoluminescence (PL) mechanism. The amorphous YAB powders exhibit bright visible PL from blue emission for powders calcined at 450 degrees C to broad white PL for higher calcination temperature. Thanks to 13 C labelling, NMR and EPR studies show that propionic acid initially used to solubilize the yttrium nitrate is decomposed into aromatic molecules confined within the inorganic matrix. DTA-TG-MS analyses show around 2 wt % of carbogenic species. The PL broadening corresponds to the apparition of a new band at 550 nm, associated with the formation of aromatic species. Furthermore, pulsed ENDOR spectroscopy combined with DFT calculations enables us to ascribe EPR spectra to free radicals derived from small (2 to 3 rings) polycyclic aromatic hydrocarbons (PAH). PAH molecules are thus at the origin of the PL as corroborated by slow afterglow decay and thermoluminescence experiments. PMID- 28892585 TI - Electron-Transfer and Hydride-Transfer Pathways in the Stoltz-Grubbs Reducing System (KOtBu/Et3 SiH). AB - Recent studies by Stoltz, Grubbs et al. have shown that triethylsilane and potassium tert-butoxide react to form a highly attractive and versatile system that shows (reversible) silylation of arenes and heteroarenes as well as reductive cleavage of C-O bonds in aryl ethers and C-S bonds in aryl thioethers. Their extensive mechanistic studies indicate a complex network of reactions with a number of possible intermediates and mechanisms, but their reactions likely feature silyl radicals undergoing addition reactions and SH 2 reactions. This paper focuses on the same system, but through computational and experimental studies, reports complementary facets of its chemistry based on a) single electron transfer (SET), and b) hydride delivery reactions to arenes. PMID- 28892586 TI - Introducing the new CoblationTM TurbinatorTM turbinate reduction wand: Our initial experience of twenty-two patients requiring surgery for nasal obstruction. PMID- 28892587 TI - Improved Biocompatibility of Black Phosphorus Nanosheets by Chemical Modification. AB - Black phosphorus nanosheets (BPs) show great potential for various applications including biomedicine, thus their potential side effects and corresponding improvement strategy deserve investigation. Here, in vitro and in vivo biological effects of BPs with and without titanium sulfonate ligand (TiL4 ) modification are investigated. Compared to bare BPs, BPs with TiL4 modification (TiL4 @BPs) can efficiently escape from macrophages uptake, and reduce cytotoxicity and proinflammation. The corresponding mechanisms are also discussed. These findings may not only guide the applications of BPs, but also propose an efficient strategy to further improve the biocompatibility of BPs. PMID- 28892588 TI - Remote Loading of Small-Molecule Therapeutics into Cholesterol-Enriched Cell Membrane-Derived Vesicles. AB - The increasing popularity of biomimetic design principles in nanomedicine has led to therapeutic platforms with enhanced performance and biocompatibility. This includes the use of naturally derived cell membranes, which can bestow nanocarriers with cell-specific functionalities. Herein, we report on a strategy enabling efficient encapsulation of drugs via remote loading into membrane vesicles derived from red blood cells. This is accomplished by supplementing the membrane with additional cholesterol, stabilizing the nanostructure and facilitating the retention of a pH gradient. We demonstrate the loading of two model drugs: the chemotherapeutic doxorubicin and the antibiotic vancomycin. The therapeutic implications of these natural, remote-loaded nanoformulations are studied both in vitro and in vivo using animal disease models. Ultimately, this approach could be used to design new biomimetic nanoformulations with higher efficacy and improved safety profiles. PMID- 28892589 TI - Single Turnover at Molecular Polymerization Catalysts Reveals Spatiotemporally Resolved Reactions. AB - Multiple active individual molecular ruthenium catalysts have been pinpointed within growing polynorbornene, thereby revealing information on the reaction dynamics and location that is unavailable through traditional ensemble experiments. This is the first single-turnover imaging of a molecular catalyst by fluorescence microscopy and allows detection of individual monomer reactions at an industrially important molecular ruthenium ring-opening metathesis polymerization (ROMP) catalyst under synthetically relevant conditions (e.g. unmodified industrial catalyst, ambient pressure, condensed phase, ca. 0.03 m monomer). These results further establish the key fundamentals of this imaging technique for characterizing the reactivity and location of active molecular catalysts even when they are the minor components. PMID- 28892590 TI - Surgeon-performed thyroid ultrasound-proving utility and credibility in selecting patients for fine needle aspiration according to the American thyroid association guidelines. A retrospective study of 500 patients. AB - DESIGN: Case series with chart review. SETTING: Single academic centre. PARTICIPANTS: The data of all patients who underwent surgeon-performed ultrasound (SUS) between 7/2009 and 9/2012 were retrospectively reviewed. MAIN OUTCOME MEASURES: A correlation between sonographic features and a non-benign cytology?malignant pathology. RESULTS: Four hundred ninety-eight nodules were included. Solid texture, irregular margins, hypo-echogenicity and intranodular vascularity were significantly associated with malignancy when benign to non benign cytology was compared, and when compared to malignant pathology. Lack of suspicious features was significantly associated with benign lesions, with a negative predictive value of 94%. Except for taller than wider shape, malignancy odds ratio was significantly higher for known suspicious features, reaching 4.81 for irregular borders (CI 2.42-9.55, P < .001). CONCLUSIONS: SUS has proven to be a reliable and consistent tool to assess the thyroid nodule risk stratification. Surgeons should recognise the potential of this tool and its implementation. PMID- 28892591 TI - A Pilot Dose-Finding Study of Etanercept in Rheumatoid Arthritis. AB - A randomized, parallel-dose study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of etanercept in 61 patients with rheumatoid arthritis (RA) who received doses from 10 mg once-weekly to 50 mg twice-weekly for 4 weeks. Empiric application of a maximal-effect (Emax ) model to pooled steady-state concentrations (Css ) and PD markers provided half-maximal-effect concentration estimates of 567, 573, 465, 87, and 159 ng/mL for change from baseline in number of swollen joints, number of painful joints, erythrocyte sedimentation rate, interleukin-6, and matrix metalloproteinase-3, respectively. Css >~2,000 ng/mL did not appear to offer additional benefit. It was concluded that the middle doses, 10 mg twice-weekly, 50 mg every 2 weeks, and 50 mg once-weekly, would provide Css in the target range of 500-2,000 ng/mL. The revised US Food and Drug Administration guideline for development of medicines for treatment of RA encourages a study design incorporating PK/PD assessment to inform later studies. PMID- 28892592 TI - Analysis of climate signals in the crop yield record of sub-Saharan Africa. AB - Food security and agriculture productivity assessments in sub-Saharan Africa (SSA) require a better understanding of how climate and other drivers influence regional crop yields. In this paper, our objective was to identify the climate signal in the realized yields of maize, sorghum, and groundnut in SSA. We explored the relation between crop yields and scale-compatible climate data for the 1962-2014 period using Random Forest, a diagnostic machine learning technique. We found that improved agricultural technology and country fixed effects are three times more important than climate variables for explaining changes in crop yields in SSA. We also found that increasing temperatures reduced yields for all three crops in the temperature range observed in SSA, while precipitation increased yields up to a level roughly matching crop evapotranspiration. Crop yields exhibited both linear and nonlinear responses to temperature and precipitation, respectively. For maize, technology steadily increased yields by about 1% (13 kg/ha) per year while increasing temperatures decreased yields by 0.8% (10 kg/ha) per degrees C. This study demonstrates that although we should expect increases in future crop yields due to improving technology, the potential yields could be progressively reduced due to warmer and drier climates. PMID- 28892593 TI - Much more than prescribing a pill - Assessment and treatment of erectile dysfunction by the general practitioner. AB - BACKGROUND: Erectile dysfunction is a common but often neglected condition. Prevalence increases with age, but is not insignificant in younger men. OBJECTIVE: This article will broadly describe the epidemiology, classification and risk factors of erectile dysfunction. It will also discuss assessment and current treatment modalities, with a particular focus on the unique role of the general practitioner (GP). DISCUSSION: Erectile dysfunction may be classified as vasculogenic, neurogenic, endocrinological, drug-related, psychogenic or mixed. Commonly, erectile dysfunction is a cause of anxiety and even depression. Risk factors, such as smoking and hypertension, and reversible causes, such as hypogonadism or offending medications, should be addressed. At present, oral pharmacotherapy represents the first-line option for most patients with erectile dysfunction. It is of utmost importance to evaluate and treat comorbidities, such as depression, metabolic syndrome and cardiovascular disease, that often accompany erectile dysfunction. Patients will undoubtedly benefit from comprehensive management by a dedicated GP. Occasionally, referral to a urologist, psychologist or sexual health physician may be required. PMID- 28892594 TI - Male infertility - The other side of the equation. AB - BACKGROUND: A male factor contributes to infertility in approximately 50% of couples who fail to conceive, causing significant psychosocial and marital stress. OBJECTIVE: This article reviews the general practitioner's (GP's) evaluation of male infertility and indications for referral to a male infertility specialist, and gives an overview of the specialist management of male infertility. DISCUSSION: Male infertility can result from anatomical or genetic abnormalities, systemic or neurological diseases, infections, trauma, iatrogenic injury, gonadotoxins and development of sperm antibodies. When a couple fails to achieve pregnancy after 12 months of regular, unprotected sexual intercourse, a screening evaluation of both partners is essential. For the male partner this includes history, physical examination, endocrine assessment and semen analysis. Several lifestyle and environmental factors can have a negative impact on male fertility, and the GP has a pivotal role in educating patients about modifiable factors. PMID- 28892595 TI - Urolithiasis - Ten things every general practitioner should know. AB - BACKGROUND: Upper urinary tract stones are a common problem in Australia, with an incidence of 0.13% per year, and a lifetime prevalence of up to 15% in males and 8% in females. Many of these patients first present to general practitioners (GPs), so a thorough understanding of the diagnosis, treatment and prevention of stone disease is an important part of any GP's arsenal. OBJECTIVE: In this article, we present evidence-based guidelines regarding urolithiasis, from diagnosis, through to conservative and operative management, and prevention, as a reference for GPs and other primary care physicians. DISCUSSION: The majority of urolithiasis cases can be conservatively managed. However, prior to conservative management, adequate imaging must be obtained and emergent conditions must be excluded. Conservative management should not be initiated without a plan in the event the management fails, and adequate analgesia and medical expulsive therapy should be prescribed. Should surgery be necessary, the majority of operations can be performed as minimally invasive day procedures. PMID- 28892596 TI - Peyronie's disease - Watch out for the bend. AB - BACKGROUND: Peyronie's disease is a relatively common condition in urological practice, but is still poorly identified and understood in the wider medical community and by most of the public. Identifying the condition and appropriate referral for expert opinion can significantly lessen the physical and psychological effect on patients. OBJECTIVE: The objective of this article is to provide general practitioners with a concise and updated review of Peyronie's disease, with the aim of helping them to provide appropriate advice to their patients. DISCUSSION: Peyronie's disease is an aberrant wound healing process culminating in excess scar formation in the penis, which may cause penile pain, shortening and curvature. It is often accompanied by erectile dysfunction, and can result in progressive and severe impairment of penetrative intercourse. The course of the disorder is divided into active inflammatory and chronic stable phases. Oral therapy is usually of limited efficacy, while penile traction may only be beneficial in motivated patients. Intralesional injections of collagenase were recently introduced as a non-surgical measure to decrease penile curvature. Surgery remains the most effective treatment for Peyronie's disease and is considered the gold standard. PMID- 28892597 TI - Adult male stress and urge urinary incontinence - A review of pathophysiology and treatment strategies for voiding dysfunction in men. AB - BACKGROUND: Male urinary incontinence adversely affects health-related quality of life and is associated with significant psychosexual and financial burden. The two most common forms of male incontinence are stress urinary incontinence (SUI) and overactive bladder (OAB) with concomitant urge urinary incontinence (UUI). OBJECTIVE: The objectives of this article are to briefly review the current understandings of the pathophysiological mechanisms in SUI and OAB/UUI, and offer a set of practical, action-based recommendations and treatment strategies. DISCUSSION: The initial evaluation of male urinary incontinence usually occurs in general practice, and the basic work-up aims to identify reversible causes. First line treatment is conservative management, such as lifestyle interventions, pelvic floor muscle training with or without biofeedback, and bladder retraining. Treatment options include male slings and artificial urinary sphincter surgery for men with persistent SUI, and medical therapy, intravesical botulinum toxin, sacral neuromodulation or surgery in refractory cases for those with predominant OAB/UUI. PMID- 28892598 TI - Helping mothers with the emotional dysregulation of borderline personality disorder and their infants in primary care settings. AB - BACKGROUND: Six per cent of patients who present to primary care have borderline personality disorder (BPD). Mothers with full or partial features of BPD, often undiagnosed and perhaps previously functioning adequately enough on the surface, may rapidly be-come emotionally dysregulated by the normal needs of an infant. Family and maternal functioning can rapidly destabilise. Management of patients with BPD in primary care may be challenging. OBJECTIVE: The objectives of this article are to provide primary care practitioners with relevant information on current knowledge of BPD and its management when mothers with BPD are caregivers to an infant. DISCUSSION: Useful guidelines for general practitioners that can help women who are emotionally dysregulated with infants include: keeping the diagnosis in mind openly discussing BPD diagnosis where relevant providing psychoeducational material and ongoing support to the woman and her familyreferring to specialised services for BPD referring to standard maternal child health services and specialised .infant mental health services ongoing communication with other services and supervision for the practitioner. PMID- 28892599 TI - Occult syphilitic chancres in the rectum and oropharynx. PMID- 28892600 TI - The suspect - SIADH. AB - BACKGROUND: Hyponatraemia is one of the most commonly encountered electrolyte abnormalities in general practice. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an important but under-recognised cause. OBJECTIVE: This article explores the presentation, investigation, diagnosis and management of SIADH. DISCUSSION: SIADH can occur secondary to medications, malignancy, pulmonary disease, or any disorder involving the central nervous system. Diagnosis is made on the basis of clinical euvolaemic state with low serum sodium and osmolality, raised urine sodium and osmolality, and exclusion of pseudohyponatraemia and diuretic use. Fluid restriction of 800-1200 mL/24 hours is the mainstay of treatment. Patients with severe hyponatraemia and symptoms of altered mental state or seizures should be admitted to hospital for monitoring of fluid restriction and consideration of hypertonic saline. A rapid increase in sodium levels can precipitate osmotic demyelination and, as such, the increase in serum sodium should not exceed 10 mmol/L in 24 hours or 18 mmol/L in 48 hours. PMID- 28892601 TI - Knowledge and practices of chronic hepatitis B virus testing by general practitioners in Victoria, Australia, 2014-15. AB - BACKGROUND: More than one-third of people living with chronic hepatitis B virus (HBV) in Australia have not been diagnosed. The aim of this study was to assess general practitioners' (GPs') knowledge and practices regarding chronic HBV diagnosis, and identify opportunities to improve testing rates. METHODS: A cross sectional survey was conducted with GPs working in Victoria, Australia. Statistically significant adjusted odds ratios for high knowledge, and ordering two or more HBV tests per week were calculated. RESULTS: Of 1000 GPs who were invited to participate, 232 completed the survey. Chronic HBV knowledge, use of interpreters, and awareness of HBV testing guidelines were low. Chronic HBV knowledge and testing were associated with age and graduation from a medical school outside Australia. Testing was also associated with gender. DISCUSSION: This study identified gaps in GPs' knowledge about chronic hepatitis. Several barriers to improving testing rates among at-risk populations were identified. We recommend revision of the guidelines for prevention in general practice, and educational activities to improve knowledge of at-risk populations for chronic HBV in Australia. PMID- 28892602 TI - Locating advance care planning facilitators in general practice increases consumer participation. AB - BACKGROUND: Advance care planning (ACP) can positively affect end-of-life care experiences. However, uptake of ACP completion is low. The aim of this study was to investigate whether co-locating ACP facilitators in general practice increased participation METHODS: Barwon Health commenced promoting its ACP program in 2008. Trained ACP facilitators assisted consumers, which usually occurred in the program's community-based consulting rooms. From 2012 onwards, ACP facilitators were co-located with 18 general practices, where they assisted consumers at the point of care. RESULTS: Referrals to the program increased from 2008-11 (n = 2520) to 2012-15 (n = 6847). Between 2012 and 2015, 48% of referrals to the program were from the 18 general practices with co-located ACP facilitators, and 93% of these referrals resulted in ACPs completed, compared with 74% from practices without co-located facilitators and 55% from all other sources (P DISCUSSION: Co-locating ACP facilitators in general practice increased the number of referrals to the program and produced higher plan completion rates. PMID- 28892603 TI - Navigating the disparate Australian regulatory minefield of cosmetic therapy. PMID- 28892604 TI - Clinical Challenge. AB - Questions for this month's clinical challenge are based on articles in this issue. The clinical challenge is endorsed by the RACGP Quality Improvement and Continuing Professional Development (QI&CPD) program and has been allocated four Category 2 points (Activity ID: 109894). Answers to this clinical challenge are available immediately following successful completion online at http://gplearning.racgp.org.au. Clinical challenge quizzes may be completed at any time throughout the 2017-19 triennium; therefore, the previous months' answers are not published. Each of the questions or incomplete statements below is followed by four suggested answers or completions. Select the most appropriate statement as your answer. PMID- 28892605 TI - Inhibitors of the Diadenosine Tetraphosphate Phosphorylase Rv2613c of Mycobacterium tuberculosis. AB - The intracellular concentration of diadenosine tetraphospate (Ap4A) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap4A are still enigmatic. If and how the varied Ap4A is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Because the turnover of Ap4A by Ap4A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap4A. Here, we describe the development of a high-throughput screening assay based on a fluorogenic Ap4A substrate for the identification and optimization of small molecule inhibitors for Ap4A cleaving enzymes. As proof-of-concept we screened a library of over 42 000 compounds toward their inhibitory activity against the Ap4A phosphorylase (Rv2613c) of Mycobacterium tuberculosis (Mtb). A sulfanylacrylonitril derivative with an IC50 of 260 +/- 50 nM in vitro was identified. Multiple derivatives were synthesized to further optimize their properties with respect to their in vitro IC50 values and their cytotoxicity against human cells (HeLa). In addition, we selected two hits to study their antimycobacterial activity against virulent Mtb to show that they might be candidates for further development of antimycobacterial agents against multidrug-resistant Mtb. PMID- 28892606 TI - CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide. AB - Intracellular signaling pathways are mediated by changes in protein abundance and post-translational modifications. A common approach for investigating signaling mechanisms and the effects induced by synthetic compounds is through overexpression of recombinant reporter genes. Genome editing with CRISPR/Cas9 offers a means to better preserve native biology by appending reporters directly onto the endogenous genes. An optimal reporter for this purpose would be small to negligibly influence intracellular processes, be readily linked to the endogenous genes with minimal experimental effort, and be sensitive enough to detect low expressing proteins. HiBiT is a 1.3 kDa peptide (11 amino acids) capable of producing bright and quantitative luminescence through high affinity complementation (KD = 700 pM) with an 18 kDa subunit derived from NanoLuc (LgBiT). Using CRISPR/Cas9, we demonstrate that HiBiT can be rapidly and efficiently integrated into the genome to serve as a reporter tag for endogenous proteins. Without requiring clonal isolation of the edited cells, we were able to quantify changes in abundance of the hypoxia inducible factor 1A (HIF1alpha) and several of its downstream transcriptional targets in response to various stimuli. In combination with fluorescent antibodies, we further used HiBiT to directly correlate HIF1alpha levels with the hydroxyproline modification that mediates its degradation. These results demonstrate the ability to efficiently tag endogenous proteins with a small luminescent peptide, allowing sensitive quantitation of the response dynamics in their regulated expression and covalent modifications. PMID- 28892607 TI - Template-Free Synthesis of Highly Porous Boron Nitride: Insights into Pore Network Design and Impact on Gas Sorption. AB - Production of biocompatible and stable porous materials, e.g., boron nitride, exhibiting tunable and enhanced porosity is a prerequisite if they are to be employed to address challenges such as drug delivery, molecular separations, or catalysis. However, there is currently very limited understanding of the formation mechanisms of porous boron nitride and the parameters controlling its porosity, which ultimately prevents exploiting the material's full potential. Herein, we produce boron nitride with high and tunable surface area and micro/mesoporosity via a facile template-free method using multiple readily available N-containing precursors with different thermal decomposition patterns. The gases are gradually released, creating hierarchical pores, high surface areas (>1900 m2/g), and micropore volumes. We use 3D tomography techniques to reconstruct the pore structure, allowing direct visualization of the mesopore network. Additional imaging and analytical tools are employed to characterize the materials from the micro- down to the nanoscale. The CO2 uptake of the materials rivals or surpasses those of commercial benchmarks or other boron nitride materials reported to date (up to 4 times higher), even after pelletizing. Overall, the approach provides a scalable route to porous boron nitride production as well as fundamental insights into the material's formation, which can be used to design a variety of boron nitride structures. PMID- 28892608 TI - Electrode-Impregnable and Cross-Linkable Poly(ethylene oxide)-Poly(propylene oxide)-Poly(ethylene oxide) Triblock Polymer Electrolytes with High Ionic Conductivity and a Large Voltage Window for Flexible Solid-State Supercapacitors. AB - We present cross-linkable precursor-type gel polymer electrolytes (GPEs) that have large ionic liquid uptake capability, can easily penetrate electrodes, have high ion conductivity, and are mechanically strong as high-performance, flexible all-solid-state supercapacitors (SC). Our polymer precursors feature a hydrophilic-hydrophobic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock main-chain structure and trifunctional silane end groups that can be multi-cross-linked with each other through a sol-gel process. The cross-linked solid-state electrolyte film with moderate IL content (200 wt %) shows a well-balanced combination of excellent ionic conductivity (5.0 * 10-3 S cm-1) and good mechanical stability (maximum strain = 194%). Moreover, our polymer electrolytes have various advantages including high thermal stability (decomposition temperature > 330 degrees C) and the capability to impregnate electrodes to form an excellent electrode-electrolyte interface due to the very low viscosity of the precursors. By assembling our GPE-impregnated electrodes and solid-state GPE film, we demonstrate an all-solid-state SC that can operate at 3 V and provides an improved specific capacitance (112.3 F g-1 at 0.1 A g-1), better rate capability (64% capacity retention until 20 A g-1), and excellent cycle stability (95% capacitance decay over 10 000 charge/discharge cycles) compared with those of a reference SC using a conventional PEO electrolyte. Finally, flexible SCs with a high energy density (22.6 W h kg-1 at 1 A g-1) and an excellent flexibility (>93% capacitance retention after 5000 bending cycles) can successfully be obtained. PMID- 28892609 TI - Molecular Engineering of Conjugated Polymers for Biocompatible Organic Nanoparticles with Highly Efficient Photoacoustic and Photothermal Performance in Cancer Theranostics. AB - Conjugated polymer nanoparticles (CP NPs) are emerging candidates of "all-in-one" theranostic nanoplatforms with dual photoacoustic imaging (PA) and photothermal therapy (PTT) functions. So far, very limited molecular design guidelines have been developed for achieving CPs with highly efficient PA and PTT performance. Herein, by designing CP1, CP2, and CP3 using different electron acceptors (A) and a planar electron donor (D), we demonstrate how the D-A strength affects their absorption, emission, extinction coefficient, and ultimately PA and PTT performance. The resultant CP NPs have strong PA signals with high photothermal conversion efficiencies and excellent biocompatibility in vitro and in vivo. The CP3 NPs show a high PA signal to background ratio of 47 in U87 tumor-bearing mice, which is superior to other reported PA/PTT theranostic agents. A very small IC50 value of 0.88 MUg/mL (CP3 NPs) was obtained for U87 glioma cell ablation under laser irradiation (808 nm, 0.8 W/cm2, 5 min). This study shows that CP NP based theranostic platforms are promising for future personalized nanomedicine. PMID- 28892610 TI - Catalysis and Inhibition in the Electrochemical Reduction of CO2 on Platinum in the Presence of Protonated Pyridine. New Insights into Mechanisms and Products. AB - In the framework of modern energy challenges, the reduction of CO2 into fuels calls for electrogenerated low-valent transition metal complexes catalysts designed with considerable ingenuity and sophistication. For this reason, the report that a molecule as simple as protonated pyridine (PyH+) could catalyze the formation of methanol from the reduction of CO2 on a platinum electrode triggered great interest and excitement. Further investigations revealed that no methanol is produced. It appears that CO2 is not really reduced but rather participates, on the basis of its aquation into carbonic acid, in hydrogen evolution. Actually, the situation is not that straightforward, as revealed by scrutinizing what happens at the platinum electrode surface. The present study confirms the lack of methanol formation upon bulk electrolysis of PyH+ solutions at Pt and provides a detailed account of the Faradaic yield for H2 production as a function of the electrode potential, but the main finding is that CO2 reduction is accompanied by a strong inhibition of the electrode process taking place when it is carried out in the presence of acids such as PyH+ and AcOH. Cyclic voltammetry and in situ infrared spectroscopy were closely combined to investigate and understand the nature and consequences of the inhibition process. Constant comparison between the two acids was required to decipher the course of the reaction owing to the fact that the IR responses are perturbed by PyH+ adsorption. It finally appears that inhibition is caused by the reduction of CO2 into CO, whose high affinity with platinum triggers the formation of a Pt-CO film that prevents the reaction process. Thus, a paradoxical situation develops in which the high affinity of Pt for CO helps to decrease the overpotential for the reduction of CO2 and therefore blocks the electrode, preventing the reaction process. PMID- 28892611 TI - Upconversion Nanoparticles/Hyaluronate-Rose Bengal Conjugate Complex for Noninvasive Photochemical Tissue Bonding. AB - The recent progress in photonic nanomaterials has contributed greatly to the development of photomedicines. However, the finite depth of light penetration is still a serious limitation, constraining their clinical applications. Here, we developed a poly(allylamine) (PAAm)-modified upconversion nanoparticle/hyaluronate-rose bengal (UCNP/PAAm/HA-RB) conjugate complex for photochemical bonding of deep tissue with near-infrared (NIR) light illumination. Compared to the conventional invasive treatment via suturing and stapling, the UCNP/PAAm/HA-RB conjugate complex could be noninvasively delivered into the deep tissue and accelerate the tissue bonding upon NIR light illumination. HA in the outer layer of the complex facilitated the penetration of RB into the collagen layer of the dermis. The NIR light triggered UCNP of NaYF4: Yb/Er (Y:Yb:Er = 78:20:2) in the complex to illuminate visible green light under the skin tissue. The activated RB in the HA-RB conjugate by the green light induced radical formation for the cross-linking of incised collagen matrix. An in vitro light propagation test and collagen fibrillogenesis analysis, an in vivo animal tissue bonding test, and an ex vivo tensile strength test of dissected skin tissues confirmed the successful photochemical tissue bonding effect of the UCNP/PAAm/HA RB conjugate complex. PMID- 28892612 TI - Medium Chain-Length Polyhydroxyalkanoate Copolymer Modified by Bacterial Cellulose for Medical Devices. AB - Medium chain-length polyhydroxyalkanoates (mPHAs) are flexible elastomeric biopolymers with valuable properties for biomedical applications like artificial arteries and other medical implants. However, an environmentally friendly and high productivity process together with the tuning of the mechanical and biological properties of mPHAs are mandatory for this purpose. Here, for the first time, a melt processing technique was applied for the preparation of bionanocomposites starting from poly(3-hydroxyoctanoate) (PHO) and bacterial cellulose nanofibers (BC). The incorporation of only 3 wt % BC in PHO improved its thermal stability with 25 degrees C and reinforced it, increasing the Young's modulus with 76% and the tensile strength with 44%. The percolation threshold calculated with the aspect ratio of the fibers after melt processing was very low and close to 3 wt %. We showed that this bionanocomposite is able to preserve the ductile behavior during storage, no important aging being noted between 3 h and one month after compression-molding. Moreover, this study is the first to investigate the melt processability of PHO nanocomposite for tube extrusion. In addition, biocompatibility study showed no proinflammatory immune response and better cell adhesion for PHO/BC nanocomposite with 3 wt % BC and demonstrated the high feasibility of this bionanocomposite for in vivo application of tissue-engineered blood vessels. PMID- 28892613 TI - Electron Density Errors and Density-Driven Exchange-Correlation Energy Errors in Approximate Density Functional Calculations. AB - Since its formal introduction, density functional theory has achieved many successes in the fields of molecular and solid-state chemistry. According to its central theorems, the ground state of a many-electron system is fully described by its electron density, and the exact functional minimizes the energy at the exact electron density. For many years of density functional development, it was assumed that the improvements in the energy are accompanied by the improvements in the density, and the approximations approach the exact functional. In a recent analysis ( Medvedev et al. Science 2017 , 355 , 49 - 52 .), it has been pointed out for 14 first row (Be-Ne) atoms and cations with 2, 4, or 10 electrons that the nowadays popular flexible but physically less rigorous approximate density functionals may provide large errors in the calculated electron densities despite the accurate energies. Although far-reaching conclusions have been drawn in this work, the methodology used by the authors may need improvements. Most importantly, their benchmark set was biased toward small atomic cations with compressed, high electron densities. In our paper, we construct a molecular test set with chemically relevant densities and analyze the performance of several density functional approximations including the less-investigated double hybrids. We apply an intensive error measure for the density, its gradient, and its Laplacian and examine how the errors in the density propagate into the semilocal exchange-correlation energy. While we have confirmed the broad conclusions of Medvedev et al., our different way of analyzing the data has led to conclusions that differ in detail. Finally, seeking for a rationale behind the global hybrid or double hybrid methods from the density's point of view, we also analyze the role of the exact exchange and second-order perturbative correlation mixing in PBE-based global hybrid and double hybrid functional forms. PMID- 28892614 TI - Realization of Red Plasmon Shifts up to ~900 nm by AgPd-Tipping Elongated Au Nanocrystals. AB - The synthesis of metal nanostructures with plasmon wavelengths beyond ~1000 nm is strongly desired, especially for those with small sizes. Herein we report on a AgPd-tipping process on Au nanobipyramids with the resultant red plasmon shifts reaching up to ~900 nm. The large red plasmon shifts are ascribed to the deposition of the metal at the tips of Au nanobipyramids, which is verified by electrodynamic simulations. The method has been successfully applied to Au nanobipyramids and nanorods with different longitudinal dipolar plasmon wavelengths, demonstrating that the plasmon wavelengths of these Au nanocrystals can be extended to the entire near-infrared region. Pt can also induce the tipping on Au nanobipyramids and nanorods to realize red plasmon shifts, suggesting the generality of our approach. We have further shown that the metal tipped Au nanobipyramids possess a high photothermal conversion efficiency and good photothermal therapy performance. This study opens up a route to the construction of Au nanostructures with plasmon resonance in a broad spectral region for plasmon-enabled technological applications. PMID- 28892615 TI - Quantitative Proteomics Reveals the Regulatory Networks of Circular RNA CDR1as in Hepatocellular Carcinoma Cells. AB - Circular RNAs (circRNAs), a class of widespread endogenous RNAs, play crucial roles in diverse biological processes and are potential biomarkers in diverse human diseases and cancers. Cerebellar-degeneration-related protein 1 antisense RNA (CDR1as), an oncogenic circRNA, is involved in human tumorigenesis and is dysregulated in hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CDR1as functions in HCC remain unclear. Here we explored the functions of CDR1as and searched for CDR1as-regulated proteins in HCC cells. A quantitative proteomics strategy was employed to globally identify CDR1as-regulated proteins in HCC cells. In total, we identified 330 differentially expressed proteins (DEPs) upon enhanced CDR1as expression in HepG2 cells, indicating that they could be proteins regulated by CDR1as. Bioinformatic analysis revealed that many DEPs were involved in cell proliferation and the cell cycle. Further functional studies of epidermal growth factor receptor (EGFR) found that CDR1as exerts its effects on cell proliferation at least in part through the regulation of EGFR expression. We further confirmed that CDR1as could inhibit the expression of microRNA-7 (miR-7). EGFR is a validated target of miR-7; therefore, CDR1as may exert its function by regulating EGFR expression via targeting miR-7 in HCC cells. Taken together, we revealed novel functions and underlying mechanisms of CDR1as in HCC cells. This study serves as the first proteome-wide analysis of a circRNA-regulated protein in cells and provides a reliable and highly efficient method for globally identifying circRNA-regulated proteins. PMID- 28892616 TI - Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity. AB - Covalent ligand discovery is a promising strategy to develop small-molecule effectors against therapeutic targets. Recent studies have shown that dichlorotriazines are promising reactive scaffolds that preferentially react with lysines. Here, we have synthesized a series of dichlorotriazine-based covalent ligands and have screened this library to reveal small molecules that impair triple-negative breast cancer cell survival. Upon identifying a lead hit from this screen KEA1-97, we used activity-based protein profiling (ABPP)-based chemoproteomic platforms to identify that this compound targets lysine 72 of thioredoxin-a site previously shown to be important in protein interactions with caspase 3 to inhibit caspase 3 activity and suppress apoptosis. We show that KEA1 97 disrupts the interaction of thioredoxin with caspase 3, activates caspases, and induces apoptosis without affecting thioredoxin activity. Moreover, KEA1-97 impairs in vivo breast tumor xenograft growth. Our study showcases how the screening of covalent ligands can be coupled with ABPP platforms to identify unique anticancer lead and target pairs. PMID- 28892617 TI - Understanding of Electrochemical Mechanisms for CO2 Capture and Conversion into Hydrocarbon Fuels in Transition-Metal Carbides (MXenes). AB - Two-dimensional (2D) transition-metal (groups IV, V, VI) carbides (MXenes) with formulas M3C2 have been investigated as CO2 conversion catalysts with well resolved density functional theory calculations. While MXenes from the group IV to VI series have demonstrated an active behavior for the capture of CO2, the Cr3C2 and Mo3C2 MXenes exhibit the most promising CO2 to CH4 selective conversion capabilities. Our results predicted the formation of OCHO* and HOCO* radical species in the early hydrogenation steps through spontaneous reactions. This provides atomic level insights into the computer-aided screening for high performance catalysts and the understanding of electrochemical mechanisms for CO2 reduction to energy-rich hydrocarbon fuels, which is of fundamental significance to elucidate the elementary steps for CO2 fixation. PMID- 28892618 TI - Consistent Integration of Experimental and Ab Initio Data into Effective Physical Models. AB - We describe and test theoretical principles for consistent integration of experimental and ab initio data from diverse sources into a single statistical mechanical model. The approach is based on the recently introduced concept of statistical distance between partition functions, uses a simple vector algebra formalism to describe measurement outcomes and coarse-graining operations, and takes advantage of thermodynamic perturbation expressions for fast exploration of the model parameter space. The methodology is demonstrated on a combination of thermodynamic, structural, spectroscopic, and imaging pseudoexperimental data along with ab initio-type trajectories, which are incorporated into models describing the behavior of a near-critical fluid, liquid water, thin-film mixed oxides, and binary alloys. We evaluate how different target data constrain the model parameters and how the uncertainty associated with incomplete target information and limited sampling of the system's phase space might influence the choice of optimal parameters. PMID- 28892619 TI - Thorium Metallacycle Facilitates Catalytic Alkyne Hydrophosphination. AB - The bis(NHC)borate-supported thorium-bis(mesitylphosphido) complex (1) undergoes reversible intramolecular C-H bond activation enabling the catalytic hydrophosphination of unactivated internal alkynes. Catalytic and stoichiometric experiments support a mechanism involving reactive Th-NHC metallacycle intermediates (Int and 2). PMID- 28892620 TI - Self-Assembly of Block Copolymer Chains To Promote the Dispersion of Nanoparticles in Polymer Nanocomposites. AB - In this paper we adopt molecular dynamics simulations to study the amphiphilic AB block copolymer (BCP) mediated nanoparticle (NP) dispersion in polymer nanocomposites (PNCs), with the A-block being compatible with the NPs and the B block being miscible with the polymer matrix. The effects of the number and components of BCP, as well as the interaction strength between A-block and NPs on the spatial organization of NPs, are explored. We find that the increase of the fraction of the A-block brings different dispersion effect to NPs than that of B block. We also find that the best dispersion state of the NPs occurs in the case of a moderate interaction strength between the A-block and the NPs. Meanwhile, the stress-strain behavior is probed. Our simulation results verify that adopting BCP is an effective way to adjust the dispersion of NPs in the polymer matrix, further to manipulate the mechanical properties. PMID- 28892621 TI - Adaptive Configuration Interaction for Computing Challenging Electronic Excited States with Tunable Accuracy. AB - We introduce and analyze various approaches for computing excited electronic states using our recently developed adaptive configuration interaction (ACI) method [ Schriber , J. B. and Evangelista , F. A. J. Chem. Phys. 2016 , 144 , 161106 ]. These ACI methods aim to describe multiple electronic states with equal accuracy, including challenging cases like multielectron, charge-transfer, and near-degenerate states. We develop both state-averaged and state-specific approaches to compute excited states whose absolute energy error can be tuned by a user-specified energy error threshold, sigma. State-averaged schemes are found to be more efficient in that they obtain all of the states simultaneously in one computation, but they lose some degree of statewise tunability. State-specific algorithms allow for direct control of the error of each state, though the states must be computed sequentially. We compare each method using methylene, LiF, and all-trans polyene benchmark data. PMID- 28892622 TI - Gold-Loaded Nanoporous Ferric Oxide Nanocubes with Peroxidase-Mimicking Activity for Electrocatalytic and Colorimetric Detection of Autoantibody. AB - The enzyme-mimicking activity of iron oxide based nanostructures has provided a significant advantage in developing advanced molecular sensors for biomedical and environmental applications. Herein, we introduce the horseradish peroxidase (HRP) like activity of gold-loaded nanoporous ferric oxide nanocubes (Au-NPFe2O3NC) for the development of a molecular sensor with enhanced electrocatalytic and colorimetric (naked eye) detection of autoantibodies. The results showed that Au NPFe2O3NC exhibits enhanced peroxidase-like activity toward the catalytic oxidation of 3,3',5,5'-tertamethylbenzidine (TMB) in the presence of H2O2 at room temperature (25 degrees C) and follows the typical Michaelis-Menten kinetics. The autoantibody sensor based on this intrinsic property of Au-NPFe2O3NC resulted in excellent detection sensitivity [limit of detection (LOD) = 0.08 U/mL] and reproducibility [percent relative standard deviation (% RSD) = <5% for n = 3] for analyzing p53-specific autoantibodies using electrochemical and colorimetric (naked eye) readouts. The clinical applicability of the sensor has been tested in detecting p53-specific autoantibody in plasma obtained from patients with epithelial ovarian cancer high-grade serous subtype (EOCHGS, number of samples = 2) and controls (benign, number of samples = 2). As Au-NPFe2O3NC possess high peroxidase-like activity for the oxidation of TMB in the presence of H2O2 [TMB is a common chromogenic substrate for HRP in enzyme-linked immunosorbent assays (ELISAs)], we envisage that our assay could find a wide range of application in developing ELISA-based sensing approaches in the fields of medicine (i.e., detection of other biomarkers the same as p53 autoantibody), biotechnology, and environmental sciences. PMID- 28892623 TI - Use of Crystal Structure Informatics for Defining the Conformational Space Needed for Predicting Crystal Structures of Pharmaceutical Molecules. AB - Determining the range of conformations that a flexible pharmaceutical-like molecule could plausibly adopt in a crystal structure is a key to successful crystal structure prediction (CSP) studies. We aim to use conformational information from the crystal structures in the Cambridge Structural Database (CSD) to facilitate this task. The conformations produced by the CSD Conformer Generator are reduced in number by considering the underlying rotamer distributions, an analysis of changes in molecular shape, and a minimal number of molecular ab initio calculations. This method is tested for five pharmaceutical like molecules where an extensive CSP study has already been performed. The CSD informatics-derived set of crystal structure searches generates almost all the low-energy crystal structures previously found, including all experimental structures. The workflow effectively combines information on individual torsion angles and then eliminates the combinations that are too high in energy to be found in the solid state, reducing the resources needed to cover the solid-state conformational space of a molecule. This provides insights into how the low energy solid-state and isolated-molecule conformations are related to the properties of the individual flexible torsion angles. PMID- 28892624 TI - In Situ Encapsulation of the Nanoscale Er2O3 Phase To Drastically Suppress Voltage Fading and Capacity Degradation of a Li- and Mn-Rich Layered Oxide Cathode for Lithium Ion Batteries. AB - A novel strategy of in situ precipitation and encapsulation of the Er2O3 phase on the Li(Li0.2Ni0.13Co0.13Mn0.54)O2 (LNCMO) cathode material for lithium ion batteries is proposed for the first time. The Er2O3 phase is precipitated from the bulk of the LNCMO material and encapsulated onto its entire surface during the calcining process. Electrochemicial performance is investigated by a galvanostatic charge and discharge test. The structure and morphology are characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, and high-resolution transmission electron microscopy. The results show that an about 10 nm Er2O3 layer is successfully encapsulated onto the entire surface of the LNCMO matrix material. This unique nanoscale Er2O3 encapsulation can significantly prevent the LNCMO cathode material from being corroded by electrolytes and stabilize the crystal structure of the LNCMO cathode during cycling. Therefore, the prepared Er2O3-coated LNCMO composite exhibits excellent cycling performace and a high initial Coulombic efficiency. PMID- 28892625 TI - Platinum Binds Proteins in the Endoplasmic Reticulum of S. cerevisiae and Induces Endoplasmic Reticulum Stress. AB - Pt(II)-based anticancer drugs are widely used in the treatment of a variety of cancers, but their clinical efficacy is hindered by undesirable side effects and resistance. While much research has focused on Pt(II) drug interactions with DNA, there is increasing interest in proteins as alternative targets and contributors to cytotoxic and resistance mechanisms. Here, we describe a chemical proteomic method for isolation and identification of cellular protein targets of platinum compounds using Pt(II) reagents that have been modified for participation in the 1,3 dipolar cycloaddition "click" reaction. Using this method to visualize and enrich for targets, we identified 152 proteins in Pt(II)-treated Saccharomyces cerevisiae. Of interest was the identification of multiple proteins involved in the endoplasmic reticulum (ER) stress response, which has been proposed to be an important cytoplasmic mediator of apoptosis in response to cisplatin treatment. Consistent with possible direct targeting of this pathway, the ER stress response was confirmed to be induced in Pt(II)-treated yeast along with in vitro Pt(II) inhibition of one of the identified proteins, protein disulfide isomerase. PMID- 28892627 TI - The Sequence Dependence of Photoinduced Single Strand Break in 5-Bromo-2' deoxyuridine Labeled DNA Supports That Electron Transfer Is Responsible for the Damage. AB - The UVB irradiation of DNA labeled with 5-bromo-2'-deoxyuridine (BrdU) leads to single-strand breaks (SSBs) as a major photochemical damage. Some time ago, we demonstrated that SSB is a secondary damage forming due to thermal dissociation of 2'-deoxyribonolactone generated photochemically in DNA labeled with BrdU. For the first time, we study here the variation of the yield of UVB generated SSBs with the alteration of 3'-neighbor nucleobase of electron donor (2'-deoxyguanine (dG)) and acceptor (excited BrdU) in double-stranded DNA. We showed that the experimental damage yields can be explained by the calculated ionization potentials of dG and electron affinities of excited BrdU via a kinetic scheme based on the Marcus model of electron transfer (ET). Hence, our studies on the sequence dependence of photochemical damage in DNA labeled with BrdU constitute a further argument that photochemically generated SSBs occur as a result of long range ET. PMID- 28892626 TI - Biomimetic Virulomics for Capture and Identification of Cell-Type Specific Effector Proteins. AB - An unmet challenge in the study of disease is to accurately streamline the identification of important virulence factors. Traditional, genetically driven approaches miss biologically relevant markers due to discordance between the genome and proteome. Here, we developed a nanotechnology-enabled affinity enrichment strategy coupled with multiplexed quantitative proteomics, namely Biomimetic Virulomics, for successful identification of cell-type specific effector proteins of both prokaryotic and eukaryotic pathogens. We highlight the power of Biomimetic Virulomics by capturing known virulence factors in a high throughput, cell-type guided fashion. Additionally, a comprehensive characterization of the membrane protein component of biomimetics utilized in this strategy is provided. Interfacing cell-derived nanomaterials with multiplexed quantitative proteomics allow for a specific targeting strategy of virulence factors that can be utilized for drug discovery against prominent human diseases. PMID- 28892628 TI - No Photon Wasted: An Efficient and Selective Singlet Oxygen Photosensitizing Protein. AB - Optogenetics has been, and will continue to be, a boon to mechanistic studies of cellular processes. Genetically encodable proteins that sensitize the production of reactive oxygen species (ROS) are expected to play an increasingly important role, particularly in elucidating mechanisms of temporally and spatially dependent cell signaling. However, a substantial challenge in developing such photosensitizing proteins has been to funnel the optical excitation energy into the initial selective production of only one ROS. Singlet molecular oxygen, O2(a1Deltag), is a ROS known to have a wide range of effects on cell function. Nevertheless, mechanistic details of singlet oxygen's behavior in a cell are lacking. On the basis of the rational optimization of a LOV-derived flavoprotein, we now report the development and photophysical characterization of a protein encased photosensitizer that efficiently and selectively produces singlet oxygen at the expense of other ROS, especially ROS that derive from photoinduced electron transfer reactions. These results set the stage for a plethora of new experiments to elucidate ROS-mediated events in cells. PMID- 28892629 TI - Development of (4-Cyanophenyl)glycine Derivatives as Reversible Inhibitors of Lysine Specific Demethylase 1. AB - Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1). A further scaffold modification to a (4 cyanophenyl)glycinamide (e.g., 29a) led to the development of compound 32, with a Kd value of 32 nM and an EC50 value of 0.67 MUM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with 1 and represents a promising lead for further development. PMID- 28892630 TI - Hamiltonian Monte Carlo with Constrained Molecular Dynamics as Gibbs Sampling. AB - Compared to fully flexible molecular dynamics, simulations of constrained systems can use larger time steps and focus kinetic energy on soft degrees of freedom. Achieving ergodic sampling from the Boltzmann distribution, however, has proven challenging. Using recent generalizations of the equipartition principle and Fixman potential, here we implement Hamiltonian Monte Carlo based on constrained molecular dynamics as a Gibbs sampling move. By mixing Hamiltonian Monte Carlo based on fully flexible and torsional dynamics, we are able to reproduce free energy landscapes of simple model systems and enhance sampling of macrocycles. PMID- 28892631 TI - Rhodium- and Non-Metal-Catalyzed Approaches for the Conversion of Isoxazol-5-ones to 2,3-Dihydro-6H-1,3-oxazin-6-ones. AB - Two approaches were developed for the conversion of isoxazol-5-ones to 2,3 dihydro-6H-1,3-oxazin-6-ones. The first involves dirhodium-catalyzed reaction of aryl diazoacetates, leading to rhodium carbene intermediates that undergo insertion into the N-O bond of isoxazol-5-ones. The second approach involves conversion of the aryldiazoacetates to the corresponding tosylates, followed by reaction with the isoxazol-5-one in a metal-free one-pot procedure. These studies illustrate an alternative method to achieve a carbene-like transformation without requiring a metal catalyst. PMID- 28892632 TI - GaN Metalens for Pixel-Level Full-Color Routing at Visible Light. AB - Metasurface-based components are known to be one of the promising candidates for developing flat optical systems. However, their low working efficiency highly limits the use of such flat components for feasible applications. Although the introduction of the metallic mirror has been demonstrated to successfully enhance the efficiency, it is still somehow limited for imaging and sensing applications because they are only available for devices operating in a reflection fashion. Here, we demonstrate three individual GaN-based metalenses working in a transmission window with extremely high operation efficiency at visible light (87%, 91.6%, and 50.6% for blue, green, and red light, respectively). For the proof of concept, a multiplex color router with dielectric metalens, which is capable of guiding individual primary colors into different spatial positions, is experimentally verified based on the design of out-of-plane focusing metalens. Our approach with low-cost, semiconductor fabrication compatibility and high working efficiency characteristics offers a way for establishing a complete set of flat optical components for a wide range of applications such as compact imaging sensors, optical spectroscopy, and high-resolution lithography, just named a few. PMID- 28892633 TI - Regioselective and Enantioselective Intermolecular Buchner Ring Expansions in Flow. AB - The first example of a regioselective and enantioselective intermolecular Buchner ring expansion is reported using continuous flow. The practicality and scope of the reaction are greatly improved under flow conditions. Reactions of ethyl diazoacetate with symmetric and nonsymmetric arenes afford cycloheptatrienes in good yield and excellent regioselectivity. The first example of an asymmetric intermolecular Buchner reaction is demonstrated with disubstituted diazo esters in good to excellent enantioselectivity. The asymmetric reactions proceed with absolute regioselectivity to afford cycloheptatrienes with an all-carbon quaternary center. PMID- 28892634 TI - Transition-Metal-Free Reductive Coupling of 1,3-Butadienes with Aldehydes Catalyzed by Dibutyliodotin Hydride. AB - In this study, the Bu2SnIH-catalyzed direct coupling of 1,3-dienes with aldehydes was developed. This reaction could be suitable for coupling without the use of transition-metal catalysts. Many types of aldehydes were applied to this reaction. The addition of MeOH promoted the catalytic cycle. PMID- 28892635 TI - Ultrafast Silicon Photonics with Visible to Mid-Infrared Pumping of Silicon Nanocrystals. AB - Dynamic optical control of infrared (IR) transparency and refractive index is achieved using boron-doped silicon nanocrystals excited with mid-IR optical pulses. Unlike previous silicon-based optical switches, large changes in transmittance are achieved without a fabricated structure by exploiting strong light coupling of the localized surface plasmon resonance (LSPR) produced from free holes of p-type silicon nanocrystals. The choice of optical excitation wavelength allows for selectivity between hole heating and carrier generation through intraband or interband photoexcitation, respectively. Mid-IR optical pumping heats the free holes of p-Si nanocrystals to effective temperatures greater than 3500 K. Increases of the hole effective mass at high effective hole temperatures lead to a subpicosecond change of the dielectric function, resulting in a redshift of the LSPR, modulating mid-IR transmission by as much as 27%, and increasing the index of refraction by more than 0.1 in the mid-IR. Low hole heat capacity dictates subpicosecond hole cooling, substantially faster than carrier recombination, and negligible heating of the Si lattice, permitting mid-IR optical switching at terahertz repetition frequencies. Further, the energetic distribution of holes at high effective temperatures partially reverses the Burstein-Moss effect, permitting the modulation of transmittance at telecommunications wavelengths. The results presented here show that doped silicon, particularly in micro- or nanostructures, is a promising dynamic metamaterial for ultrafast IR photonics. PMID- 28892636 TI - Nickel-Catalyzed Enantioselective Hydrogenation of beta-(Acylamino)acrylates: Synthesis of Chiral beta-Amino Acid Derivatives. AB - The nickel-catalyzed asymmetric hydrogenation of beta-(acylamino)acrylates has been developed, affording chiral beta-amino acid derivatives with excellent yields (95-99% yield) and enantioselectivities (97-99% ee). With the Ni-Binapine system, high enantioselectivities (98-99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of beta-alkyl and beta-aryl beta (acylamino)acrylates. The synthesis of chiral beta-amino acid derivatives on a gram scale has also been achieved with 0.2 mol % catalyst loading. PMID- 28892637 TI - Functional Circuitry on Commercial Fabric via Textile-Compatible Nanoscale Film Coating Process for Fibertronics. AB - Fabric-based electronic textiles (e-textiles) are the fundamental components of wearable electronic systems, which can provide convenient hand-free access to computer and electronics applications. However, e-textile technologies presently face significant technical challenges. These challenges include difficulties of fabrication due to the delicate nature of the materials, and limited operating time, a consequence of the conventional normally on computing architecture, with volatile power-hungry electronic components, and modest battery storage. Here, we report a novel poly(ethylene glycol dimethacrylate) (pEGDMA)-textile memristive nonvolatile logic-in-memory circuit, enabling normally off computing, that can overcome those challenges. To form the metal electrode and resistive switching layer, strands of cotton yarn were coated with aluminum (Al) using a solution dip coating method, and the pEGDMA was conformally applied using an initiated chemical vapor deposition process. The intersection of two Al/pEGDMA coated yarns becomes a unit memristor in the lattice structure. The pEGDMA-Textile Memristor (ETM), a form of crossbar array, was interwoven using a grid of Al/pEGDMA coated yarns and untreated yarns. The former were employed in the active memristor and the latter suppressed cell-to-cell disturbance. We experimentally demonstrated for the first time that the basic Boolean functions, including a half adder as well as NOT, NOR, OR, AND, and NAND logic gates, are successfully implemented with the ETM crossbar array on a fabric substrate. This research may represent a breakthrough development for practical wearable and smart fibertronics. PMID- 28892638 TI - Ensemble Perception. AB - To understand visual consciousness, we must understand how the brain represents ensembles of objects at many levels of perceptual analysis. Ensemble perception refers to the visual system's ability to extract summary statistical information from groups of similar objects-often in a brief glance. It defines foundational limits on cognition, memory, and behavior. In this review, we provide an operational definition of ensemble perception and demonstrate that ensemble perception spans across multiple levels of visual analysis, incorporating both low-level visual features and high-level social information. Further, we investigate the functional usefulness of ensemble perception and its efficiency, and we consider possible physiological and cognitive mechanisms that underlie an individual's ability to make accurate and rapid assessments of crowds of objects. PMID- 28892639 TI - Genetic Networks in Plant Vascular Development. AB - Understanding the development of vascular tissues in plants is crucial because the evolution of vasculature enabled plants to thrive on land. Various systems and approaches have been used to advance our knowledge about the genetic regulation of vasculature development, from the scale of single genes to networks. In this review, we provide a perspective on the major approaches used in studying plant vascular development, and we cover the mechanisms and genetic networks underlying vascular tissue specification, patterning, and differentiation. PMID- 28892640 TI - Beneficial effects of rosiglitazone and losartan combination in diabetic rats. AB - Diabetes with vascular complication needs strict interventions to retard possible serious complications. This research estimated the possible interaction of rosiglitazone (RGN) with losartan (Los) in diabetic rats. Male Sprague-Dawley rats were randomly divided into nondiabetic rats, diabetic rats, and diabetic rats that received RGN, Los, or a combination of RGN and Los. Measurement of serum glucose, vascular adhesion molecule-1, interleukin-6, tumor necrosis factor alpha, aortic lipid peroxide (malondialdehyde), glutathione, superoxide dismutase, and total nitrate/nitrite levels was done. Also, the effects of RGN on the relaxation created by acetylcholine and sodium nitroprusside, contraction of isolated aortic rings provoked by phenylephrine and angiotensin II were determined. Results revealed that RGN or Los had a vasodilating effect to variable degrees indicated by enhanced effects on both acetylcholine-induced relaxation and the antagonistic effect on angiotensin II and phenylephrine stimulated contraction of diabetic aortas with significant amelioration in serum glucose, vascular adhesion molecule-1, interleukin-6, and tumor necrosis factor alpha levels and aortic oxidant/antioxidant balance. Treatment of diabetic rats with a combination of RGN and Los produced a more pronounced effect on the measured parameters compared to the diabetic, RGN-, and Los-treated groups. These findings point out the beneficial effects of RGN and Los combination in diabetic rats. PMID- 28892641 TI - Independent assortment of GC gene polymorphism (rs2282679) and 25-hydroxyvitamin D levels in coronary artery disease. AB - Coronary artery disease (CAD) remains a major public health burden. Emerging research has suggested an association between vitamin D insufficiency and CAD. Vitamin D binding protein (VDBP) is the primary vitamin D carrier and many of its genetic polymorphisms are able to induce the expression of proteins with different affinities for the vitamin, which in turn might affect its serum levels and CAD incidence. One hundred and twelve male patients, aged between 35 and 50 years, with verified CAD and 109 age- and sex-matched controls were recruited. Genotyping was performed by the TaqMan allelic discrimination assay and plasma 25(OH)D levels were assessed by HPLC-UV. Serum parathyroid hormone (s-PTH) and VDBP levels were measured using ELISA. s-25(OH)D levels in CAD patients were significantly lower than in the controls, whereas s-PTH levels were significantly higher in the CAD patients than in the controls. There was no significant difference in the distribution of GC genotypes among both groups. s-25(OH)D showed a weak inverse correlation with s-PTH levels. Serum levels of vitamin D and PTH are highly correlated with CAD incidence. However, the s-VDBP level is associated neither with disease outcome nor with vitamin D status. The GC gene variant has no effect on 25(OH)D levels. PMID- 28892642 TI - The distribution of active beta-glucosidase-producing microbial communities in composting. AB - The composting ecosystem is a suitable source for the discovery of novel microorganisms and secondary metabolites. Cellulose degradation is an important part of the global carbon cycle, and beta-glucosidases complete the final step of cellulose hydrolysis by converting cellobiose to glucose. This work analyzes the succession of beta-glucosidase-producing microbial communities that persist throughout cattle manure - rice straw composting, and evaluates their metabolic activities and community advantage during the various phases of composting. Fungal and bacterial beta-glucosidase genes belonging to glycoside hydrolase families 1 and 3 (GH1 and GH3) amplified from DNA were classified and gene abundance levels were analyzed. The major reservoirs of beta-glucosidase genes were the fungal phylum Ascomycota and the bacterial phyla Firmicutes, Actinobacteria, Proteobacteria, and Deinococcus-Thermus. This indicates that a diverse microbial community utilizes cellobiose. The succession of dominant bacteria was also detected during composting. Firmicutes was the dominant bacteria in the thermophilic phase of composting; there was a shift to Actinomycetes in the maturing stage. Proteobacteria accounted for the highest proportions during the heating and thermophilic phases of composting. By contrast, the fungal phylum Ascomycota was a minor microbial community constituent in thermophilic phase of composting. Combined with the analysis of the temperature, cellulose degradation rate and the carboxymethyl cellulase and beta-glucosidase activities showed that the bacterial GH1 family beta-glucosidase genes make greater contribution in cellulose degradation at the later thermophilic stage of composting. In summary, even GH1 bacteria families beta glucosidase genes showing low abundance in DNA may be functionally important in the later thermophilic phase of composting. The results indicate that a complex community of bacteria and fungi expresses beta-glucosidases in compost. Several beta-glucosidase-producing bacteria and fungi identified in this study may represent potential indicators of composting in cellulose degradation. PMID- 28892643 TI - Comparison of the effects of IK,ACh, IKr, and INa block in conscious dogs with atrial fibrillation and on action potentials in remodeled atrial trabeculae. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of morbidity and mortality. Traditional antiarrhythmic agents used for restoration of sinus rhythm have limited efficacy in long-term AF and they may possess ventricular proarrhythmic adverse effects, especially in patients with structural heart disease. The acetylcholine receptor-activated potassium channel (IK,ACh) represents an atrial selective target for future AF management. We investigated the effects of the IK,ACh blocker tertiapin-Q (TQ), a derivative of the honeybee toxin tertiapin, on chronic atrial tachypacing-induced AF in conscious dogs, without the influence of anesthetics that modulate a number of cardiac ion channels. Action potentials (APs) were recorded from right atrial trabeculae isolated from dogs with AF. TQ significantly and dose-dependently reduced AF incidence and AF episode duration, prolonged atrial effective refractory period, and prolonged AP duration. The reference drugs propafenone and dofetilide, both used in the clinical management of AF, exerted similar effects against AF in vivo. Dofetilide prolonged atrial AP duration, whereas propafenone increased atrial conduction time. TQ and propafenone did not affect the QT interval, whereas dofetilide prolonged the QT interval. Our results show that inhibition of IK,ACh may represent a novel, atrial-specific target for the management of AF in chronic AF. PMID- 28892644 TI - Specifically Penile-Vaginal Intercourse Frequency Is Associated With Better Relationship Satisfaction: A Commentary on Hicks, McNulty, Meltzer, and Olson (2016). PMID- 28892645 TI - Self-assembling Peptide P11-4 and Fluoride for Regenerating Enamel. AB - Regenerative medicine-based approaches for caries treatment focus on biomimetic remineralization of initial carious lesions as a minimal invasive therapy. In vitro, self-assembling peptide P11-4 enhances remineralization of early carious lesions. To investigate the safety and clinical efficacy of P11-4 for treatment of initial caries, a randomized controlled single-blind study was conducted on children aged >5 y with visible active early caries on erupting permanent molars. Subjects were randomized to either the test group (P11-4 + fluoride varnish) or control group (fluoride varnish alone). Caries were assessed at baseline and at 3 and 6 mo posttreatment per laser fluorescence, a visual analog scale, the International Caries Detection and Assessment System, and Nyvad caries activity criteria. Intention-to-treat analyses were performed, and safety and clinical feasibility of the treatment approaches were assessed. Compared with the control group, the test group showed clinically and statistically significant improvement in all outcomes at 3 and 6 mo. The laser fluorescence readings (odds ratio = 3.5, P = 0.015) and visual analog scale scores (odds ratio = 7.9, P < .0001) were significantly lower for the test group, and they showed regression in the International Caries Detection and Assessment System caries index (odds ratio = 5.1, P = 0.018) and conversion from active to inactive lesions according to Nyvad criteria (odds ratio = 12.2, P < 0.0001). No adverse events occurred. The biomimetic mineralization facilitated by P11-4 in combination with fluoride application is a simple, safe, and effective noninvasive treatment for early carious lesions that is superior to the presently used gold standard of fluoride alone. By regenerating enamel tissue and preventing lesion progression, this novel approach could change clinical dental practice from a restorative to a therapeutic approach. This could avoid additional loss of healthy hard tissue during invasive restorative treatments, potentially enabling longer tooth life and thereby lowering long-term health costs ( ClinicalTrials.gov NCT02724592). PMID- 28892646 TI - Protective effects of Mentha spicata against nicotine-induced toxicity in liver and erythrocytes of Wistar rats. AB - The aim of this study was to investigate the protective effect of Mentha spicata supplementation against nicotine-induced oxidative damage in the liver and erythrocytes of Wistar rats. Bioactive substances were determined by liquid chromatography - electrospray ionization - tandem mass spectrometry analysis. Animals were divided into 4 groups of 6 rats each: a normal control group, a nicotine-treated group (1 mg/kg), a group receiving M. spicata extract (100 mg/kg), and a group receiving both M. spicata extract (100 mg/kg) and nicotine (1 mg/kg). Many phenolic acids were identified in the M. spicata aqueous extract. After 2 months of treatment, nicotine induced an increase in the level of white blood cells and a marked decrease in erythrocytes, hemoglobin, and haematocrit. Aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase activities were also found to be higher in nicotine-treated group than those of the control group. Furthermore, nicotine-treated rats exhibited oxidative stress, as evidenced by a decrease in antioxidant enzymes activities and an increase in lipid peroxidation level in liver and erythrocytes. Interestingly, the oral administration of M. spicata extract by nicotine-treated rats alleviated such disturbances. M. spicata contained bioactive compounds that possess important antioxidant potential and protected liver and erythrocytes against nicotine-induced damage. PMID- 28892647 TI - miR-96 targets SOX6 and promotes proliferation, migration, and invasion of hepatocellular carcinoma. AB - Recent research suggested that microRNA 96 (miR-96) might function as an oncogene in several types of cancers. Therefore, the purpose of this study was to probe into the mechanism of miR-96 in hepatocellular carcinoma (HCC) cells. HCC tissues and non-tumorous tissues, HCC cell lines, and healthy cell lines were all involved in this study. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect miR-96 and SOX6 mRNA and protein expressions. The direct regulation of miR96 on SOX6 was confirmed by luciferase reporter assays. Cell proliferation and growth were determined by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2-H-tetrazolium bromide) assay and colony formation assay. Wound healing and transwell assay were employed for migration and invasion analyses. Finally, SPSS 21.0 and GraphPad 7.0 were applied for statistical analyses. In HCC tissues, miR-96 was highly expressed while SOX6 was lowly expressed. The overexpression of miR-96 reversely inhibited the expression of SOX6, contributing to the promotion of the biological functions of HCC cells. miR-96 could promote cell proliferation, migration, and invasion in HCC by targeting SOX6. PMID- 28892648 TI - Long-Term Outcomes of Anterior Cruciate Ligament Reconstruction Using Either Synthetics With Remnant Preservation or Hamstring Autografts: A 10-Year Longitudinal Study. AB - BACKGROUND: The optimal graft choice of anterior cruciate ligament (ACL) reconstruction remains controversial. PURPOSE: To compare the outcomes, especially the long-term cumulative failure rate, of ACL reconstruction using either synthetics with remnant preservation or hamstring autografts (4-strand semitendinosus and gracilis tendons). STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 133 patients who underwent ACL reconstruction (synthetics: n = 43; hamstring autografts: n = 90) between July 2004 and December 2007 were included. Questionnaires (Tegner activity scale, Lysholm knee scale, and International Knee Documentation Committee [IKDC] subjective form) were completed preoperatively and at 6 months, 1 year, 5 years, and 10 years postoperatively. The Knee injury and Osteoarthritis Outcome Score (KOOS) was additionally applied at 10 years' follow-up. The physical examination was based on the 2000 IKDC form. The manual maximum side-to-side difference (KT-1000 arthrometer), single-hop test, thigh muscle atrophy, and joint degeneration (Kellgren and Lawrence classification) were evaluated. The Kaplan-Meier curve and log-rank test (Mantel-Cox, 95% CI) were used to compare graft survivorship. RESULTS: Ten years postoperatively, 111 patients were available, with 38 (88.4%) patients (mean age, 27.6 +/- 9.3 years; 28 men) with synthetics and 73 (81.1%) patients (mean age, 28.6 +/- 8.8 years; 64 men) with hamstring autografts. Among them, 104 patients (synthetics: n = 35 [81.4%]; hamstring autografts: n = 69 [76.7%]) completed subjective evaluations, and 89 patients (synthetics: n = 30 [69.8%]; hamstring autografts: n = 59 [65.6%]) completed objective evaluations. For hamstring autografts and synthetics, the cumulative failure rates were 8.2% and 7.9%, respectively, and the log-rank test demonstrated no significant difference between the 2 Kaplan-Meier survival curves ( P = .910). At 6 months postoperatively, for hamstring autografts and synthetics, the mean Lysholm score was 83.0 +/- 7.8 and 88.1 +/- 7.5, respectively ( P < .001); the mean IKDC score was 83.8 +/- 7.8 and 86.9 +/- 4.5, respectively ( P = .036); and the mean Tegner score was 3.7 +/- 1.1 and 5.0 +/- 1.5, respectively ( P < .001). At 1 year postoperatively, the mean Tegner score was 5.5 +/- 1.9 and 6.5 +/- 2.0, respectively ( P = .011). No statistically significant difference was observed on other subjective evaluation findings, physical examination findings (overall IKDC grade A: 45.8% of hamstring autografts, 50.0% of synthetics), side-to-side difference (1.5 +/- 1.5 mm for synthetics, 2.4 +/- 2.1 mm for hamstring autografts), single-hop test findings (grade A: 84.7% of hamstring autografts, 93.3% of synthetics), grade A/B thigh muscle atrophy (88.1% of hamstring autografts, 93.3% of synthetics), ipsilateral radiographic osteoarthritis (55.9% of hamstring autografts, 50.0% of synthetics), and graft survivorship. CONCLUSION: In this prospective cohort study, primary ACL reconstruction using either synthetics with remnant preservation or hamstring autografts showed satisfactory outcomes, especially the long-term cumulative failure rate, at 10 years postoperatively. Patient-reported outcomes suggested that symptom relief and restoration of function might occur earlier in those with synthetics. PMID- 28892649 TI - Expression of Phosphate Transporters during Dental Mineralization. AB - The importance of phosphate (Pi) as an essential component of hydroxyapatite crystals suggests a key role for membrane proteins controlling Pi uptake during mineralization in the tooth. To clarify the involvement of the currently known Pi transporters (Slc17a1, Slc34a1, Slc34a2, Slc34a3, Slc20a1, Slc20a2, and Xpr1) during tooth development and mineralization, we determined their spatiotemporal expression in murine tooth germs from embryonic day 14.5 to postnatal day 15 and in human dental samples from Nolla stages 6 to 9. Using real-time polymerase chain reaction, in situ hybridization, immunohistochemistry, and X-gal staining, we showed that the expression of Slc17a1, Slc34a1, and Slc34a3 in tooth germs from C57BL/6 mice were very low. In contrast, Slc34a2, Slc20a1, Slc20a2, and Xpr1 were highly expressed, mostly during the postnatal stages. The expression of Slc20a2 was 2- to 10-fold higher than the other transporters. Comparable results were obtained in human tooth germs. In mice, Slc34a2 and Slc20a1 were predominantly expressed in ameloblasts but not odontoblasts, while Slc20a2 was detected neither in ameloblasts nor in odontoblasts. Rather, Slc20a2 was highly expressed in the stratum intermedium and the subodontoblastic cell layer. Although Slc20a2 knockout mice did not show enamel defects, mutant mice showed a disrupted dentin mineralization, displaying unmerged calcospherites at the mineralization front. This latter phenotypical finding raises the possibility that Slc20a2 may play an indirect role in regulating the extracellular Pi availability for mineralizing cells rather than a direct role in mediating Pi transport through mineralizing plasma cell membranes. By documenting the spatiotemporal expression of Pi transporters in the tooth, our data support the possibility that the currently known Pi transporters may be dispensable for the initiation of dental mineralization and may rather be involved later during the tooth mineralization scheme. PMID- 28892650 TI - The contribution of muscle, kidney, and splanchnic tissues to leucine transamination in humans. AB - The first steps of leucine utilization are reversible deamination to alpha ketoisocaproic acid (alpha-KIC) and irreversible oxidation. Recently, the regulatory role of leucine deamination over oxidation was underlined in rodents. Our aim was to measure leucine deamination and reamination in the whole body, in respect to previously determined rates across individual organs, in humans. By leucine and KIC isotope kinetics, we determined whole-body leucine deamination and reamination, and we compared these rates with those already reported across the sampled organs. As an in vivo counterpart of the "metabolon" concept, we analysed ratios between oxidation and either deamination or reamination. Leucine deamination to KIC was greater than KIC reamination to leucine in the whole body (p = 0.005), muscles (p = 0.005), and the splanchnic area (p = 0.025). These rates were not significantly different in the kidneys. Muscle accounted for ~60% and ~78%, the splanchnic bed for ~15% and ~15%, and the kidney for ~12% and ~18%, of whole-body leucine deamination and reamination rates, respectively. In the kidney, percent leucine oxidation over either deamination or reamination was >3 fold greater than muscle and the splanchnic bed. Skeletal muscle contributes by the largest fraction of leucine deamination, reamination, and oxidation. However, in relative terms, the kidney plays a key role in leucine oxidation. PMID- 28892651 TI - Using Photo-Elicitation Methods to Understand Resilience Among Ultra-Poor Youth and Their Caregivers in Malawi. AB - Unconditional cash transfer programs are a form of structural intervention to address poverty, a "fundamental cause" of disease. Such programs increasingly aim to build resilience to sustain improved outcomes and provide a solid foundation for longer term transformations. As such, there is a need to understand what resilience means in specific contexts. The goal of this formative study was to explore local experiences of resilience and vulnerability among 11 youth caregiver dyads ( n = 22) who were beneficiaries of the Malawi Social Cash Transfer Program in Balaka district. We used a photo-elicitation approach informed by the participatory, visual methodology photovoice to guide the study and conducted an iterative content analysis using thematic coding of transcripts and photos. Participants took pictures of their daily struggles and shocks and participated in audio-recorded discussions to reflect on the photos using an adapted version of the SHOWeD method. We found that participants characterized resilience as a tireless process of using all available individual, family, and community resources at all times in pursuit of survival and well-being. In the context of daily struggles, resilience was an essential part of survival. Shocks, mostly health-related, were depicted through staged images candidly highlighting individual and environmental vulnerabilities. Community support was an essential component of resilience for both daily struggles and shocks. Using photo elicitation methods facilitated an intergenerational, community-driven reflection on the meaning of resilience and the multilevel determinants of health in a context of extreme poverty. Findings can inform the design of resilience-focused cash transfer programs to improve health equity. PMID- 28892652 TI - Oral Histories as Critical Qualitative Inquiry in Community Health Assessment. AB - Qualitative methods such as focus groups and interviews are common methodologies employed in participatory approaches to community health assessment to develop effective community health improvement plans. Oral histories are a rarely used form of qualitative inquiry that can enhance community health assessment in multiple ways. Oral histories center residents' lived experiences, which often reveal more complex social and health phenomena than conventional qualitative inquiry. This article examines an oral history research component of the Little Village Community Health Assessment, a collaborative research effort to promote health equity in an urban, Mexican ethnic enclave. We collected of 32 oral histories from residents to provide deeper, more grounded insight on community needs and assets. We initially used thematic data analysis. After analytic peer debriefings with the analysis team, we found the process inadvertently reductionist and instead opted for community listening events for participatory data analysis, knowledge translation, and dissemination of findings. Oral histories were most meaningful in their original audio form, adding to a holistic understanding of health by giving voice to complex problems while also naming and describing concepts that were culturally unique. Moreover, the oral histories collectively articulated a counternarrative that celebrated community cultural wealth and opposed the mainstream narrative of the community as deprived. We argue for the recognition and practice of oral histories as a more routine form of qualitative inquiry in community health assessment. In the pursuit of health equity and collaboratively working toward social justice, oral histories can push the boundaries of community health assessment research and practice. PMID- 28892653 TI - Saliva-Derived Commensal and Pathogenic Biofilms in a Human Gingiva Model. AB - In vitro models that closely mimic human host-microbiome interactions can be a powerful screening tool for antimicrobials and will hold great potential for drug validation and discovery. The aim of this study was to develop an organotypic oral mucosa model that could be exposed to in vitro cultured commensal and pathogenic biofilms in a standardized and scalable manner. The oral mucosa model consisted of a tissue-engineered human gingiva equivalent containing a multilayered differentiated gingiva epithelium (keratinocytes) grown on a collagen hydrogel, containing gingiva fibroblasts, which represented the lamina propria. Keratinocyte and fibroblast telomerase reverse transcriptase immortalized cell lines were used to overcome the limitations of isolating cells from small biopsies when scalable culture experiments were required. The oral biofilms were grown under defined conditions from human saliva to represent 3 distinct phenotypes: commensal, gingivitis, and cariogenic. The in vitro grown biofilms contained physiologic numbers of bacterial species, averaging >70 operational taxonomic units, including 20 differentiating operational taxonomic units. When the biofilms were applied topically to the gingiva equivalents for 24 h, the gingiva epithelium increased its expression of elafin, a protease inhibitor and antimicrobial protein. This increased elafin expression was observed as a response to all 3 biofilm types, commensal as well as pathogenic (gingivitis and cariogenic). Biofilm exposure also increased secretion of the antimicrobial cytokine CCL20 and inflammatory cytokines IL-6, CXCL8, and CCL2 from gingiva equivalents. This inflammatory response was far greater after commensal biofilm exposure than after pathogenic biofilm exposure. These results show that pathogenic oral biofilms have early immune evasion properties as compared with commensal oral biofilms. The novel host-microbiome model provides an ideal tool for future investigations of gingiva responses to commensal and pathogenic biofilms and for testing novel therapeutics. PMID- 28892654 TI - Single-Stage Cartilage Repair Using Platelet-Rich Fibrin Scaffolds With Autologous Cartilaginous Grafts. AB - BACKGROUND: To avoid complicated procedures requiring in vitro chondrocyte expansion for cartilage repair, the development of a culture-free, 1-stage approach combining platelet-rich fibrin (PRF) and autologous cartilage grafts may be the solution. PURPOSE: To develop a feasible 1-step procedure to combine PRF and autologous cartilage grafts for articular chondral defects. STUDY DESIGN: Controlled laboratory study Methods: The chemotactic effects of PRF on chondrocytes harvested from the primary culture of rabbit cartilage were evaluated in vitro and ex vivo. The rabbit chondrocytes were cultured with different concentrations of PRF media and evaluated for their cell proliferation, chondrogenic gene expression, cell viability, and extracellular matrix synthesis abilities. For the in vivo study, the chondral defects were created on established animal models of rabbits. The gross anatomy, histology, and objective scores were evaluated to validate the treatment results. RESULTS: PRF improved the chemotaxis, proliferation, and viability of the cultured chondrocytes. The gene expression of the chondrogenic markers, including type II collagen and aggrecan, revealed that PRF induced the chondrogenic differentiation of cultured chondrocytes. PRF increased the formation and deposition of the cartilaginous matrix produced by cultured chondrocytes. The efficacy of PRF on cell viability was comparable with that of fetal bovine serum. In animal disease models, morphologic, histological, and objectively quantitative evaluation demonstrated that PRF combined with cartilage granules was feasible in facilitating chondral repair. CONCLUSION: PRF enhances the migration, proliferation, viability, and differentiation of chondrocytes, thus showing an appealing capacity for cartilage repair. The data altogether provide evidence to confirm the feasibility of 1 stage, culture-free method of combining PRF and autologous cartilage graft for repairing articular chondral defects. CLINICAL RELEVANCE: The single-stage, culture-free method of combining PRF and autologous cartilage is useful for repairing articular chondral defects. These advantages benefit clinical translation by simplifying and potentiating the efficacy of autologous cartilage transplantation. PMID- 28892655 TI - Bonding to CAD-CAM Composites: An Interfacial Fracture Toughness Approach. AB - The objective of this study was to evaluate the interfacial fracture toughness (IFT) of composite cement with dispersed filler (DF) versus polymer-infiltrated ceramic network (PICN) computer-aided design and computer-aided manufacturing (CAD-CAM) composite blocks after 2 different surface pretreatments using the notchless triangular prism (NTP) test. Two DFs (Cerasmart [CRT] and Lava Ultimate [LVA]), 2 PICNs (Enamic [ENA] and experimental PICN [EXP]), and e.max CAD lithium disilicate glass-ceramic (EMX, control) prism samples were bonded to their counterparts with Variolink Esthetic DC composite cement after either hydrofluoric acid etching (HF) or gritblasting (GR). Both procedures were followed by silanization. All samples ( n = 30 per group) were thermocycled (10,000 cycles) and tested for their IFT in a water bath at 36 degrees C. Moreover, representative samples from each group were subjected to a developed interfacial area ratio (Sdr) measurement by profilometry and scanning electron microscopy (SEM) characterization. EXP-HF gave the highest IFT (1.85 +/- 0.39 MPa.m1/2), followed by EMX-HF and ENA-HF, while CRT-HF gave the lowest (0.15 +/- 0.22 MPa.m1/2). PICNs gave significantly better results with HF, and DF showed better results with GR. A 2-way analysis of variance indicated that there were significantly higher IFT and Sdr for PICNs than for DF. A positive correlation ( r2 = 0.872) was found between IFT and Sdr. SEM characterization showed the specific microstructure of the surface of etched PICNs, indicating the presence of a retentive polymer-based honeycomb structure. Etching of the typical double network microstructure of PICNs causes an important increase in the Sdr and IFT, while DF should be gritblasted. DF exhibited significantly lower Sdr and IFT values than PICNs. The present results show the important influence of the material class and surface texture, and consequently the micromechanical bond, on the adhesive interface performance of CAD-CAM composites. PMID- 28892656 TI - Plasma let-7i and miR-15a expression are associated with the effect of recombinant tissue plasminogen activator treatment in acute ischemic stroke patients. AB - : Circulating microRNAs (miRNAs) have been reported as diagnosis biomarkers and predictors in acute ischemic stroke (AIS). However, how the expression of circulating miRNAs changes after recombinant tissue plasminogen activator (rt-PA) treatment in AIS patients is still unknown. OBJECTIVE: To determine the expression of circulating miRNAs in AIS patients receiving rt-PA treatment and those not receiving it. METHODS: Blood samples were collected 24h after onset from 40 AIS patients receiving rt-PA treatment and 46 AIS patients (admission at 8-24h of onset) not receiving rt-PA treatment. Thirty-nine age- and sex-matched healthy volunteers were used as the control group. We used miRNA microarrays to detect plasma miRNA expression and real-time PCR to verify miRNA expression. RESULTS: Compared to the non-rt-PA treatment group, the rt-PA treatment group showed 16 differentially expressed miRNAs. The change in the expression of let-7i and miR-15a was confirmed by real-time PCR. Compared to the heathy controls, the non-rt-PA group showed decreased let-7i expression and the rt-PA group showed a 4 fold increased let-7i expression. The let-7i expression was also found to correlate with the National Institute of Health stroke scale (NIHSS) score (rho=0.297, P=0.005). On the contrary, miR-15a expression decreased by 0.5-fold in the rt-PA group compared to that in the non-rt-PA group. CONCLUSION: The circulating miRNAs let-7i and miR-15a showed differential expression between AIS patients receiving thrombolysis treatment (rt-PA group) and those not receiving it (non-rt-PA group). Compared to the non-rt-PA group, the rt-PA group showed upregulation of let-7i and downregulation of miR-15a. PMID- 28892658 TI - Homozygous antithrombin deficiency type II causing neonatal thrombosis. AB - We report four children from different families with homozygous antithrombin (AT) deficiency type II affecting the heparin binding site (p.Leu131Phe mutation). All children had severe spontaneous venous and/or arterial thromboembolic events shortly after birth. This report intends to raise awareness among clinicians about this rare but severe condition. When thrombosis occurs in an otherwise healthy newborn, a severe congenital thrombophilic disorder should be considered. In homozygous AT deficiency type II, AT activity is typically reduced but may also be in the normal range, posing a diagnostic challenge. Rapid diagnosis is important to initiate appropriate therapy. Standard anticoagulation with heparin may prove ineffective in severe AT deficiency, requiring substitution of AT concentrate and early switch to alternative anticoagulants such as vitamin K antagonists. PMID- 28892659 TI - A new insight on the risky behavior of motorists at railway level crossings: An observational field study. AB - Accidents at railway level crossings (LXs) give rise to serious material and human damage. Particularly, collisions between trains and motorized vehicles are the most critical accidents occurring at LXs. It is worth noticing that violations committed by vehicle drivers are the primary cause of such accidents. The present study is a tentative to acquire a better understanding of risky behavior of vehicle drivers while crossing LXs during the closure cycle. Namely, risk analysis based on field measurement conducted at four automated LXs with two half barriers is performed. We focus on vehicle driver behavior during the LX closure cycle while distinguishing between different phases. In fact, the closure cycle is divided into three phases which are "Ph2 Red Flash and Siren", "Ph3 Barriers Coming Down" and "Ph4 Barriers Down"; and vehicle driver behavior in each phase as time increases is scrutinized respectively. Particularly, zigzag scenarios are detected, using an original experimental setting that we have implemented, and analyzed in detail. The main findings based on the analysis demonstrate that the peak of violation rate in the morning is later than the actual rush hour in the morning; a distinct peak of the violation rate shows on Friday, while the violation rate on weekend is fairly low; the relative violation rate of vehicles with high speed decreases continuously as time advances from Ph2 to Ph3 in the daytime; the violation rate during Ph4 decreases as Ph4 duration is prolonged, which contradicts a general speculation that a higher rate of zigzag violations would appear as the duration of Ph4 is extended. These findings open the way towards determining the impacting factors which have an important contribution to the vehicle driver decision-making in this context (e.g., traffic density, time schedule and phase duration). In addition, the outputs of the present study are conducive to identifying potential interventions to improve safety at LXs. PMID- 28892660 TI - Phytotoxic triterpene saponins from Bellis longifolia, an endemic plant of Crete. AB - In a study of 62 plant species of the Cretan flora for their phytotoxic activity, plants were extracted successively with CH2Cl2, MeOH and H2O. Phytotoxicity evaluation of the 240 extracts was performed against Lactuca sativa L. and Agrostis stolonifera L.. The MeOH extract of Bellis longifolia was the most phytotoxic. Bioassay-guided fractionation revealed that a fraction consisting mainly of saponins was the most effective. Separation of the saponins was performed using initially a step-gradient Centrifugal Partition Chromatography (CPC). Investigation of the active fraction led to the isolation and structure elucidation of three previously undescribed triterpene saponins, 3-O-beta-D fucopyranosyl polygalacic acid, 28-O-alpha-L-rhamnopyranosyl-(1 -> 2)-beta-D fucopyranosyl polygalacic acid and 3-O-beta-D-fucopyranosyl-2alpha,3beta,23 trihydroxyolean-12-en-28-oic acid, which were present as the main phytotoxic compounds of the methanol extract. Two triterpenes, polygalacic acid and bellisonic acid and four kaempferol glucosides, as well as chlorogenic acid were also isolated. 3-O-beta-D-fucopyranosyl polygalacic acid and 3-O-beta-D fucopyranosyl-2alpha,3beta,23-trihydroxyolean-12-en-28-oic acid had phytotoxic activity similar to some commercial herbicides (IC50 values of ca. 25 MUM) against duckweed (Lemna paucicostata). PMID- 28892657 TI - Evaluation of dabigatran, rivaroxaban and apixaban target-specific assays in a multicenter French study. AB - : Dabigatran etexilate, rivaroxaban and apixaban (DOACs) are widely used and measurement of their concentration is desirable in certain clinical situations. Target-specific assays are available but limited information exists on their performance especially in their ability to accurately measure low and high concentrations. AIMS: To define, in a multicenter study, the precision and accuracy of DOAC measurements in daily practice. METHODS: 15 plasma samples (kindly provided by Hyphen-Biomed) spiked with 5 blinded concentrations of dabigatran, rivaroxaban or apixaban (targeted 0-40-100-250-500ng/mL, actual concentrations measured by HPLC-MS/MS), were sent to 30 haemostasis laboratories. DOAC concentration, PT and aPTT were measured once in each sample using local reagents. Interlaboratory precision was determined by its coefficient of variation (CV) and accuracy by its bias. RESULTS: 464 DOAC measurements were performed in the 30 laboratories using 4 dabigatran and 5 rivaroxaban/apixaban calibrated assays on 3 analysers. Inter-laboratory CVs were below 18% for concentrations >=100ng/mL, and higher for concentrations ~40ng/mL; biases were below 8% for all drugs and concentrations. In DOAC-free samples, concentrations were all below the lower limit of quantification except for one value (dabigatran: 35ng/mL). Depending on the concentrations, significant differences were found between reagents in rivaroxaban and apixaban concentration values. PT and aPTT ratios displayed a low sensitivity to apixaban. CONCLUSION: Our results suggest that calibrated DOAC assays allow the reliable measurement of a wide range of drug concentrations, even though improvement of their performances is necessary, especially for measuring low concentrations. PMID- 28892661 TI - Inhibition of c-REL using siRNA increased apoptosis and decreased proliferation in pre-B ALL blasts: Therapeutic implications. AB - The c-Rel transcription factor is a unique member of the NF-kB family that has a role in apoptosis, proliferation and cell survival. Overexpression of c-Rel is detected in many human B cell tumors, including B-cell leukemia and several cancers. The study aimed to investigate the effects of c-Rel siRNA on the proliferation and apoptosis of relapsed pre-B acute leukemia cells. The c-Rel siRNA was transfected into Leukemia cells using an Amaxa cell line Nucleofector kit L (Lonza). Quantitative real-time RT-PCR (qRT-PCR) and western blot were done to measure the expression levels of mRNA and protein, respectively. The flow cytometry was used to analyze the effect of c-Rel siRNA on the apoptosis and proliferation of Leukemia cells. Observed c-Rel expression in the 5 pre-B Acute lymphoblastic leukemia (ALL) patients were higher than the normal cells. The c Rel siRNA transfection significantly blocked the expression of c-Rel mRNA in a time-dependent manner, leading to a strong growth inhibition and enhanced apoptosis (P<0.05). Our results demonstrated that c-Rel plays a fundamental role in the survival. Therefore, c-Rel can be considered as an attractive target for gene therapy in ALL patients. Also siRNA-mediated silencing of this gene may be a novel strategy in ALL treatment. PMID- 28892662 TI - Livestock drivers' knowledge about dairy cow fitness for transport - A Danish questionnaire survey. AB - Dairy cows are transported by road to slaughter after their productive life. Cull cows are vulnerable to transport stress, and can only be transported when fit for the intended journey. However, the decision, as to whether a cow is fit is rather subjective and relies on the farmer and the livestock driver. Using a questionnaire survey, we aimed to describe knowledge about, and experiences with, dairy cow fitness for transport among Danish livestock drivers. During nine days of data collection at the three largest Danish cattle slaughterhouses, 66 drivers (55% of the national population of cattle drivers) answered a questionnaire (response rate: 97%). They were Danish males (mean age: 49years), of which 94% stated that they knew the rules regarding fitness for transport. More than half of the respondents said that physical conditions (light, space) before loading animals allowed proper assessment of fitness for transport, and 85% answered that time constraints were not a challenge for this. Thirty-five percent reported to be in doubt regarding fitness for transport of specific cows at least frequently, and given two specific questions on legislation concerning fitness for transport, only 52% of the respondents answered both correctly. The results add new knowledge about livestock drivers' approach to animal welfare. As drivers are held partly responsible for fitness for transport of animals sent to slaughter, and descriptions of fit/unfit are rather vague, livestock drivers seem to need additional education, training, assessment tools or feedback in order to optimize the welfare of animals to be transported. PMID- 28892663 TI - Hepatic transcriptome analysis of juvenile GIFT tilapia (Oreochromis niloticus), fed diets supplemented with different concentrations of resveratrol. AB - The GIFT (Genetically Improved Farmed Tilapia) tilapia, Oreochromis niloticus, is cultured widely for the production of freshwater fish in China. Streptococcosis, which is related to pathogenic infections, occurs frequently in juvenile and adult female GIFT individuals. Resveratrol (RES) has been used in feed to control these infections in freshwater tilapia. To address the effects of RES on tilapia, we used high-throughput RNA sequencing technology (RNA-Seq, HiSeq. 2500) to explore the global transcriptomic response and specific involvement of hepatic mRNA of juvenile O. niloticus fed with diets containing different concentrations of (0, 0.025, 0.05, and 0.1g/kg) RES. A total of > 24,513,018 clean reads were generated and then assembled into 23,244 unigenes. The unigenes were annotated by comparing them against non-redundant protein sequence (Nr), non-redundant nucleotide (Nt), Swiss-Prot, Pfam, Gene Ontology database (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, and 12,578 unigenes were annotated to the GO database. A total of 1444 (0.025g/kg RES), 1526 (0.05g/kg RES), and 3135 (0.1g/kg RES) genes were detected as significant differentially expressed genes (DEGs), when compared with the controls. A total of 6 (0.025 vs 0.05g/kg RES), 19 (0.025 vs 0.1g/kg RES), and 124 (0.05 vs 0.1g/kg RES) genes were detected as significant DEGs. Six genes, including dnah7x1, sox4, fam46a, hsp90a, ddit4, and nmrk2, were associated with an immune response. These findings provide information on the innate immunity of GIFT and might contribute to the development of strategies for the effective management of diseases and long-term sustainability of O. niloticus culture. PMID- 28892664 TI - Piezoelectric nonlinear vibration focusing on the second-harmonic vibration mode. AB - Resonant piezoelectric devices are driven under high power condition. In such condition, a nonlinear piezoelectric vibration becomes apparent and this nonlinearity should be taken into account in the design procedure using the finite elemental method (FEM). The purpose of this study is to introduce the nonlinear parameter to the FEM and to establish the method for measuring the nonlinear parameter through evaluating a nonlinear model for a piezoelectric vibration. In a previous study about the nonlinear piezoelectric vibration, the third term was mainly focused on because the third mode vibration affects the fundamental vibration in the case of a simple bar-type transducer. On the other hand, we considered the second nonlinear parameter of the compliance to the piezoelectric constitutive equation. We observed that this parameter affects the vibration amplitude with each position and the velocity at the tip of the transducer with a double frequency at resonant. It was confirmed that two measured nonlinear parameters based on these two relationships were almost same. From these values, we concluded that the proposed model is reasonable. PMID- 28892665 TI - Difference in glycogen metabolism (glycogen synthesis and glycolysis) between normal and dysplastic/malignant oral epithelium. AB - BACKGROUND: The purpose of this study was to investigate a difference in glycogen metabolism (glycogen synthesis and glycolysis) between the iodine stained (normal non-keartinized) and the unstained (dysplasctic/malignant) oral epithelium. METHODS: Twenty-one frozen tissue samples of iodine-stained and unstained mucosal tissue were obtained from 21 OSCC patients. Serial frozen sections were cut and examined with the hematoxylin-eosin and periodic acid-Schiff methods and immunohistochemical (IHC) staining for Ki67, P53, molecules associated with glycogenesis (i.e., glycogen synthase (GS) and phospho-glycogen synthase (PGS)), and molecules associated with glycogenolysis (i.e., glycogen phosphorylase isoenzyme BB (GPBB) examine the glycogen metabolism in OSCC. Additionally, in vitro study, the expression levels of GS and GPBB in the cultured cells were analyzed by immunofluorescent staining, Western blot analysis, and the real-time quantitative polymerase chain reaction (PCR). RESULTS: There was no significant difference in GS and PGS immunoactivity between iodine stained and unstained area. On the other hand, significantly greater GPBB immunoreactivity was observed in the basal and parabasal layers of iodine-unstained epithelium, where higher positivity for p53 and Ki67 was also showed. Additionally, western blot analysis, immunofluorescent staining, and real-time quantitative PCR revealed that the oral squamous cancer cells exhibited greater expression of GPBB than normal epithelial cells. CONCLUSIONS: The results of this study showed that GPBB expression, which resulted in up-regulation of glycogenolysis, is enhanced in oral dysplastic/malignant epithelium compared with non-keartinized normal epithelium, in spite of the fact that glycogenesis continues in both of them. Premalignant and malignant epithelial cells consume greater quantities of energy due to their increased proliferation, and hence, exhaust their glycogen stores, which resulting in negative stain reaction with iodine solution. PMID- 28892666 TI - Toward the lowest energy consumption and emission in biofuel production: combination of ideal reactors and robust hosts. AB - Rising feedstock costs, low crude oil prices, and other macroeconomic factors have threatened biofuel fermentation industries. Energy-efficient reactors, which provide controllable and stable biological environment, are important for the large-scale production of renewable and sustainable biofuels, and their optimization focus on the reduction of energy consumption and waste gas emission. The bioreactors could either be aerobic or anaerobic, and photobioreactors were developed for the culture of algae or microalgae. Due to the cost of producing large-volume bioreactors, various modeling strategies were developed for bioreactor design. The achievement of ideal biofuel reactor relies on not only the breakthrough of reactor design, but also the creation of super microbial factories with highest productivity and metabolic pathway flux. PMID- 28892667 TI - Bioprocess engineering for biohythane production from low-grade waste biomass: technical challenges towards scale up. AB - A concept of biohythane production by combining biohydrogen and biomethane together via two-stage anaerobic fermentation (TSAF) has been recently proposed and considered as a promising approach for sustainable hythane generation from waste biomass. The advantage of biohythane over traditional biogas are more environmentally benign, higher energy recovery and shorter fermentation time. However, many of current efforts to convert waste biomass into biohythane are still at the bench scale. The system bioprocess study and scale up for industrial application are indispensable. This paper outlines the general approach of biohythane by comparing with other biological processes. The technical challenges are highlighted towards scale up of biohythane system, including functionalization of biohydrogen-producing reactor, energy efficiency, and bioprocess engineering of TSAF. PMID- 28892668 TI - Understanding enzyme function evolution from a computational perspective. AB - In this review, we will explore recent computational approaches to understand enzyme evolution from the perspective of protein structure, dynamics and promiscuity. We will present quantitative methods to measure the size of evolutionary steps within a structural domain, allowing the correlation between change in substrate and domain structure to be assessed, and giving insights into the evolvability of different domains in terms of the number, types and sizes of evolutionary steps observed. These approaches will help to understand the evolution of new catalytic and non-catalytic functionality in response to environmental demands, showing potential to guide de novoenzyme design and directed evolution experiments. PMID- 28892669 TI - Development of a prediction model for long-term quality of life in critically ill patients. AB - PURPOSE: We developed a prediction model for quality of life (QOL) 1 year after intensive care unit (ICU) discharge based upon data available at the first ICU day to improve decision-making. METHODS: The database of a 1-year prospective study concerning long-term outcome and QOL (assessed by EuroQol-5D) in critically ill adult patients consecutively admitted to the ICU of a university hospital was used. Cases with missing data were excluded. Utility indices at baseline (UIb) and at 1 year (UI1y) were surrogates for QOL. For 1-year non-survivors UI1y was set at zero. The grouped lasso technique selected the most important variables in the prediction model. R2 and adjusted R2 were calculated. RESULTS: 1831 of 1953 cases (93.8%) were complete. UI1y depended significantly on: UIb (P<0.001); solid tumor (P<0.001); age (P<0.001); activity of daily living (P<0.001); imaging (P<0.001); APACHE II-score (P=0.001); >=80 years (P=0.001); mechanical ventilation (P=0.006); hematological patient (P=0.007); SOFA-score (P=0.008); tracheotomy (P=0.018); admission diagnosis surgical P<0.001 (versus medical); and comorbidity (P=0.049). Only baseline health status and surgical patients were positively associated with UI1y. R2 was 0.3875 and adjusted R2 0.3807. CONCLUSION: Although only 40% of variability in long-term QOL could be explained, this prediction model can be helpful in decision-making. PMID- 28892670 TI - The influence of sex and obesity on gait biomechanics in people with severe knee osteoarthritis scheduled for arthroplasty. AB - BACKGROUND: Sex and body mass may influence knee biomechanics associated with poor total knee arthroplasty (TKA) outcomes for knee osteoarthritis (OA). This study aimed to determine if gait differed between men and women, and overweight and class I obese patients with severe knee OA awaiting TKA. METHODS: 34 patients with severe knee OA (average age 70.0 (SD 7.2) years, body mass index 30.3 (4.1kg/m2)) were recruited from a TKA waiting list. Three-dimensional gait analysis was performed at self-selected walking speed. Comparisons were made between men and women, and overweight (body mass index (BMI) 25.0-29.9kg/m2) and class I obese (BMI 30.0-34.9kg/m2) participants. Biomechanical outcomes included absolute and body size-adjusted peak knee adduction moment (KAM), KAM impulse, peak knee flexion moment, as well as peak knee flexion and varus-valgus angles, peak varus-valgus thrust, and peak vertical ground reaction force (GRF). FINDINGS: Men had a higher absolute peak KAM, KAM impulse and peak GRF compared to women, and this sex-difference in frontal plane moments remained after adjusting for body size. However, when additionally adjusting for static knee alignment, differences disappeared. Knee biomechanics were similar between obesity groups after adjusting for the greater body weight of those with class I obesity. INTERPRETATION: Men had greater KAM and KAM impulse even after adjustment for body size; however adjustment for their more varus knees removed this difference. Obesity group did not influence knee joint kinematics or moments. This suggests sex- and obesity-differences in these variables may not be associated with TKA outcomes. PMID- 28892671 TI - Kinematic and kinetic gait deviations in males long after anterior cruciate ligament reconstruction. AB - BACKGROUND: Biomechanical deviations long (approx. 5years) after anterior cruciate ligament reconstruction have not been quantified in males, despite their distinct risk profile as compared to females. These deviations can indicate altered joint loading during chronic, repetitive motions. METHODS: Cross sectional study, comparing kinematic and kinetic variables between 15 male anterior cruciate ligament reconstructed patients and 15 healthy controls. During walking and running gait, measurements were taken of impact dynamics, knee and hip sagittal plane angles and moments, and knee varus angles and adduction moments. FINDINGS: Comparing affected limbs to control limbs, significantly lower maximum (P=0.001) and initial (P=0.003) loading rates were found during running, but not in walking. Hip angles were lower for affected limbs of patients compared to the control group (P=0.039) in walking, but not during running. Between-limb comparisons showed important differences in symmetry of the affected patients. Maximum force during running was higher in the unaffected limb (P=0.015), which was linked with a higher loading rate (P=0.008). Knee flexion angle was reduced by 2 degrees on average for the affected limb during running (P=0.010), and both walking and running knee and hip moments showed differences. Knee varus angle showed a 1 degrees difference during walking (P<0.001), but not during running. Knee adduction moment was significantly lower (more valgus) during both walking and running. INTERPRETATION: Male anterior cruciate ligament reconstructed patients demonstrate persistent, clinically important gait asymmetries and differences from healthy controls long after surgery in kinematics, kinetics, and impact biomechanics. PMID- 28892672 TI - Spiking neural P systems with multiple channels. AB - Spiking neural P systems (SNP systems, in short) are a class of distributed parallel computing systems inspired from the neurophysiological behavior of biological spiking neurons. In this paper, we investigate a new variant of SNP systems in which each neuron has one or more synaptic channels, called spiking neural P systems with multiple channels (SNP-MC systems, in short). The spiking rules with channel label are introduced to handle the firing mechanism of neurons, where the channel labels indicate synaptic channels of transmitting the generated spikes. The computation power of SNP-MC systems is investigated. Specifically, we prove that SNP-MC systems are Turing universal as both number generating and number accepting devices. PMID- 28892673 TI - Human papillomavirus knowledge and vaccine acceptability among adolescents in a Greek region. AB - OBJECTIVES: The aim of this research was twofold: (1) develop an instrument to assess knowledge regarding human papillomavirus (HPV) and its vaccine and utilize this instrument to measure knowledge levels of Greek adolescents in Lyceum schools of Western Thessaloniki; and (2) examine the associations of the resultant knowledge measure scores with sociodemographic characteristics. STUDY DESIGN: Cross-sectional survey with complex sampling design. METHODS: A total of 268 students of three Lyceum schools in Western Thessaloniki responded anonymously to a questionnaire during February-March 2013. The instrument was developed by literature review. Answers of respondents to individual questions were initially presented in terms of absolute and relative frequencies. Knowledge items were presented by gender along with appropriate chi-squared tests. Next, the development and validation of a knowledge score was pursued with Rasch analysis. Raw scores of dichotomous true/false items were converted to interval level adjusted student scores, and the reliability and validity of the model were assessed. Finally, the effect of sociodemographic variables on the knowledge measure was explored by multivariate linear regression. RESULTS: Analysis of individual items documented low knowledge for both female and male students along with a limited role of doctors as information agents and little associated encouragement toward vaccination. Vaccine uptake was low with many young girls being largely unwilling to vaccinate in the future primarily due to the fear of side-effects and lack of information. Person location parameters (knowledge scores) were derived from a Rasch model with satisfactory reliability and validity. The resultant validated measure confirmed the low knowledge levels of Greek students. Nationality and birthplace seemed to affect knowledge level. CONCLUSIONS: Further improvement and validation of the knowledge measure used in this study can assist nationwide surveys in order to examine student knowledge regarding HPV and its vaccine. Our findings also stress the exacerbated need for effective nationwide educational campaigns aiming to inform adolescents about HPV and the associated vaccine. Appropriate incentives should also be given to physicians to increase their involvement. Parents and students should be thoroughly informed about the value of research similar to ours, in order to increase survey participation rates. PMID- 28892674 TI - Dengue fever again in Pakistan: are we going in the right direction? PMID- 28892675 TI - Alkynyl gold(I) complex triggers necroptosis via ROS generation in colorectal carcinoma cells. AB - Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis-resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex [Au(CC-2-NC5H4)(PTA)] whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-alpha (Tumor necrosisfactor alpha) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-kappaB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of [Au(CC-2-NC5H4)(PTA)] has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound [Au(CC-2-NC5H4)(PTA)] is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance. PMID- 28892676 TI - A small-molecule acts as a 'roadblock' on DNA, hampering its fundamental processes. AB - DNA replication, RNA and protein synthesis are the most fundamental housekeeping processes involved in an organism's growth. Failure or dysregulation of these pathways are often deleterious to life. Therefore, selective inhibition of such processes can be crucial for the inhibition of the growth of any cell, including cancer cells, pathogenic bacteria or other deadly microbes. In the present study, a Zn2+ complex is shown to act as a roadblock of DNA. The Zn2+ complex inhibited DNA taq polymerase activity under the in vitro conditions of polymerase chain reaction (PCR). Under in vivo conditions, it readily crosses the cell wall of gram-negative bacteria (Escherichia coli), leading to the reduction of RNA levels as well as protein content. Growth of pathogenic bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa) was also significantly retarded. The Zn2+ complex binds to the grooves of the DNA without inducing conformational changes or exhibiting chemical nuclease activity. To the best current knowledge, this is first coordination complex exhibiting a 'roadblock' property under both in vitro and in vivo conditions (show at all three levels - DNA, RNA and protein). The label-free approach used in this study may offer an alternative route towards fighting pathogenic bacteria or cancer cells by hampering fundamental cellular processes. PMID- 28892677 TI - Acidogenic digestion of food waste in a thermophilic leach bed reactor: Effect of pH and leachate recirculation rate on hydrolysis and volatile fatty acid production. AB - The effect of pH control (4, 5, 6, 7) on volatile fatty acids (VFA) production from food waste was investigated in a leach bed reactor (LBR) operated at 50 degrees C. Stabilisation of pH at 7 resulted in hydrolysis yield of 530g soluble chemical oxygen demand (sCOD)/kg total volatile solids (TVS) added and VFA yield of 247gCOD/kg TVS added, which were highest among all pH tested. Butyric acid dominated the VFA mix (49-54%) at pH of 7 and 6, while acetate composed the primary VFA (41-56%) at pH of 4 and 5. A metabolic shift towards lactic acid production was observed at pH of 5. Improving leachate recirculation rate further improved the hydrolysis and degradation efficiency by 10-16% and the acidification yield to 340gCOD/kgTVS added. The butyric acid concentration of 16.8g/L obtained at neutral pH conditions is among the highest reported in literature. PMID- 28892678 TI - Nutrients removal and recovery from saline wastewater by Spirulina platensis. AB - As an important alternative to alleviate the pressure of fresh water shortage, seawater application is facing a great challenge on the wastewater treatment due to the salinity brought from seawater. Spirulina platensis originated from salty lake was used to treat mixed synthetic toilet flushing wastewater of seawater with washing wastewater of freshwater. It was showed that 79.96% of TN (to 15.69mg/L), 93.35% of TP (to 1.03mg/L) and 90.02% of CODCr (to 90.24mg/L) were removed with 0.76g/L of biomass production in the optimal ratio 7:3 of the above mixed synthetic wastewater. The performance was better than that of current strategy of seawater toilet flushing treatment. With the evaluation of nutrients uptake, biomass composition and microalgal aggregation, a model of nutrients recovery and metabolism of Spirulina platensis in saline wastewater treatment was proposed. It is provided a promising strategy for saline wastewater treatment with valuable biomass yield. PMID- 28892679 TI - Co-ensiling of straw with sugar beet leaves increases the methane yield from straw. AB - This study examined the effect of co-ensiling of wheat straw and sugar beet leaves on the biochemical methane potential (BMP) by both lab-scale and pilot scale co-ensiling. BMP was increased by co-ensiling, and the increase ranged from 19 to 34% after 9months of co-ensiling in lab-scale and from 18 to 32% after 6months of co-ensiling in pilot-scale. No effluent run-off was found through pilot-scale co-ensiling and there was a mass loss of only 0.1%. The study demonstrates that co-ensiling of straw and green biomass has potential as biological pretreatment and for avoiding effluent run-off from pure beet leave silage. PMID- 28892680 TI - Removal and recovery of acetic acid and two furans during sugar purification of simulated phenols-free biomass hydrolysates. AB - A cost-effective five-step sugar purification process involving simultaneous removal and recovery of fermentation inhibitors from biomass hydrolysates was first proposed here. Only the three separation steps (PB, PC and PD) in the process were investigated here. Furfural was selectively removed up to 98.4% from a simulated five-component hydrolysate in a cross-current three-stage extraction system with n-hexane. Most of acetic acid in a simulated four-component hydrolysate was selectively removed by emulsion liquid membrane, and it could be concentrated in the stripping solution up to 4.5 times its initial concentration in the feed solution. 5-Hydroxymethylfurfural was selectively removed from a simulated three-component hydrolysate in batch and continuous fixed-bed column adsorption systems with L-493 adsorbent. Also, 5-hydroxymethylfurfural could be concentrated to about 9 times its feed concentration in the continuous adsorption system through a fixed-bed column desorption experiment with aqueous ethanol solution. These results have shown that the proposed purification process was valid. PMID- 28892681 TI - Optimization of the yield of dark microaerobic production of hydrogen from lactate by Rhodopseudomonas palustris. AB - Hydrogen yields of dark fermentation are limited due to the need to also produce reduced side products, and photofermentation, an alternative, is limited by the need for light. A relatively new strategy, dark microaerobic fermentation, could potentially overcome both these constraints. Here, application of this strategy demonstrated for the first time significant hydrogen production from lactate by a single organism in the dark. Response surface methodology (RSM) was used to optimize substrate and oxygen concentration as well as inoculum using both (1) regular batch and (2) O2 fed batch cultures. The highest hydrogen yield (HY) was observed under regular batch (1.4+/-0.1molH2/mollactate) and the highest hydrogen production (HP) (173.5umolH2) was achieved using O2 fed batch. This study has provided proof of principal for the ability of microaerobic fermentation to drive thermodynamically difficult reactions, such as the conversion of lactate to hydrogen. PMID- 28892682 TI - Enhancement of methanogenesis via direct interspecies electron transfer between Geobacteraceae and Methanosaetaceae conducted by granular activated carbon. AB - To understand how granular activated carbon (GAC) promotes methanogenesis, batch tests of CH4 production potential in anaerobic serum bottles with addition of GAC or not were conducted. Tests showed that GAC promoted methanogenesis remarkably, but the non-conductive zeolite did not. The qPCR demonstrated that the biomass on GAC contributed little to the promotion. High-throughput sequencing data implied that promotion was related with direct interspecies electron transfer between Geobacteraceae and Methanosaetaceae. According to the c-type cytochromes (c-Cyts) response to the supplement of GAC, it was speculated that GAC may play the role of c-Cyts' substitution. In the undefined cultures, the phenomenon that c-Cyts were repressed by GAC was first observed. This research provided new evidence to microbial mechanism of promoting methanogenesis via GAC. PMID- 28892683 TI - Promoting electron transfer to enhance anaerobic treatment of azo dye wastewater with adding Fe(OH)3. AB - In this study, Fe(OH)3 was dosed into anaerobic reactor (R1) to stimulate the electron transfer process during the decoloration treatment. As results indicated, the chemical oxygen demand (COD) removal and decoloration efficiency were increased by 61.7% and 32.0% than that of the control reactor (R2), respectively. The cyclic-voltammetric analysis of the effluent demonstrated that the cycles of Fe(III)/Fe(II) and 1-imino-2-napthoquinone/1-amino-2-napthol (oxidative/reductive state of the decoloration intermediate product) had been established in R1. The concentration of cytochrome c and the conductivity of suspended sludge in R1 were also 3.2 and 2.1 times higher than that in R2. All experiments above indicated that the electron transfer process between substrates and azo bonds was accelerated efficiently. Furthermore, the abundance of iron reducing bacteria was higher than that of R2, indicating that dissimilatory iron reduction as a reason for the Fe(III)/Fe(II) cycle played an important role in the anaerobic decoloration treatment. PMID- 28892684 TI - Mild-temperature dilute acid pretreatment for integration of first and second generation ethanol processes. AB - The use of hot-water (100 degrees C) from the 1st generation ethanol plants for mild-temperature lignocellulose pretreatment can possibly cut down the operational (energy) cost of 2nd generation ethanol process, in an integrated model. Dilute-sulfuric and -phosphoric acid pretreatment at 100 degrees C was carried out for wheat bran and whole-stillage fibers. Pretreatment time and acid type influenced the release of sugars from wheat bran, while acid-concentration was found significant for whole-stillage fibers. Pretreatment led up-to 300% improvement in the glucose yield compared to only-enzymatically treated substrates. The pretreated substrates were 191-344% and 115-300% richer in lignin and glucan, respectively. Fermentation using Neurospora intermedia, showed 81% and 91% ethanol yields from wheat bran and stillage-fibers, respectively. Sawdust proved to be a highly recalcitrant substrate for mild-temperature pretreatment with only 22% glucose yield. Both wheat bran and whole-stillage are potential substrates for pretreatment using waste heat from the 1st generation process for 2nd generation ethanol. PMID- 28892685 TI - Using cow dung and spent coffee grounds to enhance the two-stage co-composting of green waste. AB - The objective of this study was to determine the effects of cow dung (CD) (at 0%, 20%, and 35%) and/or spent coffee grounds (SCGs) (at 0%, 30%, and 45%) as amendments in the two-stage co-composting of green waste (GW); the percentages refer to grams of amendment per 100g of GW based on dry weights. The combined addition of CD and SCGs improved the conditions during co-composting and the quality of the compost product in terms of composting temperature; particle-size distribution; mechanical properties; nitrogen changes; low-molecular weight compounds; humic substances; the degradation of lignin, cellulose, and hemicellulose; enzyme activities; the contents of total Kjeldahl nitrogen, total phosphorus, and total potassium; and the toxicity to germinating seeds. The combined addition of 20% CD and 45% SCGs to GW resulted in the production of the highest quality compost product and did so in only 21days. PMID- 28892686 TI - Autotrophic and heterotrophic microalgae and cyanobacteria cultivation for food and feed: life cycle assessment. AB - The lack of protein sources in Europe could be reduced with onsite production of microalgae with autotrophic and heterotrophic systems, owing the confirmation of economic and environmental benefits. This study aimed at the life cycle assessment (LCA) of microalgae and cyanobacteria cultivation (Chlorella vulgaris and Arthrospira platensis) in autotrophic and heterotrophic conditions on a pilot industrial scale (in model conditions of Berlin, Germany) with further biomass processing for food and feed products. The comparison of analysis results with traditional benchmarks (protein concentrates) indicated higher environmental impact of microalgae protein powders. However high-moisture extrusion of heterotrophic cultivated C. vulgaris resulted in more environmentally sustainable product than pork and beef. Further optimization of production with Chlorella pyrenoidosa on hydrolyzed food waste could reduce environmental impact in 4.5 times and create one of the most sustainable sources of proteins. PMID- 28892687 TI - Effects of carbon sources and COD/N ratio on N2O emissions in subsurface flow constructed wetlands. AB - A set of constructed wetlands under two different carbon sources, namely, glucose (CW) and sodium acetate (YW), was established at a laboratory scale with influent COD/N ratios of 20:1, 10:1, 7:1, 4:1, and 0 to analyze the influence of carbon supply on nitrous oxide emissions. Results showed that the glucose systems generated higher N2O emissions than those of the sodium acetate systems. The higher amount of N2O-releasing fluxes in the CWs than in the YWs was consistent with the higher NO2--N accumulation in the former than in the latter. Moreover, electron competition was tighter in the CWs and contributed to the incomplete denitrification with poor N2O production performance. Illumina MiSeq sequencing demonstrated that some denitrifying bacteria, such as Denitratisoma, Bacillus, and Zoogloea, were higher in the YWs than in the CWs. This result indicated that the carbon source is important in controlling N2O emissions in microbial communities. PMID- 28892688 TI - Maximizing cellulosic ethanol potentials by minimizing wastewater generation and energy consumption: Competing with corn ethanol. AB - Energy consumption and wastewater generation in cellulosic ethanol production are among the determinant factors on overall cost and technology penetration into fuel ethanol industry. This study analyzed the energy consumption and wastewater generation by the new biorefining process technology, dry acid pretreatment and biodetoxification (DryPB), as well as by the current mainstream technologies. DryPB minimizes the steam consumption to 8.63GJ and wastewater generation to 7.71tons in the core steps of biorefining process for production of one metric ton of ethanol, close to 7.83GJ and 8.33tons in corn ethanol production, respectively. The relatively higher electricity consumption is compensated by large electricity surplus from lignin residue combustion. The minimum ethanol selling price (MESP) by DryPB is below $2/gal and falls into the range of corn ethanol production cost. The work indicates that the technical and economical gap between cellulosic ethanol and corn ethanol has been almost filled up. PMID- 28892689 TI - Feedwater pH affects phosphorus transformation during hydrothermal carbonization of sewage sludge. AB - In this study, the effect of feedwater pH (3-11) on phosphorus (P) transformation during the hydrothermal carbonization (HTC) of sewage sludge (SS) was investigated at a temperature range of 200-260 degrees C. The HTC significantly accumulated P in the hydrochar. Different feedwater pH stimulated the transformation of various forms of P. An acidic feedwater pH promoted the transformation of apatite phosphorus (AP) to non-apatite inorganic phosphorus (NAIP), and of organic P (OP) to inorganic P (IP). The NAIP tended to transformation to AP and a small part of the IP was transformed to OP when the SS was treated in a basic environment. The combination of three P analysis methods (chemical extractive fractionation, X-ray powder diffraction (XRD) and energy dispersive spectroscopy (EDS)) showed that metal cations (e.g. Al and Ca) and the pH played important roles in the transformation of different forms of P during the HTC of the SS. PMID- 28892690 TI - Synthesis of magnetic biochar from bamboo biomass to activate persulfate for the removal of polycyclic aromatic hydrocarbons in marine sediments. AB - This study developed a new and cost-effective method for the remediation of marine sediments contaminated with PAHs. Fe3O4 particles were synthesized as the active component, supported on bamboo biochar (BB) to form a composite catalyst (Fe3O4-BB). The effects of critical parameters, including the initial pH, sodium persulfate (PS) concentration, and dose of catalyst were investigated. The concentration of high-molecular-weight PAHs in sediments was much higher than that of low-molecular-weight PAHs; pyrene was an especially prominent marker of PAH contamination in sediments. Fe3O4-BB/PS exhibited a substantial improvement in PAH degradation efficiency (degradation rate: Fe3O4-BB/PS, 86%; PS, 14%) at a PS concentration of 1.7*10-5M, catalyst concentration of 3.33g/L, and pH of 3.0. The results of this study demonstrate that possible activation mechanisms include Fe2+-Fe3+ redox coupling and electron shuttling that mediates electron transfer of the BB oxygen functional groups, promoting the generation of SO4- in the Fe3O4 BB/PS system. PMID- 28892691 TI - Combined pretreatment of electrolysis and ultra-sonication towards enhancing solubilization and methane production from mixed microalgae biomass. AB - This study investigated the effect of combination of pretreatment methods such as ultra-sonication and electrolysis for the minimum energy input to recover the maximal carbohydrate and solubilization (in terms of sCOD) from mixed microalgae biomass. The composition of the soluble chemical oxygen demand (COD), protein, carbohydrate revealed that the hydrolysis method had showed positive impact on the increasing quantity and thus enhanced methane yields. As a result, the combination of these 2 pretreatments showed the greatest yield of soluble protein and carbohydrate as 279 and 309mg/L, which is the recovery of nearly 85 and 90% in terms of total content of them. BMP tests showed peak methane production yield of 257mL/gVSadded, for the hydrolysate of combined pretreatment as compared to the control experiment of 138mL/gVS added. PMID- 28892692 TI - Evaluation of pilot-scale in-vessel composting for Hanwoo manure management. AB - The study investigated the effect of in-vessel composting process on Hanwoo manure in two different South Korea regions (Pyeongchang and Goechang) with sawdust using vertical cylindrical in-vessel bioreactor for 42days. The stability and quality of Hanwoo manure in both regions were improved and confirmed through the positive changes in physico-chemical and phytotoxic properties using different commercial seed crops. The pH and electrical conductivity (EC, ds/m) of composted manure in both regions were slightly increased. At the same time, carbon:nitrogen (C:N) ratio and ammonium nitrogen:nitrate nitrogen (NH4+-N:NO3- N) ratio decreased to 13.4-16.1 and 0.36-0.37, respectively. The germination index (GI, %) index was recorded in the range of 67.6-120.9%, which was greater than 50%, indicating phytotoxin-free compost. Although, composted manure values in Goechang region were better in significant parameters, overall results confirmed that the composting process could lead to complete maturation of the composted product in both regions. PMID- 28892694 TI - Effect of particle size reduction and ensiling fermentation on biogas formation and silage quality of wheat straw. AB - The effect of ensiling fermentation and mechanical pretreatment on the methane yield of lignocellulosic biomass was investigated in order to determine the optimum pretreatment conditions for biogas production. Wheat straw was treated using the following techniques: mechanical disintegration by chopping and extruder-grinding to particle sizes of 2.0 and 0.2cm, respectively, and ensiling by 30% and 45% total solids with addition of enzymatic, chemical and biological silage additives individually and in combination. The total and volatile solid content, biochemical methane potential and products of silage fermentation of 32 variants were tested. The results indicate that the methane potential increased by 26% (from 179 to 244mLCH4g-1VS) by reducing particle size. The maximum methane potential of 275mLCH4g-1VS was obtained from silage with 30% total solids and extruder grinding. However, the effect of the addition of silage additives on the methane potential was limited. PMID- 28892693 TI - A modelling approach to study the fouling of an anaerobic membrane bioreactor for industrial wastewater treatment. AB - An Anaerobic Membrane BioReactors (AnMBR) model is presented in this paper based on the combination of a simple fouling model and the Anaerobic Model 2b (AM2b) to describe biological and membrane dynamic responses in an AnMBR. In order to enhance the model calibration and validation, Trans-Membrane Pressure (TMP), Total Suspended Solid (TSS), COD, Volatile Fatty Acid (VFA) and methane production were measured. The model shows a satisfactory description of the experimental data with R2~0.9 for TMP data and R2~0.99 for biological parameters. This new model is also proposed as a numerical tool to predict the deposit mass composition of suspended solid and Soluble Microbial Products (SMP) on the membrane surface. The effect of SMP deposit on the TMP jump phenomenon is highlighted. This new approach offers interesting perspectives for fouling prediction and the on-line control of an AnMBR process. PMID- 28892695 TI - Synergistic combination of biomass torrefaction and co-gasification: Reactivity studies. AB - Two typical biomass feedstocks obtained from woody wastes and agricultural residues were torrefied or mildly pyrolized in a fixed-bed reactor. Effects of the torrefaction conditions on product distributions, compositional and energetic properties of the solid products, char gasification reactivity, and co gasification behavior between coal and torrefied solids were systematically investigated. Torrefaction pretreatment produced high quality bio-solids with not only increased energy density, but also concentrated alkali and alkaline earth metals (AAEM). As a consequence of greater retention of catalytic elements in the solid products, the chars derived from torrefied biomass exhibited a faster conversion than those derived from raw biomass during CO2 gasification. Furthermore, co-gasification of coal/torrefied biomass blends exhibited stronger synergy compared to the coal/raw biomass blends. The results and insights provided by this study filled a gap in understanding synergy during co gasification of coal and torrefied biomass. PMID- 28892696 TI - Variation in metals during wet oxidation of sewage sludge. AB - Sewage sludge is a significant by-product from wastewater treatment plants but is potentially hazardous due to its pathogenic or harmful contents, such as toxic metals. Subcritical water wet oxidation (SCWO) is one method of hydrothermal processing which has recently been used in research and industry for treating sludge. This study investigated the effect of SCWO on metals such as Al, Cu, Fe, and Zn in sludge, including the content of metals in the liquid or solid phase after SCWO and their stability distributions according to Tessier's method. During SCWO, most metals were significantly accumulated and stabilised in the solid phase with very limited leaching. The temperature was found to be the most significant factor for metals immobilisation, followed by reaction time, while pH had negligible effect. The optimal conditions of SCWO on metals were found at 240 degrees C, 60min, pH 5 in this study. PMID- 28892697 TI - Water sorption in pretreated grasses as a predictor of enzymatic hydrolysis yields. AB - This work investigated the impact of two alkaline pretreatments, ammonia fiber expansion (AFEX) and alkaline hydrogen peroxide (AHP) delignification performed over a range of conditions on the properties of corn stover and switchgrass. Changes in feedstock properties resulting from pretreatment were subsequently compared to enzymatic hydrolysis yields to examine the relationship between enzymatic hydrolysis and cell wall properties. The pretreatments function to increase enzymatic hydrolysis yields through different mechanisms; AFEX pretreatment through lignin relocalization and some xylan solubilization and AHP primarily through lignin solubilization. An important outcome of this work demonstrated that while changes in lignin content in AHP-delignified biomass could be clearly correlated to improved response to hydrolysis, compositional changes alone in AFEX-pretreated biomass could not explain differences in hydrolysis yields. We determined the water retention value, which characterizes the association of water with the cell wall of the pretreated biomass, can be used to predict hydrolysis yields for all pretreated biomass within this study. PMID- 28892698 TI - Modeling shear-sensitive dinoflagellate microalgae growth in bubble column photobioreactors. AB - The shear-sensitive dinoflagellate microalga Karlodinium veneficum was grown in a sparged bubble column photobioreactor. The influence of mass transfer and shear stress on cell growth and physiology (concentration of reactive oxygen species, membrane fluidity and photosynthetic efficiency) was studied, and a model describing cell growth in term of mass transfer and culture parameters (nozzle sparger diameter, air flow rate, and culture height) was developed. The results show that mass transfer limits cell growth at low air-flow rates, whereas the shear stress produced by the presence of bubbles is critically detrimental for air flow rates above 0.1vvm. The model developed in this paper adequately represents the growth of K. veneficum. Moreover, the parameters of the model indicate that bubble rupture is much more harmful for cells than bubble formation. PMID- 28892699 TI - Enhanced furfural production from raw corn stover employing a novel heterogeneous acid catalyst. AB - With the aim to enhance the direct conversion of raw corn stover into furfural, a promising approach was proposed employing a novel heterogeneous strong acid catalyst (SC-CaCt-700) in different solvents. The novel catalyst was characterized by elemental analysis, N2 adsorption-desorption, FT-IR, XPS, TEM and SEM. The developed catalytic system demonstrated superior efficacy for furfural production from raw corn stover. The effects of reaction temperature, residence time, catalyst loading, substrate concentration and solvent were investigated and optimized. 93% furfural yield was obtained from 150mg corn stover at 200 degrees C in 100min using 45mg catalyst in gamma-valerolactone (GVL). In comparison, 51.5% furfural yield was achieved in aqueous media under the same conditions (200 degrees C, 5h, and 45mg catalyst), which is of great industrial interest. Furfural was obtained from both hemicelluloses and cellulose in corn stover, which demonstrated a promising routine to make the full use of biomass. PMID- 28892700 TI - Modification of biochar derived from sawdust and its application in removal of tetracycline and copper from aqueous solution: Adsorption mechanism and modelling. AB - Highly efficient simultaneous removal of Cu(II) and tetracycline (TET) from aqueous solution was accomplished by iron and zinc doped sawdust biochar (Fe/Zn biochar). The mutual effects and inner mechanisms of their adsorption onto Fe/Zn biochar were systematically investigated via sole and binary systems, sorption isotherm and adsorption kinetics models. The liquid-film diffusion step might be the rate-limiting step for tetracycline, the interaction of Cu(II) was more likely controlled by both intra particle diffusion model and liquid film diffusion model. The fitting of experimental data with kinetic models, Temkin model indicates that the adsorption process of tetracycline and Cu(II) involve chemisorption, and physico-chemical adsorption, respectively. There exists site competition and enhancement of Cu(II) and tetracycline on the sorption to Fe/Zn biochar. The results of this study indicate that modification of biochar derived from sawdust shows great potential for simultaneous removal of Cu(II) and tetracycline from co-contaminated water. PMID- 28892701 TI - Co-cultivation of microalgae in aquaponic systems. AB - Aquaponics is a sustainable system for the future farming. In aquaponic systems, the nutrient-rich wastewater generated by the fish provides nutrients needed for vegetable growth. In the present study, the role of microalgae of Chlorella sp. in the floating-raft aquaponic system was evaluated for ammonia control. The yields of algal biomass, vegetable, and removal of the key nutrients from the systems were monitored during the operation of the aquaponic systems. When the systems were in full operation, the algae production was about 4.15+/ 0.19g/m2.day (dry basis) which is considered low because the growth conditions are primarily tailored to fish and vegetable production. However, it was found that algae had a positive effect on balancing pH drop caused by nitrifying bacteria, and the ammonia could be controlled by algae since algae prefer for ammonia nitrogen over nitrate nitrogen. The algae are more efficient for overall nitrogen removal than vegetables. PMID- 28892702 TI - Production of wax esters via microbial oil synthesis from food industry waste and by-product streams. AB - The production of wax esters using microbial oils was demonstrated in this study. Microbial oils produced from food waste and by-product streams by three oleaginous yeasts were converted into wax esters via enzymatic catalysis. Palm oil was initially used to evaluate the influence of temperature and enzyme activity on wax ester synthesis catalysed by Novozyme 435 and Lipozyme lipases using cetyl, oleyl and behenyl alcohols. The highest conversion yields (up to 79.6%) were achieved using 4U/g of Novozyme 435 at 70 degrees C. Transesterification of microbial oils to behenyl and cetyl esters was achieved at conversion yields up to 87.3% and 69.1%, respectively. Novozyme 435 was efficiently reused for six and three cycles during palm esters and microbial esters synthesis, respectively. The physicochemical properties of microbial oil derived behenyl esters were comparable to natural waxes. Wax esters from microbial oils have potential applications in cosmetics, chemical and food industries. PMID- 28892703 TI - Xylooligosaccharides production by crude microbial enzymes from agricultural waste without prior treatment and their potential application as nutraceuticals. AB - Aspergillus fumigatus R1, on submerged fermentation using agricultural residues as carbon source produced extracellular xylanase (152IU/ml after 96h of incubation at 37 degrees C with constant shaking at 100rpm). A maximum yield of 1gm% Xylooligosaccharides (XOS) mixture was obtained after 12h by enzymatic hydrolysis of xylan rich wheat husk without any prior pretreatment using the crude enzyme without any purification. HP-TLC data confirmed the presence of an array of XOS for its prebiotic properties by carrying out studies on ten standard probiotic cultures. Six of ten probiotic cultures were able to utilize XOS produced from agricultural wastes and showed remarkable growth in the media containing XOS as the sole source of carbon. XOS mixture also exhibited concentration dependent anti-oxidant activity. Thus, the results showed that XOS produced from agricultural residues have great prebiotic potential and good antioxidant activity; therefore, it can be used in food-related applications. PMID- 28892704 TI - Optimization of semi-continuous anaerobic digestion of sugarcane straw co digested with filter cake: Effects of macronutrients supplementation on conversion kinetics. AB - Anaerobic digestion of sugarcane straw co-digested with sugarcane filter cake was investigated with a special focus on macronutrients supplementation for an optimized conversion process. Experimental data from batch tests and a semi continuous experiment operated in different supplementation phases were used for modeling the conversion kinetics based on continuous stirred-tank reactors. The semi-continuous experiment showed an overall decrease in the performance along the inoculum washout from the reactors. By supplementing nitrogen alone or in combination to phosphorus and sulfur the specific methane production significantly increased (P<0.05) by 17% and 44%, respectively. Although the two pool one-step model has fitted well to the batch experimental data (R2>0.99), the use of the depicted kinetics did not provide a good estimation for process simulation of the semi-continuous process (in any supplementation phase), possibly due to the different feeding modes and inoculum source, activity and adaptation. PMID- 28892705 TI - Enhanced carboxylic acids production by decreasing hydrogen partial pressure during acidogenic fermentation of glucose. AB - In this study, the effect of reduced hydrogen partial pressure (PH2) on the generation of carboxylic acids from acidogenic fermentation of glucose was investigated. Three strategies were applied to reduce PH2: headspace removal (T1), CO2 sparging (T2) and H2:CO2 (80:20) sparging (T3). Results showed that the production of carboxylic acids in T1-T3 were 10.21, 11.64 and 12.71g/L, respectively, which were 1.04, 1.19 and 1.30-fold of that in the control (T4). The composition of carboxylic acids changed significantly in T3 with enhancement of homoacetogenesis, as more acetate and butyrate were produced comparing to the control. In addition, decreasing PH2 led to more carbon flow to carboxylic acids. Species of Clostridium became dominant in treatment T3, resulting in the shift of metabolic pathways. This study demonstrated that decreasing PH2 could increase the production of carboxylic acids, especially under the strategy of enhancing homoacetogenesis. PMID- 28892706 TI - Formulation of an optimized synergistic enzyme cocktail, HoloMix, for effective degradation of various pre-treated hardwoods. AB - In this study, two selected hardwoods were subjected to sodium chlorite delignification and steam explosion, and the impact of pre-treatments on synergistic enzymatic saccharification evaluated. A cellulolytic core-set, CelMix, and a xylanolytic core-set, XynMix, optimised for glucose and xylose release, respectively, were used to formulate HoloMix cocktail for optimal saccharification of various pre-treated hardwoods. For delignified biomass, the optimized HoloMix consisted of 75%:25% protein dosage, CelMix: XynMix, while for untreated and steam exploded biomass the HoloMix consisted of 93.75%:6.25% protein dosage. Saccharification by HoloMix (27.5mgprotein/gbiomass) for 24h achieved 70-100% sugar yields. Pre-treatment of the hardwoods (especially those with a higher proportion of lignin) with a laccase, improved saccharification by HoloMix. This study provided insights into enzymatic hydrolysis of various pre treated hardwood substrates and showed the same lignocellulolytic cocktail comparable to/if not better than commercial enzyme preparations can be used to efficiently hydrolyse different hardwood species. PMID- 28892707 TI - Steam explosion pretreatment improved the biomethanization of coffee husks. AB - This study evaluated the potential of energy generation using a combined heat and power co-generation system (CHP) from biogas produced during the anaerobic digestion of coffee husks (CH) pretreated with steam explosion. Pretreatment conditions assessed were time (1, 5, 15 and 60min) and temperature (120, 180 and 210 degrees C). Polysaccharides solubilisation and biogas production were not correlated. While pretreatment with severities higher than 4 resulted in a highest solubilisation of cellulose, hemicelluloses and lignin; however, furans concentration in those cases hindered biomass biodegradation. Considering a CHP, all pretreatment conditions were worthwhile when compared to non-pretreated CH. The best condition was 120 degrees C for 60min, in which a 2.37 severity showed the highest methane yield (144.96NmLCH4gCOD-1) and electricity production (0.59kWhkgCH-1). However, even better results could be achieved using 120 degrees C for only 5min, which would lead to a larger amount of CH daily processed. PMID- 28892708 TI - Combustion characteristics and retention-emission of selenium during co-firing of torrefied biomass and its blends with high ash coal. AB - The combustion characteristics, kinetic analysis and selenium retention-emission behavior during co-combustion of high ash coal (HAC) with pine wood (PW) biomass and torrefied pine wood (TPW) were investigated through a combination of thermogravimetric analysis (TGA) and laboratory-based circulating fluidized bed combustion experiment. Improved ignition behavior and thermal reactivity of HAC were observed through the addition of a suitable proportion of biomass and torrefied. During combustion of blends, higher values of relative enrichment factors in fly ash revealed the maximum content of condensing volatile selenium on fly ash particles, and depleted level in bottom ash. Selenium emission in blends decreased by the increasing ratio of both PW and TPW. Higher reductions in the total Se volatilization were found for HAC/TPW than individual HAC sample, recommending that TPW have the best potential of selenium retention. The interaction amongst selenium and fly ash particles may cause the retention of selenium. PMID- 28892709 TI - Nitrification by microalgal-bacterial consortia for ammonium removal in flat panel sequencing batch photo-bioreactors. AB - Ammonium removal from artificial wastewater by microalgal-bacterial consortia in a flat-panel reactor (FPR1) was compared with a microalgae-only flat-panel reactor (FPR2). The microalgal-bacterial consortia removed ammonium at higher rates (100+/-18mgNH4+-NL-1d-1) than the microalgae (44+/-16mgNH4+-NL-1d-1), after the system achieved a stable performance at a 2days hydraulic retention time. Nitrifiers present in the microalgae-bacteria consortia increased the ammonium removal: the ammonium removal rate by nitrifiers and by algae in FPR1 was, respectively, 50(+/-18) and 49(+/-22)mgNH4+-NL-1d-1. Apparently ammonium removal by algae was not significantly different between FPR1 and FPR2. The activity of the nitrifiers did not negatively affect the nitrogen uptake by algae, but improved the total ammonium removal rate of FPR1. PMID- 28892710 TI - Instability mechanisms and early warning indicators for mesophilic anaerobic digestion of vegetable waste. AB - In order to elucidate the instability mechanism, screen early warning indicators, and propose control measures, the mesophilic digestion of vegetable waste (VW) was carried out at organic loading rates (OLR) of 0.5, 1.0, and 1.5g volatile solid (VS)/(Ld). The process parameters, including biogas components, volatile fatty acids (VFA), ammonia, pH, total alkalinity (TA), bicarbonate alkalinity (BA), and intermediate alkalinity (IA), were monitored every day. Digestion was inhibited at OLR of 1.5gVS/(Ld). The primary causes of instability are a high sugar and negligible ammonia content, in addition to the feed without effluent recirculation, which led to BA loss. The ratios of CH4/CO2, VFA/BA, propionate, n butyrate and iso-valerate were selected as early warning indicators. In order to maintain the digestion of VW at a high OLR, control measures including effluent recirculation and trace element addition are recommended. PMID- 28892711 TI - Improvement of hydrogen production from glucose by ferrous iron and biochar. AB - Effects of biochar (BC) and ferrous iron (Fe2+) additions on hydrogen (H2) production from glucose were investigated using batch experiment. The glucose with both BC and Fe2+ additions were incubated at 37 degrees C for H2 production. As compared with the control group (without BC and Fe2+ additions), the synergic effects of BC and Fe2+ make the lag phase time decease from 4.25 to 2.12h, and H2 yield increase from 158.0 to 234.4ml/g glucose. Moreover, suitable concentrations of BC and Fe2+ serve to enhance volatile fatty acid generation during H2 evolution. These results indicate that H2 production is improved by BC and Fe2+ regulations, where synergic mechanisms are described as follows: BC acts as support carriers of anaerobes and system pH buffers, which promotes the biofilm formation and maintains suitable pH environment; Appropriate Fe2+ concentration can improve hydrogenase activity in H2 production. PMID- 28892712 TI - Relationship between serum total bilirubin levels and mortality in uremia patients undergoing long-term hemodialysis: A nationwide cohort study. AB - BACKGROUND AND AIMS: Previous studies show that serum bilirubin has potent antioxidant effect and is associated with protection from kidney damage and reduce cardiovascular events. The aim of this study was to examine the association of serum total bilirubin level and mortality in uremia patients who underwent hemodialysis. METHODS: This is a nationwide retrospective long-term cohort study. Patients were registered in the Taiwan Renal Registry Data System (TWRDS) from 2005 to 2012. A total of 115,535 hemodialysis patients were surveyed and those with valid baseline total bilirubin (TB) data were enrolled. All-cause mortality was the primary outcome. RESULTS: A total of 47,650 hemodialysis patients followed for 27.6 +/- 12 months, were divided into 3 groups according to different baseline serum total bilirubin levels (0.1-0.3, 0.3-0.7, 0.7-1.2 mg/dL). Mean age was 61.4 +/- 13.6 years, 50% were male, 13% were hepatitis B carriers, and 20% were hepatitis C carriers. Primary outcome was the 3-year mortality. The TB level 0.7-1.2 mg/dL group had high mortality, statistically significant hazard ratio of mortality was 1.14 (crude HR, 95% 1.07-1.20, p < 0.01), and adjusted HR was 1.18 (model 1, 95% CI 1.11-1.25), 1.21 (model 2, 95% CI 1.14-1.29, p < 0.01), 1.44 (model 3, 95% CI 1.06-1.96, p < 0.01), respectively. Sensitivity test showed that after excluding 14,899 patients with hepatitis B or C, or abnormal liver function, the highest level of TB associated with higher significant mortality was still robust. CONCLUSIONS: In our study, high TB level is associated with mortality in uremia patients undergoing long term hemodialysis, but further studies of the different effects of unconjugated or conjugated bilirubin on hemodialysis patients are needed. PMID- 28892713 TI - Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells. AB - BACKGROUND AND AIMS: Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms. METHODS: CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 MUM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1beta, IL-6, IL-8, MCP-1 and TNFalpha) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR. RESULTS: Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1beta, IL-6, IL-8, MCP-1 and TNFalpha) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response. CONCLUSIONS: In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs. PMID- 28892714 TI - Genetic and environmental influences on stability and change in baseline levels of C-reactive protein: A longitudinal twin study. AB - BACKGROUND AND AIMS: Cross-sectional twin and family studies report a moderate heritability of baseline levels of C-reactive protein (CRP), ranging from 0.10 to 0.65 for different age ranges. Here, we investigated the stability and relative impact of genetic and environmental factors underlying serum levels of CRP, using a longitudinal classical twin design. METHODS: A maximum of 6201 female twins from the TwinsUK registry with up to three CRP measurements (i.e. visit 1 [V1], visit 2 [V2] and visit 3 [V3]) over a 10-year follow-up period were included in this study. Structural equation modeling was applied to dissect the observed phenotypic variance into its genetic and environmental components. To estimate the heritability of CRP as well as its genetic and environmental correlations across different time points, a trivariate model was used. RESULTS: Natural log (ln) CRP levels significantly increased from V1 to V2 (p=4.4 * 10-25) and between V1 and V3 (p=1.2 * 10-15), but not between V2 and V3. The median (IQR) follow-up time between V1 and V3 was 9.58 (8.00-10.46) years. Heritability estimates for CRP were around 50% and constant over time (0.46-0.52). Additionally, adjustment for BMI did not meaningfully change the heritability estimates (0.49-0.51). The genetic correlations between visits were significantly smaller than one, ranging from 0.66 to 0.85. CONCLUSIONS: The present study provides evidence for stable heritability estimates of CRP of around 50% with advancing age. However, between visit genetic correlations are significantly lower than 1, indicating emergence of new genetic effects on CRP levels with age. PMID- 28892715 TI - Upper body accelerations during walking are altered in adults with ACL reconstruction. AB - This study was designed to assess and compare the pattern of acceleration from the lower trunk, neck and head regions for individuals with reconstructed ACL compared to healthy controls during walking. Participants with unilateral ACL reconstruction and matched control persons participated in the study. Accelerations were collected using three triaxial accelerometers attached to the head, neck, and lower trunk. Measures of amplitude and signal regularity of the acceleration data were performed. Similarities were seen between both groups with regards to the general acceleration patterns in all three axes. However, the results also revealed that the individuals with ACL reconstruction had significantly greater peak power in the AP direction at higher frequencies, indicating a reduced ability to attenuate frequency signals. Further, the ACL group had a reduced ability to control head motion during gait, as indicated by reduced regularity in VT. Both groups demonstrated a similar pattern of gait related oscillations across the head, neck and trunk segments. However, adults with a reconstructed ACL demonstrated a reduced capacity to compensate for the higher frequency components of the gait signal, which may have led to a decline in head control. Overall, these findings indicate that previous damage to the ACL is not simply localized to the knee joint, but influences upper body control, too. PMID- 28892716 TI - Neuroscience step-down unit admission criteria for patients with intracerebral hemorrhage. AB - OBJECTIVES: The goal of our study is to determine optimal criteria which can be used to avoid admission to neuroscience intensive care units for patients with intracerebral hemorrhage (ICH). PATIENTS AND METHODS: This is a retrospective cohort study of 431 patients with primary ICH from January 2013 to the end of December 2015 and reviewed multiple admitting characteristics. Based on these needs, we tested the following step-down unit admission criteria: Supratentorial ICH, ICH volume <20 cc, no Intraventricular hemorrhage (IVH), systolic BP <200mmHg, no respiratory failure, GCS>=12. We classified 431 patients into two groups; 1-Patients who met step-down unit admission Criteria (71 patients). 2 Patients who didn't meet the criteria (360 patients). RESULTS: In our patients, 16.5% fulfilled the criteria. Length of stay in the ICU was 1.43days in step-down unit admission criteria patients. None of the patients who fulfilled the criteria were readmitted to the ICU, compared to 3 readmissions among the group of patients who did not fulfill the criteria (P=0.82). None of these patients required a neurosurgical procedure vs 47 patients (10.9%) in the other group (P=0.04). Among patients who met the criteria, 83.1% were discharged home or rehab RR 0.33 CI (0.19-0.55), (P<0.0001). CONCLUSION: We propose that patients who fulfill step-down unit admission criteria can be safely monitored in stroke unit and they have no need for ICU admission. Further studies are needed to validate these criteria in a prospective manner. PMID- 28892717 TI - Predictors of hearing outcomes following low-dose stereotactic radiosurgery in patients with vestibular schwannomas: A retrospective cohort review. AB - OBJECTIVES: Hearing deterioration is a major concern for hearing-preserved patients with vestibular schwannomas who are treated with stereotactic radiosurgery (SRS). Thus, determining which patients are more likely to have worse hearing outcomes following SRS may facilitate clinicians in deciding whether conservative policy should be applied in the interest of hearing preservation. This study aimed to define the predictors of hearing outcomes following SRS. PATIENTS AND METHODS: This retrospective study included 100 patients who underwent low-dose SRS (12- to 13-Gy marginal dose) for vestibular schwannomas between January 2004 and January 2014. Clinical factors and hearing outcomes following radiosurgery were reviewed. RESULTS: All patients had serviceable hearing at diagnosis and prior to SRS. The median follow-up period was 6.5years (range, 3-10years). The hearing preservation rate in the first, third, and fifth year after radiosurgery was 89%, 68%, and 63%, respectively. A mean cochlear dose lower than 4Gy was a favorable predictor of hearing outcome. Maximal cochlear dose, patient age, pre-treatment pure-tone average, and imaging characteristics were not associated with post-treatment hearing preservation. Our study showed an accelerated rate of deterioration of serial pure-tone average in the first 3years, followed by a more gradual decline after radiosurgery. CONCLUSION: Our results suggest that cochlear dose constraint is the most crucial factor for hearing preservation. This study provides insight into the rate of hearing preservation and the pattern of hearing deterioration following radiosurgery and can help clinicians advise patients of hearing outcomes following SRS. PMID- 28892718 TI - Insight into the effects of modifying chromophores on the performance of quinoline-based dye-sensitized solar cells. AB - A series of organic dyes based on quinoline as an electron-deficient pi-linker, were designed and synthesized for dye sensitized solar cells (DSSC) application. These push-pull conjugated dyes, sharing same anchoring group with distinctive electron-rich donating groups such as N,N-diethyl (DEA-Q), 3,6-dimethoxy carbazole (CBZ-Q), bis(4-butoxyphenyl)amine (BPA-Q), were synthesized by Riley oxidation of CH3 followed by Knoevenagel condensation of the corresponding aldehyde precursors 2a-c with cyanoacrylic acid. The optical, electrochemical, theoretical calculation and photovoltaic properties with these three dyes were systematically investigated. Compared to DEA-Q and CBZ-Q, BPA-Q possesses better light harvesting properties with regard to extended conjugate length, red-shifted intramolecular charge transfer band absorption and broaden light-responsive IPCE spectrum, resulting in a greater short circuit photocurrent density output. BPA-Q also has improved open-circuit voltage due to the apparent large charge recombination resistance. Consequently, assembled with iodine redox electrolytes, the device with BPA-Q achieved the best overall conversion efficiency value of 3.07% among three dyes under AM 1.5G standard conditions. This present investigation demonstrates the importance of various N-substituent chromophores in the prevalent D-pi-A type organic sensitizers for tuning the photovoltaic performance of their DSSCs. PMID- 28892719 TI - Spectroscopic and DFT investigation on the photo-chemical properties of a push pull chromophore: 4-Dimethylamino-4'-nitrostilbene. AB - 4-Dimethylamino-4'-nitrostilbene (DANS), a pi-conjugated push-pull molecule, has been investigated by means of a combined spectroscopic and computational approach. When the Raman excitation is close to the visible electronic transition of DANS, vibrational bands not belonging to DANS appear in the spectra, increasing with the laser power. These bands are observed at room temperature in the solid phase, but not at low temperature or in solution, and we interpret them as due to a thermally-activated photoreaction occurring under laser irradiation in the visible spectral region. Density-functional calculations correctly reproducing the electronic and vibrational spectra of DANS, describe the charge transfer process, indicate that an azo-derivative is the product of the photoreaction of DANS and provide a reasonable interpretation of this process. PMID- 28892720 TI - Physicians-in-training are not prepared to prescribe medical marijuana. AB - BACKGROUND: While medical marijuana use is legal in more than half of U.S. states, evidence is limited about the preparation of physicians-in-training to prescribe medical marijuana. We asked whether current medical school and graduate medical educational training prepare physicians to prescribe medical marijuana. METHODS: We conducted a national survey of U.S. medical school curriculum deans, a similar survey of residents and fellows at Washington University in St. Louis, and a query of the Association of American Medical Colleges (AAMC) Curriculum Inventory database for keywords associated with medical marijuana. RESULTS: Surveys were obtained from 101 curriculum deans, and 258 residents and fellows. 145 schools were included in the curriculum search. The majority of deans (66.7%) reported that their graduates were not at all prepared to prescribe medical marijuana, and 25.0% reported that their graduates were not at all prepared to answer questions about medical marijuana. The vast majority of residents and fellows (89.5%) felt not at all prepared to prescribe medical marijuana, while 35.3% felt not at all prepared to answer questions, and 84.9% reported receiving no education in medical school or residency on medical marijuana. Finally, only 9% of medical school curriculums document in the AAMC Curriculum Inventory database content on medical marijuana. CONCLUSIONS: Our study highlights a fundamental mismatch between the state-level legalization of medical marijuana and the lack of preparation of physicians-in-training to prescribe it. With even more states on the cusp of legalizing medical marijuana, physician training should adapt to encompass this new reality of medical practice. PMID- 28892722 TI - Behavior of farmers in regard to erosion by water as reflected by their farming practices. AB - The interplay between natural site conditions and farming raises erosion by water above geological background levels. We examined the hypothesis that farmers take erosion into account in their farming decisions and switch to farming practices with lower erosion risk the higher the site-specific hazard becomes. Erosion since the last tillage was observed from aerial orthorectified photographs for 8100 fields belonging to 1879 farmers distributed across Bavaria (South Germany) and it was modeled by the Universal Soil Loss Equation using highly detailed input data (e.g., digital terrain model with 5*5m2 resolution, rain data with 1*1km2 and 5min resolution, crop and cropping method from annual field-specific data from incentive schemes). Observed and predicted soil loss correlated closely, demonstrating the accuracy of this method. The close correlation also indicted that the farmers could easily observe the degree of recent erosion on their fields, even without modelling. Farmers clearly did not consider erosion in their decisions. When natural risk increased, e.g. due to steeper slopes, they neither grew crops with lower erosion potential, nor reduced field size, nor used contouring. In addition, they did not compensate for the cultivation of crops with higher erosion potential by using conservation techniques like mulch tillage or contouring, or by reducing field size. Only subsidized measures, like mulch tillage or organic farming, were applied but only at the absolute minimum that was necessary to obtain subsidies. However, this did not achieve the reduction in erosion that would be possible if these measures had been fully applied. We conclude that subsidies may be an appropriate method of reducing erosion but the present weak supervision, which assumes that farmers themselves will take erosion into account and that subsidies are only needed to compensate for any disadvantages caused by erosion-reducing measures, is clearly not justified. PMID- 28892723 TI - Evaluation of a novel test design to determine uptake of chemicals by plant roots. AB - A new hydroponic study design to determine uptake of chemicals by plant roots was tested by (i) investigating uptake of [14C]-1,2,4-triazole by wheat plants in a ring test with ten laboratory organizations and (ii) studying uptake of ten other radiolabelled chemicals by potato, tomato or wheat plants in two laboratories. Replicate data from the ring test were used to calculate plant uptake factor (PUF) values (uptake into roots and shoots) and transpiration stream concentration factor (TSCF) values (uptake into shoots). Average PUF for 1,2,4 triazole was 0.73 (n=39, 95% confidence interval (CI): 0.64, 0.82) and the corresponding TSCF value was 1.03 (n=49, 95% CI: 0.76, 1.3). Boxplots and subsequent classification tree analysis of PUF and TSCF values showed that potential outlier values were >1.38 and were observed for PUF replicates with low biomass increase (ratio of final to initial biomass <=1.739) and small initial biomass (<=1.55g) and for TSCF replicates with an increase in biomass of <0.67g over a period of eight days. Considering only valid replicate data, average values of PUF and TSCF were 0.65 (n=33, 95% CI: 0.57, 0.73) and 0.64 (n=39, 95% CI: 0.58, 0.70). The additional experiments with ten chemicals and three plant species showed that uptake was low for polar substances of high molecular weight (>=394g/mol) and that TSCF values increased with log Kow values of the tested chemicals ranging from -1.54 to 1.88 (polynomial equation with R2=0.64). A cluster analysis for three of the compounds that were tested on wheat and tomato indicated that the plant uptake was mainly determined by the substance. Overall, the findings show that the hydroponic study design allows for reliable quantification of plant uptake over a range of compound/crop combinations. PMID- 28892725 TI - Supporting graduate nurse transition to practice through a quality assurance feedback loop. AB - This mixed-method study focused on new graduate nurses and their transition to practice. Transition to practice can be a time of heightened stress and anxiety, leaving many new graduates disillusioned and dissatisfied with their work. The study explored how satisfaction levels with transition may improve during their first year, using a unique approach of a continuous quality assurance feedback loop. This assurance framework is utilised in hospitality, automotive and supply chain logistics and in health, primarily to monitor patient outcomes. However, an association with graduate nurse satisfaction has not been previously reported. Graduate nurses from two health services completed a short survey questionnaire every four weeks for 12 months. De-identified aggregated data was sent to health service management, giving them an opportunity to integrate the findings with the objective of potentially increasing graduate satisfaction ratings. Quantitative findings showed no statistical significance of graduate nurse satisfaction scores between health services, however, one health service consistently outperformed the other. Qualitative findings drawn from a seminar and interviews confirmed that one health service took a more proactive stance with the monthly reports, communicating the results to ward managers. Outcomes reflected a greater commitment of support and an overall increase of satisfaction scores. PMID- 28892724 TI - Effect of biochar amendment on compost organic matter composition following aerobic composting of manure. AB - Biochar, a material defined as charred organic matter applied in agriculture, is suggested as a beneficial additive and bulking agent in composting. Biochar addition to the composting feedstock was shown to reduce greenhouse gas emissions and nutrient leaching during the composting process, and to result in a fertilizer and plant growth medium that is superior to non-amended composts. However, the impact of biochar on the quality and carbon speciation of the organic matter in bulk compost has so far not been the focus of systematic analyses, although these parameters are key to determine the long-term stability and carbon sequestration potential of biochar-amended composts in soil. In this study, we used different spectroscopic techniques to compare the organic carbon speciation of manure compost amended with three different biochars. A non-biochar amended compost served as control. Based on Fourier-transformed infrared (FTIR) and 13C nuclear magnetic resonance (NMR) spectroscopy we did not observe any differences in carbon speciation of the bulk compost independent of biochar type, despite a change in the FTIR absorbance ratio 2925cm-1/1034cm-1, that is suggested as an indicator for compost maturity. Specific UV absorbance (SUVA) and emission-excitation matrixes (EEM) revealed minor differences in the extractable carbon fractions, which only accounted for ~2-3% of total organic carbon. Increased total organic carbon content of biochar-amended composts was only due to the addition of biochar-C and not enhanced preservation of compost feedstock C. Our results suggest that biochars do not alter the carbon speciation in compost organic matter under conditions optimized for aerobic decomposition of compost feedstock. Considering the effects of biochar on compost nutrient retention, mitigation of greenhouse gas emissions and carbon sequestration, biochar addition during aerobic composting of manure might be an attractive strategy to produce a sustainable, slow release fertilizer. PMID- 28892726 TI - A safety culture training program enhanced the perceptions of patient safety culture of nurse managers. AB - Positive perceptions of patient safety culture are associated with lower rates of adverse events, but they have not been widely established in many health care organizations. The purpose of this study is to examine the impacts of a safety culture training program (SCTP) on enhancing the perceptions of patient safety in nurse managers. This was a quasi-experimental design. 83 nurse managers were recruited from five randomly selected 2nd level hospitals. Sixty-seven nurse managers received training under the educational SCTP. The Hospital Survey on Patient Safety Culture (HSPSC) and Chinese Safety Attitudes Questionnaire (C-SAQ) were administered just before and six months after the educational program. The data of hospital-acquired pressure ulcers, patient falls, and unplanned extubations were collected. The total positive scores of HSPSC were significantly improved and four dimensions of C-SAQ significantly increased six months after SCTP. The rate of patient falls and rate of hospital-acquired pressure ulcers decreased significantly six months post SCTP. In conclusion, nurse manager participation in a SCTP can enhance the perceptions of patient safety and reduce the rates of adverse events. More rigorous trials with larger numbers of participants and a control group are needed to strengthen the conclusions. PMID- 28892721 TI - Glial and neuroinflammatory targets for treating substance use disorders. AB - BACKGROUND: The plenary session at the 2016 Behavior, Biology and Chemistry: Translational Research in Addiction Conference focused on glia as potential players in the development, persistence and treatment of substance use disorders. Glia partake in various functions that are important for healthy brain activity. Drugs of abuse alter glial cell activity producing several perturbations in brain function that are thought to contribute to behavioral changes associated with substance use disorders. Consequently, drug-induced changes in glia-driven processes in the brain represent potential targets for pharmacotherapeutics treating substance use disorders. METHODS: Four speakers presented preclinical and clinical research illustrating the effects that glial modulators have on abuse-related behavioral effects of psychostimulants and opioids. This review highlights some of these findings and expands its focus to include other research focused on drug-induced glia abnormalities and glia-focused treatment approaches in substance use disorders. RESULTS: Preclinical findings show that drugs of abuse induce neuroinflammatory signals and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Preclinical and clinical studies testing the effects of glial modulators show general effectiveness in reducing behaviors associated with substance use disorders. CONCLUSIONS: The contribution of drug-induced glial activity continues to emerge as an intriguing target for substance use disorder treatments. Clinical investigations of glial modulators have yielded promising results on substance use measures and indicate that they are generally safe and well-tolerated. However, results have not been entirely positive and more questions remain for continued exploration in the development and testing of glial-directed treatments for substance use disorders. PMID- 28892727 TI - A review of simulation-enhanced, team-based cardiopulmonary resuscitation training for undergraduate students. AB - Cardiopulmonary resuscitation training is an essential element of clinical skill development for healthcare providers. The International Liaison Committee on Resuscitation has described issues related to cardiopulmonary resuscitation and emergency cardiovascular care education. Educational interventions have been initiated to try to address these issues using a team-based approach and simulation technologies that offer a controlled, safe learning environment. The aim of the study is to review and synthesize published studies that address the primary question "What are the features and effectiveness of educational interventions related to simulation-enhanced, team-based cardiopulmonary resuscitation training?" We conducted a systematic review focused on educational interventions pertaining to cardiac arrest and emergencies that addressed this main question. The findings are presented together with a discussion of the effectiveness of various educational interventions. In conclusion, student attitudes toward interprofessional learning and simulation experiences were more positive. Research reports emphasized the importance of adherence to established guidelines, adopting a holistic approach to training, and that preliminary training, briefing, deliberate practices, and debriefing should help to overcome deficiencies in cardiopulmonary resuscitation training. PMID- 28892728 TI - 'Pre-Run, Re-Run': An innovative research capacity building exercise. AB - Within higher education it is ironic that experienced and novice researchers rarely take the opportunity to come together to share their research - whether these be to discuss findings, puzzles or developing projects. Within this paper, an innovative strategy building on these assumptions is described. It is entitled: 'Pre-run, Re-run' and is a learning community where specific processes are modelled by all to help build professional communication, collegial respect, and scholarship. Our evaluation showed that there is value in bringing together researchers especially when they have diverse profiles. Also, mixing experience with naivety, by inviting professors and junior staff to fraternize equally, offers the possibility for wide ranging discussion, as well as sharing a range of successful techniques, knowledge of the big picture and ways around obstacles that would otherwise be off-putting for novices. The less experienced perspective can equally be revitalizing because newcomers to scholarship often bring a fresh focus and enthusiasm and energy for practice. While this was a local innovation, which may not be generalizable to all settings, others hoping to bring together disciplines may benefit from utilizing the successful methods to build a productive, mixed research culture. PMID- 28892730 TI - Approaches to modelling radioactive contaminations in forests - Overview and guidance. AB - Modelling the radionuclide cycle in forests is important in case of contamination due to acute or chronic releases to the atmosphere and from underground waste repositories. This article describes the most important aspects to consider in forest model development. It intends to give an overview of the modelling approaches available and to provide guidance on how to address the quantification of radionuclide transport in forests. Furthermore, the most important gaps in modelling the radionuclide cycle in forests are discussed and suggestions are presented to address the variability of forest sites. PMID- 28892731 TI - A new integrated care pathway for ambulance attended severe hypoglycaemia in the East of England: The Eastern Academic Health Science Network (EAHSN) model. AB - AIMS: We developed a new clinical integrated pathway linking a regional Ambulance Trust with a severe hypoglycaemia (SH) prevention team. We present clinical data from the first 2000 emergency calls taken through this new clinical pathway in the East of England. METHODS: SH patients attended by Ambulance crew receive written information on SH avoidance, and are contacted for further education through a new regional SH prevention team. All patients are contacted unless they actively decline. RESULTS: Median age (IQR) was 67 (50-80) years, 23.6% of calls were for patients over 80years old, and patients more than 90years old were more common than 20-25year olds in this population. Most calls were for patients (84.9%) who were insulin treated, even those over 80years (75%). One - third of patients attended after a call were unconscious on attendance. 5.6% of patients in this call population had 3 or more ambulance call outs, and they generated 17.6% of all calls. In total, 728 episodes (36.4%) were repeat calls. Insulin related events were clinically more severe than oral hypoglycaemic related events. Patients conveyed to hospitals (13.8%) were significantly older, with poorer recovery in biochemical hypoglycaemia after ambulance crew attendance. Only 19 (1%) opted out of further contact. Patients were contacted by the SH prevention team after a median 3 (0-6) days. The most common patient self - reported cause for their SH episode was related to perceived errors in insulin management (31.4%). CONCLUSIONS: This new clinical service is simple, acceptable to patients, and a translatable model for prevention of recurrent SH in this largely elderly insulin treated SH population. PMID- 28892729 TI - Immune mechanisms of food allergy and its prevention by early intervention. AB - The environmental factors driving the increase in food allergies are unclear and possibly involve dual exposure to allergens, microbiome-driven effects or other mechanisms. Until they can be better understood, early intervention aiming at establishing oral tolerance provides an effective way to decrease the window-of risk when children may develop allergic sensitisation to foods due to the absence of a protective immune response. Thus, the recent LEAP (Learning Early About Peanut allergy) and LEAP-On studies achieved a high level of peanut allergy prevention by early introduction of peanuts in the infants diet and conveyed more information regarding the evolution of IgE and IgG4 antibody responses to food antigens over time. PMID- 28892732 TI - Clinical significance of diabetes likely induced by statins: Evidence from a large population-based cohort. AB - AIM: To provide information on the extent to which type 2 diabetes more likely induced by statins affects the risk of macrovascular complications compared to diabetes unlikely induced by statins. METHODS: The 84,828 residents in the Italian Lombardy Region who were newly treated with statins between 2003 and 2005 were followed from the index statin prescription until 2009 (step-1 follow-up) to identify those starting antidiabetic therapy. The proportion of days of follow-up covered by statins measured adherence with statins. Cohort members who experienced diabetes were 1:3 matched with those who did not developed diabetes for gender, age and previous adherence with statin treatment. The 3321 diabetic - non-diabetic sets, were followed from the initial antidiabetic therapy until 2012 (step-2 follow-up) to estimate the hazard ratio (HR), and 95% Confidence Interval (CI), for macrovascular complications (proportional hazard models) associated with diabetes separately in each category of adherence with statins. RESULTS: During the step-1 follow-up, the risk of new-onset diabetes increased progressively with increasing adherence with statins. During the step-2 follow up, the risk of macrovascular complications associated with diabetes decreased progressively from 1.70 (1.18-2.44), 1.41 (1.17-1.70), 1.30 (1.07-1.57) until 1.10 (0.40-2.80) as adherence with statins during the step-1 follow-up increased. CONCLUSIONS: Type 2 diabetes lost its association with increasing macrovascular risk when previous adherence with statins was very high, and thus the chance of its induction by the drug greater. Statin-dependent type 2 diabetes might be prognostically less adverse than diabetes unlikely induced by statins. PMID- 28892733 TI - Depression in chronic ketamine users: Sex differences and neural bases. AB - Chronic ketamine use leads to cognitive and affective deficits including depression. Here, we examined sex differences and neural bases of depression in chronic ketamine users. Compared to non-drug using healthy controls (HC), ketamine-using females but not males showed increased depression score as assessed by the Center of Epidemiological Studies Depression Scale (CES-D). We evaluated resting state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC), a prefrontal structure consistently implicated in the pathogenesis of depression. Compared to HC, ketamine users (KU) did not demonstrate significant changes in sgACC connectivities at a corrected threshold. However, in KU, a linear regression against CES-D score showed less sgACC connectivity to the orbitofrontal cortex (OFC) with increasing depression severity. Examined separately, male and female KU showed higher sgACC connectivity to bilateral superior temporal gyrus and dorsomedial prefrontal cortex (dmPFC), respectively, in correlation with depression. The linear correlation of sgACC-OFC and sgACC-dmPFC connectivity with depression was significantly different in slope between KU and HC. These findings highlighted changes in rsFC of the sgACC as associated with depression and sex differences in these changes in chronic ketamine users. PMID- 28892735 TI - Expression of the chemokine receptors CCR1 and CCR2B is up-regulated in peripheral blood B cells upon EBV infection and in established lymphoblastoid cell lines. AB - In immunocompetent individuals, EBV establishes in B cells an asymptomatic lifelong latent infection controlled by the immune system. Chemokine receptors regulate immune system function. CCR1 and CCR2 share protein sequence similarity and exert responses to multiple chemokines. The role of these receptors in B cells is largely unknown. We show that the mRNA and functional protein expression of CCR1 and CCR2 is induced in ex vivo B cells upon EBV infection and in established lymphoblastoid cell lines (LCLs). The CCR1 and CCR2B ORF transcripts were determined in LCLs. In contrast, in both the EBV-negative and EBV-positive Burkitt lymphoma cell lines, neither the CCR1, CCR2A, and CCR2B ORF transcripts nor their corresponding proteins were detected. Our data suggest that CCR1/CCR2B could be involved in clearing EBV-infected latency III B cells in immunocompetent individuals via directing the migration of these cells and attracting the chemokines-expressing immune cells. PMID- 28892736 TI - Five distinct reassortants of H5N6 highly pathogenic avian influenza A viruses affected Japan during the winter of 2016-2017. AB - To elucidate the evolutionary pathway, we sequenced the entire genomes of 89 H5N6 highly pathogenic avian influenza viruses (HPAIVs) isolated in Japan during winter 2016-2017 and 117 AIV/HPAIVs isolated in Japan and Russia. Phylogenetic analysis showed that at least 5 distinct genotypes of H5N6 HPAIVs affected poultry and wild birds during that period. Japanese H5N6 isolates shared a common genetic ancestor in 6 of 8 genomic segments, and the PA and NS genes demonstrated 4 and 2 genetic origins, respectively. Six gene segments originated from a putative ancestral clade 2.3.4.4 H5N6 virus that was a possible genetic reassortant among Chinese clade 2.3.4.4 H5N6 HPAIVs. In addition, 2 NS clusters and a PA cluster in Japanese H5N6 HPAIVs originated from Chinese HPAIVs, whereas 3 distinct AIV-derived PA clusters were evident. These results suggest that migratory birds were important in the spread and genetic diversification of clade 2.3.4.4 H5 HPAIVs. PMID- 28892737 TI - Misdeed of the need: towards computational accounts of transition to addiction. AB - Drug addiction is a complex behavioral and neurobiological disorder which, in an emergent brain-circuit view, reflects a loss of prefrontal top-down control over subcortical circuits governing drug-seeking and drug-taking. We first review previous computational accounts of addiction, focusing on cocaine addiction and on prevalent dopamine-based positive-reinforcement and negative-reinforcement computational models. Then, we discuss a recent computational proposal that the progression to addiction is unlikely to result from a complete withdrawal of the goal-oriented decision system in favor the habitual one. Rather, the transition to addiction would arise from a drug-induced alteration in the structure of organismal needs which reorganizes the goal structure, ultimately favoring predominance of drug-oriented goals. Finally, we outline unmet challenges for future computational research on addiction. PMID- 28892734 TI - Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram. AB - Little is known about the acute effects of antidepressant treatments on brain glutamate and gamma-amino-butyric acid (GABA) levels, and their association with clinical response. Using proton magnetic resonance spectroscopy (1H-MRS) we examined longitudinally the effects of citalopram on glutamine/glutamate ratios and GABA levels in the pregenual anterior cingulate cortex (pgACC) of individuals with major depressive disorder (MDD). We acquired 1H-MRS scans at baseline and at days 3, 7, and 42 of citalopram treatment in nineteen unmedicated individuals with MDD. Ten age- and sex-matched non-depressed comparison individuals were scanned once. The association between 1) baseline metabolites and 2) change in metabolites from baseline to each time point and clinical response (change in Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline to day 42) was assessed by longitudinal regression analysis using generalized estimating equations. Contrary to our hypotheses, no significant associations emerged between glutamate metabolites and clinical response; however, greater increases (or smaller decreases) in pgACC GABA levels from baseline to days 3 and 7 of citalopram treatment were significantly associated with clinical response. These findings suggest that an acute change in GABA levels in pgACC predicts, and possibly mediates, later clinical response to citalopram treatment in individuals with MDD. PMID- 28892738 TI - Independent operation of implicit working memory under cognitive load. AB - Implicit working memory (WM) has been known to operate non-consciously and unintentionally. The current study investigated whether implicit WM is a discrete mechanism from explicit WM in terms of cognitive resource. To induce cognitive resource competition, we used a conjunction search task (Experiment 1) and imposed spatial WM load (Experiment 2a and 2b). Each trial was composed of a set of five consecutive search displays. The location of the first four displays appeared as per pre-determined patterns, but the fifth display could follow the same pattern or not. If implicit WM can extract the moving pattern of stimuli, response times for the fifth target would be faster when it followed the pattern compared to when it did not. Our results showed implicit WM can operate when participants are searching for the conjunction target and even while maintaining spatial WM information. These results suggest that implicit WM is independent from explicit spatial WM. PMID- 28892739 TI - Maturation of arousals during day and night in infants with non-smoking and smoking mothers. PMID- 28892741 TI - Effect of diet with omega-3 in basal brain electrical activity and during status epilepticus in rats. AB - Western diets are high in saturated fat and low in omega-3. Certain animals cannot produce omega-3 from their own lipids, making it necessary for it to be acquired from the diet. However, omega-3s are important components of the plasma membrane, and altering their proportions can promote physical and chemical alterations in the membranes, which may modify neuronal excitability. These alterations occur in healthy individuals, as well as in patients with epilepsy who are more sensitive to changes in brain electrical activity. This study evaluated the effect of a diet supplemented with omega-3 on the basal brain electrical activity both before and during status epilepticus in rats. To evaluate the brain electrical activity, we recorded electrocorticograms (ECoG) of animals both with and without omega-3 supplementation before and during status epilepticus induced by pilocarpine. Calculation of the average brain wave power by a power spectrum revealed that omega-3 supplementation reduced the average power of the delta wave by 20% and increased the average power of the beta wave by 45%. These effects were exacerbated when status epilepticus was induced in the animals supplemented with omega-3. The animals with and without omega-3 supplementation exhibited increases in basal brain electrical activities during status epilepticus. The two groups showed hyperactivity, but no significant difference between them was noted. Even though the brain activity levels observed during status epilepticus were similar between the two groups, neuron damage to the animals supplemented with omega-3 was more slight, revealing the neuroprotective effect of the omega-3. PMID- 28892740 TI - Human OGG1 activity in nucleosomes is facilitated by transient unwrapping of DNA and is influenced by the local histone environment. AB - If unrepaired, damage to genomic DNA can cause mutations and/or be cytotoxic. Single base lesions are repaired via the base excision repair (BER) pathway. The first step in BER is the recognition and removal of the nucleobase lesion by a glycosylase enzyme. For example, human oxoguanine glycosylase 1 (hOGG1) is responsible for removal of the prototypic oxidatively damaged nucleobase, 8-oxo 7,8-dihydroguanine (8-oxoG). To date, most studies of glycosylases have used free duplex DNA substrates. However, cellular DNA is packaged as repeating nucleosome units, with 145 base pair segments of DNA wrapped around histone protein octamers. Previous studies revealed inhibition of hOGG1 at the nucleosome dyad axis and in the absence of chromatin remodelers. In this study, we reveal that even in the absence of chromatin remodelers or external cofactors, hOGG1 can initiate BER at positions off the dyad axis and that this activity is facilitated by spontaneous and transient unwrapping of DNA from the histones. Additionally, we find that solution accessibility as determined by hydroxyl radical footprinting is not fully predictive of glycosylase activity and that histone tails can suppress hOGG1 activity. We therefore suggest that local nuances in the nucleosome environment and histone-DNA interactions can impact glycosylase activity. PMID- 28892742 TI - Toxicity, teratogenicity and antibacterial activity of posterior salivary gland (PSG) toxin from the cuttlefish Sepia pharaonis (Ehrenberg, 1831). AB - Toxins from the posterior salivary gland (PSG) of cuttlefishes are known toxins with pronounced toxicity. In the present study, ionic peptide rich PSG toxin from the cuttlefish S. pharaonis was isolated by ion exchange chromatography and purified by Reversed Phase High Performance Liquid Chromatography (RP-HPLC), with active fraction at a retention time of 26min. The net protein content of the PSG toxin was estimated to be 46.6mg at a proximate molecular weight of~50kDa. Fourier Transform Infrared Spectroscopy (FT-IR) of PSG toxin revealed the presence of alcoholic OH, primary NH, alkyl CH and conjugated CONH functional groups. Circular Dichroism (CD) spectroscopy and K2D analysis of the PSG toxin confirmed the presence of secondary structure with 36.77% alpha-helix,12.31% beta sheet and 50.92% random coil. Scanning Electron Microscopy (SEM) of the PSG toxin eluted amberlite IRA 900 Cl- resin showed surface abrasion and corrosive blebbing. Energy Dispersive X-ray Spectrometry (EDX) analysis of PSG toxin treated resin revealed increase in nitrogen and sulphur content corresponding to amino acid composition. Teratogenicity of PSG toxin against Zebrafish embryo demonstrated developmental malformations and premature hatching at a maximum tolerated dose of 1.25MUM. The PSG toxin (50MUM) exhibited commendable inhibitory activity with pronounced zone of inhibition against gram E. coli (10mm) and K. pneumonia (10mm). The results strongly demonstrate the toxicity of the ionic peptide rich PSG toxin from S. pharaonis and its exploitation for its promise as a potential antibacterial agent of the future. PMID- 28892743 TI - Ion-macromolecule interactions studied with model polyurethanes. AB - HYPOTHESIS: The solubility and self-assembly of macromolecules in solution can be tuned by the presence of different salts. Natural proteins have been long manipulated with the aid of salts, and natural silk is processed in the gland tip across a gradient of different salts which modifies its solubility. Hence, the comprehensive understanding of the role of ion-macromolecule interactions should pave the way towards a biomimetic processing of macromolecules. EXPERIMENTS: A model polyurethane catiomer (PU+) with high density of hydrogen donors and acceptors (similar to proteins) has been designed and synthesized in order to study ion-macromolecule interactions by means of dynamic light scattering (DLS), infrared spectroscopy (FTIR) and nuclear magnetic resonance (13C NMR). FINDINGS: The PU+ solubility in the presence of different salts exhibited a reversed anion Hofmeister series (i.e., the anion ability to precipitate the PU+ was F-123pg/mg for chronic excessive alcohol consumption, 59-123pg/mg for moderate alcohol consumption, and <59pg/mg for alcohol abstinence. In light of these results, nails may be a useful alternative to hair samples for monitoring of long-term alcohol consumption, e.g., in cases where hair is not available. Further studies are needed to establish cut-off values for EtG levels in nails. PMID- 28892762 TI - Risk factors and symptoms associated with maternal and neonatal complications in women with uterine rupture. A 16 years multicentric experience. AB - OBJECTIVE: high maternal and fetal morbidity and mortality levels have been associated with uterine ruptures. The aims of our study were to determine risk factors and signs for maternal and fetal complications in patients with uterine rupture. STUDY DESIGN: retrospective, population-based study, in all Val d'Oise public obstetrics departments, France, between 2000 and 2015. All patients with uterine rupture were analyzed using medical records. To identify risk factors and signs for maternal and fetal complications, patients were divided into two groups according to adverse maternal and fetal outcomes or not, and compared. RESULTS: During the study period, 126 patients with complete uterine rupture were identified. In all, 74 (58.7%) had maternal and fetal complications, and these were more frequently observed in patients with unscarred uterus (N=18; p<0.001 and OR 5.52, 95% CI 2.09-14.55), lateral injured uterus (N=21; p<0.001), after labour induction (N=21, p=0.01 and OR 3.69, 95% CI 1.22-13.53), and when a sudden onset of abdominal pain, in patients with previous successful epidural analgesia, occurred (75.9% vs 39.2%, p<0.001 and OR 4.88, 95% CI 1.9-12.13). CONCLUSION: Unscarred and lateral ruptures of uterus were associated with maternal vascular injuries, and higher maternal and fetal complications. Sudden onset of abdominal pain in woman with previous successful epidural analgesia might be predictive of complicated uterine rupture. PMID- 28892763 TI - Passion fruit by-product and fructooligosaccharides stimulate the growth and folate production by starter and probiotic cultures in fermented soymilk. AB - Two starter cultures (Streptococcus (St.) thermophilus ST-M6 and TA-40) and five probiotic strains (St. thermophilus TH-4, Lactobacillus (Lb.) acidophilus LA-5, Lb. rhamnosus LGG, Lb. fermentum PCC, and Lb. reuteri RC-14) were used to ferment different soymilk formulations supplemented with passion fruit by-product and/or fructo-oligosaccharides (FOS) with the aim of increasing folate concentrations. Growth and folate production of individual strains were evaluated and the results used to select co-cultures. Both St. thermophilus ST-M6 and TH-4 were the best folate producers and were able to increase the folate content of all soymilk formulations when used alone or in co-culture with lactobacilli strains, especially in the presence of both passion fruit by-product and FOS. Thus, passion fruit by-product and FOS could be used as dietary ingredients to stimulate the folate production by selected bacterial strains during the fermentation of soymilk. It was also shown that vitamin production by microorganisms is strain-dependent and may also be influenced by nutritional and environmental conditions. PMID- 28892764 TI - A European multicientre study on the comparison of HBV viral loads between VERIS HBV assay and Roche COBAS(r) TAQMAN(r) HBV test, Abbott RealTime HBV assay, Siemens VERSANT HBV assay, and Qiagen artus HBV RG kit. AB - BACKGROUND: Hepatitis B viral load testing is essential to treatment and monitoring decisions in patients with chronic Hepatitis B. Beckman Coulter has developed the VERIS HBV Assay (Veris) for use on the fully automated DxN VERIS Molecular Diagnostics System.1 OBJECTIVES: To evaluate the clinical performance of the Veris HBV Assay at multiple EU laboratories STUDY DESIGN: Method comparison was performed with a total of 344 plasma specimens from HBV infected patients tested with Veris and COBAS(r) TaqMan(r) HBV Test (Cobas), 207 specimens tested with Veris and RealTime HBV Assay (RealTime), 86 specimens tested with Veris and VERSANT(r) HBV Assay (Versant), and 74 specimens tested with Veris and artus(r) HBV RG PCR kit (artus). RESULTS: Bland-Altman analysis showed average bias of -0.46 log10 IU/mL between Veris and Cobas, -0.46 log10IU/mL between Veris and RealTime, -0.36 log10IU/mL between Veris and Versant, and -0.12 log10IU/mL between Veris and artus. Bias was consistent across the assay range. Patient monitoring results using Veris demonstrated similar viral load trends over time to Cobas, RealTime, and artus. CONCLUSIONS: The VERIS HBV Assay demonstrated comparable clinical performance, with varying degrees of negative bias, compared to other currently marketed assays for HBV DNA monitoring. This negative bias should be taken into consideration if switching monitoring methods to Veris. PMID- 28892765 TI - The performance of Luminex ARIES(r) Flu A/B & RSV and Cepheid Xpert(r) Flu/RSV XC for the detection of influenza A, influenza B, and respiratory syncytial virus in prospective patient samples. AB - BACKGROUND: The demand for rapid, accurate viral testing has increased the number of assays available for the detection of viral pathogens. One of the newest FDA cleared platforms is the Luminex ARIES(r) Flu A/B & RSV, which is a fully automated, real-time PCR-based assay used for detection of influenza A, influenza B, and respiratory syncytial virus (RSV). OBJECTIVES: We sought to compare the performance of Luminex ARIES(r) Flu A/B & RSV assay to the Cepheid Xpert(r) Flu/RSV XC assay for rapid Flu and RSV testing. STUDY DESIGN: A series of consecutive nasopharyngeal specimens received in the clinical microbiology laboratory during peak influenza season at a major academic center in Chicago, IL, were prospectively tested, using both the ARIES(r) Flu A/B & RSV and Xpert(r) Flu/RSV XC assays, side by side. Discrepant results were tested on the BioFire FilmArray(r) Respiratory Panel for resolution. RESULTS: A total of 143 consecutive nasopharyngeal specimens, obtained from patients ranging from six months to ninety-three years in age were received between January 1st, 2017 and March 21st, 2017. There was 96.6% agreement between the two assays for detection influenza A, 100% agreement for detection influenza B and RSV, and 98.9% agreement for negative results. The Xpert(r) Flu/RSV XC performed with an average turn-around time of approximately 60min, compared to the ARIES(r) Flu A/B & RSV of approximately 120min. Both assays were equally easy to perform, with a similar amount of hands-on technologist time for each platform. CONCLUSIONS: Overall, these results indicate that both tests are comparable in terms of result agreement and technical ease-of-use. The Xpert(r) Flu/RSV XC assay did produce results with less turn-around-time, approximately 60min quicker than the ARIES(r) Flu A/B & RSV. PMID- 28892766 TI - The cognitive profile of myotonic dystrophy type 1: A systematic review and meta analysis. AB - OBJECTIVE: To examine the cognitive profile of patients with myotonic dystrophy type 1 (DM1) on the basis of a systematic review and meta-analysis of the literature. METHODS: Embase, Medline and PsycInfo were searched for studies reporting >=1 neuropsychological test in both DM1 patients and healthy controls. Search, data extraction and risk of bias analysis were independently performed by two authors to minimize error. Neuropsychological tests were categorized into 12 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for tests administered in >=5 studies. RESULTS: DM1 participants demonstrated a significantly worse performance compared to controls in all cognitive domains. Effect sizes ranged from -.33 (small) for verbal memory to -1.01 (large) for visuospatial perception. Except for the domains global cognition, intelligence and social cognition, wide confidence intervals (CIs) were associated with moderate to marked statistical heterogeneity that necessitates careful interpretation of results. Out of the individual tests, the Rey-Osterrieth complex figure-copy (both non-verbal memory and visuoconstruction) showed consistent impairment with acceptable heterogeneity. CONCLUSION: In DM1 patients, cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory and visuospatial functioning. Although DM1 is a heterogeneous disorder, our study shows that meta-analysis is feasible, contributes to the understanding of brain involvement and may direct bedside testing. The protocol for this study has been registered in PROSPERO (International prospective register of systematic reviews) under ID: 42016037415. PMID- 28892767 TI - Negative bias in expression-related mismatch negativity(MMN) in remitted late life depression: An event-related potential study. AB - Negative bias in cognition is closely associated with susceptibility to recurrent episodes of depression. Given the high recurrence rate of depression, previous studies have focused on the attentive level in late-life depression (LLD), but depression relapse is difficult to detect as a lower chief complaint in elderly people. Facial expression mismatch negativity (EMMN) is a tool that can measure cognitive bias in pre-attentive processing. In this study, we sought to explore the cognitive bias in pre-attentive emotional information processing in LLD. Thirty patients with remitted LLD and 30 non-depressed, age- and gender-matched normal controls (NC) were enrolled in this study. Automatic emotional processing was elicited by using an expression-related oddball paradigm in all participants. There were no significant differences in N170 amplitude and latency between remitted LLD and NC. Compared with NC subjects, patients with remitted LLD demonstrated an attenuated mean amplitude of positive and negative EMMN, whereas the mean amplitude of negative EMMN in remitted LLD was much larger than that of positive EMMN. Our findings suggest that although basic processing of facial expressions is intact in remitted LLD, automatic processing of facial expressions in remitted LLD is impaired with a negative bias in cognition. Further investigation of the contributions of negative bias in EMMN to susceptibility to recurrence of LLD is warranted. PMID- 28892768 TI - Advanced oxidation and disinfection processes for onsite net-zero greywater reuse: A review. AB - Net-zero greywater (NZGW) reuse, or nearly closed-loop recycle of greywater for all original uses, can recover both water and its attendant hot-water thermal energy, while avoiding the installation and maintenance of a separate greywater sewer in residential areas. Such a system, if portable, could also provide wash water for remote emergency health care units. However, such greywater reuse engenders human contact with the recycled water, and hence superior treatment. The purpose of this paper is to review processes applicable to the mineralization of organics, including control of oxidative byproducts such as bromate, and maintenance of disinfection consistent with potable reuse guidelines, in NZGW systems. Specifically, TiO2-UV, UV-hydrogen peroxide, hydrogen peroxide-ozone, ozone-UV advanced oxidation processes, and UV, ozone, hydrogen peroxide, filtration, and chlorine disinfection processes were reviewed for performance, energy demand, environmental impact, and operational simplicity. Based on the literature reviewed, peroxone is the most energy-efficient process for organics mineralization. However, in portable applications where delivery of chemicals to the site is a concern, the UV-ozone process appears promising, at higher energy demand. In either case, reverse osmosis, nanofiltration, or ED may be useful in controlling the bromide precursor in make-up water, and a minor side-stream of ozone may be used to prevent microbial regrowth in the treated water. Where energy is not paramount, UV-hydrogen peroxide and UV-TiO2 can be used to mineralize organics while avoiding bromate formation, but may require a secondary process to prevent microbial regrowth. Chlorine and ozone may be useful for maintenance of disinfection residual. PMID- 28892769 TI - Perfluoroalkyl and polyfluoroalkyl substances removal in a full-scale tropical constructed wetland system treating landfill leachate. AB - Landfill leachate is often an important source of emerging organic contaminants including perfluoroalkyl and polyfluoroalkyl substances (PFASs) requiring proper treatment to protect surface water and groundwater resources. This study investigated the occurrence of PFASs in the leachate of a capped landfill site in Singapore and the efficacy of PFASs removal during flow through a constructed wetland (CW) treatment system. The CW treatment system consists of equalization tank, aeration lagoons, sedimentation tank, reed beds and polishing ponds. Target compounds included 11 perfluoroalkyl acids (PFAAs) (7 perfluoroalkyl carboxylic acids (PFCAs) and 4 perfluoroalkane sulfonates (PFSAs)) and 7 PFAA precursors. Although total PFASs concentrations in the leachate varied widely (1269 to 7661 ng/L) over the one-year sampling period, the PFASs composition remained relatively stable with PFCAs consistently being predominant (64.0 +/- 3.8%). Perfluorobutane sulfonate (PFBS) concentrations were highly correlated with total PFASs concentrations and could be an indicator for the release of PFASs from this landfill. The release of short-chain PFAAs strongly depended on precipitation whereas concentrations of the other PFASs appeared to be controlled by partitioning. Overall, the CW treatment system removed 61% of total PFASs and 50 96% of individual PFASs. PFAAs were removed most efficiently in the reed bed (42 49%), likely due to the combination of sorption to soils and sediments and plant uptake, whereas most of the PFAA precursors (i.e. 5:3 fluorotelomer carboxylate (5:3 acid), N-substituted perfluorooctane sulfonamides (N-MeFOSAA and N-EtFOSAA)) were removed in the aeration lagoon (>55%) by biodegradation. The sedimentation tank and polishing ponds were relatively inefficient, with only 7% PFASs removal. PMID- 28892770 TI - New model of chlorine-wall reaction for simulating chlorine concentration in drinking water distribution systems. AB - Accurate modelling of chlorine concentrations throughout a drinking water system needs sound mathematical descriptions of decay mechanisms in bulk water and at pipe walls. Wall-reaction rates along pipelines in three different systems were calculated from differences between field chlorine profiles and accurately modelled bulk decay. Lined pipes with sufficiently large diameters (>500 mm) and higher chlorine concentrations (>0.5 mg/L) had negligible wall-decay rates, compared with bulk-decay rates. Further downstream, wall-reaction rate consistently increased (peaking around 0.15 mg/dm2/h) as chlorine concentration decreased, until mass-transport to the wall was controlling wall reaction. These results contradict wall-reaction models, including those incorporated in the EPANET software, which assume wall decay is of either zero-order (constant decay rate) or first-order (wall-decay rate reduces with chlorine concentration). Instead, results are consistent with facilitation of the wall reaction by biofilm activity, rather than surficial chemical reactions. A new model of wall reaction combines the effect of biofilm activity moderated by chlorine concentration and mass-transport limitation. This wall reaction model, with an accurate bulk chlorine decay model, is essential for sufficiently accurate prediction of chlorine residuals towards the end of distribution systems and therefore control of microbial contamination. Implementing this model in EPANET-MSX (or similar) software enables the accurate chlorine modelling required for improving disinfection strategies in drinking water networks. New insight into the effect of chlorine on biofilm can also assist in controlling biofilm to maintain chlorine residuals. PMID- 28892771 TI - Exclusive e-cigarette use predicts cigarette initiation among college students. AB - INTRODUCTION: An increasing body of research indicates that use of electronic nicotine delivery systems (ENDS) predicts cigarette initiation. However, no studies examine if risk for cigarette initiation varies for exclusive ENDS users versus users of ENDS and other tobacco products. This study examined if: a) cigarette-naive young adults (i.e., never cigarette users) who ever used ENDS had a greater odds of initiating cigarettes than non-ENDS users over a 1.5year period and b) the odds of cigarette initiation was consistent across exclusive ENDS users and users of ENDS and at least one tobacco product. METHODS: Participants were 2558 cigarette-naive 18-25year old (M=19.71; SD=1.61) students from 24 Texas colleges who participated in a four-wave study, with six months between each wave. RESULTS: Overall, 11% of students reported cigarette initiation by wave 4. Of those, 20.1% were wave 1 ENDS users and 8.4% were non-ENDS users. Multivariable, multilevel discrete-time hazard models indicated that wave 1 ENDS use predicted subsequent cigarette initiation, over and above the significant effects of cigarette use susceptibility, family-of-origin tobacco use, friend cigarette use, and other tobacco use. Additional findings indicated that exclusive ENDS users had a greater odds than non-users of subsequent cigarette initiation. Among users of alternative tobacco products, ENDS users did not have a greater odds of initiation than non-ENDS users. CONCLUSION: Findings extend existing research by showing that ENDS use by young adults is a specific risk factor for later cigarette initiation and not an extension of a constellation of existing tobacco use behaviors. PMID- 28892772 TI - Multi-class of endocrine disrupting compounds in aquaculture ecosystems and health impacts in exposed biota. AB - Fishes are a major protein food source for humans, with a high economic value in the aquaculture industry. Because endocrine disrupting compounds (EDCs) have been introduced into aquatic ecosystems, the exposure of humans and animals that depend on aquatic foods, especially fishes, should be seriously considered. EDCs are emerging pollutants causing global concern because they can disrupt the endocrine system in aquatic organisms, mammals, and humans. These pollutants have been released into the environment through many sources, e.g., wastewater treatment plants, terrestrial run-off (industrial activities, pharmaceuticals, and household waste), and precipitation. The use of pharmaceuticals, pesticides, and fertilizers for maintaining and increasing fish health and growth also contributes to EDC pollution in the water body. Human and animal exposure to EDCs occurs via ingestion of contaminated matrices, especially aquatic foodstuffs. This paper aims to review human EDC exposure via fish consumption. In respect to the trace concentration of EDCs in fish, types of instrument and clean-up method are of great concerns. PMID- 28892773 TI - Assessment of toxicity of selenium and cadmium selenium quantum dots: A review. AB - This paper reviews the current understanding of the toxicity of selenium (Se) to terrestrial mammalian and aquatic organisms. Adverse biological effects occur in the case of Se deficiencies, associated with this element having essential biological functions and a narrow window between essentiality and toxicity. Several inorganic species of Se (-2, 0, +4, and +6) and organic species (monomethylated and dimethylated) have been reported in aquatic systems. The toxicity of Se in any given sample depends not only on its speciation and concentration, but also on the concomitant presence of other compounds that may have synergistic or antagonistic effects, affecting the target organism as well, usually spanning 2 or 3 orders of magnitude for inorganic Se species. In aquatic ecosystems, indirect toxic effects, linked to the trophic transfer of excess Se, are usually of much more concern than direct Se toxicity. Studies on the toxicity of selenium nanoparticles indicate the greater toxicity of chemically generated selenium nanoparticles relative to selenium oxyanions for fish and fish embryos while oxyanions of selenium have been found to be more highly toxic to rats as compared to nano-Se. Studies on polymer coated Cd/Se quantum dots suggest significant differences in toxicity of weathered vs. non-weathered QD's as well as a significant role for cadmium with respect to toxicity. PMID- 28892774 TI - Simultaneous leaching of arsenite, arsenate, selenite and selenate, and their migration in tunnel-excavated sedimentary rocks: II. Kinetic and reactive transport modeling. AB - Predicting the fates of arsenic (As) and selenium (Se) in natural geologic media like rocks and soils necessitates the understanding of how their various oxyanionic species behave and migrate under dynamic conditions. In this study, geochemical factors and processes crucial in the leaching and transport of arsenite (AsIII), arsenate (AsV), selenite (SeIV) and selenate (SeVI) in tunnel excavated rocks of marine origin were investigated using microscopic/extraction techniques, column experiments, dissolution-precipitation kinetics and one dimensional reactive transport modeling. The results showed that evaporite salts were important because aside from containing As and Se, they played crucial roles in the evolution of pH and concentrations of coexisting ions, both of which had strong effects on adsorption-desorption reactions of As and Se species with iron oxyhydroxide minerals/phases. The observed leaching trends of AsV, AsIII, SeIV and SeVI were satisfactorily simulated by one-dimensional reactive transport models, which predict that preferential adsorptions of AsV and SeIV were magnified by geochemical changes in the columns due to water flow. Moreover, our results showed that migrations of AsIII, SeIV and SeVI could be predicted adequately by 1D solute transport with simple activity-K'd approach, but surface complexation was more reliable to simulate adsorption-desorption behavior of AsV. PMID- 28892775 TI - Challenges and perspectives in the immunotherapy of Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) was one of the first few cancers to be cured first with radiotherapy alone and then with a combination of chemotherapy and radiotherapy. Around 80% of the patients with HL will be cured by first-line therapy. However, the ionising radiation not only produces cytotoxicity but also induces alterations in the microenvironment, and patients often struggle with the long term consequences of these treatments, such as cardiovascular disorders, lung diseases and secondary malignancies. Hence, it is essential to improve treatments while avoiding delayed side-effects. Immunotherapy is a promising new treatment option for Hodgkin lymphoma, and anti- programmed death-1 (PD1) agents have produced striking results in patients with relapsed or refractory disease. The microenvironment of Hodgkin lymphoma appears to be unique in the field of human disease: the malignant Reed-Sternberg cells only constitute 1% of the cells in the lymphoma, but they are surrounded by an extensive immune infiltrate. Reed Sternberg cells exhibit 9p24.1/PD-L1/PD-L2 copy number alterations and genetic rearrangements associated with programmed cell death ligand 1/ ligand 2 (PD-L1/2) overexpression, together with major histocompatibility complex-I (MHC-I) and major histocompatibility complex-II (MHC-II) downregulation (which may facilitate the tumour's immune evasion). Although HL may be a situation in which defective immune surveillance is restored by anti-PD1 therapy, it challenges our current explanation of how anti-PD1 agents work because MHC-I expression is required for CD8-T-cell-mediated tumour antigen recognition. Here, we review recent attempts to understand the defects in immune recognition in HL and to design an optimal evidence-based treatment for combination with anti-PD1. PMID- 28892776 TI - Clinical trial simulations in paediatric oncology: A feasibility study from the Innovative Therapies for Children with Cancer Consortium. AB - INTRODUCTION: Paediatric dose-finding studies are challenging to perform due to ethical reasons, the limited number of available patients and restricted number of blood samples. In certain cases, the adult pharmacokinetic (PK) exposure can be used as target for dose finding in paediatrics. The aim of this study was to investigate the performance of a paediatric phase I dose-finding clinical trial in silico. METHODS: Using an adult pharmacokinetic model, clinical trial simulations were performed to determine the power of a proposed clinical trial design. Power was defined as the fraction of 1000 trials with an area under the plasma concentration-time curve at steady-state (AUC0-24,SS) within +/-20% of the adult geometric mean AUC0-24,SS. Different scenarios were compared to optimise the design of the trial. To show the potential of this framework for similar compounds, the current simulation method was also evaluated with adult and paediatric data from literature on sunitinib. RESULTS: At the starting dose of 300 mg/m2, the power of the trial design was 66.9%. Power did not improve by dose escalation to 350 mg/m2 (65.3%). Power increased to 78.9% with inclusion of 10 patients per trial. Paediatric sunitinib PK data were adequately predicted from adult data with a mean prediction error of 1.80%. CONCLUSION: The performance of PK-based clinical trials in paediatrics can be predicted and optimised through PK modelling and simulation. Application of this approach enables clinical trials in paediatrics to be performed as efficiently as possible while protecting the child from unnecessary harm. PMID- 28892777 TI - Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations and colorectal cancer risk. AB - BACKGROUND: The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) released in 2007 eight recommendations for cancer prevention on body fatness, diet and physical activity. Our aim is to evaluate the relation between adherence to these recommendations and colorectal cancer (CRC) risk. METHODS: We pooled data from two Italian case-control studies including overall 2419 patients with CRC and 4723 controls. Adherence to the WCRF/AICR guidelines was summarised through a score incorporating seven of the WCRF/AICR recommendations, with higher scores indicating higher adherence to the guidelines. Odds ratios (ORs) of colorectal cancer were estimated using multiple logistic regression models. RESULTS: Higher adherence to the WCRF/AICR recommendations was associated with a significantly reduced CRC risk (OR 0.67, 95% confidence interval, CI, 0.56-0.80 for a score >=5 versus <3.5), with a significant trend of decreasing risk for increasing adherence (p < 0.001). Consistent results were found for colon (OR 0.67) and rectal cancer (OR 0.67). Inverse associations were observed with the diet-specific WCRF/AICR score (OR 0.71, 95% CI, 0.61-0.84 for >=3.5 versus <2.5 points) and with specific recommendations on body fatness (OR 0.82, 95% CI, 0.70-0.97), physical activity (OR 0.86, 95% CI, 0.75-1.00), foods and drinks that promote weight gain (OR 0.70, 95% CI, 0.56-0.89), foods of plant origin (OR 0.56, 95% CI, 0.42-0.76), limiting alcohol (OR 0.87, 95% CI, 0.77-0.99) and salt intake (OR 0.63, 95% CI, 0.48 0.84). CONCLUSION: Our study indicated that adherence to the WCRF/AICR recommendations is inversely related to CRC risk. PMID- 28892779 TI - A new method for measuring the contact angles from digital images of liquid drops. AB - The drop hitting a solid surface may be symmetric or asymmetric, which depends on the surface texture and external force orientations. The accurate measurement of the contact angle is of fundamental importance for the purpose of scientific research, while having a substantial role in a wide range of practical applications. This paper presents a new image processing based method, as a computational scheme to measure the inclination angle of apparent edge curves in digital images. The main concept of the scheme is the emulation of a moving goniometer mask coupled with a Gaussian weighted function, which does not require edge fitting with analytic curves for the angle calculation. The algorithm produces as follow: allocating the exact position of the contact points by Harris corner detector function, selecting a series of points on the drop boundary near the contact points, setting goniometric mask on each given point and calculating the angles, applying the Gaussian weighted average function on the calculated angles and measure the objective contact angle. The scheme is tested on several images from recent studies in the available literature. The comparison between analytical and calculated angles shows less than 1 degrees difference. PMID- 28892778 TI - An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling. AB - High programmed cell death 1 ligand 1 (PD-L1) expression in tumour tissues was associated with poor outcomes in non-small cell lung cancer (NSCLC) due to evasion of tumour immune surveillance. However, the role of PD-L1 in tumour invasion and resistance to tyrosine kinase inhibitor (TKI) treatments is not fully understood. Here, we provide evidence to support the involvement of PD-L1 expression in the invasiveness and TKI resistance in NSCLC cells by increased Bcl 2-associated athanogene-1 (BAG-1) expression. The upregulation of BAG-1 transcription by PD-L1 was verified by constructing the BAG-1 promoters using the polymerase chain reaction (PCR) and deletion mutations for luciferase reporter assays. The results indicated that C/EBPbeta phosphorylation by extracellular signal-regulated kinase (ERK) signalling was responsible for PD-L1-mediated BAG-1 transcription. Mechanistically, the PD-L1-induced BAG-1 expression reciprocally increased PD-L1 expression due to persistent activation of ERK signalling, and it consequently conferred TKI resistance in NSCLC cells. The mechanistic action of this cell model was further confirmed by an animal model, affirming that PD-L1 conferred tumour invasiveness and TKI resistance via persistent activation of ERK signalling by the PD-L1/BAG-1 axis. We therefore suggest a combination of an ERK inhibitor with a TKI as a potential strategy for conquering PD-L1-mediated tumour invasion and TKI resistance in NSCLC patients whose tumours harbour high PD L1/high BAG-1 expression. PMID- 28892780 TI - Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms. AB - Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds. These different responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways. PMID- 28892781 TI - Family accommodation of anxiety symptoms in youth undergoing intensive multimodal treatment for anxiety disorders and obsessive-compulsive disorder: Nature, clinical correlates, and treatment response. AB - BACKGROUND: Family accommodation is associated with a range of clinical features including symptom severity, functional impairment, and treatment response. However, most previous studies in children and adolescents investigated family accommodation in samples of youth with obsessive-compulsive disorder (OCD) or anxiety disorders receiving non-intensive outpatient services. AIMS: In this study, we aimed to investigate family accommodation of anxiety symptoms in a sample of youth with clinical anxiety levels undergoing an intensive multimodal intervention for anxiety disorders or OCD. PROCEDURES: We first assessed the internal consistency of the Family Accommodation Scale - Anxiety (FASA). We next examined family accommodation presentation and correlates. RESULTS: The FASA showed high internal consistency for all subscales and total score, and good item and subscale correlations with the total score. All parents reported at least mild accommodation, and the mean levels of family accommodation were particularly high. Child age, anxiety severity, and comorbid depressive symptoms predicted baseline accommodation. However, the association between anxiety severity and family accommodation no longer remained significant after adding the other factors to the model. In addition, family accommodation partially mediated the relationship between anxiety severity and functional impairment. Finally, post treatment changes in family accommodation predicted changes in symptom severity and functional impairment. CONCLUSIONS: These findings suggest the FASA is an appropriate tool to assess family accommodation in intensive treatment samples. Further, they underline the importance of addressing family accommodation in this population given the particularly high levels of accommodating behaviors and the evidence for adverse outcomes associated with this feature. PMID- 28892782 TI - A nontoxic, photostable and high signal-to-noise ratio mitochondrial probe with mitochondrial membrane potential and viscosity detectivity. AB - Herein, we reported a yellow emission probe 1-methyl-4-(6-morpholino-1, 3-dioxo 1H-benzo[de]isoquinolin-2(3H)-yl) pyridin-1-ium iodide which could specifically stain mitochondria in living immortalized and normal cells. In comparison to the common mitochondria tracker (Mitotracker Deep Red, MTDR), this probe was nontoxic, photostable and ultrahigh signal-to-noise ratio, which could real-time monitor mitochondria for a long time. Moreover, this probe also showed high sensitivity towards mitochondrial membrane potential and intramitochondrial viscosity change. Consequently, this probe was used for imaging mitochondria, detecting changes in mitochondrial membrane potential and intramitochondrial viscosity in physiological and pathological processes. PMID- 28892783 TI - Internal supravesical hernia repaired via the anterior approach alone: A case report. AB - INTRODUCTION: Internal supravesical hernia is one of the rarest types of inguinal hernia. The hernial orifice is surrounded by the transverse vesical fold, median umbilical fold, and medial umbilical fold. PRESENTATION OF CASE: A 75-year-old male presented with lower abdominal pain and nausea. Plain abdominal CT showed that the bladder was suppressed by small bowel near the left internal inguinal ring. A part of the small bowel wall seemed to be inlaid, and so the patient was diagnosed with a strangulated left inguinal hernia. The hernia repair operation was performed via the anterior approach. There was no internal hernial sac found, but there was a walnut-sized mass in the properitoneal space. A diagnosis was made intraoperatively of internal supravesical hernia with strangulated small bowel. Small bowel resection and hernial orifice closure were performed. DISCUSSION: Although internal supravesical hernia can present with distinctive CT findings, preoperative diagnosis is extremely difficult. Internal supravesical hernia in previous reports has been repaired via open laparotomy or laparoscopic surgery; however, we successfully repaired this intraoperatively-diagnosed internal supravesical hernia by the anterior approach alone. CONCLUSION: The patient with internal supravesical hernia diagnosed intraoperatively could be treated via the anterior approach alone successfully. Depending on the situation, the anterior approach can be an option. PMID- 28892784 TI - Ileal angiodysplasia presentation as a bowel obstruction: A case report. AB - INTRODUCTION: Angiodysplasia is a common vascular abnormality of the gastrointestinal tract, found in the elderly and most frequently revealed by gastrointestinal bleeding. We report an original case of ileal angiodysplasia in an 83-year-old woman presenting as a bowel obstruction. CASE PRESENTATION: An 83 year-old woman with a medical history of chronic untreated anemia, presented with cardinal symptoms of bowel obstruction. Computed tomography revealed diffuse ileal wall thickening with multiple zones of stenosis, which were aggravated by an ileal perforation and associated with vascular abnormalities compatible with angiodysplasia. Surgery confirmed the imaging findings. A large resection importing one meter of ileum was performed. The pathology report of the resected specimen revealed ischemic lesions of ileum associated with ileal angiodysplasia. The postoperative period was marked by an acute dehydration in the patient who died 3 weeks after surgery. DISCUSSION: Angiodysplastic lesions develop with aging due to chronic low-grade intermittent obstruction of submucosal veins. These lesions are the result of increased contractility at the level of muscularis propria, leading to congestion of the capillaries and failure of pre capillary sphincters, resulting in the formation of small arteriovenous collaterals. The acquired arteriovenous malformation consisting of multiple shunts with rapid blood flow may result in inadequate oxygenation of a segment of the intestine and lead to ischemia and eventually wall thickening, stenosis and even perforation of the small bowel. CONCLUSION: Angiodysplasia should be kept in the back of one's mind as one of the causes of acute abdomen and bowel obstruction, especially in elderly people suffering from occult gastrointestinal bleeding. PMID- 28892785 TI - Parental gamma irradiation induces reprotoxic effects accompanied by genomic instability in zebrafish (Danio rerio) embryos. AB - Gamma radiation represents a potential health risk to aquatic and terrestrial biota, due to its ability to ionize atoms and molecules in living tissues. The effects of exposure to 60Co gamma radiation in zebrafish (Danio rerio) were studied during two sensitive life stages: gametogenesis (F0: 53 and 8.7mGy/h for 27 days, total doses 31 and 5.2Gy) and embryogenesis (9.6mGy/h for 65h; total dose 0.62Gy). Progeny of F0 exposed to 53mGy/h showed 100% mortality occurring at the gastrulation stage corresponding to 8h post fertilization (hpf). Control and F0 fish exposed to 8.7mGy/h were used to create four lines in the first filial generation (F1): control, G line (irradiated during parental gametogenesis), E line (irradiated during embryogenesis) and GE line (irradiated during parental gametogenesis and embryogenesis). A statistically significant cumulative mortality of GE larva (9.3%) compared to controls was found at 96 hpf. E line embryos hatched significantly earlier compared to controls, G and GE (48-72 hpf). The deformity frequency was higher in G and GE, but not E line compared to controls at 72 hpf. One month after parental irradiation, the formation of reactive oxygen species (ROS) was increased in the G line, but did not significantly differ from controls one year after parental irradiation, while at the same time point it was significantly increased in the directly exposed E and GE lines from 60 to 120 hpf. Lipid peroxidation (LPO) was significantly increased in the G line one year after parental irradiation, while significant increase in DNA damage was detected in both the G and GE compared to controls and E line at 72 hpf. Radiation-induced bystander effects, triggered by culture media from tissue explants and observed as influx of Ca2+ ions through the cellular membrane of the reporter cells, were significantly increased in 72 hpf G line progeny one month after irradiation of the parents. One year after parental irradiation, the bystander effects were increased in the E line compared to controls, but not in progeny of irradiated parents (G and GE lines). Overall, this study showed that irradiation of parents can result in multigenerational oxidative stress and genomic instability in irradiated (GE) and non-irradiated (G) progeny of irradiated parents, including increases in ROS formation, LPO, DNA damage and bystander effects. The results therefore highlight the necessity for multi- and transgenerational studies to assess the environmental impact of gamma radiation. PMID- 28892786 TI - Gestational diabetes mellitus and exposure to ambient air pollution and road traffic noise: A cohort study. AB - BACKGROUND: Road traffic is a main source of air pollution and noise. Both exposures have been associated with type 2 diabetes, but associations with gestational diabetes mellitus (GDM) have been studied less. OBJECTIVES: We aimed to examine single and joint associations of exposure to air pollution and road traffic noise on GDM in a prospective cohort. METHODS: We identified GDM cases from self-reports and hospital records, using two different criteria, among 72,745 singleton pregnancies (1997-2002) from the Danish National Birth Cohort. We modeled nitrogen dioxide (NO2) and noise from road traffic (Lden) exposure at all pregnancy addresses. RESULTS: According to the two diagnostic criteria: the Danish clinical guidelines, which was our main outcome, and the WHO standard during recruitment period, a total of 565 and 210 women, respectively, had GDM. For both exposures no risk was evident for the common Danish criterion of GDM. A 10-MUg/m3 increase in NO2 exposure during first trimester was, however, associated with an increased risk of WHO-GDM (adjusted odds ratio (OR)=1.24; 95% confidence interval (CI): 1.03, 1.49). The corresponding OR associated with a 10 dB higher road traffic noise level was 1.15 (0.94 to 1.18). In mutually adjusted models the OR for NO2 remained similar 1.22 (0.98, 1.53) whereas that for road traffic noise decreased to 1.03 (0.80, 1.32). Significant associations were also observed for exposure averaged over the 2nd and 3rd trimesters and the full pregnancy. CONCLUSIONS: No risk was evident for the common Danish criterion of GDM. NO2 was associated with higher risk for GDM according to the WHO criterion, which might be due to selection bias. PMID- 28892787 TI - Hepatoprotective effects of crocin on biochemical and histopathological alterations following acrylamide-induced liver injury in Wistar rats. AB - The objective of the present study is the treatment of oxidative damage caused by acrylamide induced oxidative stress in rats with the administration of a strong antioxidant, namely crocin. High acrylamide (AA) levels have genotoxic, carcinogenic and neurotoxic effects on living organisms. In the present study, 40 Wistar rats were randomly divided into four equal groups. These groups were control, acrylamide (25mg/kg), crocin (50mg/kg), acrylamide+crocin (25mg/kg acrylamide and 50mg/kg crocin) groups. At the end of the application, biochemical and histological variations were examined in liver and blood samples. It was observed that acrylamide administration significantly decreased liver GSH and TAS levels when compared to the control group. On the contrary, it was also observed that AST, ALT, ALP, SOD and CAT activities and TOS and MDA levels increased as a result of acrylamide administration. Histopathological examinations demonstrated inflammatory cell infiltration, hepatocellular necrosis and hemorrhage areas in AA group liver sections. Furthermore, intracytoplasmic vacuolization was detected in hepatocytes. After crocin treatment, it was observed that GSH and TAS levels increased while AST, ALT, ALP, SOD and CAT activities and TOS and MDA levels decreased. Significant decreases were observed in inflammatory cell infiltration and vascular congestion in liver sections and intracytoplasmic vacuolization in hepatocytes after the crocin treatment, while no hepatocellular necrosis and hemorrhages were observed. In the present study, it was demonstrated that crocin treatment removed acrylamide induced liver damage due to the strong antioxidant properties of crocin. PMID- 28892788 TI - Triptolide suppresses growth and hormone secretion in murine pituitary corticotroph tumor cells via NF-kappaB signaling pathway. AB - Triptolide is a principal diterpene triepoxide from the Chinese medical plant Tripterygium wilfordii Hook. f., whose extracts have been utilized in dealing with diverse diseases in traditional Chinese medicine for centuries. Recently, the antitumor effect of triptolide has been found in several pre-clinical neoplasm models, but its effect on pituitary corticotroph adenomas has not been investigated so far. In this study, we are aiming to figure out the antitumor effect of triptolide and address the underlying molecular mechanism in AtT20 murine corticotroph cell line. Our results demonstrated that triptolide inhibited cell viability and colony number of AtT20 cells in a dose- and time-dependent pattern. Triptolide also suppressed proopiomelanocortin (Pomc) mRNA expression and extracellular adrenocorticotropic hormone (ACTH) secretion in AtT20 cells. Flow cytometry prompted that triptolide leaded to G2/M phase arrest, apoptosis program and mitochondrial membrane depolarization in AtT20 cells. Moreover, dose dependent activation of caspase-3 and decreased Bcl2/Bax proportion were observed after triptolide treatment. By western blot analysis we found that triptolide impeded phosphorylation of NF-kappaB p65 subunit and extracellular signal regulated kinase (ERK), along with reduction of cyclin D1, without any impact on other NF-kappaB related protein expression like total p65, p50, IkappaB-alpha, p IkappaB-alpha. Furthermore, the mouse xenograft model revealed the inhibition of tumor growth and hormone secretion after triptolide administration. Altogether this compound might be a potential pharmaceutical choice in managing Cushing's disease. PMID- 28892789 TI - Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Abeta40 and Abeta42 levels by modulating APP processing, up-regulating IDE and LRP1, and down regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. AB - Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-beta (Abeta) accumulation due to abnormal amyloid-beta precursor protein (APP) processing and Abeta metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Abeta metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Abeta generation; APP processing, beta-secretase 1 (BACE1), gamma-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Abeta degradation; insulin degrading enzyme (IDE), Abeta transportation; low density lipoprotein receptor related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Abeta fragment length 1 40 and 1-42 (Abeta40 and Abeta42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of beta- and gamma secretase enzyme activity, and the Abeta degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Abeta generation, degradation and transportation in the rat's brain tissue. PMID- 28892790 TI - YAP1-TEAD1-Glut1 axis dictates the oncogenic phenotypes of breast cancer cells by modulating glycolysis. AB - Altered energy metabolism is a universal property of most cancer cells. The Hippo signaling pathway and its principal downstream effector YAP1 are responsible for tissue homeostasis including organ size, cell proliferation, apoptosis, and differentiation. Dysregulation of the Hippo pathway leads to the activation of YAP1 and further culminates in the development of multiple human cancers. In this study, by loss-of-function assay, we demonstrated that YAP1 contributed to the glycolytic phenotype of breast cancer cells. Knockdown of YAP1 inhibited the extracellular acidification rates, glucose consumption, and lactate production of breast cancer cells. Moreover, YAP1 interacted with TEAD1, exerted their transcriptional control of the functional target, glucose transporter 1 (Glut1). Overexpression of Glut1 restored the inhibitory effects of YAP1 knockdown on glycolysis as demonstrated by glucose consumption and lactate production. Suppression of glycolysis by deprivation of glucose largely compromised the oncogenic roles of YAP1 on cell proliferation, apoptosis, and invasive potential. Taken together, our data identify a novel role of YAP1-TEAD1 pathway in cancer energy metabolism. PMID- 28892791 TI - In vitro, In silico and In vivo Antitumor Activity of Crude Methanolic Extract of Tetilla dactyloidea (Carter, 1869) on DEN Induced HCC in a Rat Model. AB - Tetilla dactyloidea (Carter, 1869) is a marine sponge classified under Demospongia and recent studies have demonstrated that active constituents of Demospongia class have exhibited several potential medical applications. However, no preliminary pharmacological studies have been reported so far. The present investigation was carried out to evaluate the zoo-chemical status, antioxidant potential and anticancer activity of Crude Methanolic Extract of Tetilla dactyloidea (CMETD). Hepatocellular Carcinoma (HCC) was induced in the liver of male Sprague Dawley (SD) rats by treating with diethylnitrosamine (DEN). Nodule incidence, body weight, liver marker enzymes, enzymatic and non-enzymatic antioxidant, phase I metabolizing and liver macromolecular damaging enzymes and immuno-histopathological changes were assessed in DEN and DEN+CMETD treated rats. Oral administration of CMETD at a dose of 400mg/kg body weight to DEN treated rats restored the above parameters to near normal levels compared to control. The biochemical results were consistent with histopathological observations suggesting marked hepatoprotective effect of CMETD in a dose dependent manner. The GCMS of CMETD analysis showed the presence of six compounds. In in silico analysis 9-Octadecenoic acid (Z)-, 2-hydroxy-1-(hydroxymethyl) ethyl ester ligand showed an effective binding energy of -7.1kcal/mol against Cox-2 receptor. The compounds showed desirable pharmacokinetic properties and significant molecular interactions with the HCC receptors. To conclude, our results clearly suggested that CMETD treatment prevented liver damage, protected the antioxidant defense system and possessed anti-carcinogenic potential in DEN induced hepatic carcinoma. PMID- 28892792 TI - Bamboo leaf extract ameliorates cardiac fibrosis possibly via alleviating inflammation, oxidative stress and apoptosis. AB - Previous studies have shown that inflammatory process contributes to the pathogenesis of cardiac damage induced by diabetes mellitus. However, the underlying mechanisms and strategies to alleviate inflammatory injury in the diabetic heart are not fully elucidated. In this study, we investigated the potential role and related mechanism of bamboo leaf extract (BLE) on diabetes induced cardiac fibrosis in rats. Diabetes was induced by streptozocin (STZ) in rats, blood glucose and glycosylated hemoglobin A1c (HbAlc) were measured. Super oxide dismutase (SOD) activity and malondialdehyde (MDA) level in rat heart homogenates were tested using special kits. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by hematoxylin eosin (HE) staining and Masson's trichrome staining. Furthermore, expression of transforming growth factor-beta1 (TGF-beta1), interleukin 6 (IL-6) and Cleaved-cysteinyl aspartate-specific proteinase-3 (Cleaved-caspase-3), and the activity of nuclear factor kappaB (NF-kappaB) were examined by western blot analysis. From the data, we found that the BLE treatment inhibits oxidative stress and improved cardiac function in STZ-induced diabetic rats. BLE treatment significantly ameliorated diabetes-induced myocardial morphological changes and cardiac inflammation. Moreover, the protein levels of TGF-beta1, IL-6,Cleaved-caspase-3 and the nuclear transcription of NF-kappaB in the hearts were markedly reduced in diabetic rats result from BLE treatment. In conclusion, this study suggested that BLE ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats, and this protective effect possibly through inhibiting inflammation, oxidative stress and apoptosis. BLE might serve as a potential therapeutic target for the treatment of the cardiac fibrosis in diabetic patients. PMID- 28892793 TI - Homoisoflavonoids as potential antiangiogenic agents for retinal neovascularization. AB - A number of people worldwide have been suffering from ocular neovascularization that may be treated by a variety of drugs but these may possess adverse effects. Therefore, small antiangiogenic molecules with higher potency and lower toxic effects are intended. However, homoisoflavonoids of natural origin show the potential antiangiogenic effect in ocular neovascularization. These homoisoflavonoids are judged quantitatively in terms of statistical validation through multi-chemometric modeling approaches for the betterment and refinement of their structures required for higher antiangiogenic activity targeted to ocular neovascularization. These approaches may be utilized to design better antiangiogenic homoisoflavonoids. PMID- 28892794 TI - Corrigendum to "Decreased plasma adiponectin among male firefighters with symptoms of post-traumatic stress disorder" [J. Affect. Disord. 221 (2017) 254 258]. PMID- 28892795 TI - Uniform dispersion of cobalt nanoparticles over nonporous TiO2 with low activation energy for magnesium sulfate recovery in a novel magnesia-based desulfurization process. AB - The forced oxidation of magnesium sulfite (MgSO3) aims to not only reclaim the by product in the magnesia desulfurization, but also lower the risk of secondary pollution. The non-porous titanium dioxide nanoparticle was used as a support to prepare the cobalt catalyst (Co-TiO2) in order to expedite the oxidation rate. This fabricated Co-TiO2 was characterized by inductively coupled plasma optical emission spectroscopy (ICP-OES), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), and energy dispersive spectroscopy (EDS) to figure out its catalytic mechanism. The results revealed that the cobalt nanoparticles were uniformly dispersed on the surface of the TiO2 in forms of Co3O4 and Co2O3. The kinetics of the MgSO3 oxidation catalyzed by the prepared Co TiO2 was investigated in a bubbling tank reactor, indicating that the oxidation rate was dependent on the catalyst concentration, oxygen partial pressure, pH value, and the reaction temperature. Compared with the reported porous catalyst (Co-CNTs), the activation energy with the Co-TiO2 (17.29kJmol-1) decreased by 50.9%, resulting in a good catalytic performance in sulfite oxidation. The findings will help advance the industrial application of the novel magnesia desulfurization process. PMID- 28892796 TI - A solid composite microbial inoculant for the simultaneous removal of volatile organic sulfide compounds: Preparation, characterization, and its bioaugmentation of a biotrickling filter. AB - Volatile organic sulfide compounds (VOSCs) are usually resistant to biodegradation, thereby limiting the performance of traditional biotechnology dealing with waste gas containing such pollutants especially in mixture. In this study, a solid composite microbial inoculant (SCMI) was prepared to remove dimethyl sulfide (DMS) and propanethiol (PT). Given that the DMS degradation activity of Alcaligenes sp. SY1 is inducible and the PT-degradation activity of Pseudomonas putida S-1 is constitutive, different strategies are designed for cell cultivation to obtain high VOSC removal rates of SCMI. Compared with the microbial suspension, the prepared SCMI exhibited better storage stability at 4 and 25 degrees C. Inoculation of the SCMI in biotrickling filters (BTFs) could effectively shorten the start-up period and enhance the removal performance. Microbial analysis by Illumina MiSeq indicated that Alcaligenes sp. SY1 and P. putida S-1 might be dominant and persistent among the microbial communities of the BTF during the operation. PMID- 28892797 TI - Study of the intensification of solar photo-Fenton degradation of carbamazepine with ferrioxalate complexes and ultrasound. AB - The intensification of the solar photo-Fenton system with ferrioxalate photoactive complexes and ultrasound applied to the mineralization of 15mg/L carbamazepine aqueous solution (CBZ) was evaluated. The experiments were carried out in a solar compound parabolic collector (CPC) pilot plant reactor coupled to an ultrasonic processor. The dynamic behavior of hydroxyl radicals generated under the different studied reaction systems was discussed. The initial concentrations of hydrogen peroxide and ferrous/oxalic acid and pH were found to be the most significant variables (32.79%, 25.98% and 26.04%, respectively). Under the selected optimal conditions ([H2O2]0=150mg/L; [Fe2+]0=2.5mg/L/[(COOH)2]0=12.1mg/L; pH=5) CBZ was fully degraded after 5min and 80% of TOC was removed using a solar photo-Fenton system intensified with ferrioxalate (SPFF). However, no improvement in the mineralization using SPFF process combined with ultrasound was observed. More mild pH conditions could be used in the SPFF system if compared to the traditional photo-Fenton (pH 3) acidic systems. Finally, a possible reaction pathway for the mineralization of CBZ by the SPFF system was proposed and therein discussed. PMID- 28892798 TI - A novel method for the sequential removal and separation of multiple heavy metals from wastewater. AB - A novel method was developed and applied for the treatment of simulated wastewater containing multiple heavy metals. A sorbent of ZnS nanocrystals (NCs) was synthesized and showed extraordinary performance for the removal of Hg2+, Cu2+, Pb2+ and Cd2+. The removal efficiencies of Hg2+, Cu2+, Pb2+ and Cd2+ were 99.9%, 99.9%, 90.8% and 66.3%, respectively. Meanwhile, it was determined that solubility product (Ksp) of heavy metal sulfides was closely related to adsorption selectivity of various heavy metals on the sorbent. The removal efficiency of Hg2+ was higher than that of Cd2+, while the Ksp of HgS was lower than that of CdS. It indicated that preferential adsorption of heavy metals occurred when the Ksp of the heavy metal sulfide was lower. In addition, the differences in the Ksp of heavy metal sulfides allowed for the exchange of heavy metals, indicating the potential application for the sequential removal and separation of heavy metals from wastewater. According to the cumulative adsorption experimental results, multiple heavy metals were sequentially adsorbed and separated from the simulated wastewater in the order of the Ksp of their sulfides. This method holds the promise of sequentially removing and separating multiple heavy metals from wastewater. PMID- 28892799 TI - A small-scale experimental study on the initial burst and the heterogeneous evolution process before CO2 BLEVE. AB - The sudden rupture of a vessel containing liquefied carbon dioxide (CO2) can generate a boiling liquid expanding vapor cloud explosion (BLEVE). The entire evolution process and mechanism of CO2 BLEVE has not been fully characterized, and its influencing factors have not been systematically examined. In this study, the ejection process and microphase change process in the vessel were recorded by a high-speed camera. Within 20ms, the pressure peaks surpassed the initial values and were considered to be the initiation of a sequence that generated a CO2 BLEVE under certain conditions. In addition, a critical relief caliber with a diameter of 8mm was observed under the initial burst pressures of 3 and 5MPa. This critical relief caliber is essential for risk control and management. About 52ms after the rupture, a heterogeneous nucleation center was formed in the liquefied CO2 in the vessel. Subsequent nucleation center extension and swelling generated another pressure peak. The pressure peak did not surpass the initial pressure value. However, this phenomenon did not eliminate any possible connections between the heterogeneous nucleation process and the CO2 BLEVE. If the conditions had been proper, the explosion could have happened. PMID- 28892800 TI - Polymeric nanoparticle constructs as devices for antibacterial therapy. AB - Diseases related to bacterial infections represent a relevant challenge for public health. Despite the success obtained with the conventional antibiotic therapies, indeed, new drawbacks have been identified. In addition to poor drugs solubility and stability, adverse side effects, and many other factors which together lead to a low patient compliance, the antibiotic resistance and the lack in the development of new antimicrobial agents are the main problems. On the basis of these considerations, the research interest is focused on the exploration of new strategies able to circumvent these drawbacks improving the efficacy of current antibiotics. In this context, nanosized systems, which allow to enhance both the pharmacokinetic profiles and the mechanism of action of drugs, play a key role. PMID- 28892801 TI - Minimally invasive probes for programmed microfluidic delivery of molecules in vivo. AB - Site-specific drug delivery carries many advantages of systemic administration, but is rarely used in the clinic. One limiting factor is the relative invasiveness of the technology to locally deliver compounds. Recent advances in materials science and electrical engineering allow for the development of ultraminiaturized microfluidic channels based on soft materials to create flexible probes capable of deep tissue targeting. A diverse set of mechanics, including micro-pumps and functional materials, used to deliver the drugs can be paired with wireless electronics for self-contained and programmable operation. These first iterations of minimally invasive fluid delivery devices foreshadow important advances needed for clinical translation. PMID- 28892802 TI - Regulation of cellulose synthesis in response to stress. AB - The cell wall is a complex polysaccharide network that provides stability and protection to the plant and is one of the first layers of biotic and abiotic stimuli perception. A controlled remodeling of the primary cell wall is essential for the plant to adapt its growth to environmental stresses. Cellulose, the main component of plant cell walls is synthesized by plasma membrane-localized cellulose synthases moving along cortical microtubule tracks. Recent advancements demonstrate a tight regulation of cellulose synthesis at the primary cell wall by phytohormone networks. Stress-induced perturbations at the cell wall that modify cellulose synthesis and microtubule arrangement activate similar phytohormone based stress response pathways. The integration of stress perception at the primary cell wall and downstream responses are likely to be tightly regulated by phytohormone signaling pathways in the context of cellulose synthesis and microtubule arrangement. PMID- 28892803 TI - Characterization of the key odorants of fennel essential oils of different regions using GC-MS and GC-O combined with partial least squares regression. AB - The key odorants and the aroma profile of six fennel essential oils from different regions were investigated by using gas chromatography-olfactometry (GC O), gas chromatography-mass spectrometry (GC-MS) and sensory evaluation. A total of 30 volatile compounds were determined by GC-O with aroma extract dilution analysis (AEDA) and the odor activity values (OAV) of them were calculated. Among these compounds, alpha-pinene, alpha-phellandrene, limonene, alpha-cubebene, beta caryophyllene, estragole, alpha-humulene, trans-anethole, delta-cadinene and p anisaldehyde contributed greatly to the aroma of fennel essential oil due to their high flavor dilution (FD) factors and high OAVs. The aroma of fennel essential oils was described by 7 sensory terms as spicy, woody, grassy, floral, musty, sweet and green, and was correlated to the key odorants by partial least squares regression (PLSR). It was showed that spicy, woody, grassy, musty and green attributes were covaried well with aroma compounds. In addition, hierarchical cluster analysis (HCA) was used to find out the similarities among different samples and the result indicated that three main groups were identified. PMID- 28892804 TI - Generation of a Potential Prognostic Matrix for Papillary Thyroid Cancer that Assesses Age, Tumor Size, Transforming Growth Factor-beta, and BRAFV600E Mutation. AB - BACKGROUND: Papillary thyroid cancer (PTC) is the most common differentiated thyroid cancer and is responsible for 80-90% of thyroid cancer cases. Despite typically excellent prognoses, these subclinical low-risk cancers are often treated aggressively by surgical thyroidectomy. Consequently, the objective of this study was to generate a prognostic matrix to be used prior to PTC intervention. METHODS: In this study, 80 PTC patients were assessed. Following adjustment for sex, logistic regression analysis showed that BRAFV600E mutation, transforming growth factor beta (TGF-beta) expression, age, and tumor size are risk factors that can affect tumor clinical stage (p < 0.05). Based on the results of this analysis, we generated a matrix that incorporated 4 variables: patient age, tumor size, BRAFV600E mutation, and TGF-beta expression. RESULTS: We observed that the corresponding area under curve was as high as 0.91. The sensitivity and specificity of the model were 94.74 and 83.61%, respectively. These values are significantly higher than those generated from single indexes. CONCLUSION: As a result of this analysis, it is hoped that the resultant matrix can be utilized during clinical diagnosis and treatment prior to thyroid nodule surgery. PMID- 28892805 TI - An Evaluation of the Central Nervous System Medication Use and Frailty among Residents of Aged Care Homes in Malaysia. AB - BACKGROUND/AIMS: Old age and institutionalization in care homes are associated with increased use of risk medications affecting the central nervous system (CNS). This study evaluated medication utilization and appropriateness; and assessed frailty among residents of Malaysian aged care homes. METHODS: The subjects of this study included 202 elderly (>=65 years) residents of 17 aged care homes in suburban peninsular Malaysia. Frailty was measured using the Groningen Frailty Indicator (GFI) score and independence in daily living was measured as KATZ activity of daily living score. Medication appropriateness was assessed using the Medication Appropriateness Index (MAI) and 2015 Beers' criteria for Potentially Inappropriate Medication (PIM). RESULTS: CNS medications constituted about 16% of the total, with an average of 0.8 +/- 1.1 medications per resident, which reduced to 0.5 +/- 0.8 medications after 3 months. Frailty (154/202) and polypharmacy (90/202) were highly prevalent in study subjects. Subjects on CNS medications had significantly higher GFI score (7.1 vs. 5.9; p = 0.031), polypharmacy (57.8 vs. 35.3%; p = 0.002), number of PIMs (0.9 vs. 0.2; p = 0.001), and mean summed MAI score (3.6 vs. 2.6; p = 0.015) than subjects not on CNS medications. Medication number was also significantly correlated with GFI (r = 0.194; p = 0.006) and KATZ (r = 0.141; p = 0.046) scores. CONCLUSION: Frailty and polypharmacy were highly prevalent among aged care home subjects taking CNS medications. These findings support the notion that periodic regular medication review should improve the overall use of medications in elderly patients. PMID- 28892806 TI - A Novel Missense GLA Mutation (p.G35V) Detected in Hemodialysis Screening Leads to Severe Systemic Manifestations of Fabry Disease in Men and Women. AB - BACKGROUND/AIMS: Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy. METHODS: One out of 108 male hemodialysis patients screened for FD presented low alpha-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy. RESULTS: Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively. CONCLUSION: The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non invasive markers are required for early detection of Fabry nephropathy. PMID- 28892807 TI - Effectiveness of 2 Osteopathic Treatment Approaches on Pain, Pressure-Pain Threshold, and Disease Severity in Patients with Fibromyalgia: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the effectiveness of osteopathic intervention (OI) and general osteopathic treatment (GOT) in individuals with fibromyalgia syndrome (FMS). METHODS: The trial was designed as a randomized controlled trial with 2 osteopathic interventions and 1 untreated control group. The patients in the two osteopathic groups received 10 osteopathic treatments (OI or GOT) within a time period of 12 weeks. The control group did not receive any osteopathic treatment. The primary outcome was the average pain intensity (API) assessed by visual analog scale (VAS). Secondary outcomes were the pressure-pain threshold rated by means of a tender point score, and disease severity, assessed by the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: 50 patients were randomized. The primary outcome parameter API decreased from 7.2 to 4.7 in the OI group, from 6.3 to 4.3 in the GOT group, and increased slightly in the control group from 6.2 to 6.6. There were significant differences for the change in API between the OI group and the control group (VAS: 2.9, 95% confidence interval (CI) = 1.12-4.52), and between the GOT group and the control group (VAS: 2.4, 95% CI = 0.65-4.11), but no significant differences between the OI group and the GOT group. There were no significant differences for the secondary outcome parameters between the groups. CONCLUSION: A series of osteopathic treatments might be beneficial for patients suffering from FMS. PMID- 28892808 TI - Safety and Feasibility of a Laparoscopy-Assisted Non-Anatomic Resection Technique for Hepatocellular Carcinoma Located at Right Posterior Segments in Cirrhotic Patients: A Case-Controlled Study with Propensity Score Matching. AB - PURPOSE: The aim of this study was to compare the short- and long-term outcomes of laparoscopy-assisted resection for right posterior segment (LAR-RPS) with open resection (OR-RPS) performed by experienced hepatobiliary surgeons. METHODS: This was a prospective comparative nonrandomized study. RESULTS: The groups were comparable in terms of baseline demographics and clinicopathological data. Reduced operative time (254.88 +/- 78.56 vs. 347.95 +/- 82.56 min; p = 0.04) and estimated blood loss (477 +/- 756 vs. 712 +/- 836 mL; p = 0.03) were observed in LAR-RPS. Also, significant less duration of hospital stay (7.53 +/- 2.68 vs. 12.57 +/- 3.21 days; p < 0.001) was associated with LAR-RPS compared to OR-RPS. Long-term oncologic outcomes were comparable in 2 groups, in terms of both the overall and disease-free survival rates (p = 0.450 and 0.463, respectively). CONCLUSIONS: This study confirms that laparoscopic-assisted resection is a safe and effective operative procedure in those cirrhotic patients with a lesion in the right posterior section of the liver. When compared to the open approach, the laparoscopic-assisted approach reduces operative time and blood loss, as well as the length of hospital stay. PMID- 28892809 TI - Increased Percentage of mo-MDSCs in Human Peripheral Blood May Be a Potential Indicator in the Diagnosis of Breast Cancer. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell groups that suppress T-cell responses in cancer patients and animal models. The objective of this study was to explore and evaluate the applicability of monocytic MDSCs (mo-MDSCs) in diagnosing breast cancer (BC). METHODS: In this study, we analyzed the percentage of mo-MDSCs in freshly isolated peripheral blood of patients with BC or benign tumors (BT) of the breast and healthy donors by flow cytometry. RESULTS: We found the percentage of mo-MDSCs to be 2.60 +/- 0.95% in healthy donors, 2.94 +/- 0.82% in BT patients, and 3.89 +/- 1.35% in BC patients. The percentage of circulating mo-MDSCs was significantly increased in BC patients, and this was positively correlated with clinical stage. Receiver operating characteristic curve analysis showed 80.5% sensitivity, 61.3% specificity, and a 76.6% area under the curve, suggesting a medium clinical application value of mo-MDSCs in the diagnosis of BC. CONCLUSION: Our results suggested that the percentage of circulating mo-MDSCs in human peripheral blood may be a potential indicator in the auxiliary diagnosis of BC. PMID- 28892810 TI - A spin transition mechanism for cooperative adsorption in metal-organic frameworks. AB - Cooperative binding, whereby an initial binding event facilitates the uptake of additional substrate molecules, is common in biological systems such as haemoglobin. It was recently shown that porous solids that exhibit cooperative binding have substantial energetic benefits over traditional adsorbents, but few guidelines currently exist for the design of such materials. In principle, metal organic frameworks that contain coordinatively unsaturated metal centres could act as both selective and cooperative adsorbents if guest binding at one site were to trigger an electronic transformation that subsequently altered the binding properties at neighbouring metal sites. Here we illustrate this concept through the selective adsorption of carbon monoxide (CO) in a series of metal organic frameworks featuring coordinatively unsaturated iron(ii) sites. Functioning via a mechanism by which neighbouring iron(ii) sites undergo a spin state transition above a threshold CO pressure, these materials exhibit large CO separation capacities with only small changes in temperature. The very low regeneration energies that result may enable more efficient Fischer-Tropsch conversions and extraction of CO from industrial waste feeds, which currently underutilize this versatile carbon synthon. The electronic basis for the cooperative adsorption demonstrated here could provide a general strategy for designing efficient and selective adsorbents suitable for various separations. PMID- 28892811 TI - Patterns of Sedentary Behavior and Mortality in U.S. Middle-Aged and Older Adults: A National Cohort Study. AB - Background: Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Objective: To examine the association between objectively measured sedentary behavior (its total volume and accrual in prolonged, uninterrupted bouts) and all-cause mortality. Design: Prospective cohort study. Setting: Contiguous United States. Participants: 7985 black and white adults aged 45 years or older. Measurements: Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity. Results: Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22 [95% CI, 0.74 to 2.02]; HR, 1.61 [CI, 0.99 to 2.63]; and HR, 2.63 [CI, 1.60 to 4.30]; P for trend < 0.001) and longer sedentary bout duration (HR, 1.03 [CI, 0.67 to 1.60]; HR, 1.22 [CI, 0.80 to 1.85]; and HR, 1.96 [CI, 1.31 to 2.93]; P for trend < 0.001) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [>=12.5 h/d] and high bout duration [>=10 min/bout]) had the greatest risk for death. Limitation: Participants may not be representative of the general U.S. population. Conclusion: Both the total volume of sedentary time and its accrual in prolonged, uninterrupted bouts are associated with all-cause mortality, suggesting that physical activity guidelines should target reducing and interrupting sedentary time to reduce risk for death. Primary Funding Source: National Institutes of Health. PMID- 28892812 TI - One visual search, many memory searches: An eye-tracking investigation of hybrid search. AB - Suppose you go to the supermarket with a shopping list of 10 items held in memory. Your shopping expedition can be seen as a combination of visual search and memory search. This is known as "hybrid search." There is a growing interest in understanding how hybrid search tasks are accomplished. We used eye tracking to examine how manipulating the number of possible targets (the memory set size [MSS]) changes how observers (Os) search. We found that dwell time on each distractor increased with MSS, suggesting a memory search was being executed each time a new distractor was fixated. Meanwhile, although the rate of refixation increased with MSS, it was not nearly enough to suggest a strategy that involves repeatedly searching visual space for subgroups of the target set. These data provide a clear demonstration that hybrid search tasks are carried out via a "one visual search, many memory searches" heuristic in which Os examine items in the visual array once with a very low rate of refixations. For each item selected, Os activate a memory search that produces logarithmic response time increases with increased MSS. Furthermore, the percentage of distractors fixated was strongly modulated by the MSS: More items in the MSS led to a higher percentage of fixated distractors. Searching for more potential targets appears to significantly alter how Os approach the task, ultimately resulting in more eye movements and longer response times. PMID- 28892813 TI - Attentional modulation interacts with orientation anisotropies in contrast perception. AB - Orientation perception is not comparable across all orientations-a phenomenon commonly referred to as the oblique effect. Here, we first assessed the interaction between stimulus contrast and the oblique effect. Specifically, we examined whether the impairment in behavioral performance for oblique versus cardinal orientations is best explained by a contrast or a response gain modulation of the contrast psychometric function. Results revealed a robust oblique effect, whereby asymptotic performance for oblique orientations was substantially lower than for cardinal orientations, which we interpret as the result of multiplicative attenuation of contrast responses for oblique orientations. Next, we assessed how orientation anisotropies interact with attention by measuring psychometric functions for orientations under low or high attentional load. Interestingly, attentional load affects the performance for cardinal and oblique orientations differently: While it multiplicatively attenuates contrast psychometric functions for both cardinal and oblique orientation conditions, the magnitude of this effect is greater for the obliques. Thus, having less attentional resources available seems to impair the response for oblique orientations to a larger degree than for cardinal orientations. PMID- 28892814 TI - Mitigating the Mental and Physical Health Consequences of Hurricane Harvey. PMID- 28892815 TI - Trans Male Voice in the First Year of Testosterone Therapy: Make No Assumptions. AB - Purpose: The purpose of this study was to prospectively examine changes in gender related voice domain of pitch measured by fundamental frequency, function-related domains of vocal quality, range, and habitual pitch level and the self perceptions of transmasculine people during their first year of testosterone treatment. Method: Seven trans men received 2 voice assessments at baseline and 1 assessment at 3, 6, 9, and 12 months after starting treatment. Results: Vocal quality measures varied between and within participants but were generally within normal limits throughout the year. Mean fundamental frequency (MF0) during reading decreased, although to variable extents and rates. Phonation frequency range shifted down the scale, although it increased in some participants and decreased in others. Considering MF0 and phonation frequency range together in a measure of habitual pitch level revealed that the majority of participants spoke using an MF0 that was low within their range compared with cisgender norms. Although the trans men generally self-reported voice masculinization, it was not correlated with MF0, frequency range, or habitual pitch level at any time point or with MF0 note change from baseline to 1 year of testosterone treatment, but correlations should be interpreted with caution due to the heterogeneous responses of the 7 participants. Conclusion: In trans men, consideration of voice deepening in the context of objective and subjective measures of voice can reveal unique profiles and inform patient care. PMID- 28892816 TI - Treatment of Type 1 Diabetes: Synopsis of the 2017 American Diabetes Association Standards of Medical Care in Diabetes. AB - Description: The American Diabetes Association (ADA) annually updates Standards of Medical Care in Diabetes to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of patients with diabetes. Methods: For the 2017 Standards of Care, the ADA Professional Practice Committee did MEDLINE searches from 1 January 2016 to November 2016 to add, clarify, or revise recommendations on the basis of new evidence. The committee rated the recommendations as A, B, or C, depending on the quality of evidence, or E for expert consensus or clinical experience. The Standards of Care were reviewed and approved by the Executive Committee of the ADA Board of Directors, which includes health care professionals, scientists, and laypersons. Feedback from the larger clinical community informed revisions. Recommendation: This synopsis focuses on recommendations from the 2017 Standards of Care about monitoring and pharmacologic approaches to glycemic management for type 1 diabetes. PMID- 28892817 TI - Distribution of Prescription Opioid Use Among Privately Insured Adults Without Cancer: United States, 2001 to 2013. PMID- 28892818 TI - Diagnostic Reasoning: An Endangered Competency in Internal Medicine Training. PMID- 28892819 TI - Input Subject Diversity Accelerates the Growth of Tense and Agreement: Indirect Benefits From a Parent-Implemented Intervention. AB - Purpose: This follow-up study examined whether a parent intervention that increased the diversity of lexical noun phrase subjects in parent input and accelerated children's sentence diversity (Hadley et al., 2017) had indirect benefits on tense/agreement (T/A) morphemes in parent input and children's spontaneous speech. Method: Differences in input variables related to T/A marking were compared for parents who received toy talk instruction and a quasi-control group: input informativeness and full is declaratives. Language growth on tense agreement productivity (TAP) was modeled for 38 children from language samples obtained at 21, 24, 27, and 30 months. Parent input properties following instruction and children's growth in lexical diversity and sentence diversity were examined as predictors of TAP growth. Results: Instruction increased parent use of full is declaratives (etap2 >= .25) but not input informativeness. Children's sentence diversity was also a significant time-varying predictor of TAP growth. Two input variables, lexical noun phrase subject diversity and full is declaratives, were also significant predictors, even after controlling for children's sentence diversity. Conclusions: These findings establish a link between children's sentence diversity and the development of T/A morphemes and provide evidence about characteristics of input that facilitate growth in this grammatical system. PMID- 28892820 TI - We Didn't Get Cold Feet. PMID- 28892821 TI - Readability Level of Spanish-Language Patient-Reported Outcome Measures in Audiology and Otolaryngology. AB - Purpose: The purpose of this study was to examine the readability level of the Spanish versions of several audiology- and otolaryngology-related patient reported outcome measures (PROMs) and include a readability analysis of 2 translation approaches when available-the published version and a "functionalist" version-using a team-based collaborative approach including community members. Method: Readability levels were calculated using the Fry Graph adapted for Spanish, as well as the Fernandez-Huerta and the Spaulding formulae for several commonly used audiology- and otolaryngology-related PROMs. Results: Readability calculations agreed with previous studies analyzing audiology-related PROMs in English and demonstrated many Spanish-language PROMs were beyond the 5th grade reading level suggested for health-related materials written for the average population. In addition, the functionalist versions of the PROMs yielded lower grade-level (improved) readability levels than the published versions. Conclusion: Our results suggest many of the Spanish-language PROMs evaluated here are beyond the recommended readability levels and may be influenced by the approach to translation. Moreover, improved readability may be possible using a functionalist approach to translation. Future analysis of the suitability of outcome measures and the quality of their translations should move beyond readability and include an evaluation of the individual's comprehension of the written text. PMID- 28892822 TI - Audiometric Testing With Pulsed, Steady, and Warble Tones in Listeners With Tinnitus and Hearing Loss. AB - Purpose: This study evaluated the American Speech-Language-Hearing Association's recommendation that audiometric testing for patients with tinnitus should use pulsed or warble tones. Using listeners with varied audiometric configurations and tinnitus statuses, we asked whether steady, pulsed, and warble tones yielded similar audiometric thresholds, and which tone type was preferred. Method: Audiometric thresholds (octave frequencies from 0.25-16 kHz) were measured using steady, pulsed, and warble tones in 61 listeners, who were divided into 4 groups on the basis of hearing and tinnitus status. Participants rated the appeal and difficulty of each tone type on a 1-5 scale and selected a preferred type. Results: For all groups, thresholds were lower for warble than for pulsed and steady tones, with the largest effects above 4 kHz. Appeal ratings did not differ across tone type, but the steady tone was rated as more difficult than the warble and pulsed tones. Participants generally preferred pulsed and warble tones. Conclusions: Pulsed tones provide advantages over steady and warble tones for patients regardless of hearing or tinnitus status. Although listeners preferred pulsed and warble tones to steady tones, pulsed tones are not susceptible to the effects of off-frequency listening, a consideration when testing listeners with sloping audiograms. PMID- 28892823 TI - Tracking Our Physical Inactivity and Progression to Death: Is This Evolutionary Stagnation? PMID- 28892824 TI - Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways. AB - Purpose: Goblet cells in the conjunctiva secrete mucin into the tear film protecting the ocular surface. The proresolution mediator resolvin D1 (RvD1) regulates mucin secretion to maintain homeostasis during physiological conditions and in addition, actively terminates inflammation. We determined the signaling mechanisms used by RvD1 in cultured rat conjunctival goblet cells to increase intracellular [Ca2+] ([Ca2+]i) and induce glycoconjugate secretion. Methods: Increase in [Ca2+]i were measured using fura 2/AM and glycoconjugate secretion determined using an enzyme-linked lectin assay with the lectin Ulex Europaeus Agglutinin 1. Signaling pathways activated by RvD1 were studied after goblet cells were pretreated with signaling pathway inhibitors before stimulation with RvD1. The results were compared with results when goblet cells were stimulated with RvD1 alone and percent inhibition calculated. Results: The increase in [Ca2+]i stimulated by RvD1 was blocked by inhibitors to phospholipases (PL-) -D, C, -A2, protein kinase C (PKC), extracellular signal-regulated kinases (ERK)1/2 and Ca2+/calmodulin-dependent kinase (Ca2+/CamK). Glycoconjugate secretion was significantly inhibited by PLD, -C, -A2, ERK1/2 and Ca2+/CamK, but not PKC. Conclusions: We conclude that RvD1 increases glycoconjugate secretion from goblet cells via multiple signaling pathways including PLC, PLD, and PLA2, as well as their signaling components ERK1/2 and Ca2+/CamK to preserve the mucous layer and maintain homeostasis by protecting the eye from desiccating stress, allergens, and pathogens. PMID- 28892826 TI - Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study. AB - Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients. Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy. PMID- 28892825 TI - Associations Between Vitamin D Intake and Progression to Incident Advanced Age Related Macular Degeneration. AB - Purpose: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but no prospective studies have explored the impact of vitamin D. We evaluated the association between vitamin D intake and progression to advanced AMD. Methods: Among 2146 participants (3965 eyes), 541 (777 eyes) progressed from early or intermediate AMD to advanced disease (mean follow-up: 9.4 years) based on ocular imaging. Nutrients were log transformed and calorie adjusted. Survival analysis was used to assess associations between incident advanced disease and vitamin D intake. Neovascular disease (NV) and geographic atrophy (GA) were evaluated separately. Combined effects of dietary vitamin D and calcium were assessed based on high or low consumption of each nutrient. Results: There was a lower risk of progression to advanced AMD in the highest versus lowest quintile of dietary vitamin D intake after adjustment for demographic, behavioral, ocular, and nutritional factors (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.43-0.83; P trend = 0.0007). Similar results were observed for NV (HR: 0.59; 95% CI: 0.39-0.89; P trend = 0.005) but not GA (HR: 0.83; 95% CI: 0.53-1.30; P trend = 0.35). A protective effect was observed for advanced AMD among participants with high vitamin D and low calcium compared to the group with low levels for each nutrient (HR: 0.67; 95% CI: 0.50-0.88; P = 0.005). When supplement use was considered, the effect was in the protective direction but was not significant. Conclusions: A diet rich in vitamin D may prevent or delay progression to advanced AMD, especially NV. Additional exploration is needed to elucidate the potential protective role of vitamin D and its contribution to reducing visual loss. PMID- 28892827 TI - Role of Microbiota in Strengthening Ocular Mucosal Barrier Function Through Secretory IgA. AB - Purpose: The purpose of this study was to evaluate mechanisms controlling secretory IgA (SIgA) production, thereby ensuring maintenance of ocular surface health. Methods: To determine whether the presence of specific gut commensal species regulates SIgA levels and IgA transcripts in the eye-associated lymphoid tissues (EALT), specific-pathogen-free (SPF) Swiss Webster (SW) mice were treated with antibiotic cocktails, germ-free (GF) SW mice were reconstituted with diverse commensal gut microbiota, or monocolonized with gut-specific commensals. Proteomic profiling and quantitative real-time polymerase chain reaction (qRT PCR) were used to quantify SIgA and IgA levels. 16S rDNA sequencing was carried out to characterize commensal microbiota. Results: Commensal presence regulated ocular surface SIgA levels and mRNA IgA transcripts in EALT. Oral antibiotic cocktail intake significantly reduced gut commensal presence, while maintaining ocular surface commensal levels reduced SIgA and IgA transcripts in EALT. Analysis of gut microbial communities revealed that SPF SW mice carried abundant Bacteroides organisms when compared to SPF C57BL6/N mice, with B. acidifaciens being the most prominent species in SPF SW mice. Monocolonization of GF SW mice with B. acidifaciens, a strict gut anaerobe, resulted in significant increase of IgA transcripts in the EALT, implying generation of B-cell memory. Conclusions: These data illustrated a "gut-eye" axis of immune regulation. Exposure of the host to gut commensal species may serve as a priming signal to generate B-cell repertoires at sites different from the gut, such as EALT, thereby ensuring broad protection. PMID- 28892828 TI - Optic Nerve Sheath Distention as a Protective Mechanism Against the Visual Impairment and Intracranial Pressure Syndrome in Astronauts. PMID- 28892829 TI - Author Response: Optic Nerve Sheath Distention as a Protective Mechanism Against the Visual Impairment and Intracranial Pressure Syndrome in Astronauts. PMID- 28892830 TI - Duration of Sedentary Episodes Is Associated With Risk for Death. PMID- 28892831 TI - Recognizing Difference: Augmentative and Alternative Communication in Natural Contexts. PMID- 28892832 TI - Challenges and Opportunities in Reading Instruction for Children with Limited Speech. PMID- 28892833 TI - Using Digital Texts in Interactive Reading Activities for Children with Language Delays and Disorders: A Review of the Research Literature and Pilot Study. PMID- 28892834 TI - Model for Vocabulary Selection of Sensitive Topics: An Example from Pain-Related Vocabulary. PMID- 28892835 TI - When You Can't Touch a Touch Screen. PMID- 28892836 TI - Repurposing Consumer Products as a Gateway to Just-in-Time Communication. PMID- 28892837 TI - Family Leisure as a Context to Support Augmentative and Alternative Communication Intervention for Young Children with Complex Communication Needs. PMID- 28892838 TI - Preventing Abuse and Providing Access to Justice for Individuals with Complex Communication Needs: The Role of Augmentative and Alternative Communication. PMID- 28892839 TI - Impact of feedback on adenoma detection rates: Outcomes of quality improvement program. AB - BACKGROUND AND AIM: Feedback has been shown to improve performance in colonoscopy including adenoma detection rate (ADR). The frequency at which feedback should be given is unknown. As part of a quality improvement program, we sought to measure the outcome of providing quarterly and monthly feedback on colonoscopy quality measures. METHODS: All screening colonoscopies performed at endoscopy unit at Mayo Clinic Arizona by gastroenterologists between October 2010 and December 2012 were reviewed. Quality indicators, including ADR, were extracted for each individual endoscopist, and feedback was provided. The study period was divided into four distinct groups: pre-intervention that served as baseline, quarterly feedback, monthly feedback, and post-intervention. Based on ADR, endoscopists were grouped into "low detectors" (<= 25%), "average detectors" (26-35%), and "high detectors" (> 35%). RESULTS: A total of 3420 screening colonoscopies were performed during the study period (555 patients during pre-intervention, 1209 patients during quarterly feedback, 599 during monthly feedback, and 1057 during the post-intervention period) by 16 gastroenterologists. The overall ADR for the group improved from 30.5% to 37.7% (P = 0.003). Compared with the pre interventional period, all quality indicators measured significantly improved during the monthly feedback and post-intervention periods but not in the quarterly feedback period. CONCLUSIONS: In our quality improvement program, monthly feedback significantly improved colonoscopy quality measures, including ADR, while quarterly feedback did not. The impact of the intervention was most prominent in the "low detectors" group. Results were durable up to 6 months following the intervention. PMID- 28892840 TI - Cadmium solubility and bioavailability in soils amended with acidic and neutral biochar. AB - This study was designed to investigate the effects of acidic and neutral biochars on solubility and bioavailability of cadmium (Cd) in soils with contrasting properties. Four Cd contaminated (50mg/kg) soils (EN: Entisol, AL: Andisol, VE: Vertisol, IN: Inceptisol) were amended with 5% acidic wood shaving biochar (WS, pH=3.25) and neutral chicken litter biochar (CL, pH=7.00). Following a 140-day incubation, the solubility and bioavailability/bioaccessibility of cadmium (Cd) were assessed. Results showed that both biochars had no effect on reducing soluble (pore water) and bioavailable (CaCl2 extractable) Cd for higher sorption capacity soils (AL, IN) while CL biochar reduced those in lower sorption capacity soils (EN, VE) by around 50%. Bioaccessibility of Cd to the human gastric phase (physiologically based extraction test (PBET) extractable) was not altered by the acidic WS biochar but reduced by neutral CL biochar by 18.8%, 29.7%, 18.0% and 8.82% for soil AL, EN, IN and VE, respectively. Both biochars reduced soluble Cd under acidic conditions (toxicity characteristic leaching procedure (TCLP) extractable) significantly in all soils. Pore water pH was the governing factor of Cd solubility among soils. The reduction of Cd solubility and bioavailability/bioaccessibility by CL biochar may be due to surface complexation while the reduced mobility of Cd under acidic conditions (TCLP) by both biochars may result from the redistribution of Cd to less bioavailable soil solid fractions. Hence, if only leaching mitigation of Cd under acidic conditions is required, application of low pH biochars (e.g., WS biochar) may be valuable. PMID- 28892841 TI - Movement of traditional fecal indicator bacteria and source-tracking targets through septic drainfields. AB - The past three decades' data on outbreaks in the United States indicate that homes dependent on untreated groundwater (e.g. wells) for household drinking water that are also reliant on onsite treatment of household wastewater (e.g. septic systems) may be at greater risk for waterborne disease. While groundwater quality monitoring to protect public health has traditionally focused on the detection of fecal indicator bacteria, the application of emerging source tracking strategies may offer a more efficient means to identify pollution sources and effective means of remediation. This study compares the movement of common fecal indicator bacteria (E. coli and enterococci) with a chemical (optical brighteners, OB) and a molecular (Bacteroides HF183) source tracking (ST) target in small scale septic drainfield models in order to evaluate their potential utility in groundwater monitoring. Nine PVC column drainfield models received synchronized doses of primary-treated wastewater twice daily, with influent and effluent monitored bi-weekly over a 7-month period for all targets. Results indicate that E. coli and enterococci concentrations were strongly associated (Spearman's rank, p<0.05), and correlations between enterococci and optical brighteners were moderately strong. Bacteroides HF183 was significantly, but not strongly, associated with optical brighteners and both indicator bacteria (Point-biserial correlation, p<0.05), most likely due to its sporadic detection. Application of human ST marker monitoring in groundwaters at risk of contamination by human sewage is recommended, although consistent interpretation of results will rely on more detailed evaluation of HF183 incidence in source contamination waters. PMID- 28892842 TI - Influence of climatic and geographic factors on the spatial distribution of Qinghai spruce forests in the dryland Qilian Mountains of Northwest China. AB - The effect of climate variables (temperature and precipitation) on forest spatial distribution is more prominent in dryland high mountains, where forest distribution is inherently very sensitive to and strongly limited by the substantial spatial heterogeneity of site conditions. Thus, a more reliable prediction of forest distribution under changing environment depends upon an understanding of the joint influence of climatic and topographic factors and their thresholds. This study was conducted on Qinghai spruce forests as dominant tree species in the Qilian Mountains of northwest China. The spruce forest distribution was surveyed by remote sensing in Dayekou watershed and by field investigation in a nested smaller watershed. Analyses showed that mean annual air temperature and precipitation, which vary with elevation, are the key climatic factors determining forest distribution, but slope aspect also plays an essential role. The potential core distribution area of denser forests and potential distribution area including sparse forests are between the axes of elevation (2635.5-3302.5 and 2603.4-3325.8m a.s.l.) and slope aspect (-74.4-61.2 degrees and -162.6-147.1 degrees deviated from north). The corresponding threshold of mean annual air temperature at the upper elevation boundary is -2.59 and -2.73 degrees C, while the threshold of mean annual precipitation at the lower elevation boundary is 378.1 and 372.3 mm, respectively. Using these thresholds and the elevation gradients of climatic factors, the shifting of elevation boundaries under climate change scenarios can be predicted. However, the forest distribution is also limited by a soil thickness of >=40cm; and by slope position of lower-, lower- and middle-, and entire-slope within the elevation ranges of <2800, 2800-2900, and >2900m a.s.l., respectively. This study showed that adding geographic factors will greatly improve the prediction of changes in forest distribution area in dryland mountains, in addition to the influence of climatic factors. PMID- 28892843 TI - EMD-regression for modelling multi-scale relationships, and application to weather-related cardiovascular mortality. AB - In a number of environmental studies, relationships between nat4ural processes are often assessed through regression analyses, using time series data. Such data are often multi-scale and non-stationary, leading to a poor accuracy of the resulting regression models and therefore to results with moderate reliability. To deal with this issue, the present paper introduces the EMD-regression methodology consisting in applying the empirical mode decomposition (EMD) algorithm on data series and then using the resulting components in regression models. The proposed methodology presents a number of advantages. First, it accounts of the issues of non-stationarity associated to the data series. Second, this approach acts as a scan for the relationship between a response variable and the predictors at different time scales, providing new insights about this relationship. To illustrate the proposed methodology it is applied to study the relationship between weather and cardiovascular mortality in Montreal, Canada. The results shed new knowledge concerning the studied relationship. For instance, they show that the humidity can cause excess mortality at the monthly time scale, which is a scale not visible in classical models. A comparison is also conducted with state of the art methods which are the generalized additive models and distributed lag models, both widely used in weather-related health studies. The comparison shows that EMD-regression achieves better prediction performances and provides more details than classical models concerning the relationship. PMID- 28892844 TI - Are optical indices good proxies of seasonal changes in carbon fluxes and stress related physiological status in a beech forest? AB - This study investigates the functionality of a Mediterranean-mountain beech forest in Central Italy using simultaneous determinations of optical measurements, carbon (C) fluxes, leaf eco-physiological and biochemical traits during two growing seasons (2014-2015). Meteorological variables showed significant differences between the two growing seasons, highlighting a heat stress coupled with a reduced water availability in mid-summer 2015. As a result, a different C sink capacity of the forest was observed between the two years of study, due to the differences in stressful conditions and the related plant physiological status. Spectral indices related to vegetation (VIs, classified in structural, chlorophyll and carotenoid indices) were computed at top canopy level and used to track CO2 fluxes and physiological changes. Optical indices related to structure (EVI 2, RDVI, DVI and MCARI 1) were found to better track Net Ecosystem Exchange (NEE) variations for 2014, while indices related to chlorophylls (SR red edge, CL red edge, MTCI and DR) provided better results for 2015. This suggests that when environmental conditions are not limiting for forest sink capacity, structural parameters are more strictly connected to C uptake, while under stress conditions indices related to functional features (e.g., chlorophyll content) become more relevant. Chlorophyll indices calculated with red edge bands (SR red edge, NDVI red edge, DR, CL red edge) resulted to be highly correlated with leaf nitrogen content (R2>0.70), while weaker, although significant, correlations were found with chlorophyll content. Carotenoid indices (PRI and PSRI) were strongly correlated with both chlorophylls and carotenoids content, suggesting that these indices are good proxies of the shifting pigment composition related to changes in soil moisture, heat stress and senescence. Our work suggests the importance of integrating different methods as a successful approach to understand how changing climatic conditions in the Mediterranean mountain region will impact on forest conditions and functionality. PMID- 28892845 TI - An effective and comprehensive model for optimal rehabilitation of separate sanitary sewer systems. AB - In the field of rehabilitation of separate sanitary sewer systems, a large number of technical, environmental, and economic aspects are often relevant in the decision-making process, which may be modelled as a multi-objective optimization problem. Examples are those related with the operation and assessment of networks, optimization of structural, hydraulic, sanitary, and environmental performance, rehabilitation programmes, and execution works. In particular, the cost of investment, operation and maintenance needed to reduce or eliminate Infiltration from the underground water table and Inflows of storm water surface runoff (I/I) using rehabilitation techniques or related methods can be significantly lower than the cost of transporting and treating these flows throughout the lifespan of the systems or period studied. This paper presents a comprehensive I/I cost-benefit approach for rehabilitation that explicitly considers all elements of the systems and shows how the approximation is incorporated as an objective function in a general evolutionary multi-objective optimization model. It takes into account network performance and wastewater treatment costs, average values of several input variables, and rates that can reflect the adoption of different predictable or limiting scenarios. The approach can be used as a practical and fast tool to support decision-making in sewer network rehabilitation in any phase of a project. The fundamental aspects, modelling, implementation details and preliminary results of a two-objective optimization rehabilitation model using a genetic algorithm, with a second objective function related to the structural condition of the network and the service failure risk, are presented. The basic approach is applied to three real world cases studies of sanitary sewerage systems in Coimbra and the results show the simplicity, suitability, effectiveness, and usefulness of the approximation implemented and of the objective function proposed. PMID- 28892846 TI - Caffeine and paraxanthine in aquatic systems: Global exposure distributions and probabilistic risk assessment. AB - This study presents one of the most complete applications of probabilistic methodologies to the risk assessment of emerging contaminants. Perhaps the most data-rich of these compounds, caffeine, as well as its main metabolite (paraxanthine), were selected for this study. Information for a total of 29,132 individual caffeine and 7442 paraxanthine samples was compiled, including samples where the compounds were not detected. The inclusion of non-detect samples (as censored data) in the estimation of environmental exposure distributions (EEDs) allowed for a realistic characterization of the global presence of these compounds in aquatic systems. EEDs were compared to species sensitivity distributions (SSDs), when possible, in order to calculate joint probability curves (JPCs) to describe the risk to aquatic organisms. This way, it was determined that unacceptable environmental risk (defined as 5% of the species being potentially exposed to concentrations able to cause effects in>5% of the cases) could be expected from chronic exposure to caffeine from effluent (28.4% of the cases), surface water (6.7% of the cases) and estuary water (5.4% of the cases). Probability of exceedance of acute predicted no-effect concentrations (PNECs) for paraxanthine were higher than 5% for all assessed matrices except for drinking water and ground water, however no experimental effects data was available for paraxanthine, resulting in a precautionary deterministic hazard assessment for this compound. Given the chemical similarities between both compounds, real effect thresholds, and thus risk, for paraxanthine, would be expected to be close to those observed for caffeine. Negligible Human health risk from exposure to caffeine via drinking or groundwater is expected from the compiled data. PMID- 28892847 TI - Relationship between maternal phthalate exposure and offspring size at birth. AB - Research findings on effects of prenatal phthalate exposure on fetal growth were inconsistent. Increasing evidence from animal studies has indicated a potential sex-specific effect of phthalates on fetal growth, but the current human data was limited. In this study, we aimed to estimate the relationships between maternal phthalate exposure and infant birth size. Six major phthalate metabolite levels of urine samples were measured among pregnant women (n=1002) from the Healthy Baby Cohort (HBC), China. The associations between urinary phthalate metabolites levels and birth size (birth weight, birth length, birth weight z-scores and ponderal index) were estimated using linear regression models. In boys, the ln transformed di-2-ethylhexyl phthalate (DEHP) metabolite levels were significantly associated with increased birth weight and birth weight z-scores. Additionally, each ln-unit increase in mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) was associated with a 0.25kg/m3 [95% confidence interval (CI): 0.03, 0.47] increase in ponderal index in boys. However, we did not observe any significant association of maternal phthalate metabolite levels with any of the outcomes in girls. Our data suggested potential sex-specific associations of maternal phthalate exposure with increased birth weight and ponderal index, which were merely apparent in boys. PMID- 28892848 TI - Source dynamics of radiocesium-contaminated particulate matter deposited in an agricultural water reservoir after the Fukushima nuclear accident. AB - The Fukushima nuclear accident in Japan resulted in the deposition of radiocesium over forested and rural landscapes northwest of the power plant. Although there have been several investigations into the dynamics of contaminated river sediment, less attention has been paid to the sources of deposited particulate matter in dams and reservoirs. In the Fukushima Prefecture, there are 10 significant dams and over a 1000 reservoirs for both agricultural and surface water management. These reservoirs may have trapped a significant volume of radiocesium-contaminated sediment. Therefore, characterizing the sources of contaminated particulate matter is important for the ongoing management of contamination in the region. Accordingly, the composition of particulate matter deposited in the Mano Dam reservoir, approximately 40km northwest of the power plant, was investigated with the analyses and modelling of carbon and nitrogen stable isotope ratios (delta13C and delta15N), total organic carbon (TOC) and total nitrogen (TN) concentrations. Four sediment cores, with lengths ranging 29 41cm, were sampled in the Mano Dam. Source samples from 46 forest soils, 28 cultivated soils and 25 subsoils were used to determine the source contributions of particulate matter. Carbon and nitrogen parameters were analyzed on all samples and a concentration-dependent distribution modelling approach was used to apportion source contributions. Three of the four cores sampled in the Mano Dam reservoir had distinct radiocesium peaks representative of the initial post accident wash-off phase. Cultivated sources were responsible for 48+/-7% of the deposited fine particulate matter whereas forests were modelled to contribute 27+/-6% and subsoil sources 25+/-4%. Ongoing decontamination of cultivated sources in the Fukushima region should result in a decrease of contaminated matter deposition in reservoirs. PMID- 28892849 TI - Characteristics of air pollution in different zones of Sichuan Basin, China. AB - Sichuan Basin, located in southwest China, has been ranked as the fourth of heavily air polluted regions in China partly due to its deep mountain-basin topography. However, spatial-temporal distribution of air pollution over the basin is still unclear due to the lack of monitoring data and poor knowledge. Since January 2015, six criteria air pollutants began to be monitored in 20 cities across the basin. The measured data enable us to analyze the basin-wide spatial-temporal distribution characteristics of these air pollutants. Results revealed heavy air pollution in the bottom zone, medium in the slope zone, and light pollution in the edge zone of the Basin in terms of the altitudes of air quality monitoring stations across the Basin. The average concentrations of PM2.5 and PM10 were 55.87MUg/m3 and 86.49MUg/m3 in the bottom, 33.76MUg/m3 and 63.33MUg/m3 in the slope, and 19.71MUg/m3 and 35.06MUg/m3 in the edge, respectively. In the bottom and slope of the basin, high PM2.5 concentration events occurred most frequently in winter. While in summer, ozone became primary pollutant. Among the six air pollutants, concentrations of PM2.5 and PM10 decrease dramatically with increasing altitude which was fitted by a nonlinear relationship between particulate matter (PM) concentrations and altitude. This relationship was validated by extinction coefficient profiles from CALIPSO observations and EV-lidar data, and hence used to reflect vertical distribution of air PM concentrations. It has been found that the thickness of higher PM concentrations is less than 500m in the basin. In the bottom of the basin, PM concentrations exhibited stronger horizontal homogeneities as compared with those in the North China Plain and Yangtze River Delta. However, gaseous pollutants seemed not to show clear relationships between their concentrations and altitudes in the basin. Their horizontal homogeneities were less significant compared to PM. PMID- 28892850 TI - Evaluation of EOC removal processes during artificial recharge through a reactive barrier. AB - A reactive barrier that consisted of vegetable compost, iron oxide and clay was installed in an infiltration basin to enhance the removal of emerging organic compounds (EOCs) in the recharge water. First-order degradation rates and retardation factors were jointly estimated for 10 compounds using a multilayer reactive transport model, whose flow and conservative transport parameters were previously estimated using hydraulic head values and conservative tracer tests. Reactive transport parameters were automatically calibrated against the concentration of EOCs measured at nine monitoring points. The degradation rate of each compound was estimated for three zones defined according to the redox state, and retardation coefficients were estimated in two zones defined according to the organic matter content. The fastest degradation rates were obtained for the reactive barrier, and the estimated values were similar to or higher than those estimated in column and/or field experiments for most of the compounds (8/10). Estimated retardation coefficients in the reactive barrier were higher than in the rest of the aquifer in most cases (8/10) and higher than those values estimated in previous studies. Based on the results obtained in this study the reactive barrier seems to be able to enhance the removal of EOCs. PMID- 28892851 TI - A Phosphorous Flow Analysis in Spain. AB - Phosphorus (P) is a vital macronutrient required to improve the agricultural yields but its excessive use as a fertilizer has resulted in pollution of water bodies leading to eutrophication. With no reserves of phosphorus source in Spain, increased dependence on phosphorus in agriculture have not only increased dependence on imports but also has raised concerns on its future availability as a resource. A Phosphorous Flow Analysis (PFA) was conducted for Spain for the year 2012 focusing on the food production and consumption systems. The results obtained were finally compared with PFA at both country level and continent level (EU-27). To quantify food and non-food flows systems, country specific data were considered. The sectors covered were crop production (CP), animal production (AP), food processing (FP), non-food production (NF) and consumption (HC). The findings reveal that a total of 325kt P was imported by Spain in 2012; 66% of which was accumulated in markets stock of food and feed, fertilizers and non-food (91kt P) while 33% was lost to the environment through land-fill, losses to water bodies, land accumulation and incineration. The largest proportion of losses is associated with water bodies (44.7kt P) followed by agriculture and land accumulation (42.1kt P). Wastewater treatment plants (WWTPs) received around 79.5kt P within wastewater, with 60% being removed in sewage sludge. The 31.7kt P discharged within final effluent represented the 71% of the total losses to water bodies. Around 69% of the sewage sludge was recycled to agriculture and 27% was sent directly to landfill including the ashes from incineration. Net accumulation was 1.84kg P/cap which was similar to values reported for the EU-27 average (2.5kg P/cap). PMID- 28892852 TI - Contribution of ship emissions to the concentration of PM2.5: A comprehensive study using AIS data and WRF/Chem model in Bohai Rim Region, China. AB - Compared with on-road vehicles, emission from ships is one of the least-regulated anthropogenic emission sources and non-negligible source of primary aerosols and gas-phase precursors of PM2.5. The Bohai Rim Region in China hosts dozens of large ports, two of which ranked among the top ten ports in the world. To determine the impact of ship emissions on the PM2.5 concentrations over this region, two parts of works have been conducted in this study. First, a detailed ship emission inventory with high spatiotemporal resolution was developed based on Automatic Identification System (AIS) data. Then the WRF/Chem model was applied to modeling the impact of ship emissions by comparing two scenarios: with and without ship emissions. The results indicate that the total estimated ship emissions of SO2, NOX, PM10, PM2.5, CO, HC, and CO2 from Bohai Rim Region in 2014 are 1.9*105, 2.9*105, 2.6*104, 2.4*104, 2.5*104, 1.2*104, and 1.3*107tonnes, respectively. The modeling results indicate that the annual PM2.5 concentrations increased by 5.9% on land areas of Bohai Rim Region (the continent within 115.2 degrees E-124.3 degrees E and 36.1 degrees N-41.6 degrees N) due to ship emissions. The contributions show distinctive seasonal variations of contributions, presenting highest in summer (12.5%) followed by spring (6.9%) and autumn (3.3%), and lowest in winter (0.9%). The contribution reaches up to 10.7% along the shoreline and down to 1.0% 200km inland. After examining the statistics of the modeling results during heavy and non-heavy haze days in July, it was found that 6 out of 9 cities around the Bohai Rim Region were observed with higher contributions from ship emissions during heavy haze days compared with non heavy haze days. These results indicate that the impacts of ship emissions on the ambient PM2.5 are non-negligible, especially for heavy haze days for most coastal cities in the Bohai Rim Region. PMID- 28892853 TI - Tracking trace elements into complex coral reef trophic networks. AB - The integration, accumulation and transfer of trace elements across the main tropic levels of many food webs are poorly documented. This is notably the case for the complex trophic webs of coral reef ecosystems. Our results show that in the south-west lagoon of New Caledonia both abiotic (i.e. sediments) and biotic (i.e. primary producers, consumers and predators) compartments are contaminated by trace elements. However, our analyses revealed different contamination patterns from the sources of organic matter to the predators. The trophic levels involved in the sedimentary benthic food web (S-BFW, based on the sedimentary organic matter) and to a lesser extent in the reef benthic food web (R-BFW, based on algal turf) were mainly contaminated by trace elements that originate from mining activities like Ni and associated trace elements (Co, Cr, Fe, and Mn). Trace elements linked to agro-industrial (As, Hg, and Zn) and urban (Ag, Cd, Cu, Pb, Se, and V) activities were also integrated into the S-BFW, but preferentially into the R-BFW, and to a lesser extent into the detrital benthic food web (D-BFW, supplied by sea-grass plants). Most of the trace elements were biodiminished with increasing trophic levels along food webs. However, a marked biomagnification was observed for Hg, and suspected for Se and Zn. These results provide important baseline information to better interpret trace element contamination in the different organisms and trophic levels in a highly diversified coral reef lagoon. PMID- 28892854 TI - Tissue distribution and maternal transfer of persistent organic pollutants in Kentish Plovers (Charadrius alexandrines) from Cangzhou Wetland, Bohai Bay, China. AB - Several persistent organic pollutants, including polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs), were comprehensively investigated in the egg, muscle and liver samples of Kentish Plover (Charadrius alexandrines) collected from Cangzhou Wetland in western Bohai Bay, China. DDTs were the most abundant contaminants (35.4-9853ngg-1 lipid weight, lw), followed by HCHs, PCBs, PBDEs and HCB. PCDD/Fs exhibited the lowest concentrations in all tissues (8.74-4763pgg-1 lw). PCBs and PCDD/Fs were dominated by penta- and hexa-homologs, and PBDEs mostly consisted of the signature congeners of BDE formulations, such as BDE-209, -47, -153 and -99. Significant correlations were found between the lipid-normalized concentrations in muscle and liver (r: 0.37-0.90, p<0.05) and no significant differences (p<0.05), indicating the homogenous distribution of POPs in tissue lipids at steady state. The ratios of concentrations in muscle and liver (M/L) ranged from 0.20 to 1.51, and higher ratios of M/L were found for those compounds with log Kow in the range of 6.5-7.0, suggesting the preferential accumulation of mid halogenated compounds in muscle. Significant correlations were generally observed between the concentrations in egg and the maternal tissue (p<0.05). The concentration ratios of egg to liver (E/L) were in the range of 0.10-1.24 except for p,p'-DDT (12.7), and compounds with log Kow of 6.5-7.0 exhibited higher E/L ratios, suggesting the selective maternal transfer of mid-halogenated compounds. PMID- 28892855 TI - Oxidizing capacity of the rural atmosphere in Hong Kong, Southern China. AB - Atmospheric oxidizing capacity (AOC), dominated by the hydroxyl radical (OH), is an important index of the self-cleaning capacity of atmosphere and plays a vital role in the tropospheric chemistry. To better understand the key processes governing the chemistry of rural atmosphere of southern China, we analyzed the oxidation capacity and radical chemistry at a regional background site in Hong Kong from 23 August to 22 December 2012, which covered the summer, autumn and winter seasons. A chemical box model built on the latest Master Chemical Mechanism (v3.3) was used to elucidate the OH reactivity and sources of ROX radicals (ROX=OH+HO2+RO2). The AOC showed a clear seasonal pattern with stronger intensity in late summer compared to autumn and winter. Reactions with NO2 (30%) and oxygenated volatile organic compounds (OVOCs) (31%) together dominated the OH loss in summer, while reactions with CO (38% in autumn and 39% in winter) and OVOCs (34% in autumn and 25% in winter) made larger contributions in autumn and winter. Photolysis of O3 (36%-47%) presented the major ROX source during all three seasons. The second largest ROx source was HONO photolysis (25%) in summer compared to HCHO photolysis in autumn (20%) and winter (21%). Besides, photolysis of other OVOCs was another important primary source of ROx radicals with average contributions of 14%, 13% and 20% for the summer, autumn and winter cases, respectively. Overall, the present study evaluates the oxidizing capacity of the rural atmosphere of South China and elucidates the varying characteristics of photochemical processes in different air masses. PMID- 28892856 TI - Leachate breakthrough mechanism and key pollutant indicator of municipal solid waste landfill barrier systems: Centrifuge and numerical modeling approach. AB - Groundwater pollution by leachate leakage is one of the most common environmental hazards associated with municipal solid waste (MSW) landfill sites. However, landfill leachate contains a large variety of pollutants with widely different concentrations and biotoxicity. Thus, selecting leachate pollutant indicators and levels for identifying breakthrough of barrier systems are key factors in assessing their breakthrough times. This study investigated the transport behavior of leachate pollutants through landfill barrier systems using centrifuge tests and numerical modeling. The overall objective of this study is to investigate breakthrough mechanism to facilitate the establishment of a consistent pollutant threshold concentration for use as a groundwater pollution alert. The specific objective of the study is to identify which pollutant and breakthrough threshold concentration should be used as an indicator in the transport of multiple pollutants through a landfill barrier system. The threshold concentration from the Chinese groundwater quality standards was used in the analysis of the properties of leachates from many landfill sites in China. The time for the chemical oxygen demand (COD) to reach the breakthrough threshold concentration at the bottom of a 2m compacted clay liner was 1.51years according to centrifuge tests, and 1.81years according to numerical modeling. The COD breakthrough times for single and double composite liners were within the range of 16 and 36.58years. Of all the pollutants, COD was found to consistently reach the breakthrough threshold first. Therefore, COD can be selected as the key indicator for pollution alerts and used to assess the environmental risk posed by MSW landfill sites. PMID- 28892857 TI - A risk-based approach to cumulative effect assessments for marine management. AB - Marine ecosystems are increasingly threatened by the cumulative effects of multiple human pressures. Cumulative effect assessments (CEAs) are needed to inform environmental policy and guide ecosystem-based management. Yet, CEAs are inherently complex and seldom linked to real-world management processes. Therefore we propose entrenching CEAs in a risk management process, comprising the steps of risk identification, risk analysis and risk evaluation. We provide guidance to operationalize a risk-based approach to CEAs by describing for each step guiding principles and desired outcomes, scientific challenges and practical solutions. We reviewed the treatment of uncertainty in CEAs and the contribution of different tools and data sources to the implementation of a risk based approach to CEAs. We show that a risk-based approach to CEAs decreases complexity, allows for the transparent treatment of uncertainty and streamlines the uptake of scientific outcomes into the science-policy interface. Hence, its adoption can help bridging the gap between science and decision-making in ecosystem-based management. PMID- 28892858 TI - Spatiotemporal evolution of the chlorophyll a trend in the North Atlantic Ocean. AB - Analyses of the chlorophyll a concentration (chla) from satellite ocean color products have suggested the decadal-scale variability of chla linked to the climate change. The decadal-scale variability in chla is both spatially and temporally non-uniform. We need to understand the spatiotemporal evolution of chla in decadal or multi-decadal timescales to better evaluate its linkage to climate variability. Here, the spatiotemporal evolution of the chla trend in the North Atlantic Ocean for the period 1997-2016 is analyzed using the multidimensional ensemble empirical mode decomposition method. We find that this variable trend signal of chla shows a dipole pattern between the subpolar gyre and along the Gulf Stream path, and propagation along the opposite direction of the North Atlantic Current. This propagation signal has an overlapping variability of approximately twenty years. Our findings suggest that the spatiotemporal evolution of chla during the two most recent decades is part of the multidecadal variations and possibly regulated by the changes of Atlantic Meridional Overturning Circulation, whereas the mechanisms of such evolution patterns still need to be explored. PMID- 28892859 TI - Assessment of flushing methods for the removal of heavy chlorinated compounds DNAPL in an alluvial aquifer. AB - Immiscible mobilization and foam flushing were assessed as low surfactant consuming technologies, for the enhanced recovery of dense non-aqueous phase liquid (DNAPL) residual at a site contaminated by heavy chlorinated compounds. Preliminary experiments in well-controlled conditions demonstrated the phenomena involved in these remediation technologies and their limitations. Furthermore, we characterized the technologies according to by their surfactant consumption (per kg of DNAPL recovered) and the final DNAPL saturation reached. Surfactant foam flushing (SFF) produced lower DNAPL saturation than immiscible mobilization, thanks to its higher viscosity. However, its efficiency is strongly correlated to the pressure gradient (?P) used during injection, and that is limited by risks of soil fracturing. The two technologies were tested in field cells (10m*10m*10m) delimited by cement/bentonite walls anchored in the clayey substratum. The deepest soil layer was the most contaminated. It was composed of silt-sandy soil and had an average hydraulic conductivity of 10-4ms-1. Field results show that we should now model flushing fluid propagation to design efficient set-ups for recovering the displaced DNAPL. PMID- 28892860 TI - Fine particles at a background site in Central France: Chemical compositions, seasonal variations and pollution events. AB - To expand our knowledge of regional fine particles in Central France (Centre-Val de Loire region), a field observation study of PM2.5 was carried out at Verneuil site (46.81467N, 2.61012E, 180m.a.s.l.) from 2011 to 2014. The mass concentrations of water-soluble inorganic ions (WSIIs), organic carbon (OC), elemental carbon (EC) and biomass burning tracer (Levoglucosan) in PM2.5 were measured. Annual average PM2.5 mass concentrations were 11.8, 9.5, 12.6 and 10.2MUg.m-3 in 2011, 2012, 2013 and 2014, respectively, three of four higher than the WHO guideline of 10MUg.m-3. Secondary inorganic aerosol (SIA) and organic matter (OM) appeared to be the major components in PM2.5 in Verneuil, contributing 30.1-41.8% and 36.9-46.3%, respectively. Main chemical species were observed in the following order: winter>=spring>autumn>summer. Backward atmospheric trajectories were performed using Hysplit model and suggested that the PM2.5 pollutants caused by atmospheric transport were mainly originated from European inland, mainly east to north-east areas. During the observation period, five pollution events were reported and indicated that not only the polluted air masses from central Europe but also the biomass burning from East Europe significantly influenced the air quality in Verneuil site. PMID- 28892861 TI - Assessment of the hazard of nine (doped) lanthanides-based ceramic oxides to four aquatic species. AB - The risk of environmental pollution with rare earth oxides rises in line with increasing application of these compounds in different sectors. However, data on potential environmental hazard of lanthanides is scarce and concerns mostly Ce and Gd. In this work, the aquatic toxicity of eight doped lanthanide-based ceramic oxides (Ce0.9Gd0.1O2, LaFeO3, Gd0.97CoO3, LaCoO3, (La0.5Sr0.5)0.99MnO3, Ce0.8Pr0.2O2, (La0.6Sr0.4)0.95CoO3, LaNiO4) and one non-doped oxide (CeO2) with primary size from 23 to 590nm were evaluated in four short-term laboratory assays with freshwater crustaceans and duckweeds. Results showed no acute toxicity (EC50>100mg/L) or very low acute toxicity for most studied oxides. Observed toxicity was probably due to bioavailable fraction of dopant metals (Ni and Co) but in the case of aquatic plants, decrease of nutrient availability (complexing of phosphorus by lanthanides) was also presumed. Studied oxides/metals accumulated in the aquatic plant tissue and in the gut of crustaceans and thus may be further transferred via the aquatic food chain. Accumulation of metals in the duckweed Lemna minor may be recommended as a cost-effective screening bioassay for assessment of potential hazard of poorly soluble oxides to aquatic ecosystems. PMID- 28892862 TI - Synthesis and characterization of an iron-impregnated biochar for aqueous arsenic removal. AB - : The iron (Fe)-impregnated biochar (FBC), fabricated via thermal pyrolysis of corn straw treated with FeCl3, was investigated for the sorption characteristics and mechanisms of aqueous arsenate removal. Structural and morphological analysis showed that large quantity of iron oxide particles tightly grew within the porous matrix of biochar (BC) through iron-impregnation. Batch sorption experimental results showed that the composite, with larger surface area, more functional groups, and greater thermal stability, exhibited excellent As(V) adsorption efficiency of 6.80mg/g compared to 0.017mg/g for unmodified BC (a 400-fold increase). The adsorption kinetics data were fitted well by pseudo second-order model, and sorption isotherms of As(V) were simulated well by both Freundlich and Langmuir models. XRD and FTIR analysis suggested that electrostatic attraction and precipitation were dominant mechanisms for As(V) sorption. The As(V)-loaded FBC could be easily separated from the solution by a magnet at the end of the sorption experiment. The FBC showed excellent re-sorption capacity, which account for about 70% removal efficiency for the second and third reuse in As(V) sorption. Results from this study demonstrated the promise of FBC composite as an efficient, low-cost, environmentally friendly, and regenerable adsorbent for As(V) remediation. CAPSULE: FBC showed enhanced As(V) sorption capacity, excellent re-sorption capacity, and could be easily separated by a magnet. PMID- 28892863 TI - Mercury in wintering American black ducks (Anas rubripes) downstream from a point source on the lower Penobscot River, Maine, USA. AB - Waterfowl wintering along the lower Penobscot River, Maine continue to be exposed to elevated Hg concentrations from the HoltraChem chlor-alkali plant that operated along the river between 1967 and 2000. In American black ducks (Anas rubripes) total Hg in duck breast muscle increased with residence time on contaminated marshes, reaching means of 0.82+/-0.21MUg/g ww (wet weight) by the end of the fall hunting season, and prompting Maine to issue a human consumption advisory on duck breast muscle. Methyl Hg comprised over 99% of the total Hg in breast muscle. The ratio of Hg concentrations in blood and muscle were strongly correlated and approached 1:1 after extended residence times. Primary feather (P1) total Hg concentrations averaged 2.2+/-1.3MUg/g fw (fresh weight), verifying low Hg exposure during feather growth on distant breeding grounds the preceding summer. Mercury concentrations in black ducks, following winter residence along the lower Penobscot exceeded levels associated with reproductive toxicity. Carry over of Hg to summer breeding grounds may limit the subsequent reproductive success of black ducks. PMID- 28892864 TI - Multi-sensor satellite and in situ monitoring of phytoplankton development in a eutrophic-mesotrophic lake. AB - Phytoplankton indicated by its photosynthetic pigment chlorophyll-a is an important pointer on lake ecology and a regularly monitored parameter within the European Water Framework Directive. Along with eutrophication and global warming cyanobacteria gain increasing importance concerning human health aspects. Optical remote sensing may support both the monitoring of horizontal distribution of phytoplankton and cyanobacteria at the lake surface and the reduction of spatial uncertainties associated with limited water sample analyses. Temporal and spatial resolution of using only one satellite sensor, however, may constrain its information value. To discuss the advantages of a multi-sensor approach the sensor-independent, physically based model MIP (Modular Inversion and Processing System) was applied at Lake Kummerow, Germany, and lake surface chlorophyll-a was derived from 33 images of five different sensors (MODIS-Terra, MODIS-Aqua, Landsat 8, Landsat 7 and Sentinel-2A). Remotely sensed lake average chlorophyll-a concentration showed a reasonable development and varied between 2.3+/-0.4 and 35.8+/-2.0mg.m-3 from July to October 2015. Match-ups between in situ and satellite chlorophyll-a revealed varying performances of Landsat 8 (RMSE: 3.6 and 19.7mg.m-3), Landsat 7 (RMSE: 6.2mg.m-3), Sentinel-2A (RMSE: 5.1mg.m-3) and MODIS (RMSE: 12.8mg.m-3), whereas an in situ data uncertainty of 48% needs to be respected. The temporal development of an index on harmful algal blooms corresponded well with the cyanobacteria biomass development during summer months. Satellite chlorophyll-a maps allowed to follow spatial patterns of chlorophyll-a distribution during a phytoplankton bloom event. Wind conditions mainly explained spatial patterns. Integrating satellite chlorophyll-a into trophic state assessment resulted in different trophic classes. Our study endorsed a combined use of satellite and in situ chlorophyll-a data to alleviate weaknesses of both approaches and to better characterise and understand phytoplankton development in lakes. PMID- 28892865 TI - Size characterization of silver nanoparticles after separation from silver ions in environmental water using magnetic reduced graphene oxide. AB - This study involved the synthesis of magnetic reduced graphene oxide (M-rGO) using a co-precipitation method and examined its resultant adsorption properties for mixtures containing silver ions and silver nanoparticles (AgNPs). The results indicate that M-rGO preferentially adsorbs silver ions in mixtures containing AgNPs, enabling the size characterization of smaller AgNPs (<60nm) at ultra-trace concentration levels to be more attainable. The sorbents after adsorption could be easily recovered through an external magnet. The AgNPs retained in solution were characterized using single-particle ICPMS (SP-ICPMS). The adsorption behavior of silver ions on M-rGO was well fitted with the pseudo-second-order kinetic model and the Freundlich adsorption isotherm model, with the conclusion that the adsorption of silver ions occurred primarily through the chemical bond effect and the heterogeneous surface of the sorbent. Finally, the application of M-rGO with the approach developed herein to actual environmental water samples was successful. PMID- 28892866 TI - Removal of hazardous non-steroidal anti-inflammatory drugs from aqueous solutions by biosorbent based on chitin and lignin. AB - The use of chitin modified with kraft lignin as an effective sorbent of ibuprofen and acetaminophen is described for the first time. It was determined how the parameters (contact time, pH, mass of sorbent and temperature) influence the effectiveness of the adsorption process. The adsorption kinetics were calculated using pseudo-first-order, pseudo-second-order (types 1-4) and intra-particle diffusion models, and thermodynamic parameters were determined. The experimental data better correspond to a pseudo-second-order kinetic model of type 1 in the case of both tested pharmaceuticals (r2=0.999). The negative values of DeltaH degrees show the adsorption to be exothermic (-5.515kJ/mol and -5.161kJ/mol for ibuprofen and acetaminophen respectively). Adsorption isotherms, using Langmuir isotherms of types 1-4 and Freundlich model, were also determined. The experimental data better correspond to the Langmuir type 1 model in the case of ibuprofen, and to the Freundlich model in the case of acetaminophen. Desorption tests were carried out to confirm the possibility of reusing the chitin/lignin system. A mechanism of adsorption of ibuprofen and acetaminophen on the chitin/lignin system was also proposed. PMID- 28892867 TI - Land surface temperature as an indicator of the unsaturated zone thickness: A remote sensing approach in the Atacama Desert. AB - Land surface temperature (LST) seems to be related to the temperature of shallow aquifers and the unsaturated zone thickness (?Zuz). That relationship is valid when the study area fulfils certain characteristics: a) there should be no downward moisture fluxes in an unsaturated zone, b) the soil composition in terms of both, the different horizon materials and their corresponding thermal and hydraulic properties, must be as homogeneous and isotropic as possible, c) flat and regular topography, and d) steady state groundwater temperature with a spatially homogeneous temperature distribution. A night time Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) image and temperature field measurements are used to test the validity of the relationship between LST and ?Zuz at the Pampa del Tamarugal, which is located in the Atacama Desert (Chile) and meets the above required conditions. The results indicate that there is a relation between the land surface temperature and the unsaturated zone thickness in the study area. Moreover, the field measurements of soil temperature indicate that shallow aquifers dampen both the daily and the seasonal amplitude of the temperature oscillation generated by the local climate conditions. Despite empirically observing the relationship between the LST and ?Zuz in the study zone, such a relationship cannot be applied to directly estimate ?Zuz using temperatures from nighttime thermal satellite images. To this end, it is necessary to consider the soil thermal properties, the soil surface roughness and the unseen water and moisture fluxes (e.g., capillarity and evaporation) that typically occur in the subsurface. PMID- 28892868 TI - Assessing the feasibility of integrating ecosystem-based with engineered water resource governance and management for water security in semi-arid landscapes: A case study in the Banas catchment, Rajasthan, India. AB - Much of the developing world and areas of the developed world suffer water vulnerability. Engineering solutions enable technically efficient extraction and diversion of water towards areas of demand but, without rebalancing resource regeneration, can generate multiple adverse ecological and human consequences. The Banas River, Rajasthan (India), has been extensively developed for water diversion, particularly from the Bisalpur Dam from which water is appropriated by powerful urban constituencies dispossessing local people. Coincidentally, abandonment of traditional management, including groundwater recharge practices, is leading to increasingly receding and contaminated groundwater. This creates linked vulnerabilities for rural communities, irrigation schemes, urban users, dependent ecosystems and the multiple ecosystem services that they provide, compounded by climate change and population growth. This paper addresses vulnerabilities created by fragmented policy measures between rural development, urban and irrigation water supply and downstream consequences for people and wildlife. Perpetuating narrowly technocentric approaches to resource exploitation is likely only to compound emerging problems. Alternatively, restoration or innovation of groundwater recharge practices, particularly in the upper catchment, can represent a proven, ecosystem-based approach to resource regeneration with linked beneficial socio-ecological benefits. Hybridising an ecosystem-based approach with engineered methods can simultaneously increase the security of rural livelihoods, piped urban and irrigation supplies, and the vitality of river ecosystems and their services to beneficiaries. A renewed policy focus on local-scale water recharge practices balancing water extraction technologies is consistent with emerging Rajasthani policies, particularly Jal Swavlamban Abhiyan ('water self-reliance mission'). Policy reform emphasising recharge can contribute to water security and yield socio-economic outcomes through a systemic understanding of how the water system functions, and by connecting goals and budgets across multiple, currently fragmented policy areas. The underpinning principles of this necessary paradigm shift are proven and have wider geographic relevance, though context-specific research is required to underpin robust policy and practical implementation. PMID- 28892869 TI - Structural analysis of the interaction between Jaburetox, an intrinsically disordered protein, and membrane models. AB - Jack bean urease is entomotoxic to insects with cathepsin-like digestive enzymes, and its toxicity is mainly caused by a polypeptide called Jaburetox (Jbtx), released by cathepsin-dependent hydrolysis of the enzyme. Jbtx is intrinsically disordered in aqueous solution, as shown by CD and NMR. Jbtx is able to alter the permeability of membranes, hinting to a role of Jbtx-membrane interaction as the basis for its toxicity. The present study addresses the structural aspects of this interaction by investigating the behaviour of Jbtx when in contact with membrane models, using nuclear magnetic resonance and circular dichroism spectroscopies in the absence or presence of micelles, large unilamellar vesicles, and bicelles. Fluorescence microscopy was also used to detect protein insect membrane interaction. Significant differences were observed depending on the type of membrane model used. The interaction with negatively charged SDS micelles increases the secondary and tertiary structure content of the polypeptide, while, in the case of large unilamellar vesicles and bicelles, conformational changes were observed at the terminal regions, with no significant acquisition of secondary structure motifs. These results were interpreted as suggesting that the Jbtx-lipids interaction anchors the polypeptide to the cellular membrane through the terminal portions of the polypeptide and that, following this interaction, Jbtx undergoes conformational changes to achieve a more ordered structure that could facilitate its interaction with membrane-bound proteins. Consistently with this hypothesis, the presence of these membrane models decreases the ability of Jbtx to bind cellular membranes of insect nerve cord. The collected evidence from these studies implies that the biological activity of Jbtx is due to protein-phospholipid interactions. PMID- 28892870 TI - Effects of terminal capping on the fibrillation of short (L-Glu)n peptides. AB - Several homopolypeptides including poly-l-glutamic acid (PLGA) form amyloid-like fibrils under favorable physicochemical conditions. We have shown recently that even short uncapped (Glu)n peptides (for n>3) form fibrillar beta-aggregates which cross-seed with amyloid fibrils obtained from high molecular weight fractions of PLGA. Here we investigate effects of N-terminal acetylation and C terminal amidation on the amyloidogenic tendencies of (Glu)n peptides containing 3, 4, and 5 residues. Our results based primarily on time-lapse FT-IR spectroscopy and AFM microscopy indicate that selective modifications of C termini (and, to a lesser degree, of N-termini) decrease capacity of tetra- and pentapeptides to form fibrils. On the other hand, peptides modified at both ends appear to form fibrils as fast as unmodified analogues. In fact, the double terminal modification enables fibrillation of (Glu)3 which is not fibrillogenic in the unmodified state. The AFM data suggests that the double capping results in the aggregates becoming more tape-like or acquiring noticeable tendencies to bend. According to seeding and cross-seeding experiments, there is a high degree of promiscuity between modified and unmodified peptides. Possible mechanisms explaining how amyloidogenic propensities of (Glu)n peptides are affected by terminal modifications have been discussed. PMID- 28892871 TI - Formulation by design approach for development of ultrafine self-nanoemulsifying systems of rosuvastatin calcium containing long-chain lipophiles for hyperlipidemia management. AB - The present work entails systematic development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) of rosuvastatin calcium containing long-chain lipophiles using QbD-driven Formulation by Design (FbD) approach. Elements of quality target product profile (QTPP) were defined and critical material attributes (CQAs) earmarked. Excipient screening was performed for selecting a suitable long-chain lipophile along with a surfactant and a cosolvent. Maximal drug solubility was observed in Peceol (i.e., lipid), Tween 80 (i.e., surfactant) and Transcutol HP (i.e., cosolvent), which during pseudoternary phase titration study indicated maximal nanoemulsion region at 1:1 ratio of surfactant: cosolvent mixture. Risk analysis and factor screening study indicated selection of excipient levels as the critical material attributes (CMAs). D-optimal mixture design was used for systematic optimization of L-SNEDDS, which exhibited emulsification time of 131s, globule size <100nm and faster drug release rate >80% in 15min. Ex vivo permeability showed >70% permeation of drug across the rat intestine, while in situ perfusion study indicated up to 1.8 and 2.1-folds improvement in permeability and absorptivity parameters of the drug from optimized L-SNEDDS over the plain drug suspension. In vivo pharmacokinetic studies revealed 1.8- and 5.7-folds enhancement in AUC0-t and Cmax, and 0.33 folds reduction in Tmax of drug from the optimized L-SNEDDS vis-a-vis the pure plain drug suspension. In vivo pharmacodynamic studies also indicated superior antihyperlipidemic activity of optimized L-SNEDDS in normalizing serum lipid levels. Overall, the research work construed significant role of long-chain lipophiles in enhancing biopharmaceutical attributes of the L-SNEDDS of rosuvastatin. PMID- 28892872 TI - Polymer-lipid hybrid nanoparticles-based paclitaxel and etoposide combinations for the synergistic anticancer efficacy in osteosarcoma. AB - In this study, paclitaxel and etoposide-loaded lipid-polymer hybrid nanoparticles (PE-LPN) was successful prepared and evaluated for physicochemical and anticancer effect. Nanosized PE-LPN was obtained with a perfect spherical morphology. PE-LPN exhibited a controlled release of two drugs in a sequential manner. The nanoparticles exhibited a typical endocytosis-mediated cellular uptake in cancer cells. The ratiometric combination of paclitaxel (PTX) and etoposide (ETP) were significantly more cytotoxic than individual drugs. Importantly, superior cytotoxic effect was observed for dual-drug-loaded PE-LPN than cocktail combination at a much lower dose. Similarly, PE-LPN exhibited a significantly higher apoptosis of cancer cells (~45%) compared to that of any other groups with higher caspase-3 and -8 activity. Importantly, PE-LPN showed a remarkable tumor regression effect and exhibited a 2-fold superior efficacy than free drugs. PE LPN treated group showed significantly less Ki-67 positive cells (less than 25%) than PTX/ETP and single drug treated groups, suggesting less active cell proliferation and a considerably higher tumor growth inhibition effect. The results collectively showed that combination of drugs could greatly improve the therapeutic property of chemotherapeutic drugs. By combining ETP with PTX (a powerful anticancer drug) in a polymer-lipid hybrid nanoparticle system, therapeutic efficacy could be improved in osteosarcoma treatments. PMID- 28892873 TI - Combination of PCR and dual nanoparticles for detection of Plasmodium falciparum. AB - Highly reactive particle-based DNA amplification was developed for the detection of the Pfg377 gene from P. falciparum gametocytes using functional magnetic latex particles (MLPs) and quantum dots encapsulated polymer particles (QDs-PPs). Firstly, MLPs were prepared from the precipitation of iron oxide, polymerization using initiator, and adsorption of aminodextran (AMD) so as to provide amino functionalized MLPs. Furthermore, amino-containing polymer particles (PPs) were prepared by emulsifier-free polymerization and encapsulated with fluorescent quantum dots (QDs) for use as a signaling support. Subsequently, poly(maleic anhydride-alt-methyl vinyl ether) (PMAMVE) copolymer was effectively used for rapid and simple grafting of amino-modified DNA primers onto the surface of amino functionalized particles thereby providing a promising method for particle immobilization. Herein, primer-grafted particles were applied in the amplification of the Pfg377 gene using the PCR approach. After amplification, PCR products containing PMAMVE-grafted MLPs and QDs-PPs were separated using a magnet and examined via a fluorescence microscope. PMAMVE-grafted particles were not found to inhibit the PCR reaction while facilitating efficient fluorescent detection of the PCR product. Results showed high sensitivity and specificity for the detection of amplified Pfg377 gene within only a few steps. This procedure represents a novel improvement to the post-amplification analysis. PMID- 28892874 TI - Mortality from multiple sclerosis in British military personnel. AB - BACKGROUND: While analysing trends in occupational mortality in England and Wales, we noticed an unexpectedly elevated proportion of deaths from multiple sclerosis (MS) among men in the armed forces. AIMS: To document and explore possible explanations for the observed excess. METHODS: We analysed data on underlying cause of death and last full-time occupation for 3,688,916 deaths among men aged 20-74 years in England and Wales during 1979-2010, calculating proportional mortality ratios (PMRs) standardised for age. We compared PMRs for MS in the armed forces with those for each main social class, and in selected other occupations. We also compared PMRs for MS with those for motor neurone disease (MND). RESULTS: The overall PMR for MS in the armed forces during 1979 2010 was 243 (95%CI 203-288). The excess was apparent in each of three separate decades of study (PMRs, ranging from 220 to 259), and across the entire age range. PMRs for MS were not elevated to the same extent in comparator occupations, nor in any of the main social classes. There was no parallel increase in PMRs for MND. CONCLUSIONS: These findings suggest that the high proportional mortality from MS in British military personnel is unlikely to have occurred by chance, or as an artefact of the method of investigation. However, the only military cohort study with published results on MS does not support an increased risk. It would be useful to analyse data on MS from other established military cohorts, to check for evidence of a hazard. PMID- 28892875 TI - Development of Parafollicular Cells and their Relationship with Developing Thyroid Follicles in Human Foetuses. AB - INTRODUCTION: The parafollicular cells or clear (C) cells in man are part of neuroendocrine system under Amine Precursor Uptake and Decarboxylation (APUD) cells. Their role in adults has been reputable but in foetus is still unclear. AIM: The present study was a baseline study endeavouring to describe the chronological development of the parafollicular cells with particular focus on its correlation with developing human thyroid follicles. MATERIALS AND METHODS: The study was conducted on 10 aborted foetuses (14-28 weeks), procured from the Department of Obstetrics and Gynaecology, Lok Nayak Hospital, New Delhi, India. Serial sections of foetal thyroid gland were generated, stained with haematoxylin and eosin, and immunohistochemistry using the anticalcitonin antibody and examined qualitatively. RESULTS: In our study, the parafollicular cells were seen as earlier as by 14th week. They became morphologically and functionally mature by 16th week of gestation. The parafollicular cells were getting organized from scattering to parafollicular location then to a more localized area, i.e., intrafollicular along with the follicular development. As the follicles were enlarging, the intrafollicularly located parafollicular cells which was initially present in groups was getting displaced singly between the follicular cells in the same follicle. CONCLUSION: The sequential development pattern of the parafollicular cells in relation to developing thyroid follicles was established. This immunohistochemical study also concluded that the parafollicular cells might have higher character to play in the early gestational age such as regulation of ossification in the human foetus. PMID- 28892876 TI - Effect of Radiofrequency Radiation Emitted from 2G and 3G Cell Phone on Developing Liver of Chick Embryo - A Comparative Study. AB - INTRODUCTION: The increasing scientific evidence of various health hazards on exposure of Radiofrequency Radiation (RFR) emitted from both the cell phones and base stations have caused significant media attention and public discussion in recent years. The mechanism of interaction of RF fields with developing tissues of children and fetuses may be different from that of adults due to their smaller physical size and variation in tissue electromagnetic properties. The present study may provide an insight into the basic mechanisms by which RF fields interact with developing tissues in an embryo. AIM: To evaluate the possible tissue and DNA damage in developing liver of chick embryo following chronic exposure to Ultra-High Frequency/Radiofrequency Radiation (UHF/RFR) emitted from 2G and 3G cell phone. MATERIALS AND METHODS: Fertilized chick embryos were incubated in four groups. Group A-experimental group exposed to 2G radiation (60 eggs), Group B- experimental group exposed to 3G radiation (60 eggs), Group C- sham exposed control group (60 eggs) and Group D- control group (48 eggs). On completion of scheduled duration, the embryos were collected and processed for routine histological studies to check structural changes in liver. The nuclear diameter and karyorrhexis changes of hepatocytes were analysed using oculometer and square reticule respectively. The liver procured from one batch of eggs from all the four groups was subjected to alkaline comet assay technique to assess DNA damage. The results were compared using one-way ANOVA test. RESULTS: In our study, the exposure of developing chick embryos to 2G and 3G cell phone radiations caused structural changes in liver in the form of dilated sinusoidal spaces with haemorrhage, increased vacuolations in cytoplasm, increased nuclear diameter and karyorrhexis and significantly increased DNA damage. CONCLUSION: The chronic exposure of chick embryo liver to RFR emitted from 2G and 3G cell phone resulted in various structural changes and DNA damage. The changes were more pronounced in 3G experimental group. Based on these findings it is necessary to create awareness among public about the possible ill effects of RFR exposure from cell phone. PMID- 28892877 TI - A Rare Presentation of Grossly Deformed Lungs in a Kyphoscoliotic Female Cadaver. PMID- 28892878 TI - Role of Anthropometric Measurements in Development of CVD and Stroke among T2DM in East Godavari District, Andhra Pradesh, India. AB - INTRODUCTION: Cardiovascular morbidity and mortality have been associated with different variables of anthropometric measurements. AIM: To find out the association of anthropometric measurements in the development of Cardiovascular Disease (CVD) and stroke among Type 2 Diabetes Mellitus (T2DM). MATERIALS AND METHODS: Three hundred subjects were included in the study out of which 100 subjects were known type 2 diabetics with CVD or Stroke (Group 1), 100 subjects were type 2 diabetic patients (Group 2) and 100 subjects were normal and healthy (Group 3). Blood Pressure (BP), Body Mass Index (BMI) Neck Circumference (NC), Waist Circumference (WC), Hip Circumference (HC), Glycated haemoglobin (HbA1c), high sensitive- C-Reactive Protein (hsCRP), Malondialdehyde (MDA), Homocysteine (Hcy), microalbuminuria and estimated glomerular filtration rate (eGFR) were compared between all three groups by using one-way ANOVA test, comparison between males and females by t-test and association was done by using Chi-square test. RESULTS: There were a significant difference in the means of anthropometric and biochemical parameters of the three groups (p<0.05). Diastolic BP, NC, WC, HC and homocysteine, are higher in T2DM obese patients than T2DM over weight and normal weight patients are statistically significant (p<0.05). The mean of levels systolic BP, Diastolic BP, hsCRP are higher in T2DM over weight patients than T2DM obese and normal weight patients are statistically significant (p<0.05). Association of physical activity, snoring and interrupted sleep with BMI was statistical significant (p<0.05). CONCLUSION: Obesity and overweight in T2DM patients play important role in elevation of blood pressure and inflammation markers like hsCRP, homocysteine. Snoring and interrupted sleep also involved development of CVD and Stroke among T2 diabetes. PMID- 28892879 TI - Evaluation of Anti-Cyclic Citrullinated Peptide Autoantibodies and C-Reactive Protein in Common Autoimmune Skin Diseases with and without Arthritis. AB - INTRODUCTION: Anti-Cyclic Citrullinated Peptides (CCPs) are a well known diagnostic and prognostic noble marker for rheumatoid arthritis. C-Reactive Protein (CRP) is an acute phase protein whose level rises in response to inflammation. AIM: This study was undertaken to show the role of the two markers (anti-CCPs and CRP) in autoimmune skin disorder and their association with associated arthritis in these disorder. MATERIALS AND METHODS: Serum anti-CCP antibodies and CRP was measured in 50 patients of autoimmune skin disease of which 28 were of psoriasis, 12 of Systemic Lupus Erythematosus (SLE) and 10 of Pemphigus Vulgaris (PV). These patients were categorised in two groups, with associated arthritis and without arthritis. The serum level of anti-CCP and CRP was correlated with the presence or absence of arthritis in these patients. Control group consists of 20 healthy subjects in which these two parameters were measured. RESULTS: Out of total of 50 patients, anti-CCP was raised in 36.37% of patients with associated arthritis and 12.82% of patients without arthritis whereas CRP was raised in 63.63% of patients with arthritis and 35.89% of patients without arthritis. Mean serum anti-CCP in patient with arthritis was 15.78+/-13.94 U/ml and without arthritis was 7.56+/-7.68 U/ml with p=0.01 which was statistically significant. Mean serum CRP in arthritis was 21.11+/-15.51 mg/l and CRP without arthritis was 13.14+/-12.27 mg/l with p=0.07 which was statistically not significant. CONCLUSION: Although both anti-CCP and CRP are valuable markers for autoimmune skin disorder, anti-CCP seems to show significant association with arthritis. PMID- 28892880 TI - Elevation of Oxidative Stress and Decline in Endogenous Antioxidant Defense in Elderly Individuals with Hypertension. AB - INTRODUCTION: Hypertension is becoming an important medical and public health problem all over the world and is the most common disorder of ageing. There is a growing evidence of involvement of vascular oxidative stress in the development of hypertension from animal studies. However, studies on humans with hypertension, particularly in elderly are least and data remained controversial. Moreover, studies in elderly people with hypertension are scarce. AIM: To investigate the possible role of oxidative stress and antioxidant defense in the pathogenesis of hypertension in elderly. MATERIALS AND METHODS: A cross-sectional study was conducted on elderly males (n=60) with newly diagnosed hypertension and with normal blood pressure. Oxidative stress and antioxidant status were evaluated by assessing the following parameters: plasma Malondialdehyde (MDA), and antioxidants: Superoxide Dismutase (SOD) activity, reduced Glutathione (GSH), and vitamin C levels; and total Nitric Oxide concentration in plasma (NOx). Difference between groups was determined by using unpaired t-test/Mann-Whitney U test. Bivariate correlation and multiple regression analysis were used to determine the relationship between variables. RESULTS: A significant rise in plasma MDA (p-value=0.013) and lower levels of endogenous antioxidants: SOD (p value<=0.001) and GSH (p-value<=0.001) were observed in elderly individuals with hypertension when compared to healthy controls. Though not significant, there was a mean decrease in plasma NOx in hypertensive subjects than normotensive ones. While vitamin C showed no significant difference between two groups. Decrease in GSH (beta=-0.398; p-value=0.001) and SOD (beta=-0.423; p-value<=0.001) were the significant determinants of hypertension in elderly individuals. CONCLUSION: Above findings indicate that elevation in oxidative stress and decrease in endogenous antioxidant level may be involved in the pathogenesis of hypertension. However, it remains unclear whether oxidative stress causes or augments hypertension. PMID- 28892881 TI - Thyroid Hormone Levels in Chronic Alcoholic Liver Disease Patients Before and After Treatment. AB - INTRODUCTION: Alcoholic liver disease affects almost all aspects of the thyroid gland including the thyroid hormone levels and the thyroid gland size. The altered thyroid hormone levels in alcoholic liver disease may affect alcohol abstinence in withdrawal period by changing hormone milieu in brain, increasing withdrawal dysphoria and increasing craving. AIM: The aim of the present study was to assess and compare the levels of thyroid hormones- free T3, free T4, Thyroid Stimulating Hormone (TSH) and Gamma Glutamyl Transferase (GGT) in chronic alcoholic liver disease patients before and after treatment. MATERIALS AND METHODS: This study was conducted on 70 alcoholic liver disease patients. Two serum samples were taken from the patient once at the time of admission and the other at the time of discharge after atleast ten days of treatment. Serum free T3, free T4, TSH and GGT were assessed on auto analyzer Beckman Coulter. Statistical analysis is done by paired t-test and Pearson's Correlation test. RESULTS: In present study, serum GGT levels decreased significantly (before treatment-207.46+/-66.90 U/L; after treatment-78.47+/-19.71 U/L) and free T3 levels increased significantly with treatment (before treatment-2.54+/-0.48 pg/mL; after treatment-2.88+/-0.37 pg/mL). Free T4 levels are also increased with treatment (before treatment-0.78+/-0.19 ng/dL; after treatment-0.88+/-0.13 ng/dL) and TSH levels are not altered significantly with treatment (before treatment 3.34+/-1.62 MUIU/mL; after treatment-3.32+/-1.51 MUIU/mL). Additionally, free T3 showed a significant correlation with GGT before (p-value<0.001) and after treatment (p-value-0.003) and free T4 and TSH showed a significant correlation with GGT after treatment (free T4: p-value<0.001) (TSH: p-value <0.001) and a suggestive significance exists before treatment (free T4: p-value= 0.098) (TSH: p value=0.062). CONCLUSION: Thyroid hormones levels, particularly free T3 and free T4, need to be evaluated in chronic alcoholic liver disease patients. Free T3 could be used as a marker of alcoholism and is very useful in assessing the treatment efficacy in chronic alcoholic liver disease. Also, assessing free thyroid hormones is necessary during the withdrawal and abstinent periods as decreased hormone levels may increase withdrawal effects and craving for alcohol. PMID- 28892882 TI - Circulating Protein Carbonyls, Antioxidant Enzymes and Related Trace Minerals among Preterms with Respiratory Distress Syndrome. AB - INTRODUCTION: Information about oxidative stress in preterms with Respiratory Distress Syndrome (RDS) is defective, so various researches in this area are required, which may open new roads in understanding the pathogenesis of the disease, hence provide additional helpful therapeutic approaches. AIM: To assess and compare the plasma level of protein carbonyls as a marker for oxidant status and the antioxidant enzymes; Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) and the related trace minerals in the form of Copper (Cu), Zinc (Zn) and Selenium (Se) as markers for antioxidant status, in preterms with and without RDS. MATERIALS AND METHODS: A hospital-based case-control study was conducted on fifty-seven preterm neonates (37 preterms with RDS and 20 preterms without RDS) admitted to neonatal intensive care unit of Qena University Hospitals after approval of the University Hospital Ethical Committee. Plasma protein carbonyls assay was done using commercially available ELISA assay kit. Plasma Cu, Zn, Se, erythrocyte SOD and GPx activities assays were done using commercially available colorimetric assay kits. RESULTS: Significant higher plasma levels of protein carbonyls and oxidant/antioxidants ratio (protein carbonyls/{SOD+GPx}) with significant lower plasma levels of Zn, Cu, Se, erythrocyte SOD and GPx activities were found in the preterms with RDS when compared with the preterms without RDS (p<0.001 for all measured markers for both groups). In terms of birth weights and gestational ages, they were negatively correlated with both plasma protein carbonyls and oxidant/antioxidants ratio and positively correlated with plasma copper, zinc, selenium, erythrocyte SOD and GPx activities in a statistically significant manner. Non-significant correlations were found between the measured oxidative stress markers and the severity of RDS. CONCLUSION: Oxidative stress may have a contributory role in the development of RDS among preterms. Lower birth weight and prematurity may increase the susceptibity to oxidative stress among such patients. PMID- 28892883 TI - A Case of Hyperargininaemia Presenting at Unusually Low Age. AB - Arginase or ARG1 gene deficiency is a Type V Urea Cycle Disorder (UCD) (catalysing the fifth reaction of urea cycle), associated with hyperammonaemia. Here, we discuss a rare case of a 13-month-old female, having Severe Acute Malnutrition (SAM) and failure to thrive, with serial high plasma ammonia, normal plasma lactate with high arginine and glutamine levels on Amino Acid Assay (AAA) which was performed on 1220 Agilent HPLC. She was admitted for about a month and eventually succumbed to her ailment after a month of discharge. PMID- 28892884 TI - Effect of Metaboreflex on Cardiovascular System in Subjects of Metabolic Syndrome. AB - INTRODUCTION: Metaboreflex is a reflex in which muscle receptors send signals regarding metabolic (metabolites accumulation like lactic acid, potassium, adenosine) conditions of the muscles to nucleus tractus solitarius via afferent III and IV fibres to cause haemodynamic adjustments in order to regulate blood flow on the basis of the status of contracting muscle. Dysregulation in its mechanism in metabolic syndrome is demonstrated. AIM: To study the effect of metaboreflex by both isometric and rhythmic handgrip exercise on CVS parameters {Blood Pressure (BP), Cardiac Output (CO) and Systemic Vascular Resistance (SVR)} in subjects of metabolic syndrome. MATERIALS AND METHODS: In this study, 27 subjects aged 25 to 45 years were enrolled after ethical clearance and proper consent. They were divided into: a) subjects without metabolic syndrome; and b) subjects with metabolic syndrome. Impedance cardiovasography was done to assess cardiac parameters (systolic and diastolic blood pressure, cardiac output, systemic vascular resistance). Pre-exercise parameters were assessed followed by isometric exercise and post-isometric exercise parameter measurement. Again after rest, rhythmic exercise was followed. Finally post exercise parameters were assessed. Student paired t-test for comparison between pre and post exercise parameters were done. RESULTS: Changes in diastolic BP following exercise were statistically significant in subjects without metabolic syndrome (p-value 0.01 and 0.001 following isometric and rhythmic exercise respectively). In subjects with metabolic syndrome also these changes were significant, but to a lesser extent (p-value 0.1 and 0.01 respectively for isometric and rhythmic exercise). Changes in systolic BP following exercise were statistically significant in subjects without metabolic syndrome (p-value 0.001 and 0.001 following isometric and rhythmic exercise respectively). In subjects with metabolic syndrome also these changes were significant (p-value 0.01 and 0.001 respectively for isometric and rhythmic exercise). CONCLUSION: Diminished pressor response is found after exercise in subjects with metabolic syndrome. PMID- 28892885 TI - An Analysis into Metacognition and Family History of Diabetes Mellitus among First Year Medical Students. AB - INTRODUCTION: Medical course requires immense effort by the students to deal with vast curriculum and hence, the need to adopt metacognitive skill to cope up. Diabetes mellitus has an impact on cognition. Metacognition, being a component of cognition, is likely to be affected by diabetes. Children of diabetic parents have demonstrated insulin resistance which may contribute to metacognitive dysfunction. Hence, it is important to focus into the link between family history of diabetes and metacognition. AIM: To evaluate the impact of family history (parents and grandparents) of diabetes mellitus on metacognition in medical students. MATERIALS AND METHODS: The present study was a questionnaire based cross-sectional study. Hundred first year medical students were recruited and they filled the Metacognitive Awareness (MA) questionnaire along with the details of the family history of diabetes. The metacognitive awareness questionnaire evaluated MA, its components (metacognitive knowledge and regulation) and their subcomponents. Positive history of diabetes in parents and grandparents were taken into account. The participants were then divided into two groups: with family history of diabetes (n=73) and without family history of diabetes (n=27). The metacognitive awareness and its subcomponents between the two groups were analysed using Student t-test between the groups (with and without family history). Pearson correlation was done to analyse the association between metacognition and family history of diabetes. RESULTS: Metacognitive knowledge (global score) was significantly lower in group with family history of diabetes (10.25+/-3.01 vs 12.04+/-3.2, p-value<0.05) as was metacognitive regulation global score (7.08+/-1.83 vs 7.99+/-1.36, p-value<0.05). Declarative knowledge and information management showed significant difference. Metacognitive knowledge showed a significant negative correlation with family history of diabetes (correlation coefficient = -0.263, p-value<0.01). CONCLUSION: Students with family history of diabetes had reduced metacognitive awareness. The awareness that metacognitive dysfunction can occur in early age in individuals with family history of diabetes would help us to identify them and device strategies to delay or prevent metacognitive dysfunction. PMID- 28892886 TI - Statistical Comments on "Assessment of Musculoskeletal Strength and Levels of Fatigue During Different Phases of Menstrual Cycle in Young Adults". PMID- 28892887 TI - Active Surveillance of Health Care Associated Infections in Neurosurgical Patients. AB - INTRODUCTION: Health Care Associated Infections (HCAI) are frequent complications in neurosurgery. There is limited data available on the incidence and burden of HCAI in neurosurgical patients of Southeast Asian region. AIM: To identify various HCAIs, associated aetiological agents and their antimicrobial susceptibility pattern among the patients admitted in the neurosurgery unit. MATERIALS AND METHODS: An observational prospective study was carried out for three months duration on all neurosurgical patients admitted to a tertiary-care center. The site-specific nosocomial infection rates and device utilization ratios were calculated. Data on demographic profiles, invasive procedures, HCAI, isolated microorganisms and antimicrobial susceptibilities were recorded. Statistical analysis of all the variables was done. The association between categorical variables was assessed by Chi-square/Fisher-exact test. Continuous variables such as infected and non-infected were compared by Wilcoxon rank-sum test. A p-value of less than 0.05 was considered significant. RESULTS: A total of 330 patients with 4054 patient-days were analysed for HCAI. Twenty-two HCAIs were identified in 21 patients. The overall rate of HCAI was 6.67% and 5.42 per 1000 patient-days. Urinary Tract Infection (UTI) was most common (71.4%) followed by Laboratory Confirmed Blood-Stream Infection (LCBI) (28.5%) and pneumonia (4.7%). No central line-associated blood stream infection was identified. Klebsiella pneumoniae and Escherichia coli were the most common organisms causing UTI and LCBI. All the isolates (100%) were found to be multidrug resistant. CONCLUSION: This study generates a baseline data for records of device-associated infection in neurocritical care patients, which will further help monitoring its trend of infection and antimicrobial resistance pattern. Moreover, it will help in the formulation of the antibiotic policy and the preventive measures which may reduce morbidity and mortality. PMID- 28892888 TI - Role of Herbal Agents - Tea Tree Oil and Aloe vera as Cavity Disinfectant Adjuncts in Minimally Invasive Dentistry-An In vivo Comparative Study. AB - INTRODUCTION: The prevention and control of caries necessitates the elimination of cariogenic bacteria and cavity disinfectants have proved to play a major role in achieving the goal. The use of phytotherapy is trending and many natural products have shown anti-microbial properties which can be used as cavity disinfectant in the field of dentistry. AIM: The aim of this study was to compare the efficacy of herbal antibacterial agents (Tea Tree Oil (TTO) and Aloe vera) with commercially available 2% chlorhexidine (CHX) as cavity disinfectant for use in minimally invasive dentistry. MATERIALS AND METHODS: The study included three test groups, Group I (2% chlorhexidine), Group II (tea tree oil), Group III (Aloe vera gel) with a control group (distilled water). Ten patients with atleast one tooth with an occlusal or occluso-proximal lesion suitable for Atraumatic Restorative Treatment (ART) were selected for each group, dentinal samples were collected using sterile spoon excavators at three stages from each tooth viz., pre-excavation, post-excavation and post-disinfection of the cavities. These dentinal samples were subjected to microbiological analysis for Total Viable Count (TVC). The data collected were statistically analysed using ANOVA and Bonferroni post-hoc test. RESULTS: The results of present study showed that there was a statistically significant reduction in TVC when compared between pre and post excavation in all the groups (p<0.05) and post- excavation and post disinfection in all the test groups (p<0.05) (except control group). Post disinfection, 2% chlorhexidine showed highest reduction in TVC followed by 1% tea tree oil and aloe vera gel. CONCLUSION: Natural antibacterial agents like tea tree oil and aloe vera could be effectively used as cavity disinfectants which will help in minimizing secondary caries and rendering a long term restorative success. PMID- 28892889 TI - Fungal Rhinosinusitis: Microbiological and Histopathological Perspective. AB - INTRODUCTION: On the basis of histopathology Fungal Rhinosinusitis (FRS) is categorized into non-invasive (allergic fungal rhinosinusitis, fungal ball) and invasive (acute invasive, chronic invasive and granulomatous invasive fungal sinusitis). This differentiation helps to decide the treatment. Role of latest molecular methods such as PCR and conventional methods such as KOH microscopy and culture also needs to be evaluated. Therefore, in this study we planned to categorise fungal rhinosinusitis on the basis of histopathology and compare it with other methods such as PCR, culture and KOH microscopy. AIM: To analyse fungal rhinosinusitis cases by both histopathologically and microbiologically. MATERIALS AND METHODS: A total of 76 clinically suspected fungal rhinosinusitis cases were included in the study. The tissue of suspected cases were processed and examined by KOH microscopy, histopathologically, culture and PCR. Histopathological examination was done by PAS, GMS and H&E stain. RESULTS: FRS was diagnosed in 37 (48.68%) cases out of 76 clinically suspected cases of FRS. In which 17 (22.3%) cases were positive by direct microscopy, 21 (27.6%) by culture, 27 (35.5%) by PCR and 14 (18.42%) by histopathology. Approximately 14 cases of FRS were classified according to histopathology; 10 (71.3%) as non invasive FRS. Out of these 10, 9 (64.2%) were classified as AFRS and 1 (7.14%) as fungal ball. Only 4 cases (28.5%) were diagnosed with invasive FRS. Out of these 4 cases, 2 (14.2%) were of chronic invasive fungal rhinosinusitis, 1 (7.14%) was of granulomatous invasive fungal rhinosinusitis and 1 (7.14%) was of acute fulminant invasive fungal rhinosinusitis. Allergic Fungal Rhinosinusitis (AFRS) is the most common type of FRS. Aspergillus flavus was found to be the most common fungi causing FRS. CONCLUSION: Diagnosis should not be based on the single method. It should be done by both histopathological and microbiological methods, especially for those cases which are difficult to diagnose. PMID- 28892890 TI - Virulence Factors Detection in Aspergillus Isolates from Clinical and Environmental Samples. AB - INTRODUCTION: Pathogenesis of aspergillosis is dependent on various factors of the host (immune status) and virulence factors of the pathogen which could play a significant role in the pathogenesis of invasive aspergillosis. AIM: To study the virulence factors of Aspergillus species isolated from patient samples and environmental samples. MATERIALS AND METHODS: This prospective and experimental study was carried out at Department of Microbiology, MGM Medical College and Hospital, Mumbai, Maharashtra, India, from July 2014 to June 2015. For detection of virulence factors of Aspergillus species, total 750 samples were included in this study (350 from patients and 400 samples from environment). Patient samples and hospital environment samples were subjected to standard methods for screening of Biofilm, Lipase, alpha-amylase, proteinase, haemolysin, phospholipase and pectinase. Statistical analysis was done using Chi-square test and SPSS (Version 17.0). RESULTS: American Type Culture Collection (ATCC) control of Aspergillus oryzae, Aspergillus niger and Aspergillus brasiliensis showed production of all virulence factors. In patient samples maximum virulence factor was produced i.e., alpha-amylase activity (89.74%) followed by proteinase activity (87.17%), biofilm production was (82.05%) haemolysin activity (79.48%), lipase activity (66.66%), pectinase activity and phospholipase activity (61.53%). In environment samples maximum virulence factor was produced i.e., proteinase activity (41.02%) followed by biofilm production was (38.46%), alpha-amylase activity (35.89%), haemolysin activity (33.33%), lipase activity (28.20%), phospholipase (25.64%) and pectinase activity (23.07%). The differences in patient and environment virulence factors were statistically significant (p-value <0.05). CONCLUSION: Overall the presence of virulence factors was found more in Aspergillus species isolated from patient samples then environmental samples. This could be due to invasiveness nature of Aspergilli. Aspergillusniger was common isolates from both patient and environmental samples. Our study highlights the possible transmission of Aspergilli from environment to patient. Detection of virulence factors of Aspergillus species help to differentiate between pathogenic and non-pathogenic Aspergilli. Presence of virulence factors confirmed pathogenicity of the isolates. It also helps the physicians to treat the patient when appropriate treatment is needed. PMID- 28892891 TI - Distribution of Class D Carbapenemase and Extended-Spectrum beta-Lactamase Genes among Acinetobacter Baumannii Isolated from Burn Wound and Ventilator Associated Pneumonia Infections. AB - INTRODUCTION: Resistance to Acinetobacter baumannii is dramatically on the rise in Iran. Therefore, it is important to study resistance pattern among Acinetobacter isolates which is a common cause of nosocomial infections. AIM: To investigate antibiotic resistance patterns and the role of resistant genes and biofilm formation in the induction of resistance among Acinetobacter baumannii isolated from burn wound and ventilator associated pneumonia infections. MATERIALS AND METHODS: Total 103 isolates such as 33 burn samples from Rasool Akram Hospital and 70 isolates from ventilated patients in Shahid Motahhari Hospital were identified with A. baumannii using biochemical method, and then identified to species level with PCR of gyrB and blaOXA-51 gene. Antibiotic sensitivity pattern for beta-lactam and carbapenem antibiotics was assessed using Agar disc diffusion test and E-test. The presence of different carbapenemase and metalo-beta-lactamase (blaOXA-51-like, gyrB, blaOXA-23-like, blaOXA-24-like, blaOXA-58, blaVEB, blaPER, blaGIM, blaSIM, blaIMP, blaVIM), extended-spectrum beta-lactamases (blaTEM, blaSHV) and two insertion sequences genes (ISaba1, IS1113) was assessed. Biofilm formation of all isolates was then assessed. Chi square analysis or Fisher's-exact tests were used for statistical analysis. A p value <0.05 was considered statistically significant. RESULTS: Colistin was the most effective antimicrobial agents, although 10.7% (11/103) of the isolates were resistant. The high rate of resistance to meropenem (93.2%) and imipenem (90.3%) was determined. Also, with exception of ampicillin-sulbactam, surprisingly the resistant rate was 28.2%, the resistance to beta-lactam antibiotic was dramatically increased. Co-existence of two and three blaOXA genes was also determined. The blaOXA-58 was detected in only one isolate. The blaTEM and blaOXA 23 was the most prevalent Extended-Spectrum beta-Lactamases (ESBL) gene. All isolates were biofilm producers. CONCLUSION: Antibiotic resistance is increasing among A. baumannii isolates which is due to excessive use of antibiotics and also acquired resistant genes and biofilm production. Resistance to nearly all antimicrobial agents especially colistin as end choice for treatment of multiple drug resistance A. baumannii is a big concern. PMID- 28892892 TI - Antibiotic Screening of Urine Culture for Internal Quality Audit at Amrita Hospital, Kochi. AB - INTRODUCTION: Urine antimicrobial activity is a seldom analysed laboratory test which greatly impacts the quantification of urine specimens. Presence of antimicrobial activity in the urine reduces the bacterial load in these specimens. Hence, the chances of erroneously reporting insignificant bacteriuria can be reduced on analysis of the antimicrobial activity in urine. AIM: The aim of the study was to measure the antimicrobial activity of urine samples obtained from patients in a tertiary care hospital. MATERIALS AND METHODS: A total of 100 urine specimens were collected from the study group. Tests like wet mount, Gram staining and culture were performed. Antimicrobial susceptibility testing was done on the bacteria isolated from each specimen. The urine specimens were reported as significant bacteriuria (>105 Colony Forming Unit (CFU)/ml) and insignificant bacteriuria (<105 CFU/ml - clean catch midstream urine; <102 CFU/ml - catheterized urine sample) according to the CFU/ml. Staphylococcus aureus ATCC(r) 25923TM and Escherichia coli ATCC(r) 25922TM were used to identify the presence of antimicrobial activity in the urine sample by Urine Anti-Bacterial substance Assay (UABA). McNemar test was used for statistical analysis using Statistical Package for the Social Sciences (SPSS) version 21.0. RESULTS: On analysis of the antimicrobial activity of urine sample with the prior antibiotic history of the patients, 17 were true positives and 43 were true negatives. Twenty six of samples with UABA positivity were culture negative and 28 samples with UABA positivity were culture positive. Sensitivity and specificity of the test was 85% and 53.8% respectively. Accuracy of the test was 60%. The p-value of UABA was <0.001. Enterobacteriaceae was the most common bacterial family isolated from the urine specimens. A total of 85% patients responded to treatment. CONCLUSION: Presence of antimicrobial activity in urine has a great impact on the interpretation of urine culture reports. Identification of urine antimicrobial activity helps in evaluating the quantification of bacterial growth reported in urine culture. It facilitates speedy recovery of patients by early administration of antibiotics. PMID- 28892893 TI - Distribution of SCCmec Elements and Presence of Panton-Valentine Leukocidin in Methicillin-Resistant Staphylococcusepidermidis Isolated from Clinical Samples in a University Hospital of Isfahan City, Iran. AB - INTRODUCTION: Coagulase Negative Staphylococcus (CoNS) is considered as a major pathogen of nosocomial infections among immunosuppressed patients. AIM: The aim of this study was to identify the types of Staphylococcal Cassette Chromosome mec (SCCmec) and Panton-Valentine Leukocidin (PVL) gene among clinical Methicillin Resistant S. epidermidis (MRSE) isolates collected from Isfahan. MATERIALS AND METHODS: This cross-sectional study was performed from March 2014 to January 2015 at a tertiary care hospital of Isfahan, Iran. Antimicrobial susceptibility tests of S. epidermidis isolates were performed by the disc diffusion method. All the strains were screened for methicillin resistance based on resistance to cefoxitin (30 MUg) disc and presence of mecA gene. Determination of SCCmec typing and PVL toxin gene were performed by PCR method. For categorical variables different groups were compared using the Chi-square test or Fisher exact test. A p-value of <0.05 was considered significant for all statistical tests. RESULTS: The frequency of MRSE was 53.8% according to the presence of mecA gene. The overall resistance rate was high with ciprofloxacin (81.4%). PCR analysis showed that 17% (12/70) of MRSE isolate carried the PVL gene and 43% (30/70) were SCCmec type I; 11.4% (8/70) were type II; and 34.2% (24/70) were type IV, whereas, 11.4% (8/70) of the MRSE isolates could not be typed. CONCLUSION: SCCmec type I was the major type of SCCmec, which indicates an emergence of this SCCmec type in the studied medical centers. Increased prevalence of SCCmec types in community is cause of an increase in antibiotic resistance among microorganisms. PMID- 28892895 TI - Effectivity of Titanium Oxide Based Nano Particles on E. coli from Clinical Samples. AB - INTRODUCTION: Nanoparticles composed of Titanium Oxide (TiO2) are non toxic, durable, stable and have a high refractive index with a lot of scope in biomedical applications. Due to their antibacterial effects, they can be applied to inanimate objects like glass, metal and even biomedical implants. AIM: This study was conducted to assess the antibacterial effect of Titanium Oxide (TiO2) alone or with Silver (Ag) as an additive on Escherichia coli. MATERIALS AND METHODS: Escherichia coli isolates (n=25) sensitive to most of the drugs including first generation cephalosporins, ampicillin and amoxycillin from various samples like pus, urine, sputum and blood were placed onto the glass slides containing TiO2 annealed at 200 degrees C, 400 degrees C, TiO2 with 0.1% Ag as additive, TiO2 with 0.3% Ag, and TiO2 with 0.6% Ag as additive. Samples from this were inoculated at every hour onto sterile petri plates and observed for growth after overnight incubation at 37 degrees C. RESULTS: The organisms which were inoculated onto TiO2 annealed at 200 degrees C showed a slower reduction rate from >1 * 108 cfu/ml to <1 * 10 cfu/ml only after six hours of incubation in visible light. Complete absence of colony forming units was observed after eight hours of incubation. The samples treated with TiO2 at 400 degrees C showed no growth after six hours of incubation itself. Samples treated with TiO2 with increasing gradations of silver as additives showed proportional reduction in the incubation time for the complete absence of colony forming units. CONCLUSION: Our study shows that pure titanium oxide has a high antibacterial effect on pathogenic samples of Escherichia coli from clinical isolates, which is further increased with the addition of increasing concentrations of silver. PMID- 28892894 TI - Low Rate of babA2 Genotype among Iranian Helicobacter pylori Clinical Isolates. AB - INTRODUCTION: The Blood Group Antigen-Binding Adhesion (babA), Outer Inflammatory Protein (oipA) and Sialic Acid-Binding Adhesin (sabA) as outer membrane proteins involved in Helicobacter pylori adherence to gastric mucosa have been suggested to have a role in the pathogenesis. AIM: To investigate the frequency of H. pylori isolates babA2, oipA and sabA genes in Iranian dyspeptic patients. MATERIALS AND METHODS: DNAs were extracted from H. pylori -positive cultures taken from 100 different dyspeptic patients. Genotyping was performed by Polymerase Chain Reaction (PCR), using the specific primers for babA2, oipA and sabA genes. Chi square test was used to investigate association between variables, p<0.05 was considered statistically significant. RESULTS: All (100%) isolates possessed oipA and sabA genotypes, whereas babA2 was detected in 22% of isolates. There was no significant relationship between presence of genes with clinical outcome. The combined genotype oipA +/sabA +/ babA2- was correlated with gastritis. The rate of babA2 genotype in our isolates was lower than other Iranian reports. CONCLUSION: Frequency of babA2 genotype among H. pylori isolates from Southwest of Iran is considerably less than other regions of Iran. Due to heterogeneity of H. pylori strains in different geographic regions, further work will be needed to understand the role of these virulence genes in H. pylori pathogenesis and their possible association with disease outcome. PMID- 28892896 TI - Detection of Cytomegalovirus in Bronchoalveolar Lavage Fluid from HIV-Positive Individuals with Community Acquired Pneumonia. AB - INTRODUCTION: Cytomegalovirus (CMV) pneumonia is one of the frequent viral pneumonia reported in persons with HIV infection. Knowledge of pulmonary CMV infection is important for deciding appropriate diagnostic strategies. However, there is scanty literature addressing the role of CMV aetiology among HIV positive individuals presenting with Community Acquired Pneumonia (CAP) using Bronchoalveolar Lavage (BAL) samples from India. AIM: To detect CMV in BAL fluid from HIV-positive individuals presenting with CAP. MATERIALS AND METHODS: This cross-sectional study was conducted using 107 archival BAL samples collected from consecutive HIV-positive patients presenting with CAP as per the Indian Chest Society and National College of Chest Physicians guidelines at the Department of Chest and Tuberculosis, Sassoon General Hospitals, Pune, India. The samples were tested for CMV by Polymerase Chain Reaction (PCR) targeting the IRL11 region at the National AIDS Research Institute, Pune. RESULTS: Of the 107 BAL samples tested, 8 (7.4 %) were positive for CMV, while CMV was the sole pathogen in 5 (4.7%) cases. Co-infection with other pathogens was seen in 3 patients and Mycobacterium tuberculosis, Pneumocystis jiroveci and Streptococcus pneumoniae were the co-pathogens. Five patients had fatal clinical outcome of which three had CMV as the sole pathogen. CONCLUSION: Ours is the first study to detect Cytomegalovirus (CMV) in bronchoalveolar lavage samples from HIV-positive individuals presenting with community acquired pneumonia from India and indicates the need for further multicentre studies to understand pulmonary CMV infection, which will eventually help in designing appropriate diagnostic strategies and therapeutic interventions. PMID- 28892898 TI - Atypical Presentation of Isolated Cerebral Aspergillosis in a Renal Allograft Recipient. AB - The immunosuppressive state in organ transplantation leads to infectious complications responsible for high mortality rate. Fungal infections account for 5% of all infections in Renal Transplantation (RT) recipients. Aspergillus species are filamentous fungi frequently causing fungal infections in RT recipients. Lungs and paranasal sinuses are the usual portal of entry from where it disseminates to other organs. Here, we are reporting a case of 14-year-old boy with RT from mother's kidney, who had atypical presentation of isolated cerebral aspergillosis at 19 months post-transplant without identified portal of entry. Early diagnosis and prompt treatment saved the patient and the graft. PMID- 28892897 TI - Anaerobic Bacteria in Clinical Specimens - Frequent, But a Neglected Lot: A Five Year Experience at a Tertiary Care Hospital. AB - INTRODUCTION: Anaerobic bacteria which constitute a significant proportion of the normal microbiota also cause variety of infections involving various anatomic sites. Considering the tedious culture techniques with longer turnaround time, anaerobic cultures are usually neglected by clinicians and microbiologists. AIM: To study the frequency of isolation of different anaerobic bacteria from various clinical specimens. MATERIALS AND METHODS: A retrospective study to analyse the frequency of isolation of different anaerobic bacteria, was conducted over a period of five years from 2011 to 2015 including various clinical specimens submitted to anaerobic division of Microbiology laboratory. Anaerobic bacteria were isolated and identified following standard bacteriological techniques. RESULTS: Pathogenic anaerobes (n=336) were isolated from 278 (12.48%) of overall 2227 specimens processed with an average yield of 1.2 isolates. Anaerobes were isolated as polymicrobial flora with or without aerobic bacterial pathogens in 159 (57.2%) patients. Anaerobic Gram-negative bacilli (140, 41.7%) were the predominant isolates. B. fragilis group (67, 19.9%) were the most commonly isolated anaerobic pathogens. Anaerobes were predominantly isolated from deep seated abscess (23.9%). CONCLUSION: Pathogenic anaerobes were isolated from various infection sites. Unless culture and susceptibility tests are performed as a routine, true magnitude of antimicrobial resistance among anaerobic pathogens will not be known. Knowledge of the distribution of these organisms may assist in the selection of appropriate empirical therapy for anaerobic infections. PMID- 28892899 TI - First Detection and Characterization of Streptococcus dentapri from Caries Active Subject. AB - INTRODUCTION: Mutans streptococci (MS) are a group of oral bacteria generally regarded as the principal agents in the pathogenesis of dental caries. AIM: The study aimed was characterize S. dentapri based on phylogenetic analysis and phenotypic methods from Caries Active Subject. MATERIALS AND METHODS: While sequencing MS species which were isolated from 65 caries active subjects, one strain of S. dentapri was detected. Dental plaque samples were processed and cultured on mitis salivarius bacitracin agar. S. dentapri was characterized using phylogenetic analysis, colony morphology characterization and biotyping. RESULTS: Among the study population, one strain designated as H14 was identified as S. dentapri by 16S rDNA sequencing. Morphologically, S. dentapri could not differentiate from other species of MS. S. dentapri H14 demonstrated biotype II biochemical characteristics of MS. The phylogenetic analysis showed S. dentapri is closely related to S. macacae. CONCLUSION: The study concludes that S. dentapri can inhabit the human oral cavity and therefore further investigations are warranted to determine its role in caries. PMID- 28892900 TI - Immunohistochemical Expression of Caspase-3 in Psoriasis. AB - INTRODUCTION: Psoriasis is a persistent chronic immune-mediated, relapsing, inflammatory and hyper proliferative skin disorder with genetic predisposition. Psoriasis can be considered as a T-cell mediated disease, with a complex role for a variety of cytokine interaction between keratinocytes and T-lymphocytes. Caspase-3 is an enzyme that plays a key role in apoptosis; it is a member of the family of cysteinyle aspartate specific proteases. AIM: To evaluate the expression of caspase-3 in Egyptian psoriasis patients and its role in apoptosis of keratinocytes. Also, to correlate this expression with the clinicopathological parameters in order to identify the possible hypothesized role of caspase-3 in the pathogenesis of psoriasis. MATERIALS AND METHODS: This was a case-control study conducted on patients suffering from chronic plaque psoriasis. A total of 20 psoriasis patients and 10 controls were selected from outpatient clinic of Dermatology, Menoufia University Hospital, between the period of October 2014 and January 2016. From each patient and control, a punch biopsy was taken. Evaluation of H&E stained sections and caspase-3 expression was done using standard immunohi stochemical techniques. Non-parametric chi-square test, Mann-Whitney U test, Kruskal Wallis test and Spearman's coefficient test were the statistical tests used. RESULTS: High caspase-3 H score was significantly in favour of psoriatic group in comparison with the control group. On the contrary, in the dermis, caspase-3 was significantly higher in skin adnexa while completely absent in the psoriatic group. Strong caspase-3 expression was significantly in favour of high PASI score, early onset lesions and lesions in the extremities. Significant positive correlation was found between caspase-3 percent and PASI score (r= +0.53, p-value=0.03). CONCLUSION: Caspase-3 over expression in the psoriatic lesion proposes a potential role in the pathogenesis of psoriasis. Positive correlation between the caspase-3 expression and the early onset psoriatic lesion located in the extremities implies a possible poor prognostic impact of caspase-3 over expression. PMID- 28892901 TI - Invasive Ductal Carcinoma Breast: How Neoadjuvant Chemotherapy Affects the Status of Estrogen Receptor, Progesterone Receptor and HER2/Neu-A Tertiary Care Centre Study. AB - INTRODUCTION: Determination of Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2/neu in primary Invasive Ductal Carcinoma (IDC) breast is the standard of care parameter for determining treatment options. Whether or not Neoadjuvant Chemotherapy (NAC) affects the receptor status is still an unanswered question. AIM: To compare immunohistochemical (IHC) profiles of ER, PR and HER2/neu in primary IDC breast before and after NAC to assess the subsequent effects on receptor status. MATERIALS AND METHODS: Thirty two patients diagnosed with primary IDC breast who had a previous breast core biopsy with complete IHC profile followed by NAC and Modified Radical Mastectomy (MRM) were included. For each case demographic and histologic data was collected, including age, grade, amount of necrosis post NAC and IHC panel for ER, PR and HER2/neu in core biopsies. The same IHC panel was applied on Post NAC MRM specimen. Pre- and post NAC IHC expression was compared. RESULTS: Patients ranged from 30 years to 75 years in range. ER, PR and HER2/neu status of core biopsies and MRM specimen were compared and overall agreement was noted. Comparison for each receptor was done using McNemar's test and significance was calculated. There was no statistically significant difference in ER and Her2/neu expression between pre- and post-NAC specimens. However, a statistically significant loss of PR expression was noted between the two groups. CONCLUSION: Accurate determination of ER, PR and Her2/neu status in primary IDC breast is important to guide further treatment. Change in receptor status post NAC may warrant corresponding change in hormonal therapy. PMID- 28892902 TI - Effects of Different Contraceptive Methods on Cervico-Vaginal Cytology. AB - INTRODUCTION: The vaginal flora of healthy adult women of reproductive age group constitutes predominantly Lactobacilli which inhibits the growth of other microorganisms (by maintaining acidic pH). The vaginal microflora is altered in favour of anaerobes in women using Intra Uterine Contraceptive Device (IUCD). Also, it can cause morphologic changes in both squamous and endocervical columnar cells. Similarly, the prevalence of vaginal lactobacilli is reduced among women using diaphragm-spermicide or spermicide alone. AIM: To study the effects of different contraceptive methods on cervical cytology and vaginal flora. MATERIALS AND METHODS: Two years prospective study included 120 women of reproductive age group using barrier, tubal ligation, IUCDs, Oral Contraceptive Pills (OCPs) and injectable methods of contraception and a control group including 60 women not using any contraceptive. Cervical and vaginal smears were obtained. Cervical smears were reported using the Bethesda system and Gram stained vaginal smears were scored using Nugent scoring. SPSS (Statistical Package for the Social Sciences) software for Windows Version 19.0 and test of significance applied was Chi-square test. RESULTS: The most common contraception used was barrier (68.3%) followed by tubal ligation (14.2%), IUCD (9.2%), OCPs (6.6%) and injectable (1.7%). The presenting complaints were pain lower abdomen (46.7%) followed by menstrual complaints (22.5%). Epithelium showed reactive changes (45%) followed by metaplasia (25%), koilocytotic change (5%), cytolytic effect (5%) and satellitosis (4.2%). Women showed normal flora in 51.7%, altered in 30% and bacterial vaginosis in 18.3%. CONCLUSION: Cervico-vaginal changes were more frequent in contraceptive users as compared to the control group. PMID- 28892903 TI - Immunohistochemical Study of MUC1 and MUC5AC Expression in Gall Bladder Lesions. AB - INTRODUCTION: Immunohistochemical (IHC) markers of mucin family are associated with various Gallbladder Lesions (GBLs). AIM: To study the distribution of GBL with respect to age and sex as well as to analyse the IHC profile of MUC1 and MUC5AC in GBLs and attempt correlation with clinical and histopathological findings. MATERIALS AND METHODS: The present study was conducted over a period of six years. A technique of manual tissue array was employed for cases subjected to IHC using MUC1 and MUC5AC. Results were statistically analysed using software program "The Primer of Biostatistics 5.0". RESULTS: A total of 629 GBL were encountered. Out of 605 of non-neoplastic lesions, 32 (5.29%) expressed MUC1 while 515 (85.12%) cases expressed MUC5AC. Out of 24 cases of neoplastic GBL, 20 cases (83.33%) showed positivity for MUC1 and 9 cases (37.5%) were positive for MUC5AC. The rate of MUC1 expression was significantly higher in Gall Bladder Cancer (GBC) {18GB carcinoma (ca) +3 Carcinoma In Situ (CIS)} (85.71%) than chronic cholecystitis (4.71%). The positive rate of MUC5AC expression was significantly lower in GBC (28.57%) than chronic cholecystitis (87.19%). The percentage of cases showing MUC1 expression increased as the severity of disease progressed from hyperplasia to CIS. The percentage of cases showing MUC5AC expression decreased as the severity of disease progressed from hyperplasia to CIS. CONCLUSION: In this study, 96.18% cases were non neoplastic GBL of which chronic cholecystitis (87.77%) was predominant. 3.81% of the GBL constituted for neoplastic lesions of which 75% were GBC. MUC1 showed higher rates of expression in neoplastic GBL. MUC5AC showed higher rates of expression in non neoplastic GBL. Expression of MUC1 and MUC5AC might be closely related to pathogenesis of neoplastic and non neoplastic GBL. PMID- 28892904 TI - Morphologic Spectrum of Duodenal Biopsies in Malabsorption: A Study from Southern India. AB - INTRODUCTION: Duodenal endoscopic biopsy is a common investigation for various non-neoplastic conditions. Malabsorption is a common indication for duodenal biopsy in our setting. AIM: Our study was undertaken to study the morphologic spectrum of non-neoplastic conditions of duodenum emphasizing on Intraepithelial Lymphocytes (IELs) and to have a clinico-pathologic correlation. MATERIALS AND METHODS: This was a prospective descriptive study. Duodenal biopsies from 101 patients with symptoms of malabsorption were studied according to inclusion and exclusion criteria. Informed written consent was taken. Clinical, laboratory, endoscopic, and serological parameters were collected wherever available. Histomorphological parameters were studied on Haematoxylin and Eosin (H&E) stained sections. Intraepithelial lymphocyte counts were done on CD3, CD4 and CD8 Immunohistochemical (IHC) stained sections and correlated. RESULTS: We studied 101 duodenal biopsies. Our spectrum included 16 patients of celiac disease (CD) (15.8%), 15 autoimmune duodenitis (14%), 13 nutritional deficiency associated duodenitis (12.8%), five infectious duodenitis (5%) and 41 patients of non specific duodenitis (40.6%) and 10.9% miscellaneous causes of duodenitis. Villous crypt architecture, IEL counts; villous tip IEL counts were statistically significant between CD and other disease groups. CONCLUSION: A constellation of clinical, serological, endoscopic and histopathologic features is essential in diagnosing CD and autoimmune duodenitis. Biopsy is also a useful tool in diagnosing infectious duodenitis that are missed in other investigations. PMID- 28892905 TI - An Immunohistochemical Study of Anaplastic Lymphoma Kinase and Epidermal Growth Factor Receptor Mutation in Non-Small Cell Lung Carcinoma. AB - INTRODUCTION: Lung cancer is one of the leading causes of cancer related death. Targeted treatment for specific markers may help in reducing the cancer related morbidity and mortality. AIM: To study expression of Anaplastic Lymphoma Kinase (ALK)and Epidermal Growth Factor Receptor (EGFR) mutations in patients of Non Small Cell Lung Cancer NSCLC, that are the targets for specific ALK inhibitors and EGFR tyrosine kinase inhibitors. MATERIALS AND METHODS: Total 69 cases of histologically diagnosed NSCLC were examined retrospectively for immunohistochemical expression of EGFR and ALK, along with positive control of normal placental tissue and anaplastic large cell lymphoma respectively. RESULTS: Of the NSCLC, Squamous Cell Carcinoma (SCC) accounted for 71.0% and adenocarcinoma was 26.1%. ALK expression was seen in single case of 60-year-old female, non-smoker with adenocarcinoma histology. EGFR expression was seen in both SCC (59.18%) and adenocarcinoma in (77.78%) accounting for 63.77% of all cases. Both ALK and EGFR mutation were mutually exclusive. CONCLUSION: EGFR expression was seen in 63.77% of cases, highlighting the importance of its use in routine analysis, for targeted therapy and better treatment results. Although, ALK expression was seen in 1.45% of all cases, it is an important biomarker in targeted cancer therapy. Also, the mutually exclusive expression of these two markers need further studies to develop a diagnostic algorithm for NSCLC patients. PMID- 28892906 TI - Changes in Haematological Parameters in Newborns Born to Preeclamptic Mothers - A Case Control Study in a Rural Hospital. AB - INTRODUCTION: Pregnancy is a physiological phenomenon. However, some women develop problems during pregnancy period, which puts both the mother's and the foetus health at risk. Hypertensive disorders of pregnancy are the type of the maternal diseases that can cause the most detrimental effects to the mother and foetus. AIMS: To determine the haematological parameters in neonates born to preeclamptic mothers. MATERIALS AND METHODS: It was a prospective case control study carried out on neonates born to preeclamptic mothers in our institute from March 2016 to November 2016. All the haematological parameters of the neonates were recorded and analyzed using SPSS 22.0 version software. Mean, Standard deviation, minimum and maximum values were calculated for continuous variables. The difference between the two groups was compared using independent student 't' test. The p-value <0.05 was considered as statistically significant. RESULTS: About 120 mothers were included in the study out of which 60 were of study group and 60 of control group. Mean hemoglobin, PCV, red cell count, Mean Corpuscular Volume (MCV), reticulocyte count and nRBC were significantly increased p<0.001, whereas total leucocyte count, mean neutrophil count, absolute neutrophil count, lymphocyte count, platelet count were significantly decreased p<0.001 in babies born to preeclamptic mothers. No difference was found between the two groups in the Mean Corpuscular Haemoglobin (MCH) and Mean Corpuscular Haemoglobin Concentration (MCHC) value p(>0.05). CONCLUSION: The babies born to preeclamptic mothers are more prone for development of prematurity, low birth weight, Intrauterine Growth Retardation (IUGR), sepsis, neutropenia, leucopenia, thrombocytopenia, increased RBC count, nRBC and reticulocyte count. Early haematological screening helps to decrease morbidity, improve growth, development and survival of the baby. PMID- 28892907 TI - Clear Cell Adenocarcinoma of Female Urethra. AB - Primary malignancies of female urethra are infrequent, constituting a fraction of less than 1% of genitourinary malignancies. Primary clear-cell adenocarcinoma of the urethra, is even rarer, that histomorphologically resembles clear-cell carcinoma of the female genital tract, occurs predominantly in women and is associated with a relatively poor prognosis. The histogenesis of this rare urethral neoplasm has not been completely determined. Various hypotheses concerning the origin have been postulated, including (1) diverticular origin (2) mullerian origin (3), glandular differentiation of urothelium or urothelial carcinoma. Here, we report a case of 67-year-old female with obstructive urinary symptoms and pain in abdomen, diagnosed with adenocarcinoma of urethra. Immunohistochemistry (IHC) workup of the tumour was done to find the origin of the tumour. PMID- 28892908 TI - Cytological Diagnosis of an Uncommon High Grade Malignant Thyroid Tumour: A Case Report. AB - Anaplastic Thyroid Carcinoma (ATC) is a relatively uncommon highly malignant tumour originating from the follicular cells of thyroid gland having poor prognosis. It accounts for 2% to 5% of all thyroid carcinomas and patients typically present with a rapidly growing anterior neck mass with aggressive symptoms. A 53-year-old male presented with diffuse neck swelling measuring 8x6 cm and right cervical lymph node measuring 2x2 cm since one month which was associated with dyspepsia and dyspnoea. Ultrasound and Contrast Enhanced Computed Tomography (CECT) neck revealed enlarged right lobe of thyroid and multiple enlarged cervical lymph nodes with soft tissue density nodules in bilateral lungs. Fine Needle Aspiration (FNA) from the swelling revealed giant cell, spindle cell and squamoid pattern. Focal areas showed follicular epithelial cells arranged in repeated microfollicular pattern suggesting an underlying follicular neoplasm. FNAC smears from the lymph node also revealed similar findings. Based on the cytomorphological and radiological findings, final diagnosis of ATC probably arising from underlying follicular carcinoma with cervical lymph node and lung metastasis was given. FNAC leads to prompt and definitive diagnosis, so that therapy can be initiated as soon as possible for better outcome. Multimodality therapy (surgery, external beam radiation, and chemotherapy) is the mainstay of treatment. PMID- 28892909 TI - Chondroid Syringoma: Fine-needle Aspiration Cytology of a Rare Entity at an Unusual Site. AB - Chondroid syringoma, also known as benign mixed tumour of the skin, is a rare benign adnexal tumour. It is a biphasic tumour, composed of both epithelial and mesenchymal components and constitutes <0.01% of all primary skin tumours. It is mostly located in the head and neck region, followed by the hand, foot, axillary region, abdomen, penis, vulva and scrotum. The arm is a rare site of involvement. Making a correct diagnosis of chondroid syringoma is important to guide the clinician in optimal management. We present a case of chondroid syringoma on the left arm in a 37-year-old male. Fine-needle aspiration was performed and diagnosed as chondroid syringoma, which was confirmed on histopathology. This case highlights the importance of considering chondroid syringoma in the evaluation of subcutaneous swellings of the arm and the role of Fine-Needle Aspiration Cytology (FNAC) in diagnosing this uncommon tumour. PMID- 28892910 TI - Benign Fibrous Histiocytoma: An Uncommon Presentation. AB - Intracranial fibrous histiocytomas are rare; Benign Fibrous Histiocytoma (BFH) being uncommon than its malignant counterpart. BFH comprises fibroblasts and histiocytes without any nuclear pleomorphism or atypia. We present a case of a 42 year-old male who had swelling over the occipital region for the past five years, which progressively increased in size. He developed headache, dizziness, and gait disturbance over the last six months. Computed tomographic scan revealed a posterior fossa space-occupying lesion. Fine-needle aspiration cytology from the swelling revealed spindled fibroblasts along with histiocytes and multinucleated giant cells. Later, histopathology showed presence of spindle-shaped cells in storiform pattern admixed with histiocytes and giant cells. The giant cells and histiocytes were immunopositive for CD68 and spindled cells were positive for vimentin, but immunonegative for CD34, epithelial membrane antigen, CD1a and S100. The final diagnosis was intracranial BFH. We present this case because of its extreme rarity and unusual location. PMID- 28892911 TI - Benign Beale Gland Hyperplasia Mimicking Malignant Biliary Obstruction. AB - Extrahepatic bile duct obstruction can be caused by various pathologies, most of them being malignant. Painless, progressive jaundice is the usual mode of presentation. We report a case of distal Common Bile Duct (CBD) obstruction due to a Benign Intramural Beale gland hyperplasia mimicking a periampullary carcinoma. Peribiliary glands (Beale Glands) are a group of seromucinous glands, normally seen within the fibromuscular wall and periductal connective tissue in the extrahepatic and large intrahepatic ducts and also in the neck of the Gall bladder. These glands drain into the bile duct lumen through small channels referred to as sacculi of Beale. Intramural Beale ducts are lobular aggregates of mucous glands that lie within the wall of the bile duct. Beale Gland hyperplasia is uncommon, and is rarely large enough to be visible macroscopically or with imaging as an incidental finding. There are no case reports of this rare entity. It is distinguished from well differentiated bile duct adenocarcinoma by the preservation of the lobular architecture, lack of cytological atypia and lack of perineural invasion. This case is reported for its rarity. PMID- 28892912 TI - Important Diagnostic Clues for Diagnosing Splenic Marginal Zone Lymphoma in Absence of Splenic Histology. AB - Splenic Marginal Zone Lymphoma (SMZL) is a rare B-cell neoplasm comprising less than 2% of non-Hodgkin lymphomas. We hereby report a case of SMZL in a 66-year old female who presented with fever and massive splenomegaly. Peripheral blood smear examination showed atypical lymphoid cells showing variable cytoplasmic processes. Flowcytometric immunophenotyping of peripheral blood showed tumour cells which were found to be positive for CD19, CD79b and showing kappa light chain restriction along with lack of expression for CD5, CD10, CD23, CD103 and lambda. These findings were suggestive of B cell chronic lymphoproliferative disorder. Various differential diagnoses considered in this case were analysed by using different diagnostic clues to arrive at the diagnosis. Bone marrow examination and Immunohistochemical (IHC) analysis showed tumour cells in nodular, interstitial and intrasinusoidal pattern of infiltration which were positive for CD20 and CD79b with kappa light chain restriction and lack of expression of CD5, CD10, CD23 and CD103 which further corroborated the flowcytometric immunophenotyping. The diagnosis of SMZL is arrived at by a combination of diagnostic clues like clinical features, peripheral smear findings, flowcytometric immunophenotyping, morphological and IHC findings in bone marrow biopsy. This case highlights the significance of flowcytometric immunophenotyping and bone marrow biopsy with immunohistochemistry to arrive at a diagnosis of SMZL even in absence of splenic histopathology. PMID- 28892913 TI - Candida Albicans Infection Masquerading as a Soft Tissue Tumour Diagnosed by Fine Needle Aspiration Cytology. AB - A 60-year-old male, diabetic presented with a soft tissue mass over the right forearm of 15 days duration. The swelling was 5 x 3 cm and a clinical diagnosis of neurofibroma was made. Fine Needle Aspiration Cytology (FNAC) was done using standard technique. Smears showed predominantly suppurative inflammation, foreign body giant cells, granulomas and fungal hyphae. KOH mount, culture and germ tube test was positive. Final diagnosis of fungal granuloma was made. Fungal infections should be included in the differential diagnosis of a soft tissue mass lesion. All soft tissue suppurative inflammatory lesions should be diligently screened to look for pathogens if any. Diagnostics in medicine have taken a major leap with advent of molecular technologies. Despite this, simple old traditional methods like FNAC supplemented by other basic laboratory techniques like KOH mount and culture still form the cream of a diagnostic laboratory and can come as a savior for the pathologist, the clinicians and the patients. PMID- 28892914 TI - Primary Amyloidosis - In a Case with Normal Plasma Cell Counts. AB - Amyloidosis is a group of disease that is characterized by the deposition of extracellular abnormal proteinaceous material (amyloid), in various organs. Amyloidosis involving the liver is common and the radiological findings are often nonspecific. We present the case of a 40-year-old female who presented with abdominal pain. Ultrasound abdomen was reported as massive hepatomegaly with diffuse liver parenchymal disease. Bone marrow aspiration showed normomegaloblastic erythroid hyperplasia and plasma cells were within normal limits (5%). Also, amorphous, eosinophilic fragmented to smudgy material within the interstitium of cell trails was seen. Bone marrow biopsy and liver biopsy also showed similar kind of homogenous eosinophilic material. Both liver biopsy and bone marrow biopsy were subjected to special stains which confirmed the presence of amyloid. The patient did not have clinical or laboratory findings suggestive of any other organ involvement. Thus, we conclude that clinical and imaging presentations of amyloidosis are often nonspecific, hence biopsy is always required to confirm the diagnosis. Amyloid deposits on bone marrow aspiration are a rare occurrence and are often missed. It is an unusual sighting with very few studies mentioning its occurrence. PMID- 28892915 TI - Myeloid Sarcoma Presenting as Nasal and Orbital Mass: An Initial Manifestation of an Acute Myeloid Leukaemia. AB - Myeloid sarcoma is an extramedullary manifestation of Acute Myeloid Leukaemia and sometimes is the only indicator of the disease. The incidence varies between 3 9.1% of acute leukaemia cases. The blast infiltration is seen most commonly in skin, lymph node, gastrointestinal tract, bone, soft tissue though can involve any body site usually as a solitary lesion and is rarely seen in nasal cavity. We present two cases of myeloid sarcoma presenting as a nasal mass in a six year old girl and other as orbital mass in 32-year-old as an initial manifestation of acute myeloid leukaemia. Histopathological examination along with immunohistochemistry clinched the diagnosis of myeloid sarcoma. Examination of bone marrow aspirate revealed blasts which fulfilled the criteria for acute leukaemia. These cases are usually misdiagnosed because often lymphoma and granulocytic sarcoma is not considered in initial list of differential diagnoses. These rare cases are being presented here as early recognition and diagnosis will ensure rapid treatment of the condition and improve the survival. PMID- 28892916 TI - Malignant Pilomatricoma: A Report of Two Cases and Review of Literature. AB - Malignant pilomatricoma is an extremely rare tumour arising from the hair follicle. About 80 known cases are reported in literature till date. Presented herewith are two cases of malignant pilomatricoma, occurring in young female patients, each with a different clinical presentation and outcome. It is important to be aware of this entity as malignant pilomatricoma, though, initially locally aggressive, can recur if incompletely excised and also can metastasize to lungs, bones and lymph nodes. PMID- 28892917 TI - Tubercular Thyroiditis as a Part of Disseminated Tuberculosis in a Young Male: A Rare Clinical Presentation. AB - Thyroid tuberculosis is uncommon even in countries like India where prevalence of tuberculosis is high. Bactericidal actions of colloid, excess iodine stores and high vascularity of the gland have been implicated for the very rare occurrence of thyroid tuberculosis. We present a case of a 16-year-old male with thyroid involvement as a part of disseminated tuberculosis. The clinical presentation of thyroid tuberculosis is varied and may be missed if not kept in the differential diagnosis of goitre. This case also highlights the role of fine needle aspiration cytology in management of goitre. It is an important diagnostic test as it avoids unnecessary surgical intervention. PMID- 28892918 TI - Sarcomatoid Carcinoma of Renal Pelvis with Abundant Heterologous Osteosarcomatous Element: A Case Report. AB - A 47-year-old male presented with haematuria and flank pain for two weeks. Ultrasonography and renal scan revealed a poorly functioning left kidney with multiple calculi. Simple nephrectomy was performed and the specimen revealed a mass in his renal pelvis which showed both carcinomatous and sarcomatous components on microscopy. The sarcomatous component consisted of diffuse pleomorphic osteoblasts with intervening lacy osteoid, giving an osteosarcoma like appearance. These areas of tumour were strongly positive for vimentin and osteopontin. The carcinomatous component was transitional cell carcinoma. Patchy areas of squamous cell carcinoma which were positive for pancytokeratin on immunostaining were also seen. Few weeks later, the patient presented with metastatic lesions in the sacrum. After nephrectomy, the patient underwent palliative radiotherapy of the spine followed by sunitinib therapy. A month later, there was recurrence at the site of surgery. The patient succumbed to his illness within five months of diagnosis. This report describes an extremely rare case of carcinoma, renal pelvis with predominantly osteosarcomatous areas. PMID- 28892919 TI - Plasma Exchange as a Therapeutic Modality in a Rare Case of Cryptogenic New Onset Refractory Status Epilepticus (NORSE). AB - Refractory Status Epilepticus (RSE) not responding to any therapy and not associated with any aetiology has been termed as New Onset Refractory Status Epilepticus (NORSE). Guidelines for optimal management of cryptogenic NORSE are not clearly defined so far in the literature. Other than common medication, use of high-dose steroids, IV immune globulins and plasma exchanges in NORSE of unknown aetiology have been scarcely described. Immunomodulatory therapy like plasmapheresis is based on the fact that a pathological substance exists in the plasma that contributes to the disease process and its symptoms, which gets removed. We report a case of young female patient diagnosed as NORSE who responded to treatment with plasma exchange after becoming refractory to antiepileptic therapy and treatment with anaesthetic agents for recurrent seizers. PMID- 28892920 TI - Solid Variant of Aneurysmal Bone Cyst Masquerading as Malignancy. AB - Solid Variant of Aneurysmal Bone Cyst (SVABC) is an uncommon neoplasm seen in young patients. The lesion presents clinically as well as on radiology like a malignant bone tumour. The aggressive features in most of the cases lead to a wrong diagnosis. Radiologically, it is expansile osteolytic with cortical breach being seen in many of the cases. We report two cases of SVABC which were misdiagnosed as malignant bone tumours. Both cases were seen in long bones. Radiologically both lesions were expansile, osteolytic, solid cystic, with destruction of cortex and were diagnosed as osteosarcomas. Both the cases were referred to us for further management and were subsequently diagnosed as SVABC. Being extremely rare these tumours have a high chance of getting misdiagnosed and knowledge of this entity along with close correlation with clinical, radiological and histopathological findings plays a critical role in accurately diagnosing this condition. An accurate diagnosis is of utmost importance as this changes the treatment drastically avoiding mutilating surgeries and unnecessary chemo radiotherapy. PMID- 28892921 TI - A Rare Case of Genital Malformation with Omphalocele, Exstrophy of Bladder, Imperforate Anus and Spinal Defect Complex-Autopsy Findings. AB - Omphalocele, Exstrophy of cloaca, Imperforate anus and Spinal defects (OEIS) is a severe manifestation of exstrophy-epispadias sequence with a combination of defects including OEIS. It results from improper closure of anterior abdominal wall and defective development of cloaca and urogenital septum due to defect in blastogenesis during the 4th week of gestation. Identification of this complex is important through foetal autopsy as this condition can recur in siblings. Prenatal diagnosis also helps to prevent foetal death with appropriate management in the less severe cases. In severe cases, termination of pregnancy is considered. A primigravida with 28 weeks of gestation had delivered a live baby with multiple congenital anomalies; baby died after 10 minutes. These anomalies were grouped under OEIS complex. PMID- 28892922 TI - Early T-Cell Precursor Acute Lymphoblastic Leukaemia/Lymphoma: Immunohistochemical Evaluation of Four Lymph Node Biopsies. PMID- 28892923 TI - Atorvastatin Induced Adverse Drug Reactions among South Indian Tamils. AB - INTRODUCTION: Atorvastatin is the most widely used statin world-over. Although atorvastatin is beneficial in reducing cardiovascular morbidity and mortality, they are associated with Adverse Drug Reactions (ADRs) which are under-recognized as well as under-reported. There is no data on safety of atorvastatin in ethnic populations like South Indian Tamils and hence the need for this study. AIM: To report the Adverse Events (AEs) associated with atorvastatin use, their causality and severity in dyslipidemic south Indian Tamils. MATERIALS AND METHODS: This cross-sectional study was carried out on 304 dyslipidemic Tamils. Those on any lipid lowering therapy within one month before study enrolment, those with contraindications to statin therapy, hypothyroid patients, those with LDL cholesterol >250 mg/dL or serum triglycerides >400 mg/dL and patients who were on drugs which modulate Cytochrome P 450 3A4/5 (CYP3A4/5) activity were excluded from the study. Causality assessment for atorvastatin induced AEs were done using Naranjo adverse drug reaction probability scale criteria and severity assessment was done using Hartwig scale. AEs which were causally related to atorvastatin use were reported as ADRs. RESULTS: One hundred and eighty three AEs were noted among 145 (47.7%) patients, during the course of first 45 days of atorvastatin therapy. AEs were probably due to atorvastatin in 11% of the patients and possibly due to atorvastatin in 89%. Most common ADRs were myalgia (41%), followed by nervous system ADRs (35.5%) and gastrointestinal ADRs (14%). CONCLUSION: Myalgia was the most common cause for atorvastatin discontinuation which might place these individuals at an increased risk of cardiovascular morbidity and mortality. Measures to identify and address atorvastatin induced myalgia should be given priority. PMID- 28892924 TI - Comparison of Pioglitazone and Metformin Efficacy against Glucocorticoid Induced Atherosclerosis and Hepatic Steatosis in Insulin Resistant Rats. AB - INTRODUCTION: Insulin Resistance is a major cause of Atherosclerosis (AS) and Non Alcoholic Fatty Liver Disease (NAFLD). These lipid alterations in blood vessels and liver may progress to cardiovascular abnormalities and cirrhosis respectively. Drugs like pioglitazone (PIO) and metformin (MET) are effective insulin sensitizers used in T2DM. But their efficacy and tolerability needs to be compared in IR associated abnormalities. AIM: To compare the efficacy of PIO and MET in glucocorticoid induced AS, Hepatic Steatosis (HS) and IR in albino rats. MATERIALS AND METHODS: Male Wistar albino rats were randomized into four groups (n=6). Group 1 (Normal control) rats consumed 2% gum acacia orally for 12 days. Group 2 {dexamethasone (DEX) control} rats were administered 2% gum acacia orally for 12 days and DEX (8 mg/kg) intraperitoneally (i.p.) from 7th to 12th day during the study period. Group 3 and 4 (PIO and MET control) rats received oral administration of PIO (45 mg/kg) and MET (1000 mg/kg) for 12 days respectively. Both groups were treated with DEX (8 mg/kg/i.p.) from 7th to 12th day during the study period. On last day, fasting blood was collected and rats were sacrificed by cervical dislocation; aorta and liver tissues were isolated for the histopathological examination. Body weight, liver weight and liver volume were measured. Blood samples were processed for biochemical parameters. The data were analysed by One-way Analysis of variance (ANOVA) followed by Scheffe's multiple comparison post-hoc test. The statistical significance was assumed at p<0.05. RESULTS: Our results established the possible role of DEX in the development of AS and HS. Histopathological examination of Group 2 rats treated with DEX showed a marked lipid accumulation in the aorta and liver. Administration of MET and PIO resulted in partial to complete restoration of DEX induced fatty changes in aorta and liver. Both drugs significantly (p<0.05) prevented the elevation of insulin, lipid, glucose levels, liver weight and liver volume in DEX treated rats. They had significantly (p<0.05) improved body weight and insulin sensitivity. However, PIO was highly significant (p<0.05) compared to MET in reducing DEX induced IR complications. CONCLUSION: These findings suggest that PIO was more effective insulin sensitizer compared to MET in reducing AS, HS and IR induced by glucocorticoids. PMID- 28892925 TI - Impact of Antibiotic Stewardship Program on Prescribing Pattern of Antimicrobials in Patients of Medical Intensive Care Unit. AB - INTRODUCTION: Rising concerns about antimicrobial resistance and inadequate development of effective new anti-infective drugs have stimulated universal efforts to strengthen infection-control interventions. Antimicrobial stewardship is a rational, systematic approach to promote the optimal selection, dosing, and duration of therapy for antimicrobial agents throughout the course of their use in order to improve the outcomes. AIM: Since in Shree Krishna Hospital (SKH), Antibiotic Stewardship Program (ASP) was first implemented in 2013, this study was planned to assess any change in antimicrobial use before and after implementation of ASP and to study the rate and pattern of antimicrobial use in medical ICU. MATERIALS AND METHODS: A cross-sectional study was conducted in 12 bedded medical intensive care unit, over a period of two years from October 2014 to October 2016 at SKH. Permission was taken from Institutional Human Research Ethics Committee. Total 150 case files i.e., 75 from year 2012 and 75 from year 2015 were retrieved from medical record section of the hospital. Appropriateness of prescriptions was decided on the basis of appropriateness of choice, dose, frequency and duration of antimicrobial agents. Data were analysed by using descriptive statistics. RESULTS: There were 68.67% males and the mean (+/-SD) age was 57.11 (+/-16.83) years. Majority of the patients were suffering from respiratory conditions. The most common group of drugs prescribed in MICU was beta-lactam antibiotics + beta-lactamase inhibitors during 2012 as well as 2015. Total 139 patients i.e., 69 (92%) patients in 2012 and 70 (93.33%) patients in 2015 were given antimicrobial for therapeutic purpose. During the year 2015, 67 (89.33%) antimicrobial prescriptions were adhering to antibiotic policy of SKH. Appropriateness of prescriptions had significantly improved in 2015 in MICU (p value=0.031). CONCLUSION: In-depth analysis of the study revealed a positive impact of ASP and antibiotic policy. Implementation of ASP in year 2013, brought an effective increase in the appropriate use of antimicrobials. PMID- 28892926 TI - Antidiabetic Activity of Aqueous Extract of Solanum nigrum Linn Berries in Alloxan Induced Diabetic Wistar Albino Rats. AB - INTRODUCTION: Solanum nigrum Linn. is a common medicinal plant possessing a wide variety of pharmacological activity. Current treatment of diabetes mellitus has plenty of adverse effects necessitating the search of alternate drugs. AIM: Evaluation of antidiabetic effect of Aqueous Extract of Solanum Nigrum Linn Berries (AESNB) in alloxan induced diabetic Wistar rats. MATERIALS AND METHODS: There were five groups (normal control, diabetic control, AESNB 200 mg/kg/day, ASENB 400 mg/kg/day and standard i.e., glimepride 0.1 mg/kg/day) with six animals in each group. Alloxan was used to induce diabetes in rats. The standard drug glimepride in the dose of 0.1 mg/kg/day and the test drug AESNB were given orally in the doses of 200 mg/kg/day and 400 mg/kg/day. The fasting blood glucose level was measured by glucometer on day 0, 1,7,14 and 21 after 12 hour. On 21st day after the blood glucose measurement all the animals were sacrificed and their pancreas were analysed histopathologically. The results were analysed statistically by using one-way ANOVA. RESULTS: Aqueous extract of Solanum nigrum Linn berries in the dose of 200 mg/kg/day produced significant blood glucose reduction (p<0.01) from day 7 and 400 mg/kg/day produced highly significant reduction in blood glucose from day 7 (p<0.001). The standard drug glimepride reduced the blood glucose as equal to normal on day 21 (p<0.001). Histopathological examination showed the regeneration of pancreatic beta cells in AESNB group. CONCLUSION: Aqueous extract of Solanum nigrum Linn berries possess antidiabetic activity. PMID- 28892927 TI - A Rare Instance of Levofloxacin Induced Myoclonus. AB - Levofloxacin is a widely used fluoroquinolone, mainly as a respiratory antimicrobial agent. It is employed as a second line therapeutic modality in pulmonary tuberculosis as well. The drug has been in use for ages, and is known to be both efficacious and safe. However, it is not free of adverse effects. The most dangerous ones are those involving the Central Nervous System (CNS). Although rare, levofloxacin can cause involuntary movements like chorea and myoclonus. Here by, we present a case of an elderly male patient who developed reversible myoclonus/chorea after a course of levofloxacin (which was initiated as part of his anti-tubercular therapy) following the development of peripheral neuropathy secondary to isoniazid. PMID- 28892928 TI - Anti-inflammatory and Analgesic Activities of Topical Formulations of Pterocarpus Santalinus Powder in Rat Model of Chronic Inflammation. AB - INTRODUCTION: The incidence of arthritis is quite high and there is a need for the search of natural products to halt the progression of disease or provide symptomatic relief without significant adverse effects. AIM: This study aimed at evaluating the anti-inflammatory and analgesic activities of topical Pterocarpus santalinus in an animal model of chronic inflammation. MATERIALS AND METHODS: Albino rats of either sex were divided into five groups of six rats each (Group I - Control, Group II -Gel base, Group III -P. santalinus paste, Group IV -P. santalinus gel, Group V- Diclofenac gel). Chronic inflammation was induced on day 0 by injecting 0.1 ml Complete Freund's Adjuvant (CFA) in sub-plantar tissue of left hind paw of the rats. Topical treatment was started from day 12 till day 28. Body weight and paw volume (Plethysmometer) were assessed on day 0, 12 and 28. Pain assessment was done using Randall and Selitto paw withdrawal method. Data was analysed using GraphPad Prism version 5. Unpaired students t-test and ANOVA followed by Tukey's test was used for comparison among groups. RESULTS: Only topical P.santalinus gel significantly reduced the body weight (p=0.02) due to reduction in inflammatory oedema of the left limb. P. santalinus gel also showed significant reduction (p=0.03) in paw volume of rats compared to the other groups. There was significant reduction in pain threshold (gm/sec) due to chronic inflammation, with all the study drugs (p<0.05) but with P. santalinus gel, this reduction was less (p<0.001). CONCLUSION: Gel showed significant anti inflammatory and mild analgesic activity on topical application in rat model of chronic inflammation. PMID- 28892929 TI - Connective Tissue Growth Factor Transgenic Mouse Develops Cardiac Hypertrophy, Lean Body Mass and Alopecia. AB - INTRODUCTION: Connective Tissue Growth Factor (CTGF/CCN2) is one of the six members of cysteine-rich, heparin-binding proteins, secreted as modular protein and recognised to play a major function in cell processes such as adhesion, migration, proliferation and differentiation as well as chondrogenesis, skeletogenesis, angiogenesis and wound healing. The capacity of CTGF to interact with different growth factors lends an important role during early and late development, especially in the anterior region of the embryo. CTGF Knockout (KO) mice have several craniofacial defects and bone miss shaped due to an impairment of the vascular system development during chondrogenesis. AIM: The aim of the study was to establish an association between multiple modular functions of CTGF and the phenotype and cardiovascular functions in transgenic mouse. MATERIALS AND METHODS: Bicistronic cassette was constructed using pIRES expressing vector (Clontech, Palo Alto, CA). The construct harbours mouse cDNA in tandem with LacZ cDNA as a reporter gene under the control of Cytomegalovirus (CMV) promoter. The plasmid was linearised with NotI restriction enzyme, and 50 ng of linearised plasmid was injected into mouse pronucleus for the chimaera production. Immunohistochemical methods were used to assess the colocalisation renin and CTGF as well as morphology and rheology of the cardiovascular system. RESULTS: The chimeric mice were backcrossed against the wild-type C57BL/6 to generate hemizygous (F1) mouse. Most of the offsprings died as a result of respiratory distress and those that survived have low CTGF gene copy number, approximately 40 molecules per mouse genome. The copy number assessment on the dead pups showed 5*103 molecules per mouse genome explaining the threshold of the gene in terms of toxicity. Interestingly, the result of this cross showed 85% of the progenies to be positive deviating from Mendelian first law. All F2 progenies died excluding the possibility of establishing the CTGF transgenic mouse line, situation that compelled us to work at the level of hemizygosity. The histological characterisation of left ventricle shows cardiac hypertrophy together with decrease in body mass and alopecia, this compared to the wild type. The immunohistochemical staining of aorta root showed hyperplasia with increased expression and colocalisation of renin and CTGF demonstrating that CTGF may be involved in vascular tone control. CONCLUSION: Genetic engineering is a noble avenue to investigate the function of new or existing genes. Our data have shown that CTGF transgenic mouse has cardiac and aorta root hypertrophy and abnormal renin accumulation in aorta root as compared to the wild-type animals. The transgenic animals developed alopecia and lean body mass adding two new functions on pre-existing CTGF multiple functions. PMID- 28892930 TI - The Impact of Three-month Training Programme on Foot Care and Self-efficacy of Patients with Diabetic Foot Ulcers. AB - INTRODUCTION: Patient's self-efficacy in disease management and foot care is considered as an important indicator in controlling the complications of diabetes. AIM: This study was aimed to determine the effect of three-month training programme on foot care and self-efficacy of patients with diabetic foot ulcers. MATERIALS AND METHODS: A quasi-experimental study was conducted on 60 patients with diabetic foot ulcers in Jiroft Imam Khomeini hospital from January 2016 to May 2016. These patients were randomly divided into intervention and control groups (30 patients in each group). The research instrument was a questionnaire on demographic data, self-efficacy questions for patients with diabetes and a researcher made questionnaire of diabetic foot care. Training programmes for foot ulcers care and prevention of new ulcers formation and other aspects of the disease were implemented during three months in the test group. Data were analysed using descriptive and analytic statistical tests (Mann-Whitney U, paired t-test and Pearson correlation coefficient) by SPSS version 18.0 software. RESULTS: The results showed statistically significant difference (p<0.001) in the score of self-efficacy between intervention group (182.25) and control group (93.56), and the foot care score was 47.43 in the intervention group and 30.18 in control group after the intervention. The average scores of self-efficacy and foot ulcers care significantly increased in the intervention group after training programme (p<0.001). CONCLUSION: The results showed that the implementation of training programme has been able to increase the self-efficacy of patients and the rate of their foot ulcers care and the prevention of new ulcers and effectively reduce the complications in diabetic patients. PMID- 28892931 TI - Effect of Environmental Intervention on the Consumption of Rice without Toxic Metals Based on the Health Belief Model and Ecological-Social Model. AB - INTRODUCTION: The effect of instructional models on the changing behaviour of consuming contaminated rice with toxic metals has not been investigated in Iran yet. AIM: To compare effect of Health Belief Model (HBM) and Ecological (ECO) social model on decreasing the consumption of rice contaminated with toxic metals. MATERIALS AND METHODS: The study aimed at implementing a six-month interventionist program among three groups (HBM, ECO and Control). The study population comprised of 240 women, aged 18 to 50. Questionnaires were distributed which consisted of demographic information, knowledge, constructs of the models, performance of rice consumption, and the manner of rice cooking. In HBM group participants were individually provided with instructions based on HBM. However, in ECO group participants received the instruction through social networks consisted of mothers, sisters, family members, and colleagues. RESULTS: The results of Wilcoxon test indicated improvements in people's diet including a significant increase in the number of women consuming rice without toxic metals, a significant reduction in the number of women consuming rice contaminated with toxic metals in both intervention groups. On the other hand, such an improvement was not observed in the control group. The results of repeated measures' analysis of variance suggested further improvement in healthy diet in ECO group rather than HBM group after the completion of the environmental intervention. CONCLUSION: Both methods of instructional intervention caused changes in the diet of people regarding the consumption of rice free from toxic metals and changes in the manner of cooking from Kateh (steaming rice) to Pilaw (draining rice). Development of social support had probably a more effective role on the improvement of people's diet. PMID- 28892932 TI - Comparison of Effect of Lavandula officinalis and Venlafaxine in Treating Depression: A Double Blind Clinical Trial. AB - INTRODUCTION: Major depressive disorder is a chronic disease which may be associated with other mental illnesses. Lavandula officinalis and venlafaxine, herbal and chemical drugs respectively, are used to treat depression. Despite pharmacotherapy, major depressive disorder has a complicated pattern of resistance and recurrence. AIM: The aim of this study was to determine the effect of L. officinalis and venlafaxine in treating depression. MATERIALS AND METHODS: For this study, 120 patients referred to the psychiatry clinic of the Shahrekord University of Medical Sciences, Shahrekord, Iran, were randomly selected. The participants were randomly assigned to three groups: venlafaxine (Control Group), venlafaxine + L. officinalis (L. officinalis Group), and venlafaxine + placebo (Placebo Group). All the patients underwent treatment for six weeks. Depression test was administered to the three groups at different time intervals before the treatment, four weeks after the treatment and at completion of the treatment. The data were analysed by SPSS version17.0. RESULTS: Depression scores of all the groups decreased over time (p=0.001). The depression scores were significantly different between the control and L. officinalis groups (p=0.004), and the control and placebo groups (p=0.002), but were not significantly different between the L. officinalis and placebo groups (p=0.95). CONCLUSION: Adding L. officinalis or a placebo is equally effective in decreasing mean depression score and venlafaxine obviously decreased this score. PMID- 28892933 TI - Evaluation of the Relationship between Serum 25-Hydroxy Vitamin D and Hypertension in Hamadan, Iran-A Case Control Study. AB - INTRODUCTION: Hypertension or high blood pressure is one of the main reasons of fatality in the world. The role of vitamin D in developing hypertension has not been proved yet. Some studies have shown positive correlation between low serum vitamin D level and hypertension. Due to this fact, recognising hypertension risk factors such as potential impact of low serum vitamin D level seems to be required. AIM: This study was conducted to evaluate potential impact of serum vitamin D level on hypertension. MATERIALS AND METHODS: This case-control study had 188 subjects including 55 cases suffering from hypertension and 133 controls with normal blood pressure in Hamadan, Iran. After taking the medical history and physical examination, 5 cc of their blood was taken to measure their serum 25 Hydroxyvitamin D [25(OH)D] level through ELISA test. Data analysis was done by version 16.0 of SPSS software and used independent sample t-test and Chi-square test for related comparisons. RESULTS: Mean and standard deviation of serum 25(OH)D level in patients suffering from hypertension was 13.10+/-9.7 ng/ml and in control group was 20.87+/-10.34 ng/ml. This variance was statistically significant (p<0.001). Mean serum 25(OH)D level in both case and control groups was measured after gender and age stratification. Mean serum 25(OH)D level in cases and controls was 13.12+/-11.4 ng/ml and 21.38+/-11.47 ng/ml in males (p=0.016) and 13.10+/-9.91 ng/ml and 19.19+/-10.55 ng/ml (p=0.004) in females, respectively. Mean serum 25(OH)D level in under 50-year-old was 10.82+/-8.73 ng/ml and 20.07+/-11.17 ng/ml in cases and controls respectively (p<0.001). In over 50-year-old, there was no significant relationship between mean serum 25(OH)D and blood pressure levels (p>0.05). CONCLUSION: According to this study, reverse relationship between serum 25(OH)D and blood pressure levels was seen. PMID- 28892934 TI - Why do Patients undergoing Chronic Obstructive Pulmonary Disease Treatment Turn Defaulters? A Follow up Study in a Tertiary Care Hospital in Jamnagar, India. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD), a progressive respiratory illness requiring long-term treatment, is a significant cause of morbidity, mortality and economic burden on the family as well as the country. In the tertiary health care facility where the study was carried out, it was observed that many COPD patients did not come for regular follow up. In these patients, treatment interruption may lead to increased morbidity and mortality. AIM: This study aimed to find out the reasons for defaulting follow up and treatment in COPD patients. MATERIALS AND METHODS: All patients of COPD, attending TB Chest outpatient department during the study period (September 2012 to February 2013), were classified into Group A, B, C, and D according to latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Data was collected on patient's sociodemographic profile, severity of disease and reasons for defaulting follow up and treatment using pre-tested semi-structured questionnaires, patient history and clinical examination. Data obtained were entered in Microsoft Office Excel 2007 and analysed using Chi-square test. RESULTS: The mean age of the 200 patients recruited was 59.3 years. A total of 87% patients were male. Patients belonging to Group A, B, C and D were 11%, 25.5%, 41.5% and 22% respectively. Overall, 32% patients were defaulters. Three main reasons for default were non-affordability for treatment expenses (39.07%), resolution of symptoms (26.56%), and too ill to come (18.75%). The associations between default rate and demographic variables like age and gender were found statistically significant. CONCLUSION: Default rate among COPD patients is significantly associated with GOLD Group A and D, patient's income and patient literacy level. Main reasons for default were non-affordability of treatment expenses, too ill to come and resolution of symptoms. PMID- 28892935 TI - Efficacy of Health Education using Facebook to Promote Healthy Lifestyle among Medical Students in Puducherry, India: A Non-Randomized Controlled Trial. AB - INTRODUCTION: Increasing burden of overweight and obesity among young adults is mainly due to unhealthy lifestyle especially with respect to diet and physical activity. At the same time, younger generations are spending more time with social network sites. Therefore, this study was intended to explore the role of social networking sites in promoting healthy lifestyle. AIM: To measure the efficacy of health education using social networking sites in promoting healthy lifestyle among medical students in Puducherry, India. MATERIALS AND METHODS: A non-randomized controlled trial was conducted in a private medical college located in Puducherry. The study participants were overweight/obese individuals with (intervention arm) and without Facebook account (control arm). Following a baseline survey, both the groups received health education from dietician and physical trainer using Audiovisual (AV) aids. Intervention group received health education through Facebook in the forms of messages, pictures and videos for six weeks. Then, follow up survey was done to assess the change in dietary pattern, physical activity and body weight. Data of those who attended baseline, intervention and follow up surveys (23- control and 22- intervention) were analysed. Means and proportions were calculated. Paired t-test and Chi-square test were used to calculate the p-value. The p-value<0.05 was considered as statistically significant. RESULTS: Mean number of days of junk food intake per week was reduced in both control and intervention groups from 2.91 days/week and 3.27 days/week at baseline to 2.65 days/week to two days/week at follow up respectively. A significant decrease in the Body Mass Index (BMI) (p<0.05) was found among the control group (baseline: 25.57, follow up: 25.15). No significant changes were found with respect to physical activity and intake of fruits and vegetables. CONCLUSION: Except for the decrease in junk food intake, use of Facebook as an effective tool to promote healthy lifestyle could not be proved with confidence. PMID- 28892936 TI - Hazards and Health Risks Encountered by Manual Sand Dredgers from Udupi, India: A Cross-sectional Study. AB - INTRODUCTION: Globalization and urbanization have resulted in an increased demand on sand dredging. Legal and environmental restrictions on automated dredging have led to a rise in manual technique. The working techniques and environment involved in manual sand dredging may expose the workers to multiple work related disorders. AIM: To determine the health risks and occupational hazards involved in manual sand dredging. MATERIALS AND METHODS: An assessment schedule was developed and content was validated by five experts for the study. A cross sectional study was then conducted using this assessment schedule. Thirty manual sand dredgers were recruited from three randomly selected docks on Swarna riverbed in Udupi district, Karnataka, India. A detailed work and worksite assessments were conducted using systematic observation and close-ended questions. Work-related health risk evaluation included onsite-evaluation and self-reported health complains. RESULTS: The prevalence of musculoskeletal pain and discomfort was 93.34% with lower back (70%), shoulder (56.7%) and neck (46.7%) involvements being most common regions. Prevalence of sensory deficits at multiple site and ear pain was 66.6% and 76.6% respectively. All the workers recruited, complained of dermatological and ophthalmic involvements. Also, lack of health and safety measures like personal protective devices and security schemes were identified. CONCLUSION: This study shows a high prevalence of multiple work-related disorders and hazards involved in manual sand dredging, a highly demanding job in coastal Karnataka. Lack of health and safety measures were also identified. PMID- 28892937 TI - Association between Socioeconomic Status and Diabetes Mellitus: The National Socioeconomics Survey, 2010 and 2012. AB - INTRODUCTION: The prevalence of Diabetes Mellitus (DM) is increasing, globally. However, studies on the association between Socioeconomic Status (SES) factors and DM have mostly been conducted in specific areas with rather small sample sizes or not with nationally representative samples. Their results have also been inconclusive regarding whether SES has any influence on DM or not. AIM: To determine the association between SES and DM in Thailand. MATERIALS AND METHODS: This study utilized the data from the National socioeconomics survey, a cross sectional study conducted by the National Statistical Office (NSO) in 2010 and 2012. A total of 17,045 and 16,903 participants respectively who met the inclusion criteria were included in this study. The information was collected by face-to-face interview with structured questionnaires. Multilevel mixed-effects logistic regression analysis was performed to determine the potential socioeconomic factors associated with DM. RESULTS: The prevalence of DM was 3.70% (95% CI: 3.36 to 4.05) and 8.11% (95%CI: 6.25 to 9.74) in 2010 and 2012 respectively and the prevalence of DM in 2012 was 1.36 times (95% CI: 1.25 to 1.48) when compared with 2010. The multilevel mixed-effects logistic regression observed that odds of having DM were significantly higher among those who aged 55 64 years old in 2010 and 65 years old or greater in 2012 (ORadj = 18.13; 95%CI: 9.11 to 36.08, ORadj 31.69; 95%CI: 20.78 to 48.33, respectively), females (ORadj = 2.09; 95%CI: 1.66 to 2.62, ORadj = 1.77; 95%CI: 1.54 to 2.05, respectively), and had lower education attainment (ORadj = 5.87; 95%CI: 4.70 to 7.33, ORadj= 1.22; 95%CI: 1.04 to 1.45, respectively) were also found to be associated with DM . CONCLUSION: The study indicated that SES has been associated with DM. Those with female gender, old age and low educational attainment were vulnerable to DM. PMID- 28892938 TI - Prevalence of Diabetic Retinopathy and its Associated Factors in a Rural Area of Villupuram District of Tamil Nadu, India. AB - INTRODUCTION: There is limited information on prevalence of Diabetic Retinopathy (DR) among diabetic subjects and its associated factors in a rural setting in developing countries including India. The information will be useful for initiating early screening strategies for this group in the community. AIM: To assess the prevalence and certain associated factors of DR among diabetic subjects in a rural area of Tamil Nadu, India. MATERIALS AND METHODS: This cross sectional study was conducted among 105 Type 2 diabetic subjects in Pakkam and Mandagapattu sub-center area of Kondur Primary Health Center in Villupuram district of Tamil Nadu, India. Data on associated factors which include sociodemographic factors, duration of disease, family history, and frequency of blood test, treatment regularity, hypertension, visual acuity and cataract were collected. Detailed eye examination including visual acuity, direct ophthalmoscope and Non Mydriatic Fundus Camera was done. Data was analysed by univariate analysis and described in proportion or percentages. RESULTS: The mean age of the study population was 56.69 years. About 47 (44.8%) of the subjects were more than 60 years of age followed by 44 subjects (41.9%) in age group 45-59 years. Fundus examination in at least one eye was seen in 83 people (79.0%). Prevalence of DR in any eye and both the eye was 32.53% (27/83) and 31.58% (24/76) respectively. Severity of DR was moderate (51.9%) followed by mild (44.4%) and severe (3.7%). DR prevalence was more among >60 years age group (p=0.032) and lesser education level (p=0.057). There was no association of DR with duration of disease, family history of diabetes, treatment regularity, presence of hypertension, visual acuity and cataract (p>0.05). CONCLUSION: The prevalence of DR was inferred to be high and further larger follow up studies will explore the role of associated factors and its quantification in the causation of DR. PMID- 28892939 TI - A Rare Case of Marcus Gunn Jaw Winking Phenomenon in a Community Health Setting. PMID- 28892940 TI - A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey. AB - INTRODUCTION: Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant's life. The mothers' knowledge and their attitudes towards infant hearing loss is the basis for their decisions. AIM: The present study was done to determine the mothers' knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. MATERIALS AND METHODS: In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother's responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. RESULTS: Mothers' awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. CONCLUSION: It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences. PMID- 28892941 TI - Cartilage Myringoplasty: An Ideal Grafting Technique for Complex Perforations. AB - INTRODUCTION: Tympanoplasty is one of routinely performed surgeries in ENT practice. Using cartilage-perichondrium composite graft in selective cases gives better outcome. AIM: To study the outcome and feasibility of cartilage perichondrium composite graft in repair of complex tympanic membrane perforations. MATERIALS AND METHODS: This cross-sectional, intervention study was conducted at SSIMS and RC, Tertiary Care Teaching Hospital, Davangere, Karnataka, Southern India. Study sample consisted of 30 patients with chronic otitis media- tubo tympanic type in inactive stage. Patients were randomly selected and evaluated between January 2015 to June 2016. A detailed history, clinical examination, diagnostic nasal endoscopy, otoendoscopy were done for all patients preoperatively and postoperatively at three weeks, three months and six months. Audiological evaluation was done at six months postsurgery. Cartilage perichondrium composite graft from tragal and conchal cartilage was used for the repair of tympanic membrane in all the cases. The data were presented in proportions, percentages. RESULTS: Of 30 cases who underwent surgery, 24 patients (80%) had large central and subtotal perforations. Only one patient had a total perforation. The remnant tympanic membrane showed atrophic changes in 16 cases (53%) and sclerotic plaque was seen in 14 cases (46%). In our study, tragal cartilage was used in 17 and conchal cartilage in 13 cases. All the patients underwent type-1 tympanoplasty. Successful graft uptake was seen in 28 cases (93%) by six months. Two patients (7%) had a residual perforation at three months and in four cases (13%), the neotympanum showed anterior blunting by the end of six months. With respect to hearing, maximum air bone gap closure achieved in our study was 21db in one patient and minimum was 3db. Average air bone gap closure achieved was 10.1db. CONCLUSION: Cartilage-perichondrium composite graft can be considered a good choice in repair of tympanic membrane perforations with specific selective indications. PMID- 28892942 TI - Multifocal Presentation of a Laryngeal Disorder. AB - Multifocal presentation of a laryngeal disorder is very rare. We report a case of a 48-year-old man, who presented to our hospital with hoarse voice for two years. Stroboscopic evaluation followed by surgery was done and the specimens were sent for histopathological examination from three different anatomical sites of larynx which were diagnosed as one-benign lesion, second-benign lesion but ability of malignant transformation and the third-a malignancy. PMID- 28892943 TI - Reconstruction of Maxilla with Titanium Mesh and Fascia Lata - A Case Report. AB - Maxillary defect reconstruction has been a grave challenge which unfortunately has stopped many ENT surgeons from attempting maxillectomy due to the fear of reconstruction. With our technique of reconstructing the maxillary defect with titanium mesh and fascia lata, the need for microvascular assistance is obviated. Here we describe a revision case of ameloblastoma of maxilla in a 33-year-old female for which total maxillectomy with reconstruction was done without the aid of microvascular tissue transfer. The aim of this article is to encourage and alleviate the fear among the ENT surgeons, in attempting maxillectomy and its reconstruction for delivering an equally good aesthetic and functional outcome especially at the centres where the facility of plastic assistance is not readily available. PMID- 28892944 TI - Endoscopic Endonasal Approach of Blow Out Fracture Reduction- A Novel Technique. AB - Blunt trauma to orbit can lead to orbital blow out fracture. Computerized tomography of paranasal sinuses plays the main role in diagnosing it. Repairing the defect and restoring the orbital contents is a challenging task for the surgeon. Endoscopic endonasal approach in reduction of blow out fracture provides good cosmetic outcomes and grossly minimize surgical complications. We report a case of 18-year-old male presented with diplopia, restriction of eye movements and enophthalmos due to Road traffic accident. CT paranasal sinuses showed right side floor, medial orbital wall fracture with medial rectus muscle entrapment. We planned endoscopic endonasal approach to reduce the fracture and multilayered repair done using bone resected from choncha bullosa, fat and fascia lata. Patient relieved of symptoms post operatively without any complications. PMID- 28892945 TI - Pigmented Trichoblastoma of Nose: An Unusual Occurrence. AB - Nevus sebaceus of Jadassohn is a congenital tumour affecting the scalp and face. It is usually presented as a pigmented patch or plaque. It is a complex cutaneous hamartoma which involves pilosebaceous follicle, epidermis and adnexal structures. Tumours that arise from nevus sebaceous are basal cell carcinoma, syringocystadenoma papilliferum, trichoblastoma and hidradenoma. The progression and frequency of the tumour increase with the age. Here we present a case of pigmented trichoblastoma over the external nose. It was a case of an elderly woman presenting with a painless swelling over the external nose which was soft, non-tender and with well defined margins. PMID- 28892946 TI - Indian Perspectives on Graft Materials Used for Repair of Tympanic Membrane. AB - INTRODUCTION: Repair of Tympanic Membrane (TM) is one of the most common surgeries performed by the otologists. Literature reveals that Indian surgeons have contributed substantially in the research on techniques and graft materials used for the repair of tympanic membrane, though no review has been written so far highlighting their contributions. AIM: To summarize and analyse the contributions of Indian authors who have used different graft materials for repair of TM and their studies listed in Medline search. MATERIALS AND METHODS: A literature review was conducted using a Medline search using keywords of 'myringoplasty' and 'tympanoplasty' with 'India' on 30th June 2016. A total of 243 articles were found listed onwards from year 1998. Out of these 50 articles in which type 1 tympanoplasty or myringoplasty was performed using different graft materials were selected. The content of each abstract was studied in order to identify studies related to topic. RESULTS: Authors have experimented with a variety of tissues as graft materials. Temporalis Fascia (TF) has been most widely used in 58.6% studies as graft material. The next popular graft is tragal perichondrium. The graft take up rates varied from 68.5% to 100%, while method of reporting of hearing gain in most studies was inconsistent amongst studies, though most studies have reported achievement of serviceable hearing of < 25 dB in most patients. CONCLUSION: TF was the most prefered material due to anatomic proximity, light material and strength. It was followed in popularity by tragal perichondrium and tragal cartilage. All graft materials have given satisfactory hearing results. PMID- 28892947 TI - Diabetes and Diabetic Retinopathy: Knowledge, Attitude, Practice (KAP) among Diabetic Patients in A Tertiary Eye Care Centre. AB - INTRODUCTION: Diabetic retinopathy is becoming an increasingly important cause of visual impairment in India. Many diabetic patients who come to our centre have undetected, advanced diabetic retinopathy. If diabetic retinopathy had been detected earlier in these patients, irreversible visual impairment could have been prevented. AIM: To document Knowledge, Attitude and Practice (KAP) patterns of diabetic patients regarding diabetes and diabetic retinopathy, to determine association between them, and to identify barriers to compliance with follow up and treatment regimes. MATERIALS AND METHODS: This was a hospital-based, cross sectional study, conducted at the Department of Ophthalmology at Christian Medical College, Vellore, Tamil Nadu, India, over a six-month period from June 2013 to November 2013. Two hundred and eighty eight diabetic patients, who fulfilled the eligibility criteria, were included in the study. KAP of patients was assessed using a 45-point, verbally administered questionnaire. Patients were placed in different categories, such as, 'good/ poor' knowledge, 'positive/negative' attitude and 'good/poor' practice. Data were analysed using Chi-square test and binary logistic regression, as appropriate. The proportion of patients with 'good/poor' knowledge, 'positive/negative' attitude and 'good/poor' practice, and the association between KAP were studied. Barriers to compliance with follow up/treatment regimes were identified. RESULTS: Out of the 288 patients in the study, 42% had good knowledge about diabetes, but only 4.5% had good knowledge about retinopathy. Good knowledge about diabetes was significantly associated with positive attitude towards diabetes and good practice patterns regarding retinopathy; awareness of retinopathy was also significantly associated with good practice. A total of 61.1% of patients did not have periodic eye examination; most common barrier identified was lack of awareness about the necessity for this (38.5%). CONCLUSION: Good knowledge about the disease was significantly associated with positive attitude and good practice patterns. Knowledge about diabetic retinopathy was poor among the patients in our study. Lack of awareness concerning the need for screening for retinopathy was a major barrier to regular screening. There is an urgent need to educate diabetic patients about this potentially blinding complication of diabetes. PMID- 28892948 TI - Microperimetry - A New Tool for Assessing Retinal Sensitivity in Macular Diseases. AB - INTRODUCTION: Macular disease is the leading cause of low vision in the Western world. Drusen and pigmentary irregularities are common among the rural Northern Indian population. The disease process leads to loss of central vision, metamorphopsia, macropsia or micropsia and colour vision defect. AIM: To study the retinal sensitivity changes in macular diseases using microperimetry. MATERIALS AND METHODS: It was an observational study, conducted in the Department of Ophthalmology at a rural tertiary care hospital. This study was started from December 2014 until June 2016, in all patients with macular disease above the age of 20 years attending the outpatient department. Microperimetry was done for 84 eyes of 52 patients with macular disease. Mean retinal Sensitivity (MS) and fixation stability was evaluated. The statistical analysis of mean retinal sensitivity, central 2 degrees and 4 degrees fixation was done by calculating the mean and standard deviation using 95% confidence interval. RESULTS: The range of age was between 20-81 years. Majority were 32 males (62%) and 20 females (38%). Out of the 84 eyes studied, majority of the macular disease were Age Related Macular Degeneration (AMD) (50%). Rest 50% were other macular diseases. The mean retinal sensitivity (dB) shown by microperimetry was 10.83 in AMD, 9.12 in Cystoid Macular Oedema (CME), 10.34 in Epiretinal Membrane (ERM), 10.74 in Pigment Epithelial Detachment (PED), 8.96 in Central Serous Chorioretinopathy (CSCR), 6.43 in macular dystrophy, 7.15 in Lamellar Hole (LMH), 9.8 in Pseudomacular Hole (PMH), 3 in geographic atrophy, 11.1 in macular telangiectasia, 5.6 in Berlin oedema, 12.3 in macular scar and 15.2 in haemorrhage in macula. The study showed 64% of the eyes had stable 2 degrees central fixation, 35% had relatively unstable fixation and 1% had unstable fixation. No significant correlation between retinal sensitivity and retinal thickness in AMD was found. CONCLUSION: This study shows that microperimetry can be a useful tool for objective evaluation of macular function and progression of the disease. PMID- 28892949 TI - Corneal Collagen Cross-linking for Treatment of Bacterial and Herpetic Keratitis. AB - INTRODUCTION: Optimal management of infective keratitis is a formidable challenge and subject of ongoing studies. Recently, Collagen Cross-Linking (CXL) of the cornea has been considered to be a new effective therapeutic approach for resistant infectious keratitis. AIM: Aim of the study was to evaluate the effectiveness of CXL with Ultraviolet-A (UV-A) and riboflavin for treatment of the refractory bacterial and Herpes Simplex Virus (HSV) keratitis. MATERIALS AND METHODS: In this prospective interventional study, eight patients with diagnosis of infectious keratitis who were referred to Khalili Hospital eye emergency room, between 2014 and 2015 were included in the study. There were six patients with bacterial keratitis and two patients with HSV keratitis; they were resistant to conventional treatment and underwent CXL. Response to the treatment was considered as good if rapid epithelialization and rapid decrease in stromal infiltration occurred. RESULTS: Microbial culture in the bacterial keratitis group showed coagulase negative Staphylococcus in two patients, Staphylococcus aureus in one patient, mixed infection in one patient and Pseudomonas aeruginosa in two patients. Good response and rapid epithelialization and resolution of stromal infiltration were seen in the four out of six eyes. Two patients showed no response and underwent penetrating keratoplasty for eradication of infection. Furthermore, one patient showed a good response to CXL in the HSV keratitis group and another patient had a relative response but recurrence occurred. CONCLUSION: Although, CXL seems promising in the treatment of patients with refractory bacterial keratitis, but in some cases, it is ineffective. CXL may be an alternative treatment for refractory cases of HSV keratitis but recurrence is possible. PMID- 28892950 TI - Riley-Day Syndrome in a Hispanic Infant of Non-Jewish Ashkenazi Descent. AB - Riley-Day syndrome is an autosomal recessive sensory and autonomic neuropathy. Patients present a lack of fungiform papilla, alacrima and usually feeding difficulties. It is present almost exclusively in Ashkenazi Jewish individuals and has a poor prognosis. We describe an unusual case of Riley-Day syndrome with pseudostrabismus in a non-Ashkenazi Jewish patient. A one-year-old female infant was referred for evaluation of strabismus, absence of fungiform papillae, feeding difficulty, gastroesophageal reflux and episodes of self-mutilation. Deep tendon reflexes were depressed, the blinking rate and corneal reflex were diminished as well and corneas were opaque due to corneal erosions. Reduced lacrimal production was confirmed by the Schirmer test. Eye drops were recommended every 2-3 hours for corneal erosion and the patient was referred to the genetics department for further diagnostic confirmation. PMID- 28892951 TI - Outcomes of Mechanically Ventilated Critically Ill Geriatric Patients in Intensive Care Unit. AB - INTRODUCTION: Increase in life expectancy across the globe has led to rise in geriatric population. Geriatric population is now living longer and healthier. This rise in geriatric population has also led to increase in the geriatric ailments leading to increased number of geriatric patients requiring intensive care including mechanical ventilation. Data on outcomes of geriatric patients requiring mechanical ventilation from India is scarce. AIM: To study the profile and outcome of geriatric patients more than equal to 60 years requiring mechanical ventilation in Intensive Care Unit (ICU). MATERIALS AND METHODS: The data of all the geriatric patients, more than 60 years of age, admitted to ICU between January 2008 to August 2014 requiring mechanical ventilation for various reasons were extracted from the hospital records. Various reasons for ventilation, duration of ventilation/hospital stay, mortality and associated comorbidities were recorded and analysed. RESULTS: Total 140 geriatric patients were mechanically ventilated in the study period, out of which 43.5% (61/140) were above 70 years of age and 67.8% (95/140) were above 65 years of age. Chronic Obstructive Pulmonary Disease (COPD) was the most common cause for mechanical ventilation constituting 20% of patients followed by severe sepsis (17.8%), cerebro-vascular accident (12.8%), post-surgical patients (12.8%) and Coronary Artery Disease (CAD) in 10%. In our study, 44.28% of the geriatric patients requiring mechanical ventilation in the ICU were successfully weaned off the ventilator. Early tracheostomy helped in weaning off from ventilator as 83.33% (5/6) of patients requiring tracheostomy could be weaned off the ventilator suggesting that tracheostomy may help in improving the outcome. Reintubation carried a very poor prognosis and increased mortality, as 80% (4/5) of the patients who were reintubated in our study could not survive. CONCLUSION: Our study revealed that in appropriate intensive care setting and with standard protocol based therapy for primary ailments, outcomes with mechanical ventilation in geriatric population can be comparable to outcomes in younger population. PMID- 28892952 TI - Correlation of Reciprocal Changes and QRS Amplitude in ECG to Left Ventricular Dysfunction, Wall Motion Score and Clinical Outcome in First Time ST Elevation Myocardial Infarction. AB - INTRODUCTION: Electrocardiogram (ECG) is the simplest tool for diagnosing ST Elevation Myocardial Infarction (STEMI). We can use a12 lead ECG for prognostication purposes also. AIM: The aim of the study was to find out the role of ECG as a prognostic marker in terms of clinical outcome and wall motion abnormality. MATERIALS AND METHODS: It was a prospective study done in PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India, from January 2014 to September 2014. Patients aged above 18 years admitted with first episode of ST EMI as per the inclusion and exclusion criteria were recruited for the study. Presence of reciprocal changes and QRS amplitude was measured from ECG. Presence of Left Ventricular Dysfunction (LVD) and wall motion score were calculated from ECG along with clinical outcome during first follow up visit. Statistical analysis was done using SPSS software. Probability was calculated using chi-square test, independent t-test and ANOVA analysis. RESULTS: A total of 120 patients were recruited for the study of which six were excluded based on the exclusion criteria. Among 114 patients analysed, 55 had reciprocal changes; 38 of them developed LVD which was statistically significant (p=0.002). Of the 78 patients with Anterior Wall Myocardial Infarction (AWMI), 35 had reciprocal changes; 15 (42.9%) of them had NYHA Class 1 symptoms, 14 (40%) had Class II and 4 (11%) had class III symptoms at follow up. The association was statistically significant (p=0.001). Similar statistically significant association was found in patients with Inferior Wall Myocardial Infarction (IWMI) who had reciprocal changes and NYHA symptoms at follow up (p=0.004). The mean wall motion score in patients with AWMI and reciprocal changes was 24.83 +/- 4.1; whereas, without reciprocal changes was 23.98 +/- 3.6; the association was not statistically significant. The mean QRS amplitude of all patients with LVD was 33.25 +/-16.34. The association between QRS amplitude and LVD was not statistically significant. The overall mean wall motion score was 24.86 +/- 3.91. The association between QRS amplitude and wall motion score was statistically significant (r value = 0.210). The association between QRS amplitude and wall motion score was statistically significant when we analysed AWMI (r= -0.147, p=0.199) and IWMI (r= -0.359, p=0.031) separately. CONCLUSION: ECG can be used as a tool for prognostication in acute STEMI. The presence of reciprocal changes in the ECG can signify poorer outcome on follow up. Lower QRS amplitude can be used as a predictor of larger infarct. PMID- 28892953 TI - Effect of Cycling on Glycaemia, Blood Pressure, and Weight in Young Individuals with Type 2 Diabetes. AB - INTRODUCTION: Aerobic exercise is associated with significant improvement in glycaemia and weight loss in Type 2 diabetes (T2D). Cycling, a form of aerobic exercise can benefit young (18 to <40 years) individuals with T2D. AIM: To assess effect of cycling on glycosylated haemoglobin (HbA1c), blood pressure (BP) and weight over six months in young individuals with T2D. MATERIALS AND METHODS: In this retrospective, observational study, young (18 to <40 years) T2D patients who were being treated without insulin and not on more than two Oral Antidiabetic Drugs (OADs) were identified from a group of cyclists in a metro city from Northern India. These individuals were involved in a regular exercise program (cycling 25 km/day for at least five days a week). Participants with consecutive six months of cycling were selected and those involved in other forms of exercise were excluded. From their medical records, participants' weight, BP, and HbA1c levels were noted at baseline (i.e., before the start) and post-six months of cycling program and evaluated with appropriate statistics. RESULTS: From 26 cases identified with T2D, 20 participants were included in analysis. Mean age of participants was 35.6+/-2.6 years, five were <35 years and all of them were males. Cycling resulted in significant reduction in HbA1c% (mean change from baseline at six-month: -1.18, 95% Confidence Interval (CI) 1.12, 1.24; p<0.001). Besides, systolic (-5.2, 95% CI -3.7, -6.6; p<0.001) and diastolic (-3.1, 95% CI 1.7, -4.5; p<0.001) BP and weight (kg) (-5.0, 95% CI -4.41, -5.58; p<0.001) showed significant reduction from baseline to six-months. Among two age groups (Age < 35 and >= 35 years), except for reduction of diastolic BP in age < 35 years, significant reduction in all other parameters was evident in both age groups. CONCLUSION: Regular aerobic exercise in cycling form results in significant reduction in HbA1c, BP and weight. It should be promoted as an ideal method for exercise in young T2D cases to derive maximum benefits and to improve adherence to lifestyle intervention. PMID- 28892954 TI - Serum Free T3 to Free T4 Ratio as a Useful Indicator for Differentiating Destruction Induced Thyrotoxicosis from Graves' Disease. AB - INTRODUCTION: Thyrotoxicosis is a common disease encountered in Endocrine Outpatient Department (OPD). Two common causes of thyrotoxicosis are Destruction Induced Thyrotoxicosis (DIT) and Graves' Disease (GD). Differentiating DIT and GD based on clinical findings, is often not possible due to nonspecific symptoms. Thyroid scan is considered most reliable method for differentiating DIT and GD. AIM: To differentiate DIT and GD using the ratio of free triiodothyronine (fT3) and free thyroxine (fT4) thus avoiding thyroid technetium scan which is expensive and not accessible in developing countries like Nepal. MATERIALS AND METHODS: Patients attending Endocrine OPD with diagnosis of thyrotoxicosis at their first visit in which Thyroid technetium scan could be done were taken as sample. The study was conducted from mid-June 2016 to February 2017 and total 55 samples were taken. Only selected cases were taken where diagnostic dilemma was present. Report of Thyroid Function Test (TFT) of patient at their first visit and findings of thyroid scan were recorded. Ratio of freeT3 and freeT4 was obtained in each case. ROC curve was plotted and the cut off value for differentiation of DIT and GD was obtained. All data were analysed using SPSS software version 20.0. RESULTS: Mean ratio of fT3 to fT4 in GD and DIT was 0.395 and 0.287 respectively which was significant. On ROC analysis, cut off ratio for differentiating GD and DIT was 0.30 with sensitivity of 87% and specificity of 62.5%. CONCLUSION: It is recommended that thyroid scan can be avoided if ratio of fT3 and fT4 is less than 0.3 and a diagnosis of DIT can be made. PMID- 28892955 TI - Frequent Occurrence of Faulty Practices, Misconceptions and Lack of Knowledge among Hypothyroid Patients. AB - INTRODUCTION: Hypothyroidism is a common endocrine disorder with a reported prevalence of 4%-10%. Previous studies have reported significant gaps in the basic knowledge about the condition in hypothyroid patients. It has also been observed that faulty practices prevail among these patients. There is paucity of data on the assessment of knowledge and practices among treated hypothyroid patients. AIM: The present study was aims to assess the knowledge, awareness and practices in treated hypothyroid patients. MATERIALS AND METHODS: The current cross-sectional study was conducted on 244 consecutive hypothyroid patients, attending the Endocrinology Outpatient Department (OPD). The patients were asked to fill a structured questionnaire pertaining to knowledge and practices about various aspects of hypothyroidism. RESULTS: Only two-thirds of the participants correctly identified thyroid as a gland and 41% were aware that hypothyroidism is caused due to decreased function of the thyroid gland. The most common symptom attributed to hypothyroidism was weight gain (139 responses). Nearly 45% of the patients believed alternative forms of medicine can be used for treatment of hypothyroidism. It was believed by 42% of the patients that hypothyroidism runs in the family and about 10% believed it could be transferred to their spouses. Only 33% of the patients gave one hour gap between levothyroxine and food intake. CONCLUSION: The study demonstrates the lack of knowledge about basic aspects of hypothyroidism among the patients. In addition, there is a high prevalence of misconceptions and faulty practices. The study highlights the need for comprehensive patient education to improve therapeutic outcomes and compliance among hypothyroid patients. PMID- 28892956 TI - Short Term Efficacy and Safety of Insulin Glargine in Type 2 Diabetes Inadequately Controlled with Single or Two Oral Agents: A Prospective, Open Label Study. AB - INTRODUCTION: Basal insulin is among the second line treatment options for Type 2 Diabetes Mellitus (T2DM). Efficacy and safety of basal insulin in patients of T2DM, uncontrolled with Oral Antidiabetic Agents (OAAs) remains understudied in the Indian setting. AIM: To assess the efficacy and safety of insulin glargine in patients with T2DM who have uncontrolled glycaemic levels despite single or two OAAs therapy. MATERIALS AND METHODS: In this prospective, open label study, T2DM patients above 40 years of age, having inadequate glycaemic control [Glycosylated Haemoglobin (HbA1c) above 8% and/or fasting glucose level of 140 mg/dl and above] with single or two OAAs over three consecutive months were included. Dosing of insulin glargine was adjusted as per Fasting Blood Glucose (FBG) and Post Prandial Blood Glucose (PPBG) levels. Patients were followed for 12 weeks and data was analysed by comparing 12th week findings to baseline values. RESULTS: In 40 cases included in final analysis, mean age was 56.35 +/- 6.77 years, 52.5% were females and mean body mass index was 26.96 +/- 4.59 kg/m2. Compared to baseline, significant reduction in HbA1c, FBG and PPBG blood glucose (all p<0.05) was seen. HbA1c goal of < 7% was achieved in 37.5% cases. Systolic (p>0.05) and diastolic (p<0.05) blood pressures reduced at 12 weeks as compared to baseline. Increase in weight was modest with mean increase of 1.06 kg (p>0.05). Overall, 14 symptomatic hypoglycaemia events were observed with none being severe. CONCLUSION: Short term administration of insulin glargine is effective in reducing glycaemia and is safe with lower rates of severe hypoglycaemia. It can be considered in patients with uncontrolled T2DM on mono- or two- OAAs treatment. PMID- 28892957 TI - Risk of GERD with Diabetes Mellitus, Hypertension and Bronchial Asthma - A Hospital based Retrospective Cohort Study. AB - INTRODUCTION: The rise in Gastro-Esophageal Reflux Disease (GERD) prevalence appears to have coincided with a simultaneous increase in the prevalence of diabetes mellitus, hypertension and bronchial asthma amongst the Indian population. Despite being evaluated extensively for their role as a risk factor for GERD, till date this relationship has remained a debatable one. Moreover, literature available on such studies conducted within Indian population remains scarce. AIM: The aim of the present study was to examine the risk of developing GERD in patients suffering from diabetes mellitus, hypertension and asthma in a Southern Indian population. The present retrospective, triple cohort and hospital based study was conducted by accessing the patient records from the medical records department of a tertiary care hospital in Southern India. MATERIALS AND METHODS: The patient's records were accessed from the year 2011 onwards. Relative Risk (RR) was calculated to determine the risk of development of GERD with every disease. Chi-square test was used to determine the statistical significance of the relationship between each disease and the development of GERD. A p-value of <0.05 was considered statistically significant. RESULTS: In view of the time constraints as well as the limitations of the inclusion and exclusion criteria, data pertaining to only 40, 71 and 53 patients in Cohort 1 (diabetics), 2 (hypertensives) and 3 (bronchial asthmatics) respectively could be analyzed in the present study. The relative risk of GERD development was greater than 1 for patients belonging to Cohort 2 and 3, suggesting that the risk of GERD development is higher amongst hypertensives and asthmatics. Surprisingly, the diabetics (Cohort 1) were not associated with a high risk of GERD development. However, the relationship between any of the disease and GERD development was not statistically significant. CONCLUSION: The present study found an increased risk of GERD development amongst patients suffering from hypertension and bronchial asthma, but not with diabetes mellitus. PMID- 28892958 TI - Correlation of Serum Prolactin Level to Child Pugh Scoring System in Cirrhosis of Liver. AB - INTRODUCTION: With the growing incidence of liver cirrhosis among Asians, the use of a biomarker such as prolactin, indicates the severity of the disease, its complications and serves as a tool for early intervention. AIM: To compare the efficacy of serum prolactin to the Child Pugh scoring system in cirrhosis of the liver and establish that serum prolactin is an early marker for complications of cirrhosis of the liver. MATERIALS AND METHODS: This was a comparative study on 60 patients admitted to the Department of General Medicine, KIMS from June 2014 to November 2015. Patients above the age of 18 years, diagnosed to have cirrhosis of the liver were included in the study. Patients having conditions/medications known to elevate prolactin levels such as cranial surgery/irradiation, pituitary disease, chronic renal failure, drugs such as neuroleptics, metoclopramide, aldosterone antagonists, etc., were excluded. All the patients were subjected to the routine work up for chronic liver disease including serum prolactin levels at admission. RESULTS: In the present study, the most common cause of cirrhosis was found to be alcohol (73%). The complications of cirrhosis were portal hypertension in 50 (83.3%), oesophageal varices in 39 (65%) with upper GI bleed in 22 (36.7%) patients, hepatic encephalopathy in 15 (25%) patients. Serum prolactin levels were elevated in 73% of the patients with highest levels of serum prolactin (>35 ng/ml) seen in patients of Class 'C' Child Pugh. Elevated serum prolactin was found in 66.7% of the patients with oesophageal varices, 90.9% patients with upper GI bleed and in all patients with hepatic encephalopathy (100%). CONCLUSION: Serum prolactin levels correlated with the Child Pugh score in predicting the severity of the disease. Patients with a higher serum prolactin at admission had a greater incidence of complications of cirrhosis. Hence, serum prolactin is an inexpensive, non invasive blood marker which may be used to estimate the severity and the complications of cirrhosis. PMID- 28892959 TI - Prevalence of Conventional Risk Factors and Evaluation of Baseline Indices Among Young and Elderly Patients with Coronary Artery Disease. AB - INTRODUCTION: Coronary Artery Disease (CAD) is a leading cause of morbidity and mortality worldwide, manifesting in a variety of clinical spectrums such as an asymptomatic disease or acute coronary syndrome. It has become highly prevalent in Southeast Asia, including Pakistan. There has been little work done on the prevalence of traditional risk factors in different age groups and genders and there is a dire need to gauge the importance of baseline indices in CAD patients. AIM: To determine the prevalence of conventional risk factors and evaluate the variations in lipid profiles, electrolyte levels and haematological indices among patients with CAD in different age groups and gender. MATERIALS AND METHODS: This cross-sectional study was carried out in a Tertiary Care Hospital in Karachi, Sindh, Pakistan from January to June 2016, among patients with CAD. We recorded the presence of conventional risk factors and baseline indices within the first 24 hours of admission. Continuous variables were compared using Independent t test or Mann-Whitney test and categorical variables were compared using chi square or Fisher's exact test. RESULTS: The most frequent risk factor was dyslipidemia (91.2%), followed by hypertension (70.4%), diabetes (51.2%), family history of CAD (40.0%) and smoking (29.2%). Total of 98.4% of patients had at least one risk factor. Diabetes and hypertension were found to be common in females; whereas, smoking was predominantly present in males. Diabetes and dyslipidemia were mostly encountered in elderly patients. The most frequent lipid alteration was low levels of High Density Lipoprotein (HDL). Cholesterol and HDL levels were found to be higher in females than males. Elderly patients had lower levels of HDL and higher levels of Cholesterol. The levels of haematological indices were found to be higher in males and younger patients. The median levels of serum sodium and potassium were found to be higher in elderly patients. CONCLUSION: Our study findings corroborate with the findings from previous studies regarding the significance of risk factors in causing cardiovascular pathology. Medical interventions and dietary control to improve body's lipid status would be indispensable in the prevention of CAD. Deranged electrolyte levels necessitate correction of body electrolyte parameters as an adjunct in prevention strategies. PMID- 28892960 TI - A Rare Case of Primary Calcific Pleural Tuberculosis - A Case Report. AB - Tuberculosis is a highly prevalent disease in India. It has a myriad of presentations. Usually pleural tuberculosis occur secondary to pulmonary tuberculosis which can manifest as pleural effusion leading to pleural calcification. Primary pleural calcification due to tuberculosis is an extremely rare manifestation of active tuberculosis. We present a case of a 21-year-old female presenting with fever, cough, weight loss and loss of appetite who was diagnosed to have pleural calcification due to primary tuberculosis. We highlight the need to keep primary pleural tuberculosis in mind with above symptoms suggestive of active tuberculosis even when there is no underlying lung pathology. PMID- 28892961 TI - Calcium on Mitral Valve: Decipher Aetiopathogenesis. AB - We hereby describe an unusual case of a 17-year-old female with severe mitral regurgitation secondary to heavily calcified immobile valve leaflets. Along with the mitral valve, corneas were also calcified, due to congenital systemic metabolic disorder, distal renal tubular acidosis. Histopathology proved that there was no intrinsic pathology of the mitral valve. Congenital distal renal tubular acidosis with normokalemia presenting with severe mitral and corneal calcification is not known. This case notes important clinical features and is thought to add to the existing knowledge regarding the disease. Patient succumbed to her illness during mitral valve surgery and genetic analysis was not done prior. This is the limitation of our reporting. In this modern era, specific clinical features are also important and of equal value to try and understand molecular and genetic basics of the diseases. PMID- 28892962 TI - Crigler Najjar Syndrome Type 2 (CNS Type 2): An Unwonted Cause of Jaundice in Adults. AB - Crigler Najjar Syndrome (CNS) Type 2 is an uncommon genetic disorder characterised by non-haemolytic unconjugated hyperbilirubinemia. It is caused by mutations in the UGT1A1 gene which codes for the enzyme uridine diphosphate glucoronosyl transferase- 1, required for the conjugation and further excretion of bilirubin from the body. Affected individuals are usually asymptomatic apart from the jaundice and investigations reveal isolated indirect hyperbilirubinemia. It can be conveniently diagnosed by evaluating the response to phenobarbitone in terms of fall in bilirubin levels. Genetic testing of the UGT1A1 gene for mutations is the diagnostic clincher. However, case reports documenting the genetic mutational analysis are sparse. We report one such rare case. PMID- 28892963 TI - Autoimmune Hepatitis - Primary Biliary Cirrhosis Overlap Syndrome. AB - Autoimmune Hepatitis (AIH) and Primary Biliary Cirrhosis (PBC) are important immune mediated liver diseases. They are usually differentiated based on clinical, biochemical, serological and histological parameters. The presence of autoantibodies, clinical and serological findings can sometimes occur in different combinations leading to overlap syndromes, which is rare. Early recognition of such overlap syndromes is clinically significant from treatment point of view. Here, we report a case of AIH-PBC overlap syndrome with a brief review of literature on overlap syndromes. PMID- 28892964 TI - Dengue Haemorrhagic Encephalitis: Rare Case Report with Review of Literature. AB - Dengue is an endemic arboviral infection prevalent especially in tropical countries including Southern and Southeast Asia. Central Nervous System (CNS) involvement in dengue infection is uncommon. Haemorrhagic encephalitis is a rare presentation in dengue. This is a case of a 58-year-old male who presented with fever, petechial rash and altered sensorium. Dengue serology IgM was reactive and MRI brain was suggestive of haemorrhagic encephalitis. Patient was managed in Intensive Care Unit (ICU) but eventually succumbed to his illness. We report this fatal outcome of a common viral infection with unusual neurological presentation to propose an association between dengue and neurotropism and the need to look at dengue infection beyond its classical features. PMID- 28892965 TI - Dunbar Syndrome-A Rare Cause of Foregut Ischemia. AB - Median Arcuate Ligament Syndrome (MALS) is a condition that can result from an anatomical aberration. If the median arcuate ligament is located too inferiorly in relation to the celiac axis, it can impede circulation and lead to vascular compromise. Here, we present the case of a 63-year-old woman, who came to the hospital complaining of continuous epigastric pain and who was ultimately found to have MALS. Her epigastric pain could be the result of the ischemia caused by MALS that made it difficult for the duodenal ulcer to heal properly. This case report documents an unusual presentation of an already rare condition. PMID- 28892966 TI - Longitudinal Stent Deformation at Aneurysm Site: Flexibility at the Expense of Longitudinal Integrity. AB - Longitudinal stent deformation is a recently described complication of percutaneous coronary intervention. Novel stents with thin struts and reduced number of fixed links between cells improve flexibility and deliverability but in certain cases it may reduce longitudinal strength and thereby increase the risk of longitudinal deformation. Although longitudinal deformation of coronary stents is an infrequent finding, it requires clinical attention as it may lead to catastrophic clinical outcomes. We report a case of longitudinal deformation of coronary stent observed at our institution while treating ostial lesion and aneurysm of left anterior descending artery. Longitudinal deformation was identified during the procedure and treated with the deployment of another stent. Three-month follow-up of the patient was found satisfactory without any incidence of stent thrombosis. PMID- 28892967 TI - Bilateral Single System Orthotopic Ureterocele with Bilateral Multiple Calculi Presented with Retention of Urine - an Urological Emergency. AB - The ureterocele is an uncommon congenital anomaly of the lower ureter. Ureterocele with a single pelvicalyceal system, bilateral, and orthotopic variety is less common. Calculi within bilateral ureterocele are a rare occurrence. To the best of our knowledge, only a few similar cases have been reported in the literature. Among the all reported presentations of this type of ureterocele, presentation with Acute Urinary Retention (AUR) has not been described in the literature. We present a case of nine-year-old child having bilateral, single system orthotopic ureterocele with calculi in bilateral ureterocele and presented with AUR due to obstructive bulbar urethral calculus. The bilateral endoscopic incision was given and all four calculi were removed endoscopically through percutaneous route. Voiding cystourethrography after two years follow-up was non refluxing. The purpose of reporting this case is the rarity of the disease and to emphasize that delay in diagnosis and treatment of these cases may lead to complications such as recurrent urinary tract infection and renal failure. PMID- 28892968 TI - A Rare Case of Ileocecal Tuberculosis with Pulmonary Embolism and Deep Vein Thrombosis. AB - Venous thromboembolism in tuberculosis is not a well recognised entity. It is a less frequently reported complication of severe pulmonary tuberculosis. It is exceedingly rare when it complicates extrapulmonary tuberculosis. Here, we present a case of 22-year-old young female with abdominal tuberculosis complicated with reverse ileocecal intussusception, deep vein thrombosis and pulmonary embolism. An emergency vena cava filter was inserted prior to a limited right hemicolectomy. In this article, we discuss the rare association of venous thromboembolism with ileocecal tuberculosis. PMID- 28892970 TI - Primary Tuberculotic Osteomyelitis of Rib in a Child. AB - Although extremely rare, osteomyelitis has been reported in smaller bones like ribs. A 13-year-old male child presented with a one week history of chest wall swelling. Fine Needle Aspiration Cytology (FNAC) of the lesion and initial bacterial culture could not find the aetiology of the lesion. He underwent surgical resection of entire sixth rib for osteomyelitis and was subsequently diagnosed to have tubercular osteomyelitis. Diagnosis and treatment of rib tuberculosis is both difficult and controversial. Rib tuberculosis is often not successfully treated by medical management alone and consequently needs surgery. PMID- 28892969 TI - Fistulating Richter's Hernia of Groin with Necrotizing Soft Tissue Infection: A Lethal Combination. AB - Strangulation of groin hernia can result in significant morbidity and mortality. Spontaneous external fistulation following strangulation is rare and typically occurs with Richter's hernia. Spreading Necrotizing Soft Tissue Infection (NSTI) secondary to Enterocutaneous Fistula (ECF) is an ominous sign, further worsening its prognosis. Early diagnosis and prompt surgical treatment is crucial to improve outcome. Herewith the authors are presenting a case of neglected inguinal hernia. It was complicated with ECF formation and rapidly spreading NSTI of flank. He underwent resection and anastomosis of the gangrenous bowel, anatomical repair of the hernia along with soft tissue debridement of flank region. This patient however succumbed to sepsis with multi organ dysfunction. Significant delay in seeking medical care led to dismal outcome. PMID- 28892971 TI - A Case Report of Largest Documented Multilocular Cystic Nephroma Removed by Thoracoabdominal Approach. AB - Large renal tumours are not uncommon in developing countries. Enhancing renal tumours are considered to be malignant unless proved otherwise and radical surgical resection remains the mainstay of treatment of such tumours. A giant renal tumour, especially on right side, poses a big challenge for the operating team and requires a thoracoabdominal approach for successful excision. We report successful removal of the largest documented Multilocular Cystic Nephroma (MLCN, 5.5 kg) from a 28-year-old female who presented with right abdomen lump since two years. The surgery was done through a 9th intercostal thoracoabdominal incision as the mass (31 x 19 x 19.6 cm) extended from right sub-diaphragmatic space up to the dome of the bladder. We discuss here the technique of removing such a huge renal mass and the challenges an operating surgeon may encounter. PMID- 28892972 TI - Renal Synovial Sarcoma in a Young Pregnant Lady: A Case Report and Clinico Pathological Profile. AB - Synovial sarcoma is a soft tissue neoplasm with clearly defined histologic, immunohistochemical and molecular features. These tumours usually arise in the extremities of young adults. Their occurrence in the kidney is extremely rare. A 25-year-old pregnant lady in her first trimester was incidentally found to have a left renal mass on perinatal ultrasonography. MRI showed a well encapsulated, heterointense mass replacing the left kidney. Following medical termination of her pregnancy, a radical nephrectomy was performed. Histopathology revealed a primary synovial cell sarcoma of the kidney. Postoperatively, she received ifosfamide based adjuvant chemotherapy. This report highlights the challenges involved in the diagnosis of this extremely rare neoplasm. A high index of clinical suspicion, complimented by the use of immunohistochemistry and cytogenetics during histopathological analysis aide in the diagnosis. Aggressive management with a combination of complete surgical extirpation and chemotherapy gives the best results. PMID- 28892973 TI - Large Eccrine Acrospiroma of the Hand. AB - Eccrine acrospiroma are benign skin tumours of sweat duct origin. They usually present as small solid or cystic lesions which are confused clinically with other solid or cystic lesions. These are generally benign lesions with few reports of malignant transformation. Here, we report a case of a middle aged female presenting with a swelling of the dorsum of left first web space which was histopathologically diagnosed as an eccrine acrospiroma, which was managed with surgical excision and covered with a regional flap. This case is presented due to the large size of the lesion in the hand. PMID- 28892974 TI - Squamous Cell Carcinoma Penis in a Case of Urethral Stricture Due to Lichen Sclerosus Balanitis Xerotica Obliterans: A Case Report and Review of Literature. AB - Penile carcinoma is considered a delayed sequel of lichen sclerosus. It is important to recognize this not so uncommon complication in time as survival of patients with Squamous Cell Carcinoma (SCC) depends on early diagnosis and treatment. We describe a case of a 49-year-old male presenting with urethral stricture due to lichen sclerosus. He was treated for stricture disease and later on developed SCC penis after ten years of presentation. PMID- 28892975 TI - Caudal Regression Syndrome with Pressure Ulcers of the Foot: A Case Report. AB - Caudal Regression Syndrome (CRS) is a rare disorder which consists of abnormalities in the lumbosacral spine, rectum, urinary system and lower limbs. These abnormalities also include orthopaedic deformities, such as hip dislocation, knee-flexion contracture with popliteal webbing and talipes equinovarus. Because of the rarity of this condition, few medical personnel are aware of it. Here, we present a case of CRS in a 15-year-old girl with pressure ulcers on the lateral malleolus and plantar surface of the foot, which had come into contact with the wheelchair footrest. Although the foot ulcers healed after off-loading, the ulcer on the lateral malleolus did not heal with conservative treatment and was covered by a lateral supramalleolar flap after debridement. Stable coverage and good contours were present at 18 months postoperatively. CRS patients may have a risk factor for developing pressure ulcers of the foot due to the characteristic lower limb deformities and a loss of sensation. Preventive foot care measures such as off-loading devices combined with modern dressings should be applied as routine when the medical personnel is to attend such patients. PMID- 28892977 TI - External Drainage of Giant Infantile Choledochal Cyst before Definitive Repair: Is it Worth? AB - Infantile Choledochal Cysts (IFCC) usually present with jaundice, acholic stool and abdominal lump or abdominal distension. If the surgical intervention is delayed, they rapidly progress to liver fibrosis which is considered to be irreversible if progressed to cirrhosis. We present the data of four cases (aged one month to seven months) of IFCC presented with cholangitis managed in one surgical unit in last two years. In one case, cholangitis was treated with prolonged antibiotic course before definitive repair whereas in rest, external drainage of cyst was done in addition to intravenous antibiotic to treat cholangitis. All the infants had features of cholangitis at time of presentation. Total leucocyte count ranged from 18x1000/UL to 30.6x1000/UL. Total bilirubin level at presentation ranged from 8.2 mg/dl to 18 mg/dl and Prothrombin time (INR) ranged from 1.33 to 1.9. Hepatic fibrosis was observed in all cases but cirrhosis was observed in only one case. There was no mortality but one patient had postoperative complication with prolonged hospital stay. External drainage helps in early recovery from cholangitis and better optimization of liver function. It also delays further progression to liver fibrosis by relieving the biliary outflow obstruction while waiting for definitive repair. PMID- 28892976 TI - Diagnosis and Treatment of Duodenal Lipoma: A Systematic Review and a Case Report. AB - INTRODUCTION: Duodenal lipoma is very rare with limited case reports present in literature. Owing to recent advances in endoscopy and modern imaging techniques, more cases are being diagnosed and treated. However, no systematic study of duodenal lipomas has been reported. AIM: To study the diagnosis and treatment of duodenal lipoma in a female patient and review the relative literatures to enhance the knowledge of it. MATERIALS AND METHODS: A literature search for 'duodenal lipoma' was performed on PubMed. Papers published from 1948 to 2016 in the English language were identified. Each article was then read in detail and analysed for clinical data, imaging features, diagnosis and therapy. Also, we hereby present a case of upper gastrointestinal obstruction secondary to multiple duodenal lipomas in a 67-year-old woman. The patient underwent a limited bowel resection with an uneventful recovery. RESULTS: Literature review demonstrated 59 cases of duodenal lipoma, which indicate that duodenal lipomas are rare to occur but commonly found in the second part. The peak of incidence seems to be around the fifth and seventh decade of life. Duodenal lipomas may present as gastrointestinal bleeding, abdominal pain, obstruction or upper abdominal fullness. CT, MRI, Endoscopic Ultrasound (EUS), endoscopy are highly accurate diagnostic tools. The disease could be managed by endoscopy or surgery. CONCLUSION: Our review of literature indicated duodenal lipoma is extremely rare. The symptoms are nonspecific and CT is the first choice for diagnosis. The treatment depends on the patient's condition as well as the size and position of the tumour. PMID- 28892978 TI - Maternal Outcomes Associated with Caesarean versus Vaginal Delivery. AB - INTRODUCTION: To choose the best mode of delivery (vaginal versus caesarean section) still remains a contentious issue. Caesarean section is a major abdominal surgery with its related medical, anesthetic and surgical complications. Maternal mortality and morbidity is higher in caesarean section compared with vaginal delivery. The most common causes of maternal mortality during caesarean section are due to anesthesia, bleeding and infection. AIM: The aim of this study was to determine the mode of delivery and maternal outcomes in Sanandaj's hospital, Iran, during one year. MATERIALS AND METHODS: The study population included all women who were admitted for delivery in Sanandaj's Hospital. Data collection instrument was a researcher made questionnaire. Data were entered into SPSS version 20.0 and analyzed using Chi-square test. Desired outcomes were entered into multiple logistic regression models. For estimating the parameters and increasing the level of significance we used bootstrap to generate 1000 samples. RESULTS: During the study, a total of 5984 deliveries were conducted in Sanandaj Hospital, of which 3423 (57.20%) were vaginal (vaginal, vaginal + episiotomy, instrumental delivery) and 2561 (42.80%) were caesarean section. The results showed a statistically significant association between delivery mode and demographic variables such as age, occupation and level of education; whereas, no significant association was found between place of residence and parity. CONCLUSION: The finding of this study showed that caesarean section delivery rate in Sanandaj was 42.80% in 2012-2013 which is higher than caesarean section rate recommended by WHO. Also, there was a relationship between mode of delivery and maternal outcomes. PMID- 28892979 TI - Efficacy of Foley's Catheter and the Effect of Histopathology, Age and Endometrial Thickness Relative to the Measured Outcomes in Menorrhagia. AB - INTRODUCTION: Menorrhagia adversely affects the quality of life. Hysterectomy is the definitive treatment for menorrhagia however, a number of conservative alternatives are available. AIM: Hysterectomy is the definitive treatment for menorrhagia however, a number of conservative alternatives are available. A thermal balloon is an effective but costly option. We used a Foley's catheter as an alternative to commercially available thermal balloons. If effective, it will provide a cheap alternative to the thermal balloon. MATERIALS AND METHODS: A Foley's catheter was placed in the uterine cavity for 10 minutes using 0.9% saline. The measured outcomes were amenorrhea, eumenorrhea, oligomenorrhea or failure of the therapy. Endometrial thickness, age and endometrial biopsy results were also measured to determine if these variables had any effects on the outcome. RESULTS: Out of the total 42 participants, nearly half had amenorrhea (42.9%, n=18). Furthermore, 28.6% had oligomenorrhea (n=12) and 26.2% experienced eumenorrhea (n=11). Only one participant failed to respond (2.4%, n=1). There were no differences in outcomes between the different forms of histopathology. This means that thermal balloon therapy is effective in causing amenorrhea. No significant relationships existed between participants' measured outcomes and a model containing predictor variables (age and endometrial thickness), R=0.313, R2=0.098, p=0.141. CONCLUSION: A Foley's catheter is effective with reasonable measured outcomes in cases of menorrhagia. PMID- 28892980 TI - Evaluating the Efficacy of Levonorgestrel Intrauterine System and Danazol for Relief of Postoperative Pain in Endometriosis. AB - INTRODUCTION: Endometriosis is an oestrogen-dependent disorder, manifests during reproductive years and is associated with pain and infertility. There is considerable debate about the effectiveness of various interventions for pain relief. AIM: To evaluate the efficacy of Levonorgestrel Intrauterine System (LNG IUS) and Danazol in postoperative pain relief for patients with endometriosis. MATERIALS AND METHODS: Hundred patients with diagnosis of endometriosis, who were treated laparoscopically, entered the study to receive either danazol (600 mg once daily) or LNG-IUS (inserted during immediate post operative period) postsurgery, for pain relief. Patients were analysed for pain relief according to VAS score and recurrence of disease using ultrasonography at third and sixth months of follow up. RESULTS: There were 50% patients in stage IV of endometriosis. Majority of them presented with complaint of infertility (49%) and pelvic pain (43%). It was observed that LNG-IUS was significantly more effective in relieving pain compared to danazol (65.2% vs 38.0%, p<0.05). Recurrence rate was significantly lower in LNG-IUS users compared to other group. CONCLUSION: LNG IUS was found to be more effective in relieving pain compared to danazol. PMID- 28892981 TI - Effect of Transdermal Nitroglycerine on Doppler Velocity Waveforms of the Uterine, Umbilical and Fetal Middle Cerebral Arteries in Patients with Chronic Placental Insufficiency: A Prospective RCT. AB - INTRODUCTION: Increase in Nitric Oxide (NO) may be important in vascular adaptation needed to accommodate increased uteroplacental blood flow as pregnancy advances. Hence, in certain conditions like Pregnancy Induced Hypertension (PIH) and Fetal Growth Restriction (FGR), NO donors may play an effective role in increasing uteroplacental perfusion. Transdermal route appears to be a safe and effective route. AIM: To evaluate the effect of nitroglycerine patch on Doppler velocity waveforms of the uterine, umbilical and fetal middle cerebral arteries in patients with chronic placental insufficiency. MATERIALS AND METHODS: A prospective randomized controlled clinical trial was conducted on eighty consecutive pregnant women with FGR with or without PIH and having evidence of altered waveform velocimetry in uterine, umbilical and fetal middle cerebral artery. They were divided into two groups- study and control group. Transdermal nitroglycerine patch (10 mg per 24 hours) was applied in study group for three consecutive days. Changes in various Doppler indices were noted after three days of patch application and compared between the two groups. Analysis was carried out using SPSS (Statistical Package for Social Studies) for Windows version 20.0 and online GraphPad software (Prism 5 for Windows) version 5.01. RESULTS: A significant fall in the systolic and diastolic ratio (S/D), Pulsatility Index (PI) and Resistivity Index (RI) of the uterine (3.07+/-0.52, 1.04+/-0.14 and 0.54+/-0.10 respectively, p<0.001) and umbilical artery (3.73+/-3.30, 1.18+/ 0.21and 0.64+/-0.07 respectively, p<0.001) was noted after three days of patch application. No such significant change was observed in the middle cerebral artery indices. CONCLUSION: The therapeutic approach of NO donor administration via transdermal route in pregnant patients with chronic placental insufficiency, apparently improved both maternal and fetoplacental haemodynamics, thus may help in improving perinatal outcome. PMID- 28892982 TI - Comparison of the Different Definition Criteria for the Diagnosis of Amniotic Fluid Embolism. AB - INTRODUCTION: There are several sets of criteria for the diagnosis of Amniotic Fluid Embolism (AFE), but little is known about their degree of agreement. AIM: To evaluate the concordance of the Japan criteria for AFE in comparison with two definitions: the US AFE registration entry criteria (the US criteria) and UK Obstetric Surveillance System criteria for defining cases of amniotic fluid embolism (the UK criteria). MATERIALS AND METHODS: A retrospective observational study was conducted in which the AFE cases registered in the Obstetrical Gynaecological Society of Kinki District in Japan for the period of April 2005 to December 2012 have been analysed by the expert steering obstetric committee, organized by the members of the Obstetric Research group. Cohen's kappa coefficient was used to calculate the agreement among three clinical diagnoses. For inter-group comparison, the Pearson Chi-square test was used (for categorical) and Mann-Whitney test was used (for continuous variables). RESULTS: Among the 26 cases registered for this period, a total of 18 women were selected as having AFE according to the Japan criteria. Five women died (case fatality rate 27.8%). Agreement between the Japan criteria and the US and UK criteria was k = 0.453 and k = 0.538, respectively, reflecting moderate agreement. However, only 38.9% were given a diagnosis of AFE according to all three criteria. The factor that most often caused disagreement in diagnosis between the Japan criteria and the US criteria was "onset within 30 minutes postpartum". The UK criteria excluded "women with postpartum haemorrhage as the first presenting feature in whom there was no evidence of cardiorespiratory compromise". The case fatality rates in US and UK are higher than in Japan (50.0% and 38.5% vs 27.8%), but this did not result in a significant difference (p=0.497). CONCLUSION: The groups of subjects identified as having AFE by the Japan criteria had a medium agreement with the US (k=0.453) or UK criteria (k=0.538). These three definition criteria identified different subgroups of patients. Such disagreement has serious implications for research and treatment. PMID- 28892983 TI - Transient Thyrotoxicosis in Molar Pregnancy. AB - Molar pregnancy is one of the components of a broader spectrum of diseases known as Gestational Trophoblastic Disease (GTD), presenting with amenorrhoea and irregular bleeding which may be rarely associated with passage of vesicles per vagina. However, it can rarely be associated with hyperthyroidism, which may be associated with clinical features of hyperthyroidism. The following is a report of a 20-year-old woman who presented with amenorrhea followed by irregular bleeding per vagina, thyromegaly and abnormal levels of thyroid hormones. Transvaginal ultrasound revealed features consistent with molar pregnancy. A suction evacuation was done following which serum levels of beta-hCG reduced and the levels of thyroid hormones also reduced. On follow up, six weeks later, beta hCG and thyroid hormones were within normal limits. The case and relevant literature are presented here. PMID- 28892984 TI - Thoracoscopic Diaphragmatic Plication for Eventration in Pregnant Woman: A Case Report. AB - Diaphragmatic eventration is an uncommon malady, underdiagnosed and often treated only in emergent situations. Eventration of the diaphragm is best treated by plication of diaphragm with or without meshplasty. Various studies have shown that thoracoscopic plication is as efficient as laparotomy or laparoscopic plication. We present here the report of thoracoscopic diaphragmatic plication for eventration performed in the third trimester of pregnancy in a 28-year-old woman who presented with acute respiratory distress. To our knowledge, we believe this to be the first published case in medical literature. PMID- 28892985 TI - Cellular Fibroma of Ovary Coexisting with Proliferative Endometrium Post Menopause: A Rare Presentation. AB - Ovarian fibromas are benign sex cord stromal tumours occurring in peri-menopausal and post-menopausal women. These tumours are composed of spindle fibroblastic cells producing collagen. They are almost always endocrine-inert and are rarely associated with hormone production. We report herein a case of a 60-year-old Indian woman presenting as post-menopausal bleeding. Imaging studies and endometrial biopsy revealed a right ovarian solid tumour coexisting with thickened proliferative endometrium, other causes of hyperoestrogenism being excluded in the woman. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. Histopathology showed cellular fibroma of right ovary and proliferative endometrium with foci of hyperplasia without atypia. PMID- 28892986 TI - Diagnostic Accuracy and Surgical Utility of MRI in Complicated Diabetic Foot. AB - INTRODUCTION: Diabetic foot complications pose a significant public health hazard and have negative effect on life quality. These complications are associated with increased risk of amputations and premature death. So focus is increasing on early treatment of complicated diabetic foot. AIM: To assess the diagnostic accuracy and surgical utility of MRI in complicated diabetic foot. MATERIALS AND METHODS: Thirty four complicated diabetic patients were evaluated prospectively. Initially x-ray was done and a provisional management plan was formulated. Later T1W, T2W and FSat sequences of the affected foot and ankle was carried out. The soft tissue, tendons and osseous apparatus were evaluated and subsequently compared with histopathological examination. Before and after MRI, change in management plan was marked. Previously operated cases with persistent ulcer of affected foot were excluded from the study. RESULTS: Twenty two males and 12 females with mean age of 52+/-8.8 years were analysed. The sensitivity of MRI for tenosynovitis and osteomyelitis was 88% and 100% respectively. The specificity for the same was 100% and 90%. Of all 34 cases, MRI reshapes surgical planning in 23.5% cases (8 patients). The difference between MRI and histopathological findings was evaluated statistically using Fisher-Z test and the proportion of difference between these two groups was not significant as values for tenosynovitis was Z=0.50 (p-value >0.05) and for osteomyelitis Z= 0.54 (p value>0.05). CONCLUSION: The result indicates that MRI is a sensitive and accurate imaging modality for evaluation of diabetic foot and for planning proper treatment and the MRI correlates significantly with the surgical finding. PMID- 28892987 TI - A Comparison of the Clinico-Radiological Outcomes with Proximal Femoral Nail (PFN) and Proximal Femoral Nail Antirotation (PFNA) in Fixation of Unstable Intertrochanteric Fractures. AB - INTRODUCTION: Management of unstable intertrochanteric fractures poses challenges in terms of obtaining stable fixation and good postoperative outcomes. There is a paucity of clinical data comparing the commonly used Proximal Femoral Nail (PFN) and Proximal Femoral Nail Antirotation (PFNA) implants, especially in relation to osteoporosis. AIM: To assess comparative performance of PFN and PFNA in the setting of osteoporosis. MATERIALS AND METHODS: Patients presenting with unstable intertrochanteric fractures (AO 31.A2 and 31.A3) were included and treated with either PFN or PFNA. Preoperative radiographs of normal side were used to grade osteoporosis by Singh's index. Grade 3 or less was considered significant. Postoperative radiographs were assessed for tip-apex distance, Cleveland index and quality of reduction. Patients were followed up for a minimum of nine months and any complications noted. Comparison of functional outcomes was done using the Harris Hip Score and Parker-Palmer mobility score at final follow up. Statistical analysis was done using the unpaired t-test/Mann-Whitney U test and Chi-square test/Fisher's-exact test. A p-value of < 0.05 was considered significant. RESULTS: The study included 48 patients with unstable intertrochanteric fractures, of which 23 were treated with PFN and 25 with PFNA. Average age of PFN group was 60.78 years and of PFNA group was 74.12 years. In PFN group 8 patients (38.09%) and in PFNA group 13 patients (54.1%) had Singh's osteoporotic index of <= 3. The average Harris Hip Score was 75.37 and 78.85 in PFN and PFNA groups (p=0.54) respectively. From PFN and PFNA groups, 35% and 32% patients respectively were able to return to pre-injury mobility status as assessed by the Parker-Palmer mobility score (p=0.83). Out of eight implant related complications; seven were in patients treated with PFN (p=0.02). Among patients with Singh's grade <= 3, 3 (37.5%) in PFN group suffered from implant failure whereas all 13 patients in PFNA group had successful outcome (p=0.04). CONCLUSION: Although functional outcomes achieved with both implants are similar (p=0.83), number of implant related complications were fewer with PFNA (p=0.02), even in osteoporotic group (p=0.04). We recommend use of the PFNA in unstable fractures, especially in the elderly osteoporotic population. PMID- 28892988 TI - Treatment of Proximal Humerus Fractures using PHILOS Plate. AB - INTRODUCTION: Treatment of proximal humerus fractures always holds a dilemma for the treating surgeon. AIM: To assess the functional outcome of proximal humerus fractures treated with Proximal Humerus Internal Locking System (PHILOS) plating. MATERIAL AND METHODS: Fifty three consecutive patients were treated with PHILOS plating between August 2013 and August 2014. The inclusion criteria were skeletally matured patients with closed fracture proximal humerus with displacement >1 cm and varus angulation of >450. Severely comminuted fractures, open fractures and valgus impacted fractures were excluded from the study. The outcome was assessed using Neer's scoring system. RESULTS: The average age was 54.3+/-5.8 years. As per the Neers classification system, there were 6 (11.32%) 1 part, 19 (35.85%) 2-part, 17 (32.085) and 11 (20.75%) 3 and 4-part fracture respectively. Average surgical duration was 94+/-10.2 minutes. Radiological union was seen at 12+/-4.6 weeks. There were 2 (3.77%) cases of varus collapse. Three (5.66%) cases had screw back out, which was later revised and had a favourable outcome. As per the Neer's scoring system, 7 (13.21%) cases had excellent results, 37 (69.81%) had satisfactory, 6 (11.32%) had unsatisfactory while 3 (05.66%) cases had poor outcomes. CONCLUSION: PHILOS plating has a good functional outcome. However, proper patient selection, thorough knowledge of the anatomy and biomechanical principles are the pre-requisites for a successful surgery. PMID- 28892989 TI - Blood Lead Levels in Children of Southwest Iran, Aged 2-6 Years and Associated Factors. AB - INTRODUCTION: Lead is one of the toxic metals that can cause several complications in children. AIM: This study was conducted to determine Blood Lead Levels (BLLs) in healthy children and its association with individual and environmental factors. MATERIALS AND METHODS: This descriptive-analytical study was conducted on 262 healthy children aged 2-6 years in Shahrekord, Southwest Iran in 2013. After taking serum samples from the children, the checklists of effective environmental factors on lead toxicity were completed after interviewing the parents. BLLs were determined by ICP-MS. Data were analysed by descriptive and analytical statistics (chi-square and ANOVA) in SPSS 16. RESULTS: BLLs ranged 0.4-52.8 (mean: 6.9+/-7.9) ng/ml. BLL was significantly associated with father's education level, house colour damage, canned food use and soil eating (p<0.05), but not with age, gender, economic status, proximity to factory and kohl use (p>0.05). CONCLUSION: BLL can cause serious health risks for children in Shahrekord and is associated with certain risk factors. It is necessary to screen for these risk factors. PMID- 28892990 TI - Prevalence of Acanthosis nigricans and Related Factors in Iranian Obese Children. AB - INTRODUCTION: Recognition of Acanthosis nigricans (AN) provides important opportunities for screening of obesity syndrome, dyslipidemia, hypertension and insulin resistance with diabetes mellitus 2. Considering the high prevalence of obesity among Iranian children, we designed this study to estimate the prevalence of AN and related laboratory factors in Iranian obese children. MATERIALS AND METHODS: Seventy-one obese children were enrolled in this study. Diagnosis of AN was done by clinical examination. Body mass index (BMI), fasting blood sugar, total cholesterol, triglycerides (TG), alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, high- and low-density lipoprotein cholesterol, insulin, thyroid-stimulating hormone, free thyroxin (fT4), calcium, phosphorus and 25-hydroxyvitamin D were measured with routine techniques. Collected data were compared between cases with AN and without AN. Independent t test was used for comparison of variables. RESULTS: Twenty-five of children were female (35.2%). Forty-eight children (67.6%) had AN. In 20 cases (28.2%), homeostasis model assessment-insulin resistance (HOMA-IR) was <2.5 and in 51 (71.8%), HOMA-IR was more than 2.5. Mean BMI, insulin, HOMA-IR, TG and AST levels were significantly higher in cases with AN. CONCLUSION: Obese children with AN are at risk of developing diabetes. Hence early identification of this feature and precise evaluation of children is recommended. PMID- 28892991 TI - Neisseria Meningitidis Causing Multiple Cerebral Abscesses in Early Neonatal Period: Case Report and Review of Literature. AB - Neisseria meningitidis is a rare cause of meningitis and septicemia in neonates. There are few published case reports of neonatal meningococcal meningitis complicated by subdural empyema, cerebral abscess and hydrocephalus. Few cases of neonatal meningococcal meningitis have been reported in the literature with none of them having the complication of multiple cerebral abscesses in early neonatal period (0.05). After the intervention, the rate of state and trait anxiety decreased significantly (p<0.05) in experimental group. CONCLUSION: In patients subjected to endoscopy, psychological preparation was effective in reducing their anxiety and thus this can be considered as an efficient method in decreasing anxiety. PMID- 28893021 TI - Prediction of the Dimensions of the Spiritual Well-Being of Students at Kermanshah University of Medical Sciences, Iran: The Roles of Demographic Variables. AB - INTRODUCTION: Spiritual well-being is one of the aspects of well-being which organize the physical, psychological, and social aspects. Given the outstanding and unique roles of students in society, providing spiritual well-being as well as identifying and eliminating the negative factors affecting their mental well being are of the essence. AIM: The present study aimed to predict the dimensions of the spiritual well-being of students at Kermanshah University of Medical Sciences and to investigate the roles of demographic variables in this respect. MATERIALS AND METHODS: In this descriptive and correlational study, the statistical population was comprised of 346 doctoral students in the for-profit Schools of Medicine, Dentistry and Pharmaceuticals in Kermanshah University of Medical Sciences in 2016. For data collection, an instrument comprising the demographic questions and the 20-item spiritual well-being scale by Paloutzian and Ellison (1982) was utilized. To analyze data, the descriptive (frequency distribution, mean, and standard deviation) and inferential statistics (independent t-test, one-way ANOVA, and chi-squared test) were employed in the SPSS Statistics Software Version 21.0. RESULTS: The results of the present study demonstrated that the spiritual well-being of students was average (71.86+/ 4.84), and of all demographic variables under study, only the variable of gender significantly correlated with the mean score of spiritual well-being. Also, the results revealed that the students' score of religious well-being measured higher than that of their existential well-being. However, a significant correlation was found between spiritual well-being and its dimensions. Also, the religious and existential well-being were found to be significantly related (p<0.05). CONCLUSION: The results of the present study showed the significance of addressing the issue of spirituality among the students of the for-profit Schools at Kermanshah University of Medical Sciences. Therefore, it is recommended that appropriate plans be laid by the culture and education policy makers to promote the spiritual well-being of university students. PMID- 28893022 TI - Correlation of Vitamin D3 Levels and SCORAD Index in Atopic Dermatits: A Case Control Study. AB - INTRODUCTION: Atopic Dermatitis (AD) is a common chronic inflammatory condition characterized clinically by pruritus and eczematous lesions. An inverse relationship has been suggested between serum 25-hydroxyvitamin D concentration and severity of atopic dermatitis. AIM: We carried out this controlled cross sectional study to evaluate the association between the serum vitamin D3 levels and SCORAD index. MATERIALS AND METHODS: For this study, 40 patients with clinical diagnosis of AD based on UK diagnostic criteria were enrolled and 40 patients with minor ailments like superficial bacterial, fungal or viral infections and not suffering from atopic dermatitis were taken as controls. Salient presentations were recorded in a pre-set proforma. Serum 25 hydroxyvitamin D levels were determined through Sandwich-ELISA technique. SCORAD (Scoring AD) index was used to evaluate the severity of the disease. RESULTS: Mean value of serum 25-hydroxyvitamin D levels in cases was 30.38 nmol/l whereas in controls, it was 53.46 nmol/l. The decrease in serum levels in cases was statistically highly significant (p-value <0.001). Mean+/-S.D of serum vitamin D levels in mild disease was 33.29+/-5.89 nmol/l, in moderate disease was 31.52+/ 6.04 nmol/l and in severe form of disease was 21.24+/-3.17nmol/l. The correlation between SCORAD and serum 25-hydroxyvitamin D levels was also statistically significant. CONCLUSION: The data suggests an inverse relationship between serum levels of vitamin D3 and the SCORAD Index. PMID- 28893023 TI - Itolizumab in the Management of Psoriasis with Metabolic Syndrome. AB - Psoriasis is a chronic, relapsing, inflammatory disease that has been associated with Metabolic Syndrome (MS), a cluster of cardiovascular risk factors mainly hypertension, obesity, diabetes mellitus and hyperlipidemia. A 49-year-old male patient presented with extensive plaque psoriasis from past 13 years. Past medications included methotrexate, PUVA therapy, topical immunosuppressants and corticosteroids. His baseline Psoriasis Area and Severity Index (PASI) score was 39.8. The patient was screened and diagnosed with MS as per Alberti's Criteria (his waist circumference was 100 cm, blood pressure was 160/100 mmHg and High Density Lipoprotein (HDL) was 30 mg/dl). Considering severity of the disease, in this case we used anti-CD6 humanized monoclonal antibody Itolizumab (1.6 mg/kg body weight) to treat psoriasis and concurrent MS. The patient achieved PASI 50 response in six months after treatment of 10 infusions of Itolizumab (First seven doses were given every fortnightly and the last three doses every month). Further, Itolizumab treatment was continued once every three months and PASI 75 response was achieved at the end of 15 months. His PASI score increased to 30.7 after 18 months. Contemplating link between psoriasis and MS due to possibility of overlapping inflammatory pathways, we instructed patient to reduce his weight and prescribed oral tablet metformin 500 mg twice a day. After losing 6 kg weight, his PASI score came down to 22.2 at the end of 21st month. This suggests that MS was a driving factor in worsening of his psoriasis. Psoriatic patients should be checked simultaneously for co-morbid disease conditions. The report indicates direct association of psoriasis and MS. PMID- 28893024 TI - Diagnostic Performance of Serum Human Epididymis Protein 4 in Endometrial Carcinoma: A Pilot Study. AB - INTRODUCTION: Endometrial Cancer (EC) is a common female malignant disorder. To date, there are no specific tumour markers for EC that may be routinely used in clinical practice for diagnosis. AIM: To evaluate the diagnostic performance of the serum Human Epididymis protein 4 (HE4) as biomarker for EC and to determine its association with clinicopathological variables. MATERIALS AND METHODS: The study population included 60 postmenopausal women with a diagnosis of EC and 60 healthy postmenopausal female subjects (control group). Concentrations of serum HE4 and CA-125 in EC patients and control group were determined using Enzyme Linked Immunosorbent Assays (ELISA). The value of serum HE4 and CA-125 for the diagnosis and prediction of stage, histology, myometrial invasion and lymph nodal metastasis was analysed. RESULTS: The mean serum HE4 and CA-125 levels were significantly higher in patients with EC than those with control group (p<0.05). Comparison for HE4 and CA-125 between different stages showed a statistically significant difference. Stage I EC patients with <50% myometrial invasion had a significantly lower mean serum HE4 value than patients with >50% myometrial invasion (p=0.007). Corresponding values of CA-125 showed a similar trend (p=0.023). There were significantly higher levels of HE4 and CA-125 in cases with lymph node involvement. The levels of serum HE4 and CA-125 were higher in the non endometroid histology, but the difference was not statistically significant. The Receiver Operating Characteristics (ROC) curve analysis for EC and control group showed that HE4 had greater Area Under Curve (AUC) when compared with CA-125. Using ROC curve, a serum HE4 concentration of 69.8 pmol/l (AUC 0.974) and/or serum CA-125 level of 34.50 U/mL (AUC 0.714) was used to predict malignancy. Sensitivity of combined biomarkers showed no additional improvement in comparison to HE4 or CA-125 alone. CONCLUSION: Our results show that HE4 is a sensitive diagnostic serum marker for detection of EC patients, exhibiting a better diagnostic performance compared to CA-125. Good performance of HE4 in diagnosis of early stages EC indicates its usefulness as a prognostic marker and also to monitor therapy and detect early recurrence. PMID- 28893025 TI - Primary Squamous Cell Carcinoma of Submandibular Salivary Gland: A Case Report. AB - Primary Squamous Cell Carcinoma (PSCC) of submandibular salivary gland is a rare occurrence. Careful clinical and histopathological examination is must to diagnose it. The treatment protocol of this rare disease is not clearly defined. Though surgery is primary treatment, role of adjuvant treatment is not clear. A 40-year-old male presented to us with asymptomatic upper neck swelling. Triple endoscopy, cross-sectional investigation and FNAC suggested primary squamous cell carcinoma of right submandibular salivary gland. He was treated with bilateral modified neck dissection and wide excision of sub mandibular gland with surrounding muscles. Post surgery, he had undergone interval chemotherapy followed by radiotherapy. The patient is still on regular follow up at an interval of three months without any evidence of disease recurrence. Though difficult to diagnose and treat this kind of rare variant of salivary neoplasms, awareness of the disease and aggressive treatment depending on histopathology report, can help patient to achieve health. PMID- 28893026 TI - Superior Vena Cava as Gateway to Heart: Metastatic Breast Carcinoma Causing Ball in a Loop Metastasis to Right Atrium. AB - Breast carcinoma is the most common invasive cancer in women worldwide. It metastasizes commonly to bone, lungs, regional lymph nodes and brain. Cardiac metastasis of lung and breast cancers is a known but rare complication of advanced disease with tumour metastasising to pericardium via the locoregional lymphatic system. Here we present a case of 59-year-old female presenting with right upper limb oedema, facial puffiness and features of Superior Vena Cava (SVC) syndrome 15 years after mastectomy and adjuvant chemotherapy, radiotherapy for carcinoma of the right breast. Further evaluation revealed extensive thrombus invading the right internal jugular vein, subclavian vein, SVC with intraluminal extension into right atrium causing ball in a loop obstruction at tricuspid valve. Whole body Positron emission tomography scan confirmed the diagnosis of extensive metastatic disease and patient was managed on palliative therapy. Haematogenous spread and intraluminal growth of metastatic deposits from breast carcinoma 15 years ago is rare and clinical presentation as SVC obstruction has not been reported in our review of literature. PMID- 28893027 TI - Unusual Skin Carcinomas Induced by BRAF Inhibitor for Metastatic Melanoma: A Case Report. AB - The most frequently reported skin tumours during treatment with targeted therapies for BRAF (B type Rapidly Accelerated Fibrosarcoma kinase) mutated metastatic melanoma are squamous cell carcinomas (SCCs). Basal cell carcinomas (BCCs) have been described in such setting, but no cases of multiple and recurring tumours have been reported so far. A patient with a history of chronic sun exposure and more than 10 BCCs removed since 1998 started treatment with vemurafenib for BRAF mutated metastatic melanoma. Therapy was complicated by sporadic episodes of atrial fibrillation and by the development of recurrent, multiple and diffuse BCCs. So, vemurafenib was discontinued and dabrafenib and trametinib were started. Since then, only four BCCs occurred in the patient. Histopathological re-examination showed that most BCCs occurred under vemurafenib presented with squamous features. Such characteristic was significantly less evident before therapy start and in lesions removed under treatment with dabrafenib and trametinib. BRAF inhibition (BRAFi) without MEK inhibition induces mitogen activated kinases overactivation, with consequent skin toxicity and acquired drug resistance. The BCCs removed from our patient showed squamous features, more evident during vemurafenib monotherapy. Both the switch from vemurafenib to dabrafenib and the addition of MEK inhibitor (MEKi) might have reduced the incidence of BCCs and their squamous differentiation. PMID- 28893028 TI - Synovial Sarcoma of Palmar Aspect of Hand and Survival: A Rare Case Report. AB - Synovial sarcomas of the hand are extremely rare entities than most soft tissue sarcomas. The location at finger is further rarer than carpus of the hand. Synovial sarcoma of the hand/finger initially confused with many diagnoses such as myositis, haematoma, synovitis, tendonitis, bursitis, and other inflammatory lesions and therefore needs careful handling of the case with proper evaluation. We report a case of synovial sarcoma of the palmar surface of the right hand at interface of thumb and index finger in a 22-year-old female. The case was initially misdiagnosed as an abscess/haematoma of the finger 10 years back and treated with wide local excision. Synovial sarcoma was diagnosed on microscopic examination of excised specimen. Patient developed recurrent lesion twice locally. During first recurrence, the patient was treated with wide excision followed by radiotherapy and chemotherapy. Second recurrence was with bony destruction at the same site and below elbow amputation was performed. PMID- 28893029 TI - POEMS Syndrome with Biclonal Gammopathy: A Rare Association. AB - Polyneuropathy, Organomegaly, Endocrinopathy, M protein and Skin changes (POEMS) syndrome is rare plasma cell dyscrasia with multisystem involvement. The name comes from the five characteristic features: Polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes. The presence of biclonal M band is a rare manifestation. Here, we are describing the cases of a 60-year-old lady, presented with bilateral pedal oedema and pericardial effusion and peripheral neuropathy. She also had hepatosplenomegaly, hyperpigmented rash and hypothyroidism and hyperparathyroidism. The serum protein electrophoresis and the immunofixation electrophoresis revealed two distinct monoclonal bands, immunoglobulin IgG kappa and IgA lambda. There was a mild increase in plasma cells and sclerotic bone lesion in pelvis. The POEMS syndrome is generally associated with lambda light chain restriction. The presence of biclonal gammopathy involving kappa and lambda is a rare manifestation. The pathogenic or prognostic role of different paraprotein is not known. Further studies are required to delineate such effect. PMID- 28893030 TI - Implication of Posture Analysing Software to Evaluate the Postural Changes after Corrective Exercise Strategy on Subjects with Upper Body Dysfunction-A Randomized Controlled Trial. AB - INTRODUCTION: The postural adaptation is very common now a days in school going children, office desk oriented job, computer users and frequent mobile users, and in all major industrial workers. Several studies have documented a high incidence of postural abnormalities in a given population; however, methods of postural measurement were poorly defined. The implication of postural pro software to analyse the postural imbalance of upper body dysfunction is very rare and literature studies says that the kinematic changes in particular segment will produce pain/discomfort and thereby lesser productivity of subjects. AIM: To evaluate the postural changes in subjects with upper body dysfunction after a corrective exercise strategy using postural analysis software and pectoralis minor muscle length testing. MATERIALS AND METHODS: After explaining the procedure and benefits, informed consent was taken from the participating subjects (age 25-55 years). Subjects with upper body dysfunction were randomly allocated into two groups (each group 30 subjects). The Group-A received the corrective exercise strategy and Group-B received the conventional exercise for eight weeks of study duration (15 reps each exercise, total duration of 40 min; four days/week. Pre and Post posture analysis were analysed using posture pro software along with flexibility of pectoralis minor was assessed using ruler scale method. RESULTS: After interpretation of data, both the group showed the postural alteration and pectoralis minor muscle length changes, p-value (p<0.01) of both group showed highly significant changes. But comparing the both groups, the subjects who received the corrective exercise strategy shown more percentage of improvement in posture alteration (56.25%), pectoralis minor muscle length changes (68.69%) than the conventional exercise received subjects in posture alteration (24.86%) and pectoralis minor muscle length changes (21.9%). CONCLUSION: Altered postural changes and pectoralis minor muscle flexibility before and after the corrective exercise strategy evaluated by postural analysis software method shown to be a significant tool in clinical practice, which is easier and reproducible method. PMID- 28893031 TI - Estimation of Salivary Parameters among Autoimmune Thyroiditis Patients. AB - INTRODUCTION: Saliva is a complex secretion that protects and lubricates the oral cavity. Various systemic diseases and their treatment alter the salivary gland function; one such disease is Autoimmune Thyroid Disease (AITD). AITD has been postulated to exert its hormonal influence on the salivary glands, leading to reduced salivary output. There's a paucity of literature, verifying the stated conjunction in human subjects. AIM: The aim was to investigate the salivary profile in AITD patients and its comparison with controls. MATERIALS AND METHODS: Descriptive cross-sectional comparative study was conducted using convenience sampling method for screening the presence of thyroid disorders. Two groups comprising of 30 patients in each group diagnosed with autoimmune hypothyroiditis (n=30) and hyperthyroiditis (n=30) respectively and thirty healthy volunteers who were age and sex matched were included as controls. Saliva was collected and evaluated for Unstimulated Salivary Flow Rate (USSFR), pH and buffer capacity. ANOVA and Tukey post-hoc test was performed to find the statistical significance and for pairwise comparison. RESULTS: Statistically significant difference was observed between autoimmune hypothyroiditis, autoimmune hyperthyroiditis and control group with respect to USSFR (p<0.007), pH (p<0.001) and buffer capacity (p<0.001). On pairwise comparisons statistically significant difference was observed between autoimmune hypothyroiditis and autoimmune hyperthyroiditis with respect to controls. CONCLUSION: We conclude that significant involvement of salivary glands may occur in cases of AITD. Our study showed significant reduction of sialometric values in AITD patients when compared to controls. A strong clinical suspicion of thyroid diseases should be considered when there is chronic hyposalivation; hence thyroid profile must also be done, if the known causes have been excluded. PMID- 28893032 TI - Antibacterial Activity of Freshly Prepared Ozonated Water and Chlorhexidine on Mutans Streptococcus When Used as an Oral Rinse - A Randomised Clinical Study. AB - INTRODUCTION: Dental caries is one of the most common causes of morbidity of the tooth. Attempts have been made to reduce the pathogen population size i.e., Mutans Streptococci (MS) to demote the incidence of caries and increase the resistance of the tooth to cariogenic attack. AIM: To evaluate the antibacterial efficacy of freshly prepared ozonated water, in proposing it as an alternative mouth rinse on MS in comparison to Chlorhexidine (CHX). MATERIALS AND METHODS: Subjects with high caries incidence and MS counts more than 105 Colony Forming Unit (CFU) were selected and divided by block randomization into two groups of 23 subjects each. The subjects were advised to use the respective mouth rinses under the operator surveillance, consecutively for 14 days. Stimulated salivary samples were collected from the subjects on the first day, 7th and 14th day to analyse the changes in MS counts during the course of use of oral rinses. The obtained data was tabulated and statistically analysed. RESULTS: Freshly prepared ozonated water showed a statistically significant reduction in MS counts after an interval of 7 days and 14 days when compared to CHX. CONCLUSION: Ozonated water when consecutively used as a mouth rinse resulted in a significant reduction of MS counts. Hence, it can be used as an alternative to chlorhexidine. PMID- 28893033 TI - Comparative Evaluation of Bioactive Glass Putty and Platelet Rich Fibrin in the Treatment of Human Periodontal Intrabony Defects: A Randomized Control Trial. AB - INTRODUCTION: Platelet-Rich Fibrin (PRF) and bioactive glass putty have been shown to be effective in promoting reduction in probing depth, gain in clinical attachment, and defect fill in intrabony periodontal defects. The individual role played by bioactive glass putty in combination with PRF is yet to be elucidated. AIM: To compare the clinical effectiveness of the combination of PRF and bioactive glass putty and bioactive glass putty alone as regenerative techniques for intrabony defects in humans. MATERIALS AND METHODS: Ten pairs of intrabony defects were surgically treated with PRF and bioactive glass putty (Test group) on one side or bioactive glass putty alone (Control group) on other side. The primary outcomes of the study included changes in probing depth; attachment level and bone fill of osseous defect. The clinical parameters were recorded at baseline, 3, 6, and 9 months. Radiographic assessment was done using standardized intraoral periapical radiographs. Differences between baseline and postoperative measurementsbetween the control and test groups were calculated using independent t-test. Comparisons were made within each group between baseline, 3 months, 6 months and 9 months using the ANOVA test followed by Bonferroni test. RESULTS: The mean probing depth reduction was greater in the test group (bioactive glass putty and PRF) i.e., (3.2+/-2.3 mm) than in the control group (bioactive glass putty alone) i.e., (3.15+/-1.06 mm). The mean CAL gain was also greater in the test group (4.1+/-1.73 mm) as compared to the control group (3.15+/-1.06 mm), (p value<0.95). Furthermore significantly greater mean bone fill was found in the test group (7.1+/-1.37 mm) as compared to the control group (5.7 +/- 1.64 mm), (p value<0.043). CONCLUSION: The results of this study showed both the groups bioactive glass putty alone (Control Group) and the combination of PRF and bioactive glass putty (Test Group) are effective in the treatment of intrabony defects. The bioactive glass putty appears to be a suitable vehicle to administer biologic substances like PRF and growth factors to induce the new bone regeneration. PMID- 28893034 TI - The Effect of Diabetes Mellitus Type I on Periodontal and Dental Status. AB - INTRODUCTION: Diabetes mellitus type I is a chronic metabolic disease with an autoimmune origin. The initial manifestations mainly appear during childhood and its prevalence is on the rise in many countries. Some of the complications of diabetes mellitus are problems related to oro-dental structures and periodontal diseases. AIM: The present study was undertaken to evaluate the relationship between diabetes mellitus type I and dental and periodontal status in Tehran, Iran. MATERIALS AND METHODS: This cross-sectional study was carried out on 50 patients with diabetes mellitus type I who were under treatment in the Diabetic Patients' Center in Tehran and 50 healthy individuals who did not have diabetes, all recruited from schools. The subjects were divided into two age groups of 6-12 and 13-18 years. In test group, HbA1c (glycosylated haemoglobin) level of the patients was collected from the medical records of Association of Diabetic Patients. To make sure that the control subjects did not suffer from diabetes mellitus, their blood glucose was measured with the Glucocard 01 blood glucose monitoring kit (GT-1920, Japan). The periodontal and dental status were assessed using dmft/DMFT (Decayed, Missing, Filled Permanent Teeth), GI (Gingival Index), PPD (Periodontal Pocket Depth), PI (Plaque Index) and CI (Calculus Index). The data obtained from each group were compared statistically using the Mann-Whitney test and Kruskal Wallis Test. RESULTS: There was increase in PPD, GI and DMFT values with aging, with no significant differences between the diabetic and non diabetic groups. PI and DMFT not only increased with aging but also were higher in both age groups in patients with diabetes compared to healthy subjects (p<0.05). GI was higher only in the 13-18 year age group in diabetic patients (p<0.01). There was no relation between the HbA1c (glycosylated haemoglobin) level, and periodontal indices (p<0.09). CONCLUSION: It appears that patients with diabetes mellitus type I are more susceptible to periodontal diseases and tooth loss and such problems might be aggravated with aging. PMID- 28893035 TI - Alexidine: a Safer and an Effective Root Canal Irrigant than Chlorhexidine. AB - INTRODUCTION: Chlorhexidine (CHX) is generally used as the final irrigating solution in root canal therapy. Recent studies have reported that, toxic precipitates containing parachloroaniline (PCA) are formed when CHX reacts with sodium hypochlorite (NaOCl). Whereas, Alexidine (ALX), a bisbiguanide disinfectant similar to CHX, has proven to form no precipitates with NaOCl. AIM: To compare antimicrobial activity of different concentrations of ALX with CHX individually and when combined with NaOCl against E. faecalis strains. MATERIALS AND METHODS: Different concentrations of ALX and CHX (0.5%, 1%, and 2%) were tested individually and when mixed with 2.5% NaOCl (1:1 ratio) using disc diffusion method against E. faecalis. After 24 hours incubation at 37 degrees C, zones of inhibition were measured for each solution. The results obtained were statistically analysed using one way ANOVA and Scheffe's post-hoc tests. The p value <0.001 was considered as highly significant. RESULTS: Regardless of the concentrations, ALX obtained the best results in comparison to CHX. There was no statistically significant difference between ALX + NaOCl and CHX + NaOCl mixtures. CONCLUSION: The present study showed that, the antimicrobial property of ALX against E. faecalis was found to be superior to CHX at same concentrations. PMID- 28893036 TI - Oral Candidal Carriage in Subjects with Pure Vegetarian and Mixed Dietary Habits. AB - INTRODUCTION: Candida albicans being a part of the normal oral microbial flora is one of the most commonly isolated species from the oral cavity. Recent studies have shown a steady rise in the number of non C. albicans species, which are relatively resistant to common antifungal agents and are being recognized as potential pathogens. It is vital to ascertain the predisposing factors leading to such a shift in the oral candidal flora. AIM: To estimate the prevalence of candidal species among vegetarians and non-vegetarians. MATERIALS AND METHODS: Clinical data including age, gender, and diet preference of 238 participants were noted. Participants with a history of systemic disorders, oral prosthesis, salivary gland disorders and habits such as smoking, alcoholism, and tobacco usage were excluded from the study. The participants were asked to gargle a 10 ml solution of phosphate buffered saline for one minute before depositing the same in a sterile container. The samples were cultured using Hicrome agar media. Data analysis was carried out using Statistical Package for Social Sciences (SPSS software) version 10.5 and differences between individual groups were tested by Chi-square test. RESULTS: Among 238 samples, 127 (53.3%) samples were positive for Candida. The candidal prevalence in vegetarians (68.5%) was higher than non vegetarians (40.7%). C. albicans was the most common species to be isolated in both vegetarians (35.1%) and non-vegetarians (39.2%). Candida glabrata and Candida tropicalis showed a higher prevalence in vegetarians (30.5% and 10.1%, respectively) in comparison to non-vegetarians (8.4% and 2.3%, respectively). Candida krusei was isolated only from vegetarians (4.6%). CONCLUSION: Results indicate that diet plays a major role in oral candidal prevalence and species specificity which in turn may predispose the vegetarians toward these pathogenic organisms. PMID- 28893037 TI - Periodontal Initial Radiological Findings of Genetically Predisposed Finnish Adolescents. AB - INTRODUCTION: Periodontitis is a multifactorial infectious disease of the supporting tissues of teeth in which bacterial, genetic and lifestyle factors such as smoking have an important role. AIM: The aim was to examine if Bleeding On Probing (BOP >= 20%) and >= 4 mm deep pockets correlated with any suspicion of initial radiological findings of periodontitis and bone loss. We also investigated whether any pro-inflammatory-related candidate Single Nucleotide Polymorphisms (SNPs) were associated with any suspicion of radiological findings. MATERIALS AND METHODS: Altogether 47 generally healthy adolescent patients of one birth cohort had given their approval for their saliva samples to be used for DNA analysis. One participant was excluded after discrepant gender check. An oral radiologist analysed right and left bitewing radiographs of 47 patients. Clinical parameters such as BOP >= 20%, >= 4 mm pockets, Visible Plaque Index of all teeth (VPI%), as well as smoking habits were recorded. DNA was extracted and 71 SNPs from candidate genes for initial periodontitis were genotyped. The association between >= 4 mm pockets and BOP >= 20% with radiological findings and selected SNPs was modelled using logistic regression. RESULTS: Variants in Toll-Like Receptors 4 (TLR4) gene (rs498670) (OR=5.8, {CI95% 1.6-20.7}, p=0.02, FDR q value=0.13) and TNFSF11 gene (rs2277438, OR=0.3 {CI95% 0.1-0.9}, p=0.002, FDR q value=0.56) were associated with any suspicious radiological findings; however the significance vanished after False Discovery Rate analysis (FDR). The association between BOP >= 20% and any radiographic signs of periodontitis was found to be statistically significant, OR=1.6, CI 95% 1.0-2.4, p=0.04. CONCLUSION: Only TLR4 (rs498670) and TNFSF11 (rs2277438) genes were found to have a positive correlation with radiological findings suggestive of initial periodontitis after adjustment for smoking and visible plaque. PMID- 28893038 TI - New Vision for Improving the Oral Health Education of Visually Impaired Children- A Non Randomized Control Trial. AB - INTRODUCTION: Visually impaired people have poorer oral hygiene when compared to others. Therefore, there is a necessity for individual training by making awareness in oral care and plaque control so as to improve their oral hygiene. AIM: The aim of the present study was to assess the effectiveness of oral health innovative educative method among visually impaired children of Bengaluru city of India. MATERIALS AND METHODS: A non-randomized control trial was conducted among 40 visually impaired individuals attending special school for blind. The study was conducted for a duration of six months. Baseline data regarding oral health knowledge, attitude and practices was obtained through a questionnaire in Braille and oral plaque assessment was done using Silness and Loe plaque index (1964). Music based brushing technique, cast models and an oral health education talk and booklet in Braille was delivered stressing on importance of oral health. The results of Knowledge, Attitude and Practices (KAP) before and after health education were analysed using Chi-square test with SPSS version 22.0. RESULTS: The overall KAP was lower in the preintervention period among the visually impaired children with mean score of 6.98 while after the modified oral health education session, it was increased to a mean score of 14.68 which was statistically significant at p<0.001. There was a significant change in the oral plaque scores with 80% of the children having fair scores in the preintervention period to 30% in the postintervention period. CONCLUSION: This oral health education module showed good results which can be implemented to effectively increase the awareness about dental health. PMID- 28893039 TI - Risk of Psychiatric Morbidity in Patients with Tobacco Habits: A Cross-Sectional Study. AB - INTRODUCTION: Tobacco cessation is a challenging arena for healthcare professionals. Many patients seem to be unable to quit tobacco despite of knowing its ill-effects and several efforts. It has been speculated that patients' psychosocial status may be associated with his/her dependence on tobacco and there could be some amount of psychiatric morbidity associated with chronic and compulsive use of tobacco. However, very few studies have been conducted to explore this aspect of tobacco dependence. AIM: To assess psychiatric morbidity in tobacco users as compared to non-users of tobacco. MATERIALS AND METHODS: This cross-sectional study included 200 patients reporting to a Dental College who consented to participate in the study. The study consisted of two groups; first consisting 100 tobacco users and another age and gender matched group of 100 non users of tobacco. Dependence to tobacco products amongst the study group was assessed using International classification of Diseases-10 (ICD-10) criteria. General Health Questionnaire - 28 (GHQ-28) was used to assess the psychological morbidity amongst both the groups. Statistical analysis was done using SPSS 21.0 version. Chi square test and Pearson's correlation coefficient were used to assess the difference in proportion and correlation between variables respectively. RESULTS: A 79% of tobacco users showed dependence on tobacco according to ICD-10 criteria. GHQ-28 scores analysis revealed that 61% of tobacco users with a score of 24 or above in contrast to only 17% of non-tobacco users. Tobacco users were observed to be 7.63 folds at a higher risk of developing psychiatric morbidity than non-users of tobacco (p-value< 0.001). CONCLUSION: There appears to be a significant risk of psychiatric morbidity prevalent amongst tobacco users. Hence, psychosocial counselling must be considered as a part of tobacco cessation strategy. PMID- 28893040 TI - Relationship between Parental Bonding and Tobacco Specific Practices as Predictors of Tobacco Usage in Adults. AB - INTRODUCTION: Parents influence their child's conduct and adolescence hostility either directly or indirectly. Similarly children can acquire a particular behaviour by observing and intentionally imitating their parents in order to simply copy them without understanding the positive or negative outcome. AIM: To assess and compare the association between parental tobacco usage and parental bonding with participants tobacco usage habits. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted among 130 adults. Information pertaining to demographics, parental bonding (using parental bonding index) and behavioural habits (e.g., smoking, alcohol) of both participants and their parents was collected with the use of a questionnaire-based interview. Tobacco usage was measured as categorical variable as ever chewer and never chewer. Chi square test, independent sample t-test, multinomial logistic regression and rotated factor loadings was used to analyse the data. RESULTS: Majority of the participants were males with a mean age of 30.4+/-8.5 years. Tobacco use was prevalent among less educated males. Parental smokeless tobacco use, paternal alcohol and maternal paan chewing was significantly associated with participants adverse habits. Multinomial logistic regression showed a significant association between parental and participant's tobacco usage. Perceived parental bonding were also significantly associated with participant's tobacco usage habit. CONCLUSION: Parental bonding measures and tobacco usage was significantly associated with the participant's tobacco use. Hence, interventional and educational efforts to weaken intergenerational influences should target parents. In addition to parents, the smoking behaviour of adults should also be targeted for prevention efforts. PMID- 28893041 TI - Evaluation of Oral Health Status among 5-15-Year-old School Children in Shimoga City, Karnataka, India: A Cross-sectional Study. AB - INTRODUCTION: Oral health is an integral part of general health. Dental problems can be avoided if identified at an early stage. There is no data on oral health status of school going children in Karnataka state's Shimoga city. AIM: To evaluate oral health status of school going children among 5-15-year-old in Shimoga city. MATERIALS AND METHODS: A cross-sectional study was conducted among 1458 government and private school children aged 5-6, 9-10 and 14-15 years. Dental caries (DMFT and deft Index), oral hygiene status (OHI-S Index) and dental fluorosis (Dean's Fluorosis Index) according to WHO diagnostic criteria (1997) were assessed. Data was evaluated using ANOVA and t-test by SPSS (IBM statistical software version 21.0.) at a level of 5% significance. RESULTS: The deft among 5 6-year-old children was 3.36+/-3.511, deft and DMFT among 9-10-year-old was 2.55+/-2.497 and 0.45+/-0.996 respectively and DMFT among 14-15-year-old was 1.34+/-1.832. The caries prevalence among 5-6-year-old was 68.8%, 9-10-year-old was 77.2% and 14-15-year-old was 48.9% and overall prevalence of dental caries was 65.3% which was statistically significant. Among 9-10-year-old oral hygiene was good in 85.4%, fair in 13.5% and poor in 1% of school children and among 14 15-year-old oral hygiene was good in 77.4%, fair in 22.2% and poor in 0.4%. Overall 81.7% of children had good oral hygiene. The prevalence of dental fluorosis was 14.5%. CONCLUSION: The children from government school were found to be less caries free than the private school children, but the difference was not significant. Oral hygiene status is found to be good among both the private and government school children. So the dental awareness is required among children of government school. PMID- 28893042 TI - Clinical Assessment of Various Obturating Techniques for Primary Teeth: A Comparative Study. AB - INTRODUCTION: Lifelong preservation of tooth in a healthy state is the ultimate goal of dentistry. Premature loss of primary teeth is common due to caries, dental trauma or other causes. As the primary teeth are the best space maintainers, teeth with infected pulps should be retained until exfoliation, whenever possible. AIM: The purpose of this in vivo study was to evaluate and compare the efficacy of different obturating methods used in primary teeth. MATERIALS AND METHODS: Forty one patients aged four to nine years with a total of 60 teeth were selected. Out of the 60 teeth, 32 were primary mandibular first molars and 28 were primary mandibular second molars, the sample was randomly divided into three groups. Disposable syringe, lentulo spiral and past inject were used for obturation. Postoperative evaluation was done for; quality of canal obturation, presence of voids using postoperative radiographs following obturation of teeth. The data were analysed to assess the success rate of the three methods used for obturation using Chi-square test. RESULTS: Among the three groups of the study, past inject exhibited the maximum number of optimally filled canals. Maximum number of underfilled canals was found with lentulospiral, and the maximum number of overfilled canals was seen with disposable syringe. Least number of voids was observed in canals filled with the past inject technique and disposable syringe. CONCLUSION: The results suggest that the most successful technique for obturation of primary teeth was past inject. PMID- 28893043 TI - Psychometric Utility in Determining Dental Organizational Attribute: A Cross Sectional Study in Ghaziabad, India. AB - INTRODUCTION: Psychometrics is the field of research involved with the objective measurement of finesse and intelligence, skills, temperament, personality traits, and educational success and technique of psychological measurement. Oral healthcare along with patient satisfaction and quality of care are main factors responsible for organizational attribute. Patient safety is relatively emerging domain which will result in improving patient's conditions without causing harm to them. AIM: To assess the psychometric behaviours as well as organization attribute with the help of modified version of Survey of Organizational Attributes for Primary Care (SOAPC) instrument among the dental care practitioners in Ghaziabad city, Uttar Pradesh, India. MATERIALS AND METHODS: A cross-sectional study was conducted among 268 dental practitioner of Ghaziabad city to determine psychometric behaviours and organizational attributes using SOADC instrument. Data was analysed using SPSS software version 18.0 and was subjected to descriptive and Mann-Whitney U test. RESULTS: Of the 268 dental practitioner, only 249 completed questionnaires. In communication, 70.3% agreed that they have constructive work relationship with staff with an overall mean score of 3.54+/-0.15, whereas in the subscale decision making, stress/chaos and history of change, the mean score of 2.77+/-0.98, 2.56+/-0.80 and 3.25+/-0.21 respectively were obtained. A statistical significant difference was noted between all the dimensions except stress/chaos and history of change (p<=0.05). CONCLUSION: SOADC can be used to assess psychometric behaviours and organizational attributes of dental care practice. Preference should be given to dentist's communication and reducing stress to enhance the service quality and improving safety of patient. PMID- 28893044 TI - Immuno-Histochemical and Quantitative Study of Melanocytes and Melanin Granules in Oral Epithelial Dysplasia. AB - INTRODUCTION: Oral Epithelial dysplasia (OED) is a potentially malignant disorder that is characterized by the presence of architectural and cytological changes. One of the prime factors responsible for the development of these lesions is the usage of tobacco. A variety of factors provide protective mechanism in order to prevent the effects of chemotoxic agents including tobacco products of which, melanin pigmentation is one of the vital elements. AIM: Role of melanocytes in progression of OED has remained unclear, so the present study was done to evaluate density of melanocyte and melanin granules in different grades of epithelial dysplasia and to correlate both findings with different grades of epithelial dysplasia. MATERIALS AND METHODS: The study included 60 OED cases, of which three histopathogical sections were prepared from each block. The sections were stained with Hematoxylin and Eosin, Masson Fontana and Human Melanoma Black (HMB-45), an immunohistochemical stain. Quantification of melanin granules was evaluated under 40X magnification using arbitrary scale with micrometer square as, 0= Absence of melanin granules, 1= Rare and scattered melanin granules, 2= Dense but not aggregated melanin granules, 3= Dense and aggregated melanin granules. Density of melanocytes was evaluated under 10X magnification. Five consecutive fields were evaluated for melanocytes and melanin granules starting from the field of highest density. RESULTS: There was an insignificant increase in number of melanocytes and melanin granules in mild and moderate dysplasia compared to normal but significant reduction was observed in severe dysplasia. CONCLUSION: The decrease in number of melanocytes and melanin granules was proportional to severity of epithelial dysplasia. This could be due to chronic irritation by chemical products leading to death of melanocytes. PMID- 28893045 TI - Estimation of Serum Butyryl Cholinesterase in Patients with Oral Squamous Cell Carcinoma: A Cross-Sectional Study. AB - INTRODUCTION: Oral cancer is a major global threat to public health. It is one of the most common causes of mortality and morbidity in the modern era. Oral Squamous Cell Carcinoma (OSCC) accounts for over 90% of the malignancies involving the oral cavity. The enzyme- Butyryl Cholinesterase (BChE) is proposed to have a role in cell proliferation, cell adhesion, cell differentiation, apoptosis and tumorigenesis. Few studies have been conducted for understanding the significance of serum BChE as a biomarker in oral cancer patients; however literature available is insufficient to arrive at a conclusion. There is a need of a simple, rapid, convenient, inexpensive and reliable biomarker of oral cancer. So, the present study is an attempt to estimate the level of BChE in oral cancer, prior to definitive therapy. AIM: To estimate and compare the serum BChE levels in patients with OSCC with age and gender matched healthy controls. MATERIALS AND METHODS: The study comprised of 80 subjects, of which 40 biopsy proven OSCC patients of either sex were selected as cases and 40 healthy, age and gender matched subjects as controls. Estimation of serum BChE levels was done by colorimetric method using RANDOX RX Imola Auto-Analyzer. The statistical analysis between the OSCC group and the control group were done using unpaired t-test. Comparison between serum BChE levels and TNM stages of OSCC were done using Kruskal-Wallis Test. Comparison between serum BChE levels and histopathological grades of OSCC were done using Mann-Whitney U Test. RESULTS: There was statistically highly significant decrease in the mean serum BChE levels in the OSCC group compared to the control group (p<0.001). It was revealed that the serum BChE levels were further decreased in moderately differentiated squamous cell carcinoma than well differentiated squamous cell carcinoma and the difference was statistically significant (p <0.05). CONCLUSION: The decrease in the serum BChE level demonstrates that it as a simple, rapid, convenient, inexpensive and reliable biomarker for oral cancer. Our findings support the concept of role of BChE in apoptosis, cell proliferation, differentiation and its related link in the pathophysiology of oral cancer. PMID- 28893047 TI - An Intervention Airing the Effect of Iranian Propolis on Epithelial Dysplasia of the Tongue: A Preliminary Study. AB - INTRODUCTION: Since oral cancer is one of the causes of mortality, the use of materials or methods that can reduce cancer or prevent its progression has particular importance. AIM: Aim of the study was to evaluate the antitumor effects of Iranian propolis on dysplastic changes of oral mucosa in rats. MATERIALS AND METHODS: This study was performed on 28 Wistar male rats (aged 7-11 weeks, 160+/-20 g). They were divided into four groups of seven rats. The Group 1 received: 0.5% 7,12-Dimethylbenz[a]anthracene (DMBA), the Group 2: 0.5% DMBA and 100 mg/kg propolis, the Group 3: 0.5% DMBA and 200 mg/kg propolis, and the Group 4: 0.5% DMBA and 400 mg/kg propolis. DMBA in all groups was administered topically (brush) and propolis was injected intraperitoneally. DMBA was brushed twice on the lingual dorsum three times a week for 20 weeks. Propolis injection just every other day and in the days after DMBA was administered for 20 weeks. Rats were sacrificed, and histological examinations were performed on tongue specimen. RESULTS: Propolis can reduce the degree of dysplasia in doses 100 mg/kg, 200 mg/kg, and 400 mg/kg compared to control (Group 1) (p=0.017, p=0.02, and p=0.002, respectively). CONCLUSION: The results of this study showed propolis can dose-dependently prevent DMBA-induced dysplasia of the oral mucosa in animal model. PMID- 28893046 TI - The Association between Cariogenic Factors and the Occurrence of Early Childhood Caries in Children from Salem District of India. AB - INTRODUCTION: Various aetiological factors for Early Childhood Caries (ECC) have been suggested in literature, but the role of each factor has been disputed in various studies. AIM: To evaluate the association between ECC and its related factors in children between three to six years of age, from rural, semi-urban and urban schools in the district of Salem (India). MATERIALS AND METHODS: The study consisted of children between three to six years of age, selected randomly from schools in semi-urban, urban and rural schools at Salem. Questionnaire (comprising of the factors associated with ECC) and parental consent forms were sent to each of the parents of the school children. Filled questionnaires and parental consent forms were obtained from a total of 2771 children, out of which 1771 were boys and 1000 were girls. Clinical examination for ECC was carried out according to the WHO criteria, by a single examiner and an assistant to eliminate inter-examiner variability. Statistical analysis was carried out using the student's independent t-test and ANOVA (one way analysis of variance). RESULTS: Out of a total of 2771 children examined, only 443 (315 boys and 128 girls) children were found to have ECC (16 %). Significant correlations were found between the occurrence of ECC and various factors like age of parents, number of siblings, on-demand breast feeding and bottle feeding habits and sweetened pacifier use. However, factors such as age and gender of the child, type of birth and duration of pregnancy, had no significant correlation with the occurrence of ECC. CONCLUSION: The need for educating parents on the ill effects of improper breast feeding and bottle feeding habits is important. PMID- 28893049 TI - Comparative Evaluation of the Efficacy of Bioactive Ceramic Composite Granules Alone and in Combination with Platelet Rich Fibrin in the Treatment of Mandibular Class II Furcation Defects: A Clinical and Radiographic Study. AB - INTRODUCTION: Predictable closure of furcation defects with bone grafts, Guided Tissue Regeneration (GTR) and a combination of the two has remained an elusive goal so far. Hence, evaluation of biomimetic agents as candidate technologies for periodontal regeneration merit due consideration. In this study, Choukroun's Platelet Rich Fibrin (PRF), a second generation platelet concentrate, is combined with bone graft to examine if the addition enhances the therapeutic potential of bone graft in the management of Class II furcation defects. AIM: To evaluate and compare the clinical effectiveness of Bioactive Ceramic Composite Granules (BCCG) alone and in combination with PRF in the treatment of mandibular Class II furcation defects. MATERIALS AND METHODS: Twenty mandibular Class II furcation defects in 16 systemically healthy patients were randomly allocated to test and control groups. Test sites were treated with PRF and bone graft, while control sites were treated with BCCG alone. Soft tissue parameters (probing pocket depth and clinical attachment loss), hard tissue parameters (vertical and horizontal depth of furcation defects) and radiographic parameter (radiographic alveolar bone density) were measured at baseline and six months post surgery. Statistical analysis was performed using Wilcoxon signed rank test for intragroup comparison of parameters and Mann-Whitney U test for intergroup comparison. RESULTS: Statistically significant improvement was observed in the test group compared to the control group with respect to all the measured parameters. However, complete furcation closure was not observed at any of the treated sites. CONCLUSION: Adjunctive use of PRF with bone graft may be a more effective treatment modality in the management of mandibular Class II furcation defects when compared to bone graft alone. PMID- 28893048 TI - Effect of Sugar-Free and Regular Toothpaste on Salivary Glucose and pH among Type 2 Diabetes- A Randomized Crossover Trial. AB - INTRODUCTION: Diabetes is one of the most prevalent diseases of mankind having general as well as oral health manifestations. Also, there is an increase of salivary glucose level in diabetic, inducing saccharolytic bacteria in saliva which can have adverse effects on oral tissue. AIM: To assess and compare the effect of sugar-free toothpaste on salivary glucose and pH among Type 2 diabetic and non-diabetic individuals. MATERIALS AND METHODS: A randomized controlled crossover study was carried out on 30 Type 2 diabetic (Group A) and 45 non diabetic (Group B) subjects. In first half of study, subjects in Group A and Group B were intervened with sugar-free and regular toothpaste respectively. Salivary glucose and pH was assessed before and after brushing at interval of one week for a period of four weeks. In second half, toothpastes were switched over between the groups, after sufficient washout period. Salivary glucose and pH were assessed again in the same manner for both the groups. The data was subjected to paired t-test and unpaired t-test for intragroup and intergroup comparison respectively. RESULTS: Salivary glucose level was significantly reduced and salivary pH was increased significantly (p<0.001) in both groups with sugar free toothpaste when compared to regular toothpaste. CONCLUSION: Sugar free toothpaste showed beneficial effect on salivary glucose level and salivary pH level on diabetes and non-diabetes population. PMID- 28893050 TI - "Quirky Bulb" On the Lower Jaw: An Organizing Haematoma. AB - Organizing Haematoma is a rare, non/neoplastic benign lesion with locally destructive behaviour that may mimic a malignancy. Usually symptoms do not occur, while the lesion remains localized. An Organized Haematoma is an encapsulated blood clot undergoing neovascularization and fibrosis. It has also been referred to as a hemophilic pseudotumour and/or a haematoma like tumour, which is rarely found in the head and neck region. Other reported cases have been related to trauma or an underlying haemangioma. However, most of the cases have no identifiable underlying pathology, trauma or systemic disease. We are reporting an unusual presentation of Organizing Haematoma over the edentulous mandible. PMID- 28893051 TI - Permanent Maxillary Central Incisor with Dilacerated Crown and Root and C-Shaped Root Canal. AB - Dilaceration is a rare disturbance in traumatised permanent teeth, which constitutes about 3% of the injuries to developing teeth. It usually occurs as a result of trauma to the deciduous predecessors and results in non axial displacement of the already formed hard tissue portion of the developing crown. Endodontic treatment of such teeth presents a challenge to clinicians, and careful management is required to successfully address the root canal anatomy and other possible variations. The C-shaped canal configuration is most frequently seen in mandibular second molars, but this variation may also occur in mandibular first molars, mandibular third molars, maxillary molars, mandibular first premolars, and even in maxillary lateral incisors, with rare reports of such variations occurring in the maxillary central incisors. Diagnosis, endodontic access cavity preparation, root canal preparation and filling might be complicated by the presence of dilacerations and C-shaped canals. This paper is an attempt to provide details of an unusual case of crown and root dilacerations and a C-shaped canal in the maxillary central incisor, successfully managed by using Self-Adjusting File (SAF) system. PMID- 28893052 TI - Palatogram: A Guide to Customised, Functional Palatal Contour. AB - The prime requisite of a sound and holistic prosthodontic rehabilitation from both the patient's and clinician's perspective is to be able to satiate the yardsticks of function, retention, aesthetics and comfort to the fullest. It is thereby astoundingly hard to digest that speech being an indispensably significant function of the complete denture prosthesis, is often seen upon as heedless and inconsiderate by the patient. Adaptability in speech pronunciation of complete denture prosthesis is a subjective phenomenon; cannot be predicted to entirety. To diagnose and verify speech difficulties in a complete denture patient who finds it relatively difficult to affirm to new palatal contours of prostheses, we require some simple clinical aids. Palatogram is a fairly simple, yet highly efficacious technique of assessment and verification of palatal contours, so as to improve and correct the existent speech deficiencies of affected sounds. In the present case report, readily available food colour in spray form was employed to produce and investigate inadequacies of various sounds. This case report highlights palatogram as an easy clinical technique that helps to correct, often delinquent speech difficulties, pertaining to the palatal contours of complete denture prosthesis. PMID- 28893053 TI - Denovo High Grade Salivary Duct Carcinoma: A Case Report and Review of Literature. AB - Salivary Duct Carcinoma (SDC) is a distinctive and clinically aggressive adenocarcinoma of salivary origin. It arises from the ductal epithelium, predominantly occurring in the major salivary glands, especially the parotid gland. Here, we report a case of an extensive salivary gland pathology involving the right side of face, possibly arising from the parotid gland in a 25-year-old male patient. On routine histopathology, the tumour mass revealed a papillary pattern of neoplastic ductal epithelial cells showing comedo-like-central necrosis. Immunohistochemical staining showed tumour cells in the infiltrative component to be diffusely immunopositive for cytokeratin-7 and Her-2, confirming the diagnosis of SDC. This paper presents a case report on salivary duct carcinoma and highlights a review on histological variants of salivary duct carcinoma. PMID- 28893054 TI - Effect of Methylphenidate on Orthodontic Tooth Movement and Histological Features of Bone Tissue in Rats: An Experimental Study. AB - INTRODUCTION: Methylphenidate is a psychostimulant drug, which is commonly used by children and teenagers. This age group receives most orthodontic treatment. Effect of this drug on tooth movement is unknown. AIM: The aim of this study was to evaluate the effect of methylphenidate on orthodontic tooth movement and histological features of bone tissue in rats. MATERIALS AND METHODS: Forty-two Wistar rats (male) were selected and divided to three groups, randomly (n=14). The control group (Group 1) received no drug, the experimental Group 2 received a constant dose of methylphenidate daily for 14 days while the experimental Group 3 received increasing doses of methylphenidate daily. To exert force, a NiTi coil spring was placed between the maxillary right first molar and the maxillary right central incisor. At the end of the study period, the amount of tooth movement was measured and then the rats were sacrificed for histological analysis of bone tissue. Differences between the experimental groups were analysed using Kruskal wallis and Mann-Whitney U tests. RESULTS: No significant differences were found in the amount of orthodontic tooth movement or osteoclasts and lacunae, between the experimental groups (p>0.05). Mann-Whitney U analysis showed significant differences in the depth of resorption lacuna between Group 2 and 3 (p=0.037). CONCLUSION: Methylphenidate has no significant effect on orthodontic tooth movement or histological features of bone tissue in rats. PMID- 28893055 TI - Induction with Varied Histological Patterns in Adenomatoid Odontogenic Tumour. PMID- 28893056 TI - Hyalinizing Clear Cell Carcinoma of Maxilla. PMID- 28893057 TI - Coincidental Finding of Twin Dentigerous Cyst in an Achondroplasia Patient. PMID- 28893058 TI - Serratia marcescens infection or hypoxic-ischaemic encephalopathy in neonates: Is magnetic resonance imaging a problem-solving tool? PMID- 28893059 TI - Dosimetric advantages and clinical outcomes of simultaneous integrated boost intensity-modulated radiotherapy for anal squamous cell carcinoma. AB - PURPOSE: The purpose of this study was to explore the dosimetric difference between simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) and three-dimensional conformal radiotherapy (3DCRT), and the clinical outcomes of anal squamous cell carcinoma (ASCC) chemoradiotherapy featuring SIB-IMRT. MATERIALS AND METHODS: This study included ten patients with ASCC who underwent chemoradiotherapy using SIB-IMRT with 5-fluorouracil and mitomycin C. SIB-IMRT delivered 54 Gy to each primary tumor plus metastatic lymph nodes and 45 Gy to regional lymph nodes, in 30 fractions. Four patients received additional boosts to the primary tumors and metastatic lymph nodes; the median total dose was 54 Gy (range, 54 to 60 Gy). We additionally created 3DCRT plans following the Radiation Therapy Oncology Group 9811 protocol to allow dosimetric comparisons with SIB IMRT. Locoregional control, overall survival, and toxicity were calculated for the clinical outcome evaluation. RESULTS: Compared to 3DCRT, SIB-IMRT significantly reduced doses to the external genitalia, bladder, and intestine, delivering the doses to target and elective nodal region. At a median follow-up time of 46 months, 3-year locoregional control and overall survival rates were 88.9% and 100%, respectively. Acute toxicities were treated conservatively. All patients completed radiotherapy with brief interruptions (range, 0 to 2 days). No patient experienced >=grade 3 late toxicity during the follow-up period. CONCLUSION: The dosimetric advantages of SIB-IMRT appeared to reduce the toxicity of chemoradiotherapy for ASCC achieving high locoregional control in the extended period. PMID- 28893060 TI - Clinical significance of the lymph node ratio in N1 breast cancer. AB - PURPOSE: The purpose of this study was to evaluate the prognostic value of the lymph node ratio (LNR), which was defined as the proportion of involved nodes of all dissected nodes, in pN1 breast cancer. MATERIALS AND METHODS: We retrospectively analyzed the clinical data of patients with pN1 breast cancer (N = 144) treated at Keimyung University Dongsan Medical Center, Daegu, Korea between 2001 and 2010. The median age was 46 years (range, 27 to 66 years). The LNR was 0.01-0.15 (low LNR) in 130 patients and >0.15 (high LNR) in 14 patients. Sixty-five patients (45.1%) had T1 tumors, 74 (51.4%) had T2 tumors, and 5 (3.5%) had T3 tumors. Eighty-eight patients (61.1%) underwent total mastectomy and 56 (38.9%) underwent partial mastectomy. Fifty-nine patients (41.0%) underwent radiotherapy and 12 (8.3%) underwent regional radiotherapy. The median follow-up period was 65 months. RESULTS: The 5- and 10-year disease-free survival (DFS) rates were 92.7% and 82.4%, respectively. Univariate analyses revealed that high LNR (p = 0.004), total mastectomy (p = 0.006), no local radiotherapy (p = 0.036), and stage T2 or T3 (p = 0.010) were associated with worse DFS. In multivariable analysis, only high LNR (p = 0.015) was associated with worse DFS. CONCLUSION: High LNR is an independent prognostic factor in pN1 breast cancer and could be an indication for adjuvant radiotherapy in these patients. PMID- 28893061 TI - Factors affecting the validity of the oscillometric Ankle Brachial Index to detect peripheral arterial disease. AB - BACKGROUND: The use of oscillometric Ankle Brachial Index (ABI) to diagnose peripheral arterial disease (PAD) has raised concern, especially due to a lack of agreement and sensitivity. This study aimed to evaluate those factors affecting the validity of oscillometric ABI in comparison to Doppler ABI to detect PAD. METHODS: Through univariate and multivariate linear regression, we studied those factors affecting the differences between oscillometric and Doppler ABI; through univariate and multivariate logistic regression we analyzed the false negative rate of oscillometric ABI to detect PAD. RESULTS: We analyzed 197 consecutive subjects (394 legs) from two settings: Primary Care and Vascular Service. The means of oscillometric ABI and Doppler ABI were 1.094 (95% CI: 0.843-1.345) and 1.073 (95% CI: 0.769-1.374) (P<0.001), respectively. In men, covariates explaining the differences between oscillometric and Doppler ABI were Doppler ankle blood pressure (beta=-0.610, P<0.001), ankle circumference (beta=0.176, P=0.004) and oscillometric brachial blood pressure (beta=0.136, P=0.037); in women, those were weight (beta=0.351, P<0.001) and Doppler ankle blood pressure (beta=-0.318, P<0.001). Sensitivity and specificity of oscillometric ABI to detect PAD were 80.6% and 97.4%, respectively, and covariates explaining the rate of false negatives in PAD population were setting (Exp(beta)=17.21, P=0.009) and tobacco (packs/year) (Exp(beta)=1.049, P=0.002). CONCLUSIONS: Although some factors influencing the lack of agreement between oscillometric and Doppler ABI were identified, the correction of oscillometric ABI seems impractical, since Doppler is needed, the bias is not always uniformly distributed and its clinical relevance is small. According to sensitivity, borderline oscillometric ABI in Primary Care settings and smokers suggest PAD. PMID- 28893062 TI - Dopamine-Triggered One-Step Polymerization and Codeposition of Acrylate Monomers for Functional Coatings. AB - Surface modification has been well recognized as a promising strategy to design and exploit diversified functional materials. However, conventional modification strategies usually suffer from complicated manufacture procedures and lack of universality. Herein, a facile, robust, and versatile approach is proposed to achieve the surface functionalization using dopamine and acrylate monomers via a one-step polymerization and codeposition process. The gel permeation chromatography, proton nuclear magnetic resonance, liquid chromatography-mass spectrometry, and UV-visible spectra results indicate that dopamine possesses the capability of triggering the polymerization of acrylate monomers into high molecular-weight products, and the inherent adhesive ability of polydopamine can assist the polymerized products to deposit on various substrates. Besides, protein-resistant, antibacterial, and cell adhesion-resistant surfaces can be easily fabricated via the finely designed integration of corresponding acrylate monomers into the codeposition systems. This approach of in situ polymerization and codeposition significantly simplifies the fabrication process and provides more manifold choices for surface modification, which will open a new door for broadening the applications of polydopamine-based coatings. PMID- 28893063 TI - Multistep Heterogeneous Nucleation in Binary Mixtures of Charged Colloidal Spheres. AB - Nucleation plays a decisive role in determining the crystal structure and size distribution; however, understanding of the fundamentals of nucleation is quite limited. In particular, it is unclear whether a nucleus forms spontaneously from solution via a single- or multiple-step process. Here we show how a binary mixture of charged colloidal spheres nucleates heterogeneously on a flat substrate by means of Bragg microscopy, laser diffraction, and laser microscopy. In contrast with the conventional one-step and two-step nucleation mechanisms, a novel pathway of multistep heterogeneous nucleation under certain experimental conditions is highlighted by four steps: initial homogeneous fluid -> prenucleation clusters -> preordered prenucleation clusters -> intermediate ordered phase -> final crystal. It is expected that the obtained results would be helpful in rationalizing the rich phase behavior exhibited by the binary mixture systems and in developing better and broadly applicable nucleation models as well as in designing defect-free single-crystal alloys. PMID- 28893064 TI - Aqueous RAFT Synthesis of Glycopolymers for Determination of Saccharide Structure and Concentration Effects on Amyloid beta Aggregation. AB - GM1 ganglioside is known to promote amyloid-beta (Abeta) peptide aggregation in Alzheimer's disease. The roles of the individual saccharides and their distribution in this process are not understood. Acrylamide-based glycomonomers with either beta-d-glucose or beta-d-galactose pendant groups were synthesized to mimic the stereochemistry of saccharides present in GM1 and characterized via 1H NMR and electrospray ionization mass spectrometry. Glycopolymers of different molecular weights were synthesized by aqueous reversible addition-fragmentation chain transfer (aRAFT) polymerization and characterized by NMR and GPC. The polymers were used as models to investigate the effects of molecular weight and saccharide unit type on Abeta aggregation via thioflavin-T fluorescence and PAGE. High molecular weight (~350 DP) glucose-containing glycopolymers had a profound effect on Abeta aggregation, promoting formation of soluble oligomers of Abeta and limiting fibril production, while the other glycopolymers and negative control had little effect on the Abeta propagation process. PMID- 28893065 TI - Cloning and Transplantation of the Mesoplasma florum Genome. AB - Cloning and transplantation of bacterial genomes is a powerful method for the creation of engineered microorganisms. However, much remains to be understood about the molecular mechanisms and limitations of this approach. We report the whole-genome cloning of Mesoplasma florum in Saccharomyces cerevisiae, and use this model to investigate the impact of a bacterial chromosome in yeast cells. Our results indicate that the cloned M. florum genome is subjected to weak transcriptional activity, and causes no significant impact on yeast growth. We also report that the M. florum genome can be transplanted into Mycoplasma capricolum without any negative impact from the putative restriction enzyme encoding gene mfl307. Using whole-genome sequencing, we observed that a small number of mutations appeared in all M. florum transplants. Mutations also arose, albeit at a lower frequency, when the M. capricolum genome was transplanted into M. capricolum recipient cells. These observations suggest that genome transplantation is mutagenic, and that this phenomenon is magnified by the use of genome donor and recipient cell belonging to different species. No difference in efficiency was detected after three successive rounds of genome transplantation, suggesting that the observed mutations were not selected during the procedure. Taken together, our results provide a more accurate picture of the events taking place during bacterial genome cloning and transplantation. PMID- 28893066 TI - Sizing Down a Supramolecular Gel into Micro- and Nanoparticles. AB - A low molecular weight gelator with a fluorescent 1,8-naphthalimide unit forms micro- and nanoparticles in aqueous media. Slow addition of a DMSO solution of the gelator into water affords either a self-assembled fibrillar network, sheaf like microparticles, or nanoparticles depending to the concentration used in the experiment. The micro- and nanoparticles were characterized by dynamic light scattering (DLS), electron microscopy, and fluorescence measurements. In an initial assay of particle loading, Rose Bengal and Rhodamine 123 were shown to be incorporated in the particles. Light-promoted singlet oxygen generation capabilities of Rose Bengal were modulated by its incorporation in the particles. Additionally, the particles were found to promote the transport of Rhodamine 123 into human lung carcinoma live cells. These results indicate that nanoparticles arising from low molecular weight gelators may represent a new type of nanocarriers, being a potential alternative to polymeric nanogels used in nanomedicine. PMID- 28893067 TI - Gate-Voltage-Controlled Threading DNA into Transistor Nanopores. AB - We present a simple method for DNA translocation driven by applying AC voltages, such as square and sawtooth waves, on an embedded thin film as a gate electrode inside of a dielectric nanopore, without applying a conventional bias voltage externally across the pore membrane. Square waveforms on a gate can drive a single DNA molecule into a nanopore, which often returns from the pore, causing an oscillation across the membrane. An optimized sawtooth-like negative voltage pulse on the gate can thread a fraction of a DNA molecule into a pore after a single pulse. This trapped DNA molecule continues to finish its translocation slowly through the pore. The DNA's slow speed was comparable to previous findings of the escaping DNA speed from a nanopore estimated by the Smoluchowski equation with excluded-volume interactions of a long-chain molecule and electrophoresis by extremely low electric fields. This simple scheme, controlling DNA molecules only by gate potential modulation at a nanopore, will provide an additional method to thread, translocate, or oscillate a single biomolecule at a gated nanopore. PMID- 28893068 TI - Wetting and Coalescence of Drops of Self-Healing Agents on Electrospun Nanofiber Mats. AB - Here we study experimentally the behavior of liquid healing agents released in vascular core-shell nanofiber mats used in self-healing engineered materials. It is shown that wettability-driven spreading of liquid drops is accompanied by the imbibition into the nanofiber matrix, and its laws deviate from those known for spreading on an intact surface. We also explore coalescence of the released drops on nanofiber mats, in particular, coalescence of drops of resin monomer and cure important for self-healing. The coalescence process is also affected by the imbibition into the pores of an underlying nanofiber mat. A theoretical model is developed to account for the imbibition effect on drop coalescence. PMID- 28893069 TI - Silicone Oil Swelling Slippery Surfaces Based on Mussel-Inspired Magnetic Nanoparticles with Multiple Self-Healing Mechanisms. AB - In this work, a novel substrate building block, magnetic Fe3O4 nanoparticles armed with dopamine molecules were developed via mussel-inspired metal coordination bonds. Combined with glycidyl methacrylate, polydimethylsiloxane propyl ether methacrylate, and diethylenetriamine, the original silicone oil swelling slippery liquid-infused porous surfaces (SLIPS) were first prepared by reversible coordinate bonds and strong covalent bonds cross-linking process. The matrix mechanical characteristics and surface physicochemical properties were systematically investigated. Results showed that the mechanical property of copolymer matrix and surface wettability of SLIPS can be remarkably recovered, which were due to the synergistic interactions of magnetic nanoparticles' intrinsic photothermal effect, reversible Fe-catechol coordination, and diffused lubricating liquid. After irradiating with sunlamp for 2 h and sequentially healing for 10 h under ambient conditions, the crack almost disappeared under optical microscopy with 78.25% healing efficiency (HEf) of toughness, and surface slippery was completely retrieved to water droplets. The efficient self-heal of copolymer matrix (66.5% HEf after eighth cutting-healing cycle) and recovering of slipperiness (SA < 5 degrees and 5 degrees < SA < 17 degrees after fourth and eighth cutting-centrifuging-healing cycles, respectively) would extend longevity of SLIPS when subjected to multiple damages. Moreover, the prepared SLIPS displayed superb self-cleaning and liquid-repellent properties to a wide range of particulate contaminants and fluids. PMID- 28893070 TI - Astrocyte spreading and migration on aggrecan-laminin dot gradients. AB - The surface concentration gradient of two extracellular matrix (ECM) macromolecules was developed to study the migratory and morphological responses of astrocytes to molecular cues typically found in the central nervous system injury environment. The gradient, prepared using microcontact printing, was composed of randomly positioned micrometer-sized dots of aggrecan (AGG) printed on a substrate uniformly coated with laminin (LN). AGG dots were printed in an increasing number along the 1000 MUm long and 50 MUm wide gradient area which had on each end either a full surface coverage of AGG or LN. Each dot gradient was surrounded by a 100 MUm-wide uniform field of AGG printed over laminin. Seeded astrocytes were found to predominantly attach to LN regions on the gradient. Cellular extensions of these cells were longer than the similar processes for cells seeded on uniform substrates of AGG or LN serving as controls. Astrocyte extensions were the largest and spanned a distance of 150 MUm when the cells were attached to the mixed AGG+LN patches on the gradient. As evidenced by their increased area and perimeter, the cells extended processes in a stellate fashion upon initial attachment and maintained extensions when seeded in AGG+LN regions but not on uniform laminin controls. The cells migrated short distances, ~20-35 MUm, over 24 h and in doing so preferentially shifted from AGG areas to higher LN surface coverage regions. The results indicated that presenting mixed ECM cues caused astrocytes to sample larger areas of the substrate and made the cells to preferentially relocate to a more permissive ECM region. PMID- 28893071 TI - A model of collaboration for the implementation of problem-based learning in nursing education in South Africa. AB - BACKGROUND: The idea of collaboration between key stakeholders in nursing education for the implementation of problem-based learning (PBL) may have far reaching implications for the institutions and students. MAIN OBJECTIVE: To develop a model of collaboration to facilitate the implementation of PBL in nursing education. METHODOLOGY: An exploratory sequential design was used. Qualitative data were collected from purposively recruited nurse educators from three universities in South Africa offering PBL and nurse managers from all the three hospitals in North West Province where PBL students are placed for clinical learning. A questionnaire was used to obtain data from respondents who were conveniently recruited. Model development, concept analysis, construction of relationships, description and evaluation were followed. RESULTS: This model has six elements: higher education and nursing education (context), institutions initiating PBL, clinical services, colleges affiliated to PBL universities, students and healthcare users (recipients), champions in PBL (agents), effective implementation of PBL (terminus), collaboration (process) and commitment, communication, trust and respect (dynamics). CONCLUSION: Collaboration in implementing PBL can be a functional reality in the delivery of quality educational experiences and has far-reaching implications for the institutions and students. The implementation of the model in South African nursing education institutions may be necessary for the light of the revision of the preregistration qualifications. RECOMMENDATIONS: Managerial commitment, training of collaborators on PBL and collaboration skills, memorandum of agreement, monitoring and evaluation are critical. More research is required to pilot the model and evaluate collaboration in implementing PBL at different levels of operations. PMID- 28893072 TI - Through the eyes of the student: Best practices in clinical facilitation. AB - BACKGROUND: Clinical facilitation is an essential part of the undergraduate nursing curriculum. A number of studies address the issue of clinical facilitation in South Africa, but there remains a lack of knowledge and understanding regarding what students perceive as best practice in clinical facilitation of their learning. OBJECTIVE: To determine what type of clinical facilitation undergraduate students believe should be offered by clinical facilitators (nurse educators, professional nurses and clinical preceptors) in the clinical area in order to best facilitate their learning. METHOD: A qualitative, exploratory and descriptive study was conducted. Purposive sampling was performed to select nursing students from the second, third and fourth year of studies from a selected nursing education institution in Johannesburg. The sampling resulted in one focus group for each level of nursing, namely second, third and fourth year nursing students. Interviews were digitally recorded and transcribed verbatim, thematic data analysis was used and trustworthiness was ensured by applying credibility, dependability, confirmability and transferability. MAIN FINDINGS: The data revealed that participants differentiated between best practices in clinical facilitation in the clinical skills laboratory and clinical learning environment. In the clinical skills laboratory, pre-contact preparation, demonstration technique and optimising group learning were identified as best practices. In the clinical learning environment, a need for standardisation of procedures in simulation and practice, the allocation and support for students also emerged. CONCLUSION: There is a need for all nurses involved in undergraduate nursing education to reflect on how they approach clinical facilitation, in both clinical skills laboratory and clinical learning environment. There is also a need to improve consistency in clinical practices between the nursing education institution and the clinical learning environment so as to support students' adaptation to clinical practice. PMID- 28893073 TI - Challenges faced by caregivers of children on antiretroviral therapy at Mutale Municipality selected healthcare facilities, Vhembe District, Limpopo Province. AB - BACKGROUND: Children depend solely on caregivers who can be either parents or guardians for drug administration to enhance adherence to antiretroviral treatment (ART), which might pose any number of challenges. PURPOSE: The purpose of this study was to explore and describe the challenges faced by caregivers of children on ART at Mutale Municipality, Vhembe District, Limpopo Province. RESEARCH DESIGN AND METHOD: The research design was qualitative, explorative, descriptive and contextual in nature. The population consisted of 16 caregivers who were 18 years of age and above, and mentally capable, irrespective of educational qualifications, caring for children aged between 0 and 15 years who were on ART between April 2013 and October 2014. Non-probability, purposive sampling was used to select the 16 caregivers. Required permission, approval and ethical clearance were obtained from the University of Venda Higher Degree Committee, Limpopo Provincial Health Department and relevant institutions. An in depth, individual, unstructured interview method was used to collect data. One central question was asked: 'What are the challenges you experience when caring for a child on antiretroviral treatment?' Subsequent questions were based on the participants' responses to the central question. Qualitative data were analysed by means of Tesch's open-coding method. RESULTS: The findings of this study revealed that participants, that is, caregivers of children on ART, experienced financial burdens because of transport costs needed to comply with follow-up dates and insufficient of money for food, clothing the child in need of care, pocket money for lunch boxes during school hours and time lost while waiting for consultations. Participants reported some level of stigmatisation against children on ART by family members, especially the husbands or in-laws of the secondary caregivers. Many primary and secondary caregivers seemed to have given up seeking support from government and community structures. CONCLUSION: The conclusions drawn from this research are that caregivers hardly receive any support from family members or the community. Fear of disclosing the HIV-positive status of children resulted in the delay of financial support from the government, thus leading to serious financial burden on the caregivers. PMID- 28893074 TI - The perceptions of midwives regarding audit and feedback on the use of the partogram at Vhembe District of Limpopo Province, South Africa. AB - BACKGROUND: Audit and feedback is regarded as the cornerstone of clinical teaching to guarantee good practice and to correct poor performance. Feedback given to health professionals assists in narrowing the gap between the actual and the desired information. The findings of the research study on perceptions of midwives on audit and feedback highlighted aspects that needed improvement to address challenges on the use and documentation of the partogram. OBJECTIVES: The objectives of this article were to explore and describe the perceptions of midwives on auditing of the partogram by health professionals and to explore and describe the perceptions of midwives on the feedback that was given after audit was done. METHOD: A qualitative, exploratory and descriptive study was conducted to answer the two research objectives. Semi-structured face-to-face interviews were conducted with 17 midwives who were working in the labour wards of three hospitals. Eight steps of qualitative data analysis as indicated by Tesch were used to analyse the data. RESULTS: The findings revealed that auditing and feedback is sometimes done by midwives themselves, midwives' managers and district managers. Audit is done monthly or on a daily basis and sometimes inconsistently because of shortage of staff. Challenges indicated were lack of knowledge on the use of the partogram and lack of encouragement and praise when documentation was done correctly and that emphasis was mostly placed on negative aspects. CONCLUSION: The findings revealed that auditing and feedback and in service education is done at the three hospitals, although challenges such as inconsistency in auditing because of shortage of staff, lack of knowledge on partogram use and on principles of giving feedback were highlighted. PMID- 28893075 TI - Classroom acoustics as a consideration for inclusive education in South Africa. AB - BACKGROUND: It can hardly be disputed that a school environment should be conducive or, at the very least, not prohibitive to effective learning. The provision of fair, equal and barrier-free access to education is referred to as inclusive education. South Africa supports a policy of inclusive schooling, striving to accommodate all children, including those with disabilities, in mainstream schools. This article sets out to prove that noise control in classrooms is a relevant, yet neglected, aspect of inclusive classroom design in South Africa and requires specific attention. OBJECTIVES: The objectives of this study are to: (1) establish the impact that noise has on learners with sensory, language or learning impairments; (2) establish the preferred listening conditions for these learners by examining prior research and guidelines available in other countries; and (3) outline the current South African regulations pertaining to classroom acoustics and assess them against the preferred listening environment. METHOD: This research was conducted as a systematic review with reference to the South African context. Local and international research and guidelines were used as references, providing an overview and evaluation of data concerning noise and learning. RESULTS: Noise is disadvantageous for learners, particularly those with sensory, language or learning impairments. Research and international guidelines show that the ideal ambient level is 30 dBA - 35 dBA, allowing the achievement of an ideal signal-to noise ratio (SNR) of +15 dB, and the ideal reverberation time is 0.4 s - 0.6 s. Various South African regulations discussed are inconsistent regarding ambient noise level (ranging from 35 dBA - 50 dBA) and say little about reverberation time for classrooms. CONCLUSION: South African regulations regarding classroom acoustics require revision to ensure inclusion of all learners with disabilities. The current status does not enforce barrier-free environments in mainstream schools for children with sensory, language or learning impairments. PMID- 28893076 TI - Seroprevalence and risk factors for Coxiella burnetii, the causative agent of Q fever in the dromedary camel (Camelus dromedarius) population in Algeria. AB - Query (Q) fever is a globally distributed zoonotic disease caused by Coxiella burnetii, a bacterial agent for which ruminants are the most prevalent natural reservoir. Data regarding Q fever infection in camels in Algeria are limited. Therefore, a survey to detect seroprevalence of C. burnetii antibodies was conducted among healthy camel populations in a vast area in southeastern Algeria to determine distribution of the Q fever causative organism and to identify risk factors associated with infection. Between January and March 2016, blood samples were collected from 184 camels and serum samples were subsequently analysed using a commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit. At the time of blood collection, a questionnaire investigating 13 potential predisposing factors associated with C. burnetii seropositivity was completed for every dromedary camel and herd. Results were analysed by a chi-square (chi2) test and multivariate logistic regression. The seroprevalence of C. burnetii at the animal level was 71.2% (95% CI: 65.2-78.3) and 85.3% (95% CI: 72.8-97.8) at the herd level. At the animal level, differences in seroprevalence were observed because of herd size, animal age, animal sex, presence of ticks and contact with other herds. A multivariable logistic regression model identified three main risk factors associated with individual seropositivity: (1) age class > 11 years (OR = 8.81, 95% CI: 2.55-30.41), (2) herd size > 50 head (OR = 4.46, 95% CI: 1.01 19.59) and (3) infestation with ticks (OR 2.2; 95% CI: 1.1-4.5). This study of seroprevalence of C. burnetii infection in camels in Algeria revealed a high seroprevalence of Q fever in camel populations in southeastern Algeria and provided strong evidence that Q fever represents an economic, public health and veterinary concern. Appropriate measures should be taken to prevent the spread of C. burnetii and to reduce the risk of Q fever in farm animals and humans in this agro-ecologically and strategically important region of North Africa. PMID- 28893077 TI - Economic burden of malaria on rural households in Gwanda district, Zimbabwe. AB - BACKGROUND: Malaria is a serious public health problem in sub-Saharan Africa and is a leading cause of morbidity and mortality. AIM: To estimate the economic burden of malaria in rural households. SETTING: The study was conducted in Gwanda district of Matabeleland South in Zimbabwe. A total of five malarious wards and all their households were selected for the study frame, out of which 80 households were chosen using clinic records. METHODS: A retrospective analysis of secondary data and a cross-sectional household survey were conducted to estimate the household economic burden of malaria. Eighty households from five rural wards were identified from the health facility malaria registers and followed up. A household was eligible for inclusion if there had been at least one reported malaria case during the period of 2013-2015. Interviewer administered questionnaires were used to collect household data on economic costs of malaria. RESULTS: Our findings showed that households spent an average of $3.22 and $56.60 for managing an uncomplicated and a complicated malaria episode respectively. A household lost an average of eight productive working days per each malaria episode resulting in an average loss of 24% of the monthly household income. An estimated 35%, mostly poorer households suffered catastrophic health expenditures. CONCLUSION: Malaria imposes significant economic burdens particularly on the poorer and vulnerable households. Although there are no user fees at rural clinics, households incur other costs to manage a malaria patient. These costs are far worse for complicated cases. PMID- 28893078 TI - Assessing home-based rehabilitation within the development of an integrated model of care for people living with HIV in a resource-poor community. AB - BACKGROUND: People living with HIV (PLHIV) are living longer lives but are at a greater risk of developing disability. South Africa has the largest antiretroviral therapy (ART) programme in the world, shifting HIV from a deadly to a chronic disease. The integration of rehabilitation into chronic care is therefore now crucial to ensure the highest quality of life of PLHIV. AIM: To describe how a home-based rehabilitation (HBR) programme adhered to the fundamental principles of a theoretical model of integrated care developed for the study setting in KwaZulu-Natal, South Africa. METHOD: The process and results from the HBR programme were assessed in relation to the model of care to ascertain which principles of the model were addressed with the HBR programme and which elements require further investigation. RESULTS: The HBR programme was able to apply a number of principles such as evidence-based practice, task shifting to lay personnel, enabling patient-centred care and maximising function and independence of PLHIV. Other elements such as the adoption of a multidisciplinary approach, training on the use of disability screening tools and the use of evidence to influence policy development were more difficult to implement. CONCLUSION: It is possible to implement elements of the integrated model of care. Further research is needed to understand how principles that require further training and collaboration with other stakeholders can be implemented. The results of this study provide additional evidence towards understanding the feasibility of the theoretical model and what is required to adjust and test the full model. PMID- 28893079 TI - Diagnostic comparison of Centers for Disease Control and Prevention and International Obesity Task Force criteria for obesity classification in South African children. AB - BACKGROUND: This study was designed to estimate overweight and obesity in school children by using contrasting definitions recommended by the Centers for Disease Control and Prevention (CDC) and the International Obesity Task Force (IOTF). METHOD: The sample size consisted of 1361 learners (n = 678 boys; n = 683 girls) aged 9-13 years who were randomly selected from Mpumalanga and Limpopo provinces of South Africa. A cross-sectional and descriptive design was used to measure the children's anthropometric characteristics. Based on height and weight measurements, the children's body mass index (BMI) was calculated and used to classify them as underweight, overweight and obese. Percentage body fat was calculated from the sum of two skinfolds (i.e. triceps and subscapular). Age specific BMI, percentage body fat and sum of skinfolds were examined for the boys and girls. RESULTS: A higher prevalence of overweight and obesity was found in boys and girls when the CDC BMI categories were used. In contrast, the IOTF BMI classifications indicated a strong prevalence of underweight among the children. CONCLUSION: In contrast to the IOTF index that yielded a greater occurrence of underweight among South African children, the CDC criteria indicated a higher prevalence of obesity and overweight among the same children. Future large-scale surveillance studies are needed to determine the appropriateness of different definitions in order to establish a more reliable indicator for estimating overweight and obesity in South African children. PMID- 28893080 TI - Core competencies of radiographers working in rural hospitals of KwaZulu-Natal, South Africa. AB - INTRODUCTION: Rural radiographers require, over and above traditional radiographic expertise, additional competencies which to a certain degree are unique however not limited to rural practice. Previous studies, however, have focused more attention primarily on other rural health professionals such as doctors and nurses leaving a research need in this field. This article focuses on the additional competencies that may be required for rural radiographers. AIM: To investigate and identify additional core competencies required by radiographers working in rural hospitals of KwaZulu-Natal in order to propose a continuous professional development strategy aimed at rural radiographers. METHODS: An exploratory sequential design was utilised with qualitative (Phase I) and quantitative (Phase II) strands involving seven participants and 109 respondents, respectively. Only radiographers working in rural KwaZulu-Natal hospitals were included in the study. The four major themes and categories identified in Phase I were used to develop data collection instrument for Phase II of the study. RESULTS: Collectively, the results revealed that there were a number of additional core competencies such as, but not limited to, teamwork, ability to do basic obstetric ultrasound scans, leadership, management and reporting on plain radiographs, all of which are required by rural radiographers. In 2014 when these competencies were checked against a single curriculum, it was found that majority of them were either partially covered or not at all covered. CONCLUSION: The study provides additional information on context specific core competencies and, therefore, may act as a catalyst to influence the future of radiographers working in rural areas of South Africa. PMID- 28893082 TI - Relation Between TRCA Complication Rates and Peak ACT Levels Stratified According to the BMI Tertiles. AB - We evaluated the efficacy and safety of the fixed dose of 5000 IU unfractionated heparin (UFH) represented as peak activated clotting time (ACT) according to the body mass index (BMI) tertiles in patients undergoing diagnostic transradial coronary angiography (TRCA). A total of 422 patients were included in the present study, 84 in the normal weight group, 218 in the overweight group, and the 120 in the grades 1 and 2 obesity groups. Radial artery occlusion (RAO) was observed in 29 (6.8%) patients and the hematoma was observed in 43 (10.1%) patients. The rate of RAO and hematoma did not differ across the BMI tertiles ( P = .749 and P = .066). Also, peak ACT and procedure duration did not differ between the study groups ( P = .703 and P = .999). The only independent predictor of hematoma was sheath/radial artery diameter ( P = .011) and the independent predictors for RAO were peak ACT, sheath/radial artery diameter, and procedure duration ( P = .001, P = .028, and P < .001, respectively). In conclusion, a fixed dose of 5000 IU UFH is safe and effective regardless of the BMI in diagnostic TRCA procedure. PMID- 28893081 TI - Paired box 7 (Pax7) gene: molecular characterisation, polymorphism and its association with growth performance in goose (Anser cygnoides). AB - 1. Paired box (Pax7) gene is a member of the paired box family and plays a critical role in animal growth and muscle development. However, the molecular characterisation of the goose Pax7 gene is unknown. 2. The open-reading frame of goose Pax7 is composed of 1509 bp, which encodes a protein of 503 amino acids and shares high homology with Pax7 of other birds. 3. Ten single-nucleotide polymorphisms were identified in the genomic DNA sequence, 8 located in the intron region and two located in the exon region. 4. Association analysis showed the C122T locus was significantly associated with the body weight of Zhedong White geese in week 4, 6, 8, 10 and 12. 5. It was concluded that the goose Pax7 gene may be an important candidate gene for goose growth traits and marker assisted selection. PMID- 28893083 TI - Tissue engineering of urethra: Systematic review of recent literature. AB - The purpose of this article was to perform a systematic review of the recent literature on urethral tissue engineering. A total of 31 articles describing the use of tissue engineering for urethra reconstruction were included. The obtained results were discussed in three groups: cells, scaffolds, and clinical results of urethral reconstructions using these components. Stem cells of different origin were used in many experimental studies, but only autologous urothelial cells, fibroblasts, and keratinocytes were applied in clinical trials. Natural and synthetic scaffolds were studied in the context of urethral tissue engineering. The main advantage of synthetic ones is the fact that they can be obtained in unlimited amount and modified by different techniques, but scaffolds of natural origin normally contain chemical groups and bioactive proteins which increase the cell attachment and may promote the cell proliferation and differentiation. The most promising are smart scaffolds delivering different bioactive molecules or those that can be tubularized. In two clinical trials, only onlay-fashioned transplants were used for urethral reconstruction. However, the very promising results were obtained from animal studies where tubularized scaffolds, both non seeded and cell-seeded, were applied. Impact statement The main goal of this article was to perform a systematic review of the recent literature on urethral tissue engineering. It summarizes the most recent information about cells, seeded or non-seeded scaffolds and clinical application with respect to regeneration of urethra. PMID- 28893084 TI - Fatty acid is a potential agent for bone tissue induction: In vitro and in vivo approach. AB - Our hypothesis was to investigate the fatty acid potential as a bone induction factor. In vitro and in vivo studies were performed to evaluate this approach. Oleic acid was used in a 0.5 wt.% concentration. Polycaprolactone was used as the polymeric matrix by combining solvent-casting and particulate-leaching techniques, with a final porosity of 70 wt.%, investigated by SEM images. Contact angle measurements were produced to investigate the influence of oleic acid on polycaprolactone chains. Cell culture was performed using adipocyte-derived stem cells to evaluate biocompatibility and bioactivity properties. In addition, in vivo studies were performed to evaluate the induction potential of oleic acid addition. Adipocyte-derived stem cells were used to provide differentiation after 21 days of culture. Likewise, information were obtained with in vivo data and cellular invagination was observed on both scaffolds (polycaprolactone and polycaprolactone /oleic acid); interestingly, the scaffold with oleic acid addition demonstrated that cellular migrations are not related to the surrounding tissue, indicating bioactive potential. Our hypothesis is that fatty acid may be used as a potential induction factor for bone tissue engineering. The study's findings indicate oleic acid as a possible agent for bone induction, according to data on cell differentiation, proliferation, and migration. Impact statement The biomaterial combined in this study on bone regeneration is innovative and shows promising results in the treatment of bone lesions. Polycaprolactone (PCL) and oleic acid have been studied separately. In this research, we combined biomaterials to assess the stimulus and the speed of bone healing. PMID- 28893085 TI - Worksite Health Promotion for Low-Wage Workers: A Scoping Literature Review. AB - OBJECTIVE: To determine: (1) What research has been done on health promotion interventions for low-wage workers and (2) what factors are associated with effective low-wage workers' health promotion programs. DATA SOURCE: This review includes articles from PubMed and PsychINFO published in or before July 2016. Study Inclusion/Exclusion Criteria: The search yielded 130 unique articles, 35 met the inclusion criteria: (1) being conducted in the United States, (2) including an intervention or empirical data around health promotion among adult low-wage workers, and (3) measuring changes in low-wage worker health. DATA EXTRACTION: Central features of the selected studies were extracted, including the theoretical foundation; study design; health promotion intervention content and delivery format; intervention-targeted outcomes; sample characteristics; and work, occupational, and industry characteristics. DATA ANALYSIS: Consistent with a scoping review, we used a descriptive, content analysis approach to analyze extracted data. All authors agreed upon emergent themes and 2 authors independently coded data extracted from each article. RESULTS: The results suggest that the research on low-wage workers' health promotion is limited, but increasing, and that low-wage workers have limited access to and utilization of worksite health promotion programs. CONCLUSION: Workplace health promotion programs could have a positive effect on low-wage workers, but more work is needed to understand how to expand access, what drives participation, and which delivery mechanisms are most effective. PMID- 28893086 TI - Older African American Homeless-Experienced Smokers' Attitudes Toward Tobacco Control Policies-Results from the HOPE HOME Study. AB - PURPOSE: To examine attitudes toward tobacco control policies among older African American homeless-experienced smokers. APPROACH: A qualitative study. SETTING: Oakland, California. PARTICIPANTS: Twenty-two African American older homeless experienced smokers who were part of a longitudinal study on health and health related outcomes (Health Outcomes of People Experiencing Homelessness in Older Middle Age Study). METHOD: We conducted in-depth, semistructured interviews with each participant to explore beliefs and attitudes toward tobacco use and cessation, barriers to smoking cessation, and attitudes toward current tobacco control strategies including raising cigarette prices, smoke-free policies, and graphic warning labels. We used a grounded theory approach to analyze the transcripts. RESULTS: Community social norms supportive of cigarette smoking and co-use of tobacco with other illicit substances were strong motivators of initiation and maintenance of tobacco use. Self-reported barriers to cessation included nicotine dependence, the experience of being homeless, fatalistic attitudes toward smoking cessation, substance use, and exposure to tobacco industry marketing. While participants were cognizant of current tobacco control policies and interventions for cessation, they felt that they were not specific enough for African Americans experiencing homelessness. Participants expressed strong support for strategies that de-normalized tobacco use and advertised the harmful effects of tobacco. CONCLUSION: Older African American homeless experienced smokers face significant barriers to smoking cessation. Interventions that advertise the harmful effects of tobacco may be effective in stimulating smoking cessation among this population. PMID- 28893087 TI - Protocol Modification of Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome Study. PMID- 28893088 TI - Double-locus lymphoplasmacytic aortitis. AB - Thoracic aortic aneurysm is an indication for major cardiovascular operative procedures. The etiology is usually hypertension and/or atherosclerotic disease; reaching a certain diameter often results in acute aortic syndrome. Immunoglobulin G4-related aortitis, characterized by lymphoplasmacytic vascular tunica media induration without well-defined underlying infectious or autoimmune systemic causes, is uncommon. Histological similarity to immunoglobulin G4 disease in other organs suggests that this aortitis might be a manifestation of systemic pathology. We describe a case of double-locus lymphoplasmacytic aortitis in a 72-year-old man who had the incidental finding of intramural hematoma on elective thoracic computed tomography as part of a respiratory work-up. PMID- 28893089 TI - Investigation of the solvent-dependent photolysis of a nonnucleoside reverse transcriptase inhibitor, antiviral agent efavirenz. AB - This study sought to investigate the solvent-dependency on the photolysis of efavirenz to gain insight into the photoprocesses involved. The primary mechanisms were firstly the excited-state intramolecular proton transfer (i.e. phototautomerization), which generated the imidic acid phototautomer observed as [M-H]- quasimolecular ion at m/z 314.0070 in the high-performance liquid chromatography-electrospray ionization-time-of-flight mass spectrometry in the negative mode. Secondly, the photoinduced alpha-cleavage with the loss of a carbonyl group occurred (i.e. photodecarbonylation) to form the photoproduct at m/z 286.0395. The ultraviolet-visible spectra illustrated a large, hyperchromic, and slight bathochromic effect in both the pi->pi* and n->pi* electronic transitions. The largest bathochromic effect was prevalent in the chloroform solvent, i.e. chloroform (pi* = 0.58; beta = 0.00; alpha = 0.44) > methanol (pi* = 0.60; beta = 0.66; alpha = 0.98) > acetonitrile (pi* = 0.75; beta = 0.40; alpha = 0.19). This is due to the significant interaction of the amino group with the excited carbonyl moiety which is attributed to intramolecular phototautomerization resulting in a larger energy shift of the electronic state. A plausible explanation is due to the hydrogen bond donor ability of the polar methanol and nonpolar chloroform solvents, which stabilized the polarized imidic acid phototautomer by means of hydrogen bonding interactions, as opposed to the aprotic acetonitrile which exhibits no hydrogen bonding interactions. The study would form the basis for further photolytic analyses and syntheses to generate a plethora of novel photoproducts with anti-HIV activity based on the biologically active benzoxazinone framework of efavirenz. PMID- 28893090 TI - An in-depth review of chemical angiogenesis inhibitors for treating hepatocellular carcinoma. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is a frequent and severe complication of cirrhosis. Most HCC patients initially present with or progress to advanced stage disease and require systemic treatment. As hypervascularization is a major characteristic of HCC, antiangiogenic drugs have been tested. Areas covered: In this review, we summarize data on the use of drugs targeting the angiogenesis. Despite many trials, in 2017 only 3 drugs, all antiangiogenic, have demonstrated efficacy in first (sorafenib, lenvatinib) or second line (regorafenib) treatment of advanced HCC. The heterogeneous mechanisms of action and the major reasons for failure of most trials are discussed. An English language, abstract-based literature review was performed by a PubMed-based strategy. Expert opinion: Currently all trials based on purely antiangiogenic compounds (bevacizumab, linifanib, brivanib and ramucirumab) or drugs with strong antiangiogenic properties (sunitinib) have failed (increased toxicity, minor efficacy and/or flaws in trial design); sorafenib, lenvatinib and regorafenib are multityrosine kinase inhibitors and their efficacy can be partly related to another mechanism of action. We need to better refine future trials design (randomized phase 2, good stratification factors and marker-enriched patient selection) in order to progress toward customized treatment, perhaps in association with immunotherapy. PMID- 28893091 TI - Lutein Induces Autophagy via Beclin-1 Upregulation in IEC-6 Rat Intestinal Epithelial Cells. AB - Lutein is a carotenoid with anti-oxidant properties. Autophagy, an evolutionarily conserved catabolic cellular pathway for coping with stress conditions, is responsive to reactive oxygen species (ROS) and degrades damaged organelles. We previously demonstrated that lutein can induce anti-oxidant enzymes to relieve methotrexate-induced ROS stress. We therefore hypothesized that lutein, which activates ROS-scavenging enzymes, can also induce autophagy for cell survival. In this study, we demonstrated that lutein treatment attenuated the reduction in cell viability caused by H2O2. Lutein dose-dependently induced the processing of microtubule-associated protein light chain 3 (LC3)-II, an autophagy marker protein, and accumulation of LC3-positive puncta in rat intestinal IEC-6 cells. Furthermore, (a) direct observation of autophagosome formation through transmission electron microscopy, (b) upregulation of autophagy-related genes including ATG4A, ATG5, ATG7, ATG12, and beclin-1 (BENC1), and (c) increased BECN1/Bcl-2 ratio confirmed the induction of autophagy by lutein. The results revealed that bafilomycin-A1-induced inhibition of autophagy reduced cell viability and increased apoptosis in lutein-treated cells, indicating a protective role of lutein-induced autophagy. Lutein treatment also activated adenosine monophosphate-activated protein kinase (AMPK), c-Jun N-terminal kinase (JNK), and p-38, but had no effects on the induction of extracellular signal related kinase or inhibition of mTOR; however, the inhibition of activated AMPK, JNK, or p-38 did not attenuate lutein-induced autophagy. Finally, increased BECN1 expression levels were detected in lutein-treated cells, and BECN1 knockdown abolished autophagy induction. These results suggest that lutein-induced autophagy was mediated by the upregulation of BECN1 in IEC-6 cells. We are the first to demonstrate that lutein induces autophagy. Elevated autophagy in lutein treated IEC-6 cells may have a protective role against various stresses, and this warrants further investigation. PMID- 28893092 TI - Salvianolic Acid A, a Component of Salvia miltiorrhiza, Attenuates Endothelial Mesenchymal Transition of HPAECs Induced by Hypoxia. AB - Salvianolic acid A (SAA), a polyphenols acid, is a bioactive ingredient from a traditional Chinese medicine called Dan shen (Salvia Miltiorrhiza Bunge). According to previous studies, it was shown to have various effects such as anti oxidative stress, antidiabetic complications and antipulmonary hypertension. This study aimed to investigate the effect of SAA on pulmonary arterial endothelial mesenchymal transition (EndoMT) induced by hypoxia and the underlying mechanisms. Primary cultured human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O2 for 48[Formula: see text]h with or without SAA treatment. SAA treatment improved the morphology of HPAECs and inhibited the cytoskeleton remodeling. A total of 3[Formula: see text][Formula: see text]M SAA reduced migration distances from 262.2[Formula: see text][Formula: see text]m to 198.4[Formula: see text][Formula: see text]m at 24[Formula: see text]h and 344.8[Formula: see text][Formula: see text]m to 109.3[Formula: see text][Formula: see text]m at 48[Formula: see text]h. It was observed that the production of ROS in cells was significantly reduced by the treatment of 3[Formula: see text][Formula: see text]M SAA. Meanwhile, SAA alleviated the loss of CD31 and slightly inhibited the expression of [Formula: see text]-SMA. The mechanisms study shows that SAA treatment increased the phosphorylation levels of Smad1/5, but inhibited that of Smad2/3. Furthermore, SAA attenuated the phosphorylation levels of ERK and Cofilin, which were enhanced by hypoxia. Based on these results, our study indicated that SAA treatment can protect HPAECs from endoMT induced by hypoxia, which may perform via the inhibition on ROS production and further through the downstream effectors of BMPRs or TGF[Formula: see text]R including Smads, ERK and ROCK/cofilin pathways. PMID- 28893093 TI - Practical approach to the treatment of NSAID hypersensitivity. AB - INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently involved in drug hypersensitivity reactions (DHR). NSAIDs are prescribed for different processes and some NSAIDs can be obtained over the counter. Areas covered: We analyse the practical approaches for managing and treating NSAID-DHR considering the five major groups of entities recognised, divided into two categories: those responding to strong COX-1 inhibitors and possibly weak COX-1 or selective COX-2 inhibitors named cross-intolerant (CI), and those induced by a single drug or drug group with good tolerance to strong COX-1 inhibitors, known as allergic reactions (SR). An analysis of the recent literature indicates that two approaches can be followed for CI: to give acetyl salicylic acid to confirm NSAID hypersensitivity or to give alternative drugs to provide a solution for the treatment of pain, fever, inflammation or other conditions. Desensitisation approaches have been undertaken, but mainly for CI cases with respiratory airway involvement and they are very rarely used for CI with cutaneous involvement or SR. Expert commentary: DHR to NSAIDs are now recognised as one of the most important problems in the evaluation and management of drug allergy. Because no diagnostic tests exist, important resources are needed to evaluate these patients. PMID- 28893094 TI - Retrograde magnetic internal lengthening nail for acute femoral deformity correction and limb lengthening. AB - INTRODUCTION: The Precice magnetic internal lengthening intramedullary nail is being used with great success in femur lengthening and deformity correction with a retrograde approach. Areas Covered: Our personal history of limb lengthening and the Precice nail will be reviewed. Several technical aspects are discussed including design updates, pre operative planning, selection of nail length, the use of blocking screws and intra operative temporary external fixation, osteotomy practice, post operative management, and cost analysis. Expert Commentary: The phenomenal bone healing ability for the retrograde Precice nail after femoral osteotomy for lengthening, even after acute deformity correction, is recognized throughout the growing body of scientific publications on this topic. The few failures that have occurred appear to be attributable to excessive loading of the femur and implant during a vulnerable time of bone healing. Further studies with more uniform outcome criteria need to be conducted to better standardize user's experiences. The higher one time cost of the implant is offset by the reduced number of surgeries needed when compared with the gold standard of lengthening over-nail-technique, and we suspect that patients return to work sooner due to the ability to wear normal clothing and the reduction in pain throughout the entire lengthening process. PMID- 28893095 TI - Efficacy of antidepressants: bias in randomized clinical trials and related issues. AB - INTRODUCTION: Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive. Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant. Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years. PMID- 28893097 TI - Factor validation and Rasch analysis of the individual recovery outcomes counter. AB - OBJECTIVE: The individual recovery outcomes counter is a 12-item personal recovery self-assessment tool for adults with mental health problems. Although widely used across Scotland, limited research into its psychometric properties has been conducted. We tested its' measurement properties to ascertain the suitability of the tool for continued use in its' present form. MATERIALS AND METHODS: Anonymised data from the assessments of 1743 adults using mental health services in Scotland were subject to tests based on principles of Rasch measurement theory, principal components analysis and confirmatory factor analysis. RESULTS: Rasch analysis revealed that the six-point response structure of the individual recovery outcomes counter (I.ROC) was problematic. Re-scoring on a four-point scale revealed well-ordered items that measure a single, recovery related construct, and has acceptable fit statistics. Confirmatory factor analysis supported this. Scale items covered around 75% of the recovery continuum; those individuals least far along the continuum were least well addressed. CONCLUSIONS: A modified tool worked well for many, but not all, service users. The study suggests specific developments are required if the I.ROC is to maximise its' utility for service users and provide meaningful data for service providers. Implications for Rehabilitation Agencies and services working with people with mental health problems aim to help them with their recovery. The individual recovery outcomes counter has been developed and is used widely in Scotland to help service users track their progress to recovery. Using a large sample of routinely collected data we have demonstrated that a number of modifications are needed if the tool is to adequately measure recovery. This will involve consideration of the scoring system, item content and inclusion, and theoretical basis of the tool. PMID- 28893096 TI - Assessing genetic risk of hypertension at an early age: future research directions. PMID- 28893098 TI - Chemical sensing of Benzo[a]pyrene using Corchorus depressus fluorescent flavonoids. AB - Plant phytochemicals, such as flavonoids are in use for the development of optical biosensor. Benzo[a]pyrene (B[a]P), is a pervasive environmental and dietary carcinogen. A fluorescent assay is developed using plant isolated flavonoid for the detection of B[a]P. High content saponins are excluded from the flavonoid-containing methanolic extract of Corchorus depressus by implying reduction of silver ions by saponins resulting in formation of silver nanoparticles. Isolated plant flavonoids are used to develop a spectrofluorometric assay for the detection of B[a]P. Decrease in the flavonoid fluorescence intensity by B[a]P is found to be based on both static and dynamic quenching. Specificity of the assay for B[a]P was tested for other carcinogens belonging to different classes of compounds. Flavonoids-mediated sensing can be implied for the development of new generation of nanoparticle-based biosensors that can be more sensitive and less susceptible to external factors, such as temperature and humidity. PMID- 28893099 TI - Obinutuzumab for the treatment of chronic lymphocytic leukemia and other B-cell lymphoproliferative disorders. AB - INTRODUCTION: Chemoimmunotherapeutic regimens using the anti-CD20 antibody rituximab improved significantly the survival rates in various B-cell lymphoproliferative disorders (LPDs), including chronic lymphocytic leukemia (CLL). The next-generation CD20 antibody obinutuzumab represents an addition to the drug armamentarium used for the therapeutic management of patients with LPDs. Areas covered: Herein, the authors discuss the biochemical and conformational engineering of obinutuzumab to increase antibody-dependent cell-mediated cytotoxicity and direct cell death. They also describe the available preclinical data on obinutuzumab's role in B-cell LPDs. Furthermore, the authors summarize the Phase I and II clinical trials of obinutuzumab, focusing on the main pharmacokinetic/pharmacodynamic characteristics, the most common clinically significant adverse events, dose optimization, and clinical outcomes of patients with CLL and other B-cell LPDs treated with obinutuzumab as monotherapy or in combination with other agents. To put these data in perspective, the use of obinutuzumab is compared with that of rituximab in CLL and other B-cell LPDs. Expert opinion: Clinical trials have demonstrated that obinutuzumab is well tolerated. The novel mechanism of action of obinutuzumab is associated with significant efficacy in CLL and other B-cell LPDs. Ongoing clinical trials are expected to determine the optimal use of obinutuzumab in these diseases. PMID- 28893101 TI - Improving Hepatitis C Identification: Technology Alone Is Not the Answer. AB - An estimated 3 to 5 million Americans are chronically infected with hepatitis C virus (HCV), and approximately 75% of those persons were born between 1945 and 1965 (the so-called baby boomer generation). Because of the largely asymptomatic nature of HCV, up to 50% of those infected are unaware of their disease. Risk based testing has been largely ineffective. Based on prevalence data, the Centers for Disease Control and Prevention and other organizations recommend a onetime HCV antibody test for all baby boomers. However, uptake of this recommendation requires significant changes in clinical practice for already busy primary care clinicians. We studied the effectiveness of a quality improvement initiative based on continuous audit and feedback combined with education for improving testing in alignment with guidelines; the control group was a cohort of clinicians whose only reminder was an institution-wide electronic health record prompt. Our data show improved testing rates among all clinician groups, but more significant improvement occurred among providers who received continuous feedback about their clinical performance coupled with education. PMID- 28893100 TI - One new 1,4-napthoquinone derivative from the roots of Juglans mandshurica. AB - A new 1,4-napthoquinone derivative, namely (S)-(-)-3-(8-hydroxy-1,4-dioxo-1,4 dihydro-naphthalen-2-yl)-3-(4-hydroxy-3-methoxyphenyl)-propionic acid methyl ester (1), was isolated from the roots of Juglans mandshurica Maxim. The structure was identified based on HR-ESI-MS, 1D and 2D NMR spectroscopic methods. PMID- 28893102 TI - Imaging and imagining chronic obstructive pulmonary disease (COPD): Uruguayans draw their lungs. AB - PURPOSE: This anthropological study investigated what people imagined chronic obstructive pulmonary disease to look like in their lungs, what may be influencing these images and how this imagery shapes embodiment. METHOD: Employing graphic elicitation, in one of multiple ethnographic interviews, participants were asked to draw their lungs: "If we could look inside your chest now, what would we see?" Lung drawings and accompanying narratives and fieldnotes from 14 participants were analyzed for themes and patterns. RESULTS: The theme of "imaging/imagining" emerged and three distinct patterns within this theme were identified: the microscope perspective, the X-ray perspective and the reduced pulmonary capacity perspective. These patterns demonstrate how embodiment can be shaped by an integration and reinterpretation of the medical images that form part of everyday clinic visits and pulmonary rehabilitation. CONCLUSIONS: Medical technology and images impact patients' embodiment. Understanding this is important for rehabilitation practitioners who work in a challenging space created by potentially conflicting medical narratives: on the one hand, chronic obstructive pulmonary disease is incurable permanent damage, and on the other, improvement is possible through rehabilitation. Drawing could be integrated into pulmonary rehabilitation and may help identify perceptions of the body that could hinder the rehabilitation process. Implications for rehabilitation Drawings, when combined with interviews, can lead to a deeper and more complex understanding of patients' perspectives and embodiment. Rehabilitation practitioners should be concerned with how patients embody the medical technology and imagery they are exposed to as part of the educational component of pulmonary rehabilitation and healthcare generally. Asking patients to visualize their illness through drawing may help pulmonary rehabilitation practitioners identify perceptions of the body which could hinder the patient's ability to reap the full benefit of their treatment. PMID- 28893103 TI - What's next for chronobiology and drug discovery. PMID- 28893104 TI - Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma. AB - INTRODUCTION: Among the intraocular pressure (IOP)-lowering drugs used in a clinical setting, Rho kinase (ROCK) inhibitors lower IOP by a unique mechanism, namely the depolymerization of intracellular actin in the conventional outflow tissues: the trabecular meshwork (TM) and Schlemm's canal (SC). Furthermore, ROCK inhibitors suppress the production of extracellular matrix by TM cells, which represents a potential alternative method of lowering IOP. Considering that conventional outflow is a dominant pathway in humans, IOP-lowering ROCK inhibitors, delivered in conjunction with other drugs, may be able to treat the glaucomatous eye. Areas covered: Ripasudil hydrochloride hydrate is the first ROCK inhibitor approved for clinical use in Japan (and worldwide) against glaucoma and ocular hypertension. The efficacy of ripasudil, as monotherapy and as an adjunctive medication to prostaglandin analogs and/or adrenergic beta receptor antagonists, has been confirmed in clinical trials. Expert opinion: Considering the unique ROCK-inhibiting mechanism by which ripasudil lowers IOP via its actions on TM and SC endothelial cells, it may be an ideal adjunctive medication for treating glaucoma in the clinic. PMID- 28893105 TI - Essential oil composition of aerial parts of Micromeria persica Boiss. from Western of Shiraz, Iran. AB - Micromeria persica Boiss. is medicinal and aromatic plant, belonging to the Lamiaceae family. The chemical composition of the essential oils (EOs) from aerial parts of M. persica were extracted using hydro-distillation method and analysed using GC and GC-MS. Fifty-two compounds were identified in the EOs of aerial parts of M. persica. The main chemical compositions were n-hexadecanoic acid (14.9%), thymol (9.5%), linoleic acid (8.0%), carvacrol (5.6%), (E) nerolidol (5.5%), linolenic acid (5.5%), alpha-cadinol (2.7%), linalool (2.7%), borneol (2.6%), caryophyllene oxide (2.3%) and pulegone (2.0%). Presence of borneol, thymol, carvacrol and pulegone suggests the potential of this plant as a flavouring source in the food industry, being used in perfumery and cosmetics industry, vitamin E synthesis and exhibit strong fungicidal, antibacterial and antimicrobial activities. PMID- 28893106 TI - 22G versus 25G biopsy needles for EUS-guided tissue sampling of solid pancreatic masses: a randomized controlled study. AB - BACKGROUND/OBJECTIVES: No comparative study of 22-gauge biopsy needles (PC22) and 25-gauge biopsy needles (PC25) has been conducted. We prospectively compared the diagnostic accuracy of PC22 and PC25 in patients with pancreatic and peripancreatic solid masses. METHODS: We conducted a randomized noninferiority clinical study from January 2013 to May 2014 at Samsung Medical Center. A cytological and histological specimen of each pass was analyzed separately by an experienced pathologist. The primary outcome was to assess the diagnostic accuracy using the PC22 or PC25. Secondary outcomes included the optimal number of passes for adequate diagnosis, core specimen yield, sample adequacy, and complication rates. RESULTS: Diagnostic accuracy of combining cytology with histology in three cumulative passes was 97.1% (100/103) for the PC22 and 91.3% (94/103) for the PC25 group. Thus, noninferiority of PC25 to PC22 was not shown with a 10% noninferiority margin (difference, -5.8%; 95% CI, -12.1 to -0.5%). In a pairwise comparison with each needle type, two passes was non-inferior to three passes in the PC22 (96.1% vs. 97.1%; difference, -0.97%; 95% CI -6.63 to 4.69%) but noninferiority of two passes to three passes was not shown in the PC25 group (87.4% vs. 91.3%; difference, -3.88%; 95% CI, -13.5 to 5.7%). CONCLUSIONS: Non inferiority of PC25 to PC22 diagnostic accuracy was not observed for solid pancreatic or peripancreatic masses without on-site cytology. PC22 may be a more ideal device because only two PC22 needle passes was sufficient to establish an adequate diagnosis, whereas PC25 required three or more needle passes. PMID- 28893107 TI - Applying proteomics to diagnosis of diabetic kidney disease. PMID- 28893108 TI - Comparative efficacy evaluation of catheter intraperitoneal chemotherapy, normothermic and hyperthermic chemoperfusion in a rat model of ascitic ovarian cancer. AB - OBJECTIVES: The choice of an optimal administration route for intraperitoneal (IP) chemotherapy and a suitable chemotherapeutic regime in the treatment of ovarian cancer remains a controversy. We investigated survival outcomes according to catheter intraperitoneal chemotherapy (CIPC), normothermic and hyperthermic chemoperfusion (NIPEC and HIPEC) with cytostatic drugs dioxadet and cisplatin in rats with transplantable ascitic ovarian cancer. METHODS: Ascitic liquid containing 1 * 107 tumour cells was inoculated to female Wistar rats and 48 hours after rats received dioxadet and cisplatin at the maximum tolerated doses. Dioxadet at doses 1.5, 30 and 15 mg/kg and cisplatin at doses 4, 40 and 20 mg/kg body weight were administered for CIPC, NIPEC and HIPEC, respectively. Rats in the control groups received physiological saline and CIPC with physiological saline was regarded as the untreated control. The antitumor activity of the drugs was evaluated as an increase in average life expectancy (ALE). Analysis of the data was based primarily on Bayesian statistics and included Kaplan-Meier method, log-rank test and hazard ratio (HR) estimation. RESULTS: Compared to the untreated control CIPC, NIPEC and HIPEC with dioxadet significantly increased ALE by 101316, 61524 and 1.71735 days, whereas with cisplatin by 61013, 122437 and 13523 days, respectively. CONCLUSIONS: Dioxadet and cisplatin show similar efficacy in the CIPC route. Compared with CIPC IP chemotherapy by chemoperfusions is more effective for both the drugs. Dioxadet in HIPEC showed highest survival benefit whereas largest effect during NIPEC is achieved with cisplatin. PMID- 28893109 TI - Microbial growth yield estimates from thermodynamics and its importance for degradation of pesticides and formation of biogenic non-extractable residues. AB - In biodegradation studies with isotope-labelled pesticides, fractions of non extractable residues (NER) remain, but their nature and composition is rarely known, leading to uncertainty about their risk. Microbial growth leads to incorporation of carbon into the microbial mass, resulting in biogenic NER. Formation of microbial mass can be estimated from the microbial growth yield, but experimental data is rare. Instead, we suggest using prediction methods for the theoretical yield based on thermodynamics. Recently, we presented the Microbial Turnover to Biomass (MTB) method that needs a minimum of input data. We have estimated the growth yield of 40 organic chemicals (31 pesticides) using the MTB and two existing methods. The results were compared to experimental values, and the sensitivity of the methods was assessed. The MTB method performed best for pesticides. Having the theoretical yield and using the released CO2 as a measure for microbial activity, we predicted a range for the formation of biogenic NER. For the majority of the pesticides, a considerable fraction of the NER was estimated to be biogenic. This novel approach provides a theoretical foundation applicable to the evaluation and prediction of biogenic NER formation during pesticide degradation experiments, and may also be employed for the interpretation of NER data from regulatory studies. PMID- 28893110 TI - Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges. AB - INTRODUCTION: Radioimmunotherapy (RIT) with monoclonal antibodies and their fragments labelled with radionuclides emitting alpha -particles, beta-particles or Auger electrons have been used for many years in the development of anticancer strategies. While RIT has resulted in approved radiopharmaceuticals for the treatment of hematological malignancies, its use in solid tumors still remains challenging. Areas covered: In this review, we discuss the exciting progress towards elucidating the potential of current and novel radioimmunoconjugates and address the challenges for translation into clinical practice. Expert opinion: There are still technical and logistical challenges associated with the use of RIT in routine clinical practice, including development of novel and more specific targeting moieties, broader access alpha to alpha-emitters and better tailoring of pre-targeting approaches. Moreover, improved understanding of the heterogeneous nature of solid tumors and the critical role of tumor microenvironments will help to optimize clinical response to RIT by delivering sufficient radiation doses to even more radioresistant tumor cells. PMID- 28893111 TI - Using tablet-based technology to deliver time-efficient ototoxicity monitoring. AB - OBJECTIVE: The goal of this article is to highlight mobile technology that is not yet standard of care but could be considered for use in an ototoxicity monitoring programme (OMP) as an adjunct to traditional audiometric testing. Current guidelines for ototoxicity monitoring include extensive test protocols performed by an audiologist in an audiometric booth. This approach is comprehensive, but it may be taxing for patients suffering from life-threatening illnesses and cost prohibitive if it requires serial clinical appointments. With the use of mobile technology, testing outside of the confines of the audiometric booth may be possible, which could create more efficient and less burdensome OMPs. DESIGN: A non-systematic review of new OMP technology was performed. Experts were canvassed regarding the impact of new technology on OMPs. STUDY SAMPLE: OMP devices and technologies that are commercially available and discussed in the literature. RESULTS: The benefits and limitations of portable, tablet-based technology that can be deployed for efficient ototoxicity monitoring are discussed. CONCLUSIONS: New mobile technology has the potential to influence the development and implementation of OMPs and lower barriers to patient access by providing time efficient, portable and self-administered testing options for use in the clinic and in the patient's home. PMID- 28893113 TI - An empirical Bayes method for robust variance estimation in detecting DEGs using microarray data. AB - The microarray technology is widely used to identify the differentially expressed genes due to its high throughput capability. The number of replicated microarray chips in each group is usually not abundant. It is an efficient way to borrow information across different genes to improve the parameter estimation which suffers from the limited sample size. In this paper, we use a hierarchical model to describe the dispersion of gene expression profiles and model the variance through the gene expression level via a link function. A heuristic algorithm is proposed to estimate the hyper-parameters and link function. The differentially expressed genes are identified using a multiple testing procedure. Compared to SAM and LIMMA, our proposed method shows a significant superiority in term of detection power as the false discovery rate being controlled. PMID- 28893112 TI - Evaluation of an Intimate Partner Violence Training for Home Visitors Using the Theory of Planned Behavior. AB - INTRODUCTION: Intimate partner violence (IPV) is a public health issue with recent intervention focus by home visiting programs with at-risk families in the United States. Home visitors are typically required to assess IPV but feel unprepared to do so and desire training. Our aim was to evaluate the impact of a daylong IPV training on the intention to enact three key IPV behaviors (screening, making referrals, and safety planning) using the theory of planned behavior. METHOD: Survey of 125 home visitors in West Virginia was conducted before and after a daylong IPV training. RESULTS: The IPV training had a positive impact on intention to perform the three behaviors of interest, with the greatest impact on the intention to conduct IPV screenings. DISCUSSION: Results provide important preliminary evidence supporting the effectiveness of professional development as a means of increasing intentions to conduct activities related to IPV. The impact on IPV screening intention is promising because screening is the first step in addressing IPV. CONCLUSION: The IPV training proved beneficial in increasing intentions and such trainings should be expanded, but further study is needed to link intentions to subsequent behaviors to address IPV with at-risk families. PMID- 28893114 TI - Panic disorder and cardiovascular diseases: an overview. AB - The association between panic disorder (PD) and cardiovascular diseases (CVD) has been extensively studied in recent years and, although some studies have shown anxiety disorders co-existing or increasing the risk of heart disease, no causal hypothesis has been well established. Thus, a critical review was performed of the studies that evaluated the association between PD and cardiovascular diseases; synthesizing the evidence on the mechanisms mediators that theoretically would be the responsible for the causal pathway between PD and CVD, specifically. This overview shows epidemiological studies, and discusses biological mechanisms that could link PD to CVD, such as pleiotropy, heart rate variability, unhealthy lifestyle, atherosclerosis, mental stress, and myocardial perfusion defects. This study tried to provide a comprehensive narrative synthesis of previously published information regarding PD and CVD and open new possibilities of clinical management and pathophysiological understanding. Some epidemiological studies have indicated that PD could be a risk factor for CVD, raising morbidity and mortality in PD, suggesting an association between them. These studies argue that PD pathophysiology could cause or potentiate CVD. However, there is no evidence in favour of a causal relationship between PD and CVD. Therefore, PD patients with suspicions of cardiovascular symptoms need redoubled attention. PMID- 28893115 TI - The challenges of patient satisfaction: influencing factors and the patient - provider relationship in the United States. AB - INTRODUCTION: Patient satisfaction is a phenomenon that has become influential in the inpatient setting with the introduction of the Hospital Consumer Assessment of Healthcare Practitioners and Systems (HCAHPS) survey in the United States. Patient satisfaction is a key goal of healthcare organizations and presents some challenges to providing quality patient care. Areas covered: This review will focus on the challenges patient satisfaction presents in the healthcare field, with a key focus on factors that influence patient satisfaction, the common problem of inappropriate antibiotic prescriptions and the importance of the patient-provider relationship. Expert commentary: While it is apparent that focused efforts to better understand patient satisfaction are necessary and that implementation of processes to enhance satisfaction are warranted, attention must be directed so that these interventions do not adversely influence the efficiency or quality of care. Continuous long-term relationships with healthcare providers encourage patient loyalty, effective healthcare and good lifestyle habits. PMID- 28893117 TI - Method-comparison studies in telehealth: Study design and analysis considerations. AB - When establishing telehealth services, clinicians need to be confident that the examinations, assessments and clinical decisions that they make while using technology are equivalent to conventional best practice. Method-comparison studies are ideally suited to answering these questions, however there is a lack of consistency in the telehealth literature in the study methodologies and data analysis techniques used. Methodologies should closely match clinical practice to maximise external validity and data analysis techniques should match the data types generated in order to be clinically meaningful. In this article we discuss the design, analysis and interpretation of method-comparison studies in the context of telehealth research. PMID- 28893116 TI - Imaging Hepatocellular Carcinoma With 68Ga-Citrate PET: First Clinical Experience. AB - While cross-sectional imaging with computed tomography (CT) and magnetic resonance imaging is the primary method for diagnosing hepatocellular carcinoma (HCC), they provide little biological insight into this molecularly heterogeneous disease. Nuclear imaging tools that can detect molecular subsets of tumors could greatly improve diagnosis and management of HCC. To this end, we conducted a patient study to determine whether HCC can be resolved using 68Ga-citrate positron emission tomography (PET). One patient with recurrent HCC was injected with 300 MBq of 68Ga-citrate and imaged with PET/CT 249 minutes post injection. Four (28%) of 14 hepatic lesions were avid for 68Ga-citrate. One extrahepatic lesion was not PET avid. The average maximum standardized uptake value (SUVmax) for the lesions was 7.2 (range: 6.2-8.4), while the SUVmax of the normal liver parenchyma was 4.7 and blood pool was 5.7. The avid lesions were not significantly larger than the quiescent lesions, and a prior contrast CT showed uniform enhancement among the lesions, suggesting that tumor signals are due to specific binding of the radiotracer to the transferrin receptor, rather than enhanced vascularity in the tumor microenvironment. Further studies are required in a larger patient cohort to verify the molecular basis of radiotracer uptake and the clinical utility of this tool. PMID- 28893118 TI - Emotional and Behavioral Health Needs in Elementary School Students in an Underserved Hispanic Community. AB - High rates of mental health problems in adolescents have been well documented; less is known about elementary school children in disadvantaged communities. We examined emotional and behavioral health needs in 202 third and fourth graders enrolled in a charter school in a largely Hispanic community. The child-reported Revised Child Anxiety and Depression Scale-25 and Teacher's Report Form were used to evaluate mental health needs as perceived by these children and their teachers. The prevalence of teacher-reported depression and child self-reported anxiety was 7.0% and 6.67%, respectively. Living in a single parent household was found to be a specific risk factor in that those children had higher rates of emotional and behavioral problems than children living with both parents. Evidence of higher depression and anxiety identified in this sample compared to national representative data suggests the need for development of culturally sensitive early prevention and intervention in this underserved community. PMID- 28893119 TI - Screening for psychological distress before radiotherapy for painful bone metastases may be useful to identify patients with high levels of distress. AB - BACKGROUND: Psychological distress (PD) has a major impact on quality of life. We studied the incidence of PD before and after radiotherapy for painful bone metastases. Furthermore, we aimed to identify factors predictive for PD. METHODS: Between 1996 and 1998, the Dutch Bone Metastasis Study included 1157 patients with painful bone metastases. Patients were randomized between two fractionation schedules. The study showed a pain response of 74% in both groups. Patients filled out weekly questionnaires for 13 weeks, then monthly for two years. The questionnaires included a subscale for PD on the Rotterdam Symptom Checklist. We used generalized estimating equations and multivariable logistic regression analyses. RESULTS: At baseline, 290 patients (27%) had a high level of PD. For the entire group, the level of PD remained constant over time. The majority of patients with a low level of PD at baseline remained at a low level during follow up. In patients with a high level of PD at baseline, the mean level of PD decreased after treatment and stabilized around the cutoff level. Female patients, higher age, worse performance, lower pain score and worse self-reported QoL were associated with an increased chance of PD, although the model showed moderate discriminative power. CONCLUSIONS: A substantial proportion of patients had a high level of PD before and after radiotherapy for painful bone metastases. Most patients who reported high levels of PD when referred for palliative radiotherapy remained at high levels thereafter. Therefore, screening of PD prior to treatment seems appropriate, in order to select patients requiring intervention. PMID- 28893120 TI - Increasing value-adding patient care by applying a modified TCAB program. AB - Purpose The purpose of this study is to evaluate a development process aimed at increasing registered nurses' (RNs) working time use in value-adding patient care by applying a modified Transforming Care at the Bedside (TCAB) program at inpatient units of two tertiary hospitals. Design/methodology/approach Basic data for the development process were collected on RNs' working time use via external observation in 2011 (RNs = 113). Nursing work was redesigned and implemented by 12 multi-professional teams during 2012-2013. The development process was evaluated by repeating the collection of RNs' working time use data in 2013 (RNs = 95) and by analyzing the memos of the development teams via deductive content analysis ( N = 64). Findings RNs' working time use showed statistically significant increases in value-adding care and direct patient care but decreases in non-value-added work and miscellaneous work. Changes in the nursing work model, division of labor and the nursing work environment all affected RNs' working time use. Practical implications The development process progressed distinctively in each unit, as shown by the results of the development work. Clinical RNs had key roles as innovators and change agents, yet the engagement of nursing managers was most essential for the success of the development work. Originality/value Even minor changes in nurses' daily work profile can have considerable effects on RNs' work. The TCAB program was shown to be a useful method in developing RNs' work also in psychiatric units. PMID- 28893121 TI - Clinical and economic evaluation of minimally invasive cartilaginous palisade myringoplasty. AB - OBJECTIVES: To test the clinical and audiometric efficacy of a minimally invasive myringoplasty technique, combining cartilaginous palisades while avoiding flap elevation, for small and wide perforations. METHODS: Over 4 years, this retrospective study included all patients over 6 years of age presenting an indication for myringoplasty. Several clinical and economic criteria were noted at 7 d, 2 months, 6 months and 2 years postoperative. The main outcome was the absence of perforation 2 years postoperative. The secondary outcomes were an audiometric gain at 6 months and the evaluation of the treatment cost. RESULTS: Thirty patients underwent the minimally invasive technique and 28 patients the technique with an elevation of the tympanomeatal flap. The minimally invasive surgical procedure was shorter (p = .001). At 2 years, the tympanic closure rate was equivalent (95% versus 89.5%, p = .77). The audiometric gain was similar between the two techniques (p = .09). From a medico-economic point of view, the minimally invasive procedure was the most effective because it was three times less expensive than the conventional technique with no reduction in efficacy (p = .02). CONCLUSION: This quick and easy technique could be developed in an ambulatory setting or even in conditions adapted to consultation. PMID- 28893122 TI - Recovery of Offenders Formerly Labeled as Not Criminally Responsible: Uncovering the Ambiguity From First-Person Narratives. AB - The recovery paradigm is a widely accepted strength-based approach in general mental health care. Particular challenges arise when applying this paradigm in a forensic context. To address these issues, the present study examined recovery based on first-person narratives of offenders formerly labeled as not criminally responsible of whom the judicial measure was abrogated. Eleven in-depth interviews were conducted to obtain information on lived experiences and recovery resources of this hard-to-reach and understudied population. The interviews focused on recovery and elements that indicated a sense of progress in life. Key themes were derived from the collected data. Descriptions of recovery resources followed recurrent themes, including clinical, functional, social, and personal resources. Participants also reported ambiguous experiences related to features of the judicial trajectory. This was defined as forensic recovery and can be seen as an additional mechanism, besides more established recovery dimensions, that is unique to mentally ill offenders. PMID- 28893123 TI - Eosinophil Biology in COPD. PMID- 28893124 TI - The burden of non-symptomatic cerebral ischemia on MRI and its effect on clinical outcomes in patients with first-ever intracerebral hemorrhage. AB - PURPOSE: To compare the burden of non-symptomatic cerebral ischemia (NSCI) detected on magnetic resonance imaging (MRI) and computed tomography (CT), and assess the association of MRI-NSCI with clinical outcomes among patients with first-ever intracerebral hemorrhage (ICH). METHODS: Two thousand three hundred and five consecutive ICH patients admitted to our institution from May 2012 to October 2015 were retrospectively reviewed. Data on clinical characteristics and MRI/CT scans were collected during hospitalization. Information on clinical outcomes at three-month were also obtained. RESULTS: Three hundred and seventy seven patients performed MRIs and 1966 had CTs during hospitalization. NSCI was detected in 152 (40.3%) patients with MRIs and in 638 (32.5%) with CTs. Comparing with CT, NSCI detected by MRI was more common (40.3% vs. 32.5%; P = 0.011), more likely to be multiple loci (93.4% vs. 79.6%; P < 0.001) and bilateral hemispheres (84.9% vs. 73.2%; P = 0.003). Furthermore, the presence of NSCI, multiple NSCI, bilateral NSCI and bilateral hematoma combined with bilateral NSCI were associated with poor outcomes (P < 0.001, P < 0.001, P < 0.001, P = 0.041, respectively) in univariate analysis. In multivariable logistic regression, bilateral hematoma combined with bilateral NSCI was still associated with poor outcomes (OR 3.983, 95% CI 1.172-13.539; P = 0.027). CONCLUSIONS: Compared with CT, NSCI on MRI tends to be multiple loci and located in bilateral hemispheres. The results of NSCI in ICH may be underestimated based on CT. In addition, the increased poor outcomes at three-month suggest that NSCI may play an important role in reducing clinical outcomes. PMID- 28893125 TI - Diffusion tensor magnetic resonance imaging driven growth modeling for radiotherapy target definition in glioblastoma. AB - BACKGROUND: The clinical target volume (CTV) in radiotherapy is routinely based on gadolinium contrast enhanced T1 weighted (T1w + Gd) and T2 weighted fluid attenuated inversion recovery (T2w FLAIR) magnetic resonance imaging (MRI) sequences which have been shown to over- or underestimate the microscopic tumor cell spread. Gliomas favor spread along the white matter fiber tracts. Tumor growth models incorporating the MRI diffusion tensors (DTI) allow to account more consistently for the glioma growth. The aim of the study was to investigate the potential of a DTI driven growth model to improve target definition in glioblastoma (GBM). MATERIAL AND METHODS: Eleven GBM patients were scanned using T1w, T2w FLAIR, T1w + Gd and DTI. The brain was segmented into white matter, gray matter and cerebrospinal fluid. The Fisher-Kolmogorov growth model was used assuming uniform proliferation and a difference in white and gray matter diffusion of a ratio of 10. The tensor directionality was tested using an anisotropy weighting parameter set to zero (gamma0) and twenty (gamma20). The volumetric comparison was performed using Hausdorff distance, Dice similarity coefficient (DSC) and surface area. RESULTS: The median of the standard CTV (CTVstandard) was 180 cm3. The median surface area of CTVstandard was 211 cm2. The median surface area of respective CTVgamma0 and CTVgamma20 significantly increased to 338 and 376 cm2, respectively. The Hausdorff distance was greater than zero and significantly increased for both CTVgamma0 and CTVgamma20 with respective median of 18.7 and 25.2 mm. The DSC for both CTVgamma0 and CTVgamma20 were significantly below one with respective median of 0.74 and 0.72, which means that 74 and 72% of CTVstandard were included in CTVgamma0 and CTVgamma20, respectively. CONCLUSIONS: DTI driven growth models result in CTVs with a significantly increased surface area, a significantly increased Hausdorff distance and decreased overlap between the standard and model derived volume. PMID- 28893126 TI - A case with coil embolization for ruptured aneurysm associated with fenestration of the posterior inferior cerebellar artery. AB - An 87-year-old man hospitalized for subarachnoid hemorrhage showed a ruptured aneurysm arising from fenestration of the posterior inferior cerebellar artery. Endovascular treatment was selected and the aneurysm and superior limb were embolized completely using three coils. Fenestration of the posterior cerebellar artery is exceedingly rare. In addition, we present a first case of aneurysm as fenestration of the posterior inferior cerebellar artery that was definitively identified as a cause of bleeding. PMID- 28893127 TI - Successful presurgical endovascular management of venous sinus thrombosis associated with high-grade cerebral arteriovenous malformation: A case report. AB - We report a case of a 39-year-old man presenting with a high-grade left parieto occipital arteriovenous malformation (AVM) complicated by superior sagittal sinus (SSS) stenosis, seven years after the first presentation. Magnetic resonance imaging revealed a newly developed perilesional edema. Venous sinus stenosis acutely progressed to occlusion and induced multiple intracerebral hemorrhages. An emergent balloon venoplasty of the SSS successfully recanalized the thrombosed sinus. Further, multistage transarterial nidus embolization was performed followed by surgical resection, resulting in a complete eradication of the large AVM. The emergence of perilesional edema is a key radiological feature for the early recognition of a newly developed venous drainage route disturbance, which would result in hemorrhagic events. Venous sinus thrombosis is a rare cause of drainage route disturbance in cerebral AVMs. For such cases, the recanalization of venous drainage concomitant with flow reduction by performing transarterial embolization is effective in preventing further hemorrhage, which enables a safe performance of subsequent radical surgery. PMID- 28893129 TI - The association of Mullerian anomalies and placenta abruption: a meta-analysis. AB - BACKGROUND: Several epidemiological studies have determined that Mullerian anomalies can increase the risk of placenta abruption. To date, no meta-analysis has been performed for assessing the relationship between placenta abruption and Mullerian anomalies. This meta-analysis was conducted to estimate the association between placenta abruption and Mullerian anomalies. METHODS: We conducted a computerized literature search in Pubmed, Scopus and Web of Science covering the search period until August 2017. Heterogeneity was recognized by Chi-squared test and the I2 statistic. The Egger's and Begg's tests were examined for the possibility of publication bias. We carried out a meta-analysis to obtain a summary measure of the association between of placenta abruption and Mullerian anomalies using a random-effects model. RESULTS: A total of 732 studies was search with 653,146 participants. The overall estimate of OR was 3.10 (95% CI: 1.47, 4.74). CONCLUSIONS: We reported based on odds ratio reports in epidemiological studies that Mullerian anomalies are a risk factor for placenta abruption. PMID- 28893128 TI - Urticarial reaction following endovascular embolization of an orbital arteriovenous malformation (AVM) with n-butyl cyanoacrylate (nBCA) glue. AB - Orbital arteriovenous malformations (AVMs) are rare vascular lesions that may be managed with endovascular embolization followed by surgical resection. Embolization is often accomplished with n-butyl-2-cyanoacrylate (nBCA), which is considered to be a safe and effective liquid occlusive agent. Localized vascular inflammation has been associated with endovascular nBCA use in histopathologic studies, but reports of systemic hypersensitivity reactions following endovascular embolization with nBCA are rare. We present a case of a 26-year-old male who developed an intermittent systemic urticarial reaction without cardiopulmonary compromise beginning four weeks after nBCA embolization of an orbital AVM. Subsequent skin allergy testing performed by an allergist confirmed hypersensitivity to nBCA glue and the patient has since been successfully managed with daily oral antihistamines. Awareness of this rare potential complication of endovascular embolization with nBCA will aid in the counseling and management of patients with AVMs. PMID- 28893130 TI - Clinical and patient reported outcomes of bleaching effectiveness. AB - OBJECTIVE: The objective of this study is to evaluate clinical and patient reported outcomes of different bleaching products. MATERIALS AND METHODS: Thirty participants were randomly divided into three bleaching groups (n = 10). Bleaching was performed with high concentrations of hydrogen peroxide (HP) - Boost (40%) and Dash (30%), and with prefabricated splints Bite&White (6% HP). Tooth colour was measured before, immediately after, and 1 and 6 months after the bleaching by using classical shade guide and spectrophotometer. Tooth hypersensitivity was self-rated by patients on the Wong-Baker's face scale. Patient satisfaction was evaluated on a 7-point Likert-type scales that measured perceived performance and importance of different characteristics of bleaching treatment. RESULTS: All products were effective in teeth colour change (DeltaE > 3.3), which was significantly higher for Boost (p = .016) and Dash (p = .024) than Bite&White treatment. Perception of hypersensitivity was the highest in Boost group, followed by Dash and Bite&White treatment. Most of the patients were satisfied with final tooth colour, length and comfort during treatment, but were dissatisfied with the stability of bleached tooth colour. CONCLUSION: Materials with the higher concentrations of bleaching agent demonstrated greater bleaching effectiveness than at-home bleaching product, but also a greater hypersensitivity. Lengthening the treatment process, but achieving a more stable tooth colour may improve the perceived value of a bleaching service. PMID- 28893131 TI - Delinquency Among Members of Hong Kong Youth Street Gangs: The Role of the Organizational Structures of Gangs and Triad Affiliations. AB - This study explores the importance of organizational structures and formal affiliations with the Hong Kong triads to delinquency among youth street gang members in Hong Kong. More specifically, this study examines the relative importance of the number of organizational structures and triad affiliation to patterns of delinquency in a sample of active members of youth street gangs ( N = 201). With the aid of outreach social workers, a convenience sampling method was used to recruit a gender-balanced sample of at-risk youths. Logistic regression analysis of the survey data that was gathered indicated that formal affiliation to Hong Kong triads and the presence of organizational structures significantly increased the odds of delinquency (independently of each other). Suggestions for future research on gang membership and delinquency, with particular reference to the Asian context, are provided. PMID- 28893132 TI - Prediction of infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: development of a clinical decision-making nomogram. AB - OBJECTIVE: This study aimed to assess the population at risk of infection by extended-spectrum beta-lactamase (ESBL)-producing organisms, using clinical criteria. MATERIALS AND METHODS: All urine cultures positive for Enterobacteriaceae in a Spanish hospital department from January 2010 to 2014 were reviewed. All isolates with ESBL-positive strains were collected, and isolates received during the first week of each month with ESBL-negative strains from symptomatic patients hospitalized or admitted to the emergency room. Multivariate analysis of the factors involved was undertaken and a nomogram developed to predict the probability of infection by ESBL-producing microorganisms. RESULTS: The study included 1524 patients with urinary tract infection (UTI): 416 ESBL-positive and 1108 ESBL-negative. In univariate analysis, risk factors were: male gender (p = 0.036), age (p < 0.0001), nursing home (p < 0.0001), previous antimicrobial therapy (p < 0.0001) or hospitalization (p < 0.0001), diabetes (p < 0.0001), chronic renal insufficiency (p < 0.0001), severe underlying disease (p < 0.0001), neoplasia (p = 0.0005), urological (p < 0.0001) and non-urological invasive procedure (p = 0.0003), recurrent UTI (p < 0.0001), urological (p < 0.0001) or abdominal surgery (p < 0.0001) and permanent urethral catheter (p < 0.0001). In multivariate analysis, the data set was split into a development cohort of 1067 patients and a validation cohort of 457 cases. A nomogram was developed to predict the probability of infection by ESBL producing bacteria, which included seven variables: age (p < 0.0001), gender (p = 0.004), nursing home (p < 0.0001), previous antimicrobial therapy (p = 0.04) or hospitalization (p < 0.0001), recurrent UTI (p < 0.0001) and non-urological invasive procedure (p = 0.005). The discriminative accuracy was 0.79 (95% confidence interval 0.77-0.83). CONCLUSIONS: A nomogram was developed that predicts the risk of infection by ESBL-producing Enterobacteriaceae with reasonable accuracy. It could improve clinical decision making and enable more efficient empirical treatment. PMID- 28893133 TI - RALE051: a novel established cell line of sporadic Burkitt lymphoma. PMID- 28893135 TI - Evaluation of two different alternatives of energy recovery from municipal solid waste in Brazil. AB - Brazil has a large population with a high waste generation. The municipal solid waste (MSW) generated is deposited mainly in landfills. However, a considerable fraction of the waste is still improperly disposed of in dumpsters. In order to overcome this inadequate deposition, it is necessary to seek alternative routes. Between these alternatives, it is possible to quote gasification and incineration. The objective of this study is to compare, from an energetic and economic point of view, these technologies, aiming at their possible implementation in Brazilian cities. A total of two configurations were evaluated: (i) waste incineration with energy recovery and electricity production in a steam cycle; and (ii) waste gasification, where the syngas produced is used as fuel in a boiler of a steam cycle for electricity production. Simulations were performed assuming the same amount of available waste for both configurations, with a composition corresponding to the MSW from Santo Andre, Brazil. The thermal efficiencies of the gasification and incineration configurations were 19.3% and 25.1%, respectively. The difference in the efficiencies was caused by the irreversibilities associated with the gasification process, and the additional electricity consumption in the waste treatment step. The economic analysis presented a cost of electrical energy produced of 0.113 (US$ kWh-1) and 0.139 (US$ kWh-1) for the incineration and gasification plants respectively. PMID- 28893134 TI - Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5. METHODS: We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (>=150 per cubic millimeter at screening or >=300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS: In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .). PMID- 28893136 TI - Investigation on the binding mechanism of loratinib with the c-ros oncogene 1 (ROS1) receptor tyrosine kinase via molecular dynamics simulation and binding free energy calculations. AB - The c-ros oncogene 1 (ROS1) has proven to be an important cancer target for the treatment of various human cancers. The anaplastic lymphoma kinase inhibitor crizotinib has been granted approval for the treatment of patients with ROS1 positive metastatic non-small-cell lung cancer by the Food and Drug Administration on 2016. However, serious resistance due to the secondary mutation of glycine 2032 to arginine (G2032R) was developed in clinical studies. Loratinib (PF-06463922), a macrocyclic analog of crizotinib, showed significantly improved inhibitory activity against wild-type (WT) ROS1 and ROS1G2032R mutant. To provide insights into the inhibition mechanism, molecular dynamics simulations and free energy calculations were carried out for the complexes of loratinib with WT and G2032R mutated ROS1. The apo-ROS1WT and apo-ROS1G2032R systems showed similar RMSF distributions, while ROS1G2032R-loratinib showed significantly higher than that of WT ROS1-loratinib, which revealed that the binding of loratinib to ROS1G2032R significantly interfered the fluctuation of protein. Calculations of binding free energies indicate that G2032R mutation significantly reduces the binding affinity of loratinib for ROS1, which arose mostly from the increase of conformation entropy and the decrease of solvation energy. Furthermore, detailed per-residue binding free energies highlighted the increased and decreased contributions of some residues in the G2032R mutated systems. The present study revealed the detailed inhibitory mechanism of loratinib as potent WT and G2032R mutated ROS1 inhibitor, which was expected to provide a basis for rational drug design. PMID- 28893137 TI - Building Situation Awareness on the Move: Staff Monitoring Behavior in Clinic Corridors. AB - We conducted a workplace research project on staff mobility in a Swiss hospital outpatient clinic that involved extensive fieldwork and video recordings. The article describes monitoring practices and routines that staff engage in as they walk through the corridors and in and out of the clinic's rooms. The staff perform checks on on-going activity, share their observations with colleagues, and take responsive action while engaged in away-oriented walk or in specific roaming, action-seeking, rallying, and patrolling walk. We argue that these behaviors are closely associated with building and sustaining situation awareness (SA) with regard to the status of the clinic's functioning. They contribute to the coordination of a spatially distributed team that rapidly accomplishes consequential and closely interrelated activities in constantly changing circumstances. PMID- 28893138 TI - A percutaneous repair of a coronary pseudo-aneurysm, the role of the intravascular ultrasound. PMID- 28893139 TI - Tubercular gastric fistula: apropos of two cases. PMID- 28893140 TI - The Finding of Pacific Transvenid Acanthocephalan in the Arabian Gulf, with the Description of Paratrajectura longcementglandatus N. Gen., N. Sp. from Perciform Fishes and Emendation of Transvenidae. AB - The acanthocephalan Paratrajectura longcementglandatus n. gen., n. sp. (Transvenidae) is described from specimens of 2 perciform fish species, Nemipterus japonicus Bloch (Nemipteridae) and Otolithes ruber Bloch and Schneider, collected in the marine territorial waters of Iraq and Iran in the Arabian Gulf. Metal analysis of hook tip, middle, and base is also described using energy disruptive analysis for X-ray. The new genus is distinguished from the closely related genus Trajectura Pichelin and Cribb, 2001 described from wrasses (Labridae) (Perciformes) in the Pacific off Australia and Japan by having a proboscis with apical epidermal cone, long rhadinorhynchid-like tubular cement glands, relatively short and lobulated lemnisci, all proboscis hooks with prominent roots, females with subterminal gonopore and a rounded projection on the antero-dorsal end of the trunk, and males with elongate pre-equatorial testes reaching proboscis receptacle. In Trajectura, the proboscis lacks apical epidermal cone, the cement glands are pyriform or ovoid, the lemnisci are digitiform and considerably longer than the receptacle, the posterior proboscis hooks are rootless, the females have prominent finger-like trunk projection and terminal gonopore, and males with equatorial testes that may not be elongate and may be distant from the receptacle. The importance of cement glands in the diagnosis of genera and families in acanthocephalan taxonomy is stressed. Other features especially the type and arrangement of hooks on the proboscis, but not hook roots, are comparable in the 2 genera. Diagnosis of the family Transvenidae is emended. PMID- 28893141 TI - Finger-Based Numerical Skills Link Fine Motor Skills to Numerical Development in Preschoolers. AB - Previous studies investigating the association between fine-motor skills (FMS) and mathematical skills have lacked specificity. In this study, we test whether an FMS link to numerical skills is due to the involvement of finger representations in early mathematics. We gave 81 pre-schoolers (mean age of 4 years, 9 months) a set of FMS measures and numerical tasks with and without a specific finger focus. Additionally, we used receptive vocabulary and chronological age as control measures. FMS linked more closely to finger-based than to nonfinger-based numerical skills even after accounting for the control variables. Moreover, the relationship between FMS and numerical skill was entirely mediated by finger-based numerical skills. We concluded that FMS are closely related to early numerical skill development through finger-based numerical counting that aids the acquisition of mathematical mental representations. PMID- 28893142 TI - A simulation and video-based training program to address adverse childhood experiences. AB - Adverse childhood experiences (ACEs) are 10 categories of childhood abuse and maltreatment, which have a dose-response relationship with common adult health concerns seen in primary care including health risk behaviors, chronic disease, and mental illness. Many of the ACEs-associated biopsychosocial risk factors are modifiable. However, physicians may not address these issues for fear of opening "Pandora's Box", that is, a source of extensive problems for which they are not sufficiently prepared with training, resources, or time. Residents need training in how to conduct trauma-focused conversations within the limited scope of an office visit. To address this need, a 4-hour simulation and video-based training program was developed for primary care residents about how to conduct brief interventions connecting their patients' current health concerns with their experiences of ACEs. Resident participants have evaluated this program as preparatory for real-life encounters and as being designed to allow for educational mastery. This article describes a workshop presenting this training program which was given at the 37th Annual Behavioral Science Forum in Family Medicine. Five skills targeted in the program were presented and a demonstration was made of the components, that is, didactics, provider and patient videos, simulated patient encounters, trainee feedback, and facilitated discussion that encompasses targeted skills, clinical implementation, and self-care. Companion tools were shared, including the syllabus, evaluation rubric, and provider and patient resources. Participants practiced trainee feedback and discussed the challenges in implementation. PMID- 28893143 TI - Integrating mental health professionals in residencies to reduce health disparities. AB - Health disparities in primary care remain a continual challenge for both practitioners and patients alike. Integrating mental health services into routine patient care has been one approach to address such issues, including access to care, stigma of health-care providers, and facilitating underserved patients' needs. This article addresses examples of training programs that have included mental health learners and licensed providers into family medicine residency training clinics. Descriptions of these models at two Midwestern Family Medicine residency clinics in the United States are highlighted. Examples of cross training both medical residents and mental health students are described, detailing specific areas where this integration improves mental health and medical outcomes in patients. Challenges to effective integration are discussed, including larger system buy-in, medical providers' knowledge of mental health treatment, and the skills for clinical providers to possess in order to present mental health options to patients. Patients who traditionally experience multiple barriers to mental health treatment now have increased access to comprehensive care. As a result of more primary care clinics ascribing to an integrated care model of practice, providers may benefit from not only increased coordination of patient services but also utilizing behavioral health professionals to address health barriers in patients' lives. PMID- 28893144 TI - Release with or without reconstruction of the transverse carpal ligament for severe carpal tunnel syndrome: a randomized clinical trial. AB - : The objective of this study is to compare the clinical effectiveness of two surgical techniques in patients with severe unilateral idiopathic carpal tunnel syndrome. A total of 117 patients were randomized in two groups. In the experimental group ( n = 59) reconstruction of the transverse carpal ligament was performed after open retinaculum release (TCL reconstruction group). In the control group ( n = 58) only retinaculum release was performed (TCL release group). The primary outcome measure was grip strength; secondary outcome measures were pain and response to the Boston questionnaire. Significance was analysed using the t-test or Mann-Whitney test. At 6 months, the experimental group showed clinical and statistically significant improvement in grip strength and decrease in symptom severity. Retinaculum release with reconstruction of the transverse carpal ligament results in improvement of grip strength in the medium term when compared with open retinaculotomy in patients with severe unilateral idiopathic carpal tunnel syndrome. LEVEL OF EVIDENCE: II. PMID- 28893146 TI - Diagnosis and management of hook of hamate fractures. AB - : The purpose of this study was to evaluate the time to diagnosis and management of hook of hamate fractures in an era of advanced imaging. We performed a retrospective study of 51 patients treated for hook of hamate fractures. Patients were sent a quickDASH questionnaire regarding the outcomes of their treatment. Hook of hamate fractures were diagnosed with advanced imaging at a median of 27 days. Clinical findings of hook of hamate tenderness had better sensitivity than carpal tunnel-view radiographs. Nonunion occurred in 24% of patients with non operative treatment and did not occur in the operative group. Both treatment groups achieved good clinical results, with a grip strength of 80% compared with the non-injured hand and a median quickDASH score of 2. Advanced imaging improved the time to diagnosis and treatment compared to historical case series. Nonunion is common in patients treated non-operatively. LEVEL OF EVIDENCE: IV. PMID- 28893145 TI - Non-vascularized iliac bone grafting for scaphoid nonunion with avascular necrosis. AB - : We present the surgical outcomes of non-vascularized bone grafting taken from the iliac crest in 24 patients with scaphoid nonunion and avascular necrosis. The Fisk-Fernandez technique was used in 11 patients, and cancellous bone grafting was used in 13 patients. Bony union was achieved in 22 of the 24 patients. Non vascularized iliac bone grafting can be used for the surgical management of scaphoid nonunion with avascular necrosis. Although revascularization of the proximal fragment after surgery was not evaluated, bony union was confirmed in nearly all patients. LEVEL OF EVIDENCE: IV. PMID- 28893147 TI - The Polish version of the Michigan Hand Outcomes Questionnaire: Cross-cultural adaptation, reliability, construct validity, and measurement error. AB - The aims of this study were to translate the Michigan Hand Outcomes Questionnaire into the Polish language and to test the measurement properties of its quality criteria. A total of 120 patients with hand complaints completed the Polish Michigan Hand Outcomes Questionnaire and the Disabilities of the Arm, Shoulder, and Hand questionnaire on the first assessment, along with the grip test, pinch test, and pain sore assessed using a visual analogue scale during activity. After 7 days, 76 patients completed the Michigan Hand Outcomes Questionnaire the second time. The Cronbach alpha of the Michigan Hand Outcomes Questionnaire subscales ranged from 0.79 to 0.96. The intraclass correlation coefficient varied from 0.82 0.97, and the Bland-Altman method indicated the Michigan Hand Outcomes Questionnaire total score limit of agreement was -13.2-12.3 and -9.18-9.62 for the right and left hand, respectively. The construct validity revealed a moderate to strong correlation between every subscale of the Polish Michigan Hand Outcomes Questionnaire and Disabilities of the Arm, Shoulder, and Hand, but they only correlated with the grip test and the visual analogue scale, and neither correlated with the pinch test. The study demonstrated properties similar to the original version, validating the belief that the use of this questionnaire in medical practice in Poland is justified. PMID- 28893148 TI - Comparative analyses of bicyclists and motorcyclists in vehicle collisions focusing on head impact responses. AB - To investigate the differences of the head impact responses between bicyclists and motorcyclists in vehicle collisions. A series of vehicle-bicycle and vehicle motorcycle lateral impact simulations on four vehicle types at seven vehicle speeds (30, 35, 40, 45, 50, 55 and 60 km/h) and three two-wheeler moving speeds (5, 7.5 and 10 km/h for bicycle, 10, 12.5 and 15 km/h for motorcycle) were established based on PC-Crash software. To further comprehensively explore the differences, additional impact scenes with other initial conditions, such as impact angle (0, pi/3, 2pi/3 and pi) and impact position (left, middle and right part of vehicle front-end), also were supplemented. And then, extensive comparisons were accomplished with regard to average head peak linear acceleration, average head impact speed, average head peak angular acceleration, average head peak angular speed and head injury severity. The results showed there were prominent differences of kinematics and body postures for bicyclists and motorcyclists even under same impact conditions. The variations of bicyclist head impact responses with the changing of impact conditions were a far cry from that of motorcyclists. The average head peak linear acceleration, average head impact speed and average head peak angular acceleration values were higher for motorcyclists than for bicyclists in most cases, while the bicyclists received greater average head peak angular speed values. And the head injuries of motorcyclists worsened faster with increased vehicle speed. The results may provide even deeper understanding of two-wheeler safety and contribute to improve the public health affected by road traffic accidents. PMID- 28893149 TI - How the nature of the compounds present in solid and liquid compartments of activated sludge impact its rheological characteristics. AB - Although the role of the solids concentration on the rheological characteristics of sludge is greatly documented in the literature, few studies focused on the impact of the nature of these solids. How the nature of solutes can modify the solid-liquid interactions and thus the rheological properties of the sludge are also slightly explored. Thus, the objective of this study is to investigate the rheological characteristics of activated sludge in relation with the nature of the compounds present in the solid and liquid phases. Rheological measurements were carried out on raw sludge and on sludge modified by mechanical actions and/or addition of solids or solutes. The rheological properties of raw and modified sludges were measured according to flow and dynamic measurements. Results demonstrated that if suspended solid concentration affected sludge rheological parameters, the nature of the solids was quite of importance. The key role of nature and molecular weight of solutes was also highlighted. The results contribute to a better knowledge of the relationship between sludge composition and its rheological properties, which is useful for the optimization of sludge mixing, pumping or aeration and also for the improvement of sludge dewatering, notably by a relevant choice of adjuvant. PMID- 28893150 TI - Poor metacognitive awareness of belief change. AB - When people change beliefs as a result of reading a text, are they aware of these changes? This question was examined for beliefs about spanking as an effective means of discipline. In two experiments, subjects reported beliefs about spanking effectiveness during a prescreening session. In a subsequent experimental session, subjects read a one-sided text that advocated a belief consistent or inconsistent position on the topic. After reading, subjects reported their current beliefs and attempted to recollect their initial beliefs. Subjects reading a belief inconsistent text were more likely to change their beliefs than those who read a belief consistent text. Recollections of initial beliefs tended to be biased in the direction of subjects' current beliefs. In addition, the relationship between the belief consistency of the text read and accuracy of belief recollections was mediated by belief change. This belief memory bias was independent of on-line text processing and comprehension measures, and indicates poor metacognitive awareness of belief change. PMID- 28893151 TI - Dissociating Higher and Lower Order Visual Motion Systems by Priming Illusory Apparent Motion. AB - Motion processing is thought of as a hierarchical system composed of higher and lower order components. Past research has shown that these components can be dissociated using motion priming paradigms in which the lower order system produces negative priming while the higher order system produces positive priming. By manipulating various stimulus parameters, researchers have probed these two systems using bistable test stimuli that permit only two motion interpretations. Here we employ maximally ambiguous test stimuli composed of randomly refreshing pixels in a task that allows observers to report more than just two types of motion percepts. We show that even with such stimuli, motion priming can constrain the unstructured random pixel patterns into coherent percepts of positive or negative apparent motion. Moreover, we find that the higher order system is uniquely susceptible to cognitive influences, as evidenced by a significant suppression of positive priming in the presence of alternative response options. PMID- 28893152 TI - A new percutaneous technique: N-butyl cyanoacrylate adhesive for the treatment of giant saphenous vein insufficiency. AB - Background We have made a retrospective evaluation of the results of the cyanoacrylate ablation technique which has recently started to be used in the treatment of giant saphenous vein insufficiency today and in which tumescent anesthesia is not required. Methods Giant saphenous vein was treated in 50 patients between September 2015 and September 2016 by using endovenous cyanoacrylate ablation. In the procedure, tumescent anesthesia and varsity socks were not used. Control duplex ultrasound evaluation was performed in the post procedural 1st, 6th and 12th months. Venous Clinical Severity Score and Aberdeen Varicose Vein Questionnaire scores were evaluated. Results In the 50 patients who were treated, full closure was observed in giant saphenous vein in 47 (94%) patients in the 12th month control duplex ultrasound. The mean age of the patients was 46.4 (20-70) and 30 (60%) of them were female. The median Venous Clinical Severity Score scores in the 1st, 6th and 12th months were 3, 2 and 1, respectively ( p < 0.001); the median Aberdeen Varicose Vein Questionnaire scores in the 1st, 6th and 12th months were 7, 5 and 4, respectively ( p < 0.001). In the access site, two (4%) patients developed phlebitis and one (2%) developed ecchymosis. However, deep venous thrombosis, pulmonary embolism and paresthesia were not observed. Conclusion Considering the early period results in the treatment of giant saphenous vein insufficiency, cyanoacrylate ablation makes a more reliable alternative than endovenous thermal ablation methods in that it does not require tumescent anesthesia and it has a low incidence of adverse effects. PMID- 28893153 TI - Emotion-focused perspective on generalized anxiety disorder: A qualitative analysis of clients' in-session presentations. AB - OBJECTIVE: The classification of generalized anxiety disorder (GAD) is influenced by the tradition of conceptualizing disorders in the context of their clinical presentation and subsequent professional thinking around them. Our qualitative, descriptive-interpretative study uses a theoretical framework drawn from emotion focused therapy (EFT) as the basis of our interpretation of GAD clients' presentation of their difficulties. METHOD: The current research consists of an investigation into the GAD presentation based on a multiple case study observational qualitative design. In total, 93 video/audio-taped sessions from 14 clients were used for the analyses. The sessions were analyzed using an EFT case conceptualization framework. RESULTS: The findings capture common themes across the cases covering the EFT framework domains: triggers of emotional pain (e.g., trauma, rejection), problematic self-treatment (e.g., worry, self-criticism, self interruption), global distress (e.g., anxiety, low mood, somatic symptoms), apprehension/anxiety (fear of triggers and chronic painful emotions), emotional avoidance (e.g., self-distraction), behavioral avoidance (e.g., avoidance of conflict, over-compliance), core painful feelings (e.g., sadness/loneliness, shame, fear), and unmet needs (e.g., to be loved, to be acknowledged, to be protected). CONCLUSIONS: Discussion focuses on examining findings in the context of existing psychological models of GAD. The implications for practice as well as limitations of the study are also discussed. Clinical or methodological significance of this article: This is an attempt to provide an in-depth case conceptualization based on the EFT theoretical framework of the clients with GAD that attended EFT. Thus, it should contribute to clinical understanding of the presentation of the clients with GAD. Methodologically, the study uses an original qualitative approach, in which in-session presentations of 14 clients are thoroughly tracked and analyzed within an existing theoretical framework, the domains of which serve as the domains of inquiry. PMID- 28893154 TI - Anthropogenic activity-induced water quality degradation in the Loktak lake, a Ramsar site in the Indo-Burma biodiversity hotspot. AB - Wetland contributes to human well-being and poverty alleviation. The increase in human population leads to more demand for water and degradation of the water bodies around the globe, resulting in scarcity of water. The aim of the present study was to assess the impact of anthropogenic activity on the water quality of the Loktak lake. Water samples were collected seasonally, namely, monsoon, post monsoon, winter and pre-monsoon, during 2013-2014 from 10 sites. For each water sample, 20 physicochemical parameters were analysed using the American Public Health Association method. Furthermore, 11 significant parameter values were used to develop the water quality index (WQI). The result shows high concentrations of nitrite (5.45-11.83 mg/l) and nitrate (93.67-177.75 mg/l) in rivers which is beyond the permissible limit and higher compared to the Loktak. Highest turbidity was observed at Langthabal with 21 NTU, which is above the permissible limit. The WQI of the Loktak ranged from 64 to 77, while for rivers they ranged from 53 to 95, which indicates that the water is in a very poor state. The WQI values of rivers are higher compared with those of the lake, and it was identified that water from the rivers is a major reason for increase in pollution in the lake water. The study suggests the need for long-term monitoring of the lake aquatic ecosystem and identification of pollution sites for proper management of the lake water. The WQI is an important tool to enable the public and decision makers to evaluate the water quality of the Loktak lake. PMID- 28893155 TI - Genotoxic evaluation of different sizes of iron oxide nanoparticles and ionic form by SMART, Allium and comet assay. AB - In this study, the genotoxic potential of <50 nm, <100 nm iron oxide (Fe2O3) nanoparticles (IONPs) and ionic form were investigated using the wing somatic mutation and recombination test (SMART) and Allium and comet assays. In the SMART assay, different concentrations (1, 2, 5 and 10 mM) of NPs and ionic forms were fed to transheterozygous larvae of Drosophila melanogaster. No significant genotoxic effect was observed in <100 nm NPs and ionic form, while <50 nm IONPs showed genotoxicity at 1 and 10 mM concentrations. Allium cepa root meristems were exposed to five concentrations (0.001, 0.01, 0.1, 1 and 10 mM) of <50 nm and ionic forms for 4 h and three concentrations (2.5, 5 and 10 mM) for <100 nm of IONPs for 24 and 96 h. There was a statistically significant effect at 96 h at all concentrations of <100 nm IONPs. Similarly, <50 nm of IONPs and ionic forms also showed a statistically significant effect on mitotic index frequencies for all concentrations at 4 h. There was a dose-dependent increase in chromosomal abnormalities for IONPs and ionic form. Comet assay results showed time- and concentration-dependent increases in <100 nm NPs. There was a concentration dependent increase in <50 nm NPs and ionic form ( p < 0.05). Consequently, the <50 nm of Fe2O3 was found toxic compared to 100 nm Fe2O3 and ionic form. PMID- 28893156 TI - Erythrosine B and quinoline yellow dyes regulate DNA repair gene expression in human HepG2 cells. AB - Erythrosine B (ErB) is a cherry pink food colorant and is widely used in foods, drugs, and cosmetics. Quinoline yellow (QY) is a chinophthalon derivative used in cosmetic compositions for application to the skin, lips, and/or body surface. Previously, ErB and QY synthetic dyes were found to induce DNA damage in HepG2 cells. The aim of this study was to investigate the molecular basis underlying the genotoxicity attributed to ErB and QY using the RT2 Profiler polymerase chain reaction array and by analyzing the expression profile of 84 genes involved in cell cycle arrest, apoptosis, and DNA repair in HepG2 cells. ErB (70 mg/L) significantly decreased the expression of two genes ( FEN1 and REV1) related to DNA base repair. One gene ( LIG1) was downregulated and 20 genes related to ATR/ATM signaling ( ATR, RBBP8, RAD1, CHEK1, CHEK2, TOPB1), nucleotide excision repair ( ERCC1, XPA), base excision repair ( FEN1, MBD4), mismatch repair ( MLH1, MSH3, TP73), double strand break repair ( BLM), other DNA repair genes ( BRIP1, FANCA, GADD45A, REV1), and apoptosis ( BAX, PPP1R15A) were significantly increased after treatment with QY (20 mg/L). In conclusion, our data suggest that the genotoxic mechanism of ErB and QY dyes involves the modulation of genes related to the DNA repair system and cell cycle. PMID- 28893157 TI - Basal Plate Myometrial Fibers and Hypertensive Disorders of Pregnancy: A Case Control Study. AB - Introduction Basal plate myometrium (BPMYO), the pathological presence of myometrial fibers in the basal plate, is a common finding on pathological examination of the placenta, yet its clinical correlates are not well studied. As myometrial fibers are frequently located in proximity to poorly converted maternal spiral arteries, our objective was to determine whether BPMYO is associated with hypertensive disorders of pregnancy (HDP), a well-known clinical sequela of abnormal maternal artery remodeling. Methods This case-control study included women who delivered a live-born singleton gestation whose placentas were sent for pathological examination. Cases were women with HDP (gestational hypertension, preeclampsia, or HELLP syndrome) as defined by American College of Obstetricians and Gynecologists. Controls were women without HDP. Women with chronic hypertension were excluded. The primary outcome was the presence of BPMYO. Secondary outcomes included the pathologic stage of BPMYO and the incidence of pathologically defined accreta. Each outcome was compared between cases and controls in bivariable and multivariable analyses. Results Of the 306 women who met inclusion criteria, 230 (75%) had HDP. BPMYO was present in 99 (32%) of placentas. Compared to controls, cases were younger, had higher body mass index, and were more likely to have diabetes, be nulliparous, deliver preterm, and have had a prior cesarean. There were no differences in the incidence of BPMYO, stage of BPMYO, or incidence of pathologically defined accreta between cases and controls. These findings persisted after controlling for potential confounders. Conclusions Although BPMYO may be more common in the setting of abnormal placental vasculature, there is no significant association between BPMYO and HDP. PMID- 28893158 TI - Academic ethical awareness among undergraduate nursing students. AB - BACKGROUND: Academic ethical awareness is an important aspect especially for nursing students who will provide ethical nursing care to patients in future or try to tread the path of learning toward professional acknowledgement in nursing scholarship. PURPOSE: The purpose of this study was to explore academic ethical awareness and its related characteristics among undergraduate nursing students. METHODS: This study commenced the survey with cross-sectional, descriptive questions and enrolled convenient samples of 581 undergraduate nursing students from three universities in South Korea. It was investigated with structured questionnaires including general characteristics and academic ethical awareness related. Ethical considerations: This study was reviewed and approved by the Institutional Review Board at National University. FINDINGS: Academic ethical awareness was the highest regarding behaviors violating the respect or confidentiality of patients and cheating on exams, while it was the lowest for inappropriate behaviors in class. From the result of general characteristics difference, male students showed higher score than female students in relative; first-year students showed higher score than other year students; the higher score was rated from students who were highly satisfied with their major than the other not satisfied with their major; and students with low academic stress showed higher ethical awareness score than persons with higher stress. CONCLUSION: Personal behaviors were rated with low ethical awareness in relative, but items related to public rules and actual effects on patients or others were rated with higher score. Nursing satisfaction and academic stress are main factors on ethical awareness. To improve overall ethical awareness level of nursing students, it is required to provide more education about the importance of personal behaviors in class and need to improve the understanding of how it will be connected with future situation and effect. PMID- 28893159 TI - Ethics and quality care in nursing homes: Relatives' experiences. AB - BACKGROUND: A total of 71,000 people in Norway suffer from some form of dementia in 2013, of whom approximately 30,000 are in nursing homes. Several studies focus on the experiences of those who have close relatives and who are staying in a nursing home. Results show that a greater focus on cooperation between nursing staff and relatives is a central prerequisite for an increased level of care. Benefits of developing systematic collaboration practices include relief for nursing staff, less stress, and greater mutual understanding. Going through studies focusing on the experiences of nursing home patients' relatives, negative experiences are in the majority. In this study, relatives are invited to share positive experiences regarding the care of their loved ones; a slightly different perspective, in other words. AIM: The aim of the study is to investigate relatives of persons with dementia's experiences with quality care in nursing homes. METHOD: The study is a part of a larger project called Hospice values in the care for persons with dementia and is based on a qualitative design where data are generated through narrative interviews. The chosen method of analysis is the phenomenological-hermeneutical method for the study of lived experiences. Participants and research context: Participants in the project were eight relatives of persons with dementia who were living in nursing homes, long-term residences. The sampling was targeted, enrolment happened through collective invitation. All relatives interested were included. Ethical considerations: The Norwegian Regional Ethics Committee and the Norwegian Social Science Data Services approve the study. FINDINGS: Findings show that relatives have certain expectations as to how their loved ones ought to be met and looked after at the nursing home. The results show that in those cases where the expectations were met, the relatives' experiences were associated with engagement, inclusion and a good atmosphere. When the expectations were not met, the relatives experienced powerlessness, distrust and guilt. DISCUSSION: The results are discussed considering the concepts of trust, power and asymmetry. CONCLUSION: When asked about experiences with quality care, the relatives spoke both of expectations met and of expectations not met. Results in this study are important knowledge for developing units where performing quality care is the overall aim. PMID- 28893160 TI - Relationship between ethical ideology and moral judgment: Academic nurse educators' perception. AB - BACKGROUND: Ascertaining the relationship between ethical ideology, moral judgment, and ethical decision among academic nurse educators at work appears to be a challenge particularly in situations when they are faced with a need to solve an ethical problem and make a moral decision. PURPOSE: This study aims to investigate the relationship between ethical ideology, moral judgment, and ethical decision as perceived by academic nurse educators. METHODS: A descriptive correlational research design was conducted at Faculty of Nursing, Alexandria University. All academic nurse educators were included in the study (N = 220). Ethical Position Questionnaire and Questionnaire of Moral Judgment and Ethical Decisions were proved reliable to measure study variables. Ethical considerations: Approval was obtained from Ethics Committee at Faculty of Nursing, Alexandria University. Privacy and confidentiality of data were maintained and assured by obtaining subjects' informed consent. FINDINGS: This study reveals a significant positive moderate correlation between idealism construct of ethical ideology and moral judgment in terms of recognition of the behavior as an ethical issue and the magnitude of emotional consequences of the ethical situation (p < 0.001; p = 0.031) respectively. Also, there is a positive significant moderate correlation between relativism construct of ethical ideology and overall moral judgment (p = 0.010). Approximately 3.5% of the explained variance of overall moral judgment is predicted by idealism together with relativism. DISCUSSION: The findings suggest that variations in ethical position and ideology are associated with moral judgment and ethical decision. CONCLUSION: Organizations of academic nursing education should provide a supportive work environment to help their academic staff to develop their self-awareness and knowledge of their ethical position and promoting their ethical ideologies and, in turn, enhance their moral judgment as well as develop ethical reasoning and decision-making capability of nursing students. More emphasis in nursing curricula is needed on ethical concepts for developing nursing competencies. PMID- 28893162 TI - Emotional Connection of Military Couples after 16 Years of War: Integrating Pastoral Counseling and Evidence-Based Theory. AB - Sixteen years of war created significant challenges for military couples and seems to contribute to their relational distress. Military couples seek out pastoral counselors for assistance with their relational distress. Many of these pastoral counselors are military chaplains or pastors serving close to military bases. The integration of pastoral counseling with evidence-based theory is presented as an option to serve military couples in their relational distress. Emotionally Focused Couple Therapy is presented as an example. PMID- 28893164 TI - New Film Releases. PMID- 28893165 TI - Taking A Stand. PMID- 28893166 TI - Window Horses: The Poetic Persian Epiphany of Rosie Ming (2016). PMID- 28893167 TI - The Essential Math of Love. AB - The essential math of love is subtraction; to stop doing those things that are harmful to ourselves and to others. PMID- 28893168 TI - An e-Chart Review of Chaplains' Interventions and Outcomes: A Quality Improvement and Documentation Practice Enhancement Project. AB - In Canada, the spiritual care landscape in health care settings is becoming more regulated and standardized documentation is part of this rigorous environment. Staff chaplains at The Ottawa Hospital participated in a Quality Improvement project that aimed to advance patient-centered care through better charting practices. A sample of 104 spiritual-care assessments that had been posted on the patient electronic health record was examined. This chart review focused on chaplains' activities that were reported as interventions as well as chaplain reported outcomes for the patient. These interventions and outcomes were coded into discreet categories in order to get a better sense of the activities and the impact of their work. The chaplains' electronic charting content and practices were evaluated. Chaplains found that the Quality Improvement process was beneficial as they updated their electronic templates in order to meet the new reporting requirements of the College of Registered Psychotherapists of Ontario. PMID- 28893169 TI - Final Goodbyes. PMID- 28893170 TI - Recent Progress in Chaplaincy-Related Research. AB - In light of the continued growth of chaplaincy-related research this paper presents an overview of important findings. The review summarizes research in six broad areas: what chaplains do; the importance of religion and spiritual care to patients and families; the impact of chaplains' spiritual care on the patient experience; the impact of chaplain care on other patient outcomes; spiritual needs and chaplain care in palliative and end of life care; and chaplain care for staff colleagues. It concludes with a description of several innovative and important new studies of chaplain care and notes areas for future investigation. PMID- 28893171 TI - Hospital Characteristics Affecting HealthCare Chaplaincy and the Provision of Chaplaincy Care in the United States: 2004 vs. 2016. AB - This study replicates, expands and analyzes a 2004 survey examining six hospital characteristics influencing three measures of chaplain employment in large, small, for-profit and nonprofit hospitals. The relationship between hospital characteristics and hiring Board Certified Chaplains was minor and inconsistent across time. The results indicate that religiously affiliated hospitals employed more full-time chaplains and that chaplain full-time equivalents were inversely related to hospital size in both surveys. The current survey suggests that urban and religiously affiliated hospitals were more likely to hire chaplains. The sampling method proved problematic, precluding meaningful conclusions but the study focus and questions remain important for future investigation based on this pilot effort. PMID- 28893172 TI - The Journal of Pastoral Care & Counseling Quiz September 2017. PMID- 28893173 TI - Appropriate homoplasy metrics in linked SSRs to predict an underestimation of demographic expansion times. AB - BACKGROUND: Homoplasy affects demographic inference estimates. This effect has been recognized and corrective methods have been developed. However, no studies so far have defined what homoplasy metrics best describe the effects on demographic inference, or have attempted to estimate such metrics in real data. Here we study how homoplasy in chloroplast microsatellites (cpSSR) affects inference of population expansion time. cpSSRs are popular markers for inferring historical demography in plants due to their high mutation rate and limited recombination. RESULTS: In cpSSRs, homoplasy is usually quantified as the probability that two markers or haplotypes that are identical by state are not identical by descent (Homoplasy index, P). Here we propose a new measure of multi locus homoplasy in linked SSR called Distance Homoplasy (DH), which measures the proportion of pairwise differences not observed due to homoplasy, and we compare it to P and its per cpSSR locus average, which we call Mean Size Homoplasy (MSH). We use simulations and analytical derivations to show that, out of the three homoplasy metrics analyzed, MSH and DH are more correlated to changes in the population expansion time and to the underestimation of that demographic parameter using cpSSR. We perform simulations to show that Approximate Bayesian Computation (ABC) can be used to obtain reasonable estimates of MSH and DH. Finally, we use ABC to estimate the expansion time, MSH and DH from a chloroplast SSR dataset in Pinus caribaea. To our knowledge, this is the first time that homoplasy has been estimated in population genetic data. CONCLUSIONS: We show that MSH and DH should be used to quantify how homoplasy affects estimates of population expansion time. We also demonstrate how ABC provides a methodology to estimate homoplasy in population genetic data. PMID- 28893174 TI - Antiproliferative factor (APF) binds specifically to sites within the cytoskeleton-associated protein 4 (CKAP4) extracellular domain. AB - BACKGROUND: Antiproliferative factor (APF) is a sialoglycopeptide elevated in the urine of patients with interstitial cystitis-a chronic, painful bladder disease. APF inhibits the proliferation of normal bladder epithelial cells and cancer cells in vitro, presumably by binding to its cellular receptor, cytoskeleton associated-protein 4 (CKAP4); however, the biophysical interaction of APF with CKAP4 has not been characterized previously. In this study, we used surface plasmon resonance (SPR) to explore the binding kinetics of the interaction of APF and as-APF (a desialylated APF analogue with full activity) to CKAP4. RESULTS: We immobilized non-glycosylated APF (TVPAAVVVA) to the Fc1 channel as the control and as-APF to Fc2 channel as the ligand in order to measure the binding of CKAP4 recombinant proteins encompassing only the extracellular domain (Aa 127-602) or the extracellular domain plus the transmembrane domain (Aa 106-602). Positive binding was detected to both CKAP4126-602 and CKAP4106-602, suggesting that as APF can bind specifically to CKAP4 and that the potential binding site(s) are located within the extracellular domain. To identify the primary APF binding site(s) within the CKAP4 extracellular domain, deletion mutants were designed according to structural predictions, and the purified recombinant proteins were immobilized on a CM5 chip through amine-coupling to measure as-APF binding activity. Importantly, both CKAP4127-360 and CKAP4361-524 exhibited a fast association rate (k on ) and a slow dissociation rate (k off ), thus generating high binding affinity and suggesting that both regions contribute relatively equally to overall as-APF binding. Therefore, two or more as-APF binding sites may exist within the Aa 127-524 region of the CKAP4 extracellular domain. CONCLUSIONS: We determined that the CKAP4127-360 and CKAP4361-524 mutants exhibit improved binding activity to as-APF as compared to the full-length extracellular domain, making it possible to detect low concentrations of as-APF in urine, thereby establishing a foundation for a non-invasive diagnostic assay for IC. Further, these data have revealed novel APF binding site(s) suggesting that targeting this region of CKAP4 to inhibit APF binding may be a useful strategy for treating IC-related bladder pathology. PMID- 28893175 TI - Chronic kidney disease and diabetes associated with long-term outcomes in patients receiving percutaneous coronary intervention. AB - BACKGROUND: The effect of diabetes mellitus (DM) and chronic kidney disease (CKD) on long-term outcomes in patients receiving percutaneous coronary intervention (PCI) is unclear. METHODS: A total of 1394 patients who underwent PCI were prospectively enrolled and divided into 4 groups according to the presence or absence of DM or CKD. Baseline characteristics, risk factors, medications, and angiographic findings were compared. Determinants of long-term outcomes in patients undergoing PCI were analyzed. RESULTS: Patients with DM and CKD had the highest all-cause mortality and cardiovascular mortality (both P < 0.01) but there were no differences existed in myocardial infarction (MI) or repeated PCI among the 4 groups (P = 0.19, P = 0.87, respectively). Patients with DM and CKD had the lowest even-free rate of all-cause mortality, cardiovascular mortality, MI, and repeated PCI (P < 0.001, P < 0.001, P < 0.001, and P = 0.002, respectively). In the Cox proportional hazard model, patients with both DM and CKD had the highest risk of all-cause mortality (HR: 3.25, 95% CI: 1.85-5.59), cardiovascular mortality (HR: 3.58, 95% CI: 1.97-6.49), MI (HR: 2.43, 95% CI: 1.23-4.08), and repeated PCI (HR: 1.79, 95% CI: 1.33-2.41). Patients with CKD alone had the second highest risk of all-cause mortality (HR: 2.04, 95% CI: 1.15 3.63), cardiovascular mortality (HR: 2.13, 95% CI: 1.13-4.01), and repeated PCI (HR: 1.47, 95% CI: 1.09-1.97). CONCLUSIONS: DM and CKD had additive effect on adverse long-term outcomes in patients receiving PCI; CKD was a more significant adverse predictor than DM. PMID- 28893176 TI - The path to re-evolve cooperation is constrained in Pseudomonas aeruginosa. AB - BACKGROUND: A common form of cooperation in bacteria is based on the secretion of beneficial metabolites, shareable as public good among cells within a group. Because cooperation can be exploited by "cheating" mutants, which contribute less or nothing to the public good, there has been great interest in understanding the conditions required for cooperation to remain evolutionarily stable. In contrast, much less is known about whether cheats, once fixed in the population, are able to revert back to cooperation when conditions change. Here, we tackle this question by subjecting experimentally evolved cheats of Pseudomonas aeruginosa, partly deficient for the production of the iron-scavenging public good pyoverdine, to conditions previously shown to favor cooperation. RESULTS: Following approximately 200 generations of experimental evolution, we screened 720 evolved clones for changes in their pyoverdine production levels. We found no evidence for the re-evolution of full cooperation, even in environments with increased spatial structure, and reduced costs of public good production - two conditions that have previously been shown to maintain cooperation. In contrast, we observed selection for complete abolishment of pyoverdine production. The patterns of complete trait degradation were likely driven by "cheating on cheats" in unstructured, iron-limited environments where pyoverdine is important for growth, and selection against a maladaptive trait in iron-rich environments where pyoverdine is superfluous. CONCLUSIONS: Our study shows that the path to re evolve public-goods cooperation can be constrained. While a limitation of the number of mutational targets potentially leading to reversion might be one reason for the observed pattern, an alternative explanation is that the selective conditions required for revertants to spread from rarity are much more stringent than those needed to maintain cooperation. PMID- 28893177 TI - Integrated application of transcriptomics and metabolomics provides insights into glycogen content regulation in the Pacific oyster Crassostrea gigas. AB - BACKGROUND: The Pacific oyster Crassostrea gigas is an important marine fishery resource, which contains high levels of glycogen that contributes to the flavor and the quality of the oyster. However, little is known about the molecular and chemical mechanisms underlying glycogen content differences in Pacific oysters. Using a homogeneous cultured Pacific oyster family, we explored these regulatory networks at the level of the metabolome and the transcriptome. RESULTS: Oysters with the highest and lowest natural glycogen content were selected for differential transcriptome and metabolome analysis. We identified 1888 differentially-expressed genes, seventy-five differentially-abundant metabolites, which are part of twenty-seven signaling pathways that were enriched using an integrated analysis of the interaction between the differentially-expressed genes and the differentially-abundant metabolites. Based on these results, we found that a high expression of carnitine O-palmitoyltransferase 2 (CPT2), indicative of increased fatty acid degradation, is associated with a lower glycogen content. Together, a high level of expression of phosphoenolpyruvate carboxykinase (PEPCK), and high levels of glucogenic amino acids likely underlie the increased glycogen production in high-glycogen oysters. In addition, the higher levels of the glycolytic enzymes hexokinase (HK) and pyruvate kinase (PK), as well as of the TCA cycle enzymes malate dehydrogenase (MDH) and pyruvate carboxylase (PYC), imply that there is a concomitant up-regulation of energy metabolism in high glycogen oysters. High-glycogen oysters also appeared to have an increased ability to cope with stress, since the levels of the antioxidant glutathione peroxidase enzyme 5 (GPX5) gene were also increased. CONCLUSION: Our results suggest that amino acids and free fatty acids are closely related to glycogen content in oysters. In addition, oysters with a high glycogen content have a greater energy production capacity and a greater ability to cope with stress. These findings will not only provide insights into the molecular mechanisms underlying oyster quality, but also promote research into the molecular breeding of oysters. PMID- 28893178 TI - Evaluation design of Urban Health Centres Europe (UHCE): preventive integrated health and social care for community-dwelling older persons in five European cities. AB - BACKGROUND: Older persons often have interacting physical and social problems and complex care needs. An integrated care approach in the local context with collaborations between community-, social-, and health-focused organisations can contribute to the promotion of independent living and quality of life. In the Urban Health Centres Europe (UHCE) project, five European cities (Greater Manchester, United Kingdom; Pallini (in Greater Athens Area), Greece; Rijeka, Croatia; Rotterdam, the Netherlands; and Valencia, Spain) develop and implement a care template that integrates health and social care and includes a preventive approach. The UHCE project includes an effect and process evaluation. METHODS: In a one-year pre-post controlled trial, in each city 250 participants aged 75+ years are recruited to receive the UHCE approach and are compared with 250 participants who receive 'care as usual'. Benefits of UHCE approach in terms of healthy life styles, fall risk, appropriate medication use, loneliness level and frailty, and in terms of level of independence and health-related quality of life and health care use are assessed. A multilevel modeling approach is used for the analyses. The process evaluation is used to provide insight into the reach of the target population, the extent to which elements of the UHCE approach are executed as planned and the satisfaction of the participants. DISCUSSION: The UHCE project will provide new insight into the feasibility and effectiveness of an integrated care approach for older persons in different European settings. TRIAL REGISTRATION: ISRCTN registry number is ISRCTN52788952 . Date of registration is 13/03/2017. PMID- 28893179 TI - Conservation and diversification of small RNA pathways within flatworms. AB - BACKGROUND: Small non-coding RNAs, including miRNAs, and gene silencing mediated by RNA interference have been described in free-living and parasitic lineages of flatworms, but only few key factors of the small RNA pathways have been exhaustively investigated in a limited number of species. The availability of flatworm draft genomes and predicted proteomes allowed us to perform an extended survey of the genes involved in small non-coding RNA pathways in this phylum. RESULTS: Overall, findings show that the small non-coding RNA pathways are conserved in all the analyzed flatworm linages; however notable peculiarities were identified. While Piwi genes are amplified in free-living worms they are completely absent in all parasitic species. Remarkably all flatworms share a specific Argonaute family (FL-Ago) that has been independently amplified in different lineages. Other key factors such as Dicer are also duplicated, with Dicer-2 showing structural differences between trematodes, cestodes and free living flatworms. Similarly, a very divergent GW182 Argonaute interacting protein was identified in all flatworm linages. Contrasting to this, genes involved in the amplification of the RNAi interfering signal were detected only in the ancestral free living species Macrostomum lignano. We here described all the putative small RNA pathways present in both free living and parasitic flatworm lineages. CONCLUSION: These findings highlight innovations specifically evolved in platyhelminths presumably associated with novel mechanisms of gene expression regulation mediated by small RNA pathways that differ to what has been classically described in model organisms. Understanding these phylum-specific innovations and the differences between free living and parasitic species might provide clues to adaptations to parasitism, and would be relevant for gene silencing technology development for parasitic flatworms that infect hundreds of million people worldwide. PMID- 28893180 TI - Annexin A2 (ANXA2) interacts with nonstructural protein 1 and promotes the replication of highly pathogenic H5N1 avian influenza virus. AB - BACKGROUND: Non-structural protein 1 (NS1) is a multifunctional protein and a crucial regulatory factor in the replication and pathogenesis of avian influenza virus (AIV). Studies have shown that NS1 can interact with a variety of host proteins to modulate the viral life cycle. We previously generated a monoclonal antibody against NS1 protein; In the current research study, using this antibody, we immunoprecipitated host proteins that interact with NS1 to better understand the roles played by NS1 in communications between virus and host. RESULTS: Co immunoprecipitation experiments identified annexin A2 (ANXA2) as a target molecule interacting with NS1. Results from confocal laser scanning microscopy indicated that NS1 co-localized with ANXA2 in the cell cytoplasm. Overexpression of ANXA2 significantly increased the titer of H5N1 subtype HPAIV, whereas siRNA mediated knockdown of ANXA2 markedly inhibited the expression of viral proteins and reduced the progeny virus titer. CONCLUSIONS: Our results indicate that ANXA2 interacts with NS1 and ANXA2 expression increases HPAIV replication. PMID- 28893181 TI - Meeting psychosocial needs for persons with dementia in home care services - a qualitative study of different perceptions and practices among health care providers. AB - BACKGROUND: The majority of persons with dementia are home-dwelling. To enable these persons to stay in their own homes as long as possible, a holistic, individual and flexible care is recommended. Despite a requirement for meeting psychological, social and physical needs, home care services seem to focus on patients' physical needs. Accordingly, the aim of this study was to explore how the psychosocial needs of home-dwelling, older persons with dementia were perceived, emphasized and met by home care services. METHODS: A descriptive, qualitative approach was used. Data were collected through semi-structured focus group interviews with 24 health care providers in home care services from four municipalities. Data were analysed using systematic text condensation. RESULTS: This study showed major differences in how health care providers perceived the psychosocial needs of older home-dwelling persons with dementia and how they perceived their responsibilities for meeting those psychosocial needs. The differences in the health care providers' perceptions seemed to significantly influence the provided care. Three co-existing logics of care were identified: the physical need-oriented logic, the renouncement logic and the integrated logic. CONCLUSIONS: The differences in how health care providers perceived the psychosocial needs of persons with dementia and their responsibilities for meeting those needs, influenced how the psychosocial needs were met. These differences indicates a need for a clarification of how psychosocial needs should be conceptualized and who should be responsible for meeting these needs. Further, increased competence and increased consciousness of psychosocial needs and how those needs can be met, are essential for delivering high-quality holistic care that enables persons with dementia to live in their own home for as long as possible. PMID- 28893182 TI - The dynamic landscape of gene regulation during Bombyx mori oogenesis. AB - BACKGROUND: Oogenesis in the domestic silkworm (Bombyx mori) is a complex process involving previtellogenesis, vitellogenesis and choriogenesis. During this process, follicles show drastic morphological and physiological changes. However, the genome-wide regulatory profiles of gene expression during oogenesis remain to be determined. RESULTS: In this study, we obtained time-series transcriptome data and used these data to reveal the dynamic landscape of gene regulation during oogenesis. A total of 1932 genes were identified to be differentially expressed among different stages, most of which occurred during the transition from late vitellogenesis to early choriogenesis. Using weighted gene co-expression network analysis, we identified six stage-specific gene modules that correspond to multiple regulatory pathways. Strikingly, the biosynthesis pathway of the molting hormone 20-hydroxyecdysone (20E) was enriched in one of the modules. Further analysis showed that the ecdysteroid 20-hydroxylase gene (CYP314A1) of steroidgenesis genes was mainly expressed in previtellogenesis and early vitellogenesis. However, the 20E-inactivated genes, particularly the ecdysteroid 26-hydroxylase encoding gene (Cyp18a1), were highly expressed in late vitellogenesis. These distinct expression patterns between 20E synthesis and catabolism-related genes might ensure the rapid decline of the hormone titer at the transition point from vitellogenesis to choriogenesis. In addition, we compared landscapes of gene regulation between silkworm (Lepidoptera) and fruit fly (Diptera) oogeneses. Our results show that there is some consensus in the modules of gene co-expression during oogenesis in these insects. CONCLUSIONS: The data presented in this study provide new insights into the regulatory mechanisms underlying oogenesis in insects with polytrophic meroistic ovaries. The results also provide clues for further investigating the roles of epigenetic reconfiguration and circadian rhythm in insect oogenesis. PMID- 28893183 TI - Antimicrobial resistance in Africa: a systematic review. AB - BACKGROUND: Antimicrobial resistance (AMR) is widely acknowledged as a global problem, yet in many parts of the world its magnitude is still not well understood. This review, using a public health focused approach, aimed to understand and describe the current status of AMR in Africa in relation to common causes of infections and drugs recommended in WHO treatment guidelines. METHODS: PubMed, EMBASE and other relevant databases were searched for recent articles (2013-2016) in accordance with the PRISMA guidelines. Article retrieval and screening were done using a structured search string and strict inclusion/exclusion criteria. Median and interquartile ranges of percent resistance were calculated for each antibiotic-bacterium combination. RESULTS: AMR data was not available for 42.6% of the countries in the African continent. A total of 144 articles were included in the final analysis. 13 Gram negative and 5 Gram positive bacteria were tested against 37 different antibiotics. Penicillin resistance in Streptococcus pneumoniae was reported in 14/144studies (median resistance (MR): 26.7%). Further 18/53 (34.0%) of Haemophilus influenza isolates were resistant to amoxicillin. MR of Escherichia coli to amoxicillin, trimethoprim and gentamicin was 88.1%, 80.7% and 29.8% respectively. Ciprofloxacin resistance in Salmonella Typhi was rare. No documented ceftriaxone resistance in Neisseria gonorrhoeae was reported, while the MR for quinolone was 37.5%. Carbapenem resistance was common in Acinetobacter spp. and Pseudomonas aeruginosa but uncommon in Enterobacteriaceae. CONCLUSION: Our review highlights three important findings. First, recent AMR data is not available for more than 40% of the countries. Second, the level of resistance to commonly prescribed antibiotics was significant. Third, the quality of microbiological data is of serious concern. Our findings underline that to conserve our current arsenal of antibiotics it is imperative to address the gaps in AMR diagnostic standardization and reporting and use available information to optimize treatment guidelines. PMID- 28893184 TI - The Canadian HIV and aging cohort study - determinants of increased risk of cardio-vascular diseases in HIV-infected individuals: rationale and study protocol. AB - BACKGROUND: With potent antiretroviral drugs, HIV infection is becoming a chronic disease. Emergence of comorbidities, particularly cardiovascular disease (CVD) has become a leading concern for patients living with the infection. We hypothesized that the chronic and persistent inflammation and immune activation associated with HIV disease leads to accelerated aging, characterized by CVD. This will translate into higher incidence rates of CVD in HIV infected participants, when compared to HIV negative participants, after adjustment for traditional CVD risk factors. When characterized further using cardiovascular imaging, biomarkers, immunological and genetic profiles, CVD associated with HIV will show different characteristics compared to CVD in HIV-negative individuals. METHODS/DESIGN: The Canadian HIV and Aging cohort is a prospective, controlled cohort study funded by the Canadian Institutes of Health Research. It will recruit patients living with HIV who are aged 40 years or older or have lived with HIV for 15 years or more. A control population, frequency matched for age, sex, and smoking status, will be recruited from the general population. Patients will attend study visits at baseline, year 1, 2, 5 and 8. At each study visit, data on complete medical and pharmaceutical history will be captured, along with anthropometric measures, a complete physical examination, routine blood tests and electrocardiogram. Consenting participants will also contribute blood samples to a research biobank. The primary outcome is incidence of a composite of: myocardial infarction, coronary revascularization, stroke, hospitalization for angina or congestive heart failure, revascularization or amputation for peripheral artery disease, or cardiovascular death. Preplanned secondary outcomes are all-cause mortality, incidence of the metabolic syndrome, incidence of type 2 diabetes, incidence of renal failure, incidence of abnormal bone mineral density and body fat distribution. Patients participating to the cohort will be eligible to be enrolled in four pre-planned sub-studies of cardiovascular imaging, glucose metabolism, immunological and genetic risk profile. DISCUSSION: The Canadian HIV and Aging Cohort will provide insights on pathophysiological pathways leading to premature CVD for patients living with HIV. PMID- 28893186 TI - Determining the optimal number of independent components for reproducible transcriptomic data analysis. AB - BACKGROUND: Independent Component Analysis (ICA) is a method that models gene expression data as an action of a set of statistically independent hidden factors. The output of ICA depends on a fundamental parameter: the number of components (factors) to compute. The optimal choice of this parameter, related to determining the effective data dimension, remains an open question in the application of blind source separation techniques to transcriptomic data. RESULTS: Here we address the question of optimizing the number of statistically independent components in the analysis of transcriptomic data for reproducibility of the components in multiple runs of ICA (within the same or within varying effective dimensions) and in multiple independent datasets. To this end, we introduce ranking of independent components based on their stability in multiple ICA computation runs and define a distinguished number of components (Most Stable Transcriptome Dimension, MSTD) corresponding to the point of the qualitative change of the stability profile. Based on a large body of data, we demonstrate that a sufficient number of dimensions is required for biological interpretability of the ICA decomposition and that the most stable components with ranks below MSTD have more chances to be reproduced in independent studies compared to the less stable ones. At the same time, we show that a transcriptomics dataset can be reduced to a relatively high number of dimensions without losing the interpretability of ICA, even though higher dimensions give rise to components driven by small gene sets. CONCLUSIONS: We suggest a protocol of ICA application to transcriptomics data with a possibility of prioritizing components with respect to their reproducibility that strengthens the biological interpretation. Computing too few components (much less than MSTD) is not optimal for interpretability of the results. The components ranked within MSTD range have more chances to be reproduced in independent studies. PMID- 28893185 TI - Factors that influence the levels of cerebrospinal fluid biomarkers in memory clinic patients. AB - BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid beta (Abeta), phospho tau (P-tau) and total tau (T-tau) are used increasingly to support a clinical diagnosis of Alzheimer's disease. The diagnostic power of these biomarkers has been reported to vary among different studies' results. The results are poorer when heterogeneous groups of patients have been included compared to studies where patients with Alzheimer's dementia (AD) and healthy controls have been studied. The aim of this study was to examine if age, APOE genotype and sex were associated with the levels of CSF biomarkers among patients referred to a memory clinic. METHODS: We included 257 patients from two memory clinics who had been assessed for dementia, including lumbar puncture. RESULTS: The mean age of the patients was 68.1 (SD: 8.0) years; 50.2% were women and 66.5% were APOE epsilon4 positive. Of these patients, 80.5% were diagnosed with AD or amnestic MCI. Both APOE epsilon4 and increasing age were associated with decreasing levels of Abeta, but not the levels of the tau proteins. In multiple regression analyses, disease stage, defined as a MMSE >=25 or <25, influenced factors associated with the CSF biomarkers. Among those with MMSE score >= 25, age, APOE epsilon4 genotype, and MMSE score, in addition to a diagnosis of AD, were associated with Abeta level, with an explained variance of 0.43. When using P-tau or T-tau as a dependent variable, the presence of one or two APOE epsilon4 alleles, and MMSE score influenced the results, in addition to the diagnosis of AD. The explained variance was lower for P-tau (0.26) and for T-tau (0.32). Among those with MMSE <25, these variables explained very little of the variance. There were no gender differences. CONCLUSIONS: We found that factors in addition to a diagnosis of AD, were associated with the levels of CSF biomarkers. Among those with MMSE >=25, lower levels of Abeta were associated with several factors including increasing age. This is not reflected in clinical practice, where age specific cutoffs exist only for T-tau. In this study, age was not associated with the levels of tau proteins. PMID- 28893187 TI - Does dual task training improve walking performance of older adults with concern of falling? AB - BACKGROUND: Older adults with concerns of falling show decrements of gait stability under single (ST) and dual task (DT) conditions. To compare the effects of a DT training integrating task managing strategies for independent living older adults with and without concern about falling (CoF) to a non-training control group on walking performance under ST and DT conditions. METHODS: Single center parallel group single blind randomized controlled trial with group-based interventions (DT-managing balance training) compared to a control group (Ninety five independent living older adults; 71.5 +/- 5.2 years). A progressive DT training (12 sessions; 60 min each; 12 weeks) including task-managing strategies was compared to a non-training control group. SETTING: group based intervention for independent living elderly in a gym. ST and DT walking (visual verbal Stroop task) were measured on a treadmill. Gait parameters (step length, step width, and gait line) and cognitive performance while walking were compared with a 2x2x2 Repeated Measures Analyses of Variance. RESULTS: Participants in the intervention group showed an increased step length under ST and DT conditions following the intervention, for both people with and without CoF compared to their respective control groups. Foot rolling movement and cognitive performance while walking however only improved in participants without CoF. CONCLUSIONS: The results showed that DT managing training can improve walking performance under ST and DT conditions in people with and without CoF. Additional treatment to directly address CoF, such as cognitive behavioural therapy, should be considered to further improve the cautious gait pattern (as evidenced by reduced foot rolling movements). TRIAL REGISTRATION: The study was retrospectively registered in the German Clinical Trials Register (DRKS; Identification number DRKS00012382 , 11.05.2017). PMID- 28893188 TI - Developing genome-reduced Pseudomonas chlororaphis strains for the production of secondary metabolites. AB - BACKGROUND: The current chassis organisms or various types of cell factories have considerable advantages and disadvantages. Therefore, it is necessary to develop various chassis for an efficient production of different bioproducts from renewable resources. In this context, synthetic biology offers unique potentialities to produce value-added products of interests. Microbial genome reduction and modification are important strategies for constructing cellular chassis and cell factories. Many genome-reduced strains from Escherichia coli, Bacillus subtilis, Corynebacterium glutamicum and Streptomyces, have been widely used for the production of amino acids, organic acids, and some enzymes. Some Pseudomonas strains could serve as good candidates for ideal chassis cells since they grow fast and can produce many valuable metabolites with low nutritional requirements and strong environmental adaptability. Pseudomonas chlororaphis GP72 is a non-pathogenic plant growth-promoting rhizobacterium that possesses capacities of tolerating various environmental stresses and synthesizing many kinds of bioactive compounds with high yield. These include phenazine-1 carboxylic acid (PCA) and 2-hydroxyphenazine (2-OH-PHZ), which exhibit strong bacteriostatic and antifungal activity toward some microbial pathogens. RESULTS: We depleted 685 kb (10.3% of the genomic sequence) from the chromosome of P. chlororaphis GP72(rpeA-) by a markerless deletion method, which included five secondary metabolic gene clusters and 17 strain-specific regions (525 non essential genes). Then we characterized the 22 multiple-deletion series (MDS) strains. Growth characteristics, production of phenazines and morphologies were changed greatly in mutants with large-fragment deletions. Some of the genome reduced P. chlororaphis mutants exhibited more productivity than the parental strain GP72(rpeA-). For example, strain MDS22 had 4.4 times higher production of 2-OH-PHZ (99.1 mg/L) than strain GP72(rpeA-), and the specific 2-OH-PHZ production rate (mmol/g/h) increased 11.5-fold. Also and MDS10 had the highest phenazine production (852.0 mg/L) among all the studied strains with a relatively high specific total phenazine production rate (0.0056 g/g/h). CONCLUSIONS: In conclusion, P. chlororaphis strains with reduced genome performed better in production of secondary metabolites than the parent strain. The newly developed mutants can be used for the further genetic manipulation to construct chassis cells with the less complex metabolic network, better regulation and more efficient productivity for diverse biotechnological applications. PMID- 28893189 TI - Differentially expressed genes during the imbibition of dormant and after-ripened seeds - a reverse genetics approach. AB - BACKGROUND: Seed dormancy, defined as the incapability of a viable seed to germinate under favourable conditions, is an important trait in nature and agriculture. Despite extensive research on dormancy and germination, many questions about the molecular mechanisms controlling these traits remain unanswered, likely due to its genetic complexity and the large environmental effects which are characteristic of these quantitative traits. To boost research towards revealing mechanisms in the control of seed dormancy and germination we depend on the identification of genes controlling those traits. METHODS: We used transcriptome analysis combined with a reverse genetics approach to identify genes that are prominent for dormancy maintenance and germination in imbibed seeds of Arabidopsis thaliana. Comparative transcriptomics analysis was employed on freshly harvested (dormant) and after-ripened (AR; non-dormant) 24-h imbibed seeds of four different DELAY OF GERMINATION near isogenic lines (DOGNILs) and the Landsberg erecta (Ler) wild type with varying levels of primary dormancy. T DNA knock-out lines of the identified genes were phenotypically investigated for their effect on dormancy and AR. RESULTS: We identified conserved sets of 46 and 25 genes which displayed higher expression in seeds of all dormant and all after ripened DOGNILs and Ler, respectively. Knock-out mutants in these genes showed dormancy and germination related phenotypes. CONCLUSIONS: Most of the identified genes had not been implicated in seed dormancy or germination. This research will be useful to further decipher the molecular mechanisms by which these important ecological and commercial traits are regulated. PMID- 28893190 TI - Canonical and non-canonical JAK/STAT transcriptional targets may be involved in distinct and overlapping cellular processes. AB - BACKGROUND: The Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway has been well-characterized as a crucial signal transduction cascade that regulates vital biological responses including development, immunity and oncogenesis. Additionally to its canonical pathway that uses the phosphorylated form of the STAT transcription factor, recently the non-canonical pathway involving heterochromatin formation by unphosphorylated STAT was recently uncovered. Considering the significant role of the JAK/STAT pathway, we used the simple Drosophila system in which the non-canonical pathway was initially characterized, to compare putative canonical versus non-canonical transcriptional targets across the genome. We analyzed microarray expression patterns of wildtype, Jak gain- and loss-of-function mutants, as well as the Stat loss-of function mutant during embryogenesis, since the contribution of the canonical signal transduction pathway has been well-characterized in these contexts. Previous studies have also demonstrated that Jak gain-of-function and Stat mutants counter heterochromatin silencing to de-repress target genes by the non canonical pathway. RESULTS: Compared to canonical target genomic loci, non canonical targets were significantly more associated with sites enriched with heterochromatin-related factors (p = 0.004). Furthermore, putative canonical and non-canonical transcriptional targets identified displayed some differences in biological pathways they regulate, as determined by Gene Ontology (GO) enrichment analyses. Canonical targets were enriched mainly with genes relevant to development and immunity, as expected, whereas the non-canonical target gene set mainly showed enrichment of genes for various metabolic responses and stress response, highlighting the possibility that some differences may exist between the two loci. CONCLUSIONS: Canonical and non-canonical JAK/STAT genes may regulate distinct and overlapping sets of genes and may perform specific overall functions in physiology. Further studies at different developmental stages, or using distinct tissues may identify additional targets and provide insight into which gene targets are unique to the canonical or non-canonical pathway. PMID- 28893191 TI - Recent expansion and adaptive evolution of the carcinoembryonic antigen family in bats of the Yangochiroptera subgroup. AB - BACKGROUND: Expansions of gene families are predictive for ongoing genetic adaptation to environmental cues. We describe such an expansion of the carcinoembryonic antigen (CEA) gene family in certain bat families. Members of the CEA family in humans and mice are exploited as cellular receptors by a number of pathogens, possibly due to their function in immunity and reproduction. The CEA family is composed of CEA-related cell adhesion molecules (CEACAMs) and secreted pregnancy-specific glycoproteins (PSGs). PSGs are almost exclusively expressed by trophoblast cells at the maternal-fetal interface. The reason why PSGs exist only in a minority of mammals is still unknown. RESULTS: Analysis of the CEA gene family in bats revealed that in certain bat families, belonging to the subgroup Yangochiroptera but not the Yinpterochiroptera subgroup an expansion of the CEA gene family took place, resulting in approximately one hundred CEA family genes in some species of the Vespertilionidae. The majority of these genes encode secreted PSG-like proteins (further referred to as PSG). Remarkably, we found strong evidence that the ligand-binding domain (IgV-like domain) of PSG is under diversifying positive selection indicating that bat PSGs may interact with structurally highly variable ligands. Such ligands might represent bacterial or viral pathogen adhesins. We have identified two distinct clusters of PSGs in three Myotis species. The two PSG cluster differ in the amino acids under positive selection. One cluster was only expanded in members of the Vespertilionidae while the other was found to be expanded in addition in members of the Miniopteridae and Mormoopidae. Thus one round of PSG expansion may have occurred in an ancestry of all three families and a second only in Vespertilionidae. Although maternal ligands of PSGs may exist selective challenges by two distinct pathogens seem to be likely responsible for the expansion of PSGs in Vespertilionidae. CONCLUSIONS: The rapid expansion of PSGs in certain bat species together with selection for diversification suggest that bat PSGs could be part of a pathogen defense system by serving as decoy receptors and/or regulators of feto-maternal interactions. PMID- 28893192 TI - Expression of the ZIP/SLC39A transporters in beta-cells: a systematic review and integration of multiple datasets. AB - BACKGROUND: Pancreatic beta-cells require a constant supply of zinc to maintain normal insulin secretory function. Following co-exocytosis with insulin, zinc is replenished via the Zrt- and Irt-like (ZIP; SLC39A) family of transporters. However the ZIP paralogues of particular importance for zinc uptake, and associations with beta-cell function and Type 2 Diabetes remain largely unexplored. We retrieved and statistically analysed publically available microarray and RNA-seq datasets to perform a systematic review on the expression of beta-cell SLC39A paralogues. We complemented results with experimental data on expression profiling of human islets and mouse beta-cell derived MIN6 cells, and compared transcriptomic and proteomic sequence conservation between human, mouse and rat. RESULTS: The 14 ZIP paralogues have 73-98% amino sequence conservation between human and rodents. We identified 18 datasets for beta-cell SLC39A analysis, which compared relative expression to non-beta-cells, and expression in response to PDX-1 activity, cytokines, glucose and type 2 diabetic status. Published expression data demonstrate enrichment of transcripts for ZIP7 and ZIP9 transporters within rodent beta-cells and of ZIP6, ZIP7 and ZIP14 within human beta-cells, with ZIP1 most differentially expressed in response to cytokines and PDX-1 within rodent, and ZIP6 in response to diabetic status in human and glucose in rat. Our qPCR expression profiling data indicate that SLC39A6, -9, -13, and - 14 are the highest expressed paralogues in human beta-cells and Slc39a6 and -7 in MIN6 cells. CONCLUSIONS: Our systematic review, expression profiling and sequence alignment reveal similarities and potentially important differences in ZIP complements between human and rodent beta-cells. We identify ZIP6, ZIP7, ZIP9, ZIP13 and ZIP14 in human and rodent and ZIP1 in rodent as potentially biologically important for beta-cell zinc trafficking. We propose ZIP6 and ZIP7 are key functional orthologues in human and rodent beta-cells and highlight these zinc importers as important targets for exploring associations between zinc status and normal physiology of beta-cells and their decline in Type 2 Diabetes. PMID- 28893193 TI - Light-emitting diode fluorescent microscopy and Xpert MTB/RIF(r) assay for diagnosis of pulmonary tuberculosis among patients attending Ambo hospital, west central Ethiopia. AB - BACKGROUND: The relatively simple and cheaper light-emitting diode fluorescent microscopy (LED-FM) was recommended by the World Health Organization (WHO) to replace the conventional tuberculosis (TB) microscopy in both high- and low volume laboratories. More recently the WHO also endorsed one more technique, Xpert MTB/RIF(r) assay (Xpert), for improved TB diagnosis particularly among human immunodeficiency virus (HIV)-infected cases. However, the relative performance of both of these tools differs from setting to setting in reference to the conventional TB diagnostics. This study thus aimed to evaluate these tools for TB detection in individuals visiting Ambo Hospital, west-central Ethiopia. METHODS: Cross-sectional early-morning sputum samples were collected from presumptive TB patients between January and August 2015. Socio-demographic data were captured using a structured questionnaire. Clinical information was gathered from patients' medical records. The sputum samples were diagnosed using LED-FM, Xpert, concentrated Ziehl-Neelsen (cZN) staining and Lowenstein-Jensen (LJ) culture as the gold standard. Drug sensitivity test (DST) was also conducted. RESULTS: Out of 362 sputum samples collected and processed, 36(9.9%) were positive by LED-FM, 42(11.6%) by cZN and 50(13.8%) by Xpert. But, only 340 samples could be declared culture positive or negative for mycobacteria. Of these 340, eight were non-tubercle mycobacteria (NTM). Out of the remaining 332 samples, 45(13.6%) had culture-confirmed TB with 11(24.4%) being HIV co-infected. LED-FM, Xpert and culture detected 54.5% (6/11), 90.9% (10/11) and 100% (11/11) mycobacteria in HIV-positive individuals and 81.3% (26/32), 73.7% (28/38), 78.8% (26/33) and 73.2% (30/41), in HIV negatives respectively. Two samples were rifampicin resistant by both Xpert and DST. The overall sensitivity, specificity, positive and negative predictive values of LED-FM and Xpert were 77.8, 100, 100 and 96; and 93.3, 98, 97.5 and 98.9% respectively. CONCLUSION: The data demonstrated the high diagnostic yield of Xpert. LED-FM sensitivity is higher compared to results quoted by recent systematic reviews although it appears to be lower than what was cited in the WHO policy statement (83.6%) during the recommendation of the technology. The high specificity of LED-FM in the study area is encouraging and is expected to boost its reliability and uptake. PMID- 28893194 TI - De novo metatranscriptome assembly and coral gene expression profile of Montipora capitata with growth anomaly. AB - BACKGROUND: Scleractinian corals are a vital component of coral reef ecosystems, and of significant cultural and economic value worldwide. As anthropogenic and natural stressors are contributing to a global decline of coral reefs, understanding coral health is critical to help preserve these ecosystems. Growth anomaly (GA) is a coral disease that has significant negative impacts on coral biology, yet our understanding of its etiology and pathology is lacking. In this study we used RNA-seq along with de novo metatranscriptome assembly and homology assignment to identify coral genes that are expressed in three distinct coral tissue types: tissue from healthy corals ("healthy"), GA lesion tissue from diseased corals ("GA-affected") and apparently healthy tissue from diseased corals ("GA-unaffected"). We conducted pairwise comparisons of gene expression among these three tissue types to identify genes and pathways that help us to unravel the molecular pathology of this coral disease. RESULTS: The quality filtered de novo-assembled metatranscriptome contained 76,063 genes, of which 13,643 were identified as putative coral genes. Overall gene expression profiles of coral genes revealed high similarity between healthy tissue samples, in contrast to high variance among diseased samples. This indicates GA has a variety of genetic effects at the colony level, including on seemingly healthy (GA unaffected) tissue. A total of 105 unique coral genes were found differentially expressed among tissue types. Pairwise comparisons revealed the greatest number of differentially expressed genes between healthy and GA-affected tissue (93 genes), followed by healthy and GA-unaffected tissue (33 genes), and GA-affected and -unaffected tissue (7 genes). The putative function of these genes suggests GA is associated with changes in the activity of genes involved in developmental processes and activation of the immune system. CONCLUSION: This is one of the first transcriptome-level studies to investigate coral GA, and the first metatranscriptome assembly for the M. capitata holobiont. The gene expression data, metatranscriptome assembly and methodology developed through this study represent a significant addition to the molecular information available to further our understanding of this coral disease. PMID- 28893195 TI - Antimicrobial resistance in bacterial pathogens among hospitalized children with community acquired lower respiratory tract infections in Dongguan, China (2011 2016). AB - BACKGROUND: Bacterial pathogens are a major cause of childhood community acquired lower respiratory tract infections (CA-LRTIs), and few data described the impact of antimicrobial resistance on children with CA-LRTIs. This study aims to investigate the antimicrobial resistance in common bacterial agents among hospitalized children with CA-LRTIs between 2011 and 2016 in Dongguan, China. METHODS: Sputum samples were collected from hospitalized children (0-5 years old) with CA-LRTIs in Dongguan Children's Hospital. Bacterial pathogens were detected using traditional culture methods, and disc diffusion tests were used to determine antibiotic resistance. RESULTS: Among the 2360 samples analyzed, 342 (14.5%) were positive for bacterial infection. The most prevalent pathogen was MSSA (2.3%), followed by MRSA (1.5%), E. coli (1.7%), E. coli ESBLs (1.2%), K. pneumonia ESBLs (1.5%), K. pneumonia (1.4%) and S. pneumonia (1.3%). Of the hospitalized patients with bacteria causing of CA-LRTIs, 90.1% were less than 1 year-old. MSSA and MRSA were more commonly isolated in infants less than 3 months. E. coli, K. pneumonia and K. pneumonia ESBLs were more common bacteria causing CA-LRTIs in infants less than 1 month. Resistance levels to penicillins, fluoroquinolones, macrolides, cephalosporins, carbapenems and vancomycin varied in different bacteria. CONCLUSIONS: S. aureus, E coli and K. pneumonia were the common bacterial isolates recovered from chidren with CA-LTRIs during 2011-2015. Age group of under 1 year old was at a high risk of bacterial infections. Many isolates showed antibiotic resistance level was associated with antibiotic usage in clinic. Increasing surveillance of antibiotic resistance is urgently needed and develops better strategies to cure the antibiotic abuse in China. PMID- 28893196 TI - Genome-wide analysis of WRKY gene family in the sesame genome and identification of the WRKY genes involved in responses to abiotic stresses. AB - BACKGROUND: Sesame (Sesamum indicum L.) is one of the world's most important oil crops. However, it is susceptible to abiotic stresses in general, and to waterlogging and drought stresses in particular. The molecular mechanisms of abiotic stress tolerance in sesame have not yet been elucidated. The WRKY domain transcription factors play significant roles in plant growth, development, and responses to stresses. However, little is known about the number, location, structure, molecular phylogenetics, and expression of the WRKY genes in sesame. RESULTS: We performed a comprehensive study of the WRKY gene family in sesame and identified 71 SiWRKYs. In total, 65 of these genes were mapped to 15 linkage groups within the sesame genome. A phylogenetic analysis was performed using a related species (Arabidopsis thaliana) to investigate the evolution of the sesame WRKY genes. Tissue expression profiles of the WRKY genes demonstrated that six SiWRKY genes were highly expressed in all organs, suggesting that these genes may be important for plant growth and organ development in sesame. Analysis of the SiWRKY gene expression patterns revealed that 33 and 26 SiWRKYs respond strongly to waterlogging and drought stresses, respectively. Changes in the expression of 12 SiWRKY genes were observed at different times after the waterlogging and drought treatments had begun, demonstrating that sesame gene expression patterns vary in response to abiotic stresses. CONCLUSIONS: In this study, we analyzed the WRKY family of transcription factors encoded by the sesame genome. Insight was gained into the classification, evolution, and function of the SiWRKY genes, revealing their putative roles in a variety of tissues. Responses to abiotic stresses in different sesame cultivars were also investigated. The results of our study provide a better understanding of the structures and functions of sesame WRKY genes and suggest that manipulating these WRKYs could enhance resistance to waterlogging and drought. PMID- 28893197 TI - The predictors of 3- and 30-day mortality in 660 MERS-CoV patients. AB - BACKGROUND: The mortality rate of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) patients is a major challenge in all healthcare systems worldwide. Because the MERS-CoV risk-standardized mortality rates are currently unavailable in the literature, the author concentrated on developing a method to estimate the risk-standardized mortality rates using MERS-CoV 3- and 30-day mortality measures. METHODS: MERS-CoV data in Saudi Arabia is publicly reported and made available through the Saudi Ministry of Health (SMOH) website. The author studied 660 MERS-CoV patients who were reported by the SMOH between December 2, 2014 and November 12, 2016. The data gathered contained basic demographic information (age, gender, and nationality), healthcare worker, source of infection, pre existing illness, symptomatic, severity of illness, and regions in Saudi Arabia. The status and date of mortality were also reported. Cox-proportional hazard (CPH) models were applied to estimate the hazard ratios for the predictors of 3- and 30-day mortality. RESULTS: 3-day, 30-day, and overall mortality were found to be 13.8%, 28.3%, and 29.8%, respectively. According to CPH, multivariate predictors of 3-day mortality were elderly, non-healthcare workers, illness severity, and hospital-acquired infections (adjusted hazard ratio (aHR) =1.7; 8.8; 6.5; and 2.8, respectively). Multivariate predictors of 30-day mortality were elderly, non-healthcare workers, pre-existing illness, severity of illness, and hospital-acquired infections (aHR =1.7; 19.2; 2.1; 3.7; and 2.9, respectively). CONCLUSIONS: Several factors were identified that could influence mortality outcomes at 3 days and 30 days, including age (elderly), non-healthcare workers, severity of illness, and hospital-acquired infections. The findings can serve as a guide for healthcare practitioners by appropriately identifying and managing potential patients at high risk of death. PMID- 28893200 TI - An after hours gp clinic in regional Australia: appropriateness of presentations and impact on local emergency department presentations. AB - BACKGROUND: After hours general practice clinics provide medical attention for clients with non-emergency situations but are seeking immediate treatment and unable to wait for a general practitioner during routine opening hours. Evidence on the impact that after hours clinics have on emergency department presentations is equivocal. This study explored outcomes of the Bathurst After Hours General Practice Clinic (BAHGPC). Specifically it examined: clients' perceived urgency of, and satisfaction with their presentation to the BAHGPC; general practitioners' perception of the appropriateness of presentations to the BAHGPC; and whether the frequency of non-urgent and semi-urgent emergency department presentations at Bathurst Base Hospital has changed since the opening of the BAHGPC. METHODS: Clients presenting to the BAHGPC from 01/02/2015 to 30/06/2015 were asked to participate in the client presentation survey and follow-up satisfaction survey. General practitioner surveys were completed for individual clients from 01/12/2014 to 30/06/2015 to document the appropriateness of each presentation. Descriptive statistics are used to describe survey responses. Thematic analysis was applied for qualitative responses. Emergency department presentations were retrieved from the Emergency Department Data Collection. A comparison of presentations in the two years prior and subsequent to the opening of the BAHGPC was conducted using independent T-tests and Chi-square tests to compare mean presentations and proportional data for the different time periods examined. RESULTS: Most clients (76%) presenting to the BAHGPC classified their visit as essential. General practitioners considered most presentations to be appropriate (87%). Sixty percent (60%) of clients would have gone to the emergency department had the BAHGPC not been operational. Client satisfaction was high and 99% would use the clinic again. A significant reduction in total non urgent presentations to the Emergency Department occurred in the two years since the opening of the BAHGPC clinic compared to the two years prior (418.5 vs. 245.5; P < 0.05). CONCLUSIONS: There was concordance between general practitioners and clients regarding the appropriateness of presentations to the BAHGPC. The findings of this study highlight that after hours general practitioner clinics are an essential service in regional areas and contribute to reducing the burden of non-urgent presentations to the local emergency department. PMID- 28893199 TI - Comprehensive survey and evolutionary analysis of genome-wide miRNA genes from ten diploid Oryza species. AB - BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs that play versatile roles in post-transcriptional gene regulation. Although much is known about their biogenesis, and gene regulation very little is known about their evolutionary relation among the closely related species. RESULT: All the orthologous miRNA genes of Oryza sativa (japonica) from 10 different Oryza species were identified, and the evolutionary changes among these genes were analysed. Significant differences in the expansion of miRNA gene families were observed across the Oryza species. Analysis of the nucleotide substitution rates indicated that the mature sequences show the least substitution rates among the different regions of miRNA genes, and also show a very much less substitution rates as compared to that of all protein-coding genes across the Oryza species. Evolution of miRNA genes was also found to be contributed by transposons. A non-neutral selection was observed at 80 different miRNA loci across Oryza species which were estimated to have lost ~87% of the sequence diversity during the domestication. The phylogenetic analysis revealed that O. longistaminata diverged first among the AA genomes, whereas O. brachyantha and O. punctata appeared as the eminent out groups. The miR1861 family organised into nine distinct compact clusters in the studied Oryza species except O. brachyantha. Further, the expression analysis showed that 11 salt-responsive miRNAs were differentially regulated between O. coarctata and O. glaberrima. CONCLUSION: Our study provides the evolutionary dynamics in the miRNA genes of 10 different Oryza species which will support more investigations about the structural and functional organization of miRNA genes of Oryza species. PMID- 28893198 TI - Lessons from a decade of individual-based models for infectious disease transmission: a systematic review (2006-2015). AB - BACKGROUND: Individual-based models (IBMs) are useful to simulate events subject to stochasticity and/or heterogeneity, and have become well established to model the potential (re)emergence of pathogens (e.g., pandemic influenza, bioterrorism). Individual heterogeneity at the host and pathogen level is increasingly documented to influence transmission of endemic diseases and it is well understood that the final stages of elimination strategies for vaccine preventable childhood diseases (e.g., polio, measles) are subject to stochasticity. Even so it appears IBMs for both these phenomena are not well established. We review a decade of IBM publications aiming to obtain insights in their advantages, pitfalls and rationale for use and to make recommendations facilitating knowledge transfer within and across disciplines. METHODS: We systematically identified publications in Web of Science and PubMed from 2006 2015 based on title/abstract/keywords screening (and full-text if necessary) to retrieve topics, modeling purposes and general specifications. We extracted detailed modeling features from papers on established vaccine-preventable childhood diseases based on full-text screening. RESULTS: We identified 698 papers, which applied an IBM for infectious disease transmission, and listed these in a reference database, describing their general characteristics. The diversity of disease-topics and overall publication frequency have increased over time (38 to 115 annual publications from 2006 to 2015). The inclusion of intervention strategies (8 to 52) and economic consequences (1 to 20) are increasing, to the detriment of purely theoretical explorations. Unfortunately, terminology used to describe IBMs is inconsistent and ambiguous. We retrieved 24 studies on a vaccine-preventable childhood disease (covering 7 different diseases), with publication frequency increasing from the first such study published in 2008. IBMs have been useful to explore heterogeneous between- and within-host interactions, but combined applications are still sparse. The amount of missing information on model characteristics and study design is remarkable. CONCLUSIONS: IBMs are suited to combine heterogeneous within- and between-host interactions, which offers many opportunities, especially to analyze targeted interventions for endemic infections. We advocate the exchange of (open-source) platforms and stress the need for consistent "branding". Using (existing) conventions and reporting protocols would stimulate cross-fertilization between research groups and fields, and ultimately policy making in decades to come. PMID- 28893201 TI - Determination of the optimal inspiratory pressure providing adequate ventilation while minimizing gastric insufflation using real-time ultrasonography in Chinese children: a prospective, randomized, double-blind study. AB - BACKGROUND: During facemask ventilation, gastric insufflation is defined as appearance of a comet-tail or an acoustic shadow on ultrasonography. Ultrasonographic measurement of antral cross-section area (CSA) may reflect an insufflated antrum and provide interesting semi-quantitative data in regard to the gastric insufflation. This study aimed to determine the appropriate level of inspiratory pressure sufficient to provide adequate pulmonary ventilation with a lower occurrence of gastric insufflation during facemask pressure-controlled ventilation using real-time ultrasonography in paralyzed children. METHODS: Ninety children, ASA I-II, aged from 2 to 4 years, scheduled for general anesthesia were enrolled in this randomized and double-blinded study. Children were randomized into one of the five groups (P8, P10, P12, P14, and P16) defined by the applied inspiratory pressure during facemask ventilation: 8, 10, 12, 14, and 16 cm H2O. Anesthesia induction was conducted with fentanyl and propofol. Rocuronium was administrated as a muscle relaxant. After rocuronium administration, facemask ventilation was performed for 120 s. Gastric insufflation (GI+) was detected by ultrasonography, and the antral CSA before and after facemask ventilation were also measured using ultrasonography. Respiratory variables were monitored. RESULTS: Gastric insufflation was detected in 32 children (3/18 in group P8, 5/18 in group P10, 7/18 in group P12, 8/16 in group P14, and 9/14 in group P16). The antral CSA after facemask ventilation statistically increased in subgroups P14 GI+ and P16 GI+ for whom gastric insufflation was detected by ultrasonography, whereas it did not change statistically in other groups. Lung ventilation was inadequate for group P8 or P10. CONCLUSION: We concluded that an inspiratory pressure of 12 cm H2O is sufficient to provide adequate ventilation with a lower occurrence of gastric insufflation during induction of general anesthesia in paralyzed Chinese children aged from 2 to 4 years old. TRIAL REGISTRATION: ( ChiCTR-IPR-16007960 ). Registered 21 February 2016 Conclusion heading: Ultrasound for determining gastric insufflation. PMID- 28893202 TI - Preliminary evaluation of prototype footwear and insoles to optimise balance and gait in older people. AB - BACKGROUND: Footwear has the potential to influence balance in either a detrimental or beneficial manner, and is therefore an important consideration in relation to falls prevention. The objective of this study was to evaluate balance ability and gait patterns in older women while wearing prototype footwear and insoles designed to improve balance. METHODS: Older women (n = 30) aged 65 - 83 years (mean 74.4, SD 5.6) performed a series of laboratory tests of balance ability (postural sway on a foam rubber mat, limits of stability and tandem walking, measured with the Neurocom(r) Balance Master) and gait patterns (walking speed, cadence, step length and step width at preferred speed, measured with the GAITRite(r) walkway) while wearing (i) flexible footwear (Dunlop VolleyTM), (ii) their own footwear, and (iii) prototype footwear and insoles designed to improve dynamic balance. Perceptions of the footwear were also documented using a structured questionnaire. RESULTS: There was no difference in postural sway, limits of stability or gait patterns between the footwear conditions. However, when performing the tandem walking test, there was a significant reduction in step width and end sway when wearing the prototype footwear compared to both the flexible footwear and participants' own footwear. Participants perceived their own footwear to be more attractive, comfortable, well-fitted and easier to put on and off compared to the prototype footwear. Despite this, most participants (n = 18, 60%) reported that they would consider wearing the prototype footwear to reduce their risk of falling. CONCLUSION: The prototype footwear and insoles used in this study improve balance when performing a tandem walk test, as evidenced by a narrower step width and decreased sway at completion of the task. However, further development of the design is required to make the footwear acceptable to older women from the perspective of aesthetics and comfort. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12617001128381 , 01/08/2017 (retrospectively registered). PMID- 28893203 TI - Overall Low Extended-Spectrum Cephalosporin Resistance but high Azithromycin Resistance in Neisseria gonorrhoeae in 24 European Countries, 2015. AB - BACKGROUND: Surveillance of Neisseria gonorrhoeae antimicrobial susceptibility in Europe is performed through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), which additionally provides data to inform the European gonorrhoea treatment guideline; currently recommending ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. We present antimicrobial susceptibility data from 24 European countries in 2015, linked to epidemiological data of patients, and compare the results to Euro-GASP data from previous years. METHODS: Antimicrobial susceptibility testing by MIC gradient strips or agar dilution methodology was performed on 2134 N. gonorrhoeae isolates and interpreted using EUCAST breakpoints. Patient variables associated with resistance were established using logistic regression to estimate odds ratios (ORs). RESULTS: In 2015, 1.7% of isolates were cefixime resistant compared to 2.0% in 2014. Ceftriaxone resistance was detected in only one (0.05%) isolate in 2015, compared with five (0.2%) in 2014. Azithromycin resistance was detected in 7.1% of isolates in 2015 (7.9% in 2014), and five (0.2%) isolates displayed high-level azithromycin resistance (MIC >= 256 mg/L) compared with one (0.05%) in 2014. Ciprofloxacin resistance remained high (49.4%, vs. 50.7% in 2014). Cefixime resistance significantly increased among heterosexual males (4.1% vs. 1.7% in 2014), which was mainly attributable to data from two countries with high cefixime resistance (~11%), however rates among men-who-have-sex-with-men (MSM) and females continued to decline to 0.5% and 1%, respectively. Azithromycin resistance in MSM and heterosexual males was higher (both 8.1%) than in females (4.9% vs. 2.2% in 2014). The association between azithromycin resistance and previous gonorrhoea infection, observed in 2014, continued in 2015 (OR 2.1, CI 1.2-3.5, p < 0.01). CONCLUSIONS: The 2015 Euro-GASP sentinel system revealed high, but stable azithromycin resistance and low overall resistance to ceftriaxone and cefixime. The low cephalosporin resistance may be attributable to the effectiveness of the currently recommended first-line dual antimicrobial therapy; however the high azithromycin resistance threatens the effectiveness of this therapeutic regimen. Whether the global use of azithromycin in mono- or dual antimicrobial therapy of gonorrhoea is contributing to the global increases in azithromycin resistance remains to be elucidated. The increasing cefixime resistance in heterosexual males also needs close monitoring. PMID- 28893204 TI - Predicted networks of protein-protein interactions in Stegodyphus mimosarum by cross-species comparisons. AB - BACKGROUND: Stegodyphus mimosarum is a candidate model organism belonging to the class Arachnida in the phylum Arthropoda. Studies on the biology of S. mimosarum over the past several decades have consisted of behavioral research and comparison of gene sequences based on the assembled genome sequence. Given the lack of systematic protein analyses and the rich source of information in the genome, we predicted the relationships of proteins in S. mimosarum by bioinformatics comparison with genome-wide proteins from select model organisms using gene mapping. RESULTS: The protein-protein interactions (PPIs) of 11 organisms were integrated from four databases (BioGrid, InAct, MINT, and DIP). Here, we present comprehensive prediction and analysis of 3810 proteins in S. mimosarum with regard to interactions between proteins using PPI data of organisms. Interestingly, a portion of the protein interactions conserved among Saccharomyces cerevisiae, Homo sapiens, Arabidopsis thaliana, and Drosophila melanogaster were found to be associated with RNA splicing. In addition, overlap of predicted PPIs in reference organisms, Gene Ontology, and topology models in S. mimosarum are also reported. CONCLUSIONS: Addition of Stegodyphus, a spider representative of interactomic research, provides the possibility of obtaining deeper insights into the evolution of PPI networks among different animal species. This work largely supports the utility of the "stratus clouds" model for predicted PPIs, providing a roadmap for integrative systems biology in S. mimosarum. PMID- 28893205 TI - Is additional balloon Kyphoplasty safe and effective for acute thoracolumbar burst fracture? AB - BACKGROUND: Burst fracture is a common thoracolumbar injury that is treated using posterior pedicle instrumentation and fusion combined with transpedicular intracorporeal grafting after reduction. In this study, we compared the outcome of these two techniques by using radiologic imaging and functional outcome. METHODS: Sixty-one patients with acute thoracolumbar burst fracture were operated with kyphoplasty (n = 31) or vertebroplasty (n = 30) and retrospectively reviewed in our institution between 2011 and 2014. All 61 patients underwent surgery within 5 days after admission to the hospital and then followed-up for 12 to 24 months after surgery. RESULTS: Significant improvement was found in the anterior vertebral height (92 +/- 8.9% in the kyphoplasty group, 85.6 +/- 7.2% in the vertebroplasty group, p < 0.01) at 1 month post-operatively and (89 +/- 7.9% in the kyphoplasty group, 78 +/- 6.9% in the vertebroplasty group, p < 0.01) at the 24-month follow-up. Significant improvement was also observed in the kyphotic angle (1.2 +/- 0.5 degrees in the kyphoplasty group, 10.5 +/- 1.2 degrees in the vertebroplasty group, p < 0.01) at 1 month post-operatively and (5.4 +/- 1.2 degrees in the kyphoplasty group, 11.5 +/- 8.5 degrees in the vertebroplasty group, p < 0.01) at the 24-month follow-up. Both operations led to significant improvement of the patients' pain and the Oswestry disability index (p < 0.01). Cement leakage was noted in 29% of patients after kyphoplasty and 77% of patients after vertebroplasty (p < 0.01). Only one implant failure (3.3%), which required further surgical intervention, was reported in the vertebroplasty group. CONCLUSIONS: Reduction with additional balloon at the fractured site is better than indirect reduction only by posterior instrumentation. The better reduction of kyphotic angle and the lower cement leakage rate in the kyphoplasty group indicate that additional balloon kyphoplasty is safe and effective for acute thoracolumbar burst fracture. PMID- 28893207 TI - Hepatitis B virus and HIV co-infection among pregnant women in Rwanda. AB - BACKGROUND: Hepatitis B virus (HBV) affects people worldwide but the local burden especially in pregnant women and their new born babies is unknown. In Rwanda HIV infected individuals who are also infected with HBV are supposed to be initiated on ART immediately. HBV is easily transmitted from mother to child during delivery. We sought to estimate the prevalence of chronic HBV infection among pregnant women attending ante-natal clinic (ANC) in Rwanda and to determine factors associated with HBV and HIV co-infection. METHODS: This study used a cross-sectional survey, targeting pregnant women in sentinel sites. Pregnant women were tested for hepatitis B surface antigen (HBsAg) and HIV infection. A series of tests were done to ensure high sensitivity. Multivariable logistic regression was used to identify independent predictors of HBV-HIV co-infection among those collected during ANC sentinel surveillance, these included: age, marital status, education level, occupation, residence, pregnancy and syphilis infection. RESULTS: The prevalence of HBsAg among 13,121 pregnant women was 3.7% (95% CI: 3.4-4.0%) and was similar among different socio-demographic characteristics that were assessed. The proportion of HIV-infection among HBsAg positive pregnant women was 4.1% [95% CI: 2.5-6.3%]. The prevalence of HBV-HIV co infection was higher among women aged 15-24 years compared to those women aged 25 49 years [aOR = 6.9 (95% CI: 1.8-27.0)]. Women residing in urban areas seemed having HBV-HIV co-infection compared with women residing in rural areas [aOR = 4.3 (95% CI: 1.2-16.4)]. Women with more than two pregnancies were potentially having the co-infection compared to those with two or less (aOR = 6.9 (95% CI: 1.7-27.8). Women with RPR-positive test were seemed associated with HBV-HIV co infection (aOR = 24.9 (95% CI: 5.0-122.9). CONCLUSION: Chronic HBV infection is a public health problem among pregnant women in Rwanda. Understanding that HBV-HIV co-infection may be more prominent in younger women from urban residences will help inform and strengthen HBV prevention and treatment programmes among HIV infected pregnant women, which is crucial to this population. PMID- 28893206 TI - Efficacy of blood flow restriction exercise during dialysis for end stage kidney disease patients: protocol of a randomised controlled trial. AB - BACKGROUND: Exercise during haemodialysis improves strength and physical function. However, both patients and clinicians are time poor, and current exercise recommendations add an excessive time burden making exercise a rare addition to standard care. Hypothetically, blood flow restriction exercise performed during haemodialysis can provide greater value for time spent exercising, reducing this time burden while producing similar or greater outcomes. This study will explore the efficacy of blood flow restriction exercise for enhancing strength and physical function among haemodialysis patients. METHODS: This is a randomised controlled trial design. A total of 75 participants will be recruited from haemodialysis clinics. Participants will be allocated to a blood flow restriction cycling group, traditional cycling group or usual care control group. Both exercising groups will complete 3 months of cycling exercise, performed intradialytically, three times per week. The blood flow restriction cycling group will complete two 10-min cycling bouts separated by a 20-min rest at a subjective effort of 15 on a 6 to 20 rating scale. This will be done with pressurised cuffs fitted proximally on the active limbs during exercise at 50% of a pre-determined limb occlusion pressure. The traditional cycling group will perform a continuous 20-min bout of exercise at a subjective effort of 12 on the same subjective effort scale. These workloads and volumes are equivalent and allow for comparison of a common blood flow restriction aerobic exercise prescription and a traditional aerobic exercise prescription. The primary outcome measures are lower limb strength, assessed by a three repetition maximum leg extension test, as well as objective measures of physical function: six-minute walk test, 30-s sit to stand, and timed up and go. Secondary outcome measures include thigh muscle cross sectional area, body composition, routine pathology, quality of life, and physical activity engagement. DISCUSSION: This study will determine the efficacy of blood flow restriction exercise among dialysis patients for improving key physiological outcomes that impact independence and quality of life, with reduced burden on patients. This may have broader implications for other clinical populations with similarly declining muscle health and physical function, and those contraindicated to higher intensities of exercise. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Register: ACTRN12616000121460. PMID- 28893208 TI - Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. AB - BACKGROUND: Patisiran is an investigational RNA interference (RNAi) therapeutic in development for the treatment of hereditary ATTR (hATTR) amyloidosis, a progressive disease associated with significant disability, morbidity, and mortality. METHODS: Here we describe the rationale and design of the Phase 3 APOLLO study, a randomized, double-blind, placebo-controlled, global study to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Eligible patients are 18-85 years old with hATTR amyloidosis, investigator-estimated survival of >=2 years, Neuropathy Impairment Score (NIS) of 5-130, and polyneuropathy disability score <=IIIb. Patients are randomized 2:1 to receive either intravenous patisiran 0.3 mg/kg or placebo once every 3 weeks. The primary objective is to determine the efficacy of patisiran at 18 months based on the difference in the change in modified NIS+7 (a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function) between the patisiran and placebo groups. Secondary objectives are to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). Exploratory objectives include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden. Safety of patisiran will be assessed throughout the study. DISCUSSION: APOLLO represents the largest randomized, Phase 3 study to date in patients with hATTR amyloidosis, with endpoints that capture the multisystemic nature of this disease. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov ( NCT01960348 ); October 9, 2013. PMID- 28893209 TI - Preliminary experience in laparoscopic resection of hepatic hydatidectocyst with the Da Vinci Surgical System (DVSS): a case report. AB - BACKGROUND: At present, Da Vinci robotic assisted hepatectomy has been routinely carried out in conditional units. But there is no report concerning the use of Da Vinci robots for hepatic hydatid cystectomy and experience on this aspect is seldom mentioned before. This study was to summarize the preliminary experience in laparoscopic resection of hepatic hydatidectocyst with the Da Vinci Surgical System (DVSS). CASE PRESENTATION: A 29-year-old female diagnosed as hepatic hydatid in the right anterior lobe of liver was treated with laparoscopic resection by the DVSS under general anesthesia. Appropriate disposal of tumor cell in vascular system and disinfection of surgical field with hypertonic saline were conducted. The hepatic hydatidectocyst was resected completely with an operation time of 130 min, an intraoperative blood loss of 200 ml and a length of hospital stay for five days. The vital signs of patient were stable and no cyst fluid allergy occurred after operation. CONCLUSIONS: Our result showed that laparoscopic resection of hepatic hydatidectocyst by using the DVSS is safe and feasible on the basis of hospitals have rich experience in treatment of cystic echinococcosisliver, resection with DVSS and laparoscopic excision. PMID- 28893210 TI - Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment. AB - BACKGROUND: Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. METHODS: Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. RESULTS: Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. CONCLUSIONS: We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype specific diagnosis biomarkers and therapy strategies for these tumors. PMID- 28893211 TI - Clinical performance and patient outcome after simulation-based training in prevention and management of postpartum haemorrhage: an educational intervention study in a low-resource setting. AB - BACKGROUND: Postpartum haemorrhage (PPH) is a major cause of maternal mortality. Prevention and adequate treatment are therefore important. However, most births in low-resource settings are not attended by skilled providers, and knowledge and skills of healthcare workers that are available are low. Simulation-based training effectively improves knowledge and simulated skills, but the effectiveness of training on clinical behaviour and patient outcome is not yet fully understood. The aim of this study was to assess the effect of obstetric simulation-based training on the incidence of PPH and clinical performance of basic delivery skills and management of PPH. METHODS: A prospective educational intervention study was performed in a rural referral hospital in Tanzania. Sixteen research assistants observed all births with a gestational age of more than 28 weeks from May 2011 to June 2013. In March 2012 a half-day obstetric simulation-based training in management of PPH was introduced. Observations before and after training were compared. The main outcome measures were incidence of PPH (500-1000 ml and >1000 ml), use and timing of administration of uterotonic drugs, removal of placenta by controlled cord traction, uterine massage, examination of the placenta, management of PPH (>500 ml), and maternal and neonatal mortality at 24 h. RESULTS: Three thousand six hundred twenty two births before and 5824 births after intervention were included. The incidence of PPH (500-1000 ml) significantly reduced from 2.1% to 1.3% after training (effect size Cohen's d = 0.07). The proportion of women that received oxytocin (87.8%), removal of placenta by controlled cord traction (96.5%), and uterine massage after birth (93.0%) significantly increased after training (to 91.7%, 98.8%, 99.0% respectively). The proportion of women who received oxytocin as part of management of PPH increased significantly (before training 43.0%, after training 61.2%). Other skills in management of PPH improved (uterine massage, examination of birth canal, bimanual uterine compression), but these were not statistically significant. CONCLUSIONS: The introduction of obstetric simulation-based training was associated with a 38% reduction in incidence of PPH and improved clinical performance of basic delivery skills and management of PPH. PMID- 28893212 TI - Associations between media use and health information-seeking behavior on vaccinations in South Korea. AB - BACKGROUND: Although vaccinations are critical for preventing emerging infectious diseases, scant research has been conducted on risk communication. With socio economic characteristics, health behavior, and underlying diseases under control, we investigated associations between media use, health information-seeking behavior, health information type, and vaccination in the population. METHODS: This study relied on a national survey of Korean adults (n = 1367). Participants were adult males and females age 20 and older. Web and face-to-face surveys were conducted throughout July 2014. The main outcome was vaccination (categorized as yes or no). Independent variables were time spent on media, frequency of health information-seeking behavior, and types of health information sought. RESULTS: Controlling for co-variates, logistic regression analysis was conducted to identify factors that influence Korean adults being vaccinated. Results revealed that accessible information about emerging infectious diseases, listening to the radio, and reading the newspaper were associated with increased odds of being vaccinated. Active seeking health information as well as being female and of higher socio-economic status were positively correlated with Korean adults being vaccinated. CONCLUSION: It is critical to promote health information-seeking behavior and use diverse media channels to increase acceptance and awareness of emerging infectious diseases and vaccinations. Because there are differences in vaccination awareness depending on social class, it is critical to reduce communication inequality, strengthen accessibility to vaccinations, and devise appropriate risk communication strategies that ensure Korean adults receive vaccinations. PMID- 28893213 TI - Application and analysis of retroperitoneal laparoscopic partial nephrectomy with sequential segmental renal artery clamping for patients with multiple renal tumor: initial experience. AB - BACKGROUND: To explore the feasibility and safety of retroperitoneal laparoscopic partial nephrectomy with sequential segmental renal artery clamping for the patients with multiple renal tumor of who have solitary kidney or contralateral kidney insufficiency. METHODS: Nine patients who have undergone retroperitoneal laparoscopic partial nephrectomy with sequential segmental renal artery clamping between October 2010 and January 2017 were retrospectively analyzed. Clinical materials and parameters during and after the operation were summarized. RESULTS: Nineteen tumors were resected in nine patients and the operations were all successful. The operation time ranged from 100 to 180 min (125 min); clamping time of segmental renal artery was 10 ~ 30 min (23 min); the amount of blood loss during the operation was 120 ~ 330 ml (190 ml); hospital stay after the operation is 3 ~ 6d (5d). There was no complication during the perioperative period, and the pathology diagnosis after the surgery showed that there were 13 renal clear cell carcinomas, two papillary carcinoma and four perivascular epithelioid cell tumors with negative margins from the 19 tumors. All patients were followed up for 3 ~ 60 months, and no local recurrence or metastasis was detected. At 3-month post-operation follow-up, the mean serum creatinine was 148.6 +/- 28.1 MUmol/L (p = 0.107), an increase of 3.0 MUmol/L from preoperative baseline. CONCLUSIONS: For the patients with multiple renal tumors and solitary kidney or contralateral kidney insufficiency, retroperitoneal laparoscopic partial nephrectomy with sequential segmental renal artery clamping was feasible and safe, which minimized the warm ischemia injury to the kidney and preserved the renal function effectively. PMID- 28893214 TI - A mixed methods study on evaluating the performance of a multi-strategy national health program to reduce maternal and child health disparities in Haryana, India. AB - BACKGROUND: A multi pronged community based strategy, known as National Rural Health Mission (NRHM), was implemented from 2005-06 to 2012-13 in India to curtail maternal and child health (MCH) disparities between poor and rich, rural and urban areas, and boys and girls,. This study aimed to determine the degree to which MCH plans of NRHM implemented, and resulted in improving the MCH outcomes and reducing the inequalities. METHODS: An explanatory sequential mixed methods study was conducted, first to assess the degree of implementation of MCH plans by estimating the budget utilization rates of each MCH plan, and the effectiveness of these plans by comparing demographic health surveys data conducted post (2012 13), during (2007-08) and pre- (2002-04) NRHM implementation period, in the quantitative study. Then, perceptions and beliefs of stakeholders regarding extent and effectiveness of NRHM in Haryana were explored in the qualitative study during 2013. A logistic regression analysis was done for quantitative data, and inductive applied thematic analysis for qualitative data. The findings of the quantitative and qualitative parts of study were mixed at the interpretation level. RESULTS: The MCH plans, like free ambulance service, availability of free drugs and logistics, accredited social health activists were fully implemented according to the budget spent on implementing these activities in Haryana. This was also validated by qualitative study. Availability of free medicines and treatment in the public health facilities had benefitted the poor patients the most. Accredited Social Health Activists scheme was also the most appreciated scheme that had increased the institutional delivery rates. There was acute shortage of human resources in-spite of full utilization of funds allocated for this plan. The results of the qualitative study validated the findings of quantitative study of significant (p < 0.05) improvement in MCH indicators and reduction in MCH disparities between higher and lower socioeconomic groups, and rural and urban areas. CONCLUSIONS: MCH plans of NRHM might have succeeded in improving the MCH outcomes and reducing the geographical and socioeconomic MCH inequalities by successfully implementing the schemes like accredited social health activists, free ambulance services, free treatment and medicines in hospitals for the poor and in rural areas. PMID- 28893215 TI - Translation and cultural adaptation of the Integrated Palliative care Outcome Scale including cognitive interviewing with patients and staff. AB - BACKGROUND: To expand our clinical and scientific knowledge about holistic outcomes within palliative care, there is a need for agreed-upon patient-reported outcome measures. These patient-reported outcome measures then require translation and cultural adaptation, either from country-specific languages to English, or the other way around. The aim of this study was to translate and cross-culturally adapt the Integrated Palliative care Outcome Scale (IPOS) to the Swedish care context. METHODS: Swedish versions of IPOS Patient and IPOS Staff were developed and culturally adapted using recommended guidelines including cognitive interviews with patients (n = 13) and staff (n = 15) from different care contexts including general and specialised palliative care. RESULTS: The comprehension and judgement difficulties identified in the pre-final patient and staff versions were successfully solved during the cognitive interviewing process. IPOS was well accepted by both patients and staff, none of the questions were experienced as inappropriate, and all questions were judged important. CONCLUSIONS: In this study, we translated and culturally adapted the patient and staff versions of IPOS, and demonstrated face and content validity and acceptability of the scale through cognitive interviewing with patients and staff within residential care facility, surgical and specialised palliative home care units. Cognitive interviewing in parallel with patients and staff in rounds, with tentative analysis in between, was a suitable method for identifying and solving challenges with comprehension and evaluation in the pre-final version of IPOS. The Swedish IPOS is now available for use in a variety of clinical care settings. PMID- 28893216 TI - Antimalarial efficacy of Pongamia pinnata (L) Pierre against Plasmodium falciparum (3D7 strain) and Plasmodium berghei (ANKA). AB - BACKGROUND: The objective of the current study was to assess the in vitro antiplasmodial activities of leaf, bark, flower, and the root of Pongamia pinnata against chloroquine-sensitive Plasmodium falciparum (3D7 strain), cytotoxicity against Brine shrimp larvae and THP-1 cell line. For in vivo study, the plant extract which has shown potent in vitro antimalarial activity was tested against Plasmodium berghei (ANKA strain). METHODS: The plant Pongamia pinnata was collected from the herbal garden of Acharya Nagarjuna University of Guntur district, Andhra Pradesh, India. Sequentially crude extracts of methanol (polar), chloroform (non-polar), hexane (non-polar), ethyl acetate (non-polar) and aqueous (polar) of dried leaves, bark, flowers and roots of Pongamia pinnata were prepared using Soxhlet apparatus. The extracts were screened for in vitro antimalarial activity against P. falciparum 3D7 strain. The cytotoxicity studies of crude extracts were conducted against Brine shrimp larvae and THP-1 cell line. Phytochemical analysis of the plant extracts was carried out by following the standard methods. The chemical injury to erythrocytes due to the plant extracts was checked. The in vivo study was conducted on P. berghei (ANKA) infected BALB/c albino mice by following 4-Day Suppressive, Repository, and Curative tests. RESULTS: Out of all the tested extracts, the methanol extract of the bark of Pongamia pinnata had shown an IC50 value of 11.67 MUg/mL with potent in vitro antimalarial activity and cytotoxicity evaluation revealed that this extract was not toxic against Brine shrimp and THP-1 cells. The injury to erythrocytes analysis had not shown any morphological alterations and damage to the erythrocytes after 48 h of incubation. Because methanolic bark extract of Pongamia pinnata has shown good antimalarial activity in vitro, it was also tested in vivo. So the extract had exhibited an excellent activity against P. berghei malaria parasite while decrement of parasite counts was moderately low and dose-dependent (P < 0.05) when compared to the control groups, which shown a daily increase of parasitemia, unlike the CQ-treated groups. The highest concentration of the extract (1000 mg/kg b.wt./day) had shown 83.90, 87.47 and 94.67% of chemo-suppression during Suppressive, Repository, and Curative tests respectively which is almost nearer to the standard drug Chloroquine (5 mg/kg b.wt./day). Thus, the study has revealed that the methanolic bark extract had shown promisingly high ((P < 0.05) and dose-dependent chemo-suppression. The phytochemical screening of the crude extracts had shown the presence of alkaloids, flavonoids, triterpenes, tannins, carbohydrates, phenols, coumarins, saponins, phlobatannins and steroids. CONCLUSIONS: The present study is useful to develop new antimalarial drugs in the scenario of the growing resistance to the existing antimalarials. Thus, additional research is needed to characterize the bioactive molecules of the extracts of Pongamia pinnata that are responsible for inhibition of malaria parasite. PMID- 28893217 TI - A comparative study of irrigation versus no irrigation during burr hole craniostomy to treat chronic subdural hematoma. AB - BACKGROUND: Burr hole craniostomy is a widely used method for the evacuation of CSDH. However it is not clear whether the irrigation during operation improves the prognosis or gives rise to additional complications instead. This retrospective cohort study was conducted to determine this issue. METHODS: Patients attending two medical centers in China who underwent burr hole drainage with irrigation (BHDI) or burr hole drainage without irrigation (BHD) for unilateral CSDH during January 2013 to December 2016 were included in this study. The patients' clinical information and follow-up data were retrospectively reviewed, and the radiologic findings were processed using the 3D Slicer software. The differences in outcomes were identified using t-test, chi-square test, or Fisher's exact test. RESULTS: A total of 151 patients comprising 63 patients in the BHD group and 88 patients in the BHDI group were included. Patients in the BHDI group had a higher volume of pneumocrania on the first postoperative day than that of patients in the BHD group (p < 0.05). No significant differences were observed between the two approaches in rates of rebleeding, recurrence and other complications (p > 0.05). CONCLUSIONS: Irrigation had no improvement in the long-term curative effect on CSDH, but it increased the risk of short-term complication in terms of pneumocrania. Therefore, this study suggests that irrigation is not an obligatory procedure during burr hole drainage. PMID- 28893218 TI - Contributing factors of elective surgical case cancellation: a retrospective cross-sectional study at a single-site hospital. AB - BACKGROUND: Case cancellation (CC) has significant impact on the efficiency of operating room (OR) management, which can be mitigated by taking preventive measures. In this study, using the data of the West China Hospital (WCH), we identified the effect of contributing factors and recommended hospital interventions to facilitate CC prevention. METHOD: We conducted a retrospective review of 11,331 elective surgical cases from January 1 to December 31, 2014. CC reasons were grouped into six categories. The methods of descriptive statistics and hypothesis test were used to identify the effect of factors. RESULTS: CC reasons (746) were divided into six broad categories: workup related (preoperative diagnostic assessment issues or sudden medical condition changes) (25.8%), non-specified reasons (25.8%), coordination issues (15.1%), patient related (13.0%), support system issues (11.8%), and doctor related (8.5%). The types of the most frequently performed operations are identified, as well as their CRs. The cancellation rate (CR) of males was lower than that of females (16.7% to 18.3%). A large difference in the CRs existed among doctors. The CR on Monday was significantly higher than the other four weekdays. CONCLUSIONS: Workup related issues, the types of procedures, the menstrual cycle of females, highly imbalanced CRs among doctors, and tendency of cancellation on Monday are the major identified factors, which account for a significant amount of preventable cancellations. It is suggested that corresponding hospital interventions can reduce CR and improve OR efficiency, including maintaining effective coordination, good communication and well-designed preoperative assessment processes, focusing on the type of procedures which are more time-consuming and complex, paying special attention to the physiology of females during surgery planning, taking measures to reduce CR of top eight doctors, and improving surgery scheduling on Monday. PMID- 28893219 TI - A case of a four-year-old child adopted at eight months with unusual mood patterns and significant polypharmacy. AB - BACKGROUND: Long-term effects of neglect in early life are still widely unknown. Diversity of outcomes can be explained by differences in genetic risk, epigenetics, prenatal factors, exposure to stress and/or substances, and parent child interactions. Very common sub-threshold presentations of children with history of early trauma are challenging not only to diagnose but also in treatment. CASE PRESENTATION: A Caucasian 4-year-old, adopted at 8 months, male patient with early history of neglect presented to pediatrician with symptoms of behavioral dyscontrol, emotional dysregulation, anxiety, hyperactivity and inattention, obsessions with food, and attachment issues. He was subsequently seen by two different child psychiatrists. Pharmacotherapy treatment attempted included guanfacine, fluoxetine and amphetamine salts as well as quetiapine, aripiprazole and thioridazine without much improvement. Risperidone initiated by primary care seemed to help with his symptoms of dyscontrol initially but later the dose had to be escalated to 6 mg total for the same result. After an episode of significant aggression, the patient was admitted to inpatient child psychiatric unit for stabilization and taper of the medicine. CONCLUSIONS: The case illustrates difficulties in management of children with early history of neglect. A particular danger in this patient population is polypharmacy, which is often used to manage transdiagnostic symptoms that significantly impacts functioning with long term consequences. PMID- 28893220 TI - The added value of musculoskeletal ultrasound to clinical evaluation in the treatment decision of rheumatoid arthritis outpatients: physician experience matters. AB - BACKGROUND: Musculoskeletal ultrasound improves the accuracy of detecting the level of disease activity (DA) in RA patients, although its impact on the final treatment decision in a real clinical setting is uncertain. The objectives were to define the percentage of clinical scenarios from an ongoing cohort of RA outpatients in which the German Ultrasound Score on 7 joints (GUS-7) impacted the treatment and to explore if the impact differed between a senior rheumatologist (SR) vs. a trainee (TR). METHODS: Eighty-five consecutive and randomly selected RA outpatients underwent 170 assessments, 85 each by the SR and the TR. Initially, both physicians (blinded to each other) performed a rheumatic assessment and recommended a preliminary treatment. Then, the patients underwent the GUS-7 evaluation by an experienced rheumatologist blinded to clinical evaluations; selected joints of the clinically dominant hand were assessed by gray-scale and power Doppler (PD). In the final step, the TR and the SR integrated the GUS-7 findings with their previous evaluation and reviewed their recommendations. The patients received the final recommendation from the SR to avoid patient confusion. The study was approved by the Internal Review Board and all the patients signed informed consent. GUS-7 usefulness was separately evaluated by the SR and the TR according to a visual analogue scale (0 = not useful at all, 10 = very useful). Descriptive statistics were used. RESULTS: The patients were primarily middle-aged females (91.4%) with (mean +/- SD) disease duration of 7.5 +/- 3.9 years. The majority of them (69.2% according to TR and 71.8% to SR) were in DAS28-ESR-remission. In 34 of 170 clinical scenarios (20%), the GUS-7 findings modified the final treatment proposal; 24 of these scenarios were determined by the TR vs. 10 by the SR: 70.5% vs. 29.5%, p = 0.01. Treatment changes (increase, decrease and joint injection) were similar between both specialists. As expected, the TR rated the GUS-7 usefulness higher than the SR, particularly in the clinical scenarios where the GUS-7 findings impacted treatment. CONCLUSIONS: Musculoskeletal ultrasound added to standard rheumatic assessments impacted the treatment proposal in a limited number of patients; the impact was greater in the TR. PMID- 28893221 TI - The indirect and direct pathways between physical fitness and academic achievement on commencement in post-compulsory education in a historical cohort of Danish school youth. AB - BACKGROUND: Some studies have found positive associations between physical fitness and academic achievements. Pupils' academic achievements should indicate scholastic abilities to commence a post-compulsory education. However, the effect magnitude of physical fitness and academic achievements on commencement in post compulsory education is unknown. We examined the pathways between physical fitness and academic achievement on pupils' commencement in post-compulsory education. METHODS: This historical cohort study followed 530 girls and 554 boys from the Danish municipality of Aalborg in the period 2008-2014, 13 to 15 years old in 2010. Physical fitness was assessed through a watt-max cycle ergometer test represented as VO2max (mL.kg-1.min-1). Academic achievement, commencement status and information on covariates were obtained from Danish nationwide registers. Causal inference based mediation analysis was used to investigate the indirect and direct pathways by separating the total effect of physical fitness on post-compulsory education commencement. RESULTS: Adjusting for sex, age, ethnicity and socioeconomic status, the overall mediation analysis showed an odds ratio (OR) of 1.87 (95% confidence interval (CI): 1.30; 2.73) for the total effect, corresponding to an increase in odds of post-compulsory education commencement when the physical fitness was increased by 10 units of VO2max. The separated total effect showed a natural direct OR of 1.36 (95% CI: 0.93; 1.98) and a natural indirect (i.e., through academic achievement) OR of 1.37 (95% CI: 1.20; 1.57). Thus, 51% (95% CI: 27%; 122%) of the effect of physical fitness on post-compulsory education commencement was mediated through academic achievement. CONCLUSION: Physical fitness had a positive effect on post-compulsory education commencement. A substantial part of this effect was mediated through academic achievement. PMID- 28893222 TI - Quality of antenatal care services and completion of four or more antenatal care visits in Ethiopia: a finding based on a demographic and health survey. AB - BACKGROUND: Antenatal care (ANC) is one of the core interventions for improving maternal outcomes. The average annual decline of maternal mortality rate from 1990 to 2013 was 5% in Ethiopia. This figure was below the least expected 5.5% to achieve the targeted 75% by 1990-2015. Moreover, completion of the recommended four or more ANC visits was only 32%. This study was aimed to examine individual, household and community level potential determinants of completing the recommended visits in the country. METHODS: The 2014 Ethiopian Mini Demographic and Health Survey data were used. Among women aged 15-49 years 3694 who had given birth in the 5 years preceding the survey were included in the analysis. The robust standard error method of generalized estimation equations were used for binary outcome variable from the clustered data. RESULTS: Only 33.0% (95% CI 31. 5% 34.5%) of women completed the recommended visits. Out of the total women, 56.5% had at least one ANC visit. Out of those who had at least one ANC visit, 37.4% visited in their first trimester. Completing the recommended visits was negatively associated with women in the lower educational level, lower economic conditions, higher birth order, and rural residence. But, it was positively associated with the community level high quality ANC services received. Difference in age and region also affected the completion of the recommended visits. CONCLUSION: The finding revealed the need for improving the uptake of ANC services, early arrival in the first trimester for services, and motivating mothers that begin ANC to confirm continuity. Strategies to foster completing the recommended visits should focus on upgrading quality of care services at the community level. Women in low economic level, high birth order, rural residence, and low educational status should be given special attention. Early and late age groups should be given special attention regarding the services. PMID- 28893224 TI - Relationship between sleep quality and cardiovascular disease risk in Chinese post-menopausal women. AB - BACKGROUND: Menopause is an inevitable stage affecting every middle-aged woman. China has a large and increasing group of post-menopausal women. Most post menopausal women suffer from increased risks for cardiovascular diseases (CVD) and sleep problems. Previous studies have demonstrated the associations between sleep disorders and increased CVD risks in general population. The current study is to examine the relationship between sleep quality and CVD risks among Chinese post-menopausal women. METHODS: This study was a sub-study nested in a cross sectional study that investigated the sleep quality of community-dwelling adults in Xian, Shaanxi Province, China. The Chinese version of the Pittsburgh Sleep Quality Index (PSQI) and the Framingham 10-year risk score (FRS) were used to measure sleep quality and CVD risk among 154 Chinese post-menopausal women. Multivariate regression and logistic regression were used to determine the association between sleep quality and CVD risk. RESULTS: The participants (age: 63.65 +/- 4.47 years) experienced poor sleep quality (mean score of global PSQI = 8.58) and a 10-year risk of CVD of 12.54%. The CVD risk was significantly associated with sleep duration (beta = - 0.18, p = 0.04) and sleep disturbance (beta = 0.33, p < 0.001). Women with good sleep quality (PSQI <=5) were less likely to be at high risk for CVD (FRS > 10%) (odds ratio = 0.51, p = 0.04). CONCLUSIONS: Poor sleep quality might increase the CVD risk in post-menopausal women. Interventions to promote the cardiovascular health of Chinese post menopausal women may need to include sleep promotion strategies. PMID- 28893223 TI - BRCA2 carriers with male breast cancer show elevated tumour methylation. AB - BACKGROUND: Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs. METHODS: 60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARbeta, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival. RESULTS: Tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARbeta methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARbeta and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival. CONCLUSIONS: Increased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types. PMID- 28893225 TI - Perspectives of Aboriginal women on participation in mammographic screening: a step towards improving services. AB - BACKGROUND: Early detection of breast cancer using screening mammography provides an opportunity for treatment which can lead to significantly improved outcomes. Despite considerable efforts having been made, the rate at which Aboriginal and Torres Strait Islander (hereafter respectfully referred to as Aboriginal) women in Western Australia participate in BreastScreen WA's screening mammogram program remains below that for the overall female population of Western Australia. This study aimed to examine perspectives on breast screening amongst Aboriginal women in Western Australia. We explored the factors which impact on participation in breast screening and sought to identify potential initiatives to address lower participation in screening. METHODS: Semi-structured interviews, focus group discussions and yarning sessions were conducted with a total of 65 research participants. They were all Aboriginal and comprised consumers and health professionals from locations across the state. RESULTS: Our findings show that research participants generally were willing to have a mammogram. Key reasons given were having a genetic predisposition to breast cancer and a perception of investing in health for the sake of the next generation, as well as personal well being. Barriers identified included lack of education about or understanding of screening, inadequacies in cultural appropriateness in the screening program, cultural beliefs around cancer in general and breast cancer in particular, and competing health and life priorities. However, many enablers were identified which can serve as potential strategies to assuage fear and increase screening uptake. These included increased education delivered by respected Aboriginal women, culturally appropriate promotion and the provision of care and support from other women in the community. CONCLUSION: The higher participation rates for Aboriginal women in Western Australia than are found for Aboriginal women nationally demonstrate the success of the strategies put in place by BreastScreen WA. These efforts must be supported and existing policies and practices enhanced to address the limitations in the existing program. Only by implementing and evaluating such initiatives and making breast screening programs more accessible to Aboriginal women can the current disparity between the screening participation rates of Aboriginal and non-Aboriginal women be reduced. PMID- 28893226 TI - Effect of periodontitis on the development of osteoporosis: results from a nationwide population-based cohort study (2003-2013). AB - BACKGROUND: The prevalence of osteoporosis associated with the aging process is anticipated to increase along with the rising aging population. Periodontitis that the most common chronic infections of humankind is considered the risk factor for osteoporosis. The aim of this study was to identify the association between osteoporosis and periodontitis using a population-based cohort. METHODS: The case group was defined as patients diagnosed with periodontitis and treated with subgingival curettage, root conditioning, periodontal flap operation, bone grafting for alveolar bone defects, and guided tissue regeneration. Case and control groups matched for gender, age, household income, type of social security, disability, and residential area were generated. A Cox proportional hazard model was constructed to examine the difference in the development of osteoporosis between the case and control groups. The final sample included 13,464 participants. RESULTS: The incidence of osteoporosis was 1.1% in males and 15.8% in females during a 10-year period. The risk factors for osteoporosis in males were increasing age and Charlson Comorbidity Index score. Periodontitis was not associated with the development of osteoporosis in males. The risk factors for osteoporosis in females were increasing age, body mass index, Charlson Comorbidity Index score, diabetes, and periodontitis. Women with periodontitis were more likely to also develop osteoporosis (HR: 1.22, 95% CI: 1.01-1.48). CONCLUSIONS: Periodontitis has an effect on the development of osteoporosis in females. Managing good teeth is required for the prevention and delay of osteoporosis. This includes dental examinations, regular cleanings and gum treatment. PMID- 28893227 TI - Damage control surgery - experiences from a level I trauma center. AB - BACKGROUND: There is still no evidence in literature for damage control orthopaedics (DCO), early total care (ETC) or using external fixation solely in fractures of the long bones in multi-system-trauma. The aim of this study was to determine parameters influencing the choice of treatment in clinical routine (DCO, ETC, or EF) in femoral or tibial shaft fractures in combination with multi system-trauma, severe soft tissue damage or both. METHODS: Data of 236 patients with 280 fractures of long bones of the lower extremities treated at a level I trauma center were analysed. Clinical parameters on arrival (age, sex [m/f], ISS, fracture site [femur/tibia], soft tissue damage [closed or open fractures according to the Gustilo-Anderson classification], pulmonary injury [yes/no]) were collected and analysed whether they influence the choice of upcoming treatment (DCO/ETC/EF). RESULTS: Our findings showed that high ISS and severe soft tissue damage (grade III) significantly correlated with DCO. High ISS, old age, female sex and fracture site (tibia) correlated with EF. This group of sole use of external fixation had highest rate of complications, 69% were associated with at least one complication. CONCLUSION: Severely injured patients are treated significantly more often with DCO or EF. The presence of higher ISS (>=16) and of type III open fractures increased the use of DCO. However, ISS, fracture-site, patient's age, type III open fractures or sex (female) increased the use of EF compared to ETC. PMID- 28893228 TI - XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis. AB - BACKGROUND: Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored. METHODS: We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors. RESULTS: XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo. CONCLUSION: These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells. PMID- 28893229 TI - Neuroimmune expression in hip osteoarthritis: a systematic review. AB - BACKGROUND: Neuroimmune axis is central in the physiopathology of hip osteoarthritis (OA), but its specific pathways are still unclear. This systematic review aims to assess the nervous and immune system profile of patients with hip osteoarthritis (OA) when compared to healthy controls. METHODS: A systematic review followed PRISMA guidelines was conducted. A two-step selection process was completed, and from 609 references 17 were included. The inclusion criteria were: original articles on adult patients with hip OA, with assessment of neuroimmune expression. Articles with other interventions prior to analysis and those without a control group were excluded. RESULTS: Thirty-nine relevant neuroimmune markers were identified, with assessments in bone, cartilage, synovial membrane, synovial fluid, whole blood, serum and/or immune cells. GM-CSF, IFN-gamma, IL-1alpha, IL 6, IL-8, IL-1 and TNF-alpha presented variable expression among tissues studied when compared between hip OA and controls. VEGFs and TGF-beta isoforms showed similar tendencies among tissues and studies. On nervous expression, CGRP, Tuj-1 and SP were increased in synovial membrane. Overall, patients with hip OA presented a higher number of overexpressed markers. CONCLUSIONS: For the first time a systematic review on neuroimmune expression in patients with hip OA found an upregulation of neuroimmune markers, with deregulated balance between pro and anti-inflammatory cytokines. However, no clear systematic pattern was found, and few information is available on nervous expression. This highlights the importance of future research with clear methodologies to guide the management of these patients. PMID- 28893230 TI - Assessment of free radical scavenging and anti-proliferative activities of Tinospora cordifolia Miers (Willd). AB - BACKGROUND: Tinospora cordifolia (Guduchi or Amrita) is an important drug of Ayurvedic System of Medicine and found mention in various classical texts for the treatment of diseases such as jaundice, fever, diabetes, cancer and skin disease etc. In view of its traditional claims, antioxidant and anti-proliferative activities were evaluated in the present study. METHODS: Ethanol extract (TCE) and subsequent petroleum ether (TCP), dichloromethane (TCD), n-Butanol (TCB) and aqueous (TCA) fractions of were prepared from stems of T cordifolia. Total phenolic, flavonoid content and anti-oxidant activity was assessed by different methods. Anti-proliferative activity was assessed in cervical carcinoma (HeLa) cell lines by MTT and SRB assay. RESULTS: Ethanol extract and n-butanol fractions shown to be superior in their scavenging activity in all the tested methods. n butanol fractions shown antioxidant activity with an IC50 of 14.81 +/- 0.53, 29.48 +/- 2.23, 58.20 +/- 0.70 and 21.17 +/- 1.19 MUg/mL by DPPH, ABTS, Nitric oxide and iron chelating activities respectively. Anti-proliferative activity results demonstrates that the TCD and ethanol extract of T cordifolia exhibits potent cytotoxic effect against HeLa with an IC50 of 54.23 +/- 0.94 MUg/mL and 101.26 +/- 1.42 MUg/mL respectively by MTT assay; and with an IC50 of 48.91 +/- 0.33 MUg/mL and 87.93 +/- 0.85 MUg/mL respectively by SRB assay. CONCLUSION: The outcomes of the present study support the fact that T Cordifolia is a promising source of antioxidant agent and propose its further investigation. Moreover, dichloromethane fraction of T cordifolia shown to be the most potent anti proliferative fraction and further mechanistic and phytochemical investigations are under way to identify the active principles. PMID- 28893232 TI - Plasminogen activator inhibitor-1 deficiency enhances subchondral osteopenia after induction of osteoarthritis in mice. AB - BACKGROUND: Subchondral osteopenia is important for the pathophysiology of osteoarthritis (OA). Although previous studies suggest that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is related to bone metabolism, its role in OA remains unknown. We therefore investigated the roles of PAI-1 in the subchondral bone in OA model mice. METHODS: Wild type (WT) and PAI-1 deficient (KO) mice were ovariectomized (OVX), and then destabilization of the medial meniscus (DMM) surgery was performed. RESULTS: DMM and OVX significantly decreased the trabecular bone mineral density of the subchondral bone evaluated by quantitative computed tomography in PAI-1 KO mice. The effects of OVX and/or PAI-1 deficiency on the OARSI score for the evaluation of the progression of knee degeneration were not significant. PAI-1 deficiency significantly augmented receptor activator nuclear factor kappaB ligand mRNA levels enhanced by IL-1beta in mouse primary osteoblasts, although it did not affect osteoblast differentiation. Moreover, PAI-1 deficiency significantly increased osteoclast formation from mouse bone marrow cells. CONCLUSION: We showed that PAI-1 deficiency accelerates the subchondral osteopenia after induction of OA in mice. PAI-1 might suppress an enhancement of bone resorption and subsequent subchondral osteopenia after induction of OA in mice. PMID- 28893231 TI - Involvement of DPP9 in gene fusions in serous ovarian carcinoma. AB - BACKGROUND: A fusion gene is a hybrid gene consisting of parts from two previously independent genes. Chromosomal rearrangements leading to gene breakage are frequent in high-grade serous ovarian carcinomas and have been reported as a common mechanism for inactivating tumor suppressor genes. However, no fusion genes have been repeatedly reported to be recurrent driver events in ovarian carcinogenesis. We combined genomic and transcriptomic information to identify novel fusion gene candidates and aberrantly expressed genes in ovarian carcinomas. METHODS: Examined were 19 previously karyotyped ovarian carcinomas (18 of the serous histotype and one undifferentiated). First, karyotypic aberrations were compared to fusion gene candidates identified by RNA sequencing (RNA-seq). In addition, we used exon-level gene expression microarrays as a screening tool to identify aberrantly expressed genes possibly involved in gene fusion events, and compared the findings to the RNA-seq data. RESULTS: We found a DPP9-PPP6R3 fusion transcript in one tumor showing a matching genomic 11;19 translocation. Another tumor had a rearrangement of DPP9 with PLIN3. Both rearrangements were associated with diminished expression of the 3' end of DPP9 corresponding to the breakpoints identified by RNA-seq. For the exon-level expression analysis, candidate fusion partner genes were ranked according to deviating expression compared to the median of the sample set. The results were collated with data obtained from the RNA-seq analysis. Several fusion candidates were identified, among them TMEM123-MMP27, ZBTB46-WFDC13, and PLXNB1-PRKAR2A, all of which led to stronger expression of the 3' genes. In view of our previous findings of nonrandom rearrangements of chromosome 19 in this cancer type, particular emphasis was given to changes of this chromosome and a DDA1-FAM129C fusion event was identified. CONCLUSIONS: We have identified novel fusion gene candidates in high-grade serous ovarian carcinoma. DPP9 was involved in two different fusion transcripts that both resulted in deregulated expression of the 3' end of the transcript and thus possible loss of the active domains in the DPP9 protein. The identified rearrangements might play a role in tumorigenesis or tumor progression. PMID- 28893233 TI - Clinical characteristics of adrenal crisis in adult population with and without predisposing chronic adrenal insufficiency: a retrospective cohort study. AB - BACKGROUND: Adrenal crisis (AC) occurs in various clinical conditions but previous epidemiological studies in AC are limited to chronic adrenal insufficiency (AI) and sepsis. The aim of this study was to investigate characteristics of AC patients, including predisposing diseases and to describe candidate risk factors for AC such as comorbidities and glucocorticoid (GC) therapy. METHODS: We conducted a retrospective cohort study using a claims database on 7.4 million patients from 145 acute care hospitals between January 1, 2003 and April 30, 2014. We identified AC patients who met the following criteria: 1) disease name with ICD-10 corresponded with AI; 2) therapeutic GC administration (hydrocortisone equivalent dose >=100 mg/day); 3) admission; and 4) age >=18 years. RESULTS: We identified 504 patients with AC (median age, 71 years; interquartile range, 59 to 80; 50.6% male). As predisposing conditions, primary AI and central AI accounted for 23 (4.6%) and 136 patients (27.0%), respectively. In the remaining AC patients (68.5%), comorbidities such as cancer, autoimmune diseases, and renal failure were frequent. The most frequent indication for hospitalization was AC (16.3%), followed by pituitary disease (14.7%), cancer (14.7%), AI-related clinical symptoms (11.5%), and infection (11.1%). Admission under oral GC treatment was reported in 104 patients (20.6%). Twenty-six patients were admitted within 14 days after GC cessation (5.2%). CONCLUSIONS: These findings present an overview of patients with AC in general practice settings, clarifying that predisposing factors for AC were complicated and that patients other than those with chronic AI were older and had more comorbid conditions than those with primary and central AI. PMID- 28893234 TI - Study comparing 3 hour and 24 hour post-operative removal of bladder catheter and vaginal pack following vaginal surgery: a randomised controlled trial. AB - BACKGROUND: Traditional practice after vaginal hysterectomy was to keep the vaginal pack and urinary catheter for 24 hours post operatively. But there were studies that prolonged cathterisation was associated with urinary infection. So this study was conducted to compare the post operative outcome when the urinary catheter and vaginal pack were removed after 3 hours and after 24 hours after surgery. METHODS: The study was done in the Department of Obstetrics and Gynecology, in a tertiary teaching institute of South India from September 2008 to March 2010. It was a randomised controlled trial involving 200 women undergoing vaginal surgery, who were randomly assigned to 2 groups - catheter and vaginal pack were removed either in 3 h in study group or were removed in 24 h in control group. The outcome of the study were vaginal bleeding, urinary retention, febrile morbidity, and urinary infection. RESULTS: There was no significant difference between the study and control groups with respect to vaginal bleeding (0 and 1%, p = 1), urinary retention (9 and 4%, p = 0.15), febrile morbidity (7 and 4%, p = 0.35), and urinary infection (26% in each group, p = 1.0). CONCLUSION: Keeping the urinary catheter and vaginal pack for 24 h following vaginal surgery does not offer any additional benefit against removing them after 3 h. PMID- 28893235 TI - Inadequate birth spacing is perceived as riskier than all family planning methods, except sterilization and abortion, in a qualitative study among urban Nigerians. AB - BACKGROUND: Fertility is high in Nigeria and contraceptive use is low. Little is known about how urban Nigerians perceive the risk of contraceptive use in relation to pregnancy and birth. This study examines and compares the risk perception of family planning methods and pregnancy related scenarios among urban Nigerians. METHODS: A total of 26 focus group discussions with 243 participants were conducted in September and October 2010 in Ibadan and Kaduna. The groups were stratified by sex, age, family planning use, and city. Study participants were asked to identify the risk associated with six different family planning methods and four pregnancy related risks. The data were coded in ATLAS.ti 6 and analyzed using the thematic content analysis approach. RESULTS: The ten family planning and pregnancy related items ranked as follows from most to least risky: sterilization, abortion, getting pregnant soon after having a baby (no birth spacing), pill, IUD, injectable, having a birth under 18 years of age (teenage motherhood), condom use, having six children, and fertility awareness methods. Risk of family planning methods was often categorized in terms of side effects and complications. Positive perceptions of teenage motherhood and having many children influenced the low ranking of these items. CONCLUSION: Inadequate birth spacing was rated as more risky than all contraceptive methods and pregnancy related events except for sterilization and abortion. Some of the participants' risk perceptions of contraceptives and pregnancy related scenarios does not correspond to actual risk of methods and practices. Instead, the items' perceived riskiness largely correspond with prevailing social norms. However, there was a high level of understanding of the risks of inadequate birth spacing. TRIAL REGISTRATION NUMBER: This study is not a randomized control trial so the study has not been registered as such. PMID- 28893236 TI - Neutrophil-lymphocyte ratio complements volumetric staging as prognostic factor in patients treated with definitive radiotherapy for oropharyngeal cancer. AB - BACKGROUND: Volumetric tumor staging has been shown as superior prognostic tool compared to the conventional TNM system in patients undergoing definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer. Recently, clinical immunoscores such as the neutrophil-lymphocyte ratio (NLR) have been investigated as prognostic markers in several tumor entities. The aim of this study was to assess the combined prognostic value of NLR and tumor volume in patients treated with IMRT for oropharyngeal cancer (OC). METHODS: Data on all consecutive patients treated for locally advanced or inoperable OC with IMRT from 2002-2011 was prospectively collected. Tumor volume was assessed based on the total gross tumor volume (tGTV) calculated by the treatment planning system volume algorithm. The NLR was collected by a retrospective analysis of differential blood count before initiation of therapy. RESULTS: Overall, 187 eligible patients were treated with a median IMRT dose of 69.6 Gy. Three-year recurrence-free survival (RFS) for low, intermediate, high and very high tumor volume groups was 88%, 74%, 62% and 25%, respectively (p = 0.007). Patients with elevated NLR (>4.68) showed a significantly decreased 3-year RFS of 44% vs. 81% (p < 0.001) and 3-year OS of 56% vs. 84% (p < 0.001). The NLR remained a significant prognostic factor for RFS and OS when tested among tumor volume groups. Univariate and multivariate regression analysis confirmed both tumor volume and NLR as independent prognostic factors. The NLR offered further statistically significant prognostic differentiation of the small/intermediate/large tumor volume groups. CONCLUSION: The NLR remains an independent prognostic factor for patients with OC undergoing radiotherapy independent of the tumor volume. PMID- 28893237 TI - Methods for the field evaluation of quantitative G6PD diagnostics: a review. AB - Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at risk of severe haemolysis following the administration of 8-aminoquinoline compounds. Primaquine is the only widely available 8-aminoquinoline for the radical cure of Plasmodium vivax. Tafenoquine is under development with the potential to simplify treatment regimens, but point-of-care (PoC) tests will be needed to provide quantitative measurement of G6PD activity prior to its administration. There is currently a lack of appropriate G6PD PoC tests, but a number of new tests are in development and are likely to enter the market in the coming years. As these are implemented, they will need to be validated in field studies. This article outlines the technical details for the field evaluation of novel quantitative G6PD diagnostics such as sample handling, reference testing and statistical analysis. Field evaluation is based on the comparison of paired samples, including one sample tested by the new assay at point of care and one sample tested by the gold-standard reference method, UV spectrophotometry in an established laboratory. Samples can be collected as capillary or venous blood; the existing literature suggests that potential differences in capillary or venous blood are unlikely to affect results substantially. The collection and storage of samples is critical to ensure preservation of enzyme activity, it is recommended that samples are stored at 4 degrees C and testing occurs within 4 days of collection. Test results can be visually presented as scatter plot, Bland Altman plot, and a histogram of the G6PD activity distribution of the study population. Calculating the adjusted male median allows categorizing results according to G6PD activity to calculate standard performance indicators and to perform receiver operating characteristic (ROC) analysis. PMID- 28893238 TI - Monitoring progression of clinical reasoning skills during health sciences education using the case method - a qualitative observational study. AB - BACKGROUND: Outcome- or competency-based education is well established in medical and health sciences education. Curricula are based on courses where students develop their competences and assessment is also usually course-based. Clinical reasoning is an important competence, and the aim of this study was to monitor and describe students' progression in professional clinical reasoning skills during health sciences education using observations of group discussions following the case method. METHODS: In this qualitative study students from three different health education programmes were observed while discussing clinical cases in a modified Harvard case method session. A rubric with four dimensions - problem-solving process, disciplinary knowledge, character of discussion and communication - was used as an observational tool to identify clinical reasoning. A deductive content analysis was performed. RESULTS: The results revealed the students' transition over time from reasoning based strictly on theoretical knowledge to reasoning ability characterized by clinical considerations and experiences. Students who were approaching the end of their education immediately identified the most important problem and then focused on this in their discussion. Practice knowledge increased over time, which was seen as progression in the use of professional language, concepts, terms and the use of prior clinical experience. The character of the discussion evolved from theoretical considerations early in the education to clinical reasoning in later years. Communication within the groups was supportive and conducted with a professional tone. CONCLUSIONS: Our observations revealed progression in several aspects of students' clinical reasoning skills on a group level in their discussions of clinical cases. We suggest that the case method can be a useful tool in assessing quality in health sciences education. PMID- 28893239 TI - Association of TCM body constitution with insulin resistance and risk of diabetes in impaired glucose regulation patients. AB - BACKGROUND: Impaired glucose regulation (IGR) patients have increased risk of type 2 diabetes mellitus (T2DM). Identifying relevant risk factors in IGR subjects could facilitate early detection and prevention of IGR progression to diabetes. This study investigated the association between Traditional Chinese Medicine (TCM) body constitution and serum cytokines, and whether body constitution could independently predict diabetes in IGR subjects. METHOD: Patients with IGR (n = 306) received a blood test and their body constitution type was assessed using a body constitution questionnaire (BCQ). Serum levels of cytokines were measured by ELISA. Patients were followed up for at least three years, and their status of diabetes were recorded. Multivariate logistic regression was used to estimate odds ratios (ORs) of diabetes for body constitution. RESULTS: Phlegm-damp, Damp-heat and Qi-deficiency were three most common unbanlenced constitutions among IGR subjects. Phlegm-damp and Damp-heat constitution subjects showed higher serum levels of interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), leptin and lower serum levels of adiponectin (P<0.05). Qi-deficiency constitution subjects showed higher serum levels of leptin and lower serum levels of adiponectin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) (P<0.05). Subjects with Phlegm-damp or Damp heat constitution demonstrated a significantly higher risk of diabetes (P<0.05). CONCLUSION: Phlegm-damp and Damp-heat TCM body constitution are strongly associated with abnormal serum cytokines, and could potentially serve as a predictor of diabetes in IGR subjects. Body constitution can help to identify IGR subjects who are at a high risk of progression to diabetes. PMID- 28893240 TI - The influence of age on insecticide susceptibility of Anopheles arabiensis during dry and rainy seasons in rice irrigation schemes of Northern Tanzania. AB - BACKGROUND: Insecticide resistance is the major emerging challenge facing the malaria vector control programmes in Tanzania. Proper monitoring and detection is of paramount importance guiding the vector control programmes. This paper presents the effect of mosquito aging on insecticide resistance status in Anopheles arabiensis populations in dry and rainy seasons in northern Tanzania. METHODS: Anopheles gambiae s.l. larvae were sampled from rice fields in both dry and rainy seasons and reared in the insectary to adults. The emerged females in batches of 2, 3, 5, and 10 days old were exposed to six insecticides (deltamethrin, permethrin, lambda-cyhalothrin, DDT, bendiocarb and pirimiphos methyl) to see the effects of age on insecticide resistance. Mosquitoes were exposed to insecticides using WHO standard susceptibility test kits. Knockdown was recorded during the 1-h exposure, while mortality and resistance ratio were recorded 24 h later. Mosquito specimens were identified to species level using the polymerase chain reaction (PCR) method. RESULTS: Among the 326 specimens processed by PCR, 323 (99.1%) were identified as Anopheles arabiensis. There was reduced mortality (ranging from 61 to 97.7%) when adults reared from larvae were exposed to all pyrethroids and bendiocarb in both dry and rainy seasons, while they were fully susceptible to DDT and pirimiphos-methyl. There was a significant increase in mortality rate with increase in mosquito's age in both dry and rainy seasons following exposure to pyrethroids (DF = 1, P < 0.05). Mosquitoes showed significantly higher mortality rates in the rainy season than in the dry season after being exposed to pyrethroids (DF = 1, P < 0.05). Higher mortality rates (94.0-99.8%) were observed in all ages and seasons when mosquitoes were exposed to bendiocarb compared with pyrethroids. Pirimiphos-methyl was only tested in the rainy season so no comparison with dry season mosquitoes could be made. CONCLUSIONS: Results showed that An. arabiensis were resistant to pyrethroids in both seasons and that the young age groups exhibited higher levels of resistance compared with the older age groups. Mosquitoes were full susceptible to DDT and pirimiphos-methyl irrespective of the season and age. PMID- 28893241 TI - Evidence-based selection process to the Master of Public Health program at Medical University. AB - BACKGROUND: Evaluation of the predictive validity of selected sociodemographic factors and admission criteria for Master's studies in Public Health at the Faculty of Health Sciences, Medical University of Warsaw (MUW). METHODS: For the evaluation purposes recruitment data and learning results of students enrolled between 2008 and 2012 were used (N = 605, average age 22.9 +/- 3.01). The predictive analysis was performed using the multiple linear regression method. In the proposed regression model 12 predictors were selected, including: sex, age, professional degree (BA), the Bachelor's studies grade point average (GPA), total score of the preliminary examination broken down into five thematic areas. Depending on the tested model, one of two dependent variables was used: first year GPA or cumulative GPA in the Master program. RESULTS: The regression model based on the result variable of Master's GPA program was better matched to data in comparison to the model based on the first year GPA (adjusted R2 0.413 versus 0.476 respectively). The Bachelor's studies GPA and each of the five subtests comprising the test entrance exam were significant predictors of success achieved by a student both after the first year and at the end of the course of studies. CONCLUSIONS: Criteria of admissions with total score of MCQs exam and Bachelor's studies GPA can be successfully used for selection of the candidates for Master's degree studies in Public Health. The high predictive validity of the recruitment system confirms the validity of the adopted admission policy at MUW. PMID- 28893242 TI - How is success achieved by individuals innovating for patient safety and quality in the NHS? AB - BACKGROUND: Innovation in healthcare is said to be notoriously difficult to achieve and sustain yet simultaneously the health service is under intense pressure to innovate given the ever increasing demands placed upon it. Whilst many studies have looked at diffusion of innovation from an organisational perspective, few have sought to understand how individuals working in healthcare innovate successfully. We took a positive deviance approach to understand how innovations are achieved by individuals working in the NHS. METHOD: We conducted in depth interviews in 2015 with 15 individuals who had received a national award for being a successful UK innovator in healthcare. We invited only those people who were currently (or had recently) worked in the NHS and whose innovation focused on improving patient safety or quality. Thematic analysis was used. FINDINGS: Four themes emerged from the data: personal determination, the ability to broker relationships and make connections, the ways in which innovators were able to navigate organisational culture to their advantage and their ability to use evidence to influence others. Determination, focus and persistence were important personal characteristics of innovators as were skills in being able to challenge the status quo. Innovators were able to connect sometimes disparate teams and people, being the broker between them in negotiating collaborative working. The culture of the organisation these participants resided in was important with some being able to use this (and the current patient safety agenda) to their advantage. Gathering robust data to demonstrate their innovation had a positive impact and was seen as essential to its progression. CONCLUSIONS: This paper reveals a number of factors which are important to the success of innovators in healthcare. We have uncovered that innovators have particular personal traits which encourage a propensity towards change and action. Yet, for fruitful innovation to take place, it is important for relational networks and organisational culture to be receptive to change. PMID- 28893243 TI - Impact of pharmacy worker training and deployment on access to essential medicines for children under five in Malawi: a cluster quasi-experimental evaluation. AB - BACKGROUND: Poor access to essential medicines is common in many low- and middle income countries, partly due to an insufficient and inadequately trained workforce to manage the medicines supply chain. We conducted a prospective impact evaluation of the training and deployment of pharmacy assistants (PAs) to rural health centers in Malawi. METHODS: A quasi-experimental design was used to compare access to medicines in two districts where newly trained PAs were deployed to health centers (intervention) and two districts with no trained PAs at health centers (comparison). A baseline household survey and two annual post intervention household surveys were conducted. We studied children under five years with a history of fever, cough and difficulty in breathing, and diarrhea in the previous two weeks. We collected data on access to antimalarials, antibiotics and oral rehydration salts (ORS) during the childrens' symptomatic periods. We used difference-in-differences regression models to estimate the impact of PA training and deployment on access to medicines. RESULTS: We included 3974 children across the three rounds of annual surveys: 1840 (46%) in the districts with PAs deployed at health centers and 2096 (53%) in districts with no PAs deployed at health centers. Approximately 80% of children had a fever, nearly 30% had a cough, and 43% had diarrhea in the previous two weeks. In the first year of the program, the presence of a PA led to a significant 74% increase in the odds of access to any antimalarial, and a significant 49% increase in the odds of access to artemisinin combination therapies. This effect was restricted to the first year post-intervention. There was no effect of presence of a PA on access to antibiotics or ORS. CONCLUSION: The training and deployment of pharmacy assistants to rural health centers in Malawi increased access to antimalarial medications over the first year, but the effect was attenuated over the second year. Pharmacy assistants training and deployment demonstrated no impact on access to antibiotics for pneumonia or oral rehydration salts for diarrhea. PMID- 28893244 TI - A randomized, placebo-controlled study of the cardiovascular safety of the once weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. AB - BACKGROUND: Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that is approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval of omarigliptin in the United States, the clinical development program included a cardiovascular (CV) safety study. Subsequently, a business decision was made not to submit a marketing application for omarigliptin in the United States, and the CV safety study was terminated. Herein we report an analysis of data from that early-terminated study. METHODS: In this randomized, double-blind study, 4202 patients with T2DM and established CV disease were assigned to either omarigliptin 25 mg q.w. or matching placebo in addition to their existing diabetes therapy. A Cox proportional hazards model was used to summarize the primary endpoint of time to first major adverse CV event (MACE, the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke) and the analysis of first event of hospitalization for heart failure (hHF). RESULTS: The median follow-up was approximately 96 weeks (range 1.1-178.6 weeks). The primary MACE outcome occurred in 114/2092 patients in the omarigliptin group (5.45%; 2.96/100 patient-years) and 114/2100 patients in the placebo group (5.43%; 2.97/100 patient-years), with a hazard ratio (HR) of 1.00 (95% confidence interval [CI] 0.77, 1.29). The hHF outcome occurred in 20/2092 patients in the omarigliptin group (0.96%; 0.51/100 patient-years) and 33/2100 patients in the placebo group (1.57%; 0.85/100 patient-years), with an HR of 0.60 (95% CI 0.35, 1.05). After 142 weeks, the least-squares mean difference (omarigliptin vs. placebo) in glycated hemoglobin levels was -0.3% (95% CI -0.46, -0.14). The numbers of patients with adverse events, serious adverse events or discontinued from study medication due to adverse events were similar in the omarigliptin and placebo groups. CONCLUSIONS: In this CV safety study of patients with T2DM and established CV disease, omarigliptin did not increase the risk of MACE or hHF and was generally well tolerated. Trial registration ClinicalTrials.gov: NCT01703208. Registered 05 October 2012. PMID- 28893246 TI - Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study. AB - BACKGROUND: Therapeutic drug monitoring (TDM) aims to minimize the clinical impact of posaconazole and voriconazole pharmacokinetic variability. However, its benefits on clinical outcomes are still being defined. Additionally, TDM data are limited for posaconazole IV and delayed-release tablet formulations among specific patient populations, including critically ill. The aim of this study was to determine the percentage of therapeutic posaconazole and voriconazole drug levels across all formulations in a real-world clinical setting and elucidate factors affecting attainment of target concentrations. METHODS: This study was a retrospective cohort study conducted at the University of Colorado Hospital between September 2006 and June 2015 that evaluated patients who received posaconazole or voriconazole TDM as part of routine care. RESULTS: Voriconazole (n = 250) and posaconazole (n = 100) levels were analyzed from 151 patients. Of these, 54% of voriconazole and 69% of posaconazole levels were therapeutic. For posaconazole, 14/38 (37%), 28/29 (97%) and 27/33 (82%) levels were therapeutic for the oral suspension, IV, and delayed-release tablet, respectively. Intravenous and delayed-release tablet posaconazole were 20 fold (p < 0.01) and sevenfold (p = 0.002) more likely than the oral suspension to achieve a therapeutic level. Subsequent levels were more likely to be therapeutic after dose adjustments (OR 3.31; 95% CI 1.3-8.6; p = 0.02), regardless of timing of initial non-therapeutic level. In a multivariable logistic regression analysis, no characteristics were independently predictive of therapeutic voriconazole levels and only absence of H2RA/PPI use was independently predictive of therapeutic posaconazole levels. There was no correlation between survival and therapeutic drug levels for either voriconazole (p = 0.67) or posaconazole (p = 0.50). CONCLUSIONS: A high percentage of drug levels did not achieve TDM targets for voriconazole and posaconazole oral suspension, supporting the need for routine TDM for those formulations. The utility of TDM for the IV and delayed release tablet formulations of posaconazole is less apparent. PMID- 28893245 TI - Age-dependent redox status in the brain stem of NO-deficient hypertensive rats. AB - BACKGROUND: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. METHODS: Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/kg/day), a specific nNOS inhibitor, with NG-nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. RESULTS: We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. CONCLUSION: Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME- induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level. PMID- 28893248 TI - The impact of austerity on the health workforce and the achievement of human resources for health policies in Ireland (2008-2014). AB - BACKGROUND: The global economic crisis saw recessionary conditions in most EU countries. Ireland's severe recession produced pro-cyclical health spending cuts. Yet, human resources for health (HRH) are the most critical of inputs into a health system and an important economic driver. The aim of this article is to evaluate how the Irish health system coped with austerity in relation to HRH and whether austerity allowed and/or facilitated the implementation of HRH policy. METHODS: The authors employed a quantitative longitudinal trend analysis over the period 2008 to 2014 with Health Service Executive (HSE) staff database as the principal source. For the purpose of this study, heath service employment is defined as directly employed whole-time equivalent public service staffing in the HSE and other government agencies. The authors also examined the heath sector pay bill and sought to establish linkages between the main staff database and pay expenditure, as given in the HSE Annual Accounts and Financial Statements (AFS), and key HRH policies. RESULTS: The actual cut in total whole-time equivalent (WTE) of directly employed health services human resources over the period 2008 to 2014 was 8027 WTE, a reduction of 7.2% but substantially less than government claims. There was a degree of relative protection for frontline staffing decreasing by 2.9% between 2008 and 2014 and far less than the 18.5% reduction in other staff. Staff exempted from the general moratorium also increased by a combined 12.6%. Counter to stated policy, the decline in staffing of non-acute care was over double than in acute care. Further, the reduction in directly employed staff was to a great extent matched by a marked increase in agency spending. CONCLUSIONS: The cuts forced substantial HRH reductions and yet there was some success in pursuing policy goals, such as increasing the frontline workforce while reducing support staff and protection of some cadres. Nevertheless, other policies failed such as moving staff away from acute settings and the claimed financial savings were substantially offset by overtime payments and the need to hire more expensive agency workers. There was also substantial demotivation of staff as a consequence of the changes. PMID- 28893247 TI - Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. AB - TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFkappaB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers. PMID- 28893249 TI - Assessment of the potential respiratory hazard of volcanic ash from future Icelandic eruptions: a study of archived basaltic to rhyolitic ash samples. AB - BACKGROUND: The eruptions of Eyjafjallajokull (2010) and Grimsvotn (2011), Iceland, triggered immediate, international consideration of the respiratory health hazard of inhaling volcanic ash, and prompted the need to estimate the potential hazard posed by future eruptions of Iceland's volcanoes to Icelandic and Northern European populations. METHODS: A physicochemical characterization and toxicological assessment was conducted on a suite of archived ash samples spanning the spectrum of past eruptions (basaltic to rhyolitic magmatic composition) of Icelandic volcanoes following a protocol specifically designed by the International Volcanic Health Hazard Network. RESULTS: Icelandic ash can be of a respirable size (up to 11.3 vol.% < 4 MUm), but the samples did not display physicochemical characteristics of pathogenic particulate in terms of composition or morphology. Ash particles were generally angular, being composed of fragmented glass and crystals. Few fiber-like particles were observed, but those present comprised glass or sodium oxides, and are not related to pathogenic natural fibers, like asbestos or fibrous zeolites, thereby limiting concern of associated respiratory diseases. None of the samples contained cristobalite or tridymite, and only one sample contained quartz, minerals of interest due to the potential to cause silicosis. Sample surface areas are low, ranging from 0.4 to 1.6 m2 g-1, which aligns with analyses on ash from other eruptions worldwide. All samples generated a low level of hydroxyl radicals (HO*), a measure of surface reactivity, through the iron-catalyzed Fenton reaction compared to concurrently analyzed comparative samples. However, radical generation increased after 'refreshing' sample surfaces, indicating that newly erupted samples may display higher reactivity. A composition-dependent range of available surface iron was measured after a 7-day incubation, from 22.5 to 315.7 MUmol m-2, with mafic samples releasing more iron than silicic samples. All samples were non-reactive in a test of red blood cell-membrane damage. CONCLUSIONS: The primary particle specific concern is the potential for future eruptions of Iceland's volcanoes to generate fine, respirable material and, thus, to increase ambient PM concentrations. This particularly applies to highly explosive silicic eruptions, but can also hold true for explosive basaltic eruptions or discrete events associated with basaltic fissure eruptions. PMID- 28893250 TI - Association between dietary patterns and cognitive function among 70-year-old Japanese elderly: a cross-sectional analysis of the SONIC study. AB - BACKGROUND: An increasing number of studies in Western countries have shown that healthy dietary patterns may have a protective effect against cognitive decline and dementia. However, information on this relationship among non-Western populations with different cultural settings is extremely limited. We aim to examine the relationship between dietary patterns and cognitive function among older Japanese people. METHODS: This cross-sectional study included 635 community dwelling people aged 69-71 years who participated in the prospective cohort study titled Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC). Diet was assessed over a one-month period with a validated, brief-type, self-administered diet history questionnaire. Dietary patterns from thirty-three predefined food groups [energy-adjusted food (g/d)] were extracted by factor analysis. Cognitive function was assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Multivariate regression analysis was performed to examine the relationship between dietary patterns and cognitive function. RESULTS: Three dietary patterns were identified: the 'Plant foods and fish', 'Rice and miso soup', and 'Animal food' patterns. The 'Plant foods and fish' pattern, characterized by high intakes of green and other vegetables, soy products, seaweeds, mushrooms, potatoes, fruit, fish, and green tea, was significantly associated with a higher MoCA-J score [MoCA-J score per one quartile increase in dietary pattern: beta = 0.56 (95% CI: 0.33, 0.79), P for trend <0.001]. This association was still evident after adjustment for potential confounding factors [beta = 0.41 (95% CI: 0.17, 0.65), P for trend <0.001]. In contrast, neither the 'Rice and miso soup' nor the 'Animal food' pattern was related to cognitive function. To confirm the possibility of reverse causation we also conducted a sensitivity analysis excluding 186 subjects who reported substantial changes in their diet for any reason, but the results did not change materially. CONCLUSION: This preliminary cross-sectional study suggests that a diet with high intakes of vegetables, soy products, fruit, and fish may have a beneficial effect on cognitive function in older Japanese people. Further prospective studies are needed to confirm this finding. PMID- 28893251 TI - Identification and immobilization of a novel cold-adapted esterase, and its potential for bioremediation of pyrethroid-contaminated vegetables. AB - BACKGROUND: Pyrethroids are potentially harmful to living organisms and ecosystems. Thus, concerns have been raised about pyrethroid residues and their persistence in agricultural products. To date, although several pyrethroid hydrolyzing enzymes have been cloned, very few reports are available on pyrethroid-hydrolyzing enzymes with cold adaptation, high hydrolytic activity and good reusability, indispensable properties in practical bioremediation of pyrethroid-contaminated vegetables. RESULTS: Here, a novel gene (est684) encoding pyrethroid-hydrolyzing esterase was isolated from the Mao-tofu metagenome for the first time. Est684 encoded a protein of 227 amino acids and was expressed in Escherichia coli BL21 (DE3) in soluble form. The optimum temperature was 18 degrees C. It maintained 46.1% of activity at 0 degrees C and over 50% of its maximal activity at 4-35 degrees C. With the goal of enhancing stability and recycling biocatalysts, we used mesoporous silica SBA-15 as a nanometer carrier for the efficient immobilization of Est684 by the absorption method. The best conditions were an esterase-to-silica ratio of 0.96 mg/g (w/w) and an adsorption time of 30 min at 10 degrees C. Under these conditions, the recovery of enzyme activity was 81.3%. A large improvement in the thermostability of Est684 was achieved. The half-life (T1/2) of the immobilized enzyme at 35 degrees C was 6 h, 4 times longer than the soluble enzyme. Interestingly, the immobilized Est684 had less loss in enzyme activity up to 12 consecutive cycles, and it retained nearly 54% of its activity after 28 cycles, indicating excellent operational stability. Another noteworthy characteristic was its high catalytic activity. It efficiently hydrolyzed cyhalothrin, cypermethrin, and fenvalreate in pyrethroid contaminated cucumber within 5 min, reaching over 85% degradation efficiency after four cycles. CONCLUSIONS: A novel cold-adapted pyrethroid-hydrolyzing esterase was screened from the Mao-tofu metagenome. This report is the first on immobilizing pyrethroid-hydrolyzing enzyme on mesoporous silica. The immobilized enzyme with high hydrolytic activity and outstanding reusability has a remarkable potential for bioremediation of pyrethroid-contaminated vegetables, and it is proposed as an industrial enzyme. PMID- 28893252 TI - Association between carotid plaque characteristics and acute cerebral infarction determined by MRI in patients with type 2 diabetes mellitus. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) might aggravate the carotid plaque vulnerability, and increase the risk for ischemic stroke. Few studies reported the acute stroke subtype with carotid plaque characteristics in T2DM patients. This study aimed to investigate the association between carotid plaque characteristics and acute cerebral infarct (ACI) lesion features determined by MRI in T2DM patients. METHODS: Patients with acute cerebrovascular syndrome in internal carotid artery territory were recruited. All patients were stratified into T2DM and non-T2DM groups and underwent both carotid and brain MRI scans. Ipsilateral carotid plaque morphological and compositional characteristics, intracranial and extracranial carotid artery stenosis were also determined. Stroke subtype based on the Trial of ORG 10172 in Acute Stroke Treatment classification and ACI lesion patterns were evaluated. RESULTS: Of the recruited 140 patients, 68 (48.6%) patients had T2DM (mean age 64.16 +/- 11.38 years, 40 males). T2DM patients exhibited higher prevalence of carotid type IV-VI lesions, larger plaque burden as well as larger lipid-rich necrotic core (LRNC) compared with non-T2DM patients. Among the patients with carotid LRNC on symptomatic side, more concomitant large perforating artery infarct patterns and larger ACI size in the internal carotid artery territory were found in T2DM group than those in non T2DM group. Carotid plaque with LRNC% > 22.0% was identified as an independent risk factor for the presence of ACI lesions confined to the carotid territory in T2DM patients, regardless of other risk factors. CONCLUSIONS: This study shows that more concomitant large perforating artery infarct patterns and larger ACI size in the internal carotid artery territory were found in the T2DM patients with ipsilateral carotid LRNC plaque than those in non-T2DM patients. Quantification of the carotid plaque characteristics, particularly the LRNC% by MRI has the potential usefulness for stroke risk stratification. PMID- 28893253 TI - A novel swine model for evaluation of dyslipidemia and atherosclerosis induced by human CETP overexpression. AB - BACKGROUND: The mechanism of cholesteryl ester transfer protein (CETP) in lipid metabolism is still unclear. Furthermore, the relationship of CETP and atherosclerosis (AS) has been controversial. As pigs are a good model for both lipid and AS research, we investigated the lipid metabolism of human CETP (hCETP) transgenic pigs and explored the mechanism of CETP in lipid modulation. METHODS: Plasmids expressing the hCETP gene were designed, successfully constructed, and transfected into porcine fetal fibroblasts by liposomes. Using somatic cell nuclear transfer technology and embryonic transfer, hCETP transgenic pigs were generated. After the DNA, RNA, and protein levels were identified, positive hCETP transgenic pigs were selected. Blood samples were collected at different ages to evaluate the phenotypes of biochemical markers, and the metabolomes of plasma samples were analyzed by liquid mass spectrometry. RESULTS: Eight positive hCETP transgenic pigs and five negative cloned pigs were generated by transgenic technology. Finally, five hCETP transgenic and five cloned pigs were grown healthily. After feeding with a normal diet, hCETP transgenic pigs compared with unmodified pigs had no significant differences in body weight, liver function, kidney function, or plasma ions, while total cholesterol and low-density lipoprotein were higher than in unmodified pigs, and high-density lipoprotein was significantly decreased. Metabolomics analysis showed that there were differences in metabolic components between hCETP transgenic pigs, cloned pigs, and unmodified pigs. CONCLUSIONS: In this study, we created hCETP transgenic pigs that could serve as an excellent model for lipid disorders and atherosclerosis. PMID- 28893254 TI - SKIP controls flowering time via the alternative splicing of SEF pre-mRNA in Arabidopsis. AB - BACKGROUND: Similar to other eukaryotes, splicing is emerging as an important process affecting development and stress tolerance in plants. Ski-interacting protein (SKIP), a splicing factor, is essential for circadian clock function and abiotic stress tolerance; however, the mechanisms whereby it regulates flowering time are unknown. RESULTS: In this study, we found that SKIP is required for the splicing of serrated leaves and early flowering (SEF) pre-messenger RNA (mRNA), which encodes a component of the ATP-dependent SWR1 chromatin remodeling complex (SWR1-C). Defects in the splicing of SEF pre-mRNA reduced H2A.Z enrichment at FLC, MAF4, and MAF5, suppressed the expression of these genes, and produced an early flowering phenotype in skip-1 plants. CONCLUSIONS: Our findings indicate that SKIP regulates SWR1-C function via alternative splicing to control the floral transition in Arabidopsis thaliana. PMID- 28893255 TI - Oncologist burnout and compassion fatigue: investigating time pressure at work as a predictor and the mediating role of work-family conflict. AB - BACKGROUND: Oncologists are at high risk of poor mental health. Prior research has focused on burnout, and has identified heavy workload as a key predictor. Compassion fatigue among physicians has generally received less attention, although medical specialties such as oncology may be especially at risk of compassion fatigue. We contribute to research by identifying predictors of both burnout and compassion fatigue among oncologists. In doing so, we distinguish between quantitative workload (e.g., work hours) and subjective work pressure, and test whether work-family conflict mediates the relationships between work pressure and burnout or compassion fatigue. METHODS: In a cross-sectional study, oncologists from across Canada (n = 312) completed questionnaires assessing burnout, compassion fatigue, workload, time pressure at work, work-family conflict, and other personal, family, and occupational characteristics. Analyses use Ordinary Least Squares regression. RESULTS: Subjective time pressure at work is a key predictor of both burnout and compassion fatigue. Our results also show that work-family conflict fully mediates these relationships. Overall, the models explain more of the variation in burnout as compared to compassion fatigue. CONCLUSIONS: Our study highlights the need to consider oncologists' subjective time pressure, in addition to quantitative workload, in interventions to improve mental health. The findings also highlight a need to better understand additional predictors of compassion fatigue. PMID- 28893256 TI - Prime-boost vaccination with attenuated Salmonella Typhimurium DeltaznuABC and inactivated Salmonella Choleraesuis is protective against Salmonella Choleraesuis challenge infection in piglets. AB - BACKGROUND: Salmonella enterica serovar Choleraesuis (S. Choleraesuis) infection causes a systemic disease in pigs. Vaccination could represent a solution to reduce prevalence in farms. In this study, we aimed to assess the efficacy of an attenuated strain of Salmonella enterica serovar Typhimurium (S. Typhimurium DeltaznuABC) against S. Choleraesuis infection. The vaccination protocol combined priming with attenuated S. Typhimurium DeltaznuABC vaccine and boost with an inactivated S. Choleraesuis vaccine and we compared the protection conferred to that induced by an inactivated S. Choleraesuis vaccine. METHODS: The first group of piglets was orally vaccinated with S. Typhimurium DeltaznuABC and boosted with inactivated S. Choleraesuis, the second one was intramuscularly vaccinated with S. Choleraesuis inactivated vaccine and the third group of piglets was unvaccinated. All groups of animals were challenged with a virulent S. Choleraesuis strain at day 35 post vaccination. RESULTS: The results showed that the vaccination protocol, priming with S. Typhimurium DeltaznuABC and boosted with inactivated S. Choleraesuis, applied to group A was able to limit weight loss, fever and organs colonization, arising from infection with virulent S. Choleraesuis, more effectively, than the prime-boost vaccination with homologous S. Choleraesuis inactivated vaccine (group B). CONCLUSION: In conclusion, these research findings extend the validity of attenuated S. Typhimurium DeltaznuABC strain as a useful mucosal vaccine against S. Typhimurium and S. Choleraesuis pig infection. The development of combined vaccination protocols can have a diffuse administration in field conditions because animals are generally infected with different concomitant serovars. PMID- 28893257 TI - Preoperative single ventricle function determines early outcome after second stage palliation of single ventricle heart. AB - BACKGROUND: Second-stage palliation with hemi-Fontan or bidirectional Glenn procedures has improved the outcomes of patients treated for single-ventricle heart disease. The aim of this study was to retrospectively analyze risk factors for death after second-stage palliation of single-ventricle heart and to compare therapeutic results achieved with the hemi-Fontan and bidirectional Glenn procedures. MATERIAL AND METHODS: We analyzed 60 patients who had undergone second-stage palliation for single-ventricle heart. Group HF consisted of 23 (38.3%) children who had been operated with the hemi-Fontan method; Group BDG consisted of 37 (61.7%) who had been operated with the bidirectional Glenn method. The analysis focused on 30-day postoperative mortality rates, clinical and echocardiographic data, and early complications. RESULTS: The patients' ages at the time of repair was 33 +/- 11.2 weeks; weight was 6.7 +/- 1.2 kg. The most common anatomic subtype was hypoplastic left heart syndrome, in 36 (60%) patients. The early mortality rate was 13.3%. Significant preoperative atrioventricular valve regurgitation, single-ventricle heart dysfunction, pneumonia/sepsis, and arrhythmias were associated with higher mortality rates after second-stage palliation. Multivariate analysis identified significant preoperative single-ventricle heart dysfunction as an independent predictor of early death after second-stage palliation. No differences were found in the analyzed variables after bidirectional Glenn compared with hemi-Fontan procedures. CONCLUSION: Significant preoperative atrioventricular valve regurgitation, arrhythmias and pneumonia/sepsis are closely correlated with mortality in patients with single-ventricle heart after second-stage palliation. Preoperative significant single-ventricle heart dysfunction is an independent mortality predictor in this group of patients. There are no differences in clinical, echocardiographic data, or outcomes in patients treated with the hemi Fontan compared with bidirectional Glenn procedures. PMID- 28893258 TI - Epidemiological and clinical assessment of a shared territorial malaria guideline in the 10 years of its implementation (Barcelona, North Metropolitan Area, Catalonia, Spain, 2007-2016). AB - BACKGROUND: Malaria remains a major source of morbi-mortality among travellers. In 2007, a consensual multicenter Primary Care-Hospital shared guideline on travel-prior chemoprophylaxis, diagnosis and clinical management of imported malaria was set up in the Barcelona North Metropolitan area. The aim of the study is to assess the evolution of malaria cases in the area as well as its clinical management over the 10 years of its implementation. RESULTS: A total of 190 malaria cases, all them imported, have been recorded. The overall estimated malaria crude incidence was of 0.47 cases per 10,000 population/year (95% CI 0.34 0.59) with a slight significant positive slope especially at the expense of an increase in Indian sub-continent Plasmodium vivax cases. The number of patients who attended the pre-travel consultation was low (13.7%) as well as those with prescribed chemoprophylaxis (10%). Severe malaria was diagnosed in 34 (17.9%) patients and ICU admittance was required in 2.6% of them. Organ sequelae (two renal failures and one post-acute distress respiratory syndrome) were recorded in 3 patients at hospital discharge, although all three were recovered at 30 days. None of the patients died. Patients complying with severity criteria were significantly males (p = 0.04), came from Africa (p = 0.02), were mainly non immigrant travellers (p = 0.01) and were attended in a hospital setting (p < 0.001). The most frequently identified species was Plasmodium falciparum (64.2%), P. vivax (23.2%), Plasmodium malariae (1.6%) and Plasmodium ovale (1.1%). Those patients diagnosed with P. falciparum malaria came more often from sub-Saharan Africa (p < 0.001) and those with P. vivax came largely from the Indian sub continent (p = 0.003). Among the 126 patients in whom an immunochromatographic antigenic test was performed, the result was interpreted as falsely negative in 12.1% of them. False negative results can be related to cases with <1% parasitaemia. CONCLUSIONS: After 10 years of surveillance, a moderate increase in malaria incidence was observed, mostly P. vivax cases imported from the Indian sub-continent. Although severe malaria cases have been frequently reported, none of the patients died and organ sequelae were rare. Conceivably, the participation of the Primary Care and the District and Third Level Hospital professionals defining surveillance, diagnostic tests, referral criteria and clinical management can be considered a useful tool to minimize malaria morbi-mortality. PMID- 28893259 TI - How driving endonuclease genes can be used to combat pests and disease vectors. AB - Driving endonuclease genes (DEGs) spread through a population by a non-Mendelian mechanism. In a heterozygote, the protein encoded by a DEG causes a double-strand break in the homologous chromosome opposite to where its gene is inserted and when the break is repaired using the homologue as a template the DEG heterozygote is converted to a homozygote. Some DEGs occur naturally while several classes of endonucleases can be engineered to spread in this way, with CRISPR-Cas9 based systems being particularly flexible. There is great interest in using driving endonuclease genes to impose a genetic load on insects that vector diseases or are economic pests to reduce their population density, or to introduce a beneficial gene such as one that might interrupt disease transmission. This paper reviews both the population genetics and population dynamics of DEGs. It summarises the theory that guides the design of DEG constructs intended to perform different functions. It also reviews the studies that have explored the likelihood of resistance to DEG phenotypes arising, and how this risk may be reduced. The review is intended for a general audience and mathematical details are kept to a minimum. PMID- 28893260 TI - Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports. AB - BACKGROUND: The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer. CASE PRESENTATION: Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years. Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years. CONCLUSION: We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs. PMID- 28893261 TI - A tale of two systems: practice patterns of a single group of emergency medical physicians in Taiwan and China. AB - BACKGROUND: The quality of pediatric emergency care has been a major concern in health care. Following a series of health system reforms in China, it is important to do this assessment of pediatric emergency care, and to explore potential influences of health care system. This study aimed to compare practice differences in treating children with respiratory illnesses in two emergency department (ED) settings within different health care systems: China and Taiwan. METHODS: A pooled cross-sectional hospital-based study was conducted in two tertiary teaching hospitals in Xiamen, China and Keelung, Taiwan belong to the same hospital chain group. A team of 21 pediatricians rotated between the EDs of the two hospitals from 2009 to 2012. There were 109,705 ED encounters treated by the same team of pediatricians and 6596 visits were analyzed for common respiratory illnesses. Twelve quality measures in process and outcomes of asthma, bronchiolitis and croup were reported. Descriptive statistics and multiple logistic regression models were applied to assess. In order to demonstrate the robustness of our findings, we analyzed the data using an alternative modeling technique, multilevel modeling. RESULTS: After adjustment, children with asthma presented to the ED in China had a significantly 76% lower likelihood to be prescribed a chest radiograph, and a 98% lower likelihood to be prescribed steroids and discharged home than those in Taiwan. Also, children with asthma presented to the ED in China had significantly 7.76 times higher risk to incur 24 72 h return visits. Furthermore, children with bronchiolitis in China (Odds ratio (OR): 0.21; 95% Confidence interval (CI): 0.17-0.28) were significantly less likely to be prescribed chest radiograph, but were significantly more likely to be prescribed antibiotics (OR: 2.19; 95% CI: 1.46-3.28). CONCLUSIONS: This study illustrated that although high quality care depends on better assessment of physician performance, the delivery of pediatric emergency care differed significantly between these two healthcare systems after holding the care providers the same and adjusting for important patient characteristics. The findings suggest that the features of the health care system may play a significant role. PMID- 28893262 TI - Effect of Launaea procumbens on thyroid glands lipid peroxidation and hormonal dysfunction: a randomized control trial. AB - BACKGROUND: Launaea procumbens (Roxb.) Amin is traditionally used in Pakistan for the treatment of hormonal disorders and oxidative stress. The present study was aimed to evaluate the efficacy of Launaea procumbens methanol extract (LPME) against KBrO3-induced oxidative stress and hormonal dysfunction in thyroid. METHODS: To examine the effects of LPME against the oxidative stress of KBrO3 in thyroid tissue, 36 male albino rats were used. Protective effects of LPME were observed on thyroid hormonal levels, activities of antioxidant enzymes, lipid peroxidation (TBARS) and DNA damage. RESULTS: Treatment with KBrO3 significantly (P < 0.01) reduced the levels of T3 (55.13 +/- 1.93) and T4 (14.7 +/- 1.78) and increased TSH (55.13 +/- 1.93) levels. KBrO3 exposure in rats reduced the activities of antioxidant enzymes viz.; CAT (1.16 +/- 0.08); SOD (12.0 +/- 0.08), GST (17.7 +/- 1.1) and GSR (54.3 +/- 2.1) but increased lipid peroxidation (20.3 +/- 0.71) and DNA (30.4 +/- 2.0) damage. Co-administration of LPME significantly (P < 0.01) improved these alterations with respect to hormonal levels, activities of antioxidant enzymes and lipid peroxidation close to those seen in control rats. CONCLUSION: These results suggest that LPME can protect thyroid tissue against oxidative damage, possibly through the antioxidant effects of its bioactive compounds. PMID- 28893263 TI - Evaluation of a continuous community-based ITN distribution pilot in Lainya County, South Sudan 2012-2013. AB - BACKGROUND: Continuous distribution of insecticide-treated nets (ITNs) has now been accepted as one way of sustaining ITN universal coverage. Community-based channels offer an interesting means of delivering ITNs to households to sustain universal ITN coverage. The objective of this study was to provide proof of concept for this channel. METHODS: A 9-month, community-based, distribution pilot was implemented beginning 1 year after a mass campaign in Lainya County, South Sudan from 2012 to 2013. Following social mobilization, community members could request an ITN from a net coupon holder. Eligibility criteria included having lost an ITN, giving birth outside of the health facility, or not having enough ITNs for all household members. After verification, households could exchange the coupon for an ITN at a distribution point. The evaluation was a pre/post design using representative household surveys with two-stage cluster sampling and a sample size of 600 households per survey. RESULTS: At endline, 78% of respondents were aware of the scheme and 89% of those also received an ITN through community based distribution. Population access to ITNs nearly doubled, from 38% at baseline to 66% after the pilot. Household ownership of any ITN and enough ITNs (1 for 2 people) also increased significantly, from 66 to 82% and 19 to 46%, respectively. Community-based distribution was the only source of ITNs for 53.4% of households. The proportion of the population using an ITN last night increased from 22.7% at baseline to 53.9% at endline. A logistic regression model indicates that although behaviour change communication was positively associated with an increase in ITN use, access to enough nets was the greatest determinant of use. CONCLUSIONS: ITN access and use improved significantly in the study area during the pilot, coming close to universal coverage targets. This pilot serves as proof of concept for the community-based distribution methodology implemented as a mechanism to sustain ITN universal coverage. Longer periods of implementation should be evaluated to determine whether community-based distribution can successfully maintain ITN coverage beyond the short term, and reach all wealth quintiles equitably. PMID- 28893264 TI - Maximizing research study effectiveness in malaria elimination settings: a mixed methods study to capture the experiences of field-based staff. AB - BACKGROUND: In a drug-resistant, malaria elimination setting like Western Cambodia, field research is essential for the development of novel anti-malarial regimens and the public health solutions necessary to monitor the spread of resistance and eliminate infection. Such field studies often face a variety of similar implementation challenges, but these are rarely captured in a systematic way or used to optimize future study designs that might overcome similar challenges. Field-based research staff often have extensive experience and can provide valuable insight regarding these issues, but their perspectives and experiences are rarely documented and seldom integrated into future research protocols. This mixed-methods analysis sought to gain an understanding of the daily challenges encountered by research field staff in the artemisinin resistant, malaria elimination setting of Western Cambodia. In doing so, this study seeks to understand how the experiences and opinions of field staff can be captured, and used to inform future study designs. METHODS: Twenty-two reports from six field-based malaria studies conducted in Western Cambodia were reviewed using content analysis to identify challenges to conducting the research. Informal Interviews, Focus Group Discussions and In-depth Interviews were also conducted among field research staff. Thematic analysis of the data was undertaken using Nvivo 9(r) software. Triangulation and critical case analysis was also used. RESULTS: There was a lack of formalized avenues through which field workers could report challenges experienced when conducting the malaria studies. Field research staff faced significant logistical barriers to participant recruitment and data collection, including a lack of available transportation to cover long distances, and the fact that mobile and migrant populations (MMPs) are usually excluded from studies because of challenges in follow-up. Cultural barriers to communication also hindered participant recruitment and created unexpected delays. Field staff often paid a physical, emotional and financial cost, going beyond their duty in order to keep the study running. CONCLUSIONS: Formal monthly reports filled out by field study staff could be a key tool for capturing field study staff experiences effectively, but require specific report fields to encourage staff to outline their challenges and to propose potential solutions. Forging strong bonds with communities and their leaders may improve communication, and decrease barriers to participant recruitment. Study designs that make it feasible for MMPs to participate should be pursued; in addition to increasing the potential participant pool, this will ensure that the most malaria-endemic demographic is taken into account in research studies. Overlaps between clinical care and research create ethical dilemmas for study staff, a fact that warrants careful consideration. Lessons learned from study field staff should be used to create a set of locally-relevant recommendations to inform future study designs. PMID- 28893265 TI - Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. AB - BACKGROUND: Non-coding RNAs (ncRNAs) have been shown to regulate gene expression involved in tumor progression of multiple malignancies. Our previous studies indicated that large tumor suppressor kinase 1 (LATS1), a core part of Hippo signaling pathway, functions as a tumor suppressor in gastric cancer (GC). But, the underlying molecular mechanisms by which ncRNAs modulate LATS1 expression in GC remain undetermined. METHODS: The correlation of LATS1 and has-miR-424-5p (miR 424) expression with clinicopathological characteristics and prognosis of GC patients was analyzed by TCGA RNA-sequencing data. A novel circular RNA_LARP4 (circLARP4) was identified to sponge miR-424 by circRNA expression profile and bioinformatic analysis. The binding site between miR-424 and LATS1 or circLARP4 was verified using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The expression and localization of circLARP4 in GC tissues were investigated by fluorescence in situ hybridization (FISH). MTT, colony formation, Transwell and EdU assays were performed to assess the effects of miR-424 or circLARP4 on cell proliferation and invasion. RESULTS: Increased miR-424 expression or decreased LATS1 expression was associated with pathological stage and unfavorable prognosis of GC patients. Ectopic expression of miR-424 promoted proliferation and invasion of GC cells by targeting LATS1 gene. Furthermore, circLARP4 was mainly localized in the cytoplasm and inhibited biological behaviors of GC cells by sponging miR 424. The expression of circLARP4 was downregulated in GC tissues and represented an independent prognostic factor for overall survival of GC patients. CONCLUSION: circLARP4 may act as a novel tumor suppressive factor and a potential biomarker in GC. PMID- 28893266 TI - Myocardial performance index in female athletes. AB - BACKGROUND: Long-term intensive training leads to morphological and mechanical changes in the heart generally known as "athlete's heart". Previous studies have suggested that the diastolic and systolic function of the ventricles is unaltered in athletes compared to sedentary. The purpose of this study was to investigate myocardial performance index (MPI) by pulsed wave Doppler (PWD) and by tissue Doppler imaging (TDI) in female elite athletes compared to sedentary controls. METHODS: The study consisted of 32 athletes (mean age 20 +/- 2 years) and 34 sedentary controls (mean age 23 +/- 2 years). MPI by PWD and TDI were measured in the left (LV) and right ventricle (RV) in both groups. Moreover, comparisons of MPI by the two methods and between the LV and RV within the two groups were made. RESULTS: There were no significant differences in MPI between athletes and controls (p > 0.05), whereas the LV had significantly higher MPI compared to RV (p < 0.001, in athletes and controls). The agreement and the correlation between the two methods measuring MPI showed low agreement and no correlation (athletes RV r = -0.027, LV r = 0.12; controls RV r = 0.20, LV r = 0.30). CONCLUSION: The global function of the LV and RV measured by MPI with PWD and TDI is similar in female athletes compared to sedentary controls. Conversely, both MPI by PWD and by TDI shows a significant difference between the LV and RV. However, the agreement and correlation between conventional methods of measuring MPI by PWD compared to MPI by TDI is very poor in both these populations. PMID- 28893267 TI - Is the role of Health Extension Workers in the delivery of maternal and child health care services a significant attribute? The case of Dale district, southern Ethiopia. AB - BACKGROUND: The Health Extension Program (HEP) is one of the most innovative community based health program launched by the Ethiopian Federal Ministry of Health to make health services accessible to rural communities by setting-out women Health Extension Workers (HEWs) in rural Health Posts. The HEWs are premised to provide basic, largely preventive, primary health services to rural villages and the program gives special attention to children and mothers. The objective of the study was to assess the contribution made by the Health Extension Workers in maternal and child health care service delivery in Dale district, southern Ethiopia. METHODS: Using a community based cross-sectional data; the study assessed the status of mother's health service utilization and estimated the role of HEWs in maternal and child health care delivery. Mothers of reproductive age (15-49), having at least one under-five age child, were eligible for the study. The total sample size was 617 and systemic random sampling method was used to select the study subjects from each randomly selected kebeles (lower administrative units). Structured questionnaire was applied to collect data through interviewing of the selected mothers and the data were analysed using SPSS version 16 statistical software. RESULTS: Health Posts are important health care delivery settings and their share from the overall service delivery of ANC, Family planning and child treatment services were pivotal. However, overall service coverage of ANC (four and more visits), delivery and PNC services were low in the district as compared to the national status; and the input from the HEWs, in this regard, was unsatisfactory. The number of home visits was also inadequate for the necessary support of the mothers. The results of the multiple logistic regression indicated that mothers who listen to the radio (AOR 4.62; CI 1.66-12.85) and who had received information about the MCH services by HEWs (AOR 2.09; CI 1.06-4.14) were significantly associated with good MCH service utilization status. CONCLUSION: Health Extension Workers can improve their role in the MCH service delivery in the district by delivering appropriate information about the different available services to the mothers at the community and household level. All concerned bodies, including federal, regional and local governments should support the efforts of HEWs and need to address the challenges for poor performance areas of the HEWs in MCH service delivery. PMID- 28893268 TI - A novel HIV vaccine targeting the protease cleavage sites. AB - HIV preferentially infects activated CD4+ T cells and mutates rapidly. The classical vaccine approach aimed to generate broad immune responses to full HIV proteins largely failed to address the potential adverse impact of increased number of activated CD4+ T cells as viral targets. Learning from natural immunity observed in a group of HIV resistant Kenyan female sex workers, we are testing a novel vaccine approach. It focuses immune response to the highly conserved sequences surrounding the HIV protease cleavage sites (PCS) to disrupt viral maturation, while limiting excessive immune activation. Our pilot studies using nonhuman primate SIV infection models suggest that this approach is feasible and promising. PMID- 28893269 TI - Core competencies for scientific editors of biomedical journals: consensus statement. AB - BACKGROUND: Scientific editors are responsible for deciding which articles to publish in their journals. However, we have not found documentation of their required knowledge, skills, and characteristics, or the existence of any formal core competencies for this role. METHODS: We describe the development of a minimum set of core competencies for scientific editors of biomedical journals. RESULTS: The 14 key core competencies are divided into three major areas, and each competency has a list of associated elements or descriptions of more specific knowledge, skills, and characteristics that contribute to its fulfillment. CONCLUSIONS: We believe that these core competencies are a baseline of the knowledge, skills, and characteristics needed to perform competently the duties of a scientific editor at a biomedical journal. PMID- 28893270 TI - The impact of the advanced practice nursing role on quality of care, clinical outcomes, patient satisfaction, and cost in the emergency and critical care settings: a systematic review. AB - BACKGROUND: The prevalence of chronic illness and multimorbidity rises with population aging, thereby increasing the acuity of care. Consequently, the demand for emergency and critical care services has increased. However, the forecasted requirements for physicians have shown a continued shortage. Among efforts underway to search for innovations to strengthen the workforce, there is a heightened interest to have nurses in advanced practice participate in patient care at a great extent. Therefore, it is of interest to evaluate the impact of increasing the autonomy of nurses assuming advanced practice roles in emergency and critical care settings on patient outcomes. OBJECTIVES: The objectives of this study are to present, critically appraise, and synthesize the best available evidence on the impact of advanced practice nursing on quality of care, clinical outcomes, patient satisfaction, and cost in emergency and critical care settings. REVIEW METHODS: A comprehensive and systematic search of nine electronic databases and a hand-search of two key journals from 2006 to 2016 were conducted to identify studies evaluating the impact of advanced practice nursing in the emergency and critical care settings. Two authors were involved selecting the studies based on the inclusion criteria. Out of the original search yield of 12,061 studies, 15 studies were chosen for appraisal of methodological quality by two independent authors and subsequently included for analysis. Data was extracted using standardized tools. RESULTS: Narrative synthesis was undertaken to summarize and report the findings. This review demonstrates that the involvement of nurses in advanced practice in emergency and critical care improves the length of stay, time to consultation/treatment, mortality, patient satisfaction, and cost savings. CONCLUSIONS: Capitalizing on nurses in advanced practice to increase patients' access to emergency and critical care is appealing. This review suggests that the implementation of advanced practice nursing roles in the emergency and critical care settings improves patient outcomes. The transformation of healthcare delivery through effective utilization of the workforce may alleviate the impending rise in demand for health services. Nevertheless, it is necessary to first prepare a receptive context to effect sustainable change. PMID- 28893271 TI - Erratum to: Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice. PMID- 28893272 TI - Killed whole-HIV vaccine; employing a well established strategy for antiviral vaccines. AB - The development of an efficient prophylactic HIV vaccine has been one of the major challenges in infectious disease research during the last three decades. Here, we present a mini review on strategies employed for the development of HIV vaccines with an emphasis on a well-established vaccine technology, the killed whole-virus vaccine approach. Recently, we reported an evaluation of the safety and the immunogenicity of a genetically modified and killed whole-HIV-1 vaccine designated as SAV001 [1]. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence of the Env signal peptide with that of honeybee melittin to produce an avirulent and replication efficient HIV-1. This genetically modified virus (gmHIV-1 NL4-3 ) was propagated in a human T cell line followed by virus purification and inactivation by aldrithiol-2 and gamma-irradiation. We found that SAV001 was well tolerated with no serious adverse events. HIV-1 NL4-3 -specific polymerase chain reaction showed no evidence of vaccine virus replication in participants receiving SAV001 and in human T cells infected in vitro. Furthermore, SAV001 with an adjuvant significantly increased the antibody response to HIV-1 structural proteins. Moreover, antibodies in the plasma from these vaccinations neutralized tier I and tier II of HIV-1 B, A, and D subtypes. These results indicated that the killed whole-HIV vaccine is safe and may trigger appropriate immune responses to prevent HIV infection. Utilization of this killed whole-HIV vaccine strategy may pave the way to develop an effective HIV vaccine. PMID- 28893273 TI - Food parenting practices for 5 to 12 year old children: a concept map analysis of parenting and nutrition experts input. AB - BACKGROUND: Parents are an important influence on children's dietary intake and eating behaviors. However, the lack of a conceptual framework and inconsistent assessment of food parenting practices limits our understanding of which food parenting practices are most influential on children. The aim of this study was to develop a food parenting practice conceptual framework using systematic approaches of literature reviews and expert input. METHOD: A previously completed systematic review of food parenting practice instruments and a qualitative study of parents informed the development of a food parenting practice item bank consisting of 3632 food parenting practice items. The original item bank was further reduced to 110 key food parenting concepts using binning and winnowing techniques. A panel of 32 experts in parenting and nutrition were invited to sort the food parenting practice concepts into categories that reflected their perceptions of a food parenting practice conceptual framework. Multi-dimensional scaling produced a point map of the sorted concepts and hierarchical cluster analysis identified potential solutions. Subjective modifications were used to identify two potential solutions, with additional feedback from the expert panel requested. RESULTS: The experts came from 8 countries and 25 participated in the sorting and 23 provided additional feedback. A parsimonious and a comprehensive concept map were developed based on the clustering of the food parenting practice constructs. The parsimonious concept map contained 7 constructs, while the comprehensive concept map contained 17 constructs and was informed by a previously published content map for food parenting practices. Most of the experts (52%) preferred the comprehensive concept map, while 35% preferred to present both solutions. CONCLUSION: The comprehensive food parenting practice conceptual map will provide the basis for developing a calibrated Item Response Modeling (IRM) item bank that can be used with computerized adaptive testing. Such an item bank will allow for more consistency in measuring food parenting practices across studies to better assess the impact of food parenting practices on child outcomes and the effect of interventions that target parents as agents of change. PMID- 28893274 TI - Modulation of the strength and character of HIV-specific CD8+ T cell responses with heteroclitic peptides. AB - Chronic infection with human immunodeficiency virus (HIV) causes HIV-specific CD8+ T cell dysfunction and exhaustion. The strong association between non progression and maintenance of HIV-specific CD8+ T cell cytokine production and proliferative capacities suggests that invigorating CD8+ T cell immune responses would reduce viremia and slow disease progression. A series of studies have demonstrated that sequence variants of native immunogenic peptides can generate more robust CD8+ T cell responses and that stimulation with these 'heteroclitic' peptides can steer responses away from the phenotypic and functional attributes of exhaustion acquired during chronic HIV infection. Incorporation of heteroclitic peptide stimulation within therapeutic vaccines could favour induction of more effective cellular antiviral responses, and in combination with 'shock and kill' strategies, contribute towards HIV cure. PMID- 28893275 TI - Unlocking HIV-1 Env: implications for antibody attack. AB - Collective evidence supporting a role of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in controlling HIV-1 transmission and disease progression emerged in the last few years. Non-neutralizing antibodies (nnAbs) recognizing conserved CD4-induced epitopes on Env and able to mediate potent ADCC against HIV 1-infected cells exposing Env in its CD4-bound conformation have been shown to be present in some RV144 vaccinees and most HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to decrease exposure of this Env conformation by downregulating CD4 and by limiting the overall amount of cell-surface Env. In this review, we will summarize our contribution to this rapidly evolving field, discuss how structural properties of HIV-1 Env might have contributed to the modest efficacy of the RV144 trial and how we recently used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected cells to ADCC mediated by easy to elicit nnAbs. PMID- 28893277 TI - Development of an HIV vaccine using a vesicular stomatitis virus vector expressing designer HIV-1 envelope glycoproteins to enhance humoral responses. AB - Vesicular stomatitis virus (VSV), like many other Rhabdoviruses, have become the focus of intense research over the past couple of decades based on their suitability as vaccine vectors, transient gene delivery systems, and as oncolytic viruses for cancer therapy. VSV as a vaccine vector platform has multiple advantages over more traditional viral vectors including low level, non pathogenic replication in diverse cell types, ability to induce both humoral and cell-mediate immune responses, and the remarkable expression of foreign proteins cloned into multiple intergenic sites in the VSV genome. The utility and safety of VSV as a vaccine vector was recently demonstrated near the end of the recent Ebola outbreak in West Africa where VSV pseudotyped with the Ebola virus (EBOV) glycoprotein was proven safe in humans and provided protective efficacy against EBOV in a human phase III clinical trial. A team of Canadian scientists, led by Dr. Gary Kobinger, is now working with International AIDS Vaccine Initiative (IAVI) in developing a VSV-based HIV vaccine that will combine unique Canadian research on the HIV-1 Env glycoprotein and on the VSV vaccine vector. The goal of this collaboration is to develop a vaccine with a robust and potent anti-HIV immune response with an emphasis on generating quality antibodies to protect against HIV challenges. PMID- 28893276 TI - Imipramine blocks acute silicosis in a mouse model. AB - BACKGROUND: Inhalation of crystalline silica is associated with pulmonary inflammation and silicosis. Although silicosis remains a prevalent health problem throughout the world, effective treatment choices are limited. Imipramine (IMP) is a FDA approved tricyclic antidepressant drug with lysosomotropic characteristics. The aim of this study was to evaluate the potential for IMP to reduce silicosis and block phagolysosome membrane permeabilization. METHODS: C57BL/6 alveolar macrophages (AM) exposed to crystalline silica +/- IMP in vitro were assessed for IL-1beta release, cytotoxicity, particle uptake, lysosomal stability, and acid sphingomyelinase activity. Short term (24 h) in vivo studies in mice instilled with silica (+/- IMP) evaluated inflammation and cytokine release, in addition to cytokine release from ex vivo cultured AM. Long term (six to ten weeks) in vivo studies in mice instilled with silica (+/- IMP) evaluated histopathology, lung damage, and hydroxyproline content as an indicator of collagen accumulation. RESULTS: IMP significantly attenuated silica-induced cytotoxicity and release of mature IL-1beta from AM in vitro. IMP treatment in vivo reduced silica-induced inflammation in a short-term model. Furthermore, IMP was effective in blocking silica-induced lung damage and collagen deposition in a long-term model. The mechanism by which IMP reduces inflammation was explored by assessing cellular processes such as particle uptake and acid sphingomyelinase activity. CONCLUSIONS: Taken together, IMP was anti-inflammatory against silica exposure in vitro and in vivo. The results were consistent with IMP blocking silica-induced phagolysosomal lysis, thereby preventing cell death and IL-1beta release. Thus, IMP could be therapeutic for silica-induced inflammation and subsequent disease progression as well as other diseases involving phagolysosomal lysis. PMID- 28893278 TI - Development of an anti-HIV vaccine eliciting broadly neutralizing antibodies. AB - The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV 1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response. PMID- 28893279 TI - Biomechanics and neural control of movement, 20 years later: what have we learned and what has changed? AB - We summarize content from the opening thematic session of the 20th anniversary meeting for Biomechanics and Neural Control of Movement (BANCOM). Scientific discoveries from the past 20 years of research are covered, highlighting the impacts of rapid technological, computational, and financial growth on motor control research. We discuss spinal-level communication mechanisms, relationships between muscle structure and function, and direct cortical movement representations that can be decoded in the control of neuroprostheses. In addition to summarizing the rich scientific ideas shared during the session, we reflect on research infrastructure and capacity that contributed to progress in the field, and outline unresolved issues and remaining open questions. PMID- 28893280 TI - Eradication of HIV-1 latent reservoirs through therapeutic vaccination. AB - Despite the significant success of combination anti-retroviral therapy to reduce HIV viremia and save lives, HIV-1 infection remains a lifelong infection that must be appropriately managed. Advances in the understanding of the HIV infection process and insights from vaccine development in other biomedical fields such as cancer, imaging, and genetic engineering have fueled rapid advancements in HIV cure research. In the last few years, several studies have focused on the development of "Kick and Kill" therapies to reverse HIV latency and kick start viral translational activity. This has been done with the aim that concomitant anti-retroviral treatment and the elicited immune responses will prevent de novo infections while eradicating productively infected cells. In this review, we describe our perspective on HIV cure and the new approaches we are undertaking to eradicate the established pro-viral reservoir. PMID- 28893281 TI - RNA flow cytometric FISH for investigations into HIV immunology, vaccination and cure strategies. AB - Despite the tremendous success of anti-retroviral therapy (ART) no current treatment can eradicate latent HIV reservoirs from HIV-infected individuals or generate, effective HIV-specific immunity. Technological limitations have hampered the identification and characterization of both HIV-infected cells and HIV-specific responses in clinical samples directly ex vivo. RNA-flow cytometric fluorescence in situ hybridisation (RNA Flow-FISH) is a powerful technique, which enables detection of mRNAs in conjunction with proteins at a single-cell level. Here, we describe how we are using this technology to address some of the major questions remaining in the HIV field in the era of ART. We discuss how CD4 T cell responses to HIV antigens, both following vaccination and HIV infection, can be characterized by measurement of cytokine mRNAs. We describe how our development of a dual HIV mRNA/protein assay (HIVRNA/Gag assay) enables high sensitivity detection of very rare HIV-infected cells and aids investigations into the translation-competent latent reservoir in the context of HIV cure. PMID- 28893282 TI - Development of targeted adjuvants for HIV-1 vaccines. AB - Finding new adjuvants is an integrated component of the efforts in developing an effective HIV-1 vaccine. Compared with traditional adjuvants, a modern adjuvant in the context of HIV-1 prevention would elicit a durable and potent memory response from B cells, CD8+ T cells, and NK cells but avoid overstimulation of HIV-1 susceptible CD4+ T cells, especially at genital and rectal mucosa, the main portals for HIV-1 transmission. We briefly review recent advances in the studies of such potential targeted adjuvants, focusing on three classes of molecules that we study: TNFSF molecules, TLRs agonists, and NODs agonists. PMID- 28893283 TI - Perceived fussy eating in Australian children at 14 months of age and subsequent use of maternal feeding practices at 2 years. AB - BACKGROUND: Concerns about fussy eating are common amongst parents of young children. However, studies of the long-term impact of fussy eating show mixed results with regard to adequacy of dietary intake and child growth. This may be in part because there is no accepted definition of fussy eating and studies measure the construct in different ways, commonly relying on parent perception. This longitudinal analysis explores maternal and child characteristics associated with maternal perception of her toddler as a fussy eater in early toddlerhood and subsequent use of feeding practices at 2 years. METHODS: Mothers completed a self administered questionnaire at child age 14 months, describing perception of their child as fussy/not fussy and child behaviour. Intake was assessed using a single 24-h recall and weight was measured by research staff. At child age 2 years mothers completed the validated 28-item Feeding Practices and Structure Questionnaire (FPSQ-28). Weight-for-age z-score (WAZ) was derived from WHO standards. Gram daily intake of fruit, vegetables and meat/alternative and a dietary diversity score were determined. Maternal/child characteristics independently associated (p <= 0.05) with perception of child as a fussy eater were determined using logistic regression. Variables were combined in a structural equation model assessing the longitudinal relationship between child/maternal characteristics, perception of child as a fussy eater and eight FPSQ factors. RESULTS: Mothers' (n = 330) perception of her child as a fussy eater at age 14 months, was associated with higher frequency of food refusal and lower WAZ (R 2 = 0.41) but not dietary intake. Maternal perception as fussy (age 14 months) was associated with four FPSQ factors at 2 years (n = 279) - Reward for Eating, Reward for Behaviour, Persuasive Feeding and Overt Restriction, x 2 /df = 1.42, TLI = 0.95, CFI = 0.95, RMSEA = 0.04(0.03-0.05), PCLOSE = 0.99. CONCLUSIONS: Lower relative child weight and food refusal prompted mothers to perceive their child as fussy. These behaviours in healthy weight children most likely reflect self-regulation of energy intake and neophobia. This perception was prospectively associated with use of non-responsive feeding practices, which may increase obesity risk. Future interventions could directly address perceptions of growth and fussiness, supporting parents to understand food refusal as developmentally appropriate behaviour in healthy young children. TRIAL REGISTRATION: ACTRN12608000056392 . Registered 29 January 2008. PMID- 28893284 TI - Role of sex hormones and the vaginal microbiome in susceptibility and mucosal immunity to HIV-1 in the female genital tract. AB - While the prevalence of Human immunodeficiency virus-1 (HIV-1) infection has stabilized globally, it continues to be the leading cause of death among women of reproductive age. The majority of new infections are transmitted heterosexually, and women have consistently been found to be more susceptible to HIV-1 infection during heterosexual intercourse compared to men. This emphasizes the need for a deeper understanding of how the microenvironment in the female genital tract (FGT) could influence HIV-1 acquisition. This short review focuses on our current understanding of the interplay between estrogen, progesterone, and the cervicovaginal microbiome and their immunomodulatory effects on the FGT. The role of hormonal contraceptives and bacterial vaginosis on tissue inflammation, T cell immunity and HIV-1 susceptibility is discussed. Taken together, this review provides valuable information for the future development of multi-purpose interventions to prevent HIV-1 infection in women. PMID- 28893285 TI - Estimates of individual muscle power production in normal adult walking. AB - BACKGROUND: The purpose of this study was to determine the contribution of individual hip muscles to the net hip power in normal adult self-selected speed walking. A further goal was to examine each muscle's role in propulsion or support of the body during that task. METHODS: An EMG-to-force processing (EFP) model was developed which scaled muscle-tendon unit (MTU) force output to gait EMG. Active muscle power was defined as the product of MTU forces (derived from EFP) and that muscle's contraction velocity. Passive hip power was estimated from passive moments associates with hip position (angle of flexion (extension)) and the hip's angular velocity. Net hip EFP power was determined by summing individual active hip muscle power plus the net passive hip power at each percent gait cycle interval. Net hip power was also calculated for these study participants via inverse dynamics (kinetics plus kinematics, KIN). The inverse dynamics technique - well accepted in the biomechanics literature - was used as a "gold standard" for validation of this EFP model. Closeness of fit of the power curves of the two methods was used to validate the model. RESULTS: The correlation between the EFP and KIN methods was sufficiently close, suggesting validation of the model's ability to provide reasonable estimates of power produced by individual hip muscles. Key findings were that (1) most muscles undergo a stretch-shorten cycle of muscle contraction, (2) greatest power was produced by the hip abductors, and (3) the hip adductors contribute to either hip adduction or hip extension (but not both). CONCLUSIONS: The EMG-to-force processing approach provides reasonable estimates of individual hip muscle forces in self-selected speed walking in neurologically-intact adults. PMID- 28893286 TI - The biology of how circumcision reduces HIV susceptibility: broader implications for the prevention field. AB - Circumcision reduces heterosexual HIV-1 acquisition in men by at least 60%. However, the biological mechanisms by which circumcision is protective remain incompletely understood. We test the hypothesis that the sub-preputial microenvironment created by the foreskin drives immune activation in adjacent foreskin tissues, facilitating HIV-1 infection through a combination of epithelial barrier disruption, enhanced dendritic cell maturation, and the recruitment/activation of neutrophils and susceptible CD4 T cell subsets such as Th17 cells. Furthermore, we provide evidence that the genital microbiome may be an important driver of this immune activation. This suggests that new modalities to reduce genital immune activation and/or alter the genital microbiome, used alone or in combination with topical microbicides, may be of significant benefit to HIV prevention. PMID- 28893287 TI - Natural killer (NK) cell receptor-HLA ligand genotype combinations associated with protection from HIV infection: investigation of how protective genotypes influence anti HIV NK cell functions. AB - The anti-HIV activity of natural killer (NK) cells could be induced fast enough to potentially prevent the establishment of HIV infection. Epidemiological studies identified two genotypes encoding NK receptors that contribute to NK cell function, that were more frequent in people who remained uninfected despite multiple HIV exposures than in HIV-susceptible subjects. NK cells from carriers of the *h/*y+B*57 genotype have higher NK cell functional potential and inhibit HIV replication in autologous HIV-infected CD4+ T cells (iCD4) more potently than those from carriers of non-protective genotypes. HIV suppression depends on the secretion of CC-chemokines that block HIV entry into CD4+ cells. NK cell education and the effect of HIV infection on iCD4 cell surface expression of MHC I antigens both influenced NK cell responses to autologous iCD4. The second KIR3DS1 homozygous protective genotype encodes an activating receptor that upon interacting with its HLA-F ligand on iCD4 induces anti-viral activity. PMID- 28893288 TI - Potential contribution of gut microbiota and systemic inflammation on HIV vaccine effectiveness and vaccine design. AB - The quest for an effective HIV-1 vaccine began as soon as the virus causing AIDS was identified. After several disappointing attempts, results of the Phase-III RV144 trial in Thailand were a beacon of hope for the field demonstrating correlation between protection and immunological markers. In order to optimize vaccine response, we underline results from yellow fever and hepatitis B vaccines, where protective responses were predicted by the pre-vaccination level of immune activation in healthy individuals. Such findings support the assessment and reduction of pre-vaccine immune activation in order to optimize vaccine response. Immune activation in healthy individuals can be influenced by age, presence of CMV infection, gut dysbiosis and microbial translocation. We speculate that the level of immune activation should therefore be assessed to better select participants in vaccine trials, and interventions to reduce inflammation should be used to increase protective HIV vaccine response. PMID- 28893289 TI - Recombinant expression of beak and feather disease virus capsid protein and assembly of virus-like particles in Nicotiana benthamiana. AB - BACKGROUND: Beak and feather disease virus (BFDV) is an important disease causing agent affecting psittacines. BFDV is highly infectious and can present as acute, chronic or subclinical disease. The virus causes immunodeficiency and is often associated with secondary infections. No commercial vaccine is available and yields of recombinant BFDV capsid protein (CP) expressed in insect cells and bacteria are yet to be seen as commercially viable, although both systems produced BFDV CP that could successfully assemble into virus-like particles (VLPs). Plants as expression systems are increasingly becoming favourable for the production of region-specific and niche market products. The aim of this study was to investigate the formation and potential for purification of BFDV VLPs in Nicotiana benthamiana. METHODS: The BFDV CP was transiently expressed in N. benthamiana using an Agrobacterium-mediated system and plant expression vectors that included a bean yellow dwarf virus (BeYDV)-based replicating DNA vector. Plant-produced BFDV CP was detected using immunoblotting. VLPs were purified using sucrose cushion and CsCl density gradient centrifugation and visualised using transmission electron microscopy. RESULTS: In this study we demonstrate that the BFDV CP can be successfully expressed in N. benthamiana, albeit at relatively low yield. Using a purification strategy based on centrifugation we demonstrated that the expressed CP can self-assemble into VLPs that can be detected using electron microscopy. These plant-produced BFDV VLPs resemble those produced in established recombinant expression systems and infectious virions. It is possible that the VLPs are spontaneously incorporating amplicon DNA produced from the replicating BeYDV plant vector. CONCLUSIONS: This is the first report of plant-made full-length BFDV CP assembling into VLPs. The putative pseudovirions could be used to further the efficacy of vaccines against BFDV. PMID- 28893290 TI - Evasion of adaptive immunity by HIV through the action of host APOBEC3G/F enzymes. AB - APOBEC3G (A3G) and APOBEC3F (A3F) are DNA-mutating enzymes expressed in T cells, dendritic cells and macrophages. A3G/F have been considered innate immune host factors, based on reports that they lethally mutate the HIV genome in vitro. In vivo, A3G/F effectiveness is limited by viral proteins, entrapment in inactive complexes and filtration of mutations during viral life cycle. We hypothesized that the impact of sub-lethal A3G/F action could extend beyond the realm of innate immunity confined to the cytoplasm of infected cells. We measured recognition of wild type and A3G/F-mutated epitopes by cytotoxic T lymphocytes (CTL) from HIV-infected individuals and found that A3G/F-induced mutations overwhelmingly diminished CTL recognition of HIV peptides, in a human histocompatibility-linked leukocyte antigen (HLA)-dependent manner. Furthermore, we found corresponding enrichment of A3G/F-favored motifs in CTL epitope-encoding sequences within the HIV genome. These findings illustrate that A3G/F-mediated mutations mediate immune evasion by HIV in vivo. Therefore, we suggest that vaccine strategies target T cell or antibody epitopes that are not poised for mutation into escape variants by A3G/F action. PMID- 28893291 TI - Preference for cesarean section in young nulligravid women in eight OECD countries and implications for reproductive health education. AB - BACKGROUND: Efforts to reduce unnecessary Cesarean sections (CS) in high and middle income countries have focused on changing hospital cultures and policies, care provider attitudes and behaviors, and increasing women's knowledge about the benefits of vaginal birth. These strategies have been largely ineffective. Despite evidence that women have well-developed preferences for mode of delivery prior to conceiving their first child, few studies and no interventions have targeted the next generation of maternity care consumers. The objectives of the study were to identify how many women prefer Cesarean section in a hypothetical healthy pregnancy, why they prefer CS and whether women report knowledge gaps about pregnancy and childbirth that can inform educational interventions. METHODS: Data was collected via an online survey at colleges and universities in 8 OECD countries (Australia, Canada, Chile, England, Germany, Iceland, New Zealand, United States) in 2014/2015. Childless young men and women between 18 and 40 years of age who planned to have at least one child in the future were eligible to participate. The current analysis is focused on the attitudes of women (n = 3616); rates of CS preference across countries are compared, using a standardized cohort of women aged 18-25 years, who were born in the survey country and did not study health sciences (n = 1390). RESULTS: One in ten young women in our study preferred CS, ranging from 7.6% in Iceland to 18.4% in Australia. Fear of uncontrollable labor pain and fear of physical damage were primary reasons for preferring a CS. Both fear of childbirth and preferences for CS declined as the level of confidence in women's knowledge of pregnancy and birth increased. CONCLUSION: Education sessions delivered online, through social media, and face-to-face using drama and stories told by peers (young women who have recently had babies) or celebrities could be designed to maximize young women's capacity to understand the physiology of labor and birth, and the range of methods available to support them in coping with labor pain and to minimize invasive procedures, therefore reducing fear of pain, bodily damage, and loss of control. The most efficacious designs and content for such education for young women and girls remains to be tested in future studies. PMID- 28893293 TI - HIV vaccine research in Canada. PMID- 28893292 TI - Reorganization of finger coordination patterns through motor exploration in individuals after stroke. AB - BACKGROUND: Impairment of hand and finger function after stroke is common and affects the ability to perform activities of daily living. Even though many of these coordination deficits such as finger individuation have been well characterized, it is critical to understand how stroke survivors learn to explore and reorganize their finger coordination patterns for optimizing rehabilitation. In this study, I examine the use of a body-machine interface to assess how participants explore their movement repertoire, and how this changes with continued practice. METHODS: Ten participants with chronic stroke wore a data glove and the finger joint angles were mapped on to the position of a cursor on a screen. The task of the participants was to move the cursor back and forth between two specified targets on a screen. Critically, the map between the finger movements and cursor motion was altered so that participants sometimes had to generate coordination patterns that required finger individuation. There were two phases to the experiment - an initial assessment phase on day 1, followed by a learning phase (days 2-5) where participants trained to reorganize their coordination patterns. RESULTS: Participants showed difficulty in performing tasks which had maps that required finger individuation, and the degree to which they explored their movement repertoire was directly related to clinical tests of hand function. However, over four sessions of practice, participants were able to learn to reorganize their finger movement coordination pattern and improve their performance. Moreover, training also resulted in improvements in movement repertoire outside of the context of the specific task during free exploration. CONCLUSIONS: Stroke survivors show deficits in movement repertoire in their paretic hand, but facilitating movement exploration during training can increase the movement repertoire. This suggests that exploration may be an important element of rehabilitation to regain optimal function. PMID- 28893294 TI - HIV-I Nef inhibitors: a novel class of HIV-specific immune adjuvants in support of a cure. AB - The success of many current vaccines relies on a formulation that incorporates an immune activating adjuvant. This will hold true for the design of a successful therapeutic HIV vaccine targeted at controlling reactivated virus following cessation of combined antiretroviral therapy (cART). The HIV accessory protein Nef functions by interfering with HIV antigen presentation through the major histocompatibility complex I (MHC-I) pathway thereby suppressing CD8+ cytotoxic T cell (CTL)-mediated killing of HIV infected cells. Thus, this important impediment to HIV vaccine success must be circumvented. This review covers our current knowledge of Nef inhibitors that may serve as immune adjuvants that will specifically restore and enhance CTL-mediated killing of reactivated HIV infected cells as part of an overall vaccine strategy to affect a cure for HIV infection. PMID- 28893295 TI - A brain-computer interface driven by imagining different force loads on a single hand: an online feasibility study. AB - BACKGROUND: Motor imagery (MI) induced EEG patterns are widely used as control signals for brain-computer interfaces (BCIs). Kinetic and kinematic factors have been proved to be able to change EEG patterns during motor execution and motor imagery. However, to our knowledge, there is still no literature reporting an effective online MI-BCI using kinetic factor regulated EEG oscillations. This study proposed a novel MI-BCI paradigm in which users can online output multiple commands by imagining clenching their right hand with different force loads. METHODS: Eleven subjects participated in this study. During the experiment, they were asked to imagine clenching their right hands with two different force loads (30% maximum voluntary contraction (MVC) and 10% MVC). Multi-Common spatial patterns (Multi-CSPs) and support vector machines (SVMs) were used to build the classifier for recognizing three commands corresponding to high load MI, low load MI and relaxed status respectively. EMG were monitored to avoid voluntary muscle activities during the BCI operation. The event-related spectral perturbation (ERSP) method was used to analyse EEG variation during multiple load MI tasks. RESULTS: All subjects were able to drive BCI systems using motor imagery of different force loads in online experiments. We achieved an average online accuracy of 70.9%, with the highest accuracy of 83.3%, which was much higher than the chance level (33%). The event-related desynchronization (ERD) phenomenon during high load tasks was significantly higher than it was during low load tasks both in terms of intensity at electrode positions C3 (p < 0.05) and spatial distribution. CONCLUSIONS: This paper demonstrated the feasibility of the proposed MI-BCI paradigm based on multi-force loads on the same limb through online studies. This paradigm could not only enlarge the command set of MI-BCI, but also provide a promising approach to rehabilitate patients with motor disabilities. PMID- 28893296 TI - Diagnostic performance of image navigated coronary CMR angiography in patients with coronary artery disease. AB - BACKGROUND: The use of coronary MR angiography (CMRA) in patients with coronary artery disease (CAD) remains limited due to the long scan times, unpredictable and often non-diagnostic image quality secondary to respiratory motion artifacts. The purpose of this study was to evaluate CMRA with image-based respiratory navigation (iNAV CMRA) and compare it to gold standard invasive x-ray coronary angiography in patients with CAD. METHODS: Consecutive patients referred for CMR assessment were included to undergo iNAV CMRA on a 1.5 T scanner. Coronary vessel sharpness and a visual score were assigned to the coronary arteries. A diagnostic reading was performed on the iNAV CMRA data, where a lumen narrowing >50% was considered diseased. This was compared to invasive x-ray findings. RESULTS: Image navigated CMRA was performed in 31 patients (77% male, 56 +/- 14 years). The iNAV CMRA scan time was 7 min:21 s +/- 0 min:28 s. Out of a possible 279 coronary segments, 26 segments were excluded from analysis due to stents or diameter less than 1.5 mm, resulting in a total of 253 coronary segments. Diagnostic image quality was obtained for 98% of proximal coronary segments, 94% of middle segments, and 91% of distal coronary segments. The sensitivity and specificity was 86% and 83% per patient, 80% and 92% per vessel and 73% and 95% per segment. CONCLUSION: In this study, iNAV CMRA offered a very good diagnostic performance when compared against invasive x-ray angiography. Due to the short and predictable scan time it can add clinical value as a part of a comprehensive CAD assessment protocol. PMID- 28893297 TI - Evidence-based practice within nutrition: what are the barriers for improving the evidence and how can they be dealt with? AB - BACKGROUND: Evidence-based clinical research poses special barriers in the field of nutrition. The present review summarises the main barriers to research in the field of nutrition that are not common to all randomised clinical trials or trials on rare diseases and highlights opportunities for improvements. METHODS: Systematic academic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: Many nutrients occur in multiple forms that differ in biological activity, and several factors can alter their bioavailability which raises barriers to their assessment. These include specific difficulties with blinding procedures, with assessments of dietary intake, and with selecting appropriate outcomes as patient-centred outcomes may occur decennia into the future. The methodologies and regulations for drug trials are, however, applicable to nutrition trials. CONCLUSIONS: Research on clinical nutrition should start by collecting clinical data systematically in databases and registries. Measurable patient-centred outcomes and appropriate study designs are needed. International cooperation and multistakeholder engagement are key for success. PMID- 28893298 TI - Learning from returnee Ethiopian migrant domestic workers: a qualitative assessment to reduce the risk of human trafficking. AB - BACKGROUND: International migration has become a global political priority, with growing concern about the scale of human trafficking, hazardous work conditions, and resulting psychological and physical morbidity among migrants. Ethiopia remains a significant "source" country for female domestic workers to the Middle East and Gulf States, despite widespread reports of exploitation and abuse. Prior to introduction of a "safe migration" intervention, we conducted formative research to elicit lessons learned by women who had worked as domestic workers abroad. The aim of the study was to identify realistic measures future migrants could take to protect themselves, based on the collective insights and experience of returnees. METHODS: We conducted a qualitative assessment among returnee domestic labour migrants in Amhara Region, Ethiopia, an area considered a "hotspot" for outmigration. We conducted in-depth interviews and focus group discussions with a total of 35 female returnees, exploring risk and protective factors experienced by Ethiopian women during domestic work abroad. We used thematic content analysis to identify practical messages that could improve prospective migrants' preparedness. RESULTS: Returnees described the knowledge and skills they acquired prior to departure and during migration, and shared advice they would give to prospective migrants in their community. Facilitators of positive migration included conforming to cultural and behavioural expectations, learning basic Arabic, using household appliances, and ensuring safety in employers' homes. Respondents also associated confidence and assertiveness with better treatment and respect, and emphasized the importance of access to external communication (e.g. a mobile phone, local sim card, and contact details) for help in an emergency. Following their own challenging or even traumatic experiences, returnees were keen to support resilience among the next wave of migrants. CONCLUSIONS: There is little evidence on practices that foster safer migration, yet attention to human trafficking has led to an increase in pre-migration interventions. These require robust evidence about local risk and protective factors. Our findings identify knowledge, skills, attributes and resources found useful by returnee domestic workers in Amhara region, and have been used to inform a community-based programme aiming to foster better decision making and preparation, with potential to offer insights for safer migration elsewhere. PMID- 28893299 TI - Risk for surgical complications after previous stereotactic body radiotherapy of the spine. AB - OBJECT: Stereotactic body radiotherapy (SBRT) for vertebral metastases has emerged as a promising technique, offering high rates of symptom relief and local control combined with low risk of toxicity. Nonetheless, local failure or vertebral instability may occur after spine SBRT, generating the need for subsequent surgery in the irradiated region. This study evaluated whether there is an increased incidence of surgical complications in patients previously treated with SBRT at the index level. METHODS: Based upon a retrospective international database of 704 cases treated with SBRT for vertebral metastases, 30 patients treated at 6 different institutions were identified who underwent surgery in a region previously treated with SBRT. RESULTS: Thirty patients, median age 59 years (range 27-84 years) underwent SBRT for 32 vertebral metastases followed by surgery at the same vertebra. Median follow-up time from SBRT was 17 months. In 17 cases, conventional radiotherapy had been delivered prior to SBRT at a median dose of 30 Gy in median 10 fractions. SBRT was administered with a median prescription dose of 19.3 Gy (range 15-65 Gy) delivered in median 1 fraction (range 1-17) (median EQD2/10 = 44 Gy). The median time interval between SBRT and surgical salvage therapy was 6 months (range 1-39 months). Reasons for subsequent surgery were pain (n = 28), neurological deterioration (n = 15) or fracture of the vertebral body (n = 13). Open surgical decompression (n = 24) and/or stabilization (n = 18) were most frequently performed; Five patients (6 vertebrae) were treated without complications with vertebroplasty only. Increased fibrosis complicating the surgical procedure was explicitly stated in one surgical report. Two durotomies occurred which were closed during the operation, associated with a neurological deficit in one patient. Median blood loss was 500 ml, but five patients had a blood loss of more than 1 l during the procedure. Delayed wound healing was reported in two cases. One patient died within 30 days of the operation. CONCLUSION: In this series of surgical interventions following spine SBRT, the overall complication rate was 19%, which appears comparable to primary surgery without previous SBRT. Prior spine SBRT does not appear to significantly increase the risk of intra- and post surgical complications. PMID- 28893300 TI - Stereotactic body radiotherapy for stage I non-small-cell lung cancer using higher doses for larger tumors: results of the second study. AB - BACKGROUND: Efficacy of stereotactic body radiotherapy (SBRT) in stage I non small-cell lung cancer (NSCLC) has almost been established. In Japan, the protocol of 48 Gy in 4 fractions over 4 days has been most often employed, but higher doses may be necessary to control large tumors. Previously, we conducted a clinical study using SBRT for stage I NSCLC employing different doses depending on tumor diameter, which was closed in 2008. Thereafter, a new study employing higher doses has been conducted, which is reported here. The purpose of this study was to review the safety and effectiveness of the higher doses. METHODS: We escalated the total dose for the improvement of local control for large tumors. In this study, 71 patients underwent SBRT between December 2008 and April 2014. Isocenter doses of 48, 50, and 52 Gy were administered for tumors with a longest diameter of < 1.5 cm, 1.5-3 cm, and > 3 cm, respectively. It was recommended to cover 95% of the PTV with at least 90% of the isocenter dose, and in all but one cases, 95% of the PTV received at least 80% of the prescribed dose. Treatments were delivered in 4 fractions, giving 2 fractions per week. SBRT was performed with 6-MV photons using 4 non-coplanar and 3 coplanar beams. RESULTS: The median follow-up period was 44 months for all patients and 61 months for living patients. Overall survival (OS) was 65%, progression-free survival (PFS) was 55%, and cumulative incidence of local recurrence (LR) was 15% at 5 years. The 5-year OS was 69% for 57 stage IA patients and 53% for 14 stage IB patients (p = 0.44). The 5-year PFS was 55 and 54%, respectively (p = 0.98). The 5-year cumulative incidence of LR was 11 and 31%, respectively (p = 0.09). The cumulative incidence of Grade >= 2 radiation pneumonitis was 25%. CONCLUSIONS: Our newer SBRT study yielded reasonable local control and overall survival and acceptable toxicity, but escalating the total dose did not lead to improved outcomes. TRIAL REGISTRATION: UMIN000027231 , registered on 3 May 2017. Retrospectively registered. PMID- 28893301 TI - Intussusception caused by heterotopic gastric mucosa in small intestine: a case report. AB - BACKGROUND: Intestinal intussusception is the most frequent cause of small bowel obstruction in children between the ages of 2 months and 5 years and often remains idiopathic in etiology, even after surgery. On microscopic examination, in intussusception normal mucosa is noted but in a few cases heterotopic tissue can be seen. Heterotopic gastric mucosa in the small intestine is extremely rare except for its occurrence in remnants of Meckel's diverticulum. In view of the rarity of this condition, we report a case of ectopic gastric mucosa in the small intestine that was not associated with remnants of vitelline duct. CASE PRESENTATION: A 6-year-old boy of Indo-Aryan ethnicity from India presented with episodes of acute abdominal pain and distension with vomiting and non-passage of stools. On ultrasonography intussusception was suspected. A laparotomy was done and the ileal segment (tip of intussusception) was sent for histopathological examination. On histopathology, sections from the tip of intussusception showed extensive gastric metaplasia of the mucosa. CONCLUSIONS: A definitive diagnosis of heterotopic gastric mucosa is established by histopathological examination and it is important to differentiate heterotopia, which is a developmental anomaly, from metaplasia, which is an acquired condition. Heterotopic gastric mucosa is usually clinically silent and surgical intervention can be considered in patients with complications such as gastrointestinal hemorrhage and intestinal obstruction. PMID- 28893302 TI - Comprehensive target geometric errors and margin assessment in stereotactic partial breast irradiation. AB - BACKGROUND: Recently developed stereotactic partial breast irradiation (S-PBI) allows delivery of a high biologically potent dose to the target while sparing adjacent critical organs and normal tissue. With S-PBI tumoricidal doses, accurate and precise dose delivery is critical to achieve high treatment quality. This study is to investigate both rigid and non-rigid components of target geometric error and their corresponding margins in S-PBI and identify correlated clinical factors. METHODS: Forty-three early-stage breast cancer patients with implanted gold fiducial markers were enrolled in the study. Fiducial positions recorded on the orthogonal kV images on a Cyberknife system during treatment were used to estimate intra-fraction errors and composite errors (including intra fraction errors and residual errors after patient setup). Both rigid and non rigid components of intra-fraction and composite errors were analyzed and used to estimate rigid and non-rigid margins, respectively. Univariate and multivariate linear regressions were conducted to evaluate correlations between clinical factors and errors. RESULTS: For the study group, the intra-fraction rigid and non-rigid errors are 2.0 +/- 0.6 mm and 0.3 +/- 0.2 mm, respectively. The composite rigid and non-rigid errors are 2.3 +/- 0.5 mm and 1.3 +/- 0.8 mm, respectively. The rigid margins in the left-right, anterior-posterior, and superior-inferior directions are estimated as 2.1, 2.4, and 2.3 mm, respectively. The estimated non-rigid margin, assumed to be isotropic, is 1.7 mm. The outer breast quadrants are more susceptible to composite errors occurrence than the inner breast quadrants. The target to chest wall distance is the clinical factor correlated with target geometric errors. CONCLUSIONS: This is the first comprehensive analysis of breast target geometric rigid and non-rigid errors in S PBI. Upon the estimation, the non-rigid margin is comparable to rigid margin, and therefore should be included in planning target volume as it cannot be accounted for by the Cyberknife system. Treatment margins selection also need to consider the impact of relevant clinical factor. PMID- 28893303 TI - Contrast-enhanced spectral mammography in neoadjuvant chemotherapy monitoring: a comparison with breast magnetic resonance imaging. AB - BACKGROUND: Neoadjuvant-chemotherapy (NAC) is considered the standard treatment for locally advanced breast carcinomas. Accurate assessment of disease response is fundamental to increase the chances of successful breast-conserving surgery and to avoid local recurrence. The purpose of this study was to compare contrast enhanced spectral mammography (CESM) and contrast-enhanced-MRI (MRI) in the evaluation of tumor response to NAC. METHODS: This prospective study was approved by the institutional review board and written informed consent was obtained. Fifty-four consenting women with breast cancer and indication of NAC were consecutively enrolled between October 2012 and December 2014. Patients underwent both CESM and MRI before, during and after NAC. MRI was performed first, followed by CESM within 3 days. Response to therapy was evaluated for each patient, comparing the size of the residual lesion measured on CESM and MRI performed after NAC to the pathological response on surgical specimens (gold standard), independently of and blinded to the results of the other test. The agreement between measurements was evaluated using Lin's coefficient. The agreement between measurements using CESM and MRI was tested at each step of the study, before, during and after NAC. And last of all, the variation in the largest dimension of the tumor on CESM and MRI was assessed according to the parameters set in RECIST 1.1 criteria, focusing on pathological complete response (pCR). RESULTS: A total of 46 patients (85%) completed the study. CESM predicted pCR better than MRI (Lin's coefficient 0.81 and 0.59, respectively). Both methods tend to underestimate the real extent of residual tumor (mean 4.1mm in CESM, 7.5mm in MRI). The agreement between measurements using CESM and MRI was 0.96, 0.94 and 0.76 before, during and after NAC respectively. The distinction between responders and non-responders with CESM and MRI was identical for 45/46 patients. In the assessment of CR, sensitivity and specificity were 100% and 84%, respectively, for CESM, and 87% and 60% for MRI. CONCLUSION: CESM and MRI lesion size measurements were highly correlated. CESM seems at least as reliable as MRI in assessing the response to NAC, and may be an alternative if MRI is contraindicated or its availability is limited. PMID- 28893305 TI - Trialing transparent peer review. PMID- 28893304 TI - Preventing HIV infection without targeting the virus: how reducing HIV target cells at the genital tract is a new approach to HIV prevention. AB - For over three decades, HIV infection has had a tremendous impact on the lives of individuals and public health. Microbicides and vaccines studies have shown that immune activation at the genital tract is a risk factor for HIV infection. Furthermore, lower level of immune activation, or what we call immune quiescence, has been associated with a lower risk of HIV acquisition. This unique phenotype is observed in highly-exposed seronegative individuals from different populations including female sex workers from the Pumwani cohort in Nairobi, Kenya. Here, we review the link between immune activation and susceptibility to HIV infection. We also describe a new concept in prevention where, instead of targeting the virus, we modulate the host immune system to resist HIV infection. Mimicking the immune quiescence phenotype might become a new strategy in the toolbox of biomedical methods to prevent HIV infection. Clinical trial registration on clinicaltrial.gov: #NCT02079077. PMID- 28893306 TI - MOnitored supplementation of VItamin D in preterm infants (MOSVID trial): study protocol for a randomised controlled trial. AB - BACKGROUND: The pivotal role of vitamin D (vit D) in skeletal health is well known. Neonatal vit D storage at birth is dependent on maternal levels, and newborns receive 50-70% of their mother's 25-hydroxyvitamin D [25(OH)D]. Deficiency of vit D can lead to prematurity bone disease, with an incidence of up to 55% in infants weighing < 1000 g. The aim of this study is to assess the effectiveness of monitored supplementation of vit D in a population of preterm infants. METHODS/DESIGN: Preterm infants born at 24-32 weeks of gestation will be recruited within the first 7 days of life. Depending on the type of feeding, and after reaching partial enteral feeding or at 7 days of life, vit D supplementation will consist of 500 IU and an additional 150-300 IU/kg included in human milk fortifiers (if fed exclusively with breast milk) or 190 IU/kg in milk formulas. Subjects will be randomised to either monitored (with an option of dose modification based on 25(OH)D levels as per protocol) or standard therapy up to 52 weeks of post-conceptional age (PCA). The primary outcome measure will be the number of neonates with deficiency or excess levels of 25(OH)D at 40 +/-2 weeks of PCA. Additional 25(OH)D levels will be measured at birth, at 4 and 8 weeks of age, and/or at 35 and 52 +/-2 weeks of PCA. Secondary objectives will include the incidence of osteopenia, nephrocalcinosis and nephrolithiasis. Serum parameters of calcium phosphorus metabolism will also be measured. DISCUSSION: Despite multiple years of research and numerous publications, there is still a lack of consensus in regard to how much vit D infants should receive and how long they should receive it. Because 80% of calcium and phosphorus placental transfer occurs between 24 and 40 weeks of gestation, preterm infants are especially prone to adverse effects of vit D insufficiency. However, both inadequate and excessive amounts of vit D may be unsafe and lead to serious health issues. The results of our study may shed new light on these concerns and contribute to optimising vit D supplementation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03087149 . Registered on 15 March 2017. PMID- 28893307 TI - Interventions to control myopia progression in children: protocol for an overview of systematic reviews and meta-analyses. AB - BACKGROUND: Myopia is a common visual disorder with increasing prevalence among developed countries of the world. Myopia constitutes a substantial risk factor for several ocular conditions that can lead to blindness. The purpose of this study is to conduct an overview of systematic reviews and meta-analyses in order to identify and appraise robust research evidence regarding the management of myopia progression in children and adolescents. METHODS: A literature search will be conducted in MEDLINE, EMBASE, The Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA) Database via Centre for Reviews and Dissemination (CRD). We will search for systematic reviews or meta-analyses that examine optical or pharmaceutical modalities for myopia control. Two independent overview authors will screen the titles and abstracts against the eligibility criteria. Individual study's methodological quality and quality of evidence for each outcome of interest will be assessed by two independent authors using the ROBIS tool and GRADE rating, respectively. In cases of disagreement, consensus will be reached with the help of a third author. Our primary outcomes will be the mean change in refractive error, mean axial length change, and adverse events. A citation matrix will be generated, and the corrected covered area (CCA) will be estimated, in order to identify overlapping primary studies. Possible meta-biases and measures of heterogeneity will be described, and cases of dual co-authorship will be identified and discussed. If any recently published randomized controlled trials (RCTs) are detected, these will be appraised and their findings will be presented. An overall summary of outcomes will be provided using descriptive statistics and will be supplemented by narrative synthesis. DISCUSSION: This overview will examine the high level of existing evidence for treatment of myopia progression. Efficient interventions will be identified, and side effects will be reported. The expected benefit is that all robust recent research evidence will be compiled in a single study. The results may inform future research in this area, which should provide insight into the appropriate regimes for the administration of these modalities and contribute to future guideline development. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017068204. PMID- 28893308 TI - More than 2500 years of oil exposure shape sediment microbiomes with the potential for syntrophic degradation of hydrocarbons linked to methanogenesis. AB - BACKGROUND: Natural oil seeps offer the opportunity to study the adaptation of ecosystems and the associated microbiota to long-term oil exposure. In the current study, we investigated a land-to-sea transition ecosystem called "Keri Lake" in Zakynthos Island, Greece. This ecosystem is unique due to asphalt oil springs found at several sites, a phenomenon already reported 2500 years ago. Sediment microbiomes at Keri Lake were studied, and their structure and functional potential were compared to other ecosystems with oil exposure histories of various time periods. RESULTS: Replicate sediment cores (up to 3-m depth) were retrieved from one site exposed to oil as well as a non-exposed control site. Samples from three different depths were subjected to chemical analysis and metagenomic shotgun sequencing. At the oil-exposed site, we observed high amounts of asphalt oil compounds and a depletion of sulfate compared to the non-exposed control site. The numbers of reads assigned to genes involved in the anaerobic degradation of hydrocarbons were similar between the two sites. The numbers of denitrifiers and sulfate reducers were clearly lower in the samples from the oil-exposed site, while a higher abundance of methanogens was detected compared to the non-exposed site. Higher abundances of the genes of methanogenesis were also observed in the metagenomes from other ecosystems with a long history of oil exposure, compared to short-term exposed environments. CONCLUSIONS: The analysis of Keri Lake metagenomes revealed that microbiomes in the oil-exposed sediment have a higher potential for methanogenesis over denitrification/sulfate reduction, compared to those in the non-exposed site. Comparison with metagenomes from various oil-impacted environments suggests that syntrophic interactions of hydrocarbon degraders with methanogens are favored in the ecosystems with a long-term presence of oil. PMID- 28893309 TI - Efficacy and safety of controlled-release oxycodone/naloxone versus controlled release oxycodone in Korean patients with cancer-related pain: a randomized controlled trial. AB - BACKGROUND: Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone (OX-CR) for the control of cancer-related pain in Korean patients. METHODS: In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale (NRS) pain score >=4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat (ITT) population were randomized (1:1) to OXN CR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non-inferiority margin of -1.5. Secondary endpoints included analgesic rescue medication intake, patient-reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments. RESULTS: Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group (n = 58) and the OX-CR group (n = 59) (-1.586 vs. -1.559, P = 0.948). The lower limit of the one-sided 95% confidence interval (-0.776 to 0.830) for the difference exceeded the non-inferiority margin (P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments. CONCLUSIONS: OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer-related pain are needed to further investigate the effectiveness of OXN-CR for long-term pain control and constipation alleviation. Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011. PMID- 28893310 TI - Effect of long-term storage in Safe Cell+ extender on boar sperm DNA integrity and other key sperm parameters. AB - BACKGROUND: There is some controversy about the extent of changes in different sperm cell features in stored boar semen, especially regarding the potential role of the DNA fragmentation assay for assessment of sperm fertilizing ability. The aim of this study was to assess the effect of time of storage and the dynamic changes in sperm cell characteristics in normospermic boar semen stored in long term extender, in order to determine the susceptibility to damage of particular structures of spermatozoa during cooling and storage at 17 degrees C for 240 h post collection. The study included five ejaculates from each of seven boars of the Polish Large White breed (n = 35 ejaculates). The sperm characteristics were assessed using a flow cytometer and a computer assisted sperm analyzer on samples at 0, 48, 96, 168 and 240 h post collection. RESULTS: The sperm chromatin structure assay (SCSA) showed a significant abrupt increase (P < 0.01) in the DNA fragmentation index (%DFI) after 48 h of semen storage with only subtle changes thereafter, not exceeding 5% on average after 240 h of storage. The use of a combination of SYBR-14/PI stains did not reveal any significant changes in the percentage of live sperm cells up to 168 h of semen storage. A significant (P < 0.01) decrease in the percentage of live spermatozoa with intact acrosomes was observed after prolonged semen storage (168 h). A significant and progressive decrease in sperm motility was recorded during the whole period of semen storage. CONCLUSIONS: Storage of boar semen extended in long-term diluent at 17 degrees C for 48 h initially induced a decrease in the integrity of sperm DNA. This suggests that the structure of boar sperm DNA is susceptible to damage, especially during semen extension and at the beginning of sperm storage. These findings support the opinion that the SCSA test has only a low potential for routine assessment of boar semen preserved in the liquid state and for assessment of sperm quality changes during 10 days of semen preservation. Remarkably, the integrity of acrosomes and plasma membranes remained nearly unchanged for 7 days. PMID- 28893311 TI - Evaluation of pre-symptomatic nitisinone treatment on long-term outcomes in Tyrosinemia type 1 patients: a systematic review. AB - BACKGROUND: Tyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection. METHODS: We searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second. RESULTS: We included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10-24 patients; later treatment: 25-60% of 4-15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health related outcomes were not possible because of sample size or reporting. CONCLUSIONS: There is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late treated groups included patients born prior to the availability of nitisinone. PMID- 28893312 TI - The validity and reliability of the four square step test in different adult populations: a systematic review. AB - BACKGROUND: The four square step test (FSST) was first validated in healthy older adults to provide a measure of dynamic standing balance and mobility. The FSST has since been used in a variety of patient populations. The purpose of this systematic review is to determine the validity and reliability of the FSST in these different adult patient populations. METHODS: The literature search was conducted to highlight all the studies that measured validity and reliability of the FSST. Six electronic databases were searched including AMED, CINAHL, MEDLINE, PEDro, Web of Science and Google Scholar. Grey literature was also searched for any documents relevant to the review. Two independent reviewers carried out study selection and quality assessment. The methodological quality was assessed using the QUADAS-2 tool, which is a validated tool for the quality assessment of diagnostic accuracy studies, and the COSMIN four-point checklist, which contains standards for evaluating reliability studies on the measurement properties of health instruments. RESULTS: Fifteen studies were reviewed studying community dwelling older adults, Parkinson's disease, Huntington's disease, multiple sclerosis, vestibular disorders, post stroke, post unilateral transtibial amputation, knee pain and hip osteoarthritis. Three of the studies were of moderate methodological quality scoring low in risk of bias and applicability for all domains in the QUADAS-2 tool. Three studies scored "fair" on the COSMIN four point checklist for the reliability components. The concurrent validity of the FSST was measured in nine of the studies with moderate to strong correlations being found. Excellent Intraclass Correlation Coefficients were found between physiotherapists carrying out the tests (ICC = .99) with good to excellent test retest reliability shown in nine of the studies (ICC = .73-.98). CONCLUSIONS: The FSST may be an effective and valid tool for measuring dynamic balance and a participants' falls risk. It has been shown to have strong correlations with other measures of balance and mobility with good reliability shown in a number of populations. However, the quality of the papers reviewed was variable with key factors, such as sample size and test set up, needing to be addressed before the tool can be confidently used in these specified populations. PMID- 28893313 TI - p53-Dependent PUMA to DRAM antagonistic interplay as a key molecular switch in cell-fate decision in normal/high glucose conditions. AB - BACKGROUND: As an important cellular stress sensor phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The p53 activity mainly depends on its transactivating function, however, how p53 can select one or another biological outcome is still a matter of profound studies. Our previous findings indicate that switching cancer cells in high glucose (HG) impairs p53 apoptotic function and the transcription of target gene PUMA. METHODS AND RESULTS: Here we report that, in response to drug adriamycin (ADR) in HG, p53 efficiently induced the expression of DRAM (damage-regulated autophagy modulator), a p53 target gene and a stress-induced regulator of autophagy. We found that ADR treatment of cancer cells in HG increased autophagy, as displayed by greater LC3II accumulation and p62 degradation compared to ADR-treated cells in low glucose. The increased autophagy in HG was in part dependent on p53 induced DRAM; indeed DRAM knockdown with specific siRNA reversed the expression of the autophagic markers in HG. A similar outcome was achieved by inhibiting p53 transcriptional activity with pifithrin-alpha. DRAM knockdown restored the ADR induced cell death in HG to the levels obtained in low glucose. A similar outcome was achieved by inhibition of autophagy with cloroquine (CQ) or with silencing of autophagy gene ATG5. DRAM knockdown or inhibition of autophagy were both able to re-induce PUMA transcription in response to ADR, underlining a reciprocal interplay between PUMA to DRAM to unbalance p53 apoptotic activity in HG. Xenograft tumors transplanted in normoglycemic mice displayed growth delay after ADR treatment compared to those transplanted in diabetics mice and such different in vivo response correlated with PUMA to DRAM gene expression. CONCLUSIONS: Altogether, these findings suggest that in normal/high glucose condition a mutual unbalance between p53-dependent apoptosis (PUMA) and autophagy (DRAM) gene occurred, modifying the ADR-induced cancer cell death in HG both in vitro and in vivo. PMID- 28893314 TI - Design of an extensive information representation scheme for clinical narratives. AB - BACKGROUND: Knowledge representation frameworks are essential to the understanding of complex biomedical processes, and to the analysis of biomedical texts that describe them. Combined with natural language processing (NLP), they have the potential to contribute to retrospective studies by unlocking important phenotyping information contained in the narrative content of electronic health records (EHRs). This work aims to develop an extensive information representation scheme for clinical information contained in EHR narratives, and to support secondary use of EHR narrative data to answer clinical questions. METHODS: We review recent work that proposed information representation schemes and applied them to the analysis of clinical narratives. We then propose a unifying scheme that supports the extraction of information to address a large variety of clinical questions. RESULTS: We devised a new information representation scheme for clinical narratives that comprises 13 entities, 11 attributes and 37 relations. The associated annotation guidelines can be used to consistently apply the scheme to clinical narratives and are https://cabernet.limsi.fr/annotation_guide_for_the_merlot_french_clinical_corpus Sept2016.pdf . CONCLUSION: The information scheme includes many elements of the major schemes described in the clinical natural language processing literature, as well as a uniquely detailed set of relations. PMID- 28893316 TI - Intraosseous blood samples for point-of-care analysis: agreement between intraosseous and arterial analyses. AB - BACKGROUND: Point-of-care (POC) testing is highly useful when treating critically ill patients. In case of difficult vascular access, the intraosseous (IO) route is commonly used, and blood is aspirated to confirm the correct position of the IO-needle. Thus, IO blood samples could be easily accessed for POC analyses in emergency situations. The aim of this study was to determine whether IO values agree sufficiently with arterial values to be used for clinical decision making. METHODS: Two samples of IO blood were drawn from 31 healthy volunteers and compared with arterial samples. The samples were analysed for sodium, potassium, ionized calcium, glucose, haemoglobin, haematocrit, pH, blood gases, base excess, bicarbonate, and lactate using the i-STAT(r) POC device. Agreement and reliability were estimated by using the Bland-Altman method and intraclass correlation coefficient calculations. RESULTS: Good agreement was evident between the IO and arterial samples for pH, glucose, and lactate. Potassium levels were clearly higher in the IO samples than those from arterial blood. Base excess and bicarbonate were slightly higher, and sodium and ionised calcium values were slightly lower, in the IO samples compared with the arterial values. The blood gases in the IO samples were between arterial and venous values. Haemoglobin and haematocrit showed remarkable variation in agreement. DISCUSSION: POC diagnostics of IO blood can be a useful tool to guide treatment in critical emergency care. Seeking out the reversible causes of cardiac arrest or assessing the severity of shock are examples of situations in which obtaining vascular access and blood samples can be difficult, though information about the electrolytes, acid-base balance, and lactate could guide clinical decision making. The analysis of IO samples should though be limited to situations in which no other option is available, and the results should be interpreted with caution, because there is not yet enough scientific evidence regarding the agreement of IO and arterial results among unstable patients. CONCLUSIONS: IO blood samples are suitable for analysis with the i-STAT(r) point-of-care device in emergency care. The aspirate used to confirm the correct placement of the IO needle can also be used for analysis. The results must be interpreted within a clinical context while taking the magnitude and direction of bias into account. PMID- 28893315 TI - Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors. AB - BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. METHODS: MDA-MB 231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). RESULTS: Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40 97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non carriers (ratio 0.29% (IQR 0.21-0.66%, P < 0.0001). CONCLUSIONS: PARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations. PMID- 28893317 TI - Perceived barriers and facilitators to Risk Based Monitoring in academic-led clinical trials: a mixed methods study. AB - BACKGROUND: In November 2016, the ICH published a requirement for sponsors to develop a systematic, prioritised, risk-based approach to monitoring clinical trials. This approach is more commonly known as risk-based monitoring (RBM). However, recent evidence suggests that a 'gold standard', validated approach to RBM does not exist and it is unclear how sponsors will introduce RBM into their organisations. A first step needed to inform the implementation of RBM is to explore academic trialists' readiness and ability to perform RBM. The aim of this paper is to identify the attitudes and perceived barriers and facilitators to the implementation of RBM in academic-led clinical trials in Ireland. METHODS: This is a mixed-methods, explanatory sequential design, with quantitative survey followed by semistructured interviews. Academic clinical researchers (N = 132) working in Ireland were surveyed to examine their use and perceptions of RBM. A purposive sample of survey participants (n = 22) were then interviewed to gain greater insight into the quantitative findings. The survey and interview data were merged to generate a list of perceived barriers and facilitators to RBM implementation, with suggestions for, and solutions to, these issues. RESULTS: Survey response rate was 49% (132/273). Thirteen percent (n = 18) of responders were not familiar with the term risk-based monitoring and less than a quarter of respondents (21%, n = 28) had performed RBM in a clinical trial. Barriers to RBM implementation included lack of RBM knowledge/training, increased costs caused by greater IT demands, increased workload for trial staff and lack of evidence to support RBM as an effective monitoring approach. Facilitators included participants' legal obligation to perform RBM under the new ICH-GCP guidelines, availability of RBM guidance and perception of cost savings by performing RBM in future trials. CONCLUSION: The results of this study demonstrate a need for training and regulatory-endorsed guidelines to support the implementation of RBM in academic-led clinical trials. The study provides valuable insights to inform interventions and strategies by policy-makers and clinical trial regulators to improve RBM uptake. PMID- 28893318 TI - ICG-001 suppresses growth of gastric cancer cells and reduces chemoresistance of cancer stem cell-like population. AB - BACKGROUND: ICG-001, a small molecule, binds CREB-binding protein (CBP) to disrupt its interaction with beta-catenin and inhibits CBP function as a co activator of Wnt/beta-catenin-mediated transcription. Given its ability to inhibit Wnt/beta-catenin signaling pathway, ICG-001 has been used in some tumor types to exert its anticarcinogenic effect. Here, we examined ICG-001 and its potential role as a therapeutic in gastric cancer (GC). METHODS: The gastric cancer cell lines SGC-7901, MGC-803, BGC-823 and MKN-45 were used in vitro and in vivo. The abilities of cell proliferation, tumor sphere formation, metastasis, tumorgenesis and chemoresistance to chemotherapy drugs in vitro were evaluated by MTT assay, colony formation assay, flow cytometry, migration and invasion assay, and tumor spheres culture. The in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Alterations at RNA and protein levels were followed by qRT-PCR, western blot, coimmunoprecipitations and immunofluorescence assay. RESULTS: In this study, we showed that ICG-001 significantly inhibited growth and metastasis of multiple GC cell lines, induced cell apoptosis, and augmented in vitro tumor spheres suppression when used in combination with chemotherapy drugs probably through robustly blocking association of beta-catenin with CBP and N-cadherin, but promoting association of beta-catenin with P300 and E-cadherin, instead of altering the distribution and expression of beta-catenin. CONCLUSIONS: Our findings suggest that ICG-001 suppresses GC cell line growth, metastasis and reduces its stem cell-like properties and chemoresistance, indicating that ICG-001 is a potentially useful small molecule therapeutic for GC. PMID- 28893319 TI - Sophoridine induces apoptosis and S phase arrest via ROS-dependent JNK and ERK activation in human pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Novel, selective antitumor agents are pressingly needed. METHODS: CCK-8 and colony formation assay were used to investigate the cell growth. Flow cytometry analysis was used to evaluate the cell cycle and cell apoptosis. The peroxide-sensitive fluorescent probe DCFH-DA was used to measure the intracellular ROS levels. Western blot assay was used to detect the levels of cell cycle and apoptosis related proteins. Xenografts in nude mice were used to evaluate the effect of Sophoridine on pancreatic cancer cell in vivo. RESULTS: Sophoridine killed cancer cells but had low cytotoxicity to normal cells. Pancreatic cancer cells were particularly sensitive. Sophoridine inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest at S phase and mitochondrial-related apoptosis. Moreover, Sophoridine induced a sustained activation of the phosphorylation of ERK and JNK. In addition, Sophoridine provoked the generation of reactive oxygen species (ROS) in pancreatic cancer cells. Finally, in vivo, Sophoridine suppressed tumor growth in mouse xenograft models. CONCLUSION: These findings suggest Sophoridine is promising to be a novel, potent and selective antitumor drug candidate for pancreatic cancer. PMID- 28893320 TI - Systems thinking in combating infectious diseases. AB - The transmission of infectious diseases is a dynamic process determined by multiple factors originating from disease pathogens and/or parasites, vector species, and human populations. These factors interact with each other and demonstrate the intrinsic mechanisms of the disease transmission temporally, spatially, and socially. In this article, we provide a comprehensive perspective, named as systems thinking, for investigating disease dynamics and associated impact factors, by means of emphasizing the entirety of a system's components and the complexity of their interrelated behaviors. We further develop the general steps for performing systems approach to tackling infectious diseases in the real world settings, so as to expand our abilities to understand, predict, and mitigate infectious diseases. PMID- 28893321 TI - Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999-2014. AB - BACKGROUND: Drug resistance limits options for antiretroviral therapy (ART) and results in poorer health outcomes among HIV-infected persons. We sought to characterize resistance patterns and to identify predictors of resistance in Washington, DC. METHODS: We analyzed resistance in the DC Cohort, a longitudinal study of HIV-infected persons in care in Washington, DC. We measured cumulative drug resistance (CDR) among participants with any genotype between 1999 and 2014 (n = 3411), transmitted drug resistance (TDR) in ART-naive persons (n = 1503), and acquired drug resistance (ADR) in persons with genotypes before and after ART initiation (n = 309). Using logistic regression, we assessed associations between patient characteristics and transmitted resistance to any antiretroviral. RESULTS: Prevalence of TDR was 20.5%, of ADR 40.5%, and of CDR 45.1% in the respective analysis groups. From 2004 to 2013, TDR prevalence decreased for nucleoside and nucleotide analogue reverse transcriptase inhibitors (15.0 to 5.5%; p = 0.0003) and increased for integrase strand transfer inhibitors (INSTIs) (0.0-1.4%; p = 0.04). In multivariable analysis, TDR was not associated with age, race/ethnicity, HIV risk group, or years from HIV diagnosis. CONCLUSIONS: In this urban cohort of HIV-infected persons, almost half of participants tested had evidence of CDR; and resistance to INSTIs was increasing. If this trend continues, inclusion of the integrase-encoding region in baseline genotype testing should be strongly considered. PMID- 28893322 TI - Bovine trypanosomosis: changes in parasitemia and packed cell volume in dry and wet seasons at Gidami District, Oromia Regional State, western Ethiopia. AB - BACKGROUND: Animal trypanosomosis is one of the major disease problems affecting agricultural productivity in Ethiopia. The impact of the disease is believed to vary with season and agro-ecologies in line with fly vector distribution. A cross sectional study on bovine trypanosomosis was conducted from November 2015 to June 2016, in seven selected villages of Gidami district, Oromia Regional State, western Ethiopia. A total of 930 blood samples were collected and subjected to parasitological and hematological analysis. RESULT: The overall prevalence of bovine trypanosomosis was 14.1%. The seasonal prevalence shows 9.06% in early dry and 18.4% in early rainy seasons. Three trypanosome species, Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei were identified in the examined animals. T. congolense followed by T. vivax were the predominant species (respectively 59.0 and 35.9% in early dry season and 62.0 and 22.8% in early rainy season). The prevalence of T. vivax remained similar in both early dry and early rainy seasons in both lowland and midland agroecologies whereas T. congolense was more dominant in the lowland area in both seasons compared to mid land study sites. The disease was more prevalent in lowland (23.9%) compared to midland (11.1%) during early rainy season (P < 0.001) whereas no significant difference was observed between the two agroecologies during early dry season (P = 0.165). Packed cell volume (PCV) was much lower in parasitemic animals than in aparasitemic cattle whereas the mean PCV value for parasitemic animals (20.36%; 95% CI 19.56 to 21.16) in early dry season was similar to values in early rainy season (20.46%, 95% CI 18.84 to 21.08%). A similar situation was noticed for animals in both low land and mid land study sites. CONCLUSION: Overall, the detection of trypanosomes in blood was significantly affected by agro-ecology, season and body condition of the animals. Special emphasis should be given to integrated trypanosomosis management in early rainy months where fly population is believed to start increasing. PMID- 28893323 TI - Out-of-pocket expenditure for seeking health care for sick children younger than 5 years of age in Bangladesh: findings from cross-sectional surveys, 2009 and 2012. AB - BACKGROUND: Bangladesh has committed to universal health coverage, and options to decrease household out-of-pocket expenditure (OPE) are being explored. Understanding the determinants of OPE is an essential step. This study aimed to estimate and identify determinants of OPE in seeking health care for sick under five children. METHODS: Cross-sectional data was collected by structured questionnaire in 2009 (n = 7362) and 2012 (n = 6896) from mothers of the under five children. OPE included consultation fees and costs of medicine, diagnostic tests, hospital admission, transport, accommodation, and food. Expenditure is expressed in US dollars and adjusted for inflation. Linear regression was used for ascertaining the determinants of OPE. RESULTS: Between 2009 and 2012, the median OPE for seeking care for a sick under-five child increased by ~ 50%, from USD 0.82 (interquartile range 0.39-1.49) to USD 1.22 (0.63-2.36) per child/visit. Increases were observed in every component OPE measured, except for consultation fees which decreased by 12%. Medicine contributed the major portion of overall OPE. Higher overall OPE for care seeking was associated with a priority illness (20% increase), care from trained providers (90% public/~ 2-fold private), residing in hilly/wet lands areas (20%), and for mothers with a secondary education (19%). CONCLUSION: OPE is a major barrier to quality health care services and access to appropriate medicine is increasing in rural Bangladesh. To support the goal of universal health care coverage, geographic imbalances as well as expanded health financing options need to be explored. PMID- 28893324 TI - Selecting treatment method for ovarian masses in children - 24 years of experience. AB - BACKGROUND: Epidemiology and pathology of ovarian tumors in the pediatric population are very different of these encountered in women. Few attempts have been made to analyze the whole spectrum of ovarian pathology in children, and only some of them included series of more than 200 cases. We performed a retrospective analysis of clinical and diagnostic aspects of ovarian tumors and tumor-like lesions in girls in order to identify the characteristics associated with malignancy with an attempt to elaborate a clinical management algorithm. RESULTS: The study group comprised 214 patients operated on for ovarian tumor in years 1991-2014 at the pediatric surgical center. Non-neoplastic ovarian lesion was diagnosed in 127 females. Sixty-five patients had a benign tumor and 22 had a malignant lesion. Abdominal pain was the most common symptom in the non-malignant lesion group. Patients with ovarian malignancy presented predominantly with abdominal distension and palpable mass. In the non-malignant group imaging studies revealed cystic lesion in 124 patients (68.89%) and solid mass in 10 (5.55%). Malignant lesion showed a solid or mixed structure in all cases. Positive tumor markers were noted in 14 (13.7%) patients with a benign lesion and in 14 (70%) with ovarian malignancy. Large lesions were found in 77.3% of girls with a malignant mass, while only in 32.8% of patients with a benign lesion (p < 0.001). In the group of solid tumors positive tumor marker results occurred more frequently in patients with diagnosed malignant tumors (p < 0.05). Positive tumor markers, large size of the lesion and age below 14 years were independent variables differentiating malignant tumors from non-malignant lesions (p = 0.00000). CONCLUSIONS: Predominantly solid structures noted on imaging studies, large dimension and positive tumor markers are clinical predictors of malignancy. A diagnosis of purely cystic lesions with negative markers or of a small size should be an indication for a gonad-sparing procedure. Treatment guidelines for ovarian lesions in children should be established on the basis of multicenter prospective studies and introduced as soon as possible in order to improve and unify the ovarian preservation rates across the pediatric surgical centers. PMID- 28893325 TI - The most commonly used disease severity scores are inappropriate for risk stratification of older emergency department sepsis patients: an observational multi-centre study. AB - BACKGROUND: Sepsis recognition in older emergency department (ED) patients is difficult due to atypical symptom presentation. We therefore investigated whether the prognostic and discriminative performance of the five most commonly used disease severity scores were appropriate for risk stratification of older ED sepsis patients (>=70 years) compared to a younger control group (<70 years). METHODS: This was an observational multi-centre study using an existing database in which ED patients who were hospitalized with a suspected infection were prospectively included. Patients were stratified by age < 70 and >=70 years. We assessed the association with in-hospital mortality (primary outcome) and the area under the curve (AUC) with receiver operator characteristics of the Predisposition, Infection, Response, Organ dysfunction (PIRO), quick Sequential Organ Failure Assessment (qSOFA), Mortality in ED Sepsis (MEDS), and the Modified and National Early Warning (MEWS and NEWS) scores. RESULTS: In-hospital mortality was 9.5% ((95%-CI); 7.4-11.5) in the 783 included older patients, and 4.6% (3.6 5.7) in the 1497 included younger patients. In contrast to younger patients, disease severity scores in older patients associated poorly with mortality. The AUCs of all disease severity scores were poor and ranged from 0.56 to 0.64 in older patients, significantly lower than the good AUC range from 0.72 to 0.86 in younger patients. The MEDS had the best AUC (0.64 (0.57-0.71)) in older patients. In older and younger patients, the newly proposed qSOFA score (Sepsis 3.0) had a lower AUC than the PIRO score (sepsis 2.0). CONCLUSION: The prognostic and discriminative performance of the five most commonly used disease severity scores was poor and less useful for risk stratification of older ED sepsis patients. PMID- 28893326 TI - The effects of nasal lavage with betamethasone cream post-endoscopic sinus surgery: clinical trial. AB - BACKGROUND: Steroid nasal irrigation for chronic rhinosinusitis patients following endoscopic sinus surgery reduces symptom recurrence. There are minimal safety data to recommend this treatment. This study evaluated the safety of betamethasone nasal irrigation by measuring its impact on endogenous cortisol levels. METHODS: Participants performed daily betamethasone nasal irrigation for six weeks. The impact on pre- and post-intervention serum and 24-hour urinary free cortisol was assessed. Efficacy was evaluated using the 22-item Sino-Nasal Outcome Test. RESULTS: Thirty participants completed the study (16 females and 14 males; mean age = 53.9 +/- 15.6 years). Serum cortisol levels were unchanged (p = 0.28). However, 24-hour urinary free cortisol levels decreased (47.5 vs 41.5 nmol per 24 hours; p = 0.025). Sino-Nasal Outcome Test scores improved (41.13 +/- 21.94 vs 23.4 +/- 18.17; p < 0.001). The minimal clinical important difference was reached in 63 per cent of participants. CONCLUSION: Daily betamethasone nasal irrigation is an efficacious treatment modality not associated with changes in morning serum cortisol levels. The changes in 24-hour urinary free cortisol levels are considered clinically negligible. Hence, continued use of betamethasone nasal irrigation remains a viable and safe treatment option for chronic rhinosinusitis patients following functional endoscopic sinus surgery. PMID- 28893327 TI - New activity of yamamarin, an insect pentapeptide, on immune system of mealworm, Tenebrio molitor. AB - In insects, two types of the immune responses, cellular and humoral, constitute a defensive barrier against various parasites and pathogens. In response to pathogens, insects produce a wide range of immune agents that act on pathogens directly, such as cecropins or lysozyme, or indirectly by the stimulation of hemocyte migration or by increasing phenoloxidase (PO) activity. Recently, many new immunologically active substances from insects, such as peptides and polypeptides, have been identified. Nevertheless, in the most cases, their physiological functions are not fully known. One such substance is yamamarin - a pentapeptide isolated from the silk moth Antheraea yamamai. This yamamarin possesses strong antiproliferative properties and is probably involved in diapause regulation. Here, we examined the immunotropic activity of yamamarin by testing its impact on selected functions of the immune system in heterologous bioassays with the beetle Tenebrio molitor, commonly known as a stored grains pest. Our results indicate that the pentapeptide affects the activity of immune processes in the beetle. We show that yamamarin induces changes in both humoral and cellular responses. The yamamarin increases the activity of PO, as well as causes changes in the hemocyte cytoskeleton and stimulates phagocytic activity. We detected an increased number of apoptotic hemocytes, however after the yamamarin injection, no significant variations in the antibacterial activity in the hemolymph were observed. The obtained data suggest that yamamarin could be an important controller of the immune system in T. molitor. PMID- 28893328 TI - Plasticity in host utilization by two host-associated populations of Aphis gossypii Glover. AB - Biological and morphological plasticity in polyphagous insect herbivores allow them to exploit diverse host plant species. Geographical differences in resource availability can lead to preferential host exploitation and result in inconsistent host specialization. Biological and molecular data provide insights into specialization and plasticity of such herbivore populations. In agricultural landscapes, Aphis gossypii encounters several crop and non-crop hosts, which exist in temporal and spatial proximity. We investigated the host-specialization of two A. gossypii host-associated populations (HAPs), which were field collected from cotton and squash (cotton-associated population and melon-associated population), and later maintained separately in the greenhouse. The two aphid populations were exposed to seven plant species (cotton, okra, watermelon, squash, cucumber, pigweed, and morning glory), and evaluated for their host utilization plasticity by estimating aphid's fitness parameters (nymphal period, adult period, fecundity, and intrinsic rate of increase). Four phenotypical characters (body length, head capsule width, hind tibia length and cornicle length) were also measured from the resulting 14 different HAP * host plant combinations. Phylogenetic analysis of mitochondrial COI sequences showed no genetic variation between the two HAPs. Fitness parameters indicated a significant variation between the two aphid populations, and the variation was influenced by host plants. The performance of melon-aphids was poor (up to 89% reduction in fecundity) on malvaceous hosts, cotton and okra. However, cotton aphids performed better on cucurbitaceous hosts, squash and watermelon (up to 66% increased fecundity) compared with the natal host, cotton. Both HAPs were able to reproduce on two weed hosts. Cotton-aphids were smaller than melon-aphids irrespective of their host plants. Results from this study suggest that the two HAPs in the study area do not have strict host specialization; rather they exhibit plasticity in utilizing several hosts. In this scenario, it is unlikely that host-associated A. gossypii populations would evolve into host-specific biotypes. PMID- 28893329 TI - Epidemiology of psychotic depression - systematic review and meta-analysis. AB - Large amount of data have been published on non-psychotic depression (NPD), schizophrenia (SZ), and bipolar disorder, while psychotic depression (PD) as an own entity has received much smaller attention. We performed a systematic review and meta-analyses on epidemiology, especially incidence and prevalence, risk factors, and outcomes of PD. A systematic search to identify potentially relevant studies was conducted using four electronic databases and a manual search. The search identified 1764 unique potentially relevant articles, the final study included 99 articles. We found that the lifetime prevalence of PD varies between 0.35% and 1%, with higher rates in older age. Onset age of PD was earlier than that of NPD in younger samples, but later in older samples. There were no differences in gender distribution in PD v. NPD, but higher proportion of females was found in PD than in SZ or in psychotic bipolar disorder (PBD). Risk factors have rarely been studied, the main finding being that family history of psychosis and bipolar disorder increases the risk of PD. Outcomes of PD were mostly worse when compared with NPD, but better compared with SZ and schizoaffective disorder. The outcome compared with PBD was relatively similar, and somewhat varied depending on the measure of the outcome. Based on this review, the amount of research on PD is far from that of NPD, SZ, and bipolar disorder. Based on our findings, PD seems distinguishable from related disorders and needs more scientific attention. PMID- 28893330 TI - Changes in resting-state brain networks after cognitive-behavioral therapy for chronic pain. AB - BACKGROUND: Cognitive-behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive-emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response. METHODS: We performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data. RESULTS: Abnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT related clinical improvements. CONCLUSIONS: We conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT. PMID- 28893332 TI - LEGITIMACY OF MEDICINES FUNDING IN THE ERA OF ACCELERATED ACCESS. AB - OBJECTIVES: In recent years, numerous frameworks have been developed to enhance the legitimacy of health technology assessment processes. Despite efforts to implement these "legitimacy frameworks," medicines funding decisions can still be perceived as lacking in legitimacy. We, therefore, sought to examine stakeholder views on factors that they think should be considered when making decisions about the funding of high-cost breast cancer therapies, focusing on those that are not included in current frameworks and processes. METHODS: We analyzed published discourse on the funding of high-cost breast-cancer therapies. Relevant materials were identified by searching the databases Google, Google Scholar, and Factiva in August 2014 and July 2016 and these were analyzed thematically. RESULTS: We analyzed fifty published materials and found that stakeholders, for the most part, want to be able to access medicines more quickly and at the same time as other patients and for decision makers to be more flexible with regards to evidence requirements and to use a wider range of criteria when evaluating therapies. Many also advocated for existing process to be accelerated or bypassed to improve access to therapies. CONCLUSIONS: Our results illustrate that a stakeholder-derived conceptualization of legitimacy emphasizes principles of accelerated access and is not fully accounted for by existing frameworks and processes aimed at promoting legitimacy. However, further research examining the ethical, political, and clinical implications of the stakeholder claims raised here is needed before firm policy recommendations can be made. PMID- 28893331 TI - Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD. AB - BACKGROUND: Previous research has shown relatively diminished medial prefrontal cortex activation and heightened psychophysiological responses during the recollection of personal events in post-traumatic stress disorder (PTSD), but the origin of these abnormalities is unknown. Twin studies provide the opportunity to determine whether such abnormalities reflect familial vulnerabilities, result from trauma exposure, or are acquired characteristics of PTSD. METHODS: In this case-control twin study, 26 male identical twin pairs (12 PTSD; 14 non-PTSD) discordant for PTSD and combat exposure recalled and imagined trauma-unrelated stressful and neutral life events using a standard script-driven imagery paradigm during functional magnetic resonance imaging and concurrent skin conductance measurement. RESULTS: Diminished activation in the medial prefrontal cortex during Stressful v. Neutral script-driven imagery was observed in the individuals with PTSD, relative to other groups. CONCLUSIONS: Diminished medial prefrontal cortex activation during Stressful v. Neutral script-driven imagery may be an acquired characteristic of PTSD. If replicated, this finding could be used prospectively to inform diagnosis and the assessment of treatment response. PMID- 28893333 TI - Review: Use of human-edible animal feeds by ruminant livestock. AB - The drive to increase the output of animal product in some sectors of ruminant livestock production has led to greater use of feeds such as cereal grains and soyabean meal that are potentially human-edible. This trend has caused concern since, by so doing, ruminants compete not only with monogastric livestock but also with the human population for a limited global area of cultivatable land on which to produce grain crops. Reasons for using potentially human-edible feeds in ruminant diets include increased total daily energy intake, greater supply of essential amino acids and improved ruminal balance between fermentable energy and degradable protein. Soyabean meal, produced on land that has been in arable cultivation for many years can fulfil a useful role as a supplier of undegraded dietary protein in diets for high-yielding dairy cows. However, in the context of sustaining the production of high-quality foods from livestock to meet the demands of a growing human population, the use of potentially human-edible feed resources by livestock should be restricted to livestock with the highest daily nutrient requirements; that is, potentially human-edible feed inputs should be constrained to meeting requirements for energy and protein and to rectifying imbalances in nutrient supply from pastures and forage crops such as high concentrations of nitrogen (N). There is therefore a role for human-edible feeds in milk production because forage-only systems are associated with relatively low output per head and also low N use efficiency compared with systems with greater reliance on human-edible feeds. Profitability on farm is driven by control of input costs as well as product value and examples are given of low-cost bovine milk and meat production with little or no reliance on potentially human-edible feeds. In beef production, the forage-only systems currently under detailed real time life-cycle analysis at the North Wyke Farm Platform, can sustain high levels of animal growth at low feed cost. The potential of all-forage diets should be demonstrated for a wide range of ruminant milk and meat production systems. The challenge for the future development of ruminant systems is to ensure that potentially human-edible feeds, or preferably human-inedible by-products if available locally, are used to complement pastures and forage crops strategically rather than replace them. PMID- 28893334 TI - Metabolic and stress responses in dairy cows fed a concentrate-rich diet and submitted to intramammary lipopolysaccharide challenge. AB - Feeding dairy cows diets rich in grain often leads to subacute rumen acidosis (SARA), which might affect their responsiveness to immunogenic stimuli such as exogenous lipopolysaccharide (LPS), and can lead to metabolic alterations. The main objective of this study was to investigate if SARA affects the stress and metabolic health responses resulting from an intramammary LPS challenge. Before the intramammary LPS challenge, the SARA cows showed higher blood glucose and a tendency for higher lactate and aspartate aminotransferase as well as a trend toward lower beta-hydroxybutyrate (BHBA) and gamma-glutamyltransferase compared with control cows. After the LPS challenge, the serum cortisol concentration markedly increased and the calcium concentration decreased both in SARA and control cows. In SARA-LPS cows, however, the lactate concentration increased due to the LPS infusion, whereas it remained unchanged in the control cows. A lower serum BHBA concentration was found in SARA-LPS compared with control-LPS cows. Higher non-esterified fatty acid concentrations were found in control-LPS cows shortly before the LPS challenge compared with SARA cows, challenged or not with LPS, whereas it did not differ from SARA-LPS cows thereafter. In conclusion, the results suggest that intramammary LPS challenge induced stress and lowered calcium concentration in all dairy cows, whereby this challenge showed lower BHBA and higher lactate levels in cows with SARA conditions. PMID- 28893335 TI - The effect of age on the FCSRT-IR and temporary visual memory binding. AB - : ABSTRACTBackground:Cognitive markers of early Alzheimer's disease (AD) should be sensitive and specific to memory impairments that are not associated with healthy cognitive aging. In the present study, we investigated the effect of healthy cognitive aging on two proposed cognitive markers of AD: the Free and Cued Selective Reminding Task with Immediate Recall (FCSRT-IR) and a temporary visual memory binding (TMB) task. METHOD: Free recall and the cost of holding bound information in visual memory were compared between 24 younger and 24 older participants in a mixed, fully counterbalanced experiment. RESULTS: A significant effect of age was observed on free recall in the FCSRT-IR only and not on the cost of binding in the TMB task. CONCLUSIONS: Of these two cognitive markers, the TMB task is more likely to be specific to memory impairments that are independent of age. PMID- 28893336 TI - Problematic internet use in gamblers: impact on clinical and cognitive measures. AB - OBJECTIVE: Gambling is a commonplace phenomenon, existing along a continuum from occasional gambling to functionally impairing gambling disorder. The internet may act as a conduit for some gambling behaviors. The impact of problematic internet use on clinical and cognitive features relevant to gambling has received little research attention. METHODS: A total of 206 adults aged 18-30 years who gamble at least five times per year were recruited from the general community and undertook detailed clinical and cognitive assessments. Problematic internet use was defined using a total score of 5 or more on Young's Diagnostic Questionnaire (YDQ). Linear regression was employed to evaluate the relative contribution of addictive related, impulsive-related, and compulsive-related measures in predicting YDQ total scores in gamblers. RESULTS: Gamblers with problematic internet use (18% of the sample) reported lower quality of life, lower self-esteem, elevated rates of intermittent explosive disorder, gambling disorder symptoms, attention deficit hyperactivity disorder (ADHD) symptoms, antisocial personality disorder, and posttraumatic stress disorder (PTSD), as well as relative deficits in decision making and spatial working memory. In linear regression, the extent of problematic internet use was most significantly associated with increased gambling disorder symptoms and increased ADHD symptoms. CONCLUSIONS: Problematic internet use in gamblers is associated with worse quality of life, more problem/pathological gambling symptoms, more psychiatric morbidities, and select cognitive impairment. Refinement of the definition of problematic internet use and exploration of its clinical and cognitive associations are likely to be highly relevant to the treatment of problematic gambling. PMID- 28893337 TI - Optimization of Three-Dimensional (3D) Chemical Imaging by Soft X-Ray Spectro Tomography Using a Compressed Sensing Algorithm. AB - Soft X-ray spectro-tomography provides three-dimensional (3D) chemical mapping based on natural X-ray absorption properties. Since radiation damage is intrinsic to X-ray absorption, it is important to find ways to maximize signal within a given dose. For tomography, using the smallest number of tilt series images that gives a faithful reconstruction is one such method. Compressed sensing (CS) methods have relatively recently been applied to tomographic reconstruction algorithms, providing faithful 3D reconstructions with a much smaller number of projection images than when conventional reconstruction methods are used. Here, CS is applied in the context of scanning transmission X-ray microscopy tomography. Reconstructions by weighted back-projection, the simultaneous iterative reconstruction technique, and CS are compared. The effects of varying tilt angle increment and angular range for the tomographic reconstructions are examined. Optimization of the regularization parameter in the CS reconstruction is explored and discussed. The comparisons show that CS can provide improved reconstruction fidelity relative to weighted back-projection and simultaneous iterative reconstruction techniques, with increasingly pronounced advantages as the angular sampling is reduced. In particular, missing wedge artifacts are significantly reduced and there is enhanced recovery of sharp edges. Examples of using CS for low-dose scanning transmission X-ray microscopy spectroscopic tomography are presented. PMID- 28893338 TI - A cluster of patients with rhabdomyolysis after eating crayfish. AB - Crayfish or Procambarus clarkii is a freshwater crustacean with worldwide distribution. Tons of crayfish are consumed each year. In this report, four adult patients with rhabdomyolysis after consuming crayfish were described. All of them presented to the emergency department with myalgia. The diagnosis of rhabdomyolysis was supported by an elevated creatine kinase level. All recovered with supportive treatment. The clinical picture of these 4 patients was compatible with Haff disease. Haff disease is a syndrome in which rhabdomyolysis develops subsequent to consumption of certain cooked seafood. Crayfish is a common culprit. Diagnosis depends on obtaining a diet history and creatine kinase level. Most patients recover uneventfully with supportive treatment for rhabdomyolysis. PMID- 28893339 TI - Spontaneous tumor lysis syndrome in a patient with newly diagnosed metastatic colonic adenocarcinoma. AB - Acute tumor lysis syndrome in the absence of cytotoxic therapy is an uncommon event but has been reported with hematologic malignancies. The case described below illustrates spontaneous tumor lysis syndrome in the context of a rapidly proliferating metastatic colonic adenocarcinoma. Clinicians should consider ordering phosphate, uric acid, and calcium when assessing patients with recently diagnosed or suspected malignancy. PMID- 28893340 TI - Quantitative Studies of Endothelial Cell Fibronectin and Filamentous Actin (F Actin) Coalignment in Response to Shear Stress. AB - Both fibronectin (FN) and filamentous actin (F-actin) fibers play a critical role for endothelial cells (ECs) in responding to shear stress and modulating cell alignment and functions. FN is dynamically coupled to the F-actin cytoskeleton via focal adhesions. However, it is unclear how ECs cooperatively remodel their subcellular FN matrix and intracellular F-actin cytoskeleton in response to shear stress. Current studies are hampered by the lack of a reliable and sensitive quantification method of FN orientation. In this study, we developed a MATLAB based feature enhancement method to quantify FN and F-actin orientation. The role of F-actin in FN remodeling was also studied by treating ECs with cytochalasin D. We have demonstrated that FN and F-actin codistributed and coaligned parallel to the flow direction, and that F-actin alignment played an essential role in regulating FN alignment in response to shear stress. Our findings offer insight into how ECs cooperatively remodel their subcellular ECM and intracellular F actin cytoskeleton in response to mechanical stimuli, and are valuable for vascular tissue engineering. PMID- 28893342 TI - Associations between bottle-feeding intensity and maternal encouragement of bottle-emptying. AB - OBJECTIVE: To explore longitudinal associations between bottle-feeding and maternal encouragement of infant bottle-emptying during the first 6 months of infancy. DESIGN: Mothers completed questionnaires during the third trimester of pregnancy, then monthly during the first 6 months postpartum. Questionnaires assessed family demographics, maternal and infant weight status, infant feeding patterns and maternal encouragement of infant bottle-emptying. SETTING: The Infant Feeding Practices Study 2, conducted by the US Centers for Disease Control and Prevention and the Food and Drug Administration. SUBJECTS: Mothers (n 1776). RESULTS: Repeated-measures regression was used to explore associations between bottle-feeding intensity (BFI; defined as the percentage of daily feedings that were from a bottle) and encouragement of bottle-emptying. Mothers who reported consistently high or consistently low BFI also exhibited consistently higher or lower frequency of encouraging their infants to empty the bottle (respectively) across the first 6 months of infancy, whereas mothers who reported increases in their BFI also exhibited concomitant increases in the frequency to which they encouraged their infants to finish the bottle. More frequent encouragement of bottle-emptying was also associated with feeding expressed breast milk (P<0.001), and lower parity (P=0.01), pre-pregnancy BMI (P=0.002) and infant birth weight (P=0.001). CONCLUSIONS: More frequent use of bottles for infant feeding was significantly associated with more frequent encouragement of bottle-emptying. Further research using causal designs is needed to better understand whether the use of bottles promotes this controlling feeding practice or whether mothers with more controlling feeding practices opt to bottle-feed. PMID- 28893343 TI - Physiotherapy-as-first-point-of-contact-service for patients with musculoskeletal complaints: understanding the challenges of implementation. AB - BACKGROUND: Primary care faces unprecedented challenges. A move towards a more comprehensive, multi-disciplinary service delivery model has been proposed as a means with which to secure more sustainable services for the future. One seemingly promising response has been the implementation of physiotherapy self referral schemes, however there is a significant gap in the literature regarding implementation. Aim This evaluation aimed to explore how the professionals and practice staff involved in the delivery of an in-practice physiotherapy self referral scheme understood the service, with a focus on perceptions of value, barriers and impact. Design and setting A qualitative evaluation was conducted across two UK city centre practices that had elected to participate in a pilot self-referral scheme offering 'physiotherapy-as-a-first-point-of-contact' for patients presenting with a musculoskeletal complaint. METHODS: Individual and focus group interviews were conducted amongst participating physiotherapists, administration/reception staff, general practitioners (GPs) and one practice nurse (in their capacity as practice partner). Interview data were collected from a total of 14 individuals. Data were analysed using thematic analysis. RESULTS: Three key themes were highlighted by this evaluation. First, the imperative of effecting a cultural change - including management of patient expectation with particular reference to the belief that GPs represented the 'legitimate choice', re-visioning contemporary primary care as a genuine team approach, and the physiotherapists' reconceptualisation of their role and practices. Second, the impact of the service on working practice across all stakeholders - specifically re-distribution of work to 'unburden' the GP, and the critical role of administration staff. Finally, beliefs regarding the nature and benefits of physiotherapeutic musculoskeletal expertise - fears regarding physiotherapists' ability to work autonomously or identify 'red flags' were unfounded. CONCLUSION: This qualitative evaluation draws on the themes to propose five key lessons which may be significant in predicting the success of implementing physiotherapy self referral schemes. PMID- 28893341 TI - Validation of a survey to examine drinking-water access, practices and policies in schools. AB - OBJECTIVE: Ensuring ready access to free drinking-water in schools is an important strategy for prevention of obesity and dental caries, and for improving student learning. Yet to date, there are no validated instruments to examine water access in schools. The present study aimed to develop and validate a survey of school administrators to examine school access to beverages, including water and sports drinks, and school and district-level water-related policies and practices. DESIGN: Survey validity was measured by comparing results of telephone surveys of school administrators with on-site observations of beverage access and reviews of school policy documents for any references to beverages. The semi structured telephone survey included items about free drinking-water access (sixty-four items), commonly available competitive beverages (twenty-nine items) and water-related policies and practices (twenty-eight items). Agreement between administrator surveys and observation/document review was calculated using kappa statistics for categorical variables, and Pearson correlation coefficients and t tests for continuous variables. SETTING: Public schools in the San Francisco Bay Area, California, USA. SUBJECTS: School administrators (n 24). RESULTS: Eighty one per cent of questions related to school beverage access yielded kappa values indicating substantial or almost perfect agreement (kappa>0.60). However, only one of twenty-eight questions related to drinking-water practices and policies yielded a kappa value representing substantial or almost perfect agreement. CONCLUSIONS: This school administrator survey appears reasonably valid for questions related to beverage access, but less valid for questions on water related practices and policies. This tool provides policy makers, researchers and advocates with a low-cost, efficient method to gather national data on school level beverage access. PMID- 28893344 TI - Four strategies to find, evaluate, and engage with online resources in emergency medicine. AB - Despite the rapid expansion of online educational resources for emergency medicine, barriers remain to their effective use by emergency physicians and trainees. This article expands on previous descriptions of techniques to aggregate online educational resources, outlining four strategies to help learners navigate, evaluate, and contribute online. These strategies include 1) cultivating digital mentors, 2) browsing the most popular free open access medical education (FOAM) websites, 3) using critical appraisal tools developed for FOAM, and 4) contributing new online content. PMID- 28893345 TI - A Validated High-Performance Thin-Layer Chromatographic Method for the Simultaneous Determination of Zofenopril Calcium and Hydrochlorothiazide in the Presence of the Hydrochlorothiazide Impurities: Chlorothiazide and Salamide. AB - The chromatographic analysis of either process-related impurities or degradation products is very important in the pharmaceutical industry. In this work, a simple, selective, and sensitive HPTLC method was developed and validated for the simultaneous determination of zofenopril calcium (ZOF) and hydrochlorothiazide (HCT) in the presence of the HCT impurities: A) chlorothiazide (CT) and B) salamide, in raw materials and in pharmaceutical formulation. The separation was carried out on HPTLC silica gel 60 F254 using ethyl acetate-glacial acetic acid triethylamine (10 + 0.1 + 0.1, v/v/v) as a developing system. The separated bands were scanned densitometrically at 270 nm. Polynomial equations were used for the regression. Calibration curves were constructed for ZOF, HCT, CT, and salamide in the ranges of 0.5-10, 0.2-4, 0.05-1.4, and 0.05-1.0 MUg/band, respectively. Different parameters affecting the suggested method, including developing systems of varying composition/ratios and different detection wavelengths, were studied to achieve the best resolution and precision with good sensitivity. System suitability parameters were also tested. The proposed method was validated as per the International Conference on Harmonization guidelines and was successfully applied for the quantification of the studied drugs in their pharmaceutical formulation, with no interference from excipients observed. The results obtained by the developed HPTLC method were compared statistically with those obtained by the reported HPLC method using Student's t and F ratio tests, and no significant difference was obtained, indicating the ability of the proposed method to be used for routine analysis of drug product. PMID- 28893346 TI - Overexpression of MicroRNA-34a-5p Inhibits Proliferation and Promotes Apoptosis of Human Cervical Cancer Cells by Downregulation of Bcl-2. AB - Aberrant expressions of microRNAs (miRNAs) are involved in the development and progression of various types of cancers. In this study, we investigated the roles of miR-34a-5p in the proliferation, migration, invasion, and apoptosis of cervical cancer cells (HeLa cells). We found that overexpression of miR-34a-5p significantly inhibited the viability, migration, and invasion of HeLa cells, but promoted cell apoptosis. Suppression of miR-34a-5p showed opposite effects. The mRNA and protein expression levels of Bcl-2 in HeLa cells were increased by miR 34a-5p suppression but decreased by miR-34a-5p overexpression. Bcl-2 was a direct target gene of miR-34a-5p, which participated in the effects of miR-34a-5p on HeLa cell viability, migration, invasion, and apoptosis. Suppression of miR-34a 5p promoted the viability, migration, and invasion of HeLa cells by increasing the expression of Bcl-2. Moreover, overexpression of Bcl-2 significantly promoted cell viability, migration, and invasion and had no influence on cell apoptosis. Suppression of Bcl-2 showed the opposite effects, with an increase in apoptosis. Overexpression of Bcl-2 activated the PI3K/AKT and JAK/STAT pathways in cervical cancer cells. Suppression of Bcl-2 inactivated the PI3K/AKT and JAK/STAT pathways in cervical cancer cells. PMID- 28893347 TI - miR-203 Suppresses Bladder Cancer Cell Growth and Targets Twist1. AB - miR-203 is an epigenetically silenced tumor-suppressive microRNA in tumors. This study was designed to investigate the effects of miR-203 on the proliferation, migration, invasion, and apoptosis of bladder cancer (BCa) cells. The expression levels of miR-203 in BCa tissues, normal adjacent tissues, and BCa cell lines were detected. BCa cells were transfected with miR-203 mimic and inhibitor to investigate the effect of miR-203 on cell functions and the epithelial mesenchymal transition (EMT). Cotransfection with miR-203 inhibitor and shRNA of the predicted target gene Twist1 (si-Twist1) was performed to investigate the target relationship of miR-203 and Twist1. The effects of knockdown of Twist1 on cell functions were also investigated. The expression of miR-203 was significantly reduced in BCa tissues and cells, in comparison with the control. miR-203 mimic significantly reduced cell viability, invasion, migration, and EMT, and enhanced cell apoptosis. On the contrary, miR-203 inhibitor showed the opposite results. However, the administration of si-Twist1 cancelled the effect of miR-203 inhibitor on cell proliferation, apoptosis, invasion, and migration. These demonstrated that miR-203 may function as a tumor-suppressive microRNA in BCa by negatively targeting Twist1. Both Twist1 and miR-203 might be explored as potential targets for studying the mechanism related to BCa pathogenesis and therapy. PMID- 28893348 TI - Overexpression of Glypican 5 (GPC5) Inhibits Prostate Cancer Cell Proliferation and Invasion via Suppressing Sp1-Mediated EMT and Activation of Wnt/beta-Catenin Signaling. AB - Glypican 5 (GPC5) belongs to the family of heparan sulfate proteoglycans (HSPGs). It was initially known as a regulator of growth factors and morphogens. Recently, there have been reports on its correlation with the tumorigenic process in the development of some cancers. However, little is known about its precise role in prostate cancer (PCa). In the present study, we explored the expression pattern and biological functions of GPC5 in PCa cells. Our results showed that GPC5 was lowly expressed in PCa cell lines. Upregulation of GPC5 significantly inhibited PCa cell proliferation and invasion in vitro as well as attenuated tumor growth in vivo. We also found that overexpression of GPC5 inhibited the epithelial mesenchymal transition (EMT) and Wnt/beta-catenin signaling activation, which was mediated by Sp1. Taken together, we suggest GPC5 as a tumor suppressor in PCa and provide promising therapeutic strategies for PCa. PMID- 28893349 TI - WITHDRAWN: LncRNA-HOTAIR Activates Tumor Cell Proliferation and Migration by Suppressing MiR-326 in Cervical Cancer. AB - Cervical cancer is the second most common malignant cancer in females. Recent findings indicate that LncRNA-HOTAIR played a crucial role in tumor progression. In our present study, we aimed to explore the regulating role of HOTAIR in the progression of cervical cancer. The expression of HOTAIR was found up-regulated in cervical cancer tissues and cell lines (Hela, CasKi, Me180 and C-33A) compared with the normal tissues and normal cervical cell line (Ect1/E6E7). To examine the function of HOTAIR, gene knockdown (KD) was performed using HOTAIR short hairpin RNAs (shRNAs). HOTAIR shRNA significantly suppressed cells proliferation and migration in Hela cells. Besides that, the targeting relationship between HOTAIR and miR-326 was firstly revealed by bioinformatics prediction. Simultaneously, suppressed expression of miR-326 was detected in tumor tissues and cell lines compared with the control. Then, suppressed expression level of miR-326 was elevated by adding miR-326 mimic in cervical cancer cells transfected with LncR HOTAIR. Similarly, increased expression level of miR-326 was reduced by adding miR-326 inhibitor in cervical cancer cells transfected with HOTAIR shRNA. The targeting relationship between HOTAIR and miR-326 was further been confirmed through the luciferase report assay. Moreover, there existed a negative relationship between the expression of HOTAIR and miR-326. In addition, enhanced cell proliferation and migration abilities were suppressed by HOTAIR shRNA in cells transfected with miR-326 inhibitor. Finally, the in vivo experiment revealed that tumor growth and metastasis could also be inhibited by HOTAIR shRNA. Our present study elucidated the regulating role of HOTAIR/miR-326 axis in cervical cancer progression and provided a new potential therapeutic strategy for cervical cancer. PMID- 28893350 TI - Knockdown of Gab1 Inhibits Cellular Proliferation, Migration, and Invasion in Human Oral Squamous Carcinoma Cells. AB - Grb2-associated binder 1 (Gab1) is often aberrant in cancerous cells and tissues, whose alteration is responsible for aggressive phenotypes. In this study, we examined the Gab1 expression in human oral squamous cell carcinoma (OSCC) tissues and investigated the cellular and molecular effect of Gab1 on migration, invasion, and cell growth of the OSCC cell lines SCC15 and SCC25. We found that Gab1 was overexpressed in OSCC tissues and cells, which is related to the protein levels of various molecules associated with cellular proliferation, migration, and invasion. Functional assays identified that Gab1 overexpression promoted cell proliferation and invasion of OSCC cells and inhibited cell apoptosis in the SCC15 and SCC25 cell lines. On the other hand, Gab1 silencing affected the proliferation and invasion of OSCC cells and induced cell apoptosis. Western blot assay identified that Gab1 overexpression suppressed the expression of Cdc20 homolog 1 (Cdh1) and then promoted cell invasion in OSCC cells. Furthermore, Gab1 mediated Cdh1 downregulation was significantly reversed when the cells were subjected to an inhibitor of p-Akt. In conclusion, these results suggested that Gab1 induced malignant progression of OSCC cells probably via activation of the Akt/Cdh1 signaling pathway. Thus, Gab1 may be a potential therapeutic target in the treatment of OSCC patients. PMID- 28893352 TI - Correction of the name Amycolatopsis albidoflavus to Amycolatopsis albidiflava corrig. Request for an Opinion. AB - The name Amycolatopsis albidoflavus Lee and Hah 2001 is malformed because the genus name Amycolatopsis has the feminine gender. It is here proposed to correct the name to Amycolatopsis albidiflava corrig. PMID- 28893351 TI - Hepatic Ischemia/Reperfusion: Mechanisms of Tissue Injury, Repair, and Regeneration. AB - Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury. PMID- 28893353 TI - The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis. AB - Epithelial response to injury is critical to the pathogenesis of biliary cirrhosis, and IL-6 has been suggested as a mediator of this phenomenon. Several liver cell types can secrete IL-6 following activation by various signaling molecules including circulating adenosine. The aims of this study were to assess whether adenosine can induce IL-6 secretion by cholangiocytes via the A2b adenosine receptor (A2bAR) and to determine the effect of A2bAR-sensitive IL-6 release on injury response in biliary cirrhosis. Human normal cholangiocyte H69 cells were used for in vitro studies to determine the mechanism by which adenosine and the A2bAR induce release of IL-6. In vivo, control and A2bAR deficient mice were used to determine the roles of A2bAR-sensitive IL-6 release in biliary cirrhosis induced by common bile duct ligation (BDL). Additionally, the response to exogenous IL-6 was assessed in C57BL/6 and A2bAR-deficient mice. Adenosine induced IL-6 mRNA expression and protein secretion via A2bAR activation. Although activation of A2bAR induced cAMP and intracellular Ca2+ signals, only the Ca2+ signals were linked to IL-6 upregulation. After BDL, A2bAR deficient mice have impaired survival, which is further impaired by exogenous IL 6; however, decreased survival is not due to changes in fibrosis and no changes in inflammatory cells. Exogenous IL-6 is associated with the increased presence of bile infarcts. Extracellular adenosine induces cholangiocyte IL-6 release via the A2bAR. This signaling pathway is important in the pathogenesis of injury response in biliary cirrhosis but does not alter fibrosis. Adenosine upregulates IL-6 release by cholangiocytes via the A2bAR in a calcium-sensitive fashion. Mice deficient in A2bAR experience impaired survival after biliary cirrhosis induced by common bile duct ligation independent of changes in fibrosis. PMID- 28893354 TI - Similar virulence properties of infection and colonization associated Pseudomonas aeruginosa. AB - PURPOSE: Pseudomonas aeruginosa is one of the agents that are commonly implicated in nosocomial infections. However, it is also present as a commensal in various body sites of healthy persons, making the diagnosis of infection by culture difficult. A number of virulence factors expressed by the organism have been implicated in its pathogenicity. We undertook this study to identify the host and organism factors associated with infection. METHODOLOGY: Pathogenic, colonizing and environmental isolates were tested for apr, lasB, the T3SS effector exoenzymes (exoS, exoT, exoU and exoY) and toxA genes, biofilm production and antimicrobial susceptibility. The isolates were further typed by RAPD. RESULTS: Eighty-seven isolates from 61 patients, including 11 environmental isolates, were obtained. None of the virulence factors were found to be significantly associated with infection, and nor was the antimicrobial susceptibility. The presence of the exoU gene and infection by MDR strains correlated significantly with the duration of hospital stay. Positivity for exoS and exoU genes was found to be strongly correlated with multi-drug resistance. exoU positivity correlated strongly with fluoroquinolone resistance. Sinks in the ward and intensive care unit were found to be a niche for XDR P. aeruginosa. Eighty-five isolates were typeable using the ERIC2 primer, showing 71 distinct RAPD patterns with >15 % difference in UPGMA generated dice coefficients. CONCLUSIONS: exoU positivity is associated with severe disease, as evidenced by the longer duration of hospital stay of these patients. However, the presence of virulence factors or multi-drug resistance in the cultured strain should not prompt the administration of anti-pseudomonal chemotherapy. PMID- 28893355 TI - Bifidobacterium vansinderenii sp. nov., isolated from faeces of emperor tamarin (Saguinus imperator). AB - A novel Bifidobacterium strain, Tam10BT, i.e. LMG 30126T, was isolated from emperor tamarin (Saguinus imperator). Cells were Gram-positive, non-motile, non sporulating, non-haemolytic, facultative anaerobic and fructose 6-phosphate phosphoketolase-positive. Phylogenetic analyses based on 16S rRNA genes as well as multilocus sequences (representing hsp60, rpoB, dnaJ, dnaG and clpC genes) and the core genome revealed that Bifidobacterium Tam10BT exhibited close phylogenetic relatedness to Bifidobacterium tissieri DSM 100201T. Comparative analysis of 16S rRNA gene sequences confirmed the phylogenetic results showing the highest gene sequence identity with strain B. tissieri DSM 100201T (96.5 %). Furthermore, genotyping based on the genome sequence of Tam 10B, in combination with phenotypic analyses, clearly showed that strain Tam10BT is distinct from each of the type strains of the so far recognized Bifidobacterium species. The type strain Tam10BT (=LMG 30126T=CCUG 70655T) represents a novel species, for which the name Bifidobacteriumvansinderenii sp. nov is proposed. PMID- 28893356 TI - Polaribacter insulae sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated OITF-22T, was isolated from a tidal flat of Oido, an island of South Korea, and subjected to a polyphasic taxonomic study. Strain OITF-22T grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences showed that strain OITF-22T fell within the clade comprising the type strains of Polaribacter species. Strain OITF-22T exhibited 16S rRNA gene sequence similarity values of 97.2-99.4 % to the type strains of Polaribacter vadi, P. haliotis, P. atrinae, P. dokdonensis, P. litorisediminis,P. reichenbachii, P. irgensii and P. marinaquae, and of 93.0-96.9 % to the type strains of the other Polaribacter species. Strain OITF-22T contained MK-6 as the predominant menaquinone and iso-C15 : 0 and iso C15 : 0 3-OH as the major fatty acids. The major polar lipids detected in strain OITF-22T were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain OITF-22T was 32.3 mol% and its DNA-DNA relatedness values with the type strains of the eight phylogenetically most closely related Polaribacter species were 9-32 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain OITF-22T is separated from recognized species of the genus Polaribacter. On the basis of the data presented, strain OITF-22T is considered to represent a novel species of the genus Polaribacter, for which the name Polaribacter insulae sp. nov. is proposed. The type strain is OITF-22T (=KCTC 52658T=NBRC 112706T). PMID- 28893357 TI - Fluoroquinolone resistance in extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a Japanese tertiary hospital: silent shifting to CTX-M 15-producing K. pneumoniae. AB - PURPOSE: Fluoroquinolone resistance (FQ-r) in extended-spectrum beta-lactamase (ESBL) producers is an urgent health concern in countries where ESBL-producing K. pneumoniae (ESBL-Kpn) is prevalent. We investigated FQ-r in Japan where ESBL-Kpn is less prevalent. METHODOLOGY: Clinical ESBL-Kpn isolates from 2011 to 2013 were collected in Nagasaki University Hospital. The ESBL genotypes included CTX-M-15, and the mechanisms of FQ-r through plasmid-mediated quinolone resistance (PMQR) and mutations in quinolone resistance-determining regions (QRDRs) were examined. Clonality was analysed by enterobacterial repetitive intergenic consensus (ERIC) PCR and multi-locus sequence typing was performed on selected isolates.Results/Key findings. Thirty ESBL-Kpn isolates, including seven levofloxacin-resistant isolates, were obtained from different patients. An increase in CTX-M-15-producing strains was observed during the study period (0/11 in 2011, 3/8 in 2012, and 5/11 in 2013). PMQR was detected in 53.3 % of the isolates and aac-(6')-Ib-cr was the most common (36.7 %). ST15 was observed in 60.0 % of the isolates, and for the most predominant ERIC-PCR profiles, 62.5 % of the isolates possessed the CTX-M-15 genotype and 71.4 % were levofloxacin resistant. Levofloxacin-resistance was significantly more common in CTX-M-15 isolates (62.5 %) compared to non-CTX-M-15 isolates (9.1 %). Three QRDR mutations and aac(6')-Ib-cr, but not qnrB and qnrS, were significantly enriched in the CTX M-15 isolates (100.0 %) compared to the non-CTX-M-15 isolates (13.6 %). CONCLUSION: Cumulatively, these results indicate that the epidemic strain, the CTX-M-15-producing K. pneumoniae ST15, is covertly spreading even when ESBL producers are not prevalent. Monitoring these epidemic strains and ESBLs in general is important for quickly identifying health crises and minimizing future risks from FQ-r ESBL-Kpn. PMID- 28893358 TI - Discrepant susceptibility to gentamicin despite amikacin resistance in Klebsiella pneumoniae by VITEK 2 represents false susceptibility associated with the armA 16S rRNA methylase gene. AB - Because we experienced gentamicin failure in Klebsiella pneumoniae bacteraemia that was susceptible to gentamicin despite amikacin resistance, as determined by VITEK 2, we evaluated the true susceptibility and mechanism of resistance. We screened 2818 K. pneumoniae isolates during a 1-year period at a university hospital and reviewed anti-microbial susceptibility reports using the VITEK 2 system. The minimum inhibitory concentration was substantiated by broth microdilution (BMD), and the presence of 16S rRNA methylase genes and aminoglycoside-modifying enzymes was also investigated. A total of 131 amikacin resistant isolates from 19 patients were gentamicin non-resistant according to the VITEK 2 system. Among these, we were able to collect isolates from 12 patients (63.2 %), and a single isolate from each patient was tested. Eleven of the gentamicin non-resistant isolates (91.7 %) showed high-level resistance to both amikacin and gentamicin by BMD in association with the armA gene. Gentamicin is not an adequate treatment option for amikacin-resistant K. pneumoniae, even if VITEK 2 reports susceptibility. PMID- 28893360 TI - Borderline oxacillin-resistant Staphylococcus aureus (BORSA) - a more common problem than expected? AB - Borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a quite poorly understood and inadequately defined phenotype of methicillin resistance. BORSA strains show low, borderline resistance to penicillinase-resistant penicillins (PRPs), with oxacillin MICs typically equal to 1-8 ug ml-1, and in contrast to methicillin-resistant S. aureus (MRSA), do not have an altered penicillin-binding protein, PBP2a, encoded by the mecA or mecC gene. Their resistance is typically associated with hyperproduction of beta-lactamases or, in some cases, point mutations in PBP genes. BORSA cannot be classified as either truly methicillin-resistant or truly methicillin-susceptible strains. However, they are frequently misidentified, which poses an obvious epidemiological and therapeutic threat. BORSA strains are commonly isolated from humans and animals, and are found both in hospitals and in a community setting. The epidemiology and clinical presentation of BORSA infections seem to be similar to those for MRSA; these infections are usually more severe than those caused by methicillin sensitive S. aureus (MSSA). Treatment of severe infections caused by BORSA may be ineffective, even with larger doses of oxacillin. The available evidence suggests that BORSA represent a frequently neglected problem, and their emergence in new environments implies that they need to be monitored and accurately distinguished from MSSA and MRSA. PMID- 28893359 TI - Crocinitomix algicola sp. nov., isolated from Gracilaria blodgettii. AB - A Gram-stain-negative, strictly aerobic, non-flagellated, yellow-pigmented, rod shaped bacterial strain, designated 0182T, was isolated from Gracilaria blodgettii, an algae of phylum Rhodophyta collected from coast of Lingshui county, Hainan, China (110 degrees 03' 44.2'' E, 18 degrees 24' 29.8'' N). The strain grew optimally at 30 degrees C, pH 7.0-7.5 and in the presence of 2.0-3.0 % (w/v) NaCl. Cells of strain 0182T were approximately 0.9-2.5 um in length and 0.2-0.4 um in width. The major respiratory quinone was MK-7. The predominant cellular fatty acids were iso-C15 : 0, C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids were phosphoaminolipid, glycolipid, two unknown aminolipids and four unknown lipids. The DNA G+C content was approximately 35.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 0182T was phylogenetically related to members of the genus Crocinitomix and was closely related to Crocinitomix catalasitica with 94.6 % sequence similarity. On the basis of genotypic and phenotypic characteristics and phylogenetic evidence, strain 0182T is thought to represent a novel species of the genus Crocinitomix, for which the name Crocinitomix algicola sp. nov. is proposed. The type strain is 0182T (=KCTC 42868T =MCCC 1H00128T). PMID- 28893361 TI - Colworth prize lecture 2016: exploiting new biological targets from a whole-cell phenotypic screening campaign for TB drug discovery. AB - Mycobacterium tuberculosis is the aetiological agent of tuberculosis (TB) and is the leading bacterial cause of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, primarily in the developing world. The most recent report from the World Health Organisation states that 8 million new cases of TB were reported and that ~1.5 million people died from TB. The efficacy of treatment is threatened by the emergence of multi drug and extensively drug-resistant strains of M. tuberculosis. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Our research aims to establish an academic-industrial partnership with the goal of discovering new drug targets and hit-to-lead new chemical entities for TB drug discovery. PMID- 28893362 TI - Confluentibacter citreus sp. nov., isolated from lake sediment, and emended description of the genus Confluentibacter. AB - A Gram-stain-negative, non-gliding, aerobic and rod-shaped bacterium, designated XJNYT, was isolated from Sayram Lake (44 degrees 30' 30.41" N 81 degrees 12' 39.55" E), Xinjiang Province, north-west China, and was characterized taxonomically by a polyphasic study. Strain XJNYT grew at salinities of 0-4 % (w/v) and temperatures of 4-37 degrees C. The pH range for growth was 6.5-8.5. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain XJNYT belonged to the genus Confluentibacter and was closely related to the type strain of Confluentibacter lentus with 97.8 % similarity. The DNA G+C content was 34.5 mol%. The major fatty acids were iso-C15 : 0, iso-C15 : 1 G, anteiso-C15 : 0, iso C15 : 0 3-OH, C17 : 0 2-OH and iso-C17 : 0 3-OH. The major respiratory isoprenoid quinone was menaquinone-6 (MK-6) and the polar lipids were phosphatidylethanolamine, an unidentified phospholipid, two unidentified aminolipids and four unidentified lipids. On the basis of morphological, physiological and molecular properties and phylogenetic distinctiveness, strain XJNYT represents a novel species within the genus Confluentibacter, for which the name Confluentibactercitreus sp. nov. is proposed. The type strain is XJNYT (=KCTC 52638T=MCCC 1H00183T). PMID- 28893363 TI - High levels of macrolide-resistant Mycoplasma genitalium in Queensland, Australia. AB - The macrolide azithromycin is recommended for treatment of Mycoplasma genitalium infection; however, M. genitalium strains possessing macrolide resistance mediating mutations (MRMMs) are increasingly being reported. Here, we used the SpeeDx ResistancePlus MG kit, which provides simultaneous detection of M. genitalium and MRMMs, to assess MRMM carriage among M. genitalium infections in Queensland, Australia. Performance characteristics of the ResistancePlus MG kit for M. genitalium detection were compared to in-house PCR. Available M. genitalium PCR-positive (n=67) and negative (n=281) samples from the years 2011 to 2017 were tested using the SpeeDx ResistancePlus MG kit. In total, 63.6 % M. genitalium-positive samples were indicated to harbour MRMMs. The ResistancePlus MG method provided sensitivity and specificity of 97 and 99.6 % respectively compared to in-house PCR for M. genitalium detection. Such high levels of macrolide-resistant M. genitalium raise further concerns over future use of azithromycin for treatment of M. genitalium infection. PMID- 28893365 TI - Coffee Consumption and Prevention of Cirrhosis: In Support of the Caffeine Hypothesis. AB - Coffee is acknowledged as the most widely used drug worldwide. Coffee is also a foodstuff, so its use is often used to satisfy dietary urges. When used as a drug, coffee is normally consumed as a stimulant rather than to treat or prevent particular diseases. Recently, coffee consumption has been inversely related to progression of liver fibrosis to cirrhosis and even hepatocellular carcinoma. Experiments in cellular and animal models have provided biological plausibility for coffee as an antifibrotic agent in the liver. A recent article examined one of the key questions regarding the antifibrotic role of coffee-specifically what is the primary antifibrotic agent in coffee? This article briefly reviews the relevant issues with regard to coffee as an antifibrotic agent for patients with chronic liver disease. PMID- 28893364 TI - Petrothermobacter organivorans gen. nov., sp. nov., a thermophilic, strictly anaerobic bacterium of the phylum Deferribacteres isolated from a deep subsurface oil reservoir. AB - A novel thermophilic, anaerobic, chemoheterotrophic, acetate-oxidizing and iron(III)-, manganese(IV)-, nitrate- and sulfate-reducing bacterium, designated strain ANAT, was isolated from a deep subsurface oil field in Japan (Yabase oil field, Akita Pref.). Cells of strain ANAT were Gram-stain-negative, non-motile, non-spore forming and slightly curved or twisted rods (1.5-5.0 um long and 0.6 0.7 um wide). The isolate grew at 25-60 degrees C (optimum 55 degrees C) and pH 6.0-8.0 (optimum pH 7.0). The isolate was capable of reducing iron(III), manganese(IV), nitrate and sulfate as an electron acceptor. The isolate utilized a limited range of electron donors such as acetate, lactate, pyruvate and yeast extract for iron reduction. Strain ANAT also used pyruvate, fumarate, succinate, malate, yeast extract and peptone for fermentative growth. The major respiratory quinones were menaquinone-7(H8) and menaquinone-8. The strain contained C18 : 0, iso-C18 : 0 and C16 : 0 as the major cellular fatty acids. The G+C content of the genomic DNA was 34.3 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain ANAT was closely related to Calditerrivibrio nitroreducens in the phylum Deferribacteres with low sequence similarities (89.5 %), and formed a distinct clade within the family Deferribacteraceae. In addition, the isolate is the first sulfate-reducing member of the phylum Deferribacteres. Based on phenotypic, chemotaxonomic and phylogenetic properties, a novel genus and species, Petrothermobacter organivorans gen. nov., sp. nov., is proposed for the isolate (type strain=ANAT= NBRC 112621T=DSM 105015T). PMID- 28893366 TI - Fidaxomicin reduces early toxin A and B production and sporulation in Clostridium difficilein vitro. AB - PURPOSE: Fidaxomicin, a macrocyclic antibiotic, has been approved for the treatment of Clostridium difficile infection (CDI). Previous work by our group has demonstrated that some antibiotics at sub-inhibitory concentrations stimulate early toxin production and sporulation by C. difficile. Prior studies revealed that fidaxomicin, when added to late stationary-phase organisms, reduced exotoxin production and spore formation by C. difficile. However, the ability of fidaxomicin to trigger early virulence factor production and spore formation has never been investigated. METHODOLOGY: Sub-inhibitory concentrations of the RNA synthesis inhibitor fidaxomicin (1/4*, 1/8*, 1/16* MIC) were added immediately to lag-phase cultures of historical (strain 9689) and epidemic BI/NAP1/027 (strain 5325) strains of C. difficile, and their effects on sporulation and toxin A (TcdA) and toxin B (TcdB) production were compared.Results/Key findings. Even at sub-inhibitory concentrations, all doses of fidaxomicin reduced both TcdA and TcdB gene expression and protein production in the historical and epidemic C. difficile strains. Fidaxomicin also dose-dependently reduced viable spore production by the 9689 and 5325 strains. Reductions in spore formation were also observed in both strains treated with tigecycline and vancomycin. However, all concentrations of metronidazole stimulated a ~2 log increase in spore production by the 5325 isolate. CONCLUSION: The ability of fidaxomicin to suppress early exotoxin production and endospore formation by historical and epidemic strains of C. difficile may explain its clinical success in treating severe and recurrent cases of CDI disease. PMID- 28893367 TI - Hyphococcus flavus gen. nov., sp. nov., a novel alphaproteobacterium isolated from deep seawater. AB - A Gram-staining-negative, aerobic, non-spore-forming, coccoid to rod shaped bacteria with prosthecate and flagellum, designated as HSF6T, was isolated from deep seawater samples collected from the South China Sea at depth of 2.5 km and subjected to a polyphasic taxonomic investigation. Colonies of strain HSF6T were 1-2 mm in diameter, smooth, circular, convex and yellow. Strain HSF6T was found to grow at 15-37 degrees C (optimum, 25-35 degrees C), pH 5.0-9.5 (optimum, pH 7.0-7.5) and with 0-8 % (w/v) NaCl (optimum, 2 %). Chemotaxonomic analysis showed the predominant respiratory quinone of strains HSF6T were ubiquinone-10, and the major fatty acids were C18 : 1omega7c, C16 : 0 and 11-methyl C18 : 1omega7c. The polar lipids were monoglycosyldiglyceride (MGDG), sulfo-quinovosyl diacylglycerol (SQDG), three unknown glycolipids (GL1-3) and five unknown lipids (L1-5). The DNA G+C content of strain HSF6T was determined to be 51.0 mol% with HPLC. The comparison of 16S rRNA gene sequence similarities show that strain HSF6T was related most closely to genus Parvularcula with similarity ranging from 91.0 to 91.8 %. The phylogenetic trees, using the 16S rRNA gene sequence, reconstructed with neighbour-joining, maximum-parsimony and maximum-likelihood methods showed that strain HSF6T constituted a separated branch in the family 'Parvularculaceae'. Differential phenotypic properties, together with the phylogenetic distinctiveness, demonstrated that strain HSF6T is clearly distinct from validly published genera. On the basis of these features, we propose strain HSF6T (=MCCC 1K03223T=KCTC 52486T) represents a novel species of a novel genus with the name Hyphococcus flavus gen. nov., sp. nov. PMID- 28893368 TI - Flavobacterium ardleyense sp. nov., isolated from Antarctic soil. AB - A Gram-stain-negative, aerobic, yellow-pigmented, non-flagellated, non-gliding, rod-like, oxidase- and catalase-positive bacterium, designated A2-1T, was isolated from soil on Ardley Island, South Shetland Islands, Antarctica. Strain A2-1T grew at 4-22 degrees C (optimum, 10 degrees C), at pH 6.0-8.0 (optimum, pH 6.5) and with 0-1.5 % NaCl (optimum, 0.5 %), but could not produce flexirubin type pigments. 16S rRNA gene sequence analysis showed that the isolates belonged to the genus Flavobacterium. Strain A2-1T had the highest 16S rRNA gene sequence similarity to Flavobacterium cucumis, F. ahnfeltiae and F. cheniae with 95.7, 95.6 and 95.4 %, respectively. The strain A2-1T consisted of a clade with F. cucumis and F. cheniae and simultaneously formed a distinct phyletic lineage in the neighbour-joining phylogenetic tree. Polar lipids of the strain included phosphatidylethanolamine (PE), four unidentified aminolipids and one unidentified lipid. The strain A2-1T contained anteiso-C15 : 0 (20.2 %), iso-C15 : 0 (16.2 %) and C15 : 1 G (11.0 %) as the main fatty acids and the only respiratory quinone was menaquinone MK-6. The genomic DNA G+C content was 34.0 mol%. The polyphasic taxonomic study revealed that the strain A2-1T belongs to a novel species within the genus Flavobacterium and the name Flavobacterium ardleyense sp. nov. is proposed. The type strain is A2-1T (=CCTCC AB 2017157T=KCTC 52644T). PMID- 28893369 TI - Virulence determinants of Moraxella catarrhalis: distribution and considerations for vaccine development. AB - Moraxella catarrhalis is a human-restricted opportunistic bacterial pathogen of the respiratory mucosa. It frequently colonizes the nasopharynx asymptomatically, but is also an important causative agent of otitis media (OM) in children, and plays a significant role in acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults. As the current treatment options for M. catarrhalis infection in OM and exacerbations of COPD are often ineffective, the development of an efficacious vaccine is warranted. However, no vaccine candidates for M. catarrhalis have progressed to clinical trials, and information regarding the distribution of M. catarrhalis virulence factors and vaccine candidates is inconsistent in the literature. It is largely unknown if virulence is associated with particular strains or subpopulations of M. catarrhalis, or if differences in clinical manifestation can be attributed to the heterogeneous expression of specific M. catarrhalis virulence factors in the circulating population. Further investigation of the distribution of M. catarrhalis virulence factors in the context of carriage and disease is required so that vaccine development may be targeted at relevant antigens that are conserved among disease-causing strains. The challenge of determining which of the proposed M. catarrhalis virulence factors are relevant to human disease is amplified by the lack of a standardized M. catarrhalis typing system to facilitate direct comparisons of worldwide isolates. Here we summarize and evaluate proposed relationships between M. catarrhalis subpopulations and specific virulence factors in the context of colonization and disease, as well as the current methods used to infer these associations. PMID- 28893370 TI - Inhibitory efficacy of geraniol on biofilm formation and development of adaptive resistance in Staphylococcus epidermidis RP62A. AB - PURPOSE: The current study has been designed to delineate the efficacy of geraniol (GE) on biofilm formation in Staphylococcus epidermidis as well as the effect of subinhibitory concentrations of GE on the development of adaptive resistance. METHODOLOGY: Biofilm biomass quantification assay was performed to evaluate the antibiofilm activity of GE against S. epidermidis. Microscopic observation of biofilms and extracellular polymeric substance (EPS), slime and cell surface hydrophobicity (CSH) production were also studied to support the antibiofilm potential of GE. In addition, S. epidermidis was examined for its adaptive resistance development upon continuous exposure of GE at its subinhibitory concentrations.Results/Key findings. The MIC of GE against S. epidermidis was 512 ug ml-1. Without hampering the growth of the pathogen, GE at its sub-MICs (50, 100, 150 and 200 ug ml-1) exhibited a dose-dependent increase in antibiofilm activity. The minimal biofilm inhibitory concentration (MBIC) of GE was found to be 200 ug ml-1 with a maximum biofilm inhibition of 85 %. Disintegrated biofilm architecture, reduced EPS, slime and CSH production validated the antibiofilm efficacy of GE. Although the action of GE on preformed biofilm is limited, a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide (XTT) reduction assay and live/dead cell staining method revealed reduction in the viability (47 %) of biofilm inhabitants at 2*MIC concentration. Sequential exposure of S. epidermidis to the sub-MICs of GE resulted in poor development of adaptive resistance with diminished biofilm formation. CONCLUSION: The present study highlights the potential of GE as a suitable candidate for the control of biofilm-mediated S. epidermidis infections. PMID- 28893371 TI - Heterogeneous interaction network of yeast prions and remodeling factors detected in live cells. AB - Budding yeast has dozens of prions, which are mutually dependent on each other for the de novo prion formation. In addition to the interactions among prions, transmissions of prions are strictly dependent on two chaperone systems: the Hsp104 and the Hsp70/Hsp40 (J-protein) systems, both of which cooperatively remodel the prion aggregates to ensure the multiplication of prion entities. Since it has been postulated that prions and the remodeling factors constitute complex networks in cells, a quantitative approach to describe the interactions in live cells would be required. Here, the researchers applied dual-color fluorescence cross-correlation spectroscopy to investigate the molecular network of interaction in single live cells. The findings demonstrate that yeast prions and remodeling factors constitute a network through heterogeneous protein-protein interactions. [BMB Reports 2017; 50(9): 478-483]. PMID- 28893372 TI - Dual effects of a CpG-DNAzyme targeting mutant EGFR transcripts in lung cancer cells: TLR9 activation and EGFR downregulation. AB - Non-small-cell lung cancer (NSCLC) is commonly caused by a mutation in the epidermal growth factor receptor (EGFR) and subsequent aberrant EGFR signaling with uncontrolled kinase activity. A deletion mutation in EGFR exon 19 is frequently observed in EGFR gene mutations. We designed a DNAzyme to suppress the expression of mutant EGFR by cleaving the mutant EGFR mRNA. The DNAzyme (named Ex19del Dz) specifically cleaved target RNA and decreased cancer cell viability when transfected into gefitinib-resistant lung cancer cells harboring EGFR exon 19 deletions. The DNAzyme decreased EGFR expression and inhibited its downstream signaling pathway. In addition to EGFR downregulation, Ex19del Dz containing CpG sites activated Toll-like receptor 9 (TLR9) and its downstream signaling pathway via p38 kinase, causing an immunostimulatory effect on EGFR-mutated NSCLC cells. Thus, dual effects of this DNAzyme harboring the CpG site, such as TLR9 activation and EGFR downregulation, leads to apoptosis of EGFR-mutated NSCLC cells. [BMB Reports 2018; 51(1): 27-32]. PMID- 28893373 TI - Peroxiredoxin I participates in the protection of reactive oxygen species mediated cellular senescence. AB - Peroxiredoxin I (Prx I) plays an important role as a reactive oxygen species (ROS) scavenger in protecting and maintaining cellular homeostasis; however, the underlying mechanisms are not well understood. Here, we identified a critical role of Prx I in protecting cells against ROS-mediated cellular senescence by suppression of p16INK4a expression. Compared to wild-type mouse embryonic fibroblasts (WT-MEFs), Prx I-/- MEFs exhibited senescence-associated phenotypes. Moreover, the aged Prx I-/- mice showed an increased number of cells with senescence associated-beta-galactosidase (SA-beta-gal) activity in a variety of tissues. Increased ROS levels and SA-beta-gal activity, and reduction of chemical antioxidant further in Prx I-/- MEF supported an essential role of Prx I peroxidase activity in cellular senescence that is mediated by oxidative stress. The up-regulation of p16INK4a expression in Prx I-/- and suppression by overexpression of Prx I indicate that Prx I possibly modulate cellular senescence through ROS/p16INK4a pathway. [BMB Reports 2017; 50(10): 528-533]. PMID- 28893375 TI - A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia. AB - The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia. PMID- 28893374 TI - Cell differentiation defines acute and chronic infection cell types in Staphylococcus aureus. AB - A central question to biology is how pathogenic bacteria initiate acute or chronic infections. Here we describe a genetic program for cell-fate decision in the opportunistic human pathogen Staphylococcus aureus, which generates the phenotypic bifurcation of the cells into two genetically identical but different cell types during the course of an infection. Whereas one cell type promotes the formation of biofilms that contribute to chronic infections, the second type is planktonic and produces the toxins that contribute to acute bacteremia. We identified a bimodal switch in the agr quorum sensing system that antagonistically regulates the differentiation of these two physiologically distinct cell types. We found that extracellular signals affect the behavior of the agr bimodal switch and modify the size of the specialized subpopulations in specific colonization niches. For instance, magnesium-enriched colonization niches causes magnesium binding to S. aureusteichoic acids and increases bacterial cell wall rigidity. This signal triggers a genetic program that ultimately downregulates the agr bimodal switch. Colonization niches with different magnesium concentrations influence the bimodal system activity, which defines a distinct ratio between these subpopulations; this in turn leads to distinct infection outcomes in vitro and in an in vivo murine infection model. Cell differentiation generates physiological heterogeneity in clonal bacterial infections and helps to determine the distinct infection types. PMID- 28893376 TI - Regulation of sleep homeostasis by sexual arousal. AB - In all animals, sleep pressure is under continuous tight regulation. It is universally accepted that this regulation arises from a two-process model, integrating both a circadian and a homeostatic controller. Here we explore the role of environmental social signals as a third, parallel controller of sleep homeostasis and sleep pressure. We show that, in Drosophila melanogaster males, sleep pressure after sleep deprivation can be counteracted by raising their sexual arousal, either by engaging the flies with prolonged courtship activity or merely by exposing them to female pheromones. PMID- 28893377 TI - Induced sensorimotor cortex plasticity remediates chronic treatment-resistant visual neglect. AB - Right brain injury causes visual neglect - lost awareness of left space. During prism adaptation therapy, patients adapt to a rightward optical shift by recalibrating right arm movements leftward. This can improve left neglect, but the benefit of a single session is transient (~1 day). Here we show that tonic disinhibition of left motor cortex during prism adaptation enhances consolidation, stabilizing both sensorimotor and cognitive prism after-effects. In three longitudinal patient case series, just 20 min of combined stimulation/adaptation caused persistent cognitive after-effects (neglect improvement) that lasted throughout follow-up (18-46 days). Moreover, adaptation without stimulation was ineffective. Thus stimulation reversed treatment resistance in chronic visual neglect. These findings challenge consensus that because the left hemisphere in neglect is pathologically over-excited it ought to be suppressed. Excitation of left sensorimotor circuits, during an adaptive cognitive state, can unmask latent plastic potential that durably improves resistant visual attention deficits after brain injury. PMID- 28893378 TI - Localization of spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI. AB - Electroencephalographic recordings from the developing human brain are characterized by spontaneous neuronal bursts, the most common of which is the delta brush. Although similar events in animal models are known to occur in areas of immature cortex and drive their development, their origin in humans has not yet been identified. Here, we use simultaneous EEG-fMRI to localise the source of delta brush events in 10 preterm infants aged 32-36 postmenstrual weeks. The most frequent patterns were left and right posterior-temporal delta brushes which were associated in the left hemisphere with ipsilateral BOLD activation in the insula only; and in the right hemisphere in both the insular and temporal cortices. This direct measure of neural and hemodynamic activity shows that the insula, one of the most densely connected hubs in the developing cortex, is a major source of the transient bursting events that are critical for brain maturation. PMID- 28893379 TI - Comparison of Outcomes of ST-Elevation Myocardial Infarction Treated by Percutaneous Coronary Intervention During Off-Hours Versus On-Hours. AB - Previous studies have reported worse outcomes and longer door-to-balloon times (DBTs) in patients presenting with ST-elevation myocardial infarction (STEMI) after normal working hours, during weekends, and on holidays (off-hours) compared with normal business hours (on-hours). Recent studies, however, have reported similar outcomes regardless of presentation time. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were queried from January 1990 through December 2016. Only studies comparing STEMI outcomes during off-hours versus on-hours with percutaneous coronary intervention were included. A random effects meta-analysis model was used to pool outcomes across the studies. Clinical end points included short- (<30 days of presentation), intermediate- (at 1 to 2 years), and long-term (at 3 to 4 years) stent thrombosis, mortality, recurrent myocardial infarction (MI), and major adverse cardiovascular events (MACEs). A total of 86,776 patients (62 years and 74.5% male) were identified from 39 studies. There was no significant difference between both groups with regard to mean DBT (odds ratio [OR] 0.74, 95% confidence interval [CI] -2.73 to 4.22, p = 0.67) or median DBT (p = 0.19). There was no significant difference between the 2 groups for short-term end points including mortality (OR 1.11, 95% CI 0.99 to 1.25, p = 0.08), MI (OR 1.25, 95% CI 0.90 to 1.74, p = 0.18), MACE (OR 1.06, 95% CI 0.93 to 1.20, p = 0.40), or stent thrombosis (OR 1.23, 95% CI 0.83 to 1.82, p = 0.31). Similarly, intermediate-term end points were not statistically different for mortality (OR 0.97, 95% CI 0.89 to 1.05, p = 0.46), MI (OR 0.86, 95% CI 0.73 to 1.02, p = 0.08), or MACE (OR 1.00, 95% CI 0.92 to 1.08, p = 0.98). Long-term end points did not differ statistically between groups for mortality (OR 0.95, 95% CI 0.83 to 1.09, p = 0.46), MI (OR 1.19, 95% CI 0.77 to 1.84, p = 0.44), or MACE (OR 0.98, 95% CI 0.89 to 1.08, p = 0.67). In conclusion, patients presenting with STEMI during off-hours and treated with percutaneous coronary intervention had similar short-, intermediate-, and long term outcomes compared with patients presenting during on-hours. DBT was not affected by the time of presentation. PMID- 28893380 TI - A Facial Plaque and Nodules on the Scalp. PMID- 28893381 TI - The Association Between Prenatal Stress and Externalizing Symptoms in Childhood: Evidence From the Avon Longitudinal Study of Parents and Children. AB - BACKGROUND: It has been suggested that prenatal maternal stress may increase the risk of childhood externalizing disorders, yet no large cohort study has investigated this association across a large range of acute stressors. Our objective was to estimate the association between prenatal stressful events and risk of offspring conduct disorder and hyperactivity. METHODS: We used data from 10,184 mother-offspring pairs from the United Kingdom-based Avon Longitudinal Study of Parents and Children. Mothers self-reported 42 prenatal stressful life events at 18 weeks' gestation. Symptoms of conduct disorder and hyperactivity in their offspring were measured at 6, 9, 11, 13, and 16 years of age using the Strengths and Difficulties Questionnaire. The primary outcome was membership in high-symptom trajectories of 1) conduct disorder and 2) hyperactivity throughout childhood, identified using latent class growth modeling. Multinomial logistic regression models estimated the association between prenatal stress and both conduct disorder and hyperactivity, after adjusting for sex, parental education, low birth weight, preterm birth, parental social class, maternal smoking and drinking, maternal mental health, offspring stressful life events, and offspring depressive and anxious symptoms. RESULTS: Those exposed to the highest quartile of prenatal stress were more likely to belong to the high symptom trajectory for hyperactivity (B = 0.46, p < .05) and conduct disorder (B = 0.88, p < .01), respectively. Prenatal stress further demonstrated a positive, dose-response relationship with symptoms of externalizing disorders at independent time points. CONCLUSIONS: The findings suggest that prenatal stressful events may be an independent risk factor for offspring externalizing symptoms, regardless of maternal mental health and offspring internalizing. PMID- 28893382 TI - Pain and sensory disturbances following surgical repair of pectus carinatum. AB - BACKGROUND/PURPOSE: The purpose of this study was to assess the characteristics of persistent postoperative pain and sensory disturbances following surgical repair of pectus carinatum. METHODS: Using a prospective observational design, 28 patients were assessed before, 6 weeks and 6 months after a modified Ravitch operation for pectus carinatum. Postoperative pain was assessed using the Short Form McGill Pain Questionnaire. Sensory testing was conducted to detect brush evoked allodynia and pinprick hyperalgesia. Additionally, generic and disease specific quality of life was assessed using the Short Form-36 Health Survey and the Nuss Questionnaire Modified for Adults before and after surgery. RESULTS: Six weeks after surgery, ten patients reported mild pain or discomfort. Six months after surgery, four patients reported only mild pain. Allodynia was detected in two patients 6 weeks and 6 months after surgery. Hyperalgesia was detected in eight patients 6 weeks after surgery, and in six patients 6 months after surgery. Generic quality of life was significantly improved over time. CONCLUSIONS: The study showed no significant pain problems, a tendency to reduced sensory disturbances and significant improvements in quality of life 6 months after surgical repair of pectus carinatum. Future studies should include a longer follow-up period to determine if these positive results are persistent. LEVELS OF EVIDENCE: 1 (Prognosis Study). PMID- 28893383 TI - Adaptive fractional-order total variation image restoration with split Bregman iteration. AB - Alleviating the staircase artifacts for variation method and adjusting the regularization parameters adaptively with the characteristics of different regions are two main issues in image restoration regularization process. An adaptive fractional-order total variation l1 regularization (AFOTV-l1) model is proposed, which is resolved by using split Bregman iteration algorithm (SBI) for image estimation. An improved fractional-order differential kernel mask (IFODKM) with an extended degree of freedom (DOF) is proposed, which can preserve more image details and effectively avoid the staircase artifact. With the SBI algorithm adopted in this paper, fast convergence and small errors are achieved. Moreover, a novel regularization parameters adaptive strategy is given. Experimental results, by using the standard image library (SIL), the lung imaging database consortium and image database resource initiative (LIDC-IDRI), demonstrate that the proposed methods have better approximation, robustness and fast convergence performances for image restoration. PMID- 28893384 TI - Influence of Socioeconomic Context on the Rehospitalization Rates of Infants Born Preterm. AB - OBJECTIVE: To investigate the impact of social inequalities on the risk of rehospitalization in the first year after discharge from the neonatal unit in a population of preterm-born children. STUDY DESIGN: Preterm infants were included if they were born between 2006 and 2013 at <=32 + 6 weeks of gestation and who received follow-up in a French regional medical network with a high level of healthcare. Socioeconomic context was estimated using a neighborhood-based socioeconomic deprivation index. Univariate and logistic regression analyses were used to identify risk factors associated with rehospitalization. RESULTS: For the 2325 children, the mean gestational age was 29 +/- 2 weeks and the mean birth weight was 1315 +/- 395 g. In the first year, 22% were rehospitalized (n = 589); respiratory diseases were the primary cause (44%). The multiple rehospitalization rate was 18%. Multivariable analysis showed that living in the most deprived neighborhoods (socioeconomic deprivation index of 5) was associated with overall rehospitalization (OR, 2.2; 95% CI, 1.5-3.6; P <.001), and multiple rehospitalizations (OR, 2.5; 95% CI, 1.2-4.9; P <.01); with socioeconomic deprivation index of 1 (least deprived) as reference. Deprivation was associated with all causes of hospitalization. Female sex (P <.001) and living in an urban area (P = .001) were protective factors. CONCLUSIONS: Despite regional routine follow-up for all children, rehospitalization after very preterm birth was higher for children living in deprived neighborhoods. Families' social circumstances need to be considered when evaluating the health consequences of very preterm birth. PMID- 28893385 TI - The ovary: from conception to death. PMID- 28893386 TI - Is there an excess of left-handedness after neonatal stroke? PMID- 28893387 TI - The effect of pulsed electromagnetic frequency therapy on health-related quality of life in military service members with chronic low back pain. AB - BACKGROUND: In the U.S. military, chronic low back pain is among the most frequent complaints for medical visits, lost work time, and attrition from active duty and the deployed setting by service members. PURPOSE: The aim of this pilot study was to determine whether adjunctive treatment with pulsed electromagnetic frequency (PEMF) produced significant variability in chronic low back pain symptoms and secondary health-related quality of life, mental health and disability outcomes. METHODS: Prospective, randomized pilot study with repeated measures at baseline, post-treatment, and 1 month follow-up for two groups: usual care (UC) vs. UC + PEMF. FINDINGS: In a convenience sample of 75 service members, health-related quality of life mental and physical component scores were significant: F(2, 104) = 4.20, p = .018 (eta2 = .075) and F(2, 104) = 4.75, p = .011 (eta2 = .084), respectively; as was anxiety symptom severity: F(2, 104) = 5.28, p = .007 (eta2 = .092). DISCUSSION AND RECOMMENDATIONS: Adjunctive treatment with PEMF demonstrated improvements in service members' overall physical health-related quality of life with expected, yet statistically nonsignificant improvements in reported pain and LBP-related disability. There were significant between group differences in anxiety symptom severity with higher symptoms reported by the UC + PEMF group, surprising findings that warrant further investigation. PMID- 28893388 TI - The imaging findings of impingement syndromes of the lower limb. AB - In this article we provide an overview of impingement syndromes of the lower limb. At the level of the hip, femoroacetabular and ischiofemoral impingement are recognised. At the level of the knee, we discuss Hoffa's fat pad impingement, suprapatellar fat pad impingement, pericruciate impingement, and iliotibial band syndrome. The impingement syndromes associated with anterior cruciate ligament (ACL) repair and intercondylar osteophytes are also illustrated. Most impingement syndromes are described at the level of the ankle. These include, anterior, anterolateral, posterior, anteromedial, posterior, and posterolateral impingement. For these conditions, we describe the best technique and expected imaging findings. It should be kept in mind that many of these findings have been observed in the asymptomatic population. Impingement is essentially a clinical diagnosis and imaging findings should be considered as supportive elements for this clinical diagnosis. PMID- 28893390 TI - Periodic repolarization dynamics in patients with moderate to severe aortic stenosis. AB - BACKGROUND: Periodic repolarization dynamics (PRD) refers to low-frequency oscillations of cardiac repolarization, most likely related to phasic sympathetic activation. Increased PRD is a validated predictor of mortality after myocardial infarction and in ischemic heart disease, but has not been tested in aortic valve stenosis (AS). Here, we assessed PRD in patients with AS and tested its correlation with clinical and hemodynamic parameters as well as markers of heart rate variability (HRV). MATERIALS AND METHODS: We prospectively enrolled 139 consecutive patients with moderate to severe AS in sinus rhythm. In all patients we performed a 24-h Holter ECG in Frank-leads configuration. We assessed PRD according to previously published technologies from the nocturnal hours (0am-6am) and dichotomized PRD at the established cut-off value of >=5.75deg2. In addition to clinical and hemodynamic markers, we also assessed deceleration capacity (DC) of heart rate, heart rate turbulence and standard HRV parameters. RESULTS: In the patients studied, PRD was 6.55+/-3.96deg2. Seventy-three patients (52.5%) had increased PRD. Among them, 36 (49.9%) patients were classified as being asymptomatic. There was no association between increased PRD and clinical or hemodynamic markers, including presence of symptoms, NYHA-classification, aortic valve area, and left-ventricular ejection fraction. Thirty-three of the 73 (45.2%) patients with PRD >=5.75deg2 also suffered from decreased vagal tonic activity by means of abnormal DC (<=2.5ms) indicating severe autonomic dysfunction. CONCLUSION: Prevalence of increased PRD is high among patients with moderate to severe AS. Patients with increased PRD cannot be identified by clinical or hemodynamic markers Future studies should test the prognostic value of PRD in patients with AS. PMID- 28893389 TI - Ventricular fibrillation waveform measures combined with prior shock outcome predict defibrillation success during cardiopulmonary resuscitation. AB - AIM: Amplitude Spectrum Area (AMSA) and Median Slope (MS) are ventricular fibrillation (VF) waveform measures that predict defibrillation shock success. Cardiopulmonary resuscitation (CPR) obscures electrocardiograms and must be paused for analysis. Studies suggest waveform measures better predict subsequent shock success when combined with prior shock success. We determined whether this relationship applies during CPR. METHODS: AMSA and MS were calculated from 5 second pre-shock segments with and without CPR, and compared to logistic models combining each measure with prior return of organized rhythm (ROR). RESULTS: VF segments from 692 patients were analyzed during CPR before 1372 shocks and without CPR before 1283 shocks. Combining waveform measures with prior ROR increased areas under receiver operating characteristic curves for AMSA/MS with CPR (0.66/0.68 to 0.73/0.74, p<0.001) and without CPR (0.71/0.72 to 0.76/0.76, p<0.001). CONCLUSIONS: Prior ROR improves prediction of shock success during CPR, and may enable waveform measure calculation without chest compression pauses. PMID- 28893391 TI - The effects of early stages of aging on postural sway: A multiple domain balance assessment using a force platform. AB - Technical advancements in instrumentation and analytical methods have improved the ability of assessing balance control. This study investigated the effects of early stages of aging on postural sway using traditional and contemporary postural indices from different domains. Eleven healthy young adults and fourteen healthy non-faller older adults performed two postural tasks: (a) functional limits of stability and (b) unperturbed bipedal stance for 120s. Postural indices from spatial, temporal, frequency, and structural domains were extracted from the body's center of pressure (COP) signals and its Rambling and Trembling components. Results revealed a preservation of functional limits of upright stability in older adults accompanied by larger, faster, and shakier body sway in both anterior-posterior and medio-lateral directions; increased medio-lateral sway frequency; increased irregularity of body sway pattern in time in both directions; and increased area, variability, velocity, and jerkiness of both rambling and trembling components of the COP displacement in the anterior posterior direction (p<0.02). Such changes might be interpreted as compensatory adjustments to the age-related decline of sensory, neural, and motor functions. In conclusion, balance assessment using postural indices from different domains extracted from the COP displacement was able to capture subtle effects of the natural process of aging on the mechanisms of postural control. Our findings suggest the use of such indices as potential markers for postural instability and fall risk in older adults. PMID- 28893392 TI - Computational modeling and validation of human nasal airflow under various breathing conditions. AB - The human nose serves vital physiological functions, including warming, filtration, humidification, and olfaction. These functions are based on transport phenomena that depend on nasal airflow patterns and turbulence. Accurate prediction of these airflow properties requires careful selection of computational fluid dynamics models and rigorous validation. The validation studies in the past have been limited by poor representations of the complex nasal geometry, lack of detailed airflow comparisons, and restricted ranges of flow rate. The objective of this study is to validate various numerical methods based on an anatomically accurate nasal model against published experimentally measured data under breathing flow rates from 180 to 1100ml/s. The numerical results of velocity profiles and turbulence intensities were obtained using the laminar model, four widely used Reynolds-averaged Navier-Stokes (RANS) turbulence models (i.e., k-epsilon, standard k-omega, Shear Stress Transport k-omega, and Reynolds Stress Model), large eddy simulation (LES) model, and direct numerical simulation (DNS). It was found that, despite certain irregularity in the flow field, the laminar model achieved good agreement with experimental results under restful breathing condition (180ml/s) and performed better than the RANS models. As the breathing flow rate increased, the RANS models achieved more accurate predictions but still performed worse than LES and DNS. As expected, LES and DNS can provide accurate predictions of the nasal airflow under all flow conditions but have an approximately 100-fold higher computational cost. Among all the RANS models tested, the standard k-omega model agrees most closely with the experimental values in terms of velocity profile and turbulence intensity. PMID- 28893393 TI - The influence of cryopreservation and quick-freezing on the mechanical properties of tendons. AB - In order to maintain their native properties, cryopreserved tendons are usually used in biomechanical research and in transplantation of allogenic tendon grafts. The use of different study protocols leads to controversy in literature and thus complicates the evaluation of the current literature. The aim of this study consisted in examining the influence of different freezing and thawing temperatures on the mechanical properties of tendons. 60 porcine tendons were frozen at either -80 degrees C or -20 degrees C for 7days and thawed at room or body temperature for 240 or 30min, respectively. A subgroup of ten tendons was quick-frozen with liquid nitrogen (-196 degrees C) for 2s before cryopreservation. Biomechanical testing was performed with a material testing machine and included creep, cyclic and load-to-failure tests. The results showed that freezing leads to a reduced creep strain after constant loading and to an increased secant modulus. Freezing temperature of -80 degrees C increased the secant modulus and decreased the strain at maximum stress, whereas thawing at room temperature reduced the maximum stress, the strain at initial tendon failure and the Young's Modulus. Quick-freezing led to increased creep strain after constant loading, increased strain at initial failure in the load-to-failure test, and decreased strain at maximum stress. When cryopreserving, tendons for scientific or medical reasons, freezing temperature of -20 degrees C and thawing temperature of 37.5 degrees C are recommended to maintain the native properties of tendons. A treatment with liquid nitrogen in the sterilization process of tendon allografts is inadvisable because it alters the tendon properties negatively. PMID- 28893395 TI - Morphologic variability of the mitral valve leaflets. AB - OBJECTIVES: The rapid development of surgical and less-invasive percutaneous mitral valve repair procedures has increased interest in mitral valve anatomy. We characterize the morphologic variability of the mitral valve leaflets and provide the size of their particular parts. METHODS: We studied 200 autopsied human hearts from white individuals without any valvar diseases. We measured the intercommissural and aorto-mural diameters of the mitral annulus and identified the leaflets and their scallops. We also noted the base and the height of the inferoseptal commissure, superolateral commissure, anterior mitral leaflet, and posterior mitral leaflet with their scallops. RESULTS: Variations in posterior mitral leaflet were found in 55 specimens (27.5%), and variations in anterior mitral leaflet were found in 5 hearts (2.5%). The most common variations included valves with 1 accessory scallop between P3 and inferoseptal commissure (7%), accessory scallop between P1 and superolateral commissure (4%), connections of P2 and P3 scallops (4%), connections of P1 and P2 scallops (3%), and accessory scallop in anterior mitral leaflet (2.5%). CONCLUSIONS: In all cases, the mitral valve is built by 2 main leaflets with possible variants in scallops (29.5%). The variations are largely associated with posterior mitral leaflet and are mostly related to the presence of accessory scallop. Anatomically, the anterior mitral leaflet is not divided into scallops, but could have an accessory scallop (2.5%). Understanding the anatomy of the mitral valve leaflets helps with the planning and performing of mitral valve repair procedures. Variations in scallops may affect repair procedures, but unfortunately cannot be predicted by any of the annular sizes. PMID- 28893394 TI - Biceps tenotomy in the presence of a supraspinatus tear alters the adjacent intact tendons and glenoid cartilage. AB - A rotator cuff tear is a common injury in athletes and workers who repeatedly perform overhead movements, and it is not uncommon for this demographic to return to activity shortly after treatment. A biceps tenotomy is often performed in the presence of a rotator cuff tear to help reduce pain and improve joint function. However, the effect of this procedure on the surrounding tissues in the glenohumeral joint is unknown. Therefore, the purpose of this study was to investigate the effect of a biceps tenotomy in the presence of a supraspinatus rotator cuff tear followed by overuse activity on ambulatory function and mechanical and histologic properties of the remaining rotator cuff tendons and glenoid cartilage. 46 rats underwent 4weeks of overuse activity to create a tendinopathic condition, then were randomized into two groups: unilateral detachment of the supraspinatus tendon or detachment of the supraspinatus and long head of the biceps tendons. Ambulatory measurements were performed throughout the 8weeks prior to euthanasia, followed by analysis of the properties of the remaining intact tendons and glenoid cartilage. Results demonstrate that shoulder function was not effected in the biceps tenotomy group. However, the intact tendons and glenoid cartilage showed altered mechanical and histologic properties. This study provides evidence from an animal model that does not support the use of tenotomy in the presence of a supraspinatus tendon rotator cuff tear, and provides a framework for physicians to better prescribe long-term treatment strategies for patients. PMID- 28893397 TI - Discussion. PMID- 28893396 TI - Early results of robotically assisted mitral valve surgery: Analysis of the first 1000 cases. AB - OBJECTIVE: The study objective was to assess the technical and process improvement and clinical outcomes of robotic mitral valve surgery by examining the first 1000 cases performed in a tertiary care center. METHODS: We reviewed the first 1000 patients (mean age, 56 +/- 10 years) undergoing robotic primary mitral valve surgery, including concomitant procedures (n = 185), from January 2006 to November 2013. Mitral valve disease cause was degenerative (n = 960, 96%), endocarditis (n = 26, 2.6%), rheumatic (n = 10, 1.0%), ischemic (n = 3, 0.3%), and fibroelastoma (n = 1, 0.1%). All procedures were performed via right chest access with femoral perfusion for cardiopulmonary bypass. RESULTS: Mitral valve repair was attempted in 997 patients (2 planned replacements and 1 resection of fibroelastoma), 992 (99.5%) of whom underwent valve repair, and 5 (0.5%) of whom underwent valve replacement. Intraoperative postrepair echocardiography showed that 99.7% of patients receiving repair (989/992) left the operating room with no or mild mitral regurgitation, and predischarge echocardiography showed that mitral regurgitation remained mild or less in 97.9% of patients (915/935). There was 1 hospital death (0.1%), and 14 patients (1.4%) experienced a stroke; stroke risk declined from 2% in the first 500 patients to 0.8% in the second 500 patients. Over the course of the experience, myocardial ischemic and cardiopulmonary bypass times (P < .0001), transfusion (P = .003), and intensive care unit and postoperative lengths of stay (P < .05) decreased. CONCLUSIONS: Robotic mitral valve surgery is associated with a high likelihood of valve repair and low operative mortality and morbidity. The combination of algorithm-driven patient selection and increased experience enhanced clinical outcomes and procedural efficiency. PMID- 28893398 TI - Timing of surgery in infective endocarditis with cerebral complications: Time to think outside the nonexistent box. PMID- 28893399 TI - Determination of geochemical background values on a tropical estuarine system in a densely urban area. Case study: Capibaribe estuary, Northeastern Brazil. AB - This study aims to infer the background values of several metals in the Capibaribe estuary and to identify the likely impact of anthropic activities during 200-years of sedimentation. Two cores were sampled, with subsamples at intervals of 2cm. Sedimentation rates and metal concentrations were analyzed. The Al-normalized method was used to infer the background values, and to identify anthropic influences, the enrichment factor, the contamination factor and the geoaccumulation index were employed. The background values showed concentrations for Mn of 292.2, for Co of 10.4, for Ni of 22.3, for Cu of 60.8, for Zn of 105.5, for As of 106.0, for Pb of 52.9 (all in mgkg-1) and for Fe of 2.7%, The higher values, mainly for As, Zn and Pb, are associated with the influence of the Barreiras Formation. The geogenic inputs are significantly greater than the anthropic activities, masking the contamination. PMID- 28893400 TI - 'The dissemination diamond' and paradoxes of science-to-science and science-to policy communication: Lessons from large marine research programmes. PMID- 28893401 TI - Presence of trace elements in the silverside Odontesthes argentinensis. AB - The silverside Odontesthes argentinensis is an economically significant resource for commercial fisheries in South America. We evaluated the presence of trace elements in the stomach content and fish tissues (muscle and otoliths) of O. argentinensis. In addition, we assessed the presence of trace elements in its prey (zooplankton) and in seawater in a coastal temperate area. The most abundant trace elements found in the water, zooplankton, stomach content, and fish tissues (muscle and otoliths) constituted of Ba, Mn, Sr and Zn, while Cd, Cu and Pb were observed in lower concentrations. We concluded that O. argentinensis specimens captured from the environment, within the length range analyzed for muscle samples (total length: <21cm), are deemed fit for human consumption because the concentrations of trace elements mostly meet the standards established in the Argentine Food Code. The information obtained in this study is vital for O. argentinensis farming in closed systems. PMID- 28893402 TI - A large-scale investigation of microplastic contamination: Abundance and characteristics of microplastics in European beach sediment. AB - Here we present the large-scale distribution of microplastic contamination in beach sediment across Europe. Sediment samples were collected from 23 locations across 13 countries by citizen scientists, and analysed using a standard operating procedure. We found significant variability in the concentrations of microplastics, ranging from 72+/-24 to 1512+/-187 microplastics per kg of dry sediment, with high variability within sampling locations. Three hotspots of microplastic accumulation (>700 microplastics per kg of dry sediment) were found. There was limited variability in the physico-chemical characteristics of the plastics across sampling locations. The majority of the microplastics were fibrous, <1mm in size, and blue/black in colour. In addition, using Raman spectrometry we identified particles as polyester, polyethylene, and polypropylene. Our research is the first large spatial-scale analysis of microplastics on European beaches giving insights into the nature and extent of the microplastic challenge. PMID- 28893403 TI - Energy restriction affect liver development in Hu sheep ram lambs through Hippo signaling pathway. AB - This study aimed to evaluate the effects of dietary energy restriction on postnatal liver development in Hu sheep ram lambs. A total of 16 ram lambs were randomly divided into two groups: 100% energy requirements diet and 55% energy requirements diet, which were fed for 75 d. Results showed that the final body and liver weights decreased with energy restriction (p <0.05). Energy restriction caused a significant decrease in the levels of circulating insulin-like growth factor 1 (IGF1) and an increase in growth hormone secretion (p <0.05), which can be explained by the decreased mRNA expression levels of the growth hormone receptor (GHR) and IGF1 (p <0.05). The proliferating cell nuclear antigen (PCNA), Ki-67 and apoptosis-related proteins (BAX and BCL2) were mainly located in the nucleus and the cytoplasm of hepatocytes, respectively. The transcription and protein levels of PCNA and BAX were significantly decreased and increased by energy restriction, respectively (p <0.05). The caspase9 and caspase3 mRNA and activity were increased in energy restriction group (p <0.05). Moreover, Hippo signaling pathway proteins [mammalian sterile 20-like protein kinase 1 (MST1), large tumor suppressor kinase 1 (LATS1), and yes-associated protein 1 (YAP1)] were mainly observed around the hepatic portal area, and the expression levels of their mRNA and proteins were significantly decreased in energy restriction group (p <0.05). In summary, energy restriction in ram lambs impairs liver development by increasing apoptosis, which may occur via the Hippo signaling pathway. PMID- 28893404 TI - 3D Quantitative Chemical Imaging of Tissues by Spectromics. AB - Mid-infrared (IR), Raman, and X-ray fluorescence (XRF) spectroscopy methods, as well as mass spectrometry (MS), can be used for 3D chemical imaging. These techniques offer an invaluable opportunity to access chemical features of biological samples in a nonsupervised way. The global chemical information they provide enables the exploitation of a large array of chemical species or parameters, so-called 'spectromics'. Extracting chemical data from spectra is critical for the high-quality chemical analysis of biosamples. Furthermore, these are the only currently available techniques that can quantitatively analyze tissue content (e.g., molecular concentrations) and substructures (e.g., cells or blood vessels). The development of chemical-derived biological metadata appears to be a new way to exploit spectral information with machine learning algorithms. PMID- 28893405 TI - Genome Editing for Global Food Security. AB - Global food security is increasingly challenging in light of population increase, the impact of climate change on crop production, and limited land available for agricultural expansion. Here we outline how genome editing provides excellent and timely methods to optimize crop plants, and argue the urgency for societal acceptance and support. PMID- 28893406 TI - Legal access to alcohol and criminality. AB - Previous research has found strong evidence that legal access to alcohol is associated with sizable increases in criminality. We revisit this relationship using the census of judicial records on criminal charges filed in Oregon Courts, the ability to separately track crimes involving firearms, and to track individuals over time. We find that crime increases at age 21, with increases mostly due to assaults that lack premeditation, and alcohol-related nuisance crimes. We find no evident increases in rape or robbery. Among those with no prior criminal records, increases in crime are 50% larger-still larger for the most socially costly crimes of assault and drunk driving. PMID- 28893407 TI - Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. AB - BACKGROUND: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood. OBJECTIVE: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-alpha (TNF-alpha) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy. RESULTS: Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (>=12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-alpha inhibitor was associated with increased malignancy risk. LIMITATIONS: Cases and controls could belong to 1 or more therapy categories. CONCLUSIONS: Long-term (>=12 months) treatment with a TNF-alpha inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis. PMID- 28893408 TI - Inflammatory myopathy associated with anti-mitochondrial antibodies: A distinct phenotype with cardiac involvement. AB - OBJECTIVE: In the context of clinical evaluations performed on our prospective myositis cohort, we noted a striking association of severe cardiac disease in myositis patients with anti-mitochondrial antibodies. We sought to review all cases of anti-mitochondrial antibody (AMA) associated myositis in our cohort to describe the clinical features of this disease subset. METHODS: We identified 7 patients with confirmed anti-mitochondrial antibodies who presented as an inflammatory myopathy. A retrospective chart review was completed to assess their clinical presentation, laboratory, imaging, electrophysiologic, and histopathologic features. RESULTS: One patient presented with dermatomyositis and 6 were classified as polymyositis using Bohan and Peter criteria. In all but one patient, a chronic course of muscle involvement was appreciated with an average of 6.5 years of weakness prior to presentation. Muscle atrophy was often noted, as well as atypical findings of scapular winging in 2 of the patients. Muscle biopsies were consistent with immune-mediated necrotizing myopathy in 4 patients, dermatomyositis in 1, polymyositis in 1 and nonspecific or granulomatous myositis in 1 patient. Changes pointing to mitochondrial alterations were seen in 2 of the 7 patients. Cardiac involvement (including myocarditis, atrial and ventricular arrhythmias, and cardiomyopathy), was seen in 5 out of 7 (71%) of the patients, and usually preceded the muscle involvement. Coexisting autoimmune conditions were seen in 3/7of the patients and included primary biliary cirrhosis, autoimmune hepatitis, psoriasis, and Hashimoto's thyroiditis. CONCLUSIONS: Anti mitochondrial antibodies identify a distinct inflammatory myopathy phenotype that is frequently associated with chronic skeletal muscle disease and severe cardiac involvement. Early recognition of this rare entity as an immune-mediated process is important due to implications for treatment. We propose that anti mitochondrial antibody status should be determined in patients with a compatible clinical picture. PMID- 28893409 TI - Equivalence in the Health Assessment Questionnaire (HAQ) across socio-demographic determinants: Analyses within QUEST-RA. AB - OBJECTIVES: To investigate potential bias in scores of the Health Assessment Questionnaire (HAQ) related to socio-demographic (SD) background of patients with rheumatoid arthritis (RA). METHODS: Data from the Quantitative Standard Monitoring of Rheumatoid Arthritis study (QUEST-RA), comprising 9022 patients were analysed. Physical function was assessed through 30 items of four HAQ versions: the HAQ-Disability scale, HAQ-II, modified HAQ and multi-dimensional HAQ (MD-HAQ). DIF was investigated using item response theory models implemented in a latent variable modelling framework. Models were equivalent to ordinal logistic regression models with HAQ score (item level) as outcome, the latent trait 'physical function' and individual SD factors (age, gender, education, and employment status) as predictors. Next, scores of composite HAQs were adjusted for DIF. To assess the impact of DIF on associations between SD factors and HAQs, multilevel mixed-effect linear regression models with individuals nested in country were estimated with DIF-adjusted or unadjusted HAQ as outcome. RESULTS: Relevant DIF (OR > 1.1 or <0.90) was found in several HAQ items primarily for age, gender and work status. Adjustment of composite HAQs for DIF resulted in small increases (Delta0.02-0.07); MD-HAQ best compensated for bias related to SD factors (Delta0.02). In regressions, all SD factors remained significantly related to DIF-adjusted HAQs, with differences in coefficients largest for gender (Delta0.02-0.07) but overall negligible. CONCLUSIONS: SD factors produce response bias in individual HAQ items but have little impact on composite HAQs. When interpreting HAQ across SD factors, MD-HAQ is preferred, but caution remains when comparing function across gender. PMID- 28893410 TI - An artificial neural network to predict resting energy expenditure in obesity. AB - BACKGROUND & AIMS: The resting energy expenditure (REE) determination is important in nutrition for adequate dietary prescription. The gold standard i.e. indirect calorimetry is not available in clinical settings. Thus, several predictive equations have been developed, but they lack of accuracy in subjects with extreme weight including obese populations. Artificial neural networks (ANN) are useful predictive tools in the area of artificial intelligence, used in numerous clinical fields. The aim of this study was to determine the relevance of ANN in predicting REE in obesity. METHODS: A Multi-Layer Perceptron (MLP) feed forward neural network with a back propagation algorithm was created and cross validated in a cohort of 565 obese subjects (BMI within 30-50 kg m-2) with weight, height, sex and age as clinical inputs and REE measured by indirect calorimetry as output. The predictive performances of ANN were compared to those of 23 predictive REE equations in the training set and in two independent sets of 100 and 237 obese subjects for external validation. RESULTS: Among the 23 established prediction equations for REE evaluated, the Harris & Benedict equations recalculated by Roza were the most accurate for the obese population, followed by the USA DRI, Muller and the original Harris & Benedict equations. The final 5-fold cross-validated three-layer 4-3-1 feed-forward back propagation ANN model developed in that study improved precision and accuracy of REE prediction over linear equations (precision = 68.1%, MAPE = 8.6% and RMSPE = 210 kcal/d), independently from BMI subgroups within 30-50 kg m-2. External validation confirmed the better predictive performances of ANN model (precision = 73% and 65%, MAPE = 7.7% and 8.6%, RMSPE = 187 kcal/d and 200 kcal/d in the 2 independent datasets) for the prediction of REE in obese subjects. CONCLUSIONS: We developed and validated an ANN model for the prediction of REE in obese subjects that is more precise and accurate than established REE predictive equations independent from BMI subgroups. For convenient use in clinical settings, we provide a simple ANN-REE calculator available at: https://www.crnh-rhone-alpes.fr/fr/ANN-REE Calculator. PMID- 28893411 TI - Suicidal thoughts in persons treated for alcohol dependence: The role of selected demographic and clinical factors. AB - Greater knowledge is needed of potential predictive factors for suicide in cases of alcohol addiction. Therefore, the aim of the study was to identify the socio demographic variables and clinical factors associated with alcohol dependence which may have an influence on the occurrence of suicidal thoughts in alcohol dependent patients. A group of 510 patients (396 male and 114 female) diagnosed with alcohol dependence syndrome were interviewed during the third week of therapy according to the Beck Depression Inventory (BDI), the Penn Alcohol Craving Scale (PACS) and the Short Alcohol Dependence Data Questionnaire (SADD). Socio-demographic data was also collected. The results of a binary logistic regression with suicidal thoughts as a dependent variable show that 63 out of the 510 participants (12% of the sample) reported the presence of suicidal thoughts. Alcohol dependence and alcohol craving appear to increase the likelihood of suicidal thoughts, and participants presenting psychiatric disorders were twice as likely to demonstrate suicidal ideation as those who did not. Alcohol dependence, alcohol craving and psychiatric comorbidity may be regarded as risk factors for suicidal ideation in the studied sample, with the only protective factor being living in a relationship. PMID- 28893413 TI - Fish oil emulsion supplementation might improve quality of life of diabetic patients due to its antioxidant and anti-inflammatory properties. AB - Diabetes-related complications, including cardiovascular disease, retinopathy, nephropathy, and neuropathy, are a significant cause of increased morbidity and mortality among people with diabetes. Previous studies have confirmed that hyperglycemia has pro-oxidative and proinflammatory properties which cause diabetic complications. We hypothesized that supplementation of fish oil emulsion (FOE), rich in omega-3 polyunsaturated fatty acids, to diabetic patients might reduce hyperglycemia-induced pathological changes due to specific properties of FOE. Omega-3 polyunsaturated fatty acids have a wide range of biological effects. In this project, we have examined the potential protective effect of the FOE on hyperglycemia-induced oxidative stress and cytokine generation in monocytes/macrophages U937 system in vitro. The monocytes/macrophages U937 were cultivated under normal or hyperglycemic (35 mmol/L glucose) conditions with/without FOE for 72 hours. We have focused on specific markers of oxidative stress (antioxidant capacity; superoxide dismutase activity; oxidative damage to DNA, proteins, and lipids) and inflammation (tumor necrosis factor, interleukin 6, interleukin-8, monocytic chemotactic protein-1). Hyperglycemia caused reduction of antioxidant capacity, induction of DNA damage, and proinflammatory cytokine secretion. FOE significantly increased antioxidant capacity of cells as well as superoxide dismutase activity and significantly reduced tumor necrosis factor, interleukin-6, interleukin-8, and monocytic chemotactic protein-1 release. No effect was observed on oxidative damage to DNA, proteins, and lipids. Our results indicate that FOE can reduce hyperglycemia-induced pathological mechanisms by its antioxidant and anti-inflammatory properties. PMID- 28893412 TI - Attention-deficit/hyperactivity disorder and callous-unemotional traits as moderators of conduct problems when examining impairment in emerging adults. AB - This study examines attention-deficit/hyperactivity disorder (ADHD) and callous unemotional (CU) traits as moderators of the association between conduct problems (CP) and young adult functioning. Young adults (n = 283; Mage = 20.82 years; 53.4% female), oversampled for attention and behavior problems, provided self ratings of ADHD, CP, and CU, and adaptive functioning and psychopathology. ADHD and CU simultaneously moderated relationships between CP and family functioning, tobacco use, and internalizing symptoms. In addition, ADHD moderated the relation between CP and job functioning, and main effects of ADHD in the expected direction were found for educational performance and drug use. CU was associated with poorer educational outcomes. Interestingly, no ADHD, CU, or CP effects were observed for reported alcohol use. Our results highlight the importance of considering ADHD and CU in understanding the impact of CP on young adult functioning and psychopathology, and point to the importance of continued work on this topic. PMID- 28893414 TI - Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. AB - BACKGROUND AND PURPOSE: We recently reported a time-sensitive, cooperative, anti tumor effect elicited by radiation (RT) and intra-tumoral-immunocytokine injection in vivo. We hypothesized that RT triggers transcriptional-mediated changes in tumor expression of immune susceptibility markers at delayed time points, which may explain these previously observed time-dependent effects. MATERIALS AND METHODS: We examined the time course of changes in expression of immune susceptibility markers following in vitro or in vivo RT in B78 murine melanoma and A375 human melanoma using flow cytometry, immunoblotting, and qPCR. RESULTS: Flow cytometry and immunoblot revealed time-dependent increases in expression of death receptors and T cell co-stimulatory/co-inhibitory ligands following RT in murine and human melanoma. Using high-throughput qPCR, we observed comparable time courses of RT-induced transcriptional upregulation for multiple immune susceptibility markers. We confirmed analogous changes in B78 tumors irradiated in vivo. We observed upregulated expression of DNA damage response markers days prior to changes in immune markers, whereas phosphorylation of the STAT1 transcription factor occurred concurrently with changes following RT. CONCLUSION: This study highlights time-dependent, transcription-mediated changes in tumor immune susceptibility marker expression following RT. These findings may help in the design of strategies to optimize sequencing of RT and immunotherapy in translational and clinical studies. PMID- 28893415 TI - The prognostic value of derived neutrophil to lymphocyte ratio in oesophageal cancer treated with definitive chemoradiotherapy. AB - BACKGROUND AND PURPOSE: The derived neutrophil-lymphocyte ratio (dNLR) is a validated prognostic biomarker for cancer survival but has not been extensively studied in locally-advanced oesophageal cancer treated with definitive chemoradiotherapy (dCRT). We aimed to identify the prognostic value of dNLR in patients recruited to the SCOPE1 trial. MATERIALS AND METHODS: 258 patients were randomised to receive dCRT+/-cetuximab. Kaplan-Meier's curves and both univariable and multivariable Cox regression models were calculated for overall survival (OS), progression free survival (PFS), local PFS inside the radiation volume (LPFSi), local PFS outside the radiation volume (LPFSo), and distant PFS (DPFS). RESULTS: An elevated pre-treatment dNLR>=2 was significantly associated with decreased OS in univariable (HR 1.74 [95% CI 1.29-2.35], p<0.001) and multivariable analyses (HR 1.64 [1.17-2.29], p=0.004). Median OS was 36months (95% CI 27.8-42.4) if dNLR<2 and 18.4months (95% CI 14.1-24.9) if dNLR>=2. All measures of PFS were also significantly reduced with an elevated dNLR. dNLR was prognostic for OS in cases of squamous cell carcinoma with a non-significant trend for adenocarcinoma/undifferentiated tumours. CONCLUSIONS: An elevated pre treatment dNLR may be an independent prognostic biomarker for OS and PFS in oesophageal cancer patients treated with definitive CRT. dNLR is a simple, inexpensive and readily available tool for risk-stratification and should be considered for use in future oesophageal cancer clinical trials. The SCOPE1 trial was an International Standard Randomised Controlled Trial [number 47718479]. PMID- 28893416 TI - NMR studies of the non-haem Fe(II) and 2-oxoglutarate-dependent oxygenases. AB - The non-haem Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases belong to a superfamily of structurally-related enzymes that play important biological roles in plants, microorganisms and animals. Structural, mechanistic and functional studies of 2OG oxygenases require efficient and effective biophysical tools. Nuclear magnetic resonance (NMR) spectroscopy is a useful tool to study this enzyme superfamily. It has been applied to obtain information about enzyme kinetics, identify and characterise 2OG oxygenase-catalysed oxidation products, elucidate the catalytic mechanism, monitor ligand binding and study protein dynamics. This review summarises the types of information that NMR spectroscopy can provide in the studies of 2OG oxygenases, highlights the advantages of the technique and describes its drawbacks. PMID- 28893417 TI - Kinetic analysis of and platinum(II) migration in the reactions of tetrazolato bridged dinuclear platinum(II) complexes with nucleotides. AB - The series of tetrazolato-bridged complexes with the formula [{cis-Pt(NH3)2}2(MU OH)(MU-5-H-tetrazolato-N1,N2)]2+ (5-H-X) or [{cis-Pt(NH3)2}2(MU-OH)(MU-5-R tetrazolato-N2,N3)]n+ (R=H (5-H-Y), CH3 (1), CH2COOCH2CH3 (2), CH2COO- (3), n=2 (5-H-Y, 1, 2) or 1 (3)) are promising candidate complexes for formulation as next generation platinum-based anticancer drugs that form multimodal bindings with DNA molecules. These multimodal bindings involve both non-covalent and covalent interactions, the latter of which are acknowledged to be essential for platinum based drugs to exert their anticancer activity. In the present study, the tetrazolato-bridged complexes reacted with two molar equivalents of guanosine-5' monophosphate (GMP) to yield the 1:2 reaction products [{cis-Pt(NH3)2(GMP N7)}2(MU-5-R-tetrazolato-N1,N3)]2- or 1-. This reaction was accompanied by an intramolecular Pt(II) migration that contributed to the formation of diverse DNA crosslinking, such as interhelical crosslinks. The second-order reaction rate constants for the reactions performed in phosphate-buffered D2O solution showed that the reactivity of the complexes decreased in the order 5-H-X?5-H-Y>2?1>3 and that reactivity was correlated with the cytotoxicity of the complexes. A similar result was obtained for the reaction of the complexes with calf thymus DNA in which the formation of covalent DNA adducts was quantified by means of inductively coupled plasma mass spectrometry. These results suggest that overall charge affects the kinetics of the reactions of platinum complexes with GMP and calf thymus DNA. Thus, the positive charge of the complexes affects not only the non-covalent but also the covalent interactions between the complexes and nucleotides and DNA, which are negatively charged molecules. PMID- 28893419 TI - Telenephrology: current perspectives and future directions. AB - There is increasing interest in telemedicine among physicians and patients; however, the evidence regarding the quality of care delivered by telemedicine, and telenephrology in particular, compared with in-person care is limited. In this review, different electronic modalities used to deliver nephrology care are reviewed and critiqued, with a focused analysis from the Australian and United States perspectives. Both countries are geographically expansive with significant rural populations where access to nephrology care is limited. However, their health care systems are organized differently. The Australian health care system is a mostly nonprofit, single-payer system, whereas the United States system is more fractured with a greater proportion of patients covered by for-profit private insurance or no insurance coverage. Videoconferencing is widely used in Australia to manage kidney disease including chronic kidney disease, dialysis, pediatric nephrology, and post-kidney transplantation care. In contrast, the United States telenephrology experience is limited, with most reports originating from the Veterans Health Administration, a single-payer system providing care for nearly 9 million veterans, ~3 million of whom reside in rural communities. Preliminary reports from the Veterans Health Administration suggest that that delivery of nephrology care via videoconferencing results in clinical outcomes that are at least equivalent to in-person care and improved patient adherence to scheduled appointments. Nevertheless, large, adequately controlled studies are needed to identify patient populations that are most likely to benefit from telenephrology and to determine the optimal systems for the delivery of telenephrology care. PMID- 28893418 TI - The promise of single-cell RNA sequencing for kidney disease investigation. AB - Recent techniques for single-cell RNA sequencing (scRNA-seq) at high throughput are leading to profound new discoveries in biology. The ability to generate vast amounts of transcriptomic data at cellular resolution represents a transformative advance, allowing the identification of novel cell types, states, and dynamics. In this review, we summarize the development of scRNA-seq methodologies and highlight their advantages and drawbacks. We discuss available software tools for analyzing scRNA-Seq data and summarize current computational challenges. Finally, we outline ways in which this powerful technology might be applied to discovery research in kidney development and disease. PMID- 28893420 TI - The hallmarks of mitochondrial dysfunction in chronic kidney disease. AB - Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases because they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease, with special emphasis on its role in the development of diabetic nephropathy. We examine the current understanding of the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure are closely linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and long noncoding RNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases. PMID- 28893422 TI - The Brain Is Needed to Cure Spinal Cord Injury. AB - Damage to corticospinal fibers in the cervical spinal cord is known to impair dexterous hand movements. However, accumulating evidence has shown that precision grip can recover considerably through rehabilitative training. Recent multidisciplinary studies have revealed that, at the spinal level, this recovery is possible due to an indirect neural pathway through propriospinal neurons (PNs), which relay cortical commands to hand motoneurons. Although this indirect spinal pathway is heavily involved in recovery, its role is dwarfed by a simultaneous large-scale network reorganization spanning motor-related cortices and mesolimbic structures. This large-scale network reorganization is key to the regulation of recovery and future therapeutic strategies will need to take into account the involvement of these supraspinal centers in addition to the known role of the spinal cord. PMID- 28893423 TI - [Incisions and baseline operative technique of cervicofacial lifting]. AB - Cervicofacial lifting is one of the most iconic procedure of plastic surgery and is about hundred years old. In the following chapters of this report, numerous technical points will be specify. A baseline reliable and reproducible technique, appealing to the largest possible audience is presented in order to begin this surgery in optimum conditions. Pre- and postoperative management is also exposed. The aim of this chapter is to precise incisions and baseline operative technique of cervicofacial lifting, with description of SMAS and platysma suspensions as well as complementary procedures like liposuccion and lipofilling. This chapter will lay the foundation of more complex elements that will be described in the various following chapters. PMID- 28893421 TI - Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. AB - The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years. PMID- 28893424 TI - Quantifying the influence of 5'-RNA modifications on RNA polymerase I activity. AB - For ensemble and single-molecule analyses of transcription, the use of synthetic transcription elongation complexes has been a versatile and powerful tool. However, structural analyses demonstrate that short RNA substrates, often employed in these assays, would occupy space within the RNA polymerase. Most commercial RNA oligonucleotides do not carry a 5'-triphosphate as would be present on a natural, de novo synthesized RNA. To examine the effects of 5' moities on transcription kinetics, we measured nucleotide addition and 3' dinucleotide cleavage by eukaryotic RNA polymerase I using 5'-hydroxyl and 5' triphosphate RNA substrates. We found that 5' modifications had no discernable effect on the kinetics of nucleotide addition; however, we observed clear, but modest, effects on the rate of backtracking and/or dinucleotide cleavage. These data suggest that the 5'-end may influence RNA polymerase translocation, consistent with previous prokaryotic studies, and these findings may have implications on kinetic barriers that confront RNA polymerases during the transition from initiation to elongation. PMID- 28893425 TI - Protocol for Robust In Vivo Measurements of Erythrocyte Aggregation Using Ultrasound Spectroscopy. AB - Erythrocyte aggregation is a non-specific marker of acute and chronic inflammation. Although it is usual to evaluate this phenomenon from blood samples analyzed in laboratory instruments, in vivo real-time assessment of aggregation is possible with spectral ultrasound techniques. However, variable blood flow can affect the interpretation of acoustic measures. Therefore, flow standardization is required. Two techniques of flow standardization were evaluated with porcine and equine blood samples in Couette flow. These techniques consisted in either stopping the flow or reducing it. Then, the sensibility and repeatability of the retained method were evaluated in 11 human volunteers. We observed that stopping the flow compromised interpretation and repeatability. Conversely, maintaining a low flow provided repeatable measures and could distinguish between normal and high extents of erythrocyte aggregation. Agreement was observed between in vivo and ex vivo measures of the phenomenon (R2 = 82.7%, p value < 0.0001). These results support the feasibility of assessing in vivo erythrocyte aggregation in humans by quantitative ultrasound means. PMID- 28893426 TI - Outcomes After Double-Bundle Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To identify the risk factors predicting unsatisfactory postoperative clinical outcomes after double-bundle (DB) anterior cruciate ligament (ACL) reconstruction using multivariate logistic regression. METHODS: Inclusion criteria were consecutive DB ACL reconstructions from January 2006 to September 2012 with a minimum 3-year follow-up. Exclusion criteria included (1) a delay to surgery from initial injury of more than 4 years (210 weeks); (2) contralateral knee pathology; (3) the lack of postoperative 3-dimensional computed tomography; (4) single-bundle ACL reconstruction; (5) revision ACL reconstruction; (6) meniscus allograft transplantation after total or subtotal meniscectomy; (7) multiple ligament surgeries. According to the overall International Knee Documentation Committee (IKDC) rating at the last follow-up, we sorted all enrolled subjects into superior (IKDC grade A or B) and inferior outcome groups (IKDC grade C or D). Multivariate logistic regression was used to analyze risk factors, including age, gender, body mass index, time from injury to surgery, posterior tibial slope, notch width index, cartilage injury, meniscus injury, and femoral and tibial tunnel positions. RESULTS: In comparison between the superior outcome group (n = 240) and inferior outcome group (n = 50), anterior (adjusted odds ratio [OR]: 0.902, 95% confidence interval [CI]: 0.846-0.962) or distal (adjusted OR: 1.025, 95% CI: 1.006-1.060) femoral anteromedial tunnel position was a significant risk factor for the inferior outcomes. Partial meniscectomy of medial (adjusted OR: 49.002, 95% CI: 7.047-340.717) or lateral (adjusted OR: 14.974, 95% CI: 2.181-102.790) meniscus and delayed time from injury to surgery (adjusted OR: 1.062, 95% CI: 1.023-1.102) were also a significant predictor. CONCLUSION: Anterior or distal anteromedial femoral tunnel position, partial meniscectomy of medial or lateral meniscus, and prolonged surgical delay of more than 11.5 weeks from injury were significant risk factors for the inferior clinical outcomes after DB ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective therapeutic case series. PMID- 28893427 TI - Nomograms for echocardiographic right ventricular sub-costal view dimensions in healthy Caucasian children: A new approach to measure the right ventricle. AB - BACKGROUND: The sub-costal examination of the heart is part of routine examination in pediatric echocardiography, and has the advantage to visualize also the infundibulum part of the right ventricle (RV). Despite this fact, currently nomograms for sub-costal RV dimensions are lacking. METHODS: We prospectively studied healthy Caucasian Italian children by two-dimensional echocardiography. Measurements included: sub-costal end diastolic basal-apical and latero-lateral diameters, end diastolic and end systolic area, 4 chamber end diastolic and end systolic area and length, end diastolic basal (RV1) and mid cavity (RV2) diameters. Age, weight, height, heart rate (HR), and body surface area (BSA) were used as independent variables in different analyses to predict the mean values of each measurement. Structured Z scores were then computed. Agreement of RV diameters and areas in subcostal view and 4-chamber view were investigated. RESULTS: 732 subjects (age 0 days-17 years; 48% female; BSA 0.12 2.12 m2) were studied. The Haycock formula was used when presenting data as predicted values (mean +/- 2 SDs) for a given BSA and within equations relating echocardiographic measurements to BSA. The predicted values and Z-score boundaries for all measurements are presented. Excellent correlations were found among two-dimensional diameters and area calculated in sub-costal view with those evaluated in 4-chamber view. CONCLUSIONS: We report echocardiographic nomograms for RV diameters and areas measured in the sub-costal view. Our data may implement normative data for 2D echocardiography evaluation of the RV in children. PMID- 28893428 TI - Correlation between preoperative serum alpha-fetoprotein levels and survival with respect to the surgical treatment of hepatocellular carcinoma at a tertiary care hospital in Veracruz, Mexico. AB - INTRODUCTION: Preoperative serum alpha-fetoprotein levels can have predictive value for hepatocellular carcinoma survival. AIM: Our aim was to analyze the correlation between preoperative serum alpha-fetoprotein levels and survival, following the surgical treatment of hepatocellular carcinoma. METHODS: Nineteen patients were prospectively followed (07/2005-01/2016). An ROC curve was created to determine the sensitivity and specificity of alpha-fetoprotein in relation to survival (Kaplan-Meier). RESULTS: Of the 19 patients evaluated, 57.9% were men. The mean patient age was 68.1 +/- 8.5 years and survival at 1, 3, and 5 years was 89.4, 55.9, and 55.9%. The alpha-fetoprotein cutoff point was 15.1 ng/ml (sensitivity 100%, specificity 99.23%). Preoperative alpha-fetoprotein levels below 15.1, 200, 400, and 463 ng/ml correlated with better 1 and 5-year survival rates than levels above 15.1, 200, 400, and 463 ng/ml (P<.05). CONCLUSIONS: Elevated preoperative serum alpha-fetoprotein levels have predictive value for hepatocellular carcinoma survival. PMID- 28893429 TI - c-Jun dimerization protein 2 (JDP2) deficiency promotes cardiac hypertrophy and dysfunction in response to pressure overload. PMID- 28893430 TI - Excessive atrial ectopic activity as an independent risk factor for ischemic stroke. AB - BACKGROUND: Excessive atrial ectopic activity (EAEA) has been related with an increased risk of atrial fibrillation (AF) and stroke but different cutoff values have been used. We aimed to determine the association between EAEA and stroke, AF and overall death. METHODS: Consecutive 24-hour Holter monitoring performed between 2005 and 2010 in a single center was evaluated. Patients with a previous diagnosis of stroke or AF were excluded. The number of premature atrial contractions (PACs) during 24h was analyzed in 2480 subjects and according to that 3 sub-groups were defined: >97PACs/h (above the top 5th percentile of the population) (EAEA+); intermediate value of PACs/h (below the top 5th percentile but above 30PACs/h) (EAEA+/-) and <30PACs/h (EAEA-). RESULTS: After adjusting for risk factors, laboratory findings and medication, EAEA+ was associated with ischemic stroke (hazard ratio [HR] 2.83; 95% confidence interval [CI], 1.65-4.84, p<0.001). Both EAEA+ and EAEA+/- were independently associated with AF (HR 2.05; 95% CI 1.31-3.23, p=0.010 for EAEA+ and HR 1.90; 95% CI 1.10-2.78, p=0.020 for EAEA+/-) and overall death (HR 2.17; 95% CI 1.48-3.28, p=0.031 for EAEA+; HR 2.01; 95% CI 1.06-2.52, p=0.029 for EAEA+/-). CONCLUSION: In this population, having >30PACs/h was independently associated with a higher risk of AF and overall death but only subjects with >97PACs/h had a higher risk of ischemic stroke. In the majority of subjects with stroke and EAEA+, AF has not been detected before stroke event. PMID- 28893431 TI - Pulse pressure amplification and its relationship with age in young, apparently healthy black and white adults: The African-PREDICT study. AB - BACKGROUND: Pulse pressure amplification (PPA), i.e. the amplification from central arteries to the periphery, is inversely related to arterial stiffness, organ damage and mortality. It is known that arterial stiffness is higher in black than white populations, but it is unclear if this is due to early vascular aging. We therefore investigated whether PPA declines earlier in young normotensive black South Africans, when compared to their white counterparts. METHODS: We included 875 black and white men and women from the African-PREDICT study (55% black, 41% men), aged 20-30years, with no prior diagnosis of chronic disease, screened for normotensive clinic blood pressure (BP). We determined supine central PP (cPP), and supine brachial systolic- and diastolic BP, from which brachial PP (bPP) was calculated. PPA was defined as the ratio of the amplitude of the PP between these distal and proximal locations (bPP/cPP). RESULTS: We found the mean PPA to be lower in black compared to white participants (1.43 vs. 1.46; P=0.013). In black adults PPA declined earlier with increasing age (P-trend<0.001), with a weak trend in whites (P=0.069) after adjustment for sex, socio-economic status, height, heart rate and mean arterial pressure. In multivariable-adjusted regression, we found an independent inverse association between PPA and age only in the black group (beta=-0.18, P=0.002). CONCLUSION: PPA declines earlier with age in normotensive black adults younger than 30years, exemplifying early vascular aging which may predispose black individuals to future cardiovascular outcomes. PMID- 28893432 TI - Effects of person-centred care after an event of acute coronary syndrome: Two year follow-up of a randomised controlled trial. AB - AIM: To assess the long-term effect of person-centred care (PCC) in patients with acute coronary syndrome (ACS). METHOD: Patients with ACS were randomly assigned to treatment as usual (control group) or an added PCC intervention for six months. The primary endpoint was a composite score of changes in general self efficacy>=five units, return to work or to a prior activity level and re hospitalisation or death. RESULTS: The composite score improved in the PCC intervention group (n=94) at a two-year follow-up compared with the control group (n=105) (18.1%, n=17 vs. 10.5%, n=11; P=0.127). In the per-protocol analysis (n=183) the improvement was significant in favour of the PCC intervention (n=78) compared with usual care (n=105) (21.8%, n=17 vs. 10.5%, n=11; P=0.039). This effect was driven by the finding that more patients in the PCC group improved their general self-efficacy score>=5units (32.2%, n=19 vs. 17.3%, n=14; P=0.046). The composite score improvement was significantly higher in the PCC intervention group without post-secondary education (n=33) in comparison with corresponding patients in the control group (n=50) (30.3%, n=10 vs. 10.0%, n=5; P=0.024). CONCLUSION: Implementation of PCC results in sustained improvements in health outcome in patients with ACS. PCC can be incorporated into conventional cardiac prevention programmes to improve equity in uptake and patient health outcomes. TRIAL REGISTRATION: Swedish registry, Researchweb.org, ID NR 65791. PMID- 28893433 TI - Effects of remote ischemic preconditioning in patients with concentric myocardial hypertrophy: A randomized, controlled trial with molecular insights. AB - BACKGROUND: Efficacy of remote ischemic preconditioning (RIPC) for cardioprotection in cardiac surgery is controversial. We aimed to evaluate the clinical and molecular effects of RIPC on the concentrically hypertrophied myocardium. METHODS: Seventy-two aortic stenosis patients receiving aortic valve replacement (AVR) under sevoflurane anesthesia were randomly allocated to RIPC (3cycles of 5-min inflation [300mmHg] and deflation on the left arm) or control (deflated cuff placement) group. The primary endpoints were 24-h area under the curve (AUC) for serum creatine kinase (CK)-MB and troponin (Tn)-T levels. The secondary endpoints were myocardial activation of cell signaling pathways, including reperfusion injury salvage kinases (RISK), signal transducer and activator of transcription (STAT), nitric oxide synthase (NOS), and apoptosis related molecules, obtained from right atrial tissue before and after cardiopulmonary bypass (CPB). RESULTS: There were no intergroup differences in 24 h AUCs of CK-MB and Tn-T. Phosphorylations of RISK pathway molecules were not enhanced by RIPC before and after CPB. Phosphorylation of STAT5 was significantly lower in the RIPC group before and after CPB. Phosphorylations of STAT3 and endothelial NOS were not enhanced by RIPC before and after CPB. Expression level of cleaved caspases-3/caspase-3 was significantly higher in the RIPC group before CPB. CONCLUSIONS: RIPC did not provide clinical benefits or activate protective signaling in patients with concentric left ventricular hypertrophy undergoing AVR. PMID- 28893434 TI - Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum. AB - Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs*42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum. PMID- 28893435 TI - Gradual bone transfer for the correction of the pubic diastasis using the Ilizarov technique in closure of bladder and cloacal exstrophy. AB - BACKGROUND: In the patient of the cloacal exstrophy, cloaca with local abdominal wall is disrupted and exposed inner surface of the bladder needs early closure. Pelvic osteotomies are required for severe cases whose bladder cannot be closed by the suture of soft tissue only. We developed a technique involving the gradual positioning of bone fragments using a light, Ilizarov external fixator. The usefulness of the technique was assessed. METHODS: We enrolled 3 patients with cloacal exstrophy and 1 with bladder exstrophy as a gradual transfer group and 6 patients who were treated by other osteotomies as a control group. The patients aged 6.7-8.4 months at the time of surgery were followed up for 4.0-8.6 years. An external fixator with carbon fiber half-rings was placed to internally rotate and anteriorly move the distal bone fragment over 2 weeks. Then, the bladder was closed. Computed tomography (CT) images were used to assess the pelvis form. Wound dehiscence and number of the surgeries after the osteotomies are also compared between the two groups. RESULTS: CT analysis of correction of the pelvic deformity achieved more and less decreasing its volumetric capacity in the gradual transfer group. No patients had wound dehiscence after the primary closure with pelvic osteotomy in the gradual transfer group but all had them in the control group. The mean number of the surgeries after the osteotomies were 2.25 in the gradual transfer group whereas 5.5 in the control group. CONCLUSIONS: Sufficient closure of the abdominal wall and bladder was achieved in all cases in the gradual transfer group. The correction of pelvic bones were more with less decreasing of their pelvic capacities, no patients had wound dehiscence after the closure and there was an effect to decrease the number of the surgeries after the treatment by this method. PMID- 28893436 TI - Death after 25C-NBOMe and 25H-NBOMe consumption. AB - A teenager male was found dead in a waterway after he was spotted jumping off into the water stream. The boy looked agitated and confused after a party with friends. At the gathering place, investigators seized packages of blotter papers. A complete autopsy and a histological evaluation of the main tissues were performed; although the death occurred by drowning, the prosecutor requested toxicological exams, in order to evaluate the potential role of drugs of abuse in the episode. Blood (both peripheral and central) and urine samples as well as seized blotter papers were collected and analyzed as follows. The blotter paper, analyzed through a GC-MS method, revealed the presence of 25-NBOMes. A liquid chromatography tandem mass spectrometric (LC-MS/MS) system was used to identify and quantify 5 different 25-NBOMes (namely 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25H NBOMe, 25I-NBOMe) in blood and urine. 25E-NBOMe was used as internal standard (IS). 1mL of urine and 1mL of blood (both peripheral and cardiac) were diluted in 2mL phosphate buffer at pH 6.0, containing IS and purified on a solid phase extraction (SPE) cartridge. LOD and LOQ for the five 25-NBOMes were calculated at 0.05 and 0.1ng/mL respectively. Linearity, accuracy, precision, ion suppression, carry over and recovery were tested and all parameters fulfilled the acceptance criteria. Blood and urine provided positive results for 25C-NBOMe and 25H-NBOMe. Eventually, the seized blotter papers were analyzed by means of LC-MS/MS and the presence of the two NBOMes was confirmed: 25C-NBOMe and 25H-NBOMe were measured at the concentration of 2.80 and 0.29ng/mL in peripheral blood, of 1.43 and 0.13ng/mL in central blood and of 0.94 and 0.14ng/mL in urine, respectively. THC and THCCOOH were also detected in biological fluids, at the concentration of 15.5 and 56.0ng/mL in peripheral blood, 9.9 and 8.5ng/mL in central blood, respectively. NBOMes can produce severe hallucination even at very low doses, and the 25C-NBOMe levels measured in the subject's blood are considered potentially toxic. PMID- 28893437 TI - Functional trade-offs in the aquatic feeding performance of salamanders. AB - During aquatic feeding salamanders use the hyobranchial apparatus to capture prey. The hyobranchial apparatus depresses the floor of the mouth, effectively expanding the oropharyngeal cavity and generating suction. Within the family Salamandridae, there is a wide range of ecological diversity, with salamanders being terrestrial, semi-aquatic, or aquatic as adults. The purpose of this research was to quantify the diverse morphology and suction feeding performance of aquatically feeding salamandrids. We hypothesized that a more robust hyobranchial apparatus morphology would yield increased aquatic feeding performance. When compared to semi-aquatic newts, the fully aquatic species Paramesotriton labiatus had greater mineralization of the hyobranchial apparatus, as well as relatively more narrow basibranchial and wider ceratobranchial I+II complexes. These morphological differences coincide with greater aquatic feeding performance. Kinematics from high-speed videography revealed that maximum mouth opening velocity and acceleration were approximately two and five times greater, respectively, in Paramesotriton, and hyobranchial depression acceleration was found to be approximately three times greater than in the semi-aquatic species Pleurodeles waltl, Notophthalmus viridescens, Triturus dobrogicus, and Cynops cyanurus. Using digital particle image velocimetry, peak and average fluid velocity generated in Paramesotriton during suction feeding events were found to be 0.5ms-1 and 0.2ms-1, respectively, doubling that of all semi-aquatic species. These findings reveal that specialized morphology increases aquatic feeding performance in a fully aquatic newt. PMID- 28893438 TI - Diplopia secondary to orbital fracture in adults. AB - OBJECTIVE: To evaluate the incidence and evolution of diplopia as a complication of orbital fractures in adults. PATIENTS AND METHODS: A review was conducted on medical records of all consecutive adults with orbital fracture referred between January 2014 and December 2015. An analysis was made of the incidence of diplopia secondary to fracture in the acute phase and its evolution. A descriptive study was performed on the variables related to patients, fractures, and fracture and diplopia treatment. RESULTS: The study included 39patients with a mean age of 48years (17-85). Of all the patients, 17 (43.6%) presented with diplopia in the acute phase. Differences were found between the groups with and without diplopia in relation to muscle entrapment diagnosed by orbital computed tomography, duction limitation, and fracture surgery <=1week (P=.02, P=.00, P=.04, respectively). Out of the 17patients with diplopia, 12 had a mean follow-up of 18weeks (1-72), and in 10 (83.3%) diplopia was resolved in a mean time of 10weeks (1-72). There were spontaneous resolution in 4 (33.3%) patients, and resolution after fracture surgery in 4 (57%) of the 7 that underwent surgery. In 4cases (33.3%) prisms were prescribed, and 2 (16.6%) required strabismus surgery. CONCLUSIONS: Diplopia secondary to orbital fracture in adults is frequent, but it is resolved in most cases spontaneously or after fracture surgery. A few patients will require prisms and/or strabismus surgery. PMID- 28893439 TI - Re: "Safety and long-term efficacy of fractional CO2 laser treatment in women suffering from genitourinary syndrome of menopause" [Eur. J. Obstet. Gynecol. Reprod. Biol. 213 (2017) 39-44]. PMID- 28893440 TI - Fluid resuscitation of patients with severe infection in Uganda: less is more. PMID- 28893441 TI - Response to 'Code ICU - A great opportunity for patients and critical care management'. PMID- 28893443 TI - Isolation and identification of human coronavirus 229E from frequently touched environmental surfaces of a university classroom that is cleaned daily. AB - Frequently touched surfaces of a university classroom that is cleaned daily contained viable human coronavirus 229E (CoV-229E). Tests of a CoV-229E laboratory strain under conditions that simulated the ambient light, temperature, and relative humidity conditions of the classroom revealed that some of the virus remained viable on various surfaces for 7 days, suggesting CoV-229E is relatively stable in the environment. Our findings reinforce the notion that contact transmission may be possible for this virus. PMID- 28893442 TI - Meta-analyses on Vitamin D in critically ill patients: What data can tell us. PMID- 28893444 TI - Evaluation of surgical glove integrity and factors associated with glove defect. AB - BACKGROUND: Surgical glove perforation may expose both patients and staff members to severe complications. This study aimed to determine surgical glove perforation rate and the factors associated with glove defect. MATERIAL AND METHODS: This descriptive cross-sectional study was conducted between January and March 2017 at a Tunisian university hospital center in 3 different surgical departments: urology, maxillofacial, and general and digestive. The gloves were collected and tested to detect perforations using the water-leak test as described in European Norm NF EN 455-1. For percentage comparisons, the chi2 test was used with a significance threshold of 5%. RESULTS: A total of 284 gloves were collected. Of these, 47 were found to be perforated, a rate of 16.5%. All perforations were unnoticed by the surgical team members. The majority of perforated gloves (61.7%) were collected after urology procedures (P = .00005), 77% of perforated gloves were detected when the duration of the procedure exceeded 90 minutes (P = .001), and 96% were from brand A, which were the thicker gloves (P = .015). CONCLUSIONS: This study highlighted an important problem neglected by surgical teams. The findings reaffirm the importance of double-gloving and changing gloves in surgeries of more than 90 minutes' duration. PMID- 28893445 TI - Cost-benefit analysis of different air change rates in an operating room environment. AB - BACKGROUND: Hospitals face growing pressure to meet the dual but often competing goals of providing a safe environment while controlling operating costs. Evidence based data are needed to provide insight for facility management practices to support these goals. METHODS: The quality of the air in 3 operating rooms was measured at different ventilation rates. The energy cost to provide the heating, ventilation, and air conditioning to the rooms was estimated to provide a cost benefit comparison of the effectiveness of different ventilation rates currently used in the health care industry. RESULTS: Simply increasing air change rates in the operating rooms tested did not necessarily provide an overall cleaner environment, but did substantially increase energy consumption and costs. Additionally, and unexpectedly, significant differences in microbial load and air velocity were detected between the sterile fields and back instrument tables. CONCLUSIONS: Increasing the ventilation rates in operating rooms in an effort to improve clinical outcomes and potentially reduce surgical site infections does not necessarily provide cleaner air, but does typically increase operating costs. Efficient distribution or management of the air can improve quality indicators and potentially reduce the number of air changes required. Measurable environmental quality indicators could be used in lieu of or in addition to air change rate requirements to optimize cost and quality for an operating room and other critical environments. PMID- 28893446 TI - Use of an annual art competition to promote Web site traffic and engage children in antimicrobial stewardship in Pennsylvania. AB - We used Google Analytics to assess whether annual kids' art competitions changed traffic to a Web site on appropriate antibiotic use. We found that announcements about kids' art competitions correlated with increased traffic to the Web site, suggesting that this innovation has promise in promoting antimicrobial stewardship efforts. PMID- 28893447 TI - Control of multidrug-resistant Acinetobacter baumannii in Hong Kong: Role of environmental surveillance in communal areas after a hospital outbreak. AB - BACKGROUND: Environmental reservoir is an important source of multidrug-resistant Acinetobacter baumannii (MRAB) outbreaks. The role of postoutbreak environmental surveillance for guiding sustained infection control effort has not been examined. METHODS: Enhanced environmental disinfection and regular environmental surveillance of ward communal areas after an outbreak were performed in a university-affiliated hospital. To assess the usefulness of environmental culture in predicting patients with MRAB, weekly surveillance of communal areas was continued for 3 months after the outbreak in intervention wards. The incidence of MRAB in intervention and nonintervention wards (control) was compared, whereas the other infection control measures remained identical. RESULTS: Postoutbreak weekly surveillance of communal areas showed that identification of newly diagnosed MRAB patients was significantly correlated with preceding environmental contamination with MRAB (P = .001). The incidence of nosocomial MRAB infection was significantly lower in the intervention compared with nonintervention wards (0.55 vs 2.28 per 1,000 patient days, respectively; P = .04). All MRAB isolated from the environmental and patients' samples belonged to multilocus sequence typing ST457 and were blaOXA23-like positive. CONCLUSIONS: Environmental surveillance may serve as a surrogate marker for the presence of MRAB carriers. Implementation of timely infection control measures should be guided by environmental culture for MRAB to minimize the risk of MRAB outbreak. PMID- 28893448 TI - Knowledge, attitude, and practice of Iranian health sciences students regarding hepatitis B and C virus infections: A national survey. AB - BACKGROUND: The World Health Organization seeks to achieve the goal of viral hepatitis elimination by 2030 and lack of general knowledge about viral hepatitis seems to be a barrier to reaching this goal. This study was designed to evaluate the knowledge, attitude, and practice (KAP) regarding hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among Iranian health sciences students in 12 Iranian medical sciences universities using a national survey. METHODS: This survey was conducted during the second Hepatitis Awareness Campaign, which was held during the Iranian National Hepatitis Week (October 22-28, 2016). Students who visited our booths and were willing to participate in our survey were selected using convenience sampling and their HBV- and HCV-related KAP were evaluated. RESULTS: Two thousand one hundred fifty-six health sciences students with mean age of 21.24 years participated in our survey. The mean KAP scores were 7.35 (out of 10), 4.88 (possible score, -20 to +20), and 5.67 (out of 9). Students with experience of accidental exposures to blood (21.6%) had better KAP scores compared with the students without such experiences. The mean KAP scores were associated with subjects' year of education, field of study, university, and province (P < .05). CONCLUSIONS: Our study showed that HBV- and HCV-related KAP in a sample of Iranian health sciences students was not satisfying. The results also demonstrated priority of needing intervention regarding KAP in some subject areas, lower years of education, and some universities compared with others. PMID- 28893449 TI - Successful control of 2 simultaneous outbreaks of OXA-48 carbapenemase-producing Enterobacteriaceae and multidrug-resistant Acinetobacter baumannii in an intensive care unit. AB - BACKGROUND: This report describes a double outbreak of OXA-48-producing Enterobacteriaceae (OXA-48-PE) and multidrug-resistant Acinetobacter baumannii (MRAB) in an intensive care unit (ICU) and the effectiveness of measures implemented, including decontamination with vaporized hydrogen peroxide (VHP). METHODS: Affected patients were isolated in a confined area and cared for by dedicated personnel. Four percent chlorhexidine soap was used for patient daily hygiene. All patients are subjected to contact precautions. An in-depth cleaning of the ICU was performed with a chlorine solution, followed by decontamination with VHP. Environmental samples were taken before and after the decontamination. RESULTS: From July-October 2015, 13 patients were colonized or infected by OXA-48 PE and 18 by MRAB in the ICU. The cumulative incidence of OXA-48-PE and MRAB was 3.48% and 4.81%, respectively. In the period after the intervention, they were 0.8% and 0%, respectively (P < .001). Before the VHP biodecontamination, 4.5% of environmental samples were positive for OXA-48-PE and none for MRAB. After biodecontamination, 1.4% of samples were positive for OXA-48-PE. CONCLUSIONS: This study emphasizes the importance of environmental hygiene in the control of outbreaks caused by microorganisms of high environmental impact. The rapid effect after the VHP treatment suggests an influence of this measure in eradication. PMID- 28893450 TI - Emergency medicine evaluation and management of the end stage renal disease patient. AB - BACKGROUND: End stage renal disease (ESRD) is increasing in the U.S., and these patients demonstrate greater all-cause mortality, cardiovascular events, and hospitalization rates when compared to those with normal renal function. These patients may experience significant complications associated with loss of renal function and dialysis. OBJECTIVE: This review evaluates complications of ESRD including cardiopulmonary, neurologic, infectious disease, vascular, and access site complications, as well as medication use in this population. DISCUSSION: ESRD incidence is rapidly increasing, and patients commonly require renal replacement therapy including hemodialysis (HDS) or peritoneal dialysis (PD), each type with specific features. These patients possess greater risk of neurologic complications, cardiopulmonary pathology, infection, and access site complications. Focused history and physical examination are essential. Neurologic issues include uremic encephalopathy, cerebrovascular pathology, and several others. Cardiopulmonary complications include pericarditis, pericardial effusion/tamponade, acute coronary syndrome, sudden cardiac death, electrolyte abnormalities, pulmonary edema, and air embolism. Infections are common, with patients more commonly presenting in atypical fashion. Access site infections and metastatic infections must be treated aggressively. Access site complications include bleeding, aneurysm/pseudoaneurysm, thrombosis/stenosis, and arterial steal syndrome. Specific medication considerations are required for analgesics, sedatives, neuromuscular blocking agents, antimicrobials, and anticoagulants. CONCLUSIONS: Consideration of renal physiology with complications in ESRD can assist emergency providers in the evaluation and management of these patients. ESRD affects many organ systems, and specific pharmacologic considerations are required. PMID- 28893451 TI - Battlefield to bedside: Translating wartime innovations to civilian Emergency Medicine. PMID- 28893452 TI - Assessing the use of composts from multiple sources based on the characteristics of carbon mineralization in soil. AB - In order to improve soil quality, reduce wastes and mitigate climate change, it is necessary to understand the balance between soil organic carbon (SOC) accumulation and depletion under different organic waste compost amended soils. The effects of proportion (5%, 15%, 30%), compost type (sewage sludge (SS), tomato stem waste (TSW), municipal solid waste (MSW), kitchen waste (KW), cabbage waste (CW), peat (P), chicken manure (CM), dairy cattle manure (DCM)) and the black soil (CK). Their initial biochemical composition (carbon, nitrogen, C:N ratio) on carbon (C) mineralization in soil amended compost have been investigated. The CO2-C production of different treatments were measured to indicate the levels of carbon (C) mineralization during 50d of laboratory incubation. And the one order E model (M1E) was used to quantify C mineralization kinetics. The results demonstrated that the respiration and C mineralization of soil were promoted by amending composts. The C mineralization ability increased when the percentage of compost added to the soil also increased and affected by compost type in the order CM>KW, CW>SS, DCM, TSW>MSW, P>CK at the same amended level. Based on the values of C0 and k1 from M1E model, a management method in agronomic application of compost products to the precise fertilization was proposed. The SS, DCM and TSW composts were more suitable in supplying fertilizer to the plant. Otherwise, The P and MSW composts can serve the purpose of long term nutrient retention, whereas the CW and KW composts could be used as soil remediation agent. PMID- 28893453 TI - Corrigendum to "Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension" [J Hepatol 62 (2015) 325-331]. PMID- 28893454 TI - Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration: Results with Ranibizumab from the TREND Study. AB - PURPOSE: To evaluate the efficacy and safety of ranibizumab 0.5 mg treat-and extend (T&E) versus monthly regimens in patients with neovascular age-related macular degeneration (nAMD) from the TReat and extEND (TREND) study. DESIGN: A 12 month phase 3b visual acuity (VA) assessor-masked, multicenter, randomized, interventional study. PARTICIPANTS: Six hundred fifty patients. METHODS: Treatment-naive nAMD patients (age, >=50 years) were randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n = 323) or monthly (n = 327) regimen. MAIN OUTCOMES MEASURES: The primary objective was to show noninferiority of ranibizumab 0.5 mg T&E versus monthly regimen, as assessed by the change in best corrected VA (BCVA) from baseline to the end of the study. Secondary objectives included change in retinal central subfield thickness (CSFT) from baseline to the end of study, treatment exposure, and safety. RESULTS: Overall, 89.8% (T&E) and 90.2% (monthly) of patients completed the study. Patient demographic and baseline characteristics were well balanced between the 2 treatment groups. The T&E regimen was noninferior (P < 0.001) to the monthly regimen, with a least squares mean BCVA change from baseline of 6.2 versus 8.1 letters to the end of study, respectively. In both treatment groups, most BCVA improvements occurred during the first 6 months and were maintained until the end of the study. The mean change in CSFT from baseline to the end of study was -169.2 MUm and -173.3 MUm in the T&E and monthly groups, respectively. Fewer injections were required in patients receiving the T&E (8.7) versus monthly (11.1) regimen, with mean number of postbaseline visits of 8.9 and 11.2, respectively. Types and rates of adverse events were comparable between the treatment groups. CONCLUSIONS: Ranibizumab 0.5 mg administered according to a T&E regimen was statistically noninferior and clinically comparable with a monthly regimen in improving VA from baseline to the end of study. No new safety signals for ranibizumab were identified. PMID- 28893455 TI - 'Enjoying the kick': Locating pleasure within the drug consumption room. AB - BACKGROUND: Harm reduction policy and praxis has long struggled to accommodate the pleasures of alcohol and other drug use. Whilst scholars have consistently highlighted this struggle, how pleasure might come to practically inform the design and delivery of harm reduction policies and programs remains less clear. The present paper seeks to move beyond conceptual critiques of harm reduction's 'pleasure oversight' to more focused empirical analysis of how flows of pleasure emerge, circulate and, importantly, may be reoriented in the course of harm reduction practice. METHODS: We ground our analysis in the context of detailed ethnographic research in a drug consumption room in Frankfurt, Germany. Drawing on recent strands of post-humanist thought, the paper deploys the concept of the 'consumption event' to uncover the manner in which these facilities mediate the practice and embodied experience of drug use and incite or limit bodily potentials for intoxication and pleasure. RESULTS: Through the analysis, we mapped a diversity of pleasures as they emerged and circulated through events of consumption at the consumption room. Beyond the pleasurable intensities of intoxication's kick, these pleasures were expressed in a range of novel capacities, practices and drug using bodies. In each instance, pleasure could not be reduced to a simple, linear product of drug use. Rather, it arose for our participants through distinctive social and affective transformations enabled through events of consumption at the consumption room and the generative force of actors and associations of which these events were composed. CONCLUSION: Our research suggests that the drug consumption room serves as a conduit through which its clients can potentially enact more pleasurable, productive and positive relations to both themselves and their drug use. Acknowledging the centrality of pleasure to client engagement with these facilities, the paper concludes by drawing out the implications of these findings for the design and delivery of consumption room services. PMID- 28893456 TI - [Rare causes of childhood leukocoria]. AB - PURPOSE: The purpose was to record the causes of leukocoria among children under 10years of age and to determine the proportion of rare causes of leukocoria. PATIENTS AND METHODS: This retrospective study was conducted over a period of ten years, from January 1, 2004 to December 31, 2013, in patients under 10years of age who were referred for leukocoria. RESULTS: Leukocoria represented one of the ten reasons for consultation among children under 10years of age. The mean age of our patients was 42.5months. In 76 % of cases, the leukocoria patients were children under 6years of age. Male patients were affected more commonly, with a sex-ratio of 1.5. Patients coming from Dakar and its suburbs represented two thirds of the total. Bilateral involvement represented 53.7 % of the total. Cataracts were responsible for 74.3 % of cases, retinoblastoma 20.58 %, retinal detachment 0.96 %, retinopathy of prematurity 0.96 %, pupillary membrane persistence 0.96 %, persistent hyperplastic primary vitreous 0.64 %, endophthalmitis 0.64 %, optic nerve coloboma 0.32 %, iris heterochromia 0.32 % and ametropia 0.32 %. DISCUSSION: The total percentage of rare causes was 5.12 % in our study, including one case of hyperopia. These etiologies, although rare, do exist. CONCLUSION: Rare causes of leukocoria require special attention. The discovery of leukocoria necessitates rigorous etiological work-up. Ametropia must be a diagnosis of exclusion. PMID- 28893458 TI - [Retinal arteriovenous malformation without visual impairment]. PMID- 28893457 TI - [Treatment of choroidal noevascularization secondary to angioid streaks with bevacizumab and response: Experience of the ophthalmology department of Hassan II university hospital]. AB - PURPOSE: To evaluate the efficacy of intravitreal bevacizumab in the treatment of choroidal neovascularization (CNV) secondary to angioid streaks. METHODS: We conducted a prospective study in the ophthalmology department of Hassan II university hospital in Fez, including 12 eyes of 7 patients with CNV associated with angioid streaks. We injected 8 eyes with bevacizumab 1.25mg; best corrected visual acuity (BCVA), fundus examination, fluorescein angiography and optical coherence tomography were performed and analyzed for all patients before and after treatment. The goal of the study was to determine the percentage of patients with stabilization or improvement in BCVA and decreased central macular thickness. RESULTS: Visual acuity on admission was <1/10 in 75% of patients. We injected 8 eyes with anti-VEGF, whereas abstention was appropriate for 4 eyes with disciform scarring. The average number of bevacizumab injections was 4.3+/ 1.3 over a mean follow-up of 14.57 months+/-5.3. After treatment, BCVA was <1/10 in 12.5% of cases, between 1/10 and 5/10 in 50% of cases, and in 37.5% of patients, it was >=5/10. Mean central macular thickness decreased from 424.25+/ 137.03MUm on admission to 255.75 microns+/-50.14 post-treatment (P=0.005). CONCLUSION: Intravitreal bevacizumab is a promising and effective treatment option for the management of CNV associated with angioid streaks, with the requirement however of early treatment and extended follow-up. PMID- 28893459 TI - Placing the patient at the centre of chronic wound care: A qualitative evidence synthesis. AB - BACKGROUND: Chronic wounds are a major health burden and have a severe impact on well-being. This synthesis of qualitative studies was undertaken to inform a health technology assessment of antimicrobial wound dressings. It aimed to explore patients' experiences of chronic wounds and determine improvements for clinical practice. METHOD: Inclusion criteria included use of qualitative methods, and English language publication. Databases searched included MEDLINE (Ovid), MEDLINE in Process (Ovid), EMBASE (Ovid), CINAHL (EBSCOHost), and PsychInfo (EBSCOHost). Searches were limited to 1990-2014. The method of analysis was Framework synthesis. RESULTS: A total of 20 studies were included. The synthesis confirmed the severe physical, social and psychological impact of the chronic wound. Inadequately controlled pain and sleeplessness, restrictions to lifestyle, and the loss of previous life roles can lead to feelings of hopelessness and helplessness and therefore depression and anxiety. Dressings and dressing changes are a key aspect of treatment and provide opportunities for positive interaction and person centred-care. CONCLUSION: People with chronic wounds can be supported to live well within the severe physical, psychological and social restrictions of a chronic wound. Effective clinical pain management and the recognition of the experience of acute and chronic pain are of the utmost importance to people with a chronic wound. Treatment should not be purely focused on healing but incorporate symptom management, coping and wellbeing via person centred and holistic care. PMID- 28893461 TI - Nuclear Lamins: Thin Filaments with Major Functions. AB - The nuclear lamina is a nuclear peripheral meshwork that is mainly composed of nuclear lamins, although a small fraction of lamins also localizes throughout the nucleoplasm. Lamins are classified as type V intermediate filament (IF) proteins. Mutations in lamin genes cause at least 15 distinct human diseases, collectively termed laminopathies, including muscle, metabolic, and neuronal diseases, and can cause accelerated aging. Most of these mutations are in the LMNA gene encoding A type lamins. A growing number of nuclear proteins are known to bind lamins and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, signaling, gene regulation, genome stability, and cell differentiation. Recent studies reveal the organization of the lamin filament meshwork in somatic cells where they assemble as tetramers in cross section of the filaments. PMID- 28893463 TI - WITHDRAWN: Author's Response. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28893460 TI - Stress-Activated Chaperones: A First Line of Defense. AB - Proteins are constantly challenged by environmental stress conditions that threaten their structure and function. Especially problematic are oxidative, acid, and severe heat stress which induce very rapid and widespread protein unfolding and generate conditions that make canonical chaperones and/or transcriptional responses inadequate to protect the proteome. We review here recent advances in identifying and characterizing stress-activated chaperones which are inactive under non-stress conditions but become potent chaperones under specific protein-unfolding stress conditions. We discuss the post-translational mechanisms by which these chaperones sense stress, and consider the role that intrinsic disorder plays in their regulation and function. We examine their physiological roles under both non-stress and stress conditions, their integration into the cellular proteostasis network, and their potential as novel therapeutic targets. PMID- 28893462 TI - Developing drugs in cancer-related bone pain. AB - INTRODUCTION: Cancer-related bone pain is a frequent and important key problem for metastatic patients that may reduce quality of life, with related limitations in daily activities and morbidity. Often traditional approach to pain may fail given the complex pathophysiology of this phenomenon. METHODS: The aim of this review is to describe promising therapies for cancer-related bone pain, from the pathophysiology to the clinical trials currently ongoing. Moreover, any new evidence for better approach to cancer-related bone pain with the traditional drugs is also considered. CONCLUSIONS: In clinical practice opioids remain the most important pharmacologic treatment for severe pain related to bone cancer. Regard developing drugs, anti-NGF and anti-TrkA are the most investigated new drug in this setting, but a future role in clinical practice is still uncertain. PMID- 28893464 TI - A Pilot Randomized Controlled Trial of Novel Dressing and Securement Techniques in 101 Pediatric Patients. AB - PURPOSE: To evaluate feasibility of an efficacy trial comparing peripherally inserted central catheter (PICC) dressing and securement techniques to prevent complications and failure. MATERIALS AND METHODS: This pilot, 3-armed, randomized controlled trial was undertaken at Royal Children's Hospital and Lady Cilento Children's Hospital, Brisbane, Australia, between April 2014 and September 2015. Pediatric participants (N = 101; age range, 0-18 y) were assigned to standard care (bordered polyurethane [BPU] dressing, sutureless securement device), tissue adhesive (TA) (plus BPU dressing), or integrated securement dressings (ISDs). Average PICC dwell time was 8.1 days (range, 0.2-27.7 d). Primary outcome was trial feasibility including PICC failure. Secondary outcomes were PICC complications, dressing performance, and parent and staff satisfaction. RESULTS: Protocol feasibility was established. PICC failure was 6% (2/32) with standard care, 6% (2/31) with ISD, and 3% (1/32) with TA. PICC complications were 16% across all groups. TA provided immediate postoperative hemostasis, prolonging the first dressing change until 5.5 days compared with 3.5 days and 2.5 days with standard care and ISD respectively. Bleeding was the most common reason for first dressing change: standard care (n = 18; 75%), ISD (n = 11; 69%), TA (n = 4; 27%). Parental satisfaction (median 9.7/10; P = .006) and staff feedback (9.2/10; P = .002) were most positive for ISD. CONCLUSIONS: This research suggests safety and acceptability of different securement dressings compared with standard care; securement dressings may also reduce dressing changes after insertion. Further research is required to confirm clinically cost-effective methods to prevent PICC failure. PMID- 28893465 TI - Recurrent Benign Urethral Strictures Treated with Covered Retrievable Self Expandable Metallic Stents: Long-Term Outcomes over an 18-Year Period. AB - PURPOSE: To assess the long-term outcomes of covered retrievable self-expandable metallic stent (REMS) placement for recurrent benign urethral stricture and to compare the outcomes associated with 3 types of covered REMSs. MATERIALS AND METHODS: A retrospective study was performed in 54 male patients in whom 114 REMSs were placed between November 1998 and December 2016. These included 26 polyurethane-covered REMSs in 13 patients (group A), 47 internally polytetrafluoroethylene (PTFE)-covered REMSs in 21 patients (group B), and 41 externally PTFE-covered REMSs in 20 patients (group C). The outcomes were analyzed and compared between the groups. RESULTS: Overall clinical success was achieved in 14 of the 54 patients (24%) at 5-year follow-up (group A, 12%; group B, 19%; group C, 40%). The overall complication rate was 60.5%, and the complication rate was significantly higher in group B than in groups A or C (group A vs B, P = .018; group B vs C, P = .002). The median stent indwelling time and maintained patency period were 3.1 months and 108 months, respectively. In multivariate analysis, stent indwelling time was the only significant factor associated with maintained patency. CONCLUSIONS: The long-term outcome of covered REMSs has not achieved the desired success rate for the standard treatment of recurrent urethral stricture. However, externally PTFE-covered REMSs showed a better long-term outcome than the other studied types. PMID- 28893467 TI - Controversies in Oral and Maxillofacial Pathology. AB - Several benign pathologic entities that are commonly encountered by the oral and maxillofacial surgeon remain controversial. From etiology to treatment, no consensus exists in the literature regarding the best treatment of benign lesions, such as the keratocystic odontogenic tumor, giant cell lesion, or ameloblastoma. Given the need for often-morbid treatment to prevent recurrence of these lesions, multiple less-invasive treatments exist in the literature for each entity with little agreement. As the molecular and genomic pathogenesis of these lesions are better understood, directed treatments will hopefully lessen the contention in management. PMID- 28893466 TI - Physical Activity Dose for Hemodialysis Patients: Where to Begin? Results from a Prospective Cohort Study. AB - OBJECTIVE: Greater physical activity is associated with lower risk of mortality in persons with kidney disease; however, little is known about the appropriate dose of physical activity among hemodialysis patients. Here detected the minimum level of habitual physical activity to help inform interventions aimed at improving outcomes in the dialysis population. DESIGN: The design was prospective cohort study. SUBJECTS: Clinically stable outpatients in a hemodialysis unit from October 2002 to March 2014 were assessed for their eligibility to be included in this 7-year prospective cohort study. We used the Youden index to determine the optimal cutoff points for physical activity. The prognostic effect of physical activity on survival was estimated by Cox proportional hazards regression analysis. The number of steps per nondialysis day was recorded by accelerometer at study entry. MAIN OUTCOME MEASURE: The main outcome measure was all-cause mortality. RESULTS: There were 282 participants who had a mean age of 65 +/- 11 years and 45% were female. A total of 56 deaths occurred during the follow-up period (56 months [interquartile range: 29-84 months]). The cutoff value for the physical activity discriminating those at high risk of mortality was 3,752 steps. After adjustment for the effect of confounders, the hazard ratio in the group of <4,000 steps was 2.37 (95% confidence interval: 1.22-4.60, P = .01) compared with the others. CONCLUSIONS: Engaging in physical activity is associated with decreased mortality risk among hemodialysis patients. Our findings of a substantial mortality benefit among those who engage in at least 4,000 steps provide a basis for as a minimum initial recommendation kidney health providers can provide for mobility disability-free hemodialysis patients. PMID- 28893468 TI - Chinese Herbal Medicine for Osteoporosis: A Meta-analysis of Randomized Controlled Trials. AB - Osteoporosis is a major public health problem in the elderly population. Several studies have suggested that Chinese herbal medicine has antiosteoporotic activities that might be beneficial for osteoporosis. This study aimed to assess the effectiveness of Chinese herbal medicine in osteoporosis patients. We comprehensively searched for randomized controlled trials (until December 2016) that compared Chinese herbal medicine with Western medicine in adults with osteoporosis and reported bone mineral densities (BMDs). A total of 10 randomized controlled trials were included. The pooled results suggested that the increased spine BMD was lower but not significant in the Chinese herbal medicine group than in the Western drug group (standard mean difference [SMD] = -0.11, 95% confidence interval [CI]: -0.62 to 0.39, p > 0.05). In the subgroup analysis, in postmenopausal women, Chinese herbal medicine also showed a insignificantly higher increment in BMD than the control group (SMD = 0.22, 95% CI: -0.00 to 0.43, p = 0.05). For different treatment durations, subgroups over 6 mo (SMD = 0.09, 95% CI: -0.24 to 0.41, p > 0.05) and less than 6 mo (SMD = -0.25, 95% CI: 1.14 to 0.64, p > 0.05) showed comparable BMDs between the 2 therapies. Our study demonstrated that Chinese herbal medicine alone did not significantly increase lumbar spine BMD. Further studies with better adherence to the intervention are needed to confirm the results of this meta-analysis. PMID- 28893469 TI - 68Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing tumors. AB - Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with 68Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with 68Ga in 95+/-2% yield, as evidenced by HPLC characterization. The logP value of 68Ga-NOTA-Erlotinib was - (0.6+/-0.1). The 68Ga-NOTA-Erlotinib conjugate was characterized using its natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, 68Ga-NOTA Erlotinib exhibited an uptake of 9.8+/-0.4% in A431 cells which was inhibited by 55.1+/-0.2% on addition of cold Erlotinib (10ug) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, 68Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5+/-0.1% ID/g at 30minp.i.; 0.7+/-0.2% ID/g at 1hp.i.). Hepatobiliary clearance of the radioconjugate was observed. The 68Ga NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of 68Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a 68Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of 68Ga labeled TKI for imaging of EGFR over-expressing tumors. PMID- 28893471 TI - Illness perceptions and negative responses from medical professionals in patients with fibromyalgia: Association with patient satisfaction and number of hospital visits. AB - OBJECTIVE: To examine whether illness perceptions among patients with fibromyalgia and negative responses from medical professionals correlate with their satisfaction with their physicians or with their number of hospital visits. METHODS: Questionnaires were sent by post to members of the Japan Fibromyalgia Support Association. Measures collected included, as independent variables, the Brief Illness Perception Questionnaire and the Illness Invalidation Inventory; and as outcomes, the Patient Satisfaction Consultation Questionnaire and the number of hospital visits. RESULTS: We analyzed data from 304 patients. Multiple logistic regressions showed that perception of poor treatment control and the experience of being discounted and misunderstood by medical professionals were strongly correlated with dissatisfaction with attending physicians. Patients who perceived poor treatment control visited the hospital fewer times, while patients who reported being discounted by medical professionals visited more times. Patients' negative emotions correlated neither with patient satisfaction nor with the number of hospital visits. CONCLUSION: Treatment effectiveness and the respect accorded to patients were the key factors significantly correlated both with patient satisfaction and the number of hospital visits. PRACTICE IMPLICATIONS: Physicians should not emphasize only patients' negative psychological status but also should convey a respectful attitude and help patients understand their current treatment is useful. PMID- 28893470 TI - Elucidation of antimicrobial activity and mechanism of action by N-substituted carbazole derivatives. AB - Compounds belonging to a carbazole series have been identified as potent fungal plasma membrane proton adenosine triphophatase (H+-ATPase) inhibitors with a broad spectrum of antifungal activity. The carbazole compounds inhibit the adenosine triphosphate (ATP) hydrolysis activity of the essential fungal H+ ATPase, thereby functionally inhibiting the extrusion of protons and extracellular acidification, processes that are responsible for maintaining high plasma membrane potential. The compound class binds to and inhibits the H+-ATPase within minutes, leading to fungal death after 1-3h of compound exposure in vitro. The tested compounds are not selective for the fungal H+-ATPase, exhibiting an overlap of inhibitory activity with the mammalian protein family of P-type ATPases; the sarco(endo)plasmic reticulum calcium ATPase (Ca2+-ATPase) and the sodium potassium ATPase (Na+,K+-ATPase). The ion transport in the P-type ATPases is energized by the conversion of ATP to adenosine diphosphate (ADP) and phosphate and a general inhibitory mechanism mediated by the carbazole derivative could therefore be blocking of the active site. However, biochemical studies show that increased concentrations of ATP do not change the inhibitory activity of the carbazoles suggesting they act as allosteric inhibitors. Furthermore decreased levels of intracellular ATP would suggest that the compounds inhibit the H+ ATPase indirectly, but Candida albicans cells exposed to potent H+-ATPase inhibitory carbazoles result in increased levels of intracellular ATP, indicating direct inhibition of H+-ATPase. PMID- 28893472 TI - Canadian school-based HPV vaccine programs and policy considerations. AB - BACKGROUND: The National Advisory Committee on Immunization in Canada recommends human papillomavirus (HPV) vaccination for females and males (ages 9-26). In Canada, the HPV vaccine is predominantly administered through publicly funded school-based programs in provinces and territories. This research provides an overview of Canadian provincial and territorial school-based HPV vaccination program administration and vaccination rates, and identifies foreseeable policy considerations. METHODS: We searched the academic and grey literature and contacted administrators of provincial and territorial vaccination programs to compile information regarding HPV vaccine program administration and vaccination rates in Canada's 13 provincial and territorial jurisdictions. RESULTS: As of October 2016, all 13 Canadian jurisdictions vaccinate girls, and six jurisdictions include boys in school-based publicly funded HPV vaccination programs. Eleven jurisdictions administer the HPV vaccine in a two-dose schedule. The quadrivalent vaccine (HPV4) has been the vaccine predominantly used in Canada; however, the majority of provinces will likely adopt the nonavalent vaccine in the future. According to available data, vaccination uptake among females ranged between 46.7% and 93.9%, while vaccination uptake among males (in programs with available data to date) ranged between 75.0% and 87.4%. CONCLUSIONS: Future research and innovation will beneficially inform Canadian jurisdictions when considering whether to administer the nonavalent vaccine, whether to implement a two or one-dose vaccination schedule, and how to improve uptake and rates of completion. The usefulness of standardizing methodologies for collecting and reporting HPV vaccination coverage and implementing a national registry were identified as important priorities. PMID- 28893473 TI - Data and product needs for influenza immunization programs in low- and middle income countries: Rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines. AB - In 2017, WHO convened a working group of global experts to develop the Preferred Product Characteristics (PPC) for Next-Generation Influenza Vaccines. PPCs are intended to encourage innovation in vaccine development. They describe WHO preferences for parameters of vaccines, in particular their indications, target groups, implementation strategies, and clinical data needed for assessment of safety and efficacy. PPCs are shaped by the global unmet public health need in a priority disease area for which WHO encourages vaccine development. These preferences reflect WHO's mandate to promote the development of vaccines with high public health impact and suitability in Low- and Middle-Income Countries (LMIC). The target audience is all entities intending to develop or to achieve widespread adoption of a specific influenza vaccine product in these settings. The working group determined that existing influenza vaccines are not well suited for LMIC use. While many developed country manufactures and research funders prioritize influenza vaccine products for use in adults and the elderly, most LMICs do not have sufficiently strong health systems to deliver vaccines to these groups. Policy makers from LMICs are expected to place higher value on vaccines indicated for prevention of severe illness, however the clinical development of influenza vaccines focuses on demonstrating prevention of any influenza illness. Many influenza vaccine products do not meet WHO standards for programmatic suitability of vaccines, which introduces challenges when vaccines are used in low-resource settings. And finally, current vaccines do not integrate well with routine immunization programs in LMICs, given age of vaccine licensure, arbitrary expiration dates timed for temperate country markets, and the need for year-round immunization in countries with prolonged influenza seasonality. While all interested parties should refer to the full PPC document for details, in this article we highlight data needs for new influenza vaccines to better demonstrate the value proposition in LMICs. PMID- 28893474 TI - Assessing care-givers' satisfaction with child immunisation services in Zambia: Evidence from a national survey. AB - AIM: The main aim of this study was to assess care-giver satisfaction with vaccination services in public health facilities in Zambia, and examine its determinants. METHODS: This study used data from a recent population-based household survey, conducted from May to August 2015. Respondent satisfaction with vaccination services received during the last visit was measured on a five point Likert scale ranging from 1 to 5. We used an ordered logistic regression model to analyse the significance of perceived quality of vaccination services, immunisation delivery mode and a range of individual characteristics in predicting care-giver satisfaction. RESULTS: Findings show that one in five care givers were unsatisfied with the vaccination services that they had received, with rural populations showing a significantly higher level of satisfaction. Poor quality of care, defined by long waiting times, poor quality of communication between health staff and care givers, long distance to vaccination sites, mode of delivery, and personal characteristics were among major factors driving care giver satisfaction ratings. We also find that receiving a vaccination at outreach mode of delivery was associated with higher odds of greater satisfaction compared to on-facility vaccination services. The odds of satisfaction were lower for respondents living further away from a health facility, which emphasizes the importance of access in seeking vaccination services. CONCLUSION: These findings suggest that major improvements in quality of vaccination and service organisation will be needed to increase client satisfaction and service utilisation. PMID- 28893475 TI - Impact of five years of rotavirus vaccination in Finland - And the associated cost savings in secondary healthcare. AB - INTRODUCTION: This study aimed to estimate the impact of the national rotavirus (RV) vaccination programme, starting 2009, on the total hospital-treated acute gastroenteritis (AGE) and severe RV disease burden in Finland during the first five years of the programme. This study also evaluated the costs saved in secondary healthcare by the RV vaccination programme. METHODS: The RV related outcome definitions were based on ICD10 diagnostic codes recorded in the Care Register for Health Care. Incidences of hospitalised and hospital outpatient cases of AGE (A00-A09, R11) and RVGE (A08.0) were compared prior (1999-2005) and after (2010-2014) the start of the programme among children less than five years of age. RESULTS: The reduction in disease burden in 2014, when all children under five years of age have been eligible for RV vaccination, was 92.9% (95%CI: 91.0% 94.5%) in hospitalised RVGE and 68.5% (66.6%-70.3%) in the total hospitalised AGE among children less than five years of age. For the corresponding hospital outpatient cases, there was a reduction of 91.4% (82.4%-96.6%) in the RVGE incidence, but an increase of 6.3% (2.7%-9.9%) in the AGE incidence. The RV vaccination programme prevented 2206 secondary healthcare AGE cases costing ?4.5 million annually. As the RV immunisation costs were ?2.3 million, the total net savings just in secondary healthcare costs were ?2.2 million, i.e. ?33 per vaccinated child. DISCUSSION: The RV vaccination programme clearly controlled the severe, hospital-treated forms of RVGE. The total disease burden is a more valuable end point than mere specifically diagnosed cases as laboratory confirmation practises usually change after vaccine introduction. The RV vaccination programme annually pays for itself at least two times over. PMID- 28893476 TI - Growth hormone releasing peptide-6 enhanced antibody titers against subunit antigens in mice (BALB/c), tilapia (Oreochromis niloticus) and African catfish (Clarias gariepinus). AB - Modern subunit vaccines have excellent safety profiles and improved tolerability, but do not elicit strong immune responses without the addition of adjuvants. Developing a safe and affective adjuvant remains a challenge for peptide-based vaccine design. Growth Hormone Releasing Peptide-6 (GHRP-6) is one of the earliest-developed, synthetic, peptidyl growth hormone secretagogue receptor agonists. These compounds mimic the effect of the endogenous ligand, ghrelin. In the present study, we evaluated the ability of GHRP-6 to enhance the humoral immune response against co-injected antigens in mice, tilapia and African catfish. This peptide was able to increase the antigen-specific antibody response using heterologous proteins and peptides as antigens, which were also formulated in "water in oil" emulsions (Freund and Montanide). As long as we know there is no previous report describing any ghrelin analogous as molecular immunomodulator stimulating a humoral immune response. Further studies will be conducted to evaluate the functionality of this humoral immune response in challenge trials. PMID- 28893477 TI - Live-attenuated tetravalent dengue vaccines: The needs and challenges of post licensure evaluation of vaccine safety and effectiveness. AB - Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance systems accordingly. Targeted studies are needed, especially to better understand the effects of vaccinating seronegative individuals. PMID- 28893478 TI - Pain caused by measles, mumps, and rubella vaccines: A systematic literature review. AB - PURPOSE: The risk of post-vaccination adverse events (AEs) is a primary public health concern. Among the AEs, pain is a significant source of anxiety for both children and their parents. This review describes and assesses the intensity of pain experienced by children post-vaccination with widely used Measles-Mumps Rubella (MMR) vaccines. METHODS: A systematic literature search was conducted in Pubmed, Embase and Cochrane to identify publications describing immediate pain at injection site (primary objective) or pain within days (secondary objective) after 2 specific MMR vaccines. Immediate pain ('acute pain' according to the Brighton Collaboration case definition) was defined as pain occurring at the time or within 5min of injection. RESULTS: Four studies, which compared the intensity of immediate injection site pain experienced by children after MMR vaccination, were identified. Various pain assessment tools and methods were used to quantify the intensity of pain, including the median difference in Visual Analog Scale scores between vaccine groups. All four studies showed significantly less immediate pain caused by Priorix (GSK Vaccines) compared with M-M-R II (Merck & Co., Inc.). CONCLUSIONS: To our knowledge, this review summarizes for the first time the available scientific evidence on the intensity of pain following different MMR vaccines. It highlights that MMR vaccines can differ in terms of immediate pain. Further research may be needed to better understand the underlying reason for this observation. In this context, it is very important to understand which physicochemical properties are most relevant for the immediate pain profile of a vaccine to thereby support the development of vaccines with the best possible immediate pain profile. PMID- 28893479 TI - Reaching every child with rotavirus vaccine: Report from the 10th African rotavirus symposium held in Bamako, Mali. AB - The Center for Vaccine Development - Mali (CVD - Mali), the World Health Organization's regional office in Africa (WHO/AFRO), and the CVD at the University of Maryland School of Medicine hosted the 10th African Rotavirus Symposium in Bamako, Mali on 1-2 June 2016. The symposium is coordinated by WHO/AFRO, the Regional Rotavirus Reference Laboratories, and the African Rotavirus Network (ARN), with support from the Bill & Melinda Gates Foundation. The event brings together leading rotavirus researchers, scientists, and policy makers from across Africa and the world. Over 150 participants, from 31 countries, including 27 in Africa, joined forces to address the theme "Reaching Every Child in Africa with Rotavirus Vaccines." This symposium, the first in francophone Africa, occurred at an unprecedented time when 33 African countries had introduced rotavirus vaccines into their national immunization programs. The symposium concluded with a Call to Action to introduce rotavirus vaccines in the 21 remaining African countries, to increase access in countries with existing vaccination programs, and to continue surveillance and research on rotavirus and other diarrheal diseases. PMID- 28893480 TI - Production of highly immunogenic virus-like particles of bovine papillomavirus type 6 in silkworm pupae. AB - Bovine papillomaviruses (BPVs) are the causative agent of bovine teat papillomatosis, which can lead to severe economic losses in dairy cattle. Among the 14 identified BPV genotypes, BPV type 6 (BPV6) is the most frequently detected in teat papilloma lesions, and is therefore thought to play a major role in teat papillomatosis. To develop an effective vaccine against BPV6 infection, we produced virus-like particles of BPV6 (BPV6-VLP) in silkworm (Bombyx mori) pupae and purified these by heparin affinity chromatography using a single column. About 0.7mg purified BPV6-VLP was obtained from one pupa. BPV6-VLP immunized mice produced a specific IgG to BPV6 that recognized BPV6 antigen with high sensitivity in an immunohistochemical analysis. Thus, silkworm pupae are a useful bioreactor for the production of BPV6-VLP, which can potentially be used as a vaccine for bovine teat papillomatosis. PMID- 28893481 TI - Telomerase based anticancer immunotherapy and vaccines approaches. AB - Telomerase is a Reverse Transcriptase that maintains the telomere length. It is absent in most somatic cells but is found in stem cells, germ cells and around 90% of cancers. It plays a crucial role in developing and maintaining cancer cells. Telomerase, a HLA class-I antigen, is able to stimulate cell mediated immune response by inducing cytotoxic T-cells. This property of telomerase is being exploited in targeting cancers by host's own immune responses; stimulated by various Human Telomerase Reverse Transcriptase (hTERT) derived vaccines. Many approaches and studies including clinical trials have shown effective anticancer responses of these vaccines, without toxicity to non cancer cells. In this article we have compiled different hTERT based anticancer immunotherapy approaches, vaccines and their performances. PMID- 28893482 TI - Editor's Choice - Comparison of Early Outcomes and Restenosis Rate Between Carotid Endarterectomy and Carotid Artery Stenting Using Propensity Score Matching Analysis. AB - OBJECTIVE/BACKGROUND: Despite randomised evidence, the debate continues about the preferred treatment strategy for carotid stenosis in routine clinical practice. The aim of this study was to compare early outcomes and restenosis rates after carotid endarterectomy (CEA) and carotid stenting (CAS) in unselected patients using propensity score matching (PSM). METHODS: The 30 day incidence of major adverse clinical events (MACE; defined as stroke, transient ischaemic attack, myocardial infarction, or death) and procedure related complications, as well as restenosis rates during follow-up were compared between unselected patients undergoing CEA or CAS between January 2002 and December 2015 at a single institution. PSM was used to balance the following factors between the CEA and CAS cohorts: age, sex, hypertension, diabetes, dyslipidaemia, smoking, atrial fibrillation, previous percutaneous coronary intervention or coronary artery bypass grafting, valvular heart disease, contralateral carotid occlusion, degree of carotid stenosis, and symptomatic status. Statistical comparisons of outcomes were based on logistic regression analysis and log rank test. RESULTS: Of 1184 patients (654 CEA and 530 CAS), 452 PSM pairs of CEA and CAS patients were created. The CAS group showed a relatively higher 30 day incidence of MACE (7.5% vs. 2.4%; odds ratio [OR] 3.261, 95% confidence interval [CI] 1.634-6.509; p = .001) but a lower incidence of procedure related complications (1.5% vs. 5.3%; OR 0.199, 95% CI 0.075-0.528; p = .001). During a mean follow-up of 49.1 months (range 1-180 months), restenosis rates were higher after CAS than after CEA (1.5% vs. 1.0% at 12 months and 5.4% vs. 1.2% at 24 months, respectively; p = .008). CONCLUSION: This PSM based observation reconfirmed previous trial results in both asymptomatic and symptomatic patients with carotid artery stenosis in routine clinical practice: CEA showed lower 30 day MACE and mid-term restenosis rates than CAS. PMID- 28893483 TI - [Evaluation of professional practices of hospital pediatricians in the management of febrile infants at low risk of bacterial infection]. PMID- 28893484 TI - [Renal abnormalities in Down syndrome: A review]. AB - Down syndrome (DS) is often associated with cardiac malformations, so that kidney damage is little known. The objective of this study was to present the diversity of renal abnormalities and their potential progression to chronic renal failure. Among congenital abnormalities of the kidney and urinary tract (CAKUT) abnormalities appear to be frequent: pyelectasis, megaureters, posterior urethra valves, as well as renal malformations such as renal hypoplasia, horseshoe kidney, or renal ectopia. Contributing factors to acute kidney failure have been described in patients with DS: bilateral lesions and minor renal injury, such as glomerular microcysts, tubular dilation, and immature glomeruli. Histological lesions can be found, albeit nonspecific; they occur earlier than in the general population. Two metabolic specificities have also been described: decreased clearance of uric acid and a hypercalciuria by passive hyperabsorption. End-stage renal disease can occur, thus raising the problem of the best choice of management. In conclusion, renal abnormalities in patients in DS should be known so as to preserve a good renal functional prognosis: systematic screening with renal ultrasound can be proposed. PMID- 28893485 TI - [Clinical characteristics and course of hand, foot, and mouth disease]. AB - Hand, foot and mouth disease (HFMD) and herpangina (HA) are common childhood diseases mostly associated with human enteroviruses (EV). Although usually benign illnesses, neurological complications may be observed during large epidemics when enterovirus A71 (EV-A71) is involved, as observed in the Asia Pacific Region and in China since the late 1990s. The occurrence of these complications warrants reinforcing the surveillance of the emergence of EV-A71 infections in France and Europe. Monitoring EV infections associated with HFMD can be considered as an effective tool to detect an upsurge of EV-A71 infections in a timely manner. In 2014, a national sentinel surveillance system for HFMD/HA was set up in France through a network of volunteer pediatricians and coordinated by the National Reference Center for Enteroviruses and Parechoviruses. Although classical manifestations of HFMD/HA can be easily recognized, there are several atypical presentations of the disease that can be confused with other skin conditions. Delayed cutaneous manifestations, such as onychomadesis and acral desquamation, may also occur and should prompt consideration of HFMD in the preceding weeks. Severe complications following HFMD include neurological manifestations (mainly rhombencephalitis) or less frequently cardiopulmonary failure and can sometimes be fatal. In China, the case severity rate has been estimated at 1%, with a case fatality rate at 0.03%. EV-A71 was involved in more than 90% of the fatal cases. Diagnosis of EV infections associated with severe neurological manifestations is based on the molecular detection of the EV genome in vesicles, cerebrospinal fluid (CSF), throat and stool given that EV-A71 is rarely recovered from the CSF. Positive EV genome detection should be followed by EV genotyping to identify the type of the EV. In temperate-climate countries, outbreaks of HFMD occur mostly but not exclusively during summer and autumn months. Adults may also present with HFMD. In 2016, an upsurge of severe neurological manifestations was reported in France; EV-A71 accounted for 50% of the cases. No specific treatment is available, but two inactivated EV-A71 vaccines are currently available in China. PMID- 28893486 TI - [Anti-D prophylaxis in fetal-maternal erythrocyte incompatibility in Tunisia]. AB - Generalization of postnatal prophylaxis using anti-D immunoglobulins decreased the incidence of erythrocyte fetal-maternal incompatibility (EFMI) in the Rhesus system. Few recent studies have investigated the situation of anti-D prophylaxis in Tunisia and its effects on maternal and neonatal health. The aim of this study was therefore to analyze the situation of anti-D prophylaxis in Tunisia to detect defects and propose solutions. We conducted a retrospective descriptive study of IFME cases in the rhesus system in the Department of Medicine and Neonatal Resuscitation of the Tunis Maternity and Neonatology Center (CMNT) during an 8 year period from 1 January 2006 to 31 December 2015. We collected 51 cases of IFME. The prevalence of IFME was 3.4 per 10 000 live births; 41 % of the patients were transferred in utero and they were from the northwest of the country (17 %). The rate of women with a history of at least one spontaneous miscarriage (SCF) was 45 %. In 42 % of the cases, pregnancies were monitored at local clinics. The search for irregular agglutinins (RAI) was performed in 86 % of the women studied. RAI was positive in 97 % of the cases. Anti-D prophylaxis was correctly performed in only 27 % of the cases. The systematic prophylaxis of the third trimester and a systematic Kleihauer test must be combined with postpartum prophylaxis to better identify dysfunctions and improve the application of the recommendations. PMID- 28893487 TI - [The advantages of 3D imagery in diagnosing and supervising children's and teenagers' scoliosis]. AB - Scoliosis is an abnormal curvature of the spine. One or several curves of more than 10 degrees in the frontal plane can be seen with the rotation of vertebrae in the axial plane, which modifies sagittal curves. In addition to esthetic harm, the morbidity of a scoliosis depends on the extent of the deformation. Treatment, whether it be orthopedic or surgical, is aggressive and never completely cures the condition. At best the deformation will be stabilized at the end of growth. Therefore, it is essential to detect any slight curve and quickly identify any potential progressive form in order to treat it. Visualization of scoliosis in 3D through spine modeling has several advantages at each stage of care. First, with slight curvatures, 3D modeling allows the medical staff to confirm the scoliosis by showing the modification in the three different planes. All curvatures will not progress. Orthopedic treatment is constraining and expensive; only progressive forms will receive it. When the curvature is slight and does not need immediate treatment, 3D modeling at each successive check-up will help detect any sign of likely progression quickly and reliably. Moreover, the medical observation of corset treatment and the preoperative work-up are improved because all 3D parameters of the deformation are accessible. The need for 3D modeling for scoliosis has been known for a long time, but no tool allowing a vertical study with a low level of radiation was available. The EOS imagery system meets these criteria through an optimal analysis of deformations caused by scoliosis. PMID- 28893488 TI - [Clinical criteria for pathogen bacteria in term newborn suspected of neonatal sepsis]. AB - BACKGROUND: Neonatal early onset sepsis (EOS) remains an important etiology of neonatal morbidity and mortality. Diagnosis is difficult due to a lack of sensitivity and specificity markers. In France, the management of newborn infants suspected of infection includes the analysis of gastric suction. The objective of the study was to identify early clinical signs in newborn infants with suspected neonatal sepsis to differentiate a likely infection with pathogen bacteria in the gastric suction culture (Streptococcus agalactiae or Escherichia coli) from a possible infection without such pathogen bacteria. METHODS: We conducted a retrospective study in the Amiens University Hospital. All term newborn infants born between 1 January and 31 December 2013 and hospitalized for suspected EOS were included. Suspicion of EOS was considered when there were arguments to treat by antibiotics for a period of at least 5 days. RESULTS: Fifty-eight newborn infants were included, 25 had a likely EOS and 33 a possible EOS. Newborn infants with a likely EOS were less mature (P<0.01) with more clinical signs at birth (P<0.01). The most common clinical signs were: hyperthermia (P=0.01), somnolence (P<0.01), and hypotonia (P=0.01). After adjusting for the term, the presence of hyperthermia was no longer significantly different between the two groups (P=0.059), the other clinical signs remained significantly different. CONCLUSION: The presence of neonatal symptoms at birth appears to be a useful clinical marker of probable neonatal EOS. PMID- 28893489 TI - Review of aspirin and clopidogrel resistance in peripheral arterial disease. AB - OBJECTIVE: Aspirin resistance (AR) and clopidogrel resistance (CR) are terms used to describe a reduction in the medication's efficacy in inhibiting platelet aggregation despite regular dosing. This review gives context to the clinical role and implications of antiplatelet resistance in peripheral arterial disease (PAD). METHODS: A review of English-language literature on AR and CR in PAD involving human subjects using PubMed and MEDLINE databases was performed in April 2017. A total of 2075 patients in 22 relevant studies were identified. To give this issue context, a review of the larger, more established literature on antiplatelet resistance in coronary disease was undertaken, identifying significant research associating resistance to major adverse cardiovascular events (MACEs). RESULTS: Studies in the coronary arterial disease literature have strongly associated antiplatelet resistance with increased MACE. Prevalence of AR or CR in coronary disease appears to be >55% for each in some studies. Meta analyses of >50 studies revealed that AR and CR are significantly associated with MACE (relative risk of 2.09 and 2.8, respectively). This adds further weight to the literature reporting antiplatelet resistance as an independent predictor of and a threefold risk factor for major adverse cardiovascular events. The prevalence of resistance in PAD in this review was comparable to that in the coronary disease literature, with AR and CR prevalence up to 60% and 65%, respectively. There is evidence that the adverse effects of antiplatelet resistance are significant in PAD. In fact, research directly studying stent thrombosis populations with either coronary arterial disease or PAD revealed more significantly impaired platelet responsiveness to clopidogrel and aspirin in PAD compared with similar individuals with coronary disease. AR in PAD was found in studies to be a significant risk factor for iliofemoral stent reocclusion (P = .0093) and stroke in patients with symptomatic carotid disease (P = .018). CR was found to be a significant, independent risk factor in predicting ischemic outcomes in several recent PAD studies (P < .0001). Loss-of-function carriers of enzyme CYP2C19, important in clopidogrel metabolism, have a 30% greater risk of ischemic events (P < .001). Importantly, less antiplatelet drug resistance may be encountered with newer antiplatelet agents, including ticagrelor and prasugrel, because of reduced enzymatic polymorphisms. CONCLUSIONS: The limited research addressing AR and CR in PAD suggests that further research is required to clarify the role of platelet assays and potential for individualized antiplatelet therapy. PMID- 28893490 TI - Partial renal coverage in endovascular aneurysm repair causes unfavorable renal flow patterns in an infrarenal aneurysm model. AB - OBJECTIVE: To achieve an optimal sealing zone during endovascular aneurysm repair, the intended positioning of the proximal end of the endograft fabric should be as close as possible to the most caudal edge of the renal arteries. Some endografts exhibit a small offset between the radiopaque markers and the proximal fabric edge. Unintended partial renal artery coverage may thus occur. This study investigated the consequences of partial coverage on renal flow patterns and wall shear stress (WSS). METHODS: In vitro models of an abdominal aortic aneurysm were used to visualize pulsatile flow using two-dimensional particle image velocimetry under physiologic resting conditions. One model served as control and two models were stented with an Endurant endograft (Medtronic Inc, Minneapolis, Minn), one without and one with partial renal artery coverage with 1.3 mm of stent fabric extending beyond the marker (16% area coverage). The magnitude and oscillation of WSS, relative residence time, and backflow in the renal artery were analyzed. RESULTS: In both stented models, a region along the caudal renal artery wall presented with low and oscillating WSS, not present in the control model. A region with very low WSS (<0.1 Pa) was present in the model with partial coverage over a length of 7 mm compared with a length of 2 mm in the model without renal coverage. Average renal backflow area percentage in the renal artery incrementally increased from control (0.9%) to the stented model without (6.4%) and with renal coverage (18.8%). CONCLUSIONS: In this flow model, partial renal coverage after endovascular aneurysm repair causes low and marked oscillations in WSS, potentially promoting atherosclerosis and subsequent renal artery stenosis. Awareness of the device-dependent offset between the fabric edge and the radiopaque markers is therefore important in endovascular practice. PMID- 28893491 TI - Micro-finite-element method to assess elastic properties of trabecular bone at micro- and macroscopic level. AB - OBJECTIVE OF THE STUDY: The objective of the present study is to assess the mechanical behavior of trabecular bone based on microCT imaging and micro-finite element analysis. In this way two methods are detailed: (i) direct determination of macroscopic elastic property of trabecular bone; (ii) inverse approach to assess mechanical properties of trabecular bone tissue. PATIENTS: Thirty-five females and seven males (forty-two subjects) mean aged (+/-SD) 80+/-11.7 years from hospitals of Assistance publique-Hopitaux de Paris (AP-HP) diagnosed with osteoporosis following a femoral neck fracture due to a fall from standing were included in this study. MATERIALS AND METHODS: Fractured heads were collected during hip replacement surgery. Standardized bone cores were removed from the femoral head's equator by a trephine in a water bath. MicroCT images acquisition and analysis were performed with CTan(r) software and bone volume fraction was then determined. Micro-finite-element simulations were per-formed using Abaqus 6.9-2(r) software in order to determine the macroscopic mechanical behaviour of the trabecular bone. After microCT acquisition, a longitudinal compression test was performed and the experimental macroscopic Young's Modulus was extracted. An inverse approach based on the whole trabecular bone's mechanical response and micro-finite-element analysis was performed to determine microscopic mechanical properties of trabecular bone. RESULTS: In the present study, elasticity of the tissue was shown to be similar to that of healthy tissue but with a lower yield stress. CONCLUSION: Classical histomorphometric analysis form microCT imaging associated with an inverse micro-finite-element method allowed to assess microscopic mechanical trabecular bone parameters. PMID- 28893492 TI - Rural counties chlamydia and gonorrhea rates in Pennsylvania among adolescents and young adults. AB - BACKGROUND: American adolescents and young adults between the ages of 15 and 24 account for 50% of all sexually transmitted diseases (STDs) annually. Rural populations in this age group are often understudied, despite having factors that place them at higher risk for STDs. PURPOSE: The purpose of this study was to evaluate the utility of time series analysis in the assessment of rural Pennsylvania county-level chlamydia and gonorrhea rates overtime (2004-2014) for 15- to 19- and 20- to 24-year-old age groups by gender. METHODS: An exploratory analysis was completed using Pennsylvania STD surveillance case report and census data, to develop a linear mixed-effects model of the STD rate for each Pennsylvania county for the years 2004 through 2014 using 3-month increments. A cubic polynomial spline regression model was assumed over the 44 time points for each county to account for possible oscillations in the STD rate during the 11 year period. RESULTS: Eight out of 12 rural counties had a significant increase in chlamydia or gonorrhea rates, and five rural counties had significant decreases in chlamydia or gonorrhea rates from 2004 to 2014. CONCLUSIONS: Results from this study provide the first analysis of change in rates of STDs in rural settings and demonstrate the utility of time series analysis for populations with small sample sizes. PMID- 28893494 TI - Multimorbidity is associated with increased rates of depression in patients hospitalized with diabetes mellitus in the United States. AB - AIMS: Information on the burden and risk factors for diabetes-depression comorbidity in the US is sparse. We used data from the largest all-payer, nationally-representative inpatient database in the US to estimate the prevalence, temporal trends, and risk factors for comorbid depression among adult diabetic inpatients. METHODS: We conducted a retrospective analysis using the 2002-2014 Nationwide Inpatient Sample databases. Depression and other comorbidities were identified using ICD-9-CM codes. Logistic regression was used to investigate the association between patient characteristics and depression. RESULTS: The rate of depression among patients with type 2 diabetes increased from 7.6% in 2002 to 15.4% in 2014, while for type 1 diabetes the rate increased from 8.7% in 2002 to 19.6% in 2014. The highest rates of depression were observed among females, non-Hispanic whites, younger patients, and patients with five or more chronic comorbidities. CONCLUSIONS: The prevalence of comorbid depression among diabetic inpatients in the US is increasing rapidly. Although some portion of this increase could be explained by the rising prevalence of multimorbidity, increased awareness and likelihood of diagnosis of comorbid depression by physicians and better documentation as a result of the increased adoption of electronic health records likely contributed to this trend. PMID- 28893493 TI - Brain TSPO imaging and gray matter volume in schizophrenia patients and in people at ultra high risk of psychosis: An [11C]PBR28 study. AB - : Patients with schizophrenia show whole brain and cortical gray matter (GM) volume reductions which are progressive early in their illness. Microglia, the resident immune cells in the CNS, phagocytose neurons and synapses. Some post mortem and in vivo studies in schizophrenia show evidence for elevated microglial activation compared to matched controls. However, it is currently unclear how these results relate to changes in cortical structure. METHODS: Fourteen patients with schizophrenia and 14 ultra high risk for psychosis (UHR) subjects alongside two groups of age and genotype matched healthy controls received [11C]PBR28 PET scans to index TSPO expression, a marker of microglial activation and a 3T MRI scan. We investigated the relationship between the volume changes of cortical regions and microglial activation in cortical GM (as indexed by [11C]PBR28 distribution volume ratio (DVR). RESULTS: The total cortical GM volume was significantly lower in SCZ than the controls [mean (SD)/cm3: SCZ=448.83 (39.2) and controls=499.6 (59.2) (p=0.02) but not in UHR (mean (SD)=503.06 (57.9) and controls=524.46 (45.3) p=0.3). Regression model fitted the total cortical GM DVR values with the cortical regional volumes in SCZ (r=0.81; p<0.001) and in UHR (r=0.63; p=0.02). We found a significant negative correlation between the TSPO signal and total cortical GM volume in SCZ with the highest absolute correlation coefficient in the right superior-parietal cortex (r=-0.72; p=0.006). CONCLUSIONS: These findings suggest that microglial activity is related to the altered cortical volume seen in schizophrenia. Longitudinal investigations are required to determine whether microglial activation leads to cortical gray matter loss. PMID- 28893495 TI - The association between pulse wave velocity and peripheral neuropathy in patients with type 2 diabetes mellitus. AB - AIMS: Diabetic peripheral neuropathy (DPN) is the most common diabetic complication, affecting up to half of the patients with type 2 diabetes mellitus (T2DM). Increased aortic stiffness, measured with the carotid-femoral pulse wave velocity (PWV), has been associated with incidence of cardiovascular disease independently of traditional risk factors. Previous data showed associations between risk factors for macroangiopathy and DPN in diabetes. However, the association between PWV and DPN is not well known. In this study we examined the association between PWV and presence as well as severity of DPN in subjects with T2DM. MATERIAL AND METHODS: A total of 381 patients with T2DM were recruited. Participants were classified as having DPN and not having DPN. PWV was measured at the carotid-femoral segment with a non-invasive method using applanation tonometry. DPN was assessed by determination of the Neuropathy Symptom Score (NSS) and the Neuropathy Disability Score (NDS). RESULTS: A hundred and seven participants (28.1%) had DPN. Patients with DPN were significantly more often male and older, had longer diabetes duration, higher height, larger waist circumference, higher systolic arterial blood pressure (SBP) and higher PWV (all P<0.05). Furthermore, participants with DPN were treated more often with statins and had lower low density lipoprotein cholesterol; in addition, they were treated more often with antiplatelets, b-blockers and insulin than those without DPN. Univariative logistic regression analysis demonstrated that presence of DPN was significantly associated with age, male gender, longer diabetes duration, height, waist circumference, SBP, PWV, dyslipidemia, HbA1c, retinopathy, nephropathy and peripheral arterial disease. Multivariate logistic regression analysis, after adjustment for age, gender, waist circumference, SBP, nephropathy and use of b blockers, demonstrated that the odds [OR (95% confidence intervals)] of peripheral neuropathy were associated significantly and independently only with diabetes duration [1.044 (1.009-1.081), P=0.013], height [1.075 (1.041-1.110), P<0.001], HbA1c [1.468 (1.164-1.851), P<0.001], PWV [1.174 (1.054-1.309), P=0.004], dyslipidemia [1.941 (1.015-3.713), P=0.045], retinopathy [4.426 (2.217 8.837), P<0.001] and peripheral arterial disease [4.658 (2.264-9.584), P<0.001]. In addition, multivariate linear regression analysis, after controlling for age, gender, diabetes duration, SBP, HbA1c and nephropathy, demonstrated that an increased NDS was significantly and independently associated with height [standardized regression coefficient (beta=0.229, P<0.001)], PWV (beta=0.197, P<0.001), retinopathy (beta=0.268, P<0.001) and peripheral arterial disease (beta=0.374, P<0.001). CONCLUSION: Increased PWV is associated strongly and independently not only with the presence but also with the severity of DPN in patients with T2DM, irrespective of known risk factors. PMID- 28893496 TI - The short-term effects of hot packs vs therapeutic whirlpool on active wrist range of motion for patients with distal radius fracture: A randomized controlled trial. AB - STUDY DESIGN: Blinded randomized controlled trial. INTRODUCTION: It is generally accepted that heat is beneficial for improving range of motion (ROM). However, the mechanism of action is not clearly understood, and the optimal method of heat application has not been established. PURPOSE OF THE STUDY: To investigate the immediate effects of using a moist hot pack (MHP) vs therapeutic whirlpool bath (WB) for improving wrist ROM during a therapy session for patients with distal radius fracture. METHODS: About 60 adult patients, with a mean age of 54 years in the MHP group and 53 years in the WB group, with healed distal radius fracture were randomized into 2 groups of 30. Patients in group 1 were placed in an MHP for 15 minutes during therapy. Patients in group 2 had their arm placed in a WB and were asked to perform active wrist ROM exercises for the same period. This occurred for 3 consecutive therapy visits, with wrist and forearm ROM being measured before and after heat during each visit. RESULTS: The multivariate analysis of variance demonstrated that the canonical variate for ROM was significantly different between groups (F[6,53] = 6.01; P < .05), indicating that patients in the WB group had a significantly larger increase in ROM than patients receiving MHP application. DISCUSSION: Both WB and MHP improved wrist ROM during therapy sessions in this study, making both these acceptable options for clinical use when the goal is to precondition a patient for other treatments. CONCLUSIONS: Individuals who received WB showed a statistically greater increase in wrist ROM than those receiving MHP during a therapy session, although the difference between groups may or may not be clinically important considering the small changes in ROM observed in this study. LEVEL OF EVIDENCE: Level II. PMID- 28893497 TI - Utilization of whey powder as substrate for low-cost preparation of beta galactosidase as main product, and ethanol as by-product, by a litre-scale integrated process. AB - Whey powder, a by-product of dairy industry, is an attractive raw material for value-added products. In this study, utilization of whey powder as substrate for low-cost preparation of beta-galactosidase as main product and ethanol as by product were investigated by a litre-scale integrated strategy, encompassing fermentation, isolation, permeabilization and spray drying. Firstly, through development of low-cost industrial culture and fed-batch strategies by Kluyveromyces lactis, 119.30U/mL beta-galactosidase activity and 16.96mg/mL by product ethanol were achieved. Afterward, an up-dated mathematic model for the recycling permeabilization was established successfully and 30.4g cells sediment isolated from 5L fermentation broth were permeabilized completely by distilled ethanol from broth supernatant. Then beta-galactosidase product with 5.15U/mg from protection of gum acacia by spray drying was obtained. Furthermore, by product ethanol with 31.08% (v/v) was achieved after permeabilization. Therefore, the integrated strategy using whey powder as substrate is a feasible candidate for industrial-scale implementation. PMID- 28893498 TI - Hydrothermal liquefaction of agricultural and forestry wastes: state-of-the-art review and future prospects. AB - Hydrothermal liquefaction has been widely applied to obtain bioenergy and high value chemicals from biomass in the presence of a solvent at moderate to high temperature (200-550 degrees C) and pressure (5-25MPa). This article summarizes and discusses the conversion of agricultural and forestry wastes by hydrothermal liquefaction. The history and development of hydrothermal liquefaction technology for lignocellulosic biomass are briefly introduced. The research status in hydrothermal liquefaction of agricultural and forestry wastes is critically reviewed, particularly for the effects of liquefaction conditions on bio-oil yield and the decomposition mechanisms of main components in biomass. The limitations of hydrothermal liquefaction of agricultural and forestry wastes are discussed, and future research priorities are proposed. PMID- 28893499 TI - Influence of pretreatment techniques on anaerobic digestion of pulp and paper mill sludge: A review. AB - Pulp and paper industry is one of the most polluting, energy and water intensive industries in the world. Produced pulp and paper mill sludge (PPMS) faces a major problem for handling and its management. An anaerobic digestion has become an alternative source. This review provides a detailed summary of anaerobic digestion of PPMS - An overview of the developments and improvement opportunities. This paper explores the different pretreatment methods to enhance biogas production from the PPMS. First, the paper gives an overview of PPMS production, and then it reviews PPMS as a substrate for anaerobic digestion with or without pretreatment. Finally, it discuss the optimal condition and concentration of organic and inorganic compounds required for the anaerobic metabolic activity. Future research should focus on the combination of different pretreatment technologies, relationship between sludge composition, reactor design and its operation, and microbial community dynamics. PMID- 28893500 TI - Improved production of 2,5-furandicarboxylic acid by overexpression of 5 hydroxymethylfurfural oxidase and 5-hydroxymethylfurfural/furfural oxidoreductase in Raoultella ornithinolytica BF60. AB - 2,5-Furandicarboxylic acid (FDCA) is a promising bio-based building block and can be produced by biotransformation of 5-hydroxymethylfurfural (HMF). To improve the FDCA production, two genes-one encoding HMF oxidase (HMFO; from Methylovorus sp. strain MP688) and another encoding for HMF/Furfural oxidoreductase (HmfH; from Cupriavidus basilensis HMF14)-were introduced into Raoultella ornithinolytica BF60. The FDCA production in the engineered whole-cell biocatalyst increased from 51.0 to 93.6mM, and the molar conversion ratio of HMF to FDCA increased from 51.0 to 93.6%. PMID- 28893501 TI - The structure evolution of biochar from biomass pyrolysis and its correlation with gas pollutant adsorption performance. AB - Biochar is carbon-rich, porous and with a great potential in gas pollutant controlling. The physical-chemical structure of biochar is important for the application. This paper firstly reviewed the evolution behavior of physical chemical structure for biochar during pyrolysis. At lower temperature (<500 degrees C), biomass firstly transformed to "3D network of benzene rings" with abundant functional groups. With temperature increasing (500-700 degrees C), it converted to "2D structure of fused rings" with abundant porosity. As temperature increasing further (>700 degrees C), it may transit into a "graphite microcrystalline structure", the porosity and functional groups were diminished correspondingly. The modification of biochar and its application as sorbent for gas pollutant were also reviewed. Activation and doping can significantly increase the porosity and special functional groups in biochar, which is favorable for gas pollutant adsorption. With a higher porosity, the adsorption capacity of gas pollutant is bigger, however, the functional groups determined the sorption stability of gas pollutant. PMID- 28893502 TI - Recent advances in nanoscale-metal assisted biochar derived from waste biomass used for heavy metals removal. AB - Pollution of heavy metals (HMs) is a detrimental treat to human health and need to be cleaned up in a proper way. Biochar (BC), a low-cost and "green" adsorbent, has attracted significant attention due to its considerable HMs removal capacity. In particular, nano-metals have recently been used to assist BC in improving its reactivity, surface texture and magnetism. Synthesis methods and metal precursors greatly influence the properties and structures of the nanocomposites, thereby affecting their HMs removal performance. This review presents advances in synthesis methods, formation mechanisms and surface characteristics of BC nanocomposites, along with the discussions on HMs removal mechanisms and the effects of environmental factors on HMs removal efficiency. Performance of using BC nanocomposites to remediate real HMs-containing wastewater and issues associated with its process scale-up are also discussed. This review aims to provide useful information to facilitate the development of HMs removal by nanoscale-metal assisted BC. PMID- 28893503 TI - Biological hydrogen methanation - A review. AB - Surplus energy out of fluctuating energy sources like wind and solar energy is strongly increasing. Biological hydrogen (H2) methanation (BHM) is a highly promising approach to move the type of energy from electricity to natural gas via electrolysis and the subsequent step of the Sabatier-reaction. This review provides an overview of the numerous studies concerning the topic of BHM. The technical and biological parameters regarding the research results of these studies are compared and analyzed hereafter. A holistic view on how to overcome physical limitations of the fermentation process, such as gas-liquid mass transfer or a rise of the pH value, and on the enhancement of environmental circumstances for the bacterial biomass are delivered within. With regards to ex situ methanation, the evaluated studies show a distinct connection between methane production and the methane percentage in the off-gas. PMID- 28893504 TI - A review on organic waste to energy systems in India. AB - Waste generation is increasing day-by-day with the growth of population which directly affects the environment and economy. Organic municipal solid waste (MSW) and agriculture sectors contribute towards maximum waste generation in India. Thus, management of organic waste is very much essential with the increasing demand for energy. The present paper mainly focusses on reviewing waste to energy (WtE) potentials, its technologies, and the associated challenges. Different substrates are utilized through various technological options in India. Organic waste has good potential to attain sustainable energy yields with and without affecting the environment. A realistic scenario of WtE technologies and their challenges in line with the existing Indian condition is presented in this paper. PMID- 28893505 TI - Inactivation and adaptation of ammonia-oxidizing bacteria and nitrite-oxidizing bacteria when exposed to free nitrous acid. AB - Inactivation and adaptation of ammonia-oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) to free nitrous acid (FNA) was investigated. Batch test results showed that AOB and NOB were inactivated when treated with FNA. After an 85-day operating period, AOB in a continuous pre-denitrification reactor did not adapt to the FNA that was applied to treat some of the return activated sludge. In contrast, NOB did adapt to FNA. NOB activity in the seed sludge was only 11% of the original activity after FNA batch treatment, at 0.75mg HNO2-N/L. NOB activity in the pre-denitrification reactor was not affected after being exposed to this FNA level. Nitrosomonas was the dominant AOB before and after long-term FNA treatment. However, dominant NOB changed from Nitrospira to Candidatus Nitrotoga, a novel NOB genus, after long-term FNA treatment. This adaptation of NOB to FNA may be due to the shift in NOB population makeup. PMID- 28893506 TI - Cytochrome b561, copper, beta-cleaved amyloid precursor protein and niemann-pick C1 protein are involved in ascorbate-induced release and membrane penetration of heparan sulfate from endosomal S-nitrosylated glypican-1. AB - Ascorbate-induced release of heparan sulfate from S-nitrosylated heparan sulfate proteoglycan glypican-1 takes place in endosomes. Heparan sulfate penetrates the membrane and is transported to the nucleus. This process is dependent on copper and on expression and processing of the amyloid precursor protein. It remains unclear how exogenously supplied ascorbate can generate HS-anMan in endosomes and how passage through the membrane is facilitated. Here we have examined wild-type, Alzheimer Tg2576 and amyloid precursor protein (-/-) mouse fibroblasts and human fetal and Niemann-Pick C1 fibroblasts by using deconvolution immunofluorescence microscopy, siRNA technology and [S35]sulfate-labeling, vesicle isolation and gel chromatography. We found that ascorbate-induced release of heparan sulfate was dependent on expression of endosomal cytochrome b561. Formation and nuclear transport of heparan sulfate was suppressed by inhibition of beta-processing of the amyloid precursor protein and formation was restored by copper (I) ions. Membrane penetration was not dependent on amyloid beta channel formation. Inhibition of endosomal exit resulted in accumulation of heparan sulfate in vesicles that exposed the C-terminal of the amyloid precursor protein externally. Endosome-to-nucleus transport was also dependent on expression of the Niemann Pick C1 protein. We propose that ascorbate is taken up from the medium and is oxidized by cytochrome b561 which, in turn, reduces copper (II) to copper (I) present in the N-terminal, beta-cleaved domain of the amyloid precursor protein. Re-oxidation of copper (I) is coupled to reductive, deaminative release of heparan sulfate from glypican-1. Passage through the membrane may be facilitated by the C-terminal, beta-cleaved fragment of the amyloid precursor protein and the Niemann-Pick C1 protein. PMID- 28893507 TI - Race as a predictor of postoperative hospital readmission after spine surgery. AB - Hospital readmission after surgery results in a substantial economic burden, and several recent studies have investigated the impact of race and ethnicity on hospital readmission rates, with the goal to identify hospitals and patients with high readmission risk. This single-institution, retrospective cohort study assesses the impact of race, along with other risk factors, on 30-day readmission rates following spinal surgery. This study is a single-institution retrospective cohort study with accrual from January 1, 2008, to December 31, 2010. Inclusion criteria included adult patients who underwent anterior and/or posterior spinal surgery. The primary aim of this study was to assess the impact of patient race and other risk factors for postoperative hospital readmission within 30days following spine surgery. A total of 1346 patients (654 male, 692 female) were included in the study. Overall, 159 patients (11.8%) were readmitted in the 30days following their surgery. Multivariate logistic regression found significant risk factors for 30-day readmission, including Black race (OR: 2.20, C.I. 95% (1.04, 4.64)) and total length of stay greater than 7days (OR: 4.73, C.I. 95% (1.72, 12.98)). Cervical surgery was associated with decreased odds of readmission (OR: 0.27, C.I. 95% (0.08, 0.91)). Our study demonstrates that race and length of hospital stay influence the incidence of 30-day readmission rates after spinal surgery. Studies such as ours will aid in identifying patients with postoperative readmission risk and help elucidate the underlying factors that may be contributing to disparities in readmission after surgery. PMID- 28893508 TI - Regulation of protein phosphatase 2A during embryonic diapause process in the silkworm, Bombyx mori. AB - Regulation of protein phosphorylation requires coordinated interactions between protein kinases and protein phosphatases. In the present study, we investigated regulation of protein phosphatase 2A (PP2A) during the embryonic diapause process of B. mori. An immunoblotting analysis showed that Bombyx eggs contained a catalytic C subunit, a major regulatory B subunit (B55/PR55 subunit), and a structural A subunit, with the A and B subunits undergoing differential changes between diapause and non-diapause eggs during embryonic process. In non-diapause eggs, eggs whose diapause initiation was prevented by HCl, and eggs in which diapause had been terminated by chilling of diapausing eggs at 5 degrees C for 70days and then were transferred to 25 degrees C, protein levels of the A and B subunits of PP2A gradually increased toward embryonic development. However, protein levels of the A and B subunits in diapause eggs remained at low levels during the first 8days after oviposition. The direct determination of PP2A enzymatic activity showed that the activity remained at low levels in diapause eggs during the first 8days after oviposition. However, in non-diapause eggs, eggs whose diapause initiation was prevented by HCl, and eggs in which diapause had been terminated by chilling, PP2A enzymatic activity sharply increased during the first several days, reached a peak during the middle embryonic development, and then greatly decreased 3 or 4days before hatching. Examination of temporal changes in mRNA expression levels of the catalytic beta subunit and regulatory subunit of PP2A showed high levels in eggs whose diapause initiation was prevented by HCl compared to those in diapause eggs. These results demonstrate that the higher PP2A gene expression and PP2A A and B subunit protein levels and increased enzymatic activity are related to embryonic development of B. mori. PMID- 28893509 TI - Non-thermal plasma induces mitochondria-mediated apoptotic signaling pathway via ROS generation in HeLa cells. AB - Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. Although increasing evidence suggests that NTP selectively induces apoptosis in some types of tumor cells, the molecular mechanisms underlying this phenomenon remain unclear. In this study, we further investigated possible molecular mechanisms for NTP-induced apoptosis of HeLa cells. The results showed that NTP exposure significantly inhibited the growth and viability of HeLa cells. Morphological observation and flow cytometry analysis demonstrated that NTP exposure induced HeLa cell apoptosis. NTP exposure also activated caspase-9 and caspase-3, which subsequently cleaved poly (ADP- ribose) polymerase. Furthermore, NTP exposure suppressed Bcl-2 expression, enhanced Bax expression and translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, followed by the release of cytochrome c. Further studies showed that NTP treatment led to ROS generation, whereas blockade of ROS generation by N-acetyl-l-cysteine (NAC, ROS scavengers) significantly prevented NTP-induced mitochondrial alteration and subsequent apoptosis of HeLa cells via suppressing Bax translocation, cytochrome c and caspase-3 activation. Taken together, our results indicated that NTP exposure induced mitochondria-mediated intrinsic apoptosis of HeLa cells was activated by ROS generation. These findings provide insights to the therapeutic potential and clinical research of NTP as a novel tool in cervical cancer treatment. PMID- 28893510 TI - The soluble domains of Gpi8 and Gaa1, two subunits of glycosylphosphatidylinositol transamidase (GPI-T), assemble into a complex. AB - Glycosylphosphatidylinositol transamidase (GPI-T) catalyzes the post translational addition of the GPI anchor to the C-terminus of some proteins. In most eukaryotes, Gpi8, the active site subunit of GPI-T, is part of a hetero pentameric complex containing Gpi16, Gaa1, Gpi17, and Gab1. Gpi8, Gaa1, and Gpi16 co-purify as a heterotrimer from Saccharomyces cerevisiae, suggesting that they form the core of the GPI-T. Details about the assembly and organization of these subunits have been slow to emerge. We have previously shown that the soluble domain of S. cerevisiae Gpi8 (Gpi823-306) assembles as a homodimer, similar to the caspases with which it shares weak sequence homology (Meitzler, J. L. et al., 2007). Here we present the characterization of a complex between the soluble domains of Gpi8 and Gaa1. The complex between GST-Gpi823-306 (alpha) and His6 Gaa150-343 (beta) was characterized by native gel analysis and size exclusion chromatography (SEC) and results are most consistent with an alpha2beta2 stoichiometry. These results demonstrate that Gpi8 and Gaa1 interact specifically without a requirement for other subunits, bring us closer to determining the stoichiometry of the core subunits of GPI-T, and lend further credence to the hypothesis that these three subunits assemble into a dimer of a trimer. PMID- 28893511 TI - Near infra red spectroscopy: a tool for solid state characterization. AB - Physical characterization of solid form of drug is of paramount importance as its biopharmaceutical properties and/or its processing behavior may be altered. Early identification and monitoring of solid state transformation is a critical requirement for pharmaceutical product development. In combination with chemometrics, a non destructive and non invasive technique like NIR is a powerful tool for solid state characterization. Main focus of this review is application of NIR for qualitative and quantitative analysis of solid forms of drugs and excipients. In addition, this review also sheds light on recent advancement in NIR, such as NIR chemical imaging and NIR based hyphenated techniques. PMID- 28893512 TI - Pulmonary Embolism Presenting as Persistent Hiccups. PMID- 28893513 TI - The Joy of Medicine. PMID- 28893514 TI - Nurse Practitioners, Physician Assistants, and Physicians Are Comparable in Managing the First Five Years of Diabetes. AB - BACKGROUND: Increasing use of nurse practitioners and physician assistants is a possible solution to the shortage of primary care providers in the United States, but the quality of care they provide is not well understood. METHODS: Because the scope of practice of the 3 provider types is similar in the Veterans Health Administration, we determined whether patients managed by primary care nurse practitioners, physician assistants, or physicians had similar hemoglobin A1c levels at comparable times in the natural history of diabetes. Our retrospective cohort study examined veterans with newly diagnosed diabetes in 2008, continuous primary care from 2008 to 2012, and more than 75% of primary care visits with nurse practitioner, physician assistant, or physician. RESULTS: Of the 19,238 patients, 95.3% were male, 77.7% were white, and they had a mean age 68.5 years; 14.7%, 7.1%, and 78.2% of patients were managed by nurse practitioners, physician assistants, and physicians, respectively. Median hemoglobin A1c was comparable at diagnosis (6.6%, 6.7%, 6.7%, P > .05) and after 4 years (all 6.5%, P > .5). Hemoglobin A1c levels at initiation of the first (7.5%-7.6%) and second (8.0% 8.2%) oral medications for patients of nurse practitioners and physician assistants compared with that of physicians was also similar after adjusting for patient characteristics (all P > .05). Nurse practitioners started insulin at a lower hemoglobin A1c (9.4%) than physicians (9.7%), which remained significant after adjustment (P < .05). CONCLUSIONS: At diagnosis and during 4 years of follow-up, diabetes management by nurse practitioners and physician assistants was comparable to management by physicians. The Veterans Health Administration model for roles of nurse practitioners and physician assistants may be broadly useful to help meet the demand for primary care providers in the United States. PMID- 28893515 TI - Weaning practices of mothers in eastern Turkey. AB - OBJECTIVE: The study aimed to determine the practices used by breastfeeding mothers to wean their children from the breast. METHOD: This qualitative quantitative research was conducted with mothers whose children were registered the pediatric clinics of a state hospital between June and September 2016. In accordance with a purposeful sampling method, 232 mothers of children between the ages of 2 and 5 years were included in the study. Data were collected through face-to-face interviews using a questionnaire with demographic characteristics of mothers as well as their weaning practices. The data obtained were analyzed with a computer-assisted program using number and percentage distributions. RESULTS: The mean breastfeeding duration was 19.00+/-7.11 months. It was determined that the majority of mothers (56.5%) used traditional methods for weaning their children. These included applying substances with a bad taste (58.1%) to their breasts, covering their breasts with various materials (26.2%) to make the child not want to nurse anymore, and using a pacifier or feeding bottle (9.2%) to substitute for the mother's breast. CONCLUSIONS: It was observed that more than half of the mothers were used some traditional practices that could cause trauma in their children, instead of natural weaning. PMID- 28893516 TI - Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension. AB - BACKGROUND: An elevated serum level of interleukin-6 (IL-6) in pulmonary arterial hypertension (PAH) patients results in a greater symptom burden and increased mortality; however, the mechanisms underlying these observations remain unclear. Because both pre-clinical and clinical data associate elevated IL-6 levels with impaired cardiac function, we hypothesized that the adverse effects of IL-6 in PAH result, in part, from right ventricular (RV) dysfunction. METHODS: We analyzed the relationship between IL-6 and RV function in 40 patients with PAH identified in our institutional PAH registry. Serum IL-6 levels was quantified by enzyme-linked immunoassay. RESULTS: PAH patients had higher IL-6 levels than age- and gender-matched controls. Circulating IL-6 levels correlated inversely with echocardiography-based measures of RV function and RV-pulmonary artery (RV-PA) coupling. When dividing PAH patients by median IL-6 level, patients with higher IL-6 had significantly worse RV function (fractional area change [FAC] 23 +/- 12% vs 38 +/- 11%, tricuspid annular plane systolic excursion [TAPSE] 1.3 +/- 0.3 cm vs 2.1 +/- 0.5 cm), impaired RV-PA coupling (0.6 +/- 0.5%/mm Hg vs 0.9 +/- 0.5%/mm Hg), higher right atrial pressure (13 +/- 7 mm Hg vs 9 +/- 5 mm Hg), reduced cardiac index (2.0 +/- 0.5 liters/min/m2 vs 2.8 +/- 1.0 liters/min/m2) and lower stroke volume (48 +/- 20 ml vs 70 +/- 28 ml). In contrast, the relationships between IL-6 and mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were not significant. Finally, IL-6 was independently associated with RV function and RV PA coupling after adjusting for static (PVR) and pulsatile (PAC) after-load on the RV. CONCLUSIONS: Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease. PMID- 28893517 TI - Differential effects of levodopa and apomorphine on neuronal population oscillations in the cortico-basal ganglia loop circuit in vivo in experimental parkinsonism. AB - The current pharmacotherapy of Parkinson's disease (PD) is primarily based on two classes of drugs: dopamine precursors, namely levodopa, and dopamine receptor agonists, such as apomorphine. Although both types of agents exert their beneficial clinical effects on motor and non-motor symptoms in PD via dopamine receptors, clinical efficiency and side effects differ substantially between levodopa and apomorphine. Levodopa can provide a greater symptomatic relief than dopamine receptor agonists. However, because long-term levodopa use is associated with early debilitating motor fluctuations, dopamine receptor agonists are often recommended in younger patients. The pharmacodynamic basis of these profound differences is incompletely understood. It has been hypothesized that levodopa and dopamine receptor agonists may have diverging effects on beta and gamma oscillations that have been shown to be of importance for the pathophysiology of PD. Here, we used electrophysiological recordings in anesthetized dopamine-intact and dopamine-depleted rats to systemically compare the impact of levodopa or apomorphine on neuronal population oscillations in three nodes of the cortico basal ganglia loop circuit. Our results showed that levodopa had a higher potency than apomorphine to suppress the abnormal beta oscillations often associated with bradykinesia while simultaneously enhancing the gamma oscillations often associated with increased movement. Our data suggests that the higher clinical efficacy of levodopa as well as some of its side effects, as e.g. dyskinesias may be based on its characteristic ability to modulate beta-/gamma-oscillation dynamics in the cortico-basal ganglia loop circuit. PMID- 28893518 TI - Curative approaches for sickle cell disease: A review of allogeneic and autologous strategies. AB - Despite sickle cell disease (SCD) first being reported >100years ago and molecularly characterized >50years ago, patients continue to experience severe morbidity and early mortality. Although there have been substantial clinical advances with immunizations, penicillin prophylaxis, hydroxyurea treatment, and transfusion therapy, the only cure that can be offered is hematopoietic stem cell transplantation (HSCT). In this work, we summarize the various allogeneic curative approaches reported to date and discuss open and upcoming clinical research protocols. Then we consider gene therapy and gene editing strategies that may enable cure based on autologous HSCs. PMID- 28893519 TI - Editorial commentary: What can lung transplantation teach us about the mechanisms of atrial arrhythmias? PMID- 28893520 TI - Chagas diseases: Opportunities for internists. PMID- 28893521 TI - Body mass index and all-cause mortality among type 2 diabetes mellitus patients. PMID- 28893522 TI - Systolic blood pressure target in systemic arterial hypertension: Is lower ever better? Results from a community-based Caucasian cohort. AB - BACKGROUND: Extensive evidence exists about the prognostic role of systolic blood pressure (SBP) reduction <=140mmHg. Recently, the SPRINT trial successfully tested the strategy of lowering SBP<120mmHg in patients with arterial hypertension (AH). AIM: To assess whether the SPRINT results are reproducible in a real world community population. METHODS: Cross-sectional, population-based study analyzing data of 24,537 Caucasian people with AH from the Trieste Observatory of CV disease, 2010 to 2015. We selected and divided 2306 subjects with AH according to the SPRINT trial criteria; similarly, SPRINT clinical outcomes were considered. RESULTS: Study patients median age was 75+/-8years, two third male, one third had ischemic heart disease. They were older, with lower body mass index, higher SBP and Framingham CV risk score than the SPRINT patients. Three-hundred-sixty-eight patients (16%) had SBP<120mmHg. During 48 [36 60] months of follow-up, 751 patients (32%) experienced a major adverse cardiac event (MACE). The SBP <120mmHg group had higher incidence of MACE, CV deaths and all-cause death than SBP>=120mmHg group (37% vs 31%; 10% vs 4%; 19% vs 10%, all p<0.05). The condition of SBP<120mmHg was an independent predictor of MACE in multivariate Cox analysis together with older age, male gender, higher Charlson score. CONCLUSIONS: In our experience, the SBP<120mmHg condition is associated with worse clinical outcomes, suggesting the SPRINT results are not reproducible tout court in Caucasian community populations. These differences should be taken as a warning against aggressive reducing of SBP<120mmHg. PMID- 28893523 TI - [Therapeutic innovations in urology for localized prostate cancer]. AB - The management of localized prostate cancer has been marked over these last years by the importance of Active Surveillance for low risk forms. Indeed, the long follow-up and the quality of the results are now sufficient to offer this option even in relatively young people. However, the question is still under investigation concerning intermediate risk of prostate cancer. Patients' selection and follow-up management are of very high importance. Another major evolution is the robotic assistance for radical prostatectomy. Even if the level of evidence is still low, the global utilization all over the world of robotic assistance is a major fact of these last years mostly explained by the difficulty to correctly perform manual laparoscopic surgical procedure. Lastly, the focal therapy of prostate cancer is a new concept. The development of this approach is authorized by the improvement of the quality of prostate MRI and the accuracy of prostate biopsy. Presently, the focal treatment has to be performed in clinical trials or maybe with the help of national database validated by all the actors concerned by the treatment of prostate cancer. PMID- 28893524 TI - [Hippocampus, brainstem and brain dose-volume constraints for fractionated 3-D radiotherapy and for stereotactic radiation therapy: Limits and perspectives]. AB - Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of alpha/beta ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain. PMID- 28893525 TI - [Doses to organs at risk in conformational and stereotactic body radiation therapy: Liver]. AB - The liver is an essential organ that ensures many vital functions such as metabolism of bilirubin, glucose, lipids, synthesis of coagulation factors, destruction of many toxins, etc. The hepatic parenchyma can be irradiated during the management of digestive tumors, right basithoracic, esophagus, abdomen in toto or TBI. In addition, radiotherapy of the hepatic area, which is mainly stereotactic, now occupies a central place in the management of primary or secondary hepatic tumors. Irradiation of the whole liver, or part of it, may be complicated by radiation-induced hepatitis. It is therefore necessary to respect strict dosimetric constraints both in stereotactic and in conformational irradiation in order to limit the undesired irradiation of the hepatic parenchyma which may vary according to the treatment techniques, the basic hepatic function or the lesion size. The liver is an organ with a parallel architecture, so the average tolerable dose in the whole liver should be considered rather than the maximum tolerable dose at one point. The purpose of this article is to propose a development of dose recommendations during conformation or stereotactic radiotherapy of the liver. PMID- 28893526 TI - Neural correlates of working memory in children and adolescents with agenesis of the corpus callosum: An fMRI study. AB - The ability to temporarily maintain relevant information in mind in the presence of interference or distracting information, also called working memory (WM), is critical for higher cognitive functions and cognitive development. In typically developing (TD) children, WM is underpinned by a fronto-parietal network of interacting left and right brain regions. Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation. This study aims to investigate functional organisation of WM in children and adolescents with AgCC using functional magnetic resonance imaging (fMRI). Nine children with AgCC and a comparison group of sixteen TD children aged 8-17 years completed an fMRI WM paradigm designed to enable investigation of different WM processes, i.e., encoding, maintenance and retrieval. We found that AgCC children recruited globally similar brain regions as the TD comparison group during the WM task, despite significant disparity in brain development, i.e., bilateral occipito frontal activations during verbal encoding, and bilateral fronto-parietal executive control network during retrieval. However, compared to their TD peers, children with AgCC seemed less able to engage lateralised brain systems specialised for particular memory material (i.e. less supramarginal activations for verbal material and less fusiform activations for face processing) and particular memory process (i.e. absence of right-predominant activations during retrieval). Group differences in the pattern of activation might also reflect different cognitive strategies to cope with competition in processing resources with different susceptibility to concurrent tasks (verbal vs visual), such as differential recruitment of associative visual areas and executive prefrontal regions in the AgCC compared with the TD group depending on the concurrent task completed during maintenance. This study provides a first step towards a better understanding of functional brain networks underlying higher cognitive functions in children with AgCC. PMID- 28893527 TI - Management of premature rupture of membranes at term: the need to correct a recurring mistake in articles, chapters, and recommendations of professional organizations. AB - Recommendations about the management of premature rupture of membranes at term are based, in part, on a large, randomized controlled trial published in 1996: the TERMPROM trial. The original article contained an error in Table 1, in which "Interval from membrane rupture to delivery" was listed instead of "Interval from membrane rupture to study entry." While the authors and journal corrected this error, the mistake published in the original paper has made its way into subsequent publications and even in guidelines or practice bulletins issued by professional organizations, textbooks, and other publications around the world. The mistake, that half of women with premature rupture of membranes at term who were managed expectantly delivered within 5 hours and 95% delivered within 28 hours of membrane rupture, should be replaced with the actual fact that half of women with premature rupture of membranes at term who were managed expectantly delivered within 33 hours, and 95% delivered within 94-107 hours of membrane rupture. Correcting this error in contemporary health care information and publications is important to counsel patients accurately and to optimize the clinical care of women with premature rupture of membranes at term. PMID- 28893528 TI - Ultrasound estimated fetal weight. PMID- 28893529 TI - Passive immunity to control Bovine coronavirus diarrhea in a dairy herd in Argentina. AB - Bovine coronavirus (BCoV) is a viral enteric pathogen associated with calf diarrhea worldwide being, in Argentina, mostly detected in dairy husbandry systems. The aim of the present work was to study if maternal IgG1 antibodies (Abs) to BCoV acquired by colostrum intake modulate the development of BCoV infection in calves reared in a dairy farm in Argentina. Thirty Holstein calves were monitored during their first 60 days of age. Animals were classified into two groups depending on their initial BCoV IgG1 Ab titers. The "failure of passive transfer" (FPT) group had significantly lower IgG1 Abs to BCoV than the "acceptable passive transfer" (APT) group of calves (log10 1.98 vs. 3.38 respectively) (p<0.0001). These differences were also observed when the total protein levels in both groups were compared (p=0.0081). Moreover, 71% (5/7) of calves from the FPT group showed IgG1 seroconversion to BCoV compared to 29.4% (5/17) of animals from the APT group. Regarding viral circulation, BCoV was detected in 10% (3/30) of all calves and BCoV IgG1 Ab seroconversion was detected in 42% of the total animals showing that almost half of the calves were infected with BCoV. In conclusion, calves with high titers of specific BCoV IgG1 (>=1024) were mostly protected against viral infection, while animals with low titers of IgG1 (<1024) were mostly infected with BCoV. IgG1 Abs from colostrum origin are critical for prevention of BCoV infection. PMID- 28893530 TI - [Combination of phosphorus solubilizing and mobilizing fungi with phosphate rocks and volcanic materials to promote plant growth of lettuce (Lactuca sativa L.)]. AB - Arbuscular mycorrhizal fungi (AMF) increase the uptake of soluble phosphates, while phosphorus solubilizing fungi (S) promote solubilization of insoluble phosphates complexes, favoring plant nutrition. Another alternative to maintaining crop productivity is to combine minerals and rocks that provide nutrients and other desirable properties. The aim of this work was to combine AMF and S with pyroclastic materials (ashes and pumices) from Puyehue volcano and phosphate rocks (PR) from Rio Chico Group (Chubut) - to formulate a substrate for the production of potted Lactuca sativa. A mixture of Terrafertil(r):ashes was used as substrate. Penicillium thomii was the solubilizing fungus and Rhizophagus intraradices spores (AMF) was the P mobilizer (AEGIS(r) Irriga). The treatments were: 1) Substrate; 2) Substrate+AMF; 3) Substrate+S; 4) Substrate+AMF+S; 5) Substrate: PR; 6) Substrate: PR+AMF; 7) Substrate: PR+S and 8) Substrate: PR+AMF+S. Three replicates were performed per treatment. All parameters evaluated (total and assimilable P content in substrate, P in plant tissue and plant dry biomass) were significantly higher in plants grown in substrate containing PR and inoculas with S and AMF. This work confirms that the combination of S/AMF with Puyehue volcanic ashes, PR from the Rio Chico Group and a commercial substrate promote the growth of L. sativa, thus increasing the added value of national geomaterials. PMID- 28893531 TI - A Systematic Review of Plantar Plate Repair in the Management of Lesser Metatarsophalangeal Joint Instability. AB - The plantar plate is a major structure that maintains metatarsophalangeal joint (MTPJ) stability and has only recently gained attention. Anatomic plantar plate repair can directly address the pathologic entity, rather than relying on indirect reduction of the MTPJ instability by osteotomy or tendon transfer techniques. The present report aimed to determine the effectiveness of plantar plate repair for the treatment of patients with lesser MTPJ instability. Different databases were searched using the guidelines in the Cochrane Handbook and recommendations from the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. Six case series, describing 162 patients who had undergone plantar plate repair in conjunction with either Weil osteotomy or flexor digitorum longus transfer, were retrieved. Favorable outcomes were described in each of the studies included in the present systematic review. However, these results should be interpreted with caution because of the methodologic limitations and biases inherent in the included studies. More rigorous clinical investigations are required to fully understand the effectiveness of plantar plate repair for the management of lesser MTPJ instability. PMID- 28893532 TI - Passport to pathology: transforming the medical student pathology elective from a passive educational experience to an exciting, immersive clinical rotation. PMID- 28893533 TI - Capturing Structural Heterogeneity in Chromatin Fibers. AB - Chromatin fiber organization is implicated in processes such as transcription, DNA repair and chromosome segregation, but how nucleosomes interact to form higher-order structure remains poorly understood. We solved two crystal structures of tetranucleosomes with approximately 11-bp DNA linker length at 5.8 and 6.7 A resolution. Minimal intramolecular nucleosome-nucleosome interactions result in a fiber model resembling a flat ribbon that is compatible with a two start helical architecture, and that exposes histone and DNA surfaces to the environment. The differences in the two structures combined with electron microscopy reveal heterogeneous structural states, and we used site-specific chemical crosslinking to assess the diversity of nucleosome-nucleosome interactions through identification of structure-sensitive crosslink sites that provide a means to characterize fibers in solution. The chromatin fiber architectures observed here provide a basis for understanding heterogeneous chromatin higher-order structures as they occur in a genomic context. PMID- 28893534 TI - Solution Structure of the N-Terminal Domain of Mediator Subunit MED26 and Molecular Characterization of Its Interaction with EAF1 and TAF7. AB - MED26 is a subunit of Mediator, a large complex central to the regulation of gene transcription by RNA Polymerase II. MED26 plays a role in the switch between the initiation and elongation phases of RNA Polymerase II-mediated transcription process. Regulation of these steps requires successive binding of MED26 N terminal domain (NTD) to TATA-binding protein-associated factor 7 (TAF7) and Eleven-nineteen lysine-rich in leukemia-Associated Factor 1 (EAF1). In order to investigate the mechanism of regulation by MED26, MED26-NTD structure was solved by NMR, revealing a 4-helix bundle. EAF1 (239-268) and TAF7 (205-235) peptide interactions were both mapped to the same groove formed by H3 and H4 helices of MED26-NTD. Both interactions are characterized by dissociation constants in the 10-MUM range. Further experiments revealed a folding-upon-binding mechanism that leads to the formation of EAF1 (N247-S260) and TAF7 (L214-S227) helices. Chemical shift perturbations and nuclear Overhauser enhancement contacts support the involvement of residues I222/F223 in anchoring TAF7 helix to a hydrophobic pocket of MED26-NTD, including residues L48, W80 and I84. In addition, Ala mutations of charged residues located in the C-terminal disordered part of TAF7 and EAF1 peptides affected the binding, with a loss of affinity characterized by a 10-time increase of dissociation constants. A structural model of MED26-NTD/TAF7 complex shows bi-partite components, combining ordered and disordered segments, as well as hydrophobic and electrostatic contributions to the binding. This study provides molecular detail that will help to decipher the mechanistic basis for the initiation to elongation switch-function mediated by MED26-NTD. PMID- 28893535 TI - Down-regulate of Djrfc2 causes tissues hypertrophy during planarian regeneration. AB - Planarians are an ideal model organism for regeneration research due to their amazing ability to regenerate. DNA replication is crucial for genome stability. Replication factor C (RFC), which is a replication factor C-like complex and plays an important role during DNA replication in eukaryotes, has been reported as a wound response factor during planarian regeneration. However, how RFC controls regeneration in planarians by regulating DNA replication remains to be explained. Here, we used a two-dimensional electrophoresis (2-DE) proteomic approach to identify differentially expressed proteins in intact and regenerated planarians. Approximately 132 protein spots showed differences between intact and regenerative tissues. We selected 21 significantly expressed protein spots and processed them using TOF MS analysis. Finally, we cloned three of these candidate genes (Djhsp70, Djrfc2, Djfaim), focusing on the function of Djrfc2 during regeneration. We found that the distribution of Djrfc2 tends toward the wound site. RNA interference (RNAi) of Djrfc2 increases the number of dividing cells and the expression level of planarian neoblast marker genes, which may result in hyper-proliferation. Our studies use an available approach to directly study the regeneration dynamic at the protein level and provide further evidence to support a function of Djrfc2 in planarian regeneration. PMID- 28893536 TI - CREPT regulated by miR-138 promotes breast cancer progression. AB - CREPT (also known as RPRD1B) function as an oncogene and is highly expressed in several kinds of cancers. However, the distribution and clinical significance of CREPT in breast cancer (BC) still not clarified. In this study, we found that the CREPT expression is greatly upregulated in BC tissues and cell lines. Moreover, the CREPT expression was significantly associated with tumor differentiation and metastasis. Next, the functional assay of CREPT showed that CREPT could promote BC proliferation and invasion both in vitro and in vivo. Dual-luciferase reporter assay indicated that miR-138 regulated the expression of CREPT by binding to its 3'-UTR. miR-138 is downregulated and inversely correlated with CREPT expression in BCs. Overexpression of miR-138 suppressed tumor growth and invasion, these effects could be reversed by re-expressing CREPT. Mechanistically, CREPT regulated beta-catenin/TCF4/cyclin D1 pathway in BC. In conclusion, the data suggested that miR-138/CREPT involved BC progression, providing potential therapeutic targets for BC. PMID- 28893537 TI - Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice. AB - In a previous study, we generated transmitochondrial P29mtSAMP1 cybrids, which had nuclear DNA from the C57BL6 (referred to as B6) mouse strain-derived P29 tumor cells and mitochondrial DNA (mtDNA) exogenously-transferred from the allogeneic strain SAMP1. Because P29mtSAMP1 cybrids did not form tumors in syngeneic B6 mice, we proposed that allogeneic SAMP1 mtDNA suppressed tumor formation of P29mtSAMP1 cybrids. To test this hypothesis, current study generated P29mt(sp)B6 cybrids carrying all genomes (nuclear DNA and mtDNA) from syngeneic B6 mice by eliminating SAMP1 mtDNA from P29mtSAMP1 cybrids and reintroducing B6 mtDNA. However, the P29mt(sp)B6 cybrids did not form tumors in B6 mice, even though they had no SAMP1 mtDNA, suggesting that SAMP1 mtDNA is not involved in tumor suppression. Then, we examined another possibility of whether SAMP1 mtDNA fragments potentially integrated into the nuclear DNA of P29mtSAMP1 cybrids are responsible for tumor suppression. We generated P29H(sp)B6 cybrids by eliminating nuclear DNA from P29mt(sp)B6 cybrids and reintroducing nuclear DNA with no integrated SAMP1 mtDNA fragment from mtDNA-less P29 cells resistant to hygromycin in selection medium containing hygromycin. However, the P29H(sp)B6 cybrids did not form tumors in B6 mice, even though they carried neither SAMP1 mtDNA nor nuclear DNA with integrated SAMP1 mtDNA fragments. Moreover, overproduction of reactive oxygen species (ROS) and bacterial infection were not involved in tumor suppression. These observations suggest that tumor suppression was caused not by mtDNA with polymorphic mutations or infection of cytozoic bacteria but by hypothetical heritable cytoplasmic elements other than mtDNA from SAMP1 mice. PMID- 28893538 TI - Indispensable role of lipoprotein bound-ApoE in adipogenesis and endocytosis induced by postprandial TRL. AB - Diet-associated obesity is coexisted with postprandial hypertriglyceridemia that indicates increased number of triglyceride-rich lipoproteins (TRL). This study aimed to investigate the effect of postprandial TRL-bound apolipoprotein E (ApoE) on adipogenesis and potential mechanisms. 3T3-L1 cells were cultured with (i) human TRL (h-TRL) with or without insulin, or (ii) TRL from wild type mice (WT TRL) or ApoE knock-out mice (EKO-TRL) and insulin. The differentiating adipocytes were incubated with different kinds of TRL labeled by red fluorescence and confocal microscopy was performed. Receptor associated protein (RAP), heparin or both were added to inhibit low density lipoprotein receptor family receptors, heparan sulfate proteoglycan or both, respectively. With the aid of insulin, postprandial h-TRL or WT-TRL, instead of EKO-TRL, successfully induced adipogenesis. Confocal microscopy revealed red fluorescence in the differentiating adipocytes treated with h-TRL or WT-TRL, but not with EKO-TRL. RAP markedly reduced red fluorescence within the differentiating adipocytes, while heparin had little impact. The low density lipoprotein receptor related protein 1 protein showed upward trend with the increase of TRL concentrations. Taken together, lipoprotein-bound ApoE was required in both postprandial TRL induced adipogenesis and TRL endocytosis by the differentiating adipocytes, the latter could be partially through low density lipoprotein receptor family dependent-pathway. PMID- 28893539 TI - Functional analysis of a SOX10 gene mutation associated with Waardenburg syndrome II. AB - Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3. Therefore, the mutant cannot transactivate the MITF promoter effectively, inhibiting melanin synthesis and leading to WS2. Our study confirmed haploinsufficiency as the underlying pathogenesis for WS2. PMID- 28893540 TI - The Use of Antibiotics in Odontogenic Infections: What Is the Best Choice? A Systematic Review. AB - PURPOSE: Odontogenic infections are a common problem in dentistry, and their treatment often requires the use of antibiotics besides the removal of the source of infection, which frequently makes it more difficult for clinicians to make a decision regarding the choice of antibiotic. This study aimed to answer the following questions through the Patient, Intervention, Comparison, Outcome (PICO) format: When should antibiotics be used in dental infections (DIs)? Which are the most effective drugs? How long should antibiotics be administered? MATERIALS AND METHODS: This was a systematic review using the PubMed, Scopus, and Cochrane databases without restriction as to the period researched. The variables analyzed in each article were the number of odontogenic infections in each study, type of study, surgical intervention performed, antibiotics administered, statistical differences between groups studied, and patients' evolution after treatment. RESULTS: The search included 1,109 articles. After the full reading of 46 articles, 16 were included in the final review and 30 were excluded. A sample of 2,197 DI cases was obtained, in which 15 different antibiotics were used, with a 98.2% overall cure rate. CONCLUSIONS: The studies showed that antibiotics were prescribed only in situations of regional and/or systemic body manifestations. In the case of DIs, once drainage has been performed and/or the cause of infection has been removed, all antibiotics tested are equally effective with respect to clinical cure, and the choice of antibiotics is not as successful as the local intervention treatment procedure. When the real need for antibiotic therapy is detected, antibiotics should be used for the shortest time possible until the patient's clinical cure is achieved. PMID- 28893541 TI - Nanomechanical Assessment of Bone Surrounding Implants Loaded for 3 Years in a Canine Experimental Model. AB - PURPOSE: This work evaluated the nanomechanical properties of bone surrounding submerged and immediately loaded implants after 3 years in vivo. It was hypothesized that the nanomechanical properties of bone would markedly increase in immediately and functionally loaded implants compared with submerged implants. MATERIALS AND METHODS: The second, third, and fourth right premolars and the first molar of 10 adult Doberman dogs were extracted. After 6 months, 4 implants were placed in 1 side of the mandible. The mesial implant received a cover screw and remained unloaded. The remaining 3 implants received fixed dental prostheses within 48 hours after surgery that remained in occlusal function for 3 years. After sacrifice, the bone was prepared for histologic and nanoindentation analysis. Nanoindentation was carried out under wet conditions on bone areas within the plateaus. Indentations (n = 30 per histologic section) were performed with a maximum load of 300 MUN (loading rate, 60 MUN per second) followed by a holding and unloading time of 10 and 2 seconds, respectively. Elastic modulus (E) and hardness (H) were computed in giga-pascals. The amount of bone-to-implant contact (BIC) also was evaluated. RESULTS: The E and H values for cortical bone regions were higher than those for trabecular bone regardless of load condition, but this difference was not statistically significant (P > .05). The E and H values were higher for loaded implants than for submerged implants (P < .05) for cortical and trabecular bone. For the same load condition, the E and H values for cortical and trabecular bone were not statistically different (P > .05). The loaded and submerged implants presented BIC values (mean +/- standard deviation) of 57.4 +/- 12.1% and 62 +/- 7.5%, respectively (P > .05). CONCLUSION: The E and H values of bone surrounding dental implants, measured by nanoindentation, were higher for immediately loaded than for submerged implants. PMID- 28893542 TI - Application of Denaturing Gradient Gel Electrophoresis to the Analysis of Bacterial Communities Associated With Asymptomatic and Symptomatic Pericoronitis. AB - PURPOSE: Denaturing gradient gel electrophoresis (DGGE) was used to investigate the bacterial communities associated with asymptomatic and symptomatic pericoronitis. The aim of the study was to compare the fingerprinting patterns of these 2 clinical conditions. MATERIALS AND METHODS: The microbiota of mandibular third molar pockets associated with asymptomatic or symptomatic pericoronitis cases were collected and profiled by the polymerase chain reaction DGGE method. Banding patterns were compared by cluster analysis techniques. RESULTS: Thirteen symptomatic pericoronitis and 7 asymptomatic pericoronitis samples were collected. Comparative analysis of the 2 clinical conditions showed bands that were common to the symptomatic and asymptomatic cases, but most DGGE bands appeared to be unique to the clinical condition. No single band occurred in all profiles. The mean number of bands detected in the 16S rDNA community profiles was 23.8 +/- 4.2 (range, 19 to 34) for samples from symptomatic cases and 24.1 +/ 2.4 (range, 21 to 29) for those from asymptomatic cases. Cluster analysis and multidimensional scaling analysis of the DGGE banding pattern showed a distinction in the similarity of banding patterns according to the presence or absence of symptoms. CONCLUSIONS: These results suggest that the diversity of pericoronal pocket microbiota in asymptomatic pericoronitis cases differs markedly from that of symptomatic cases. PMID- 28893543 TI - Effect of Piezoelectric Sutural Ostectomies on Accelerated Bone-Borne Sutural Expansion. AB - PURPOSE: The present study investigated the effect of piezoelectric sutural ostectomies on accelerated bone-borne sutural expansion. MATERIALS AND METHODS: Sixteen male New Zealand white rabbits (20 to 24 weeks old) were randomly divided into 4 experimental groups (n = 4): group 1, conventional rapid sutural expansion; group 2, accelerated sutural expansion; group 3, accelerated sutural expansion with continuous ostectomy; and group 4, accelerated sutural expansion with discontinuous ostectomy. All sutural ostectomies were performed using a piezoelectric instrument (Woodpecker DTE, DS-II, Guangxi, China) before expander application with the rabbits under anesthesia. Modified hyrax expanders were placed across the midsagittal sutures of the rabbits and secured with miniscrew implants located bilaterally in the frontal bone. The hyrax expanders were activated 0.5 mm/day for 12 days (group 1) or with a 2.5-mm initial expansion, followed by 0.5 mm/day for 7 days (groups 2 to 4). After 6 weeks of retention, the bone volume fraction, sutural separation, and new bone formation were evaluated using micro-computed tomography and histomorphometry. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests and Spearman's rho correlation (P < .05). RESULTS: Ranking of the median sutural separation was as follows: group 1, 3.05 mm; group 2, 3.97 mm; group 4, 4.78 mm; and group 3, 5.66 mm. The least and most bone formation were observed in groups 1 (63.63%) and 3 (75.93%), respectively. Spearman's correlation showed a strong, positive, and significant correlation (r = 0.932; P < .01) between the new sutural bone formation and amount of sutural separation. CONCLUSIONS: Piezoelectric sutural ostectomies increased the rate of sutural separation and promoted new sutural bone formation/osteogenesis. Continuous ostectomy gave better results than discontinuous ostectomy. PMID- 28893544 TI - Myxofibrosarcoma in Head and Neck: Case Report of Unusually Aggressive Presentation. AB - Myxofibrosarcoma (MFS) is a malignant fibroblastic tumor that primarily affects the lower and upper extremities. It is usually described as a slow-growing tumor with high recurrence rates but low metastatic potential. The reported incidence of head and neck MFS is 2 to 4% and rarely presents with distant metastases. This report describes a case of maxillary MFS in a 72-year-old woman whose disease progression followed an atypical course with an extremely rapid rate of growth and early pulmonary and central nervous system lesions. The pulmonary symptoms at initial presentation made a final diagnosis a challenge. Various diagnostic modalities and multidisciplinary collaboration were required. The disease course and management are outlined. To the authors' knowledge, this is the first case of MFS originating in the maxillary alveolus with multiple metastases, including the brain and lungs, in the early course of the disease. PMID- 28893545 TI - Neer Award 2017: wear rates of 32-mm and 40-mm glenospheres in a reverse total shoulder arthroplasty wear simulation model. AB - BACKGROUND: Larger glenosphere diameters have been used recently to increase prosthesis stability and impingement-free range of motion in reverse total shoulder arthroplasty. The goal of this study was to evaluate the rate of polyethylene wear for 32-mm and 40-mm glenospheres. METHODS: Glenospheres (32 mm and 40 mm, n = 6/group) and conventional polyethylene humeral liners underwent a 5-million cycle (MC) wear simulation protocol. Abduction-adduction and flexion extension motion profiles were alternated every 250,000 cycles. At each interval, mass loss was determined and converted to volume loss and wear rate. At 0, 2.5 MC, and 5 MC, liners were imaged using micro-computed tomography to determine surface deviation. White light interferometry was performed on liners and glenospheres at 0 and 5 MC to quantify surface roughness. Wear particle morphology was characterized by environmental scanning electron microscopy. RESULTS: Total volume loss was significantly higher in 40-mm liners from 1.5 MC onward (P < .05). Overall, volumetric wear rate was significantly higher in 40-mm liners compared with 32-mm glenospheres (81.7 +/- 23.9 mm3/MC vs. 68.0 +/- 18.9 mm3/MC; P < .001). However, micro-computed tomography surface deviation results demonstrated increased linear penetration on 32-mm glenospheres compared with 40 mm glenospheres (0.36 +/- 0.03 um vs. 0.28 +/- 0.01 um; P = .002). Surface roughness measurements showed no difference for liners; however, increased roughness was noted for 40-mm glenospheres at 5 MC compared with 32 mm (P < .05). CONCLUSION: Larger glenospheres underwent significantly greater polyethylene volume loss and volumetric wear rates, whereas smaller glenospheres underwent greater polyethylene surface deviations. The enhanced stability provided by larger glenospheres must be weighed against the potential for increased polyethylene wear. PMID- 28893546 TI - Cost-effectiveness of magnetic resonance imaging versus ultrasound for the detection of symptomatic full-thickness supraspinatus tendon tears. AB - BACKGROUND: The purpose of this study was to determine the value of magnetic resonance imaging (MRI) and ultrasound-based imaging strategies in the evaluation of a hypothetical population with a symptomatic full-thickness supraspinatus tendon (FTST) tear using formal cost-effectiveness analysis. METHODS: A decision analytic model from the health care system perspective for 60-year-old patients with symptoms secondary to a suspected FTST tear was used to evaluate the incremental cost-effectiveness of 3 imaging strategies during a 2-year time horizon: MRI, ultrasound, and ultrasound followed by MRI. Comprehensive literature search and expert opinion provided data on cost, probability, and quality of life estimates. The primary effectiveness outcome was quality-adjusted life-years (QALYs) through 2 years, with a willingness-to-pay threshold set to $100,000/QALY gained (2016 U.S. dollars). Costs and health benefits were discounted at 3%. RESULTS: Ultrasound was the least costly strategy ($1385). MRI was the most effective (1.332 QALYs). Ultrasound was the most cost-effective strategy but was not dominant. The incremental cost-effectiveness ratio for MRI was $22,756/QALY gained, below the willingness-to-pay threshold. Two-way sensitivity analysis demonstrated that MRI was favored over the other imaging strategies over a wide range of reasonable costs. In probabilistic sensitivity analysis, MRI was the preferred imaging strategy in 78% of the simulations. CONCLUSION: MRI and ultrasound represent cost-effective imaging options for evaluation of the patient thought to have a symptomatic FTST tear. The results indicate that MRI is the preferred strategy based on cost-effectiveness criteria, although the decision between MRI and ultrasound for an imaging center is likely to be dependent on additional factors, such as available resources and workflow. PMID- 28893547 TI - 17beta-Estradiol modulates cell proliferation of medullary cords during ovarian differentiation of the Lepidochelys olivacea sea turtle. AB - In turtles undergoing temperature sex determination (TSD), bipotential gonads express Sox9 in medullary cords at both female- (FPT) and male-producing temperatures (MPT). Subsequently, when the sex fate of medullary cords becomes dimorphic, at FPT, Sox9 is downregulated, whereas at MPT, its expression is maintained. Medullary cords in the ovary turn into ovarian lacuna, whereas in the testis they differentiate as seminiferous cords. When embryos of Lepidochelys olivacea sea turtle are incubated at MPT and treated with estradiol, Sox9 expression persists in the medullary cords in the form of tiny ovotestis-like formations. The perturbed development of the treated gonads is due to a significant decrease in the number of proliferating cells. This suggests that the disturbed effect caused by exogenous estradiol may be due to a conflict between the gene networks regulated by temperature and the increased level of endogenous estrogens, induced by the treatment. Here, we decided to use fadrozole and fulvestrant, an aromatase inhibitor and an estrogen-receptor antagonist, respectively, to provide insights into the role played by endogenous estrogens in regulating the cell proliferation of the two main gonadal compartments: the medullary cords and the cortex. Comparing cell proliferation patterns, our current results suggest that the endogenous estrogens are involved in determining the sex fate of medullary cords, by repressing proliferation. Interestingly, our results showed that endogenous estradiol levels are unnecessary for the thickening of the ovarian cortex. PMID- 28893548 TI - Meeting the HIV Prevention Needs of Older Adults. PMID- 28893549 TI - Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial. AB - BACKGROUND: Data from randomized trials have suggested a modest or no effect of conventional cardiac resynchronization therapy (convCRT) on the incidence of atrial fibrillation (AF). AdaptivCRT (aCRT, Medtronic, Mounds View, MN) is a recently described algorithm for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT). OBJECTIVE: We compared the long-term effects of aCRT with convCRT pacing on the incidence of AF. METHODS: The Adaptive CRT trial randomized CRT-defibrillator (CRT-D) indicated patients (2:1) to receive either aCRT or convCRT pacing. The aCRT algorithm evaluates intrinsic conduction every minute, providing LV-only pacing during normal atrioventricular (AV) conduction and AV and ventriculoventricular timing adjustments during prolonged AV conduction. The primary outcome of this subanalysis was an episode of AF >48 consecutive hours as detected by device diagnostics. RESULTS: Over a follow-up period with a mean and standard deviation of 20.2 +/- 5.9 months, 8.7% of patients with aCRT and 16.2% with convCRT experienced the primary outcome (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.31-0.93; P = .03). In patients with prolonged baseline AV, the incidence of the primary outcome was 12.8% in patients randomized to aCRT compared with 27.4% in convCRT patients (HR = 0.45; 95% CI = 0.24-0.85; P = .01). Also, patients with AF episodes adjudicated as clinical adverse events were less common with aCRT (4.3%) than with convCRT (12.7%) (HR = 0.39; 95% CI = 0.19-0.79; P = .01). CONCLUSION: Patients receiving aCRT had a reduced risk of AF compared with those receiving convCRT. Most of the reduction in AF occurred in subgroups with prolonged AV conduction at baseline and with significant left atrial reverse remodeling. PMID- 28893550 TI - Specificity of two HIV screening tests detecting simultaneously HIV-1 p24 antigen and antibodies to HIV-1 and -2. AB - This study aimed at assessing the specificity of the Elecsys(r) HIV combi PT in comparison to the ARCHITECT(r) HIV Ag/Ab Combo. With both of these assays, 3997 unselected sera from patients of a tertiary health care centre in Basel, Switzerland, were screened for HIV. Reactive sera were reanalysed on the VIDAS(r) HIV Duo Ultra to identify false-reactive specimens prior to confirmation by quantitative PCR and line immunoassay. The Elecsys(r) compared to the ARCHITECT(r) shows a similar specificity (99.7% versus 99.8%) but a slightly lower positive predictive value (71.8% versus 80%). Samples tested with a cut-off index (COI) between 0.91 and 4.85 (cut-off <0.9) with the Elecsys(r) and with a signal to cut-off index (S/CO) between 1.09 and 12.49 (cut-off <1.0) with the ARCHITECT(r) were false-reactive. There was no false-reactive result with the VIDAS(r). Of the false-reactive samples, 66.7% could be related to patient specific underlying conditions. The HIV two-tiered diagnostic algorithm proposed in this work improved the positive predictive values of the Elecsys(r) or ARCHITECT(r) to 100% when the results of the VIDAS(r) were included. Values just above the cut-off are highly suspicious to be false-reactive and high COI or S/CO ratios are associated with true positivity. PMID- 28893552 TI - Applicability of the grip strength and automated von Frey tactile sensitivity tests in the mouse photothrombotic model of stroke. AB - Improvement of impaired neurological function(s) is a primary endpoint in experimental stroke recovery studies, making the choice and nature of the functional tests crucial for proper execution and interpretation of such studies. Currently, there are a limited number of neurological tests which reliably evaluate functional deficit in mice over a long period of time after stroke. In this study, we evaluated the applicability of forepaw grip strength and automated von Frey tactile sensitivity tests to assess forelimb dysfunction in mice following photothrombosis in the sensorimotor cortex, and compared them with two well-established tests, grid-walking and cylinder, for up to 21days after stroke. Our results indicate that the length of time required to conduct the two new tests is comparable to that of the grid-walking and cylinder tests, however the data from the new tests is obtained and ready for analysis upon completion of the testing session. In addition, our observations indicate that the automated von Frey test detected substantial and sustained deficit in the withdrawal threshold of the mice on all evaluation days after stroke, whereas the forepaw grip strength test was only marginally sensitive to document functional impairment. Our data demonstrate that the automated von Frey tactile sensitivity test is a time efficient and sensitive method which can be used together with other established tests to evaluate long-term functional outcome in the mouse photothrombotic stroke model. PMID- 28893551 TI - Targeting and isolation of cancer cells using micro/nanomotors. AB - Micro/nanomotors distinguish themselves with in situ energy conversion capability for autonomous movement, a feature that confers remarkable potential to improve cancer treatment. In this review article, three areas are highlighted where micro/nanomotors have established themselves with unique contributions, including propelled navigation to promote cancer cell targeting, powered cell membrane penetration to enhance intracellular delivery, and steered isolation of circulating tumor cells for detection. Progress made in these areas has offered promising inspiration and opportunities aimed for enhancing the efficiency and precision of drug targeting to cancer cells, improving the capability of delivering anticancer drug into cytoplasm for bioactivity, and enabling more rapid and sensitive cancer cell detection. Herein, we review each area with highlights of the current and forthcoming micro/nanomotor techniques in advancing cancer diagnosis and treatment. PMID- 28893553 TI - Caffeine has no effect on eyeblink conditioning in mice. AB - Caffeine is one of the most widely used drugs in the world. In the brain, caffeine acts as an antagonist for the adenosine A1 and A2B receptors. Since A1 receptors are highly concentrated in the cortex of the cerebellum, we hypothesized that caffeine could potentially affect learning tasks that require the cerebellar cortex, such as eyeblink conditioning. To test this hypothesis, we examined the effect of low (5mg/kg) and high (50mg/kg) doses of caffeine, injected intraperitoneally before training, on eyeblink conditioning in mice. The results show that, at the dosages we used, caffeine affects neither the rate of acquisition, nor the timing of the onset or peak of the conditioned blink responses. Therefore, we conclude that caffeine neither improves nor worsens performance on eyeblink conditioning. PMID- 28893554 TI - Functional gait analysis in a spinal contusion rat model. AB - Evaluating functional performance of spinal cord injury (SCI) rat models is essential for the development of novel treatments and breakthroughs. However, due to the variety of functional analysis methods available - each with its own strengths and weaknesses - it can be challenging to choose the most appropriate functional analysis test for the animal model. Therefore, we analyzed the strengths and weaknesses of five methods in order to determine which test is not only accurate and easily reproducible, but also relatively inexpensive so that it can be adopted universally. When comparing the Basso, Beattie, and Bresnahan (BBB) test, Ladder walking test, CatWalk test, Rotating Rod test, Microsoft Kinect system and VICON, we used the criteria of sensitivity, quality of data generated, statistical analysis of data, and rate of human error. These specific tests were chosen in order to compare the advantages and disadvantages of simple yet effective methods (BBB, Ladder test, and Rotating Rod test) to more complex and computerized methods (Catwalk, Microsoft Kinect and VICON). PMID- 28893555 TI - Pacing stereotypies in laboratory rhesus macaques: Implications for animal welfare and the validity of neuroscientific findings. AB - Stereotypic behaviours are commonly observed in captive animals and are usually interpreted as a sign of poor welfare. Stereotypies have also been linked with brain abnormalities. However, stereotypies are a heterogeneous class of behaviours and mounting evidence indicates that different stereotypies can have different causes, and can be linked to different affective states. As a consequence, the implications of a specific stereotypy in a specific species cannot be safely inferred from evidence on other stereotypies or species. Here we review what is known about pacing behaviour in laboratory rhesus macaques, a common stereotypy in this species. Our review highlights the current lack of understanding of the causal factors underlying pacing behaviour. According to current knowledge, the welfare of pacing macaques could be either better, worse or equivalent to that of non-pacing individuals. It is also unclear whether pacing results from brain abnormalities. Since rhesus macaques are widely used as a model of healthy humans in neuroscience research, determining if pacing behaviour reflects an abnormal brain and/or poor welfare is urgent. PMID- 28893556 TI - The ILK-MMP9-MRTF axis is crucial for EndMT differentiation of endothelial cells in a tumor microenvironment. AB - Increasing evidence indicates that the tumor microenvironment is a critical factor supporting cancer progression, chemoresistance and metastasis. Recently, cancer-associated fibroblasts (CAFs) have been recognized as a crucial tumor stromal component promoting cancer growth and invasiveness via modulation of the extracellular matrix (ECM) structure, tumor metabolism and immune reprogramming. One of the main sources of CAFs are endothelial cells undergoing the endothelial mesenchymal transition (EndMT). EndMT is mainly promoted by the Transforming Growth Factor-beta (TGF-beta) family secreted by tumor cells, though the role of particular members in EndMT regulation remains poorly understood. Our findings demonstrate that TGF-beta2 induces mesenchymal transdifferentiation of human microvascular endothelial cells (HMEC-1 cells) to CAF-like cells in association with elongated cell morphology, modulation of stress fiber organization, higher alpha-SMA protein levels and activation of RhoA and Rac-1 pathways. Such regulation is similar to that observed in cells maintained using conditioned medium from invasive colorectal cancer cell line culture. Furthermore, TGF-beta2 stimulation resulted in myocardin-related transcription factor (MRTF) activation and upregulation. Our results demonstrate for the first time that such interaction is sufficient for integrin-linked kinase (ILK) overexpression. ILK upregulation also enhanced MRTF activation via RhoA and Rac-1-MMP9 via inside-out integrin activation. Herein, we propose a new ILK-MMP9-MRTF axis that appears to be critical for EndMT differentiation of endothelial to CAF-like cells. Thus, it might be an attractive target for cancer treatment. PMID- 28893557 TI - Transcription factor CUX1 is required for intestinal epithelial wound healing and targets the VAV2-RAC1 Signalling complex. AB - Intestinal epithelial cells form a protective barrier in limiting gut luminal content potentially harmful to the host. Upon gut epithelium injury, several signals instruct epithelial cells to undergo a rapid healing process. Defects in this process induce inflammatory responses and can further evolve into chronic gut inflammatory diseases. We previously identified the transcription factor CUX1 as crucial for protecting against experimental colitis in mice. However, the precise molecular mechanisms by which CUX1 intervenes during this biological process are unknown. Our aim was to evaluate CUX1 biological and functional roles during intestinal epithelial cell wound healing. RNAi knockdown of CUX1 in intestinal epithelial cells revealed a crucial role for this regulator in migratory response following wounding assays. Gene expression profiling identified several gene transcripts modulated in absence of CUX1 during wound healing for which a significant number was associated with cell motility and cytoskeleton function. Chromatin immunoprecipitation assays identified the guanine nucleotide exchange factor Vav2 gene as a direct target for CUX1. Coincidently, reduction of VAV2 in absence of CUX1 was associated with a significant decrease of RAC1 activity in response to epithelial wounding. Our results identify a novel pathway by which CUX1 regulates normal intestinal epithelial cell restitution. PMID- 28893558 TI - The effects of chronic testosterone administration on body weight, food intake, and fat weight were age-dependent. AB - Previously, we showed that chronic testosterone administration increased body weight (BW) and food intake (FI), but did not alter fat weight, in young female rats. To examine our hypothesis that the effects of androgens on BW, FI and body composition might be age-dependent, the effects of chronic testosterone administration were evaluated in rats of different ages; i.e., young and middle aged rats. Although chronic testosterone administration increased BW gain, FI, and feed efficiency in both young and middle-aged rats, it increased visceral fat weight in middle-aged rats, but not in young rats. Therefore, it is possible that testosterone promotes the conversion of energy to adipose tissue and exacerbates fat accumulation in older individuals. In addition, although the administration of testosterone increased the serum leptin level, it did not alter hypothalamic neuropeptide Y mRNA expression in middle-aged rats. On the contrary, the administration of testosterone did not affect the serum leptin levels of young rats. Thus, testosterone might induce hypothalamic leptin resistance, which could lead to fat accumulation in older individuals. Testosterone might disrupt the mechanisms that protect against adiposity and hyperphagia and represent a risk factor for excessive body weight and obesity, especially in older females. PMID- 28893559 TI - Twenty-four hour urinary cortisol excretion and the metabolic syndrome in prednisolone-treated renal transplant recipients. AB - Chronic prednisolone treatment in renal transplant recipients (RTR) causes metabolic abnormalities, which cluster in the metabolic syndrome (MS). It also suppresses the hypothalamic-pituitaryadrenal (HPA)-axis. We investigated whether HPA-axis suppression, as measured by 24h urinary cortisol excretion, is associated with presence of the MS and its individual components, in outpatient RTR with a functioning graft for >1year. Urinary cortisol was measured in 24h urine, using LC-MS/MS (LOQ 0.30nmol/L). We included 563 RTR (age 51+/-12years; 54% male) at median 6.0 [IQR, 2.6-11.5] years post-transplantation. MS was present in 439/563 RTR (78%). Median 24h urinary cortisol excretion was 2.0 [IQR, 0.9-5.1]nmol/24h. Twenty-four hour urinary cortisol excretion was independently associated with MS presence (OR=0.80 [95% CI, 0.66-0.98], P=0.02). It was also independently associated with bodyweight (st.beta=-0.11, P=0.007), waist circumference (st.beta=-0.10, P=0.01), BMI (st.beta=-0.14, P=0.001), fasting triglycerides (st.beta=-0.15, P=0.001), diabetes (st.beta=-0.12, P=0.005), and number of antihypertensives used (st.beta=-0.13, P=0.003). Suppressed HPA-axis activity, as reflected by decreased 24h urinary cortisol excretion, is associated with higher prevalence of MS and its individual components (i.e. central obesity, dyslipidemia, diabetes, hypertension) in prednisolone-treated RTR. Assessment of 24h urinary cortisol excretion by LC-MS/MS may be a tool to monitor metabolic side-effects of prednisolone in RTR. PMID- 28893560 TI - EMR is superior to rectal suction biopsy for analysis of enteric ganglia in constipation and dysmotility. AB - BACKGROUND AND AIMS: Patients with chronic constipation or motility disorders may be referred for rectal suction biopsy (RSB) to rule out Hirschsprung's disease (HD). RSB may not be successful beyond infancy because of the increased thickness of the rectal mucosa. EMR could improve the diagnostic yield for HD when compared with traditional RSB because larger and deeper samples are acquired for analysis. METHODS: In this prospective, single-center study, patients referred for RSB were offered enrollment for concurrent EMR. Specimens were analyzed pathologically for size, submucosal ganglionic tissue, and acetylcholinesterase or calretinin staining. Biopsy results were compared with transit studies, anorectal manometry, and constipation severity through validated questionnaires. RESULTS: Seventeen patients (2 male, 15 female; mean age, 35.8 years; range, 22-61 years) were enrolled in the study from 2008 to 2014. All patients underwent anorectal manometry (88% with anorectal dysfunction, 68% with outlet obstruction) and transit studies (41% with delayed transit). There were no reports of adverse events from the RSB and EMR procedures. The RSB sample volumes were significantly lower than the EMR sample volumes (0.023 cm3 vs 0.26 cm3, P = .001). There was diagnostic tissue for submucosal visualization by RSB in 53% (9/17) of cases compared with 100% (17/17) with EMR (P = .003). No cases of HD were diagnosed by RSB; one patient had rare ganglions observed by EMR. CONCLUSIONS: EMR provides greater tissue volume and can improve the characterization of ganglion cells in rectal tissue compared with RSB in patients with moderate to severe constipation with suspected HD. PMID- 28893561 TI - Genotyping of single nucleotide polymorphism by probe-gated silica nanoparticles. AB - The development of simple, reliable, and rapid approaches for molecular detection of common mutations is important for prevention and early diagnosis of genetic diseases, including Thalessemia. Oligonucleotide-gated mesoporous nanoparticles based analysis is a new platform for mutation detection that has the advantages of sensitivity, rapidity, accuracy, and convenience. A specific mutation in beta thalassemia, one of the most prevalent inherited diseases in several countries, was used as model disease in this study. An assay for detection of IVS110 point mutation (A > G reversion) was developed by designing probe-gated mesoporous silica nanoparticles (MCM-41) loaded with reporter fluorescein molecules. The silica nanoparticles were characterized by AFM, TEM and BET analysis for having 180 nm diameter and 2.83 nm pore size regular hexagonal shape. Amine group functionalized nanoparticles were analysed with FTIR technique. Mutated and normal sequence probe oligonucleotides)about 12.7 nmol per mg nanoparticles) were used to entrap reporter fluorescein molecules inside the pores and hybridization with single stranded DNA targets amplified by PCR gave different fluorescent signals for mutated targets. Samples from IVS110 mutated and normal patients resulted in statistically significant differences when the assay procedure were applied. PMID- 28893563 TI - The impact of murine LRRK2 G2019S transgene overexpression on acute responses to inflammatory challenge. AB - The most common Parkinson's disease (PD) mutation is the gain-of-function LRRK2 G2019S variant, which has also been linked to inflammatory disease states. Yet, little is known of the role of G2019S in PD related complex behavioral or immune/hormonal processes in response to inflammatory/toxicant challenges. Hence, we characterized the behavioral, neuroendocrine-immune and central monoaminergic responses in G2019S overexpressing mutants following systemic interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) administration. Although LPS markedly (and IFN-gamma modestly in some cases) increased cytokine and corticosterone levels, while inducing pronounced sickness and home-cage activity deficits, the G2019S mutation had no effect on these parameters. No differences were observed with regards to brain microglia with the acute LPS injection, regardless of genotype. Nor did the G2019S mutation influence neurotransmitter levels within the medial prefrontal cortex or paraventricular nucleus of the hypothalamus. However, the LRRK2 G2019S transgenic mice did have altered monoamine levels within the striatum and hippocampus. Indeed, G2019S mice had altered basal levels and turnover of dopamine within the striatum, along with changes in hippocampal serotonin and norepinephrine activity in response to LPS and IFN-gamma. The present findings suggest the importance of murine G2019S in hippocampal and striatal neurotransmission, but that the transgene didn't appear to be involved in functional behavioral and stress-like hormonal and cytokine changes provoked by inflammatory insults. PMID- 28893564 TI - 5-Aza-2'-deoxycytidine induces human Tenon's capsule fibroblasts differentiation and fibrosis by up-regulating TGF-beta type I receptor. AB - The principle reason of high failure rate of glaucoma filtration surgery is the loss of filtration function caused by postoperative scar formation. We investigated the effects of 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA methyltransferases inhibitor, on human Tenon's capsule fibroblasts (HTFs) differentiation and fibrosis and its mechanism of action, especially in relation to transforming growth factor (TGF)-beta1 signaling. TGF-beta1 was used to induce differentiation of cultured HTFs. 5-Aza-dc suppressed DNA methyltransferases (DNMTs) activity 6 h after treatment with a course corresponding to that of TGF beta1-induced reduction of DNMT activity without affecting cell viability as measured by Cell Counting Kit-8 assay. 5-Aza-dc also reduced DNMT1 and DNMT3a protein expression from 24 to 48 h. HTFs migration evaluated by scratch-wound assay were significantly increased 24 h after 5-Aza-dc treatment, a time course similar to that of TGF-beta1. Treatment with 5-Aza-dc significantly increased the mRNA and protein levels of alpha-smooth muscle actin (alpha-SMA), collagen-1A1 (Col1A1), fibronectin (FN) and TGF-beta type I receptor (TGFbetaRI). Furthermore, the effects of 5-Aza-dc on DNMT activity suppression, cell migration, and fibrosis were all reversed by a TGFbetaRI inhibitor- SB-431542. Meanwhile, knockdown of DNMT1 upregulated TGFbetaRI expression and had the same fibrosis inducing effect in HTFs, which was also inhibited by SB-431542. Thus, the results indicate that DNA hypomethylation induces HTFs differentiation and fibrosis through up-regulation of TGFbetaRI. DNA methylation status plays an important role in subconjunctival wound healing. PMID- 28893565 TI - A review of the effects of physical activity and sports concussion on brain function and anatomy. AB - Physical activity has been associated with widespread anatomical and functional brain changes that occur following acute exercise or, in the case of athletes, throughout life. High levels of physical activity through the practice of sports also lead to better general health and increased cognitive function. Athletes are at risk, however, of suffering a concussion, the effects of which have been extensively described for brain function and anatomy. The level to which these effects are modulated by increased levels of fitness is not known. Here, we review literature describing the effects of physical activity and sports concussions on white matter, grey matter, neurochemistry and cortical excitability. We suggest that the effects of sports concussion can be coufounded by the effects of exercise. Indeed, available data show that the brain of athletes is different from that of healthy individuals with a non-active lifestyle. As a result, sports concussions take place in a context where structural/functional plasticity has occurred prior to the concussive event. The sports concussion literature does not permit, at present, to separate the effects of intense and repeated physical activity, and the abrupt removal from such activities, from those of concussion on brain structure and function. PMID- 28893566 TI - Does fear extinction in the laboratory predict outcomes of exposure therapy? A treatment analog study. AB - Fear extinction models have a key role in our understanding of anxiety disorders and their treatment with exposure therapy. Here, we tested whether individual differences in fear extinction learning and fear extinction recall in the laboratory were associated with the outcomes of an exposure therapy analog (ETA). Fifty adults with fear of spiders participated in a two-day fear-learning paradigm assessing fear extinction learning and fear extinction recall, and then underwent a brief ETA. Correlational analyses indicated that enhanced extinction learning was associated with better ETA outcome. Our results partially support the idea that individual differences in fear extinction learning may be associated with exposure therapy outcome, but suggest that further research in this area is needed. PMID- 28893562 TI - Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia. AB - Current antipsychotic drugs provide symptomatic relief for positive symptoms of schizophrenia, but do not offer symptom management for negative and cognitive symptoms. In addition, many patients discontinue treatment due to adverse side effects. Therefore, there is a critical need to develop more effective and safe treatment options. Although the etiology of schizophrenia is unclear, considerable data from post-mortem, neuroimaging and neuropharmacology studies support a role of the muscarinic acetylcholine (mAChRs) in the pathophysiology of schizophrenia. Substantial evidence suggests that activation of mAChRs has the potential to treat all symptom domains of schizophrenia. Despite encouraging results in demonstrating efficacy, clinical trials of nonselective mAChR agonists were limited in their clinical utility due to dose-limiting peripheral side effects. Accordingly, efforts have been made to specifically target centrally located M1 and M4 mAChR subtypes devoid of adverse-effect liability. To circumvent this limitation, there have been tremendous advances in the discovery of ligands that bind at allosteric sites, binding sites distinct from the orthosteric site, which are structurally less conserved and thereby afford high levels of receptor subtype selectivity. The discovery of subtype-specific allosteric modulators has greatly advanced our understanding of the physiological role of various muscarinic receptor subtypes in schizophrenia and the potential utility of M1 and M4 mAChR subtypes as targets for the development of novel treatments for schizophrenia and related disorders. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 28893567 TI - Molecular basis of androgen action on human sexual desire. AB - Reproduction is a fundamental process for the species maintenance and the propagation of genetic information. The energy expenditure for mating is overtaken by motivational stimuli, such as orgasm, finely regulated by steroid hormones, gonadotropins, neurotransmitters and molecules acting in the brain and peripheral organs. These functions are often investigated using animal models and translated to humans, where the androgens action is mediated by nuclear and membrane receptors converging in the regulation of both long-term genomic and rapid non-genomic signals. In both sexes, testosterone is a central player of this game and is involved in the regulation of sexual desire and arousal, and, finally, in reproduction through cognitive and peripheral physiological mechanisms which may decline with aging and circadian disruption. Finally, genetic variations impact on reproductive behaviours, resulting in sex-specific effect and different reproductive strategies. In this review, androgen actions on sexual desire are evaluated, focusing on the molecular levels of interaction. PMID- 28893569 TI - Fatty acid binding protein 4 promotes epithelial-mesenchymal transition in cervical squamous cell carcinoma through AKT/GSK3beta/Snail signaling pathway. AB - Fatty acid binding protein 4 (FABP4) is a member of the fatty acid binding protein family which involved in a variety of biological cellular processes, including tumorigenesis. However, the role of this key adipokine in cervical cancer is still unclear. In this study, we explored the function of FABP4 in cervical cancer and the underlying molecular mechanisms. FABP4 was specifically elevated in tissue samples from patients with cervical squamous cell carcinoma (CSCC) but not with cervical adenocarcinoma, and the level of FABP4 was correlated with E-cadherin and Vimentin expression. In vitro, exogenous FABP4 promoted the migration and invasion of CSCC cells in a dose-dependent manner, and reorganized the actin cytoskeletons in F-Actin staining and TGF-beta induced EMT assays. Importantly, the AKT/GSK3beta/Snail pathway appears to be involved in FABP4-induced EMT in CSCC cells. In conclusion, our research demonstrated elevated FABP4 promoted EMT via the activation of AKT/GSK3beta/Snail pathway in CSCC. PMID- 28893568 TI - Endocrine and physiological regulation of neutral fat storage in Drosophila. AB - After having revolutionized our understanding of the mechanisms of animal development, Drosophila melanogaster has more recently emerged as an equally valid genetic model in the field of animal metabolism. An increasing number of studies have revealed that many signaling pathways that control metabolism in mammals, including pathways controlled by nutrients (insulin, TOR), steroid hormone, glucagon, and hedgehog, are functionally conserved between mammals and Drosophila. In fact, genetic screens and analyses in Drosophila have identified new players and filled in gaps in the signaling networks that control metabolism. This review focuses on data that show how these networks control the formation and breakdown of triacylglycerol energy stores in the fat tissue of Drosophila. PMID- 28893570 TI - Phytoestrogenic effect of Inula racemosa Hook f - A cardioprotective root drug in traditional medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Roots of Inula racemosa are used as a cardio protective in Ayurveda in India, being prescribed as a medicine for precordial chest pain, cough and dyspnoea, both singly and as a poly herbal. AIM: Evaluation of Phytoestrogenic activity of the root extracts of Inula racemosa and compounds isolated therefrom in vivo, in silico and in vitro. MATERIALS AND METHODS: Alcohol (IrA) and hexane (IrH) extracts characterized by HPTLC/GC-MS analysis respectively and processed for compound isolation were evaluated for estrogenic activity (100 & 250mg/kg bw) by the Immature rat uterotrophic assay using ethinylestradiol (EE -30ug/kg bw) as standard drug. Alantolactone (ALT), Isoalantolactone (IALT) and Stigmasterolglucoside (SG) isolated from the extracts were characterized and screened in silico for ERalpha, ERbeta binding affinity, assessed in vitro for growth modulatory effects on MCF-7 cells by MTT assay and cell cycle distribution analysis using Flow cytometry. RT-PCR analysis evaluated the mRNA expression of pS2 in these cells post exposure to ALT, IALT and SG. RESULTS: In the IrA treated groups there has been a statistically significant increase (P < 0.05) in absolute and normalised uterine weight, uterine diameter, endometrial thickness, luminal epithelial cell height,diameter of ovary and in the number of primary and secondary ovarian follicles relative to untreated controls. Presence of ciliated epithelial cells in the oviduct, elevated number of early growing follicles characterized by an increased oocyte diameter, and signs of vascularization in the cortex of ovarian sections in this group relative to EE treated group are indicative of pervasive activation of follicular growth and initiation. Virtual docking demonstrated ERalpha affinity for IALT, ERbeta affinity for ALT, while SG showed a high binding affinity to both with a relatively greater ERbeta binding affinity. Dose dependent decrease in cell viability mediated by IALT and SG in the MTT assay is corroborated by a statistically significant increase (p < 0.05) in sub G0-G1 cells by SG at 200 and 400uM in cell cycle analysis and there has been an induction of pS2 by IALT and SG in the ER regulated MCF-7 cells. CONCLUSIONS: Demonstration of classical morphological changes induced by estrogen stimulation mediated by IrA in vivo at both the tested doses, isolation of the antioxidant SG from IrA and its dose dependent growth inhibitory effect on estrogen sensitive MCF-7 cells through apoptotic induction and an up regulation of pS2 are suggestive of an anti estrogenic effect through estrogen receptor binding affinity, typical of phytoestrogens that bind to ER but do not elicit a full estrogenic response. The observed estrogenic effect of IrA suggests a multi mechanistic molecular action involving antioxidant as well as redox signalling pathways acting in consonance with their anti-estrogenic effects owing to the weak estrogen like competitive receptor binding of SG. PMID- 28893571 TI - Most systematic reviews of high methodological quality on psoriasis interventions are classified as high risk of bias using ROBIS tool. AB - OBJECTIVES: No gold standard exists to assess methodological quality of systematic reviews (SRs). Although Assessing the Methodological Quality of Systematic Reviews (AMSTAR) is widely accepted for analyzing quality, the ROBIS instrument has recently been developed. This study aimed to compare the capacity of both instruments to capture the quality of SRs concerning psoriasis interventions. STUDY DESIGN AND SETTING: Systematic literature searches were undertaken on relevant databases. For each review, methodological quality and bias risk were evaluated using the AMSTAR and ROBIS tools. Descriptive and principal component analyses were conducted to describe similarities and discrepancies between both assessment tools. RESULTS: We classified 139 intervention SRs as displaying high/moderate/low methodological quality and as high/low risk of bias. A high risk of bias was detected for most SRs classified as displaying high or moderate methodological quality by AMSTAR. When comparing ROBIS result profiles, responses to domain 4 signaling questions showed the greatest differences between bias risk assessments, whereas domain 2 items showed the least. CONCLUSION: When considering SRs published about psoriasis, methodological quality remains suboptimal, and the risk of bias is elevated, even for SRs exhibiting high methodological quality. Furthermore, the AMSTAR and ROBIS tools may be considered as complementary when conducting quality assessment of SRs. PMID- 28893572 TI - Reduced Severity of Outcome of Recurrent Ipsilateral Transient Cerebral Ischemia Compared with Contralateral Transient Cerebral Ischemia in Rats. AB - BACKGROUND: To investigate whether prior transient ischemic attack (TIA) had a preconditioning effect on subsequent cerebral infarction in a rat model using middle cerebral artery occlusion (MCAO). METHODS: Thirty-six adult male Sprague Dawley rats were divided into 3 groups: those with transient (5 minutes) left MCAO (left TIA) (n = 15), those with transient right MCAO (right TIA) (n = 15), and a sham operation group (n = 6). Seven days after the initial transient MCAO, rats in all groups underwent permanent left MCAO. After 24 hours, all rats underwent motor function measurement (the Garcia score and tilting plane test), magnetic resonance imaging, postmortem brain examination, and biomarkers of stroke. RESULTS: Following permanent MCAO, the Garcia score, the brain edema area of T2-weighted images, brain infarction volume, and the level of tumor necrosis factor alpha mRNA of the ipsilateral and contralateral TIA groups showed no significant difference. The angle of sliding off in the tilting plane test, the mean intensity of the brain edema area of T2-weighted images, levels of matrix metalloproteinase 9, interleukin-1beta, inducible nitric oxide synthase mRNA, and apoptosis-related proteins, BAX, and phosphorylated-p38, were lower in the ipsilateral TIA group compared with the contralateral TIA group. CONCLUSION: The main finding of this study was that a transient, mild, unilateral focus of cerebral ischemia (or TIA) in either the left or right hemisphere, which is then followed by a second unilateral severe and focal ischemic event, results in brain injury. The severity of the brain injury following this second ischemic event will be alleviated when the second insult is ipsilateral to the first TIA. PMID- 28893573 TI - Measurement of Nutritional Status Using Body Mass Index, Waist-to-Hip Ratio, and Waist Circumference to Predict Treatment Outcome in Females and Males with Acute First-Ever Ischemic Stroke. AB - BACKGROUND: We aimed to investigate whether increased waist-to-hip ratio (WHR), waist circumference (WC), or improper body mass index (BMI) may differently predict short-term outcomes in females and males with first-ever acute ischemic stroke. METHODS: This was a retrospective study of consecutive patients (1109 females and 939 males) admitted for first-ever ischemic stroke between 2003 and 2015. Data were collected in a detailed hospital stroke registry. BMI of 18.5 24.9 kg/m2 and gender-specific normal values of WHC and WC were used as references for comparisons. Logistic regression was used to calculate the odds of in-hospital death or being dead or dependent at discharge, adjusted for patients' age and prestroke disability. RESULTS: In both sexes a high WHR increased the odds of death or dependency at discharge (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.05-3.08 for females and 1.43; 95% CI, 1.00-2.04 for males), but not in-hospital death alone. Increased WC was significantly associated with lower odds of either death or death and dependency at discharge in females only (OR, .36; 95% CI, .22-.58 and .69; 95% CI, .48-.97, respectively). BMI did not show any clear predictive value in either sex. CONCLUSIONS: Our findings suggest that being overweight measured with WC is a strong predictor of good outcome in women but not in men. The WHR less consistently predicts stroke outcome, as it is not associated with death at discharge alone; however, the WHR seems to be of similar clinical relevance in both genders. BMI seems to have the least clinical value in predicting stroke outcome in both genders. PMID- 28893574 TI - Enhancement of Motor Recovery through Left Dorsolateral Prefrontal Cortex Stimulation after Acute Ischemic Stroke. AB - BACKGROUND: Two previous studies, which investigated transcranial direct current stimulation (tDCS) use in motor recovery after acute ischemic stroke, did not show tDCS to be effective in this regard. We speculated that additional left dorsolateral prefrontal cortex (DLPFC) stimulation may enhance poststroke motor recovery. METHODS: In the present randomized clinical trial, 20 acute ischemic stroke patients were recruited. Patients received real motor cortex (M1) stimulation in both arms of the trial. The 2 arms differed in terms of real versus sham stimulation over the left DLPFC. The motor component of the Fugl Meyer upper extremity assessment (FM) and Action Research Arm Test (ARAT) scores were used to assess primary outcomes, and nonlinear mixed effects models were used for data analyses. RESULTS: Primary outcome measures improved more and faster among the real stimulation group. During the first days of stimulations, the sham group's FM scores increased by 1.2 per day, while the real group's scores increased by 1.7 per day (P = .003). In the following days, FM improvement decelerated in both groups. Based on the derived models, a stroke patient with a baseline FM score of 15 improves to 32 in the sham stimulation group and to 41 in the real stimulation group within the first month after stroke. Models with ARAT scores yielded nearly similar results. No significant adverse effect was reported. CONCLUSION: The current study results showed that left DLPFC stimulation in conjunction with M1 stimulation resulted in better motor recovery than M1 stimulation alone. PMID- 28893575 TI - Clinical Characteristics and Outcomes of Intracerebral Hemorrhage in Very Elderly. AB - BACKGROUND: Intracerebral hemorrhage (ICH) incidences increase with age. Patients of advanced age may have limitations during acute care and recovery. We investigated baseline characteristics, hematoma features, and outcomes of very elderly ICH patients (>=80 years old) and compared them with those of younger ICH patients (<80 years old). METHODS: We studied 377 patients (122 women; 69 +/- 11 years old) admitted within 24 hours of ICH onset. Outcome measures included hematoma volumes, National Institutes of Health Stroke Scale scores on admission, and vital and functional prognoses at 30 days. RESULTS: After adjustments for sex, very elderly patients had a higher subcortical hematoma prevalence (odds ratio [OR], 2.62; 95% confidence interval [CI], 1.39-4.86]. On multivariate analyses, very elderly patients had larger hematoma volumes (OR, 1.33; 95% CI, 1.01-1.75, per 10-mL increase). After adjustments for risk factors and comorbidities, modified Rankin scale scores of 0-2 in very elderly patients occurred less often (OR, .34; 95% CI, .14-.82), and those with scores of 5-6 occurred more often (OR, 3.01; 95% CI, 1.09-8.54). CONCLUSIONS: Hematomas were relatively large and often found in the subcortex in very elderly ICH patients. Outcomes of very elderly ICH patients were relatively poor. PMID- 28893576 TI - Isolated Internal Carotid Artery Thrombus and Cerebral Infarction in a Patient with Necrotizing Pancreatitis: Case Report. AB - Isolated internal carotid artery (ICA) thrombus in the absence of underlying atherosclerotic disease is a rare entity. We report a case of a patient presenting with right arm weakness, slurred speech, and altered mental status in the setting of acute on chronic pancreatitis. The patient was found to have scattered left cerebral hemisphere cortical infarctions, and catheter angiography confirmed the presence of intraluminal left ICA thrombus, with no evidence of atherosclerotic disease in the cervical or intracranial vasculature. Further workup also demonstrated the presence of anemia of chronic disease. The patient was initiated on anticoagulation, and follow-up imaging demonstrated a complete resolution of the left ICA thrombus. In the reported case, coagulopathy in the setting of acute on chronic pancreatitis was presumably the primary etiology. Anemia of chronic disease, related to a proinflammatory state, may also play a contributory role. PMID- 28893577 TI - Metalloproteinases in atherosclerosis. AB - Atherosclerosis underlies most cardiovascular diseases, and is accepted as a primary cause of mortality worldwide. Proteases have been implicated in the development and progression of atherosclerosis, due to their ability to provoke focal destruction of the vascular extracellular matrix. Members of the metalloproteinase family, especially matrix metalloproteinases (MMPs), and their endogenous tissue inhibitors (TIMPs) have been suggested to perform complex dual roles during late-stage progression and rupture of atherosclerotic plaques. Proposed favourable actions of metalloproteinases include the promotion of vascular smooth muscle growth and survival which stabilises plaques, while conversely extracellular matrix destruction alongside interminable monocyte/macrophage accumulation can encourage plaque rupture. This review provides a summary of the cogent evidence connecting the contribution of individual metalloproteinases to atherosclerotic plaque development, progression, and instability. Topics discussed include structural, functional and cell specific diversity of MMP members; evidence from animal models of atherosclerosis and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the need for efficient surrogate markers of MMP inhibition. Accordingly, as our knowledge of the complex roles individual MMPs play especially during the progression and rupture of atherosclerotic plaques expands, new impetus is required for clinical trials evaluating the therapeutic potential of selective MMP inhibition, which could limit cardiovascular morbidity and mortality worldwide. PMID- 28893578 TI - Protective effect of cinnamaldehyde against glutamate-induced oxidative stress and apoptosis in PC12 cells. AB - Cinnamaldehyde is a main ingredient of cinnamon oils from the stem bark of Cinnamomum cassia, which has been widely used in food and traditional herbal medicine in Asia. In the present study, the neuroprotective effects and the potential mechanisms of cinnamaldehyde against glutamate-induced oxidative stress in PC12 cells were investigated. Exposure to 4mM glutamate altered the GSH, MDA levels and SOD activity, caused the generation of reactive oxygen species, resulted in the induction of oxidative stress in PC12 cell, ultimately induced cell death. However, pretreatment with cinnamaldehyde at 5, 10 and 20MUM significantly attenuated cell viability loss, reduced the generation of reactive oxygen species, stabilised mitochondrial membrane potential (MMP), decreased the release of cytochrome c and limited the activities of caspase-9 and -3. In addition, cinnamaldehyde also markedly increased Bcl-2 while inhibiting Bax expression,and decreased the LC3-II/LC3-I ratio. These results indicate that cinnamaldehyde exists a potential protective effect against glutamate-induced oxidative stress and apoptosis in PC12 cells. PMID- 28893579 TI - The brain during free movement - What can we learn from the animal model. AB - Animals, just like humans, can freely move. They do so for various important reasons, such as finding food and escaping predators. Observing these behaviors can inform us about the underlying cognitive processes. In addition, while humans can convey complicated information easily through speaking, animals need to move their bodies to communicate. This has prompted many creative solutions by animal neuroscientists to enable studying the brain during movement. In this review, we first summarize how animal researchers record from the brain while an animal is moving, by describing the most common neural recording techniques in animals and how they were adapted to record during movement. We further discuss the challenge of controlling or monitoring sensory input during free movement. However, not only is free movement a necessity to reflect the outcome of certain internal cognitive processes in animals, it is also a fascinating field of research since certain crucial behavioral patterns can only be observed and studied during free movement. Therefore, in a second part of the review, we focus on some key findings in animal research that specifically address the interaction between free movement and brain activity. First, focusing on walking as a fundamental form of free movement, we discuss how important such intentional movements are for understanding processes as diverse as spatial navigation, active sensing, and complex motor planning. Second, we propose the idea of regarding free movement as the expression of a behavioral state. This view can help to understand the general influence of movement on brain function. Together, the technological advancements towards recording from the brain during movement, and the scientific questions asked about the brain engaged in movement, make animal research highly valuable to research into the human "moving brain". PMID- 28893580 TI - High intraocular pressure produces learning and memory impairments in rats. AB - Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Previous MRI studies have revealed that POAG can be associated with alterations in hippocampal function. Thus, the aim of this study was to investigate a relationship between chronic high intraocular pressure (IOP) and hippocampal changes in a rat model. We used behavioural tests to assess learning and memory ability, and additionally investigated the hippocampal expression of pathological amyloid beta (Abeta), phospho-tau, and related pathway proteins. Chronic high IOP impaired learning and memory in rats and concurrently increased Abeta and phospho-tau expression in the hippocampus by altering the activation of different kinase (GSK-3beta, BACE1) and phosphatase (PP2A) proteins in the hippocampus. This study provides novel evidence for the relationship between high IOP and hippocampal alterations, especially in the context of learning and memory. PMID- 28893581 TI - Tryptophan circuit in fatigue: From blood to brain and cognition. AB - Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction. PMID- 28893582 TI - Designing lipid nanoparticles for topical ocular drug delivery. AB - Topically-applied dosage forms, such eye drops, are the most used formulations in the treatment of ocular diseases. Nonetheless, because of the special protection of the eye associated with the ocular surface, drug bioavailability and subsequent therapeutic efficiency obtained with these conventional dosage forms are very low. Recently, novel drug delivery systems have been proposed to solve the main drawbacks of conventional formulations. Nanotechnology, and more specifically lipid nanoparticles, have emerged as promising "modified eyedrops" with the purpose of improving therapeutic efficiency without compromising drug safety and patient compliance. The purpose of this review is to offer an overview of lipid nanoparticles as feasible alternatives to the conventional topically applied dosage forms. We discuss the main limitations of topical ocular drug delivery and describe how correctly designed lipid nanoparticles can be highly valuable tools to overcome the constraints imposed by the ocular surface. Special emphasis is placed on the description of production methods and bulk materials used in the development of lipid nanoparticles for ophthalmic use and how both issues will determine the physicochemical and biopharmaceutical properties of the developed nanosystems. PMID- 28893583 TI - Facile formation of co-amorphous atenolol and hydrochlorothiazide mixtures via cryogenic-milling: Enhanced physical stability, dissolution and pharmacokinetic profile. AB - The development of poorly water-soluble drugs faces the risk of low bioavailability and therapeutic efficacy. The co-amorphous drug delivery system has recently gained considerable interest because it offers an alternative approach to modify properties of poorly water-soluble drugs. Herein, we developed a co-amorphous system of atenolol (ATE) and poorly water-soluble hydrochlorothiazide (HCT) by means of cryogenic milling. The co-administration of ATE and HCT has been reported to show therapeutic advantages for patients with uncomplicated hypertension. The co-amorphous ATE-HCT sample with 1:1 molar ratio showed excellent physical stability, which could be attributed to the formation of strong molecular interactions between ATE and HCT as evidenced by FT-IR spectra. Compared to the pure crystalline form, amorphous form and physical mixture, HCT in the co-amorphous form exhibited the significantly increased intrinsic dissolution rate, as well as the enhanced bioavailability in the pharmacokinetic study. It was found that the enhanced bioavailability of HCT in the co-amorphous formulation was achieved by the synergistic effect of amorphized HCT and the water-soluble coformer ATE. The present study provides an improved approach to implement the combination therapy of ATE and HCT for potential clinical treatments. PMID- 28893584 TI - Levetiracetam+nonsteroidal anti-inflammatory drug binary systems: A contribution to the development of new solid dosage forms. AB - A study has been carried out of binary solid systems made up of the antiepileptic drug levetiracetam, LEV, and a nonsteroidal anti-inflammatory drug, NSAID, capable of managing the inflammation that accompanies epileptic activity. One aim of this research was to identify eutectic mixtures and co-crystals, which are able to impact positively on their biopharmaceutical properties. The NSAIDs studied are (S)- and (R,S)-ibuprofen, (S)- and (R,S)-naproxen, (R,S)-ketoprofen and (R,S)-flurbiprofen, all class II in the Biopharmaceutical Classification System. A green mechanochemical methodology has been used to prepare binary mixtures with different molar ratios, and the binary solid-liquid phase diagrams established. For LEV+(S)-ibuprofen, formation of a single (1:1) co-crystal was confirmed; this was found to melt incongruently. The co-crystal was found to be stable in accelerated stability tests. For the other systems, interesting eutectic mixtures were identified, which showed enhanced dissolution rates of the NSAID relative to the pure drug. For LEV+(R,S)-ibuprofen, LEV+(S)-naproxen and LEV+(R,S)-naproxen, the eutectic mixture compositions have the effective doses of both components. All the NSAIDs investigated are chiral, and their racemates are racemic compounds. Levetiracetam, the (S)-enantiomer of etiracetam, was not efficient in enantiomer discrimination, as all the racemic compound structures are present as the prepared solid mixtures. PMID- 28893585 TI - Thermo-responsive magnetic Fe3O4@P(MEO2MAX-OEGMA100-X) NPs and their applications as drug delivery systems. AB - The unique physical properties of the superparamagnetic nanoparticles (SPIONs) have made them candidates of choice in nanomedicine especially for diagnostic imaging, therapeutic applications and drug delivery based systems. In this study, superparamagnetic Fe3O4 NPs were synthesized and functionalized with a biocompatible thermoresponsive copolymer to obtain temperature responsive core/shell NPs. The ultimate goal of this work is to build a drug delivery system able to release anticancer drugs in the physiological temperatures range. The core/shell NPs were first synthesized and their chemical, physical, magnetic and thermo-responsive properties where fully characterized in a second step. The lower critical solution temperature (LCST) of the core/shell NPs was tuned in physiological media in order to release the cancer drug at a controlled temperature slightly above the body temperature to avoid any premature release of the drug. The core/shell NPs exhibiting the targeted LCST were then loaded with Doxurubicin (DOX) and the drug release properties were then studied with the temperature. Moreover the cytotoxicity tests have shown that the core/shell NPs had a very limited cytotoxicity up to concentration of 25MUg/mL. This investigation showed that the significant release occurred at the targeted temperature in the physiological media making those nano-systems very promising for further use in drug delivery platform. PMID- 28893586 TI - Effects of diisononyl phthalate on osteopenia in intact mice. AB - Osteopenia is characterized by bone loss and deterioration of trabecular bone, which leads to osteoporotic fractures. This disease is highly prevalent in industrialized areas and is associated with exposure to endocrine disrupting chemicals (EDCs). Diisononyl phthalate (DINP) is one of these EDCs and is mainly used as a plasticizer in flexible polyvinyl chloride (PVC) products. Although it is well known that exposure to DINP is harmful to humans, no studies have been reported concerning its contribution to osteopenia. Therefore, in this study, we injected DINP (2, 20, and 200mg/kg) into C3H/HeN mice for 6weeks and found that the uterus weight, bone (femur and tibia) weight, and bone length of the DINP exposed mice were reduced compared to those of the SHAM group. On the other hand, body weight, the serum alkaline phosphatase (ALP) and inorganic phosphorus (IP) levels in the DINP treated mice were increased compared with those of the SHAM group. The tartrate-resistant acid phosphatase (TRAP) activity (bone resorption marker) was increased and the bone alkaline phosphatase (BALP) activity was lowered by the treatment with DINP as compared with the SHAM group. Furthermore, the microarchitecture of the femur and tibia in the intact mice was destroyed by the DINP injection. The tissue volume (TV), bone volume (BV), BV/TV, bone surface (BS), BS/TV, trabecular thickness (Tb.Th), and trabecular number (Tb.N) were reduced and the trabecular pattern factor (Tb.Pf), structure model index (SMI), and trabecular separation (Tb.Sp) were increased by the DINP injection. The bone mineral density (BMD) of the femur and tibia was lower in the DINP group than in the SHAM group. These results indicate that DINP contributes to an increased risk of osteopenia via destruction of the microarchitecture and enhancement of osteoclast activity. PMID- 28893587 TI - Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database. AB - The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2*2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models. PMID- 28893588 TI - Resting state fMRI observations of baseline brain functional activities and connectivities in primary blepharospasm. AB - Primary blepharospasm (BPS) is a focal dystonia characterized by involuntary eyelid spasms and blinking. The pathophysiology of BPS remains unclear. Several functional and structural neuroimaging studies have demonstrated abnormalities of sensorimotor structures such as the sensorimotor cortex, the basal ganglia, the thalamus and the cerebellum in BPS patients. However, some of the results of these studies were inconsistent. In addition, the relationship between the motor and sensory structures in patients with BPS still needs to be investigated. Therefore, the purpose of this study was to investigate the abnormal alterations in both the intra-regional brain activities and inter-regional functional connectivities (FC) in patients with BPS using resting-state functional MRI(rs fMRI) and to explore possible correlations between these rs-fMRI indices and clinical variables. The rs-fMRI images of the two groups of subjects (26 BPS patients and 26 healthy controls) were acquired using a 3.0T MRI scanner. The regional rs-fMRI indices, i.e., the fractional amplitude of the low-frequency fluctuation (fALFF) and the regional homogeneity (ReHo), were computed for all subjects. Then, two-sample t-tests were conducted to assess the significant differences between the two groups of subjects. To investigate the alterations in brain networks, cerebral regions with significant differences were used as regions of interest in the whole brain FC analysis. Compared to the control group, the BPS patients revealed significantly increased fALFF and ReHo values in the right caudate head. Significantly strengthened FC values were observed between the right caudate head and the left striatum and the right supplementary motor area in the BPS group. The fALFF and ReHo values in the right caudate head and the FC values between the right caudate head and the left striatum were positively correlated with the Jankovic Rating Scale sum score. In conclusion, this study indicated that BPS patients have both abnormal intra-regional spontaneous brain activities and inter-regional functional connectivities. PMID- 28893589 TI - Leptin status alters buprenorphine-induced antinociception in obese mice with dysfunctional leptin receptors. AB - Buprenorphine is an opiate used for pain management and to treat opiate addiction. The cytokine leptin can modulate nociception, but the extent to which buprenorphine-induced antinociception varies as a function of leptin signaling has not been characterized. Four congenic mouse lines with phenotypes that include differences in body weight and leptin status were used to test the hypothesis that the antinociceptive effects of buprenorphine vary as function of sex and leptin signaling. Each mouse line was comprised of males (n=12) and females (n=12) for a total of 96 animals. Groups included C57BL/6J (B6) mice (wild type), B6 mice with diet-induced obesity (DIO), obese B6.Cg-Lepob/J (ob/ob) mice lacking leptin, and obese B6.BKS(D)-Leprdb/J (db/db) mice with dysfunctional leptin receptors. The dependent measure was tail flick latency (TFL) in seconds for mouse-initiated tail removal from a warm water bath. Independent variables were intraperitoneal administration of saline (control) or buprenorphine (0.3mg/kg). Within every mouse line, buprenorphine significantly increased TFL relative to saline. Compared to the other mouse lines, db/db mice with dysfunctional leptin receptors had a significantly longer TFL after saline and after buprenorphine. TFL did not vary significantly by body weight or sex. The results provide novel support for the interpretation that acute thermal nociception is associated with altered leptin signaling. PMID- 28893590 TI - Design principles of electrical synaptic plasticity. AB - Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between neurons, provide rapid, bidirectional communication that accomplishes tasks distinct from and complementary to chemical synapses. These include coordination of neuron activity, suppression of voltage noise, establishment of electrical pathways that define circuits, and modulation of high order network behavior. In keeping with the omnipresent demand to alter neural network function in order to respond to environmental cues and perform tasks, electrical synapses exhibit extensive plasticity. In some networks, this plasticity can have dramatic effects that completely remodel circuits or remove the influence of certain cell types from networks. Electrical synaptic plasticity occurs on three distinct time scales, ranging from milliseconds to days, with different mechanisms accounting for each. This essay highlights principles that dictate the properties of electrical coupling within networks and the plasticity of the electrical synapses, drawing examples extensively from retinal networks. PMID- 28893591 TI - Neurosteroid dehydroepiandrosterone improves active avoidance retrieval and induces antidepressant-like behavior in rats. AB - Various studies reported beneficial effects of dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), the neurosteroids involved in various brain functions, on synaptic plasticity, neuronal survival, memory, learning and behavior. This study aimed to investigate the behavioral profile of acute DHEA treatment by using active avoidance (AA) task, primarily predictive of the effects on the retrieval based learning, and by applying forced swim test (FST), for assessment of antidepressant-like potential. Adult male Wistar rats received intraperitoneal injections of either DHEA (2, 10, 20mg/kg) or solvent, 30min prior to testing. DHEA, in a manner resembling an inverted U shape, influenced the retrieval imposed to rats in AA paradigm. The significant improvement of the performance in the retention session was observed following 10mg/kg DHEA treatment and it was not due to the changes in the motor activity, as indicated by unaltered locomotor parameters (inter-trial crossing). Moreover, 10mg/kg of DHEA significantly decreased the duration of immobility in FST, demonstrating antidepressant-like effects. The capability of bicuculline (2mg/kg) to antagonize the effects of DHEA has been evaluated simultaneously. The retrieval-facilitating as well as antidepressant-like effects of 10mg/kg DHEA were counteracted by bicuculline, a competitive antagonist of GABAA receptors, suggesting involvement of GABAergic system. These results support administration of DHEA as potential therapeutic strategy for treating depression and related cognitive impairments, but emphasized the importance of adequate dosing, as DHEA levels that are too high or too low may not be beneficial. PMID- 28893592 TI - Connexins and pannexins in Alzheimer's disease. AB - By 2040 neurodegenerative diseases will become the world's second leading cause of death after cardiovascular disease (WHO). Major efforts are required to elucidate the underlying molecular and cellular mechanisms of neurodegenerative diseases. Connexin and pannexin membrane channel proteins are conduits through which neuronal, glial, and vascular tissues interact. In the normal brain, this interaction underlies homeostasis, metabolic supply and neuroprotection. In models of neuroinflammation these channels present aberrant functioning. Validation of the molecular mechanisms by which these membrane channels influence neurodegeneration particularly in Alzheimer's disease could lead to new and alternative therapeutic strategies targeting these channels. PMID- 28893593 TI - Monoaminergic neurotransmission is mediating the antidepressant-like effects of Passiflora edulis Sims fo. edulis. AB - The genus Passiflora is popularly used to treat anxiety. Recent studies showed antidepressant-like effects of two varieties of P. edulis (edulis and flavicarpa) in mice. However, the mechanisms of antidepressant actions are still unknown. Here, the effects of P. edulis fo. edulis aqueous extract (AE, 100-300mg/kg, po), and ethyl acetate (AcOEt, 25-50mg/kg, po), butanol (BuOH, 25-50mg/kg, po) and residual aqueous (25-100mg/kg, po) fractions were investigated in the mouse forced swimming test. In addition, the involvement of monoamines in the P. edulis fractions-induced antidepressant actions was approached. HPLC analyses showed that AcOEt and BuOH, but not residual, fractions shared with AE the main peaks between 25 and 70min (UV 340nm), which are suggestive of flavonoids. Nortriptyline and fluoxetine reduced the immobility time and similar results were observed for AE, AcOEt and BuOH but not residual fractions. PCPA (inhibitor of 5 HT synthesis), AMPT (inhibitor of catecholamine synthesis) and sulpiride (selective D2 receptor antagonist), but not DSP-4 (noradrenergic neurotoxin), blocked the antidepressant actions of AcOEt and BuOH. In conclusion, AcOEt and BuOH fractions shared with AE similar phytochemical composition and antidepressant actions. Preserved 5-HT and dopamine transmissions were required for the antidepressant effects of P. edulis fractions. PMID- 28893594 TI - Nitric oxide in the medial prefrontal cortex contributes to the acquisition of cocaine place preference and synaptic plasticity in the laterodorsal tegmental nucleus. AB - Nitric oxide (NO), a gaseous neurotransmitter, is involved in a variety of brain functions, including drug addiction. Although previous studies have suggested that NO plays an important role in the development of cocaine addiction, the brain region(s) in which NO acts and how it contributes to cocaine addiction remain unclear. In this study, we examined these issues using a cocaine-induced conditioned place preference (CPP) paradigm and ex vivo electrophysiological recordings in rats. Specifically, we focused on the medial prefrontal cortex (mPFC) and laterodorsal tegmental nucleus (LDT), brain regions associated with cocaine CPP development and cocaine-induced plasticity. Intra-mPFC injection of the non-selective NO synthase (NOS) inhibitor L-NAME or the neuronal NOS (nNOS) selective inhibitor L-NPA during the conditioning phase disrupted cocaine CPP. Additionally, intra-mPFC injection of L-NPA prior to each cocaine injection prevented the induction of presynaptic plasticity, induced by repeated cocaine administration, in LDT cholinergic neurons. These findings indicate that NO generated in the mPFC contributes to the acquisition of cocaine CPP and the induction of neuroplasticity in LDT cholinergic neurons. Together with previous studies showing that NO induces membrane plasticity in mPFC neurons, that mPFC neurons project to the LDT, and that LDT activity is critical for the acquisition of cocaine CPP, the present findings suggest that NO-mediated neuroplasticity induced in the mPFC-LDT circuitry is critical for the development of cocaine addiction. PMID- 28893595 TI - Modeling multiple health behaviors and general health. AB - Multiple Health Behavior Change assumes health behaviors are related to one another, although research evidence is mixed. More research is needed to understand which behaviors are most closely related and how they collectively predict health. Principle component analysis and structural equation modeling were used to establish a model showing relations between health behaviors, including fruit/vegetable consumption, aerobic and strength exercise, alcohol intake, and smoking, and how these behaviors relate to general physical and mental health functioning in a large, national sample. Although health behaviors were found to coalesce into a health-promoting factor of diet, and exercise, a better overall model fit was found when all behaviors were modeled as separate independent variables. Results suggest that health behaviors relate to one another in complex ways, with perceived health status serving as a mediating variable between specific health behaviors and a factor of physical and mental health. Future research should further investigate how other health behaviors relate to perceptions and overall health, especially among subpopulations. PMID- 28893597 TI - Evaluation of a provincial intervention to reduce redundant hemoglobin A1c testing. AB - BACKGROUND: The Canadian Diabetes Association recommends testing most individuals with diabetes mellitus using HbA1c once every 3months. In Alberta, Canada, a provincial intervention to reduce inappropriate HbA1c test orders was implemented to align with this guideline, where only one HbA1c test request every 90days for most individuals can be processed. Here, we evaluated the provincial intervention to reduce redundant HbA1c testing in Alberta. METHODS: Total counts of all HbA1c tests ordered within Edmonton and Calgary, Alberta, were collected from the respective Laboratory Information Systems each month between January 2013 and December 2016. Winters' Additive time series model was built to predict the HbA1c test volume after intervention (November 1, 2015 onwards) and compared with the observed test volume to estimate the effect of the intervention. The estimated change in test volume was then multiplied by the estimated cost to determine the economic impact. RESULTS: During the first 14months of the intervention for Alberta, there was a 3.3% reduction in the number of observed HbA1c tests compared to the predicted volume. With an estimated marginal reagent cost of $3.50 per unit, this resulted in a cost savings of $145,422 in the first 14months of the provincial intervention. CONCLUSION: A modest reduction in HbA1c test orders was observed in the urban areas of Alberta since the implementation of this provincial initiative. PMID- 28893596 TI - Sustained engagement of attention is associated with increased negative self referent processing in major depressive disorder. AB - This study investigated the link between self-reference and attentional engagement in adults with (n=22) and without (HC; n=24) Major Depressive Disorder (MDD). Event-related potentials (ERPs) were recorded while participants completed the Self-Referent Encoding Task (SRET). MDD participants endorsed significantly fewer positive words and more negative words as self-descriptive than HC participants. A whole-scalp data analysis technique revealed that the MDD participants had larger difference wave (negative words minus positive words) ERP amplitudes from 380 to 1000ms across posterior sites, which positively correlated with number of negative words endorsed. No group differences were observed for earlier attentional components (P1, P2). The results suggest that among adults with MDD, negative stimuli capture attention during later information processing; this engagement is associated with greater self-referent endorsement of negative adjectives. Sustained cognitive engagement for self-referent negative stimuli may be an important target for neurocognitive depression interventions. PMID- 28893598 TI - Microcystins: Synthesis and structure-activity relationship studies toward PP1 and PP2A. AB - Microcystins are highly toxic cyanotoxins responsible for plant, animal and human poisoning. Exposure to microcystins, mainly through drinkable water and contaminated food, is a current world health concern. Although it is quite challenging, the synthesis of these potent cyanotoxins, analogs and derivatives helps to evaluate their toxicological properties and to elucidate their binding mechanisms to their main targets Protein Phosphatase-1 (PP1) and -2A (PP2A). This review focuses on synthetic approaches to prepare microcystins and analogs and compiles structure-activity relationship (SAR) studies that describe the unique features of microcystins that make them so potent. PMID- 28893600 TI - Synthesis and preliminary in vivo evaluation of new [18F]fluoro-inositols as Positron Emission Tomography radiotracers. AB - This study describes the synthesis and radiosynthesis of eight new [18F]fluoro inositol-based radiotracers in myo- and scyllo-inositol configuration. These radiotracers are equipped with a propyl linker bearing fluorine-18. This fluorinated arm is either on a hydroxyl group, i.e. O-alkylated inositols, or on the cyclohexyl backbone, i.e. C-branched derivatives. To modulate lipophilicity, inositols were synthesized in acetylated or hydroxylated form. Automated radiosynthesis was performed on the AllInOne module and the radiotracers were produced in good radiochemical yields (15-31.5% dc). Preliminary in vivo preclinical evaluation of these eight [18F]fluoro-inositols as Positron Emission Tomography (PET) imaging agents in a breast tumour-bearing mouse model was performed and compared with [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG). Amongst the different inositols, [18F]myo-2 showed the highest tumour uptake 2.34+/ 0.39%ID/g, revealing the potential of this tracer for monitoring breast cancer. PMID- 28893601 TI - Seek & Destroy, use of targeting peptides for cancer detection and drug delivery. AB - Accounting for 16 million new cases and 9 million deaths annually, cancer leaves a great number of patients helpless. It is a complex disease and still a major challenge for the scientific and medical communities. The efficacy of conventional chemotherapies is often poor and patients suffer from off-target effects. Each neoplasm exhibits molecular signatures - sometimes in a patient specific manner - that may completely differ from the organ of origin, may be expressed in markedly higher amounts and/or in different location compared to the normal tissue. Although adding layers of complexity in the understanding of cancer biology, this cancer-specific signature provides an opportunity to develop targeting agents for early detection, diagnosis, and therapeutics. Chimeric antibodies, recombinant proteins or synthetic polypeptides have emerged as excellent candidates for specific homing to peripheral and central nervous system cancers. Specifically, peptide ligands benefit from their small size, easy and affordable production, high specificity, and remarkable flexibility regarding their sequence and conjugation possibilities. Coupled to imaging agents, chemotherapies and/or nanocarriers they have shown to increase the on-site delivery, thus allowing better tumor mass contouring in imaging and increased efficacy of the chemotherapies associated with reduced adverse effects. Therefore, some of the peptides alone or in combination have been tested in clinical trials to treat patients. Peptides have been well-tolerated and shown absence of toxicity. This review aims to offer a view on tumor targeting peptides that are either derived from natural peptide ligands or identified using phage display screening. We also include examples of peptides targeting the high-grade malignant tumors of the central nervous system as an example of the complex therapeutic management due to the tumor's location. Peptide vaccines are outside of the scope of this review. PMID- 28893599 TI - Natural products and morphogenic activity of gamma-Proteobacteria associated with the marine hydroid polyp Hydractinia echinata. AB - Illumina 16S rRNA gene sequencing was used to profile the associated bacterial community of the marine hydroid Hydractinia echinata, a long-standing model system in developmental biology. 56 associated bacteria were isolated and evaluated for their antimicrobial activity. Three strains were selected for further in-depth chemical analysis leading to the identification of 17 natural products. Several gamma-Proteobacteria were found to induce settlement of the motile larvae, but only six isolates induced the metamorphosis to the primary polyp stage within 24h. Our study paves the way to better understand how bacterial partners contribute to protection, homeostasis and propagation of the hydroid polyp. PMID- 28893604 TI - Redox signalling in development and regeneration. PMID- 28893602 TI - Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3-/- mice transplanted with human PBMCs. AB - Employing NOD/SCID/Jak3-/- mice transplanted with human PBMCs (hNOJ mice) and replication-competent, red-fluorescent-protein (mCherry; mC)-labeled HIV-1JR-FL (HIVmC), we examined whether early antiretroviral treatment blocked the establishment of HIV-1 infection. The use of hNOJ mice and HIVmC enabled us to visually locate infection foci and to examine the early dynamics of HIVmC infection without using a large amount of antiretroviral unlike in non-human primate models. Although when raltegravir (RAL) administration was begun 1 day after intraperitoneal (ip) inoculation of HIVmC, no plasma p24 or plasma HIV-1 RNA (pRNA) were detected in 10 of 12 hNOJ (hNOJmCRAL+) mice as assessed on the last day of the 14-day continuous twice-daily RAL administration, all 10 untreated hNOJmC (hNOJmCRAL-) mice became positive for p24 and pRNA and had significantly swollen lymph nodes in peritoneal cavity and abundant p24+/mC+/CD3+/CD4+ T cells and p24+/mC+/CD68+ monocytes/macrophages were identified in their omenta and mesenteric lymphoid tissues/lymph nodes upon necropsy of the mice on day 14. In 12 hNOJmCRAL+ mice, no significantly swollen lymph nodes were seen compared to hNOJmCRAL- mice; however, in the omentum of the 2 hNOJmCRAL+ mice that were positive for pRNA and in site RNA, mC+/p24+/CD3+/CD83+ cells were identified, suggesting that viral breakthrough occurred later in the observation period. The present data suggest that the use of hNOJ mouse model and HIVmC may shed light on the study of early-phase dynamics of HIV-1 infection and cellular events in post-exposure/pre-exposure prophylaxis. PMID- 28893605 TI - Oscillator networks with tissue-specific circadian clocks in plants. AB - Many organisms rely on circadian clocks to synchronize their biological processes with the 24-h rotation of the earth. In mammals, the circadian clock consists of a central clock in the suprachiasmatic nucleus and peripheral clocks in other tissues. The central clock is tightly coupled to synchronize rhythmicity and can organize peripheral clocks through neural and hormonal signals. In contrast to mammals, it has long been assumed that the circadian clocks in each plant cell is able to be entrained by external light, and they are only weakly coupled to each other. Recently, however, several reports have demonstrated that plants have unique oscillator networks with tissue-specific circadian clocks. Here, we introduce our current view regarding tissue-specific properties and oscillator networks of plant circadian clocks. Accumulating evidence suggests that plants have multiple oscillators, which show distinct properties and reside in different tissues. A direct tissue-isolation technique and micrografting have clearly demonstrated that plants have hierarchical oscillator networks consisting of multiple tissue-specific clocks. PMID- 28893603 TI - Human polyclonal antibodies produced in transchromosomal cattle prevent lethal Zika virus infection and testicular atrophy in mice. AB - Zika virus (ZIKV) is rapidly spreading throughout the Americas and is associated with significant fetal complications, most notably microcephaly. Treatment with polyclonal antibodies for pregnant women at risk of ZIKV-related complications could be a safe alternative to vaccination. We found that large quantities of human polyclonal antibodies could be rapidly produced in transchromosomal bovines (TcB) and successfully used to protect mice from lethal infection. Additionally, antibody treatment eliminated ZIKV induced tissue damage in immunologically privileged sites such as the brain and testes and protected against testicular atrophy. These data indicate that rapid development and deployment of human polyclonal antibodies could be a viable countermeasure against ZIKV. PMID- 28893606 TI - Expression of stable and active human DNA topoisomerase I in Pichia pastoris. AB - This study described the isolation of the coding region of human topoisomerase I (TopoI) from MDA-MB-231 and the expression of multiple copy recombinant genes in four Pichia pastoris strains. First, polymerase chain reaction (PCR) amplification of the enzyme coding region was performed. The PCR fragment was cloned into pPICZ-alpha-A vector and sequenced. It was then transformed into X33, GS115, SMD1168H and KM71H strains of Pichia. PCR-screening for positive clones was performed, and estimation of multiple copy integrants in each Pichia strain was carried out using agar plates containing increasing concentrations of Zeocin(r). The selected clones of multiple copy recombinant genes were then induced for TopoI expression in shaker flasks. GS115 and SMD1168 were found to be better Pichia strains to accommodate the recombinant gene for the expression of TopoI extracellularly. However, the DNA relaxation activity revealed that only the target enzyme in the culture supernatants of GS115-pPICZ-alpha-A-TopoI exhibited consistent enzyme activity over the cultivation time-points. Active enzyme activity was inhibited by Camptothecin. The enzyme produced can be used for in-house gel-based DNA relaxation assay development in performing high throughput screening for target-specific growth inhibitors that display similar effect as the TopoI inhibitors. These inhibitors may contribute to the improvement of the treatment of cancer patients. PMID- 28893607 TI - Modification of adverse health effects of maternal active and passive smoking by genetic susceptibility: Dose-dependent association of plasma cotinine with infant birth size among Japanese women-The Hokkaido Study. AB - OBJECTIVES: We aimed to assess the individual dose-response effects of eight maternal polymorphisms encoding polycyclic aromatic hydrocarbon-metabolizing and DNA-repair genes on prenatal cotinine levels according to infant birth size. METHODS: In total, 3263 Japanese pregnant women were assigned to five groups based on plasma cotinine levels during the 8th month of pregnancy, as measured using ELISA (cut-offs: 0.21, 0.55, 11.48, and 101.67ng/mL). Analyses were performed using multiple linear regression. RESULTS: Birth weight reduction showed a dose-dependent relationship with prenatal cotinine levels (P for trend<0.001). When considering the specific aromatic hydrocarbon receptor (AHR) (G>A, Arg554Lys; db SNP ID: rs2066853) and X-ray cross-complementing gene 1 (XRCC1) (C>T, Arg194Trp, rs1799782) genotypes, a larger birth weight reduction was noted among infants born to mothers with the highest cotinine level. CONCLUSION: Infants born to women with specific AHR and XRCC1 genotypes may have higher genetic risks for birth weight reduction. PMID- 28893608 TI - Adaptive cortical parcellations for source reconstructed EEG/MEG connectomes. AB - There is growing interest in the rich temporal and spectral properties of the functional connectome of the brain that are provided by Electro- and Magnetoencephalography (EEG/MEG). However, the problem of leakage between brain sources that arises when reconstructing brain activity from EEG/MEG recordings outside the head makes it difficult to distinguish true connections from spurious connections, even when connections are based on measures that ignore zero-lag dependencies. In particular, standard anatomical parcellations for potential cortical sources tend to over- or under-sample the real spatial resolution of EEG/MEG. By using information from cross-talk functions (CTFs) that objectively describe leakage for a given sensor configuration and distributed source reconstruction method, we introduce methods for optimising the number of parcels while simultaneously minimising the leakage between them. More specifically, we compare two image segmentation algorithms: 1) a split-and-merge (SaM) algorithm based on standard anatomical parcellations and 2) a region growing (RG) algorithm based on all the brain vertices with no prior parcellation. Interestingly, when applied to minimum-norm reconstructions for EEG/MEG configurations from real data, both algorithms yielded approximately 70 parcels despite their different starting points, suggesting that this reflects the resolution limit of this particular sensor configuration and reconstruction method. Importantly, when compared against standard anatomical parcellations, resolution matrices of adaptive parcellations showed notably higher sensitivity and distinguishability of parcels. Furthermore, extensive simulations of realistic networks revealed significant improvements in network reconstruction accuracies, particularly in reducing false leakage-induced connections. Adaptive parcellations therefore allow a more accurate reconstruction of functional EEG/MEG connectomes. PMID- 28893609 TI - Supramolecular cisplatin-vorinostat nanodrug for overcoming drug resistance in cancer synergistic therapy. AB - Cisplatin is a widely used anticancer drug in clinic. However, it may induce drug resistance after a course of treatment and it is difficult to accumulate at tumor site selectively, which result in clinic failure and side effects. We successfully bound cisplatin with vorinostat (a FDA-approved histone deacetylase inhibitor) to form a supramolecular conjugate, which can further self-assemble into nanoparticles. The nanodrug can retain in blood stream for a long time, accumulate in tumor site and hydrolyze to release the two drugs for synergistic therapy. In vivo experiments highlighted the great advantage of the supramolecular nanodrug, because it ensured the two drugs reaching cancer tissue simutaneously. Free cisplatin or cisplatin/vorinostat mixture had negligible or limited effects on A549/DR tumor growth. On the contrary, the tumor inhibitory rate approached 99% with little systemic toxicity if the dose of cisplatin vorinostat nanodrug reached 10mg/kg body weight, thus suggesting this supramolecular nanodrug as a promising treatment of drug resistance cancer. PMID- 28893610 TI - Sex differences in the respiratory-sympathetic coupling in rats exposed to chronic intermittent hypoxia. AB - Obstructive sleep apnea (OSA) is a complex disease in which humans face episodes of intermittent hypoxia and it affects men and women. Patients with OSA present hypertension and sympathetic overactivity among several other dysfunctions. Therefore, one important question remains: are the autonomic dysfunctions associated with OSA similar in male and female? This is an unresolved question since sex factors are overlooked in most clinical and experimental studies. Epidemiological data indicate that sex exerts an important influence in the prevalence of OSA and associated comorbidities, such as hypertension. Sex hormones, genetic and neural factors probably are the main players underlying sex differences in the pathophysiology of OSA but they are not yet fully understood. We are using chronic intermittent hypoxia (CIH) as an experimental model of intermittent hypoxia such as those observed in OSA patients to investigate the cardiovascular, sympathetic and respiratory responses in female rats. Our recent studies show that adult and juvenile female rats exposed to CIH develop hypertension similar to age-matched CIH-male rats. Although both males and females develop hypertension after CIH, the most remarkable finding was that CIH female rats develop changes in the respiratory modulation of sympathetic activity different from those observed in CIH-male rats, characterizing sex differences in the respiratory-sympathetic coupling in response to CIH. Specifically, in CIH female rats, sympathetic overactivity is linked to inspiration while in CIH-male rats it is linked to the late phase of expiration. In this review we discuss the pathophysiological consequences of CIH, focusing in adult and juvenile female rats and how changes in the respiratory-sympathetic coupling may play a key role in CIH-induced sympathetic overactivity and hypertension in both male and female rats. PMID- 28893611 TI - Emerging peak on the phylogeographic landscape of Mycobacterium tuberculosis in West Asia: Definitely smoke, likely fire. AB - To date, a major attention was justly given to the global lineages of Mycobacterium tuberculosis. Here, we demonstrated an importance of the minor ones, on an example of intriguing and underestimated NEW-1 family that belongs to Euro-American lineage (lineage 4). Analysis of the global WGS/NGS datasets (5715 strains) identified 2235 strains of Lineage 4 and 66 strains of sublineage L4.5. This latter is marked with RD122 genomic deletion and includes NEW-1 family. Phylogenomic analysis confirmed a separate position of the NEW-1 family that we tentatively designate L4.5.1/Iran. We propose an evolution/migration scenario starting with origin of L4.5 1000-1300 ya in China, subsequent origin of the pre NEW-1 intermediate genotype in Tibet, further migration to Xinjiang/Uyghur, and finally to Iran since 800 ya (origin of NEW-1), possibly, via expansion of the Mongol Yuan empire. Analysis of longitudinal phylogeographic datasets revealed a sharp increase in prevalence of NEW-1 strains in Iran and its eastwards neighbors in the last 20years; most alarmingly, it is accompanied with significant association with multidrug resistance (MDR). Ongoing migration, especially, Afghan refugees flows to developed countries emphasize a risk of the wider spread of the epidemic MDR subtype within NEW-1 family that we coin as emerging resistant clone of M. tuberculosis in West Asia. PMID- 28893613 TI - Genotoxic effects in transformed and non-transformed human breast cell lines after exposure to silver nanoparticles in combination with aluminium chloride, butylparaben or di-n-butylphthalate. AB - In the present study genotoxic effects after combined exposure of human breast cell lines (MCF-10A, MCF-7 and MDB-MB-231) to silver nanoparticles (AgNP, citrate stabilized, 15 and 45nm by STEM, Ag15 and Ag45, respectively) with aluminium chloride, butylparaben, or di-n-butylphthalate were studied. In MCF-10A cells exposed for 24h to Ag15 at the concentration of 23.5MUg/mL a statistically significant increase in DNA damage in comet assay (SSB) was observed. In the presence of the test chemicals the genotoxic effect was decreased to a level comparable to control values. In MCF-7 cells a significant increase in SSB level was observed after exposure to Ag15 at 16.3MUg/mL. The effect was also diminished in the presence of the three test chemicals. In MDA-MB-231 cells no significant increase in SSB was observed, however increased level of oxidative DNA damage (incubation with Fpg enzyme) was observed after exposure to combinations of both AgNP with aluminium chloride. No increase in micronuclei formation was observed in neither cell line after the single nor combined treatments. Our results point to a low risk of increased genotoxic effects of AgNP when used in combination with aluminium salts, butylparaben or di-n-butylphthalate in consumer products. PMID- 28893612 TI - Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines. AB - The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2 overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2 overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors. PMID- 28893614 TI - Impact of electronic healthcare-associated infection surveillance software on infection prevention resources: a systematic review of the literature. AB - BACKGROUND: Surveillance of healthcare-associated infections is fundamental for infection prevention. The methods and practices for surveillance have evolved as technology becomes more advanced. The availability of electronic surveillance software (ESS) has increased, and yet adoption of ESS is slow. It is argued that ESS delivers savings through automation, particularly in terms of human resourcing and infection prevention (IP) staff time. AIM: To describe the findings of a systematic review on the impact of ESS on IP resources. METHODS: A systematic search was conducted of electronic databases Medline and the Cumulative Index to Nursing and Allied Health Literature published between January 1st, 2006 and December 31st, 2016 with analysis using the Newcastle Ottawa Scale. FINDINGS: In all, 2832 articles were reviewed, of which 16 studies met the inclusion criteria. IP resources were identified as time undertaken on surveillance. A reduction in IP staff time to undertake surveillance was demonstrated in 13 studies. The reduction proportion ranged from 12.5% to 98.4% (mean: 73.9%). The remaining three did not allow for any estimation of the effect in terms of IP staff time. None of the studies demonstrated an increase in IP staff time. CONCLUSION: The results of this review demonstrate that adopting ESS yields considerable dividends in IP staff time relating to data collection and case ascertainment while maintaining high levels of sensitivity and specificity. This has the potential to enable reinvestment into other components of IP to maximize efficient use of scarce IP resources. PMID- 28893616 TI - Does antero-lateral ankle impingement exist? AB - Antero-lateral ankle impingement syndrome (ALAIS) is a well-established clinical entity that is a common consequence of ankle sprains. Injury to the anterior talo fibular ligament plays a key role in the genesis of ALAIS. Arthroscopic antero lateral synovectomy is the standard of care. However, this treatment approach may deserve to be challenged, as it does not include any procedure on the ligaments, despite the presence in some patients of lateral rotational micro-instability of the ankle, without objective laxity. Consequently, we reviewed current data on ALAIS and its links to ankle instability, from the dual perspective of diagnosis and treatment. PMID- 28893615 TI - Molecular epidemiology and environmental contamination during an outbreak of parainfluenza virus 3 in a haematology ward. AB - BACKGROUND: Although fomites or contaminated surfaces have been considered as transmission routes, the role of environmental contamination by human parainfluenza virus type 3 (hPIV-3) in healthcare settings is not established. AIM: To describe an hPIV-3 nosocomial outbreak and the results of environmental sampling to elucidate the source of nosocomial transmission and the role of environmental contamination. METHODS: During an hPIV-3 outbreak between May and June 2016, environmental surfaces in contact with clustered patients were swabbed and respiratory specimens used from infected patients and epidemiologically unlinked controls. The epidemiologic relatedness of hPIV-3 strains was investigated by sequencing of the haemagglutinin-neuraminidase and fusion protein genes. FINDINGS: Of 19 hPIV-3-infected patients, eight were haematopoietic stem cell recipients and one was a healthcare worker. In addition, four had upper and 12 had lower respiratory tract infections. Of the 19 patients, six (32%) were community-onset infections (symptom onset within <7 days of hospitalization) and 13 (68%) were hospital-onset infections (>=7 days of hospitalization). Phylogenetic analysis identified two major clusters: five patients, and three patients plus one healthcare worker. Therefore, seven (37%) were classified as nosocomial transmissions. hPIV-3 was detected in 21 (43%) of 49 environmental swabs up to 12 days after negative respiratory polymerase chain reaction conversion. CONCLUSION: At least one-third of a peak season nosocomial hPIV-3 outbreak originated from nosocomial transmission, with multiple importations of hPIV-3 from the community, providing experimental evidence for extensive environmental hPIV-3 contamination. Direct contact with the contaminated surfaces and fomites or indirect transmission from infected healthcare workers could be responsible for nosocomial transmission. PMID- 28893617 TI - Therapeutic potential of carbohydrates as regulators of macrophage activation. AB - It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal "classically activated" M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial - for example the successful introduction of biomedical implants. Although there are numerous endogenous and exogenous factors that have an impact on the macrophage polarisation spectrum, this review will focus specifically on prominent macrophage-modulating carbohydrate motifs with a view towards highlighting structure-function relationships and therapeutic potential. PMID- 28893618 TI - Lenalidomide modulates gene expression in human ABC-DLBCL cells by regulating IKAROS interaction with an intronic control region of SPIB. AB - Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) is associated with a poor prognosis compared with other DLBCL types and therefore represents a top priority for developing novel therapies. Lenalidomide, an immunomodulatory drug in trials for treatment of ABC-DLBCL, targets the transcription factor IKAROS for degradation by the cereblon E3 ubiquitin ligase complex. In this study, we investigated whether the gene encoding the transcription factor SPI-B is a target of IKAROS. Using cultured ABC-DLBCL cell lines, we found that high levels of SPI B expression conferred resistance to lenalidomide. Lenalidomide treatment of ABC DLBCL cells resulted in downregulation of SPIB at the level of transcription. SPIB was regulated directly by IKAROS through a binding site located in the first intron of the gene. Inhibition of IKAROS binding using CRISPR/Cas9-mediated transcriptional repression downregulated endogenous SPIB transcription. Finally, ectopic expression of IKAROS protected SPIB from downregulation. These results show that the mechanism of action of lenalidomide in ABC-DLBCL cells involves downregulation of SPIB transcription by cereblon-induced degradation of IKAROS. These results have implications for the design of synthetic lethal therapy for the treatment of ABC-DLBCL. PMID- 28893619 TI - Evaluation of the effect of brominated flame retardants on hemoglobin oxidation and hemolysis in human erythrocytes. AB - Brominated flame retardants (BFRs) are widely used in many everyday products. Numerous studies have shown that BFRs can be released into the environment. Environmental pollution with these compounds raises concerns about their potentially adverse health effects. The aim of this study was to evaluate the effect of tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4 dibromophenol (2,4-DBP), 2,4,6- tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) on hemolysis induction and hemoglobin oxidation in human erythrocytes. The erythrocytes were incubated with selected BFRs in a wide concentrations ranging from 0.01 to 100 MUg/ml for 24 h, 48 h and 72 h. All compounds studied, exhibited hemolytic potential and induced methemoglobin formation. Hemolytic and oxidative potential of BFRs increased along with the increasing concentrations of the compounds studied and elongation of the incubation time. Our study showed that both the number of aromatic rings and the number of bromine atoms in the molecule of the compounds examined influence hemoglobin oxidation and damage to the cellular membrane. Furthermore, we may conclude that 2,4-DBP is potentially most toxic compound because it causes statistically significant changes at the lowest concentration, while the highest toxicity at the highest concentrations was noted for TBBPA. PMID- 28893620 TI - Protective effects of tea, red wine and cocoa in diabetes. Evidences from human studies. AB - Prevention of diabetes through the diet has recently received an increasing interest, and polyphenolic compounds, such as flavanols, have become important potential chemopreventive natural agents due to their proved benefits on health, with low toxicity and cost. Tea, red wine and cocoa are good sources of flavanols and these highly consumed foods might contribute to prevent diabetes. In this regard, there is increasing evidence for a protective effect of tea, red wine and cocoa consumption against this disorder. This review summarizes the available epidemiological and interventional human studies providing evidence for and against this effect. Overall observational data suggest a benefit, but results are still equivocal and likely confounded by lifestyle and background dietary factors. The weight of data indicate favourable effects on diabetes risk factors for tea, red wine and cocoa intake, and a number of plausible mechanisms have been elucidated in human studies. However, despite the growing evidence it remains uncertain whether tea, red wine and cocoa consumption should be recommended to the general population or to patients as a strategy to reduce the risk of diabetes. PMID- 28893621 TI - Rare genetic variants in the sodium-dependent organic anion transporter SOAT (SLC10A6): Effects on transport function and membrane expression. AB - Sulfo-conjugated steroid hormones, such as dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate or estrone-3-sulfate are abundant in the body, but are biologically inactive at classical androgen and estrogen steroid receptors. However, after carrier-mediated import and de-conjugation by the steroid sulfatase, these compounds participate in the overall steroid regulation of reproductive organs. The sodium-dependent organic anion transporter SOAT, coded by the SLC10A6 gene, is specific for the transport of steroid sulfates and is highly expressed in testicular germ cells, including pachytene spermatocytes, secondary spermatocytes, and round spermatids. Therefore, SOAT is supposed to be involved in the regulation of spermatogenesis and male fertility. In the present study, the SLC10A6 gene was analyzed for rare genetic variants, which might affect transport function or membrane expression of SOAT. Among the 31 SOAT variants analyzed, L44P, Q75R, P107L, G109S, S112F, N113K, S133F, G241D, G263E, G294R, and Y308N showed no transport activity for DHEAS at all. In the case of P107L, G241D, G263E, and Y308N, this was most likely due to significantly reduced expression in the plasma membrane. Other variants are located directly at (Q75R, S112F, N113K) or close to (G109S, S133F, and G263E) the supposed SOAT Na+ binding sites and thus could disable the sodium-coupled transport cycle. If these loss-of function SOAT variants are more frequent in men with impaired spermatogenesis or infertility needs further investigation. PMID- 28893622 TI - Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes. AB - Accumulating evidence indicates that the active form of vitamin D, 1,25(OH)2D3, can be considered as a neurosteroid. However, the cerebral expression of vitamin D-associated enzymes and receptors remains controversial. With the idea of carrying out a comparative study in mind, we compared the transcript expression of Cyp27a1, Cyp27b1, Cyp24a1, Vdr and Pdia3 in purified cultures of astrocytes, endothelial cells, microglia, neurons and oligodendrocytes. We observed that endothelial cells and neurons can possibly transform the inactive cholecalciferol into 25(OH)D3. It can then be metabolised into 1,25(OH)2D3, by neurons or microglia, before being transferred to astrocytes where it can bind to VDR and initiate gene transcription or be inactivated when in excess. Alternatively, 1,25(OH)2D3 can induce autocrine or paracrine rapid non-genomic actions via PDIA3 whose transcript is abundantly expressed in all cerebral cell types. Noticeably, brain endothelial cells appear as a singular subtype as they are potentially able to transform cholecalciferol into 25(OH)D3 and exhibit a variable expression of Pdia3, according to 1,25(OH)2D3 level. Altogether, our data indicate that, within the brain, vitamin D may trigger major auto-/paracrine non genomic actions, in addition to its well documented activities as a steroid hormone. PMID- 28893623 TI - CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21 hydroxylase activity of CYP21A2. AB - Abiraterone is an inhibitor of CYP17A1 which is used for the treatment of castration resistant prostate cancer. Abiraterone is known to inhibit several drug metabolizing cytochrome P450 enzymes including CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, but its effects on steroid metabolizing P450 enzymes are not clear. In preliminary results, we had observed inhibition of CYP21A2 by 1MUM abiraterone. Here we are reporting the effect of abiraterone on activities of CYP21A2 in human adrenal cells as well as with purified recombinant CYP21A2. Cells were treated with varying concentrations of abiraterone for 24h and CYP21A2 activity was measured using [3H] 17-hydroxyprogesterone as substrate. Whole steroid profile changes were determined by gas chromatography-mass spectrometry. Binding of abiraterone to purified CYP21A2 protein was measured spectroscopically. Computational docking was used to study the binding and interaction of abiraterone with CYP21A2. Abiraterone caused significant reduction in CYP21A2 activity in assays with cells and an inhibition of CYP21A2 activity was also observed in experiments using recombinant purified proteins. Abiraterone binds to CYP21A2 with an estimated Kd of 6.3MUM. These inhibitory effects of abiraterone are at clinically used concentrations. A loss of CYP21A2 activity in combination with reduction of CYP17A1 activities by abiraterone could result in lower cortisol levels and may require monitoring for any potential adverse effects. PMID- 28893624 TI - CD8+T cells expressing both PD-1 and TIGIT but not CD226 are dysfunctional in acute myeloid leukemia (AML) patients. AB - Acute myeloid leukemia (AML) is one of the most common types of leukemia among adults with an overall poor prognosis and very limited treatment management. Immune checkpoint blockade of PD-1 alone or combined with other immune checkpoint blockade has gained impressive results in murine AML models by improving anti leukemia CD8+T cell function, which has greatly promoted the strategy to utilize combined immune checkpoint inhibitors to treat AML patients. However, the expression profiles of these immune checkpoint receptors, such as co-inhibitory receptors PD-1 and TIGIT and co-stimulatory receptor CD226, in T cells from AML patients have not been clearly defined. Here we have defined subsets of CD8+ and CD4+ T cells in the peripheral blood (PB) from newly diagnosed AML patients and healthy controls (HCs). We have observed increased frequencies of PD-1- and TIGIT expressing CD8+ T cells but decreased occurrence of CD226-expressing CD8+T cells in AML patients. Further analysis of these CD8+ T cells revealed a unique CD8+ T cell subset that expressed PD-1 and TIGIT but displayed lower levels of CD226 was associated with failure to achieve remission after induction chemotherapy and FLT3-ITD mutations which predict poor clinical prognosis in AML patients. Importantly, these PD-1+TIGIT+CD226-CD8+T cells are dysfunctional with lower expression of intracellular IFN-gamma and TNF-alpha than their counterparts in HCs. Therefore, our studies revealed that an increased frequency of a unique CD8+ T cell subset, PD-1+TIGIT+CD226-CD8+T cells, is associated with CD8+T cell dysfunction and poor clinical prognosis of AML patients, which may reveal critical diagnostic or prognostic biomarkers and direct more efficient therapeutic strategies. PMID- 28893625 TI - Improvement in the water solubility of drugs with a solid dispersion system by spray drying and hot-melt extrusion with using the amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and d-mannitol. AB - The aim of this study was to prepare and characterize solid dispersion particles with a novel amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, as a water-soluble carrier. Solid dispersion particles were prepared by hot-melt extrusion and spray drying. Indomethacin (IMC) was used as a model comprising drugs with low solubility in water and d-mannitol (MAN) was used as an excipient. The physicochemical properties of prepared particles were characterized by scanning electron microscopy, thermal analysis, powder X-ray diffraction (PXRD) analysis, FTIR spectra analysis, and drug release studies. Stability studies were also conducted under stress conditions at 40 degrees C, 75% relative humidity. We found that dissolution behavior of the original drug crystal could be improved by solid dispersion with the polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer. The PXRD pattern and thermal analysis indicated that the solid dispersion prepared with the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC was in an amorphous state. FTIR spectra analysis indicated that the interaction manner between the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and IMC may differ with the preparation method and formulation of solid dispersions. Stability studies proved that the amorphous state of IMC in solid dispersion particles was preserved under stress conditions for more than two weeks. PMID- 28893627 TI - Guest editorial. PMID- 28893628 TI - A combination of nanosystems for the delivery of cancer chemoimmunotherapeutic combinations: 1-Methyltryptophan nanocrystals and paclitaxel nanoparticles. AB - IDO is an enzyme that tumors use to create a state of immunosupression. 1-d methyltryptophan (1-MT) is an IDO pathway inhibitor. After being successfully evaluated in preclinical studies, current clinical trials are actually analyzing its efficacy as monotherapy or in combination with multiple chemotherapeutic agents such as paclitaxel. 1-MT very poor solubility in water and many other solvents precludes its ease parenteral administration. It is currently administered by oral route because high daily doses were well-tolerated and effectively inhibited the IDO activity although only 25% of dose was recovered in plasma. The present work describes the preparation and characterization of 1-MT nanocrystals in order to enhance its solubility, dissolution rate, biodisponibility as well as facilitate its administration by parenteral route. A bottom-down approach of nanoprecipitation with an antisolvent was used for the fabrication of the nanocrystals and the choice of stabilizers was critical for reducing the size. Thermal analysis and x-ray diffraction indicated modifications in the drug crystalline state by the process. Through the reduction size and crystalline state modifications the dissolution characteristics of raw material were significantly increased. In a Lewis Lung cancer mice model, the nanocrystals strategy facilitated the sc administration and its antitumoral activity was similar to that of i.v. paclitaxel. The best efficacy was achieved when sc 1-MT nanocrystals were administered in combination with oral paclitaxel loaded in poly(anhydride) nanoparticles. Take together, 1-MT nanocrystals delivery performs a nanotechnological strategy suitable to modify the current route and schedule for its administration. PMID- 28893626 TI - Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma. AB - : Low-density lipoprotein nanoparticles reconstituted with the natural omega-3 fatty acid, docosahexaenoic acid (LDL-DHA), have been reported to selectively kill hepatoma cells and reduce the growth of orthotopic liver tumors in the rat. To date, little is known about the cell death pathways by which LDL-DHA nanoparticles kill tumor cells. Here we show that the LDL-DHA nanoparticles are cytotoxic to both rat hepatoma and human hepatocellular carcinoma (HCC) cell lines. Following LDL-DHA treatment both rat and human HCC cells experience pronounced lipid peroxidation, depletion of glutathione and inactivation of the lipid antioxidant glutathione peroxidase-4 (GPX4) prior to cell death. Inhibitor studies revealed that the treated HCC cells die independent of apoptotic, necroptotic or autophagic pathways, but require the presence of cellular iron. These hallmark features are consistent and were later confirmed to reflect ferroptosis, a novel form of nonapoptotic iron-dependent cell death. In keeping with the mechanisms of ferroptosis cell death, GPX4 was also found to be a central regulator of LDL-DHA induced tumor cell killing. We also investigated the effects of LDL-DHA treatments in mice bearing human HCC tumor xenografts. Intratumoral injections of LDL-DHA severely inhibited the growth of HCC xenografts long term. Consistent with our in vitro findings, the LDL-DHA treated HCC tumors experienced ferroptotic cell death characterized by increased levels of tissue lipid hydroperoxides and suppression of GPX4 expression. CONCLUSION: LDL-DHA induces cell death in HCC cells through the ferroptosis pathway, this represents a novel molecular mechanism of anticancer activity for LDL-DHA nanoparticles. PMID- 28893629 TI - Obesity and type 2 diabetes, not a diet high in fat, sucrose, and cholesterol, negatively impacts bone outcomes in the hyperphagic Otsuka Long Evans Tokushima Fatty rat. AB - BACKGROUND: Obesity and type 2 diabetes (T2D) increase fracture risk; however, the association between obesity/T2D may be confounded by consumption of a diet high in fat, sucrose, and cholesterol (HFSC). OBJECTIVE: The study objective was to determine the main and interactive effects of obesity/T2D and a HFSC diet on bone outcomes using hyperphagic Otuska Long Evans Tokushima Fatty (OLETF) rats and normophagic Long Evans Tokushima Otsuka (LETO) controls. METHODS: At 8weeks of age, male OLETF and LETO rats were randomized to either a control (CON, 10 en% from fat as soybean oil) or HFSC (45 en% from fat as soybean oil/lard, 17 en% sucrose, and 1wt%) diet, resulting in four treatment groups. At 32weeks, total body bone mineral content (BMC) and density (BMD) and body composition were measured by dual-energy X-ray absorptiometry, followed by euthanasia and collection of blood and tibiae. Bone turnover markers and sclerostin were measured using ELISA. Trabecular microarchitecture of the proximal tibia and geometry of the tibia mid-diaphysis were measured using microcomputed tomography; whole-bone and tissue-level biomechanical properties were evaluated using torsional loading of the tibia. Two-factor ANOVA was used to determine main and interactive effects of diet (CON vs. HFSC) and obesity/T2D (OLETF vs. LETO) on bone outcomes. RESULTS: Hyperphagic OLEFT rats had greater final body mass, body fat, and fasting glucose than normophagic LETO, with no effect of diet. Total body BMC and serum markers of bone formation were decreased, and bone resorption and sclerostin were increased in obese/T2D OLETF rats. Trabecular bone volume and microarchitecture were adversely affected by obesity/T2D, but not diet. Whole bone and tissue-level biomechanical properties of the tibia were not affected by obesity/T2D; the HFSC diet improved biomechanical properties only in LETO rats. CONCLUSIONS: Obesity/T2D, regardless of diet, negatively impacted the balance between bone formation and resorption and trabecular bone volume and microarchitecture in OLETF rats. PMID- 28893631 TI - A 75-Year-Old African American Woman With an Incidentally Identified Renal Mass After Traumatic Fall. PMID- 28893630 TI - Engineered, axially-vascularized osteogenic grafts from human adipose-derived cells to treat avascular necrosis of bone in a rat model. AB - BACKGROUND: Avascular necrosis of bone (AVN) leads to sclerosis and collapse of bone and joints. The standard of care, vascularized bone grafts, is limited by donor site morbidity and restricted availability. The aim of this study was to generate and test engineered, axially vascularized SVF cells-based bone substitutes in a rat model of AVN. METHODS: SVF cells were isolated from lipoaspirates and cultured onto porous hydroxyapatite scaffolds within a perfusion-based bioreactor system for 5days. The resulting constructs were inserted into devitalized bone cylinders mimicking AVN-affected bone. A ligated vascular bundle was inserted upon subcutaneous implantation of constructs in nude rats. After 1 and 8weeks in vivo, bone formation and vascularization were analyzed. RESULTS: Newly-formed bone was found in 80% of SVF-seeded scaffolds after 8weeks but not in unseeded controls. Human ALU+cells in the bone structures evidenced a direct contribution of SVF cells to bone formation. A higher density of regenerative, M2 macrophages was observed in SVF-seeded constructs. In both experimental groups, devitalized bone was revitalized by vascularized tissue after 8 weeks. CONCLUSION: SVF cells-based osteogenic constructs revitalized fully necrotic bone in a challenging AVN rat model of clinically-relevant size. SVF cells contributed to accelerated initial vascularization, to bone formation and to recruitment of pro-regenerative endogenous cells. STATEMENT OF SIGNIFICANCE: Avascular necrosis (AVN) of bone often requires surgical treatment with autologous bone grafts, which is surgically demanding and restricted by significant donor site morbidity and limited availability. This paper describes a de novo engineered axially-vascularized bone graft substitute and tests the potential to revitalize dead bone and provide efficient new bone formation in a rat model. The engineering of an osteogenic/vasculogenic construct of clinically relevant size with stromal vascular fraction of human adipose, combined to an arteriovenous bundle is described. This construct revitalized and generated new bone tissue. This successful approach proposes a novel paradigm in the treatment of AVN, in which an engineered, vascularized osteogenic graft would be used as a germ to revitalize large volumes of necrotic bone. PMID- 28893632 TI - Patients' Experiences With Extramammary Paget Disease: An Online Pilot Study Querying a Patient Support Group. AB - OBJECTIVE: To illustrate the heterogeneous care delivered to patients with extramammary Paget disease (EMPD), a rare and lethal malignancy with poorly described treatment methodologies, by characterizing the clinical and pathologic characteristics of an international patient support group. MATERIALS AND METHODS: Institutional review board approval was obtained to develop and distribute a nonvalidated survey to patients from an international, online EMPD support group. The survey was developed to capture patient clinical and pathologic details and was distributed between January 2017 and February 2017. RESULTS: Forty-two patients completed the survey. At a mean age of 64 years, patients most commonly developed rash, pruritus, or erythema in the genital and perianal regions. Patients presented to their primary care physician, gynecologist, or dermatologist and were initially treated with topical agents for benign diagnoses. After failing conservative treatments, patients underwent biopsy by a dermatologist or gynecologist and were diagnosed with EMPD on average 21 months after the onset of symptoms. Wide local and Mohs excisions were the most frequently administered treatments with positive margins reported in 43% of patients. Fewer patients underwent noninvasive treatment with imiquimod cream and radiation. In total, 29% of patients developed regional recurrence and distant disease. There was wide variation regarding medical specialties involved, diagnostic evaluation, treatment, and clinical follow-up. CONCLUSION: This study provides a novel view of the varied clinical and pathologic details from patients treated across varying institutions and medical specialties. This study will hopefully educate providers of the overall disease process of EMPD and encourage the development of standardized treatment recommendations. PMID- 28893633 TI - Enhanced Recovery Open vs Laparoscopic Left Donor Nephrectomy: A Randomized Controlled Trial. AB - OBJECTIVE: To compare recovery outcomes between laparoscopic donor nephrectomy (LDN) and open donor nephrectomy within a specified enhanced recovery program (ERP) for left kidney donations. PATIENTS AND METHODS: A phase III randomized trial was conducted between January 2013 and June 2015; eligible left-side donors were randomized to laparoscopic or open donor nephrectomy in a 1:1 ratio with recovery optimized within a standardized ERP. The primary outcome was patient reported measure of physical fatigue, as measured by the physical fatigue domain of the translated Multidimensional Fatigue Inventory 20. Secondary outcomes included other donor recovery outcomes, postoperative pain scores, hospital stay, perioperative complications, and graft outcomes. RESULTS: A total of 224 donors (laparoscopy, n = 113; open surgery, n = 111) were randomly allocated. Six weeks postoperatively, physical fatigue domain scores in Multidimensional Fatigue Inventory 20 were significantly lower in the LDN group (mean: laparoscopy, 8.2 +/ 3.2 vs open surgery, 13.05 +/- 2.9) (P = .007). Median total hospital stay was also significantly shorter in the LDN group (median: laparoscopy, 2; interquartile range, 1-5 vs open surgery, 4; interquartile range, 2-9 days) (P = .002). LDN was associated with less pain scores and less non-opioid analgesic requirements. Warm ischemia times were not significantly different in both groups (mean: laparoscopy, 2.5 +/- 0.8 vs open surgery, 2.2 +/- 0.6) (P = .431). CONCLUSION: Even when optimized within an ERP, LDN was associated with less general and physical fatigue and better physical function at 6 weeks postoperatively when compared with open surgery for left kidney donations. PMID- 28893634 TI - Metabolism and DNA repair shape a specific modification pattern in mitochondrial DNA. AB - The mitochondrial DNA (mtDNA) resides in the vicinity of energy-rich reactions. Thus, chemical modifications of mtDNA might mirror mitochondrial processes and could serve as biomarkers of metabolic processes in the mitochondria. This hypothesis was tested by assessing modifications at 17 different sites in the mtDNA as a function of cell type, oxidative stress and mitochondrial activity. Two mouse mutants with a metabolic phenotype were compared to wild-type (WT) mice: the ogg1-/- mouse that lacks the 8-oxoguanine DNA glycosylase (OGG1), and the alkbh7-/- mouse missing the ALKBH7 protein that has been implicated in fatty acid oxidation. It was found that cell type, oxidative stress and mitochondrial complex activity shaped distinct modification patterns in mtDNA, and that OGG1 and ALKBH7 independently modulated these modification patterns. The modifications included ribonucleotides, which also accumulated in mtDNA with age. Interestingly, this age-dependent accumulation most likely involves DNA repair, as mtDNA from ogg1-/- mice did not accumulate modifications with age. On the other hand, alkbh7-/- mtDNA accumulated more modifications with age than WT mtDNA. Our results show that mtDNA is dynamically modified with metabolic activity and imply a novel synergy between metabolism and mtDNA repair proteins. PMID- 28893635 TI - Emendation and new species of Hapalorhynchus Stunkard, 1922 (Digenea: Schistosomatoidea) from musk turtles (Kinosternidae: Sternotherus) in Alabama and Florida rivers. AB - Hapalorhynchus Stunkard, 1922 is emended based on morphological study of existing museum specimens (type and voucher specimens) and newly-collected specimens infecting musk turtles (Testudines: Kinosternidae: Sternotherus spp.) from rivers in Alabama and Florida (USA). Hapalorhynchus conecuhensis n. sp. is described from an innominate musk turtle, Sternotherus cf. minor, (type host) from Blue Spring (31 degrees 5'27.64"N, 86 degrees 30'53.21"W; Pensacola Bay Basin, Alabama) and the loggerhead musk turtle, Sternotherus minor (Agassiz, 1857) from the Wacissa River (30 degrees 20'24.73"N, 83 degrees 59'27.56"W; Apalachee Bay Basin, Florida). It differs from congeners by lacking a body constriction at level of the ventral sucker, paired anterior caeca, and a transverse ovary as well as by having a small ventral sucker, proportionally short posterior caeca, nearly equally-sized anterior and posterior testes, a small cirrus sac, and a uterus extending dorsal to the ovary and the anterior testis. Specimens of Hapalorhynchus reelfooti Byrd, 1939 infected loggerhead musk turtles, stripe necked musk turtles (Sternotherus peltifer Smith and Glass, 1947), Eastern musk turtles (Sternotherus odoratus [Latreille in Sonnini and Latreille, 1801]), and S. cf. minor. Those of Hapalorhynchus cf. stunkardi infected S. minor and S. odoratus. Sternothorus minor, S. peltifer, and S. cf. minor plus S. minor and S. odoratus are new host records for H. reelfooti and H. cf. stunkardi, respectively. This is the first report of an infected musk turtle from the Coosa and Tallapoosa Rivers (Mobile-Tensaw River Basin), Pensacola Bay Basin, or Apalachee Bay Basin. Sequence analysis of the large subunit rDNA (28S) showed a strongly-supported clade for Hapalorhynchus. PMID- 28893636 TI - Advances in the application of genetic manipulation methods to apicomplexan parasites. AB - Apicomplexan parasites such as Babesia, Theileria, Eimeria, Cryptosporidium and Toxoplasma greatly impact animal health globally, and improved, cost-effective measures to control them are urgently required. These parasites have complex multi-stage life cycles including obligate intracellular stages. Major gaps in our understanding of the biology of these relatively poorly characterised parasites and the diseases they cause severely limit options for designing novel control methods. Here we review potentially important shared aspects of the biology of these parasites, such as cell invasion, host cell modification, and asexual and sexual reproduction, and explore the potential of the application of relatively well-established or newly emerging genetic manipulation methods, such as classical transfection or gene editing, respectively, for closing important gaps in our knowledge of the function of specific genes and proteins, and the biology of these parasites. In addition, genetic manipulation methods impact the development of novel methods of control of the diseases caused by these economically important parasites. Transient and stable transfection methods, in conjunction with whole and deep genome sequencing, were initially instrumental in improving our understanding of the molecular biology of apicomplexan parasites and paved the way for the application of the more recently developed gene editing methods. The increasingly efficient and more recently developed gene editing methods, in particular those based on the CRISPR/Cas9 system and previous conceptually similar techniques, are already contributing to additional gene function discovery using reverse genetics and related approaches. However, gene editing methods are only possible due to the increasing availability of in vitro culture, transfection, and genome sequencing and analysis techniques. We envisage that rapid progress in the development of novel gene editing techniques applied to apicomplexan parasites of veterinary interest will ultimately lead to the development of novel and more efficient methods for disease control. PMID- 28893637 TI - Advances in the diagnosis of bovine besnoitiosis: current options and applications for control. AB - Bovine besnoitiosis, which is caused by the tissue cyst-forming intracellular parasite Besnoitia besnoiti, is a chronic and debilitating disease that is responsible for severe economic losses in the cattle raised under extensive husbandry systems. The absence of vaccines, treatments or a health scheme at local, national and international levels has led to a rapid spread of bovine besnoitiosis from western Europe towards eastern countries and northwards. Moreover, this parasitic disease is widely present in many sub-Saharan countries. Thus, bovine besnoitiosis should be included in the animal health scheme of beef cattle herds. Accurate diagnostic tools and common diagnostic procedures are mandatory in any control programme. Relevant advances have been made in this field during the last decade. Succeeding with accurate diagnosis relies on the technique employed and the antibody and parasite kinetics of the infection stage, which may notably influence control programmes and surveillance. Moreover, control programmes should be adapted to the epidemiological status of the disease, as the disease presentation in a herd has important implications for prospective control. Herein, we review the clinical disease presentation of bovine besnoitiosis and the correlation between its clinical course and laboratory parameters. We also provide an update on the available diagnostic tools, discuss their strengths and pitfalls, and provide guidelines for their use in control, surveillance and epidemiological studies. A rational control strategy is also recommended. PMID- 28893638 TI - Innate immune responses play a key role in controlling infection of the intestinal epithelium by Cryptosporidium. AB - Cryptosporidium infection leads to acute diarrhea worldwide. The development of cryptosporidiosis is closely related to the immune status of its host, affecting primarily young ruminants, infants, and immunocompromised individuals. In recent years, several studies have improved our knowledge on the immune mechanisms responsible for the control of the acute phase of the infection and have highlighted the importance of innate immunity. The parasite develops in the apical side of intestinal epithelial cells, giving these cells a central role, as they are both the exclusive host cell for replication of the parasite and participate in the protective immune response. Epithelial cells signal the infection by producing chemokines, attracting immune cells to the infected area. They also actively participate in host defense by inducing apoptosis and releasing antimicrobial peptides, free or incorporated into luminal exosomes, with parasiticidal activity. The parasite has developed several escape mechanisms to slow down these protective mechanisms. Recent development of several three dimensional culture models and the ability to genetically manipulate Cryptosporidium will greatly help to further investigate host-pathogen interactions and identify virulence factors. Intestinal epithelial cells require the help of immune cells to clear the infection. Intestinal dendritic cells, well known for their ability to induce and orchestrate adaptive immunity, play a key role in controlling the very early steps of Cryptosporidium parvum infection by acting as immunological sentinels and active effectors. However, inflammatory monocytes, which are quickly and massively recruited to the infected mucosa, seem to participate in the loss of epithelial integrity. In addition to new promising chemotherapies, we must consider stimulating the innate immunity of neonates to strengthen their ability to control Cryptosporidium development. The microbiota plays a fundamental role in the development of intestinal immunity and may be considered to be a third actor in host-pathogen interactions. There is an urgent need to reduce the incidence of this yet poorly controlled disease in the populations of developing countries, and decrease economic losses due to infected livestock. PMID- 28893639 TI - On the application of reverse vaccinology to parasitic diseases: a perspective on feature selection and ranking of vaccine candidates. AB - Reverse vaccinology has the potential to rapidly advance vaccine development against parasites, but it is unclear which features studied in silico will advance vaccine development. Here we consider Neospora caninum which is a globally distributed protozoan parasite causing significant economic and reproductive loss to cattle industries worldwide. The aim of this study was to use a reverse vaccinology approach to compile a worthy vaccine candidate list for N. caninum, including proteins containing pathogen-associated molecular patterns to act as vaccine carriers. The in silico approach essentially involved collecting a wide range of gene and protein features from public databases or computationally predicting those for every known Neospora protein. This data collection was then analysed using an automated high-throughput process to identify candidates. The final vaccine list compiled was judged to be the optimum within the constraints of available data, current knowledge, and existing bioinformatics programs. We consider and provide some suggestions and experience on how ranking of vaccine candidate lists can be performed. This study is therefore important in that it provides a valuable resource for establishing new directions in vaccine research against neosporosis and other parasitic diseases of economic and medical importance. PMID- 28893640 TI - Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats. AB - AIMS: Oxidative stress and inflammatory response are major factors causing several tissue injuries in intestinal ischemia and reperfusion (I/R). Agmatine has been reported to attenuate I/R injury of various organs. The present study aims to analyze the possible protective effects of agmatine on intestinal I/R injury in rats. MAIN METHODS: Four groups were designed: sham control, agmatine treated control, I/R control, and agmatine-treated I/R groups. IR injury of small intestine was induced by the occlusion of the superior mesenteric artery for half an hour to be followed by a 3-hour-long reperfusion. Agmatine (10mg/kg) was administered intraperitoneally before reperfusion period. After 180min of reperfusion period, the contractile responses to both carbachol and potassium chloride (KCl) were subsequently examined in an isolated-organ bath. Malondialdehyde (MDA), reduced glutathione (GSH), and the activity of myeloperoxidase (MPO) were measured in intestinal tissue. Plasma cytokine levels were determined. The expression of the intestinal inducible nitric oxide synthase (iNOS) was also assessed by immunohistochemistry. KEY FINDINGS: The treatment with agmatine appeared to be significantly effective in reducing the MDA content and MPO activity besides restoring the content of GSH. The treatment also attenuated the histological injury. The increases in the I/R induced expressions of iNOS, IFN-gamma, and IL-1alpha were brought back to the sham control levels by the treatment as well. SIGNIFICANCE: Our findings indicate that the agmatine pretreatment may ameliorate reperfusion induced injury in small intestine mainly due to reducing inflammatory response and oxidative stress. PMID- 28893641 TI - High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high fructose diets. AB - AIMS: HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed. MAIN METHODS: Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12 week HIIT protocol (T=trained group), while the other subgroup remained non exercised (NT=not-trained group). KEY FINDINGS: HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT. SIGNIFICANCE: This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT. PMID- 28893642 TI - Enzyme-inducing effects of berberine on cytochrome P450 1A2 in vitro and in vivo. AB - AIMS: Berberine (BER) is an important anti-bacterial drug from Chinese herbal medicine and a novel drug candidate for preclinical development in recent years. Here we provide evidence that the effects of berberine on cytochrome P450 (CYP) 1A2 in vitro and in vivo. MAIN METHODS: Real-time polymerase chain reaction and western blotting analysis were employed to evaluate the CYP1A2 mRNA levels and protein expression. The enzyme activity was assessed by the metabolic rate of phenacetin to acetaminophen by LC-MS/MS method. KEY FINDINGS: The results indicated that the CYP1A2 mRNA expression and enzyme activity in HepG2 cells after treated with BER (4.5MUg/ml) exhibited a significant induction (16.11-fold and 5.0-fold, respectively), which was consistent with those on rat liver microsomes (4.5-fold and 1.98-fold, respectively) by BER induction (10mg/kg/day, i.p.) ex vivo. Beside, BER induced CYP1A2 activity with increases in AUC0-t and Cmax of acetaminophen and the Ke and t1/2 of phenacetin after oral administration of phenacetin (p<0.05) in vivo. SIGNIFICANCE: This study firstly reported the induction effect of BER on rats CYP1A2 by intraperitoneal route. But, BER didn't show significant induction effect on CYP1A2 by high-dose orally administrating to rats for 6 consecutive days due to the extremely low bioavailability. The potential drug-drug interactions were supposed to happen when the liver exposed to high dose of BER in vivo by changing administration route. PMID- 28893643 TI - Neuropeptide discovery in Proasellus cavaticus: Prediction of the first large scale peptidome for a member of the Isopoda using a publicly accessible transcriptome. AB - In silico transcriptome mining is one of the most effective methods for neuropeptide discovery in crustaceans, particularly for species that are small, rare or from geographically inaccessible habitats that make obtaining the large pools of tissue needed for other peptide discovery platforms impractical. Via this approach, large peptidomes have recently been described for members of many of the higher crustacean taxa, one notable exception being the Isopoda; no peptidome has been predicted for any member of this malacostracan order. Using a publicly accessible transcriptome for the isopod Proasellus cavaticus, a subcentimeter subterranean ground water dweller, the first in silico-predicted peptidome for a member of the Isopoda is presented here. BLAST searches employing known arthropod neuropeptide pre/preprohormone queries identified 49 transcripts as encoding putative homologs within the P. cavaticus transcriptome. The proteins deduced from these transcripts allowed for the prediction of 171 distinct mature neuropeptides. The P. cavaticus peptidome includes members of the adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon alpha, bursicon beta, CCHamide, crustacean cardioactive peptide, crustacean hyperglycemic hormone/molt-inhibiting hormone, diuretic hormone 31, eclosion hormone, elevenin, FMRFamide-like peptide, glycoprotein hormone alpha2, leucokinin, myosuppressin, neuroparsin, neuropeptide F, pigment dispersing hormone, pyrokinin, red pigment concentrating hormone, RYamide, short neuropeptide F, sulfakinin, tachykinin-related peptide and trissin families, as well as many linker/precursor-related sequences that may or may not represent additional bioactive molecules. Interestingly, many of the predicted P. cavaticus neuropeptides possess structures identical (or nearly so) to those previously described from members of several other malacostracan orders, i.e., the Decapoda, Amphipoda and Euphausiacea, a finding that suggests broad phylogenetic conservation of bioactive peptide structures, and possibly functions, may exist within the Malacostraca. PMID- 28893644 TI - High bone mass due to novel LRP5 and AMER1 mutations. AB - WNT signaling is a key regulator of bone metabolism and its increased or decreased activity leads to skeletal disorders. Here we describe two patients with high bone mass (HBM) caused by novel mutations in two different WNT pathway components. The first patient is a 53-year-old male with HBM. He was diagnosed at adult age based on significantly increased bone mineral density (BMD). He has undergone several surgeries due to excessive bone in ear canals, bilateral jaw exostoses and mandibular tori. Radiographs show severe cortical thickening of cranial and long bones. Sanger sequencing identified a novel heterozygous mutation c.592A>T (p.N198Y) in LRP5 (Low-density lipoprotein receptor-related protein 5). The second patient, an adolescent female, was diagnosed with skeletal dysplasia in early childhood. She had macrocephaly (head circumference +6.0 SD), facial dysmorphism, delayed motor development, laryngomalasia and epilepsy. Radiographic findings were consistent with osteopathia striata with cranial sclerosis. A novel heterozygous frameshift mutation c.655del (p.E219Rfs*63) in AMER1 (APC Membrane Recruiting Protein 1) was identified. Although both mutations are predicted to lead to increased WNT signaling with a consequent increase in bone formation, the resulting phenotypes are different; cranial sclerosis versus macrocephaly, long bone cortical thickening versus vertical striations and discordant neurological development. This report underscores the diversity of genotypes and phenotypes of HBM and facilitates their differential diagnosis. PMID- 28893645 TI - A novel toll-like receptor from the pearl oyster Pinctada fucata martensii is induced in response to stress. AB - Graft rejection due to immune incompatibility is a common occurrence in pearl culture, which often cause death to the host oyster. To improve cultured pearl production, host mortality and bead rejection rates must be reduced. Toll-like receptor 4 (TLR4) plays an important role in innate immunity, and may be related to allograft rejection. Here, we cloned the TLR4 cDNA from the pearl oyster Pinctada fucata martensii (PmTLR4). PmTLR4 cDNA was 3138bp, including a 2625bp open reading frame encoding 874 amino acids. The predicted PmTLR4 protein was structurally typical of the TLR family. PmTLR4 had relatively high sequence similarity and identity to the TLR4 of the Cyclina sinensis (48.1% and 27.6%, respectively). Multiple alignment of TLR4 sequences across species indicated that the Toll/interleukin-1 (IL-1) receptor domain was conserved among species. PmTLR4 mRNA was expressed in all tissues tested, with the most abundant mRNA expression in hepatopancreas and gill in P. fucata martensii. After being stressed by either lipopolysaccharide (LPS) exposure or the nucleus insertion operation, PmTLR4 mRNA expression increased significantly in the hemocytes as compared to controls. Peak level of PmTLR4 mRNA was observed 6h after the LPS injection, and 2d after the nucleus insertion operation. These data suggest that PmTLR4 may play a vital role in the induction of innate immunity and is therefore associated with allograft immunity in the pearl oyster P. fucata martensii. PMID- 28893646 TI - Whole-genome sequence of a carbapenem-resistant hypermucoviscous Klebsiella pneumoniae isolate SWU01 with capsular serotype K47 belonging to ST11 from a patient in China. AB - OBJECTIVES: In recent years, Klebsiella pneumoniae has emerged as a leading cause of nosocomial infection owing to the rising prevalence of multidrug-resistant strains, particularly carbapenem-resistant isolates. In this study, the complete genome sequence of carbapenem-resistant K. pneumoniae SWU01 was determined. METHODS: Antimicrobial susceptibilities and hypermucoviscous phenotype were determined by the disk diffusion method and positive string test, respectively. Multilocus sequence typing (MLST) was performed using the K. pneumoniae MLST database, and capsular serotype was analysed using the BIGSdb-Kp database with the nucleotide sequence of the variable region (CD1-VR2-CD2) of wzc. The complete genome sequence was obtained via the PacBio RS II platform, and antimicrobial resistance genes were identified using ResFinder 2.1. RESULTS: SWU01 was resistant to all antibiotics tested except polymyxin B and minocycline. This strain showed a hypermucoviscous phenotype with serotype K47 belonging to the ST11 clone. The complete genome consists of a 5536506-bp circular chromosome and a 162552-bp plasmid, with a G+C content of 57.4%. A total of 5537 protein-coding sequences, 85 tRNAs, 25 rRNAs, 12 non-coding RNA genes and 157 pseudogenes were identified in the genome. Thirteen acquired antibiotic resistance genes were detected (eight in the chromosome and five in the plasmid). CONCLUSIONS: Here we present the first whole-genome sequence of a carbapenem-resistant hypermucoviscous K. pneumoniae isolate SWU01 with capsular serotype K47 belonging to ST11 from a patient in China, which may serve as a reference sequence for further understanding of the pathogenesis and multidrug resistance mechanisms of this species. PMID- 28893647 TI - Coexistence of multidrug resistance mechanisms and virulence genes in carbapenem resistant Pseudomonas aeruginosa strains from a tertiary care hospital in South India. AB - OBJECTIVES: This study aimed to identify the multiple drug resistance mechanisms and various virulence genes in high-level carbapenem-resistant Pseudomonas aeruginosa (CARPA) isolates collected from patients hospitalised in a tertiary care hospital in South India. METHODS: A total of 156 CARPA isolates were included in the study. Multiplex PCR was optimised to detect carbapenemase and extended-spectrum beta-lactamase (ESBL) genes. Semi-quantitative reverse transcription PCR (RT-PCR) was optimised to evaluate oprD deficiency. Efflux pump activity was determined by phenylalanine-arginine beta-naphthylamide (PAbetaN) assay, and expression of mexA and mexC genes was evaluated by real-time quantitative PCR (qRT-PCR). Presence of the virulence genes exoS, algD, algU, lasR and rhlR were detected by qRT-PCR and plcH and lasB by RT-PCR. RESULTS: Genes encoding carbapenemases and ESBLs were detected in 48.7% (blaVIM, 23.1%; blaNDM-1, 17.3%; blaVIM+blaNDM-1, 7.1%; and blaIMP, 1.3%) and 4% (blaVEB, 4.5%) of CARPA isolates, respectively. Loss of porin OprD was observed in nine isolates (5.8%), two of which harboured the blaVIM gene. Among efflux pump-positive isolates, mexA expression was significantly upregulated. algD expression was detected in 93% of CARPA isolates, followed by algU (89%), rhlR (84%), lasR (81%) and exoS (76%). The lasB and plcH genes were detected in 94% and 92% of isolates, respectively. CONCLUSIONS: Co-existence of multiple antimicrobial resistance mechanisms together with virulence genes in carbapenem-resistant isolates has become an alarming emerging threat. Continuous monitoring of multidrug-resistant pathogens is important for clinicians in order to determine therapeutic options against such infections. PMID- 28893648 TI - Initial activation state, stimulation intensity and timing of stimulation interact in producing behavioral effects of TMS. AB - Behavioral effects of transcranial magnetic stimulation (TMS) have been shown to depend on various factors, such as neural activation state, stimulation intensity, and timing of stimulation. Here we examined whether these factors interact, by applying TMS at either sub- or suprathreshold intensity (relative to phosphene threshold, PT) and at different time points during a state-dependent TMS paradigm. The state manipulation involved a behavioral task in which a visual prime (color grating) was followed by a target stimulus which could be either congruent, incongruent or partially congruent with the color and orientation of the prime. In Experiment 1, single-pulse TMS was applied over the early visual cortex (V1/V2) or Vertex (baseline) at the onset of the target stimulus - timing often used in state-dependent TMS studies. With both subthreshold and suprathreshold stimulation, TMS facilitated the detection of incongruent stimuli while not significantly affecting other stimulus types. In Experiment 2, TMS was applied at 100ms after target onset -a time window in which V1/V2 is responding to visual input. Only TMS applied at suprathreshold intensity facilitated the detection of incongruent stimuli, with no effect with subthreshold stimulation. The need for higher stimulation intensity is likely to reflect reduced susceptibility to TMS of neurons responding to visual stimulation. Furthermore, the finding that in Experiment 2 only suprathreshold TMS induced a behavioral facilitation on incongruent targets (whereas facilitations in the absence of priming have been reported with subthreshold TMS) indicates that priming, by reducing neural excitability to incongruent targets, shifts the facilitatory/inhibitory range of TMS effects. PMID- 28893649 TI - Endothelial cells maintain neural stem cells quiescent in their niche. AB - Niches are specialized microenvironments that regulate stem cells' activity. The neural stem cell (NSC) niche defines a zone in which NSCs are retained and produce new cells of the nervous system throughout life. Understanding the signaling mechanisms by which the niche controls the NSC fate is crucial for the success of clinical applications. In a recent study, Sato and colleagues, by using state-of-the-art techniques, including sophisticated in vivo lineage tracing technologies, provide evidence that endothelial amyloid precursor protein (APP) is an important component of the NSC niche. Strikingly, depletion of APP increased NSC proliferation in the subventricular zone, indicating that endothelial cells negatively regulate NSCs' growth. The emerging knowledge from this research will be important for the treatment of several neurological diseases. PMID- 28893650 TI - Adversity in early adolescence promotes an enduring anxious phenotype and increases serotonergic innervation of the infralimbic medial prefrontal cortex. AB - Stress during early development produces lasting effects on psychopathological outcomes. We analysed the impact of prior intermittent, physical stress (IPS) during early adolescence (PD 22-33) on anxiety-like behaviour of female rats in adulthood. After behavioural testing, we used immunohistochemistry for the 5-HT transporter (SERT) to evaluate 5-HT innervation profiles in the medial prefrontal cortex (mPFC) and ventral hippocampus (VH). Administration of IPS (i.e., water immersion, elevated platform, foot shock) in early adolescence increased rats' anxiety-like behaviour in the elevated plus-maze but had no effects in the shock probe burying test. In the social interaction test, IPS decreased social interaction, and this effect was driven by selective decreases in the frequency of playfighting with no evident changes in contact and investigative behaviours. Selective stress-induced increases in the density of SERT-ir positive fibres were found in the infralimbic (IL) subregion of the mPFC but not in the cingulate or prelimbic (PL) subregions. IPS in early adolescence did not affect 5-HT innervation profiles in any sub-fields of the VH. Our findings confirm and extend on earlier evidence that stress during early adolescence promotes the emergence of an anxious phenotype and provide novel evidence that these effects are associated with increased 5-HT innervation of the IL mPFC. PMID- 28893652 TI - A new threat to human reproduction system posed by Zika virus (ZIKV): From clinical investigations to experimental studies. AB - Zika virus (ZIKV) was first isolated in 1947 from a rhesus monkey in the Zika forest of Uganda. ZIKV has since been silently circulating in a number of equatorial countries for over 50 years. The largest outbreak in humans occurred in Brazil in 2015-2016. Unlike its flavivirus relatives, sexual and post transfusion transmissions of ZIKV have been reported. In addition, fetal infection can result in microcephaly and congenital Zikv syndrome has been reported in neonates. Moreover, ZIKV RNA can persist for at least 6 months in semen and 11 weeks in vaginal secretions after the infection, suggesting potential tropism for the male and female genital tracts. Accordingly, it is important to determine whether genital ZIKV infection could have deleterious effects on the male and female reproductive systems. PMID- 28893651 TI - Obstructive sleep apnea is associated with altered midbrain chemical concentrations. AB - Obstructive sleep apnea (OSA) is accompanied by altered structure and function in cortical, limbic, brainstem, and cerebellar regions. The midbrain is relatively unexamined, but contains many integrative nuclei which mediate physiological functions that are disrupted in OSA. We therefore assessed the chemistry of the midbrain in OSA in this exploratory study. We used a recently developed accelerated 2D magnetic resonance spectroscopy (2D-MRS) technique, compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (4D-EP-JRESI), to measure metabolites in the midbrain of 14 OSA (mean age+/-SD:54.6+/-10.6years; AHI:35.0+/-19.4; SAO2 min:83+/-7%) and 26 healthy control (50.7+/-8.5years) subjects. High-resolution T1-weighted scans allowed voxel localization. MRS data were processed with custom MATLAB-based software, and metabolite ratios calculated with respect to the creatine peak using a prior knowledge fitting (ProFit) algorithm. The midbrain in OSA showed decreased N-acetylaspartate (NAA; OSA:1.24+/-0.43, Control:1.47+/-0.41; p=0.03; independent samples t-test), a marker of neuronal viability. Increased levels in OSA over control subjects appeared in glutamate (Glu; OSA:1.23+/-0.57, Control:0.98+/-0.33; p=0.03), ascorbate (Asc; OSA:0.56+/-0.28, Control:0.42+/-0.20; (50.7+/-8.5years; p=0.03), and myo-inositol (mI; OSA:0.96+/-0.48, Control:0.72+/-0.35; p=0.03). No differences between groups appeared in gamma-aminobutyric acid (GABA) or taurine. The midbrain in OSA patients shows decreased NAA, indicating neuronal injury or dysfunction. Higher Glu levels may reflect excitotoxic processes and astrocyte activation, and higher mI is also consistent with glial activation. Higher Asc levels may result from oxidative stress induced by intermittent hypoxia in OSA. Additionally, Asc and Glu are involved with glutamatergic processes, which are likely upregulated in the midbrain nuclei of OSA patients. The altered metabolite levels help explain dysfunction and structural deficits in the midbrain of OSA patients. PMID- 28893653 TI - Hepatitis C virus-induced innate immune responses in human iPS cell-derived hepatocyte-like cells. AB - Hepatitis C virus (HCV) infection is a major cause of liver-related morbidity and mortality. In order to develop effective remedies for hepatitis C, it is important to understand the HCV infection profile and host-HCV interaction. HCV induced innate immune responses play a crucial role in spontaneous HCV clearance; however, HCV-induced innate immune responses have not been fully evaluated in hepatocytes, partly because there are few in vitro models of HCV-induced innate immunity. Recently, human induced pluripotent stem (iPS) cells have received much attention as an in vitro model of infection with various pathogens, including HCV. We previously established highly functional hepatocyte-like cells differentiated from human iPS cells (iPS-HLCs). Here, we examined the potential of iPS-HLCs as an in vitro HCV infection model, especially for evaluation of the relationship between HCV infection levels and HCV-induced innate immunity. Significant expressions of type I and III interferons (IFNs) and IFN-stimulated genes (ISGs) were induced following transfection with HCV genomic replicon RNA in iPS-HLCs. Following inoculation with the HCV JFH-1 strain in iPS-HLCs, peaks of HCV genome replication and HCV protein expression were observed on day 2, and then both the HCV genome and protein levels gradually declined, while the mRNA levels of type III IFNs and ISGs peaked at day 2 following inoculation. These results suggest that the HCV genome efficiently replicates in iPS-HLCs, resulting in HCV genome-induced up-regulation of IFNs and ISGs, and thereafter, HCV genome induced up-regulation of IFNs and ISGs mediates a reduction in the HCV genome and protein levels in iPS-HLCs. PMID- 28893654 TI - Strain-specific association of soybean dwarf virus small subgenomic RNA with virus particles. AB - Soybean dwarf virus (SbDV) produces a large subgenomic RNA (LsgRNA) for expression of structural and movement proteins and a small subgenomic RNA (SsgRNA) that does not contain an open reading frame. Sucrose gradient-purified SbDV virions from soybean plants systemically infected with SbDV by aphids and Nicotiana benthamiana leaves agroinfiltrated with infectious clones of two red clover SbDV isolates encapsidated genomic RNA and were associated with SsgRNA in a strain-specific manner. The LsgRNA was protected from RNase degradation, but not packaged into virions as indicated by its presence primarily in ELISA negative fractions near the tops of sucrose gradients even in mutants that did not express coat protein. Nucleotide differences in the SsgRNA region between isolates conferred differential association of SsgRNA with virions. PMID- 28893655 TI - Laparoscopic Blinded Endometrial Cavity Resection for Robert's Uterus. AB - STUDY OBJECTIVE: To demonstrate that laparoscopic excision of the endometrial tissue of a blind endometrial cavity in a patient with a Robert's uterus who did not consent to hysteroscopic surgery due to her virgin state and religious beliefs was an effective alternative treatment option for progressive dismenorrhea and pelvic pain. DESIGN: Presentation of a rare mullerian anomaly and a step-by-step demonstration of a laparoscopic excision technique in the endometrium of a blind uterine cavity (educative video) (Canadian Task Force classification III). SETTING: Robert's uterus is a rare mullerian anomaly characterized by the presence of a blind endometrial cavity and an asymmetric septum. Endometriosis may be encountered in 40% of patients with this anomaly. A 15-year-old virgin patient with progressive dysmenorrhea was diagnosed with a Robert's uterus anomaly on magnetic resonance imaging. Hysteroscopic surgery was suggested to form a communication between the blind endometrial cavity and the hemiuterus; however, the patient refused to undergo any vaginal surgery due to her virgin state and religous beliefs. A decision to excise the endometrial tissue of the blind cavity laparoscopically instead of performing a hemihysterectomy was made to prevent any adverse effects on the ovarian blood supply and damage to the myometrial wall of the unicornuate uterus. INTERVENTION: Laparoscopic resection of the blind endometrial cavity in a patient with a Robert's uterus anomaly. CONCLUSION: Laparoscopic resection of a blind endometrial cavity is a safe and effective surgical alternative in patients who refuse vaginal surgery. PMID- 28893656 TI - Hysteroscopic Isthmoplasty: Step-by-Step Technique. AB - STUDY OBJECTIVE: To demonstrate our technique for surgical hysteroscopy performed with a standard-size resectoscope or miniresectoscope in 3 cases of isthmocele. DESIGN: Step-by-step demonstration of the technique using slides, pictures, and video (educative video) (Canadian Task Force classification III). SETTING: Isthmocele is a characteristic semidiverticular anomaly of the anterior isthmic wall of the uterus, located at the site of a previous cesarean delivery scar. The etiopathogenesis of isthmocele remains poorly understood, although several hypotheses have been proposed. Factors that may possibly play a role in niche development include a very low incision through cervical tissue, inadequate suturing technique during closure of the uterine scar, surgical interventions that increase adhesion formation, and patient-related factors that impair wound healing or increase inflammation or adhesion formation. The treatment of isthmocele focuses on relieving symptoms (i.e., postmenstrual spotting, suprapubic pelvic pain, dysmenorrhea, dyspareunia, and infertility), and, consequently, asymptomatic cases should not be treated. Various surgical approaches have been described to treat isthmocele-related symptoms, including hysteroscopy, laparoscopy, vaginal, robotic, and combined techniques. INTERVENTION: Our local Institutional Review Board approved the study protocol. The procedures were performed in operative room using a 26 Fr and 16 Fr continuous-flow resectoscope under general anesthesia. The surgical technique involves resection of the fibrotic tissue of the lower margin and then the upper margin of the pouch using a cutting loop, until the underlying muscular tissue is reached, followed by resection of the inflamed and necrotic tissue of the base of the pouch. Similar surgical maneuvers are performed on the contralateral side (right anterolateral wall) for complete ablation of the isthmic region (inverted ablation). CONCLUSION: According to the most recent literature, hysteroscopic hystmoplasty appears to be a safe and effective treatment option in cases of isthmocele with a niche at least 2 mm deep and a residual myometrial thickness of at least 3 mm to improve postmenstrual bleeding. When residual myometrial thickness is <3 mm, the hysteroscopic approach is not recommended, mainly because of the risk of bladder injury. In these symptomatic cases, laparoscopic or vaginal repair may be considered. PMID- 28893657 TI - The Effect of Adjuvant Treatment to Prevent and Treat Intrauterine Adhesions: A Network Meta-Analysis of Randomized Controlled Trials. AB - Intrauterine adhesions (IUAs) can lead to partial or complete closure of the uterine cavity, which may result in symptoms including abnormal menstruation, infertility, and pelvic pain. A network meta-analysis was performed to assess the effect of adjuvant therapy on the prevention and treatment of IUAs. We searched electronic databases, including PubMed, Embase, and the Cochrane Library, up to May 5, 2017, without language restrictions. The primary outcomes in the present analysis were the rate of IUAs for prevention and the rate of IUA recurrence for treatment. The secondary outcomes included the IUA score and the rate of severity of IUAs. The treatments were then ranked by the surface under the cumulative ranking curve (SUCRA). We included 20 articles that involved a total of 1891 patients in our analysis. In the outcomes of prevention-related studies, an alginate hyaluronate-carboxymethylcellulose membrane (ACH) (n = 10, SUCRA score = 93.3%) was the adjuvant treatment that most effectively reduced IUA incidence. It was followed by intercoat (n = 10, SUCRA score = 74.7%) and misoprostol (n = 10, SUCRA score = 68.6%). In addition, auto-cross-linked hyaluronic acid (ACP) (n = 3, SUCRA score = 83.2%) and intercoat (n = 3, SUCRA score = 66.4%) each corresponded to a relatively high preventive effect against severe IUAs. In the treatment-related studies, ACP plus a balloon (n = 4, SUCRA score = 96.3%) and a freeze-dried amnion graft plus a balloon (n = 4, SUCRA score = 62.7%) most effectively reduced IUA recurrence and had a high probability of most effectively reducing IUA scores. Therefore, according to the prophylactic analysis, ACH and intercoat were most likely to prevent IUA development. In our analysis of agents used to prevent severe IUAs, we found that ACP and intercoat provided significant advantages and had high reliability. In our analysis of treatments, ACP plus a balloon and freeze-dried amniotic agents plus a balloon were most likely to reduce IUA recurrence and IUA scores after adhesiolysis. PMID- 28893658 TI - Multiple Nodule Removal by Disc Excision and Segmental Resection in Multifocal Colorectal Endometriosis. AB - STUDY OBJECTIVE: To report postoperative outcomes after dual digestive resection for deep endometriosis infiltrating the rectum and the colon. DESIGN: A retrospective study using data prospectively recorded in the CIRENDO database (Canadian Task Force classification II-2). SETTING: A university tertiary referral center. PATIENTS: Twenty-one patients managed for multiple colorectal deep endometriosis infiltrating nodules. INTERVENTIONS: Concomitant disc excision and segmental resection of both the rectum and sigmoid colon. MEASUREMENTS AND MAIN RESULTS: The assessment of postoperative outcomes was performed. Rectal nodules were managed by disc excision and segmental resection in 20 patients and 1 patient, respectively. Sigmoid colon nodules were removed by short segmental resection and disc excision in 15 and 6 patients, respectively. The rectal nodule diameter was between 1 and 3 cm and over 3 cm in 33% and 67% of patients, respectively. Associated vaginal infiltration requiring vaginal excision was recorded in 76.2% of patients. The mean diameter of the rectal disc removed averaged 4.6 cm, and the mean height of the rectal suture was 5.8 cm. The length of the sigmoid colon specimen and the height of the anastomosis were 7.3 cm and 18.5 cm, respectively. The mean operative time was 290 minutes, and the mean postoperative follow-up averaged 30 months. Clavien-Dindo 3 complications occurred in 28% of patients, including 4 with rectal fistulae (19%). The pregnancy rate was 67% among patients with pregnancy intention. CONCLUSION: Our data suggest that combining disc excision and segmental resection to remove multiple deep endometriosis nodules infiltrating the rectum and the sigmoid colon can preserve the healthy bowel located between 2 consecutive nodules. However, the rate of postoperative complications is high, particularly in patients with large low rectal nodules. PMID- 28893659 TI - A halotolerant Enterobacter sp. displaying ACC deaminase activity promotes rice seedling growth under salt stress. AB - Agricultural productivity is proven to be hampered by the synthesis of reactive oxygen species (ROS) and production of stress-induced ethylene under salinity stress. One-aminocyclopropane-1-carboxylic acid (ACC) is the direct precursor of ethylene synthesized by plants. Bacteria possessing ACC deaminase activity can use ACC as a nitrogen source preventing ethylene production. Several salt tolerant bacterial strains displaying ACC deaminase activity were isolated from rice fields, and their plant growth-promoting (PGP) properties were determined. Among them, strain P23, identified as an Enterobacter sp. based on phenotypic characteristics, matrix-assisted laser desorption ionization-time of flight mass spectrometry data and the 16S rDNA sequence, was selected as the best-performing isolate for several PGP traits, including phosphate solubilization, IAA production, siderophore production, HCN production, etc. Enterobacter sp. P23 was shown to promote rice seedling growth under salt stress, and this effect was correlated with a decrease in antioxidant enzymes and stress-induced ethylene. Isolation of an acdS mutant strain enabled concluding that the reduction in stress-induced ethylene content after inoculation of strain P23 was linked to ACC deaminase activity. PMID- 28893661 TI - Effect of castration on social behavior and hormones in male Japanese macaques (Macaca fuscata). AB - Population control is essential for animal welfare and human safety in free ranging or captive settings, especially when resources are limited. As an alternative to lethal control, contraceptive methods such as castration in males can be a practical solution, because the testicles are a visual cue to determine which males have been sterilized. However, careful analyses should be carried out to ensure no disruption in the social structure of the population. Japanese macaques (Macaca fuscata) live in a society centered around dominance rank and matrilineal kin relationships. Testosterone and glucocorticoids have been correlated with dominance rank in humans and other species, but previous studies in Japanese macaques were inconclusive. This study aimed to investigate behavioral and physiological differences between castrated and intact male Japanese macaques, and to examine the effect of season and behavior in hormonal concentrations in intact males. Our subjects were six intact males from Jigokudani Monkey Park (Japan) and 13 castrated males from Born Free Primate Sanctuary (USA). We collected behavioral data using both focal and ad libitum sampling, and fecal samples for determination of testosterone (fT) and glucocorticoids (fGC) by enzyme immunoassay. We found that castrated males exhibited a social hierarchy, but not a linear hierarchy, as was the case in intact males. Castrated males were less aggressive than intact males, probably because fT concentrations were lower in the castrated males. Age was positively correlated with fGC levels, while fT concentrations were lower in old males than younger adult males. Fecal T levels correlated with both rank and atmospheric temperature. In intact males, both fGC and fT levels were elevated during the mating season. We found a negative correlation between fGC levels and the amount of grooming received. Our findings indicate that castration had a minimal impact on sociality, with season, temperature, and rank all influencing male sex steroid levels in intact males. Our study indicates that castration can be adopted as a population control mechanism without drastically altering the social relationships of males. PMID- 28893660 TI - A new RF transmit coil for foot and ankle imaging at 7T MRI. AB - A four-channel Tic-Tac-Toe (TTT) transmit RF coil was designed and constructed for foot and ankle imaging at 7T MRI. Numerical simulations using an in-house developed FDTD package and experimental analyses using a homogenous phantom show an excellent agreement in terms of B1+ field distribution and s-parameters. Simulations performed on an anatomically detailed human lower leg model demonstrated an B1+ field distribution with a coefficient of variation (CV) of 23.9%/15.6%/28.8% and average B1+ of 0.33MUT/0.56MUT/0.43MUT for 1W input power (i.e., 0.25W per channel) in the ankle/calcaneus/mid foot respectively. In-vivo B1+ mapping shows an average B1+ of 0.29MUT over the entire foot/ankle. This newly developed RF coil also presents acceptable levels of average SAR (0.07W/kg for 10g per 1W of input power) and peak SAR (0.34W/kg for 10g per 1W of input power) over the whole lower leg. Preliminary in-vivo images in the foot/ankle were acquired using the T2-DESS MRI sequence without the use of a dedicated receive-only array. PMID- 28893662 TI - Spatial memory-related brain activity in normally reared and different maternal separation models in rats. AB - Early life stress comprises a wide range of adverse events that can occur in the subject's early developmental stages: from child abuse to rodent repeated maternal separation models. This study used young adult male Wistar rats that were maternally raised (AFR), maternally separated from post-natal day (PND) 1 to PND10 (MS10), or maternally separated from PND1 to PND21 (MS21), to assess the effects of maternal separation on spatial learning and memory using the Morris Water Maze (MWM). We also performed quantitative cytochrome oxidase (COx) histochemistry on some selected brain areas in order to find out whether maternal separation affects brain energy metabolism. We obtained a similar spatial learning pattern in maternally raised and maternally separated subjects, with MS10 showing faster acquisition; however, different brain networks with different energy consumptions were used by each group. MS10 spent more energy to get the same behavioral outputs, whereas MS21 resembled AFR more in term of energy demands. PMID- 28893663 TI - Reward-related decision making and long-term weight loss maintenance. AB - BACKGROUND: Heightened sensitivity towards reward and insensitivity towards disadvantageous consequences may constitute a driving factor underlying unrestricted food intake and consequent weight gain in people with overweight and obesity. Therefore, the present study applied a behavioral economics approach to investigate the potential contribution of poor reward-related decision making to unsuccessful long-term weight loss maintenance (i.e. weight cycling). Based on previous research, it was expected that successful long-term weight loss maintainers would show a better performance in a gambling task than their less successful counterparts. METHODS: Reward-related decision making was assessed post hoc using the Game of Dice Task in a total of 33 overweight and obese women who had either (a) successfully maintained initial weight loss of at least 10% of their body weight over one year or (b) had regained weight until at least their initial body weight prior to weight reduction (i.e. showed weight cycling). RESULTS: The groups did not differ in terms of age, current body weight, magnitude of initial weight reduction, educational level, and global intelligence level. As hypothesized, however, the group of successful long-term weight loss maintainers performed significantly better (i.e. showed less impulsive, more advantageous choices) in the Game of Dice Task than their less successful counterparts. CONCLUSIONS: The findings suggest that poor reward-related decision making is associated with weight cycling which is considered a key concern in weight loss treatments for overweight and obesity. Furthermore, the findings speak in favor of specific psychological interventions that are designed to bolster reward-related decision making. PMID- 28893664 TI - Single cell transcriptome analysis of muscle satellite cells reveals widespread transcriptional heterogeneity. AB - Tissue specific stem cells are indispensable contributors to adult tissue maintenance, repair, and regeneration. In skeletal muscle, satellite cells (SCs) are the resident muscle stem cell population and are required to maintain skeletal muscle homeostasis throughout life. Increasing evidence suggests that SCs are a heterogeneous cell population with substantial biochemical and functional diversity. A major limitation in the field is an incomplete understanding of the nature and extent of this cellular heterogeneity. Single cell analyses are well suited to addressing this issue, especially when coupled to unbiased profiling paradigms such as high throughout RNA sequencing. We performed single cell RNA sequencing (scRNA-seq) on freshly isolated muscle satellite cells and found a surprising degree of heterogeneity at multiple levels, from muscle-specific transcripts to the broader SC transcriptome. We leveraged several comparative bioinformatics techniques and found that individual SCs enrich for unique transcript clusters. We propose that these gene expression "fingerprints" may contribute to observed functional SC diversity. Overall, these studies underscore the importance of several established SC signaling pathways/processes on a single cell level, implicate novel regulators of SC heterogeneity, and lay the groundwork for further investigation into SC heterogeneity in health and disease. PMID- 28893665 TI - Does aerobic capacity predict the spatial position of individuals within schools in juvenile qingbo (Spinibarbus sinensis)? AB - Schooling behavior is an adaptive trait of important biological and ecological significance in fish species. However, the question of how aerobic capacity and environmental factors (i.e., food and water velocity) affect the spatial positioning within fish schools has received little attention. Our study measured the aerobic capacity-as indicated by standard metabolic rate (SMR), maximum metabolic rate (MMR) and aerobic scope (AS)-and swimming performance of juvenile qingbo (Spinibarbus sinensis) and filmed their schooling behavior in a swim tunnel under both a control treatment and food stimulus treatment at three water velocities (20, 30 and 40cms-1). Neither aerobic capacity nor swimming performance was related to spatial position within schools. Food stimulation did not trigger any change in the characteristics of spatial position at three water velocities. However, an intra-school positional preference was found between water velocities under the control treatment and food stimulus treatment. Individuals who preferred the rear of the school had smaller coefficients of variation in position under the two treatments, but this behavior was not correlated with any parameters for metabolic rates. Inter-school social interaction level, as indicated by total chase times, was not affected by either water velocity or food appearance. Although aerobic capacity and food stimulus did not influence the spatial position of individuals within schools, individual qingbo had spatial positional preferences within schools between different water speeds. PMID- 28893666 TI - Physiological and behavioral responses to salinity in coastal Dice snakes. AB - Secondarily marine tetrapods have evolved adaptations to maintain their osmotic balance in a hyperosmotic environment. During the transition to a marine habitat, the evolution of a euryhaline physiology likely encompassed successive changes in behavior and physiology that released organisms from regular access to fresh water. Deciphering these key steps is a complicated task. In this study, we investigated a species of freshwater natricine snake in which some populations are known to use marine environments. We experimentally subjected 30 adult Dice snakes (Natrix tessellata) from a population inhabiting the Black Sea coast to three salinities corresponding to freshwater (~0.10/00), brackish water (~15.00/00), and full-strength seawater (~34.00/00) in order to investigate their physiological (variation of body mass, osmolality) and behavioral (activity, drinking behavior) responses to salinity. Our results show that coastal Dice snakes from the study population are relatively tolerant to salinity close to that recorded in the Black Sea, but that prolonged exposure to full-strength seawater increases osmolality, stimulates thirst, decreases the activity of snakes and may ultimately jeopardize survival. Collectively with previously published data, our results strongly suggest specific physiological adaptations to withstand hyperosmolality rather than to reduce intake of salt, in coastal populations or species of semi-aquatic snakes. Future comparative investigations of Dice snakes from populations restricted to freshwater environment might reveal the functional traits and the behavioral and physiological responses of coastal N. tessellata to life in water with elevated salinity. PMID- 28893667 TI - Amnestic drugs in the odor span task: Effects of flunitrazepam, zolpidem and scopolamine. AB - The odor span task is an incrementing non-matching-to-sample procedure designed to provide an analysis of working memory capacity in rodents. The procedure takes place in an arena apparatus and rats are exposed to a series of odor stimuli in the form of scented lids with the selection of new stimuli reinforced. This procedure makes it possible to study drug effects as a function of the number of stimuli to remember. In the present study, the non-selective positive allosteric GABAA receptor modulator flunitrazepam impaired odor span performance at doses that did not affect a control odor discrimination. In contrast, the alpha-1 selective positive GABAA receptor modulator zolpidem and the cholinergic receptor antagonist scopolamine only impaired odor span at doses that produced more global impairment, including decreased accuracy in the control discrimination and increased response omissions in the both the odor span and control discrimination procedures. Even though the effects of flunitrazepam were selective to odor span performance, they did not depend on the number of stimuli to remember-the same degree of impairment occurred regardless of the memory load. These findings suggest that flunitrazepam interfered selectively with conditional discrimination performance rather than working memory and tentatively suggest that flunitrazepam's selective effects in the odor span task relative to the control odor discrimination are mediated by one or more non-alpha1 GABAA receptor subtypes. PMID- 28893668 TI - Learning mechanisms underlying threat absence and threat relief: Influences of trait anxiety. AB - Impaired safety learning has been proposed asa risk factor for anxiety disorders, but safety can be indicated by either threat absence or threat termination (i.e., relief). Here, we investigated the role of trait anxiety for both kinds of safety learning. Ninety-one participants underwent an acquisition phase during which one shape (threatCS) predicted a painful electric shock (unconditioned stimulus, US), one shape (reliefCS) followed the US, and one shape (absenceCS) became never associated with the US. In a following extinction phase, the three cues were presented again plus a control shape (controlCS). We found successful threat conditioning as threatCS was rated as more aversive (negative, arousing, anxiogenic and associated with US) than the other cues, and it elicited startle potentiation as well asa larger skin conductance response (SCR). Safety cues were rated equally positive and (non-)anxiogenic, but still lower than controlCS, whereas physiologically reliefCS elicited stronger appetitive responses (startle attenuation and low SCR) than absenceCS. Interestingly, an increase in trait anxiety was associated with a decrease in the differences between absenceCS and threatCS responses reflected in contingency ratings during extinction as well as stronger fear-startle responses to absenceCS. In sum, physiological responses but not ratings triggered by a relief signal compared to a threat-absence signal, indicated that the former is more appetitive than the latter. Strikingly, trait anxiety specifically mediated learning of threat absence, but not of threat termination, indicating that high trait anxious individuals experience relief normally, but have deficits in identifying signals of threat absence. PMID- 28893669 TI - Mismatch novelty exploration training enhances hippocampal synaptic plasticity: A tool for cognitive stimulation? AB - Memory formation relies on experience-dependent changes in synaptic strength such as long-term potentiation (LTP) or long-term depression (LTD) of synaptic activity, that in turn depend on previous learning experiences through metaplasticity. Novelty detection is a particularly important cognitive stimulus in this respect, and mismatch novelty has been associated with the activation of the hippocampal CA1 area in human studies. A single exposure to a new location of known objects in a familiar environment, a behavioural mismatch novelty paradigm, is known to favour the expression of LTD in hippocampal CA3 to CA1 synaptic transmission in vivo, through short-term metaplasticity. Aiming to shape hippocampal responsiveness to synaptic plasticity phenomena we developed a training program based on exploration of a known environment containing familiar objects, everyday presented in a new location. Repeated exposure to this new location of objects for two weeks caused a mild long-lasting decrease in synaptic efficacy. Furthermore, it enhanced both LTP evoked by theta-burst stimulation and depotentiation evoked by low-frequency stimulation of CA3 to CA1hippocampal synaptic transmission in juvenile rats. This suggests that training programs using these behavioural tasks involving mismatch novelty can be used to reshape brain circuits and promote cognitive recovery in pathologies where LTP/LTD imbalance occurs, such as epilepsy, aging or Down's syndrome, an approach that requires further investigation at the behavioural level. PMID- 28893670 TI - Acute psychophysiological stress impairs human associative learning. AB - Addiction is increasingly discussed asa disorder of associative learning processes, with both operant and classical conditioning contributing to the development of maladaptive habits. Stress has long been known to promote drug taking and relapse and has further been shown to shift behavior from goal directed actions towards more habitual ones. However, it remains to be investigated how acute stress may influence simple associative learning processes that occur before a habit can be established. In the present study, healthy young adults were exposed to either acute stress or a control condition half an hour before performing simple classical and operant conditioning tasks. Psychophysiological measures confirmed successful stress induction. Results of the operant conditioning task revealed reduced instrumental responding under delayed acute stress that resembled behavioral responses to lower levels of reward. The classical conditioning experiment revealed successful conditioning in both experimental groups; however, explicit knowledge of conditioning as indicated by stimulus ratings differentiated the stress and control groups. These findings suggest that operant and classical conditioning are differentially influenced by the delayed effects of acute stress with important implications for the understanding of how new habitual behaviors are initially established. PMID- 28893671 TI - Combining multivariate statistics and the think-aloud protocol to assess Human Computer Interaction barriers in symptom checkers. AB - Symptom checkers are software tools that allow users to submit a set of symptoms and receive advice related to them in the form of a diagnosis list, health information or triage. The heterogeneity of their potential users and the number of different components in their user interfaces can make testing with end-users unaffordable. We designed and executed a two-phase method to test the respiratory diseases module of the symptom checker Erdusyk. Phase I consisted of an online test with a large sample of users (n=53). In Phase I, users evaluated the system remotely and completed a questionnaire based on the Technology Acceptance Model. Principal Component Analysis was used to correlate each section of the interface with the questionnaire responses, thus identifying which areas of the user interface presented significant contributions to the technology acceptance. In the second phase, the think-aloud procedure was executed with a small number of samples (n=15), focusing on the areas with significant contributions to analyze the reasons for such contributions. Our method was used effectively to optimize the testing of symptom checker user interfaces. The method allowed kept the cost of testing at reasonable levels by restricting the use of the think-aloud procedure while still assuring a high amount of coverage. The main barriers detected in Erdusyk were related to problems understanding time repetition patterns, the selection of levels in scales to record intensities, navigation, the quantification of some symptom attributes, and the characteristics of the symptoms. PMID- 28893672 TI - A situational analysis of current antimicrobial governance, regulation, and utilization in South Africa. AB - The Global Action Plan on antimicrobial resistance calls for the use of antimicrobial medicines in human and animal health to be optimized, in tandem with a strengthening of the knowledge and evidence base through surveillance and research. However, there is a paucity of consumption data for African countries such as South Africa. Determining antimicrobial consumption data in low-resource settings remains a challenge. This article describes alternative mechanisms of assessing antimicrobial consumption data, such as the use of Intercontinental Marketing Services (IMS) data and contract data arising from tenders (an open Request for Proposal, RFP), as opposed to the international norms of daily defined doses per 100 patient-days or per 1000 population. Despite their limitations, these serve as indicators of antimicrobial exposure at the population level and represent an alternative method for ascertaining antimicrobial consumption in human health. Furthermore, South Africa has the largest antiretroviral treatment programme globally and carries a high burden of tuberculosis. This prompted the inclusion of antiretroviral and anti-tuberculosis antibiotic consumption data. Knowledge of antimicrobial utilization is imperative for meaningful future interventions. Baseline antimicrobial utilization data could guide future research initiatives that could provide a better understanding of the different measures of antibiotic use and the level of antibiotic resistance. PMID- 28893673 TI - Extracorporeal membrane oxygenation (ECMO) as salvage treatment for pulmonary Echinococcus granulosus infection with acute cyst rupture. AB - Extracorporeal membrane oxygenation (ECMO) has been used successfully for the treatment of patients with respiratory failure due to severe infections. Although rare, parasites can also cause severe pulmonary disease. Tapeworms of the genus Echinococcus give rise to the development of cystic structures in the liver, lungs, and other organs. Acute cyst rupture leads to potentially life-threatening infection, and affected patients may deteriorate rapidly. The case of a young woman from Bulgaria who was admitted to hospital with severe dyspnoea, progressive chest pain, and haemoptysis is described. Computed tomography of the chest was pathognomonic for cystic echinococcosis with acute cyst rupture. Following deterioration on mechanical ventilation, she was cannulated for veno venous ECMO. The patient's condition improved considerably, and she was weaned successfully from ECMO and mechanical ventilation. Following lobectomy of the affected left lower lobe, the patient was discharged home in good condition. This appears to be the first report of the successful use of ECMO as salvage treatment for a severe manifestation of a helminthic disease. Due to recent migration to Western Europe, the number of patients presenting with respiratory failure due to pulmonary echinococcosis with cyst rupture is likely to increase. PMID- 28893674 TI - Seroepidemiology of leptospirosis among febrile patients in a rapidly growing suburban slum and a flood-vulnerable rural district in Mozambique, 2012-2014: Implications for the management of fever. AB - OBJECTIVE: Leptospirosis is one of the most widespread zoonoses in the world and is caused by spirochetes of the genus Leptospira. In Mozambique, the disease is largely ignored and its epidemiology is unknown. The objective of this study was to investigate the occurrence of leptospirosis in febrile patients. METHODS: This cross-sectional study was performed between July 2012 and September 2015 among febrile patients. A total of 373 paired serum samples were drawn from febrile patients; 208 were from Caia District Hospital (rural setting) in Sofala Province and 165 were from Polana Canico General Hospital (suburban setting) in Maputo City. Samples were initially screened using an in-house ELISA for IgM and IgG antibodies. Double positive samples were confirmed using a microagglutination test (MAT). RESULTS: Of the 373 febrile patients, five (1.3%) had acute leptospirosis (MAT >=400) and 38 (10.2%) had a presumptive infection (IgM positive/MAT <400). While most of the patients with a presumptive infection lived in the rural setting (84.2%, 32/38), the majority of patients with acute infections (60%, 3/5) and with negative results (60.3%, 199/330) lived in the suburban setting (p=0.000). Contact with rodents was significantly higher in patient with acute leptospirosis (100%, 5/5) than in those with a presumptive infection (39.5%, 15/38) or negative results (41.8%, 138/330) (p=0.031). Four out of the five patients (80%) with acute leptospirosis were treated with antimalarial drugs although malaria results were negative. The prevailing serogroup, according to MAT results, was Australis (40%; 4/10), followed by Icterohaemorrhagiae (30%, 3/10). CONCLUSIONS: This study found that leptospirosis is prevalent among Mozambicans, and most cases are misdiagnosed as malaria. PMID- 28893675 TI - Design, recruitment outcomes, and sample characteristics of the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial. AB - This manuscript describes the study protocol, recruitment outcomes, and baseline participant characteristics for the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial. SPACE is a pragmatic randomized comparative effectiveness trial conducted in multiple VA primary care clinics within one VA health care system. The objective was to compare benefits and harms of opioid therapy versus non-opioid medication therapy over 12months among patients with moderate-to-severe chronic back pain or hip/knee osteoarthritis pain despite analgesic therapy; patients already receiving regular opioid therapy were excluded. Key design features include comparing two clinically-relevant medication interventions, pragmatic eligibility criteria, and flexible treat-to target interventions. Screening, recruitment and study enrollment were conducted over 31months. A total of 4491 patients were contacted for eligibility screening; 53.1% were ineligible, 41.0% refused, and 5.9% enrolled. The most common reasons for ineligibility were not meeting pain location and severity criteria. The most common study-specific reasons for refusal were preference for no opioid use and preference for no pain medications. Of 265 enrolled patients, 25 withdrew before randomization. Of 240 randomized patients, 87.9% were male, 84.1% were white, and age range was 21-80years. Past-year mental health diagnoses were 28.3% depression, 17% anxiety, 9.4% PTSD, 7.9% alcohol use disorder, and 2.6% drug use disorder. In conclusion, although recruitment for this trial was challenging, characteristics of enrolled participants suggest we were successful in recruiting patients similar to those prescribed opioid therapy in usual care. PMID- 28893677 TI - Accuracy of Self-Reported Heart Failure. The Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVE: The aim of this work was to estimate agreement of self-reported heart failure (HF) with physician-diagnosed HF and compare the prevalence of HF according to method of ascertainment. METHODS AND RESULTS: ARIC cohort members (60-83 years of age) were asked annually whether a physician indicated that they have HF. For those self-reporting HF, physicians were asked to confirm their patients' HF status. Physician-diagnosed HF included surveillance of hospitalized HF and hospitalized and outpatient HF identified in administrative claims databases. We estimated sensitivity, specificity, positive predicted value, kappa, prevalence and bias-adjusted kappa (PABAK), and prevalence. Compared with physician-diagnosed HF, sensitivity of self-report was low (28%-38%) and specificity was high (96%-97%). Agreement was poor (kappa 0.32-0.39) and increased when adjusted for prevalence and bias (PABAK 0.73-0.83). Prevalence of HF measured by self-report (9.0%), ARIC-classified hospitalizations (11.2%), and administrative hospitalization claims (12.7%) were similar. When outpatient HF claims were included, prevalence of HF increased to 18.6%. CONCLUSIONS: For accurate estimates HF burden, self-reports of HF are best confirmed by means of appropriate diagnostic tests or medical records. Our results highlight the need for improved awareness and understanding of HF by patients, because accurate patient awareness of the diagnosis may enhance management of this common condition. PMID- 28893676 TI - Rationale and design of the Staying Positive with Arthritis (SPA) Study: A randomized controlled trial testing the impact of a positive psychology intervention on racial disparities in pain. AB - Knee osteoarthritis is a painful, disabling condition that disproportionately affects African Americans. Existing arthritis treatments yield small to moderate improvements in pain and have not been effective at reducing racial disparities in the management of pain. The biopsychosocial model of pain and evidence from the positive psychology literature suggest that increasing positive psychological skills (e.g., gratitude, kindness) could improve pain and functioning and reduce disparities in osteoarthritis pain management. Activities to cultivate positive psychological skills have been developed and validated; however, they have not been tested in patients with osteoarthritis, their effects on racial differences in health outcomes have not been examined, and evidence of their effects on health outcomes in patients with other chronic illnesses is of limited quality. In this article we describe the rationale and design of Staying Positive with Arthritis (SPA) study, a randomized controlled trial in which 180 African American and 180 White primary care patients with chronic pain from knee osteoarthritis will be randomized to a 6-week program of either positive skill building activities or neutral control activities. The primary outcomes will be self-reported pain and functioning as measured by the WOMAC Osteoarthritis Index. We will assess these primary outcomes and potential, exploratory psychosocial mediating variables at an in-person baseline visit and by telephone at 1, 3, and 6months following completion of the assigned program. If effective, the SPA program would be a novel, theoretically-informed psychosocial intervention to improve quality and equity of care in the management of chronic pain from osteoarthritis. PMID- 28893678 TI - Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis. AB - OBJECTIVE: To assess predictors of response, according to hip MRI inflammatory scoring system (HIMRISS), in a sample of patients with hip osteoarthritis (OA) treated by hyaluronic acid (HA) injection. METHOD: Sixty patients with hip OA were included. Clinical outcomes were assessed at baseline and three months after HA injection by WOMAC. On hip MRI performed before HA injection, bone marrow lesion (BML) and synovitis were assessed by HIMRISS by four readers. The inter reader reliability of HIMRISS was for HIMRISS total, acetabular BML, femoral BML and synovitis-effusion respectively 0.86, 0.64, 0.83 and 0.78. Associations between MRI features and clinical data were assessed. Logistic regression (univariate and multivariate) was used to explore associations between MRI features and response to HA injection, according to WOMAC50 response at three months. RESULTS: In total, 45.5% of patients met WOMAC50 response. Five adverse events were reported. At baseline, WOMAC function correlated significantly to HIMRISS synovitis-effusion (r=0.27, P=0.03). In univariate analysis, BML femoral according to binary assessment (P=0.025), HIMRISS BML femoral (P=0.0038), HIMRISS BML acetabular (P=0.042), HIMRISS total (P=0.0092) were associated negatively with WOMAC50 response. In multivariate analysis, adjusted for age and BMI, HIMRISS femoral BML (P=0.02) and HIMRISS total (P=0.016) were negatively associated with response. At a HIMRISS threshold of<15, 82% of patients were responders, with specificity SP=0.97, sensitivity SN=0.39, and positive and negative predictive values of 0.91 and 0.64, respectively. CONCLUSION: HIMRISS is reliable for total scores and sub-domains. It permits identification of responders to HA injection in hip OA patients. PMID- 28893679 TI - Incidence of cancer in patients with spondyloarthritis treated with anti-TNF drugs. AB - OBJECTIVE: To determine the incidence of cancer in TNF inhibitor (TNFi)-treated spondyloarthritis (SpA) patients entered in the GISEA registry, and identify the factors associated with its development. METHODS: This observational study involved an open cohort of 3321 SpA patients selected from the GISEA registry, designed to collect real-world clinical data concerning patients with RA or SpA treated with biological drugs. The baseline information includes demographics and clinical parameters. The overall incidence of neoplasias was compared to this observed in the general population according to the Italian Association of Medical Oncology. RESULTS: Of the 3321 SpA patients (1731 males, 52.2%; mean age 47+/-13years; median disease duration three years, interquartile range [IQR] 0 8), 50 developed at least one of 56 malignancies during the follow-up period of up to 12years of treatment with TNFi. The overall incidence was 6.3/1000 patient years of follow-up (95% confidence interval [CI] 4.7-8.2): 7.3/1000 patient-years (95% CI 4.1-11.8) in those treated with ADA; 6.1/1000 patient-years (95% CI 3.8 9.4) in those treated with ETN; and 5.8/1000 patient-years (95% CI 3.5-9.1) in those treated with INF while in the general population was 5.1/1000 patient years. Univariate analysis showed that age at the time of starting TNFi (P=0.001), the presence of comorbidities (P=0.012), the number of comorbidities (P<0.001), and HAQ-DI score (P=0.002) were associated with a higher risk of malignancies. Stepwise regression models showed that only previous neoplasia was a significant predictor of a new malignancy. The type of drug was not associated with the risk of malignancy. CONCLUSIONS: The incidence of malignancies among SpA patients treated with the three TNFi was higher than in general population; having had a previous solid cancer is predictive of a new malignancy. PMID- 28893680 TI - Reply. PMID- 28893681 TI - Boerhaave's Syndrome: A Window to the Heart. PMID- 28893682 TI - Effects of flavonoids incorporated biological macromolecules based scaffolds in bone tissue engineering. AB - Skeletal tissue damage caused by trauma, injury, or disease can often result in considerable morbidity and the need for new, more reliable strategies for skeletal regeneration. So, to address the unmet need for bone augmentation, bone tissue engineering and regenerative medicine have evolved in the recent years. Bone tissue engineering harnesses novel scaffolds, stem cells and biological factors that promise enhanced and more reliable bone formation. Increasingly phytochemicals, particularly flavonoids are gaining renowned interest lately for their therapeutic potential on bone. Intake of flavonoids has shown to improve bone health due to their antioxidant and anti-inflammatory properties. Inclusion of biomaterials for flavonoids delivery has potential towards bone tissue engineering. Hence, this review was aimed to provide an overview of recent developments in bone tissue engineering focusing on flavonoids and their potent biological properties that enhance bone health. PMID- 28893683 TI - Sulfation can enhance antitumor activities of Artemisia sphaerocephala polysaccharide in vitro and vivo. AB - In this study, a sulfated Artemisia sphaerocephala polysaccharide (ASPs) was prepared and its antitumor activity was evaluated in tumor cells and Hepatoma 22 (H22) tumor-bearing mice. In vitro experiments, ASPs significantly inhibited the growth of HepG2 and Hela cells with the IC50 values of 172.03 and 161.42MUg/mL, respectively. Moreover, no direct cytotoxicity against mouse fibroblast L929 normal cells was observed in vitro. After oral administration for 12days, the tumor growth was significantly suppressed by ASPs at the doses of 200mg/kg (inhibition rate of 60.85%). Results of tumor histological morphology and cell cycle analysis showed that ASPs could arrest H22 cells at S phase and promote cell apoptosis. Additionally, immunohistochemical analysis demonstrated that ASPs caused the down-regulation of mutant p53 protein expression in a dose-dependent manner. Therefore, these findings proposed new insight into antitumor properties of sulfated polysaccharide as a promising agent in cancer treatment. PMID- 28893684 TI - Gelatin based bio-films prepared from grey triggerfish' skin influenced by enzymatic pretreatment. AB - Gelatins from grey triggerfish skin were extracted with different methods. The treatment by pepsin (PG) improved the yield of extraction when compared with untreated gelatin (UG) and acidic gelatin (AG). The outputs of gelatins AG, UG and PG, obtained respectively, with acitic acid, glycine buffer and glycine buffer added with 5U of pepsin/g of the skin beforehand treated by alkali, were 6.9%, 7.9% and 9.7%, respectively. The enzymatic treatment of the alkali pretreated skin of grey triggerfish altered the electrophoresis profile, biophysical, gellification, rheological and thermal properties of the prepared gelatins extracted under acidic condition. However, the untreated gelatin obtained without pepsin exhibited the highest transition and enthaply temperatures. In addition, the properties of the prepared films were interconnected to their microstructure as demonstrated by scanning electron microscopy. Furthermore, films with PG and UG had a regular surface and a more condensed structure, whereas films prepared with AG had rougher surface. PMID- 28893685 TI - Protective effects of a G. lucidum proteoglycan on INS-1 cells against IAPP induced apoptosis via attenuating endoplasmic reticulum stress and modulating CHOP/JNK pathways. AB - Fudan-Yueyang-G. lucidum (FYGL) is a water-soluble macromolecular proteoglycan extracted from Ganoderma lucidum which has been used for health promotion for a long time in China. The aim of this study was to investigate the protective effects of FYGL on INS-1 rat insulinoma beta cells against IAPP-induced cell apoptosis, as well as the underlying mechanisms. The results showed that apoptotic cells were significantly increased when incubated with islet amyloid polypeptide (IAPP). However, cytotoxicity of IAPP was significantly attenuated by co-incubation of the cells with FYGL. The results of RT-PCR showed that mRNA expression of caspase-3, caspase-12 and C/EBP homologous protein (CHOP) in IAPP treated cells were inhibited by FYGL. Moreover, FYGL significantly prevented the IAPP-induced abnormal expression of inositol-requiring protein-1alpha (IRE1alpha), protein kinase RNA (PKR)-like ER kinase (PERK), activating transcription factor 6 (ATF6), as well as suppressed the activation of CHOP and c Jun N-terminal kinase (JNK). Taken together, our results suggest that FYGL protects INS-1 pancreatic beta cells against IAPP-induced apoptosis through attenuating endoplasmic reticulum stress (ERS) and modulating CHOP/JNK pathways. PMID- 28893686 TI - Expression and degradation patterns of chitinase purified from Xuehuali (Pyrus bretschneiderilia) pollen. AB - The present study investigated the expression pattern of chitinase in Xuehuali (Pyrus bretschneiderilia) pollen, as well as its subsequent degradation. The chitinase was purified and collected using chitin affinity column chromatography with regenerated chitin. After purification, four additional chitinase isozymes (chiA, chiB, chiC, and chiD) and chitinase (Chi II) were clearly expressed on SDS PAGE gels that contained 0.01% glycol chitin. The chitinase reaction products were examined using GlcNAc, (GlcNAc)2, (GlcNAc)3, (GlcNAc)4, (GlcNAc)5, and (GlcNAc)6 as substrates at 2 and 24h after reaction via TLC and HPLC. The (GlcNAc)4 oligosaccharide was slightly degraded to (GlcNAc)2 after 24h of reaction with Xuehuali pollen chitinase on TLC. Meanwhile, (GlcNAc)5 was degraded to (GlcNAc)2-4, and 2300ppm (GlcNAc)6 was degraded to 246ppm (GlcNAc)2, 208ppm (GlcNAc)3, 572ppm (GlcNAc)4, and 336ppm (GlcNAc)5 on HPLC. With regard to temperature, the strongest Xuehuali pollen chitinase activity (0.69 unit/mL) was observed at 37 degrees C after 3h of incubation, and with regard to pH, the strongest activity (0.72unit/mL) was observed at pH 3 after 3h of incubation. The main chitin oligomers degraded from (GlcNAc)6 were (GlcNAc)2 and (GlcNAc)4. PMID- 28893687 TI - Genetic analysis of ID1-DBL2X predicts its validity as a vaccine candidate in Colombia and supports at least two independently introduced Plasmodium falciparum populations in the region. AB - Pregnancy-associated malaria (PAM) poses a threat to both the mother and fetus, increasing the risk of severe maternal anemia, fetal growth restriction and low birth weight infants. Two vaccines are currently in development to protect women from Plasmodium falciparum in pregnancy. Both vaccine constructs target the ID1 DBL2X domain of VAR2CSA, a protein expressed on the surface of infected erythrocytes (IEs) that mediates parasite sequestration in the placenta. Although development of an effective vaccine may be hampered by ID1-DBL2X polymorphisms expressed by field isolates, a recent study showed that genetic variation of this domain in South American parasite populations is much lower than in other geographical locations. This suggests that a recombinant vaccine designed to be efficacious in Africa and Asia is likely to be efficacious in South America. However, these studies did not include Colombian parasite populations in their analyses, which are known to be genetically distinct from other South American parasite populations due to their independent introduction from Africa. Therefore, we sought to determine the genetic variation of the ID1-DBL2X domain in Colombian parasites to assess the potential efficacy of the vaccine against PAM in this region. Through sequence analysis and population genetics, we show that there is a low degree of genetic variation amongst Colombian parasite populations and that a vaccine containing conserved antigen variants for worldwide populations is likely to be protective against PAM in Colombia. Our analysis also points towards an African origin for Colombian parasite populations, and suggests that their introduction into Colombia was a recurrent process encompassing multiple introduction events. PMID- 28893688 TI - Whole-genome sequencing identification of a multidrug-resistant Salmonella enterica serovar Typhimurium strain carrying blaNDM-5 from Guangdong, China. AB - A carbapenem-resistant Salmonella enterica serovar Typhimurium (sequence type 34 [ST34]) strain was isolated from a fecal specimen from a child with acute diarrhea. Whole-genome sequencing revealed that the 84.5-kb IncFII plasmid pST41 NDM carrying the NDM-5 carbapenemase gene possesses a structure identical to that of the IncFII-type plasmid backbone. However, the blaNDM-5 flanking sequence found in this plasmid is identical to the blaNDM-5-positive IncX3 plasmids carried by 10 strains of Enterobacteriaceae identified in the same hospital. PMID- 28893689 TI - Management of KPC-producing Klebsiella pneumoniae infections. AB - BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) has become one of the most important contemporary pathogens, especially in endemic areas. AIMS: To provide practical suggestion for physicians dealing with the management of KPC-KP infections in critically ill patients, based on expert opinions. SOURCES: PubMed search for relevant publications related to the management of KPC-KP infections. CONTENTS: A panel of experts developed a list of 12 questions to be addressed. In view of the current lack of high-level evidence, they were asked to provide answers on the bases of their knowledge and experience in the field. The panel identified several key aspects to be addressed when dealing with KPC-KP in critically ill patients (preventing colonization in the patient, preventing infection in the colonized patient and colonization of his or her contacts, reducing mortality in the infected patient by rapidly diagnosing the causative agent and promptly adopting the best therapeutic strategy) and provided related suggestions that were based on the available observational literature and the experience of panel members. IMPLICATIONS: Diagnostic technologies could speed up the diagnosis of KPC-KP infections. Combination treatment should be preferred to monotherapy in cases of severe infections. For non-critically ill patients without severe infections, results from randomized clinical trials are needed for ultimately weighing benefits and costs of using combinations rather than monotherapy. Multifaceted infection control interventions are needed to decrease the rates of colonization and cross transmission of KPC-KP. PMID- 28893690 TI - New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? AB - BACKGROUND: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made. AIMS: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram negative organisms. SOURCES: A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies. CONTENT: Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the beta-lactam/beta lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline. IMPLICATIONS: The development of new agents with activity against multidrug resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-beta-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development. PMID- 28893691 TI - Folate appended cyclodextrins for drug, DNA, and siRNA delivery. AB - Drug, DNA, and siRNA delivery systems based on cyclodextrin (CD) core and connected with folate (FA) via various linkers are presented. They include simple mono-derivatized cyclodextrins as well as cyclodextrins with higher degree of substitution, both in their primary and secondary sides. Examples of simple polymers and dendrimers are also discussed. Such carriers possess properties inherent to both of their components. Cyclodextrin provides the ability to encapsulate organic molecules in its inner cavity, thus improving their solubility in water, bioavailability, and stability, while FA assures targeting folate receptor overexpressing cancer cells. Drug delivery systems loaded with drugs such as e.g. methotrexate, doxorubicin, paclitaxel, vinblastine, and docetaxel were found to have superior properties as compared to the free drug. Dendritic folate appended cyclodextrins were also found to be good sustained release systems for DNA and siRNA. The recent progress in the synthesis and drug, DNA, and siRNA delivery application of folate appended cyclodextrins is presented. PMID- 28893692 TI - Formation of mannitol core microparticles for sustained release with lipid coating in a mini fluid bed system. AB - The goal of this study was to prepare sustained release microparticles for methyl blue and aspartame as sparingly and freely water-soluble model drugs by lipid film coating in a Mini-Glatt fluid bed, and to assess the effect of coating load of two of lipids, hard fat and glyceryl stearate, on the release rates. 30g drug loaded mannitol carrier microparticles with average diameter of 500 or 300MUm were coated with 5g, 10g, 20g and 30g lipids, respectively. The model drugs were completely released in vitro through pores which mainly resulted from dissolution of the polyol core beads. The release of methyl blue from microparticles based on 500MUm carrier beads extended up to 25days, while aspartame release from microparticles formed from 300MUm carrier beads was extended to 7days. Although glyceryl stearate exhibits higher wettability, burst and release rates were similar for the two lipid materials. Polymorphic transformation of the hart fat was observed upon release. The lipid-coated microparticles produced with 500MUm carrier beads showed slightly lower burst release compared to the microparticles produced with 300MUm carrier beads as they carried relatively thicker lipid layer based on an equivalent lipid to mannitol ratio. Aspartame microparticles showed a much faster release than methyl blue due to the higher water-solubility of aspartame. PMID- 28893693 TI - Current Status of Worldwide Use of Patient-Reported Outcome Measures (PROMs) in Spine Care. AB - OBJECTIVES: Patient-reported outcome measures (PROMs) are the most widely accepted means of measuring outcomes after spine procedures. We sought to determine the current status of worldwide use of PROMs in Latin America (LA), Europe (EU), Asia Pacific (AP), North America (NA), and Middle East (ME) to determine the barrier to its full implementation. METHODS: A questionnaire survey was sent by e-mail to members of AOSpine to evaluate their familiarity and use of PROMs instruments and to assess the barriers to their use in spine care practice in LA, EU, AP, NA, and ME. RESULTS: A total of 1634 AOSpine members from LA, EU, AP, NA, and ME answered the electronic questionnaire. The percentage of spine surgeons who were familiar with the generic health-related quality of life questionnaire was 71.7%. In addition, 31.9% of respondents did not use any PROMs routinely. The main barriers to implementing PROMs were lack of time to administer the questionnaires (57%) followed by lack of staff to assist in data collection (55%), and the long time to fill out the questionnaires (46%). The routine use of questionnaires was more frequent in NA and EU and less common in LA and ME (P < 0.001). CONCLUSIONS: We found that 31.9% of spine surgeons do not use the PROMs questionnaire routinely. This appears to occur because of lack of knowledge regarding their importance, absence of reimbursement for this extra work, minimal financial support for clinical research, the cost of implementation, and lack of concern among physicians. PMID- 28893694 TI - Altered Expression of MicroRNA-15a and Kruppel-Like Factor 4 in Cerebrospinal Fluid and Plasma After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Cerebral vasospasm (CVS) is a major determinant of prognosis in patients with subarachnoid hemorrhage (SAH). Alteration in the vascular phenotype contributes to development of CVS. However, little is known about the role of microRNAs (miRNAs) in the phenotypic alteration after SAH. We investigated the expression profile of miRNAs and the chronologic changes in the expression of microRNA-15a (miR-15a) and Kruppel-like factor 4 (KLF4), a potent regulator of vascular phenotype modulation that modulates the expression of miR-15a, in the plasma and cerebrospinal fluid (CSF) of patients with SAH. METHODS: Peripheral blood and CSF samples were collected from 8 patients with aneurysmal SAH treated with endovascular obliteration. Samples obtained from 3 patients without SAH were used as controls in the analysis. Exosomal miRNAs were isolated and subjected to microarray analysis with the three-dimensional-gene miRNA microarray kit. The time course of the expression of miR-15a and KLF4 was analyzed using quantitative real-time polymerase chain reaction. RESULTS: Microarray analysis showed that 12 miRNAs including miR-15a were upregulated or downregulated both in the CSF and in plasma after SAH within 3 days. Quantitative real-time polymerase chain reaction showed that miR-15a expression was significantly increased in both the CSF and plasma, with a peak around 3-5 days after SAH, whereas the expression of KLF4 was significantly decreased around 1-3 days after SAH and remained lower than in controls. CONCLUSIONS: Our results suggest that an early and persistent decrease in KLF4 followed by an increase in miR-15a may contribute to the altered vascular phenotype, resulting in development of CVS. PMID- 28893695 TI - Chronologic Evaluation of Cerebral Hemodynamics by Dynamic Susceptibility Contrast Magnetic Resonance Imaging After Indirect Bypass Surgery for Moyamoya Disease. AB - OBJECTIVE: Although indirect bypass surgery is an effective treatment option for patients with ischemic-onset moyamoya disease (MMD), the time point after surgery at which the patient's hemodynamic status starts to improve and the time point at which the improvement reaches a maximum have not been known. The objective of the present study is to evaluate the hemodynamic status time course after indirect bypass surgery for MMD, using dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI). METHODS: We retrospectively analyzed the cases of 25 patients with MMD (37 sides; mean age, 14.7 years; range, 3-36 years) who underwent indirect bypass surgery and repeated DSC-MRI measurement within 6 months after the operation. The difference in the mean transit time (MTT) between the target regions and the control region (cerebellum) was termed the MTT delay, and we measured the MTT delay's chronologic changes after surgery. RESULTS: The postoperative MTT delay was 1.81 +/- 1.16 seconds within 1 week after surgery, 1.57 +/- 1.01 at weeks 1-2, 1.55 +/- 0.68 at weeks 2-4, 1.32 +/- 0.68 at months 1 2, 0.95 +/- 0.32 at months 2-3, and 0.77 +/- 0.33 at months 3-6. Compared with the preoperative value (2.11 +/- 0.98 seconds), the MTT delay decreased significantly from 2 to 4 weeks after surgery (P < 0.05). CONCLUSIONS: The amelioration of cerebral hemodynamics by indirect bypass surgery began soon after surgery and gradually reached a maximum at 3 months after surgery. DSC-MRI detected small changes in hemodynamic improvement, which are suspected to be caused by the initiation of angiogenesis and arteriogenesis in the early postoperative period. PMID- 28893696 TI - Medullary Decompression by Sling Repositioning of Vertebral Artery with Operative Video. AB - BACKGROUND: Vascular compression of the medullary pyramid resulting in neurologic compromise is rare; therefore diagnosis is difficult and ultimately delayed. Most patients present with a combination of cranial nerve, autonomic, and/or motor and sensory dysfunction. Presentation with a single sign such as hemiparesis is rare. The low number of cases reported has made it impossible to define a standard treatment for this unusual disorder. CASE DESCRIPTION: Here, we present a patient with progressive left hemiparesis due to compression of the upper medulla by the vertebral artery, which was treated with repositioning of the artery using a sling. Clinical and radiologic features including upper medullary compression by the left vertebral artery with effacement of the left medullary pyramid and T2/fluid-attenuated inversion recovery signal changes in the right medulla are illustrated. The patient underwent a standard left retrosigmoid craniectomy for mobilization of the left vertebral artery with a Hemashield (Maquet Cardiovascular, San Jose, California, USA) sling (see video). Postoperatively, the patient had significant improvement of the left hemiparesis and follow-up imaging showed decompression of the medulla with edema reduction. CONCLUSIONS: Vascular decompression using a sling has proven to be a valuable option for treatment of symptomatic vascular brainstem compression. PMID- 28893697 TI - Incidence of Postoperative Hematomas Requiring Surgical Treatment in Neurosurgery: A Retrospective Observational Study. AB - OBJECTIVE: We aimed to characterize the occurrence of postoperative hematoma (POH) after neurosurgery overall and according to procedure type and describe the prevalence of possible confounders. METHODS: Patient data between 2010 and 2012 at the Department of Neurosurgery in Helsinki University Hospital were retrospectively analyzed. A data search was performed according to the type of surgery including craniotomies; shunt procedures, spine surgery, and spinal cord stimulator implantation. We analyzed basic preoperative characteristics, as well as data about the initial intervention, perioperative period, revision operation and neurologic recovery (after craniotomy only). RESULTS: The overall incidence of POH requiring reoperation was 0.6% (n = 56/8783) to 0.6% (n = 26/4726) after craniotomy, 0% (n = 0/928) after shunting procedure, 1.1% (n = 30/2870) after spine surgery, and 0% (n = 0/259) after implantation of a spinal cord stimulator. Craniotomy types with higher POH incidence were decompressive craniectomy (7.9%, n = 7/89), cranioplasty (3.6%, n = 4/112), bypass surgery (1.7%, n = 1/60), and epidural hematoma evacuation (1.6%, n = 1/64). After spinal surgery, POH was observed in 1.1% of cervical and 2.1% of thoracolumbar operations, whereas 46.7% were multilevel procedures. 64.3% of patients with POH and 84.6% of patients undergoing craniotomy had postoperative hypertension (systolic blood pressure >160 mm Hg or lower if indicated). Poor outcome (Glasgow Outcome Scale score 1 3), whereas death at 6 months after craniotomy was detected in 40.9% and 21.7%. respectively, of patients with POH who underwent craniotomy. CONCLUSIONS: POH after neurosurgery was rare in this series but was associated with poor outcome. Identification of risk factors of bleeding, and avoiding them, if possible, might decrease the incidence of POH. PMID- 28893698 TI - Clinical Manifestations of Isolated Chronic Middle Cerebral Artery Occlusion in Relation to Angiographic Features. AB - OBJECTIVE: Isolated chronic middle cerebral artery occlusion (ChMCAO) is not a rare condition and is known to cause hemodynamic stroke. The purpose of this study was to evaluate differences in clinical manifestations and prognosis of isolated ChMCAO in relation to angiographic features. METHODS: This retrospective study enrolled 56 patients with isolated ChMCAO. In accordance with degree of anterograde collateral flow (AF) on angiography, patients were categorized into poor and good AF groups. The 2 groups were assessed and compared for the presence and recurrence of neurologic symptoms. RESULTS: Of 56 patients, 33 were in the poor AF group and 23 were in the good AF group. The prevalence of ischemic symptoms was significantly higher in the poor AF group compared with the good AF group (P < 0.05). During an average follow-up period of 33.8 months, recurrent ipsilateral symptoms occurred in 6 of 45 patients. The hazard ratio conferred by poor AF was 5.36 (95% confidence interval, 1.08-26.57) for recurrent symptoms. CONCLUSIONS: AF through the basal collateral network may be related to clinical manifestations of ChMCAO. Good AF in isolated ChMCAO may play an important role in preventing recurrence of an ischemic event. PMID- 28893699 TI - Cervical En-Plaque Extradural Meningioma Involving Brachial Plexus. AB - BACKGROUND: Meningioma is one of the commonest spinal tumors, with a predilection for intradural occurrence. Its occurrence as an extradural, en plaque variety with extension into the brachial plexus is unusual. CASE DESCRIPTION: A 50-year old male patient presented with progressive spastic quadriparesis. Magnetic resonance imaging showed an en plaque, epidural soft tissue tumor at C5-C7 levels on the right side with extraforaminal extension into the paraspinal region and the brachial plexus laterally. The patient underwent a C5-7 laminectomy and partial excision of the tumor. Histopathology was reported as psammomatous meningioma (World Health Organization grade I). CONCLUSIONS: An extradural spinal meningioma should be considered in the differential diagnosis of an exclusively extradural spinal tumor. Its occurrence as an en plaque variety is uncommon. We report an unusual case of the en plaque form of extradural cervical meningioma with diffuse involvement of the brachial plexus. PMID- 28893700 TI - Comparison of Radiation Exposure during Endovascular Treatment of Peripheral Arterial Disease with Flat-Panel Detectors on Mobile C-arm versus Fixed Systems. AB - BACKGROUND: Flat-panel detectors on mobile C-arm (MC-arm) systems are currently challenging fixed C-arm (FC-arm) systems used in hybrid operating rooms. MC-arm systems offer an alternative to FC-arm systems in the endovascular treatment of peripheral arterial disease (PAD) but their efficiency has not been evaluated comparatively. METHODS: Two series of patients undergoing arteriography with intention to treat were included. Each series consisted of 2 nonrandomized groups: an MC-arm group and an FC-arm group. Series 1 evaluated exposure to the patient (MC-arm, n = 113; FC-arm, n = 206) while series 2 evaluated exposure to patients and also health care personnel (MC-arm, n = 24; FC-arm, n = 76). The primary end points for evaluating exposure were air kerma (AK, in mGy) for patients and effective dose for health care personnel (in MUSv). RESULTS: After adjustment for the effect of body mass index (analysis of covariance test), AK was found to be lower in the MC-arm group than in the FC-arm group (124.1 +/- 142 vs. 173.3 +/- 248.7, P = 0.025). There was no difference between the groups with regard to effective dose recorded for senior surgeons or for operating room nurses. However, a higher effective dose was recorded by the MC-arm group external dosimeter for the trainee resident and for nurse anesthetists. CONCLUSIONS: In endovascular treatment of lower limb PAD, use of an FC-arm system is associated with more radiation exposure to the patient than an MC-arm system. However, this type of imaging system does not appear to affect exposure to health care personnel. PMID- 28893701 TI - Impact of Vascular Calcifications on Long Femoropopliteal Stenting Outcomes. AB - BACKGROUND: Vascular calcifications (VCs) may be a prognostic factor for outcome after endovascular treatment of peripheral arterial disease (PAD). Semiquantitative analysis with X-ray imaging is the main limiting factor for assessing VCs. The aim of the present study was to find a correlation between the amount of VC with computed tomography (CT) scan quantification and midterm results of endovascular treatment of Trans-Atlantic Inter-Society Consensus C/D femoropopliteal (FP) lesions. METHODS: Patients belonging to 2 previously published registries (STELLA and STELLA PTX) and who underwent a preoperative CT scan were retrospectively included in the study. VC quantification was performed with a dedicated workstation (EndoSize, Therenva) on the basis of Hounsfield units (HU). The VC percentage was calculated as the ratio between VC volume and the volume of the region of interest. For the analysis, patients were divided into 3 groups according to VC percentage, from lowest to highest: group 1 (G1) included the first quartile of VCs, group 2 (G2) included the second and third quartiles, and group 3 (G3) included the fourth quartile. Risk of in-stent thrombosis was analysed using a multivariate model. RESULTS: Thirty-nine patients were included (10 in G1, 19 in G2, and 10 in G3), and mean follow-up duration was 24 +/- 14.6 months. Patients in G1 and G3 had, respectively, a VC rate of <1% (no VC) and >20% (severe VC). In G2, VC was considered to be intermediate. There was no statistical difference in the cardiovascular risk factors and preoperative medication. A significant difference was found for the healthy FP diameter between G1 (4.6 +/- 0.8 mm) and G3 (6.8 +/- 0.8 mm, P < 0.0001) and between G2 (5.2 +/- 1 mm) and G3 (P < 0.0001). The rate of drug-eluting stents was similar in all groups. There was no difference between groups concerning the rate of in stent restenosis, target lesion revascularization, and target extremity revascularization. There was a higher rate of in-stent thrombosis for G1 versus G2 (P = 0.037), and no difference was noted between G1 versus G3 (P = 0.86) or G2 versus G3 (P = 0.12). G3 was associated with early stent thrombosis (<1 month), while G1 was associated with late stent thrombosis (6-24 months). On multivariate analysis, only one predictive factor for stent thrombosis was found: patients with intermediate VC seemed to be protected against in-stent thrombosis (odds ratio = 0.27, 95% confidence interval: 0.1-0.77; P = 0.014). CONCLUSIONS: The study showed that VC quantification with CT imaging is feasible and useful for comparing outcomes following PAD endovascular revascularization. Below a certain threshold, the presence of VC might be necessary for plaque stability and may protect against in-stent thrombosis. PMID- 28893702 TI - Risk Factors Associated with Perioperative Myocardial Infarction in Major Open Vascular Surgery. AB - BACKGROUND: Among patients undergoing noncardiac surgery, major vascular surgery is associated with a high risk of perioperative myocardial infarction (MI). Currently, there are no perioperative MI risk calculators accounting for intraoperative and postoperative risk factors in vascular surgery patients. We aimed to investigate specific risk factors for perioperative MI after major open vascular surgery to determine which patients are at highest risk of MI and the association of perioperative MI with perioperative transfusion. METHODS: This statewide, retrospective cohort study analyzed risk factors for perioperative MI in major open vascular surgery between July 2012 and December 2015 using the Michigan Surgical Quality Collaborative, a multicenter quality collaborative. Patients were identified using current procedure terminology codes including open abdominal aortic aneurysm repairs (oAAA), aortobifemoral bypasses (AFB), and lower extremity bypasses (LEB). Rates of myocardial infarction were described for each procedure. A priori, preoperative, intraoperative, and postoperative variables were evaluated using univariate and multivariable statistics after adjusting for intraoperative factors including anesthesia type, intraoperative blood loss, intraoperative transfusion, and intraoperative vasopressor medications. RESULTS: A total of 3,689 patients underwent major open vascular surgery, including 375 oAAA, 392 AFB, and 2,922 LEB procedures. The overall incidence of MI was 2.4%, varying from 1.8% for aortobifemoral bypass, 2.4% for lower extremity bypass, and 3.7% for open abdominal aortic aneurysm repair. Although preoperative risk factors for myocardial infarction included age, American Society of Anesthesiologists score, diabetes, coronary artery disease, congestive heart failure, use of beta blocker, lower preoperative hematocrit, and surgical priority (urgent/emergent cases), after adjusting for intraoperative risk factors, all preoperative risk factors were not significant with the exception of surgical priority. After adjusting for intraoperative factors, only surgical priority (odds ratio [OR] = 1.70, 95% confidence interval [CI] [1.01 2.85], P < 0.001) and postoperative transfusion (OR = 2.65, 95% CI [1.59-4.44], P < 0.001) was associated with myocardial infarction, and higher nadir hematocrit was inversely associated with myocardial infarction (OR = 0.89, 95% CI [0.85 0.94], P < 0.001). CONCLUSIONS: Among vascular surgery patients undergoing major open vascular surgery, surgical priority was the only preoperative risk factors independently associated with MI, and only postoperative variables such as nadir hematocrit and postoperative transfusion were associated with MI. This suggests minimizing intraoperative blood loss and prioritizing early intraoperative transfusion may be the potential targets for process improvement. PMID- 28893703 TI - Emergent Treatment of Ruptured Axillary Artery Aneurysm. AB - The axillary artery aneurysm (AxAA) is a rare entity, with a diverse range of proposed etiologic mechanisms. Although usually asymptomatic, thromboembolic or hemorrhagic complications leave many with vascular and neurologic compromise. Both open and endovascular treatment approaches have been reported. However, no consensus has been reached on the management of AxAAs. This case illustrates a unique emergent treatment approach for a ruptured AxAA, involving endovascular plugging and immediate subsequent open hematoma evacuation. Although there was no restoration of vessel continuity, reasonable recovery of motor function on follow up suggests this treatment approach may be considered in emergent settings. PMID- 28893704 TI - Late Complication after Thoracic Endovascular Aortic Repair: What Is the Role of an Open Surgical Conversion? AB - BACKGROUND: The aim was to evaluate the causes of thoracic endovascular aortic repair (TEVAR) failure and conversion to open surgery (COS) in a vascular center with high-volume open surgery and low-volume TEVAR procedures. METHODS: A total of 8 patients (6 men; mean age, 55.14 years) underwent COS after TEVAR. The indications for COS, intraoperative strategy, and early postoperative and mid follow-up results were analyzed. RESULTS: The indications for COS were persistent proximal type I endoleak with progressive aneurysm enlargement in 2 patients, type III endoleak in 1 patient, progressive aneurysm enlargement with no endoleak in 1 patient, stent-graft migration in 2 patients, secondary aortoesophageal fistula in 1 patient, secondary aortoesophageal and aortobronchial fistula in 1 patient, and distal progression of the aneurysmal disease in 2 patients. In all but one patient, thoracic stent grafts were explanted, and replacement with a Dacron graft was performed using left partial cardiopulmonary bypass. In the remaining patients with disconnection of the distal component and unfavorable anatomy, the proximal stent graft was recycled, and the Dacron prosthesis was sewn to it. Patients with secondary aortobronchial and aortoesophageal fistulas required additional bronchial and esophageal repair. The in-hospital mortality rate was 50% (4 patients). Four (50%) patients were followed up between 7 and 24 months (mean, 16.75 months) without mortality. CONCLUSIONS: COS after TEVAR has a high mortality rate, and endovascular techniques should be considered as the first line of treatment. Those procedures should be performed by surgeons experienced in open repair which one might expect to be a challenging problem in the era of endovascular therapy. PMID- 28893705 TI - Safety and Feasibility of Temporary Superior Vena Cava Filter Combined with Balloon Dilatation and Catheter-Directed Thrombolysis for Catheter-Related Thrombosis. AB - BACKGROUND: The objective was to evaluate the safety and feasibility of temporary superior vena cava (SVC) filter combined with balloon dilatation and catheter directed thrombolysis for the treatment of catheter-related thrombosis (CRT) caused by implanted ports. METHODS: Between February 2014 and October 2016, 13 patients with implanted port-related CRT in internal jugular vein, brachiocephalic vein, and/or subclavian vein were treated by temporary SVC filter, balloon dilatation, and catheter-directed thrombolysis. Clinical data were retrospectively analyzed with respect to clinical characteristics, SVC filter placement and retrieval, balloon dilatation, and catheter-directed thrombolysis. RESULTS: Filter placement and retrieval, balloon dilatation, and catheter-directed thrombolysis were successful in all patients with complete patency of the suffered vessels. No complications such as local infection, filter migration, bleeding, and pulmonary embolism were found. CONCLUSIONS: Based on the small number of patients, it appears that temporary SVC filter combined with balloon dilatation and catheter-directed thrombolysis is a safe and effective method for the treatment of CRT associated with malfunction of the implanted ports and complete obstruction of affected veins. Further studies are required to demonstrate the cost-effectiveness and complications compared to conventional therapy. PMID- 28893706 TI - Hypertension, Acute Stent Thrombosis, and Paraplegia 6 Months after Thoracic Endovascular Aortic Repair for Blunt Thoracic Aortic Injury in a 22-Year-Old Patient. AB - Thoracic endovascular aortic repair (TEVAR) is a less invasive option for managing traumatic injuries of the descending aorta in polytraumatized patients. Concerns arise when treating young patients with TEVAR. A 22-year-old male was admitted to the emergency department following a high-impact road traffic collision. Whole-body computed tomography (CT) scan documented multiple injuries, including rupture of descending thoracic aorta just below the isthmus. There was no evidence of paraplegia or stroke. We decided to treat him in an endovascular fashion with a Zenith Cook (Cook Incorporated, Bloomington, IN) endograft. Final angiography confirmed the proper positioning of the device, no infoldings, and the optimal filling of the thoracic aorta downstream of the endoprosthesis. In the postoperative period, the patient showed high blood pressure which was treated with 4 different antihypertensive drugs. He was discharged on cardioaspirine. CT scan control was scheduled after 30 days and 6 months, but he referred to our emergency department after less than 6 months with paraplegia, abdominal pain, and acute renal failure. He had independently discontinued antiplatelet therapy 3 months before. Emergency CT control documented the presence of intimal flap and thrombus at the distal edge of the device. The magnetic resonance imaging revealed ischemic damage of the spinal cord. We decided to reline the endograft using another Zenith Cook device with very good results. Renal failure and bowel pain gradually improved, but paraplegia is still present. TEVAR is the most suitable treatment for blunt thoracic aortic injury in the modern era. Concerns arise from what can happen to a young aorta receiving a stiff endovascular graft that should be carried all lifelong. These devices have been associated with acute hypertension and cardiac remodeling. Less stiffer stent grafts should be studied for young patients. High attention must be posed in the follow-up for the immediate resolution of eventual problems. PMID- 28893707 TI - Endovascular Aortoiliac Revascularization in a Patient with Spinal Cord Injury and Hip Contracture. AB - Treatment of chronic peripheral ischemic wounds in patients with spinal cord injury (SCI) can be technically challenging, especially if they have significant hip contracture. This article describes the endovascular aortoiliac revascularization of a paraplegic patient with hip contracture and a hostile abdomen. It also reviews the particularity of the peripheral arterial system in SCI patients. PMID- 28893708 TI - Ex Vivo Reconstruction and Autotransplantation for Hilar Renal Artery Aneurysms in Patients with Congenital Anomalies. AB - Renal artery aneurysms (RAAs) are an uncommon finding but are more often associated with other congenital disorders. The complex (hilar) RAAs constitute a subset of RAAs that present a therapeutic dilemma for the vascular surgeon because of their anatomic location. This dilemma worsens when hilar RAAs occur with a solitary kidney where organ preservation is vital. Ex vivo reconstruction with autotransplantation is especially suitable for hilar RAAs, even when they are associated with a solitary kidney. We report 2 of such cases of RAAs with a solitary kidney in patients with pertinent congenital anomalies. In 1 case, the hilar RAA was associated with a significant accessory renal artery, whereas in the other case, the hilar RAA was associated with a significant connective tissue disorder. Ex vivo reconstruction and autotransplantation was successful in both cases; however, treatment modalities had to be adapted to the patient's unique conditions. PMID- 28893709 TI - Novel Application of Branched Endograft for Preservation of Pelvic Circulation. AB - BACKGROUND: Endovascular repair of a proximal anastomotic pseudoaneurysm (APSA) of an end-to-side aortobifemoral bypass (ABF) can lead to pelvic ischemia. We present a novel application of branched aortic endograft to repair such pseudoaneurysm while preserving flow into the ABF and native aortoiliac system. METHODS: A 71-year-old male with history of aortoiliac occlusive disease resulting in lifestyle limiting claudication was treated with an aortobifemoral bypass in 1999. The patient developed an 8.8 cm pseudoaneurysm at the aortic anastomosis. CTA demonstrated patent right common and internal iliac arteries with an occluded right external iliac artery and occluded left common and external iliac arteries. RESULTS: A 24 * 80 mm endograft with an 8 * 15 mm posterior branch based on the Cook Zenith device (Bloomington, IN) was delivered via a right femoral artery exposure. The preloaded wire of the main body was snared via left brachial access. A 10F sheath was advanced into the side branch of the graft to deliver a 10 * 10-mm Bard Fluency (Covington, Georgia) stent graft into the right common iliac artery. The branch was reinforced proximally with an 8 * 17 mm Boston Scientific Express (Marlborough, MA) stent. The patient was discharged after 5 days. At 1 month, CTA demonstrated patent ABF, patent branch graft into the pelvis, and exclusion of the pseudoaneurysm. CONCLUSIONS: Branch grafts can provide minimally invasive revision of a failing ABF, in this case an APSA, while preserving pelvic circulation and lower extremity perfusion. PMID- 28893710 TI - User Preferences for Mobile Health Interventions: A Survey among Intermittent Claudication Patients and Their Physical Therapists. AB - BACKGROUND: Smartphone apps provide novel ways for triggering lifestyle change by coupling objective measurements of health behavior with tailored feedback. Little is known about end-user preferences regarding the content of mobile health (mHealth) interventions. The aim of this study was to assess smartphone use and preferences regarding app content among intermittent claudication patients and their treating physical therapists. METHODS: A cross-sectional survey was sent via an internal email system to 1,514 physical therapists specialized in treating patients with intermittent claudication. They were asked to complete one questionnaire themselves and administer a second to their intermittent claudication patients currently under treatment. Data on participant characteristics and smartphone use were collected from all respondents. The preferred app components were obtained from participants owning a smartphone. Binary logistic regression analysis was used to explore the adjusted association between age and attained educational level, and smartphone use. RESULTS: The response rate of therapists was 40.8% (617/1,514), and a total of 488 patients completed the survey. After excluding incomplete forms, a total of 615 physical therapist forms and 483 patient forms were analyzed. Overall, 40.6% of patients and 95% of therapists owned a smartphone. Higher educational level was associated with smartphone ownership (adjusted odds ratio = 2.46, 95% confidence interval (CI) = 1.41-4.27, P = 0.001). Compared to patients aged >=75 years, lower age was associated with higher odds of owning a smartphone (adjusted odds ratios for patients aged <=54 years = 21.27, 95% CI = 6.82-66.30, P < 0.001; aged 55-64 years = 4.76, 95% CI = 2.52-9.00, P < 0.001; and aged 65-74 years = 2.58, 95% CI = 1.54-4.33, P < 0.001). The most preferred app components for intermittent claudication patients in possession of a smartphone included monitoring treadmill measured walking distances (71%), global positioning system tracking of walks (50%), and daily physical activity monitoring (49%). Physical therapists were most interested in global positioning system tracking of walks (89%), daily physical activity monitoring (82%), keeping track of treadmill-measured walking distance (79%), help with smoking cessation (65%). CONCLUSIONS: Smartphone ownership is associated with younger age and a higher educational level in patients with intermittent claudication. This study provides a framework of end user preferences regarding desired features to guide the development of an app to potentiate health outcomes of intermittent claudication treatment. PMID- 28893711 TI - Supervised Exercise Therapy for Intermittent Claudication Is Increasingly Endorsed by Dutch Vascular Surgeons. AB - BACKGROUND: Although supervised exercise therapy (SET) is generally accepted as an effective noninvasive treatment for intermittent claudication (IC), Dutch vascular surgeons were initially somewhat hesitant as reported by a 2011 questionnaire study. Later on, a nationwide multidisciplinary network for SET was introduced in the Netherlands. The aim of this questionnaire study was to determine possible trends in conceptions among Dutch vascular surgeons regarding the prescription of SET. METHODS: In the year of 2015, Dutch vascular surgeons, fellows, and senior residents were asked to complete a 26-item questionnaire including issues that were considered relevant for prescribing SET such as patient selection criteria and comorbidity. Outcome was compared to the 2011 survey. RESULTS: Data of 124 respondents (82% males; mean age 46 years; 64% response rate) were analyzed. SET referral rate of new IC patients was not different over time (2015: 81% vs. 2011: 75%; P = 0.295). However, respondents were more willing to prescribe SET in IC patients with chronic obstructive pulmonary disease (2015: 86% vs. 2011: 69%; P = 0.002). Nevertheless, a smaller portion of respondents found that SET was also indicated for aortoiliac disease (2015: 63% vs. 2011: 76%; P = 0.049). Insufficient health insurance coverage and/or personal financial resources were the most important presumed barriers preventing patients from initiating SET (80% of respondents). Moreover, 94% of respondents judged that SET should be fully reimbursed by all Dutch basic health insurances. CONCLUSIONS: The concept of SET for IC is nowadays generally embraced by the vast majority of Dutch vascular surgeons. SET may have gained in popularity in IC patients with cardiopulmonary comorbidity. However, SET remains underutilized for aortoiliac disease. Reimbursement is considered crucial for a successful SET implementation. PMID- 28893712 TI - Single-Session Percutaneous Endovascular Mesocaval Shunt Creation and Balloon Occluded Retrograde Transvenous Obliteration for the Treatment of Gastric Varices. AB - In the setting of portal hypertension, the body responds by creating portosystemic venous shunts, which may lead to the development of varices. Endoscopic treatment of these varices is often warranted to prevent catastrophic bleeding. During the course of variceal treatment, 1 or more portosystemic shunts may be sacrificed, which may acutely exacerbate portal hypertension and reduce systemic venous return. This report describes percutaneous creation of a mesocaval shunt and balloon-occluded retrograde transvenous obliteration (BRTO) in a patient with cavernous transformation of the portal vein. The patient had previously undergone an unsuccessful attempt at transjugular intrahepatic portosystemic shunt (TIPS) creation with postoperative bleeding requiring splenectomy. As TIPS was not feasible, creation of a percutaneous mesocaval shunt provided an alternate pathway for portosystemic decompression, facilitating safe treatment of gastric varices with BRTO via a gastrorenal shunt. These procedures were performed simultaneously to reduce the risk of variceal bleeding from acute changes in portal venous pressures and redirect blood flow through the shunt to maintain patency. This is the first reported case of combined mesocaval shunt placement and BRTO in a single session. PMID- 28893713 TI - Next-Generation Plant Metabolic Engineering, Inspired by an Ancient Chinese Irrigation System. AB - Specialized secondary metabolites serve not only to protect plants against abiotic and biotic challenges, but have also been used extensively by humans to combat diseases. Due to the great importance of medicinal plants for health, we need to find new and sustainable ways to improve the production of the specialized metabolites. In addition to direct extraction, recent progress in metabolic engineering of plants offers an alternative supply option. We argue that metabolic engineering for producing the secondary metabolites in plants may have distinct advantages over microbial production platforms, and thus propose new approaches of plant metabolic engineering, which are inspired by an ancient Chinese irrigation system. Metabolic engineering strategies work at three levels: introducing biosynthetic genes, using transcription factors, and improving metabolic flux including increasing the supply of precursors, energy, and reducing power. In addition, recent progress in biotechnology contributes markedly to better engineering, such as the use of specific promoters and the deletion of competing branch pathways. We propose that next-generation plant metabolic engineering will improve current engineering strategies, for the purpose of producing valuable metabolites in plants on industrial scales. PMID- 28893715 TI - Class I and Class II TCP Transcription Factors Modulate SOC1-Dependent Flowering at Multiple Levels. PMID- 28893716 TI - Surgical management of lower lip pits in Van der Woude syndrome. AB - Van der Woude syndrome (VDWS) is characterized by the presence of lower lip pits which may be of concern to patients due to aesthetic considerations. By presenting three clinical cases, we provide an overview of the surgical techniques currently available to treat labial pits. Fusiform excision with dissection of the entire pit is still the most commonly used procedure and it generally yields good functional and aesthetic outcomes. The split-lip advancement technique and the inverted T-lip reduction nonetheless represent good surgical alternatives. Proper management of the lower pits that occur with VDWS requires thorough knowledge of the available surgical procedures. PMID- 28893714 TI - Transcriptional Regulation of the Ambient Temperature Response by H2A.Z Nucleosomes and HSF1 Transcription Factors in Arabidopsis. AB - Temperature influences the distribution, range, and phenology of plants. The key transcriptional activators of heat shock response in eukaryotes, the heat shock factors (HSFs), have undergone large-scale gene amplification in plants. While HSFs are central in heat stress responses, their role in the response to ambient temperature changes is less well understood. We show here that the warm ambient temperature transcriptome is dependent upon the HSFA1 clade of Arabidopsis HSFs, which cause a rapid and dynamic eviction of H2A.Z nucleosomes at target genes. A transcriptional cascade results in the activation of multiple downstream stress responsive transcription factors, triggering large-scale changes to the transcriptome in response to elevated temperature. H2A.Z nucleosomes are enriched at temperature-responsive genes at non-inducible temperature, and thus likely confer inducibility of gene expression and higher responsive dynamics. We propose that the antagonistic effects of H2A.Z and HSF1 provide a mechanism to activate gene expression rapidly and precisely in response to temperature, while preventing leaky transcription in the absence of an activation signal. PMID- 28893717 TI - Secondary surgical decompression of the inferior alveolar nerve after overfilling of endodontic sealer into the mandibular canal: Case report and literature review. AB - The authors report the case of a 43-year-old woman who underwent endodontic treatment of the right second mandibular molar with substantial extrusion of endodontic material into the mandibular canal. The patient presented at the Department of Oral and Maxillofacial Surgery with a persistent total anaesthesia of the lower lip and chin after two months. 2D panoramic view and 3D CT-scan examination highlighted the overfilling into the mandibular canal with a more than 50% stenosis of the canal and a consequently significant compression of the dental pedicle. A surgical decompression of the inferior alveolar nerve was performed through an inferior vestibular approach, using PiezoSurgery(r). The tooth was conserved. After a period of 8days, paraesthesia of the lower lip and chin appeared. Thermoalgic sensitivity was recovered at 1month. At 3months postoperatively, the patient had recovered protopathic and epicritic sensitivity. Dental prosthetic rehabilitation was finally achieved one year postoperatively. The authors discuss the physiopathology of nervous injuries during dental procedures, and further strategies in the case of persistent neurologic disorders. PMID- 28893718 TI - Alternatives to connective tissue graft in the treatment of localized gingival recessions: A systematic review. AB - AIM: The aim of this Systematic Review (SR) was to assess the clinical efficacy of alternatives procedures; Acellular Dermal Matrix (ADM), Xenogeneic Collagen Matrix (XCM), Enamel Matrix Derivative (EMD) and Platelet Rich Fibrin (PRF), compared to conventional procedures in the treatment of localized gingival recessions. MATERIAL AND METHODS: Electronic searches were performed to identify randomized clinical trials (RCTs) on treatment of single gingival recession with at least 6 months of follow-up. Applying guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA). The risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool. RESULTS: Eighteen randomized controlled trials (RCTs) with a total of 390 treated patients (606 recessions) were included. This systematic review showed that: Coronally Advanced Flap (CAF) in conjunction with ADM was significantly better than CAF alone, while the comparison between CAF+ADM and CTG was affected by large uncertainty. The CAF+EMD was significantly better than CAF alone, whereas the comparison between CAF+EMD and CTG was affected by large uncertainty. No significant difference was recorded when comparing CAF+XCM with CAF alone, and the comparison between CAF+XCM and CTG was affected by large uncertainty. The comparison between PRF and others technique was affected by large uncertainty. CONCLUSION: ADM, XCM and EMD assisted to CAF might be considered alternatives of CTG in the treatment of Miller class I and II gingival recession. PMID- 28893719 TI - Erratum: "Prenatal PBDE and PCB Exposures and Reading, Cognition, and Externalizing Behavior in Children". AB - [This corrects the article DOI: 10.1289/EHP478.]. PMID- 28893720 TI - The Case for Universal Screening of Private Well Water Quality in the U.S. and Testing Requirements to Achieve It: Evidence from Arsenic. AB - BACKGROUND: The 1974 Safe Drinking Water Act (SDWA) regulates >170,000 public water systems to protect health, but not >13 million private wells. State and local government requirements for private well water testing are rare and inconsistent; the responsibility to ensure water safety remains with individual households. Over the last two decades, geogenic arsenic has emerged as a significant public health concern due to high prevalence in many rural American communities. OBJECTIVES: We build the case for universal screening of private well water quality around arsenic, the most toxic and widespread of common private water contaminants. We argue that achieving universal screening will require policy intervention, and that testing should be made easy, accessible, and in many cases free to all private well households in the United States, considering the invisible, tasteless, odorless, and thus silent nature of arsenic. DISCUSSION: Our research has identified behavioral, situational and financial barriers to households managing their own well water safety, resulting in far from universal screening despite traditional public health outreach efforts. We observe significant socioeconomic disparities in arsenic testing and treatment when private water is unregulated. Testing requirements can be a partial answer to these challenges. CONCLUSIONS: Universal screening, achieved through local testing requirements complemented by greater community engagement targeting biologically and socioeconomically vulnerable groups, would reduce population arsenic exposure greater than any promotional efforts to date. Universal screening of private well water will identify the dangers hidden in America's drinking water supply and redirect attention to ensure safe water among affected households. https://doi.org/10.1289/EHP629. PMID- 28893721 TI - Exposure to Ambient Particulate Matter during Specific Gestational Periods Produces Adverse Obstetric Consequences in Mice. AB - BACKGROUND: Epidemiological studies associate inhalation of fine-sized particulate matter (PM2.5) during pregnancy with preterm birth (PTB) and low birth weight (LBW) but disagree over which time frames are most sensitive, or if effects are cumulative. OBJECTIVES: Our objective was to provide experimental plausibility for epidemiological observations by testing the hypothesis that exposure to PM2.5 during discrete periods of pregnancy results in PTB and LBW. METHODS: For the first study, timed-pregnant B6C3F1 mice were exposed to concentrated ambient PM2.5 (CAPs) or filtered air (FA) throughout pregnancy [6 h/d from gestational day (GD) 0.5 through GD16.5]. A follow-up study examined the effects of CAPs exposure during discrete gestational periods (1: GD0.5-5.5; 2: GD6.5-14.5; 3: GD14.5-16.5; 4: GD0.5-16.5) aligning to milestones during human development. RESULTS: In the first experiment, exposure to 160 MUg CAPs/m3 throughout pregnancy decreased gestational term by 0.5 d (~1.1 wk decrease for humans) and birth weight by 11.4% compared with FA. The follow-up experiment investigated timing of CAPs exposure (mean concentrations at 178, 193, 171, and 173 MUg/m3 for periods 1-4, respectively). Pregnancy was significantly shortened (vs. FA) by ~0.4d when exposure occurred during gestational periods 2 and 4, and by ~0.5d if exposure occurred during period 3. Exposure during periods 1, 2, and 4 reduced birth weight by ~10% compared with FA, and placental weight was reduced (~8%) on GD17.5 if exposure occurred only during period 3. CONCLUSIONS: Adverse PM2.5-induced outcomes such as PTB and LBW are dependent upon the periods of maternal exposure. The results of these experimental studies could contribute significantly to air pollution policy decisions in the future. https://doi.org/10.1289/EHP1029. PMID- 28893722 TI - Parental Occupational Exposure to Organic Solvents and Testicular Germ Cell Tumors in their Offspring: NORD-TEST Study. AB - BACKGROUND: Testicular germ cell tumors (TGCT) were suggested to have a prenatal environmentally related origin. The potential endocrine disrupting properties of certain solvents may interfere with the male genital development in utero. OBJECTIVES: We aimed to assess the association between maternal and paternal occupational exposures to organic solvents during the prenatal period and TGCT risk in their offspring. METHODS: This registry-based case control study included TGCT cases aged 14-49 y (n=8,112) diagnosed from 1978 to 2012 in Finland, Norway, and Sweden. Controls (n=26,264) were randomly selected from the central population registries and were individually matched to cases on year and country of birth. Occupational histories of parents prior to the child's birth were extracted from the national censuses. Job codes were converted into solvent exposure using the Nordic job-Nordic Occupational Cancer Study Job-Exposure Matrix. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Overall, no association was found between prenatal maternal exposure to solvents and TGCT risk. In subset analyses using only mothers for whom occupational information was available in the year of or in the year prior to the child's birth, there was an association with maternal exposure to aromatic hydrocarbon solvents (ARHC) (OR=1.53; CI: 1.08, 2.17), driven by exposure to toluene (OR=1.67; CI: 1.02, 2.73). No association was seen for any paternal occupational exposure to solvents with the exception of exposure to perchloroethylene in Finland (OR=2.42; CI: 1.32, 4.41). CONCLUSIONS: This study suggests a modest increase in TGCT risk associated with maternal prenatal exposure to ARHC. https://doi.org/10.1289/EHP864. PMID- 28893723 TI - Scientific Challenges in the Risk Assessment of Food Contact Materials. AB - BACKGROUND: Food contact articles (FCAs) are manufactured from food contact materials (FCMs) that include plastics, paper, metal, glass, and printing inks. Chemicals can migrate from FCAs into food during storage, processing, and transportation. Food contact materials' safety is evaluated using chemical risk assessment (RA). Several challenges to the RA of FCAs exist. OBJECTIVES: We review regulatory requirements for RA of FCMs in the United States and Europe, identify gaps in RA, and highlight opportunities for improving the protection of public health. We intend to initiate a discussion in the wider scientific community to enhance the safety of food contact articles. DISCUSSION: Based on our evaluation of the evidence, we conclude that current regulations are insufficient for addressing chemical exposures from FCAs. RA currently focuses on monomers and additives used in the manufacture of products, but it does not cover all substances formed in the production processes. Several factors hamper effective RA for many FCMs, including a lack of information on chemical identity, inadequate assessment of hazardous properties, and missing exposure data. Companies make decisions about the safety of some food contact chemicals (FCCs) without review by public authorities. Some chemical migration limits cannot be enforced because analytical standards are unavailable. CONCLUSION: We think that exposures to hazardous substances migrating from FCAs require more attention. We recommend a) limiting the number and types of chemicals authorized for manufacture and b) developing novel approaches for assessing the safety of chemicals in FCAs, including unidentified chemicals that form during or after production. https://doi.org/10.1289/EHP644. PMID- 28893725 TI - Improvements in Patient Acceptance by Hospitals Following the Introduction of a Smartphone App for the Emergency Medical Service System: A Population-Based Before-and-After Observational Study in Osaka City, Japan. AB - BACKGROUND: Recently, the number of ambulance dispatches has been increasing in Japan, and it is therefore difficult for hospitals to accept emergency patients smoothly and appropriately because of the limited hospital capacity. To facilitate the process of requesting patient transport and hospital acceptance, an emergency information system using information technology (IT) has been built and introduced in various communities. However, its effectiveness has not been thoroughly revealed. We introduced a smartphone app system in 2013 that enables emergency medical service (EMS) personnel to share information among themselves regarding on-scene ambulances and the hospital situation. OBJECTIVE: The aim of this study was to assess the effects of introducing this smartphone app on the EMS system in Osaka City, Japan. METHODS: This retrospective study analyzed the population-based ambulance records of Osaka Municipal Fire Department. The study period was 6 years, from January 1, 2010 to December 31, 2015. We enrolled emergency patients for whom on-scene EMS personnel conducted hospital selection. The main endpoint was the difficulty experienced in gaining hospital acceptance at the scene. The definition of difficulty was making >=5 phone calls by EMS personnel at the scene to hospitals until a decision to transport was determined. The smartphone app was introduced in January 2013, and we compared the patients treated from 2010 to 2012 (control group) with those treated from 2013 to 2015 (smartphone app group) using an interrupted time-series analysis to assess the effects of introducing this smartphone app. RESULTS: A total of 600,526 emergency patients for whom EMS personnel selected hospitals were eligible for our analysis. There were 300,131 emergency patients in the control group (50.00%, 300,313/600,526) from 2010 to 2012 and 300,395 emergency patients in the smartphone app group (50.00%, 300,395/600,526) from 2013 to 2015. The rate of difficulty in hospital acceptance was 14.19% (42,585/300,131) in the control group and 10.93% (32,819/300,395) in the smartphone app group. No change over time in the number of difficulties in hospital acceptance was found before the introduction of the smartphone app (regression coefficient: -2.43, 95% CI -5.49 to 0.64), but after its introduction, the number of difficulties in hospital acceptance gradually decreased by month (regression coefficient: -11.61, 95% CI 14.57 to -8.65). CONCLUSIONS: Sharing information between an ambulance and a hospital by using the smartphone app at the scene was associated with decreased difficulty in obtaining hospital acceptance. Our app and findings may be worth considering in other areas of the world where emergency medical information systems with IT are needed. PMID- 28893724 TI - The Digital Divide and Health Disparities in China: Evidence From a National Survey and Policy Implications. AB - BACKGROUND: The digital divide persists despite broad accessibility of mobile tools. The relationship between the digital divide and health disparities reflects social status in terms of access to resources and health outcomes; however, data on this relationship are limited from developing countries such as China. OBJECTIVE: The aim of this study was to examine the current rates of access to mobile tools (Internet use and mobile phone ownership) among older Chinese individuals (aged >=45 years), the predictors of access at individual and community levels, and the relationship between access to mobile tools and health outcomes. METHODS: We drew cross-sectional data from a national representative survey, the China Health and Retirement Longitudinal Study (CHARLS), which focused on the older population (aged >=45 years). We used two-level mixed logistic regression models, controlling for unobserved heterogeneity at the community and individual levels for data analysis. In addition to individual level socioeconomic status (SES), we included community-level resources such as neighborhood amenities, health care facilities, and community organizations. Health outcomes were measured by self-reported health and absence of disability based on validated scales. RESULTS: Among the 18,215 participants, 6.51% had used the Internet in the past month, and 83% owned a mobile phone. In the multivariate models, Internet use was strongly associated with SES, rural or urban residence, neighborhood amenities, community resources, and geographic region. Mobile phone ownership was strongly associated with SES and rural/urban residence but not so much with neighborhood amenities and community resources. Internet use was a significant predictor of self-reported health status, and mobile phone ownership was significantly associated with having disability even after controlling for potential confounders at the individual and community levels. CONCLUSIONS: This study is one of the first to examine digital divide and its relationship with health disparities in China. The data showed a significant digital divide in China, especially in the older population. Internet access is still limited to people with higher SES; however, the mobile phone has been adopted by the general population. The digital divide is associated with not only individual SES but also community resources. Future electronic health (eHealth) programs need to consider the accessibility of mobile tools and develop culturally appropriate programs for various social groups. PMID- 28893726 TI - A Web-Based Lifestyle Medicine Curriculum: Facilitating Education About Lifestyle Medicine, Behavioral Change, and Health Care Outcomes. AB - BACKGROUND: Lifestyle medicine is the science and application of healthy lifestyles as interventions for the prevention and treatment of disease, and has gained significant momentum as a specialty in recent years. College is a critical time for maintenance and acquisition of healthy habits. Longer-term, more intensive web-based and in-person lifestyle medicine interventions can have a positive effect. Students who are exposed to components of lifestyle medicine in their education have improvements in their health behaviors. A semester-long undergraduate course focused on lifestyle medicine can be a useful intervention to help adopt and sustain healthy habits. OBJECTIVE: To describe a novel, evidence based curriculum for a course teaching the concepts of Lifestyle Medicine based on a web-based course offered at the Harvard Extension School. METHODS: The course was delivered in a web-based format. The Lifestyle Medicine course used evidence based principles to guide students toward a "coach approach" to behavior change, increasing their self-efficacy regarding various lifestyle related preventive behaviors. Students are made to understand the cultural trends and national guidelines that have shaped lifestyle medicine recommendations relating to behaviors. They are encouraged to engage in behavior change. Course topics include physical activity, nutrition, addiction, sleep, stress, and lifestyle coaching and counseling. The course addressed all of the American College of Preventive Medicine/American College of Lifestyle Medicine competencies save for the competency of office systems and technologies to support lifestyle medicine counseling. RESULTS: The course was well-received, earning a ranking of 4.9/5 at the school. CONCLUSIONS: A novel, semester-long course on Lifestyle Medicine at the Harvard Extension School is described. Student evaluations suggest the course was well-received. Further research is needed to evaluate whether such a course empowers students to adopt behavior changes. PMID- 28893727 TI - Development of a Virtual Reality Exposure Tool as Psychological Preparation for Elective Pediatric Day Care Surgery: Methodological Approach for a Randomized Controlled Trial. AB - BACKGROUND: Preoperative anxiety in children is highly prevalent and is associated with adverse outcomes. Existing psychosocial interventions to reduce preoperative anxiety are often aimed at distraction and are of limited efficacy. Gradual exposure is a far more effective way to reduce anxiety. Virtual reality (VR) provides a unique opportunity to gradually expose children to all aspects of the operating theater. OBJECTIVE: The aims of our study are (1) to develop a virtual reality exposure (VRE) tool to prepare children psychologically for surgery; and (2) to examine the efficacy of the VRE tool in a randomized controlled trial (RCT), in which VRE will be compared to care as usual (CAU). METHODS: The VRE tool is highly realistic and resembles the operating room environment accurately. With this tool, children will not only be able to explore the operating room environment, but also get accustomed to general anesthesia procedures. The PREoperative Virtual reality Intervention to Enhance Wellbeing (PREVIEW) study will be conducted. In this single-blinded RCT, 200 consecutive patients (aged 4 to 12 years) undergoing elective day care surgery for dental, oral, or ear-nose-throat problems, will be randomly allocated to the preoperative VRE intervention or CAU. The primary outcome is change in child state anxiety level between baseline and induction of anesthesia. Secondary outcome measures include child's postoperative anxiety, emergence delirium, postoperative pain, use of analgesics, health care use, and pre- and postoperative parental anxiety. RESULTS: The VRE tool has been developed. Participant recruitment began March 2017 and is expected to be completed by September 2018. CONCLUSIONS: To our knowledge, this is the first RCT evaluating the effect of a VRE tool to prepare children for surgery. The VRE intervention is expected to significantly diminish preoperative anxiety, postoperative pain, and the use of postoperative analgesics in pediatric patients. The tool could create a less stressful experience for both children and their parents, in line with the modern emphasis on patient- and family-centered care. TRIAL REGISTRATION: Netherlands Trial Registry: NTR6116; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6116 (Archived by WebCite at http://www.webcitation.org/6ryke7aep). PMID- 28893728 TI - Antiretroviral therapy in pregnant women living with HIV: a clinical practice guideline. PMID- 28893730 TI - Diagnosis and management of endometriosis: summary of NICE guidance. PMID- 28893729 TI - Expansion of inpatient clinical pharmacy services through reallocation of pharmacists. AB - PURPOSE: The redesign of an inpatient pharmacy practice model through reallocation of pharmacy resources in order to expand clinical services is described. METHODS: A pharmacy practice model change was implemented at a nonprofit academic medical center to meet the increasing demand for direct patient care services. In order to accomplish this change, the following steps were completed: reevaluation of daily tasks and responsibilities, reallocation of remaining tasks to the most appropriate pharmacy staff member, determination of the ideal number of positions needed to complete each task, and reorganization of the model into a collection of teams. Data were collected in both the preimplementation and postimplementation periods to assess the impact of the model change on operational workflow and clinical service expansion. RESULTS: The mean +/- S.D. times to order verification were 17 +/- 52 minutes during the preimplementation period and 21 +/- 70 minutes in the postimplementation period (p < 0.001). During the 3 months before and after implementation of the model change, the mean number of medication reconciliations performed increased from 114 to 144. After implementation of the model change, total interventions increased 194%. Notably, there was a 736% increase in the number of interventions focused on facilitating safe discharge. CONCLUSION: A pharmacy practice model change was successfully implemented by reallocating existing pharmacist and technician roles and increasing incorporation of pharmacy residents and students. This change led to an expansion of direct patient care coordination services without negatively affecting the operational responsibilities of the pharmacy or the need to hire additional staff. PMID- 28893731 TI - Autopsy results confirm 4 year old Italian girl died from malaria. PMID- 28893732 TI - What are the risks of oestrogens in women assigned male at birth and how should they be monitored? PMID- 28893733 TI - Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed Sternberg cells in Hodgkin lymphoma. AB - Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs, which physically colocalize with PD L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched for contacts with T cells, and PD-L1+ HRS cells are enriched for contacts with CD4+ T cells, a subset of which are PD-1+ Our data define a unique topology of cHL in which PD-L1+ TAMs surround HRS cells and implicate CD4+ T cells as a target of PD 1 blockade. PMID- 28893734 TI - Origins of myelodysplastic syndromes after aplastic anemia. PMID- 28893735 TI - Access to healthcare for men and women with disabilities in the UK: secondary analysis of cross-sectional data. AB - OBJECTIVES: The aim of this study was to investigate differences in access to healthcare between people with and without disabilities in the UK. The hypotheses were that: (1) people with disabilities would be more likely to have unmet healthcare needs and (2) there would be gender differences, with women more likely to report unmet needs. SETTING AND PARTICIPANTS: We performed secondary analysis, using logistic regressions, of deidentified cross-sectional data from the European Health Interview Survey, Wave 2. The sample included 12 840 community-dwelling people over the age of 16 from across the UK, 5 236 of whom had a disability. The survey method involved face-to-face and telephone interviews. OUTCOME MEASURES: Unmet need for healthcare due to long waiting lists or distance or transportation problems; not being able to afford medical examination, treatment, mental healthcare or prescribed medicines. All measures were self-reported. RESULTS: Adjusting for age, sex and other factors, people with a severe disability had higher odds of facing unmet needs. The largest gap was in 'unmet need for mental healthcare due to cost', where people with a severe disability were 4.5 times (CI 95% 2.2 to 9.2) more likely to face a problem, as well as in 'unmet need due to cost of prescribed medicine', where people with a mild disability had 3.6 (CI 95% 2.2 to 5.9) higher odds of facing a difficulty. Women with a disability were 7.2 times (CI 95% 2.7 to 19.4) more likely to have unmet needs due to cost of care or medication, compared with men with no disability. CONCLUSIONS: People with disabilities reported worse access to healthcare, with transportation, cost and long waiting lists being the main barriers. These findings are worrying as they illustrate that a section of the population, who may have higher healthcare needs, faces increased barriers in accessing services. PMID- 28893736 TI - Implementing person centred approaches. PMID- 28893738 TI - State educated children do better medical school. PMID- 28893739 TI - Access to psychiatrists varies widely across UK, royal college says. PMID- 28893740 TI - An unusual presentation of chronic cyanide toxicity from self-prescribed apricot kernel extract. AB - Hypoxia under general anaesthesia is a potentially life-threatening condition. A seemingly well 67-year-old man appeared hypoxic with peripheral pulse oximetric measurement during routine anaesthesia. Postoperatively, the patient admitted to daily self-prescription of apricot kernel extract for a period of 5 years. Apricot kernel is a commonly taken extract used for a range of ailments, and is associated with cyanide toxicity, which was confirmed through blood analysis. Our explanation for the hypoxic measurement was the presence of free cyanide interfering with functioning of the peripheral pulse oximeter. On cessation of the apricot kernel extract, peripheral oxygen saturations returned to normal. Cardiac and respiratory causes together with rare haemoglobinopathies were excluded. This case illustrates how chronic dosing of complementary medicines can result in harmful toxicities, which may carry potential for serious consequences and how these chronic toxicities may present to physicians in atypical ways. PMID- 28893741 TI - Prevention and assessment of infectious diseases among children and adult migrants arriving to the European Union/European Economic Association: a protocol for a suite of systematic reviews for public health and health systems. AB - INTRODUCTION: The European Centre for Disease Prevention and Control is developing evidence-based guidance for voluntary screening, treatment and vaccine prevention of infectious diseases for newly arriving migrants to the European Union/European Economic Area. The objective of this systematic review protocol is to guide the identification, appraisal and synthesis of the best available evidence on prevention and assessment of the following priority infectious diseases: tuberculosis, HIV, hepatitis B, hepatitis C, measles, mumps, rubella, diphtheria, tetanus, pertussis, poliomyelitis (polio), Haemophilus influenza disease, strongyloidiasis and schistosomiasis. METHODS AND ANALYSIS: The search strategy will identify evidence from existing systematic reviews and then update the effectiveness and cost-effectiveness evidence using prospective trials, economic evaluations and/or recently published systematic reviews. Interdisciplinary teams have designed logic models to help define study inclusion and exclusion criteria, guiding the search strategy and identifying relevant outcomes. We will assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: There are no ethical or safety issues. We anticipate disseminating the findings through open-access publications, conference abstracts and presentations. We plan to publish technical syntheses as GRADEpro evidence summaries and the systematic reviews as part of a special edition open-access publication on refugee health. We are following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols reporting guideline. This protocol is registered in PROSPERO: CRD42016045798. PMID- 28893743 TI - An analysis of redactions in Canada's Common Drug Review Clinical Review Reports and how they relate to the patients' voice. AB - IMPORTANCE: Canada's Common Drug Review (CDR) evaluates drug data from published and unpublished research, as well as input from patient groups, to recommend provincial coverage. Currently, the CDR process gives manufacturers the opportunity to redact information in the final publicly available report. Patients often have strong feelings regarding the efficacy, harms, health-related quality of life (HRQL), and cost associated with the drugs under review and their redacted data. Highlighting Canada's approach will hopefully build on the growing international concern regarding transparency of clinical study data. OBJECTIVE: The purpose was to objectively examine and classify completed, publicly available CDR-Clinical Review Reports (CRR) for redactions, and compare them to the patients' reported interests as patient-centred outcomes. METHODS: Two independent reviewers searched for and examined publicly available CDR-CRR from November 2013-September 2016 through the Canadian Agency for Drugs and Technologies in Health (CADTH) on-line database. Both reviewers separately classified the redactions and patient-reported interests into the following categories: efficacy, harms, HRQL and costs. All discrepancies were rectified by consensus involving a third reviewer. RESULTS: Fifty-two completed CDR-CRR were reviewed. 48 (92%) included patient-reported interests and 40 (77%) had redactions classified in the following categories: efficacy (75%), costs (48%), harms (38%), HRQL (23%). 89% of redactions were outcomes identified as patient reported interests (69% efficacy, 42% harms, 36% cost, 33% HRQL). When examining drug characteristics, biological agents were statistically associated with increased odds of redactions with respect to either efficacy (OR 3.4, 95% CI 1.0 to 11.6) or harms (OR 3.5, 95% CI 1.02 to 12.4) compared with non-biological agents. CONCLUSIONS: Whether data from the CDR-CRR used in the decision-making should be fully disclosed to the public is controversial. Our findings suggest clinical data (efficacy, harms, HRQL) matters to patients and should be publicly available within the CDR-CRR. Canada trails Europe and the USA regarding the transparency of clinical study data. This lack of transparency relates to the patient voice, and limits movement towards patient-centred care and patient engaged research, restricting real-world value measurement. PMID- 28893742 TI - Living with Crohn's disease: an exploratory cross-sectional qualitative study into decision-making and expectations in relation to autologous haematopoietic stem cell treatment (the DECIDES study). AB - BACKGROUND/OBJECTIVES: Severe Crohn's disease impacts negatively on individual quality of life, with treatment options limited once conventional therapies have been exhausted. The aim of this study was to explore factors influencing decision making and expectations of people considering or participating in the Autologous Haematopoietic Stem Cell Treatment trial. METHODS: An international, cross sectional qualitative study, involving semistructured face to face interviews across five sites (four UK and one Spain). 38 participants were interviewed (13 men, 25 women; age range 23-67 years; mean age 37 years). The mean age at diagnosis was 20 years. Interviews were audio recorded and transcribed verbatim and transcripts were analysed using a framework approach. RESULTS: Four themes emerged from the analysis: (1) 'making your mind up'-a determination to receive stem cell treatment despite potential risks; (2) communicating and understanding risks and benefits; (3) non-participation-your choice or mine? (4) recovery and reframing of personal expectations. CONCLUSIONS: Decision-making and expectations of people with severe Crohn's disease in relation to autologous haematopoietic stem cell treatment is a complex process influenced by participants' histories of battling with their condition, a frequent willingness to consider novel treatment options despite potential risks and, in some cases, a raised level of expectation about the benefits of trial participation. Discussions with patients who are considering novel treatments should take into account potential 'therapeutic misestimation', thereby enhancing shared decision-making, informed consent and the communication with those deemed non-eligible. ASTIC TRIAL EUDRACT NUMBER: 2005-003337-40: results. PMID- 28893744 TI - Survival after bone metastasis by primary cancer type: a Danish population-based cohort study. AB - OBJECTIVE: In the 10 most common primary types with bone metastases, we aimed to examine survival, further stratifying on bone metastases only or with additional synchronous metastases. METHODS: We included all patients aged 18 years and older with incident hospital diagnosis of solid cancer between 1994 and 2010, subsequently diagnosed with BM until 2012. We followed patients from date of bone metastasis diagnosis until death, emigration or 31 December 2012, whichever came first. We computed 1-year, 3-year and 5-year survival (%) and the corresponding 95% CIs stratified on primary cancer type. Comparing patients with bone metastasis only and patients with other synchronous metastases, we estimated crude and adjusted HRs and corresponding 95% CI for mortality. RESULTS: We included 17 251 patients with bone metastasis. The most common primary cancer types with bone metastasis were prostate (34%), breast (22%) and lung (20%). One year survival after bone metastasis diagnosis was lowest in patients with lung cancer (10%, 95% CI 9% to 11%) and highest in patients with breast cancer (51%, 50% to 53%). At 5 years of follow-up, only patients with breast cancer had over 10% survival (13%, 11% to 14%). The risk of mortality was increased for the majority of cancer types among patients with bone and synchronous metastases compared with bone only (adjusted relative risk 1.29-1.57), except for cervix, ovarian and bladder cancer. CONCLUSIONS: While patients with bone metastases after most primary cancers have poor survival, one of ten patients with bone metastasis from breast cancer survived 5 years. PMID- 28893745 TI - A new risk locus in CHCHD5 for hypertension and obesity in a Chinese child population: a cohort study. AB - OBJECTIVE: Coiled-coil-helix-coiled-coil-helix domain containing 5 (CHCHD5), a mitochondrial protein, is involved in the oxidative folding process in the mitochondrial intermembrane space. A previous study identified a hypertension related single nucleotide polymorphism (SNP), rs3748024, in CHCHD5 in adults, but there are no reports regarding the association between CHCHD5 and obesity, which is a known risk factor for hypertension. The aim of the present study is to investigate the associations of the SNP rs3748024 with hypertension and obesity. DESIGN: Cohort study. SETTING: Institute of Pediatrics in China. PARTICIPANTS: We genotyped the SNP rs3748024 in the Beijing Child and Adolescent Metabolic Syndrome study. A total of 3503 children participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Genotyping of rs3748024 was conducted using the TaqMan Allelic Discrimination Assay. Lipids and glucose were analysed by an automatic biochemical analyser using a kit assay. The levels of adipocytokines (leptin, adiponectin and resistin) were measured by ELISA techniques. RESULTS: There was a statistically significant association between rs3748024 and systolic blood pressure (SBP) (beta=-0.853, 95% CI -1.482 to -0.024, p=0.044) under an additive model adjusted for age, gender and body mass index (BMI) after correction for multiple testing. The SNP was also significantly associated with BMI (beta=-0.286, 95% CI -0.551 to -0.021, p=0.043), obesity (OR=0.828, 95% CI 0.723 to 0.949, p=0.018) and triglycerides (beta=-0.039, 95% CI -0.070 to -0.007, p=0.044) after correction for multiple testing. CONCLUSIONS: We demonstrate for the first time that the SNP rs3748024 in CHCHD5 is associated with SBP, BMI, obesity and triglycerides in Chinese children. Our study identifies a new risk locus for hypertension and obesity in a child population. The function of CHCHD5 remains to be further studied to help elucidate the pathogenic role of CHCHD5 in hypertension and obesity. PMID- 28893746 TI - Demographic profile and pregnancy outcomes of adolescents and older mothers in Saudi Arabia: analysis from Riyadh Mother (RAHMA) and Baby cohort study. AB - OBJECTIVES: To investigate the impact of maternal age on pregnancy outcomes with special emphasis on adolescents and older mothers and to investigate the differences in demographic profile between adolescents and older mothers. METHODS: This study is a secondary analysis of pregnancy outcomes of women in Riyadh Mother and Baby cohort study according to maternal age. The study population was grouped according to maternal age into five subgroups; <20, 20-29, 30-34, 35-39 and 40+years. The age group 20-29 years was considered as a reference group. Investigation of maternal age impact on maternal and neonatal outcomes was conducted with adjustment of confounders using regression models. RESULTS: All mothers were married when conceived with the index pregnancy. Young mothers were less likely to be illiterate, more likely to achieve higher education and be employed compared with mothers >= 40 years. Compared with the reference group, adolescents were more likely to have vaginal delivery (and least likely to deliver by caesarean section (CS); OR=0.6, 95% CI 0.4 to 0.9, while women >=40 years, were more likely to deliver by CS; OR 2.9, 95% CI 2.3 to 3.7. Maternal age was a risk factor for gestational diabetes in women >=40 years; OR 1.7, 95% CI 1.3 to 2.1. Adolescents had increased risk of preterm delivery; OR 1.5, 95% CI 1.1 to 2.1 and women >=40 years had similar risk; OR, 1.3, 95% CI 1.1 to 1.6. CONCLUSION: Adverse pregnancy outcomes show a continuum with the advancement of maternal age. Adolescents mother are more likely to have vaginal delivery; however, they are at increased risk of preterm delivery. Advanced maternal age is associated with increased risk of preterm delivery, gestational diabetes and CS. PMID- 28893747 TI - The health and well-being of Australia's future medical doctors: protocol for a 5 year observational cohort study of medical trainees. AB - INTRODUCTION: Clinical training in the undergraduate medical course places multiple stressors on trainees, which have been held to lead to heightened distress, depression, suicide, substance misuse/abuse and poor mental health outcomes. To date, evidence for morbidity in trainees is largely derived from cross-sectional survey-based research. This limits the accuracy of estimates and the extent to which predispositional vulnerabilities (biological and/or psychological), contextual triggers and longer-term consequences can be validly identified. Longitudinal clinical assessments embedded within a biopsychosocial framework are needed before effective preventative and treatment strategies can be put in place. METHODS AND ANALYSIS: This study is an observational longitudinal cohort study of 330 students enrolled in the undergraduate medicine course at the University of New South Wales (UNSW) Sydney, Australia. Students will be recruited in their fourth year of study and undergo annual assessments for 4 consecutive years as they progress through increasingly demanding clinical training, including internship. Assessments will include clinical interviews for psychiatric morbidity, and self-report questionnaires to obtain health, psychosocial, performance and functioning information. Objective measures of cognitive performance, sleep/activity patterns as well as autonomic and immune function (via peripheral blood samples) will be obtained. These data will be used to determine the prevalence, incidence and severity of mental disorder, elucidate contextual and biological triggers and mechanisms underpinning psychopathology and examine the impact of psychopathology on performance and professional functioning. ETHICS AND DISSEMINATION: Ethics approval has been granted by the UNSW human research ethics committee (reference HC16340). The findings will be disseminated through peer-reviewed publications and conference presentations, and distributed to key stakeholders within the medical education sector. The outcomes will also inform targeted preventative and treatment strategies to enhance stress resilience in trainee doctors. PMID- 28893748 TI - Effect of individual patient risk, centre, surgeon and anaesthetist on length of stay in hospital after cardiac surgery: Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) consecutive cases series study of 10 UK specialist centres. AB - OBJECTIVES: To determine the relative contributions of patient risk profile, local and individual clinical practice on length of hospital stay after cardiac surgery. DESIGN: Ten-year audit of prospectively collected consecutive cardiac surgical cases. Case-mix adjusted outcomes were analysed in models that included random effects for centre, surgeon and anaesthetist. SETTING: UK centres providing adult cardiac surgery. PARTICIPANTS: 10 of 36 UK specialist centres agreed to provide outcomes for all major cardiac operations over 10 years. After exclusions (duplicates, cases operated by more than one consultant, deaths and procedures for which the EuroSCORE risk score for cardiac surgery is not appropriate), there were 107 038 cardiac surgical procedures between April 2002 and March 2012, conducted by 127 consultant surgeons and 190 consultant anaesthetists. MAIN OUTCOME MEASURE: Length of stay (LOS) up to 3 months postoperatively. RESULTS: The principal component of variation in outcomes was patient risk (represented by the EuroSCORE and remaining patient heterogeneity), accounting for 95.43% of the variation for postoperative LOS. The impact of the surgeon and centre was moderate (intra-class correlation coefficients ICC=2.79% and 1.59%, respectively), whereas the impact of the anaesthetist was negligible (ICC=0.19%). Similarly, 96.05% of the variation for prolonged LOS (>11 days) was attributable to the patient, with surgeon and centre less but still influential components (ICC=2.12% and 1.66%, respectively, 0.17% only for anaesthetists). Adjustment for year of operation resulted in minor reductions in variation attributable to surgeons (ICC=2.52% for LOS and 2.23% for prolonged LOS). CONCLUSIONS: Patient risk profile is the primary determinant of variation in LOS, and as a result, current initiatives to reduce hospital stay by modifying consultant performance are unlikely to have a substantial impact. Therefore, substantially reducing hospital stay requires shifting away from a one-size-fits all approach to cardiac surgery, and seeking alternative treatment options personalised to high-risk patients. PMID- 28893749 TI - Cross-sectional comparative study of risky sexual behaviours among HIV-infected persons initiated and waiting to start antiretroviral therapy in rural Rakai, Uganda. AB - OBJECTIVES: To compare risky sexual behaviours between HIV-positive persons initiated on antiretroviral therapy (ART) (ART-experienced) and persons waiting to start on ART (ART-naive) and assess predictors of risky sexual behaviours among HIV-infected patients in rural Rakai district, Uganda. STUDY DESIGN: This is a cross-sectional study that used data from the Rakai Community Cohort Study (RCCS) database between 2013 and 2014. A structured questionnaire was used for data collection. We used stepwise logistic regression as an index to estimate the adjusted ORs for the association between risky sexual behaviours and ART treatment status. STUDY SETTING: This study was conducted in Rakai district, located in south-western Uganda. The data for this study were extracted from the RCCS. RCCS is an open prospective cohort of approximately 15 000 consenting participants aged 15-49 years. PARTICIPANTS: HIV-positive participants aged 18-49 years who had sex at least once a month with any partner prior to the start of the study. MAIN OUTCOME MEASURES: Inconsistent/no condom use in the last 12 months, alcohol use at last sexual encounter, and two or more sexual partners. RESULTS: ART-naive participants were more likely to report inconsistent condom use (OR=1.74, 95% CI 1.11 to 2.73) and more likely to drink alcohol at last sexual encounter (OR=1.65, 95% CI 1.11 to 2.46), compared with ART-experienced patients. ART treatment status (p<0.001) was a significant predictor of risky sexual behaviours. Both marital status (p=0.016) and occupation level (p=0.009) were positively associated with inconsistent condom use, while sex (p<0.001) correlated with alcohol use at last sexual encounter. CONCLUSION: ART-naive participants were more likely to exhibit risky sexual behaviours than the ART experienced participants. The intensity of risk reduction counselling should be increased for HIV-positive persons waiting to start ART but already in HIV care. PMID- 28893750 TI - Cost-effectiveness of planned birth in a birth centre compared with alternative planned places of birth: results of the Dutch Birth Centre study. AB - OBJECTIVES: To estimate the cost-effectiveness of a planned birth in a birth centre compared with alternative planned places of birth for low-risk women. In addition, a distinction has been made between different types of locations and integration profiles of birth centres. DESIGN: Economic evaluation based on a prospective cohort study. SETTING: 21 Dutch birth centres, 46 hospital locations where midwife-led birth was possible and 110 midwifery practices where home birth was possible. PARTICIPANTS: 3455 low-risk women under the care of a community midwife at the start of labour in the Netherlands within the study period 1 July 2013 to 31 December 2013. MAIN OUTCOME MEASURES: Costs and health outcomes of birth for different planned places of birth. Healthcare costs were measured from start of labour until 7 days after birth. The health outcomes were assessed by the Optimality Index-NL2015 (OI) and a composite adverse outcomes score. RESULTS: The total adjusted mean costs for births planned in a birth centre, in a hospital and at home under the care of a community midwife were ?3327, ?3330 and ?2998, respectively. There was no difference between the score on the OI for women who planned to give birth in a birth centre and that of women who planned to give birth in a hospital. Women who planned to give birth at home had better outcomes on the OI (higher score on the OI). CONCLUSIONS: We found no differences in costs and health outcomes for low-risk women under the care of a community midwife with a planned birth in a birth centre and in a hospital. For nulliparous and multiparous low-risk women, planned birth at home was the most cost-effective option compared with planned birth in a birth centre. PMID- 28893751 TI - Non-typhoidal Salmonella in Calabria, Italy: a laboratory and patient-based survey. AB - INTRODUCTION: Although there has been a decrease in the number of cases of salmonellosis in the European Union, it still represents the primary cause of foodborne outbreaks. In Calabria region, data are lacking for the incidence of human non-typhoid salmonellosis as active surveillance has never been carried out. OBJECTIVE: To report the results of a laboratory and patient-based morbidity survey in Calabria to describe the incidence and distribution of Salmonella serovars isolated from humans, with a focus on antimicrobial resistance patterns. METHODS: Positive cultures from human samples were collected from every laboratory participating in the surveillance, with a minimum set of information about each isolate. A questionnaire was then administered to the patients by telephone interview to assess the potential risk exposures.Salmonella isolates underwent biochemical identification, molecular analysis by PCR and antimicrobial susceptibility testing by the disk-diffusion method. RESULTS: During a 2-year period, 105 strains of Salmonella spp were isolated from samples of patients with diarrhoea, with the highest isolation rate for children aged 1-5 years. The standardised rate was 2.7 cases per 1 00 000 population. The most common Salmonella isolates belonged to monophasic variant of S. Typhimurium (S. 4,[5],12:i:-) (33.3%), followed by S. Typhimurium (21.9%). 30.5% of the isolates were susceptible to all microbial agents tested and the most common pan susceptible serotype was S. Napoli (100%). S. 4,[5],12:i:- was resistant to ampicillin, streptomycin, sulfonamides and tetracyclines in 42.9% cases, while resistance to quinolones was seen in 14.3% of the isolates. CONCLUSIONS: The results provide evidence that an active surveillance system effectively enhances Salmonella notifications. The high prevalence of antimicrobial resistance, including resistance to quinolones and multiresistance, enforces the need to strengthen strategies of surveillance and monitoring of antimicrobial use. PMID- 28893753 TI - A randomised controlled trial comparing venous stenting with conservative treatment in patients with deep venous obstruction: research protocol. AB - INTRODUCTION: Deep venous obstruction (DVO) has a great impact on quality of life (QoL) comparable to angina pectoris or chronic pulmonary disease. Post-thrombotic scar formation and May-Thurner syndrome (MTS) are the most common causes of DVO. Conventional treatment of DVO focuses on reducing pain or leg swelling by use of (pain) medication and therapeutic elastic stockings. In the past, a venous bypass was offered in severe post-thrombotic cases, but this procedure showed bad clinical and patency outcomes. With the introduction of percutaneous angioplasty and dedicated venous stents new opportunities were created. Deep venous stenting has been shown to be effective in retrospective case series. However, there is no prior research in which QoL after interventional treatment is compared with QoL after conventional treatment. Currently, there is a debate about the true additional value of interventional treatment. We investigate whether those patients who are treated with stenting experience a change in short form 36 (SF 36) and the Veines-QoL/Sym questionnaires compared with conventionally treated patients. METHODS AND ANALYSIS: This is a randomised trial comparing conservative deep venous management to interventional treatment. A total of 130 patients with post-thrombotic syndrome (PTS) or MTS, eligible for interventional percutaneous treatment, who did not have previous deep venous intervention will be included. Patients will be randomised to conservative treatment or venous stenting and stratified for the PTS or MTS subgroup. Conservative treatment consists of either one or a combination of pain medications, manual lymphatic drainage, compression stockings and regular post-thrombotic anticoagulant therapy.The primary outcome is the QoL change after 12 months compared with baseline QoL. Secondary outcomes are QoL changes at 6 weeks, clinical assessment of DVO, recurrence rate of deep venous thrombosis at 6 weeks and 12 months, and the total amount of working days lost. Intervention-specific outcomes include complications and patency. ETHICS AND DISSEMINATION: The protocol is approved by the Medical Ethics Committee of Academisch ziekenhuis Maastricht/Universiteit Maastricht, The Netherlands (protocol number NLNL55641.068.15 / METC 161008).We aim to publish the results of this study in a peer reviewed journal and present our findings at national or international conferences. TRIAL REGISTRATION NUMBER: The study protocol was registered at www.clinicaltrials.gov (registration number: NCT03026049) on 17 January 2017. PMID- 28893752 TI - Using environmental engineering to increase hand hygiene compliance: a cross-over study protocol. AB - INTRODUCTION: Compliance with hand hygiene recommendations in hospital is typically less than 50%. Such low compliance inevitably contributes to hospital acquired infections that negatively affect patients' well-being and hospitals' finances. The design of the present study is predicated on the assumption that most people who fail to clean their hands are not doing so intentionally, they just forget. The present study will test whether psychological priming can be used to increase the number of people who clean their hands on entering a ward. Here, we present the protocol for this study. METHODS AND ANALYSIS: The study will use a randomised cross-over design. During the study, each of four wards will be observed during four conditions: olfactory prime, visual prime, both primes and neither prime. Each condition will be experienced for 42 days followed by a 7-day washout period (total duration of trial=189 days). We will record the number of people who enter each ward and whether they clean their hands during observation sessions, the amount of cleaning material used from the dispensers each week and the number of hospital-acquired infections that occur in each period. The outcomes will be compared using a regression analysis. Following the initial trail, the most effective priming condition will be rolled out for 3 months in all the wards. ETHICS AND DISSEMINATION: Research ethics approval was obtained from the South Central-Oxford C Research Ethics Committee (16/SC/0554), the Health Regulatory Authority and the sponsor. TRIAL REGISTRATION NUMBER: ISRCTN (15397624); Edge ID 86357. PMID- 28893754 TI - Failures to further developing orphan medicinal products after designation granted in Europe: an analysis of marketing authorisation failures and abandoned drugs. AB - OBJECTIVES: The research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures. DESIGN: Drugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000-2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development.Possible risk factors for failure were analysed using statistically validated methods. RESULTS: This study points out that 437 out of 788 designations are still under development, while 219 failed the developmental process. Among the latter, 34 failed the marketing authorisation process and 185 were abandoned during the developmental process. In the first group of drugs (marketing authorisation failures), 50% reached phase II, 47% reached phase III and 3% reached phase I, while in the second group (abandoned drugs), the majority of orphan medicinal products apparently never started the development process, since no data on 48.1% of them were published and the 3.2% did not progress beyond the non-clinical stage.The reasons for failures of marketing authorisation were: efficacy/safety issues (26), insufficient data (12), quality issues (7), regulatory issues on trials (4) and commercial reasons (1). The main causes for abandoned drugs were efficacy/safety issues (reported in 54 cases), inactive companies (25.4%), change of company strategy (8.1%) and drug competition (10.8%). No information concerning reasons for failure was available for 23.2% of the analysed products. CONCLUSIONS: This analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues. Moreover, the stage of development reached by drugs represents a specific risk factor for failures. PMID- 28893756 TI - The incidence and healthcare costs of persistent postoperative pain following lumbar spine surgery in the UK: a cohort study using the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). AB - OBJECTIVE: To characterise incidence and healthcare costs associated with persistent postoperative pain (PPP) following lumbar surgery. DESIGN: Retrospective, population-based cohort study. SETTING: Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases. PARTICIPANTS: Population-based cohort of 10 216 adults who underwent lumbar surgery in England from 1997/1998 through 2011/2012 and had at least 1 year of presurgery data and 2 years of postoperative follow-up data in the linked CPRD-HES. PRIMARY AND SECONDARY OUTCOMES MEASURES: Incidence and total healthcare costs over 2, 5 and 10 years attributable to persistent PPP following initial lumbar surgery. RESULTS: The rate of individuals undergoing lumbar surgery in the CPRD-HES linked data doubled over the 15-year study period, fiscal years 1997/1998 to 2011/2012, from 2.5 to 4.9 per 10 000 adults. Over the most recent 5-year period (2007/2008 to 2011/2012), on average 20.8% (95% CI 19.7% to 21.9%) of lumbar surgery patients met criteria for PPP. Rates of healthcare usage were significantly higher for patients with PPP across all types of care. Over 2 years following initial spine surgery, the mean cost difference between patients with and without PPP was L5383 (95% CI L4872 to L5916). Over 5 and 10 years following initial spine surgery, the mean cost difference between patients with and without PPP increased to L10 195 (95% CI L8726 to L11 669) and L14 318 (95% CI L8386 to L19 771), respectively. Extrapolated to the UK population, we estimate that nearly 5000 adults experience PPP after spine surgery annually, with each new cohort costing the UK National Health Service in excess of L70 million over the first 10 years alone. CONCLUSIONS: Persistent pain affects more than one-in-five lumbar surgery patients and accounts for substantial long-term healthcare costs. There is a need for formal, evidence-based guidelines for a coherent, coordinated management strategy for patients with continuing pain after lumbar surgery. PMID- 28893755 TI - A randomised controlled trial of an online menu planning intervention to improve childcare service adherence to dietary guidelines: a study protocol. AB - INTRODUCTION: The implementation of dietary guidelines in childcare settings is recommended to improve child public health nutrition. However, foods provided in childcare services are not consistent with guidelines. The primary aim of the trial is to assess the effectiveness of a web-based menu planning intervention in increasing the mean number of food groups on childcare service menus that comply with dietary guidelines regarding food provision to children in care. METHODS AND ANALYSIS: A parallel group randomised controlled trial will be undertaken with 54 childcare services that provide food to children within New South Wales, Australia. Services will be randomised to a 12-month intervention or usual care. The experimental group will receive access to a web-based menu planning and decision support tool and online resources. To support uptake of the web program, services will be provided with training and follow-up support. The primary outcome will be the number of food groups, out of 6 (vegetables, fruit, breads and cereals, meat, dairy and 'discretionary'), on the menu that meet dietary guidelines (Caring for Children) across a 1-week menu at 12-month follow-up, assessed via menu review by dietitians or nutritionists blinded to group allocation. A nested evaluation of child dietary intake in care and child body mass index will be undertaken in up to 35 randomly selected childcare services and up to 420 children aged approximately 3-6 years. ETHICS AND DISSEMINATION: Ethical approval has been provided by Hunter New England and University of Newcastle Human Research Ethics Committees. This research will provide high quality evidence regarding the impact of a web-based menu planning intervention in facilitating the translation of dietary guidelines into childcare services. Trial findings will be disseminated widely through national and international peer-reviewed publications and conference presentations. TRIAL REGISTRATION: Prospectively registered with Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN12616000974404. PMID- 28893757 TI - Effectiveness and cost-effectiveness of duloxetine added to usual care for patients with chronic pain due to hip or knee osteoarthritis: protocol of a pragmatic open-label cluster randomised trial (the DUO trial). AB - INTRODUCTION: Osteoarthritis (OA) is a highly prevalent painful condition of the musculoskeletal system. The effectiveness of current analgesic options has proven to be limited and improved analgesic treatment is needed. Several randomised placebo-controlled trials have now demonstrated the efficacy of duloxetine, an antidepressant with a centrally acting effect, in the treatment of OA pain. The aim of the current study is to investigate if duloxetine is effective and cost effective as a third-choice analgesic added to usual care for treating chronic pain compared with usual care alone in general practice. METHODS AND ANALYSIS: A pragmatic open, cluster randomised trial is conducted. Patients with pain due to hip or knee OA on most days of the past 3 months with insufficient benefit of non steroidal anti-inflammatory drugs or contraindications or intolerable side effects are included. General practices are randomised to either (1) duloxetine and usual care or (2) usual care only. Primary outcome is pain at 3 months measured on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Secondary outcomes at 3 months and 1 year are pain (WOMAC, at 1 year), function (WOMAC), adverse reactions, quality of life and modification of the response to treatment by the presence of centrally sensitised pain (modified PainDETECT). At 1 year, medical and productivity costs will be assessed. Analyses will be performed following the intention-to-treat principle taking the cluster design into account. ETHICS AND DISSEMINATION: The study is approved by the local Medical Ethics Committee (2015-293). Results will be published in a scientific peer-reviewed journal and will be communicated at conferences. TRIAL REGISTRATION NUMBER: Dutch Trial Registry(ntr4798); Pre results. PMID- 28893760 TI - Characteristics of early filtering blebs that predict successful trabeculectomy identified via three-dimensional anterior segment optical coherence tomography. AB - BACKGROUND/AIMS: To identify the cross-sectional characteristics of filtering blebs at 2 weeks post-trabeculectomy associated with intraocular pressure (IOP) control at 1 year post-trabeculectomy. METHODS: Ninety-nine eyes of 94 patients who had undergone primary trabeculectomy were included in this retrospective consecutive case series study. Surgical success was defined as an IOP <=15 mm Hg and a >20% reduction in IOP without glaucoma medication or additional glaucoma surgeries at 1 year post-trabeculectomy. Subjects were classified into two groups according to whether surgery was successful or unsuccessful. Blebs were examined using swept-source three-dimensional anterior segment optical coherence tomography and evaluated for quantitative parameters, including maximum height, maximum wall thickness and ratio of hyporeflective space of the wall, as well as qualitative parameters, including multiple parallel hyporeflective layers within the wall (striping phenomenon), decreased visibility of the sclera underlying the bleb (shading phenomenon) and cyst-like structures of the wall. RESULTS: Seventy seven eyes (77.8%) were assigned to the successful group and 22 (22.2%) to the unsuccessful group. Univariate analysis showed significant differences between the groups regarding maximum bleb height (p=0.044), maximum bleb wall thickness (p=0.017) and the striping phenomenon of the bleb wall (p=0.007). Multivariate logistic regression analysis confirmed that the striping phenomenon at 2 weeks post-trabeculectomy was significantly associated with success at 1 year post trabeculectomy (OR 3.405; 95% CI 1.059 to 10.947; p=0.040). CONCLUSION: Taller blebs with thicker walls that showed the striping phenomenon at 2 weeks post trabeculectomy appeared to predict good IOP control at 1 year post trabeculectomy. PMID- 28893758 TI - Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the impact of various antiretroviral/antiviral regimens in pregnant women living with HIV or hepatitis B virus (HBV). DESIGN: We performed random effects meta-analysis for HIV-related outcomes and network meta-analysis for HBV outcomes, and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess quality separately for each outcome. DATA SOURCES: Embase and Medline to February 2017. ELIGIBILITY CRITERIA: For maternal outcomes, we considered randomised controlled trials (RCTs) comparing tenofovir-based regimens with those with alternative nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). For child outcomes, we included RCTs and comparative observational studies of tenofovir-based regimens versus alternative NRTIs regimens or, for HBV, placebo. RESULTS: Ten studies (seven RCTs) met the inclusion criteria for maternal and child outcomes, and an additional 33 studies (12 RCTs) met the inclusion criteria for HBV-specific outcomes. The most common comparison was tenofovir and emtricitabine versus zidovudine and lamivudine. There was no apparent difference between tenofovir based regimens and alternatives in maternal outcomes, including serious laboratory adverse events (low certainty) and serious clinical adverse events (moderate certainty). There was no difference between NRTIs in vertical transmission of HIV: 1 more per 1000, 8 fewer to 10 more, low certainty; or vertical transmission of HBV: 7 fewer per 1000, 10 fewer to 38 more, moderate certainty. We found moderate certainty evidence that tenofovir/emtricitabine increases the risk of stillbirths and early neonatal mortality (51 more per 1000, 11 more to 150 more) and the risk of early premature delivery at <34 weeks (42 more per 1000, 2 more to 127 more). CONCLUSIONS: Tenofovir/emtricitabine is likely to increase stillbirth/early neonatal death and early premature delivery compared with zidovudine/lamivudine, but certainty is low when they are not coprescribed with lopinavir/ritonavir. Other outcomes are likely similar between antiretrovirals. TRIAL REGISTRATION NUMBER: PROSPERO CRD42017054392. PMID- 28893759 TI - Values and preferences of women living with HIV who are pregnant, postpartum or considering pregnancy on choice of antiretroviral therapy during pregnancy. AB - OBJECTIVE: To investigate women's values and preferences regarding antiretroviral therapy (ART) during pregnancy to inform a BMJ Rapid Recommendation. SETTING: Primary studies reporting patient-reported outcomes relevant to decision-making regarding ART in any clinical and geographical setting. PARTICIPANTS: Women living with HIV who are pregnant, postpartum or considering pregnancy. OUTCOME MEASURES: Quantitative measurements and qualitative descriptions of values and preferences in relation to ART during pregnancy. We also included studies on women's reported barriers and facilitators to adherence. We excluded studies correlating objective measures (eg, CD4 count) with adherence, or reporting only outcomes which are not expected to differ between ART alternatives (eg, access to services, knowledge about ART). RESULTS: We included 15 qualitative studies reporting values and preferences about ART in the peripartum period; no study directly studied choice of ART therapy during pregnancy. Six themes emerged: a desire to reduce vertical transmission (nine studies), desire for child to be healthy (five studies), concern about side effects to the child (eight studies), desire for oneself to be healthy (five studies), distress about side effect to oneself (10 studies) and pill burden (two studies). None of the studies weighed the relative importance of these outcomes directly, but pill burden/medication complexity appears to be a lower priority for most women compared with other factors. Overall, the body of evidence was at low risk of bias, with minor limitations. CONCLUSIONS: Women who are or may become pregnant and who are considering ART appear to place a high value on both their own and their children's health. Evidence on the relative importance between these values when choosing between ART regimens is uncertain. There is variability in individual values and preferences among women. This highlights the importance of an individualised women-centred approach, such as shared decision-making when choosing between ART alternatives. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews:CRD42017057157. PMID- 28893761 TI - Effectiveness of expanding annual mass azithromycin distribution treatment coverage for trachoma in Niger: a cluster randomised trial. AB - BACKGROUND/AIMS: The WHO recommends 3-5 years of annual mass azithromycin distribution with at least 80% treatment coverage to districts with active trachoma prevalence over 10% among children. Here, we assess the efficacy of expanding the coverage target to at least 90% for trachoma control in a mesoendemic region of Niger. METHODS: Twenty-four communities were randomised to a single day of azithromycin distribution with a coverage target of 80% of the community or up to 4 days of treatment, aiming for greater than 90% coverage. Distributions were annual and individuals above 6 months of age were treated. Children under 5 years of age were monitored for ocular chlamydia infection and active trachoma. RESULTS: At baseline, ocular chlamydia prevalence was 20.5% (95% CI 9.8% to 31.2%) in the standard coverage arm and 21.9% (95% CI 11.3% to 32.5%) in the enhanced coverage arm, which reduced to 4.6% (95% CI 0% to 9.5%, p=0.008) and 7.1% (95% CI 2.7% to 11.4%, p<0.001) at 36 months, respectively. There was no significant difference in 36-month ocular chlamydia prevalence between the two arms (p=0.21). There was no difference in the rate of decline in ocular chlamydia between the two arms in a repeated measures model (p=0.80). CONCLUSIONS: For annual mass azithromycin distribution programme to an entire community, there may be no additional benefit of increasing antibiotic coverage above the WHO's 80% target. TRIAL REGISTRATION NUMBER: NCT00792922, post-results. PMID- 28893762 TI - Sleep-Disordered Breathing in Acute Ischemic Stroke: A Mechanistic Link to Peripheral Endothelial Dysfunction. AB - BACKGROUND: Sleep-disordered breathing (SDB) after acute ischemic stroke is frequent and may be linked to stroke-induced autonomic imbalance. In the present study, the interaction between SDB and peripheral endothelial dysfunction (ED) was investigated in patients with acute ischemic stroke and at 1-year follow-up. METHODS AND RESULTS: SDB was assessed by transthoracic impedance records in 101 patients with acute ischemic stroke (mean age, 69 years; 61% men; median National Institutes of Health Stroke Scale, 4) while being on the stroke unit. SDB was defined by apnea-hypopnea index >=5 episodes per hour. Peripheral endothelial function was assessed using peripheral arterial tonometry (EndoPAT-2000). ED was defined by reactive hyperemia index <=1.8. Forty-one stroke patients underwent 1 year follow-up (390+/-24 days) after stroke. SDB was observed in 57% patients with acute ischemic stroke. Compared with patients without SDB, ED was more prevalent in patients with SDB (32% versus 64%; P<0.01). After adjustment for multiple confounders, presence of SDB remained independently associated with ED (odds ratio, 3.1; [95% confidence interval, 1.2-7.9]; P<0.05). After 1 year, the prevalence of SDB decreased from 59% to 15% (P<0.001). Interestingly, peripheral endothelial function improved in stroke patients with normalized SDB, compared with patients with persisting SDB (P<0.05). CONCLUSIONS: SDB was present in more than half of all patients with acute ischemic stroke and was independently associated with peripheral ED. Normalized ED in patients with normalized breathing pattern 1 year after stroke suggests a mechanistic link between SDB and ED. CLINICAL TRIAL REGISTRATION: URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00000514. PMID- 28893763 TI - PEA-15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia. AB - BACKGROUND: Neointimal hyperplasia following angioplasty occurs via vascular smooth muscle cell proliferation. The mechanisms involved are not fully understood but include mitogen-activated protein kinases ERK1/2 (extracellular signal-regulated kinases 1 and 2). We recently identified the intracellular mediator PEA-15 (phosphoprotein enriched in astrocytes 15) in vascular smooth muscle cells as a regulator of ERK1/2-dependent proliferation in vitro. PEA-15 acts as a cytoplasmic anchor for ERK1/2, preventing nuclear localization and thereby reducing ERK1/2-dependent gene expression. The aim of the current study was to examine the role of PEA-15 in neointimal hyperplasia in vivo. METHOD AND RESULTS: Mice deficient in PEA-15 or wild-type mice were subjected to wire injury of the carotid artery. In uninjured arteries from PEA-15-deficient mice, ERK1/2 had increased nuclear translocation and increased basal ERK1/2-dependent transcription. Following wire injury, arteries from PEA-15-deficient mice developed neointimal hyperplasia at an increased rate compared with wild-type mice. This occurred in parallel with an increase in a proliferative marker and vascular smooth muscle cell proliferation. In wild-type mice, PEA-15 expression was decreased in vascular smooth muscle cells at an early stage before any increase in intima:media ratio. This regulation of PEA-15 expression following injury was also observed in an ex vivo human model of hyperplasia. CONCLUSIONS: These results indicate, for the first time, a novel protective role for PEA-15 against inappropriate vascular proliferation. PEA-15 expression may also be repressed during vascular injury, suggesting that maintenance of PEA-15 expression is a novel therapeutic target in vascular disease. PMID- 28893764 TI - Prevalence of Cerebral Microbleeds in Patients With Continuous-Flow Left Ventricular Assist Devices. AB - BACKGROUND: The prevalence of cerebral microbleeds (CMBs) in gradient echo T2* weighted brain MRI has a positive correlation with hemorrhagic stroke incidence. However, the prevalence of CMBs in patients with left ventricular assist devices (LVADs) has not been evaluated. We evaluated the prevalence of CMBs and the relationship with hemorrhagic stroke incidence in patients with LVADs. METHOD AND RESULTS: We analyzed results from brain MRI in prospective examinations of 35 consecutive patients who had undergone LVAD explantation for heart transplantation or recovery since 2011. The number and distribution of CMBs were counted, then the relationship between baseline characteristics and adverse events during LVAD support were analyzed. The mean age was 37.7+/-12.4 years and the mean LVAD duration was 2.43+/-1.08 years. Thirty-four (97%) patients had at least one CMB. Nine (26%) developed hemorrhagic stroke during LVAD support, and patients with hemorrhagic stroke had a significantly greater number of CMBs compared with patients without hemorrhagic stroke (5 [interquartile range (IQR), 4-7] versus 9 [IQR, 5-23]; odds ratio 1.14 [95% Confidence Interval (CI), 1.02 1.32], P=0.05). There was no significant relationship between age, LVAD support duration, or systolic blood pressure during LVAD. However, patients who had at least one episode of bacteremia (9 [IQR, 4-16] versus 5 [IQR, 3-7], P=0.06) and pump pocket infection (14 [IQR, 4-27] versus 5 [IQR, 3-7], P=0.08) showed a trend toward a greater number of CMBs than patients without bacteremia. CONCLUSIONS: Thirty-four (97%) patients with continuous-flow LVAD had at least one CMB, and the number of CMBs were more prevalent in patients with hemorrhagic stroke and in patients with LVAD-related infection. PMID- 28893765 TI - Requirement for cystatin C testing in chronic kidney disease: a retrospective population-based study. AB - BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFR) determines chronic kidney disease (CKD) stage, but underestimates renal function. The 2014 updated guidance from the National Institute for Health and Care Excellence (NICE) recommends that GPs reduce overdiagnosis of CKD stage 3a (eGFR 45-60 ml/min/1.73 m2) by using the renal biomarker cystatin C. AIM: To determine the population requirement for cystatin C testing, compared with current national availability of the assay. DESIGN AND SETTING: Retrospective study of primary care laboratory requests in Oxfordshire, England. METHOD: The first creatinine results from tests ordered in primary care over a 6-year period (2008-2014) in a population of 600 000 in Oxfordshire were analysed and the number of patients with CKD stage 3a without proteinuria (who, in accordance with NICE guidance, required cystatin C) was determined. A conservative estimate of the national need was provided by scaling the population of Oxfordshire to the national population (CKD prevalence in the county is below the national average). Cystatin C assay availability was determined using national databases of laboratory assay provision. RESULTS: From a population of 600 000, there were 22 240 individuals with stable stage 3a CKD and no proteinuria. As the population of Oxfordshire equates to 1% of the UK population, there is an initial requirement for at least 2 million people to have their CKD status determined with cystatin C testing. Eight laboratories (2.1% of UK laboratories) reported cystatin C assay provision. CONCLUSION: There is a substantial gap between cystatin C assay requirements in primary care and national assay provision. This is a major barrier to implementing NICE guidance. PMID- 28893766 TI - Barriers, facilitators, and survival strategies for GPs seeking treatment for distress: a qualitative study. AB - BACKGROUND: GPs are under increasing pressure due to a lack of resources, a diminishing workforce, and rising patient demand. As a result, they may feel stressed, burnt out, anxious, or depressed. AIM: To establish what might help or hinder GPs experiencing mental distress as they consider seeking help for their symptoms, and to explore potential survival strategies. DESIGN AND SETTING: The authors recruited 47 GP participants via e-mails to doctors attending a specialist service, adverts to local medical committees (LMCs) nationally and in GP publications, social media, and snowballing. Participants self-identified as either currently living with mental distress, returning to work following treatment, off sick or retired early as a result of mental distress, or without experience of mental distress. Interviews were conducted face to face or over the telephone. METHOD: Transcripts were uploaded to NVivo 11 and analysed using thematic analysis. RESULTS: Barriers and facilitators were related to work, stigma, and symptoms. Specifically, GPs discussed feeling a need to attend work, the stigma surrounding mental ill health, and issues around time, confidentiality, and privacy. Participants also reported difficulties accessing good-quality treatment. GPs also talked about cutting down or varying work content, or asserting boundaries to protect themselves. CONCLUSION: Systemic changes, such as further information about specialist services designed to help GPs, are needed to support individual GPs and protect the profession from further damage. PMID- 28893767 TI - GPs' perceptions of resilience training: a qualitative study. AB - BACKGROUND: GPs are reporting increasing levels of burnout, stress, and job dissatisfaction, and there is a looming GP shortage. Promoting resilience is a key strategy for enhancing the sustainability of the healthcare workforce and improving patient care. AIM: To explore GPs' perspectives on the content, context, and acceptability of resilience training programmes in general practice, in order to build more effective GP resilience programmes. DESIGN AND SETTING: This was a qualitative study of the perspectives of GPs currently practising in England. METHOD: GPs were recruited through convenience sampling, and data were collected from two focus groups (n = 15) and one-to-one telephone interviews (n = 7). A semi-structured interview approach was used and data were analysed using thematic analysis. RESULTS: Participants perceived resilience training to be potentially of value in ameliorating workplace stresses. Nevertheless, uncertainty was expressed regarding how best to provide training for stressed GPs who have limited time. Participants suspected that GPs most likely to benefit from resilience training were the least likely to engage, as stress and being busy worked against engagement. Conflicting views were expressed about the most suitable training delivery method for promoting better engagement. Participants also emphasised that training should not only place the focus on the individual, but also focus on organisation issues. CONCLUSION: A multimodal, flexible approach based on individual needs and learning aims, including resilience workshops within undergraduate training and in individual practices, is likely to be the optimal way to promote resilience. PMID- 28893768 TI - Building managed primary care practice networks to deliver better clinical care: a qualitative semi-structured interview study. AB - BACKGROUND: Primary care practices are increasingly working in larger groups. In 2009, all 36 primary care practices in the London borough of Tower Hamlets were grouped geographically into eight managed practice networks to improve the quality of care they delivered. Quantitative evaluation has shown improved clinical outcomes. AIM: To provide insight into the process of network implementation, including the aims, facilitating factors, and barriers, from both the clinical and managerial perspectives. DESIGN AND SETTING: A qualitative study of network implementation in the London borough of Tower Hamlets, which serves a socially disadvantaged and ethnically diverse population. METHOD: Nineteen semi structured interviews were carried out with doctors, nurses, and managers, and were informed by existing literature on integrated care and GP networks. Interviews were recorded and transcribed, and thematic analysis used to analyse emerging themes. RESULTS: Interviewees agreed that networks improved clinical care and reduced variation in practice performance. Network implementation was facilitated by the balance struck between 'a given structure' and network autonomy to adopt local solutions. Improved use of data, including patient recall and peer performance indicators, were viewed as critical key factors. Targeted investment provided the necessary resources to achieve this. Barriers to implementing networks included differences in practice culture, a reluctance to share data, and increased workload. CONCLUSION: Commissioners and providers were positive about the implementation of GP networks as a way to improve the quality of clinical care in Tower Hamlets. The issues that arose may be of relevance to other areas implementing similar quality improvement programmes at scale. PMID- 28893769 TI - Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets. PMID- 28893771 TI - MitraClip and Transcatheter Aortic Valve Replacement in a Patient With Recurrent Heart Failure. PMID- 28893770 TI - Serial 5-Year Evaluation of Side Branches Jailed by Bioresorbable Vascular Scaffolds Using 3-Dimensional Optical Coherence Tomography: Insights From the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). AB - BACKGROUND: The long-term fate of Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, CA) struts jailing side branch ostia has not been clarified. We therefore evaluate serially (post-procedure and at 6 months, 1, 2, 3, and 5 years) the appearance and fate of jailed Absorb bioresorbable vascular scaffold struts. METHODS AND RESULTS: We performed 3-dimensional optical coherence tomographic analysis of the ABSORB Cohort B trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) up to 5 years using a novel, validated cut-plane analysis method. We included 29 patients with a total of 85 side branch ostia. From the 12 ostia which could be assessed in true serial fashion, 7 showed a pattern of initial decrease in the ostial area free from struts, followed by an increase in strut-free ostial area toward the end of the 5 years of follow-up. In a repeated-measures analysis with time as fixed variable and ostial area free from struts as dependent variable, we showed a numeric decrease in the estimated ostial area free from struts from 0.75 mm2 (baseline) to 0.68 mm2 (first follow-up visit at 6 months or 1 year) and 0.63 mm2 (second follow-up visit at 2 or 3 years). However, from the second visit to the 5 year follow-up visit, there was a statistically significant increase from 0.63 to 0.89 mm2 (P=0.001). Struts overlying an ostium divided the ostium into compartments, and the number of these compartments decreased over time. CONCLUSIONS: This study showed that in most cases, the side branch ostial area free from struts initially decreased. However, with full scaffold bioresorption, the ostial area free from scaffold increased between 2 to 3 years and 5 years in the vast majority of patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856856. PMID- 28893772 TI - Triazole Resistance Is Still Not Emerging in Aspergillus fumigatus Isolates Causing Invasive Aspergillosis in Brazilian Patients. AB - Aspergillus fumigatus azole resistance has emerged as a global health problem. We evaluated the in vitro antifungal susceptibility of 221 clinical A. fumigatus isolates according to CLSI guidelines. Sixty-one isolates exhibiting MICs at the epidemiological cutoff value (ECV) for itraconazole or above the ECV for any triazole were checked for CYP51A mutations. No mutations were documented, even for the isolates (1.8%) with high voriconazole MICs, indicating that triazoles may be used safely to treat aspergillosis in Brazil. PMID- 28893773 TI - Colistin Is Extensively Lost during Standard In Vitro Experimental Conditions. AB - Colistin adheres to a range of materials, including plastics in labware. The loss caused by adhesion influences an array of methods detrimentally, including MIC assays and in vitro time-kill experiments. The aim of this study was to characterize the extent and time course of colistin loss in different types of laboratory materials during a simulated time-kill experiment without bacteria or plasma proteins present. Three types of commonly used large test tubes, i.e., soda-lime glass, polypropylene, and polystyrene, were studied, as well as two different polystyrene microplates and low-protein-binding microtubes. The tested concentration range was 0.125 to 8 mg/liter colistin base. Exponential one-phase and two-phase functions were fitted to the data, and the adsorption of colistin to the materials was modeled with the Langmuir adsorption model. In the large test tubes, the measured start concentrations ranged between 44 and 102% of the expected values, and after 24 h, the concentrations ranged between 8 and 90%. The half-lives of colistin loss were 0.9 to 12 h. The maximum binding capacities of the three materials ranged between 0.4 and 1.1 MUg/cm2, and the equilibrium constants ranged between 0.10 and 0.54 ml/MUg. The low-protein-binding microtubes showed start concentrations between 63 and 99% and concentrations at 24 h of between 59 and 90%. In one of the microplates, the start concentrations were below the lower limit of quantification at worst. In conclusion, to minimize the effect of colistin loss due to adsorption, our study indicates that low-protein binding polypropylene should be used when possible for measuring colistin concentrations in experimental settings, and the results discourage the use of polystyrene. Furthermore, when diluting colistin in protein-free media, the number of dilution steps should be minimized. PMID- 28893774 TI - External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models. AB - Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetic (PK) models of fluconazole in infants have been previously published by Wade et al. (Antimicrob Agents Chemother 52:4043-4049, 2008, https://doi.org/10.1128/AAC.00569-08) and Momper et al. (Antimicrob Agents Chemother 60:5539-5545, 2016, https://doi.org/10.1128/AAC.00963-16). Here we report the results of the first external evaluation of the predictive performance of both models. We used patient-level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), prediction-corrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE). The values of the parameters of each model were reestimated using both the external and merged data sets. When evaluated with the external data set, the model proposed by Wade et al. showed lower median PE, MPE, and MAPE (0.429 MUg/ml, 41.9%, and 57.6%, respectively) than the model proposed by Momper et al. (2.45 MUg/ml, 188%, and 195%, respectively). The values of the majority of reestimated parameters were within 20% of their respective original parameter values for all model evaluations. Our analysis determined that though both models are robust, the model proposed by Wade et al. had greater accuracy and precision than the model proposed by Momper et al., likely because it was derived from a patient population with a wider age range. This study highlights the importance of the external evaluation of infant population PK models. PMID- 28893776 TI - Mycobacterium tuberculosis Subculture Results in Loss of Potentially Clinically Relevant Heteroresistance. AB - Multidrug-resistant tuberculosis (TB) presents a major public health dilemma. Heteroresistance, the coexistence of drug-resistant and drug-susceptible strains or of multiple drug-resistant strains with discrete haplotypes, may affect accurate diagnosis and the institution of effective treatment. Subculture, or passage of cells onto fresh growth medium, is utilized to preserve Mycobacterium tuberculosis cell lines and is universally employed in TB diagnostics. The impact of such passages, typically performed in the absence of drug, on drug-resistant subpopulations is hypothesized to vary according to the competitive costs of genotypic resistance-associated variants. We applied ultradeep next-generation sequencing to 61 phenotypically rifampin-monoresistant (n = 17) and preextensively (n = 41) and extensively (n = 3) drug-resistant isolates with presumptive heteroresistance at two time points in serial subculture. We found significant dynamic loss of minor-variant resistant subpopulations across all analyzed resistance-determining regions, including eight isolates (13%) whose antibiogram data would have transitioned from resistant to susceptible for at least one drug through subculture. Surprisingly, some resistance-associated variants appeared to be selected for in subculture. PMID- 28893775 TI - Nosocomial Outbreak of Extensively Drug-Resistant Acinetobacter baumannii Isolates Containing blaOXA-237 Carried on a Plasmid. AB - Carbapenem antibiotics are among the mainstays for treating infections caused by Acinetobacter baumannii, especially in the Northwest United States, where carbapenem-resistant A. baumannii remains relatively rare. However, between June 2012 and October 2014, an outbreak of carbapenem-resistant A. baumannii occurred in 16 patients from five health care facilities in the state of Oregon. All isolates were defined as extensively drug resistant. Multilocus sequence typing revealed that the isolates belonged to sequence type 2 (international clone 2 [IC2]) and were >95% similar as determined by repetitive-sequence-based PCR analysis. Multiplex PCR revealed the presence of a blaOXA carbapenemase gene, later identified as blaOXA-237 Whole-genome sequencing of all isolates revealed a well-supported separate branch within a global A. baumannii phylogeny. Pacific Biosciences (PacBio) SMRT sequencing was also performed on one isolate to gain insight into the genetic location of the carbapenem resistance gene. We discovered that blaOXA-237, flanked on either side by ISAba1 elements in opposite orientations, was carried on a 15,198-bp plasmid designated pORAB01-3 and was present in all 16 isolates. The plasmid also contained genes encoding a TonB dependent receptor, septicolysin, a type IV secretory pathway (VirD4 component, TraG/TraD family) ATPase, an integrase, a RepB family plasmid DNA replication initiator protein, an alpha/beta hydrolase, and a BrnT/BrnA type II toxin antitoxin system. This is the first reported outbreak in the northwestern United States associated with this carbapenemase. Particularly worrisome is that blaOXA 237 was carried on a plasmid and found in the most prominent worldwide clonal group IC2, potentially giving pORAB01-3 great capacity for future widespread dissemination. PMID- 28893777 TI - Modulation of Staphylococcus aureus Response to Antimicrobials by the Candida albicans Quorum Sensing Molecule Farnesol. AB - In microbial biofilms, microorganisms utilize secreted signaling chemical molecules to coordinate their collective behavior. Farnesol is a quorum sensing molecule secreted by the fungal species Candida albicans and shown to play a central physiological role during fungal biofilm growth. Our pervious in vitro and in vivo studies characterized an intricate interaction between C. albicans and the bacterial pathogen Staphylococcus aureus, as these species coexist in biofilm. In this study, we aimed to investigate the impact of farnesol on S. aureus survival, biofilm formation, and response to antimicrobials. The results demonstrated that in the presence of exogenously supplemented farnesol or farnesol secreted by C. albicans in biofilm, S. aureus exhibited significantly enhanced tolerance to antimicrobials. By using gene expression studies, S. aureus mutant strains, and chemical inhibitors, the mechanism for the enhanced tolerance was attributed to upregulation of drug efflux pumps. Importantly, we showed that sequential exposure of S. aureus to farnesol generated a phenotype of high resistance to antimicrobials. Based on the presence of intracellular reactive oxygen species upon farnesol exposure, we hypothesize that antimicrobial tolerance in S. aureus may be mediated by farnesol-induced oxidative stress triggering the upregulation of efflux pumps, as part of a general stress response system. Hence, in mixed biofilms, C. albicans may influence the pathogenicity of S. aureus through acquisition of a drug-tolerant phenotype, with important therapeutic implications. Understanding interspecies signaling in polymicrobial biofilms and the specific drug resistance responses to secreted molecules may lead to the identification of novel targets for drug development. PMID- 28893778 TI - Protocol for Identifying Natural Agents That Selectively Affect Adhesion, Thickness, Architecture, Cellular Phenotypes, Extracellular Matrix, and Human White Blood Cell Impenetrability of Candida albicans Biofilms. AB - In the screening of natural plant extracts for antifungal activity, assessment of their effects on the growth of cells in suspension or in the wells of microtiter plates is expedient. However, microorganisms, including Candida albicans, grow in nature as biofilms, which are organized cellular communities with a complex architecture capable of conditioning their microenvironment, communicating, and excluding low- and high-molecular-weight molecules and white blood cells. Here, a confocal laser scanning microscopy (CLSM) protocol for testing the effects of large numbers of agents on biofilm development is described. The protocol assessed nine parameters from a single z-stack series of CLSM scans for each individual biofilm analyzed. The parameters included adhesion, thickness, formation of a basal yeast cell polylayer, hypha formation, the vertical orientation of hyphae, the hyphal bend point, pseudohypha formation, calcofluor white staining of the extracellular matrix (ECM), and human white blood cell impenetrability. The protocol was applied first to five plant extracts and derivative compounds and then to a collection of 88 previously untested plant extracts. They were found to cause a variety of phenotypic profiles, as was the case for 64 of the 88 extracts (73%). Half of the 46 extracts that did not affect biofilm thickness affected other biofilm parameters. Correlations between specific effects were revealed. The protocol will be useful not only in the screening of chemical libraries but also in the analysis of compounds with known effects and mutations. PMID- 28893779 TI - Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers. AB - Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 MUg/ml (range, 40.9 to 169.3 MUg/ml); half life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 MUg . h/ml (range, 147.1 to 286.6 MUg . h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 MUg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 14.2 MUg/ml (range, 7.6 to 64.2 MUg/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 MUg . h/ml (range, 15.0 to 70.0 MUg . h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: Cmax, 91.5 MUg/ml (range, 65.7 to 110.7 MUg/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 MUg . h/ml (range, 118.1 to 274.3 MUg . h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 MUg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 17.5 MUg/ml (range, 15.4 to 27.3 MUg/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 MUg . h/ml (range, 19.2 to 36.4 MUg . h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.). PMID- 28893780 TI - Pharmacokinetic/Toxicodynamic Analysis of Colistin-Associated Acute Kidney Injury in Critically Ill Patients. AB - Acute kidney injury (AKI) occurs in a substantial proportion of critically ill patients receiving intravenous colistin. In the pharmacokinetic/toxicodynamic analysis reported here, the relationship of the occurrence of AKI to exposure to colistin and a number of potential patient factors was explored in 153 critically ill patients, none of whom were receiving renal replacement therapy. Tree-based modeling revealed that the rates of AKI were substantially higher when the average steady-state plasma colistin concentration was greater than ~2 mg/liter. PMID- 28893781 TI - Identification of Heparin Modifications and Polysaccharide Inhibitors of Plasmodium falciparum Merozoite Invasion That Have Potential for Novel Drug Development. AB - Despite recent successful control efforts, malaria remains a leading global health burden. Alarmingly, resistance to current antimalarials is increasing and the development of new drug families is needed to maintain malaria control. Current antimalarials target the intraerythrocytic developmental stage of the Plasmodium falciparum life cycle. However, the invasive extracellular parasite form, the merozoite, is also an attractive target for drug development. We have previously demonstrated that heparin-like molecules, including those with low molecular weights and low anticoagulant activities, are potent and specific inhibitors of merozoite invasion and blood-stage replication. Here we tested a large panel of heparin-like molecules and sulfated polysaccharides together with various modified chemical forms for their inhibitory activity against P. falciparum merozoite invasion. We identified chemical modifications that improve inhibitory activity and identified several additional sulfated polysaccharides with strong inhibitory activity. These studies have important implications for the further development of heparin-like molecules as antimalarial drugs and for understanding merozoite invasion. PMID- 28893782 TI - Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa Determined via Mechanistic Studies and Modeling. AB - This study aimed to systematically identify the aminoglycoside concentrations required for synergy with a carbapenem and characterize the permeabilizing effect of aminoglycosides on the outer membrane of Pseudomonas aeruginosa Monotherapies and combinations of four aminoglycosides and three carbapenems were studied for activity against P. aeruginosa strain AH298-GFP in 48-h static-concentration time kill studies (SCTK) (inoculum: 107.6 CFU/ml). The outer membrane-permeabilizing effect of tobramycin alone and in combination with imipenem was characterized via electron microscopy, confocal imaging, and the nitrocefin assay. A mechanism based model (MBM) was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by imipenem combined with each of the four aminoglycosides. Notably, 0.25 mg/liter of tobramycin, which was inactive in monotherapy, achieved synergy (i.e., >=2-log10 more killing than the most active monotherapy at 24 h) combined with imipenem. Electron micrographs, confocal image analyses, and the nitrocefin uptake data showed distinct outer membrane damage by tobramycin, which was more extensive for the combination with imipenem. The MBM indicated that aminoglycosides enhanced the imipenem target site concentration up to 4.27-fold. Tobramycin was the most potent aminoglycoside to permeabilize the outer membrane; tobramycin (0.216 mg/liter), gentamicin (0.739 mg/liter), amikacin (1.70 mg/liter), or streptomycin (5.19 mg/liter) was required for half-maximal permeabilization. In summary, our SCTK, mechanistic studies and MBM indicated that tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill patients. PMID- 28893783 TI - Evolution of Antibiotic Resistance without Antibiotic Exposure. AB - Antibiotic use is the main driver in the emergence of antibiotic resistance. Another unexplored possibility is that resistance evolves coincidentally in response to other selective pressures. We show that selection in the absence of antibiotics can coselect for decreased susceptibility to several antibiotics. Thus, genetic adaptation of bacteria to natural environments may drive resistance evolution by generating a pool of resistance mutations that selection could act on to enrich resistant mutants when antibiotic exposure occurs. PMID- 28893784 TI - Dual Mechanism of Action of 5-Nitro-1,10-Phenanthroline against Mycobacterium tuberculosis. AB - New chemotherapeutic agents with novel mechanisms of action are urgently required to combat the challenge imposed by the emergence of drug-resistant mycobacteria. In this study, a phenotypic whole-cell screen identified 5-nitro-1,10 phenanthroline (5NP) as a lead compound. 5NP-resistant isolates harbored mutations that were mapped to fbiB and were also resistant to the bicyclic nitroimidazole PA-824. Mechanistic studies confirmed that 5NP is activated in an F420-dependent manner, resulting in the formation of 1,10-phenanthroline and 1,10 phenanthrolin-5-amine as major metabolites in bacteria. Interestingly, 5NP also killed naturally resistant intracellular bacteria by inducing autophagy in macrophages. Structure-activity relationship studies revealed the essentiality of the nitro group for in vitro activity, and an analog, 3-methyl-6-nitro-1,10 phenanthroline, that had improved in vitro activity and in vivo efficacy in mice compared with that of 5NP was designed. These findings demonstrate that, in addition to a direct mechanism of action against Mycobacterium tuberculosis, 5NP also modulates the host machinery to kill intracellular pathogens. PMID- 28893785 TI - In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae. AB - We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (n = 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including in vitro selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials. PMID- 28893786 TI - Novel Cell-Killing Mechanisms of Hydroxyurea and the Implication toward Combination Therapy for the Treatment of Fungal Infections. AB - We have previously reported that an erg11 mutation affecting ergosterol synthesis and a hem13 mutation in the heme synthesis pathway significantly sensitize the fission yeast Schizosaccharomyces pombe to hydroxyurea (HU) (1, 2). Here we show that treatment with inhibitors of Erg11 and heme biosynthesis phenocopies the two mutations in sensitizing wild-type cells to HU. Importantly, HU synergistically interacts with the heme biosynthesis inhibitor sampangine and several Erg11 inhibitors, the antifungal azoles, in causing cell lethality. Since the synergistic drug interactions are also observed in the phylogenetically divergent Saccharomyces cerevisiae and the opportunistic fungal pathogen Candida albicans, the synergism is likely conserved in eukaryotes. Interestingly, our genetic data for S. pombe has also led to the discovery of a robust synergism between sampangine and the azoles in C. albicans Thus, combinations of HU, sampangine, and the azoles can be further studied as a new method for the treatment of fungal infections. PMID- 28893787 TI - A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia in Patients without HIV Infection. AB - The dose of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) infection has not been verified. The aim of this study was to investigate the efficacy and toxicity of a low-dose TMP-SMX regimen in such patients. A retrospective study was conducted in four hospitals. We reviewed the medical records of patients with PCP but not HIV (non-HIV-PCP) who were treated with TMP SMX between 2003 and 2016. The patients were divided into conventional-dose (TMP, 15 to 20 mg/kg/day) and low-dose (TMP, <15 mg/kg/day) groups after patients who received high-dose (TMP, >20 mg/kg/day) treatment were excluded. Grouping was done according to a correction dose, which was based on renal function. Eighty two patients had non-HIV-PCP. The numbers of patients who received high-, conventional-, and low-dose treatments were 5, 36, and 41, respectively. Kaplan Meier analysis for death associated with PCP showed no statistically significant difference in survival rates between the conventional- and low-dose groups. Ninety-day cause-specific mortality rates were 25.0% and 19.5% in the conventional-dose and low-dose groups (P = 0.76), respectively. Adverse events that were graded as >=3 according to the Common Terminology Criteria for Adverse Events (version 4.0) (National Cancer Institute, 2010) were 41.7% and 17.1% in the conventional-dose and low-dose groups (P = 0.02), respectively. Moreover, vomiting (P = 0.03) and a decrease in platelet count (P = 0.03) occurred more frequently in the conventional-dose group. Treatment of non-HIV-PCP with low-dose or conventional-dose TMP-SMX produces comparable survival rates; however, the low dose regimen is better tolerated and associated with fewer adverse effects. PMID- 28893788 TI - Genomic and Molecular Characterization of Clinical Isolates of Enterobacteriaceae Harboring mcr-1 in Colombia, 2002 to 2016. AB - Polymyxins are last-resort antimicrobial agents used to treat infections caused by carbapenem-resistant Enterobacteriaceae Due to the worldwide dissemination of polymyxin resistance in animal and human isolates, we aimed to characterize polymyxin resistance associated with the presence of mcr-1 in Enterobacteriaceae and nonfermenter Gram-negative bacilli, using isolates collected retrospectively in Colombia from 2002 to 2016. A total of 5,887 Gram-negative clinical isolates were studied, and 513 were found to be resistant to the polymyxins. Susceptibility to colistin was confirmed by broth microdilution for all mcr-1 positive isolates, and these were further subjected to whole-genome sequencing (WGS). The localization of mcr-1 was confirmed by S1 pulsed-field gel electrophoresis (S1-PFGE) and CeuI-PFGE hybridization. Transferability was evaluated by mating assays. A total of 12 colistin-resistant isolates recovered after 2013 harbored mcr-1, including 8 Escherichia coli, 3 Salmonella enterica serovar Typhimurium, and 1 Klebsiella pneumoniae isolate. E. coli isolates were unrelated by PFGE and belonged to 7 different sequence types (STs) and phylogroups. S Typhimurium and K. pneumoniae isolates belonged to ST34 and ST307, respectively. The mcr-1 gene was plasmid borne in all isolates but two E. coli isolates which harbored it on the chromosome. Conjugation of mcr-1 was successful in 8 of 10 isolates (8.2 * 10-5 to 2.07 * 10-1 cell per recipient). Plasmid sequences showed that the mcr-1 plasmids belonged to four different Inc groups (a new IncP-1 variant and the IncFII, IncHI1, and IncH families). Our results indicate that mcr-1 is circulating in clinical isolates of colistin-resistant Enterobacteriaceae in Colombia and is mainly harbored in transferable plasmids. PMID- 28893789 TI - Gemini Cationic Amphiphiles Control Biofilm Formation by Bacterial Vaginosis Pathogens. AB - Antibiotic resistance and recurrence of bacterial vaginosis (BV), a polymicrobial infection, justify the need for novel antimicrobials to counteract microbial resistance to conventional antibiotics. Previously, two series of cationic amphiphiles (CAms) which self-assemble into supramolecular nanostructures with membrane-lytic properties were designed with hydrophilic head groups and nonpolar domains. The combination of CAms and commonly prescribed antibiotics is suggested as a promising strategy for targeting microorganisms that are resistant to conventional antibiotics. Activities of the CAms against Gardnerella vaginalis ATCC 14018, a representative BV pathogen, ranged from 1.1 to 24.4 MUM. Interestingly, the tested healthy Lactobacillus species, especially Lactobacillus plantarum ATCC 39268, were significantly more tolerant of CAms than the selected pathogens. In addition, CAms prevented biofilm formation at concentrations which did not influence the normal growth ability of G. vaginalis ATCC 14018. Furthermore, the biofilm minimum bactericidal concentration (MBC-Bs) of CAms against G. vaginalis ATCC 14018 ranged from 58.8 to 425.6 MUM, while much higher concentrations (>=850 MUM) were required to produce >=3-log reductions in the number of biofilm-associated lactobacilli. The conventional antibiotic metronidazole synergized strongly with all tested CAms against planktonic cells and biofilms of G. vaginalis ATCC 14018. The synergism between CAms and the tested conventional antibiotic may be considered a new, effective, and beneficial method of controlling biofilm-associated bacterial vaginosis. PMID- 28893790 TI - Combinatorial CRISPR-Cas9 and RNA Interference Attack on HIV-1 DNA and RNA Can Lead to Cross-Resistance. AB - Many potent antiviral drugs have been developed against HIV-1, and their combined action is usually successful in achieving durable virus suppression in infected individuals. This success is based on two effects: additive or even synergistic virus inhibition and an increase in the genetic threshold for development of drug resistance. More recently, several genetic approaches have been developed to attack the HIV-1 genome in a gene therapy setting. We set out to test the combinatorial possibilities for a therapy based on the CRISPR-Cas9 and RNA interference (RNAi) mechanisms that attack the viral DNA and RNA, respectively. When two different sites in the HIV-1 genome were targeted, either with dual CRISPR-Cas9 antivirals or with a combination of CRISPR-Cas9 and RNAi antivirals, we observed additive inhibition, much like what was reported for antiviral drugs. However, when the same or overlapping viral sequence was attacked by the antivirals, rapid escape from a CRISPR-Cas9 antiviral, assisted by the error prone nonhomologous end joining (NHEJ) DNA repair machinery, accelerated the development of cross-resistance to the other CRISPR-Cas9 or RNAi antiviral. Thus, genetic antiviral approaches can be combined, but overlap should be avoided. PMID- 28893791 TI - Development and Validation of a High-Resolution Melting Assay To Detect Azole Resistance in Aspergillus fumigatus. AB - The global emergence of azole-resistant Aspergillus fumigatus strains is a growing public health concern. Different patterns of azole resistance are linked to mutations in cyp51A Therefore, accurate characterization of the mechanisms underlying azole resistance is critical to guide selection of the most appropriate antifungal agent for patients with aspergillosis. This study describes a new sequencing-free molecular screening tool for early detection of the most frequent mutations known to be associated with azole resistance in A. fumigatus PCRs targeting cyp51A mutations at positions G54, Y121, G448, and M220 and targeting different tandem repeats (TRs) in the promoter region were designed. All PCRs were performed simultaneously, using the same cycling conditions. Amplicons were then distinguished using a high-resolution melting assay. For standardization, 30 well-characterized azole-resistant A. fumigatus strains were used, yielding melting curve clusters for different resistance mechanisms for each target and allowing detection of the most frequent azole resistance mutations, i.e., G54E, G54V, G54R, G54W, Y121F, M220V, M220I, M220T, M220K, and G448S, and the tandem repeats TR34, TR46, and TR53 Validation of the method was performed using a blind panel of 80 A. fumigatus azole-susceptible or azole-resistant strains. All strains included in the blind panel were properly classified as susceptible or resistant with the developed method. The implementation of this screening method can reduce the time needed for the detection of azole-resistant A. fumigatus isolates and therefore facilitate selection of the best antifungal therapy in patients with aspergillosis. PMID- 28893792 TI - Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients. AB - Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], -0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter). PMID- 28893796 TI - Letter by Mewton and Croisille Regarding Article, "Identification of High-Risk Patients After ST-Segment-Elevation Myocardial Infarction: Comparison Between Angiographic and Magnetic Resonance Parameters". PMID- 28893793 TI - Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis. AB - Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in Mycobacterium tuberculosis, we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action. This screen identified the M. tuberculosis cell envelope to be a major determinant of antibiotic susceptibility but did not yield mutants whose increase in susceptibility was due to transposon insertions in genes encoding efflux pumps. Intrinsic antibiotic resistance determinants affecting resistance to multiple antibiotics included the peptidoglycan arabinogalactan ligase Lcp1, the mycolic acid synthase MmaA4, the protein translocase SecA2, the mannosyltransferase PimE, the cell envelope-associated protease CaeA/Hip1, and FecB, a putative iron dicitrate-binding protein. Characterization of a deletion mutant confirmed FecB to be involved in the intrinsic resistance to every antibiotic analyzed. In contrast to its predicted function, FecB was dispensable for growth in low-iron medium and instead functioned as a critical mediator of envelope integrity. PMID- 28893795 TI - Serial 3-Vessel Optical Coherence Tomography and Intravascular Ultrasound Analysis of Changing Morphologies Associated With Lesion Progression in Patients With Stable Angina Pectoris. AB - BACKGROUND: Optical coherence tomographic (OCT) morphologies associated with lesion progression are not well studied. The aim of this study was to determine the morphological change for untreated lesion progression using both OCT and intravascular ultrasound (IVUS). METHODS AND RESULTS: We used baseline and 8 month follow-up 3-vessel OCT and IVUS to assess 127 nonculprit lesions (IVUS plaque burden >=40%) in 45 patients with stable angina after target lesion treatment. Lesion progression was defined as an IVUS lumen area decrease >0.5 mm2. A layered pattern was identified as a superficial layer that had a different optical intensity and a clear demarcation from underlying plaque. Lesion progression was observed in 19% (24/127) lesions, and its pattern was characterized into 3 types: type I, new superficial layered pattern at follow-up that was not present at baseline (n=9); type II, a layered pattern at baseline whose layer thickness increased at follow-up (n=7); or type III, no layered pattern at baseline or follow-up (n=8). The increase of IVUS plaque+media area was largest in type I and least in type III (1.9 mm2 [1.6-2.1], 1.1 mm2 [0.9 1.4], and 0.3 mm2 [-0.2 to 0.8], respectively; P=0.002). Type III, but not types I or II, showed negative remodeling during follow-up (IVUS vessel area; from 14.3 mm2 [11.4-17.2] to 13.5 mm2 [10.4-16.7]; P=0.02). OCT lipidic plaque was associated with lesion progression (odds ratio, 13.6; 95% confidence interval, 3.7-50.6; P<0.001). CONCLUSIONS: Lesion progression was categorized to distinct OCT morphologies that were related to changes in plaque mass or vessel remodeling. PMID- 28893797 TI - Response by Durante and Camici to Letter Regarding Article, "Identification of High-Risk Patients After ST-Segment-Elevation Myocardial Infarction: Comparison Between Angiographic and Magnetic Resonance Parameters". PMID- 28893794 TI - Effects of HIV-1 Tat and Methamphetamine on Blood-Brain Barrier Integrity and Function In Vitro. AB - Human immunodeficiency (HIV) infection results in neurocognitive deficits in about one half of infected individuals. Despite systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting central nervous system (CNS)-localized infection. Drug abuse exacerbates HIV-induced cognitive and pathological CNS changes. This study's purpose was to investigate the effects of the HIV-1 protein Tat and methamphetamine on factors affecting drug penetration across an in vitro BBB model. Factors affecting paracellular and transcellular flux in the presence of Tat and methamphetamine were examined. Transendothelial electrical resistance, ZO 1 expression, and lucifer yellow (a paracellular tracer) flux were aspects of paracellular processes that were examined. Additionally, effects on P glycoprotein (P-gp) and multidrug resistance protein 1 (MRP-1) mRNA (via quantitative PCR [qPCR]) and protein (via immunoblotting) expression were measured; Pgp and MRP-1 are drug efflux proteins. Transporter function was examined after exposure of Tat with or without methamphetamine using the P-gp substrate rhodamine 123 and also using the dual P-gp/MRP-1 substrate and protease inhibitor atazanavir. Tat and methamphetamine elicit complex changes affecting transcellular and paracellular transport processes. Neither Tat nor methamphetamine significantly altered P-gp expression. However, Tat plus methamphetamine exposure significantly increased rhodamine 123 accumulation within brain endothelial cells, suggesting that treatment inhibited or impaired P gp function. Intracellular accumulation of atazanavir was not significantly altered after Tat or methamphetamine exposure. Atazanavir accumulation was, however, significantly increased by simultaneous inhibition of P-gp and MRP. Collectively, our investigations indicate that Tat and methamphetamine alter aspects of BBB integrity without affecting net flux of paracellular compounds. Tat and methamphetamine may also affect several aspects of transcellular transport. PMID- 28893798 TI - Letter by Saito Regarding Article, "Visual and Quantitative Assessment of Coronary Stenoses at Angiography Versus Fractional Flow Reserve: The Impact of Risk Factors". PMID- 28893799 TI - Plaque Progression: Slow Linear or Rapid Stepwise? PMID- 28893800 TI - VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. AB - Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivoVHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2alpha-HIF1beta heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2alpha and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305. (c)2017 AACR.See related commentary by Ricketts and Linehan, p. 1221This article is highlighted in the In This Issue feature, p. 1201. PMID- 28893802 TI - Successful ultrasound-guided drainage of an intra-abdominal collection in late pregnancy. AB - Pregnancy complicated by an intra-abdominal collection is uncommon and poses a challenge in the management. We present a case that illustrates successful treatment via ultrasound-guided drainage of a collection associated with a dermoid cyst in a 30 weeks pregnant patient presenting with fever and right-sided abdominal pain. Following treatment, the patient clinically improved rapidly. The drain was removed 3 days later and a repeat ultrasound scan showed no collection. PMID- 28893801 TI - Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers. AB - Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin alphavbeta3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting alphavbeta3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate alphavbeta3-expressing KRAS mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS addicted lung and pancreas cancers, and indicates integrin alphavbeta3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin alphavbeta3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin alphavbeta3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1355. PMID- 28893803 TI - Pure red cell aplasia and myasthenia gravis: a patient having both autoimmune conditions in the absence of thymoma. AB - This is a patient who was presented initially with symptoms of malaise, tiredness and exertional dyspnoea and found to have a severe normocytic normochromic anaemia with low reticulocyte counts. Bone marrow confirmed the diagnosis of pure red cell aplasia (PRCA) and at the time serology for recent parvovirus infection was positive. He was successfully treated with transfusions and intravenous Ig. Six years later, he had a mild relapse of his PRCA and subsequently developed severe dysphagia and dysarthria which were fatigable. Positive antiacetylcholine receptor antibodies confirmed the diagnosis of myasthenia gravis. The two conditions are both known to be associated with thymoma. Imaging and resection of the thymus gland showed only the presence of a thymic cyst. Treatment with pyrdistogmine and intravenous Ig have kept the patient asymptomatic and in remission. The rare association of the two autoimmune conditions associated in the same patient without thymoma is discussed. PMID- 28893804 TI - Immune thrombocytopenic purpura associated with fingolimod. AB - Fingolimod is an oral sphingosine-1-phosphate receptor modulator which causes lymphocyte sequestration in lymph nodes and is approved for relapsing multiple sclerosis. The Therapeutic Goods Administration of Australia is aware of only one case where fingolimod preceded immune thrombocytopenic purpura (ITP) by 5 weeks. Here we report three such cases.None were on any medications known to cause ITP and routine investigations were unremarkable. All cases were treated with immunosuppression. Case 1 successfully weaned prednisolone after fingolimod cessation whereas case 2 weaned slowly while continuing fingolimod therapy. Case 3 had more refractory ITP and re-exposure to fingolimod worsened thrombocytopenia.There was a temporal association between fingolimod exposure and ITP however dose-effect association and pathogenesis remain less clear.In conclusion, our cases highlight that clinicians should be aware of the possible association between ITP and fingolimod. PMID- 28893805 TI - MELAS syndrome associated with a new mitochondrial tRNA-Val gene mutation (m.1616A>G). AB - We describe the case of a 40-year-old-man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, with cardiomyopathy and severe heart failure. He had a mitochondrial transfer RNA (tRNA) mutation (m.1616A>G) of the (tRNA-Val) gene, and it was not found in MELAS syndrome ever before. The presence of this newly observed tRNA-Val mutation (m.1616A>G) may induce multiple respiratory chain enzyme deficiencies and contribute to MELAS syndrome symptoms that are associated with mitochondrial DNA (mtDNA) mutations. We report that the pathognomonic symptom in MELAS syndrome caused by this newly observed mtDNA mutation may be rapid progression of cardiomyopathy and severe heart failure. PMID- 28893806 TI - Low-dose intrapleural alteplase (without deoxyribonuclease) in complicated parapneumonic effusion: case series and literature reviews. AB - This case series reviews two cases of elderly patients who presented with fever, cough and shortness of breath. Clinical examinations and initial chest radiographs confirmed unilateral pleural effusion. Thoracenteses were consistent with exudative pleural effusion. We commenced intravenous antibiotics treating for parapneumonic effusions. The first case showed persistent effusion despite drainage, and the second case had a little aspirate from pleural tapping. Subsequent ultrasound of the thorax showed multiloculated effusions. We made the decisions for intrapleural fibrinolytic therapy using low-dose alteplase 2.5 mg each time, in view of the elderly patient as sacrosanct for risk of bleeding. Furthermore, DNase was not used, as it is not yet available in our setting. Both of our patients had good clinical and radiological outcomes, without the need for surgical interventions. PMID- 28893807 TI - Neostigmine and glycopyrronium: a potential safe alternative for patients with pseudo-obstruction without access to conventional methods of decompression. AB - Intestinal pseudo-obstruction mimics bowel obstruction. However, on examination, no mechanical cause is identified. This condition will often resolve when managed conservatively, yet in some cases decompression is required to avoid the serious complications of bowel ischaemia and perforation. This is performed endoscopically, and due to the invasive nature and limited access to this service, an alternative treatment option is deemed appealing. Neostigmine has good efficacy in the decompression of pseudo-obstruction but is hindered by its wide side effect profile. In this context, neostigmine requires careful monitoring, which limits its appeal. This side effect profile is minimised when neostigmine is administered in conjunction with glycopyrronium.This case demonstrates the novel use of neostigmine and glycopyrronium in decompression of the bowel in a patient with pseudo-obstruction. Furthermore, it highlights its value, particularly when conventional techniques for decompression are not accessible. PMID- 28893808 TI - Clinical Population Medicine: Integrating Clinical Medicine and Population Health in Practice. PMID- 28893809 TI - From Authority- to Evidence-Based Medicine: Are Clinical Practice Guidelines Moving us Forward or Backward? PMID- 28893810 TI - Developing a Clinician Friendly Tool to Identify Useful Clinical Practice Guidelines: G-TRUST. AB - BACKGROUND: Clinicians are faced with a plethora of guidelines. To rate guidelines, they can select from a number of evaluation tools, most of which are long and difficult to apply. The goal of this project was to develop a simple, easy-to-use checklist for clinicians to use to identify trustworthy, relevant, and useful practice guidelines, the Guideline Trustworthiness, Relevance, and Utility Scoring Tool (G-TRUST). METHODS: A modified Delphi process was used to obtain consensus of experts and guideline developers regarding a checklist of items and their relative impact on guideline quality. We conducted 4 rounds of sampling to refine wording, add and subtract items, and develop a scoring system. Multiple attribute utility analysis was used to develop a weighted utility score for each item to determine scoring. RESULTS: Twenty-two experts in evidence-based medicine, 17 developers of high-quality guidelines, and 1 consumer representative participated. In rounds 1 and 2, items were rewritten or dropped, and 2 items were added. In round 3, weighted scores were calculated from rankings and relative weights assigned by the expert panel. In the last round, more than 75% of experts indicated 3 of the 8 checklist items to be major indicators of guideline usefulness and, using the AGREE tool as a reference standard, a scoring system was developed to identify guidelines as useful, may not be useful, and not useful. CONCLUSION: The 8-item G-TRUST is potentially helpful as a tool for clinicians to identify useful guidelines. Further research will focus on its reliability when used by clinicians. PMID- 28893811 TI - Tethered to the EHR: Primary Care Physician Workload Assessment Using EHR Event Log Data and Time-Motion Observations. AB - PURPOSE: Primary care physicians spend nearly 2 hours on electronic health record (EHR) tasks per hour of direct patient care. Demand for non-face-to-face care, such as communication through a patient portal and administrative tasks, is increasing and contributing to burnout. The goal of this study was to assess time allocated by primary care physicians within the EHR as indicated by EHR user event log data, both during clinic hours (defined as 8:00 am to 6:00 pm Monday through Friday) and outside clinic hours. METHODS: We conducted a retrospective cohort study of 142 family medicine physicians in a single system in southern Wisconsin. All Epic (Epic Systems Corporation) EHR interactions were captured from "event logging" records over a 3-year period for both direct patient care and non-face-to-face activities, and were validated by direct observation. EHR events were assigned to 1 of 15 EHR task categories and allocated to either during or after clinic hours. RESULTS: Clinicians spent 355 minutes (5.9 hours) of an 11.4-hour workday in the EHR per weekday per 1.0 clinical full-time equivalent: 269 minutes (4.5 hours) during clinic hours and 86 minutes (1.4 hours) after clinic hours. Clerical and administrative tasks including documentation, order entry, billing and coding, and system security accounted for nearly one-half of the total EHR time (157 minutes, 44.2%). Inbox management accounted for another 85 minutes (23.7%). CONCLUSIONS: Primary care physicians spend more than one-half of their workday, nearly 6 hours, interacting with the EHR during and after clinic hours. EHR event logs can identify areas of EHR related work that could be delegated, thus reducing workload, improving professional satisfaction, and decreasing burnout. Direct time-motion observations validated EHR-event log data as a reliable source of information regarding clinician time allocation. PMID- 28893812 TI - Impact of Scribes on Physician Satisfaction, Patient Satisfaction, and Charting Efficiency: A Randomized Controlled Trial. AB - PURPOSE: Scribes are increasingly being used in clinical practice despite a lack of high-quality evidence regarding their effects. Our objective was to evaluate the effect of medical scribes on physician satisfaction, patient satisfaction, and charting efficiency. METHODS: We conducted a randomized controlled trial in which physicians in an academic family medicine clinic were randomized to 1 week with a scribe then 1 week without a scribe for the course of 1 year. Scribes drafted all relevant documentation, which was reviewed by the physician before attestation and signing. In encounters without a scribe, the physician performed all charting duties. Our outcomes were physician satisfaction, measured by a 5 item instrument that included physicians' perceptions of chart quality and chart accuracy; patient satisfaction, measured by a 6-item instrument; and charting efficiency, measured by time to chart close. RESULTS: Scribes improved all aspects of physician satisfaction, including overall satisfaction with clinic (OR = 10.75), having enough face time with patients (OR = 3.71), time spent charting (OR = 86.09), chart quality (OR = 7.25), and chart accuracy (OR = 4.61) (all P values <.001). Scribes had no effect on patient satisfaction. Scribes increased the proportion of charts that were closed within 48 hours (OR =1.18, P =.028). CONCLUSIONS: To our knowledge, we have conducted the first randomized controlled trial of scribes. We found that scribes produced significant improvements in overall physician satisfaction, satisfaction with chart quality and accuracy, and charting efficiency without detracting from patient satisfaction. Scribes appear to be a promising strategy to improve health care efficiency and reduce physician burnout. PMID- 28893813 TI - Uninsured Primary Care Visit Disparities Under the Affordable Care Act. AB - PURPOSE: Health insurance coverage affects a patient's ability to access optimal care, the percentage of insured patients on a clinic's panel has an impact on the clinic's ability to provide needed health care services, and there are racial and ethnic disparities in coverage in the United States. Thus, we aimed to assess changes in insurance coverage at community health center (CHC) visits after the Patient Protection and Affordable Care Act (ACA) Medicaid expansion by race and ethnicity. METHODS: We undertook a retrospective, observational study of visit payment type for CHC patients aged 19 to 64 years. We used electronic health record data from 10 states that expanded Medicaid and 6 states that did not, 359 CHCs, and 870,319 patients with more than 4 million visits. Our analyses included difference-in-difference (DD) and difference-in-difference-in-difference (DDD) estimates via generalized estimating equation models. The primary outcome was health insurance type at each visit (Medicaid-insured, uninsured, or privately insured). RESULTS: After the ACA was implemented, uninsured visit rates decreased for all racial and ethnic groups. Hispanic patients experienced the greatest increases in Medicaid-insured visit rates after ACA implementation in expansion states (rate ratio [RR] = 1.77; 95% CI, 1.56-2.02) and the largest gains in privately insured visit rates in nonexpansion states (RR = 3.63; 95% CI, 2.73 4.83). In expansion states, non-Hispanic white patients had twice the magnitude of decrease in uninsured visits compared with Hispanic patients (DD = 2.03; 95% CI, 1.53-2.70), and this relative change was more than 2 times greater in expansion states compared with nonexpansion states (DDD = 2.06; 95% CI, 1.52 2.78). CONCLUSION: The lower rates of uninsured visits for all racial and ethnic groups after ACA implementation suggest progress in expanding coverage to CHC patients; this progress, however, was not uniform when comparing expansion with nonexpansion states and among all racial and ethnic minority subgroups. These findings suggest the need for continued and more equitable insurance expansion efforts to eliminate health insurance disparities. PMID- 28893814 TI - Physician Support of Smoking Cessation After Diagnosis of Lung, Bladder, or Upper Aerodigestive Tract Cancer. AB - PURPOSE: Smoking cessation after a diagnosis of lung, bladder, and upper aerodigestive tract cancer appears to improve survival, and support to quit would improve cessation. The aims of this study were to assess how often general practitioners provide active smoking cessation support for these patients and whether physician behavior is influenced by incentive payments. METHODS: Using electronic primary care records from the UK Clinical Practice Research Datalink, 12,393 patients with incident cases of cancer diagnosed between 1999 and 2013 were matched 1 to 1 to patients with incident cases of coronary heart disease (CHD) diagnosed during the same time. We assessed differences in the proportion for whom physicians updated smoking status, advised quitting, and prescribed cessation medications, as well as the proportion of patients who stopped smoking within a year of diagnosis. We further examined whether any differences arose because the physicians were offered incentives to address smoking in patients with CHD and not cancer. RESULTS: At diagnosis, 32.0% of patients with cancer and 18.2% of patients with CHD smoked tobacco. Patients with cancer were less likely than patients with CHD to have their general practitioners update smoking status (OR = 0.18; 95% CI, 0.17-0.19), advise quitting (OR = 0.38; 95% CI, 0.36-0.40), or prescribe medication (OR = 0.67; 95% CI, 0.63-0.73), and they were less likely to have stopped smoking (OR = 0.76; 95% CI, 0.69-0.84). One year later 61.7% of patients with cancer and 55.4% with CHD who were smoking at diagnosis were still smoking. Introducing incentive payments was associated with more frequent interventions, but not for patients with CHD specifically. CONCLUSIONS: General practitioners were less likely to support smoking cessation in patients with cancer than with CHD, and patients with cancer were less likely to stop smoking. This finding is not due to the difference in incentive payments. PMID- 28893815 TI - Risk Stratification Methods and Provision of Care Management Services in Comprehensive Primary Care Initiative Practices. AB - PURPOSE: Risk-stratified care management is essential to improving population health in primary care settings, but evidence is limited on the type of risk stratification method and its association with care management services. METHODS: We describe risk stratification patterns and association with care management services for primary care practices in the Comprehensive Primary Care (CPC) initiative. We undertook a qualitative approach to categorize risk stratification methods being used by CPC practices and tested whether these stratification methods were associated with delivery of care management services. RESULTS: CPC practices reported using 4 primary methods to stratify risk for their patient populations: a practice-developed algorithm (n = 215), the American Academy of Family Physicians' clinical algorithm (n = 155), payer claims and electronic health records (n = 62), and clinical intuition (n = 52). CPC practices using practice-developed algorithm identified the most number of high-risk patients per primary care physician (282 patients, P = .006). CPC practices using clinical intuition had the most high-risk patients in care management and a greater proportion of high-risk patients receiving care management per primary care physician (91 patients and 48%, P =.036 and P =.128, respectively). CONCLUSIONS: CPC practices used 4 primary methods to identify high-risk patients. Although practices that developed their own algorithm identified the greatest number of high-risk patients, practices that used clinical intuition connected the greatest proportion of patients to care management services. PMID- 28893816 TI - Nature of Blame in Patient Safety Incident Reports: Mixed Methods Analysis of a National Database. AB - PURPOSE: A culture of blame and fear of retribution are recognized barriers to reporting patient safety incidents. The extent of blame attribution in safety incident reports, which may reflect the underlying safety culture of health care systems, is unknown. This study set out to explore the nature of blame in family practice safety incident reports. METHODS: We characterized a random sample of family practice patient safety incident reports from the England and Wales National Reporting and Learning System. Reports were analyzed according to prespecified classification systems to describe the incident type, contributory factors, outcomes, and severity of harm. We developed a taxonomy of blame attribution, and we then used descriptive statistical analyses to identify the proportions of blame types and to explore associations between incident characteristics and one type of blame. RESULTS: Health care professionals making family practice incident reports attributed blame to a person in 45% of cases (n = 975 of 2,148; 95% CI, 43%-47%). In 36% of cases, those who reported the incidents attributed fault to another person, whereas 2% of those reporting acknowledged personal responsibility. Blame was commonly associated with incidents where a complaint was anticipated. CONCLUSIONS: The high frequency of blame in these safety, incident reports may reflect a health care culture that leads to blame and retribution, rather than to identifying areas for learning and improvement, and a failure to appreciate the contribution of system factors in others' behavior. Successful improvement in patient safety through the analysis of incident reports is unlikely without achieving a blame-free culture. PMID- 28893817 TI - Preventable Emergency Hospital Admissions Among Adults With Intellectual Disability in England. AB - PURPOSE: Adults with intellectual disabilities experience poorer physical health and health care quality, but there is limited information on the potential for reducing emergency hospital admissions in this population. We describe overall and preventable emergency admissions for adults with vs without intellectual disabilities in England and assess differences in primary care management before admission for 2 common ambulatory care-sensitive conditions (ACSCs). METHODS: We used electronic records to study a cohort of 16,666 adults with intellectual disabilities and 113,562 age-, sex-, and practice-matched adults without intellectual disabilities from 343 English family practices. Incident rate ratios (IRRs) from conditional Poisson regression were analyzed for all emergency and preventable emergency admissions. Primary care management of lower respiratory tract infections and urinary tract infections, as exemplar ACSCs, before admission were compared in unmatched analysis between adults with and without intellectual disabilities. RESULTS: The overall rate for emergency admissions for adults with vs without intellectual disabilities was 182 vs 68 per 1,000 per year (IRR = 2.82; 95% CI, 2.66-2.98). ACSCs accounted for 33.7% of emergency admissions among the former compared with 17.3% among the latter (IRR = 5.62; 95% CI, 5.14-6.13); adjusting for comorbidity, smoking, and deprivation did not fully explain the difference (IRR = 3.60; 95% CI, 3.25-3.99). Although adults with intellectual disability were at nearly 5 times higher risk for admission for lower respiratory tract infections and urinary tract infections, they had similar primary care use, investigation, and management before admission as the general population. CONCLUSIONS: Adults with intellectual disabilities are at high risk for preventable emergency admissions. Identifying strategies for better detecting and managing ACSCs, including lower respiratory and urinary tract infections, in primary care could reduce hospitalizations. PMID- 28893818 TI - Health Care Disparities of Ohioans With Developmental Disabilities Across the Lifespan. AB - We explored health care differences across the lifespan comparing people with developmental disabilities to people without developmental disabilities. Health care disparities are inequities occurring during the provision of and in access to health care that are experienced by socially disadvantaged populations. We discovered significant disparities between persons with and without developmental disabilities in health status, quality, utilization, access, and unmet health care needs. Our results highlight the need to educate health care clinicians on the care of patients with developmental disabilities of all ages. PMID- 28893819 TI - Agriculture and Health Sectors Collaborate in Addressing Population Health. AB - PURPOSE: Population health is of growing importance in the changing health care environment. The Cooperative Extension Service, housed in each state's land grant university, has a major impact on population health through its many community based efforts, including the Supplemental Nutrition Assistance Program - Education (SNAP-Ed) nutrition programs, 4-H youth engagement, health and wellness education, and community development. Can the agricultural and health sectors, which usually operate in parallel, mostly unknown to each other, collaborate to address population health? We set out to provide an overview of the collaboration between the Cooperative Extension Service and the health sector in various states and describe a case study of 1 model as it developed in New Mexico. METHODS: We conducted a literature review and personally contacted states in which the Cooperative Extension Service is collaborating on a "Health Extension" model with academic health centers or their health systems. We surveyed 6 states in which Health Extension models are being piloted as to their different approaches. For a case study of collaboration in New Mexico, we drew on interviews with the leadership of New Mexico State University's Cooperative Extension Service in the College of Agricultural, Consumer and Environmental Sciences; the University of New Mexico (UNM) Health Science Center's Office for Community Health; and the personal experiences of frontline Cooperative Extension agents and UNM Health Extension officers who collaborated on community projects. RESULTS: A growing number of states are linking the agricultural Cooperative Extension Service with academic health centers and with the health care system. In New Mexico, the UNM academic health center has created "Health Extension Rural Offices" based on principles of the Cooperative Extension model. Today, these 2 systems are working collaboratively to address unmet population health needs in their communities. Nationally, the Cooperative Extension Service has formed a steering committee to guide its movement into the health arena. CONCLUSION: Resources of the agricultural and health sectors offer communities complementary expertise and resources to address adverse population health outcomes. The collaboration between Cooperative Extension and the health sector is 1 manifestation of this emerging collaboration model termed Health Extension. Initial skepticism and protection of funding sources and leadership roles can be overcome with shared funding from new sources, shared priority setting and decision making, and the initiation of practical, collaborative projects that build personal relationships and trust. PMID- 28893820 TI - Providing Office-Based Treatment of Opioid Use Disorder. PMID- 28893821 TI - Fall Prevention: Empowering People Through Online Education. PMID- 28893829 TI - A brief history of post-truth in medicine. PMID- 28893830 TI - Assessment of paravalvular leakage after transcatheter aortic valve implantation: add clinical signs to echocardiographic data. PMID- 28893832 TI - Multidisciplinary Clinic to Identify Near Misses and Decrease Readmission Rates After Hospitalization for Myocardial Infarction. PMID- 28893833 TI - Anticoagulation for Nonvalvular Atrial Fibrillation: Influence of Epidemiologic Trends and Clinical Practice Patterns on Risk Stratification and Net Clinical Benefit. PMID- 28893831 TI - Patient and Physician Perspectives on Public Reporting of Mortality Ratings for Percutaneous Coronary Intervention in New York State. AB - BACKGROUND: Public reporting of physician-specific outcome data for procedures, such as percutaneous coronary intervention (PCI), can influence physicians to avoid high-risk patients who may benefit from treatment. Prior physician attitudes toward public scorecards in New York State (NYS) have been studied, but the exclusion criteria have evolved. Additionally, patient perceptions toward such reports remain poorly understood. This study evaluates (1) whether exclusion of certain high-risk patients from public reporting of PCI outcomes in NYS has influenced physician attitudes, (2) current patient awareness and use of publicly reported outcome data, and (3) differences in physician and patient attitudes toward public reporting. METHODS AND RESULTS: A questionnaire was administered to interventional cardiologists in NYS with specific emphasis on how modifications in publicly reported outcome data have influenced their practice. The results were compared with a 2003 survey administered by our group. A separate questionnaire regarding the publicly available NYS PCI Report was administered to patients referred to our center for possible PCI. The majority of interventional cardiologists indicated that the exclusion of patients with anoxic brain injury and refractory cardiogenic shock from public reporting has made them more likely to perform PCI for these subgroups. While patient awareness of the NYS PCI Report was low, patients were significantly more likely than physicians to think that publication of physician-specific mortality data can provide an accurate measure of physician quality, serve to improve patient care, and provide useful information in terms of physician selection. CONCLUSIONS: The study provides further evidence that public reporting of physician-specific outcome data influences physician behavior and indicates that significant discrepancies exist in how scorecards are perceived by physicians versus patients. PMID- 28893834 TI - Public Reporting of Percutaneous Coronary Intervention Mortality in New York State: Are We Helping Our Patients? PMID- 28893835 TI - Genomic basis of atrial fibrillation. AB - Atrial fibrillation (AF) is a prevalent arrhythmia associated with substantial morbidity, mortality and costs. Available management strategies generally have limited efficacy and are associated with potential adverse effects. In part, the limited efficacy of approaches to managing AF reflect an incomplete understanding of the biological mechanisms underlying the arrhythmia, and only a partial understanding of how best to individualise management. Over the last several decades, a greater understanding of genome biology has led to recognition of a widespread genetic susceptibility to AF. Through genome-wide association studies, at least 30 genetic loci have been identified in association with AF, most of which implicate mechanisms not previously appreciated to be involved in the development of AF. We now recognise that AF is a polygenic condition, yet a great deal of work lies ahead to better understand the precise mechanisms by which genomic variation causes AF. Understanding the genetic basis of AF could provide a better understanding of AF mechanisms and cardiovascular biology, inform the management of patients through risk-guided approaches and facilitate the development of novel therapeutics. PMID- 28893836 TI - Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way. AB - Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged. PMID- 28893838 TI - Biology of Bone: The Vasculature of the Skeletal System. AB - Blood vessels are essential for the distribution of oxygen, nutrients, and immune cells, as well as the removal of waste products. In addition to this conventional role as a versatile conduit system, the endothelial cells forming the innermost layer of the vessel wall also possess important signaling capabilities and can control growth, patterning, homeostasis, and regeneration of the surrounding organ. In the skeletal system, blood vessels regulate developmental and regenerative bone formation as well as hematopoiesis by providing vascular niches for hematopoietic stem cells. Here we provide an overview of blood vessel architecture, growth and properties in the healthy, aging, and diseased skeletal system. PMID- 28893837 TI - Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs in the Porphyromonas gingivalis CRISPR-Cas I-C System. AB - The CRISPR-Cas (clustered regularly interspaced short palindromic repeat-CRISPR associated protein) system is unique to prokaryotes and provides the majority of bacteria and archaea with immunity against nucleic acids of foreign origin. CRISPR RNAs (crRNAs) are the key element of this system, since they are responsible for its selectivity and effectiveness. Typical crRNAs consist of a spacer sequence flanked with 5' and 3' handles originating from repeat sequences that are important for recognition of these small RNAs by the Cas machinery. In this investigation, we studied the type I-C CRISPR-Cas system in Porphyromonas gingivalis, a human pathogen associated with periodontitis, rheumatoid arthritis, cardiovascular disease, and aspiration pneumonia. We demonstrated the importance of the 5' handle for crRNA recognition by the effector complex and consequently activity, as well as secondary trimming of the 3' handle, which was not affected by modifications of the repeat sequence.IMPORTANCEPorphyromonas gingivalis, a clinically relevant Gram-negative, anaerobic bacterium, is one of the major etiologic agents of periodontitis and has been linked with the development of other clinical conditions, including rheumatoid arthritis, cardiovascular disease, and aspiration pneumonia. The presented results on the biogenesis and functions of crRNAs expand our understanding of CRISPR-Cas cellular defenses in P. gingivalis and of horizontal gene transfer in bacteria. PMID- 28893840 TI - The monoplastidic bottleneck in algae and plant evolution. AB - Plastids in plants and algae evolved from the endosymbiotic integration of a cyanobacterium by a heterotrophic eukaryote. New plastids can only emerge through fission; thus, the synchronization of bacterial division with the cell cycle of the eukaryotic host was vital to the origin of phototrophic eukaryotes. Most of the sampled algae house a single plastid per cell and basal-branching relatives of polyplastidic lineages are all monoplastidic, as are some non-vascular plants during certain stages of their life cycle. In this Review, we discuss recent advances in our understanding of the molecular components necessary for plastid division, including those of the peptidoglycan wall (of which remnants were recently identified in moss), in a wide range of phototrophic eukaryotes. Our comparison of the phenotype of 131 species harbouring plastids of either primary or secondary origin uncovers that one prerequisite for an algae or plant to house multiple plastids per nucleus appears to be the loss of the bacterial genes minD and minE from the plastid genome. The presence of a single plastid whose division is coupled to host cytokinesis was a prerequisite of plastid emergence. An escape from such a monoplastidic bottleneck succeeded rarely and appears to be coupled to the evolution of additional layers of control over plastid division and a complex morphology. The existence of a quality control checkpoint of plastid transmission remains to be demonstrated and is tied to understanding the monoplastidic bottleneck. PMID- 28893839 TI - Mitochondrial fission facilitates the selective mitophagy of protein aggregates. AB - Within the mitochondrial matrix, protein aggregation activates the mitochondrial unfolded protein response and PINK1-Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates protein aggregates from within mitochondria and the role of mitochondrial fission in mitophagy. We show that PINK1 recruits Parkin onto mitochondrial subdomains after actinonin-induced mitochondrial proteotoxicity and that PINK1 recruits Parkin proximal to focal misfolded aggregates of the mitochondrial-localized mutant ornithine transcarbamylase (DeltaOTC). Parkin colocalizes on polarized mitochondria harboring misfolded proteins in foci with ubiquitin, optineurin, and LC3. Although inhibiting Drp1-mediated mitochondrial fission suppresses the segregation of mitochondrial subdomains containing DeltaOTC, it does not decrease the rate of DeltaOTC clearance. Instead, loss of Drp1 enhances the recruitment of Parkin to fused mitochondrial networks and the rate of mitophagy as well as decreases the selectivity for DeltaOTC during mitophagy. These results are consistent with a new model that, instead of promoting mitophagy, fission protects healthy mitochondrial domains from elimination by unchecked PINK1-Parkin activity. PMID- 28893841 TI - Endogenous signalling pathways and caged IP3 evoke Ca2+ puffs at the same abundant immobile intracellular sites. AB - The building blocks of intracellular Ca2+ signals evoked by inositol 1,4,5 trisphosphate receptors (IP3Rs) are Ca2+ puffs, transient focal increases in Ca2+ concentration that reflect the opening of small clusters of IP3Rs. We use total internal reflection fluorescence microscopy and automated analyses to detect Ca2+ puffs evoked by photolysis of caged IP3 or activation of endogenous muscarinic receptors with carbachol in human embryonic kidney 293 cells. Ca2+ puffs evoked by carbachol initiated at an estimated 65+/-7 sites/cell, and the sites remained immobile for many minutes. Photolysis of caged IP3 evoked Ca2+ puffs at a similar number of sites (100+/-35). Increasing the carbachol concentration increased the frequency of Ca2+ puffs without unmasking additional Ca2+ release sites. By measuring responses to sequential stimulation with carbachol or photolysed caged IP3, we established that the two stimuli evoked Ca2+ puffs at the same sites. We conclude that IP3-evoked Ca2+ puffs initiate at numerous immobile sites and the sites become more likely to fire as the IP3 concentration increases; there is no evidence that endogenous signalling pathways selectively deliver IP3 to specific sites. PMID- 28893842 TI - HDL structure and function is profoundly affected when stored frozen in the absence of cryoprotectants. AB - Analysis of structural and functional parameters of HDL has gained significant momentum in recent years because they are stronger predictors of cardiovascular risk than HDL-cholesterol levels. Surprisingly, in most HDL studies, very low attention is paid to HDL storage, which might critically affect functional properties. In the present study, we systematically examined the impact of storage and freezing on the structural/functional properties of freshly isolated HDL. Initial damage to HDL starts between week 1 and week 4 of storage. We observed that prolonged freezing at -20 degrees C or -70 degrees C led to a shedding of apoA-I from HDL and to the formation of large protein-poor particles, indicating that HDL is irreversibly disrupted. These structural alterations profoundly affected key metrics of HDL function, including HDL-cholesterol efflux capacity and HDL paraoxonase activity. Flash-freezing of isolated HDL prior to storage at -70 degrees C did not preserve HDL structure. However, addition of the cryoprotectants, sucrose or glycerol, completely preserved structure and function of HDL when stored for at least 2 years. Our data clearly indicate that HDL is a complex particle requiring special attention when stored. Addition of cryoprotectants to isolated HDL samples before storage will make biochemical and clinical HDL research studies more reproducible and comparable. PMID- 28893843 TI - Timing of Angiography and Outcomes in High-Risk Patients With Non-ST-Segment Elevation Myocardial Infarction Managed Invasively: Insights From the TAO Trial (Treatment of Acute Coronary Syndrome With Otamixaban). AB - BACKGROUND: In patients with non-ST-segment-elevation myocardial infarction (NSTEMI) and GRACE (Global Registry of Acute Coronary Events) score >140, coronary angiography (CAG) is recommended by European and American guidelines within 24 hours. We sought to study the association of very early (ie, <=12 hours), early (12-24 hours), and delayed (>24 hours) CAG in patients with NSTEMI with GRACE score >140 with ischemic outcomes. METHODS: The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with NSTEMI and CAG scheduled within 72 hours to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with a GRACE score >140 were categorized into 3 groups according to timing of CAG from admission (<12, >=12-<24, and >=24 hours). The primary ischemic outcome was the composite of all-cause death and myocardial infarction within 180 days of randomization. RESULTS: CAG was performed in 4071 patients (<12 hours, n=1648 [40.5%]; 12-24 hours, n=1420 [34.9%]; >=24 hours, n=1003 [24.6%]). With CAG >=24 hours as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio, 0.96; 95% confidence interval, 0.75-1.23), whereas CAG <12 hours was associated with a lower risk of death and myocardial infarction (odds ratio, 0.71; 95% confidence interval, 0.55-0.91). Performing CAG <12 hours was also associated with a lower risk of death and myocardial infarction (odds ratio, 0.76; 95% confidence interval, 0.61-0.94; P=0.01) compared with CAG performed at 12 to 24 hours. No difference was observed in bleeding complications. CONCLUSIONS: In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12-24 or >=24 hours) was associated with lower risk of ischemic outcomes at 180 days. PMID- 28893844 TI - Accuracy and predictive value of incarcerated adults' accounts of their self-harm histories: findings froman Australian prospective data linkage study. AB - BACKGROUND: Self-harm is prevalent in prison populations and is a well established risk factor for suicide. Researchers typically rely on self-report to measure self-harm, yet the accuracy and predictive value of self-report in prison populations is unclear. Using a large, representative sample of incarcerated men and women, we aimed to examine the level of agreement between self-reported self harm history and historical medical records, and investigate the association between self-harm history and medically verified self-harm after release from prison. METHODS: During confidential interviews with 1315 adults conducted within 6 weeks of expected release from 1 of 7 prisons in Queensland, Australia, participants were asked about the occurrence of lifetime self-harm. Responses were compared with prison medical records and linked both retrospectively and prospectively with ambulance, emergency department and hospital records to identify instances of medically verified self-harm. Follow-up interviews roughly 1, 3 and 6 months after release covered the same domains assessed in the baseline interview as well as self-reported criminal activity and contact with health care, social and criminal justice services since release. RESULTS: Agreement between self-reported and medically verified history of self-harm was poor, with 64 (37.6%) of 170 participants with a history of medically verified self-harm disclosing a history of self-harm at baseline. Participants with a medically verified history of self-harm were more likely than other participants to self harm during the follow-up period. Compared to the unconfirmed-negative group, the true-positive (adjusted hazard ratio [HR] 6.2 [95% confidence interval (CI) 3.3 10.4]), false-negative (adjusted HR 4.0 [95% CI 2.2-6.7]) and unconfirmed positive (adjusted HR 2.2 [95% CI 1.2-3.9]) groups were at increased risk for self-harm after release from prison. INTERPRETATION: Self-reported history of self-harm should not be considered a sensitive indicator of prior self-harm or of future self-harm risk in incarcerated adults. To identify those who should be targeted for preventive strategies, triangulation of data from multiple verifiable sources should be performed whenever possible. PMID- 28893845 TI - Highly Efficient, Rapid and Co-CRISPR-Independent Genome Editing in Caenorhabditis elegans. AB - We describe a rapid and highly efficient method to generate point mutations in Caenorhabditis elegans using direct injection of CRISPR-Cas9 ribonucleoproteins. This versatile method does not require sensitized genetic backgrounds or co CRISPR selection-based methods, and represents a single strategy that can be used for creating genomic point mutations, regardless of location. As proof of principle, we show that knock-in mutants more faithfully report variant associated phenotypes as compared to transgenic overexpression. Data for nine knock-in mutants across five genes are presented that demonstrate high editing efficiencies (60%), a reduced screening workload (24 F1 progeny), and a rapid timescale (4-5 d). This optimized method simplifies genome engineering and is readily adaptable to other model systems. PMID- 28893847 TI - France to prosecute its drug regulator and Servier in scandal over diabetes drug. PMID- 28893846 TI - Comparison of Single Genome and Allele Frequency Data Reveals Discordant Demographic Histories. AB - Inference of demographic history from genetic data is a primary goal of population genetics of model and nonmodel organisms. Whole genome-based approaches such as the pairwise/multiple sequentially Markovian coalescent methods use genomic data from one to four individuals to infer the demographic history of an entire population, while site frequency spectrum (SFS)-based methods use the distribution of allele frequencies in a sample to reconstruct the same historical events. Although both methods are extensively used in empirical studies and perform well on data simulated under simple models, there have been only limited comparisons of them in more complex and realistic settings. Here we use published demographic models based on data from three human populations (Yoruba, descendants of northwest-Europeans, and Han Chinese) as an empirical test case to study the behavior of both inference procedures. We find that several of the demographic histories inferred by the whole genome-based methods do not predict the genome-wide distribution of heterozygosity, nor do they predict the empirical SFS. However, using simulated data, we also find that the whole genome methods can reconstruct the complex demographic models inferred by SFS-based methods, suggesting that the discordant patterns of genetic variation are not attributable to a lack of statistical power, but may reflect unmodeled complexities in the underlying demography. More generally, our findings indicate that demographic inference from a small number of genomes, routine in genomic studies of nonmodel organisms, should be interpreted cautiously, as these models cannot recapitulate other summaries of the data. PMID- 28893848 TI - A review of 10 years of scapula injuries sustained by UK military personnel on operations. AB - BACKGROUND: Scapula fractures are relatively uncommon injuries, mostly occurring due to the effects of high-energy trauma. Rates of scapula fractures are unknown in the military setting. The aim of this study is to analyse the incidence, aetiology, associated injuries, treatment and complications of these fractures occurring in deployed military personnel. METHODS: All UK military personnel returning with upper limb injuries from Afghanistan and Iraq were retrospectively reviewed using the Royal Centre for Defence Medicine database and case notes (2004-2014). RESULTS: Forty-four scapula fractures out of 572 upper limb fractures (7.7%) were sustained over 10 years. Blast and gunshot wounds (GSW) were leading causative factors in 85%. Over half were open fractures (54%), with open blast fractures often having significant bone and soft tissue loss requiring extensive reconstruction. Multiple injuries were noted including lung, head, vascular and nerve injuries. Injury Severity Scores (ISS) were significantly higher than the average upper limb injury without a scapula fracture (p<0.0001). Brachial plexus injuries occurred in 17%. While military personnel with GSW have a favourable chance of nerve recovery, 75% of brachial plexus injuries that are associated with blast have poorer outcomes. Fixation occurred with either glenoid fractures or floating shoulders (10%); these were as a result of high velocity GSW or mounted blast ejections. There were no cases of deep soft tissue infection or osteomyelitis and all scapula fractures united. CONCLUSION: Scapula fractures have a 20 times higher incidence in military personnel compared with the civilian population, occurring predominantly as a result of blast and GSW, and a higher than average ISS. These fractures are often associated with multiple injuries, including brachial plexus injuries, where those sustained from blast have less favourable outcome. High rates of union following fixation and low rates of infection are expected despite significant contamination and soft tissue loss. PMID- 28893849 TI - Handoffs: what's good for residents is good for nurses...so what's next? PMID- 28893850 TI - Age Legislation and Off-Road Vehicle Injuries in Children. AB - BACKGROUND AND OBJECTIVES: In 2010, the Massachusetts Legislature passed a comprehensive law that restricted off-road vehicle (ORV) use by children <14 years old and regulated ORV use by children up to the age of 18 years. We aimed to examine the impact of the 2010 Massachusetts law on the rates of ORV-related injuries. METHODS: A retrospective analysis was performed of Massachusetts emergency department (ED) and inpatient discharges between 2002 and 2013 as found in the Center for Health Information and Analysis database by using external causes of injury codes specific to ORV-related injuries. Yearly population-based rates were compared before and after the implementation of the law (2002-2010 vs 2011-2013) by using Poisson regression analysis and segmented regression. RESULTS: There were 3638 ED discharges and 481 inpatient discharges for ORV related injuries in children across the 12-year study period. After the implementation of the law, the rate of ED discharges declined by 33% in 0- to 9 year-olds, 50% in 10- to 13-year-olds, and 39% in 14 to 17-year-olds (P < .0001). There was no significant decline in ED discharges for 25- to 34-year-olds. Inpatient hospital discharges were also reduced by 41% in 0- to 17-year-olds after implementation (P < .001). CONCLUSIONS: As compared with adults (ages 25-34 years), the population-based ORV-related injury rate of residents <18 years old significantly declined after the passage of legislation that imposed age restrictions and other safeguards for youth riders. PMID- 28893851 TI - Synthetic Cannabinoid Use Among High School Seniors. AB - OBJECTIVES: In this study, we examined the prevalence and correlates of current synthetic cannabinoid (SC) use among high school seniors in the United States. METHODS: Monitoring the Future, an annual nationally representative survey of high school seniors, began querying current (30-day) SC use in 2014. Data were examined from the 2 most recent cohorts (2014-2015; N = 7805). Prevalence of self reported use was examined and differences in demographics and recency and frequency of other drug use was compared between current marijuana-only users and current SC (plus marijuana) users using chi2 and generalized linear model using Poisson. RESULTS: We found that 2.9% of students reported current SC use; 1.4% of students (49.7% of users) reported using SCs on >=3 days in the past month. SC users were more likely to report more recent (and often more frequent) use of lysergic acid diethylamide, cocaine, heroin, and/or nonmedical use of opioids compared with marijuana-only users. Compared with current marijuana-only users, SC users were more likely to report lower parent education (P < .05) and current use of a higher number of illegal drugs other than marijuana (Ps < .001). Students using SCs >=10 times in the past month were more likely to be boys, frequent marijuana users (Ps < .01), African American, and users of multiple other illegal drugs (Ps < .001). CONCLUSIONS: SC use is typically part of a repertoire of polydrug use, and polydrug use is less prevalent among marijuana only users. Current SC users are at risk for poisoning from use of the newest generation of SCs and from concurrent drug use. PMID- 28893853 TI - A Powerful Framework for Integrating eQTL and GWAS Summary Data. AB - Two new gene-based association analysis methods, called PrediXcan and TWAS for GWAS individual-level and summary data, respectively, were recently proposed to integrate GWAS with eQTL data, alleviating two common problems in GWAS by boosting statistical power and facilitating biological interpretation of GWAS discoveries. Based on a novel reformulation of PrediXcan and TWAS, we propose a more powerful gene-based association test to integrate single set or multiple sets of eQTL data with GWAS individual-level data or summary statistics. The proposed test was applied to several GWAS datasets, including two lipid summary association datasets based on [Formula: see text] and [Formula: see text] samples, respectively, and uncovered more known or novel trait-associated genes, showcasing much improved performance of our proposed method. The software implementing the proposed method is freely available as an R package. PMID- 28893852 TI - Changes in Gene Expression in Space and Time Orchestrate Environmentally Mediated Shaping of Root Architecture. AB - Shaping of root architecture is a quintessential developmental response that involves the concerted action of many different cell types, is highly dynamic, and underpins root plasticity. To determine to what extent the environmental regulation of lateral root development is a product of cell-type preferential activities, we tracked transcriptomic responses to two different treatments that both change root development in Arabidopsis thaliana at an unprecedented level of temporal detail. We found that individual transcripts are expressed with a very high degree of temporal and spatial specificity, yet biological processes are commonly regulated, in a mechanism we term response nonredundancy. Using causative gene network inference to compare the genes regulated in different cell types and during responses to nitrogen and a biotic interaction, we found that common transcriptional modules often regulate the same gene families but control different individual members of these families, specific to response and cell type. This reinforces that the activity of a gene cannot be defined simply as molecular function; rather, it is a consequence of spatial location, expression timing, and environmental responsiveness. PMID- 28893854 TI - Will Big Data Close the Missing Heritability Gap? AB - Despite the important discoveries reported by genome-wide association (GWA) studies, for most traits and diseases the prediction R-squared (R-sq.) achieved with genetic scores remains considerably lower than the trait heritability. Modern biobanks will soon deliver unprecedentedly large biomedical data sets: Will the advent of big data close the gap between the trait heritability and the proportion of variance that can be explained by a genomic predictor? We addressed this question using Bayesian methods and a data analysis approach that produces a surface response relating prediction R-sq. with sample size and model complexity (e.g., number of SNPs). We applied the methodology to data from the interim release of the UK Biobank. Focusing on human height as a model trait and using 80,000 records for model training, we achieved a prediction R-sq. in testing (n = 22,221) of 0.24 (95% C.I.: 0.23-0.25). Our estimates show that prediction R-sq. increases with sample size, reaching an estimated plateau at values that ranged from 0.1 to 0.37 for models using 500 and 50,000 (GWA-selected) SNPs, respectively. Soon much larger data sets will become available. Using the estimated surface response, we forecast that larger sample sizes will lead to further improvements in prediction R-sq. We conclude that big data will lead to a substantial reduction of the gap between trait heritability and the proportion of interindividual differences that can be explained with a genomic predictor. However, even with the power of big data, for complex traits we anticipate that the gap between prediction R-sq. and trait heritability will not be fully closed. PMID- 28893855 TI - Mitigating Mitochondrial Genome Erosion Without Recombination. AB - Mitochondria are ATP-producing organelles of bacterial ancestry that played a key role in the origin and early evolution of complex eukaryotic cells. Most modern eukaryotes transmit mitochondrial genes uniparentally, often without recombination among genetically divergent organelles. While this asymmetric inheritance maintains the efficacy of purifying selection at the level of the cell, the absence of recombination could also make the genome susceptible to Muller's ratchet. How mitochondria escape this irreversible defect accumulation is a fundamental unsolved question. Occasional paternal leakage could in principle promote recombination, but it would also compromise the purifying selection benefits of uniparental inheritance. We assess this tradeoff using a stochastic population-genetic model. In the absence of recombination, uniparental inheritance of freely-segregating genomes mitigates mutational erosion, while paternal leakage exacerbates the ratchet effect. Mitochondrial fusion-fission cycles ensure independent genome segregation, improving purifying selection. Paternal leakage provides opportunity for recombination to slow down the mutation accumulation, but always at a cost of increased steady-state mutation load. Our findings indicate that random segregation of mitochondrial genomes under uniparental inheritance can effectively combat the mutational meltdown, and that homologous recombination under paternal leakage might not be needed. PMID- 28893857 TI - Changes in dynamic lung mechanics after lung volume reduction coil treatment of severe emphysema. AB - We assessed the relationships between changes in lung compliance, lung volumes and dynamic hyperinflation in patients with emphysema who underwent bronchoscopic treatment with nitinol coils (coil treatment) (n=11) or received usual care (UC) (n=11). Compared with UC, coil treatment resulted in decreased dynamic lung compliance (CLdyn) (p=0.03) and increased endurance time (p=0.010). The change in CLdyn was associated with significant improvement in FEV1 and FVC, with reduction in residual volume and intrinsic positive end-expiratory pressure, and with increased inspiratory capacity at rest/and at exercise. The increase in end expiratory lung volume (EELV) during exercise (EELVdyn-ch=EELVisotime EELVrest) demonstrated significant attenuation after coil treatment (p=0.02). PMID- 28893858 TI - Signaling by Small GTPases at Cell-Cell Junctions: Protein Interactions Building Control and Networks. AB - A number of interesting reports highlight the intricate network of signaling proteins that coordinate formation and maintenance of cell-cell contacts. We have much yet to learn about how the in vitro binding data is translated into protein association inside the cells and whether such interaction modulates the signaling properties of the protein. What emerges from recent studies is the importance to carefully consider small GTPase activation in the context of where its activation occurs, which upstream regulators are involved in the activation/inactivation cycle and the GTPase interacting partners that determine the intracellular niche and extent of signaling. Data discussed here unravel unparalleled cooperation and coordination of functions among GTPases and their regulators in supporting strong adhesion between cells. PMID- 28893856 TI - Distinct and Cooperative Roles of amh and dmrt1 in Self-Renewal and Differentiation of Male Germ Cells in Zebrafish. AB - Spermatogenesis is a fundamental process in male reproductive biology and depends on precise balance between self-renewal and differentiation of male germ cells. However, the regulative factors for controlling the balance are poorly understood. In this study, we examined the roles of amh and dmrt1 in male germ cell development by generating their mutants with Crispr/Cas9 technology in zebrafish. Amh mutant zebrafish displayed a female-biased sex ratio, and both male and female amh mutants developed hypertrophic gonads due to uncontrolled proliferation and impaired differentiation of germ cells. A large number of proliferating spermatogonium-like cells were observed within testicular lobules of the amh-mutated testes, and they were demonstrated to be both Vasa- and PH3 positive. Moreover, the average number of Sycp3- and Vasa-positive cells in the amh mutants was significantly lower than in wild-type testes, suggesting a severely impaired differentiation of male germ cells. Conversely, all the dmrt1 mutated testes displayed severe testicular developmental defects and gradual loss of all Vasa-positive germ cells by inhibiting their self-renewal and inducing apoptosis. In addition, several germ cell and Sertoli cell marker genes were significantly downregulated, whereas a prominent increase of Insl3-positive Leydig cells was revealed by immunohistochemical analysis in the disorganized dmrt1-mutated testes. Our data suggest that amh might act as a guardian to control the balance between proliferation and differentiation of male germ cells, whereas dmrt1 might be required for the maintenance, self-renewal, and differentiation of male germ cells. Significantly, this study unravels novel functions of amh gene in fish. PMID- 28893859 TI - Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. AB - Cadherin-based adherens junctions (AJs) and desmosomes are crucial to couple intercellular adhesion to the actin or intermediate filament cytoskeletons, respectively. As such, these intercellular junctions are essential to provide not only integrity to epithelia and other tissues but also the mechanical machinery necessary to execute complex morphogenetic and homeostatic intercellular rearrangements. Moreover, these spatially defined junctions serve as signaling hubs that integrate mechanical and chemical pathways to coordinate tissue architecture with behavior. This review takes an evolutionary perspective on how the emergence of these two essential intercellular junctions at key points during the evolution of multicellular animals afforded metazoans with new opportunities to integrate adhesion, cytoskeletal dynamics, and signaling. We discuss known literature on cross-talk between the two junctions and, using the skin epidermis as an example, provide a model for how these two junctions function in concert to orchestrate tissue organization and function. PMID- 28893860 TI - Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior. AB - Specialized groups of neurons in the brain are key mediators of circadian rhythms, receiving daily environmental cues and communicating those signals to other tissues in the organism for entrainment and to organize circadian physiology. In Drosophila, the "circadian clock" is housed in seven neuronal clusters, which are defined by their expression of the main circadian proteins, Period, Timeless, Clock, and Cycle. These clusters are distributed across the fly brain and are thereby subject to the respective environments associated with their anatomical locations. While these core components are universally expressed in all neurons of the circadian network, additional regulatory proteins that act on these components are differentially expressed, giving rise to "local clocks" within the network that nonetheless converge to regulate coherent behavioral rhythms. In this review, we describe the communication between the neurons of the circadian network and the molecular differences within neurons of this network. We focus on differences in protein-expression patterns and discuss how such variation can impart functional differences in each local clock. Finally, we summarize our current understanding of how communication within the circadian network intersects with intracellular biochemical mechanisms to ultimately specify behavioral rhythms. We propose that additional efforts are required to identify regulatory mechanisms within each neuronal cluster to understand the molecular basis of circadian behavior. PMID- 28893861 TI - Adrenal venous sampling for primary aldosteronism: laboratory medicine best practice. AB - Primary aldosteronism (PA) is the most common form of secondary hypertension and is critical to identify because when caused by an aldosterone-producing adenoma (APA) or another unilateral form, it is potentially curable, and even when caused by bilateral disease, antihypertensives more specific to PA treatment can be employed (ie, aldosterone antagonists). Identification of unilateral forms is not generally accomplished with imaging because APAs may be small and elude detection, and coincidental identification of a non-functioning incidentaloma contralateral to an APA may lead to removal of an incorrect gland. For this reason, the method of choice for identifying unilateral forms of PA is selective adrenal venous sampling (AVS) followed by aldosterone and cortisol analysis on collected samples. This procedure is technically difficult from a radiological standpoint and, from the laboratory perspective, is fraught with opportunities for preanalytical, analytical and postanalytical error. We review the process of AVS collection, analysis and reporting. Suggestions are made for patient preparation, specimen labelling practices and nomenclature, analytical dilution protocols, which numerical results to report, and the necessary subsequent calculations. We also identify and explain frequent sources of confusion in the aldosterone and cortisol results and provide an example of tabular reporting to facilitate interpretation and communication between laboratorian, radiologist and clinician. PMID- 28893862 TI - Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification. AB - AIMS: To assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options. METHODS: We evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed. RESULTS: Hypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022). CONCLUSION: There are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC. PMID- 28893863 TI - Bin1 directly remodels actin dynamics through its BAR domain. AB - Endocytic processes are facilitated by both curvature-generating BAR-domain proteins and the coordinated polymerization of actin filaments. Under physiological conditions, the N-BAR protein Bin1 has been shown to sense and curve membranes in a variety of cellular processes. Recent studies have identified Bin1 as a risk factor for Alzheimer's disease, although its possible pathological function in neurodegeneration is currently unknown. Here, we report that Bin1 not only shapes membranes, but is also directly involved in actin binding through its BAR domain. We observed a moderate actin bundling activity by human Bin1 and describe its ability to stabilize actin filaments against depolymerization. Moreover, Bin1 is also involved in stabilizing tau-induced actin bundles, which are neuropathological hallmarks of Alzheimer's disease. We also provide evidence for this effect in vivo, where we observed that downregulation of Bin1 in a Drosophila model of tauopathy significantly reduces the appearance of tau-induced actin inclusions. Together, these findings reveal the ability of Bin1 to modify actin dynamics and provide a possible mechanistic connection between Bin1 and tau-induced pathobiological changes of the actin cytoskeleton. PMID- 28893864 TI - The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing. AB - Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model. PMID- 28893866 TI - Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a devastating disease characterised by occlusive pulmonary vasculopathy. Activation of bone morphogenetic protein receptor 2 (BMPR2) signalling by FK506 (tacrolimus) reverses occlusive vasculopathy in rodent PAH models. Here, we determined the safety and tolerability of low-level FK506 therapy in stable PAH patients.We performed a randomised, double-blind, placebo-controlled, 16-week, single-centre, phase IIa trial in PAH patients with New York Heart Association functional class II/III symptoms using three FK506 target levels (<2, 2-3 and 3-5 ng.mL-1). 23 patients were randomised and 20 patients completed the trial.FK506 was generally well tolerated, with nausea/diarrhoea being the most commonly reported adverse event and no observation of line infections in patients on intravenous prostacyclin therapy. PAH patients had significantly lower BMPR2 expression in peripheral blood mononuclear cells versus healthy controls (n=13; p=0.005), which improved after FK506 treatment. While we observed that some patients responded with a pronounced increase in BMPR2 expression as well as improvement in 6-min walk distance, and serological and echocardiographic parameters of heart failure, these changes were not significant.Low-level FK506 is well tolerated and increases BMPR2 in subsets of PAH patients. These results support the study of FK506 in a phase IIb efficacy trial. PMID- 28893867 TI - Mechanistic insight into the function of the microbiome in lung diseases. AB - The lung harbours a diverse array of microbes whose dynamic composition is influenced by both host and environmental factors. Thus far, most studies have described the microbial composition of healthy or diseased lungs and provided an overview of the differences between topographical locations within the respiratory tract. However, insight into the functional mechanisms underlying host-microbe interactions and how they might drive lung health and disease are limited. This review provides an overview of the current mechanistic understanding of the microbiome, crosstalk between tissue compartments, and its involvement in respiratory diseases. PMID- 28893865 TI - ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation. AB - OBJECTIVES: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. DESIGN: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. RESULTS: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54+/ 18/100 enterocytes in CD and 13+/-8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. CONCLUSION: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence. PMID- 28893868 TI - Official ERS technical standards: Global Lung Function Initiative reference values for the carbon monoxide transfer factor for Caucasians. AB - There are numerous reference equations available for the single-breath transfer factor of the lung for carbon monoxide (T LCO); however, it is not always clear which reference set should be used in clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for T LCOData from 19 centres in 14 countries were collected to define T LCO reference values. Similar to the GLI spirometry project, reference values were derived using the LMS (lambda, mu, sigma) method and the GAMLSS (generalised additive models for location, scale and shape) programme in R.12 660 T LCO measurements from asymptomatic, lifetime nonsmokers were submitted; 85% of the submitted data were from Caucasians. All data were uncorrected for haemoglobin concentration. Following adjustments for elevation above sea level, gas concentration and assumptions used for calculating the anatomic dead space volume, there was a high degree of overlap between the datasets. Reference values for Caucasians aged 5-85 years were derived for T LCO, transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative T LCO data, and the first global reference values available for T LCO. PMID- 28893870 TI - Do community demographics, environmental characteristics and access to care affect risks of developing ACOS and mortality in people with asthma? PMID- 28893871 TI - Neither genotyping nor contact tracing allow correct understanding of multidrug resistant tuberculosis transmission. PMID- 28893869 TI - The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. AB - The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung abnormalities (ILA) in white participants from the general population; whether these findings are replicated and influenced by the ILA subtype is not known. We evaluated the associations between the MUC5B genotype and ILA in cohorts with extensive imaging characterisation.We performed ILA phenotyping and MUC5B promoter genotyping in 5308 and 9292 participants from the AGES-Reykjavik and COPDGene cohorts, respectively.We found that ILA was present in 7% of participants from the AGES-Reykjavik, 8% of non-Hispanic white participants from COPDGene and 7% of African-American participants from COPDGene. Although the MUC5B genotype was strongly associated (after correction for multiple testing) with ILA (OR 2.1, 95% CI 1.8-2.4, p=1*10-26), there was evidence of significant heterogeneity between cohorts (I2=81%). When narrowed to specific radiologic subtypes, (e.g. subpleural ILA), the MUC5B genotype remained strongly associated (OR 2.6, 95% CI 2.2-3.1, p=1*10-30) with minimal heterogeneity (I2=0%). Although there was no evidence that the MUC5B genotype influenced survival, there was evidence that MUC5B genotype improved risk prediction for possible usual interstitial pneumonia (UIP) or a UIP pattern in non-Hispanic white populations.The MUC5B promoter polymorphism is strongly associated with ILA and specific radiologic subtypes of ILA, with varying degrees of heterogeneity in the underlying populations. PMID- 28893872 TI - Targeting bone morphogenic protein receptor 2 (BMPR2) signalling to treat pulmonary arterial hypertension. PMID- 28893873 TI - Sepsis, one of CMAJ's four new areas of focus. PMID- 28893874 TI - The quadruple burden of sepsis. PMID- 28893875 TI - Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial. AB - BACKGROUND: Intravenous zoledronate 5 mg annually reduces fracture risk, and 5 mg every 2 years prevents bone loss, but the optimal dosing regimens for these indications are uncertain. METHODS: We conducted a 3-year open-label extension of a 2-year randomized, placebo-controlled, double-blind study. Late postmenopausal women with osteopenia were assigned to receive a single baseline dose of 1 mg, 2.5 mg or 5 mg of zoledronate or placebo. The primary outcome was change in spine bone mineral density (BMD). Secondary outcomes were changes in hip BMD and serum markers of bone turnover. RESULTS: The study involved 160 women. Zoledronate increased BMD and reduced markers of bone turnover in a dose-dependent manner. After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased spine BMD over placebo by 5.0% (95% confidence interval [CI] 3.0% to 7.0%), 5.7% (95% CI 3.7% to 7.7%) and 5.7% (95% CI 3.7% to 7.6%), respectively; after 5 years, the respective increases were 2.0% (95% CI -1.1% to 5.0%), 2.2% (95% CI -1.0% to 5.4%) and 5.1% (95% CI 2.2% to 8.1%). After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased total hip BMD over placebo by 2.6% (95% CI 1.3% to 3.9%), 4.1% (95% CI 2.9% to 5.4%) and 4.7% (95% CI 3.4% to 5.9%), respectively; after 5 years, the respective increases were 1.8% (95% CI -0.1% to 3.8%), 2.8% (95% CI 0.8% to 4.8%) and 5.4% (95% CI 3.5% to 7.3%). BMD remained above baseline values for 2-3 years in the 1-mg group, 3-4 years in the 2.5-mg group and at least 5 years in the 5-mg group. INTERPRETATION: The antiresorptive activity of single zoledronate doses of 1-5 mg persist for at least 3 years in postmenopausal women with osteopenia. Clinical trials would be justified to evaluate the effects on fracture risk of less frequent or lower doses of zoledronate than are currently recommended. TRIAL REGISTRATION: www.anzctr.org.au, no. ACTRN12607000576426. PMID- 28893876 TI - Recommendations on screening for abdominal aortic aneurysm in primary care. PMID- 28893877 TI - Superimposed lateralized exanthem in a 30-year-old woman. PMID- 28893878 TI - Canadian hepatitis C virus screening guideline: a disconnect between evidence and recommendations. PMID- 28893879 TI - Extrapolation warning. PMID- 28893880 TI - How physicians can "flex their advocacy muscles". PMID- 28893881 TI - CMA votes for review of medical liability system. PMID- 28893882 TI - Harm reduction is about providing safety for patients. PMID- 28893883 TI - CMA's new mission and vision statements rankle some members. PMID- 28893884 TI - Doctors and health funding must focus on most vulnerable: Philpott. PMID- 28893885 TI - Physicians debate tax reforms at CMA annual meeting. PMID- 28893886 TI - Doctors dissect medicine's bullying problem. PMID- 28893887 TI - Doctors should buckle up for health reforms: Barrette. PMID- 28893888 TI - Focus on patients, the rest will follow, says new CMA pres. PMID- 28893889 TI - Lively debate on disability insurance for medical students at CMA meeting. PMID- 28893890 TI - Healthier doctors means healthier patients: CMA president-elect. PMID- 28893891 TI - Health leaders must share the reins of reform: outgoing CMA pres. PMID- 28893892 TI - CMA must address physician burnout, pharmacare, say doctors. PMID- 28893893 TI - Physicians support assisted death for mature minors, but not mental illness. PMID- 28893894 TI - Fees for medical liability protection decrease in populous regions. PMID- 28893895 TI - All Hypertensive Disorders of Pregnancy Increase the Risk of Future Cardiovascular Disease. AB - Hypertensive disorders of pregnancy are associated with vascular dysfunction in the pregnancy and an increased risk of long-term cardiovascular disease (CVD) in the mother. What remains to be understood is whether the length, severity of the disease, the treatment of hypertension in pregnancy, or the subtype of hypertensive disorders of pregnancy are significant predictors of future CVD. We undertook a retrospective cohort study to review all women who gave birth at a tertiary hospital in Sydney between the years 1980 and 1989 (n=31 656). A cohort of women was further defined by having hypertension during the antenatal, intrapartum, or postnatal periods (n=4387). Randomly selected records of women (n=1158) with a hypertensive disorder of pregnancy were individually reviewed to collect data on their pregnancy and pregnancy outcomes. The entire cohort then underwent linkage analysis to future CVDs. Women who presented with gestational hypertension were at greater risk of future hypertension and ischemic heart disease compared with the women who were diagnosed with preeclampsia. There was no significant difference between the women who were treated with antihypertensive medication and the women who did not receive antihypertensive medication or the duration of hypertensive disorders of pregnancy and future admission for CVD, although severity of hypertension tracked with increased risk of future hypertension in all groups. This study demonstrated that all women who present with any of the subtypes of hypertensive disorders in pregnancy are at significant risk of future CVD compared with women who remain normotensive during their pregnancy. PMID- 28893896 TI - Sildenafil During Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure. AB - Sildenafil is a new approach to treat fetal growth restriction (FGR) and preeclampsia. We performed a systematic meta-analysis to evaluate effects of sildenafil. Our search identified 22 animal studies (mouse, rat, rabbit, sheep, and guinea pigs) and 2 human randomized controlled trials. Data were pooled using ratio of means and mean differences with 95% confidence intervals for fetal growth and maternal blood pressure, respectively. Meta-regression analyses were performed for study-related factors that might affect efficacy of sildenafil, including the model used (healthy pregnancy versus FGR/preeclampsia) and route of administration. Dose-response curves with dose per metabolic weight (mg/kg0.75 per 24 hours) were fitted using splines. Our analyses show that sildenafil increases fetal growth during FGR/preeclampsia pregnancy compared with healthy pregnancy (1.10 [1.06-1.13] versus 1.03 [0.99-1.06]; P=0.006). There was no significant effect on fetal growth in the absence of FGR/preeclampsia. Effects were similar among different species and largest after oral and continuous administration. There was a positive relation between dose and fetal growth up to a human equivalent dose of ~450 mg/d. A significant blood pressure-lowering effect of sildenafil is present during FGR/preeclampsia pregnancy only (-19 [-25 to -13] mm Hg; P<0.01), with the effect size being highly dependent on baseline blood pressure and without effect in the absence of hypertension. This meta analysis supports that sildenafil improves fetal growth and maternal blood pressure regulation during FGR and preeclampsia pregnancy. The greatest beneficial effects on fetal growth are with dosages greater than those currently used in human studies. PMID- 28893897 TI - Atrial Fibrillation and Hypertension. PMID- 28893898 TI - Left Ventricular Mass, Brain Magnetic Resonance Imaging, and Cognitive Performance: Results From the Strong Heart Study. AB - Left ventricular mass (LVM) has been shown to serve as a measure of target organ damage resulting from chronic exposure to several risk factors. Data on the association of midlife LVM with later cognitive performance are sparse. We studied 721 adults (mean age 56 years at baseline) enrolled in the Strong Heart Study (SHS, 1993-1995) and the ancillary CDCAI (Cerebrovascular Disease and Its Consequences in American Indians) Study (2010-2013), a study population with high prevalence of cardiovascular disease. LVM was assessed with transthoracic echocardiography at baseline in 1993 to 1995. Cranial magnetic resonance imaging and cognitive testing were undertaken between 2010 and 2013. Generalized estimating equations were used to model associations between LVM and later imaging and cognition outcomes. The mean follow-up period was 17 years. A difference of 25 g in higher LVM was associated with marginally lower hippocampal volume (0.01%; 95% confidence interval, 0.02-0.00; P=0.001) and higher white matter grade (0.10; 95% confidence interval, 0.02-0.18; P=0.014). Functionally, participants with higher LVM tended to have slightly lower scores on the modified mini-mental state examination (0.58; 95% confidence interval, 1.08-0.08; P=0.024). The main results persisted after adjusting for blood pressure levels or vascular disease. The small overall effect sizes are partly explained by survival bias because of the high prevalence of cardiovascular disease in our population. Our findings emphasize the role of cardiovascular health in midlife as a target for the prevention of deleterious cognitive and functional outcomes in later life. PMID- 28893899 TI - Impact of Age and Target-Organ Damage on Prognostic Value of 24-Hour Ambulatory Blood Pressure. AB - Markers of target-organ damage and 24-hour ambulatory blood pressure (BP) measurement improve cardiovascular risk stratification. The prevalence of target organ damage and raised BP increases with aging. The study aim was to evaluate the impact of age and target-organ damage on the prognostic value of ambulatory BP. Markers of target-organ damage and ambulatory BP were measured in 1408 healthy people aged 41 or 51 (middle-aged group), and 61 or 71 (older group) years. The primary outcome was cardiovascular events after 16 years of follow-up, with data obtained from national registries. The prognostic value of BP was evaluated with Cox regression models, adjusted for traditional risk factors and target-organ damage, including left ventricular mass, pulse wave velocity, carotid plaques, and urine albumin/creatinine ratio. A total of 323 events were observed. In comparison with traditional risk factors, adding systolic BP and presence of target-organ damage improved risk stratification by increasing concordance index from 0.711 to 0.728 (P=0.01). In middle-aged subjects with target-organ damage, increment in pulse pressure (hazard ratio, 1.70; 95% confidence interval, 1.31-2.21; P<0.01) and increment in average real variability (hazard ratio, 1.29; 95% confidence interval, 1.05-1.59; P=0.02) were associated with a greater risk of cardiovascular disease compared with subjects without target-organ damage: hazard ratio, 1.04 (95% confidence interval, 0.74-1.46; P=0.81); P for interaction, 0.02; and hazard ratio, 0.89 (95% confidence interval, 0.69-1.14; P=0.36); P for interaction, 0.01. Target-organ damage may be a marker of individual susceptibility to the harmful effects of pulse pressure and BP variability on the cardiovascular system in middle-aged individuals. PMID- 28893900 TI - Labetalol Versus Nifedipine as Antihypertensive Treatment for Chronic Hypertension in Pregnancy: A Randomized Controlled Trial. AB - : Data from randomized controlled trials to guide antihypertensive agent choice for chronic hypertension in pregnancy are limited; this study aimed to compare labetalol and nifedipine, additionally assessing the impact of ethnicity on treatment efficacy. Pregnant women with chronic hypertension (12+0-27+6 weeks' gestation) were enrolled at 4 UK centers (August 2014 to October 2015). Open label first-line antihypertensive treatment was randomly assigned: labetalol- (200-1800 mg/d) or nifedipine-modified release (20-80 mg/d). Analysis included 112 women (98%) who completed the study (labetalol n=55, nifedipine n=57). Maximum blood pressure after randomization was 161/101 mm Hg with labetalol versus 163/105 mm Hg with nifedipine (mean difference systolic: 1.2 mm Hg [-4.9 to 7.2 mm Hg], diastolic: 3.3 mm Hg [-0.6 to 7.3 mm Hg]). Mean blood pressure was 134/84 mm Hg with labetalol and 134/85 mm Hg with nifedipine (mean difference systolic: 0.3 mm Hg [-2.8 to 3.4 mm Hg], and diastolic: -1.9 mm Hg [-4.1 to 0.3 mm Hg]). Nifedipine use was associated with a 7.4-mm Hg reduction (-14.4 to -0.4 mm Hg) in central aortic pressure, measured by pulse wave analysis. No difference in treatment effect was observed in black women (n=63), but a mean 4 mm Hg reduction (-6.6 to -0.8 mm Hg; P=0.015) in brachial diastolic blood pressure was observed with labetalol compared with nifedipine in non-black women (n=49). Labetalol and nifedipine control mean blood pressure to target in pregnant women with chronic hypertension. This study provides support for a larger definitive trial scrutinizing the benefits and side effects of first-line antihypertensive treatment. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. Unique identifier: ISRCTN40973936. PMID- 28893901 TI - Expression of PD-L1 in Hormone-naive and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide. AB - Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8+ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.Results: Neo-AAPL treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having >=1% positive tumor cells; P = 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8+ cells (P = 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.Conclusions: A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic. Clin Cancer Res; 23(22); 6812 22. (c)2017 AACR. PMID- 28893902 TI - The cytosolic domain of T-cell receptor zeta associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer. AB - Interactions between lipid bilayers and the membrane-proximal regions of membrane associated proteins play important roles in regulating membrane protein structure and function. The T-cell antigen receptor is an assembly of eight single-pass membrane-spanning subunits on the surface of T lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its zeta-subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events. Interactions of the cytosolic domain of zeta (zetacyt) with acidic lipids have been implicated in the initiation and regulation of transmembrane signaling. zetacyt is unstructured in solution. Interaction with acidic phospholipids induces structure, but its disposition when bound to lipid bilayers is controversial. Here, using surface plasmon resonance and neutron reflection, we characterized the interaction of zetacyt with planar lipid bilayers containing mixtures of acidic and neutral lipids. We observed two binding modes of zetacyt to the bilayers in dynamic equilibrium: one in which zetacyt is peripherally associated with lipid headgroups and one in which it penetrates deeply into the bilayer. Such an equilibrium between the peripherally bound and embedded forms of zetacyt apparently controls accessibility of the immunoreceptor tyrosine-based activation signal transduction pathway. Our results reconcile conflicting findings of the zeta structure reported in previous studies and provide a framework for understanding how lipid interactions regulate motifs to tyrosine kinases and may regulate the T-cell antigen receptor biological activities for this cell-surface receptor system. PMID- 28893903 TI - Estrogen receptor beta-dependent Notch1 activation protects vascular endothelium against tumor necrosis factor alpha (TNFalpha)-induced apoptosis. AB - Unlike age-matched men, premenopausal women benefit from cardiovascular protection. Estrogens protect against apoptosis of endothelial cells (ECs), one of the hallmarks of endothelial dysfunction leading to cardiovascular disorders, but the underlying molecular mechanisms remain poorly understood. The inflammatory cytokine TNFalpha causes EC apoptosis while dysregulating the Notch pathway, a major contributor to EC survival. We have previously reported that 17beta-estradiol (E2) treatment activates Notch signaling in ECs. Here, we sought to assess whether in TNFalpha-induced inflammation Notch is involved in E2 mediated protection of the endothelium. We treated human umbilical vein endothelial cells (HUVECs) with E2, TNFalpha, or both and found that E2 counteracts TNFalpha-induced apoptosis. When Notch1 was inhibited, this E2 mediated protection was not observed, whereas ectopic overexpression of Notch1 diminished TNFalpha-induced apoptosis. Moreover, TNFalpha reduced the levels of active Notch1 protein, which were partially restored by E2 treatment. Moreover, siRNA-mediated knockdown of estrogen receptor beta (ERbeta), but not ERalpha, abolished the effect of E2 on apoptosis. Additionally, the E2-mediated regulation of the levels of active Notch1 was abrogated after silencing ERbeta. In summary, our results indicate that E2 requires active Notch1 through a mechanism involving ERbeta to protect the endothelium in TNFalpha-induced inflammation. These findings could be relevant for assessing the efficacy and applicability of menopausal hormone treatment, because they may indicate that in women with impaired Notch signaling, hormone therapy might not effectively protect the endothelium. PMID- 28893904 TI - Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation. AB - Anthrax is a life-threatening disease caused by infection with Bacillus anthracis, which expresses lethal factor and the receptor-binding protective antigen. These two proteins combine to form anthrax lethal toxin (LT), whose proximal targets are mitogen-activated kinase kinases (MKKs). However, the downstream mediators of LT toxicity remain elusive. Here we report that LT exposure rapidly reduces the levels of c-Jun, a key regulator of cell proliferation and survival. Blockade of proteasome-dependent protein degradation with the 26S proteasome inhibitor MG132 largely restored c-Jun protein levels, suggesting that LT promotes degradation of c-Jun protein. Using the MKK1/2 inhibitor U0126, we further show that MKK1/2-Erk1/2 pathway inactivation similarly reduces c-Jun protein, which was also restored by MG132 pre-exposure. Interestingly, c-Jun protein rebounded to normal levels 4 h following U0126 exposure but not after LT exposure. The restoration of c-Jun in U0126-exposed cells was associated with increased c-Jun mRNA levels and was blocked by inactivation of the JNK1/2 signaling pathway. These results indicate that LT reduces c-Jun both by promoting c-Jun protein degradation via inactivation of MKK1/2-Erk1/2 signaling and by blocking c-Jun gene transcription via inactivation of MKK4-JNK1/2 signaling. In line with the known functions of c-Jun, LT also inhibited cell proliferation. Ectopic expression of LT-resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT-exposed cells, enabling the cells to maintain relatively normal c-Jun protein levels and cell proliferation. Taken together, these findings indicate that LT reduces c-Jun protein levels via two distinct mechanisms, thereby inhibiting critical cell functions, including cellular proliferation. PMID- 28893905 TI - Lysine acetylation stoichiometry and proteomics analyses reveal pathways regulated by sirtuin 1 in human cells. AB - Lysine acetylation is a widespread posttranslational modification affecting many biological pathways. Recent studies indicate that acetylated lysine residues mainly exhibit low acetylation occupancy, but challenges in sample preparation and analysis make it difficult to confidently assign these numbers, limiting understanding of their biological significance. Here, we tested three common sample preparation methods to determine their suitability for assessing acetylation stoichiometry in three human cell lines, identifying the acetylation occupancy in more than 1,300 proteins from each cell line. The stoichiometric analysis in combination with quantitative proteomics also enabled us to explore their functional roles. We found that higher abundance of the deacetylase sirtuin 1 (SIRT1) correlated with lower acetylation occupancy and lower levels of ribosomal proteins, including those involved in ribosome biogenesis and rRNA processing. Treatment with the SIRT1 inhibitor EX-527 confirmed SIRT1's role in the regulation of pre-rRNA synthesis and processing. Specifically, proteins involved in pre-rRNA transcription, including subunits of the polymerase I and SL1 complexes and the RNA polymerase I-specific transcription initiation factor RRN3, were up-regulated after SIRT1 inhibition. Moreover, many protein effectors and regulators of pre-rRNA processing needed for rRNA maturation were also up regulated after EX-527 treatment with the outcome that pre-rRNA and 28S rRNA levels also increased. More generally, we found that SIRT1 inhibition down regulates metabolic pathways, including glycolysis and pyruvate metabolism. Together, these results provide the largest data set thus far of lysine acetylation stoichiometry (available via ProteomeXchange with identifier PXD005903) and set the stage for further biological investigations of this central posttranslational modification. PMID- 28893906 TI - N-terminal splicing extensions of the human MYO1C gene fine-tune the kinetics of the three full-length myosin IC isoforms. AB - The MYO1C gene produces three alternatively spliced isoforms, differing only in their N-terminal regions (NTRs). These isoforms, which exhibit both specific and overlapping nuclear and cytoplasmic functions, have different expression levels and nuclear-cytoplasmic partitioning. To investigate the effect of NTR extensions on the enzymatic behavior of individual isoforms, we overexpressed and purified the three full-length human isoforms from suspension-adapted HEK cells. MYO1CC favored the actomyosin closed state (AMC), MYO1C16 populated the actomyosin open state (AMO) and AMC equally, and MYO1C35 favored the AMO state. Moreover, the full-length constructs isomerized before ADP release, which has not been observed previously in truncated MYO1CC constructs. Furthermore, global numerical simulation analysis predicted that MYO1C35 populated the actomyosin.ADP closed state (AMDC) 5-fold more than the actomyosin.ADP open state (AMDO) and to a greater degree than MYO1CC and MYO1C16 (4- and 2-fold, respectively). On the basis of a homology model of the 35-amino acid NTR of MYO1C35 (NTR35) docked to the X-ray structure of MYO1CC, we predicted that MYO1C35 NTR residue Arg-21 would engage in a specific interaction with post-relay helix residue Glu-469, which affects the mechanics of the myosin power stroke. In addition, we found that adding the NTR35 peptide to MYO1CC yielded a protein that transiently mimics MYO1C35 kinetic behavior. By contrast, NTR35, which harbors the R21G mutation, was unable to confer MYO1C35-like kinetic behavior. Thus, the NTRs affect the specific nucleotide-binding properties of MYO1C isoforms, adding to their kinetic diversity. We propose that this level of fine-tuning within MYO1C broadens its adaptability within cells. PMID- 28893907 TI - Compositional and expression analyses of the glideosome during the Plasmodium life cycle reveal an additional myosin light chain required for maximum motility. AB - Myosin A (MyoA) is a Class XIV myosin implicated in gliding motility and host cell and tissue invasion by malaria parasites. MyoA is part of a membrane associated protein complex called the glideosome, which is essential for parasite motility and includes the MyoA light chain myosin tail domain-interacting protein (MTIP) and several glideosome-associated proteins (GAPs). However, most studies of MyoA have focused on single stages of the parasite life cycle. We examined MyoA expression throughout the Plasmodium berghei life cycle in both mammalian and insect hosts. In extracellular ookinetes, sporozoites, and merozoites, MyoA was located at the parasite periphery. In the sexual stages, zygote formation and initial ookinete differentiation precede MyoA synthesis and deposition, which occurred only in the developing protuberance. In developing intracellular asexual blood stages, MyoA was synthesized in mature schizonts and was located at the periphery of segmenting merozoites, where it remained throughout maturation, merozoite egress, and host cell invasion. Besides the known GAPs in the malaria parasite, the complex included GAP40, an additional myosin light chain designated essential light chain (ELC), and several other candidate components. This ELC bound the MyoA neck region adjacent to the MTIP-binding site, and both myosin light chains co-located to the glideosome. Co-expression of MyoA with its two light chains revealed that the presence of both light chains enhances MyoA dependent actin motility. In conclusion, we have established a system to study the interplay and function of the three glideosome components, enabling the assessment of inhibitors that target this motor complex to block host cell invasion. PMID- 28893908 TI - The intrinsically disordered N-terminal domain of galectin-3 dynamically mediates multisite self-association of the protein through fuzzy interactions. AB - Galectins are a family of lectins that bind beta-galactosides through their conserved carbohydrate recognition domain (CRD) and can induce aggregation with glycoproteins or glycolipids on the cell surface and thereby regulate cell activation, migration, adhesion, and signaling. Galectin-3 has an intrinsically disordered N-terminal domain and a canonical CRD. Unlike the other 14 known galectins in mammalian cells, which have dimeric or tandem-repeated CRDs enabling multivalency for various functions, galectin-3 is monomeric, and its functional multivalency therefore is somewhat of a mystery. Here, we used NMR spectroscopy, mutagenesis, small-angle X-ray scattering, and computational modeling to study the self-association-related multivalency of galectin-3 at the residue-specific level. We show that the disordered N-terminal domain (residues ~20-100) interacts with itself and with a part of the CRD not involved in carbohydrate recognition (beta-strands 7-9; residues ~200-220), forming a fuzzy complex via inter- and intramolecular interactions, mainly through hydrophobicity. These fuzzy interactions are characteristic of intrinsically disordered proteins to achieve liquid-liquid phase separation, and we demonstrated that galectin-3 can also undergo liquid-liquid phase separation. We propose that galectin-3 may achieve multivalency through this multisite self-association mechanism facilitated by fuzzy interactions. PMID- 28893910 TI - Protonation equilibria and pore-opening structure of the dual-histidine influenza B virus M2 transmembrane proton channel from solid-state NMR. AB - The influenza A and B viruses are the primary cause of seasonal flu epidemics. Common to both viruses is the M2 protein, a homotetrameric transmembrane proton channel that acidifies the virion after endocytosis. Although influenza A M2 (AM2) and B M2 (BM2) are functional analogs, they have little sequence homology, except for a conserved HXXXW motif, which is responsible for proton selectivity and channel gating. Importantly, BM2 contains a second titratable histidine, His 27, in the tetrameric transmembrane domain that forms a reverse WXXXH motif with the gating tryptophan. To understand how His-27 affects the proton conduction property of BM2, we have used solid-state NMR to characterize the pH-dependent structure and dynamics of His-27. In cholesterol-containing lipid membranes mimicking the virus envelope, 15N NMR spectra show that the His-27 tetrad protonates with higher pKa values than His-19, indicating that the solvent accessible His-27 facilitates proton conduction of the channel by increasing the proton dissociation rates of His-19. AM2 is inhibited by the amantadine class of antiviral drugs, whereas BM2 has no known inhibitors. We measured the N-terminal interhelical separation of the BM2 channel using fluorinated Phe-5. The interhelical 19F-19F distances show a bimodal distribution of a short distance of 7 A and a long distance of 15-20 A, indicating that the phenylene rings do not block small-molecule entry into the channel pore. These results give insights into the lack of amantadine inhibition of BM2 and reveal structural diversities in this family of viral proton channels. PMID- 28893909 TI - Processive searching ability varies among members of the gap-filling DNA polymerase X family. AB - DNA repair proteins must locate rare damaged sites within the genome. DNA polymerase beta (Pol beta), a member of the DNA polymerase X family that is involved in base excision repair, uses a processive hopping search mechanism to locate substrates. This effectively enhances its search footprint on DNA, increasing the probability of locating damaged sites. Processive searching has been reported or proposed for many DNA-binding proteins, raising the question of how widespread or specific to certain enzymes the ability to perform this function is. To provide insight into this question, we compared the ability of three homologous DNA Pol X family members to perform a processive search for 1 nucleotide gaps in DNA using a previously developed biochemical assay. We found that at near-predicted physiological ionic strengths, the intramolecular searching ability of Pol beta is at least 4-fold higher than that of Pol MU and ~2-fold higher than that of Pol lambda. Pol beta also was able to perform intersegmental transfer with the intersegmental searching ability of Pol beta being at least 6- and ~2-fold higher than that of Pols MU and lambda, respectively. Mutational analysis suggested that differences in the N-terminal domains of these polymerases are responsible for the varying degrees of searching competence. Of note, the differences in processive searching ability observed among the DNA Pol X family members correlated with their proposed biological functions in base excision repair and nonhomologous end joining. PMID- 28893911 TI - Molecular and functional characterization of the endothelial ATP-sensitive potassium channel. AB - ATP-sensitive potassium (KATP) channels are widely expressed in the cardiovascular system, where they regulate a range of biological activities by linking cellular metabolism with membrane excitability. KATP channels in vascular smooth muscle have a well-defined role in regulating vascular tone. KATP channels are also thought to be expressed in vascular endothelial cells, but their presence and function in this context are less clear. As a result, we aimed to investigate the molecular composition and physiological role of endothelial KATP channels. We first generated mice with an endothelial specific deletion of the channel subunit Kir6.1 (eKO) using cre-loxP technology. Data from qRT-PCR, patch clamp, ex vivo coronary perfusion Langendorff heart experiments, and endothelial cell Ca2+ imaging comparing eKO and wild-type mice show that Kir6.1-containing KATP channels are indeed present in vascular endothelium. An increase in intracellular [Ca2+], which is central to changes in endothelial function such as mediator release, at least partly contributes to the endothelium-dependent vasorelaxation induced by the KATP channel opener pinacidil. The absence of Kir6.1 did not elevate basal coronary perfusion pressure in eKO mice. However, vasorelaxation was impaired during hypoxia in the coronary circulation, and this resulted in greater cardiac injury during ischemia-reperfusion. The response to adenosine receptor stimulation was impaired in eKO mice in single cells in patch clamp recordings and in the intact coronary circulation. Our data support the existence of an endothelial KATP channel that contains Kir6.1, is involved in vascular reactivity in the coronary circulation, and has a protective role in ischemia reperfusion. PMID- 28893912 TI - The Gene tia, Harbored by the Subtilase-Encoding Pathogenicity Island, Is Involved in the Ability of Locus of Enterocyte Effacement-Negative Shiga Toxin Producing Escherichia coli Strains To Invade Monolayers of Epithelial Cells. AB - Locus of enterocyte effacement (LEE)-negative Shiga toxin (Stx)-producing Escherichia coli (STEC) strains are human pathogens that lack the LEE locus, a pathogenicity island (PAI) involved in the intimate adhesion of LEE-positive strains to the host gut epithelium. The mechanism used by LEE-negative STEC strains to colonize the host intestinal mucosa is still not clear. The cell invasion determinant tia, previously described in enterotoxigenic E. coli strains, has been identified in LEE-negative STEC strains that possess the subtilase-encoding pathogenicity island (SE-PAI). We evaluated the role of the gene tia, present in these LEE-negative STEC strains, in the invasion of monolayers of cultured cells. We observed that these strains were able to invade Caco-2 and HEp-2 cell monolayers and compared their invasion ability with that of a mutant strain in which the gene tia had been inactivated. Mutation of the gene tia resulted in a strong reduction of the invasive phenotype, and complementation of the tia mutation with a functional copy of the gene restored the invasion activity. Moreover, we show that the gene tia is overexpressed in bacteria actively invading cell monolayers, demonstrating that tia is involved in the ability to invade cultured monolayers of epithelial cells shown by SE-PAI positive E. coli, including STEC, strains. However, the expression of the tia gene in the E. coli K-12 strain JM109 was not sufficient, in its own right, to confer to this strain the ability to invade cell monolayers, suggesting that at least another factor must be involved in the invasion ability displayed by the SE PAI-positive strains. PMID- 28893913 TI - Interleukin-17A-Deficient Mice Are Highly Susceptible to Toxoplasma gondii Infection Due to Excessively Induced T. gondii HSP70 and Interferon Gamma Production. AB - Interleukin17A (IL-17A) is known to be involved in the host defense against pathogens and the pathogenesis of autoimmune diseases. Previously, we showed that excessive amounts of interferon gamma (IFN-gamma) play an important role in the pathogenesis of the lethal effects of Toxoplasma gondii by inducing anaphylactic responses. In the study described in this report, we examined the effects of IL 17A deficiency on murine host defense against oral T. gondii infection. IL-17A deficient C57BL/6 (B6) mice exhibited higher rates of mortality than wild-type (WT) mice during the acute phase of T. gondii infection. CD4+ T cells in the mesenteric lymph nodes (mLNs) and ileum of T. gondii-infected IL-17A-deficient mice produced higher levels of IFN-gamma than did those of WT mice. In addition, the level of T. gondii HSP70 (T.gHSP70) expression was also significantly increased in the ileum, mLNs, liver, and spleen of infected IL-17A-deficient mice compared with that in WT mice. These elevated levels of expression of T.gHSP70 and IFN-gamma in infected IL-17A-deficient mice were presumably linked to the IL 17A defect since they decreased to WT levels after treatment with recombinant IL 17A. Furthermore, IL-17A-deficient mice were highly susceptible to the anaphylactic effect of T.gHSP70, and the survival of IL-17A-deficient mice during the acute phase was improved by treatment with an anti-T.gHSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against T. gondii infection by protecting the host from an anaphylactic reaction via the downregulation of T.gHSP70 and IFN-gamma production. PMID- 28893914 TI - Stenotrophomonas maltophilia Serine Protease StmPr1 Induces Matrilysis, Anoikis, and Protease-Activated Receptor 2 Activation in Human Lung Epithelial Cells. AB - Stenotrophomonas maltophilia is an emerging, opportunistic nosocomial pathogen that can cause severe disease in immunocompromised individuals. We recently identified the StmPr1 and StmPr2 serine proteases to be the substrates of the Xps type II secretion system in S. maltophilia strain K279a. Here, we report that a third serine protease, StmPr3, is also secreted in an Xps-dependent manner. By constructing a panel of protease mutants in strain K279a, we were able to determine that StmPr3 contributes to the previously described Xps-mediated rounding and detachment of cells of the A549 human lung epithelial cell line as well as the Xps-mediated degradation of fibronectin, fibrinogen, and the cytokine interleukin-8 (IL-8). We also determined that StmPr1, StmPr2, and StmPr3 account for all Xps-mediated effects toward A549 cells and that StmPr1 contributes the most to Xps-mediated activities. Thus, we purified StmPr1 from the S. maltophilia strain K279a culture supernatant and evaluated the protease's activity toward A549 cells. Our analyses revealed that purified StmPr1 behaves more similarly to subtilisin than to trypsin. We also determined that purified StmPr1 likely induces cell rounding and detachment of A549 cells by targeting cell integrin extracellular matrix connections (matrilysis) as well as adherence and tight junction proteins for degradation. In this study, we also identified anoikis as the mechanism by which StmPr1 induces the death of A549 cells and found that StmPr1 induces A549 IL-8 secretion via activation of protease-activated receptor 2. Altogether, these results suggest that the degradative and cytotoxic activities exhibited by StmPr1 may contribute to S. maltophilia pathogenesis in the lung by inducing tissue damage and inflammation. PMID- 28893915 TI - Hyperbiofilm Formation by Bordetella pertussis Strains Correlates with Enhanced Virulence Traits. AB - Pertussis, or whooping cough, caused by the obligate human pathogen Bordetella pertussis is undergoing a worldwide resurgence. The majority of studies of this pathogen are conducted with laboratory-adapted strains which may not be representative of the species as a whole. Biofilm formation by B. pertussis plays an important role in pathogenesis. We conducted a side-by-side comparison of the biofilm-forming abilities of the prototype laboratory strains and the currently circulating isolates from two countries with different vaccination programs. Compared to the reference strain, all strains examined herein formed biofilms at high levels. Biofilm structural analyses revealed country-specific differences, with strains from the United States forming more structured biofilms. Bacterial hyperaggregation and reciprocal expression of biofilm-promoting and -inhibitory factors were observed in clinical isolates. An association of increased biofilm formation with augmented epithelial cell adhesion and higher levels of bacterial colonization in the mouse nose and trachea was detected. To our knowledge, this work links for the first time increased biofilm formation in bacteria with a colonization advantage in an animal model. We propose that the enhanced biofilm forming capacity of currently circulating strains contributes to their persistence, transmission, and continued circulation. PMID- 28893916 TI - Role of Activins in Hepcidin Regulation during Malaria. AB - Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei-infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting. PMID- 28893917 TI - Phenol-Soluble Modulin Peptides Contribute to Influenza A Virus-Associated Staphylococcus aureus Pneumonia. AB - Influenza A virus (IAV) infection is often followed by secondary bacterial lung infection, which is a major reason for severe, often fatal pneumonia. Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains such as USA300 cause particularly severe and difficult-to-treat cases of IAV-associated pneumonia. CA-MRSA strains are known to produce extraordinarily large amounts of phenol-soluble modulin (PSM) peptides, which are important cytotoxins and proinflammatory molecules that contribute to several types of S. aureus infection. However, their potential role in pneumonia has remained elusive. We determined the impact of PSMs on human lung epithelial cells and found that PSMs are cytotoxic and induce the secretion of the proinflammatory cytokine interleukin-8 (IL-8) in these cells. Both effects were boosted by previous infection with the 2009 swine flu pandemic IAV H1N1 strain, suggesting that PSMs may contribute to lung inflammation and damage in IAV-associated S. aureus pneumonia. Notably, the PSM-producing USA300 strain caused a higher mortality rate than did an isogenic PSM-deficient mutant in a mouse IAV-S. aureus pneumonia coinfection model, indicating that PSMs are major virulence factors in IAV associated S. aureus pneumonia and may represent important targets for future anti-infective therapies. PMID- 28893918 TI - Enterococcus faecalis Promotes Innate Immune Suppression and Polymicrobial Catheter-Associated Urinary Tract Infection. AB - Enterococcus faecalis, a member of the human gastrointestinal microbiota, is an opportunistic pathogen associated with hospital-acquired wound, bloodstream, and urinary tract infections. E. faecalis can subvert or evade immune-mediated clearance, although the mechanisms are poorly understood. In this study, we examined E. faecalis-mediated subversion of macrophage activation. We observed that E. faecalis actively prevents NF-kappaB signaling in mouse RAW264.7 macrophages in the presence of Toll-like receptor agonists and during polymicrobial infection with Escherichia coliE. faecalis and E. coli coinfection in a mouse model of catheter-associated urinary tract infection (CAUTI) resulted in a suppressed macrophage transcriptional response in the bladder compared to that with E. coli infection alone. Finally, we demonstrated that coinoculation of E. faecalis with a commensal strain of E. coli into catheterized bladders significantly augmented E. coli CAUTI. Taken together, these results support the hypothesis that E. faecalis suppression of NF-kappaB-driven responses in macrophages promotes polymicrobial CAUTI pathogenesis, especially during coinfection with less virulent or commensal E. coli strains. PMID- 28893920 TI - Are SGLT2 Inhibitors Ready for Prime Time for CKD? PMID- 28893919 TI - Antigen Localization Influences the Magnitude and Kinetics of Endogenous Adaptive Immune Response to Recombinant Salmonella Vaccines. AB - The use of recombinant attenuated Salmonella vaccine (RASV) strains is a promising strategy for presenting heterologous antigens to the mammalian immune system to induce both cellular and humoral immune responses. However, studies on RASV development differ on where heterologous antigens are expressed and localized within the bacterium, and it is unclear how antigen localization modulates the immune response. Previously, we exploited the plasmid-encoded toxin (Pet) autotransporter system for accumulation of heterologous antigens in cell culture supernatant. In the present study, this Pet system was used to express early secretory antigen 6 (ESAT-6), an immunodominant and diagnostic antigen from Mycobacterium tuberculosis, in Salmonella enterica serovar Typhimurium strain SL3261. Three strains were generated, whereby ESAT-6 was expressed as a cytoplasmic (SL3261/cyto), surface-bound (SL3261/surf), or secreted (SL3261/sec) antigen. Using these RASVs, the relationship between antigen localization and immunogenicity in infected C57BL/6 mice was systematically examined. Using purified antigen and specific tetramers, we showed that mice infected with the SL3261/surf or SL3261/sec strain generated large numbers of Th1 CD4+ ESAT-6+ splenic T cells compared to those of mice infected with SL3261/cyto. While all mice showed ESAT-6-specific antibody responses when infected with SL3261/surf or SL3261/sec, peak total serum IgG antibody titers were reached more rapidly in mice that received SL3261/sec. Thus, how antigen is localized after production within bacteria has a more marked effect on the antibody response than on the CD4+ T cell response, which might influence the chosen strategy to localize recombinant antigen in RASVs. PMID- 28893922 TI - Challenges in Developing New Therapies for Vascular Access Dysfunction. PMID- 28893921 TI - Randomized, Controlled Trial of the Effect of Dietary Potassium Restriction on Nerve Function in CKD. AB - BACKGROUND AND OBJECTIVES: Neuromuscular complications are almost universal in CKD by the time that a patient commences dialysis. Recent studies have indicated that chronic hyperkalemia may contribute to the development of neuropathy in CKD. This study was undertaken to determine whether dietary restriction of potassium intake may be a neuroprotective factor in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 24-month prospective, single-blind, randomized, controlled trial was undertaken in 47 consecutively recruited patients with stages 3 and 4 CKD. The intervention arm (n=23) was prescribed a diet focusing on potassium restriction to meet a monthly serum potassium level of <=4.5 mEq/L, with oral sodium polystyrene sulfonate provided if dietary advice failed to achieve the target. The control arm (n=24) received dietary advice regarding general nutrition. The primary outcome was the change in the total neuropathy score evaluated by a blinded observer. Secondary outcomes included electrolyte levels, gait speed, neurophysiologic parameters, and health-related quality of life scores. Five patients withdrew before initiation of treatment, and final analysis consisted of n=21 in each group. RESULTS: There was a greater increase in total neuropathy score from baseline to final assessment in the control arm compared with the intervention arm (6.1+/-6.2-8.6+/-7.9 controls; 7.8+/-7.4-8.2+/-7.5 intervention; change 2.8+/-3.3-0.4+/-2.2, respectively; P<0.01). The intervention significantly reduced mean serum potassium compared with controls (4.6+/-0.1 4.8+/-0.1 mEq/L mean recorded every 6 months over the trial duration; P=0.03). There were no adverse changes in other nutritional parameters. Improved gait speed was also noted in the intervention arm compared with the control arm, with a mean increase of 0.15+/-0.17 m/s in the intervention group versus 0.02+/-0.16 m/s in the control group (P=0.01). CONCLUSIONS: Our results provide important preliminary evidence that dietary potassium restriction confers neuroprotection in CKD and should be confirmed in a larger multicenter trial. PMID- 28893923 TI - Drug-Induced Acute Interstitial Nephritis. PMID- 28893925 TI - Approaches to and Clinical Benefits of Reducing Dietary K in CKD. PMID- 28893924 TI - Changes in Albuminuria and Subsequent Risk of Incident Kidney Disease. AB - BACKGROUND AND OBJECTIVES: Albuminuria is a robust predictor of CKD progression. However, little is known about the associations of changes in albuminuria with the risk of kidney events outside the settings of clinical trials. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a nationwide cohort of 56,946 United States veterans with an eGFR>=60 ml/min per 1.73 m2, we examined the associations of 1-year fold changes in albuminuria with subsequent incident CKD (>25% decrease in eGFR reaching <60 ml/min per 1.73 m2) and rapid eGFR decline (eGFR slope <-5 ml/min per 1.73 m2 per year) assessed using Cox models and logistic regression, respectively, with adjustment for confounders. RESULTS: The mean age was 64 (SD, 10) years old; 97% were men, and 91% were diabetic. There was a nearly linear association between 1-year fold changes in albuminuria and incident CKD. The multivariable-adjusted hazard ratios (95% confidence intervals) of incident CKD associated with more than twofold decrease, 1.25- to twofold decrease, 1.25- to twofold increase, and more than twofold increase (versus <1.25-fold decrease to <1.25-fold increase) in albuminuria were 0.82 (95% confidence interval, 0.77 to 0.89), 0.93 (95% confidence interval, 0.86 to 1.00), 1.12 (95% confidence interval, 1.05 to 1.20), and 1.29 (95% confidence interval, 1.21 to 1.38), respectively. Qualitatively similar associations were present for rapid eGFR decline (adjusted odds ratios; 95% confidence intervals for corresponding albuminuria changes: adjusted odds ratio, 0.86; 95% confidence interval, 0.78 to 0.94; adjusted odds ratio, 0.98; 95% confidence interval, 0.89 to 1.07; adjusted odds ratio, 1.18; 95% confidence interval, 1.08 to 1.29; and adjusted odds ratio, 1.67; 95% confidence interval, 1.54 and 1.81, respectively). CONCLUSIONS: Relative changes in albuminuria over a 1-year interval were linearly associated with subsequent risk of kidney outcomes. Additional studies are warranted to elucidate the underlying mechanisms of the observed associations and test whether active interventions to lower elevated albuminuria can improve kidney outcomes. PMID- 28893926 TI - Limited Contribution of Primary Motor Cortex in Eye-Hand Coordination: A TMS Study. AB - The ability to track a moving target with the eye is substantially improved when the target is self-moved compared with when it is moved by an external agent. To account for this observation, it has been postulated that the oculomotor system has access to hand efference copy, thereby allowing to predict the motion of the visual target. Along this scheme, we tested the effect of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when human participants (50% females) are asked to track with their eyes a visual target whose horizontal motion is driven by their grip force. We reasoned that, if the output of M1 is used by the oculomotor system to keep track of the target, on top of inducing short latency disturbance of grip force, single-pulse TMS should also quickly disrupt ongoing eye motion. For comparison purposes, the effect of TMS over M1 was monitored when subjects tracked an externally moved target (while keeping their hand at rest or not). In both cases, results showed no alterations in smooth pursuit, meaning that its velocity was unaffected within the 25-125 ms epoch that followed TMS. Overall, our results imply that the output of M1 has limited contribution in driving the eye motion during our eye-hand coordination task. This study suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1.SIGNIFICANCE STATEMENT The ability to coordinate eye and hand actions is central in everyday activity. However, the neural mechanisms underlying this coordination remain to be clarified. A leading hypothesis is that the oculomotor system has access to hand motor signals. Here we explored this possibility by means of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when humans tracked with the eyes a visual target that was moved by the hand. As expected, ongoing hand action was perturbed 25-30 ms after TMS, but our results fail to show any disruption of eye motion, smooth pursuit velocity being unaffected. This work suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1. PMID- 28893928 TI - Content-Specific Codes of Parametric Vibrotactile Working Memory in Humans. AB - To understand how the brain handles mentally represented information flexibly in the absence of sensory stimulation, working memory (WM) studies have been essential. A seminal finding in monkey research is that neurons in the prefrontal cortex (PFC) retain stimulus-specific information when vibrotactile frequencies were memorized. A direct mapping between monkey studies and human research is still controversial. Although oscillatory signatures, in terms of frequency dependent parametric beta-band modulation, have been observed recently in human EEG studies, the content specificity of these representations in terms of multivariate pattern analysis has not yet been shown. Here, we used fMRI in combination with multivariate classification techniques to determine which brain regions retain information during WM. In a retro-cue delayed-match-to-sample task, human subjects memorized the frequency of vibrotactile stimulation over a 12 s delay phase. Using an assumption-free whole-brain searchlight approach, we tested with support vector regression which brain regions exhibited multivariate parametric WM codes of the maintained frequencies during the WM delay. Interestingly, our analysis revealed an overlap with regions previously identified in monkeys composed of bilateral premotor cortices, supplementary motor area, and the right inferior frontal gyrus as part of the PFC. Therefore, our results establish a link between the WM codes found in monkeys and those in humans and emphasize the importance of the PFC for information maintenance during WM also in humans.SIGNIFICANCE STATEMENT Working memory (WM) research in monkeys has identified a network of regions, including prefrontal regions, to code stimulus-specific information when vibrotactile frequencies are memorized. Here, we performed an fMRI study during which human subjects had to memorize vibratory frequencies in parallel to previous monkey research. Using an assumption-free, whole-brain searchlight decoding approach, we identified for the first time regions in the human brain that exhibit multivariate patterns of activity to code the vibratory frequency parametrically during WM. Our results parallel previous monkey findings and show that the supplementary motor area, premotor, and the right prefrontal cortex are involved in vibrotactile WM coding in humans. PMID- 28893927 TI - Mutant Huntingtin Inhibits alphaB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes. AB - In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of alphaB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the alphaB-crystallin gene. Importantly, overexpression of alphaB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of alphaB crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non-cell-autonomous neurotoxicity in HD.SIGNIFICANCE STATEMENT Huntington's disease (HD) is characterized by selective neurodegeneration that preferentially occurs in the striatal medium spiny neurons. Recent studies in different HD mouse models demonstrated that dysfunction of astrocytes, a major type of glial cell, leads to neuronal vulnerability. Emerging evidence shows that exosomes secreted from astrocytes contain neuroprotective cargoes that could support the survival of neighboring neurons. We found that mHtt in astrocytes impairs exosome secretion by decreasing alphaB-crystallin, a protein that is expressed mainly in glial cells and mediates exosome secretion. Overexpression of alphaB-crystallin could alleviate the deficient exosome release and neuropathology in HD mice. Our results revealed a new pathological pathway that affects the critical support of glial cells to neurons in the HD brain. PMID- 28893929 TI - Distinct Patterns of Temporal and Directional Connectivity among Intrinsic Networks in the Human Brain. AB - To determine the spatiotemporal relationships among intrinsic networks of the human brain, we recruited seven neurosurgical patients (four males and three females) who were implanted with intracranial depth electrodes. We first identified canonical resting-state networks at the individual subject level using an iterative matching procedure on each subject's resting-state fMRI data. We then introduced single electrical pulses to fMRI pre-identified nodes of the default network (DN), frontoparietal network (FPN), and salience network (SN) while recording evoked responses in other recording sites within the same networks. We found bidirectional signal flow across the three networks, albeit with distinct patterns of evoked responses within different time windows. We used a data-driven clustering approach to show that stimulation of the FPN and SN evoked a rapid (<70 ms) response that was predominantly higher within the SN sites, whereas stimulation of the DN led to sustained responses in later time windows (85-200 ms). Stimulations in the medial temporal lobe components of the DN evoked relatively late effects (>130 ms) in other nodes of the DN, as well as FPN and SN. Our results provide temporal information about the patterns of signal flow between intrinsic networks that provide insights into the spatiotemporal dynamics that are likely to constrain the architecture of the brain networks supporting human cognition and behavior.SIGNIFICANCE STATEMENT Despite great progress in the functional neuroimaging of the human brain, we still do not know the precise set of rules that define the patterns of temporal organization between large-scale networks of the brain. In this study, we stimulated and then recorded electrical evoked potentials within and between three large-scale networks of the brain, the default network (DN), frontoparietal network (FPN), and salience network (SN), in seven subjects undergoing invasive neurosurgery. Using a data-driven clustering approach, we observed distinct temporal and directional patterns between the three networks, with FPN and SN activity predominant in early windows and DN stimulation affecting the network in later windows. These results provide important temporal information about the interactions between brain networks supporting human cognition and behavior. PMID- 28893930 TI - How Human Amygdala and Bed Nucleus of the Stria Terminalis May Drive Distinct Defensive Responses. AB - The ability to adaptively regulate responses to the proximity of potential danger is critical to survival and imbalance in this system may contribute to psychopathology. The bed nucleus of the stria terminalis (BNST) is implicated in defensive responding during uncertain threat anticipation whereas the amygdala may drive responding upon more acute danger. This functional dissociation between the BNST and amygdala is however controversial, and human evidence scarce. Here we used data from two independent functional magnetic resonance imaging studies [n = 108 males and n = 70 (45 females)] to probe how coordination between the BNST and amygdala may regulate responses during shock anticipation and actual shock confrontation. In a subset of participants from Sample 2 (n = 48) we demonstrate that anticipation and confrontation evoke bradycardic and tachycardic responses, respectively. Further, we show that in each sample when going from shock anticipation to the moment of shock confrontation neural activity shifted from a region anatomically consistent with the BNST toward the amygdala. Comparisons of functional connectivity during threat processing showed overlapping yet also consistently divergent functional connectivity profiles for the BNST and amygdala. Finally, childhood maltreatment levels predicted amygdala, but not BNST, hyperactivity during shock anticipation. Our results support an evolutionary conserved, defensive distance-dependent dynamic balance between BNST and amygdala activity. Shifts in this balance may enable shifts in defensive reactions via the demonstrated differential functional connectivity. Our results indicate that early life stress may tip the neural balance toward acute threat responding and via that route predispose for affective disorder.SIGNIFICANCE STATEMENT Previously proposed differential contributions of the BNST and amygdala to fear and anxiety have been recently debated. Despite the significance of understanding their contributions to defensive reactions, there is a paucity of human studies that directly compared these regions on activity and connectivity during threat processing. We show strong evidence for a dissociable role of the BNST and amygdala in threat processing by demonstrating in two large participant samples that they show a distinct temporal signature of threat responding as well as a discriminable pattern of functional connections and differential sensitivity to early life threat. PMID- 28893931 TI - Human oncogenic viruses: nature and discovery. AB - Seven kinds of virus collectively comprise an important cause of cancer, particularly in less developed countries and for people with damaged immune systems. Discovered over the past 54 years, most of these viruses are common infections of humankind for which malignancy is a rare consequence. Various cofactors affect the complex interaction between virus and host and the likelihood of cancer emerging. Although individual human tumour viruses exert their malignant effects in different ways, there are common features that illuminate mechanisms of oncogenesis more generally, whether or not there is a viral aetiology.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893932 TI - Tumour virology in the era of high-throughput genomics. AB - With the advent of massively parallel sequencing, oncogenic viruses in tumours can now be detected in an unbiased and comprehensive manner. Additionally, new viruses or strains can be discovered based on sequence similarity with known viruses. Using this approach, the causative agent for Merkel cell carcinoma was identified. Subsequent studies using data from large collections of tumours have confirmed models built during decades of hypothesis-driven and low-throughput research, and a more detailed and comprehensive description of virus-tumour associations have emerged. Notably, large cohorts and high sequencing depth, in combination with newly developed bioinformatical techniques, have made it possible to rule out several suggested virus-tumour associations with a high degree of confidence. In this review we discuss possibilities, limitations and insights gained from using massively parallel sequencing to characterize tumours with viral content, with emphasis on detection of viral sequences and genomic integration events.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893933 TI - Tumour virus epidemiology. AB - A viral etiology of cancer was first demonstrated in 1911 by Peyton Rous who injected cell-free filtrate from a chicken sarcoma into healthy chickens and found it induced a tumour. Since the discovery over 50 years ago of the Epstein Barr virus as the cause of Burkitt lymphoma, seven other human viruses or groups of viruses-hepatitis B virus, hepatitis C virus, human immunodeficiency virus type 1, some human papillomaviruses, human T-cell lymphotropic virus type 1, Kaposi sarcoma-associated herpesvirus and Merkel cell polyomavirus-have been linked to human cancer. Collectively, these eight viruses cause over 20 different types of cancer and contribute to 10-12% of all cancer, with a greater burden in low- and middle-income countries. For many viruses, immunosuppression greatly increases the risks of persistent infection, development of chronic sequelae and cancer. Although several viruses share similar routes of transmission (especially sexual activity, injection drug use and mother-to-child transmission), the predominant route of transmission varies across viruses, and for the same virus can vary by geographical location. In general, vulnerable populations at the greatest risk for viral infections and their associated diseases include people, especially children, living in low- to middle-income countries, men who have sex with men, people who use injection drugs and female sex workers.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893934 TI - Tumour viruses and innate immunity. AB - Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma associated herpesvirus, Epstein-Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893935 TI - Tumour virus vaccines: hepatitis B virus and human papillomavirus. AB - Two of the most important human oncogenic viruses are hepatitis B virus (HBV) and human papillomavirus (HPV). HBV infection has been preventable by vaccination since 1982; vaccination of neonates and infants is highly effective, resulting already in decreased rates of new infections, chronic liver disease and hepato cellular carcinoma. Nonetheless, HBV remains a global public health problem with high rates of vertical transmission from mother to child in some regions. Prophylactic HPV vaccines composed of virus-like particles (VLPs) of the L1 capsid protein have been licensed since 2006/2007. These target infection by the oncogenic HPVs 16 and 18 (the cause of 70% of cervical cancers); a new vaccine licensed in 2014/2015 additionally targets HPVs 31, 33, 45, 52, 58. HPV vaccines are now included in the national immunization programmes in many countries, with young adolescent peri-pubertal girls the usual cohort for immunization. Population effectiveness in women is now being demonstrated in countries with high vaccine coverage with significant reductions in high-grade cervical intra epithelial neoplasia (a surrogate for cervical cancer), genital warts and vaccine HPV type genoprevalence. Herd effects in young heterosexual men and older women are evident. Cancers caused by HBV and HPV should, in theory, be amenable to immunotherapies and various therapeutic vaccines for HPV in particular are in development and/or in clinical trial.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893936 TI - Take your PIKK: tumour viruses and DNA damage response pathways. AB - Viruses regulate cellular processes to facilitate viral replication. Manipulation of nuclear proteins and pathways by nuclear replicating viruses often causes cellular genome instability that contributes to transformation. The cellular DNA damage response (DDR) safeguards the host to maintain genome integrity, but DNA tumour viruses can manipulate the DDR to promote viral propagation. In this review, we describe the interactions of DNA tumour viruses with the phosphatidylinositol 3-kinase-like protein kinase (PIKK) pathways, which are central regulatory arms of the DDR. We review how signalling through the ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and DNA-dependent protein kinases (DNA-PK) influences viral life cycles, and how their manipulation by viral proteins may contribute to tumour formation.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893937 TI - Epstein-Barr virus infection and nasopharyngeal carcinoma. AB - Epstein-Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-kappaB signalling. Dysregulated NF-kappaB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893938 TI - Epstein-Barr virus-associated lymphomas. AB - Epstein-Barr virus (EBV), originally discovered through its association with Burkitt lymphoma, is now aetiologically linked to a remarkably wide range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. Some occur as rare accidents of virus persistence in the B lymphoid system, while others arise as a result of viral entry into unnatural target cells. The early finding that EBV is a potent B-cell growth transforming agent hinted at a simple oncogenic mechanism by which this virus could promote lymphomagenesis. In reality, the pathogenesis of EBV-associated lymphomas involves a complex interplay between different patterns of viral gene expression and cellular genetic changes. Here we review recent developments in our understanding of EBV associated lymphomagenesis in both the immunocompetent and immunocompromised host.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893939 TI - Human T-cell leukaemia virus type 1: parasitism and pathogenesis. AB - Human T-cell leukaemia virus type 1 (HTLV-1) causes not only adult T-cell leukaemia-lymphoma (ATL), but also inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis. HTLV-1 transmits primarily through cell-to-cell contact, and generates abundant infected cells in the host in order to survive and transmit to a new host. The resulting high proviral load is closely associated with the development of ATL and inflammatory diseases. To increase the number of infected cells, HTLV-1 changes the immunophenotype of infected cells, induces proliferation and inhibits apoptosis through the cooperative actions of two viral genes, tax and HTLV-1 bZIP factor (HBZ). As a result, infected cells survive, proliferate and infiltrate into the tissues, which is critical for transmission of the virus. Thus, the strategy of this virus is indivisibly linked with its pathogenesis, providing a clue for prevention and treatment of HTLV-1-induced diseases.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893940 TI - Oncogenic human papillomaviruses. AB - Human papillomaviruses (HPVs) are an ancient group of viruses with small, double stranded DNA circular genomes. They are species-specific and have a strict tropism for mucosal and cutaneous stratified squamous epithelial surfaces of the host. A subset of these viruses has been demonstrated to be the causative agent of several human cancers. Here, we review the biology, natural history, evolution and cancer association of the oncogenic HPVs.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893941 TI - Viral hepatitis and liver cancer. AB - Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893943 TI - Merkel cell polyomavirus and Merkel cell carcinoma. AB - Merkel cell polyomavirus (MCPyV) causes the highly aggressive and relatively rare skin cancer known as Merkel cell carcinoma (MCC). MCPyV also causes a lifelong yet relatively innocuous infection and is one of 14 distinct human polyomaviruses species. Although polyomaviruses typically do not cause illness in healthy individuals, several can cause catastrophic diseases in immunocompromised hosts. MCPyV is the only polyomavirus clearly associated with human cancer. How MCPyV causes MCC and what oncogenic events must transpire to enable this virus to cause MCC is the focus of this essay.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893944 TI - Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer. AB - Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti tumour mechanisms.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893942 TI - Kaposi sarcoma herpesvirus pathogenesis. AB - Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission.This article is part of the themed issue 'Human oncogenic viruses'. PMID- 28893946 TI - A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis. AB - The islets of Langerhans are endocrine organs characteristically dispersed throughout the pancreas. During development, endocrine progenitors delaminate, migrate radially and cluster to form islets. Despite the distinctive distribution of islets, spatially localized signals that control islet morphogenesis have not been discovered. Here, we identify a radial signaling axis that instructs developing islet cells to disperse throughout the pancreas. A screen of pancreatic extracellular signals identified factors that stimulated islet cell development. These included semaphorin 3a, a guidance cue in neural development without known functions in the pancreas. In the fetal pancreas, peripheral mesenchymal cells expressed Sema3a, while central nascent islet cells produced the semaphorin receptor neuropilin 2 (Nrp2). Nrp2 mutant islet cells developed in proper numbers, but had defects in migration and were unresponsive to purified Sema3a. Mutant Nrp2 islets aggregated centrally and failed to disperse radially. Thus, Sema3a-Nrp2 signaling along an unrecognized pancreatic developmental axis constitutes a chemoattractant system essential for generating the hallmark morphogenetic properties of pancreatic islets. Unexpectedly, Sema3a- and Nrp2 mediated control of islet morphogenesis is strikingly homologous to mechanisms that regulate radial neuronal migration and cortical lamination in the developing mammalian brain. PMID- 28893945 TI - Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors. AB - The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies. PMID- 28893947 TI - Small-molecule Wnt agonists correct cleft palates in Pax9 mutant mice in utero. AB - Clefts of the palate and/or lip are among the most common human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9-/- mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2, proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 are shown by the genetic rescue of secondary palate clefts in Pax9 /-Dkk1f/+;Wnt1Cre embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant Pax9+/- mice restored Wnt signaling and led to the growth and fusion of palatal shelves, as marked by an increase in cell proliferation and osteogenesis in utero, while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that this functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single-gene disorders. PMID- 28893948 TI - Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in vivo in planarians. AB - Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that snail-1, snail-2 and zeb-1 EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant notum Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration in vivo. PMID- 28893949 TI - Timing of adrenal regression controlled by synergistic interaction between Sf1 SUMOylation and Dax1. AB - The nuclear receptor steroidogenic factor 1 (Sf1, Nr5a1, Ad4bp) is crucial for formation, development and function of steroidogenic tissues. A fetal adrenal enhancer (FAdE) in the Sf1 gene was previously identified to direct Sf1 expression exclusively in the fetal adrenal cortex and is bound by both Sf1 and Dax1. Here, we have examined the function of Sf1 SUMOylation and its interaction with Dax1 on FAdE function. A diffused prolonged pattern of FAdE expression and delayed regression of the postnatal fetal cortex (X-zone) were detected in both the SUMOylation-deficient-Sf12KR/2KR and Dax1 knockout mouse lines, with FAdE expression/activity retained in the postnatal 20alphaHSD-positive postnatal X zone cells. In vitro studies indicated that Sf1 SUMOylation, although not directly influencing DNA binding, actually increased binding of Dax1 to Sf1 to further enhance transcriptional repression of FAdE. Taken together, these studies define a crucial repressor function of Sf1 SUMOylation and Dax1 in the physiological cessation of FAdE-mediated Sf1 expression and the resultant regression of the postnatal fetal cortex (X-zone). PMID- 28893950 TI - The TAF10-containing TFIID and SAGA transcriptional complexes are dispensable for early somitogenesis in the mouse embryo. AB - During development, tightly regulated gene expression programs control cell fate and patterning. A key regulatory step in eukaryotic transcription is the assembly of the pre-initiation complex (PIC) at promoters. PIC assembly has mainly been studied in vitro, and little is known about its composition during development. In vitro data suggest that TFIID is the general transcription factor that nucleates PIC formation at promoters. Here we show that TAF10, a subunit of TFIID and of the transcriptional co-activator SAGA, is required for the assembly of these complexes in the mouse embryo. We performed Taf10 conditional deletions during mesoderm development and show that Taf10 loss in the presomitic mesoderm (PSM) does not prevent cyclic gene transcription or PSM segmental patterning, whereas lateral plate differentiation is profoundly altered. During this period, global mRNA levels are unchanged in the PSM, with only a minor subset of genes dysregulated. Together, our data strongly suggest that the TAF10-containing canonical TFIID and SAGA complexes are dispensable for early paraxial mesoderm development, arguing against the generic role in transcription proposed for these fully assembled holo-complexes. PMID- 28893951 TI - The cancer-associated U2AF35 470A>G (Q157R) mutation creates an in-frame alternative 5' splice site that impacts splicing regulation in Q157R patients. AB - Recent work has identified cancer-associated U2AF35 missense mutations in two zinc-finger (ZnF) domains, but little is known about Q157R/P substitutions within the second ZnF. Surprisingly, we find that the c.470A>G mutation not only leads to the Q157R substitution, but also creates an alternative 5' splice site (ss) resulting in the deletion of four amino acids (Q157Rdel). Q157P, Q157R, and Q157Rdel control alternative splicing of distinct groups of exons in cell culture and in human patients, suggesting that missplicing of different targets may contribute to cellular aberrations. Our data emphasize the importance to explore missense mutations beyond altered protein sequence. PMID- 28893952 TI - IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage. AB - Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Ralpha and IL-13Ralpha1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR+ ETPs, but not HR- ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPalpha, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR+ ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR- ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development. PMID- 28893953 TI - Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors. AB - The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34+ hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR+ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR+ILC3 differentiation, but conversely suppressed IL-15-dependent cNK cell generation in CD45RA+Flt-3-c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA-Flt-3+c-Kithigh multipotent HPCs to generate CD34+CD7+CD62Lhigh, the earliest thymic progenitor-like cells, which preserved high cNK/T cell potential, but lost NCR+ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR+ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor-like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR+ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte-committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR+ILC3 commitment. PMID- 28893954 TI - The Orphan Nuclear Receptor NR4A3 Is Involved in the Function of Dendritic Cells. AB - NR4A3/NOR1 belongs to the NR4A subfamily of the nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3 in gene expression of dendritic cells (DCs), we introduced NR4A3 small interfering RNA (siRNA) into bone marrow-derived DCs and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NF kappaB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly upregulated by TLR-mediated stimulation in DCs. NR4A3 knockdown significantly suppressed LPS, CpG, or poly(I:C)-mediated upregulation of CD80, CD86, IL-10, IL-6, and IL-12. Proliferation and IL-2 production levels of T cells cocultured with NR4A3 knocked-down DCs were significantly lower than that of T cells cocultured with control DCs. Furthermore, the expression of IKKbeta, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced bone marrow-derived DCs. The knockdown experiments using siRNAs for IKKbeta, IRF4, and/or IRF8 indicated that LPS-induced upregulation of IL-10 and IL-6 was reduced in IKKbeta knocked-down cells, and that the upregulation of IL-12 was suppressed by the knockdown of IRF4 and IRF8. Taken together, these results indicate that NR4A3 is involved in TLR-mediated activation and gene expression of DCs. PMID- 28893955 TI - NKG2D Signaling between Human NK Cells Enhances TACE-Mediated TNF-alpha Release. AB - NK group 2 member D (NKG2D) is a strong NK cell-activating receptor, with engagement by ligands triggering granule release and cytokine production. The function of NKG2D signaling in NK cells has largely been studied in the context of engagement of the receptor by ligands expressed on the surface of target cells. We report that upon activation with IL-12, IL-15, and IL-18 human NK cells express NKG2D ligands of the UL16 binding protein family on the cell surface. NKG2D-ligand interaction between cytokine-stimulated NK cells increases the activity of the metalloprotease TNF-alpha-converting enzyme. This enhanced TNF alpha-converting enzyme activity significantly increases the release of TNF-alpha and UL16 binding protein from the surface of the NK cells. These results demonstrate that NKG2D signaling is critical for maximal TNF-alpha release by NK cells. Further, they demonstrate a role for NKG2D-ligand interaction via homotypic NK cell contact in NK cell effector function. PMID- 28893956 TI - Cutting Edge: Genetic Association between IFI16 Single Nucleotide Polymorphisms and Resistance to Genital Herpes Correlates with IFI16 Expression Levels and HSV 2-Induced IFN-beta Expression. AB - IFN-gamma-inducible protein 16 (IFI16) is an immunological DNA sensor proposed to act in the cyclic GMP-AMP synthase-stimulator of IFN genes pathway. Because mice do not have a clear ortholog of IFI16, this system is not suitable for genetic studies of IFI16. In this study, we have compared the dependency on IFI16, cyclic GMP-AMP synthase, and stimulator of IFN genes for type I IFN induction by a panel of pathogenic bacteria and DNA viruses. The IFN response induced by HSV-2 was particularly dependent on IFI16. In a cohort of patients with genital herpes and healthy controls, the minor G allele of the IFI16 single nucleotide polymorphism rs2276404 was associated with resistance to infection. Furthermore, the combination of this allele with the C allele of rs1417806 was significantly overrepresented in uninfected individuals. Cells from individuals with the protective GC haplotype expressed higher levels of IFI16 and induced more IFN beta upon HSV-2 infection. These data provide genetic evidence for a role for IFI16 in protection against genital herpes. PMID- 28893957 TI - Anti-Inflammatory Role of Langerhans Cells and Apoptotic Keratinocytes in Ultraviolet-B-Induced Cutaneous Inflammation. AB - UV radiation, particularly UVB, is the major risk factor for the induction of skin cancer, and it induces skin inflammation and immunosuppression. Although reports documented that Langerhans cells (LCs) play various roles in photobiology, little is known about whether they contribute to UVB-induced cutaneous inflammation. Recently, the anti-inflammatory effect of apoptotic cells was noted. This study focuses on the roles of LCs and apoptotic cells in UVB induced cutaneous inflammation. We show that LCs are essential for resolution of UVB-induced cutaneous inflammation. Administration of quinolyl-valyl-O methylaspartyl-[2,6-difluophenoxy]-methyl ketone, a broad-spectrum caspase inhibitor with potent antiapoptotic properties, inhibited the formation of UVB induced apoptotic cells and aggravated UVB-induced cutaneous inflammation in wild type mice. In contrast, exacerbation of UVB-induced cutaneous inflammation following quinolyl-valyl-O-methylaspartyl-[2,6-difluophenoxy]-methyl ketone administration was not observed in LC-depleted mice. These results suggest that the interaction between LCs and apoptotic cells is critical for resolution of UVB induced cutaneous inflammation. Interestingly, UVB-induced apoptotic keratinocytes were increased in LC-depleted mice. In addition, we revealed that UVB-induced apoptotic keratinocytes were phagocytosed by LCs ex vivo and that prolongation of UVB-induced cutaneous inflammation following treatment with Cytochalasin D, an inhibitor of phagocytosis, was partially attenuated in LC depleted mice. Collectively, our findings demonstrate that the interaction between LCs and apoptotic cells, possibly via LC-mediated phagocytosis of apoptotic keratinocytes, has an essential anti-inflammatory role in the resolution of UVB-induced cutaneous inflammation. PMID- 28893959 TI - Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. PMID- 28893960 TI - Physical Activity in Heart Failure With Preserved Ejection Fraction: Moving Toward a Newer Treatment Paradigm. PMID- 28893961 TI - Conduction Disturbances After Transcatheter Aortic Valve Replacement: Current Status and Future Perspectives. AB - Transcatheter aortic valve replacement (TAVR) has become a well-accepted option for treating patients with aortic stenosis at intermediate to high or prohibitive surgical risk. TAVR-related conduction disturbances, mainly new-onset left bundle branch block and advanced atrioventricular block requiring permanent pacemaker implantation, remain the most common complication of this procedure. Furthermore, improvements in TAVR technology, akin to the increasing experience of operators/centers, have translated to a major reduction in periprocedural complications, yet the incidence of conduction disturbances has remained relatively high, with perhaps an increasing trend over time. Several factors have been associated with a heightened risk of conduction disturbances and permanent pacemaker implantation after TAVR, with prior right bundle-branch block and transcatheter valve type and implantation depth being the most commonly reported. New-onset left bundle-branch block and the need for permanent pacemaker implantation may have a significant detrimental association with patients' prognosis. Consequently, strategies intended to reduce the risk and to improve the management of such complications are of paramount importance, particularly in an era when TAVR expansion toward treating lower-risk patients is considered inevitable. In this article, we review the available evidence on the incidence, predictive factors, and clinical association of conduction disturbances after TAVR and propose a strategy for the management of these complications. PMID- 28893962 TI - Irregular Narrow Complex Tachycardia in a 29-Year-Old Woman. PMID- 28893958 TI - Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2. AB - Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor alpha subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2. PMID- 28893964 TI - Letter by Ferrero et al Regarding Article, "Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study". PMID- 28893963 TI - Origin of Cardiac Troponin T Elevations in Chronic Kidney Disease. PMID- 28893965 TI - Response by Kempny et al to Letter Regarding Article, "Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study". PMID- 28893966 TI - Letter by Ciliberti and Capucci Regarding Article, "Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease". PMID- 28893968 TI - Correction to: When Lightning Strikes: Fulminant Myocarditis in the Realm of Inflammatory Cardiomyopathies. PMID- 28893967 TI - Response by Lindahl et al to Letter Regarding Article, "Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease". PMID- 28893969 TI - Correction to: Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification. PMID- 28893970 TI - Has respiratory cryptosporidiosis spread to black grouse Tetrao tetrix? AB - Infection by Cryptosporidium baileyi was first confirmed in red grouse in northern England in 2010 and within three years spread to 48 per cent of moors. These form the last English stronghold for the rarer black grouse, and given the rapid spread of respiratory cryptosporidiosis among red grouse, concern has been expressed about possible infection. In 2010, the authors started screening black grouse for cryptosporidiosis in (1) dead birds taken for postmortem examination, (2) sample birds caught at night and (3) an observational study of birds attending leks. Between 2011 and 2016, five males were sent for postmortem examination, of which three had suspected cryptosporidiosis. No disease was found in one; the second had extensive, subacute to chronic sinusitis; and the third had severe sinusitis and unilateral conjunctivitis. PCR analysis detected cryptosporidial DNA in the third bird only; however, the parasite was not seen in stained preparations or on histopathology. No cryptosporidiosis clinical signs were observed in 69 birds caught at night or in 170 birds attending leks. The authors have no conclusive evidence that cryptosporidiosis is causing sinusitis in black grouse. However, a single positive cryptosporidia PCR result from an affected bird does raise the possibility that they may be infected with the parasite. PMID- 28893971 TI - Computed tomographic assessment of equine maxillary cheek teeth anatomical relationships, and paranasal sinus volumes. AB - Disorders affecting the equine maxillary cheek teeth and paranasal sinuses are relatively common, but limited objective information is available on the dimensions and relationships of these structures in horses of different ages. The aims of this study were to assess age-related changes in the positioning and anatomical relationships of the individual maxillary cheek teeth with the infraorbital canal and maxillary septum and the volumes of the individual sinus compartments. CT and gross examination were performed on 60 normal equine cadaver heads that were aged by their dentition. The intrasinus position of cheek teeth, length of reserve crowns, relationship to the infraorbital canal and measurements of rostral drift and sinus compartment volumes were assessed from CT images. The findings included that Triadan 10 alveoli lay fully or partially in the rostral maxillary sinus (RMS) in 60% of cases. The infraorbital canal lay directly on the medial aspect of the alveolar apex in younger horses. The Triadan 11'sclinical crowns and apices drifted a mean of 2.48 and 2.83 cm more rostral to the orbit, respectively, in the >15 years old vs the <6 years old age group. The mean volumes of sinus compartments ranged from 175 cm3 for the caudal maxillary sinus (CMS) to 4 cm3 for the ethmoidal sinus (ES). This information should be of value in the diagnosis and treatment of equine dental and sinus disorders and as reference values for further studies. PMID- 28893972 TI - Cross-sectional study of antimicrobials used for surgical prophylaxis by bovine veterinary practitioners in Australia. AB - Antimicrobials are widely used in veterinary practices, but there has been no investigation of antimicrobial classes used or the appropriateness of their use in bovine practice. This study investigated antimicrobial use for surgical prophylaxis in bovine practice in Australia. A cross-sectional study of veterinarian antimicrobial usage patterns was conducted using an online questionnaire. Information solicited included respondent's details, the frequency with which antimicrobials were used for specific surgical conditions (including the dose, timing and duration of therapy) and details of practice antimicrobial use policies and sources of information about antimicrobials. In total, 212 members of the Australian veterinary profession working in bovine practice completed the survey. Antimicrobials were always or frequently used by more than 75 per cent of respondents in all scenarios. Generally, antimicrobial drug choice was appropriate for the reported surgical conditions. Procaine penicillin and oxytetracycline accounted for 93 per cent of use. However, there was a wide range of doses used, with underdosing and inappropriate timing of administration being common reasons for inappropriate prophylactic treatment. There was very low use of critically important antimicrobials (3.3 per cent of antimicrobials reported). Antimicrobial use guidelines need to be developed and promoted to improve the responsible use of antimicrobials in bovine practice. PMID- 28893973 TI - Understanding the primary care paradigm: an experiential learning focus of the early veterinary graduate. AB - At a time where high levels of stress are reported in the veterinary profession, this study explores the challenges that veterinary graduates encounter when they enter general (first opinion) practice. Participants had written reflective accounts of their 'Most Puzzling Cases' for the postgraduate Professional Key Skills module of the Certificate in Advanced Veterinary Practice, offered by the Royal Veterinary College. Reasons that a case was puzzling, or became challenging, were thematically analysed. Fifteen summaries were analysed. Three core themes were identified: 'clinical reasoning', centred on the limitations of pattern recognition and the methods used to overcome this; the 'veterinary healthcare system', focusing on the need for continuity of care, time pressure and support in the transition to practice; and the 'owner', looking at the broader clinical skills needed to succeed in general practice. Clinical reasoning was raised as an issue; discussion of when pattern recognition is not appropriate and what to do in these cases was common. A lack of experience in general practice case types, and how to best operate in the resource-constrained environment in which they present, is the likely cause of this, suggesting that a greater focus on the primary care paradigm is needed within veterinary education. PMID- 28893974 TI - Field study on the safety and efficacy of intradermal versus intramuscular vaccination against Mycoplasma hyopneumoniae. AB - The present study compares the safety and efficacy of a needle-free, intradermal Mycoplasma hyopneumoniae vaccine to an intramuscular one. 420 piglets (21+3 days of age) were randomly assigned to two vaccination groups (intradermal vaccination V1 (n=138), intramuscular vaccination V2 (n=144)) and one unvaccinated control group (CG, n=138). As safety parameters clinical observations, local injection site reactions (ISR) and rectal temperatures were assessed. Average daily weight gain (ADWG) and pneumonic lung lesions (LL) were measured as efficacy parameters. ISRs were minor in V1. After both vaccinations, no adverse impact on appetite was observed and mean rectal temperatures remained within physiological range. ADWG during the fattening period was significantly higher in vaccinated groups (V1: 913.4 g, V2: 924.5 g) compared with CG (875.6 g). No differences in ADWG were observed between V1 and V2. Vaccinated pigs had a significantly reduced mean extent of LL compared with CG. V1 was superior in reducing the extent and prevalence of LL compared with V2. These results reveal that a needle-free intradermal vaccination is safe and efficacious in reducing both the prevalence and extent of lung lesions, as well as in improving performance parameters, in a farrow-to-finish farm with a late onset of M hyopneumoniae infection. PMID- 28893975 TI - Agonist-Dependent and -Independent kappa Opioid Receptor Phosphorylation: Distinct Phosphorylation Patterns and Different Cellular Outcomes. AB - We reported previously that the selective agonist U50,488H promoted phosphorylation of the mouse kappa opioid receptor (KOPR) at residues S356, T357, T363, and S369. Here, we found that agonist (U50,488H)-dependent KOPR phosphorylation at all the residues was mediated by Gi/o alpha proteins and multiple protein kinases [GRK2, GRK3, GRK5, GRK6 and protein kinase C (PKC)]. In addition, PKC activation by phorbol ester induced agonist-independent KOPR phosphorylation. Compared with U50,488H, PKC activation promoted much higher S356/T357 phosphorylation, much lower T363 phosphorylation, and similar levels of S369 phosphorylation. After U50,488H treatment, GRKs, but not PKC, were involved in agonist-induced KOPR internalization. In contrast, PKC activation caused a lower level of agonist-independent KOPR internalization, compared with U50,488H. U50,488H-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was G protein-, but not beta-arrestin-, dependent. After U50,488H treatment, GRK mediated, but not PKC-mediated, KOPR phosphorylation followed by beta-arrestin recruitment desensitized U50,488H-induced ERK1/2 response. Therefore, agonist dependent (GRK- and PKC-mediated) and agonist-independent (PKC-promoted) KOPR phosphorylations show distinct phosphorylation patterns, leading to diverse cellular outcomes. PMID- 28893976 TI - Teaching an Old Drug New Tricks: Agonism, Antagonism, and Biased Signaling of Pilocarpine through M3 Muscarinic Acetylcholine Receptor. AB - Pilocarpine is a prototypical drug used to treat glaucoma and dry mouth and is classified as either a full or partial muscarinic agonist. Here, we report several unexpected results pertaining to its interaction with muscarinic M3 receptor (M3R). We found that pilocarpine was 1000 times less potent in stimulating mouse-eye pupil constriction than muscarinic agonists oxotremorin-M (Oxo-M) or carbachol (CCh), although all three ligands have similar Kd values for M3R. In contrast to CCh or Oxo-M, pilocarpine does not induce Ca2+ mobilization via endogenous M3R in human embryonic kidney cell line 293T (HEK293T) or mouse insulinoma (MIN6) cells. Pilocarpine also fails to stimulate insulin secretion and, instead, antagonizes the insulinotropic effect of Oxo-M and CCh-induced Ca2+ upregulation; however, in HEK293T or Chinese hamster ovary-K1 cells overexpressing M3R, pilocarpine induces Ca2+ transients like those recorded with another cognate G protein-coupled muscarinic receptor, M1R. Stimulation of cells overexpressing M1R or M3R with CCh resulted in a similar reduction in phosphatidylinositol 4,5-bisphosphate (PIP2). In contrast to CCh, pilocarpine stimulated PIP2 hydrolysis only in cells overexpressing M1R but not M3R. Moreover, pilocarpine blocked CCh-stimulated PIP2 hydrolysis in M3R overexpressing cells, thus, it acted as an antagonist. Pilocarpine activates extracellular regulated kinase 1/2 in MIN6 cells. The stimulatory effect on extracellular regulated kinase (ERK1/2) was blocked by the Src family kinase inhibitor PP2, indicating that the action of pilocarpine on endogenous M3R is biased toward beta-arrestin. Taken together, our findings show that pilocarpine can act as either an agonist or antagonist of M3R, depending on the cell type, expression level, and signaling pathway downstream of this receptor. PMID- 28893977 TI - Open fontanelles in an elderly man. PMID- 28893978 TI - Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. AB - The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS. PMID- 28893979 TI - Exposure to unpredictable maternal sensory signals influences cognitive development across species. AB - Maternal care is a critical determinant of child development. However, our understanding of processes and mechanisms by which maternal behavior influences the developing human brain remains limited. Animal research has illustrated that patterns of sensory information is important in shaping neural circuits during development. Here we examined the relation between degree of predictability of maternal sensory signals early in life and subsequent cognitive function in both humans (n = 128 mother/infant dyads) and rats (n = 12 dams; 28 adolescents). Behaviors of mothers interacting with their offspring were observed in both species, and an entropy rate was calculated as a quantitative measure of degree of predictability of transitions among maternal sensory signals (visual, auditory, and tactile). Human cognitive function was assessed at age 2 y with the Bayley Scales of Infant Development and at age 6.5 y with a hippocampus-dependent delayed-recall task. Rat hippocampus-dependent spatial memory was evaluated on postnatal days 49-60. Early life exposure to unpredictable sensory signals portended poor cognitive performance in both species. The present study provides evidence that predictability of maternal sensory signals early in life impacts cognitive function in both rats and humans. The parallel between experimental animal and observational human data lends support to the argument that predictability of maternal sensory signals causally influences cognitive development. PMID- 28893980 TI - New evidence on the impact of sustained exposure to air pollution on life expectancy from China's Huai River Policy. AB - This paper finds that a 10-MUg/m3 increase in airborne particulate matter [particulate matter smaller than 10 MUm (PM10)] reduces life expectancy by 0.64 years (95% confidence interval = 0.21-1.07). This estimate is derived from quasiexperimental variation in PM10 generated by China's Huai River Policy, which provides free or heavily subsidized coal for indoor heating during the winter to cities north of the Huai River but not to those to the south. The findings are derived from a regression discontinuity design based on distance from the Huai River, and they are robust to using parametric and nonparametric estimation methods, different kernel types and bandwidth sizes, and adjustment for a rich set of demographic and behavioral covariates. Furthermore, the shorter lifespans are almost entirely caused by elevated rates of cardiorespiratory mortality, suggesting that PM10 is the causal factor. The estimates imply that bringing all of China into compliance with its Class I standards for PM10 would save 3.7 billion life-years. PMID- 28893981 TI - U-Th dating reveals regional-scale decline of branching Acropora corals on the Great Barrier Reef over the past century. AB - Hard coral cover on the Great Barrier Reef (GBR) is on a trajectory of decline. However, little is known about past coral mortality before the advent of long term monitoring (circa 1980s). Using paleoecological analysis and high-precision uranium-thorium (U-Th) dating, we reveal an extensive loss of branching Acropora corals and changes in coral community structure in the Palm Islands region of the central GBR over the past century. In 2008, dead coral assemblages were dominated by large, branching Acropora and living coral assemblages by genera typically found in turbid inshore environments. The timing of Acropora mortality was found to be occasionally synchronous among reefs and frequently linked to discrete disturbance events, occurring in the 1920s to 1960s and again in the 1980s to 1990s. Surveys conducted in 2014 revealed low Acropora cover (<5%) across all sites, with very little evidence of change for up to 60 y at some sites. Collectively, our results suggest a loss of resilience of this formerly dominant key framework builder at a regional scale, with recovery severely lagging behind predictions. Our study implies that the management of these reefs may be predicated on a shifted baseline. PMID- 28893982 TI - Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA binding protein PSF. AB - Developing therapeutic approaches are necessary for treating hormone-refractory prostate cancer. Activation of androgen receptor (AR) and its variants' expression along with the downstream signals are mostly important for disease progression. However, the mechanism for marked increases of AR signals and its expression is still unclear. Here, we revealed that various spliceosome genes are aberrantly induced by RNA-binding protein PSF, leading to enhancement of the splicing activities for AR expression. Our high-speed sequence analyses identified global PSF-binding transcripts. PSF was shown to stabilize and activate key long noncoding RNAs and AR-regulated gene expressions in prostate cancer cells. Interestingly, mRNAs of spliceosome-related genes are putative primary targets of PSF. Their gene expressions are up-regulated by PSF in hormone refractory prostate cancer. Moreover, PSF coordinated these spliceosome proteins to form a complex to promote AR splicing and expression. Thus, targeting PSF and its related pathways implicates the therapeutic possibility for hormone refractory prostate cancer. PMID- 28893983 TI - Mechanisms for restraining cAMP-dependent protein kinase revealed by subunit quantitation and cross-linking approaches. AB - Protein phosphorylation by cyclic AMP-dependent protein kinase (PKA) underlies key cellular processes, including sympathetic stimulation of heart cells, and potentiation of synaptic strength in neurons. Unrestrained PKA activity is pathological, and an enduring challenge is to understand how the activity of PKA catalytic subunits is directed in cells. We developed a light-activated cross linking approach to monitor PKA subunit interactions with temporal precision in living cells. This enabled us to refute the recently proposed theory that PKA catalytic subunits remain tethered to regulatory subunits during cAMP elevation. Instead, we have identified other features of PKA signaling for reducing catalytic subunit diffusion and increasing recapture rate. Comprehensive quantitative immunoblotting of protein extracts from human embryonic kidney cells and rat organs reveals that regulatory subunits are always in large molar excess of catalytic subunits (average ~17-fold). In the majority of organs tested, type II regulatory (RII) subunits were found to be the predominant PKA subunit. We also examined the architecture of PKA complexes containing RII subunits using cross-linking coupled to mass spectrometry. Quantitative comparison of cross linking within a complex of RIIbeta and Cbeta, with or without the prototypical anchoring protein AKAP18alpha, revealed that the dimerization and docking domain of RIIbeta is between its second cAMP binding domains. This architecture is compatible with anchored RII subunits directing the myristylated N terminus of catalytic subunits toward the membrane for release and recapture within the plane of the membrane. PMID- 28893984 TI - Nanoswitch-linked immunosorbent assay (NLISA) for fast, sensitive, and specific protein detection. AB - Protein detection and quantification play critical roles in both basic research and clinical practice. Current detection platforms range from the widely used ELISA to more sophisticated, and more expensive, approaches such as digital ELISA. Despite advances, there remains a need for a method that combines the simplicity and cost-effectiveness of ELISA with the sensitivity and speed of modern approaches in a format suitable for both laboratory and rapid, point-of care applications. Building on recent developments in DNA structural nanotechnology, we introduce the nanoswitch-linked immunosorbent assay (NLISA), a detection platform based on easily constructed DNA nanodevices that change conformation upon binding to a target protein with the results read out by gel electrophoresis. NLISA is surface-free and includes a kinetic-proofreading step for purification, enabling both enhanced sensitivity and reduced cross reactivity. We demonstrate femtomolar-level detection of prostate-specific antigen in biological fluids, as well as reduced cross-reactivity between different serotypes of dengue and also between a single-mutation and wild-type protein. NLISA is less expensive, uses less sample volume, is more rapid, and, with no washes, includes fewer hands-on steps than ELISA, while also achieving superior sensitivity. Our approach also has the potential to enable rapid point of-care assays, as we demonstrate by performing NLISA with an iPad/iPhone camera for imaging. PMID- 28893985 TI - Coupling of pollination services and coffee suitability under climate change. AB - Climate change will cause geographic range shifts for pollinators and major crops, with global implications for food security and rural livelihoods. However, little is known about the potential for coupled impacts of climate change on pollinators and crops. Coffee production exemplifies this issue, because large losses in areas suitable for coffee production have been projected due to climate change and because coffee production is dependent on bee pollination. We modeled the potential distributions of coffee and coffee pollinators under current and future climates in Latin America to understand whether future coffee-suitable areas will also be suitable for pollinators. Our results suggest that coffee suitable areas will be reduced 73-88% by 2050 across warming scenarios, a decline 46-76% greater than estimated by global assessments. Mean bee richness will decline 8-18% within future coffee-suitable areas, but all are predicted to contain at least 5 bee species, and 46-59% of future coffee-suitable areas will contain 10 or more species. In our models, coffee suitability and bee richness each increase (i.e., positive coupling) in 10-22% of future coffee-suitable areas. Diminished coffee suitability and bee richness (i.e., negative coupling), however, occur in 34-51% of other areas. Finally, in 31-33% of the future coffee distribution areas, bee richness decreases and coffee suitability increases. Assessing coupled effects of climate change on crop suitability and pollination can help target appropriate management practices, including forest conservation, shade adjustment, crop rotation, or status quo, in different regions. PMID- 28893986 TI - Atmospheric evidence for a global secular increase in carbon isotopic discrimination of land photosynthesis. AB - A decrease in the 13C/12C ratio of atmospheric CO2 has been documented by direct observations since 1978 and from ice core measurements since the industrial revolution. This decrease, known as the 13C-Suess effect, is driven primarily by the input of fossil fuel-derived CO2 but is also sensitive to land and ocean carbon cycling and uptake. Using updated records, we show that no plausible combination of sources and sinks of CO2 from fossil fuel, land, and oceans can explain the observed 13C-Suess effect unless an increase has occurred in the 13C/12C isotopic discrimination of land photosynthesis. A trend toward greater discrimination under higher CO2 levels is broadly consistent with tree ring studies over the past century, with field and chamber experiments, and with geological records of C3 plants at times of altered atmospheric CO2, but increasing discrimination has not previously been included in studies of long term atmospheric 13C/12C measurements. We further show that the inferred discrimination increase of 0.014 +/- 0.0070/00 ppm-1 is largely explained by photorespiratory and mesophyll effects. This result implies that, at the global scale, land plants have regulated their stomatal conductance so as to allow the CO2 partial pressure within stomatal cavities and their intrinsic water use efficiency to increase in nearly constant proportion to the rise in atmospheric CO2 concentration. PMID- 28893987 TI - Acidophilic green algal genome provides insights into adaptation to an acidic environment. AB - Some microalgae are adapted to extremely acidic environments in which toxic metals are present at high levels. However, little is known about how acidophilic algae evolved from their respective neutrophilic ancestors by adapting to particular acidic environments. To gain insights into this issue, we determined the draft genome sequence of the acidophilic green alga Chlamydomonas eustigma and performed comparative genome and transcriptome analyses between Ceustigma and its neutrophilic relative Chlamydomonas reinhardtii The results revealed the following features in Ceustigma that probably contributed to the adaptation to an acidic environment. Genes encoding heat-shock proteins and plasma membrane H+ ATPase are highly expressed in Ceustigma This species has also lost fermentation pathways that acidify the cytosol and has acquired an energy shuttle and buffering system and arsenic detoxification genes through horizontal gene transfer. Moreover, the arsenic detoxification genes have been multiplied in the genome. These features have also been found in other acidophilic green and red algae, suggesting the existence of common mechanisms in the adaptation to acidic environments. PMID- 28893988 TI - Cryo-EM structure of the bacteriophage T4 isometric head at 3.3-A resolution and its relevance to the assembly of icosahedral viruses. AB - The 3.3-A cryo-EM structure of the 860-A-diameter isometric mutant bacteriophage T4 capsid has been determined. WT T4 has a prolate capsid characterized by triangulation numbers (T numbers) Tend = 13 for end caps and Tmid = 20 for midsection. A mutation in the major capsid protein, gp23, produced T=13 icosahedral capsids. The capsid is stabilized by 660 copies of the outer capsid protein, Soc, which clamp adjacent gp23 hexamers. The occupancies of Soc molecules are proportional to the size of the angle between the planes of adjacent hexameric capsomers. The angle between adjacent hexameric capsomers is greatest around the fivefold vertices, where there is the largest deviation from a planar hexagonal array. Thus, the Soc molecules reinforce the structure where there is the greatest strain in the gp23 hexagonal lattice. Mutations that change the angles between adjacent capsomers affect the positions of the pentameric vertices, resulting in different triangulation numbers in bacteriophage T4. The analysis of the T4 mutant head assembly gives guidance to how other icosahedral viruses reproducibly assemble into capsids with a predetermined T number, although the influence of scaffolding proteins is also important. PMID- 28893989 TI - Structures of the peptide-modifying radical SAM enzyme SuiB elucidate the basis of substrate recognition. AB - Posttranslational modification of ribosomally synthesized peptides provides an elegant means for the production of biologically active molecules known as RiPPs (ribosomally synthesized and posttranslationally modified peptides). Although the leader sequence of the precursor peptide is often required for turnover, the exact mode of recognition by the modifying enzymes remains unclear for many members of this class of natural products. Here, we have used X-ray crystallography and computational modeling to examine the role of the leader peptide in the biosynthesis of a homolog of streptide, a recently identified peptide natural product with an intramolecular lysine-tryptophan cross-link, which is installed by the radical S-adenosylmethionine (SAM) enzyme, StrB. We present crystal structures of SuiB, a close ortholog of StrB, in various forms, including apo SuiB, SAM-bound SuiB, and a complex of SuiB with SAM and its peptide substrate, SuiA. Although the N-terminal domain of SuiB adopts a typical RRE (RiPP recognition element) motif, which has been implicated in precursor peptide recognition, we observe binding of the leader peptide in the catalytic barrel rather than the N-terminal domain. Computational simulations support a mechanism in which the leader peptide guides posttranslational modification by positioning the cross-linking residues of the precursor peptide within the active site. Together the results shed light onto binding of the precursor peptide and the associated conformational changes needed for the formation of the unique carbon-carbon cross-link in the streptide family of natural products. PMID- 28893991 TI - Correction for Harris et al., Young children communicate their ignorance and ask questions. PMID- 28893990 TI - CD1d-Restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. AB - Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal triglyceride transfer protein (MTP), a protein involved in the transfer of lipids onto CD1d, regulates liver iNKT cell homeostasis in a manner dependent on hepatocyte CD1d. Mice with hepatocyte-specific loss of MTP exhibit defects in the function of CD1d and show increased hepatic iNKT cell numbers as a consequence of altered iNKT cell apoptosis. Similar findings were made in mice with hepatocyte-specific loss of CD1d, confirming a critical role of CD1d in this process. Moreover, increased hepatic iNKT cell abundance in the absence of MTP is associated with susceptibility to severe iNKT cell-mediated hepatitis, thus demonstrating the importance of CD1d-dependent control of liver iNKT cells in maintaining immunological homeostasis in the liver. Together, these data demonstrate an unanticipated role of parenchymal cells, as shown here for hepatocytes, in tissue-specific regulation of CD1d-restricted immunity and further suggest that alterations in lipid metabolism may affect iNKT cell homeostasis through effects on CD1d-associated lipid antigens. PMID- 28893992 TI - Profile of Daniel H. Janzen. PMID- 28893993 TI - Arresting dissolution by interfacial rheology design. AB - A strategy to halt dissolution of particle-coated air bubbles in water based on interfacial rheology design is presented. Whereas previously a dense monolayer was believed to be required for such an "armored bubble" to resist dissolution, in fact engineering a 2D yield stress interface suffices to achieve such performance at submonolayer particle coverages. We use a suite of interfacial rheology techniques to characterize spherical and ellipsoidal particles at an air water interface as a function of surface coverage. Bubbles with varying particle coverages are made and their resistance to dissolution evaluated using a microfluidic technique. Whereas a bare bubble only has a single pressure at which a given radius is stable, we find a range of pressures over which bubble dissolution is arrested for armored bubbles. The link between interfacial rheology and macroscopic dissolution of [Formula: see text] 100 [Formula: see text]m bubbles coated with [Formula: see text] 1 [Formula: see text]m particles is presented and discussed. The generic design rationale is confirmed by using nonspherical particles, which develop significant yield stress at even lower surface coverages. Hence, it can be applied to successfully inhibit Ostwald ripening in a multitude of foam and emulsion applications. PMID- 28893994 TI - Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. AB - There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS. PMID- 28893997 TI - Thomas E. Starzl: Transplantation pioneer. PMID- 28893996 TI - Evolution of flexibility and rigidity in retaliatory punishment. AB - Natural selection designs some social behaviors to depend on flexible learning processes, whereas others are relatively rigid or reflexive. What determines the balance between these two approaches? We offer a detailed case study in the context of a two-player game with antisocial behavior and retaliatory punishment. We show that each player in this game-a "thief" and a "victim"-must balance two competing strategic interests. Flexibility is valuable because it allows adaptive differentiation in the face of diverse opponents. However, it is also risky because, in competitive games, it can produce systematically suboptimal behaviors. Using a combination of evolutionary analysis, reinforcement learning simulations, and behavioral experimentation, we show that the resolution to this tension-and the adaptation of social behavior in this game-hinges on the game's learning dynamics. Our findings clarify punishment's adaptive basis, offer a case study of the evolution of social preferences, and highlight an important connection between natural selection and learning in the resolution of social conflicts. PMID- 28893995 TI - N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils. AB - Biosynthesis of the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc) was lost during human evolution due to inactivation of the CMAH gene, possibly expediting divergence of the Homo lineage, due to a partial fertility barrier. Neu5Gc catabolism generates N-glycolylhexosamines, which are potential precursors for glycoconjugate biosynthesis. We carried out metabolic labeling experiments and studies of mice with human-like Neu5Gc deficiency to show that Neu5Gc degradation is the metabolic source of UDP-GlcNGc and UDP-GalNGc and the latter allows an unexpectedly selective incorporation of N-glycolyl groups into chondroitin sulfate (CS) over other potential glycoconjugate products. Partially N-glycolylated-CS was chemically synthesized as a standard for mass spectrometry to confirm its natural occurrence. Much lower amounts of GalNGc in human CS can apparently be derived from Neu5Gc-containing foods, a finding confirmed by feeding Neu5Gc-rich chow to human-like Neu5Gc-deficient mice. Unlike the case with Neu5Gc, N-glycolyl-CS was also stable enough to be detectable in animal fossils as old as 4 My. This work opens the door for investigating the biological and immunological significance of this glycosaminoglycan modification and for an "ancient glycans" approach to dating of Neu5Gc loss during the evolution of Homo. PMID- 28893998 TI - Engineering a light-activated caspase-3 for precise ablation of neurons in vivo. AB - The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV-induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms. PMID- 28893999 TI - Cortically coordinated NREM thalamocortical oscillations play an essential, instructive role in visual system plasticity. AB - Two long-standing questions in neuroscience are how sleep promotes brain plasticity and why some forms of plasticity occur preferentially during sleep vs. wake. Establishing causal relationships between specific features of sleep (e.g., network oscillations) and sleep-dependent plasticity has been difficult. Here we demonstrate that presentation of a novel visual stimulus (a single oriented grating) causes immediate, instructive changes in the firing of mouse lateral geniculate nucleus (LGN) neurons, leading to increased firing-rate responses to the presented stimulus orientation (relative to other orientations). However, stimulus presentation alone does not affect primary visual cortex (V1) neurons, which show response changes only after a period of subsequent sleep. During poststimulus nonrapid eye movement (NREM) sleep, LGN neuron overall spike-field coherence (SFC) with V1 delta (0.5-4 Hz) and spindle (7-15 Hz) oscillations increased, with neurons most responsive to the presented stimulus showing greater SFC. To test whether coherent communication between LGN and V1 was essential for cortical plasticity, we first tested the role of layer 6 corticothalamic (CT) V1 neurons in coherent firing within the LGN-V1 network. We found that rhythmic optogenetic activation of CT V1 neurons dramatically induced coherent firing in LGN neurons and, to a lesser extent, in V1 neurons in the other cortical layers. Optogenetic interference with CT feedback to LGN during poststimulus NREM sleep (but not REM or wake) disrupts coherence between LGN and V1 and also blocks sleep dependent response changes in V1. We conclude that NREM oscillations relay information regarding prior sensory experience between the thalamus and cortex to promote cortical plasticity. PMID- 28894000 TI - Disassembly of the Staphylococcus aureus hibernating 100S ribosome by an evolutionarily conserved GTPase. AB - The bacterial hibernating 100S ribosome is a poorly understood form of the dimeric 70S particle that has been linked to pathogenesis, translational repression, starvation responses, and ribosome turnover. In the opportunistic pathogen Staphylococcus aureus and most other bacteria, hibernation-promoting factor (HPF) homodimerizes the 70S ribosomes to form a translationally silent 100S complex. Conversely, the 100S ribosomes dissociate into subunits and are presumably recycled for new rounds of translation. The regulation and disassembly of the 100S ribosome are largely unknown because the temporal abundance of the 100S ribosome varies considerably among different bacterial phyla. Here, we identify a universally conserved GTPase (HflX) as a bona fide dissociation factor of the S. aureus 100S ribosome. The expression levels hpf and hflX are coregulated by general stress and stringent responses in a temperature-dependent manner. While all tested guanosine analogs stimulate the splitting activity of HflX on the 70S ribosome, only GTP can completely dissociate the 100S ribosome. Our results reveal the antagonistic relationship of HPF and HflX and uncover the key regulators of 70S and 100S ribosome homeostasis that are intimately associated with bacterial survival. PMID- 28894002 TI - Universal nanodroplet branches from confining the Ouzo effect. AB - We report the self-organization of universal branching patterns of oil nanodroplets under the Ouzo effect [Vitale S, Katz J (2003) Langmuir 19:4105 4110]-a phenomenon in which spontaneous droplet formation occurs upon dilution of an organic solution of oil with water. The mixing of the organic and aqueous phases is confined under a quasi-2D geometry. In a manner analogous to the ramification of ground stream networks [Devauchelle O, Petroff AP, Seybold HF, Rothman DH (2012) Proc Natl Acad Sci USA 109: 20832-20836 and Cohen Y, et al. (2015) Proc Natl Acad Sci USA 112:14132-14137] but on a scale 10 orders of magnitude smaller, the angles between the droplet branches are seen to exhibit remarkable universality, with a value around 74 degrees +/- 2 degrees , independent of the various control parameters of the process. Numerical simulations reveal that these nanodroplet branching patterns are governed by the interplay between the local concentration gradient, diffusion, and collective interactions. We further demonstrate the ability of the local concentration gradient to drive autonomous motion of colloidal particles in the highly confined space, and the possibility of using the nucleated nanodroplets for nanoextraction of a hydrophobic solute. The understanding obtained from this work provides a basis for quantitatively understanding the complex dynamical aspects associated with the Ouzo effect. We expect that this will facilitate improved control in nanodroplet formation for many applications, spanning from the preparation of pharmaceutical polymeric carriers, to the formulation of cosmetics and insecticides, to the fabrication of nanostructured materials, to the concentration and separation of trace analytes in liquid-liquid microextraction. PMID- 28894001 TI - Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. AB - Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL 10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10-producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas. The ability of Tr1 cells to cure diabetes in NOD mice required IL-10 signaling, as Tr1 cells could not suppress CD4+ T cells with a dominant-negative IL-10R. Taken together, our data show a key role of intestinal Tr1 cells in the control of effector T cells and development of diabetes. Therefore, modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management. PMID- 28894003 TI - Reexamining the origin of the directionality of myosin V. AB - The nature of the conversion of chemical energy to directional motion in myosin V is examined by careful simulations that include two complementary methods: direct Langevin Dynamics (LD) simulations with a scaled-down potential that provided a detailed time-resolved mechanism, and kinetic equations solution for the ensemble long-time propagation (based on information collected for segments of the landscape using LD simulations and experimental information). It is found that the directionality is due to the rate-limiting ADP release step rather than the potential energy of the lever arm angle. We show that the energy of the power stroke and the barriers involved in it are of minor consequence to the selectivity of forward over backward steps and instead suggest that the selective release of ADP from a postrigor myosin motor head promotes highly selective and processive myosin V. Our model is supported by different computational methods-LD simulations, Monte Carlo simulations, and kinetic equations solution-as well as by structure-based binding energy calculations. PMID- 28894004 TI - Waiting can be an optimal conservation strategy, even in a crisis discipline. AB - Biodiversity conservation projects confront immediate and escalating threats with limited funding. Conservation theory suggests that the best response to the species extinction crisis is to spend money as soon as it becomes available, and this is often an explicit constraint placed on funding. We use a general dynamic model of a conservation landscape to show that this decision to "front-load" project spending can be suboptimal if a delay allows managers to use resources more strategically. Our model demonstrates the existence of temporal efficiencies in conservation management, which parallel the spatial efficiencies identified by systematic conservation planning. The optimal timing of decisions balances the rate of biodiversity decline (e.g., the relaxation of extinction debts, or the progress of climate change) against the rate at which spending appreciates in value (e.g., through interest, learning, or capacity building). We contrast the benefits of acting and waiting in two ecosystems where restoration can mitigate forest bird extinction debts: South Australia's Mount Lofty Ranges and Paraguay's Atlantic Forest. In both cases, conservation outcomes cannot be maximized by front-loading spending, and the optimal solution recommends substantial delays before managers undertake conservation actions. Surprisingly, these delays allow superior conservation benefits to be achieved, in less time than front-loading. Our analyses provide an intuitive and mechanistic rationale for strategic delay, which contrasts with the orthodoxy of front-loaded spending for conservation actions. Our results illustrate the conservation efficiencies that could be achieved if decision makers choose when to spend their limited resources, as opposed to just where to spend them. PMID- 28894005 TI - Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila. AB - The transmembrane semaphorin Sema-1a acts as both a ligand and a receptor to regulate axon-axon repulsion during neural development. Pebble (Pbl), a Rho guanine nucleotide exchange factor, mediates Sema-1a reverse signaling through association with the N-terminal region of the Sema-1a intracellular domain (ICD), resulting in cytoskeletal reorganization. Here, we uncover two additional Sema-1a interacting proteins, varicose (Vari) and cheerio (Cher), each with neuronal functions required for motor axon pathfinding. Vari is a member of the membrane associated guanylate kinase (MAGUK) family of proteins, members of which can serve as scaffolds to organize signaling complexes. Cher is related to actin filament cross-linking proteins that regulate actin cytoskeleton dynamics. The PDZ domain binding motif found in the most C-terminal region of the Sema-1a ICD is necessary for interaction with Vari, but not Cher, indicative of distinct binding modalities. Pbl/Sema-1a-mediated repulsive guidance is potentiated by both vari and cher Genetic analyses further suggest that scaffolding functions of Vari and Cher play an important role in Pbl-mediated Sema-1a reverse signaling. These results define intracellular components critical for signal transduction from the Sema-1a receptor to the cytoskeleton and provide insight into mechanisms underlying semaphorin-induced localized changes in cytoskeletal organization. PMID- 28894006 TI - Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. AB - Membrane encapsulation is frequently used by the cell to sequester biomolecules and compartmentalize their function. Cells also concentrate molecules into phase separated protein or protein/nucleic acid "membraneless organelles" that regulate a host of biochemical processes. Here, we use solution NMR spectroscopy to study phase-separated droplets formed from the intrinsically disordered N-terminal 236 residues of the germ-granule protein Ddx4. We show that the protein within the concentrated phase of phase-separated Ddx4, [Formula: see text], diffuses as a particle of 600-nm hydrodynamic radius dissolved in water. However, NMR spectra reveal sharp resonances with chemical shifts showing [Formula: see text] to be intrinsically disordered. Spin relaxation measurements indicate that the backbone amides of [Formula: see text] have significant mobility, explaining why high resolution spectra are observed, but motion is reduced compared with an equivalently concentrated nonphase-separating control. Observation of a network of interchain interactions, as established by NOE spectroscopy, shows the importance of Phe and Arg interactions in driving the phase separation of Ddx4, while the salt dependence of both low- and high-concentration regions of phase diagrams establishes an important role for electrostatic interactions. The diffusion of a series of small probes and the compact but disordered 4E binding protein 2 (4E-BP2) protein in [Formula: see text] are explained by an excluded volume effect, similar to that found for globular protein solvents. No changes in structural propensities of 4E-BP2 dissolved in [Formula: see text] are observed, while changes to DNA and RNA molecules have been reported, highlighting the diverse roles that proteinaceous solvents play in dictating the properties of dissolved solutes. PMID- 28894007 TI - RABIF/MSS4 is a Rab-stabilizing holdase chaperone required for GLUT4 exocytosis. AB - Rab GTPases are switched from their GDP-bound inactive conformation to a GTP bound active state by guanine nucleotide exchange factors (GEFs). The first putative GEFs isolated for Rabs are RABIF (Rab-interacting factor)/MSS4 (mammalian suppressor of Sec4) and its yeast homolog DSS4 (dominant suppressor of Sec4). However, the biological function and molecular mechanism of these molecules remained unclear. In a genome-wide CRISPR genetic screen, we isolated RABIF as a positive regulator of exocytosis. Knockout of RABIF severely impaired insulin-stimulated GLUT4 exocytosis in adipocytes. Unexpectedly, we discovered that RABIF does not function as a GEF, as previously assumed. Instead, RABIF promotes the stability of Rab10, a key Rab in GLUT4 exocytosis. In the absence of RABIF, Rab10 can be efficiently synthesized but is rapidly degraded by the proteasome, leading to exocytosis defects. Strikingly, restoration of Rab10 expression rescues exocytosis defects, bypassing the requirement for RABIF. These findings reveal a crucial role of RABIF in vesicle transport and establish RABIF as a Rab-stabilizing holdase chaperone, a previously unrecognized mode of Rab regulation independent of its GDP-releasing activity. Besides Rab10, RABIF also regulates the stability of two other Rab GTPases, Rab8 and Rab13, suggesting that the requirement of holdase chaperones is likely a general feature of Rab GTPases. PMID- 28894010 TI - Heartbeat: Virtual histopathology after myocardial infarction. PMID- 28894009 TI - Trichromacy increases fruit intake rates of wild capuchins (Cebus capucinus imitator). AB - Intraspecific color vision variation is prevalent among nearly all diurnal monkeys in the neotropics and is seemingly a textbook case of balancing selection acting to maintain genetic polymorphism. Clear foraging advantages to monkeys with trichromatic vision over those with dichromatic "red-green colorblind" vision have been observed in captive studies; however, evidence of trichromatic advantage during close-range foraging has been surprisingly scarce in field studies, perhaps as a result of small sample sizes and strong impacts of environmental or individual variation on foraging performance. To robustly test the effects of color vision type on foraging efficiency in the wild, we conducted an extensive study of dichromatic and trichromatic white-faced capuchin monkeys (Cebus capucinus imitator), controlling for plant-level and monkey-level variables that may affect fruit intake rates. Over the course of 14 months, we collected behavioral data from 72 monkeys in Sector Santa Rosa, Costa Rica. We analyzed 19,043 fruit feeding events within 1,602 foraging bouts across 27 plant species. We find that plant species, color conspicuity category, and monkey age class significantly impact intake rates, while sex does not. When plant species and age are controlled for, we observe that trichromats have higher intake rates than dichromats for plant species with conspicuously colored fruits. This study provides clear evidence of trichromatic advantage in close-range fruit feeding in wild monkeys. Taken together with previous reports of dichromatic advantage for finding cryptic foods, our results illuminate an important aspect of balancing selection maintaining primate opsin polymorphism. PMID- 28894008 TI - Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder. AB - Genome-wide association studies have implicated the ANK3 locus in bipolar disorder, a major human psychotic illness. ANK3 encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS). We generated a mouse model with conditional disruption of ANK3 in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to "depression-like" behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics. PMID- 28894011 TI - Palpitations in a 72-year-old woman. AB - CLINICAL INTRODUCTION: A 72-year-old woman presented with an 8-year history of palpitations occurring every few weeks. They were sudden in onset, were associated with dizziness and could last for up to 2 hours. She was prescribed bisoprolol which reduced the frequency of events but did not abolish them. Baseline ECG and echocardiography were normal. She was referred for electrophysiological study. Despite initial difficulties, diagnostic catheters were placed in the right ventricular (RV) apex and in the coronary sinus (CS) via the right internal jugular vein and superior vena cava (SVC) (figure 1A). A narrow complex tachycardia was easily induced, and ablation was then delivered during tachycardia with the ablation catheter positioned as shown in (figure 1A). This terminated tachycardia 4 s after onset of energy delivery and on follow-up she has remained asymptomatic. She later underwent a CT scan (figure 1B,C; online supplementary video).DC1SP110.1136/heartjnl-2017-311734.supp1Supplementary file 1 heartjnl;103/19/1554/F1F1F1Figure 1(A) Fluoroscopy of catheter placement. (B) Sagittal contrast-enhanced CT image. (C) Axial contrast-enhanced CT. QUESTION: What anatomical abnormality caused difficulty in catheter placement during the procedure?Azygous continuation of the inferior vena cava (IVC)Giant Eustachian valveDextrocardiaRenal tumour compressing IVC. PMID- 28894012 TI - Mechanical prosthetic heart valves (MPHV) in pregnancy are associated with a high risk of maternal and fetal morbidity and mortality. PMID- 28894013 TI - Moderate sedation in cardiac electrophysiology laboratory: a retrospective safety analysis. PMID- 28894014 TI - Correction: Altered biophysical properties of the voltage-gated sodium channels in mouse atrial and ventricular cardiomyocytes. PMID- 28894015 TI - Propensity Score Analysis of Regorafenib Versus Trifluridine/Tipiracil in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy (REGOTAS): A Japanese Society for Cancer of the Colon and Rectum Multicenter Observational Study. AB - BACKGROUND: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. MATERIALS AND METHODS: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. RESULTS: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95% CI, 0.98-1.69), whereas TFTD was favored in patients aged >=65 years (HR, 0.78; 95% CI, 0.59 1.03). CONCLUSION: No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. IMPLICATIONS FOR PRACTICE: Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged >=65 years in the subgroup analysis. PMID- 28894016 TI - The Issue of Tissue in Molecular Stratification. PMID- 28894018 TI - In Reply. PMID- 28894017 TI - Effects of Early Integrated Palliative Care on Caregivers of Patients with Lung and Gastrointestinal Cancer: A Randomized Clinical Trial. AB - BACKGROUND: The family and friends (caregivers) of patients with advanced cancer often experience tremendous distress. Although early integrated palliative care (PC) has been shown to improve patient-reported quality of life (QOL) and mood, its effects on caregivers' outcomes is currently unknown. MATERIALS AND METHODS: We conducted a randomized trial of early PC integrated with oncology care versus oncology care alone for patients who were newly diagnosed with incurable lung and noncolorectal gastrointestinal cancers and their caregivers. The early PC intervention focused on addressing the needs of both patients and their caregivers. Eligible caregivers were family or friends who would likely accompany patients to clinic visits. The intervention entailed at least monthly patient visits with PC from the time of diagnosis. Caregivers were encouraged, but not required, to attend the palliative care visits. We used the Hospital Anxiety and Depression Scale (HADS) and Medical Health Outcomes Survey Short-Form to assess caregiver mood and QOL. RESULTS: Two hundred seventy-five caregivers (intervention n = 137; control n = 138) of the 350 patients participated. The intervention led to improvement in caregivers' total distress (HADS-total adjusted mean difference = -1.45, 95% confidence interval [CI] -2.76 to -0.15, p = .029), depression subscale (HADS-depression adjusted mean difference = -0.71, 95% CI -1.38 to -0.05, p = .036), but not anxiety subscale or QOL at week 12. There were no differences in caregivers' outcomes at week 24. A terminal decline analysis showed significant intervention effects on caregivers' total distress (HADS-total), with effects on both the anxiety and depression subscales at 3 and 6 months before patient death. CONCLUSION: Early involvement of PC for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. This work demonstrates that the benefits of early, integrated PC models in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. IMPLICATIONS FOR PRACTICE: Early involvement of palliative care for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. The findings of this trial demonstrate that the benefits of the early, integrated palliative care model in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. These findings contribute novel data to the growing evidence base supporting the benefits of integrating palliative care earlier in the course of disease for patients with advanced cancer and their caregivers. PMID- 28894019 TI - Iron-Nicotianamine Transporters Are Required for Proper Long Distance Iron Signaling. AB - The mechanisms of root iron uptake and the transcriptional networks that control root-level regulation of iron uptake have been well studied, but the mechanisms by which shoots signal iron status to the roots remain opaque. Here, we characterize an Arabidopsis (Arabidopsis thaliana) double mutant, yellow stripe1 like yellow stripe3-like (ysl1ysl3), which has lost the ability to properly regulate iron deficiency-influenced gene expression in both roots and shoots. In spite of markedly low tissue levels of iron, the double mutant does not up- and down-regulate iron deficiency-induced and -repressed genes. We have used grafting experiments to show that wild-type roots grafted to ysl1ysl3 shoots do not initiate iron deficiency-induced gene expression, indicating that the ysl1ysl3 shoots fail to send an appropriate long-distance signal of shoot iron status to the roots. We present a model to explain how impaired iron localization in leaf veins results in incorrect signals of iron sufficiency being sent to roots and affecting gene expression there. Improved understanding of the mechanism of long distance iron signaling will allow improved strategies for the engineering of staple crops to accumulate additional bioavailable iron in edible parts, thus improving the iron nutrition of the billions of people worldwide whose inadequate diet causes iron deficiency anemia. PMID- 28894020 TI - Transcription Factor OsWRKY53 Positively Regulates Brassinosteroid Signaling and Plant Architecture. AB - Brassinosteroids (BRs) are a class of steroid hormones regulating multiple aspects of plant growth, development, and adaptation. Compared with extensive studies in Arabidopsis (Arabidopsis thaliana), the mechanism of BR signaling in rice (Oryza sativa) is less understood. Here, we identified OsWRKY53, a transcription factor involved in defense responses, as an important regulator of rice BR signaling. Phenotypic analyses showed that OsWRKY53 overexpression led to enlarged leaf angles and increased grain size, in contrast to the erect leaves and smaller seeds in oswrky53 mutant. In addition, the oswrky53 exhibited decreased BR sensitivity, whereas OsWRKY53 overexpression plants were hypersensitive to BR, suggesting that OsWRKY53 positively regulates rice BR signaling. Moreover, we show that OsWRKY53 can interact with and be phosphorylated by the OsMAPKK4-OsMAPK6 cascade, and the phosphorylation is required for the biological function of OsWRKY53 in regulating BR responses. Furthermore, we found that BR promotes OsWRKY53 protein accumulation but represses OsWRKY53 transcript level. Taken together, this study revealed the novel role of OsWRKY53 as a regulator of rice BR signaling and also suggested a potential role of OsWRKY53 in mediating the cross talk between the hormone and other signaling pathways. PMID- 28894021 TI - Microtubule Array Patterns Have a Common Underlying Architecture in Hypocotyl Cells. AB - Microtubules at the plant cell cortex influence cell shape by patterning the deposition of cell wall materials. The elongated cells of the hypocotyl create a variety of microtubule array patterns with differing degrees of polymer coalignment and orientation to the cell's growth axis. To gain insight into the mechanisms driving array organization, we investigated the underlying microtubule array architecture in light-grown epidermal cells with explicit reference to array pattern. We discovered that all nontransverse patterns share a common underlying array architecture, having a core unimodal peak of coaligned microtubules in a split bipolarized arrangement. The growing microtubule plus ends extend toward the cell's apex and base with a region of antiparallel microtubule overlap at the cell's midzone. This core coalignment continuously shifts between +/-30 degrees from the cell's longitudinal growth axis, forming a continuum of longitudinal and oblique arrays. Transverse arrays exhibit the same unimodal core coalignment but form local domains of microtubules polymerizing in the same direction rather than a split bipolarized architecture. Quantitative imaging experiments and analysis of katanin mutants showed that the longitudinal arrays are created from microtubules originating on the outer periclinal cell face, pointing to a cell-directed, rather than self-organizing, mechanism for specifying the major array pattern classes in the hypocotyl cell. PMID- 28894022 TI - Highly Decorated Lignins in Leaf Tissues of the Canary Island Date Palm Phoenix canariensis. AB - The cell walls of leaf base tissues of the Canary Island date palm (Phoenix canariensis) contain lignins with the most complex compositions described to date. The lignin composition varies by tissue region and is derived from traditional monolignols (ML) along with an unprecedented range of ML conjugates: ML-acetate, ML-benzoate, ML-p-hydroxybenzoate, ML-vanillate, ML-p-coumarate, and ML-ferulate. The specific functions of such complex lignin compositions are unknown. However, the distribution of the ML conjugates varies depending on the tissue region, indicating that they may play specific roles in the cell walls of these tissues and/or in the plant's defense system. PMID- 28894024 TI - The synergistic antimicrobial effects of novel bombinin and bombinin H peptides from the skin secretion of Bombina orientalis. AB - Bombinin and bombinin H are two antimicrobial peptide (AMP) families initially discovered from the skin secretion of Bombina that share the same biosynthetic precursor-encoding cDNAs, but have different structures and physicochemical properties. Insight into their possible existing relationship lead us to perform the combination investigations into their anti-infectious activities. In this work, we report the molecular cloning and functional characterization of two novel AMPs belonging to bombinin and bombinin H families from secretions of Bombina orientalis Their mature peptides (BHL-bombinin and bombinin HL), coded by single ORF, were chemically synthesized along with an analogue peptide that replaced L-leucine with D-leucine from the second position of the N-terminus (bombinin HD). CD analysis revealed that all of them displayed well-defined alpha helical structures in membrane mimicking environments. Furthermore, BHL-bombinin displayed broad-spectrum bactericidal activities on a wide range of microorganisms, while bombinin H only exhibited a mildly bacteriostatic effect on the Gram-positive bacteria Staphylococcus aureus The combination potency of BHL bombinin with either bombinin HL or bombinin HD showed the synergistic inhibition activities against S. aureus (fractional inhibitory concentration index (FICI): 0.375). A synergistic effect has also been observed between bombinin H and ampicillin, which was further systematically evaluated and confirmed by in vitro time-killing investigations. Haemolytic and cytotoxic examinations exhibited a highly synergistic selectivity and low cytotoxicity on mammalian cells of these three peptides. Taken together, the discovery of the potent synergistic effect of AMPs in a single biosynthetic precursor with superior functional selectivity provides a promising strategy to combat multidrug-resistant pathogens in clinical therapy. PMID- 28894025 TI - Attenuation of miR-34a protects cardiomyocytes against hypoxic stress through maintenance of glycolysis. AB - MiRNAs are a class of endogenous, short, single-stranded, non-coding RNAs, which are tightly linked to cardiac disorders such as myocardial ischemia/reperfusion (I/R) injury. MiR-34a is known to be involved in the hypoxia-induced cardiomyocytes apoptosis. However, the molecular mechanisms are unclear. In the present study, we demonstrate that under low glucose supply, rat cardiomyocytes are susceptible to hypoxia. Under short-time hypoxia, cellular glucose uptake and lactate product are induced but under long-time hypoxia, the cellular glucose metabolism is suppressed. Interestingly, an adaptive up-regulation of miR-34a by long-time hypoxia was observed both in vitro and in vivo, leading to suppression of glycolysis in cardiomyocytes. We identified lactate dehydrogenase-A (LDHA) as a direct target of miR-34a, which binds to the 3'-UTR region of LDHA mRNA in cardiomyocytes. Moreover, inhibition of miR-34a attenuated hypoxia-induced cardiomyocytes dysfunction through restoration of glycolysis. The present study illustrates roles of miR-34a in the hypoxia-induced cardiomyocytes dysfunction and proposes restoration of glycolysis of dysfunctional cardiomyocytes by inhibiting miR-34a during I/R might be an effectively therapeutic approach against I/R injury. PMID- 28894023 TI - Cytokinin-Auxin Crosstalk in the Gynoecial Primordium Ensures Correct Domain Patterning. AB - The Arabidopsis (Arabidopsis thaliana) gynoecium consists of two congenitally fused carpels made up of two lateral valve domains and two medial domains, which retain meristematic properties and later fuse to produce the female reproductive structures vital for fertilization. Polar auxin transport (PAT) is important for setting up distinct apical auxin signaling domains in the early floral meristem remnants allowing for lateral domain identity and outgrowth. Crosstalk between auxin and cytokinin plays an important role in the development of other meristematic tissues, but hormone interaction studies to date have focused on more accessible later-stage gynoecia and the spatiotemporal interactions pivotal for patterning of early gynoecium primordia remain unknown. Focusing on the earliest stages, we propose a cytokinin-auxin feedback model during early gynoecium patterning and hormone homeostasis. Our results suggest that cytokinin positively regulates auxin signaling in the incipient gynoecial primordium and strengthen the concept that cytokinin regulates auxin homeostasis during gynoecium development. Specifically, medial cytokinin promotes auxin biosynthesis components [YUCCA1/4 (YUC1/4)] in, and PINFORMED7 (PIN7)-mediated auxin efflux from, the medial domain. The resulting laterally focused auxin signaling triggers ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN6 (AHP6), which then represses cytokinin signaling in a PAT-dependent feedback. Cytokinin also down-regulates PIN3, promoting auxin accumulation in the apex. The yuc1, yuc4, and ahp6 mutants are hypersensitive to exogenous cytokinin and 1-napthylphthalamic acid (NPA), highlighting their role in mediolateral gynoecium patterning. In summary, these mechanisms self-regulate cytokinin and auxin signaling domains, ensuring correct domain specification and gynoecium development. PMID- 28894026 TI - Associations of TGFBR1 and TGFBR2 gene polymorphisms with the risk of hypospadias: a case-control study in a Chinese population. AB - This case-control study investigated the association of transforming growth factor-beta (TGF-beta) receptor type I and II (TGFBR1 and TGFBR2) gene polymorphisms with the risk of hypospadias in a Chinese population. One hundred and sixty two patients suffering from hypospadias were enrolled as case group and 165 children who underwent circumcision were recruited as control group. Single nucleotide polymorphisms (SNPs) in TGFBR1 and TGFBR2 genes were selected on the basis of genetic data obtained from HapMap. PCR-restriction fragment length polymorphism (PCR-RFLP) was performed to identify TGFBR1 and TGFBR2 gene polymorphisms and analyze genotype distribution and allele frequency. Logistic regression analysis was conducted to estimate the risk factors for hypospadias. No significant difference was found concerning the genotype and allele frequencies of TGFBR1 rs4743325 polymorphism between the case and control groups. However, genotype and allele frequencies of TGFBR2 rs6785358 in the case group were significantly different in contrast with those in the control group. Patients carrying the G allele of TGFBR2 rs6785358 polymorphism exhibited a higher risk of hypospadias compared with the patients carrying the A allele (P<0.05). The TGFBR2 rs6785358 genotype was found to be significantly related to abnormal pregnancy and preterm birth (both P<0.05). The frequency of TGFBR2 rs6785358 GG genotype exhibited significant differences amongst patients suffering from four different pathological types of hypospadias. Logistic regression analysis revealed that preterm birth, abnormal pregnancy, and TGFBR2 rs6785358 were the independent risk factors for hypospadias. Our study provides evidence that TGFBR2 rs6785358 polymorphism might be associated with the risk of hypospadias. PMID- 28894027 TI - Corrected and Republished from: Activation Status-Coupled Transient S-Acylation Determines Membrane Partitioning of a Plant Rho-Related GTPase. AB - ROPs or RACs are plant Rho-related GTPases implicated in the regulation of a multitude of signaling pathways that function at the plasma membrane via posttranslational lipid modifications. The relationships between ROP activation status and membrane localization has not been established. Here, we show that endogenous ROPs, as well as a transgenic His6-green fluorescent protein (GFP) Arabidopsis thaliana ROP6 (AtROP6) fusion protein, were partitioned between Triton X-100-soluble and -insoluble membranes. In contrast, the His6-GFP-Atrop6CA activated mutant accumulated exclusively in detergent-resistant membranes. GDP induced accumulation of ROPs in Triton-soluble membranes, whereas GTPgammaS induced accumulation of ROPs in detergent-resistant membranes. Recombinant wild type and constitutively active AtROP6 proteins were purified from Arabidopsis plants, and in turn, their lipids were cleaved and analyzed by gas chromatography coupled mass spectrometry. In Triton-soluble membranes, the wild-type AtROP6 was only prenylated, primarily by geranylgeranyl. The activated AtROP6 that accumulated in detergent-resistant membranes was modified by prenyl and acyl lipids, identified as palmitic and stearic acids. Consistently, activated His6 GFP-Atrop6CAmS156, in which C156 was mutated into serine, accumulated in Triton soluble membranes. These findings show that upon GTP binding and activation, AtROP6, and possibly other ROPs, are transiently S-acylated, inducing their partitioning into detergent-resistant membranes. PMID- 28894030 TI - Proptosis: A forgotten observation by Miller Fisher on his syndrome. PMID- 28894031 TI - Editors' Note. PMID- 28894028 TI - MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling. AB - The mechanistic target of rapamycin complex 1 (MTORC1) is a critical negative regulator of general autophagy. We hypothesized that MTORC1 may specifically regulate autophagic clearance of damaged mitochondria. To test this, we used cells lacking tuberous sclerosis complex 2 (TSC2 -/-), which show constitutive MTORC1 activation. TSC2 -/- cells show MTORC1-dependent impaired autophagic flux after chemical uncoupling of mitochondria, increased mitochondrial protein aging and accumulation of p62/SQSTM1 positive mitochondria. Mitochondrial autophagy (mitophagy) was also deficient in cells lacking TSC2, associated with altered expression of PTEN-induced kinase 1 (PINK1) and PARK2 translocation to uncoupled mitochondria, all of which were recovered by MTORC1 inhibition or expression of constitutively active FoxO1. These data prove the necessity of intact MTORC1 signaling to regulate two synergistic processes required for clearance of damaged mitochondria: 1) general autophagy initiation, and 2) PINK1/PARK2-mediated selective targeting of uncoupled mitochondria to the autophagic machinery. PMID- 28894032 TI - Letter re: Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis. PMID- 28894033 TI - Author response: Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis. PMID- 28894029 TI - PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice. AB - DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stability in vivo and ex vivo Of note, Pari-deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice. PMID- 28894034 TI - Letter re: A model for predicting the growth of unruptured intracranial aneurysms: Beyond fortune telling. PMID- 28894036 TI - Motor neuron disease in patients with HIV infection. PMID- 28894035 TI - Editorialist response: A model for predicting the growth of unruptured intracranial aneurysms: Beyond fortune telling. PMID- 28894037 TI - Emerging Subspecialties in Neurology: Autoimmune neurology. PMID- 28894038 TI - Teaching NeuroImages: Early-onset dementia and demyelinating neuropathy disclosing cerebrotendinous xanthomatosis. PMID- 28894039 TI - Translational Approaches In Cardiovascular Diseases by Omics. AB - Cardiovascular diseases are among the leading causes of morbidity and mortality. Despite scientific and technical progress in risk prediction, diagnostics, prognostication and therapy of cardiovascular pathologies, new biomarkers and therapeutic targets remain the subject of intense research to reduce the burden of these diseases. High throughput analyses, termed "omics", are a promising avenue of research. These recently developed technical fields have revolutionized biological and medical research in a very short time. By their interdisciplinary nature, these new methods have already provided a wide vision of cell and tissue pathways and functions. Here, we review how these methods can help to discover new biomarkers and therapeutic targets in cardiovascular diseases. PMID- 28894040 TI - The role of vitamin D in the development of autoimmune diseases. AB - Witamina D, poza istotna rola w utrzymaniu homeostazy wapnia i metabolizmie kostnym, odgrywa wazna role w funkcjonowaniu ukladu odpornosciowego. Niedobor witaminy D wiaze sie z wieloma niekorzystnymi dla zdrowia skutkami, wlaczajac w to m.in. oslabienie odpornosci, czego skutkiem jest zwiekszona podatnosc na zakazenia wirusowe, bakteryjne oraz grzybicze. W artykule opisano podstawy metabolizmu witaminy D oraz jej role fizjologiczna, ze szczegolnym uwzglednieniem wplywu na komorki ukladu odpornosciowego. Ze wzgledu na jej istotna role w regulacji odpowiedzi zapalnej oraz wytwarzaniu cytokin zwraca sie uwage na jej role w rozwoju chorob o podlozu autoimmunologicznym, takich jak cukrzyca typu 1, toczen rumieniowaty, reumatoidalne zapalenie stawow, stwardnienie rozsiane, nieswoiste zapalenia jelit, luszczyca, bielactwo, czy twardzina, w ktorych witamina D ma potencjalne szerokie zastosowanie zarowno w prewencji, jak i wspomaganiu dzialan terapeutycznych. PMID- 28894041 TI - Analysis of the relationship between single nucleotide polymorphism of the CD209, IL-10, IL-28 and CCR5 D32 genes with the human predisposition to developing tick borne encephalitis. AB - Introduction: It is known that in the pathogenesis of tick-borne encephalitis (TBE) various molecules play a significant role. The most prominent factors include IL-10, IL-28B, CD-209 and CCR5. It is reasonable to search for genetic predispositions to the development of various clinical forms of TBE related to the genetic variation of IL-10, IL-28B, CD-209 and CCR5. In this study we aimed to search for the relationship between single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and 32 base pair deletion in CCR5 coding region (Delta 32) with the human predisposition to development of various clinical presentations of TBE. We tried to assess the relation between the presence of particular alleles and genotypes with laboratory and clinical parameters. Material/Methods 59 patients with TBE and 57 people, bitten by a tick who never developed TBE (Polish cohort), were included in the study. To assess the distribution of single nucleotide polymorphisms, TaqMan SNP genotyping assays were used for IL10: rs1800872 and rs1800896, for CD 209 rs4804803 and rs2287886, rs12979860 for IL 28B SNPs according to the manufacturer's protocol using real-time PCR technology on the StepOne thermal cycler. Results Comparison between TBE patients and CG showed that in SNP rs2287886 CD 209 AG heterozygotes were more frequent in the TBE group, while homozygotes GG were more frequent in the CG group. Conclusions SNP rs2287886 CD 209 AG heterozygotes predispose humans to develop TBE. Single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and CCR5 D32 genes does not correlate with the severity of TBE. PMID- 28894042 TI - The role of the BLCA-4 nuclear matrix protein in bladder cancer. AB - Bladder cancer (BC) affects usually older people. According to information provided by the National Cancer Registry in 2012. BC was the 4th, in terms of illness, cancer in men and 11th in women. Early diagnosis of bladder cancer is important because detected later has worse prognosis.Diagnosis of bladder cancer is not simple and it is still very invasive. Usually the cystoscopy or endoscopic bladder biopsy with histopathological evaluation and cytology of urine sediment is used. This prompted researchers to look for alternative noninvasive methods of diagnosis of bladder cancer. Recently, it was described the group of six proteins (BLCA) specific for BC, with special attention to BLCA-4.BLCA-4 belongs to the nuclear matrix protein and has a high specificity for this type of cancer however the value of this marker in BC diagnosis is not yet established. Oxidative DNA damage play an important role in the pathogenesis of some human diseases, including cancer. Determination of 8-hydroxy-2'deoksyguanozyne (8-OHdG) is currently used in the evaluation of genotoxic damage.The aim of the work was to review information on BLCA-4, its function in the process of BC carcinogenesis and diagnostic value also in exposure to genotoxic compounds measured by 8 hydroxy-2'deoksyguanozyne (8-OHdG) level. PMID- 28894043 TI - Immune disorders in sepsis and their treatment as a significant problem of modern intensive care. AB - Despite the great advances in the treatment of sepsis over the past 20 years, sepsis remains the main cause of death in intensive care units. In the context of new possibilities of treating sepsis, a comprehensive response of the immune system to the infection, immunosuppression, in particular, has in recent years gained considerable interest. There is vast evidence pointing to the correlation between comorbid immunosuppression and an increased risk of recurrent infections and death. Immune disorders may impact the clinical course of sepsis. This applies in particular to patients with deteriorated clinical response to infections. They usually suffer from comorbidities and conditions accompanied by immunosuppression. Sepsis disrupts innate and adaptive immunity. The key to diagnose the immune disorders in sepsis and undertake targeted immunomodulatory therapy is to define the right biomarkers and laboratory methods, which permit prompt "bedside" diagnosis. Flow cytometry is a laboratory tool that meets these criteria. Two therapeutic methods are currently being suggested to restore the immune homeostasis of sepsis patients. Excessive inflammatory response may be controlled through extracorporeal blood purification techniques, in large part derived from renal replacement therapy. These are such techniques as high-volume haemofiltration, cascade haemofiltration, plasma exchange, coupled plasma filtration and adsorption, high-absorption membranes, high cut-off membranes. The main task of theses techniques is the selective elimination of middle molecular weight molecules, such as cytokines. Pharmacotherapy with the use of such immunostimulants as interleukin 7, granulocyte-macrophage colony-stimulating factor, interferon gamma, PD-1, PD-L1 and CTLA-4 antagonists, intravenous immunoglobulins may help fight immunosuppressive immune disorders. PMID- 28894044 TI - Mitochondrial functionality in female reproduction. AB - In most animal species female germ cells are the source of mitochondrial genome for the whole body of individuals. As a source of mitochondrial DNA for future generations the mitochondria in the female germ line undergo dynamic quantitative and qualitative changes. In addition to maintaining the intact template of mitochondrial genome from one generation to another, mitochondrial role in oocytes is much more complex and pleiotropic. The quality of mitochondria determines the ability of meiotic divisions, fertilization ability, and activation after fertilization or sustaining development of a new embryo. The presence of normal number of functional mitochondria is also crucial for proper implantation and pregnancy maintaining. This article addresses issues of mitochondrial role and function in mammalian oocyte and presents new approaches in studies of mitochondrial function in female germ cells. PMID- 28894045 TI - Neopterin as a marker of cellular immunological response. AB - Neopterin is a pyrazino-pyrimidine compound that belongs to the pteridine group. It is known to be a biochemical marker associated with cell-mediated immunity. It is produced by human monocytes/macrophages and dendritic cells from guanosine triphosphate (GTP) upon stimulation with interferon gamma (IFNgamma), which is released by activated limphocytes Th. Neopterin is a very important clinic parameter, though the physiological role has not been exactly definited thus far. The level of neopterin reflects the stage of activation of the cellular immune system, which is important in the pathogenesis and progression of various diseases. Measuring its concentration in body fluids is used in many different areas of modern medicine, such as infectious disease, gastroenterology, transplantology and transfusiology, rheumatology or oncology. In neurological, cardio-vascular and autoimmune diseases, cell-mediated immunity is also activated, which is proved by the elevated level of this marker. Measurements of neopterin concentrations are also helpful in monitoring the therapy of patients infected with the HIV virus or treated by using immunomudulating therapy. As a result of measuring levels of neopterin in patients with neoplasms of digestive tract, increased concentration was proved, but it is not routinely used in everyday clinic practice. PMID- 28894046 TI - The role of trophic factors and inflammatory processes in physical activity induced neuroprotection in Parkinson's disease. AB - Glial cells and neurotrophins play an important role in maintaining homeostasis of the CNS. Disturbances of their function can lead to a number of nervous system diseases, including Parkinson's disease (PD). Current clinical studies provide evidence that moderate physical activity adapted to the health status of PD patients can support pharmacological treatment, slow down the onset of motor impairments, and extend the patients period of independence. Physical activity, by stimulating the production and release of endogenous trophic factors, prevents the neurodegeneration of dopaminergic neurons via inhibition of inflammatory processes and the reduction of oxidative stress. The aim of this study is to present the current state of knowledge for the anti-inflammatory and neuroprotective properties of physical activity as a supportive therapy in Parkinson's disease. PMID- 28894047 TI - The role of vitamin C in epigenetic regulation. AB - Vitamin C (L-ascorbic acid) is a micronutrient best known for its anti-scurvy activity in humans. Vitamin C is involved in many biological processes involving enzymatic reactions that are catalyzed by members of dioxygenases which use Fe(II) and 2-oxoglutarate as a co-substrate.The article reviews recent data that suggest the involvement of ascorbate in dioxygenases catalyzed chromatin and DNA modifications which thereby contribute to epigenetic regulation. Concerning chromatin modification, the dioxygenases are involved in distinct demethylation reactions with varying specificity for the position of the lysine on the target histone. TET hydroxylases catalyse the oxidation of methyl groups in the 5 position of cytosine in DNA yielding 5-hydroxymethylcytosine, while further iterative oxidation reactions results in the formation of 5-formylcytosine and 5 carboxylcytosine. A few previous studies demonstrated that ascorbate may enhance generation of 5-hydroxymethylcytosine in cultured cells, probably acting as a cofactor of TETs during hydroxylation of 5-methylcytosine. Physiological concentrations of ascorbate in human serum (10-100 MUM) may guarantee stable level of 5-hydroxymethylcytosine, a modification necessary for epigenetic function of the cell. 5-Hydroxymethylcytosine level is substantially decreased in almost all investigated cancers, what may be linked with cancer development. Therefore, it is possible that supplementation with ascorbate could contribute to better management of individual cancer patient. This issue is also discussed in our paper. PMID- 28894048 TI - The role of bile acids in the pathogenesis of bowel diseases. AB - Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription factors. Genetic factors associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium homotaurocholic acid test, serum C4 and fibroblast growth factor 19 (FGF19), as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention. PMID- 28894049 TI - The pathophysiological basis of the protective effects of metformin in heart failure. AB - Metformin, currently recommended as the drug of first choice in type 2 diabetes mellitus (T2DM), is one of the few antihiperglycemic drugs to reduce cardiovascular risk. Nonetheless, due to the risk of lactic acidosis during metformin therapy, its usage in patients with diabetes and heart failure (HF) is still a matter of debate. The aim of this review is to present data supporting the possibility of using metformin in the treatment of diabetic patients with concomitant heart failure. In the failing heart, metformin through the mechanism related to AMP-activated protein kinase (AMPK) activity, improves free fatty acids (FFA) and glucose metabolism, mitochondrial biogenesis, as well as nitric oxide (NO)-NO synthase pathway. Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium.In summary, experimental and clinical data indicate the ability of metformin to prevent the development of the structural and functional changes in myocardium, although further basic research and clinical studies assessing benefits and safety of metformin therapy in patients with HF are required. PMID- 28894050 TI - Compounds of psoriasis with obesity and overweight. AB - Many epidemiological studies have confirmed the relationship of obesity and psoriasis, and it is believed that obesity is an independent risk factor for its development and is associated with a worse prognosis. Furthermore, the reduction of body weight, using low-calorie diet combined with exercise, reduces the severity of psoriasis.Visceral adipose tissue is the largest endocrine organ, producing proinflammatory cytokines (TNF-alpha, IL-6, IL-17) and adipokines (adiponectin, omentin, chemerin). They participate in the development of dyslipidemia, insulin resistance, diabetes, and consequently of the cardiovascular diseases. Macrophages of visceral adipose tissue have a special role and they increase significantly in obesity. They are responsible for the development of inflammation in adipose tissue and produce inflammatory cytokines (TNF alpha, IL-6, Il-8, Il-17, Il-18, MCP-1) and other adipokines: resistin, visfatin, retinol-binding protein 4. This explains the concept of "psoriatic march "and observations of the frequent coexistence of psoriasis with obesity. Inflammation associated with systemic disease, fanned by pro-inflammatory cytokines and adipokines produced by the visceral adipose tissue lead to the development of insulin resistance, endothelial cell damage. Endothelial dysfunction predisposes to the formation of atherosclerotic plaques and faster development of cardiovascular events. Complication of obesity is the development of non-alcoholic fatty liver disease (NAFLD), which states twice as likely in patients with plaque psoriasis and is associated with the severity of the disease. Another consequence is the development of depression. Probably the proinflammatory cytokines can interact with metabolism of neurotransmitters. Obesity also has a significant impact on the treatment of psoriasis, increasing the risk of adverse effects of systemic drugs, reducing the efficacy of biological agents which dose should be adjusted to the weight of the patient. It is a factor responsible for the increased volume of distribution and it causes low titter of drug concentration. PMID- 28894052 TI - [Three Surgical Cases of Quadricuspid Aortic Valve]. AB - Quadricuspid aortic valve is a rare congenital disease. We experienced 3 surgical cases of quadricuspid aortic valve. Patient 1 was a 72-year-old man who was noted to have a quadricuspid aortic valve associated with aortic regurgitation and an ascending aortic aneurysm(51 mm in diameter). He underwent replacement of the aortic valve and the ascending aorta. Patient 2 was a 71-year-old man with severe aortic stenosis, regurgitation, and coronary triple vessel disease. He underwent aortic valve replacement and coronary artery bypass grafting. Preoperative echocardiography revealed no abnormalities in the number of valve leaflets, but quadricuspid aortic valve was identified during surgery. Patient 3 was a 79-year old man with severe aortic regurgitation, who underwent aortic valve replacement. In all patients, the 4 valve cusps were approximately of the same size. Multi detector computed tomography is useful for evaluation of valve morphology. Indication of prophylactic ascending aorta replacement in patients with aortic dilatation requires further study. PMID- 28894053 TI - [Prediction of Pleural Adherence Area Used by Ultrasound Sonography]. AB - Video-assisted thoracoscopic surgery has been used to treat lung cancer. However, pleural adhesions may increase the risk of lung injury while making the access port. We report a case of lung cancer in which preoperative lung ultrasound sonography was used to predict the pleural adherence area. An octogenarian man had undergone chest surgery for right spontaneous pneumothorax 20 years ago. He was recently diagnosed with a right middle lobe carcinoma and thoracoscopic surgery was scheduled. On preoperative lung ultrasound sonography, adhesion in the area surrounding the previous incision line was predicted to be strong. However, a sliding lung sign was observed in the pleura on the caudal side, where no adhesions were expected. The thoracoscopic findings during the operation revealed that adhesions were present in the upper and middle regions of the pleural cavity in the locations and to the extent predicted before surgery, but no adhesion was observed on the caudal side. We were able to make an access port avoiding the adherence area in the pleural cavity. Lung ultrasound sonography was useful for detection of the adherence area between the parietal and visceral pleura in this case. PMID- 28894051 TI - Standardization of the collection of exhaled breath condensate and exhaled breath aerosol using a feedback regulated sampling device. AB - Exhaled breath condensate (EBC) and associated exhaled breath aerosols (EBA) are valuable non-invasive biological media used for the quantification of biomarkers. EBC contains exhaled water vapor, soluble gas-phase (polar) organic compounds, ionic species, plus other species including semi- and non-volatile organic compounds, proteins, cell fragments, DNA, dissolved inorganic compounds, ions, and microbiota (bacteria and viruses) dissolved in the co-collected EBA. EBC is collected from subjects who breathe 'normally' through a chilled tube assembly for approximately 10 min and is then harvested into small vials for analysis. Aerosol filters without the chilled tube assembly are also used to separately collect EBA. Unlike typical gas-phase breath samples used for environmental and clinical applications, the constituents of EBC and EBA are not easily characterized by total volume or carbon dioxide (CO2) concentration, because the gas-phase is vented. Furthermore, EBC and associated EBA are greatly affected by breathing protocol, more specifically, depth of inhalation and expelled breath velocity. We have tested a new instrument developed by Loccioni Gruppa Humancare (Ancona, Italy) for implementation of EBC collection from human subjects to assess EBC collection parameters. The instrument is the first EBC collection device that provides instantaneous visual feedback to the subjects to control breathing patterns. In this report we describe the operation of the instrument, and present an overview of performance and analytical applications. PMID- 28894054 TI - [Surgical Treatment for Synchronous Double Cancer of the Thoracic Esophagus and Lung]. AB - We herein report 2 cases of radical operation for synchronous double cancer of the thoracic esophagus and each side of the lung. Case 1:A 71-year-old woman with synchronous double cancer of the thoracic esophagus (Mt, T3N2M0, Stage III) and right lung (M, T2aN0M0, Stage I B) underwent esophagectomy concomitantly with right middle lobectomy through right thoracotomy (single-stage operation) after 2 courses of systemic chemotherapy with docetaxel, cisplatin and 5-fluorouracil( DCF regimen). Case 2:A 72-year-old man with synchronous double cancer of the thoracic esophagus( MtLt, T3N2M0, Stage III) and left lung( U, T1aN0M0, Stage I A) underwent 2-stage operation after 2 courses of the DCF therapy. Esophagectomy through right thoracotomy was performed followed by left upper lobectomy through left thoracotomy 3 months later. Treatment strategy for synchronous double cancer of the thoracic esophagus and lung is discussed based on our experiences and previous reports. PMID- 28894055 TI - [IgG4-related Periaortitis Manifested as Contained Rupture of Penetrating Atherosclerotic Ulcer]. AB - We report a case of IgG4-related periaortitis of the descending aorta manifested as a contained rupture of penetrating atherosclerotic ulcer(PAU). A 67-year-old male was admitted to our hospital complaining about chest pain. Computed tomography(CT) and magnetic resonance imaging revealed PAU with extravasation of the descending aorta and thickening of surrounding tissues. Fluorodeoxyglucose positron emission tomography (FDG-PET) CT demonstrated abnormal accumulation of FDG at the thickening sites, and serum IgG4 value was abnormally high. The descending aorta replacement was performed and intraoperative findings showed a marked thickening of the mediastinal tissue around the descending aorta and the ulceration of the intima penetrating to the mediastinum. In histopathological examination, the adventitial thickening due to marked fibrosis and the ulceration of the intima accompanying infiltration of IgG4 positive plasma cells were observed. IgG4-related thoracic periaortitis can invade not only to the adventitia but to the intima, and can cause PAU. For aortic diseases with thickening of periaotic tissues, it is necessary to keep in mind the possibility of IgG4-related aortic disease, and serum IgG4 values are useful for diagnosis. PMID- 28894056 TI - [Emergency Mitral Valvoplasty for Papillary Muscle Rupture]. AB - We experienced 2 emergency surgical cases of severe mitral valve regurgitation due to papillary muscle rupture. Case 1:a 69-year-old man presented with respiratory and cardiac failure due to mitral regurgitation. He had no history of myocardial infarction. Mitral valve repair with artificial cords was performed. The papillary muscle of the anterior leaflet was ruptured. The postoperative course was uneventful. Case 2:a 80-year-old man came to our hospital with cardiac arrest. Emergency coronary intervention was performed to the right coronary and intraaortic balloon pumping was inserted. However his condition remained unstable. Severe mitral regurgitation was found by teansesophageal echo cardiography, and he underwent emergency mitral valve repair and single coronary bypass grafting. His cardiac function recovered quickly, but severe brain damage remained. PMID- 28894058 TI - [Ruptured Aneurysm of the Sinus of Valsalva Accompanied with a Bicuspid Aortic Valve in an Elderly Man;Report of a Case]. AB - The combination of ruptured aneurysm of the sinus of Valsalva and a bicuspid aortic valve is very rare in an elderly person. A 71-year-old man with ruptured aneurysm of the sinus of Valsalva and a bicuspid aortic valve had undergone an operation. He was admitted to his other hospital because of heart failure. He was transferred to our hospital to undergo treatment for ruptured aneurysm of sinus of Valsalva. At our hospital, echocardiography findings showed ruptured aneurysm of the sinus of Valsalva, a ventricular septal defect (VSD), and severe aortic regurgitation with moderate stenosis of the bicuspid aortic valve. An aneurysm originating from the anterior sinus of Valsalva had ruptured into the right ventricular outflow tract. The ruptured aneurysm and VSD were repaired by patch closure through the right ventricular outflow tract. Additionally, the aneurysm of the sinus of Valsalva was repaired with direct closure through aortotomy. The insufficient bicuspid aortic valve was replaced with a bioprosthetic valve. After the operation, heart failure improved promptly, and he was making satisfactory progress in his recovery. PMID- 28894059 TI - [Re-operation for Saccular Aneurysm after Ascending Aortic Replacement with Homograft;Report of a Case]. AB - A 62-years-old female had undergone ascending aortic replacement with homograft for graft infection and mediastinitis after initial replacement of ascending aorta due to acute type A dissection. Ten years after homograft replacement, follow up computed tomography showed acute growing saccular aneurysm of the homograft without infectious symptoms. We urgently performed Bentall procedure and hemiarch replacement successfully. Pathological diagnosis was true aneurysm of the homograft. She was discharged from hospital without any complication and has been quite uneventful 7 years after surgery. True aneurysm of the homograft is very rare and our case is the 1st report of successful reoperation. PMID- 28894057 TI - [Successful Treatment of Ascending Aortic Graft Infection with a Rifampicin soaked Vascular Prosthesis and Continuous Irrigation]. AB - A 68-year-old woman underwent replacement of the ascending aorta for acute type A aortic dissection. She was then diagnosed with postoperative methicillin resistant Staphylococcus aureus (MRSA) infection, and the infected aortic graft was replaced with a rifampicin-soaked vascular prosthesis, which was followed by continuous irrigation using a 0.1% povidone-iodine solution. The postoperative course was uneventful, and she has been doing well for 5 years with no recurrence of infection. Prosthetic graft replacement using a rifampicin-soaked graft followed by continuous irrigation with povidone-iodine is useful for treatment of an MRSA-infected prosthetic vascular graft. PMID- 28894060 TI - [Redo Off-pump Coronary Artery Bypass for Postoperative Vein Graft Stenosis of Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery;Report of a Case]. AB - Bland-White-Garland (BWG) syndrome (anomalous origin of the left coronary artery from the pulmonary artery) is a rare disease which may result in myocardial infarction, congestive heart failure or sometimes death during the early infantile period. We present a 57-year-old female with BWG syndrome. At the age of 20, she was diagnosed with BWG syndrome and underwent coronary artery bypass grafting of a saphenous vein to the proximal portion of the anterior descending branch of the left coronary artery and ligation of the anomalous artery. Thirty seven years later, she presented with symptoms of angina pectoris and congestive heart failure. Coronary angiography (CAG) revealed stenosis of the saphenous vein graft. Bare metal stent implantation for the saphenous vein graft was performed, but at the 6 months' follow-up CAG revealed restenosis. Drug-eluting stent was then implanted, but in-stent restenosis recurred 4 months later. We performed off pump coronary artery bypass grafting to the left anterior descending artery using the left internal thoracic artery. The postoperative course was uneventful. PMID- 28894062 TI - [Fifteen-year Follow-up of a Patient with Aortitis, Treated by Sino-tubular Junction Plication Using a Prosthetic Tube Graft for Aortic Regurgitation;Report of a Case]. AB - A 43-year-old woman was diagnosed with aortitis associated with mild aortic regurgitation (AR) at the age of 25, which advanced to a severe grade requiring surgical treatment at age 28. Dilation of the sinotubular junction (STJ) was treated with ascending aortic replacement (Hemashield Gold 24 mm), which reduced AR from severe to mild. The patient conceived 9 years later and delivered a baby by cesarean section at 38 weeks of gestation. By appropriate control of inflammation with steroid, neither deterioration of the aortic valve nor cardiac function has been noted during the 15 years of follow-up after surgery. PMID- 28894061 TI - [Successful Repair of Chronic Expanding Hematoma after Coronary Artery Bypass Grafting by Lower Partial Sternotomy Approach;Report of a Case]. AB - Chronic expanding hematoma (CEH) after coronary artery bypass grafting (CABG) is extremely rare. We reported a case of successful surgical repair of CEH through lower partial sternotomy approach. The patient was a 73-year-old man who underwent CABG. Fifteen years after the operation, he was admitted to referral hospital because of dyspnea on exertion. Echocardiography and computed tomography revealed a giant intrapericardial mass, which was pressing on the inferior wall of the ventricle. To avoid injury of the aorta and the patent bypass graft in the reentry of the chest, we selected lower partial sternotomy approach. The mass was encapsulated with thick fibrous membrane containing old degenerated coagula and was histopathologically diagnosed as CEH. Postoperative course was uneventful and diastolic heart failure was relieved. PMID- 28894063 TI - [Pneumothorax Caused by Multiple Pulmonary Metastases of a Uterine Endometrial Stromal Sarcoma;Report of a Case]. AB - A 53-year-old woman who had undergone hystero-oophorectomy for uterine endometrial stromal sarcoma in our hospital 9 months previously was referred to our hospital because of bilateral pneumothorax. Chest computed tomography scan on admission revealed multiple thin-walled cavity nodules in both lung and a bilateral pneumothorax, suggesting pulmonary metastases of the uterine endometrial stromal sarcoma. We surgically treated the pneumothorax and diagnosed the nodules as metastatic lesions. They were pathologically diagnosed as metastatic uterine endometrial stromal sarcoma. PMID- 28894064 TI - [Establishment of Preoperative Diagnosis Helpful in Choosing Minimal Surgical Procedure for Resecting Intrapulmonary Solitary Fibrous Tumor;Report of a Case]. AB - Intrapulmonary solitary fibrous tumor (SFT) arising from the parenchyma of the lung is very rare. Few limited surgery have been performed because preoperative and intraoperative diagnosises of SFT are so difficult. We here report a case of intrapulmonary SFT which was able to be resected by segmentectomy by preoperative diagnosis. A 77-year-old man, who was found to have an abnormal nodule in right lower lobe on computed tomography (CT), was admitted to our hospital. Fluorodeoxyglucose-positron emission tomography (PET) showed a slight uptake in the nodule. By CT guided needle biopsy, the nodule was diagnosed as intrapulmonary SFT pathologically. We could choose segmentectomy as a surgical procedure by preoperative diagnosis. PMID- 28894065 TI - [Mucosa-associated Lymphoid Tissue Lymphoma in the Thymus;Report of a Case]. AB - A 64-years-old woman with chronic thyroiditis was refered to our hospital because of anterior mediastinum tumors identified by chest computed tomography (CT). The lesions with increased fluoro-2-deoxy-D-glucose (FDG) uptake was noted by CT and positron emission tomography (PET). Extended thymo-thymectomy was performed, and the tumors was completely resected. Pathologically, the tumors were diagnosed as mucosa-associated lymphoid tissue( MALT) lymphoma of the thymus. Postoperative chemotherapy was not performed and the patient has been well for 4 years without recurrence. But she has developed the symptoms of Sjogren syndrome 3 years after operation. PMID- 28894066 TI - [Thymoma with Pure Red Cell Aplasia;Report of a Case]. AB - A thymoma with pure red cell aplasia (PRCA) is relatively rare. A 71-year-old woman complainted of dizziness and her blood cell count showed a severe anemia. She was diagnosed as PRCA by bone marrow aspiration biopsy, which showed marked decrease in number of erythroblasts. In addition, the chest computed tomography revealed a solid tumor in the anterior mediastinum. She underwent extended thymothymectomy through median sternotomy. The resected specimen was 10.5*9.7 cm in diameter. The pathological diagnosis was type AB thymoma of the World Health Organization classification, and Masaoka stage I. Ciclosporin was started to treat PRCA 3 months after the surgery, and she has been well for about 1 year after surgery without recurrence of thymoma or relapse of anemia. PMID- 28894067 TI - [The Effects of an Empowerment Education Program for Kidney Transplantation Patients]. AB - PURPOSE: This study was conducted to develop an Empowerment Education Program (EEP) for kidney transplant patients and to test the program's effects on uncertainty, self-care ability, and compliance. METHODS: The research was conducted using a nonequivalent control group with a pretest-posttest design. The participants were 53 outpatients (experimental group: 25, control group: 28) who were receiving hospital treatment after kidney transplants. After the pre-test, patients in the experimental group underwent a weekly EEP for six weeks. The post test was conducted immediately after, and four weeks after the program's completion in the same manner as the pre-test. For the control group, we conducted a post-test six and ten weeks after the pre-test, without and program intervention. A repeated measure ANOVA was performed to compare the change scores on main outcomes. RESULTS: Uncertainty was significantly lower in the experimental group than in the control group, both immediately after (t=-3.84, p=<.001) and 4 weeks after (t=-4.51 p=<.001) the program, whereas self-care ability (t=5.81, p=<.001), (t=5.84, p=<.001) and compliance (t=5.07, p=<.001), (t=5.45, p=<.001) were significantly higher. CONCLUSION: Kidney transplant patients who underwent an EEP showed a decrease in uncertainty and an improvement in self-care ability and compliance. Thus, our findings confirmed that an EEP can be an independent intervention method for improving and maintaining the health of kidney transplant patients. PMID- 28894068 TI - [The Effects of 30-Minutes of Pre-Warming on Core Body Temperature, Systolic Blood Pressure, Heart Rate, Postoperative Shivering, and Inflammation Response in Elderly Patients with Total Hip Replacement under Spinal Anesthesia: A Randomized Double-blind Controlled Trial]. AB - PURPOSE: This study was designed to determine the effects of pre-warming on core body temperature (CBT) and hemodynamics from the induction of spinal anesthesia until 30 min postoperatively in surgical patients who undergo total hip replacement under spinal anesthesia. Our goal was to assess postoperative shivering and inflammatory response. METHODS: Sixty-two surgical patients were recruited by informed notice. Data for this study were collected at a 1,300-bed university hospital in Incheon, South Korea from January 15 through November 15, 2013. Data on CBT, systemic blood pressure (SBP), and heart rate were measured from arrival in the pre-anesthesia room to 3 hours after the induction of spinal anesthesia. Shivering was measured for 30 minutes post-operatively. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured pre operatively, and 1 and 2 days postoperatively. The 62 patients were randomly allocated to an experimental group (EG), which underwent pre-warming for 30 minutes, or a control group (CG), which did not undergo pre-warming. RESULTS: Analysis of CBT from induction of spinal anesthesia to 3 hours after induction revealed significant interaction between group and time (F=3.85, p=.008). In addition, the incidence of shivering in the EG was lower than that in the CG (chi2=6.15, p=.013). However, analyses of SBP, heart rate, CRP, and ESR did not reveal significant interaction between time and group. CONCLUSION: Pre-warming for 30 minutes is effective in increasing CBT 2 and 3 hours after induction of spinal anesthesia. In addition, pre-warming is effective in decreasing post operative shivering. PMID- 28894069 TI - [Health Promoting Behavior in Pregnant Couples: Actor-Partner Interdependence Model Analysis]. AB - PURPOSE: This study aimed to identify the actor and partner effects of self efficacy, marital adjustment, and social support on the health promoting behavior of Korean pregnant couples. METHODS: Participants were 132 couples who met the eligibility criteria. Data were collected from June to November, 2016 at a community health center. The Actor-Partner Interdependence Model was used for analyzing the actor and partner effects of self-efficacy, marital adjustment, and social support on health promoting behavior. RESULTS: The fitness indices for the model were GFI=0.90, NFI=0.92, CFI=0.91, TLI=0.90, and RMSEA=0.04, which satisfied the criteria. Self-efficacy had actor and partner effect on health promoting behavior of wives, but had only actor effect of on health promoting behavior of husbands. Marital adjustment showed actor and partner effect on the health promoting behavior of pregnant couples. Social support only had an actor effect on the health promoting behavior of wives. And, marital adjustment and social support had a mutual effect. CONCLUSION: This study indicates that the partner involvement is needed to develop health promotion programs for pregnant couples. PMID- 28894070 TI - [The Effects of Mobile Social Networking Service-Based Cognitive Behavior Therapy on Insomnia in Nurses]. AB - PURPOSE: This study aimed to examine the effects of cognitive behavior therapy for insomnia (CBT-I) based on the mobile social networking service (SNS) on dysfunctional beliefs and attitudes about sleep, sleep quality, daytime sleepiness, depression, and quality of life among rotating-shift nurses in a hospital in Korea. METHODS: A nonequivalent control group pre-post test design was used. The participants included 55 nurses with rotating three-shift work (25 in the experimental group and 30 in the control group). For the experimental group, CBT-I using mobile SNS was provided once a week for 60 minutes over six weeks. Data were analyzed using descriptive statistics, chi2-test, independent samples t-test, and Mann-whitney U test with the SPSS 21.0 program. RESULTS: In the homogeneity test of the general characteristics and study variables, there were no significant differences between the two groups. Nurses in the experimental group had significantly lower scores on dysfunctional beliefs and attitudes regarding sleep and sleepiness than nurses in the control group. Nurses in the experimental group had significantly higher scores on sleep quality and quality of life than nurses in the control group. CONCLUSION: These findings indicate that using the mobile SNS-based CBT-I is feasible and has significant and positive treatment-related effects on rotating-shift nurses' irrational thoughts and beliefs in association with sleep, sleep quality, daytime sleepiness, and quality of life. These contribute to expanding our knowledge of rotating-shift nurses' sleep issues and their preferences for intervention. PMID- 28894071 TI - [Structural Equation Modeling on Successful Aging in Elders with Chronic Obstructive Pulmonary Disease Based on Selection-Optimization-Compensation Strategy]. AB - PURPOSE: The focus of the study was on the selection-optimization-compensation (SOC) strategy to predict successful aging mediated by dyspnea symptoms in older adults with chronic obstructive pulmonary disease. The model was constructed based on the hypotheses that coping strategy and social support of the elders predict successful aging through the SOC strategies. METHODS: Participants were 218 outpatients with chronic obstructive pulmonary disease recruited for the study. Data collection was done from March 25 to September 11, 2015, and analyzed using SPSSWIN 22.0 and AMOS 21.0. RESULTS: The hypothetical model appeared to be fit to the data. Seven of eight hypotheses selected for hypothetical model were statistically significant. The SOC strategy has only significant indirect effects through dyspnea symptoms on successful aging. Coping strategy, social support, SOC strategies and dyspnea symptoms explained 62% of variance in successful aging. CONCLUSION: The SOC strategies with social support and dyspnea symptoms significantly explained successful aging among patients with chronic obstructive pulmonary disease. Nursing strategies should be focused on social support and coping strategies to optimize SOC strategies so that older adults with chronic obstructive pulmonary disease are able to manage dyspnea symptoms and eventually achieve successful aging. PMID- 28894072 TI - [A Concept Analysis of Uncertainty in Epilepsy]. AB - PURPOSE: This concept analysis was done to clarify 'uncertainty in epilepsy'. METHODS: Walker and Avant's methodology guided the analysis. In addition, the concept was compared with uncertainty in other health problems. RESULTS: 'Uncertainty in epilepsy' was defined as being in the condition as seen from the epilepsy experience where cues were difficult to understand because they changed, were in discord with past ones, or they had two or more contradictory values at the same time. Uncertainty in epilepsy is evolved from appraisal of the epilepsy experience. As a result, uncertainty leads epilepsy patients, their family or health care providers to impaired functioning and proactive/passive coping behavior. CONCLUSION: Epilepsy patients with uncertainty need to be supported by nursing strategies for proactive, rational coping behavior. This achievement has implications for interventions aimed at changing perception of epilepsy patients, their families or health care providers who must deal with uncertainty. PMID- 28894073 TI - [Structural Equation Modeling on Self-Care Behavior and Quality of Life in Older Adults with Diabetes Using Citizen Health Promotion Centers]. AB - PURPOSE: The purpose of this study was to construct and test a structural equation model for Diabetes self-management (DSM) behavior and Quality of life (QoL) in older adults with diabetes who use Citizen Health Promotion Centers. The theory used this study was a combination of the Information-Motivation-Behavioral Model (IMB) and Self-Determination Theory (SDT) to reflect autonomous characteristics of participants. METHODS: Data were collected from April 20 to August 31, 2015 using a self-report questionnaire. The sample was 205 patients with type 2 Diabetes who regularly visited a Citizen Health Promotion Center. SPSS 22.0 and AMOS 22.0 programs were used to analyze the efficiency of the hypothesized model and calculate the direct and indirect effects of factor affecting the participants' DSM behavior and QoL. RESULTS: The supported hypotheses were as follows; 1) The variable that had a direct effect on QoL was health behavior adherence (gamma=.55, p=.007). 2) The variables that had a direct effect on DSM behavior were DSM information (gamma=.15, p=.023), DSM confidence (gamma=.25, p<.001), and autonomous motivation (gamma=.13, p=.048). 3) The variable that had a direct effect on DSM confidence was autonomy support (gamma=.33, p<.001). CONCLUSION: The major findings of this study are that supporting patient's autonomous motivation is an influential predictor for adherence to DSM behavior, and integrative intervention strategies which include knowledge, experience and psychosocial support are essential for older adults with diabetes to continue DSM behavior and improve QoL. PMID- 28894074 TI - [Development and Testing of a Mastery Learning Program of Nursing Skills for Undergraduate Nursing Students]. AB - PURPOSE: This study was undertaken to develop and test a mastery learning program of nursing skills for undergraduate nursing students. METHODS: In this methodological study, first, the preliminary draft of a mastery learning program to provide training for nursing skills was developed based on Bloom's framework for mastery learning. Second, to test the developed program, a single-blinded, nonequivalent control group nonsynchronized study was conducted on 50 senior nursing students in a University selected by convenient sampling. Thirteen students were assigned to a control group; 13, 12, and 13 of them were assigned to intravenous therapy, transfusion, and patient transfer groups, respectively. The achievement levels and performance scores of the selected nursing skills were measured before and after the completion of the program in all the groups. Lastly, the final program was confirmed based on the results of the program testing. RESULTS: Intravenous therapy, transfusion, and patient transfer were selected as essential nursing skills for the program based on the priorities rated by clinical instructors and staff nurses. The achievement levels of selected nursing skills were determined by Angoff scores. After participating in the program, the proportion of passers and performance scores of the nursing skills in the experimental groups were significantly higher than those in the control group. The final program was confirmed which included a diagnostic test, enrichment activities for the passers and three repetitions of corrective activities and formative assessments for non-passers. CONCLUSION: The results suggest that a mastery learning program for undergraduate students can lead to better improvement and performance of essential nursing skills. PMID- 28894075 TI - [The Effect of Dongchimi Juice Containing Kimchi Lactobacillus on the Oral Health of Patients at a Long-Term Care Hospital: Comparison with Chlorhexidine Solution]. AB - PURPOSE: The aim of this study was to identify the effect of Dongchimi juice containing kimchi Lactobacillus as an oral hygiene agent and to compare it with that of chlorhexidine solution (0.12% dilution). METHODS: This study employed a pretest-posttest experimental design in which a single group of patients was exposed to two different treatments over a period of time. The study included 32 patients hospitalized at a long-term care hospital in Korea. Data were collected between August 12, 2016 and September 28, 2016. The patients first used chlorhexidine solution as an oral care agent for 1 week. After an interval of 2 weeks, they used Dongchimi juice for 1 week. Each agent was applied 2 times a day depending on the protocol. The oral status of the patients was measured using Beck's Oral Exam Guide (OEG) scores. The number of pathogens in the oral cavity was counted by culture, and the patients' subjective satisfaction score for each oral agent was measured using a visual analogue scale. T-test and Mann-Whitney test were performed to identify significant differences between Dongchimi juice and chlorhexidine solution by using PASW Statistics for Windows, Version 18.0 (SPSS Inc., Chicago, IL, USA). RESULTS: The OEG score was not statistically different with the use of chlorhexidine solution and Dongchimi juice. However, decreasing number of pathogens and the subjective satisfaction score were higher with Dongchimi juice than with the chlorhexidine solution. CONCLUSION: These findings support the use of Dongchimi juice containing kimchi Lactobacillus as an oral hygiene agent for Korean patients. PMID- 28894076 TI - [A Model for Predicting Career Satisfaction of Nurses Experiencing Rotation]. AB - PURPOSE: This study aimed to present and test a structural model for describing and predicting the factors affecting subjective career satisfaction of nurses experiencing rotation and to develop human resources management strategies for promoting their career satisfaction related to rotation. METHODS: In this cross sectional study, we recruited 233 nurses by convenience sampling who had over 1 year of career experience and who had experienced rotation at least once at G university hospital. Data were collected from August to September in 2016 using self-reported questionnaires. The exogenous variables consisted of rotation perception and rotation stress. Endogenous variables consisted of career growth opportunity, work engagement, and subjective career satisfaction. A hypothetical model was tested by asymptotically distribution-free estimates, and model goodness of fit was examined using absolute fit, incremental fit measures. RESULTS: The final model was approved and had suitable fit. We found that subjective career satisfaction was directly affected by rotation stress (beta=.20, p=.019) and work engagement (beta=.58, p<.001), indirectly affected by rotation perception (beta=.43, p<.001) through career growth opportunity and work engagement. However, there was no total effect of rotation stress on subjective career satisfaction (beta=-.09, p=.270). Career growth opportunity directly and indirectly affected subjective career satisfaction (beta=.29, p<.001; beta=.28, p<.001). These variables accounted for 65% of subjective career satisfaction. CONCLUSION: The results of this study suggest that it is necessary to establish systematic and planned criteria for rotation so that nurses can grow and develop through sustained work and become satisfied with their career. PMID- 28894077 TI - [Experience of Frailty in Korean Elderly: A Phenomenological Study Utilizing the Colaizzi Method]. AB - PURPOSE: This study attempts to explore the subjective experience of frailty among elderly individuals in Korea. METHODS: From June to August in 2014, 11 elderly persons who had experienced frailty in a community were interviewed. For data analysis, the method suggested by Colaizzi was applied as a phenomenological method. RESULTS: According to the analysis, the study participants' frailty process was structured in seven categories: (a) 'natural phenomenon with ageing,' (b) 'life force comes to an end,' (c) 'the light in my heart turns off,' (d) 'unavoidable situation,' (e) 'continuous and connected vicious cycle,' (f) 'the limit of recovery energy already passes,' and (g) 'life is supported by someones help.' CONCLUSION: The frailty experience in the participants is a natural process of aging, which cause vicious cycle acting with each other among physical, psychological, and social health. It is said that the cycle of frailty was started from weight loss and insufficient sleep, and boostered by pain. The participants from repetition of the vicious cycle become exhausted and pass the threshold of their recovery energy at some points. If they meet with sudden accidents such as falling, traffic accident and so on, they become to live a dependent life supported by someone's help in a moment. To prevent frailty and worsening conditions in Korean elderly individuals, it is recommended to provide a interventional programs using this study's results. PMID- 28894078 TI - [Corrigendum: Multiple Factors in the Second Trimester of Pregnancy on Preterm Labor Symptoms and Preterm Birth]. AB - This corrects the article on p. 357 in vol. 47, PMID: 28706170. PMID- 28894080 TI - The Portuguese Society of Rheumatology position paper on the use of biosimilars - 2017 update. AB - Biosimilars are new and more affordable similar versions of previously approved reference biological drugs. Following the approval of the first monoclonal antibody biosimilar in 2013, the Portuguese Society of Rheumatology issued a position paper on the use of biosimilars in rheumatic conditions covering efficacy, safety, extrapolation, interchangeability, substitution and pharmacovigilance. However, as this is a rapidly evolving field, it was felt that the knowledge and evidence gathered since then justified an update of these statements. Literature searches on these issues were performed and the search results were presented and discussed in a national meeting. Portuguese rheumatologists considered that affordability should be taken into consideration when initiating a biological drug, but other factors were equally important. In patients already on reference biological treatment, switch to a more affordable biosimilar is desirable, provided a set of conditions is rigorously met. Automatic substitution is not acceptable and current evidence is insufficient to support interchangeability. Extrapolation of clinical indications is endorsed by Portuguese rheumatologists, and the statements on safety, pharmacovigilance and traceability are in accordance with the previous position paper. PMID- 28894081 TI - Eculizumab in Renal Transplantation: A 2017 Update. AB - Despite ongoing progress in renal transplantation, there are still emerging challenges in this field, including consequences of ischemia-reperfusion injury (IRI), pre-existing and produced de novo anti-HLA donor-specific antibodies (DSA), and acute/chronic humoral rejection (AMR), as well as the recurrence of atypical hemolytic-uremic syndrome (aHUS) in genetically predisposed patients. All these conditions are related to the prominent role of the complement system and are deleterious to the fate of the renal graft. Eculizumab, a humanized monoclonal antibody directed against the complement C5a component, is currently being used in renal transplantation and was evaluated in several clinical trials to minimize the consequences of IRI, prevent or treat relapsing or de novo aHUS, and to prevent and cure humoral rejection in patients at high immunological risk. There are remaining issues in terms of defining precise indications, dosing, monitoring, and optimal duration of the therapy with this drug; however, eculizumab is an emerging drug in renal transplantation. PMID- 28894079 TI - Portuguese recommendations for the use of biological therapies in patients with axial spondyloarthritis - 2016 update. AB - OBJECTIVE: To update the recommendations for the treatment of axial spondyloarthritis (axSpA) with biological therapies, endorsed by the Portuguese Society of Rheumatology. METHODS: These treatment recommendations were formulated by Portuguese rheumatologists based on literature evidence and consensus opinion. At a national meeting, the 7 recommendations included in this document were discussed and updated. A draft of the full text of the recommendations was then circulated and suggestions were incorporated. A final version was again circulated before publication and the level of agreement among Portuguese Rheumatologists was anonymously assessed using an online survey. RESULTS: A consensus was achieved regarding the initiation, assessment of response and switching of biological therapies in patients with axSpA. In total, seven recommendations were produced. The first recommendation is a general statement indicating that biological therapy is not a first-line drug treatment option and should only be used after conventional treatment has failed. The second recommendation is also a general statement about the broad concept of axSpA adopted by these recommendations that includes both non-radiographic and radiographic axSpA. Recommendations 3 to 7 deal with the definition of active disease (including the recommended threshold of 2.1 for the Ankylosing Spondylitis Disease Activity Score [ASDAS] or the threshold of 4 [0-10 scale] for the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), conventional treatment failure (nonsteroidal anti-inflammatory drugs being the first-line drug treatment), assessment of response to treatment (based on an ASDAS improvement of at least 1.1 units or a BASDAI improvement of at least 2 units [0-10 scale] or at least 50%), and strategy in the presence of an inadequate response (where switching is recommended) or in the presence of long-term remission (where a process of biological therapy optimization can be considered, either a gradual increase in the interval between doses or a decrease of each dose of the biological therapy). CONCLUSION: These recommendations may be used for guidance in deciding which patients with axSpA should be treated with biological therapies. They cover a rapidly evolving area of therapeutic intervention. As more evidence becomes available and more biological therapies are licensed, these recommendations will have to be updated. PMID- 28894082 TI - Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): An Uncommon Manifestation of Systemic Lupus Erythematosus (SLE). AB - BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE). We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP. CASE REPORT A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy. Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait. Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia. Electromyography (EMG) confirmed the diagnosis of CIDP. The patient's neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids. CONCLUSIONS The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids. Most patients with CIDP are treated successfully with steroids if the diagnosis is made early. IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids. PMID- 28894083 TI - Ataxia-Telangiectasia Mutated (ATM) Protein Signaling Participates in Development of Pulmonary Arterial Hypertension in Rats. AB - BACKGROUND Previous studies revealed physiological and pathogenetic similarity between vascular smooth muscles cells with severe pulmonary arterial hypertension and tumors. The DNA damage response was found in both pulmonary arterial hypertension (PAH) cells and tumors. The ataxia-telangiectasia mutated proteins (ATM) pathway is considered an important factor in the DNA damage response of tumor formation, but its function in the development of PAH remains unknown. MATERIAL AND METHODS The Sprague-Dawley rat PAH model was established. Three weeks (Group M1), 5 weeks (Group M2), and 7 weeks (Group M3) after drug injection, pulmonary expression of ATM, Checkpoint kinase 2 (Chk2), P53, and P21 were measured. A section of the lungs from Group M2 was used for pulmonary artery vascular smooth muscles cells (PA-SMCs) isolation and culture. The effect of KU60019 in the proliferation and apoptosis of primary cultured rat PA-SMCs was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL), respectively. RESULTS Immunohistochemistry results show that the expression of ATM, Chk2, and P21 increased in Groups M1 and M2, and decreased in Group M3. Additionally, expression of P53 increased in Group M1, and decreased in Groups M2 and M3. RT PCR and Western blotting demonstrated that in Groups M1 and M2, the expression of ATM, Chk2, P53, and P21 increased, whereas it decreased in Group M3. In cell culture, 0.3 MUM and 0.5 MUM KU60019 increased the growth of PA-SMCs, and 0.5 MUM KU60019 reduced cell apoptosis. CONCLUSIONS Expression of the ATM-Chk2 pathway increased in early stages of PAH formation, but decreased in late stages. In primary cultured PA-SMCs, KU60019 increased cell proliferation and inhibited cell apoptosis. PMID- 28894084 TI - Tbx3-dependent amplifying stem cell progeny drives interfollicular epidermal expansion during pregnancy and regeneration. AB - The skin surface area varies flexibly in response to body shape changes. Skin homeostasis is maintained by stem cells residing in the basal layer of the interfollicular epidermis. However, how the interfollicular epidermal stem cells response to physiological body shape changes remains elusive. Here, we identify a highly proliferative interfollicular epidermal basal cell population in the rapidly expanding abdominal skin of pregnant mice. These cells express Tbx3 that is necessary for their propagation to drive skin expansion. The Tbx3+ basal cells are generated from Axin2+ interfollicular epidermal stem cells through planar oriented asymmetric or symmetric cell divisions, and express transit-amplifying cell marker CD71. This biased division of Axin2+ interfollicular epidermal stem cells is induced by Sfrp1 and Igfbp2 proteins secreted from dermal cells. The Tbx3+ basal cells promote wound repair, which is enhanced by Sfrp1 and Igfbp2. This study elucidates the interfollicular epidermal stem cell/progeny organisation during pregnancy and suggests its application in regenerative medicine.The abdominal skin expands rapidly during pregnancy. Here the authors show that a population of highly proliferative stem cell progenies expressing the transcription factor Tbx3 is required for abdominal skin expansion in pregnant mice. PMID- 28894086 TI - Molecular analogue of the perovskite repeating unit and evidence for direct MnIII CeIV-MnIII exchange coupling pathway. AB - The perovskite manganites AMnO3 and their doped analogues A1-x B x MnO3 (A and B = main group and lanthanide metals) are a fascinating family of magnetic oxides exhibiting a rich variety of properties. They are thus under intense investigation along multiple fronts, one of which is how their structural and physical properties are modified at the nanoscale. Here we show that the molecular compound [Ce3Mn8O8(O2CPh)18(HO2CPh)2] (CeIII2CeIVMnIII8; hereafter Ce3Mn8) bears a striking structural resemblance to the repeating unit seen in the perovskite manganites. Further, magnetic studies have established that Ce3Mn8 exhibits both the combination of pairwise MnIII2 ferromagnetic and antiferromagnetic exchange interactions, and the resultant spin vector alignments that are found within the 3-D C-type antiferromagnetic perovskites. First principles theoretical calculations reveal not only the expected nearest-neighbor MnIII2 exchange couplings via superexchange pathways through bridging ligands but also an unusual, direct MnIII-CeIV-MnIII metal-to-metal channel involving the CeIV f orbitals.Perovskite manganites exhibit intriguing but poorly understood properties, including multiferroicity. Here, the authors synthesize a Ce3Mn8 cluster that structurally resembles a perovskite repeat unit, and use this molecular analogue to elucidate mechanisms driving bulk perovskite properties. PMID- 28894087 TI - Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. AB - Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5' AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5'-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation. PMID- 28894085 TI - p190RhoGAP proteins contain pseudoGTPase domains. AB - The two p190RhoGAP proteins, p190RhoGAP-A and -B, are key regulators of Rho GTPase signaling and are essential for actin cytoskeletal structure and contractility. Here we report the discovery of two evolutionarily conserved GTPase-like domains located in the 'middle domain', previously thought to be unstructured. Deletion of these domains reduces RhoGAP activity. Crystal structures, MANT-GTPgammaS binding, thermal denaturation, biochemical assays and sequence homology analysis all strongly support defects in nucleotide-binding activity. Analysis of p190RhoGAP proteins therefore indicates the presence of two previously unidentified domains which represent an emerging group of pseudoenzymes, the pseudoGTPases.A growing number of 'pseudoenzymes' with a regulatory role in signal transduction processes but without catalytic activity are being identified. Here, the authors identify two pseudoGTPase domains in p190RhoGAP, characterize them biochemically and structurally and show that they influence RhoGAP activity. PMID- 28894088 TI - A de novo substructure generation algorithm for identifying the privileged chemical fragments of liver X receptorbeta agonists. AB - Liver X receptorbeta (LXRbeta) is a promising therapeutic target for lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Druggable LXRbeta agonists have been explored over the past decades. However, the pocket of LXRbeta ligand-binding domain (LBD) is too large to predict LXRbeta agonists with novel scaffolds based on either receptor or agonist structures. In this paper, we report a de novo algorithm which drives privileged LXRbeta agonist fragments by starting with individual chemical bonds (de novo) from every molecule in a LXRbeta agonist library, growing the bonds into substructures based on the agonist structures with isomorphic and homomorphic restrictions, and electing the privileged fragments from the substructures with a popularity threshold and background chemical and biological knowledge. Using these privileged fragments as queries, we were able to figure out the rules to reconstruct LXRbeta agonist molecules from the fragments. The privileged fragments were validated by building regularized logistic regression (RLR) and supporting vector machine (SVM) models as descriptors to predict a LXRbeta agonist activities. PMID- 28894089 TI - Heparan sulfate proteoglycans present PCSK9 to the LDL receptor. AB - Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels. PMID- 28894090 TI - Seed-induced acceleration of amyloid-beta mediated neurotoxicity in vivo. AB - Seeded propagation of amyloid-beta (Abeta) pathology is suggested to contribute to the progression of Alzheimer's disease. Local overproduction of aggregation prone Abeta variants could explain the focal initiation of a seeding cascade that subsequently triggers widespread pathology. Several animal models support this seeding concept by demonstrating accelerated Abeta deposition following inoculation with Abeta-containing homogenates, however its role in progressive neurodegeneration remains unclear. Here, we present a non-invasive approach to study Abeta seeding processes in vivo using Drosophila models. We show that small amounts of aggregation-competent Abeta42 seeds, generated in selected neuronal clusters, can induce the deposition of the pan-neuronally expressed and otherwise soluble Abeta40. Moreover, our models visualize the accelerated formation and propagation of amyloid pathology throughout the brain, which correlates with severe neurotoxicity. Taken together, these in vivo models provide mechanistic insights into disease-related processes and represent versatile genetic tools to determine novel modifiers of the Abeta seeding cascade.Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer's disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo. PMID- 28894092 TI - Coherent long-distance displacement of individual electron spins. AB - Controlling nanocircuits at the single electron spin level is a possible route for large-scale quantum information processing. In this context, individual electron spins have been identified as versatile quantum information carriers to interconnect different nodes of a spin-based semiconductor quantum circuit. Despite extensive experimental efforts to control the electron displacement over long distances, maintaining electron spin coherence after transfer remained elusive up to now. Here we demonstrate that individual electron spins can be displaced coherently over a distance of 5 um. This displacement is realized on a closed path made of three tunnel-coupled lateral quantum dots at a speed approaching 100 ms-1. We find that the spin coherence length is eight times longer than expected from the electron spin coherence without displacement, pointing at a process similar to motional narrowing observed in nuclear magnetic resonance experiments. The demonstrated coherent displacement will open the route towards long-range interaction between distant spin qubits.The spin states of electrons in quantum dots have well-established potential for use as qubits but some proposed developments require the ability to move the quantum spin state across a larger device. Here, the authors experimentally demonstrate coherent shuttling of spins in a ring of three dots. PMID- 28894091 TI - Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. AB - Natural killer (NK) cells are considered a promising strategy for cancer treatment. Various methods for large-scale NK cell expansion have been developed, but they should guarantee that no viable cells are mixed with the expanded NK cells because most methods involve cancer cells or genetically modified cells as feeder cells. We used an anti-CD16 monoclonal antibody (mAb) and irradiated autologous peripheral blood mononuclear cells (PBMCs) (IrAPs) to provide a suitable environment (activating receptor-ligand interactions) for the NK cell expansion. This method more potently expanded NK cells, and the final product was composed of highly purified NK cells with lesser T-cell contamination. The expanded NK cells showed greater upregulation of various activation receptors, CD107a, and secreted larger amounts of interferon gamma. IrAPs expressed NKG2D ligands and CD48, and coengagement of CD16 with NKG2D and 2B4 caused potent NK cell activation and proliferation. The expanded NK cells were cytotoxic toward various cancer cells in vitro and in vivo. Moreover, irradiation or a chemotherapeutic drug further enhanced this antitumor effect. Therefore, we developed an effective in vitro culture method for large-scale expansion of highly purified cytotoxic NK cells with potent antitumor activity using IrAPs instead of cancer cell-based feeder cells. PMID- 28894093 TI - Greenberger-Horne-Zeilinger states-based blind quantum computation with entanglement concentration. AB - In blind quantum computation (BQC) protocol, the quantum computability of servers are complicated and powerful, while the clients are not. It is still a challenge for clients to delegate quantum computation to servers and keep the clients' inputs, outputs and algorithms private. Unfortunately, quantum channel noise is unavoidable in the practical transmission. In this paper, a novel BQC protocol based on maximally entangled Greenberger-Horne-Zeilinger (GHZ) states is proposed which doesn't need a trusted center. The protocol includes a client and two servers, where the client only needs to own quantum channels with two servers who have full-advantage quantum computers. Two servers perform entanglement concentration used to remove the noise, where the success probability can almost reach 100% in theory. But they learn nothing in the process of concentration because of the no-signaling principle, so this BQC protocol is secure and feasible. PMID- 28894094 TI - Children's, parents' and health professionals' views on the management of childhood asthma: a qualitative study. AB - : The management of childhood asthma is often sub-optimal. Parents and other caregivers are primarily responsible for disease management and this responsibility includes communication with health professionals. The aim of this multi-perspective qualitative study was to explore the views of children, parents and health professionals to gain insight into the approach to clinical care in the management of childhood asthma. Interviews were held with nine parent-child (6-8 years) dyads, and 13 health professionals working in primary and secondary care. Interviews were transcribed verbatim and analysed thematically. Three key themes emerged that were common to all data sets; (1) Child and parent awareness of symptoms; (2) Management and child wellbeing; and (3) Professional communication education and consultation with families. Although some children demonstrate good awareness of symptoms and appropriate use of medication, some parents expressed difficulty in identifying triggers and symptoms of asthma. Furthermore, parents lacked awareness regarding appropriate use of medication for preventing and managing symptoms of asthma. Health professionals believed that communication and education was lacking. Data from all participants suggested that consultations could be enhanced with greater emphasis on children's and parents' perceptions of asthma in the development of asthma management plans. CHILDHOOD ASTHMA: GUIDING FAMILIES THROUGH DISEASE MANAGEMENT: Both parents' and children's perceptions and understanding of childhood asthma should be considered when developing asthma management plans. The management of asthma is challenging and can result in poor disease outcomes if care is not taken. An individual's perception of their (or their child's) asthma can also affect the efficacy of treatment. Aidan Searle at the Bristol Biomedical Research Centre, UK, and co workers, interviewed nine parent-child groups and thirteen health professionals to determine their perceptions of childhood asthma management in primary care. While some children had a strong awareness of symptoms and appropriate medication use, some parents found it difficult to identify asthma triggers and symptoms. Parents also displayed a lack of understanding of management through medication. Health professionals focused on the need for clearer information for families when guiding management of childhood asthma. PMID- 28894096 TI - Aerosols as a source of dissolved black carbon to the ocean. AB - Dissolved black carbon (DBC) is the largest known slow-cycling organic carbon pool in the world's oceans. Atmospheric deposition could significantly contribute to the oceanic DBC pool, but respective information is lacking. Here we estimate that, during the dust outbreak season, the atmospheric dry deposition of water soluble black carbon (WSBC) is ~ 40% of the riverine input to the China coastal seas. The molecular composition of atmospheric WSBC determined by ultrahigh resolution mass spectrometry, reveals similar soil-derived sources as for riverine discharge. WSBC is significantly positively correlated with water soluble organic carbon (WSOC) in marine aerosols, and water-soluble black carbon contributes on average 2.8 +/- 0.65% to the total WSOC. Based on this relationship, the global atmospheric deposition of DBC to the ocean is estimated to be 1.8 +/- 0.83 Tg yr-1. Anticipated future changes in biomass burning and dust mobilization might increase these numbers, with consequences for regional ecosystems and global carbon reservoirs.The contribution of atmospheric deposition to the oceanic dissolved black carbon pool (DBC) is unclear. Here, the authors show that water-soluble black carbon is positively correlated with water soluble organic carbon in marine aerosols, and that atmospheric deposition is a significant source of oceanic DBC. PMID- 28894095 TI - Atomic structures of Coxsackievirus A6 and its complex with a neutralizing antibody. AB - Coxsackievirus A6 (CVA6) has recently emerged as a major cause of hand, foot and mouth disease in children worldwide but no vaccine is available against CVA6 infections. Here, we demonstrate the isolation of two forms of stable CVA6 particles-procapsid and A-particle-with excellent biochemical stability and natural antigenicity to serve as vaccine candidates. Despite the presence (in A particle) or absence (in procapsid) of capsid-RNA interactions, the two CVA6 particles have essentially identical atomic capsid structures resembling the uncoating intermediates of other enteroviruses. Our near-atomic resolution structure of CVA6 A-particle complexed with a neutralizing antibody maps an immune-dominant neutralizing epitope to the surface loops of VP1. The structure guided cell-based inhibition studies further demonstrate that these loops could serve as excellent targets for designing anti-CVA6 vaccines.Coxsackievirus A6 (CVA6) causes hand, foot and mouth disease in children. Here the authors present the CVA6 procapsid and A-particle cryo-EM structures and identify an immune dominant neutralizing epitope, which can be exploited for vaccine development. PMID- 28894097 TI - Photo-triggered solvent-free metamorphosis of polymeric materials. AB - Liquefaction and solidification of materials are the most fundamental changes observed during thermal phase transitions, yet the design of organic and polymeric soft materials showing isothermal reversible liquid-nonliquid conversion remains challenging. Here, we demonstrate that solvent-free repeatable molecular architectural transformation between liquid-star and nonliquid-network polymers that relies on cleavage and reformation of a covalent bond in hexaarylbiimidazole. Liquid four-armed star-shaped poly(n-butyl acrylate) and poly(dimethyl siloxane) with 2,4,5-triphenylimidazole end groups were first synthesized. Subsequent oxidation of the 2,4,5-triphenylimidazoles into 2,4,5 triphenylimidazoryl radicals and their coupling with these liquid star polymers to form hexaarylbiimidazoles afforded the corresponding nonliquid network polymers. The resulting nonliquid network polymers liquefied upon UV irradiation and produced liquid star-shaped polymers with 2,4,5-triphenylimidazoryl radical end groups that reverted to nonliquid network polymers again by recoupling of the generated 2,4,5-triphenylimidazoryl radicals immediately after terminating UV irradiation.The design of organic and polymeric soft materials showing isothermal reversible liquid-nonliquid conversion is challenging. Here, the authors show solvent-free repeatable molecular architectural transformation between liquid star and non-liquid-network polymers by the cleavage and reformation of covalent bonds in the polymer chain. PMID- 28894098 TI - Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat. AB - The most prominent defence of the unicellular parasite Trypanosoma brucei against the host immune system is a dense coat that comprises a variant surface glycoprotein (VSG). Despite the importance of the VSG family, no complete structure of a VSG has been reported. Making use of high-resolution structures of individual VSG domains, we employed small-angle X-ray scattering to elucidate the first two complete VSG structures. The resulting models imply that the linker regions confer great flexibility between domains, which suggests that VSGs can adopt two main conformations to respond to obstacles and changes of protein density, while maintaining a protective barrier at all times. Single-molecule diffusion measurements of VSG in supported lipid bilayers substantiate this possibility, as two freely diffusing populations could be detected. This translates into a highly flexible overall topology of the surface VSG coat, which displays both lateral movement in the plane of the membrane and variation in the overall thickness of the coat. PMID- 28894099 TI - Statistical modelling predicts almost complete loss of major periglacial processes in Northern Europe by 2100. AB - The periglacial realm is a major part of the cryosphere, covering a quarter of Earth's land surface. Cryogenic land surface processes (LSPs) control landscape development, ecosystem functioning and climate through biogeochemical feedbacks, but their response to contemporary climate change is unclear. Here, by statistically modelling the current and future distributions of four major LSPs unique to periglacial regions at fine scale, we show fundamental changes in the periglacial climate realm are inevitable with future climate change. Even with the most optimistic CO2 emissions scenario (Representative Concentration Pathway (RCP) 2.6) we predict a 72% reduction in the current periglacial climate realm by 2050 in our climatically sensitive northern Europe study area. These impacts are projected to be especially severe in high-latitude continental interiors. We further predict that by the end of the twenty-first century active periglacial LSPs will exist only at high elevations. These results forecast a future tipping point in the operation of cold-region LSP, and predict fundamental landscape level modifications in ground conditions and related atmospheric feedbacks.Cryogenic land surface processes characterise the periglacial realm and control landscape development and ecosystem functioning. Here, via statistical modelling, the authors predict a 72% reduction of the periglacial realm in Northern Europe by 2050, and almost complete disappearance by 2100. PMID- 28894100 TI - Structural Basis for the Bidirectional Activity of Bacillus nanoRNase NrnA. AB - NanoRNAs are RNA fragments 2 to 5 nucleotides in length that are generated as byproducts of RNA degradation and abortive transcription initiation. Cells have specialized enzymes to degrade nanoRNAs, such as the DHH phosphoesterase family member NanoRNase A (NrnA). This enzyme was originally identified as a 3' -> 5' exonuclease, but we show here that NrnA is bidirectional, degrading 2-5 nucleotide long RNA oligomers from the 3' end, and longer RNA substrates from the 5' end. The crystal structure of Bacillus subtilis NrnA reveals a dynamic bi lobal architecture, with the catalytic N-terminal DHH domain linked to the substrate binding C-terminal DHHA1 domain via an extended linker. Whereas this arrangement is similar to the structure of RecJ, a 5' -> 3' DHH family DNase and other DHH family nanoRNases, Bacillus NrnA has gained an extended substrate binding patch that we posit is responsible for its 3' -> 5' activity. PMID- 28894101 TI - Intense natural selection preceded the invasion of new adaptive zones during the radiation of New World leaf-nosed bats. AB - The family Phyllostomidae, which evolved in the New World during the last 30 million years, represents one of the largest and most morphologically diverse mammal families. Due to its uniquely diverse functional morphology, the phyllostomid skull is presumed to have evolved under strong directional selection; however, quantitative estimation of the strength of selection in this extraordinary lineage has not been reported. Here, we used comparative quantitative genetics approaches to elucidate the processes that drove cranial evolution in phyllostomids. We also quantified the strength of selection and explored its association with dietary transitions and specialization along the phyllostomid phylogeny. Our results suggest that natural selection was the evolutionary process responsible for cranial diversification in phyllostomid bats. Remarkably, the strongest selection in the phyllostomid phylogeny was associated with dietary specialization and the origination of novel feeding habits, suggesting that the adaptive diversification of phyllostomid bats was triggered by ecological opportunities. These findings are consistent with Simpson's quantum evolutionary model of transitions between adaptive zones. The multivariate analyses used in this study provides a powerful tool for understanding the role of evolutionary processes in shaping phenotypic diversity in any group on both micro- and macroevolutionary scales. PMID- 28894102 TI - Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life. AB - Challenges in cultivating microorganisms have limited the phylogenetic diversity of currently available microbial genomes. This is being addressed by advances in sequencing throughput and computational techniques that allow for the cultivation independent recovery of genomes from metagenomes. Here, we report the reconstruction of 7,903 bacterial and archaeal genomes from >1,500 public metagenomes. All genomes are estimated to be >=50% complete and nearly half are >=90% complete with <=5% contamination. These genomes increase the phylogenetic diversity of bacterial and archaeal genome trees by >30% and provide the first representatives of 17 bacterial and three archaeal candidate phyla. We also recovered 245 genomes from the Patescibacteria superphylum (also known as the Candidate Phyla Radiation) and find that the relative diversity of this group varies substantially with different protein marker sets. The scale and quality of this data set demonstrate that recovering genomes from metagenomes provides an expedient path forward to exploring microbial dark matter. PMID- 28894105 TI - A duality principle for the multi-block entanglement entropy of free fermion systems. AB - The analysis of the entanglement entropy of a subsystem of a one-dimensional quantum system is a powerful tool for unravelling its critical nature. For instance, the scaling behaviour of the entanglement entropy determines the central charge of the associated Virasoro algebra. For a free fermion system, the entanglement entropy depends essentially on two sets, namely the set A of sites of the subsystem considered and the set K of excited momentum modes. In this work we make use of a general duality principle establishing the invariance of the entanglement entropy under exchange of the sets A and K to tackle complex problems by studying their dual counterparts. The duality principle is also a key ingredient in the formulation of a novel conjecture for the asymptotic behavior of the entanglement entropy of a free fermion system in the general case in which both sets A and K consist of an arbitrary number of blocks. We have verified that this conjecture reproduces the numerical results with excellent precision for all the configurations analyzed. We have also applied the conjecture to deduce several asymptotic formulas for the mutual and r-partite information generalizing the known ones for the single block case. PMID- 28894103 TI - The Candida albicans transcription factor Cas5 couples stress responses, drug resistance and cell cycle regulation. AB - The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit beta-1,3 glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.Cas5 is a transcriptional regulator of responses to cell wall stress in the fungal pathogen Candida albicans. Here, Xie et al. show that Cas5 also modulates cell cycle dynamics and responses to antifungal drugs. PMID- 28894104 TI - NFATc1 controls the cytotoxicity of CD8+ T cells. AB - Cytotoxic T lymphocytes are effector CD8+ T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1 -/- cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1 -/- CD8+ T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1 -/- , but not Nfatc2 -/- CD8+ T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.NFAT nuclear translocation has been shown to be required for CD8+ T cell cytokine production in response to viral infection. Here the authors show NFATc1 controls the cytotoxicity and metabolic switching of activated CD8+ T cells required for optimal response to bacteria and tumor cells. PMID- 28894106 TI - Heightened aversion to risk and loss in depressed patients with a suicide attempt history. AB - Suicide attempters have been found to be impaired in decision-making; however, their specific biases in evaluating uncertain outcomes remain unclear. Here we tested the hypothesis that suicidal behavior is associated with heightened aversion to risk and loss, which might produce negative predictions about uncertain future events. Forty-five depressed patients with a suicide attempt history, 47 nonsuicidal depressed patients, and 75 healthy controls participated in monetary decision-making tasks assessing risk and loss aversion. Suicide attempters compared with the other groups exhibited greater aversion to both risk and loss during gambles involving potential loss. Risk and loss aversion correlated with each other in the depressed patients, suggesting that a common pathophysiological mechanism underlies these biases. In addition, emotion regulation via suppression, a detrimental emotional control strategy, was positively correlated with loss aversion in the depressed patients, also implicating impairment in regulatory processes. A preliminary fMRI study also found disrupted neural responses to potential gains and losses in the subgenual anterior cingulate cortex, insula cortex, and left amygdala, brain regions involved in valuation, emotion reactivity, and emotion regulation. The findings thus implicate heightened negative valuation in decision-making under risk, and impaired emotion regulation in depressed patients with a history of suicide attempts. PMID- 28894107 TI - Sample space reducing cascading processes produce the full spectrum of scaling exponents. AB - Sample Space Reducing (SSR) processes are simple stochastic processes that offer a new route to understand scaling in path-dependent processes. Here we define a cascading process that generalises the recently defined SSR processes and is able to produce power laws with arbitrary exponents. We demonstrate analytically that the frequency distributions of states are power laws with exponents that coincide with the multiplication parameter of the cascading process. In addition, we show that imposing energy conservation in SSR cascades allows us to recover Fermi's classic result on the energy spectrum of cosmic rays, with the universal exponent -2, which is independent of the multiplication parameter of the cascade. Applications of the proposed process include fragmentation processes or directed cascading diffusion on networks, such as rumour or epidemic spreading. PMID- 28894108 TI - Description of two three-gendered nematode species in the new genus Auanema (Rhabditina) that are models for reproductive mode evolution. AB - The co-existence of males, females and hermaphrodites, a rare mating system known as trioecy, has been considered as an evolutionarily transient state. In nematodes, androdioecy (males/hermaphrodites) as found in Caenorhabditis elegans, is thought to have evolved from dioecy (males/females) through a trioecious intermediate. Thus, trioecious species are good models to understand the steps and requirements for the evolution of new mating systems. Here we describe two new species of nematodes with trioecy, Auanema rhodensis and A. freiburgensis. Along with molecular barcodes, we provide a detailed analysis of the morphology of these species, and document it with drawings and light and SEM micrographs. Based on morphological data, these free-living nematodes were assigned to a new genus, Auanema, together with three other species described previously. Auanema species display convergent evolution in some features with parasitic nematodes with complex life cycles, such as the production of few males after outcrossing and the obligatory development of dauers into self-propagating adults. PMID- 28894109 TI - Stress behaviours buffer macaques from aggression. AB - Primates (including humans) scratch when stressed. So far, such scratching has been seen as a by-product of physiological processes associated with stress, and attributed proximate, regulatory function. However, it is possible that others could use this relationship between scratching and stress as an indication of the animal's stress state, and thus scratching could potentially have social function. As a test of this theory, we measured the production of, and social responses to scratching in a group of free-ranging rhesus macaques (Macaca mulatta). Firstly, we found that the likelihood of scratching was greater around periods of heightened social stress, such as being in proximity to high-ranking individuals, or non-friends. Secondly, when macaques scratched, subsequent interactions were less likely to be aggressive and more likely to be affiliative. Potential attackers may avoid attacking stressed individuals as stressed individuals could behave unpredictably or be weakened by their state of stress (rendering aggression risky and/or unnecessary). Observable stress behaviour could therefore have additional adaptive value by reducing the potential for escalated aggression, benefiting both senders and receivers by facilitating social cohesion. This basic ability to recognise stress in others could also be an important component in the evolution of social cognition such as empathy. PMID- 28894110 TI - Omega-3 fatty acids correlate with gut microbiome diversity and production of N carbamylglutamate in middle aged and elderly women. AB - Omega-3 fatty acids may influence human physiological parameters in part by affecting the gut microbiome. The aim of this study was to investigate the links between omega-3 fatty acids, gut microbiome diversity and composition and faecal metabolomic profiles in middle aged and elderly women. We analysed data from 876 twins with 16S microbiome data and DHA, total omega-3, and other circulating fatty acids. Estimated food intake of omega-3 fatty acids were obtained from food frequency questionnaires. Both total omega-3and DHA serum levels were significantly correlated with microbiome alpha diversity (Shannon index) after adjusting for confounders (DHA Beta(SE) = 0.13(0.04), P = 0.0006 total omega-3: 0.13(0.04), P = 0.001). These associations remained significant after adjusting for dietary fibre intake. We found even stronger associations between DHA and 38 operational taxonomic units (OTUs), the strongest ones being with OTUs from the Lachnospiraceae family (Beta(SE) = 0.13(0.03), P = 8 * 10-7). Some of the associations with gut bacterial OTUs appear to be mediated by the abundance of the faecal metabolite N-carbamylglutamate. Our data indicate a link between omega 3 circulating levels/intake and microbiome composition independent of dietary fibre intake, particularly with bacteria of the Lachnospiraceae family. These data suggest the potential use of omega-3 supplementation to improve the microbiome composition. PMID- 28894111 TI - Induction of high titred, non-neutralising antibodies by self-adjuvanting peptide epitopes derived from the respiratory syncytial virus fusion protein. AB - Respiratory syncytial virus (RSV) causes severe lower respiratory tract illness in infants and young children. The significant morbidity and mortality rates associated with RSV infection make an effective RSV vaccine development a priority. Two neutralising antibody binding sites, O and II, located on the pre fusion RSV F glycoprotein are prime candidates for epitope-focused vaccine design. We report on a vaccine strategy that utilises a lipid core peptide (LCP) delivery system with self-adjuvanting properties in conjunction with either the antigenic site O or II (B cell epitopes) along with PADRE as a T helper cell epitope. These LCP constructs adopted the desired helical conformation in solution and were recognised by their cognate antibodies D25 and Motavizumab, specific for site O and II on RSV F protein, respectively. The LCP constructs were capable of eliciting higher levels of antigen specific antibodies than those induced by antigens administered with complete Freund's adjuvant, demonstrating the potent adjuvanting properties of LCP delivery. However, the antibodies induced failed to recognise native F protein or neutralise virus infectivity. These results provide a note of caution in assuming that peptide vaccines, successfully designed to structurally mimic minimal linear B cell epitopes, will necessarily elicit the desired immune response. PMID- 28894112 TI - Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain. AB - Childhood malnutrition is a risk factor for mental disorders, such as major depression and anxiety. Evidence shows that similar early life adversities induce sex-dependent epigenetic reprogramming. However, little is known about how genes are specifically affected by early malnutrition and the implications for males and females respectively. One relevant target is neuropeptide Y (NPY), which regulates both stress and food-intake. We studied maternal low protein diet (LPD) during pregnancy/lactation in mice. Male, but not female, offspring of LPD mothers consistently displayed anxiety- and depression-like behaviors under acute stress. Transcriptome-wide analysis of the effects of acute stress in the amygdala, revealed a list of transcription factors affected by either sex or perinatal LPD. Among these immediate early genes (IEG), members of the Early growth response family (Egr1/2/4) were consistently upregulated by perinatal LPD in both sexes. EGR1 also bound the NPY receptor Y1 gene (Npy1r), which co occurred with sex-specific effects of perinatal LPD on both Npy1r DNA-methylation and gene transcription. Our proposed pathway connecting early malnutrition, sex independent regulatory changes in Egr1, and sex-specific epigenetic reprogramming of its effector gene, Npy1r, represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders. PMID- 28894113 TI - Microwaves effectively examine the extent and type of coking over acid zeolite catalysts. AB - Coking leads to the deactivation of solid acid catalyst. This phenomenon is a ubiquitous problem in the modern petrochemical and energy transformation industries. Here, we show a method based on microwave cavity perturbation analysis for an effective examination of both the amount and the chemical composition of cokes formed over acid zeolite catalysts. The employed microwave cavity can rapidly and non-intrusively measure the catalytically coked zeolites with sample full body penetration. The overall coke amount is reflected by the obtained dielectric loss (epsilon") value, where different coke compositions lead to dramatically different absorption efficiencies (epsilon"/cokes' wt%). The deeper-dehydrogenated coke compounds (e.g., polyaromatics) lead to an apparently higher epsilon"/wt% value thus can be effectively separated from lightly coked compounds. The measurement is based on the nature of coke formation during catalytic reactions, from saturated status (e.g., aliphatic) to graphitized status (e.g., polyaromatics), with more delocalized electrons obtained for enhanced Maxwell-Wagner polarization.Catalyst deactivation by coke deposition is a major drawback in industrial processes. Here, the authors show a non-intrusive microwave cavity perturbation technique as a powerful tool to determine the nature and extent of coke accumulation in industrially-relevant zeolite catalysts. PMID- 28894114 TI - Cinaciguat ameliorates glomerular damage by reducing ERK1/2 activity and TGF-beta expression in type-1 diabetic rats. AB - Decreased soluble guanylate cyclase activity and cGMP levels in diabetic kidneys were shown to influence the progression of nephropathy. The regulatory effects of soluble guanylate cyclase activators on renal signaling pathways are still unknown, we therefore investigated the renal molecular effects of the soluble guanylate cyclase activator cinaciguat in type-1 diabetic (T1DM) rats. Male adult Sprague-Dawley rats were divided into 2 groups after induction of T1DM with 60 mg/kg streptozotocin: DM, untreated (DM, n = 8) and 2) DM + cinaciguat (10 mg/kg per os daily, DM-Cin, n = 8). Non-diabetic untreated and cinaciguat treated rats served as controls (Co (n = 10) and Co-Cin (n = 10), respectively). Rats were treated for eight weeks, when renal functional and molecular analyses were performed. Cinaciguat attenuated the diabetes induced proteinuria, glomerulosclerosis and renal collagen-IV expression accompanied by 50% reduction of TIMP-1 expression. Cinaciguat treatment restored the glomerular cGMP content and soluble guanylate cyclase expression, and ameliorated the glomerular apoptosis (TUNEL positive cell number) and podocyte injury. These effects were accompanied by significantly reduced TGF-beta overexpression and ERK1/2 phosphorylation in cinaciguat treated diabetic kidneys. We conclude that the soluble guanylate cyclase activator cinaciguat ameliorated diabetes induced glomerular damage, apoptosis, podocyte injury and TIMP-1 overexpression by suppressing TGF-beta and ERK1/2 signaling. PMID- 28894116 TI - Characterization of tonsillar IL10 secreting B cells and their role in the pathophysiology of tonsillar hypertrophy. AB - The comprehension of unconventional immune functions of tonsillar B cells, their role in tolerance induction and protective immune responses, is crucial to unveil the dynamic interactions of the upper aero digestive tract with polymicrobial commensal flora and pathogens, in health and disease. Here, we describe the kinetics of IL10 intracellular expression and compare it with that of cytokines known to be produced by tonsillar B cells. Additionally, we detected a relevant proportion of IL17-expressing tonsillar B cells, which has not previously been reported. We immunophenotyped tonsillar IL10-expressing B cells (B10) and observed IL10 production in activated B cells at every developmental stage. Finally, we identified a relationship between decreased B10 percentages, increased proportion of the germinal centre (GC) population and hypertrophied tonsils (HT). Our findings provide greater insight into the role of B10 in GC reactions and characterized their involvement in the pathogenesis of tonsillar dysfunction. PMID- 28894115 TI - In silico prediction of drug-target interaction networks based on drug chemical structure and protein sequences. AB - Analysis of drug-target interactions (DTIs) is of great importance in developing new drug candidates for known protein targets or discovering new targets for old drugs. However, the experimental approaches for identifying DTIs are expensive, laborious and challenging. In this study, we report a novel computational method for predicting DTIs using the highly discriminative information of drug-target interactions and our newly developed discriminative vector machine (DVM) classifier. More specifically, each target protein sequence is transformed as the position-specific scoring matrix (PSSM), in which the evolutionary information is retained; then the local binary pattern (LBP) operator is used to calculate the LBP histogram descriptor. For a drug molecule, a novel fingerprint representation is utilized to describe its chemical structure information representing existence of certain functional groups or fragments. When applying the proposed method to the four datasets (Enzyme, GPCR, Ion Channel and Nuclear Receptor) for predicting DTIs, we obtained good average accuracies of 93.16%, 89.37%, 91.73% and 92.22%, respectively. Furthermore, we compared the performance of the proposed model with that of the state-of-the-art SVM model and other previous methods. The achieved results demonstrate that our method is effective and robust and can be taken as a useful tool for predicting DTIs. PMID- 28894117 TI - Preparation of Monolayer MoS2 Quantum Dots using Temporally Shaped Femtosecond Laser Ablation of Bulk MoS2 Targets in Water. AB - Zero-dimensional MoS2 quantum dots (QDs) possess distinct physical and chemical properties, which have garnered them considerable attention and facilitates their use in a broad range of applications. In this study, we prepared monolayer MoS2 QDs using temporally shaped femtosecond laser ablation of bulk MoS2 targets in water. The morphology, crystal structures, chemical, and optical properties of the MoS2 QDs were characterized by transmission electron microscopy, X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, UV-vis absorption spectra, and photoluminescence spectra. The analysis results show that highly pure, uniform, and monolayer MoS2 QDs can be successfully prepared. Moreover, by temporally shaping a conventional single pulse into a two-subpulse train, the production rate of MoS2 nanomaterials (including nanosheets, nanoparticles, and QDs) and the ratio of small size MoS2 QDs can be substantially improved. The underlying mechanism is a combination of multilevel photoexfoliation of monolayer MoS2 and water photoionization-enhanced light absorption. The as-prepared MoS2 QDs exhibit excellent electrocatalytic activity for hydrogen evolution reactions because of the abundant active edge sites, high specific surface area, and excellent electrical conductivity. Thus, this study provides a simple and green alternative strategy for the preparation of monolayer QDs of transition metal dichalcogenides or other layered materials. PMID- 28894118 TI - Persistence of Zika virus in conjunctival fluid of convalescence patients. AB - A widespread epidemic of Zika fever, caused by Zika virus (ZIKAV) has spread throughout the Pacific islands, the Americas and Southeast Asia. The increased incidences of ocular anomalies observed in ZIKAV-infected infants and adults may be associated with the rapid spread of ZIKAV. The objective of this study was to check if ZIKAV could be detected in human tears after the first week of infection. Twenty-nine patients with PCR confirmed ZIKAV infection during the Singapore August 2016 ZIKAV outbreak were enrolled for the study. Detection and quantification of ZIKAV RNA was performed on conjunctival swabs collected from both eyes of these patients at the late convalescent phase (30 days post illness). Efficiency of viral isolation from swab samples was confirmed by the limit of detection (as low as 0.1 PFU/uL, equivalent to copy number of 4.9) in spiked swabs with different concentrations of ZIKAV (PFU/uL). Samples from three patients were found positive by qRT-PCR for ZIKAV and the viral RNA copy numbers detected in conjunctival swabs ranged from 5.2 to 9.3 copies respectively. ZIKAV could persist in the tears of infected patients for up to 30 days post-illness, and may therefore possess a potential public health risk of transmission. PMID- 28894121 TI - Development of a novel surface assisted volume negative hydrogen ion source. AB - H- ion based neutral beam injector is a critical heating and current drive system in a fusion reactor. However, the present H- ion source configuration has limitations in terms of production, extraction, cesium (Cs) inventory and management. To overcome these limitations, a proof-of-principle experiment based on a novel concept regarding surface assisted volume H- ions production by sprinkling Cs coated tungsten (W) dust grains (low work function surface) into a hydrogen plasma is carried out. Four different diagnostics have been used to validate the concept. The H- ion fraction is estimated from (a) Langmuir probe diagnostic, (b) phase velocity of ion acoustic waves, (c) dust current and confirmed by the measurement of (d) Balmer line ratio. The measured H- ion fraction with respect to the plasma density for different discharge conditions varies from ~0.2 to 0.3 in presence of Cs coated W dust particles. The experimental results show good agreement with the theoretical estimation. PMID- 28894119 TI - Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis. AB - Psoriasis is a chronic inflammatory skin disease affecting 2.5-6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration. PMID- 28894120 TI - Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH. AB - Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 * 10-6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets. PMID- 28894122 TI - Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43. AB - We have investigated the behavior of second RNA-recognition motif (RRM2) of neuropathological protein TDP43 under the effect of oxidative stress as modeled in vitro. Toward this end we have used the specially adapted version of H/D exchange experiment, NMR relaxation and diffusion measurements, dynamic light scattering, controlled proteolysis, gel electrophoresis, site-directed mutagenesis and microsecond MD simulations. Under oxidizing conditions RRM2 forms disulfide-bonded dimers that experience unfolding and then assemble into aggregate particles (APs). These particles are strongly disordered, highly inhomogeneous and susceptible to proteolysis; some of them withstand the dithiothreitol treatment. They can recruit/release monomeric RRM2 through thiol disulfide exchange reactions. By using a combination of dynamic light scattering and NMR diffusion data we were able to approximate the size distribution function for the APs. The key to the observed aggregation behavior is the diminished ability of disulfide-bonded RRM2 dimers to refold and their increased propensity to misfold, which makes them vulnerable to large thermal fluctuations. The emerging picture provides detailed insight on how oxidative stress can contribute to neurodegenerative disease, with unfolding, aggregation, and proteolytic cleavage as different facets of the process. PMID- 28894123 TI - Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility. AB - Prostate specific antigen (PSA/KLK3) is known to be the chief executor of the fragmentation of semenogelins, dissolution of semen coagulum, thereby releasing sperm for active motility. Recent research has found that semenogelins also play significant roles in sperm fertility by affecting hyaluronidase activity, capacitation and motility, thereby making PSA important for sperm fertility beyond simple semen liquefaction. PSA level in semen has been shown to correlate with sperm motility, suggesting that PSA level/activity can affect fertility. However, no study investigating the genetic variations in the KLK3/PSA gene in male fertility has been undertaken. We analyzed the complete coding region of the KLK3 gene in ethnically matched 875 infertile and 290 fertile men to find if genetic variations in KLK3 correlate with infertility. Interestingly, this study identified 28 substitutions, of which 8 were novel (not available in public databases). Statistical comparison of the genotype frequencies showed that five SNPs, rs266881 (OR = 2.92, P < 0.0001), rs174776 (OR = 1.91, P < 0.0001), rs266875 (OR = 1.44, P = 0.016), rs35192866 (OR = 4.48, P = 0.025) and rs1810020 (OR = 2.08, P = 0.034) correlated with an increased risk of infertility. On the other hand, c.206 + 235 T > C, was more freuqent in the control group, showing protective association. Our findings suggest that polymorphisms in the KLK3 gene correlate with infertility risk. PMID- 28894124 TI - Effects of purified or plant-produced Cry proteins on Drosophila melanogaster (Diptera: Drosophilidae) larvae. AB - Although genetically engineered crops producing insecticidal Cry proteins from Bacillus thuringiensis (Bt) are grown worldwide, few studies cover effects of Bt crops or Cry proteins on dipteran species in an agricultural context. We tested the toxicity of six purified Cry proteins and of Bt cotton and Bt maize tissue on Drosophila melanogaster (Diptera: Drosophilidae) as a surrogate for decomposing Diptera. ELISA confirmed the presence of Cry proteins in plant material, artificial diet, and fly larvae, and concentrations were estimated. Median concentrations in emerging adult flies were below the limit of detection. Bioactivity of purified Cry proteins in the diet was confirmed by sensitive species assays using Heliothis virescens (Lepidoptera: Noctuidae). Purified Cry1Ab, Cry1Ac, Cry1B, Cry1C, Cry1F, or Cry2Aa, or leaf material from stacked Bt cotton (Bollgard II producing Cry1Ac and Cry2Ab) or Bt maize (SmartStax producing Cry1A.105, Cry1Fa2, Cry2Ab2, Cry3Bb1, Cry34Ab1 and Cry35Ab1) had no consistent effects on D. melanogaster survival, developmental time, adult body mass or morphometrics. However, D. melanogaster showed longer developmental time and smaller wing size when fed with cotton leaves from plants infested with H. virescens caterpillars compared to flies fed with leaves from uninfested plants, while no such effects were obvious for maize. PMID- 28894126 TI - Microbes in Infant Gut Development: Placing Abundance Within Environmental, Clinical and Growth Parameters. AB - Sound and timely microbial gut colonization completes newborn's healthy metabolic programming and manifests in infant appropriate growth and weight development. Feces, collected at 3, 30, and 90 days after birth from 60 breastfed Slovenian newborns, was submitted to microbial DNA extraction and qPCR quantification of selected gut associated taxa. Multivariate regression analysis was applied to evaluate microbial dynamics with respect to infant demographic, environmental, clinical characteristics and first year growth data. Early microbial variability was marked by the proportion of Bacilli, but diminished and converged in later samples, as bifidobacteria started to prevail. The first month proportions of enterococci were associated with maternity hospital locality and supplementation of breastfeeding with formulae, while Enterococcus faecalis proportion reflected the mode of delivery. Group Bacteroides-Prevotella proportion was associated with infant weight and ponderal index at first month. Infant mixed feeding pattern and health issues within the first month revealed the most profound and extended microbial perturbations. Our findings raise concerns over the ability of the early feeding supplementation to emulate and support the gut microbiota in a way similar to the exclusively breastfed infants. Additionally, practicing supplementation beyond the first month also manifested in higher first year weight and weight gain Z-score. PMID- 28894125 TI - Elongation factor Tu is a multifunctional and processed moonlighting protein. AB - Many bacterial moonlighting proteins were originally described in medically, agriculturally, and commercially important members of the low G + C Firmicutes. We show Elongation factor Tu (Ef-Tu) moonlights on the surface of the human pathogens Staphylococcus aureus (SaEf-Tu) and Mycoplasma pneumoniae (MpnEf-Tu), and the porcine pathogen Mycoplasma hyopneumoniae (MhpEf-Tu). Ef-Tu is also a target of multiple processing events on the cell surface and these were characterised using an N-terminomics pipeline. Recombinant MpnEf-Tu bound strongly to a diverse range of host molecules, and when bound to plasminogen, was able to convert plasminogen to plasmin in the presence of plasminogen activators. Fragments of Ef-Tu retain binding capabilities to host proteins. Bioinformatics and structural modelling studies indicate that the accumulation of positively charged amino acids in short linear motifs (SLiMs), and protein processing promote multifunctional behaviour. Codon bias engendered by an A + T rich genome may influence how positively-charged residues accumulate in SLiMs. PMID- 28894127 TI - Dichotomy between in-plane magnetic susceptibility and resistivity anisotropies in extremely strained BaFe2As2. AB - High-temperature superconductivity in the Fe-based materials emerges when the antiferromagnetism of the parent compounds is suppressed by either doping or pressure. Closely connected to the antiferromagnetic state are entangled orbital, lattice, and nematic degrees of freedom, and one of the major goals in this field has been to determine the hierarchy of these interactions. Here we present the direct measurements and the calculations of the in-plane uniform magnetic susceptibility anisotropy of BaFe2As2, which help in determining the above hierarchy. The magnetization measurements are made possible by utilizing a simple method for applying a large symmetry-breaking strain, based on differential thermal expansion. In strong contrast to the large resistivity anisotropy above the antiferromagnetic transition at T N, the anisotropy of the in-plane magnetic susceptibility develops largely below T N. Our results imply that lattice and orbital degrees of freedom play a subdominant role in these materials.Interplay between lattice, orbital, magnetic and nematic degrees of freedom is crucial for the superconductivity in Fe-based materials. Here, the authors demonstrate the subdominant roles of pure lattice distortions and/or orbital ordering in BaFe2As2 by characterizing the in-plane magnetic susceptibility anisotropy. PMID- 28894128 TI - Microbial colonization is required for normal neurobehavioral development in zebrafish. AB - Changes in resident microbiota may have wide-ranging effects on human health. We investigated whether early life microbial disruption alters neurodevelopment and behavior in larval zebrafish. Conventionally colonized, axenic, and axenic larvae colonized at 1 day post fertilization (dpf) were evaluated using a standard locomotor assay. At 10 dpf, axenic zebrafish exhibited hyperactivity compared to conventionalized and conventionally colonized controls. Impairment of host colonization using antibiotics also caused hyperactivity in conventionally colonized larvae. To determine whether there is a developmental requirement for microbial colonization, axenic embryos were serially colonized on 1, 3, 6, or 9 dpf and evaluated on 10 dpf. Normal activity levels were observed in axenic larvae colonized on 1-6 dpf, but not on 9 dpf. Colonization of axenic embryos at 1 dpf with individual bacterial species Aeromonas veronii or Vibrio cholerae was sufficient to block locomotor hyperactivity at 10 dpf. Exposure to heat-killed bacteria or microbe-associated molecular patterns pam3CSK4 or Poly(I:C) was not sufficient to block hyperactivity in axenic larvae. These data show that microbial colonization during early life is required for normal neurobehavioral development and support the concept that antibiotics and other environmental chemicals may exert neurobehavioral effects via disruption of host-associated microbial communities. PMID- 28894129 TI - Designing functionality in perovskite thin films using ion implantation techniques: Assessment and insights from first-principles calculations. AB - Recent experimental findings have demonstrated that low doses of low energy helium ions can be used to tailor the structural and electronic properties of single crystal films. These initial studies have shown that changes to lattice expansion were proposed to be the direct result of chemical pressure originating predominantly from the implanted He applying chemical pressure at interstitial sites. However, the influence of possible secondary knock-on damage arising from the He atoms transferring energy to the lattice through nuclear-nuclear collision with the crystal lattice remains largely unaddressed. Here, we study SrRuO3 to provide a comprehensive examination of the impact of common defects on structural and electronic properties. We found that, while interstitial He can modify the properties, a dose significantly larger than those reported in experimental studies would be required. Our study suggests that true origin of the observed changes is from combination of secondary defects created during He implantation. Of particular importance, we observe that different defect types can generate greatly varied local electronic structures and that the formation energies and migration energy barriers vary by defect type. Thus, we may have identified a new method of selectively inducing controlled defect complexes into single crystal materials. PMID- 28894130 TI - A Chinese Pane-Like 2D Metal-Organic Framework Showing Magnetic Relaxation and Luminescence Dual-Functions. AB - The discovery of graphene kicked off the curtain of atom-type two-dimensional (2D) materials. Layered metal-organic frameworks (MOFs) as parallel molecule based 2D materials are more designable and more diverse, and magnetism may be induced by their metal ion nodes. However, the multifunctional 2D plane-like MOFs are very difficult to obtain. Here we describe a Chinese pane-like 2D MOF constructed from the Ln3+ cation and the nanoscale luminescent tritopic ligand tris(4'-carboxybiphenyl)-amine, responding to the slow magnetic relaxation and luminescence properties, respectively. Notably, the Dy-Dy distances separated by the tritopic ligand are up to 2 nm. Such a 2D molecular material is expected to have potential applications in optoelectronics and multimodal sensing. PMID- 28894131 TI - ECG features and methods for automatic classification of ventricular premature and ischemic heartbeats: A comprehensive experimental study. AB - Accurate detection of cardiac pathological events is an important part of electrocardiogram (ECG) evaluation and subsequent correct treatment of the patient. The paper introduces the results of a complex study, where various aspects of automatic classification of various heartbeat types have been addressed. Particularly, non-ischemic, ischemic (of two different grades) and subsequent ventricular premature beats were classified in this combination for the first time. ECGs recorded in rabbit isolated hearts under non-ischemic and ischemic conditions were used for analysis. Various morphological and spectral features (both commonly used and newly proposed) as well as classification models were tested on the same data set. It was found that: a) morphological features are generally more suitable than spectral ones; b) successful results (accuracy up to 98.3% and 96.2% for morphological and spectral features, respectively) can be achieved using features calculated without time-consuming delineation of QRS-T segment; c) use of reduced number of features (3 to 14 features) for model training allows achieving similar or even better performance as compared to the whole feature sets (10 to 29 features); d) k-nearest neighbours and support vector machine seem to be the most appropriate models (accuracy up to 98.6% and 93.5%, respectively). PMID- 28894132 TI - Testing Gait with Ankle-Foot Orthoses in Children with Cerebral Palsy by Using Functional Mixed-Effects Analysis of Variance. AB - Existing statistical methods extract insufficient information from 3-dimensional gait data, rendering clinical interpretation of impaired movement patterns sub optimal. We propose an alternative approach based on functional data analysis that may be worthy of exploration. We apply this to gait data analysis using repeated-measurements data from children with cerebral palsy who had been prescribed fixed ankle-foot orthoses as an example. We analyze entire gait curves by means of a new functional F test with comparison to multiple pointwise F tests and also to the traditional method - univariate repeated-measurements analysis of variance of joint angle minima and maxima. The new test maintains the nominal significance level and can be adapted to test hypotheses for specific phases of the gait cycle. The main findings indicate that ankle-foot orthoses exert significant effects on coronal and sagittal plane ankle rotation; and both sagittal and horizontal plane foot rotation. The functional F test provided further information for the stance and swing phases. Differences between the results of the different statistical approaches are discussed, concluding that the novel method has potential utility and is worthy of validation through larger scale patient and clinician engagement to determine whether it is preferable to the traditional approach. PMID- 28894133 TI - 5-methoxytryptophan protects MSCs from stress induced premature senescence by upregulating FoxO3a and mTOR. AB - 5-methoxytryptophan (5-MTP) is a newly discovered tryptophan metabolite which controls stress-induced inflammatory signals. To determine whether 5-MTP protects against stress-induced mesenchymal stem cell (MSC) senescence, we incubated bone marrow-derived MSC (BM-MSC) in high-glucose medium or regular medium for 2 weeks followed by addiction of 5-MTP (10 MUM) or vehicle for 48 h. 5-MTP reduced p16 and p21 expression, senescence-associated beta-Gal (SA-beta-Gal) and IL-6 secretion and increased BrdU incorporation. 5-MTP exerted a similar effect on BM MSC senescence induced by a sublethal concentration of H2O2. 5-MTP enhanced FoxO3a expression and increased superoxide dismutase and catalase activities in HG BM-MSCs. Silencing of FoxO3a with siRNA abrogated 5-MTP-mediated reduction of SA-beta-Gal and IL-6 secretion but not p21 or p16. Since mechanistic target of rapamycin (mTOR) is involved in cellular senescence, we determined whether 5-MTP influences mTOR expression. Our data reveal that mTOR protein level was depressed in HG-MSC which was rescued by 5-MTP. Rapamycin abrogated 5-MTP-mediated suppression of p16, p21, SA-beta-Gal and IL-6 and rise of BrdU incorporation. Our findings suggest that 5-MTP protects MSCs against stress-induced senescence via FoxO3a and mTOR upregulation and has potential to improve cell expansion for cell therapy. PMID- 28894134 TI - Probing microwave fields and enabling in-situ experiments in a transmission electron microscope. AB - A technique is presented whereby the performance of a microwave device is evaluated by mapping local field distributions using Lorentz transmission electron microscopy (L-TEM). We demonstrate the method by measuring the polarisation state of the electromagnetic fields produced by a microstrip waveguide as a function of its gigahertz operating frequency. The forward and backward propagating electromagnetic fields produced by the waveguide, in a specimen-free experiment, exert Lorentz forces on the propagating electron beam. Importantly, in addition to the mapping of dynamic fields, this novel method allows detection of effects of microwave fields on specimens, such as observing ferromagnetic materials at resonance. PMID- 28894135 TI - Observing a scale anomaly and a universal quantum phase transition in graphene. AB - One of the most interesting predictions resulting from quantum physics, is the violation of classical symmetries, collectively referred to as anomalies. A remarkable class of anomalies occurs when the continuous scale symmetry of a scale-free quantum system is broken into a discrete scale symmetry for a critical value of a control parameter. This is an example of a (zero temperature) quantum phase transition. Such an anomaly takes place for the quantum inverse square potential known to describe 'Efimov physics'. Broken continuous scale symmetry into discrete scale symmetry also appears for a charged and massless Dirac fermion in an attractive 1/r Coulomb potential. The purpose of this article is to demonstrate the universality of this quantum phase transition and to present convincing experimental evidence of its existence for a charged and massless fermion in an attractive Coulomb potential as realized in graphene.When the continuous scale symmetry of a quantum system is broken, anomalies occur which may lead to quantum phase transitions. Here, the authors provide evidence for such a quantum phase transition in the attractive Coulomb potential of vacancies in graphene, and further envision its universality for diverse physical systems. PMID- 28894136 TI - Soluble intercellular adhesion molecule-1 is associated with hepatocellular carcinoma risk: multiplex analysis of serum markers. AB - Individualized assessment of hepatocellular carcinoma (HCC) risk in chronic liver disease remains challenging. Serum biomarkers including cytokines may offer helpful adjuncts to standard parameters for risk prediction. Our aim was to identify markers associated with increased HCC incidence. This was a prospective cohort study of 282 patients with both viral or non-viral chronic liver disease. Baseline serum cytokines and other markers were measured in multiplex with a commercially-available Luminex-based system. Patients were followed until death or HCC diagnosis. We performed Lasso-based survival analysis to determine parameters associated with HCC development. Cytokine mean florescence intensity (MFI) was the primary predictor and HCC development the primary outcome. 25 patients developed HCC with total follow-up of 1,363 person-years. Parameters associated with increased HCC incidence were cirrhosis, hepatic decompensation, and soluble serum intercellular adhesion molecule 1 (sICAM-1) MFI. No other molecules increased predictive power for HCC incidence. On univariate analysis, the parameters associated with HCC incidence in patients with cirrhosis were age, antiviral treatment, and high sICAM-1 MFI; on multivariate analysis, sICAM-1 remained associated with HCC development (adjusted HR = 2.75). On unbiased screening of serum cytokines and other markers in a diverse cohort, baseline sICAM-1 MFI is associated with HCC incidence. PMID- 28894137 TI - Emergence of charge density waves and a pseudogap in single-layer TiTe2. AB - Two-dimensional materials constitute a promising platform for developing nanoscale devices and systems. Their physical properties can be very different from those of the corresponding three-dimensional materials because of extreme quantum confinement and dimensional reduction. Here we report a study of TiTe2 from the single-layer to the bulk limit. Using angle-resolved photoemission spectroscopy and scanning tunneling microscopy and spectroscopy, we observed the emergence of a (2 * 2) charge density wave order in single-layer TiTe2 with a transition temperature of 92 +/- 3 K. Also observed was a pseudogap of about 28 meV at the Fermi level at 4.2 K. Surprisingly, no charge density wave transitions were observed in two-layer and multi-layer TiTe2, despite the quasi-two dimensional nature of the material in the bulk. The unique charge density wave phenomenon in the single layer raises intriguing questions that challenge the prevailing thinking about the mechanisms of charge density wave formation.Due to reduced dimensionality, the properties of 2D materials are often different from their 3D counterparts. Here, the authors identify the emergence of a unique charge density wave (CDW) order in monolayer TiTe2 that challenges the current understanding of CDW formation. PMID- 28894138 TI - Mechanical bone growth stimulation by magnetic fibre networks obtained through a competent finite element technique. AB - Fibre networks combined with a matrix material in their void phase make the design of novel and smart composite materials possible. Their application is of great interest in the field of advanced paper or as bioactive tissue engineering scaffolds. In the present study, we analyse the mechanical interaction between metallic fibre networks under magnetic actuation and a matrix material. Experimentally validated FE models are combined for that purpose in one joint simulation. High performance computing facilities are used. The resulting strain in the composite's matrix is not uniform across the sample volume. Instead we show that boundary conditions and proximity to the fibre structure strongly influence the local strain magnitude. An analytical model of local strain magnitude is derived. The strain magnitude of 0.001 which is of particular interest for bone growth stimulation is achievable by this assembly. In light of these findings, the investigated composite structure is suitable for creating and for regulating contactless a stress field which is to be imposed on the matrix material. Topics for future research will be the advanced modelling of the biological components and the potential medical utilisation. PMID- 28894139 TI - The [Formula: see text] toric-code and the double-semion topological order of hardcore Bose-Hubbard-type models in the strong-interaction limit. AB - We present a generic framework for the emergence of the [Formula: see text] toric code and the double-semion topological order in a wide class of hardcore Bose Hubbard-type models governed by density-density interaction and in the strong interaction regime. We fix fractional filling factor and study under which conditions the density-density interaction gives rise to topological degeneracy. We further specify which dynamics determines the toric-code and the double-semion topological order. Our results indicate that the specifics of the density-density interaction determine the long-range entanglement of the model which possesses "restricted patterns" of the long-range entanglement realized in corresponding string-net models with the same topological order. PMID- 28894140 TI - D-serine, a novel uremic toxin, induces senescence in human renal tubular cells via GCN2 activation. AB - The prevalence of chronic kidney disease (CKD), characterized by progressive renal dysfunction with tubulointerstitial fibrosis, is increasing because of societal aging. Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2/M cell cycle arrest and senescence-associated secretory phenotype, including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by the general control nonderepressible 2 played an important role in D-serine-induced tubular cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway. Furthermore, D-serine induced suppression of tubular cell proliferation was ameliorated by L-serine administration, indicating that D-serine exposure induced an L-serine-deprived state in tubular cells, compensated by L-serine synthesis. Thus, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis. PMID- 28894141 TI - Formation of ferromagnetic Co-H-Co complex and spin-polarized conduction band in Co-doped ZnO. AB - Magnetic oxide semiconductors with wide band gaps have promising spintronic applications, especially in the case of magneto-optic devices. Co-doped ZnO (ZnCoO) has been considered for these applications, but the origin of its ferromagnetism has been controversial for several decades and no substantial progress for a practical application has been made to date. In this paper, we present direct evidence of hydrogen-mediated ferromagnetism and spin polarization in the conduction band of ZnCoO. Electron density mapping reveals the formation of Co-H-Co, in agreement with theoretical predictions. Electron spin resonance measurement elucidates the ferromagnetic nature of ZnCoO by the formation of Co-H Co. We provide evidence from magnetic circular dichroism measurements supporting the hypothesis that Co-H-Co contributes to the spin polarization of the conduction band of hydrogen-doped ZnCoO. PMID- 28894142 TI - Matrix Analysis of Warped Stretch Imaging. AB - Sensitive and fast optical imaging is needed for scientific instruments, machine vision, and biomedical diagnostics. Many of the fundamental challenges are addressed with time stretch imaging, which has been used for ultrafast continuous imaging for a diverse range of applications, such as biomarker-free cell classification, the monitoring of laser ablation, and the inspection of flat panel displays. With frame rates exceeding a million scans per second, the firehose of data generated by the time stretch camera requires optical data compression. Warped stretch imaging technology utilizes nonuniform spectrotemporal optical operations to compress the image in a single-shot real time fashion. Here, we present a matrix analysis method for the evaluation of these systems and quantify important design parameters and the spatial resolution. The key principles of the system include (1) time/warped stretch transformation and (2) the spatial dispersion of ultrashort optical pulse, which are traced with simple computation of ray-pulse matrix. Furthermore, a mathematical model is constructed for the simulation of imaging operations while considering the optical and electrical response of the system. The proposed analysis method was applied to an example time stretch imaging system via simulation and validated with experimental data. PMID- 28894143 TI - 3D calcite heterostructures for dynamic and deformable mineralized matrices. AB - Scales are rooted in soft tissues, and are regenerated by specialized cells. The realization of dynamic synthetic analogues with inorganic materials has been a significant challenge, because the abiological regeneration sites that could yield deterministic growth behavior are hard to form. Here we overcome this fundamental hurdle by constructing a mutable and deformable array of three dimensional calcite heterostructures that are partially locked in silicone. Individual calcite crystals exhibit asymmetrical dumbbell shapes and are prepared by a parallel tectonic approach under ambient conditions. The silicone matrix immobilizes the epitaxial nucleation sites through self-templated cavities, which enables symmetry breaking in reaction dynamics and scalable manipulation of the mineral ensembles. With this platform, we devise several mineral-enabled dynamic surfaces and interfaces. For example, we show that the induced growth of minerals yields localized inorganic adhesion for biological tissue and reversible focal encapsulation for sensitive components in flexible electronics.Minerals are rarely explored as building blocks for dynamic inorganic materials. Here, the authors derive inspiration from fish scales to create mutable surfaces based on arrays of calcite crystals, in which one end of each crystal is immobilized in and regenerated from silicone, and the other functional end is left exposed. PMID- 28894144 TI - Molecular details of secretory phospholipase A2 from flax (Linum usitatissimum L.) provide insight into its structure and function. AB - Secretory phospholipase A2 (sPLA2) are low molecular weight proteins (12-18 kDa) involved in a suite of plant cellular processes imparting growth and development. With myriad roles in physiological and biochemical processes in plants, detailed analysis of sPLA2 in flax/linseed is meagre. The present work, first in flax, embodies cloning, expression, purification and molecular characterisation of two distinct sPLA2s (I and II) from flax. PLA2 activity of the cloned sPLA2s were biochemically assayed authenticating them as bona fide phospholipase A2. Physiochemical properties of both the sPLA2s revealed they are thermostable proteins requiring di-valent cations for optimum activity.While, structural analysis of both the proteins revealed deviations in the amino acid sequence at C & N-terminal regions; hydropathic study revealed LusPLA2I as a hydrophobic protein and LusPLA2II as a hydrophilic protein. Structural analysis of flax sPLA2s revealed that secondary structure of both the proteins are dominated by alpha-helix followed by random coils. Modular superimposition of LusPLA2 isoforms with rice sPLA2 confirmed monomeric structural preservation among plant phospholipase A2 and provided insight into structure of folded flax sPLA2s. PMID- 28894146 TI - Investigation on the Conductive Filament Growth Dynamics in Resistive Switching Memory via a Universal Monte Carlo Simulator. AB - In resistive random access memories, modeling conductive filament growing dynamics is important to understand the switching mechanism and variability. In this paper, a universal Monte Carlo simulator is developed based on a cell switching model and a tunneling-based transport model. Driven by external electric field, the growing process of the nanoscale filament occurring in the gap region is actually dominated by cells' conductive/insulating switching, modeled through a phenomenological physics-based probability function. The electric transport through the partially formed CF is considered as current tunneling in the framework of the Quantum Point Contact model, and the potential barrier is modulated during cells' evolution. To demonstrate the validity and universality of our simulator, various operation schemes are simulated, with the simulated I - V characteristics well explaining experimental observations. Furthermore, the statistical analyses of simulation results in terms of Weibull distribution and conductance evolution also nicely track previous experimental results. Representing a simulation scale that links atomic-scale simulations to compact modeling, our simulator has the advantage of being much faster comparing with other atomic-scale models. Meanwhile, our simulator shows good universality since it can be applied to various operation signals, and also to different electrodes and dielectric layers dominated by different switching mechanisms. PMID- 28894145 TI - Characterization of Volume-Based Changes in Cortical Auditory Evoked Potentials and Prepulse Inhibition. AB - The auditory evoked startle reflex is a conserved response resulting in neurological and motor activity. The presence of a mild prepulse immediately before the main pulse inhibits startle responses, though the mechanism for this remains unknown. In this study, the electroencephalography (EEG) data recorded from 15 subjects was analyzed to study the N1 and P2 components of cortical auditory evoked potentials (CAEPs) evoked by 70, 80, 90, 100, and 110 dB stimuli both in the presence and absence of 70 dB prepulses. Results without a prepulse showed an evolution of N1 amplitudes, increasing with stimulus intensity and showing largely significant differences. Results from prepulse trials only showed noteworthy changes in peak-to-peak amplitude in the 100 dB condition. Prepulse and non-prepulse conditions were then compared using peak amplitudes and theta power. Prepulse conditions significantly decreased the amplitude for both components in the 110 dB condition, i.e., pre-pulse inhibition, but significantly increased the N1 amplitude in the 70 dB condition, i.e., pre-pulse facilitation. Similarly theta band power significantly increased in the 70 dB prepulse condition and significantly decreased in the 110 dB prepulse condition. These results expand the basis of knowledge regarding how CAEPs change and elaborate on their neural function and representation. PMID- 28894147 TI - Intrinsic property of phenylalanine to trigger protein aggregation and hemolysis has a direct relevance to phenylketonuria. AB - Excess accumulation of phenylalanine is the characteristic of untreated Phenylketonuria (PKU), a well-known genetic abnormality, which triggers several neurological, physical and developmental severities. However, the fundamental mechanism behind the origin of such diverse health problems, particularly the issue of how they are related to the build-up of phenylalanine molecules in the body, is largely unknown. Here, we show cross-seeding ability of phenylalanine fibrils that can effectively initiate an aggregation process in proteins under physiological conditions, converting native protein structures to beta-sheet assembly. The resultant fibrils were found to cause severe hemolysis, yielding a plethora of deformed erythrocytes that is highly relevant to phenylketonuria. Unique arrangement of zwitterionic phenylalanine molecules in their amyloid-like higher order entities is predicted to promote both hydrophobic and electrostatic interaction, sufficient enough to trap proteins and to preferentially interact with the membrane components of RBCs. Since the prevalence of hemolysis and amyloid related psychoneurological severities are mostly observed in PKU patients, we propose that the inherent property of phenylalanine fibrils to trigger hemolysis and to induce protein aggregation may have direct relevance to the disease mechanism of PKU. PMID- 28894148 TI - Generative Models for Global Collaboration Relationships. AB - When individuals interact with each other and meaningfully contribute toward a common goal, it results in a collaboration. The artifacts resulting from collaborations are best captured using a hypergraph model, whereas the relation of who has collaborated with whom is best captured via an abstract simplicial complex (SC). We propose a generative algorithm GENESCs for SCs modeling fundamental collaboration relations. The proposed network growth process favors attachment that is preferential not to an individual's degree, i.e., how many people has he/she collaborated with, but to his/her facet degree, i.e., how many maximal groups or facets has he/she collaborated within. Based on our observation that several real-world facet size distributions have significant deviation from power law-mainly since larger facets tend to subsume smaller ones-we adopt a data driven approach. We prove that the facet degree distribution yielded by GENESCs is power law distributed for large SCs and show that it is in agreement with real world co-authorship data. Finally, based on our intuition of collaboration formation in domains such as collaborative scientific experiments and movie production, we propose two variants of GENESCs based on clamped and hybrid preferential attachment schemes, and show that they perform well in these domains. PMID- 28894149 TI - A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity. AB - Broad-spectrum antibiotics are frequently prescribed to children. Early childhood represents a dynamic period for the intestinal microbial ecosystem, which is readily shaped by environmental cues; antibiotic-induced disruption of this sensitive community may have long-lasting host consequences. Here we demonstrate that a single pulsed macrolide antibiotic treatment (PAT) course early in life is sufficient to lead to durable alterations to the murine intestinal microbiota, ileal gene expression, specific intestinal T-cell populations, and secretory IgA expression. A PAT-perturbed microbial community is necessary for host effects and sufficient to transfer delayed secretory IgA expression. Additionally, early-life antibiotic exposure has lasting and transferable effects on microbial community network topology. Our results indicate that a single early-life macrolide course can alter the microbiota and modulate host immune phenotypes that persist long after exposure has ceased.High or multiple doses of macrolide antibiotics, when given early in life, can perturb the metabolic and immunological development of lab mice. Here, Ruiz et al. show that even a single macrolide course, given early in life, leads to long-lasting changes in the gut microbiota and immune system of mice. PMID- 28894150 TI - Melatonin enhances the developmental competence of porcine somatic cell nuclear transfer embryos by preventing DNA damage induced by oxidative stress. AB - Melatonin has antioxidant and scavenger effects in the cellular antioxidant system. This research investigated the protective effects and underlying mechanisms of melatonin action in porcine somatic cell nuclear transfer (SCNT) embryos. The results suggested that the developmental competence of porcine SCNT embryos was considerably enhanced after melatonin treatment. In addition, melatonin attenuated the increase in reactive oxygen species levels induced by oxidative stress, the decrease in glutathione levels, and the mitochondrial dysfunction. Importantly, melatonin inhibited phospho-histone H2A.X (gammaH2A.X) expression and comet tail formation, suggesting that gammaH2A.X prevents oxidative stress-induced DNA damage. The expression of genes involved in homologous recombination and non-homologous end-joining pathways for the repair of double-stranded breaks (DSB) was reduced upon melatonin treatment in porcine SCNT embryos at day 5 of development under oxidative stress condition. These results indicated that melatonin promoted porcine SCNT embryo development by preventing oxidative stress-induced DNA damage via quenching of free radical formation. Our results revealed a previously unrecognized regulatory effect of melatonin in response to oxidative stress and DNA damage. This evidence provides a novel mechanism for the improvement in SCNT embryo development associated with exposure to melatonin. PMID- 28894151 TI - The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3. AB - Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to beta-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/DeltaKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following beta agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/DeltaKPQ and age. Ventricular activation was prolonged in old Scn5a+/DeltaKPQ mice (p = 0.03). We associated Scn5a+/DeltaKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/DeltaKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/DeltaKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/DeltaKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to beta adrenergic challenge, have therapeutic implications for ageing LQTS patients. PMID- 28894152 TI - Combination of tomographic ultrasound imaging and three-dimensional magnetic resonance imaging-based model to diagnose postpartum levator avulsion. AB - Vaginal delivery may cause levator avulsion, which may increase the risk of pelvic floor dysfunction (PFD). To explore the morphological changes of the levator ani muscle (including the puborectalis and iliococcygeus) and levator avulsion after vaginal delivery, translabial tomographic ultrasound imaging (TUI) was used to examine 80 women 45-60 days after their vaginal delivery. Subsequently, magnetic resonance imaging (MRI) was performed if at least one sided puborectalis avulsion was found on TUI. The incidence of puborectalis avulsion in these postpartum women was 13.75% in this study. Both MRI and TUI can detect puborectalis avulsion well, and their results have good consistency. Iliococcygeus muscle injury is difficult to detect using TUI. However, MRI is a good way to observe the morphological changes of the iliococcygeus, which may also be damaged during vaginal delivery. Interestingly, our study reveals that iliococcygeus muscle injury is often associated with severe puborectalis muscle tear. PMID- 28894153 TI - Molecular insights into photosynthesis and carbohydrate metabolism in Jatropha curcas grown under elevated CO2 using transcriptome sequencing and assembly. AB - Jatropha curcas L. (Family - Euphorbiaceae) is a perennial tree of special interest due to its potential as a biofuel plant with high carbon sequestration. In this study, physiological investigations coupled with transcriptomics in relation to photosynthesis were evaluated in Jatropha grown under ambient (395 ppm) and elevated (550 ppm) CO2 atmosphere. Morphophysiological analysis revealed that Jatropha sustained enhanced photosynthesis during its growth under elevated CO2 for one year which might be linked to improved CO2 assimilation physiology and enhanced sink activity. We sequenced and analyzed the leaf transcriptome of Jatropha after one year of growth in both conditions using Illumina HiSeq platform. After optimized assembly, a total of 69,581 unigenes were generated. The differential gene expression (DGE) analysis revealed 3013 transcripts differentially regulated in elevated CO2 conditions. The photosynthesis regulatory genes were analysed for temporal expression patterns at four different growth phases which highlighted probable events contributing to enhanced growth and photosynthetic capacity including increased reducing power, starch synthesis and sucrose mobilization under elevated CO2. Overall, our data on physiological and transcriptomic analyses suggest an optimal resource allocation to the available and developing sink organs thereby sustaining improved photosynthetic rates during long-term growth of Jatropha under CO2 enriched environment. PMID- 28894154 TI - N-terminomics identifies widespread endoproteolysis and novel methionine excision in a genome-reduced bacterial pathogen. AB - Proteolytic processing alters protein function. Here we present the first systems wide analysis of endoproteolysis in the genome-reduced pathogen Mycoplasma hyopneumoniae. 669 N-terminal peptides from 164 proteins were identified, demonstrating that functionally diverse proteins are processed, more than half of which 75 (53%) were accessible on the cell surface. Multiple cleavage sites were characterised, but cleavage with arginine in P1 predominated. Putative functions for a subset of cleaved fragments were assigned by affinity chromatography using heparin, actin, plasminogen and fibronectin as bait. Binding affinity was correlated with the number of cleavages in a protein, indicating that novel binding motifs are exposed, and protein disorder increases, after a cleavage event. Glyceraldehyde 3-phosphate dehydrogenase was used as a model protein to demonstrate this. We define the rules governing methionine excision, show that several aminopeptidases are involved, and propose that through processing, genome reduced organisms can expand protein function. PMID- 28894155 TI - Controlling selectivities in CO2 reduction through mechanistic understanding. AB - Catalytic CO2 conversion to energy carriers and intermediates is of utmost importance to energy and environmental goals. However, the lack of fundamental understanding of the reaction mechanism renders designing a selective catalyst inefficient. Here we show the correlation between the kinetics of product formation and those of surface species conversion during CO2 reduction over Pd/Al2O3 catalysts. The operando transmission FTIR/SSITKA (Fourier transform infrared spectroscopy/steady-state isotopic transient kinetic analysis) experiments demonstrates that the rate-determining step for CO formation is the conversion of adsorbed formate, whereas that for CH4 formation is the hydrogenation of adsorbed carbonyl. The balance of the hydrogenation kinetics between adsorbed formates and carbonyls governs the selectivities to CH4 and CO. We apply this knowledge to the catalyst design and achieve high selectivities to desired products.Understanding the mechanism of CO2 reduction on a catalyst surface is essential for achieving the desired product selectivity. Here, the authors show an operando kinetic analysis of CO2 hydrogenation over a palladium catalyst in order to address the factors governing the selectivity of the process. PMID- 28894156 TI - Complex dynamics at the nanoscale in simple biomembranes. AB - Nature is known to engineer complex compositional and dynamical platforms in biological membranes. Understanding this complex landscape requires techniques to simultaneously detect membrane re-organization and dynamics at the nanoscale. Using super-resolution stimulated emission depletion (STED) microscopy coupled with fluorescence correlation spectroscopy (FCS), we reveal direct experimental evidence of dynamic heterogeneity at the nanoscale in binary phospholipid cholesterol bilayers. Domain formation on the length scale of ~200-600 nm due to local cholesterol compositional heterogeneity is found to be more prominent at high cholesterol content giving rise to distinct intra-domain lipid dynamics. STED-FCS reveals unique dynamical crossover phenomena at length scales of ~100 150 nm within each of these macroscopic regions. The extent of dynamic heterogeneity due to intra-domain hindered lipid diffusion as reflected from the crossover length scale, is driven by cholesterol packing and organization, uniquely influenced by phospholipid type. These results on simple binary model bilayer systems provide novel insights into pathways leading to the emergence of complex nanodomain substructures with implications for a wide variety of membrane mediated cellular events. PMID- 28894157 TI - Utilization of photographs taken by citizens for estimating bumblebee distributions. AB - Citizen science is a powerful tool for collecting large volumes of observational data on various species. These data are used to estimate distributions using environmental factors with Species Distribution Models (SDM). However, if citizens are inexperienced in recognizing organisms, they may report different species as the subject species. Here we show nation-wide bumblebee distributions using photographs taken by citizens in our project, and estimated distributions for six bumblebee species using land use, climate, and altitude data with SDM. We identified species from photographic images, and took their locations from GPS data of photographs or the text in e-mails. When we compared our data with conventional data for specimens in the Global Biodiversity Information Facility (GBIF), we found that the volume and the number of species were larger, and the bias of spatial range was lower, than those of GBIF. Our estimated distributions were more consistent with bumblebee distributions reported in previous studies than with those of GBIF. Our method was effective for collecting distribution data, and estimating distributions with SDM. The estimated SDM allows us to predict the previous and future species distributions, and to develop conservation policies taking account of future city planning and/or global climate changes. PMID- 28894158 TI - Biophysical characterisation of the novel zinc binding property in Suppressor of Fused. AB - Suppressor of Fused (SUFU) is a highly conserved protein that acts as a negative regulator of the Hedgehog (HH) signalling pathway, a major determinant of cell differentiation and proliferation. Therefore, SUFU deletion in mammals has devastating effects on embryo development. SUFU is part of a multi-protein cytoplasmic signal-transducing complex. Its partners include the Gli family of transcription factors that function either as repressors, or as transcription activators according to the HH activation state. The crystal structure of SUFU revealed a two-domain arrangement, which undergoes a closing movement upon binding a peptide from Gli1. There remains however, much to be discovered about SUFU's behaviour. To this end, we expressed recombinant, full-length SUFU from Drosophila, Zebrafish and Human. Guided by a sequence analysis that revealed a conserved potential metal binding site, we discovered that SUFU binds zinc. This binding was found to occur with a nanomolar affinity to SUFU from all three species. Mutation of one histidine from the conserved motif induces a moderate decrease in affinity for zinc, while circular dichroism indicates that the mutant remains structured. Our results reveal new metal binding affinity characteristics about SUFU that could be of importance for its regulatory function in HH. PMID- 28894159 TI - Thrombin-derived host defence peptide modulates neutrophil rolling and migration in vitro and functional response in vivo. AB - Host defence peptides (HDPs) derived from the C-terminus of thrombin are proteolytically generated by enzymes released during inflammation and wounding. In this work, we studied the effects of the prototypic peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), on neutrophil functions. In vitro, GKY25 was shown to decrease LPS-induced neutrophil activation. In addition, the peptide induced CD62L shedding on neutrophils without inducing their activation. Correspondingly, GKY25-treated neutrophils showed reduced attachment and rolling behaviour on surfaces coated with the CD62L ligand E-selectin. The GKY25-treated neutrophils also displayed a dampened chemotactic response against the chemokine IL-8. Furthermore, in vivo, mice treated with GKY25 exhibited a reduced local ROS response against LPS. Taken together, our results show that GKY25 can modulate neutrophil functions in vitro and in vivo. PMID- 28894160 TI - Preparation of porous Fe2O3 nanorods-reduced graphene oxide nanohybrids and their excellent microwave absorption properties. AB - In this paper, alpha-Fe2O3 nanoparticles (NPs)-reduced graphene oxide (RGO), alpha-FeOOH nanorods (NRs)-RGO and porous alpha-Fe2O3 NRs-RGO could be selectively synthesized by hydrothermal method. The investigations indicated that the obtained alpha-Fe2O3 NPs, alpha-FeOOH NRs and porous alpha-Fe2O3 NRs were either attached on the surface of RGO sheets or coated uniformly by the RGO sheets. And the as-prepared nanohybrids exhibited excellent microwave absorption performance, which was proved to be ascribed to the quarter-wavelength matching model. The optimum reflection loss (RL) values for alpha-Fe2O3 NPs-RGO, alpha FeOOH NRs-RGO and porous alpha-Fe2O3 NRs-RGO were ca. -32.3, -37.4 and -71.4 dB, respectively. Moreover, compared to the obtained alpha-Fe2O3 NPs-RGO and alpha FeOOH NRs-RGO, the as-prepared porous alpha-Fe2O3 NRs-RGO nanohybrids exhibited enhanced microwave absorption properties because of their special structure and synergetic effect. The possible enhanced microwave absorption mechanisms were discussed in details. Our results confirmed that the geometrical morphology had a great influence on their microwave absorption properties, which provided a promising approach to exploit high performance microwave absorbing materials. PMID- 28894161 TI - Microbial communities in placentas from term normal pregnancy exhibit spatially variable profiles. AB - The placenta is the principal organ nurturing the fetus during pregnancy and was traditionally considered to be sterile. Recent work has suggested that the placenta harbours microbial communities, however the location and possible function of these microbes remain to be confirmed and elucidated. Here, we employed genomic DNA sequencing of multiple variable (V) regions of the bacterial 16S ribosomal gene, to interrogate microbial profiles in term pregnancies, from the basal plate, which is in direct contact with maternal uterine, endothelial, and immune cells; placental villi, which are bathed in maternal blood, and fetal membranes, which encapsulate the amniotic cavity. QIIME, R package "Phyloseq" analysis was used to assess alpha and beta diversity and absolute abundance of the 16S rRNA gene per location. We demonstrate that (1) microbiota exhibit spatially distinct profiles depending on the location within the placenta and (2) "semi-composite" 16S profiles using multiple V regions validated by quantitative PCR analysis confirmed that distinct bacterial taxa dominate in different placental niches. Finally, profiles are not altered by mode of delivery. Together these findings suggest that there is niche-specificity to the placental microbiota and placental microbiome studies should consider regional differences, which may affect maternal, fetal, and/or neonatal health and physiology. PMID- 28894162 TI - A regime shift in the Sun-Climate connection with the end of the Medieval Climate Anomaly. AB - Understanding the influence of changes in solar activity on Earth's climate and distinguishing it from other forcings, such as volcanic activity, remains a major challenge for palaeoclimatology. This problem is best approached by investigating how these variables influenced past climate conditions as recorded in high precision paleoclimate archives. In particular, determining if the climate system response to these forcings changes through time is critical. Here we use the Wiener-Granger causality approach along with well-established cross-correlation analysis to investigate the causal relationship between solar activity, volcanic forcing, and climate as reflected in well-established Intertropical Convergence Zone (ITCZ) rainfall proxy records from Yok Balum Cave, southern Belize. Our analysis reveals a consistent influence of volcanic activity on regional Central American climate over the last two millennia. However, the coupling between solar variability and local climate varied with time, with a regime shift around 1000 1300 CE after which the solar-climate coupling weakened considerably. PMID- 28894163 TI - The behaviour of stacking fault energy upon interstitial alloying. AB - Stacking fault energy is one of key parameters for understanding the mechanical properties of face-centered cubic materials. It is well known that the plastic deformation mechanism is closely related to the size of stacking fault energy. Although alloying is a conventional method to modify the physical parameter, the underlying microscopic mechanisms are not yet clearly established. Here, we propose a simple model for determining the effect of interstitial alloying on the stacking fault energy. We derive a volumetric behaviour of stacking fault energy from the harmonic approximation to the energy-lattice curve and relate it to the contents of interstitials. The stacking fault energy is found to change linearly with the interstitial content in the usual low concentration domain. This is in good agreement with previously reported experimental and theoretical data. PMID- 28894164 TI - Investigating the Relationship between Cerebrospinal Fluid and Magnetic Induction Phase Shift in Rabbit Intracerebral hematoma expansion Monitoring by MRI. AB - In a prior study of intracerebral hemorrhage monitoring using magnetic induction phase shift (MIPS), we found that MIPS signal changes occurred prior to those seen with intracranial pressure. However, the characteristic MIPS alert is not yet fully explained. Combining the brain physiology and MIPS theory, we propose that cerebrospinal fluid (CSF) may be the primary factor that leads to hematoma expansion being alerted by MIPS earlier than with intracranial pressure monitoring. This paper investigates the relationship between CSF and MIPS in monitoring of rabbit intracerebral hemorrhage models, which is based on the MIPS measurements data, the quantified data on CSF from medical images and the amount of injected blood in the rabbit intracerebral hemorrhage model. In the investigated results, a R value of 0.792 with a significance of 0.019 is observed between the MIPS and CSF, which is closer than MIPS and injected blood. Before the reversal point of MIPS, CSF is the leading factor in MIPS signal changing in an early hematoma expansion stage. Under CSF compensation, CSF reduction compensates for hematoma expansion in the brain to keep intracranial pressure stable. MIPS decrease results from the reducing CSF volume. This enables MIPS to detect hematoma expansion earlier than intracranial pressure. PMID- 28894165 TI - Evolution analysis of heterogeneous non-small cell lung carcinoma by ultra-deep sequencing of the mitochondrial genome. AB - Accurate assessment of tumour heterogeneity is an important issue that influences prognosis and therapeutic decision in molecular pathology. Due to the shortage of protective histones and a limited DNA repair capacity, the mitochondrial (mt) genome undergoes high variability during tumour development. Therefore, screening of mt-genome represents a useful molecular tool for assessing precise cell lineages and tracking tumour history. Here, we describe a highly specific and robust multiplex PCR-based ultra-deep sequencing technology for analysis of the whole mt-genome (wmt-seq) on low quality-DNA from formalin-fixed paraffin embedded tissues. As a proof of concept, we applied the wmt-seq technology to characterize the clonal relationship of non-small cell lung cancer (NSCLC) specimens with multiple lesions (N = 43) that show either different histological subtypes (group I) or pulmonary adenosquamous carcinoma as striking examples of a mixed-histology tumour (group II). The application of wmt-seq demonstrated that most samples bear common mt-mutations in each lesion of an individual patient, indicating a single cell progeny and clonal relationship. Hereby we show the monoclonal origin of histologically heterogeneous NSCLC and demonstrate the evolutionary relation of NSCLC cases carrying heteroplasmic mt-variants. PMID- 28894166 TI - Flavonoid allosteric modulation of mutated visual rhodopsin associated with retinitis pigmentosa. AB - Dietary flavonoids exhibit many biologically-relevant functions and can potentially have beneficial effects in the treatment of pathological conditions. In spite of its well known antioxidant properties, scarce structural information is available on the interaction of flavonoids with membrane receptors. Advances in the structural biology of a specific class of membrane receptors, the G protein-coupled receptors, have significantly increased our understanding of drug action and paved the way for developing improved therapeutic approaches. We have analyzed the effect of the flavonoid quercetin on the conformation, stability and function of the G protein-coupled receptor rhodopsin, and the G90V mutant associated with the retinal degenerative disease retinitis pigmentosa. By using a combination of experimental and computational methods, we suggest that quercetin can act as an allosteric modulator of opsin regenerated with 9-cis-retinal and more importantly, that this binding has a positive effect on the stability and conformational properties of the G90V mutant associated with retinitis pigmentosa. These results open new possibilities to use quercetin and other flavonoids, in combination with specific retinoids like 9-cis-retinal, for the treatment of retinal degeneration associated with retinitis pigmentosa. Moreover, the use of flavonoids as allosteric modulators may also be applicable to other members of the G protein-coupled receptors superfamily. PMID- 28894167 TI - Carbon sequestration potential and physicochemical properties differ between wildfire charcoals and slow-pyrolysis biochars. AB - Pyrogenic carbon (PyC), produced naturally (wildfire charcoal) and anthropogenically (biochar), is extensively studied due to its importance in several disciplines, including global climate dynamics, agronomy and paleosciences. Charcoal and biochar are commonly used as analogues for each other to infer respective carbon sequestration potentials, production conditions, and environmental roles and fates. The direct comparability of corresponding natural and anthropogenic PyC, however, has never been tested. Here we compared key physicochemical properties (elemental composition, delta13C and PAHs signatures, chemical recalcitrance, density and porosity) and carbon sequestration potentials of PyC materials formed from two identical feedstocks (pine forest floor and wood) under wildfire charring- and slow-pyrolysis conditions. Wildfire charcoals were formed under higher maximum temperatures and oxygen availabilities, but much shorter heating durations than slow-pyrolysis biochars, resulting in differing physicochemical properties. These differences are particularly relevant regarding their respective roles as carbon sinks, as even the wildfire charcoals formed at the highest temperatures had lower carbon sequestration potentials than most slow pyrolysis biochars. Our results challenge the common notion that natural charcoal and biochar are well suited as proxies for each other, and suggest that biochar's environmental residence time may be underestimated when based on natural charcoal as a proxy, and vice versa. PMID- 28894168 TI - The association of young age with local recurrence in women with early-stage breast cancer after breast-conserving therapy: a meta-analysis. AB - The aim of this meta-analysis is to determine the relationship between young age and local recurrence in patients with early-stage breast cancer after breast conserving therapy. Eligible studies were retrieved from various electronic databases. Among the 19 studies included, 14 studies were analyzed for 5-year local recurrence rate and 8 studies for 10-year local recurrence rate using random effects models. Both results showed that young patients were at higher risk of local recurrence compared to old patients (5-year: RR = 2.64, 95% CI (1.94-3.60); 10-year: RR = 2.37, 95% CI (1.57-3.58)). Harbord's modified test showed the presence of publication bias in both 5- and 10-year local recurrence rates (P = 0.019 and P = 0.01, respectively). While the Trim and Fill analysis showed that the presence of publication bias did not affect the overall outcome of the 5-year local recurrence rate (RR = 2.21, 95% CI (1.62, 3.02)), it significantly affected the effect size of the 10-year local recurrence rate (RR = 1.47, 95% CI (0.96, 2.27)). Young age is a significant risk factor for local recurrence developed within 5 years of breast-conserving therapy in patients with early-stage breast cancer. Further high-quality studies are needed to elucidate the relationship between young age and the risk of local recurrence developed within 10 years. PMID- 28894170 TI - Room temperature self-assembled growth of vertically aligned columnar copper oxide nanocomposite thin films on unmatched substrates. AB - In this work, we report the self-assembled growth of vertically aligned columnar Cu2O + Cu4O3 nanocomposite thin films on glass and silicon substrates by reactive sputtering at room temperature. Microstructure analyses show that each phase in nanocomposite films has the columnar growth along the whole thickness, while each column exhibits the single phase characteristics. The local epitaxial growth behavior of Cu2O is thought to be responsible for such an unusual microstructure. The intermediate oxygen flow rate between those required to synthesize single phase Cu2O and Cu4O3 films produces some Cu2O nuclei, and then the local epitaxial growth provides a strong driving force to promote Cu2O nuclei to grow sequentially, giving rise to Cu2O columns along the whole thickness. Lower resistivity has been observed in such kind of nanocomposite thin films than that in single phase thin films, which may be due to the interface coupling between Cu2O and Cu4O3 columns. PMID- 28894171 TI - Separability of neural responses to standardised mechanical stimulation of limbs. AB - Considerable scientific and technological efforts are currently being made towards the development of neural prostheses. Understanding how the peripheral nervous system responds to electro-mechanical stimulation of the limb, will help to inform the design of prostheses that can restore function or accelerate recovery from injury to the sensory motor system. However, due to differences in experimental protocols, it is difficult, if not impossible, to make meaningful comparisons between different peripheral nerve interfaces. Therefore, we developed a low-cost electronic system to standardise the mechanical stimulation of a rat's hindpaw. Three types of mechanical stimulations, namely, proprioception, touch and nociception were delivered to the limb and the electroneurogram signals were recorded simultaneously from the sciatic nerve with a 16-contact cuff electrode. For the first time, results indicate separability of neural responses according to stimulus type as well as intensity. Statistical analysis reveal that cuff contacts placed circumferentially, rather than longitudinally, are more likely to lead to higher classification rates. This flexible setup may be readily adapted for systematic comparison of various electrodes and mechanical stimuli in rodents. Hence, we have made its electro mechanical design and computer programme available online. PMID- 28894169 TI - An embryonic system to assess direct and indirect Wnt transcriptional targets. AB - During animal development, complex signals determine and organize a vast number of tissues using a very small number of signal transduction pathways. These developmental signaling pathways determine cell fates through a coordinated transcriptional response that remains poorly understood. The Wnt pathway is involved in a variety of these cellular functions, and its signals are transmitted in part through a beta-catenin/TCF transcriptional complex. Here we report an in vivo Drosophila assay that can be used to distinguish between activation, de-repression and repression of transcriptional responses, separating upstream and downstream pathway activation and canonical/non-canonical Wnt signals in embryos. We find specific sets of genes downstream of both beta catenin and TCF with an additional group of genes regulated by Wnt, while the non canonical Wnt4 regulates a separate cohort of genes. We correlate transcriptional changes with phenotypic outcomes of cell differentiation and embryo size, showing our model can be used to characterize developmental signaling compartmentalization in vivo. PMID- 28894172 TI - Extraordinary Transport Characteristics and Multivalue Logic Functions in a Silicon-Based Negative-Differential Transconductance Device. AB - High-performance negative-differential transconductance (NDT) devices are fabricated in the form of a gated p+-i-n+ Si ultra-thin body transistor. The devices clearly display a Lambda-shape transfer characteristic (i.e., Lambda-NDT peak) at room temperature, and the NDT behavior is fully based on the gate modulation of the electrostatic junction characteristics along source-channel drain. The largest peak-to-valley current ratio of the Lambda-NDT peak is greater than 104, the smallest full-width at half-maximum is smaller than 170 mV, and the best swing-slope at the Lambda-NDT peak region is ~70 mV/dec. The position and the current level of the Lambda-NDT peaks are systematically-controllable when modulating the junction characteristics by controlling only bias voltages at gate and/or drain. These unique features allow us to demonstrate the multivalue logic functions such as a tri-value logic and a quattro-value logic. The results suggest that the present type of the Si Lambda-NDT device could be prospective for next-generation arithmetic circuits. PMID- 28894173 TI - Lipidomes of lung cancer and tumour-free lung tissues reveal distinct molecular signatures for cancer differentiation, age, inflammation, and pulmonary emphysema. AB - Little is known about the human lung lipidome, its variability in different physiological states, its alterations during carcinogenesis and the development of pulmonary emphysema. We investigated how health status might be mirrored in the lung lipidome. Tissues were sampled for both lipidomic and histological analysis. Using a screening approach, we characterised lipidomes of lung cancer tissues and corresponding tumour-free alveolar tissues. We quantified 311 lipids from 11 classes in 43 tissue samples from 26 patients. Tumour tissues exhibited elevated levels of triacylglycerols and cholesteryl esters, as well as a significantly lower abundance of phosphatidylglycerols, which are typical lung surfactant components. Adenocarcinomas and squamous cell carcinomas were distinguished with high specificity based on lipid panels. Lipidomes of tumour biopsy samples showed clear changes depending on their histology and, in particular, their proportion of active tumour cells and stroma. Partial least squares regression showed correlations between lipid profiles of tumour-free alveolar tissues and the degree of emphysema, inflammation status, and the age of patients. Unsaturated long-chain phosphatidylserines and phosphatidylinositols showed a positive correlation with a worsened emphysema status and ageing. This work provides a resource for the human lung lipidome and a systematic data analysis strategy to link clinical characteristics and histology. PMID- 28894174 TI - In vivo pH measurement at the site of calcification in an octocoral. AB - Calcareous octocorals are ecologically important calcifiers, but little is known about their biomineralization physiology, relative to scleractinian corals. Many marine calcifiers promote calcification by up-regulating pH at calcification sites against the surrounding seawater. Here, we investigated pH in the red octocoral Corallium rubrum which forms sclerites and an axial skeleton. To achieve this, we cultured microcolonies on coverslips facilitating microscopy of calcification sites of sclerites and axial skeleton. Initially we conducted extensive characterisation of the structural arrangement of biominerals and calcifying cells in context with other tissues, and then measured pH by live tissue imaging. Our results reveal that developing sclerites are enveloped by two scleroblasts and an extracellular calcifying medium of pH 7.97 +/- 0.15. Similarly, axial skeleton crystals are surrounded by cells and a calcifying medium of pH 7.89 +/- 0.09. In both cases, calcifying media are more alkaline compared to calcifying cells and fluids in gastrovascular canals, but importantly they are not pH up-regulated with respect to the surrounding seawater, contrary to what is observed in scleractinians. This points to a potential vulnerability of this species to decrease in seawater pH and is consistent with reports that red coral calcification is sensitive to ocean acidification. PMID- 28894175 TI - Sexual congruency in the connectome and translatome of VTA dopamine neurons. AB - The ventral tegmental area (VTA) dopamine system is important for reward, motivation, emotion, learning, and memory. Dysfunctions in the dopamine system are linked to multiple neurological and neuropsychiatric disorders, many of which present with sex differences. Little is known about the extent of heterogeneity in the basic organization of VTA dopamine neurons with regard to sex. Here, we characterized the cell-specific connectivity of VTA dopamine neurons, their mRNA translational profile, and basic electrophysiological characteristics in a common strain of mice. We found no major differences in these metrics, except for differential expression of a Y-chromosome associated mRNA transcript, Eif2s3y, and the X-linked, X-inactivation transcript Xist. Of note, Xist transcript was significantly enriched in dopamine neurons, suggesting tight regulation of X linked gene expression to ensure sexual congruency. These data indicate that the features that make dopamine neurons unique are highly concordant and not a principal source of sexual dimorphism. PMID- 28894176 TI - Overlapping and Specific Functions of the Hsp104 N Domain Define Its Role in Protein Disaggregation. AB - Hsp104 is a ring-forming protein disaggregase that rescues stress-damaged proteins from an aggregated state. To facilitate protein disaggregation, Hsp104 cooperates with Hsp70 and Hsp40 chaperones (Hsp70/40) to form a bi-chaperone system. How Hsp104 recognizes its substrates, particularly the importance of the N domain, remains poorly understood and multiple, seemingly conflicting mechanisms have been proposed. Although the N domain is dispensable for protein disaggregation, it is sensitive to point mutations that abolish the function of the bacterial Hsp104 homolog in vitro, and is essential for curing yeast prions by Hsp104 overexpression in vivo. Here, we present the crystal structure of an N terminal fragment of Saccharomyces cerevisiae Hsp104 with the N domain of one molecule bound to the C-terminal helix of the neighboring D1 domain. Consistent with mimicking substrate interaction, mutating the putative substrate-binding site in a constitutively active Hsp104 variant impairs the recovery of functional protein from aggregates. We find that the observed substrate-binding defect can be rescued by Hsp70/40 chaperones, providing a molecular explanation as to why the N domain is dispensable for protein disaggregation when Hsp70/40 is present, yet essential for the dissolution of Hsp104-specific substrates, such as yeast prions, which likely depends on a direct N domain interaction. PMID- 28894177 TI - A viral protein antibiotic inhibits lipid II flippase activity. AB - For bacteriophage infections, the cell walls of bacteria, consisting of a single highly polymeric molecule of peptidoglycan (PG), pose a major problem for the release of progeny virions. Phage lysis proteins that overcome this barrier can point the way to new antibacterial strategies 1 , especially small lytic single stranded DNA (the microviruses) and RNA phages (the leviviruses) that effect host lysis using a single non-enzymatic protein 2 . Previously, the A2 protein of levivirus Qbeta and the E protein of the microvirus phiX174 were shown to be 'protein antibiotics' that inhibit the MurA and MraY steps of the PG synthesis pathway 2-4 . Here, we investigated the mechanism of action of an unrelated lysis protein, LysM, of the Escherichia coli levivirus M 5 . We show that LysM inhibits the translocation of the final lipid-linked PG precursor called lipid II across the cytoplasmic membrane by interfering with the activity of MurJ. The finding that LysM inhibits a distinct step in the PG synthesis pathway from the A2 and E proteins indicates that small phages, particularly the single-stranded RNA (ssRNA) leviviruses, have a previously unappreciated capacity for evolving novel inhibitors of PG biogenesis despite their limited coding potential. PMID- 28894178 TI - Effect of prenatal DINCH plasticizer exposure on rat offspring testicular function and metabolism. AB - In 2002, the plasticizer 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) was introduced in the European market as a substitute for endocrine disrupting phthalates. We found that in utero exposure of rats to DINCH from gestational day 14 until parturition affected reproductive organ physiology and reduced circulating testosterone levels at post-natal day 60, indicating a long term effect on Leydig cells of the testis. Metabolically, animals exhibited randomly increased serum glucose concentrations not associated with impaired glucose utilization. Analysis of liver markers in the serum showed a hepatic effect; e.g. reduced bilirubin levels and albumin/globulin ratio. At post-natal day 200, random appearance of testicular atrophy was noted in exposed offspring, and limited changes in other reproductive parameters were observed. In conclusion, DINCH exposure appears to directly affect Leydig cell function, likely causing premature aging of the testes and impaired liver metabolic capacity. These effects might be attenuated with physiologic aging. PMID- 28894179 TI - Ambient air pollution, smog episodes and mortality in Jinan, China. AB - We aimed to assess the acute effects of ambient air pollution and weather conditions on mortality in the context of Chinese smog episodes. A total of 209,321 deaths were recorded in Jinan, a large city in eastern China, during 2011 15. The mean concentrations of daily particulate matter <=10 MUm (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2) and nitrogen dioxide (NO2) were 169 MUg/m3, 100 MUg/m3, 77 MUg/m3, and 54 MUg/m3, respectively. Increases of 10 MUg/m3 in PM10, PM2.5, SO2 and NO2 were associated with 1.11% (95% CI 0.96 1.26%), 0.71% (95% CI 0.60-0.82%), 1.69% (95% CI 1.56-1.83%), and 3.12% (95% CI 2.72-3.53%) increases in daily non-accidental mortality rates, respectively. Moreover, the risk estimates for these 4 pollutants were higher in association with respiratory and cardiovascular mortality. The effects of all the evaluated pollutants on mortality were greater in winter than in summer. Smog episodes were associated with a 5.87% (95% CI 0.16-11.58%) increase in the rate of overall mortality. This study highlights the effect of exposure to air pollution on the rate of mortality in China. PMID- 28894180 TI - The contrasting roles of creep and stress relaxation in the time-dependent deformation during in-situ cooling of a nickel-base single crystal superalloy. AB - Time dependent plastic deformation in a single crystal nickel-base superalloy during cooling from casting relevant temperatures has been studied using a combination of in-situ neutron diffraction, transmission electron microscopy and modelling. Visco-plastic deformation during cooling was found to be dependent on the stress and constraints imposed to component contraction during cooling, which mechanistically comprises creep and stress relaxation. Creep results in progressive work hardening with dislocations shearing the gamma' precipitates, a high dislocation density in the gamma channels and near the gamma/gamma' interface and precipitate shearing. When macroscopic contraction is restricted, relaxation dominates. This leads to work softening from a decreased dislocation density and the presence of long segment stacking faults in gamma phase. Changes in lattice strains occur to a similar magnitude in both the gamma and gamma' phases during stress relaxation, while in creep there is no clear monotonic trend in lattice strain in the gamma phase, but only a marginal increase in the gamma' precipitates. Using a visco-plastic law derived from in-situ experiments, the experimentally measured and calculated stresses during cooling show a good agreement when creep predominates. However, when stress relaxation dominates accounting for the decrease in dislocation density during cooling is essential. PMID- 28894181 TI - Rigidly connected multispecific artificial binders with adjustable geometries. AB - Multivalent binding proteins can gain biological activities beyond what is inherent in the individual binders, by bringing together different target molecules, restricting their conformational flexibility or changing their subcellular localization. In this study, we demonstrate a method to build up rigid multivalent and multispecific scaffolds by exploiting the modular nature of a repeat protein scaffold and avoiding flexible linkers. We use DARPins (Designed Ankyrin Repeat Proteins), synthetic binding proteins based on the Ankyrin-repeat protein scaffold, as binding units. Their ease of in vitro selection, high production yield and stability make them ideal specificity-conferring building blocks for the design of more complex constructs. C- and N-terminal DARPin capping repeats were re-designed to be joined by a shared helix in such a way that rigid connector modules are formed. This allows us to join two or more DARPins in predefined geometries without compromising their binding affinities and specificities. Nine connector modules with distinct geometries were designed; for eight of these we were able to confirm the structure by X-ray crystallography, while only one did not crystallize. The bispecific constructs were all able to bind both target proteins simultaneously. PMID- 28894182 TI - The sinking of the El Faro: predicting real world rogue waves during Hurricane Joaquin. AB - We present a study on the prediction of rogue waves during the 1-hour sea state of Hurricane Joaquin when the Merchant Vessel El Faro sank east of the Bahamas on October 1, 2015. High-resolution hindcast of hurricane-generated sea states and wave simulations are combined with novel probabilistic models to quantify the likelihood of rogue wave conditions. The data suggests that the El Faro vessel was drifting at an average speed of approximately 2.5 m/s prior to its sinking. As a result, we estimated that the probability that El Faro encounters a rogue wave whose crest height exceeds 14 meters while drifting over a time interval of 10 (50) minutes is ~1/400 (1/130). The largest simulated wave is generated by the constructive interference of elementary spectral components (linear dispersive focusing) enhanced by bound nonlinearities. Not surprisingly then, its characteristics are quite similar to those displayed by the Andrea, Draupner and Killard rogue waves. PMID- 28894183 TI - Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. AB - Reduced biodiversity and increased representation of opportunistic pathogens are typical features of gut microbiota composition in aging. Few studies have investigated their correlation with polypharmacy, multimorbidity and frailty. To assess it, we analyzed the fecal microbiota from 76 inpatients, aged 83 +/- 8. Microbiome biodiversity (Chao1 index) and relative abundance of individual bacterial taxa were determined by next-generation 16S rRNA microbial profiling. Their correlation with number of drugs, and indexes of multimorbidity and frailty were verified using multivariate linear regression models. The impact of gut microbiota biodiversity on mortality, rehospitalizations and incident sepsis was also assessed after a 2-year follow-up, using Cox regression analysis. We found a significant negative correlation between the number of drugs and Chao1 Index at multivariate analysis. The number of drugs was associated with the average relative abundance of 15 taxa. The drug classes exhibiting the strongest association with single taxa abundance were proton pump inhibitors, antidepressants and antipsychotics. Conversely, frailty and multimorbidity were not significantly associated with gut microbiota biodiversity. Very low Chao1 index was also a significant predictor of mortality, but not of rehospitalizations and sepsis, at follow-up. In aging, polypharmacy may thus represent a determinant of gut microbiota composition, with detrimental clinical consequences. PMID- 28894184 TI - IL-7 plays a critical role for the homeostasis of allergen-specific memory CD4 T cells in the lung and airways. AB - Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways. Using a murine model of airway inflammation, we found that allergen-specific CD4 T cells survived longer than 70 days in the lung and airways in an IL-7 dependent fashion. These T cells showing homeostatic proliferation were largely found in the mediastinal lymph node (mLN), rather than the airways; however, cells residing in the lung and airways developed recall responses successfully. We also found that CD4 T cells exhibited differential phenotypes in the mLN and in the lung. Altogether, we believe that allergen specific memory T cells reside and function in the lung and airways, while their numbers are replenished through homeostatic turnover in the mLNs. Furthermore, we determined that IL-7 signaling is important for the homeostasis of these cells. PMID- 28894185 TI - Identification of prognostic genes through expression differentiation during metastatic process in lung adenocarcinoma. AB - Cancer is a highly complicated biological process due to large scale heterogeneity. Identification of differentially expressed genes between normal and cancer samples is widely utilized in the discovery of prognostic factors. In this study, based on RNA sequencing data of lung adenocarcinoma, we focused on the expression differentiation during confined (with neither lymph node invasion nor distant metastasis) primary tumors and lymphnode (with only lymph node invasion but not distant metastasis) primary tumors. The result indicated that differentially expressed genes during confined-lymphnode transition were more closely related to patient's overall survival comparing with those identified from normal-cancer transition. With the aid of public curated biological network, we successfully retrieved the biggest connected module composed of 135 genes, of which the expression was significantly associated with patient's overall survival, confirmed by 9 independent microarray datasets. PMID- 28894186 TI - Contributions of cuticle permeability and enzyme detoxification to pyrethroid resistance in the major malaria vector Anopheles gambiae. AB - To tackle the problem of insecticide resistance, all resistance mechanisms need to be studied. This study investigated the involvement of the cuticle in pyrethroid resistance in a strain of Anopheles gambiae, MRS, free of kdr mutations. Bioassays revealed MRS to be resistant to pyrethroids and DDT, indicated by increasing knockdown times and resistance ratios. Moreover, biochemical analysis indicated that metabolic resistance based on enhanced CYP450 activity may also play a role. Insecticide penetration assays showed that there were significantly lower amounts of insecticide in the MRS strain than in the susceptible control. Analysis of the levels of the selected transcripts by qPCR showed that CYP6M2, a major pyrethroid metaboliser, CYP4G16, a gene implicated in resistance via its contribution to the biosynthesis of elevated epicuticular hydrocarbons that delay insecticide uptake, and the cuticle genes CPAP3-E and CPLCX1 were upregulated after insecticide exposure. Other metabolic (CYP6P3, GSTe2) and cuticle (CPLCG3, CPRs) genes were also constitutively upregulated. Microscopic analysis showed that the cuticle layers of the MRS strain were significantly thicker than those of the susceptible strain. This study allowed us to assess the contribution made by the cuticle and metabolic mechanisms to pyrethroid resistance in Anopheles gambiae without target-site mutations. PMID- 28894187 TI - Small RNAs in vancomycin-resistant Enterococcus faecium involved in daptomycin response and resistance. AB - Vancomycin-resistant Enterococcus faecium is a leading cause of hospital-acquired infections and outbreaks. Regulatory RNAs (sRNAs) are major players in adaptive responses, including antibiotic resistance. They were extensively studied in gram negative bacteria, but less information is available for gram-positive pathogens. No sRNAs are described in E. faecium. We sought to identify a set of sRNAs expressed in vancomycin-resistant E. faecium Aus0004 strain to assess their roles in daptomycin response and resistance. Genomic and transcriptomic analyses revealed a set of 61 sRNA candidates, including 10 that were further tested and validated by Northern and qPCR. RNA-seq was performed with and without subinhibitory concentrations (SICs) of daptomycin, an antibiotic used to treat enterococcal infections. After daptomycin SIC exposure, the expression of 260 coding and srna genes was altered, with 80 upregulated and 180 downregulated, including 51% involved in carbohydrate and transport metabolisms. Daptomycin SIC exposure significantly affected the expression of seven sRNAs, including one experimentally confirmed, sRNA_0160. We studied sRNA expression in isogenic mutants with increasing levels of daptomycin resistance and observed that expression of several sRNAs, including sRNA_0160, was modified in the stepwise mutants. This first genome-wide sRNA identification in E. faecium suggests that some sRNAs are linked to antibiotic stress response and resistance. PMID- 28894188 TI - Second-generation Flagellin-rPAc Fusion Protein, KFD2-rPAc, Shows High Protective Efficacy against Dental Caries with Low Potential Side Effects. AB - Dental caries is one of the most common global chronic diseases affecting all ages of the population; thus a vaccine against caries is urgently needed. Our previous studies demonstrated that a fusion protein, KF-rPAc, in which rPAc of S. mutans is directly fused to the C-terminal of E. coli-derived flagellin (KF), could confer high prophylactic and therapeutic efficiency against caries. However, possible side effects, including the high antigenicity of flagellin and possible inflammatory injury induced by flagellin, may restrict its clinical usage. Here, we produced a second-generation flagellin-rPAc fusion protein, KFD2 rPAc, by replacing the main antigenicity region domains D2 and D3 of KF with rPAc. Compared with KF-rPAc, KFD2-rPAc has lower TLR5 agonist efficacy and induces fewer systemic inflammatory responses in mice. After intranasal immunization, KFD2-rPAc induces significantly lower flagellin-specific antibody responses but a comparable level of rPAc-specific antibody responses in mice. More importantly, in rat challenge models, KFD2-rPAc induces a robust rPAc specific IgA response, and confers efficient prophylactic and therapeutic efficiency against caries as does KF-rPAc, while the flagellin-specific antibody responses are highly reduced. In conclusion, low side effects and high protective efficiency against caries makes the second-generation flagellin-rPAc fusion protein, KFD2-rPAc, a promising vaccine candidate against caries. PMID- 28894189 TI - Hypo-hydroxymethylation of rRNA genes in the precocious Eriocheir sinensis testes revealed using hMeDIP-seq. AB - Precocious puberty is a common phenomenon in crab breeding that seriously reduces the economic benefits for crab farmers. To address this problem, this study aimed to explore the potential functions of both methylation and hydroxymethylation of testis rRNA genes with respect to precocious puberty in Eriocheir sinensis. The results showed that the rRNA genes in normally developing testes of E. sinensis had low levels of methylation and high levels of hydroxymethylation; however, although methylation levels were similar, the level of hydroxymethylation in precocious testes was lower than normal. Highly significant differences (P < 0.01) in the hydroxymethylation of the 18S and 28S rRNA genes were found between precocious and normal testes. Our results suggested that both the 18S and 28S rRNA genes, which are normally downregulated by hypo-hydroxymethylation, might be involved in the process of precocious puberty. Our results also implied that hydroxymethylation of the 18S and 28S rRNA genes might be used as an important epigenetic molecular marker to evaluate economically significant potential for growth and breeding in this species. PMID- 28894190 TI - Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac. AB - Previous reports on epigenetic mechanisms involved in alcohol abuse have focus on hepatic and neuronal regions, leaving the immune system and specifically monocyte derived dendritic cells (MDDCs) understudied. Our lab has previously shown histone deacetylases are modulated in cells derived from alcohol users and after in vitro acute alcohol treatment of human MDDCs. In the current study, we developed a novel screening tool using matrix assisted laser desorption ionization-fourier transform-ion cyclotron resonance mass spectrometry (MALDI-FT ICR MS) and single cell imaging flow cytometry to detect post-translational modifications (PTMs) in human MDDCs due to chronic alcohol exposure. Our results demonstrate, for the first time, in vitro chronic alcohol exposure of MDDCs modulates H3 and H4 and induces a significant increase in acetylation at H4K12 (H4K12ac). Moreover, the Tip60/HAT inhibitor, NU9056, was able to block EtOH induced H4K12ac, enhancing the effect of EtOH on IL-15, RANTES, TGF-beta1, and TNF-alpha cytokines while restoring MCP-2 levels, suggesting that H4K12ac may be playing a major role during inflammation and may serve as an inflammation regulator or a cellular stress response mechanism under chronic alcohol conditions. PMID- 28894191 TI - Non-cell-autonomous effects yield lower clonal diversity in expanding tumors. AB - Recent cancer research has investigated the possibility that non-cell-autonomous (NCA) driving tumor growth can support clonal diversity (CD). Indeed, mutations can affect the phenotypes not only of their carriers ("cell-autonomous", CA effects), but also sometimes of other cells (NCA effects). However, models that have investigated this phenomenon have only considered a restricted number of clones. Here, we designed an individual-based model of tumor evolution, where clones grow and mutate to yield new clones, among which a given frequency have NCA effects on other clones' growth. Unlike previously observed for smaller assemblages, most of our simulations yield lower CD with high frequency of mutations with NCA effects. Owing to NCA effects increasing competition in the tumor, clones being already dominant are more likely to stay dominant, and emergent clones not to thrive. These results may help personalized medicine to predict intratumor heterogeneity across different cancer types for which frequency of NCA effects could be quantified. PMID- 28894192 TI - Angstrom-Resolved Metal-Organic Framework-Liquid Interfaces. AB - Metal-organic frameworks (MOFs) are a class of crystalline materials with a variety of applications in gas storage, catalysis, drug delivery or light harvesting. The optimization of those applications requires the characterization of MOF structure in the relevant environment. Dynamic force microscopy has been applied to follow dynamic processes of metal-organic-framework material. We provide images with spatial and time resolutions, respectively, of angstrom and seconds that show that Ce-RPF-8 surfaces immersed in water and glycerol experience a surface reconstruction process that is characterized by the diffusion of the molecular species along the step edges of the open terraces. The rate of the surface reconstruction process depends on the liquid. In water it happens spontaneously while in glycerol is triggered by applying an external force. PMID- 28894193 TI - Sub-picosecond temporal resolution of anomalous Hall currents in GaAs. AB - The anomalous Hall (AH) and spin Hall effects are important tools for the generation, control, and detection of spin and spin-polarized currents in solids and, thus, hold promises for future spintronic applications. Despite tremendous work on these effects, their ultrafast dynamic response is still not well explored. Here, we induce ultrafast AH currents in a magnetically-biased semiconductor by optical femtosecond excitation at room temperature. The currents' dynamics are studied by detecting the simultaneously emitted THz radiation. We show that the temporal shape of the AH currents can be extracted by comparing its THz radiation to the THz radiation emitted from optically induced currents whose temporal shape is well known. We observe a complex temporal shape of the AH currents suggesting that different microscopic origins contribute to the current dynamics. This is further confirmed by photon energy dependent measurements revealing a current inversion at low optical excitation intensities. Our work is a first step towards full time resolution of AH and spin Hall currents and helps to better understand the underlying microscopic origins, being a prerequisite for ultrafast spintronic applications using such currents. PMID- 28894195 TI - Nuisance Flooding and Relative Sea-Level Rise: the Importance of Present-Day Land Motion. AB - Sea-level rise is beginning to cause increased inundation of many low-lying coastal areas. While most of Earth's coastal areas are at risk, areas that will be affected first are characterized by several additional factors. These include regional oceanographic and meteorological effects and/or land subsidence that cause relative sea level to rise faster than the global average. For catastrophic coastal flooding, when wind-driven storm surge inundates large areas, the relative contribution of sea-level rise to the frequency of these events is difficult to evaluate. For small scale "nuisance flooding," often associated with high tides, recent increases in frequency are more clearly linked to sea-level rise and global warming. While both types of flooding are likely to increase in the future, only nuisance flooding is an early indicator of areas that will eventually experience increased catastrophic flooding and land loss. Here we assess the frequency and location of nuisance flooding along the eastern seaboard of North America. We show that vertical land motion induced by recent anthropogenic activity and glacial isostatic adjustment are contributing factors for increased nuisance flooding. Our results have implications for flood susceptibility, forecasting and mitigation, including management of groundwater extraction from coastal aquifers. PMID- 28894194 TI - Streptococcus salivarius MS-oral-D6 promotes gingival re-epithelialization in vitro through a secreted serine protease. AB - Gingival re-epithelialization represents an essential phase of oral wound healing in which epithelial integrity is re-establish. We developed an automated high throughput re-epithelialization kinetic model, using the gingival epithelial cell line Ca9-22. The model was employed to screen 39 lactic acid bacteria, predominantly including oral isolates, for their capacity to accelerate gingival re-epithelialization. This screen identified several strains of Streptococcus salivarius that stimulated re-epithelialization. Further analysis revealed that S. salivarius strain MS-oral-D6 significantly promoted re-epithelialization through a secreted proteinaceous compound and subsequent experiments identified a secreted serine protease as the most likely candidate to be involved in re epithelialization stimulation. The identification of bacteria or their products that stimulate gingival wound repair may inspire novel strategies for the maintenance of oral health. PMID- 28894196 TI - First record of an Icacinaceae Miers fossil flower from Le Quesnoy (Ypresian, France) amber. AB - Flowers embedded in amber are rare. Only about 70 flowers or inflorescences have been described among which only one lamiid is known. Nevertheless, these fossils are important to our understanding of evolutionary process and past diversity due to the exceptional preservation of fragile structures not normally preserved. In this work, a new flower named Icacinanthium tainiaphorum sp. nov. from Le Quesnoy (Houdancourt, Oise, France) is described. Our phylogenetic analysis with extant species suggests that the affinity of this flower lies with the family Icacinaceae, close to Natsiatum or Hosiea. The fossil shows a combination of features unknown in extant Icacinaceae and we thus propose the description of a new fossil genus. It reveals a previously unknown diversity in the family and demonstrates the complementarity of different types of fossil preservation for a better understanding of past floral diversity. PMID- 28894197 TI - A Multi-Institutional Comparison of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameter Calculations. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides quantitative metrics (e.g. Ktrans, ve) via pharmacokinetic models. We tested inter-algorithm variability in these quantitative metrics with 11 published DCE MRI algorithms, all implementing Tofts-Kermode or extended Tofts pharmacokinetic models. Digital reference objects (DROs) with known Ktrans and ve values were used to assess performance at varying noise levels. Additionally, DCE-MRI data from 15 head and neck squamous cell carcinoma patients over 3 time-points during chemoradiotherapy were used to ascertain Ktrans and ve kinetic trends across algorithms. Algorithms performed well (less than 3% average error) when no noise was present in the DRO. With noise, 87% of Ktrans and 84% of ve algorithm-DRO combinations were generally in the correct order. Low Krippendorff's alpha values showed that algorithms could not consistently classify patients as above or below the median for a given algorithm at each time point or for differences in values between time points. A majority of the algorithms produced a significant Spearman correlation in ve of the primary gross tumor volume with time. Algorithmic differences in Ktrans and ve values over time indicate limitations in combining/comparing data from distinct DCE-MRI model implementations. Careful cross-algorithm quality-assurance must be utilized as DCE-MRI results may not be interpretable using differing software. PMID- 28894198 TI - Functional modulation of LHCSR1 protein from Physcomitrella patens by zeaxanthin binding and low pH. AB - Light harvesting for oxygenic photosynthesis is regulated to prevent the formation of harmful photoproducts by activation of photoprotective mechanisms safely dissipating the energy absorbed in excess. Lumen acidification is the trigger for the formation of quenching states in pigment binding complexes. With the aim to uncover the photoprotective functional states responsible for excess energy dissipation in green algae and mosses, we compared the fluorescence dynamic properties of the light-harvesting complex stress-related (LHCSR1) protein, which is essential for fast and reversible regulation of light use efficiency in lower plants, as compared to the major LHCII antenna protein, which mainly fulfills light harvesting function. Both LHCII and LHCSR1 had a chlorophyll fluorescence yield and lifetime strongly dependent on detergent concentration but the transition from long- to short-living states was far more complete and fast in the latter. Low pH and zeaxanthin binding enhanced the relative amplitude of quenched states in LHCSR1, which were characterized by the presence of 80 ps fluorescence decay components with a red-shifted emission spectrum. We suggest that energy dissipation occurs in the chloroplast by the activation of 80 ps quenching sites in LHCSR1 which spill over excitons from the photosystem II antenna system. PMID- 28894199 TI - Improving the Accuracy of the Hyperspectral Model for Apple Canopy Water Content Prediction using the Equidistant Sampling Method. AB - The influence of the equidistant sampling method was explored in a hyperspectral model for the accurate prediction of the water content of apple tree canopy. The relationship between spectral reflectance and water content was explored using the sample partition methods of equidistant sampling and random sampling, and a stepwise regression model of the apple canopy water content was established. The results showed that the random sampling model was Y = 0.4797 - 721787.3883 * Z3 - 766567.1103 * Z5 - 771392.9030 * Z6; the equidistant sampling model was Y = 0.4613 - 480610.4213 * Z2 - 552189.0450 * Z5 - 1006181.8358 * Z6. After verification, the equidistant sampling method was verified to offer a superior prediction ability. The calibration set coefficient of determination of 0.6599 and validation set coefficient of determination of 0.8221 were higher than that of the random sampling model by 9.20% and 10.90%, respectively. The root mean square error (RMSE) of 0.0365 and relative error (RE) of 0.0626 were lower than that of the random sampling model by 17.23% and 17.09%, respectively. Dividing the calibration set and validation set by the equidistant sampling method can improve the prediction accuracy of the hyperspectral model of apple canopy water content. PMID- 28894200 TI - Soluble HLA-associated peptide from PSF1 has a cancer vaccine potency. AB - Partner of sld five 1 (PSF1) is an evolutionary conserved DNA replication factor involved in DNA replication in lower species, which is strongly expressed in normal stem cell populations and progenitor cell populations. Recently, we have investigated PSF1 functions in cancer cells and found that PSF1 plays a significant role in tumour growth. These findings provide initial evidence for the potential of PSF1 as a therapeutic target. Here, we reveal that PSF1 contains an immunogenic epitope suitable for an antitumour vaccine. We analysed PSF1 peptides eluted from affinity-purified human leukocyte antigen (HLA) by mass spectrometry and identified PSF179-87 peptide (YLYDRLLRI) that has the highest prediction score using an in silico algorithm. PSF179-87 peptide induced PSF1 specific cytotoxic T lymphocyte responses such as the production of interferon gamma and cytotoxicity. Because PSF1 is expressed in cancer cell populations and highly expressed in cancer stem cell populations, these data suggest that vaccination with PSF179-87 peptide may be a novel therapeutic strategy for cancer treatment. PMID- 28894201 TI - Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia. AB - Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11beta-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. PMID- 28894202 TI - Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population. AB - Identification of the primary allele(s) in HLA class II associated diseases remains challenging because of a tight linkage between alleles of HLA-DR and -DQ loci. In the present study, we determined the genotypes of seven HLA loci (HLA-A, -B, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) for 1200 Japanese patients with primary biliary cholangitis and 1196 controls. Observation of recombination derivatives facilitated an evaluation of the effects of individual HLA alleles consisting of disease-prone/disease-resistant HLA haplotypes. Consequently, a primary contribution of DQB1*06:04 (odds ratio: 0.19, p = 1.91 * 10-22), DQB1*03:01 (odds ratio: 0.50, p = 6.76 * 10-10), DRB1*08:03 (odds ratio: 1.75, p = 1.01 * 10-7) and DQB1*04:01 (odds ratio: 1.50, p = 9.20 * 10-6) was suggested. Epistasis of the protective DQB1*06:04 to risk conferred by DRB1*08:03 was demonstrated by subpopulation analysis, implicating the presence of an active immunological mechanism that alleviates pathogenic autoimmune reactions. Further, the contribution of the aforementioned HLA alleles as well as an HLA-DP allele, DPB1*02:01 to the association signals of 304 loci among 4103 SNPs in the HLA region at the genome-wide level of significance (p values less than 5 * 10-8) was demonstrated by the stepwise exclusion of the individuals possessing these HLA alleles from the comparison. PMID- 28894203 TI - The combined effect of cigarette smoking and occupational noise exposure on hearing loss: evidence from the Dongfeng-Tongji Cohort Study. AB - Combined effect of cigarette smoking and occupational noise exposure on hearing loss has rarely been evaluated among Chinese population, especially among females. This cross-sectional study was conducted in 11196 participants of Dongfeng-Tongji cohort study. Smoking status was self-reported through questionnaire and occupational noise exposure was evaluated through workplace noise level and/or the job titles. Hearing loss was defined as a pure-tone mean of 25 dB or higher at 0.5, 1, 2, and 4 kHz in both ears. Compared with participants without occupational noise exposure, the risk of hearing loss was significantly higher for noise exposure duration >=20 (OR = 1.45, 95%CI = 1.28 1.65). The association was particularly evident among individuals who were males (OR = 1.74, 95%CI = 1.45-2.08) and aged >= 70 (OR = 1.74, 95%CI = 1.30-2.33). Similarly, the risks increased with the increasing of pack-years in males and all age groups except for those aged <60. As to the combined effect, the hearing loss risk was highest for noise exposure duration >=20 and pack-years >=25 (OR = 2.41, 95%CI = 1.78-3.28), especially among males (OR = 2.42, 95%CI = 1.74-3.37) and those aged >=70 (OR = 2.76, 95%CI = 1.36-5.60). Smoking may be an independent risk factor for hearing loss. And it may synergistically affect hearing when combined with occupational noise exposure, especially among males and older participants. PMID- 28894205 TI - The quantum-optics Hamiltonian in the Multipolar gauge. AB - This article deals with the fundamental problem of light-matter interaction in the quantum theory. Although it is described through the vector potential in quantum electrodynamics, it is believed by some that a hamiltonian involving only the electric and the magnetic fields is preferable. In the literature this hamiltonian is known as the Power-Zienau-Woolley hamiltonian. We question its validity and show that it is not equivalent to the minimal-coupling hamiltonian. In this article, we show that these two hamiltonians are not connected through a gauge transformation. We find that the gauge is not fixed in the Power-Zienau Woolley hamiltonian. The interaction term is written in one gauge whereas the rest of the hamiltonian is written in another gauge. The Power-Zienau-Woolley hamiltonian and the minimal-coupling one are related through a unitary transformation that does not fulfill the gauge fixing constraints. Consequently, they predict different physical results. In this letter, we provide the correct quantum theory in the multipolar gauge with a hamiltonian involving only the physical fields. PMID- 28894204 TI - Novel arsenic-transforming bacteria and the diversity of their arsenic-related genes and enzymes arising from arsenic-polluted freshwater sediment. AB - Bacteria are essential in arsenic cycling. However, few studies have addressed 16S rRNA and arsenic-related functional gene diversity in long-term arsenic contaminated tropical sediment. Here, using culture-based, metagenomic and computational approaches, we describe the diversity of bacteria, genes and enzymes involved in AsIII and AsV transformation in freshwater sediment and in anaerobic AsIII- and AsV-enrichment cultures (ECs). The taxonomic profile reveals significant differences among the communities. Arcobacter, Dechloromonas, Sedimentibacter and Clostridium thermopalmarium were exclusively found in ECs, whereas Anaerobacillus was restricted to AsV-EC. Novel taxa that are both AsV reducers and AsIII-oxidizers were identified: Dechloromonas, Acidovorax facilis, A. delafieldii, Aquabacterium, Shewanella, C. thermopalmarium and Macellibacteroides fermentans. Phylogenic discrepancies were revealed among the aioA, arsC and arrA genes and those of other species, indicating horizontal gene transfer. ArsC and AioA have sets of amino acids that can be used to assess their functional and structural integrity and familial subgroups. The positions required for AsV reduction are conserved, suggesting strong selective pressure for maintaining the functionality of ArsC. Altogether, these findings highlight the role of freshwater sediment bacteria in arsenic mobility, and the untapped diversity of dissimilatory arsenate-reducing and arsenate-resistant bacteria, which might contribute to arsenic toxicity in aquatic environments. PMID- 28894206 TI - Caring Cooperators and Powerful Punishers: Differential Effects of Induced Care and Power Motivation on Different Types of Economic Decision Making. AB - Standard economic theory postulates that decisions are driven by stable context insensitive preferences, while motivation psychology suggests they are driven by distinct context-sensitive motives with distinct evolutionary goals and characteristic psycho-physiological and behavioral patterns. To link these fields and test how distinct motives could differentially predict different types of economic decisions, we experimentally induced participants with either a Care or a Power motive, before having them take part in a suite of classic game theoretical paradigms involving monetary exchange. We show that the Care induction alone raised scores on a latent factor of cooperation-related behaviors, relative to a control condition, while, relative to Care, Power raised scores on a punishment-related factor. These findings argue against context insensitive stable preferences and theories of strong reciprocity and in favor of a motive-based approach to economic decision making: Care and Power motivation have a dissociable fingerprint in shaping either cooperative or punishment behaviors. PMID- 28894207 TI - Positive feedback of the amphiregulin-EGFR-ERK pathway mediates PM2.5 from wood smoke-induced MUC5AC expression in epithelial cells. AB - Biomass fuel smoke is thought to contribute to chronic obstructive pulmonary disease, which is characterized by mucous cell metaplasia and enhanced mucus secretion. We investigated the effect of particulate matter (PM) with a diameter <2.5 MUm (PM2.5) from wood smoke (WSPM2.5) on the expression of the most prominent secreted mucin, MUC5AC. Wood smoke was able to induce MUC5AC expression in the rat respiratory tract after 3 months of exposure. WSPM2.5 could induce MUC5AC production in both primary human airway epithelial cells and the NCI-H292 cell line. This induction process was mediated by activation of epithelial growth factor receptor (EGFR)-extracellular signal-regulated kinase (ERK) signaling through an EGFR ligand-dependent mechanism. Amphiregulin (AR) was identified as the major ligand responsible for EGFR-ERK signaling activation and MUC5AC expression. In turn, EGFR-ERK pathway activation was found to contribute to the de novo synthesis of AR. This positive feedback loop might play an important role in a sustained mucus hypersecretion response. PMID- 28894208 TI - Analyzing intrinsic plasmonic chirality by tracking the interplay of electric and magnetic dipole modes. AB - Plasmonic chirality represents significant potential for novel nanooptical devices due to its association with strong chiroptical responses. Previous reports on plasmonic chirality mechanism mainly focus on phase retardation and coupling. In this paper, we propose a model similar to the chiral molecules for explaining the intrinsic plasmonic chirality mechanism of varies 3D chiral structures quantitatively based on the interplay and mixing of electric and magnetic dipole modes (directly from electromagnetic field numerical simulations), which forms mixed electric and magnetic polarizability. PMID- 28894210 TI - Enhancing elevated temperature strength of copper containing aluminium alloys by forming L12 Al3Zr precipitates and nucleating theta" precipitates on them. AB - Strengthening by precipitation of second phase is the guiding principle for the development of a host of high strength structural alloys, in particular, aluminium alloys for transportation sector. Higher efficiency and lower emission demands use of alloys at higher operating temperatures (200 degrees C-250 degrees C) and stresses, especially in applications for engine parts. Unfortunately, most of the precipitation hardened aluminium alloys that are currently available can withstand maximum temperatures ranging from 150-200 degrees C. This limit is set by the onset of the rapid coarsening of the precipitates and consequent loss of mechanical properties. In this communication, we present a new approach in designing an Al-based alloy through solid state precipitation route that provides a synergistic coupling of two different types of precipitates that has enabled us to develop coarsening resistant high temperature alloys that are stable in the temperature range of 250-300 degrees C with strength in excess of 260 MPa at 250 degrees C. PMID- 28894209 TI - The role of the secretin/secretin receptor axis in inflammatory cholangiocyte communication via extracellular vesicles. AB - Small and large intrahepatic bile ducts consist of small and large cholangiocytes, respectively, and these cholangiocytes have different morphology and functions. The gastrointestinal peptide hormone, secretin (SCT) that binds to secretin receptor (SR), is a key mediator in cholangiocyte pathophysiology. Extracellular vesicles (EVs) are membrane-bound vesicles and cell-cell EV communication is recognized as an important factor in liver pathology, although EV communication between cholangiocytes is not identified to date. Cholangiocytes secrete proinflammatory cytokines during bacterial infection leading to biliary inflammation and hyperplasia. We demonstrate that cholangiocytes stimulated with lipopolysaccharide (LPS), which is a membrane component of gram-negative bacteria, secrete more EVs than cholangiocytes incubated with vehicle. These LPS derived EVs induce inflammatory responses in other cholangiocytes including elevated cytokine production and cell proliferation. Large but not small cholangiocytes show inflammatory responses against large but not small cholangiocyte-derived EVs. Large cholangiocytes with knocked down either SCT or SR by short hairpin RNAs show reduced EV secretion during LPS stimulation, and EVs isolated from SCT or SR knocked down cholangiocytes fail to induce inflammatory reactions in control large cholangiocytes. This study identifies cholangiocyte EV communication during LPS stimulation, and demonstrates that the SCT/SR axis may be important for this event. PMID- 28894211 TI - Emerging negative Atlantic Multidecadal Oscillation index in spite of warm subtropics. AB - Sea surface temperatures in the northern North Atlantic have shown a marked decrease over the past several years. The sea surface in the subpolar gyre is now as cold as it was during the last cold phase of the Atlantic Multidecadal Oscillation index in the 1990s. This climate index is associated with shifts in hurricane activity, rainfall patterns and intensity, and changes in fish populations. However, unlike the last cold period in the Atlantic, the spatial pattern of sea surface temperature anomalies in the Atlantic is not uniformly cool, but instead has anomalously cold temperatures in the subpolar gyre, warm temperatures in the subtropics and cool anomalies over the tropics. The tripole pattern of anomalies has increased the subpolar to subtropical meridional gradient in SSTs, which are not represented by the AMO index value, but which may lead to increased atmospheric baroclinicity and storminess. Here we show that the recent Atlantic cooling is likely to persist, as predicted by a statistical forecast of subsurface ocean temperatures and consistent with the irreversible nature of watermass changes involved in the recent cooling of the subpolar gyre. PMID- 28894212 TI - Daytime REM sleep affects emotional experience but not decision choices in moral dilemmas. AB - Moral decision-making depends on the interaction between automatic emotional responses and rational cognitive control. A natural emotional regulator state seems to be sleep, in particular rapid eye movement (REM) sleep. We tested the impact of daytime sleep, either with or without REM, on moral decision. Sixty participants were presented with 12 sacrificial (6 Footbridge- and 6 Trolley type) and 8 everyday-type moral dilemmas at 9 AM and at 5 PM. In sacrificial dilemmas, participants had to decide whether or not to kill one person to save more people (utilitarian choice), and to judge how morally acceptable the proposed choice was. In everyday-type dilemmas, participants had to decide whether to endorse moral violations involving dishonest behavior. At 12 PM, 40 participants took a 120-min nap (17 with REM and 23 with NREM only) while 20 participants remained awake. Mixed-model analysis revealed that participants judged the utilitarian choice as less morally acceptable in the afternoon, irrespective of sleep. We also observed a negative association between theta activity during REM and increased self-rated unpleasantness during moral decisions. Nevertheless, moral decision did not change across the day and between groups. These results suggest that although both time and REM sleep may affect the evaluation of a moral situation, these factors did not ultimately impact the individual moral choices. PMID- 28894213 TI - Ultraviolet Radiation-Induced Production of Nitric Oxide:A multi-cell and multi donor analysis. AB - Increasing evidence regarding positive effects of exposure to sunlight has led to suggestions that current advice may be overly weighted in favour of avoidance. UV A has been reported to lower blood pressure, possibly through nitric oxide (NO) production in skin. Here, we set out to investigate effects of UV-A and solar simulated radiation on the potential source of dermal NO, the effective doses and wavelengths, the responsiveness of different human skin cells, the magnitude of inter-individual differences and the potential influence of age. We utilised isogenic keratinocytes, microvascular endothelial cells, melanocytes and fibroblasts isolated from 36 human skins ranging from neonates to 86 years old. We show that keratinocytes and microvascular endothelial cells show greatest NO release following biologically relevant doses of UV-A. This was consistent across multiple neonatal donors and the effect is maintained in adult keratinocytes. Our observations are consistent with a bi-phasic mechanism by which UV-A can trigger vasodilatory effects. Analyses of NO-production spectra adds further evidence that nitrites in skin cells are the source of UV-mediated NO release. These potentially positive effects of ultraviolet radiation lend support for objective assessment of environmental influence on human health and the idea of "healthy sun exposure". PMID- 28894214 TI - The Novel Compound Sul-121 Preserves Endothelial Function and Inhibits Progression of Kidney Damage in Type 2 Diabetes Mellitus in Mice. AB - Diabetic nephropathy is still a common complication of type 2 diabetes mellitus (T2DM) and improvement of endothelial dysfunction (ED) and inhibition of reactive oxygen species (ROS) are considered important targets for new therapies. Recently, we developed a new class of compounds (Sul compounds) which inhibit mitochondrial ROS production. Here, we tested the therapeutic effects of Sul-121 on ED and kidney damage in experimental T2DM. Diabetic db/db and lean mice were implanted with osmotic pumps delivering Sul-121 (2.2 mg/kg/day) or vehicle from age 10 to 18 weeks. Albuminuria, blood pressure, endothelial mediated relaxation, renal histology, plasma creatinine, and H2O2 levels were assessed. Sul-121 prevented progression of albuminuria and attenuated kidney damage in db/db, as evidenced by lower glomerular fibronectin expression (~50%), decreased focal glomerular sclerosis score (~40%) and normalization of glomerular size and kidney weight. Further, Sul-121 restored endothelium mediated vasorelaxation through increased production of Nitric Oxide production and normalized plasma H2O2 levels. Sul-121 treatment in lean mice demonstrated no observable major side effects, indicating that Sul-121 is well tolerated. Our data show that Sul-121 inhibits progression of diabetic kidney damage via a mechanism that involves restoration of endothelial function and attenuation of oxidative stress. PMID- 28894215 TI - Gene expression of NOX family members and their clinical significance in hepatocellular carcinoma. AB - Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-derived reactive oxygen species (ROS) promote chronic liver inflammation and remodeling that can drive hepatocellular carcinoma development. The role of NOX expression in hepatocellular carcinoma (HCC) has been partially investigated; however, the clinical relevance of collective or individual NOX family member expression for HCC survival remains unclear. Here, we obtained NOX mRNA expression data for 377 HCC samples and 21 normal liver controls from the TCGA data portal and performed Kaplan-Meier survival, gene ontology functional enrichment, and gene set enrichment analyses. Although most NOX genes exhibited little change, some were significantly induced in HCC compared to that in normal controls. In addition, HCC survival analyses indicated better overall survival in patients with high NOX4 and DUOX1 expression, whereas patients with high NOX1/2/5 expression showed poor prognoses. Gene-neighbour and gene set enrichment analyses revealed that NOX1/2/5 were strongly correlated with genes associated with cancer cell survival and metastasis, whereas increased NOX4 and DUOX1 expression was associated with genes that inhibit tumour progression. On the basis of these data, NOX family gene expression analysis could be a predictor of survival and identify putative therapeutic targets in HCC. PMID- 28894216 TI - Correlative Evaluation of Mental and Physical Workload of Laparoscopic Surgeons Based on Surface Electromyography and Eye-tracking Signals. AB - Surgeons' mental and physical workloads are major focuses of operating room (OR) ergonomics, and studies on this topic have generally focused on either mental workload or physical workload, ignoring the interaction between them. Previous studies have shown that physically demanding work may affect mental performance and may be accompanied by impaired mental processing and decreased performance. In this study, 14 participants were recruited to perform laparoscopic cholecystectomy (LC) procedures in a virtual simulator. Surface electromyography (sEMG) signals of the bilateral trapezius, bicipital, brachioradialis and flexor carpi ulnaris (FCU) muscles and eye-tracking signals were acquired during the experiment. The results showed that the least square means of muscle activity during the LC phases of surgery in an all-participants mixed effects model were 0.79, 0.81, and 0.98, respectively. The observed muscle activities in the different phases exhibited some similarity, while marked differences were found between the forearm bilateral muscles. Regarding mental workload, significant differences were observed in pupil dilation between the three phases of laparoscopic surgery. The mental and physical workloads of laparoscopic surgeons do not appear to be generally correlated, although a few significant negative correlations were found. This result further indicates that mental fatigue does markedly interfere with surgeons' operating movements. PMID- 28894217 TI - The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity. AB - Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy. However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naive and in MDA-kindled anaesthetised rats. We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti seizure effects. WIN55,212-2, dose-dependently (0.5-2 mg/kg, i.p.) impaired short term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naive rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP. Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy. PMID- 28894218 TI - Lactate-utilizing community is associated with gut microbiota dysbiosis in colicky infants. AB - The aetiology of colic, a functional gastrointestinal disorder in infants, is not yet resolved. Different mechanisms have been suggested involving the gut microbiota and intermediate metabolites such as lactate. Lactate can be metabolized by lactate-utilizing bacteria (LUB) to form different end-products. Using a functional approach, we hypothesized that H2 production and accumulation by LUB is associated with the development of colic. The LUB communities in the feces of forty infants, including eight colicky infants, were characterized using a combination of culture- and molecular-based methods, and metabolite concentrations were measured by HPLC. Interactions among LUB strains isolated from feces were investigated with pure and mixed cultures using anaerobic techniques. We emphasized high prevalence of crying, flatulence, colic and positive correlations thereof in the first 3 months of life. Crying infants showed significantly higher ratio of LUB non-sulfate-reducing bacteria (LUB non SRB) (H2-producer), to LUB SRB (H2-utilizer) at 3 months. Colicky infants had significantly higher number of H2-producing Eubacterium hallii at 2 weeks compared to non-colicky infants. We revealed the function of Desulfovibrio piger and Eubacterium limosum to reduce H2 accumulation in co-cultures with H2 producing Veillonella ratti. Our data suggest that the balance between H2 producing and H2-utilizing LUB might contribute to colic symptoms. PMID- 28894219 TI - Control of antiferromagnetic spin axis orientation in bilayer Fe/CuMnAs films. AB - Using x-ray magnetic circular and linear dichroism techniques, we demonstrate a collinear exchange coupling between an epitaxial antiferromagnet, tetragonal CuMnAs, and an Fe surface layer. A small uncompensated Mn magnetic moment is observed which is antiparallel to the Fe magnetization. The staggered magnetization of the 5 nm thick CuMnAs layer is rotatable under small magnetic fields, due to the interlayer exchange coupling. This allows us to obtain the x ray magnetic linear dichroism spectra for different crystalline orientations of CuMnAs in the (001) plane. This is a key parameter for enabling the understanding of domain structures in CuMnAs imaged using x-ray magnetic linear dichroism microscopy techniques. PMID- 28894220 TI - Binding modes of environmental endocrine disruptors to human serum albumin: insights from STD-NMR, ITC, spectroscopic and molecular docking studies. AB - Given that bisphenols have an endocrine-disrupting effect on human bodies, thoroughly exposing their potential effects at the molecular level is important. Saturation transfer difference (STD) NMR-based binding studies were performed to investigate the binding potential of two bisphenol representatives, namely, bisphenol B (BPB) and bisphenol E (BPE), toward human serum albumin (HSA). The relative STD (%) suggested that BPB and BPE show similar binding modes and orientations, in which the phenolic rings were spatially close to HSA binding site. ITC analysis results showed that BPB and BPE were bound to HSA with moderately strong binding affinity through electrostatic interactions and hydrogen bonds. The order of binding affinity of HSA for two test bisphenols is as follows: BPE > BPB. The results of fluorescence competitive experiments using 5-dimethylaminonaphthalene-1-sulfonamide and dansylsarcosine as competitors, combined with molecular docking indicated that both bisphenols are prone to attach to the binding site II in HSA. Spectroscopic results (FT-IR, CD, synchronous and 3D fluorescence spectra) showed that BPB/BPE induces different degrees of microenvironmental and conformational changes to HSA. PMID- 28894221 TI - Temperature-Controlled Direct Imprinting of Ag Ionic Ink: Flexible Metal Grid Transparent Conductors with Enhanced Electromechanical Durability. AB - Next-generation transparent conductors (TCs) require excellent electromechanical durability under mechanical deformations as well as high electrical conductivity and transparency. Here we introduce a method for the fabrication of highly conductive, low-porosity, flexible metal grid TCs via temperature-controlled direct imprinting (TCDI) of Ag ionic ink. The TCDI technique based on two-step heating is capable of not only stably capturing the Ag ionic ink, but also reducing the porosity of thermally decomposed Ag nanoparticle structures by eliminating large amounts of organic complexes. The porosity reduction of metal grid TCs on a glass substrate leads to a significant decrease of the sheet resistance from 21.5 to 5.5 Omega sq-1 with an optical transmittance of 91% at lambda = 550 nm. The low-porosity metal grid TCs are effectively embedded to uniform, thin and transparent polymer films with negligible resistance changes from the glass substrate having strong interfacial fracture energy (~8.2 J m-2). Finally, as the porosity decreases, the flexible metal grid TCs show a significantly enhanced electromechanical durability under bending stresses. Organic light-emitting diodes based on the flexible metal grid TCs as anode electrodes are demonstrated. PMID- 28894222 TI - Discovery of carotenoid red-shift in endolithic cyanobacteria from the Atacama Desert. AB - The biochemical responses of rock-inhabiting cyanobacteria towards native environmental stresses were observed in vivo in one of the Earth's most challenging extreme climatic environments. The cryptoendolithic cyanobacterial colonization, dominated by Chroococcidiopsis sp., was studied in an ignimbrite at a high altitude volcanic area in the Atacama Desert, Chile. Change in the carotenoid composition (red-shift) within a transect through the cyanobacteria dominant microbial community (average thickness ~1 mm) was unambiguously revealed in their natural endolithic microhabitat. The amount of red shifted carotenoid, observed for the first time in a natural microbial ecosystem, is depth dependent, and increased with increasing proximity to the rock surface, as proven by resonance Raman imaging and point resonance Raman profiling. It is attributed to a light-dependent change in carotenoid conjugation, associated with the light adaptation strategy of cyanobacteria. A hypothesis is proposed for the possible role of an orange carotenoid protein (OCP) mediated non-photochemical quenching (NPQ) mechanism that influences the observed spectral behavior. Simultaneously, information about the distribution of scytonemin and phycobiliproteins was obtained. Scytonemin was detected in the uppermost cyanobacteria aggregates. A reverse signal intensity gradient of phycobiliproteins was registered, increasing with deeper positions as a response of the cyanobacterial light harvesting complex to low-light conditions. PMID- 28894223 TI - Long-term Administration of Nuclear Bile Acid Receptor FXR Agonist Prevents Spontaneous Hepatocarcinogenesis in Abcb4-/- Mice. AB - Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6alpha-ethyl-3alpha,7alpha,23-trihydroxy-24-nor-5beta-cholan-23-sulphate) to Fxr /- and Abcb4-/- mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr-/- mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro inflammatory cytokines. Moreover, in Abcb4-/- mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC. PMID- 28894224 TI - Associations between aldehyde dehydrogenase 2 (ALDH2) rs671 genetic polymorphisms, lifestyles and hypertension risk in Chinese Han people. AB - Hypertension is a multiple factor disease which was influenced by gene, environment, and lifestyle. Several studies confirmed that the ALDH2 rs671 polymorphism is associated with hypertension. However, the evidence remains inconclusive. Whether lifestyle affects blood pressure in different genotype groups have not been clarified, either. The subjects were adult Chinese Han people who received health examination in the period from December 2014 to December 2015. Detection of the ALDH2 r671 polymorphism was determined by polymerase chain reaction. Lifestyle data were collected using self-administered questionnaires. Basic characteristics and fasting venous blood sample were collected at baseline. 4018 subjects were eligible for participation.The frequencies of the ALDH2 rs671 genotype were 68.67% (GG), 28.67%(GL), 2.66%(LL), respectively. Pepole who harbored the L allele were less likely to develop incident hypertension. There was a significant association between food frequency and hypertension in the L genotype group. Fried food intake was significantly increased the risk of hypertension in the L genotype group. Our study suggested that ALDH2 rs671 L-genotypes are protective factors for hypertension in Han Chinese. Consumption of fried food accelerated the development of hypertension in individuals with poor metabolism of acetaldehyde. PMID- 28894225 TI - A signal-on built in-marker electrochemical aptasensor for human prostate specific antigen based on a hairbrush-like gold nanostructure. AB - A green electrodeposition method was firstly employed for the synthesis of round hairbrush-like gold nanostructure in the presence of cadaverine as a size and shape directing additive. The nanostructure which comprised of arrays of nanospindles was then applied as a transducer to fabricate a signal-on built in marker electrochemical aptasensor for the detection of human prostate-specific antigen (PSA). The aptasensor detected PSA with a linear concentration range of 0.125 to 128 ng mL-1 and a limit of detection of 50 pg mL-1. The aptasensor was then successfully applied to detect PSA in the blood serum samples of healthy and patient persons. PMID- 28894226 TI - Assessing the ecosystem services provided by urban green spaces along urban center-edge gradients. AB - Urban green spaces provide various ecosystem services, especially cultural services. Previous assessment methods depend either on hypothetic payments for ecosystems or real payments not directly related to ecosystems. In this paper, we established a method for assessing the cultural ecosystem services in any location in urban area using only two variables, green space (ecosystem) and land rent (real payment). We integrated the cultural and the regulating services into the total ecosystem services because urban green spaces provide almost no provisioning services. Results showed that the same area of green spaces near the center provided much higher cultural services than that near the urban edge; the regulating services accounted for 5% to 40% of the total ecosystem services from the center to the edge of urban area; along the center-edge gradient, there was a threshold out which the ecosystem services were lower than the maintenance cost of green spaces. PMID- 28894227 TI - Generation of convergent light beams by using surface plasmon locked Smith Purcell radiation. AB - An electron bunch passing through a periodic metal grating can emit Smith-Purcell radiation (SPR). Recently, it has been found that SPR can be locked and enhanced at some emission wavelength and angle by excitation of surface plasmon (SP) on the metal substrate. In this work, the generation of a convergent light beam via using the SP-locked SPR is proposed and investigated by computer simulations. The proposed structure is composed of an insulator-metal-insulator (IMI) substrate with chirped gratings on the substrate. The chirped gratings are designed such that a convergent beam containing a single wavelength is formed directly above the gratings when an electron bunch passes beneath the substrate. The wavelength of the convergent beam changes with the refractive index of dielectric layer of the IMI structure, which is determined by the frequency of SP on the IMI substrate excited by the electron bunch. Moreover, reversing the direction of electron bunch will make the emitted light from the proposed structure to switch from a convergent beam to a divergent beam. Finally, the formation of a convergent beam containing red, green and blue lights just above the chirped gratings is also demonstrated. This work offers potential applications in the fields of optical imaging, optical beam steering, holography, microdisplay, cryptography and light source. PMID- 28894228 TI - Ascorbic acid tethered polymeric nanoparticles enable efficient brain delivery of galantamine: An in vitro-in vivo study. AB - The aim of this work was to enhance the transportation of the galantamine to the brain via ascorbic acid grafted PLGA-b-PEG nanoparticles (NPs) using SVCT2 transporters of choroid plexus. PLGA-b-PEG copolymer was synthesized and characterized by 1H NMR, gel permeation chromatography, and differential scanning calorimetry. PLGA-b-PEG-NH2 and PLGA-b-mPEG NPs were prepared by nanoprecipitation method. PLGA-b-PEG NPs with desirable size, polydispersity, and drug loading were used for the conjugation with ascorbic acid (PLGA-b-PEG-Asc) to facilitate SVCT2 mediated transportation of the same into the brain. The surface functionalization of NPs with ascorbic acid significantly increased cellular uptake of NPs in SVCT2 expressing NIH/3T3 cells as compared to plain PLGA and PLGA-b-mPEG NPs. In vivo pharmacodynamic efficacy was evaluated using Morris Water Maze Test, Radial Arm Maze Test and AChE activity in scopolamine induced amnetic rats. In vivo pharmacodynamic studies demonstrated significantly higher therapeutic and sustained action by drug loaded PLGA-b-PEG-Asc NPs than free drugs and drug loaded plain PLGA as well as PLGA-b-mPEG NPs. Additionally, PLGA-b PEG-Asc NPs resulted in significantly higher biodistribution of the drug to the brain than other formulations. Hence, the results suggested that targeting of bioactives to the brain by ascorbic acid grafted PLGA-b-PEG NPs is a promising approach. PMID- 28894229 TI - VEGF expression correlates with neuronal differentiation and predicts a favorable prognosis in patients with neuroblastoma. AB - Neuroblastoma (NB) is a childhood cancer with a low survival rate and great metastatic potential. Vascular endothelial growth factor (VEGF), an angiogenesis factor, has been found to be involved in CRT-related neuronal differentiation of NB cells. In this study, we further confirmed the role VEGF in NB through mouse xenograft model and clinical analysis from NB patients. In xenograft experiments, CRT overexpression effectively inhibited the tumor growth. In addition, the mRNA and protein levels of VEGF and differentiation marker GAP-43 were upregulated by induced CRT expression. However, no significant correlation between the expression level of VEGF and microvessel density was observed in human NB tumors, suggesting a novel mechanism of VEGF participating in NB tumorigenesis through an angiogenesis-independent pathway. In NB patients' samples, mRNA expression levels of CRT and VEGF were positively correlated. Furthermore, positive VEGF expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. In conclusion, our findings suggest that VEGF is a favorable prognostic factor of NB and might affect NB tumor behavior through CRT-driven neuronal differentiation rather than angiogenesis that might shed light on a novel therapeutic strategy to improve the outcome of NB. PMID- 28894230 TI - Light guiding and switching using eccentric core-shell geometries. AB - High Refractive Index (HRI) dielectric nanoparticles have been proposed as an alternative to metallic ones due to their low absorption and magnetodielectric response in the VIS and NIR ranges. For the latter, important scattering directionality effects can be obtained. Also, systems constituted by dimers of HRI dielectric nanoparticles have shown to produce switching effects by playing with the polarization, frequency or intensity of the incident radiation. Here, we show that scattering directionality effects can be achieved with a single eccentric metallo-HRI dielectric core-shell nanoparticle. As an example, the effect of the metallic core displacements for a single Ag-Si core-shell nanoparticle has been analyzed. We report rotation of the main scattering lobe either clockwise or counterclockwise depending on the polarization of the incident radiation leading to new scattering configurations for switching purposes. Also, the efficiency of the scattering directionality can be enhanced. Finally, chains of these scattering units have shown good radiation guiding effects, and for 1D periodic arrays, redirection of diffracted intensity can be observed as a consequence of blazing effects. The proposed scattering units constitute new blocks for building systems for optical communications, solar energy harvesting devices and light guiding at the nanoscale level. PMID- 28894231 TI - Development of Monetary and Social Reward Processes. AB - The current study investigated monetary and social reward processing in children, adolescents and adults with adapted incentive-delay tasks and self-report questionnaires. Both tasks had three levels of reward magnitudes (no, low, and high). Qualified participants received 15 Chinese Yuan and an honor certificate as monetary and social rewards, respectively. The results indicated that both monetary and social rewards effectively speeded up responses for all three age groups as reward magnitude increased in the choice reaction time task. Among adolescents and adults, males exhibited faster responses in high reward than in low reward condition, while females responded equally fast in both conditions. Among children, girls responded faster to high reward than low reward condition. However, boys committed more errors than girls in low and high reward conditions, and they had exhibited more errors in high reward than that in no reward condition for social reward. Regarding the subjective ratings, both children and adolescents reported higher motivation for social reward than for monetary reward. These findings indicated that the males in the adolescent and adult groups were more sensitive to reward than were the females. Moreover, tangible and quantitative social reward had stronger incentive power than monetary reward among children and adolescents. PMID- 28894232 TI - Antennal transcriptome and expression analyses of olfactory genes in the sweetpotato weevil Cylas formicarius. AB - The sweetpotato weevil, Cylas formicarius (Fabricius), is a serious pest of sweetpotato. Olfaction-based approaches, such as use of synthetic sex pheromones to monitor populations and the bait-and-kill method to eliminate males, have been applied successfully for population management of C. formicarius. However, the molecular basis of olfaction in C. formicarius remains unknown. In this study, we produced antennal transcriptomes from males and females of C. formicarius using high-throughput sequencing to identify gene families associated with odorant detection. A total of 54 odorant receptors (ORs), 11 gustatory receptors (GRs), 15 ionotropic receptors (IRs), 3 sensory neuron membrane proteins (SNMPs), 33 odorant binding proteins (OBPs), and 12 chemosensory proteins (CSPs) were identified. Tissue-specific expression patterns revealed that all 54 ORs and 11 antennal IRs, one SNMP, and three OBPs were primarily expressed in antennae, suggesting their putative roles in olfaction. Sex-specific expression patterns of these antenna-predominant genes suggest that they have potential functions in sexual behaviors. This study provides a framework for understanding olfaction in coleopterans as well as future strategies for controlling the sweetpotato weevil pest. PMID- 28894233 TI - A pH-dependent Antibacterial Peptide Release Nano-system Blocks Tumor Growth in vivo without Toxicity. AB - In this study, we designed a nano-system where a novel antibacterial peptide RGD hylin a1 with reduced hemolysis than the commonly studied melittin was loaded onto mesoporous silica (HMS). We found out that the designed nano-system, RGD hylin a1-HMS, released RGD-hylin a1 in a pH-dependent manner. It caused apoptosis of cancer cells at low dosage of the antibacterial peptide at pH = 5.5, but was safe to the cells at pH = 7. The hemolytic activity of RGD-hylin a1 itself was reduced by 50~100% by the nano-system depending on the dosage. When this nano system was administered to tumor-bearing mice at low dosage via intravenous injection, the growth of the solid tumor was blocked by the RGD-hylin a1-HMS nano system with a 50-60% inhibition rate relative to the PBS-treated control group in terms of tumor volume and weight. Further, the hemolytic activity of RGD-hylin a1 was completely eliminated within the delivery system with no other side effects observed. This study demonstrates that this smart pH-dependent antibacterial peptide release nano-system has superior potential for solid tumor treatments through intravenous administration. This smart-releasing system has great potential in further clinical applications. PMID- 28894234 TI - Elevated UMOD methylation level in peripheral blood is associated with gout risk. AB - Uromodulin (UMOD) encodes an uromodulin glycoprotein, and its mutation results in uromodulin glycoprotein dysfunction and the occurrence of gout. The aim of our study was to assess whether UMOD methylation could predict the risk of gout. A total of 89 sporadic gout cases and 103 age and gender-matched healthy controls were recruited in this study. UMOD methylation level was determined by quantitative methylation-specific PCR (qMSP) in peripheral blood, and the percentage of methylated reference (PMR) was described to represent the methylation level. Our results showed that UMOD methylation was significantly higher in gout cases than controls (median: 1.45 versus 0.75, P < 0.001). The area under curve (AUC) of UMOD methylation in gout was 0.764 (P = 2.90E-10) with a sensitivity of 65.2% and a specificity of 88.3%. UMOD methylation level was shown to be significantly correlated with the serum level of uric acid (UA) (r = 0.208, P = 0.035). Besides, the luciferase reporter assay showed that UMOD CpG island region was able to upregulate gene expression (fold change = 2, P = 0.004). In conclusion, UMOD methylation assessment might be used to predict the occurrence of gout. PMID- 28894235 TI - Temporally and spatially distinct theta oscillations dissociate a language specific from a domain-general processing mechanism across the age trajectory. AB - The cognitive functionality of neural oscillations is still highly debated, as different functions have been associated with identical frequency ranges. Theta band oscillations, for instance, were proposed to underlie both language comprehension and domain-general cognitive abilities. Here we show that the ageing brain can provide an answer to the open question whether it is one and the same theta oscillation underlying those functions, thereby resolving a long standing paradox. While better cognitive functioning is predicted by low theta power in the brain at rest, resting state (RS) theta power declines with age, but sentence comprehension deteriorates in old age. We resolve this paradox showing that sentence comprehension declines due to changes in RS theta power within domain-general brain networks known to support successful sentence comprehension, while low RS theta power within the left-hemispheric dorso-frontal language network predicts intact sentence comprehension. The two RS theta networks were also found to functionally decouple relative to their independent internal coupling. Thus, both temporally and spatially distinct RS theta oscillations dissociate a language-specific from a domain-general processing mechanism. PMID- 28894237 TI - High coercivity, anisotropic, heavy rare earth-free Nd-Fe-B by Flash Spark Plasma Sintering. AB - ABSTARCT: In the drive to reduce the critical Heavy Rare Earth (HRE) content of magnets for green technologies, HRE-free Nd-Fe-B has become an attractive option. HRE is added to Nd-Fe-B to enhance the high temperature performance of the magnets. To produce similar high temperature properties without HRE, a crystallographically textured nanoscale grain structure is ideal; and this conventionally requires expensive "die upset" processing routes. Here, a Flash Spark Plasma Sintering (FSPS) process has been applied to a Dy-free Nd30.0Fe61.8Co5.8Ga0.6Al0.1B0.9 melt spun powder (MQU-F, neo Magnequench). Rapid sinter-forging of a green compact to near theoretical density was achieved during the 10 s process, and therefore represents a quick and efficient means of producing die-upset Nd-Fe-B material. The microstructure of the FSPS samples was investigated by SEM and TEM imaging, and the observations were used to guide the optimisation of the process. The most optimal sample is compared directly to commercially die-upset forged (MQIII-F) material made from the same MQU-F powder. It is shown that the grain size of the FSPS material is halved in comparison to the MQIII-F material, leading to a 14% increase in coercivity (1438 kA m-1) and matched remanence (1.16 T) giving a BHmax of 230 kJ m-3. PMID- 28894236 TI - Genome-wide functional analysis reveals that autophagy is necessary for growth, sporulation, deoxynivalenol production and virulence in Fusarium graminearum. AB - Autophagy is a conserved cellular recycling and trafficking pathway in eukaryotic cells and has been reported to be important in the virulence of a number of microbial pathogens. Here, we report genome-wide identification and characterization of autophagy-related genes (ATGs) in the wheat pathogenic fungus Fusarium graminearum. We identified twenty-eight genes associated with the regulation and operation of autophagy in F. graminearum. Using targeted gene deletion, we generated a set of 28 isogenic mutants. Autophagy mutants were classified into two groups by differences in their growth patterns. Radial growth of 18 Group 1 ATG mutants was significantly reduced compared to the wild-type strain PH-1, while 10 Group 2 mutants grew normally. Loss of any of the ATG genes, except FgATG17, prevented the fungus from causing Fusarium head blight disease. Moreover, subsets of autophagy genes were necessary for asexual/sexual differentiation and deoxynivalenol (DON) production, respectively. FgATG1 and FgATG5 were investigated in detail and showed severe defects in autophagy. Taken together, we conclude that autophagy plays a critical role in growth, asexual/sexual sporulation, deoxynivalenol production and virulence in F. graminearum. PMID- 28894238 TI - Prevalence and causes of low vision and blindness in a Chinese population with type 2 diabetes: the Dongguan Eye Study. AB - To assess the prevalence and causes of low vision and blindness in type 2 diabetes patients, a population-based cross-sectional study including 8952 rural dwelling residents aged 40 years or older from Hengli Town in Southern China was conducted. Participants underwent standard interviews, physical measurements, laboratory tests, and comprehensive eye examinations. Low vision and blindness were defined based on WHO criteria. Visual acuity data were available for 1348 (89.9%) of the 1500 subjects with type 2 diabetes. Age-standardized prevalence of bilateral low vision and blindness assessed in the better-seeing eye was 2.9% (95% confidence interval [CI]: 2.0-3.8) and 0.7% (95% CI: 0.2-1.1) based on best corrected visual acuity (BCVA). Cataracts were the primary cause of low vision and blindness. Visual impairment was associated with age (odds ratio [OR]: 3.73, 95% CI: 2.39-5.83), education level (OR: 3.21, 95% CI: 1.63-6.29), duration of diabetes (OR: 1.14, 95% CI: 1.04-1.25) and body mass index (OR: 0.86, 95% CI: 0.77-0.95). Our data suggest that approximately 70% of visual impairment in this diabetic population could be eliminated with appropriate cataract surgery or spectacle correction. Greater consideration should be given to older type 2 diabetes patients with a level of lower education. PMID- 28894239 TI - Dissecting the link between the enzymatic activity and the SaPI inducing capacity of the phage 80alpha dUTPase. AB - The trimeric staphylococcal phage-encoded dUTPases (Duts) are signalling molecules that induce the cycle of some Staphylococcal pathogenicity islands (SaPIs) by binding to the SaPI-encoded Stl repressor. To perform this regulatory role, these Duts require an extra motif VI, as well as the Dut conserved motifs IV and V. While the apo form of Dut is required for the interaction with the Stl repressor, usually only those Duts with normal enzymatic activity can induce the SaPI cycle. To understand the link between the enzymatic activities and inducing capacities of the Dut protein, we analysed the structural, biochemical and physiological characteristics of the Dut80alpha D95E mutant, which loses the SaPI cycle induction capacity despite retaining enzymatic activity. Asp95 is located at the threefold central channel of the trimeric Dut where it chelates a divalent ion. Here, using state-of-the-art techniques, we demonstrate that D95E mutation has an epistatic effect on the motifs involved in Stl binding. Thus, ion binding in the central channel correlates with the capacity of motif V to twist and order in the SaPI-inducing disposition, while the tip of motif VI is disturbed. These alterations in turn reduce the affinity for the Stl repressor and the capacity to induce the SaPI cycle. PMID- 28894240 TI - Understanding of multi-level resistive switching mechanism in GeOx through redox reaction in H2O2/sarcosine prostate cancer biomarker detection. AB - Formation-free multi-level resistive switching characteristics by using 10 nm thick polycrystalline GeOx film in a simple W/GeOx/W structure and understanding of switching mechanism through redox reaction in H2O2/sarcosine sensing (or changing Ge degrees /Ge4+ oxidation states under external bias) have been reported for the first time. Oxidation states of Ge0/Ge4+ are confirmed by both XPS and H2O2 sensing of GeOx membrane in electrolyte-insulator-semiconductor structure. Highly repeatable 1000 dc cycles and stable program/erase (P/E) endurance of >106 cycles at a small pulse width of 100 ns are achieved at a low operation current of 0.1 uA. The thickness of GeOx layer is found to be increased to 12.5 nm with the reduction of polycrystalline grain size of <7 nm after P/E of 106 cycles, which is observed by high-resolution TEM. The switching mechanism is explored through redox reaction in GeOx membrane by sensing 1 nM H2O2, which is owing to the change of oxidation states from Ge0 to Ge4+ because of the enhanced O2- ions migration in memory device under external bias. In addition, sarcosine as a prostate cancer biomarker with low concentration of 50 pM to 10 uM is also detected. PMID- 28894241 TI - An enhanced electrochemical and cycling properties of novel boronic Ionic liquid based ternary gel polymer electrolytes for rechargeable Li/LiCoO2 cells. AB - A new generation of boronic ionic liquid namely 1-ethyl-3-methylimidazolium difluoro(oxalate)borate (EMImDFOB) was synthesized by metathesis reaction between 1-ethyl-3-methylimiazolium bromide and lithium difluoro(oxalate)borate (LiDFOB). Ternary gel polymer electrolyte membranes were prepared using electrolyte mixture EMImDFOB/LiDFOB with poly vinylidenefluoride-co-hexafluoropropylene (PVdF-co-HFP) as a host matrix by facile solvent-casting method and plausibly demonstrated its feasibility to use in lithium ion batteries. Amongst ternary gel electrolyte membrane, DFOB-GPE3, which contained 80 wt% of EMImDFOB/LiDFOB and 20 wt% PVdF-co HFP, showed excellent electrochemical and cycling behaviors. The highest ionic conductivity was found to be 10-3 Scm-1 at 378 K. Charge-discharge profile of Li/DFOB-GPE3/LiCoO2 coin cell displayed a maximum discharge capacity of 148.4 mAhg-1 at C/10 rate with impressive capacity retention capability and columbic efficiency at 298 K. PMID- 28894242 TI - Complementary ACSL isoforms contribute to a non-Warburg advantageous energetic status characterizing invasive colon cancer cells. AB - Metabolic reprogramming is one of cancer hallmarks. Here, we focus on functional differences and individual contribution of acyl coA synthetases (ACSL) isoforms to the previously described ACSL/stearoyl-CoA desaturase (ACSL1/ACSL4/SCD) metabolic network causing invasion and poor prognosis in colorectal cancer (CRC). ACSL4 fuels proliferation and migration accompanied by a more glycolytic phenotype. Conversely, ACSL1 stimulates invasion displaying a lower basal respiratory rate. Acylcarnitines elevation, polyunsaturated fatty acids (PUFA) lower levels, and monounsaturated fatty acids (MUFA) upregulation characterize the individual overexpression of ACSL1, ACSL4 and SCD, respectively. However, the three enzymes simultaneous overexpression results in upregulated phospholipids and urea cycle derived metabolites. Thus, the metabolic effects caused by the network are far from being caused by the individual contributions of each enzyme. Furthermore, ACSL/SCD network produces more energetically efficient cells with lower basal respiration levels and upregulated creatine pathway. These features characterize other invasive CRC cells, thus, ACSL/SCD network exemplifies specific metabolic adaptations for invasive cancer cells. PMID- 28894243 TI - High-Capacitance Hybrid Supercapacitor Based on Multi-Colored Fluorescent Carbon Dots. AB - Multi-colored, water soluble fluorescent carbon nanodots (C-Dots) with quantum yield changing from 4.6 to 18.3% were synthesized in multi-gram using dated cola beverage through a simple thermal synthesis method and implemented as conductive and ion donating supercapacitor component. Various properties of C-Dots, including size, crystal structure, morphology and surface properties along with their Raman and electron paramagnetic resonance spectra were analyzed and compared by means of their fluorescence and electronic properties. alpha Manganese Oxide-Polypyrrole (PPy) nanorods decorated with C-Dots were further conducted as anode materials in a supercapacitor. Reduced graphene oxide was used as cathode along with the dicationic bis-imidazolium based ionic liquid in order to enhance the charge transfer and wetting capacity of electrode surfaces. For this purpose, we used octyl-bis(3-methylimidazolium)diiodide (C8H16BImI) synthesized by N-alkylation reaction as liquid ionic membrane electrolyte. Paramagnetic resonance and impedance spectroscopy have been undertaken in order to understand the origin of the performance of hybrid capacitor in more depth. In particular, we obtained high capacitance value (C = 17.3 MUF/cm2) which is exceptionally related not only the quality of synthesis but also the choice of electrode and electrolyte materials. Moreover, each component used in the construction of the hybrid supercapacitor is also played a key role to achieve high capacitance value. PMID- 28894245 TI - An extremely simple macroscale electronic skin realized by deep machine learning. AB - Complicated structures consisting of multi-layers with a multi-modal array of device components, i.e., so-called patterned multi-layers, and their corresponding circuit designs for signal readout and addressing are used to achieve a macroscale electronic skin (e-skin). In contrast to this common approach, we realized an extremely simple macroscale e-skin only by employing a single-layered piezoresistive MWCNT-PDMS composite film with neither nano-, micro , nor macro-patterns. It is the deep machine learning that made it possible to let such a simple bulky material play the role of a smart sensory device. A deep neural network (DNN) enabled us to process electrical resistance change induced by applied pressure and thereby to instantaneously evaluate the pressure level and the exact position under pressure. The great potential of this revolutionary concept for the attainment of pressure-distribution sensing on a macroscale area could expand its use to not only e-skin applications but to other high-end applications such as touch panels, portable flexible keyboard, sign language interpreting globes, safety diagnosis of social infrastructures, and the diagnosis of motility and peristalsis disorders in the gastrointestinal tract. PMID- 28894246 TI - The Vicissicaudata revisited - insights from a new aglaspidid arthropod with caudal appendages from the Furongian of China. AB - Cambrian marine ecosystems were dominated by arthropods, and more specifically artiopods. Aglaspidids represent an atypical group amongst them, not the least because they evolved and rapidly diversified during the late Cambrian, a time interval between the two diversification events of the Early Palaeozoic. Recent phylogenetic analyses have retrieved aglaspidids within the Vicissicaudata, a potentially important, but difficult to define clade of artiopods. Here we describe a new aglaspidid from the Furongian Guole Konservat-Lagerstatte of South China. This taxon displays a pretelsonic segment bearing non-walking appendages, features as-yet known in all vicissicaudatans, but aglaspidids. A new comprehensive phylogenetic analysis provides strong support for the legitimacy of a monophyletic clade Vicissicaudata, and demonstrates the pertinence of new characters to define Aglaspidida. It also motivates important changes to the systematics of the phylum, including the elevation of Artiopoda to the rank of subphylum, and the establishment of a new superclass Vicissicaudata and a new aglaspidid family Tremaglaspididae. Two diversification pulses can be recognized in the early history of artiopods - one in the early Cambrian (trilobitomorphs) and the other in the late Cambrian (vicissicaudatans). The discrepancy between this pattern and that traditionally depicted for marine invertebrates in the Early Palaeozoic is discussed. PMID- 28894244 TI - Impact of protein O-GlcNAcylation on neural tube malformation in diabetic embryopathy. AB - Diabetes mellitus in early pregnancy can cause neural tube defects (NTDs) in embryos by perturbing protein activity, causing cellular stress, and increasing programmed cell death (apoptosis) in the tissues required for neurulation. Hyperglycemia augments a branch pathway in glycolysis, the hexosamine biosynthetic pathway (HBP), to increase uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). GlcNAc can be added to proteins by O-GlcNAc transferase (OGT) to regulate protein activity. In the embryos of diabetic mice, OGT is highly activated in association with increases in global protein O-GlcNAcylation. In neural stem cells in vitro, high glucose elevates O-GlcNAcylation and reactive oxygen species, but the elevations can be suppressed by an OGT inhibitor. Inhibition of OGT in diabetic pregnant mice in vivo decreases NTD rate in the embryos. This effect is associated with reduction in global O-GlcNAcylation, alleviation of intracellular stress, and decreases in apoptosis in the embryos. These suggest that OGT plays an important role in diabetic embryopathy via increasing protein O-GlcNAcylation, and that inhibiting OGT could be a candidate approach to prevent birth defects in diabetic pregnancies. PMID- 28894247 TI - Interface topology for distinguishing stages of sintering. AB - Sintering is a common process during which nanoparticles and microparticles are bonded, leading to the shrinkage of interstitial pore space. Understanding morphological evolution during sintering is a challenge, because pore structures are elusive and very complex. A topological model of sintering is presented here, providing insight for understanding 3-D microstructures observed by X-ray microtomography. We find that the topological evolution is described by Euler characteristics as a function of relative density. The result is general, and applicable not only to viscous sintering of glasses but also to sintering of crystalline particles. It provides criteria to distinguish the stages of sintering, and the foundations to identify the range of applicability of the methods for determining the thermodynamic driving force of sintering. PMID- 28894248 TI - Chronic treatment with Tempol during acquisition or withdrawal from CPP abolishes the expression of cocaine reward and diminishes oxidative damage. AB - In previous studies, we reported that pretreatment with the antioxidant Tempol attenuated the development and expression of cocaine-induced psychomotor sensitization in rats and diminished cocaine-induced oxidative stress (OS) in the prefrontal cortex (PFC) and nucleus accumbens (NAc), suggesting a potential role for Tempol in interfering with cocaine-related psychomotor sensitization. The aim of the current study was to examine the role of Tempol in reward and reinforcement using the conditioned place preference (CPP) paradigm. We found that administration of Tempol during the conditioning session abolished the expression of cocaine-induced CPP. We also found that OS was significantly elevated following the establishment of CPP, and that cocaine-induced OS was significantly diminished by pretreatment with Tempol during conditioning. Furthermore, we found that repeated, but not single, administration of Tempol for seven days during withdrawal from CPP resulted in significant attenuation in the expression of CPP. Moreover, Tempol did not affect the expression of food reward. Taken together, these findings provide evidence for the involvement of Tempol in regulating cocaine rewarding properties without affecting natural rewards. Since Tempol was found to be effective in reducing OS and expression of CPP following withdrawal, it may be a potential treatment for cocaine addiction. PMID- 28894249 TI - Functional characterization of Vip3Ab1 and Vip3Bc1: Two novel insecticidal proteins with differential activity against lepidopteran pests. AB - In this work, we characterized 2 novel insecticidal proteins; Vip3Ab1 and Vip3Bc1. These proteins display unique insecticidal spectra and have differential rates of processing by lepidopteran digestive enzymes. Furthermore, we have found that both proteins exist as tetramers in their native state before and after proteolysis. In addition, we expressed truncated forms and protein chimeras to gain a deeper understanding of toxin specificity and stability. Our study confirms a role for the C-terminal 65 kDa domain in directing insect specificity. Importantly, these data also indicate a specific interaction between the 20 kDa amino terminus and 65 kDa carboxy terminus, after proteolytic processing. We demonstrate the C-terminal 65 kDa to be labile in native proteolytic conditions in absence of the 20 kDa N-terminus. Thus, the 20 kDa fragment functions to provide stability to the C-terminal domain, which is necessary for lethal toxicity against lepidopteran insects. PMID- 28894250 TI - Identification of endoxylanase XynE from Clostridium thermocellum as the first xylanase of glycoside hydrolase family GH141. AB - Enzymes that cleave polysaccharides in lignocellulose, i. e., cellulases, xylanases, and accessory enzymes, play crucial roles in the natural decomposition of plant-derived biomass and its efficient and sustainable processing into biofuels or other bulk chemicals. The analysis of open reading frame cthe_2195 from the thermophilic, cellulolytic anaerobe Clostridium thermocellum (also known as 'Ruminiclostridium thermocellum') suggested that it encoded a cellulosomal protein comprising a dockerin-I module, a carbohydrate-binding module, and a module of previously unknown function. The biochemical characterisation upon recombinant expression in Escherichia coli revealed that the protein is a thermostable endoxylanase, named Xyn141E with an optimal pH of 6.0-6.5 and a temperature optimum of 67-75 degrees C. The substrate spectrum of Xyn141E resembles that of GH10 xylanases, because of its side activities on carboxymethyl cellulose, barley beta-glucan, and mannan. Conversely, the product spectrum of Xyn141E acting on arabinoxylan is similar to those of GH11, as established by HPAEC-PAD analysis. Xyn141E is weakly related (20.7% amino acid sequence identity) to the founding member of the recently established GH family 141 and is the first xylanase in this new family of biomass-degrading enzymes. PMID- 28894251 TI - Spraying Brassinolide improves Sigma Broad tolerance in foxtail millet (Setaria italica L.) through modulation of antioxidant activity and photosynthetic capacity. AB - To explore the role of Brassinolide (BR) in improving the tolerance of Sigma Broad in foxtail millet (Setaria italica L.), effects of 0.1 mg/L of BR foliar application 24 h before 3.37 g/ha of Sigma Broad treatment at five-leaf stage of foxtail millet on growth parameters, antioxidant enzymes, malondialdehyde (MDA), chlorophyll, net photosynthetic rate (P N), chlorophyll fluorescence and P700 parameters were studied 7 and 15 d after herbicide treatment, respectively. Results showed that Sigma Broad significantly decreased plant height, activities of superoxide dismutase (SOD), chlorophyll content, P N, PS II effective quantum yield (Y (II)), PS II electron transport rate (ETR (II)), photochemical quantum yield of PSI(Y (I)) and PS I electron transport rate ETR (I), but significantly increased MDA. Compared to herbicide treatment, BR dramatically increased plant height, activities of SOD, Y (II), ETR (II), Y (I) and ETR (I). This study showed BR pretreatment could improve the tolerance of Sigma Broad in foxtail millet through improving the activity of antioxidant enzymes, keeping electron transport smooth, and enhancing actual photochemical efficiency of PS II and PSI. PMID- 28894252 TI - BOF steel slag as a low-cost sorbent for vanadium (V) removal from soil washing effluent. AB - Soil washing is an effective remediation method to remove heavy metals from contaminated soil. However, it produces wastewater that contains large amounts of heavy metals, which lead to serious pollution. This study investigated the removal of vanadium (V) from synthetic soil washing effluent using BOF steel slag. The effects of particle size, slag dosage, initial pH, and initial vanadium concentration on removal behavior were studied. Adsorption kinetics and isotherms were also analyzed. The results showed that the vanadium removal efficiency increased as the steel slag particle size decreased and as the amount of slag increased. The initial pH and vanadium concentration did not play key roles. At the optimum particle size (<0.15 mm) and dosage (50 g/L), the removal rate reached 97.1% when treating 100 mg/L of vanadium. The influence of the washing reagent residue was studied to simulate real conditions. Citric acid, tartaric acid, and Na2EDTA all decreased the removal rate. While oxalic acid did not have negative effects on vanadium removal at concentrations of 0.05-0.2 mol/L, which was proved by experiments using real washing effluents. Considering both soil washing effect and effluent treatment, oxalic acid of 0.2 mol/L is recommended as soil washing reagent. PMID- 28894253 TI - ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer. AB - Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (KrasG12D). We show that partial or total ATM deficiency cooperates with KrasG12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16Ink4a and p19Arf. However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability. PMID- 28894254 TI - Theta waves in children's waking electroencephalogram resemble local aspects of sleep during wakefulness. AB - Vyazovskiy and colleagues found in rats' multi-unit recordings brief periods of silence (off-states) in local populations of cortical neurons during wakefulness which closely resembled the characteristic off-states during sleep. These off states became more global and frequent with increasing sleep pressure and were associated with the well-known increase of theta activity under sleep deprivation in the surface EEG. Moreover, the occurrence of such off-states was related to impaired performance. While these animal experiments were based on intracranial recordings, we aimed to explore whether the human surface EEG may also provide evidence for such a local sleep-like intrusion during wakefulness. Thus, we analysed high-density wake EEG recordings during an auditory attention task in the morning and evening in 12 children. We found that, theta waves became more widespread in the evening and the occurrence of widespread theta waves was associated with slower reaction times in the attention task. These results indicate that widespread theta events measured on the scalp might be markers of local sleep in humans. Moreover, such markers of local sleep, seem to be related to the well described performance decline under high sleep pressure. PMID- 28894255 TI - Multiple Streptomyces species with distinct secondary metabolomes have identical 16S rRNA gene sequences. AB - Microbial diversity studies using small subunit (SSU) rRNA gene sequences continue to advance our understanding of biological and ecological systems. Although a good predictor of overall diversity, using this gene to infer the presence of a species in a sample is more controversial. Here, we present a detailed polyphasic analysis of 10 bacterial strains isolated from three coastal lichens Lichina confinis, Lichina pygmaea and Roccella fuciformis with SSU rRNA gene sequences identical to the type strain of Streptomyces cyaneofuscatus. This analysis included phenotypic, microscopic, genetic and genomic comparisons and showed that despite their identical SSU rRNA sequences the strains had markedly different properties, and could be distinguished as 5 different species. Significantly, secondary metabolites profiles from these strains were also found to be different. It is thus clear that SSU rRNA based operational taxonomy units, even at the most stringent cut-off can represent multiple bacterial species, and that at least for the case of Streptomyces, strain de-replication based on SSU gene sequences prior to screening for bioactive molecules can miss potentially interesting novel molecules produced by this group that is notorious for the production of drug-leads. PMID- 28894256 TI - A scaling law for distinct electrocaloric cooling performance in low-dimensional organic, relaxor and anti-ferroelectrics. AB - Electrocaloric (EC) materials show promise in eco-friendly solid-state refrigeration and integrable on-chip thermal management. While direct measurement of EC thin-films still remains challenging, a generic theoretical framework for quantifying the cooling properties of rich EC materials including normal-, relaxor-, organic- and anti-ferroelectrics is imperative for exploiting new flexible and room-temperature cooling alternatives. Here, we present a versatile theory that combines Master equation with Maxwell relations and analytically relates the macroscopic cooling responses in EC materials with the intrinsic diffuseness of phase transitions and correlation characteristics. Under increased electric fields, both EC entropy and adiabatic temperature changes increase quadratically initially, followed by further linear growth and eventual gradual saturation. The upper bound of entropy change (?Smax) is limited by distinct correlation volumes (V cr ) and transition diffuseness. The linearity between V cr and the transition diffuseness is emphasized, while ?Smax = 300 kJ/(K.m3) is obtained for Pb0.8Ba0.2ZrO3. The ?Smax in antiferroelectric Pb0.95Zr0.05TiO3, Pb0.8Ba0.2ZrO3 and polymeric ferroelectrics scales proportionally with V cr-2.2, owing to the one-dimensional structural constraint on lattice-scale depolarization dynamics; whereas ?Smax in relaxor and normal ferroelectrics scales as ?Smax ~ V cr-0.37, which tallies with a dipolar interaction exponent of 2/3 in EC materials and the well-proven fractional dimensionality of 2.5 for ferroelectric domain walls. PMID- 28894257 TI - Stress Granules Contain Rbfox2 with Cell Cycle-related mRNAs. AB - Rbfox RNA-binding proteins play important roles in the regulation of alternative pre-mRNA splicing, but their role in other gene regulatory mechanisms is not well understood. Here, we show that Rbfox2 is a novel constituent of cytoplasmic stress granules, the translational silencing machinery assembled in response to cellular stress. We also show that the RNA binding activity of the Rbfox family protein is crucial for its localization into stress granules. To investigate the role of Rbfox2 in stress granules we used RNA-immunoprecipitation sequencing to identify cytoplasmic transcriptome-wide targets of Rbfox2. We report that a subset of cell cycle-related genes including retinoblastoma 1 is the target of Rbfox2 in cytoplasmic stress granules, and Rbfox2 regulates the retinoblastoma 1 mRNA and protein expression levels during and following stress exposure. Our study proposes a novel function for Rbfox2 in cytoplasmic stress granules. PMID- 28894258 TI - Preferential synthesis of (6,4) single-walled carbon nanotubes by controlling oxidation degree of Co catalyst. AB - Chirality-selective synthesis of single-walled carbon nanotubes (SWNTs) has been a research goal for the last two decades and is still challenging due to the difficulty in controlling the atomic structure in the one-dimensional material. Here, we develop an optimized approach for controlling the chirality of species by tuning the oxidation degree of Co catalyst. Predominant synthesis of (6,4) SWNTs is realized for the first time. The detailed mechanism is investigated through a systematic experimental study combined with first-principles calculations, revealing that the independent control of tube diameter and chiral angle achieved by changing the binding energy between SWNTs (cap and tube edge) and catalyst causes a drastic transition of chirality of SWNTs from (6,5) to (6,4). Since our approach of independently controlling the diameter and chiral angle can be applied to other chirality species, our results can be useful in achieving the on-demand synthesis of specific-chirality SWNTs. PMID- 28894259 TI - CD161 identifies polyfunctional Th1/Th17 cells in the genital mucosa that are depleted in HIV-infected female sex workers from Nairobi, Kenya. AB - CD161 identifies a subset of circulating Th17 cells that are depleted in the blood and gut of HIV-infected individuals. In the female reproductive tract (FRT), the pattern of CD161 expression on CD4+ cells remains unknown. Here, we characterized CD161 expression in the FRT of Kenyan female sex workers (FSW). Compared to the blood, CD161+CD4+ T cells were enriched in the FRT of uninfected FSWs. These cells were depleted in FRT of HIV-infected FSWs. Cervical CD161+ cells harboured an activated phenotype (CD69, CD95, HLA-DR) with elevated expression of tissue-homing markers (CCR6, beta7 integrin) and HIV co-receptor (CCR5). Mitogen-stimulated production of IL-17 confirmed the Th17 commitment of CD161+CD4+ T cells in the FRT with a predominance of polyfunctional Th1/Th17 cells. Here, we showed that the expression of CD161 on CD4+T cells is modulated at the FRT, but still identified a highly activated cellular subset, which differentiates into pro-inflammatory Th1/Th17 cells, expresses multiple HIV susceptibility markers and are depleted in HIV-infected individuals. The use of CD161 as a biomarker of HIV targets in the FRT reduces the need for functional assessment of cells and could have important implications in better understanding HIV pathogenesis and Th17 fate in the FRT of high-risk women. PMID- 28894260 TI - A New Tactic for Label-Free Recognition of beta-Trophin via Electrochemiluminescent Signalling on an AuNPs Supported Immuno-Interface. AB - In this paper, a new strategy is reported for preparing a label-free beta-trophin electrochemiluminescent (ECL) immunosensor with good specificity, reproducibility and stability. An aquagel polymer from the hydrolysis of (3-aminopropyl) trimethoxysilane acted as the linker to catch the Au nanoparticles (AuNPs) on the indium-tin oxide (ITO) substrate by a two-step method. The AuNPs play an important role in enhancing ECL and immobilizing the beta-trophin antibody. This immunosensor can test for beta-trophin using luminol as an ECL probe. The ECL intensity at the resultant sensor, after the direct immuno-interaction, was proportional to the concentration of beta-trophin and had a low limit of quantification as 4.2 ng mL-1. After deep discussions on the ECL mechanism of this immunosensor, we found that its sensitivity is greatly affected by the presence of oxygen and improved under deoxygenation. We believe that this sensor can be used for clinical cases. PMID- 28894261 TI - Unique diversity of radioactive particles found in the Yenisei River floodplain. AB - The long-term operation of three reactors and the radiochemical plant of the Mining-and-Chemical Combine (MCC), Russia's largest producer of weapons-grade plutonium, has resulted in radioactive contamination of the Yenisei River floodplain. From 1995 to 2016, we found more than 200 radioactive particles (RP) in the Yenisei floodplain, downstream of the MCC. Analytical characterization showed that most of the RP were fuel particles, which were carried into the river after incidents at the MCC reactors. Having compared the 137Cs/134Cs ratios in the particles, we determined three time intervals when the RP were formed. The plutonium isotope ratios (238Pu/239,240Pu) vary substantially between the particles and indicate several different source terms. In addition to fuel RP, we found particles that only contained activation products (60Co or europium isotopes). SEM and gamma-spectrometry showed that the cobalt particles could have originated from the corrosion of the reactor coolant system and the europium particles - from the damaged compensating rods. No europium particles have been found anywhere else in the world. The presence of RP from different sources (fuel, cobalt, and europium particles) in the Yenisei River floodplain makes this region a unique site for studying environmental effects of the particles. These RP represent point sources of radioecological significance. PMID- 28894262 TI - Role of sonication pre-treatment and cation valence in the sol-gel transition of nano-cellulose suspensions. AB - Sol-gel transition of carboxylated cellulose nanocrystals has been investigated using rheology, SAXS, NMR and optical spectroscopies to unveil the distinctive roles of ultrasound treatments and addition of various cations. Besides cellulose fiber fragmentation, sonication treatment induces fast gelling of the solution. The gelation is independent of the addition of cations, while the final rheological properties are highly influenced by the type, concentration and sequence of the operations since the cations must be added prior to sonication to produce stiff gels. The gel elastic modulus was found to increase proportionally to the ionic charge rather than the cationic size. In cases where ions were added after sonication, SAXS analysis of the Na+ hydrogel and Ca2+ hydrogel indicated the presence of structurally ordered domains in which water is confined, and 1H NMR investigation showed the dynamics of water exchange within the hydrogels. Conversely, separated phases containing essentially free water were characteristic of the hydrogels obtained by sonication after Ca2+ addition, confirming that this ion induces irreversible fiber aggregation. The rheological properties of the hydrogels depend on the duration of the ultrasound treatments, enabling the design of programmed materials with tailored energy dissipation response. PMID- 28894263 TI - The parathyroid hormone regulates skin tumour susceptibility in mice. AB - Using a forward genetics approach to map loci in a mouse skin cancer model, we previously identified a genetic locus, Skin tumour modifier of MSM 1 (Stmm1) on chromosome 7, conferring strong tumour resistance. Sub-congenic mapping localized Parathyroid hormone (Pth) in Stmm1b. Here, we report that serum intact-PTH (iPTH) and a genetic polymorphism in Pth are important for skin tumour resistance. We identified higher iPTH levels in sera from cancer-resistant MSM/Ms mice compared with susceptible FVB/NJ mice. Therefore, we performed skin carcinogenesis experiments with MSM-BAC transgenic mice (Pth MSM-Tg) and Pth knockout heterozygous mice (Pth +/-). As a result, the higher amounts of iPTH in sera conferred stronger resistance to skin tumours. Furthermore, we found that the coding SNP (rs51104087, Val28Met) localizes in the mouse Pro-PTH encoding region, which is linked to processing efficacy and increased PTH secretion. Finally, we report that PTH increases intracellular calcium in keratinocytes and promotes their terminal differentiation. Taken together, our data suggest that Pth is one of the genes responsible for Stmm1, and serum iPTH could serve as a prevention marker of skin cancer and a target for new therapies. PMID- 28894264 TI - Seasonal variation of the dominant allergenic fungal aerosols - One year study from southern Indian region. AB - Quantitative estimations of fungal aerosols are important to understand their role in causing respiratory diseases to humans especially in the developing and highly populated countries. In this study we sampled and quantified the three most dominantly found allergenic airborne fungi, Aspergillus fumigatus, Cladosporium cladosporioides, and Alternaria alternata from ambient PM10 samples using the quantitative PCR (qPCR) technique in a southern tropical Indian region, for one full year. Highest concentrations of A. fumigatus and C. cladosporioides were observed during monsoon whereas A. alternata displayed an elevated concentration in winter. The meteorological parameters such as temperature, relative humidity, wind speed, and precipitation exhibited a substantial influence on the atmospheric concentrations of allergenic fungal aerosols. The morphological features of various allergenic fungal spores present in the PM10 were investigated and the spores were found to possess distinct structural features. In a maiden attempt over this region we correlate the ambient fungal concentrations with the epidemiological allergy occurrence to obtain firsthand and preliminary information about the causative fungal allergen to the inhabitants exposed to bioaerosols. Our findings may serve as an important reference to atmospheric scientists, aero-biologists, doctors, and general public. PMID- 28894265 TI - Thiosemicarbazone scaffold for the design of antifungal and antiaflatoxigenic agents: evaluation of ligands and related copper complexes. AB - The issue of food contamination by aflatoxins presently constitutes a social emergency, since they represent a severe risk for human and animal health. On the other hand, the use of pesticides has to be contained, since this generates long term residues in food and in the environment. Here we present the synthesis of a series of chelating ligands based on the thiosemicarbazone scaffold, to be evaluated for their antifungal and antiaflatoxigenic effects. Starting from molecules of natural origin of known antifungal properties, we introduced the thio- group and then the corresponding copper complexes were synthesised. Some molecules highlighted aflatoxin inhibition in the range 67-92% at 100 MUM. The most active compounds were evaluated for their cytotoxic effects on human cells. While all the copper complexes showed high cytotoxicity in the micromolar range, one of the ligand has no effect on cell proliferation. This hit was chosen for further analysis of mutagenicity and genotoxicity on bacteria, plants and human cells. Analysis of the data underlined the importance of the safety profile evaluation for hit compounds to be developed as crop-protective agents and at the same time that the thiosemicarbazone scaffold represents a good starting point for the development of aflatoxigenic inhibitors. PMID- 28894266 TI - Generation of a new mouse model of glaucoma characterized by reduced expression of the AP-2beta and AP-2delta proteins. AB - We generated 6 transgenic lines with insertion of an expression plasmid for the R883/M xanthine dehydrogenase (XDH) mutant protein. Approximately 20% of the animals deriving from one of the transgenic lines show ocular abnormalities and an increase in intra-ocular pressure which are consistent with glaucoma. The observed pathologic phenotype is not due to expression of the transgene, but rather the consequence of the transgene insertion site, which has been defined by genome sequencing. The insertion site maps to chromosome 1qA3 in close proximity to the loci encoding AP-2beta and AP-2delta, two proteins expressed in the eye. The insertion leads to a reduction in AP-2beta and AP-2delta levels. Down regulation of AP-2beta expression is likely to be responsible for the pathologic phenotype, as conditional deletion of the Tfap2b gene in the neural crest has recently been shown to cause defective development of the eye anterior segment and early-onset glaucoma. In these conditional knock-out and our transgenic mice, the morphological/histological features of the glaucomatous pathology are surprisingly similar. Our transgenic mouse represents a model of angle-closure glaucoma and a useful tool for the study of the pathogenesis and the development of innovative therapeutic strategies. PMID- 28894267 TI - Optogenetic approach for targeted activation of global calcium transients in differentiated C2C12 myotubes. AB - Excitation-contraction coupling in muscle cells is initiated by a restricted membrane depolarization delimited within the neuromuscular junction. This targeted depolarization triggers an action potential that propagates and induces a global cellular calcium response and a consequent contraction. To date, numerous studies have investigated this excitation-calcium response coupling by using different techniques to depolarize muscle cells. However, none of these techniques mimic the temporal and spatial resolution of membrane depolarization observed in the neuromuscular junction. By using optogenetics in C2C12 muscle cells, we developed a technique to study the calcium response following membrane depolarization induced by photostimulations of membrane surface similar or narrower than the neuromuscular junction area. These stimulations coupled to confocal calcium imaging generate a global cellular calcium response that is the consequence of a membrane depolarization propagation. In this context, this technique provides an interesting, contactless and relatively easy way of investigation of calcium increase/release as well as calcium decrease/re-uptake triggered by a propagated membrane depolarization. PMID- 28894268 TI - Recycling of a selectable marker with a self-excisable plasmid in Pichia pastoris. AB - Pichia pastoris is a widely used heterologous protein production workhorse. However, with its multiple genetic modifications to solve bottlenecks for heterologous protein productivity, P. pastoris lacks selectable markers. Existing selectable marker recycling plasmids have drawbacks (e.g., slow growth and conditional lethality). Here, zeocin-resistance marker recycling vectors were constructed using the Cre/loxP recombination system. The vectors were used to (i) knock in heterologous phytase, xylanase and lipase expression cassettes, (ii) increase the phytase, xylanase and lipase gene copy number to 13, 5, and 5, respectively, with vector introduction and (iii) engineer the secretion pathway by co-overexpressing secretion helper factors (Sly1p and Sec1p) without introducing selectable markers, giving a phytase field of 0.833 g/L. The vectors allow selectable marker recycling and would be a useful tool to engineer P. pastoris for high heterologous protein productivity. PMID- 28894269 TI - Effect of Mesoporous Nano Water Reservoir on MR Relaxivity. AB - In the present work, an attempt was made to engineer a mesoporous silica coated magnetic nanoparticles (MNF@mSiO2) for twin mode contrast in magnetic resonance imaging (MRI) with reduced toxicity. Superparamagnetic manganese ferrite nanoparticles were synthesized with variable mesoporous silica shell thickness to control the water molecules interacting with metal oxide core. 178 nm was the optimum hydrodynamic diameter of mesoporous ferrite core-shell nanoparticles that showed maximum longitudinal relaxation time (T1) and transverse relaxation time (T2) in MRI due to the storage of water molecules in mesoporous silica coating. Besides the major role of mesoporous silica in controlling relaxivity, mesoporous silica shell also reduces the toxicity and enhances the bioavailability of superparamagnetic manganese ferrite nanoparticles. The in vitro toxicity assessment using HepG2 liver carcinoma cells shows that the mesoporous silica coating over ferrite nanoparticles could exert less toxicity compared to the uncoated particle. PMID- 28894270 TI - A Novel Role For Nanog As An Early Cancer Risk Marker In Patients With Laryngeal Precancerous Lesions. AB - NANOG is a master regulator of embryonic stem cell pluripotency, found to be frequently aberrantly expressed in a variety of cancers, including laryngeal carcinomas. This study investigates for the first time the role of NANOG expression in early stages of laryngeal tumourigenesis and its potential utility as cancer risk marker. NANOG protein expression was evaluated by immunohistochemistry using two large independent cohorts of patients with laryngeal precancerous lesions, and correlated with clinicopathological parameters and laryngeal cancer risk. NANOG expression was detected by immunohistochemistry in 49 (60%) of 82 laryngeal dysplasias, whereas expression was negligible in patient-matched normal epithelia. Strong NANOG expression was found in 22 (27%) lesions and was established as cut-off point, showing the most robust association with laryngeal cancer risk (P = 0.003) superior to the histological classification (P = 0.320) the current gold standard in the clinical practice. Similar trends were obtained using a multicenter validation cohort of 86 patients with laryngeal dysplasia. Our findings uncover a novel role for NANOG expression in laryngeal tumourigenesis, and its unprecedented application as biomarker for cancer risk assessment. PMID- 28894271 TI - Laser-Induced Linear-Field Particle Acceleration in Free Space. AB - Linear-field particle acceleration in free space (which is distinct from geometries like the linac that requires components in the vicinity of the particle) has been studied for over 20 years, and its ability to eventually produce high-quality, high energy multi-particle bunches has remained a subject of great interest. Arguments can certainly be made that linear-field particle acceleration in free space is very doubtful given that first-order electron photon interactions are forbidden in free space. Nevertheless, we chose to develop an accurate and truly predictive theoretical formalism to explore this remote possibility when intense, few-cycle electromagnetic pulses are used in a computational experiment. The formalism includes exact treatment of Maxwell's equations and exact treatment of the interaction among the multiple individual particles at near and far field. Several surprising results emerge. We find that electrons interacting with intense laser pulses in free space are capable of gaining substantial amounts of energy that scale linearly with the field amplitude. For example, 30 keV electrons (2.5% energy spread) are accelerated to 61 MeV (0.5% spread) and to 205 MeV (0.25% spread) using 250 mJ and 2.5 J lasers respectively. These findings carry important implications for our understanding of ultrafast electron-photon interactions in strong fields. PMID- 28894272 TI - T-cell tolerance and exhaustion in the clearance of Echinococcus multilocularis: role of inoculum size in a quantitative hepatic experimental model. AB - The local immune mechanisms responsible for either self-healing or sustained chronic infection are not clear, in the development of E. multilocularis larvae. Here, we developed a suitable experimental model that mimics naturally infected livers, according to the parasite load. We demonstrated that local cellular immunity and fibrogenesis are actually protective and fully able to limit metacestode growth in the liver of low or medium dose-infected mice (LDG or MDG), or even to clear it, while impairment of cellular immunity is followed by a more rapid and severe course of the disease in high dose-infected mice (HDG). And recruitment and/ or proliferation of memory T cells (including CD4 Tem, CD8 Tcm and CD8 Tem) and imbalance of T1/T2/T17/Treg-type T cells in liver were not only associated with clearance of the parasite infection in LDG, but also with increased hepatic injury in HDG; in particular the dual role of CD8 T cells depending on the parasite load and the various stages of metacestode growth. Besides, we first demonstrate the association between LAG3- or 2B4-expressing T cells exhaustion and HD inocula in late stages. Our quantitative experimental model appears fully appropriate to study immunomodulation as a therapeutic strategy for patients with Alveolar Echinococcosis. PMID- 28894273 TI - Impacts of aquaculture wastewater irrigation on soil microbial functional diversity and community structure in arid regions. AB - Aquaculture wastewater is one of the most important alternative water resources in arid regions where scarcity of fresh water is common. Irrigation with this kind of water may affect soil microbial functional diversity and community structure as changes of soil environment would be significant. Here, we conducted a field sampling to investigate these effects using Biolog and metagenomic methods. The results demonstrated that irrigation with aquaculture wastewater could dramatically reduce soil microbial functional diversity. The values of diversity indices and sole carbon source utilization were all significantly decreased. Increased soil salinity, especially Cl concentration, appeared primarily associated with the decreases. Differently, higher bacterial community diversity was obtained in aquaculture wastewater irrigated soils. More abundant phyla Actinobacteria, Chloroflexi, Acidobacteria, Gemmatimonadetes and fewer members of Proteobacteria, Bacteroidetes and Planctomycetes were found in this kind of soils. Changes in the concentration of soil Cl mainly accounted for the shifts of bacterial community composition. This research can improve our understanding of how aquaculture wastewater irrigation changes soil microbial process and as a result, be useful to manage soil and wastewater resources in arid regions. PMID- 28894274 TI - KDM4A regulates HIF-1 levels through H3K9me3. AB - Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF 1alpha are directly controlled by the repressive chromatin mark, H3K9me3. In conditions where the histone demethylase KDM4A is depleted or inactive, H3K9me3 accumulates at the HIF-1alpha locus, leading to a decrease in HIF-1alpha mRNA and a reduction in HIF-1alpha stabilisation. Loss of KDM4A in hypoxic conditions leads to a decreased HIF-1alpha mediated transcriptional response and correlates with a reduction in the characteristics associated with tumour aggressiveness, including invasion, migration, and oxygen consumption. The contribution of KDM4A to the regulation of HIF-1alpha is most robust in conditions of mild hypoxia. This suggests that KDM4A can enhance the function of HIF-1alpha by increasing the total available protein to counteract any residual activity of prolyl hydroxylases. PMID- 28894275 TI - Direct laser writing of a new type of waveguides in silver containing glasses. AB - Direct laser writing in glasses is a growing field of research in photonics since it provides a robust and efficient way to directly address 3D material structuring. Generally, direct laser writing in glasses induces physical modifications such as refractive index changes that have been classified under three different types (Type I, II & III). In a silver-containing zinc phosphate glass, direct laser writing additionally proceeds via the formation of silver clusters at the periphery of the interaction voxel. In this paper, we introduce a novel type of refractive index modification based on the creation of the photo induced silver clusters allowing the inscription of a new type of optical waveguides. Various waveguides as well as a 50-50 beam splitter were written inside bulk glasses and characterized. The waveguiding properties observed in the bulk of such silver-containing glass samples were further transposed to ribbon shaped fibers made of the same material. Our results pave the way for the fabrication of 3D integrated circuits and fiber sensors with original fluorescent, nonlinear optical and plasmonic properties. The universality of these new findings should further extend in any silver-containing glasses that show similar laser-induced behavior in terms of silver cluster production. PMID- 28894276 TI - An Affordable Wet Chemical Route to Grow Conducting Hybrid Graphite-Diamond Nanowires: Demonstration by A Single Nanowire Device. AB - We report an affordable wet chemical route for the reproducible hybrid graphite diamond nanowires (G-DNWs) growth from cysteamine functionalized diamond nanoparticles (ND-Cys) via pH induced self-assembly, which has been visualized through SEM and TEM images. Interestingly, the mechanistic aspects behind that self-assembly directed G-DNWs formation was discussed in details. Notably, above self-assembly was validated by AFM and TEM data. Further interrogations by XRD and Raman data were revealed the possible graphite sheath wrapping over DNWs. Moreover, the HR-TEM studies also verified the coexistence of less perfect sp2 graphite layer wrapped over the sp3 diamond carbon and the impurity channels as well. Very importantly, conductivity of hybrid G-DNWs was verified via fabrication of a single G-DNW. Wherein, the better conductivity of G-DNW portion L2 was found as 2.4 +/- 1.92 * 10-6 mS/cm and revealed its effective applicability in near future. In addition to note, temperature dependent carrier transport mechanisms and activation energy calculations were reported in details in this work. Ultimately, to demonstrate the importance of our conductivity measurements, the possible mechanism behind the electrical transport and the comparative account on electrical resistivities of carbon based materials were provided. PMID- 28894277 TI - Host Expression of the CD8 Treg/NK Cell Restriction Element Qa-1 is Dispensable for Transplant Tolerance. AB - Disruption of the non-classical Major Histocompatibility Complex (MHC) Ib molecule Qa-1 impairs CD8 Treg and natural killer (NK) cell function and promotes a lupus-like autoimmune disease. This immune perturbation would be expected to enhance anti-transplant responses and impair tolerance induction, but the effect of Qa-1 deficiency on the transplant response has not been previously reported. Qa-1 deficiency enhanced CD4 TFH and germinal center (GC) B cell numbers in naive mice and hastened islet allograft rejection. Despite enhanced immunity in B6.Qa-1 /- mice, these mice did not generate an excessive primary CD4 TFH cell response nor an enhanced alloantibody reaction. Both CD8 Tregs and NK cells, which often regulate other cells through host Qa-1 expression, were targets of anti-CD45RB therapy that had not been previously recognized. However, B6.Qa-1-/- mice remained susceptible to anti-CD45RB mediated suppression of the alloantibody response and transplant tolerance induction to mismatched islet allografts. Overall, despite enhanced immunity as demonstrated by augmented CD4 TFH/GC B cell numbers and hastened islet allograft rejection in naive 12-week old Qa-1 deficient mice, the CD8 Treg/NK cell restriction element Qa-1 does not regulate the primary cellular or humoral alloresponse and is not required for long-term transplant tolerance. PMID- 28894278 TI - Agerarin, identified from Ageratum houstonianum, stimulates circadian CLOCK mediated aquaporin-3 gene expression in HaCaT keratinocytes. AB - The juice of Ageratum houstonianum is used in folk medicine as an external wound healing aid for skin injuries. However, the active component of A. houstonianum and its mode of action in skin wound healing has not been investigated. This study was conducted to investigate the effect of A. houstonianum ethanolnolic extract (AHE) on the expression of aquaporin-3 (AQP3), an integral membrane protein for water and glycerol transport in keratinocytes, and to identify the structure of the A. houstonianum bioactive compound. Here, we show that AHE increased AQP3 gene expression at the transcriptional level through the p38 MAPK pathway in HaCaT cells. Furthermore, AHE ameliorated suppression of AQP3 expression caused by ultraviolet B (UVB) irradiation. Agerarin (6,7-dimethoxy-2,2 dimethyl-2H-chromene) was identified as the bioactive compound responsible for the up-regulation of AQP3 expression by enhancing the expression of the transcription factor circadian locomotor output cycles kaput (CLOCK). In conclusion, agerarin is a bioactive compound in AHE responsible for CLOCK mediated AQP3 expression in keratinocytes. PMID- 28894279 TI - Generation of octave-spanning mid-infrared pulses from cascaded second-order nonlinear processes in a single crystal. AB - We report on experimental generation of a 6.8 MUJ laser pulse spanning from 1.8 to 4.2 MUm from cascaded second-order nonlinear processes in a 0.4-mm BiB3O6 (BIBO) crystal. The nonlinear processes are initiated by intra-pulse difference frequency generation (DFG) using spectrally broadened Ti:Sapphire spectrum, followed by optical parametric amplification (OPA) of the DFG pulse. The highest energy, 12.6 MUJ, is achieved in a 0.8-mm BIBO crystal with a spectrum spanning from 1.8 to 3.5 MUm. Such cascaded nonlinear processes are enabled by the broadband pump and the coincident phase matching angle of DFG and OPA. The spectrum is initiated from the DFG process and is thus expected to have passive stable carrier-envelope phase, which can be used to seed either a chirped pulse amplifier (CPA) or an optical parametric chirped pulse amplifier (OPCPA) for achieving high-energy few-cycle mid-infrared pulses. Such cascaded second-order nonlinear processes can be found in many other crystals such as KTA, which can extend wavelengths further into mid-infrared. We achieved a 0.8 MUJ laser pulse spanning from 2.2 to 5.0 MUm in KTA. PMID- 28894280 TI - Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines. AB - Patients with scirrhous gastric cancer (SGC) frequently develop peritoneal dissemination, which leads to poor prognosis. The secreted protein angiopoietin like-4 (ANGPTL4), which is induced by hypoxia, exerts diverse effects on cancer progression. Here, we aimed to determine the biological function of ANGPTL4 in SGC cells under hypoxia. ANGPTL4 levels were higher in SGC cells under hypoxia than in other types of gastric cancer cells. Hypoxia-induced ANGPTL4 mRNA expression was regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). Under hypoxic conditions, monolayer cultures of ANGPTL4 knockdown (KD) 58As9 SGC (58As9 KD) cells were arrested in the G1 phase of the cell cycle through downregulation of c-Myc and upregulation of p27, in contrast to control 58As9-SC cells. Moreover, the ability of 58As9-KD xenografts to form tumours in nude mice was strongly suppressed. When 58As9-KD cells were cultured in suspension, hypoxia strongly increased their susceptibility to anoikis through suppression of the FAK/Src/PI3K-Akt/ERK pro-survival pathway, followed by activation of the apoptotic factors caspases-3, -8 and -9. The development of peritoneal dissemination by 58As9-KD cells was completely inhibited compared with that by 58As9-SC cells. In conclusion, ANGPTL4 is uniquely induced by hypoxia in cultured SGC cells and is essential for tumour growth and resistance to anoikis through different mechanisms. PMID- 28894281 TI - The ancient cline of haplogroup K implies that the Neolithic transition in Europe was mainly demic. AB - Using a database with the mitochondrial DNA (mtDNA) of 513 Neolithic individuals, we quantify the space-time variation of the frequency of haplogroup K, previously proposed as a relevant Neolithic marker. We compare these data to simulations, based on a mathematical model in which a Neolithic population spreads from Syria to Anatolia and Europe, possibly interbreeding with Mesolithic individuals (who lack haplogroup K) and/or teaching farming to them. Both the data and the simulations show that the percentage of haplogroup K (%K) decreases with increasing distance from Syria and that, in each region, the %K tends to decrease with increasing time after the arrival of farming. Both the model and the data display a local minimum of the genetic cline, and for the same Neolithic regional culture (Sweden). Comparing the observed ancient cline of haplogroup K to the simulation results reveals that about 98% of farmers were not involved in interbreeding neither acculturation (cultural diffusion). Therefore, cultural diffusion involved only a tiny fraction (about 2%) of farmers and, in this sense, the most relevant process in the spread of the Neolithic in Europe was demic diffusion (i.e., the dispersal of farmers), as opposed to cultural diffusion (i.e., the incorporation of hunter-gatherers). PMID- 28894282 TI - Idiopathic male infertility and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. AB - The purpose of this study was to investigate the association between male infertility and single-nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMT) genes (DNMT3B: rs2424909, DNMT1: rs4804490, DNMT3A: rs1550117 and DNMT3L: rs7354779). Eight hundred and thirty three idiopathic infertile males and four hundred and ten fertile controls from the hospitals affiliated to Nanjing Medical University between 2010 and 2012 were recruited in the study. We demonstrated a significantly increased risk of idiopathic infertility with abnormal semen parameters in association with the heterozygous genotype of variant rs4804490. Moreover, the AA genotype of variant rs4804490 was associated with significantly decreased risk for male infertility with abnormal semen parameters. A decreased risk of idiopathic infertility with abnormal semen parameters was associated with the homozygous genotype of variant rs2424909. These results suggested that variants in different DNMT genes have different relationships with idiopathic male infertility, and Chinese men carrying these variants have an increased or decreased risk of abnormal semen parameters. PMID- 28894284 TI - TREM2 promotes Abeta phagocytosis by upregulating C/EBPalpha-dependent CD36 expression in microglia. AB - TREM2 plays a critical role in the alleviation of Alzheimer's disease by promoting Abeta phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic activity of Abeta remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Abeta was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice. The expression of C/EBPalpha, an upstream transcriptional activator of CD36, was also elevated in primary microglia of TG mice but decreased in KO mice. The transcription of CD36 was markedly increased by TREM2 overexpression, and this effect was suppressed by a mutation of the C/EBPalpha binding site on the CD36 promoter. The TREM2-induced expression of CD36 and C/EBPalpha was inhibited by treatment with PI3K/AKT signaling blockers, and phosphorylation of AKT was elevated in TREM2-overexpressing BV2 cells. The present study provides evidence that TREM2 is required for preventing loss of memory and learning in Alzheimer's disease by regulating C/EBPalpha-dependent CD36 expression and the consequent Abeta phagocytosis. PMID- 28894283 TI - JinqiJiangtang tablets for pre-diabetes: A randomized, double-blind and placebo controlled clinical trial. AB - This study observed the efficacy and safety of JinqiJiangtang tablets (JQJT tablets, a traditional Chinese patent medicine) for pre-diabetes. Four hundred patients with pre-diabetes at five centres were treated for 12months and followed for an additional 12months to investigate the preventative effects of JQJT tablets (Registration ID: ChiCTR-PRC-09000401). The incidence rate of diabetes mellitus was the primary endpoint. The risk of converting from pre-diabetes to diabetes was 0.58-fold less in the JQJT tablets group than in the placebo group [HR (95% CI): 0.58 (0.384, 0.876), P = 0.010]. Furthermore, the probability of achieving normalized blood glucose was 1.41-fold greater in the JQJT tablets group than in the placebo group [HR (95% CI): 1.41 (1.002, 1.996), P = 0.0049]. ITT analysis revealed that the incidence of diabetes upon treatment completion was 16.5% in the JQJT tablets group compared with 28.9% in the control group. The percentage of patients with normalized blood glucose upon 12-month intervention was 41.8% in the JQJT tablets group compared with 27.8% in the control group. JQJT tablets could be an effective intervention for preventative treatment of Type 2 diabetes mellitus. PMID- 28894285 TI - Bandgap renormalization in single-wall carbon nanotubes. AB - Single-wall carbon nanotubes (SWNTs) have been extensively explored as an ultrafast nonlinear optical material. However, due to the numerous electronic and morphological arrangements, a simple and self-contained physical model that can unambiguously account for the rich photocarrier dynamics in SWNTs is still absent. Here, by performing broadband degenerate and non-degenerate pump-probe experiments on SWNTs of different chiralities and morphologies, we reveal strong evidences for the existence of bandgap renormalization in SWNTs. In particularly, it is found that the broadband transient response of SWNTs can be well explained by the combined effects of Pauli blocking and bandgap renormalization, and the distinct dynamics is further influenced by the different sensitivity of degenerate and non-degenerate measurements to these two concurrent effects. Furthermore, we attribute optical-phonon bath thermalization as an underlying mechanism for the observed bandgap renormalization. Our findings provide new guidelines for interpreting the broadband optical response of carbon nanotubes. PMID- 28894286 TI - Intermittent hypoxia-induced insulin resistance is associated with alterations in white fat distribution. AB - Sleep apnea syndrome is characterized by repetitive upper airway collapses during night leading to intermittent hypoxia (IH). The latter is responsible for metabolic disturbances that rely, at least in part, on abdominal white fat inflammation. Besides qualitative alterations, we hypothesized that IH could also modify body fat distribution, a key factor for metabolic complications. C57BL6 mice exposed to IH (21-5% FiO2, 60 s cycle, 8 h/day) or air for 6 weeks were investigated for topographic fat alterations (whole-body MRI). Specific role of epididymal fat in IH-induced metabolic dysfunctions was assessed in lipectomized or sham-operated mice exposed to IH or air. Whereas total white fat volume was unchanged, IH induced epididymal adipose tissue (AT) loss with non-significant increase in subcutaneous and mesenteric fat. This was associated with impaired insulin sensitivity and secretion. Epididymal lipectomy led to increased subcutaneous fat in the perineal compartment and prevented IH-induced metabolic disturbances. IH led to reduced epididymal AT and impaired glucose regulation. This suggests that, rather than epididymal AT volume, qualitative fat alterations (i.e. inflammation) could represent the main determinant of metabolic dysfunction. This deterioration of glucose regulation was prevented in epididymal lipectomized mice, possibly through prevention of IH-induced epididymal AT alterations and compensatory increase in subcutaneous AT. PMID- 28894287 TI - Prognostic significance of high GFI1 expression in AML of normal karyotype and its association with a FLT3-ITD signature. AB - Growth Factor Independence 1 (GFI1) is a transcriptional repressor that plays a critical role during both myeloid and lymphoid haematopoietic lineage commitment. Several studies have demonstrated the involvement of GFI1 in haematological malignancies and have suggested that low expression of GFI1 is a negative indicator of disease progression for both myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study, we have stratified AML patients into those defined as having a normal karyotype (CN-AML). Unlike the overall pattern in AML, those patients with CN-AML have a poorer survival rate when GFI1 expression is high. In this group, high GFI1 expression is paralleled by higher FLT3 expression, and, even when the FLT3 gene is not mutated, exhibit a FLT3-ITD signature of gene expression. Knock-down of GFI1 expression in the human AML Fujioka cell line led to a decrease in the level of FLT3 RNA and protein and to the down regulation of FLT3-ITD signature genes, thus linking two major prognostic indicators for AML. PMID- 28894288 TI - Altered Adipose-Derived Stem Cell Characteristics in Macrodactyly. AB - Macrodactyly is a congenital disease characterized by aggressive overgrowth of adipose tissue in digits or limbs frequently accompanied with hyperostosis and nerve enlargement; its pathological mechanism is poorly understood. Adipose derived stem cells (ASCs) have been extensively studied in tissue engineering and regenerative medicine as an ideal alternative substitute for bone marrow-derived mesenchymal stem cells (BM-MSCs), but their pathological role is largely unknown. In this study, ASCs from macrodactyly adipose tissues (Mac-ASCs) were isolated and compared to ASCs derived from the normal abdominal subcutaneous adipose tissue (Sat-ASCs) for cell morphology, surface marker expression, proliferation rate, and tri-lineage differentiation potential. Despite similar cell morphology and cell surface marker expression, Mac-ASCs showed higher cell proportion in the S phase and increased proliferation compared with Sat-ASCs. Moreover, osteogenic and chondrogenic differentiation capacities were enhanced in Mac-ASCs, with reduced adipogenic potential. In addition, the expression levels of adipogenic genes were lower in undifferentiated Mac-ASCs than in Sat-ASCs. These findings unraveled enhanced proliferation activity, a regression in the differentiation stage, and greater potentiality of ASCs in macrodactyly, which could contribute to hyperostosis and nerve enlargement in addition to adipose tissue overgrowth in patients. PMID- 28894289 TI - Factors associated with long-term weight-loss maintenance following bariatric surgery in adolescents with severe obesity. AB - BACKGROUND/OBJECTIVES: Bariatric surgery produces robust weight loss, however, factors associated with long-term weight-loss maintenance among adolescents undergoing Roux-en-Y gastric bypass surgery are unknown. SUBJECTS/METHODS: Fifty adolescents (mean+/-s.d. age and body mass index (BMI)=17.1+/-1.7 years and 59+/ 11 kg m-2) underwent Roux-en-Y gastric bypass surgery, had follow-up visits at 1 year and at a visit between 5 and 12 years following surgery (Follow-up of Adolescent Bariatric Surgery at 5 Plus years (FABS-5+) visit; mean+/-s.d. 8.1+/ 1.6 years). A non-surgical comparison group (n=30; mean+/-s.d. age and BMI=15.3+/ 1.7 years and BMI=52+/-8 kg m-2) was recruited to compare weight trajectories over time. Questionnaires (health-related and eating behaviors, health responsibility, impact of weight on quality of life (QOL), international physical activity questionnaire and dietary habits via surgery guidelines) were administered at the FABS-5+ visit. Post hoc, participants were split into two groups: long-term weight-loss maintainers (n=23; baseline BMI=58.2 kg m-2; 1-year BMI=35.8 kg m-2; FABS-5+ BMI=34.9 kg m-2) and re-gainers (n=27; baseline BMI=59.8 kg m-2; 1-year BMI=36.8 kg m-2; FABS-5+ BMI=48.0 kg m-2) to compare factors which might contribute to differences. Data were analyzed using generalized estimating equations adjusted for age, sex, baseline BMI, baseline diabetes status and length of follow-up. RESULTS: The BMI of the surgical group declined from baseline to 1 year (-38.5+/-6.9%), which, despite some regain, was largely maintained until FABS-5+ (-29.6+/-13.9% change). The BMI of the comparison group increased from baseline to the FABS-5+ visit (+10.3+/-20.6%). When the surgical group was split into maintainers and re-gainers, no differences in weight-related and eating behaviors, health responsibility, physical activity/inactivity, or dietary habits were observed between groups. However, at FABS-5+, maintainers had greater overall QOL scores than re-gainers (87.5+/-10.5 vs 65.4+/-20.2, P<0.001) and in each QOL sub-domain (P<0.01 all). CONCLUSIONS: Long-term weight outcomes for those who underwent weight-loss surgery were superior to those who did not undergo surgical treatment. While no behavioral factors were identified as predictors of success in long-term weight-loss maintenance, greater QOL was strongly associated with maintenance of weight loss among adolescents who underwent Roux-en-Y gastric bypass surgery surgery. PMID- 28894290 TI - Association of proton density fat fraction in adipose tissue with imaging-based and anthropometric obesity markers in adults. AB - BACKGROUND/OBJECTIVES: The purpose of this study was to examine the relationship of the proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), of supraclavicular and gluteal adipose tissue with subcutaneous and visceral adipose tissue (SAT and VAT) volumes, liver fat fraction and anthropometric obesity markers. The supraclavicular fossa was selected as a typical location where brown adipocytes may be present in humans and the gluteal region was selected as a typical location enclosing primarily white adipocytes. SUBJECTS/METHODS: In this cross-sectional study, 61 adults (44 women, median age 29.3 years, range 21-68 years) underwent an MRI examination of the neck and the abdomen/pelvis (3T, Ingenia, Philips Healthcare). PDFF maps of the supraclavicular and gluteal adipose tissue and the liver were generated. Volumes of SAT and VAT were calculated and supraclavicular and subcutaneous fat were segmented using custom-built post-processing algorithms. Body mass index (BMI), waist circumference and waist-to-height ratio were recorded. Statistical analysis was conducted using the Student's t-test and Pearson correlation analysis. RESULTS: Mean supraclavicular PDFF was 75.3+/-4.7% (range 65.4-83.8%) and mean gluteal PDFF was 89.7+/-2.9% (range 82.2-94%), resulting in a significant difference (P<0.0001). Supraclavicular PDFF was positively correlated with VAT (r=0.76, P<0.0001), SAT (r=0.73, P<0.0001), liver PDFF (r=0.42, P=0.0008) and all measured anthropometric obesity markers. Gluteal subcutaneous PDFF also correlated with VAT (r=0.59, P<0.0001), SAT (r=0.63, P<0.0001), liver PDFF (r=0.3, P=0.02) and anthropometric obesity markers. CONCLUSIONS: The positive correlations between adipose tissue PDFF and imaging, as well as anthropometric obesity markers suggest that adipose tissue PDFF may be useful as a biomarker for improving the characterization of the obese phenotype, for risk stratification and for selection of appropriate treatment strategies. PMID- 28894291 TI - Neural predictors of 12-month weight loss outcomes following bariatric surgery. AB - BACKGROUND/OBJECTIVES: Despite the effectiveness of bariatric surgery, there is still substantial variability in long-term weight outcomes and few factors with predictive power to explain this variability. Neuroimaging may provide a novel biomarker with utility beyond other commonly used variables in bariatric surgery trials to improve prediction of long-term weight-loss outcomes. The purpose of this study was to evaluate the effects of sleeve gastrectomy (SG) on reward and cognitive control circuitry postsurgery and determine the extent to which baseline brain activity predicts weight loss at 12-month postsurgery. SUBJECTS/METHODS: Using a longitudinal design, behavioral, hormone and neuroimaging data (during a desire for palatable food regulation paradigm) were collected from 18 patients undergoing SG at baseline (<1 month prior) and 12 month post-SG. RESULTS: SG patients lost an average of 29.0% of their weight (percentage of total weight loss (%TWL)) at 12-month post-SG, with significant variability (range: 16.0-43.5%). Maladaptive eating behaviors (uncontrolled, emotional and externally cued eating) improved (P<0.01), in parallel with reductions in fasting hormones (acyl ghrelin, leptin, glucose, insulin; P<0.05). Brain activity in the nucleus accumbens (NAcc), caudate, pallidum and amygdala during desire for palatable food enhancement vs regulation decreased from baseline to 12 months (P (family-wise error (FWE))<0.05). Dorsolateral and dorsomedial prefrontal cortex activity during desire for palatable food regulation (vs enhancement) increased from baseline to 12 months (P(FWE)<0.05). Baseline activity in the NAcc and hypothalamus during desire for palatable food enhancement was significantly predictive of %TWL at 12 months (P (FWE)<0.05), superior to behavioral and hormone predictors, which did not significantly predict %TWL (P>0.10). Using stepwise linear regression, left NAcc activity accounted for 54% of the explained variance in %TWL at 12 months. CONCLUSIONS: Consistent with previous obesity studies, reward-related neural circuit activity may serve as an objective, relatively robust predictor of postsurgery weight loss. Replication in larger studies is necessary to determine true effect sizes for outcome prediction. PMID- 28894292 TI - Partitioning of adipose lipid metabolism by altered expression and function of PPAR isoforms after bariatric surgery. AB - BACKGROUND: Bariatric surgery remains the most effective treatment for reducing adiposity and eliminating type 2 diabetes; however, the mechanism(s) responsible have remained elusive. Peroxisome proliferator-activated receptors (PPAR) encompass a family of nuclear hormone receptors that upon activation exert control of lipid metabolism, glucose regulation and inflammation. Their role in adipose tissue following bariatric surgery remains undefined. MATERIALS AND METHODS: Subcutaneous adipose tissue biopsies and serum were obtained and evaluated from time of surgery and on postoperative day 7 in patients randomized to Roux-en-Y gastric bypass (n=13) or matched caloric restriction (n=14), as well as patients undergoing vertical sleeve gastrectomy (n=33). Fat samples were evaluated for changes in gene expression, protein levels, beta-oxidation, lipolysis and cysteine oxidation. RESULTS: Within 7 days, bariatric surgery acutely drives a change in the activity and expression of PPARgamma and PPARdelta in subcutaneous adipose tissue thereby attenuating lipid storage, increasing lipolysis and potentiating lipid oxidation. This unique metabolic alteration leads to changes in downstream PPARgamma/delta targets including decreased expression of fatty acid binding protein (FABP) 4 and stearoyl-CoA desaturase-1 (SCD1) with increased expression of carnitine palmitoyl transferase 1 (CPT1) and uncoupling protein 2 (UCP2). Increased expression of UCP2 not only facilitated fatty acid oxidation (increased 15-fold following surgery) but also regulated the subcutaneous adipose tissue redoxome by attenuating protein cysteine oxidation and reducing oxidative stress. The expression of UCP1, a mitochondrial protein responsible for the regulation of fatty acid oxidation and thermogenesis in beige and brown fat, was unaltered following surgery. CONCLUSIONS: These results suggest that bariatric surgery initiates a novel metabolic shift in subcutaneous adipose tissue to oxidize fatty acids independently from the beiging process through regulation of PPAR isoforms. Further studies are required to understand the contribution of this shift in expression of PPAR isoforms to weight loss following bariatric surgery. PMID- 28894293 TI - Tannerella forsythia and coating color on the tongue dorsum, and fatty food liking associate with fat accumulation and insulin resistance in adult catch-up fat. AB - BACKGROUND/OBJECTIVES: We aimed to determine the alteration of Tannerella forsythia and coating color on the dorsal tongue, and fatty food liking in catch up fat in adult (CUFA), as well as the probable associations between fat accumulation, insulin resistance (IR) and these changes. SUBJECTS/METHODS: T. forsythia on the tongue dorsum, fatty food liking, fat accumulation and insulin sensitivity were investigated in CUFA humans and rats, and tongue-coating color was observed in CUFA individuals. We further determined the changes of fatty food liking, fat accumulation and IR in T. forsythia-infected rodents by oral lavage. RESULTS: Increases in fat accumulation, IR, percentage of subjects with yellow tongue coating and that with T. forsythia detected were observed in CUFA individuals. Additionally, the fat ranking scores were significantly lower and the hedonic ratings of low-fat options of sampled food were lower, while the ratings of high-fat options were remarkably higher in CUFA subjects. Additionally, T. forsythia level elevated in CUFA rats, and fatty food liking, fat accumulation and IR increased in CUFA and T. forsythia-infected animals, with the increases in T. forsythia infection and fatty food liking preceding the occurrence of fat accumulation and IR. CONCLUSIONS: T. forsythia and yellow coating on the dorsal tongue and fatty food liking associate fat accumulation and IR in CUFA. Moreover, we tentatively put forward that T. forsythia, which is very important in yellow tongue-coating microbiota, and its consequent increases in fatty food liking, might be crucial in the development of fat accumulation and IR in CUFA. PMID- 28894294 TI - Synchronous precipitation reduction in the American Tropics associated with Heinrich 2. AB - During the last ice age temperature in the North Atlantic oscillated in cycles known as Dansgaard-Oeschger (D-O) events. The magnitude of Caribbean hydroclimate change associated with D-O variability and particularly with stadial intervals, remains poorly constrained by paleoclimate records. We present a 3.3 thousand year long stalagmite delta18O record from the Yucatan Peninsula (YP) that spans the interval between 26.5 and 23.2 thousand years before present. We estimate quantitative precipitation variability and the high resolution and dating accuracy of this record allow us to investigate how rainfall in the region responds to D-O events. Quantitative precipitation estimates are based on observed regional amount effect variability, last glacial paleotemperature records, and estimates of the last glacial oxygen isotopic composition of precipitation based on global circulation models (GCMs). The new precipitation record suggests significant low latitude hydrological responses to internal modes of climate variability and supports a role of Caribbean hydroclimate in helping Atlantic Meridional Overturning Circulation recovery during D-O events. Significant in-phase precipitation reduction across the equator in the tropical Americas associated with Heinrich event 2 is suggested by available speleothem oxygen isotope records. PMID- 28894295 TI - Reversible naftifine-induced carotenoid depigmentation in Rhodotorula mucilaginosa (A. Jorg.) F.C. Harrison causing onychomycosis. AB - Rhodotorula mucilaginosa was isolated from a patient with onychomycosis, and identification was confirmed by morphological and cultural characteristics as well as by DNA molecular analysis. Antifungal agents naftifine (10 mg/mL, active substance in Exoderil) and bifonazole (10 mg/mL, active substance in Canespor) were tested in different concentrations to assess in vitro effects on fungal growth and carotenoid synthesis. The antifungal mechanisms of action of naftifine and bifonazole against R. mucilaginosa isolates were similar and affected the biosynthetic pathway of ergosterol. For the first time, this research demonstrates that naftifine affects the carotenoid biosynthetic pathway, producing depigmentation of R. mucilaginosa in solid and liquid media. Furthermore, depigmentation was a reversible process; naftifine-treated yeast cells that were depigmented resumed carotenoid production upon transfer to fresh media. Raman and UV-vis spectrophotometry in conjunction with chromatographic analysis detected changes in carotenoids in yeast cells, with torulene decreasing and B-carotene increasing after repigmentation. Transmission electron micrographs revealed critical ultrastructural modifications in the depigmented cells after naftifine treatment, i.e., a low-electron-density cell wall without visible mucilage or lamellate structure. PMID- 28894296 TI - Test-retest reliability of high spatial resolution diffusion tensor and diffusion kurtosis imaging. AB - We assessed the test-retest reliability of high spatial resolution diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). Diffusion MRI was acquired using a Siemens 3 Tesla Prisma scanner with 80 mT/m gradients and a 32 channel head coil from each of 3 concussive traumatic brain injury (cTBI) patients and 4 controls twice 0 to 24 days apart. Coefficients of variation (CoV) for DTI parameters were calculated in each DTI Studio parcellated white matter tract at 1.25 mm and 1.75 mm isotropic voxel resolution, as well as DKI parameters at 1.75 mm isotropic. Overall, fractional anisotropy had the best reliability, with mean CoV at 5% for 1.25 mm and 3.5% for 1.75 mm isotropic voxels. Mean CoV for the other DTI metrics were <7.0% for both 1.25 and 1.75 mm isotropic voxels. The mean CoV was <=4.5% across the DKI metrics. In the commonly injured orbitofrontal and temporal pole regions CoV was <3.5% for all parameters. Thus, with appropriate processing, high spatial resolution advanced diffusion MRI has good to excellent test-retest reproducibility in both human cTBI patients and controls. However, further technical improvements will be needed to reliably discern the most subtle diffusion abnormalities, especially at high spatial resolution. PMID- 28894297 TI - The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family. AB - Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes within multiplex families have been identified. This report examines whole exomes of affected and unaffected individuals in a multiplex TD family to discover genes involved in the TD etiology. We performed whole exome sequencing on six out of nine members in a three-generation TD multiplex family. Putative deleterious sequence variants co-segregating with TD patients were identified by our in-house bioinformatics pipeline. Induced pluripotent stem cells (iPSCs) were generated from one unaffected and two TD affected individuals. Neurons were derived from the iPSCs and biochemical assays were conducted to evaluate possible molecular differences between affected and unaffected. A rare heterozygous nonsense mutation in PNKD was co-segregated with TD in this multiplex family. Transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD due to the nonsense mutation, indicating nonsense mediated mRNA decay. We demonstrated that the PNKD long isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1alpha. We concluded that reduced PNKD long isoform levels are detected in all affected individuals and we provide evidence for a mechanism whereby this might contribute to the TD phenotype. PMID- 28894298 TI - Molecular basis of dendritic atrophy and activity in stress susceptibility. AB - Molecular and cellular adaptations in nucleus accumbens (NAc) medium spiny neurons (MSNs) underlie stress-induced depression-like behavior, but the molecular substrates mediating cellular plasticity and activity in MSN subtypes in stress susceptibility are poorly understood. We find the transcription factor early growth response 3 (EGR3) is increased in D1 receptor containing MSNs of mice susceptible to social defeat stress. Genetic reduction of Egr3 levels in D1 MSNs prevented depression-like outcomes in stress susceptible mice by preventing D1-MSN dendritic atrophy, reduced frequency of excitatory input and altered in vivo activity. Overall, we identify NAc neuronal-subtype molecular control of dendritic morphology and related functional adaptations, which underlie susceptibility to stress. PMID- 28894299 TI - DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway. AB - Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies. PMID- 28894300 TI - Striatal dopamine D1-type receptor availability: no difference from control but association with cortical thickness in methamphetamine users. AB - Chronic methamphetamine use poses potentially devastating consequences for directly affected individuals and for society. Lower dopamine D2-type receptor availability has been observed in striata of methamphetamine users as compared with controls, but an analogous comparison of D1-type receptors has been conducted only on post-mortem material, with no differences in methamphetamine users from controls in the caudate nucleus and putamen and higher D1-receptor density in the nucleus accumbens. Released from neurons when methamphetamine is self-administered, dopamine binds to both D1- and D2-type receptors in the striatum, with downstream effects on cortical activity. Thus, both receptor subtypes may contribute to methamphetamine-induced alterations in cortical morphology and behavior. In this study, 21 methamphetamine-dependent subjects and 23 healthy controls participated in positron emission tomography and structural magnetic resonance imaging for assessment of striatal D1- and D2-type receptor availability and cortical gray-matter thickness, respectively. Although D2-type receptor availability (BPnd) was lower in the methamphetamine group, as shown previously, the groups did not differ in D1-type BPnd. In the methamphetamine group, mean cortical gray-matter thickness was negatively associated with cumulative methamphetamine use and craving for the drug. Striatal D1-type but not D2-type BPnd was negatively associated with global mean cortical gray-matter thickness in the methamphetamine group, but no association was found between gray matter thickness and BPnd for either dopamine receptor subtype in the control group. These results suggest a role of striatal D1-type receptors in cortical adaptation to chronic methamphetamine use. PMID- 28894301 TI - Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. AB - Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors. PMID- 28894303 TI - Overestimation of the classification accuracy of a biomarker for assessing heavy alcohol use. PMID- 28894302 TI - Gbetagamma subunit activation promotes dopamine efflux through the dopamine transporter. AB - The dopamine transporter (DAT) is an important regulator of brain dopamine (DA) homeostasis, controlling the intensity and duration of DA signaling. DAT is the target for psychostimulants-like cocaine and amphetamine-and plays an important role in neuropsychiatric disorders, including attention-deficit hyperactivity disorder and drug addiction. Thus, a thorough understanding of the mechanisms that regulate DAT function is necessary for the development of clinical interventions to treat DA-related brain disorders. Previous studies have revealed a plethora of protein-protein interactions influencing DAT cellular localization and activity, suggesting that the fine-tuning of DA homeostasis involves multiple mechanisms. We recently reported that G-protein beta-gamma (Gbetagamma) subunits bind directly to DAT and decrease DA clearance. Here we show that Gbetagamma induces the release of DA through DAT. Specifically, a Gbetagamma binding/activating peptide, mSIRK, increases DA efflux through DAT in heterologous cells and primary dopaminergic neurons in culture. Addition of the Gbetagamma inhibitor gallein or DAT inhibitors prevents this effect. Residues 582 to 596 in the DAT carboxy terminus were identified as the primary binding site of Gbetagamma. A TAT peptide containing the Gbetagamma-interacting domain of DAT blocked the ability of mSIRK to induce DA efflux, consistent with a direct interaction of Gbetagamma with the transporter. Finally, activation of a G protein-coupled receptor, the muscarinic M5R, results in DAT-mediated DA efflux through a Gbetagamma-dependent mechanism. Collectively, our data show that Gbetagamma interacts with DAT to promote DA efflux. This novel mechanism may have important implications in the regulation of brain DA homeostasis. PMID- 28894304 TI - Quantification of brain cholinergic denervation in Alzheimer's disease using PET imaging with [18F]-FEOBV. AB - 18F-fluoroethoxybenzovesamicol (FEOBV) is a new PET radiotracer that binds to the vesicular acetylcholine transporter. In both animals and healthy humans, FEOBV was found sensitive and reliable to characterize presynaptic cholinergic nerve terminals in the brain. It has been used here for we believe the first time in patients with Alzheimer's disease (AD) to quantify brain cholinergic losses. The sample included 12 participants evenly divided in healthy subjects and patients with AD, all assessed with the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) cognitive scales. Every participant underwent three consecutive PET imaging sessions with (1) the FEOBV as a tracer of the cholinergic terminals, (2) the 18F-NAV4694 (NAV) as an amyloid-beta tracer, and (3) the 18F-Fluorodeoxyglucose (FDG) as a brain metabolism agent. Standardized uptake value ratios (SUVRs) were computed for each tracer, and compared between the two groups using voxel wise t-tests. Correlations were also computed between each tracer and the cognitive scales, as well as between FEOBV and the two other radiotracers. Results showed major reductions of FEOBV uptake in multiple cortical areas that were evident in each AD subject, and in the AD group as a whole when compared to the control group. FDG and NAV were also able to distinguish the two groups, but with lower sensitivity than FEOBV. FEOBV uptake values were positively correlated with FDG in numerous cortical areas, and negatively correlated with NAV in some restricted areas. The MMSE and MoCA cognitive scales were found to correlate significantly with FEOBV and with FDG, but not with NAV. We concluded that PET imaging with FEOBV is more sensitive than either FDG or NAV to distinguish AD patients from control subjects, and may be useful to quantify disease severity. FEOBV can be used to assess cholinergic degeneration in human, and may represent an excellent biomarker for AD. PMID- 28894305 TI - Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients. AB - Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Although gene- and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials. PMID- 28894307 TI - Evidence-Based Pharmacy Practice? PMID- 28894306 TI - Advances in multi-dimensional coherent spectroscopy of semiconductor nanostructures. AB - Multi-dimensional coherent spectroscopy (MDCS) has become an extremely versatile and sensitive technique for elucidating the structure, composition, and dynamics of condensed matter, atomic, and molecular systems. The appeal of MDCS lies in its ability to resolve both individual-emitter and ensemble-averaged dynamics of optically created excitations in disordered systems. When applied to semiconductors, MDCS enables unambiguous separation of homogeneous and inhomogeneous contributions to the optical linewidth, pinpoints the nature of coupling between resonances, and reveals signatures of many-body interactions. In this review, we discuss the implementation of MDCS to measure the nonlinear optical response of excitonic transitions in semiconductor nanostructures. Capabilities of the technique are illustrated with recent experimental studies that advance our understanding of optical decoherence and dissipation, energy transfer, and many-body phenomena in quantum dots and quantum wells, semiconductor microcavities, layered semiconductors, and photovoltaic materials. PMID- 28894308 TI - ? PMID- 28894309 TI - Reliability of Best Possible Medication Histories Completed by Non-admitted Patients in the Emergency Department. AB - BACKGROUND: Accreditation standards have outlined the need for staff in emergency departments to initiate the medication reconciliation process for patients who are at risk of adverse drug events. The authors hypothesized that a guided form could be used by non-admitted patients in the emergency department to assist with completion of a best possible medication history (BPMH). OBJECTIVE: To determine the percentage of patients in the non-acute care area of the emergency department who could complete a guided BPMH form with no clinically significant discrepancies (defined as no major discrepancies and no more than 1 moderate discrepancy). METHODS: This prospective exploratory study was conducted over 4 weeks in February and March 2016. Data were collected using the self-administered BPMH form, patient interviews, and a data collection form. After completion of the guided BPMH form, patients were randomly selected for interview by a pharmacy team member to ensure their self-completed BPMH forms were complete and accurate. Eligible patients were those with non-acute needs who had undergone triage to the waiting room. Patients who were already admitted and those with immediate triage to the acute care or trauma area of the emergency department were excluded. RESULTS: Of the 160 patients who were interviewed, 146 (91.3%) completed the form with no more than 1 moderate discrepancy (but some number of minor discrepancies). There were no discrepancies in 31 (19.4%) of the BPMH forms, and 101 (63.1%) of the forms had only minor discrepancies. CONCLUSIONS: Most of the patients interviewed by the pharmacy team were able to complete the BPMH form with no clinically significant discrepancies. The self-administered BPMH form would be a useful tool to initiate medication reconciliation in the emergency department for this patient population, but used on its own, it would not be a reliable source of BPMH information, given the relatively low number of patients who completed the form with no discrepancies. PMID- 28894311 TI - Pharmacy Student Facilitation of Reporting of Adverse Drug Reactions in a Hospital. AB - BACKGROUND: Health Canada relies on health professionals to voluntarily report adverse reactions to the Canada Vigilance Program. Current rates of reporting adverse drug reactions (ADRs) are inadequate to detect important safety issues. OBJECTIVE: To assess the impact of pharmacy student facilitation of ADR reporting by pharmacists at a tertiary care teaching hospital in Canada. METHODS: The intervention of interest, implemented at one campus of the hospital, was facilitation of ADR reporting by pharmacy students. The students received training on how to submit ADR reports and presented information sessions on the topic to hospital pharmacists; the pharmacists were then encouraged to report ADRs to a designated student for formal reporting. Frequency of reporting by pharmacists at the intervention campus was compared with reporting at a control campus of the same hospital. Data were collected prospectively over a 6-month pilot period, starting in April 2015. RESULTS: During the pilot period, 27 ADR reports were submitted at the intervention campus, and 3 reports at the control campus. All student participants strongly agreed that they would recommend that responsibility for submitting ADR reports to the Canada Vigilance Program remain with pharmacy students during future rotations. CONCLUSIONS: Availability of a pharmacy student to facilitate reporting of ADRs may increase the frequency of ADR reporting and could alleviate pharmacist workload; this activity is also a potentially valuable learning experience for students. PMID- 28894310 TI - Chemical Stability of Plerixafor after Opening of Single-Use Vial. AB - BACKGROUND: The addition of the immunostimulant plerixafor to the current standard-of-care regimens of granulocyte colony-stimulating growth factor with or without chemotherapy has improved clinical results in terms of successful stem cell mobilization and the outcomes of stem cell transplant in various settings. With this medical innovation has come an added financial cost for institutions where stem cell transplants are routinely performed, and there may be a further financial burden when the contents of partial vials of the drug are wasted, given that plerixafor vials (Mozobil, Sanofi-Aventis Canada Inc) are currently deemed suitable only for single use. OBJECTIVE: To determine whether the portion of plerixafor remaining in an opened vial of the Mozobil product after administration of a single dose is chemically stable, by comparison with the original product. METHODS: Stability testing of partial drug contents of an opened vial, stored at room temperature or under refrigeration (4 degrees C), was conducted using liquid chromatography-tandem mass spectrometry analysis. The mean concentration of plerixafor (MUmol/L), standard deviation, coefficient of variation, and bias were determined on days 2, 3, 11, 17, 24, and 31. Method validation included determination of precision, sensitivity, recovery, dilution linearity, and carryover. RESULTS: Throughout the 4-week testing period, measured plerixafor concentration in aliquots stored at room temperature and under refrigeration, tested in series over time, appeared similar. The mean residual drug concentration after initial opening was slightly, but not significantly, higher for the sample designated for storage at room temperature than the one designated for refrigerated storage (40.4 versus 39.9 MUmol/L; p = 0.37). CONCLUSIONS: Residual plerixafor after initial opening of a vial of the Mozobil product remained chemically stable for at least 2 weeks both at room temperature and under refrigeration. The results of this study provide in vitro evidence to support multiple uses, instead of single use, of vials of this drug in an aseptic, controlled environment. PMID- 28894312 TI - "There's No Touching in Pharmacy": Training Pharmacists for Australia's First Pharmacist Immunization Pilot. AB - BACKGROUND: Vaccination is a safe, efficient, and cost-effective means of preventing, controlling, and eradicating many life-threatening infections and diseases. Globally, the World Health Organization estimates that vaccination saves between 2 million and 3 million lives annually. However, low immunization rates are a significant public health concern. Individual factors, along with the vaccination process and system, have been reported as perceived barriers and challenges to immunization. Lack of time, on the part of both health care professionals and patients, has also been reported as a key factor influencing patterns of immunization. Despite the accessibility of pharmacists in community pharmacies in Australia, and initiatives by other countries to introduce pharmacist vaccination services, pharmacists in Australia had not previously delivered this service. The Queensland Pharmacist Immunisation Pilot (QPIP), initially implemented for the 2014 influenza season and later expanded, as QPIP2, to include other vaccines, allowed Australian pharmacists to vaccinate for the first time. OBJECTIVES: To develop, implement, and evaluate a training program for pharmacists undertaking vaccination services in community pharmacies in Australia. METHODS: Background content was developed and delivered through 2 online modules. Pharmacists were required to successfully answer a series of multiple-choice questions related to the background reading before attending a face-to-face workshop. The workshop provided practical training in injection skills and anaphylaxis management. Participants were also asked to evaluate the training program. RESULTS: Of the 339 pharmacists who completed the training program, 286 (84%) provided an evaluation. Participants were satisfied with the training, as indicated by consistently high scores on the "overall satisfaction" question (mean 4.65/5 for the QPIP and QPIP2 training combined). Participants described the background reading as relevant to their practice and stated that it met their expectations. They also valued the opportunity to practise injections on each other during the face-to-face workshop, and this aspect was noted as a key component of the training. CONCLUSIONS: QPIP demonstrated that a pharmacist specific training program could produce competent and confident immunizers and could be used to "retrofit" the profession, to facilitate delivery of vaccination services in Australia. PMID- 28894313 TI - Need for a Randomized Controlled Trial of Stress Ulcer Prophylaxis in Critically Ill Children: A Canadian Survey. AB - BACKGROUND: Stress ulcer prophylaxis is commonly used in pediatric critical care, to prevent upper gastrointestinal bleeding. The most frequently used agents are histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). The risk-benefit ratio for stress ulcer prophylaxis is uncertain, because data from randomized clinical trials (RCTs) on the effectiveness and harms of prophylaxis in children are limited. OBJECTIVE: To describe the views of Canadian pediatric intensivists about a future RCT of stress ulcer prophylaxis. METHODS: We conducted an online survey of Canadian pediatric critical care physicians. We e mailed information about the study and a link to a 10-item survey to 111 potential respondents, with 2 reminders for nonrespondents. We assessed the relationship between respondents' characteristics and their views about the need for and potential participation in a trial using logistic regression and assessed regional differences using the chi2 test. RESULTS: The 68 physicians who replied (61% of potential respondents) had a median of 12 (interquartile range 5-20) years of experience. Forty-four (65%) of the respondents stated that a large, rigorous RCT of stress ulcer prophylaxis in children is needed, and 94% (62 of 66) indicated that it should include a placebo group. The 3 most common designs suggested were a 3-arm trial comparing PPI, H2RA, and placebo (56% [37 of 66 respondents to this question]) and 2-arm trials comparing PPI with placebo (15% [n = 10]) and H2RA with placebo (8% [n = 5]). The 5 patient groups that respondents most commonly stated should be excluded (because they should not receive placebo) were children receiving acid suppression at home (66% [42 of 64 respondents to this question]) or corticosteroids (59% [n = 38]), those with severe coagulopathy or receiving extracorporeal membrane oxygenation (both 36% [n = 23]), and those with burns (31% [n = 20]). Most respondents indicated a willingness to participate in an RCT (64% [42 of 66 respondents to this question]), whereas some (29% [n = 19]) indicated that participation would depend on trial design or funding; only 8% (n = 5) were disinclined to participate. CONCLUSIONS: There is considerable interest in a placebo-controlled RCT of stress ulcer prophylaxis among pediatric critical care physicians in Canada, but consensus on key elements of the trial design is needed. PMID- 28894314 TI - Home Care Pharmacy Practice in Canada: A Cross-Sectional Survey of Services Provided, Remuneration, Barriers, and Facilitators. AB - BACKGROUND: As the population ages, and individuals desire to remain in their homes as long as possible, the need for in-home care is expected to increase. However, pharmacists have rarely been included in studies of in-home care, and little is known about the prevalence or effectiveness of pharmacists' home-based services in Canada. OBJECTIVE: To identify pharmacy practices in Canada that regularly provide in-home patient care and to identify specific services provided, remuneration obtained, and barriers and facilitators influencing the provision of home-based care. METHODS: A link to a web-based survey was posted in e-newsletters of provincial, territorial, and national pharmacy associations in Canada. In addition, pharmacists known to the researchers as providing in-home clinical services were contacted directly. The survey was open from October to December 2015. Practices or organizations that performed at least one home visit per week for clinical purposes, with documentation of the services provided, were eligible to participate. One response per practice or organization was allowed. RESULTS: Seventeen practices meeting the inclusion criteria were identified, representing community, hospital, and clinic settings. Home visits were most commonly performed for individuals with complex medication regimens or nonadherence to medication therapy. The most common services were conducting medication reconciliation and reviews and counselling patients about medication adherence. No practices or organizations billed patients for these services, yet lack of remuneration was an important barrier identified by many respondents. Although 12 (71%) of the respondents collected data for evaluative purposes, collection of clinical or health system outcome data was rare. CONCLUSIONS: Few Canadian pharmacy practices that provide in-home patient care at least once a week could be identified. Data collection suitable to establish an evidence base for this service was infrequently performed by practices and organizations providing home-based care. Such evidence is needed to justify the expansion of this service nationally, including consistent and adequate remuneration from governments or other payers. PMID- 28894315 TI - Rivaroxaban-Induced Hypersensitivity Syndrome. PMID- 28894316 TI - Erratum: Should Patients Continue to Receive Statins Once They Reach 80 Years of Age? The "Con" Side: Correction. AB - [This corrects the article on p. 244 in vol. 70.]. PMID- 28894317 TI - Pharmacist Performance of Physical Assessment: Perspectives of Clinical Pharmacists Working in Different Practice Settings. PMID- 28894318 TI - Roles of Hospital and Territorial Pharmacists within the Italian National Healthcare Service. PMID- 28894319 TI - Should We Continue to Use Stress Ulcer Prophylaxis for Critically Ill Patients? PMID- 28894320 TI - Effect of Tubing Flush or Preconditioning on Available Insulin Concentration for IV Infusion: A Pilot Project. PMID- 28894321 TI - Patient-Centred Care through Storytelling. PMID- 28894322 TI - Implications of Changes to the Mefloquine Product Monograph. PMID- 28894323 TI - ? PMID- 28894324 TI - The Past, the Present, and a Very Bright Future. PMID- 28894325 TI - Special Section on Structure Ignition in Wildland-Urban Interface (WUI) Fires. PMID- 28894326 TI - Calcite dissolution rate spectra measured by in situ digital holographic microscopy. AB - Digital holographic microscopy in reflection mode is used to track in situ, real time nanoscale topography evolution of cleaved (104) calcite surfaces exposed to flowing or static deionized water. The method captures full-field holograms of the surface at frame rates of up to 12.5 s-1. Numerical reconstruction provides 3D surface topography with vertical resolution of a few nanometers and enables measurement of time-dependent local dissolution fluxes. A statistical distribution, or spectrum, of dissolution rates is generated by sampling multiple area domains on multiple crystals. The data show, as has been demonstrated by Fischer et al. (2012), that dissolution is most fully described by a rate spectrum, although the modal dissolution rate agrees well with published mean dissolution rates (e.g., 0.1 umol m-2 s-1 to 0.3 umol m-2 s-1). Rhombohedral etch pits and other morphological features resulting from rapid local dissolution appear at different times and are heterogeneously distributed across the surface and through the depth. This makes the distribution in rates measured on a single crystal dependent both on the sample observation field size and on time, even at nominally constant undersaturation. Statistical analysis of the inherent noise in the DHM measurements indicates that the technique is robust and that it likely can be applied to quantify and interpret rate spectra for the dissolution or growth of other minerals. PMID- 28894327 TI - Detection of distant metastases in patients with locally advanced breast cancer: role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography and conventional imaging with computed tomography scans. AB - OBJECTIVE: To evaluate positron emission tomography/computed tomography (PET/CT) and conventional imaging tests for the detection of distant metastases in patients with locally advanced breast cancer. MATERIALS AND METHODS: We included 81 patients with breast cancer who had undergone 18F-fluorodeoxyglucose (FDG) PET/CT before treatment. Conventional imaging included the following: bone scintigraphy; chest X-ray (in 14.5%) or CT (in 85.5%); and abdominal ultrasound (in 10.8%), CT (in 87.8%), or magnetic resonance imaging (in 1.4%). Histopathology and clinical/imaging follow-up served as reference. RESULTS: Distant metastases were observed in nine patients (11.1%). On patient-based analysis, conventional imaging identified distant metastases in all 9 patients. In one patient, the initial 18F-FDG PET/CT failed to demonstrate bone metastases that was evident on bone scintigraphy. In two patients, the CT scan failed to show extra-axillary lymph node metastases that were identified on 18F-FDG PET/CT. There was no significant difference between 18F-FDG PET/CT and conventional imaging in terms of their sensitivity for the detection of distant metastases in patients with locally advanced breast cancer. CONCLUSION: This study showed that 18F-FDG PET/CT and conventional imaging with CT scans had similar sensitivity for the diagnosis of distant metastases in patients with locally advanced breast cancer. 18F-FDG PET/CT can add information about extra-axillary lymph node involvements. PMID- 28894328 TI - Comparison of Cartesian and radial acquisition on short-tau inversion recovery (STIR) sequences in breast MRI. AB - OBJECTIVE: The purpose of this study was to compare two short-tau inversion recovery (STIR) sequences, Cartesian and radial (BLADE) acquisitions, for breast magnetic resonance imaging (MRI) examinations. MATERIALS AND METHODS: Ninety-six women underwent 1.5 T breast MRI exam (48 Cartesian and 48 BLADE). Qualitative analysis including image artifacts, image quality, fat-suppression, chest-wall depiction, lesion detection, lymph node depiction and overall impression were evaluated by three blinded readers. Signal to noise ratios (SNRs) were calculated. Cronbach's alpha test was used to assess inter-observer agreement. Subanalyses of image quality, chest-wall depiction and overall impression in 15 patients with implants and image quality in 31 patients with clips were correlated using Pearson test. Wilcoxon rank sum test and t-test were performed. RESULTS: Motion artifacts were present in 100% and in 0% of the Cartesian and the BLADE exams, respectively. Chemical-shift artifacts were present in 8% of the Cartesian exams. Flow artifacts were more frequent on BLADE. BLADE sequence was statistically superior to Cartesian for all qualitative features (p < 0.05) except for fat-suppression (p = 0.054). In the subanalysis, BLADE was superior for implants and clips (p < 0.05). SNR was statistically greater for BLADE (48.35 vs. 16.17). Cronbach ranged from 0.502 to 0.813. CONCLUSION: BLADE appears to be superior to Cartesian acquisition of STIR imaging as measured by improved image quality, fewer artifacts, and improved chest wall and lymph node depiction. PMID- 28894329 TI - Accuracy of contrast-enhanced spectral mammography for estimating residual tumor size after neoadjuvant chemotherapy in patients with breast cancer: a feasibility study. AB - OBJECTIVE: To assess the feasibility of contrast-enhanced spectral mammography (CESM) of the breast for assessing the size of residual tumors after neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: In breast cancer patients who underwent NAC between 2011 and 2013, we evaluated residual tumor measurements obtained with CESM and full-field digital mammography (FFDM). We determined the concordance between the methods, as well as their level of agreement with the pathology. Three radiologists analyzed eight CESM and FFDM measurements separately, considering the size of the residual tumor at its largest diameter and correlating it with that determined in the pathological analysis. Interobserver agreement was also evaluated. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value were higher for CESM than for FFDM (83.33%, 100%, 100%, and 66% vs. 50%, 50%, 50%, and 25%, respectively). The CESM measurements showed a strong, consistent correlation with the pathological findings (correlation coefficient = 0.76-0.92; intraclass correlation coefficient = 0.692-0.886). The correlation between the FFDM measurements and the pathological findings was not statistically significant, with questionable consistency (intraclass correlation coefficient = 0.488-0.598). Agreement with the pathological findings was narrower for CESM measurements than for FFDM measurements. Interobserver agreement was higher for CESM than for FFDM (0.94 vs. 0.88). CONCLUSION: CESM is a feasible means of evaluating residual tumor size after NAC, showing a good correlation and good agreement with pathological findings. For CESM measurements, the interobserver agreement was excellent. PMID- 28894330 TI - Metastatic pulmonary calcification: high-resolution computed tomography findings in 23 cases. AB - OBJECTIVE: The aim of this study was to evaluate the high-resolution computed tomography (HRCT) findings in patients diagnosed with metastatic pulmonary calcification (MPC). MATERIALS AND METHODS: We retrospectively reviewed the HRCT findings from 23 cases of MPC [14 men, 9 women; mean age, 54.3 (range, 26-89) years]. The patients were examined between 2000 and 2014 in nine tertiary hospitals in Brazil, Chile, and Canada. Diagnoses were established by histopathologic study in 18 patients and clinical-radiological correlation in 5 patients. Two chest radiologists analyzed the images and reached decisions by consensus. RESULTS: The predominant HRCT findings were centrilobular ground-glass nodules (n = 14; 60.9%), consolidation with high attenuation (n = 10; 43.5%), small dense nodules (n = 9; 39.1%), peripheral reticular opacities associated with small calcified nodules (n = 5; 21.7%), and ground-glass opacities without centrilobular ground-glass nodular opacity (n = 5; 21.7%). Vascular calcification within the chest wall was found in four cases and pleural effusion was observed in five cases. The abnormalities were bilateral in 21 cases. CONCLUSION: MPC manifested with three main patterns on HRCT, most commonly centrilobular ground glass nodules, often containing calcifications, followed by dense consolidation and small solid nodules, most of which were calcified. We also described another pattern of peripheral reticular opacities associated with small calcified nodules. These findings should suggest the diagnosis of MPC in the setting of hypercalcemia. PMID- 28894331 TI - Influence of bladder fullness on the detection of urinary tract obstruction by dynamic renal scintigraphy. AB - OBJECTIVE: To investigate the influence of bladder fullness on the diagnosis of urinary tract obstruction during dynamic renal scintigraphy with a diuretic stimulator. MATERIALS AND METHODS: We studied 82 kidneys in 82 patients submitted to dynamic renal scintigraphy with a diuretic stimulator. We compared the proportional elimination of the radiopharmaceutical 99mTc-DTPA from the kidneys before and after bladder emptying in post-diuretic images, classifying each image as representing an obstructed, indeterminate, or unobstructed kidney. RESULTS: The overall elimination of 99mTc-DTPA from the kidneys was 10.4% greater after bladder emptying than before. When the analysis was performed with a full bladder, we classified 40 kidneys as obstructed, 16 as indeterminate, and 26 as unobstructed. When the 40 kidneys classified as obstructed were analyzed after voiding, 11 were reclassified as indeterminate and 3 were reclassified as unobstructed. Of the 16 kidneys classified as indeterminate on the full-bladder images, 13 were reclassified as unobstructed after voiding. CONCLUSION: In dynamic renal scintigraphy with a diuretic stimulator, it is important to obtain images after voiding, in order to perform a reliable analysis of the proportional excretion of 99mTc-DTPA from the kidneys, avoiding possible false-positive results for urinary tract obstruction. PMID- 28894332 TI - Breast cancer screening: updated recommendations of the Brazilian College of Radiology and Diagnostic Imaging, Brazilian Breast Disease Society, and Brazilian Federation of Gynecological and Obstetrical Associations. AB - OBJECTIVE: To present the current recommendations for breast cancer screening in Brazil, as devised by the Brazilian College of Radiology and Diagnostic Imaging, the Brazilian Breast Disease Society, and the Brazilian Federation of Gynecological and Obstetrical Associations. MATERIALS AND METHODS: We analyzed scientific studies available in the Medline and Lilacs databases. In the absence of evidence, the recommendations reflected the consensus of a panel of experts. RECOMMENDATIONS: Annual mammography screening is recommended for women 40-74 years of age. Among women >= 75 years of age, annual mammography screening should be reserved for those with an expected survival > 7 years. Complementary ultrasound should be considered for women with dense breasts. Complementary magnetic resonance imaging is recommended for women at high risk. When available, an advanced form of mammography known as tomosynthesis can be considered as a means of screening for breast cancer. PMID- 28894334 TI - Spondyloarthropathy: diagnostic imaging criteria for the detection of sacroiliitis. AB - Diagnostic imaging is crucial to the diagnosis and monitoring of spondyloarthropathies. Magnetic resonance imaging is the most relevant tool for the early detection of sacroiliitis, allowing the institution of therapeutic strategies to impede the progression of the disease. This study illustrates the major criteria for a magnetic resonance imaging-based diagnosis of spondyloarthropathy. The cases selected here present images obtained from the medical records of patients diagnosed with sacroiliitis over a two-year period at our facility, depicting the active and chronic, irreversible forms of the disease. Although computed tomography and conventional radiography can also identify structural changes, such as subchondral sclerosis, erosions, fat deposits, and ankylosis, only magnetic resonance imaging can reveal active inflammatory lesions, such as bone edema, osteitis, synovitis, enthesitis, and capsulitis. PMID- 28894333 TI - The role of diffusion magnetic resonance imaging in Parkinson's disease and in the differential diagnosis with atypical parkinsonism. AB - Parkinson's disease is one of the most common neurodegenerative diseases. Clinically, it is characterized by motor symptoms. Parkinson's disease should be differentiated from atypical parkinsonism conditions. Conventional magnetic resonance imaging is the primary imaging method employed in order to facilitate the differential diagnosis, and its role has grown after the development of advanced techniques such as diffusion-weighted imaging. The purpose of this article was to review the role of magnetic resonance imaging in Parkinson's disease and in the differential diagnosis with atypical parkinsonism, emphasizing the diffusion technique. PMID- 28894335 TI - Primary osteosarcoma of the cranial vault. AB - Only 5-10% of osteosarcomas arise from the craniofacial bones. We report the case of a 14-year-old female patient who presented with headache and a mass that had been growing in the left frontoparietal region for six months. We describe the findings on conventional radiography, computed tomography, and magnetic resonance imaging. PMID- 28894336 TI - Sliding inguinoscrotal hernia insinuating itself into the bladder, with calculi in the bladder and distal ureter. PMID- 28894337 TI - Primary tracheobronchial amyloidosis. PMID- 28894338 TI - Xanthogranulomatous cystitis in a child. PMID- 28894339 TI - Giant cyamella: a rare sesamoid bone. PMID- 28894340 TI - Hemangioma of the urinary bladder: an atypical location. PMID- 28894341 TI - Subconjunctival fat prolapse: a disease little known to radiologists. PMID- 28894342 TI - Ogilvie syndrome after use of vincristine: tomographic findings. PMID- 28894343 TI - Pontine tegmental cap dysplasia accompanied by a duplicated internal auditory canal. PMID- 28894344 TI - Neurography - a new look at the peripheral nervous system. PMID- 28894345 TI - Parkinson's disease and atypical parkinsonism: the importance of magnetic resonance imaging as a potential biomarker. PMID- 28894346 TI - High-resolution computed tomography findings in hantavirus pulmonary syndrome. PMID- 28894347 TI - Solid tumors are poroelastic solids with a chemo-mechanical feedback on growth. AB - The experimental evidence that a feedback exists between growth and stress in tumors poses challenging questions. First, the rheological properties (the "constitutive equations") of aggregates of malignant cells are still a matter of debate. Secondly, the feedback law (the "growth law") that relates stress and mitotic-apoptotic rate is far to be identified. We address these questions on the basis of a theoretical analysis of in vitro and in vivo experiments that involve the growth of tumor spheroids. We show that solid tumors exhibit several mechanical features of a poroelastic material, where the cellular component behaves like an elastic solid. When the solid component of the spheroid is loaded at the boundary, the cellular aggregate grows up to an asymptotic volume that depends on the exerted compression. Residual stress shows up when solid tumors are radially cut, highlighting a peculiar tensional pattern. By a novel numerical approach we correlate the measured opening angle and the underlying residual stress in a sphere. The features of the mechanobiological system can be explained in terms of a feedback of mechanics on the cell proliferation rate as modulated by the availability of nutrient, that is radially damped by the balance between diffusion and consumption. The volumetric growth profiles and the pattern of residual stress can be theoretically reproduced assuming a dependence of the target stress on the concentration of nutrient which is specific of the malignant tissue. PMID- 28894348 TI - Laser-Driven Calorimetry of Single-Component Liquid Hydrocarbons. AB - A novel laser-heating technique, referred to as the laser-driven thermal reactor (LDTR), was used to determine sample thermal (exothermic/endothermic) behavior, specific heat release rate, and total specific heat release of three volatile single-component liquid hydrocarbons, i.e., n-decane, n-butylcyclohexane and n butylbenzene. The objective was to demonstrate measurement repeatability and extend the LDTR model from earlier investigations. The experimental apparatus consists of a copper sphere-shaped reactor mounted within a vacuum chamber, with sample and substrate supported on a thermocouple near the center of the reactor. The reactor is heated from opposing sides by a near-infrared laser to achieve nearly uniform sample temperature. The change in temperature with time (i.e., thermogram) is compared to a previously recorded baseline (no liquid sample) thermogram. A model, based on thermal energy conservation, is used to evaluate the thermograms for the thermochemical characteristics of interest. This study represents a step toward applying this technique to more complex volatile multi component fuels of unspecified composition. Results for the LDTR were compared with a differential scanning calorimetry/thermal gravimetric analysis (DSC/TGA) instrument. The model analysis was extended to include an estimation of the hydrocarbon mass change with increasing temperature, based on the temporal change in the specific heat release rate. An estimate of the total specific heat release was obtained for these three liquid hydrocarbons and found to be consistent with the literature values when the measurements were carried out under suitable operating conditions. PMID- 28894349 TI - EPR Line Shifts and Line Shape Changes Due to Spin Exchange Between Nitroxide Free Radicals in Liquids 10. Spin-Exchange Frequencies of the Order of the Nitrogen Hyperfine Interaction: A Hypothesis. AB - The behavior of Electron paramagnetic resonance spectra due to 15N and 14N nitroxide free radicals undergoing spin exchange in liquids at high frequencies omegaex , of the same order of magnitude as the nitrogen hyperfine coupling constant A0 is investigated. The well known features are reconfirmed: (1) at low values of omegaex where the lines broaden, shift toward the center of the spectrum, and change shape due to the introduction of a resonance of the form of a dispersion component; (2) at values of omegaex comparable to A0, the line merge into one; and (3) at values much larger than A0, the merged line narrows. It is found that each line of a spectrum may be decomposed into an admixture of a single absorption and a single dispersion component of Lorentzian shape. These two- or three-line absorption-dispersion admixtures, for 15N and 14N, respectively, retain their individual identities even after the spectrum has merged and has begun to narrow. For both isotopes, the average broadening and integrated intensities are equal to the predictions of perturbation theory although, in the case of 14N the outer lines broaden faster than the central line and intensity moves from the outer lines to the center line. In fact, the outer line intensity becomes zero and then negative at higher values of omegaex which is compensated by the center line becoming more intense than the overall integrated intensity. For both isotopes, the dispersion components and the line shift depart from the perturbation prediction. The results are presented in terms of measurable quantities normalized to A0 so that they may be applied to any two- or three-line spectrum. PMID- 28894351 TI - Prediction of Epileptic Seizure by Analysing Time Series EEG Signal Using k-NN Classifier. AB - Electroencephalographic signal is a representative signal that contains information about brain activity, which is used for the detection of epilepsy since epileptic seizures are caused by a disturbance in the electrophysiological activity of the brain. The prediction of epileptic seizure usually requires a detailed and experienced analysis of EEG. In this paper, we have introduced a statistical analysis of EEG signal that is capable of recognizing epileptic seizure with a high degree of accuracy and helps to provide automatic detection of epileptic seizure for different ages of epilepsy. To accomplish the target research, we extract various epileptic features namely approximate entropy (ApEn), standard deviation (SD), standard error (SE), modified mean absolute value (MMAV), roll-off (R), and zero crossing (ZC) from the epileptic signal. The k-nearest neighbours (k-NN) algorithm is used for the classification of epilepsy then regression analysis is used for the prediction of the epilepsy level at different ages of the patients. Using the statistical parameters and regression analysis, a prototype mathematical model is proposed which helps to find the epileptic randomness with respect to the age of different subjects. The accuracy of this prototype equation depends on proper analysis of the dynamic information from the epileptic EEG. PMID- 28894350 TI - Short-Term Regulation of FcgammaR-Mediated Phagocytosis by TLRs in Macrophages: Participation of 5-Lipoxygenase Products. AB - TLRs recognize a broad spectrum of microorganism molecules, triggering a variety of cellular responses. Among them, phagocytosis is a critical process for host defense. Leukotrienes (LTs), lipid mediators produced from 5-lipoxygenase (5-LO) enzyme, increase FcgammaR-mediated phagocytosis. Here, we evaluated the participation of TLR2, TLR3, TLR4, and TLR9 in FcgammaR-mediated phagocytosis and whether this process is modulated by LTs. Rat alveolar macrophages (AMs), murine bone marrow-derived macrophages (BMDMs), and peritoneal macrophages (PMs) treated with TLR2, TLR3, and TLR4 agonists, but not TLR9, enhanced IgG-opsonized sheep red blood cell (IgG-sRBC) phagocytosis. Pretreatment of AMs or BMDMs with drugs that block LT synthesis impaired the phagocytosis promoted by TLR ligands, and TLR potentiation was also abrogated in PMs and BMDMs from 5-LO-/- mice. LTB4 production induced by IgG engagement was amplified by TLR ligands, while cys-LTs were amplified by activation of TLR2 and TLR4, but not by TLR3. We also noted higher ERK1/2 phosphorylation in IgG-RBC-challenged cells when preincubated with TLR agonists. Furthermore, ERK1/2 inhibition by PD98059 reduced the phagocytic activity evoked by TLR agonists. Together, these data indicate that TLR2, TLR3, and TLR4 ligands, but not TLR9, amplify IgG-mediated phagocytosis by a mechanism which requires LT production and ERK-1/2 pathway activation. PMID- 28894352 TI - Hierarchical Association Coefficient Algorithm: New Method for Genome-Wide Association Study. AB - Hierarchical association coefficient algorithm calculates the degree of association between observations and categories into a value named hierarchical association coefficient (HA-coefficient) between 0 for the lower limit and 1 for the upper limit. The HA-coefficient algorithm can be operated with stratified ascending categories based on the average of observations in each category. The upper limit refers to a condition where observations are increasingly ordered into the stratified ascending categories, whereas the lower limit refers to a condition where observations are decreasingly ordered into the stratified ascending categories. An HA-coefficient represents how close an observed categorization is to the upper limit, or how distant an observed categorization is from the lower limit. To demonstrate robustness and reliability, the HA coefficient algorithm was applied to 3 different simulated data sets with the same pattern in terms of the association between observations and categories. From all simulated data sets, the same result was obtained, indicating that the HA-coefficient algorithm is robust and reliable. PMID- 28894353 TI - Optimized Next-Generation Sequencing Genotype-Haplotype Calling for Genome Variability Analysis. AB - The accurate estimation of nucleotide variability using next-generation sequencing data is challenged by the high number of sequencing errors produced by new sequencing technologies, especially for nonmodel species, where reference sequences may not be available and the read depth may be low due to limited budgets. The most popular single-nucleotide polymorphism (SNP) callers are designed to obtain a high SNP recovery and low false discovery rate but are not designed to account appropriately the frequency of the variants. Instead, algorithms designed to account for the frequency of SNPs give precise results for estimating the levels and the patterns of variability. These algorithms are focused on the unbiased estimation of the variability and not on the high recovery of SNPs. Here, we implemented a fast and optimized parallel algorithm that includes the method developed by Roesti et al and Lynch, which estimates the genotype of each individual at each site, considering the possibility to call both bases from the genotype, a single one or none. This algorithm does not consider the reference and therefore is independent of biases related to the reference nucleotide specified. The pipeline starts from a BAM file converted to pileup or mpileup format and the software outputs a FASTA file. The new program not only reduces the running times but also, given the improved use of resources, it allows its usage with smaller computers and large parallel computers, expanding its benefits to a wider range of researchers. The output file can be analyzed using software for population genetics analysis, such as the R library PopGenome, the software VariScan, and the program mstatspop for analysis considering positions with missing data. PMID- 28894354 TI - Switching to preservative-free latanoprost: impact on tolerability and patient satisfaction. PMID- 28894355 TI - Erratum: Intravitreal aflibercept for choroidal neovascularization associated with chorioretinitis: a pilot study [Corrigendum]. AB - [This corrects the article on p. 1315 in vol. 11, PMID: 28769551.]. PMID- 28894356 TI - Refractive lens exchange in younger and older presbyopes: comparison of complication rates, 3 months clinical and patient-reported outcomes. AB - PURPOSE: To compare refractive and visual outcomes, patient satisfaction, and complication rates among different age categories of patients who underwent refractive lens exchange (RLE). METHODS: A stratified, simple random sample of patients matched on preoperative sphere and cylinder was selected for four age categories: 45-49 years (group A), 50-54 years (group B), 55-59 years (group C), and 60-65 years (group D). Each group contained 320 patients. All patients underwent RLE with a multifocal intraocular lens at least in one eye. Three months postoperative refractive/visual and patient-reported outcomes are presented. RESULTS: The percentage of patients that achieved binocular uncorrected distance visual acuity 20/20 or better was 91.6% (group A), 93.8% (group B), 91.6% (group C), 88.8% (group D), P=0.16. Binocularly, 80.0% of patients in group A, 84.7% in group B, 78.9% in group C, and 77.8% in group D achieved 20/30 or better uncorrected near visual acuity (P=0.13). The proportion of eyes within 0.50 D of emmetropia was 84.4% in group A, 86.8% in group B, 85.7% in group C, and 85.8% in group D (P=0.67). There was no statistically significant difference in postoperative satisfaction, visual phenomena, dry eye symptoms, distance or near vision activities. Apart from higher rate of iritis in the age group 50-55 years, there was no statistically significant difference in postoperative complication rates. CONCLUSION: RLE can be safely performed in younger as well as older presbyopes. No significant difference was found in clinical or patient-reported outcomes. PMID- 28894358 TI - Therapy with pamidronate in children with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a genetic disease characterized by excessive bone fragility with fractures consecutive to minor trauma. Considering lack of standardization of therapy with pamidronate in children, it was our aim to present our experience over a period of 10 years regarding evolution and treatment in patients diagnosed with osteoporosis and OI. Nine patients diagnosed with OI were admitted to the First Pediatric Clinic, Timisoara. They were investigated (clinical, biomarkers of bone metabolism and imaging studies), and a quality-of-life questionnaire was used to evaluate the impact of OI. Treatment was performed with pamidronate 1 mg/kg/cycle, every 3 months. The patients were evaluated every 3 months. The most frequent was type III (three patients), and two patients were diagnosed with type II, while the other patients were diagnosed with other forms such as types IV, V, VI and VIII. The clinical expression was polymorphic, and the number of fractures was variable. Bone pain ameliorated just after the first cycle of pamidronate, while the activity and mobility increased quickly. Osteodensitometry in children over 12 years showed a decreased bone mineral density (BMD) with a significant improvement after treatment. The values of the bone alkaline phosphatase and osteocalcin changed after the antiresorptive treatment, and the quality of life of the children and their family improved. Treatment with pamidronate is beneficial for the patient, family and society, increases mobility and bone density, improves quality of life and reduces family dependence in children with OI. PMID- 28894357 TI - Advances in the delivery of buprenorphine for opioid dependence. AB - Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but MU-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a MU-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD. PMID- 28894359 TI - Analysis of the dynamics of venous blood flow in the context of lower limb temperature distribution and tissue composition in the elderly. AB - OBJECTIVE: The elderly are particularly vulnerable to degenerative diseases, such as circulatory and respiratory system and vascular system diseases. The objective of this study was therefore to evaluate the distribution of temperature and the dynamics of venous blood flow in the lower limbs (LLs) and to assess the interdependence of these parameters in terms of the somatic components in males and females participating in activities at the University of the Third Age. MATERIALS AND METHODS: The study included 60 females (mean age 67.4 years) and 40 males (mean age 67.5 years). A body composition assessment was performed using the bioimpedance technique - Tanita BC-418MA. The following parameters were examined: fat%, fat mass, fat-free mass, and total body water. The minimal, maximal, and mean temperature values and their distributions were examined using infrared thermographic camera VarioCAM Head. Measurements of the venous refilling time and the work of the LL venous pump were examined using a Rheo Dopplex II PPG. RESULTS: In males, the mean value of the right LL temperature was 30.58 and the mean value of the left LL was 30.28; the P-value was 0.805769. In females, the mean value of the right LL temperature was 29.58 and the mean value of the left limb was 29.52; the P-value was 0.864773. In males, the right limb blood flow was 34.17 and the left limb blood flow was 34.67; the P-value was 0.359137. In females, the right limb blood flow was 26.89 and the left limb blood flow was 26.09; the P-value was 0.796348. CONCLUSION: Research results showed that the temperature distribution and the dynamics of blood flow are not significantly different between the right and left extremities in both males and females. However, significant temperature differences were found between the gender groups. Significantly higher temperature values in both the right and left extremities were recorded in males than in females. PMID- 28894360 TI - The evaluation of beta-adrenoceptor blocking agents in patients with COPD and congestive heart failure: a nationwide study. AB - OBJECTIVE: beta-Blockers are safe and improve survival in patients with both congestive heart failure (CHF) and COPD. However, the superiority of different types of beta-blockers is still unclear among patients with CHF and COPD. The association between beta-blockers and CHF exacerbation as well as COPD exacerbation remains unclear. The objective of this study was to compare the outcome of different beta-blockers in patients with concurrent CHF and COPD. PATIENTS AND METHODS: We used the National Health Insurance Research Database in Taiwan to conduct a retrospective cohort study. The inclusion criteria for CHF were patients who were >20 years old and were diagnosed with CHF between January 1, 2005 and December 31, 2012. COPD patients included those who had outpatient visit claims >=2 times within 365 days or 1 claim for hospitalization with a COPD diagnosis. A time-dependent Cox proportional hazards regression model was applied to evaluate the effectiveness of beta-blockers in the study population. RESULTS: We identified 1,872 patients with concurrent CHF and COPD. Only high-dose bisoprolol significantly reduced the risk of death and slightly decreased the hospitalization rate due to CHF exacerbation (death: adjusted hazard ratio [aHR] =0.51, 95% confidence interval [CI] =0.29-0.89; hospitalization rate due to CHF exacerbation: aHR =0.48, 95% CI =0.23-1.00). No association was observed between beta-blocker use and COPD exacerbation. CONCLUSION: In patients with concurrent CHF and COPD, beta-blockers reduced mortality, CHF exacerbation, and the need for hospitalization. Bisoprolol was found to reduce mortality and CHF exacerbation compared to carvedilol and metoprolol. PMID- 28894362 TI - Erratum: Gentamicin coating of nanotubular anodized titanium implant reduces implant-related osteomyelitis and enhances bone biocompatibility in rabbits [Corrigendum]. AB - [This corrects the article on p. 5461 in vol. 12, PMID: 28814863.]. PMID- 28894361 TI - Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: a pilot trial. AB - BACKGROUND: Although vitamin D is well known for its function in calcium homeostasis and bone mineralization, several studies have shown positive effects on muscle strength and physical function. In addition, vitamin D has been associated with pulmonary function and the incidence of airway infections. As vitamin D deficiency is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, supplementation might have a beneficial effect in these patients. OBJECTIVE: To assess the effect of vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients. Secondary outcomes are pulmonary function, handgrip strength, exacerbation rate, and quality of life. METHODS: We performed a randomized, double-blind, placebo-controlled pilot trial. Participants were randomly allocated to receive 1,200 IU vitamin D3 per day (n=24) or placebo (n=26) during 6 months. Study visits were conducted at baseline, and at 3 and 6 months after randomization. During the visits, blood was collected, respiratory muscle strength was measured (maximum inspiratory and expiratory pressure), physical performance and 6-minute walking tests were performed, and handgrip strength and pulmonary function were assessed. In addition, participants kept a diary card in which they registered respiratory symptoms. RESULTS: At baseline, the mean (standard deviation [SD]) serum 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) was 42.3 (15.2) in the vitamin D group and 40.6 (17.0) in the placebo group. Participants with vitamin D supplementation had a larger increase in serum 25(OH)D compared to the placebo group after 6 months (mean difference (SD): +52.8 (29.8) vs +12.3 (25.1), P<0.001). Primary outcomes, respiratory muscle strength and physical performance, did not differ between the groups after 6 months. In addition, no differences were found in the 6-minute walking test results, handgrip strength, pulmonary function, exacerbation rate, or quality of life. CONCLUSION: Vitamin D supplementation did not affect (respiratory) muscle strength or physical performance in this pilot trial in vitamin D-deficient COPD patients. PMID- 28894363 TI - Ketoprofen-loaded polymer carriers in bigel formulation: an approach to enhancing drug photostability in topical application forms. AB - The purpose of the study was to investigate the stability and biopharmaceutical characteristics of ketoprofen, loaded in polymeric carriers, which were included into a bigel in a semisolid dosage form. The polymer carriers with in situ included ketoprofen were obtained by emulsifier-free emulsion polymerization of the monomers in aqueous medium or a solution of the polymers used. The morphological characteristics of the carriers, the in vitro release and the photochemical stability of ketoprofen were evaluated. The model with optimal characteristics was included in a bigel formulation. The bigel was characterized in terms of pH, rheological behavior, spreadability, and in vitro drug release. Acute skin toxicity, antinociceptive activity, anti-inflammatory activity, and antihyperalgesic effects of the prepared bigel with ketoprofen-loaded polymer carrier were evaluated. The carriers of ketoprofen were characterized by a high yield and drug loading. The particle size distribution varied widely according to the polymer used, and a sustained release was provided for up to 6 hours. The polymer mixture poly(vinyl acetate) and hydroxypropyl cellulose as a drug carrier, alone or included in the bigel composition, improved the photostability of the drug compared with unprotected ketoprofen. The bigel with ketoprofen loaded particles provided sustained release of the drug and had optimal rheological parameters. In vivo experiments on the bigel showed no skin inflammation or irritation. Four hours after its application, a well-defined analgesic, anti-inflammatory, and antihyperalgesic effect was registered. The polymer mixture of poly(vinyl acetate) and hydroxypropyl cellulose as a carrier of ketoprofen and the bigel in which it was included provided an enhanced photostability and sustained drug release. PMID- 28894364 TI - EpCAM aptamer-functionalized polydopamine-coated mesoporous silica nanoparticles loaded with DM1 for targeted therapy in colorectal cancer. AB - DM1, a maytansine derivative, is a highly potential cytotoxic agent but with severe side effects; therefore, its application in clinical cancer therapy is limited. Here, in order to mitigate this intrinsic drawback of DM1, we developed mesoporous silica nanoparticles (MSNs) loaded with DM1 and surface-decorated with hydrochloride dopamine (PDA), polyethylene glycol (PEG), and epithelial cell adhesion molecule (EpCAM) aptamer (APt) for the targeted treatment of colorectal cancer (CRC). In this system, the PDA coating could be used as pH-sensitive gatekeepers to control the release of DM1 from MSNs in response to the pH stimulus and EpCAM APt-guided active targeting enables the increased delivery of DM1 to CRC as well as a reduction in toxicity and side effects by minimizing the exposure of normal tissues to DM1. Results demonstrated that DM1 inhibited the formation of microtubules and induced apoptosis in tumor cells via caspase signaling. In comparison with the control groups, the MSNs-DM1@PDA-PEG-APt bioconjugates exhibited increased binding ability and much higher cytotoxicity to the CRC SW480 cell line. Furthermore, in vivo assays confirmed the advantages of such a strategy. These findings suggested that MSNs-DM1@PDA-PEG-APt could represent a promising therapeutic platform for EpCAM-positive CRC. PMID- 28894366 TI - Effective heating of magnetic nanoparticle aggregates for in vivo nano theranostic hyperthermia. AB - Magnetic resonance (MR) nano-theranostic hyperthermia uses magnetic nanoparticles to target and accumulate at the lesions and generate heat to kill lesion cells directly through hyperthermia or indirectly through thermal activation and control releasing of drugs. Preclinical and translational applications of MR nano theranostic hyperthermia are currently limited by a few major theoretical difficulties and experimental challenges in in vivo conditions. For example, conventional models for estimating the heat generated and the optimal magnetic nanoparticle sizes for hyperthermia do not accurately reproduce reported in vivo experimental results. In this work, a revised cluster-based model was proposed to predict the specific loss power (SLP) by explicitly considering magnetic nanoparticle aggregation in in vivo conditions. By comparing with the reported experimental results of magnetite Fe3O4 and cobalt ferrite CoFe2O4 magnetic nanoparticles, it is shown that the revised cluster-based model provides a more accurate prediction of the experimental values than the conventional models that assume magnetic nanoparticles act as single units. It also provides a clear physical picture: the aggregation of magnetic nanoparticles increases the cluster magnetic anisotropy while reducing both the cluster domain magnetization and the average magnetic moment, which, in turn, shift the predicted SLP toward a smaller magnetic nanoparticle diameter with lower peak values. As a result, the heating efficiency and the SLP values are decreased. The improvement in the prediction accuracy in in vivo conditions is particularly pronounced when the magnetic nanoparticle diameter is in the range of ~10-20 nm. This happens to be an important size range for MR cancer nano-theranostics, as it exhibits the highest efficacy against both primary and metastatic tumors in vivo. Our studies show that a relatively 20%-25% smaller magnetic nanoparticle diameter should be chosen to reach the maximal heating efficiency in comparison with the optimal size predicted by previous models. PMID- 28894365 TI - Photothermal ablation of inflammatory breast cancer tumor emboli using plasmonic gold nanostars. AB - Inflammatory breast cancer (IBC) is rare, but it is the most aggressive subtype of breast cancer. IBC has a unique presentation of diffuse tumor cell clusters called tumor emboli in the dermis of the chest wall that block lymph vessels causing a painful, erythematous, and edematous breast. Lack of effective therapeutic treatments has caused mortality rates of this cancer to reach 20%-30% in case of women with stage III-IV disease. Plasmonic nanoparticles, via photothermal ablation, are emerging as lead candidates in next-generation cancer treatment for site-specific cell death. Plasmonic gold nanostars (GNS) have an extremely large two-photon luminescence cross-section that allows real-time imaging through multiphoton microscopy, as well as superior photothermal conversion efficiency with highly concentrated heating due to its tip-enhanced plasmonic effect. To effectively study the use of GNS as a clinically plausible treatment of IBC, accurate three-dimensional (3D) preclinical models are needed. Here, we demonstrate a unique in vitro preclinical model that mimics the tumor emboli structures assumed by IBC in vivo using IBC cell lines SUM149 and SUM190. Furthermore, we demonstrate that GNS are endocytosed into multiple cancer cell lines irrespective of receptor status or drug resistance and that these nanoparticles penetrate the tumor embolic core in 3D culture, allowing effective photothermal ablation of the IBC tumor emboli. These results not only provide an avenue for optimizing the diagnostic and therapeutic application of GNS in the treatment of IBC but also support the continuous development of 3D in vitro models for investigating the efficacy of photothermal therapy as well as to further evaluate photothermal therapy in an IBC in vivo model. PMID- 28894367 TI - Simple nanoliposomes encapsulating Lycium barbarum polysaccharides as adjuvants improve humoral and cellular immunity in mice. AB - The success of subunit vaccines has been hampered by the problems of weak or short-term immunity and the lack of availability of nontoxic, potent adjuvants. It would be desirable to develop safe and efficient adjuvants with the aim of improving the cellular immune response against the target antigen. In this study, the targeting and sustained release of simple nanoliposomes containing Lycium barbarum polysaccharides (LBP) as an efficacious immune adjuvant to improve immune responses were explored. LBP liposome (LBPL) with high entrapment efficiency (86%) were obtained using a reverse-phase evaporation method and then used to encapsulate the model antigen, ovalbumin (OVA). We demonstrated that the as-synthesized liposome loaded with OVA and LBP (LBPL-OVA) was stable for 45 days and determined the encapsulation stability of OVA at 4 degrees C and 37 degrees C and the release profile of OVA from LBPL-OVA was investigated in pH 7.4 and pH 5.0. Further in vivo investigation showed that the antigen-specific humoral response was correlated with antigen delivery to the draining lymph nodes. The LBPL-OVA were also associated with high levels of uptake by key dendritic cells in the draining lymph nodes and they efficiently stimulated CD4+ and CD8+ T cell proliferation in vivo, further promoting antibody production. These features together elicited a significant humoral and celluar immune response, which was superior to that produced by free antigen alone. PMID- 28894369 TI - Erratum: Early predictors of brain damage in full-term newborns with hypoxic ischemic encephalopathy [Corrigendum]. AB - [This corrects the article on p. 2133 in vol. 13, PMID: 28860770.]. PMID- 28894368 TI - A systematic identification of species-specific protein succinylation sites using joint element features information. AB - Lysine succinylation, an important type of protein posttranslational modification, plays significant roles in many cellular processes. Accurate identification of succinylation sites can facilitate our understanding about the molecular mechanism and potential roles of lysine succinylation. However, even in well-studied systems, a majority of the succinylation sites remain undetected because the traditional experimental approaches to succinylation site identification are often costly, time-consuming, and laborious. In silico approach, on the other hand, is potentially an alternative strategy to predict succinylation substrates. In this paper, a novel computational predictor SuccinSite2.0 was developed for predicting generic and species-specific protein succinylation sites. This predictor takes the composition of profile-based amino acid and orthogonal binary features, which were used to train a random forest classifier. We demonstrated that the proposed SuccinSite2.0 predictor outperformed other currently existing implementations on a complementarily independent dataset. Furthermore, the important features that make visible contributions to species-specific and cross-species-specific prediction of protein succinylation site were analyzed. The proposed predictor is anticipated to be a useful computational resource for lysine succinylation site prediction. The integrated species-specific online tool of SuccinSite2.0 is publicly accessible. PMID- 28894370 TI - Reversible global aphasia as a side effect of quetiapine: a case report and literature review. AB - Quetiapine is an atypical antipsychotic agent which is also prescribed for delirium due to its anti-dopaminergic effects; aphasia is an unusual side effect associated with the drug. Here, we report the case of an 83-year-old woman who was prescribed quetiapine (50 mg per day) for delirium. Unexpected, global aphasia occurred 3 days after treatment began. Complete recovery occurred following discontinuation of the drug. A brain computed tomography scan excluded intracranial hemorrhage and the laboratory results confirmed that no exacerbation of infection or electrolyte imbalances were present. During the aphasic episode, the patient's condition did not deteriorate and no new neurological symptoms occurred. We suspect that the occurrence of aphasia was directly due to an adverse reaction to quetiapine. To our knowledge, this is the first case report of reversible, global aphasia as a side effect of quetiapine. We propose that this occurrence of aphasia may be due to the action of quetiapine as a dopamine receptor antagonist. Clinicians should use quetiapine with caution, especially in elderly patients. On observation of aphasia, a review of the patient's medical history is required to assess for the usage of quetiapine. PMID- 28894371 TI - Radiologic findings of thoracic trauma. AB - INTRODUCTION: Chest trauma may be blunt or penetrating and the chest is the third most common trauma region. It is a significant cause of mortality. Multidetector computed tomography (MDCT) has been an increasingly used method to evaluate chest trauma because of its high success in detecting tissue and organ injuries. Herein, we aimed to present MDCT findings in patients with blunt and penetrating chest trauma admitted to our department. METHODS: A total of 240 patients admitted to the emergency department of our hospital between April 2012 and July 2013 with a diagnosis of chest trauma who underwent MDCT evaluations were included. Most of the patients were male (83.3%) and victims of a blunt chest trauma. The images were analyzed with respect to the presence of fractures of bony structures, hemothorax, pneumothorax, mediastinal organ injury, and pulmonary and vascular injuries. RESULTS: MDCT images of the 240 patients yielded a prevalence of 41.7% rib fractures, 11.2% scapular fractures, and 7.5% clavicle fractures. The prevalence of thoracic vertebral fracture was 13.8% and that of sternal fracture was 3.8%. The prevalence of hemothorax, pneumothorax, pneumomediastinum, and subcutaneous emphysema was 34.6%, 62.1%, 9.6%, and 35.4%, respectively. The prevalence of rib, clavicle, and thoracic vertebral fractures and pulmonary contusion was higher in the blunt trauma group, whereas the prevalence of hemothorax, subcutaneous emphysema, diaphragmatic injury, and other vascular lacerations was significantly higher in the penetrating trauma group than in the blunt trauma group (p<0.05). CONCLUSION: MDCT images may yield a high prevalence of fracture of bony structures, soft tissue lacerations, and vascular lesions, which should be well understood by radiologists dealing with trauma. PMID- 28894372 TI - Frequent respiratory events in postoperative patients aged 60 years and above. AB - There is limited information on the occurrence of respiratory events in postoperative patients after discharge from the postanesthesia care unit. We studied the respiratory rate (RR) of 68 patients aged 60 years and above during the first 6 hours following elective surgery under general anesthesia to assess the frequency of respiratory events in the care unit and on the ward. RR was derived from the continuous RR counter RespiR8, measuring RR by quantifying the humidity of exhaled air. One-minute-averaged RRs were collected and analyzed to assess the frequency of postoperative bradypnea (RR 1-6 breaths/minute) and apnea (cessation of inspiratory flow >=60 seconds). Values were median (interquartile range) or mean (SD). The median RR was 13 (10-15) breaths/minute. In the 6-hour postoperative period, 78% and 57% of patients experienced at least one bradypnea or apnea event, respectively. A median of ten (3.5-24) bradypnea and three (1-11) apnea events were detected per patient. The occurrence of respiratory events in the postanesthesia care unit (PACU) was a predictor of events on the ward (bradypnea, r2=0.4, P<0.001; apnea, r2=0.2, P<0.001). Morphine consumption correlated weakly with respiratory events in the PACU, but not on the ward. Patients with apnea had significantly larger neck circumference than patients without (39.6 [0.7] versus 37.4 [0.8] cm, P<0.05). Bradypneic or apneic respiratory events are frequent in postoperative elderly patients and even occur relatively late after surgery. Continuous respiratory monitoring on the ward, especially in patients with risk factors, such as early occurrence of events, opioid use, and larger neck circumference, is likely warranted. PMID- 28894373 TI - Curcumin inhibits apoptosis by modulating Bax/Bcl-2 expression and alleviates oxidative stress in testes of streptozotocin-induced diabetic rats. AB - SCOPE: The present study was designed to examine the damage caused by high-fat diet and streptozotocin-induced diabetes on the testis of rats and the effects of curcumin against oxidative stress and apoptosis from high-fat diet and diabetes. METHODS: Diabetes was induced by intraperitoneal injection of streptozotocin (30 mg/kg in 0.1 M sodium citrate buffer, pH 4.5) in obese rats. The rats in the obese and diabetic groups were treated with a daily dose of curcumin by intragastric intubation (100 mg/kg body weight) for 8 weeks. Testis tissue sections were stained with hematoxylin-eosin, and apoptosis was identified in situ by using terminal deoxynucleotidyl transferase dUTP nick end labeling. RESULTS: Curcumin treatment improved the histological appearance of the testis and significantly reduced the apoptosis level in the testicular cells of the obese and the diabetic rats. The expression of proliferating cell nuclear antigen (PCNA) was restored in the testis tissues of diabetic rats at the end of curcumin treatment. Molecular analysis demonstrated that curcumin treatment significantly and simultaneously decreased Bax and increased Bcl-2 expressions, therefore elevating the ratio of Bcl-2/Bax. Furthermore, curcumin treatment significantly decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) levels in testis tissue samples of the diabetic rats. CONCLUSION: Curcumin treatment preserved the morphology of testes; restored the expression of PCNA, MDA, and SOD; and inhibited testicular cell death in diabetic rats. The capability of curcumin in inhibiting oxidative stress and modulating the Bax/Bcl-2-mediated cell death pathway reveals its potential as a therapeutic agent against diabetes. PMID- 28894375 TI - Impact of T1 slope on surgical and adjacent segment degeneration after Bryan cervical disc arthroplasty. AB - BACKGROUND: This retrospective study investigated an association between preoperative T1 slope and surgical and adjacent segment degeneration (SASD) after Bryan cervical disc arthroplasty (BCDA) in patients with cervical degenerative disc disease. METHODS: Based on preoperative standing lateral radiographs, 90 patients were classified according to T1 slope that was higher or lower than the 50th percentile (high T1 or low T1, 28 and 62 patients, respectively). Patients were also classified as SASD or non-SASD (38 and 52 patients, respectively) determined by radiographs at final follow-up. Visual analog scale (VAS) and Neck Disability Index (NDI) scores for neck and arm pain were noted, and changes in the sagittal alignment of the cervical spine (SACS), functional spinal unit (FSU) angle, and FSU range of motion (ROM) were also noted. Univariate and multivariate logistic regression analyses were performed to determine the risk factors for SASD. RESULTS: The overall rate of SASD was 42.2% (38/90). The SACS, FSU angle, FSU ROM, and SASD rates of the high T1 and low T1 slope groups were significantly different at the last follow-up. The NDI and VAS scores of the high T1 slope group were significantly greater than those of the low T1 slope. The multivariate logistic regression analysis showed that high T1 slope and endplate coverage discrepancy (ie, residual space behind the prosthesis) were significant risk factors for SASD after BCDA. CONCLUSION: High T1 slope and endplate coverage discrepancy were associated with SASD after BCDA. Patients with a high preoperative T1 slope have a smaller FSU angle and more neck pain after BCDA. PMID- 28894374 TI - Predicting and managing sepsis in burn patients: current perspectives. AB - Modern burn care has led to unprecedented survival rates in burn patients whose injuries were fatal a few decades ago. Along with improved survival, new challenges have emerged in the management of burn patients. Infections top the list of the most common complication after burns, and sepsis is the leading cause of death in both adult and pediatric burn patients. The diagnosis and management of sepsis in burns is complex as a tremendous hypermetabolic response secondary to burn injury can be superimposed on systemic infection, leading to organ dysfunction. The management of a septic burn patient represents a challenging scenario that is commonly encountered by providers caring for burn patients despite preventive efforts. Here, we discuss the current perspectives in the diagnosis and treatment of sepsis and septic shock in burn patients. PMID- 28894376 TI - Operative and nonoperative management for renal trauma: comparison of outcomes. A systematic review and meta-analysis. AB - INTRODUCTION: Preservation of kidney and renal function is the goal of nonoperative management (NOM) of renal trauma (RT). The advantages of NOM for minor blunt RT have already been clearly described, but its value for major blunt and penetrating RT is still under debate. We present a systematic review and meta analysis on NOM for RT, which was compared with the operative management (OM) with respect to mortality, morbidity, and length of hospital stay (LOS). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses statement was followed for this study. A systematic search was performed on Embase, Medline, Cochrane, and PubMed for studies published up to December 2015, without language restrictions, which compared NOM versus OM for renal injuries. RESULTS: Twenty nonrandomized retrospective cohort studies comprising 13,824 patients with blunt (2,998) or penetrating (10,826) RT were identified. When all RT were considered (American Association for the Surgery of Trauma grades 1-5), NOM was associated with lower mortality and morbidity rates compared to OM (8.3% vs 17.1%, odds ratio [OR] 0.471; 95% confidence interval [CI] 0.404-0.548; P<0.001 and 2% vs 53.3%, OR 0.0484; 95% CI 0.0279-0.0839, P<0.001). Likewise, NOM represented the gold standard treatment resulting in a lower mortality rate compared to OM even when only high-grade RT was considered (9.1% vs 17.9%, OR 0.332; 95% CI 0.155-0.708; P=0.004), be they blunt (4.1% vs 8.1%, OR 0.275; 95% CI 0.0957-0.788; P=0.016) or penetrating (9.1% vs 18.1%, OR 0.468; 95% CI 0.398 0.0552; P<0.001). CONCLUSION: Our meta-analysis demonstrated that NOM for RT is the treatment of choice not only for AAST grades 1 and 2, but also for higher grade blunt and penetrating RT. PMID- 28894377 TI - HPIP: a predictor of lymph node metastasis and poor survival in cervical cancer. AB - BACKGROUND: The aim of this study was to explore the relationships of HPIP expression status with the clinicopathological variables and survival outcomes of patients with cervical cancer (CC). METHODS: We compared the HPIP expression of 119 samples from CC tissues, 20 from cervical intraepithelial tissues, and 20 from normal cervical tissues by using immunohistochemical staining. RESULTS: It was observed that the ratio of elevated HPIP expression was higher in CC tissues than in cervical intraepithelial neoplasia (P=0.017) and normal cervical tissues (P=0.001). In addition, there was an association between HPIP and clinicopathological factors, such as histological grade (P<0.001), stromal infiltration (P=0.015), lymph node metastasis (P<0.001), lymphovascular space invasion (LVSI; P=0.026), and recurrence (P=0.029). Furthermore, multivariate Cox regression analysis revealed that high HPIP expression (P=0.027 and P=0.042) as well as the International Federation of Gynaecology and Obstetrics stage (P=0.003 and P=0.009), lymph node metastasis (P=0.031 and P=0.017), and LVSI (P=0.024 and P=0.046) were independent prognostic factors. In addition, we demonstrated that high HPIP expression (P=0.003) and LVSI (P<0.001) were independently related to lymph node metastasis. CONCLUSION: Elevated HPIP expression may contribute to the progression and metastasis of CC and may also serve as a new biomarker to predict the prognosis of CC. PMID- 28894378 TI - Initial experience of correlating diffusion spectral parameters with histopathologic indexes in murine colorectal tumor homografts. AB - PURPOSE: To determine the correlation between continuously distributed diffusion weighted image (DWI)-derived parameters and histopathologic indexes. METHODS: Fifty-four mice bearing HCT-116 colorectal tumors were included for analysis; 12 mice were used for continuous observation, and the other 42 mice were used for break-point observation. All mice were randomly divided into radiotherapy and non radiotherapy groups. Optical imaging and MRI were performed at different time points according to radiotherapy regimen (baseline, 24 h, 48 h, 72 h, 7 d, 14 d, and 28 d). Continuous observation data were analyzed to show the difference of dynamic changing trends of optical and MR-DWI-derived parameters between radiotherapy and non-radiotherapy groups (photon numbers, D_max, full width half maximum [FWHM], and apparent diffusion coefficient [ADC] value). Break-point observation data were used to analyze the correlation between histopathologic indices and DWI-derived parameters. RESULTS: There was a significant difference in the changing trends of photon numbers, D_max, FWHM, and ADC value between radiotherapy and non-radiotherapy groups, especially at early time points. There was moderate negative correlation between Ki67 and percentage changes of D_max, FWHM, and ADC values (the correlation coefficients were 0.632, 0.449, and 0.586, P<0.001, P=0.008, and P<0.001, respectively). There was moderate negative correlation between survivin and percentage changes of D_max and ADC values (correlation coefficients were 0.496 and 0.473, P=0.004 and P=0.006, respectively). CONCLUSION: The continuously distributed DWI-derived parameters could reflect histological behavior to some extent and, thus, are potential markers for early noninvasive monitoring of tumor cell apoptosis and proliferation. PMID- 28894379 TI - miRNA expression profiling in formalin-fixed paraffin-embedded endometriosis and ovarian cancer samples. AB - Endometriosis is an inflammatory pathology associated with a negative effect on life quality. Recently, this pathology was connected to ovarian cancer, in particular with endometrioid ovarian cancer. microRNAs (miRNAs) are a class of RNA transcripts ~19-22 nucleotides in length, the altered miRNA pattern being connected to pathological status. miRNAs are highly stable transcripts, and these can be assessed from formalin-fixed paraffin-embedded (FFPE) samples leading to the identification of miRNAs that could be developed as diagnostic and prognostic biomarkers, in particular those involved in malignant transformation. The aim of our study was to evaluate miRNA expression pattern in FFPE samples from endometriosis and ovarian cancer patients using PCR-array technology and also to compare the differential expression pattern in ovarian cancer versus endometriosis. For the PCR-array study, we have used nine macrodissected FFPE samples from endometriosis tissue, eight samples of ovarian cancers and five normal ovarian tissues. Quantitative real-time PCR (qRT-PCR) was used for data validation in a new patient cohort of 17 normal samples, 33 endometriosis samples and 28 ovarian cancer macrodissected FFPE samples. Considering 1.5-fold expression difference as a cut-off level and a P-value <0.05, we have identified four miRNAs being overexpressed in endometrial tissue, while in ovarian cancer 15 were differentially expressed (nine overexpressed and six downregulated). The expression level was confirmed by qRT-PCR for miR-93, miR-141, miR-155, miR-429, miR-200c, miR-205 and miR-492. Using the interpretative program Ingenuity Pathway Analysis revealed several deregulated pathways due to abnormal miRNA expression in endometriosis and ovarian cancer, which in turn is responsible for pathogenesis; this differential expression of miRNAs can be exploited as a therapeutic target. A higher number of altered miRNAs were detected in endometriosis versus ovarian cancer tissue, most of them being linked with epithelial-to-mesenchymal transition. PMID- 28894380 TI - LEF1-AS1, a long-noncoding RNA, promotes malignancy in glioblastoma. AB - OBJECTIVES: The long-noncoding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes in glioblastoma (GBM) tissues. However, the expression pattern and biological function of lncRNAs remain largely unknown. Here, for the first time, the effects of lncRNA lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) on GBM progression both in vitro and in vivo are investigated. MATERIALS AND METHODS: Expression profiles of LEF1-AS1 in GBM specimens were investigated by bioinformatics analyses. LEF1-AS1 expression in GBM tissues was detected using a quantitative polymerase chain reaction. LEF1-AS1 expression was inhibited by transfecting the LEF1-AS1-specific small interfering RNAs (siRNAs) and stable cell lines established were inhibited by transfecting si LEF1-AS1 viruses. The Cell Counting Kit-8, ethynyl deoxyuridine, and colony formation assay were used to examine proliferation function. The flow cytometry detected cell-cycle change and apoptosis. Migration effects were detected by a Transwell assay. The tumor xenografts and immunohistochemistry were performed to evaluate tumor growth in vivo. RESULTS: In this study, LEF1-AS1 expression was found significantly upregulated in GBM specimens compared with normal tissues. The 5-year overall survival in GBM patients from The Cancer Genome Atlas with high expression of LEF1-AS1 was inferior to that with low expression. It was confirmed that expression of LEF1-AS1 was higher in GBM tissues than normal ones. Knockdown of LEF1-AS1 significantly inhibited the malignancy of GBM cells, including proliferation and invasion, and promoted cell apoptosis. The result of Western blot assays indicated that knockdown of LEF1-AS1-mediated tumor suppression in GBM cells may be via the reduction of ERK and Akt/mTOR signaling activities. Finally, the in vivo experiment also demonstrated that knockdown LEF1 AS1 inhibited the growth-promoting effect of LEF1-AS1 of U87 cells. CONCLUSION: Our result indicated that lncRNA LEF1-AS1 acts as an oncogene in GBM and may be a pivotal target for this disease. PMID- 28894381 TI - Continuous EGFR tyrosine kinase inhibitor treatment with or without chemotherapy beyond gradual progression in non-small cell lung cancer patients. AB - BACKGROUND: Several clinical studies have demonstrated that continuous administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could provide additional survival benefit for advanced non-small cell lung cancer (NSCLC) patients who had benefited from prior EGFR TKI therapy. However, whether EGFR TKI combined with chemotherapy could further prolong survival in patients with gradual progression is still unclear. The present study was conducted to evaluate the clinical outcome of continuous EGFR TKI treatment in combination with chemotherapy (combination group) versus continuous EGFR TKI treatment only (monotherapy group) in such a clinical setting. METHODS: We designed a cohort study to collect all chart data of NSCLC patients treated with EGFR TKI in our institution from February 2012 to December 2015 retrospectively and followed up the clinical outcome of EGFR TKI monotherapy or therapy in combination with chemotherapy until April 2017 prospectively. All eligible patients had to meet the criteria of gradual progression. The time interval of progression-free survival 1 (PFS1, gradual progression or death) to PFS2 (off EGFR TKI progression), and overall survival (OS) between the above 2 groups were used in survival analysis. RESULTS: In all, 50 patients were included in our study. Patients' baseline characteristics were well balanced. Exon 19 deletion mutations and L858R point mutations were detected in 16 and 8 patients, respectively. Twenty, 22, and 8 patients were treated with EGFR TKI in the first, second, and third line setting, respectively. The time interval from PFS1 to PFS2 was 92 and 37 days (monotherapy vs combination), respectively (hazard ratio [HR] =1.16, 95% confidence interval [CI]: 0.61-2.21, P=0.652). The median OS in the monotherapy group and combination group was 696 and 799 days, respectively (HR =0.74, 95% CI: 0.33-1.71, P=0.501). There were no statistical differences between the 2 groups in terms of the time interval from PFS1 to PFS2 and OS. CONCLUSION: Our results suggested that compared with EGFR TKI monotherapy, its combination with chemotherapy beyond gradual progression may not confer a significant survival benefit to NSCLC patients. Further prospective studies are warranted to reinforce the results of the study. PMID- 28894382 TI - Apatinib in the treatment of advanced lung adenocarcinoma with KRAS mutation. AB - Activating KRAS mutations in lung adenocarcinoma are characterized with treatment resistance and poor prognosis. As a small molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, apatinib has been proven successful in advanced gastric cancer and breast cancer. In this study, we show the result of apatinib as salvage treatment in lung adenocarcinoma patients with KRAS mutation. Four advanced lung adenocarcinoma patients with KRAS mutation were orally administered apatinib (250 mg/d) after second-line treatment. One patient showed progressive disease, while 3 patients showed stable disease response to apatinib, with a median progression-free survival (PFS) of 3.8 months (1.5-5.5 months). The main toxicities were hoarseness and hemoptysis, which were manageable. Therefore, apatinib might be an optional choice for advanced lung adenocarcinoma patients with KRAS mutation in post second-line treatment. PMID- 28894383 TI - Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer. AB - In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK) cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18) and allogeneic NK cells immunotherapy group (group II, n=18). The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC) level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3) expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer. PMID- 28894384 TI - Technology that achieves the Triple Aim: an economic analysis of the BrainPathTM approach in neurosurgery. AB - BACKGROUND: The Triple Aim is defined as: improving the patient experience of care, improving the health of populations, and reducing the per capita cost of health care. The purpose of this analysis was to evaluate the economic value of a new neurosurgical technique, the BrainPathTM approach, for use in patients with subcortical tumors and intracerebral hemorrhage (ICH). METHODS: Inpatient length of stay (LOS) data were collected for ICH and brain tumor surgical patient cases between August 2013 and November 2015. Patient cases were separated into two groups; BrainPath approach (n = 28) and conventional techniques, such as craniotomy, (n = 208). The average intensive care unit (ICU) LOS was calculated for each group by diagnosis-related group and compared between groups. RESULTS: The new surgical technology resulted in surgical intervention in 14 ICH cases which otherwise would have been medically managed due to the hemorrhage location or size of the ICH. A reduction in ICU LOS was seen in this group. Based on the variable direct cost per day in the neuro critical care unit at this academic medical center, 14 patient cases incurred ~ US$210,000 less in direct ICU costs. Surgical resection was possible in two tumor patient cases which would have been biopsied, rather than surgically resected, also due to location of the abnormalities. A total net value of > US$329,000 is attributable to the analyzed approach over a 28-month period. CONCLUSION: This analysis shows positive economic value for the new technology group when ICU LOS and reimbursement are considered against equipment costs, thus achieving Triple Aim objectives. PMID- 28894385 TI - Genetic and epigenetic epidemiology of chronic widespread pain. AB - The etiology underlying chronic widespread pain (CWP) remains largely unknown. An integrative biopsychosocial model seems to yield the most promising explanations for the pathogenesis of the condition, with genetic factors also contributing to disease development and maintenance. Here, we conducted a search of studies investigating the genetic and epigenetic epidemiology of CWP through electronic databases including Web of Science, Medline, PubMed, EMBASE, and Google Scholar. Combinations of keywords including CWP, chronic pain, musculoskeletal pain, genetics, epigenetics, gene, twins, single-nucleotide polymorphism, genotype, and alleles were used. In the end, a total of 15 publications were considered relevant to be included in this review: eight were twin studies on CWP, six were molecular genetic studies on CWP, and one was an epigenetic study on CWP. The findings suggest genetic and unique environmental factors to contribute to CWP. Various candidates such as serotonin-related pathway genes were found to be associated with CWP and somatoform symptoms. However, studies show some limitations and need replication. The presented results for CWP could serve as a template for genetic studies on other chronic pain conditions. Ultimately, a more in-depth understanding of disease mechanisms will help with the development of more effective treatment, inform nosology, and reduce the stigma still lingering on this diagnosis. PMID- 28894386 TI - Oxidative stress in patients with endodontic pathologies. AB - BACKGROUND: Apical periodontitis (AP) is an inflammatory disease affecting periradicular tissues. It is a widespread condition but its etiopathogenetic mechanisms have not been completely elucidated and the current treatment options are not always successful. PURPOSE: To compare oxidative stress (OxS) levels in the saliva and the endodontium (root canal [RC] contents) in patients with different endodontic pathologies and in endodontically healthy subjects. PATIENTS AND METHODS: The study group of this comparison study included 22 subjects with primary chronic apical periodontitis (pCAP), 26 with posttreatment or secondary chronic apical periodontitis (sCAP), eight with acute periapical abscess, 13 with irreversible pulpitis, and 17 healthy controls. Resting saliva samples were collected before clinical treatment. Pulp samples (remnants of the pulp, tooth tissue, and/or previous root filling material) were collected under strict aseptic conditions using the Hedstrom file. The samples were frozen to -80 degrees C until analysis. OxS markers (myeloperoxidase [MPO], oxidative stress index [OSI], 8-isoprostanes [8-EPI]) were detected in the saliva and the endodontium. RESULTS: The highest MPO and 8-EPI levels were seen in pCAP and pulpitis, while the highest levels of OSI were seen in pCAP and abscess patients, as well as the saliva of sCAP patients. Controls showed the lowest OxS levels in both RC contents and saliva. Significant positive correlations between OxS markers, periapical index, and pain were revealed. Patients with pain had significantly higher OxS levels in both the endodontium (MPO median 27.9 vs 72.6 ng/mg protein, p=0.004; OSI 6.0 vs 10.4, p<0.001; 8-EPI 50.0 vs 75.0 pg/mL, p<0.001) and saliva (MPO 34.2 vs 117.5 ng/mg protein, p<0.001; 8-EPI 50.0 vs 112.8 pg/mL, p<0.001) compared to pain-free subjects. CONCLUSION: OxS is an important pathomechanism in endodontic pathologies that is evident at both the local (RC contents) and systemic (saliva) level. OxS is significantly associated with dental pain and bone destruction. PMID- 28894387 TI - Modic changes of the cervical spine: T1 slope and its impact on axial neck pain. AB - BACKGROUND: The purpose of the research was to evaluate cervical sagittal parameters on magnetic resonance imaging (MRI) in patients with Modic changes and its impact on axial neck pain. METHODS: This study consisted of 266 consecutive asymptomatic or symptomatic patients with Modic changes, whose average age was 50.9+/-12.6 years from January 2015 to December 2016. Cervical sagittal parameters included sagittal alignment of the cervical spine (SACS), T1 slope, thoracic inlet angle (TIA), and neck tilt (NT). The Modic changes group was compared with an asymptomatic control group of 338 age- and gender-matched adults. RESULTS: In the Modic changes group, T1 slope was significantly higher (25.8 degrees +/-6.3 degrees ) compared with that in the control group (22.5 degrees +/-6.8 degrees ) (P=0.000). However, there was no significant difference of the NT, TIA, and SACS between the two groups. Patients in the Modic changes group were more likely to have experienced historical axial neck pain compared with the control group (P=0.000). With regard to the disc degeneration, it indicated that the disc in the Modic changes group had more severe disc degeneration (P=0.032). CONCLUSION: T1 slope in the Modic changes group was significantly higher compared to that of the control group. The findings suggested that a higher T1 slope with broken compensation of cervical sagittal mechanism may be associated with the development of Modic changes in the cervical spine. PMID- 28894388 TI - Bone-anchored annular closure following lumbar discectomy reduces risk of complications and reoperations within 90 days of discharge. AB - PURPOSE: The purpose of this study was to evaluate perioperative complications of lumbar discectomy with or without bone-anchored annular closure device (ACD) implant in patients at high risk of recurrent disc herniation. METHODS: This was a post hoc analysis of a randomized controlled trial that compared outcomes of lumbar discectomy with or without additional placement of an ACD. Patients presented with imaging evidence of lumbar disc herniation and radicular pain that was unresponsive to conservative care. Randomization occurred intraoperatively following discectomy completion and confirmation of annular defect width >=6 mm. Main outcomes included serious adverse events (SAEs) from any cause, device- or procedure-related SAEs, and reoperations at the index level. The perioperative period included all outcomes occurring between the day of surgery and 90 days following hospital discharge. RESULTS: Analyses were performed on a modified intention-to-treat population consisting of 272 patients treated with ACD and 278 patients treated with lumbar discectomy only (controls). Mean patient age was 44 years, 59% were men, and mean body mass index was 26 kg/m2. Baseline patient characteristics and operative outcomes were comparable between groups. The risks of all-cause SAE (9.7% vs 16.3%, p=0.056), device- or procedure-related SAE (4.5% vs 10.2%, p=0.02), and index-level reoperation (1.9% vs 5.4%, p=0.03) were lower with ACD vs controls. In multivariable logistic regression, control group assignment and female gender were independently associated with higher risk of device- or procedure-related SAE and index-level reoperation, respectively. CONCLUSION: In patients undergoing lumbar discectomy to treat symptomatic intervertebral disc herniation, adjunctive placement of an ACD reduces the risk for perioperative complications occurring through 90 days following hospital discharge. PMID- 28894389 TI - Quantification of small fiber pathology in patients with sarcoidosis and chronic pain using cornea confocal microscopy and skin biopsies. AB - Small fiber pathology with concomitant chronic neuropathic pain is a common complication of sarcoidosis. The gold standard of diagnosis of small fiber neuropathy (SFN) is the quantification of small nerve fibers in skin biopsies in combination with patient history and psychophysical tests; a new technique is the quantification of small nerve fibers in the cornea using cornea confocal microscopy (CCM). Here, we studied small fiber morphology in sarcoidosis patients with neuropathic pain using skin biopsies, CCM, and quantitative sensory testing (QST). Our aim was to construct specific phenotypes of neuropathic pain in sarcoidosis. Fifty-eight patients with a confirmed diagnosis of sarcoidosis and with moderate-to-severe neuropathic pain were tested. Decreased intraepidermal nerve fiber density (IENFD) from skin biopsies was found in 28% of patients, and CCM abnormalities were observed in 45% of patients. There was no correlation between CCM and IENFD abnormalities. Eighty-three percent of patients had abnormal thermal detection thresholds, a sign of small fiber dysfunction. Based on the presence or absence of abnormalities in IENFD and CCM, four distinct phenotypes were identified with a distinct homogeneous pattern of somatosensory symptoms. We argue that these distinct phenotypes have a similar mechanistic construct with specific phenotype-specific treatment options. Additionally, our data suggest the presence of patients with length- and nonlength-dependent SFN within this population of sarcoidosis patients. PMID- 28894391 TI - Comment on "Fecal occult blood versus DNA testing: indirect comparison in a colorectal cancer screening population". PMID- 28894390 TI - Preeclampsia and cardiovascular disease: interconnected paths that enable detection of the subclinical stages of obstetric and cardiovascular diseases. AB - The potent and now longstanding evidence of the association between placentation related disorders and cardiovascular disease should be translated into clinical practice in order to introduce a preventive approach to future obstetric and cardiovascular diseases. The purpose of this review is to integrate cardiovascular risk/disease and obstetric complications, which are linked by endothelial dysfunction, as windows of opportunity for improving women's health. Questionnaires adaptable to local practices are proposed to incorporate cardiovascular and obstetrical indexes into two stages of a woman's lifetime. PMID- 28894392 TI - Fractional CO2 laser treatment for vulvovaginal atrophy symptoms and vaginal rejuvenation in perimenopausal women. AB - BACKGROUND: This study investigated a novel fractional carbon dioxide (CO2) laser for treatment of symptoms associated with vulvovaginal atrophy (VVA) in perimenopausal women. METHODS: The study included 21 perimenopausal women (mean age 45+/-7 years) treated three times by CO2 laser resurfacing and coagulation of the vaginal canal tissue and mucosal tissue of the introitus. Vaginal health index (VHI) scores were computed by the investigator at baseline and follow-ups. Subjects reported on sexual function, satisfaction, and improvement with treatment. A visual analog scale was used to measure discomfort with treatment. RESULTS: Vaginal health and subject assessment of vaginal symptoms improved with successive treatments. At 12 weeks following the third treatment, 82% of the patients showed a statistically significant improvement in VHI (P<0.05). Additionally, 81% of subjects reported improvement in sexual gratification, 94% reported improvement in vaginal rejuvenation, and 100% reported satisfaction with treatment. VHI improvement remained significant at 6-8 months after treatments (P<0.01). Most patients (97%) reported no to mild discomfort with treatment. Responses were mild and transient following treatment, with itching being the most commonly reported (20%) side effect. CONCLUSION: In this study, fractional CO2 laser treatment was associated with improvement of vaginal health and amelioration of symptoms of VVA, resulting in improved sexual function in perimenopausal women. Treatment time was quick, and there was minimal discomfort associated with treatment. Investigation of clinical outcome in a larger study population is warranted. PMID- 28894393 TI - Review of Rifaximin: Latest Treatment Frontier for Irritable Bowel Syndrome Mechanism of Action and Clinical Profile. AB - BACKGROUND: Irritable bowel syndrome is classified as a functional gastrointestinal disorder with the primary symptom of abdominal pain in conjunction with bloating and bowel movement disorder. It affects up to 15% of the world's population. Among its subtypes, the most common is diarrhoea predominant. However, the current treatment options for diarrhoea-predominant irritable bowel syndrome have had not very promising results; most, such as antispasmodics, only provide partial symptomatic relief. Treatment with antidepressants and alosetron (a 5HT3 antagonist) has shown the most promise to date. The latest drug to be approved for the treatment of irritable bowel syndrome-diarrhoea is rifaximin, which was approved in May 2015. It is a minimally absorbed antibiotic that is used to change the gut microbiota. Small intestinal bacterial overgrowth is one of the causes suggested for irritable bowel syndrome, particularly for the diarrhoea-predominant type. There are various methods for detecting bacterial overgrowth, the simplest of which is breath tests. Rifaximin has been shown to be of benefit to these patients. PURPOSE: The purpose of the study is to discuss the potential mechanism of action of rifaximin, a minimally absorbed antibiotic. In addition, we evaluate the various clinical trials undertaken to study the efficacy and safety profile of rifaximin. PMID- 28894394 TI - Normative Values for Colonic Transit Time and Patient Assessment of Constipation in Adults With Functional Constipation: Systematic Review With Meta-Analysis. AB - Availability of normative patient outcome data may assist in designing experiments and estimating sample sizes. The purpose of this review was to determine normative ranges for colonic transit time (CTT), Patient Assessment of Constipation-Symptoms (PAC-SYM), and Patient Assessment of Constipation-Quality of Life (PAC-QOL) in adults diagnosed with functional constipation per Rome III guidelines. Pooled estimates were derived from random-effects meta-analysis. Meta regression was used to explore sources of heterogeneity among studies. A total of 24 studies (3786 patients) were included in the review. In 10 studies with 1119 patients, pooled CTT was 58 hours (95% confidence interval [CI]: 50-65 hours). Publication bias was not evident (Egger P = .51); heterogeneity was high (I2 = 92%, P < .001). In meta-regression, geographical location explained 57% of the between-study variance, with CTT significantly longer in studies conducted in Europe (71 hours) compared with Asia (49 hours) or the Americas (44 hours). In 9 studies with 2061 patients, pooled PAC-SYM was 1.70 (95% CI: 1.58-1.83). Publication bias was not evident (Egger P = .44). Heterogeneity was high (I2 = 90%, P < .001); however, no study or patient factor influenced PAC-SYM in meta regression. In 12 studies with 1805 patients, pooled PAC-QOL was 1.97 (95% CI: 1.70-2.24). Publication bias was not evident (Egger P = .28); heterogeneity was high (I2 = 98%, P < .001). In meta-regression, age explained 52% of the between study variance, with older age associated with lower PAC-QOL scores. Overall, in adults diagnosed with functional constipation per Rome III criteria, significant heterogeneity in CTT, PAC-SYM, and PAC-QOL exists among studies. Variability among studies may be explained by geography and patient factors. PMID- 28894395 TI - Factors Affecting Adjuvant Therapy in Stage III Pancreatic Cancer-Analysis of the National Cancer Database. AB - BACKGROUND: Adjuvant therapy after curative resection is associated with survival benefit in stage III pancreatic cancer. We analyzed the factors affecting the outcome of adjuvant therapy in stage III pancreatic cancer and compared overall survival with different modalities of adjuvant treatment. METHODS: This is a retrospective study of patients with stage III pancreatic cancer listed in the National Cancer Database (NCDB) who were diagnosed between 2004 and 2012. Patients were stratified based on adjuvant therapy they received. Unadjusted Kaplan-Meier and multivariable Cox regression analysis were performed. RESULTS: We analyzed a cohort included 1731 patients who were recipients of adjuvant therapy for stage III pancreatic cancer within the limits of our database. Patients who received adjuvant chemoradiation had the longest postdiagnosis survival time, followed by patients who received adjuvant chemotherapy, and finally patients who received no adjuvant therapy. On multivariate analysis, advancing age and patients with Medicaid had worse survival, whereas Spanish origin and lower Charlson comorbidity score had better survival. CONCLUSIONS: Our study is the largest trial using the NCDB addressing the effects of adjuvant therapy specifically in stage III pancreatic cancer. Within the limits of our study, survival benefit with adjuvant therapy was more apparent with longer duration from date of diagnosis. PMID- 28894396 TI - A validation of clinical data captured from a novel Cancer Care Quality Program directly integrated with administrative claims data. AB - BACKGROUND: Data from a Cancer Care Quality Program are directly integrated with administrative claims data to provide a level of clinical detail not available in claims-based studies, and referred to as the HealthCore Integrated Research Environment (HIRE)-Oncology data. This study evaluated the validity of the HIRE Oncology data compared with medical records of breast, lung, and colorectal cancer patients. METHODS: Data elements included cancer type, stage, histology (lung only), and biomarkers. A sample of 300 breast, 200 lung, and 200 colorectal cancer patients within the HIRE-Oncology data were identified for medical record review. Statistical measures of validity (agreement, positive predictive value [PPV], negative predictive value [NPV], sensitivity, specificity) were used to compare clinical information between data sources, with medical record data considered the gold standard. RESULTS: All 300 breast cancer records reviewed were confirmed breast cancer, while 197 lung and 197 colorectal records were confirmed (PPV =0.99 for each). The agreement of disease stage was 85% for breast, 90% for lung, and 94% for colorectal cancer. The agreement of lung cancer histology (small cell vs non-small cell) was 97%. Agreement of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 status biomarkers in breast cancer was 92%, 97%, and 92%, respectively; epidermal growth factor receptor and anaplastic lymphoma kinase agreement in lung was 97% and 92%, respectively; and agreement of KRAS status in colorectal cancer was 95%. Measures of PPV, NPV, sensitivity, and specificity showed similarly strong evidence of validity. CONCLUSION: Good agreement between the HIRE-Oncology data and medical records supports the validity of these data for research. PMID- 28894397 TI - Fauna Europaea: Hymenoptera - Symphyta & Ichneumonoidea. AB - Fauna Europaea provides a public web-service with an index of scientific names (including important synonyms) of all extant European terrestrial and freshwater animals, their geographical distribution at the level of countries and major islands (west of the Urals and excluding the Caucasus region), and some additional information. The Fauna Europaea project comprises about 230,000 taxonomic names, including 130,000 accepted species and 14,000 accepted subspecies, which is much more than the originally projected number of 100,000 species. Fauna Europaea represents a huge effort by more than 400 contributing specialists throughout Europe and is a unique (standard) reference suitable for many users in science, government, industry, nature conservation and education. For the Hymenoptera, taxonomic data from one grade (Symphyta) and one Superfamily (Ichneumonoidea), including 15 families and 10,717 species, are included. Ichneumonoidea is the largest superfamily of Hymenoptera and consisting of two extant families, Ichneumonidae and Braconidae. The costal cell of the fore wing is absent, the fore wing has at least two closed cells, the constriction between the mesosoma (thorax + first abdominal segment or propodeum) and the metasoma (remainder of abdomen) is distinct and the parasitoid larvae usually spin a silken cocoon. Also, the metasoma is ventrally partly desclerotized in the vast majority of ichneumonoids. PMID- 28894398 TI - Cultural Construction of Psychiatric Illness in Malaysia. AB - The concept of the cultural construction of illness is important in terms of understanding people's behaviour. In this article, this idea is applied to psychiatric illness in Malaysia to explore how it is informed by sociocultural elements, a process that will help us understand the psychiatric expression and help-seeking behaviour of the country's population. PMID- 28894399 TI - Drosophila melanogaster: Deciphering Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide. Its pathogenesis involves two hallmarks: aggregation of amyloid beta (Abeta) and occurrence of neurofibrillary tangles (NFTs). The mechanism behind the disease is still unknown. This has prompted the use of animal models to mirror the disease. The fruit fly, Drosophila melanogaster has garnered considerable attention as an organism to recapitulate human disorders. With the ability to monopolise a multitude of traditional and novel genetic tools, Drosophila is ideal for studying not only cellular aspects but also physiological and behavioural traits of human neurodegenerative diseases. Here, we discuss the use of the Drosophila model in understanding AD pathology and the insights gained in discovering drug therapies for AD. PMID- 28894400 TI - A Combination of Trimethoprim-sulfamethoxazole and Ceftazidime Showed Good In Vitro Activity against Stenotrophomonas maltophilia. AB - BACKGROUND: Stenotrophomonas maltophilia has emerged as an important nosocomial pathogen, capable of causing a wide spectrum of infections. Treatment is difficult because it is resistant to many antimicrobial agents, thus reducing the treatment options. The aims of this study were to describe the antimicrobial susceptibility patterns and synergistic effect of selected antimicrobial combinations against S. maltophilia isolates. METHODS: This was a descriptive cross-sectional study undertaken in the Hospital Universiti Sains Malaysia from April 2011 to March 2012. S. maltophilia isolated from various clinical specimens were included in the study. Antimicrobial susceptibility testing was done using the epsilometer test (E-test) and interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. In the synergy test, the isolates were tested against six different antimicrobial combinations. RESULTS: In total, 84 S. maltophilia isolates were collected and analysed. According to the E-test, the antimicrobial susceptibility of trimethoprim-sulfamethoxazole (TMP-SMX), tigecycline, and ciprofloxacin was 100%, 91.1%, and 88.9% respectively. The antimicrobial combination of TMP-SMX and ceftazidime showed the highest synergistic effect. CONCLUSION: TMP-SMX remains the antimicrobial of choice to treat S. maltophilia infection. TMP-SMX and ceftazidime was the most effective combination in vitro. PMID- 28894401 TI - Soluble Fas Ligand as a Potential Marker of Severity of Dengue Infection. AB - BACKGROUND: The apoptosis of microvascular endothelial cells causes plasma leakage in dengue haemorrhagic fever patients. The soluble Fas ligand is a protein with molecular weight of 40 kDa that acts as a mediator of apoptosis. This study aimed to prove whether soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection by comparing the soluble Fas ligand levels in dengue fever (DF) and dengue haemorrhagic fever (DHF) patients early in the course of illness. METHOD: This was a prospective study. It included 42 dengue patients (22 DF patients and 20 DHF patients) and 20 healthy people as a control group. The soluble Fas ligand was measured by the enzyme-linked immunosorbent assay (ELISA). RESULT: Soluble Fas ligand was increased significantly (P < 0.001) in DHF patients (median = 130.19, IQR = 36.26) compared to DF patients (median = 104.73, IQR = 53.94) and the control group (median = 87.16, IQR = 24.91). CONCLUSION: Soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection in the early course of the illness. However, a larger sample size and further objective studies are needed to confirm these findings. PMID- 28894402 TI - Attachment, Proliferation, and Morphological Properties of Human Dermal Fibroblasts on Ovine Tendon Collagen Scaffolds: A Comparative Study. AB - INTRODUCTION: Collagen type I is widely used as a biomaterial for tissue engineered substitutes. This study aimed to fabricate different three-dimensional (3D) scaffolds using ovine tendon collagen type I (OTC-I), and compare the attachment, proliferation and morphological features of human dermal fibroblasts (HDF) on the scaffolds. METHODS: This study was conducted between the years 2014 to 2016 at the Tissue Engineering Centre, UKM Medical Centre. OTC-I was extracted from ovine tendon, and fabricated into 3D scaffolds in the form of sponge, hydrogel and film. A polystyrene surface coated with OTC-I was used as the 2D culture condition. Genipin was used to crosslink the OTC-I. A non-coated polystyrene surface was used as a control. The mechanical strength of OTC-I scaffolds was evaluated. Attachment, proliferation and morphological features of HDF were assessed and compared between conditions. RESULTS: The mechanical strength of OTC-I sponge was significantly higher than that of the other scaffolds. OTC-I scaffolds and the coated surface significantly enhanced HDF attachment and proliferation compared to the control, but no differences were observed between the scaffolds and coated surface. In contrast, the morphological features of HDF including spreading, filopodia, lamellipodia and actin cytoskeletal formation differed between conditions. CONCLUSION: OTC-I can be moulded into various scaffolds that are biocompatible and thus could be suitable as scaffolds for developing tissue substitutes for clinical applications and in vitro tissue models. However, further study is required to determine the effect of morphological properties on the functional and molecular properties of HDF. PMID- 28894403 TI - Corneal Cell Morphology in Keratoconus: A Confocal Microscopic Observation. AB - PURPOSE: To evaluate corneal cell morphology in patients with keratoconus using an in vivo slit scanning confocal microscope. METHODS: A cross-sectional study was conducted to evaluate the corneal cell morphology of 47 keratoconus patients and 32 healthy eyes without any ocular disease. New keratoconus patients with different disease severities and without any other ocular co-morbidity were recruited from the ophthalmology department of a public hospital in Malaysia from June 2013 to May 2014. Corneal cell morphology was evaluated using an in vivo slit-scanning confocal microscope. Qualitative and quantitative data were analysed using a grading scale and the Nidek Advanced Visual Information System software, respectively. RESULTS: The corneal cell morphology of patients with keratoconus was significantly different from that of healthy eyes except in endothelial cell density (P = 0.072). In the keratoconus group, increased level of stromal haze, alterations such as the elongation of keratocyte nuclei and clustering of cells at the anterior stroma, and dark bands in the posterior stroma were observed with increased severity of the disease. The mean anterior and posterior stromal keratocyte densities and cell areas among the different stages of keratoconus were significantly different (P < 0.001 and P = 0.044, respectively). However, the changes observed in the endothelium were not significantly different (P > 0.05) among the three stages of keratoconus. CONCLUSION: Confocal microscopy observation showed significant changes in corneal cell morphology in keratoconic cornea from normal healthy cornea. Analysis also showed significant changes in different severities of keratoconus. Understanding the corneal cell morphology changes in keratoconus may help in the long-term monitoring and management of keratoconus. PMID- 28894404 TI - An Internal Audit of Diabetes Care for Type 2 Diabetic Patients in a Public Hospital Diabetes Clinic in Malaysia. AB - INTRODUCTION: Earlier studies have identified a gap between guidelines and actual clinical diabetes care in Malaysia. OBJECTIVE: We audited the quality of care for patients with type 2 diabetes mellitus (T2DM) attending our diabetes clinic at a public hospital. METHODS: A structured review of the outpatient clinic cards, prescriptions and laboratory results was conducted for patients attending the diabetes clinic at Sibu Hospital in October and November 2014. RESULTS: For the total of 233 patients who were audited, the levels of fasting blood sugar, blood pressure, body mass index and fasting lipid profile were satisfactory at 99.1%, 99.6%, 92.6% and 99.6% respectively. 79.7% of the subjects had had HbA1c performed at least once over the previous six months. Only 25.8% had annual foot screening, while the eye screening rate was 71.2% and the albuminuria screening rate was 93.6%. For outcome measures, the mean (SD) HbA1c level was 9.2% (1.91%), with 13 patients (6.7%) having HbA1c less than 6.5%; 36.4% of participants achieved BP < 130/80 mmHg; and 69.4% had LDL < 2.6 mmol/L. The majority of the patients were overweight or obese (91.4%). CONCLUSIONS: Overall, the performance of diabetic care processes at our hospital was satisfactory, except for foot examination. The glycaemic and weight control among the subjects were suboptimal and warrant an optimised and comprehensive approach on the part of the management. PMID- 28894405 TI - Reliability and Validity of the Cross-Culturally Adapted Thai Version of the Tampa Scale for Kinesiophobia in Knee Osteoarthritis Patients. AB - PURPOSE: The aim of this study was to develop a cross-culturally adapted Thai version of the Tampa Scale for Kinesiophobia (TSK) and investigate its reliability and validity among patients with knee osteoarthritis. METHODS: The TSK was translated into Thai language and culturally adapted in line with the international standards. The Thai TSK questionnaire was then tested for internal consistency, test-retest reliability, and convergent validity by comparing it with the visual analogue scale, Western Ontario and McMaster Universities Osteoarthritis Index, State-Trait Anxiety Inventory, and Timed Up and Go Test. RESULTS: Eighty patients with knee osteoarthritis were included in the study. The Thai version of the TSK was easily comprehended and completed within 6 minutes. The questionnaire showed a good internal consistency (alpha = 0.90) and high test retest reliability {ICC (2,1) = 0.934}. Convergent validity showed high correlations with the visual analogue scale, Western Ontario and McMaster Universities Osteoarthritis Index, and State-Trait Anxiety Inventory (r = 0.741, 0.856, and 0.817, respectively). However, there was no significant correlation between the Thai version of the TSK scores and the Timed Up and Go Test results. CONCLUSION: The Thai version of the TSK has satisfactory reliability and validity for the evaluation of pain-related fear of movement/(re)injury in patients with knee osteoarthritis. PMID- 28894407 TI - Fluorescence-Guided versus Conventional Surgical Resection of High Grade Glioma: A Single-Centre, 7-Year, Comparative Effectiveness Study. AB - BACKGROUND: High grade gliomas (HGGs) are locally invasive brain tumours that carry a dismal prognosis. Although complete resection increases median survival, the difficulty in reliably demonstrating the tumour border intraoperatively is a norm. The Department of Neurosurgery, Hospital Sungai Buloh is the first public hospital in Malaysia to overcome this problem by adopting fluorescence-guided (FG) surgery using 5-aminolevulinic acid (5-ALA). METHODS: A total of 74 patients with histologically proven HGGs treated between January 2008 and December 2014, who fulfilled the inclusion criteria, were enrolled. Kaplan-Meier survival estimates and Cox proportional hazard regression were used. RESULTS: Significant longer survival time (months) was observed in the FG group compared with the conventional group (12 months versus 8 months, P < 0.020). Even without adjuvant therapy, HGG patients from FG group survived longer than those from the conventional group (8 months versus 3 months, P = 0.006). No significant differences were seen in postoperative Karnofsky performance scale (KPS) between the groups at 6 weeks and 6 months after surgery compared to pre-operative KPS. Cox proportional hazard regression identified four independent predictors of survival: KPS > 80 (P = 0.010), histology (P < 0.001), surgical method (P < 0.001) and adjuvant therapy (P < 0.001). CONCLUSION: This study showed a significant clinical benefit for HGG patients in terms of overall survival using FG surgery as it did not result in worsening of post-operative function outcome when compared with the conventional surgical method. We advocate a further multicentered, randomised controlled trial to support these findings before FG surgery can be implemented as a standard surgical adjunct in local practice for the benefit of HGG patients. PMID- 28894406 TI - Identification of Rotavirus Strains Causing Diarrhoea in Children under Five Years of Age in Yogyakarta, Indonesia. AB - BACKGROUND: Rotavirus is an important cause of severe diarrhoea in children. The aims of this study were to identify the rotavirus strains that cause diarrhoea in children in Yogyakarta and to determine the association between rotavirus positivity and its clinical manifestations. METHODS: Clinical data and stool samples were collected from children hospitalised at Kodya Yogyakarta Hospital, Indonesia. Rotavirus was detected in stool samples using an enzyme immunoassay (EIA), which was followed by genotyping using reverse transcriptase polymerase chain reaction (RT-PCR). Electropherotyping was performed for the rotavirus positive samples. RESULTS: In total, 104 cases were included in the study, 57 (54.8%) of which were rotavirus-positive. Based on a multiple logistic regression analysis, age group, vomiting and stool mucous were associated with rotavirus positivity. Most of the 56 samples subjected to genotyping were classified as G1 (80.36%) and P[8] (69.64%) genotypes. The genotype combination G1P[8] was identified as the most prevalent strain (66.07%). Of the 19 samples subjected to electropherotyping, 17 G1 isolates and 1 G3 isolate had long patterns, and 1 G1 isolate had a short pattern. CONCLUSION: G1P[8] was the most dominant strain of rotavirus causing diarrhoea in children in Yogyakarta. Age group, vomiting and stool mucous were associated with rotavirus positivity. PMID- 28894408 TI - Deep Brain Stimulation (DBS) for Movement Disorders: An Experience in Hospital Universiti Sains Malaysia (HUSM) Involving 12 Patients. AB - Deep brain stimulation (DBS) was first introduced in 1987 to the developed world. As a developing country Malaysia begun its movement disorder program by doing ablation therapy using the Radionics system. Hospital Universiti Sains Malaysia a rural based teaching hospital had to take into consideration both health economics and outcomes in the area that it was providing neurosurgical care for when it initiated its Deep Brain Stimulation program. Most of the patients were from the low to medium social economic groups and could not afford payment for a DBS implant. We concentrated our DBS services to Parkinson's disease, Tourette's Syndrome and dystonia patients who had exhausted medical therapy. The case series of these patients and their follow-up are presented in this brief communication. PMID- 28894409 TI - The Effect of 4-hydroxybenzaldehyde on the gamma-aminobutyric Acid Type A Receptor. AB - The alpha1beta2gamma2 subtype of GABAA receptors is the most commonly found GABAA receptor subtype in the mammalian cortex and hippocampus. It is expressed heterologously in the Xenopus laevis oocyte as a alpha1beta2gamma2S/L subtype for application as an in vitro model for the screening of compounds that modulate receptor activities. In fact, 4-hydroxybenzaldehyde (4-HB) has been identified as one of the major components in Dendrocalamus asper bamboo shoots in our previous study, and the current study showed that at 101.7 MUM, 4-HB significantly reduced the GABA-induced chloride current of GABAA receptors expressed on Xenopus oocytes, indicating a possible GABAergic antagonistic effect at high concentrations. PMID- 28894410 TI - Life-Threatening Dyskalaemia after Barbiturate Coma Therapy: The Strategy of Management. AB - Barbiturate coma therapy (BCT) is a treatment option that is used for refractory intracranial hypertension after all other options have been exhausted. Although BCT is a brain protection treatment, it also has several side effects such as hypotension, hepatic dysfunction, renal dysfunction, respiratory complications and electrolyte imbalances. One less concerning but potentially life-threatening complication of BCT is dyskalaemia. This complication could present as severe refractory hypokalaemia during the therapy with subsequent rebound hyperkalaemia after cessation of the therapy. Judicious potassium replacement during severe refractory hypokalaemia and gradual cessation of the therapy to prevent rebound hyperkalaemia are recommended strategies to deal with this complication, based on previous case series and reports. In this case report, we show that these strategies were applicable in improving severe hypokalaemia and preventing sudden, life-threatening rebound hyperkalaemia. However, even with use of these strategies, BCT patients could still present with mild, asymptomatic hyperkalaemia. PMID- 28894411 TI - Bilateral Hydroureteronephrosis with a Hypertrophied, Trabeculated Urinary Bladder. AB - Bilateral hydroureteronephrosis involves the dilatation of the renal pelvis, calyces and ureter; it develops secondary to urinary tract obstruction and leads to a build-up of back pressure in the urinary tract, and it may lead to impairment of renal function and ultimately culminate in renal failure. Although clinically silent in most cases, it can be diagnosed as an incidental finding during evaluation of an unrelated cause. In a minority of patients, it presents with signs and symptoms. Renal calculus is the most common cause, but there are multiple non-calculus aetiologies, and they depend on age and sex. Pelviureteric junction obstruction, benign prostatic hypertrophy, urethral stricture, neurogenic bladder, retroperitoneal mass and bladder outlet obstruction are some of the frequent causes of hydroureteronephrosis in adults. The incidence of non calculus hydronephrosis is more common in males than in females. Ultrasonography is the most important baseline investigation in the evaluation of patients with hydronephrosis. Here, we report a rarely seen case of bilateral hydroureteronephrosis associated with a hypertrophied, trabeculated bladder in an adult male cadaver, suspected to be due to a primary bladder neck obstruction, and analyse its various other causes, clinical presentations and outcomes. PMID- 28894412 TI - Recording Spikes Activity in Cultured Hippocampal Neurons Using Flexible or Transparent Graphene Transistors. AB - The emergence of nanoelectronics applied to neural interfaces has started few decades ago, and aims to provide new tools for replacing or restoring disabled functions of the nervous systems as well as further understanding the evolution of such complex organization. As the same time, graphene and other 2D materials have offered new possibilities for integrating micro and nano-devices on flexible, transparent, and biocompatible substrates, promising for bio and neuro electronics. In addition to many bio-suitable features of graphene interface, such as, chemical inertness and anti-corrosive properties, its optical transparency enables multimodal approach of neuronal based systems, the electrical layer being compatible with additional microfluidics and optical manipulation ports. The convergence of these fields will provide a next generation of neural interfaces for the reliable detection of single spike and record with high fidelity activity patterns of neural networks. Here, we report on the fabrication of graphene field effect transistors (G-FETs) on various substrates (silicon, sapphire, glass coverslips, and polyimide deposited onto Si/SiO2 substrates), exhibiting high sensitivity (4 mS/V, close to the Dirac point at VLG < VD) and low noise level (10-22 A2/Hz, at VLG = 0 V). We demonstrate the in vitro detection of the spontaneous activity of hippocampal neurons in-situ-grown on top of the graphene sensors during several weeks in a millimeter size PDMS fluidics chamber (8 mm wide). These results provide an advance toward the realization of biocompatible devices for reliable and high spatio-temporal sensing of neuronal activity for both in vitro and in vivo applications. PMID- 28894413 TI - The Attentional Drift Diffusion Model of Simple Perceptual Decision-Making. AB - Perceptual decisions requiring the comparison of spatially distributed stimuli that are fixated sequentially might be influenced by fluctuations in visual attention. We used two psychophysical tasks with human subjects to investigate the extent to which visual attention influences simple perceptual choices, and to test the extent to which the attentional Drift Diffusion Model (aDDM) provides a good computational description of how attention affects the underlying decision processes. We find evidence for sizable attentional choice biases and that the aDDM provides a reasonable quantitative description of the relationship between fluctuations in visual attention, choices and reaction times. We also find that exogenous manipulations of attention induce choice biases consistent with the predictions of the model. PMID- 28894414 TI - Hemodynamic Perturbations in Deep Brain Stimulation Surgery: First Detailed Description. AB - Background: Hemodynamic perturbations can be anticipated in deep brain stimulation (DBS) surgery and may be attributed to multiple factors. Acute changes in hemodynamics may produce rare but severe complications such as intracranial bleeding, transient ischemic stroke and myocardium infarction. Therefore, this retrospective study attempts to determine the incidence of hemodynamic perturbances (rate) and related risk factors in patients undergoing DBS surgery. Materials and Methods: After institutional approval, all patients undergoing DBS surgery for the past 10 years were recruited for this study. Demographic characteristics, procedural characteristics and intraoperative hemodynamic changes were noted. Event rate was calculated and the effect of all the variables on hemodynamic perturbations was analyzed by regression model. Results: Total hemodynamic adverse events during DBS surgery was 10.8 (0-42) and treated in 57% of cases. Conclusion: Among all the perioperative variables, the baseline blood pressure including systolic, diastolic, and mean arterial pressure was found to have highly significant effect on these intraoperative hemodynamic perturbations. PMID- 28894415 TI - Loss of FMRP Impaired Hippocampal Long-Term Plasticity and Spatial Learning in Rats. AB - Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene that inactivate expression of the gene product, the fragile X mental retardation 1 protein (FMRP). In this study, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology to generate Fmr1 knockout (KO) rats by disruption of the fourth exon of the Fmr1 gene. Western blotting analysis confirmed that the FMRP was absent from the brains of the Fmr1 KO rats (Fmr1exon4-KO ). Electrophysiological analysis revealed that the theta-burst stimulation (TBS)-induced long-term potentiation (LTP) and the low-frequency stimulus (LFS)-induced long-term depression (LTD) were decreased in the hippocampal Schaffer collateral pathway of the Fmr1exon4-KO rats. Short-term plasticity, measured as the paired-pulse ratio, remained normal in the KO rats. The synaptic strength mediated by the alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was also impaired. Consistent with previous reports, the Fmr1exon4-KO rats demonstrated an enhanced 3,5-dihydroxyphenylglycine (DHPG)-induced LTD in the present study, and this enhancement is insensitive to protein translation. In addition, the Fmr1exon4-KO rats showed deficits in the probe trial in the Morris water maze test. These results demonstrate that deletion of the Fmr1 gene in rats specifically impairs long-term synaptic plasticity and hippocampus-dependent learning in a manner resembling the key symptoms of FXS. Furthermore, the Fmr1exon4-KO rats displayed impaired social interaction and macroorchidism, the results consistent with those observed in patients with FXS. Thus, Fmr1exon4-KO rats constitute a novel rat model of FXS that complements existing mouse models. PMID- 28894416 TI - Insm1a Regulates Motor Neuron Development in Zebrafish. AB - Insulinoma-associated1a (insm1a) is a zinc-finger transcription factor playing a series of functions in cell formation and differentiation of vertebrate central and peripheral nervous systems and neuroendocrine system. However, its roles on the development of motor neuron have still remained uncovered. Here, we provided evidences that insm1a was a vital regulator of motor neuron development, and provided a mechanistic understanding of how it contributes to this process. Firstly, we showed the localization of insm1a in spinal cord, and primary motor neurons (PMNs) of zebrafish embryos by in situ hybridization, and imaging analysis of transgenic reporter line Tg(insm1a: mCherry)ntu805 . Then we demonstrated that the deficiency of insm1a in zebrafish larvae lead to the defects of PMNs development, including the reduction of caudal primary motor neurons (CaP), and middle primary motor neurons (MiP), the excessive branching of motor axons, and the disorganized distance between adjacent CaPs. Additionally, knockout of insm1 impaired motor neuron differentiation in the spinal cord. Locomotion analysis showed that swimming activity was significantly reduced in the insm1a-null zebrafish. Furthermore, we showed that the insm1a loss of function significantly decreased the transcript levels of both olig2 and nkx6.1. Microinjection of olig2 and nkx6.1 mRNA rescued the motor neuron defects in insm1a deficient embryos. Taken together, these data indicated that insm1a regulated the motor neuron development, at least in part, through modulation of the expressions of olig2 and nkx6.1. PMID- 28894417 TI - Myosin-V Induces Cargo Immobilization and Clustering at the Axon Initial Segment. AB - The selective transport of different cargoes into axons and dendrites underlies the polarized organization of the neuron. Although it has become clear that the combined activity of different motors determines the destination and selectivity of transport, little is known about the mechanistic details of motor cooperation. For example, the exact role of myosin-V in opposing microtubule-based axon entries has remained unclear. Here we use two orthogonal chemically-induced heterodimerization systems to independently recruit different motors to cargoes. We find that recruiting myosin-V to kinesin-propelled cargoes at approximately equal numbers is sufficient to stall motility. Kinesin-driven cargoes entering the axon were arrested in the axon initial segment (AIS) upon myosin-V recruitment and accumulated in distinct actin-rich hotspots. Importantly, unlike proposed previously, myosin-V did not return these cargoes to the cell body, suggesting that additional mechanism are required to establish cargo retrieval from the AIS. PMID- 28894418 TI - What Is Art Good For? The Socio-Epistemic Value of Art. AB - Scientists, humanists, and art lovers alike value art not just for its beauty, but also for its social and epistemic importance; that is, for its communicative nature, its capacity to increase one's self-knowledge and encourage personal growth, and its ability to challenge our schemas and preconceptions. However, empirical research tends to discount the importance of such social and epistemic outcomes of art engagement, instead focusing on individuals' preferences, judgments of beauty, pleasure, or other emotional appraisals as the primary outcomes of art appreciation. Here, we argue that a systematic neuroscientific study of art appreciation must move beyond understanding aesthetics alone, and toward investigating the social importance of art appreciation. We make our argument for such a shift in focus first, by situating art appreciation as an active social practice. We follow by reviewing the available psychological and cognitive neuroscientific evidence that art appreciation cultivates socio epistemic skills such as self- and other-understanding, and discuss philosophical frameworks which suggest a more comprehensive empirical investigation. Finally, we argue that focusing on the socio-epistemic values of art engagement highlights the important role art plays in our lives. Empirical research on art appreciation can thus be used to show that engagement with art has specific social and personal value, the cultivation of which is important to us as individuals, and as communities. PMID- 28894419 TI - Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity. AB - Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015) have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels) shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process. Additionally, synergistic effects may be obtained by library design toward polypharmacology. PMID- 28894420 TI - Exosomes As Potential Biomarkers and Targeted Therapy in Colorectal Cancer: A Mini-Review. AB - The number of colorectal cancer (CRC) cases have increased gradually year by year. In fact, CRC is one of the most widely diagnosed cancer in men and women today. This disease is usually diagnosed at a later stage of the development, and by then, the chance of survival has declined significantly. Even though substantial progress has been made in understanding the basic molecular mechanism of CRC, there is still a lack of understanding in using the available information for diagnosing CRC effectively. Liquid biopsies are minimally invasive and have become the epitome of a good screening source for stage-specific diagnosis, measuring drug response and severity of the disease. There are various circulating entities that can be found in biological fluids, and among them, exosomes, have been gaining considerable attention. Exosomes can be found in almost all biological fluids including serum, urine, saliva, and breast milk. Furthermore, exosomes carry valuable molecular information such as proteins and nucleic acids that directly reflects the source of the cells. Nevertheless, the inconsistent yield and isolation process and the difficulty in obtaining pure exosomes have become major obstacles that need to be addressed. The potential usage of exosomes as biomarkers have not been fully validated and explored yet. This review attempts to uncover the potential molecules that can be derived from CRC-exosomes as promising biomarkers or molecular targets for effective diagnosing of CRC. PMID- 28894421 TI - Impact of Different Personal Protective Clothing on Wildland Firefighters' Physiological Strain. AB - Wildfire firefighting is an extremely demanding occupation performed under hot environment. The use of personal protective clothing (PPC) is needed to protect subjects from the thermal exposure. However, the additional use of PPC may increase the wildland firefighters' physiological strain, and consequently limit their performance. The aim of this study was to analyze the effect of four different PPC on the physiological strain of wildland firefighters under moderate conditions (30 degrees C and 30% RH). Eight active and healthy wildland firefighters performed a submaximal walking test wearing a traditional short sports gear and 4 different PPC. The materials combination (viscose, Nomex, Kevlar, P-140 and fire resistant cotton) used during the PPC manufacturing process was different. During all tests, to simulate a real scenario subjects wore a backpack pump (20 kg). Heart rate, respiratory gas exchange, gastrointestinal temperature, blood lactate concentration, perceived exertion and temperature and humidity underneath the PPC were recorded throughout tests. Additionally, parameters of heat balance were estimated. Wearing a PPC did not cause a significant increase in the subjects' physiological response. The gastrointestinal temperature increment, the relative humidity of the microclimate underneath the PPC, the sweat residue in PPC, the sweat efficiency, the dry heat exchange and the total clothing insulation were significantly affected according to the PPC fabric composition. These results suggest that the PPC composition affect the moisture management. This might be taken into account to increase the wildland firefighters' protection in real situations, when they have to work close to the flames. PMID- 28894422 TI - Does Heel Height Cause Imbalance during Sit-to-Stand Task: Surface EMG Perspective. AB - The purpose of this study was to determine whether electromyography (EMG) muscle activities around the knee differ during sit-to-stand (STS) and returning task for females wearing shoes with different heel heights. Sixteen healthy young women (age = 25.2 +/- 3.9 years, body mass index = 20.8 +/- 2.7 kg/m2) participated in this study. Electromyography signals were recorded from the two muscles, vastus medialis (VM) and vastus lateralis (VL) that involve in the extension of knee. The participants wore shoes with five different heights, including 4, 6, 8, 10, and 12 cm. Surface electromyography (sEMG) data were acquired during STS and stand-to-sit-returning (STSR) tasks. The data was filtered using a fourth order Butterworth (band pass) filter of 20-450 Hz frequency range. For each heel height, we extracted median frequency (MDF) and root mean square (RMS) features to measure sEMG activities between VM and VL muscles. The experimental results (based on MDF and RMS-values) indicated that there is imbalance between vasti muscles for more elevated heels. The results are also quantified with statistical measures. The study findings suggest that there would be an increased likelihood of knee imbalance and fatigue with regular usage of high heel shoes (HHS) in women. PMID- 28894424 TI - Editorial: Function of Renal Sympathetic Nerves. PMID- 28894423 TI - beta-Adrenergic Inhibition Prevents Action Potential and Calcium Handling Changes during Regional Myocardial Ischemia. AB - beta-adrenergic receptor (beta-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of beta-AR blockers on ventricular electrophysiology and intracellular Ca2+ handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca2+ (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts (n = 19). The impact of beta-AR inhibition on isolated hearts was assessed by pre-treatment with 100 nM propranolol (Prop) prior to ischemia (n = 7). To control for chronotropy and inotropy, hearts were continuously paced at 3.3 Hz and contraction was inhibited with 20 MUM blebbistatin. Untreated ischemic hearts displayed prototypical shortening of action potential duration (APD80) in the ischemic zone (IZ) compared to the non-ischemic zone (NI) at 10 and 15 min ischemia, whereas APD shortening was prevented with Prop. Untreated ischemic hearts also displayed significant changes in SR Ca2+ handling in the IZ, including prolongation of SR Ca2+ reuptake and SR Ca2+ alternans, which were prevented with Prop pre treatment. At 5 min ischemia, Prop pre-treated hearts also showed larger SR Ca2+ release amplitude in the IZ compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, beta-AR inhibition has a favorable effect during acute regional ischemia via direct effects on APD and Ca2+ handling. PMID- 28894425 TI - Analysis of Wearable and Smartphone-Based Technologies for the Measurement of Barbell Velocity in Different Resistance Training Exercises. AB - The purpose of this study was to analyze the validity, reliability, and accuracy of new wearable and smartphone-based technology for the measurement of barbell velocity in resistance training exercises. To do this, 10 highly trained powerlifters (age = 26.1 +/- 3.9 years) performed 11 repetitions with loads ranging 50-100% of the 1-Repetition maximum in the bench-press, full-squat, and hip-thrust exercises while barbell velocity was simultaneously measured using a linear transducer (LT), two Beast wearable devices (one placed on the subjects' wrist -BW-, and the other one directly attached to the barbell -BB-) and the iOS PowerLift app. Results showed a high correlation between the LT and BW (r = 0.94 0.98, SEE = 0.04-0.07 m*s-1), BB (r = 0.97-0.98, SEE = 0.04-0.05 m*s-1), and the PowerLift app (r = 0.97-0.98, SEE = 0.03-0.05 m*s-1) for the measurement of barbell velocity in the three exercises. Paired samples T-test revealed systematic biases between the LT and BW, BB and the app in the hip-thrust, between the LT and BW in the full-squat and between the LT and BB in the bench press exercise (p < 0.001). Moreover, the analysis of the linear regression on the Bland-Altman plots showed that the differences between the LT and BW (R2 = 0.004-0.03), BB (R2 = 0.007-0.01), and the app (R2 = 0.001-0.03) were similar across the whole range of velocities analyzed. Finally, the reliability of the BW (ICC = 0.910-0.988), BB (ICC = 0.922-0.990), and the app (ICC = 0.928-0.989) for the measurement of the two repetitions performed with each load were almost the same than that observed with the LT (ICC = 0.937-0.990). Both the Beast wearable device and the PowerLift app were highly valid, reliable, and accurate for the measurement of barbell velocity in the bench-press, full-squat, and hip-thrust exercises. These results could have potential practical applications for strength and conditioning coaches who wish to measure barbell velocity during resistance training. PMID- 28894426 TI - More Reasons to Move: Exercise in the Treatment of Alcohol Use Disorders. PMID- 28894427 TI - Hypernetworks Reveal Compound Variables That Capture Cooperative and Competitive Interactions in a Soccer Match. AB - The combination of sports sciences theorization and social networks analysis (SNA) has offered useful new insights for addressing team behavior. However, SNA typically represents the dynamics of team behavior during a match in dyadic interactions and in a single cumulative snapshot. This study aims to overcome these limitations by using hypernetworks to describe illustrative cases of team behavior dynamics at various other levels of analyses. Hypernetworks simultaneously access cooperative and competitive interactions between teammates and opponents across space and time during a match. Moreover, hypernetworks are not limited to dyadic relations, which are typically represented by edges in other types of networks. In a hypernetwork, n-ary relations (with n > 2) and their properties are represented with hyperedges connecting more than two players simultaneously (the so-called simplex-plural, simplices). Simplices can capture the interactions of sets of players that may include an arbitrary number of teammates and opponents. In this qualitative study, we first used the mathematical formalisms of hypernetworks to represent a multilevel team behavior dynamics, including micro (interactions between players), meso (dynamics of a given critical event, e.g., an attack interaction), and macro (interactions between sets of players) levels. Second, we investigated different features that could potentially explain the occurrence of critical events, such as, aggregation or disaggregation of simplices relative to goal proximity. Finally, we applied hypernetworks analysis to soccer games from the English premier league (season 2010-2011) by using two-dimensional player displacement coordinates obtained with a multiple-camera match analysis system provided by STATS (formerly Prozone). Our results show that (i) at micro level the most frequently occurring simplices configuration is 1vs.1 (one attacker vs. one defender); (ii) at meso level, the dynamics of simplices transformations near the goal depends on significant changes in the players' speed and direction; (iii) at macro level, simplices are connected to one another, forming "simplices of simplices" including the goalkeeper and the goal. These results validate qualitatively that hypernetworks and related compound variables can capture and be used in the analysis of the cooperative and competitive interactions between players and sets of players in soccer matches. PMID- 28894428 TI - An Integrative Perspective on Interpersonal Coordination in Interactive Team Sports. AB - Interpersonal coordination is a key factor in team performance. In interactive team sports, the limited predictability of a constantly changing context makes coordination challenging. Approaches that highlight the support provided by environmental information and theories of shared mental models provide potential explanations of how interpersonal coordination can nonetheless be established. In this article, we first outline the main assumptions of these approaches and consider criticisms that have been raised with regard to each. The aim of this article is to define a theoretical perspective that integrates the coordination mechanisms of the two approaches. In doing so, we borrow from a theoretical outline of group action. According to this outline, group action based on a priori shared mental models is an example of how interpersonal coordination is established from the top down. Interpersonal coordination in reaction to the perception of affordances represents the bottom-up component of group action. Both components are inextricably involved in the coordination of interactive sports teams. We further elaborate on the theoretical outline to integrate a third, constructivist approach. Integrating this third approach helps to explain interpersonal coordination in game situations for which no shared mental models are established and game situations that remain ambiguous in terms of perceived affordances. The article describes how hierarchical, sequential, and complex dimensions of action organization are important aspects of this constructivist perspective and how mental models may be involved. A basketball example is used to illustrate how top-down, bottom-up and constructivist processes may be simultaneously involved in enabling interpersonal coordination. Finally, we present the implications for research and practice. PMID- 28894429 TI - Circumventing the "Ick" Factor: A Randomized Trial of the Effects of Omitting Affective Attitudes Questions to Increase Intention to Become an Organ Donor. AB - Objectives: Including or excluding certain questions about organ donation may influence peoples' intention to donate. We investigated the effect of omitting certain affective attitudinal items on potential donors' intention and behavior for donation. Design: A cross-sectional survey with a subgroup nested randomized trial. Methods: A total of 578 members of the public in four shopping centers were surveyed on their attitudes to organ donation. Non-donors (n = 349) were randomly assigned to one of three groups: Group 1 completed items on affective and cognitive attitudes, anticipated regret, intention, subjective norm and perceived behavioral control. Group 2 completed all items above but excluded affective attitudes. Group 3 completed all items but omitted negatively worded affective attitudes. The primary outcome was intention to donate, taking a donor card after the interview was a secondary behavioral outcome, and both were predicted using linear and logistic regression with group 1 as the reference. Results: Mean (SD) 1-7 intention scores for groups 1, 2 and 3 were, respectively: 4.43 (SD 1.89), 4.95 (SD 1.64) and 4.88 (SD 1.81), with group 2 significantly higher than group 1 (beta = 0.518, 95% confidence interval [CI] 0.18 to 0.86).At the end of the interview, people in group 2 (66.7%; OR = 1.40, 95% CI 0.94 to 2.07, p = 0.096) but not those in group 3 (61.7%; OR = 1.10, 95% CI 0.69 to 1.75, p = 0.685), were marginally more likely to accept a donor card from the interviewer than people in group 1 (59.7%). Conclusion: Omitting affective attitudinal items results in higher intention to donate organs and marginally higher rates of acceptance of donor cards, which has important implications for future organ donation public health campaigns. PMID- 28894430 TI - Associations between a Leader's Work Passion and an Employee's Work Passion: A Moderated Mediation Model. AB - Based on the theory of emotional contagion and goal content, this study explored the positive associations between a leader's work passion and employees' work passion. This study investigated 364 employees and their immediate leaders from China, constructed a moderated mediation model, and used SPSS-PROCESS in conjunction with the Johnson-Neyman technique to analyze the data. The results showed that a leader's work passion was transferred to employees via emotional contagion, and the contagion process was moderated by leader-employee goal content congruence. This study provides a potential way to stimulate employees' work passion from the perspective of leader-employee interactions. Moreover, the limitations of the study and potential topics for future research are discussed. PMID- 28894431 TI - "I Want, Therefore I Am" - Anticipated Upward Mobility Reduces Ingroup Concern. AB - Empirical findings suggest that members of socially disadvantaged groups who join a better-valued group through individual achievement tend to express low concern for their disadvantaged ingroup (e.g., denial of collective discrimination, low intent to initiate collective action). In the present research, we investigated whether this tendency occurs solely for individuals who have already engaged in social mobility, or also for individuals who psychologically prepare themselves, that is 'anticipate', social mobility. Moreover, we examined the role of group identification in this process. In two studies, we looked at the case of 'frontier workers', that is people who cross a national border every day to work in another country where the salaries are higher thereby achieving a better socio economic status than in their home-country. Study 1 (N = 176) examined attitudes of French nationals (both the socially mobile and the non-mobile) and of Swiss nationals toward the non-mobile group. As expected, results showed that the mobile French had more negative attitudes than their non-mobile counterparts, but less negative attitudes than the Swiss. In Study 2 (N = 216), we examined ingroup concern at different stages of the social mobility process by comparing the attitudes of French people who worked in Switzerland (mobile individuals), with those who envisioned (anticipators), or not (non-anticipators), to work in Switzerland. The findings revealed that anticipators' motivation to get personally involved in collective action for their French ingroup was lower than the non-anticipators', but higher than the mobile individuals'. Moreover, we found that the decrease in ingroup concern across the different stages of social mobility was accounted for by a lower identification with the inherited ingroup. These findings corroborate the deleterious impact of social mobility on attitudes toward a low-status ingroup, and show that the decrease in ingroup concern already occurs among individuals who anticipate moving up the hierarchy. The discussion focuses on the role of the discounting of inherited identities in both the anticipation and the achievement of a higher-status identity. PMID- 28894432 TI - Behavioral Changes in Patients with Multiple Sclerosis. AB - BACKGROUND: Behavioral changes are common in patients with multiple sclerosis (MS), however not as readily recognized as cognitive impairments. OBJECTIVE: The aim of this study was to analyze behavioral changes and its relation to disease characteristics, disability, and cognitive impairments in patients with MS. METHOD: This is a single-center cross-sectional study. A detailed neuropsychological examination, including the Frontal Systems Behavior Scale (FrSBe), the Beck depression inventory (BDI), and the Wuerzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) test, was performed. FrSBe results were correlated with disease characteristics, disability, and cognitive assessments. RESULTS: 66 patients were enrolled (mean age: 43.4 years; disease duration: 9.3 years; Expanded Disability Status Scale: 3.0). Up to one third of patients showed behavioral changes in at least one domain or the total score of the FrSBe. Patients were mildly affected with regard to cognitive functioning. Consistent correlation was found between behavioral changes and fatigue (WEIMuS) and depressive symptoms (BDI), but not with disease characteristics, disability, or cognitive functions. There was an increase of behavioral changes on all FrSBe scales in the current status compared to the retrospectively rated status before disease onset. Self- and family ratings with regard to current behavioral changes were similar. CONCLUSION: Behavioral changes are common in otherwise mildly affected MS patients with up to one third being affected. In this patient cohort, behavioral changes occur largely independent of disease characteristics, physical disability, and cognitive functioning but correlate with both fatigue and depressive symptoms. Therefore, they should be tested specifically. PMID- 28894433 TI - Amino Acids in Cerebrospinal Fluid of Patients with Aneurysmal Subarachnoid Haemorrhage: An Observational Study. AB - BACKGROUND: The authors are aware of only one article investigating amino acid concentrations in cerebrospinal fluid (CSF) in patients with ruptured intracranial aneurysms, and this was published 31 years ago. Since then, both management of subarachnoid haemorrhage (SAH) and amino acid assay techniques have seen radical alterations, yet the pathophysiology of SAH remains unclear. OBJECTIVE: To analyse the pattern of concentrations of amino acids and related compounds in patients with different outcomes following aneurysmal SAH. METHODS: 49 CSF samples were collected from 23 patients on days 0-3, 5, and 10 post-SAH. Concentrations of 33 amino acids and related compounds were assayed by liquid chromatography tandem mass spectrometry in patients with good [Glasgow Outcome Scale (GOS) 1-3] and poor (GOS 4-5) outcome. RESULTS: Of the 33 compounds assayed, only hydroxyproline and 3-aminoisobutyric acid appeared not to increase significantly following SAH. In poor outcome patients, we found significantly higher concentrations of aspartic acid (p = 0.038), glutamic acid (p = 0.038), and seven other compounds on days 0-3 post-SAH; glutamic acid (p = 0.041) on day 5 post-SAH, and 2-aminoadipic acid (p = 0.033) on day 10 post-SAH. The most significant correlation with GOS at 3 months was found for aminoadipic acid on day 10 post-SAH (cc = -0.81). CONCLUSION: Aneurysmal rupture leads to a generalised increase of amino acids and related compounds in CSF. The patterns differ between good and poor outcome cases. Increased excitatory amino acids are strongly indicative of poor outcome. PMID- 28894434 TI - Tinnitus Patients with Comorbid Headaches: The Influence of Headache Type and Laterality on Tinnitus Characteristics. AB - BACKGROUND: Both clinical experience and clinical studies suggest a relationship between tinnitus and headache. Here, we aimed to investigate the influence of comorbid headache type and headache laterality on tinnitus characteristics. METHOD: The Tinnitus Research Initiative database was screened for patients of the Tinnitus Center of the University Regensburg who reported comorbid headaches. These patients were contacted to complete additional validated questionnaires. Based on these data, patients were categorized according to headache type and headache laterality, and their clinical characteristics were compared with tinnitus patients, who did not report comorbid headaches. RESULTS: Data from 193 patients with tinnitus and comorbid headaches were compared with those from 765 tinnitus patients without comorbid headaches. Tinnitus patients with comorbid headache have higher scores in tinnitus questionnaires, a lower quality of life and more frequently comorbidities such as painful sensation to loud sounds, vertigo, pain (neck, temporomandibular, and general), and depressive symptoms when compared with tinnitus patients without headaches. Both headache laterality and headache type interact with the degree of comorbidity with higher impairment in patients with left-sided and bilateral headaches as well as in patients with migraine or cluster headache. CONCLUSION: The observed increased impairment in tinnitus patients with comorbid headache can be explained as an additive effect of both disorders on health-related quality of life. The more frequent occurrence of further comorbidities suggests a generally increased amplification of sensory signals in a subset of tinnitus patients with comorbid headaches. PMID- 28894435 TI - Neuroactive Steroids: Receptor Interactions and Responses. AB - Neuroactive steroids (NASs) are naturally occurring steroids, which are synthesized centrally as de novo from cholesterol and are classified as pregnane, androstane, and sulfated neurosteroids (NSs). NASs modulate many processes via interacting with gamma-aminobutyric acid (GABA), N-methyl-d-aspartate, serotonin, voltage-gated calcium channels, voltage-dependent anion channels, alpha adrenoreceptors, X-receptors of the liver, transient receptor potential channels, microtubule-associated protein 2, neurotrophin nerve growth factor, and sigma1 receptors. Among these, NSs (especially allopregnanolone) have high potency and extensive GABA-A receptors and hence demonstrate anticonvulsant, anesthetic, central cytoprotectant, and baroreflex inhibitory effects. NSs are also involved in mood and learning via serotonin and anti-nociceptive activity via T-type voltage-gated Ca2+ channels. Moreover, they are modulators of mitochondrial function, synaptic plasticity, or regulators of apoptosis, which have a role in neuroprotective via voltage-dependent anion channels receptors. For proper functioning, NASs need to be in their normal level, whereas excess and deficiency may lead to abnormalities. When they are below the normal, NSs could have a part in development of depression, neuro-inflammation, multiple sclerosis, experimental autoimmune encephalitis, epilepsy, and schizophrenia. On the other hand, stress and attention deficit disorder could occur during excessive level. Overall, NASs are very important molecules with major neuropsychiatric activity. PMID- 28894436 TI - Serum Thyroid Hormone Antibodies Are Frequent in Patients with Polyglandular Autoimmune Syndrome Type 3, Particularly in Those Who Require Thyroxine Treatment. AB - Polyglandular autoimmune syndrome (PAS) type 3 consists of autoimmune thyroid disease (AITD) coexisting with >=1 non-thyroidal autoimmune disease (NTAID) other than Addison's disease and hypoparathyroidism. We evaluated the prevalence and repertoire of thyroid hormones antibodies (THAb) in PAS-3 patients. Using a radioimmunoprecipation technique, we measured THAb (T3IgM, T3IgG, T4IgM, and T4IgG) in 107 PAS-3 patients and 88 controls (patients with AITD without any NTAID). Based on the selective coexistence of AITD with one NTAID (chronic autoimmune gastritis, non-segmental vitiligo or celiac disease), patients were divided into group 1 (chronic autoimmune gastritis positive, n = 64), group 2 (non-segmental vitiligo positive, n = 24), and group 3 (celiac disease positive, n = 15). At least one of the four THAb was detected in 45 PAS-3 patients (42.1%) and 28 controls (31.8%, P = 0.14), with similar rates in the three PAS-3 groups. The rates of T3Ab, T4Ab, and T3 + T4Ab were similar in groups 1 and 2, while in group 3, T3Ab was undetected (P = 0.02). In PAS-3 patients, the rate of levothyroxine treatment was greater in THAb-positive patients compared to THAb negative patients (76.7 vs. 56.1%, P = 0.03, RR = 1.4, 95% CI 1.03-1.81). Not unexpectedly, levothyroxine daily dose was significantly higher in group 1 and group 3, namely in patients with gastrointestinal disorders, compared to group 2 (1.9 +/- 0.4 and 1.8 +/- 0.3 vs. 1.5 +/- 0.2 MUg/kg body weight, P = 0.0005 and P = 0.004). Almost half of PAS-3 patients have THAb, whose repertoire is similar if chronic autoimmune gastritis or celiac disease is present. A prospective study would confirm whether THAb positivity predicts greater likelihood of requiring levothyroxine treatment. PMID- 28894437 TI - Evolution of Stenotrophomonas maltophilia in Cystic Fibrosis Lung over Chronic Infection: A Genomic and Phenotypic Population Study. AB - Stenotrophomonas maltophilia has been recognized as an emerging multi-drug resistant opportunistic pathogen in cystic fibrosis (CF) patients. We report a comparative genomic and phenotypic analysis of 91 S. maltophilia strains from 10 CF patients over a 12-year period. Draft genome analyses included in silico Multi Locus Sequence Typing (MLST), Single-Nucleotide Polymorphisms (SNPs), and pangenome characterization. Growth rate, biofilm formation, motility, mutation frequency, in vivo virulence, and in vitro antibiotic susceptibility were determined and compared with population structure over time. The population consisted of 20 different sequence types (STs), 11 of which are new ones. Pangenome and SNPs data showed that this population is composed of three major phylogenetic lineages. All patients were colonized by multiple STs, although most of them were found in a single patient and showed persistence over years. Only few phenotypes showed some correlation with population phylogenetic structure. Our results show that S. maltophilia adaptation to CF lung is associated with consistent genotypic and phenotypic heterogeneity. Stenotrophomonas maltophilia infecting multiple hosts likely experiences different selection pressures depending on the host environment. The poor genotype-phenotype correlation suggests the existence of complex regulatory mechanisms that need to be explored in order to better design therapeutic strategies. PMID- 28894438 TI - Characterization of Enterococcus Isolates Colonizing the Intestinal Tract of Intensive Care Unit Patients Receiving Selective Digestive Decontamination. AB - Enterococci have emerged as important opportunistic pathogens in intensive care units (ICUs). In this study, enterococcal population size and Enterococcus isolates colonizing the intestinal tract of ICU patients receiving Selective Digestive Decontamination (SDD) were investigated. All nine patients included in the study showed substantial shifts in the enterococcal 16S rRNA gene copy number in the gut microbiota during the hospitalization period. Furthermore, 41 Enterococcus spp. strains were isolated and characterized from these patients at different time points during and after ICU hospitalization, including E. faecalis (n = 13), E. faecium (n = 23), and five isolates that could not unequivocally assigned to a specific species (E. sp. n = 5) Multi locus sequence typing revealed a high prevalence of ST 6 in E. faecalis isolates (46%) and ST 117 in E. faecium (52%). Furthermore, antibiotic resistance phenotypes, including macrolide and vancomycin resistance, as well as virulence factor-encoding genes [asa1, esp fm, esp-fs, hyl, and cyl (B)] were investigated in all isolates. Resistance to ampicillin and tetracycline was observed in 25 (61%) and 19 (46%) isolates, respectively. Furthermore, 30 out of 41 isolates harbored the erm (B) gene, mainly present in E. faecium isolates (78%). The most prevalent virulence genes were asa1 in E. faecalis (54%) and esp (esp-fm, 74%; esp-fs, 39%). Six out of nine patients developed nosocomial enterococcal infections, however, corresponding clinical isolates were unfortunately not available for further analysis. Our results show that multiple Enterococcus species, carrying several antibiotic resistance and virulence genes, occurred simultaneously in patients receiving SDD therapy, with varying prevalence dynamics over time. Furthermore, simultaneous presence and/or replacement of E. faecium STs was observed-, reinforcing the importance of screening multiple isolates to comprehensively characterize enterococcal diversity in ICU patients. PMID- 28894439 TI - Phenotypic Changes Exhibited by E. coli Cultured in Space. AB - Bacteria will accompany humans in our exploration of space, making it of importance to study their adaptation to the microgravity environment. To investigate potential phenotypic changes for bacteria grown in space, Escherichia coli was cultured onboard the International Space Station with matched controls on Earth. Samples were challenged with different concentrations of gentamicin sulfate to study the role of drug concentration on the dependent variables in the space environment. Analyses included assessments of final cell count, cell size, cell envelope thickness, cell ultrastructure, and culture morphology. A 13-fold increase in final cell count was observed in space with respect to the ground controls and the space flight cells were able to grow in the presence of normally inhibitory levels of gentamicin sulfate. Contrast light microscopy and focused ion beam/scanning electron microscopy showed that, on average, cells in space were 37% of the volume of their matched controls, which may alter the rate of molecule-cell interactions in a diffusion-limited mass transport regime as is expected to occur in microgravity. TEM imagery showed an increase in cell envelope thickness of between 25 and 43% in space with respect to the Earth control group. Outer membrane vesicles were observed on the spaceflight samples, but not on the Earth cultures. While E. coli suspension cultures on Earth were homogenously distributed throughout the liquid medium, in space they tended to form a cluster, leaving the surrounding medium visibly clear of cells. This cell aggregation behavior may be associated with enhanced biofilm formation observed in other spaceflight experiments. PMID- 28894440 TI - Otitis Media Caused by V. cholerae O100: A Case Report and Review of the Literature. AB - Infections due to Vibrio cholerae are rarely documented in Israel. Here we report a case of recurrent otitis media in a young male, caused by V. cholerae non O1/O139. This extra-intestinal infection was caused by V. cholerae O100 and has been associated with freshwater exposure and travel. Symptoms of chronic periodic earaches along with purulent exudate began about one week after the patient suffered a water skiing accident on a river in Australia. The condition lasted for three years, until his ear exudate was examined in a clinical laboratory, diagnosed and treated. Five bacterial isolates were identified as V. cholerae O100. The isolates were screened for genetic characteristics and were found positive for the presence of hapA, hlyA, and ompU virulence genes. All isolates were negative for the presence of ctxA. Based on antibiogram susceptibility testing, ciprofloxacin ear drops were used until the patient's symptoms disappeared. This case demonstrates that exposure to freshwater can cause otitis media by V. cholerae non-O1/O139 in young and otherwise healthy humans. PMID- 28894441 TI - The Fitness Cost of Fluoride Resistance for Different Streptococcus mutans Strains in Biofilms. AB - The cariogenic bacterium Streptococcus mutans can develop stable resistance to fluoride through chromosomal mutations in vitro. Fluoride-resistant S. mutans has seldom been isolated in clinical settings, despite the wide application of fluoride in oral-care products. One explanation is that the fluoride-resistant S. mutans strains have decreased fitness. However, so far, there has been no conclusive evidence to support this idea. The aim of this study was to investigate the fitness cost of 48-h biofilms of two fluoride-resistant S. mutans strains, UF35 and UA159-FR (UAFR), using the wild-type fluoride-sensitive strain UA159 as a reference. The engineered UF35 strain contains one point mutation, whereas UAFR, selected from NaF-containing agar plates, has multiple chromosomal mutations. All biofilms were formed for 48 h under a constantly neutral pH or a pH-cycling (8 h of neutral pH and 16 h of pH 5.5) condition in the absence of fluoride. The biomass of the biofilms was quantified with a crystal violet assay. The biofilms were also treated with chlorhexidine or solutions at pH 3.0, after which their lactic acid production was quantified. Compared to the UF35 and UA159 biofilms, the biomass of UAFR biofilms was two-four fold higher, and the UAFR biofilms were more resistant to chlorhexidine and low pH in terms of lactic acid production. No difference in biomass and lactic acid production was detected between UF35 and UA159 biofilms. The fluoride resistance of UAFR and UF35 strains in biofilms was further confirmed by treating the biofilms with NaF solutions. The level of NaF resistance of the three biofilms is generally ranked as follows: UAFR > UF35 > UA159. In conclusion, there is indeed a fitness consequence in UAFR, but surprisingly, this fluoride-resistant strain performs better than UF35 and UA159 under the described conditions. In addition, UF35 did not display a reduced fitness; it performed as well as the wild-type fluoride-sensitive strain. PMID- 28894442 TI - Isolation and Characterization of Phenanthrene Degrading Bacteria from Diesel Fuel-Contaminated Antarctic Soils. AB - Antarctica is an attractive target for human exploration and scientific investigation, however the negative effects of human activity on this continent are long lasting and can have serious consequences on the native ecosystem. Various areas of Antarctica have been contaminated with diesel fuel, which contains harmful compounds such as heavy metals and polycyclic aromatic hydrocarbons (PAH). Bioremediation of PAHs by the activity of microorganisms is an ecological, economical, and safe decontamination approach. Since the introduction of foreign organisms into the Antarctica is prohibited, it is key to discover native bacteria that can be used for diesel bioremediation. By following the degradation of the PAH phenanthrene, we isolated 53 PAH metabolizing bacteria from diesel contaminated Antarctic soil samples, with three of these isolates exhibiting a high phenanthrene degrading capacity. In particular, the Sphingobium xenophagum D43FB isolate showed the highest phenanthrene degradation ability, generating up to 95% degradation of initial phenanthrene. D43FB can also degrade phenanthrene in the presence of its usual co-pollutant, the heavy metal cadmium, and showed the ability to grow using diesel-fuel as a sole carbon source. Microtiter plate assays and SEM analysis revealed that S. xenophagum D43FB exhibits the ability to form biofilms and can directly adhere to phenanthrene crystals. Genome sequencing analysis also revealed the presence of several genes involved in PAH degradation and heavy metal resistance in the D43FB genome. Altogether, these results demonstrate that S. xenophagum D43FB shows promising potential for its application in the bioremediation of diesel fuel contaminated Antarctic ecosystems. PMID- 28894443 TI - Improved Vaccine against PRRSV: Current Progress and Future Perspective. AB - Porcine reproductive and respiratory syndrome virus (PRRSV), one of the most economically significant pathogens worldwide, has caused numerous outbreaks during the past 30 years. PRRSV infection causes reproductive failure in sows and respiratory disease in growing and finishing pigs, leading to huge economic losses for the swine industry. This impact has become even more significant with the recent emergence of highly pathogenic PRRSV strains from China, further exacerbating global food security. Since new PRRSV variants are constantly emerging from outbreaks, current strategies for controlling PRRSV have been largely inadequate, even though our understanding of PRRSV virology, evolution and host immune response has been rapidly expanding. Meanwhile, practical experience has revealed numerous safety and efficacy concerns for currently licensed vaccines, such as shedding of modified live virus (MLV), reversion to virulence, recombination between field strains and MLV and failure to elicit protective immunity against heterogeneous virus. Therefore, an effective vaccine against PRRSV infection is urgently needed. Here, we systematically review recent advances in PRRSV vaccine development. Antigenic variations resulting from PRRSV evolution, identification of neutralizing epitopes for heterogeneous isolates, broad neutralizing antibodies against PRRSV, chimeric virus generated by reverse genetics, and novel PRRSV strains with interferon-inducing phenotype will be discussed in detail. Moreover, techniques that could potentially transform current MLV vaccines into a superior vaccine will receive special emphasis, as will new insights for future PRRSV vaccine development. Ultimately, improved PRRSV vaccines may overcome the disadvantages of current vaccines and minimize the PRRS impact to the swine industry. PMID- 28894444 TI - Modeling Kick-Kill Strategies toward HIV Cure. AB - Although combinatorial antiretroviral therapy (cART) potently suppresses the virus, a sterile or functional cure still remains one of the greatest therapeutic challenges worldwide. Reservoirs are infected cells that can maintain HIV persistence for several years in patients with optimal cART, which is a leading obstacle to eradicate the virus. Despite the significant progress that has been made in our understanding of the diversity of cells that promote HIV persistence, many aspects that are critical to the development of effective therapeutic approaches able to purge the latent CD4+ T cell reservoir are poorly understood. Simultaneous purging strategies known as "kick-kill" have been pointed out as promising therapeutic approaches to eliminate the viral reservoir. However, long term outcomes of purging strategies as well as the effect on the HIV reservoir are still largely fragmented. In this context, mathematical modeling can provide a rationale not only to evaluate the impact on the HIV reservoir but also to facilitate the formulation of hypotheses about potential therapeutic strategies. This review aims to discuss briefly the most recent mathematical modeling contributions, harnessing our knowledge toward the uncharted territory of HIV eradication. In addition, problems associated with current models are discussed, in particular, mathematical models consider only T cell responses but HIV control may also depend on other cell responses as well as chemokines and cytokines dynamics. PMID- 28894445 TI - Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging. AB - Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies. PMID- 28894446 TI - Neutrophil Evolution and Their Diseases in Humans. AB - Granulocytes have been preserved and have evolved across species, developing into cells that provide one of the first lines of host defense against pathogens. In humans, neutrophils are involved in early recognition and killing of infectious pathogens. Disruption in neutrophil production, emigration, chemotaxis, and function cause a spectrum of primary immune defects characterized by host susceptibility to invasive infections. PMID- 28894447 TI - The Microbial Metabolite Butyrate Induces Expression of Th1-Associated Factors in CD4+ T Cells. AB - Short-chain fatty acids (SCFAs), which are generated by the bacterial fermentation of dietary fibers, promote expansion of regulatory T cells (Tregs). Potential therapeutic value of SCFAs has been recently highlighted in the experimental models of T cell-mediated autoimmunity and allergic inflammation. These studies suggest that physiological intestinal concentrations of SCFAs within the millimolar range are crucial for dampening inflammation-mediated processes. Here, we describe opposing effects of SCFAs on T cell-mediated immune responses. In accordance with published data, lower butyrate concentrations facilitated differentiation of Tregs in vitro and in vivo under steady-state conditions. In contrast, higher concentrations of butyrate induced expression of the transcription factor T-bet in all investigated T cell subsets resulting in IFN-gamma-producing Tregs or conventional T cells. This effect was mediated by the inhibition of histone deacetylase activity and was independent of SCFA receptors FFA2 and FFA3 as well as of Na+-coupled SCFA transporter Slc5a8. Importantly, while butyrate was not able to induce the generation of Tregs in the absence of TGF-beta1, the expression of T-bet and IFN-gamma was triggered upon stimulation of CD4+ T cells with this SCFA alone. Moreover, the treatment of germ free mice with butyrate enhanced the expression of T-bet and IFN-gamma during acute colitis. Our data reveal that, depending on its concentration and immunological milieu, butyrate may exert either beneficial or detrimental effects on the mucosal immune system. PMID- 28894448 TI - Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection. AB - Sirtuin 2 (SIRT2) is one of the seven members of the family of NAD+-dependent histone deacetylases. Sirtuins target histones and non-histone proteins according to their subcellular localization, influencing various biological processes. SIRT2 resides mainly in the cytoplasm and regulates cytoskeleton dynamics, cell cycle, and metabolic pathways. As such, SIRT2 has been implicated in the pathogenesis of neurodegenerative, metabolic, oncologic, and chronic inflammatory disorders. This motivated the development of SIRT2-directed therapies for clinical purposes. However, the impact of SIRT2 on antimicrobial host defense is largely unknown. Here, we address this question using SIRT2 knockout mice. We show that SIRT2 is the most highly expressed sirtuin in myeloid cells, especially macrophages. SIRT2 deficiency does not affect immune cell development and marginally impacts on intracellular signaling and cytokine production by splenocytes and macrophages. However, SIRT2 deficiency enhances bacterial phagocytosis by macrophages. In line with these observations, in preclinical models, SIRT2 deficiency increases survival of mice with chronic staphylococcal infection, while having no effect on the course of toxic shock syndrome toxin-1, LPS or TNF-induced shock, fulminant Escherichia coli peritonitis, sub-lethal Klebsiella pneumoniae pneumonia, and chronic candidiasis. Altogether, these data support the safety profile of SIRT2 inhibitors under clinical development in terms of susceptibility to infections. PMID- 28894449 TI - Type I Interferon Induced by Streptococcus suis Serotype 2 is Strain-Dependent and May Be Beneficial for Host Survival. AB - Streptococcus suis serotype 2 is an important porcine bacterial pathogen and emerging zoonotic agent mainly responsible for sudden death, septic shock, and meningitis, with exacerbated inflammation being a hallmark of the infection. However, serotype 2 strains are genotypically and phenotypically heterogeneous, being composed of a multitude of sequence types (STs) whose virulence greatly varies: the virulent ST1 (Eurasia), highly virulent ST7 (responsible for the human outbreaks in China), and intermediate virulent ST25 (North America) are the most important worldwide. Even though type I interferons (IFNs) are traditionally associated with important antiviral functions, recent studies have demonstrated that they may also play an important role during infections with extracellular bacteria. Upregulation of IFN-beta levels was previously observed in mice following infection with this pathogen. Consequently, the implication of IFN-beta in the S. suis serotype 2 pathogenesis, which has always been considered a strict extracellular bacterium, was evaluated using strains of varying virulence. This study demonstrates that intermediate virulent strains are significantly more susceptible to phagocytosis than virulent strains. Hence, subsequent localization of these strains within the phagosome results in recognition of bacterial nucleic acids by Toll-like receptors 7 and 9, leading to activation of the interferon regulatory factors 1, 3, and 7 and production of IFN-beta. Type I IFN, whose implication depends on the virulence level of the S. suis strain, is involved in host defense by participating in the modulation of systemic inflammation, which is responsible for the clearance of blood bacterial burden. As such, when induced by intermediate, and to a lesser extent, virulent S. suis strains, type I IFN plays a beneficial role in host survival. The highly virulent ST7 strain, however, hastily induces a septic shock that cannot be controlled by type I IFN, leading to rapid death of the host. A better understanding of the underlying mechanisms involved in the control of inflammation and subsequent bacterial burden could help to develop control measures for this important porcine and zoonotic agent. PMID- 28894451 TI - Inflammatory Conditions Dictate the Effect of Mesenchymal Stem or Stromal Cells on B Cell Function. AB - The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are characterized by an abrogation of plasmablast formation and induction of regulatory B cells (Bregs). It is, however, unknown how MSC interact with B cells under inflammatory conditions. In this study, adipose tissue-derived MSC were pretreated with 50 ng/ml IFN-gamma for 96 h (MSC IFN-gamma) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43- selection. B cells were co-cultured with MSC and stimulated with anti-IgM, anti-CD40, and IL-2; and after 7 days, B cell proliferation, phenotype, Immunoglobulin-G (IgG), and IL-10 production were analyzed. MSC did not inhibit B cell proliferation but increased the percentage of CD38high CD24high B cells (Bregs) and IL-10 production, while MSC-IFN-gamma significantly reduced B cell proliferation and inhibited IgG production by B cells in a more potent fashion but did not induce Bregs or IL-10 production. Both MSC and MSC-IFN-gamma required proximity to target cells and being metabolically active to exert their effects. Indoleamine 2,3 dioxygenase expression was highly induced in MSC-IFN-gamma and was responsible of the anti-proliferative and Breg reduction since addition of tryptophan (TRP) restored MSC properties. Immunological conditions dictate the effect of MSC on B cell function. Under immunological quiescent conditions, MSC stimulate Breg induction; whereas, under inflammatory conditions, MSC inhibit B cell proliferation and maturation through depletion of TRP. This knowledge is useful for customizing MSC therapy for specific purposes by appropriate pretreatment of MSC. PMID- 28894450 TI - Dual Face of Vgamma9Vdelta2-T Cells in Tumor Immunology: Anti- versus Pro-Tumoral Activities. AB - Vgamma9Vdelta2-T cells are considered as potent effector cells for tumor immunotherapy through directly killing tumor cells and indirectly regulating other innate and adaptive immune cells to establish antitumoral immunity. The antitumoral activity of Vgamma9Vdelta2-T cells is governed by a complicated set of activating and inhibitory cell receptors. In addition, cytokine milieu in tumor microenvironment can also induce the pro-tumoral activities and functional plasticity of Vgamma9Vdelta2-T cells. Here, we review the anti- versus pro tumoral activities of Vgamma9Vdelta2-T cells and discuss the mechanisms underlying the recognition, activation, differentiation and regulation of Vgamma9Vdelta2-T cells in tumor immunosurveillance. The comprehensive understanding of the dual face of Vgamma9Vdelta2-T cells in tumor immunology may improve the therapeutic efficacy and clinical outcomes of Vgamma9Vdelta2-T cell based tumor immunotherapy. PMID- 28894452 TI - Raw Cow's Milk Prevents the Development of Airway Inflammation in a Murine House Dust Mite-Induced Asthma Model. AB - Epidemiological studies show an inverse relation between raw cow's milk consumption and the development of asthma. This protective effect seems to be abolished by milk processing. However, evidence for a causal relationship is lacking, and direct comparisons between raw and processed milk are hardly studied. Therefore, this study investigated the preventive capacity of raw and heated raw milk on the development of house dust mite (HDM)-induced allergic asthma in mice. Six- to seven-week-old male BALB/c mice were intranasally (i.n.) sensitized with 1 ug HDM or PBS on day 0, followed by an i.n. challenge with 10 ug HDM or PBS on days 7-11. In addition, mice were fed 0.5 mL raw cow's milk, heated raw cow's milk, or PBS three times a week throughout the study, starting 1 day before sensitization. On day 14, airway hyperresponsiveness (AHR) in response to increasing doses of methacholine was measured to assess lung function. Bronchoalveolar lavage fluid (BALF) and lungs were furthermore collected to study the extent of airway inflammation. Raw milk prevented both HDM-induced AHR and pulmonary eosinophilic inflammation, whereas heated raw milk did not. Both milk types suppressed the Th2-polarizing chemokine CCL17 in lung homogenates and reduced lung Th2 and Th17 cell frequency. IL-4 and IL-13 production after ex vivo restimulation of lung T cells with HDM was also reduced by both milk types. However, local IL-5 and IL-13 concentrations were only suppressed by raw milk. These findings support the asthma-protective capacity of raw cow's milk and show the importance of reduced local type 2 cytokine levels. Heated raw milk did not show an asthma-protective effect, which indicates the involvement of heat sensitive components. Besides causal evidence, this study provides the basis for further mechanistic studies. PMID- 28894453 TI - Interspecific Potato Breeding Lines Display Differential Colonization Patterns and Induced Defense Responses after Ralstonia solanacearum Infection. AB - Potato (Solanum tuberosum L.) is one of the main hosts of Ralstonia solanacearum, the causative agent of bacterial wilt. This plant pathogen bacteria produce asymptomatic latent infections that promote its global spread, hindering disease control. A potato breeding program is conducted in Uruguay based on the introgression of resistance from the wild native species S. commersonii Dun. Currently, several backcrosses were generated exploiting the high genetic variability of this wild species resulting in advanced interspecific breeding lines with different levels of bacterial wilt resistance. The overall aim of this work was to characterize the interaction of the improved potato germplasm with R. solanacearum. Potato clones with different responses to R. solanacearum were selected, and colonization, dissemination and multiplication patterns after infection were evaluated. A R. solanacearum strain belonging to the phylotype IIB sequevar 1, with high aggressiveness on potato was genetically modified to constitutively generate fluorescence and luminescence from either the green fluorescence protein gene or lux operon. These reporter strains were used to allow a direct and precise visualization of fluorescent and luminescent cells in plant tissues by confocal microscopy and luminometry. Based on wilting scoring and detection of latent infections, the selected clones were classified as susceptible or tolerant, while no immune-like resistance response was identified. Typical wilting symptoms in susceptible plants were correlated with high concentrations of bacteria in roots and along the stems. Tolerant clones showed a colonization pattern restricted to roots and a limited number of xylem vessels only in the stem base. Results indicate that resistance in potato is achieved through restriction of bacterial invasion and multiplication inside plant tissues, particularly in stems. Tolerant plants were also characterized by induction of anatomical and biochemical changes after R. solanacearum infection, including hyperplasic activity of conductor tissue, tylose production, callose and lignin deposition, and accumulation of reactive oxygen species. This study highlights the potential of the identified tolerant interspecific potato clones as valuable genetic resources for potato-breeding programs and leads to a better understanding of resistance against R. solanacearum in potato. PMID- 28894454 TI - Fine Mapping of a Clubroot Resistance Gene in Chinese Cabbage Using SNP Markers Identified from Bulked Segregant RNA Sequencing. AB - Clubroot, caused by Plasmodiophora brassicae, is an important disease of canola (Brassica napus) in western Canada and worldwide. In this study, a clubroot resistance gene (Rcr2) was identified and fine mapped in Chinese cabbage cv. "Jazz" using single-nucleotide polymorphisms (SNP) markers identified from bulked segregant RNA sequencing (BSR-Seq) and molecular markers were developed for use in marker assisted selection. In total, 203.9 million raw reads were generated from one pooled resistant (R) and one pooled susceptible (S) sample, and >173,000 polymorphic SNP sites were identified between the R and S samples. One significant peak was observed between 22 and 26 Mb of chromosome A03, which had been predicted by BSR-Seq to contain the causal gene Rcr2. There were 490 polymorphic SNP sites identified in the region. A segregating population consisting of 675 plants was analyzed with 15 SNP sites in the region using the Kompetitive Allele Specific PCR method, and Rcr2 was fine mapped between two SNP markers, SNP_A03_32 and SNP_A03_67 with 0.1 and 0.3 cM from Rcr2, respectively. Five SNP markers co-segregated with Rcr2 in this region. Variants were identified in 14 of 36 genes annotated in the Rcr2 target region. The numbers of poly variants differed among the genes. Four genes encode TIR-NBS-LRR proteins and two of them Bra019410 and Bra019413, had high numbers of polymorphic variants and so are the most likely candidates of Rcr2. PMID- 28894455 TI - DNA-Demethylase Regulated Genes Show Methylation-Independent Spatiotemporal Expression Patterns. AB - Recent research has indicated that a subset of defense-related genes is downregulated in the Arabidopsis DNA demethylase triple mutant rdd (ros1 dml2 dml3) resulting in increased susceptibility to the fungal pathogen Fusarium oxysporum. In rdd plants these downregulated genes contain hypermethylated transposable element sequences (TE) in their promoters, suggesting that this methylation represses gene expression in the mutant and that these sequences are actively demethylated in wild-type plants to maintain gene expression. In this study, the tissue-specific and pathogen-inducible expression patterns of rdd downregulated genes were investigated and the individual role of ROS1, DML2, and DML3 demethylases in these spatiotemporal regulation patterns was determined. Large differences in defense gene expression were observed between pathogen infected and uninfected tissues and between root and shoot tissues in both WT and rdd plants, however, only subtle changes in promoter TE methylation patterns occurred. Therefore, while TE hypermethylation caused decreased gene expression in rdd plants it did not dramatically effect spatiotemporal gene regulation, suggesting that this latter regulation is largely methylation independent. Analysis of ros1-3, dml2-1, and dml3-1 single gene mutant lines showed that promoter TE hypermethylation and defense-related gene repression was predominantly, but not exclusively, due to loss of ROS1 activity. These data demonstrate that DNA demethylation of TE sequences, largely by ROS1, promotes defense-related gene expression but does not control spatiotemporal expression in Arabidopsis. Summary: Ros1-mediated DNA demethylation of promoter transposable elements is essential for activation of defense-related gene expression in response to fungal infection in Arabidopsis thaliana. PMID- 28894456 TI - Effects of Combined Low Glutathione with Mild Oxidative and Low Phosphorus Stress on the Metabolism of Arabidopsis thaliana. AB - Plants possess highly sensitive mechanisms that monitor environmental stress levels for a dose-dependent fine-tuning of their growth and development. Differences in plant responses to severe and mild abiotic stresses have been recognized. Although many studies have revealed that glutathione can contribute to plant tolerance to various environmental stresses, little is known about the relationship between glutathione and mild abiotic stress, especially the effect of stress-induced altered glutathione levels on the metabolism. Here, we applied a systems biology approach to identify key pathways involved in the gene-to metabolite networks perturbed by low glutathione content under mild abiotic stress in Arabidopsis thaliana. We used glutathione synthesis mutants (cad2-1 and pad2-1) and plants overexpressing the gene encoding gamma-glutamylcysteine synthetase, the first enzyme of the glutathione biosynthetic pathway. The plants were exposed to two mild stress conditions-oxidative stress elicited by methyl viologen and stress induced by the limited availability of phosphate. We observed that the mutants and transgenic plants showed similar shoot growth as that of the wild-type plants under mild abiotic stress. We then selected the synthesis mutants and performed multi-platform metabolomics and microarray experiments to evaluate the possible effects on the overall metabolome and the transcriptome. As a common oxidative stress response, several flavonoids that we assessed showed overaccumulation, whereas the mild phosphate stress resulted in increased levels of specific kaempferol- and quercetin-glycosides. Remarkably, in addition to a significant increased level of sugar, osmolytes, and lipids as mild oxidative stress-responsive metabolites, short-chain aliphatic glucosinolates over accumulated in the mutants, whereas the level of long-chain aliphatic glucosinolates and specific lipids decreased. Coordinated gene expressions related to glucosinolate and flavonoid biosynthesis also supported the metabolite responses in the pad2-1 mutant. Our results suggest that glutathione synthesis mutants accelerate transcriptional regulatory networks to control the biosynthetic pathways involved in glutathione-independent scavenging metabolites, and that they might reconfigure the metabolic networks in primary and secondary metabolism, including lipids, glucosinolates, and flavonoids. This work provides a basis for the elucidation of the molecular mechanisms involved in the metabolic and transcriptional regulatory networks in response to combined low glutathione content with mild oxidative and nutrient stress in A. thaliana. PMID- 28894458 TI - The Atg8 Family of Proteins-Modulating Shape and Functionality of Autophagic Membranes. AB - Aging is a multifactorial process involving an accumulation of alterations on various organizational levels, which finally compromises viability and limits the lifespan of organisms. It is now well-established that many aspects of aging can be positively affected by (macro)autophagy, a mechanism of self-digestion found in virtually all eukaryotic cells. A comprehensive understanding of autophagy is thus expected to not only deepen our insight into the mechanisms of aging but to also open up new avenues toward increasing the healthy lifespan in humans. In this review, we focus on the Atg8 family of ubiquitin-like proteins, which play a crucial role in the autophagy process by virtue of their unique mode of reversible membrane association. PMID- 28894457 TI - Strigolactones Biosynthesis and Their Role in Abiotic Stress Resilience in Plants: A Critical Review. AB - Strigolactones (SLs), being a new class of plant hormones, play regulatory roles against abiotic stresses in plants. There are multiple hormonal response pathways, which are adapted by the plants to overcome these stressful environmental constraints to reduce the negative impact on overall crop plant productivity. Genetic modulation of the SLs could also be applied as a potential approach in this regard. However, endogenous plant hormones play central roles in adaptation to changing environmental conditions, by mediating growth, development, nutrient allocation, and source/sink transitions. In addition, the hormonal interactions can fine-tune the plant response and determine plant architecture in response to environmental stimuli such as nutrient deprivation and canopy shade. Considerable advancements and new insights into SLs biosynthesis, signaling and transport has been unleashed since the initial discovery. In this review we present basic overview of SL biosynthesis and perception with a detailed discussion on our present understanding of SLs and their critical role to tolerate environmental constraints. The SLs and abscisic acid interplay during the abiotic stresses is particularly highlighted. Main Conclusion: More than shoot branching Strigolactones have uttermost capacity to harmonize stress resilience. PMID- 28894459 TI - A Preliminary List of Horizontally Transferred Genes in Prokaryotes Determined by Tree Reconstruction and Reconciliation. AB - Genome-wide global detection of genes involved in horizontal gene transfer (HGT) remains an active area of research in medical microbiology and evolutionary genomics. Utilizing the explicit evolutionary method of comparing topologies of a total of 154,805 orthologous gene trees against corresponding 16S rRNA "reference" trees, we previously detected a total of 660,894 candidate HGT events in 2,472 completely-sequenced prokaryotic genomes. Here, we report an HGT-index for each individual gene-reference tree pair reconciliation, representing the total number of detected HGT events on the gene tree divided by the total number of genomes (taxa) member of that tree. HGT-index is thus a simple measure indicating the sensitivity of prokaryotic genes to participate (or not participate) in HGT. Our preliminary list provides HGT-indices for a total of 69,365 genes (detected in >10 and <50% available prokaryotic genomes) that are involved in a wide range of biological processes such as metabolism, information, and bacterial response to environment. Identification of horizontally-derived genes is important to combat antibiotic resistance and is a step forward toward reconstructions of improved phylogenies describing the history of life. Our effort is thus expected to benefit ongoing research in the fields of clinical microbiology and evolutionary biology. PMID- 28894460 TI - An Automatic Gastrointestinal Polyp Detection System in Video Endoscopy Using Fusion of Color Wavelet and Convolutional Neural Network Features. AB - Gastrointestinal polyps are considered to be the precursors of cancer development in most of the cases. Therefore, early detection and removal of polyps can reduce the possibility of cancer. Video endoscopy is the most used diagnostic modality for gastrointestinal polyps. But, because it is an operator dependent procedure, several human factors can lead to misdetection of polyps. Computer aided polyp detection can reduce polyp miss detection rate and assists doctors in finding the most important regions to pay attention to. In this paper, an automatic system has been proposed as a support to gastrointestinal polyp detection. This system captures the video streams from endoscopic video and, in the output, it shows the identified polyps. Color wavelet (CW) features and convolutional neural network (CNN) features of video frames are extracted and combined together which are used to train a linear support vector machine (SVM). Evaluations on standard public databases show that the proposed system outperforms the state-of-the-art methods, gaining accuracy of 98.65%, sensitivity of 98.79%, and specificity of 98.52%. PMID- 28894461 TI - A Grey Wolf Optimizer for Modular Granular Neural Networks for Human Recognition. AB - A grey wolf optimizer for modular neural network (MNN) with a granular approach is proposed. The proposed method performs optimal granulation of data and design of modular neural networks architectures to perform human recognition, and to prove its effectiveness benchmark databases of ear, iris, and face biometric measures are used to perform tests and comparisons against other works. The design of a modular granular neural network (MGNN) consists in finding optimal parameters of its architecture; these parameters are the number of subgranules, percentage of data for the training phase, learning algorithm, goal error, number of hidden layers, and their number of neurons. Nowadays, there is a great variety of approaches and new techniques within the evolutionary computing area, and these approaches and techniques have emerged to help find optimal solutions to problems or models and bioinspired algorithms are part of this area. In this work a grey wolf optimizer is proposed for the design of modular granular neural networks, and the results are compared against a genetic algorithm and a firefly algorithm in order to know which of these techniques provides better results when applied to human recognition. PMID- 28894462 TI - A Novel Strategy for Minimum Attribute Reduction Based on Rough Set Theory and Fish Swarm Algorithm. AB - For data mining, reducing the unnecessary redundant attributes which was known as attribute reduction (AR), in particular, reducts with minimal cardinality, is an important preprocessing step. In the paper, by a coding method of combination subset of attributes set, a novel search strategy for minimal attribute reduction based on rough set theory (RST) and fish swarm algorithm (FSA) is proposed. The method identifies the core attributes by discernibility matrix firstly and all the subsets of noncore attribute sets with the same cardinality were encoded into integers as the individuals of FSA. Then, the evolutionary direction of the individual is limited to a certain extent by the coding method. The fitness function of an individual is defined based on the attribute dependency of RST, and FSA was used to find the optimal set of reducts. In each loop, if the maximum attribute dependency and the attribute dependency of condition attribute set are equal, then the algorithm terminates, otherwise adding a single attribute to the next loop. Some well-known datasets from UCI were selected to verify this method. The experimental results show that the proposed method searches the minimal attribute reduction set effectively and it has the excellent global search ability. PMID- 28894463 TI - Joint Extraction of Entities and Relations Using Reinforcement Learning and Deep Learning. AB - We use both reinforcement learning and deep learning to simultaneously extract entities and relations from unstructured texts. For reinforcement learning, we model the task as a two-step decision process. Deep learning is used to automatically capture the most important information from unstructured texts, which represent the state in the decision process. By designing the reward function per step, our proposed method can pass the information of entity extraction to relation extraction and obtain feedback in order to extract entities and relations simultaneously. Firstly, we use bidirectional LSTM to model the context information, which realizes preliminary entity extraction. On the basis of the extraction results, attention based method can represent the sentences that include target entity pair to generate the initial state in the decision process. Then we use Tree-LSTM to represent relation mentions to generate the transition state in the decision process. Finally, we employ Q Learning algorithm to get control policy pi in the two-step decision process. Experiments on ACE2005 demonstrate that our method attains better performance than the state-of-the-art method and gets a 2.4% increase in recall-score. PMID- 28894464 TI - Inflammatory Markers as Prognostic Factors of Survival in Patients Affected by Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization. AB - INTRODUCTION: Transarterial chemoembolization (TACE) is a good choice for hepatocellular carcinoma (HCC) treatment when surgery and liver transplantation are not feasible. Few studies reported the value of prognostic factors influencing survival after chemoembolization. In this study, we evaluated whether preoperative inflammatory factors such as neutrophil to lymphocyte ratio and platelet to lymphocyte ratio affected our patient survival when affected by hepatocellular carcinoma. METHODS: We retrospectively evaluated a total of 72 patients with hepatocellular carcinoma that underwent TACE. We enrolled patients with different etiopathogeneses of hepatitis and histologically proven HCC not suitable for surgery. The overall study population was dichotomized in two groups according to the median NLR value and was analyzed also according to other prognostic factors. RESULTS: The global median overall survival (OS) was 28 months. The OS in patients with high NLR was statistically significantly shorter than that in patients with low NLR. The following pretreatment variables were significantly associated with the OS in univariate analyses: age, Child-Pugh score, BCLC stage, INR, and NLR. Pretreated high NLR was an independently unfavorable factor for OS. CONCLUSION: NLR could be considered a good prognostic factor of survival useful to stratify patients that could benefit from TACE treatment. PMID- 28894466 TI - Clinical Factors of Delayed Perforation after Endoscopic Submucosal Dissection for Gastric Neoplasms. AB - BACKGROUND: Delayed perforation is a rare but severe complication of endoscopic submucosal dissection (ESD) for early gastric neoplasm (EGN). The aim of this study was to clarify clinical factors related to delayed perforation after ESD. METHODS: A total of 1158 consecutive patients with 1199 EGNs underwent ESD at our hospital between January 2000 and December 2015. Univariate analysis was used to identify clinicopathological factors related to delayed perforation. Moreover, duration of cautery needed for hemostasis was measured by comparison between perforated and nonperforated points in patients with delayed perforation. RESULTS: Delayed perforation occurred in 5 of 1158 consecutive patients with 1199 EGNs who underwent ESD (0.42%). All cases were diagnosed within 24 h after ESD and recovered with conservative management. On univariate analysis, location in the upper stomach was the factor most significantly associated with delayed perforation (P < 0.01). Duration of cautery needed for hemostasis was significantly longer at perforated points (9 s) than at nonperforated points (3.5 s) in five patients. CONCLUSIONS: Location in the upper stomach was the risk factor most prominently associated with delayed perforation after ESD for EGNs. In addition, delayed perforation appears associated with excessive electrocautery for hemostasis. PMID- 28894465 TI - A Comprehensive Review of Bioelectrical Impedance Analysis and Other Methods in the Assessment of Nutritional Status in Patients with Liver Cirrhosis. AB - It is assumed that approximately 24-66% of patients with liver cirrhosis develop malnutrition. Numerous pathological processes lead to serious disorders of nutritional status in this group of patients. Malnutrition in the course of liver cirrhosis is associated with increased morbidity, complications, and low quality of life. Under these conditions, detection of malnutrition is of crucial importance. This review explores the complex mechanisms that lead to malnutrition in the course of liver cirrhosis and focuses on methods used in the assessment of nutritional status in cirrhotic patients. Among others, the role of bioelectrical impedance is highlighted. This noninvasive tool is promising and quite an accurate method of estimating body composition. PMID- 28894468 TI - A Case of Immediate Hypersensitivity Reaction to Maltitol. AB - BACKGROUND: Maltitol is a sugar alcohol that is frequently used as a noncaloric sweetener, although it is also used as an excipient, a plasticizer in gelatin capsules, and an emollient. It has not been previously described as an agent involved in immediate hypersensitivity reactions. METHODS: We report on an anaphylactoid reaction with pharyngeal occlusion suffered by a 60-year-old man after ingestion of a candy containing maltitol syrup. A prick-to-prick test was performed with the candy and maltitol powder. Other allergens were excluded as causative agents of the adverse reaction, although the patient refused to undergo an oral challenge test with the candy. A basophil activation test (BAT) was performed with maltitol powder, and a dose-response curve was generated. The test was also performed in 3 healthy controls. RESULTS: Both prick-to-prick tests were negative. The result of the BAT was positive at all the concentrations tested in the patient's blood and negative in all the controls. CONCLUSIONS: The BAT can help to clarify the agents implicated in an adverse reaction and can reduce the risk involved in diagnosis. The BAT can also prove useful in the study of reactions caused by low-molecular-weight antigens, for which routine diagnostic tests are not feasible. PMID- 28894467 TI - Racial and Socioeconomic Disparities Are More Pronounced in Inflammatory Breast Cancer Than Other Breast Cancers. AB - Inflammatory breast cancer (IBC) is a rare yet aggressive form of breast cancer. We examined differences in patient demographics and outcomes in IBC compared to locally advanced breast cancer (LABC) and all other breast cancer patients from the Breast and Prostate Cancer Data Quality and Patterns of Care Study (POC-BP), containing information from cancer registries in seven states. Out of 7,624 cases of invasive carcinoma, IBC and LABC accounted for 2.2% (N = 170) and 4.9% (N = 375), respectively. IBC patients were more likely to have a higher number (P = 0.03) and severity (P = 0.01) of comorbidities than other breast cancer patients. Among IBC patients, a higher percentage of patients with metastatic disease versus nonmetastatic disease were black, on Medicaid, and from areas of higher poverty and more urban areas. Black and Hispanic IBC patients had worse overall and breast cancer-specific survival than white patients; moreover, IBC patients with Medicaid, patients from urban areas, and patients from areas of higher poverty and lower education had worse outcomes. These data highlight the effects of disparities in race and socioeconomic status on the incidence of IBC as well as IBC outcomes. Further work is needed to reveal the causes behind these disparities and methods to improve IBC outcomes. PMID- 28894469 TI - Ex Vivo Expansion of Human Limbal Epithelial Cells Using Human Placenta-Derived and Umbilical Cord-Derived Mesenchymal Stem Cells. AB - Ex vivo culture of human limbal epithelial cells (LECs) is used to treat limbal stem cell (LSC) deficiency, a vision loss condition, and suitable culture systems using feeder cells or serum without animal elements have been developed. This study evaluated the use of human umbilical cord or placenta mesenchymal stem cells (C-MSCs or P-MSCs, resp.) as feeder cells in an animal/serum-free coculture system with human LECs. C-/P-MSCs stimulated LEC colony formation of the stem cell markers (p63, ABCG2) and secreted known LEC clonal growth factors (keratinocyte growth factor, beta-nerve growth factor). Transforming growth factor-beta-induced protein (TGFBIp), an extracellular matrix (ECM) protein, was produced by C-/P-MSCs and resulted in an increase in p63+ ABCG2+ LEC colonies. TGFBIp-activated integrin signaling molecules (FAK, Src, and ERK) were expressed in LECs, and TGFBIp-induced LEC proliferation was effectively blocked by a FAK inhibitor. In conclusion, C-/P-MSCs enhanced LEC culture by increasing growth of the LSC population by secreting growth factors and the ECM protein TGFBIp, which is suggested to be a novel factor for promoting the growth of LECs in culture. C /P-MSCs may be useful for the generation of animal-free culture systems for the treatment of LSC deficiency. PMID- 28894470 TI - Trends in Medicinal Uses of Edible Wild Vertebrates in Brazil. AB - The use of food medicines is a widespread practice worldwide. In Brazil, such use is often associated with wild animals, mostly focusing on vertebrate species. Here we assessed taxonomic and ecological trends in traditional uses of wild edible vertebrates in the country, through an extensive ethnobiological database analysis. Our results showed that at least 165 health conditions are reportedly treated by edible vertebrate species (n = 204), mostly fishes and mammals. However, reptiles stand out presenting a higher plasticity in the treatment of multiple health conditions. Considering the 20 disease categories recorded, treatment prescriptions were similar within continental (i.e., terrestrial and freshwater) and also within coastal and marine habitats, which may reflect locally related trends in occurrence and use of the medicinal fauna. The comprehension of the multiplicity and trends in the therapeutic uses of Brazilian vertebrates is of particular interest from a conservation perspective, as several threatened species were recorded. PMID- 28894471 TI - Practice of Comparative Effectiveness Research to Identify Treatment Characteristics of Similar Chinese Patent Medicine for Angina Pectoris. AB - OBJECTIVE: Individualized application of TCM is not easy and may lead to undesirable results, such as poor effect or even adverse reactions. This trial aims to compare two common Chinese patent medicines with similar effects. BACKGROUND OF THE RESEARCH: Four hospitals carried out the test at the same time in Tianjin city of China. PARTICIPANTS: 144 patients were involved in this study; all patients must meet the diagnostic criteria. INTERVENTIONS: Qishen Yiqi pills, compound danshen pills, and their placebos; an efficacy analysis was conducted after the first medication and after crossover medication. PRIMARY OUTCOME MEASURES: The primary index of end point includes Seattle Angina Questionnaire score-7 and score of 7-point Likert Scale; the curative effect was compared with minimal clinically important differences value. RESULT: Two drugs have their respective advantages in treating SAP. In practical application, the two drugs shall be discriminated in use based on patients' specific symptoms. TRIAL REGISTRATION: Chinese clinical trials register is ChiCTR-TTRCC-14004406 (registered 23 March 2014). PMID- 28894472 TI - Effective Heart Disease Detection Based on Quantitative Computerized Traditional Chinese Medicine Using Representation Based Classifiers. AB - At present, heart disease is the number one cause of death worldwide. Traditionally, heart disease is commonly detected using blood tests, electrocardiogram, cardiac computerized tomography scan, cardiac magnetic resonance imaging, and so on. However, these traditional diagnostic methods are time consuming and/or invasive. In this paper, we propose an effective noninvasive computerized method based on facial images to quantitatively detect heart disease. Specifically, facial key block color features are extracted from facial images and analyzed using the Probabilistic Collaborative Representation Based Classifier. The idea of facial key block color analysis is founded in Traditional Chinese Medicine. A new dataset consisting of 581 heart disease and 581 healthy samples was experimented by the proposed method. In order to optimize the Probabilistic Collaborative Representation Based Classifier, an analysis of its parameters was performed. According to the experimental results, the proposed method obtains the highest accuracy compared with other classifiers and is proven to be effective at heart disease detection. PMID- 28894473 TI - Computational and Mathematical Methods to Estimate the Basic Reproduction Number and Final Size for Single-Stage and Multistage Progression Disease Models for Zika with Preventative Measures. AB - We present new mathematical models that include the impact of using selected preventative measures such as insecticide treated nets (ITN) in controlling or ameliorating the spread of the Zika virus. For these models, we derive the basic reproduction number and sharp estimates for the final size relation. We first present a single-stage model which is later extended to a new multistage model for Zika that incorporates more realistic incubation stages for both the humans and vectors. For each of these models, we derive a basic reproduction number and a final size relation estimate. We observe that the basic reproduction number for the multistage model converges to expected values for a standard Zika epidemic model with fixed incubation periods in both hosts and vectors. Finally, we also perform several computational experiments to validate the theoretical results obtained in this work and study the influence of various parameters on the models. PMID- 28894476 TI - Breathe: global networks in respiratory disease. AB - The September issue of Breathe looks at global networks in respiratory disease http://ow.ly/QkT830e4HvE. PMID- 28894474 TI - A Novel Dynamic Model Describing the Spread of the MERS-CoV and the Expression of Dipeptidyl Peptidase 4. AB - The Middle East respiratory syndrome (MERS) coronavirus, a newly identified pathogen, causes severe pneumonia in humans. MERS is caused by a coronavirus known as MERS-CoV, which attacks the respiratory system. The recently defined receptor for MERS-CoV, dipeptidyl peptidase 4 (DPP4), is generally expressed in endothelial and epithelial cells and has been shown to be present on cultured human nonciliated bronchiolar epithelium cells. In this paper, a class of novel four-dimensional dynamic model describing the infection of MERS-CoV is given, and then global stability of the equilibria of the model is discussed. Our results show that the spread of MERS-CoV can also be controlled by decreasing the expression rate of DPP4. PMID- 28894477 TI - Clinical exercise testing: basic principles and practice. AB - Faculty and delegates of an @ERStalk course on clinical exercise testing describe their experiences http://ow.ly/dPwB30dxr8v. PMID- 28894478 TI - Diagnosis of primary ciliary dyskinesia: summary of the ERS Task Force report. AB - KEY POINTS: Primary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous disease characterised by abnormal motile ciliary function.There is no "gold standard" diagnostic test for PCD.The European Respiratory Society (ERS) Task Force Guidelines for diagnosing PCD recommend that patients should be referred for diagnostic testing if they have several of the following features: persistent wet cough; situs anomalies; congenital cardiac defects; persistent rhinitis; chronic middle ear disease with or without hearing loss; or a history, in term infants, of neonatal upper and lower respiratory symptoms or neonatal intensive care admission.The ERS Task Force recommends that patients should be investigated in a specialist PCD centre with access to a range of complementary tests: nasal nitric oxide, high-speed video microscopy analysis and transmission electron microscopy. Additional tests including immunofluorescence labelling of ciliary proteins and genetic testing may also help determine the diagnosis. EDUCATIONAL AIMS: This article is intended for primary and secondary care physicians interested in primary ciliary dyskinesia (PCD), i.e. those who identify patients for testing, and those involved in diagnosing and managing PCD patients. It aims: to inform readers about the new European Respiratory Society Task Force Guidelines for diagnosing patients with PCDto enable primary and secondary care physicians to: identify patients who need diagnostic testing; understand the diagnostic tests that their patients will undergo, the results of the tests and their limitations; and ensure that appropriate care is subsequently delivered. PMID- 28894479 TI - The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC): experiences from a successful ERS Clinical Research Collaboration. AB - : In contrast to airway diseases like chronic obstructive pulmonary disease or asthma, and rare diseases such as cystic fibrosis, there has been little research and few clinical trials in bronchiectasis. Guidelines are primarily based on expert opinion and treatment is challenging because of the heterogeneous nature of the disease. In an effort to address decades of underinvestment in bronchiectasis research, education and clinical care, the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) was established in 2012 as a collaborative pan-European network to bring together bronchiectasis researchers. The European Respiratory Society officially funded EMBARC in 2013 as a Clinical Research Collaboration, providing support and infrastructure to allow the project to grow. EMBARC has now established an international bronchiectasis registry that is active in more than 30 countries both within and outside Europe. Beyond the registry, the network participates in designing and facilitating clinical trials, has set international research priorities, promotes education and has participated in producing the first international bronchiectasis guidelines. This manuscript article the development, structure and achievements of EMBARC from 2012 to 2017. EDUCATIONAL AIMS: To understand the role of Clinical Research Collaborations as the major way in which the European Respiratory Society can stimulate clinical research in different disease areasTo understand some of the key features of successful disease registriesTo review key epidemiological, clinical and translational studies of bronchiectasis contributed by the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) project in the past 5 yearsTo understand the key research priorities identified by EMBARC for the next 5 years. PMID- 28894480 TI - Patient participation in ERS guidelines and research projects: the EMBARC experience. AB - : The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is a European Respiratory Society (ERS) Clinical Research Collaboration dedicated to improving research and clinical care for people with bronchiectasis. EMBARC has created a European Bronchiectasis Registry, funded by the ERS and by the European Union (EU) Innovative Medicines Initiative Programme. From the outset, EMBARC had the ambition to be a patient-focussed project. In contrast to many respiratory diseases, however, there are no specific patient charities or European patient organisations for patients with bronchiectasis and no existing infrastructure for patient engagement. This article describes the experience of EMBARC and the European Lung Foundation in establishing a patient advisory group and then engaging this group in European guidelines, an international registry and a series of research studies. Patient involvement in research, clinical guidelines and educational activities is increasingly advocated and increasingly important. Genuine patient engagement can achieve a number of goals that are critical to the success of an EU project, including focussing activities on patient priorities, allowing patients to direct the clinical and research agenda, and dissemination of guidelines and research findings to patients and the general public. Here, we review lessons learned and provide guidance for future ERS task forces, EU-funded projects or clinical research collaborations that are considering patient involvement. EDUCATIONAL AIMS: To understand the different ways in which patients can contribute to clinical guidelines, research projects and educational activities.To understand the barriers and potential solutions to these barriers from a physician's perspective, in order to ensure meaningful patient involvement in clinical projects.To understand the barriers and potential solutions from a patient's perspective, in order to meaningfully involve patients in clinical projects. PMID- 28894481 TI - Respiratory research networks in Europe and beyond: aims, achievements and aspirations for the 21st century. AB - Healthcare-associated infection, such as intensive care unit (ICU)-related respiratory infections, remain the most frequently encountered morbidity of ICU admission, prolonging hospital stay and increasing mortality rates. The epidemiology of ICU-related respiratory infections, particularly nonventilated ICU-associated pneumonia and ventilator-associated tracheobronchitis, appears to be quite different among different countries. European countries have different prevalence, patterns and mechanism of resistance, as well as different treatments chosen by different attending physicians. The classical clinical research process in respiratory infections consists of the following loop: 1) identification of knowledge gaps; 2) systematic review and search for adequate answers; 3) generation of study hypotheses; 4) design of study protocols; 5) collection clinical data; 6) analysis and interpretation of the results; and 7) implementation of the results in clinical practice. PMID- 28894482 TI - A middle-aged man with generalised weakness and dyspnoea. AB - Can you diagnose this middle-aged man with generalised weakness and dyspnoea? http://ow.ly/mSuQ30dxQ5o. PMID- 28894483 TI - Increased exercise tolerance using daytime mouthpiece ventilation for patients with diaphragm paralysis. AB - Mouthpiece ventilation can improve exercise tolerance in patients with unilateral or bilateral diaphragm paralysis http://ow.ly/X2Pd30dCT7n. PMID- 28894484 TI - ERS Early Career Members meet EAACI Junior Members: the launch of a strong, fruitful collaboration. AB - Learn about the collaboration between @EarlyCareerERS and @EAACI_JM http://ow.ly/WUTO30d7dpC. PMID- 28894485 TI - Asbestos and the lung: highlights of a detrimental relationship. AB - Novel aspects of the pathogenesis of asbestos-related diseases are still coming to light http://ow.ly/EPDa30e8JqK. PMID- 28894486 TI - Hot Topics from the Assemblies. AB - Both acute bronchoconstriction, which often manifests as wheeze and shortness of breath, and the neuronal cough reflex are key symptoms of asthma. However, the interaction between airway smooth muscle and nerve responses in disease are unclear. The authors had undertaken a study in which they examined the acute effects of bronchoconstriction on cough, and vice versa, in subjects with mild atopic asthma. PMID- 28894487 TI - Radiology corner. PMID- 28894488 TI - Respiratory medicine training in Malta. AB - In Malta, respiratory medicine is quite a popular speciality. It is attractive because of the interesting case mix and the interventional element of the speciality. PMID- 28894489 TI - Respiratory training in Egypt. AB - In Egypt, respiratory medicine (more commonly termed "chest diseases") is regarded as a separate speciality rather than a subspecialty of internal medicine. All graduates of Egyptian Medical Schools have to complete a year of internship at teaching hospitals rotating between different medical and surgical departments. Following internship and obtaining licence to practice, doctors are required to work for 6-12 months at primary healthcare facilities around the country. At the end of this period, a doctor can start their specialty training; the choice of which depends on the cumulative score they achieved at medical school. PMID- 28894490 TI - Respiratory training in Greece. AB - In Greece, respiratory medicine is a stand-alone specialty requiring a 5-year training programme. Acquisition of the general medicine specialty is not a prerequisite for entering the respiratory training programme. As background information, Greece's population is approximately 11 million and there are tertiary hospitals covering specific geographical areas of the country. The majority of the tertiary hospitals include respiratory wards and also train registrars. Although there is heterogeneity between different hospitals, our article highlights the training of respiratory physicians in the majority of respiratory departments in the country. PMID- 28894491 TI - Respiratory physiologist training in Ireland. AB - Respiratory physiologists are part of a large multidisciplinary team. Their role is to investigate respiratory and sleep disorders through various diagnostic tools and methodologies. In Ireland, respiratory physiologists complete a 4-year Bachelor of Science (BSc) degree in clinical measurement science. PMID- 28894492 TI - Confidences de Salon. AB - Breathe Chief Editor @sleepresearcher gives an insight into her life http://ow.ly/bt1W3062Qho. PMID- 28894493 TI - Quitting smoking: the benefits. AB - Quitting smoking improves the quality and length of your life. Immediately after your last cigarette, your body will feel the benefits. PMID- 28894494 TI - Predatory publishers: Implications for pharmacy practice and practitioners. PMID- 28894495 TI - Assessments: Great hockey players and great pharmacists share skill sets. PMID- 28894496 TI - Indigenous identity and traditional medicine: Pharmacy at the crossroads. PMID- 28894497 TI - Part 4: Professional satisfaction and the priorities to advance the pharmacy profession. PMID- 28894498 TI - Guidelines for the management of atopic dermatitis (eczema) for pharmacists. PMID- 28894499 TI - The assessment and management of urinary tract infections in adults: Guidelines for pharmacists. PMID- 28894500 TI - Human papilloma virus (HPV) vaccination: Questions and answers. PMID- 28894501 TI - Incorporating assessment and prescribing for ambulatory ailments skills into practice: An environmental scan of continuing education for pharmacist prescribing in Canada. AB - OBJECTIVES: Pharmacists in Canadian provinces are at different stages of applying prescribing legislation into practice. The purpose of this environmental scan was to examine differences in legislation, remuneration, professional uptake, continuing education requirements and continuing education resources relating to pharmacist prescribing for ambulatory ailments, with a focus on continuing education. METHODS: Data were collected between May and December 2016 using websites and communication with provincial professional regulatory bodies, advocacy bodies, drug coverage programs and other organizations that offer continuing education for pharmacists. RESULTS: Training requirements to prescribe for ambulatory ailments vary provincially, including no training requirements, online tutorials and a comprehensive application process. Government-funded remuneration for prescribing services is absent in most provinces. Pharmacist uptake of the training required to obtain prescribing authority ranges from 30% to 100% of pharmacists. Continuing education programs on the topic of prescribing across the country include online courses, in-person courses, webinars, panel discussions and preparation courses. CONCLUSION: Many aspects of pharmacist prescribing for ambulatory ailments, including the style and content of continuing education resources, vary from province to province. Further research on this topic would help to determine the effect of these differences on the success of incorporating pharmacist prescribing into practice. PMID- 28894502 TI - Use of smoking cessation products: A survey of patients in community pharmacies. AB - OBJECTIVES: At 17.3%, smoking rates in Manitoba continue to exceed the national average. In this province, a total health care spending of more than $200 million per year has been attributed to smoking. This study examined the use of smoking cessation agents, including nicotine replacement products and prescription medications, in a sample of smokers in the city of Winnipeg. METHODS: A simple multiple-choice questionnaire was administered to willing individuals attending 2 community pharmacies in Winnipeg, Manitoba. Data on demographics, smoking habits, previous attempts of smoking cessation and previous and current use of over-the counter and prescription smoking cessation products were collected anonymously. RESULTS: Of the 2237 individuals who were approached, 586 were smokers (26.2%) and 180 responded to the survey (30.7%); 48.9% were female. A majority of smokers (32.8%) reported smoking 16 to 25 cigarettes per day. More than 90% had smoked for more than 5 years, 27.2% had more than 5 previous quit attempts and 82.1% used smoking cessation products with the intention to quit. Self-motivation (44.4%) and family/friend advice (28.3%) were major reasons for quitting. Impact of health care practitioners' advice was low (6.4%). More than 80% of respondents reported that they had no insurance coverage for their smoking cessation products. Despite having the highest rate of use, both nicotine gum (33.3%) and patches (24.4%) were reported to have lower rates of perceived efficacy. Electronic cigarette (97.9%) and varenicline (70.6%) had the highest rates of reported effectiveness. CONCLUSION: Smokers wanting to quit undergo many attempts. Pharmacists should assume a key role in reaching out to smokers. PMID- 28894503 TI - Canadian Pharmacists Conference 2017 pharmacy practice research highlights. PMID- 28894504 TI - An Extract from the Plant Deschampsia antarctica Protects Fibroblasts from Senescence Induced by Hydrogen Peroxide. AB - The Antarctic plant Deschampsia antarctica (DA) is able to survive in extreme conditions thanks to its special mechanism of protection against environmental aggressions. In this work, we investigated whether an aqueous extract of the plant (EDA) retains some of its defensive properties and is able to protect our skin against common external oxidants. We evaluated EDA over young human fibroblasts and exposed to H2O2, and we measured cell proliferation, viability, and senescence-associated beta-galactosidase (SA-beta-Gal). We also tested the expression of several senescence-associated proteins including sirtuin1, lamin A/C, the replicative protein PCNA, and the redox protein thioredoxin 2. We found that EDA promoted per se cell proliferation and viability and increased the expression of anti-senescence-related markers. Then, we selected a dose of H2O2 as an inductor of senescence in human fibroblasts, and we found that an EDA treatment 24 h prior H2O2 exposure increased fibroblast proliferation. EDA significantly inhibited the increase in SA-beta-Gal levels induced by H2O2 and promoted the expression of sirtuin 1 and lamin A/C proteins. Altogether, these results suggest that EDA protects human fibroblasts from cellular senescence induced by H2O2, pointing to this compound as a potential therapeutic agent to treat or prevent skin senescence. PMID- 28894505 TI - Increased Mitochondrial Mass and Cytosolic Redox Imbalance in Hippocampal Astrocytes of a Mouse Model of Rett Syndrome: Subcellular Changes Revealed by Ratiometric Imaging of JC-1 and roGFP1 Fluorescence. AB - Rett syndrome (RTT) is a neurodevelopmental disorder with mutations in the MECP2 gene. Mostly girls are affected, and an apparently normal development is followed by cognitive impairment, motor dysfunction, epilepsy, and irregular breathing. Various indications suggest mitochondrial dysfunction. In Rett mice, brain ATP levels are reduced, mitochondria are leaking protons, and respiratory complexes are dysregulated. Furthermore, we found in MeCP2-deficient mouse (Mecp2-/y ) hippocampus an intensified mitochondrial metabolism and ROS generation. We now used emission ratiometric 2-photon imaging to assess mitochondrial morphology, mass, and membrane potential (DeltaPsim) in Mecp2-/y hippocampal astrocytes. Cultured astrocytes were labeled with the DeltaPsim marker JC-1, and semiautomated analyses yielded the number of mitochondria per cell, their morphology, and DeltaPsim. Mecp2-/y astrocytes contained more mitochondria than wild-type (WT) cells and were more oxidized. Mitochondrial size, DeltaPsim, and vulnerability to pharmacological challenge did not differ. The antioxidant Trolox opposed the oxidative burden and decreased the mitochondrial mass, thereby dampening the differences among WT and Mecp2-/y astrocytes; mitochondrial size and DeltaPsim were not markedly affected. In conclusion, mitochondrial alterations and redox imbalance in RTT also involve astrocytes. Mitochondria are more numerous in Mecp2-/y than in WT astrocytes. As this genotypic difference is abolished by Trolox, it seems linked to the oxidative stress in RTT. PMID- 28894506 TI - A Cystine-Rich Whey Supplement (Immunocal(r)) Provides Neuroprotection from Diverse Oxidative Stress-Inducing Agents In Vitro by Preserving Cellular Glutathione. AB - Oxidative stress is a principal mechanism underlying the pathophysiology of neurodegeneration. Therefore, nutritional enhancement of endogenous antioxidant defenses may represent a viable treatment option. We investigated the neuroprotective properties of a unique whey protein supplement (Immunocal(r)) that provides an essential precursor (cystine) for synthesis of the endogenous antioxidant, glutathione (GSH). Primary cultures of rat cerebellar granule neurons (CGNs), NSC34 motor neuronal cells, or HT22 hippocampal cells were preincubated in medium containing Immunocal and then subsequently treated with agents known to induce oxidative stress. Immunocal protected CGNs against neurotoxicity induced by the Bcl-2 inhibitor, HA14-1, the nitric oxide donor, sodium nitroprusside, CuCl2, and AlCl3. Immunocal also significantly reduced NSC34 cell death due to either H2O2 or glutamate and mitigated toxicity in HT22 cells overexpressing beta-amyloid1-42. The neuroprotective effects of Immunocal were blocked by inhibition of gamma-glutamyl-cysteine ligase, demonstrating dependence on de novo GSH synthesis. These findings indicate that sustaining GSH with Immunocal significantly protects neurons against diverse inducers of oxidative stress. Thus, Immunocal is a nutritional supplement worthy of testing in preclinical animal models of neurodegeneration and in future clinical trials of patients afflicted by these diseases. PMID- 28894507 TI - FOXO Transcriptional Factors and Long-Term Living. AB - Several pathologies such as neurodegeneration and cancer are associated with aging, which is affected by many genetic and environmental factors. Healthy aging conceives human longevity, possibly due to carrying the defensive genes. For instance, FOXO (forkhead box O) genes determine human longevity. FOXO transcription factors are involved in the regulation of longevity phenomenon via insulin and insulin-like growth factor signaling. Only one FOXO gene (FOXO DAF 16) exists in invertebrates, while four FOXO genes, that is, FOXO1, FOXO3, FOXO4, and FOXO6 are found in mammals. These four transcription factors are involved in the multiple cellular pathways, which regulate growth, stress resistance, metabolism, cellular differentiation, and apoptosis in mammals. However, the accurate mode of longevity by FOXO factors is unclear until now. This article describes briefly the existing knowledge that is related to the role of FOXO factors in human longevity. PMID- 28894510 TI - Antioxidant and Anti-Inflammatory Effects of Shungite against Ultraviolet B Irradiation-Induced Skin Damage in Hairless Mice. AB - As fullerene-based compound applications have been rapidly increasing in the health industry, the need of biomedical research is urgently in demand. While shungite is regarded as a natural source of fullerene, it remains poorly documented. Here, we explored the in vivo effects of shungite against ultraviolet B- (UVB-) induced skin damage by investigating the physiological skin parameters, immune-redox profiling, and oxidative stress molecular signaling. Toward this, mice were UVB-irradiated with 0.75 mW/cm2 for two consecutive days. Consecutively, shungite was topically applied on the dorsal side of the mice for 7 days. First, we found significant improvements in the skin parameters of the shungite-treated groups revealed by the reduction in roughness, pigmentation, and wrinkle measurement. Second, the immunokine profiling in mouse serum and skin lysates showed a reduction in the proinflammatory response in the shungite treated groups. Accordingly, the redox profile of shungite-treated groups showed counterbalance of ROS/RNS and superoxide levels in serum and skin lysates. Last, we have confirmed the involvement of Nrf2- and MAPK-mediated oxidative stress pathways in the antioxidant mechanism of shungite. Collectively, the results clearly show that shungite has an antioxidant and anti-inflammatory action against UVB-induced skin damage in hairless mice. PMID- 28894509 TI - Effects of Polyphenol Intake on Metabolic Syndrome: Current Evidences from Human Trials. AB - Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors which severely increases the risk of type II diabetes and cardiovascular disease. Several epidemiological studies have observed a negative association between polyphenol intake and MetS rates. Nevertheless, there are relatively small numbers of interventional studies evidencing this association. This review is focused on human interventional trials with polyphenols as polyphenol-rich foods and dietary patterns rich in polyphenols in patients with MetS. Current evidence suggests that polyphenol intake has the potential to alleviate MetS components by decreasing body weight, blood pressure, and blood glucose and by improving lipid metabolism. Therefore, high intake of polyphenol-rich foods such as nuts, fruits, vegetables, seasoning with aromatic plants, spices, and virgin olive oil may be the cornerstone of a healthy diet preventing the development and progression of MetS, although there is no polyphenol or polyphenol-rich food able to influence all MetS features. However, inconsistent results have been found in different trials, and more long-term randomized trials are warranted to develop public health strategies to decrease MetS rates. PMID- 28894508 TI - Protein Posttranslational Modifications: Roles in Aging and Age-Related Disease. AB - Aging is characterized by the progressive decline of biochemical and physiological function in an individual. Consequently, aging is a major risk factor for diseases like cancer, obesity, and type 2 diabetes. The cellular and molecular mechanisms of aging are not well understood, nor is the relationship between aging and the onset of diseases. One of the hallmarks of aging is a decrease in cellular proteome homeostasis, allowing abnormal proteins to accumulate. This phenomenon is observed in both eukaryotes and prokaryotes, suggesting that the underlying molecular processes are evolutionarily conserved. Similar protein aggregation occurs in the pathogenesis of diseases like Alzheimer's and Parkinson's. Further, protein posttranslational modifications (PTMs), either spontaneous or physiological/pathological, are emerging as important markers of aging and aging-related diseases, though clear causality has not yet been firmly established. This review presents an overview of the interplay of PTMs in aging-associated molecular processes in eukaryotic aging models. Understanding PTM roles in aging could facilitate targeted therapies or interventions for age-related diseases. In addition, the study of PTMs in prokaryotes is highlighted, revealing the potential of simple prokaryotic models to uncover complex aging-associated molecular processes in the emerging field of microbiogerontology. PMID- 28894511 TI - The Evaluation of Antioxidant and Anti-Inflammatory Effects of Eucommia ulmoides Flavones Using Diquat-Challenged Piglet Models. AB - This study was designed to evaluate the antioxidant and anti-inflammatory effects of Eucommia ulmoides flavones (EUF) using diquat-challenged piglet models. A total of 96 weaned piglets were randomly allotted to 1 of 3 treatments with 8 replication pens per treatment and 4 piglets per pen. The treatments were basal diet, basal diet + diquat, and 100 mg/kg EUF diet + diquat. On day 7 after the initiation of treatment, the piglets were injected intraperitoneally with diquat at 8 mg/kg BW or the same amount of sterilized saline. The experiment was conducted for 21 days. EUF supplementation improved the growth performance of diquat-treated piglets from day 14 to 21. Diquat also induced oxidative stress and inflammatory responses and then impaired intestinal morphology. But EUF addition alleviated these negative effects induced by diquat that showed decreasing serum concentrations of proinflammatory cytokines but increasing antioxidant indexes and anti-inflammatory cytokines on day 14. Supplementation of EUF also increased villi height and villous height, crypt depth, but decreased the histopathological score and MPO activity compared with those of diquat challenged pigs fed with the basal diet on day 14. Results indicated that EUF attenuated the inflammation and oxidative stress of piglets caused by diquat injection. PMID- 28894512 TI - Treatment Effects of Ischemic Stroke by Berberine, Baicalin, and Jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) Explored by an Integrated Metabolomics Approach. AB - Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the 1H NMR metabolomics approach was used to assess the metabolic profiles, which combined with correlation network analysis successfully revealed metabolic disorders in ischemic stroke concerning the treatment of the three principal compounds from HLJDD for the first time. The combined results suggested that berberine, baicalin, and jasminoidin are responsible for the effectiveness of HLJDD on the treatment of ischemic stroke by amelioration of abnormal metabolism and regulation of oxidative stress, neuron autophagy, and inflammatory response. This integrated metabolomics approach showed its potential in understanding the function of complex formulae and clarifying the role of its components in the overall treatment effects. PMID- 28894514 TI - Prevalence and Correlates of Gastroesophageal Reflux Disease in Southern Iran: Pars Cohort Study. AB - BACKGROUND Prevalence of gastroesophageal reflux disease (GERD) is increasing worldwide. We aimed to estimate the prevalence of GERD in Pars Cohort Study (PCS) and to find its correlates. METHODS We used the baseline data from PCS. PCS was conducted in the district of Valashahr in Fars province in southern Iran from 2012 to 2014. 9264 inhabitants who were 40-75 years old, and agreed to participate were enrolled. Data were collected by a structured questionnaire and simple physical examination of all participants. RESULTS Generally, 58.50% (95% CI 57.49 - 59.51) of the participants had GERD and 25.10% (95% CI 24.22 - 25.99) experienced it at least weekly. Approximately, 32.0%, 52.0%, and 24.4% of the participants reported heart burn sensation, regurgitation, and both symptoms, respectively. Being female (OR: 1.45, 95% CI 1.27 - 1.65), being older (OR: 1.20, 95% CI 1.06 - 1.36), being divorced/ widowed/separated (OR: 1.38, 95% CI 1.01 - 1.91), and lower education (OR: 1.43, 95% CI 1.02 - 2.03) were associated with frequent GERD. CONCLUSION GERD is common in PCS and its prevalence is close to that in western countries. Being female, higher age, being divorced/widowed/separated, lower education, history of hypertension, anxiety, insomnia, and non-cigarette tobacco smoking were associated with frequent GERD. We are going to investigate the causal relationship between these risk factors and GERD in the next stages of PCS. PMID- 28894513 TI - Diagnostic Methods, Risk Factors, Prevention, and Management of Breast Cancer Related Lymphedema: Past, Present, and Future Directions. AB - PURPOSE OF REVIEW: Breast cancer-related lymphedema (BCRL) is a chronic, adverse, and much feared complication of breast cancer treatment, which affects approximately 20% of patients following breast cancer treatment. BCRL has a tremendous impact on breast cancer survivors, including physical impairments and significant psychological consequences. The intent of this review is to discuss recent studies and analyses regarding the risk factors, diagnosis, prevention through early screening and intervention, and management of BCRL. RECENT FINDINGS: Highly-evidenced risk factors for BCRL include axillary lymph node dissection, lack of reconstruction, radiation to the lymph nodes, high BMI at diagnosis, weight fluctuations during and after treatment, subclinical edema within and beyond 3 months after surgery, and cellulitis in the at-risk arm. Avoidance of potential risk factors can serve as a method of prevention. Through establishing a screening program by which breast cancer patients are measured pre operatively and at follow-ups, are objectively assessed through a weight-adjusted analysis, and are clinically assessed for signs and symptoms, BCRL can be tracked accurately and treated effectively. Management of BCRL is done by a trained professional, with research mounting towards the use of compression bandaging as a first line intervention against BCRL. Finally, exercise is safe for breast cancer patients with and without BCRL and does not incite or exacerbate symptoms of BCRL. SUMMARY: Recent research has shed light on BCRL risk factors, diagnosis, prevention, and management. We hope that education on these aspects of BCRL will promote an informed, consistent approach and encourage additional research in this field to improve patient outcomes and quality of life in breast cancer survivors. PMID- 28894515 TI - Association of Gastrointestinal Functional Disorders and Migraine Headache: a Population Base Study. AB - BACKGROUND Migraine is one of the prevalent headaches. Many of patients with migraine, complain of gastrointestinal symptoms. There is limited studies on relation of gastrointestinal symptoms and migraine headache at population level. METHODS In this population-based study, 1038 subjects older than 15 year from a rural area in Fars province, south of Iran. were investigated for functional gastrointestinal disorders. By cluster random sampling, 160 of these persons invited to receive endoscopy along with histopathology samples of upper gastrointestinal tract. Data were analyzed using Pearson chi-square and Fisher exact. RESULTS Mean age of participations were 34.3 years with female to male of 3:1. The prevalence of migraine, irritable bowel syndrome (IBS), reflux, and dyspepsia were 24.6%, 17.7%, 17.4%, and 32.1%, respectively. There were significant relationship between migraine and functional gastrointestinal diseases (odds ratio of association for migraine with IBS, reflux, and dyspepsia were 3.43, 1.68, and 1.68 with p-value < 0.001 for all). In endoscopic findings, only presence of hiatal hernia was associated significantly with migraine (p = 0.011). No histopathologic findings in antral or duodenal biopsies were associated with migraine. CONCLUSION In this population based study we found significant association between migraines and gastrointestinal functional disorders including IBS, reflux and dyspepsia. This may have implication in better management of patients with migraine headache. PMID- 28894516 TI - Menstrual and Reproductive Factors and Risk of Pancreatic Cancer in Women. AB - BACKGROUND Pancreatic cancer (PC) is a deadly disease with a 5-year survival of less than 5%. Worldwide PC incidence rates are lower among women than men. While this suggests a protective role for steroid hormones in PC risk, results from epidemiological studies are not consistent. METHODS 153 new incident PC cases and 202 controls were recruited from a prospective case-control study, running in a referral center for endoscopic ultrasonography during 2011-2017. A structured valid and reliable questionnaire was used for data collection by a few trained interviewers. Odds ratios and 95% confidence intervals for reproductive factors and PC were estimated using logistic regression methods. RESULTS Mean age (SD) of the cases and the controls were 63.18 (11.4) and 63.37 (12.0) years, respectively. Age at menarche, age at menopause, number of parity, gravidity, and abortion were not associated with PC risk. CONCLUSION This study does not support the hypothesis that menstrual and reproductive factors are associated with PC risk. PMID- 28894517 TI - Effects of Probiotic and Prebiotic Supplementation on Leptin, Adiponectin, and Glycemic Parameters in Non-alcoholic Fatty Liver Disease: A Randomized Clinical Trial. AB - BACKGROUND According to previous studies, probiotic and prebiotic supplementation have desirable effects on glycemic parameters. Thus far, the effect of supplementation on the glycemic parameters and adipokines in non-alcoholic fatty liver disease (NAFLD) has not been assessed. Therefore, the aim of this study was to determine the effects of supplementation with probiotic and prebiotic on adiokines and glycemic parameters in the patients with NAFLD. METHODS In the present randomized, double-blind, placebo-controlled trial, 89 patients with NAFLD were randomly divided into three groups to receive one probiotic capsule + 16 g/d maltodextrin (probiotic group) or 16 g/d oligofructose powder + one placebo capsule (prebiotic group), and one placebo capsule + 16 g/d maltodextrin (control group) for 12 weeks. All the subjects in the study were advised to follow the weight loss diet and physical activity recommendations during the intervention. Fasting blood samples were taken at baseline and after the intervention to measure leptin, adiponectin, insulin, and fasting blood sugar. RESULTS At the end of the study, serum concentrations of leptin, insulin, and HOMA-IR decreased significantly in the probiotic and prebiotic groups compared with the control group. Despite the changes within the groups, serum concentrations of adiponectin did not change significantly between the three groups. Also, fasting blood sugar did not change between the groups, but decreased in the prebiotic group. Quantitative insulin-sensitivity check index (QUICKI) increased significantly in probiotic and prebiotic groups compared with the control group. CONCLUSION Probiotic and prebiotic supplementation along with lifestyle intervention has a favorable impact on glycemic parameters and leptin levels compared with lifestyle intervention alone. PMID- 28894518 TI - Assessment of Bone Morphogenetic Protein 3 Methylation in Iranian Patients with Colorectal Cancer. AB - BACKGROUND Colorectal cancer (CRC) is a common cancer that results in outstanding morbidity and mortality worldwide. DNA methylation is one of the most important epigenetic events that is thought to occur during the early stages of oncogenic transformation especially in CRC. The aim of this study was to investigate whether hypermethylation of bone morphogenetic protein 3 (BMP3) in tissue samples is implicated in Iranian patients with CRC. METHODS From fresh frozen tissue samples of 30 patients with CRC, the DNA was isolated, treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction with primers specific for methylated or unmethylated promoter sequences of the BMP3 gene. Demographic characteristics of the patients including age, sex, tumor grade, location, stage, and TNM classification were evaluated and the relationship between hypermethylation of the gene and clinicopathological features was analyzed. RESULTS Methylation of the BMP3 promoter was often present in the DNA extracted from the tumoral tissues. A sensitivity of 56.66% and specificity of 93.3% were attained in the detection of colorectal neoplasia. CONCLUSION We assumed that solely BMP3 methylation analysis in our population is not sufficient to select the gene as a screening biomarker and it should be considered in combination with other markers to screen for detection of colorectal cancer. PMID- 28894520 TI - Cocoon Peritonitis Secondary to Perforated Appendicitis. AB - A young man was admitted due to gastrointestinal obstruction and was diagnosed as having cocoon peritonitis secondary to perforated appendicitis. He suffered from small intestine partial obstruction because of multiple adhesion bands whose obstructive symptoms completely resolved after single balloon enteroscopy. So balloon enteroscopy could be offered as a therapeutic option for partial small intestine obstruction. PMID- 28894519 TI - Epidemiologic Characteristics of Patients with Inflammatory Bowel Disease in Kermanshah, Iran. AB - BACKGROUND This study was done to define some epidemiological aspects of inflammatory bowel disease (IBD), and to describe its characteristics in west of Iran. METHODS In this descriptive study all patient with the diagnosis of IBD who were visited in universityaffiliated medical centers, between 2014 and 2015 were recruited. Their demographic characteristics, disease-related manifestations, complications, disease course and their chief complaints were analyzed. RESULTS Of 156 referred individuals, 153 patients had ulcerative colitis (UC) and 3 patients had Crohn's diseases (CD). The mean age of the patients at diagnosis was 35.69+/-12.35 (range: 17-80) years with the most common age group of 25-35 years and slight female predominance (51.9%). More urban patients were registered (90.4%) and 57% had high school or upper education. Positive family history of the disease was in 25.6% and 66.6% had four or more family members. Furthermore, 51.9% had left sided colitis and 40.4% had pancolitis with bloody diarrhea (79.5%) and abdominal pain (68.6%) as the most common manifestations. 36.5% had other autoimmune diseases. Multiple flare was seen in 47.4%, most commonly due to drug discontinuation (26.28%). Hospital admission was reported in 34.6%. History of contraceptive pill use was in 38.8% of the female patients. CONCLUSION The demographic and clinical manifestations of IBD are usually the same as other developing countries; however, the rarity of CD is eminent. Although the accurate epidemiological characteristic of IBD in Iran is still obscure, it is not a rare disease as previously thought and it seems that gradual reception of a western lifestyle may be linked to the ongoing rise in IBD. PMID- 28894521 TI - A Large Intracolonic Mass in a Patient with Peutz-Jeghers Syndrome. AB - Peutz-Jeghers syndrome (PJS) is characterized by scattered black pigmentations on fingers and lips and multiple polyps in the gastrointestinal tract. Patients with PJS often have severe complications secondary to multiple large polyps. Herein, we present a young woman complicated with a large polyp in her colon without any clinical symptoms. We also emphasized the necessity of early diagnosis and treatment of multiple polyps in such patients. PMID- 28894522 TI - Multilocular Cystic Mass Located in Epigastric Region and Right Area of the Abdomen in an old man. PMID- 28894523 TI - Correlation between Cut-off Level of Tissue Transglutaminase Antibody and Marsh Classification. PMID- 28894524 TI - Spider Bite in Iran. AB - Some of the world's most dangerous spiders have been certified in some areas of Iran. Spider bites are common in some geographical areas, and are sporadic in some regions. Spider bites can be classified as latrodectism or loxoscelism. If the patient had not seen the spider, the clinical manifestations of latrodectism could be easily mistaken for other types of bite or sting; or an infectious disease, and withdrawal symptoms, and also loxoscelism could be mistaken for cellulitis, various types of skin infection, or even a sting from a Gadim scorpion (Hemiscorpius lepturus). Given the nonspecific presentation of spider bites, one must keep the diagnosis in mind, and question patients, regarding possible exposure to spiders. Physicians recommend becoming familiar with the geographical distribution of Iranian dangerous spiders, clinical manifestations, and management of their bites. The most useful treatment for spider bite is anti venom administration. Producing spider bite anti-venom in the Razi Vaccine and Serum Research Institute is under investigation. PMID- 28894525 TI - Evaluation of CD44 and CD133 as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus hepatocellular carcinoma. AB - BACKGROUND: Cancer stem cells (CSCs) play a critical role in tumor development, progression, metastasis and recurrence. AIM: To evaluate hepatic expression of CD44 and CD133 in Egyptian patients with HCV-induced chronic liver diseases and hepatocellular carcinomas (HCCs), and to assess its correlation with inflammatory activity scores, stages of fibrosis (in chronic hepatitis with or without cirrhosis) and grades of HCC. METHODS: This prospective case-control study was conducted on eighty subjects who attended the Tropical Diseases Department, Al Azhar University Hospital, and in collaboration with Theodor Bilharz Research Institute (2014-2016). They were divided as follows: A) Control healthy group: Ten individuals with serologically negative HCV-Ab and HBsAg, and histopathologically normal liver, B) Seventy patients subdivided into 3 groups; Twenty subjects each, as: HCV-Ab+ non-cirrhotic, HCV-Ab+ cirrhotic and HCC. Necroinflammatory activity and fibrosis in non-neoplastic liver biopsies were scored according to the METAVIR scoring system. CD44 and CD133 immunostaining was evaluated in all groups semi-quantitatively using H score. Statistical analysis was performed by SPSS version 22, using independent-samples t-test. RESULTS: Our study showed a significant increase of mean CD44 & CD133 expression values with disease progression among the groups (p<0.05). Their expressions increased significantly with the inflammatory activity scores and stages of fibrosis, reaching the highest values in A3F4 score compared to A1F1 (p<0.05). Moreover, there was a significant increase of their expressions across HCC grades (p<0.05), however with no significant correlation with focal lesions size. CONCLUSION: CSCs clusters exhibiting CD133+ and/or CD44+ profiles were identified in chronic hepatitis, liver cirrhosis and HCC. CD133 and CD44 expressions significantly corresponded to the increased inflammatory activity, fibrosis stages and higher tumor grades. Therefore, evaluation of CD44 and CD133 expression profiles as CSCs markers in non-neoplastic liver and HCCs can help in development of novel therapeutic agents for HCC targeting and prevention. PMID- 28894526 TI - Qualitative study of HIV related stigma and discrimination: What women say in Iran. AB - INTRODUCTION: HIV-related stigma is a major social problem of people living with HIV. Stigma against these people, especially women, interferes with the prevention, diagnosis and treatment of HIV. This study examined the experiences of HIV infected women who were stigmatized, as well as the strategies used to tackle the issue. METHODS: Twenty-five women living with HIV were examined using in-depth, semi-structured interviews. The data obtained was analyzed using content analysis method in MAXQDA10. RESULTS: The finding of this study was classified into four themes: fear, shame, rejection by family or friends and feelings of frustration. The participant strategies adopted to the perceived stigma and discrimination included isolation, nondisclosure, and loss of follow up. CONCLUSIONS: HIV in women has different social interposition. It is necessary to intervene, so as to alleviate the effect of stigma on HIV infected women, in order that they gain the ability to accomplish wellness, increase life span and improve quality of life. Nurses, midwives and other professionals need to be involved to ensure public policy in providing supportive environments, and decrease stigma. PMID- 28894527 TI - Factors contributing to fear of childbirth among pregnant women in Hamadan (Iran) in 2016. AB - BACKGROUND: Fear of childbirth is a considerable mental, social, and physiological phenomenon among women as well as their families, which can be effective in choosing cesarean section for delivery. AIM: To determine some factors contributing to the fear of childbirth among pregnant women. METHOD: This cross-sectional study was conducted on 335 pregnant women referred to health centers in Toyserkan in 2016. Pregnant women with the gestational age of 16-40 weeks filled out Harman's Childbirth Attitude Questionnaire (CAQ) as well as stating demographic and obstetrics characteristics. Data were analyzed by Software SPSS/19 through chi-square, ANOVA, and Pearson's correlation tests. RESULTS: The mean age and mean gestational age of the pregnant women were 26.5+/ 4.9 years old and 26.52 weeks, respectively; 89.3% of the women reported fear of childbirth. There was a significant difference among the mean scores of the women's fear of childbirth and education level, household income adequacy, gravidity, being familiar with the delivery process, and pre-pregnancy cares (p<0.05). CONCLUSION: The present study found the relationship between women's fear of childbirth and their education level, household income, gravidity, familiarity with delivery process, and pre-pregnancy cares. It is necessary for health caregivers to take into consideration the vulnerable groups, especially nulliparous women during pre-pregnancy care as well as the social, and cultural status of women in order to identify the pregnant women exposed to fear of childbirth and reduce the chance of choosing cesarean section by providing appropriate services. PMID- 28894528 TI - Notification of international normalized ratio test in atrial fibrillation patients treated with warfarin via short message service: Study protocol for a randomized controlled trial. AB - BACKGROUND: Atrial Fibrillation (AF) is the most common abnormal heart rhythm. AF patients usually use warfarin therapy. Safety and efficacy of warfarin are dependent on maintaining the International Normalized Ratio (INR) within the therapeutic range. OBJECTIVE: We will use a Short Message Service (SMS) to evaluate the effect of a reminder on carrying out the INR laboratory test in a timely manner. METHODS: This study (a Randomized Controlled Trial) will be done in Loghman hospital Tehran, Iran. Convenience sampling will be done and 400 AF patients that have inclusion criteria will be randomized equally to an intervention or control group. Patients in the intervention group will receive an SMS that will remind them of the INR test date. The SMS will be sent at 6 PM on the day before and 8 AM on the scheduled date but the patients of the control group will receive usual care without any SMS reminders. We will evaluate the effect of reminders on carrying out the INR test in a timely manner and maintaining the INR in the therapeutic range. Patients' follow-up will be done via telephone conversation to identify thromboembolic events, bleeding and mortality. The data will be analyzed by IBM SPSS version 24. We will use independent samples t-test or Mann-Whitney and Chi-square tests for the analyses of outcomes. DISCUSSION: This protocol describes the randomized control trial to study the effects of the SMS reminder system on adherence to the timing of INR test in AF patients treated with warfarin. The research will also form the basis for future decision support systems for monitoring of patients who receive oral anticoagulants. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (http://www.irct.ir) was used to register the trial and IRCT ID was IRCT2016052528070N1. FUNDING: This research was supported by Mashhad University of Medical Sciences. PMID- 28894529 TI - Exploration of pioneering as a major element of ethical leadership in nursing: A qualitative study. AB - BACKGROUND: Commitment to ethical behavior is considered as an essential part of occupational responsibilities of nursing, and leaders' pioneering in ethical growth and development has led to the emergence of the concept of ethical leadership. OBJECTIVE: The purpose of this study was to explain the nursing leaders' perception and experiences of pioneering in the field of ethical leadership. METHODS: In this qualitative study, data were collected through semi structured individual interviews. A total of 14 nursing leaders at different levels who were selected by purposeful sampling method participated in the study. Latent content analysis was used to analyze the data. RESULTS: Of 14 participants of the study, 8 were male and 6 were female aged 38 to 56 years old with a mean managerial experience of 12 years. In the analysis of interviews, 4 subcategories of "Role Modeling", "Empowerment", "Knowledge and Skill", and "Recognition" were obtained which formed two main categories. These categories included "Leader as mentor" and "Professional insight". CONCLUSION: Pioneering leaders are an important part of ethical leadership, and nursing leaders should not only be moral people, but also go a step further and actively promote moral behavior with a role as a mentor and model as well as having professional insight. Nursing leaders with a better understanding of these aspects can develop their capacity of strong ethical leadership and consider the aspects in their activities. PMID- 28894530 TI - Knowledge and attitudes toward brain death and organ donation in Bojnurd. AB - BACKGROUND: Organ donation in Iran is common. Bojnurd (North Khorasan, Iran) is a multi-ethnic city, and people with different religions and cultures live together and that could be associated with their behavior and attitude towards health related issues. So far, no study has taken place on brain death and organ donation in the province of North Khorasan. OBJECTIVE: The aim of this study was to determine the knowledge and attitudes of citizens of Bojnurd toward brain death and organ donation. METHODS: This cross-sectional study was conducted from March to September 2014, on 380 Bojnurd citizens who were selected through multi stage sampling. The tool was a researcher-made questionnaire in three parts (demographic information, awareness and attitude surveys), containing 10 questions on awareness and 18 questions on attitude. The questionnaire validity and reliability were confirmed by content validity and Cronbach's alpha (0.76). The data were analyzed by using SPSS version 16, using Chi-square, independent samples t-test, and Spearman correlation coefficient. Significance level was set at p<0.05. RESULTS: Three hundred and eighty participants with the average age of 29.91+/-9.32 were studied, of which 55% were female. The average score of awareness and attitude was 11.42 (+/-2.40) and 39.8 (+/-6.01) respectively. The awareness of the majority of the people (63%) regarding organ donation was moderate and the attitude toward organ donation in the majority (74.1%) was poor. In people with poor attitudes, awareness was also lower, and this was statistically significant (p=0.047). CONCLUSION: the attitude towards organ donation was negative in the majority of the citizens. In order to correct the beliefs, develop positive attitude and increase citizens' knowledge, public education is essential. PMID- 28894531 TI - The effectiveness of mindfulness training on reducing the symptoms of postpartum depression. AB - BACKGROUND AND AIM: Postpartum depression is one of the prevalent disorders among new mothers. The present research aimed to examine the effectiveness of mindfulness training on reducing the symptoms of postpartum depression. METHOD: The present quasi-experimental research was conducted on 410 new mothers in Shahid Chamran Hospital, Tehran in 2014. Using the Beck Depression Inventory (BDI), Structured Clinical Interview and Psychological Clinical Diagnosis, 67 mothers were selected and then randomly divided into experimental and control groups, each of which with 32 applicants. Afterwards, the experimental group received mindfulness training for 8 sessions, each lasting for two hours while the control group received no training. The data were analyzed through descriptive statistics and Analysis of Covariance (ANCOVA) in SPSS, version 20. RESULTS: Results showed that based on Beck Inventory, the scores for the experimental group in post-test were significant (p<0.001), compared to those for the control group. Also, it was revealed that pre- and posttest mean scores for postpartum depression in the control group were 25.81 and 25.12 respectively while the scores for the experimental group were 24.75 and 18.5 respectively. Since the posttest mean score in the experimental group was lower than that in the pretest, it can be said that the treatment, i.e., mindfulness training, was effective in reducing depression symptoms in mothers. CONCLUSION: Findings proved that mindfulness training was effective in reducing the symptoms of postpartum depression in new mothers. PMID- 28894532 TI - An ethno-pharmacological study of plants used for traditional medication in Tangail district, Bangladesh. AB - BACKGROUND: In Bangladesh, folk medicinal practitioners are called "Kaviraj" and are consulted for treatment of various ailments by a large part of the rural and urban population. There are some previous studies conducted in the Tangail district of Bangladesh about medicinal plants, but there is no relevant information about this aspect in some parts of this district. AIM: To conduct an ethno-pharmacological survey among the "Kaviraj" of two upazilas (regions) in Tangail district, namely Tangail Sadar Upazila and Nagarpur Upazila, to identify the trouble-free formulations of medicinal plants for various diseases used by the folk medicine practitioners on or after other forms of medical practices. METHODS: A guided field-walk survey was carried out employing a local guide and asking local people about practicing "Kaviraj"; four of the "Kaviraj" convened and after receiving permission from the "Kaviraj", interviews were conducted through focused group discussion. RESULTS: It was observed that the "Kaviraj" of the two upazilas used a total of 25 plants distributed into 20 families for healing of various diseases. In most of the cases, leaves were the key part of most of the plants used for treatment. Plants were mainly used for treating gastrointestinal tract disorders, fever, constipation, and diarrhea, and indigestion, loss of appetite, pain and skin disorders. "Kaviraj" also treat complicated diseases such as tuberculosis, hypertension, sexual disorders, infections, urinary problems, hepatic disorders, pneumonia, stomach stones, diabetes, swellings, debility, kidney problems, tumor, vitamin C deficiency and poisoning by using medicinal plants. CONCLUSION: For a country such as Bangladesh, and particularly the district studied, medicinal plants are essential assets and have a major role in people's health care structure. Also, appropriate research should be conducted for using these medicinal plants in possible new drug designs as well as many other pharmaceutical benefits. PMID- 28894533 TI - The residual monomer content and mechanical properties of CAD?CAM resins used in the fabrication of complete dentures as compared to heat cured resins. AB - BACKGROUND: The utilization of computer-assisted designing and computer-assisted milling CAD?CAM resins in the fabrication of removable prostheses is a modern-day concept that offers many advantages over the use of the traditional polymethylmethacrylate (PMMA). AIM: This study instigated some of the mechanical properties of CAD?CAM denture base resin including the amount of residual monomer. METHODS: This study was conducted at the Faculty of Dentistry, King Abdulaziz University from October 2016 to February 2017. A total of seventy rectangular specimens were fabricated (group A: 35 heat-cured PMMA and group B: 35 CAD/CAM pre-polymerized acrylic resin blocks). The flexural strength and surface hardness were tested while the residual monomer content at baseline, two day and seven-day intervals was estimated using gas chromatography (GC). Means and standard deviations were determined for each group as well as independent samples t-test and ANOVA with repeated measures for comparison between the groups and subgroups of varying time intervals. RESULTS: Heat cured PMMA (A), displayed higher flexural strength and low value flexural modulus compared to CAD/CAM acrylic resin denture base material (B). Student t-test indicated highly significant differences (p<0.001) of the flexural strength (t=37.911) and flexural modulus (t=88.559). The surface hardness of group (B) was significantly higher compared to group (A) as indicated by the t-test (t=20.430). Higher release of the monomer content was detected by GC in group (A) at different time intervals with a statistically significant difference (p<0.001) in residual monomer content. CONCLUSION: CAD/CAM resin may be considered suitable for use in the construction of denture bases. PMID- 28894534 TI - Exploring the perception of aid organizations' staff about factors affecting management of mass casualty traffic incidents in Iran: a grounded theory study. AB - BACKGROUND: Traffic incidents are of main health issues all around the world and cause countless deaths, heavy casualties, and considerable tangible and intangible damage. In this regard, mass casualty traffic incidents are worthy of special attention as, in addition to all losses and damage, they create challenges in the way of providing health services to the victims. AIM: The present study is an attempt to explore the challenges and facilitators in management of mass casualty traffic incidents in Iran. METHODS: This qualitative grounded theory study was carried out with participation of 14 purposively selected experienced managers, paramedics and staff of aid organizations in different provinces of Iran in 2016. Semi-structured interviews were conducted in order to develop the theory. The transcribed interviews were analyzed through open, axial and selective coding. RESULTS: Despite the recent and relatively good improvements in facilities and management procedure of mass casualty traffic incidents in Iran, several problems such as lack of coordination, lack of centralized and integrated command system, large number of organizations participating in operations, duplicate attempts and parallel operations carried out by different organizations, intervention of lay people, and cultural factors halt provision of effective health services to the victims. CONCLUSION: It is necessary to improve the theoretical and practical knowledge of the relief personnel and paramedics, provide public with education about first aid and improve driving culture, prohibit laypeople from intervening in aid operations, and increase quality and quantity of aid facilities. PMID- 28894535 TI - The psychometric properties of exercise benefits/barriers scale among women. AB - BACKGROUND AND OBJECTIVE: Despite the numerous health benefits of regular physical activity (PA), physical inactivity is a major health issue among women. The goal of the current study was to measure the validity and reliability assessment of the exercise benefits/barriers scale among women between the ages of 18 and 65 years. This study was carried out among women residing in Khoramroudi neighborhood in Tehran between December 2013 and February 2014. METHODS: In this descriptive, methodological study, 278 women residing in Khoramroudi neighborhood in Tehran between December 2013 and February 2014 completed three questionnaires: the demographic data form, the Exercise Benefits/Barriers Scale. The construct validity, internal consistency, and stability of the study were measured by confirmatory factor analyses, Cronbach's alpha, and Spearman Brown correlation coefficient by using SPSS 21 and LISREL 8.80, respectively. RESULTS: The confirmatory factor analysis showed the Persian version of EBBS was structured well. The Cronbach's alpha coefficients for the total scale and its subscales were 0.927, 0.94 and 0.82, respectively. Spearman Brown correlation coefficient also showed good test-retest reliability. CONCLUSION: The results of this study verified the reliability and validity of the applied instrument and introduced it as a tool to measure the benefits and barriers of physical activity among Iranian women. PMID- 28894536 TI - Structural investigation of websites of selected educational hospitals of Shiraz University of Medical Sciences from Patient Relationship Management (PRM) perspective. AB - BACKGROUND: Hospital websites are considered as an appropriate system for exchanging information and establishing communication between patients, hospitals, and medical staff. Website character, website contact interactivity, shopping convenience, as well as care and service are the factors that the present study investigated as far as the patient relationship management is concerned. METHODS: This descriptive-analytical study was conducted on 206 patients visiting Shahid Faghihi and Ali Asghar Hospitals in Shiraz, which were capable of offering electronic services. The data collection tool was a researcher-made questionnaire based on the Mekkamol model and other similar studies, as well as investigations into the websites of the world's top hospitals. The questionnaire's validity was approved by a committee of experts and its reliability was approved based on a 54-patient sample with a Cronbach's alpha of 0.94. The data were analyzed using the Structural Equation Modeling (SEM) with partial least squares (PLS) approach and by utilizing SPSS and Smart PLS V2 software programs. RESULTS: The results showed that there are significant relationships between "website character" and "website contact interactivity" (p=0.00), between "shopping convenience" and "website contact interactivity" (p=0.00), and between "website contact interactivity" and "care and service" (p=0.00). CONCLUSION: Website design with such characteristics as website simplicity, shopping convenience, authenticity of information, and provision of such services as admission, scheduling appointments, and electronic payment of bills will result in interaction and communication between patients and hospital websites. This will, for its turn, pave the way for attracting more patients. PMID- 28894537 TI - Lifestyles in suburban populations: A systematic review. AB - BACKGROUND: Lifestyle and suburban population are important issues in the field of health. The living conditions of informal settlements can lead to acquisition of an unhealthy lifestyle. OBJECTIVE: This study has been designed to investigate the articles that have been published regarding lifestyle in suburban populations. METHODS: The present research was a systematic review of studies in databases including Iranmedex, Magiran, SID, Irandoc, PubMed, Google Scholar, Science Direct and Scopus, in 2017. All Persian and English papers written from 2000 to 2017 were evaluated by two reviewers using an advanced search of the databases with keywords related to lifestyles and suburban population. After completion of the search, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist was used to evaluate the articles. RESULTS: In total, 19 articles were found to have addressed the lifestyle in suburban populations. The results of these studies showed an unhealthy lifestyle in the most informal settlements. There was no food diversity. Malnutrition was common, especially overweight. The majority of the people did not have enough physical activity, and smoking and alcohol consumption were common, especially in men. CONCLUSION: Studies showed that suburban populations are among the groups that have unfavorable environmental conditions to acquiring healthy lifestyle and maintaining appropriate health. Therefore, developing infrastructure, improving health services (environment, treatment of diseases, reduction of malnutrition and infant mortality, access to safe drinking water and sanitation, improving waste disposal and recycling it), improving education and smoking prevention programs in improving lifestyle is recommended. PMID- 28894538 TI - The effect of music on pain and vital signs of children before and after endoscopy. AB - BACKGROUND AND AIM: Gentle music has relaxing and pain reducing effects. In this study, the effect of music on patients' vital signs and pain was investigated before and after endoscopy. METHODS: This clinical trial study was conducted on 100 children from seven to fourteen years of age in Gha'em Hospital, Mashhad in 2015. Children were divided into two equal groups (case group=50 and control group=50). The control group received endoscopy according to the standards, without any other procedure. For the case group, a classic musical piece by Clayderman was played during endoscopy (from the time of entering the endoscopy room to the end of the process). After conducting endoscopy, FALCC scale and Baker-Wong pain scale were filled for both groups. In addition, children's vital signs including: heart rate (pulse), diastolic and systolic blood pressure were measured before and after endoscopy for both groups. Data analysis was conducted using SPSS16 with the help of Mann-Whitney and Chi-square tests. RESULTS: No significant difference was found in age, gender distribution of case or control groups (p>0.05). Heart rate and diastolic blood pressure was significantly lower in the music (case) group compared to the control group before endoscopy (p=0.012). In addition, pain score in patients of the music group was lower than the control group (p<0.05). CONCLUSION: Playing music for children during endoscopy can reduce pain and anxiety in patients before and after endoscopy. PMID- 28894539 TI - Prevalence, risk factors and character of abdominal hernia in Arar City, Northern Saudi Arabia in 2017. AB - BACKGROUND: Abdominal wall hernias are a very common surgical condition affecting all ages and both sexes. The main risk factors of hernias include pregnancy, weight lifting, constipation, and weight gain. OBJECTIVE: The aim of this study was to determine the prevalence and risk factors of abdominal hernias, their causes, treatment and complications among both sexes of the Arar population (Saudi Arabia). METHODS: A cross-sectional study was conducted among 1,567 adults living in Arar city in 2017. Data was collected by personal interview via questionnaire translated into Arabic, and general and local examination. Data were analyzed by SPSS version 16, using descriptive statistics and Chi Square test. RESULTS: The overall prevalence of abdominal hernias was 11.7%, hernias were more prevalent in females than in males (63.4% vs. 36.6%), the most common cases were para-umbilical 33.9%, inguinal 27.3%, and umbilical in 20.8% of the cases, 51.9% were obese, 53.6% had previous abdominal surgery, 19.1% had previous abdominal trauma, 28.4% had positive family history of hernia and 39.9% were grand multipara. Hernias were significantly affected by sex, obesity, previous abdominal surgery, previous abdominal trauma, positive family history of hernias and being grand multipara (p<0.05). Treatment of hernias was surgical in 47.5% and conservative in 47.0%, complications occurred in 20.2% and 25.1% were recurrent after treatment. CONCLUSION: Abdominal wall hernias are a common clinical presentation in Arar, KSA. Abdominal hernias are more common in women than men, there is an obvious relationship between obesity and hernias. Early diagnosis, easily accessible health facilities and health education are important to prevent complications. New modality of treatment should be adopted as the standard choice of care to prevent recurrence. PMID- 28894540 TI - Change processes questionnaire for treatment of drug dependents based on transtheoretical model: Psychometric properties in Iran 2016. AB - BACKGROUND: Drug abuse is a serious subject that can lead to social, economic, cultural and health problems. The routine approaches in treatment of drug abuse are either medication or non-medication methods. Non-medication approach is focused on mental and social health. Non-drug treatment requires appropriate tools. OBJECTIVE: To determine the validity, reliability, and structure of the Processes of Change Questionnaire. METHODS: In this cross-sectional study, which was conducted in 2016, three hundred sixty-two drug dependents in Sabzevar Substance Abuse Treatment Centers (Iran) were enrolled in the study. Samples were selected through the multi-stage sampling method. They completed the 40-item Processes of Change Questionnaire (drug version). In this study, Backward-Forward method, confirmatory factor analysis (CFA), test-retest, Cronbach's alpha, content validity ratio (CVR) and content validity index (CVI) were used, using AMOS 5.0 and SPSS version 11.5. RESULTS: Findings of the CFA showed the questionnaire has a good fit. The fit index of the CFA was calculated as 0.75. Cronbach's alpha was 0.93 for the whole questionnaire, and ranged from 0.51 to 0.88 for its different domains. Also, intraclass correlation coefficient (ICC) and content validity were satisfactory. CONCLUSION: Based on the findings of this study, the processes of change 40-item questionnaire: drug version was a credible, reliable and valid tool to identify effective factors in the treatment drug abuse among the population of the Sabzevar, Iran. PMID- 28894541 TI - Correlation between social support, self-efficacy and health-promoting behavior in hemodialysis patients hospitalized in Karaj in 2015. AB - BACKGROUND: In hemodialysis, as a choice of treatment due to long treatment duration, the patient encounters limitations. Perceived social support, perceived self-efficacy and health promoting activities are important strategies to facilitate and maintain their health. AIM: To determine the correlation between social support, self-efficacy and health promoting behaviors in hemodialysis patients hospitalized in Karaj city in 2015. METHODS: This cross-sectional descriptive correlational study was carried out on 200 hemodialysis patients who were selected from four hospitals in Karaj based on cluster sampling. Data were collected using these methods: "General Questionnaire", "Perceived Self-Efficacy Scale", "Multidimensional Perceived Social Support Scale" and "Health-Promoting Lifestyle Profile 2". Data were analyzed by SPSS version 22 and the EQS 6.1. Independent t-test, Mann-Whitney U, Kruskal-Wallis test, spearman correlation coefficient was used to analyze the data. To determine the relation between perceived self-efficacy, perceived social support and health promoting behavior, structural equation modeling was applied. RESULTS: Self-efficacy has a significant positive correlation with social support (r=0.592, p<0.001) and significant negative correlation with health-promoting behaviors (r=-0.709, p<0.001), and social support has a significant negative correlation with health promoting behaviors (r=-0.709, p<0.001). Also, results showed that perceived self efficacy had a greater role than perceived social support in explaining health promoting behaviors. CONCLUSION: The relationship between health promoting behaviors, self-efficacy and social support reveals a necessity for Community Health Nursing planners, matrons and hospital managers and nurses to pay more attention to the needs of patients under hemodialysis. It is recommended that due to some unexpected findings in this study, further studies shall be fulfilled on the factors effective on the discussed variables. PMID- 28894542 TI - Perceptions of an integrated curriculum among dental students in a public university in Saudi Arabia. AB - BACKGROUND: Being aware of the limits of traditional discipline-based education, the Faculty of Dentistry at King Abdulaziz University (KAU) tasked basic medical science faculty members with developing a new integrated curriculum for undergraduate dental students to be applied in the 2014/2015 academic year. OBJECTIVE: To determine the students' perceptions of the restructured curriculum and elicit student suggestions for improvement. METHODS: A questionnaire was distributed to all first-year dental undergraduate students (n=192) enrolled in the academic year of 2014/2015. The questionnaire was written in English and included standard questions designed to determine student satisfaction toward the restructured curriculum. The different variables in the study were analyzed with descriptive statistics and the significance level was measured by SPSS version 16, using the descriptive statistics and Chi-square test. RESULTS: At the end of the first year, a large majority of students rated their overall experience with the course as good or excellent and agreed that the connection between basic and clinical sciences was made clear in the dental relevance sessions. In general, students' experience with the instructors was positive. However, although most students felt that assessment methods were fair and reflected the curriculum, the overall success rate was lower than that of the previous academic year (2013/2014) (P=0.002), when the traditional-discipline based curriculum was still in place. CONCLUSION: Having completed the first step of the restructuring of the first-year basic science dental curriculum, our plan for the next phase in the curriculum integration process is to increase inter-course and inter-topic integration and supplement the delivery of the course material with more clinical case scenarios. PMID- 28894543 TI - The relationship between organizational commitment and nursing care behavior. AB - INTRODUCTION: Nursing care encompasses physical, emotional, mental and social needs, in order to improve a patient's health and wellbeing. Caring is the central core and the essence of nursing. The important issue of care is access to proper care and increasing patients' satisfaction. Job performance of nurses is affected by many factors including organizational commitment. This study aimed to determine the relationship between organizational commitment and nurses caring behavior. METHODS: In this cross-sectional study, 322 nurses from selected Hospitals of Shahid Beheshti University of Medical Sciences in Tehran were randomly selected and enrolled in the study in 2015. The self-reported data by nurses were collected through demographic characteristics questionnaire, Meyer & Allen organizational commitment model and Caring Behavior Inventory (CBI). Data were analyzed with SPSS statistical software version 20, using t-test and ANOVA. FINDINGS: The majority of nurses (63%) were female. The mean score and standard deviation of organizational commitment and caring behavior of nurses were 74.12+/ 9.61 and 203.1+/-22.46, respectively. The results showed a significantly positive correlation between organizational commitment and caring behavior (p=0.001). CONCLUSION: In this study the caring behavior of nurses with higher organizational commitment were significantly better than the others. Managers and nurse leaders should pay more attention to improve organizational commitment of nurses, in order to improve nurses' performance. PMID- 28894544 TI - Success rate evaluation of clinical governance implementation in teaching hospitals in Kerman (Iran) based on nine steps of Karsh's model. AB - BACKGROUND: One of the ways to improve the quality of services in the health system is through clinical governance. This method aims to create a framework for clinical services providers to be accountable in return for continuing improvement of quality and maintaining standards of services. OBJECTIVE: To evaluate the success rate of clinical governance implementation in Kerman teaching hospitals based on 9 steps of Karsh's Model. METHODS: This cross sectional study was conducted in 2015 on 94 people including chief executive officers (CEOs), nursing managers, clinical governance managers and experts, head nurses and nurses. The required data were collected through a researcher-made questionnaire containing 38 questions with three-point Likert Scale (good, moderate, and weak). The Karsh's Model consists of nine steps including top management commitment to change, accountability for change, creating a structured approach for change, training, pilot implementation, communication, feedback, simulation, and end-user participation. Data analysis using descriptive statistics and Mann-Whitney-Wilcoxon test was done by SPSS software version 16. RESULTS: About 81.9 % of respondents were female and 74.5 have a Bachelor of Nursing (BN) degree. In general, the status of clinical governance implementation in studied hospitals based on 9 steps of the model was 44 % (moderate). A significant relationship was observed among accountability and organizational position (p=0.0012) and field of study (p=0.000). Also, there were significant relationships between structure-based approach and organizational position (p=0.007), communication and demographic characteristics (p=0.000), and end-user participation with organizational position (p=0.03). CONCLUSION: Clinical governance should be implemented by correct needs assessment and participation of all stakeholders, to ensure its enforcement in practice, and to enhance the quality of services. PMID- 28894545 TI - Comparing performances of intelligent classifier algorithms for predicting type of pain in patients with spinal cord injury. AB - BACKGROUND AND AIM: In this study, performances of classification techniques were compared in order to predict type of pain in patients with spinal cord injury. Pain is one of the main problems in people with spinal cord injury. Identifying the optimal classification technique will help improve decision support systems in clinical settings. METHODS: A descriptive retrospective analysis was performed in 253 patients. We compared performances of "Bayesian Networks", "Decision Tree", neural networks: "Multi-Layer Perceptron" (MLP), and "Support Vector Machines" (SVM). Predictor variables were collected in data set in SCI patients referred to Shefa Neuroscience Research Center, Tehran, Iran from 2010 through 2016. Performances of classification techniques were compared using "Accuracy", "Sensitivity or True Positive Rate" (TPR), "Specificity or True Negative Rate" (SPC), "Positive Predictive Value" (PPV), "Negative Predictive Value" (NPV). RESULTS: MLP with Boosting technique was found to have the best accuracy (91%), best sensitivity (89%), best specificity (95%) best PPV (91%), and best NPV (96%) to predict spinal cord injury in this data set, given its good classificatory performance. CONCLUSION: Computer-aided decision support systems (CAD) are dependent on a wide range of classification methods such as statistical methods, Bayesian methods, deductive classifiers based on the state or case, decision making trees and neural networks: Multi-Layer Perceptron. Neural network classifiers especially, are very popular choices for medical decision-making, with proven effectiveness in the clinical field. PMID- 28894546 TI - Nurses' perception of the strategies to gaining professional power: A qualitative study. AB - BACKGROUND: Power in nursing is a broad concept that has a determining effect on the achievement of professional goals. Gaining power is essential for promoting the roles of nurses, improving their professional image and the consistent improvement of healthcare systems. OBJECTIVES: This study was conducted to identify and clarify strategies for gaining power in the nursing profession through the experiences of Iranian nurses. METHODS: The present qualitative grounded theory study was conducted on fifteen participants selected through purposive sampling. Data were collected through individual, in-depth, semi structured interviews. The data obtained were analyzed using the guidelines provided by Corbin and Strauss, (2008 edition). This study was carried out in Qazvin city of Iran and lasted fourteen months (2015-2016). RESULTS: The analysis of the data were classified under the main theme of gaining human-professional power based on individual and organizational capacities, divided into four main categories, including respecting human values and ethical principles (with two subcategories, keeping the human symbols of power and commitment to moral obligations of power), promoting professional interactions (with two subcategories, paying attention to intraprofessional communication and paying attention to interprofessional communication), attempting professional endurance (with two subcategories, raising self-confidence and having professional commitment), and valuing potential capacities (with two subcategories, regard for individual capacities and regard for organizational capacities). CONCLUSION: The findings obtained suggest that success in gaining power in nursing, requires a cumulative focus on human, ethical, professional, individual and organizational capacities. PMID- 28894547 TI - A Novel Therapy for cocaine dependence during abstinence: A randomized clinical trial. AB - BACKGROUND: Topiramate is an anticonvulsant drug and an ideal candidate for reducing the craving in people relying on cocaine. Contingency management is one of the common therapies in the domain of addiction. OBJECTIVE: The present study aimed to evaluate and compare three medication methods of Topiramate (TPM), Contingency Management (CM) and the combined TPM treatment and cash intervention on craving during abstinence. METHODS: This randomized clinical trial was conducted at Bijan Center for Substance Abuse Treatment in Tehran, Iran, from December 15, 2014 to November 20, 2015. One hundred males (Age range=18-34; SD=4.11) undergoing abstinence were assigned randomly to four groups (n=25) of Topiramate (TPM), Contingency Management (CM) and the Combined Method plus a placebo control group. Treatment was provided for twelve weeks for the experiment groups, and only the control group received the placebo. Participants in the Cash based and CM Condition had an identical 12-week escalating schedule of reinforcement (cash-based incentives worth $0, $20, $40, and $80). Also, in the Topiramate group, participants' dosage ranged between 25-300 mg/day in escalating doses) 25, 50, 100, 150, 200, 250, 300). In addition, all subjects received brief behavioral compliance enhancement treatment (BBCET). Participants took a urine test twice a week, with a given threshold of > 300 ng/ml, and indicators of cocaine craving (response rate= 91%) was evaluated in two phases of pre-test and post-test. We used Chi square, ANCOVA Univariate Model and Scheffe's post hoc to analyze the primary and secondary outcomes. Also, the qualitative data resulted from demographic evaluations were coded and analyzed by the instrument of analysis of qualitative data i.e. Atlas.ti, Version 5.2. RESULTS: The results showed that all three types of treatment played a significant efficacy in reducing the craving. The mean (95% CI) scores of craving was 12.04 (p=0.05) with TPM, 13.89 (p=0.05) with CM, 10.92 (p=0.01) with Mix and 16.89 (p>0.05) with control. Moreover, the highest variance explaining the changes in craving was assigned to the combined treatment (p<0.01). CONCLUSIONS: The findings of this study, while having applicable aspects in this domain, can be helpful in planning supplementary remedial procedures. TRIAL REGISTRATION: The trial was registered at the Thai Clinical Trial Registration Center with the TCR ID: TCTR20170112001. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 28894548 TI - A novel algorithm for PET and MRI fusion based on digital curvelet transform via extracting lesions on both images. AB - BACKGROUND AND AIM: Merging multimodal images is a useful tool for accurate and efficient diagnosis and analysis in medical applications. The acquired data are a high-quality fused image that contains more information than an individual image. In this paper, we focus on the fusion of MRI gray scale images and PET color images. METHODS: For the fusion of MRI gray scale images and PET color images, we used lesion region extracting based on the digital Curvelet transform (DCT) method. As curvelet transform has a better performance in detecting the edges, regions in each image are perfectly segmented. Curvelet decomposes each image into several low- and high-frequency sub-bands. Then, the entropy of each sub band is calculated. By comparing the entropies and coefficients of the extracted regions, the best coefficients for the fused image are chosen. The fused image is obtained via inverse Curvelet transform. In order to assess the performance, the proposed method was compared with different fusion algorithms, both visually and statistically. RESULT: The analysis of the results showed that our proposed algorithm has high spectral and spatial resolution. According to the results of the quantitative fusion metrics, this method achieves an entropy value of 6.23, an MI of 1.88, and an SSIM of 0.6779. Comparison of these experiments with experiments of four other common fusion algorithms showed that our method is effective. CONCLUSION: The fusion of MRI and PET images is used to gather the useful information of both source images into one image, which is called the fused image. This study introduces a new fusion algorithm based on the digital Curvelet transform. Experiments show that our method has a high fusion effect. PMID- 28894549 TI - Predictive value of copeptin as a severity marker of community-acquired pneumonia. AB - BACKGROUND: Pneumonia is the leading cause of death in children. Few studies have explored the predictive value of copeptin in pediatric pneumonia. AIM: This study aimed to assess the role of copeptin as a marker of severity of community acquired pneumonia (CAP). METHODS: This prospective case-control study was carried out at Minia University Children's Hospital in Minia (Egypt) from January to December 2016. Eighty children aged from 2 months to 42 months were enrolled in this study and were classified into group 1 (40 children with clinical, laboratory and radiological evidence of pneumonia) and group 2 (40 apparently healthy control). Serum copeptin level was assayed for all enrolled children. RESULTS: Mean serum copeptin level was significantly higher in pneumonic patients (985.7+/-619) pg/ml compared to controls (519+/-308.2) pg/ml (p<0.001). Serum copeptin was significantly elevated in survivors of pneumonia more than non survivors (p=0.001). Also, copeptin was significantly higher in the group of non survivors (1811.8+/-327.1) compared to 745.4+/-472.5 for survivors (p=0.01). There was a significant positive correlation between serum copeptin levels and the degree of respiratory distress (p=0.02). CONCLUSION: Copeptin seems a reliable and available predictor marker for assessing the severity and prognosis of pediatric community acquired pneumonia. PMID- 28894550 TI - Evaluation prevalence of Pompe disease in Iranian patients with myopathies of unknown etiology. AB - BACKGROUND: Pompe disease is a rare but potentially treatable metabolic disorder having an estimated worldwide incidence of one in forty thousand live births. While the introduction of enzyme replacement therapy (ERT) has considerably increased the awareness of the disease, the delay in diagnosis is still consistent and most patients go undetected. OBJECTIVE: This study aimed to determine the prevalence of late-onset Pompe disease (LOPD) in a high-risk population, using dried blood spot (DBS) as a main screening tool. METHODS: This cross-sectional study was performed on the 93 patients who attended to the neuromuscular center of Bu-ali hospital in Tehran, Iran, during 2014-2015. Inclusion criteria were: 1) age >=1 years, 2) proximal myopathies of unknown etiology in lower limbs or symptoms of limb girdle muscle weakness (LGMW), and 3) unexplained elevated CPK (>174). Acid alpha-glucosidase (GAA) activity was measured separately on DBS by fluorometric method. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. All statistical tests were performed using the SPSS version 16. Results are presented as mean (SD) or median (IQR), as appropriate. RESULTS: In a 12-month period, we studied 93 cases: 5 positive samples (5.3%) were detected by DBS screening, biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 3 cases (3.22%). Among the 93 patients, 100% showed hyperCKemia, 89 patients (95.7%) showed LGMW and 4 patients had symptoms of proximal myopathies in the lower limb. CONCLUSIONS: Results from the LOPED study suggest that GAA activity requires accurate screening by DBS in all patients referred for hyperCKemia and/or LGMW. PMID- 28894551 TI - Montelukast versus inhaled mometasone for treatment of otitis media with effusion in children: A randomized controlled trial. AB - BACKGROUND: Otitis media is one of the most common infections among children and is a complication in about 30% of common colds. The most common complication of acute otitis media is otitis media with effusion. Some studies have reported the effects of montelukast and mometasone nasal spray in treatment of otitis media with effusion. However, current information is inadequate in this issue. OBJECTIVE: To compare the effectiveness of montelukast and mometasone nasal spray in treatment of otitis media with effusion in children attending Koodakan hospital in Bandar Abbas, Iran. METHODS: This randomized controlled trial was done on 2- to 6-year-old children attending Koodakan Hospital in Bandar Abbas, southern Iran, in 2014. Patients were divided into three groups of montelukast, mometasone, and control group. Audiometry was done for all patients at baseline and four weeks after treatment. Patients were compared for treatment results. Data were analyzed using SPSS 21.0 software. RESULTS: A total of 143 children were included in the study. Mean age of the participants were 44.64 +/- 18.03 months. There was no significant difference in treatment results in different treatment groups (p>0.05). CONCLUSION: Mometasone and montelukast are not effective and not recommended in treatment of otitis media with effusion in children. More studies are needed in this regard. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov with ClinicalTrials.gov Identifier: NCT02541760. FUNDING: The authors received financial support for this research from Hormozgan University of Medical Sciences. PMID- 28894552 TI - Status of antioxidant and homocysteine-lowering vitamins related to cardiovascular diseases in hemodialysis patients. AB - BACKGROUND AND AIM: Cardiovascular disease is the major cause of mortality in hemodialysis patients. Oxidative stress and hyperhomocysteinemia may contribute to an increased risk of CVD. Therefore, we assessed the status of antioxidant and homocysteine-lowering vitamins related to cardiovascular disease in hemodialysis patients at Vasei hospital in Sabzevar. METHODS: In this cross-sectional study, we enrolled 75 hemodialysis patients by using census method at Vasei Hospital in Sabzevar (Iran) in 2014. After measuring height and body weight, food intake was assessed by a 24-hour dietary recall questionnaire for at least two days (a non dialysis and dialysis day), and food frequency was recorded with Nutritionist IV software. Data were analyzed by SPSS version 16, using descriptive statistical tests, one sample t-test and independent samples t-test and p<0.05 was considered statistically significant. RESULTS: This study was carried out on 75 patients. Mean age and BMI of patients were 49.95+/-17.22 years and 20.04+/-3.38 kg/m2, respectively. Intake of all vitamins with the exception of vitamin B12 in hemodialysis patients studied, were less than the recommended dietary allowance (RDA) (p<0.05). CONCLUSION: According to the survey, consumption of antioxidants and B-vitamins related to cardiovascular disease was less than RDA in hemodialysis patients. PMID- 28894553 TI - Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: A randomized clinical trial. AB - BACKGROUND: Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. Oxidative stress plays a major role in the onset and progression of MS. Asymmetric dimethylarginine (ADMA) formation is dependent on oxidative stress status. OBJECTIVE: We examined whether alpha-lipoic acid (ALA) as a potent antioxidant could improve the Expanded Disability Status Scale (EDSS) and decrease plasma level of ADMA in multiple sclerosis patients. METHODS: In a randomized, double-blinded clinical trial conducted at Sina Hospital in Tehran, Iran, from September 2009 to July 2011, 24 patients with relapsing remitting MS were divided into a treatment group receiving ALA (1200mg/day) for 12 weeks and a control group receiving placebo. Then patients' EDSS and Plasma levels of ADMA were measured at baseline and 12 weeks later. Statistical analysis was done by SPSS software version 16 using the K-S test, Chi square, Mann-Whitney U-test and Wilcoxon test. RESULTS: The plasma levels of ADMA in the intervention group were decreased significantly (p=0.04). Also, no patient had increased EDSS score in the supplement group, where 2 out of 12 patients in the placebo group experienced so. Comparing the serum level of ADMA between the two groups failed to show any significant change in the supplement group compared with the control group. CONCLUSION: Considering that ADMA is produced by oxidative stress in MS patients and leads to increase of inflammation, ALA may have the potential of beneficial effects in them, in part, by decreasing the plasma level of ADMA and stopping progression. TRIAL REGISTRATION: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: No. IRCT138812222602N2. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 28894554 TI - Exploring the adaptive experiences of children with parents of myocardial infarction: A Qualitative Study. AB - BACKGROUND: Cardiovascular diseases are the world's leading cause of mortality. These diseases are rooted in an unhealthy lifestyle. In order to confront this subject, it is essential to identify several risk factors that contribute to heart disease (HD) in people with different attitudes, values, beliefs, expectations and motivations. This study was therefore an attempt to explain the adaptive experiences of children whose parents were involved in myocardial infarction since they were more likely subjected to get the so-called disease. OBJECTIVE: To identify the risk factors and to clear ambiguity using a qualitative research method from the experiences of people at risk of the above mentioned disease. METHODS: This qualitative study was a directed content analysis. Eighteen children (above 18 years old) of parents with a history of myocardial infarction participated, and were chosen with purposive sampling and the highest diversity. Data were collected through deep and semi structure interviews based on Protection Motivation Theory (PMT) from March to November 2015, and were analyzed along with their data collection and with usage of Lundman and Graneheim method. Interviews were conducted in non-stressful conditions with a place and time agreement. RESULTS: During content analysis process, 220 codes were extracted. After reviewing several times and summarizing, the codes were categorized based on similarity and proportion, and finally 12 subcategories and three categories were elicited including efforts to perform self-care in order to prevent HD, poor life style as a factor not to do preventive HD and health continuation with positive changes in life style. CONCLUSIONS: Most participants, despite intending to do self-care behaviors to prevent HD, due to factors such as time constraint, high costs, laziness, impatience and prioritizing other life affairs, did not pay attention to their health. Therefore, providing the training programs with an emphasis on life skills can play an important role in reducing perceived response cost and promoting health. PMID- 28894555 TI - Information management in Iranian Maternal Mortality Surveillance System. AB - BACKGROUND: Maternal mortality is preventable by proper information management and is the main target of the Maternal Mortality Surveillance System (MMSS). AIM: This study aimed to determine the status of information management in the Iranian Maternal Mortality Surveillance System (IMMSS). METHODS: The population of this descriptive and analytical study, which was conducted in 2016, included 96 administrative staff of health and treatment deputies of universities of medical sciences and the Ministry of Health in Iran. Data were gathered by a five-part questionnaire with confirmed validity and reliability. A total of 76 questionnaires were completed, and data were analyzed using SPSS software, version 19, by descriptive and inferential statistics. The relationship between variables "organizational unit" and the four studied axes was studied using Kendall's correlation coefficient test. RESULTS: The status of information management in IMMSS was desirable. Data gathering and storage axis and data processing and compilation axis achieved the highest (2.7+/-0.46) and the lowest (2.4+/-0.49) mean scores, respectively. The data-gathering method, control of a sample of women deaths in reproductive age in the universities of medical sciences, use of international classification of disease, and use of this system information by management teams to set resources allocation achieved the lowest mean scores in studied axes. Treatment deputy staff had a more positive attitude toward the status of information management of IMMSS than the health deputy staff (p=0.004). CONCLUSION: Although the status of information management in IMMSS was desirable, it could be improved by modification of the data-gathering method; creating communication links between different data resources; a periodic sample control of women deaths in reproductive age in the universities of medical sciences; and implementing ICD-MM and integration of its rules on a unified system of death. PMID- 28894556 TI - How We Manage Invasive Fungal Disease in Acute Myeloid Leukemia Patients with Glucose 6 Dehydrogenase Deficiency. AB - Glucose-6-phosphate dehydrogenase (G6PD) represents a common human enzyme defect, particularly prevalent in the Mediterranean, African e Asian area, where malaria was or is still endemic. Recently, we identified G6PD deficiency as a risk factor for developing invasive fungal disease (IFD) and particularly Candida Sepsis in patients undergoing intensive chemotherapy for acute myeloid leukemia (AML), suggesting that there is an urgent need for strategies to properly manage this kind of patients at high risk of invasive mycoses. Here we propose our algorithm for correct identification, prophylaxis, and treatment of IFD in patients with G6PD deficiency undergoing intensive chemotherapy for AML. PMID- 28894557 TI - Clinico-Pathological Spectrum and Novel Karyotypic Findings in Myelodysplastic Syndrome: Experience of Tertiary Care Center in India. AB - BACKGROUND: Myelodysplastic syndrome (MDS) is a heterogeneous disorder characterized clinically by the presence of cytopenia/s. Limited data are available about the morphological spectrum and cytogenetic profile of Indian MDS patients. The aim of the study was to ascertain the clinico-pathological, morphological and cytogenetic spectrum of Indian MDS patients. MATERIAL AND METHODS: A retrospective analysis of all patients diagnosed with MDS from June 2012 to December 2016 was performed. Their clinical and laboratory data were collated and reviewed. RESULTS: A total of 150 patients with primary MDS were evaluated with M: F ratio of 1.6:1 and the median age of 55.5 years. 64% patients presented with pancytopenia and 31% with bicytopenia. Morphologically they included MDS-MLD [63 (42%)], MDS-EB 2, [33 (22%)], MDS-EB 1 [32 (21.3%)], MDS-SLD [13 (8.6%)] and two cases (1.4%) each of MDS-SLD-RS, MDS-MLD-RS, and RCC. An abnormal cytogenetic profile was detected in 50% patients. Complex karyotype was observed to be the commonest abnormality (32.5%), and chromosome 7 was the most frequently involved chromosome. Isolated deletion 5q was seen in 6.9 % cases. Novel translocations like t(9;22)(q11.2;q34.2), t(1;5)(p22;q33), t(1;12)(p34;p11.2) and t(5;7;9)(q13;q32;p22) were observed in addition to other complex abnormalities. The majority of the patients belonged to the high risk IPSS-R prognostic groups (31.4%); followed by intermediate and very high-risk groups, 29% and 24.4% respectively. CONCLUSION: The median age of patients in India is a decade younger than the western population. Complex karyotype was observed to be the commonest cytogenetic abnormality, while the frequency of deletion 5q and trisomy 8 was much lower as compared to the west. The majority of the patients were in high to very high IPSS-R risk categories and seventy percent individuals below 40 years showed abnormal karyotype, indicating that Indian MDS patients have high disease burden at a young age and thus more likelihood for leukemic transformation. PMID- 28894558 TI - EBV and HHV-6 Circulating Subtypes in People Living with HIV in Burkina Faso, Impact on CD4 T cell count and HIV Viral Load. AB - Epstein Barr Virus (EBV) and Human Herpes Virus 6 (HHV-6) are responsible for severe diseases, particularly in immunocompromised persons. There is limited data of the infection of these opportunistic viruses in Burkina Faso. The purpose of this study was to characterize EBV and HHV-6 subtypes and to assess their impact on CD4 T cell count, HIV-1 viral load and antiretroviral treatment in people living with HIV-1. The study population consisted of 238 HIV-positive patients with information on the CD4 T cell count, HIV-1 viral load and HAART. Venous blood samples collected in EDTA tubes were used for EBV and HHV-6 Real Time PCR subtyping. An infection rate of 6.7% (16/238) and 7.1% (17/238) were found respectively for EBV and HHV-6 in the present study. Among EBV infections, similar prevalence was noted for both subtypes (3.9% (9/238) for EBV-1 vs 4.6% (11/238) for EBV-2) with 2.1% (5/238) of co-infection. HHV-6A infection represented 6.3% (15/238) of the study population against 5.0% (12/238) for HHV 6B. EBV-2 infection was significantly higher in patients with CD4 T cell count >= 500 compared to those with CD4 T cell count less than 500 cells (1.65% vs 8.56%, p = 0,011). The prevalence of EBV and HHV-6 infections was almost similar in HAART-naive and HAART-experienced patients. The present study provides information on the prevalence of EBV and HHV-6 subtypes in people living with HIV 1 in Burkina Faso. The study also suggests that HAART treatment has no effect on infection with these opportunistic viruses in people living with HIV-1. PMID- 28894559 TI - Pattern of Cerebral Blood Flow Velocity Using Transcranial Doppler Ultrasonography in Children with Sickle Cell Disorder in Lagos State, Nigeria. AB - : Cerebrovascular accident (CVA) is a common, devastating neurological complication of sickle cell disorder (SCD) with a high recurrent and mortality rate. The Stroke Prevention Trial in Sickle Cell Anaemia study (STOP) recommends routine screening with transcranial Doppler ultrasonography in children aged two to sixteen years with SCD. The present study assessed cerebral blood flow velocities of children with SCD in accordance with the recommendation of routine screening by the STOP study. METHODS: Transcranial Doppler ultrasonography was done for children with SCD that attended Sickle Cell Foundation, Nigeria between July and November 2015. RESULTS: In all, 388 subjects were screened within the study period (360 HbSS and 28 HbSC). The prevalence of abnormal Time-Averaged Maximum Mean Velocity (TAMMV) of at least 200 cm/second was 10.8%: this was seen solely in HbSS subjects. The mean Time-averaged mean of the maximum (TAMM) velocity were 163+/-25 cm/sec, 162+/-30 cm/sec and 150+/-30 cm/sec for children less than five years, five to ten years and eleven to sixteen years respectively. CONCLUSION: The prevalence of abnormal TAMM velocity in children with HbSS is 10.8%. Identification of subjects at risk helped in primary CVA prevention by prompt therapy institution. PMID- 28894560 TI - POEMS SYNDROME: an Update. AB - POEMS syndrome is a rare, chronic and disabling condition. The causes of this condition remain unknown; however, chronic overproduction of proinflammatory cytokines appears to be a major contributor. Early diagnosis is essential to start treatment before the clinical state of the patient becomes compromised. A complete evaluation of the disease at its onset is critical to the treatment decision. In localized disease, curative doses of radiation (50 Gy) is the recommended therapy. On the other hand, patients with disseminated disease should be given systemic therapy. Treatment-related morbidity can be minimized by an efficient induction therapy that modifies the cytokine status, improving clinical condition and control disease severity before mobilization and transplantation. Patients not suitable for hematopoietic stem cell transplantation (HSCT) are usually treated with alkylator-based therapy. Novel agents may also offer benefits to patients with a poor performance status or renal dysfunction, and induce transplantation eligibility. Given the biological characteristics of POEMS, immunomodulatory effects and the absence of neurotoxicity, lenalidomide appears to be an effective therapy for the treatment of POEMS, both as short induction therapy before PBSCT and in non-transplant eligible patients, as it showed high response rate and durable responses. At present, however, guidelines for the diagnosis and treatment of POEMS are not available and appear advocated. PMID- 28894561 TI - Solitary Plasmacytoma. AB - Solitary plasmacytoma is a rare disease characterized by a localized proliferation of neoplastic monoclonal plasma cells, without evidence of systemic disease. It can be subdivided into solitary bone plasmacytoma if the lesion originates in bone, or solitary extramedullary plasmacytoma if the lesion involves a soft tissue. The incidence of solitary bone plasmacytoma is higher than solitary extramedullary plasmacytoma. Also, the prognosis is different: even if both forms respond well to treatment, overall survival and progression-free survival of solitary bone plasmacytoma are poorer than solitary extramedullary plasmacytoma due to its higher rate of evolution in multiple myeloma. However, the recent advances in the diagnosis of multiple myeloma can better refine also the diagnosis of plasmacytoma. Flow cytometry studies and molecular analysis may reveal clonal plasma cells in the bone marrow; magnetic resonance imaging or 18 Fluorodeoxyglucose positron emission tomography could better define osteolytic bone lesions. A more explicit exclusion of possible occult systemic involvement can avoid cases of misdiagnosed multiple myeloma patients, which were previously considered solitary plasmacytoma and less treated, with an unavoidable poor prognosis. Due to the rarity of the disease, there is no uniform consensus about prognostic factors and treatment. Radiotherapy is the treatment of choice; however, some authors debate about the radiotherapy dose and the relationship with the response rate. Moreover, the role of surgery and chemotherapy is still under debate. Nevertheless, we must consider that the majority of studies include a small number of patients and analyze the efficacy of conventional chemotherapy; few cases are reported concerning the efficacy of novel agents. PMID- 28894562 TI - Non-Secretory Myeloma: Ready for a new Definition? AB - Non-secretory myeloma is a rare myeloma subtype whose diagnosis, until a few years ago, was established by demonstration of monoclonal plasma cells >=10% in the bone marrow and by negative results on serum and urine electrophoresis and immunofixation studies. However, this type of myeloma could be misdiagnosed if the workup does not include an accurate study of serum free light chain test since some of the patients diagnosed as non-secretory could be light chain only with small amounts monoclonal proteinuria. Due to this limit in classification, all the information available today, generally coming from retrospective studies including patients studied completely and incompletely, could be misleading. A new definition is, thus, needed to distinguish between the true non-secretory, with a possible better prognosis, and the other forms of oligo-secretory myeloma with a prognosis more similar to the secretory form of myeloma. With all the data of the literature, the availability of laboratory and radiological tools, times are mature to depict a new definition of nonsecretory myeloma that deserves a peculiar work up and different response evaluation and, may be, a different therapeutic approach. PMID- 28894563 TI - Hairy B-Cell Lymphoproliferative Disorder and its Differential Diagnosis: a Case with Long-Term Follow-Up. AB - Hairy B-cell lymphoproliferative disorder (HBLD) is one of chronic polyclonal B cell lymphocytosis. We report a 47-year-old female Japanese patient diagnosed as having HBLD based on lymphocytosis with hairy cell appearance and characteristic phenotypes including CD11c+ and without B-cell monoclonality. She was a non smoker and possessed HLA-DR4. She has been closely followed up without treatment and lymphoma development for over five years. Although this disease is quite rare and has been reported, to our knowledge, in only 13 Japanese cases, an accurate diagnosis, particularly differential diagnosis from persistent polyclonal B-cell lymphocytosis or hairy cell leukemia-Japanese variant is essential for the prevention of unnecessary treatments. PMID- 28894564 TI - Should every Patient with MDS get Iron Chelation - Probably Yes. PMID- 28894565 TI - Hematological Characteristics of Yemeni Adults and Children with Visceral Leishmaniasis. Could Eosinopenia be a Suspicion Index? AB - BACKGROUND AND OBJECTIVES: Delay in the diagnosis of visceral leishmaniasis (VL) particularly in non-endemic areas is associated with higher mortality. In our experience, we found that marked bone marrow eosinopenia was a very frequent accompaniment of VL and might be a useful clue for the diagnosis, which indicates the opportunity for further morphological assessment. The aim of this study was to describe the hematological characteristics including peripheral blood and bone marrow findings of Yemeni adults and children with VL. METHODS: We conducted a descriptive analytic study to evaluate systematically peripheral blood and bone marrow findings of Yemeni adults and children with VL. Peripheral blood and bone marrow aspiration of patients with bone marrow aspirate confirmed VL were examined. Forty-seven patients with the main age (+/-SD) of 17.34+/-11.37 years (Range: 1-60) were included in the study. Fifty-one non-VL subjects with splenomegaly and pancytopenia or bicytopenia served as control group. RESULTS: All patients with VL had anemia, 41 (87%) leukopenia, 42 (89%) neutropenia, 44 (94%) thrombocytopenia, 42 (89%) eosinopenia, 34 (72%) pancytopenia and 13 (28%) had bicytopenia. In bone marrow examination 40 (85%) showed hypercellularity, 44 (94%) eosinopenia, 24 (51%) dyserythropoiesis, 22 (47%) lymphocytosis, 8 (17%) plasmacytosis, 27 (57%) decreased iron stores and 20 (43%) showed decreased sideroblasts. Comparison of VL patients with the control group showed significantly more frequent peripheral blood eosinopenia and lymphopenia and marrow eosinopenia. There was no significant difference between adults and children in any of the hematological features. CONCLUSION: Anemia, leukopenia, neutropenia, thrombocytopenia, eosinopenia, pancytopenia and marked bone marrow eosinopenia were the most common findings. The finding of marked bone marrow eosinopenia is a significant clue for the diagnosis of visceral leishmaniasis in patients who present with splenomegaly associated with cytopenias. This finding is particularly valuable in non-endemic areas. PMID- 28894566 TI - Methyl jasmonate induction of cotton: a field test of the 'attract and reward' strategy of conservation biological control. AB - Natural or synthetic elicitors can affect plant physiology by stimulating direct and indirect defence responses to herbivores. For example, increased production of plant secondary metabolites, a direct response, can negatively affect herbivore survival, development and fecundity. Indirect responses include increased emission of plant volatiles that influence herbivore and natural enemy behaviour, and production of extrafloral nectar that serves as a food source for natural enemies after their arrival on induced plants. Therefore, the use of elicitors has potential for the study of basic aspects of tritrophic interactions, as well as application in biorational pest control, i.e. an 'attract and reward' strategy. We conducted a field study to investigate the effects of methyl jasmonate, an elicitor of plant defence responses, on three trophic levels: the plant, herbivores and natural enemies. We made exogenous applications of methyl jasmonate to transgenic cotton and measured volatile emission, extrafloral nectar production and plant performance (yield). We also assessed insect abundance, insect performance, and parasitism and predation of brown stink bug, Euschistus servus, eggs in methyl jasmonate-treated and untreated control plots. Application of methyl jasmonate increased emission of volatiles, in particular, (+)-limonene and (3E)-4,8-dimethyl-1,3,7-nonatriene, and production of extrafloral nectar, but not yield, compared with the control treatment. Despite increased volatile and extrafloral nectar production, methyl jasmonate application did not affect plant bug performance, or mortality of E. servus egg masses, and only marginally influenced insect abundance. Mortality of E. servus eggs varied over the course of the study. Overall, methyl jasmonate treatment affected cotton plant-induced responses, but not the insects that inhabit the plants. Our results were probably influenced by reduced natural enemy colonization of cotton from adjacent non-crop habitats, and subsequent low within field population recruitment. Much remains to be learned about the effects of exogenous application of plant-produced 'enhancers' on the behaviour of natural enemies before crop physiology can be manipulated to enhance pest control. PMID- 28894567 TI - An indicator approach to capture impacts of white-tailed deer and other ungulates in the presence of multiple associated stressors. AB - Management of ungulates is contested ground that lacks stakeholder agreement on desirable population sizes and management approaches. Unfortunately, we often miss information about extent of local impacts, for example on plant communities, to guide management decisions. Typical vegetation impact assessments like the woody browse index do not assess herbaceous plants, and differences in browse severity can be a function of deer density, deer legacy effects, localized deer feeding preferences and/or differences in plant community composition. Furthermore, in heavily affected areas, few remnant plants may remain for assessments. We used a sentinel approach to assess impact of white-tailed deer (Odocoileus virginianus), rodent attack, invasive earthworms and three invasive plants on survival and growth of 3-month-old red oak (Quercus rubra) individuals. We planted cohorts in 2010 and 2011 into deer accessible and fenced 30 * 30 m plots at 12 forests in New York State. We found year and site-specific effects with high deer herbivory of unprotected individuals (70-90 % of oaks browsed by deer versus none in fenced areas) far exceeding importance of rodent attacks. Oaks planted at low earthworm density sites were at significantly higher risk of being browsed compared with oaks at high earthworm density sites, but there was no detectable negative effect of invasive plants. Surviving oaks grew (~2 cm per year) under forest canopy cover, but only when fenced. We consider planting of oak or other woody or herbaceous sentinels to assess deer browse pressure a promising method to provide quantifiable evidence for deer impacts and to gauge success of different management techniques. The strength of this approach is that typical problems associated with multiple stressor impacts can be avoided, areas devoid of forest floor vegetation but under heavy deer browse pressure can still be assessed and the method can be implemented by non-specialists. Implementation of regular assessments can guide ungulate management based on meaningful evidence. PMID- 28894568 TI - Perspectives on non-target site mechanisms of herbicide resistance in weedy plant species using evolutionary physiology. AB - Evolutionary physiology merges the disciplines of evolution and physiology, and it is a research approach that has not received much attention for studying the development of herbicide resistance. This paper makes a case for using evolutionary physiology more frequently when studying herbicide resistance, and illustrates this using three areas where more work would be useful: (i) the interaction among major and minor alleles over many generations during the evolution of physiological responses that lead to specific mechanisms of resistance; (ii) the role of epigenetic factors, especially at an early stage of evolution, on the physiological modifications that result in phenotypes that become insensitive to herbicides; and (iii) the interaction between fitness and physiological performance over time, with emphasis on understanding mechanisms that improve the fitness of herbicide-resistant phenotypes during selection. PMID- 28894569 TI - Substantial variation in the timing of pollen production reduces reproductive synchrony between distant populations of Pinus sylvestris L. in Scotland. AB - The ability of a population to genetically adapt to a changing environment is contingent not only on the level of existing genetic variation within that population, but also on the gene flow received from differently adapted populations. Effective pollen-mediated gene flow among plant populations requires synchrony of flowering. Therefore differences in timing of flowering among genetically divergent populations may reduce their ability to adapt to environmental change. To determine whether gene flow among differently adapted populations of native Scots pine (Pinus sylvestris) in Scotland was restricted by differences in their flowering phenology, we measured timing of pollen release among populations spanning a steep environmental gradient over three consecutive seasons (2014-2016). Results showed that, over a distance of 137 km, there were as many as 15.8 days' difference among populations for the predicted timing of peak pollen shedding, with the earliest development in the warmer west of the country. There was much variation between years, with the earliest development and least synchrony in the warmest year (2014) and latest development and greatest synchrony in the coolest year (2015). Timing was negatively correlated with results from a common-garden experiment, indicative of a pattern of countergradient variation. We conclude that the observed differences in reproductive synchrony were sufficient to limit gene flow via pollen between populations of P. sylvestris at opposite ends of the environmental gradient across Scotland. We also hypothesize that continually warming, or asymmetrically warming spring temperatures will decrease reproductive synchrony among pine populations. PMID- 28894570 TI - NADPH oxidase inhibitor, diphenyleneiodonium prevents necroptosis in HK-2 cells. AB - The aim of the present study was to investigate the protective effect of the NADPH oxidase inhibitor, diphenyleneiodonium (DPI) against necroptosis in renal tubular epithelial cells. A necroptosis model of HK-2 cells was established using tumor necrosis factor-alpha, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and antimycin A (collectively termed TZA), as in our previous research. The necroptosis inhibitor, necrostatin-1 (Nec-1) or the NADPH oxidase inhibitor, DPI were administered to the necroptosis model. Production of reactive oxygen species (ROS) was detected by dichlorodihydrofluorescein diacetate in the different groups, and the manner of cell death was identified by flow cytometry. Western blot analysis was used to determine the levels of phosphorylation of receptor interacting protein kinase 3 (RIP-3) and mixed lineage kinase domain-like (MLKL), which are essential to necroptosis. The results revealed that TZA increased the percentages of propidium iodide-positive HK-2 cells from 1.22+/-0.69 to 8.98+/ 0.73% (P<0.001), and augmented the phosphorylation of RIP-3 and MLKL. ROS levels were increased in the TZA group compared with the control group (27.74+/-1.60*104 vs. 18.51+/-1.10*104, respectively; P<0.001), and could be inhibited by Nec-1 (TZA + Nec-1 group, 22.90+/-2.22*104 vs. TZA group, 27.74+/-1.60*104; P=0.01). DPI decreased ROS production (TZA + DPI group, 22.13+/-1.86*104 vs. TZA group, 27.74+/-1.60*104; P<0.001) and also reduced the proportions of necrosis in the necroptosis model (TZA + DPI group, 4.40+/-1.51% vs. TZA group, 8.98+/-0.73%; P<0.001). Phosphorylated RIP-3 and MLKL were also decreased by DPI treatment. The results indicate that ROS production increases in HK-2 cells undergoing necroptosis, and that the NADPH oxidase inhibitor, DPI may protect HK-2 cells from necroptosis via inhibition of ROS production. PMID- 28894571 TI - Vonoprazan 10 mg daily is effective for the treatment of patients with proton pump inhibitor-resistant gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is commonly treated by primary care physicians. Although proton pump inhibitors (PPI) have been the mainstay of GERD treatment for two decades, in some patients GERD is refractory to standard dose PPI for more than eight weeks and is referred to as PPI-resistant GERD. Vonoprazan, a novel competitive acid blocker, became available in Japan for the treatment of patients with GERD, and has greater acid inhibition than existing PPIs. The aim of the present study was to determine the effect of vonoprazan 10 mg daily on PPI-resistant GERD. We retrospectively reviewed 24 patients with PPI resistant GERD treated with vonoprazan 10 mg daily. The Izumo scale was used to evaluate the effect of vonoprazan before and one month after treatment, which reflects quality of life related to gastrointestinal symptoms. The overall rates of improvement and resolution of GERD symptoms were 88% (21/24) and 42% (10/24), respectively, and the score was significantly decreased (before 5.8+/-1.7, at one month 1.9+/-1.9, P<0.001). To evaluate the influence of esophageal erosions despite prior PPI treatment, the patients were divided into erosive (n=6) and non erosive groups (n=18). Vonoprazan achieved 100% (6/6) improvement in the erosive group and 83% (15/18) in the non-erosive group. Patients in the erosive group had a significantly higher rate of resolution than in the non-erosive group [83% (5/6) vs 28% (5/18), P=0.017]. No adverse events occurred. Other GI symptoms in patients with PPI-resistant GERD were evaluated. The scores for epigastric pain, postprandial distress, constipation and diarrhea were unchanged during the treatment period. In conclusion, vonoprazan 10 mg daily is effective for the treatment of patients with PPI-resistant GERD. Vonoprazan resolves GERD symptoms in patients with erosions more than in those without erosions. This is the first report on the effect of vonoprazan 10 mg on PPI-resistant GERD. PMID- 28894572 TI - Comparison between digital and optical microscopy: Analysis in a mouse gut inflammation model. AB - Virtual microscopy is currently widely used for various purposes, such as teaching, archiving, collaborations and research. Although the cost of this technique has reduced, it continues to be expensive for the majority of laboratories in developing countries. The Graduate Program in Pathology at the Federal Fluminense University (Niteroi, Brazil) has acquired equipment for virtual microscopy. However, this novel method faced prejudice, as students and technicians were skeptical about its reliability. Thus, the aim of the current study was to evaluate whether virtual microscopy is a reliable method of analysis for our research. Thus, a mouse gut inflammation model developed by our research group was used in the present study. Analysis was performed using optical microscopy and digital imaging using the APERIO scanning system and the ImageScope(r) software. Intestinal epithelial cells (IECs), intra epithelial leucocytes (IEL), and villi number and area were evaluated. No significant differences were observed in villi number, IEC and IEL; however, the villi area was significantly smaller when measured using the computer. Thus, the present study indicates that virtual microscopy is a trustworthy method for research purposes. PMID- 28894573 TI - Prevalence of hepatitis C in people who inject drugs in the cities of Rawalpindi and Islamabad, Pakistan. AB - Pakistan has the second highest burden of hepatitis C (HCV) in the world. The major route of HCV transmission is contaminated blood or needle sharing. Seventy percent of people who inject drugs (PWIDs) shared needles at some time in their addiction history. The aim of the present study was to estimate the prevalence of HCV in PWIDs in cities of Pakistan. We enrolled 100 PWIDs from the Rawalpindi and Islamabad cities of Pakistan. Blood samples were taken in collection tubes and were subjected to HCV screening by using three rapid HCV screening kits including one step anti-HCV test, onsite HCV Ab rapid test and advance quality rapid anti HCV test. All 100 blood samples were also subjected to HCV detection by using Elecsys anti-HCV II performed on the Roche Cobas 601 platform based on the ECLIA principle. Seventy-two percent of PWIDs showed the presence of HCV antibodies using the Roche anti-HCV II ECLIA test. We also compared the performance of different rapid kits in comparison with the anti-HCV II by Roche. The sensitivity of CTK kit was 84.72%, which was almost equal to the sensitivity by the SD Bioline HCV and Advanced Quality Rapid HCV tests, which was 83.33%. All three kits showed 100% specificity and positive predictive values. The results showed that the three market competitors of HCV rapid test showed almost equal results. The prevalence of HCV is very high in PWIDs in the capital twin cities of Pakistan. There is dire need to initiate the administration of a hepatitis test and treatment program for both high-risk and the general HCV-positive population. This is the optimal way to achieve HCV control targets established by the United Nations Sustainable Development Goals and Global Health Sector Strategy by WHO. PMID- 28894575 TI - Genomic imbalances and MYB fusion in synchronous bilateral adenoid cystic carcinoma and invasive lobular carcinoma of the breast. AB - The incidence of synchronous bilateral breast carcinomas (BBCs) has increased with a more frequent use of magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer. A total of 30% of all BBCs occur synchronously. In the present study, we describe a unique case of synchronous BBC in a 59-year-old previously healthy woman with no known family history of breast or ovarian cancer. At the time of diagnosis the patient had an invasive lobular carcinoma (ILC) in the right breast and an adenoid cystic carcinoma (ACC) in the left breast. To the best of our knowledge, this is the first published case of bilateral, simultaneously occurring ACC and ILC of the breast. Genome-wide genomic profiling of the tumors revealed that they had distinctly different genomic imbalances. The ACC had a 5.7 Mb interstitial 6q deletion with a breakpoint located in the 3'-part of MYB, resulting in loss of the last coding exon of MYB and its 3'-UTR. RT-PCR analysis confirmed that the tumor expressed an ACC-specific MYB-NFIB fusion transcript. In contrast, the ILC had no rearrangements of 6q or MYB-NFIB gene fusion but showed instead gain of 1q21.1-qter, loss of 16q11.2-qter, and 22q12.2-q12.3 as the sole genomic imbalances. Notably, concurrent gains of 1q and losses of 16q are characteristic features of ILC. Collectively, our findings indicate that the ACC and ILC had originated independently of each other and that the MYB-NFIB fusion is a specific biomarker for breast ACC. PMID- 28894574 TI - Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure. AB - Deficient ADAM metalloproteinase with thrombospondin type-1 motif, member 13 (ADAMTS13) activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and causes microcirculatory disturbances and multiple organ failure, while endotoxins trigger the activation of a coagulation cascade. The objective of the present study was to explore the role of ADAMTS13 in endotoxemia in patients with acute liver failure (ALF). Plasma concentrations of endotoxin and cytokines, including interleukin (IL)-6 and IL-8, and activity of the plasma ADAMTS13 inhibitor were determined, along with ADAMTS13:AC, the VWF antigen (VWF:Ag) and UL-VWFM, in 27 patients with acute hepatitis (AH), 11 patients with ALF, and 10 healthy controls. IL-6 and IL-8 concentrations on admission were significantly higher in patients with ALF than in those with AH or in healthy controls. ADAMTS13:AC concomitantly decreased and VWF:Ag progressively increased with increasing cytokine concentrations from the normal range to >100 pg/ml. The inhibitor was detected in 8 patients with ALF (0.6 to 2.4 BU/ml) and 6 patients with AH (0.6 to 0.8 BU/ml). Patients with the inhibitor reported lower ADAMTS13:AC, higher VWF:Ag and lower functional liver capacity than those without the inhibitor. Collectively, the findings suggested that decreased ADAMTS13:AC and increased VWF:Ag may be induced by pro inflammatory cytokinemia as well as the presence of the ADAMTS13 inhibitor, both of which may be closely related to enhanced endotoxemia in patients with ALF. PMID- 28894576 TI - First-line chemotherapy with capecitabine/oxaliplatin for advanced gastric cancer: A phase I study. AB - Combination chemotherapy with capecitabine and oxaliplatin for gastric cancer (G XELOX) is considered as a potentially promising regimen. However, the use of the G-XELOX regimen in Japanese patients has not been investigated to date, and recommended doses of G-XELOX for Japanese patients with metastatic gastric cancer have not been established. The aim of the present study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for systemic chemotherapy with G-XELOX for metastatic gastric cancer. The enrolled patients received systemic chemotherapy with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day, b.i.d. for 14 days, repeated every 3 weeks. A decrease in oxaliplatin dose was planned from start level 1 (130 mg/m2). A total of 6 patients were enrolled between January and July 2015. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d. could be administered with acceptable toxicity, and all patients were treated at these doses. One case of grade 3 stomatitis was considered as a dose-limiting toxicity at level 1; however, excluding this case, no grade 3 or 4 non hematological toxicity was observed. There were no treatment-related deaths. The median relative dose intensity was 71.3% for capecitabine and 92.1% for oxaliplatin. Of the 6 patients, 3 had measurable lesions according to the Response Evaluation Criteria In Solid Tumors; the response rate and disease control rate were both 67%. Therefore, systemic chemotherapy with G-XELOX was well-tolerated by patients with advanced gastric cancer. The RD was defined as oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d. PMID- 28894577 TI - Effects of neoadjuvant chemotherapy on patients with primary vaginal squamous cell carcinoma. AB - Vaginal cancer is a rare gynecological malignancy, mainly treated by radiotherapy and surgery. However, the effect of neoadjuvant chemotherapy on patients with vaginal cancer has not been extensively evaluated. The aim of the present study was to assess the feasibility and efficacy of irinotecan and cisplatin in the management of patients with vaginal squamous cell cancer (SCC). Two patients with International Federation of Obstetrics and Gynecology (FIGO) stage I and one patient with FIGO stage II vaginal SCC were treated with irinotecan (240 mg) and cisplatin (100 mg) every 3-4 weeks. The effect of chemotherapy after 2-4 courses was assessed and the next step of treatment was determined according to the outcome. In the present study, all 3 patients had complete remission after 2-4 courses of chemotherapy. In case 1, the patient received a total of 6 courses of chemotherapy and had no recurrence after 45 months of follow-up. In case 2, the patient received 4 courses of chemotherapy and partial vaginal resection, and had no recurrence after 48 months of follow-up. In case 3, the patient underwent laparoscopic radical surgery and peritoneal vaginoplasty after 2 courses of chemotherapy, and no residual tumors were identified in the resected tissues on postoperative pathological examination. Effective neoadjuvant chemotherapy may decrease the size of the tumor, induce tumor regression, or even achieve pathologically-confirmed complete tumor eradication. Thus, neoadjuvant chemotherapy with irinotecan combined with cisplatin is a feasible treatment for patients with early-stage vaginal SCC. In the present study, all the patients achieved good therapeutic results following chemotherapy. PMID- 28894578 TI - Giant gastrointestinal stromal tumor of the vermiform appendix: A case report. AB - Gastrointestinal stromal tumors (GISTs) of the vermiform appendix are rare, measuring <3 cm in 82.4% of the reported cases. Neoadjuvant therapy with the receptor tyrosine kinase inhibitor imatinib mesylate has the potential to improve resectability and organ preservation rates in locally advanced or metastatic/recurrent GISTs. We herein report the case of a 67-year-old male patient with an unusually large GIST (22 cm in diameter) of uncertain origin in the right lower abdominal quadrant, with a solitary peritoneal metastasis. Due to the size of this GIST and presence of metastatic disease, neoadjuvant therapy with imatinib (400 mg/day orally) was administered. Follow-up imaging studies revealed marked shrinkage of the primary and metastatic tumors. Subsequently, laparoscopic exploration revealed that the main tumor originated from the tip of the vermiform appendix, and that the peritoneal metastasis was located in the ascending mesocolon. The patient underwent laparoscopic appendectomy and excision of the peritoneal metastasis, without tumor rupture. Therefore, in appropriately selected patients, neoadjuvant imatinib for borderline resectable or oligometastatic GISTs may be a reasonable choice. PMID- 28894579 TI - Metanephric adenoma treated with laparoscopic nephrectomy: A case report. AB - Metanephric adenoma is an uncommon benign renal tumor that occurs predominantly in adult females and rarely in children. Its histomorphology resembles that of epithelial Wilms' tumor and papillary renal cell carcinoma. From a diagnostic and therapeutic perspective, recognition of this entity is important as it has a more favorable clinical outcome compared with Wilms' tumor and renal cell carcinoma. Metanephric adenoma should not be treated with nephrectomy if the tumor size is small. However, preoperative diagnosis of this disease is extremely challenging. The present study describes a case of this rare disease, which was treated with laparoscopic nephrectomy. The tumor was not clearly enhanced in the early phase on contrast-enhanced computed tomography imaging. The immunohistochemical analysis revealed positive immunoreactivity for vimentin and Wilms' tumor 1, and partial positivity for cytokeratin (CK) AE1/AE3, CK56, and CK34, consistent with metanephric adenoma. Although metanephric adenoma is difficult to diagnose preoperatively, this rare disease must be considered in order to avoid unnecessary surgical procedures in these patients. PMID- 28894580 TI - Safety of total gastrectomy without nasogastric and nutritional intubation. AB - The aim of the present study was to evaluate the safety of gastrectomy without nasogastric and nutritional intubations. Between January 2010 and August 2015, 74 patients with gastric cancer received total gastric resection and esophagogastric anastomosis without nasogastric and nutritional intubations at the First Department of Digestive Surgery of the XiJing Hospital of Digestive Diseases (Xi'an, China), of whom 42 were also received earlier oral feeding within 48 h. The data were retrospectively analyzed. An additional 301 cases who underwent traditional postoperative intubation were used for comparison. In patients without intubation compared with those managed traditionally with intubation, the mean operative time was decreased (190.97+/-38.18 vs. 216.12+/-59.52 min, respectively; P=0.026). In addition, the postoperative activity was resumed earlier (1.16+/-0.47 vs. 1.36+/-0.84 days, respectively; P=0.009), oral food intake was started earlier (4.28+/-1.79 vs. 5.71+/-2.66 days, respectively; P=0.009), the incidence of fever was lower (12.16 vs. 29.23%, respectively; P=0.003), and the incidence of total complications was not statistically significantly different between the two groups (9.41 vs. 6.31%, respectively; P=0.317). There were no significant differences regarding complications of the anastomotic port (1.37 vs. 1.69%, respectively; P=0.849). Compared with traditional postoperative management, earlier oral feeding did not increase the incidence of complications (7.21 vs. 4.76%, respectively; P=0.557). Our results suggest that total gastric resection without nasogastric and nutritional intubation is a safe and feasible option for patients undergoing total gastrectomy. PMID- 28894581 TI - Positron emission tomography/computed tomography for osseous and soft tissue sarcomas: A systematic review of the literature and meta-analysis. AB - In order to elucidate the value of positron emission tomography (PET)/computed tomography (CT) in the clinical diagnosis and treatment of osseous and soft tissue malignancies, two authors independently searched the PubMed, Medline, Elsevier, Embase and Cochrane Library databases for literature published between January 2003 and February 2016, using the key words 'PET/CT', 'positron emission tomography/computed tomography', 'osseous sarcoma', 'bone tumor', 'soft tissue sarcoma' and 'neoadjuvant', to identify prospective and retrospective studies on the applicability of PET/CT on the clinical diagnosis of bone and soft tissue lesions, and evaluation of their response to neoadjuvant therapies. Data were independently extracted by the two authors and any disagreements were resolved by a third author when necessary. Extracted data were analyzed by Meta-Disc 1.6 software. As a result, 16 trials with a total of 883 patients and 2,214 lesions were included in the present study. The overall diagnostic accuracy of PET/CT exhibited a sensitivity and specificity of 0.90 (0.86-0.92) and 0.89 (0.85-0.92), respectively, and the effect of neoadjuvant therapy was assessed with a sensitivity and specificity of 0.79 (0.30-0.93) and 0.79 (0.69-0.89), respectively. Thus, it may be concluded from the present study that PET/CT is a reliable imaging method to be applied in the diagnosis and treatment of osseous and soft tissue malignancies. PMID- 28894582 TI - Prediction model and treatment of high-output ileostomy in colorectal cancer surgery. AB - The aim of the present study was to examine the risk factors of high-output ileostomy (HOI), which is associated with electrolyte abnormalities and/or stoma complications, and to create a prediction model. The medical records of 68 patients who underwent colorectal cancer surgery with ileostomy between 2011 and 2016 were retrospectively investigated. All the patients underwent surgical resection for colorectal cancer at the Osaka Medical Center for Cancer and Cardiovascular Diseases (Osaka, Japan). A total of 7 patients with inadequate data on ileostomy output were excluded. Using a group of 50 patients who underwent surgery between 2011 and 2013, the risk of HOI was classified by a decision tree model using a partition platform. The HOI prediction model was validated in an additional group of 11 patients who underwent surgery between 2014 and 2016. Univariate analysis of clinical factors demonstrated that young age (P=0.003) and high white blood cell (WBC) count (P<0.001) after surgery were significantly correlated with HOI. Operative factors, such as surgical procedure, approach, operative time and blood loss, were not significantly correlated with HOI. Using these clinical factors, the risk of HOI was classified by statistical partition. In this model, three factors (gender, age and WBC on postoperative day 1) were generated for the prediction of HOI. The patients were classified into five groups, and HOI was observed in 0-88% of patients in each group. The area under the curve (AUC) was 0.838. The model was validated by an external dataset in an independent patient group, for which the AUC was 0.792. In conclusion, HOI patients were classified and an HOI prediction model was developed that may help clinicians in postoperative care. PMID- 28894583 TI - Evaluation of treatment for rectal neuroendocrine tumors sized under 20 mm in comparison with the WHO 2010 guidelines. AB - Rectal neuroendocrine tumor (NET) is a relatively rare lesion of the gastrointestinal tract, but the prospective examination with colonofiberoscopy or endoscopic ultrasound has increased the frequency of its detection. It is often difficult to determine the optimal treatment for NETs sized <20 mm in the clinical setting. Other clinicopathological variables are not considered in the current guidelines and staging systems. Although the effects of lymphovascular invasion are not covered by the World Health Organization (WHO) 2010 guidelines or tumor-node-metastasis (TNM) staging system, this may be promising for the establishment of improved guidelines and staging systems, particularly for early stage colorectal carcinoids. The aim of the present study was to evaluate rectal NETs sized <20 mm in comparison with the WHO 2010 guidelines. Between January 2005 and December 2013, 40 consecutive patients [26 men and 14 women; median age, 59.3 years (range, 34-81 years)] who underwent endoscopic resection of rectal NETs, and 12 patients undergoing surgical resection of rectal NETs, were enrolled in this retrospective study. The median tumor size was 7.4 mm (range, 3-15 mm). The locations of the NET were the rectosigmoid colon (n=3), the upper rectum (n=13), and the lower rectum (n=25). The NETs were classified by size as 0-5 (n=7), 6-10 (n=29) and 11-15 mm (n=4). The surgical procedures performed included low anterior resection plus esophagectomy (n=1), laparoscopic low anterior resection (n=7) and laparoscopic intersphincteric resection (n=4). Only 1 patient had lymph node metastasis (tumor sized 6-10 mm, with lymphovascular invasion). NET recurrence was not detected in any of the patients. According to the WHO guidelines, the tumors were classified as grade (G)1 (n=8), G2 (n=3) and G1/G2 (n=1). The tumor in the patient with lymph node metastasis was G1. NETs sized <10 mm may be curatively treated by endoscopic resection. However, NETs with either lymphovascular invasion or sized >1 cm carry a risk for metastasis equivalent to that of adenocarcinomas. Therefore, it is mandatory to histologically examine lymphovascular invasion in specimens retrieved via endoscopic resection to determine the necessity for further radical surgery with regional lymph node dissection. The treatment of NETs sized <20 mm as presently defined in the WHO 2010 guidelines requires further evaluation. PMID- 28894584 TI - Serum human epididymis protein 4 levels in colorectal cancer patients. AB - Tumour markers are widely used for the diagnosis, staging and monitoring of colorectal cancer (CRC) patients in clinical practice. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are the most frequently used biomarkers in CRC patients. A number of studies have recently investigated the presence of human epididymis protein 4 (HE4) overexpression in certain cancer types. Its significance in ovarian and endometrial cancer has been well demonstrated. The aim of the present study was to evaluate the significance of serum HE4 levels in CRC patients. A total of 46 newly diagnosed CRC patients and 36 age- and gender-matched healthy subjects were included in the study. The concentrations of CEA and CA19-9 were also determined and compared according to HE4 levels. HE4 positivity was determined in 13 of the 46 cases (28.3%) in the CRC group, but no HE4-positive subjects were identified in the control group (0%; P=0.009). The area under the receiver operating characteristic curve for HE4 positivity was 0.641 (95% CI: 0.523-0.760). HE4 was statistically significantly positive in patients with stage III-IV disease and in those with high CA 19-9 levels (all P<0.01). To the best of our knowledge, this is the first study to investigate HE4 expression in CRC patients, and the findings suggest that it may be a useful biomarker, particularly in stage III-IV patients. PMID- 28894585 TI - Cell-based immunotherapy in stage IIIA inflammatory breast cancer with declining innate immunity following successive chemotherapies: A case report. AB - Cancer stem cells in breast cancer migrating to the bone marrow may cause future metastasis, particularly during periods of decreased immunity. Natural killer (NK) cells have a role in immune surveillance and are able to target cancer stem cells. The present study reported a case in which NK cell-based autologous immune enhancement therapy was used combined with conventional treatments in a patient with stage IIIA breast cancer, yielding >28 months of disease-free survival. However, there was a gradual decline in the in vitro expansion of NK cells with subsequent chemotherapeutic treatments. As this NK cell decline following chemotherapy may contribute to cancer cell immune evasion and future metastasis; modifying current cancer therapies in order to avoid potentially compromising the immune system may lead to improved treatment outcomes. PMID- 28894586 TI - A pilot study on the impact of dopamine, serotonin, and brain-derived neurotrophic factor genotype on long-term functional outcomes after subarachnoid hemorrhage. AB - OBJECTIVES: Many that survive an aneurysmal subarachnoid hemorrhage experience lasting physical disability, which might be improved by medications with effects on the dopaminergic, serotonergic, and brain-derived neurotrophic factor neurotransmitter systems. But it is not clear which patients are most likely to benefit from these therapies. The purpose of this pilot study was to explore the relationship of genetic polymorphisms in these pathways with 12-month functional outcomes after aneurysmal subarachnoid hemorrhage. METHODS: Subjects were recruited at the time of admission as a part of a larger parent study. Genotypes were generated using the Affymetrix genome-wide human single-nucleotide polymorphism array 6.0. Those within dopaminergic, serotonergic, and brain derived neurotrophic factor pathways were analyzed for associations with functional outcomes at 12 months post aneurysmal subarachnoid hemorrhage using the Glasgow Outcome Scale and the Modified Rankin Scale. RESULTS: The 154 subjects were 55.8 +/- 11.3 years old and 74% female; they had Fisher scores of 2.95 +/- 0.67, Hunt/Hess scores of 2.66 +/- 1.13, and admission Glasgow Coma Scale scores of 12.52 +/- 3.79. Single-nucleotide polymorphisms in the serotonin receptor genes 1B and 1E and dopamine receptor D2 were associated with greater disability (odds ratio: 3.88-3.25, confidence interval: 1.01-14.77), while single nucleotide polymorphisms in the serotonin receptor genes 2A and 2C and dopamine receptor D5 conferred a risk of poor recovery (odds ratio: 3.31-2.32, confidence interval: 1.00-10.80). Single-nucleotide polymorphisms within the same serotonin genes, and within the dopamine receptor gene D2, were associated with greater recovery after aneurysmal subarachnoid hemorrhage (odds ratio: 0.17-0.34, confidence interval: 0.05-0.89). CONCLUSIONS: These data demonstrate that there may be an association between genetic factors and functional outcomes post stroke. PMID- 28894587 TI - Comparison of claims data on hospitalization rates and repeat procedures in patients receiving a bowel preparation prior to colonoscopy. AB - OBJECTIVES: To evaluate outcomes of colorectal screening using sodium picosulfate and magnesium citrate compared with other prescription bowel-preparation agents. Primary endpoints were rates of procedure-associated hospitalizations, diagnosis at hospitalization, and rates of early repeat screenings. METHODS: This retrospective cohort study identified patients using the Truven Health Analytics MarketScan databases, which contain fully adjudicated, de-identified, medical- and prescription-drug claims, as well as demographic and enrollment information for individuals with commercial, Medicaid, and Medicare supplemental insurance coverage. Patients who had a colonoscopy or sigmoidoscopy over a 3-year period were identified using International Classification of Diseases Clinical Modification procedure codes, recorded on claims from physicians and facilities. First, screening colonoscopy was identified for each patient, and the study was limited to those patients who could be observed for >=6 months before and 3 months after the screening procedure. Total number of hospitalizations and rates of early repeat screenings were evaluated for all patients who received sodium picosulfate and magnesium citrate and compared with those who received other bowel-preparation agents. Individual prescription medications that could affect the outcome of the cleansing agent were identified; further evaluations were made to establish whether patients had comorbid conditions, such as chronic kidney disease, cardiovascular disease, or psychiatric illness. Statistical methods included descriptive statistics, two-tailed t-tests, and multivariate logistic regression. RESULTS: A total of 566,628 procedures were identified in the MarketScan databases and included in the study. Sodium picosulfate and magnesium citrate performed well in terms of safety outcomes, with no hospitalizations due to diagnosis of hyponatremia, dehydration, or other fluid disorders in the 10 days after procedure. Early repeat rates among sodium picosulfate and magnesium citrate patients were comparable with rates observed for all other cleansing agents. CONCLUSION: Outcomes of colorectal screening using sodium picosulfate and magnesium citrate were not significantly different compared with other prescription bowel-preparation agents. PMID- 28894588 TI - Dysplastic pulmonary valve stenosis associated with unilateral absent first metacarpal: A rare association. AB - CONTEXT: Dysplastic pulmonary valve stenosis is a less common variety of valvular pulmonary stenosis. It is known to be part of Noonan syndrome. Bony hand anomalies in patients of pulmonary stenosis are very rare. CASE REPORT: A 50-year old lady, with no significant past history, presented with slowly progressive breathlessness and fatigue, and had progressed from NYHA class 1 to 2 over 2 years. She had unilateral absent first metacarpal and diagnosed on workup to have dysplastic pulmonary valve stenosis and was treated with balloon valvuloplasty. CONCLUSION: Dysplastic pulmonary valve stenosis can rarely be associated with bony hand anomalies like absent first metacarpal. PMID- 28894589 TI - Automated detection of heart ailments from 12-lead ECG using complex wavelet sub band bi-spectrum features. AB - The complex wavelet sub-band bi-spectrum (CWSB) features are proposed for detection and classification of myocardial infarction (MI), heart muscle disease (HMD) and bundle branch block (BBB) from 12-lead ECG. The dual tree CW transform of 12-lead ECG produces CW coefficients at different sub-bands. The higher-order CW analysis is used for evaluation of CWSB. The mean of the absolute value of CWSB, and the number of negative phase angle and the number of positive phase angle features from the phase of CWSB of 12-lead ECG are evaluated. Extreme learning machine and support vector machine (SVM) classifiers are used to evaluate the performance of CWSB features. Experimental results show that the proposed CWSB features of 12-lead ECG and the SVM classifier are successful for classification of various heart pathologies. The individual accuracy values for MI, HMD and BBB classes are obtained as 98.37, 97.39 and 96.40%, respectively, using SVM classifier and radial basis function kernel function. A comparison has also been made with existing 12-lead ECG-based cardiac disease detection techniques. PMID- 28894590 TI - TRPA1 channel mediates organophosphate-induced delayed neuropathy. AB - The organophosphate-induced delayed neuropathy (OPIDN), often leads to paresthesias, ataxia and paralysis, occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate (OP) insecticides or nerve agents, and may contribute to the Gulf War Syndrome. The acute phase of OP poisoning is often attributed to acetylcholinesterase inhibition. However, the underlying mechanism for the delayed neuropathy remains unknown and no treatment is available. Here we demonstrate that TRPA1 channel (Transient receptor potential cation channel, member A1) mediates OPIDN. A variety of OPs, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels. Malathion increases the intracellular calcium levels and upregulates the excitability of mouse dorsal root ganglion neurons in vitro. Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors, which resembles OPIDN. Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene. In the classic hens OPIDN model, malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri ortho-cresyl phosphate (TOCP), which also activates TRPA1 channel. Treatment with HC030031 reduces the damages caused by malathion or tri-ortho-cresyl phosphate. Duloxetine and Ketotifen, two commercially available drugs exhibiting TRPA1 inhibitory activity, show neuroprotective effects against OPIDN and might be used in emergency situations. The current study suggests TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN. PMID- 28894591 TI - Efficacy of oral contrast agents for upper gastrointestinal signal suppression in MRCP: A systematic review of the literature. AB - BACKGROUND: Orally administered substances which suppress signals from gastrointestinal fluid can be used to enhance image quality in magnetic resonance cholangiopancreatography (MRCP). In daily practice, the available substances range from commercial products to regular viands such as fruit juices. PURPOSE: To provide an overview on the significance of and the substances used as gastrointestinal fluid signal suppressors in MRCP. MATERIAL AND METHODS: A systematic review of the existing literature was performed to evaluate the efficacy and efficiency of oral T2-signal suppressors in MRCP. RESULTS: Twenty five publications on 16 different oral contrast media were identified. The most commonly used substances were ferumoxsil, ferric ammonium citrate, and pineapple juice. Twenty-three out of 25 publications supported the use of oral signal suppressors in MRCP. Advantages of oral signal suppressors include improved visualization of the pancreatobiliary ductal system, increased help with differential diagnoses, and higher detection rates of relevant diagnoses due to a reduction of overlaying signals. CONCLUSION: The application of oral substances for gastrointestinal signal suppression in MRCP is recommendable. A variety of substances are used in daily routine with good but varying effectivity and patient tolerance. PMID- 28894593 TI - Bioresorbable coronary scaffolds in 2017. PMID- 28894592 TI - Changes in delta ADC reflect intracranial pressure changes in craniosynostosis. AB - BACKGROUND: In patients with craniosynostosis, intracranial pressure (ICP) has been reported to increase even in the absence of overt symptoms. The early and non-invasive detection of intracranial hypertension is important for reducing the risk of abnormal brain development in pediatric patients. PURPOSE: To assess whether the apparent diffusion coefficient (ADC) of white matter during the cardiac cycle (DeltaADC) would change after surgery to relieve ICP in children with craniosynostosis. MATERIAL AND METHODS: This prospective study included ten patients diagnosed with craniosynostosis and four normal controls. All ten patients underwent magnetic resonance (MR) examinations before and after surgical treatment. Single-shot diffusion MR imaging (MRI) triggered by an electrocardiogram was performed, with regions of interest (ROIs) placed on frontal white matter and basal ganglia. RESULTS: In all ten patients, DeltaADC values after surgery were higher than those before surgery. This difference was statistically significant (Wilcoxon signed-rank test, P = 0.005). CONCLUSION: The change in DeltaADC in the frontal white matter before and after surgery in patients with craniosynostosis indicates that it might reflect the change in ICP. Measurements of DeltaADC could be a promising tool for non-invasive monitoring of ICP. PMID- 28894594 TI - Effectiveness and safety of the ABSORB bioresorbable vascular scaffold for the treatment of coronary artery disease: systematic review and meta-analysis of randomized clinical trials. AB - BACKGROUND: In the last years bioresorbable vascular scaffold (BVS) become a new therapeutic option for interventional cardiologists, with the advantage of a scaffold inducing a possible vessel wall restoration. Nevertheless, several trials tried to prove the safety and efficacy profile of scaffolds, but with conflicting results. METHODS: A systematic review and meta-analysis was performed. The search was carried out in PubMed, Google Scholar, Biomed Central and Cochrane Library between January and March 2017. Inclusion criteria: randomized clinical trials (RCT) comparing the Absorb BVS versus durable polymer cobalt-chromium Everolimus Eluting Stent. The outcomes analysed were all-cause mortality, cardiac death, ischemia-driven target lesion revascularization, target vessel myocardial infarction (MI), target lesion failure (TLF)/device oriented composite endpoints (DOCE), and device thrombosis. Fixed-effect meta-analysis was performed. Data were expressed as odds ratio (OR). RESULTS: Overall 5,674 patients were included (mean age 62.2+/-1.31 in drug eluting stents (DES) group vs. 62+/-1,47 in BVS group; P=0.942). DOCE (OR 1.16, 95% CI: 0.90-1.48; P=0.259, I2=0%), cardiac death (OR 0.86, 95% CI: 0.52-1.40; P=0.537, I2=0%) and all-cause death (OR 0.78, 95% CI: 0.53-1.15; P=0.205, I2=15%) did not differ between BVS and DES. Conversely, ischemia-driven target lesion revascularization was more frequent in the BVS group (OR 1.32, 95% CI: 1.01-1.73; P=0.039, I2=0%), as well as device thrombosis (2.2% vs. 0.6%, OR 2.94, 95% CI: 1.71-5.05, P=0.0001, I2=0%) and target-vessel MI (5.4% vs. 3%, OR 1.66, 95% CI: 1.25-2.21, P=0.001, I2=0%). CONCLUSIONS: The implantation of BVS is associated with an increased risk of device thrombosis, ischemia-driven target lesion revascularization and target vessel MI. If longer follow-up or different implantation technique may change these findings should be addressed in future trials. PMID- 28894595 TI - The impact of the 3-year ABSORB II trial results on my clinical practice: an Italian survey. AB - BACKGROUND: To evaluate how the 3-year results from the "A clinical evaluation to compare the safety, efficacy and performance of ABSORB everolimus eluting bioresorbable vascular scaffold (BVS) system against XIENCE everolimus eluting coronary stent system in the treatment of subjects with ischemic heart disease caused by de novo native coronary artery lesions" (ABSORB II) trial have influenced clinical practice among Italian interventional cardiologists. METHODS: We performed a survey among 95 interventional cardiologists sending a brief questionnaire by electronic mail. We collected 65 replies and analysed the data. RESULTS: The opinion of the operators regarding the two main endpoints of the study ABSORB II was conflicting. However, 66% of the operators considered at least one of the two co-primary endpoints (late lumen loss or vasomotion) unreliable and not reflecting clinical practice. Asking about an explanation for the negative results of the study, we found that the 91% of the operators considered the implantation technique the main limit of the ABSORB II. Furthermore, 74% of the operators affirmed that the results from the study did not decrease the number of scaffold implanted in their cath-lab. CONCLUSIONS: Absorb II trial did not influence clinical practice among Italian interventional cardiologists mainly due to the overall idea that the co-primary endpoints were not adequate to provide a robust evidence on device clinical safety and also because the lack of experience on device implantation may have influenced the outcomes. PMID- 28894596 TI - Magmaris: a new generation metallic sirolimus-eluting fully bioresorbable scaffold: present status and future perspectives. AB - Drug-eluting stents (DES) have reached a high safety and efficacy profile, becoming the best option for percutaneous coronary interventions (PCI) based revascularization. However, despite their optimal performance, a few concerns remain regarding their use, mainly due to permanent caging of the vessels and its consequences, first of all late stent thrombosis (ST). Bioresorbable scaffolds (BRS) aim to overcome these issues. The results achieved in randomized controlled trials (RCT) by the first generation of poly-L-lactic acid (PLLA) based scaffolds were promising at 1 year, but the first long term reports (albeit flawed by non optimal implantation technique) have been disappointing, showing, for instance, an increased risk of ST and target vessel myocardial infarction (TV-MI). In such a scenario the advent of a newer generation magnesium (Mg) based BRS is welcome, mainly because of its innovative mechanical and chemical features coupled with well proven biocompatibility. Despite being in its infancy, this technology seems to promise a great potential. In our article, we review the Magmaris (Biotronik AG, Bulach, Switzerland) Mg BRS development from animal models to human use, underscore its best qualities and weaknesses, and provide hints of its possible future perspectives. PMID- 28894597 TI - BRS implantation in long lesions requiring device overlapping: myth or reality? AB - Dealing with bioresorbable vascular scaffolds (BVS) implantation in long lesions requiring device overlapping in this particular moment might seem a little provocative for several reasons. First, most studies testing BVS have focused on their safety and efficacy profile in simple patients with simple lesions. Second, ABSORB II did not meet its primary endpoint, while ABSORB III showed a higher rate of target vessel-myocardial infarction (TV-MI) at 2 years. Third, data on porcine model showed that overlapping zone has delayed but greater neointimal proliferation with consequent higher risk for scaffold thrombosis in the short term and of in-scaffold restenosis in the long-term. Fourth, recently published data showed higher risk of TVF in patients treated with >=60 mm BVS. Given all these premises, it may seem right to put aside this technology, while it may seem inappropriate to hypothesize the use of BVS in long lesions. The aim of the present review is precisely to critically review the available evidences regarding BVS with particular regard to overlapping BVS in order to understand whether this technology has a future per se and especially in long coronary lesions requiring overlap. PMID- 28894598 TI - Mechanical behavior of polymer-based vs. metallic-based bioresorbable stents. AB - Bioresorbable scaffolds (BRS) were developed to overcome the drawbacks of current metallic drug-eluting stents (DES), such as late in-stent restenosis and caging of the vessel permanently. The concept of the BRS is to provide transient support to the vessel during healing before being degraded and resorbed by the body, freeing the vessel and restoring vasomotion. The mechanical properties of the BRS are influenced by the choice of the material and processing methods. Due to insufficient radial strength of the bioresorbable material, BRS often required large strut profile as compared to conventional metallic DES. Having thick struts will in turn affect the deliverability of the device and may cause flow disturbance, thereby increasing the incidence of acute thrombotic events. Currently, the bioresorbable poly-l-lactic acid (PLLA) polymer and magnesium (Mg) alloys are being investigated as materials in BRS technologies. The bioresorption process, mechanical properties, in vitro observations and clinical outcomes of PLLA-based and Mg-based BRS will be examined in this review. PMID- 28894599 TI - Occurrence and management of bioresorbable vascular scaffold failure in real-life studies. AB - Bioresorbable vascular scaffold (BVS) has emerged as a new technology aiming at overcoming some drawbacks of the conventional metallic stent. In spite of the initial promising results, this technology stumbled upon numerous challenges, which were revealed in the real world studies. Thanks to real world trials and registries findings, our knowledge about the BVS has grown over time, thus we have understood on BVS behavior in various settings and formulated better implantation techniques. In this article, we will review the incidence of BVS failure in real world studies, its different etiologies and management strategies. PMID- 28894600 TI - Current concepts on coronary revascularization using BRS in patients with diabetes and small vessels disease. AB - Diabetes mellitus (DM) and small vessel (SV) disease are two major predictors of adverse outcome in patients treated by percutaneous coronary intervention (PCI), even when last generation metallic drug-eluting stents (DES) are used. Bioresorbable scaffold (BRS) technology has been recently developed to overcome the disadvantages of metallic DES due to their permanent struts. Through the resorption process, BRS may provide a vascular restoration that appears very attractive especially when distal or diffusely diseased coronary segments are involved, as in diabetic patients and SV disease. However, robust evidence on the use of BRS in diabetics is lacking, and recent data have raised concerns on the use of BRS in SVs, particularly when reference vessel diameter (RVD) is <2.25 mm. This review aims at summarizing current evidence related to the use of BRS in diabetics and SV disease. PMID- 28894601 TI - The DESolve novolimus bioresorbable Scaffold: from bench to bedside. AB - The DESolve (Elixir Medical Corporation, Sunnyvale, California, USA) is a poly-L lactide-based polymer scaffold coated with the antiproliferative and anti inflammatory drug novolimus. The scaffold biodegrades within one year with a complete resorption in two years and in vitro bench test have shown the ability to supply the necessary radial strength to support the vessel for the critical 3- to 4-month period after implant. The DESolve showed the unique self-correction property, which may reduce the incidence of minor malapposition after deployment. Overexpansion with DESolve is safe since a high capability resistance to fracture has been demonstrated with this scaffold. The aim of this review is to provide a comprehensive overview of the available preclinical and clinical data regarding the DESolve. PMID- 28894602 TI - Methods to assess bioresorbable vascular scaffold devices behaviour after implantation. AB - Bioresorbable vascular scaffolds (BRS) represent a novel approach for coronary revascularization offering several advantages as compared to current generation DES, potentially reducing rate of late adverse events and avoiding permanent vessel caging. Nevertheless, safety concerns have been raised for an increased risk of scaffold thrombosis (ScT) in both early and late phases, probably related to a suboptimal scaffold implantation. In this context, the use of different imaging methodologies has been strongly suggested in order to guarantee an optimal implantation. We herein analyze the different imaging methodologies available to assess BRS after implantation and at follow-up. PMID- 28894603 TI - Are acute coronary syndromes an ideal scenario for bioresorbable vascular scaffold implantation? AB - Bioresorbable vascular scaffolds (BRS) represent the latest innovation in the field of interventional cardiology. BRS have recently been introduced in routine clinical practice and their use has progressively extended in everyday clinical practice. The BRS use appears theoretically attractive in patients presenting with acute coronary syndromes (ACS) as they are generally young with long life expectancy, thus possibly benefiting more of the so-called vascular reparative therapy. Furthermore, "culprit" lesions are usually softer and more easily expandable by current BRS compared to stable chronic lesions. However an increased risk of BRS thrombosis has been reported in clinical trials excluding ACS patients. Therefore, concerns have been raised on the safety of BRS implantation in the ACS setting in which the risk of thrombotic recurrences is definitely higher (compared to stable lesions) independently by the device implanted. Aim of this review is to provide an overview of the available data on the BRS performance in ACS patients. PMID- 28894604 TI - New generation bioresorbable scaffold technologies: an update on novel devices and clinical results. AB - Bioresorbable scaffolds (BRS) represent a novel horizon in interventional cardiology and may lead to some potential long-term advantages including the restoration of vasomotion, positive remodeling and a reduced incidence of late and very-late scaffold thrombosis (ScT). This technology, introduced to overcome limitations of current metallic drug-eluting stents (DES), is constantly and rapidly evolving with many companies working on bioresorbable devices. The aim of this review is to present an update on the most promising scaffolds that are under development. PMID- 28894605 TI - Optical coherence tomography guidance during bioresorbable vascular scaffold implantation. AB - Bioresorbable vascular scaffold (BRS) represent a revolutionary concept in interventional cardiology. After initial enthusiasm, recent real world registries, including patients with increasing lesion complexity, reported not trivial rates of scaffold thrombosis (ScT). The importance of correct patients selection as well as technical aspects during BRS implantation procedures has been highlighted in several studies suggesting that the high rate of ScT might be related to uncorrected patients/lesions selection together with underutilization of intracoronary imaging guidance leading to suboptimal BRS implantation. The high-resolution power together with the lack of shadowing observed beyond polymer struts makes optical coherence tomography (OCT) the optimal imaging technique to guide BRS implantation and identifies eventually scaffolds failures. PMID- 28894606 TI - Corneal Nerve Regeneration after Self-Retained Cryopreserved Amniotic Membrane in Dry Eye Disease. AB - PURPOSE: To evaluate the efficacy of self-retained cryopreserved amniotic membrane (CAM) in promoting corneal nerve regeneration and improving corneal sensitivity in dry eye disease (DED). METHODS: In this prospective randomized clinical trial, subjects with DED were randomized to receive CAM (study group) or conventional maximum treatment (control). Changes in signs and symptoms, corneal sensitivity, topography, and in vivo confocal microscopy (IVCM) were evaluated at baseline, 1 month, and 3 months. RESULTS: Twenty subjects (age 66.9 +/- 8.9) were enrolled and 17 completed all follow-up visits. Signs and symptoms were significantly improved in the study group yet remained constant in the control. IVCM showed a significant increase in corneal nerve density in the study group (12,241 +/- 5083 MUm/mm2 at baseline, 16,364 +/- 3734 MUm/mm2 at 1 month, and 18,827 +/- 5453 MUm/mm2 at 3 months, p = 0.015) but was unchanged in the control. This improvement was accompanied with a significant increase in corneal sensitivity (3.25 +/- 0.6 cm at baseline, 5.2 +/- 0.5 cm at 1 month, and 5.6 +/- 0.4 cm at 3 months, p < 0.001) and corneal topography only in the study group. CONCLUSIONS: Self-retained CAM is a promising therapy for corneal nerve regeneration and accelerated recovery of the ocular surface health in patients with DED. The study is registered at clinicaltrials.gov with trial identifier: NCT02764814. PMID- 28894607 TI - Evaluation of Cholinergic Deficiency in Preclinical Alzheimer's Disease Using Pupillometry. AB - Cortical cholinergic deficiency is prominent in Alzheimer's disease (AD), and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR) in AD (N = 14) and cognitively normal healthy control (HC, N = 115) participants, with the HC group stratified according to high (N = 38) and low (N = 77) neocortical amyloid burden (NAB). Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p < 0.05, maximum velocity p < 0.0005, average velocity p < 0.005, and constriction amplitude p < 0.00005). The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD. PMID- 28894608 TI - Analysis of T Cell Subsets in Adult Primary/Idiopathic Minimal Change Disease: A Pilot Study. AB - AIM: To characterise infiltrating T cells in kidneys and circulating lymphocyte subsets of adult patients with primary/idiopathic minimal change disease. METHODS: In a cohort of 9 adult patients with primary/idiopathic minimal change recruited consecutively at disease onset, we characterized (1) infiltrating immune cells in the kidneys using immunohistochemistry and (2) circulating lymphocyte subsets using flow cytometry. As an exploratory analysis, association of the numbers and percentages of both kidney-infiltrating immune cells and the circulating lymphocyte subsets with kidney outcomes including deterioration of kidney function and proteinuria, as well as time to complete clinical remission up to 48 months of follow-up, was investigated. RESULTS: In the recruited patients with primary/idiopathic minimal change disease, we observed (a) a dominance of infiltrating T helper 17 cells and cytotoxic cells, comprising cytotoxic T cells and natural killer cells, over Foxp3+ Treg cells in the renal interstitium; (b) an increase in the circulating total CD8+ T cells in peripheral blood; and (c) an association of some of these parameters with kidney function and proteinuria. CONCLUSIONS: In primary/idiopathic minimal change disease, a relative numerical dominance of effector over regulatory T cells can be observed in kidney tissue and peripheral blood. However, larger confirmatory studies are necessary. PMID- 28894609 TI - An Online Platform to Support the Network of Caregivers of People with Dementia. AB - Increasing numbers of persons with dementia (PWD) augment the pressure on dementia care, especially informal care. Care technology can support the network of PWD. We tested the usability and perceived value of an online platform that aims to support the communication and collaboration between family and professional caregivers of PWD. A mixed methods design was used for this pilot study, including semistructured interviews, a postal questionnaire, and monitoring of log data. Seven family and thirty-two professional caregivers involved with four PWD participated during a 10-week period. Overall, the results indicate that the platform is easy to use and valuable for both family and professional caregivers. They felt better informed and prepared regarding the situation of the PWD and felt supported by the more direct lines of communication within the network. Also, a broadening and deepening of the relationship between family and professional caregivers was experienced. Although connecting care organizations' record systems with the platform and an active contribution of all care professionals involved (e.g., general practitioners and those working at day care units) were suggested for optimal use of the platform, family and professional caregivers positively valued the platform for improving the efficiency and ease of communication and collaboration. PMID- 28894611 TI - Cigarette Lighter Fluid Induced Gastric Ulcer: A Severe Complication of Delayed Foreign Body Removal. AB - The majority of foreign bodies ingested pass uneventfully through the gastrointestinal tract without endoscopic intervention. Nevertheless, certain ingested objects pose a greater risk for complications and are more challenging to remove than others. This case report describes a 49-year-old male who swallowed a cigarette lighter causing a gastric ulcer. The lighter was successfully removed by flexible endoscopy using a polypectomy snare. Urgent removal is required due to the shape of the object and its hazardous contents. This is the first case report published in the United States describing cigarette lighter ingestion and management. PMID- 28894612 TI - Combined Dorsal and Ulnarward Carpometacarpal Dislocation Associated with Open Fracture of the Base of First Metacarpal and Severe Degloving Injury. AB - We report a rare case of dislocation of second to fourth carpometacarpal (CMC) joints of the right hand with combined dorsal and ulnarward displacement of the second to fourth digits and fracture of the shaft of the first metacarpal associated with degloving injury. These injuries were diagnosed early and treated successfully with closed reduction and internal fixation using Kirschner wires. The functional outcome was good at follow-up at 5 years. A high index of suspicion is required to successfully diagnose and treat this condition. PMID- 28894613 TI - Pneumonia due to a Rare Pathogen: Achromobacter xylosoxidans, Subspecies denitrificans. AB - Achromobacter xylosoxidans, subspecies denitrificans, is a gram-negative rod recently implicated as an emerging cause of infection in both immunosuppressed and immunocompetent populations. Few cases are reported in literature involving multiple body systems. Diagnosis depends on cultures of appropriate specimens, and management usually is by administration of appropriate antibiotics (usually agents with antipseudomonal activity). We report a rare case of pneumonia due to infection with this organism, in a patient with preexisting bronchiectasis secondary to chronic aspiration. PMID- 28894614 TI - Pancreatic Adenocarcinoma Producing Parathyroid Hormone-Related Protein. AB - A 48-year-old woman presented to our hospital with a 1-year history of a continuous high fever. She was diagnosed with metastatic pancreatic adenocarcinoma accompanied by leukocytosis without infection. Her serum concentration of granulocyte colony-stimulating factor was highly elevated. Forty five days after initiating chemotherapy, she was readmitted because of a neuropsychiatric disturbance and hypercalcemia. Her serum concentration of parathyroid hormone-related protein (PTH-rP) was elevated. A pretreatment biopsy specimen showed strong cytoplasmic immunoreactivity to anti-PTH-rP antibody, suggesting that overproduction of PTH-rP accounted for the hypercalcemia. Although the patient regained consciousness after treatment, she died of progressive disease 60 days after chemotherapy. PMID- 28894610 TI - Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism. AB - The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization. PMID- 28894615 TI - Chronic Osteomyelitis of the Distal Femur Treated with Resection and Delayed Endoprosthetic Reconstruction: A Report of Three Cases. AB - Chronic osteomyelitis involving the distal femur often results in amputation or arthrodesis. This article presents three cases of chronic osteomyelitis treated with a staged approach culminating in endoprosthetic reconstruction. Stage one involved resection of infected bone and placement of an intramedullary nail spanning the bony defect between proximal femur and tibia, with antibiotic cement packed around the nail. Patients were then placed on long-term IV +/- oral antibiotics to clear the infection. A "cooldown" period was then used between stages where patients were off antibiotics and inflammatory markers were monitored for signs of remaining infection. Stage two then involved reconstruction of the distal femur and knee with an endoprosthesis. In the appropriate patient, this treatment strategy offers another option in this challenging population. PMID- 28894616 TI - Esophageal Squamous Cell Carcinoma Presenting with Streptococcus intermedius Cerebral Abscess. AB - BACKGROUND: Cerebral abscess is caused by inoculation of an organism into the brain parenchyma from a site distant from the central nervous system. Streptococcus intermedius (S. intermedius) is a commensal organism that is normally present in the aerodigestive tract and was reported to be the cause of brain abscesses after esophageal dilatation or upper endoscopy. CASE PRESENTATION: We report the case of a 53-year-old female who presented with hematemesis and melena followed by left-sided weakness. Initially, her hemiplegia was found to be secondary to a right thalamic brain abscess caused by S. intermedius. Investigations led to the diagnosis of a mid-esophageal squamous cell carcinoma. We hypothesize that the cause of the abscess with this bacterium that naturally resides in the digestive tract and oral cavity is secondary to hematogenous spread from breach in the mucosal integrity from ulceration due to the cancer. CONCLUSION: To our knowledge, our case is the first in the literature to describe a brain abscess caused by S. intermedius in association with a previously undiagnosed esophageal squamous cell carcinoma without any prior esophageal intervention. PMID- 28894617 TI - Idiopathic Myointimal Hyperplasia of Mesenteric Veins of the Ileum and Colon in a Patient with Crohn's Disease: A Case Report and Brief Review of the Literature. AB - Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a rare disease characterized by intimal smooth muscle proliferation, leading to the thickening of small to medium-sized mesenteric veins. This vascular disease mimics inflammatory bowel disease (IBD) clinically and endoscopically, while showing ischemic mucosal changes without the classic features of IBD on biopsy. Given the mixed picture, this entity is frequently misdiagnosed. Surgical resection of the diseased bowel segment reveals the true etiology of the pathology and is curative. We describe a case of a 59-year-old man with a long standing history of Crohn's disease refractory to medical therapy and status after multiple small bowel resections. The patient underwent a subtotal abdominal colectomy with pathology showing dense, indurated mesenteric adipose tissue, significant muscularis propria hypertrophy, and myointimal hyperplasia of the mesenteric veins in a peri-ileal and pericolic distribution, as confirmed by elastin stain. No evidence of mucosal ischemic changes or findings of chronicity or acuity were seen. IMHMV, a rare disease with a mixed presentation, poses a significant diagnostic challenge to clinicians and pathologists. PMID- 28894618 TI - Percutaneous Emergency Needle Caecostomy for Prevention of Caecal Perforation. AB - Caecal perforation is a life-threatening complication of large bowel obstruction with a reported mortality of 34% to 72%. This case describes the novel use of percutaneous needle caecostomy as a life-saving measure to prevent imminent caecal perforation in a 68-year-old lady with large bowel obstruction secondary to an incarcerated incisional hernia. After careful review of computed tomography images and measurement of distances from the abdominal wall to the caecum, the patient's caecum was decompressed in the emergency department using a needle under local anaesthetic. The patient subsequently underwent laparoscopic hernia repair and had an uncomplicated recovery. When conducted safely and with precision in an appropriate patient, percutaneous needle caecostomy can provide immediate symptom relief, reduce risk of caecal perforation, and allow a laparoscopic surgical approach. PMID- 28894619 TI - Immunological Reactivity Using Monoclonal and Polyclonal Antibodies of Autoimmune Thyroid Target Sites with Dietary Proteins. AB - Many hypothyroid and autoimmune thyroid patients experience reactions with specific foods. Additionally, food interactions may play a role in a subset of individuals who have difficulty finding a suitable thyroid hormone dosage. Our study was designed to investigate the potential role of dietary protein immune reactivity with thyroid hormones and thyroid axis target sites. We identified immune reactivity between dietary proteins and target sites on the thyroid axis that includes thyroid hormones, thyroid receptors, enzymes, and transport proteins. We also measured immune reactivity of either target specific monoclonal or polyclonal antibodies for thyroid-stimulating hormone (TSH) receptor, 5'deiodinase, thyroid peroxidase, thyroglobulin, thyroxine-binding globulin, thyroxine, and triiodothyronine against 204 purified dietary proteins commonly consumed in cooked and raw forms. Dietary protein determinants included unmodified (raw) and modified (cooked and roasted) foods, herbs, spices, food gums, brewed beverages, and additives. There were no dietary protein immune reactions with TSH receptor, thyroid peroxidase, and thyroxine-binding globulin. However, specific antigen-antibody immune reactivity was identified with several purified food proteins with triiodothyronine, thyroxine, thyroglobulin, and 5'deiodinase. Laboratory analysis of immunological cross-reactivity between thyroid target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune thyroid disease. PMID- 28894620 TI - Programming for Stimulation-Induced Transient Nonmotor Psychiatric Symptoms after Bilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease. AB - BACKGROUND: Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. MATERIALS AND METHODS: 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. RESULTS: Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (p = 1.000). CONCLUSION: The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective. PMID- 28894621 TI - Stereospecific Assay of (R)- and (S)-Goitrin in Commercial Formulation of Radix Isatidis by Reversed Phase High-Performance Liquid Chromatography. AB - Radix isatidis (Banlangen) is a widely used traditional Chinese medicine for treating fever and removing toxic heat. Pharmacological studies have indicated that (R)-goitrin (epigoitrin) is one of the main constituents accounting for its antiviral activity, while (S)-goitrin (goitrin) is known as an antithyroid factor. To better control the quality of radix isatidis and its formulations, it is imperative to enantiomerically determine the contents of R- and S-goitrin. In this study, an enantioselective method based on reversed phase chromatography was developed for the assay of (R, S)-goitrin enantiomers. Optimum separation was obtained on an S-Chiral A column (4.6 mm * 250 mm, 5 MUm) using methanol/water (30 : 70, v/v) as the mobile phase. After validation, the method was applied to quantify the enantiomers in Banlangen granules, which is the most prescribed commercial formulation of radix isatidis. Compared to enantioselective resolution approaches based on normal phase chromatography, the new method could be conveniently performed using regular reversed phase high-performance liquid chromatography (RP-HPLC) equipment and was found to be more suitable for the enantioselective quality control of water-extracted and soluble medicines. PMID- 28894622 TI - A Liquid Chromatography-Tandem Mass Spectrometry Method for Evaluation of Two Brands of Enalapril 20 mg Tablets in Healthy Human Volunteers. AB - Enalapril is an angiotensin-converting enzyme inhibitor used for treatment of hypertension and chronic heart disease. Enalaprilat is its active metabolite responsible for the activity. This study aimed to develop and validate a method for enalapril and enalaprilat analysis and to determine the bioequivalence of two tablet formulae of enalapril. LC-MS/MS bioanalytical method was developed and validated and then applied to evaluate the bioavailability of two enalapril formulae. Antihyperglycemic sitagliptin was used as internal standard (IS). The method was accurate for the within- and between-days analysis, and precise CV% was <5%, being linear over the calibration range 1.0-200.0 ng/ml. Stability was >85% and the LOD was 0.907 and 0.910 ng/ml for enalapril and enalaprilat, respectively, and LLOQ was 1 ng/ml. The pharmacokinetic parameters Cmax, tmax, AUC0-72, and AUC0-infinity values of enalapril and enalaprilat of the two formulae were calculated and nonsignificant differences were found. A linearity, specific, accurate, and precise method was developed and applied for the analysis of enalapril and enalaprilat in human plasma after oral administration of two formulae of enalapril 20 mg tablets in healthy volunteers. Depending on the statistical analysis it was concluded that the two enalapril formulae were bioequivalent. PMID- 28894623 TI - Ethnopharmacological values of cassava and its potential for diabetes and dyslipidemia management: Knowledge survey and critical review of report. AB - BACKGROUND: Beyond nutritional values are the pharmacological potentials of cassava comparative with other staple carbohydrate plant-based foods such as wheat. The knowledge of applicability to diabetes and its cardiovascular complications management seems not just limited but unacknowledged. As a preliminary study, a community's knowledge of pharmacological value of cassava is investigated. METHODS: Descriptive observational study using questionnaire-based "cross-sectional" survey was conducted. 136 Participants completed the survey and 101 respondents were selected for evaluation. Open-ended questions were used qualitatively to generate experience and view cassava values for diabetes and dyslipidemia. While categorical (yes or no) questions were used quantitatively to generate numerical results for diabetes, critical reanalysis of a report data was performed, especially comparing carbohydrate/fiber and fat/fiber ratios of cassava with wheat in view of dyslipidemia. RESULT: On the positive side, 42% of the participants believe that cassava has medicinal values. This includes 6% (among the 42) who believes that the plant is useful in treating diabetes and 24% who do not know it may be useful in diabetes management. Critical review showed that cassava may contribute up to sixteen times more fiber and four times less digestible sugar, as well as carbohydrate/fiber and fat/fiber ratios being 14 and 55 times less than wheat. CONCLUSION: There is evidence that relative to wheat flour meal, for instance, cassava contributes less fat and much more fiber. Since fat is pro-obesity, which in turn is pro-diabetic/metabolic syndrome; and fiber is anti-dyslipidemic; cassava has pharmacological values to be appreciated over some carbohydrate plant-based foods. PMID- 28894624 TI - Use of traditional plants in management of halitosis in a Moroccan population. AB - INTRODUCTION: The use of medicinal plants was a very spread therapeutic way. At present, several studies are moving toward this ancestral option, seen the emergence of several bacterial resistance and for the large number of side effects of some synthetic drugs. OBJECTIVE: The objective of this study was to collect and evaluate information on medicinal plants commonly used in five Moroccan cities: Rabat, Sale, Temara, Khemisset, and Tiflet for the management of halitosis. METHODS: This is a cross-sectional survey; conducted among 171 herbalists. The tool of the study was a questionnaire filled by herbalists. SPSS in its version 13 was used for statistical calculations. Quantitative variables were expressed as a mean and standard deviation. Categorical variables were expressed as numbers and percentage. RESULTS: Analysis of the results of this study identified 23 plants that are used the most. The herbal knowledge herbalists prescribed on the toxicity of plants and their side effects were appreciated. CONCLUSIONS: Preliminary results presented in this work allow knowing the plants used by this population. This data could be the basis for experimental and clinical studies to promote the use of natural agents in the treatment of bad breath. PMID- 28894625 TI - Exploratory studies of some Mexican medicinal plants: Cardiovascular effects in rats with and without hypertension. AB - BACKGROUND: Papaveraceae Argemone mexicana L., Burseraceae Bursera simaruba (L.) Sarg., Acanthaceae Justicia spicigera Schltdl. and Selaginellaceae Selaginella lepidophylla (Hook. & Grev.) Spring., have been used in Mexican traditional medicine to treat hypertension. The objective of this study was to further characterize the cardiovascular effects of the methanol extracts of such plants. METHODS: The medicinal plants were collected and taxonomically identified; the methanol extract of each explored plant were administrated to conscious and unconscious male Wistar rats with and without glucose-induced hypertension. The blood pressure (BP) and heart rate (HR) were evaluated before and after the extract administration. Vascular reactivity experiments were conducted in rat aortic rings obtained from rats with and without sugar-induced hypertension, a model widely used to study such effects with cardiovascular agents. RESULTS: After oral administration in normotensive conscious rats all tested extracts decreased the HR, such effect was only observed in hypertensive conscious rats after the administration of B. simaruba; only A. mexicana and B. simaruba decreased the BP after oral administration. All extracts administrated by intravenous injection diminished the mean arterial pressure. Dose-response curves to cumulative concentrations of all the extracts promote vascular relaxation in precontracted aortas from rats with and without sugar-induced hypertension. CONCLUSIONS: The present study indicated that B. simaruba is worthy of further investigation as a potential phytotherapeutic agent for treating hypertension. PMID- 28894626 TI - Ultraviolet light assisted extraction of flavonoids and allantoin from aqueous and alcoholic extracts of Symphytum officinale. AB - AIM: Symphytum officinale (comfrey) is a medicinal plant commonly used in decoction and to treat ailments. It protects the skin against ultraviolet (UV) irradiation. UV irradiation may induce variable effects on the constituents of herbal extracts and thereby may limit or improve the advantages of using these extracts as medicinal supplements. This study aimed to assess the effect of UV radiations including UV-A, UV-B, and UV-C on the constituents of S. officinale aqueous and alcoholic extracts. MATERIALS AND METHODS: Comfrey extracts (1% w/v) were prepared using distilled water, ethanol, and methanol. They were exposed to wavelengths of UV-A, UV-B, and UV-C for 10 min. The principal peak on the UV spectroscopy scanning, the flavonoids, reducing power, and the allantoin levels were determined before and after irradiation. RESULTS: UV irradiation reduces the magnitude of the principle peak at 355 nm wavelength of the aqueous infusion and methanol extracts. It improves the levels of flavonoids and reducing power of the aqueous extracts and increases the levels of allanotoin in aqueous and methanol extracts. CONCLUSIONS: UV-radiation enhances the yields of active ingredient of comfrey extracted with methanol, whereas improves the flavonoids, reducing power, and allantoin levels of comfrey extracted by the aqueous infusion method. UV radiation reduces the levels of flavonoids, reducing power and allantoin when the comfrey extracted by alcohols. PMID- 28894627 TI - Mangifera indica L. leaf extract alleviates doxorubicin induced cardiac stress. AB - AIM: The study was undertaken to evaluate the cardioprotective effect of the alcoholic leaf extract of Mangifera indica L. against cardiac stress caused by doxorubicin (DOX). MATERIALS AND METHODS: Rats were treated with 100 mg/kg of M. indica leaf extract (MILE) in alone and interactive groups for 21 days. Apart from the normal and MILE control groups, all the groups were subjected to DOX (15 mg/kg, i.p.) toxicity for 21 days and effects of different treatments were analyzed by changes in serum biomarkers, tissue antioxidant levels, electrocardiographic parameters, lipid profile, and histopathological evaluation. RESULTS: The MILE treated group showed decrease in serum biomarker enzyme levels and increase in tissue antioxidants levels. Compared to DOX control group, MILE treated animals showed improvement in lipid profile, electrocardiographic parameters, histological score, and mortality. CONCLUSION: These findings clearly suggest the protective role of alcoholic leaf extract of M. indica against oxidative stress induced by DOX. PMID- 28894628 TI - Tigernut (Cyperus esculentus L.) "milk" as a potent "nutri-drink" for the prevention of acetaminophen-induced hepatotoxicity in a murine model. AB - AIM/BACKGROUND: Given the prevalence of toxicants in foods, beauty products, etc., and the increasing demand for "green" products, there is a need for the development of "nutri-drinks" with hepatoprotective properties. The usefulness of tigernut milk (TNM) in preventing acetaminophen (APAP)-induced liver injury was, therefore, investigated. MATERIALS AND METHODS: A total of 25 rats were randomized into five equal groups. Four groups were treated with 0, 500, 1000, and 2000 kg/mg body weight (bw) TNM, respectively, per os for 2 weeks before they were challenged with 2500 mg/kg bw APAP. Biochemical markers of hepatotoxicity and oxidative stress were determined in the sera of the rats at the end of the study. RESULTS: Serum alanine aminotransferase concentrations decreased significantly (P < 0.001) and dose-dependently from 334.3 +/- 16.1 in the negative control group to 65.4 +/- 8.3 in the 2000 mg/kg bw TNM group. Other studied liver enzymes were similarly dose-dependently reduced. These data are corroborated by histological findings. Superoxide dismutase activity (U/mg protein) was increased significantly (P < 0.001) from 108.0 +/- 7.4 in the negative control group to 291.0 +/- 11.3 in the 2000 mg/kg bw TNM group, and indeed all the test groups. The malondialdehyde concentrations in the test rats were slightly lower than that of the negative control group. CONCLUSION: TNM at the tested concentrations significantly prevented liver injury. Phytochemicals in TNM, working directly as antioxidants or indirectly by inducing the synthesis of glutathione, may be responsible for the observed effect. PMID- 28894630 TI - An ethnobotanical survey of galactogenic plants of the Berhoum District (M'sila, Algeria). AB - BACKGROUND/AIM: This work aimed an ethnobatanical study on the galactogenic plants used in the Berhoum region (East of M'sila, Algeria) as a part of different studies on the medicinal plants related to M'sila region. METHODS: The fieldwork was undertaken as an ethnobotanical survey involving 76 informants (mean age: 50; 64% women, 36% men). Used the medicinal plants were identified, and the results were analyzed according to literature investigation dealing with ethnobotany. Use value (UV), fidelity level, and informant consensus factor (ICF) were used to analyze the obtained data. RESULTS: A total of 29 plant species belonging to 29 genera and 12 families (mainly, Apiaceae and Fabaceae) have been registered. Fruits and seeds were the most commonly used plant parts (80%). The used plants are mainly prepared as an infusion and decoction (69%). Trigonella foenum-graecum L. (UV = 0.58) were the species most commonly used by local healers. The FIC factors ranging from 0.45 to 0.89 for the six uses categories retained for this study. The ICF (0.65) was registered for the use galactogenic category with 29 species. CONCLUSION: This work showed that the population of the Berhoum District uses various medicinal plants for galactogenic purposes. Furthermore, ethnobotanical analysis will provide data on sustainable use and valorization of this plant heritage for ethnopharmacological and phytochemical studies. PMID- 28894629 TI - Isolation, characterization and in silico docking studies of synergistic estrogen receptor a anticancer polyphenols from Syzygium alternifolium (Wt.) Walp. AB - AIM: This study aims to isolate, characterize, and in silico evaluate of anticancer polyphenols from different parts of Syzygium alternifolium. MATERIALS AND METHODS: The polyphenols were isolated by standard protocol and characterized using Fourier-transform infrared (FT-IR), High performance liquid chromatography Photodiode array detector coupled with Electrospray ionization - mass spectrometry (MS/MS). The compounds were elucidated based on retention time and molecular ions (m/z) either by [M+H]+/[M-H]- with the comparison of standard phenols as well as ReSpect software tool. Furthermore, absorption, distribution, metabolism, and excretion (ADME)/toxicity properties of selected phenolic scaffolds were screened using OSIRIS and SwissADME programs, which incorporate toxicity risk assessments, pharmacokinetics, and rule of five principles. Molecular docking studies were carried out for selected toxicity filtered compounds against breast cancer estrogen receptor a (ERa) structure (protein data bank-ID: 1A52) through AutoDock scoring functions by PyRx virtual screening program. RESULTS: The obtained results showed two intensive peaks in each polyphenol fraction analyzed with FT-IR, confirms O-H/C-O stretch of the phenolic functional group. A total of 40 compounds were obtained, which categorized as 9 different classes. Among them, flavonol group represents more number of polyphenols. In silico studies suggest seven compounds have the possibility to use as future nontoxic inhibitors. Molecular docking studies with ERa revealed the lead molecules unequivocally interact with Leu346, Glu353, Leu391, Arg394, Gly521, Leu525 residues, and Phe404 formed atomic pi-stacking with dihydrochromen 4-one ring of ligands as like estrodial, which stabilizes the receptor structure and complicated to generate a single mutation for drug resistance. CONCLUSION: Overall, these results significantly proposed that isolated phenolics could be served as potential ER mitigators for breast cancer therapy. PMID- 28894631 TI - Ethnopharmacological survey on traditional medicinal plants at Kalaroa Upazila, Satkhira District, Khulna Division, Bangladesh. AB - AIM: The traditional source of medicinal plants is an important way for daily curative uses in the rural area throughout Bangladesh. An ethnomedicinal survey was conducted in a randomized manner among traditional medicinal practitioners to find out about the medicinal plants of Kalaroa, Bangladesh. MATERIALS AND METHODS: The information was collected through conducting interviews, discussion, and field observations with herbal healers and knowledgeable elders of the study areas from November 01, 2015, to December 31, 2015, who pointed out various medicinal plants and described their uses, using semi-structured questionnaires. RESULTS: A total of 29 plants distributed into 21 families had found to be used by the 3 Kavirajes interviewed for the treatment of various ailments. 42 different individual sicknesses were claimed to be cured by plants mentioned by the Kavirajes. The Malvaceae family contributed the highest number of plants with four plants, followed by the Amaranthaceae family with three plants, and the Leguminosae and Euphorbiaceae families with two plants each. Leaves were the major plant parts used solely or mixed with other parts forming 33% of total users. This was followed by roots 22%, whole plant 12%, stem and bark, fruit and seeds, and flowers 10% each, and pods, rhizomes, and sap 2% each. Seven plants for skin diseases. Four plants for erectile dysfunction. Cough, diabetes, diarrhea, dysentery, and ulcer were treated by five plants each. Asthma, diuretic, and leukorrhea were treated by three plants each. Hypertension was treated by two plants. CONCLUSION: It is expected that the other plants observed to be used for the treatment of various diseases by the Kavirajes can be subjected to further bioactivity and phytochemical studies, which can lead to the discovery of newer drugs. PMID- 28894632 TI - Dietary incorporation of whey protein isolate and galactooligosaccharides exhibits improvement in glucose homeostasis and insulin resistance in high fat diet fed mice. AB - BACKGROUND: This study was planned to investigate the effectiveness of the whey protein isolate (WPI) of high purity and a galactooligosaccharides (GOS) preparation on glucose homeostasis and insulin resistance in high fat diet (HFD) (45.47% energy from fat) fed conditions in C57BL/6J mice. METHODS: Fasting blood glucose level, serum insulin, and glucagon-like peptide-1 (enzyme-linked immunosorbent assay) were measured; also, homeostasis model assessment of insulin resistance (HOMA-IR) was determined in different treatment groups. mRNA expression of gluconeogenesis genes in liver and small intestine tissues was analyzed by quantitative real time-polymerase chain reaction. RESULTS: Dietary incorporation of WPI and GOS was observed to significantly resist (P < 0.001) the HFD-induced increase in blood glucose levels indicating a mitigating effect on glycemic load. It is important to note that no additive effects of administration of WPI and GOS could be observed. The administration of WPI and GOS exhibited maximum resistance (37.8%) to the rise in insulin level. Thus, the resistance to the increase in HOMA-IR was also noticed on the dietary incorporation of two functional ingredients . The positive effects on mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase could be detected in liver only. CONCLUSION: Both types of functional components exhibit potential to improve glucose homeostasis under HFD fed conditions. Resistance to HFD-induced hyperinsulinemia and HOMA-IR is also recorded . PMID- 28894633 TI - Establishment of Application Guidance for OTC non-Kampo Crude Drug Extract Products in Japan. AB - Currently, there are no standardized regulatory systems for herbal medicinal products worldwide. Communication and sharing of knowledge between different regulatory systems will lead to mutual understanding and might help identify topics which deserve further discussion in the establishment of common standards. Regulatory information on traditional herbal medicinal products in Japan is updated by the establishment of Application Guidance for over-the-counter non Kampo Crude Drug Extract Products. We would like to report on updated regulatory information on the new Application Guidance. Methods for comparison of Crude Drug Extract formulation and standard decoction and criteria for application and the key points to consider for each criterion are indicated in the guidance. Establishment of the guidance contributes to improvements in public health. We hope that the regulatory information about traditional herbal medicinal products in Japan will be of contribution to tackling the challenging task of regulating traditional herbal products worldwide. PMID- 28894634 TI - Grapefruit: Some perspectives in pharmacology and nutrition. PMID- 28894635 TI - Topical Naltrexone Is a Safe and Effective Alternative to Standard Treatment of Diabetic Wounds. AB - Objective: Diabetes affects more than 29 million individuals in the United States, resulting in healthcare costs approaching $245 billion. Approximately 15% of these individuals will develop a chronic, non-healing foot ulcer (diabetic foot ulcer [DFU]) that, if untreated, may lead to amputation. The current treatments for DFU are expensive, have significant side-effects, and often result in non-compliance. A new topical treatment is described that accelerates cutaneous wound repair and is disease modifying by targeting underlying aberrant diabetic pathways. Approach: The efficacy of naltrexone (NTX), an opioid receptor antagonist, and Regranex(r) was compared in preclinical studies using type 1 diabetic rats. Dorsal cutaneous wounds were treated topically with 0.03% NTX, Regranex, or moisturizing cream alone. Wound closure, DNA synthesis, and cytokine production were monitored. Results: Wound closure rates with topical NTX in type 1 diabetic rats were comparable to Regranex. Topical NTX accelerated DNA synthesis, as measured by BrdU incorporation, increased mast cells, and enhanced expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), a marker for angiogenesis. Regranex had little effect on DNA synthesis, mast cells, and VEGF expression relative to vehicle-treated wounds, and it only temporarily increased PDGF expression. Fibroblast growth factor expression was not altered by either treatment. Innovation: Topical application of 0.03% NTX cream accelerates diabetic wound closure. Conclusion: Blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis utilizing 0.03% NTX cream is comparable to standard care in preclinical studies, and it provides a safe, inexpensive, and effective alternative for treatment of diabetic wounds. PMID- 28894636 TI - Fournier's Gangrene: A Review and Outcome Comparison from 2009 to 2016. AB - Objective: The outcome of Fournier's gangrene (FG) may be affected by comorbidities, demographics, and choice of treatment modality. We sought to evaluate our institution's management protocol of FG measured by mortality rate (MR) and length of hospital stay (LHS) in a retrospective cohort study. Approach: A database of 20 FG cases at our institution throughout the 2009-2016 study period was assembled by a retrospective review of medical records. A Fournier's Gangrene Severity Index Score (FGSIS) was calculated for each case. Data were analyzed for statistical significance using logistic regression. Results: The most common presentation of FG at our institution was a hyperglycemic diabetic male in his fifth decade of life with a second risk factor such as recent surgery or active malignancy. The average FGSIS was 9 overall and 14 for the mortalities. An increased FGSIS was predictive of having an increased MR or hospital stay above the median (>25 days) (p = 0.0194). The average LHS was 32 days overall, 22 days for patients treated with hyperbaric oxygen therapy and 40 days for patients treated with tangential hydrosurgery. Overall MR was 15%. Innovation: This is the second known study to characterize usage of tangential hydrosurgery in the management of FG. Conclusion: Treatment outcomes at our institution are comparable to those reported in recent literature, a significant decline from the historical MR of 50-60%. PMID- 28894638 TI - Is there genetic variation in mycorrhization of Medicago truncatula? AB - Differences in the plant's response among ecotypes or accessions are often used to identify molecular markers for the respective process. In order to analyze genetic diversity of Medicago truncatula in respect to interaction with the arbuscular mycorrhizal (AM) fungus Rhizophagus irregularis, mycorrhizal colonization was evaluated in 32 lines of the nested core collection representing the genetic diversity of the SARDI collection. All studied lines and the reference line Jemalong A17 were inoculated with R. irregularis and the mycorrhization rate was determined at three time points after inoculation. There were, however, no reliable and consistent differences in mycorrhization rates among all lines. To circumvent possible overlay of potential differences by use of the highly effective inoculum, native sandy soil was used in an independent experiment. Here, significant differences in mycorrhization rates among few of the lines were detectable, but the overall high variability in the mycorrhization rate hindered clear conclusions. To narrow down the number of lines to be tested in more detail, root system architecture (RSA) of in vitro-grown seedlings of all lines under two different phosphate (Pi) supply condition was determined in terms of primary root length and number of lateral roots. Under high Pi supply (100 uM), only minor differences were observed, whereas in response to Pi-limitation (3 uM) several lines exhibited a drastically changed number of lateral roots. Five lines showing the highest alterations or deviations in RSA were selected and inoculated with R. irregularis using two different Pi-fertilization regimes with either 13 mM or 3 mM Pi. Mycorrhization rate of these lines was checked in detail by molecular markers, such as transcript levels of RiTubulin and MtPT4. Under high phosphate supply, the ecotypes L000368 and L000555 exhibited slightly increased fungal colonization and more functional arbuscules, respectively. To address the question, whether capability for mycorrhizal colonization might be correlated to general invasion by microorganisms, selected lines were checked for infection by the root rot causing pathogen, Aphanoymces euteiches. The mycorrhizal colonization phenotype, however, did not correlate with the resistance phenotype upon infection with two strains of A. euteiches as L000368 showed partial resistance and L000555 exhibited high susceptibility as determined by quantification of A. euteiches rRNA within infected roots. Although there is genetic diversity in respect to pathogen infection, genetic diversity in mycorrhizal colonization of M. truncatula is rather low and it will be rather difficult to use it as a trait to access genetic markers. PMID- 28894637 TI - Epidermal Stem Cells in Skin Wound Healing. AB - Significance: Skin serves as a protective barrier for mammals. Epidermal stem cells are responsible for maintaining skin homeostasis. When cutaneous injuries occur, skin homeostasis and integrity are damaged, leading to dire consequences such as acute, chronic, or infected wounds. Skin wound healing is an intrinsic self-saving chain reaction, which is crucial to facilitating the replacement of damaged or lost tissue. Recent Advances: An immense amount of research has uncovered the underlying mechanisms behind the complex and highly regulated wound healing process. In this review, we will dissect the biological process of adult skin wound healing and emphasize the importance of epidermal stem cells during the wound healing. Critical Issues: We will comprehensively discuss the current clinical practices used on patients with cutaneous wounds, including both traditional skin grafting procedures and advanced grafting techniques with cultured skin stem cells. The majority of these leading techniques still retain some deficiencies during clinical use. Moreover, the regeneration of skin appendages after severe injuries remains a challenge in treatment. Future Directions: Understanding epidermal stem cells and their essential functions during skin wound healing are fundamental components behind the development of clinical treatment on patients with cutaneous wounds. It is important to improve the current standard of care and to develop novel techniques improving patient outcomes and long-term rehabilitation, which should be the goals of future endeavors in the field of skin wound healing. PMID- 28894639 TI - Fungi found in Mediterranean and North Sea sponges: how specific are they? AB - Fungi and other eukaryotes represent one of the last frontiers of microbial diversity in the sponge holobiont. In this study we employed pyrosequencing of 18S ribosomal RNA gene amplicons containing the V7 and V8 hypervariable regions to explore the fungal diversity of seven sponge species from the North Sea and the Mediterranean Sea. For most sponges, fungi were present at a low relative abundance averaging 0.75% of the 18S rRNA gene reads. In total, 44 fungal OTUs (operational taxonomic units) were detected in sponges, and 28 of these OTUs were also found in seawater. Twenty-two of the sponge-associated OTUs were identified as yeasts (mainly Malasseziales), representing 84% of the fungal reads. Several OTUs were related to fungal sequences previously retrieved from other sponges, but all OTUs were also related to fungi from other biological sources, such as seawater, sediments, lakes and anaerobic digesters. Therefore our data, supported by currently available data, point in the direction of mostly accidental presence of fungi in sponges and do not support the existence of a sponge-specific fungal community. PMID- 28894640 TI - Coral larvae for restoration and research: a large-scale method for rearing Acropora millepora larvae, inducing settlement, and establishing symbiosis. AB - Here we describe an efficient and effective technique for rearing sexually derived coral propagules from spawning through larval settlement and symbiont uptake with minimal impact on natural coral populations. We sought to maximize larval survival while minimizing expense and daily husbandry maintenance by experimentally determining optimized conditions and protocols for gamete fertilization, larval cultivation, induction of larval settlement by crustose coralline algae, and inoculation of newly settled juveniles with their dinoflagellate symbiont Symbiodinium. Larval rearing densities at or below 0.2 larvae mL-1 were found to maximize larval survival and settlement success in culture tanks while minimizing maintenance effort. Induction of larval settlement via the addition of a ground mixture of diverse crustose coralline algae (CCA) is recommended, given the challenging nature of in situ CCA identification and our finding that non settlement-inducing CCA assemblages do not inhibit larval settlement if suitable assemblages are present. Although order of magnitude differences in infectivity were found between common Great Barrier Reef Symbiodinium clades C and D, no significant differences in Symbiodinium uptake were observed between laboratory-cultured and wild-harvested symbionts in each case. The technique presented here for Acropora millepora can be adapted for research and restoration efforts in a wide range of broadcast spawning coral species. PMID- 28894641 TI - Laboratory evaluation of different formulations of Stress Coat(r) for slime production in goldfish (Carassius auratus) and koi (Cyprinus carpio). AB - A study was carried out to assess the effect of Stress Coat(r) on slime production in goldfish (Carassius auratus) and koi (Cyprinus carpio). The study also investigated histological changes that might be associated with slime producing cells, and wound healing in koi. Several formulations of Stress Coat(r) were investigated and the results showed that polyvinylpyrrolidone (PVP), also known as povidone, an ingredient of Stress Coat(r), when used alone, showed significantly higher slime production in goldfish than salt and Stress Coat(r) without PVP after 25 h. The results also showed that koi treated with compounds containing PVP showed better wound healing than those not exposed to PVP. Histology results showed no difference between compounds tested with regards to density and number of slime producing cells. PMID- 28894642 TI - Contrast based circular approximation for accurate and robust optic disc segmentation in retinal images. AB - A new method for automatic optic disc localization and segmentation is presented. The localization procedure combines vascular and brightness information to provide the best estimate of the optic disc center which is the starting point for the segmentation algorithm. A detection rate of 99.58% and 100% was achieved for the Messidor and ONHSD databases, respectively. A simple circular approximation to the optic disc boundary is proposed based on the maximum average contrast between the inner and outer ring of a circle centered on the estimated location. An average overlap coefficient of 0.890 and 0.865 was achieved for the same datasets, outperforming other state of the art methods. The results obtained confirm the advantages of using a simple circular model under non-ideal conditions as opposed to more complex deformable models. PMID- 28894643 TI - Status of gastrointestinal parasites in Red Panda of Nepal. AB - Red pandas are known to be highly susceptible to endoparasites, which can have a prominent impact on the population dynamics of this endangered species. There are very limited published reports on prevalence and risk of parasites in wild populations of red panda, especially localized reports. This study attempts to provide an in-depth insight of the status of endoparasites in red pandas, which is critical for strengthening conservation efforts. A total of 272 fecal samples were collected through systematic sampling across the red panda distribution range in Nepal and coprological examination was completed using standard techniques. It was followed by an estimation of prevalence and mean intensity of parasites, as well as statistical analysis, which was carried out using R statistical software. Parasite prevalence was documented in 90.80% (n = 247) out of 272 samples examined which includes seven different species along with three genera of parasites belonging to Protozoans (3 species), Cestodes (1 genus, 1 species) and Nematodes (2 genera, 3 species). Nematodes predominated in all infected samples (87.62%). Prevalence of Ancyclostoma duodenale (n = 227, 70.06%), having a mean intensity of 3.45 +/- 2.88 individuals per sample, was observed, followed by Ascaris lumbricoides (n = 19, 5.86%) and Entamoeba histolytica (n = 24, 7.41%). Eight variables for assessing the determinants of infestation were tested: protected areas; non-protected areas; aspect; elevation; slope; and distance to water sources, herding stations, and settlements. Only the settlement displayed significant association (beta = -1534e-04, t = - 2.192, p = 0.0293) though each parasite species displayed dissimilar association with different variables. This study indicates the urgent need of improving existing herding practice through habitat zonation, rotational grazing, medication of livestock, and prohibition of open defecation within and around red panda habitat. PMID- 28894644 TI - Anthropometric, physical function and general health markers of Masters athletes: a cross-sectional study. AB - Once the general decline in muscle mass, muscle strength and physical performance falls below specific thresholds, the middle aged or older adult will be diagnosed as having sarcopenia (a loss of skeletal muscle mass and strength). Sarcopenia contributes to a range of adverse events in older age including disability, hospitalisation, institutionalisation and falls. One potentially relevant but understudied population for sarcopenia researchers would be Masters athletes. Masters sport is becoming more common as it allows athletes (typically 40 years and older) the opportunity to participate in individual and/or team sports against individuals of similar age. This study examined a variety of measures of anthropometric, physical function and general health markers in the male and female Masters athletes who competed at the 2014 Pan Pacific Masters Games held on the Gold Coast, Australia. Bioelectrical impedance analysis was used to collect body fat percentage, fat mass and fat-free mass; with body mass, height, body mass index (BMI) and sarcopenic status also recorded. Physical function was quantified by handgrip strength and habitual walking speed; with general health described by the number of chronic diseases and prescribed medications. Between group analyses utilised ANOVA and Tukey's post-hoc tests to examine the effect of age group (40-49, 50-59, 60-69 and >70 years old) on the outcome measures for the entire sample as well as the male and female sub-groups. A total of 156 athletes (78 male, 78 female; mean 55.7 years) provided informed consent to participate in this study. These athletes possessed substantially better anthropometric, physical function and general health characteristics than the literature for their less physically active age-matched peers. No Masters athletes were categorised as being sarcopenic, although one participant had below normal physical performance and six participants had below normal muscle strength. In contrast, significant age-related reductions in handgrip strength and increases in the number of chronic diseases and prescribed medications were observed for the overall cohort as well as the male and female sub-groups. Nevertheless, even those aged over 70 years only averaged one chronic disease and one prescribed medication. These results may suggest that participation in Masters sport helps to maintain anthropometry, physical function and general health in middle-aged and older adults. However, it is also possible that only healthier middle-aged and older adults with favourable body composition and physical function may be able to participate in Masters sport. Future research should therefore utilise longitudinal research designs to determine the health and functional benefits of Master sports participation for middle-aged and older adults. PMID- 28894645 TI - Re-examination of the contribution of substrates to energy expenditure during high-intensity intermittent exercise in endurance athletes. AB - BACKGROUND: It has been believed that the contribution of fat oxidation to total energy expenditure is becoming negligible at higher exercise intensities (about 85% VO2max). The aim of the present study was to examine the changes in substrate oxidation during high-intensity interval exercise in young adult men. METHODS: A total of 18 healthy well-trained (aged 19.60 +/- 0.54 years, BMI = 22.19 +/- 0.64 kg/m2, n = 10) and untrained (aged 20.25 +/- 0.41 years, BMI = 22.78 +/- 0.38 kg/m2, n = 8) young men volunteered to participate in this study. After an overnight fast, subjects were tested on a cycle ergometer and completed six 4-min bouts of cycling (at ~80% VO2max) with 2 min of rests between intervals. Energy expenditure and the substrate oxidation rate were measured during the experiment by using indirect calorimetry. The blood lactate concentration was collected immediately after each interval workout. RESULTS: The fat oxidation rate during each workout was significantly different between the untrained and the athlete groups (p < 0.05), and the carbohydrate (CHO) oxidation rate during the experiment was similar between groups (p > 0.05). Moreover, lactate concentration significantly increased in the untrained group (p < 0.05), whereas it did not significantly change in the athlete group during the workouts (p > 0.05). Fat contribution to energy expenditure was significantly higher in the athlete group (~25%) than in the untrained group (~2%). CONCLUSIONS: The present study indicates that 17 times more fat oxidation was measured in the athlete group compared to the untrained group. However, the athletes had the same CHO oxidation rate as the recreationally active subjects during high-intensity intermittent exercise. Higher fat oxidation rate despite the same CHO oxidation rate may be related to higher performance in the trained group. PMID- 28894646 TI - Canopy soil bacterial communities altered by severing host tree limbs. AB - Trees of temperate rainforests host a large biomass of epiphytic plants, which are associated with soils formed in the forest canopy. Falling of epiphytic material results in the transfer of carbon and nutrients from the canopy to the forest floor. This study provides the first characterization of bacterial communities in canopy soils enabled by high-depth environmental sequencing of 16S rRNA genes. Canopy soil included many of the same major taxonomic groups of Bacteria that are also found in ground soil, but canopy bacterial communities were lower in diversity and contained different operational taxonomic units. A field experiment was conducted with epiphytic material from six Acer macrophyllum trees in Olympic National Park, Washington, USA to document changes in the bacterial communities of soils associated with epiphytic material that falls to the forest floor. Bacterial diversity and composition of canopy soil was highly similar, but not identical, to adjacent ground soil two years after transfer to the forest floor, indicating that canopy bacteria are almost, but not completely, replaced by ground soil bacteria. Furthermore, soil associated with epiphytic material on branches that were severed from the host tree and suspended in the canopy contained altered bacterial communities that were distinct from those in canopy material moved to the forest floor. Therefore, the unique nature of canopy soil bacteria is determined in part by the host tree and not only by the physical environmental conditions associated with the canopy. Connection to the living tree appears to be a key feature of the canopy habitat. These results represent an initial survey of bacterial diversity of the canopy and provide a foundation upon which future studies can more fully investigate the ecological and evolutionary dynamics of these communities. PMID- 28894647 TI - Divergence of compost extract and bio-organic manure effects on lucerne plant and soil. AB - AIM: Application of organic materials into agricultural systems enhances plant growth and yields, and improves soil fertility and structure. This study aimed to examine the effects of "compost extract (CE)", a soil conditioner, and bio organic manure (BOM) on the growth of lucerne (Medicago sativa), and compare the efficiency between BOM (including numbers of microorganisms) and CE (including no added microorganisms). METHOD: A greenhouse experiment was conducted with four soil amendment treatments (control, BOM, CE and CEBOM), and was arranged in a completely randomized design with 10 replicates for each treatment. Plant biomass, nutritive value and rhizobia efficacy as well as soil characteristics were monitored. RESULT: CE rather than BOM application showed a positive effect on plant growth and soil properties when compared with the control. Lucerne nodulation responded equally to CE addition and rhizobium inoculation. CE alone and in combination with BOM significantly increased plant growth and soil microbial activities and improved soil structure. The synergistic effects of CE and BOM indicate that applying CE and BOM together could increase their efficiency, leading to higher economic returns and improved soil health. However, CE alone is more effective for legume growth since nodulation was suppressed by nitrogen input from BOM. CE had a higher efficiency than BOM for enriching soil indigenous microorganisms instead of adding microorganisms and favouring plant nodulation. PMID- 28894648 TI - Impact of litter quantity on the soil bacteria community during the decomposition of Quercus wutaishanica litter. AB - The forest ecosystem is the main component of terrestrial ecosystems. The global climate and the functions and processes of soil microbes in the ecosystem are all influenced by litter decomposition. The effects of litter decomposition on the abundance of soil microorganisms remain unknown. Here, we analyzed soil bacterial communities during the litter decomposition process in an incubation experiment under treatment with different litter quantities based on annual litterfall data (normal quantity, 200 g/(m2/yr); double quantity, 400 g/(m2/yr) and control, no litter). The results showed that litter quantity had significant effects on soil carbon fractions, nitrogen fractions, and bacterial community compositions, but significant differences were not found in the soil bacterial diversity. The normal litter quantity enhanced the relative abundance of Actinobacteria and Firmicutes and reduced the relative abundance of Bacteroidetes, Plantctomycets and Nitrospiare. The Beta-, Gamma-, and Deltaproteobacteria were significantly less abundant in the normal quantity litter addition treatment, and were subsequently more abundant in the double quantity litter addition treatment. The bacterial communities transitioned from Proteobacteria-dominant (Beta-, Gamma-, and Delta) to Actinobacteria-dominant during the decomposition of the normal quantity of litter. A cluster analysis showed that the double litter treatment and the control had similar bacterial community compositions. These results suggested that the double quantity litter limited the shift of the soil bacterial community. Our results indicate that litter decomposition alters bacterial dynamics under the accumulation of litter during the vegetation restoration process, which provides important significant guidelines for the management of forest ecosystems. PMID- 28894649 TI - Particle bombardment and subcellular protein localization analysis in the aquatic plant Egeria densa. AB - Particle bombardment is a powerful and relatively easy method for transient expression of genes of interest in plant cells, especially those that are recalcitrant to other transformation methods. This method has facilitated numerous analyses of subcellular localization of fluorescent fusion protein constructs. Particle bombardment delivers genes to the first layer of plant tissue. In leaves of higher plants, epidermal cells are the first cell layer. Many studies have used the epidermal cell layer of onion bulb (Allium cepa) as the experimental tissue, because these cells are relatively large. However, onion epidermal cells lack developed plastids (i.e., chloroplasts), thereby precluding subcellular localization analysis of chloroplastic proteins. In this study, we developed a protocol for particle bombardment of the aquatic plant Egeria densa, and showed that it is a useful system for subcellular localization analysis of higher plant proteins. E. densa leaflets contain only two cell layers, and cells in the adaxial layer are sufficiently large for observation. The cells in both layers contain well-developed chloroplasts. We fused fluorescent proteins to conventional plant localization signals for the nucleus, cytosol, mitochondria, peroxisome, and chloroplast, and used particle bombardment to transiently express these fusion constructs in E. densa leaves. The plant subcellular localization signals functioned normally and displayed the expected distributions in transiently transformed E. densa cells, and even chloroplastic structures could be clearly visualized. PMID- 28894651 TI - MetaCRAST: reference-guided extraction of CRISPR spacers from unassembled metagenomes. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) systems are the adaptive immune systems of bacteria and archaea against viral infection. While CRISPRs have been exploited as a tool for genetic engineering, their spacer sequences can also provide valuable insights into microbial ecology by linking environmental viruses to their microbial hosts. Despite this importance, metagenomic CRISPR detection remains a major challenge. Here we present a reference-guided CRISPR spacer detection tool (Metagenomic CRISPR Reference-Aided Search Tool-MetaCRAST) that constrains searches based on user-specified direct repeats (DRs). These DRs could be expected from assembly or taxonomic profiles of metagenomes. We compared the performance of MetaCRAST to those of two existing metagenomic CRISPR detection tools-Crass and MinCED-using both real and simulated acid mine drainage (AMD) and enhanced biological phosphorus removal (EBPR) metagenomes. Our evaluation shows MetaCRAST improves CRISPR spacer detection in real metagenomes compared to the de novo CRISPR detection methods Crass and MinCED. Evaluation on simulated metagenomes show it performs better than de novo tools for Illumina metagenomes and comparably for 454 metagenomes. It also has comparable performance dependence on read length and community composition, run time, and accuracy to these tools. MetaCRAST is implemented in Perl, parallelizable through the Many Core Engine (MCE), and takes metagenomic sequence reads and direct repeat queries (FASTA or FASTQ) as input. It is freely available for download at https://github.com/molleraj/MetaCRAST. PMID- 28894652 TI - Double-Pedicled Free Deep Inferior Epigastric Perforator Flap for the Coverage of Thigh Soft-Tissue Defect. AB - Soft-tissue defects caused by radiation injury are a challenging task for the reconstructive surgeon, due to the extent of the soft-tissue damage and the associated injuries of the local blood vessels and bone tissue. We present the application of the versatile deep inferior epigastric perforator (DIEP) flap for the coverage of an extended lateral thigh soft-tissue defect after the surgical resection of an undifferentiated pleomorphic high-grade sarcoma, neoadjuvant chemotherapy, and adjuvant chemo- and radiotherapy. A double-pedicled free DIEP flap (756 cm2) was harvested and anastomosed to the transverse branch of the lateral femoral circumflex artery and a lateral branch of the popliteal artery (P1). The flap survived completely without serious complications, and the patient was able to walk with crutches 3 months postoperatively. This is the first case report of a free bipedicled DIEP flap for the coverage of a thigh defect in a male patient. PMID- 28894650 TI - Lectins: an effective tool for screening of potential cancer biomarkers. AB - In recent years, the use of lectins for screening of potential biomarkers has gained increased importance in cancer research, given the development in glycobiology that highlights altered structural changes of glycans in cancer associated processes. Lectins, having the properties of recognizing specific carbohydrate moieties of glycoconjugates, have become an effective tool for detection of new cancer biomarkers in complex bodily fluids and tissues. The specificity of lectins provides an added advantage of selecting peptides that are differently glycosylated and aberrantly expressed in cancer patients, many of which are not possibly detected using conventional methods because of their low abundance in bodily fluids. When coupled with mass spectrometry, research utilizing lectins, which are mainly from plants and fungi, has led to identification of numerous potential cancer biomarkers that may be used in the future. This article reviews lectin-based methods that are commonly adopted in cancer biomarker discovery research. PMID- 28894653 TI - A Proposal for Updated Standards of Photographic Documentation in Aesthetic Medicine. AB - In 1998, DiBernardo et al. published a very helpful standardization of comparative (before and after) photographic documentation. These standards prevail to this day. Although most of them are useful for objective documentation of aesthetic results, there are at least 3 reasons why an update is necessary at this time: First, DiBernardo et al. focused on the prevalent standards of medical photography at that time. From a modern perspective, these standards are antiquated and not always correct. Second, silver-based analog photography has mutated into digital photography. Digitalization offers virtually unlimited potential for image manipulation using a vast array of digital Apps and tools including, but not limited to, image editing software like Photoshop. Digitalization has given rise to new questions, particularly regarding appropriate use of editing techniques to maximize or increase objectivity. Third, we suggest changes to a very small number of their medical standards in the interest of obtaining a better or more objective documentation of aesthetic results. This article is structured into 3 sections and is intended as a new proposal for photographic and medical standards for the documentation of aesthetic interventions: 1. The photographic standards. 2. The medical standards. 3. Description of editing tools which should be used to increase objectivity. PMID- 28894654 TI - Evaluation of a Novel Hybrid Viable Bioprosthetic Mesh in a Model of Mesh Infection. AB - BACKGROUND: The reported incidence of mesh infection in contaminated operative fields is as high as 30% regardless of material used. Our laboratory previously showed that augmenting acellular bioprosthetic mesh with allogeneic mesenchymal stem cells (MSC) enhances resistance to bacterial colonization in vivo and preserves mesh integrity. This study's aim was to determine whether augmentation of non-crosslinked porcine dermis (Strattice) with commercially available, cryopreserved, viable MSC-containing human placental tissue (Stravix) similarly improves infection resistance after inoculation with Escherichia coli (E. coli) using an established mesh infection model. METHODS: Stravix was thawed per manufacturer's instructions and 2 samples were tested for cell viability using a Live/Dead Cell assay at the time of surgery. Rats (N = 20) were implanted subcutaneously with 1 piece of Strattice and 1 piece of hybrid mesh (Strattice + Stravix sutured at the corners). Rats were inoculated with either sterile saline or 106 colony-forming units of E. coli before wound closure (n = 10 per group). At 4 weeks, explants underwent microbiologic and histologic analyses. RESULTS: In E. coli-inoculated animals, severe or complete mesh degradation concurrent with abscess formation was observed in 100% (10/10) hybrid meshes and 90% (9/10) Strattice meshes. Histologic evaluation determined that meshes inoculated with E. coli exhibited severe acute inflammation, which correlated with bacterial recovery (P < 0.001). Viability assays performed at the time of surgery failed to verify the presence of numerous live cells in Stravix. CONCLUSIONS: Stravix cryopreserved MSC-containing human umbilical tissue does not improve infection resistance of a bioprosthetic mesh in vivo in rats after inoculation with E. coli. PMID- 28894655 TI - Intraoperative Evaluation of Body Surface Improvement by an Augmented Reality System That a Clinician Can Modify. AB - BACKGROUND: Augmented reality (AR) technology that can combine computer-generated images with a real scene has been reported in the medical field recently. We devised the AR system for evaluation of improvements of the body surface, which is important for plastic surgery. METHODS: We constructed an AR system that is easy to modify by combining existing devices and free software. We superimposed the 3-dimensional images of the body surface and the bone (obtained from VECTRA H1 and CT) onto the actual surgical field by Moverio BT-200 smart glasses and evaluated improvements of the body surface in 8 cases. RESULTS: In all cases, the 3D image was successfully projected on the surgical field. Improvement of the display method of the 3D image made it easier to distinguish the different shapes in the 3D image and surgical field, making comparison easier. In a patient with fibrous dysplasia, the symmetrized body surface image was useful for confirming improvement of the real body surface. In a patient with complex facial fracture, the simulated bone image was useful as a reference for reduction. In a patient with an osteoma of the forehead, simultaneously displayed images of the body surface and the bone made it easier to understand these positional relationships. CONCLUSIONS: This study confirmed that AR technology is helpful for evaluation of the body surface in several clinical applications. Our findings are not only useful for body surface evaluation but also for effective utilization of AR technology in the field of plastic surgery. PMID- 28894656 TI - Wide Awake Trapeziectomy for Thumb Basal Joint Arthritis. AB - Supplemental Digital Content is available in the text. PMID- 28894657 TI - Optimization of an Arterialized Venous Fasciocutaneous Flap in the Abdomen of the Rat. AB - BACKGROUND: Although numerous experimental models of arterialized venous flaps (AVFs) have been proposed, no single model has gained widespread acceptance. The main aim of this work was to evaluate the survival area of AVFs produced with different vascular constructs in the abdomen of the rat. METHODS: Fifty-three male rats were divided into 4 groups. In group I (n = 12), a 5-cm-long and 3-cm wide conventional epigastric flap was raised on the left side of the abdomen. This flap was pedicled on the superficial caudal epigastric vessels caudally and on the lateral thoracic vein cranially. In groups II, III, and IV, a similar flap was raised, but the superficial epigastric artery was ligated. In these groups, AVFs were created using the following arterial venous anastomosis at the caudal end of the flap: group II (n = 13) a 1-mm-long side-to-side anastomosis was performed between the femoral artery and vein laterally to the ending of the superficial caudal epigastric vein. In group III (n = 14), in addition to the procedure described for group II, the femoral vein was ligated medially. Finally, in group IV (n = 14), the superficial caudal epigastric vein was cut from the femoral vein with a 1-mm-long ellipse of adjacent tissue, and an end-to-side arterial venous anastomosis was established between it and the femoral artery. RESULTS: Seven days postoperatively, the percentage of flap survival was 98.89 +/ 1.69, 68.84 +/- 7.36, 63.84 +/- 10.38, 76.86 +/- 13.67 in groups I-IV, respectively. CONCLUSION: An optimized AVF can be produced using the vascular architecture described for group IV. PMID- 28894658 TI - Prioritization for Plastic Surgery Procedures Aimed to Improve Quality of Life: Moral Considerations. AB - BACKGROUND: Different health conditions are treated in a Plastic Surgery unit, including those cases whose main goal is to enable patients to feel and integrate better within society and therefore improving quality of life, rather then physical functions. METHODS: We discuss moral principles that can be used as a guide for health professionals to revise and create policies for plastic surgery patients presenting with non-life-threatening conditions. RESULTS: A specific anatomical feature is not always an indicator of patient's well-being and quality of life, and therefore it cannot be used as the sole parameter to identify the worst-off and prioritize the provision of health care. A policy should identify who preoperatively are the worst-off and come to some plausible measure of how much they can be expected to benefit from an operation. Policies that do not track these principles in any reliable way can cause discrimination. CONCLUSIONS: A patient-centered operating system and patient's informed preferences might be implemented in the process of prioritizing health. In circumstances when the effectiveness of a specific treatment is unproven, professionals should not make assumptions based on their own values. PMID- 28894659 TI - Prevention of Mandible Reconstruction Plate Exposure by Costal Cartilage Wrapping. AB - After mandibulectomy in cancer surgery, reconstruction is often performed with a reconstruction plate covered with a soft-tissue free flap in patients in poor condition. However, the rate of complications for mandibular reconstruction is higher with a reconstruction plate than with vascularized bone grafts. We have developed a costal cartilage wrapping method to prevent exposure of the mandible reconstruction plate. The eighth costal cartilage was removed and split into 2 pieces to wrap around the reconstruction plate. In our case, the artificial plate wrapped with costal cartilage graft was not exposed and the skin over the plate did not become atrophic over 27 months follow-up even after irradiation. Wrapping around an artificial reconstruction plate with autologous costal cartilage grafts may be more effective than using only a flap covering to prevent exposure of the plate after tumor ablation and radiation therapy. PMID- 28894660 TI - Mastectomy Flap Thickness and Complications in Nipple-Sparing Mastectomy: Objective Evaluation using Magnetic Resonance Imaging. AB - BACKGROUND: Ischemic complications after nipple-sparing mastectomy (NSM) have been associated with numerous variables. However, the impact of NSM flap thickness has been incompletely evaluated. METHODS: NSM flap thickness was determined for all NSMs from 2006 to 2016 with available pre- or postoperative breast magnetic resonance imaging (MRIs). Demographics and outcomes were stratified by those with and without ischemic complications. RESULTS: Of 1,037 NSM reconstructions, 420 NSMs had MRI data available, which included 379 preoperative MRIs and 60 postoperative MRIs. Average total preoperative skin/subcutaneous tissue NSM flap thickness was 11.4 mm. Average total postoperative NSM flap thickness was 8.7 mm. NSMs with ischemic complications were found to have significantly thinner overall postoperative NSM flap thickness compared with those without ischemic complications (P = 0.0280). Average overall postoperative NSM flap thickness less than 8.0 mm was found to be an independent predictor of ischemic complications (odds ratio, 6.5263; P = 0.026). In NSMs with both pre- and postoperative MRIs, the overall average postoperative NSM flap thickness was 68.2% of preoperative measurements. Average overall postoperative NSM flap thickness was significantly less than average overall preoperative NSM flap thickness (P < 0.0001). NSMs with ischemic complications were found to have a significantly lower ratio of overall postoperative to preoperative flap thickness (52.0% versus 74.0%; P < 0.0001). CONCLUSIONS: Ischemic complications after NSM are significantly associated with thinner postoperative NSM flap thickness. Particularly, NSM flap thickness less than 8.0 mm is a positive independent predictor of ischemic complications. The ratio of postoperative to preoperative NSM flap thickness was significantly lower in reconstructions with ischemic complications. PMID- 28894661 TI - Patient-Reported Disability Measures Do Not Correlate with Electrodiagnostic Severity in Carpal Tunnel Syndrome. AB - BACKGROUND: Electrophysiologic studies including electromyography and nerve conduction studies play a role in the evaluation of carpal tunnel syndrome (CTS), despite evidence that these studies do not correlate with CTS-specific symptom scores. There is a lack of evidence comparing electrophysiologic data with general measures of function. METHODS: Fifty patients presenting for CTS treatment over an 8-month period were analyzed retrospectively. All patients completed surveys including the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) and the Medical Outcomes Study 12-Item Short-Form Survey [(physical component summary 12, mental component summary (MCS-12)]. Electromyography and nerve conduction studies were performed on all patients and compared with outcome scores. RESULTS: Analysis demonstrated no relationship between DASH or MCS-12 and electrodiagnostic severity. No significant correlations were noted between DASH or MCS-12 and median motor or sensory latency. There was a moderate-weak correlation (rho = 0.34) between more severe electrophysiologic grade and better function based on physical component summary 12. CONCLUSIONS: Electrodiagnostic severity grades do not correlate with patient reported disability, including the DASH and MCS-12 surveys. There is a counterintuitive correlation between more-severe electrodiagnostic findings and decreased physical disability. These findings indicate that disability may not correlate with electrodiagnostic severity of median neuropathy in CTS. PMID- 28894662 TI - Acellular Dermal Matrix: Treating Periocular Melanoma in a Patient with Xeroderma Pigmentosa. AB - We report a 7-year-old girl with xeroderma pigmentosum (XP), who presented in our clinic with a large melanoma (35 * 50 * 20 mm, Breslow depth 18 mm) in the zygomatic-malar area. Palliative surgery was performed to maintain her residual vision and to reduce the pain caused by the compression of local structures. Because of the limited access of autologous skin grafts in pediatric patients with XP who are severely affected, we opted to use an acellular dermal matrix. There was 100% graft uptake, and the pain due to compression by the tumor was alleviated. This case demonstrates that acellular dermal matrices can be safely and effectively used in oncological facial reconstruction, especially in patients with progressive conditions such as XP. PMID- 28894663 TI - Deltopectoral and Pectoralis Musculocutaneous Flap Technique for Cervical Esophageal Reconstruction after Free-Jejunal-Flap Necrosis. AB - BACKGROUND: Free jejunal transfer has a high success rate, but if vascular thrombosis occurs, the salvage of failing flap with reanastomosis is difficult. This study described a combined deltopectoral (DP) and pectoralis major musculocutaneous (PMMC) flap 2-step technique for cervical esophageal reconstruction after free-jejunal-flap necrosis. METHODS: In step 1, the detection of free jejunal flap with the subsequent debridement of necrotic and infected tissue was followed by the construction of external fistula on the pharyngeal side with the hole in cervical skin and the construction of another external fistula on the esophageal side and tracheal stoma with a single or double DP flap. In step 2, after the primary healing of all wounds was confirmed, a wide hinge flap was elevated for reconstructing the posterior wall or full circumferential defect of cervical esophagus. PMMC flap harvested from either the left or right anterior chest wall was used for reconstructing the cervical surface defect or anterior pharyngeal wall. RESULTS: This technique was used for cervical esophageal reconstruction after free-jejunal-flap necrosis in 5 patients. Step 1 surgery was performed at an average of 10 days after primary free-jejunal flap transfer. Oral intake was resumed in all cases at an average of 117 days after step 2 surgery. No complications including esophageal stricture were found during a 6-month follow-up period. CONCLUSIONS: Combined DP and PMMC flap technique was useful for cervical esophageal reconstruction after free jejunal-flap necrosis and applicable to patients with the late detection of jejunal necrosis and surgical-site infection. PMID- 28894664 TI - Aesthetic Female-to-Male Chest Transformation: Power of Combining Modified Mastectomy with a Pectoral Implant. AB - Gender reassignment surgery has gained in popularity with increased media exposure and society's recognition of gender dysphoria. Female-to-male gender reassignment often begins with the "top" or chest surgery. Mastectomy with free nipple grafting is the most frequently described technique in the literature. This technique is reliable yet lacks the ability to provide a true male chest shape. We discuss our technique for female-to-male "top" surgery combining traditional mastectomy techniques with a lower pole pedicle vascularized areola and a pectoral implant. A 32-year-old African American female with bilateral C cup breast with grade 2/3 ptosis presented for "top" surgery. Intraoperatively, the nipple areola complex was maintained on a lower pole pedicle at a thickness of 1.5 cm to maintain neurovascularity. A superior mastectomy flap was raised at the level of the breast capsule and remaining breast tissue excised. A lateral subpectoral pocket was created for insertion of a silicone pectoral implant. The new nipple position matured in the infero-lateral quadrant of greatest projecting portion of the chest. Lower pole pedicle provided vascularity to the areola, which avoids the need for a free nipple graft and potential hypopigmentation. Pectoral silicone implant provided upper pole fullness to mimic the male chest muscular distribution. Modification of mastectomy-based female-to-male gender reassignment surgery with a lower pole pedicle-based areola and pectoral implant provides an aesthetic improvement over the classic mastectomy with free nipple graft technique. PMID- 28894665 TI - Late Arterial Thrombosis after Microvascular Head and Neck Reconstruction due to Combined Factors of Pedicle Artery Loop and Submandibular Gland Swelling. AB - Late arterial thrombosis of a free flap is rare and usually unsalvageable because it is hard to detect. We herein report 2 cases of arterial thrombosis of a free flap after microvascular head and neck reconstruction due to the combined factors of pedicle artery loop and compression by a swollen submandibular gland, the occurrence of thrombosis in both of which was > 72 hours after the operation. In case 1, the arterial thrombosis was undetectable, and it was too late for a successful take-back operation, so the flap was lost. However, we applied the lessons learned from case 1 and were able to detect the late arterial thrombosis of case 2 at an early stage; we subsequently salvaged the flap successfully. During the take-back operation in both cases, it was found that the submandibular gland became swollen and compressed the pedicle artery, which then became occluded due to a steep loop formation. Postoperative swelling of the submandibular gland can sometimes compress the vascular pedicle, and complete occlusion of the pedicle artery may occur when it is looped. Meticulous care concerning the geometry of the vascular pedicle is required to avoid such complications. PMID- 28894666 TI - Optimizing Aesthetic Outcomes in Delayed Breast Reconstruction. AB - BACKGROUND: The need to restore both the missing breast volume and breast surface area makes achieving excellent aesthetic outcomes in delayed breast reconstruction especially challenging. Autologous breast reconstruction can be used to achieve both goals. The aim of this study was to identify surgical maneuvers that can optimize aesthetic outcomes in delayed breast reconstruction. METHODS: This is a retrospective review of operative and clinical records of all patients who underwent unilateral or bilateral delayed breast reconstruction with autologous tissue between April 2014 and January 2017. Three groups of delayed breast reconstruction patients were identified based on patient characteristics. RESULTS: A total of 26 flaps were successfully performed in 17 patients. Key surgical maneuvers for achieving aesthetically optimal results were identified. A statistically significant difference for volume requirements was identified in cases where a delayed breast reconstruction and a contralateral immediate breast reconstruction were performed simultaneously. CONCLUSIONS: Optimal aesthetic results can be achieved with: (1) restoration of breast skin envelope with tissue expansion when possible, (2) optimal positioning of a small skin paddle to be later incorporated entirely into a nipple areola reconstruction when adequate breast skin surface area is present, (3) limiting the reconstructed breast mound to 2 skin tones when large area skin resurfacing is required, (4) increasing breast volume by deepithelializing, not discarding, the inferior mastectomy flap skin, (5) eccentric division of abdominal flaps when an immediate and delayed bilateral breast reconstructions are performed simultaneously; and (6) performing second-stage breast reconstruction revisions and fat grafting. PMID- 28894667 TI - Dual Vascular Free Anterolateral Thigh Flap. AB - BACKGROUND: The optimum number of microvascular anastomoses for safe free tissue transfer is controversial. Although the case for 2 venous anastomoses versus 1 anastomosis has been argued, the use of an additional arterial anastomosis has not been examined in detail. METHODS: Twelve patients who underwent 2 arterial anastomoses for a free flap transfer were identified retrospectively from the medical records of patients undergoing reconstruction for head and neck cancer. The free flaps were limited to anterolateral thigh (ALT) flaps. RESULTS: All flaps survived. Complications included venous thrombosis (n = 1), reexploration (n = 1), and leakage (n = 3). The vascular patterns of dual-arterialized ALT flaps were classified into 3 groups. Types 1 and 2 were ALT flaps that had 2 vascular sources from the descending and lateral branches of the lateral circumflex femoral artery. The number of accompanying veins differed between type 1 (3 veins) and type 2 (2 veins). Type 3 differed from a conventional ALT flap nourished by the descending branch of the lateral circumflex femoral artery (1 vein) by the addition of anastomosis of an artery branching from the descending branch to the vastus medialis muscle. The total operation times for these 3 types of ALT were similar. CONCLUSIONS: An additional arterial anastomosis to the free cutaneous flap did not cause any congestion or disturb the balance between inflow and outflow. If the surgeon considers that the first arterial anastomosis is unreliable, an additional anastomosis might be an option in ALT transfer. PMID- 28894669 TI - What Is the Ideal Neophallus? Response to Frey et al. (2017): An Update on Genital Reconstruction Options for the Female-to-Male Transgender Patient: A Review of the Literature. PMID- 28894668 TI - Mucosal Perfusion Preservation by a Novel Shapeable Tissue Expander for Oral Reconstruction. AB - BACKGROUND: There are few methods for expanding oral mucosa, and these often cause complications such as tissue necrosis and expander eruption. This study examines mucosal blood perfusion following insertion of a novel shapeable hydrogel tissue expander (HTE). The canine model used subgingival insertion of HTE following tooth extraction and alveolar bone reduction. The primary goal of this study was to gain understanding of epithelial perfusion and reparative responses of gingival mucosa during HTE expansion. METHODS: Nine Beagle dogs underwent bilateral premolar maxillary and mandibular tooth extraction. Three to four months later, HTE-contoured inserts were implanted submucosally under the buccal surface of the alveolar ridge. After removal and following a 6- to 7-month period of healing, new HTE implants were inserted at the same sites. The area was assessed weekly for tissue perfusion and volume of expansion. Biopsies for histological analysis were performed at the time of expander removal. RESULTS: Within 2 weeks following the second insertion, blood flow returned to baseline (defined as the values of perfusion measurements at the presurgery assessment) and remained normal until hydrogel full expansion and removal. Volume expansion analysis revealed that the hydrogel doubled in volume. Histological assessment showed no macrophage or inflammatory infiltration of the mucosa. No superficial fibrosis, decreased vascularity, or mucosal change was seen. CONCLUSION: Maintenance of adequate tissue perfusion is a clinically important aspect of tissue expander performance to reduce risk of device loss or injury to the patient, particularly for areas with a history of previous surgeries. PMID- 28894670 TI - Reply: What Is the Ideal Neophallus? Response to Frey et al. (2017): An Update on Genital Reconstruction Options for the Female-to-Male Transgender Patient: A Review of the Literature. PMID- 28894671 TI - Interosseous Membrane Release for Long-Standing Upper Limb Lymphedema: A Procedure Often Neglected. PMID- 28894672 TI - Living with Dead Spaces: Closing Complex Posterior Midline Defects with Midline Based Perforator Flaps. PMID- 28894673 TI - Defining the Association between Diabetes and Plastic Surgery Outcomes: An Analysis of Nearly 40,000 Patients. AB - BACKGROUND: Diabetes is an increasingly prevalent comorbidity in patients presenting for surgery, impacting nearly 14% of adults in the United States. Although it is known that diabetic patients are at an increased risk for postoperative complications, there is a paucity of literature on the specific ramifications of diabetes on different surgical procedures. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program dataset, demographics, outcomes, and length of in-patient hospitalization were examined for patients who underwent plastic surgery between 2007 and 2012. Adjusted multivariable logistic regression models were used to assess the relationship between diabetes status and a spectrum of medical and surgical postoperative outcomes. RESULTS: Thirty-nine thousand four hundred seventy-five plastic surgery patients were identified, including 1,222 (3.10%) with insulin dependent diabetes mellitus (IDDM) and 1,915 (4.75%) with non-insulin-dependent diabetes mellitus (NIDDM), who had undergone breast, hand/upper and lower extremity, abdominal, or craniofacial procedures. Logistic regression analyses showed that only insulin-dependent diabetics had a higher likelihood of surgical complications (IDDM: P value < 0.0001; NIDDM: P value < 0.103), whereas patients with both IDDM and NIDDM had increased likelihoods of medical complications (IDDM: P value < 0.001; NIDDM: P value = 0.0093) compared with nondiabetics. Average hospital stay for diabetics was also longer than for nondiabetics. CONCLUSIONS: Diabetes is associated with an increase in a multitude of postoperative complications and in hospital length of stay, in patients undergoing plastic surgery. Diabetes status should thus be evaluated and addressed when counseling patients preoperatively. Risks may be further stratified based on IDDM versus NIDDM status. PMID- 28894674 TI - Lymphedema of the Lower Extremities due to Refractory Malignant Lymphoma Treated by Lymphaticovenous Anastomosis. AB - Lymphaticovenous anastomosis (LVA) is primarily performed for lymphedema of the lower extremities after surgical treatment of gynecologic cancer and lymphedema of the upper extremities after surgical resection of breast cancer; however, LVA for lymphedema due to malignant lymphoma has not been reported to date. We herein present a patient with severe lymphedema of the lower extremities due to refractory malignant lymphoma, which markedly improved with LVA. LVA could contribute to improve quality of life in patients with end-stage disease with lymphedema of the lower extremities due to refractory malignant lymphoma. PMID- 28894675 TI - Carpal Tunnel Syndrome in the Setting of Mucopolysaccharidosis II (Hunter Syndrome). AB - BACKGROUND: Carpal tunnel syndrome (CTS) is a rare finding in children, but heavily represented in pediatric patients with mucopolysaccharidoses. Diagnosis is a challenge due to lack of the stereotypical symptomatic complaints and relies on examination and objective nerve conduction studies. METHODS: We present a case of delayed presentation of CTS in a 12-year-old boy with Hunter syndrome, followed by a review of the literature. RESULTS: Patient Z.D. presented with minimal reported CTS symptoms but advanced median nerve damage on electromyography. He underwent bilateral carpal tunnel release with median nerve neurolysis and flexor tenosynovectomies. Intraoperative examination demonstrated the presence of a "waist sign" of the median nerve and moderate flexor tenosynovial hypertrophy bilaterally. Parents reported mild subjective improvement of dexterity and fine motor skills postoperatively. CONCLUSION: To optimize functional outcome, routine screening for CTS and intervention at an early age are emphasized in the mucopolysaccharidoses population. PMID- 28894676 TI - Meta-Analysis of Long Thoracic Nerve Decompression and Neurolysis Versus Muscle and Tendon Transfer Operative Treatments of Winging Scapula. AB - BACKGROUND: Injury to long thoracic and the spinal accessory nerves can cause winging scapula as a result of weakness and paralysis of the trapezius and serratus anterior muscles. Although these nerve and muscle operations have been reported to correct winging scapula due to various causes, there is no report on comparing the outcomes of these procedures in peer-reviewed Pubmed-indexed literature. In this article, we compared the improvements in the restoration of shoulder functions in winging scapula patients after long thoracic nerve decompression (LTND) in our present study with outcomes of muscle and tendon transfer operations published in the literature (Aetna cited articles). METHODS: Twenty-five winging scapula patients met the inclusion criteria, who had LTND and neurolysis at our clinic since 2008. Electromyographic evaluation of the brachial plexus and long thoracic nerve distribution was performed preoperatively for all our patients in this study. Operating surgeon (R.K.N.) examined all patients and measured pre- and postoperative range of motion of the affected shoulder. The mean follow-up was 23 months (range, 13-46 months). Age of our patients in this study at the time of surgery was between 13 and 63 years. These patients had winging scapula between 5 days (tennis injury) and several years before surgery and some were unknown. RESULTS: Shoulder flexion and abduction improved to an average of 163 (P < 0.000006) and 157 (P < 0.0000005) from 104 and 97 at least 1 year post-LTND in 25 winging scapula patients in our present study. This is statistically significant in comparison to the reported improvements resulting from muscle and tendon transfer procedures in the Pubmed-indexed (Aetna cited) literature. CONCLUSION: This meta-analysis suggests that nerve surgeries such as LTND and neurolysis are effective techniques in correcting winging scapula in comparison with muscle transfer operations. PMID- 28894677 TI - Do We Really Understand Spine Treatments and Science Around the World? PMID- 28894678 TI - Radiographic Risk Factors of Reoperation Following Minimally Invasive Decompression for Lumbar Canal Stenosis Associated With Degenerative Scoliosis and Spondylolisthesis. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: Microsurgical bilateral decompression via a unilateral approach (MBDU), a minimally invasive surgical (MIS) decompression method, has been performed for numerous degenerative lumbar diseases, including degenerative lumbar scoliosis (DLS) or degenerative spondylolisthesis (DS), at our institution. In this study, we evaluated the appropriateness of MBDU for DLS or DS patients. METHODS: A total of 207 patients treated by MBDU were included (88 women and 119 men; mean age, 70 [40-86] years). Thirty-seven cases were diagnosed as DLS (group A), 51 as DS (group B), and 119 as lumbar canal stenosis (group C). Patient clinical status assessed by JOA score was evaluated preoperatively and 2 years postoperatively. We evaluated the prevalence of cases that required reoperation among the groups and the radiographic risk factors related to reoperation. RESULTS: There was no significant difference in recovery ratios of JOA scores among the groups. Reoperation after MBDU was needed in 13 cases (6.3%); the revision rate did not significantly differ among the groups. Reoperation was associated with poor clinical status, low visual analog scale score for low back pain, and low SF-36 mental component summary score. Reoperation was significantly associated with preoperative scoliotic disc wedging with Cobb's angle >=3 degrees in L4-5 (odds ratio = 9.88) and lateral listhesis (odds ratio = 5.22 [total], 12.9 [L4-5]). CONCLUSIONS: When we are careful to indicate decompression for patients with these risk factors related to reoperation, MIS decompression alone can successfully improve DLS patients with a Cobb's angle of <=20 degrees or DS patients. PMID- 28894679 TI - Management of Thoracic Disc Herniations via Posterior Unilateral Modified Transfacet Pedicle-Sparing Decompression With Segmental Instrumentation and Interbody Fusion. AB - STUDY DESIGN: Retrospective consecutive case series. OBJECTIVE: The objective of this case series was to demonstrate the safety of a modified transfacet pedicle sparing decompression and instrumented fusion in patients with thoracic disc herniations (TDHs). METHODS: Consecutive patients undergoing operative management of TDH from July 2007 to December 2011 using a posterior unilateral modified transfacet pedicle-sparing approach were identified. All patients underwent open or minimally invasive modified transfacet pedicle-sparing discectomy and segmental instrumentation with interbody fusion, performed by four different surgeons. Pre- and postoperative visual analog scale (VAS) pain scores, Nurick grade, and American Spinal Injury Association Impairment Scale (AIS) were analyzed from a retrospective chart review. Estimated blood loss and complications were also obtained. RESULTS: Fifty-one patients were included that had operations for TDH. Thirty-nine patients had single level decompression and 12 had multilevel decompression. The total number of levels operated on was 64. Five patients were treated with minimally invasive surgery. A herniated disc level of T11-12 (n = 17) was treated most often. One major complication of epidural hematoma occurred. Minor complications such as malpositioned hardware, postoperative hematoma, wound infection, pseudoarthrosis, and pulmonary complications occurred in a few patients. Follow-up ranged from 1 to 46 months with 1 patient lost to follow-up. From preoperative to final postoperative: mean VAS scores improved from 8.31 to 4.05, AIS in all patients remained stable or improved, and Nurick scores improved from 3 to 2.6 on average. No intraoperative or permanent neurological deficit occurred. CONCLUSION: In our surgical series, 51 consecutive patients underwent modified transfacet pedicle-sparing approach to TDHs and experienced improvement of functional status as well as improvement of objective pain scales with no neurological complications. The posterior unilateral modified transfacet pedicle-sparing decompression and instrumented fusion approach to the thoracic spine is a safe and reproducible procedure for the treatment of TDHs. PMID- 28894680 TI - Multi-Rod Constructs Can Prevent Rod Breakage and Pseudarthrosis at the Lumbosacral Junction in Adult Spinal Deformity. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine if patients fused with multi-rod constructs to the pelvis have a lower incidence of lumbosacral rod failure and pseudarthrosis than those fused with dual-rod constructs. METHODS: We performed a retrospective review of consecutive adult spinal deformity patients who underwent long fusion to the pelvis. Inclusion criteria were >5 levels, primary fusion or revision for L5-S1 pseudarthrosis, and minimum 1-year follow-up. Revision patients with indications other than L5-S1 pseudarthrosis were excluded. One-year follow-up plain radiographs were reviewed for rod integrity, and computed tomography scan (CT) was obtained whenever rod breakage was observed. Dual-rod and multi-rod (3 or 4 rods) cohorts were statistically compared. RESULTS: There were 31 patients with 15 in the dual-rod group and 16 in the multi-rod group, with average ages of 68 +/- 9 and 63 +/- 12 years, respectively. No patients in the multi-rod group experienced rod fracture, whereas 6 in the dual-rod group fractured a rod (P = .007), with 4 occurring at the lumbosacral junction (P = .04). CT scan in the 4 lumbosacral rod fracture cases, and surgical exploration in 3, confirmed pseudarthrosis and hypertrophic nonunion at the L5-S1 junction. CONCLUSION: Patients with dual-rod constructs had a statistically greater incidence of lumbosacral pseudarthrosis with implant failure than those with multi-rod constructs. CT and surgical exploration showed hypertrophic nonunion as opposed to oligo- or atrophic nonunion. This suggests that mechanical instability, not biology, is the main reason for failure, and could be addressed with the use of multi-rods. PMID- 28894681 TI - Preoperative Computed Tomography Myelography Parameters as Predictors of Outcome in Patients With Degenerative Cervical Myelopathy: Results of a Systematic Review. AB - STUDY DESIGN: Systematic review. OBJECTIVES: To determine the preoperative computed tomography (CT) myelogram imaging parameters in patients diagnosed with degenerative cervical myelopathy (DCM) that correlate with severity of DCM and predict postoperative patients' functional outcome. METHODS: An electronic database search was performed using Ovid Medline and Embase. CT myelogram studies investigating the correlation between imaging characteristics and DCM severity or postoperative outcomes were included. Two independent reviewers performed citation screening, selection, qualitative assessment, and data extraction using an objective and blinded protocol. RESULTS: A total of 5 studies (402 patients) were included in this review and investigated the role of preoperative CT myelogram parameters in predicting the functional outcome after surgical treatment of DCM. All studies were retrospective cohort studies. CT myelogram characteristics included the transverse area of the spinal cord at maximum level of compression, spinal canal narrowing, number of blocks, spinal canal diameter, and flattening ratio. There is low evidence suggesting that patients with a preoperative transverse area of the spinal cord >30 mm2 at the level of maximum compression have better postoperative recovery and outcome. We found no studies investigating the correlation between preoperative CT myelogram parameters and DCM severity. CONCLUSIONS: Patients with greater transverse area of spinal cord at the level of maximum compression on the preoperative CT myelogram are more likely to have better neurological outcome after surgery. There is insufficient evidence to suggest that any of the other CT myelogram parameters investigated are predictors of postoperative outcomes in patients with DCM. PMID- 28894682 TI - Frailty Is Predictive of Adverse Postoperative Events in Patients Undergoing Lumbar Fusion. AB - STUDY DESIGN: Retrospective study of prospectively collected data. OBJECTIVE: To analyze the modified frailty index (mFI) as a predictor of adverse postoperative events following posterior lumbar fusion. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database including all adult patients undergoing posterior lumbar interbody fusion or transforaminal lumbar interbody fusion between 2005 and 2012. Outcomes measured included mortality, postoperative complications, length of stay, reoperations, and readmissions. The previously described mFI was calculated, and univariate and multivariate logistic regression analysis were used to analyze risk factors associated with morbidity, mortality, and adverse postoperative events. This study was qualified as exempt by the Mount Sinai Hospital Institutional Review Board. RESULTS: A total of 6094 patients met inclusion criteria. The mean mFI was 0.087(0-0.545). Increasing mFI score was associated with increased complications, reoperations, prolonged length of stay (LOS), and morbidity (P < .05). As the mFI score increased from 0.27 (3/11 variables present) to >=0.36 (4/11), the rate of any complication increased from 26.8% to 35% (P < .0001), sepsis 2.4% to 5.2% (P < .0001), wound complications 4.4% to 6.5% (P < .0001), unplanned readmissions 4.7% to 20% (P = .02), and urinary tract infection 4.1% to 10.4% (P < .0001). An mFI of >=0.36 was an independent predictor of any complication (odds ratio [OR]= 2.2, 95% confidence interval [CI] = 1.3-3.7), sepsis (OR = 6.3, 95%, CI = 1.8 21), wound complications (OR = 2.9, 95% CI = 1.1-8.2), prolonged LOS (OR = 2.3, 95% CI = 1.4-3.7), and readmission (OR = 4.3, 95% CI = 1.5-12.7). CONCLUSION: Patients with higher mFI scores (>= 4/11 variables) are at a significantly higher risk of major complications, readmissions, and prolonged LOS following lumbar fusion. PMID- 28894683 TI - Beyond Pelvic Incidence-Lumbar Lordosis Mismatch: The Importance of Assessing the Entire Spine to Achieve Global Sagittal Alignment. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To investigate which sagittal parameters contribute to a normal sagittal vertical axis (SVA) when there is a pelvic incidence-lumbar lordosis (PI-LL) mismatch >10 degrees following adult spinal deformity (ASD) correction. METHODS: We performed a retrospective review of ASD patients with >5 levels fused. Sagittal measurements between cohorts of postoperative PI-LL >10 degrees and PI-LL<10 degrees were compared. We correlated SVA to pelvic tilt (PT), thoracic kyphosis (TK), PI-LL, cervical lordosis (CL), and correlated the pre- to postoperative change in SVA to change in PT, change in TK, change in PI-LL, and change in CL. We also correlated SVA and the change in SVA to combined parameters of ((PI-LL) - PT + TK). RESULTS: We analyzed 52 patients with a mean age of 59 +/- 16 years. In patients with a postoperative SVA <5cm, a smaller TK was seen when PI-LL >10 degrees than when PI-LL<10 degrees (15.45 degrees vs 33.04 degrees , P = .0004). Additionally, PT was larger when PI-LL >10 degrees than when PI-LL <10 degrees (25.73 degrees vs 19.07 degrees , P = .006). SVA correlated better with ((PI-LL) - PT + TK) (R2 = 0.51) than with PI-LL alone (R2 = 0.33). Lastly, there was no significant correlation between change in pre- to postoperative SVA with change in TK for all cases (P = .73), but in cases where change in PI-LL was <10 degrees , there was a significant correlation between change in TK and change in SVA (P = .009). CONCLUSION: Our results demonstrate that PT and TK, and not just PI-LL, play an important role in maintaining sagittal balance when there is a PI-LL mismatch >10 degrees . PMID- 28894684 TI - A Preliminary Algorithm Using Spine Measurement Software to Predict Sagittal Alignment Following Pedicle Subtraction Osteotomy. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To evaluate if spine measurement software can simulate sagittal alignment following pedicle subtraction osteotomy (PSO). METHODS: We retrospectively reviewed consecutive adult spinal deformity patients who underwent lumbar PSO. Sagittal measurements were performed on preoperative lateral, standing radiographs. Sagittal measurements after simulated PSO were compared to actual postoperative measurements. A regression equation was developed using cases 1-7 to determine the amount of manual rotation required of each film to match the simulated sagittal vertical axis (SVA) to the actual postoperative SVA. The equation was then applied to cases 8-13. RESULTS: For all 13 cases, the spine software accurately simulated lumbar lordosis, pelvic incidence lumbar lordosis mismatch, and T1 pelvic angle, with no significant differences between actual and simulated measurements. The pelvic tilt (PT), sacral slope (SS), thoracolumbar alignment (TL), thoracic kyphosis (TK), T9 spino-pelvic inclination (T9SPi), T1 spino pelvic inclination (T1SPi), and SVA were inaccurately simulated. The PT, SS, T9SPi, T1SPi, and SVA all change with manual rotation of the film, and by using the regression equation developed with cases 1-7, we were able to improve the accuracy and decrease the variability of the simulated PT, SS, T9SPi, T1SPi, and SVA for cases 8-13. CONCLUSIONS: Dedicated spine measurement software can accurately simulate certain sagittal measurements, such as LL, PI-LL, and TPA, following PSO. A number of measurements, including PT, SS, TL, TK, T9SPi, T1SPi, and SVA were inaccurately simulated. Our preliminary algorithm improved the accuracy and decreased the variability of certain measurements, but requires future prospective studies for further validation. PMID- 28894685 TI - Return to Play in Elite Contact Athletes After Anterior Cervical Discectomy and Fusion: A Meta-Analysis. AB - STUDY DESIGN: Systematic literature review and meta-analysis of studies published in English language. OBJECTIVE: Return to play after anterior cervical discectomy and fusion (ACDF) in contact athletes remains a controversial topic with no consensus opinion in the literature. Additional information is needed to properly advise and treat this population of patients. This study is a meta-analysis assessing return to competitive contact sports after undergoing an ACDF. METHODS: A literature search of Medline, Embase, and Cochrane Reviews was performed to identify investigations reporting return to play following ACDF in professional contact athletes. The pooled results were performed by calculating the effect size based on the logic event rate. Studies were weighted by the inverse of the variance, which included both within and between-study error. Confidence intervals (CIs) were reported at 95%. Heterogeneity was assessed using the Q statistic and I2. Sensitivity analysis and publication bias calculations were performed. RESULTS: The initial literature search resulted in 166 articles, of which 5 were determined relevant. Overall, return to play data was provided for 48 patients. The pooled clinical success rate for return to play was 73.5% (CI = 56.7%, 85.8%). The logit event rate was calculated to be 1.036 (CI = 0.270, 1.802), which was statistically significant (P = .008). The studies included in this meta-analysis demonstrated minimal heterogeneity with Q value of 4.038 and I2 value of 0.956. CONCLUSIONS: Elite contact athletes return to competition 73.5% of the time after undergoing ACDF. As this is the first study to pool results from existing studies, it provides strong evidence to guide decision making and expectations in this patient population. PMID- 28894687 TI - The Pedicles Are Not the Densest Regions of the Lumbar Vertebrae: Implications for Bone Quality Assessment and Surgical Treatment Strategy. AB - STUDY DESIGN: Cadaver study. OBJECTIVE: To determine the bone density of lumbar vertebral anatomic subregions. Bone mineral density (BMD) is a major factor in osseous fixation construct strength. The standard region for implant fixation of the spine is the pedicle; however, other regions may be more viable options with higher bone quality. METHODS: Using computed tomography images, the spine was digitally isolated by applying a filter for adult bone. The spine model was separated into 5 lumbar vertebrae, followed by segmentation of each vertebra into 7 regions and determination of average Hounsfield units (HU). HU was converted to BMD with calibration phantoms of known BMD. RESULTS: Overall mean BMD in vertebral regions ranged from 172 to 393 mg/cm3 with the highest and lowest BMD in the lamina and vertebral body, respectively. Vertebral regions formed 3 distinct groups (P < .03). The vertebral body and transverse processes represent one group with significantly lower BMD than other regions. Spinous process, pedicles, and superior articular processes represent a second group with moderate BMD. Finally, inferior articular process (IAP) and lamina represent a third group with significantly higher BMD than other regions. CONCLUSIONS: Standard lumbar fusion currently uses the vertebral body and pedicles as primary locations for fixation despite their relatively low BMD. Utilization of posterior elements, especially the lamina and IAP, may be advantageous as a supplement to modern constructs or the primary site for fixation, possibly mitigating construct failures due to loosening or pullout. PMID- 28894686 TI - Risk Factors for Delirium After Spine Surgery in Extremely Elderly Patients Aged 80 Years or Older and Review of the Literature: Japan Association of Spine Surgeons with Ambition Multicenter Study. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: Spine surgeries in elderly patients have increased in recent years due to aging of society and recent advances in surgical techniques, and postoperative complications have become more of a concern. Postoperative delirium is a common complication in elderly patients that impairs recovery and increases morbidity and mortality. The objective of the study was to analyze postoperative delirium associated with spine surgery in patients aged 80 years or older with cervical, thoracic, and lumbar lesions. METHODS: A retrospective multicenter study was performed in 262 patients 80 years of age or older who underwent spine surgeries at 35 facilities. Postoperative complications, incidence of postoperative delirium, and hazard ratios of patient-specific and surgical risk factors were examined. RESULTS: Postoperative complications occurred in 59 of the 262 spine surgeries (23%). Postoperative delirium was the most frequent complication, occurring in 15 of 262 patients (5.7%), and was significantly associated with hypertension, cerebrovascular disease, cervical lesion surgery, and greater estimated blood loss (P < .05). In multivariate logistic regression using perioperative factors, cervical lesion surgery (odds ratio = 4.27, P < .05) and estimated blood loss >=300 mL (odds ratio = 4.52, P < .05) were significantly associated with postoperative delirium. CONCLUSIONS: Cervical lesion surgery and greater blood loss were perioperative risk factors for delirium in extremely elderly patients after spine surgery. Hypertension and cerebrovascular disease were significant risk factors for postoperative delirium, and careful management is required for patients with such risk factors. PMID- 28894688 TI - Current Diagnosis and Management of Cervical Spondylotic Myelopathy. AB - STUDY DESIGN: Review. OBJECTIVES: Cervical spondylotic myelopathy (CSM) is a major cause of disability, particular in elderly patients. Awareness and understanding of CSM is imperative to facilitate early diagnosis and management. This review article addresses CSM with regard to its epidemiology, anatomical considerations, pathophysiology, clinical manifestations, imaging characteristics, treatment approaches and outcomes, and the cost-effectiveness of surgical options. METHODS: The authors performed an extensive review of the peer reviewed literature addressing the aforementioned objectives. RESULTS: The clinical presentation and natural history of CSM is variable, alternating between quiescent and insidious to stepwise decline or rapid neurological deterioration. For mild CSM, conservative options could be employed with careful observation. However, surgical intervention has shown to be superior for moderate to severe CSM. The success of operative or conservative management of CSM is multifactorial and high-quality studies are lacking. The optimal surgical approach is still under debate, and can vary depending on the number of levels involved, location of the pathology and baseline cervical sagittal alignment. CONCLUSIONS: Early recognition and treatment of CSM, before the onset of spinal cord damage, is essential for optimal outcomes. The goal of surgery is to decompress the cord with expansion of the spinal canal, while restoring cervical lordosis, and stabilizing when the risk of cervical kyphosis is high. Further high-quality randomized clinical studies with long-term follow up are still needed to further define the natural history and help predict the ideal surgical strategy. PMID- 28894689 TI - Is Stand-Alone Anterior Lumbar Interbody Fusion a Safe and Efficacious Treatment for Isthmic Spondylolisthesis of L5-S1? AB - STUDY DESIGN: A systematic review. OBJECTIVE: The objective of this study was to determine the safety and efficacy of stand-alone anterior lumbar interbody fusion (sa-ALIF) for the treatment of symptomatic isthmic spondylolisthesis of L5-S1 by assessing the level of available clinical and radiographic evidence. METHODS: A systematic review utilizing Medline, Embase, and Scopus online databases was undertaken. Clinical, radiographic, and adverse outcome data were extracted for the relevant isthmic spondylolisthesis cases with the intention of undertaking a meta-analysis. RESULTS: The database search between January 1980 and December 2015 yielded 23 articles that concerned sa-ALIF for isthmic spondylolisthesis of L5-S1. Only in 9 of the 23 articles data could be extracted specific to sa-ALIF for isthmic spondylolisthesis of L5-S1. There was considerable inconsistency in the standards for reporting outcomes of the surgery due to which meta-analysis could not be undertaken, and hence each article was reviewed. CONCLUSIONS: There was insufficient evidence to support the safety and efficacy of sa-ALIF for the treatment of isthmic spondylolisthesis of L5-S1. Although sa-ALIF is widely documented in the literature, there was insufficient evidence to support its use in treating this specific pathology. The unique pathological and anatomical situation that isthmic spondylolisthesis of L5-S1 presents must be recognized and its treatment with sa-ALIF should be well thought out. PMID- 28894690 TI - Management of Asymptomatic Bacteriuria, Urinary Catheters and Symptomatic Urinary Tract Infections in Patients Undergoing Surgery for Joint Replacement: A Position Paper of the Expert Group 'Infection' of swissorthopaedics. AB - In this position paper, we review definitions related to this subject and the corresponding literature. Our recommendations include the following statements. Asymptomatic bacteriuria, asymptomatic leukocyturia, urine discolouration, odd smell or positive nitrite sediments are not an indication for antimicrobial treatment. Antimicrobial treatment of asymptomatic bacteriuria does not prevent periprosthetic joint infection, but is associated with adverse events, costs and antibiotic resistance development. Urine analyses or urine cultures in asymptomatic patients undergoing orthopaedic implants should be avoided. Indwelling urinary catheters are the most frequent reason for healthcare associated urinary tract infections and should be avoided or removed as soon as possible. PMID- 28894691 TI - Gonococcal Prosthetic Joint Infection. AB - Neisseria gonorrhoea is a common sexually transmitted infection worldwide. Disseminated gonococcal infection is an infrequent presentation and rarely can be associated with septic arthritis. Incidence of this infection is rising, both internationally and in older age groups. We present the first documented case of N. gonorrhoea prosthetic joint infection which was successfully treated with laparoscopic debridement and antimicrobial therapy. PMID- 28894692 TI - Case Report - Infection of Total Knee Arthroplasty Treated with One-Stage Surgery and Linezolid. AB - Staphylococcus spp meticillin resistant infection can be treated with Linezolid. This is a case report of an orthopaedic implant infection in a 60 year-old male treated orally with Linezolid and Rifampicin for three months after one-stage arthroplasty. This is possible provided that platelet count is closely monitored throughout the course of treatment. PMID- 28894693 TI - Association Between Body Mass index and Prevalence of Multimorbidity in Low-and Middle-income Countries: A Cross-Sectional Study. AB - BACKGROUND: Chronic diseases are increasingly becoming a health burden in terms of both morbidity and mortality in low and middle-income countries (LMICs). The role of body mass index (BMI) especially overweight and obesity in the prevalence of multimorbidity, the occurrence of two or more chronic conditions, is understudied in LMICs where two thirds of the world's obese individuals reside. We estimated the association between BMI and prevalence of chronic non communicable disease multimorbidity in six LMICs. METHODS: Cross-sectional data of total of 40,166 participants from China (n=13,970), India (10,915), Mexico (2,4 26), Russia (3,892), South Africa (4,000) and Ghana (4,971), aged 18 years and above included in the WHO Study on Global Ageing and adult health (SAGE), 2007-2010 were analyzed. Multimorbidity was measured as the simultaneous presence of two or more of the nine chronic conditions including angina pectoris, arthritis, asthma, chronic lung disease, diabetes mellitus, hypertension, stroke, depression, and vision impairment. Multivariable logistic regression models were fitted to test for associations between overweight/obesity and prevalence of non communicable multimorbidity after adjusting for age, sex, rural/urban residence, education, marital status, occupation, household wealth, tobacco smoking, alcohol drinking, fruits and vegetable intake and health insurance status. Data were analyzed country wise as well as pooled together to give overall LMIC estimates. RESULTS: The mean BMI was 24.4 [+/-7.3SD] in the pooled countries, being as low as 20.8 [+/-8.0 SD] in India to 23.4 [+/-6.3 SD] in Ghana, 23.9 [+/-4.9 SD] in China, 28.4 [+/-5.4 SD] in Mexico, 28.6 [+/-6.3 SD] in Russia, to as high as 30.5 [+/-12.0 SD] in South Africa. The prevalence of overweight was 13% and obesity was 24% in the pooled sample. The prevalence of non communicable disease multimorbidity was 23% in the pooled sample of six countries-the highest being in Russia (50%), followed by Mexico (27%), India (24%), Ghana (23%), South Africa (32%) and China (22%). The prevalence of multimorbidity was 37% among obese population and 27% among overweight population in the pooled sample-highest prevalence was in Russia (59% among obese; 45% among overweight) and lowest in Ghana (28% among obese; 23% among overweight). Being obese (OR:5.78;95%CI:3.55 9.40;p<0.0001) was associated with significantly higher likelihood of having multimorbidity as compared to normal weight category in the pooled sample. The likelihood of multimorbidity among obese were almost ten times higher in Russia (OR:9.90;95%CI:3.90-25.17;p=<0.0001), seven times higher in China (OR:7.06;95%CI:2.47-20.21;p=0.003), six times higher in Ghana (OR:5.61;95%CI:1.21 26.02;p= 0.007) and five times higher in South Africa (OR:4.66;95%CI:2.16 10.08;p=0.005). Non-significant but positive association were also observed in case of India and Mexico. The likelihood of multimorbidity was more than two times higher among overweight population in India (OR:2.33;95%CI:1.35 4.02;p=0.003) and pooled countries (OR:1.47;95%CI:1.05-2.07;p=0.004) while non significant but positive association were also observed in case of China, Russia, and Ghana. CONCLUSIONS: The prevalence of non communicable disease multimorbidity in the LMICs is high, one and half times higher in obese than in normal weight individual. Obesity was independently associated with the occurrence of multimorbidity in the six LMICs. These findings may be vital for public health surveillance, prevention and management strategies for non communicable disease multimorbidity in the LMICs. PMID- 28894694 TI - Evaluation of Partial Breast Reirradiation with Intraoperative Radiotherapy after Prior Thoracic Radiation: A Single-Institution Report of Outcomes and Toxicity. AB - INTRODUCTION: Mastectomy is the current standard of care for ipsilateral breast tumor recurrences after prior whole breast irradiation (WBI). We report our single-institution experience with breast-conserving surgery (BCS) followed by intraoperative radiotherapy (IORT) as an alternative to salvage mastectomy for new or recurrent breast cancers that develop in the setting of prior thoracic radiation. METHODS: We performed an IRB-approved retrospective review of patients treated with breast IORT between September 2013 and November 2016. We identified 12 patients who declined salvage mastectomy for their breast cancer after prior thoracic radiation. IORT was delivered using the IntrabeamTM device (Carl Zeiss, Germany). A dose of 20 Gy was prescribed to the lumpectomy cavity surface using 50 kV X-rays. We graded both acute and late treatment-related breast toxicities using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Local control, mastectomy-free survival, distant metastasis, and overall survival were determined. RESULTS: Our study included nine patients who developed a new or recurrent ipsilateral breast cancer after prior WBI for early-stage breast cancer, two patients with primary breast cancer after mantle field radiation for Hodgkin's lymphoma, and one patient with a synchronous stage III non-small cell lung cancer treated with definitive radiation to the ipsilateral lung and mediastinum. The median time from prior radiation to presentation was 18 years (range: 2 months to 46 years). All patients successfully underwent partial breast reirradiation with IORT and were able to preserve their breast. At a median follow-up of 14 months (4-25 months), there were no local or distant recurrences. There was a single non-cancer-related death. In the acute setting, we observed grade 1 toxicity in 58% (n = 7), grade 2 toxicity in 17% (n = 2), and no grade 3 or higher toxicity. In the late setting, at least 3 months after IORT, we observed grade 1 hyperpigmentation and/or fibrosis in 50% (n = 6), symptomatic seroma requiring drainage in 33% (n = 4). A single patient developed an abscess requiring hospitalization and intravenous antibiotic therapy. CONCLUSION: BCS with IORT is a feasible salvage option for patients who present with localized breast cancer after prior thoracic radiation treatment. Continued follow-up of these patients is warranted given the incidence of delayed toxicity. PMID- 28894695 TI - Which Obstacles Prevent Us from Recruiting into Clinical Trials: A Survey about the Environment for Clinical Studies at a German University Hospital in a Comprehensive Cancer Center. AB - BACKGROUND: Prospective clinical studies are the most important tool in modern medicine. The standard in good clinical practice in clinical trials has constantly improved leading to more sophisticated protocols. Moreover, translational questions are increasingly addressed in clinical trials. Such trials must follow elaborate rules and regulations. This is accompanied by a significant increase in documentation issues which require substantial manpower. Furthermore, university-based clinical centers are interested in increasing the amount of patients treated within clinical trials, and this number has evolved to be a key quality criterion. The present study was initiated to elucidate the obstacles that limit clinical scientists in screening and recruiting for clinical trials. METHODS: A specific questionnaire with 28 questions was developed focusing on all aspects of clinical trial design as well as trial management. This included questions on organizational issues, medical topics as well as potential patients' preferences and physician's goals. The questionnaire was established to collect data anonymously on a web-based platform. The survey was conducted within the Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich; physicians of all levels (Department Chairs, attending physicians, residents, as well as study nurses, and other study-related staff) were addressed. The answers were analyzed using the Survio analyzing tool (http://www.survio.com/de/). RESULTS: We collected 42 complete sets of answers; in total 28 physicians, 11 study nurses, and 3 persons with positions in administration answered our survey. The study centers reported to participate in a range of 3-160 clinical trials with a recruitment rate of 1-80%. Main obstacles were determined: 31/42 (74%) complained about limited human resources and 22/42 (52%) reported to have a lack on technical resources, too. 30/42 (71%) consented to the answer, that the documentation effort of clinical trials is too large. A possible increase of the patients' study participation rate up to over 20% was deemed to be possible if the described limitations could be overcome. DISCUSSION: The increasing documentation effort in clinical trials has led to a strong increase in the work load of scientific personnel. Recruiting of patients into clinical trials therefore is not only limited by patient issues, but also by the infrastructure of the centers. Especially the lack of study nurses is likely to be a major limitation. Furthermore, technical resources for time efficient and safe documentation within clinical routine as well as in clinical trials are required. By optimization of these factors, a significant increase in the amount of patients treated in clinical trials seems to be possible. PMID- 28894696 TI - Quo natas, Danio?-Recent Progress in Modeling Cancer in Zebrafish. AB - Over the last decade, zebrafish has proven to be a powerful model in cancer research. Zebrafish form tumors that histologically and genetically resemble human cancers. The live imaging and cost-effective compound screening possible with zebrafish especially complement classic mouse cancer models. Here, we report recent progress in the field, including genetically engineered zebrafish cancer models, xenotransplantation of human cancer cells into zebrafish, promising approaches toward live investigation of the tumor microenvironment, and identification of therapeutic strategies by performing compound screens on zebrafish cancer models. Given the recent advances in genome editing, personalized zebrafish cancer models are now a realistic possibility. In addition, ongoing automation will soon allow high-throughput compound screening using zebrafish cancer models to be part of preclinical precision medicine approaches. PMID- 28894698 TI - Paradigm Shift toward Reducing Overtreatment of Ductal Carcinoma In Situ of Breast. AB - The prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially after the introduction of breast cancer screening programs, although the clinical effects of early DCIS detection and treatment remain unclear. The standard treatment for DCIS has involved local breast-conserving surgery (BCS) followed by radiotherapy (RT) or total mastectomy with/without endocrine therapy, and the choice of local treatment is not usually based on clinicopathologic or biological factors. However, we have investigated the effectiveness of local treatment using breast surgery and RT using Surveillance, Epidemiology, and End Results data, and found that the effectiveness of breast surgery was modified by the nuclear grade. Furthermore, breast cancer-specific survival was identical between patients with low-grade DCIS who did and did not undergo surgery. Moreover, we found that RT after BCS for DCIS was only associated with a survival benefit among patients with risk factors for local recurrence, such as nuclear grade, age, and tumor size. Ongoing clinical trials and translational research have attempted to develop a treatment strategy that prevents the overdiagnosis and overtreatment of low-risk DCIS, as well as a biology-based treatment strategy for using targeted therapy. Therefore, to develop a tailored treatment strategy for DCIS, we need to identify molecular and biological classifications based on the results from translational research, national databases, and clinical trials. PMID- 28894697 TI - The Potential Role of Senescence As a Modulator of Platelets and Tumorigenesis. AB - In addition to thrombus formation, alterations in platelet function are frequently observed in cancer patients. Importantly, both thrombus and tumor formation are influenced by age, although the mechanisms through which physiological aging modulates these processes remain poorly understood. In this context, the potential effects of senescent cells on platelet function represent pathophysiological mechanisms that deserve further exploration. Cellular senescence has traditionally been viewed as a barrier to tumorigenesis. However, far from being passive bystanders, senescent cells are metabolically active and able to secrete a variety of soluble and insoluble factors. This feature, known as the senescence-associated secretory phenotype (SASP), may provide senescent cells with the capacity to modify the tissue environment and, paradoxically, promote proliferation and neoplastic transformation of neighboring cells. In fact, the SASP-dependent ability of senescent cells to enhance tumorigenesis has been confirmed in cellular systems involving epithelial cells and fibroblasts, leaving open the question as to whether similar interactions can be extended to other cellular contexts. In this review, we discuss the diverse functions of platelets in tumorigenesis and suggest the possibility that senescent cells might also influence tumorigenesis through their ability to modulate the functional status of platelets through the SASP. PMID- 28894699 TI - Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification. AB - Lung cancer is the leading cause of cancer-related death worldwide due to late diagnoses and limited treatment interventions. Recently, comprehensive molecular profiles of lung cancer have been identified. These novel characteristics have enhanced the understanding of the molecular pathology of lung cancer. The identification of driver genetic alterations and potential molecular targets has resulted in molecular-targeted therapies for an increasing number of lung cancer patients. Thus, the histopathological classification of lung cancer was modified in accordance with the increased understanding of molecular profiles. This review focuses on recent developments in the molecular profiling of lung cancer and provides perspectives on updated diagnostic concepts in the new 2015 WHO classification. The WHO classification will require additional revisions to allow for reliable, clinically meaningful tumor diagnoses as we gain a better understanding of the molecular characteristics of lung cancer. PMID- 28894700 TI - Targeting the Type II Secretion System: Development, Optimization, and Validation of a High-Throughput Screen for the Identification of Small Molecule Inhibitors. AB - Nosocomial pathogens that develop multidrug resistance present an increasing problem for healthcare facilities. Due to its rapid rise in antibiotic resistance, Acinetobacter baumannii is one of the most concerning gram-negative species. A. baumannii typically infects immune compromised individuals resulting in a variety of outcomes, including pneumonia and bacteremia. Using a murine model for bacteremia, we have previously shown that the type II secretion system (T2SS) contributes to in vivo fitness of A. baumannii. Here, we provide support for a role of the T2SS in protecting A. baumannii from human complement as deletion of the T2SS gene gspD resulted in a 100-fold reduction in surviving cells when incubated with human serum. This effect was abrogated in the absence of Factor B, a component of the alternative pathway of complement activation, indicating that the T2SS protects A. baumannii against the alternative complement pathway. Because inactivation of the T2SS results in loss of secretion of multiple enzymes, reduced in vivo fitness, and increased sensitivity to human complement, the T2SS may be a suitable target for therapeutic intervention. Accordingly, we developed and optimized a whole-cell high-throughput screening (HTS) assay based on secreted lipase activity to identify small molecule inhibitors of the T2SS. We tested the reproducibility of our assay using a 6,400 compound library. With small variation within controls and a dynamic range between positive and negative controls, the assay had a z-factor of 0.65, establishing its suitability for HTS. Our screen identified the lipase inhibitors Orlistat and Ebelactone B demonstrating the specificity of the assay. To eliminate inhibitors of lipase activity and lipase expression, two counter assays were developed and optimized. By implementing these assays, all seven tricyclic antidepressants present in the library were found to be inhibitors of the lipase, highlighting the potential of identifying alternative targets for approved pharmaceuticals. Although no T2SS inhibitor was identified among the compounds that reduced lipase activity by >=30%, our small proof-of-concept pilot study indicates that the HTS regimen is simple, reproducible, and specific and that it can be used to screen larger libraries for the identification of T2SS inhibitors that may be developed into novel A. baumannii therapeutics. PMID- 28894701 TI - Relationship between Diet and Non-alcoholic Fatty Liver Disease: A Review Article. AB - BACKGROUND: Diet plays a key role in the development of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to review systematically observational studies available regarding the relationship between food intakes and NAFLD. METHODS: We searched Scopus, PubMed, and Cochrane Library databases to identify English observational studies on food groups, dietary patterns, and NAFLD. Cross sectional, case-control and cohort studies were selected and then duplication, topic, type of study, study population, variables examined and quality of data reporting of the articles were evaluated. RESULTS: We identified 2128 studies in the initial search, of which 33 were reviewed in full text and 7 articles were included in this systematic review. Intakes of red meat, fats, and sweets were high whereas consumption of whole grains, fruits and vegetables were less in NAFLD patients. Moreover, there was a positive association between the Western dietary pattern and the risk of NAFLD, while adherence to the Mediterranean diet was significantly associated with the severity of hepatic steatosis. CONCLUSION: Generally, different food group intakes and dietary patterns are associated with the progression of NAFLD and its risk factors. Because of the many limitations of available studies reviewed on this topic, more prospective studies are suggested. PMID- 28894702 TI - Effects of Hair Metals on Body Weight in Iranian Children Aged 20 to 36 Months. AB - BACKGROUND: Although the level of exposure to many toxic metals decreased recently, the adverse effects of these metals on children's growth and development remain a serious public health issue. METHODS: The present study was conducted in three teaching hospitals affiliated with Tehran University of Medical Sciences (Tehran, Iran) from Sep 2012 to Mar 2013. To study the relationship between metals and childhood growth, concentrations of zinc and several potentially toxic metals (lead, cadmium, antimony, cobalt, and molybdenum) were measured in scalp hair for 174 children, aged 20 to 36 months. RESULTS: The hair concentrations of cobalt were significantly (P<0.05) higher in children at the lower percentile of weight than in higher-weight children (0.026 +/- 0.04 vs. 0.015 +/- 0.01 MUg/g, respectively). Hair contents of lead, cobalt, and antimony were significantly higher (P<0.05) in girls than in boys (8.08 +/- 8.7 vs. 4.92 +/- 5.6 MUg/g for lead, 0.026 +/- 0.03 vs. 0.16 +/- 0.02 MUg/g for cobalt, and 0.188 +/- 0.29 vs. 0.102 +/- 0.12 MUg/g for antimony). There were also significant correlations between lead and other metals in the children's hair. CONCLUSION: Gender may play a significant role in absorption and/or accumulation of metals. It should be considered when we study metal toxicity in children. PMID- 28894703 TI - Health-related Quality of Life and Mental Health of Elderly by Occupational Status. AB - BACKGROUND: This study aimed to identify the association between health-related quality of life and mental health by elderly Koreans' occupational status. METHODS: This descriptive cross-sectional study consisted of a secondary analysis of data from the Korea National Health and Nutrition Examination Survey V-3 (2012). The sample comprised 1431 people aged 65 yr and older. RESULTS: Compared to participants employed, those not showed lower HRQOL. Occupational status significantly affected all of the EuroQoL-5 Dimensions (EQ-5D): mobility, self care, usual activity, pain/discomfort, and anxiety/depression. Unemployed participants had more suicidal ideation. Among employed elderly persons, significant differences were found between manual and non-manual workers in the EQ-5D index and EQ-5D for mobility and pain/discomfort. Manual workers experienced more depression and suicidal ideation than did non-manual workers. CONCLUSION: The occupational status of elderly individuals accounts for differences in their quality of life and mental health status. Therefore, additional jobs should be created for the elderly in order to improve their quality of life and mental health. PMID- 28894705 TI - A Cross-sectional Assessment of Health-related Quality of Life among Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality characterized by progressive airflow obstruction and inflammation in the airways, which has an impact on health-related quality of life. The EQ-5D-5L is one of the most used preference-based, health-related quality of life questionnaire. The objective of this study was to provide normative values of EQ 5D-5L for Spanish people suffering from COPD. METHODS: Data were extracted from the Spanish National Health Survey (2011/2012). Overall, 1130 people with COPD participated in this survey. The utility index of EQ-5D-5L and the Visual Analog Scale (VAS) score were defined by gender, region, and age. RESULTS: Mean (SD) EQ 5D-5L utility index and VAS score for Spanish people with COPD were 0.742 (0.309) and 60.466 (21.934) respectively. In general, men reported better health status than women. Ceiling effect of the whole sample was 30.35%. CONCLUSION: The current study provides normative values of EQ-5D-5L for Spanish people affected by COPD. Ceiling effect was high and better results were observed in men compared with women. PMID- 28894704 TI - Appropriate Body Mass Index and Waist-hip Ratio Cutoff Points for Overweight and Obesity in Adults of Northeast China. AB - BACKGROUND: The current overweight and obesity guidelines based on the Westerners are not consistent with many studies based on the Asians. The guidelines may be different because of regional diversity. This study aimed to determine the appropriate body mass index (BMI) and waist-hip ratio (WHR) cutoff points in the adults of Northeast China. METHODS: Overall, 21206 adults were selected from Jilin Province Adult Chronic Disease and Risk Factor Survey conducted in 2012. A representative sample was collected in the Jilin Province of northeast China by a multistage stratified random cluster sampling design. The age of participants was from 20 to 79 yr old. The test items were clustered by risk factors, and receiver operating characteristic (ROC) curves were computed to analyze. RESULTS: Under different risk factors, BMI cutoff points were affected greatly. Especially for diabetes, the cutoff value was apparently larger than others were. WHR increased with age in both genders. From a general view, male WHR was slightly larger than female. In the male, WHR cutoff point was near 0.88 with a tiny change, as for in the female was near 0.86. CONCLUSION: The cutoff values of sensitivity and specificity are relatively good and false positives rate is relatively low. BMI cutoffs values of overweight and obesity are 24.5 kg/m2 and 29.0 kg/m2, WHR cutoff values of the male are 0.88, the female is 0.86. PMID- 28894706 TI - The Effectiveness of Electrical Acupuncture Stimulation in Reducing Levels of Self-reported Anxiety of Lung Cancer Patients during Palliative Care: A Pilot Study. AB - BACKGROUND: Lung cancer is a serious threat to human health and life worldwide. Anxiety is common amongst palliative care patients with lung cancer and adversely affects quality of life. Acupuncture is an effective and safe treatment method used for the treatment of depressive mood status. We aimed to assess the influence of electrical acupuncture stimulation on self-reported anxiety in palliative care among patients with lung cancer. METHODS: This pilot study had an experimental, 3-group, research plan. A total of 188 participants were enrolled from the Shanghai Pulmonary Hospital, Tongji University, Shanghai, China from 2014-2015. This pilot study had an experimental, 3-group, research plan. In TEAS group, participants received standardized palliative care and electrical acupuncture stimulation in Zusanli, Sanyinjiao and Hegu acu-points. Group MS received standardized palliative care and muscle stimulation nearby nonacupoint. Controlled group received standardized palliative care. The patients maintained their assigned acupuncture stimulation for 7 days. Demographic Instrument, Karnofsky Performance Scale Index, SF-16 health questionnaire and Self-Rating Anxiety Scale (SAS) were used. RESULTS: The mean SAS scores in TEAS Group before and after electrical intervention in palliative care intervention were 31.17+/ 7.55,34.58+/-13.98 and 27.86+/-6.73, (P=0.00) QoL score showed elevation from 57.13 in 8th day to 60.12 in 28th day, rising further to 5%. Comfort Score showed continuous elevation trend for 28 days. CONCLUSION: Electric acupuncture stimulation could reduce the anxiety of patients, promote rehabilitation and increase the quality of life among patients with lung cancer in palliative care. PMID- 28894707 TI - Health Literacy among Visitors of District Polyclinics in Almaty, Kazakhstan. AB - BACKGROUND: This study aimed to evaluate health literacy levels of patients in Almaty City, Kazakhstan and to identify socio-demographics and socio-economic factors related to their health literacy. METHODS: An international survey instrument HLS-EU-Q developed by the European Health Literacy Consortium was used in a cross-sectional study with 1000 citizens in the Almaty City at the age of 18 and over who visited the out-patient departments in the polyclinics between Feb and Oct 2014. RESULTS: There were 552 women and 446 men completed the survey, with mean ages as (41.8 +/- 13.9) and (44.7 +/- 15.2) yr old respectively, and women were significantly younger than men (P<0.001). Their general health literacy was (34.0 +/- 8.6) for men and (33.49 +/- 9.4) for women, without significant difference. In them, 15.5% or 30.0% were with inadequate or problematic health literacy. Multivariate linear regression analysis showed that higher general health literacy was positively and significantly associated with high self-assessed social status (B=3.86, P<0.001), ability to pay for medications (B=3.42, P<0.001), low frequency of watching health related TV programs (B=2.37, P<0.001), moderate community involvement (B=2.23, P=0.03). CONCLUSION: Specific demographic and socio-economic determinants related to health literacy were identified the first time in Kazakhstan. This would facilitate programs to improve health outcomes in Kazakhstan. PMID- 28894708 TI - Hepatic Proteins and Inflammatory Markers in Rheumatoid Arthritis Patients. AB - BACKGROUND: Rheumatoid arthritis is an autoimmune inflammatory rheumatic disease that causes chronic synovial inflammation eventually leading to joint destruction and disability. The aim of this study was to determine the variations of hepatic proteins, myeloperoxidase, and iron in rheumatoid arthritis Tunisian patients and their implications in inflammation and in iron metabolism. METHODS: Overall, 172 patients from the Rheumatology Department of the University Hospital "Farhat Hached", Sousse-Tunisia between 2011 and 2012, with rheumatoid arthritis (97.1% women, average age: 48+/-13 yr) and 147 healthy volunteers (70.1% women, average age: 46+/- 7 yr) were included in this study. Serum hepatic proteins (high sensitive C-reactive protein, ceruloplasmin, albumin, transferrin, alpha-1-acid glycoprotein and haptoglobin) were assessed by immunoturbidimetry (COBAS INTEGRA 400, Roche) and ferritin was measured by a microparticulate immunoenzymatic technic (AxSYM, ABBOTT, Germany), Plasma myeloperoxidase was determined by Enzyme Linked Immunosorbent Assay. Serum iron was measured according to a colorimetric method at 595 nm (CX9-BECKMANN Coulter-Fuller-Ton, CA). RESULTS: Significantly higher levels of high-sensitive C-reactive protein, alpha-1-acid glycoprotein, Haptoglobin and myeloperoxidase in patients compared to controls (P<10-3). Albumin and iron rates were significantly decreased in patients compared to healthy group (P=0.026 and P<10-3, respectively). There were no differences between cases and controls for levels of ceruloplasmin, transferrin and ferritin (P=0.782, P=0.808, and P=0.175, respectively). CONCLUSION: The high-sensitive C reactive protein, alpha-1-acid glycoprotein, and haptoglobin increased in acute phase proteins in rheumatoid arthritis disease. The pro-inflammatory cytokines affect iron metabolism leading to the iron deficiency and rheumatoid anemia, which influenced Tf and ferritin levels. PMID- 28894710 TI - Incidence of Medication Discrepancies and Its Predicting Factors in Emergency Department. AB - BACKGROUND: This study was conducted to evaluate the incidence of medication discrepancies and its related factors using medication reconciliation method in patients admitted to the emergency department of Tehran University of Medical Sciences hospitals. METHODS: In this cross-sectional study, 200 adult patients with at least one chronic disease that used two regular prescription medications were included in 2015. After 24 h of admission, demographic data and patient's home medications were collected. Medication discrepancies were assessed through comparison of a best possible medication history list with the physician's orders. RESULTS: Out of 200 patients (mean age, 61.5 yr; 86 males, 114 women), 77.5% of patients had one or more medication discrepancies. The most common discrepancies were medication omission (35.49%), change (14.22%) and substitution (10.97%), respectively. The relationship between number of comorbid conditions (P=0.025), regular home medications (P=<0.001), high-risk medications (P=0.032), medications pharmacological classes (P=<0.001) and medication discrepancies were statistically significant. Cardiovascular drugs compared to other medications classes showed the highest discrepancies (36.2%). Multiple logistic regression showed that the drug groups, including anti-infective for systemic use (OR=8.43; 95%CI 2.5-28.2; P=0.001), Antineoplastic and Immuno-modulator Agents (OR=0.49; 95%CI 0.27-0.87; P=0.016), Blood and Blood-Forming Organs (OR=0.33; 95%CI 0.21 0.52; P<0.001), Muscular-Skeletal System (OR=2.4; 95%CI 1.13-5.1; P=0.022), Nervous-System (OR=2.75; 95%CI 1.7-4.4; P<0.001), Respiratory-System (OR=0.38; 95%CI 0.22-0.67; P=0.001) were associated with the drug discrepancy. CONCLUSION: A medication discrepancy occurs commonly at hospital emergency department. Understanding the type and frequency of discrepancies with using structured medication reconciliation process can help clinicians to prevent them. PMID- 28894709 TI - Prognosis and Risk Factors Influencing Recurrence in Surgery-treated Patients with Primary Sacral Tumors. AB - BACKGROUND: We aimed to explore the prognosis and risk factors influencing tumor recurrence in surgery-treated patients with primary sacral tumors. METHODS: Fifty six patients between February 2011 and December 2016 in Yishui Central Hospital with primary sacral tumors were selected and treated with radical surgeries. The perioperative outcomes and postoperative neurological functions were observed. After postoperative follow-up, the overall survival time (OS), disease-free survival time (DFS), and recurrence were recorded to analyze the potential risk factors influencing tumor recurrence. RESULTS: The average surgical duration and intraoperative hemorrhagic volume were 3.92 +/- 1.46 h and 2, 348.21 +/- 813.67 ml, respectively. The postoperative short-term complications included three patients with infection from obstructed drainage and two with skin flap necrosis induced infection, who recovered after anti-infection therapies; nine with incision-edge necrosis; two with calf muscle venous thrombosis; and one with an endorhachis cerebrospinal fluid fistula, who recovered after conventional treatment. Among patients, the 1-, 2- and 3-year survival rates were 91.07% (51/56), 82.14% (46/56), and 75.00% (42/56) while the 1-, 2- and 3-year DFS rates were 89.29% (50/56), 78.57% (44/56) and 71.43% (40/56), respectively. Of the 56 patients, 16 had recurrence after surgery, with recurrence rate of 28.57%. It was predicated that surgical methods and local infiltration were the independent risk factors influencing tumor recurrence (P<0.01). CONCLUSION: The reservation of bilateral S3 or > unilateral S3 nerves can improve quality of life of patients. Surgical methods and local infiltration are the independent risk factors influencing tumor recurrence, and extensive resection can effectively control the recurrence rate. PMID- 28894711 TI - The Increasing Trend in Global Ranking of Websites of Iranian Medical Universities during January 2012-2015. AB - BACKGROUND: Researchers and academic institutions need assessment and rating to measure their performance. The criteria are designed to evaluate quality and adequacy of research and welcome by most universities as an international process to increase monitoring academic achievements. The study aimed to evaluate the increasing trend in global ranking of Iranian medical universities websites emphasizing on comparative approach. METHODS: This is a cross-sectional study involving websites of Iranian medical universities. Sampling was conducted by census selecting universities affiliated to the Ministry of Health in webometrics rating system. Web sites of Iranian medical universities were investigated based on the webometrics indicators, global ranking as well as the process of changing their rating. Universities of medical sciences were associated with improved ratings in seven periods from Jan 2012 until Jan 2015. RESULTS: The highest rank was in Jan 2014. Tehran University of Medical Sciences ranked the first in all periods. The highest ratings were about impact factor in universities of medical sciences reflecting the low level of this index in university websites. The least ranking was observed in type 1 universities. CONCLUSION: Despite the criticisms and weaknesses of these webometrics criteria, they are critical to this equation and should be checked for authenticity and suitability of goals. Therefore, localizing these criteria by the advantages model, ranking systems features, continuous development and medical universities evaluation based on these indicators provide new opportunities for the development of the country especially through online media. PMID- 28894712 TI - Evaluation of the Level of Zinc and Malondialdehyde in Basal Cell Carcinoma. AB - BACKGROUND: Basal Cell Carcinoma (BCC) is one of the most common skin cancers in the world and that use to lifestyle, increasing chemical pollutions, environmental factors and poor nutrition. The most important cause of this cancer is oxidative stress and free radicals so antioxidant activities for the body are so important. The aim of this study was to determine the variation of zinc and (Malondialdehyde) MDA in BCC patients. METHODS: This study has been performed on case and control patients from 2013 to 2014. The samples were collected from cell carcinoma patients at Razi Hospital in Tehran, Iran. We evaluated the level of zinc with the use of Atomic Absorption Spectroscopy (AAS) method. Besides, we evaluated MDA with colorimetric assay. RESULTS: The concentration of MDA was significantly higher in case group in comparison to control group (P=0.001). In addition, case group had lower concentration of zinc than the control group (P=0.000). There was no correlation between MDA and body mass index (BMI) and between zinc and BMI. CONCLUSION: All the patients with BCC showed a significant MDA serum in comparison with control group. However, significant decrease in zinc serum of the patients was seen that is because of consuming zinc during oxidative stress process so topical use of zinc in the form of 2+ ions could be effective on antioxidant protection against the sun UV radiation. PMID- 28894713 TI - Malignant Transformation in Leukoplakia and Its Associated Factors in Southern Iran: A Hospital Based Experience. AB - BACKGROUND: We evaluated factors that affect malignant transformation of leukoplakia in a sample of the Iranian population. METHODS: The records of patients with a clinical diagnosis of leukoplakia during a 20-year period from 1989-2009 referred to two of the largest referral centers in southern Iran were studied. Patients that developed malignant transformation were compared with patients that did not have malignant changes. RESULTS: Of 522 patients, female patients, those over 50 yr old and with lesions located on the tongue had the highest rate of malignant changes. Female patients with malignant changes were mostly non-smokers (76.4%), while male patients with malignant changes were mostly smokers (63.8% in non-smokers) (P<0.001). In our univariate analysis, male sex and smoking showed lower chances for malignant transformation (OR: 0.57; CI=0.397-0.822 and OR: 0.025; CI=0.141-0.299, respectively), while age above 50 was a risk factor for malignant transformation (OR: 3.57; CI=2.32-5.42). In the multivariate analysis, smoking (OR: 0.317; 95% CI=0.16-0.626) and morphological presentation as erythroplakia (OR: 0.025; 95% CI=0.005-0.131) had low chances for developing malignant changes, while site of lesion on the tongue (OR: 774; 95% CI=60-9838) and morphological presentation as erythroleukoplakia (OR: 6.26; 95% CI=3.16-12.38) were a risk factor for developing malignant changes. CONCLUSION: A follow-up program and further work-up should be considered for Iranian patients who have a leukoplakia lesion that is flat and are white patch or plaques with red components, in addition for patients who have lesions located on the tongue and for nonsmokers who develops leukoplakia lesions. PMID- 28894714 TI - Quantification of CDR1 Gene Expression in Fluconazole Resistant Candida Glabrata Strains Using Real-time PCR. AB - BACKGROUND: The opportunistic fungi, particularly Candida glabrata has been known as main etiologic agents of life-threating infections in some patients. Although fluconazole is the most effective antifungal agent against candidiasis, C. glabrata, fluconazole-resistant strains have been increased recently overexpression or mutations of ATP-binding cassette (ABC) transporter family membrane proteins such as; Cg CDR1, Cg CDR2 are responsible for fluconazole resistance in a large proportion of candidiasis cases. The aim of this study was to evaluate CDR1 gene expression level as one of main mechanism involved in this resistance using. METHODS: Candida glabrata strains were collected from various clinical samples in hospitals of Tehran in 2015 . After validation of all isolates by conventional and molecular methods, the susceptibility analysis to fluconazole of all isolates was performed using CLSI broth microdilution M27-A3 and M27-S4 protocols. Two isolates have been selected based on difference in susceptibility and CDR1-mRNA expression level of isolates was measured by Real time PCR method. RESULTS: Susceptibility results revealed that 32%, 64% and 4% of strains were susceptible, dose-dependent (DD) and resistant to fluconazole respectively. Furthermore, resistance strain of C. glabrata (MIC>=64 MUg/ml) showed overexpression of CDR1 compared with sensitive strain in Real-time PCR analysis. CONCLUSION: Thus, it is necessary to investigate the functions of CgCDR1 genes as a transporter-related gene. PMID- 28894715 TI - Survival Rates among Co-infected Patients with Human Immunodeficiency Virus/Tuberculosis in Tehran, Iran. AB - BACKGROUND: The number of deaths related with co-infection of tuberculosis (TB) and HIV remains inappropriately high worldwide. TB is anticipated to be the major reason of HIV-related deaths globally. This study aimed to find out and evaluate the characteristics of the possible risk factors influencing the survival time of co-infected patients with HIV/TB in Tehran the capital of Iran. METHODS: This retrospective study was performed on the referred patients to the one of two Behavioral Diseases Counseling Centers, Imam Khomeini, and Zamzam Centers, Tehran, Iran, in 2004-2013. Data were analyzed by Cox PH model utilizing SPSS16 statistical software. RESULTS: Multivariate analysis confirmed that the age at diagnosis (P=0.014), gender (P=0.002), sexual transmission (P=0.01), cotrimoxazole preventive therapy (P<0.001), and onset to TB after post-HIV diagnosis (P=0.01) were the parameters which had significant effects on the death of HIV/TBco-infected patients. CONCLUSION: The results, recommend interplay between different risk factors and the risk of death in co-infected patients with HIV/TB. We presented the barriers to higher-level organizational and functional integration for commitment to interfere with the modifiable risk factors, which effect on the mortality of patients. PMID- 28894717 TI - HBsAb and HBcAb Have No Significant Effect on the Progression of SLE and RA. PMID- 28894718 TI - Representative Characteristics of the HIV/AIDS-infected Young Persons in Romania in Terms of Their Personal and Professional Values, Needs and Resources. PMID- 28894719 TI - Patients Satisfaction with Dental Care in the Slovak Republic: A Cross-sectional Questionnaire Study. PMID- 28894716 TI - Seroprevalence of IgG Antibodies against Echinococcus granulosus by ELISA Method Using Recombinant Agb in Lorestan Province, Western Iran. AB - BACKGROUND: Cystic echinococcosis (CE) is a zoonotic disease with global prevalence, which causes considerable health problems and economic losses throughout the world. The aim of this study was to assess the seroepidemiology of CE in Doroud City, Lorestan Province, Iran, considered a neglected endemic location. METHODS: An ELISA was performed using recombinant AgB from Apr to Jul 2015 in Lorestan Province, Western Iran. The commercial Hydatidosis IgG ELISA kit (Vircell SL, Granada, Spain) was used to confirm the obtained results. RESULTS: In the present study, out of 927 collected sera, 25 samples (2.6%) were found as seropositive for E. granulosus IgG antibodies. The prevalence of IgG antibodies against E. granulosus was significantly higher in rural areas (3.24%) than in urban area (1.20%) (P<0.001). Moreover, there was no significant relationship between age, occupation, sex, and literacy with seropositivity (P>0.05). Moreover, there was no statistically significant difference between the prevalence of CE in males (13/349, 3.72%) and females (12/553, 2.12%). With regard to occupation, farmers and ranchmen had the highest rate of infection (5.5%). There was a significant association between eating unwashed vegetables and seropositivity (P<0.001). Seropositive cases in rural areas were more than in urban areas. CONCLUSION: Since all the seropositive cases used unwashed local vegetables, the contamination may occur through the consumption of such vegetables. PMID- 28894720 TI - Childhood Cancer Patterns in Iran: Challenges and Future Directions. PMID- 28894722 TI - The Relationship between Homocysteine Levels and Spontaneous Abortion in Iranian Women with Migraine. PMID- 28894721 TI - The Applications of Health Informatics in Medical Tourism Industry of Iran. PMID- 28894723 TI - Lead Poisoning among Opium Users in Iran: A Possible New Emerging Epidemic in the Region. PMID- 28894724 TI - Suppression of Expression Levels of Constitutive Androstane Receptor by Moderate Exercise in BALB/c Nude Mice with Breast Cancer. PMID- 28894725 TI - Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. AB - Immune checkpoint inhibitors (ICPIs), in the form of monoclonal antibodies against CTLA-4, PD-1, and PD-L1, have dramatically changed the treatment approach in several advanced cancers. Due to their mechanism of action, these novel agents are associated with a unique spectrum of immune-mediated adverse events (imAEs), with a safety profile that indicates they are better tolerated than traditional chemotherapeutic agents. This article aims to provide education on the current knowledge about imAEs associated with ICPI treatment, including strategies and tools for the prompt identification, evaluation, and optimal management of these events. The identification and management of imAEs are reviewed based on published literature, labeling guidelines, and the authors' personal experience with patients. The imAE safety profiles of ICPIs vary, depending on the specific antibody and the type of cancer being treated. Although most imAEs are mild and easily managed, early identification and proactive treatment are essential actions serving both to reduce the risk of developing severe imAEs and to maximize the potential for patients to receive the benefits of ongoing ICPI treatment. As a primary point of contact for patients undergoing oncology treatment, nurses play a critical role in identifying imAEs, educating patients about the importance of timely reporting of potentially relevant symptoms, and assisting in the treatment and follow-up of patients who develop imAEs while on ICPI therapy. PMID- 28894726 TI - Validation of a new three-dimensional imaging system using comparative craniofacial anthropometry. AB - BACKGROUND: The aim of this study is to validate a new three-dimensional craniofacial stereophotogrammetry imaging system (3dMDface) through comparison with manual facial surface anthropometry. The null hypothesis was that there is no difference between craniofacial measurements using anthropometry vs. the 3dMDface system. METHODS: Facial images using the new 3dMDface system were taken from six randomly selected subjects, sitting in natural head position, on six separate occasions each 1 week apart, repeated twice at each sitting. Exclusion criteria were excess facial hair, facial piercings and undergoing current dentofacial treatment. 3dMDvultus software allowed facial landmarks to be marked and measurements recorded. The same measurements were taken using manual anthropometry, using soluble eyeliner to pinpoint landmarks, and sliding and spreading callipers and measuring tape to measure distances. The setting for the investigation was a dental teaching hospital and regional (secondary and tertiary care) cleft centre. The main outcome measure was comparison of the craniofacial measurements using the two aforementioned techniques. RESULTS: The results showed good agreement between craniofacial measurements using the 3dMDface system compared with manual anthropometry. For all measurements, except chin height and labial fissure width, there was a greater variability with the manual method compared to 3D assessment. Overall, there was a significantly greater variability in manual compared with 3D assessments (p < 0.02). CONCLUSIONS: The 3dMDface system is validated for craniofacial measurements. PMID- 28894727 TI - Flap necrosis after palatoplasty in irradiated patient and its reconstruction with tunnelized-facial artery myomucosal island flap. AB - BACKGROUND: Tunneled transposition of the facial artery myomucosal (FAMM) island flap on the lingual side of the mandible has been reported for intraoral as well as oropharyngeal reconstruction. This modified technique overcomes the limitations of short range and dentition and further confirms the flexibility of the flap. This paper presents a case of reconstructing secondary soft palatal defect due to flap necrosis following two-flap palatoplasty in irradiated patient with lingually transposed facial artery myomucosal island flap. CASE PRESENTATION: The authors successfully reconstructed secondary soft palatal defect due to flap necrosis following two-flap palatoplasty in an irradiated 59 year-old female patient with tunnelized-facial artery myomucosal island flap (t FAMMIF). CONCLUSIONS: Islanding and tunneling modification extends the versatility of the FAMM flap in the reconstruction of soft palatal defects post tumor excision and even after radiation, giving a great range of rotation and eliminating the need for revision in a second stage procedure. The authors thus highly recommend this versatile flap for the reconstruction of small and medium sized oral defects. PMID- 28894728 TI - Treatment of the Enlarged Clitoris. AB - Management of the enlarged clitoris, because of its import for sexual function, has been and remains one of the most controversial topics in pediatric urology. Early controversy surrounding clitoroplasty resulted from many factors including an incomplete understanding of clitoral anatomy and incorrect assumptions of the role of the clitoris in sexual function. With a better understanding of anatomy and function, procedures have evolved to preserve clitoral tissue, especially with respect to the neurovascular bundles. These changes have been made in an effort to preserve clitoral sensation and preserve orgasmic potential. It is the goal of this manuscript to describe the different procedures that have been developed for the surgical management of clitoromegally, with emphasis on the risks and benefits of each. Equally important to any discussion of such a sensitive topic is an understanding of long-term patient outcomes. As we will see, despite its importance, there has been a dearth of data in this regard. Future work in the arena of patient satisfaction will undoubtedly play a major role in directing our surgical approach. PMID- 28894729 TI - Procalcitonin for Diagnostics and Treatment Decisions in Pediatric Lower Respiratory Tract Infections. AB - Mortality and morbidity remain high in pediatric lower respiratory tract infections (LRTIs) despite progress in research and implementation of global diagnostic and treatment strategies in the last decade. Still, 120 million annual episodes of pneumonia affect children younger than 5 years each year leading to 1.3 million fatalities with the major burden of disease carried by low- and middle-income countries (95%). The definition of pneumonia is still challenging. Traditional diagnostic measures (i.e., chest radiographs, C-reactive protein) are unable to distinguish viral and from bacterial etiology. As a result, common antibiotic overuse contributes to growing antibiotic resistance. We present an overview of current evidence from observational and randomized controlled trials on a procalcitonin (PCT)-based diagnosis of pediatric LRTIs and discuss the need for an adequate PCT threshold for antibiotic treatment decision-making. PMID- 28894730 TI - Specialty Grand Challenge In Pediatric Infectious Diseases. PMID- 28894731 TI - Prevalence of Genotypes That Determine Resistance of Staphylococci to Macrolides and Lincosamides in Serbia. AB - Macrolides, lincosamides, and streptogramins (MLS) resistance genes are responsible for resistance to these antibiotics in Staphylococcus infections. The purpose of the study was to analyze the distribution of the MLS resistance genes in community- and hospital-acquired Staphylococcus isolates. The MLS resistance phenotypes [constitutive resistance to macrolide-lincosamide-streptogramin B (cMLSb), inducible resistance to macrolide-lincosamide-streptogramin B (iMLSb), resistance to macrolide/macrolide-streptogramin B (M/MSb), and resistance to lincosamide-streptogramin A/streptogramin B (LSa/b)] were determined by double disc diffusion method. The presence of the MLS resistance genes (ermA, ermB, ermC, msrA/B, lnuA, lnuB, and lsaA) were determined by end-point polymerase chain reaction in 179 isolates of staphylococci collected during 1-year period at the Center for Microbiology of Public Health Institute in Vranje. The most frequent MLS phenotype among staphylococcal isolates, both community-acquired and hospital acquired, was iMLSb (33.4%). The second most frequent was M/MSb (17.6%) with statistically significantly higher number of hospital-acquired staphylococcal isolates (p < 0.05). MLS resistance was mostly determined by the presence of msrA/B (35.0%) and ermC (20.8%) genes. Examined phenotypes were mostly determined by the presence of one gene, especially by msrA/B (26.3%) and ermC (14.5%), but 15.6% was determined by a combination of two or more genes. M/MSb phenotype was the most frequently encoded by msrA/B (95.6%) gene, LSa/b phenotype by lnuA (56.3%) gene, and iMLSb phenotype by ermC (29.4%) and ermA (25.5%) genes. Although cMLSb phenotype was mostly determined by the presence of ermC (28.9%), combinations of two or more genes have been present too. This pattern was particularly recorded in methicillin-resistant Staphylococcus aureus (MRSA) (58.3%) and methicillin-resistant coagulase-negative staphylococci (MRCNS) (90.9%) isolates with cMLSB phenotype. The msrA/B gene and M/MSb phenotype were statistically significantly higher in hospital-acquired than community-acquired staphylococci strains (p < 0.05). There are no statistically significant differences between staphylococci harboring the rest of MLS resistance genes acquired in community and hospital settings (p > 0.05). The prevalence of iMLSb phenotypes may change over time, so it is necessary to perform periodic survey of MLS resistance phenotypes, particularly where the D-test is not performed routinely. PMID- 28894732 TI - Analysis of Historical Trends and Recent Elimination of Malaria from Sri Lanka and Its Applicability for Malaria Control in Other Countries. AB - Sri Lanka is a tropical island located South of India in the Indian Ocean. Malaria has been prevalent in the island for centuries but the country succeeded in eliminating the disease in 2013. Factors governing the past endemicity of malaria and its successful elimination from Sri Lanka in 2013 are analyzed. There is evidence that malaria might have been first introduced in the thirteenth century into a dry zone area with extensive irrigation works. Regular widespread epidemics of the disease have been documented in the twentieth century. The island nature of Sri Lanka, generally low transmission rates, widespread and accessible government hospitals and clinics that provide free and readily available diagnosis and treatment for malaria, adequate financial support and commitment to the Antimalaria Campaign (AMC), national and decentralized malaria control efforts sustained over a long period by dedicated and competent AMC staff, and the absence of zoonotic malaria are recognized as key factors responsible for eliminating malaria from Sri Lanka. These factors are analyzed in the context of their relevance to the present malaria elimination efforts in other countries with the overall aim of globally eradicating the disease. PMID- 28894733 TI - The Impact of Maternal Self-Efficacy and Oral Health Beliefs on Early Childhood Caries in Latino Children. AB - OBJECTIVES: Latino children experience one of the highest rates of early childhood caries requiring interventions based on valid conceptual frameworks. The Health Belief Model has relevance as a predictor of compliance with health recommendations based on perceptions of a health condition and behaviors to avoid the condition. The model encompasses four perceptual constructs (susceptibility, severity, benefits, barriers) and, for complex conditions, includes self-efficacy as an extended model. This study evaluated individual (self-efficacy and health beliefs) and cultural (acculturation status) level factors and the inter relationship to determine if items assessed for the Extended Health Belief Model (EHBM) were valid measures of maternal factors. METHODS: A cross-sectional study was conducted with 100 mother-child dyads at the Dental Center of Children's Hospital Colorado, Aurora, CO, USA. Participating mothers completed a survey in English or Spanish with items from the Basic Research Factors Questionnaire encompassing sociodemographic characteristics, oral health knowledge and behavior, and psychosocial measures including the EHBM. Language preference was a proxy for maternal acculturation. Children were examined to measure decayed, missing, and filled tooth surfaces. Internal consistency reliability of each subscale was evaluated using Cronbach's alpha. Convergent validity was assessed using linear regression to evaluate the association of the EHBM subscales with oral health-related measures and language preference. RESULTS: The benefits and self-efficacy scales reflected good reliability. Maternal education was the strongest predictor of health beliefs with significant associations for barriers, benefits, and susceptibility. Perceived benefits increased with each additional year in the household. There was a significant association between maternal oral health knowledge and higher perceived benefits and increased self-efficacy, and the same was found for higher knowledge of dental utilization which was also associated with children perceived as having increased susceptibility to early childhood caries. Less acculturated participants perceived more barriers to behavioral adherence and fewer barriers as knowledge increased. As dental utilization knowledge improved for Spanish-speaking participants, they perceived greater benefits from adherent oral health behavior compared to English-speaking participants. CONCLUSION: Items assessed for the EHBM were valid as measures of maternal factors influencing children's oral health outcomes in a Latino population. PMID- 28894734 TI - Rugged Large Volume Injection for Sensitive Capillary LC-MS Environmental Monitoring. AB - A rugged and high throughput capillary column (cLC) LC-MS switching platform using large volume injection and on-line automatic filtration and filter back flush (AFFL) solid phase extraction (SPE) for analysis of environmental water samples with minimal sample preparation is presented. Although narrow columns and on-line sample preparation are used in the platform, high ruggedness is achieved e.g., injection of 100 non-filtrated water samples did not result in a pressure rise/clogging of the SPE/capillary columns (inner diameter 300 MUm). In addition, satisfactory retention time stability and chromatographic resolution were also features of the system. The potential of the platform for environmental water samples was demonstrated with various pharmaceutical products, which had detection limits (LOD) in the 0.05-12.5 ng/L range. Between-day and within-day repeatability of selected analytes were <20% RSD. PMID- 28894735 TI - Navigating the Functional Landscape of Transcription Factors via Non-Negative Tensor Factorization Analysis of MEDLINE Abstracts. AB - In this study, we developed and evaluated a novel text-mining approach, using non negative tensor factorization (NTF), to simultaneously extract and functionally annotate transcriptional modules consisting of sets of genes, transcription factors (TFs), and terms from MEDLINE abstracts. A sparse 3-mode term * gene * TF tensor was constructed that contained weighted frequencies of 106,895 terms in 26,781 abstracts shared among 7,695 genes and 994 TFs. The tensor was decomposed into sub-tensors using non-negative tensor factorization (NTF) across 16 different approximation ranks. Dominant entries of each of 2,861 sub-tensors were extracted to form term-gene-TF annotated transcriptional modules (ATMs). More than 94% of the ATMs were found to be enriched in at least one KEGG pathway or GO category, suggesting that the ATMs are functionally relevant. One advantage of this method is that it can discover potentially new gene-TF associations from the literature. Using a set of microarray and ChIP-Seq datasets as gold standard, we show that the precision of our method for predicting gene-TF associations is significantly higher than chance. In addition, we demonstrate that the terms in each ATM can be used to suggest new GO classifications to genes and TFs. Taken together, our results indicate that NTF is useful for simultaneous extraction and functional annotation of transcriptional regulatory networks from unstructured text, as well as for literature based discovery. A web tool called Transcriptional Regulatory Modules Extracted from Literature (TREMEL), available at http://binf1.memphis.edu/tremel, was built to enable browsing and searching of ATMs. PMID- 28894737 TI - FMECA Application to Intraoperative Electron Beam Radiotherapy Procedure As a Quality Method to Prevent and Reduce Patient's Risk in Conservative Surgery for Breast Cancer. AB - INTRODUCTION: Failure Mode Effects and Criticalities Analysis (FMECA) represents a prospective method for risk assessment in complex medical practices. Our objective was to describe the application of FMECA approach to intraoperative electron beam radiotherapy (IOERT), delivered using a mobile linear accelerator, for the treatment of early breast cancer as an anticipated boost. MATERIALS AND METHODS: A multidisciplinary Working Group, including several different professional profiles, was created before the beginning of clinical practice in 2012, with the purpose of writing the Flow Chart and applying the FMECA methodology to IOERT procedure. Several criticalities were identified a priori in the different steps of the procedure and a list of all potential failure modes (FMs) was drafted and ranked using the risk priority number (RPN) scoring system, based on the product of three parameters: severity, occurrence, and detectability (score between 1 and 5). The actions aimed at reducing the risk were then defined by the Working Group and the risk analysis was repeated in 2014 and in 2016, in order to assess the improvement achieved. RESULTS: Fifty-one FMs were identified, which represented the issues prospectively investigated according to the FMECA methodology. Considering a set threshold of 30, the evaluated RPNs show that 33 out of 51 FMs are critical; 6 are included in the moderate risk class (RPN: 31 40); 16 in the intermediate risk class (RPN: 41-50), and 11 in the high risk class (RPN: >50). DISCUSSION: The most critical steps concerned the surgical procedure and IOERT set-up. The introduction of the corrective actions into the clinical practice achieved the reduction of the RPNs in the re-analysis of the FMECA worksheet after 2 and 4 years, respectively. CONCLUSION: FMECA proved to be a useful tool for prospective evaluation of potential failures in IOERT and contributed to optimize patient safety and to improve risk management culture among all the professionals of the Working Group. PMID- 28894736 TI - Synthetic Gene Expression Circuits for Designing Precision Tools in Oncology. AB - Precision medicine in oncology needs to enhance its capabilities to match diagnostic and therapeutic technologies to individual patients. Synthetic biology streamlines the design and construction of functionalized devices through standardization and rational engineering of basic biological elements decoupled from their natural context. Remarkable improvements have opened the prospects for the availability of synthetic devices of enhanced mechanism clarity, robustness, sensitivity, as well as scalability and portability, which might bring new capabilities in precision cancer medicine implementations. In this review, we begin by presenting a brief overview of some of the major advances in the engineering of synthetic genetic circuits aimed to the control of gene expression and operating at the transcriptional, post-transcriptional/translational, and post-translational levels. We then focus on engineering synthetic circuits as an enabling methodology for the successful establishment of precision technologies in oncology. We describe significant advancements in our capabilities to tailor synthetic genetic circuits to specific applications in tumor diagnosis, tumor cell- and gene-based therapy, and drug delivery. PMID- 28894738 TI - Cancer-Associated Venous Thromboembolism: A Practical Review Beyond Low-Molecular Weight Heparins. AB - Patients with cancer are at significantly higher risk of developing, and dying from, venous thromboembolism (VTE). The CLOT trial demonstrated superiority of low-molecular-weight heparins (LMWH) over warfarin for recurrent VTE and established LMWH as the standard of care for cancer-associated VTE. However, with patients living longer with metastatic cancer, long-term injections are associated with significant cost and injection fatigue. Direct oral anticoagulants (DOACs) are an attractive alternative for treatment of cancer associated VTE. Meta-analysis of subgroup data of patients with cancer from the large DOAC VTE trials and small non-randomized studies have found no difference in VTE recurrence or major bleeding. With this limited evidence, clinicians may decide to switch their patients who require long-term anticoagulation from LMWH to a DOAC. This requires careful consideration of the interplay between the patient's cancer and treatment course, with their underlying comorbidities. PMID- 28894739 TI - Immune-modulating Activity of Hydrogel Microparticles Contributes to the Host Defense in a Murine Model of Cutaneous Anthrax. AB - We recently reported that the open-mesh (0.7 MU) polyacrylamide microparticles (MPs) with internally-coupled Cibacron affinity dye demonstrate protective effect in mice challenged into footpads with high doses (200 LD50) of anthrax (Sterne) spores. A single injection of MPs before spore challenge reduces inflammatory response, delays onset of mortality and promotes survival. In this study, we show that the effect of MPs was substantially increased at the lower spore dose (7 LD50). The inflammation of footpads was reduced to the background level, and 60% of animals survived for 16 days while all untreated infected animals died within 6 days with strong inflammation. The effects of MPs were promoted when the MPs were loaded with a combination of neutrophil-attracting chemokines IL-8 and MIP 1alpha which delayed the onset of mortality in comparison with untreated mice for additional 8 days. The MPs were not inherently cytotoxic against the bacteria or cultured murine Raw 264.7 cells, but stimulated these cells to release G-CSF, MCP 1, MIP-1alpha, and TNF-alpha. Consistent with this finding the injection of MPs induced neutrophil influx into footpads, stimulated production of TNF-alpha associated with migration of pERK1/2-positive cells with the Langerhans phenotype from epidermis to regional lymph nodes. Our data support the mechanism of protection in which the immune defense induced by MPs along with the exogenous chemokines counterbalances the suppressive effect caused by anthrax infection. PMID- 28894740 TI - Increased whole cerebellar serotonin in aged C57BL/6 mice. AB - Mobility and locomotor impairments have high prevalence, morbidity, and significant mortality in older adult populations. Cerebellar functional changes have been implicated in the pathogenesis of these age-related mobility and gait deficits unrelated to stroke, Parkinson's disease, or degenerative joint disease. We thus examined total cerebellar glutamate, glutamine, GABA, glycine, dopamine, norepinephrine, tryptophan, serotonin, alanine, threonine, and asparagine content from male 2-3-month (young, n = 6) and 21-24-month-old (aged, n = 6) C57BL/6 mice. Neurotransmitter and amino acid concentrations were determined by high performance liquid chromatography followed with mass spectroscopy. We found a significant increase in cerebellar serotonin in aged versus young mice, but otherwise no significant phenotypic differences in measured neurotransmitter concentrations. Applying current thought about cerebellar aging and cerebellar serotonergic systems, we consider how this age-related increase in cerebellar serotonin may contribute to gait ataxia. PMID- 28894741 TI - Digital health and the challenge of health systems transformation. AB - Information and communication technologies have transformed all sectors of society. The health sector is no exception to this trend. In light of "digital health", we see multiplying numbers of web platforms and mobile health applications, often brought by new unconventional players who produce and offer services in non-linear and non-hierarchal ways, this by multiplying access points to services for people. Some speak of a "uberization" of healthcare. New realities and challenges have emerged from this paradigm, which question the abilities of health systems to cope with new business and economic models, governance of data and regulation. Countries must provide adequate responses so that digital health, based increasingly on disruptive technologies, can benefit for all. PMID- 28894742 TI - Challenges in implementing mHealth interventions: a technical perspective. AB - Over the years, the healthcare community has witnessed many improvements in methods and technologies used in healthcare delivery, including mHealth as an emerging area of healthcare applications to improve access to health services. However, challenges involved in implementing mHealth to optimal advantage do exist. In this article, we identify some of the most important challenges and propose feasible solutions. PMID- 28894743 TI - mHealth based interventions for the assessment and treatment of psychotic disorders: a systematic review. AB - The relative burden of mental health disorders is increasing globally, in terms of prevalence and disability. There is limited data available to guide treatment choices for clinicians in low resourced settings, with mHealth technologies being a potentially beneficial avenue to bridging the large mental health treatment gap globally. The aim of the review was to search the literature systematically for studies of mHealth interventions for psychosis globally, and to examine whether mHealth for psychosis has been investigated. A systematic literature search was completed in Embase, Medline, PsychINFO and Evidence Based Medicine Reviews databases from inception to May 2016. Only studies with a randomised controlled trial design that investigated an mHealth intervention for psychosis were included. A total of 5690 records were identified with 7 studies meeting the inclusion criteria. The majority of included studies, were conducted across Europe and the United Sates with one being conducted in China. The 7 included studies examined different parameters, such as Experiential Sampling Methodology (ESM), medication adherence, cognitive impairment, social functioning and suicidal ideation in veterans with schizophrenia. Considering the increasing access to mobile devices globally, mHealth may potentially increase access to appropriate mental health care. The results of this review show promise in bridging the global mental health treatment gap, by enabling individuals to receive treatment via their mobile phones, particularly for those individuals who live in remote or rural areas, areas of high deprivation and for those from low resourced settings. PMID- 28894745 TI - Monitoring intervention fidelity of a lifestyle behavioral intervention delivered through telehealth. AB - BACKGROUND: Technology-based lifestyle behavioral interventions (i.e., telehealth, mHealth, eHealth, and/or digital health) are becoming an alternative standard of care and possess several advantages over traditional clinical settings such as convenience, cost, and the ability to tailor plans and feedback to a participant's individual needs. These technology-based interventions also present unique challenges to intervention fidelity due to extra elements involved in executing the intervention. Intervention fidelity monitoring is essential to ensure internal and external validity, yet the development and utilization of fidelity protocols is under-reported in the literature. The purpose of this paper is to describe the intervention fidelity protocol for the 24-START study, a behavior change intervention delivered through telephone and internet. This paper also discusses the results of a pilot audit conducted to determine the feasibility of monitoring adherence to the fidelity protocol. METHODS: The 24 START fidelity protocol was developed in accordance with the five fidelity areas outlined by the NIH Behavior Change Consortium (NIH BCC) including: design of study, provider training, delivery of treatment, receipt of treatment, and enactment of treatment. The fidelity strategies provided by the NIH BCC in each area were tailored to fit the specific design of the 24-START study. Twenty-six total fidelity strategies were developed in accordance with the five areas and a corresponding fidelity monitoring plan was created. Because these strategies are only beneficial if implemented, the fidelity monitoring plan was developed to ensure the fidelity strategies are consistently implemented over the course of the intervention. RESULTS: A pilot audit of nine participant files was conducted to test the feasibility of the fidelity protocol developed. Out of the nine participant files reviewed, 89% of scheduled phone calls between a telehealth coach and participant were successfully completed. Of the completed calls, telehealth coaches delivered the intervention as intended 85.3% of the time, and 74% of planned secondary contacts made through the internet were delivered successfully. Additionally, between treatment group dosing was found to be equal. Several weak areas in the fidelity protocol were identified for improvement. The results were satisfactory and the audit was deemed feasible for ongoing use. CONCLUSIONS: The NIH BCC provides a valuable framework for telehealth interventions to develop fidelity protocols ultimately contributing to improved internal and external validity, better translation of results, increased transparency, and increased opportunities for replication within the field. The 24-START pilot audit found the fidelity protocol efficacious and feasible while also identifying areas of weakness in need of revision. The refined protocol will continue to be utilized throughout the data collection phase. Future telehealth interventions should develop and disclose fidelity protocols to improve the overall quality and standard of telehealth interventions. PMID- 28894744 TI - Advances in mobile mental health: opportunities and implications for the spectrum of e-mental health services. AB - Mobile health (mHealth), telemedicine and other technology-based services facilitate mental health service delivery and may be considered part of an e mental health (eMH) spectrum of care. Web- and Internet-based resources provide a great opportunity for the public, patients, healthcare providers and others to improve wellness, practice prevention and reduce suffering from illnesses. Mobile apps offer portability for access anytime/anywhere, are inexpensive versus traditional desktop computers, and have additional features (e.g., context-aware interventions and sensors with real-time feedback. This paper discusses mobile mental health (mMH) options, as part of a broader framework of eMH options. The evidence-based literature shows that many people have an openness to technology as a way to help themselves, change behaviors and engage additional clinical services. Studies show that traditional video-based synchronous telepsychiatry (TP) is as good as in-person service, but mHealth outcomes have been rarely, directly compared to in-person and other eMH care options. Similarly, technology options added to in-person care or combined with others have not been evaluated nor linked with specific goals and desired outcomes. Skills and competencies for clinicians are needed for mHealth, social media and other new technologies in the eMH spectrum, in addition to research by randomized trials and study of health service delivery models with an emphasis on effectiveness. PMID- 28894746 TI - Behavioral health characteristics of a technology-enabled sample of Alzheimer's caregivers with high caregiver burden. AB - BACKGROUND: Caregivers of persons with dementia/Alzheimer's disease (AD) experience considerable physical and psychological burdens associated with their caregiving role. Although mobile technologies have the potential to deliver caregiver supports, it is necessary to demonstrate that caregivers in need of these supports are technology-enabled, that they can be identified and accessed, and that they experience the same unfavorable mental health outcomes characteristic of the broader caregiving population. Our objective was to enroll a cohort of technology-enabled caregivers to determine basic demographic characteristics and assess level of caregiver burden, depression, anxiety, and sleep disturbance as part of a larger project to deliver caregiver support. METHODS: Web-based enrollment and data collection measuring caregiver burden with the Zarit Burden Interview (ZBI), anxiety and depression with the M-3, and sleep disturbance with the PROMIS Sleep Disturbance form. RESULTS: A total of 165 caregivers enrolled via an online portal, all of whom provided care for someone with AD and owned a smart phone. Mean age of this group with 57.9 years, 90.3% was female, 88.5% was White, 51.5% reported providing care for a parent, 9.3% reported providing care for more than 10 years, and 24.8% reported providing more than 100 hours of care each week. Sixty-four percent of caregivers screened positive for both anxiety and depression, and nearly 62% of the sample had moderate or severe caregiver burden. Scores on depression, anxiety, and sleep quality assessments correlated moderately or strongly with caregiver burden. CONCLUSIONS: Dementia caregivers with Internet and smartphone access demonstrate high levels of caregiver burden, depression, and anxiety, and are well-suited to receive caregiver support services delivered via mobile devices that target these issues. PMID- 28894747 TI - miRNA Expression Profile and Effect of Wenxin Granule in Rats with Ligation Induced Myocardial Infarction. AB - Wenxin Granule (WXKL) is a traditional Chinese medicine used for treatment of myocardial infarction (MI) and arrhythmias. However, the genomic pathological mechanisms of MI and mechanisms of WXKL are largely unknown. This study aims to investigate a comprehensive miRNA expression profile, and the predicted correlation pathways to be targeted by differentially expressed miRNAs in MI, and mechanisms of WXKL from a gene level. MI rat model was established by a coronary artery ligation surgery. miRNA expression microarrays were performed and the data were deposited in Gene Expression Omnibus (GEO number GSE95855). And, pathway analysis was performed by using the DIANA-miRPath v3.0 online tool. The expressions of miR-1, miR-133, Cx43, and Cx45 were detected by quantitative real time PCR. It was found that 35 differentially expressed miRNAs and 23 predicted pathways, including miR-1, miR-133, and gap junction pathway, are involved in the pathogenesis of MI. And, WXKL increased the expressions of miR-1 and miR-133, while also increased the mRNA levels of Cx43 and Cx45, and, especially, recovered the Cx43/Cx45 ratio near to normal level. The results suggest that regulatory effects on miR-1, miR-133, Cx43, and Cx45 might be a possible mechanism of WXKL in the treatment of MI at the gene level. PMID- 28894748 TI - New Antihyperglycemic Drugs and Heart Failure: Synopsis of Basic and Clinical Data. AB - The assessment of the cardiovascular safety profile of any newly developed antihyperglycemic drug is mandatory before registration, as a meta-analysis raised alarm describing a significant increase in myocardial infarction with the thiazolidinedione rosiglitazone. The first results from completed cardiovascular outcome trials are already available: TECOS, SAVOR-TIMI, and EXAMINE investigated dipeptidyl peptidase 4 (DPP-4) inhibitors, ELIXA, LEADER, and SUSTAIN-6 investigated glucagon-like peptide 1 (GLP-1) receptor agonists, and EMPA-REG OUTCOME and CANVAS investigated sodium-dependent glucose transporter 2 (SGLT-2) inhibitors. LEADER, SUSTAIN-6, EMPA-REG OUTCOME, and CANVAS showed potential beneficial results, while the SAVOR-TIMI trial had an increased rate of hospitalization for heart failure. Meanwhile, the same drugs are investigated in preclinical experiments mainly using various animal models, which aim to find interactions and elucidate the underlying downstream mechanisms between the antihyperglycemic drugs and the cardiovascular system. Yet the direct link for observed effects, especially for DPP-4 and SGLT-2 inhibitors, is still unknown. Further inquiry into these mechanisms is crucial for the interpretation of the clinical trials' outcome and, vice versa, the clinical trials provide hints for an involvement of the cardiovascular system. The synopsis of preclinical and clinical data is essential for a detailed understanding of benefits and risks of new antihyperglycemic drugs. PMID- 28894749 TI - Efficacy of Blood Sources and Artificial Blood Feeding Methods in Rearing of Aedes aegypti (Diptera: Culicidae) for Sterile Insect Technique and Incompatible Insect Technique Approaches in Sri Lanka. AB - INTRODUCTION: Selection of the artificial membrane feeding technique and blood meal source has been recognized as key considerations in mass rearing of vectors. METHODOLOGY: Artificial membrane feeding techniques, namely, glass plate, metal plate, and Hemotek membrane feeding method, and three blood sources (human, cattle, and chicken) were evaluated based on feeding rates, fecundity, and hatching rates of Aedes aegypti. Significance in the variations among blood feeding was investigated by one-way ANOVA, cluster analysis of variance (ANOSIM), and principal coordinates (PCO) analysis. RESULTS: Feeding rates of Ae. aegypti significantly differed among the membrane feeding techniques as suggested by one way ANOVA (p < 0.05). The metal plate method was identified as the most efficient and cost-effective feeding technique. Blood feeding rate of Ae. aegypti was higher with human blood followed by cattle and chicken blood, respectively. However, no significant difference was observed from the mosquitoes fed with cattle and human blood, in terms of fecundity, oviposition rate, and fertility as suggested by one-way ANOVA (p > 0.05). CONCLUSIONS: Metal plate method could be recommended as the most effective membrane feeding technique for mass rearing of Ae. aegypti, due to its high feeding rate and cost effectiveness. Cattle blood could be recommended for mass rearing Ae. aegypti. PMID- 28894750 TI - Factor XIII Subunit A in the Skin: Applications in Diagnosis and Treatment. AB - The role of factor XIII subunit A (FXIII-A) is not restricted to hemostasis. FXIII-A is also present intracellularly in several human cells and serves as a diagnostic marker in a wide range of dermatological diseases from inflammatory conditions to malignancies. In this review, we provide a guide on the still controversial interpretation of dermal cell types expressing FXIII-A and assess the previously described mechanisms behind their accumulation under physiological and pathological conditions of the human skin. We summarize the intracellular functions of FXIII-A as well as its possible sources in the extracellular space of the dermis with a focus on its relevance to skin homeostasis and disease pathogenesis. Finally, the potential role of FXIII-A in wound healing, as a field with long-term therapeutic implications, is also discussed. PMID- 28894751 TI - Peripheral Inhibitor of AChE, Neostigmine, Prevents the Inflammatory Dependent Suppression of GnRH/LH Secretion during the Follicular Phase of the Estrous Cycle. AB - The study was designed to test the hypothesis that the inhibition of acetylcholinesterase (AChE) activity at the periphery by Neostigmine (0.5 mg/animal) will be sufficient to prevent inflammatory dependent suppression of the gonadotropin-releasing hormone (GnRH)/luteinising hormone (LH) secretion in ewes in the follicular phase of the estrous cycle, and this effect will be comparable with the systemic AChE inhibitor, Donepezil (2.5 mg/animal). An immune/inflammatory challenge was induced by peripheral administration of lipopolysaccharide (LPS; 400 ng/kg). Peripheral treatment with Donepezil and Neostigmine prevented the LPS-induced decrease (P < 0.05) in LHbeta gene expression in the anterior pituitary gland (AP) and in LH release. Moreover, Donepezil completely abolished (P < 0.05) the suppressory effect of inflammation on GnRH synthesis in the preoptic area, when pretreatment with Neostigmine reduced (P < 0.05) the decrease in GnRH content in this hypothalamic structure. Moreover, administration of both AChE inhibitors diminished (P < 0.05) the inhibitory effect of LPS treatment on the expression of GnRH receptor in the AP. Our study shows that inflammatory dependent changes in the GnRH/LH secretion may be eliminated or reduced by AChE inhibitors suppressing inflammatory reaction only at the periphery such as Neostigmine, without the need for interfering in the central nervous system. PMID- 28894752 TI - Identification of Multiple Dehalogenase Genes Involved in Tetrachloroethene-to Ethene Dechlorination in a Dehalococcoides-Dominated Enrichment Culture. AB - Chloroethenes (CEs) are widespread groundwater toxicants that are reductively dechlorinated to nontoxic ethene (ETH) by members of Dehalococcoides. This study established a Dehalococcoides-dominated enrichment culture (designated "YN3") that dechlorinates tetrachloroethene (PCE) to ETH with high dechlorination activity, that is, complete dechlorination of 800 MUM PCE to ETH within 14 days in the presence of Dehalococcoides species at 5.7 +/- 1.9 * 107 copies of 16S rRNA gene/mL. The metagenome of YN3 harbored 18 rdhA genes (designated YN3rdhA1 18) encoding the catalytic subunit of reductive dehalogenase (RdhA), four of which were suggested to be involved in PCE-to-ETH dechlorination based on significant increases in their transcription in response to CE addition. The predicted proteins for two of these four genes, YN3RdhA8 and YN3RdhA16, showed 94% and 97% of amino acid similarity with PceA and VcrA, which are well known to dechlorinate PCE to trichloroethene (TCE) and TCE to ETH, respectively. The other two rdhAs, YN3rdhA6 and YN3rdhA12, which were never proved as rdhA for CEs, showed particularly high transcription upon addition of vinyl chloride (VC), with 75 +/- 38 and 16 +/- 8.6 mRNA copies per gene, respectively, suggesting their possible functions as novel VC-reductive dehalogenases. Moreover, metagenome data indicated the presence of three coexisting bacterial species, including novel species of the genus Bacteroides, which might promote CE dechlorination by Dehalococcoides. PMID- 28894753 TI - Evaluation of Epigallocatechin-3-gallate Modified Collagen Membrane and Concerns on Schwann Cells. AB - Collagen is an essential component of the extracellular matrix (ECM) and is a suitable material for nerve repair during tissue remodeling for fracture repair. Epigallocatechin-3-gallate (EGCG), an extract of green tea, shows various biological activities that are beneficial to nerve repair. Here, we developed modified collagen containing different concentrations of EGCG (0.0064%, 0.064%, and 0.64%, resp.) to induce Schwann cell proliferation and differentiation. Cell Counting Kit-8 test, live/dead assay, and SEM showed that collagen cross-linked by EGCG induced Schwann cell proliferation. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting revealed that EGCG modified collagen induced Schwann cell differentiation and downregulated reactive oxygen species (ROS) levels by downregulating the MAPK P38 signaling pathway. Our results indicate that collagen cross-linked with an appropriate concentration of EGCG induces the proliferation and differentiation of Schwann cells. The EGCG modified collagen membrane may be applicable for nerve repair and guided tissue regeneration applications. PMID- 28894755 TI - Cereblon: A Protein Crucial to the Multiple Functions of Immunomodulatory Drugs as well as Cell Metabolism and Disease Generation. AB - It is well known that cereblon is a key protein in autosomal recessive nonsyndromic mental retardation. Studies have reported that it has an intermediary role in helping immunomodulatory drugs perform their immunomodulatory and tumoricidal effects. In addition, cereblon also regulates the expression, assembly, and activities of other special proteins related to cell proliferation and metabolism, resulting in the occurrence and development of metabolic diseases. This review details the multiple functions of cereblon and the underlying mechanisms. We also put forward some unsolved problems, including the intrinsic mechanism of cereblon function and the possible regulatory mechanisms of its expression. PMID- 28894757 TI - A Biomechanical and Clinical Comparison of Midshaft Clavicle Plate Fixation: Are 2 Screws as Good as 3 on Each Side of the Fracture? AB - BACKGROUND: The standard of care for plating displaced midshaft clavicle fractures has been 6 cortices of purchase on each side of the fracture. The use of locking plates and screws may afford equivalent biomechanical strength with fewer cortices of purchase on each side of the fracture. PURPOSE: To compare the biomechanical and clinical performance of 3- versus 2-screw constructs for plating displaced midshaft clavicle fractures. STUDY DESIGN: Controlled laboratory study/cohort study; Level of evidence, 3. METHODS: Lateral fragments of simulated midshaft fractures in 10 pairs of cadaveric clavicles were randomly assigned to plate fixation with either 3 nonlocking screws or 2 locking screws. Cyclic tensile loads were applied along the long axis of the clavicle. The constructs were then loaded to failure with pullout forces applied parallel to the long axis of the screws. Additionally, clinical outcomes of patients who had midshaft clavicle fractures that were surgically repaired were retrospectively identified and compared; 21 patients were treated with 3-screw constructs and 20 with 2-screw constructs. RESULTS: Biomechanically, there were no significant differences for cyclic displacement, stiffness, yield load, or ultimate load between groups. Forces required for screw pullout were considerably higher than physiologic forces experienced by a healing clavicle in vivo. Clinically, there were no significant differences in American Shoulder and Elbow Surgeons, Constant, visual analog scale, and Single Assessment Numeric Evaluation scores; complications; or mean time to union. Additionally, we found that the plates used in the 2-screw group were consistently shorter. CONCLUSION: Plate fixation of displaced midshaft clavicle fractures with 4 cortices of purchase with 2 locking screws demonstrated no significant differences biomechanically when compared with fixation with 6 cortices of purchase and 3 nonlocking screws. Clinically, there were no significant differences in outcomes or complications seen in patients receiving 2- or 3-screw constructs. CLINICAL RELEVANCE: Clinical benefits of using the 3-screw construct for plate fixation include decreased surgical exposure, morbidity, and cost, and the use of shorter and noncontoured straight plates eliminates the extra time and technical difficulty associated with matching longer contoured plates to the complex morphology of the clavicle. PMID- 28894756 TI - Relationships Between Tibiofemoral Contact Forces and Cartilage Morphology at 2 to 3 Years After Single-Bundle Hamstring Anterior Cruciate Ligament Reconstruction and in Healthy Knees. AB - BACKGROUND: Prevention of knee osteoarthritis (OA) following anterior cruciate ligament (ACL) rupture and reconstruction is vital. Risk of postreconstruction knee OA is markedly increased by concurrent meniscal injury. It is unclear whether reconstruction results in normal relationships between tibiofemoral contact forces and cartilage morphology and whether meniscal injury modulates these relationships. HYPOTHESES: Since patients with isolated reconstructions (ie, without meniscal injury) are at lower risk for knee OA, we predicted that relationships between tibiofemoral contact forces and cartilage morphology would be similar to those of normal, healthy knees 2 to 3 years postreconstruction. In knees with meniscal injuries, these relationships would be similar to those reported in patients with knee OA, reflecting early degenerative changes. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Three groups were examined: (1) 62 patients who received single-bundle hamstring reconstruction with an intact, uninjured meniscus (mean age, 29.8 +/- 6.4 years; mean weight, 74.9 +/- 13.3 kg); (2) 38 patients with similar reconstruction with additional meniscal injury (ie, tear, repair) or partial resection (mean age, 30.6 +/- 6.6 years; mean weight, 83.3 +/- 14.3 kg); and (3) 30 ligament-normal, healthy individuals (mean age, 28.3 +/- 5.2 years; mean weight, 74.9 +/- 14.9 kg) serving as controls. All patients underwent magnetic resonance imaging to measure the medial and lateral tibial articular cartilage morphology (volumes and thicknesses). An electromyography-driven neuromusculoskeletal model determined medial and lateral tibiofemoral contact forces during walking. General linear models were used to assess relationships between tibiofemoral contact forces and cartilage morphology. RESULTS: In control knees, cartilage was thicker compared with that of isolated and meniscal-injured ACL-reconstructed knees, while greater contact forces were related to both greater tibial cartilage volumes (medial: R2 = 0.43, beta = 0.62, P = .000; lateral: R2 = 0.19, beta = 0.46, P = .03) and medial thicknesses (R2 = 0.24, beta = 0.48, P = .01). In the overall group of ACL reconstructed knees, greater contact forces were related to greater lateral cartilage volumes (R2 = 0.08, beta = 0.28, P = .01). In ACL-reconstructed knees with lateral meniscal injury, greater lateral contact forces were related to greater lateral cartilage volumes (R2 = 0.41, beta = 0.64, P = .001) and thicknesses (R2 = 0.20, beta = 0.46, P = .04). CONCLUSION: At 2 to 3 years postsurgery, ACL-reconstructed knees had thinner cartilage compared with healthy knees, and there were no positive relationships between medial contact forces and cartilage morphology. In lateral meniscal-injured reconstructed knees, greater contact forces were related to greater lateral cartilage volumes and thicknesses, although it was unclear whether this was an adaptive response or associated with degeneration. Future clinical studies may seek to establish whether cartilage morphology can be modified through rehabilitation programs targeting contact forces directly in addition to the current rehabilitation foci of restoring passive and dynamic knee range of motion, knee strength, and functional performance. PMID- 28894754 TI - Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation. AB - Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, including IMO-3100, IMO 8400, and CPG-52364, that block the interaction between endosomal TLRs and their ligands are under clinical investigation for their effectiveness in the treatment of psoriasis. In addition, several chemical compounds, including AS-2444697, PF 05387252, PF-05388169, PF-06650833, ML120B, and PHA-408, can inhibit TLR signaling. Although these compounds have demonstrated anti-inflammatory activity in animal models, their therapeutic potential for the treatment of psoriasis has not yet been tested. Recent studies demonstrated that natural compounds derived from plants, fungi, and bacteria, including mustard seed, Antrodia cinnamomea extract, curcumin, resveratrol, thiostrepton, azithromycin, and andrographolide, inhibited psoriasis-like inflammation induced by the TLR7 agonist imiquimod in animal models. These natural modulators employ different mechanisms to inhibit endosomal TLR activation and are administered via different routes. Therefore, they represent candidate psoriasis drugs and might lead to the development of new treatment options. PMID- 28894758 TI - The Latarjet Procedure at the National Football League Scouting Combine: An Imaging and Performance Analysis. AB - BACKGROUND: The Latarjet procedure is commonly performed in the setting of glenoid bone loss for treatment of recurrent anterior shoulder instability; however, little is known regarding the outcomes of this procedure in elite American football players. PURPOSE: (1) Determine the prevalence, clinical features, and imaging findings of elite college football athletes who present to the National Football League (NFL) Combine with a previous Latarjet procedure and (2) describe these athletes' performance in the NFL in terms of draft status and initial playing time. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: After review of all football players who participated in the NFL Combine from 2009 to 2016, any player with a previous Latarjet procedure was included in this study. Medical records, position on the field, and draft position were recorded for each player. In addition, imaging studies were reviewed to determine fixation type, hardware complications, and status of the bone block. For those players who were ultimately drafted, performance was assessed based on games played and started, total snaps, and percentage of eligible snaps in which the player participated during his rookie season. RESULTS: Overall, 13 of 2617 (<1%) players at the combine were identified with a previous Latarjet procedure. Radiographically, 8 of 13 (61%) showed 2-screw fixation, while 5 of 13 (39%) had 1 screw. Of the 13 players, 6 (46%) players demonstrated hardware complications. All players had evidence of degenerative changes on plain radiographs, with 10 (77%) graded as mild, 1 (8%) as moderate, and 2 (15%) as severe according to the Samilson Prieto classification. Six of the 13 (46%) players went undrafted, while the remaining 7 (54%) were drafted; however, no player participated in more than half of the plays for which he was eligible during his rookie season. CONCLUSION: Only a small percentage of players at the NFL Combine (<1%) had undergone a Latarjet procedure. High rates of postoperative complications and radiographically confirmed degenerative change were observed. Athletes who had undergone a Latarjet procedure demonstrated a variable amount of playing time, but none participated in more than half of their eligible plays during their rookie season. PMID- 28894759 TI - Differential efficiency of transcutaneous electrical nerve stimulation in dominant versus nondominant hands in fibromyalgia: placebo-controlled functional near-infrared spectroscopy study. AB - Using functional near-infrared spectroscopy (fNIRS), modulation of hemodynamic responses by transcutaneous electrical nerve stimulation (TENS) during delivery of nociceptive stimulation was investigated in fibromyalgia (FM) patients and healthy controls for both hands. Two experiments were conducted: (1) median nerve stimulation with TENS and (2) painful stimulation using electronic von Frey filaments with TENS/placebo TENS. Mean [Formula: see text] brain activity was compared across groups and conditions using factorial ANOVA. Dominant (right) hand stimulation indicated significant interactions between group and condition in both hemispheres. Post hoc results revealed that FM patients showed an increased activation in "pain + TENS" condition compared to the "pain + placebo TENS" condition while the brain activity patterns for these conditions in controls were reversed. Left-hand stimulation resulted in similar TENS effects (reduced activation for "pain + TENS" than "pain + placebo TENS") in both groups. TENS effects in FM patients might be manipulated by the stimulation side. While the nondominant hand was responsive to TENS treatment, the dominant hand was not. These results indicate that stimulation side might be an effective factor in FM treatment by using TENS. Future studies are needed to clarify the underlying mechanism for these findings. PMID- 28894761 TI - Multiprotocol, multiatlas statistical fusion: theory and application. AB - Multiatlas segmentation offers an exceedingly convenient process by which image segmentation tools can be created from a series of labeled atlases (i.e., raters). However, creation of the atlases is exceedingly time consuming and prone to shifts in clinical/research demands as anatomical definitions are refined, combined, or subdivided. Hence, a process by which atlases from distinct, but complementary, anatomical "protocols" could be combined would allow for greater innovation in structural analysis and efficiency of data (re)use. Recent innovation in protocol fusion has shown that propagation of information across distinct protocols is feasible. However, how to effectively include this information in simultaneous truth and performance level estimation (STAPLE) has been elusive. We present a generalization of the STAPLE framework to account for multiprotocol rater performance (i.e., accuracy of registered atlases). This approach, multiset STAPLE (MS-STAPLE), provides a statistical framework for combining label information from atlases that have been labeled with distinct protocols (i.e., whole brain versus subcortical) and is compatible with the current local, nonlocal, probabilistic, log-odds, and hierarchical innovations in STAPLE theory. Using the MS-STAPLE approach, information from a broad range of datasets can be combined so that each available dataset contributes in a spatially dependent manner to local labels. We evaluate the model in simulations and in the context of an experiment where an existing set of whole-brain labels (14 structures) is refined to include parcellation of subcortical structures (26 structures). In the empirical results, we see significant improvement in the Dice similarity coefficient when comparing MS-STAPLE to STAPLE and nonlocal MS-STAPLE to nonlocal STAPLE. PMID- 28894760 TI - Recent advances in cardiac computed tomography dose reduction strategies: a review of scientific evidence and technical developments. AB - Cardiac imagers worldwide are bracing for increased utilization of cardiac computed tomography (CT) in clinical practice. This expanding opportunity brings along a responsibility to produce diagnostic quality images with optimized radiation dose. The following review aims to address the dose reduction strategies in cardiac CT in light of recent scientific evidence and technical developments. PMID- 28894762 TI - MIRank-KNN: multiple-instance retrieval of clinically relevant diabetic retinopathy images. AB - Diabetic retinopathy (DR) is a consequence of diabetes and is the leading cause of blindness among 18- to 65-year-old adults. Regular screening is critical to early detection and treatment of DR. Computer-aided diagnosis has the potential of improving the practice in DR screening or diagnosis. An automated and unsupervised approach for retrieving clinically relevant images from a set of previously diagnosed fundus camera images for improving the efficiency of screening and diagnosis of DR is presented. Considering that DR lesions are often localized, we propose a multiclass multiple-instance framework for the retrieval task. Considering the special visual properties of DR images, we develop a feature space of a modified color correlogram appended with statistics of steerable Gaussian filter responses selected by fast radial symmetric transform points. Experiments with real DR images collected from five different datasets demonstrate that the proposed approach is able to outperform existing methods. PMID- 28894763 TI - Adaptive anatomical preservation optimal denoising for radiation therapy daily MRI. AB - Low-field magnetic resonance imaging (MRI) has recently been integrated with radiation therapy systems to provide image guidance for daily cancer radiation treatments. The main benefit of the low-field strength is minimal electron return effects. The main disadvantage of low-field strength is increased image noise compared to diagnostic MRIs conducted at 1.5 T or higher. The increased image noise affects both the discernibility of soft tissues and the accuracy of further image processing tasks for both clinical and research applications, such as tumor tracking, feature analysis, image segmentation, and image registration. An innovative method, adaptive anatomical preservation optimal denoising (AAPOD), was developed for optimal image denoising, i.e., to maximally reduce noise while preserving the tissue boundaries. AAPOD employs a series of adaptive nonlocal mean (ANLM) denoising trials with increasing denoising filter strength (i.e., the block similarity filtering parameter in the ANLM algorithm), and then detects the tissue boundary losses on the differences of sequentially denoised images using a zero-crossing edge detection method. The optimal denoising filter strength per voxel is determined by identifying the denoising filter strength value at which boundary losses start to appear around the voxel. The final denoising result is generated by applying the ANLM denoising method with the optimal per-voxel denoising filter strengths. The experimental results demonstrated that AAPOD was capable of reducing noise adaptively and optimally while avoiding tissue boundary losses. AAPOD is useful for improving the quality of MRIs with low-contrast-to noise ratios and could be applied to other medical imaging modalities, e.g., computed tomography. PMID- 28894764 TI - Improved reconstruction of phase-stepping data for Talbot-Lau x-ray imaging. AB - Grating-based Talbot-Lau x-ray interferometry is a popular method for measuring absorption, phase shift, and small-angle scattering. The standard acquisition method for this modality is phase stepping, where the Talbot pattern is reconstructed from multiple images acquired at different grating positions. We review the implicit assumptions in phase-stepping reconstruction, and find that the assumptions of perfectly known grating positions and homoscedastic noise variance are violated in some scenarios. Additionally, we investigate a recently reported estimation bias in the visibility and dark-field signal. To adapt the phase-stepping reconstruction to these findings, we propose three improvements to the reconstruction. These improvements are (a) to use prior knowledge to compute more accurate grating positions to reduce moire artifacts, (b) to utilize noise variance information to reduce dark-field and phase noise in high-visibility acquisitions, and (c) to perform correction of an estimation bias in the interferometer visibility, leading to more quantitative dark-field imaging in acquisitions with a low signal-to-noise ratio. We demonstrate the benefit of our methods on simulated data, as well as on images acquired with a Talbot-Lau interferometer. PMID- 28894765 TI - Active phantoms: a paradigm for ultrasound calibration using phantom feedback. AB - In ultrasound (US)-guided medical procedures, accurate tracking of interventional tools is crucial to patient safety and clinical outcome. This requires a calibration procedure to recover the relationship between the US image and the tracking coordinate system. In literature, calibration has been performed on passive phantoms, which depend on image quality and parameters, such as frequency, depth, and beam-thickness as well as in-plane assumptions. In this work, we introduce an active phantom for US calibration. This phantom actively detects and responds to the US beams transmitted from the imaging probe. This active echo (AE) approach allows identification of the US image midplane independent of image quality. Both target localization and segmentation can be done automatically, minimizing user dependency. The AE phantom is compared with a crosswire phantom in a robotic US setup. An out-of-plane estimation US calibration method is also demonstrated through simulation and experiments to compensate for remaining elevational uncertainty. The results indicate that the AE calibration phantom can have more consistent results across experiments with varying image configurations. Automatic segmentation is also shown to have similar performance to manual segmentation. PMID- 28894766 TI - Potentially Preventable Hospitalizations and the Burden of Healthcare-Associated Infections. AB - BACKGROUND: An estimated 4% of hospital admissions acquired healthcare-associated infections (HAIs) and accounted for $9.8 (USD) billion in direct cost during 2011. In 2010, nearly 140 000 of the 3.5 million potentially preventable hospitalizations (PPHs) may have acquired an HAI. There is a knowledge gap regarding the co-occurrence of these events. AIMS: To estimate the period occurrences and likelihood of acquiring an HAI for the PPH population. METHODS: Retrospective, cross-sectional study using logistic regression analysis of 2011 Texas Inpatient Discharge Public Use Data File including 2.6 million admissions from 576 acute care hospitals. Agency for Healthcare Research and Quality Prevention Quality Indicator software identified PPH, and existing administrative data identification methodologies were refined for Clostridium difficile infection, central line-associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia. Odds of acquiring HAIs when admitted with PPH were adjusted for demographic, health status, hospital, and community characteristics. FINDINGS: We identified 272 923 PPH, 14 219 HAI, and 986 admissions with PPH and HAI. Odds of acquiring an HAI for diabetic patients admitted for lower extremity amputation demonstrated significantly increased odds ratio of 2.9 (95% confidence interval: 2.16-3.91) for Clostridium difficile infection. Other PPH patients had lower odds of acquiring HAI compared to non-PPH patients, and results were frequently significant. CONCLUSIONS: Clinical implications include increased risk of HAI among diabetic patients admitted for lower extremity amputation. Methodological implications include identification of rare events for inpatient subpopulations and the need for improved codification of HAIs to improve cost and policy analyses regarding allocation of resources toward clinical improvements. PMID- 28894767 TI - Who Works Among Older Black and White, Well-Functioning Adults in the Health, Aging, and Body Composition Study? AB - Objective: The aim of this study is to examine social, economic, and health factors related to paid work in well-functioning older adults and if and how these factors vary by race. Method: We used sex-stratified logistic and multinomial logistic regression to examine cross-sectional data in the Health, Aging, and Body Composition cohort study. The sample included 3,075 community dwelling Black (42%) and White adults aged 70 to 79 at baseline. Results: Multinomial logistic regression analyses show Black men were more likely to work full-time, and Black women were more likely to work part-time. Men with >=US$50,000 family income were more likely to work full-time. Men with better physical functioning were more likely to work full- and part-time. Women with >=US$50,000 family income and fewer chronic diseases were more likely to work full-time. Women who were overweight and had fewer chronic diseases were more likely to work part-time. Discussion: Results suggest that well-functioning, older Black adults were more likely to work than their White counterparts, and working relates to better health and higher income, providing support for a productive or successful aging perspective. PMID- 28894768 TI - Clinical Improvement of Subacute and Chronic Otitis Media With Effusion Treated With Hyaluronic Acid Plus Hypertonic Solution via Nasal Lavage: A Randomized Controlled Trial. AB - Background. This study, a randomized controlled trial, aims to demonstrate a clinically significant improvement in subacute and chronic otitis media with effusion through the administration of hyaluronic acid associated with hypertonic solution compared with the administration of hypertonic solution alone. The setting was an outpatient clinic of 20 primary care pediatrician offices affiliated with the 3 Local Health Units (Azienda Sanitaria Locale) of Naples. Materials and Methods. The study was conducted for 6 months, from October 2014 to the end of March 2015. The study saw the participation of 20 pediatricians who were experts in pneumatic otoscopy, each of whom enrolled 15 children. Each investigator was randomized to carry out the treatment with 3% hypertonic solution or high-molecular-weight hyaluronic acid + 3% hypertonic solution. Results. A total of 275 children were enrolled, of whom 11(equal to 4% ) were lost to follow-up. A total of 264 children completed the trial according to the protocol, 120 in the hyaluronic acid + hypertonic solution group and 144 in the hypertonic solution group. Hyaluronic acid associated with hypertonic solution and hypertonic solution alone administered by nasal lavage have proven to be safe and effective in the treatment of prolonged otitis media with effusion (initial score of -0.5, final score of 0.9, P < 001, for the hypertonic + hyaluronic acid group; initial score of -0.3, final score of 0.2, P < .001, for the hypertonic solution group). Though starting from a less favorable initial clinical score ( 0.5 vs -0.3, P < .016), hyaluronic acid associated with hypertonic solution resulted in a significant increase in clinical healing (0.9 vs 0.2, P < .001). One interesting outcome was the significant reduction in the consumption of drugs (cortisone and antibiotics) during the follow-up. PMID- 28894769 TI - Severe Mitral Regurgitation in a Child With Henoch-Schonlein Purpura and Pulmonary Hemorrhage. AB - Introduction: Henoch-Schonlein purpura (HSP) is the most common vasculitis of childhood. The classic triad of HSP consists of nonthrombocytopenic purpura, arthritis/arthralgia, and gastrointestinal complaints. Pulmonary hemorrhage and cardiac involvement are rare complications of HSP. Case Report: We report the case of a 10-year-old girl with HSP complicated by both severe mitral regurgitation and pulmonary hemorrhage. Discussion: HSP is typically a self limited illness with an excellent prognosis in children. Pulmonary hemorrhage is a rare complication that increases morbidity and mortality; it generally indicates the presence of severe vasculitis. Cardiac involvement in HSP is extremely rare and associated with a poor prognosis. Conclusion: Cardiac involvement in HSP may be more common than believed. Because of the increased morbidity and mortality associated with HSP complicated by pulmonary hemorrhage and cardiac involvement, it is important for clinicians to be aware of these potential complications. PMID- 28894770 TI - Deterministic implementation of a bright, on-demand single photon source with near-unity indistinguishability via quantum dot imaging. AB - Deterministic techniques enabling the implementation and engineering of bright and coherent solid-state quantum light sources are key for the reliable realization of a next generation of quantum devices. Such a technology, at best, should allow one to significantly scale up the number of implemented devices within a given processing time. In this work, we discuss a possible technology platform for such a scaling procedure, relying on the application of nanoscale quantum dot imaging to the pillar microcavity architecture, which promises to combine very high photon extraction efficiency and indistinguishability. We discuss the alignment technology in detail, and present the optical characterization of a selected device which features a strongly Purcell-enhanced emission output. This device, which yields an extraction efficiency of eta = (49 +/- 4) %, facilitates the emission of photons with (94 +/- 2.7) % indistinguishability. PMID- 28894771 TI - Baseline Characteristics of fall from Height Victims Presenting to Emergency Department; a Brief Report. AB - INTRODUCTION: Trauma due to accidents or fall from height is a major cause of disability and mortality. The present study was designed aiming to evaluate the baseline characteristics of fall from height victims presenting to emergency department (ED). METHODS: This prospective cross-sectional study evaluates the baseline characteristics of fall from height cases presenting to EDs of three educational Hospitals, Tehran, Iran, during one year. Data were analyzed using SPSS 21 and presented using descriptive statistics. RESULTS: 460 patients with the mean age of 27.89 +/- 20.95 years were evaluated (76.5% male). 191 (41.5%) falls occurred when working, 27 (5.9%) during play, and 242 (52.6%) in other times. Among construction workers, 166 (81.4%) had not used any safety equipment. Fracture and dislocation with 180 (39.1%) cases and soft tissue injury with 166 (36.1%) were the most common injuries inflicted. Mean height of falling was 3.41 +/- 0.34 (range: 0.5 - 20) meters. Finally, 8 (1.7%) of the patients died (50% intentional) and 63% were discharged from ED. A significant correlation was detected between mortality and the falls being intentional (p < 0.0001) as well as greater height of fall (p < 0.0001). CONCLUSION: Based on the findings, most fall from height victims in the present study were young men, single, construction workers, with less than high school diploma education level. Intentional fall and greater height of falling significantly correlated with mortality. PMID- 28894772 TI - Epidemiologic Features and Outcomes of Caustic Ingestions; a 10-Year Cross Sectional Study. AB - INTRODUCTION: Caustic ingestions are among the most prevalent causes of toxic exposure. The present 10-year survey aimed to evaluate the epidemiologic features and outcomes of caustic ingestion cases presenting to emergency department. METHODS: This is a retrospective cross-sectional study on patients who were admitted to a referral toxicology center during 2004 to 2014, following caustic ingestion. Baseline characteristics, presenting chief complaint, severity of mucosal injury, complications, imaging and laboratory findings as well as outcomes (need for ICU admission, need for surgery, mortality) were recorded, reviewing patients' medical profile, and analyzed using SPSS 22. RESULTS: 348 patients with mean age of 37.76 +/- 17.62 years were studied (55.6% male). The mean amount of ingested caustic agent was 106.69 +/- 100.24 mL (59.2 % intentional). Intentional ingestions (p < 0.0001), acidic substance (p = 0.054), and higher volume of ingestion (p = 0.021) were significantly associated with higher severity of mucosal damage. 28 (8%) cases had died, 53 (15.2%) were admitted to ICU, and 115 (33%) cases underwent surgery. CONCLUSION: It seems that, suicidal intention, higher grade of mucosal injury, higher volume of ingestion, lower level of consciousness, lower serum pH, and higher respiratory rate are among the most important predictors of need for ICU admission, need for surgery, and mortality. PMID- 28894773 TI - The Pattern of Pre-hospital Medical Service Delivery in Iran; a Cross Sectional Study. AB - INTRODUCTION: Pre-hospital emergency systems provide service by Franco-German and Anglo American models. This study was carried out to compare the Iranian emergency medical service (EMS) with the two models regarding timing and equipment. METHODS: In this cross sectional study, response time, scene time, and transport time to hospital as well as ambulance equipment of five hundred thousand Tehran EMS recorded missions, during one year, were compared with Franco German and Anglo American models, trying to determine the pattern of EMS delivery in Iran. RESULTS: The mean response time, scene time, and transport time to hospital were 15.00 +/-10.88, 18 +/-11.48, and 15.00 +/-11.20 minutes, respectively. The mean response time (p<0.035), scene time (p<0.033), and transport time to hospital (p<0.015) were more than the standard time. Percentage of ambulances quipped with automated external defibrillator (45%, p<0.001), ventilator (2%, p<0.001), disposable splint (0%, p<0.001), and wheelchair (0%, p<0.001) were very far from standards. CONCLUSION: The pattern of EMS delivery in Iran was a combination of Anglo American and Franco-German system. PMID- 28894774 TI - Spontaneous Adrenal Hematoma in a Pregnant Woman; a Case Report. AB - Spontaneous adrenal hematoma is a very rare condition and its prevalence has been reported to be about 1% in previous studies. Although various causes have been proposed to explain its incidence in existing case reports, the etiology and pathology of this condition is still not known. The present study presents a case of spontaneous adrenal hematoma in a pregnant 31 year old womanwithout history of trauma or other probable risk factors of hemorrhage, presenting to the emergency department with chief complaint of pain in the right flank.Diagnostic measures, imaging and laparotomy,confirmed the diagnosis of spontaneous adrenal hematomafor her. PMID- 28894775 TI - Pregnancy Screening before Diagnostic Radiography in Emergency Department; an Educational Review. AB - In modern medical practice, there is an increasing dependence on imaging techniques in most medical specialties. Radiation exposure during pregnancy may have serious teratogenic effects to the fetus. Therefore, checking the pregnancy status before imaging women of child bearing age can protect against these effects. Lack of international regulations and standard protocols exposes the patient to unexpected fetal radiation effects and the health professionals to medicolegal suits. Recently, the American Academy of Radiology and the European community of Medical Ionizing Radiation Protection released national guidelines regarding pregnancy screening before imaging potentially pregnant females. However, different methods of pregnancy screening exist among different radiology centers. This review aims to discuss the most recent guidelines for imaging females of childbearing age and highlight the need for an international regulation to guide pregnancy screening before diagnostic radiation exposure. PMID- 28894776 TI - Diagnostic Accuracy of Computed Tomography Scan in Detection of Upper Gastrointestinal Tract Injuries Following Caustic Ingestion. AB - INTRODUCTION: Endoscopy is an invasive procedure and finding noninvasive alternative tools in detection of probable upper gastrointestinal (GI) tract injuries following caustic ingestion is an area of interest. The present study aimed to evaluate the screening performance characteristics of thoraco-abdominal computed tomography (CT) scan in this regard. METHODS: This prospective cross sectional study was conducted on patients presenting to emergency department following acute caustic ingestion. The findings of CT scan and endoscopy regarding the presence of upper GI tract damage were compared and screening performance characteristics of CT scan were calculated using MedCalc software. RESULTS: 34 patients with the mean age of 35.38+/-13.72 years were studied (58.8% male). The agreement rate between CT scan and endoscopy regarding the grade of esophageal and gastric injuries was moderate (K= 0.38; p = 0.001) and fair (K= 0.17; p = 0.038), respectively. The sensitivity and specificity of CT scan in detection of esophageal damage were 96.29) 79.11- 99.80) and 57.14 (20.23 - 88.19), respectively. These measures were 89.65 (71.50 - 97.28) and 40.00 (7.25 - 82.95), respectively for gastric damage. The area under the ROC curve of CT scan in detection of esophageal and gastric damages was 0.76 (95% CI: 0.52 - 1.00) and 0.64 (95% CI: 0.35 - 0.94), respectively. CONCLUSION: Based on the findings of the present study, CT scan could be considered as a sensitive tool in ruling out upper gastrointestinal mucosal injuries following acute caustic ingestions. However, the correlation between endoscopy and CT scan findings regarding the grading of injury is not high enough to eliminate the need for endoscopy. PMID- 28894777 TI - Relationship between Dyspnea Descriptors and Underlying Causes of the Symptom; a Cross-sectional Study. AB - INTRODUCTION: History taking and physical examination help clinicians identify the patient's problem and effectively treat it. This study aimed to evaluate the descriptors of dyspnea in patients presenting to emergency department (ED) with asthma, congestive heart failure (CHF), and chronic obstructive pulmonary disease (COPD). METHOD: This cross-sectional study was conducted on all patients presenting to ED with chief complaint of dyspnea, during 2 years. The patients were asked to describe their dyspnea by choosing three items from the valid and reliable questionnaire or articulating their sensation. The relationship between dyspnea descriptors and underlying cause of symptom was evaluated using SPSS version 16. RESULTS: 312 patients with the mean age of 60.96+/-17.01 years were evaluated (53.2% male). Most of the patients were > 65 years old (48.7%) and had basic level of education (76.9%). "My breath doesn't go out all the way" with 83.1%, "My chest feels tight " with 45.8%, and "I feel that my airway is obstructed" with 40.7%, were the most frequent dyspnea descriptors in asthma patients. "My breathing requires work" with 46.3%, "I feel that I am suffocating" with 31.5%, and "My breath doesn't go out all the way" with 29.6%, were the most frequent dyspnea descriptors in COPD patients. "My breathing is heavy" with 74.4%, "A hunger for more air" with 24.4%, and "I cannot get enough air" with 23.2%, were the most frequent dyspnea descriptors in CHF patients. Except for "My breath does not go in all the way", there was significant correlation between studied dyspnea descriptors and underlying disease (p = 0.001 for all analyses). CONCLUSION: It seems that dyspnea descriptors along with other findings from history and physical examination could be helpful in differentiating the causes of the symptom in patients presenting to ED suffering from dyspnea. PMID- 28894778 TI - Role of Serum Creatinine Phosphokinase in Outcome Prediction of Intoxicated Patients; a Brief Report. AB - INTRODUCTION: Several mechanisms were introduced as causes of serum creatinine phosphokinase (CPK) raise in intoxicated patients. This study aimed to assess the relationship between serum CPK level in the first 24 hours and baseline characteristics as well as outcomes of these patients. METHODS: This one year retrospective cross-sectional study was conducted on all intoxicated patients, who were admitted to a referral toxicology center, Northwest of Iran, stayed for at least 24 hours and had serum CPK level more than 500 IU/L in the first 24 hours of admission. The relationship between serum CPK level and some baseline and outcome variables were studied using SPSS version 21. RESULTS: 413 patients with the mean age of 34.52 +/- 15.24 years were studied (78.7% male). The mean CPK level at the time of presentation to ED was 3702.85 +/- 6375.29 IU/L. There was not any significant relationship between presenting CPK level and type of poisoning (p = 0.258), sex (p = 0.587), and age (p = 0.817). The area under the ROC curve of CPK in prediction of need for dialysis, need for intensive care unit (ICU) admission, and mortality was 0.67 (95% CI: 0.57 - 0.77), 0.60 (95% CI: 0.52 - 0.69), and 0.60 (95% CI: 0.51 - 0.68), respectively. CONCLUSION: Based on the finding of present study, there was no significant association between serum CPK level in the first 24 hours and age, sex, and type of poisoning of intoxicated patients and it had poor accuracy in prediction of their need to do dialysis, need for ICU admission, and mortality. PMID- 28894779 TI - Emergency Department Readmission Rate within 72 Hours after Discharge; a Letter to Editor. PMID- 28894780 TI - A 41-Year-Old Woman with Seizure. PMID- 28894781 TI - Diagnostic Accuracy of Quick Stick for Identifying Traumatic Patients in Need of Tetanus Prophylaxis; a Cross-sectional Study. AB - INTRODUCTION: Based on the existing studies, measuring serum level of immunoglobulin for making decisions regarding prescription of tetanus prophylaxis seems logical and cost effective. Therefore, the present study was done with the aim of evaluating the diagnostic accuracy of tetanus quick stick (TQS) in comparison with ELISA method in this regard. METHODS: The present diagnostic accuracy study was carried out on trauma patients presenting to emergency department, who were in need of receiving tetanus prophylaxis due to dirty wounds or injuries. Patients' blood was evaluated regarding presence of anti-tetanus antibody via TQS and ELISA methods and screening performance characteristics of TQS in identifying the cases in need of receiving prophylaxis was calculated compared to ELISA as the reference test. RESULTS: 148 patients with the mean age of 34.58 +/- 15.86 years (4-86) were studied (87.8% male). Agreement rate between the results of TQS and ELISA was 0.78 based on calculation of kappa coefficient. Sensitivity, specificity and area under the ROC curve of TQS were estimated to be 100 (95% CI: 96.50 - 100), 66.66 (95% CI: 38.68 - 86.01), and 0.83 (95% CI: 0.68 0.98), respectively. If TQS was used, the cost of treatment regarding use of tetabulin could have a 91.7% reduction. CONCLUSION: Based on the findings of the present study, TQS has good diagnostic accuracy in comparison with ELISA and considering its 100% sensitivity and negative predictive value in cases with dirty wound, it can be considered as a reliable tool for screening patients that do not need to receive anti-tetanus prophylaxis. PMID- 28894782 TI - Accidental Chronic Poisoning with Methotrexate; Report of Two Cases. AB - Methotrexate has been used widely in dermatology, oncology and rheumatology fields. However, methotrexate-induced mucocutaneous lesions may occur in rare cases. In this case presentation, we report two cases of accidental poisoning with methotrexate. They had accidentally used methotrexate instead of digoxin. This case report emphasizes that early diagnosis and appropriate management is critical in order to improve outcome. PMID- 28894783 TI - Intravenous Lidocaine versus Morphine Sulfate in Pain Management for Extremity Fractures; a Clinical Trial. AB - INTRODUCTION: Considering the existing contradictions regarding effectiveness of intravenous (IV) lidocaine, especially in emergency department (ED), the present study was designed to compare the analgesic effect of IV lidocaine and morphine sulfate in pain management for extremity bone fractures. METHOD: In this triple blind clinical trial, 15 to 65 year-old patients with extremity fractures and in need of pain management were randomly allocated to either IV lidocaine or morphine sulfate group and were compared regarding severity of pain 5, 10, 15, 20, 25, and 30 minutes after infusion via intention to treat analysis. The absolute risk reduction, number needed to treat and relative risk of IV lidocaine after 30 minutes were 0.40 (95%CI: 0.25 - 0.64), 7 (95%CI: 3.7 - 23.1), and 20.71 (95%CI: 10.91 - 30.51), respectively. RESULTS: 280 patients with the mean age of 32.50 +/- 12.77 years were randomly divided into 2 equal groups of 140 (73.9% male). The 2 groups had similar baseline characteristics. 15 minutes after injection success rate was 49.28% in lidocaine and 33.57% in morphine sulfate group (p = 0.011), and after 30 minutes it reached 85.71% and 65.00%, respectively (p < 0.001). CONCLUSION: Based on the results of the present study, IV lidocaine could be considered as a reasonable alternative choice for pain management in ED. PMID- 28894784 TI - Blood Lead Levels in Asymptomatic Opium Addict Patients; a Case Control Study. AB - INTRODUCTION: One of the newest non-occupational sources of lead contamination is drug addiction, which has recently been addressed as a major source of lead poisoning in some countries. The present study aimed to investigate the blood lead level (BLL) of asymptomatic opium addicts. METHODS: This case-control study was conducted during a one-year period to compare BLL of three groups consisting of opium addicts, patients under methadone maintenance therapy (MMT), and healthy individuals. RESULTS: 99 participants with the mean age of 55.43+/-12.83 years were studied in three groups of 33 cases (53.5% male). The mean lead level in opium addicts, MMT and control groups were 80.30 +/- 6.03 MUg/L, 67.94 +/- 4.42 MUg/L, and 57.30+/-4.77 MUg/L, respectively (p=0.008). There was no significant difference in BLL between MMT and healthy individuals (p=0.433) and also between opium addicts and MMT individuals (p=0.271).Oral opium abusers had significantly higher lead levels (p = 0.036). There was a significant correlation between BLL and duration of drug abuse in opium addict cases (r=0.398, p=0.022). The odds ratio of having BLL >= 100 in oral opium users was 2.1 (95% CI: 0.92 - 4.61; p = 0.43). CONCLUSION: Based on the result of present study, when compared to healthy individuals, opium addicts, especially those who took substance orally had significantly higher levels of blood lead, and their odds of having BLL >= 100 was two times. Therefore, screening for BLL in opium addicts, particularly those with non-specific complaints, could be useful. PMID- 28894785 TI - Experimental Study of a Pack of Supercapacitors Used in Electric Vehicles. AB - Electric vehicles have recently attracted research interest. An electric vehicle is composed of two energy sources, such as fuel cells and ultracapacitors, which are employed to provide, respectively, the steady-state and transient power demanded by the vehicle. A bidirectional DC-DC converter is needed to interface the ultracapacitor to a DC bus. The pack of ultracapacitor consists of many cells in series and possibly also in parallel. In this regard, this paper introduces a comparative study between two packs of supercapacitors. The first supercapacitor pack is composed of ten cells in series but the second supercapacitor pack is composed of five cells in series and two parallel circuits. Each cell is characterized by 2.5 V and 100 F. A number of practical tests are presented. PMID- 28894786 TI - Methylene Blue Effectiveness as Local Analgesic after Anorectal Surgery: A Literature Review. AB - BACKGROUND: Methylene blue (MB) has been found to have unique analgesic property through temporary disruption of sensory nerve conduction. In anorectal surgery, MB is widely used as a biologic stain but the analgesic effect has never been studied. Thus, a literature review completed with critical appraisal is required to find out its efficacy. METHODS: A review has been run to find out its efficacy. Literature search proceeded in database sites, namely, PubMed, EBSCO, Cochrane, Wiley, and ProQuest using the following keywords: "anorectal" OR "hemorrhoid" OR "anal fistula" OR "anal fissure" OR "anal abscess" OR "anal pruritus" AND "methylene blue" AND "analgesic"; then the critical appraisal and its implication were discussed. RESULT: There were 491 articles in full text found, and four studies met the inclusion criteria. Two studies were focused on the evaluation of VAS in hemorrhoid surgery whereas the rest were focused on the evaluation of symptom score in anal pruritus. CONCLUSIONS: A study with level of evidence 2 on VAS showed the efficacy. The rest showed insufficient evidence due to variations of anorectal surgery and the methods and techniques of MB application. A further prospective clinical study is required. PMID- 28894787 TI - Prevalence of Anemia, Overweight/Obesity, and Undiagnosed Hypertension and Diabetes among Residents of Selected Communities in Ghana. AB - The increasing numbers of lifestyle related chronic diseases in developing countries call for awareness, early detection, and effective management. The objective of this paper is to report the prevalence of undiagnosed hypertension, diabetes, overweight/obesity, and anemia among residents of selected communities in Ghana. The data comes from a community screening conducted in Ghana as part of the University of Georgia Summer Service Learning Program. Descriptive statistics were used to summarize the data while chi-square and independent t-test compared groups. A total of 976 participants (37.9% males and 62.1% females), 18 years and older, were screened. Mean age was 46.25 +/- 17.14 years, BMI was 25.44 +/- 5.26 kgm-2, and hemoglobin was 12.04 +/- 2.22 g/dL. 3.1% and 12.6% reported existing diagnosis for diabetes and hypertension, respectively. Almost half (47.8%) were overweight/obese; 27.0% were hypertensive while 34.0% had diabetes. Also, 28.8% males compared to 37.8% females had diabetes (P = 0.015), while 28.2% males compared to 26.2% females were hypertensive (P = 0.635). There were differences in BMI (P < 0.0001), anemia (P = 0.007), and undiagnosed diabetes (P < 0.0001) and hypertension (P < 0.0001) by community (Takoradi versus Cape Coast) where the screening took place. Findings from the screening exercise call for improved public health education with a focus on lifestyle habits and health seeking behaviors among Ghanaians. PMID- 28894788 TI - Accuracy of Preoperative Scoring Systems for the Prognostication and Treatment of Patients with Spinal Metastases. AB - BACKGROUND: In patients with spinal metastatic disease, survival prognosis is a key consideration in selection for surgery and determining the extent of treatment. Individual survival prediction however remains difficult. We sought to validate the prognostic accuracy of seven preoperative scoring systems. METHODS: 61 patients surgically treated for spinal metastases were retrospectively reviewed. Preoperative scores were calculated for Tokuhashi, Revised Tokuhashi, Bauer, Modified Bauer, Sioutos, Tomita, and van der Linden scoring systems. Prognostic value was determined by comparison of predicted and actual survival. RESULTS: The Revised Tokuhashi and Modified Bauer scoring systems had the best survival predictive accuracy. Rate of agreement for survival prognosis was the greatest for the Modified Bauer score. There was a significant difference in survival of the prognostic groups for all but the van der Linden score, being most significant for the Revised Tokuhashi, Bauer, Modified Bauer, and Tomita scoring systems (p <= 0.001). CONCLUSION: Overall, the scoring systems are accurate at differentiating patients into short-, intermediate-, and long-term survivors. More precise prediction of actual survival is limited and the decision for or against surgery should never be based on survival prognostication alone but should take into account symptoms such as neurological deficit or pain from pathological fracture and instability. PMID- 28894789 TI - Impact of the Mk VI SkinSuit on skin microbiota of terrestrial volunteers and an International Space Station-bound astronaut. AB - Microgravity induces physiological deconditioning due to the absence of gravity loading, resulting in bone mineral density loss, atrophy of lower limb skeletal and postural muscles, and lengthening of the spine. SkinSuit is a lightweight compression suit designed to provide head-to-foot (axial) loading to counteract spinal elongation during spaceflight. As synthetic garments may impact negatively on the skin microbiome, we used 16S ribosomal RNA (rRNA) gene amplicon procedures to define bacterial skin communities at sebaceous and moist body sites of five healthy male volunteers undergoing SkinSuit evaluation. Each volunteer displayed a diverse, distinct bacterial population at each skin site. Short (8 h) periods of dry hyper-buoyancy flotation wearing either gym kit or SkinSuit elicited changes in the composition of the skin microbiota at the genus level but had little or no impact on community structure at the phylum level or the richness and diversity of the bacterial population. We also determined the composition of the skin microbiota of an astronaut during pre-flight training, during an 8-day visit to the International Space Station involving two 6-7 h periods of SkinSuit wear, and for 1 month after return. Changes in composition of bacterial skin communities at five body sites were strongly linked to changes in geographical location. A distinct ISS bacterial microbiota signature was found which reversed to a pre-flight profile on return. No changes in microbiome complexity or diversity were noted, with little evidence for colonisation by potentially pathogenic bacteria; we conclude that short periods of SkinSuit wear induce changes to the composition of the skin microbiota but these are unlikely to compromise the healthy skin microbiome. PMID- 28894790 TI - Aortic Dissection and Severe Renal Failure 6 Years After Kidney Transplantation. AB - We report the case of a patient with long-term history of hypertension, presenting with transient neurological disorders and severe graft failure several years after kidney transplantation. Cause of end-stage renal disease was hypertensive nephrosclerosis. Chronic hemodialysis lasted for 1 year. After transplantation and throughout follow-up, serum creatinine ranged from 200 to 230 MUmol/L and maintenance immunosuppression included sirolimus and low-dose steroids. Six years after transplantation, the patient presented with right hip pain radiating to the lower back, transient aphasia, confusion, and hemiparesis. Surprisingly, progressive anuria was established requiring dialysis. After numerous nonconclusive investigations including renal histology, a contrast computed tomography scan discovered a Stanford B aortic dissection from the left common carotid artery and left subclavian artery to bilateral internal and external iliac arteries, including the right femoral artery. No surgical treatment was opted and hemodialysis, tight control of blood pressure and oral anticoagulation were established. Immunosuppression was lightened to low-dose steroids alone. After 8 months, chronic dialysis was stopped, and today, 22 months after the diagnosis of aortic dissection, the patient is doing well with a still functioning graft (creatinine, 377 MUmol/L; modification of diet in renal disease-glomerular filtration rate, 15 mL/min), and without any other immunosuppression than low-dose steroids. PMID- 28894791 TI - Pancreas Transplantation With Portal-Enteric Drainage for Patients With Endocrine and Exocrine Insufficiency From Extensive Pancreatic Resection. AB - Although the primary indication for pancreas transplantation is type I diabetes, a small number of patients requires pancreas transplantation to manage combined endocrine and exocrine insufficiency that develops after extensive native pancreatic resection. The objective of this case report was to describe the operative and clinical course in 3 such patients and present an alternative technical approach. PMID- 28894792 TI - Influence of HLA Matching on the Efficacy of Allogeneic Mesenchymal Stromal Cell Therapies for Osteoarthritis and Degenerative Disc Disease. AB - BACKGROUND: The necessity for more effective therapies for chronic osteoarticular diseases has led to the development of treatments based on mesenchymal stem cells (MSCs), the natural precursors of musculoskeletal tissue. Treatments with autologous MSCs yielded excellent results, with nearly 70% improvement of pain and disability in osteoarthritis and degenerative disc disease. Using allogeneic MSCs is logistically more convenient and would widen the pool of eligible patients, but potential immune rejection should be considered. In this context, MSCs are purportedly immune evasive and better tolerated than other cell types. METHODS: We used samples collected during the performance of 2 randomized clinical trials using allogeneic bone marrow MSCs for treatment of osteoarthritis (NCT01586312) and degenerative disc disease (NCT01860417). Serum samples were used to determine anti-HLA antibodies, whereas either blood or MSC samples were used for HLA typing of recipients and donors, respectively. Algofunctional indexes were used as indicators of clinical evolution, and the correlation between the number of donor-host HLA mismatches and the efficacy of treatment was determined. RESULTS: Immune response was weak and transient, with reactivity decaying during the first year. Consistently, better donor-recipient HLA matching did not enhance efficacy. CONCLUSIONS: This lack of reactivity is presumably due to the cooperation of 2 factors, (1) downregulation of the host immune responses by the transplanted MSCs and (2) effective insulation of these cells inside the articular cavity or the intervertebral disc, respectively. Interestingly, better HLA matching did not enhance efficacy. These observations have medical relevance as they support the clinical use of allogeneic cells, at least as a single-dose administration. Multiple-dose applications will require further research to exclude possible sensitization. PMID- 28894793 TI - Infiltrative Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis Treated With a Single High-Dose Y90 Radioembolization and Subsequent Liver Transplantation Without a Recurrence. AB - BACKGROUND: Infiltrative hepatocellular carcinoma with macrovascular invasion is a relatively rare presentation and usually fatal disease. METHODS: Both patients exceeded Milan and University of California-San Francisco (UCSF) criteria, and per Barcelona Clinic Liver Cancer group guidelines, they were enrolled in a prospective open-label radioembolization phase II trial that gave them optimized lobar doses of Yttrium-90 as solely the first-line therapy without concomitant or additional pharmacological or locoregional therapies. RESULTS: Three months after radioembolization, the patients demonstrated no residual viable disease on surveillance imaging. The patients were then followed up with serial imaging for 2 years in 3-month intervals, without documenting recurrence or extrahepatic disease. Finally, both patients underwent transplantation and after more than 20 months of imaging surveillance, no locoregional or systemic recurrence have been observed. CONCLUSIONS: We present, to our knowledge, the first 2 reports of transplantation after successfully downstaging infiltrative disease with portal vein tumoral thrombosis, which traditionally poses as a relative contraindication for resection or transplantation. PMID- 28894794 TI - Short- and Long-term Outcomes of De Novo Liver Transplant Patients Treated With Once-Daily Prolonged-Release Tacrolimus. AB - BACKGROUND: Tacrolimus is the key immunosuppressive drug for liver transplantation. Once-daily prolonged-release tacrolimus (TAC-PR) exhibits good drug adherence but has difficulty controlling the trough level in the early phase of liver transplantation. The aim of this study was to compare the feasibility and efficacy of immediately starting oral TAC-PR versus traditional twice-daily tacrolimus (TAC-BID) in de novo liver transplantation recipients. METHODS: The study included 28 patients treated with conventional TAC-BID and 60 patients treated with TAC-PR (median follow-up 70.5 months). Short-term and long-term outcomes were compared. RESULTS: Patient characteristics were similar except for the incidence of hepatocellular carcinoma and type of graft. Dose adjustment was more frequently required for TAC-PR than TAC-BID (73.3% vs 42.9%, P = 0.006), but trough levels of TAC during the first 3 months after liver transplantation were controlled well in both groups. The rate of acute cellular rejection and long term renal function were similar in both groups. In both groups, renal function worsened during the first 6 months after transplantation and remained stable until the end of the follow-up period. The 1-year, 3-year, and 5-year survival rates were 96.4%, 85.7%, and 85.7% for TAC-BID and 96.7%, 94.8%, and 94.8% for TAC-PR, respectively. The overall survival curve for TAC-PR was not inferior to that of TAC-BID. CONCLUSIONS: The TAC-PR protocol was feasible and effective with strict adjustment. PMID- 28894796 TI - Editorial. PMID- 28894795 TI - Liver Enzymes and the Development of Posttransplantation Diabetes Mellitus in Renal Transplant Recipients. AB - BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is common in renal transplant recipients (RTR), increasing the risk of graft failure, cardiovascular disease, and mortality. Early detection of a high risk for PTDM is warranted. Because liver function and liver fat are involved, we investigated whether serum liver markers are associated with future PTDM in RTR. METHODS: Between 2001 and 2003, 606 RTR with a functioning allograft beyond the first year after transplantation were included of which 500 participants (56% men; age, 50 +/- 12 years) were free of diabetes at baseline and had liver enzyme values (1 missing) available. Serum concentrations of alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase were measured at baseline at 6.0 (6.2 11.5) years posttransplantation. PTDM cases were recorded until April 2012. RESULTS: During median follow-up for 9.6 years (interquartile range [IQR], 6.2 10.2) beyond baseline, 76 (15.2%) patients developed PTDM. Comparing the highest to the lower tertiles, higher liver enzyme activities were significantly related to incident PTDM for ALT (hazard ratio [HR], 2.22; IQR, 1.42-3.48), for GGT (HR, 2.93; IQR, 1.87-4.61), and for alkaline phosphatase (HR, 1.78; IQR, 1.13-2.80). The associations of ALT and GGT with development of PTDM were independent of potential confounders and risk factors, including age, sex, renal function, medication use, lifestyle factors, adiposity, presence of the metabolic syndrome, fasting glucose, HbA1c, proinsulin, and cytomegalovirus status. CONCLUSIONS: Markers for liver function and liver fat in the subclinical range are potential markers for future PTDM, independent of other known risk factors. This may allow for early detection and management of PTDM development. PMID- 28894797 TI - Tumoral Expression of CD44 and HIF1alpha Predict Stage I Oral Cavity Squamous Cell Carcinoma Outcome. AB - OBJECTIVES/HYPOTHESIS: No biomarkers are used to estimate the prognosis in oral cavity squamous cell carcinoma (OSCC). In our previously published work, we have reported the prognostic value of CD44 and hypoxia inducible factor (HIF)-1alpha in patients with stage I disease. STUDY DESIGN: In this study, we tested our previous observations in a larger cohort. We also studied the predictive value of common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in this material. METHODS: CD44, HIF1alpha, and CLEVER-1 were immunohistochemically analyzed in paraffin-embedded tissue material of stage I OSCC patients treated at three Finnish university hospitals. Microscopy results were correlated with OSCC outcome. RESULTS: As in our pilot study, the CD44lowHIF1alphahigh signature was associated with poorer disease-free survival. Clear correlations between CLEVER-1 expression and clinical outcome were not evident. CONCLUSION: Our results suggest that immunohistochemistry of CD44 and HIF1alpha may be useful in identification of patients with poor prognoses. These parameters could be used to select the optimal treatment modalities for stage I OSCC patients. LEVEL OF EVIDENCE: 2b. PMID- 28894798 TI - Perineural Invasion in Squamous Cell Carcinoma of the Oral Cavity: Histology, Tumor Stage, and Outcome. AB - OBJECTIVES/HYPOTHESIS: To analyze the impact of different types of perineural invasion (PNI) in squamous cell carcinoma (SCC) of the oral cavity on overall survival and recurrence rate, with a special focus on histologic subtypes and tumor stage. STUDY DESIGN: Retrospective case-control study with clinicopathological analysis. METHODS: Seventeen patients who received primary surgical treatment for SCC of the oral cavity with PNI were matched to a control group. In a histologic review, PNI was classified into subtypes according to an adapted Liebig classification. The term type A was used to describe tumor invasion into the nerve, whereas type B was used to describe circumferential growth around the nerve. Clinical charts were reviewed, and a Kaplan-Meier survival analysis was performed. RESULTS: The recurrence-free survival rates were 47.1% versus 80.4% (PNI vs. matched control group, P < 0.05), 60.0% versus 94.1% (PNI in stage I and II disease vs. matched control group, P < 0.05) and 41.7% versus 73.5% (PNI in stage III and IV disease vs. matched control group, P < 0.05). In most cases (n = 9) of PNI, both histologic subtypes (type A and type B) were present. Five cases exclusively showed type A, and three cases exclusively showed type B. CONCLUSIONS: Perineural invasion in early disease oral carcinoma has a particularly high impact on survival. Both histologic subtypes showed a significantly worse recurrence-free survival rate when compared to the control group. LEVEL OF EVIDENCE: 3. PMID- 28894800 TI - IIF-Cover. PMID- 28894799 TI - Guide to Academic Research Career Development. AB - OBJECTIVES/HYPOTHESIS: Development of an academic career easily follows a clinical course for which there are multiple role models; however, development of an academic research career involves few role models, and rarely do instructional guides reach out to the new faculty. The purpose of this article is to present the cumulative experiences of previously and currently funded authors to serve as a guide to young as well as older faculty for developing their research careers. STUDY DESIGN: Cumulative experiences of research-dedicated faculty. METHODS: This article is the result of lessons learned from developing a Triological Society National Physician-Scientist Program and Network, as well as the cumulative experiences of the authors. RESULTS: Table I illustrates key elements in developing a serious research career. Table II records the career courses of five surgeon-scientists, highlighting the continued theme focus with theme-specific publications and progressive grants. These cumulative experiences have face validity but have not been objectively tested. The value added is a composite of 50 years of experiences from authors committed to research career development for themselves and others. CONCLUSION: Crucial elements in developing a research career are a desire for and commitment to high-quality research, a focus on an overall theme of progressive hypothesis-driven investigations, research guidance, a willingness to spend the time required, and an ability to learn from and withstand failure. LEVEL OF EVIDENCE: 5. PMID- 28894801 TI - Induction Chemotherapy for p16 Positive Oropharyngeal Squamous Cell Carcinoma. AB - OBJECTIVES/HYPOTHESIS: We aimed to determine the effectiveness of induction chemotherapy for treating p16-positive oropharyngeal cancer in our department. STUDY DESIGN: This was a retrospective case series to assess treatment effectiveness. METHODS: We administered induction chemotherapy to patients with stage III to IV oropharyngeal p16-positive squamous cell carcinoma between 2008 and 2013. Induction chemotherapy was administered using combinations of docetaxel, cisplatin, and 5-fluorouracil. We measured the survival rates using the Kaplan-Meier method and log-rank test. RESULTS: We reviewed 23 patients (18 men and 5 women; age, 42-79 years). Induction chemotherapy resulted in partial or complete remission (20 patients) and in stable (2 patients) or progressive (1 patient) disease. In partial or complete remission, subsequent radiotherapy was performed in 16 patients, chemoradiotherapy in two, and transoral resection in two. In stable or progressive disease, subsequent open surgery was performed. Overall, one patient died of cervical lymph node metastasis, one died of kidney cancer, and one died of myocardial infarction. Event-free, distant-metastasis free survival was present for 20 patients. The 3-year disease-specific survival was 95%; the overall survival was 87%. Two patients required gastrostomies during chemoradiotherapy and three required tracheotomies, but these were closed in all patients. CONCLUSION: The therapeutic response to induction chemotherapy for p16 positive oropharyngeal cancer was good. Partial or complete remission was achieved in almost 90% patients, and control of local and distant metastases was possible when it was followed by radiotherapy alone or with transoral resection of the primary tumor. A multicenter study is required to confirm these findings. LEVEL OF EVIDENCE: 4. PMID- 28894802 TI - Adipose-Derived Mesenchymal Stem Cell Features in Patients with a History of Head and Neck Radiation. AB - OBJECTIVES/HYPOTHESIS: Radiation plays a prominent role in advanced stage head and neck tumors. Often, the radiated area includes adjacent nonmalignant mesenchymal tissue, which contains a mixture of cells that has been shown to accelerate wound healing. The purpose of this study is to determine the long-term effect of radiation on the expansion potential of adipose-derived stromal/stem cell (ADSC) tissue and on the ability of resident stem cells in this fraction to undergo phenotypic differentiation. Study Design/Methods: After institutional review board approval, 12 patients with a history of head and neck radiation and pending surgery were enrolled. Adipose tissue was collected from irradiated tissue (XRT) and nonirradiated tissue (NRT) sites. Mesenchymal stem cells were isolated from these populations, with subsequent assessment of cellular kinetics and differentiation potential between harvest sites. RESULTS: Adipose-derived stromal/stem cells could not be isolated from XRT in six patients due to lack of in vitro cell proliferation. For the remaining six patients, overall cumulative population-doubling time was longer for XRT relative to NRT (29.3 vs. 11.5 days; P = 0.02). However, no significant differences were observed in cell generation time or viability. When XRT and NRT ADSC fractions were grown to standardized concentrations and incubated under conditions that induce phenotypic differentiation of resident stem cells, no significant changes in chondrogenic, adipogenic, or osteogenic differentiation were observed. CONCLUSION: These preliminary observations suggest that irradiated ADSCs close to the surgical site undergo long-term changes in proliferative capacity. The potential for phenotypic differentiation is retained, however, in ADSCs that survive the irradiation process. LEVEL OF EVIDENCE: 2b. PMID- 28894803 TI - Postoperative Rehabilitation Strategies Used by Adults With Cochlear Implants: A Pilot Study. AB - OBJECTIVES/HYPOTHESIS: Aural rehabilitation is not standardized for adults after cochlear implantation. Most cochlear implant (CI) centers in the United States do not routinely enroll adult CI users in focused postoperative rehabilitation programs due to poor reimbursement and lack of data supporting (or refuting) the efficacy of any one specific approach. Consequently, patients generally assume a self-driven approach toward rehabilitation. This exploratory pilot study examined rehabilitation strategies pursued by adults with CIs and associated these strategies with speech recognition and CI-specific quality of life (QOL). STUDY DESIGN: Cross-sectional study of 23 postlingually deafened adults with CIs. METHODS: Participants responded to an open-ended questionnaire regarding rehabilitation strategies. A subset underwent in-depth interviews. Thematic content analysis was applied to the questionnaires and interview transcripts. Participants also underwent word recognition testing and completed a CI-related QOL measure. Participants were classified as having good or poor performance (upper or lower quartile for speech recognition) and high or low QOL (upper or lower quartile for QOL). Rehabilitation themes were compared and contrasted among groups. RESULTS: Five rehabilitation themes were identified: 1) Preimplant expectations of postoperative performance, 2) personal motivation, 3) social support, 4) specific rehabilitation strategies, and 5) patient-perceived role of the audiologist. Patients with good speech recognition and high QOL tended to pursue more active rehabilitation and had greater social support. Patient expectations and motivation played significant roles in postoperative QOL. CONCLUSION: Postoperative patient-driven rehabilitation strategies are highly variable but appear to relate to outcomes. Larger-scale extensions of this pilot study are needed. PMID- 28894805 TI - The true malignancy rate in 135 patients with preoperative diagnosis of a lateral neck cyst. AB - OBJECTIVE: In this study, the true malignancy rate in 135 patients with a preoperative tentative diagnosis of a lateral neck cyst (LNC) was assessed. Furthermore, the sensitivity and specificity of fine needle aspiration of suspected LNC were evaluated and the diagnostic delay was analyzed. STUDY DESIGN: This study was retrospective in design and included all patients who had undergone surgery for a suspected LNC in four secondary hospitals in the eastern regions of Denmark during the period of 2009 to 2012. METHODS: One hundred thirty five patients were identified and included by means of a search strategy for NOMECO surgical procedure codes KENB40A+B in the electronic surgical booking systems. Because the procedure codes also include median neck cysts and fistulas, the latter were excluded manually. RESULTS: Of the 135 patients preoperatively diagnosed with LNC, a malignant postoperative histopathological diagnosis was revealed in 19 patients (14.4%). Of these, three individuals were between 35 to 40 years of age. In 17 cases, preoperative fine-needle aspiration biopsy showed benign cytology, whereas histopathology postoperatively proved to be malignant. This renders a sensitivity of 88.8% and a specificity of 60.0% for fine needle aspiration biopsy with regard to LNC diagnostics. CONCLUSION: This study suggests that, for patients older than 35 years, a cystic lateral neck mass should be considered potentially malignant; by contrast, LNC is a diagnosis of exclusion. Any delay in treatment should be avoided until final histopathological diagnosis has been obtained. Arguably, all patients older than 35 years with a cystic lesion laterally on the neck should be included in the fast-track cancer referral program. LEVEL OF EVIDENCE: 2b. PMID- 28894806 TI - CT imaging of the eustachian tube using focal contrast medium administration: a feasibility study. AB - OBJECTIVES: We aim to develop an imaging technique for visualization of the Eustachian tube (ET) lumen. STUDY DESIGN: A prospective, experimental study in an animal model and in human cadaver specimens. METHODS: Applying iodixanol to the middle ear in two human temporal bone specimens, followed by computed tomography (CT) examinations, we optimized contrast dilution, CT algorithm, and head positioning for visualization of contrast passage through the ET. Myringotomy was performed on eight rabbits. Based on the cadaver study, a 20% iodixanol solution was applied to the middle ear, and subsequent CT scans were performed to observe iodixanol in the epipharynx. For some animals, the procedure was repeated on the contralateral ear. We performed the procedure twice on four subjects. Twenty examinations were included. Iodixanol appearance in the ET and the epipharyngeal orifice was assessed qualitatively on CT scans. The tympanic membrane was inspected after 1 or 2 weeks, and histopathological examination of six contrast exposed temporal bones was performed. RESULTS: The cadaver study provided information on imaging technique and contrast dosage. In rabbits, iodixanol passed through the ET in 19 of the 20 ears. Qualitatively, optimal visualization was seen after 9 to 12 minutes. Clinical inspection after 1 or 2 weeks revealed normal middle ear status. Histopathological samples showed no sign of inflammatory reaction in the tympanic membrane, middle ear, or ET. CONCLUSION: Iodixanol application to the middle ear is feasible, safe, and demonstrates patency of the ET. LEVEL OF EVIDENCE: N/A. PMID- 28894807 TI - Factors affecting revision rate of chronic rhinosinusitis. AB - OBJECTIVE: Chronic rhinosinusitis (CRS) is a variable multifactorial disease. It can be divided into forms with nasal polyps (CRSwNP) and without (CRSsNP). Sinus and/or nasal polypectomy surgery are considered if maximal conservative treatment is insufficient. The predictive factors of the need of revision surgery comprise mostly the CRSwNP phenotype and are not fully understood. STUDY DESIGN: The aim of this follow-up study was to evaluate the factors associated with the revision surgery rate in CRS patients with variable extent of disease. METHODS: Data of CRS patients (N = 178) undergoing sinus surgery and/or nasal polypectomy in 2001 to 2010 were used. Patient characteristics and follow-up data were collected from patient records and questionnaires. Associations were analyzed by Fisher's exact, Mann Whitney U, and the Kaplan-Meier method with log-rank test. Unadjusted Cox's proportional hazard models were used for 12 variables and were fitted for the need for revision sinus surgery and/or nasal polypectomy during follow-up of in average 9 years. RESULTS: The proportion of CRS patients who had undergone revision in 5 years was 9.6%. After adjustment, the following factors associated significantly with the need for recurrent CRS surgery: allergic rhinitis, corticosteroid treatment, previous surgery of CRS, and recurrent NP. CONCLUSION: Increased risk of progressive CRS phenotypes with the need for revision surgery would putatively be recognized by relatively simple clinical questions. Further studies with increased sample size are needed to evaluate whether these predictive factors would be relevant for developing better detection and management of progressive CRS. LEVEL OF EVIDENCE: 2b. PMID- 28894804 TI - Clinical and molecular insights into adenoid cystic carcinoma: Neural crest-like stemness as a target. AB - OBJECTIVES: This review surveys trialed therapies and molecular defects in adenoid cystic carcinoma (ACC), with an emphasis on neural crest-like stemness characteristics of newly discovered cancer stem cells (CSCs) and therapies that may target these CSCs. DATA SOURCES: Articles available on Pubmed or OVID MEDLINE databases and unpublished data. REVIEW METHODS: Systematic review of articles pertaining to ACC and neural crest-like stem cells. RESULTS: Adenoid cystic carcinoma of the salivary gland is a slowly growing but relentless cancer that is prone to nerve invasion and metastases. A lack of understanding of molecular etiology and absence of targetable drivers has limited therapy for patients with ACC to surgery and radiation. Currently, no curative treatments are available for patients with metastatic disease, which highlights the need for effective new therapies. Research in this area has been inhibited by the lack of validated cell lines and a paucity of clinically useful markers. The ACC research environment has recently improved, thanks to the introduction of novel tools, technologies, approaches, and models. Improved understanding of ACC suggests that neural crest like stemness is a major target in this rare tumor. New cell culture techniques and patient-derived xenografts provide tools for preclinical testing. CONCLUSION: Preclinical research has not identified effective targets in ACC, as confirmed by the large number of failed clinical trials. New molecular data suggest that drivers of neural crest-like stemness may be required for maintenance of ACC; as such, CSCs are a target for therapy of ACC. PMID- 28894808 TI - Animal Models in CRS and Pathophysiologic Insights Gained: A Systematic Review. AB - OBJECTIVE: Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease. In particular, CRS with eosinophilic features and/or nasal polyps (NPs) is often recalcitrant to current treatment; thus, appropriate animal models are mandatory to elucidate the pathogenesis of CRS and develop novel and efficient treatment modalities. The author reviewed the recently proposed animal models in CRS and discussed the pathophysiologic insights gained. Data Sources: Articles in the English language referenced in MEDLINE/PubMed from the year 2006 onward (for last 10 years). Review Methods: Review of the literature regarding animal models and related pathologic insights in CRS. RESULTS: Mouse, rabbit, and sheep models of CRS have been used for studying the pathogenesis of CRS. Most of researchers adopted animal models of CRS to prove any molecular mechanisms or therapeutic efficacy. In vitro or human findings and related hypothesis were evaluated in vivo using these models. In addition, novel therapeutic candidates for CRS with or without NP have been applied to animal models. CONCLUSION: Animal models have elicited insights into the pathogenesis of CRS and also have been useful in testing new treatment modalities. Although there are still clear limitations in the animal studies, newly proposed or revised animal models would be helpful to understand the exact pathophysiology of CRS. PMID- 28894809 TI - Tympanic Plexus Neurectomy for Intractable Otalgia. AB - OBJECTIVE: The goal of this study was to analyze whether tympanic plexus neurectomy is a successful surgical option in patients with intractable otalgia. STUDY DESIGN: A retrospective single institution study from the experience of two surgeons was conducted. METHODS: Records of adult patients with intractable unilateral otalgia of likely glossopharyngeal origin were reviewed, with institutional review board approval. Patients who responded to a tympanic plexus block were considered for tympanic neurectomy. Twelve patients (13 ears) underwent the procedure. Surgical outcomes and the presence of persistent otalgia were evaluated. RESULTS: Persistent otalgia was present for 16.7 months +/- 8.6 standard-error-of-the-mean months prior to an intervention. Narcotic medication was used in 41.7% of patients prior to surgery. Patients received tympanic plexus blocks (median: 1, range 1-3) prior to tympanic neurectomy to evaluate candidacy for surgery. Intractable otalgia resolved in six of 13 ears (46.2%) after one surgery, with an average follow-up of 25.5 months. A significant reduction in pain occurred in two of 13 ears (15.4%) after an initial surgery. One patient received no benefit from the initial procedure. Revision surgery occurred in four ears, resulting in pain relief in three of four cases. All together, nine of 13 ears received complete resolution of pain, and an additional two of 13 ears received partial benefit using our algorithm for treatment of intractable otalgia of tympanic plexus origin. CONCLUSION: Intractable otalgia treated with tympanic neurectomy is a viable treatment option in cases of failed medical management. These findings provide important information that will aid clinicians in counseling chronic otalgia patients. LEVEL OF EVIDENCE: NA. PMID- 28894811 TI - Serum vitamin D and recurrent benign paroxysmal positional vertigo. AB - OBJECTIVES: The objective of the present study was to examine the effects of serum 25-hydroxyvitamin D concentrations on patients diagnosed with benign paroxysmal positional vertigo (BPPV) on BPPV recurrence. STUDY DESIGN: Case series. METHODS: A retrospective review of 232 patients diagnosed with BPPV visiting the clinic between June 2014 and June 2015 was performed. All patients underwent a complete otolaryngological, audiologic, and neurologic evaluation. The appropriate particle-repositioning maneuver was performed depending on the type of BPPV. The patients were divided into the recurrence group and the nonrecurrence group. Age, gender, follow-up period, type of BPPV, and vitamin D concentrations in the two groups were compared and analyzed through binary logistic regression analyses. RESULTS: The average follow-up period after treatment was 10.2 months. Forty-one (17.7%) of 232 patients suffered a recurrence during the follow-up period. The mean vitamin D concentration of 191 patients who did not suffer any recurrence was 16.63 ng/mL, whereas that of 41 patients who suffered a recurrence was 13.64 ng/mL. This difference in vitamin D concentrations was statistically significant (P < 0.019). The patients' age, gender, follow-up period, and type of BPPV had no statistically significant impact. CONCLUSION: Vitamin D is assumed to affect BPPV as a recurrence factor independent of age, gender, follow-up period, and type of BPPV. LEVEL OF EVIDENCE: 4. PMID- 28894810 TI - Sialendoscopy for non-stone disorders: The current evidence. AB - OBJECTIVE: Review the current literature on the use of sialendoscopy in the treatment of non-stone disorders of the major salivary glands. DATA SOURCES: Eligible articles that reported on the use of sialendoscopy in the treatment of non-stone disorders were identified using MEDLINE, Embase, and Google Scholar through May 2016. The search used key words sialendoscopy, salivary endoscopy, salivary scope, salivary duct stenosis, salivary duct stricture, Sjogren's disease, radioiodine sialadenitis, salivary duct obstruction, sialadenitis, chronic sialadenitis, juvenile recurrent parotitis, parotitis, and radiation sialadenitis. REVIEW METHODS: Full-length prospective and retrospective original articles; systemic reviews; and meta-analysis, including adults and children with adequate data for evaluating the sialendoscopy for non-stone disorders, were included. Individual case reports were excluded. RESULTS: There is an increasing trend for the use of sialendoscopy for salivary obstruction caused by a wide variety of non-stone disorders worldwide. The studies of sialendoscopy for non stone disorders are often retrospective, of smaller sample size, and more subjective in measurement of patient outcome. The most common indications currently for the procedure are scars, juvenile recurrent parotitis, radioiodine sialadenitis, and Sjogren syndrome, respectively. CONCLUSION: Although the initial evidence for the use of sialendoscopy for non-stone disorders is not as established as that for stones, it remains a promising gland-preserving tool in the management of non-stone disorders of major salivary glands. PMID- 28894812 TI - Caloric testing in patients with heavy or light cupula of the lateral semicircular canal. AB - OBJECTIVE: To clarify whether the dysfunction of the lateral semicircular canal remain or not in patients with heavy or light cupula. STUDY DESIGN: Prospective case series. METHODS: The subjects were 19 patients with heavy cupula (3 males, 16 females; mean age, 62.8 years) and 14 patients with light cupula (5 males, 9 females; mean age, 63 years). Caloric testing (iced water) was carried out after complete disappearance of positional nystagmus. We measured maximum slow-phase velocity and calculated asymmetry. RESULTS: In heavy cupula group, no one revealed canal paresis (CP) and 4 patients (21%) showed inverse CP (affected ear response is greater than healthy ear response). In light cupula group, 3 patients (21%) revealed CP. CONCLUSIONS: Dysfunction of the lateral semicircular canal does not always remain in either heavy cupula or light cupula. The caloric response increases in some cases with heavy cupula. We can explain this phenomenon based on the hydrostatic pressure theory involved in ossicles. LEVEL OF EVIDENCE: 4. PMID- 28894813 TI - The importance of electrode location in cochlear implantation. AB - OBJECTIVES: As indications for cochlear implantation have expanded to include patients with more residual hearing, increasing emphasis has been placed on minimally traumatic electrode insertion. Histopathologic evaluation remains the gold standard for evaluation of cochlear trauma, but advances in imaging techniques have allowed clinicians to determine scalar electrode location in vivo. This review will examine the relationship between scalar location of electrode arrays and audiologic outcomes. In addition, the impact that surgical approach, electrode design, and insertion depth have on scalar location will be evaluated. Data Sources: PubMed literature review Review Methods: A review of the current literature was conducted to analyze the relationship between scalar location of cochlear implant electrode arrays and speech perception outcomes. Further, data were reviewed to determine the impact that surgical variables have on scalar electrode location. RESULTS: Electrode insertions into the scala tympani are associated with superior speech perception and higher rates of hearing preservation. Lateral wall electrodes, and round window/extended round window approaches appear to maximize the likelihood of a scala tympani insertion. It does not appear that deeper insertions are associated with higher rates of scalar translocation. CONCLUSION: Superior audiologic outcomes are observed for electrode arrays inserted entirely within the scala tympani. The majority of clinical data demonstrate that lateral wall design and a round window approach increase the likelihood of a scala tympani insertion. LEVEL OF EVIDENCE: N/A. PMID- 28894814 TI - Minimally invasive and remote-access thyroid surgery in the era of the 2015 American Thyroid Association guidelines. AB - Thyroid surgery has evolved throughout the years from being one of the most dangerous surgeries to becoming one of the safest surgical procedures performed today. Recent technologic innovations have allowed surgeons to remove the thyroid gland from a remote site while avoiding visible neck scars. There are many endoscopic approaches for thyroidectomy. The most common cervical approach is the minimally invasive video-assisted technique developed by Miccoli et al. The robotic transaxillary and axillary breast approaches avoid a neck scar and have been demonstrated to be safe and effective in international populations. Novel approaches under investigation include face-lift robotic thyroidectomy and the transoral approach. This article aims to provide the reader with an overview of the current minimally invasive and alternate-site approaches used and their capability to assist the surgeons in accomplishing remote-access thyroid surgery under the scope of the 2015 American Thyroid Association Guidelines. PMID- 28894815 TI - Development of a voice disorder work productivity inventory utilizing cognitive interviewing technique. AB - OBJECTIVES/HYPOTHESIS: Voice disorders have been shown to impair workplace productivity primarily by reduced efficiency while at work (presenteeism) versus increased days missed (absenteeism). Work productivity measures such as the Work Productivity and Activity Impairment (WPAI) Questionnaire or the World Health Organization Health - Work Performance Questionnaire (HPQ) can be customized to a specific disease but do not fully capture impaired work productivity associated with voice disorders. The purpose of this study was to develop a novel questionnaire to evaluate work productivity in patients with voice disorders. STUDY DESIGN: Descriptive. METHODS: At a tertiary medical center, patients with gainful employment and with chronic voice disorders were given the WPAI, HPQ, and 20 voice-related statements (VRS-20). Cognitive interviews were conducted and recorded with all patients. RESULTS: Ten patients (7 females, 3 males) completed the questionnaires and subsequent cognitive interviews. One patient had spasmodic dysphonia, 6 had benign vocal fold lesions, and 3 had vocal fold motion disorders. The median VHI-10 was 18 (9-40). Themes that emerged during interviews include: avoiding oral communication/telephone, use of voice associated with strain/fatigue, frustration and stress at work, and workplace integrity. Conclusions: In cognitive interviews, participants felt the VRS-20 captured the impact of their voice disorder at work better than the WPAI and HPQ. Participants also felt some statements were more important than others. LEVEL OF EVIDENCE: 5. PMID- 28894816 TI - Evaluation of peripheral nerve regeneration through biomaterial conduits via micro-CT imaging. AB - OBJECTIVE: Hollow nerve conduits made of natural or synthetic biomaterials are used clinically to aid regeneration of peripheral nerves damaged by trauma or disease. To support healing, conduit lumen patency must be maintained until recovery occurs. New methods to study conduit structural integrity would provide an important means to optimize conduits in preclinical studies. We explored a novel combined technique to examine structural integrity of two types of nerve conduits after in vivo healing. STUDY DESIGN: Micro-CT imaging with iodine contrast was combined with histological analysis to examine two different nerve conduits after in vivo nerve reconstruction in rats. MATERIALS AND METHODS: Sciatic nerve gaps in adult Lewis rats were reconstructed with poly(caprolactone) (PCL, 1.6 cm gap, 14-week survival) or silicone (1 cm gap, 6-week survival) conduits (N = 12 total). Conduits with regenerating tissues were imaged by micro CT with iodine contrast and compared to the histology (hematoxylin and eosin, immunostaining for axons) of regenerated tissues after iodine removal. RESULTS: PCL nerve conduits showed extensive breakage throughout their length, but all showed successful nerve growth through the conduits. The silicone conduits remained intact, although significant constriction was uniquely detected by micro CT, with 1 of 6 animals showing incomplete tissue regeneration. CONCLUSIONS: Micro-CT with iodine contrast offers a unique and valuable means to determine 3D structural integrity of nerve conduits and nerve healing following reconstruction. Furthermore, this paper shows that even if conduit compression and degradation occur, nerve regeneration can still take place. PMID- 28894818 TI - Right dominance in the incidence of external auditory canal squamous cell carcinoma in the Japanese population: Does handedness affect carcinogenesis? AB - OBJECTIVES/HYPOTHESIS: To investigate the relationship between handedness and the incidence of squamous cell carcinoma in the external auditory canal (EACSCC). MATERIALS AND METHODS: Sixty-eight cases of EACSCC were enrolled in this study, and their affected side was checked. Handedness and ear-picking habits were also investigated in 34 EACSCC cases. Handedness was judged based on self categorization, and the relationship between handedness and the affected side was investigated. RESULTS: Fifty-two cases occurred on the right side, and 16 cases occurred on the left side of patients with EACSCC. The incidence of laterality in EACSCC showed a statistically significant right dominance. Concerning handedness, 29 cases were right-handed, 4 cases were left-handed, and 1 case was ambidextrous. Twenty-seven out of the 29 right-handed cases and 1 ambidextrous case suffered from carcinoma on the right side, whereas 3 left-handed cases suffered from carcinoma on the left side. That is, most of the cases suffered from EACSCC on the same side as their handedness, and this tendency showed a statistically significant difference. Most of the patients with EACSCC experienced itching and habitual ear-picking in the affected side. CONCLUSION: Mechanical stimulations to the EAC, such as ear picking, may plausibly cause EACSCC. In Japan, ear picking, also called "mimikaki," is a popular habit and an established unique culture. Because ear picking requires delicate handling and manipulation, this tends to occur on the same side as the handedness in the Japanese population. This is the first report about the relationship between handedness and carcinogenesis. LEVEL OF EVIDENCE: N/A. PMID- 28894817 TI - Emerging insights into recurrent and metastatic human papillomavirus-related oropharyngeal squamous cell carcinoma. AB - OBJECTIVE: To review recent literature on human papillomavirus-related (HPV positive) oropharyngeal squamous cell carcinoma (OPC) and focus on implications of recurrent and metastatic disease. METHODS: Primary articles from 1990 to 2016 indexed in MEDLINE (1) pertaining to the epidemiology of HPV-positive OPC and (2) providing clinical insight into recurrent and metastatic OPC. RESULTS: The incidence of HPV-positive OPC is increasing globally. HPV-positive OPC is a subtype with distinct molecular and clinical features including enhanced treatment response and improved overall survival. While disease recurrence is less common in patients with HPV-positive OPC, up to 36% of patients experience treatment failure within eight years. Recurrent and metastatic OPC has historically signified poor prognosis, however recent data are challenging this dogma. Here, we discuss recurrent and metastatic OPC in the context of HPV tumor status. CONCLUSION: HPV-positive OPC exhibits distinct genetic, cellular, epidemiological, and clinical features from HPV-negative OPC. HPV tumor status is emerging as a marker indicative of improved prognosis after disease progression in both locoregionally recurrent and distant metastatic OPC. LEVEL OF EVIDENCE: N/A. PMID- 28894819 TI - Computational Modelling of Cough Function and Airway Penetrant Behavior in Patients with Disorders of Laryngeal Function. AB - OBJECTIVE/HYPOTHESIS: Patients with laryngeal disorders often exhibit changes to cough function contributing to aspiration episodes. Two primary cough variables (peak cough flow: PCF and compression phase duration: CPD) were examined within a biomechanical model to determine their impact on characteristics that impact airway compromise. STUDY DESIGN: Computational study. METHODS: A Computational Fluid Dynamics (CFD) technique was used to simulate fluid flow within an upper airway model reconstructed from patient CT images. The model utilized a finite volume numerical scheme to simulate cough-induced airflow, allowing for turbulent particle interaction, collision, and break-up. Liquid penetrants at 8 anatomical release locations were tracked during the simulated cough. Cough flow velocity was computed for a base case and four simulated cases. Airway clearance was evaluated through assessment of the fate of particles in the airway following simulated cough. RESULTS: Peak-expiratory phase resulted in very high airway velocities for all simulated cases modelled. The highest velocity predicted was 49.96 m/s, 88 m/s, and 117 m/s for Cases 1 and 3, Base case, and Cases 2 and 4 respectively. In the base case, 25% of the penetrants cleared the laryngeal airway. The highest percentage (50%) of penetrants clearing the laryngeal airway are observed in Case 2 (with -40% CPD, +40% PCF), while only 12.5% cleared in Case 3 (with +40% CPD, -40% PCF). The proportion that cleared in Cases 1 and 4 was 37.5%. CONCLUSION: Airway modelling may be beneficial to the study of aspiration in patients with impaired cough function including those with upper airway and neurological diseases. It can be used to enhance understanding of cough flow dynamics within the airway and to inform strategies for treatment with "cough-assist devices" or devices to improve cough strength. LEVEL OF EVIDENCE: N/A. PMID- 28894820 TI - Indwelling voice prosthesis insertion after total pharyngolaryngectomy with free jejunal reconstruction. AB - OBJECTIVES: Total pharyngolaryngectomy with free jejunal reconstruction is often performed in patients with hypopharyngeal carcinoma. However, postoperative speechlessness significantly decreases patient quality of life. We investigated whether Provox(r) insertion could preserve speech after total pharyngolaryngectomy with free jejunal reconstruction. STUDY DESIGN: Retrospective chart review. METHODS: A total of 130 cases of secondary Provox(r) insertions after total pharyngolaryngectomy with free jejunal reconstruction were analyzed. Communication outcomes were compared using the Head and Neck Cancer Understandability of Speech Subscale. Outcomes and complications associated with insertion site (jejunal insertion vs. esophageal insertion) and adjuvant irradiation therapy were also evaluated. RESULTS: Provox(r) insertion had favorable communication outcomes in 102 cases (78.4%). Neither the insertion site nor irradiation affected the communication outcome. Complications were observed in 20 cases (15.4%). Local infection was the most common complication. Free jejunal insertion, in which the resection range was enlarged, had a lower complication rate than did esophageal insertion, and its complication rate was unaffected by previous irradiation. For all patients, the hospitalization duration and duration of speechlessness were 13.4 days and 14.6 months, respectively. Patients receiving jejunal insertions had a significantly shorter hospitalization duration than did those receiving esophageal insertions. Unlike Provox(r)2, Provox(r)Vega significantly reduced the complication rate to zero. CONCLUSION: For jejunal inserson of a Provox(r) prosthetic, a sufficient margin can be maintained during total pharyngolaryngectomy and irradiation can be performed, and satisfactory communication outcomes were observed. Provox(r) insertion after total pharyngolaryngectomy with free jejunal reconstruction should be considered the standard therapy for voice restoration. LEVEL OF EVIDENCE: 4. PMID- 28894821 TI - The role of infection and antibiotics in chronic rhinosinusitis. AB - OBJECTIVE: To review the current understanding of the role of infection and antibiotics in chronic rhinosinusitis. REVIEW METHODS: PubMed literature search. RESULTS: Chronic rhinosinusitis (CRS) in adults is an inflammatory condition and the role of infection is unclear. Biofilms are present in both CRS and normal patients so their role in CRS is unknown. Sinus cultures in CRS demonstrate a mixture of aerobic and anaerobic bacteria but may be hard to interpret due to contaminating nasal flora. Staphylococcus aureus is common in CRS patients but also present in 20-30% of nasal cultures in the normal population; eradicating this organism did not lead to symptom improvement versus placebo in a randomized controlled trial (RCT). In CRS patients who develop an episode of acute rhinosinusitis (ARS), bacteria typical of ARS can generally be cultured and require short-course treatment. For CRS, topical antibacterial or antifungal agents have shown no benefit over placebo in RCTs, although RCTs of topical antibacterial agents have been small. Oral macrolides and doxycycline, antibiotics with anti-inflammatory properties, are the only systemic antibiotics that have been evaluated in RCTs. One RCT found 3 weeks of doxycycline beneficial in patients with polyps but follow up was short (<3 months); RCTs of prolonged macrolide therapy have produced mixed results, and most show no benefit after cessation of therapy. Long-term antibiotic therapy may produce side effects and select increasingly resistant flora. The American Academy of Otolaryngology-Head and Neck Surgery guidelines recommend against treatment of CRS with antifungal agents but do not comment on the role of antibacterial treatment. CONCLUSION: The role of infection in CRS is unknown, and the only well-defined role for antibiotics is for treatment of ARS episodes or their infectious complications. LEVEL OF EVIDENCE: N/A. PMID- 28894822 TI - Randomized Controlled Trial Demonstrating Cost-Effective Method of Olfactory Training in Clinical Practice: Essential Oils at Uncontrolled Concentration. AB - OBJECTIVES: Published data examining the efficacy of olfactory training (OT) has used standardized concentrations of odorants and the Sniffin' Sticks testing method. Although well-validated, these methods are costly and time-intensive for the average otolaryngology practice. The purpose of our study was to evaluate the efficacy of using essential oils at random concentrations and the University of Pennsylvania Smell Test (UPSIT) for training and testing, and compare this with the existing data on OT. STUDY DESIGN: Randomized Clinical TrialMethods: Patients presenting to a tertiary care rhinology center with subjective loss of smell and olfactory loss measured by UPSIT were randomized to OT or control for 6 months. Only patients with loss of smell greater than one-year duration, and loss associated with post-infectious and idiopathic etiologies were included. Baseline UPSIT was compared to 6-month UPSIT. An accepted 10% change or better was used to establish a significant improvement on UPSIT. RESULTS: 43 patients were enrolled. Eight patients were lost to follow-up, with a total of 35 completing the study. Age ranged from 39-71 with an average of 56. Of 19 patients in the OT group, 6 showed significant improvement (32%), while only two out of 16 patients (13%) in the control group improved. Increasing age and duration of loss were significantly correlated to lack of improvement. CONCLUSION: Allowing patients to use random concentrations of essential oils to perform OT is as effective as published data using controlled concentrations of odorants for post-infectious and idiopathic olfactory loss. LEVEL OF EVIDENCE: 1b. PMID- 28894823 TI - The Benefit of Adjuvant Radiation in Surgically-Treated T1-2 N1 Oropharyngeal Squamous Cell Carcinoma. AB - IMPORTANCE: The benefit of adjuvant radiation in surgically treated T1-2N1 oropharyngeal cancer without adverse pathologic features remains unclear. OBJECTIVES: To compare population-level survival outcomes in surgically-treated T1-2N1 oropharyngeal squamous cell carcinoma (OPSCC) with and without the use of adjuvant radiation. STUDY DESIGN: Retrospective population-based study using the Surveillance, Epidemiology, and End Results (SEER) registry data from 1998-2011. SETTING: Population-level study. PARTICIPANTS: Patients with T1-2N1 OPSCC treated with surgical resection and neck dissection with or without adjuvant radiation. INTERVENTIONS FOR CLINICAL TRIALS OR EXPOSURES FOR OBSERVATIONAL STUDIES: The use of postoperative adjuvant radiation. MAIN OUTCOMES AND MEASURES: Overall and disease-specific survival. RESULTS: Radiation was utilized in 74% of patients and was positively associated with extracapsular extension and well-differentiated histology. The use of radiation was associated with improved mean overall survival (124 v. 108 months, p=0.023) and a non-significant increase in mean disease-specific survival (138 v. 131 months, p=0.053). CONCLUSIONS AND RELEVANCE: The use of adjuvant radiation is associated with improved survival in surgically-treated T1-2N1 squamous cell carcinoma of the oropharynx with unknown HPV status. LEVEL OF EVIDENCE: IV. PMID- 28894824 TI - Avoidance of postoperative irradiation for cervical lymph node metastases of human papillomavirus-related tonsillar cancer. AB - BACKGROUND: Several reports have suggested that selected patients with human papillomavirus-related oropharyngeal cancer can be managed with surgery alone. We retrospectively reviewed tonsillar cancer cases to analyze treatment de intensification after transoral resection. METHODS: Eighteen patients with tonsillar cancer who had undergone transoral resection were included. The patients' characteristics, p16 status, adverse features, clinical course, overall survival, and relapse-free survival according to p16 status were retrospectively examined. RESULTS: Four lesions showed positive surgical margins and one lesion showed close surgical margin; these patients were treated with postoperative irradiation. Seven p16-positive patients had multiple node metastases and two had extracapsular spread. No p16-positive patients agreed to postoperative irradiation, and recurrence within the surgical field was not observed. The five year overall and relapse-free survival rates were 89% and 74%, respectively. The five-year relapse-free survival rates of p16-positive and p16-negative patients were 81% and 50%, respectively (p = .075). CONCLUSIONS: Postoperative irradiation for cervical lymph node metastases might be avoidable in selected patients with human papillomavirus-related tonsillar cancer. LEVEL OF EVIDENCE: 4. PMID- 28894825 TI - Hearing loss as a risk factor for dementia: A systematic review. AB - OBJECTIVES: To review evidence of hearing loss as a risk factor for dementia. Data Sources: PubMed Review methods: A systematic review was conducted using the PubMed database using the search terms (hearing loss OR presbycusis) AND (dementia OR cognitive decline). Initially, 488 articles were obtained. Only those studies evaluating an association between hearing loss and incident dementia or cognitive decline were included in the analysis. This resulted in 17 articles which were thoroughly evaluated with consideration for study design, method for determining hearing loss and cognitive status, relevant covariates and confounding factors, and key findings. RESULTS: All of the 17 articles meeting inclusion criteria indicate that hearing loss is associated with dementia or cognitive decline. The methods used among the studies for ascertaining hearing loss and dementia were notably varied. For hearing loss, peripheral auditory function was tested far more than central auditory function. For peripheral audition, pure tone audiometry was the most commonly reported method for defining hearing loss. Only a few studies measured central auditory function by using the Synthetic Sentence Identification with Ipsilateral Competing Message test (SSI ICM) and the Staggered Spondaic Word Test (SSW). Dementia was most often defined using the Mini Mental State Exam (MMSE). However, many studies used extensive batteries of tests to define cognitive status, often including a neuropsychologist. Confounding variables such as cardiovascular risk factors were measured in 17 studies and family history of dementia was only evaluated in 1 study. Overall, the methods used by studies to ascertain hearing loss, cognitive status and other variables are valid, making their evaluation appear reliable. CONCLUSION: While each of the studies included in this study utilized slightly different methods for evaluating participants, each of them demonstrated that hearing loss is associated with higher incidence of dementia in older adults. LEVEL OF EVIDENCE: Level V, systematic review. PMID- 28894827 TI - The genetic landscape of programmed death ligand-1 (PD-L1) alterations in head and neck cancer. AB - OBJECTIVES: Nivolumab has recently been shown in the phase III clinical trial CheckMate-141 to have superior survival rates compared to the current standard of care chemotherapy for recurrent or metastatic platinum-resistant head and neck squamous cell carcinoma (HNSCC). Nivolumab targets the immune inhibitory receptor programmed cell death 1 (PD-1). Programmed cell death ligand 1 (PD-L1) genomics have been poorly characterized in the context of HNSCC, including expression levels of PD-L1 in individual tumors as well as related up or down-regulated genes that might function as co-targets. STUDY DESIGN: Data mining of The Cancer Genome Atlas (TCGA). METHODS: 530 patients with HNSCC were pulled from the TCGA using cBioPortal. Primary tumor site data was available in 279 of the samples (52.6%), of which oral cavity was the most common site (61.6%) followed by larynx (25.8%). Other PD-1-sensitive tumors were analyzed to compare PD-L1 expression in HNSCC relative to other tumors including bladder, renal cell carcinoma, melanoma, and lung carcinomas. RESULTS: A significant fraction of HNSCC tumors have genetic alterations in PD-L1 (6.2%). HNSCC has the highest PD-L1 expression of all of the tumor types examined, with a median 60-fold increase. Several important genes were identified in this study including Caspase 7, ZFYVE9, and Plg-R(KT) that have a strong relationship with alterations in PD-L1. CONCLUSION: In light of the role of PD-1 and PD-L1 as key immunotherapy targets in HNSCC, several potential co-targets identified in this study warrant further investigation. Further, while the number of genetic alterations were small in head and neck carcinomas, alterations in PD-L1 expression were highly significant. LEVEL OF EVIDENCE: NA. PMID- 28894826 TI - Functional and Histological Effects of Chronic Neural Electrode Implantation. AB - OBJECTIVES: Permanent injury to the cranial nerves can often result in a substantial reduction in quality of life. Novel and innovative interventions can help restore form and function in nerve paralysis, with bioelectric interfaces among the more promising of these approaches. The foreign body response is an important consideration for any bioelectric device as it influences the function and effectiveness of the implant. The purpose of this review is to describe tissue and functional effects of chronic neural implantation among the different categories of neural implants and highlight advances in peripheral and cranial nerve stimulation. Data Sources: PubMed, IEEE, and Web of Science literature search. Review Methods: A review of the current literature was conducted to examine functional and histologic effects of bioelectric interfaces for neural implants. RESULTS: Bioelectric devices can be characterized as intraneural, epineural, perineural, intranuclear, or cortical depending on their placement relative to nerves and neuronal cell bodies. Such devices include nerve-specific stimulators, neuroprosthetics, brainstem implants, and deep brain stimulators. Regardless of electrode location and interface type, acute and chronic histological, macroscopic and functional changes can occur as a result of both passive and active tissue responses to the bioelectric implant. CONCLUSION: A variety of chronically implantable electrodes have been developed to treat disorders of the peripheral and cranial nerves, to varying degrees of efficacy. Consideration and mitigation of detrimental effects at the neural interface with further optimization of functional nerve stimulation will facilitate the development of these technologies and translation to the clinic. LEVEL OF EVIDENCE: 3. PMID- 28894828 TI - The role of antibiotics in pediatric chronic rhinosinusitis. AB - OBJECTIVES: Presenting the role of antibiotics in pediatric chronic rhinosinusitis based on its pathophysiology and microbiology. DATA SOURCE: Review of the literature searching PubMed for microbiology and treatment of pediatric chronic rhinosinusitis. RESULTS: Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses that persists for 12 weeks or longer, despite medical management. The microbiology of rhinosinusitis evolves through several stages. The early phase (acute) is generally caused by a virus that may be followed by an aerobic bacterial infection in 2% to 10% of patients. Aerobic (Staphylococcus aureus) and anaerobic (Prevotella and Fusobacteria) members of the oral flora emerge as predominant sinus cavity isolates. Antimicrobials are one component of comprehensive medical and surgical management for this disorder. Because most of these infections are polymicrobial and many include beta lactamase producing aerobic and anaerobic organisms, amoxicillin-clavulanate is the first-line regimen for most patients. Clindamycin is adequate for penicillin allergic children and is also generally appropriate for methicillin resistant Staphylococcus aureus treatment is administered for at least three weeks and may be extended for up to 10 weeks in refractory cases. A culture preferably from the sinus cavity should be obtained from individuals who have not shown improvement or deteriorated despite therapy. CONCLUSIONS: Antimicrobial therapy of pediatric chronic rhinosinusitis should be adequate against the potential aerobic and anaerobic pathogens. LEVEL OF EVIDENCE: 7. PMID- 28894829 TI - The effect of n-acetyl-cysteine on recovery of the facial nerve after crush injury. AB - OBJECTIVE: Facial nerve dysfunction can vary in severity and recovery is dependent on the character of the injury. N-acetyl-cysteine prevents oxidative stress and cellular damage, and its use in the setting of nerve dysfunction from crush injury has not yet been established. In this study, rats with facial nerve crush injury will be treated with n-acetyl-cysteine or control and functional recovery and electrophysiologic outcome will be compared. STUDY DESIGN: Prospective, randomized animal study. METHODS: Twenty-four Wistar rats underwent unilateral facial nerve crush injury. Rats were implanted with a subcutaneous osmotic pump filled with saline (n = 12) or n-acetyl-cysteine 50 mg/kg/day (n = 12). Functional and electromyographic recovery was recorded at two and four weeks postoperatively. RESULTS: When compared to untreated rats, n-acetyl-cysteine treated rats had a greater electromyography amplitude recovery at 2 weeks with regard to eye blink (p=0.006) but not vibrissae function. At four weeks, the electromyography amplitude recovery of the vibrissae function was greater in n acetyl-cysteine treated rats (P=0.001), but the amplitude recovery difference in eye blink was only marginally significant between groups (p=0.07). The functional score was higher in n-acetyl-cysteine-treated rats than in untreated rats at all of the time points. CONCLUSION: This study demonstrated that n-acetyl-cysteine facilitated facial nerve recovery with improved functional and electromyography outcomes in the setting of crush injury. LEVEL OF EVIDENCE: NA. PMID- 28894830 TI - A study of otolaryngology resident quality of life and sleepiness. AB - OBJECTIVES: This study aimed to determine otolaryngology residents' quality of life and sleepiness. METHODS: An electronic survey was distributed to otolaryngology residents in the United States in October 2014 and May 2015. The survey included questions from the Physician Well-Being Index (PWBI) and Epworth Sleepiness Scale (ESS). Data were analyzed using standard descriptive and frequency analyses, Spearman correlations, and Student's t-test. RESULTS: The 196 respondents (13% response rate) had a mean age of 29.9 years and worked an average of 70.88 hours/week. Higher PWBI score (lower quality of life) correlated with higher ESS (more sleepiness) for all respondents regardless of rotation (Spearman coefficient of .45; p = .001). PWBI scores were higher for head/neck oncology. Both PWBI and ESS scores were highest for postgraduate year two. PWBI showed a significant positive correlation with hours worked (correlation coefficient .35; p = .001) as well as a significant negative correlation with exercise time (correlation coefficient -.18; p = .010). There was a positive correlation between hours worked and ESS (correlation coefficient .48; p = .001). CONCLUSION: For the otolaryngology survey respondents, sleepiness and overall well-being were better during the first year with a dramatic worsening during junior years followed by an improvement in the senior years. More work hours and poor quality of life was associated with less physically active residents. Focused interventions during these rotations may reduce distress, improve quality of life, and enhance learning. LEVEL OF EVIDENCE: NA. PMID- 28894831 TI - Assessment and improvement of sound quality in cochlear implant users. AB - OBJECTIVES: Cochlear implants (CIs) have successfully provided speech perception to individuals with sensorineural hearing loss. Recent research has focused on more challenging acoustic stimuli such as music and voice emotion. The purpose of this review is to evaluate and describe sound quality in CI users with the purposes of summarizing novel findings and crucial information about how CI users experience complex sounds. DATA SOURCES: Here we review the existing literature on PubMed and Scopus to present what is known about perceptual sound quality in CI users, discuss existing measures of sound quality, explore how sound quality may be effectively studied, and examine potential strategies of improving sound quality in the CI population. RESULTS: Sound quality, defined here as the perceived richness of an auditory stimulus, is an attribute of implant-mediated listening that remains poorly studied. Sound quality is distinct from appraisal, which is generally defined as the subjective likability or pleasantness of a sound. Existing studies suggest that sound quality perception in the CI population is limited by a range of factors, most notably pitch distortion and dynamic range compression. Although there are currently very few objective measures of sound quality, the CI-MUSHRA has been used as a means of evaluating sound quality. There exist a number of promising strategies to improve sound quality perception in the CI population including apical cochlear stimulation, pitch tuning, and noise reduction processing strategies. CONCLUSIONS: In the published literature, sound quality perception is severely limited among CI users. Future research should focus on developing systematic, objective, and quantitative sound quality metrics and designing therapies to mitigate poor sound quality perception in CI users. LEVEL OF EVIDENCE: NA. PMID- 28894832 TI - Visual effects on the subjective visual vertical and subjective postural head vertical during static roll-tilt. AB - OBJECTIVES: Tilt perception is part of the perception of spatial orientation. It is determined not only by the allocentric gravity axis, but also by a second allocentric axis induced by visual information as well as by the egocentric body (head) axis induced by somatosensory information. The aim of this study was to quantify roll-tilt perception using the subjective visual vertical (SVV) and the newly developed subjective postural head vertical (SPHV) and to investigate the visual effects on both during static roll-tilt. STUDY DESIGN: Basic science. METHODS: Nine male volunteers participated in this study. A flight simulator was used to create several roll-tilt environments that were then combined with visual information. SVV and SPHV were evaluated in healthy participants during static roll-tilt. RESULTS: The SVV evaluation revealed significant differences between the dark condition (control) and other visual conditions with respect to some of the body roll-tilt environments, and between a body roll-tilt of 0 degrees and >= 20 degrees . The SPHV evaluation revealed a significant difference between the dark condition and the visual condition that was always roll-tilted 20 degrees to the right of the body axis. However, there were no significant differences in SPHV error between a body roll-tilt of 0 degrees and other tilt angles for every visual condition, unlike SVV error. CONCLUSIONS: Our data indicate that human susceptibility to spatial disorientation is dependent on roll-tilt angle and visual information. They also suggest that the SPHV is not affected by roll-tilt angle, and thus differs from SVV. LEVEL OF EVIDENCE: NA. PMID- 28894833 TI - Ethmoidectomy combined with superior meatus enlargement increases olfactory airflow. AB - OBJECTIVES: The relationship between a particular surgical technique in endoscopic sinus surgery (ESS) and airflow changes in the post-operative olfactory region has not been assessed. The present study aimed to compare olfactory airflow after ESS between conventional ethmoidectomy and ethmoidectomy with superior meatus enlargement, using virtual ESS and computational fluid dynamics (CFD) analysis. STUDY DESIGN: Prospective computational study. MATERIALS AND METHODS: Nasal computed tomography images of four adult subjects were used to generate models of the nasal airway. The original preoperative model was digitally edited as virtual ESS by performing uncinectomy, ethmoidectomy, antrostomy, and frontal sinusotomy. The following two post-operative models were prepared: conventional ethmoidectomy with normal superior meatus (ESS model) and ethmoidectomy with superior meatus enlargement (ESS-SM model). The calculated three-dimensional nasal geometries were confirmed using virtual endoscopy to ensure that they corresponded to the post-operative anatomy observed in the clinical setting. Steady-state, laminar, inspiratory airflow was simulated, and the velocity, streamline, and mass flow rate in the olfactory region were compared among the preoperative and two postoperative models. RESULTS: The mean velocity in the olfactory region, number of streamlines bound to the olfactory region, and mass flow rate were higher in the ESS-SM model than in the other models. CONCLUSION: We successfully used an innovative approach involving virtual ESS, virtual endoscopy, and CFD to assess postoperative outcomes after ESS. It is hypothesized that the increased airflow to the olfactory fossa achieved with ESS SM may lead to improved olfactory function; however, further studies are required. LEVEL OF EVIDENCE: NA. PMID- 28894835 TI - The use of oculomotor, vestibular, and reaction time tests to assess mild traumatic brain injury (mTBI) over time. AB - OBJECTIVES: The objective of this work is to examine the outcomes of a set of objective measures for evaluating individuals with minor traumatic brain injury (mTBI) over the sub-acute time period. These methods involve tests of oculomotor, vestibular, and reaction time functions. This work expands upon published work examining these test results at the time of presentation. STUDY DESIGN: This study is a prospective age- and sex-matched controlled study. MATERIALS AND METHODS: The subject group was composed of 106 individuals with mTBI and 300 age- and sex-matched controls without a history of mTBI. All individuals agreeing to participate in the study underwent a battery of oculomotor, vestibular, and reaction time tests (OVRT). Those subjects with mTBI underwent these tests at presentation (within 6 days of injury) and 1 and 2weeks post injury. These outcomes were compared to each other over time as well as to results from the controls that underwent 1 test session. RESULTS: Six measures from 5 tests can classify the control and mTBI during Session 1 with a true positive rate (sensitivity) of 84.9% and true negative rate (specificity) of 97.0%. Patterns of abnormalities changed over time in the mTBI group and overall normalized in a subset of individuals at the third (final) testing session. CONCLUSIONS: We describe an objective and effective second generation testing algorithm for diagnosing and following the prognosis of mTBI/concussion. This testing paradigm will allow investigators to institute better treatments and provide more accurate return to activity advice. LEVEL OF EVIDENCE: 3. PMID- 28894834 TI - Auditory processing in the human cortex: An intracranial electrophysiology perspective. AB - OBJECTIVE: Direct electrophysiological recordings in epilepsy patients offer an opportunity to study human auditory cortical processing with unprecedented spatiotemporal resolution. This review highlights recent intracranial studies of human auditory cortex and focuses on its basic response properties as well as modulation of cortical activity during the performance of active behavioral tasks. Data Sources: Literature review. Review Methods: A review of the literature was conducted to summarize the functional organization of human auditory and auditory-related cortex as revealed using intracranial recordings. RESULTS: The tonotopically organized core auditory cortex within the posteromedial portion of Heschl's gyrus represents spectrotemporal features of sounds with high temporal precision and short response latencies. At this level of processing, high gamma (70-150 Hz) activity is minimally modulated by task demands. Non-core cortex on the lateral surface of the superior temporal gyrus also maintains representation of stimulus acoustic features and, for speech, subserves transformation of acoustic inputs into phonemic representations. High gamma responses in this region are modulated by task requirements. Prefrontal cortex exhibits complex response patterns, related to stimulus intelligibility and task relevance. At this level of auditory processing, activity is strongly modulated by task requirements and reflects behavioral performance. CONCLUSIONS: Direct recordings from the human brain reveal hierarchical organization of sound processing within auditory and auditory-related cortex. LEVEL OF EVIDENCE: Level V. PMID- 28894836 TI - The effect of tinnitus retraining therapy on chronic tinnitus: A controlled trial. AB - OBJECTIVES: The goal of this study was to compare treatment outcomes for chronic bothersome tinnitus after Tinnitus Retraining Therapy (TRT) versus standard of care treatment (SC) and to determine the longevity of the effect over an 18-month period. STUDY DESIGN: A randomized controlled trial comparing TRT to SC for chronic tinnitus. METHODS: Adults with subjective, stable, bothersome chronic tinnitus associated with hearing loss amenable to aural rehabilitation with hearing aids were recruited. The Tinnitus Handicap Inventory (THI) was the primary outcome measure and the Tinnitus Functional Index (TFI) the secondary outcome measure of tinnitus severity and impact. Data were collected at screening, entry (0 months), and 6, 12, and 18 months after the beginning of treatment, using an integrated digitized suite of evaluation modules. TRT consisted of directive counseling and acoustic enrichment using combination hearing aids and sound generators; SC consisted of general aural rehabilitation counseling and hearing aids. RESULTS: Significant improvement in tinnitus impact occurred after both TRT and SC therapy, with a larger treatment effect obtained in the TRT group. Lasting therapeutic benefit was evident at 18 months in both groups. THI initial scores were unstable in 10% of enrolled participants, showing moderate bidirectional fluctuation between screening and baseline (0 month) assessment. CONCLUSION: Adults with moderate to severe tinnitus and hearing loss amenable to amplification, benefit from either TRT or SC treatment when combined with hearing aid use. TRT benefit may exceed that of SC. The global improvement in tinnitus severity that accrued over an 18-month period appeared to be robust and clinically significant. LEVEL OF EVIDENCE: I. PMID- 28894837 TI - Dental occlusion ties: A rapid, safe, and non-invasive maxillo-mandibular fixation technology. AB - OBJECTIVES: For decades, Erich arch bars have been a standard in establishing maxillo-mandibular fixation (MMF). While reliable, the approach risks sharps injury, consumes operating room time, and inflicts gingival trauma. Newer technologies including screw-based techniques and "hybrid" techniques have improved MMF by reducing sharps injuries and operating room time, but risk injury to tooth roots, nerves, and gingiva. This study aims to establish the application, strengths, and limitations of dental occlusion ties as a novel alternative in maxillo-mandibular fixation. STUDY DESIGN: Prospective, non blinded, human feasibility clinical trial. MATERIALS AND METHODS: An iterative prototyping process was used to invent dental occlusion ties (brand name: Minne Ties). Development included 3D printing, cadaver prototype testing, human apical embrasure measurement, and ultimately non-significant risk human clinical trial testing. In the IRB-approved feasibility clinical trial, the devices were applied to mandible and maxilla fracture candidates with fractures amenable to intra operative MMF with open reduction with internal fixation. The ties were removed prior to extubation. Pre-teens, comminuted fracture patients, and patients requiring post-operative MMF were excluded. RESULTS: Manufactured, sterile prototypes secured MMF successfully in management of unilateral and bilateral mandible and maxilla fractures. All patients reported correction of pre-operative malocclusion. Application times were typically 12-15 minutes for a single surgeon to achieve MMF. Patients incurred negligible gingival trauma from the technology as the ties require no tissue penetration for application. CONCLUSIONS: Dental occlusion ties offer a non-invasive solution featuring operating room efficiency, minimized sharps risk, and less bony and soft tissue trauma than current commercialized solutions. LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28894838 TI - Recurrent respiratory papillomatosis (RRP)-time for a reckoning? AB - OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a rare disease, but one with severe morbidity and occasional mortality. The aetiological agent is human papillomavirus (HPV), and HPV types 6 and 11 account for over 90% of all cases. In the active phase of the disease, patients require multiple hospital admissions for surgical removal or ablation of these benign tumors, which are likely to obstruct the airways if left unchecked. Long-term sequelae include scarring of the vocal cords, change in voice timbre, or even muteness if a tracheostomy is required. The aim of this study was to determine if adjuvant vaccination with the quadrivalent HPV L1 vaccine (GardasilTM) would decrease numbers of surgical treatments post-vaccination. METHODS: A prospective pilot study following a cohort of 12 RRP patients, all of whom gave fully informed consent to participate. All patients had their papillomas typed and if they were found to have types 6 or 11, were vaccinated at the time of first surgical treatment in the hospital, according to the manufacturer's protocols. Patients were followed up closely with 3 or 6 month follow-up visits. Standard surgical treatments were given and were not affected by whether they participated in the study. RESULTS: We found a >7-fold decrease in the incidence rates of papillomatosis requiring surgical intervention from the pre-vaccination period (47.44/1000 patient-months) compared to the post-vaccination period (6.71/1000 patient-months). DISCUSSION: Surgical treatments for RRP are robust markers for papillomata which require treatment because of the dangers of obstruction of the airway. Despite the small size of this cohort (due to the rarity of this disease), the data suggests that adjuvant use of quadrivalent HPV L1 vaccine imparts significant benefit to this group of patients. A large multi-center randomized placebo controlled trial is required to definitively establish whether this hypothesis is true and can become the new standard of therapy. LEVEL OF EVIDENCE: 3b. PMID- 28894839 TI - Disparities in health in the United States: An overview of the social determinants of health for otolaryngologists. AB - OBJECTIVES: Social determinants of health include social and demographic factors such as poverty, education status, race and ethnicity, gender, insurance status, and other factors that influence (1) development of illness, (2) ability to obtain and utilize healthcare, and (3) health and healthcare outcomes. In otolaryngology, as in other subspecialty surgical fields, we are constantly confronted by patients' social and demographic circumstances including poverty, language barriers, and lack of health insurance and yet there is limited research on how these factors impact health equity in our field, or how attention to these patient characteristics may improve health equity. This review provides the reader with a framework to understand the social determinants of health including how socioeconomic status, insurance status, race, gender, and other factors impact health. DATA SOURCES AND REVIEW METHODS: Foundational papers on the social determinants of health are reviewed, as well as otolaryngology publications focused on health and healthcare disparities. RESULTS: The social determinants of health have a major impact on patient health as well as healthcare utilization, but there is a relative lack of data on these factors and how they can be addressed within otolaryngology. Incorporating tools to measure social and demographic characteristics and actually report on these measures is a first simple step to increase the data on the social determinants of health as they pertain to otolaryngology. CONCLUSION: More research is needed on the social determinants of health, and how they impact otolaryngic disease. Medicare's Accountable Care Organization models will increasingly change the way in which physicians are reimbursed, making the social determinants of health central not only to our moral conscience but also the bottom line. LEVEL OF EVIDENCE: 4. PMID- 28894840 TI - Cell line dependent expression of EpCAM influences the detection of circulating tumor cells with CellSearch. AB - OBJECTIVES: The existence of circulating tumor cells has emerged as an important factor for prognosis and survival. The CellSearch method is the only circulating tumor cell detection method approved by the US Food and Drug Administration for clinical use. It relies on the detection of EpCAM (epithelial cell adhesion molecule) and is approved for colon cancer, breast cancer and prostate cancer. We now investigated whether CellSearch can be used to quantify circulating tumor cells in head and neck squamous cell cancer. STUDY DESIGN AND METHODS: In this study, we investigated the expression of EpCAM in 12 head and neck squamous cell cancer cell lines using Western blot and how this affected their detectability with CellSearch in peripheral blood. RESULTS: We found a great variation in the expression of EpCAM between our head and neck squamous cell cancer cell lines. This was accompanied by variations in counting efficiency. CONCLUSION: We suggest that for reliable quantification of circulating tumor cells in blood from patients with head and neck squamous cell cancer cell, an epitope independent method is preferable. LEVEL OF EVIDENCE: NA. PMID- 28894841 TI - Symptomatic Distal Ureteral Stone in an Ileal Ureter: Treatment by Combined Supine Ureteroscopy and Mini Percutaneous Nephrolithotomy. AB - Urolithiasis is a well-known and common late complication in patients with urinary diversion. Patients without urinary diversion lead to symptoms such as hematuria and ureteral colic, whereas stones in patients with urinary diversion tend to be asymptomatic and are often diagnosed incidentally during staging examinations of oncologic diseases. We report the case of a 64-year-old male patient with a lower pole kidney stone and a stone in the ileal ureter substitution. He presented with diffuse abdominal and left-sided flank pain. CT revealed the diagnosis of urolithiasis in the ileal ureter substitution and the lower pole of the left kidney. We performed a combined retrograde, flexible ureteroscopy and a mini percutaneous nephrolithotomy (combined intrarenal surgery) without any complications and no residual stone fragments postoperatively. This case presentation demonstrates that in patients with urinary tract diversion, urolithiasis can still cause problems. PMID- 28894842 TI - Retroperitoneal Actinomycosis: A Rare Sequela of an Infected Obstructing Ureteral Stone. AB - Background: Actinomycosis is a condition in which Actinomyces, a normal component of the oral and gastrointenstial flora, becomes pathogenic in the setting of damaged tissue, leading to widespread tissue destruction across fascial planes. Prior literature describing this condition is rare, particularly cases involving the retroperitoneum. In this study, we report a case of retroperitoneal actinomycosis caused by an infected, obstructing ureteral stone. Case Presentation: A 48-year-old woman with a history of substance abuse, malnutrition, and gastric bypass presented to the emergency room with a 3-week history of abdominal pain and fevers. Workup revealed a 9 mm obstructing right ureteral stone with associated perinephric fluid collection that was concerning for forniceal rupture. There was left hydronephrosis and a 3 mm lower pole renal calculus as well. The patient underwent emergent decompression where bilateral duplicated collecting systems were identified, requiring stenting of all four moieties to ensure maximal decompression in the setting of obstructive pyelonephritis. Urine cultures grew Escherichia coli and Candida. The patient continued to deteriorate despite culture appropriate antibiotic therapy; repeat scan revealed progression of her perinephric fluid collection into a loculated retroperitoneal abscess. A percutaneous drain was placed, and nearly half a liter of pus was evacuated. Fluid cultures grew Actinomyces, and she ultimately recovered after a prolonged course of antibiotics, including 1 month of intravenous therapy and an additional 6 months of oral treatment. All stones were ultimately removed via ureteroscopy. Conclusion: Actinomycosis is a rare invasive infection that is caused when the Actinomyces bacteria colonizes damaged tissue. We present the first reported case of urolithiasis inciting this process via tissue damage caused by obstruction and infection. Although rare, heightened suspicion is warranted among immunocompromised hosts who do not improve after decompression in such scenarios. PMID- 28894843 TI - Robot-Assisted Laparoscopic Repair of Extraperitoneal Ureteral Inguinal Hernia with Mesh Placement. AB - Background: Ureter involvement within indirect hernias is a rare phenomenon usually identified incidentally during herniorrhaphy. Even more rare are extraperitoneal ureteral inguinal hernias, which represent about 20% of these cases and are characterized by a substantial amount of extraperitoneal fat in the hernia defect, the absence of a peritoneal sac, and associated with hydroureteronephrosis and nephroptosis. To date, repair of ureteral inguinal hernias has been performed exclusively using open surgical techniques. We report the first case of successful robot-assisted laparoscopic repair of this rare presentation. Case Presentation: A morbidly obese 70-year-old male with an unremarkable surgical and urological history presents with a 15-year history of nonpainful, enlarging right scrotal swelling measuring 25 cm in diameter. CT imaging revealed right nephroptosis and a hernia defect containing a dilated right ureter looping into the scrotum surrounded by significant extraperitoneal fat. Retrograde pyelography and ureteral catheter placement confirmed a >100 cm ureter. The patient underwent a robot-assisted laparoscopic repair. The inferior epigastric artery, spermatic cord vessels, vas deferens, and ureter were identified. The defect was reduced using external scrotal pressure and reinforced with ProGripTM self-fixating laparoscopic mesh. The patient was discharged 2 days later following an uneventful postoperative course. Conclusion: Although rare and usually incidentally discovered, extraperitoneal ureteral inguinal hernias can be identified preoperatively by the astute clinician. Preoperative identification allows for improved surgical planning, including a minimally invasive approach. Robot-assisted laparoscopic repair with mesh placement is a feasible alternative to traditional open techniques. PMID- 28894844 TI - MicroRNA Let-7g Directly Targets Forkhead Box C2 (FOXC2) to Modulate Bone Metastasis in Breast Cancer. AB - Aberrantly expressed microRNAs have been implicated in lots of cancers. Reduced amounts of let-7g have been found in breast cancer tissues. The function of let 7g in bone metastasis of breast cancer remains poorly understood. This study is to explore the significance of let-7g and its novel target gene in bone metastasis of breast cancer. The expression of let-7g or forkhead box C2 (FOXC2) was measured in human clinical breast cancer tissues with bone metastasis by using quantitative real-time Polymerase Chain Reaction (qRT-PCR). After transfection with let-7g or anti-let-7g in breast cancer cell linesMDA-MB-231or SK-BR3, qRT-PCR and Western blot were done to test the levels of let-7g and FOXC2. The effect of anti-let-7g and/ or FOXC2 RNA interference (RNAi) on cell migration in breast cancer cells was evaluated by using wound healing assay. Clinically, qRT-PCR showed that FOXC2 levels were higher in breast cancer tissues with bone metastasis than those in their noncancerous counterparts. Let-7g was showed to be negatively correlated with FOXC2 in human breast cancer samples with bone metastasis. We found that enforced expression of let-7g reduced levels of FOXC2 protein by using Western blot in MDA-MB-231 cells. Conversely, anti-let-7g enhanced levels of FOXC2 in SK-BR3 cells. In terms of function, anti-let-7g accelerated migration of SK-BR3 cells. Interestingly, FOXC2 RNAi abrogated anti let-7g-mediated migration in breast cancer cells. Thus, we conclude that let-7g suppresses cell migration through targeting FOXC2 in breast cancer. Our finding provides a new perspective for understanding the mechanism of bone metastasis in breast cancer. PMID- 28894845 TI - Relationship Between PD-L1 Expression and Clinical Characteristics in Patients with Breast Invasive Ductal Carcinoma. AB - OBJECTIVE: To evaluate the expression of PD-L1 (programmed death 1 ligand 1, PD L1) and its clinical significance in breast invasive ductal carcinoma. METHODS: Tumor samples were collected from 64 cases of breast invasive ductal carcinoma patients, and tumor adjacent normal breast tissue were obtained as normal control. The expression of PD-L1 were examined by immunohistochemical staining and real time PCR assay, its correlations with patients' clinical pathological characteristics were analyzed. RESULTS: PD-L1 was found to be over-expressed in 24 of 64 (37.5%) breast invasive ductal carcinoma samples, while in 1 of 22 (4.5%) tumor adjacent normal breast tissue which indicated PD-L1 was higher expressed in breast invasive ductal carcinoma samples than the tumor adjacent normal breast tissue (P < 0.05). PD-L1 positive expression was associated with clinical pathological characteristics of TNM stage and pathology grading (P < 0.05). However, PD-L1 positive expression was not correlated with age (P > 0.05), menstruation status (P >0.05), family history of breast cancer (P > 0.05), tumor diameter (P > 0.05), lymph node metastasis (P > 0.05) and tumor location (P > 0.05). CONCLUSION: PD-L1 may play an important role in invasive ductal carcinoma, which could be a potential indicator for advanced clinical stage and poor prognosis. PMID- 28894846 TI - Trypsinogen Activation Peptide Induces HMGB1 Release from Rat Pancreatic Acinar Cells. AB - BACKGROUND: The development of acute pancreatitis (AP) is associated with intracellular events in pancreatic cells, as well as with early and late inflammatory responses; however, their underlying mechanisms remain unclear. This study investigated trypsinogen activation peptide (TAP)-induced release of high mobility group box-l (HMGB1) from pancreatic acinar cells and how ethyl pyruvate (EP) affects this release. METHODOLOGY: Pancreatic acinar cells from Sprague Dawley rats were divided into control, TAP (administered TAP), and EP (administered TAP and EP) groups. Cells were collected at 3, 6, 12, and 24 hours after TAP administration to detect HMGB1 mRNA and protein levels using quantitative PCR (qPCR) and Western blotting, respectively. RESULTS: The TAP and EP groups exhibited higher levels of HMGB1 mRNA and protein expression (P<0.05) than the control group. The HMGB1 mRNA and protein expression levels also increased with prolonged TAP activity (P<0.05)-especially at 12 and 24 hours (P<0.01)-and showed positive correlations with TAP activity duration (3, 6, 12, and 24 hours) (r=0.971, P<0.01; r=0.966, P<0.01, respectively). CONCLUSION: TAP induces HMGB1 release from pancreatic acinar cells. A positive temporal link exists between early TAP activity and late HMGB1 expression in AP, and EP inhibits HMGB1 release. PMID- 28894847 TI - Community engagement for the rapid elimination of malaria: the case of Kayin State, Myanmar. AB - BACKGROUND: Currently, malaria elimination efforts are ongoing in several locations across Southeast Asia, including in Kayin State (also known as Karen State), Myanmar . This paper describes the community engagement efforts for a pilot malaria elimination project, the challenges encountered and lessons learnt. METHODS: Between May 2013 and June 2015, a study on targeted malaria elimination (TME) that included mass drug administration was conducted in four villages (TPN, TOT, KNH, and HKT) of Kayin State. Community engagement efforts included workshops, meetings and house-to-house visits with community members. Exhibitions related to malaria and fun activities were organized for children. In addition, we provided primary care, small individual incentives and village-level incentives. This paper is based on our analysis of data extracted from meeting minutes, field notes, feedback sessions among staff and with community members as well as our own reflections. RESULTS: Average participation across three rounds of MDA were 84.4%, 57.4%, 88.6% and 59.3% for TPN, TOT, KNH and HKT, respectively. Community engagement was fraught with practical challenges such as seasonal tasks of the villagers. There were challenges in explaining difficult concepts like drug resistance and submicroscopic infection. Another was understanding and navigating the politics of these villages, which are located in politically contested areas. Managing expectations of villagers was difficult as they assumed that the community team must know everything related to health. CONCLUSIONS: In the TME project, many different community engagement strategies were employed. We encountered many challenges which included logistical, scientific and political difficulties. An approach that is tailored to the local population is key. PMID- 28894848 TI - Risk Reduction Strategies in Breast Cancer Prevention. AB - Evaluating the risk of breast cancer makes it possible to identify women with a high risk of developing breast cancer in the future. Adopting a healthier lifestyle, involving diet and exercise, is one way of reducing this risk-but there are other, non-modifiable risk factors, such as family history, genetics and diagnosis of premalignant lesions. In this high-risk population, the tracking must be rigorous and involve the participation of the patient herself, earlier and more frequent clinical assessment, and the use of imaging screening. Agents such as tamoxifen, raloxifene and aromatase inhibitors may be used in chemoprevention and may reduce the risk substantially. The risks and benefits must be assessed, and one must discuss with the patient her adverse events and the decision regarding the best treatment. Women who carry the BRCA1/2 mutation (very high risk) can benefit from prophylactic surgical interventions, such as bilateral mastectomy and/or bilateral salpingo-oophorectomy. This group of patients must be monitored by a multidisciplinary team, providing explanations prior to surgery regarding the surgical treatment offered, the reconstruction techniques, and the risks and complications. PMID- 28894849 TI - Educational Study to Increase Breast Cancer Knowledge Level and Scanning Participation among Women Working at a University. AB - OBJECTIVE: The aim of the study is to increase the participation level of women in screening programs by increasing the level of knowledge about early diagnosis and screening methods for breast cancer (BC). MATERIALS AND METHODS: This was a pretest-posttest one group design study held in Eskisehir Osmangazi University, Turkey. The sample consisted of 405 women in all departments of the University. Data were collected using socio-demographic forms and questionnaires. Training about BC was provided for participants. The questionnaire used prior to the training to measure levels of knowledge about BC was re-administered 3 weeks after the training. RESULTS: The women were most commonly aware of the breast self-examination (68.1%). The ratio of women who had had mammography in the previous year was 11.4%. The BC knowledge level significantly increased after the training (p=0.001). CONCLUSION: This study determined that the level of knowledge about BC in terms of early detection and screening was low and that the percentage of participation in screening was also low. PMID- 28894850 TI - Cost-Effectiveness of Breast Cancer Screening in Turkey, a Developing Country: Results from Bahcesehir Mammography Screening Project. AB - OBJECTIVE: We used the results from the first three screening rounds of Bahcesehir Mammography Screening Project (BMSP), a 10-year (2009-2019) and the first organized population-based screening program implemented in a county of Istanbul, Turkey, to assess the potential cost-effectiveness of a population based mammography screening program in Turkey. MATERIALS AND METHODS: Two screening strategies were compared: BMSP (includes three biennial screens for women between 40-69) and Turkish National Breast Cancer Registry Program (TNBCRP) which includes no organized population-based screening. Costs were estimated using direct data from the BMSP project and the reimbursement rates of Turkish Social Security Administration. The life-years saved by BMSP were estimated using the stage distribution observed with BMSP and TNBCRP. RESULTS: A total of 67 women (out of 7234 screened women) were diagnosed with breast cancer in BMSP. The stage distribution for AJCC stages O, I, II, III, IV was 19.4%, 50.8%, 20.9%, 7.5%, 1.5% and 4.9%, 26.6%, 44.9%, 20.8%, 2.8% with BMSP and TNBCRP, respectively. The BMSP program is expected to save 279.46 life years over TNBCRP with an additional cost of $677.171, which implies an incremental cost effectiveness ratio (ICER) of $2.423 per saved life year. Since the ICER is smaller than the Gross Demostic Product (GDP) per capita in Turkey ($10.515 in 2014), BMSP program is highly cost-effective and remains cost-effective in the sensitivity analysis. CONCLUSION: Mammography screening may change the stage distribution of breast cancer in Turkey. Furthermore, an organized population based screening program may be cost-effective in Turkey and in other developing countries. More research is needed to better estimate life-years saved with screening and further validate the findings of our study. PMID- 28894851 TI - Translation and Validation of the Turkish Version of Lymphedema Quality of Life Tool (LYMQOL) in Patients with Breast Cancer Related Lymphedema. AB - OBJECTIVE: Breast cancer related lymphedema (BCRL) is a drastic situation that affects patients who have undergone breast cancer surgery. The impact of this condition on individuals' quality of life should be investigated in more detail to obtain better treatment results. MATERIALS AND METHODS: In total, 65 patients with BCRL participated in this study. Nottingham Health Profile (NHP) was used to evaluate the validity of associated domains in Lymphedema Quality of Life Tool (LYMQoL). Both the LYMQoL and NHP were filled out by BCRL patients. To evaluate its test-retest reliability, the LYMQoL was subsequently performed seven days following its initial application. Measurement properties such as internal consistency, test-retest reliability, criterion validity and factor structure were tested. The internal consistency was assessed via Cronbach's alpha; test retest reliability was assessed by the intra-class correlation coefficient (ICC). RESULTS: Cronbach's alpha values ranged from 0.74 to 0.91 for the LYMQoL total and domain scores. Test-retest reliability was excellent (ICC=0.92-0.99). When the relation between LYMQoL and NHP was investigated, 'good' to 'very good' correlations were obtained (r=0.539-0.643, p<0.05) for all domains of LYMQoL. Exploratory factor analyses demonstrated a four-factor structure. CONCLUSION: Turkish version of LYMQoL is a valid and reliable measurement tool to evaluate the quality of life in patients with BCRL. PMID- 28894852 TI - Top 100 Cited Classic Articles in Breast Cancer Research. AB - OBJECTIVE: This study aimed to analyze 100 most cited articles in breast cancer research. MATERIALS AND METHODS: The data in this study were obtained by a search conducted on the Web of Science (WOS). In brief, the term "breast cancer" was typed in the search box of WOS basic research including all the years and the data. The analysis was carried out by compiling the top 100 cited articles in the shortlist as sorted by the journals, categories of the studies, the countries, the centers, the authors and the publication date. No statistical methods were used in the study. All data were reported as percentages, numbers and bar charts on tables. RESULTS: Our findings showed that the most frequently cited article received 7609 citations to date. Most articles were published in the New England Journal of Medicine. 81% of the studies originated from the USA. The National Institutes of Health (NIH USA) was ranked the first with 21% and it was followed by Harvard University in terms of number of published articles. 42% of the articles were published under the category of medicine and general internal medicine. CONCLUSION: Top 100 most cited articles originated from the United States. The highest number of articles among the top 100 articles were published in New England Journal of Medicine and National Institutes of Health NIH USA was the leading institutes published the most articles. PMID- 28894853 TI - The Effect of Peer Education upon Breast Self-Examination Behaviors and Self Esteem among University Students. AB - OBJECTIVE: The current study was semi-experimentally designed in order to identify the effect of peer education upon breast self-examination (BSE) behaviors and self-esteem among university students. MATERIALS AND METHODS: The study was undertaken with 100 female students who studied at Erzincan University. Peer educators were recruited from the 4th year students. The data were collected with a questionnaire form, BSE skill form and Rosenberg Self-esteem Scale in two phases one month before and after the BSE peer education. For the data assessment; percentage distributions, frequency, mean, standard deviation and Simple T test were employed. RESULTS: The mean age of the participant students was 20.45+/-1.67 year and all of them were single. It was found that during the first data collection phase, only 16 % of the students performed BSE while during the final data collection phase, the rate of the students performing BSE rose to 77 %. During the first data collection phase, students received a mean score of 2.36+/-4.13 from BSE skill form while during the last data collection phase they had a mean score of 10.70+/-3.40 from BSE skill form. When the scores obtained from Rosenberg Self-esteem Scale by the students were examined, it was seen that they received a mean score of 1.20+/-1.34 during the first data collection phase while they had a mean score of 0.84+/-1.07 during the final data collection phase. CONCLUSION: Although short-term feedback was obtained, it was noted that students' BSE knowledge and skills increased considerably. PMID- 28894854 TI - The Relationship Between Breast Cancer and Risk Factors: A Single-Center Study. AB - OBJECTIVE: To determine the relationship between breast cancer and known risk factors in patients who had mammography (MG) for breast cancer screening or ultrasonography and/or MG for diagnostic purposes. MATERIALS AND METHODS: In the period of January-December, 2011, a questionnaire composed of 17 questions was applied to 2862 female patients and MG and/or US examination was performed afterwards. Chi-square and Kruskal-Wallis tests were used for statistical analysis. RESULTS: The mean age was 51.05+/-8.98, age at menarche was 13.0+/-1.6 and age at menopause was 47+/-5.2. The first pregnancy was at 20+/-4.6. Out of 2862 cases, 242 had breast cancer diagnosis and 32 were newly diagnosed. There was no correlation between menarche age, age at menopause or first pregnancy and breast cancer. There was no relationship between breast cancer risk and hormone replacement therapy or oral contraceptive use. In patients with the diagnosis of breast cancer (242 cases), 61 had (25%) a positive family history. There was a significant correlation between the presence of a positive family history and having breast cancer (p=0.003). CONCLUSION: The presence of breast cancer in the family has the strongest relationship among all risk factors. It is important to have regular followup of these patients and to raise the awareness of patients. PMID- 28894855 TI - Evaluation on the Practice and Behaviour of Women Applied for Gynecology Outpatient Clinics About Screening Methods for Early Diagnosis of Breast Cancer. AB - OBJECTIVE: Breast self-examination (BSE), clinical breast exam (CBE), mammography and ultrasound imaging (UI) are screening methods used for early diagnosis of breast cancer (BC). The purpose of this study is to put forth the utilization frequency of these screening methods among women presenting to the gynecology outpatient clinics and the relation of these data with the socio-demographic characteristics of the women. MATERIALS AND METHODS: A survey was conducted among 429 women (age, 16-80 years) who were admitted to the gynecology outpatient clinics. The survey inquired about the rate and frequency of the performance of BSE, CBE, mammography and UI; personal and family history of breast cancer and social-demographic characteristics of the women. RESULTS: The mean age was 40.08 (SD: 3.67). More than half of the women above 40 years of age (59.7 %) had never undergone mammography. 99.8 % of the women who had undergone mammography had also received ultrasound imaging. A significant relationship was identified between the BSE performance and having mammography. 57.4% of the women above 40 years of age (117) had UI, 53.9% (110) had CBE and 57.3% (117) performed BSE. There was a significant relationship between the age, education status and regular BSE; positive family history of BC and having CBE and mammography. CONCLUSION: The results reveal that the rate of BSE performance, having mammography and CBE are at less-than-ideal levels. In this context, it is apparent that breast cancer screening methods are needed to be introduced and guidance about their application frequency should be provided for women in gynecology outpatient clinics. PMID- 28894856 TI - Intraparenchymal Leiomyoma of the Breast: A Rare Location for an Infrequent Tumor. AB - Intraparenchymal leiomyoma of the breast are among benign non-epithelial tumors with the lowest incidence. Although it displays a benign histology, it may be confused with malignant lesions and create diagnostic confusion. In this paper, we report a 44-year-old woman with a painless mass with a diameter of 1.5 cm in the upper medial quadrant of her right breast. The lesion was removed surgically. The lesion's histologic examination and immunohistochemical analysis revealed a smooth muscle tumor of the breast. The patient was initially diagnosed with fibroadenoma and was followed in terms of the epicenter for six months before she underwent surgery. Her mammography and histopathology results are discussed in this report. PMID- 28894858 TI - Erratum. AB - [This corrects the article on p. 88 in vol. 13.]. PMID- 28894857 TI - Extraction of a Foreign Body from the Breast Using Radio-guided Occult Lesion Localization (ROLL): Metallic Foreign Body in the Breast. AB - The most common clinical causes of metallic foreign body in the breast are surgical clips, pieces of guide-wire and gunshot wounds. Metallic foreign bodies can lead to local breast pain, abscesses, pneumothorax after granulomas or migration, and cardiac tamponade. Mammotome biopsy, fluoroscopy, guide-wire biopsy and radio-guided occult lesion localization (ROLL) are the standard techniques applied for surgical excision of non-palpable breast lesions. This article presents the second case in the literature undergoing the ROLL technique for the removal of a metallic foreign body from the breast. PMID- 28894859 TI - Changes in dynamics of alpha-chymotrypsin due to covalent inhibitors investigated by elastic incoherent neutron scattering. AB - An essential role of enzymes is to catalyze various chemical reactions in the human body and inhibition of the enzymatic activity by small molecules is the mechanism of action of many drugs or tool compounds used to study biological processes. Here, we investigate the effect on the dynamics of the serine protease alpha-chymotrypsin when in complex with two different covalently bound inhibitors using elastic incoherent neutron scattering. The results show that the inhibited enzyme displays enhanced dynamics compared to the free form. The difference was prominent at higher temperatures (240-310 K) and the type of motions that differ include both small amplitude motions, such as hydrogen atom rotations around a methyl group, and large amplitude motions, such as amino acid side chain movements. The measurements were analyzed with multivariate methods in addition to the standard univariate methods, allowing for a more in-depth analysis of the types of motions that differ between the two forms. The binding strength of an inhibitor is linked to the changes in dynamics occurring during the inhibitor enzyme binding event and thus these results may aid in the deconvolution of this fundamental event and in the design of new inhibitors. PMID- 28894860 TI - Elastic and viscous bond components in the adhesion of colloidal particles and fibrillated streptococci to QCM-D crystal surfaces with different hydrophobicities using Kelvin-Voigt and Maxwell models. AB - A quartz-crystal-microbalance with dissipation (QCM-D) can measure molecular mass adsorption as well as register adhesion of colloidal particles. However, analysis of the QCM-D output to quantitatively analyze adhesion of (bio)colloids to obtain viscoelastic bond properties is still a subject of debate. Here, we analyze the QCM-D output to analyze the bond between two hydrophilic streptococcal strains 91 nm long and without fibrillar surface appendages and micron-sized hydrophobic polystyrene particles on QCM-D crystal surfaces with different hydrophobicities, using the Kelvin-Voigt model and the Maxwell model. A Poisson distribution was implemented in order to determine the possible virtues of including polydispersity when fitting model parameters to the data. The quality of the fits did not indicate whether the Kelvin-Voigt or the Maxwell model is preferable and only polydispersity in spring-constants improved the fit for polystyrene particles. The Kelvin-Voigt and Maxwell models both yielded higher spring constants for the bald streptococcus than for the fibrillated one. In both models, the drag coefficients increased for the bald streptococcus with the ratio of electron-donating over electron-accepting parameters of the crystal surface, while for the fibrillated strain the drag coefficient was similar on all crystal surfaces. Combined with the propensity of fibrillated streptococci to bind to the sensor crystal as a coupled-resonator above the crystal surface, this suggests that the drag experienced by resonator-coupled, hydrophilic particles is more influenced by the viscosity of the bulk water than by interfacial water adjacent to the crystal surface. Hydrophilic particles that lack a surface tether are mass coupled just above the crystal surface and accordingly probe the drag due to the thin layer of interfacial water that is differently structured on hydrophobic and hydrophilic surfaces. Hydrophobic particles without a surface tether are also mass-coupled, but their drag coefficient decreases when the ratio of electron donating over electron-accepting parameters increases, suggesting that hydrophobic particles experience less drag due to the structured water adjacent to the surface. PMID- 28894861 TI - In operando studies on the electrochemical oxidation of water mediated by molecular catalysts. AB - Homogeneous reactions in general are relatively easy to study with respect to heterogeneous systems since all catalytic sites are uniform and can be addressed simultaneously. The latter feature is fully out of the window in an electrochemical context, where only the few catalytic species that are sufficiently close to the electrode undergo redox reactions. Especially in the water oxidation reaction where harsh reaction conditions are employed, a clear picture of what is the active species, what products are formed, how one can steer this, and how it all depends on the exact reaction conditions is important to be able to fully unravel the key reaction paths. The combination of electrochemical experiments with on-line detection of the catalytic species and reaction products is a powerful approach to successfully address these questions. Recently, a significant progress has been made in on-line studies on molecular water oxidation catalysts during electrochemical experiments. These are reviewed here. PMID- 28894862 TI - A novel polyoxometalate-based hybrid containing a 2D [CoMo8O26]infinity structure as the anode for lithium-ion batteries. AB - The proof-of-principle of an unusual fused gamma-[Mo8O26]4- chain as an inorganic ligand is presented for the first time. By sharing two Mo-O edges, the gamma [Mo8O26]4- subunits are propagated into a one-dimensional (1D) zig-zag chain, which acts as a purely inorganic ligand binding octahedral Co(ii) centers into a two-dimensional (2D) [CoMo8O26]infinity sheet. This material exhibits high initial reversible specific capacity and stable reversible capacity when applied as an anode for lithium-ion batteries (LIBs). PMID- 28894863 TI - Circular torsion induced fan-blade shaped wrinkling in two-dimensional nano rings. AB - Molecular dynamics (MD) simulations are conducted to study the deformation behavior and strain distribution in two-dimensional (2D) nano-rings of graphene, single-layer black phosphorus (SLBP) and single-layer MoS2 (SLMoS2) under circular torsion. Interestingly, fan-blade shaped wrinkling is generated, in which the maximum torsion angle (Deltatheta) and the potential energy change per atom (DeltaPe) increase with increasing inner radius but decrease with increasing temperature. As the inner radius is increased, the wave number of wrinkling increases but the wave amplitude decreases. The geometrical characteristics of wrinkling are closely related to the intrinsic elastic modulus (E) and Poisson's ratio (nu). Specifically, the graphene nano-rings possess the largest Deltatheta and DeltaPe but the smallest wave amplitude, while the SLBP nano-rings exhibit the smallest Deltatheta and DeltaPe but the largest wave amplitude. Furthermore, the strongly anisotropic E and nu values of SLBP result in orientation-dependent geometrical characteristics of wrinkles, and fan-blade shaped wrinkling with a strain vortex is induced, which might substantially enhance the pseudomagnetic fields and optical funnel effect for the separation of photon-induced electron hole pairs, and thus be exploited to improve the photoelectric properties of 2D materials. PMID- 28894864 TI - Neural stem cell proliferation and differentiation in the conductive PEDOT HA/Cs/Gel scaffold for neural tissue engineering. AB - Engineering scaffolds with excellent electro-activity is increasingly important in tissue engineering and regenerative medicine. Herein, conductive poly(3,4 ethylenedioxythiophene) doped with hyaluronic acid (PEDOT-HA) nanoparticles were firstly synthesized via chemical oxidant polymerization. A three-dimensional (3D) PEDOT-HA/Cs/Gel scaffold was then developed by introducing PEDOT-HA nanoparticles into a chitosan/gelatin (Cs/Gel) matrix. HA, as a bridge, not only was used as a dopant, but also combined PEDOT into the Cs/Gel via chemical crosslinking. The PEDOT-HA/Cs/Gel scaffold was used as a conductive substrate for neural stem cell (NSC) culture in vitro. The results demonstrated that the PEDOT-HA/Cs/Gel scaffold had excellent biocompatibility for NSC proliferation and differentiation. 3D confocal fluorescence images showed cells attached on the channel surface of Cs/Gel and PEDOT-HA/Cs/Gel scaffolds with a normal neuronal morphology. Compared to the Cs/Gel scaffold, the PEDOT-HA/Cs/Gel scaffold not only promoted NSC proliferation with up-regulated expression of Ki67, but also enhanced NSC differentiation into neurons and astrocytes with up-regulated expression of beta tubulin-III and GFAP, respectively. It is expected that this electro-active and bio-active PEDOT-HA/Cs/Gel scaffold will be used as a conductive platform to regulate NSC behavior for neural tissue engineering. PMID- 28894865 TI - Transport features of nano-hydroxylapatite (n-HA) embedded silicone rubber (SR) systems: influence of SR/n-HA interaction, degree of reinforcement and morphology. AB - We report the transport characteristics of silicone rubber/nano-hydroxylapatite (SR/n-HA) systems at room temperature with reference to the effects of n-HA loading, morphology and penetrant nature, using toluene, xylene, ethyl acetate and butyl acetate in the liquid phase and methanol, ethanol, 1-propanol, 2 propanol and butanol in the vapour phase as probe molecules. The interaction between the n-HA particles and SR matrix has been confirmed by FTIR analysis. As the n-HA content in the SR matrix increased, the penetrant uptake has been found to decrease. The observations have been correlated with the density and void content of the systems. Scanning electron microscopy images have been found to be complementary to the observed transport features. The reinforcement effect of n HA particles on the SR matrix has been verified by Kraus equation. Molecular mass between the cross links has been observed to decrease with an increase in n-HA loading. The results have been compared with affine, phantom network, parallel, series and Maxwell models. The transport data have been complemented by observations on biological fluid uptake with urea, d-glucose, KI, saline water, phosphate buffer and artificial urine as the media. PMID- 28894866 TI - Optimal geometrical design of inertial vibration DC piezoelectric nanogenerators based on obliquely aligned InN nanowire arrays. AB - Piezoelectric nanogenerators have been investigated to generate electricity from environmental vibrations due to their energy conversion capabilities. In this study, we demonstrate an optimal geometrical design of inertial vibration direct current piezoelectric nanogenerators based on obliquely aligned InN nanowire (NW) arrays with an optimized oblique angle of ~58 degrees , and driven by the inertial force of their own weight, using a mechanical shaker without any AC/DC converters. The nanogenerator device manifests potential applications not only as a unique energy harvesting device capable of scavenging energy from weak mechanical vibrations, but also as a sensitive strain sensor. The maximum output power density of the nanogenerator is estimated to be 2.9 nW cm-2, leading to an improvement of about 3-12 times that of vertically aligned ZnO NW DC nanogenerators. Integration of two nanogenerators also exhibits a linear increase in the output power, offering an enormous potential for the creation of self powered sustainable nanosystems utilizing incessantly natural ambient energy sources. PMID- 28894867 TI - Do alkyl groups on aromatic or aliphatic structure directing agents affect water stabilities and properties of hybrid iodoargentates? AB - Two types of in situ formed structure directing agents (SDAs) including aromatic triphenylphosphine (PPh3)- and aliphatic piperazine (H2pp)-derivative cations were used to synthesize five new hybrid iodoargentates, namely (EtPPh3)Ag3I4 (1, Et = ethyl), (n-PrPPh3)Ag3I4 (2, n-Pr = n-propyl), (i-PrPPh3)Ag5I6 (3, i-Pr = isopropyl), (Me4pp)0.5AgI2 (4, Me = methyl), and (H3app)2(Ag2I6).2I.2H2O (5, app = N-aminoethylpiperazine). A comparative study of the two types of SDAs on the structures, stabilities and properties of hybrid iodoargentates was performed in detail. Structurally, except for (EtPPh3)+ and (n-PrPPh3)+, which both directly form (Ag3I4)- anionic chains in 1 and 2, three SDAs generate hybrid iodoargentates different from each other with inorganic anions ranging from a 0-D (Ag2I6)4- dimer to 1-D alpha-type (AgI2)- and (Ag5I6)- chains. With regard to the electronic structures, aromatic PPh3-derivative cations make noticeable contributions to the bottom of the conduction bands, while aliphatic pp derivative cations make nearly no contribution to the frontier orbitals, clearly indicating their different ways to adjust the band gaps. With regard to stability, the decomposition temperatures of 1-3 in the range of 324-349 degrees C are noticeably higher than the values of 217 and 225 degrees C for 4 and 5. Furthermore, 1-4 exhibit good water stabilities, which is ascribed to the alkylation reactions precluding the formation of strong hydrogen bonds between alkylated SDAs and extraneous H2O molecules. Contrarily, the presence of typical hydrophilic [double bond, length as m-dash]NH2+, [triple bond, length as m dash]NH+ and -NH3+ groups on the protonated (H3app)3+ cation makes 5 sensitive to water and a hydrolysis reaction occurs to generate a cubic AgI phase. Finally, 1 3 exhibit high photocatalytic efficiencies for the degradation of rhodamine B (RhB) dye in wastewater under visible light. All conclusions obtained here will help a lot in the synthesis of stable functional metal halide-based hybrids. PMID- 28894868 TI - Rare earth ions enhanced near infrared fluorescence of Ag2S quantum dots for the detection of fluoride ions in living cells. AB - In this work, a novel phenomenon was discovered that the fluorescence intensity of silver sulfide quantum dots (Ag2S QDs) could be enhanced in the presence of rare earth ions through aggregation-induced emission (AIE). Based on the strong coordination between rare earth ions and F-, a facile and label-free strategy was developed for the detection of F- in living cells. Ag2S QDs were synthesized using 3-mercaptopropionic acid as sulfur source and stabilizer in aqueous solution. The near infrared (NIR) emitting QDs exhibited excellent photostalilty, high quantum yield and low toxic. Interestingly, the fluorescence intensity of QDs was obviously enhanced upon the addition of various rare earth ions, especially in the presence of Gd3+. The AIE mechanism was proved via the TEM, zeta potential and dynamic light scattering analysis. Moreover, the coordination between rare earth ions and F- could lead to the quenching of fluorescence QDs due to the weakening the AIE. Based on these findings, we developed a highly sensitive and selective method for detection of F-. The label-free NIR fluorescence probe was successfully used for F- bioimaging in live cells. PMID- 28894869 TI - Black phosphorus transistors with van der Waals-type electrical contacts. AB - Contact engineering is a possible solution to decrease the pervasive Schottky barrier in a two dimensional (2D) material transistor with bulk metal electrodes. In this paper, two kinds of typical van der Waals (vdW)-type electrical contacts (a 2D metal contact and a 2D material/bulk metal hybrid contact) in monolayer (ML) black phosphorus (BP) transistors are investigated by ab initio energy band calculations and quantum transport simulations. Compared with the traditional bulk metal Ni contact, the gate electrostatic control is significantly improved by using both 2D graphene and borophene electrodes featuring a decrease of 30-50% in the subthreshold swing and an increase by a factor of 4-7 in the on-state current due to the depressed metal induced gap states and reduced screening of the 2D metal electrodes to the gate. In contrast, graphene insertion between the Ni electrode and ML BP shows only a slight improvement in the gate electrostatic control ability and BN insertion shows almost no improvement. The higher efficiency using the 2D metal contact than the 2D material/bulk metal hybrid contact in improving the ML BP FET device performance also provides helpful guidance in the selection of vdW-type electrical contacts of other 2D transistors. PMID- 28894870 TI - Rate constants for H abstraction from benzo(a)pyrene and chrysene: a theoretical study. AB - Density functional B3LYP/6-31G(d) and ab initio G3(MP2,CC) calculations have been carried out to determine thermal rate constants of direct H abstraction reactions from four- and five-ring polycyclic aromatic hydrocarbons (PAH) chrysene and benzo[a]pyrene by various radicals abundant in combustion flames, such as H, CH3, C3H3, and OH, using transition state theory. The results show that the H abstraction reactions with OH have the lowest barriers of ~4 kcal mol-1, followed by those with H and CH3 with barriers of 16-17 kcal mol-1, and then with propargyl radicals with barriers of 24-26 kcal mol-1. Thus, the OH radical is predicted to be the fastest H abstractor from PAH. Even at 2500 K, the rate constant for H abstraction by H is still 34% lower than the rate constant for H abstraction by OH. The reaction with H is calculated to have rate constants 35-19 times higher than those for the reaction with CH3 due to a more favorable entropic factor. The reactions of H abstraction by C3H3 are predicted to be orders of magnitude slower than the other reactions considered and their equilibrium is strongly shifted toward the reactants, making propargyl an inefficient H abstractor from the aromatics. The calculations showed strong similarity of the reaction energetics in different H abstraction positions of benzo[a]pyrene and chrysene within armchair and zigzag edges in these molecules, but clear distinction between the armchair and zigzag sites. The zigzag sites appear to be more reactive, with H abstraction rate constants by H, CH3, and OH being respectively 37-42%, a factor of 2.1, and factors of 8-9 higher than the corresponding rate constants for the H abstraction reactions from armchair sites. Although the barrier heights for the two types of edges are similar, the entropic factor makes zigzag sites more favorable for H abstraction. Rate expressions have been generated for all studied reactions with the goal to rectify current combustion kinetics mechanisms. PMID- 28894871 TI - Correction: Folic acid-functionalized up-conversion nanoparticles: toxicity studies in vivo and in vitro and targeted imaging applications. AB - Correction for 'Folic acid-functionalized up-conversion nanoparticles: toxicity studies in vivo and in vitro and targeted imaging applications' by Lining Sun et al., Nanoscale, 2014, 6, 8878-8883. PMID- 28894872 TI - Lithium cell-assisted low-overpotential Li-O2 batteries by in situ discharge activation. AB - We report a novel and facile route to improve the catalytic performance of carbon paper-based electrocatalysts, which can be activated by in situ discharging with the assistance of a Li cell. Our results show that the OER potentials were successfully reduced to ~3.5 V, much lower than the value of 4.5 V for graphite paper, which is the best result recorded amongst the reported carbon-based electrocatalysts. PMID- 28894873 TI - Shear induced formation of lubrication layers of negative normal stress gels. AB - Many biopolymer gels generate negative normal stress, with which the polymer networks shrink in the normal of applied shear. Here we theoretically predict the sliding velocity of such a gel on a solid surface when a constant shear stress is applied to the gel. Our theory predicts that the negative normal stress drives the flow of the solvent in the gel and this produces a solvent layer between the gel and the surface. The sliding velocity of the gel is proportional to the thickness of the solvent layer and is a cubic function of the applied shear stress. With constant applied normal and shear stresses, the thickness of the solvent layer is a non-monotonic function of time with a maximum because the solvent flow from the gel to the solvent layer is dominant in the short time scale and the solvent flow from the solvent layer to the outside is dominant in a longer time scale. The maximum layer thickness depends on the ratio of the time scales of the solvent flow in the gel and in the solvent layer. PMID- 28894874 TI - Specific and spatial labeling of choline-containing teichoic acids in Streptococcus pneumoniae by click chemistry. AB - Propargyl-choline was efficiently incorporated into teichoic acid (TA) polymers on the surface of Streptococcus pneumoniae. The introduction of a fluorophore by click chemistry enabled sufficient labeling of the pneumococcus, as well as its specific detection when mixed with other bacterial species. The labeling is localized at the septal site, suggesting a similar location of the TA and peptidoglycan (PG) synthetic machineries. This method is a unique opportunity to improve our understanding of the spatial location of pneumococcal TA biosynthesis. PMID- 28894875 TI - MOF-derived iron as an active energy storage material for intermediate temperature solid oxide iron-air redox batteries. AB - We here demonstrate that the iron derived from an iron-based metal-organic framework (MOF), with exposed high-density Fe-atom planes, exhibits improved reduction activity, enabling good rechargeability of solid oxide iron-air redox batteries at 500 degrees C. The discharge mass specific energies are 226.5 W h kg-1-Fe and 214.8 W h kg-1-Fe at C/4 and C/3, respectively, at a constant Fe utilization of 20%. PMID- 28894876 TI - Erratum to: Per-oral endoscopic myotomy (POEM): mid-term efficacy and safety. AB - The Given Names and Family Names were all inadvertently inverted. The correct order is: Jan Martinek, Hana Svecova, Zuzana Vackova, Radek Dolezel, Ondrej Ngo, Jana Krajciova, Eva Kieslichova, Radim Janousek, Alexander Pazdro, Tomas Harustiak, Lucie Zdrhova, Pavla Loudova, Petr Stirand, Julius Spicak. The original article was corrected. PMID- 28894877 TI - Yellow urticaria following plasma transfusion. PMID- 28894878 TI - Erratum to: One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years. PMID- 28894880 TI - EANM'17. PMID- 28894879 TI - Erratum to: Simple scoring system for prediction of mortality in Fournier's gangrene. PMID- 28894881 TI - Erratum to: Diet Versus Phylogeny: a Comparison of Gut Microbiota in Captive Colobine Monkey Species. PMID- 28894882 TI - ? PMID- 28894883 TI - [Indoor air guide value for propan-1,2-diol (propylene glycol) : Communication from the Committee on Indoor Guide Values]. AB - The Committee on Indoor Guide Values is issuing indoor air guide values to protect public health. At present, no suitable human studies are available for health evaluation of propan-1,2-diol in indoor air. In a well-documented subchronic inhalation animal study with rats, assessed as reliable, nasal hemorrhages were observed. This study leads to a LOAEC of 28.6 mg/m3 propan-1,2 diol for continuous exposure for the endpoint nasal hemorrhages. By applying a conversion factor of 2 from subchronic to chronic exposure, an interspecies factor of 2.5, and a factor of 10 for interindividual variability a health hazard guide value (RW II) of 0.6 mg/m3 propan-1,2-diol is obtained. A health precaution guide value (RW I) of 0.06 mg/m3 is recommended. PMID- 28894884 TI - Characterization of Skull Base Lesions Using Pseudo-Continuous Arterial Spin Labeling. AB - PURPOSE: Pseudo-continuous arterial spin labeling (pCASL) is a non-invasive magnetic resonance (MR) perfusion technique. Our study aimed at estimating the diagnostic performance of the pCASL sequence in assessing the perfusion of skull base lesions both qualitatively and quantitatively and at providing cut-off values for differentiation of specific skull base lesions. METHODS: In this study 99 patients with histopathologically confirmed skull base lesions were retrospectively enrolled. Based on a pathological analysis, the lesions were classified as hypervascular and non-hypervascular. Patients were divided into two subgroups according to the anatomical origin of each lesion. The MRI study included pCASL and 3D T1-weighted fat-saturated post-contrast sequences. Of the patients seven were excluded due to technical difficulties or patient movement. The lesions were classified by two raters, blinded to the diagnosis as either hyperperfused or non-hyperperfused, based on the pCASL sequence. The normalized tumor blood flow (nTBF) of each lesion was determined. Qualitative and quantitative characteristics of hypervascular and non-hypervascular lesions were compared. RESULTS: Visual assessment enabled correct classification of 98% of the lesions to be performed. Quantitatively, we found significant differences between the nTBF values for hypervascular and non-hypervascular lesions (p < 0.001) and provided cut-off values, allowing meningioma and schwannoma to be distinguished from meningioma and adenoma. Significant differences were also found within the hypervascular group, namely, paraganglioma was more hyperperfused than meningioma (p = 0.003) or metastases (p = 0.009). CONCLUSION: The present study demonstrates the high diagnostic performance of pCASL in characterizing skull base lesions by either visual assessment or nTBF quantification. Adding the pCASL sequence to the conventional protocol of skull base assessment can be recommended. PMID- 28894885 TI - [Intensive care medicine-survival and prospect of life]. AB - Intensive care medicine has achieved a significant increase in survival rates from critical illness. In addition to short-term outcomes like intensive care unit or hospital mortality, long-term prognosis and prospect of life of intensive care patients have recently become increasingly important. Pure survival is no longer a sole goal of intensive care medicine. The prediction of an intensive care patient's individual course should include the period after intensive care. A relevant proportion of all intensive care patients is affected by physical, psychological, cognitive, and social limitations after discharge from the intensive care unit. The prognosis of the status of the patient after discharge from the intensive care unit is an important part of the decision-making process with respect to the implementation or discontinuation of intensive care measures. The heavy burden of intensive care treatment should not solely be argued by pure survival but an anticipated sound prospect of life. PMID- 28894886 TI - Adolescent gambling in greater Athens area: a cross-sectional study. AB - PURPOSE: Problem gambling in adolescents has recently emerged as a pressing public health concern. In this context and in light of the pervasive financial crisis in Greece, the present study aimed to explore adolescents' gambling involvement in Athens region to estimate the prevalence of its problematic form and to identify its risk/protective factors. METHODS: A total of 2141 students were recruited from a representative sample of 51 schools located in greater Athens area. The presence of problem gambling was assessed through the use of the DSM-IV-MR-J questionnaire. Data were collected in the form of a self-reported questionnaire during one school hour. RESULTS: Results indicate that 1-year prevalence of high severity problem gambling was found to be 5.6%. Regarding the risk factors for problem gambling; male gender, parental engagement with gambling activities, living without the parents, low grades at school, foreign nationality and the referent absence of availability of food in the household, increased the risk of suffering from the disorder. CONCLUSION: Gambling behavior among adolescents constitutes a problem in Greece and highlights the need for designing and implementing appropriate preventive interventions, especially amid the ongoing financial crisis. PMID- 28894887 TI - [Endovascular thrombectomy for ischemic stroke]. AB - The standard of care for patients with acute stroke of the anterior circulation and large vessel occlusion is the combined treatment with intravenous rt-PA (recombinant tissue-type plasminogen activator) and endovascular thrombectomy. The therapy is highly effective while reducing functional deficits and long-term disability. International guidelines recommend thrombectomy during the first 6 h after symptom onset, but new evidence supports its use in selected patients within a time window of up to 24 h. Eligible patients show a clinical core mismatch, i. e. severe neurologic deficits contrasting to a small core of cerebral infarction. Future research questions regard the treatment of vessel occlusion at the M2 segments as well as the best anesthetic management during the intervention. The infrastructure of stroke care especially in rural areas is based on the drip-and-ship paradigm that implies emergency treatment with the start of intravenous thrombolysis at the nearest hospital followed by transport to an interventional center in case of large vessel occlusion. PMID- 28894888 TI - [Posttherapeutic changes in bone marrow]. AB - The bone marrow basically consists of red blood-forming bone marrow and yellow fat. In the skeleton, there is an age-dependent distribution of these two parts. In the context of medical interventions or therapies, bone marrow changes can occur, whereby the normal bone marrow can basically be replaced by fat, edema, or fibrosis/sclerosis. Here, specific signal intensities and patterns are shown in imaging. After irradiation therapies, edematous changes, hemorrhages, and osteoradionecroses are observed. Likewise, insufficiency fractures, impairment of the growth gaps, or the development of tumors is possible. In patients on dialysis, deposit of protein in the bone marrow is possible in the case of the so called amyloidosis osteoarthropathy. Postoperative bone marrow edema, insufficiency fractures, or osteonecrosis can be observed after arthroscopy. Changes in the distribution of fat markers and blood-forming bone marrow can be observed after stem cell transplants. In the therapy with cortisone, insufficiency fractures and osteonecroses are possible. Depending on their effect on the hematopoietic system, chemotherapyies can first lead to edematous changes and then to fatty bone marrow, which is reversible after therapy. Angiogenesis inhibitors in combination with other chemotherapeutic agents often lead to mixed images of stimulated and fatty bone marrow. PMID- 28894889 TI - Influence of contrast-enhanced ultrasound administration setups on microbubble enhancement: a focus on pediatric applications. AB - BACKGROUND: In pediatrics, contrast-enhanced ultrasound offers high-quality imaging with an excellent safety profile. OBJECTIVE: To investigate the effects of varying intravenous administration setups on in vitro enhancement and concentration of two commercially available ultrasound contrast agents, taking into consideration potential pediatric applications. MATERIALS AND METHODS: We quantified in vitro enhancement using a flow phantom (ATS Laboratories, Bridgeport, CT) and Acuson S3000 ultrasound system (Siemens Healthineers, Mountain View, CA) with a 9L4 probe in Cadence pulse sequencing mode. We determined microbubble concentration with an LSRII flow cytometer (BD Biosciences, San Jose, CA). We investigated Optison (GE Healthcare, Princeton, NJ) and Lumason (Bracco, Geneva, Switzerland) ultrasound contrast agents. The ultrasound (US) contrast agent was injected via a 1 mL syringe and flushed with 5 mL of saline through a 22-gauge diffusion catheter (BD Medical, Franklin Lakes, NJ) with the following variations: in-line injection through a 3-way stopcock with and without a neutral displacement connector (ICU Medical, San Clemente, CA), perpendicular through a 3-way stopcock with and without a connector, and without a 3-way stopcock. We also conducted injections through a 22-gauge standard angiocatheter. RESULTS: Injection through the connector and perpendicular injection via the 3-way stopcock resulted in significant decreases in enhancement for both ultrasound contrast agents (P<0.0001). Injection through the connector resulted in significant decrease in concentration for Optison (P<0.05). Neither addition of the 3-way stopcock (P>0.24) nor use of a pediatric diffusion catheter (P>0.28) affected the enhancement. CONCLUSION: Ultrasound contrast agent enhancement depends on the administration route, although some effects appear to be specific to the ultrasound contrast agent used. To avoid loss of enhancement, neutral displacement connectors and perpendicular injection should be avoided. PMID- 28894890 TI - New prognostic factor telomerase reverse transcriptase promotor mutation presents without MR imaging biomarkers in primary glioblastoma. AB - PURPOSE: Magnetic resonance (MR) imaging biomarkers can assist in the non invasive assessment of the genetic status in glioblastomas (GBMs). Telomerase reverse transcriptase (TERT) promoter mutations are associated with a negative prognosis. This study was performed to identify MR imaging biomarkers to forecast the TERT mutation status. METHODS: Pre-operative MRIs of 64/67 genetically confirmed primary GBM patients (51/67 TERT-mutated with rs2853669 polymorphism) were analyzed according to Visually AcceSAble Rembrandt Images (VASARI) ( https://wiki.cancerimagingarchive.net/display/Public/VASARI+Research+Project ) imaging criteria by three radiological raters. TERT mutation and O6-methylguanine DNA methyltransferase (MGMT) hypermethylation data were obtained through direct and pyrosequencing as described in a previous study. Clinical data were derived from a prospectively maintained electronic database. Associations of potential imaging biomarkers and genetic status were assessed by Fisher and Mann-Whitney U tests and stepwise linear regression. RESULTS: No imaging biomarkers could be identified to predict TERT mutational status (alone or in conjunction with TERT promoter polymorphism rs2853669 AA-allele). TERT promoter mutations were more common in patients with tumor-associated seizures as first symptom (26/30 vs. 25/37, p = 0.07); these showed significantly smaller tumors [13.1 (9.0-19.0) vs. 24.0 (16.6-37.5) all cm3; p = 0.007] and prolonged median overall survival [17.0 (11.5-28.0) vs. 9.0 (4.0-12.0) all months; p = 0.02]. TERT-mutated GBMs were underrepresented in the extended angularis region (p = 0.03), whereas MGMT methylated GBMs were overrepresented in the corpus callosum (p = 0.03) and underrepresented temporomesially (p = 0.01). CONCLUSION: Imaging biomarkers for prediction of TERT mutation status remain weak and cannot be derived from the VASARI protocol. Tumor-associated seizures are less common in TERT mutated glioblastomas. PMID- 28894891 TI - Characterization and Synergistic Effect of Antifungal Volatile Organic Compounds Emitted by the Geotrichum candidum PF005, an Endophytic Fungus from the Eggplant. AB - Plant-associated endophytes are recognized as sources of novel bioactive molecules having diverse applications. In this study, an endophytic yeast-like fungal strain was isolated from the fruit of eggplant (Solanum melongena) and identified as Geotrichum candidum through phenotypic and genotypic characterizations. This endophytic G. candidum isolate PF005 was found to emit fruity scented volatiles. The compositional profiling of volatile organic compounds (VOCs) revealed the presence of 3-methyl-1-butanol, ethyl 3 methylbutanoate, 2-phenylethanol, isopentyl acetate, naphthalene, and isobutyl acetate in significant proportion when analyzed on a time-course basis. The VOCs from G. candidum exhibited significant mycelial growth inhibition (54%) of phytopathogen Rhizoctonia solani, besides having mild antifungal activity against a few other fungi. The source of carbon as a nutrient was found to be an important factor for the enhanced biosynthesis of antifungal VOCs. The antifungal activity against phytopathogen R. solani was improved up to 91% by feeding the G. candidum with selective precursors of alcohol and ester volatiles. Furthermore, the antifungal activity of VOCs was enhanced synergistically up to 92% upon the exogenous addition of naphthalene (1.0 mg/plate). This is the first report of G. candidum as an endophyte emitting antifungal VOCs, wherein 2-penylethanol, isopentyl acetate, and naphthalene were identified as important contributors to its antifungal activity. Possible utilization of G. candidum PF005 as a mycofumigant has been discussed based upon its antifungal activity and the qualified presumption of safety status. PMID- 28894892 TI - Using emergency trauma team activations to measure trauma activity and injury severity: 10 years of experience using an Australian major trauma centre registry. AB - OBJECTIVES: To describe the outcomes of Emergency Department trauma team activations over a 10-year period with respect to injury severity and hospital length of stay. METHODS: This was a retrospective study using trauma registry data at a single Major Trauma Centre in Australia. All trauma team activations and arrivals on pre-hospital major trauma (T1) protocol recorded in the trauma registry between June 2006 and July 2016 were included. The outcome of interest was major trauma, defined as an Injury Severity Score (ISS) >12 or length of stay >3 days or requiring urgent operative intervention or admission to the Intensive Care Unit following trauma. RESULTS: A total of 9876 hospital trauma activations were analysed from January 2006 to June 2016. Of these 53.3% were admitted as an in-patient and 16.6% were classified as having an ISS >15. Major trauma occurred in 38% of cases. With respect to hospital utilisation, patients with an ISS <16 accounted for around half of total cumulative in-patient bed-days. CONCLUSIONS: Analysis of data from trauma team activations in ED has allowed a description of trauma activity and hospital bed day utilisation as a function of injury severity. The results confirm that those with minor trauma accounted for the vast majority of cases and around half of all hospital in-patient bed-days. PMID- 28894893 TI - Termination of pregnancy and sterilisation in women with childhood-onset type 1 diabetes. AB - AIMS/HYPOTHESIS: The aim of this study was to explore the association between type 1 diabetes and reproductive health indicators in women, focusing on termination of pregnancy and sterilisation. METHODS: We conducted a registry based cohort study involving 2281 women with childhood-onset type 1 diabetes, matched for age and birthplace with women without diabetes: two control participants for each woman with diabetes. We compared the frequencies of termination of pregnancy and sterilisation over a 25 year period between women with type 1 diabetes and women without, and estimated standardised incidence ratios (SIRs). Smoothed age and period effects in the incidence of termination of pregnancy or sterilisation were tested statistically. RESULTS: There were more terminations of pregnancy (SIR 1.67; 95% CI 1.51, 1.86) and sterilisations (SIR 1.69; 95% CI 1.56, 1.83) in women with diabetes than in control women. During recent years, sterilisations in women with diabetes have decreased and the difference compared with control women has vanished. The indications for both procedures showed a statistically highly significant difference: maternal medical indications were almost absent (< 1%) in procedures among control women, but comprised 23.6% of terminations of pregnancy and 22.9% of sterilisations in women with diabetes. CONCLUSIONS/INTERPRETATION: The indications for termination of pregnancy and sterilisation are different in women with diabetes compared with other women. Pregnancies in women with type 1 diabetes are still terminated more often than in women without diabetes, but the difference in sterilisation rates has disappeared during recent years. PMID- 28894894 TI - Advanced microbial analysis for wastewater quality monitoring: metagenomics trend. AB - Urban Wastewater treatment plants (UWWTPs) have played an important and fundamental role in society for water purification of contaminated human wastewaters over the last decades. Microorganisms are very important in UWWTP as their metabolic activity significantly reduces the organic load of the UWW, although there is an uncertain gap in our knowledge regarding microbial consortium structure and their activity in UWWTP operation on a large scale. On the other hand, effluents of UWWTPs have come to be a new source of fresh water to ease water scarcity in many regions of the world, especially in intensive irrigation practices. Many concerns over health risks relating to the direct reuse of this water are very well known. However, if a proper disinfection treatment is applied, these are strongly reduced as conventional methodologies have demonstrated over the last decades. In line with this, the continuous development of new devices for analytical measurement that increase the sensitivities (limit of detection) are showing that other potential risks for both environmental and human health may be associated with UWW reuse. In this work, the most important aspects related to microorganisms in UWWTPs and UWW effluents are presented. Moreover, the new developments on genetic tools for detection of microorganisms are presented, with special emphasis on metagenomic methodology. A bibliometric analysis of what has been published so far is also carried out. PMID- 28894896 TI - [Hypospadias : Insights and challenges]. AB - Disorders of the ventral tubularization of the urethra, such as the hypospadias, are among the second most frequent congenital childhood malformations. An increasing incidence has been observed suggesting a doubling in the US, which could not be documented for the European area. The underlying causes of this congenital defect remain unidentified. Genetic risk constellations or environmental influences, in particular by so-called endocrine disrupting chemicals (EDCs), are discussed as triggering factors. Boys after in vitro fertilization are more likely to have hypospadias than in nonreproductive assisted pregnancies. Animal models (especially mice) elicited causal relationships between prenatal hormonal exposure (estrogens, progesterone) and antiandrogens such as flutamide, finasteride, antiandrogenic fungicides (vinclozolin) and phthalates and the formation of hypospadias. An aesthetic and/or functional deficit are indications for surgical correction. The indications and the complications of hypospadias surgery must be in detail and realistically discussed with the parents and patients. Recent publications demonstrated that the risk of complications increases with the increase of the follow-up time. High-volume centers with extensive experience have a positive effect on the complication rate. Competent follow-up to adult age should be ensured. PMID- 28894897 TI - Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single institution retrospective analysis. AB - PURPOSE: Grade 3 NENs are aggressive tumours with poor prognosis. PRRT+/- radiosensitising chemotherapy is a potential treatment for disease with high somatostatin receptor (SSTR) expression without spatially discordant FDG-avid disease. We retrospectively evaluated the efficacy of PRRT in G3 NEN. METHODS: Kaplan-Meier estimation was used to determine progression-free survival (PFS) and overall survival (OS) defined from start of PRRT. Subgroup analysis was performed for patients with Ki-67 <= 55% and >55%. Anatomical response (RECIST 1.1) and toxicity 3 months after PRRT was determined. Disease control rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD) of those with prior progression. RESULTS: 28 patients (M = 17; age 16-78 years; Ki-67 <= 55% = 22) were reviewed. 17 patients had pancreatic, 5 small bowel, 3 large bowel, 2 bronchial and 1 unknown primary disease. 25/28 had significant FDG avid disease prior to treatment. Most had 177Lu-DOTA-octreotate (median cumulative activity 24.4 GBq, median 4 cycles). Twenty patients had radiosensitising chemotherapy. 89% were treated for disease progression; 79% after prior chemotherapy. Median follow-up was 29 months. The median PFS was 9 months for all patients. 16 patients died (Ki-67 <= 55% = 11; Ki-67 > 55% = 5) with median OS of 19 months. For Ki-67 <= 55% (N = 22), the median PFS was 12 months and median OS 46 months. For Ki-67 > 55% (N = 6), the median PFS was 4 months and median OS 7 months. On CT imaging, DCR at 3 months post-PRRT was 74%, 35% (8/23) PR and 39% (9/23) SD. Eleven patients received further PRRT due to recrudescent disease after response. Five patients developed progression of discordant FDG-avid disease and were referred for targeted therapy/chemotherapy. Grade 3 and 4 lymphopenia and thrombocytopenia occurred in five and five patients, respectively. No renal or liver toxicity related to treatment was seen. CONCLUSIONS: PRRT achieves clinically relevant disease control with acceptable toxicity in G3 NENs. PMID- 28894898 TI - Effective collateral circulation may indicate improved perfusion territory restoration after carotid endarterectomy. AB - OBJECTIVES: To investigate the relationship between the level of collateral circulation and perfusion territory normalisation after carotid endarterectomy (CEA). METHODS: This study enrolled 22 patients with severe carotid stenosis that underwent CEA and 54 volunteers without significant carotid stenosis. All patients were scanned with ASL and t-ASL within 1 month before and 1 week after CEA. Collateral circulation was assessed on preoperative ASL images based on the presence of ATA. The postoperative flow territories were considered as back to normal if they conformed to the perfusion territory map in a healthy population. Neuropsychological tests were performed on patients before and within 7 days after surgery. RESULTS: ATA-based collateral score assessed on preoperative ASL was significantly higher in the flow territory normalisation group (n=11, 50 %) after CEA (P < 0.0001). The MMSE (mean change=1.36+/-0.96) and MOCA (mean change=1.18+/-0.95) test scores showed a significant postoperative (7 days after CEA) improvement in the flow territory normalisation group [>mean differences+2SD among control (MMSE=1.35, MOCA=1.02)]. CONCLUSIONS: This study demonstrated that effective collateral flow in carotid stenosis patients was associated with normalisation of t-ASL perfusion territory after CEA. The perfusion territory normalisation group tends to have more cognitive improvement after CEA. KEY POINTS: * Evaluation of collaterals before CEA is helpful for avoiding ischaemia during clamping. * There was good agreement on ATA-based ASL collateral grading. * Perfusion territories in carotid stenosis patients are altered. * Patients have better collateral circulation with perfusion territory back to normal. * MMSE and MOCA test scores improved more in the territory normalisation group. PMID- 28894899 TI - Clinical impact of PSMA-based 18F-DCFBC PET/CT imaging in patients with biochemically recurrent prostate cancer after primary local therapy. AB - PURPOSE: The purpose of our study was to assess 18F-DCFBC PET/CT, a PSMA targeted PET agent, for lesion detection and clinical management of biochemical relapse in prostate cancer patients after primary treatment. METHODS: This is a prospective IRB-approved study of 68 patients with documented biochemical recurrence after primary local therapy consisting of radical prostatectomy (n = 50), post radiation therapy (n = 9) or both (n = 9), with negative conventional imaging. All 68 patients underwent whole-body 18F-DCFBC PET/CT, and 62 also underwent mpMRI within one month. Lesion detection with 18F-DCFBC was correlated with mpMRI findings and pre-scan PSA levels. The impact of 18F-DCFBC PET/CT on clinical management and treatment decisions was established after 6 months' patient clinical follow-up. RESULTS: Forty-one patients (60.3%) showed at least one positive 18F-DCFBC lesion, for a total of 79 lesions, 30 in the prostate bed, 39 in lymph nodes, and ten in distant sites. Tumor recurrence was confirmed by either biopsy (13/41 pts), serial CT/MRI (8/41) or clinical follow-up (15/41); there was no confirmation in five patients, who continue to be observed. The 18F DCFBC and mpMRI findings were concordant in 39 lesions (49.4%), and discordant in 40 lesions (50.6%); the majority (n = 32/40) of the latter occurring because the recurrence was located outside the mpMRI field of view. 18F-DCFBC PET positivity rates correlated with PSA values and 15%, 46%, 83%, and 77% were seen in patients with PSA values <0.5, 0.5 to <1.0, 1.0 to <2.0, and >=2.0 ng/mL, respectively. The optimal cut-off PSA value to predict a positive 18F-DCFBC scan was 0.78 ng/mL (AUC = 0.764). A change in clinical management occurred in 51.2% (21/41) of patients with a positive 18F-DCFBC result, generally characterized by starting a new treatment in 19 patients or changing the treatment plan in two patients. CONCLUSIONS: 18F-DCFBC detects recurrences in 60.3% of a population of patients with biochemical recurrence, but results are dependent on PSA levels. Above a threshold PSA value of 0.78 ng/mL, 18F-DCFBC was able to identify recurrence with high reliability. Positive 18F-DCFBC PET imaging led clinicians to change treatment strategy in 51.2% of patients. PMID- 28894900 TI - Interaction Between Luteinizing Hormone-Releasing Hormone and GM1-Doped Cholesterol/Sphingomyelin Vesicles: A Spectroscopic Study. AB - Understanding the role of neural membrane in translocation and action of neurohormone is of great importance. Luteinizing hormone-releasing hormone (LHRH) is a neuropeptide hormone and it acts as a final signaling molecule by stimulating the synthesis of LH and FSH to maintain reproduction in all vertebrates. The receptors of LHRH are found in breast tumors and pituitary gland in the brain. Moreover, neural plasma membrane is also found to contain specific binding site for LHRH. The mechanism by which LHRH binds to membrane before it binds to the receptors is a very critical step and can have a profound impact upon the translation of peptide across the membrane. A complex form of glycosphingolipids known as Ganglioside is an important component of plasma membrane of nerve cells and breast tumor tissues. They play an important role in various physiological membrane processes. Therefore, the interaction of ganglioside-containing membrane with LHRH might be crucial in aiding the LHRH to translate through the neural membrane and reach its receptor for binding and activation. Using CD, UV-Absorbance, and fluorescence spectroscopy, the effect of Ganglioside Monosialo 1(GM1)-induced conformational changes of LHRH in the presence of Cholesterol (CHOL)/Sphingomyelin (SM) and GM1/CHOL/SM vesicles was studied. The aforesaid spectroscopic studies show that LHRH is able to bind with both the vesicles, but GM1-containing vesicles interact more effectively than vesicles without GM1. CHOL/SM vesicles partially disturb the conformation of the peptide. Moreover, binding of LHRH to GM1/CHOL/SM vesicles induces loss of conformational rigidity and attainment of a random coil. PMID- 28894901 TI - Imaging features of microvascular invasion in hepatocellular carcinoma developed after direct-acting antiviral therapy in HCV-related cirrhosis. AB - OBJECTIVES: To evaluate imaging features of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) developed after direct-acting antiviral (DAA) therapy in HCV-related cirrhosis. METHODS: Retrospective cohort study on 344 consecutive patients with HCV-related cirrhosis treated with DAA and followed for 48-74 weeks. Using established imaging criteria for MVI, HCC features were analysed and compared with those in nodules not occurring after DAA. RESULTS: After DAA, HCC developed in 29 patients (single nodule, 18 and multinodular, 11). Median interval between therapy end and HCC diagnosis was 82 days (0-318). Forty one HCC nodules were detected (14 de novo, 27 recurrent): maximum diameter was 10 20 mm in 27, 20-50 mm in 13, and > 50 mm in 1. Imaging features of MVI were present in 29/41 nodules (70.7%, CI: 54-84), even in 17/29 nodules with 10-20 mm diameter (58.6%, CI: 39-76). MVI was present in only 17/51 HCC nodules that occurred before DAA treatment (33.3%, CI: 22-47) (p= 0.0007). MVI did not correlate with history of previous HCC. CONCLUSIONS: HCC occurs rapidly after DAA therapy, and aggressive features of MVI characterise most neoplastic nodules. Close imaging evaluations are needed after DAA in cirrhotic patients. KEY POINTS: * In HCV cirrhosis, hepatocellular carcinoma develops soon after direct-acting antiviral therapy. * HCC presents imaging features of microvascular invasion, predictive of more aggressive progression. * Cirrhotic patients need aggressive and close monitoring after direct-acting antiviral therapy. PMID- 28894902 TI - Development and validation of a Medicines Comorbidity Index for older people. AB - PURPOSE: An index for estimating multimorbidity based on prescription claims data is important for predicting health outcomes for older people in pharmacoepidemiological studies. We aimed to develop a Medicines Comorbidity Index (MCI) based on nationwide prescription claims data and evaluate its performance in predicting adverse outcomes in older individuals. METHODS: The index was developed on a retrospective cohort comprising of all individuals aged >= 65 years old, captured in the claims dataset from 1st January to 31st December 2012. The cohort was followed for 1 year to identify an event of hospitalisation or mortality. A list of medications for 20 comorbidities based on the Chronic Disease Score framework was collated. Predictive performance of the MCI was evaluated against the Charlson Comorbidity Index (CCI) using measures of discrimination (Receiver Operating Characteristic curves), sensitivity and specificity (c-statistic) and calibration (Brier scores) for regression models. RESULTS: The MCI was validated for an outcome of mortality (n = 161,461) and hospitalisation (n = 149,729). For mortality, MCI had a marginally lower c statistic in comparison to CCI (0.70, 95% CI 0.70-0.71 vs 0.72, 95% CI 0.71-0.72 at p < 0.05) with Brier scores of 0.07 at p < 0.05. For hospitalisation, the Hazard Ratio was higher with MCI (1.08, 95% CI 1.08-1.08, p < 0.001) compared to CCI (0.92, 95% CI 0.91-0.92, p < 0.001). CONCLUSION: Initial testing indicates that the MCI is a valid and appropriate tool for measuring multimorbidity and predicting health outcomes for older individuals, and can be an important index for adjusting comorbidity in pharmacoepidemiological studies. PMID- 28894903 TI - In Response to: Ventilation in Trauma Patients: The First 24 h is Different! PMID- 28894904 TI - Factors influencing the outcome of surgery for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) surgery is a common gynecological procedure. Our aim was to assess the influence of obesity and other risk factors on the outcome of anterior and posterior colporrhaphy with and without mesh. METHODS: Data were retrieved from the Swedish National Register for Gynecological Surgery on 18,554 women undergoing primary and repeat POP surgery without concomitant urinary incontinence (UI) surgery between 2006 and 2015. Multivariate logistic regression analyses were used to identify independent risk factors for a sensation of a vaginal bulge, de novo UI, and residual UI 1 year after surgery. RESULTS: The overall subjective cure rate 1 year after surgery was 80% (with mesh 86.4% vs 77.3% without mesh, p < 0.001). The complication rate was low, but was more frequent in repeat surgery that were mainly mesh related. The use of mesh was also associated with more frequent de novo UI, but patient satisfaction and cure rates were higher compared with surgery without mesh. Preoperative sensation of a vaginal bulge, severe postoperative complications, anterior colporrhaphy, prior hysterectomy, postoperative infections, local anesthesia, and body mass index (BMI) >=30 were risk factors for sensation of a vaginal bulge 1 year postsurgery. Obesity had no effect on complication rates but was associated increased urinary incontinence (UI) after primary surgery. Obesity had no influence on cure or voiding status in women undergoing repeat surgery. CONCLUSIONS: Obesity had an impact on the sensation of a vaginal bulge and the presence of UI after primary surgery but not on complications. PMID- 28894905 TI - [Knowledge, trust, and the decision to donate organs : A comparison of medical students and students of other disciplines in Germany]. AB - BACKGROUND: Following the organ transplant scandal in Germany in 2011, the willingness to donate organs postmortem decreased dramatically. This was explained by a loss of confidence in the German organ donation system. OBJECTIVES: The aim of this study was to evaluate the relationship between knowledge, trust, and fear in respect to organ donation and the explicit willingness to potentially act as an organ donor by comparing medical students to students of other disciplines. MATERIAL AND METHODS: We conducted a Facebook based online survey (June-July 2013). The participating students were divided into two groups according to their discipline: medical students and other students. Based on questions covering different aspects of organ donation, a knowledge, trust, and fear score was established and calculated. The answers were related to an explicitly expressed decision to donate organs as expressed in a signed organ donor card. RESULTS: In total, 2484 participants took part in our survey. Of these, 1637 were students, 83.7% (N = 1370) of which were medical students and 16.3% (N = 267) other students. As expected, medical students reached a higher knowledge score regarding organ donation compared with other students (knowledge score 4.13 vs. 3.38; p < 0.001). They also demonstrated more confidence in organ donation, resulting in a higher confidence score (3.94 vs. 3.33; p < 0.001) and expressed less fear towards organ donation as indicated by the lower fear score (1.76 vs. 2.04; p < 0.01). Medical students declared their written willingness to donate organs more often than did other students (78.2% vs. 55.2%; p < 0.001). Entries on organ donation cards did not differ significantly between medical students and other students. Medical students possessing an organ donor card showed a higher knowledge and a higher trust score than did medical students without an organ donor card. In contrast, other students possessing an organ donor card showed a higher trust score but did not show a higher knowledge score. CONCLUSIONS: The higher level of knowledge and trust demonstrated by the medical students was associated with a higher rate of written decisions to donate organs. In contrast, the lower level of knowledge and trust observed in the non-medical students was associated with a lower rate of organ donor cards. Interestingly, in the group of non-medical students, the decision regarding organ donation was associated with a higher level of trust, but not with a higher level of knowledge. It would appear that knowledge, trust, and the decision to donate organs are closely related. In cases of a low level of knowledge, confidence is even more important. Therefore, organ donation campaigns should focus on increasing knowledge and fostering trust. PMID- 28894906 TI - Whole exome sequencing reveals a functional mutation in the GAIN domain of the Bai2 receptor underlying a forward mutagenesis hyperactivity QTL. AB - The identification of novel genes underlying complex mouse behavioral traits remains an important step in understanding normal brain function and its dysfunction in mental health disorders. To identify dominant mutations that influence locomotor activity, we performed a mouse N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen and mapped several loci as quantitative traits. Here we describe the fine-mapping and positional cloning of a hyperactivity locus mapped to the medial portion of mouse chromosome four. We employed a modified recombinant progeny testing approach to fine-map the confidence interval from ~20 Mb down to ~5 Mb. Whole exome resequencing of all exons in this region revealed a single missense mutation in the adhesion G protein-coupled receptor brain specific angiogenesis inhibitor 2 (Bai2). This mutation, R619W, is located in a critical extracellular domain that is a hotspot for mutations in this receptor class. We find that in two different mammalian cell lines, surface expression of Bai2 R619W is markedly reduced relative to wild-type Bai2, suggesting that R619W is a loss-of-function mutation. Our results highlight the powerful combination of ENU mutagenesis and next-generation sequencing to identify specific mutations that manifest as subtle behavioral phenotypes. PMID- 28894908 TI - Discoid lateral meniscus can be overlooked by magnetic resonance imaging in patients with meniscal tears. AB - PURPOSE: MRI evaluation of torn lateral meniscus was compared with arthroscopy. This study calculates the sensitivity, specificity, and accuracy of MRI in determining the presence or absence of discoid lateral meniscus (DLM) for different tear types. METHODS: MR imaging of 156 knees with arthroscopically confirmed lateral meniscus tears was analysed. There were 78 knees (70 patients) in non-DLM group and 78 knees (74 patients) in DLM group on arthroscopy as the reference standard. The presence of DLM on MRI was determined by an orthopaedic surgeon and a radiologist, who were blinded to the arthroscopic findings. The presence of discoid meniscus on MRI was determined by coronal and sagittal measurements, considering the tear pattern of lateral meniscus. The tear pattern was categorized into six types based on arthroscopic findings: horizontal, longitudinal, radial, combined radial, degenerative, and complex tear. The sensitivity, specificity, and accuracy of MRI were calculated for each type of lateral meniscus tear. In addition, we analysed the reason for non-detection of discoid meniscus on preoperative MRI. RESULT: The sensitivity for determining the presence of discoid meniscus was 58% for radial tear, 57% for combined radial tear, and 65% for longitudinal tear, whereas the specificity was 100% for all tear groups. In the presence of radial or longitudinal tear, the accuracy of MRI was significantly lower than having no radial and longitudinal tear (p < 0.001). The presence of discoid meniscus was not recognized on MRI because of large radial tear (12 knees), deformed bucket-handle tear (6 knees), and inverted flap tear (3 knees). CONCLUSIONS: MRI was not successful in determining the presence or absence of DLM in radial tear, combined radial tear, and longitudinal tear. When there are large radial tear, deformed bucket-handle tear, and inverted flap tear in lateral meniscus, it is recommended to consider the possibility of DLM. This information can help to make accurate diagnosis of DLM, which allows appropriate surgical planning and facilitates patient's information on poor prognosis of DLM. LEVEL OF EVIDENCE: Level I. PMID- 28894909 TI - [What is a seriously injured person? : Differentiated view of the severity of the injuries in a trauma patient]. PMID- 28894907 TI - Challenges in translational drug research in neuropathic and inflammatory pain: the prerequisites for a new paradigm. AB - AIM: Despite an improved understanding of the molecular mechanisms of nociception, existing analgesic drugs remain limited in terms of efficacy in chronic conditions, such as neuropathic pain. Here, we explore the underlying pathophysiological mechanisms of neuropathic and inflammatory pain and discuss the prerequisites and opportunities to reduce attrition and high-failure rate in the development of analgesic drugs. METHODS: A literature search was performed on preclinical and clinical publications aimed at the evaluation of analgesic compounds using MESH terms in PubMed. Publications were selected, which focused on (1) disease mechanisms leading to chronic/neuropathic pain and (2) druggable targets which are currently under evaluation in drug development. Attention was also given to the role of biomarkers and pharmacokinetic-pharmacodynamic modelling. RESULTS: Multiple mechanisms act concurrently to produce pain, which is a non-specific manifestation of underlying nociceptive pathways. Whereas these manifestations can be divided into neuropathic and inflammatory pain, it is now clear that inflammatory mechanisms are a common trigger for both types of pain. This has implications for drug development, as the assessment of drug effects in experimental models of neuropathic and chronic pain is driven by overt behavioural measures. By contrast, the use of mechanistic biomarkers in inflammatory pain has provided the pharmacological basis for dose selection and evaluation of non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSION: A different paradigm is required for the identification of relevant targets and candidate molecules whereby pain is coupled to the cause of sensorial signal processing dysfunction rather than clinical symptoms. Biomarkers which enable the characterisation of drug binding and target activity are needed for a more robust dose rationale in early clinical development. Such an approach may be facilitated by quantitative clinical pharmacology and evolving technologies in brain imaging, allowing accurate assessment of target engagement, and prediction of treatment effects before embarking on large clinical trials. PMID- 28894910 TI - Drought Alleviated the Negative Effects of Elevated O3 on Lonicera maackii in Urban Area. AB - Open top chambers were used to study the changes in photosynthesis, physiology and stomata characteristics in 1-year-old Lonicera maackii seedlings exposed to drought (DT, 30%-35% soil saturated water content) or/and elevated ozone (EO, 80 ppb). The results showed that DT or/and EO significantly decreased net photosynthetic rate (Pn), stomatal conductance (gs), maximum photochemical efficiency (Fv/Fm), but increased the activity of superoxide dismutase (SOD), and malondialdehyde content (p < 0.05). Compared with EO alone, the combination of EO and DT caused higher values in Pn, Fv/Fm, SOD activity (p < 0.05), and smaller stomata size and lower visible injury rate. DT alleviated the adverse impact of EO on the shrub by increasing enzyme activity and decreasing stomatal size, particularly stomatal width. The study provided increasing evidence that moderate drought might exert a beneficial effect on the tested plants to adapt to the future climate change, particularly in high ozone regions. PMID- 28894911 TI - Diminished Conspecific Odor Recognition in the Rusty Crayfish (Orconectes rusticus) Following a 96-h Exposure to Atrazine. AB - The presence of agricultural contaminants has been shown to disrupt olfactory mediated behaviors in aquatic animals. We assessed the effects of atrazine on the ability of reproductively active (form I), male crayfish (Orconectes rusticus) to identify and respond to conspecific chemical signals involved in mating. Male crayfish were exposed to atrazine (80 ppb) and water (control) for 96 h. We analyzed odor localization and locomotor behaviors of herbicide-treated and control male crayfish to two different odor sources: female odor or water (control) delivered from the proximal end of a test arena. Control crayfish spent more time in the proximal region of the test arena and at the odor source. Atrazine-exposed crayfish showed no preference for the proximal region of the test arena and odor source when female odor was delivered. Atrazine exposure did not affect locomotor behaviors. Overall, atrazine-mediated chemosensory deficits have the potential to disrupt mating and affect population size. PMID- 28894912 TI - Optimisation of the MR protocol in pregnant women with suspected acute appendicitis. AB - PURPOSE: To investigate the optimal magnetic resonance (MR) imaging protocol in pregnant women suspected of having acute appendicitis. MATERIALS AND METHODS: One hundred and forty-six pregnant women with suspected appendicitis were included. MR images were reviewed by two radiologists in three separate sessions. In session 1, only axial single-shot turbo spin echo (SSH-TSE) T2-weighted images (WI) were included with other routine sequences. In sessions 2 and 3, coronal and sagittal T2WI were sequentially added. The visibility of the appendix and diagnostic confidence of appendicitis were evaluated in each session using a 5 point grading scale. If diseases other than appendicitis were suspected, specific diagnosis with a 5-point confidence scale was recorded. Diagnostic performance for appendicitis and other diseases were evaluated. RESULTS: Twenty-five patients (17.1%) were diagnosed with appendicitis. Among the patients with normal appendix, 28 were diagnosed with other disease. Diagnostic performance including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve values for diagnosing appendicitis and other diseases showed no significant difference among sets for both reviewers (p>0.05). CONCLUSION: Diagnostic performance of MR in pregnant patients with suspected appendicitis can be preserved with omission of sagittal or both coronal and sagittal SSH-T2WI. KEY POINTS: * Diagnostic performance of appendicitis is preserved with omission of sagittal/coronal T2WIs. * Diagnosis of other disease may be sufficient with axial T2WIs only. * Careful serial omission of sagittal and coronal T2WIs can be considered. PMID- 28894913 TI - European otorhinolaryngology training programs: results of a European survey about training satisfaction, work environment and conditions in six countries. AB - ORL-students and residents have an ongoing debate about the "best" programme in Europe. Aim of this study was to comparatively assess differences among programmes in training, satisfaction, quality of life (QoL) of residents and recent otorhinolaryngologist (ORL) specialists in France, Germany, Spain, Italy, Austria, and Belgium. A self-administered anonymous questionnaire, structured in ten sections including general information, provided guidance, working environment, training structure, teaching of medical students, publication work, QoL, and satisfaction with training, were emailed to residents and recent ORL specialists. 476 returned questionnaires from 6 countries revealed that daily work hours were the highest in France and Belgium with 11 and 10.4 h on average, respectively. QoL, work conditions, and salary were best in Germany followed by Austria in terms of possibility of part-time contracts, better respect for post duty day off, and compensation for overtime. Satisfaction with training including support and guidance of seniors was lowest in Italy, but, on the other hand, the publication work and support had a more important place than in other countries. In Belgium, there was some gap between the quality of teaching and feedback from seniors as well as apprenticeship. The highest satisfaction with training was in France and Spain followed by Austria. The study results provide guidance before choosing an ORL training programme in Europe. Country-specific strengths could be included into future harmonization efforts to improve all programmes, facilitate professional exchange and, finally, establish standards-of-care carried out by well-trained doctors also looking after a satisfying work-life balance. PMID- 28894914 TI - Effect of Rituximab on Pulmonary Function in Bronchiolitis Obliterans Syndrome due to Graft-Versus-Host-Disease. AB - PURPOSE: Rituximab is an anti-CD20 monoclonal antibody that is used to suppress B cell function in graft-versus-host-disease (GVHD). We sought to determine the effects of rituximab treatment on lung function in those patients with bronchiolitis obliterans syndrome (BOS) as a manifestation of GVHD. METHODS: Thirteen patients were treated with rituximab with a diagnosis of BOS and a significant reduction in the forced expiratory volume in 1 s (FEV1) after hematopoietic stem cell transplantation (HSCT). The changes in their pulmonary function for 12 months following treatment with rituximab were followed, along with other intervention performed and daily average dosing of prednisone. RESULTS: Following rituximab administration, there was an improvement in the slope of decline in lung function from -5.12 ml/month prior to rituximab infusion to -0.31 ml/month after 3 months and to +2.27 ml/month 12 months later. Seven of the 13 patients had an increase in their FEV1 after treatment with rituximab. Additionally, the mean daily dose of prednisone decreased from 27 mg prior to rituximab treatment to 11 mg 12 months after treatment. Nine out of 13 patients survived 12 months after rituximab treatment. All of the patients with improvement in FEV1 following rituximab treatment were receiving concomitant extracorporeal photopheresis. CONCLUSION: Rituximab is safe with the potential to stabilize or improve lung function in patients with BOS after HSCT and should be considered as a treatment option in those patients. PMID- 28894915 TI - Chronobiological theories of mood disorder. AB - Major depressive disorder (MDD) remains the most prevalent mental disorder and a leading cause of disability, affecting approximately 100 million adults worldwide. The disorder is characterized by a constellation of symptoms affecting mood, anxiety, neurochemical balance, sleep patterns, and circadian and/or seasonal rhythm entrainment. However, the mechanisms underlying the association between chronobiological parameters and depression remain unknown. A PubMed search was conducted to review articles from 1979 to the present, using the following search terms: "chronobiology," "mood," "sleep," and "circadian rhythms." We aimed to synthesize the literature investigating chronobiological theories of mood disorders. Current treatments primarily include tricyclic antidepressants and selective serotonin reuptake inhibitors, which are known to increase extracellular concentrations of monoamine neurotransmitters. However, these antidepressants do not treat the sleep disturbances or circadian and/or seasonal rhythm dysfunctions associated with depressive disorders. Several theories associating sleep and circadian rhythm disturbances with depression have been proposed. Current evidence supports the existence of associations between these, but the direction of causality remains elusive. Given the existence of chronobiological disturbances in depression and evidence regarding their treatment in improving depression, a chronobiological approach, including timely use of light and melatonin agonists, could complement the treatment of MDD. PMID- 28894917 TI - Identification and characterization of the ficellomycin biosynthesis gene cluster from Streptomyces ficellus. AB - Ficellomycin is a peptide-like antibiotic which exhibits potent in vitro activity against Penicillium oxalicum and Staphylococcus aureus, even against strains resistant to most clinically used antibiotics. The gene cluster responsible for ficellomycin biosynthesis was cloned from Streptomyces ficellus and sequenced. It was found to contain 26 ORFs and is located within 30 kb of contiguous DNA. Targeted disruption of the encoding genes revealed that most were involved in the functional section of ficellomycin biosynthesis, such as peptide assembly, regulation, resistance, and biosynthesis of the precursor of ficellomycin 2-[4 guanidyl-1-azabicyclo[3.1.0]hexan-2-yl] glycine (2-GAHG). Within the 2-GAHG synthesis pathway, a sulfate adenylyltransferase appears to be involved in the synthesis of the pharmaceutically important 1-azabicyclo[3.1.0]hexane ring moiety, which has been reported to cause DNA cross-linking or impairment of semiconservative DNA replication. PMID- 28894916 TI - Structural and functional diversity of collectins and ficolins and their relationship to disease. AB - Pattern recognition molecules are sensors for the innate immune system and trigger a number of pathophysiological functions after interaction with the corresponding ligands on microorganisms or altered mammalian cells. Of those pattern recognition molecules used by the complement system, collagen-like lectins (collectins) are an important subcomponent. Whereas the best known of these collectins, mannose-binding lectin, largely occurs as a circulating protein following production by hepatocytes, the most recently described collectins exhibit strong local biosynthesis. This local production and release of soluble collectin molecules appear to serve local tissue functions at extravascular sites, including a developmental function. In this article, we focus on the characteristics of collectin-11 (CL-11 or CL-K1), whose ubiquitous expression and multiple activities likely reflect a wide biological relevance. Collectin-11 appears to behave as an acute phase protein whose production associated with metabolic and physical stress results in locally targeted inflammation and tissue cell death. Early results indicate the importance of fucosylated ligand marking the injured cells targeted by collectin-11, and we suggest that further characterisation of this and related ligands will lead to better understanding of pathophysiological significance and exploitation for clinical benefit. PMID- 28894918 TI - Comment on Andrei Diana et al.: The variability of vertebral body volume and pain associated with osteoporotic vertebral fractures: conservative treatment versus percutaneous transpedicular vertebroplasty. PMID- 28894919 TI - 'Timed up and go' and brain atrophy: a preliminary MRI study to assess functional mobility performance in multiple sclerosis. AB - Motor and cognitive disabilities are related to brain atrophy in multiple sclerosis (MS). 'Timed up and go' (TUG) has been recently tested in MS as functional mobility test, as it is able to evaluate ambulation/coordination related tasks, as well as cognitive function related to mobility. The objective of this study is to evaluate the relationship between brain volumes and TUG performances. Inclusion criteria were a diagnosis of MS and the ability to walk at least 20 m. TUG was performed using a wearable inertial sensor. Times and velocities of TUG sub-phases were calculated by processing trunk acceleration data. Patients underwent to a brain MRI, and volumes of whole brain, white matter (WM), grey matter (GM), and cortical GM (C) were estimated with SIENAX. Sixty patients were enrolled. Mean age was 41.5 +/- 11.6 years and mean EDSS 2.3 +/- 1.2. Total TUG duration was correlated to lower WM (rho = 0.358, p = 0.005) and GM (rho = 0.309, p = 0.017) volumes. A stronger association with lower GM volume was observed for intermediate (rho = 0.427, p = 0.001) and final turning (rho = 0.390, p = 0.002). TUG is a useful tool in a clinical setting as it can not only evaluate patients' disability in terms of impaired functional mobility, but also estimate pathological features, such as grey atrophy. PMID- 28894920 TI - Sacrococcygeal teratoma: late recurrence warrants long-term surveillance. AB - BACKGROUND: Sacrococcygeal teratoma (SCT) is a rare childhood malignancy. Although overall survival is favorable, recurrent tumors are associated with poor outcomes. As most recurrences occur within 3 years of presentation, the utility of long-term surveillance is uncertain. METHODS: Patients with SCTs evaluated and managed by our pediatric surgery department between 1986 and 2013 were included. Details pertaining to laboratory values, operative findings, tumor histology, management, recurrence, and outcomes were recorded and analyzed. RESULTS: During the study period, 40 children with the diagnosis of SCT were managed by our practice. Five (13%) developed a recurrence. The median age at the initial resection was day of life two (range day of life 0-2.5 years). The median time to recurrence was 5 years (range 5 months-15 years). Among those with recurrences, mature teratoma was the most common histological type on the initial resection (n = 3), with yolk sac and immature teratomas comprising the other two. At the time of recurrence, three patients had mature teratomas, and all are alive and well following resection. Two patients had yolk sac tumors at the time of recurrence and both died. CONCLUSION: SCT can recur many years after the initial resection. Our findings suggest that all patients with SCT should be closely followed into adulthood. PMID- 28894921 TI - Structural and functional variability in root-associated bacterial microbiomes of Cd/Zn hyperaccumulator Sedum alfredii. AB - Interactions between roots and microbes affect plant's resistance to abiotic stress. However, the structural and functional variation of root-associated microbiomes and their effects on metal accumulation in hyperaccumulators remain poorly understood. Here, we characterize the root-associated microbiota of a hyperaccumulating (HP) and a non-hyperaccumulating (NHP) genotype of Sedum alfredii by 16S ribosomal RNA gene profiling. We show that distinct microbiomes are observed in four spatially separable compartments: the bulk soil, rhizosphere, rhizoplane, and endosphere. Both the rhizosphere and rhizoplane were preferentially colonized by Proteobacteria, and the endosphere by Actinobacteria. The rhizosphere and endophytic microbiomes were dominated by the family of Sphingomonadaceae and Streptomycetaceae, respectively, which benefited for their survival and adaptation. The bacterial alpha-diversity decreases along the spatial gradient from the rhizosphere to the endosphere. Soil type and compartment were strongest determinants of root-associated community variation, and host genotype explained a small, but significant amount of variation. The enrichment of Bacteroidetes and depletion of Firmicutes and Planctomycetes in the HP endosphere compared with that of the NHP genotype may affect metal hyperaccumulation. Program PICRUSt predicted moderate functional differences in bacterial consortia across rhizocompartments and soil types. The functional categories involved in membrane transporters (specifically ATP-binding cassette transporters) and energy metabolism were overrepresented in endosphere of HP in comparison with NHP genotypes. Taken together, our study reveals substantial variation in structure and function of microbiomes colonizing different compartments, with the endophytic microbiota potentially playing an important role in heavy metal hyperaccumulation. PMID- 28894922 TI - Morphology and relationships of the biceps brachii and brachialis with the musculocutaneous nerve. AB - INTRODUCTION: Major anatomical textbooks generally state that the biceps brachii muscle (BB) is composed of long and short heads, whereas the brachialis muscle (BR) consists of a single head. However, the numbers of heads comprising the BB and the BR are very variable. The purpose of this study was to investigate how the branching patterns of the musculocutaneous nerve (MC) influence the number of heads of the BB and the BR. MATERIALS AND METHODS: Morphological examinations of the BB and MC were conducted using cadavers of 22 Japanese individuals, and morphological examinations of the BR and the MC were conducted in 9 of those 22 individuals. RESULTS: A three-headed BB was observed in 7 of the 22 specimens (31.8%). Most of these specimens showed a Type III branch pattern (after penetrating the long head or the short head, the MC innervated the supernumerary head or communicated with the main root again). The number of BR heads was categorized into three types: Type A, two heads (superficial and deep heads, 22.2%); Type B, three or four heads (two or three superficial heads and one deep head, 44.4%); and Type C, multiple heads (33.3%). Among these categories, branches of the MC in Type A specimens were most simple. CONCLUSION: A supernumerary head of the BB seemed to be present if the MC penetrates it. The BR basically consists of superficial and deep heads, and the number of superficial heads is affected by branches of the MC. PMID- 28894923 TI - Differences in myocardial strain between pectus excavatum patients and healthy subjects assessed by cardiac MRI: a pilot study. AB - OBJECTIVES: To evaluate differences in myocardial strain between pectus excavatum (PE) patients and healthy subjects (HS) assessed by cardiac MRI using the feature tracking algorithm. METHODS: Cardiac MRI was performed in 14 PE patients and 14 HS (9:5 male to female in each group; age 11-30 years) using a 3T scanner. Post examination analysis included manual biventricular contouring with volumetry and ejection fraction measurement by two independent radiologists. Dedicated software was used for automated strain assessment. RESULTS: In five of the PE patients, the right ventricular ejection fraction was slightly impaired (40-44 %). PE patients had a significantly higher left ventricular longitudinal strain (P=0.004), mid (P=0.035) and apical (P=0.001) circumferential strain as well as apical circumferential strain rate (P=0.001), mid right ventricular circumferential strain (P=0.008) and strain rate (P=0.035), and apical right ventricular circumferential strain (P=0.012) and strain rate (P=0.044) than HS. The right ventricular longitudinal strain and strain rate did not differ significantly between PE patients and HS. CONCLUSIONS: Myocardial strain differs significantly between PE patients and HS. Higher myocardial strain in the mid and apical ventricles of PE patients indicates a compensation mechanism to enhance ventricular output against basal sternal compression. KEY POINTS: * The right ventricle is frequently affected by the pectus excavatum deformity. * Cardiac MRI revealed differences in myocardial strain in pectus excavatum patients. * Pectus excavatum patients exhibited higher strain in the mid/apical ventricles. * A compensation mechanism to enhance ventricular output against sternal compression is possible. PMID- 28894924 TI - Cyclical vomiting syndrome secondary to a Chiari I malformation-a case report. AB - BACKGROUND: Cyclical vomiting syndrome is a disorder characterised by recurrent episodes of profuse vomiting. There are no cases in the literature on the management of children with presenting with cyclical vomiting syndrome and a Chiari malformation type I. DISCUSSION: We report the case of a 12-year-old child diagnosed with cyclical vomiting syndrome and a Chiari malformation type I. The patient received symptomatic relief following a craniocervical decompression. PMID- 28894925 TI - Alligator wrestling: morphological, molecular, and phylogenetic data on Odhneriotrema incommodum (Leidy, 1856) (Digenea: Clinostomidae) from Alligator mississippiensis Daudin, 1801 in Mississippi, USA. AB - Based on specimens collected from harvested American alligator Alligator mississippiensis Daudin, 1801 in Mississippi, USA, novel molecular data for both nuclear ribosomal genes (18S, ITS1-5.8S, ITS2, and 28S) and mitochondrial genes (cytochrome c oxidase subunit 1 and nicotinamide adenine dinucleotide dehydrogenase subunit 1) are provided for Odhneriotrema incommodum (Leidy, 1856), a trematode of the family Clinostomidae Luhe, 1901 infecting A. mississippiensis and the Florida spotted gar Lepisosteus platyrhincus DeKay, 1842. This represents the first sequencing data available for the genus Odhneriotrema and the subfamily Nephrocephalinae Travassos, 1928. Additionally, the results of phylogenetic analyses, additional morphometric data, a photomicrograph, and a line drawing supporting the present identification of O. incommodum are provided. These data will aid in elucidating the life cycle of O. incommodum through molecular identification of larval stages as well as understanding the evolutionary history of Clinostomidae and its subfamilies. Implications for the currently accepted organization of the Clinostomidae are discussed. PMID- 28894926 TI - Brainstem stroke preceded by transient isolated vertigo attacks. PMID- 28894927 TI - How to differentiate acute pelvic inflammatory disease from acute appendicitis ? A decision tree based on CT findings. AB - PURPOSE: To construct a decision tree based on CT findings to differentiate acute pelvic inflammatory disease (PID) from acute appendicitis (AA) in women with lower abdominal pain and inflammatory syndrome. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board and informed consent was waived. Contrast-enhanced CT studies of 109 women with acute PID and 218 age-matched women with AA were retrospectively and independently reviewed by two radiologists to identify CT findings predictive of PID or AA. Surgical and laboratory data were used for the PID and AA reference standard. Appropriate tests were performed to compare PID and AA and a CT decision tree using the classification and regression tree (CART) algorithm was generated. RESULTS: The median patient age was 28 years (interquartile range, 22-39 years). According to the decision tree, an appendiceal diameter >= 7 mm was the most discriminating criterion for differentiating acute PID and AA, followed by a left tubal diameter >= 10 mm, with a global accuracy of 98.2 % (95 % CI: 96-99.4). CONCLUSION: Appendiceal diameter and left tubal thickening are the most discriminating CT criteria for differentiating acute PID from AA. KEY POINTS: * Appendiceal diameter and marked left tubal thickening allow differentiating PID from AA. * PID should be considered if appendiceal diameter is < 7 mm. * Marked left tubal diameter indicates PID rather than AA when enlarged appendix. * No pathological CT findings were identified in 5 % of PID patients. PMID- 28894928 TI - Enhanced dendritic cells and regulatory T cells in the dermis of porokeratosis. AB - Porokeratosis is characterized clinically by annular lesions and histologically by the presence of a cornoid lamella (CL) in the epidermis. The underlying mechanism of porokeratosis development remains unclear. We performed immunohistochemical staining of CD1a, langerin, Ki67, CD3, CD4, CD8, FOXP3, and RANKL (receptor activator of nuclear factor kappaB ligand) in samples from 17 porokeratosis lesions and analyzed the differences in staining patterns among the CL, the inner part of the annular ridge (IC), and the adjacent normal skin (ANS). Numbers of CD1a+ Langerhans cells in the epidermis were reduced and numbers of CD1a+ dermal dendritic cells were significantly increased in the CL and IC compared to those in the ANS. In addition, there was also an increase in FOXP3+ cells in the dermis below the CL and IC. Our findings suggest that Langerhans cells are downregulated in the epidermis in CL and that regulatory T cells and dendritic cells are upregulated in the dermis below the CL. This alteration in the distribution of immune cells, such as various lymphocyte subsets, Langerhans cells, and dermal dendritic cells, may play a key role in the pathomechanisms of porokeratosis. PMID- 28894930 TI - Oncological Safety and Technical Feasibility of Nipple-Sparing Mastectomy for Breast Cancer: The Hong Kong Experience. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) has gained widespread popularity in recent years. Nonetheless, patient selection, technical consideration and oncological safety of its extension to breast cancer treatment remain uncertain. Few publications have reviewed the application of NSM in Asian populations. METHODS: We retrospectively reviewed 91 women with malignant breast tumours, who underwent 97 NSM in Hong Kong Sanatorium and Hospital from 2009 to 2015. Breast cancer patients who required mastectomy and opted for immediate reconstruction were considered for NSM if they showed no obvious nipple involvement clinically. All breast specimens were subjected to intraoperative pathological examination of the retroareolar tissue to exclude occult tumour infiltration before the final decision of nipple-areola complex (NAC) preservation. Clinical parameters, tumour characteristics and oncological outcomes were analyzed. RESULTS: Carcinoma of the breast accounts for 99.0% of our indications for therapeutic NSM. Almost all NSM were accompanied with immediate reconstruction. Abnormal pathology was shown in retroareolar tissue of ten patients (10.3%), and seven of these NAC were excised due to tumour involvement detected by intraoperative frozen section. Six (6.2%) NSM were complicated with superficial epidermolysis. Yet, there was no delayed NAC excision because of nipple necrosis. Overall NAC preservation rate reached 92.8%. Local and/or distant recurrences occurred in four patients (4.1%) after a mean follow-up of 20.6 months. One NAC recurrence was documented. CONCLUSION: Our series support the oncological safety of NSM after exclusion of neoplastic NAC involvement preliminarily by intraoperative frozen section and definitively by final pathology. Its technical feasibility is well proven by the low nipple necrosis rate. PMID- 28894929 TI - Recalling feature bindings differentiates Alzheimer's disease from frontotemporal dementia. AB - It has been challenging to identify clinical cognitive markers that can differentiate patients with Alzheimer's disease (AD) from those with behavioral variant frontotemporal dementia (bvFTD). The short-term memory binding (STMB) test assesses the ability to integrate colors and shapes into unified representations and to hold them temporarily during online performance. The objective of this study is to investigate whether free recall deficits during short-term memory binding (STMB) test can differentiate patients with AD from those with bvFTD and controls. Participants were 32 cognitively intact adults, 35 individuals with AD and 18 with bvFTD. All patients were in the mild dementia stage. Receiver-operating characteristic (ROC) analyses were used to examine the diagnostic accuracy of the STMB. The results showed that AD patients performed significantly worse than controls and bvFTD patients in the STMB test, while the latter groups showed equivalent performance. The bound condition of the STMB test showed an AUC of 0.853, with 84.4% of sensitivity and 80% of specificity to discriminate AD from controls and an AUC of 0.794, with 72.2% of sensitivity and 80% of specificity to differentiate AD from bvFTD. Binding deficits seem specific to AD. The free recall version of the STMB test can be used for clinical purposes and may aid in the differential diagnosis of AD. Findings support the view that the STMB may be a suitable cognitive marker for AD. PMID- 28894931 TI - Radiographic evaluation of condylar positioning in patients undergoing orthognathic surgery. AB - OBJECTIVE: The aim of this study was to evaluate alterations in condylar positioning through submentovertex projection (Hirtz Radiographic Technique) in patients who underwent orthognathic surgery for maxillary advancement and mandibular setback with stable internal fixation. METHODS: A prospective longitudinal clinical study of 40 surgical patients presenting dentofacial deformity admitted in the Oral and Maxillofacial Surgery Department of Federal University of Parana (UFPR) in the period between March 2013 and December 2015. We performed two submentovertex digital radiographs, one 7 days before surgery and the other one 30 days after the procedure. Cephalometric tracings were made using Radiocef(r) Studio 2 Software and measured the intercondylar and condylar angles (right and left). RESULTS: There was a decrease in the intercondylar angle (p < 0.001) and an increase in condylar angles both the right and the left side (p < 0.001) when compared with the pre and postoperative period. There was a larger increase in condylar angle on the right side in males (p = 0.007). CONCLUSION: There is a tendency of decreasing of the intercondylar angle after orthognathic surgery, regardless of the alteration in the condylar angles, creating a new position of the condyle in the glenoid fossa. Patients with asymmetry may present greater alterations in the positioning of the opposite condylar to the deviation of the mandibular midline. PMID- 28894932 TI - Genomic insights into temperature-dependent transcriptional responses of Kosmotoga olearia, a deep-biosphere bacterium that can grow from 20 to 79 degrees C. AB - Temperature is one of the defining parameters of an ecological niche. Most organisms thrive within a temperature range that rarely exceeds ~30 degrees C, but the deep subsurface bacterium Kosmotoga olearia can grow over a temperature range of 59 degrees C (20-79 degrees C). To identify genes correlated with this flexible phenotype, we compared transcriptomes of K. olearia cultures grown at its optimal 65 degrees C to those at 30, 40, and 77 degrees C. The temperature treatments affected expression of 573 of 2224 K. olearia genes. Notably, this transcriptional response elicits re-modeling of the cellular membrane and changes in metabolism, with increased expression of genes involved in energy and carbohydrate metabolism at high temperatures and up-regulation of amino acid metabolism at lower temperatures. At sub-optimal temperatures, many transcriptional changes were similar to those observed in mesophilic bacteria at physiologically low temperatures, including up-regulation of typical cold stress genes and ribosomal proteins. Comparative genomic analysis of additional Thermotogae genomes indicates that one of K. olearia's strategies for low temperature growth is increased copy number of some typical cold response genes through duplication and/or lateral acquisition. At 77 degrees C one-third of the up-regulated genes are of hypothetical function, indicating that many features of high-temperature growth are unknown. PMID- 28894933 TI - Particulate versus non-particulate corticosteroids for transforaminal nerve root blocks: Comparison of outcomes in 494 patients with lumbar radiculopathy. AB - PURPOSE: We set out to compare outcomes in CT-guided lumbar transforaminal nerve root block patients receiving either particulate or non-particulate corticosteroids. MATERIALS AND METHODS: This was a retrospective comparative effectiveness outcomes study on two cohorts of lumbar radiculopathy patients. 321 received particulate and 173 non-particulate corticosteroids at CT-guided transforaminal lumbar nerve root injections. The particulate steroid was used from October 2009 until May 2014 and the non-particulate steroid was used from May 2014. Pain levels were collected at baseline using an 11-point numerical rating scale (NRS) and at 1 day, 1 week and 1 month. Overall 'improvement' was assessed using the Patients' Global Impression of Change (PGIC) at these same time points (primary outcome). The proportions of patients 'improved' were compared between the two groups using the Chi-square test. The NRS change scores were compared using the unpaired t-test. RESULTS: A significantly higher proportion of patients treated with particulate steroids were improved at 1 week (43.2 % vs. 27.7 %, p = 0.001) and at 1 month (44.3 % vs. 33.1 %, p = 0.019). Patients receiving particulate steroids also had significantly higher NRS change scores at 1 week (p = 0.02) and 1 month (p = 0.007). CONCLUSION: Particulate corticosteroids have significantly better outcomes than non-particulate corticosteroids. KEY POINTS: * Better pain relief is achieved with particulate steroids. * Significantly more patients report overall 'improvement' with particulate steroids. * Significantly more patients report 'worsening' at 1 week with non-particulate steroids. PMID- 28894934 TI - Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease. AB - Prognosis of metastatic melanoma improved with the development of checkpoint inhibitors. The role of tumor infiltrating lymphocytes (TILs) in lymph node metastases of stage III melanoma remains unclear. We retrospectively characterized TILs in primary melanomas and matched lymph node metastases (stage III melanoma) of patients treated with the checkpoint inhibitor ipilimumab. Tumor infiltrating lymphocytes were characterized for CD3, CD4, and CD8 expressions by immunohistochemistry. 4/9 patients (44%) responded to treatment with ipilimumab (1 complete and 2 partial remissions, 1 stable disease). All responders exhibited CD4 and CD8 T-cell infiltration in their lymph node metastases, whereas all non responders did not show an infiltration of the lymph node metastasis with TILs. The correlation between the presence and absence of TILs in responders vs. non responders was statistically significant (p = 0.008). Median distant metastases free survival, i.e., progression from stage III to stage IV melanoma, was similar in responders and non-responders (22.1 vs. 19.3 months; p = 0.462). Median progression free and overall survival show a trend in favor of the patients having TIL rich lymph node metastases (6.8 vs. 3.3 months, p = 0.09; and all alive at last follow-up vs. 8.2 months, respectively, p = 0.08). Our data suggest a correlation between the T-cell infiltration of the lymph node metastases in stage III melanoma and the response to ipilimumab once these patients progress to stage IV disease. PMID- 28894936 TI - Thermal ablation of thyroid nodules: are radiofrequency ablation, microwave ablation and high intensity focused ultrasound equally safe and effective methods? AB - OBJECTIVES: This study compares volume reduction of benign thyroid nodules three months after Radiofrequency Ablation (RFA), Microwave Ablation (MWA) or High Intensity Focused Ultrasound (HIFU) to evaluate which of these methods is the most effective and safe alternative to thyroidectomy or radioiodine therapy. MATERIAL AND METHODS: Ninety-four patients (39 male, 55 female) with a total of 118 benign, symptomatic thyroid nodules were divided into three subgroups. HIFU was applied to 14 patients with small nodules. The other 80 patients were divided up into two groups of 40 patients each for RFA and MWA in the assumption that both methods are comparable effective. The pre-ablative and post-ablative volume was measured by ultrasound. RESULTS: RFA showed a significant volume reduction of nodules of 50 % (p<0.05), MWA of 44 % (p<0.05) and HIFU of 48 % (p<0.05) three months after ablation. None of the examined ablation techniques caused serious or permanent complications. CONCLUSION: RFA, MWA and HIFU showed comparable results considering volume reduction. All methods are safe and effective treatments of benign thyroid nodules. KEY POINTS: * Thermal Ablation can be used to treat benign thyroid nodules * Thermal Ablation can be an alternative to thyroidectomy or radioiodine therapy * Radiofrequency Ablation, Microwave Ablation, High Intensity Focused Ultrasound are safe and effective. PMID- 28894935 TI - Tissue compartmentalization of T cell responses during early life. AB - The immune system in early life is tasked with transitioning from a relatively protected environment to one in which it encounters a wide variety of innocuous antigens and dangerous pathogens. The immaturity of the developing immune system, and particularly the distinct functionality of T lymphocytes in early life, has been implicated in increased susceptibility to infection. Previous work has demonstrated that immune responses in early life are skewed toward limited inflammation and atopy; however, there is mounting evidence that such responses are context- and tissue-dependent. The regulation, differentiation, and maintenance of infant T cell responses, particularly as it relates to tissue compartmentalization, remains poorly understood. How the tissue environment impacts early-life immune responses and whether the development of localized protective immune memory cell subsets are established is an emerging area of research. As infectious diseases affecting the respiratory and digestive tracts are a leading cause of morbidity and mortality worldwide in infants and young children, a deeper understanding of site-specific immunity is essential to addressing these challenges. Here, we review the current paradigms of T cell responses during infancy as they relate to tissue localization and discuss implications for the development of vaccines and therapeutics. PMID- 28894937 TI - Gadoxetate disodium-induced tachypnoea and the effect of dilution method: a proof of-concept study in mice. AB - OBJECTIVES: To directly investigate the rapid respiratory effect of gadoxetate disodium in an experimental study using mice. METHODS: After confirming the steady respiratory state under general anaesthesia, eight mice were injected with all test agents in the following order: phosphate-buffered saline (A, control group), 1.25 mmol/kg of gadoteridol (B) or gadopentetate dimeglumine (C), or 0.31 mmol/kg of gadoxetate disodium (D, E). The experimenter was not blinded to the agents. The injection dose was fixed as 100 MUL for Groups A-D and 50 MUL for Group E. We continuously monitored and recorded respiratory rate (RR), peripheral oxygen saturation (SpO2), and heart rate. The time-series changes from 0 to 30 s were compared by the linear mixed method RESULTS: Groups D and E showed the largest RR increase (20.6 and 20.3 breaths/min, respectively) and were significantly larger compared to Group A (3.36 breaths/min, both P<0.001). RR change of Groups D and E did not differ. RR change of Groups B and C was smaller (0.72 and 12.4 breaths/min, respectively) and did not differ statistically with Group A. Significant bradycardia was observed only in Group C (P<0.001). SpO2 was constant in all groups. CONCLUSIONS: Gadoxetate disodium causes a rapid tachypnoea without significant change of SpO2 and heart rate regardless of the dilution method. KEY POINTS: * Injection of gadoxetate disodium causes tachypnoea. * Dilution method did not alter the rapid respiratory effect of gadoxetate disodium. * The respiratory effect of gadoxetate disodium was larger than other contrast agents. PMID- 28894938 TI - Development of a new host-vector system for colour selection of cloned DNA inserts using a newly designed beta-galactosidase gene containing multiple cloning sites in Thermus thermophilus HB27. AB - We constructed a new Thermus thermophilus cloning vector which enables the colour selection of cloned DNA inserts in the T. thermophilus HB27 host strain (beta-gal ) on growth plates containing 3,4-cyclohexenoesculetin beta-D-galactopyranoside (S-gal) in the medium. This vector harbors a modified beta-galactosidase gene (TTP0042 of T. thermophilus HB27) with 12 unique restriction enzyme sites (Acc65I, AvrII, BlpI, BssHII, EcoRI, EcoRV, HindIII, NruI, SalI, SpeI, SphI and XbaI) as multiple cloning sites under the control of the T. thermophilus slpA promoter. This host-vector system facilitates cloning procedures in T. thermophilus HB27. PMID- 28894939 TI - Identification and characterization of novel broad-spectrum amino acid racemases from Escherichia coli and Bacillus subtilis. AB - The peptidoglycan layer of the bacterial cell wall typically contains D-alanine (D-Ala) and D-glutamic acid (D-Glu), and also various non-canonical D-amino acids that have been linked to peptidoglycan remodeling, inhibition of biofilm formation, and triggering of biofilm disassembly. Bacteria produce D-amino acids when adapting to environmental changes as a common survival strategy. In our previous study, we detected non-canonical D-amino acids in Escherichia coli grown in minimal medium. However, the biosynthetic pathways of non-canonical D-amino acids remain poorly understood. In the present study, we identified amino acid racemases in E. coli MG1655 (YgeA) and Bacillus subtilis (RacX) that produce non canonical D-amino acids other than D-Ala and D-Glu. We characterized their enzymatic properties, and both displayed broad substrate specificity but low catalytic activity. YgeA preferentially catalyzes the racemization of homoserine, while RacX preferentially racemizes arginine, lysine, and ornithine. RacX is dimeric, and appears not to require pyridoxal 5'-phosphate (PLP) as a coenzyme as is the case with YgeA. To our knowledge, this is the first report on PLP independent amino acid racemases possessing broad substrate specificity in E. coli and B. subtilis. PMID- 28894940 TI - Creatinine-based estimated glomerular filtration rate for children younger than 2 years. PMID- 28894941 TI - Evolutionary coincidence of adaptive changes in exuperantia and the emergence of bicoid in Cyclorrhapha (Diptera). AB - The great radiation in the infraorder Cyclorrhapha involved several morphological and molecular changes, including important changes in anterior egg development. During Drosophila oogenesis, exuperantia (exu) is critical for localizing bicoid (bcd) messenger RNA (mRNA) to the anterior region of the oocyte. Because it is phylogenetically older than bcd, which is exclusive to Cyclorrhapha, we hypothesize that exu has undergone adaptive changes to enable this new function. Although exu has been well studied in Drosophila, there is no functional or transcriptional information about it in any other Diptera. Here, we investigate exu in the South American fruit fly Anastrepha fraterculus, a Cyclorrhapha of great agricultural importance that have lost bcd, aiming to understand the evolution of exu in this infraorder. We assessed its pattern of gene expression in A. fraterculus by analyzing transcriptomes from cephalic and reproductive tissues. A combination of next-generation data with classical sequencing procedures enabled identification of the structure of exu and its alternative transcripts in this species. In addition to the sex-specific isoforms described for Drosophila, we found that not only exu is expressed in heads, but this is mediated by two transcripts with a specific 5'UTR exon-likely a result from usage of a third promoter. Furthermore, we tested the hypothesis that exu is evolving under positive selection in Cyclorrhapha after divergence from lower Diptera. We found evidence of positive selection at two important exu domains, EXO-like and SAM-like, both involved with mRNA binding during bcd mRNA localization in Drosophila, which could reflect its cooptation for the new function of bcd mRNA localization in Cyclorrhapha. PMID- 28894942 TI - First Steps Towards Development of an Instrument for the Reproducible Quantification of Oropharyngeal Swallow Physiology in Bottle-Fed Children. AB - The incidence of feeding/swallowing impairments (deglutition disorders) in young children is rising and poses serious acute and long-term health consequences. Accurate detection and prompt intervention can lessen the impact of dysphagia induced sequelae. Videofluoroscopic Swallow Studies (VFSSs) are used to make critical decisions for medically fragile children despite procedural variability and the lack of agreed upon measures for interpreting and reporting results. This investigation represents the first steps in the development of a novel tool for the quantification of oropharyngeal swallow physiology from full-length VFSS examinations in bottle-fed children. The Modified Barium Swallow Impairment Profile MBSImPTM(c) served as the conceptual assessment model for development of components and operational score variants to characterize distinguishable VFSS observations. Twenty-four components of swallowing physiology were validated via expert consensus. Training materials included a library of 94 digitized video images comprised of distinct score variants for each component. Materials were disseminated to seven speech-language pathologists (SLPs) who participated in didactic and self-training sessions, and rated components. All SLPs achieved >=80% reliability criterion after completing two or three training sessions. Agreement for 17 (71%) components was achieved after two sessions. Nutritive sucking/oral and airway-related components were most difficult to distinguish. Three sessions were required for 2 (33%) of the sucking/oral components and 4 (57%) of the airway-related components. These findings support the feasibility to standardize training and reliably score swallowing physiology using precise definitions and unambiguous visual images, and represent preliminary steps towards content validity and reliability of a standardized VFSS tool for bottle fed children. PMID- 28894943 TI - Swirl sign in traumatic acute epidural hematoma: prognostic value and surgical management. AB - The swirl sign is identified as a small area of low attenuation within an intracranial hyperattenuating clot on non-enhanced computed tomography (CT) scans of the brain, which represents active bleeding. The purpose of this study was to evaluate the incidence of the swirl sign among patients with acute epidural hematoma (AEDH) and to identify its prognostic value and impact on surgical treatment. A retrospective review was performed of patients with a diagnosis of traumatic EDH by CT scan who were surgically treated at the Department of Neurosurgery of the First People's Hospital of Jingmen between January 2010 and January 2014. Patients with combined or open craniocerebral injuries and those who did not undergo surgical treatment were excluded. Of the 147 patients evaluated, 21 (14%) exhibited the swirl sign on non-enhanced CT scans of the brain. Univariate analysis revealed a significant correlation between the occurrence of the swirl sign and preoperative Glasgow coma scale scores, preoperative mydriasis, time from injury to CT scan, and intraoperative hematoma volume. Compared with patients without this sign, those exhibiting the swirl sign had a higher mortality rate (24 vs. 6%, respectively; P = 0.028) and a worse outcome (Glasgow Outcome Scale score <= 3: 38 vs. 15%, respectively; P = 0.027) at 3 months. An adjusted analysis showed that the occurrence of the swirl sign was an independent predictor of poor outcome (death: odds ratio (OR) = 4.61; 95% confidence interval (CI): 1.34-15.82; P < 0.05; 3-month Glasgow Outcome Scale score <= 3: OR = 3.47; 95% CI: 1.27-9.49; P < 0.05). In conclusion, the occurrence of the swirl sign on the head CT scan of patients with AEDH was found to be significantly associated with poor outcome. Therefore, early identification of this sign and aggressive management with early surgical evacuation is crucial for improving patient outcome. PMID- 28894944 TI - Higher out-of-pocket expenses for tyrosine kinase-inhibitor therapy is associated with worse health-related quality-of-life in persons with chronic myeloid leukemia. AB - PURPOSE: To explore health-related quality-of-life (HRQoL) profiles and identify socio-demographic and clinical variables associated with HRQoL in persons with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). METHODS: A cross-sectional questionnaire was distributed to adults with chronic phase CML receiving tyrosine kinase-inhibitor (TKI) therapy >3 months in complete cytogenetic response (CCyR). Respondents were anonymous. SF-36 Health Survey was used to measure HRQoL. RESULTS: Data from 828 respondents were analyzable. 524 (63%) were male. Median age was 42 years (range 18-88 years). 648 (78%) were receiving imatinib. Median TKI-therapy duration was 36 months (range 3-178 months). 638 (77%) paid some or all of their TKI costs. Annual out-of-pocket expenses >$4600 USD was associated with lower physical component summary (PCS; 2.8 to -3.8; P = 0.0081 and 0.0009) and mental component summary (MCS; -2.1 to 4.3; P = 0.0394 and 0.0080) in multivariate analyses. Other variables significantly associated with a lower PCS and/or MCS included: (1) female sex; (2) increasing age; (3) education level < bachelor degree; (4) co-morbidity(ies); and (5) generic drug use. TKI-therapy duration 3-5 years was associated with higher PCS and MCS. CONCLUSIONS: Higher out-of-pocket expense for TKI therapy is significantly associated with worse HRQoL in persons with chronic-phase CML in CCyR receiving TKI therapy. These data indicate the importance of drug cost and health insurance policies on people's HRQoL. PMID- 28894945 TI - A tabersonine 3-reductase Catharanthus roseus mutant accumulates vindoline pathway intermediates. AB - MAIN CONCLUSION: Monoterpenoid indole alkaloids (MIAs) have remarkable biological properties that have led to their medical uses for a variety of human diseases. Mutagenesis has been used to generate plants with new alkaloid profiles and a useful screen for rapid comparison of MIA profiles is described. The MIA mutants identified are useful for investigating MIA biosynthesis and for targeted production of these specialised metabolites. The Madagascar periwinkle (Catharanthus roseus) is the sole source of the dimeric anticancer monoterpenoid indole alkaloids (MIAs), 3',4'-anhydrovinblastine and derivatives, which are formed via the coupling of the MIAs, catharanthine and vindoline. While intense efforts to identify parts of the complex pathways involved in the assembly of these dimers have been successful, our understanding of MIA biochemistry in C. roseus remains limited. A simple thin layer chromatography screen of 4000 ethyl methanesulfonate-metagenized M2 plants is described to identify mutant lines with altered MIA profiles. One mutant (M2-1865) accumulated reduced levels of vindoline inside the leaves in favour of high levels of tabersonine-2,3-epoxide and 16-methoxytabersonine-2,3-epoxide on the leaf surface. This MIA profile suggested that changes in tabersonine 3-reductase (T3R) activity might be responsible for the observed phenotype. Molecular cloning of mutant and wild type T3R revealed two nucleotide substitutions at cytosine residues 565 (CAT to TAT) and 903 (ACC to ACA) in the mutant corresponding to substitution (H189Y) and silent (T305T) amino acid mutations, respectively, in the protein. The single amino acid substitution in the mutant T3R protein diminished the biochemical activity of T3R by 95% that explained the reason for the low vindoline phenotype of the mutant. This phenotype was recessive and exhibited standard Mendelian single-gene inheritance. The stable formation and accumulation of epoxides in the M2-1865 mutant provides a dependable biological source of these two MIAs. PMID- 28894947 TI - Thalamic transitory ischemic attacks presenting as Jacksonian sensory march. AB - Spreading somatosensory symptoms appearing as Jacksonian sensory march are usually considered to be due to an epileptic seizure. We report on three cases in which these symptoms were caused by thalamic ischemia. Two patients presented with stereotypically recurring hemiparesthesias lasting 2-5 min that gradually spread from the face to the arm and leg on one side. A first cerebral magnetic resonance imaging including DWI was negative in both cases, whereas new thalamic infarctions appeared on repeated imaging when clinical symptoms remained. A third case with a thalamic ischemia did not show recurring events, but also presented with purely sensory spreading symptoms. In all three cases EEG and cardiovascular diagnostics revealed normal results. Pure sensory stroke has previously been described as a result of ischemia of the thalamus or the internal capsule presenting as a sudden onset hemisensory deficit, but spreading symptoms have rarely been reported. According to our observations, thalamic TIAs are an important differential diagnosis of somatosensory epileptic auras presenting with Jacksonian sensory march which require a different clinical management. PMID- 28894946 TI - An international SUrvey on non-iNvaSive tecHniques to assess the mIcrocirculation in patients with RayNaud's phEnomenon (SUNSHINE survey). AB - To canvas opinion concerning the role of non-invasive techniques in the assessment of patients with Raynaud's phenomenon (Rp) in clinical and research settings: four nailfold capillaroscopy methods [videocapillaroscopy (NVC), dermoscopy, stereomicroscopy, digital USB microscopy], four laser Doppler methods (laser Doppler flowmetry, imaging, anemometry/velocimetry, laser speckle contrast analysis), thermographic imaging, and upper limb arterial Doppler ultrasound. Emails with a link to the survey were sent to physicians from the European Scleroderma Trials and Research group (EUSTAR), the EULAR Study Group on Microcirculation in Rheumatic Diseases (SG_MC/RD) and members of the pediatric rheumatology Email board. The main descriptive analysis related to physicians looking after adult patients, with some analysis also of opinions from paediatric rheumatologists. 106 'adult physicians' responded (a response rate of 25.8%), of whom 68.9% were European, and 81.1% practising for more than 10 years. Nineteen paediatricians responded. The most widely available technique was NVC (72.7%). Nailfold capillaroscopy was most frequently performed by the physician him/herself, using different types of equipment relating to availability. Most rheumatologists reported high levels of appropriateness for NVC in both clinical and research settings for global assessment and differential diagnosis of Rp. Other techniques were less used. Of all the different techniques, nailfold capillaroscopy was the one most used in both clinical and research settings by adult physicians, the majority of whom use NVC in their everyday practice. The low proportion of clinicians using other techniques suggests that these are currently mainly research tools, available only in specialist centres. PMID- 28894948 TI - Cardiorespiratory fitness and inflammatory profile on cardiometabolic risk in adolescents from the LabMed Physical Activity Study. AB - PURPOSE: We investigated the combined effect of cardiorespiratory fitness and the clustered score of inflammatory biomarkers (InflaScore) on the cardiometabolic risk score in adolescents. METHODS: This is a cross-sectional analysis with 529 adolescents (267 girls) aged 12-18 years. The shuttle run test was used to assess cardiorespiratory fitness. Continuous scores of clustered inflammatory biomarkers (high sensitivity C-reactive protein, complement factors C3 and C4, fibrinogen and leptin); cardiometabolic risk score (systolic blood pressure, triglycerides, ratio total cholesterol/HDL, HOMA-IR and waist circumference) were computed. RESULTS: Adolescents with a higher inflammatory profile had the highest cardiometabolic risk score; adolescents with high InflaScore and low fitness had the highest odds of having a high cardiometabolic risk (OR 16.5; 95% CI 7.8 34.5), followed by adolescents with a higher InflaScore but fit (OR 7.5; 95% CI 3.7-8.4), and then by adolescents with a low InflaScore and unfit (OR 3.7; 95% CI 1.6-8.4) when compared to those with low InflaScore and fit, after adjustments for age, sex, pubertal stage, adherence to a Mediterranean dietary pattern and socioeconomic status. CONCLUSIONS: The findings of our study suggest that the combination of high inflammatory state and low cardiorespiratory fitness is synergistically associated with a significantly higher cardiometabolic risk score and thus supports the relevance of early targeted interventions to promote physical activity and preservation as part of primordial prevention. PMID- 28894949 TI - Diet and feeding ecology of the western hoolock gibbon (Hoolock hoolock) in a tropical forest fragment of Northeast India. AB - Forest fragmentation alters plant species diversity and composition, and causes diverse affects on the feeding behavior of wild primates. We investigated the feeding behavior and diet of two groups of western hoolock gibbon (Hoolock hoolock) inhabiting a small isolated forest patch (21 km2) in Hollongapar Gibbon Wildlife Sanctuary, Assam, Northeast India, over a year using focal animal sampling. H. hoolock adults spent, on average, 35.2% of their total annual activity budget on feeding, and fed on young leaves, mature leaves, flowers, fruits, petioles, buds and also on animal matter. There was marked seasonal variation in the proportions of the dietary items consumed. Fruits accounted for an average of 51% (range 34-71% per month) of feeding time over the year. This highly frugivorous diet may limit the ability of the species to survive in small and disturbed forest fragments. A total of 54 plant species (32 families) were consumed by the focal groups during the study period, but there were variations between months in the selection of these plant species. Non-tree species such as lianas were among the most highly selected species in the diet. Moraceae, comprising ten species, was the most dominant family among the food plants, accounting for 36% of annual feeding time. The present study presents quantitative and qualitative data on dietary composition, preference and selection of food plants of H. hoolock in a fragmented habitat, which can contribute to the restoration and manipulation of degraded habitats of H. hoolock. PMID- 28894950 TI - Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis. AB - BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients. METHODS: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD. RESULTS: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients. CONCLUSIONS: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD. PMID- 28894951 TI - Structural and functional characterization of mercuric reductase from Lysinibacillus sphaericus strain G1. AB - In response to the widespread presence of inorganic Hg in the environment, bacteria have evolved resistance systems with mercuric reductase (MerA) as the key enzyme. MerA enzymes have still not been well characterized from gram positive bacteria. Current study reports physico-chemical, kinetic and structural characterization of MerA from a multiple heavy metal resistant strain of Lysinibacillus sphaericus, and discusses its implications in bioremediation application. The enzyme was homodimeric with subunit molecular weight of about 60 kDa. The Km and Vmax were found to be 32 uM of HgCl2 and 18 units/mg respectively. The enzyme activity was enhanced by beta-mercaptoethanol and NaCl up to concentrations of 500 uM and 100 mM respectively, followed by inhibition at higher concentrations. The enzyme showed maximum activity in the pH range of 7 7.5 and temperature range of 25-50 degrees C, with melting temperature of 67 degrees C. Cu2+ exhibited pronounced inhibition of the enzyme with mixed inhibition pattern. The enzyme contained FAD as the prosthetic group and used NADPH as the preferred electron donor, but it showed slight activity with NADH as well. Structural characterization was carried out by circular dichroism spectrophotometry and X-ray crystallography. X-ray confirmed the homodimeric structure of enzyme and gave an insight on the residues involved in catalytic binding. In conclusion, the investigated enzyme showed higher catalytic efficiency, temperature stability and salt tolerance as compared to MerA enzymes from other mesophiles. Therefore, it is proposed to be a promising candidate for Hg2+ bioremediation. PMID- 28894952 TI - Characterization of brain tumours with spin-spin relaxation: pilot case study reveals unique T 2 distribution profiles of glioblastoma, oligodendroglioma and meningioma. AB - Prolonged spin-spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted. PMID- 28894953 TI - Significant genetic association of a functional TFPI variant with circulating fibrinogen levels and coronary artery disease. AB - The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P = 0.017 under a recessive model), but not with PT, APTT or TT (P > 0.05). Using a large case-control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD. PMID- 28894954 TI - Maternal allocation of carotenoids increases tolerance to bacterial infection in brown trout. AB - Life-history theory predicts that iteroparous females allocate their resources differently among different breeding seasons depending on their residual reproductive value. In iteroparous salmonids there is typically much variation in egg size, egg number, and in the compounds that females allocate to their clutch. These compounds include various carotenoids whose functions are not sufficiently understood yet. We sampled 37 female and 35 male brown trout from natural streams, collected their gametes for in vitro fertilizations, experimentally produced 185 families in 7 full-factorial breeding blocks, raised the developing embryos singly (n = 2960), and either sham-treated or infected them with Pseudomonas fluorescens. We used female redness (as a measure of carotenoids stored in the skin) and their allocation of carotenoids to clutches to infer maternal strategies. Astaxanthin contents largely determined egg colour. Neither egg weight nor female size was correlated with the content of this carotenoid. However, astaxanthin content was positively correlated with larval growth and with tolerance against P. fluorescens. There was a negative correlation between female skin redness and the carotenoid content of their eggs. Although higher astaxanthin contents in the eggs were associated with an improvement of early fitness-related traits, some females appeared not to maximally support their current offspring as revealed by the negative correlation between female red skin colouration and egg carotenoid content. This correlation was not explained by female size and supports the prediction of a maternal trade-off between current and future reproduction. PMID- 28894955 TI - A flexible cell concentrator using inertial focusing. AB - Cell concentration adjustment is intensively implemented routinely both in research and clinical laboratories. Centrifuge is the most prevalent technique for tuning biosample concentration. But it suffers from a number of drawbacks, such as requirement of experienced operator, high cost, low resolution, variable reproducibility and induced damage to sample. Herein we report on a cost efficient alternative using inertial microfluidics. While the majority of existing literatures concentrate on inertial focusing itself, we identify the substantial role of the outlet system played in the device performance that has long been underestimated. The resistances of the outlets virtually involve in defining the cutoff size of a given inertial filtration channel. Following the comprehensive exploration of the influence of outlet system, we designed an inertial device with selectable outlets. Using both commercial microparticles and cultured Hep G2 cells, we have successfully demonstrated the automated concentration modification and observed several key advantages of our device as compared with conventional centrifuge, such as significantly reduced cell loss (only 4.2% vs. ~40% of centrifuge), better preservation of cell viability and less processing time as well as the increased reproducibility due to absence of manual operation. Furthermore, our device shows high effectiveness for concentrated sample (e.g., 1.8 * 106 cells/ml) as well. We envision its promising applications in the circumstance where repetitive sample preparation is intensely employed. PMID- 28894956 TI - The effect of laser power, blood perfusion, thermal and optical properties of human liver tissue on thermal damage in LITT. AB - In this work, the finite-element method (FEM) was used to predict the temperature distribution, and the thermal damage volume in human liver tissue subjected to laser in laser-induced interstitial thermotherapy (LITT). The effect of laser power, blood perfusion, and thermal and optical properties on maximum temperature and thermal damage volume were predicted using the finite-element method. A computer program was written in visual basic language, which was verified by comparing its result with data published elsewhere. The bio-heat equation together with the effect of linear laser source were used to simulate heat transfer through tissue from which the temperature distributions, and the subsequent thermal damage, were obtained based on Arrhenius equation. In this mathematical model for LITT, it was found that increasing laser power, absorption, and scattering coefficient increased the damage zone while increasing tissue water content, perfusion rate, and tissue anisotropy factor decreased the damage zone. These findings are important aspects for doctors in the pre estimation of the damage zone before starting the therapy so as to kill only the desired zone. PMID- 28894958 TI - Attitude Toward One's Circumcision Status Is More Important than Actual Circumcision Status for Men's Body Image and Sexual Functioning. AB - Research exploring the impact of circumcision on the sexual lives of men has failed to consider men's attitudes toward their circumcision status, which may, in part, help to explain inconsistent findings in the literature. The current study explored the potential relationship between attitudinal factors toward one's circumcision status, timing of one's circumcision, and sexual correlates. A total of 811 men (367 circumcised as neonates, 107 circumcised in childhood, 47 circumcised in adulthood, and 290 intact) aged 19-84 years (M = 33.02, SD = 12.54) completed an online survey. We assessed attitudes toward one's circumcision status, three domains of body image (Male Genital Image Scale, Body Exposure during Sexual Activities Questionnaire, Body Image Satisfaction Scale), and self-reported sexual functioning (International Index of Erectile Function). Men who were circumcised as adults or intact men reported higher satisfaction with their circumcision status than those who were circumcised neonatally or in childhood. Lower satisfaction with one's circumcision status-but not men's actual circumcision status-was associated with worse body image and sexual functioning. These findings identify the need to control for attitudes toward circumcision status in the study of sexual outcomes related to circumcision. Future research is required to estimate the number of men who are dissatisfied with their circumcision status, to explore the antecedents of distress in this subpopulation, and to understand the extent of negative sexual outcomes associated with these attitudes. PMID- 28894957 TI - Efficacy of a multidisciplinary pulmonary rehabilitation outpatient program on exacerbations in overweight and obese patients with asthma. AB - BACKGROUND: Even though many studies have investigated the effectiveness of weight loss interventions, the efficacy of pulmonary rehabilitation (PR) has not yet been proven in obese patients with asthma. The aims of this study were to investigate the efficacy of PR on asthma exacerbations in the first year after PR and to evaluate the efficacy of PR in exercise capacity, quality of life, psychosocial symptoms and control of asthma in overweight patients. METHODS: The exercise capacity, health-related quality of life scores, psychosocial symptoms, asthma control test (ACT) data, number of emergency admissions and hospitalizations of 35 overweight patients with asthma who completed a 1-year multidisciplinary PR program were recorded and analyzed. RESULTS: Of the participants 30 were female, the mean age was 45 +/- 9 years, 13 (37%) patients were overweight and 22 (63%) were obese. The average number of emergency admissions (from 1.2 +/- 1.1 to 0.3 +/- 0.8) and hospitalizations (from 0.6 +/- 0.9 to 0.0 +/- 0.1) decreased significantly 1 year after PR (both p<0.001). After PR, statistically significant improvements in exercise capacity as measured by the incremental shuttle walking test (ISWT) from 281 +/- 104 m to 339 +/- 95 m (p < 0.001), the endurance shuttle walking test (ESWT) from 13.3 +/- 7.4 min to 17.5 +/- 4.5 min (p = 0.005), quality of life measured by the St. George's respiratory questionnaire (SGRQ total from 64 +/- 14 to 28 +/- 10, p < 0.001), dyspnea sensation with the Medical Research Council (MRC) scale (from 2.6 +/- 0.6 to 2.1 +/- 0.4, p <0.001) and hospital anxiety depression scores (HADS, anxiety score from 9.9 +/- 1.6 to 7.1 +/- 2.1, depression score from 9.4 +/- 1.9 to 7.2 +/- 2.3, both p < 0.001) were found. A reduction in body mass index (BMI) was found in obese patients only, but the fat-free mass index (FFMI) improved in both overweight and obese patients (from 19.00 +/- 1.90 to 19.45 +/- 2.04, p = 0.01). The mean ACT score increased significantly (from 18 to 21 points, p < 0.001). The number of patients with poorly controlled asthma decreased from 21 (60%) to 10 (28%). CONCLUSION: This study showed that comprehensive multidisciplinary PR was associated with a decreased number of emergency admissions and hospitalizations for asthma exacerbations in 1 year, and improvements of dyspnea sensation, quality of life, exercise capacity, and psychosocial status in overweight and obese patients. PMID- 28894959 TI - Variation in phenology and density differentially affects predator-prey interactions between salamanders. AB - Variation in the timing of breeding (i.e., phenological variation) can affect species interactions and community structure, in part by shifting body size differences between species. Body size differences can be further altered by density-dependent competition, though synergistic effects of density and phenology on species interactions are rarely evaluated. We tested how field realistic variation in phenology and density affected ringed salamander (Ambystoma annulatum) predation on spotted salamanders (Ambystoma maculatum), and whether these altered salamander dynamics resulted in trophic cascades. In outdoor mesocosms, we experimentally manipulated ringed salamander density (low/high) and breeding phenology (early/late) of both species. Ringed salamander body size at metamorphosis, development, and growth were reduced at higher densities, while delayed phenology increased hatchling size and larval development, but reduced relative growth rates. Survival of ringed salamanders was affected by the interactive effects of phenology and density. In contrast, spotted salamander growth, size at metamorphosis, and survival, as well as the biomass of lower trophic levels, were negatively affected primarily by ringed salamander density. In an additional mesocosm experiment, we isolated whether ringed salamanders could deplete shared resources prior to their interactions with spotted salamanders, but instead found direct interactions (e.g., predation) were the more likely mechanism by which ringed salamanders limited spotted salamanders. Overall, our results indicate the effects of phenological variability on fitness-related traits can be modified or superseded by differences in density dependence. Identifying such context dependencies will lead to greater insight into when phenological variation will likely alter species interactions. PMID- 28894960 TI - Cadmium effects on some energy metabolism variables in Cnesterodon decemmaculatus adults. AB - This work is focused on the responses of some energy metabolism variables in Cnesterodon decemmaculatus adults exposed to cadmium under controlled laboratory conditions. This species has been used as bioindicator for evaluating the effects of different chemicals on diverse biological processes and is frequently used as test organism in ecotoxicity studies that include cadmium as reference toxicant. Animals were exposed for 12 days to the following concentrations: 0, 0.45, and 0.8 mg Cd/L. Food intake, fecal production, specific assimilation, condition factor, mortality percentage, oxygen consumption, oxygen extraction efficiency, specific metabolic rate, ammonia excretion, and ammonia quotient were measured. The overall balance was expressed as scope for growth (SFG). Cadmium-exposed groups showed a significant decrease in food assimilation and condition factor at the end of the exposure. There was an increase in specific metabolic rate and a decrease in SFG in the group exposed to 0.8 mg Cd/L. The condition factor and the SFG appeared as sensitive biomarkers of health status and growth of the animals, respectively. Cadmium-exposed fish reduced food intake, which was reflected in a decreased assimilation with concomitant decline in the external energy supply from feeding. Our results highlight the importance of considering the metabolic status of the test organisms when analyzing the responses of the biomarkers usually used as effect parameters in ecotoxicological evaluations under experimental conditions. PMID- 28894961 TI - Digital soil mapping using remote sensing indices, terrain attributes, and vegetation features in the rangelands of northeastern Iran. AB - Digital soil mapping has been introduced as a viable alternative to the traditional mapping methods due to being fast and cost-effective. The objective of the present study was to investigate the capability of the vegetation features and spectral indices as auxiliary variables in digital soil mapping models to predict soil properties. A region with an area of 1225 ha located in Bajgiran rangelands, Khorasan Razavi province, northeastern Iran, was chosen. A total of 137 sampling sites, each containing 3-5 plots with 10-m interval distance along a transect established based on randomized-systematic method, were investigated. In each plot, plant species names and numbers as well as vegetation cover percentage (VCP) were recorded, and finally one composite soil sample was taken from each transect at each site (137 soil samples in total). Terrain attributes were derived from a digital elevation model, different bands and spectral indices were obtained from the Landsat7 ETM+ images, and vegetation features were calculated in the plots, all of which were used as auxiliary variables to predict soil properties using artificial neural network, gene expression programming, and multivariate linear regression models. According to R 2 RMSE and MBE values, artificial neutral network was obtained as the most accurate soil properties prediction function used in scorpan model. Vegetation features and indices were more effective than remotely sensed data and terrain attributes in predicting soil properties including calcium carbonate equivalent, clay, bulk density, total nitrogen, carbon, sand, silt, and saturated moisture capacity. It was also shown that vegetation indices including NDVI, SAVI, MSAVI, SARVI, RDVI, and DVI were more effective in estimating the majority of soil properties compared to separate bands and even some soil spectral indices. PMID- 28894963 TI - Efficacy of hemofiltration with PEPA membrane for IL-6 removal in a rat sepsis model. AB - Recently, intensive care physicians have focused on continuous hemodiafiltration with a cytokine-adsorbing hemofilter in the treatment of sepsis. We aimed to establish extracorporeal circulation in a rat sepsis model to evaluate the cytokine removal properties of mini-modules using two types of membrane materials. Rats were divided into polyester polymer alloy (PEPA) and cellulose triacetate (CTA) groups as membrane materials of mini-modules. One hour after 0.1 mg/kg of lipopolysaccharide administration, continuous hemofiltration (CHF) was started in each group. Plasma interleukin-6 (IL-6), an important mediator of sepsis, was measured over time during hemofiltration. The peak IL-6 concentration in PEPA group was approximately 13,000 pg/mL, in comparison to approximately 31,000 pg/mL in CTA group. IL-6 clearance in PEPA group was much more than CTA group. Since IL-6 was not detected in the filtrate in PEPA group, it was considered that IL-6 was adsorbed to the membrane. In conclusion, our results suggest that CHF with PEPA hemofilter can be suitable for removing IL-6 from the blood stream efficiently. PMID- 28894962 TI - Ring chromosomes: from formation to clinical potential. AB - Ring chromosomes (RCs) are circular DNA molecules, which occur rarely in eukaryotic nuclear genomes. Lilian Vaughan Morgan first described them in the fruit fly. Human embryos very seldom have RCs, about 1:50,000. Carriers of RCs may have varying degrees of symptoms, from healthy phenotype to serious pathologies in physical and intellectual development. Many authors describe common symptoms of RC presence: short stature and some developmental delay that could be described as a "ring chromosome syndrome." As a rule, RCs arise de novo through the end-joining of two DNA double-strand breaks, telomere-subtelomere junction, or inv dup del rearrangement in both meiosis and mitosis. There are family cases of RC inheritance. The presence of RCs causes numerous secondary chromosome rearrangements in vivo and in vitro. RCs can change their size, become lost, or increase their copy number and cause additional deletions, duplication, and translocations, affecting both RCs and other chromosomes. In this review, we examine RC inheritance, instability, mechanisms of formation, and potential clinical applications of artificially created RCs for large-scale chromosome rearrangement treatment. PMID- 28894965 TI - Quantifying the effects of LUCCs on local temperatures, precipitation, and wind using the WRF model. AB - Land use/cover changes (LUCCs) are an important cause of regional climate changes, but the contribution of LUCCs to regional climate changes is not clear. In this study, the Weather Research and Forecasting (WRF) model and statistical methods were used to investigate changes in meteorologic variables in January, April, July, and October 2013 due to local LUCCs from 1990 to 2010 in southern Shandong province, China. The results indicate that the WRF model simulates temperatures in the region well, with high correlation coefficients (0.86-0.97, p < 0.001) between the modeled and measured values. The model simulates precipitation less well, with correlation coefficients of 0.41-0.91, but they are all at statistically significant levels, with p < 0.05. During the 20-year period, the LUCCs in the study area consisted mainly of conversions from dry land to urbanized land (747.3 km2) and bare/sparse vegetation (132.4 km2). The LUCCs caused a 0.16 degrees C temperature increase in January and October and 0.01 and 0.18 degrees C temperature decreases in April and July, respectively. The range of temperature changes over mixed forest and water bodies due to the LUCCs was wide (0.39-1.31 degrees C) and was narrower over deciduous broadleaf forest and wetland (0.01 to 0.06 degrees C). The LUCCs did not change the precipitation greatly in January, April, and October but did affect the precipitation in July substantially, causing a decrease of 23.71 mm. The LUCCs did not affect wind speed and direction substantially during these four months: average wind speeds increased by 0.02 and 0.01 m/s in January and October, respectively, and decreased by 0.02 and 0.05 m/s in April and July, respectively. Overall, The LUCCs affected spring temperatures the least and summer precipitation the most. PMID- 28894964 TI - Macrophages Generate Pericytes in the Developing Brain. AB - Pericytes are defined by their anatomical location encircling blood vessels' walls with their long projections. The exact embryonic sources of cerebral pericytes remain poorly understood, especially because of their recently revealed diversity. Yamamoto et al. (Sci Rep 7(1):3855, 2017) using state-of-the-art techniques, including several transgenic mice models, reveal that a subpopulation of brain pericytes are derived from phagocytic macrophages during vascular development. This work highlights a new possible ancestor of brain pericytes. The emerging knowledge from this research may provide new approaches for the treatment of several neurodevelopmental disorders in the future. PMID- 28894967 TI - Villaret syndrome as clinical presentation of occult metastatic breast cancer. PMID- 28894966 TI - Targeting cancer-specific glycans by cyclic peptide lectinomimics. AB - The transformation from normal to malignant phenotype in human cancers is associated with aberrant cell-surface glycosylation. Thus, targeting glycosylation changes in cancer is likely to provide not only better insight into the roles of carbohydrates in biological systems, but also facilitate the development of new molecular probes for bioanalytical and biomedical applications. In the reported study, we have synthesized lectinomimics based on odorranalectin 1; the smallest lectin-like cyclic peptide isolated from the frog Odorrana grahami skin, and assessed the ability of these peptides to bind specific carbohydrates on molecular and cellular levels. In addition, we have shown that the disulfide bond found in 1 can be replaced with a lactam bridge. However, the orientation of the lactam bridge, peptides 2 and 3, influenced cyclic peptide's conformation and thus these peptides' ability to bind carbohydrates. Naturally occurring 1 and its analog 3 that adopt similar conformation in water bind preferentially L-fucose, and to a lesser degree D galactose and N-acetyl-D-galactosamine, typically found within the mucin O-glycan core structures. In cell-based assays, peptides 1 and 3 showed a similar binding profile to Aleuria aurantia lectin and these two peptides inhibited the migration of metastatic breast cancer cell lines in a Transwell assay. Altogether, the reported data demonstrate the feasibility of designing lectinomimics based on cyclic peptides. PMID- 28894968 TI - Lysosomal defects in ATP13A2 and GBA associated familial Parkinson's disease. AB - Genes encoding lysosomal proteins, such as ATP13A2 and GBA, are associated with familial Parkinson's disease (PD). Heterozygous mutations in GBA are strongly associated with familial PD. ATP13A2, which encodes a lysosomal P-type ATPase, has been identified as the causative gene for Kufor-Rakeb syndrome. While lysosomal dysfunction due to these mutations exhibited early onset Parkinsonism, each animal model demonstrated different pathological mechanisms. Clinicogenetic and animal model studies recently identified several lysosomal alterations that play a role in the pathogenesis of PD. PMID- 28894969 TI - Categorical Speech Perception in Adults with Autism Spectrum Conditions. AB - This study tested whether individuals with autism spectrum conditions (n = 23) show enhanced discrimination of acoustic differences that signal a linguistic contrast (i.e., /g/ versus /k/ as in 'goat' and 'coat') and whether they process such differences in a less categorical fashion as compared with 23 IQ-matched typically developed adults. Tasks administered were nonverbal IQ, verbal IQ, 5 language measures, a speech perception task, and the ADOS. The speech perception task measured the discrimination of paired exemplars along the /g/-/k/ continuum. Individuals with autism spectrum conditions did not show enhanced discrimination of speech perception. Categorical speech perception was correlated with verbal ability of reading, lexical decision, and verbal IQ in individuals with autism spectrum conditions. PMID- 28894970 TI - Timing of surgery for ruptured supratentorial arteriovenous malformations. AB - BACKGROUND: There are conflicting opinions regarding the optimal waiting time to perform surgery after rupture of supratentorial arteriovenous malformations (AVMs) to achieve the best possible outcome. OBJECTIVE: To analyze factors influencing outcomes for ruptured supratentorial AVMs after surgery, paying particular attention to the timing of the surgery. METHODS: We retrospectively investigated 59 patients admitted to our center between 2000 and 2014 for surgical treatment of ruptured supratentorial AVMs. We evaluated the effect of timing of surgery and other variables on the outcome at 2-4 months (early outcome), at 12 months (intermediate outcome) after surgery, and at final follow up at the end of 2016 (late outcome). RESULTS: Age over 40 years (OR 18.4; 95% CI 1.9-172.1; p = 0.011), high Hunt and Hess grade (4 or 5) before surgery (OR 13.5; 95% CI 2.1-89.2; p = 0.007), hydrocephalus on admission (OR 12.9; 95% CI 1.8 94.4; p = 0.011), and over 400 cm3 bleeding during surgery (OR 11.5; 95% CI 1.5 86.6; p = 0.017) were associated with an unfavorable early outcome. Age over 40 years (OR 62.8; 95% CI 2.6-1524.9; p = 0.011), associated aneurysms (OR 34.7; 95% CI 1.4-829.9; p = 0.029), high Hunt and Hess grade before surgery (OR 29.2; 95% CI 2.6-332.6; p = 0.007), and over 400 cm3 bleeding during surgery (OR 35.3; 95% CI 1.7-748.7; p = 0.022) were associated with an unfavorable intermediate outcome. Associated aneurysms (OR 8.2; 95% CI 1.2-55.7; p = 0.031), high Hunt and Hess grade before surgery (OR 5.7; 95% CI 1.3-24.3; p = 0.019), and over 400 cm3 bleeding during surgery (OR 5.8; 95% CI 1.2-27.3; p = 0.027) were associated with an unfavorable outcome at last follow-up. Elapsed time between rupture and surgery did not affect early or final outcome. CONCLUSIONS: Early surgery in patients with ruptured supratentorial arteriovenous malformation is feasible strategy, with late results comparable to those achieved with delayed surgery. Many other factors than timing of surgery play significant roles in long-term outcomes for surgically treated ruptured supratentorial AVMs. PMID- 28894971 TI - Identification of genes associated with primary open-angle glaucoma by bioinformatics approach. AB - PURPOSE: This study aimed to identify associated genes with primary open-angle glaucoma (POAG) and explore the potentially modular mechanism underlying POAG. METHODS: We downloaded gene expression profiles data GSE27276 from gene expression omnibus and identified differentially expressed genes between POAG patients and normal controls. Then, gene ontology analysis and kyoto encyclopedia of genes and genomes pathway enrichment were performed to predict the DEGs functions, followed with the construction, centrality analysis, and module mining of protein-protein interaction network. RESULTS: A total of 552 DEGs including 249 up-regulated and 303 down-regulated genes were identified. The up-regulated DEGs were significantly involved in cell adhesion molecule, while the down regulated DEGs were significantly involved in complement and coagulation cascades. Centrality analysis screened out 20 genes, among which COL4A4, COL3A1, COL1A2, ITGB5, COL5A2, and COL5A1 were shared in ECM-receptor interaction and focal adhesion pathways. In the sub-network, COL5A2, COL8A2, and COL5A1 were significantly enriched in biological function of eye morphogenesis and eye development, while LAMA5, COL3A1, COL1A2, and COL5A1 were significantly enriched in vasculature development and blood vessel development. CONCLUSIONS: Six genes, including COL4A4, COL3A1, COL1A2, ITGB5, COL5A2, and COL5A1, ECM-receptor interaction and focal adhesion pathway, are potentially involved in the pathogenesis of POAG via participating in pathways of ECM-receptor interaction and focal adhesion. PMID- 28894973 TI - Decreased serum extracellular superoxide dismutase activity is associated with albuminuria in Chinese patients with type 2 diabetes mellitus. AB - AIMS: The aim of this study was to determine the activity of serum extracellular superoxide dismutase (ecSOD) in patients with type 2 diabetes mellitus (T2DM) and healthy subjects, and to determine the prospective association between baseline serum ecSOD activity and the subsequent risk of albuminuria progression in a cohort of Chinese T2DM patients. METHODS: A total of 458 T2DM patients and 100 healthy subjects were assessed. After a median follow-up of 7.7 months, 319 patients with baseline normoalbuminuria (urinary albumin-to-creatinine ratio [UACR] <30 mg/g) and 77 patients with baseline microalbuminuria (UACR = 30-299 mg/g) were divided into progression and non-progression groups according to UACR changes. Serum ecSOD activity was determined by the autoxidation of pyrogallol method. Multivariate Cox regression analysis was used for investigating the predictors for albuminuria progression. RESULTS: Compared with healthy controls (174.5 +/- 25.1 U/mL), serum ecSOD activity significantly decreased in T2DM patients with normoalbuminuria (114.9 +/- 13.2 U/mL), with microalbuminuria (106.6 +/- 16.3 U/mL), and with macroalbuminuria (97.1 +/- 18.2 U/mL) (all P < 0.001). Serum ecSOD activity was associated with albuminuria (odds ratio [OR] = 1.028, P = 0.004) in T2DM patients. Baseline serum ecSOD activity (hazard ratio [HR] = 0.902, 95% CI 0.877-0.928, P < 0.001) was an independent predictor for albuminuria progression. CONCLUSION: Serum ecSOD activity may be useful for predicting the future risk of albuminuria progression in Chinese T2DM patients. PMID- 28894972 TI - Gene regulation of mammalian long non-coding RNA. AB - RNA polymerase II (Pol II) transcribes two classes of RNAs, protein-coding and non-protein-coding (ncRNA) genes. ncRNAs are also synthesized by RNA polymerases I and III (Pol I and III). In humans, the number of ncRNA genes exceeds more than twice that of protein-coding genes. However, the history of studying Pol II synthesized ncRNA is relatively short. Since early 2000s, important biological and pathological functions of these ncRNA genes have begun to be discovered and intensively studied. And transcription mechanisms of long non-coding RNA (lncRNA) have been recently reported. Transcription of lncRNAs utilizes some transcription factors and mechanisms shared in that of protein-coding genes. In addition, tissue specificity in lncRNA gene expression has been shown. LncRNAs play essential roles in regulating the expression of neighboring or distal genes through different mechanisms. This leads to the implication of lncRNAs in a wide variety of biological pathways and pathological development. In this review, the newly discovered transcription mechanisms, characteristics, and functions of lncRNA are discussed. PMID- 28894974 TI - FOXP3+ T cells are present in kidney biopsy samples in children with tubulointerstitial nephritis and uveitis syndrome. AB - BACKGROUND: Tubulointerstitial nephritis (TIN) is an inflammatory disease of unknown pathogenesis. To evaluate a possible role of regulatory T cells (Tregs) in the pathophysiology of TIN with (TINU) and without uveitis, we investigated the presence and quantity of FOXP3+ T regulatory lymphocytes in diagnostic kidney biopsies from pediatric patients. METHODS: A total of 33 patients (14 TIN and 19 TINU) were enrolled. The quantity of CD4+, FOXP3+ and double-positive T cells in formalin-fixed kidney biopsies was determined using double label immunohistochemistry with anti-human CD4 and FOXP3 antibodies. RESULTS: FOXP3 staining was successful in all 33 patients. In patients with chronic uveitis, the density of FOXP3+ cells was significantly lower (p = 0.046) than in TIN patients without uveitis or with uveitis lasting <3 months. CD4+ staining was successful in 23 patients. The density of all lymphocytes (CD4+, CD4+FOXP3+ and FOXP3+ cells) was significantly lower (p = 0.023) in patients with chronic uveitis than in other patients. CONCLUSIONS: FOXP3+ T cells are present in kidney biopsy samples from TIN and TINU patients. In patients with chronic uveitis, the density of FOXP3+ T cells is significantly lower than in other patients, suggesting a different pathomechanism for these clinical conditions. PMID- 28894975 TI - Reperfusion of the choriocapillaris observed using optical coherence tomography angiography in hypertensive choroidopathy. AB - PURPOSE: Optical coherence tomography angiography (OCTA) can visualize the vascular status of the choriocapillaris noninvasively and separately from the other vascular beds. We describe focal ischemia in the choriocapillaris and reperfusion of the area in hypertensive choroidopathy using en-face OCTA. CASE: A 32-year-old woman diagnosed with pregnancy-induced hypertension presented with acute anorthopia in the right eye after delivery via Caesarian section. Fundus examination showed an Elschnig's spot and serous retinal detachment (SRD) in the inferior perifoveal region. Early-phase fluorescein angiography and indocyanine green angiography images showed focally delayed choroidal perfusion, i.e., regional absence of choroidal flush. OCTA also showed a focal dark area in a slab of the choriocapillaris corresponding to the angiographic observation. After oral antihypertensive treatment, the dark area on the OCTA image of the choriocapillaris resolved over time in association with the resolving SRD. CONCLUSION: En-face OCTA is a useful technology to follow noninvasively the circulatory status of the choriocapillaris in hypertensive choroidopathy. PMID- 28894977 TI - Varicella Coinfection in Patients with Active Monkeypox in the Democratic Republic of the Congo. AB - From 2006 to 2007, an active surveillance program for human monkeypox (MPX) in the Democratic Republic of the Congo identified 151 cases of coinfection with monkeypox virus and varicella zoster virus from 1158 suspected cases of human MPX (13%). Using clinical and socio-demographic data collected with standardized instruments by trained, local nurse supervisors, we examined a variety of hypotheses to explain the unexpectedly high proportion of coinfections among the sample, including the hypothesis that the two viruses occur independently. The probabilities of disease incidence and selection necessary to yield the observed sample proportion of coinfections under an assumption of independence are plausible given what is known and assumed about human MPX incidence. Cases of human MPX are expected to be underreported, and more coinfections are expected with improved surveillance. PMID- 28894976 TI - Implicating anaesthesia and the perioperative period in cancer recurrence and metastasis. AB - Cancer, currently the leading cause of death in the population aged less than 85 years, poses a significant global disease burden and is anticipated to continue to increase in incidence in both developed and developing nations. A substantial proportion of cancers are amenable to surgery, with more than 60% of patients undergoing tumour resection. Up to 80% of patients will receive anaesthesia for diagnostic, therapeutic or palliative intervention. Alarmingly, retrospective studies have implicated surgical stress in disease progression that is predominantly characterised by metastatic disease-the primary cause of cancer associated mortality. Our understanding of the mechanisms of surgical stress and impact of perioperative interventions is, however, far from complete. Accumulating evidence from preclinical studies suggests that adrenergic inflammatory pathways may contribute to cancer progression. Importantly, these pathways are amenable to modulation by adapting surgical (e.g. minimally invasive surgery) and anaesthetic technique (e.g. general vs. neuraxial anaesthesia). Disturbingly, drugs used for general anaesthesia (e.g. inhalational vs. intravenous anaesthesia and potentially opioid analgesia) may also affect behaviour of tumour cells and immune cells, suggesting that choice of anaesthetic agent may also be linked to adverse long-term cancer outcomes. Critically, current clinical practice guidelines on the use of anaesthetic techniques, anaesthetic agents and perioperative adjuvants (e.g. anti-inflammatory drugs) during cancer surgery do not take into account their potential effect on cancer outcomes due to a lack of robust prospective data. To help address this gap, we provide an up-to-date review of current clinical evidence supporting or refuting the role of perioperative stress, anaesthetic techniques and anaesthetic agents in cancer progression and review pre-clinical studies that provide insights into biological mechanisms. PMID- 28894978 TI - Hydrogen-Rich Saline Ameliorates Allergic Rhinitis by Reversing the Imbalance of Th1/Th2 and Up-Regulation of CD4+CD25+Foxp3+Regulatory T Cells, Interleukin-10, and Membrane-Bound Transforming Growth Factor-beta in Guinea Pigs. AB - It is well known that CD4+CD25+Foxp3+Treg cells play an important role in the development of allergic rhinitis (AR); the defect of cell numbers and functions contribute to AR. Hydrogen has been proven effective in alleviating symptoms of AR. We herein aim to verify the protective effects of hydrogen on CD4+CD25+Foxp3+Treg cells in guinea pigs with AR and to explore the effect of hydrogen-rich saline (HRS) on CD4+CD25+Foxp3+Treg cells in animals with AR and investigate the underlying anti-inflammatory mechanism. Eighteen guinea pigs were randomly divided into three groups (control group/AR group/AR-HRS group). The guinea pigs were injected with hydrogen-rich saline (AR-HRS group) for 10 days after sensitization. The control group was injected with an equal volume of normal saline. The number of sneezes, degree of runny nose, and nasal-rubbing movements were scored. Peripheral blood eosinophil count was recorded. The proportions of Th1/Th2 of the peripheral blood and the CD4+CD25+Foxp3+T cells in the CD4+T cells of the spleen and peripheral blood were determined by flow cytometry. The content of interleukin (IL)-10 and transforming growth factor (TGF)-beta in the serum was detected by enzyme-linked immunosorbent assay (ELISA). The protein and mRNA expression of Foxp3, IL-10, and TGF-beta were determined by Western blot, immunofluorescence, and real-time PCR analysis, respectively. Scores of symptoms, number of eosinophils,and nasal mucosa damage were dramatically reduced after HRS treatment. HRS increased the expression of Foxp3, IL-10, TGF-beta, and number of CD4+CD25+Foxp3+Treg cells, which were reduced in AR. HRS also revised the dysregulation of Th1/Th2 balance. Both the number and biological activity of CD4+CD25+Foxp3+Treg cells increased with up regulation of Th1/Th2 after HRS administration. HRS could play a protective role in attenuating AR through improving the proportion and functions of CD4+CD25+Foxp3+Treg cells. PMID- 28894979 TI - Cuticular Hydrocarbons of Tribolium confusum Larvae Mediate Trail Following and Host Recognition in the Ectoparasitoid Holepyris sylvanidis. AB - Parasitic wasps which attack insects infesting processed stored food need to locate their hosts hidden inside these products. Their host search is well-known to be guided by host kairomones, perceived via olfaction or contact. Among contact kairomones, host cuticular hydrocarbons (CHCs) may provide reliable information for a parasitoid. However, the chemistry of CHC profiles of hosts living in processed stored food products is largely unknown. Here we showed that the ectoparasitoid Holepyris sylvanidis uses CHCs of its host Tribolium confusum, a worldwide stored product pest, as kairomones for host location and recognition at short range. Chemical analysis of T. confusum larval extracts by gas chromatography coupled with mass spectrometry revealed a rich blend of long-chain (C25-C30) hydrocarbons, including n-alkanes, mono-, and dimethylalkanes. We further studied whether host larvae leave sufficient CHCs on a substrate where they walk along, thus allowing parasitoids to perceive a CHC trail and follow it to their host larvae. We detected 18 CHCs on a substrate that had been exposed to host larvae. These compounds were also found in crude extracts of host larvae and made up about a fifth of the CHC amount extracted. Behavioral assays showed that trails of host CHCs were followed by the parasitoids and reduced their searching time until successful host recognition. Host CHC trails deposited on different substrates were persistent for about a day. Hence, the parasitoid H. sylvanidis exploits CHCs of T. confusum larvae for host finding by following host CHC trails and for host recognition by direct contact with host larvae. PMID- 28894980 TI - Short communication: using infrared thermography as an in situ measure of core body temperature in lot-fed Angus steers. AB - Thirty-six Black Angus steers were used in a replicated study; three replicates of 12 steers/replicate. Steers had an initial non-fasted BW of 392.3 +/- 5.1, 427.5 +/- 6.3, and 392.7 +/- 3.7 kg for each replicate, respectively. Steers were housed outside in individual animal pens (10 m * 3.4 m). Each replicate was conducted over a 6-day period where infrared thermography (IRT) images were collected at 3-h intervals, commencing at 0600 h on day 1 and concluding at 0600 h on day 6. Rumen temperatures (T RUM) were measured at 10-min intervals for the duration of each replicate using a radio-frequency identification (RFID) rumen bolus. These data were used to determine the relationship with surface temperature of the cattle, which was determined using IRT. Individual T RUM were converted to an hourly average. The relationship between T RUM and surface temperature was determined using Pearson's correlation coefficient. There were no linear trends between mean hourly T RUM and mean surface temperature. Pearson's correlation coefficient indicated that there were weak associations (r <= 0.1; P < 0.003) between T RUM and body surface temperature. These data suggest that there was little relationship between the surface temperature and T RUM. PMID- 28894981 TI - Comparative study of esterases in deltamethrin and diazinon resistant Rhipicephalus microplus and Hyalomma anatolicum ticks collected from the Trans Gangetic plains of India. AB - A comparative analysis of esterases in susceptible and resistant ticks revealed six types of esterases (EST-1b, EST-2b, EST-3b, EST-4b, EST-5b and EST-6b) in Rhipicephalus microplus and four types (EST-1h, EST-2h, EST-3h, EST-4h) in Hyalomma anatolicum using alpha-naphthyl acetate substrate. Inhibition studies with eserine sulfate, p-chloromercuribenzoate, copper sulphate and phenylmethylsulfonyl fluoride revealed a marked variation in band intensity between susceptible and resistant ticks, with the latter being more intense. Qualitative expression of EST-4b along with an extra band of EST-5b and EST-6b were indicative of deltamethrin and diazinon resistance in R. microplus, whereas qualitative expression of EST-4h was probably responsible for diazinon resistance in H. anatolicum. The data suggest that increased esterase activity may represent a detoxification strategy leading to the development of resistance in these tick populations. PMID- 28894982 TI - Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients. AB - PURPOSE: Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients. METHODS: DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early IBC patients. RESULTS: DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups. CONCLUSION: Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed. PMID- 28894983 TI - Earlier day of blastocyst development is predictive of embryonic euploidy across all ages: essential data for physician decision-making and counseling patients. AB - PURPOSE: The purpose of this study is to evaluate whether day of blastocyst development is associated with embryo chromosomal status as determined by high density oligonucleotide microarray comparative genomic hybridization (aCGH). METHODS: This is a retrospective cohort analysis, including women who underwent in vitro fertilization (IVF) with trophectoderm biopsy at a single private fertility center from January 2014 to December 2014. Repeat cycles were excluded. Cycles were assessed for percentage of blastocysts biopsied on days 5, 6, or 7 and rate of euploid embryos per cycle. Cycles were stratified by Society for Assisted Reproductive Technology (SART) age groups (< 35, 35-37, 38-40, 41-42, > 42) and by donor status. RESULTS: A total of 388 IVF cycles and 2132 biopsied blastocysts were evaluated. The percentages of blastocysts biopsied on days 5, 6, and 7 were 62.5, 35.8, and 1.7%, respectively. Blastocyst euploid rates on days 5, 6, and 7 were 49.5, 36.5, and 32.9%, respectively. Earlier blastocyst development was associated with a significantly increased euploid rate (p < 0.0001). Younger maternal age (p < 0.0001) and higher number of blastocysts biopsied per patient (p = 0.0063) were both independently associated with greater percentage of euploidy. CONCLUSIONS: Earlier blastocyst development is independently associated with a higher likelihood of embryonic euploidy in both autologous and donor embryos. In non-biopsied embryos, these data support selection of day 5 blastocysts for transfer over later-developing embryos. These results can assist with patient counseling regarding expectations and outcomes. To our knowledge, this is the first study to examine embryonic euploidy as stratified by both day of blastocyst development and SART age group. PMID- 28894984 TI - Multifidelity-CMA: a multifidelity approach for efficient personalisation of 3D cardiac electromechanical models. AB - Personalised computational models of the heart are of increasing interest for clinical applications due to their discriminative and predictive abilities. However, the simulation of a single heartbeat with a 3D cardiac electromechanical model can be long and computationally expensive, which makes some practical applications, such as the estimation of model parameters from clinical data (the personalisation), very slow. Here we introduce an original multifidelity approach between a 3D cardiac model and a simplified "0D" version of this model, which enables to get reliable (and extremely fast) approximations of the global behaviour of the 3D model using 0D simulations. We then use this multifidelity approximation to speed-up an efficient parameter estimation algorithm, leading to a fast and computationally efficient personalisation method of the 3D model. In particular, we show results on a cohort of 121 different heart geometries and measurements. Finally, an exploitable code of the 0D model with scripts to perform parameter estimation will be released to the community. PMID- 28894985 TI - Virulence analysis of Staphylococcus aureus in a rabbit model of infected full thickness wound under negative pressure wound therapy. AB - The aim of this study was to evaluate the virulence of Staphylococcus aureus in a controlled animal study using the standard sterile gauze and negative pressure wound therapy (NPWT), including activation of agr, gene expression and production of virulence foctors and depth of bacterial invasion. The tissue specimens were harvested on days 0 (6 h after bacterial inoculation), 2, 4, 6, and 8 at the center of wound beds. Laser scanning confocal microscopy was performed to obtain bioluminescent images which were used to measure the depth of bacterial invasion. The agrA expression of S.aureus and the transcription and production of virulence factors including Eap, Spa and alpha-toxin were significantly different. The bacterial invasion depth was significantly less with effect of NPWT. The markedly different activation of quorum sensing systems that enable cell-to-cell communication and regulation of numerous colonization and virulence factors result in distinct gene expression and pathogenicity over time in different microenvironment. Thus, the agr system represents a fundamental regulatory paradigm that can encompass different adaptive strategies and accommodate horizontally acquired virulence determinants. PMID- 28894986 TI - Fertility Intentions, Pregnancy, and Use of PrEP and ART for Safer Conception Among East African HIV Serodiscordant Couples. AB - African HIV serodiscordant couples often desire pregnancy, despite sexual HIV transmission risk during pregnancy attempts. Pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) reduce HIV risk and can be leveraged for safer conception but how well these strategies are used for safer conception is not known. We conducted an open-label demonstration project of the integrated delivery of PrEP and ART among 1013 HIV serodiscordant couples from Kenya and Uganda followed quarterly for 2 years. We evaluated fertility intentions, pregnancy incidence, the use of PrEP and ART during peri-conception, and peri conception HIV incidence. At enrollment, 80% of couples indicated a desire for more children. Pregnancy incidence rates were 18.5 and 18.7 per 100 person years among HIV-uninfected and HIV-infected women, and higher among women who recently reported fertility intention (adjusted odds ratio 3.43, 95% CI 2.38-4.93) in multivariable GEE models. During the 6 months preceding pregnancy, 82.9% of couples used PrEP or ART and there were no HIV seroconversions. In this cohort with high pregnancy rates, integrated PrEP and ART was readily used by HIV serodiscordant couples, including during peri-conception periods. Widespread scale-up of safer conception counseling and services is warranted to respond to strong desires for pregnancy among HIV-affected men and women. PMID- 28894987 TI - The induction of apoptosis and autophagy in human hepatoma SMMC-7721 cells by combined treatment with vitamin C and polysaccharides extracted from Grifola frondosa. AB - Polysaccharides extracted from the mushroom Grifola frondosa (GFP) are a potential anticancer agent. The objective of this study was to investigate the effect of GFP and vitamin C (VC) alone and in combination on the viability of human hepatocarcinoma SMMC-7721 and HepG2 cells. Studies designed to detect cell apoptosis and autophagy were also conducted to investigate the mechanism. Results from the cell viability assay indicated that a combination of GFP (0.2 or 0.25 mg/mL) and VC (0.3 mmol/L) (GFP/VC) led to 52.73 and 53.93% reduction in cell viability of SMMC-7721 and HepG2 cells separately after 24 h. Flow cytometric analysis indicated that GFP/VC treatment induced cell cycle arrest at the G2/M phase, and apoptosis occurred in approximately 43.62 and 42.46% of the SMMC-7721 and HepG2 cells separately. Moreover, results of Hoechst33258 and monodansylcadaverine staining, and transmission electron microscopy, showed that GFP/VC induced apoptosis and autophagy in SMMC-7721 and HepG2 cells. Western blot analysis showed changes in the expression of apoptosis-related proteins [upregulation of BAX and caspase-3, downregulation of Bcl-2, and activation of poly-(ADP-ribose)-polymerase] and autophagy protein markers (upregulation of beclin-1 and microtubule-associated protein 1A/1B light chain-3). We also demonstrated that the expression of both Akt and p-Akt was enhanced, suggesting the PI3K/Akt/mTOR pathway might not be involved in this process. Our study shows that the combined application of GFP and VC induced cell apoptosis and autophagy in vitro, and might have antitumor activity in vivo. PMID- 28894988 TI - How tandem gait stumbled into the neurological exam: a review. AB - Tandem gait testing is an integral part of the neurological exam. It is informative in a wide variety of disorders ranging from cerebellar disease to vestibular and peripheral neuropathies, parkinsonism, and other neurodegenerative conditions. We discuss the history and development of tandem gait testing as well as its technique, utility, and limitations in the assessment of neurological conditions. Tandem gait has emerged as a tool in the assessment of cerebellar disease, Huntington disease, idiopathic Parkinson's disease, atypical parkinsonism, peripheral neuropathies, and vestibulopathies. Its origin can be deduced from experimental observation and clinical experience as far back as the early nineteenth century. Despite the long history and ubiquitous performance of tandem gait testing, there is no standardized, guideline-based protocol to model for more homogenous research and clinical practices. Such a protocol should be developed using historical texts and manuscripts as well as the consensus of the medical research community. With standard protocols, further studies could define the sensitivity of abnormal tandem gait testing in cerebellar disorders, more diffuse neurodegeneration, and peripheral pathologies. Tandem gait can be a useful marker of dysfunction in neurologic conditions whose pathologies extend beyond the vermis or vestibulocerebellar module to include interconnected networks throughout the nervous system. PMID- 28894989 TI - Collective invasion in ductal and lobular breast cancer associates with distant metastasis. AB - Breast cancer undergoes collective tissue invasion and, in experimental models, can collectively metastasize. The prevalence of collective invasion and its contribution to distant metastasis in clinical disease, however, remains poorly defined. We here scored the adipose tissue invasion of primary invasive ductal carcinoma (IDC), expressing E-cadherin, and E-cadherin negative invasive lobular carcinoma (ILC) and identified predominantly collective invasion patterns (86/86 samples) in both carcinoma types. Whereas collective invasion in IDC lesions retained adherens junctions, multicellular clusters and "Indian files" in ILC, despite the absence of adherens junctions (AJ) proteins E-cadherin and beta catenin, retained CD44 at cell-cell contacts. By histomorphological scoring and semi-automated image analysis, we show that the extent of collective invasion into the adipose tissue correlated with decreased distant metastasis-free survival (5-year follow-up; hazard ratio: 2.32 and 2.29, respectively). Thus, collective invasion represents the predominant invasion mode in breast cancer, develops distinct junctional subtypes in IDC and ILC, and associates with distant metastasis, suggesting a critical role in systemic dissemination. PMID- 28894990 TI - Feeding preference and daily ration of 12 dominant copepods on mono and mixed diets of phytoplankton, rotifers, and detritus in a tropical coastal water. AB - Results of the experimental studies on the feeding habit and daily ration (DR) of 12 dominant copepods from a tropical coastal water (off Kochi, Southwest coast of India) on different food items (phytoplankton, rotifers, and detritus) are presented. Even though, all species of copepods consumed all types of food items in the experiments, they showed noticeable feeding preferences, having important ecological implications. Calanoid Paracalanus parvus and Acrocalanus gracilis consumed phytoplankton and rotifers equally in mono diets (74-89% of DR) and mixed diets (53-82% of DR), which indicated their ability to shift their diet in natural environment based on the availability of food items. Calanoid Acartia erythraea and A. danae consumed more phytoplankton (DR 83 and 72%, respectively) than rotifers (DR 51 and 46%, respectively) in mono diets, and in mixed diets, their consumption was high in phytoplankton combined food mixtures (P + R DR and P + D DR) rather than the R + D food type, indicated their preference for mixed diets of phytoplankton. Similarly, Calanoid Temora turbinata, Pseudodiaptomus serricaudatus, and Centropages tenuiremis preferred a herbivorous diet as evidenced by their high ingestion rate on phytoplankton mono (70 to 87% to their DR) and mixed diets (58 to 80% of DR). On the other hand, Cyclopoid Oithona similis and Poecilostomatoid Corycaeus danae preferred a carnivorous diet, consuming more rotifers (> 80% of DR) than phytoplankton (18-20% of DR) and detritus (5-6% of DR). Harpacticoids Macrosetella gracilis and Euterpina acutifrons equally preferred phytoplankton (78-92% of DR) and detritus (65-89% of DR). The study showed that the dominant copepods in the coastal waters off Kochi occupy different trophic niches available in the environment, which may be applicable in other similar environments as well. PMID- 28894991 TI - Preoperatively determining the margins of subcutaneous malignant soft tissue tumours using contrast-enhanced ultrasonography. AB - The purpose of this technical report is to demonstrate the feasibility of contrast-enhanced ultrasonography for preoperative evaluation of the lateral extent of subcutaneous malignant soft tissue tumours. Patients with subcutaneous malignant soft tissue tumours who underwent surgery between March 2016 and May 2016 were selected for inclusion. Contrast-enhanced ultrasonography using Sonazoid(r) was performed 1 day before the operation. The tumour margin was determined based on contrast-enhanced ultrasonography and marked on the skin using a permanent marker. After surgery, the extent of the tumour area was determined based on microscopic findings. The distance between the edge of the tumour and the skin markings was histologically measured. The mean distance between the extent of infiltrative tumour growth based on the microscopic findings and the skin marking was 1.3 +/- 1.6 mm. The greatest distance between microscopically determined tumour invasion and the skin marking was 4 mm. Contrast-enhanced ultrasonography of subcutaneous malignant soft tissue tumours was not only feasible, but also highly accurate in estimating tumour margins as well as infiltrative tumour growth compared with macroscopic and microscopic analysis, respectively. PMID- 28894992 TI - Fractional carbon dioxide laser for the treatment of facial atrophic acne scars: prospective clinical trial with short and long-term evaluation. AB - The aim of this study was to evaluate the efficacy and safety of fractional carbon dioxide laser for the treatment of acne scars. Thirty-one participants, 15 female and 16 male, whose mean age was 34.84 +/- 10.94 years, were included in this prospective study. The study took place between 2012 and 2016. Participants were evaluated with the "ECCA Grading Scale" before the first session, 3 months (short-term evaluation) and 3 years after the last session (long-term evaluation). Participants received two or three treatment sessions at 4-week intervals, with a 10,600 nm fractional carbon dioxide laser with pulse energies ranging between 100 and 160 mJ, 120 spot type, 75-100 spot/cm2 density, and 30 W power. Self-assessments by the participants were done 3 months and 3 years after the last session. The mean ECCA score was 107.90 +/- 39.38 before the first session, and 82.17 +/- 36.23 at the time of short-term evaluation (p = 0.000). The grade of improvement at the short-term evaluation was as follows: no improvement, mild, moderate, and significant improvement for 7 (22.6%), 11 (35.5%), 9 (29%), and 4 (12.9%) of the participants, respectively. Regarding self assessments, 80.6 and 61.3% of the participants rated themselves as having at least mild improvement at the short-term and the long-term follow-up periods, respectively. The results of this study suggest that fractional carbon dioxide laser is an efficient treatment option for acne scars. Furthermore, self assessment results show that more than half of the participants still experience at least mild improvement at the end of 3 years. PMID- 28894994 TI - Mining noise affects loud call structures and emission patterns of wild black fronted titi monkeys. AB - Anthropogenic noise pollution is increasing and can constrain acoustic communication in animals. Our aim was to investigate if the acoustic parameters of loud calls and their diurnal pattern in the black-fronted titi monkey (Callicebus nigrifrons) are affected by noise produced by mining activity in a fragment of Atlantic Forest in Brazil. We installed two passive acoustic monitoring devices to record sound 24 h/day, 7 days every 2 months, for a year; one unit was close to an opencast mine and the other 2.5 km away from it. Both sites presented similar habitat structures and were inhabited by groups of black fronted titi monkeys. We quantified the noise at both sites by measuring the equivalent continuous sound level every 2 months for 1 year and quantified the emission of loud calls by titi monkeys through visual inspection of the recordings. The close site presented higher ambient noise levels than the far site. The quantitative comparison of loud calls of black-fronted titi monkeys between the two sites showed less calling activity in the site close to the mine than in the site further away. Approximately 20 % of the calls detected at the site close to the mine were masked by noise from truck traffic. Loud calls were longer at the site far from the mine and the diurnal patterns of vocal activity differed in the amount of calling as well as in the timing of peak calling activity between the two sites. Our results indicate that mining noise may constrain titi monkeys' long-distance vocal communication. Loud calls occupy a similar frequency band to mining noise, and an increase in ambient noise may be triggering black-fronted titi monkeys to adjust their long-distance communication patterns to avoid masking of their calls. Given that vocalizations are an important means of social interaction in this species, there are concerns about the impact of mining noise on populations exposed to this human activity. PMID- 28894993 TI - Effect of growth hormone overexpression on gastric evacuation rate in coho salmon. AB - Growth hormone (GH) transgenic (T) coho salmon consistently show remarkably enhanced growth associated with increased appetite and food consumption compared to non-transgenic wild-type (NT) coho salmon. To improve understanding of the mechanism by which GH overexpression mediates food intake and digestion in T fish, feed intake and gastric evacuation rate (over 7 days) were measured in size matched T and NT coho salmon. T fish displayed greatly enhanced feed intake levels (~ 2.5-fold), and more than 3-fold increase in gastric evacuation rates relative to NT coho salmon. Despite the differences in feed intake, no differences were noted in the time taken from first ingestion of food to stomach evacuation between genotypes. These results indicate that enhanced feed intake is coupled with an overall increased processing rate to enhance energy intake by T fish. To further investigate the molecular basis of these responses, we examined the messenger RNA (mRNA) levels of several genes in appetite- and gastric regulation pathways (Agrp1, Bbs, Cart, Cck, Glp, Ghrelin, Grp, Leptin, Mc4r, Npy, and Pomc) by qPCR analyses in the brain (hypothalamus, preoptic area) and pituitary, and in peripheral tissues associated with digestion (liver, stomach, intestine, and adipose tissue). Significant increases in mRNA levels were found for Agrp1 in the preoptic area (POA) of the brain, and Grp and Pomc in pituitary for T coho salmon relative to NT. Mch and Npy showed significantly lower mRNA levels than NT fish in all brain tissues examined across all time-points after feeding. Mc4r and Cart for T showed significantly lower mRNA levels than NT in the POA and hypothalamus, respectively. In the case of peripheral tissues, T fish had lower mRNA levels of Glp and Leptin than NT fish in the intestine and adipose tissue, respectively. Grp, Cck, Bbs, Glp, and Leptin in stomach, adipose tissue, and/or intestine showed significant differences across the time-points after feeding, but Ghrelin showed no significant difference between T and NT fish in all tested tissues. PMID- 28894995 TI - Ibuprofen-loaded fibrous patches-taming inhibition at the spinal cord injury site. AB - It is now widely accepted that a therapeutic strategy for spinal cord injury (SCI) demands a multi-target approach. Here we propose the use of an easily implantable bilayer polymeric patch based on poly(trimethylene carbonate-co epsilon-caprolactone) (P(TMC-CL)) that combines physical guidance cues provided by electrospun aligned fibres and the delivery of ibuprofen, as a mean to reduce the inhibitory environment at the lesion site by taming RhoA activation. Bilayer patches comprised a solvent cast film onto which electrospun aligned fibres have been deposited. Both layers were loaded with ibuprofen. In vitro release (37 degrees C, in phosphate buffered saline) of the drug from the loaded scaffolds under sink condition was found to occur in the first 24 h. The released ibuprofen was shown to retain its bioactivity, as indicated by the reduction of RhoA activation when the neuronal-like cell line ND7/23 was challenged with lysophosphatidic acid. Ibuprofen-loaded P(TMC-CL) bilayer scaffolds were successfully implanted in vivo in a dorsal hemisection rat SCI model mediating the reduction of RhoA activation after 5 days of implantation in comparison to plain P(TMC-CL) scaffolds. Immunohistochemical analysis of the tissue shows betaIII tubulin positive cells close to the ibuprofen-loaded patches further supporting the use of this strategy in the context of regeneration after a lesion in the spinal cord. PMID- 28894996 TI - The Relationship Between Parents' Intimate Partner Victimization and Youths' Adolescent Relationship Abuse. AB - Witnessing inter-parental intimate partner violence has been found to be associated with adolescents' own relationship abuse. This study investigates the relationship between patterns of inter-parental intimate partner verbal and physical violence victimization reported by parents and their children's reports of dating abuse experiences and behavior. Latent class analysis was performed on a sample of 610 parents (42% male and 67% white) and their dating adolescent children (ages 12-21 years; 52% male). Parents reported five types of victimization by their partners in the past year, while youth concurrently reported their own victimization and perpetration within their dating relationships. Three profiles of parents' intimate partner victimization were related to youth relationship abuse experiences and behaviors. Children of parents who experienced verbal abuse were more likely to experience similar patterns in their own relationships, whereas children of parents who report physical and verbal abuse were more likely to report psychological, physical and sexual abusive encounters in their partnerships. Findings indicate that parents' relationship quality and abusive behaviors may have a long lasting effect on their children as they enter mid and late adolescence. Parents should pay attention to their own relationship quality and behavior even as their teen-age children gain independence. PMID- 28894997 TI - A novel framework for evaluating the image accuracy of dynamic MRI and the application on accelerated breast DCE MRI. AB - OBJECTIVE: To develop a novel framework for evaluating the accuracy of quantitative analysis on dynamic contrast-enhanced (DCE) MRI with a specific combination of imaging technique, scanning parameters, and scanner and software performance and to test this framework with breast DCE MRI with Time-resolved angiography WIth Stochastic Trajectories (TWIST). MATERIALS AND METHODS: Realistic breast tumor phantoms were 3D printed as cavities and filled with solutions of MR contrast agent. Full k-space raw data of individual tumor phantoms and a uniform background phantom were acquired. DCE raw data were simulated by sorting the raw data according to TWIST view order and scaling the raw data according to the enhancement based on pharmaco-kinetic (PK) models. The measured spatial and temporal characteristics from the images reconstructed using the scanner software were compared with the original PK model (ground truth). RESULTS: Images could be reconstructed using the manufacturer's platform with the modified 'raw data.' Compared with the 'ground truth,' the RMS error in all images was <10% in most cases. With increasing view-sharing acceleration, the error of the initial uptake slope decreased while the error of peak enhancement increased. Deviations of PK parameters varied with the type of enhancement. CONCLUSION: A new framework has been developed and tested to more realistically evaluate the quantitative measurement errors caused by a combination of the imaging technique, parameters and scanner and software performance in DCE-MRI. PMID- 28894998 TI - New Species Spiromastigoides albida from a Lung Biopsy. AB - The new species Spiromastigoides albida (Onygenales, Eurotiomycetes, Ascomycota), from a lung biopsy in USA, is proposed and described based on morphological data and the analysis of rRNA, and fragments of actin and beta-tubulin gene sequences. This species is characterized by white colonies and a malbranchea-like asexual morph with profusely branching curved conidiophores forming sporodochia-like structures. Moreover, new combinations for Gymnoascus alatosporus, and for some new species recently described under the generic name Spiromastix, are provided. PMID- 28894999 TI - Needs of Adolescents and Young Adults with Neurodevelopmental Disorders: Comparisons of Young People and Parent Perspectives. AB - This study used the Camberwell Assessment of Need for adults with Developmental and Intellectual Disabilities (CANDID) to examine the social, physical health and mental health needs of 168 young people (aged 14-24 years) with neurodevelopmental disorders and compared young person and parent ratings of need. Agreement was poor in 21 out of 25 domains. Parents consistently reported higher levels of need than young people in the majority of domains although young people with ADHD reported significantly more needs in physical health, eyesight/hearing, seizures, other mental health problems and safety of others than their parents. Both parent and young person perspectives of needs are necessary to ensure that needs that are predictive of current or future poor outcomes are not missed. PMID- 28895000 TI - Endoscopic diode laser therapy for chronic radiation proctitis. AB - The purpose of this study is to determine the effectiveness of endoscopic diode laser therapy in patients presenting rectal bleeding due to chronic radiation proctitis (CRP). A retrospective analysis of CRP patients who underwent diode laser therapy in a single institution between 2010 and 2016 was carried out. The patients were treated by non-contact fibers without sedation in an outpatient setting. Fourteen patients (median age 77, range 73-87 years) diagnosed with CRP who had undergone high-dose radiotherapy for prostatic cancer and who presented with rectal bleeding were included. Six required blood transfusions. Antiplatelet (three patients) and anticoagulant (two patients) therapy was not suspended during the treatments. The patients underwent a median of two sessions; overall, a mean of 1684 J of laser energy per session was used. Bleeding was resolved in 10/14 (71%) patients, and other two patients showed improvement (93%). Only one patient, who did not complete the treatment, required blood transfusions after laser therapy; no complications were noted during or after the procedures. Study findings demonstrated that endoscopic non-contact diode laser treatment is safe and effective in CRP patients, even in those receiving antiplatelet and/or anticoagulant therapy. PMID- 28895003 TI - Reduction of water losses by rehabilitation of water distribution network. AB - Physical or real losses may be indicated as the most important component of the water losses occurring in a water distribution network (WDN). The objective of this study is to examine the effects of piping material management and network rehabilitation on the physical water losses and water losses management in a WDN. For this aim, the Denizli WDN consisting of very old pipes that have exhausted their economic life is selected as the study area. The fact that the current network is old results in the decrease of pressure strength, increase of failure intensity, and inefficient use of water resources thus leading to the application of the rehabilitation program. In Denizli, network renewal works have been carried out since the year 2009 under the rehabilitation program. It was determined that the failure rate at regions where network renewal constructions have been completed decreased down to zero level. Renewal of piping material enables the minimization of leakage losses as well as the failure rate. On the other hand, the system rehabilitation has the potential to amortize itself in a very short amount of time if the initial investment cost of network renewal is considered along with the operating costs of the old and new systems, as well as water loss costs. As a result, it can be stated that renewal of piping material in water distribution systems, enhancement of the physical properties of the system, provide significant contributions such as increase of water and energy efficiency and more effective use of resources. PMID- 28895001 TI - Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex. AB - Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors. Norepinephrine (NE) signaling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release. However, there is also evidence for NE inhibition of CRH neurons (possibly via beta receptors), an effect that may occur at higher levels of stimulation, suggesting that NE effects on the HPA axis may be context-dependent. Lesions of ascending NE inputs to the paraventricular nucleus attenuate stress-induced ACTH but not corticosterone release after chronic stress, indicating reduction in central HPA drive and increased adrenal sensitivity. Non-catecholaminergic NTS glucagon-like peptide 1/glutamate neurons play a broader role in stress regulation, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress. Overall, the data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress. PMID- 28895002 TI - Synaptic convergence regulates synchronization-dependent spike transfer in feedforward neural networks. AB - Correlated neural activities such as synchronizations can significantly alter the characteristics of spike transfer between neural layers. However, it is not clear how this synchronization-dependent spike transfer can be affected by the structure of convergent feedforward wiring. To address this question, we implemented computer simulations of model neural networks: a source and a target layer connected with different types of convergent wiring rules. In the Gaussian Gaussian (GG) model, both the connection probability and the strength are given as Gaussian distribution as a function of spatial distance. In the Uniform Constant (UC) and Uniform-Exponential (UE) models, the connection probability density is a uniform constant within a certain range, but the connection strength is set as a constant value or an exponentially decaying function, respectively. Then we examined how the spike transfer function is modulated under these conditions, while static or synchronized input patterns were introduced to simulate different levels of feedforward spike synchronization. We observed that the synchronization-dependent modulation of the transfer function appeared noticeably different for each convergence condition. The modulation of the spike transfer function was largest in the UC model, and smallest in the UE model. Our analysis showed that this difference was induced by the different spike weight distributions that was generated from convergent synapses in each model. Our results suggest that, the structure of the feedforward convergence is a crucial factor for correlation-dependent spike control, thus must be considered important to understand the mechanism of information transfer in the brain. PMID- 28895004 TI - Positive Cognitive Effects of Bilingualism and Multilingualism on Cerebral Function: a Review. AB - A review of the current literature regarding bilingualism demonstrates that bilingualism is linked to higher levels of controlled attention and inhibition in executive control and can protect against the decline of executive control in aging by contributing to cognitive reserve. Bilinguals may also have smaller vocabulary size and slower lexical retrieval for each language. The joint activation theory is proposed to explain these results. Older trilingual adults experience more protection against cognitive decline and children and young adults showed similar cognitive advantages to bilinguals in inhibitory control. Second language learners do not yet show cognitive changes associated with multilingualism. The Specificity Principle states that the acquisition of multiple languages is moderated by multiple factors and varies between experiences. Bilingualism and multilingualism are both associated with immigration but different types of multilingualism can develop depending on the situation. Cultural cues and language similarity also play a role in language switching and multiple language acquisition. PMID- 28895005 TI - Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis. AB - PURPOSE: Though advanced and metastatic epidermal growth factor receptor 2 (HER2) positive disease is not curable, a small proportion of patients with HER2 positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab. METHODS: We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated. RESULTS: The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor's recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9-9.3 years). CONCLUSION: We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial. PMID- 28895006 TI - Bergenin increases osteogenic differentiation and prevents methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblasts. AB - Bergenin, an active component of plants in the genus Bergenia, has multiple biological activities, including anti-inflammatory and immunomodulatory properties. We investigated the effects of bergenin on MC3T3-E1 osteoblasts. Bergenin treatment significantly elevated collagen synthesis, alkaline phosphatase activity, osteocalcin synthesis, and mineralization in the cells (p < 0.05). Additionally, bergenin increased the ratio of osteoprotegerin to receptor activator of nuclear factor kappa-B ligand, and cyclophilin B release. Methylglyoxal (MG), a highly reactive dicarbonyl compound, is the major precursor in the formation of advanced glycation end products. Pretreatment of MC3T3-E1 cells with bergenin prevented MG-induced cell death. Furthermore, bergenin treatment significantly reduced the induction of activating transcription factor 6 and autophagy by MG. These results indicate that bergenin may have positive effects on critical osteoblastic cell functions. PMID- 28895007 TI - Analysis of trace metal concentrations in raw cow's milk from three dairy farms in North Gondar, Ethiopia: chemometric approach. AB - Concentrations of essential (Cu, Mn, and Zn) and toxic (Cr, Cd, and Pb) trace metals in 30 raw cow's milk samples were quantified using flame atomic absorption spectrometry. The samples were collected from the Nara-Awudarda, Tana-Abo, and Kosoye Amba-Rass sites in North Gondar, Ethiopia, preserved in a deep freezer ( 20 degrees C), and then digested by Kjeldahl apparatus with HNO3/H2O2 (5:2; v/v) at 300 degrees C for 2.5 h. The data were subject to principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA). Overall hazard quotient (HQ) and carcinogenic risk (CR) values were also estimated to assess metal-related health risks. The mean concentrations of Cr, Mn, Cu, Zn, Cd, and Pb in the milk samples ranged 0.468-0.828, 1.614-2.806, 0.840-1.532, 1.208 5.267, ND-0.330, and ND-0.186 mg/kg, respectively. The lowest values were obtained for Kosoye Amba-Rass milk samples, while the highest were found for those collected from Nara-Awudarda milk samples, probably due to high mineral enrichment and metal leaching (especially Cd and Pb) from coal deposits. PCA revealed clustering of samples with respect to their geographic origin. Validation of PLS-DA model showed 100% classification efficiency using external validation samples and detected Cd and Cu as trace metal markers. The HQ and CR values were within the safe level; however, the former is close to the alert threshold level for Nara-Awudarda milk samples. Thus, further studies on common foodstuffs, constituting a higher proportion in the local diet, are required in this area to provide a complete risk assessment. PMID- 28895008 TI - Spatial downscaling of soil prediction models based on weighted generalized additive models in smallholder farm settings. AB - Digital soil mapping (DSM) is gaining momentum as a technique to help smallholder farmers secure soil security and food security in developing regions. However, communications of the digital soil mapping information between diverse audiences become problematic due to the inconsistent scale of DSM information. Spatial downscaling can make use of accessible soil information at relatively coarse spatial resolution to provide valuable soil information at relatively fine spatial resolution. The objective of this research was to disaggregate the coarse spatial resolution soil exchangeable potassium (Kex) and soil total nitrogen (TN) base map into fine spatial resolution soil downscaled map using weighted generalized additive models (GAMs) in two smallholder villages in South India. By incorporating fine spatial resolution spectral indices in the downscaling process, the soil downscaled maps not only conserve the spatial information of coarse spatial resolution soil maps but also depict the spatial details of soil properties at fine spatial resolution. The results of this study demonstrated difference between the fine spatial resolution downscaled maps and fine spatial resolution base maps is smaller than the difference between coarse spatial resolution base maps and fine spatial resolution base maps. The appropriate and economical strategy to promote the DSM technique in smallholder farms is to develop the relatively coarse spatial resolution soil prediction maps or utilize available coarse spatial resolution soil maps at the regional scale and to disaggregate these maps to the fine spatial resolution downscaled soil maps at farm scale. PMID- 28895009 TI - Effect of different methods of Ca2+ extraction from PSII oxygen-evolving complex on the QA- oxidation kinetics. AB - Lumenal extrinsic proteins PsbO, PsbP, and PsbQ of photosystem II (PSII) protect the catalytic cluster Mn4CaO5 of oxygen-evolving complex (OEC) from the bulk solution and from soluble compounds in the surrounding medium. Extraction of PsbP and PsbQ proteins by NaCl-washing together with chelator EGTA is followed also by the depletion of Ca2+ cation from OEC. In this study, the effects of PsbP and PsbQ proteins, as well as Ca2+ extraction from OEC on the kinetics of the reduced primary electron acceptor (QA-) oxidation, have been studied by fluorescence decay kinetics measurements in PSII membrane fragments. We found that in addition to the impairment of OEC, removal of PsbP and PsbQ significantly slows the rate of electron transfer from QA- to the secondary quinone acceptor QB. Electron transfer from QA- to QB in photosystem II membranes with an occupied QB site was slowed down by a factor of 8. However, addition of EGTA or CaCl2 to NaCl-washed PSII did not change the kinetics of fluorescence decay. Moreover, the kinetics of QA- oxidation by QB in Ca-depleted PSII membranes obtained by treatment with citrate buffer at pH 3.0 (such treatment keeps all extrinsic proteins in PSII but extracts Ca2+ from OEC) was not changed. The results obtained indicate that the effect of NaCl-washing on the QA- to QB electron transport is due to PsbP and PsbQ extrinsic proteins extraction, but not due to Ca2+ depletion. PMID- 28895010 TI - Quaternary Ammonium Polyamidoamine Dendrimer Modified Quantum Dots as Fluorescent Probes for p-Fluorophenoxyacetic Acid Detection in Aqueous Solution. AB - The wide use of pesticide p-fluorophenoxyacetic acid has caused the serious environmental contaminant. A novel fluorescent probe for sensitive detection of p fluorophenoxyacetic acid in aqueous solutions based on 3.0G quaternary ammonium polyamidoamine (PAMAM) dendrimer modified quantum dots (QDs) (PAMAM@QDs) was reported. Through the solvent-evaporation method, quaternary ammonium PAMAM was employed to modify the QDs. Poloxamer 188 was used to improve the solubility and stability. The resultant PAMAM@QDs dispersed well in water. Fluorescence (FL) spectroscopic study showed that the FL intensity of the PAMAM@QDs was enhanced in the presence of p-fluorophenoxyacetic acid. Under optimal conditions, the enhanced FL intensity as a function of concentration matched very well in the range of 1 ~ 200 ug/mL of p-fluorophenoxyacetic acid, while the lower limits of detection were found to be 0.16 ug/mL. These results show that PAMAM@QDs is a promising luminescent probe for the detection of pesticides. PMID- 28895011 TI - Caligus fajerae n. sp. (Copepoda: Caligidae) parasitic on the Pacific sierra Scomberomurus sierra Jordan & Starks (Actinopterygii: Scombridae) in the Pacific Ocean off Mexico. AB - A new species of parasitic copepod, Caligus fajerae n. sp. (Caligidae), is described from Scomberomorus sierra Jordan & Starks (Scombridae) caught off the northwestern coast of Mexico. The new species morphologically resembles Caligus cybii Bassett-Smith, 1898, Caligus kanagurta Pillai, 1961, Caligus pelamydis Kroyer, 1863 and Caligus robustus Bassett-Smith, 1898, all of which have been reported from scombrid hosts. Caligus fajerae n. sp. differs from these species by having spinules on the abdomen and caudal ramus, two processes on the proximal antennulary segment, fine striations on the claw of the antenna and maxilliped, a stouter and more recurved maxillulary dentiform process, shorter tines on the sternal furca, two additional patches of spinules on the distal endopodal segment of leg 2, a sclerotised lobe on the anteromedian surface of the leg 3 protopod and serrations on both margins of the first exopodal spine of leg 3. Analysis of the DNA sequences of the mitochondrial cytochrome c oxidase subunit 1 gene for Caligus fajerae n. sp. and 28 congeners, including C. pelamydis and C. robustus, showed that the new species grouped with Caligus belones Kroyer, 1863 (with 20% divergence), a species known to occur predominantly on needlefishes. Caligus fajerae n. sp. is the fifth species of Caligus reported from S. sierra. An updated host-parasite list for Caligus spp. on scombrids is provided. PMID- 28895012 TI - Biologic Agents Are Associated with Excessive Weight Gain in Children with Inflammatory Bowel Disease. AB - BACKGROUND: Children with active inflammatory bowel disease (IBD) are frequently underweight. Anti-tumor necrosis factor (anti-TNF) agents may induce remission and restore growth. However, its use in other autoimmune diseases has been associated with excess weight gain. Our aim was to examine whether children with IBD could experience excess weight gain. METHODS: A centralized diagnostic index identified pediatric IBD patients evaluated at our institution who received anti TNF therapy for at least 1 year between August 1998 and December 2013. Anthropometric data were collected at time of anti-TNF initiation and annually. Excess weight gain was defined as DeltaBMI SDS (standard deviation score) where patients were (1) reclassified from "normal" to "overweight/obese," (2) "overweight" to "obese," or (2) a final BMI SDS >0 and DeltaSDS >0.5. RESULTS: During the study period, 268 children received anti-TNF therapy. Of these, 69 had sufficient follow-up for a median of 29.3 months. Median age at first anti-TNF dose was 12.8 years. At baseline, mean weight SDS was -0.7 (SD 1.4), while mean BMI SDS was -0.6 (1.3). Using baseline BMI SDS, 11.6% were overweight/obese. At last follow-up (LFU), however, the mean DeltaBMI SDS was 0.50 (p < 0.0001). However, 10 (17%) patients had excess weight gain at LFU; 3 patients were reclassified from "normal" to "obese," and 7 had a final BMI SDS >0 and DeltaSDS >0.5. CONCLUSIONS: Pediatric patients with IBD may experience excess weight gain when treated with anti-TNF agents. Monitoring for this side effect is warranted. PMID- 28895013 TI - Non-donors' attitudes towards sperm donation and their willingness to donate. AB - PURPOSE: The aim of this article is to study attitudes about sperm donation and willingness to donate sperm in students who have never shown an interest in sperm donation. METHODS: The method used in this study is an electronic survey of 1012 male students. RESULTS: Only one third of the respondents (34.3%) would consider donating sperm. Overall, 85.7% indicated a positive attitude towards sperm donation while 14.3% indicated a neutral or negative attitude. The highest scored barriers to donating were the lack of practical information and the fear that the partner would not agree. Almost 40% of the respondents feared that the donation might have a negative impact on their current or future relationship. The majority (83.6%) of those who considered donating thought donors should receive a financial compensation. Money was also one of the main motivators. CONCLUSIONS: About 85% of the students thought positively about sperm donation but several factors such as perceived negative views by the social environment, especially the partner, may deter students from donating. This study indicates that the effect of strong incentives, for instance in monetary terms, on a donor pool consisting of students could be limited and that relational factors and donor's perceptions of the views of the wider social network should be taken into account when recruiting donors. PMID- 28895014 TI - The responses of two native plant species to soil petroleum contamination in the Yellow River Delta, China. AB - Petroleum contamination is a significant environmental problem in the Yellow River Delta. The responses of two native salt-tolerant plant species, alfalfa (Medicago sativa) and bristle grass (Setaria uiridis Beauv), to soil petroleum contamination were investigated at five levels between 0 and 2.0% (w/w). Results showed that the total, aboveground and underground plant biomasses of both species were significantly reduced by petroleum contamination (p < 0.05), with the inhibition enhanced with increased petroleum levels. However, the emergence rate of bristle grass was promoted by petroleum contamination. Following 100 days of exposure, the number of soil petroleum degraders increased greatly, with a trend of initial increase followed by a decrease at 1.5% contamination or higher. Compared to bulk soils, bacteria-degrading alkanes, total hydrocarbons and PAHs in alfalfa rhizosphere soils increased by 1.33-4.18-, 0.85-3.01- and 4.12-12.75 fold, respectively, with an increase of 2.80-10.00-, 4.42-14.44- and 7.30-26.00 fold in bristle grass rhizosphere soils, respectively. The greatest number of petroleum degraders in bristle grass rhizosphere soils resulted in the highest petroleum degradation rate. Bristle grass may be the optimal species for petroleum remediation in the studied area. PMID- 28895015 TI - Does Quality of Life Differ for Children With Autism Spectrum Disorder and Intellectual Disability Compared to Peers Without Autism? AB - The main goal was to test if children with intellectual disability (ID) and autism spectrum disorder (ASD) show lower quality of life (QOL) in comparison to those with only ID. The KidsLife Scale was applied to 1060 children with ID, 25% of whom also had ASD, aged 4-21 years old. Those with ASD showed lower scores in several QOL domains but, when the effect of other variables was controlled, lower scores were only kept for interpersonal relationships, social inclusion, and physical wellbeing. Slightly higher scores were found for material wellbeing. ASD, Level of ID and support needs were the covariables with the greatest influence in most domains, while gender was only significant for social inclusion (girls scored lower than boys). PMID- 28895016 TI - The association between previous success with weight loss through dietary change and success in a lifestyle modification program. AB - Prior work has yielded mixed results regarding the association between previous weight loss and success in a current weight loss attempt. The present study evaluated differences in baseline psychosocial processes, changes in these over time, and weight loss during a yearlong behavioral weight loss program between individuals who have and have not previously been successful losing weight through self-regulating dietary intake. Individuals with prior success had greater weight losses over time than those without. Differences in baseline and change over time in some facets of motivation and self-efficacy were observed, but only differences in attendance accounted for differential weight loss. Prior success with dietary self-regulation may predict better adherence to and success in behavioral weight control programs. Evaluating the type of weight control efforts that have previously helped induce weight losses may help to better match individuals to treatments likely to yield success. PMID- 28895017 TI - Total Pancreatectomy With Islet Autotransplantation for Acute Recurrent and Chronic Pancreatitis. AB - PURPOSE OF REVIEW: The first total pancreatectomy and islet autotransplantation (TP-IAT) was performed for chronic pancreatitis in 1977 with the goal to ameliorate the pain and simultaneously preserve islet function. We reviewed the recent medical literature regarding indications, patient suitability, current outcomes, and challenges in TP-IAT. RECENT FINDINGS: Current indications for TP IAT include intractable pain secondary to chronic pancreatitis (CP) or acute recurrent pancreatitis (ARP) with failed medical and endoscopic/surgical management. Independent studies have shown that TP-IAT is associated with elimination or significant improvement in pain control and partial or full islet graft function in the majority of patients. In single-center cost analyses, TP IAT has been suggested to be more cost-effective than medical management of chronic pancreatitis. While initially introduced as a surgical option for adults with long-standing chronic pancreatitis, TP-IAT is now often utilized in children with chronic pancreatitis and in children and adults with intractable acute recurrent pancreatitis. The surgical procedure has evolved over time with some centers offering minimally invasive operative options, although the open approach remains the standard. Despite many advances in TP-IAT, there is a need for further research and development in disease diagnosis, patient selection, optimization of surgical technique, islet isolation and quality assessment, postoperative patient management, and establishment of uniform metrics for data collection and multicenter studies. TP-IAT is an option for patients with otherwise intractable acute recurrent or chronic pancreatitis which presents potential for pain relief and improved quality of life, often with partial or complete diabetes remission. PMID- 28895018 TI - Promotional effect of rare earth-doped manganese oxides supported on activated semi-coke for selective catalytic reduction of NO with NH3. AB - A composite catalyst for the selective catalytic reduction (SCR) of NOx with NH3 is investigated, in which the rare earth (RE, including La, Ce, Pr, and Nd) is doped into manganese oxides supported on activated semi-coke (MnOx/ASC) via hydrothermal method at the molar ratio of Mn:RE = 1:5. It is evidenced that the addition of RE at a rather low molar ratio can enhance the catalytic activity of MnOx/ASC. The catalyst with a Mn:Ce molar ratio of 10:1 yields an over 90% NOx removal efficiency in the temperature range of 150-250 degrees C. An approximate 100% NO conversion and 95% N2 selectivity are achieved at about 200 degrees C. The catalysts are characterized by N2 physisorption, X-ray powder diffraction (XRD), scanning electron microscope (SEM), hydrogen temperature-programmed reduction (H2-TPR) and X-ray photoelectron spectroscopy (XPS). The results indicated that the Ce additive is conducive to the NOx adsorption and then accelerates the SCR reaction due to the formation of more chemisorbed oxygen (Obeta), which is favored during the oxidation of NH3 and NO. Moreover, the in situ diffused reflectance infrared Fourier transform spectroscopy (DRIFTS) results confirm that the Ce additive on MnOx/ASC catalyst could provide more active Bronsted acid sites, which eventually contributes to the SCR reaction. The generation of ad-NH4+ and nitrite species is proved to play the crucial role in the promotional effect of RE addition. PMID- 28895019 TI - Narrative self-appropriation: embodiment, alienness, and personal responsibility in the context of borderline personality disorder. AB - It is often emphasised that persons diagnosed with borderline personality disorder (BPD) show difficulties in understanding their own psychological states. In this article, I argue that from a phenomenological perspective, BPD can be understood as an existential modality in which the embodied self is profoundly saturated by an alienness regarding the person's own affects and responses. However, the balance of familiarity and alienness is not static, but can be cultivated through, e.g., psychotherapy. Following this line of thought, I present the idea that narrativising experiences can play an important role in processes of appropriating such embodied self-alienness. Importantly, the notion of narrative used is that of a scalar conception of narrativity as a variable quality of experience that comes in degrees. From this perspective, narrative appropriation is a process of gradually attributing the quality of narrativity to experiences, thereby familiarising the moods, affects, and responses that otherwise govern 'from behind'. Finally, I propose that the idea of a narrative appropriation of embodied self-alienness is also relevant to the much-debated question of personal responsibility in BPD, particularly as this question plays out in psychotherapeutic contexts where a narrative self-appropriation may facilitate an increase in sense of autonomy and reduce emotions of guilt and shame. PMID- 28895020 TI - Role of Type 2 Innate Lymphoid Cells in Allergic Diseases. AB - PURPOSE OF REVIEW: The adaptive immune response orchestrated by type 2 T helper (Th2) lymphocytes, strictly cooperates with the innate response of group 2 innate lymphoid cells (ILC2), in the protection from helminths infection, as well as in the pathogenesis of allergic disease. The aim of this review is to explore the pathogenic role of ILC2 in different type 2-mediated disorders. RECENT FINDINGS: Recent studies have shown that epithelial cell-derived cytokines and their responding cells, ILC2, play a pathogenic role in bronchial asthma, chronic rhinosinusitis, and atopic dermatitis. The growing evidences of the contribution of ILC2 in the induction and maintenance of allergic inflammation in such disease suggest the possibility to target them in therapy. Biological therapies blocking ILC2 activation or neutralizing their effector cytokines are currently under evaluation to be used in patients with type 2-dominated diseases. PMID- 28895021 TI - K-band Doppler radar for contact-less overnight sleep marker assessment: a pilot validation study. AB - An estimated 45 million persons in Europe are annually subjected to sleep-wake disorders. State-of-the-art polysomnography provides sophisticated insights into sleep (patho)physiology. A drawback of the method, however, is the obtrusive setting dependent on a clinical-based sleep laboratory with high operational costs. A contact-less prototype was developed to monitor limb movements and vital signs during sleep. A dual channel K-band Doppler radar transceiver captured limb movements and periodic chest wall motion due to respiration and heart activity. A wavelet transform based multi-resolution analysis (MRA) approach isolated limb movements, respiration, and heart rate from the demodulated signal. A test bench setup characterized the prototype simulating near physiological chest wall motions caused by periodic respiration and heartbeats in humans. Single- and multi-tone test bench simulations showed extremely low relative percentage errors of the prototype for respiratory and heart rate within -2 and 1%. The performance of the prototype was validated in overnight comparative studies, involving two healthy volunteers, with polysomnography as the reference. The prototype has successfully classified limb movements, with a sensitivity and specificity of 88.9 and 76.8% respectively, and has achieved accurate respiratory and heart rate measurement performance with overall absolute errors of 1 breath per minute for respiration and 3 beats per minute for heart rate. This pilot study shows that K band Doppler radar and wavelet transform MRA seem to be valid for overnight sleep marker assessment. The contact-less approach might offer a promising solution for home-based sleep monitoring and assessment. PMID- 28895023 TI - Israel rake retractor modification to improve exposure during oropharyngeal surgery on patients with larger body habitus. AB - PURPOSE: Elective oropharyngeal surgery including tonsillectomy and uvulopalatopharyngoplasty performed for obstructive sleep apnea is increasingly performed on patients of larger body habitus. The use of the Crowe-Davis retractor in such patients may be complicated by a large barrel-chest making it difficult to anchor the retractor to the Mayo stand for suspension limiting oropharyngeal exposure. Here, we present a simple modification using the Israel Retractor to facilitate suspension of the Crowe-Davis mouth gag. METHODS: Operational instructions were followed for Israel retractor modification in oropharyngeal surgery. RESULTS: The Crowe-Davis retractor is able to anchor to the Israel retractor, whose prongs articulate on the Mayo Stand for suspension. This extension allows suspension of patients with larger body habitus in oropharyngeal surgery. CONCLUSIONS: Use of the Israel retractor as an extension of the Crowe-Davis retractor handle provides an easy, quick, safe, and reliable method for placing patients of larger body habitus into suspension. PMID- 28895022 TI - Subcellular pigment distribution is altered under far-red light acclimation in cyanobacteria that contain chlorophyll f. AB - Far-Red Light (FRL) acclimation is a process that has been observed in cyanobacteria and algae that can grow solely on light above 700 nm. The acclimation to FRL results in rearrangement and synthesis of new pigments and pigment-protein complexes. In this study, cyanobacteria containing chlorophyll f, Synechococcus sp. PCC 7335 and Halomicronema hongdechloris, were imaged as live cells with confocal microscopy. H. hongdechloris was further studied with hyperspectral confocal fluorescence microscopy (HCFM) and freeze-substituted thin section transmission electron microscopy (TEM). Under FRL, phycocyanin-containing complexes and chlorophyll-containing complexes were determined to be physically separated and the synthesis of red-form phycobilisome and Chl f was increased. The timing of these responses was observed. The heterogeneity and eco physiological response of the cells was noted. Additionally, a gliding motility for H. hongdechloris is reported. PMID- 28895024 TI - Tuberculosis Meningitis. AB - PURPOSE OF REVIEW: As the most severe form of tuberculosis (TB), TB meningitis disproportionately affects developing countries and results in significant morbidity and mortality. In this report, we review recent updates in the epidemiology, diagnosis, and management of TB meningitis. RECENT FINDINGS: Young children and people living with HIV continue to be at highest risk for TB meningitis. Early diagnosis remains challenging, especially since conventional diagnostic tests have sub-optimal sensitivity and specificity. Recently, nucleic acid amplification testing emerged as the preferred diagnostic modality due to its rapid turnaround time and high specificity. Several recent studies have assessed the optimal treatment for TB meningitis. While the benefit of treatment intensification, by increasing rifampin dosing or adding a fluoroquinolone, is unclear, a growing body of evidence suggests that steroids confer a survival advantage, particularly in patients with mild disease. Additionally, TB meningitis management is further complicated by high rates of HIV co-infection. Recent data suggest that unlike other forms of TB, early initiation of antiretroviral therapy in patients with TB meningitis is associated with higher rates of adverse reactions, without improved survival. TB meningitis continues to be a significant problem worldwide. Despite recent advances, more studies are warranted to improve early disease detection and optimize therapy. PMID- 28895025 TI - Leaching variations of heavy metals in chelator-assisted phytoextraction by Zea mays L. exposed to acid rainfall. AB - Chelant-enhanced phytoextraction method has been put forward as an effective soil remediation method, whereas the heavy metal leaching could not be ignored. In this study, a cropping-leaching experiment, using soil columns, was applied to study the metal leaching variations during assisted phytoextraction of Cd- and Pb polluted soils, using seedlings of Zea mays, applying three different chelators (EDTA, EDDS, and rhamnolipid), and artificial rainfall (acid rainfall or normal rainfall). It showed that artificial rainfall, especially artificial acid rain, after chelator application led to the increase of heavy metals in the leaching solution. EDTA increased both Cd and Pb concentrations in the leaching solution, obviously, whereas EDDS and rhamnolipid increased Cd concentration but not Pb. The amount of Cd and Pb decreased as the leaching solution increased, the patterns as well matched LRMs (linear regression models), with R-square (R 2) higher than 90 and 82% for Cd and Pb, respectively. The maximum cumulative Cd and Pb in the leaching solutions were 18.44 and 16.68%, respectively, which was amended by EDTA and acid rainwater (pH 4.5), and followed by EDDS (pH 4.5), EDDS (pH 6.5), rhamnolipid (0.5 g kg-1 soil, pH 4.5), and rhamnolipid (pH 6.5). PMID- 28895027 TI - The Aging Urban Brain: Analyzing Outdoor Physical Activity Using the Emotiv Affectiv Suite in Older People. AB - This research directly assesses older people's neural activation in response to a changing urban environment while walking, as measured by electroencephalography (EEG). The study builds on previous research that shows changes in cortical activity while moving through different urban settings. The current study extends this methodology to explore previously unstudied outcomes in older people aged 65 years or more (n = 95). Participants were recruited to walk one of six scenarios pairing urban busy (a commercial street with traffic), urban quiet (a residential street) and urban green (a public park) spaces in a counterbalanced design, wearing a mobile Emotiv EEG headset to record real-time neural responses to place. Each walk lasted around 15 min and was undertaken at the pace of the participant. We report on the outputs for these responses derived from the Emotiv Affectiv Suite software, which creates emotional parameters ('excitement', 'frustration', 'engagement' and 'meditation') with a real-time value assigned to them. The six walking scenarios were compared using a form of high dimensional correlated component regression (CCR) on difference data, capturing the change between one setting and another. The results showed that levels of 'engagement' were higher in the urban green space compared to those of the urban busy and urban quiet spaces, whereas levels of 'excitement' were higher in the urban busy environment compared with those of the urban green space and quiet urban space. In both cases, this effect is shown regardless of the order of exposure to these different environments. These results suggest that there are neural signatures associated with the experience of different urban spaces which may reflect the older age of the sample as well as the condition of the spaces themselves. The urban green space appears to have a restorative effect on this group of older adults. PMID- 28895026 TI - Growth arrest-specific protein 7 regulates the murine M1 alveolar macrophage polarization. AB - : Growth arrest-specific gene 7 (Gas7) is preferentially expressed in terminally differentiated brain cells and plays a crucial role during neuronal development and neurite outgrowth. Apart from that, Gas7 was found to be abundantly expressed in immune cells like murine macrophage without knowing the actual roles in immune reaction. By using the Illumina microarray analysis, we observed a clear induction of Gas7 but no other Gas family members in murine M1-polarized alveolar macrophage, which was further confirmed by RT-qPCR, Western blotting, and immunostaining analysis, suggesting a likelihood that Gas7 may participate in murine alveolar macrophage polarization. Moreover, we found that the upregulation of Gas7 in M1-polarized alveolar macrophage was almost fully blocked by IKK selective inhibitor BMS, which links Gas7 induction to nuclear factor kappa beta (NF-kappaB) signaling activation. Interestingly, we found that Gas7 knockdown by small interfering RNA transfection did not affect the pro-inflammatory cytokine gene Tnf and Ilb expression, whereas the expressions of canonic M1 marker gene Nos2 and other M1-dependent genes Il12b, Il6, Cxcl1, Cxcl2, and Cxcl9 were found to be reduced. Furthermore, Gas7-related M1 gene expression in alveolar macrophage was not dependent on NF-kappaB and STAT1 pathway. Our results demonstrate that Gas7 is potentially involved in regulation of murine M1 alveolar macrophage polarization. HIGHLIGHTS: Gas7 was induced in LPS/IFNgamma mediated M1 polarization. Gas7 are induced during time course of M1 polarization. Gas7 upregulation was dependent on NF-kappaB pathway in M1 polarized AMs. Gas7 knockdown reduced the M1 markers gene expression in M1 polarized AMs. PMID- 28895028 TI - Prevalence of QT interval prolonging drug-drug interactions (QT-DDIs) in psychiatry wards of tertiary care hospitals in Pakistan: a multicenter cross sectional study. AB - Background QT prolongation and associated arrhythmias, torsades de pointes (TdP), are considerable negative outcomes of many antipsychotic and antidepressant agents frequently used by psychiatric patients. Objective To identify the prevalence, levels, and predictors of QT prolonging drug-drug interactions (QT DDIs), and AZCERT (Arizona Center for Education and Research on Therapeutics) classification of drugs involved in QT-DDIs. Setting Psychiatry wards of three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. Method This was a multicenter cross-sectional study. Micromedex DrugReax was used for identification of QT-DDIs. TdP risks were identified by the AZCERT classification. Multivariate logistic regression analysis was performed to identify predictors of QT-DDIs. Main outcome measure Prevalence of QT-DDIs (overall, age-wise and gender-wise) and their levels of severity and documentation; AZCERT classes of drugs involved in QT-DDIs; and odds ratios for predictors of QT-DDIs. Results Of 600 patients, 58.5% were female. Median age was 25 years (IQR = 20-35). Overall 51.7% patients had QT-DDIs. Of total 698 identified QT-DDIs, most were of major-severity (98.4%) and fair-documentation (93.7%). According to the AZCERT classification, 36.4% of the interacting drugs were included in list-1 (known risk of TdP), 26.9% in list-2 (possible risk of TdP) and 27.5% in list-3 (conditional risk of TdP). Drugs commonly involved in QT DDI were olanzapine (n = 146), haloperidol (138), escitalopram (122), risperidone (91), zuclopenthixol (87), quetiapine (n80) and fluoxetine (74). In multivariate logistic regression analysis, QT-DDIs were significantly associated with 6-7 prescribed medications (p = 0.04) and >7 medications (p = 0.03). Similarly, there was significant association of occurrence of QT-DDIs with 2-3 QT drugs (p < 0.001) and >3 QT drugs (p < 0.001). Conclusion A considerable number of patients are exposed to QT-DDIs in psychiatry. There is a need to implement protocol for monitoring the outcomes of QT-DDIs. PMID- 28895029 TI - Chemical characteristics of soluble aerosols over the central Himalayas: insights into spatiotemporal variations and sources. AB - In order to investigate the spatial and temporal variations of aerosols and its soluble chemical compositions of the data gap zone in the central Himalayan region, aerosol samples were collected at four sites. The sampling location were characterized by four different categories, such as urban (Bode), semi-urban site in the northern Indo-Gangetic Plain (Lumbini), rural (Dhunche), and semiarid rural (Jomsom). A total of 230 aerosol samples were collected from four representative sites for a yearlong period and analyzed for water-soluble inorganic ions (WSIIs). The annual average aerosol mass concentration followed the sequence as Bode (238.24 +/- 162.24 MUg/m3)> Lumbini (161.14 +/- 105.95 MUg/m3)> Dhunche (112.40 +/- 40.30 MUg/m3)> Jomsom (78.85 +/- 34.28 MUg/m3), suggesting heavier particulate pollution in the urban and semi-urban sites. The total soluble ions contributed to 12.61-28.19% of TSP aerosol mass. The results revealed that SO42- and NO3- were the major anion and Ca2+ and NH4+ were the major cation influencing the aerosol composition over the central Himalayas. Calcium played a major role in neutralizing aerosol acidity followed by NH4+ at all the sites. The major compound of aerosol was (NH4)2SO4 and NH4HSO4 in the central Himalayas. Clear seasonality was observed at three observation sites, with higher concentrations during non-monsoon (dry periods) and lower during monsoon (wet period), suggesting washing out of aerosol particles by heavy precipitation during monsoon. In contrast, semiarid sites did not show the clear seasonal trend due to limited precipitation. Stationary sources were predominant over the mobile sources mostly in the remote sites. Principal component analysis confirmed that the major sources of WSIIs in the region were industrial emissions, fossil fuel and biomass burning, and crustal fugitive dusts. Nevertheless, transboundary aerosol transport over the region from polluted cities from south Asia could not be ignored as indicated by the clusters of air mass backward trajectory analysis. PMID- 28895030 TI - Type 2 diabetes and cardiovascular prevention: the dogmas disputed. AB - In randomized controlled trials (RCTs), more intensive glucose control in patients with type 2 diabetes leads to a modest (9%) reduction in major cardiovascular events (MACE), associated with a 20% reduction of kidney events and 13% reduction of eye events. The FDA issued guidance in 2008 led to the conduct of numerous cardiovascular outcomes (CVOT) trials to assess cardiovascular safety of new antihyperglycemic therapies in patients with type 2 diabetes. The results of these trials show that insulin glargine, three different dipeptidyl peptidase-4 (DPP-4) inhibitors (saxagliptin, alogliptin, and sitagliptin) and lixisenatide (a glucagon like peptide-1 receptor agonist) produce no significant difference in CVOT when compared with usual care or placebo. Other trials with newer diabetes drugs, including empagliflozin and canagliflozin (two sodium-glucose co-transporter-2 inhibitors), liraglutide and semaglutide (two GLP-1 receptor agonists) succeeded in demonstrating CV benefit in people with type 2 diabetes. In the last two decades, the equation "diabetes equals myocardial infarction" have contributed to the development of preventive therapy for risk factors in diabetes. In both primary and secondary prevention, the diabetic patients with high rates of statin and aspirin treatment have improved CV outcome, as compared with non-users. The drugs used to reduce glucose levels in patients with type 2 diabetes seem important for the ultimate cardiovascular outcome: the combination of intensive glycemic control, when safely attainable, with newer diabetes drugs (empagliflozin, canagliflozin, liraglutide, and semaglutide) may decrease the incidence of MACE, nephropathy and retinopathy. Moreover, depending on the drug used, CV mortality and heart failure may also be reduced. PMID- 28895031 TI - Utility of Endoanal Ultrasonography in Assessment of Primary and Recurrent Anal Fistulas and for Detection of Associated Anal Sphincter Defects. AB - BACKGROUND: Tridimensional endoanal ultrasonography (3D-EAUS) has been used for the assessment of various anorectal lesions. Previous studies have reported good accuracy of 3D-EAUS in preoperative assessment of fistula-in-ano (FIA). This study aimed to assess the diagnostic utility of 3D-EAUS in preoperative evaluation of primary and recurrent FIA and its role in detection of associated anal sphincter (AS) defects. PATIENTS AND METHODS: Prospectively collected data of patients with FIA who were investigated with 3D-EAUS were reviewed. The findings of EAUS were compared with the intraoperative findings, the reference standard, to find the degree of agreement regarding the position of the internal opening (IO) and primary tract (PT), and presence of secondary tracts using kappa (k) coefficient test. A subgroup analysis was performed to compare the accuracy and sensitivity of EAUS for primary and recurrent FIA. RESULTS: Of the patients, 131 were included to the study. EAUS had an overall accuracy of 87, 88.5, and 89.5% in detection of IO, PT, and AS defects, respectively. There was very good concordance between the findings of EAUS and intraoperative findings for the investigated parameters (kappa = 0.748, 0.83, 0.935), respectively. Accuracy and sensitivity of EAUS in recurrent FIA were insignificantly lower than primary cases. EAUS detected occult AS defects in 5.3% of the patients studied. CONCLUSION: The diagnostic utility of 3D-EAUS was comparable in primary and recurrent FIA. 3D-EAUS was able to detect symptomatic and occult AS defects with higher accuracy than clinical examination. PMID- 28895032 TI - Resection of Locally Advanced Pancreatic Cancer without Regression of Arterial Encasement After Modern-Era Neoadjuvant Therapy. AB - INTRODUCTION: Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy. METHODS: Sixty one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database. RESULTS: Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27-32.33) and 8.5 months (95%CI 6.0-15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0-79.7) and 39.0% (95%CI 23.7-53.8), respectively. CONCLUSION: With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging. PMID- 28895033 TI - Three-Category Classification of Magnetic Resonance Hearing Loss Images Based on Deep Autoencoder. AB - Hearing loss, a partial or total inability to hear, is known as hearing impairment. Untreated hearing loss can have a bad effect on normal social communication, and it can cause psychological problems in patients. Therefore, we design a three-category classification system to detect the specific category of hearing loss, which is beneficial to be treated in time for patients. Before the training and test stages, we use the technology of data augmentation to produce a balanced dataset. Then we use deep autoencoder neural network to classify the magnetic resonance brain images. In the stage of deep autoencoder, we use stacked sparse autoencoder to generate visual features, and softmax layer to classify the different brain images into three categories of hearing loss. Our method can obtain good experimental results. The overall accuracy of our method is 99.5%, and the time consuming is 0.078 s per brain image. Our proposed method based on stacked sparse autoencoder works well in classification of hearing loss images. The overall accuracy of our method is 4% higher than the best of state-of-the-art approaches. PMID- 28895034 TI - Whole-body biodistribution and the influence of body activity on brain kinetic analysis of the 11C-PiB PET scan. AB - Dynamic 11C-PiB PET imaging with kinetic analysis has been performed for accurate quantification of amyloid binding in patients with Alzheimer's disease (AD). In this study, we measured the whole-body biodistribution of 11C-PiB in nine subjects. We then evaluated the effect of body activity on quantitative accuracy of brain 11C-PiB three-dimensional (3D) dynamic PET. Based on clinical biodistribution data, we conducted phantom experiments to estimate the effect of body activity on quantification of the brain 3D dynamic 11C-PiB PET data and the error introduced by body activity using six different PET camera models. One of the PET cameras was used to acquire 11C-PiB brain 3D dynamic PET data on a patient with AD. We calculated the distribution volume ratio (DVR) in two kinetic methods using both the original human time-activity-curve (TAC) data and the TAC corrected for the error caused by body activity. In the early phase, both healthy subjects and patients with AD showed a biodistribution of 11C-PiB that reflected regional blood flow. In the simulated early phase of the phantom experiments, activity outside the field of view led to a maximum 6.0% overestimation of brain activity in the vertex region. Conversely, the effect of body activity on the DVR estimate was small (<=1.2%), probably because the tested kinetic methods did not rely heavily on early phase data. These results indicate that the effect of body activity on brain 11C-PiB PET quantification is generally small and that it depends on the method of kinetic analysis, the region of interest, and the PET camera model used. PMID- 28895035 TI - Splenectomy vs. rituximab as a second-line therapy in immune thrombocytopenic purpura: a single center experience. AB - Immune thrombocytopenic purpura (ITP) is a common hematological disease treated primarily by corticosteroids. The aim of the present study was to compare response rate between patients, underwent splenectomy vs. rituximab as second line therapy. Adult patients diagnosed with ITP who did not respond to corticosteroids or relapsed during the period 1990-2014 were included in a quasi experimental study. Categorical variables were compared using Fisher exact test. Response to treatment was compared using logistic regression. Data were analyzed using SAS V9.2. One-hundred and forty-three patients with ITP were identified through medical records. Of 62 patients treated, 30 (48.38%) required second-line therapy. 19 (63%) patients received rituximab, and 11 (37%) underwent splenectomy. Platelets at diagnosis were not different between study groups (p = 0.062). Splenectomy group patients were younger (p = 0.011). Response to second line therapy showed no significant difference between two groups (OR 2.03, 95% CI (0.21-22.09), p = 0.549). Results did not show a statistically significant difference in platelet counts over time between treatment groups (p = 0.101). When used exclusively as a second-line therapy for steroid-refractory ITP, the response rate was not statistically different between rituximab and splenectomy. However, further large studies are needed to assess the response rates for these treatment modalities as a second-line therapy. PMID- 28895036 TI - Independent Effects of Neighborhood Poverty and Psychosocial Stress on Obesity Over Time. AB - The objective of the study was to examine the independent effects of neighborhood poverty and psychosocial stress on increases in central adiposity over time. Data are from a community sample of 157 Non-Hispanic Black, Non-Hispanic White, and Hispanic adults collected in 2002-2003 and 2007-2008, and from the 2000 Decennial Census. The dependent variable was waist circumference. Independent variables included neighborhood poverty, perceived neighborhood physical environment, family stress, safety stress, everyday unfair treatment, and a cumulative stress index. Weighted 3-level hierarchical linear regression models for a continuous outcome were used to assess the effects of neighborhood poverty and psychosocial stress on central adiposity over time. We also assessed whether psychosocial stress mediated the association between neighborhood poverty and central adiposity. Neighborhood poverty and everyday unfair treatment at baseline were independently associated with increases in central adiposity over time, accounting for the other indicators of stress. Perceptions of the neighborhood physical environment and cumulative stress mediated associations between neighborhood poverty and central adiposity. Results suggest that residing in neighborhoods with higher concentrations of poverty and exposure to everyday unfair treatment independently heighten risk of increased central adiposity over time. Associations between neighborhood poverty and central adiposity were mediated by perceptions of the neighborhood physical environment and by the cumulative stress index. Public health strategies to reduce obesity should consider neighborhood poverty and exposure to multiple sources of psychosocial stress, including everyday unfair treatment. PMID- 28895037 TI - Management of Acute Sleeve Gastrectomy Leaks by Conversion to Roux-en-Y Gastric Bypass: a Small Case Series. AB - Management of early sleeve gastrectomy leak remains challenging. The recommended approach is endoscopic stenting and abdominal drainage. Conversion to a Roux-en-Y gastric bypass (RYGB) is a common procedure used for late fistulas with distal obstruction. Here, we have presented three cases of early staple line leaks treated by conversion to RYGB. These patients had uncontrolled abdominal infections despite intensive medical treatments, and surgery was elected for abdominal drainage as well as to control the source of sepsis. All the patients were discharged without problems, and successful weight loss processes continued. Conversion to RYGB of a sleeve gastrectomy leak in an acute setting can be a feasible method in the case of inevitable surgical drainage for abdominal sepsis. PMID- 28895038 TI - A retrospective external validation study of the HEART score among patients presenting to the emergency department with chest pain. AB - Emergency physicians must be able to effectively prognosticate outcomes for patients presenting to the Emergency Department (ED) with chest pain. The HEART score offers a prognostication tool, but external validation studies are limited. We conducted an external retrospective validation study of the HEART score among ED patients presenting to our ED with chest pain from 1 January 2014 to 9 June 2014. We utilized chart review methodology to abstract data from each patient's electronic medical record. We collected data relevant to each of the five elements of the HEART score: history, electrocardiogram (ECG) interpretation, patient age, patient risk factors, and troponin levels. We calculated the diagnostic accuracy of the HEART score (0-10) for predicting the primary outcome of major adverse cardiac events (MACE) over 6 weeks following the ED visit (coronary revascularization, myocardial infarction, or mortality). We randomly selected 10% of patient charts from which a second investigator abstracted all data to assess inter-rater reliability for all study variables. Of 625 charts reviewed, we abstracted data on 417 (66.7%) consecutive patients meeting study inclusion criteria. Thirty-one (7.4%) of these patients experienced 6-week MACE. We observed no instances of MACE within 6 weeks among subjects with a HEART score of 3 or less. The area under the receiver operator curve (AUROC) is 0.885 (95% confidence interval 0.838-0.931). Patients with a HEART score <=3 are at low risk for 6-week MACE. Hence, these patients may be candidates for outpatient follow-up instead of inpatient admission for cardiac risk stratification. PMID- 28895039 TI - Wheezing in Infancy: An Overview of Recent Literature. AB - PURPOSE OF REVIEW: Wheezing in infancy is a common presentation with many potential causes. In writing this review, we sought to summarize the newest recommendations and testing available for the more common etiologies of wheezing. RECENT FINDINGS: Regarding the diagnosis of asthma, the modified asthma predictive index has recently been established as a useful predictive tool. Non breath held multidetector CT with 3D volume rendering airway images is also a newer helpful diagnostic tool for tracheomalacia due to ease of use and its 100% positive predictive value. We found vaccines have greatly reduced the prevalence of epiglottitis, while advances in surgery are improving outcomes in infants with vascular rings. Wheezing in infants is a common problem with an extensive differential diagnosis from relatively benign to life threatening. To prevent over-looking a diagnosis that potentially requires surgical correction or emergent care, we recommend a structured approach to the history and physical exam with targeted testing directed towards the most likely diagnoses as outlined in this review. PMID- 28895040 TI - Clinical utility of ultra-low-dose pre-test exposure to avoid unnecessary patient exposure due to positioning errors: a simulation study. AB - The use of digital radiographic systems has decreased the frequency of image retakes due to over/underexposure in general radiography. However, image retakes owing to patient positioning errors are likely to increase because of the convenience of a real-time image check on a console table. The purpose of the present study is to propose a novel radiographic examination procedure with an ultra-low-dose pre-test exposure that may be utilized to check patient positioning prior to taking an actual image, thereby reducing unnecessary patient exposure owing to image retakes. In this study, examination data from 714 knee joint radiographs, both submitted and retaken images, were included. Twelve radiological technologists (RTs) took all images. The actual total exposure dose for each patient was compared with simulated total doses utilized in the proposed procedure. The simulation assumed that each examination was completed following pre-test exposure. Therefore, this method did not involve retaking images although at least one pre-test exposure had been applied to all patients. Pre test exposures at four dose levels corresponding to 25, 10, 5, and 2% of the actual exposure dose were evaluated to determine whether each dose level could be used to check patient positioning. The results indicated that when the pre-test exposure dose rate was 10% or lower, the total exposure dose reduction equaled or exceeded 8% for all patients. The use of the proposed procedure reduced the total exposure dose for all patients when compared to the exposure dose calculated from records. PMID- 28895042 TI - Next Generation Sequencing in Diagnosis of MLPA Negative Cases Presenting as Duchenne/ Becker Muscular Dystrophies. PMID- 28895043 TI - Effects of Long-Term Caffeine Consumption on the Adenosine A1 Receptor in the Rat Brain: an In Vivo PET Study with [18F]CPFPX. AB - PURPOSE: Caffeine, a nonselective antagonist of adenosine receptors, is the most popular psychostimulant worldwide. Recently, a protective role of moderate chronic caffeine consumption against neurodegenerative diseases such as Alzheimer's and Parkinson's disease has been discussed. Thus, aim of the present study was an in vivo investigation of effects of long-term caffeine consumption on the adenosine A1 receptor (A1AR) in the rat brain. PROCEDURES: Sixteen adult, male rats underwent five positron emission tomography (PET) scans with the highly selective A1AR radioligand [18F]CPFPX in order to determine A1AR availability. After the first baseline PET scan, the animals were assigned to two groups: Caffeine treatment and control group. The caffeine-treated animals received caffeinated tap water (30 mg/kg bodyweight/day, corresponding to 4-5 cups of coffee per day in humans) for 12 weeks. Subsequently, caffeine was withdrawn and repeated PET measurements were performed on day 1, 2, 4, and 7 of caffeine withdrawal. The control animals were measured according to the same time schedule. RESULTS: At day 1, after 4.4 h of caffeine withdrawal, a significant decrease (- 34.5%, p < 0.001) of whole brain A1AR availability was observed. Unlike all other investigated brain regions in caffeine-treated rats, the hypothalamus and nucleus accumbens showed no significant intraindividual differences between baseline and first withdrawal PET scan. After approximately 27 h of caffeine withdrawal, the region- and group-specific effects disappeared and A1AR availability settled around baseline. CONCLUSIONS: The present study provides evidence that chronic caffeine consumption does not lead to persistent changes in functional availability of cerebral A1ARs which have previously been associated with neuroprotective effects of caffeine. The acute and region specific decrease in cerebral A1AR availability directly after caffeine withdrawal is most likely caused by residual amounts of caffeine metabolites disguising an unchanged A1AR expression at this early time-point. PMID- 28895041 TI - Unmet Needs in the Pathogenesis and Treatment of Vasculitides. AB - Despite the progress in the last years on the field of vasculitides, there are several unmet needs regarding classification, disease activity assessment, predictors of flares and complications, and type of treatment for the different forms. The 1990 American College of Rheumatology (ACR) classification criteria currently used to define giant cell arteritis and Takayasu arteritis were designed to discriminate between different types of vasculitides but not to differentiate vasculitis from other disorders. Recently, efforts have been made to overcome the shortcomings of the ACR criteria. The lack of an accepted definition of disease activity in large-vessel vasculitides presents a major challenge in creating useful and valid outcome tools for the assessment of disease course. Identification of predictors of flares can aid in optimizing therapeutic strategies, minimizing disease flares, and reducing treatment-related side effects. It is furthermore important to recognize and characterize the risk factor that might predict the manifestations associated with poor outcome and prognosis. Two RCTs have evidenced the efficacy of tocilizumab in addition to glucocorticoids (GCs) in the treatment of giant cell arteritis (GCA). However, the role of tocilizumab or other biological agents without GCs needs to be investigated. Recent observational studies have suggested that rituximab is also effective in patients with eosinophilic granulomatosis with polyangiitis and in antineutrophil cytoplasmic antibodies (ANCA)-negative patients with granulomatosis with polyangiitis and microscopic polyangiitis. Rituximab or anti TNF alfa may represent a possible alternative therapy in case of refractory or difficult to treat polyarteritis nodosa (PAN) patients. The new International Criteria for Behcet's Disease have shown a better sensitivity and a better accuracy compared to the older International Study Group on Behcet's Disease criteria. The EULAR recommendations for the management of Behcet's disease (BD) have been recently updated. However, the treatment of refractory disease is still a real challenge. PMID- 28895044 TI - Effect of Zinc Supplementation on Growth Performance, Intestinal Development, and Intestinal Barrier-Related Gene Expression in Pekin Ducks. AB - The current study was conducted to investigate the effect of zinc supplementation on the growth performance, intestinal morphology, and the transcription of the barrier function related genes in Pekin ducks. Seven-hundred and sixty-eight 1 day-old Pekin ducks were randomly assigned into six dietary treatments. Each treatment had eight replicates with 16 ducks per replicates. The ducks were fed either a corn-soybean meal basal diet or basal diets supplemented with 15, 30, 60, 120, and 240 mg zinc/kg from zinc sulfate. This experiment lasted for 5 weeks, and the jejunum sample were harvested at 14 and 35 days of age. Results have shown that diets supplemented with zinc significantly increased the duck body weight, average daily gain, and average daily feed intake in different period of experiment (P < 0.05); feed to gain ratio was decreased as the zinc level increased (P < 0.05). Zinc supplementation increased the villus height and decreased the crypt depth in jejunum of ducks (P < 0.05) at 14 and 35 days of age. The transcription of tight junction protein CLDN1, OCND, ZO-1, and ZO-3 in jejunum were increased (P < 0.05), and the messenger RNA (mRNA) levels of leak protein CLDN2 were decreased as the dietary zinc level increased (P < 0.05) at 14 and 35 days of age. The mRNA levels of chemical barrier-related genes MUC2 and TFF-2 in jejunum at 14 and 35 days of age were increased (P < 0.05) by zinc supplementation, and so did the transcription of immunological barrier-related genes lgA, pIgR, LYZ, and AvBD2 (P < 0.05). In conclusion, dietary zinc supplementation exhibited growth-promoting effect on Pekin duck, improved intestinal morphology, and enhanced the intestinal barrier integrity. PMID- 28895045 TI - Influence of Gd-EOB-DTPA on proton density fat fraction using the six-echo Dixon method in 3 Tesla magnetic resonance imaging. AB - The purpose of this study was to evaluate whether disodium gadoxetate (Gd-EOB DTPA) affects proton density fat fractions (PDFFs) during use of the multiecho Dixon (meDixon) method in phantom and simulation magnetic resonance imaging (MRI) studies at 3 T. Fat-water phantoms comprising vegetable fat-water emulsions with varying fat volume percentages (0, 5, 10, 15, 20, 30, 40, and 50) and Gd-EOB-DTPA concentrations (0 and 0.4 mM) were prepared. Phantoms without Gd-EOB-DTPA were defined as precontrast, and those with Gd-EOB-DTPA were defined as postcontrast. All phantoms were scanned with a 3 T MRI system using the meDixon method, and precontrast and postcontrast PDFFs were calculated. Simulated pre and postcontrast PDFFs in the liver were calculated using a theoretical formula. The relationship between PDFFs measured in the pre and postcontrast phantoms was evaluated using linear regression and Bland-Altman analysis. The regression analysis comparing the pre and postcontrast PDFFs yielded a slope of 0.77 (P < 0.001). The PDFFs on the postcontrast phantom were smaller than those on the precontrast phantom. The mean difference between the PDFFs on the pre and postcontrast phantoms was 6.12% (95% confidence interval 3.13 to 9.10%; limits of agreement -0.88 to 13.11%). The simulated PDFF on the postcontrast phantom was smaller than that on the precontrast phantom. We demonstrated that the PDFF measured using the meDixon was smaller on postcontrast than on precontrast at 3 T, if a low flip angle was used. This tendency was also seen in the simulation study results. PMID- 28895046 TI - Characterization of cadmium-resistant Klebsiella pneumoniae MCC 3091 promoted rice seedling growth by alleviating phytotoxicity of cadmium. AB - Cadmium (Cd) phytotoxicity in agricultural land is a major global concern now-a days resulting in very poor yield. Plant growth-promoting rhizobacteria (PGPR) mediated bioremediation is one of the convenient strategies for detoxification of Cd from the soil and for plant growth promotion under Cd stress. The selected strain K5 was identified as Klebsiella pneumoniae based on MALDI-TOF MS ribosomal protein and 16S rDNA sequence-based homology. The strain possessed several PGP traits viz. IAA production (3413 MUg/mL), phosphate solubilization (80.25 ppm), ACC deaminase activity (40 ng alpha-ketobutyrate/mg protein/h), N2 fixation ability (1.84 MUg N2 fixed/h), etc. and has the highest Cd resistance (4000 MUg/mL) among Cd-resistant PGPR so far reported. This strain efficiently accumulated Cd and remained viable under Cd stress as confirmed by AAS-TEM-EDX analysis and viability test, respectively. The significant (p < 0.05) positive effect of the strain was reflected in various plant growth parameters like increased seed germination (50 to 90%), root length (5-fold), shoot length (about 2-fold), root fresh weight (> 2-fold), and shoot fresh weight (1.23-fold) under Cd stress compared with uninoculated set. Moreover, the positive impact of this strain on antioxidant enzyme activity (CAT, MDA, SOD) and several other biochemical parameters (proline, alpha-amylase, protease, total sugar, total protein, chlorophyll content) were also measured that favors plant growth promotion under Cd stress. Besides, the K5 strain also decreased stress-ethylene level under Cd stress and reduction of Cd accumulation in seedling (> 1.5-fold) was conducive to alleviate Cd phytotoxicity. Hence, K. pneumoniae strain K5 can be used as a phytostimulating and Cd-bioremediating biofertilizer for sustainable agriculture in heavy metal-contaminated sites. PMID- 28895047 TI - Biochemical, hematological, and pathological related healing effects of Elaeagnus angustifolia hydroalcoholic extract in 5-fluorouracil-induced oral mucositis in male golden hamster. AB - Oral mucositis (OM) is one of the cancer chemotherapy-related side effects which can affect the quality of life of affected patients. This study was designed to investigate the healing effect of Elaeagnus angustifolia in 5-flurouracil (5-FU) induced OM in golden hamster. Fifty-six adult male golden hamsters received three intraperitoneal injections of 5-FU at a dose of 60 mg/kg on days 0, 5, and 10. The cheek pouch mucosa was scratched superficially under local anesthesia. Then, two horizontal scratches were made across the everted cheek pouch on days 3 and 4. All treatments were started on day 12 for equal number of animals in control group with no treatments, gel base group that was treated with carboxy methyl cellulose as gel base which used in preparation of the topical gel, topical gel group that used gel containing 10% hydroalcoholic extract of E. angustifolia (HEEA) topically, and dietary group which was treated with 300 mg/kg HEEA. At 2 and 5 days after treatment, blood and pouch tissue sampling were done and analyzed for blood composition, tissue malondialdehyde (MDA) level, and myeloperoxidase (MPO) and superoxide dismutase (SOD) activities plus histopathological evaluations. Both topically and orally HEEA-treated groups showed a significant relief in OM compared to the control and base gel groups. However, the systemic form had higher efficiency in some parts especially decreasing the MPO (0.27 +/- 0.17 vs. 0.56 +/- 0.17 IU/L) and increasing SOD (6.46 +/- 0.15 vs. 5.36 +/- 0.18 IU/L) activities in pouch tissue in comparison to topical form mostly at 5 days after treatment. It seems that hydroalcoholic extract of E. angustifolia can be used as an appropriate drug choice for the treatment of oral mucositis based on its healing stimulatory and anti inflammatory properties. PMID- 28895048 TI - Effects of abamectin on bullfrog tadpoles: insights on cytotoxicity. AB - Abamectin is one of the most used pesticides worldwide. However, investigations about its effects on amphibian populations are rare. Thus, the present study sought to investigate possible cytotoxic effects on Lithobates catesbeianus tadpoles exposed to low abamectin concentrations diluted in water. Accordingly, four experimental groups were set: negative control, positive control (cyclophosphamide-40 mL L-1), abamectin at concentrations 36 MUg a.i./L (ABA36 group), and 72 MUg a.i./L (ABA72 group), applied as Kraft(r) 36EC. The micronucleus test was conducted and other nuclear abnormalities in peripheral blood erythrocytes were checked after 24, 48, and 72 h of exposure to the treatments. The total of other nuclear abnormalities was influenced by the treatments, whereas the frequency of micronuclei was influenced by the exposure time. Such frequency was higher in the animals comprising the ABA72 group, which was assessed 72 h after the exposure had begun. The total of other nuclear abnormalities was influenced by the treatments. Animals in the positive control, ABA36, and ABA72 groups showed similar frequency of these abnormalities at 48 and 72 h. However, this frequency was statistically higher than that of animals in their respective negative control groups. Thus, the present study confirmed the hypothesis that the exposure of L. catesbeianus tadpoles to abamectin caused cytotoxic effects on them, although this exposure lasted short and the concentrations were low. It disclosed prospects for variations in the nucleus of erythrocytes circulating in amphibians, a fact that may provide an important/complementary approach for the detection of cytotoxicity caused by abamectin exposure. PMID- 28895049 TI - Mutation in GNE Downregulates Peroxiredoxin IV Altering ER Redox Homeostasis. AB - GNE myopathy is a rare neuromuscular genetic disorder characterized by early adult onset and muscle weakness due to mutation in sialic acid biosynthetic enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). More than 180 different GNE mutations are known all over the world with unclear pathomechanism. Although hyposialylation of glycoproteins is speculated to be the major cause, but cellular mechanism leading to loss of muscle mass has not yet been deciphered. Besides sialic acid biosynthesis, GNE affects other cellular functions such as cell adhesion and apoptosis. In order to understand the effect of mutant GNE protein on cellular functions, differential proteome profile of HEK293 cells overexpressing pathologically relevant recombinant mutant GNE protein (D207V and V603L) was analyzed. These cells, along with vector control and wild-type GNE-overexpressing cells, were subjected to two-dimensional gel electrophoresis coupled with mass spectrometry (MALDI-TOF/TOF MS/MS). In the study, 10 differentially expressed proteins were identified. Progenesis same spots software revealed downregulation of peroxiredoxin IV (PrdxIV), an ER resident H2O2 sensor that regulates neurogenesis. Significant reduction in mRNA and protein levels of PrdxIV was observed in GNE mutant cell lines compared with vector control. However, neither total reactive oxygen species was altered nor H2O2 accumulation was observed in GNE mutant cell lines. Interestingly, ER redox state was significantly affected due to reduced normal GNE enzyme activity. Our study indicates that downregulation of PrdxIV affects ER redox state that may contribute to misfolding and aggregation of proteins in GNE myopathy. PMID- 28895050 TI - Design of 2-Nitroimidazooxazine Derivatives as Deazaflavin-Dependent Nitroreductase (Ddn) Activators as Anti-Mycobacterial Agents Based on 3D QSAR, HQSAR, and Docking Study with In Silico Prediction of Activity and Toxicity. AB - Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q 2) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis. PMID- 28895051 TI - Polymyxin Resistance in Gram-negative Pathogens. AB - PURPOSE OF REVIEW: The polymyxins are one of the last line antimicrobial classes to retain activity against multidrug-resistant Gram-negative bacilli. However, with the increased use of polymyxins in recent years, reports of resistance have also been increasing. We aimed to describe the mechanisms and occurrence of polymyxin resistance in Gram-negative organisms and propose strategies to overcome resistance. RECENT FINDINGS: The most common mechanism of acquired resistance to the polymyxins is via modification of the bacterial outer membrane lipopolysaccharide. Global epidemiological surveillance studies have reported the occurrence of polymyxin resistance to be most common in Enterobacteriaceae, specifically Enterobacter species and Acinetobacter baumannii. Prevalence of polymyxin-resistant Gram-negative organisms varies significantly by geographical location. Emergence of polymyxin resistance is of great concern, given the limited number of agents available to treat infections caused by multidrug resistant Gram-negative organisms. Strategies to mitigate the development of polymyxin resistance include dose optimization and using polymyxin agents in combination with other highly active antimicrobial agents. PMID- 28895052 TI - The Effects of Periostin in a Rat Model of Isoproterenol: Mediated Cardiotoxicity. AB - Periostin is an extracellular matrix protein from fasciclin family, and it plays an important role in the cell adhesion, migration, and growth of the organism. Periostin prevents apoptosis while stimulating cardiomyocytes. The present study was designed to investigate cardioprotective effects of the recombinant murine periostin peptide administration in a rat model of isoproterenol (ISO)-induced myocardial injury. The experiment was performed on 84 adult male Sprague Dawley rats in 4 groups (n = 21): control group (1), periostin-treated group (2), ISO treated group (3), and ISO + periostin-treated group (4). The groups were further divided into three subgroups based on the duration of the experiment in which rats were killed on days 1, 7, and 28 (n = 7). Growth factors (VEGF, ANGPT, FGF 2, TGFbeta), mitosis and apoptosis (Bcl-2, Bax, PCNA, Ki-67, phospho-histone H3), cell cycle activators and inhibitors (cyclin D1, D2, A2, Cdc2), the origin of regenerating cells (cKit and CD45) mRNA were detected using quantitative real time polymerase chain reaction (PCR) and PCR array. Immunohistochemistry staining was used to directly detect protein level and distribution in the heart tissues. Administration of periostin following ISO-induced cardiotoxicity revealed that periostin alleviated deleterious effects of ISO through several pathways: (1) periostin induced mitotic activity of endothelial/fibroblastic cells, (2) periostin drives cardiomyocytes into S and M phases, thus promoting proliferation of cardiomyocytes, (3) periostin contributed to collagen degradation, tissue remodeling, and reduced cardiac fibrosis during the healing process following myocardial damage while preserving tissue matrix, (4) periostin stimulated angiogenesis by upregulating THBS1, TGFB2, and HGF genes, (5) periostin regulated cell growth and proliferation while maintaining cell shape and cellular muscle contractions (ACTB) and functioned as chemoattractant factor (CCL2) at the beginning of myocardial damage. PMID- 28895053 TI - Drug delivery in female reproductive health. PMID- 28895054 TI - A Neuron-Specific Gene Therapy Relieves Motor Deficits in Pompe Disease Mice. AB - In Pompe disease, deficient lysosomal acid alpha-glucosidase (GAA) activity causes glycogen accumulation in the muscles, which leads to weakness, cardiomyopathy, and respiratory failure. Although glycogen accumulation also occurs in the nervous system, the burden of neurological deficits in Pompe disease remains obscure. In this study, a neuron-specific gene therapy was administered to Pompe mice through intracerebroventricular injection of a viral vector carrying a neuron-specific promoter. The results revealed that gene therapy increased GAA activity and decreased glycogen content in the brain and spinal cord but not in the muscles of Pompe mice. Gene therapy only slightly increased the muscle strength of Pompe mice but substantially improved their performance on the rotarod, a test measuring motor coordination. Gene therapy also decreased astrogliosis and increased myelination in the brain and spinal cord of Pompe mice. Therefore, a neuron-specific treatment improved the motor coordination of Pompe mice by lowering glycogen accumulation, decreasing astrogliosis, and increasing myelination. These findings indicate that neurological deficits are responsible for a significant burden in Pompe disease. PMID- 28895055 TI - Maqasid al-Shariah as a Complementary Framework for Conventional Bioethics: Application in Malaysian Assisted Reproductive Technology (ART) Fatwa. AB - Rapid development in the area of assisted reproductive technology (ART), has benefited mankind by addressing reproductive problems. However, the emergence of new technologies and techniques raises various issues and discussions among physicians and the masses, especially on issues related to bioethics. Apart from solutions provided using conventional bioethics framework, solutions can also be derived via a complementary framework of bioethics based on the Higher Objectives of the Divine Law (Maqasid al-Shariah) in tackling these problems. This approach in the Islamic World has been applied and localised in the Malaysian context. Thus, this paper highlights a conceptual theoretical framework for solving current bioethical issues, with a special focus on ART in the Malaysian context, and compares this theory with conventional theories of bioethics. PMID- 28895056 TI - Weaning from mechanical ventilation using tracheostomy cuff deflation and a one way speaking valve: a historical-cohort series. PMID- 28895057 TI - Triterpenoid saponins from Clinopodium chinense (Benth.) O. Kuntze and their biological activity. AB - Four new ursane-type triterpenoid saponins, clinopoursaponins A-D (1-4), six new oleanane-type triterpenoid saponins, clinopodiside VII-XII (5-10), as well as eight known triterpene analogues (11-18), were isolated from the aerial parts of Clinopodium chinense (Benth.) O. Kuntze. The structures of the new compounds were determined based on extensive spectral analyses, including 1D (1H and 13C) and 2D NMR experiments (COSY, NOESY, HSQC, 2D TOCSY, HSQC-TOCSY and HMBC), HR-ESI-MS and chemical methods. Compounds 1-18 were evaluated for their protective effects against anoxia/reoxygenation-induced apoptosis in H9c2 cells and cytotoxicities against murine mammary carcinoma cell line 4T1. Compounds 8, 9 and 18 exhibited significant protective effects, while compound 1 exhibited cytotoxic activity with IC50 value of 7.4 MUm compared to 7.6 MUm for the positive control 10 hydroxycamptothecin. PMID- 28895058 TI - A neuropathic pain syndrome associated with hantavirus infection. AB - Hantaviruses are a group of single-stranded RNA viruses of the Bunyaviridae family. "New World" hantaviruses cause hantavirus cardiopulmonary syndrome (HCPS) in North America. HCPS carries with it significant mortality and those patients who survive the disease are often left with substantial morbidity. Neurologic complications of hantavirus infections are rare, with only sparse cases of central nervous system involvement having been documented in the literature. To our knowledge, there are no reports of hantavirus infection contributing to peripheral nervous system dysfunction. Here we report a case of possible small fiber neuropathy associated with hantavirus infection, in a patient who survived HCPS. Persistent and treatment-resistant neuropathic pain may be a prominent feature in hantavirus-associated peripheral neuropathy. PMID- 28895060 TI - Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue. AB - The present investigation is an expansion of previous studies which all share a basic experimental protocol of a porcine-induced cardiac arrest (CA) of 12 min followed by 8 min of cardiopulmonary resuscitation (CPR), different experimental treatments (immediate as well as postponed induced mild hypothermia and administration of much or less cool intravenous fluids), and a follow-up period of 3 h after which the animals were sacrificed. Another group of animals was studied according to the same protocol after 12-min CA and "standard CPR." After death (within 1 min), the brains were harvested and frozen in liquid nitrogen awaiting analysis. Control brains of animals were collected in the same way after short periods of untreated CA (0 min, 5 min, and 15-30 min). Previous studies concerning chiefly neuropathological changes were now expanded with analyses of different tissue indicators (glutathione, luminol, leucigenin, malonialdehyde, and myeloperoxidase) of cerebral oxidative injury. The results indicate that a great part of oxidative injury occurs within the first 5 min after CA. Immediate cooling by administration of much intravenous fluid results in less cerebral oxidative injury compared to less intravenous fluid administration. A 30-min postponement of induction of hypothermia results in a cerebral oxidative injury comparable to that of "standard CPR" or the oxidative injury found after 5 min of untreated CA. Intravenous administration of methylene blue (MB) during and immediately after CPR in combination with postponed cooling resulted in no statistical difference in any of the indicators of oxidative injury, except myeloperoxidase, and glutathione, when this treatment was compared with the negative controls, i.e., animals subjected to anesthesia alone. PMID- 28895059 TI - Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals. AB - The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection. PMID- 28895061 TI - Valvular Heart Disease in Women, Differential Remodeling, and Response to New Therapies. AB - OPINION STATEMENT: In the United States, valvular heart disease (VHD) has a prevalence of 2.5%, most commonly presenting as aortic stenosis (AS) or mitral valve regurgitation (MR) and increasingly observed to be of a degenerative etiology. Women frequently have latent symptoms despite significant disease, and it is therefore pertinent to consider both clinical symptoms and imaging findings for decision-making on treatment. Indeed, significant advances have been made in noninvasive imaging allowing for more accurate diagnosis and disease prognostication. While echo remains the standard diagnostic test, multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) provide complementary information on aortic valve calcification and left ventricular (LV) function, respectively. For any given calcification load or increase in calcification density of the aortic valve, women have greater increase in aortic valve stenosis severity than men; thus, moderate AS in women warrants closer attention. MRI allows identification of different patterns of hypertrophy and remodeling, extent of LV fibrosis, and insights into differential reverse remodeling and clinical outcomes in men and women. In conjunction with surgical treatment, percutaneous technologies are being increasingly used in the management of VHD. Nearly 50% of patients undergoing transcatheter aortic valve replacement (TAVR) are women. In high- or intermediate-risk subjects with significant symptomatic AS, TAVR has been shown to be noninferior to surgical AVR (SAVR). Notably, whereas both treatment strategies are equally effective in men, transfemoral TAVR has been shown to be superior to SAVR resulting in better survival in women. Analogously, few data have examined sex differences with percutaneous MitraClip devices in the treatment of degenerative MR, and men and women appear to have equivalent composite outcomes. Randomized clinical trial data are presently awaited for outcomes in the percutaneous treatment of functional MR secondary to ischemic heart disease. This review discusses the current evidence in the diagnosis and treatment of VHD with a focus on sex differences in left-sided VHD and management in women. PMID- 28895062 TI - Effect of electrospinning parameters on morphological properties of PVDF nanofibrous scaffolds. AB - Smart materials like piezoelectric polymers represent a new class of promising scaffold in neural tissue engineering. In the current study, the fabrication processing parameters of polyvinylidine fluoride (PVDF) nanofibrous scaffold are found as a potential scaffold with nanoscale morphology and microscale alignment. Electrospinning technique with the ability to mimic the structure and function of an extracellular matrix is a preferable method to customize the scaffold features. PVDF nanofibrous scaffolds were successfully fabricated by the electrospinning technique. The influence of PVDF solution concentration and other processing parameters like applied voltage, tip-to-collector distance, feeding rate, collector speed and the solvent were studied. The optimal parameters were 30 w/v% PVDF concentration, 15 kV applied voltage, 18 cm tip-to-collector distance, 0.5 ml/h feeding rate, 2500 rpm collector speed and N,N' dimethylacetamide/acetone as a solvent. The mean fiber diameter of the obtained scaffold was 352.9 +/- 24 nm with uniform and aligned morphology. Finally, the cell viability and morphology of PC-12 cells on the optimum scaffold indicated the potential of PVDF nanofibrous scaffold for neural tissue engineering. PMID- 28895063 TI - Considerations in the Use of Body Mass Change to Estimate Change in Hydration Status During a 161-Kilometer Ultramarathon Running Competition. AB - Hydration guidelines found in the scientific and popular literature typically advise that body mass losses beyond 2% should be avoided during exercise. In this work, we demonstrate that these guidelines are not applicable to prolonged exercise of several hours where body mass loss does not reflect an equivalent loss of body water due to the effects of body mass change from substrate use, release of water bound with muscle and liver glycogen, and production of water during substrate metabolism. These effects on the body mass loss required to maintain body water balance are shown for a 161-km mountain ultramarathon running competition participant utilizing published data for the total energy cost, exogenous energy consumption and percentage from each fuel source, average participant body mass, and the extent of soft tissue fluid accumulation during an ultramarathon. We assumed that total energy derived from protein ranges from 5 to 10%, all exogenous energy is used to support the energy cost of the race, glycogen utilization ranges from 300 to 500 g, water linked with glycogen ranges from 1 to 3 g per g of glycogen, and the mass of the bladder and gastrointestinal tract is unchanged from pre-race to post-race body mass measurements. These calculations show that the average participant of 68.8 kg must lose 1.9-5.0% body mass to maintain the water supporting body water balance while also avoiding overhydration. Future hydration guidelines should consider these findings so that the proper hydration message is conveyed to those who participate in prolonged exercise. PMID- 28895064 TI - A mouse model of HIV-associated neurocognitive disorders: a brain-behavior approach to discover disease mechanisms and novel treatments. AB - HIV-associated neurocognitive disorders (HAND) remain highly prevalent despite combined antiretroviral therapy (cART). Although the most common forms of HAND are mild and identified through neuropsychological testing, there is evidence that with aging these mild forms become more prevalent and may advance to the most severe form of HAND, HIV-associated dementia. Therefore, novel therapies must be developed that can be used adjunctively with cART to prevent deterioration or restore normal cognitive function. In order to develop innovative treatments, animal models are used for preclinical testing. Ideally, a HAND animal model should portray similar mild cognitive deficits that are found in humans. A mouse model of HAND is discussed, which demonstrates mild behavioral deficits and has been used to investigate cART and novel treatments for HAND. This model also shows correlations between abnormal mouse behavior due to HIV in the brain and pathological parameters such as gliosis and neuronal abnormalities. A recent advancement utilizes the object recognition test to monitor mouse behavior before and after treatment. It is postulated that this model is well suited for preclinical testing of novel therapies and provides correlations of mild cognitive impairment with pathological markers that can give further insight into the pathophysiology of HAND. PMID- 28895065 TI - Structural Characterization of the Trimerization of TRAF6 Protein Through Molecular Dynamics Simulations. AB - The tumour necrosis factor (TNF) receptor-associated factor (TRAF) family of proteins having E3 ligase activity are the key molecules involved in cellular immune response pathways. TRAF6 is a unique member of the TRAF superfamily differing from other members of the family, owing to its specific interactions with molecules outside the TNF receptor superfamily. The C-terminal domain of TRAF proteins contains the catalytic residues and are known to be involved in self-oligomerization forming a mushroom-shaped trimeric structure, which is the functional form of the protein. However, the monomeric crystal structure of TRAF6 C-terminal domain has been already determined, but the trimeric structure of the same is still not available. We here applied computational structural modelling and molecular dynamics simulations studies to get insights into the molecular interactions involved in determining the trimeric structure of the TRAF6 C terminal domain. The non-availability of the trimeric structure of the TRAF6 C terminal domain prevented the elucidation of the molecular mechanism of many different biological processes. Our results suggest that the trimer complex is transient in nature. The amino acid residues Lys340 and Glu345 in the coiled coil domain in the C-terminus of TRAF6 play a critical role in trimer structure formation. This structural modelling study may therefore be utilized to obtain the experimentally validated trimeric structure of this important protein. PMID- 28895066 TI - The effect of short-term treatment with lithium carbonate on the outcome of radioiodine therapy in patients with long-lasting Graves' hyperthyroidism. AB - OBJECTIVE: The outcome of radioiodine therapy (RIT) in Graves' hyperthyroidism (GH) mainly depends on radioiodine (131I) uptake and the effective half-life of 131I in the gland. Studies have shown that lithium carbonate (LiCO3) enhances the 131I half-life and increases the applied thyroid radiation dose without affecting the thyroid 131I uptake. We investigated the effect of short-term treatment with LiCO3 on the outcome of RIT in patients with long-lasting GH, its influence on the thyroid hormones levels 7 days after RIT, and possible side effects. METHODS: Study prospectively included 30 patients treated with LiCO3 and 131I (RI-Li group) and 30 patients only with 131I (RI group). Treatment with LiCO3 (900 mg/day) started 1 day before RIT and continued 6 days after. Anti-thyroid drugs withdrawal was 7 days before RIT. Patients were followed up for 12 months. We defined a success of RIT as euthyroidism or hypothyroidism, and a failure as persistent hyperthyroidism. RESULTS: In RI-Li group, a serum level of Li was 0.571 +/- 0.156 mmol/l before RIT. Serum levels of TT4 and FT4 increased while TSH decreased only in RI group 7 days after RIT. No toxic effects were noticed during LiCO3 treatment. After 12 months, a success of RIT was 73.3% in RI and 90.0% in RI-Li group (P < 0.01). Hypothyroidism was achieved faster in RI-Li (1st month) than in RI group (3rd month). Euthyroidism slowly decreased in RI-Li group, and not all patients became hypothyroid for 12 months. In contrast, euthyroidism rapidly declined in RI group, and all cured patients became hypothyroid after 6 months. CONCLUSION: The short-term treatment with LiCO3 as an adjunct to 131I improves efficacy of RIT in patients with long-lasting GH. A success of RIT achieves faster in lithium-treated than in RI group. Treatment with LiCO3 for 7 days prevents transient worsening of hyperthyroidism after RIT. Short-term use of LiCO3 shows no toxic side effects. PMID- 28895067 TI - A GC-MS untargeted metabolomics analysis in the plasma and liver of rats lacking dipeptidyl-peptidase type IV enzyme activity. AB - This study was achieved with the aim to find metabolic changes between Fischer rats with different dipeptidyl peptidase-type 4 (DPPIV) expression. The DPPIV is an enzyme expressed in several tissues and is critically involved in the regulation of meal-related insulin secretion in healthy individuals. The metabolic consequences of chronic DPPIV inhibition were analyzed in a surrogate animal model of genetic enzyme deficiency. Hyphenated gas chromatography-mass spectrometry (GC-MS) and multivariate data analysis techniques were used to study the metabolic aqueous fraction profile of 18 plasma and liver samples in two syngeneic rat strains differing in DPPIV activity (DPPIV+ vs. DPPIV-). The hyperglycemic response following oral glucose administration was attenuated in DPPIV- rats, as expected. Statistical significant differences between the two strains were observed among the low molecular weight polar metabolites analyzed from plasma and liver.These included a decrease in malic acid and glutamine and an increase in pyroglutamic acid, serine, and alanine in plasma of DPPIV- rats. In addition, palmitic acid, L-proline, and ribitol were decreased in the liver of DPPIV- strain. Such alterations were compatible with a normal phenotype. These results suggest that long-term exposure to DPPIV inhibitors looks compatible with an overall balanced metabolism. PMID- 28895068 TI - Hughlings Jackson and the "doctrine of concomitance": mind-brain theorising between metaphysics and the clinic. AB - John Hughlings Jackson (1835-1911) is a major figure at the origins of neurology and neuroscience in Britain. Alongside his contributions to clinical medicine, he left a large corpus of writing on localisation of function in the nervous system and other theoretical topics. In this paper I focus on Jackson's "doctrine of concomitance"-his parallelist theory of the mind-brain relationship. I argue that the doctrine can be given both an ontological and a causal interpretation, and that the causal aspect of the doctrine is especially significant for Jackson and his contemporaries. I interpret Jackson's engagement with the metaphysics of mind as an instance of what I call meta-science-the deployment by scientists of metaphysical positions and arguments which help streamline empirical investigations by bracketing off unanswerable questions and focussing attention on matters amenable to the current tools of experimental research. PMID- 28895069 TI - Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study. AB - BACKGROUND: Standard treatment with sunitinib for patients with metastatic renal cancer provides an 'on-off' schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity. OBJECTIVE: The objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment. METHODS: Patients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles). RESULTS: Twenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension -82%, stomatitis -71%, cutaneous toxicity -69%). A reduction in 'on-off symptoms' (-86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression free survival was 16.4 months and median overall survival was 41.3 months. CONCLUSIONS: Despite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life. PMID- 28895070 TI - Needs for Professional Education to Optimize Cervical Cancer Screenings in Low Income Countries: a Case Study from Tanzania. AB - Cervical cancer is a significant health problem in many developing countries. Due to limited treatment facilities for cancer in Tanzania, a screening referral program was developed between two urban clinics and Ocean Road Cancer Institute (ORCI), the only cancer treatment center in Tanzania. This study aimed to evaluate the effectiveness of the program and to identify opportunities for professional education. The study included 139 patients who were referred to ORCI from the screening clinics of Magomeni and Temeke between January 2015 and May 2016. Abstracted data from the medical records included patient age, screening results, and treatment. Eight nurses performing screening at the three locations were interviewed about their screening experience. Over half of the referrals (51.9%) were false positives. False positive diagnosis was more common among younger patients (35.68 +/- 8.6 years) (p < 0.001) and those referred from Magomeni (59.8%) (p < 0.01) than referrals of older patients (42.46 +/- 11.1 years) or those from Temeke (33.3%). Interviews of nurses showed differences among clinics, including resources, experience, and documentation of screening results. The high false positive rates and the variation of accuracy of screening between the two clinics showed a need for professional education of nurses and improvement in the health systems. Continuous education of nurses may increase the effectiveness of cervical screening. Health system enhancement of screening facilities such as provision of Lugol's iodine, more space for screening, and consistency and completion of screening records are needed to increase the accuracy of cervical screening and referrals in Tanzania and other similar low income countries. PMID- 28895073 TI - Efficacy and Time Sensitivity of Amniotic Membrane treatment in Patients with Diabetic Foot Ulcers: A Systematic Review and Meta-analysis. AB - INTRODUCTION: Diabetic foot ulcers (DFUs) are complex chronic wounds which have a major long-term impact on the morbidity, mortality and quality of patients. The objective of this study was to assess the efficacy and time sensitivity of human amnion/chorion membrane treatment in patients with chronic DFUs. METHODS: The Cochrane Library, PubMed, Embase and Web of Science databases were systematically searched to identify relevant articles up to 10 April 2017. All randomized controlled trials (RCTs) comparing human amnion/chorion membrane + standard therapy and standard therapy alone in patients with DFUs were included in the analysis. Eligible studies were reviewed and data extracted into standard form. The Cochrane Collaboration's tool for assessing the risk of bias was used. Review manager version 5.3 software was used for statistical analysis. Data were analyzed using a random effect model. RESULTS: Overall, the initial search of the four databases identified 352 published studies; of these, seven RCTS were ultimately included in the meta-analysis. The overall test effect in the group assessed at 4 weeks was Z = 4.14 [P < 0.0001; odds ratio (OR) 0.05; 95% confidence interval (CI) 0.01-0.21]. The overall test effect in the group assessed at 6 weeks was Z = 4.28 (P < 0.0001; OR 0.07; 95% CI 0.02-0.23). The overall effect in the group assessed at 12 weeks was Z = 4.96 (P < 0.00001; OR 0.10; 95% CI 0.04-0.24. The results showed that patients receiving amniotic membrane + standard therapy had far fewer incomplete healing wounds than those receiving standard of care alone. Assessment of the wound healing state at 4 and 6 weeks revealed that the wound healing state was almost the same, but there was a net difference of wound healing state at 12 weeks. CONCLUSION: Human amnion/chorion membrane + standard of care treatment heals DFUs significantly faster than standard of care alone. When using the amnion in patients with DFUs, the optimal times to assess progress in wound healing should be 4 and 12 weeks. PMID- 28895071 TI - Bringing the HEET: The Argument for High-Efficacy Early Treatment for Pediatric Onset Multiple Sclerosis. AB - Pediatric-onset multiple sclerosis (POMS) is rarer than adult-onset disease, and represents a different diagnostic and treatment challenge to clinicians. We review POMS clinical and radiographic presentations, and explore important differences between POMS and adult-onset MS natural histories and long-term outcomes. Despite having more active disease, current treatment guidelines for patients with POMS endorse the off-label use of lower-efficacy disease-modifying therapies (DMTs) as first line. We review the available MS DMTs, their evidence for use in POMS, and the contrasting treatment strategies of high-efficacy early treatment and escalation therapy. We introduce a new treatment approach, the "high-efficacy early treatment", or HEET strategy, based on using directly observed, high-efficacy intravenously infused DMTs as first-line therapies. Like other proposed POMS treatment strategies, HEET will need to be prospectively studied, and all treatment decisions should be determined by an experienced neurologist, the patient, and his/her parents. PMID- 28895072 TI - Role of the inflammasome-related cytokines Il-1 and Il-18 during infection with murine coronavirus. AB - The inflammasome, a cytosolic protein complex that mediates the processing and secretion of pro-inflammatory cytokines, is one of the first responders during viral infection. The cytokines secreted following inflammasome activation, which include IL-1 and IL-18, regulate cells of both the innate and adaptive immune system, guiding the subsequent immune responses. In this study, we used murine coronavirus, mouse hepatitis virus (MHV), infection of the central nervous system and liver to assess of the role of the inflammasome and its related cytokines on pathogenesis and host defense during viral infection. Mice lacking all inflammasome signaling due to the absence of caspase-1 and -11 were more vulnerable to infection, with poor survival and elevated viral replication compared to wild-type mice. Mice lacking IL-1 signaling experienced elevated viral replication but similar survival compared to wild-type controls. In the absence of IL-18, mice had elevated viral replication and poor survival, and this protective effect of IL-18 was found to be due to promotion of interferon gamma production in alphabeta T cells. These data suggest that inflammasome signaling is largely protective during murine coronavirus infection, in large part due to the pro-inflammatory effects of IL-18. PMID- 28895074 TI - In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition. AB - BACKGROUND: Pharmacokinetics of direct oral anticoagulants (DOACs) are influenced by ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). OBJECTIVES: To better understand the role of transporters in DOAC disposition, we evaluated and compared the permeabilities and transport properties of these drugs. METHODS: Bidirectional permeabilities of DOACs were investigated across Caco-2 cells monolayer. Transport assays were performed using different concentrations of DOAC and specific inhibitors of ABC transporters. Cell model functionality was evaluated by transport assay of two positive control substrates. RESULTS: The results of transport assays suggest a concentration-dependent efflux of apixaban, dabigatran etexilate and edoxaban, whereas the efflux transport of rivaroxaban did not seem to depend on concentration. Verapamil, a strong inhibitor of P-gp, decreased DOAC efflux in the Caco-2 cell model by 12-87%, depending on the drug tested. Ko143 reduced BCRP-mediated DOAC efflux in Caco-2 cells by 46-76%. CONCLUSION: This study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP dependent transport (apixaban) and approximately equivalent P-gp and BCRP mediated transport (edoxaban and rivaroxaban). PMID- 28895075 TI - Milestones of Parkinson's Disease Research: 200 Years of History and Beyond. PMID- 28895077 TI - Vasospastic angina in a 16-year-old female. PMID- 28895076 TI - New Botanical Anxiolytics for Use in Companion Animals and Humans. AB - As part of our ongoing research into botanical therapies for anxiety disorders, the neotropical vine Souroubea sympetala was chosen for study as a phytochemical discovery strategy focusing on rare Central American plant families. When orally administered to male Sprague-Dawley rats, the crude plant extract, its ethyl acetate fraction, supercritical carbon dioxide fraction, or its isolated triterpenes reduced anxiety and/or fear-related behavior in standardized behavioral models. Pharmacological studies showed that the extracts acted at the benzodiazepine GABAA receptor and reduced corticosterone levels. A preparation containing Souroubea fortified with a second triterpene containing plant, Platanus occidentalis, was shown to be safe in a 28-day feeding trial with beagles at 5 times the intended dose. Subsequent trials with beagles in a thunderstorm model of noise aversion showed that the material reduced anxiety behaviors and cortisol levels in dogs. The formulation has been released for the companion animal market in Canada and the USA under the Trademark "Zentrol." Ongoing research is exploring the use of the material in treatment of anxiety and post-traumatic stress in humans. PMID- 28895078 TI - The Growth, Scope, and Spatial Distribution of People With Felony Records in the United States, 1948-2010. AB - The steep rise in U.S. criminal punishment in recent decades has spurred scholarship on the collateral consequences of imprisonment for individuals, families, and communities. Several excellent studies have estimated the number of people who have been incarcerated and the collateral consequences they face, but far less is known about the size and scope of the total U.S. population with felony convictions beyond prison walls, including those who serve their sentences on probation or in jail. This article develops state-level estimates based on demographic life tables and extends previous national estimates of the number of people with felony convictions to 2010. We estimate that 3 % of the total U.S. adult population and 15 % of the African American adult male population has ever been to prison; people with felony convictions account for 8 % of all adults and 33 % of the African American adult male population. We discuss the far-reaching consequences of the spatial concentration and immense growth of these groups since 1980. PMID- 28895079 TI - Visceral Adipose Tissue as a Risk Factor for Diabetes Mellitus in Patients with Chronic Pancreatitis: A Cross-sectional, Observational Study. AB - INTRODUCTION: Visceral adipose tissue (VAT) is a risk factor for diabetes and we investigated the amount of VAT in patients with chronic pancreatitis (CP). METHODS: Serial patients with CP seen between January 2015 and June 2016 were included in this cross-sectional, observational study. The study population was divided into alcoholic CP (group 1; N = 67) and tropical CP (group 2; N = 35). VAT was estimated using bioelectric impedance analysis (BIA) and dual energy X ray absorptiometry (DEXA) methods. The results were analyzed by appropriate statistical methods. RESULTS: The study participants (85 male, 17 female) had a mean (SD) age of 40.8 (12.6) years, CP duration of 3.7 (4.7) years, and body mass index of 22.5 (3.2) kg/m2. Pancreatogenic diabetes was seen in 54 patients and the total body fat percentage was lower in the alcoholic CP group. VAT mass was similar in both the groups (p = 0.8749). CP patients with diabetes had a higher VAT mass (436 vs. 341 g) than those without diabetes (p = 0.0132). DEXA and BIA correlated in estimation of total body fat (p < 0.0001) but not in VAT (p = 0.0922). CONCLUSION: VAT is a determinant in the development of diabetes, even in patients with CP. DEXA is a better modality for VAT estimation in comparison to BIA. PMID- 28895080 TI - Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia. AB - Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing. PMID- 28895081 TI - Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia. AB - Spinocerebellar ataxia 19/22 (SCA19/22) is a rare type of autosomal dominant SCA that was previously described in 11 families. We report the case of a 30-year-old Japanese man presenting with intellectual disability, early onset cerebellar ataxia, myoclonus, and dystonia without a family history. MRI showed cerebellar atrophy, and electroencephalograms showed paroxysmal sharp waves during hyperventilation and photic stimulation. Trio whole-exome sequencing analysis of DNA samples from the patient and his parents revealed a de novo novel missense mutation (c.1150G>A, p.G384S) in KCND3, the causative gene of SCA19/22, substituting for evolutionally conserved glycine. The mutation was predicted to be functionally deleterious by bioinformatic analysis. Although pure cerebellar ataxia is the most common clinical feature in SCA19/22 families, extracerebellar symptoms including intellectual disability and myoclonus are reported in a limited number of families, suggesting a genotype-phenotype correlation for particular mutations. Although autosomal recessive diseases are more common in patients with early onset sporadic cerebellar ataxia, the present study emphasizes that such a possibility of de novo mutation should be considered. PMID- 28895082 TI - Clinical manifestations and treatment outcomes of parvovirus B19 encephalitis in immunocompetent adults. AB - Parvovirus B19 (PVB19) has rarely been identified as a cause of encephalitis in immunocompetent adults, in whom clinical information regarding PVB19 encephalitis has remained unclear. Herein, we report the clinical presentations, laboratory and imaging findings, and treatment outcomes of five immunocompetent adults with PVB19 encephalitis. Although none of the patients showed any distinctive features of PVB19 infection, they showed various clinical manifestations, including one instance of brainstem involvement. Additionally, immunotherapy can be considered an effective approach, especially in immunocompetent adults with PVB19 encephalitis who are resistant to the initial management. PMID- 28895083 TI - Influence of Transition Metal Cationization versus Sodium Cationization and Protonation on the Gas-Phase Tautomeric Conformations and Stability of Uracil: Application to [Ura+Cu]+ and [Ura+Ag]. AB - The gas-phase conformations of transition metal cation-uracil complexes, [Ura+Cu]+ and [Ura+Ag]+, were examined via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical calculations. IRMPD action spectra were measured over the IR fingerprint and hydrogen-stretching regions. Structures and linear IR spectra of the stable tautomeric conformations of these complexes were initially determined at the B3LYP/6-31G(d) level. The four most stable structures computed were also examined at the B3LYP/def2-TZVPPD level to improve the accuracy of the predicted IR spectra. Two very favorable modes of binding are found for [Ura+Cu]+ and [Ura+Ag]+ that involve O2N3 bidentate binding to the 2 keto-4-hydroxy minor tautomer and O4 monodentate binding to the canonical 2,4 diketo tautomer of Ura. Comparisons between the measured IRMPD and calculated IR spectra enable elucidation of the conformers present in the experiments. These comparisons indicate that both favorable binding modes are represented in the experimental tautomeric conformations of [Ura+Cu]+ and [Ura+Ag]+. B3LYP suggests that Cu+ exhibits a slight preference for O4 binding, whereas Ag+ exhibits a slight preference for O2N3 binding. In contrast, MP2 suggests that both Cu+ and Ag+ exhibit a more significant preference for O2N3 binding. The relative band intensities suggest that O4 binding conformers comprise a larger portion of the population for [Ura+Ag]+ than [Ura+Cu]+. The dissociation behavior and relative stabilities of the [Ura+M]+ complexes, M+ = Cu+, Ag+, H+, and Na+) are examined via energy-resolved collision-induced dissociation experiments. The IRMPD spectra, dissociation behaviors, and binding preferences of Cu+ and Ag+ are compared with previous and present results for those of H+ and Na+. Graphical Abstract ?. PMID- 28895084 TI - The Oncologic Impact of Postoperative Complications Following Resection of Truncal and Extremity Soft Tissue Sarcomas. AB - INTRODUCTION: Postoperative complications (POCs) negatively impact oncologic outcomes in some malignancies; however, little is known regarding their effect in soft tissue sarcoma (STS). The aim of this study was to determine the impact of POCs on survival after resection of truncal and extremity STS. METHODS: All patients who underwent resection for a primary truncal or extremity STS at a single academic institution from 2000 to 2015 were included and analyzed. Primary outcome was disease-specific survival (DSS). RESULTS: Among 546 STS patients, POCs occurred in 159 (29%) patients; 57% were major and 55% were surgical site infections. Patients with POCs were older (61 vs. 53 years), had more comorbidities (50 vs. 38%), longer operative time (127 vs. 93 min), higher-grade tumors (93 vs. 86%), and were more likely to receive preoperative radiation (42 vs. 33%; all p < 0.05). There was no difference in receipt of postoperative therapy between the POCs and no POCs groups (19 vs. 18%, p = 0.74). Median follow up for survivors was 37 months, and the 5-year DSS for the entire cohort was 78%. Compared with patients without POCs, patients with POCs had a worse DSS (68% vs. 81%, p = 0.001). Predictors for decreased DSS on univariate analysis included POCs (hazard ratio [HR] 2.12, 95% confidence interval [CI] 1.37-3.28, p = 0.001), advanced age, neurovascular/bone resection, positive margin, high grade, and preoperative and postoperative therapy (all p < 0.05). POCs (HR 1.76, 95% CI 1.08 2.87, p = 0.02) remained an independent predictor for reduced DSS on multivariate analysis, along with age (HR 1.02, p = 0.046) and tumor grade (HR 7.62, p = 0.046). CONCLUSIONS: POCs following resection of truncal and extremity STS are associated with decreased DSS. Efforts to optimize modifiable risk factors and decrease the rate of POCs warrant further investigation. PMID- 28895085 TI - Use of an Open Port Sampling Interface Coupled to Electrospray Ionization for the On-Line Analysis of Organic Aerosol Particles. AB - A simple design for an open port sampling interface coupled to electrospray ionization (OPSI-ESI) is presented for the analysis of organic aerosols. The design uses minimal modifications to a Bruker electrospray (ESI) emitter to create a continuous flow, self-aspirating open port sampling interface. Considerations are presented for introducing aerosol to the open port sampling interface including aerosol gas flow and solvent flow rates. The device has been demonstrated for use with an aerosol of nicotine as well as aerosol formed in the pyrolysis of biomass. Upon comparison with extractive electrospray ionization (EESI), this device has similar sensitivity with increased reproducibility by nearly a factor of three. The device has the form factor of a standard Bruker/Agilent ESI emitter and can be used without any further instrument modifications. Graphical Abstract ?. PMID- 28895086 TI - Risk of look-a-like equipment in anesthesiology: it's not just medications. PMID- 28895087 TI - Benefit of Adjuvant Radiotherapy for Local Control, Distant Metastasis, and Survival Outcomes in Patients with Localized Soft Tissue Sarcoma: Comparative Effectiveness Analysis of an Observational Cohort Study. AB - BACKGROUND: This study aimed to quantify the benefit of adjuvant radiotherapy (AXRT) for local control, distant metastasis, and long-term survival outcomes in patients with localized soft tissue sarcoma (STS). METHODS: This single-center retrospective observational study enrolled 433 STS patients who underwent surgery with curative intent. An inverse probability of treatment-weighted (IPTW) analysis was implemented to account rigorously for imbalances in prognostic variables between the adjuvant treatment groups. RESULTS: During a median follow up period of 5.5 years, the study observed 38 local recurrences (9%), 73 occurrences of distant metastasis (17%), 63 STS-related deaths (15%), and 57 deaths from other causes (13%). As expected, patients receiving AXRT (n = 258, 60%) were more likely to have high-grade G3 tumors (p < 0.0001) than patients not receiving AXRT. A crude analysis showed that AXRT was not associated with improved recurrence-free survival [hazard ratio (HR) 1.00; 95% confidence interval (CI) 0.72-1.38; p = 0.98]. However, after IPTW, AXRT was associated with a 38% relative reduction in the risk of recurrence or death (HR 0.62; 95% CI 0.39 1.00; p = 0.05). This benefit was driven by a strong reduction in the risk of local recurrence (HR 0.42; 95% CI 0.19-0.91; p = 0.03), whereas the relative risk of distant metastasis (HR 0.69; 95% CI 0.39-1.25; p = 0.22) and overall survival (HR 0.76; 95% CI 0.44-1.30; p = 0.32) were only nonsignificantly in favor of AXRT. An exploratory analysis showed an overall survival benefit of AXRT for patients with high-grade G3 tumors (HR 0.51; 95% CI 0.33-0.78; p = 0.002). However, this finding may have been attributable to residual confounding. CONCLUSION: In this observational cohort, AXRT was associated with a 58% reduction in the relative risk of local recurrence. No consistent association between AXRT and lower risks of distant metastasis or death was observed. PMID- 28895088 TI - Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis. AB - Varicella zoster virus (VZV) infection has been implicated in multiple sclerosis (MS), but direct causal involvement has been disputed. Nevertheless, knowledge of VZV exposure is important, given the risk of serious complications of first exposure while undergoing immunosuppressive treatment, in particular with fingolimod. We distributed questionnaires to MS clinic patients, requesting information about history of chickenpox, sibling/household/occupational exposure, history of zoster (shingles), and disease-modifying treatment. A random, proportionally representative sample of 51 patients that included patients with positive, negative, and unknown chickenpox history were selected for determination of VZV IgG by ELISA. Of 1206 distributed questionnaires, 605 were returned (50% response rate). Of these, 86% reported history of chickenpox, 5.6% gave negative history, and 8.5% did not know. Of 594 who answered the zoster question, 78% gave a negative response, 4% did not know, and 104 (17%) answered yes. Of these, 83 reported 1 episode; 12 had 2; 5 had 3; and 1 each reported 5, 6, and 15 episodes. Of 51 patients tested for VZV IgG (44 "yes," 4 "no," and 3 "I don't know" answers to the question of whether they had chickenpox), 48 were seropositive; the 3 seronegative all had reported having had chickenpox. The high rate of MS patients reporting prior chickenpox infection is comparable with previous reports. A substantial proportion of MS patients, estimated to be higher than an age-matched general population, report single or multiple episodes of zoster. These data are useful for consideration of immunosuppressive treatments and/or VZV and zoster vaccination. PMID- 28895089 TI - Bilateral Salpingo-Oophorectomy Versus GnRH Analogue in the Adjuvant Treatment of Premenopausal Breast Cancer Patients: Cost-Effectiveness Evaluation of Breast Cancer Outcome, Ovarian Cancer Prevention and Treatment. AB - : BACKGROUND AND OBJECTIVE: There is no available evidence to recommend gonadotropin-releasing hormone (GnRH) analogue-based ovarian suppression versus bilateral salpingo-oophorectomy (BSO) in the adjuvant treatment of early breast cancer, since the two approaches are considered equivalent in terms of oncologic outcome. The role of surgical ovarian ablation has been revitalized based on the advances of minimally invasive surgery, and a better understanding of clinical and molecular basis of hereditary breast/ovarian cancer syndromes. The aim of this study is to analyze the cost-effectiveness of laparoscopic BSO and GnRH analogue administration in patients aged 40-49 years with hormone-sensitive breast cancer. METHODS: A probabilistic decision tree model was developed to evaluate costs and outcomes of ovarian ablation through laparoscopic BSO, or ovarian suppression through monthly injections of GnRH analogue. Results were expressed as incremental costs per quality-adjusted life years (QALYs) gained. RESULTS: Laparoscopic BSO strategy was associated with a lower mean total cost per patient than GnRH treatment, and considering the difference in terms of QALYs, the incremental effectiveness did not demonstrate a notable difference between the two approaches. From the National Health Service perspective, and for a time horizon of 5 years, laparoscopic BSO was the dominant option compared to GnRH treatment; laparoscopic BSO was less expensive than GnRH, ?2385 [95% confidence interval (CI) = 2044, 2753] vs ?7093 (95% CI = 3409, 12,105), respectively, and more effective. CONCLUSION: Surgical ovarian ablation is more cost-effective than GnRH administration in the adjuvant treatment of hormone sensitive breast cancer patients aged 40-49 years, and the advantage of preventing ovarian cancer through laparoscopic BSO should be considered. PMID- 28895090 TI - Effort and neuropsychological performance in HIV-infected individuals on stable combination antiretroviral therapy. AB - The expression of cognitive symptoms associated with HIV varies over time and across individuals. This pattern may reflect transient contextual factors, including the degree of effort exerted by individuals undergoing cognitive testing. The present study examined whether effort corresponds to the expression of persistent HIV-related cognitive impairment among individuals receiving combination antiretroviral therapy (cART). HIV+ individuals (n = 111) averaged 48.2 (14.9) years of age and 13.0 (2.7) years of education and HIV- individuals (n = 92) averaged 34.9 (17.2) years of age and 13.5 (1.9) years of education. Participants completed a neuropsychological battery and a clinically validated measure of effort (Test of Memory Malingering, trial 1). Results revealed that the vast majority of HIV+ (85%) and HIV- (89%) individuals performed above published guidelines for adequate effort. Furthermore, the expression of cognitive impairment in HIV was not related to effort performance. The results were unchanged when examining HIV+ individuals with and without viral suppression. Finally, disability and disability-seeking status, and a proxy measure of apathy did not correspond to effort levels in HIV+ individuals. These findings suggest that variability in the expression of cognitive impairment in the cART era is unlikely to represent overt effort failures or other confounds unrelated to the disease. Persistent cognitive impairment in HIV likely represents historical and/or ongoing disease mechanisms despite otherwise successful treatment. PMID- 28895092 TI - Neural response to evaluating depression predicts perceivers' mental health treatment recommendations. AB - Nonstigmatized perceivers' initial evaluations of stigmatized individuals have profound consequences for the well-being of those stigmatized individuals. However, the mechanism by which this occurs remains underexplored. Specifically, what beliefs about the stigmatized condition (stigma-related beliefs) shape how nonstigmatized perceivers evaluate and behave toward stigmatized individuals? We examined these questions with respect to depression-related stigmatization because depression is highly stigmatized and nondepressed individuals' behavior (e.g., willingness to recommend treatment) directly relates to removing stigma and increasing well-being. In Study 1, we identified common stigma-related beliefs associated with depression (e.g., not a serious illness, controllable, threatening), and found that only perceptions that depression is a serious condition predicted nondepressed perceivers' willingness to recommend mental health treatment. Moreover, perceivers' beliefs that depression is a distressing condition mediated the relationship between perceived seriousness and treatment recommendations (Study 1). In Study 2, we used fMRI to disentangle the potential processes connecting distress to nondepressed perceivers' self-reported treatment intentions. Heightened activity in the dorsomedial prefrontal cortex (dmPFC)-a region widely implicated in evaluating others-and the ventrolateral prefrontal cortex (vlPFC)-a region widely implicated in regulating negative emotions-emerged when nondepressed perceivers evaluated individuals who were ostensibly depressed. Beliefs that depression is a distressing condition mediated the relationship between dmPFC (but not vlPFC) activity and nondepressed individuals' self reported treatment recommendations. PMID- 28895093 TI - siRNA-Mediated RNA Interference in Precision-Cut Tissue Slices Prepared from Mouse Lung and Kidney. AB - Small interfering RNA (siRNA)-mediated RNAi interference (RNAi) is a powerful post-transcriptional gene silencing mechanism which can be used to study the function of genes in vitro (cell cultures) and in vivo (animal models). However, there is a translational gap between these models. Hence, there is a need for novel experimental models that combine the advantages of in vitro and in vivo models (e.g., simplicity, flexibility, throughput, and representability) to study the effects of siRNA. This need may be addressed by precision-cut tissue slices (PCTS), which represent an ex vivo model that mimics the structural and functional characteristics of a whole organ. The goal of this study was to investigate whether self-deliverable siRNA (Accell siRNA) can be used in precision-cut lung slices (PCLuS) and precision-cut kidney slices (PCKS) to achieve RNAi ex vivo. PCLuS and PCKS were prepared from mouse tissue, and they were subsequently incubated up to 48 h with no siRNA (untransfected), non targeting Accell siRNA, or Gapdh-targeting Accell siRNA. Significant Gapdh mRNA silencing was achieved (PCLuS ~ 55%; PCKS ~ 40%) without compromising the viability and morphology of slices. Fluorescence microscopy confirmed that Accell siRNA diffused into PCLuS and PCKS. Spontaneous inflammation upon incubation was observed in PCLuS and PCKS as shown by a higher mRNA expression of pro inflammatory cytokines Il1b, Il6, and Tnfa, although Accell siRNA appeared to diminish this response in PCLuS after 24 h. In conclusion, this ex vivo transfection model can be used to evaluate the effects of siRNA in relevant biological environments. PMID- 28895095 TI - My Teacher Baymax: Lessons from the Film Big Hero 6. PMID- 28895094 TI - Fluid loading and norepinephrine infusion mask the left ventricular preload decrease induced by pleural effusion. AB - BACKGROUND: Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE. METHODS: In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 +/- 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 MUg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements. RESULTS: PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values < 0.001), but fluid loading (20 mL/kg) and norepinephrine infusion (0.05 MUg/kg/min) restored these values (p values > 0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values >= 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006). CONCLUSIONS: PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE. PMID- 28895096 TI - Palivizumab Prophylaxis Against Respiratory Syncytial Virus Infection in Children with Immunocompromised Conditions or Down Syndrome: A Multicenter, Post-Marketing Surveillance in Japan. AB - OBJECTIVE: The aim of this study was to assess the safety and effectiveness of palivizumab for the prevention of lower respiratory tract infection (LRI) caused by respiratory syncytial virus (RSV) in children with immunocompromised conditions or Down syndrome. METHODS: In this multicenter, post-marketing surveillance study (December 2013 to December 2015), children aged <=24 months with immunocompromised conditions or Down syndrome (without hemodynamically significant congenital heart disease) receiving palivizumab immunoprophylaxis during two RSV seasons were observed until 30 days after the final palivizumab injection. Safety [adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), serious ADRs (SADRs)] and effectiveness (frequency, incidence, and duration of hospitalization due to RSV infections) were assessed. RESULTS: Of 304 patients receiving palivizumab, 167 (54.9%) had immunocompromised conditions, and 138 (45.4%) had Down syndrome; 260 (85.5%) completed palivizumab immunoprophylaxis. The annual mean (+/-standard deviation) number of doses was 5.3 (+/-2.4) per season. Overall, 220 AEs occurred in 99 patients (32.6%), including 89 SAEs in 53 patients (17.4%). Of these, 33 AEs in 25 patients (8.22%) were considered ADRs, and 13 ADRs in 11 patients (3.62%) were considered SADRs. In four patients, five SADRs (nephroblastoma and asthma in the same patient, septic shock, device-related infection, and drug-induced liver injury) were previously unreported; however, none were considered drug-related. During the observation period, five RSV infections occurred and two patients required hospitalization. CONCLUSION: Palivizumab was generally safe and effective for the prevention of LRI caused by RSV in newborns, infants, and children with immunocompromised conditions or Down syndrome up to the age of 24 months. PMID- 28895097 TI - Combination therapies for primary hepatic neuroendocrine carcinoma: a case report. AB - BACKGROUND: Primary hepatic neuroendocrine carcinomas are extremely rare. Because of the rarity of PHNEC, its clinical features and treatment outcomes are not well understood. A proper diagnosis and the correct therapeutic approach therefore remain clinically challenging. CASE PRESENTATION: A 67-year-old man was admitted to our department because of a liver tumor. Computed tomography revealed a single liver tumor 50 mm in diameter and located in the S3 region. Biopsy and imaging findings resulted in a diagnosis of primary hepatic neuroendocrine carcinoma. Left lateral segmentectomy was performed. Immunohistochemically, the tumor cells were positive for synaptophysin, chromogranin A, and CD56. Ki-67 was positive in > 90% of the tumor cells. The final diagnosis was primary hepatic neuroendocrine carcinoma. The patient suffered two episodes of lymph node recurrence. Nonetheless, the tumor was excised to prolong survival. Thus, after lymphadenectomy, he received adjuvant chemotherapy for 6 months. Two years after surgery, the patient remains alive and in good general condition. CONCLUSIONS: In most cases, primary hepatic neuroendocrine carcinoma, while extremely rare, has a poor prognosis. At present, surgical resection is a priority for curative treatment, but in patients with recurrence, combined therapies are recommended. PMID- 28895098 TI - Recurrent cerebral attack caused by thrombosis in the pulmonary vein stump in a patient with left upper lobectomy on anticoagulant therapy: case report and literature review. AB - BACKGROUND: Thrombus formation in the pulmonary vein stump after pulmonary resection has recently been identified as a cause of systemic thrombosis including brain infarction. However, there is limited research focusing on the clinical course of pulmonary vein stump thrombus, and optimal treatment and prevention strategies of this important complication have not been established. CASE PRESENTATION: A 77-year-old woman was diagnosed with lung cancer of the left upper lobe, cT4N2M0, cStage IIIB. As the tumor was considered to be completely resectable, the patient underwent a left upper lobectomy with angioplasty of the left pulmonary artery. The final pathological stage was pT4N2M0, pStage IIIB. The patient developed paralysis of the right upper limb and dysarthria on the 8th postoperative day. Diffusion-weighted magnetic resonance imaging (MRI) of the brain showed multiple high-intensity signals in the area of the left middle cerebral artery, which were not detected on preoperative MRI. She was diagnosed with a cerebral infarction and started on acute-phase treatment including anticoagulation with continuous intravenous heparin infusion. The neurological symptoms improved the following day. Contrast-enhanced chest CT scan revealed thrombus in the left superior pulmonary vein stump measuring 10 mm in diameter. She had no comorbidity related to the cerebral attack. After the treatment was initiated, her symptoms became stable. However, symptoms of altered consciousness, dysarthria, and hemiparesis re-occurred on the 19th postoperative day and improved within an hour. The thrombus in the left superior pulmonary vein stump disappeared on follow-up contrast-enhanced chest CT performed the same day. CONCLUSIONS: This is the first report of recurrent brain attack caused by thrombosis in the pulmonary vein stump in a patient receiving anticoagulant therapy. The present case suggests the possibility of thrombus mobilization causing recurrent systemic thrombosis, and this important complication needs to be considered in future clinical practice. PMID- 28895100 TI - An Artificial Biomimetic Catalysis Converting CO2 to Green Fuels. AB - Researchers devote to design catalytic systems with higher activity, selectivity, and stability ideally based on cheap and earth-abundant elements to reduce CO2 to value-added hydrocarbon fuels under mild conditions driven by visible light. This may offer profound inspirations on that. A bi-functional molecular iron catalyst designed could not only catalyze two-electron reduction from CO2 to CO but also further convert CO to CH4 with a high selectivity of 82% stably over several days. PMID- 28895099 TI - Neurological and multiple organ involvement due to Paracoccidioides brasiliensis and HIV co-infection diagnosed at autopsy. AB - Paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis, is the most prevalent systemic mycosis among immunocompetent patients in Latin America; it is rare in immunocompromised patients. The estimated frequency of central nervous system (CNS) involvement in the HIV/PCM population was 2.5%. We report a case of HIV/P. brasiliensis co-infection, with neurological (NPCM) and multiple organ involvement, indicating a diagnosis of AIDS. PCM diagnosis was established during the autopsy. This is the first described case of HIV/P. brasiliensis co infection with CNS involvement diagnosed at autopsy. In conclusion, the diagnosis of NPCM is challenging, and it must be considered in the differential diagnosis in HIV-positive patients who reside in or have visited areas in which the condition is endemic and who present with neurological symptoms. PMID- 28895101 TI - Solid-State Stability Issues of Drugs in Transdermal Patch Formulations. AB - The transdermal patch formulation has many advantages, including noninvasiveness, an ability to bypass the first-pass metabolism, low dosage requirements, and prolonged drug delivery. However, the instability of solid-state drugs is one of the most critical problems observed in transdermal patch products. Therefore, a well-characterized approach for counteracting stability problems in solid-state drugs is crucial for improving the performance of transdermal patch products. This review provides insight into the solid-state stability of drugs associated with transdermal patch products and offers a comprehensive update on the various approaches being used for improving the stability of the active pharmaceutical ingredients currently being used. PMID- 28895102 TI - The Impact of Nodal Dissection on Staging in Adrenocortical Carcinoma. AB - BACKGROUND: The role of lymphadenectomy in adrenocortical carcinoma (ACC) is controversial, and formal lymph node (LN) dissection is not routine. We sought to determine the minimum number of LNs that must be examined to accurately identify a patient as node negative. METHODS: The National Cancer Database was used to identify patients diagnosed with ACC from 2004 to 2013 who underwent surgical resection. Patients with distant metastases, multivisceral resection, or missing surgical or lymphadenectomy data were excluded. The primary outcome was overall survival (OS). RESULTS: LNs were identified on histopathology in 156 patients. Of these, 35 (22%) had at least one positive LN. Positive LNs were associated with positive surgical margins (odds ratio [OR] 5.80, p = 0.002) and increasing LN yield (OR 1.06, p = 0.02). Overall, on Cox regression analysis, LN positivity (hazard ratio [HR] 3.02, p < 0.001) and positive surgical margins (HR 2.06, p = 0.048) independently predicted poor OS after controlling for other factors that may influence survival. LN(-) disease in patients with one to three LNs examined had poorer overall survival compared with when at least four LNs were examined (p = 0.02). None of the other patient, tumor, and treatment variables had any impact on OS of the LN(-) cohort. The likelihood of identifying nodal involvement was higher on examination of at least four LNs compared with examination of one to three LNs (30 vs. 16%, p = 0.03). CONCLUSIONS: LN positivity in ACC tumors independently predicts worse 5-year OS and a minimum of four LNs may be required to accurately determine LN negativity. PMID- 28895103 TI - A case of perirenal extramedullary hematopoiesis in a patient with primary myelofibrosis. AB - Extramedullary hematopoiesis (EMH) is hematopoiesis in organs outside the bone marrow and most frequently occurs in the liver, spleen, and lymph nodes. We report a case of perirenal EMH revealed by kidney biopsy in a patient with primary myelofibrosis. We observed only bilateral kidney enlargement with plain computed tomography (CT) and ultrasonography before obtaining a renal biopsy. We obtained a percutaneous biopsy from the lower pole of the left kidney using ultrasonographic guidance. Ultrasonography just after the renal biopsy revealed no bleeding around the kidney. However, early the next morning, the patient developed severe hemorrhagic shock. Contrast-enhanced CT at that time revealed a massive hematoma in the left posterior perirenal space and bilateral abnormalities of the perirenal soft tissues. In patients with primary myelofibrosis, if plain CT shows an abnormal renal enlargement, EMH should be considered. In addition, a contrast-enhanced CT should be obtained before performing a percutaneous renal biopsy to assess for the possibility of perirenal EMH in these patients. PMID- 28895104 TI - Concordance of Adherence Measurement Using Self-Reported Adherence Questionnaires and Medication Monitoring Devices: An Updated Review. AB - INTRODUCTION: As medication adherence continues to be a prevalent issue in today's society, the methods used to monitor medication-taking behaviors are constantly being re-evaluated and compared in search of the 'gold standard' measure. Our review aimed to assess the current literature surrounding the correlation between self-reported questionnaires (SRQs) and electronic monitoring devices to determine if these measures produce similar results. METHODS: We performed a literature search from 2009 to 2017 using PubMed, PubMed In-Process and Non-Indexed, EMBASE, Ovid MEDLINE, and Ovid MEDLINE In-Process. A keyword search using the terms 'patient compliance', 'treatment compliance', 'medication adherence', 'drug monitoring', 'drug therapy', 'electronic', 'digital', 'computer', 'monitor', 'monitoring', 'drug', 'pharmaceutical preparations', 'compliance', and 'medications' was done to capture all articles. We included articles measuring adherence using both monitoring devices and SRQs. RESULTS: Thirty-five articles were included in this review. The average difference in measured adherence rates between the two measures was 9.2% (range -66.3 to 61.5). A majority (62.7%) of articles reported moderate (n = 12; 27.9%), high (n = 5, 11.6%), or significant (n = 10, 23.3%) correlations between SRQs and monitoring devices. CONCLUSION: Results from our review are consistent with previous studies, as we found that many of our studies produced moderate to high correlation between both SRQs and monitoring devices [Farmer, Clin Ther 21(6):1074-90 (1999), IMS Institute for Healthcare Informatics. Avoidable costs in US health care (2012), Patel et al., Respirology 18(3):546-52 (2013), Siracusa et al., J Cyst Fibros 14(5):621-6 (2015), Smith et al., Int J Cardiol 145(1):122 3 (2010)]. Our findings demonstrate that self-reported adherence produces comparable results to electronic monitoring devices. As there is not yet a 'gold standard' measure for monitoring patient adherence, SRQs and Medication Event Monitoring Systems (MEMS) operating together continue to emerge as the preferred effective method for measuring medication adherence. PMID- 28895105 TI - 1,3-Diphenylisobenzofuran: a Model Chromophore for Singlet Fission. AB - In this review we first provide an introductory description of the singlet fission phenomenon and then describe the ground and electronically excited states of the parent 1,3-diphenylisobenzofuran chromophore (1) and about a dozen of its derivatives. A discussion of singlet fission in thin polycrystalline layers of these materials follows. The highest quantum yield of triplet formation by singlet fission, 200% at 80 K, is found in one of the two known crystal modification of the parent. In the other modification and in many derivatives, excimer formation competes successfully and triplet yields are low. A description of solution photophysics of covalent dimers is described in the next section. Triplet yields are very low, but interesting phenomena are uncovered. One is an observation of a separated-charges (charge-transfer) intermediate in highly polar solvents. The other is an observation of excitation isomerism in both singlet and triplet states, where in one isomer the excitation is delocalized over both halves of the covalent dimer, whereas in the other it is localized on one of the halves. In the last section we present the operation of a simple device illustrating the use of triplets generated by singlet fission for charge separation. PMID- 28895106 TI - Excipient Stability in Oral Solid Dosage Forms: A Review. AB - The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug excipient interactions. PMID- 28895108 TI - Sepsis 2017 Paris : Paris, France. September 11-13, 2017. PMID- 28895107 TI - External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis. AB - PURPOSE: The aim of this study was to evaluate the role of preoperative and postoperative external beam radiation therapy (EBRT) in the treatment of resectable soft tissue sarcomas (STSs) of different tumor locations. METHODS: A systematic literature search was performed to identify studies investigating the effects of EBRT (versus no EBRT) on local recurrence (LR) and overall survival (OS) or comparing different EBRT sequences. Random effects meta-analyses were calculated and presented as cumulative odds ratios (ORs). RESULTS: Sixteen studies (n = 3958 patients) comparing EBRT versus no EBRT, including one randomized controlled trial (RCT) in extremity sarcoma, were analyzed. EBRT appeared to reduce LR in both retroperitoneal tumors (OR 0.47, p < 0.0001) and other locations (OR 0.49, p = 0.001). OS was improved by EBRT in retroperitoneal STSs (OR 0.37, p < 0.0001) but not in other tumor locations. Eleven studies (n = 2140), including one RCT, compared preoperative and postoperative radiotherapy. LR was less frequent following preoperative EBRT in retroperitoneal STSs (OR 0.03, p = 0.02), as well as in other tumor locations (OR 0.67, p = 0.01), while wound complications in extremity sarcoma were more frequent following preoperative EBRT (OR 2.92, p < 0.0001). Several studies included in this meta analysis bear a high risk of bias and no RCT has been published for retroperitoneal STS. CONCLUSIONS: This meta-analysis supports the use of EBRT for local tumor control in patients with resectable STSs. Based on a small number of non-randomized studies, a positive effect on OS may exist in the subgroup of retroperitoneal STSs. PMID- 28895111 TI - Phonological recoding under articulatory suppression. AB - We report data from an experiment in which participants performed immediate serial recall of visually presented words with or without articulatory suppression, while also performing homophone or rhyme detection. The separation between homophonous or rhyming pairs in the list was varied. According to the working memory model (Baddeley, 1986; Baddeley & Hitch, 1974), suppression should prevent articulatory recoding. Nevertheless, rhyme and homophone detection was well above chance. However, with suppression, participants showed a greater tendency to false-alarm to orthographically related foils (e.g., GIVE-FIVE). This pattern is similar to that observed in short-term memory patients. PMID- 28895112 TI - External Validation of the Prognostic Nomogram (COMPASS) for Patients with Peritoneal Carcinomatosis of Colorectal Cancer. AB - BACKGROUND: To optimize outcome, selection of patients for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critical. Recently, Simkens et al.7 evaluated the peritoneal surface disease severity score (PSDSS) and suggested a new prognostic nomogram, the colorectal peritoneal metastases prognostic surgical score (COMPASS) based on age, peritoneal carcinomatosis index score, locoregional lymph node status, and signet ring cell histology. This COMPASS nomogram had better discriminative ability according to the Harrell c-index than PSDSS (c = 0.72 vs. 0.62). This study aimed to validate the COMPASS nomogram externally. METHODS: Data were retrieved from a prospectively maintained database, and all patients who underwent surgery between May 2005 and May 2016 were included in the study. For each patient, the PSDSS and COMPASS were calculated and then divided into subgroups. The discriminative ability of both scores for overall survival were quantified using Harrell c indices. RESULTS: A total of 153 patients underwent CRS + HIPEC for peritoneal carcinomatosis (PC) of colorectal cancer. The median overall survival (OS) was 46 months, and the mean PSDSS was 7.8 +/- 3.7. When the PSDSS was divided into subgroups, the c index was 0.67. The mean COMPASS was 55.5 +/- 25.6. When the patients were divided into four groups according to cutpoints of Simkens et al.7 a c index of 0.72 was obtained, showing its significant superiority over the discriminative ability of the PSDSS (p = 0.016). CONCLUSION: External validation of the COMPASS confirms its moderate to good discriminative ability and its superiority over the PSDSS. Nevertheless, discrimination with the COMPASS score remains suboptimal, and further research on prognostic variables is essential for optimal patient selection. PMID- 28895113 TI - Validation of the 8th Edition of the AJCC TNM Staging System for Gastric Cancer using the National Cancer Database. AB - BACKGROUND: The 8th edition AJCC gastric cancer staging manual was refined using Japanese and Korean data from the International Gastric Cancer Association (IGCA). This study evaluated the eighth edition's validity for U.S. POPULATIONS: METHODS: National Cancer Database (NCDB) was used to obtain data on gastric cancer patients diagnosed from 2004 to 2008 who underwent surgery and to examine differences in stage grouping and survival between AJCC 7th and 8th editions. Discrimination of models derived from NCDB and IGCA data was compared. RESULTS: Of 12,041 patients, median age was 65, 57.6% were male, median lymph nodes retrieved was 2 (0-76), 30.9% underwent distal/partial gastrectomy, and 49.8% received no adjuvant treatment. The 8th edition differed in that T1-T3 disease was upstaged with N3b, T4aN3a was downstaged from IIIC to IIIB, and T4bN0 and T4aN2 were downstaged from IIIB to IIIA. These changes resulted in increased patients in IIIA (1436 in the 7th edition to 2310 in the 8th) and IIIB (1737 1896) and decreased in IIIC (2100-1067). This also resulted in lower median survival for IIIA (28.7-25.0 months), IIIB (19.6-17.4), IIIC (13.7-11.8). The concordance index for the 8th edition applied to NCDB data was 0.719 [95% confidence interval (CI) 0.703-0.734), which is comparable to that for the 8th edition developed from IGCA data (0.775, 95% CI 0.770-0.780) and the 7th edition applied to NCDB data (0.720, 95% CI 0.704-0.735). CONCLUSIONS: The 8th edition is valid for U.S. populations, showing clear separation of data with preservation of group order. PMID- 28895114 TI - Erratum to: Preliminary assessment of surface soil lead concentrations in Melbourne, Australia. PMID- 28895115 TI - Sumoylation of SUVR2 contributes to its role in transcriptional gene silencing. AB - The SU(VAR)-3-9-related protein family member SUVR2 has been previously identified to be involved in transcriptional gene silencing both in RNA-dependent and -independent pathways. It interacts with the chromatin-remodeling proteins CHR19, CHR27, and CHR28 (CHR19/27/28), which are also involved in transcriptional gene silencing. Here our study demonstrated that SUVR2 is almost fully mono sumoylated in vivo. We successfully identified the exact SUVR2 sumoylation site by combining in vitro mass spectrometric analysis and in vivo immunoblotting confirmation. The luminescence imaging assay and quantitative RT-PCR results demonstrated that SUVR2 sumoylation is involved in transcriptional gene silencing. Furthermore, we found that SUVR2 sumoylation is required for the interaction of SUVR2 with CHR19/27/28, which is consistent with the fact that SUMO proteins are necessary for transcriptional gene silencing. These results suggest that SUVR2 sumoylation contributes to transcriptional gene silencing by facilitating the interaction of SUVR2 with the chromatin-remodeling proteins CHR19/27/28. PMID- 28895117 TI - Updated view on epidemiology and clinical aspects of pilomatricoma in adults. AB - BACKGROUND: Clinically, pilomatricoma offers potential for a wide spectrum of differential diagnoses. It typically occurs in pediatric patients with the head being the most common location. A second peak of clinical presentation occurs in adults at age 50-65 years, suggesting a bimodal pattern of occurrence. OBJECTIVE: To investigate the clinical and epidemiological features of pilomatricoma in adults over 20 years old, as it is a common and frequently misdiagnosed tumor. METHODS: This was a retrospective study of pilomatricomas surgically removed at a tertiary hospital between January 1994 and December 2014. A search of the all pathological database of patients aged over 20 years old with a pathological diagnosis of pilomatricoma was carried out. RESULTS: The clinical preoperative diagnosis of pilomatricoma was made in 34.0% of cases. Tumor location showed a predilection to the head and neck. Of the reported concomitant neoplasm, a majority had accompanying skin tumors. CONCLUSION: We conclude that clinical features in adults were similar to those of children. This study outlines clinical presentations that should help to guide differential diagnoses. Additionally, because of similarities between the distribution and depth of vellus hair follicles and pilomatricomas, it is probable that vellus hair bulbs may be the origin of this tumor. PMID- 28895116 TI - Age at reproductive debut: Developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). AB - OBJECTIVES: The age at which females initiate their reproductive career is a critical life-history parameter with potential consequences on their residual reproductive value and lifetime fitness. The age at reproductive debut may be intimately tied to the somatic capacity of the mother to rear her young, but relatively little is known about the influence of age of first birth on milk synthesis within a broader framework of reproductive scheduling, infant outcomes, and other life-history tradeoffs. MATERIAL AND METHODS: Our study investigated the predictors of age at first reproduction among 108 captive rhesus macaque (Macaca mulatta) females, and associations with their milk synthesis at peak lactation, infant mass, and ability to subsequently conceive and reproduce. RESULTS: The majority of females reproduced in their fourth year (typical breeders); far fewer initiated their reproductive career one year earlier or one year later (respectively early and late breeders). Early breeders (3-year-old) benefited from highly favorable early life development (better juvenile growth, high dominance rank) to accelerate reproduction, but were impaired in milk synthesis due to lower somatic resources and their own continued growth. Comparatively, late breeders suffered from poor developmental conditions, only partially compensated by their delayed reproduction, and evinced compromised milk synthesis. Typical breeders not only produced higher available milk energy but also had best reproductive performance during the breeding and birth seasons following primiparity. DISCUSSION: Here, we refine and extend our understanding of how life-history tradeoffs manifest in the magnitude, sources, and consequences of variation in age of reproductive debut. These findings provide insight into primate reproductive flexibility in the context of constraints and opportunities. PMID- 28895118 TI - Distressing Symptoms, Disability, and Hospice Services at the End of Life: Prospective Cohort Study. AB - OBJECTIVES: To evaluate the relationship between the presence and number of restricting symptoms and number of disabilities and subsequent admission to hospice at the end of life. DESIGN: Prospective cohort study. SETTING: Greater New Haven, Connecticut, from March 1998 to December 2014. PARTICIPANTS: Decedents from a cohort of 754 persons aged 70 and older (N = 562). MEASUREMENTS: Hospice admissions were identified primarily from Medicare claims, and 15 restricting symptoms and disability in 13 activities were assessed during monthly interviews. RESULTS: During their last year of life, 244 (43.4%) participants were admitted to hospice. The median duration of hospice was 12.5 days (interquartile range 4 43 days). Although the largest increases were observed in the last 2 months of life, the prevalence of restricting symptoms and mean number of restricting symptoms and disabilities in the preceding months were high and trending upward. During a specific month, the likelihood of hospice admission increased by 66% (adjusted hazard ratio (aHR) = 1.66, 95% confidence interval (CI) = 1.30-2.12) in the setting of any restricting symptoms, by 9% (aHR = 1.09, 95% CI = 1.05-1.12) for each additional restricting symptom, and by 10% (aHR = 1.10, 95% CI = 1.05 1.14) for each additional disability. Each additional month with any restricting symptoms increased the likelihood of hospice admission by 7% (aHR = 1.07, 95% CI = 1.01-1.13). CONCLUSION: Hospice services appear to be suitably targeted to older persons with the greatest needs at the end of life, although the short duration of hospice suggests that additional strategies are needed to better address the high burden of distressing symptoms and disability at the end of life. PMID- 28895120 TI - Inflammation: Treatment Progress and Limitations. AB - There is an increasing understanding on the etiology of chronic immune-mediated inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, or rheumatoid arthritis. Large consortia contributed to the elucidation of the genetics, for instance, of IBD identifying a number of genes involved in innate mucosal defense and immune tolerance (most prominent, e.g., NOD2) and other related processes. For a number of such diseases, common genetic susceptibility loci were identified, suggesting overlapping immune response pathways, although there is no causality of single genetic traits.2 In particular, the elucidation of main triggers of inflammation like tumor necrosis factor alpha (TNFalpha), integrins, specific cytokines like interleukin (IL)-6 or IL-23 launched the successful development of new pharmacological approaches, leading to a tremendous improvement of therapeutic outcomes. PMID- 28895119 TI - FXR controls CHOP expression in steatohepatitis. AB - The farnesoid X receptor (FXR) and C/EBP homologous protein (CHOP) have critical functions in hepatic lipid metabolism. Here, we aimed to explore a potential relationship between FXR and CHOP. We fed wild-type (WT) and FXR KO mice a MCD diet (model of steatohepatitis) and found that Chop mRNA expression is upregulated in WT but not FXR KO mice. The absence of FXR aggravates hepatic inflammation after MCD feeding. In HepG2 cells, we found that Chop expression is regulated in a FXR/Retinoid X receptor (RXR)-dependent manner. We identified a FXR/RXR-binding site in the human CHOP promoter, demonstrating a highly conserved regulatory pathway. Our study shows that FXR/RXR regulates Chop expression in a mouse model of steatohepatitis, providing novel insights into pathogenesis of this disorder. PMID- 28895124 TI - Ecological opportunity alters the timing and shape of adaptive radiation. AB - The uneven distribution of diversity is a conspicuous phenomenon across the tree of life. Ecological opportunity is a prominent catalyst of adaptive radiation and therefore may alter patterns of diversification. We evaluated the distribution of shifts in diversification rates across the cichlid phylogeny and the distribution of major clades across phylogenetic space. We also tested if ecological opportunity influenced these patterns. Colonization-associated ecological opportunity altered the tempo and mode of diversification during the adaptive radiation of cichlid fishes. Clades that arose following colonization events diversified faster than other clades. Speciation rate shifts were nonrandomly distributed across the phylogeny such that they were disproportionally concentrated around nodes that corresponded with colonization events (i.e., of continents, river basins, or lakes). Young clades tend to expand faster than older clades; however, colonization-associated ecological opportunity accentuated this pattern. There was an interaction between clade age and ecological opportunity that explained the trajectory of clades through phylogenetic space over time. Our results indicate that ecological opportunities afforded by continental and ecosystem-scale colonization events explain the dramatic speciation rate heterogeneity and phylogenetic imbalance that arose during the evolutionary history of cichlid fishes. PMID- 28895126 TI - Construction of an Exome-Wide Risk Score for Schizophrenia Based on a Weighted Burden Test. AB - Polygenic risk scores obtained as a weighted sum of associated variants can be used to explore association in additional data sets and to assign risk scores to individuals. The methods used to derive polygenic risk scores from common SNPs are not suitable for variants detected in whole exome sequencing studies. Rare variants, which may have major effects, are seen too infrequently to judge whether they are associated and may not be shared between training and test subjects. A method is proposed whereby variants are weighted according to their frequency, their annotations and the genes they affect. A weighted sum across all variants provides an individual risk score. Scores constructed in this way are used in a weighted burden test and are shown to be significantly different between schizophrenia cases and controls using a five-way cross-validation procedure. This approach represents a first attempt to summarise exome sequence variation into a summary risk score, which could be combined with risk scores from common variants and from environmental factors. It is hoped that the method could be developed further. PMID- 28895127 TI - Evaluation of CCAAT/Enhancer Binding Protein (C/EBP) Alpha (CEBPA) and Runt Related Transcription Factor 1 (RUNX1) Expression in Patients with De Novo Acute Myeloid Leukemia. AB - The CCAAT/enhancer binding protein (C/EBP) alpha (CEBPA) and Runt-related transcription factor 1 (RUNX1) genes have been traditionally regarded as two essential genes involved in normal myeloid maturation. Although the link between mutations in these genes and the development of acute myeloid leukemia (AML) has been extensively documented, the ramifications of gene expression dysregulations of CEBPA and RUNX1 has drawn less attention. The present study investigated CEBPA and RUNX1 gene expression levels in 96 primary AML specimens against a normal control group by way of real-time RT-PCR. Our results reveal that CEBPA and RUNX1 gene expression levels were unexpectedly and significantly higher in patients with AML when compared to the levels detected in the normal control group (P < 0.0001). Furthermore, the correlation between CEBPA and RUNX1 was significant and positive (P-value: 0.011, r: 0.257). Our data contradicts the widely established role of CEBPA and RUNX1 in myeloid differentiation, as we saw lower levels of CEBPA and RUNX1 expression to be exhibited in patients with AML. Likely, our data demonstrates that higher levels of CEBPA and RUNX1 expression were closely correlated with reduced myeloid maturation, but this idea needs to approved. It suggests that despite the current established functions of genes involved in cell differentiation, the leukemogenesis process has the capability to transform normal hematopoietic precursors in a manner that may employ the differentiation related gene at the service of malignancy. PMID- 28895125 TI - Governance arrangements for health systems in low-income countries: an overview of systematic reviews. AB - BACKGROUND: Governance arrangements include changes in rules or processes that determine authority and accountability for health policies, organisations, commercial products and health professionals, as well as the involvement of stakeholders in decision-making. Changes in governance arrangements can affect health and related goals in numerous ways, generally through changes in authority, accountability, openness, participation and coherence. A broad overview of the findings of systematic reviews can help policymakers, their technical support staff and other stakeholders to identify strategies for addressing problems and improving the governance of their health systems. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of governance arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on governance arrangements and informing refinements of the framework for governance arrangements outlined in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of governance arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use (health expenditures, healthcare provider costs, out-of-pocket payments, cost effectiveness), healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty, employment) and that were published after April 2005. We excluded reviews with limitations that were important enough to compromise the reliability of the findings of the review. Two overview authors independently screened reviews, extracted data and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence) and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 21 of them in this overview (19 primary reviews and 2 supplementary reviews). We focus here on the results of the 19 primary reviews, one of which had important methodological limitations. The other 18 were reliable (with only minor limitations).We grouped the governance arrangements addressed in the reviews into five categories: authority and accountability for health policies (three reviews); authority and accountability for organisations (two reviews); authority and accountability for commercial products (three reviews); authority and accountability for health professionals (seven reviews); and stakeholder involvement (four reviews).Overall, we found desirable effects for the following interventions on at least one outcome, with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects. Decision making about what is covered by health insurance- Placing restrictions on the medicines reimbursed by health insurance systems probably decreases the use of and spending on these medicines (moderate-certainty evidence). Stakeholder participation in policy and organisational decisions- Participatory learning and action groups for women probably improve newborn survival (moderate-certainty evidence).- Consumer involvement in preparing patient information probably improves the quality of the information and patient knowledge (moderate-certainty evidence). Disclosing performance information to patients and the public- Disclosing performance data on hospital quality to the public probably encourages hospitals to implement quality improvement activities (moderate-certainty evidence).- Disclosing performance data on individual healthcare providers to the public probably leads people to select providers that have better quality ratings (moderate-certainty evidence). AUTHORS' CONCLUSIONS: Investigators have evaluated a wide range of governance arrangements that are relevant for low-income countries using sound systematic review methods. These strategies have been targeted at different levels in health systems, and studies have assessed a range of outcomes. Moderate-certainty evidence shows desirable effects (with no undesirable effects) for some interventions. However, there are important gaps in the availability of systematic reviews and primary studies for the all of the main categories of governance arrangements. PMID- 28895128 TI - Transitional justice as social control: political transitions, human rights norms and the reclassification of the past. AB - This article offers an interpretation of transitional justice policies - the efforts of post-conflict and post-dictatorship societies to address the legacy of past abuses - as a form of social control. While transitional justice is commonly conceptualized as responding to a core problem of impunity, this article argues that such formulation is too narrow and leads to lack of coherence in the analysis of the diverse array of transitional mechanisms, which include among others trials, truth commissions, reparations for victims and apologies. Building on the work of Stanley Cohen, the article contends that the core transitional problem is the denial of human rights violations, and consequently that the common purpose of all transitional justice mechanisms is to reclassify the past: redefining as deviant some acts and individuals which prior to the transition were considered 'normal'. The article identifies and analyses three themes in the application of a social control framework to transitional justice: (1) truth, memory and retroactive social control, pertains to the way truth-seeking transitional justice mechanisms reclassify past events by engaging in social control of and through memory; (2) censure, celebration and transitional social control refers to the reclassification of categories of individuals through expressions of both social disapproval and praise; and (3) civil society and social control from below concerns the role of social movements, organizations and groups as informal agents of social control during transitions. The concluding section recaps and briefly explores the concept of 'good moral panic' in the context of political transitions. While the concept of social control tends to have negative connotations for critical sociologists, this work suggests that efforts to categorize, punish and disapprove certain behaviours as deviant may not only be viewed as supporting a conservative status-quo, but also as promoting fledging human rights norms. PMID- 28895129 TI - The role of sustained attention, maternal sensitivity, and infant temperament in the development of early self-regulation. AB - This study investigated infant predictors of early cognitive and emotional self regulation from an intrinsic and caregiving environmental perspective. Sustained attention, reactive aspects of infant temperament, and maternal sensitivity were assessed at 10 months (n = 124) and early self-regulation (including executive functions, EF, and emotion regulation) was assessed at 18 months. The results indicated that sustained attention predicted early EF, which provide empirical support for the hierarchical framework of EF development, advocating early attention as a foundation for the development of cognitive self-regulation. Maternal sensitivity and surgency predicted emotion regulation, in that infants of sensitive mothers showed more regulatory behaviours and a longer latency to distress, whereas high levels of surgency predicted low emotion regulation, suggesting both the caregiving environment and temperament as important in the development of self-regulation. Interaction effects suggested high sustained attention to be a protective factor for children of insensitive mothers, in relation to emotion regulation. In addition, high levels of maternal sensitivity seemed to foster development of emotion regulation among children with low to medium levels of sustained attention and/or surgency. In all, our findings point to the importance of both intrinsic and extrinsic factors in infant development of self-regulation. PMID- 28895130 TI - Ancestry Informative Marker Panel to Estimate Population Stratification Using Genome-wide Human Array. AB - Case-control studies are a powerful strategy to identify candidate genes in complex diseases. In admixed populations, association studies can be affected by population stratification, leading to spurious genetic associations. Ancestry informative markers (AIMs) can be used to minimise this effect. The aim of this work was to select a set of AIMs to estimate population stratification in a Brazilian case-control study performed using a genome-wide array. A total of 345 single nucleotide polymorphism (SNP) AIMs, selected from the Cytoscan HD array and based on previously reported panels, was used to discriminate between European, African, and Amerindian populations. These SNP-AIMs were used to infer ancestry in systemic lupus erythematosus (SLE) patients (n = 23) and in healthy subjects (n = 110). Moderate population substructure was observed between SLE and control groups (Fst = 0.0113). Although patients and controls have shown a major European genomic contribution, significant differences in the European (P = 6.47 * 10-5 ) and African (P = 1.14 * 10-3 ) ancestries were detected between the two groups. We performed a two-step validation of the 345 SNP-AIMs panel estimating the ancestral contributions using a panel of 12 AIMs and approximately 70K SNPs from the array. Evaluation of population substructure in case-control studies, avoiding spurious genetic associations, can be performed using our panel of 345 SNP-AIMs. PMID- 28895131 TI - Social mobility and the well-being of individuals. AB - Several papers published in recent years have revived interest in Sorokin's dissociative thesis: the view that intergenerational social mobility has detrimental effects on the social relationships and wellbeing of individuals. In this paper, I test the dissociative thesis using data from the British Household Panel Survey and Understanding Society. On a wide range of indicators that measure participation in civic associations, contact with parents, close personal relationships, social support, subjective wellbeing, etc. individuals who have achieved long-range upward mobility (i.e. those who move from working class origin to salariat destination) tend to fare better than those who are immobile in the working class. Those who have experienced long-range downward mobility (moving from salariat origin to working class destination) do about as well as second-generation members of the working class. Overall, there is no support for Sorokin's thesis. PMID- 28895132 TI - The genesis of victimization surveys and of the realist-constructionist divide. AB - The invention of victimization surveys is often presented as a synthesis of the two theoretical attitudes that, supposedly, dominated the 1960s debate over official crime statistics: realism and social constructionism. This paper turns this genesis story on its head. Using original archives, I argue that victimization surveys responded to organizational opportunities in the field of applied research. It was only after the fact that two of their architects seized the debate on crime measurement to broadcast their invention. In so doing they strategically recast the terms of this debate into a binary division between two antithetical social ontologies. This case is used to discuss how social scientists come to reinterpret and misunderstand their history. PMID- 28895133 TI - Coupling progenitor and neuronal diversity in the developing neocortex. AB - The adult neocortex is composed of several types of glutamatergic neurons, which are sequentially born from progenitors during development. The extent and nature of progenitor diversity, and how it relates to neuronal diversity, is still poorly understood. In this review, we discuss key features of neocortical progenitors across several species, including their morphological properties, cell cycling behaviour and molecular signatures, and how these features relate to the competence of these cells to generate distinct types of progenies. PMID- 28895134 TI - New primate locality from the early Miocene of Patagonia, Argentina. AB - OBJECTIVES: The purpose of this work is to present a new primate locality with evidence that increases the knowledge on the radiation of the extinct platyrrhine primates. MATERIALS AND METHODS: We studied the new specimen and compared it to specimens identified as Mazzonicebus almendrae. RESULTS: The new first and second molars were comparable to Mazzonicebus almendrae in all morphological details, allowing us to allocate the new specimen to M. almendrae and add comments on morphological variation in this species regarding the orientation of the labial cristae and development of the anterolingual cingulum. This new maxilla also present the first known M3 for the species. DISCUSSION: The new specimen increases our knowledge of the extinct platyrrhines from Patagonia. Their age and geographical distribution ranges from early to middle Miocene in an area between 40 degrees to 47 degrees of southern latitude. PMID- 28895135 TI - Paired associative stimulation goes spinal. PMID- 28895136 TI - The evolution of hominoid cranial diversity: A quantitative genetic approach. AB - Hominoid cranial evolution is characterized by substantial phenotypic diversity, yet the cause of this variability has rarely been explored. Quantitative genetic techniques for investigating evolutionary processes underlying morphological divergence are dependent on the availability of good ancestral models, a problem in hominoids where the fossil record is fragmentary and poorly understood. Here, we use a maximum likelihood approach based on a Brownian motion model of evolutionary change to estimate nested hypothetical ancestral forms from 15 extant hominoid taxa. These ancestors were then used to calculate rates of evolution along each branch of a phylogenetic tree using Lande's generalized genetic distance. Our results show that hominoid cranial evolution is characterized by strong stabilizing selection. Only two instances of directional selection were detected; the divergence of Homo from its last common ancestor with Pan, and the divergence of the lesser apes from their last common ancestor with the great apes. In these two cases, selection gradients reconstructed to identify the specific traits undergoing selection indicated that selection on basicranial flexion, cranial vault expansion, and facial retraction characterizes the divergence of Homo, whereas the divergence of the lesser apes was defined by selection on neurocranial size reduction. PMID- 28895137 TI - Bringing radical behaviorism to revolutionary Brazil and back: Fred Keller's Personalized System of Instruction and Cold War engineering education. AB - This article traces the shifting epistemic commitments of Fred S. Keller and his behaviorist colleagues during their application of Skinnerian radical behaviorism to higher education pedagogy. Building on prior work by Alexandra Rutherford and her focus on the successive adaptation of Skinnerian behaviorism during its successive applications, this study utilizes sociologist of science Karin Knorr Cetina's concept of epistemic cultures to more precisely trace the changes in the epistemic commitments of a group of radical behaviorists as they shifted their focus to applied behavioral analysis. The story revolves around a self-paced system of instruction known as the Personalized System of Instruction, or PSI, which utilized behaviorist principles to accelerate learning within the classroom. Unlike Skinner's entry into education, and his focus on educational technologies, Keller developed a mastery-based approach to instruction that utilized generalized reinforcers to cultivate higher-order learning behaviors. As it happens, the story also unfolds across a rather fantastic political terrain: PSI originated in the context of Brazilian revolutionary history, but circulated widely in the U.S. amidst Cold War concerns about an engineering manpower(sic) crisis. This study also presents us with an opportunity to test Knorr Cetina's conjecture about the possible use of a focus on epistemic cultures in addressing a classic problem in the sociology of science, namely unpacking the relationship between knowledge and its social context. Ultimately, however, this study complements another historical case study in applied behavioral analysis, where a difference in outcome helps to lay out the range of possible shifts in the epistemic commitments of radical behaviorists who entered different domains of application. The case study also has some practical implications for those creating distance learning environments today, which are briefly explored in the conclusion. PMID- 28895139 TI - Non-inferiority and equivalence trials. PMID- 28895140 TI - Improving outcomes in patients with resectable pancreatic cancer. PMID- 28895138 TI - Feed-backs among inbreeding, inbreeding depression in sperm traits, and sperm competition can drive evolution of costly polyandry. AB - Ongoing ambitions are to understand the evolution of costly polyandry and its consequences for species ecology and evolution. Emerging patterns could stem from feed-back dynamics between the evolving mating system and its genetic environment, defined by interactions among kin including inbreeding. However, such feed-backs are rarely considered in nonselfing systems. We use a genetically explicit model to demonstrate a mechanism by which inbreeding depression can select for polyandry to mitigate the negative consequences of mating with inbred males, rather than to avoid inbreeding, and to elucidate underlying feed-backs. Specifically, given inbreeding depression in sperm traits, costly polyandry evolved to ensure female fertility, without requiring explicit inbreeding avoidance. Resulting sperm competition caused evolution of sperm traits and further mitigated the negative effect of inbreeding depression on female fertility. The evolving mating system fed back to decrease population-wide homozygosity, and hence inbreeding. However, the net overall decrease was small due to compound effects on the variances in sex-specific reproductive success and paternity skew. Purging of deleterious mutations did not eliminate inbreeding depression in sperm traits or hence selection for polyandry. Overall, our model illustrates that polyandry evolution, both directly and through sperm competition, might facilitate evolutionary rescue for populations experiencing sudden increases in inbreeding. PMID- 28895142 TI - Randomized clinical trial of laparoscopic versus open pancreatoduodenectomy for periampullary tumours. AB - BACKGROUND: Laparoscopic resection as an alternative to open pancreatoduodenectomy may yield short-term benefits, but has not been investigated in a randomized trial. The aim of this study was to compare laparoscopic and open pancreatoduodenectomy for short-term outcomes in a randomized trial. METHODS: Patients with periampullary cancers were randomized to either laparoscopic or open pancreatoduodenectomy. The outcomes evaluated were hospital stay (primary outcome), and blood loss, radicality of surgery, duration of operation and complication rate (secondary outcomes). RESULTS: Of 268 patients, 64 who met the eligibility criteria were randomized, 32 to each group. The median duration of postoperative hospital stay was longer for open pancreaticoduodenectomy than for laparoscopy (13 (range 6-30) versus 7 (5-52) days respectively; P = 0.001). Duration of operation was longer in the laparoscopy group. Blood loss was significantly greater in the open group (mean(s.d.) 401(46) versus 250(22) ml; P < 0.001). Number of nodes retrieved and R0 rate were similar in the two groups. There was no difference between the open and laparoscopic groups in delayed gastric emptying (7 of 32 versus 5 of 32), pancreatic fistula (6 of 32 versus 5 of 32) or postpancreatectomy haemorrhage (4 of 32 versus 3 of 32). Overall complications (defined according to the Clavien Dindo classification) were similar (10 of 32 versus 8 of 32). There was one death in each group. CONCLUSION: Laparoscopy offered a shorter hospital stay than open pancreatoduodenectomy in this randomized trial. Registration number: NCT02081131( http://www.clinicaltrials.gov). PMID- 28895143 TI - Randomized clinical trial of laparoscopic ultrasonography before laparoscopic colorectal cancer resection. AB - BACKGROUND: Intraoperative ultrasonography during open surgery for colorectal cancer may be useful for the detection of unrecognized liver metastases. Laparoscopic ultrasonography (LUS) for the detection of unrecognized liver metastasis has not been studied in a randomized trial. This RCT tested the hypothesis that LUS would change the TNM stage and treatment strategy. METHODS: Patients with colorectal cancer and no known metastases were randomized (1 : 1) to laparoscopic examination (control or laparoscopy plus LUS) in three Danish centres. Neither participants nor staff were blinded to the group assignment. RESULTS: Three hundred patients were randomized, 150 in each group. After randomization, 43 patients were excluded, leaving 128 in the control group and 129 in the LUS group. Intraoperative T and N categories were not altered by LUS, but laparoscopy alone identified previously undetected M1 disease in one patient (0.8 per cent) in the control group and three (2.3 per cent) in the LUS group. In the latter group, LUS suggested that an additional six patients (4.7 per cent) had M1 disease with liver (4) or para-aortal lymph node (2) metastases. The change in treatment strategy was greater in the LUS than in the control group (7.8 (95 per cent c.i. 3.8 to 13.8) and 0.8 (0 to 4.2) per cent respectively; P = 0.010), but the suspected M1 disease was benign in half of the patients. CONCLUSION: Routine LUS during resection of colorectal cancer is not recommended. Registration number: NCT02079389 (http://www.clinicaltrials.gov). PMID- 28895144 TI - Spanish translation section. PMID- 28895145 TI - In between mental evolution and unconscious memory: Lamarckism, Darwinism, and professionalism in late Victorian Britain. AB - In 1884 Samuel Butler published a collection of essays entitled Remarks on George Romanes' Mental Evolution, where he attempted to show how Romanes' idea of mental evolution presented similarities with his theory of unconscious memory. By looking at Romanes' work through Butler's writing, this article will reevaluate some aspects of their works regarding the complex debate about memory, heredity, and instinct. This paper will explore the main differences and similarities between Romanes' science and Butler's writing on science both in terms of their ideas and contents. It will then look into their different professional relationships with Darwin and how this determined the professional and public reception of their theories. PMID- 28895146 TI - Differential diagnosis and comorbidity of ADHD and anxiety in adults. AB - OBJECTIVES: The aim of this study was to examine symptom profiles of people diagnosed with attention-deficit/hyperactivity disorder (ADHD) and/or anxiety (ANX) in order to determine the validity of widely used ADHD and ANX rating scales for differential diagnostic use and to develop modified measures that take symptom overlap into account. DESIGN: A cross-sectional design was used to assess differences in rating scale scores between clinical (n = 52) and control (n = 74) samples as well as differences among subgroups of the clinical sample (22 ADHD; 16 ADHD + ANX; 14 ANX). METHOD: Participants completed an online questionnaire where they responded to the Conners Adult ADHD Rating Scale (CAARS; Conners, Erhardt, & Sparrow, ) and State Trait Anxiety Inventory scales (STAI; Spielberger, Gorsuch, Lushene, Vagg, & Jacobs, ). RESULTS: Results showed that the CAARS and STAI had limited sensitivity and specificity and may lack in ability to differentially diagnose ADHD and/or ANX. Cluster analysis was used to guide the proposal of modifications for the two scales, which were to use inattentive items only for the CAARS and to exclude state ANX-present items on the STAI for use in differential diagnosis. Further parametric analysis supported these proposed modifications. CONCLUSIONS: Clinicians should be made aware of the limitations of the CAARS and STAI scales in terms of specificity, when used to inform differential diagnosis of ADHD and ANX. Further analysis on the psychometric properties of these modified scales is needed in order to confirm that they are valid and reliable scales. PRACTITIONER POINTS: Clinical implications It is possible that widely used self-report rating scales are not valid for use in the context of assessing adult ADHD when ANX is present. Clinicians should take alternative approaches to measuring ADHD symptoms in the context of ANX. Findings of the present study suggest the use of inattentive items only for the CAARS and to exclude state ANX-present items on the STAI for differential diagnostic use. Limitations of the study The sample sizes of the clinical subgroups were relatively small. Diagnoses were not confirmed using a semi-structured clinical interview. Alternative cluster approaches (e.g., two step clustering using larger samples) would provide further insight. PMID- 28895147 TI - Root traits are more than analogues of leaf traits: the case for diaspore mass. AB - Root traits are often thought to be analogues of leaf traits along the plant economics spectrum. But evolutionary pressures have most likely shaped above- and belowground patterns differentially. Here, we aimed to identify the most important aboveground traits for explaining root traits without an a priori focus on known concepts. We measured morphological root traits in a glasshouse experiment on 141 common Central European grassland species. Using random forest algorithms, we built predictive models of six root traits from 97 aboveground morphological, ecological and life history traits. Root tissue density was best predicted by leaf dry matter content, whereas traits related to root fineness were best predicted by diaspore mass: the heavier the diaspore, the coarser the root system. Specific leaf area (SLA) was not an important predictor for any of the root traits. This study confirms the hypothesis that root traits are more than analogues of leaf traits within a plant economics spectrum. The results reveal a novel ecological pattern and highlight the power of root data to close important knowledge gaps in trait-based ecology. PMID- 28895148 TI - Critical roles of hMAGEA2 in induced pluripotent stem cell pluripotency, proliferation, and differentiation. AB - Induced pluripotent stem (iPS) cells are important for clinical application and stem cell research. Although human melanoma-associated antigen A2 (hMAGEA2) expression is known to affect differentiation in embryonic stem cells, its specific role in iPS cells remains unclear. To evaluate the function of hMAGEA2 and its characteristics in iPS cells, we produced hMAGEA2-overexpressing iPS cells from hMAGEA2-overexpressing transgenic mice. Although the iPS cells with overexpressed hMAGEA2 did not differ in morphology, their pluripotency, and self renewal related genes (Nanog, Oct3/4, Sox2, and Stat3), expression level was significantly upregulated. Moreover, hMAGEA2 contributed to the promotion of cell cycle progression, thereby accelerating cell proliferation. Through embryoid body formation in vitro and teratoma formation in vivo, we demonstrated that hMAGEA2 critically decreases the differentiation ability of iPS cells. These data indicate that hMAGEA2 intensifies the self-renewal, pluripotency, and degree of proliferation of iPS cells, while significantly repressing their differentiation efficiency. Therefore, our findings prove that hMAGEA2 plays key roles in iPS cells. PMID- 28895149 TI - Efficacy of dexmedetomidine for perioperative morbidities in pediatric tonsillectomy: A metaanalysis. AB - OBJECTIVES: This study aimed to assess the effects of perioperative dexmedetomidine as an adjuvant to tonsillectomy compared with opioid or sham in children. DATA SOURCE: Five databases (PubMed, SCOPUS, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) were searched from inception of article collections to April 2017. REVIEW METHODS: Prospective, randomized controlled studies that compared outcomes between children who underwent tonsillectomy plus dexmedetomidine administration (intervention) and children who underwent tonsillectomy with placebo or opioid (control) were systemically and independently reviewed by two researchers. The outcomes of interest were emergence agitation, postoperative pain intensity, rescue analgesic consumption, and other morbidities (nausea and vomiting and agitation). RESULTS: Fifteen studies with n = 1,552 met the inclusion criteria. Postoperative pain scores and the need for analgesics in the postanesthesia care unit (PACU) were significantly decreased in the dexmedetomidine group versus the control group. The incidence and degree of agitation and desaturation incidence in the PACU also were significantly lower in the dexmedetomidine group than in the control group. Additionally, there was no significant difference in the duration of staying PACU between both groups. In subgroup analyses by administration method (bolus injection or continuous injection), dexmedetomidine was shown to be effective at reducing postoperative morbidities regardless of administration method. CONCLUSION: Perioperative administration of dexmedetomidine can provide pain and agitation relief without side effects in children undergoing adenotonsillectomy. Considering the high heterogeneity of results within some parameters; however, further clinical trials with robust research methodology should be conducted to confirm the results of this study. Laryngoscope, 128:E184-E193, 2018. PMID- 28895150 TI - Chemosensory function before and after multimodal treatment in chronic rhinosinusitis patients. AB - OBJECTIVES/HYPOTHESIS: Olfactory dysfunction is common among the general population, with chronic rhinosinusitis (CRS) as one of the leading causes. Patients affected by CRS often report changes in taste sensations; however, quantitative measurements have not been performed to date. Therefore, the present study aimed to investigate gustatory and olfactory function in CRS patients prior to and after multimodal treatment. STUDY DESIGN: Prospective cohort study. METHODS: Twenty-one patients suffering from CRS with nasal polyps (14 male, seven female) with a mean age of 48 +/- 15 years were included in the study. Chemosensory function was assessed prior to and approximately 190 days after multimodal treatment, which included endoscopic sinus surgery, oral antibiotics for 5 days, oral steroids for 12 days, and at least 6 weeks of topical nasal steroids. Olfactory function was tested with the Sniffin' Sticks test battery, whereas gustatory function was measured with taste strips. A clinically relevant change in olfactory function was defined as a change of >=5 points in the threshold, discrimination, and identification scores. RESULTS: Compared to normative data, patients baseline gustatory and olfactory function was impaired. After multimodal treatment, improvements were seen in olfactory function for eight patients (42%), remained stable in 10 patients (53%), and deteriorated in one patient (5%). Taste function remained unchanged following sinus surgery. CONCLUSIONS: Patients suffering from CRS with polyps exhibit olfactory and taste dysfunctions. Multimodal treatment leads to an improvement in olfactory, but not gustatory functionality. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:E86-E90, 2018. PMID- 28895151 TI - Role of closed loop stimulation pacing (CLS) in vasovagal syncope. AB - Vasovagal syncope (VVS) or neurocardiogenic syncope is defined by transient loss of consciousness with spontaneous and rapid recovery. Recently, a closed loop stimulation (CLS) pacing system has emerged as a new strategy which appears superior to conventional pacing for patients with refractory syncope. However, its efficacy remains of considerable debate and large randomized controlled clinical trials are needed. Between 2002 and 2017, 12 total studies evaluated the use of CLS pacing in patients with refractory VVS, and are summarized in this article. PMID- 28895152 TI - Clinical predictors of multiple tympanostomy tube placements in Ontario children. AB - OBJECTIVES: To characterize risk factors that predict the need for multiple tympanostomy tube (TT) procedures. STUDY DESIGN: Retrospective population-based cohort study of children aged 18 years and younger in Ontario, Canada, who underwent at least one TT placement between January 1, 1994, and October 31, 2013. METHODS: The relative risk (RR) of need for multiple TT procedures was determined using log-binomial regression. RESULTS: There were 193,880 children who underwent TT insertion included in this cohort. Of these, 28.58% underwent at least two separate TT procedures. Over time, the RR of undergoing multiple TT procedures is decreasing for all children. In general, the younger the child was at the first TT procedure, the more likely the child was to undergo multiple TT procedures. Significantly higher RR for multiple TT procedures also was associated with male sex, the second-highest neighborhood income quintile, asthma or reactive airways, gastrointestinal disease, prematurity, or cleft lip and/or palate. Significantly lower RR for multiple TT procedures was associated with adenoidectomy or tonsillectomy (with or without adenoidectomy) at first TT placement or within 3 years prior. Furthermore, the benefit of adjuvant adenoidectomy or tonsillectomy was present for children aged under 4 years, in addition to those aged 4 years and older. CONCLUSION: Among Ontario children who have had TT placement, more than one in four will have multiple sets placed. These identified risk factors permit improved preoperative counseling and enable identification of children who need closer follow-up. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:991-997, 2018. PMID- 28895153 TI - Characterization of an antimicrobial and phytotoxic ribonuclease secreted by the fungal wheat pathogen Zymoseptoria tritici. AB - The fungus Zymoseptoria tritici is the causal agent of Septoria Tritici Blotch (STB) disease of wheat leaves. Zymoseptoria tritici secretes many functionally uncharacterized effector proteins during infection. Here, we characterized a secreted ribonuclease (Zt6) with an unusual biphasic expression pattern. Transient expression systems were used to characterize Zt6, and mutants thereof, in both host and non-host plants. Cell-free protein expression systems monitored the impact of Zt6 protein on functional ribosomes, and in vitro assays of cells treated with recombinant Zt6 determined toxicity against bacteria, yeasts and filamentous fungi. We demonstrated that Zt6 is a functional ribonuclease and that phytotoxicity is dependent on both the presence of a 22-amino-acid N-terminal 'loop' region and its catalytic activity. Zt6 selectively cleaves both plant and animal rRNA species, and is toxic to wheat, tobacco, bacterial and yeast cells, but not to Z. tritici itself. Zt6 is the first Z. tritici effector demonstrated to have a likely dual functionality. The expression pattern of Zt6 and potent toxicity towards microorganisms suggest that, although it may contribute to the execution of wheat cell death, it is also likely to have an important secondary function in antimicrobial competition and niche protection. PMID- 28895154 TI - Perceptions of pain of laryngeal electromyography. AB - OBJECTIVE: To evaluate pain associated with laryngeal electromyography (LEMG). STUDY DESIGN: A prospective case series. METHODS: Adult patients scheduled for LEMG in a tertiary care laryngology practice were recruited between July 20, 2016, and March 1, 2017. Demographic and clinical data were extracted from the charts. Study participants reported their anticipated pain level using a visual analog scale (VAS) prior to the procedure. VAS was administered again within 10 minutes after the procedure, along with the validated McGill Pain Questionnaire, to gauge patient's pain perception after undergoing LEMG. RESULTS: Results were reviewed for 80 patients (mean age 48.2 +/- 16.6 years, 37.5% male). Preprocedure VAS pain scores (4.59 +/- 2.3 out of 10) were not significantly different than postprocedure VAS pain scores (4.61 +/- 2.4) (P = 0.95). The McGill Pain Questionnaire reported a moderate pain level (32.1 +/- 12.7 out of 78). Females anticipated a higher preprocedure VAS pain score (5.04 +/- 2.3) than males (3.85 +/- 2.2) (P = 0.02); however, postprocedure scores were not significantly different between genders. The following factors did not influence the pain scores: age, professional voice use, history of previous EMG, chronic pain diagnosis, psychiatric diagnosis, or current treatment with pain/psychiatric medications. All LEMGs were completed without any complications. CONCLUSION: Patients appropriately anticipated their pain levels for the LEMG, which may be attributed to proper patient education and counselling before the procedure. Overall pain levels were mild to moderate, and all LEMGs were completed; thus, LEMG was well tolerated. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:896-900, 2018. PMID- 28895155 TI - Work-related musculoskeletal symptoms among otolaryngologists by subspecialty: A national survey. AB - OBJECTIVE: Given the high prevalence of work-related musculoskeletal symptoms, increased appreciation for workplace ergonomics is critical. The purpose of this study is to assess work-related musculoskeletal symptoms and injury among otolaryngologists across subspecialties, as well as to quantify the understanding and application of ergonomic principles in the operating room. STUDY DESIGN: Cross-sectional study. METHODS: An online REDCap survey was distributed electronically to University of Kansas faculty, alumni, and residents; members of the American Academy of Facial Plastic and Reconstructive Surgery; and residency program coordinators for distribution to residents and faculty between August 2016 and March 2017. The survey assessed caseload, ergonomic practices, and associated musculoskeletal symptoms by type of procedure and impact of symptoms on surgeon practice. RESULTS: The survey was distributed to 3,006 individuals. We received 377 responses (12.5%), with 63.9% reporting symptoms. The majority of respondents began to experience symptoms in residency or fellowship. Neck and shoulder were the most affected body areas across all types of surgeries. One third of surgeons were formally taught or actively sought information on ergonomics principles. Among those who applied ergonomics in practice, 69.6% observed improvement in their symptoms. CONCLUSION: Although musculoskeletal issues are prevalent among otolaryngologists, awareness of surgical ergonomics principles among otolaryngologists remains limited. Early instruction in ergonomic principles is important because work-related musculoskeletal symptoms commonly present in residency. Most respondents reporting the application of ergonomic principles also acknowledge symptom improvement. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:632-640, 2018. PMID- 28895156 TI - What is the optimal time for removing drains in uncomplicated head and neck surgery? PMID- 28895157 TI - Laryngeal exposure and margin status in glottic cancer treated by transoral laser microsurgery. AB - OBJECTIVE: Laryngeal exposure is one of the most limiting factors in transoral laser microsurgery (TLM) for glottic cancer. We evaluated the correlation between the degree of laryngeal exposure, as assessed by an easy previously described scoring tool (Laryngoscore), and histopathologic surgical margin status after TLM. STUDY DESIGN: Prospective evaluation of 147 patients affected by Tis-T2 glottic cancer treated by TLM with curative intent between January 2012 and April 2016. METHODS: All patients were preoperatively assessed and classified as having good (group A including Laryngoscore class 0-I) or suboptimal laryngeal exposure (group B including class II-III). Margins were classified as negative (more than 1 mm margin between healthy tissue and tumor) or positive (one/multiple superficial or deep margins involved by invasive or in situ carcinoma). Patients with multiple superficial or deep margin positivity were scheduled for TLM re excision, open partial laryngectomy, or postoperative radiotherapy. RESULTS: Twenty-one type I, 54 type II, 19 type III, 7 type IV, 41 type V, and 5 type VI cordectomies (according to the European Laryngological Society classification) were performed with an en-bloc or multi-bloc technique according to the size, site, and exposure of the lesion. Group A included 109 (74%) and group B included 38 (26%) patients. Positive surgical margins were overall observed in 39 (26.5%) cases: 21 (19.2%) in group A versus 18 (47.4%) in group B (P = 0.001). CONCLUSION: Laryngeal exposure is one of the most important factors influencing TLM resection of glottic cancer within safe surgical margins. The importance of its adequate preoperative assessment cannot be overemphasized. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1146-1151, 2018. PMID- 28895158 TI - Effect of identity fusion on decision to make extreme sacrifices in romantic relationships: The moderating role of impulsiveness. AB - The present research investigated the roles of identity fusion and impulsiveness in extreme sacrifices for romantic partners. After completing questionnaires assessing identity fusion, inclusion of other in the self, passionate love, and communal orientation, participants responded to the trolley dilemma in which they could save their partner by sacrificing themselves. Participants in the time pressure condition were given eight-seconds to respond to the dilemma; the other group had no time constraints. Identity fusion was the only variable that significantly predicted ultimate sacrifice. Hurrying participants' response to the dilemma (i.e., inducing impulsive decision-making) increased self-sacrifice in highly fused but not in weakly fused individuals. PMID- 28895159 TI - Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites. AB - WHAT IS KNOWN: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the development of essential hypertension (EH). Genetic factors remarkably influence circulating ACE2 level. OBJECTIVE: Because heritability had remarkable effects on circulating ACE2, we designed this study to shed light on whether circulating levels of ACE2, angiotensin-(1-7) and angiotensin-(1-9) were linked to single nucleotide polymorphisms (SNPs) and haplotypes in ACE2 gene. METHODS: A total of 213 patients with newly diagnosed mild to moderate EH were enrolled in the present study. Four ACE2 tag SNPs (rs2074192, rs4646171, rs4646155 and rs2106809) were genotyped, and major haplotypes consisting of these 4 SNPs were reconstructed for all subjects. Circulating levels of ACE2, angiotensin-(1-7) and angiotensin-(1-9) were measured using enzyme-linked immunosorbent assay. RESULTS: In female subjects, linear regression analysis suggested that rare alleles of ACE2 rs2074192 and rs2106809 were associated with reduced circulating angiotensin (1-7) levels (P=.007 and P=.006, respectively). ACE2 haplotype CAGC was associated with elevated circulating angiotensin-(1-7) levels (P=.03) whereas TAGT was associated with reduced circulating angiotensin-(1-7) levels in females (P<.001). Univariate linear regression analysis revealed that circulating ACE2 levels were positively associated with systolic blood pressure (P=.02), mean arterial pressure (P=.02) and serum creatinine (P<.001) in females whereas circulating ACE2 levels were positively associated with age (P<.001) and serum creatinine (P<.001) in males. WHAT IS NEW AND CONCLUSION: ACE2 SNPs and haplotypes are associated with circulating angiotensin-(1-7) levels. ACE2 genetic variants may be the determinants of circulating angiotensin-(1-7) levels in hypertensive females. PMID- 28895160 TI - Oncologic outcomes of KTP laser surgery versus radiation for T1 glottic carcinoma. AB - OBJECTIVES/HYPOTHESIS: To characterize outcomes for patients who underwent transoral microsurgery with potassium titanyl phosphate (KTP) laser resection of early glottic cancers and to compare outcomes with patients who received external beam radiation therapy. STUDY DESIGN: Retrospective cohort study. METHODS: The history of patients with T1 glottic carcinoma treated with curative primary radiation or transoral KTP laser resection was reviewed. Oncologic outcomes for both radiation and surgery cohorts including disease-free and overall survival were calculated. RESULTS: Eighty-seven patients met inclusion criteria from 2011 to 2016; 47 patients (54%) received primary KTP laser ablation, and 40 patients (46%) received primary external beam radiotherapy. The average length of follow up was 924 +/- 529 days in the KTP laser group and 994 +/- 603 days in the radiation group (P = .26). There were no significant differences between the two treatment groups in terms of medical or demographic variables. There were six recurrences in the KTP laser group (13%), versus six in the radiotherapy group (15%) (P = .77). The laryngeal preservation rate for the cohort of patients who initially received KTP laser treatment was 46 out of 47 patients (98%). Of the cohort that received primary radiation therapy, the laryngeal preservation rate was 36 out of 40 patients (90%, P = .18). Disease-free and overall survival were 88% and 98% in the KTP laser cohort and 85% and 95% in the radiation cohort (P = .78, P = .56), respectively. CONCLUSIONS: KTP laser ablation is a modality equivalent to primary radiation therapy in oncologic outcomes for T1 glottic squamous cell carcinoma. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1052-1056, 2018. PMID- 28895161 TI - Therapeutic drug monitoring of antitubercular agents for disseminated Mycobacterium tuberculosis during intermittent haemodialysis and continuous venovenous haemofiltration. AB - WHAT IS KNOWN AND OBJECTIVE: There is a lack of data regarding therapeutic drug monitoring (TDM) of antitubercular agents in the setting of continuous venovenous haemofiltration (CVVH). We describe TDM results of numerous antitubercular agents in a critically ill patient during CVVH and haemodialysis. CASE SUMMARY: A 49 year-old man was initiated on treatment for disseminated Mycobacterium tuberculosis. During hospital admission, the patient developed critical illness and required renal replacement therapy. TDM results and pharmacokinetic calculations showed adequate serum concentrations of rifampin, ethambutol and amikacin during CVVH and of rifampin, pyrazinamide, ethambutol and levofloxacin during intermittent haemodialysis. WHAT IS NEW AND CONCLUSION: The presence of critical illness and renal replacement therapy can induce pharmacokinetic changes that may warrant vigilant TDM to ensure optimal therapy. To our knowledge, this is the first report to describe TDM for several antitubercular agents during CVVH in a critically patient with disseminated M. tuberculosis. PMID- 28895162 TI - Laryngeal EMG: Preferential damage of the posterior cricoarytenoid muscle branches especially in iatrogenic recurrent laryngeal nerve lesions. AB - OBJECTIVE: Laryngeal electromyography (LEMG) of the thyroarytenoid (TA) muscle alone may not be sufficient in all patients to characterize or prove a recurrent laryngeal nerve (RLN) lesion in cases of vocal fold immobility. LEMG of the posterior cricoarytenoid (PCA) muscle may provide additional information. STUDY DESIGN: Retrospective review. METHOD: Between 2008 and 2016, 339 patients in our laryngeal paralysis clinic were examined by transcutaneous needle TA-LEMG and, if tolerated, by PCA-LEMG. LEMGs were rated and compared according to criteria of the European Laryngological Society. Etiology was categorized as iatrogenic, noniatrogenic, or malignancy related. RESULTS: A total of 282 out of 339 patients had a partial or complete RLN or vagal nerve lesion: 178 iatrogenic, 74 noniatrogenic, and 30 because of nerve involvement by malignancies. Of paralytic vocal folds, 35.7% had normal or near-normal TA innervation, whereas corresponding PCA traces (if present) were pathologic in 94.6%. Comparing pairs of TA and PCA-LEMGs in paralysis of less than 4 months duration showed a predominance of PCA branch injuries in iatrogenic lesions (71.7 %), while in noniatrogenic lesions this was less pronounced (44.4%). In the few malignancy cases, there was an almost even distribution. Synkinetic reinnervation was earlier in iatrogenic RLN lesions. CONCLUSION: PCA-LEMG was better in proving an RLN lesion than TA-EMG alone. Our findings suggest etiology-dependent differences in the TA/PCA lesion pattern. To confirm this, larger sample sizes are needed. A preferential damage to PCA innervation in iatrogenic lesions could be relevant for further improvements of intraoperative neuromonitoring. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1152-1156, 2018. PMID- 28895163 TI - Off the pedal: Fluoroless transseptal puncture in pediatric supraventricular tachycardia ablation. AB - BACKGROUND: Fluoroless transseptal (TS) puncture may represent the final step toward elimination of fluoroscopy in pediatric supraventricular tachycardia ablation in normal hearts. We aimed to demonstrate the safety and feasibility of fluoroless TS puncture in pediatric patients and compare procedural timing with the fluoroscopic approach. METHODS: We performed a retrospective cohort analysis of all TS procedures performed without fluoroscopy at our institution; fluoroless TS procedures were performed under intracardiac echocardiography (ICE) guidance after the creation of a 3D electroanatomic map and identification of fossa ovalis (FO) on 3D map. TS procedure times reported are the time from sheath insertion (8.5F short sheath for ICE catheter and SL-1 for TS needle) to the time of confirmed left atrial access. Prior TS procedures performed by the same operator utilizing a combination of ICE and fluoroscopy and by a second operator utilizing fluoroscopic guidance alone were used for comparison. RESULTS: Fluoroless TS puncture was performed in nine patients (mean age 13.8 years); the site of TS puncture was within 2 mm of the FO identified on the EA map. The mean TS procedure time was 22.2 minutes (range 10-45). There was no significant difference in TS procedure times between the three groups. There were no complications related to any TS procedure. CONCLUSION: Fluoroless TS procedures utilizing ICE can safely be performed in pediatric patients without adding substantial procedural times compared with those utilizing fluoroscopic guidance. PMID- 28895164 TI - Bacterial Translocation Ratchets: Shared Physical Principles with Different Molecular Implementations: How bacterial secretion systems bias Brownian motion for efficient translocation of macromolecules. AB - Secretion systems enable bacteria to import and secrete large macromolecules including DNA and proteins. While most components of these systems have been identified, the molecular mechanisms of macromolecular transport remain poorly understood. Recent findings suggest that various bacterial secretion systems make use of the translocation ratchet mechanism for transporting polymers across the cell envelope. Translocation ratchets are powered by chemical potential differences generated by concentration gradients of ions or molecules that are specific to the respective secretion systems. Bacteria employ these potential differences for biasing Brownian motion of the macromolecules within the conduits of the secretion systems. Candidates for this mechanism include DNA import by the type II secretion/type IV pilus system, DNA export by the type IV secretion system, and protein export by the type I secretion system. Here, we propose that these three secretion systems employ different molecular implementations of the translocation ratchet mechanism. PMID- 28895165 TI - Preliminary results of tissue-engineered injection laryngoplasty material in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: Design and test a novel biomaterial for injection laryngoplasty aimed to increase the duration of effectiveness of micronized acellular dermis. STUDY DESIGN: Animal model. METHODS: Injection laryngoplasty was performed in three groups (n = 5) of New Zealand White rabbits. Acellular dermis was either used alone as a control (group 1), was combined with undifferentiated stem cells (group 2), or with predifferentiated chondrocytic cells (group 3). Groups 2 and 3 were supplemented with growth factors. Animals were sacrificed 4 and 12 weeks after laryngoplasty and histologic analysis was completed. The major outcome measure was volume of tissue remaining. RESULTS: After 4 weeks, the mean volume of tissue remaining was 341 +/- 89 mm3 , 295 +/- 102 mm3 , and 133 +/- 15 mm3 , for groups 1 to 3, respectively. At the 12-week time point, volumes were 62 +/- 62 mm3 , 235 +/- 35 mm3 , and 107 +/- 99 mm3 . After 12 weeks, there was a significantly higher volume in group 2 compared to group 1 or 3 (P = .01, P = .04). Volumes between week 4 and week 12 were significantly lower in group 1 (P = .02), but not significantly different for groups 2 and 3 (P = .38, P = .74). Histologic evaluation revealed a robust lymphocytic infiltration in all cases as well as morphologic and immunophenotypic features suggestive of chondrogenic differentiation in a single animal. CONCLUSIONS: Micronized acellular dermis combined with stem cells and growth factors showed significantly less resorption 12 weeks after injection laryngoplasty compared to micronized acellular dermis alone. Groups using novel tissue-engineered biomaterial showed a lower resorption rate over time compared with acellular dermis alone. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:160-167, 2018. PMID- 28895166 TI - Diabetes insipidus after discontinuation of vasopressin infusion for septic shock. AB - WHAT IS KNOWN AND OBJECTIVE: Despite widespread use of vasopressin for the treatment of septic shock, few cases of diabetes insipidus (DI) following its discontinuation have been reported. CASE SUMMARY: A 54-year-old man presented with pneumonia progressing to septic shock, requiring norepinephrine and vasopressin for refractory hypotension. After clinical improvement, the patient on 3 separate occasions developed polyuria and severe hypernatremia upon discontinuation of vasopressin, with prompt recovery upon its resumption. WHAT IS NEW AND CONCLUSION: Occurrence of DI upon discontinuation of vasopressin infusion appears to be rare, but incidence may be underestimated due to a paucity of published reports. Actual incidence and underlying mechanism of this phenomenon remain to be elucidated. PMID- 28895167 TI - The genetics of drought tolerance in conifers. AB - Contents 1034 I. 1034 II. 1035 III. 1037 IV. 1038 V. 1042 VI. 1043 VII. 1045 References 1045 SUMMARY: As temperatures warm and precipitation patterns shift as a result of climate change, interest in the identification of tree genotypes that will thrive under more arid conditions has grown. In this review, we discuss the multiple definitions of 'drought tolerance' and the biological processes involved in drought responses. We describe the three major approaches taken in the study of genetic variation in drought responses, the advantages and shortcomings of each, and what each of these approaches has revealed about the genetic basis of adaptation to drought in conifers. Finally, we discuss how a greater knowledge of the genetics of drought tolerance may aid forest management, and provide recommendations for how future studies may overcome the limitations of past approaches. In particular, we urge a more direct focus on survival, growth and the traits that directly predict them (rather than on proxies, such as water use efficiency), combining research approaches with complementary strengths and weaknesses, and the inclusion of a wider range of taxa and life stages. PMID- 28895168 TI - 9-cis-Retinoic acid induces a distinct regulatory dendritic cell phenotype that modulates murine delayed-type allergy. AB - BACKGROUND: Hand eczema, which is frequently caused by delayed-type allergy, is treated with 9-cis-retinoic acid (9cisRA). However, knowledge on how 9cisRA modulates skin immunity is sparse. OBJECTIVE: As dendritic cells (DCs) are central in the pathogenesis of contact allergy, we investigated 9cisRA modulation of DC function in murine contact hypersensitivity (CHS). METHODS: 9cisRA differentiated DCs (9cisRA-DCs) were analysed for phenotype and function. In vivo 9cisRA-DCs were tested in the CHS model. RESULTS: 9cisRA induces the differentiation of a distinct CD103- CD207- regulatory DC phenotype. CD11c+ DCs differentiated with 9cisRA have lower expression of major histocompatibility complex-II and costimulatory molecules, but conversely have higher expression of the inhibitory coreceptor PD1-L. 9cisRA-DC culture does not induce the expression of proinflammatory cytokines, but strongly enhances osteopontin (OPN) secretion. 9cisRA-DCs are compromised in the induction of T cell proliferation in vitro, but efficiently convert naive T cells into regulatory T cells (Tregs). Notably, OPN deficient 9cisRA-DCs show a loss of Treg-inducing function, which is re established by substituting OPN. In vivo, in allergic mice, allergen-primed 9cisRA-DCs suppress allergic inflammation and induce Treg accumulation in skin draining lymph nodes. CONCLUSIONS: This study describes 9cisRA-mediated differentiation of a distinct DC phenotype that relies on OPN for Treg transformation and suppresses established CHS through Treg induction. PMID- 28895169 TI - We have had a gutful: The need for deprescribing proton pump inhibitors. AB - WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitor (PPI) prescribing may often be inappropriate and expose patients to a risk of adverse effects, while incurring unnecessary healthcare expenditure. Our objective was to determine PPI usage in Australia since 2002 and review international studies investigating inappropriate PPI prescribing, including those that discussed interventions to address this issue. METHODS: Australian Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS) data were analysed. A narrative literature review relevant to the objective was conducted. Time series analysis was also used to examine the trend of reported PPI appropriate use across the international studies included in this review. RESULTS AND DISCUSSION: Proton pump inhibitor use in Australia increased between 2002 and 2010 and then gradually decreased. Estimates of the extent of inappropriate use in the international literature had a wide variation (11-84%). There appeared to be little change in the extent of appropriate PPI use reported through 34 international studies from 2000 to 2016. Interventions to address inappropriate use included patient-centred deprescribing, academic detailing, educational programmes and drug safety notifications. WHAT IS NEW AND CONCLUSION: Proton pump inhibitors continue to be overused worldwide and should be a focus for deprescribing programmes. Ongoing education and awareness campaigns for health professionals and patients, including electronic reminders at the point of prescribing, are strategies that have potential to reduce PPI use in individuals who do not have an evidence-based clinical indication for their long-term use. PMID- 28895170 TI - Serial order working memory and numerical ordinal processing share common processes and predict arithmetic abilities. AB - Recent studies have demonstrated that both ordinal number processing and serial order working memory (WM) abilities predict calculation achievement. This raises the question of shared ordinal processes operating in both numerical and WM domains. We explored this question by assessing the interrelations between numerical ordinal, serial order WM, and arithmetic abilities in 102 7- to 9-year old children. We replicated previous studies showing that ordinal numerical judgement and serial order WM predict arithmetic abilities. Furthermore, we showed that ordinal numerical judgement abilities predict arithmetic abilities after controlling for serial order WM abilities while the relationship between serial order WM and arithmetic abilities was mediated by numerical ordinal judgement performance. We discuss these results in the light of recent theoretical frameworks considering that numerical ordinal codes support the coding of order information in verbal WM. Statement of contribution What is already known on this subject? Numerical ordinal processes predict mathematical achievement in adults. Order WM processing predicts first mathematical abilities. What the present study adds? Numerical ordinal processes predict mathematical achievement in children and independently of order WM. The link between order WM and mathematical abilities was mediated by long-term ordinal processes. PMID- 28895171 TI - Effect of aging and direction of impulse in video head impulse test. AB - OBJECTIVE: The aim of this study was to identify the difference of gain value in the video head impulse test (vHIT) according to the age of the patient and the direction of the impulse. METHOD: All participants were subjected to vHIT with horizontal semicircular canal (HSCC). vHIT with vertical canal (posterior and anterior semicircular canal [PSCC and ASCC]) additionally was performed in 434 participants. RESULTS: The mean vestibulo-ocular reflex (VOR) gain was maintained in patients in the HSCC at below 70 years (1.025 +/- 0.08) and in the vertical canal at below 80 years (PSCC: 0.965 +/- 0.12, ASCC: 0.975 +/- 0.14). However, the decrease of VOR gain was significant in patients over 70 years in the HSCC (0.978 +/- 0.35, P < .001) and in patients over 80 years in the vertical canal (PSCC: 0.828 +/- 0.16, ASCC: 0.851 +/- 0.13, P < .001). In addition, a VOR gain of rightward impulse was higher than the leftward impulse, but there was no difference based on the direction of impulse in the vertical impulse test. CONCLUSION: VOR gain declines with increasing age, over 70 years on the horizontal canal, and over 80 years on the vertical canal. Additionally, horizontal VOR gain of rightward impulse was higher than the leftward impulse in right-eye recordings only, but the vertical canal showed no difference of gain according to the direction of impulse. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:E228-E233, 2018. PMID- 28895172 TI - A new method for microsurgery training using a smartphone and a laptop computer. PMID- 28895173 TI - Cardiac changes in moderately malnourished children and their correlations with anthropometric and electrolyte changes. AB - OBJECTIVE: To evaluate electrocardiographic and echocardiographic changes in moderately malnourished children and to correlate them with both anthropometric and electrolyte changes. PATIENTS AND METHOD: Sixty moderately malnourished children were taken as patient group, and 60 healthy children of matched age and sex were taken as control group. Weight, height, body mass index (BMI), serum albumin, and electrolytes were measured for all children. Electrocardiographic evaluation for calculated QT (QTc) and QT dispersion (QTd) was performed. Left ventricular (LV) function was also evaluated using conventional echocardiography, tissue Doppler, and strain methods. Left ventricular mass index (LVMI) was also calculated. RESULTS: Weight, BMI, serum levels of albumin, total calcium, and ionized calcium were significantly lower, while QTc and QTd were significantly prolonged in malnourished children (P = .001 for all). There was significant reduction in LV fraction shortening (FS), LV E'/A', LV strain (S), LV myocardial performance index (MPI), LV global systolic strain (GLSS), and LVMI (P = .001 for all) in malnourished children. There was significant correlation between BMI and all cardiac variables. Moreover, there was significant positive correlation between serum albumin level and LV E'/A' (P = .02), LV GLSS (P = .03), and LVMI (P = .03).Total and ionized calcium level were significantly correlated with QTc, QTd, and LVMI (P < .05 for all). BMI was the most powerful predictor of these electrocardiographic and echocardiographic changes. CONCLUSION: Cardiac changes were present in moderately malnourished children as documented by electrocardiographic and echocardiographic changes, and these changes are in strong association with BMI and for a lesser extent with electrolyte changes especially serum calcium. PMID- 28895174 TI - Team-, case-, lecture- and evidence-based learning. PMID- 28895175 TI - The use of case management for community-dwelling older people: the effects on loneliness, symptoms of depression and life satisfaction in a randomised controlled trial. AB - AIM: To investigate the effects of a case management intervention for community dwelling frail older people, with functional dependency and repeated contacts with the healthcare services, focusing on loneliness, depressive symptoms and life satisfaction. DESIGN: A two-armed, nonblinded, randomised control trial with repeated follow-ups, of N = 153 participants at baseline allocated to an intervention (n = 80) and control (n = 73) group. METHOD: Inclusion criteria were the following: >=65 years of age, living in ordinary housing, in need of assistance in two or more self-reported activities of daily living, having at least two hospital admissions or at least four visits in outpatient care 12 months prior to enrolment. Case managers (nurses and physiotherapists) provided an intervention of general case management, general information, specific information and continuity and safety. The intervention ranged over 12 months with one or more home visit(s) being conducted per month. An intention-to-treat analysis was applied for the primary outcomes of loneliness, depressive symptoms and life satisfaction, along with complete case and sensitivity analyses. RESULTS: During the trial period n = 12 died and n = 33 dropped out. No significant difference was found between the groups at baseline regarding sociodemographic characteristics, subjective health or primary outcomes. The intention-to-treat analysis did not result in any significant effects for the primary outcomes at any of the follow-ups (6 and 12 months). The complete case analysis resulted in a significant difference in favour of the intervention regarding loneliness (RR = 0.49, p = 0.028) and life satisfaction (ES = 0.41, p = 0.028) at 6 months and for depressive symptoms (ES = 0.47, p = 0.035) at 12 months. CONCLUSIONS: The use of case management for frail older people did not result in clear favourable effects for the primary outcomes. However, the study indicates that case management may be beneficial in terms of these outcomes. Due to the complexity of the outcomes, an elaboration of the components and assessments is suggested. PMID- 28895176 TI - Reply to "Why do you not call the condition takotsubo syndrome triggered by acute coronary ischemia?" PMID- 28895177 TI - A Novel Use of Olaparib for the Treatment of Metastatic Castration-Recurrent Prostate Cancer. AB - Although mortality from prostate cancer has declined over the past 20 years as a result of early detection and treatment, the 5-year survival rate for men with prostate cancer who develop metastatic disease is only 29%. Current treatment options for metastatic castration-recurrent prostate cancer (mCRPC) are associated with toxicity and a limited durable response; therefore, additional lines of efficacious and minimally toxic therapy are needed. Olaparib, a poly(adenosine 5'-diphosphate) ribose polymerase (PARP) inhibitor, received a U.S. Food and Drug Administration breakthrough therapy designation in January 2016 for the treatment of patients with BRCA1/2 or ATM gene-mutated mCRPC based on results of a compelling phase II trial of olaparib in patients with advanced castration-resistant prostate cancer (TOPARP-A). This study found that men with mCRPC and genetic mutations in DNA damage repair genes had an overall response rate of nearly 90% with olaparib treatment. In this review, we describe current therapies for mCRPC, the rationale for anti-PARP therapies, the pharmacology of olaparib for prostate cancer, clinical trials of olaparib for mCRPC, our clinical experience with olaparib for prostate cancer at a comprehensive cancer center, and future directions of olaparib for the treatment of mCRPC. Olaparib may constitute a promising treatment to prolong survival in patients with mCRPC, with an acceptable adverse effect profile. As the role of PARP inhibition in prostate cancer and other malignancies becomes further elucidated, olaparib may be shown to be beneficial for other patient populations. PMID- 28895178 TI - Interprofessional drug safety: enhancing collaborative knowledge exchange. PMID- 28895179 TI - Enhancing legume growing through sustainable cropping for protein supply. PMID- 28895180 TI - Recent progress using the Staudinger ligation for radiolabeling applications. AB - The increasing application of positron emission tomography and single-photon emission computer tomography in radiopharmacy and nuclear medicine has stimulated the development of a multitude of novel and versatile bioorthogonal conjugation techniques. Currently, there is particular interest in radiolabeling biologically active, high molecular weight compounds like peptides, proteins, or antibodies, but also for the labeling of small organic compounds. An enormous challenge in radiolabeling these biologically active molecules is that the introduction of radiohalogens like fluorine-18 as well as various radiometals proceeds under harsh conditions, which could destroy the biomolecule. The Staudinger ligation is one of the most powerful bioorthogonal conjugation techniques. The reaction proceeds over wide temperature and pH ranges; an amide (peptide) bond is formed as the ligation unit, which minimizes distortion of the structure; no isomers are obtained; and the reaction proceeds without any metal catalyst. Due to this adaptability, this robust ligation type is a perfect candidate with a high potential for various applications in the field of radiopharmacy for the labeling of biomolecules under mild conditions. This review summarizes recent research concerning the implementation of the Staudinger ligation for radiolabeling applications. PMID- 28895181 TI - Simultaneous double free radial forearm flaps combined with coronoidectomy and myotomy to release bilateral severe trismus: A case report. AB - Oral cancers associated with submucosal fibrosis-induced trismus are common. They may affect the patients' quality of life, cause nutritional deficits, and interfere with postoperative cancer surveillance. In such cases, locating desirable recipient vessels in the head and neck can be difficult. This report presents a 47-year-old man with severe trismus caused by recurrent head and neck cancer, who had received multiple free-flap reconstructions after cancer ablation. Reconstruction was successfully achieved for the bilateral defects and releasing the trismus by using simultaneous double free radial forearm flaps as a chained flow-through pattern with one residual recipient vessel combined with the bilateral myotomy of the medial pterygoid and masseter muscles, and coronoidectomy. Both flaps survived without any postoperative complication. The maximal mouth opening measured by interincisal distance was 38 mm intraoperative and 32 mm during the 3-year follow-up period. This approach may be an effective option for releasing trismus when recipient vessels are lacking. PMID- 28895182 TI - Transition to consultant: a critical career point. PMID- 28895183 TI - Self-concept in institutionalized children with disturbed attachment: The mediating role of exploratory behaviours. AB - BACKGROUND: Self-concept is seen as both an outcome of sociocognitive and emotional development, and a factor in social and mental health outcomes. Although the contribution of attachment experiences to self-concept has been limited to quality of primary attachment relationships, little is known of the effects of disturbed attachment on self-concept in institutionalized children. Thus, the current study examined associations between disturbed attachment behaviours in institutionalized children and self-concept, testing limited exploration as an explanatory factor. METHODS: Thirty-three institutionalized children, aged 4-12, participated in a multimethod and multi-informant assessment of disturbed attachment behaviours (i.e., Disturbances of Attachment Interview and Behavioral Signs of Disturbed Attachment in Young Children), self-concept (i.e., Pictorial Scale of Perceived Competence and Social Acceptance for Young Children), and exploratory behaviours (i.e., Student Exploratory Behaviours Observation Scale). Analyses were conducted using bootstrapping techniques. RESULTS: Global self-concept converged with teacher-rated children's self concept, except for physical competence domain. Disturbed attachment behaviours were identified in 62.5% of the children, and this was associated with lower levels of exploration and lower scores on self-concept, compared with children without disturbed attachment behaviours. Furthermore, exploratory behaviours mediated the effects of disturbed attachment behaviours on self-concept. CONCLUSIONS: Institution-reared children with disturbed attachment behaviours were likely to have a negative perception of self and one's own competences. Limited exploratory behaviours explained this linkage. Targeting disordered attachment in children reared in institutions and their caregivers should become a high priority as a means for preventing socioemotional development issues. PMID- 28895184 TI - When I say ... hermeneutic phenomenology. PMID- 28895185 TI - Venule valve graft in lymphatic supermicrosurgery: A novel strategy for managing blood backflow. PMID- 28895187 TI - Education-related inequality in restorative dental treatment need over 11 years in two areas of Finland. AB - OBJECTIVES: This study aimed to analyse education-related inequality in restorative dental treatment need among adults aged 30 years and older living in Northern and Southern Finland in 2000 and 2011. METHODS: Data were taken from the Health 2000 and 2011 population-based follow-up surveys, including information gathered by interviews and clinical dental examination. Final effective sample sizes were 2423 people in 2000 and 1192 people in 2011. Restorative dental treatment need was measured with number of decayed and/or fractured teeth (DT + FrT). Education-related inequality in number of DT + FrT and factors explaining it were analysed using the Poisson regression analysis, relative index of inequality and slope index of inequality. RESULTS: Average number of DT + FrT decreased from 2000 to 2011. Absolute and relative education-related inequalities in them decreased approximately 50% and 25% from 2000 to 2011, respectively. Tooth brushing frequency and time since last dental visit explained approximately 30%-40% of the education-related inequality. The contribution of time since last dental visit to the education-related inequality was smaller in 2011 than in 2000. CONCLUSIONS: It seems that, from 2000 to 2011, the need for restorative dental treatment decreased simultaneously with the education-related inequality in it among adults aged 30 years and older living in Northern and Southern Finland. PMID- 28895186 TI - The placebo effect on bradykinesia in Parkinson's disease with and without prior drug conditioning. AB - BACKGROUND: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease. METHODS: We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer. RESULTS: We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine. CONCLUSIONS: These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28895188 TI - An alternative technique of atrial septectomy during bidirectional superior cavopulmonary anastomosis. AB - An atrial septectomy is often required to create or enlarge a pre-existing restrictive atrial septal defect in patients with univentricular hearts undergoing the bidirectional superior cavopulmonary anastomosis. We describe an alternative surgical technique through the transected cardiac end of the superior vena cava without a right atriotomy successfully performed in 26 patients. PMID- 28895189 TI - "Diagnosis" of a hiatal hernia from a CT coronary artery calcium scan. AB - Identification of a hiatal hernia by computed tomography (CT) scanning, and particularly with axial imaging from a coronary artery calcium score exam, is often subjective. There are several CT features that are diagnostic or at least suggestive of a hiatal hernia. As a hiatal hernia may be the etiology of a chest pain syndrome, it is important to be aware of CT findings suggestive of such. PMID- 28895190 TI - Safe sternal reentry in all age groups with the Rultract Resternotomy RetractorTM. AB - In patients undergoing repeat sternotomy, the risk of injury to cardiac structures can be reduced by utilizing a technique that provides sustained visualization of structures adherent to underside of the sternum. We discuss the use of a retractor specifically designed for this purpose: the Rultract Resternotomy RetractorTM. PMID- 28895191 TI - Early assessment of the left ventricular function by epirubicin-induced cardiotoxicity in postoperative breast cancer patients. AB - OBJECTIVE: Epirubicin (Epi) is a potent and effective drug for many malignant cancers with serious cardiotoxicity. Therefore, layer-specific two-dimensional speckle tracking echocardiography (2D-STE) was used to evaluate the longitudinal and circumferential systolic function of the left ventricular for the early detection of cardiotoxicity in this retrospective work. METHODS: Overall, 130 female patients with postoperative breast cancer who did not receive radiotherapy were classified into three groups: Group A (control group, n = 40) without any chemotherapy; Group B (n = 44) administered Epi at 180 ~ 240 mg/m2 ; and Group C (n = 46) administered Epi at >=360 mg/m2 . Peak and global systolic longitudinal strains (GLS) in the total and endocardium, mid-myocardium, and epicardium were measured and calculated from apical four-chamber, apical two-chamber, and left ventricular long-axis views, respectively. Peak and global circumferential strains (GCS) in the total and endocardium, mid-myocardium, and epicardium were measured and calculated from mitral annulus, papillary muscle, and apical levels of the short-axis view, respectively. RESULTS: The total GLS and GLS of the endocardium in every view were significantly reduced in group C compared with both groups A and B (P < .05), but there was no significant difference between groups A and B (P > .05). The GLS of the epicardium and mid-myocardium in groups B and C were not significantly reduced (P > .05). There were no significant differences in the total GCS and layer-specific GCS of endocardium, mid myocardium, and epicardium among the three groups (P > .05). CONCLUSIONS: Left ventricular longitudinal systolic dysfunction was detected. Moreover, an impaired endocardium was also detected in an early assessment by layer-specific 2DSTE. PMID- 28895192 TI - Prevalence and extent of enamel defects in the permanent teeth of 8-year-old Nigerian children. AB - OBJECTIVES: Enamel formation is a vulnerable developmental process, susceptible to environmental influences such as excessive systemic fluoride (F) exposure and infant/childhood disease. This study determined prevalence and extent of developmental enamel defects (DDE) and dental fluorosis in 8-year-old Nigerians and explored associations with key predictors. METHODS: A sample of 322 healthy 8 year-olds (155 males, 167 females) from primary schools in lower and higher water F areas of (i) rural and (ii) urban parts of Oyo State in south-west Nigeria (n = 4 areas) (in which the mean (SD) F concentration of community water supplies ranged from 0.07 (0.02) to 2.13 (0.64) mg F/L) were dentally examined using modified DDE (mDDE) and Thylstrup and Fejerskov (TF) indices. Drinking waters, cooking waters and toothpaste samples were analysed for F concentration using a F ion-selective electrode (F-ISE). Information on infant/childhood diseases, infant feeding and tooth cleaning practices was obtained from parents/legal guardians. Data were analysed using ANOVA, chi-square tests, Spearman correlation and binary logistic regression as appropriate. RESULTS: Mean (SD) F concentration of actual drinking and actual cooking waters consumed by participants was 0.25 (0.20) and 0.24 (0.14) mg F/L respectively in the urban higher F area; 1.11 (1.00) and 1.16 (1.02) mg F/L, respectively in the rural higher F area (P < .05). Overall, mouth prevalence of DDE in the permanent dentition was 61.2% with a mean (SD) of 2.4 (2.2) index teeth affected. Dental fluorosis mouth prevalence was 29.8% with a mean of 2.1 (3.7) teeth affected. Prevalence and extent of DDE and dental fluorosis were greater in higher F than lower water F areas (P < .001). A weak positive correlation was seen between extent of dental fluorosis and drinking water F concentration (rho = 0.28). The absence of infant/childhood disease was associated with a lower risk of DDE being present (P = .001), with an odds ratio of 0.43 (95% CI = 0.26, 0.71). Gender was a statistically significant (P = .014) predictor for dental fluorosis with females having a higher risk OR 1.94 (95% CI = 1.14, 3.28) of dental fluorosis than males. CONCLUSIONS: In these Nigerian 8 year-olds (n = 322), mouth prevalence of DDE was 61.2% (mean (SD) teeth affected = 2.4 (2.2)), and a key positive predictor was a history of infant/childhood disease. With 29.8% of these children exhibiting dental fluorosis (mean (SD) teeth affected = 2.1(3.7)), drinking water F concentration was identified as a positive predictor, along with gender, with females more at risk of dental fluorosis than males. PMID- 28895193 TI - Improving resident wellness using a moderated faculty panel. PMID- 28895194 TI - Durable left ventricular assist device as a bridge to recovery for addisonian crisis related cardiomyopathy. AB - A 19-year-old female with addisonian crisis-related cardiomyopathy underwent temporary mechanical circulatory support followed by insertion of a durable left ventricular assist device. Successful device explanation was possible 2.5 years following implantation. PMID- 28895195 TI - Estimation of DIEP flap weight for breast reconstruction by the pinch test. AB - BACKGROUND: Various methods have been introduced for estimating deep inferior epigastric artery perforator (DIEP) flap volume based on computed tomography or magnetic resonance angiographic images. However, when radiologic images cannot be obtained, estimations are subjective. The purpose of this study was to develop a prediction model for estimating DIEP flap weight using the pinch test. METHODS: The pinch test was performed at three paraumbilical sites using a skin-fold caliper in 107 consecutive patients who underwent DIEP flap breast reconstruction. Multiple linear regression analysis was used to develop a formula to estimate flap weight. Predictor variables included body mass index (BMI, kg/m2 ), flap height (H, cm), flap width (W, cm), and flap thickness (mm) measured by the pinch test at the following three paraumbilical sites: 5 cm right (R), left (L), and inferior (I) of the umbilicus. The model accuracy was tested using leave one-out cross-validation. RESULTS: A prediction model was developed from the multiple regression analysis (R2 = 89.03%, P < .001); flap weight, g = -1308 + 24.57 * BMI + 6.80 * (R + L)/2 + 7.89 * I + 20.51 * H + 32.55 * W. The formula was implemented in a smartphone application, DIEP-W version 2.0, for real-time use. The mean absolute percentage error in the cross-validation was 12.15%. CONCLUSIONS: DIEP flap weight can be estimated by the pinch test with the developed prediction model in an easy, cost-effective, and relatively accurate manner. This method will improve surgical planning and allow surgeons to provide better counselling for patients when radiologic images are not available. PMID- 28895196 TI - Ninth Congress of World Society for Reconstructive Microsurgery. PMID- 28895197 TI - Impact of cardiac resynchronization therapy on mitral valve apparatus geometry and clinical outcomes in patients with secondary mitral regurgitation. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) may improve secondary mitral regurgitation (MR) in patients with cardiomyopathy. The effects on mitral valve (MV) and left ventricular (LV) geometry, however, have not been clearly defined. METHODS: Between 2009 and 2012, 229 CRT implants were performed at a single academic center. Seventy-one had >=mild MR at baseline and serial echocardiography, without subsequent MV intervention. The pre-CRT and follow-up echocardiograms were retrospectively reviewed for (1) MV and LV geometry measurements; (2) MR grade; and (3) LV remodeling indices. RESULTS: The mean age was 67 +/- 15 years, and the cardiomyopathy was ischemic in 37 (52%). At a mean follow-up of 4.0 +/- 1.9 years, there were significant improvements in LV ejection fraction and size, MR grade, MV tenting area and anterior leaflet tethering angle, and end-systolic interpapillary muscle distance (IPMD), and reductions in moderate-to-severe or severe MR (27% vs 15%; P = .04) and New York Heart Association functional class III/IV symptoms (83% vs 41%; P < .001). Multivariable analysis revealed the pre-CRT MV tenting height (OR 1.25, 95% CI 1.01-1.56; P = .04) and end-systolic IPMD (OR 1.14, 95% CI 0.99-1.32; P = .08) as independently associated with moderate or greater MR at follow-up. Finally, at 5 years post-CRT implantation, the estimated survival and freedom from LV assist device or cardiac transplantation was 61%. CONCLUSIONS: CRT results in favorable effects on MV and LV geometry and decreases the prevalence of moderate-to-severe or severe MR and heart failure symptoms. The pre-CRT MV tenting height and IPMD are independently associated with persistent MR at follow-up. PMID- 28895198 TI - Building research capacity through administration of an intramural grant. PMID- 28895199 TI - Percutaneous closure of left ventricular pseudoaneurysm caused by a central venting cannula. PMID- 28895201 TI - Long-term kidney transplant survival in patients with continent urinary diversion. AB - OBJECTIVES: To report the long-term survival of transplanted kidneys in patients with a continent urinary diversion. METHODS: Between January 1987 and July 2015, 16 patients with a median age of 37 years (range 21-63 years) underwent kidney transplantation on a continent urinary diversion. A total of 14 patients presented irreversible dysfunction of the lower urinary tract, and two patients had required radical cystectomy because of bladder cancer. All continent urinary diversions were carried out before the transplantation. There were nine Kock pouches, five Mainz pouches, one Mainz neobladder and one Hautmann neobladder. A total of 11 patients had a previous non-continent urinary diversion. Of the transplants, 14 came from brain-dead donors and two from related living donors. RESULTS: The median post-transplantation follow up was 171 months (range 30-298 months). Two patients died, while six patients lost their transplant and resumed hemodialysis. Nine patients (56.2%) were alive with a functional transplant at the end of follow up. The most common allograft complication was acute pyelonephritis, but no graft was lost as a result of urinary diversion complications. The kidney transplant survival rate was 73.3% after 10 years, and 66.6% after 15 years. Among patients who still had a functional transplant at the time of the study, creatinine clearance was >30 mL/min for seven patients and <30 mL/min for two patients. CONCLUSIONS: The present study is the longest series to date of renal transplantation on continent urinary diversions. The long-term outcome shows that the presence of a continent urinary diversion does not reduce transplant survival. PMID- 28895200 TI - Effects of 6 Weeks of Parenteral Cobalamin Supplementation on Clinical and Biochemical Variables in Cats with Gastrointestinal Disease. AB - BACKGROUND: Effects and duration of commonly used protocols for cobalamin (Cbl) supplementation on cellular Cbl deficiency have not been determined in hypocobalaminemic cats. HYPOTHESIS/OBJECTIVES: To evaluate effect of Cbl supplementation on clinical signs, serum and urine methylmalonic acid (MMA) concentrations over 16 weeks. ANIMALS: Twenty client-owned hypocobalaminemic cats with enteropathy. METHODS: Prospective study. Serum Cbl and serum and urine MMA concentrations were determined prospectively in cats at enrollment (t0), immediately before (t6), and 4 (t10) and 10 weeks (t16) after 6th Cbl injection (250 MUg, IM q 7 days). Clinical signs severity (activity, appetite, vomiting, diarrhea, body weight) graded at each time point and expressed as clinical disease activity score. RESULTS: Clinical disease activity score decreased during supplementation and increased after treatment discontinuation. Median serum Cbl concentration increased significantly from t0 (111 pmol/L, range 111-212) to t6 (2,332.5 pmol/L, range 123-22,730) (P < 0.01). Values at t10 were 610.5 pmol/L (range, 111-2,527) and 180.5 pmol/L (range, 111-2,262) at t16 (P < 0.01). Median baseline serum MMA concentration (372 MUmol/L, range 0.39-147,000) decreased significantly to 1.62 MUmol/L (range, 0.18-806) at t6 (P < 0.01) and gradually increased to 5.34 MUmol/L (range, 0.13-1,730) at t10 and 189 MUmol/L (range, 0.4 983) at t16. Similar, nonsignificant, pattern observed for urine MMA concentration. Serum and urine MMA concentrations had not normalized in 12 and 6 cats, respectively, at t6. CONCLUSION AND CLINICAL IMPORTANCE: The Cbl supplementation protocol used here did not lead to complete normalization of cellular Cbl deficiency in all examined cats, and biochemical improvements were transient. PMID- 28895202 TI - European S3-Guideline on the systemic treatment of psoriasis vulgaris - Update Apremilast and Secukinumab - EDF in cooperation with EADV and IPC. PMID- 28895205 TI - Baseline low serum dehydroepiandrosterone sulfate can predict poor responsiveness to hormone therapy in patients with hormone-naive prostate cancer with skeletal metastases. PMID- 28895203 TI - Rapid reduction in BCR-ABL1 transcript predicts deep molecular response in dasatinib-treated chronic-phase chronic myeloid leukaemia patients. AB - OBJECTIVES: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). METHODS: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m ) were the post-treatment factors investigated to predict the molecular response. RESULTS: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. CONCLUSIONS: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR ABL1 IS. PMID- 28895204 TI - Liver transplantation in critically ill patients: Preoperative predictive factors of post-transplant mortality to avoid futility. AB - BACKGROUND: The allocation of liver transplants to patients with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) with multi-organ failure who are admitted in ICU remains controversial due to their high post-transplant mortality rate and the absence of identified mortality risk factors. METHODS: We performed a single-center retrospective cohort study to determine the post transplant mortality rate of patients with ALF and ACLF requiring ICU care prior to liver transplant (LT) and identified pretransplant factors of post-transplant mortality. RESULTS: Eighty-four patients (29 with ALF and 55 with ACLF) received a liver transplant while they were hospitalized at the ICU. Their mean model for end-stage liver disease (MELD) score was 41, and their mean sequential organ failure assessment (SOFA) was 15 the day before transplant. The overall 1-year survival rate was 66%. In multivariate analysis, pretransplant lactate level and acute respiratory distress syndrome (ARDS) were the only two independent factors associated with post-transplant mortality. The absence of ARDS and a pretransplant lactate level< 5 mmol/L led to the identification of a subgroup of ICU patients with a good 1-year post-transplant survival (>80%). CONCLUSIONS: Low lactatemia lactate level and the absence of ARDS could be useful criteria in selecting those patients in ICU who could be eligible for liver transplant. PMID- 28895206 TI - Inpatient vs outpatient autologous hematopoietic stem cell transplantation for multiple myeloma. AB - BACKGROUND: High-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) are commonly performed for multiple myeloma (MM) patients and may be as safe in the outpatient setting as in the inpatient setting. METHODS: We performed a single-center retrospective analysis of all MM patients undergoing auto-HCT between January 2008 and December 2012. We categorized patients as outpatient vs inpatient auto-HCT and compared clinical characteristics and outcomes between the groups. RESULTS: One thousand and forty six patients were included (669 inpatients, 377 outpatients). Patients transplanted as outpatients were significantly younger (58 [34-78] vs 62 [31-82], P < .001) and more likely to have an hematopoietic stem cell comorbidity index (HCT-CI) score <2 (P = .003) and creatinine <2 (P < .001). There were no differences in treatment-related mortality (TRM) but the inpatient group experienced significantly more grade 2-5 (P = .003) and grade 3-5 (P = .003) adverse events (AEs). 2 year progression-free survival (PFS) was significantly longer in the outpatient group (60% vs 50%, HR =HR 0.7, 95% CI 0.6-0.9, P = .005). 2 year OS was also longer in the outpatient group (83% vs 77%, HR 0.6, 95% CI 04-0.9, P = .01). CONCLUSION: Outpatient auto-HCT can be safely performed for selected patients with MM. Differences in outcomes are likely related to baseline clinical characteristics rather than choice of treatment setting. PMID- 28895207 TI - Structural Characterisation of Alkaloids in Leaves and Roots of Stephania kwangsiensis by LC-QTOF-MS. AB - INTRODUCTION: The tuberous roots of Stephania kwangsiensis, which contain bioactive alkaloids, are used as a traditional Chinese medicine. Overexploitation of the roots has made the plant increasingly rare, and the abundant leaves of the same plant may offer a potential alternative. However, there is insufficient phytochemical information for a comparison of alkaloid compositions in the two parts. OBJECTIVE: To characterise and compare the alkaloids in the leaves and roots of S. kwangsiensis. METHODS: The alkaloids in S. kwangsiensis were characterised using high pressure liquid chromatography coupled with positive electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (HPLC (+)ESI-QTOF-MS/MS). The alkaloid compositions in the leaves and roots were compared by visual inspection combined with principal component analysis (PCA) of the HPLC-MS data. RESULTS: Seventy-five alkaloids comprising aporphine-, proaporphine-, protoberberine-, benzylisoquinoline-, bisbenzylisoquinoline- and morphine-type alkaloids were identified or tentatively identified in the roots and leaves of S. kwangsiensis. Sixty-three of these alkaloids have not been previously reported in this species, and three have not been previously reported in the literature. The roots and leaves had similarities in alkaloid composition but differences in the peak intensities of most alkaloids. The PCA revealed that the samples were clustered into two distinct groups, which corresponded to leaves and roots. CONCLUSION: This study further clarified the chemical constituents in the roots of S. kwangsiensis, and revealed that diverse alkaloids were also present in the leaves. The comparative chemical profiling of the two parts provides useful information on their potential medicinal use. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895209 TI - Focal hyperkeratosis overlying the palmar faces of interphalangeal and metacarpophalangeal joints revealing a juvenile dermatomyositis. PMID- 28895208 TI - Thrombocytosis in 715 Dogs (2011-2015). AB - BACKGROUND: Thrombocytosis is a hematologic abnormality in dogs that has been associated with various neoplastic, metabolic, and inflammatory conditions. OBJECTIVE: To classify thrombocytosis in dogs based on severity and evaluate whether there are associations between severity and underlying disease processes. ANIMALS: Seven hundred and fifteen dogs with thrombocytosis and 1,430 dogs with normal numbers of platelets. METHODS: Retrospective study. Medical records of dogs with increased (>500 * 103 /MUL; thrombocytosis group) and normal (300-500 * 103 /MUL; control group) platelet counts between 2011 and 2015 were reviewed. Dogs were characterized by severity of platelet increase and diagnosis. Diagnostic categories included neoplasia, endocrine disease, inflammatory disease, or miscellaneous. RESULTS: A total of 1,254 complete blood counts with thrombocytosis from 715 dogs were included in the study. Median platelet count in this population was 582 * 103 /MUL (500-1,810 * 103 /MUL). No correlation between severity of thrombocytosis and diagnosis was identified. Causes of secondary thrombocytosis included neoplasia (55.7%), endocrine disease (12.0%), and inflammatory disease (46.6%). Immune-mediated disease was common (22.2%), associated with frequent glucocorticoid administration, and had a significantly higher median platelet count (636 * 103 /MUL [500-1,262 * 103 /MUL] versus 565 * 103 /MUL [500-1,810 * 103 /MUL]) when compared to the other inflammatory processes (P < 0.001). The diagnoses in the thrombocytosis dogs differed significantly from the control population (P < 0.001). CONCLUSIONS AND CLINICAL IMPORTANCE: Thrombocytosis is commonly associated with carcinoma and immune mediated disease in dogs. PMID- 28895210 TI - Experimental and Computational Studies of the Structure of Sulfonimidoyl Vinyllithiums. AB - tBuCH=C(Li)S(O)(NSO2 Tol)Ph?L (L=2THF, TMEDA) (1?L) in THF solution is a monomer with a C-Li bond according to NMR spectroscopy and cryoscopy. It was identified as CIP through the scalar 13 C,6 Li coupling and 6 Li,{1 H} NOE experiments. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure. 6 Li,1 H FUCOUP and 6 Li,1 H HMQC NMR experiments of 1?TMEDA revealed a scalar 6 Li,1 H coupling across the Li-C=C-H bonds. According to the NMR data the pi-bond of 1?L is polarized by the negative charge of the anionic C atom. tBuCH=C(Li)S(O)(NMe)Ph (2?L) is most likely also a monomer with a C-Li bond. According to 6 Li,{1 H} NOE experiments it has a four-membered C-Li-N-S chelate ring structure. 13 C NMR spectroscopy showed the C-Li bonds of 1?L and 2?L to be fluxional. 1 H NMR spectroscopy and 1D TOCSY experiments of Ph2 C=C(Li)S(O)(NSO2 Tol)Ph revealed topomerization of the phenyl groups, which is attributed to a fast positional exchange of the Li atom and the sulfonimidoyl group. The fluxionality of the C-Li bond and the interchange of the Li atom and the sulfonimidoyl group at the anionic C atom of sulfonimidoyl vinyllithiums, which result in a low configurational stability, most likely involve the formation of O,Li and N,Li CIPs through heterolysis of the C-Li bond. Ab initio calculation of MeCH=C(Li)S(O)(NMe)Ph yielded an energy minimum structure with a C-Li bond, a four-membered C-Li-N-S chelate ring and a strongly expanded C=C-Li bond angle. According to calculation of MeCH=C(Li)S(O)(NMe)Ph, [MeCH=CS(O)(NMe)Ph]- and MeCH=C(H)S(O)(NMe)Ph deprotonation is not accompanied by a shortening of the C-S bond. Ab initio calculation of MeCH=C(Li)S(O)(NSO2 Me)Ph gave a structure with a C-Li bond and a six-membered C-Li-O-S-N-S chelate ring. 6 Li,1 H NOE experiments and cryoscopy of LiCH2 S(O)(NSO2 Tol)Ph (3) revealed a monomeric CIP with a C-Li bond. The CIP has a six-membered C-Li-O-S-N-S chelate ring structure found in polymeric 3 in the crystal. PMID- 28895211 TI - The Chameleonic Nature of Platinum(II) Imidazopyridine Complexes. AB - The synthesis and characterization of cyclometalated C^C* platinum(II) complexes with unique photophysical properties, aggregation induced enhancement of the quantum yields with a simultaneous decrease of phosphorescence lifetimes, is reported. Additionally, a change of emission color is induced by variation of the excitation wavelength. The aggregation behavior of these complexes is controlled by the steric demand of the substituents. The photophysical properties of these complexes are investigated through emission-excitation matrix analysis (EEM). The monomeric complexes are excellent room temperature phosphorescent blue emitters with emission maxima below 470 nm and quantum yields of up to 93 %. PMID- 28895212 TI - Syntheses, Properties, and Catalytic Activities of Metal(II) Complexes and Free Bases of Redox-Switchable 20pi, 19pi, and 18pi 5,10,15,20-Tetraaryl-5,15 diazaporphyrinoids. AB - In spite of significant advances in redox-active porphyrin-based materials and catalysts, little attention has been paid to 20pi and 19pi porphyrins because of their instability in air. Here we report the meso-modification of 5,10,15,20 tetraarylporphyrin with two nitrogen atoms, which led to redox-switchable 20pi, 19pi, and 18pi 5,10,15,20-tetraaryl-5,15-diazaporphyrinoids (TADAPs). Three kinds of metal(II) complexes and free bases of TADAP were prepared by the metal templated annulation of the corresponding metal-bis(dipyrrin) complexes. The inductive and resonance effects of the meso-nitrogen atoms on the aromatic, optical, electrochemical, and magnetic properties of the entire TADAP pi-systems were assessed by using various spectroscopic measurements and density functional theory calculations. The aromaticity and pi-pi* electronic transition energies of the TADAPs varied considerably, and were shown to be dependent on the oxidation states of the pi-systems. In contrast to the isoelectronic 5,10,15,20 tetraarylporphyrin derivatives, the 20pi and 19pi TADAPs were chemically stable under air. In particular, the 19pi TADAP radical cations were extremely stable towards dioxygen, moisture, and silica gel. This reflected the low-lying singly occupied molecular orbitals of their pi-systems and the efficient delocalization of their unshared electron spin. The capability of MgTADAP to catalyze aerobic biaryl formation from aryl Grignard reagents was demonstrated, which presumably involved a 19pi/20pi redox cycle. PMID- 28895213 TI - Supramolecular Synthon Approach in Developing Anti-Inflammatory Topical Gels for In Vivo Self-Delivery. AB - A new series of tertiary-butyl ammonium (TBA) salts of various nonsteroidal anti inflammatory drugs (NSAIDs) have been synthesized and characterized. Nearly 90 % of the NSAID-derived primary ammonium monocarboxylate (PAM) salts displayed remarkable gelation ability with various solvents including methyl salicylate. Single crystal X-ray diffraction data (SXRD) revealed the existence of 1D PAM synthon in the gelator salts. Structure-property correlation studies based on SXRD and powder X-ray diffraction (PXRD) data established the presence of the 1D PAM synthon in the bulk salts as well as in the corresponding xerogels. A parallel series of salts derived from TRIS (2-amino-2-(hydroxymethyl)-1,3 propanediol) and the same set of NSAIDs displayed poor gelation ability; only 33 % of the salts in the series displayed gelation ability. A few selected gelator salts of both TBA and TRIS were found to be biocompatible (MTT assay with RAW 264.7 cell line) and two of the selected salts (FLR.TBA and FLR.TRIS) possessed anti-inflammatory properties equal to the parent drug FLR (flurbiprofen). Finally a methyl salicylate topical gel derived from FLR.TRIS was successfully delivered in a self-delivery fashion to treat inflamed skin conditions in the mice model. Histological studies of the dorsal tissues of the untreated and treated mice clearly demonstrated the effect of topical gels in such treatment. PMID- 28895214 TI - Highly K+ -Selective Fluorescent Probes for Lifetime Sensing of K+ in Living Cells. AB - The new K+ -selective fluorescent probes 1 and 2 were obtained by CuI -catalyzed 1,3-dipolar azide alkyne cycloaddition (CuAAC) reactions of an alkyne-substituted [1,3]dioxolo[4,5-f][1,3]benzodioxole (DBD) ester fluorophore with azido functionalized N-phenylaza-18-crown-6 ether and N-(o-isopropoxy) phenylaza-18 crown-6 ether, respectively. Probes 1 and 2 allow the detection of K+ in the presence of Na+ in water by fluorescence enhancement (2.2 for 1 at 2000 mm K+ and 2.5 for 2 at 160 mm K+ ). Fluorescence lifetime measurements in the absence and presence of K+ revealed bi-exponential decay kinetics with similar lifetimes, however with different proportions changing the averaged fluorescence decay times (tauf(av) ). For 1 a decrease of tauf(av) from 12.4 to 9.3 ns and for 2 an increase from 17.8 to 21.8 ns was observed. Variation of the substituent in ortho position of the aniline unit of the N-phenylaza-18-crown-6 host permits the modulation of the Kd value for a certain K+ concentration. For example, substitution of H in 1 by the isopropoxy group (2) decreased the Kd value from >300 mm to 10 mm. 2 was chosen for studying the efflux of K+ from human red blood cells (RBC). Upon addition of the Ca2+ ionophor ionomycin to a RBC suspension in a buffer containing Ca2+ , the fluorescence of 2 slightly rose within 10 min, however, after 120 min a significant increase was observed. PMID- 28895215 TI - An Explosive Bomb-Inspired Method to Prepare Collapsed and Ruptured Fe2 O3 /Nitrogen-Doped Carbon Capsules as Catalyst Support. AB - Compared with integrated capsules, ruptured ones have better mass diffusion and transport properties due to large gaps in the shells. However, most studies focus on integrated capsules, whereas little attention has been paid to the ruptured counterparts. Herein, an explosive bomb-inspired method was employed to prepare collapsed and ruptured Fe2 O3 /nitrogen-doped carbon (CR-Fe2 O3 /NC) capsules by using polystyrene (PS) nanoparticles (NPs) as a hard template, and polypyrrole (PPy) with embedded Prussian blue (PB) NPs as the shell. During pyrolysis, PB is converted into Fe2 O3 , and PPy is carbonized to form NC. Importantly, the PS core decomposes into gas molecules, leading to high pressure inside of the capsule, which explodes the thin shell into pieces. The roles of shell thickness and amount of Fe2 O3 on determining the spherical or collapsed, and integrated or ruptured morphology were revealed. Taking advantage of structural merits, including large gaps, thin shells, low density, and high surface area, CR-Fe2 O3 /NC capsules were used as supports for Pd NPs. These capsules exhibited better catalytic activity than that of integrated ones. Due to the magnetic properties, they could be reused at least five times. PMID- 28895216 TI - Metabolic Alterations in Two Cirsium Species Identified at Distinct Phenological Stages using UPLC-QTOF/MS. AB - INTRODUCTION: Cirsium chanroenicum and C. setidens are commonly used both in traditional folk medicine and as a food source. The quality of different species of Cirsium at different harvest times is a function of their metabolite composition, which is determined by the phenological stage. OBJECTIVE: We sought to determine the differences in the metabolite composition of two species of Cirsium during different phenological stages using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (QTOF) mass spectrometry (MS). METHODOLOGY: Cirsium chanroenicum and C. setidens plants were collected at the floral budding and full flowering stages. Metabolic profiles of Cirsium extracts were determined using UPLC-QTOF/MS to characterise the differences between phenological stages, and the major metabolites were quantified using UPLC-QTOF/MS multiple reaction monitoring (MRM). RESULTS: At the full flowering stage, the levels of phenolic acids as well as components of the phenylpropanoid pathway were increased. Flavonoids predominated at the full flowering stage in both species. The levels of coumaric acid, kaempferol, and pectolinarigenin differed between the two species of Cirsium. Overall, these results suggest that components of the phenylpropanoid metabolic pathway are upregulated in the full flowering stage in Cirsium, although we did observe some variation between the species. CONCLUSION: These results will help elucidate the metabolic pathways related to the different phases of the vegetative cycle, and may help determine the optimal season for the harvest of Cirsium with the highest levels of bioactive compounds. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895217 TI - Determination of Tanshinones in Danshen (Salvia miltiorrhiza) by High-Performance Liquid Chromatography with Fluorescence Detection after pre-Column Derivatisation. AB - INTRODUCTION: Tanshinones are a major class of bioactive ingredients in the traditional herbal medicines, Danshen (Salvia miltiorrhiza). A sensitive and reliable determination method for tanshinones is useful to ensure the quality of Danshen. OBJECTIVE: To develop a sensitive and selective analytical method for tanshinones by high-performance liquid chromatography (HPLC) with fluorescence detection after pre-column derivatisation. METHODOLOGY: The proposed method depends on derivatisation reaction of tanshinones with 4-carbomethoxybenzaldehyde and ammonium acetate forming intensely fluorescent imidazole derivative. RESULTS: The proposed method provided excellent sensitivity with the detection limits of 3.3 nM (66 fmol/injection), 3.2 nM (64 fmol/injection) and 2.0 nM (40 fmol/injection) for cryptotanshinone, tanshinone I and tanshinone IIA, respectively, without the necessity of complicated instrumentations. The developed method is successfully applied to quantify the contents of tanshinones in Danshen. CONCLUSION: The developed method is the first analytical method for tanshinones by fluorescence detection. Since the derivatisation reaction is selective for the o-quinone structure of tanshinone, the developed method will become a suitable mean for the discovering of tanshinone type diterpenoids from herbal samples. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895218 TI - Strengthening Multipayer Collaboration: Lessons From the Comprehensive Primary Care Initiative. AB - : Policy Points: Collaboration across payers to align financial incentives, quality measurement, and data feedback to support practice transformation is critical, but challenging due to competitive market dynamics and competing institutional priorities. The Centers for Medicare & Medicaid Services or other entities convening multipayer initiatives can build trust with other participants by clearly outlining each participant's role and the parameters of collaboration at the outset of the initiative. Multipayer collaboration can be improved if participating payers employ neutral, proactive meeting facilitators; develop formal decision-making processes; seek input on decisions from practice representatives; and champion the initiative within their organizations. CONTEXT: With increasing frequency, public and private payers are joining forces to align goals and resources for primary care transformation. However, sustaining engagement and achieving coordination among payers can be challenging. The Comprehensive Primary Care (CPC) initiative is one of the largest multipayer initiatives ever tested. Drawing on the experience of the CPC initiative, this paper examines the factors that influence the effectiveness of multipayer collaboration. METHODS: This paper draws largely on semistructured interviews with CPC-participating payers and payer conveners that facilitated CPC discussions and on observation of payer meetings. We coded and analyzed these qualitative data to describe collaborative dynamics and outcomes and assess the factors influencing them. FINDINGS: We found that several factors appeared to increase the likelihood of successful payer collaboration: contracting with effective, neutral payer conveners; leveraging the support of payer champions, and seeking input on decisions from practice representatives. The presence of these factors helped some CPC regions overcome significant initial barriers to achieve common goals. We also found that leadership from the Centers for Medicare & Medicaid Services (CMS) was key to achieving broad payer engagement in CPC, but CMS's dual role as initiative convener and participating payer at times made collaboration challenging. CMS was able to build trust with other payers by clarifying which parts of CPC could be adapted to regional contexts, deferring to other payers for these decisions, and increasing opportunities for payers to meet with CMS representatives. CONCLUSIONS: CPC demonstrates that when certain facilitating factors are present, payers can overcome competitive market dynamics and competing institutional priorities to align financial incentives, quality measurement, and data feedback to support practice transformation. Lessons from this large-scale, multipayer initiative may be helpful for other multipayer efforts getting under way. PMID- 28895219 TI - Public Health Bundles. PMID- 28895221 TI - Lavatories of Democracy? Health Reform and Federalism in the Trump Era. PMID- 28895222 TI - Corrigendum. PMID- 28895220 TI - Consumers' Response to an On-Shelf Nutrition Labelling System in Supermarkets: Evidence to Inform Policy and Practice. AB - : Policy Points: On-shelf nutrition labelling systems in supermarkets, such as the Guiding Stars system, are intended to provide consumers with simple, standardized nutrition information to support more informed and healthier food choices. Policies that support the provision of simplified nutrition labelling systems may encourage consumers to make positive shifts in food-purchasing behaviors. The shifts in consumer food-purchasing patterns observed in our study after the introduction of the Guiding Stars system in supermarkets translated into measurable nutritional benefits, including more items purchased with slightly less trans fat and sugar and more fiber and omega-3 fatty acids. This study is one of the first to report the positive impact of an on-shelf nutrition labelling system on supermarket sales and revenues-key information that was specifically requested by the US National Academies, as such labelling interventions may be more sustainable if they lead to higher revenues. CONTEXT: Providing a nutrition rating system on the front of food packages or on retail shelf tags has been proposed as a policy strategy for supporting healthier food choices. Guiding Stars is an on-shelf nutrition labelling system that scores foods in a supermarket based on nutritional quality; scores are then translated into ratings of 0 to 3 stars. It is consistent with evidence-informed recommendations for well-designed labels, except for not labelling 0-star products. The largest supermarket retailer in Canada rolled out the Guiding Stars system in supermarkets across Ontario, Canada. The aim of our study was to examine the extent to which consumers respond to an on-shelf nutrition labelling system in supermarkets to inform current and future nutrition labelling policies and practices. METHODS: Capitalizing on a natural experiment, we conducted a quasi-experimental study across 3 supermarket banners (or "chains") in Ontario, one of which implemented the Guiding Stars system in 2012. We used aggregated supermarket transaction data to test the effect of Guiding Stars on the nutritional quality of food purchases in intervention supermarkets relative to control supermarkets. We also conducted exit surveys among 783 randomly selected shoppers from intervention and control supermarkets to assess consumer awareness, understanding, trust, and self-reported use of the labelling system. FINDINGS: Relative to control supermarkets, shoppers in intervention supermarkets made small but significant shifts toward purchasing foods with higher nutritional ratings; however, shifts varied in direction and magnitude across food categories. These shifts translated into foods being purchased with slightly less trans fat and sugar and more fiber and omega-3 fatty acids. We also found increases in the number of products per transaction, price per product purchased, and total revenues. Results of the exit surveys indicate a modest proportion of consumers were aware of, understood, and trusted Guiding Stars in intervention supermarkets, and a small proportion of consumers reported using this system when making purchasing decisions. However, 47% of shoppers exposed to Guiding Stars were confused when asked to interpret the meaning of a 0-star product that does not display a rating on the shelf tag. CONCLUSIONS: This study demonstrates support for policies promoting on-shelf nutrition labels designed according to evidence-informed principles, but policymakers should move forward with caution when investing in such systems until research has confirmed optimal label design, clarified the mechanisms through which dietary intake is improved, and assessed associations with nutrition-related health outcomes. PMID- 28895223 TI - Fifty-two Years Later, We Are Still Arguing About LBJ's Promise. PMID- 28895224 TI - In Defense of the Independent Payment Advisory Board. PMID- 28895226 TI - An Unhealthy Mismatch. PMID- 28895228 TI - Epic Failure. PMID- 28895229 TI - Crisis and Change: The Making of a French FDA. AB - : Policy Points: Introducing a recent special issue of The Lancet on the health system in France, Horton and Ceschia observe that "the dominance of English as the language of science and, increasingly, global health too often closes the door on the history and experiences of others."1 In that spirit, this manuscript presents a detailed case study of public health policy transformation in France in the early 1990s. It casts light on processes of policy change in a political and cultural environment very different from that of the United States, showing how the public health policy process is shaped by multiple contingencies of history, ideology, and politics. More specifically, we describe the transformation of a disease catastrophe into a political crisis and the deployment of that crisis to precipitate reform of the French public health system. CONTEXT: Until the last decade of the 20th century, France had no equivalent to the US Food and Drug Administration. In this paper we describe and interpret the complex series of events that led to the passage by the French Parliament in December 1992 of a law incorporating such an agency, the Agence du Medicament (literally, "medicines agency"). The broad aim of this project was to learn how public health policy change comes about by detailed analysis of a specific instance. More specifically, we aimed to better understand the circumstances under which public health crisis leads to significant public health policy reform. METHODS: This paper is based on detailed analysis of primary documents (eg, archived French health ministry papers, recorded parliamentary debates, government reports, newspaper articles) and oral history interviews covering a period from 1988 to 1993. Thematic analysis of these materials was initially grounded in theories of organizational change, moving to constructs that emerged from the data themselves. FINDINGS: Policy entrepreneurs positioned to frame adverse events and seize opportunities are key to public health policy reform. However, whether these entrepreneurs will have the requisite institutional power is contingent both on political structure and on the power of competing institutional actors. Health crises may catalyze institutional reform, but our analysis suggests that whether reform occurs, or even whether adverse episodes are labeled as crises, is highly contingent on circumstances of history, political structure, and political ideology and is extremely difficult to predict or control. CONCLUSIONS: Actors positioned to shape public health policy need to have a detailed understanding of the circumstances that facilitate or impede policy reform. Health crises are now more often global than not. Comparative, theoretically grounded, cross-national research that looks in detail at how different countries respond to similar health crises would be extremely valuable in informing both policymakers and researchers. PMID- 28895230 TI - Sophie's Choice on the Nation's Health. PMID- 28895227 TI - Comparing Generic Drug Markets in Europe and the United States: Prices, Volumes, and Spending. AB - : Policy Points: Our study indicates that there are opportunities for cost savings in generic drug markets in Europe and the United States. Regulators should make it easier for generic drugs to reach the market. Regulators and payers should apply measures to stimulate price competition among generic drugmakers and to increase generic drug use. To meaningfully evaluate policy options, it is important to analyze historical context and understand why similar initiatives failed previously. CONTEXT: Rising drug prices are putting pressure on health care budgets. Policymakers are assessing how they can save money through generic drugs. METHODS: We compared generic drug prices and market shares in 13 European countries, using data from 2013, to assess the amount of variation that exists between countries. To place these results in context, we reviewed evidence from recent studies on the prices and use of generics in Europe and the United States. We also surveyed peer-reviewed studies, gray literature, and books published since 2000 to (1) outline existing generic drug policies in European countries and the United States; (2) identify ways to increase generic drug use and to promote price competition among generic drug companies; and (3) explore barriers to implementing reform of generic drug policies, using a historical example from the United States as a case study. FINDINGS: The prices and market shares of generics vary widely across Europe. For example, prices charged by manufacturers in Switzerland are, on average, more than 2.5 times those in Germany and more than 6 times those in the United Kingdom, based on the results of a commonly used price index. The proportion of prescriptions filled with generics ranges from 17% in Switzerland to 83% in the United Kingdom. By comparison, the United States has historically had low generic drug prices and high rates of generic drug use (84% in 2013), but has in recent years experienced sharp price increases for some off-patent products. There are policy solutions to address issues in Europe and the United States, such as streamlining the generic drug approval process and requiring generic prescribing and substitution where such policies are not yet in place. The history of substitution laws in the United States provides insights into the economic, political, and cultural issues influencing the adoption of generic drug policies. CONCLUSIONS: Governments should apply coherent supply- and demand-side policies in generic drug markets. An immediate priority is to convince more physicians, pharmacists, and patients that generic drugs are bioequivalent to branded products. Special-interest groups continue to obstruct reform in Europe and the United States. PMID- 28895231 TI - Software-Related Recalls of Health Information Technology and Other Medical Devices: Implications for FDA Regulation of Digital Health. AB - : Policy Points: Medical software has become an increasingly critical component of health care, yet the regulation of these devices is inconsistent and controversial. No studies of medical devices and software assess the impact on patient safety of the FDA's current regulatory safeguards and new legislative changes to those standards. Our analysis quantifies the impact of software problems in regulated medical devices and indicates that current regulations are necessary but not sufficient for ensuring patient safety by identifying and eliminating dangerous defects in software currently on the market. New legislative changes will further deregulate health IT, reducing safeguards that facilitate the reporting and timely recall of flawed medical software that could harm patients. CONTEXT: Medical software has become an increasingly critical component of health care, yet the regulatory landscape for digital health is inconsistent and controversial. To understand which policies might best protect patients, we examined the impact of the US Food and Drug Administration's (FDA's) regulatory safeguards on software-related technologies in recent years and the implications for newly passed legislative changes in regulatory policy. METHODS: Using FDA databases, we identified all medical devices that were recalled from 2011 through 2015 primarily because of software defects. We counted all software related recalls for each FDA risk category and evaluated each high-risk and moderate-risk recall of electronic medical records to determine the manufacturer, device classification, submission type, number of units, and product details. FINDINGS: A total of 627 software devices (1.4 million units) were subject to recalls, with 12 of these devices (190,596 units) subject to the highest-risk recalls. Eleven of the devices recalled as high risk had entered the market through the FDA review process that does not require evidence of safety or effectiveness, and one device was completely exempt from regulatory review. The largest high-risk recall categories were anesthesiology and general hospital, with one each in cardiovascular and neurology. Five electronic medical record systems (9,347 units) were recalled for software defects classified as posing a moderate risk to patient safety. CONCLUSIONS: Software problems in medical devices are not rare and have the potential to negatively influence medical care. Premarket regulation has not captured all the software issues that could harm patients, evidenced by the potentially large number of patients exposed to software products later subject to high-risk and moderate-risk recalls. Provisions of the 21st Century Cures Act that became law in late 2016 will reduce safeguards further. Absent stronger regulations and implementation to create robust risk assessment and adverse event reporting, physicians and their patients are likely to be at risk from medical errors caused by software-related problems in medical devices. PMID- 28895232 TI - Anion-Directed Metallocages: A Study on the Tendency of Anion Templation. AB - Self-assembly of Cu(NO3 )2 ?3 H2 O and di(3-pyridylmethyl)amine (dpma) with addition of different acids (HNO3 , HOAc, HCl, HClO4 , HOTf, HPF6 , HBF4 , and H2 SO4 ) afforded a family of anion-templated tetragonal metallocages with a cationic prismatic structure of [(Gn- )?{Cu2 (Hdpma)4 }](8-n)+ (Gn- =NO3- , PF6- , SiF62- ) with different ligating anions/solvents (NO3- , Cl- , ClO4- , OTf- , H2 O) outside the cage. Systematic competitive experiments have rationalized the tendency of anion templation towards the formation of metallocages [(Gn- )?{Cu2 (Hdpma)4 }](8-n)+ as occurring in the order SiF62- ~PF6- >NO3- >SO42- ~ClO4- ~BF4 . This sequence is mostly elucidated by shape control over size selectivity and electrostatic attraction between the cationic {Cu2 (Hdpma)4 }8+ host and the anionic guests. In addition, these results have also roughly ranked the anion coordination ability in the order Cl- , ClO4- , OTf- >NO3- >BF4- , CH3 SO4- . Magnetic studies of metallocages 1 t and 2-4 suggest that the fitted magnetic interaction, being weakly magnetically coupled overall, is interpreted as a result of the combination of intracage ferromagnetic coupling integrals and intercage antiferromagnetic exchange; both contributions are very weak and comparable in strength. PMID- 28895233 TI - Validation of the OPportunity for Treatment In ONcology (OPTION) questionnaire measuring continuity of care. AB - Increasing efforts are ongoing to deliver effective cancer care through integrated networks of services. Measuring patients' experience of care is essential to identify problematic areas that require organisational adjustments. The aim of the present study was to examine the validity of OPTION questionnaire, designed to measure patient's perceived continuity of care across different phases of their care pathway. The study was carried at the Institute for Cancer Treatment and Research, Meldola and the oncology departments of the Local Health Authority of Romagna, Italy. Principal component analysis (PCA) was performed to identify factors underlying patients' perception of continuity of care. Factor scores were compared between patients with or without a care coordinator using Mann-Whitney test. The study sample consisted of 214 patients with breast or colorectal cancer, with a mean age of 62.3 years. Most patients identified the oncologist as their care coordinator. Five factors were extracted using PCA: (1) "trustful relationship with health care staff," (2) "information on care pathway," (3) "information on changes related to the illness," (4) "feelings of abandonment" and (5) "collaboration among health care professionals." The scores of factors 2 and 3 were significantly higher among those with a care coordinator. The OPTION questionnaire is a reliable instrument that can help clinicians and administrative stakeholder target efforts and resources in the pursuit of quality of care. PMID- 28895234 TI - Runt-Related Transcription Factor 2 Induction During Differentiation of Wharton's Jelly Mesenchymal Stem Cells to Osteoblasts Is Regulated by Jumonji AT-Rich Interactive Domain 1B Histone Demethylase. AB - Novel bone regeneration approaches aim to obtain immature osteoblasts from somatic stem cells. Umbilical cord Wharton's jelly mesenchymal stem cells (WJ MSCs) are an ideal source for cell therapy. Hence, the study of mechanisms involved in WJ-MSC osteoblastic differentiation is crucial to exploit their developmental capacity. Here, we have assessed epigenetic control of the Runt related transcription factor 2 (RUNX2) osteogenic master regulator gene in WJ MSC. We present evidence indicating that modulation of RUNX2 expression through preventing Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase activity is relevant to enhance WJ-MSC osteoblastic potential. Hence, JARID1B loss of function in WJ-MSC results in increased RUNX2/p57 expression. Our data highlight JARID1B activity as a novel target to modulate WJ-MSC osteoblastic differentiation with potential applications in bone tissue engineering. Stem Cells 2017;35:2430-2441. PMID- 28895235 TI - Infrared-Assisted Extraction and HPLC-Analysis of Prunus armeniaca L. Pomace and Detoxified-Kernel and their Antidiabetic Effects. AB - INTRODUCTION: Prunus armeniaca L. (P. armeniaca) is one of the medicinal plants with a high safety-profile. OBJECTIVES: The aim of this work was to make an infrared-assisted extraction (IR-AE) of P. armeniaca fruit (pomace) and kernel, and analyse them using reverse phase high-performance liquid chromatography (RP HPLC) aided method. METHODS: IR-AE is a novel-technique aimed at increasing the extraction-efficiency. The antidiabetic-potentials of the P. armeniaca pomace (AP) and the detoxified P. armeniaca kernel extract (DKAP) were monitored exploring their possible hypoglycemic-mechanisms. Acute (6 h), subchronic (8 days) and long-term (8 weeks) assessment of Diabetes mellitus (DM) using glucometers and glycated hemoglobin (HbA1c) methods were applied. RESULTS: Serum insulin levels, the inhibitory effects on alpha-glucosidase, serum-catalase (CAT) and lipid peroxidation (LPO) levels were also monitored. AP was shown to be rich in polyphenolics like trans-lutein (14.1%), trans-zeaxanthin (10.5%), trans-beta cryptoxanthin (11.6%), 13, cis-beta-carotene (6.5%), trans 9, cis-beta-carotene (18.4%), and beta-carotene (21.5%). Prunus armeniaca kernel extract before detoxification (KAP) was found to be rich in amygdaline (16.1%), which caused a high mortality rate (50.1%), while after detoxification (amygdaline, 1.4%) a lower mortality rate (9.1%) was found. AP showed significant (p <= 0.05, n = 7/group) antidiabetic-activity more prominent than DKAP acutely, subchronically and on longer-terms. IR-AEs displayed more efficient acute and subchronic blood glucose level (BGL) reduction than a conventional extraction method, which might be attributed to IR-AE superiority in extraction of active ingredients. AP showed more-significant and dose-dependent increase in serum-insulin, CAT-levels and body-weights more prominent than those of DKAP. Alpha-glucosidase and LPO levels were inhibited with AP-groups more-significantly. CONCLUSION: In comparison to conventional-methods, IR-AE appeared to be an efficient and time-conserving novel extraction method. The antidiabetic-potentials of pomace and detoxified-kernels of P. armeniaca were probably mediated via the attenuation of glucose-provoked oxidative-stress, the inhibition of alpha-glucosidase and the marked insulin secretagogue effect. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895236 TI - Protein surface roughness accounts for binding free energy of Plasmepsin II ligand complexes. AB - The calculation of absolute binding affinities for protein-inhibitor complexes remains as one of the main challenges in computational structure-based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high-resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave-one-out cross-validation showed that our model reproduced accurately the absolute binding free energies for our training set (R2 = 0.76; <|error|> =0.55 kcal/mol; SDerror = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article. PMID- 28895237 TI - A Comprehensive Characterisation of Rosemary tea Obtained from Rosmarinus officinalis L. Collected in a sub-Humid Area of Tunisia. AB - INTRODUCTION: Rosemary (Rosmarinus officinalis L.) is an aromatic plant common in Tunisia and it is widely consumed as a tea in traditional cuisine and in folk medicine to treat various illnesses. Currently, most research efforts have been focused on rosemary essential oil, alcoholic and aqueous extracts, however, little is reported on rosemary infusion composition. OBJECTIVE: To investigate compounds present in rosemary tea obtained from Rosmarinus officinalis L. collected in a sub-humid area of Tunisia in order to assess whether the traditional rosemary tea preparation method could be considered as a reference method for rosemary's compounds extraction. METHODOLOGY: Qualitative characterisation of Rosmarinus officinalis tea obtained after rosemary infusion in boiled water was determined by high performance liquid chromatography coupled with electrospray ionisation quadrupole time-of-flight mass spectrometry (HPLC ESI-QTOF-MS). Quantitative analysis relies on high performance liquid chromatography with diode array detector (HPLC-DAD). RESULTS: Forty-nine compounds belonging to six families, namely flavonoids, phenolic acids, phenolic terpenes, jasmonate, phenolic glycosides, and lignans were identified. To the best of the authors' knowledge eucommin A is characterised for the first time in rosemary. Rosmarinic acid (158.13 MUg/g dried rosemary) was the main compound followed then by feruloylnepitrin (100.87 MUg/g) and luteolin-3'-O-(2"-O-acetyl) beta-d-glucuronide (44.04 MUg/g). Among quantified compounds, luteolin-7-O rutinoside was the compound with the lowest concentration. CONCLUSION: The infusion method allows several polyphenols present in rosemary tea to be extracted, therefore it could be a reference method for rosemary's compounds extraction. Moreover, traditional Tunisian Rosmarinus officinalis tea consumption is of interest for its rich phenolic content. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895238 TI - The use of 1 H-NMR Metabolomics to Optimise the Extraction and Preliminary Identification of Anthelmintic Products from the Leaves of Lysiloma latisiliquum. AB - INTRODUCTION: Tannin-rich forages are recognised as an important alternative for the control of gastrointestinal nematodes in small ruminants. Lysiloma latisiliquum, a forage commonly consumed by goats and sheep, has shown anthelmintic activity when tested against Haemonchus contortus. However, to date, the metabolites responsible for the activity are not known. OBJECTIVE: To use 1 H NMR metabolomics in the extraction and identification of anthelmintic metabolites from L. latisiliquum. METHODOLOGY: Eight different solvent systems were compared for the optimum extraction of anthelmintic metabolites from L. latisiliquum. 1 H NMR spectra of the tannin-free extracts were measured in methanol-d4 using trimethylsilylpropanoic acid (TSP) as internal standard. Extracts were also evaluated for their anthelmintic activity using the larval exsheathment inhibition assay against H. contortus. These data were correlated by multivariate analysis [principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA)] and analysed. To validate the results obtained after the OPLS-DA, a bioassay-guided isolation of bioactive metabolites was conducted. RESULTS: The PCA of the 1 H-NMR data allowed the identification of hydrophilic solvents as those best suited for the extraction of anthelmintics from L. latisiliquum and indicated that the bioactive metabolites are high polarity, glycosylated products. Similarly, OPLS-DA of the data enabled the detection of activity-related signals, assigned to the glycosylated metabolites quercitrin and arbutin obtained from the bioassay-guided purification of the extract. CONCLUSION: The results of this investigation confirm metabolomics as a useful tool in the detection of bioactive metabolites in plants without previous phytochemical studies. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895239 TI - Trends and age, period and cohort effects for marijuana use prevalence in the 1984-2015 US National Alcohol Surveys. AB - BACKGROUND AND AIMS: Epidemiological trends show marijuana use in the United States to have increased in recent years. Previous research has identified cohort effects as contributing to the rising prevalence, in particular birth cohorts born after 1945. However, given recent policy efforts to regulate marijuana use at the state level, period effects could also play a contributory role. This study aimed to examine whether cohort or period effects play a larger role in explaining trends in marijuana use. DESIGN: Using data from seven National Alcohol Surveys, we estimated age-period-cohort decomposition models for marijuana use, controlling for socio-demographic measures. SETTING: United States. PARTICIPANTS: US general population aged 18 and older from 1984 to 2015. MEASUREMENTS: Any past-year marijuana use. FINDINGS: Results indicated that period effects were the main driver of rising marijuana use prevalence. Models including indicators of medical and recreational marijuana policies did not find any significant positive impacts. CONCLUSIONS: The steep rise in marijuana use in the United States since 2005 occurred across the population and is attributable to general period effects not linked specifically to the liberalization of marijuana policies in some states. PMID- 28895240 TI - Thermally Reversible and Irreversible Phase Transition Behaviors in Poly(ethylene oxide)/Ionic Liquid Mixtures. AB - The irreversible and reversible phase transition behaviors during phase separation-recovery (heating-cooling) cycles for poly(ethylene oxide)/1-ethyl-3 methylimidazolium tetrafluoroborate ionic liquid (PEO/[EMIM][BF4 ]) mixtures with a lower critical solution temperature phase diagram are reported for the first time. The evident differential scanning calorimetry endothermic and exothermic peaks are observed during the heating-cooling scan cycles near the phase boundary, in which the large heat loss for samples below the critical composition (60 wt% PEO) and obvious downward shift of phase transition temperature for all the compositions between the first and second cycles are particularly attractive. After the first recovery process, a reversible behavior during the next cycles is expected. These interesting phenomena are further confirmed by optical microscopy and Fourier-transform infrared measurements. It is demonstrated that the disruption and partial recovery of the hydrogen bonds, combined with the conformational change of PEO chains, can contribute to this irreversible behavior as well as a conversion to reversible phase transition behavior. PMID- 28895241 TI - Thermoresponsive Double Network Hydrogels with Exceptional Compressive Mechanical Properties. AB - The utility of thermoresponsive hydrogels, such as those based on poly(N isopropylacrylamide) (PNIPAAm), is severely limited by their deficient mechanical properties. In particular, the simultaneous achievement of high strength and stiffness remains unreported. In this work, a thermoresponsive hydrogel is prepared having the unique combination of ultrahigh compressive strength (~23 MPa) and excellent compressive modulus (~1.5 MPa). This is accomplished by employing a double network (DN) design comprised of a tightly crosslinked, highly negatively charged 1st network based on poly(2-acrylamido-2-methylpropane sulfonic acid (PAMPS) and a loosely crosslinked, zwitterionic 2nd network based on a copolymer of thermoresponsive NIPAAm and zwitterionic 2 (methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (MEDSAH). Comparison to other DN designs reveals that this PAMPS/P(NIPAAm-co-MEDSAH) DN hydrogel's remarkable properties stem from the intra- and internetwork ionic interactions of the two networks. Finally, this mechanically robust hydrogel retains the desirable thermosensitivity of PNIPAAm hydrogels, exhibiting a volume phase transition temperature of ~35 degrees C. PMID- 28895243 TI - Controlling Complex Stability in Photoresponsive Macromolecular Host-Guest Systems: Toward Reversible Capture of DNA by Cyclodextrin Vesicles. AB - An effective and universal method for delivering structurally diverse biomolecules in vivo would greatly benefit modern drug therapy, but has yet to be discovered. Self-assembled supramolecular complexes containing vesicles of amphiphilic cyclodextrin and linker molecules with an azobenzene guest unit and a charged functionality have been established as nanoscale carriers for proteins and DNA, making use of multivalent electrostatic attraction. However, light induced cargo release is only feasible up to a maximum net charge of the biomacromolecules. Herein, it is shown that it is possible to fine-tune macromolecular complex stability and size by addition of a competitive guest molecule that acts as a stopper, partly blocking the vesicle surface. The superior performance of arylazopyrazoles in photoisomerization compared to azobenzenes, which enables a lower surface charge density of the vesicles in the photostationary state, is also demonstrated. Both strategies allow reversible supramolecular aggregation of high molecular weight DNA (2 and 4.8 kbp). PMID- 28895242 TI - Hepatocellular carcinoma in a mouse model fed a choline-deficient, L-amino acid defined, high-fat diet. AB - Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, details of the liver-specific molecular mechanisms responsible for the NAFLD-NASH HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis-associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis. PMID- 28895244 TI - Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy. AB - Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)), and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca2+ concentrations, showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca2+ -dependent aggregation for the p.Ile385Thr. Accordingly, limited trypsin proteolysis assay showed that p.Asp44Asn and p.Gly103Asp were more susceptible to trypsin cleavage in the presence of Ca2+ in comparison with WT and p.Ile385Thr. Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in response to caffeine stimulation, compared with normal control fibers. Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca2+ and a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry. These results widen the spectrum of skeletal muscle diseases associated with CASQ1 and indicate that these mutations affect properties critical for correct Ca2+ handling in skeletal muscle fibers. PMID- 28895245 TI - Genetic Evolution of Glioblastoma Stem-Like Cells From Primary to Recurrent Tumor. AB - Glioblastoma (GBM) is a lethal tumor that displays remarkable genetic heterogeneity. It is also known that GBM contains a cell hierarchy driven by GBM stem-like cells (GSCs), responsible for tumor generation, therapeutic resistance, and relapse. An important and still open issue is whether phylogenetically related GSCs can be found in matched primary and recurrent GBMs, and reflect tumor genetic evolution under therapeutic pressure. To address this, we analyzed the mutational profile of GSCs isolated from either human primary GBMs (primary GSCs) or their matched tumors recurring after surgery and chemoradiotherapy (recurrent GSCs). We found that recurrent GSCs can accumulate temozolomide related mutations over primary GSCs, following both linear and branched patterns. In the latter case, primary and recurrent GSCs share a common set of lesions, but also harbor distinctive mutations indicating that primary and recurrent GSCs derive from a putative common ancestor GSC by divergent genetic evolution. Interestingly, TP53 mutations distinctive of recurrent GSCs were detectable at low frequency in the corresponding primary tumors and likely marked pre-existent subclones that evolved under therapeutic pressure and expanded in the relapsing tumor. Consistently, recurrent GSCs displayed in vitro greater therapeutic resistance than primary GSCs. Overall, these data indicate that (a) phylogenetically related GSCs are found in matched primary and recurrent GBMs and (b) recurrent GSCs likely pre-exist in the untreated primary tumor and are both mutagenized and positively selected by chemoradiotherapy. Stem Cells 2017;35:2218 2228. PMID- 28895246 TI - Influence of indigenous microbiota on experimental toxoplasmosis in conventional and germ-free mice. AB - Toxoplasmosis represents one of the most common zoonoses worldwide. Its agent, Toxoplasma gondii, causes a severe innate pro-inflammatory response. The indigenous intestinal microbiota promotes host animal homoeostasis and may protect the host against pathogens. Germ-free (GF) animals provide an important tool for the study of interactions between host and microbiota. In this study, we assessed the role of indigenous microorganisms in disease development utilizing a murine toxoplasmosis model, which includes conventional (CV) and GF NIH Swiss mice. CV and GF mice orally inoculated with T. gondii had similar survival curves. However, disease developed differently in the two animal groups. In CV mice, intestinal permeability increased and levels of intestinal pro-inflammatory cytokines were altered. In GF animals, there were discrete epithelial degenerative changes and mucosal oedema, but the liver and lungs displayed significant lesions. We conclude that, despite similar survival curves, CV animals succumb to an exaggerated inflammatory response, whereas GF mice fail to produce an adequate systemic response. PMID- 28895247 TI - The prevalence of pain and analgesia use in the Australian population: Findings from the 2011 to 2012 Australian National Health Survey. AB - BACKGROUND: Opioid analgesic use and associated adverse events have increased over the last 15 years, including in Australia. Whether this is associated with increased chronic pain prevalence in the Australian population is unknown. This study aimed to estimate (1) the prevalence of chronic pain and analgesia use in the Australian population by age and sex; (2) the severity of pain in the population with chronic pain by sex; and (3) the distribution of recent pain severity in those using analgesia by age and sex. METHODS: This study used cross sectional, nationally representative data collected by the Australian Bureau of Statistics 2011 to 2012 National Health Survey. A total of n = 20 426 participants were included with an overall response rate of 84.8%. Weighting procedures were applied to obtain population estimates, confidence intervals, and when testing for statistical significance. RESULTS: The prevalence of chronic and reoccurring pain (over a 6-month period) was 15.4% (2.75 million) for Australians aged >=15 years. Prevalence increased with age for both sexes. Significantly more females reported moderate-to-very severe pain overall (P < 0.001), and within most age groups. Recent use of opioid analgesia was reported by 12.0% of males and 13.4% of females with chronic pain. CONCLUSION: Chronic pain and opioid analgesic use are important public health issues in Australia. Study estimates of chronic pain and recent pain were no greater than earlier estimates. The acknowledged increase of opioid use in the literature thus appears consistent with changing treatment and/or prescribing patterns over time. Sex differences regarding pain prevalence, severity, and opioid use were apparent. PMID- 28895248 TI - Nano-Star-Shaped Polymers for Drug Delivery Applications. AB - With the advancement of polymer engineering, complex star-shaped polymer architectures can be synthesized with ease, bringing about a host of unique properties and applications. The polymer arms can be functionalized with different chemical groups to fine-tune the response behavior or be endowed with targeting ligands or stimuli responsive moieties to control its physicochemical behavior and self-organization in solution. Rheological properties of these solutions can be modulated, which also facilitates the control of the diffusion of the drug from these star-based nanocarriers. However, these star-shaped polymers designed for drug delivery are still in a very early stage of development. Due to the sheer diversity of macromolecules that can take on the star architectures and the various combinations of functional groups that can be cross-linked together, there remain many structure-property relationships which have yet to be fully established. This review aims to provide an introductory perspective on the basic synthetic methods of star-shaped polymers, the properties which can be controlled by the unique architecture, and also recent advances in drug delivery applications related to these star candidates. PMID- 28895249 TI - Salt Responsive Morphologies of ssDNA-Based Triblock Polyelectrolytes in Semi Dilute Regime: Effect of Volume Fractions and Polyelectrolyte Length. AB - A comprehensive study is reported on the effect of salt concentration, polyelectrolyte block length, and polymer concentration on the morphology and structural properties of nanoaggregates self-assembled from BAB single-strand DNA (ssDNA) triblock polynucleotides in which A represents polyelectrolyte blocks and B represents hydrophobic neutral blocks. A morphological phase diagram above the gelation point is developed as a function of solvent ionic strength and polyelectrolyte block length utilizing an implicit solvent ionic strength method for dissipative particle dynamics simulations. As the solvent ionic strength increases, the self-assembled DNA network structures shrinks considerably, leading to a morphological transition from a micellar network to worm-like or hamburger-shape aggregates. This study provides insight into the network morphology and its changes by calculating the aggregation number, number of hydrophobic cores, and percentage of bridge chains in the network. The simulation results are corroborated through cryogenic transmission electron microscopy on the example of the self-assembly of ssDNA triblocks. PMID- 28895250 TI - CO2 -Induced Morphological Transition of Co-Assemblies from Block-Random Segmented Polymers. AB - The co-assembly process is an effective approach to construct hierarchically nanostructured soft materials, but morphological transition of co-assemblies upon external stimuli, particularly the "green" trigger CO2 , is not unraveled yet. Here, a segmented copolymer, poly(styrene)-block-poly[(4-vinyl pyridine)-random ((2-(diethylamino)ethyl methacrylate)] (P1), is used to co-assemble in the mixed solvent of dimethyl formamide and water with poly(ethylene oxide)-block-poly[(4 vinyl pyridine)-random-((2-(diethylamino)ethyl methacrylate)] (P2) and poly(ethylene oxide)-block-poly(acrylic acid) (P3), respectively. It is found that Janus micelles are generated from the P1-P2 pair in the presence of ferric ion, while wormlike micelles are formed from the P1-P3 duad. Upon stimulation with CO2 , Janus and wormlike aggregates are transferred into core-shell and spherical micelles, respectively. PMID- 28895251 TI - Taming Macromolecules with Light: Lessons Learned from Vibrational Spectroscopy. AB - Exciting new applications, from large-area nanopatterning and templating to soft light-powered robotics, are emerging from the fundamental research on light triggered changes in macromolecular systems upon photoisomerization of azobenzene based molecular photoswitches. The understanding of how the initial molecular scale photoisomerization of azobenzene, a complex photochemical event in itself, is translated into the response of macromolecules and even into macroscopic-scale motion of illuminated azomaterials is an enormous task. The focus here is on how this knowledge has advanced by applying different vibrational spectroscopy techniques that provide rich molecular insight into the photoresponse of chemically specific molecular moieties. In particular, infrared and Raman spectroscopy studies are highlighted, in the context of phototriggered perturbation of self-assembled structures and photoinduced linear and circular anisotropy, as well as photoinduced surface patterning, with the objective of offering a perspective on how vibrational spectroscopy can help in answering an array of essential yet unsettled questions. PMID- 28895252 TI - New psychoactive substances: a public health issue. PMID- 28895253 TI - Characterisation of the l-Cystine beta-Lyase PatB from Phaeobacter inhibens: An Enzyme Involved in the Biosynthesis of the Marine Antibiotic Tropodithietic Acid. AB - The l-cystine beta-lyase from Phaeobacter inhibens is involved in the biosynthesis of the sulfur-containing antibiotic tropodithietic acid. The recombinant enzyme was obtained by heterologous expression in Escherichia coli and biochemically characterised by unambiguous chemical identification of the products formed from the substrate l-cystine, investigation of the substrate spectrum, determination of the enzyme kinetics, sequence alignment with closely related homologues and site-directed mutagenesis to identify a highly conserved lysine residue that is critical for functionality. PatB from P. inhibens is a new member of the small group of characterised l-cystine beta-lyases and the first example of an enzyme with such an activity that is required for the biosynthesis of an antibiotic. A comparison of PatB to previously reported enzymes with l cystine beta-lyase activity from bacteria and plants is given. PMID- 28895254 TI - Cancer is an independent predictor of poor outcomes in patients following intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Patients with cancer have been reported to have poorer outcomes following intracerebral hemorrhage (ICH) than those without cancer, but the findings were not consistent between studies. The aim of this study was to test the hypothesis that cancer is associated with poor outcomes following ICH. METHODS: In all, 3137 consecutive patients admitted to the stroke unit of Osaka University Hospital were reviewed. Patients diagnosed with ICH were extracted and divided into two groups according to the presence of cancer. ICH characteristics were compared between the groups. The outcomes were measured using the 30-day and 90-day modified Rankin Scale (mRS). RESULTS: Amongst the 399 ICH patients (37.1% women; median age 66 years), the frequency of cancer was 15.3%. Of these, 70.5% of patients had distant metastatic cancers. Compared to controls, cancer patients were comparable in the Glasgow Coma Scale, hematoma volume and the frequency of infratentorial location and intraventricular hemorrhage extension, but had poorer outcomes following ICH. Ordinal logistic regression analysis revealed that cancer was independently associated with poor outcomes following ICH (odds ratio 5.14; 95% confidence interval 2.63-10.06). Adjustment was made for the covariates age, sex, time from onset to admission, prior use of antithrombotic agents, pre-stroke mRS, Glasgow Coma Scale, hematoma volume, infratentorial location and intraventricular hemorrhage extension. When the analysis was performed using data from individuals with localized cancer, the effect remained significant after assessment with 90-day mRS but not after that with 30-day mRS. CONCLUSIONS: The results suggest that cancer, especially distant metastatic cancer, is an independent predictor of poorer outcomes following ICH. PMID- 28895255 TI - UBR2 Enriched in p53 Deficient Mouse Bone Marrow Mesenchymal Stem Cell-Exosome Promoted Gastric Cancer Progression via Wnt/beta-Catenin Pathway. AB - The deficiency or mutation of p53 has been linked to several types of cancers. The mesenchymal stem cell (MSC) is an important component in the tumor microenvironment, and exosomes secreted by MSCs can transfer bioactive molecules, including proteins and nucleic acid, to other cells in the tumor microenvironment to influence the progress of a tumor. However, whether the state of p53 in MSCs can impact the bioactive molecule secretion of exosomes to promote cancer progression and the regulatory mechanism remains elusive. Our study aimed to investigate the regulation of ubiquitin protein ligase E3 component n-recognin 2 (UBR2) enriched in exosomes secreted by p53 deficient mouse bone marrow MSC (p53 /- mBMMSC) in gastric cancer progression in vivo and in vitro. We found that the concentration of exosome was significantly higher in p53-/- mBMMSC than that in p53 wild-type mBMMSC (p53+/+ mBMMSC). In particular, UBR2 was highly expressed in p53-/- mBMMSC cells and exosomes. P53-/- mBMMSC exosomes enriched UBR2 could be internalized into p53+/+ mBMMSC and murine foregastric carcinoma (MFC) cells and induce the overexpression of UBR2 in these cells which elevated cell proliferation, migration, and the expression of stemness-related genes. Mechanistically, the downregulation of UBR2 in p53-/- mBMMSC exosomes could reverse these actions. Moreover, a majority of Wnt family members, beta-catenin, and its downstream genes (CD44, CyclinD1, CyclinD3, and C-myc) were significantly decreased in MFC knockdown UBR2 and beta-catenin depletion, an additional depletion of UBR2 had no significant difference in the expression of Nanog, OCT4, Vimentin, and E-cadherin. Taken together, our findings indicated that p53-/- mBMMSC exosomes could deliver UBR2 to target cells and promote gastric cancer growth and metastasis by regulating Wnt/beta-catenin pathway. Stem Cells 2017;35:2267-2279. PMID- 28895256 TI - Relevant Anatomy, Morphology, and Implantation Techniques of the Dorsal Root Ganglia at the Lumbar Levels. AB - OBJECTIVES: While dorsal root ganglion (DRG) stimulation has been available in Europe and Australia for the past five years and in the United States for the past year, there are no published details concerning the optimal procedures for DRG lead implantation. MATERIALS AND METHODS: We describe several techniques that can be applied to implant cylindrical leads over the DRG, highlighting some tips and tricks according to our experiences. Focus is mainly shifted toward implantations in the lumbar area. We furthermore give some insights in the results we experienced in Spain as well as some worldwide numbers. IMPLANT TECHNIQUES AND RESULTS: A 14-gauge needle is placed using a "2-Level Technique (2 LT)" or exceptionally a "1-Level Technique (1-LT)" or a "Primary- or Secondary Technique" at the level of L5. The delivery sheath, loaded with the lead, is advanced toward the targeted neural foramen. The lead is placed over the dorsal aspect of the DRG. A strain relief loop is created in the epidural space. Sheath and needle are retracted and the lead is secured using an anchor or anchorless technique. In Spain, 87.2% (N = 78) of the selected patients have been successfully implanted. Seven (8.9%) had a negative trial and three (4.2%) were explanted. Average VAS score decreased from 8.8 to 3.3 and on average 94.5% of the pain area was covered. In our center's subjects (N = 47 patients, 60.3% of all implanted patients in Spain), VAS scores decreased from an average of 8.8-1.7 and pain coverage averaged 96.4%. We used an average of 1.8 electrodes. Worldwide more than 4000 permanent cases have been successfully performed. CONCLUSIONS: We present implantation techniques whereby a percutaneous lead is placed over the DRG through the use of a special designed delivery sheath. Further investigation of the safety, efficacy, and sustainability of clinical outcomes using these devices is warranted. PMID- 28895257 TI - Do negative screening test results cause false reassurance? A systematic review. AB - PURPOSE: It has been suggested that receiving a negative screening test result may cause false reassurance or have a 'certificate of health effect'. False reassurance in those receiving a negative screening test result may result in them wrongly believing themselves to be at lower risk of the disease, and consequently less likely to engage in health-related behaviours that would lower their risk. METHODS: The present systematic review aimed to identify the evidence regarding false reassurance effects due to negative screening test results in adults (over 18 years) screened for the presence of a disease or its precursors, where disease or precursors are linked to lifestyle behaviours. MEDLINE and PsycINFO were searched for trials that compared a group who had received negative screening results to an unscreened control group. The following outcomes were considered as markers of false reassurance: perceived risk of disease; anxiety and worry about disease; health-related behaviours or intention to change health related behaviours (i.e., smoking, diet, physical activity, and alcohol consumption); self-rated health status. RESULTS: Nine unique studies were identified, reporting 55 measures in relation to the outcomes considered. Outcomes were measured at various time points from immediately following screening to up to 11 years after screening. Despite considerable variation in outcome measures used and timing of measurements, effect sizes for comparisons between participants who received negative screening test results and control participants were typically small with few statistically significant differences. There was evidence of high risk of bias, and measures of behaviours employed were often not valid. CONCLUSIONS: The limited evidence base provided little evidence of false reassurance following a negative screening test results on any of four outcomes examined. False reassurance should not be considered a significant harm of screening, but further research is warranted. Statement of contribution What is already known on this subject? It has been argued that screening for disease may cause 'false reassurance' whereby those who receive a negative screening test result wrongly interpret their result as indicating they are less likely to develop the disease in future. There is some evidence for false reassurance, but the relevant studies consider a range of diseases and possible indicators of false reassurance (i.e., risk perceptions, lifestyle behaviours, emotional outcomes, and quality of life). For these reasons, it is currently unclear that the extent to receive negative screening test results is likely to impact on participants' lifestyle behaviours, or other possible indicators of false reassurance. What does this study add? Current available evidence shows that negative screening test results are unlikely to cause false reassurance and, in particular, are unlikely to have a negative impact on lifestyle behaviours. Given the limitations of the current evidence base in terms of number of studies and study quality, future research should continue to explore this issue, where this can be done at low cost. PMID- 28895258 TI - Erratum. PMID- 28895259 TI - Control of Head/Tail Isomeric Structure in Polyimide and Isomerism-Derived Difference in Molecular Packing and Properties. AB - Two sequence isomeric poly(amic acid)s (PAAs) are successfully synthesized from 3,3',4,4'-biphenyltetracarboxylic dianhydride and unsymmetrical 5(6)-amino-2-(4 aminobenzene) benzimidazole (PABZ). The syntheses are based on the site-selective reactivity of head/tail amino groups of PABZ and solubility differences of PABZ in good solvent (dimethyl sulfoxide, DMSO) and poor solvent (N-methyl-2 pyrrolidone, NMP). The proton nuclear magnetic resonance (1 H-NMR) results reveal that the content of head tail-head tail (HT?HT) bonding units in PAA-DMSO (PAA synthesized in DMSO) is 37%, while this content increases to 54% in PAA-NMP (PAA synthesized in NMP). The wide-angle X-ray diffraction (WAXD) results indicate polyimide (PI)-NMP film with high HT?HT content exhibits a semicrystalline structure, while PI-DMSO film is amorphous. Moreover, PI-NMP also shows higher in plane orientation than PI-DMSO. The ordered molecular packing and higher in-plane orientation of PI-NMP lead to an increase in mechanical properties and a decrease in in-plane thermal expansion coefficient. PMID- 28895260 TI - Changes in serum chitinase 3-like 1 levels correlate with changes in liver fibrosis measured by two established quantitative methods in chronic hepatitis B patients following antiviral therapy. AB - AIM: Non-invasive assessment of changes in liver fibrosis is still an unmet medical need in the era of antiviral therapy. Therefore, we explore whether chitinase 3-like 1 (CHI3L1), a serum marker of liver fibrosis, can be used as a non-invasive surrogate marker of fibrosis change during treatment. METHODS: We correlated serum CHI3L1 levels with liver tissue collagen proportionate area (CPA) in a cohort of 131 patients with chronic hepatitis B (CHB) receiving entecavir-based antiviral therapy for 78 weeks. In addition, we compared this marker with the liver stiffness measurement (LSM). Multivariate regression analyses were undertaken to determine the clinical factors associated with the CHI3L1 levels. RESULTS: Before treatment, correlation analysis showed that there were positive correlations between CHI3L1 levels and the CPA (r = 0.351, P < 0.001), and between CHI3L1 and LSM (r = 0.412, P < 0.001). After 78 weeks treatment, serum CHI3L1 levels decreased compared with that at baseline (87.8 vs. 69.6 ng/mL, P < 0.001), and CHI3L1 levels were also correlated with CPA (r = 0.293, P = 0.001) and LSM (r = 0.443, P < 0.001). Furthermore, there were positive correlations between the changes in CHI3L1 and CPA (r = 0.366, P<0.001), and changes in CHI3L1 and LSM (r = 0.438, P<0.001). Multivariate regression analyses indicated that CPA values were related with pre- (beta = 5.450, P = 0.019) and post-treatment CHI3L1 levels (beta = 7.460, P = 0.023). CONCLUSIONS: Chitinase 3-like 1 is not only a useful non-invasive marker for the assessment of liver fibrosis in CHB patients before treatment, but also a potential useful marker for monitoring the change in liver fibrosis during therapy. PMID- 28895261 TI - The effects of optimism, religion, and hope on mood and anxiety disorders in women with the FMR1 premutation. AB - BACKGROUND: The FMR1 premutation, caused by a CGG trinucleotide repeat expansion on the FMR1 gene, has been identified as a genetic risk factor for mood and anxiety disorders. Building on recent studies identifying increased risk for mood and affective disorders in this population, we examined effects of potential protective factors (optimism, religion, hope) on depression and anxiety diagnoses in a prospective, longitudinal cohort. METHODS: Eighty-three women with the FMR1 premutation participated in the Structured Clinical Interview for DSM-IV-TR Disorders at two-time points, 3 years apart. Participants also completed measures of optimism, religion, personal faith, hope, and child and family characteristics. We used logistic regression to examine correlates of major depressive disorder (MDD) and anxiety disorders at the initial assessment, as well as predictors of the diagnostic course over time. RESULTS: Lower optimism and higher religious participation relevant to fragile X syndrome at the initial assessment were associated with a lifetime history of MDD. Lower optimism also predicted the occurrence and reoccurrence of an anxiety disorder 3 years later. CONCLUSIONS: In women with the FMR1 premutation, elevated optimism may reduce the occurrence or severity of MDD and anxiety disorders. These findings underscore the importance of supporting mental health across the FMR1 spectrum of involvement. PMID- 28895262 TI - Physical and mental health of young people with and without intellectual disabilities: cross-sectional analysis of a whole country population. AB - BACKGROUND: Transition to adulthood may be a period of vulnerability for health for individuals with intellectual disabilities. No large-scale studies have compared the health of individuals with and without intellectual disabilities undergoing transition. The aims of this study were (1) to compare health during transition for individuals with and without intellectual disabilities across a whole country population and (2) to establish whether transition is associated with health in the population with intellectual disabilities. METHODS: Data were drawn from Scotland's Census, 2011. Frequency data were calculated for young people with and without intellectual disabilities. Logistic regressions were used to determine the extent to which intellectual disabilities account for seven health outcomes (general health, mental health, physical disabilities, hearing impairment, visual impairment, long-term illness and day-to-day activity limitations), adjusted for age and gender. Within the intellectual disabilities population, logistic regressions were then used to determine whether age group (13-18 or 19-24 years) is associated with the seven health outcomes, adjusted by gender. RESULTS: A total of 5556/815 889 young people aged 13-24 years had intellectual disabilities. Those with intellectual disabilities were 9.6-125.0 times more likely to have poor health on the seven outcomes. Within the population with intellectual disabilities, the 19- to 24-year-olds with intellectual disabilities were more likely to have mental health problems than the 13- to 18-year-olds, but did not have poorer health on the other outcomes. The difference between age groups for mental health problems was greater for young people who did not have intellectual disabilities, but their overall level of mental health problems was substantially lower than for the young people with intellectual disabilities. CONCLUSIONS: This largest-to-date study quantifies the extent of the substantial health disparities experienced by young people with intellectual disabilities compared with people without intellectual disabilities. The young population with intellectual disabilities have substantial health problems; therefore, transition between child and adult services must be carefully planned in order to ensure that existing health conditions are managed and emerging problems minimised. PMID- 28895263 TI - Pseudouridimycin: The First Nucleoside Analogue That Selectively Inhibits Bacterial RNA Polymerase. AB - Seek, and ye shall find: After years of focusing research on synthetic antibiotics out of fear that all the useful natural ones had already been found, a novel antibacterial compound has been discovered through conventional microbial extract screening. The broad-spectrum nucleoside-analogue inhibitor pseudouridimycin is selective for bacterial RNA polymerase and elicits very low resistance rates. PMID- 28895264 TI - Phenolic Compound Diversity Explored in the Context of Photo-Oxidative Stress Protection. AB - INTRODUCTION: Phenolic compounds are a chemically diverse group of plant secondary metabolites with important roles both in plant stress defence and human nutrition. OBJECTIVE: To explore structure-function relations potentiating phenolic compounds to promote leaf acclimation to light stress by excess photosynthetically active radiation (photoinhibition) and by solar ultraviolet (UV) radiation. METHODOLOGY: We report singlet oxygen and hydrogen peroxide antioxidant capacities and UV-absorbing properties of 27 flavonoids and 11 phenolic acids. Correlations of these characteristics in the whole data set and related activity-structure relationships in flavonoid data were investigated using simple statistical methods. RESULTS: In comparison to flavonoids, phenolic acids are relatively ineffective reactive oxygen neutralising antioxidants; and - with the exception of gallic acid - have poor reactivity to hydrogen peroxide. Singlet oxygen and hydrogen peroxide detoxifying capacities of flavonoids are positively correlated, largely due to the strong positive effect of the hydroxylation of the C-ring in position-3. 3-O-Glycosylation halves reactive oxygen species (ROS) reactivities of quercetin and myricetin but eradicates the hydrogen peroxide reactivity of kaemferol. B-ring polyhydroxylation (cathecol structure) increases the hydrogen peroxide antioxidant function but decreases UV B (280-315 nm) absorption. UV-A (315-400 nm) absorption is increased by the B ring C2-C3 double bond either in itself or in combination with the C4 oxo-group. CONCLUSION: Among the studied compounds, anthocyanins and flavonols were the strongest singlet oxygen and hydrogen peroxide scavengers, and are thus capable of supporting defence against both photoinhibition by visible light and UV stress in leaves, while flavanols may only be effective against the latter. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28895265 TI - Graphene Oxide Facilitates Solvent-Free Synthesis of Well-Dispersed, Faceted Zeolite Crystals. AB - Zeolites with molecular dimension pores are widely used in petrochemical and fine chemical industries. While traditional solvothermal syntheses suffer from environmental, safety, and efficiency issues, the newly developed solvent-free synthesis is limited by zeolite crystal aggregation. Herein, we report well dispersed and faceted silicalite ZSM-5 zeolite crystals obtained using a solvent free synthesis facilitated by graphene oxide (GO). The selective interactions between the GO sheets and different facets, which are confirmed by molecular dynamics simulations, result in oriented growth of the ZSM-5 crystals along the c axis. More importantly, the incorporation of GO sheets into the ZSM-5 crystals leads to the formation of mesopores. Consequently, the faceted ZSM-5 crystals exhibit hierarchical pore structures. This synthetic method is superior to conventional approaches because of the features of the ZSM-5 zeolite. PMID- 28895266 TI - Sequence-Independent DNA Nanogel as a Potential Drug Carrier. AB - DNA nanostructures largely rely on pairing DNA bases; thus, sequence designing is required. Here, this study demonstrates a sequence-independent strategy to fabricate DNA nanogel (NG) inspired by cisplatin, a chemotherapeutic drug that acts as a DNA crosslinker. A simple heating and cooling of the genomic DNA extracts and cisplatin produces DNA NG with a size controlled by the heating time. Furthermore, the drug-loaded NG is formulated by spontaneously mixing DNA segments, cisplatin, and doxorubicin. The in vitro cell studies demonstrate that the doxorubicin-loaded NG alters the drug distribution in cells while its cytotoxic potential is well-maintained. This chemotherapeutic-inspired method provides a facile one-pot and cost-effective strategy to fabricate size controllable DNA NG that potentially acts as drug carrier. PMID- 28895267 TI - Long-Lived Supramolecular Helices Promoted by Fluorinated Photoswitches. AB - Chiral azobenzenes can be used as photoswitchable dopants to control supramolecular helices in liquid crystals. However, the lack of thermal stability of the cis-isomer precludes envisioning the generation of long-lived supramolecular helices with light. Here, this study demonstrates thermally stable and axially chiral azobenzene switches that can be used as chiral dopants to create supramolecular helices from (achiral) nematic liquid crystals. Their trans to-cis photoisomerization leads to a variation of helical twisting power that reaches up to 60%, and the helical superstructure that is engineered with light displays a relaxation time that reaches tens of hours. These results demonstrate that combining ortho-fluorination with axial chirality in molecular photoswitches constitutes an efficient strategy to promote long-lived helical states. Further, this approach shows potential to design supramolecular machines that are controlled by light entirely. PMID- 28895268 TI - Lithium reduces the span of G protein-activated K+ (GIRK) channel inhibition in hippocampal neurons. AB - OBJECTIVES: Lithium (Li+ ) is one of the most widely used treatments for bipolar disorder (BD). However, the molecular and neuronal basis of BD, as well as the mechanisms of Li+ actions are poorly understood. Cellular and biochemical studies identified G proteins as being among the cellular targets for Li+ action, while genetic studies indicated an association with the KCNJ3 gene, which encodes the G protein-activated inwardly rectifying K+ (GIRK) channels. GIRK channels regulate neuronal excitability by mediating the inhibitory effects of multiple neurotransmitters and contribute to the resting potassium conductance. Here, we explored the effects of therapeutic dose of Li+ on neuronal excitability and the role of GIRK channels in Li+ actions. METHODS: Effects of Li+ on excitability were studied in hippocampal brain slices using whole-cell electrophysiological recordings. RESULTS: A therapeutic dose of Li+ (1 mM) dually regulated the function of GIRK channels in hippocampal slices. Li+ hyperpolarized the resting membrane potential of hippocampal CA1 pyramidal neurons and prolonged the latency to reach the action potential threshold and peak. These effects were abolished in the presence of tertiapin, a specific GIRK channel blocker, and at doses above the therapeutic window (2 mM). In contrast, Li+ reduced GIRK channel opening induced by GABAB receptor (GABAB R) activation, causing reduced hyperpolarization of the membrane potential, attenuated reduction of input resistance, and a smaller decrease of neuronal firing. CONCLUSIONS: A therapeutic dose of Li+ reduces the span of GIRK channel-mediated inhibition due to enhancement of basal GIRK currents and inhibition of GABAB R evoked responses, providing an important link between Li+ action, neuronal excitability, and cellular and genetic targets of BD. PMID- 28895269 TI - Lithium and suicide in mood disorders: Updated meta-review of the scientific literature. AB - OBJECTIVES: Suicide and suicidal behaviour are increased in mood disorders, particularly bipolar disorders. Observational studies and small randomized controlled trials (RCTs) support the idea that taking lithium is associated with a reduction in these rates. This paper aims to review the best evidence for the effect of lithium on rates of suicide and self harm. METHODS: We searched PubMed, PsycINFO, and the Cochrane Library systematically for systematic reviews and meta analyses of RCTs of lithium and suicide and self harm published between January 1980 and June 2017. In the case of multiple publications on the same topic, only the most recent or most comprehensive review was considered. RESULTS: A large number of reviews were identified, but only 16 publications were systematic reviews. Of these, three systematic reviews of lithium and suicide rates and one of lithium and self harm confined only to RCTs were identified. Despite some methodological concerns and heterogeneity in terms of participants, diagnoses, comparators, durations, and phase of illness, the evidence to date is overwhelmingly in favour of lithium as an antisuicidal agent, even balanced against any potential disadvantages of its use in regular clinical practice. CONCLUSIONS: The anti-suicidal effects of lithium have been consistently reported over the past 40 years. The most robust evidence comes from RCTs, but these results are also discussed in the context of the difficulties in conducting high quality studies in this area, and the supporting evidence that observational and non-randomized studies can also provide. Given this evidence, however, the use of lithium is still underrepresented in clinical practice and should be incorporated more assertively into current guidelines. PMID- 28895270 TI - Does a "whiff" of mania in a major depressive episode shift treatment from a classical antidepressant to an atypical/second-generation antipsychotic? PMID- 28895271 TI - Multi-model comparison highlights consistency in predicted effect of warming on a semi-arid shrub. AB - A number of modeling approaches have been developed to predict the impacts of climate change on species distributions, performance, and abundance. The stronger the agreement from models that represent different processes and are based on distinct and independent sources of information, the greater the confidence we can have in their predictions. Evaluating the level of confidence is particularly important when predictions are used to guide conservation or restoration decisions. We used a multi-model approach to predict climate change impacts on big sagebrush (Artemisia tridentata), the dominant plant species on roughly 43 million hectares in the western United States and a key resource for many endemic wildlife species. To evaluate the climate sensitivity of A. tridentata, we developed four predictive models, two based on empirically derived spatial and temporal relationships, and two that applied mechanistic approaches to simulate sagebrush recruitment and growth. This approach enabled us to produce an aggregate index of climate change vulnerability and uncertainty based on the level of agreement between models. Despite large differences in model structure, predictions of sagebrush response to climate change were largely consistent. Performance, as measured by change in cover, growth, or recruitment, was predicted to decrease at the warmest sites, but increase throughout the cooler portions of sagebrush's range. A sensitivity analysis indicated that sagebrush performance responds more strongly to changes in temperature than precipitation. Most of the uncertainty in model predictions reflected variation among the ecological models, raising questions about the reliability of forecasts based on a single modeling approach. Our results highlight the value of a multi-model approach in forecasting climate change impacts and uncertainties and should help land managers to maximize the value of conservation investments. PMID- 28895272 TI - Stretchable Electronic Sensors of Nanocomposite Network Films for Ultrasensitive Chemical Vapor Sensing. AB - A stretchable, transparent, and body-attachable chemical sensor is assembled from the stretchable nanocomposite network film for ultrasensitive chemical vapor sensing. The stretchable nanocomposite network film is fabricated by in situ preparation of polyaniline/MoS2 (PANI/MoS2 ) nanocomposite in MoS2 suspension and simultaneously nanocomposite deposition onto prestrain elastomeric polydimethylsiloxane substrate. The assembled stretchable electronic sensor demonstrates ultrasensitive sensing performance as low as 50 ppb, robust sensing stability, and reliable stretchability for high-performance chemical vapor sensing. The ultrasensitive sensing performance of the stretchable electronic sensors could be ascribed to the synergistic sensing advantages of MoS2 and PANI, higher specific surface area, the reliable sensing channels of interconnected network, and the effectively exposed sensing materials. It is expected to hold great promise for assembling various flexible stretchable chemical vapor sensors with ultrasensitive sensing performance, superior sensing stability, reliable stretchability, and robust portability to be potentially integrated into wearable electronics for real-time monitoring of environment safety and human healthcare. PMID- 28895273 TI - Protecting and Leaving Functions of Trimethylsilyl Groups in Trimethylsilylated Silicates for the Synthesis of Alkoxysiloxane Oligomers. AB - The concept of protecting groups and leaving groups in organic synthesis was applied to the synthesis of siloxane-based molecules. Alkoxy-functionalized siloxane oligomers composed of SiO4 , RSiO3 , or R2 SiO2 units were chosen as targets (R: functional groups, such as Me and Ph). Herein we describe a novel synthesis of alkoxysiloxane oligomers based on the substitution reaction of trimethylsilyl (TMS) groups with alkoxysilyl groups. Oligosiloxanes possessing TMS groups were reacted with alkoxychlorosilane in the presence of BiCl3 as a catalyst. TMS groups were substituted with alkoxysilyl groups, leading to the synthesis of alkoxysiloxane oligomers. Siloxane oligomers composed of RSiO3 and R2 SiO2 units were synthesized more efficiently than those composed of SiO4 units, suggesting that the steric hindrance around the TMS groups of the oligosiloxanes makes a difference in the degree of substitution. This reaction uses TMS groups as both protecting and leaving groups for SiOH/SiO- groups. PMID- 28895274 TI - Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force. AB - OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies. PMID- 28895275 TI - Incidence and outcome of infective endocarditis following percutaneous versus surgical pulmonary valve replacement. AB - OBJECTIVES: To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR). BACKGROUND: Although TPVR is thought to be associated with a higher risk of IE than SPVR, there is paucity of data to support this. METHODS: Patients who underwent TPVR or SPVR at UCLA between October 2010 and September 2016 were included and retrospectively analyzed. RESULTS: Three hundred forty-two patients underwent PVR at UCLA including 134 SPVR and 208 TPVR. Patients undergoing TPVR were more likely to have had a history of endocarditis than those undergoing SPVR (5.3% vs. 0.7%, P = 0.03) and a right ventricle to pulmonary artery (RV to PA) conduit (37% vs. 17%, P = 0.0001). Two SPVR and seven TPVR patients developed IE with a 4-year freedom from endocarditis of 94.0% in the SPVR versus 84% in the TPVR group (P = 0.13). In patients who underwent TPVR and developed endocarditis, the mean gradient across the RVOT prior to intervention was higher (28.1 +/- 4.5 vs. 17.4 +/- 0.6 mmHg, P = 0.02) and were more likely to have a conduit (71% vs. 36%, P = 0.049). CONCLUSIONS: In this study, patients undergoing TPVR were not at a higher risk of IE than patients undergoing SPVR. TPVR patients were more likely to have had a prior history of IE and RV-PA conduit. The patients at highest risk were those with stenotic RV to PA conduits who were treated with TPVR. PMID- 28895276 TI - Osteoporotic fractures may impair life as much as the complications of diabetes. AB - RATIONALE, AIMS, AND OBJECTIVES: To compare the effect of osteoporotic fractures and complications of diabetes mellitus on quality of life (QoL). METHOD: A cross sectional study was performed in 840 patients with osteoporosis and in 943 patients with diabetes in Hungary to estimate the effect of osteoporotic fractures and microvascular and macrovascular complications of diabetes on QoL using the EQ-5D questionnaire. Ordinary least-squares regression was performed for the analysis to control for age and gender. RESULTS: The effects of certain of osteoporotic fractures and diabetes complications were similar in size measured by the EQ-5D. Patients with hip fractures and compressions of the vertebrae suffered more than 0.2 drop in their QoL, which is comparable in size to the most severe complications of diabetes, such as vision loss and amputations. CONCLUSIONS: The use of mortality and premature mortality as the traditional measures of disease burden in public health policy making means that diseases which strongly affect QoL but less survival might not get the necessary priority. This is especially the case in low-income and middle-income countries where studies on QoL are scarce. Our comparative analysis, which showed that osteoporotic fractures reduce QoL as much as major complications of diabetes, highlights the need for comprehensive disease burden assessment, including losses in functionality and QoL, to support decision making. PMID- 28895277 TI - Evaluation of a fever-management algorithm in a pediatric cancer center in a low resource setting. AB - BACKGROUND: In low- and middle-income countries (LMICs), inconsistent or delayed management of fever contributes to poor outcomes among pediatric patients with cancer. We hypothesized that standardizing practice with a clinical algorithm adapted to local resources would improve outcomes. Therefore, we developed a resource-specific algorithm for fever management in Davao City, Philippines. The primary objective of this study was to evaluate adherence to the algorithm. PROCEDURE: This was a prospective cohort study of algorithm adherence to assess the types of deviation, reasons for deviation, and pathogens isolated. All pediatric oncology patients who were admitted with fever (defined as an axillary temperature >37.7 degrees C on one occasion or >=37.4 degrees C on two occasions 1 hr apart) or who developed fever within 48 hr of admission were included. Univariate and multiple linear regression analyses were used to determine the relation between clinical predictors and length of hospitalization. RESULTS: During the study, 93 patients had 141 qualifying febrile episodes. Even though the algorithm was designed locally, deviations occurred in 70 (50%) of 141 febrile episodes on day 0, reflecting implementation barriers at the patient, provider, and institutional levels. There were 259 deviations during the first 7 days of admission in 92 (65%) of 141 patient episodes. Failure to identify high risk patients, missed antimicrobial doses, and pathogen isolation were associated with prolonged hospitalization. CONCLUSIONS: Monitoring algorithm adherence helps in assessing the quality of pediatric oncology care in LMICs and identifying opportunities for improvement. Measures that decrease high-frequency/high-impact algorithm deviations may shorten hospitalizations and improve healthcare use in LMICs. PMID- 28895279 TI - Posttransplantation relapse of pediatric chronic myelomonocytic leukemia cured using donor lymphocyte infusion. PMID- 28895278 TI - Contrast enhancement for portal images by combination of subtraction and reprojection processes for Compton scattering. AB - For patient setup of the IGRT technique, various imaging systems are currently available. MV portal imaging is performed in identical geometry with the treatment beam so that the portal image provides accurate geometric information. However, MV imaging suffers from poor image contrast due to larger Compton scatter photons. In this work, an original image processing algorithm is proposed to improve and enhance the image contrast without increasing the imaging dose. Scatter estimation was performed in detail by MC simulation based on patient CT data. In the image processing, scatter photons were eliminated and then they were reprojected as primary photons on the assumption that Compton interaction did not take place. To improve the processing efficiency, the dose spread function within the EPID was investigated and implemented on the developed code. Portal images with and without the proposed image processing were evaluated by the image contrast profile. By the subtraction process, the image contrast was improved but the EPID signal was weakened because 15.2% of the signal was eliminated due to the contribution of scatter photons. Hence, these scatter photons were reprojected in the reprojection process. As a result, the tumor, bronchi, mediastinal space and ribs were observed more clearly than in the original image. It was clarified that image processing with the dose spread functions provides stronger contrast enhancement while maintaining a sufficient signal-to-noise ratio. This work shows the feasibility of improving and enhancing the contrast of portal images. PMID- 28895280 TI - Addition of oral iron to plasma transfusion in human congenital hypotransferrinemia: A 10-year observational follow-up with the effects on hematological parameters and growth. AB - Congenital hypotransferrinemia (OMIM 209300) is an extremely rare disorder of inherited iron metabolism. Since its description in 1961, only 16 cases have been reported. The defective gene and molecular defect causing this disorder and clinicolaboratory findings seen in the homozygous and heterozygous states have been documented in both humans and mice. However, due to the lack of follow-up studies of the described cases, the long-term prognosis remains unknown. We present a 10-year observational follow-up of a patient previously diagnosed on a molecular basis who was treated with a unique therapy of plasma transfusion fortified with oral iron, with satisfactory clinicolaboratory responses. PMID- 28895281 TI - Encapsulated Vanadium-Based Hybrids in Amorphous N-Doped Carbon Matrix as Anode Materials for Lithium-Ion Batteries. AB - Recently, researchers have made significant advancement in employing transition metal compound hybrids as anode material for lithium-ion batteries and developing simple preparation of these hybrids. To this end, this study reports a facile and scalable method for fabricating a vanadium oxide-nitride composite encapsulated in amorphous carbon matrix by simply mixing ammonium metavanadate and melamine as anode materials for lithium-ion batteries. By tuning the annealing temperature of the mixture, different hybrids of vanadium oxide-nitride compounds are synthesized. The electrode material prepared at 700 degrees C, i.e., VM-700, exhibits excellent cyclic stability retaining 92% of its reversible capacity after 200 cycles at a current density of 0.5 A g-1 and attractive rate performance (220 mAh g-1 ) under the current density of up to 2 A g-1 . The outstanding electrochemical properties can be attributed to the synergistic effect from heterojunction form by the vanadium compound hybrids, the improved ability of the excellent conductive carbon for electron transfer, and restraining the expansion and aggregation of vanadium oxide-nitride in cycling. These interesting findings will provide a reference for the preparation of transition metal oxide and nitride composites as well. PMID- 28895283 TI - Right ventricle outflow tract prestenting: In vitro testing of rigidity and corrosion properties. AB - BACKGROUND: The aim of this study was to assess the resistance to compression (stiffness) of frequently used stents for right ventricular outflow tract prestenting. In addition, to assess the corrosion potential when different types of stent alloys come into contact with each other. METHOD: Different stents were tested in vitro in various combinations at specialized metallurgic laboratories. A bench compression test was used to assess resistance to compression of singular and joined combinations of stents. Corrosion was evaluated by standardized electrochemical galvanic tests in physiological solutions at 37 degrees C. Single stents and combinations of stents were evaluated over a period of 4-12 weeks. RESULTS: Relative stiffness of the stents Optimus/Andrastent XXL/Intrastent LD Max/8zig Cheatham-Platinum, expressed as load per length to deform the stent for 1 mm at 22 mm was 100/104/161/190. Adding additional stents to a single stent significantly strengthened the joined couples (P < 0.001). The lowest galvanic corrosion rates (about 0.000001 mm/year) were observed for the joined CP Andrastent, Andra-Sapien, and Andra-SapienXT. The corrosion rate for coupled CP Sapien and CP-SapienXT was somewhat higher (about 0.000003 mm/year). The materials with the highest corrosion rates resulted in material losses of, respectively, 17 and 24 ug/year, which is negligible over a lifetime. CONCLUSION: Adding stents to a single stent significantly increases stiffness which will reduce the risk of metal fatigue failure. Corrosion of individual stents or stent combinations occurs, but is negligible over a human lifetime with low risk of biological effects. No mechanical integrity problems are thus expected as there is only 0.3% of the initial diameter of the struts of a stent that will be lost as a consequence of corrosion after 100 years. PMID- 28895282 TI - A patient safety education program in a medical physics residency. AB - Education in patient safety and quality of care is a requirement for radiation oncology residency programs according to accrediting agencies. However, recent surveys indicate that most programs lack a formal program to support this learning. The aim of this report was to address this gap and share experiences with a structured educational program on quality and safety designed specifically for medical physics therapy residencies. Five key topic areas were identified, drawn from published recommendations on safety and quality. A didactic component was developed, which includes an extensive reading list supported by a series of lectures. This was coupled with practice-based learning which includes one project, for example, failure modes and effect analysis exercise, and also continued participation in the departmental incident learning system including a root-cause analysis exercise. Performance was evaluated through quizzes, presentations, and reports. Over the period of 2014-2016, five medical physics residents successfully completed the program. Evaluations indicated that the residents had a positive experience. In addition to educating physics residents this program may be adapted for medical physics graduate programs or certificate programs, radiation oncology residencies, or as a self-directed educational project for practicing physicists. Future directions might include a system that coordinates between medical training centers such as a resident exchange program. PMID- 28895284 TI - Usefulness of the SYNTAX score II to validate 2-year outcomes in patients with complex coronary artery disease undergoing percutaneous coronary intervention: A large single-center study. AB - OBJECTIVE: This study aimed to assess the prognostic ability of synergy between percutaneous coronary intervention with Taxus and cardiac surgery score II (SS II) in a large cohort of patients with complex coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) in clinical practice. BACKGROUND: Few studies have explored the usefulness of SS-II in nonrandomized clinical patients with complex CAD undergoing temporary PCI. METHODS: We prospectively enrolled 4398 consecutive patients undergoing three-vessel and/or unprotected left main PCI in a single center from January 2013 to December 2013. Patients were stratified according to SS-II for PCI tertiles as follows: SS-II <= 20 (n = 1474); SS-II 20-26 (n = 1462); and SS-II > 26 (n = 1462). The predictive ability for 2-year mortality was compared between angiographic scores and scores combining both angiographic and clinical variables. RESULTS: Mortality was significantly higher in the upper tertile than in the intermediate or lower tertiles during the 2-year follow-up (2.7% vs 1.7% vs 0.5%, respectively; P < 0.001). Multivariate analysis showed that SS-II was an independent predictor of 2 year mortality (hazard ratio: 1.66, 95% confidence interval: 1.03-2.68; P = 0.04). After adjusting for multivariable factors, SS-II had better prediction of 2-year mortality than baseline SS (C-index: SS-II = 0.740 vs baseline SS = 0.620; P < 0.001). CONCLUSIONS: As a risk score combining both anatomical and clinical variables, SS-II demonstrated superiority compared with the purely angiographic SS to predict 2-year mortality in a clinical population of patients with severe CAD undergoing temporary PCI. PMID- 28895285 TI - Complete filter-based cerebral embolic protection with transcatheter aortic valve replacement. AB - OBJECTIVES: To evaluate the value of left vertebral artery filter protection in addition to the current filter-based embolic protection technology to achieve complete cerebral protection during TAVR. BACKGROUND: The occurrence of cerebrovascular events after transcatheter aortic valve replacement (TAVR) has fueled concern for its potential application in younger patients with longer life expectancy. Transcatheter cerebral embolic protection (TCEP) devices may limit periprocedural cerebrovascular events by preventing macro and micro-embolization to the brain. Conventional filter-based TCEP devices cover three extracranial contributories to the brain, yet leave the left vertebral artery unprotected. METHODS: Patients underwent TAVR with complete TCEP. A dual-filter system was deployed in the brachiocephalic trunk and left common carotid artery with an additional single filter in the left vertebral artery. After TAVR all filters were retrieved and sent for histopathological evaluation by an experienced pathologist. RESULTS: Eleven patients received a dual-filter system and nine of them received an additional left vertebral filter. In the remaining two patients, the left vertebral filter could not be deployed. No periprocedural strokes occurred. We found debris in all filters, consisting of thrombus, tissue derived debris, and foreign body material. The left vertebral filter contained debris in an equal amount of patients as the Sentinel filters. The size of the captured particles was similar between all filters. CONCLUSIONS: The left vertebral artery is an important entry route for embolic material to the brain during TAVR. Selective filter protection of the left vertebral artery revealed embolic debris in all patients. The clinical value of complete filter-based TCEP during TAVR warrants further research. PMID- 28895286 TI - Authors' reply re: Comparison of management regimens following ultrasound diagnosis of non-tubal ectopic pregnancies: a retrospective cohort study. PMID- 28895287 TI - When simulation becomes too real. PMID- 28895289 TI - Comment on: Insurance coverage decisions for pediatric proton therapy. PMID- 28895288 TI - Association between HIV and blood pressure in adults and role of body weight as a mediator: Cross-sectional study in Uganda. AB - The authors sought to describe the association between human immunodeficiency virus (HIV) and blood pressure (BP) levels, and determined the extent to which this relationship is mediated by body weight in a cross-sectional study of HIV infected and HIV-uninfected controls matched by age, sex, and neighborhood. Mixed effects models were fit to determine the association between HIV and BP and amount of effect of HIV on BP mediated through body mass index. Data were analyzed from 577 HIV-infected and 538 matched HIV-uninfected participants. HIV infection was associated with 3.3 mm Hg lower systolic BP (1.2-5.3 mm Hg), 1.5 mm Hg lower diastolic BP (0.2-2.9 mm Hg), 0.3 m/s lower pulse wave velocity (0.1-0.4 mm Hg), and 30% lower odds of hypertension (10%-50%). Body mass index mediated 25% of the association between HIV and systolic BP. HIV infection was inversely associated with systolic BP, diastolic BP, and pulse wave velocity. Comprehensive community-based programs to routinely screen for cardiovascular risk factors irrespective of HIV status should be operationalized in HIV-endemic countries. PMID- 28895290 TI - Design of a Novel Two-Component Hybrid Dermal Scaffold for the Treatment of Pressure Sores. AB - The aim of this study is to design a novel two-component hybrid scaffold using the fibrin/alginate porous hydrogel Smart Matrix combined to a backing layer of plasma polymerized polydimethylsiloxane (Sil) membrane to make the fibrin-based dermal scaffold more robust for the treatment of the clinically challenging pressure sores. A design criteria are established, according to which the Sil membranes are punched to avoid collection of fluid underneath. Manual peel test shows that native silicone does not attach to the fibrin/alginate component while the plasma polymerized silicone membranes are firmly bound to fibrin/alginate. Structural characterization shows that the fibrin/alginate matrix is intact after the addition of the Sil membrane. By adding a Sil membrane to the original fibrin/alginate scaffold, the resulting two-component scaffolds have a significantly higher shear or storage modulus G'. In vitro cell studies show that dermal fibroblasts remain viable, proliferate, and infiltrate the two-component hybrid scaffolds during the culture period. These results show that the design of a novel two-component hybrid dermal scaffold is successful according to the proposed design criteria. To the best of the authors' knowledge, this is the first study that reports the combination of a fibrin-based scaffold with a plasma polymerized silicone membrane. PMID- 28895291 TI - Revolving Vernier Mechanism Controls Size of Linear Homomultimer. AB - A new kind of the Vernier mechanism that is able to control the size of linear assembly of DNA origami nanostructures is proposed. The mechanism is realized by mechanical design of DNA origami, which consists of a hollow cylinder and a rotatable shaft in it connected through the same scaffold. This nanostructure stacks with each other by the shape complementarity at its top and bottom surfaces of the cylinder, while the number of stacking is limited by twisting angle of the shaft. Experiments have shown that the size distribution of multimeric assembly of the origami depends on the twisting angle of the shaft; the average lengths of the multimer are decamer, hexamer, and tetramer for 0 degrees , 10 degrees , and 20 degrees twist, respectively. In summary, it is possible to affect the number of polymerization by adjusting the precise shape and movability of a molecular structure. PMID- 28895292 TI - Pathology and genomics of pediatric melanoma: A critical reexamination and new insights. AB - The clinicopathologic features of pediatric melanoma are distinct from those of the adult counterpart. For example, most childhood melanomas exhibit a uniquely favorable biologic behavior, save for those arising in large/giant congenital nevi. Recent studies suggest that the characteristically favorable biologic behavior of childhood melanoma may be related to extreme telomere shortening and dysfunction in the cancer cells. Herein, we review the genomic profiles that have been defined for the different subtypes of pediatric melanoma and particularly emphasize the potential prognostic value of telomerase reverse transcriptase alterations for these tumors. PMID- 28895293 TI - Photoactuation Healing of alpha-FeOOH@g-C3 N4 Catalyst for Efficient and Stable Activation of Persulfate. AB - Inspired by living systems, the construction of smart devices that can self-heal in response to structural damage is a promising technology for maintaining the high activity and stability of catalysts during heterocatalytic reactions. Here this study demonstrates an ingenious platform that enabled efficient persulfate (PS) activation for contaminant degradation via integrating a catalyst with photoactuation regeneration. Under irradiation, it is unambiguously confirmed that the collective properties of a tailored FeOOH@C3 N4 catalyst permit interfacial photoexcited electron transport from the photocatalyst substrate to needle-shaped FeOOH. This results in the simultaneous recovery of Fe(III) and optimization of the Fe(II)/Fe(III) ratio on FeOOH surface during PS activation process, so that the healed chemical structure ensures that subsequent PS activation remains unimpaired. Aqueous organic contaminant (bisphenol A) oxidation efficacy in this system is almost 20 times higher than for photo- or Fenton-oxidation alone. This work highlights the concept of catalyst regeneration for stable reactive species generation in solution, which represents alternative application of photocatalysis for practical environmental remediation. Further, the photoactuation healing approach can be expanded into various domains, such as material fabrication or chemical synthesis. PMID- 28895294 TI - Pathology of self-expanding transcatheter aortic valves: Findings from the CoreValve US pivotal trials. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has recently become an alternative to surgical aortic valve replacement for patients with severe aortic stenosis. However, paravalvular leaks, possible leaflet thrombosis, and device durability following TAVR remain unresolved issues. METHODS AND RESULTS: We conducted the first systematic microscopic and macroscopic pathologic analysis of self-expanding CoreValve transcatheter aortic valves removed at autopsy or surgically from the U.S. pivotal trial of extreme- and high-risk patients. Implants were evaluated for histopathologic changes in the valve frame and leaflets. Thrombus/neointima on the leaflets was graded depending on the leaflet thickness and the extent of leaflet involvement. Inflammation, calcification, and structural integrity were also assessed. A total of 21 cases (median age 86.0 years [IQR, 79.0-91.0]), with median duration of implant duration of 17.0 days ranged from 0 to 503 days were evaluated. No valve frame fracture was observed and severe paravalvular gaps were uncommon. Inflammation and thrombus in the valve frame was minimal, but neointimal growth increased overtime. Symptomatic valve thrombosis was observed in one case (5%) and subclinical moderate leaflet thrombus was observed in four additional cases (19%). Inflammation of the leaflets was mild, while structural changes were minimal, and one case had infective endocarditis. Pannus or leaflet calcification were not observed. CONCLUSIONS: This first systematic macroscopic and microscopic pathologic analysis of self-expanding transcatheter aortic valves demonstrates favorable short-term pathologic findings. However, our finding of subclinical leaflet thrombus formation confirms prior observations and warrants further investigation. PMID- 28895295 TI - Medical curricular reform in Iraq. PMID- 28895296 TI - Decongestion Versus Cytokine Clearance in Acute Heart Failure: Not All that Glitters is Gold. PMID- 28895297 TI - Changing Trends in Therapeutic Plasmapheresis: An Indian Perspective. AB - Indications for therapeutic apheresis (TA) are dynamic; they keep changing and expanding because of introduction of newer treatment modalities and accumulating evidence in the form of case-reports, case-series and original articles. We evaluated our therapeutic plasmapheresis (TP) data and compared this data with an earlier published Indian report for indications, frequency, response rate and adverse reactions. We conducted a retrospective analysis of all TP procedures performed from January 2014 to June 2016 in department of Transfusion Medicine at a tertiary care hospital. All TP procedures performed for various clinical disorders including neurological, hematological, renal, hepatic and rheumatologic indications were included in the study. Analysis was performed with respect to demography, procedure details and response. 187 patients (118 Males and 69 females) underwent 683 TP procedures during study period. According to 2013 ASFA guidelines, 99, 59 and 29 patients belonged to category I, II and III respectively. In comparison with the earlier report, the number of patients and procedures have increased, indications have changed, response rate is comparable, and the frequency of adverse reactions have decreased. In the last decade there has been increase in number and spectrum of indications for therapeutic apheresis and frequency of procedures. The response rate and safety of these procedures have also improved. PMID- 28895299 TI - Case of lipoatrophic diabetes induced by juvenile dermatomyositis. AB - Lipodystrophy is a rare condition that is often accompanied by one or more metabolic diseases. Here, we report a case of lipoatrophic diabetes induced by juvenile dermatomyositis. Although pioglitazone was not effective for lowering blood glucose levels, our observation suggested that it improved liver function slightly. The effectiveness of metreleptin for lowering blood glucose levels could not be determined, as we administered it in a short period. Liver biopsy showed burned-out non-alcoholic steatohepatitis. The present results show that the successful treatment of lipoatrophic diabetes induced by juvenile dermatomyositis requires an early diagnosis and therapeutic intervention. PMID- 28895298 TI - Two decades of dendrimers as versatile MRI agents: a tale with and without metals. AB - Dendrimers or dendritic polymers are a class of compounds with great potential for nanomedical use. Some of their properties, including their rigidity, low polydispersity and the ease with which their surfaces can be modified make them particularly well suited for use as MRI diagnostic or theranostic agents. For the past 20 years, researchers have recognized this potential and refined dendrimer formulations to optimize these nanocarriers for a host of MRI applications, including blood pool imaging agents, lymph node imaging agents, tumor-targeted theranostic agents and cell tracking agents. This review summarizes the various types of dendrimers according to the type of MR contrast they can provide. This includes the metallic T1 , T2 and paraCEST imaging agents, and the non-metallic diaCEST and fluorinated (19 F) heteronuclear imaging agents. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanomaterials and Implants. PMID- 28895301 TI - Early leaflet thrombosis complicating transcatheter implantation of a Sapien 3 valve in a native right ventricular outflow tract. AB - A 59-year-old female with Tetralogy of Fallot had a previous complete repair with RVOT patch enlargement. She developed subsequent severe symptomatic (NYHA III) pulmonary regurgitation with severe RV dilatation. She had a concomitant interstitial lung disease secondary to hypersensitivity pneumonitis that precluded her from cardiac surgery. After preprocedural assessment using computed tomography, echocardiography and invasive angiography we decided to implant a 29 mm Edwards Sapien 3 valve without pre-stenting. The Sapien 3 valve was implanted in a satisfactory position using rapid RV pacing. The valve appeared well expanded with good circularity on fluoroscopy. A transthoracic echocardiography on the following day showed no pulmonary regurgitation with a peak gradient of 14 mmHg across the prosthesis. At 4 weeks follow-up, the patient felt a marked improvement (NYHA II) but a CT scan showed bileaflet valve thickening with preserved stent expansion. A concomitant echo-doppler showed a significant increase of peak pulmonary gradient to 26 mmHg. After a six weeks course of warfarin therapy, the transpulmonary valve peak gradient came down to 16 mmHg and leaflet thickening resolved on CT. The Sapien 3 system helped achieve a successful transfemoral percutaneous pulmonary valve implantation in a challenging native RVOT anatomy. This case was complicated by early valve thrombosis as documented by CT and was successfully treated with oral anticoagulation. PMID- 28895300 TI - ExSTA: External Standard Addition Method for Accurate High-Throughput Quantitation in Targeted Proteomics Experiments. AB - PURPOSE: Targeted proteomics using MRM with stable-isotope-labeled internal standard (SIS) peptides is the current method of choice for protein quantitation in complex biological matrices. Better quantitation can be achieved with the internal standard-addition method, where successive increments of synthesized natural form (NAT) of the endogenous analyte are added to each sample, a response curve is generated, and the endogenous concentration is determined at the x intercept. Internal NAT-addition, however, requires multiple analyses of each sample, resulting in increased sample consumption and analysis time. EXPERIMENTAL DESIGN: To compare the following three methods, an MRM assay for 34 high-to moderate abundance human plasma proteins is used: classical internal SIS addition, internal NAT-addition, and external NAT-addition-generated in buffer using NAT and SIS peptides. Using endogenous-free chicken plasma, the accuracy is also evaluated. RESULTS: The internal NAT-addition outperforms the other two in precision and accuracy. However, the curves derived by internal vs. external NAT addition differ by only ~3.8% in slope, providing comparable accuracies and precision with good CV values. CONCLUSIONS AND CLINICAL RELEVANCE: While the internal NAT-addition method may be "ideal", this new external NAT-addition can be used to determine the concentration of high-to-moderate abundance endogenous plasma proteins, providing a robust and cost-effective alternative for clinical analyses or other high-throughput applications. PMID- 28895303 TI - Coronary angiography with or without percutaneous coronary intervention in patients with hemophilia-Systematic review. AB - OBJECTIVES: We aimed to summarize the evidence for periprocedural and long-term strategies to both minimize the bleeding risk and ensure sufficient anticoagulation and antiaggregation in hemophilia patients undergoing coronary angiography with or without percutaneous coronary interventions (PCI). BACKGROUND: Hemophilia patients undergoing coronary angiography and PCI are at risk of bleeding due to deficiency of the essential clotting factors VIII or IX combined with the need of peri-interventional anticoagulation and antiaggregation and dual antiplatelet therapy (DAPT) after PCI. METHODS: We report on a patient with moderate hemophilia B undergoing single-vessel PCI with administration of factor IX concentrate during the procedure and during the 1-month DAPT period. In addition, a systematic review of patients (n = 54, mean age 58 +/- 10 years) with hemophilia A (n = 45, 83%) or B (n = 9, 17%) undergoing coronary angiography with or without PCI is presented. RESULTS: Peri-interventional factor substitution was performed in the majority (42 of 54, 78%) but not all patients. In 38 of 54 (70%) patients undergoing coronary angiography, PCI with balloon dilation (n = 5), bare metal (n = 31), or drug-eluting stents (n = 2) was performed. For PCI unfractioned heparin (n = 24), low molecular weight heparin (n = 2), bivalirudin (n = 4), or no periprocedural anticoagulation at all (n = 8) were used. PCI was successful in all cases. After stenting, the majority (28 of 33; 85%) was treated with DAPT (median duration 1 month). Major periprocedural bleeding episodes occurred in 3 of 54 (6%) patients. Bleeding during follow-up occurred in 11 of 54 (20%) patients. CONCLUSIONS: Coronary angiography and PCI in patients with hemophilia are effective and safe when applying individualized measures to prevent bleeding. PMID- 28895302 TI - Catalytic Upgrading of Ethanol to n-Butanol: Progress in Catalyst Development. AB - Because n-butanol as a fuel additive has more advantageous physicochemical properties than those of ethanol, ethanol valorization to n-butanol through homo- or heterogeneous catalysis has received much attention in recent decades in both scientific and industrial fields. Recent progress in catalyst development for upgrading ethanol to n-butanol, which involves homogeneous catalysts, such as iridium and ruthenium complexes, and heterogeneous catalysts, including metal oxides, hydroxyapatite (HAP), and, in particular, supported metal catalysts, is reviewed herein. The structure-activity relationships of catalysts and underlying reaction mechanisms are critically examined, and future research directions on the design and improvement of catalysts are also proposed. PMID- 28895304 TI - A hindsight reflection on the clinical studies of poly(l-glutamic acid) paclitaxel. AB - Chemotherapy for cancer treatment is limited by the excessive toxicity to normal tissues. The design of chemodrug-loaded nanoformulations provides a unique approach to improve the treatment efficacy while minimizing toxicity. Despite the numerous publications of nanomedicine for the last several decades, however, only a small fraction of the developed nanoformulations have entered clinical trials, with even fewer being approved for clinical application. Poly(l-glutamic acid) paclitaxel (PG-TXL) belongs to the few formulations that reached phase III clinical trials. Unfortunately, the development of PG-TXL stopped in 2016 due to the inability to show significant improvement over current standard care. This review will provide an overview of the preclinical and clinical evaluations of PG TXL, and discuss lessons to be learned from this ordeal. The precise identification of suitable patients for clinical trial studies, deep understanding of the mechanisms of action, and an effective academic-industry partnership throughout all phases of drug development are important for the successful bench-to-bedside translation of new nanoformulations. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Peptide-Based Structures. PMID- 28895305 TI - Reflections from wound workshops. PMID- 28895306 TI - Hybrid Organic-Inorganic Perovskite Photodetectors. AB - Hybrid organic-inorganic perovskite materials garner enormous attention for a wide range of optoelectronic devices. Due to their attractive optical and electrical properties including high optical absorption coefficient, high carrier mobility, and long carrier diffusion length, perovskites have opened up a great opportunity for high performance photodetectors. This review aims to give a comprehensive summary of the significant results on perovskite-based photodetectors, focusing on the relationship among the perovskite structures, device configurations, and photodetecting performances. An introduction of recent progress in various perovskite structure-based photodetectors is provided. The emphasis is placed on the correlation between the perovskite structure and the device performance. Next, recent developments of bandgap-tunable perovskite and hybrid photodetectors built from perovskite heterostructures are highlighted. Then, effective approaches to enhance the stability of perovskite photodetector are presented, followed by the introduction of flexible and self-powered perovskite photodetectors. Finally, a summary of the previous results is given, and the major challenges that need to be addressed in the future are outlined. A comprehensive summary of the research status on perovskite photodetectors is hoped to push forward the development of this field. PMID- 28895307 TI - Cadmium Chalcogenide Nano-Heteroplatelets: Creating Advanced Nanostructured Materials by Shell Growth, Substitution, and Attachment. AB - The current direction in the evolution of 2D semiconductor nanocrystals involves the combination of metal and semiconductor components to form new nanoengineered materials called nano-heteroplatelets. This Review covers different heterostructure architectures that can be applied to cadmium chalcogenide nanoplatelets, including variously shaped shell, metal nanoparticle decoration, and doped and alloy systems. Here, for the first time a complete classification of nano-heteroplatelet types is provided with recommended notations and a systematization of the existing knowledge and experience concerning heterostructure formation techniques, addressing the morphology, optoelectronic and magnetic properties, and novel features of different heterostructures. This Review is also devoted to possible applications of these heterostructures and of one-component nanoplatelets in multiple fields, including light-emitting devices and biological imaging. PMID- 28895308 TI - Abnormal findings in peers during skills learning. PMID- 28895309 TI - Impact of medical school surgical conferences. PMID- 28895311 TI - Response: the use of mobile technology in feedback. PMID- 28895313 TI - 'Dear editors': the art of letter writing. PMID- 28895312 TI - The impact of surgical conferences: a response. PMID- 28895314 TI - Implementing collaborative and peer-assisted learning (CPAL). PMID- 28895315 TI - Single-Atom Catalysts of Precious Metals for Electrochemical Reactions. AB - Single-atom catalysts (SACs), in which metal atoms are dispersed on the support without forming nanoparticles, have been used for various heterogeneous reactions and most recently for electrochemical reactions. In this Minireview, recent examples of single-atom electrocatalysts used for the oxygen reduction reaction (ORR), hydrogen oxidation reaction (HOR), hydrogen evolution reaction (HER), formic acid oxidation reaction (FAOR), and methanol oxidation reaction (MOR) are introduced. Many density functional theory (DFT) simulations have predicted that SACs may be effective for CO2 reduction to methane or methanol production while suppressing H2 evolution, and those cases are introduced here as well. Single atoms, mainly Pt single atoms, have been deposited on TiN or TiC nanoparticles, defective graphene nanosheets, N-doped covalent triazine frameworks, graphitic carbon nitride, S-doped zeolite-templated carbon, and Sb-doped SnO2 surfaces. Scanning transmission electron microscopy, extended X-ray absorption fine structure measurement, and in situ infrared spectroscopy have been used to detect the single-atom structure and confirm the absence of nanoparticles. SACs have shown high mass activity, minimizing the use of precious metal, and unique selectivity distinct from nanoparticle catalysts owing to the absence of ensemble sites. Additional features that SACs should possess for effective electrochemical applications were also suggested. PMID- 28895316 TI - Action observation produces motor resonance in Parkinson's disease. AB - Observation of movement activates the observer's own motor system, influencing the performance of actions and facilitating social interaction. This motor resonance is demonstrated behaviourally through visuomotor priming, whereby response latencies are influenced by the compatibility between an intended action and an observed (task-irrelevant) action. The impact of movement disorders such as Parkinson's disease (PD) on motor resonance is unclear, as previous studies of visuomotor priming have not separated imitative compatibility (specific to human movement) from general stimulus-response compatibility effects. We examined visuomotor priming in 23 participants with mild-to-moderate PD and 24 healthy older adults, using a task that pitted imitative compatibility against general stimulus-response compatibility. Participants made a key press after observing a task-irrelevant moving human finger or rectangle that was either compatible or incompatible with their response. Imitative compatibility effects, rather than general stimulus-response compatibility effects, were found specifically for the human finger. Moreover, imitative compatibility effects did not differ between groups, indicating intact motor resonance in the PD group. These findings constitute the first unambiguous demonstration of imitative priming in both PD and healthy ageing, and have implications for therapeutic techniques to facilitate action, as well as the understanding of social cognition in PD. PMID- 28895317 TI - Assessment of a noninvasive optical photoplethysmography imaging device with dynamic tissue phantom models. AB - Noncontact photoplethysmography (PPG) has been studied as a method to provide low cost, noninvasive, two-dimensional blood oxygenation measurements and medical imaging for a variety of near-surface pathologies. To evaluate this technology in a laboratory setting, dynamic tissue phantoms were developed with tunable parameters that mimic physiologic properties of the skin, including blood vessel volume change, pulse wave frequency, and tissue scattering and absorption. Tissue phantoms were generated using an elastic tubing to represent a blood vessel where the luminal volume could be modulated with a pulsatile fluid flow. The blood was mimicked with a scattering and absorbing motility standard, and the tissue with a gelatin-lipid emulsion hydrogel. A noncontact PPG imaging system was then evaluated using the phantoms. Noncontact PPG imaging accurately identified pulse frequency, and PPG signals from these phantoms suggest that the phantoms can be used to evaluate noncontact PPG imaging systems. Such information may be valuable to the development of future PPG imaging systems. PMID- 28895318 TI - [Relationship between law on the protection of wildlife and animal-derived drugs]. AB - In most countries, the protection of wildlife resources is in a negative way, the state do not put emphasis on or even oppose artificial breeding, with the poor results. In our country, the state shall pursue a policy of strengthening the protection of wildlife resources, actively domesticating and breeding the species of wildlife, which has made great achievements. Traditional Chinese medicine(TCM) is one pillar of medical and health service in China, animal-derived drugs which are effective drugs for the treatment of certain critical cases have been used in clinic for 2 000 years. Prohibition or limited use of animal-derived drugs could affect the curative effect, hindering TCM from healthy development. The state shall encourage the protection and domestication, breeding of wildlife accords with our national conditions, which is not only beneficial to the protection of wildlife, but also favors the development of the cause of TCM. PMID- 28895319 TI - [Interaction of effective ingredients from traditional Chinese medicines with intestinal microbiota]. AB - A large number and wide varieties of microorganisms colonize in the human gastrointestinal tract. They construct an intestinal microecological system in the intestinal environment. The intestinal symbiotic flora regulates a series of life actions, including digestion and absorption of nutrient, immune response, biological antagonism, and is closely associated with the occurrence and development of many diseases. Therefore, it is greatly essential for the host's health status to maintain the equilibrium of intestinal microecological environment. After effective compositions of traditional Chinese medicines are metabolized or biotransformed by human intestinal bacteria, their metabolites can be absorbed more easily, and can even decrease or increase toxicity and then exhibit significant different biological effects. Meanwhile, traditional Chinese medicines can also regulate the composition of the intestinal flora and protect the function of intestinal mucosal barrier to restore the homeostasis of intestinal microecology. The relevant literatures in recent 15 years about the interactive relationship between traditional Chinese medicines and gut microbiota have been collected in this review, in order to study the classification of gut microflora, the relationship between intestinal dysbacteriosis and diseases, the important roles of gut microflora in intestinal bacterial metabolism in effective ingredients of traditional Chinese medicines and bioactivities, as well as the modulation effects of Chinese medicine on intestinal dysbacteriosis. In addition, it also makes a future prospect for the research strategies to study the mechanism of action of traditional Chinese medicines based on multi-omics techniques. PMID- 28895320 TI - [Research progress on chemical compounds and pharmacological effects of Caesalpinia]. AB - Consult literature, the chemical composition of the type of system Caesalpinia plants were summarized and discussed in detail its pharmacological effects. The genus contains major chemical components of high isoflavones, chalcones and diterpenoids, pharmacological effects inhibit melanin production, anti inflammatory, antioxidant, antibacterial, immune regulation, and further research in this genus offer reference. PMID- 28895321 TI - [Identification and prevention of root rot pathogen in model of ginseng cultivated in farmlands]. AB - Root rot is one of the major diseases of Panax ginseng cultivated in northeastern farmlands. This study aims to identify pathogens that causing ginseng root rot disease, verify inhibiting effects of perilla crude extracts on the pathogens and present the basis for control of ginseng root rot. The species of root rot pathogens was isolated using the tissue isolation. The morphological analysis showed that the strain contained two forms of conidia, one was sickle-shaped or columnar and the other was large oval. There were obvious separations in the conidia. Based on the molecular analysis, sequence of 18s rDNA from this strain showed 100% homology with that of Fusarium oxysporum JF807402.1 by Blast. The results confirmed that F. oxysporum was the pathogenic strain for root rot of ginseng cultivated in farmlands. Inhibiting effects of perilla crude extracts were evaluated by the method of Oxford cup. The results indicated that 0.50 g*L-1 of the perilla crude extract showed better sensitivity on the pathogenic strain, and its bacteriostatic diameters were 11.75 mm. The species of root rot pathogens of ginseng cultivated in farmlands was confirmed in this study. Our results presented materials for exploitation of botanical pesticide against root rot, and guaranteed the successful development of ginseng cultivated in farmland. PMID- 28895322 TI - [Hydrophidae identification through analysis on cytochrome c oxydase I(COI) and ribosome 16s rDNA gene barcode]. AB - Hydrophidae, one of the precious traditional Chinese medicines, is generally drily preserved to prevent corruption, but it is hard to identify the species of Hydrophidae through the appearance because of the change due to the drying process. The identification through analysis on gene barcode, a new technique in species identification, can avoid this problem. The gene barcodes of the 5 species of Hydrophidae, Lapemis hardwickii, Hydrophis fasciatus, Aipysurus eydouxii, Hydrophis belcher and Hydrophis lamberti, were acquired through DNA extraction and gene sequencing. These barcodes were then in sequence alignment and test the identification efficiency by BLAST. Our results showed that the 16S rDNA sequences identified Hydrophidae briefly and the COI sequenceshad obvious difference between intra-and inter-species, indicating that DNA bar-coding was an efficiency method of Hydrophidae identification. PMID- 28895323 TI - [Regional characteristic analysis of alkaloids and chlorogenic acid in wild Phellodendri Amurensis Cortex]. AB - In the present research, 674 wild medicinal material samples of Phellodendri amurensis Cortex were collected from 31 sampling sites in the whole distribution of its original plant Phellodendron amurense. The samples were collected under the premise that the stem diameter of sampling plant, sampling position and time were controlled. And the sampling sites were set at the interval of a latitude. The content of 6 kinds of active ingredients, palmatine chloride, berberine hydrochloride, phellodendrine chloride, jatrorrhizine hydrochloride, magnoflorine, chlorogenic acid, etc in the medicinal material samples were determined, and the results showed that the content of most active ingredients in the medicinal materials showed significant differences due to the difference of sampling sites. Among them, the medicinal materials from Liaoning region had the highest content of active ingredients, followed by Beijing and Jilin regions, and that from Heilongjiang region had the lowest content. The study has important directive significance to the exploration of environmental factors for the formation of active constituent and artificial planting regionalization of high quality Phellodendri amurensis Cortex. PMID- 28895324 TI - [Influence of continuous cropping on growth of Artemisia annua and bacterial communities in soil]. AB - In this study, several types of Artemisia annua in soil, including the soil which had not been planted, or planted for one year, or continuously planted for three or five years were collected, in order to study the influences of continuous cropping on the growth of A. annua, content of artemisinin, available nutrient of soil, and bacterial community structure through adopting routine analysis and Illumina MiSeq high-throughput sequencing. The results showed that continuous cropping inhibited significantly the growth of A. annua and reduced leaf biomass, content and yield of artemisinin, with the maximum decreasing amplitude of 30.20%, 7.70% and 35.58% respectively. The content of soil organic matter, available nitrogen, available phosphorus and 16S rRNA sequence number were increased to different extents after continuous cropping of A. annua. According to the results of high-throughput sequencing, 634-812 types of common bacteria belonged to 21 categories were planted in different soil of A. annua with different planting years, which represented that the distribution distance of the point of bacterial community with different years among coordinate system of principal component was relative distant, and community structure had significant changes (P<0.05). As the planting years increased, the abundance of Actinobacteria, Chloroflexi, Gemmatimonadetes decreased in contrast to Proteobacteria, Acidobacteria and Verrucomicrobia. In the top 20 types of predominant bacteria,Nitrospira japonica and Nitrospira disappeared, among which, only Gemmatimonadaceae, Micromonosporaceae, Nitrosomonadaceae, Xanthobacteraceae, and unculture bacterium JG30-KF-AS9 were similar, indicating that the planting and continuous cropping of A. annua selectively inhibited the growth and reproduction of soil bacteria, and influenced the supply and transform of soil nutrient, leading to a poor growth and resulting in reduction of artemisinin content and yield. Therefore, it is necessary to advocate crop rotation in the process of planting A. annua. PMID- 28895325 TI - [Effect of herb residue on growth and active ingredient content of licorice]. AB - Traditional Chinese medicine industry product a lot of herb residue. Herb residue was treated as household waste. This treatment leads to environmental pollution and resource waste. For this case, we study the effect of different herb residues on the growth and active ingredient content of Licorice by random control experiment. Our results showed that the effects of different herb residues were difference. Atractylodes macrocephala residue and Forsythia suspense residue had the stronger effect and the effect of A. macrocephala residue was inferior to the effect of F. suspense residue. A.macrocephala residue significantly improved the shoot biomass banch number, leaf number, root diameter and root biomass by 0.53 1.81 fold. A. macrocephala residue also increased the glycyrrhizic acid content of root by 1.54 fold. F. suspense residue significantly improved the shoot biomass,branch number, root diameter and root biomass by 0.43-1.13 fold. Four kind herb residues all improved the shoot biomass by 0.43-1.81fold. So, the authors recommand to considered that we can apply A. macrocephala residue and F. suspense residue in Licorice cultivation. PMID- 28895326 TI - [Residue degradation dynamics of spinetoram in wolfberry]. AB - The safety interval period and residue dynamics of two main components (XDE-175-J and XDE-175-L) of spinetoram in wolfberry were measured. Field experiment design and sampling method were carried out according to the "Guideline on pesticide residue trials". The wolfberry samples were extracted with acetonitrile by ultrasonic, and analyzed by UPLC-MS/MS. The wolfberry was sprayed with 6% spinetoram suspension concentrate (SC) at recommended dosage (1 500 times) and doubling dosage (750 times) (one time) at fructescence of wolfberry. The half lives of spinetoram residue under recommended dosage treatment was 3.65-4.25 d, and all the fresh and dried fruits conform to first order kinetics equation. The dissipation rate was over 95% in fresh and dried fruits at 14 d after application. In conclusion, spinetoram belongs to the easily degradable pesticide type. PMID- 28895327 TI - [Astragali Radix and Hedysari Radix molecular identification of SSR primers screening and fingerprints code]. AB - Leguminous related SSR primers were collected, core primers used for Astragali Radix and Hedysari Radix identification were screened and validated by using molecular marker techniques. 6 core primers were selected from 101 pairs of primers, the molecular weight of PCR products was 100-500 bp, which formed 7-12 electrophoresis bands with 55 amplified loci. The percentage of polymorphic loci was 100%, and the average polymorphism information content was 0.371. According to the results of cluster analysis, obtained core primer could completely distinguish 62 mixture samples of Astragali Radix and Hedysari Radix in similarity coefficient of 0.46. Core primers and the corresponding characteristics from gel electrophoresis were tagged. The results provide identification basis for Astragali Radix and Hedysari Radix. PMID- 28895328 TI - [Perilla resources of China and essential oil chemotypes of Perilla leaves]. AB - This study, based on the findings for Perilla resources, aimed to describe the species, distribution, importance, features, utilization and status of quantitative Perilla resources in China. This not only helps people to know well about the existing resources and researching development, but also indicates the overall distribution, selection and rational use of Perilla resource in the future. According to the output types, Perilla resources are divided into two categories: wild resources and cultivated resources; and based on its common uses, the cultivated resources are further divided into medicine resources, seed used resources and export resources. The distribution areas of wild resources include Henan, Sichuan, Anhui, Jiangxi, Guangxi, Hunan, Jiangsu and Zhejiang. The distribution areas of medicine resources are concentrated in Hebei, Anhui, Chongqing, Guangxi and Guangdong. Seed-used resources are mainly distributed in Gansu, Heilongjiang, Jilin, Chongqing and Yunnan. Export resource areas are mainly concentrated in coastal cities, such as Zhejiang, Jiangsu, Shandong and Zhejiang. For the further study, the essential oil of leaf samples from different areas were extracted by the steam distillation method and analyzed by GC-MS. The differences in essential oil chemotypes among different Perilla leaves were compared by analyzing their chemical constituents. The main 31 constituents of all samples included: perillaketone (0.93%-96.55%), perillaldehyde (0.10% 61.24%), perillene (52.15%), caryophyllene (3.22%-26.67%), and alpha-farnesene (2.10%-21.54%). These samples can be classified into following five chemotypes based on the synthesis pathways: PK-type, PA-type, PL-type, PP-type and EK-type. The chemotypes of wild resources included PK-type and PA-type, with PK-type as the majority. All of the five chemotypes are included in cultivated resources, with PA-type as the majority. Seed-used resources are all PK-type, and export resources are all PA-type. The P. frutescens var. frutescens include five chemotypes, with PK-type as the majority. The PK-type leaves of P. frutescens var. acuta are green, while the PA-type leaves are reddish purple. The P. fruteseens var. crispa was mainly PA type with reddish purple leaves. The differences of the main chemotypes provide a scientific basis for distinguishing between Zisu and Baisu in previous literatures. Based on the lung toxicity of PK and the traditional use of Perilla, the testing standard of essential oil and Perilla herb shall be built, and PA type is recommended to be used in traditional Chinese medicine. PMID- 28895329 TI - [Comparison of chemical compositions in Moutan Cortex, Paeoniae Rubra Radix and Paeoniae Alba Radix based on "component structure" theory]. AB - To analyze and compare the chemical compositions of Moutan Cortex, Paeoniae Rubra Radix and Paeoniae Alba Radix based on "component structure" theory. Thirteen batches of Moutan Cortex, 14 batches of Paeoniae Rubra Radix from different origins and 10 batches of Paeoniae Alba Radix from different origins were analyzed by HPLC-DAD method. Hierarchical cluster analysis and principal component analysis were used for analysis. The significant differences of principal component from Moutan Cortex, Paeoniae Rubra Radix and Paeoniae Alba Radix were investigated by using F test. HPLC fingerprints were established for 13 batches of Moutan Cortex, 14 batches of Paeoniae Rubra Radix and 10 batches of Paeoniae Alba Radix, and 7 glycosides and phenolic acids components were identified. Comparative study of Moutan Coetex, Paeoniae Rubra Radix and Paeoniae Alba Radix was conducted according to the results of hierarchical cluster analysis, principal component analysis and "component structure" theory. Moutan Cortex, Paeoniae Rubra Radix and Paeoniae Alba Radix have significant differences in mass fraction of major chemical components and their ratios, leading to different curative effects. PMID- 28895330 TI - [In vitro anticoagulant activity of different processed products of Whitmania pigra by water extraction and bionic extraction]. AB - In order to determine the scientificalness of traditionally processed Whitmania pigra, water extraction method and bionic extraction method were used respectively to extract the anticoagulating active components in W. pigra hanging dry products, talcum powder fried products and wine immersing-baked products. Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and antithrombin activity were selected as the activity indexes to evaluate the anticoagulant activities of different processed W. pigra. Then the contents of protein in different processed W. pigra were measured by Coomassie brilliant blue method to preliminarily explain the reason of anticoagulant activity changes. When water extraction method was used, the results of APTT, PT, TT and antithrombin activity showed that the anticoagulant activities of W. pigra were decreased both in talcum powder fried products and wine immersing-baked products, and the activity order was as follows: hanging dried products> wine immersing-baked products>talcum powder fried products. This order was same as the protein content order. While when bionic extraction was used, APTT was shortened in talcum powder fried products, but all the other results indicated the anticoagulant activities of W. pigra processed products were increased, and the activity order was as follows: wine immersing-baked products>talcum powder fried products>hanging dry products. As compared with water extraction, the bionic extraction was more similar to the absorption process of W. pigra in human digestive system after oral administration and was more scientific. Therefore, the traditional processing method can not only modify the taste and smell, but also enhance the anticoagulant activity of W. pigra. PMID- 28895331 TI - [Solubilization characteristics of licorice based on supramolecular "imprinted template" theory]. AB - To investigate the effect of the ingredient group of traditional Chinese medicine (TCM) with different "imprinted template" on the supramolecular solubilization ability of licorice, in order to lay a theoretical foundation for explaining the solubilization phenomenon of the components of TCM. Based on the independent supramolecular "imprinted template" rules, molecular connectivity index (MCI) and the correlation of n-octanol-water partition coefficient (logP) were used to indicate hydrophilic lipophilic capacity of TCM, and the extractum rate was used to indicate the solubilization effect of licoriceon single TCM herbs or compounds. The solubilization ability of licorice was evaluated based on MCI, logP and the extractum rate. According to the results, the correlation coefficient between MCI and logP for single herbs was 0.942, and that for single herb adding licorice was 0.916. The extractum rate of most herbs was increased after adding licorice. The correlation coefficient among the extractum rate as well as MCI and logP change values before and after adding licorice were respectively 0.837, 0.405. The correlation coefficient between MCI and logP for eight compounds was 0.937. Meanwhile, licorice had a solubilization effect on the remaining 7 compound except for Huangqi decoction. Therefore, licorice shows the solubilization effect through the independent supramolecular "imprinted template", so as to improve the hydrophilic lipophilic ability. There was a high positive correlation between the MCI and logP in ingredients for TCM, which could be used as important parameters to indicate the "imprinted template" feature for components of TCM. The study on the solubilizing effect of TCM with the supramolecular "imprinted template" theory was feasible, and will lay a foundation for the reform of single-herb dosage form. PMID- 28895332 TI - [Effect of D-cellobiose on oral bioavailability of gentiopicroside]. AB - In this study, the effect of D-cellobiose on oral bioavailability of gentiopicroside (GPS) was investigate. The influence of D-cellobiose on GPS was achieved by calculating the residual GPS after being degraded with beta glucosidase or intestinal flora, and the data demonstrated D-cellobiose could inhibit the degradation of GPS in intestines; in bioavailability experiment, D cellobiose could significantly improve the oral bioavailability (P<0.05) of GPS at the mass ratio of 1?5, 1?10 (GPS-D-cellobiose). D-cellobiose applied in this study may improve the oral bioavailability of GPS through delaying the degradation in intestines. PMID- 28895333 TI - [Two new lactone derivatives from an endophyte Diaporthe sp. XZ-07 cultivated on Camptotheca acuminata]. AB - To study the secondary metabolites and their cytotoxic activities of an endophytic fungus Diaporthe sp. XZ-07cultivated on Camptotheca acuminata. Colum chromatography by RP-18, Sephadex LH-20 and silica gel was used to isolate and purify the chemical constituent. Two new compounds were isolatedand identified as 5-((E)-1,4,5-trihydroxyhex-2-enyl)furan-2(5H)-one(1)and(5Z)-5-(2,3,4,5 tetrahydroxyhexylidene)furan-2(5H)-one(2)by spectroscopic analysis. Cytotoxic activities were evaluated by MTT method. Compound 1 showed strong inhibitory activity against Human cervical carcinoma cell line Hela, and compound 2 showed strong inhibitory activity against breast cancer cell line MCF-7, Human neuroblastoma SH-SY5Y and Lewis lung carcinoma cells 3LL. PMID- 28895334 TI - [Phenolic constituents from lichen Usnea longissima]. AB - Sixteen compounds were isolated from lichen Usnea longissima using of various chromatographic techniques including silica gel, Sephadex LH-20, ODS, and semi preparative HPLC. By spectroscopic data analyses, their structures were identified by as useanol(1), lecanorin(2), 3-hydroxy-5-methylphenyl 2-hydroxy-4 methoxy-6-methylbenzoate(3), lecanorin E(4), 3'-methylevernic acid(5), evernic acid(6), barbatinic acid(7), 3,7-dihydroxy-1,9-dimethyldibenzofuran(8), orcinol(9), O-methylorcinol(10), methyl orsellinate(11), methyl everninate(12), 2,5-dimethyl-1,3-benzenediol(13), 2-hydroxy-4-methoxy-3,6-dimethyl benzoic acid(14), ethyl everninate(15), and ethyl 2,4-dihydroxy-6-methylbenzoate(16). Compound 1 was obtained as a natural product for the first time, and 3,4, 8,10,12, and 13 were isolated from Usneaceae family for the first time. Compound 1, 8, and 13 showed significant anti-inflammatory activity against NO production in RAW 267.4 cells with IC50 values of 6.8, 3.9 and 4.8 MUmol*L-1, respectively, compared with the positive controls curcumin(IC50 15.3 MUmol*L-1) and indomethacin(IC50 42.9 MUmol*L-1). PMID- 28895335 TI - [Simultaneous determination of ten bioactive constituents in Lonicerae Flos by HPLC-MS-MS]. AB - In this study, an HPLC-MS/MS method was developed and validated for simultaneous determination of six iridoids and four flavonoids in batches of Lonicerae Flos samples. Chromatographic separation was performed on a Shiseido Capcell Pak-C18 column (4.6 mm*250 mm, 5 MUm). 0.1% Aqueous formic and acid (A) and acetonitrile (B) were adopted as mobile phase. Detection was carried out on a triple quadrupole mass spectrometer in the negative ion mode using an electrospray source. Multiple reaction monitoring (MRM) mode was employed. The developed method showed good linearity (R2 >=0.999 0) for all the analytes within the test ranges and the limits of quantification (LOQs) ranged from 7.4 to 31.0 MUg*L-1. The recoveries varied between 94.16% and 105.3%. The quantitative data indicated that the total content of iridoids (0.338%-1.440%) was much higher than that of flavonoids (0.015 4%-0.057 5%) in all samples. Moreover, it was found that there were significant differences in the content of six compounds among the samples from three different original plants, which might provide scientific evidences for the origin identification and quality control of Lonicerae Flos. PMID- 28895336 TI - [Determination of stachydrine hydrochloride and leonurine hydrochloride in Yimucao preparations by HPLC-MS]. AB - To establish the quantitative method of stachydrine hydrochloride and leonurine hydrochloride in the preparations of Leonuri Herba. The contents of stachydrine hydrochloride and leonurine hydrochloride in the preparations of Leonuri Herba were determined by HPLC-MS. The chromatographic column was Waters XBridge Amide(4.6 mm*250 mm,5 MUm). The mobile phase was acetonitrile-0.1% formic acid in gradient mode,at the flow rate of 1.0 mL* min-1,with the split ratio of 1?4. MS conditions for the ESI ion source,positive ion mode,selective ion scan(SIM) of stachydrine hydrochloride(m/z 144.0) and leonurine hydrochloride(m/z 312.0) was measured. The linear ranges of stachydrine hydrochloride was 0.562 8-281.4 MUg*L 1(r=0.999 8). The linear ranges of leonurine hydrochloride was 0.521 2-260.6 MUg*L-1(r=0.999 8). The method is accurate,simple,and reliable,and can be used to determine the contents of stachydrine hydrochloride and leonurine hydrochloride in the preparations of Leonuri Herba. PMID- 28895337 TI - [Preparation and identification of Jujuboside A artificial antigen]. AB - Immunogenic antigen (jujuboside A-BSA) and coating antigen (jujuboside A-OVA) of jujuboside A were synthesized by sodium periodate oxidation method for the first time. Jujuboside A artificial antigen was confirmed by matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF-MS). The titer and specificity of the antibody in serum of immunized mice were detected by enzyme-linked immunosorbent assay (ELISA). The corrected relation curve of inhibition rate showed that the antibody against Jujuboside A obtained from immunized mice could bind to jujuboside A and the titer was up to 1?4 000. The jujuboside A artificial antigen was synthesized, which can be used further to preparation of monoclonal antibody and the pharmacokinetics study of jujuboside A in laboratory animals. PMID- 28895338 TI - [Structure activity relationship of annonaceous acetogenins against multidrug resistant human lung cancer cell line A549/Taxol in vitro]. AB - 10 kinds of annonaceous acetogenins were selected for antitumor activity testing against human lung cancer cell line A549/Taxol and the structure activity relationship was analyzed.MTT assay was used to detect the inhibitory activities of 10 kinds of annonaceous acetogenins and positive drugs against A549/Taxol cells, respectively uvariamicin-III(1), uvariamicin-II(2), annosquacin D(3), desacetyluvaricin(4), annosquatin A(5), squamostatin D(6), bullatacin(7), squamocin(8), motrilin(9), annosquatin B(10), verapamil and cisplatin. Annonaceous acetogenins showed significant inhibitory activities against A549/Taxol cells, and were more potent than the positive drug verapamil and cisplatin.The more carbon atoms between the tetrahydrofuran ring and the lactone ring of annonaceous acetogenins exhibited more potency.Besides,ACGs with two substituted hydroxyl showed more potency than the compounds with three substituted hydroxyl in the bis-adjacent-THF ACGs. Furthermore, ACGs with three substituted hydroxyl showed more potency than the compounds with four substituted hydroxyl among the no bis-adjacent-THF ACGs. PMID- 28895339 TI - [Effects of glycosides components and combinations of Buyang Huanwu decoction on vascular smooth muscle cells proliferation and related signaling pathway]. AB - This paper was aimed to explore the effects of glycosides, the effective component of Buyang Huanwu decoction, and its main active components such as astragaloside IV, amygdalin, peoniflorin and their combinations on vascular smooth muscle cells (VSMC) proliferation, clarify the major active materials of anti-VSMC proliferation and investigate the mechanisms via the signal transduction pathway. Plasma containing drug was prepared via oral administration in rats. VSMCs of rats aorta were cultured, and then VSMC proliferation was stimulated by using platelet derived growth factor (PDGF).The plasma containing drug was added to detect the activity of cell proliferation, cell cycle and related protein expressions of signaling pathway such as extracellular signal regulated kinase (ERK), phos-phatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and Janus kinase/signal transducer and activator of transcription (JAK/STAT). After being stimulated by PDGF, the proliferation activity of VSMC was strengthened (P<0.01), G0/G1 phase cells were decreased (P<0.01), S/M phase cells were increased (P<0.01), and PcNA, cyclin D1 protein expressions related to cell cycle were up-regulated (P<0.01). Glycosides, astragaloside IV, amygdalin, peoniflorin and their combinations could inhibit the cell proliferation (P<0.05 or P<0.01) in a dose-effect relationship and time-effect relationship. They could increase G0/G1 phase cells (P<0.01), decrease S/M phase cells (P<0.01), and down regulate the protein expressions of PCNA, cyclin D1 (P<0.01); and the effects of the combinations were greater than those of single active component (P<0.05). After VSMC proliferation was induced by PDGF, p-ERK1/2 expression was increased (P<0.01), PI3K expression was down-regulated while p-PI3K expression was up regulated (all P<0.01), and STAT3expression was reduced while p-STAT3 expression was increased (all P<0.01). Glycosides, astragaloside IV, amygdalin, peoniflorin and the combinations of these active components could reduce p-ERK1/2 expression (P<0.05), increase PI3K expression (P<0.01), decreasep-PI3K expression (P<0.05 or P<0.01), increase STAT3 expression (P<0.01), and decrease p-STAT3 expression (P<0.05 or P<0.01). These results suggested that PDGF could induce the cell cycle conversion of VSMC, leading to VSMC proliferation. The mechanism was related to the activation of ERK, PI3K/Akt and JAK/STAT signaling pathways. Glycosides and its main active components such as astragaloside IV, amygdalin, peoniflorin and their combinations can inhibit the cell cycle conversion of VSMC, with the effect against VSMC proliferation, and the mechanisms may be associated with the inhibition of PI3K/Akt, mitogen-activated protein kinase (MAPK) and JAK/STAT signaling pathways. astragaloside IV, amygdalin and peoniflorin were the major active materials of anti-VSMC proliferation, and their combination showed enhanced effect. PMID- 28895340 TI - [Effect of Kaixinsan on monoamine oxidase activity]. AB - To observe the effect of antidepressant medicine prescription, Kaixinsan (KXS) on monoamine oxidase (MAO) activity, and explore the mechanism of KXS in elevating the levels of monoamine neurotransmitter from the perspective of metabolism, in vitro enzyme reaction system and C6 neuroglial cells, the effect of KXS at different concentrations on MAO-A and MAO-B activity was observed. In animal studies, the effect of KXS at different concentrations on MAO-A and MAO-B activities of brain mitochondrialin normal rats and solitary chronic unpredictable moderate stress (CMS) model rats after intragastric administration for 1, 2, 3 weeks. Results showed that 10 g*L-1 KXS could significantly reduce the activity of MAO-A and MAO-B in enzyme reaction system; and in C6 cells, KXS within 0.625-10 g*L-1 concentration range had no significant effect on the activity of MAO-A, but had obvious inhibitory effect on the activity of MAO-B in a dose dependent manner. KXS had no significant effect on the activity of MAO-A and MAO-B in brains of normal rats after action for 1, 2, 3 weeks. After 2 and 3 weeks treatment with 338 mg*kg-1 dose KXS, MAO-A activity in the brain of CMS rats was decreased as compared with the model group (P<0.05), while KXS had no significant effect on MAO-B activity after 1, 2, 3 weeks of treatment. The results indicated that KXS had certain effect on in vitro MAO-A and MAO-B activity, had no effect on brain MAO-A and MAO-B activity in vivo in normal rats, and had certain inhibitory effect on MAO-A activity in brains of CMS rats. PMID- 28895341 TI - [A high content screening method for detection of anaphylactoid reaction of injection formulations]. AB - Anaphylactoid reaction (AR) is the most common adverse reaction of injection formulations, however, there are obvious drawbacks in available methods for AR detection. A novel in vitro detection method for AR was established based on fluorescent labeling and high content screen (HCS) system in present study. With the use of RBL-2H3 cells degranulation model, positive cell count was determined with specific cellular membrane fluorescent dye FM4-64 labeling vesicle recycle, and total cells count was determined with specific nucleus fluorescent dye Hochest 3334, and then the ratio of cells degranulation after drug stimulation was calculated. In order to verify the reliability of this HCS method, positive drug Compound 48/80 was first used to confirm the consistence of HCS method with the traditional beta-hexosaminidase release test and the Evans blue staining ears test in mice. The results showed high consistence between HCS method and traditional testing methods, and the HCS method showed higher sensitivity than the other two tests. Then 30 samples of Danhong injection (DHI) with clinical allergy symptoms further were used to confirm the reliability of this HCS method. The HCS results showed high consistence with the clinical report, and the HCS method had the advantage in reducing the interference by drug color. Therefore, this HCS method is reliable, sensitive, simple and high-throughput method in detection of AR, applicable for the AR evaluation of injection formulations, and can provide guidance for safety of clinical application in clinical practice. PMID- 28895342 TI - [Neuro-protective effects and mechanism of Terminalia chebula extract HZ4 on cerebral infarction models]. AB - To study the effect and possible molecular mechanisms of Terminalia chebula extract HZ4 on focal cerebral infarction in rats, 90 healthy male SD rats were randomly divided into sham-operation group, model group, T. chebula extract HZ4 high dose, middle dose and low dose groups (80, 40, 20 mg*kg -1*d -1, ig) and positive control group (Panax notoginseng saponins, PNS 30 mg*kg -1*d -1, ig). The focal cerebral infarction models were established by photochemical method. After the rats were administered for 7 consecutive days, neurogenic behavior rating of these rats was done by balance beam test and foot fault test. The cells morphological changes of penumbra in focal cerebral infarction were investigated by HE staining method; the infarct volume was detected by TTC staining. The expression levels of beta-catenin and cyclin D1, the key node genes in Wnt signaling pathway of the focal penumbra tissues were detected via RT-PCR. The results showed that, as compared with the model group, behavioural indicators were improved significantly in the rats of administration groups, and the infarct volume and pathological changes of penumbra tissues were also improved at the same time. Compared with the model group, the expression levels of beta-catenin and cyclin D1 in Wnt signaling pathway were significantly up-regulated in administration groups(P<0.01). This study first confirmed that T. chebula extract HZ4 can decrease infarct volume, improve the sport ability score, and promote rehabilitation of model animals. In addition, it could significant up-regulated the expression levels of beta-catenin and cyclin D1, and the mechanism may be associated with Wnt signaling pathway. The study is innovative to a certain extent. PMID- 28895343 TI - [Explore pharmacological mechanism of glycyrrhizin based on systems pharmacology]. AB - To explore the pharmacological mechanism of glycyrrhizin with series methods of systems pharmacology, main diseases related to glycyrrhizin were obtained by text mining tool; and the target proteins of glycyrrhizin were obtained via the database of Polysearch and PubChem. Then, the target proteins interaction network of glycyrrhizin was built using the software called Cytoscape. Next, the protein groups related to glycyrrhizin were analyzed by using Gene Ontology (GO) tool, and the action pathway of its target proteins was analyzed by using enrichment method. Text mining results showed that the related diseases of glycyrrhizin included chronic hepatitis C, chronic hepatitis, hepatitis, HIV virus, liver cancer and so on. Gene ontology analysis indicated that glycyrrhizin played a role mainly through modification of proteins and chromatin. The signaling pathway enrichment results showed that the main action proteins of glycyrrhizin were related to MAPK signaling pathway, toll-like receptor signaling pathway, neurotrophic factor signaling pathway, cancer and apoptosis pathways. So we can conclude that glycyrrhizin may exert its biological functions primarily by regulating multiple pathways such as MAPK signaling pathway and Toll-like receptors signaling pathway. The pharmacological action of a drug can be rapidly and comprehensively analyzed by the ways of systems pharmacology. PMID- 28895344 TI - [Effect of rat intestinal flora on in vitro metabolic transformation of pumiloside]. AB - To study the metabolic transformation of pumiloside by rat intestinal flora in vitro and identify its metabolites. Pumiloside was incubated in the rat intestinal flora in vitro. HPLC was used to monitor the metabolic process, and HPLC-Q-TOF-MS was used to identify the structures of biotransformation products. In vitro, pumiloside was easily metabolized by rat intestinal flora, and with the prolongation of metabolic time, pumiloside was transformed into several metabolites. Three metabolites were initially identified in this experiment. The study indicated that pumiloside could be extensively metabolized in the rat intestinal flora in vitro. PMID- 28895345 TI - [Species differences in caffeine metabolism in liver microsomes of rats and mice]. AB - Caffeine and its metabolic products play an important role in clinical applications. An ultra-high performance liquid chromatography/quadrupole time-of flight mass spectrometry (UPLC-Q-TOF MS/MS) method was applied to systemically study the caffeine metabolism in liver microsomes of rats and mice, and comprehensively evaluate caffeine metabolites in vitro and metabolism differences between species. The caffeine metabolites and metabolism differences between species in liver microsomes of rats and mice were analyzed by UPLC-Q-TOF-MS/MS high resolution mass spectrometry system and metabolitepolite software. The results showed that in addition to the demethylated and oxidized products in previous analysis, methylated, double oxidized, dehydrated and decarbonylated metabolites were also found in caffeine metabolism in liver microsomes of rats and mice, with significant difference in metabolism in vitro between rats and mice. The demethylated metabolite M2(C7H8N4O2) and decarbonylated metabolite M6(C7H10N4) in metabolism in vitro of mice were not found in rats, and the in vitro metabolite M7(C8H12N4O5) in rats were not found in mice. There was significant species difference in caffeine metabolism in vitro between rats and mice, providing important reference value for the further metabolism study and safety evaluation of caffeine. PMID- 28895346 TI - [Antirheumatic substance and meridian tropism of Loranthus parasiticus based on "syndrome-efficacy-analysis of biological samples"]. AB - To study the antirheumatic substance of Loranthus parasiticus and observe the relationship between its in vivo distribution and meridian tropism in rats by establishing adjuvant arthritis models corresponding to effectiveness. All rats except the negative control group were injected with 0.1 mL Freund's complete adjuvant on the left foot. After 8 days, the rats in negative control group and model group were given with normal saline while the rats in positive control group were given with tripterygium glycosides suspension 10 mg*kg-1, and the rats in L. parasiticus treatment groups were given with high(10 g*kg -1), medium(5 g*kg -1) and low(2.5 g*kg -1) dose decoction for 21 days. The left rear ankle joint diameter of rats were measured every 7 days from the 9th day of modeling. On the 22nd day, eyeball blood of part rats in L. parasiticus high-dose group was taken at different time points, and then they were sacrificed to take heart, liver, spleen, lung, kidney, stomach, large intestine, small intestine and brain tissues. For the remaining rats, eyeball blood was taken 30 min after drug treatment, and their left rear ankle joints were taken to detect interleukin (IL) 1beta and tumor necrosis factor (TNF)-alpha levels in serum by ELISA method; rutin, avicularin and quercitrin levels in the tissues of high-dose group were detected by HPLC; pharmacokinetic parameters were analyzed by using DAS 2.0. Our results showed that L. parasiticus decoction could significantly improve the paw edema situation of adjuvant arthritis model rats, and reduce IL-1beta and TNF alpha levels in rat serum. The in vivo efficacy substance analysis in rats showed that rutin was only present in the stomach with a small amount. AUC0-t of avicularin was stomach > small intestine > kidney, and the duration time in vivo was kidney=stomach > small intestine > lung > heart. AUC0-t of quercitrin was stomach > kidney > liver > heart > lung > spleen > small intestine > brain > large intestine > serum, and the duration time in vivo was kidney=liver=small intestine=brain=lung=spleen=heart=stomach > large intestine > serum. The research indicated that L. parasiticus decoction was effective in treating rats with adjuvant arthritis. Avicularin and quercitrin are important ingredients of L. parasiticus in antirheumatism therapy. The distribution of avicularin and quercitrin in rats were consistent with traditional understanding that L. parasiticus could attribute to the kidney and liver meridians. PMID- 28895347 TI - [Clinical characteristics and medicinal analysis for osteoporosis based on real world]. AB - To understand the actual clinical situation of osteoporosis patients in our country, 9 731 hospitalized patients with osteoporosis from HIS system of 20 national 3A-grade hospitals were selected as the research objects to analyze their general information, western medicine combined diseases, diagnostic information, relationship with the onset of 24 solar terms, and the therapeutics application. Results showed that the median age of hospitalized patients with osteoporosis disease was 72 years old, more common in women aged 60 to 74; mainly in manual workers (73.87%); most in general outpatient clinic during the admission; conditions of the most patients (81.61%) were general during hospital admission; patients were more likely hospitalized from orthopaedics department (21.94%); hospital length of stay was mainly of 8-14 days (39.96%); 34.34% of the patients had a total hospitalization cost of 5 000 yuan to 10 000 yuan; 75.01% of the patients were beneficial from national health medical insurance. The complications mainly included hypertension, diabetes, and osteoarthritis, and the complication rate was as high as 34.67% for hypertension; the most common traditional Chinese medicine syndrome was deficiency of liver-Yin and kidney-Yin (36.62%); the patients were admitted to the hospital most during 3 solar terms: beginning of summer, summer solstice and cold dew. Calcitonin salmon and calcium carbonate were most widely used in western medicine and Zhengqing Fengtongning was most widely used in traditional Chinese medicine. In conclusion, osteoporosis is more common in elderly patients, and is closely related to solar terms; integrated treatment strategies of traditional Chinese medicine and western medicine can be widely used in clinical application and have certain advantages. PMID- 28895348 TI - [Open, multicenter, phase IV clinical trial of Shenbei Guchang capsules in treatment of diarrhea type irritable bowel syndrome]. AB - To evaluate the safety and effectiveness of Shenbei Guchang capsules in treatment of diarrhea type irritable bowel syndrome (yang deficiency of spleen and kidney) under widely used conditions, an open, multicenter, controlled, phase IV clinical trial was conducted in the drug clinical trial centers of 16 domestic hospitals. 2 123 patients from June 10, 2011 to November 29, 2012 were enrolled in the trial. Drug clinical trial was approved by Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital Ethics Committee before implementation. Before the start of trial, subjects were selected according to the research scheme and inclusion criteria, then they would step into the 14 d study after signing Informed Consent Form. All subjects were treated according to the research scheme, evaluated the conditions and filled in CFR sheet, to provide the evaluation data and information on safety and efficacy of Shenbei Guchang capsules. Shenbei Guchang capsules were used to treat diarrhea type irritable bowel syndrome in widely used conditions (2 123 cases), and 2 029 cases of them entered FAS set, cure+markedly effective in 1 921 cases, with a comprehensive curative effect rate of 94.68%; 2 010 cases of them entered PPS set, cure+markedly effective in 1 906 cases, with a comprehensive curative effect rate of 94.83%. The primary symptoms of IBS were abdominal pain and diarrhea. After treatment, both abdominal pain and diarrhea were improved, with significant differences (P<0.000 1). There were significant differences in traditional Chinese medicine symptom scores on both post-treatment day 7 and day 14 as compared with the conditions before treatment (P<0.000 1). 35 cases of adverse events occurred during the trial with an incidence of 1.65%, including 12 cases of drug-related adverse events (adverse reaction) with an incidence of 0.57%, mainly manifested as nausea, abdominal distension and dry mouth, most of which would be spontaneously relieved without any measures. No serious adverse events occurred. The commercially available Shenbei Guchang capsules are proved safe and effective for the treatment of diarrhea type irritable bowel syndrome (yang deficiency of spleen and kidney) under widely used conditions (2 123 cases), and can be continued for clinical promotion and application. PMID- 28895349 TI - [National physician master Jin Shiyuan's dispensing technology of Aconiti Lateralis Radix Praeparata based on Li Shizhen's pharmaceutical academic thought]. AB - To collect Li Shizhen's experience in Aconiti Lateralis Radix Praeparata identification and clinical application, compare and analyze national physician master Jin Shiyuan's practical operation and theoretical knowledge, which is beneficial for the inheritance and improvement of Aconiti Lateralis Radix Praeparata clinical dispensing technology. In the analysis process, CNKI, Wanfang and other databases were searched with "Aconiti Lateralis Radix Praeparata", "Li Shizhen", "pharmacological method state theory" "Jin Shiyuan" and "Chinese medicine dispensing technology" as the key words. In addition, Treatise on Febrile Disease, Compendium of Materia Medica, Chinese Pharmacopoeia(2015 edition), Notes to Medical Professions(Yi Zong Shuo Yue), and other medicine books were accessed to summarize the processing methods and decoction dosage of Aconiti Lateralis Radix Praeparata in both ancient and modern medicine, and in consideration of technical research and practice operation, Li Shizhen's description of Aconiti Lateralis Radix Praeparata and Professor Jin Shiyuan's research on Aconiti Lateralis Radix Praeparata dispensing technology were analyzed and collected. Li Shizhen recorded the nature identification and clinical application of Aconiti Lateralis Radix Praeparata by using pharmacological method state theory in Compendium of Materia Medica. National physician master Jin Shiyuan carries forward the essence of Li Shizhen's pharmaceutical academic thought with his own proficient knowledge structure in medicine, providing scientific pharmaceutical service for clinical application of Aconiti Lateralis Radix Praeparata Professor. Jin Shiyuan put forward the dispensing technology for the first time, including nature identification technology, clinical processing technology, clinical decocting technology, prescription coping technology, and class specifications of Aconiti Lateralis Radix Praeparata. In this paper, Aconiti Lateralis Radix Praeparata was used as an example to analyze the key dispensing technology of traditional Chinese medicine, and apply the key dispensing technology of traditional Chinese medicine in various commonly used Chinese medicines in the future. PMID- 28895350 TI - [Investigation of original materials under traditonal Chinese medicine names of "Jinchai" and "Jinchai Shihu"]. AB - To clear from botanical view the original materials under the traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" within the genus Dendrobium of the family Orchidaceae. Combined of different methods including study of historical records from the local chronicles and historical accounts of past event in Hubei, Sichuan, Chongqing, Henan and Shaanxi provinces, interviewing face to face with the old traditional Chinese workers and folk doctors in 20 downtowns and countrysides, such as, Laohekou, Lichuan, Fangxian, Xixia, Neixiang, and Ankang, and collecting a few plants of "Jinchai" for taxonomic identification. The traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" were widely used by the local people from the eastern Chongqing, western Hubei, northeasten Sichuan, southeastern Shaanxi, western Henan. Those two names were frequently found in the local Chronicles and historical accounts of past event, even in the local daily life such as folk songs and stories. The botanical identification results showed that a endemic species of D. flexicaule is the original materials of the traditional Chinese medicine names "Jinchai" and "Jinchai Shihu", and this species are also called "Longtoujin", "Renzijin", "Huanzijin" and "Longtoufengweijin" by the local people. The dried artifactitious specimens of D. flexicaule are traditionally named as "Jinerhuan". The botanic resource plants of the traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" are the endemic species of D. flexicaule that is distributed mainly in central areas of China including eastern Chongqing, western Hubei, northeasten Sichuan, southeastern Shaanxi, and western Henan, rather than D. nobile as referring in both Chinese and English version of Flora of China, and in official recorded serious versions of The Chinese Pharmacopoeia since 1977. In order to avoid confusion in the traditional Chinese medicine dendrobiums industry, the Chinese name of D. nobile is suggested as "Biancao Shihu", which characterized one stem feature of this species, and the traditional Chinese medicine names "Jinchai" or "JinchaiShihu" is suggested to refer to the species D. flexicaule. PMID- 28895351 TI - [Research thoughts on tumor immune responses by polysaccharide of Chinese medicine via oral administration]. AB - Tumor immunotherapy is one of the most significant scientific progresses. The idea of applying the traditional Chinese theory of "the balance of Yin and Yang" to treat cancer is in accordance with that of modern tumor immune strategy. Researches indicated that polysaccharide of Chinese medicine through regulation in immune responses could offer better paradigm for tumor immune treatment under the traditional Chinese theory. However, current studies related to tumor immunotherapy largely focus on the immunity enhancement while lack of the exploration of suppressive factors. Meanwhile, the complex analysis and detection on composition as well as structure definitely increase the difficulty in mechanism of oral absorption and function in vivo. To better exploit novel Chinese medicine of polysaccharide for tumor immune treatment, this article will provide some constructive thoughts on regulation of tumor immune responses based on up to date researches of structure-function relationship, absorbent process and molecular mechanisms responsible for tumor immune as well. PMID- 28895352 TI - [Cyanobacteria cell factories for ethanol photosynthetic production: development and prospect]. AB - Bioethanol is one of the most promising and representative biofuel products. Photosynthetic production of ethanol using CO2 and solar energy based on cyanobacteria is of great significance for research and application, due to the potential to reduce CO2 emission and to provide renewable energy simultaneously. Here we review the history and updated development of cyanobacteria cell factories for ethanol photosynthetic production, the progress and problems in pathway optimization, chassis selection, and metabolic engineering strategies, and finally indicate the future development in this area. PMID- 28895353 TI - [Circulating long noncoding RNAs as biomarkers in tumor diagnosis]. AB - Long noncoding RNAs (lncRNAs) are involved in vital life processes of gene expression, epigenetic regulation and X-chromosome inactivation. lncRNAs are also closely associated with tumor initiation and progression. Moreover, lncRNAs may enter human circulation system in the form of microvesicle or exosome, or in combination with RNA binding protein. Interestingly, the circulating lncRNAs are widely existed in body fluids, such as blood and urine. We review the origin of circulating lncRNAs, and the detection methods as potential biomarkers. We focus on the early diagnosis value of circulating lncRNAs as tumor biomarkers in lung, breast, gastric, liver, colorectal and prostate cancers. Compared with the traditional biomarkers, the circulating lncRNAs show the unique advantages and clinical values as novel biomarkers. PMID- 28895354 TI - [Fermentations of xylose and arabinose by Kluyveromyces marxianus]. AB - Kluyveromyces marxianus, as unconventional yeast, attracts more and more attention in the biofuel fermentation. Although this sort of yeasts can ferment pentose sugars, the fermentation capacity differs largely. Xylose and arabinose fermentation by three K. marxianus strains (K. m 9009, K. m 1911 and K. m 1727) were compared at different temperatures. The results showed that the fermentation performance of the three strains had significant difference under different fermentation temperatures. Especially, the sugar consumption rate and alcohol yield of K. m 9009 and K. m 1727 at 40 C were better than 30 C. This results fully reflect the fermentation advantages of K. marxianus yeast under high temperature. On this basis, five genes (XR, XDH, XK, AR and LAD) coding key metabolic enzymes in three different yeasts were amplified by PCR, and the sequence were compared by Clustalx 2.1. The results showed that the amino acid sequences coding key enzymes have similarity of over 98% with the reference sequences reported in the literature. Furthermore, the difference of amino acid was not at the key site of its enzyme, so the differences between three stains were not caused by the gene level, but by transcribed or translation regulation level. By real-time PCR experiment, we determined the gene expression levels of four key enzymes (XR, XDH, XK and ADH) in the xylose metabolism pathway of K. m 1727 and K. m 1911 at different fermentation time points. The results showed that, for thermotolerant yeast K. m 1727, the low expression level of XDH and XK genes was the main factors leading to accumulation of xylitol. In addition, according to the pathway of Zygosaccharomyces bailii, which have been reported in NCBI and KEGG, the xylose and arabinose metabolic pathways of K. marxianus were identified, which laid foundation for further improving the pentose fermentation ability by metabolic engineering. PMID- 28895355 TI - [Optimization of heparosan synthetic pathway in Bacillus subtilis 168]. AB - Heparosan is the start point for chemoenzymatic synthesis of heparin and it is of great significance to efficiently synthesize heparosan in microorganisms. The effects of overexpressing key enzyme genes of the UDP-glucuronic acid (UDP-GlcUA) pathway (pgcA, gtaB and tuaD) or the UDP-N-acetyl-glucosamine (UDP-GlcNAc) pathway (glmS, glmM and glmU) on the heparosan production and molecular mass were analyzed in the constructed heparosan-producing Bacillus subtilis ((1.71+/-0.08) g/L). On this basis, heparosan production was increased to (2.89+/-0.11) g/L with the molecular mass of (75.90+/-1.18) kDa through co-overexpressing the tuaD, gtaB, glmU, glmM and glmS genes in shake flask cultivation. In the 3 L fed-batch fermentation, heparosan production was improved to (7.25+/-0.36) g/L with the molecular mass of (46.66+/-2.71) kDa, providing the potential for heparosan industrial production. PMID- 28895356 TI - [Pathogenicity of white-spot syndrome virus in Macrobrachium nipponensis via different infection routes]. AB - Macrobrachium nipponensis is delicious and has high economic value, but its susceptibility to white-spot syndrome virus (WSSV) is unknown. Susceptibility, morbidity, and multiplication of WSSV in M. nipponense were studied by epidemiological survey, infection experiment and qPCR. M. nipponense was the natural host of WSSV, and the natural carrying rate was about 8.33%. M. nipponense could be infected with WSSV via oral administration, muscle injection and immersion, and the cumulative infection rate of 10 d exposure was 100%, and the cumulative mortality rates were 100%, 75% and 0%, respectively. The infection of WSSV is fast by muscle injection. The virus content after 5 day's injection is 1 000 times higher than that of the first day of infection, and the mortality rate reached 100% after 8 days. The median lethal dose (LD50) measured as the mortality of infected M. nipponense via injection indicated the LD50 in the concentration of WSSV of 2.71*105 virions/MUL. In shrimp farming, M. nipponense can be infected by ingesting WSSV infected shrimp or dead shrimp, and also by soaking in WSSV-containing water and thus become a vector, consequently affecting the spread and pathogenicity of WSSV. PMID- 28895357 TI - [Bioremediation of oil-contaminated field by two Pseudomonas aeruginosa strains]. AB - We studied the remediation of petroleum-contaminated soils. Two Pseudomonas aeruginosa strains were screened from soil samples in the mine environment. The degradation rate of crude oil was 95.67% after 10 days by mixed culture of the two strains, which was 32% higher than that of single bacterium. It means that the two bacteria had synergistic effect on degrading crude oil. Based on the result, bacterial agent was prepared, and the oil pollution sites were artificially constructed to simulate the degradation of crude oil under different operating conditions. During the experiment, the petroleum hydrocarbon content of the sites after treating with the bacterial agent, decreased obviously in 60 days. The content decreased to among 0.1% and 0.3% from the initial 0.8% per gram of soil. Then, the site with organic manure as supplemental source of carbon and nitrogen had the highest degradation rate of 85.28%, compared to that without adding bacterial agent of only 25.85%. PMID- 28895358 TI - [Influence of oil pollution on soil microbial community diversity]. AB - Bacteria, actinomycetes and fungi are the three major groups of soil microbes. Soil microbes play a critical role in ecological and biodegradation processes in petroleum-contaminated soils. Based on the actual situation, this study took the oil polluted soil around the abandoned oil well in Shehong County, Suining City, Sichuan Province as the test soil. First, we determined the physiochemical properties of the tested soil; then we analyzed the changes of physiochemical properties and the three major microbes in petroleum contaminated soils. The number of the three major microbes in contaminated soils was relatively fewer than uncontaminated samples, and the water content of the soil was in positive correlation with the number of microbes. Also we assessed the soil bacteria community diversity and changes therein in petroleum-contaminated soils using 454 pyrosequencing of 16S rRNA genes. No less than 23 982 valid reads and 6 123 operational taxonomic units (OTUs) were obtained from all 4 studied samples. OTU richness was relatively higher in contaminated soils than uncontaminated samples. Acidobacteria, Actinobacteria, Bacteroidetes, Chloroflexi, Planctomycetes and Proteobacteria were the dominant phyla among all the soil samples. However, the prokaryotes community abundance of phyla was significantly different in the four samples. The most abundant OTUs associated with petroleum-contaminated soil sample were the sequences related to Acidobacteria, Actinobacteria and Proteobacteria, whereas the most abundance sequences with uncontaminated sample were those related to Actinobacteria, Bacteroidetes and Proteobacteria. PMID- 28895359 TI - [Establishment and optimization of systems for protoplasts isolation of soybean and chickpea that used in subcellular location]. AB - Young leaves of Kabuli chickpea as well as soybean Xiangdou No.3, which are the current plants that studied in our laboratory were selected as materials. Effects on protoplasts yield and survival rate of different enzyme combination, concentration of D-Mannitol in enzyme combinations, pH of enzyme combinations and enzymolysis time are detected. The results showed that, the best condition for Xiangdou No.3 leaf protoplasts isolation is to rotate the cut materials for 6 hours in enyzme solution under temperature of 27 C and rotate speed of 45 r/min for 6 h. Onozuka R-10 (0.5%), Hemicellulase (0.8%), Macerozyme R-10 (0.8%) in combination with Pectolyase Y-23 (0.4%) dissolving in CPW solution with MES (0.1%) and Mannitol (10%), pH 6.0 was found best for protoplasts isolation of Xiangdou No.3 leaves.The best condition for protoplasts isolation of Kabuli chickpea is to put the cut materials into enzymatic hydrolysate enzymolyse for 7 to 8 hours under temperature of 27 C and rotate speed of 45 r/min on water bath shaker, the optimum combination of enzyme consists of Onozuka R-10 (0.5%), Hemicellulase (0.8%), Macerozyme R-10 (0.8%), MES (0.1%) and Mannitol (10%) dissolved in CPW solution with pH 4.8. The protoplasts prepared with the methods above are used in subcellular location and the effects show well. PMID- 28895360 TI - [Construction of Setosphaeria turcica STK1-EGFP fusion gene vector and its expression in Pichia pastoris]. AB - STK1 is one important MAPK gene regulating the conidial development, osmotic stress and pathogenicity of Setosphaeria turcica. At first, the Pichia pastoris GS115 expression vector pPIC3.5K-EGFP containing enhanced green fluorescent protein gene (EGFP) was constructed, then STK1 gene was first amplified by PCR with the template of cDNA of S. turcica model isolate 01-23, and then cloned into the vector pPIC3.5K-EGFP with enhanced green fluorescent protein gene (EGFP) to construct the STK1-EGFP fusion gene expression vector pPIC3.5K-STK1-EGFP. The vector was transformed into the susceptible cells of Pichia pastoris GS115 by electric shock process, and the transformants were identified by MD medium screening and PCR determination. The STK1 gene and EGFP gene could be expressed effectively and stably in the transformants as detected by RT-PCR and fluorescence observation. In addition, we also found that the Kozak sequence before the start codon of STK1 gene could increase 4.8 folds expression level of STK1- EGFP fusion gene. The above research results laid a good foundation for subcellular localization and antibody preparation of STK1 protein. PMID- 28895361 TI - [Cloning and characterization of two glutathione S-transferases cDNAs in Foc4 and expression under exogenous oxidative stress]. AB - In order to identify two putative glutathione S-transferase (GSTs) genes in Fusarium oxysporum f. sp. cubense race 4 (Foc4), cDNA sequences of the entire coding regions of the two genes were cloned from Foc4 using RT-PCR method. Subsequently, the two genes were named Fogst1 and Fogst2 respectively. The length of open reading frame of Fogst1 was 609 bp and encoded a protein including 202 amino acid residues, Fogst2 possessed an open reading frame with 693 bp which encoded a 230-amino acid protein. Phylogenetic analysis showed that Fogst1 belonged to sigma (sigma) subtype members of the GSTs superfamily, and Fogst2 was a new member of an unknown subfamily in the GSTs superfamily. To verify the expression of Fogst1 and Fogst2, the recombinant prokaryotic expression vector pET28a-Fogst1 and pET28a-Fogst2 were constructed and transformed into Escherichia coli expression strain BL21(DE3). The soluble recombinant proteins Fogst1 and Fogst2 were obtained after being induced by IPTG. GSTs activity assays showed that both of the two recombinant proteins had specific activity with CDNB. For real time RT- PCR analysis, the mycelium samples of Foc4 were collected after treatment by H2O2 for 1, 5, 12, 24 hours. The results showed that the expression of Fogst1 and Fogst2 were significantly up-regulated in the first 5 hours, and then decreased and returned to normal level. These results suggested that Fogst1 and Fogst2 may be involved in the process of Foc4 resistance to exogenous oxidative stress. PMID- 28895362 TI - [CD133 epitope vaccine with gp96 as adjuvant elicits an antitumor T cell response against leukemia]. AB - Cancer stem cells are currently under intensive investigation due to their capabilities for tumor initiation, self-renewal, and resistance to chemotherapy. CD133 is implicated in stemness and the malignancy of tumor cells. Here, we explored heat shock protein gp96 adjuvanted CD133 epitope vaccine against leukemia. We screened and identified three H2-Kd-restricted cytotoxic T lymphocyte (CTL) epitopes derived from CD133, CD133419-428, CD133702-710 and CD133760-769. The immunogenicity and antitumor activity of the epitope vaccine using heat shock protein gp96 as adjuvant were further determined in CD133+ leukemia xenograft mice. Finally, we demonstrate that adoptive transfer of epitope-specific CTLs led to suppression of leukemia growth. Our data therefore provide the basis for designing a CD133 epitope vaccine to activate specific CTLs against CD133+ leukemia and other cancers. PMID- 28895363 TI - [Characterization of N-glycosylation in an anti-EGFR monoclonal antibody produced by different expression systems]. AB - The use of mammalian expression systems results in a remarkable heterogeneity of mAb products, generally due to post-translational modifications, and glycosylation is a critical post-translation modification because it has a profound impact on the safety and efficacy of mAbs. The present study was designed to explore the impact of a different expression system on mAb N glycosylation. The detailed structures of individual glycans between anti-EGFR monoclonal antibodies produced by different expression systems were successfully characterized at the level of free oligosaccharides using liquid chromatography electrospray ionization quadrupole time-of-fight mass spectrometry (LC-ESI-QTof MS). An alternating low and elevated collision energy scan, in source collision induced dissociation and MS/MS in combination with exoglycosidase digestion method was also adopted. The combined data revealed that the Fab region of anti EGFR antibody produced by CHO cell expression system had a pattern of glycosylation differing from that of the SP2/0 cell expression system whereas the Fc region remained basically unchanged. We confirmed that anti-EGFR antibody produced by SP2/0 cell expression system had a much more diverse mixture of glycans with alpha-Gal and an undesired, aberrant form of sialylation N glycolylneuraminic acid (NGNA). The alpha-Gal was absent in mAb produced by CHO cell expression system containing sialic acid predominantly N-acetyl neuraminic acid (NANA) which is the desired, normal human-type sialylation. This study theoretically predicts that anti-EGFR antibody produced by CHO cell expression system may show better clinical tolerance, and very low potential for active hypersensitivity reactions, CHO cell lines can be the preferred expression system for producing anti-EGFR biobetter. PMID- 28895364 TI - [Development of tumor targeting PHBHHx nanoparticles by PhaP mediated immobilization of EGFR-targeting peptide]. AB - PHA granule binding protein phasin (PhaP) has a high affinity for hydrophobic materials and can bind to hydrophobic polymers via strong hydrophobic interaction. In this study, an EGFR-targeting peptide (ETP) was fused with PhaP and the fusion protein ETP-PhaP was produced in recombinant Escherichia coli BL21 (DE3) (pPI-ETP-P) and then purified by Ni affinity purification. The tumor targeting PHBHHx nanoparticles were developed based on PhaP mediated ETP immobilization and the cellular uptake of the ETP-PhaP modified PHBHHx NPs and none modified PHBHHx NPs by cervical cancer cell lines SiHa (EGFR over expressed) and CaSKi (EGFR low expressed) were analyzed. The purified ETP-PhaP could be adsorbed onto the hydrophobic surface of PHBHHx NPs. The ETP-PhaP modified PHBHHx NPs could target to EGFR over expressed cervical cancer cells SiHa more efficiently than to the EGFR low expressed CaSKi cells. These results demonstrated the advantage in effectiveness and convenience of PhaP mediated ETP adsorption on PHBHHx nanoparticles, providing a novel strategy for hydrophobic nanocarrier surface modification. PMID- 28895365 TI - [Expression of Leafy Cotyledon 2 from Arabidopsis increased the content of lipid in Chlorella sorokiniana]. AB - The low lipid content is one of the major bottlenecks to realize the industrialization of the algae biodiesel. Improvement of lipid content through global regulation to get high-yield generating algae is a good strategy. Leafy Cotyledon 2 (LEC2) is an important transcription factor for seed maturation and oil accumulation in Arabidopsis. However, there are few reports regarding adoption of LEC2 for lipid accumulation until now. In this study, LEC2 from Arabidopsis was cloned into the plant expression vector pCIMBIA1300 and transformed into C. sorokiniana through particle bombardment. One recombinant was screened by PCR, RT-PCR and Western blot analyses. Compared with the wild type one, the total lipid content in the recombinant increased one fold, which did not show effect on cell growth, indicating that LEC2 can efficiently enhance the lipid accumulation in C. sorokiniana. PMID- 28895366 TI - [Purification, identification and characterization of an anti-microbial hexapeptide from Sus scrofa lysozyme]. AB - Sus scrofa lysozyme (SSL) was digested by different proteases to find peptides with enhanced antibacterial activity against gram-negative bacteria. Hydrolysate with the highest anti-bacterial activity was loaded onto a gel filtration chromatography column followed by a reversed-phase one. The obtained substance was identified by liquid chromatography-mass spectrometry, synthesized to test its antibacterial spectrum and analyzed for bioinformatics. The hydrolysate of trypsin showed the highest antibacterial activity. By purification and identification, the functional peptide with sequence of A-W-V-A-W-K was obtained. The peptide was synthesized and proved to retain partial function of SSL and had activity against gram-negative bacteria. By bioinformatics analysis, the peptide was found to locate in a helix-loop-helix structure, suggesting that the peptide may kill cells by penetrating cell membrane and cause the outflow of cell contents. The discovery of the peptide could lay the foundation for improving the antibacterial activity of SSL. PMID- 28895367 TI - Is the management of complex abdominal aortic aneurysms consistent across the UK? A questionnaire-based survey. AB - BACKGROUND: Our objective was to quantify variability across the UK in the management of a complex abdominal aortic aneurysm (AAA). METHODS: An online survey was emailed to all members of the Vascular Society for Great Britain and Ireland. The survey presented a vignette of a 63-year-old woman with significant respiratory co-morbidity whose computed tomographic (CT) angiogram demonstrated a 54 mm AAA with a short (7 mm) proximal neck but no other adverse morphological features for a standard or complex endovascular aneurysm repair (EVAR). The survey included images and questions related to AAA management as well as surgeon access to operating facilities. 111 responses were received. RESULTS: 47% of participants indicated a preference for continuing surveillance, 29% for fenestrated EVAR and 7% each for no operative intervention and open surgical repair. The remainder indicated various preferences including standard EVAR (3%), standard EVAR with endoanchors (3%), chimney EVAR (2%), EVAS (endovascular aneurysm sealing) (1%) and chimney EVAS (1%). Of the 47% who wanted to continue surveillance, once their threshold was reached, 73% would manage with a fenestrated EVAR, 17% with open repair and the remainder with standard EVAR with endoanchors (2%), EVAS (2%) or chimney EVAS (2%). 49% of participants carried out endovascular procedures in hybrid theatres, 36% in radiology angiosuites and 15% in standard operating theatres. The location had no significant effect on the consultant choice of treatment method. CONCLUSIONS: The study results support anecdotal variation in practice among vascular specialists. This reflects the lack of solid evidence on the optimal management of complex AAA. PMID- 28895368 TI - Gestational lower limb edema and venous reflux in healthy primigravidae. AB - BACKGROUND: Analyze the association of lower limb edema with venous reflux in healthy primigravidae during pregnancy and in the postpartum. METHODS: Cohort with primigravidae evaluated in the three trimesters of pregnancy and postpartum. Edema was assessed by physical examination. Duplex evaluated venous reflux in both limbs. RESULTS: In the first trimester, no woman presented edema or venous reflux. In the second trimester, venous reflux was found in one patient (5%) and edema was found in four women (20%). Venous reflux and edema were not associated (P=1). In the third trimester, two other patients developed venous reflux (15%) and eleven women developed lower limb edema (55%). Venous reflux and edema were also not associated (P=0.21). In the postpartum period, neither venous reflux nor lower limb edema were found. CONCLUSIONS: In healthy primigravidae, lower limb edema was not associated with venous reflux. Both were present in the second and in the third trimesters of pregnancy and resolved spontaneously in the postpartum period. Both are products of the same physiological changes that occur in pregnancy. PMID- 28895370 TI - Eosinophilic esophagitis: current evidence-based diagnosis and treatment in children and adults. AB - Eosinophilic esophagitis (EoE) is a disease caused by an immune response to food antigens in contact with the esophageal mucosa that has arisen as a common disorder in current clinical practice. Its diagnosis is defined by the combination of symptoms of esophageal dysfunction and inflammation of the esophageal mucosa predominantly by eosinophils. Its chronic course and frequent progression to subepithelial fibrosis leading to strictures and narrow esophagus indicate the need for treatment. Information provided by recent clinical trials and systematic reviews allowed for the development of new clinical guidelines, endorsed by several European scientific societies. This review summarizes its most relevant aspects, updates the concept of EoE, reports its epidemiology and risk factors, associated conditions and its natural history in children and adults. Diagnostic criteria of EoE were updated, after the relationships discovered between the disease and gastroesophageal reflux disease. Endoscopy with biopsies remains as the only accurate test for diagnosis and monitoring, which warrants research on minimally invasive methods. Therapeutic options for EoE are analyzed based on best scientific evidence and expert opinion. Drugs with anti-inflammatory efficacy include proton pump inhibitors and topic swallowed steroids. Empiric food elimination diets have been shown to be superior to skin allergy testing food elimination. Since only one or two foods are involved in causing EoE in 90% of patients who respond to diets, novel steep-up schemes on empiric elimination diets warrant further evaluation. Endoscopic dilation should be considered in patients with esophageal narrowing and persistent symptoms unresponsive to diet or drugs-based anti-inflammatory treatments. PMID- 28895369 TI - The role of intravascular ultrasound in lower limb revascularization in patients with peripheral arterial disease. AB - INTRODUCTION: The aim of this review is to explore the safety and effectiveness of intravascular ultrasound (IVUS) during lower limb endovascular interventions in patients with peripheral arterial disease (PAD). EVIDENCE ACQUISITION: A systematic review of the PubMed and Scopus databases was performed according to PRISMA guidelines. Clinical studies evaluating IVUS as an adjunct to angiography during revascularization procedures in patients with PAD were included. EVIDENCE SYNTHESIS: Thirteen studies were identified, with a total number of 2258 patients having had IVUS for PAD intervention. Seven investigated the role of IVUS for angioplasty and stenting, with the majority being retrospective cohorts. Technical success and patency rates ranged from 90-100% and 45-100%, respectively, with a follow-up that ranged from 4.3-63 months. Three of these studies compared IVUS and non-IVUS guided angioplasty and demonstrated a significant difference in the events of amputations or re-interventions in favor of the IVUS group. Furthermore, five studies evaluated IVUS use in true-lumen re entry, with the technical success ranging between 97-100%. In one study, where IVUS was used for atherectomy, the technical success was 100% and the long-term patency was 90% during a 12-month follow-up. Overall, no significant peri/postoperative IVUS related complications were reported, whereas, 2 studies suggested an IVUS-associated increase in procedure costs that ranged from $1080 $1333. CONCLUSIONS: There is limited and heterogeneous evidence regarding the use of IVUS for the management of PAD. Further research is required to elucidate the optimal role of IVUS in PAD as well as the cost effectiveness of this approach for routine use in the management of PAD. PMID- 28895371 TI - Performance of the over-the-scope clip system in the endoscopic closure of iatrogenic gastrointestinal perforations and post-surgical leaks and fistulas. AB - The increased invasiveness of endoscopic procedures and complex surgical interventions has resulted in an increased number of gastrointestinal iatrogenic defects, such as perforations, leak and fistulas. The conventional treatment for these gastrointestinal defects is surgery, with considerable risks especially in emergency situations and in patients with comorbidities. The Ovesco over-the scope clip (OTSC) system (Ovesco Endoscopy AG, Tubingen, Germany) and more recently, the Padlock ClipTM (Aponos Medical, Kingston, NH, USA) have shown promising results in the treatment of gastrointestinal defects. Several case reports and case series have demonstrated the efficacy of the OTSC system for the closure of full-thickness defects. Clinical success is best achieved in patients undergoing closure of a perforation or a leak. Closure of fistulas remains a clinical challenge since fibrosis or necrotic and inflamed tissue surrounding lesions may cause clip failure. Over-the-scope clips are a less invasive endoscopic option for managing patients with gastrointestinal defects before a more invasive surgical approach is attempted. Moreover, a failed attempt of OTSC deployment does not preclude subsequent surgical treatment. PMID- 28895372 TI - "Tipping" extracellular matrix remodeling towards regression of liver fibrosis: novel concepts. AB - Fibrosis development was initially conceived as an incessant progressive condition. Nowadays, it has become evident that fibrotic tissue undergoes a continuous two-way process: fibrogenesis and fibrinolysis, characterizing the remodeling of extracellular matrix (ECM). However, in established fibrosis, this two-way process is tipped towards fibrogenesis and this leads to a self perpetuating accumulation of ECM, a distinct metabolic unit, together with other cells and processes promoting fibrosis deposition. Several mechanisms promote fibrosis regression, such as degradation of ECM, infiltration of restorative macrophages, prevention of the epithelial-mesenchymal transition of hepatocytes, restoration of the liver sinusoidal endothelial cells' differentiation phenotype, and reversion to quiescence, apoptosis and senescence of hepatic stellate cells (HSC). Hence, fibrosis is the result of an unbalanced two-way process of matrix remodeling. At the late stage of the disease, antifibrotic interventions could become necessary to reverse self-perpetuating fibrogenesis and accelerate regression of fibrosis even if cause and cofactors of hepatic injury have been eliminated. This review outlines some of the important mechanisms leading towards regression of liver fibrosis. PMID- 28895373 TI - Nodular morphea in a patient with Steinert disease. PMID- 28895374 TI - Can environmental factors contribute in triggering vitiligo and associated autoimmune thyroid diseases? Possible connection to the Chernobyl nuclear accident. PMID- 28895375 TI - Knowledge, attitudes, and sun-safety practices among agricultural workers in the Autonomous Province of Trento, North-Eastern Italy (2016). AB - BACKGROUND: The purpose of this study was to determine evaluate sun safety knowledge, attitudes and practices (KAP) among agricultural workers (AWs) in the Autonomous Province of Trento (North-Eastern Italy). METHODS: A cross sectional study was performed among AWs who attended pesticide training courses (2016). Participants received a structured questionnaire focusing on KAP towards sun protective behaviours. Synthetic scores for knowledge (GKS), risk perception (RPS), behavioural adaptation and use of personal protective equipment (SPPS) were calculated. Regression analysis was modelled in order to assess GKS, RPS and individual factors as predictors of SPPS. RESULTS: The sample included 204 AWs (89.7% males, 10.3% females, mean age 43.9 +/- 15.9 years). Sun protective behaviours were irregularly referred by participants, in particular receiving medical skin assessment by a dermatologist (33.8%), avoiding sun radiations at noon and taking rest breaks in shady areas (30.9%), and wearing sunscreen (13.3%). GKS was correlated with RPS, and RPS was characterized as a significant predictor of SPPS (B = .307; 95%CI .224 - .389, P < .001), alongside increased seniority (B = 4.957: 95%CI 3.064 - 6.851, P < 0.001) and previous history of sunburns (B = 5.829; 95%CI 1.520 - 10.139, P = .008). CONCLUSIONS: Our findings indicate that AWs are not appropriately aware of the risks associated with occupational exposure to solar radiation, and eventually report inadequate skin cancer prevention practices. Since SPPS found significant predictors in individual factors, tailored interventions and training may contribute to fill knowledge gaps and raise the concerns of AWs towards occupational dermatological disorders. PMID- 28895376 TI - Erosive pustular dermatosis of the scalp induced by ingenol mebutate. PMID- 28895377 TI - Herpes infection: from skin to panniculitis involvement. PMID- 28895378 TI - Complete regression of keratoacanthoma with topical tazarotene gel 0.1%: therapeutic and pathophysiological perspectives. PMID- 28895379 TI - The analgesic potency dose of remifentanil to minimize stress response induced by intubation and measurement uncertainty of Surgical Pleth Index. AB - BACKGROUND: The aim of this study was to evaluate the analgesic potency dose of remifentanil to maintain Surgical Pleth Index (SPI) values at less than 50 after intubation in patients undergoing general anesthesia with target-controlled infusion of propofol and remifentanil. METHODS: We randomly allocated 120 patients to receive one of three remifentanil target effect-site concentrations (5, 7, or 9 ng*mL-1) during intubation. The target effect-site concentrations of propofol were adjusted within a range of 2.5-3 MUg*mL-1 to maintain bispectral index values at less than 60 during anesthesia induction. A reusable SPI sensor was placed on the index finger of the arm, and the SPI values were continuously recorded. The predicted probability for maintaining the SPI values at less than 50 after intubation against the cumulative amount of remifentanil was analyzed using logistic regression. The measurands were the baseline SPI value in patients without pain scheduled for surgery, and the maximal SPI value after intubation in patients receiving remifentanil with a target effect-site concentration of 7 ng*mL-1. RESULTS: The estimated cumulative amount of remifentanil associated with a 50% and 95% probability of maintaining the SPI values at less than 50 after intubation were 135.0 ug and 330.4 ug, respectively. The estimated expanded uncertainty for the baseline and maximal SPI values after intubation in patients scheduled for surgery were 54.9+/-44.4 and 54.1+/-37.9, respectively, which corresponded to a confidence level of approximately 95%. CONCLUSIONS: The analgesic potency dose of remifentanil to maintain SPI values at less than 50 after intubation was 135.0 ug. PMID- 28895380 TI - How to optimize the lung donor. AB - Over the last two decades, lung transplantation emerged as the standard of care for patients with advanced and terminal lung disease. Despite the increment in lung transplantation rates, in 2016 the overall mortality while on waiting list in Italy reached 10%, whereas only 39% of the wait-list patients were successfully transplanted. A number of approaches, including protective ventilatory strategy, accurate management of fluid balance, and administration of a hormonal resuscitation therapy, have been reported to improve lung donor performance before organ retrieval. These approaches, in conjunction with the use of ex-vivo lung perfusion technique contributed to expand the lung donor pool, without affecting the harvest of other organs and the outcomes of lung recipients. However, the efficacy of issues related to the ex-vivo lung perfusion technique, such as the optimal ventilation strategy, the ischemia-reperfusion induced lung injury management, the prophylaxis of germs transmission from donor to recipient and the application of targeted pharmacologic therapies to treat specific donor lung injuries are still to be explored. The main objective of the present review is to summarize the "state-of-art" strategies to optimize the donor lungs and to present the actual role of ex-vivo lung perfusion in the process of lung transplant. Moreover, different approaches about the technique reported in literature and several issues that are under investigation to treat specific donor lung injury will be discussed. PMID- 28895381 TI - Penicillin G susceptibility in Staphylococcus aureus is not so infrequent. PMID- 28895382 TI - Widespread upper extremity pain and weakness as main symptom for Mycoplasma pneumoniae infection. PMID- 28895383 TI - Robotic-assisted thoracoscopic lung surgery: anesthetic impact and perioperative experience. AB - Anesthesiologists and the perioperative team have a tremendous impact upon clinical outcomes in robotic-assisted thoracoscopic surgery. As anesthesiology is developing its role outside the operating room, the patient population benefits from an expanded focus on perioperative critical care and pain management. This article focuses upon the preoperative optimization, unique intraoperative considerations for surgeons and anesthesiologists, and postoperative management of patients undergoing robotic-assisted thoracoscopic surgery. PMID- 28895384 TI - Securing the airway in patients with cervical spine injury: the pursuit of the ideal airway gadget. PMID- 28895385 TI - Personalized intraoperative positive end-expiratory pressure: a further step in protective ventilation. PMID- 28895386 TI - The totaltrack VLM: a novel video-assisted intubating laryngeal mask. PMID- 28895387 TI - Chaenomeles - health promoting benefits AB - Chaenomeles is a genus of deciduous spiny in the family of Rosaceae (Pomoideae subfamily). For centuries, the plant was used for a treatment of anemia, rheumatism, gout and cardiovascular diseases. The chemical composition studies of Chaenomeles showed the presence of many biologically active compounds, such as: phenolic compounds, organic acids, terpenoids, alcohols, ketones or aldehydes. Fruit of Chaenomeles has the largest applying potential due to extensive use of medicinal and high concentration of vitamin C. Recent in vivo and in vitro studies suggest that Chaenomeles fruit can help in the healing process of diabetes, tumor, allergies and liver diseases. Futhermore the plant has many positive qualities, like: hepatoprotective effect, anti-inflammatory properties, antioxidant action, antimicrobial and neuroprotective effect. Chaenomeles fruit may promote the growth of beneficial intestinal microflora and contribute to the regulation of body weight. The aim of this review was to summarize the information and data on the chemical composition and therapeutic properties of Chaenomeles. PMID- 28895388 TI - Probiotic strains as the element of nutritional profile in physical activity - new trend or better sports results? AB - A diet, individually customized to the needs of sportsmen and sportswomen prepares them better for competition and achievement of better sports results. However, disorders of the gastrointestinal tract and frequently recurrent upper respiratory tract infections pose a common problem observed among athletes of disciplines such as triathlon, cycling and marathon. Diarrhea, splashing in the intestines or gastrointestinal bleeding make it difficult to start and win in the race. Recently researchers have paid special attention to the therapeutic effect of probiotic strains on the human body. Various probiotic strains may have a beneficial effect on elimination of disorders mentioned above among athletes of these disciplines. Still, researchers continue looking for answers to the question how a specific probiotic strain is able to reduce the risk of the gastrointestinal tract and the respiratory system disorders appearing during training or competition. Attention is also drawn to the possible impact of probiotics on the physical capacity athletes and their athletic performance. Probiotic strains properly applied may have a positive influence on the athletes' bodies, but still randomized controlled trials are required to prove this thesis. PMID- 28895389 TI - Study of nutritional value of dried tea leaves and infusions of black, green and white teas from Chinese plantations AB - Background: The processing of tea leaves determines the contents of bioactive ingredients, hence it should be expected that each variety of tea, black, red or green, will represent a different package of compounds of physiological importance. Taste and aroma, as well as price and brand are the main factors impacting consumers' preferences with regard to tea of their choice; on the other hand consumers less frequently pay attention to the chemical composition and nutritional value of tea. Objective: The purpose of the study was assessment of the nutritional value of black, green and white high-quality tea leaf from Chinese plantations based on the chemical composition of the dried leaves as well as minerals and caffeine content in tea infusions. Material and methods: The research material included 18 high-quality loose-leaf teas produced at Chinese plantations, imported to Poland, and purchased in an online store. The analyses included examination of the dried tea leaves for their chemical composition (contents of water, protein, volatile substances and ash) and assessment of selected minerals and caffeine contents in the tea infusions. Results: High quality Chinese green teas were found with the most valuable composition of minerals, i.e. the highest contents of Zn, Mn, Mg, K, Ca and Al and the highest contents of protein in comparison to the other products. Chinese black teas had the highest contents of total ash and caffeine and white teas were characterized with high content of volatile substances, similar to the black teas, and the highest content of water and the lowest content of total ash. Conclusions: The three types of tea brews examined in the present study, in particular green tea beverages, significantly enhance the organism's mineral balance by providing valuable elements PMID- 28895390 TI - A universal method for the identification of genes encoding amatoxins and phallotoxins in poisonous mushrooms AB - Background: As the currently known diagnostic DNA targets amplified in the PCR assays for detection of poisonous mushrooms have their counterparts in edible species, there is a need to design PCR primers specific to the genes encoding amanitins and phallotoxins, which occur only in poisonous mushrooms. Objective: The aim of the study was testing of PCR-based method for detection of all genes encoding hepatotoxic cyclic peptides - amanitins and phallotoxins present in the most dangerous poisonous mushrooms. Material and Methods: Degenerate primers in the PCR were designed on the basis of amanitins (n=13) and phallotoxins (n=5) genes in 18 species of poisonous mushrooms deposited to Genbank of the National Center for Biotechnology Information. Results: The specificity of the PCR assays was confirmed against 9 species of edible mushrooms, death cap - Amanita phalloides and panther cap - Amanita pantherina. Conclusions: Designed two couples of PCR-primers specific to amanitins and phallotoxins genes can be recommended for detection of Amanita phalloides and other mushroom species producing hepatotoxic cyclic peptides - amanitins and phallotoxins. PMID- 28895391 TI - Potential Opportunities and Challenges for Research Collaboration with Latin America in Agriculture and Food Science. PMID- 28895392 TI - Theoretical Prediction of Surface Stability and Morphology of LiNiO2 Cathode for Li Ion Batteries. AB - Ni-rich layered oxides are considered to be a promising cathode material with high capacity, and their surface structure should be extensively explored to understand the complex associated phenomena. We investigated the surface stability and morphology of LiNiO2 as a representative of these materials by using density functional theory calculations. The results reveal that the Li exposed surfaces have lower energies than the oxygen surfaces, irrespective of the facets, and the Ni-exposed ones are the least stable. The equilibrium morphology can vary from truncated trigonal bipyramid to truncated egg shape, according to the chemical potential, whose range is confined by the phase diagram. Moreover, the electrochemical window of stable facets is found to strongly depend on the surface elements rather than the facet directions. Contrary to the stable Li surfaces, oxygen exposure on the surface considerably lowers the Fermi level to the level of electrolyte, thereby accelerating oxidative decomposition of the electrolyte on the cathode surface. PMID- 28895393 TI - Synthesis of Sulfur Perfluorophenyl Compounds Using a Pentafluorobenzenesulfonyl Hypervalent Iodonium Ylide. AB - A novel pentafluorobenzenesulfonyl hypervalent iodonium ylide 3 was designed and synthesized as a useful tool for the preparation of sulfur pentafluorophenyl compounds containing a C6F5S or C6F5SO2 unit. Electrophilic pentafluorophenylthiolation of enamines, formal [3+2] cycloaddition reaction of nitriles and alkynes, and intramolecular SNAr cyclization were achieved using iodonium ylide 3. The fluoro-click reaction was also demonstrated using one of the products via an intermolecular SNAr reaction with heterocentered nucleophiles. PMID- 28895394 TI - Antineoplastic Agents. 604. The Path of Quinstatin Derivatives to Antibody Drug Conjugates. AB - To further evaluate the exceptional cancer cell growth inhibition by the quinstatins, of which one of the series, quinstatin 8, approaches the exceptional cytotoxic activity of the parent dolastatin 10 (1), four of the quinstatins have been converted to desmethyl derivatives. Three of the four (4, 5, and 8 [7b-d]) were next bonded to the linker (8) employed in the synthesis of the very successful and structurally related anticancer drug Adcetris (3). Owing to these structural modifications, a next step could be taken by bonding to a monoclonal antibody, thereby producing an antibody drug conjugate (ADC) related to Adcetris structurally but with the possibility of a wider spectrum of activity and utility. PMID- 28895395 TI - Thermoelectric Properties of SnS with Na-Doping. AB - Tin sulfide (SnS), a low-cost compound from the IV-VI semiconductors, has attracted particular attention due to its great potential for large-scale thermoelectric applications. However, pristine SnS shows a low carrier concentration, which leads to a low thermoelectric performance. In this work, sodium is utilized to substitute Sn to increase the hole concentration and consequently improve the thermoelectric power factor. The resultant Hall carrier concentration up to ~1019 cm-3 is the highest concentration reported so far for this compound. This further leads to the highest thermoelectric figure of merit, zT of 0.65, reported so far in polycrystalline SnS. The temperature-dependent Hall mobility shows a transition of carrier-scattering source from a grain boundary potential below 400 K to acoustic phonons at higher temperatures. The electronic transport properties can be well understood by a single parabolic band (SPB) model, enabling a quantitative guidance for maximizing the thermoelectric power factor. Using the experimental lattice thermal conductivity, a maximal zT of 0.8 at 850 K is expected when the carrier concentration is further increased to ~1 * 1020 cm-3, according to the SPB model. This work not only demonstrates SnS as a promising low-cost thermoelectric material but also details the material parameters that fundamentally determine the thermoelectric properties. PMID- 28895396 TI - Hybrid WSe2-In2O3 Phototransistor with Ultrahigh Detectivity by Efficient Suppression of Dark Currents. AB - Photodetectors based on low-dimensional materials have attracted tremendous attention because of their high sensitivity and compatibility with conventional semiconductor technology. However, up until now, developing low-dimensional phototransistors with high responsivity and low dark currents over broad-band spectra still remains a great challenge because of the trade-offs in the potential architectures. In this work, we report a hybrid phototransistor consisting of a single In2O3 nanowire as the channel material and a multilayer WSe2 nanosheet as the decorating sensitizer for photodetection. Our devices show high responsivities of 7.5 * 105 and 3.5 * 104 A W-1 and ultrahigh detectivities of 4.17 * 1017 and 1.95 * 1016 jones at the wavelengths of 637 and 940 nm, respectively. The superior detectivity of the hybrid architecture arises from the extremely low dark currents and the enhanced photogating effect in the depletion regime by the unique design of energy band alignment of the channel and sensitizer materials. Moreover, the visible to near-infrared absorption properties of the multilayer WSe2 nanosheet favor a broad-band spectral response for the devices. Our results pave the way for developing ultrahigh-sensitivity photodetectors based on low-dimensional hybrid architectures. PMID- 28895397 TI - Screen-Printed Polyaniline-Based Electrodes for the Real-Time Monitoring of Loop Mediated Isothermal Amplification Reactions. AB - Nucleic acid amplification testing is a very powerful method to perform efficient and early diagnostics. However, the integration of a DNA amplification reaction with its associated detection in a low-cost, portable, and autonomous device remains challenging. Addressing this challenge, the use of screen-printed electrochemical sensor is reported. To achieve the detection of the DNA amplification reaction, a real-time monitoring of the hydronium ions concentration, a byproduct of this reaction, is performed. Such measurements are done by potentiometry using polyaniline (PAni)-based working electrodes and silver/silver chloride reference electrodes. The developed potentiometric sensor is shown to enable the real-time monitoring of a loop-mediated isothermal amplification (LAMP) reaction with an initial number of DNA strands as low as 10 copies. In addition, the performance of this PAni-based sensor is compared to fluorescence measurements, and it is shown that similar results are obtained for both methods. PMID- 28895398 TI - Nearly Blinking-Free, High-Purity Single-Photon Emission by Colloidal InP/ZnSe Quantum Dots. AB - Colloidal core/shell InP/ZnSe quantum dots (QDs), recently produced using an improved synthesis method, have a great potential in life-science applications as well as in integrated quantum photonics and quantum information processing as single-photon emitters. Single-particle spectroscopy of 10 nm QDs with 3.2 nm cores reveals strong photon antibunching attributed to fast (70 ps) Auger recombination of multiple excitons. The QDs exhibit very good photostability under strong optical excitation. We demonstrate that the antibunching is preserved when the QDs are excited above the saturation intensity of the fundamental-exciton transition. This result paves the way toward their usage as high-purity on-demand single-photon emitters at room temperature. Unconventionally, despite the strong Auger blockade mechanism, InP/ZnSe QDs also display very little luminescence intermittency ("blinking"), with a simple on/off blinking pattern. The analysis of single-particle luminescence statistics places these InP/ZnSe QDs in the class of nearly blinking-free QDs, with emission stability comparable to state-of-the-art thick-shell and alloyed-interface CdSe/CdS, but with improved single-photon purity. PMID- 28895399 TI - Deep-Eutectic Solvents Derived Nitrogen-Doped Graphitic Carbon as a Superior Electrocatalyst for Oxygen Reduction. AB - The activity and stability of electrocatalyst for oxygen reduction reaction (ORR) essentially depends on its structural and compositional properties. Herein, we report the facile preparation of nitrogen-doped graphitic carbon (NGC) via the pyrolysis of deep-eutectic solvents (DESs) as a superior electrocatalyst for ORR. The resulting NGCs possess high surface areas, rich nitrogen content, and favorable graphitization degree, all of which are highly desired for the ORR catalysts. The effects of the pyrolysis temperature on the ORR performance of the final products are explored. The results implied that the material fabricated at 900 degrees C (NGC900) is identified as the best ORR catalyst in the series of samples. Specifically, NGC900 shows efficient performance toward ORR with an onset potential of 0.97 V and a half potential of 0.84 V, which bears comparison with the commercial Pt/C catalyst with enhanced stability in the alkaline media. The superior ORR performance of NGC900 may be ascribed to the balance between the surface area, pyridinic nitrogen, and defect of NGCs. The rational design of NGCs with an efficient ORR activity and stability based on the low-cost DESs implies adequate support for the development of energy devices in practical application. PMID- 28895400 TI - The Role of Electrode-Catalyst Interactions in Enabling Efficient CO2 Reduction with Mo(bpy)(CO)4 As Revealed by Vibrational Sum-Frequency Generation Spectroscopy. AB - Group 6 metal carbonyl complexes ([M(bpy)(CO)4], M = Cr, Mo, W) are potentially promising CO2 reduction electrocatalysts. However, catalytic activity onsets at prohibitively negative potentials and is highly dependent on the nature of the working electrode. Here we report in situ vibrational SFG (VSFG) measurements of the electrocatalyst [Mo(bpy)(CO)4] at platinum and gold electrodes. The greatly improved onset potential for electrocatalytic CO2 reduction at gold electrodes is due to the formation of the catalytically active species [Mo(bpy)(CO)3]2- via a second pathway at more positive potentials, likely avoiding the need for the generation of [Mo(bpy)(CO)4]2-. VSFG studies demonstrate that the strength of the interaction between initially generated [Mo(bpy)(CO)4]*- and the electrode is critical in enabling the formation of the active catalyst via the low energy pathway. By careful control of electrode material, solvent and electrolyte salt, it should therefore be possible to attain levels of activity with group 6 complexes equivalent to their much more widely studied group 7 analogues. PMID- 28895401 TI - Serum Metabolic Fingerprinting Identified Putatively Annotated Sphinganine Isomer as a Biomarker of Wolfram Syndrome. AB - Wolfram syndrome (WFS) is an example of a rare neurodegenerative disease with coexisting endocrine symptoms including diabetes mellitus as the first clinical symptom. Treatment of WFS is still only symptomatic and associated with poor prognosis. Potential markers of disease progression that could be useful for possible intervention trials are not available. Metabolomics has potential to identify such markers. In the present study, serum fingerprinting by LC-QTOF-MS was performed in patients with WFS (n = 13) and in patients with T1D (n = 27). On the basis of the obtained results, aminoheptadecanediol (17:0 sphinganine isomer) (+50%, p = 0.02), as the most discriminatory metabolite, was selected for validation. The 17:0 sphinganine isomer level was determined using the LC-QQQ method in the samples from WFS patients at two time points and compared with samples obtained from patients with T1D (n = 24) and healthy controls (n = 24). Validation analysis showed higher 17:0 sphinganine isomer level in patients with WFS compared to patients with T1D (p = 0.0097) and control group (p < 0.0001) with progressive reduction of its level after two-year follow-up period. Patients with WFS show a unique serum metabolic fingerprint, differentiating them from patients with T1D. Sphinganine derivate seems to be a marker of the ongoing process of neurodegeneration in WFS patients. PMID- 28895402 TI - Acetate-Induced Disassembly of Spherical Iron Oxide Nanoparticle Clusters into Monodispersed Core-Shell Structures upon Nanoemulsion Fusion. AB - It has been long known that the physical encapsulation of oleic acid-capped iron oxide nanoparticles (OA-IONPs) with the cetyltrimethylammonium (CTA+) surfactant induces the formation of spherical iron oxide nanoparticle clusters (IONPCs). However, the behavior and functional properties of IONPCs in chemical reactions have been largely neglected and are still not well-understood. Herein, we report an unconventional ligand-exchange function of IONPCs activated when dispersed in an ethyl acetate/acetate buffer system. The ligand exchange can successfully transform hydrophobic OA-IONP building blocks of IONPCs into highly hydrophilic, acetate-capped iron oxide nanoparticles (Ac-IONPs). More importantly, we demonstrate that the addition of silica precursors (tetraethyl orthosilicate and 3-aminopropyltriethoxysilane) to the acetate/oleate ligand-exchange reaction of the IONPs induces the disassembly of the IONPCs into monodispersed iron oxide acetate-silica core-shell-shell (IONPs@acetate@SiO2) nanoparticles. Our observations evidence that the formation of IONPs@acetate@SiO2 nanoparticles is initiated by a unique micellar fusion mechanism between the Pickering-type emulsions of IONPCs and nanoemulsions of silica precursors formed under ethyl acetate buffered conditions. A dynamic rearrangement of the CTA+-oleate bilayer on the IONPC surfaces is proposed to be responsible for the templating process of the silica shells around the individual IONPs. In comparison to previously reported methods in the literature, our work provides a much more detailed experimental evidence of the silica-coating mechanism in a nanoemulsion system. Overall, ethyl acetate is proven to be a very efficient agent for an effortless preparation of monodispersed IONPs@acetate@SiO2 and hydrophilic Ac-IONPs from IONPCs. PMID- 28895404 TI - Exosomes of human mesenchymal stem/stromal/medicinal signaling cells. AB - In this review, we intend to explore the potential therapeutic effects of exosomes released from mesenchymal stem/stromal cells (MSCs). MSCs gained credibility as a therapeutic tool due to their potential to differentiate into many cell types like osteoblasts, chondrocytes, adipocytes, muscular, endothelial, cardiovascular, and neurogenic cells. They possess potent wound healing activity due to their immunosuppressive and anti-inflammatory properties. MSCs are tested in large number of clinical trials for treatment of diseases, which do not have adequate therapy at present. MSCs engineered to express suicide genes in preclinical studies have shown promising tumor targeting therapeutic tool for malignancies difficulty treatable at present. It has been increasingly observed in many different kinds of regenerative medicine and in MSCs mediated prodrug gene therapy for cancer that the intravenously administered of MSCs did not necessarily engraft at the site of injury or tumor. The therapeutic effect was exerted mainly through a paracrine action of rich secretome released from the cells. The main biocomponent of secretome are exosomes - naturally occurring membrane nanoparticles of 30-120 nm in diameter that mediate intercellular communication by delivering biomolecules like mRNA, miRNA into recipient cells. These nanosized exosomes derived from MSCs promise to be a new and valuable therapeutic strategy in regenerative medicine and cancer therapy compared with transplanted exogenous MSCs. Advantage of nanosized exosomes compared with administration of exogenous MSCs is multiple. Exosomes are easier to preserve and be transferred, have lower immunogenicity and therefore are safer for therapeutic administration. PMID- 28895405 TI - Screening key miRNAs for human hepatocellular carcinoma based on miRNA-mRNA functional synergistic network. AB - The safety of miRNAs has been proven and the prophylactic use of miRNA-based approaches may be foreseen for patients with hepatocellular carcinoma (HCC). However, the underlying regulatory mechanism of miRNAs in HCC has not been fully clarified. Using bioinformatic analyses, we compared data of miRNA and mRNA expression profiling of HCC from Gene Expression Omnibus (GEO) database, respectively. Differentially expressed miRNAs and differentially expressed genes (DEGs) were identified. Based on the miRTarBase predictions, the miRNA-dependent regulatory network was constructed. In total, comparative analysis of five mRNA datasets and two miRNA datasets led to 1449 DEGs and 17 differentially expressed miRNAs, respectively. Based on the predictions, a global miRNA-mRNA regulatory network was then constructed, which encompassed 451 miRNA target gene pairs whose expressions were inversely correlated. Three miRNAs (miR-641, miR-507 and miR-501 5p) were the most connected miRNAs that regulated a large number of genes, among which miR-641 and miR-507 were novel miRNAs altered in HCC. We suggested that miR 501-5p will represent a powerful therapeutic target for HCC. Moreover, four up regulated miRNAs (miR-769-3p, miR-941, miR-362-3p and miR-16-1) and one down regulated miRNA (miR-581) may be involved in HCC. Additionally, two targets of MAPK8 and SRPK2 were also detected in this study, whose roles in HCC will be notable. In conclusion, we developed an integrative approach to construct an interactive global network of miRNA-mRNA, which can contribute to refine miRNA target predictions for developing new therapeutic approaches. PMID- 28895403 TI - Injectable Carbon Nanotube-Functionalized Reverse Thermal Gel Promotes Cardiomyocytes Survival and Maturation. AB - The ability of the adult heart to regenerate cardiomyocytes (CMs) lost after injury is limited, generating interest in developing efficient cell-based transplantation therapies. Rigid carbon nanotubes (CNTs) scaffolds have been used to improve CMs viability, proliferation, and maturation, but they require undesirable invasive surgeries for implantation. To overcome this limitation, we developed an injectable reverse thermal gel (RTG) functionalized with CNTs (RTG CNT) that transitions from a solution at room temperature to a three-dimensional (3D) gel-based matrix shortly after reaching body temperature. Here we show experimental evidence that this 3D RTG-CNT system supports long-term CMs survival, promotes CMs alignment and proliferation, and improves CMs function when compared with traditional two-dimensional gelatin controls and 3D plain RTG system without CNTs. Therefore, our injectable RTG-CNT system could potentially be used as a minimally invasive tool for cardiac tissue engineering efforts. PMID- 28895406 TI - Identification of potential key genes associated with diffuse large B-cell lymphoma based on microarray gene expression profiling. AB - The study aimed to screen potential key genes, and their targeted miRNAs and transcription factors (TFs) that were related to diffuse large B-cell lymphoma (DLBCL), and explore potential therapeutic targets for the progression of DLBCL. Dataset GSE56315 extracted from human tonsils was downloaded from Gene Expression Omnibus. Limma package was used to identify differential expression genes (DEG) between DLBCL and normal human tonsils samples, and the function and pathway enrichment analyses were performed. Then, functional interaction (FI) networks analyses of DEGs were implemented, and modules were extracted. Additionally, DLBCL-related miRNAs were predicted based on miR2disease database. Thereafter, TF target DEGs and miRNAs targeted genes were respectively obtained. Finally, the integrated network of TF-target-miRNA was constructed. A total of 4,495 DEGs were identified between DLBCL and NHT samples. Among them, 114 up-regulated DEGs were contained in 8 modules of FI network, while 189 down-regulated DEGs were contained in 12 sub-modules. In addition, most DEGs were enriched in the function of "DNA binding" and pathways of "chemokine signaling pathway", "phosphatidylinositol signaling system" and "RNA degradation". Moreover, 19 miRNAs related with DLBCL were downloaded from Mirwalk2. Furthermore, miRNAs of miR-21-5p, miR-155 and miR-17-5p, the TF of STAT1, and DEGs such as NUF2, CCR1, PIK3R1, SMC1A, FOXK1 and CNOT6L had high degrees in the integrated networks of TF target-miRNA. DEGs like NUF2, CCR1, PIK3R1, SMC1A, FOXK1 and CNOT6L might be closely associated with the pathogenesis of DLBCL. PMID- 28895407 TI - Cordycepin inhibits cell growth and induces apoptosis in human cholangiocarcinoma. AB - The purpose of this study was to explore the role of cordycepin in human cholangiocarcinoma (CCA) cell growth and apoptosis. In the present study, colony formation assay, cell-counting kit-8 (CCK-8) assay and tumor xenograft experiment were performed to evaluate the effect of cordycepin on human CCA cell growth in vitro and in vivo; flow cytometric analysis was performed to evaluate the effect of cordycepin on cell apoptosis; quantitative real-time reverse transcription PCR (qRT-PCR) and western blot assays were performed to evaluate the expression levels of Caspase-3, Bcl-2 and Bax. The results showed that cordycepin inhibited cell growth in QBC939 and RBE cells in vitro and it could also inhibit QBC939 cells growth in vivo. Furthermore, the flow cytometric analysis, qRT-PCR and western blot assays showed that cordycepin could trigger QBC939 and RBE cells apoptosis by regulating the expression levels of Caspase-3, Bcl-2 and Bax. And we proposed that cordycepin could inhibit human CCA cell growth in vitro and in vivo, while, this function is related to the induction of cell apoptosis. PMID- 28895408 TI - Sympathetic and parasympathetic innervation in hepatocellular carcinoma. AB - Autonomic nervous system plays an important role in the development of multiple cancers via regulating cancer cell proliferation, differentiation, apoptosis, migration and invasion. However, no detailed studies have been performed to study the role of autonomic nerve fibers in hepatocellular carcinoma (HCC) as well as its correlation with the progression of HCC. Here, we examined the distribution of the autonomic nerve fibers and analyzed the correlation between autonomic nerve fibers and the pathological characteristics of HCC patients. The transcriptional expression of adrenergic and cholinergic receptors was evaluated in both hepatoma cell lines and primary hepatoma cells. In addition, we summarized the function of receptors for neurotransmitters in different cancers recently reported. Our findings indicate that tissue of liver cancer is innervated by both sympathetic and parasympathetic nerves and the density of the nerve fibers is associated with patients' poor prognosis. Additionally, we report that adrenergic receptors beta2 and cholinergic receptors alpha7, M1 and M3 are high expressed in both hepatoma cell lines and primary hepatoma cells, indicating these receptors may play essential roles in the regulation of autonomic nervous system triggered HCC. PMID- 28895409 TI - Long noncoding RNA ASAP1-IT1 promotes cancer stemness and predicts a poor prognosis in patients with bladder cancer. AB - Urinary bladder cancer (UBC) is one of the most common urogenital malignancies. Cancer stem-like cells (CSCs) play a vital role in tumor development and recurrence. Long noncoding RNAs (lncRNAs) are reported to influence cancer progression via transcriptional, posttranscriptional or epigenetic regulation. Dysregulation of several lncRNAs has been implicated in UBC. In our study, we found that an uncharacterized lncRNA, ASAP1-IT1, was overexpressed in UBC tissues compared with adjacent non-malignant tissues. High ASAP1-IT1 expression levels in UBC specimens were correlated with advanced tumor stage, higher clinical stage, poor pathological differentiation and bad overall survival. We further found that depletion of ASAP1-IT1 in T24 cells by RNA interference reduced the stemness of bladder cancer, whereas forced overexpression of ASAP1-IT1 in J82 cells enhanced cancer cell stemness by sphere assay, ALDEFLUOR and flow cytometry assay on CD44+ population. Our data suggest that ASAP1-IT1 plays an oncogenic role in bladder cancer and can be used as a potential prognostic and therapeutic target. PMID- 28895410 TI - Chromatographic analyses of Lavandula angustifolia and Rosmarinus officinalis extracts and their biological effects in mammalian cells and cell-free systems. AB - Knowledge of biological properties of natural compounds allows to understand their therapeutic value, efficacy and security. We investigated: composition of Lavandula angustifolia (LA) and Rosmarinus officinalis (RO) extracts, their antioxidant capacity, cytotoxicity and genotoxicity, their DNA-protective potential against DNA damage induced in hamster V79 cells by several genotoxins or in plasmid DNA by Fe2+ ions and activity of antioxidant enzymes in cells treated with these extracts. Higher cytotoxicity, observed at higher concentrations of extracts, was accompanied by the increased level of single strand (ss) DNA breaks as well as formamidopyrimidine DNA glycosylase (Fpg) sensitive sites. LA and RO extracts were able to protect DNA of hamster cells as well as plasmid DNA against ss DNA breaks induced by genotoxins and Fe2+. LA extract mildly increased the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), while RO extract decreased the activity of SOD, but increased the activity of CAT and GPx. Cell-free tests confirmed antioxidant activity of both extracts. The biological properties of LA and RO extracts showed that they could have a positive impact on human health. PMID- 28895411 TI - Knockdown of human serine/threonine kinase 33 suppresses human small cell lung carcinoma by blocking RPS6/BAD signaling transduction. AB - Small cell lung cancer (SCLC) is characterized by rapid growth rate and a tendency to metastasize to distinct sites of patients' bodies. The human serine/threonine kinase 33 (STK33) gene has shown its potency as a therapeutic target for prevention of lung carcinomas including non-small cell lung cancer (NSCLC), but its function in the oncogenesis and development of SCLC remains unrevealed. In the current study, it was hypothesized that STK33 played a key role in the proliferation, survival, and invasion of SCLC cells. The expression of STK33 in human SCLC cell lines NCI-H466 and DMS153 was inhibited by specific shRNA. The cell proliferation, cell apoptosis, and cell invasion of the cells were assessed with a series of in vitro assays. To explore the mechanism through which STK33 gene exerted its function in the carcinogenesis of SCLC cells, the effect of STK33 knockdown on the activity of S6K1/RPS6/BAD signaling was detected. Then the results were further confirmed with STK33 inhibitor ML281 and in vivo assays. The results demonstrated that inhibition of STK33 in SCLC cells suppressed the cell proliferation and invasion while induced cell apoptosis. Associated with the change in the phenotypic features, knockdown of STK33 also decreased the phosphorylation of RPS6 and BAD while increased the expression of cleaved caspase 9, indicating that apoptosis induced by STK33 suppression was mediated via mitochondrial pathway. Similar to the results of STK33 knockdown, incubating NCI-H466 cells with STK33 inhibitor also reduced the cell viability by suppressing RPS6/BAD pathways. Additionally, STK33 knockdown also inhibited tumor growth and RPS6/BAD activity in mice models. Findings outlined in our study were different from that in NSCLC to some extent: knockdown of STK33 in SCLC cells induced the apoptosis through mitochondrial pathway but independent of S6K1 function, inferring that the function of STK33 might be cancer type specific. PMID- 28895412 TI - Predictive values of FAP and HGF for tumor angiogenesis and metastasis in colorectal cancer. AB - This study aims to explore the correlation of hepatocyte growth factor (HGF) and fibroblast activation protein (FAP) expressions with the angiogenesis and metastasis in colorectal cancer (CRC). The immunohistochemical SABC method was used to detect HGF and FAP expressions in 127 CRC tissues, 51 colorectal polyp tissues and 28 normal tissues. HGF and FAP expressions in liver metastasis were detected using western blot to analyze the correlation of their expressions with lymph node metastasis and liver metastasis. Micro-vessel density (MVD) and clinic pathologic information of CRC patients were recorded and analyzed. In CRC group, HGF and FAP expressions were greatly higher than those in normal group and colorectal polyps group (P < 0.05). Moreover, the positive rates of HGF and FAP expressions in lymph node metastasis were evidently higher than those in non lymph node metastasis (P < 0.05). In liver metastasis group, HGF and FAP expressions were obviously higher than non-liver metastasis group (P < 0.05). CRC group had much more MVD in comparison with normal group and colorectal polyps group (P < 0.05).When compared with negative group, MVD was significantly higher than that in CRC tissue with positive HGF and FAP (P < 0.05). Spearman rank correlation analysis showed that HGF and FAP were in positive correlation with MVD (r = 0.542, P < 0.001; r = 0.753, P < 0.001). These results indicate that FAP and HGF play an important role in CRC angiogenesis, and their expression levels are valuable to predict CRC liver metastasis and lymph node metastasis. PMID- 28895413 TI - The E3 ubiquitin ligase Cbl-b inhibits tumor growth in multidrug-resistant gastric and breast cancer cells. AB - Most receptor tyrosine kinases (RTKs) contribute to tumor growth, and their ubiquitination and degradation is related to the inhibition of tumor growth. Our previous study showed that the ubiquitin ligase Cbl-b was expressed at low levels in multidrug-resistant (MDR) gastric cancer cells compared with their parental cells. However, whether enhancement of Cbl-b expression in MDR cancer cells could prevent tumor proliferation via ubiquitination and degradation of RTK remains unclear. In the present study, Cbl-b overexpression reduced cell proliferation in MDR gastric and breast cancer cells, and effectively inhibited tumor growth in vivo. Additionally, Cbl-b overexpression reduced the total protein level of insulin-like growth factor 1 (IGF-1R), an important member of the RTK family. Moreover, Cbl-b overexpression promoted interaction of Cbl-b with IGF-1R, and induced ubiquitination and degradation of IGF-1R and inactivation of the IGF-1R pathway. These results suggest that the ubiquitin ligase Cbl-b inhibited tumor growth via ubiquitination and degradation of IGF-1R in MDR gastric and breast cancer cells. PMID- 28895414 TI - Knockdown of Tripartite Motif Containing 28 suppresses the migration, invasion and epithelial-mesenchymal transition in ovarian carcinoma cells through down regulation of Wnt/beta-catenin signaling pathway. AB - Tripartite motif containing 28 (TRIM28) is a transcriptional corepressor of Kruppel-associated box zinc finger protein, which has been reported to participate in carcinogenesis. Nonetheless, whether TRIM28 plays a role in the metastasis of ovarian carcinoma (OC) is unclear and requires further investigation. In this study, two OC cell lines (A2780 and OVCAR-3) with stable low expression of TRIM28 were established via RNA interference. We found that the migratory and invasive ability of TRIM28-silenced OC cells significantly decreased. The expression and activity of matrix metallopeptidase (MMP)-2 and MMP 9 in these OC cells were inhibited. The TRIM28 shRNA also suppressed the epithelial-mesenchymal transition (EMT) of OC cells as evidenced by the up regulated E-cadherin and the downregulated Vimentin and N-cadherin. Additionally, the Wnt/beta-catenin signaling pathway was suppressed in TRIM28-silenced OC cells: the activity of beta-catenin was inhibited, the expression of total and nuclear beta-catenin, Axin 2, T-cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1) were decreased, whereas the phosphorylation of beta catenin at Ser33/37 was enhanced. Further, re-expression of active beta-catenin in TRIM28-silenced OC cells partly restored their metastasis in vitro. Taken together, our study demonstrates a contributory role of TRIM28 in OC metastasis in vitro, suggesting TRIM28 as a novel therapeutic target for this malignant tumor. PMID- 28895415 TI - Hyaluronic acid/ Hyaluronidase as biomarkers for bladder cancer: a diagnostic meta-analysis. AB - This study aimed to determine the value of HA/HAase for detecting bladder cancer on the basis of preceding statistical performance. PubMed, Springer Link, Web of Science and Cochrane Library were systematically searched to identify potentially relevant published articles by using the key words: "bladder cancer or bladder tumor or bladder carcinoma", "hyaluronic acid or hyaluronan", "hyaluronidase or HAase". The methodological quality of each study was assessed by QUADAS-2. According to the inclusive and exclusive criteria, 8 articles were identified and methodologically analyzed by STATA 12.0 software package.The results showed that the pooled sensitivity of HA and HAase was 0.832 (95% confidence interval [CI]: 0.798, 0.861) and 0.834 (95% CI: 0.756, 0.891) respectively, the pooled specificity was 0.886 (95% CI: 0.852, 0.913) and 0.860 (95% CI: 0.801, 0.904), and the area under the summary ROC cure (AUC) was 0.90 (95% CI: 0.87, 0.92) and 0.91 (95% CI: 0.88, 0.93), respectively. Simultaneously the diagnostic accuracy of the combination of HA and HAase showed that the pooled sensitivity was 0.908 (95% CI: 0.879, 0.931), the pooled specificity was 0.825 (95% CI: 0.789, 0.856) and AUC was 0.94 (95% CI: 0.91, 0.95), indicating a relatively higher accuracy than HA and HAase alone. This meta-analysis strongly suggests that HA/HAase could be used as biomarkers for the diagnosis of bladder cancer. PMID- 28895416 TI - Prospective study on diagnostic and prognostic significance of postoperative FDG PET/CT in recurrent colorectal carcinoma patients: comparison with MRI and tumor markers. AB - Current guidelines for follow-up after resection of colorectal cancer (CRC) recommend regular measurements of carcinoembryogenic antigen (CEA) and imaging tests. Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) are currently primary imaging modalities, while the role of fluorine-18 fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), which is recommended in patients with negative MDCT and increased CEA, is still uncertain. Our aim was to compare diagnostic performance and prognostic significance of 18F-FDG PET/CT with MRI and tumor markers CEA and carbohydrate antigen 19-9 (CA 19-9) in detection of recurrent CRC. This prospective study included 35 patients with resected CRC, referred to 18F-FDG PET/CT examination for suspected recurrence. During median follow-up of 24.4+/-1.5 months 18F-FDG PET/CT and MRI results and tumor marker levels were compared with findings of histopathological examination or with results of clinical and imaging follow-up. Management plan before the 18F-FDG PET/CT scan was considered and compared to the final treatment decision. The sensitivity, specificity, positive and negative predictive value and accuracy of 18F-FDG PET/CT and MRI in detection of recurrent colorectal cancer in patient-based analysis were 92.6%, 75%, 92.6%, 75% and 88.6%, and 65.4%, 66.7%, 85%, 40% and 65.7%, respectively. In lesion-based analysis the sensitivity of 18F-FDG PET/CT and MRI was 83.1% and 68.2%, respectively. The overall accuracy of CEA and CA 19-9 in recurrence detection was 48.6% and 54.3%, respectively. PET/CT induced therapy alterations in 13/35 (37.1%) patients. Progression was observed in 16/35 patients during follow-up, with significantly lower risk of progression in patients with treatment changes based on PET findings (Multivariate Cox regression; p=0.017). In addition, elevated CA 19-9 levels in time of PET scan and male gender carried significantly higher risk of progression (p=0.007 and p=0.016, respectively). Kaplan-Meier Log rank test showed significantly longer progression-free survival time in patients who had treatment plan changed based on PET/CT (p=0.046). We can conclude that 18F-FDG PET/CT showed better sensitivity and accuracy compared to MRI in detection of recurrent colorectal cancer, with much better sensitivity compared to CEA and CA 19-9. Patients with treatment changes based on 18F-FDG PET/CT had significantly better prognosis and longer progression-free survival, while elevated values of CA 19-9 and male gender were associated with worse prognosis. PMID- 28895417 TI - The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy. AB - Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting. PMID- 28895418 TI - Expression of thymidylate synthase (TS) and its prognostic significance in patients with cutaneous angiosarcoma. AB - : Cutaneous angiosarcoma (CA) is extremely rare, and little is known about the biological significance of possible biomarkers for chemotherapeutic agents. Thymidylate synthase (TS) is an attractive target for cancer treatment in various human neoplasms. It remains unclear whether the expression of TS is associated with the clinicopathological features of CA patients. The aim of this study was to elucidate the relationship between TS expression and the clinicopathological significance in CA patients. Fifty-one patients with CA were included in this study. TS expression and Ki-67 labeling index were examined using immunohistochemical analysis. TS was positively expressed in 39% (20/51) of CA patients. No statistically significant prognostic factor was identified as a predictor of overall survival (OS) for all patients by univariate analysis, whereas a significant prognostic variable for progression free survival (PFS) was found to be the clinical stage. In addition, both univariate and multivariate analyses confirmed that positive expression of TS was a significant predictor of worse PFS in CA patients of clinical stage 1. CONCLUSION: Positive TS expression in CA was identified as a significant predictor of worse outcome in patients of clinical stage 1. PMID- 28895419 TI - Role of obesity and abdominal shape morphometric features to predict postoperative complications and quality of lymph node dissection of gastrectomy for gastric cancer. AB - Obesity and abdominal shape morphometric features have been thought to be independent risk factors for surgical outcomes after gastrectomy.A total of 113 patients undergoing surgery for primary gastric adenocarcinoma from June 2011 to January 2015 were retrospectively included. Body mass index, visceral fatty area, anterior-posterior abdominal and transverse diameters and depth ratio at levels of the umbilicus, the gastroesophageal junction and the root of the celiac artery were measured or calculated. Patients were grouped according to body mass index (<25.0 kg/m2or >=25.0 kg/m2) or median value of these parameters. Surgical outcomes including postoperative complications, total and metastatic lymph node numbers and their ratio were compared.There was a significant association between body mass index and abdominal shape indexes. Body mass index and abdominal shape indexes showed no statistical significance on development of complications. But, lymph node numbers and their ratio were negatively affected by depth ratio at the root of the celiac artery.Our findings showed that gastrectomy with curative intent can be performed safely in patients with higher body mass index and abdominal shape indexes. Therefore, there is no need to perform any change in surgical strategy according to these measurements and calculations. PMID- 28895420 TI - Retrospective analysis of 20 cases of refractory Hodgkin's lymphoma. AB - We investigate the clinical characteristics, prognosis and treatment of relapsed and refractory Hodgkin's lymphoma. Twenty patients with relapsed and refractory Hodgkin lymphoma were treated by chemotherapy or autologous stem cell transplantation in our hospital from April 2006 to August 2012. The retrospective analysis of the records from the 20 patients reflected both 5-year overall survival (OS) and progression-free survival (PFS). The overall effectiveness was 80% for the 20 patients. The 5-year overall survival rate and 5-year progression free survival rate were 73.5% and 62.7%, respectively. Therefore, comprehensive treatment should be actively utilized in the case of invalid second-line regimen for the refractory HL patients. PMID- 28895421 TI - In-vivo isolation of circulating tumor cells in non-small cell lung cancer patients by CellCollector. AB - In non-small cell lung cancer (NSCLC) circulating tumor cells (CTCs) can provide information on patient prognosis and treatment efficacy. Currently CTCs are mostly isolated in vitro from small volumes of patient blood samples. The aim of the study was to assess a medical device for in vivo isolation of CTCs directly from the blood of NSCLC patients. The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the CellCollector was mediated by an antibody directed against the epithelial cell adhesion molecule. There were 60 applications of the wire in 48 stage I-IIIB NSCLC patients and 12 non-cancer patients. The device was well tolerated in all applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. In the non-cancer patients, no CTCs were detected. The safety and efficacy of an in vivo CTC detection method directly from the bloodstream of patients with NSCLC has been demonstrated. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. PMID- 28895422 TI - The value of Gd-BOPTA- enhanced MRIs and DWI in the diagnosis of intrahepatic mass-forming cholangiocarcinoma. AB - The aim of this study is to explore the value of unenhanced magnetic resonance imaging (MRI), gadobenate dimeglumine injection (Gd-BOPTA)-enhanced MRI and diffusion-weighted imaging (DWI) in the diagnosis of intrahepatic mass-forming cholangiocarcinoma (IMCC). Totally 59 IMCC patients who underwent Gd-BOPTA enhanced MRIs were recruited. The time-signal intensity curves and lesion periphery enhancement rates of the IMCC and liver parenchyma was drawn using apparent diffusion coefficient (ADC) values. The Gd-BOPTA-enhanced MRI showed that the peripheries of 30 lesions in the arterial phase exhibited irregular ring enhancement. However, lesions in the portal and delayed phases (which were gradually filled with a contrast agent), presented a patchy or latticed enhancement. Twenty-two lesions in the arterial and delayed phases exhibited uneven mild/moderate patchy enhancements with a progressive and centripetal lesion. Five lesions emerged from the arterial phase without any significant enhancement and had only gradual enhancement during the delayed phase. The remaining 2 lesions had a decreased mild enhancement, presented comparatively high signals and the lesion center had visible small spotted low signals. The DWI signals displayed a slightly high or high unevenness. Some lesion peripheries had a high signal but lesion centers displayed a relatively low or slightly low signal and irregular patches. There were significant differences between the ADC values of the lesion edge, lesion center and liver parenchyma. The IMCC detection rates of the Gd-BOPTA-enhanced MRI and DWI were higher than those of the unenhanced MRI. Our study demonstrated that both the Gd-BOPTA-enhanced MRI and DWI had higher accuracies rates than an unenhanced MRI. Furthermore, the hepatobiliary phase of IMCC plays an important role in the diagnosis and identification of IMCC constituents. PMID- 28895423 TI - Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe. AB - Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data. PMID- 28895424 TI - Comment: Translating Guidelines Into Practice: Interpreting the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. PMID- 28895425 TI - Predictors of subsequent myocardial infarction, stroke, and death in stable post myocardial infarction patients: A nationwide cohort study. AB - BACKGROUND: This study investigated the predictors of subsequent cardiovascular events in stable post-myocardial infarction patients in Taiwan. METHODS: A total of 11,183 patients were recruited who had survived one year post-myocardial infarction without subsequent events of recurrent myocardial infarction or stroke from the Taiwan National Health Insurance Research Database. Their composite cardiovascular event rates were identified. RESULTS: The composite cardiovascular events rate in three year follow-up in the post-myocardial infarction population was 13.8%. Corresponding event rates were 5.8% recurrent myocardial infarction, 5.0% stroke, and 5.2% death. Independent factors associated with a higher risk of ischemic events or death included heart failure (hazard ratio (HR)=1.19), hypertension (HR=1.16), age (65-75 vs <65 years: HR=1.29; 75-85 vs <65 years: HR=1.50; >85 vs <65 years: HR=1.70), diabetes (HR=1.33), prior stroke (HR=1.24), chronic kidney disease (HR=1.4), atrial fibrillation (HR=1.27), and underutilization of guideline-based medication (HR=1.73). Composite risk for myocardial infarction, stroke and death increased progressively from 4.9% in patients with zero risk factor to 100.0% in patients with eight risk factors. CONCLUSIONS: For acute myocardial infarction patients surviving one year without subsequent events of recurrent myocardial infarction or stroke, the risk of cardiovascular events remained high. Eight predictors identified patients at increased risk for subsequent cardiovascular events within the next three years. These results suggest an unmet need, particularly in patients with additional risk factors. PMID- 28895426 TI - Music for the ageing brain: Cognitive, emotional, social, and neural benefits of musical leisure activities in stroke and dementia. AB - Music engages an extensive network of auditory, cognitive, motor, and emotional processing regions in the brain. Coupled with the fact that the emotional and cognitive impact of music is often well preserved in ageing and dementia, music is a powerful tool in the care and rehabilitation of many ageing-related neurological diseases. In addition to formal music therapy, there has been a growing interest in self- or caregiver-implemented musical leisure activities or hobbies as a widely applicable means to support psychological wellbeing in ageing and in neurological rehabilitation. This article reviews the currently existing evidence on the cognitive, emotional, and neural benefits of musical leisure activities in normal ageing as well as in the rehabilitation and care of two of the most common and ageing-related neurological diseases: stroke and dementia. PMID- 28895427 TI - The impact of self-perceived limitations, stigma and sense of coherence on quality of life in multiple sclerosis patients: results of a cross-sectional study. AB - OBJECTIVE: To examine the impact of perceived limitations, stigma and sense of coherence on quality of life in multiple sclerosis patients. DESIGN: Cross sectional survey. SETTING: Department of Neurology, University Medical Center Groningen, the Netherlands. SUBJECTS: Multiple sclerosis patients. MAIN MEASURES: World Health Organization Quality of Life - abbreviated version, Stigma Scale for Chronic Illness, Sense of Coherence Scale, background and disease-related questions. RESULTS: In total, 185 patients (61% response rate) participated in the study with moderate to severe limitations. Stigma was highly prevalent but low in severity. Patients with a higher sense of coherence experienced a lower level of limitations ( B = -0.063, P < 0.01) and less stigma (enacted stigma B = 0.030, P < 0.01; self-stigma B = -0.037, P < 0.01). Patients with a higher level of limitations experienced more stigma (enacted stigma B = 0.044, P < 0.05; self stigma B = 0.063, P < 0.01). Patients with a higher sense of coherence experienced better quality of life (physical health B = 0.059, P < 0.01; psychological health B = 0.062, P < 0.01; social relationships B = 0.052, P < 0.01; environmental aspects B = 0.030, P < 0.01). Patients with a higher level of limitations experienced poorer quality of life (physical health B = -0.364, P < 0.01; psychological health B = -0.089, P < 0.05) and patients with more stigma also experienced poorer quality of life (self-stigma: physical health B = -0.073, P < 0.01; psychological health B = -0.089, P < 0.01; social relationships B = 0.124, P < 0.01; environmental aspects B = -0.052, P < 0.01, and enacted stigma: physical health B = -0.085, P < 0.10). CONCLUSION: Patients with less perceived limitations and stigma and a higher level of sense of coherence experienced better quality of life. Patients with a higher sense of coherence experienced a lower level of limitations and less stigma. PMID- 28895428 TI - Decreased migration with locally administered bisphosphonate in cemented cup revisions using impaction bone grafting technique. AB - Background and purpose - Impaction bone grafting (IBG) in revision hip surgery is an established method in restoring bone stock deficiencies. We hypothesized that local treatment of the morsellized allograft with a bisphosphonate in cemented revision would, in addition to increased bone density, also reduce the early migration of the cup as measured by radiostereometry (RSA). Patients and methods 20 patients with aseptic cup loosening underwent revision using the IBG technique. The patients were randomized to either clodronate (10 patients) or saline (10 patients, control group) as local adjunct to the morsellized bone. The outcome was evaluated by dual-energy X-ray absorptiometry (DXA) during the first year regarding periacetabular bone density and with radiostereometric analysis (RSA) for the first 2 years regarding cup migration. Results - 2 patients were lost to follow-up: 9 patients remained in the clodronate and 9 in the control group. Less proximal migration was found in the clodronate group compared with the controls, measured both over time (mixed-models analysis, p = 0.02) as well as at the specified time points up to 2 years (0.22 mm and 0.59 mm respectively, p = 0.02). Both groups seemed to have stabilized at 1 year. We found similar bone mineral density measured by DXA, and similar RSA migration in the other directions. No cups were re-revised. Interpretation - Local treatment of the allograft bone with clodronate reduced early proximal migration of the revised cup but without any measurable difference in periacetabular bone density. PMID- 28895429 TI - Effectiveness of Adenotonsillectomy and Risk of Velopharyngeal Insufficiency in Children With Prader-Willi Syndrome. AB - OBJECTIVES: (1) Review effectiveness of adenotonsillectomy (T&A) for obstructive sleep apnea (OSA) in children with Prader-Willi syndrome (PW). (2) Examine the incidence of velopharyngeal insufficiency (VPI) after T&A in this population. (3) Compare outcomes of T&A in PW and Trisomy 21 (T21) patients. METHODS: Outcomes after T&A in a PW cohort were retrospectively reviewed and compared to those in patients with T21. RESULTS: The study cohort included 22 PW patients. They were compared to 47 T21 patients who also underwent T&A. Eighteen percent (N = 4) of the PW patients had postoperative VPI requiring a corrective procedure, while there were no patients within the T21 cohort who had identified VPI ( P < .05). In those patients that had a postoperative polysomnogram, the mean decrease in obstructive apnea-hypopnea index (OAHI) of the PW and T21 patients measured 8.4 and 4.7 points, respectively ( P = .3). CONCLUSIONS: This study demonstrated a higher rate of VPI after T&A in PW children as compared to another at-risk cohort, T21 patients. While the OAHI decreased after T&A in both groups, a significant number of children with PW or T21 had persistent OSA. Further investigation into the optimal management of OSA, while preventing treatment complications such as VPI, is needed for children with these high-risk conditions. PMID- 28895430 TI - A homozygous mutation in the PSMB8 gene in a case with proteasome-associated autoinflammatory syndrome. PMID- 28895431 TI - Timing of Meal Insulin and Its Relation to Adherence to Therapy in Type 1 Diabetes. AB - The purpose of this study is to examine timing of meal insulin and further determine whether an association exists between timing of meal insulin and missed meal insulin doses. The cohort included 4768 T1D Exchange clinic registry participants <26 years with type 1 diabetes >=1 year. Chi-square tests, t-tests, and regression were used to assess the relationship between participant characteristics and timing of meal insulin and missed meal doses, respectively. Timing of meal insulin and association with missed meal doses was analyzed using logistic regression. In all, 21% reported administering insulin several minutes before, 44% immediately before, 10% during, and 24% after meal. Participants who gave insulin prior to a meal had significantly lower HbA1c than those who gave insulin during or after meal (8.4% +/- 1.5% vs 8.8% +/- 1.6%, adjusted P < .001), but no significant association was observed regarding DKA events. Those who reported missing >=1 insulin dose per week had higher HbA1c (9.8% +/- 1.9% vs 8.3% +/- 1.3%, adjusted P < .001) and were more likely to experience at least one DKA event (9% vs 5%, adjusted P = .001) compared with those who rarely missed a meal insulin dose. Participants who reported administering insulin during or after a meal were more likely to report missing >=1 meal insulin dose per week compared with those who administered insulin before a meal (28% vs 14%, adjusted P < .001). Premeal insulin was associated with lower HbA1c and fewer missed meal insulin doses. Providers may use this information to discuss the benefits of premeal insulin on glycemic control and adherence to therapy. PMID- 28895432 TI - Intraductal Laser Fiber Tip Fracture and Retrieval During Sialendoscopic Laser Assisted Lithotripsy. AB - Fragmentation of flexible laser fiber tips has been reported to occur during therapeutic bronchoscopy and urologic stone treatment. We report fragmentation of 200-um single-use silica-based fibers during sialendoscopy-controlled Holmium:YAG laser treatment of a parotid and a submandibular stone. The technique employed to successfully retrieve the fiber tips is described in the context of identifying this potential complication from endoscopic management of sialolithiasis. PMID- 28895433 TI - Corrective Osteotomies of Phalangeal and Metacarpal Malunions Using Patient Specific Guides: CT-Based Evaluation of the Reduction Accuracy. AB - BACKGROUND: Surgical planning of corrective osteotomies is traditionally based on conventional radiographs and clinical findings. In the past 10 years, 3 dimensional (3D) preoperative planning approaches with patient-specific guides have been developed. However, the application of this technology to posttraumatic deformities of the metacarpals and phalangeal bones has not yet been investigated. Our goal was to evaluate the feasibility of the surgical application to the latter and to evaluate the extent and precision of correction. METHODS: We present results of 6 patients (8 osteotomies) treated with phalangeal or metacarpal corrective osteotomy. Deformities were located in the third ray in 1, fourth ray in 3, and fifth ray in 4 cases. Six malunited metacarpal bones (1 intra-articular) and 2 deformed proximal phalanges were treated. Computer-based 3D preoperative planning using the contralateral hand as a template allowed the production of 3D-printed patient-specific guides that were used intraoperatively for navigation. The precision of the reduction was assessed using pre- and postoperative computed tomography by comparing the postoperative bone model with the preoperatively simulated osteotomy. Range of motion and grip strength were documented pre- and postoperatively. RESULTS: The mean follow-up time was 6 months (range: 5-11 months). Rotational deformity was reduced from a mean of 10.0 degrees (range: 7.2 degrees -19.3 degrees ) preoperatively to 2.3 degrees (range: 0.7 degrees -3.7 degrees ) postoperatively, and translational incongruency decreased from a mean of 1.4 mm (range: 0.7-2.8 mm) to 0.4 mm (range: 0.1-0.9 mm). CONCLUSION: Preliminary results indicate that a precise reduction for corrective osteotomies of metacarpal and phalangeal bones can be achieved by using 3D planning and patient-specific guides. PMID- 28895434 TI - Genetic variation and risk of DNA damage in peripheral blood lymphocytes of Iranian formaldehyde-exposed workers. AB - Formaldehyde (FA) has given positive results for the genetic damage evaluated in human peripheral blood lymphocytes. Polymorphism plays a special role in the toxicity of chemicals. DNA damage in blood cells was evaluated in workers who were occupationally exposed to FA. This study tested the association of alcohol dehydrogenase III (ADH3) and manganese-superoxide dismutase (Mn-SOD) gene polymorphism, with DNA damage of peripheral blood lymphocytes. Gene polymorphisms were evaluated in 54 workers from melamine dinnerware workshops and 34 workers from dairy production workshops. The control and exposed population were matched based on age, smoking, work history and socioeconomic status. DNA damage was evaluated by alkaline comet assay in the peripheral blood lymphocytes. ADH3 and Mn-SOD genotypes were determined in all workers using polymerase chain reaction restriction fragment length polymorphism method. DNA damage of lymphocyte cells was significantly higher ( p < 0.001) in the exposed individuals in comparison with the control population. The examinations of the exposed group had revealed significantly higher ( p < 0.01) variant of Val/Val of Mn-SOD compared to control group. In workers with ADH32-2 variant, significantly higher levels of DNA damage ( p < 0.01) were observed than the control population with the same genotype. It could be concluded that enzymes involved in the metabolism of FA and oxidative stress controlling are two important effective parameters for DNA damage of peripheral blood lymphocytes in exposed people. These results are regarded as a pioneer investigation for the management of health risks assessment. PMID- 28895436 TI - Evaluation of Normative Data of a Widely Used Computerized Neuropsychological Battery: Applicability and Effects of Sociodemographic Variables in a Dutch Sample. AB - INTRODUCTION: Central Nervous System Vital Signs (CNS VS) is a computerized neuropsychological battery that is translated into many languages. However, published CNS VS' normative data were established over a decade ago, are solely age-corrected, and collected in an American population only. METHOD: Mean performance of healthy Dutch participants on CNS VS was compared with the original CNS VS norms ( N = 1,069), and effects of sociodemographic variables were examined. RESULTS: z tests demonstrated no significant differences in performance on four out of seven cognitive domains; however, Dutch participants ( N = 158) showed higher scores on processing and psychomotor speed, as well as on cognitive flexibility. Although the original CNS VS norms are solely age corrected, effects of education and sex on CNS VS performance were also identified in the Dutch sample. DISCUSSION: Users should be cautious when interpreting CNS VS performance based on the original American norms, and sociodemographic factors must also be considered. PMID- 28895435 TI - Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies. AB - INTRODUCTION: Glioblastoma (GBM) is the most aggressive malignant brain cancer in adults, and its poor prognosis and resistance to the existing standard of care require the development of innovative therapeutic modalities. The local delivery of stem cells as therapeutic carriers against glioma has produced encouraging results, but encounters obstacles with regards to the repeatability and invasiveness of administration. Intranasal delivery of therapeutic stem cells could overcome these obstacles, among others, as a noninvasive and easily repeatable mode of administration. Areas covered: This review describes nasal anatomy, routes of stem cell migration, and factors affecting stem cell delivery to hard-to-reach tumors. Furthermore, this review discusses the molecular mechanisms underlying stem cell migration following delivery, as well as possible stem cell effector functions to be considered in combination with intranasal delivery. Expert opinion: Further research is necessary to elucidate the dynamics of stem cell effector functions in the context of intranasal delivery and optimize their therapeutic potency. Nonetheless, the technique represents a promising tool against brain cancer and has the potential to be expanded for use against other brain pathologies. PMID- 28895437 TI - Mechanism underlying gender difference in heart disease risks and corresponding preventive measures. PMID- 28895438 TI - Why the Mediterranean diet lowers the risk of heart disease. PMID- 28895441 TI - Successful Placement of a BAHA Implant in a Patient With Epidermolysis Bullosa: A Case Report and Review of the Literature. AB - INTRODUCTION: Epidermolysis bullosa (EB) is a spectrum of mechanobullous disorders characterized by blistering following minor trauma or traction to the skin. Hearing loss in this population is poorly described in the otolaryngology literature, and its treatment oftentimes results in external auditory canal skin irritation. CASE PRESENTATION: We present the case of a 26-year-old female with EB and mixed hearing loss unable to wear conventional hearing aids due to sequelae of the external auditory canals. An osseointegrated implant was used as other hearing aids were deemed to be too destructive of the external auditory canal skin. Management and Outcome: Our patient underwent placement of a right bone-anchored hearing aid with minimal disruption of the surrounding skin using a minimally invasive punch technique. Over 1 year of follow-up, her course was complicated by 1 simple cellulitic infection at the surgical site treated successfully with oral antibiotics. DISCUSSION: The literature regarding the otolaryngologic manifestations of EB is sparse. The otologic sequelae are particularly overlooked in the workup and management. Based on the results of this case study, it appears that an osseointegrated implant can be safely utilized to treat significant mixed or conductive hearing loss in patients with EB. PMID- 28895439 TI - Preventing cardiovascular disease after hypertensive disorders of pregnancy: Searching for the how and when. AB - Background Women with a history of a hypertensive disorder during pregnancy (HDP) have an increased risk of cardiovascular events. Guidelines recommend assessment of cardiovascular risk factors in these women later in life, but provide limited advice on how this follow-up should be organized. Design Systematic review and meta-regression analysis. Methods The aim of our study was to provide an overview of existing knowledge on the changes over time in three major modifiable components of cardiovascular risk assessment after HDP: blood pressure, glucose homeostasis and lipid levels. Data from 44 studies and up to 6904 women with a history of a HDP were compared with risk factor levels reported for women of corresponding age in the National Health And Nutrition Examination Survey, Estudio Epidemiologico de la Insuficiencia Renal en Espana and Hong Kong cohorts ( N = 27,803). Results Compared with the reference cohort, women with a HDP presented with higher mean blood pressure. Hypertension was present in a higher rate among women with a previous HDP from 15 years postpartum onwards. At 15 years postpartum (+/-age 45), one in five women with a history of a HDP suffer from hypertension. No differences in glucose homeostasis parameters or lipid levels were observed. Conclusions Based on our analysis, it is not possible to point out a time point to commence screening for cardiovascular risk factors in women after a HDP. We recommend redirection of future research towards the development of a stepwise approach identifying the women with the highest cardiovascular risk. PMID- 28895442 TI - An Alternate Technique of Applying Lag Screw for Fixation of Distal Fibula Fracture: Posterior to Anterior Interfragmentary Compression Screw. AB - : Ankle fractures are one of the most common lower limb fractures, representing a significant portion of the trauma workload. Marked proportion of these is isolated intraarticular lateral malleolus fractures. Anatomical reduction and rigid internal fixation using lag screw (interfragmentary screw) to provide interfragmentary compression has remained the choice of treatment in selected lateral malleolus fractures. Applying interfragmentary compression screw from anterior to the posterior surface of the fibula has been the traditional method of performing this. In this article, we describe an alternate method of applying posterior-anterior interfragmentary compression screw to the fibula fractures. We will also discuss the benefits it provides such as minimizing the chances of hardware-related peroneal tendon irritation. Further argument will focus on the mechanical benefit this will render while providing equal clinical outcome of the time tested anterior-posterior interfragmentary compression screw. LEVELS OF EVIDENCE: Level V: Therapeutic comparison. PMID- 28895440 TI - Unravelling the biology of chromatin in health and cancer using proteomic approaches. AB - INTRODUCTION: Chromatin remodeling complexes play important roles in the control of genome regulation in both normal and diseased states, and are therefore critical components for the regulation of epigenetic states in cells. Given the role epigenetics plays in cancer, for example, chromatin remodeling complexes are routinely targeted for therapeutic intervention. Areas covered: Protein mass spectrometry and proteomics are powerful technologies used to study and understand chromatin remodeling. While impressive progress has been made in this area, there remain significant challenges in the application of proteomic technologies to the study of chromatin remodeling. As parts of large multi subunit complexes that can be heavily modified with dynamic post-translational modifications, challenges in the study of chromatin remodeling complexes include defining the content, determining the regulation, and studying the dynamics of the complexes under different cellular states. Expert commentary: Impwortant considerations in the study of chromatin remodeling complexes include the complexity of sample preparation, the choice of proteomic methods for the analysis of samples, and data analysis challenges. Continued research in these three areas promise to yield even greater insights into the biology of chromatin remodeling and epigenetics and the dynamics of these systems in human health and cancer. PMID- 28895443 TI - Cytotoxic 8,9-seco-ent-kaurane diterpenoids from Croton kongensis. AB - Chemical study on the ethanolic extract generated from the aerial parts of Croton kongensis led to the isolation of three new 8,9-seco-ent-kaurane diterpenoids, kongeniods A-C (1-3), together with seven known analogs (4-10). The structures of these compounds were assigned by spectroscopic data analysis. The vitro cytotoxic tests showed that compounds 1-3 exhibited strong activities against HL-60 cell lines with IC50 values of 0.47, 0.58, and 1.27 MUM, respectively. PMID- 28895444 TI - D-Dimer Elevation as a Blood Biomarker for Detection of Structural Disorder in Mild Traumatic Brain Injury. AB - CT scans are useful in patients with traumatic brain injury (TBI), but the potential risks associated with ionizing radiation are unknown. Further, CT scans are not commonly available in developing countries. In this study, coagulopathy and abnormal fibrinolysis were investigated as blood biomarkers for detection of structural disorder in mild traumatic brain injury (TBI). A total of 88 patients with mild and isolated TBI (Glasgow Coma Scale [GCS] score 14-15) were admitted to Kenwakai Ootemachi Hospital between October 2014 and March 2016. After exclusion of those treated with oral antiplatelet agents and anticoagulants, 73 patients were included in this study. Patients were classified into those with (lesion [+]) and without (lesion [-]) intracranial structural disorder, based on CT scans at admission and follow-up CT or MRI. Age, GCS score, and blood test findings (platelet count, international normalized ratio of prothrombin time [PT INR], activated partial thromboplastin time [APTT], fibrinogen, fibrin/fibrinogen degradation products [FDP], and D-dimer) on admission were compared between the two groups. The lesion(+) and lesion(-) groups comprised 54 (74%) and 19 patients (26%), respectively. In multivariate logistic regression analysis, D-dimer (3.6 vs. 0.8 MUg/mL) was the only significant independent risk factor for structural disorder (p < 0.001). Platelet counts (23.9 vs. 23.5 * 104 /MUL), PT-INR (1.05 vs. 1.07), APTT (29.3 vs. 31.7 sec), FDP (12 vs. 2.4 MUg/mL), and fibrinogen levels (260.6 vs. 231.3 mg/dL) were not associated with structural disorder. These results show that D-dimer is associated with intracranial structural disorder in mild TBI. PMID- 28895445 TI - Strategic infarct location for post-stroke cognitive impairment: A multivariate lesion-symptom mapping study. AB - Lesion location is an important determinant for post-stroke cognitive impairment. Although several 'strategic' brain regions have previously been identified, a comprehensive map of strategic brain regions for post-stroke cognitive impairment is lacking due to limitations in sample size and methodology. We aimed to determine strategic brain regions for post-stroke cognitive impairment by applying multivariate lesion-symptom mapping in a large cohort of 410 acute ischemic stroke patients. Montreal Cognitive Assessment at three to six months after stroke was used to assess global cognitive functioning and cognitive domains (memory, language, attention, executive and visuospatial function). The relation between infarct location and cognition was assessed in multivariate analyses at the voxel-level and the level of regions of interest using support vector regression. These two assumption-free analyses consistently identified the left angular gyrus, left basal ganglia structures and the white matter around the left basal ganglia as strategic structures for global cognitive impairment after stroke. A strategic network involving several overlapping and domain-specific cortical and subcortical structures was identified for each of the cognitive domains. Future studies should aim to develop even more comprehensive infarct location-based models for post-stroke cognitive impairment through multicenter studies including thousands of patients. PMID- 28895446 TI - Serositis in a child with scleredema of Buschke: an unusual association and improvement following glucocorticoids. PMID- 28895447 TI - Early Experience With Endovascular Aneurysm Sealing in Combination With Parallel Grafts for the Treatment of Complex Abdominal Aneurysms: The ASCEND Registry. AB - PURPOSE: To report the results of the ASCEND Registry of cases involving endovascular aneurysm sealing (EVAS) in combination with chimney grafts (chEVAS) for the treatment of para- and juxtarenal aortic aneurysms (AAA). METHODS: A retrospective, multicenter registry established in 8 vascular centers between 2013 and 2016 recorded the treatment results and follow-up of chEVAS procedures for nonruptured AAAs; data were analyzed using standardized outcome measures. In the observation period, 154 patients (mean age 72.3+/-7.7 years; 124 men) underwent elective treatment for de novo juxtarenal and pararenal aneurysms and formed the study group. RESULTS: Sixty-two (40.3%) of the cohort were treated using a single parallel graft, 54 (35.1%) with double chimneys, 27 (17.5%) with triple chimneys, and 11 (7.1%) with 4 chimneys. The 30-day mortality was 2.8%, and there were 4 perioperative strokes (1 fatal). At 1 year, the freedom from all cause mortality was 89.8% and the freedom from aneurysm-related mortality was 94.3%. There were 3 endoleaks within 90 days of the procedure, one type Ia and 2 type Ib. The freedom from type Ia endoleaks was 95.7% at 1 year. There were no types II or III endoleaks in this series; the freedom from all endoleaks was 94.2% at 1 year. Freedom from reintervention at 1 year was 89.2%. Target vessel patency rates at 1 year were 97.7%, 99.3%, 100%, and 100% for the left renal, right renal, superior mesenteric artery, and celiac axis stents, respectively. CONCLUSION: The ASCEND Registry supports a proof of concept for the use of polymer technology and EVAS with parallel grafts in managing patients with complex aortic disease. The future role of chEVAS will be defined by studies that assess mid- to long-term durability. PMID- 28895448 TI - Anatomical Applicability of Endovascular Aneurysm Sealing Techniques in a Consecutive Cohort of Fenestrated Endovascular Aneurysm Repairs. AB - PURPOSE: To determine how many endovascular aneurysm sealing (EVAS) procedures with/without off-label use of chimneys (ChEVAS) could have been performed in a cohort of patients who had undergone fenestrated endovascular aneurysm repair (FEVAR). METHODS: Sixty patients (median age 76.3 years; 54 men) who underwent FEVAR in our institution between 2013 and 2015 were selected for the study. The median aneurysm diameter was 62.0 mm (interquartile range 59.3, 69.0). Preoperative computed tomography angiograms (CTA) were anonymized and sent to 2 physicians with experience of more than 40 ChEVAS interventions. These ChEVAS planners were blinded to the study purpose and asked to agree upon an EVAS/ChEVAS plan. The primary outcome was the percentage of the FEVAR patients in whom an EVAS/ChEVAS was technically possible. The secondary outcomes were a comparison of seal zones, number of target vessels, and device cost. RESULTS: An EVAS-based intervention would have been technically possible in 56 (93.3%) of the FEVAR patients. The median proximal aortic seal zone was significantly more distal in the EVAS/ChEVAS procedures vs the FEVAR cases (zone 8 vs zone 7, p<0.001) and fewer target vessels were involved (median 2 vs 3, p<0.001). The cost of the EVAS/ChEVAS device was 66% of the FEVAR device. Planners would not currently advocate an EVAS-based intervention in 43 (76.8%) of these 56 patients due to concerns regarding the risk of migration associated with the lumen thrombus ratios observed. CONCLUSION: EVAS is technically feasible in the majority of patients undergoing FEVAR in our institution but currently advocated in only 23.2%. The seal zone was more distal, fewer target vessels were involved, and the device cost was lower in the planned EVAS/ChEVAS interventions. PMID- 28895449 TI - Stratifying the Risk of Developing Clinical Hypocalcemia after Thyroidectomy with Parathyroid Hormone. AB - Objective To identify the risk of clinical hypocalcemia in the first hours after thyroidectomy. Study Design Prospective observational study. Setting Single institution tertiary hospital in Madrid, Spain. Subjects and Methods A total of 123 patients who underwent total or completion thyroidectomy between June 2010 and March 2012 were included. Pre- and postoperative intact parathyroid hormone (iPTH) levels were obtained. Patients remain hospitalized a minimum of 48 hours until blood calcium stabilized. Calcium and/or vitamin D supplements were prescribed only when signs or symptoms of hypocalcemia developed. Receiver operating characteristic curve analysis was employed to evaluate the postoperative iPTH level and the pre- to postoperative decrease in iPTH levels. Two cutoff values were determined to stratify the risk of developing clinical hypocalcemia into 3 groups. Results The areas under the receiver operating characteristic curve were 0.991 for the postoperative iPTH and 0.998 for the decrease in iPTH. An iPTH decrease of 80% had 100% sensitivity to detect patients who developed clinical hypocalcemia, while a postoperative iPTH <3 pg/mL had 100% specificity. Thus, patients with an iPTH decrease <=80% are at a very low risk of clinical hypocalcemia, and patients with a postoperative iPTH <3 pg/mL are at a very high risk. Patients with an iPTH decrease >80% and a postoperative iPTH >=3 pg/mL are at intermediate risk. No significant correlation was found between the time when the sample was obtained and iPTH values. Conclusion This study stablishes a very accurate test to stratify the risk of clinical postthyroidectomy hypocalcemia based on pre- and postoperative iPTH levels. PMID- 28895450 TI - Identifying Occupations at Risk for Laryngeal Disorders Requiring Specialty Voice Care. AB - Objective To identify occupational groups' use of specialty voice clinic evaluation. Study Design Retrospective cohort study. Setting Tertiary subspecialty clinic. Subjects and Methods We analyzed data collected on patients presenting to the Massachusetts Eye and Ear Infirmary Voice and Speech Laboratory over a 20-year period (1993-2013). The relative risk (RR) and 99% confidence interval (CI) of presentation were calculated for each occupational category in the greater Boston population using year-matched data from the Bureau of Labor Statistics (BLS). Results The records of 12,120 new patients were reviewed. Using year- and occupation-matched BLS data from 2005 to 2013, 2726 patients were included in the cohort analysis. Several occupations had significantly higher risk of presentation. These included arts and entertainment (RR 4.98, CI 4.18 5.95), law (RR 3.24, CI 2.48-4.23), education (RR 3.08, CI 2.70-3.52), and social services (RR 2.07, CI 1.57-2.73). In contrast, many occupations had significantly reduced risk of presentation for laryngological disorders, for example, maintenance (RR 0.25, CI 0.15-0.42), food preparation (RR 0.35, CI 0.26-0.48), and administrative support (RR 0.49, CI 0.41-0.57). Conclusion Certain occupations are associated with higher use of laryngological services presumably because of their vocational voice needs. In addition to confirming findings from other studies, we identified several new occupation groups with increased or decreased risk for laryngologic disorders. Understanding what factors predispose to requiring specialty voice evaluation may help in targeting preventative efforts. PMID- 28895451 TI - Risk Factors for Mild Traumatic Brain Injury and Subsequent Post-Traumatic Stress Disorder and Mental Health Disorders among United States Army Soldiers. AB - The purpose of this study was to determine the association of mild traumatic brain injury (mTBI) with subsequent post-traumatic stress disorder (PTSD) and mental health disorders (MHD), and the intervening role of acute stress disorder (ASD). This matched case-control study utilized the Total Army Injury and Health Outcomes Database (TAIHOD) to analyze soldiers' (n = 1,261,297) medical encounter data between 2002 and 2011. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to identify: mTBI (following Centers for Disease Control [CDC] surveillance definition for mTBI), MHD (ICD-9 codes for depression and anxiety, excluding PTSD), PTSD (ICD-9 309.81), and ASD (ICD-9 308.3). Incident cases of mTBI (n = 79,505), PTSD (n = 71,454), and MHD (n = 285,731) were identified. Overall incidence rates per 1000 soldier years were: mTBI = 17.23, PTSD = 15.37, and MHD = 67.99. mTBI was associated with increased risk for PTSD (risk ratio [RR] 5.09, 95% confidence interval [CI] 4.82-5.37) and MHD (RR 2.94, 95% CI 2.84-3.04). A sub-analysis of the mTBI-only soldiers found that a diagnosis ASD, compared with a diagnosis of no ASD, was associated with greater risk for subsequent PTSD (RR 2.13, 95% CI 1.96-2.32) and MHD (RR 1.90, 95% CI 1.72-2.09) following mTBI. Results indicate that soldiers with previous mTBI have a higher risk for PTSD and MHD, and that ASD may also mediate PTSD and MHD risk subsequent to mTBI. These data may help guide important surveillance and clinical rehabilitation considerations for high-risk populations. PMID- 28895452 TI - Debunking: A Meta-Analysis of the Psychological Efficacy of Messages Countering Misinformation. AB - This meta-analysis investigated the factors underlying effective messages to counter attitudes and beliefs based on misinformation. Because misinformation can lead to poor decisions about consequential matters and is persistent and difficult to correct, debunking it is an important scientific and public-policy goal. This meta-analysis ( k = 52, N = 6,878) revealed large effects for presenting misinformation ( ds = 2.41-3.08), debunking ( ds = 1.14-1.33), and the persistence of misinformation in the face of debunking ( ds = 0.75-1.06). Persistence was stronger and the debunking effect was weaker when audiences generated reasons in support of the initial misinformation. A detailed debunking message correlated positively with the debunking effect. Surprisingly, however, a detailed debunking message also correlated positively with the misinformation persistence effect. PMID- 28895453 TI - Extracranial internal carotid artery vasospasm during thrombectomy. AB - The use of a stent retriever increases the risk of intracranial vasospasm. Here, we report the case of a man who developed severe vasospasm in a long segment of the extracranial internal carotid artery after mechanical irritation by a stent retriever inserted for the treatment of acute cerebral ischemia. A 47-year-old right-handed man presented with sudden-onset right-sided weakness and difficulty speaking. The patient's National Institutes of Health Stroke Scale score was 6 and he had an Alberta Stroke Program Early Computed Tomography Score of 9. The patient was started on intravenous alteplase therapy, and an acute thrombectomy was performed. Left internal carotid digital subtraction angiography showed narrowing of the left common and internal carotid arteries and occlusion of the proximal left M1 segment of the middle cerebral artery. A stent retriever was retracted into a guiding catheter placed at the left carotid bulb under continuous suction. Recanalization of the middle cerebral artery was not achieved and there was significant narrowing in a long segment of the extracranial internal carotid artery associated with exacerbation of the patient's aphasia. The cervical vasospasm improved after nicardipine infusion via the catheter. We encountered vasospasm in a long segment of the extracranial internal carotid artery after mechanical irritation by a stent retriever. If a stent retriever is used in a patient with a narrow extracranial internal carotid artery, consideration should be given to using a Penumbra or smaller guiding catheter located in the distal internal carotid artery to prevent irritation to the cervical vessel wall. PMID- 28895454 TI - The effectiveness of nutritional education among women aged 60-85 on the basis of anthropometric parameters and lipid profiles AB - Background: After several years of experience with guiding of an original program on health-promoting nutritional education for women during menopause, which by inducing changes in nutritional behaviour resulted in many favorable health promoting effects, on request of the students of the Association of Third Age University, an original educational program "Comprehensive stimulation of senior citizens to activity" was developed out and implemented. Objective: The objective of this study was to assess the effectiveness of four-month nutritional education and adjustments in diets of women aged 60-85, on the basis of the measurements of the selected lipid parameters in their blood tests Material and methods: This research project was joined by 37 female subjects aged 60-85, who are the members of the University of the Third Age in Szczecin, and whose average BMI was 31.7 kg/m2. Before the nutritional education commenced and after it was completed, the female subjects' nutritional status was assessed (BMI, WC, WHR, WHtR) and the energy and nutritional value of their diets was examined based on the subjects' regular journalkeeping. Keys' atherogenic score in their diets were also computed. Results: The applied nutritional education led to changes in the energy and nutritional value of the female subjects' diets, which specifically improved their anthropometric parameters and the resulting BMI, WC and WHtR parameters. This fact was also reflected in a substantial decrease of the glucose level and a substantial increase of HDL-C level in the blood of the examined female subjects, as well as in the improvements in the assessed parameters TC/HDL-C, LDL-C/ HDL-C, TG/HDL-C. Conclusions: The analysis of the results allows to confirm, that the four-month nutritional education of elderly women resulted in changes of their erroneous dietary habits and an improvement in their nutrition. PMID- 28895455 TI - Cross-sectional Analysis of the Relationship between Paranasal Sinus Balloon Catheter Dilations and Industry Payments among Otolaryngologists. AB - Objective To characterize the relationship between industry payments and use of paranasal sinus balloon catheter dilations (BCDs) for chronic rhinosinusitis. Study Design Cross-sectional analysis of Medicare B Public Use Files and Open Payments data. Setting Two national databases, 2013 to 2014. Subjects and Methods Physicians with Medicare claims with Current Procedural Terminology codes 31295 to 31297 were identified and cross-referenced with industry payments. Multivariate linear regression controlling for age, race, sex, and comorbidity in a physician's Medicare population was performed to identify associations between use of BCDs and industry payments. The final analysis included 334 physicians performing 31,506 procedures, each of whom performed at least 11 balloon dilation procedures. Results Of 334 physicians, 280 (83.8%) received 4392 industry payments in total. Wide variation in payments to physicians was noted (range, $43.29-$111,685.10). The median payment for food and beverage was $19.26 and that for speaker or consulting fees was $409.45. One payment was associated with an additional 3.05 BCDs (confidence interval [95% CI],1.65-4.45; P < .001). One payment for food and beverages was associated with 3.81 additional BCDs (95% CI, 2.13-5.49; P < .001), and 1 payment for speaker or consulting fees was associated with 5.49 additional BCDs (95% CI, 0.32-10.63; P = .04). Conclusion Payments by manufacturers of BCD devices were associated with increased use of BCD for chronic rhinosinusitis. On separate analyses, the number of payments for food and beverages as well as that for speaker and consulting fees was associated with increased BCD use. This study was cross-sectional and cannot prove causality, and several factors likely exist for the uptrend in BCD use. PMID- 28895456 TI - Spatial and Cellular Expression Patterns of Erythropoietin-Receptor and Erythropoietin during a 42-Day Post-Lesional Time Course after Graded Thoracic Spinal Cord Impact Lesions in the Rat. AB - Erythropoietin (Epo) exhibits promising neuroregenerative potential for spinal cord injury (SCI), and might be involved in other long-term sequelae, such as neuropathic pain development. The current studies investigated the time courses and spatial and cellular patterns of Epo and erythropoietin receptor (EpoR) expression along the spinal axis after graded SCI. Male Long Evans rats received 100 kdyn, 150 kdyn, and 200 kdyn thoracic (T9) contusions from an Infinite Horizon impactor. Sham controls received laminectomies. Anatomical and quantitative immunohistochemical analyses of the EpoR/Epo expression along the whole spinal axis were performed 7, 15, and 42 postoperative days (DPO) after the lesioning. Cellular expression was investigated by double- and triple-labeling for EpoR/Epo with cellular markers and proliferating cells in subgroups of 5 bromo-2-deoxyuridine pre-treated animals. Prolonged EpoR/Epo-expression was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantified EpoR/Epo immunoreactivities in pain-related spinal cord regions and ventrolateral white matter (VLWM) were correlated with the mechanical sensitivity thresholds and locomotor function of the respective animals. EpoR and Epo were constitutively expressed in the ventral horn neurons and vascular and glial cells in the dorsal columns (DC) and the VLWM. After SCI, in addition to expression in the lesion core, EpoR/Epo immunoreactivities exhibited significant time- and lesion grade-dependent induction in the DC and VLWM along the spinal axis. EpoR and Epo immunoreactive cells were co-stained with markers for astroglial, neural precursor cell and vascular markers. In the VLWM, EpoR- and Epo-positive proliferating cells were co-stained with glial fibrillary acidic protein (GFAP) and nestin. The DC EpoR/Epo immunoreactivities exhibited linear relationships with the behavioral correlates of post-lesional chronic pain development at DPO 42. SCI leads to long-lasting multicellular EpoR/Epo induction beyond the lesion core in the spinal cord regions that are involved in central pain development and regenerative processes. Our studies provide a time frame to investigate the effects of Epo application on motor function or pain development, especially in the later time course after lesioning. PMID- 28895457 TI - Polysomnography in Pediatric Otolaryngology: If Not Obstructive Sleep Apnea, What Is It? AB - Objective To determine common polysomnographic (PSG) diagnoses for children referred by otolaryngologists. Study Design Retrospective case series with chart review. Setting Single tertiary pediatric hospital (2010-2015). Subjects and Methods Review of the medical records of 1258 patients undergoing PSG by otolaryngology referral. Patients who underwent previous otolaryngologic surgery were excluded. Data distributions were evaluated using means with standard deviations for continuous variables and frequencies with percentages for categorical variables. Results A total of 1258 patients were included; 55.9% were male, 64.5% were Caucasian, 16.6% had Down syndrome, and 48% had public insurance. The median age at the time of PSG was 5.2 years (range = 0.2-18.94). Indications for PSG were sleep-disordered breathing (SDB; 69.4%), restless sleep (12.7%), airway anomalies (7.5%), and laryngomalacia (7.2%). SDB was seen in 73.4%, obstructive sleep apnea (OSA) in 53.2%, OSA + central sleep apnea (CSA) in 4.5%, CSA in 0.9%, and non-OSA snoring in 15%. Other diagnoses included periodic limb movements of sleep (PLMS; 7.4%), hypoventilation (6.8%), and nonapneic hypoxemia (2.6%). SDB was more common in younger children and seen in 91.4% of children <12 months and in 69.2% of children >=24 months, while non-OSA snoring was more common with increasing age (3.7% in children <12 months, 17.7% of children >=24 months). PLMS were seen in 8.9% of children >=24 months and in no children <12 months. Conclusion While OSA and snoring were the most common diagnoses reported, PLMS, alveolar hypoventilation, and CSA occurred in 7.4%, 6.8%, and 5.4%, respectively. These findings indicate that additional diagnoses other than OSA should be considered for children seen in an otolaryngology clinic setting who undergo PSG for sleep disturbances. PMID- 28895458 TI - The role of psychotherapy in domestic violence. PMID- 28895459 TI - Hearing Loss following Posterior Fossa Microvascular Decompression: A Systematic Review. AB - Objectives (1) Determine the prevalence of hearing loss following microvascular decompression (MVD) for trigeminal neuralgia (TN) and hemifacial spasm (HFS). (2) Demonstrate factors that affect postoperative hearing outcomes after MVD. Data Sources PubMed-NCBI, Scopus, CINAHL, and PsycINFO databases from 1981 to 2016. Review Methods Systematic review of prospective cohort studies and retrospective reviews in which any type of hearing loss was recorded after MVD for TN or HFS. Three researchers extracted data regarding operative indications, procedures performed, and diagnostic tests employed. Discrepancies were resolved by mutual consensus. Results Sixty-nine references with 18,233 operations met inclusion criteria. There were 7093 patients treated for TN and 11,140 for HFS. The overall reported prevalence of hearing loss after MVD for TN and HFS was 5.58% and 8.25%, respectively. However, many of these studies relied on subjective measures of reporting hearing loss. In 23 studies with consistent perioperative audiograms, prevalence of hearing loss was 13.47% for TN and 13.39% for HFS, with no significant difference between indications ( P = .95). Studies using intraoperative brainstem auditory evoked potential monitoring were more likely to report hearing loss for TN (relative risk [RR], 2.28; P < .001) but not with HFS (RR, 0.88; P = .056). Conclusion Conductive and sensorineural hearing loss are important complications following posterior fossa MVD. Many studies have reported on hearing loss using either subjective measures and/or inconsistent audiometric testing. Routine perioperative audiogram protocols improve the detection of hearing loss and may more accurately represent the true risk of hearing loss after MVD for TN and HFS. PMID- 28895460 TI - Comparison of Neuropsychological Functioning Between Adults With Early- and Late Onset DSM-5 ADHD. AB - OBJECTIVE: We aimed to compare the visually dependent neuropsychological functioning among adults with Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) ADHD who recalled symptom onset by and after age 7 and non-ADHD controls. METHOD: We divided the participants, aged 17 to 40 years, into three groups-(a) ADHD, onset <7 years (early-onset, n = 142); (b) ADHD, onset between 7 and <12 years (late-onset, n = 41); (c) non-ADHD controls ( n = 148) and compared their neuropsychological functioning, measured by the Cambridge Neuropsychological Testing Automated Battery. RESULTS: Both ADHD groups had deficits in attention and signal detectability, spatial working memory, and short term spatial memory, but only the early-onset group showed deficits in alertness, set-shifting, and planning after controlling for age, sex, and psychiatric comorbidities. There was no statistical difference between the two ADHD groups in neuropsychological functioning. CONCLUSION: DSM-5 criteria for diagnosing adult ADHD are not too lax regarding neuropsychological functioning. PMID- 28895461 TI - Skeletal Muscle Atrophy and Degeneration in a Mouse Model of Traumatic Brain Injury. AB - Atrophy is thought to be a primary mode of muscle loss in neuromuscular injuries. The differential effects of central and peripheral injuries on atrophy and degeneration/regeneration in skeletal muscle tissue have not been well described. This study investigated skeletal muscle atrophy and degeneration/regeneration in an animal model of traumatic brain injury (TBI). Eight 8-month-old wild-type C57BL6 mice underwent either a sham craniotomy or TBI targeting the motor cortex. Atrophy (fiber area; FA) and degeneration/regeneration (centralized nuclei proportions; CN) of the soleus and tibialis anterior (TA) muscles were measured 2 months post-injury. Injured soleus FAs were smaller than sham soleus (p = 0.02) and injured TA (p < 0.001). Mean CNs were higher in the TBI-injured TA than in other muscles. Differential TBI-induced atrophy and degeneration/regeneration in lower limb muscles suggests that muscle responses to cortical injury involve more complex changes than those observed with simple disuse atrophy. PMID- 28895462 TI - Is Hospitalization Necessary after Ear Surgery? A National Survey and Retrospective Review of Postoperative Events. AB - Objective First, to survey our national otolaryngology colleagues on their postoperative care habits (hospitalization vs day surgery) after elective middle ear surgery. Second, to evaluate the necessity of hospitalization and safety of day surgery after these procedures. Methods A national survey regarding postoperative habits after elective middle ear surgery was launched. Then, the cases of all patients having undergone these surgical procedures at our center between 2010 and 2016 were reviewed. They were divided into 2 groups: hospitalization and day surgery. Postoperative events during hospitalization and rate of consultation/readmission for day surgery were recorded. Results Heterogeneity in postoperative habits for most elective otologic surgery exists among otolaryngologists. For tympanoplasty, however, day surgery was uniformly favored. At our institution, 88.6% of hospitalization patients had no complications during their stay. Complications noted for others were nausea (7.2%), bleeding (3.1%), hematoma (0.5%), and sensorineural hearing loss (0.5%). In the day surgery group, 3.0% consulted within 48 hours following their procedure, and the readmission rate was 1.3%. Nausea was the only cause for readmission, and stapes surgery accounted for 100% of readmissions. Discussion Most elective middle ear surgery can be safely performed as day care. Hospitalization does not provide care that could not have been provided at home in the majority of cases. Overnight hospital stay may be considered for stapes surgery. Implications for Practice Day surgery for elective middle ear surgery is sufficient for most cases. Transferring these cases to day care should lower costs to our health care system and increase bed availability. PMID- 28895463 TI - Impact of Primary Language and Insurance on Pediatric Hearing Health Care in a Multidisciplinary Clinic. AB - Objective This study aims to describe the effects of primary language and insurance status on care utilization among deaf or hard-of-hearing children under active otolaryngologic and audiologic care. Study Design Cross-sectional analysis. Setting Multidisciplinary hearing loss clinic at a tertiary center. Subjects and Methods Demographics, hearing loss data, and validated survey responses were collected from 206 patients aged 0 to 19 years. Two-sided t tests and chi2 tests were used to obtain descriptive statistics and hypothesis testing. Results Of the sample, 52.4% spoke primarily English at home. Non-English speaking children and families were less likely to receive psychiatric counseling (12.2% vs 35.2% in the English group, P < .001) and reported more difficulty obtaining educational interventions ( P = .016), and 68.9% had public insurance. Parents of publicly insured children were less likely to know the type or degree of their child's hearing loss (56.9% vs 75.4%, P = .022), and these children were older on presentation to the clinic (8.5 vs 6.5 years of age, P = .01) compared to privately insured children. Publicly insured children were less likely to receive cochlear implants ( P = .046) and reported increased difficulty obtaining hearing aids ( P = .047). While all patients reported impairment in hearing related quality of life, publicly insured children aged 2 to 7 years were more likely to perform below minimum thresholds on measures of auditory/oral functioning. Conclusion Even when under active care, deaf or hard-of-hearing children from families who do not speak English at home or with public insurance face more difficulty obtaining educational services, cochlear implants, and hearing aids. These findings represent significant disparities in access to necessary interventions. PMID- 28895465 TI - Paraneoplastic Cushing syndrome, case-series and review of the literature. AB - OBJECTIVES: Paraneoplastic Cushing syndrome is a rare condition, representing a small fraction of the adrenocorticotropic hormone (ACTH)-dependent cases of Cushing syndrome Methods: Four case descriptions and literature review, highlighting the diagnostic challenges and treatment options are presented. RESULTS: Different tumor types can be associated with ectopic ACTH secretion. The most common types are bronchial carcinoids and small cell lung carcinoma (SCLC). However, in approximately 10 to 20% of the cases, no overt tumor (occult tumor) can be found. The diagnosis is made in a multistep process. Firstly, hypercortisolemia and adrenocorticotropin hormone dependency have to be confirmed. Distinction between a pituitary or ectopic cause can be cumbersome. MRI of the pituitary gland, a corticotropin releasing hormone stimulation test and a sinus petrosus sampling can be used. Treatment options consist of tumor management, somatostatin analogs, steroidogenesis inhibitors, and bilateral adrenalectomy. CONCLUSION: Clinicians should consider the diagnosis, and opt for specific treatment, especially in patients with a history of neuroendocrine tumors. PMID- 28895464 TI - Use of a Novel Polymer in an Animal Model of Head and Neck Squamous Cell Carcinoma. AB - Objective To evaluate the adverse effects and therapeutic efficacy of our biocompatible polymer platform delivering targeted local therapy of cytokine CCL21 and cisplatin in a partially resected xenograft animal model of head and neck squamous cell carcinoma. In addition, to evaluate the efficacy of cotreatment with radiotherapy and assess the biocompatibility of the cisplatin eluting polymer in the murine neck. Study Design Experimental animal study. Setting Academic research laboratory. Subjects and Methods SCCVII/SF cell injection established head and neck squamous cell carcinoma tumors in C3H/HeJ mice. Subjects underwent surgery, and a chemokine-eluting polymer was implanted into the resected site. Subjects treated with cisplatin received radiation or no radiation, and tissue was harvested after 8 weeks to assess polymer biocompatibility. Results Our results with the polymer platform significantly ( P < .05) reduced SCCVII/SF tumor size in C3H/HeJ mice with cisplatin (49% +/- 8.7%, Delta3.4 +/- 0.6 cm3 [95% CI]), CCL21 (42% +/- 4.8%, Delta3.5 +/- 0.4 cm3), and cisplatin/CCL21 dual-agent polymer (82% +/- 4.4%, Delta8.0 +/- 0.4 cm3) as compared with controls. Cisplatin polymer with high-dose (16 Gy) and low-dose (4 Gy) radiation reduced tumor mass (respectively, 92% +/- 7.2%, Delta6.1 +/- 0.5 cm3; 85% +/- 7.4%, Delta5.7 +/- 0.5 cm3) as compared with the reduction from high dose radiotherapy alone (70% +/- 7.9%, Delta4.7 +/- 0.5 cm3). No significant toxicity or inflammation was noted on histopathology after radiotherapy and cisplatin-eluting polymer treatment. Conclusion Cisplatin, CCL21, and cisplatin/CCL21 dual-agent polymer all exhibit significant antitumor effects and decrease tumor burden. Moreover, combination cisplatin polymer with radiotherapy may permit a decrease in intensity of radiation therapy in patients having received the cisplatin polymer. Histopathologic analysis suggests that the polymer is free from significant adverse effects in this model and warrants clinical trial. PMID- 28895466 TI - Lower limb muscle activity during table tennis strokes. AB - This study aimed to compare the muscle activity of lower limbs across typical table tennis strokes. Fourteen high-level players participated in this study in which five typical strokes (backhand top, forehand top, forehand spin, forehand smash, flick) were analysed. Surface electromyography activity (EMG) of eight muscles was recorded (gluteus maximus, biceps femoris, vastus medialis, vastus lateralis, rectus femoris, gastrocnemius medialis, gastrocnemius lateralis, soleus) and normalised to the maximal activity measured during squat jump or isometric maximal voluntary contractions. The forehand spin, the forehand top and the forehand smash exhibited significant higher EMG amplitude when compared with other strokes. Both biceps femoris and gluteus maximus were strongly activated during the smash, forehand spin and forehand top (from 62.8 to 91.7% of maximal EMG activity). Both vastii and rectus femoris were moderately to strongly activated during the forehand spin (from 50.4 to 62.2% of maximal EMG activity) whereas gastrocnemii and soleus exhibited the highest level of activity during the smash (from 67.1 to 92.1% of maximal EMG activity). Our study demonstrates that offensive strokes, such as smash or forehand top, exhibit higher levels of activity than other strokes. PMID- 28895467 TI - Kinetic and kinematic patterns during high intensity clean movement: searching for optimal load. AB - The aim of the present study was to investigate loading effects on kinematic and kinetic variables among elite-weightlifters in order to identify an optimal training load to maximize power production for clean-movement. Nine elite weightlifter (age: 24 +/- 4years, body-mass: 77 +/- 6.5kg, height: 176 +/- 6.1cm and 1RM clean: 170 +/- 5kg) performed 2 separate repetitions of the clean using 85, 90, 95% and 100%, in a randomized order, while standing on a force platform and being recorded using 3D-capture-system. Differences in kinematics (barbell displacement, velocity and acceleration) and kinetics (power, vertical ground reaction force (vGRF), rate of force development (RFD), and work) across the loads were statistically assessed. Results revealed significant load effects for the majority of the studied parameters (p < 0.01) and showed that typical bar displacement, greatest bar-velocity and peak-power were achieved at 85 and 90% 1RM (p < 0.001). Additionally greater average power was shown for 90 and 95% (p < 0.01) and greater work and vGRF were shown for 90, 95 and 100% than 85% 1RM (p < 0.05). Load had no significant effect on peak-vGRF and peak-RFD (p > 0.05). The results of this study, suggest 90% 1RM to be the most advantageous load to train explosive-force and to enhance power-outputs while maintaining technical efficiency in elite-weightlifters. PMID- 28895468 TI - Prevalence of Ideal Cardiovascular Health and Its Association with Cognitive Function in Older Adults: The Chilean National Health Survey (2009-2010). AB - Health behaviors and risk factors are independently related with cognitive function in older adults. This study aimed at examining the prevalence and relationship between cognitive function and a number of ideal cardiovascular health (CVH) metrics in older adults from the 2009 to 2010 Chilean National Health Survey. Data from 460 older adults (mean age 73.5 years old, 59.3% women) from the 2009 to 2010 Chilean Health Survey were analyzed. Ideal CVH was defined as meeting the ideal levels of the following components: four behaviors (smoking, body mass index, physical activity, and diet adherence) and three factors (total cholesterol, blood pressure, and fasting glucose). Older adults were grouped into three categories according to their number of ideal CVH metrics: ideal (5-7 metrics), intermediate (3-4 metrics), and poor (0-2 metrics). Cognitive function was assessed by using the modified Mini-Mental Status Examination (mMMSE). Of the 460 participants, 2% had 0 ideal metrics, 11.3% had 1, 23.9% had 2, 32.2% had 3, 20.7% had 4, 9.6% had 5, 0.4% had 6, and 0% had 7. Cognitive function was greater in older adults who met the ideal smoking, physical activity, and fasting blood glucose criteria. Logistic regression analysis suggested that ideal physical activity (Odds Ratio [OR] = 0.411 95% confidence interval [95% CI], 0.209-0.807) and smoking (OR = 0.429 95% CI, 0.095-0.941) behaviors reduced the likelihood of cognitive impairment. Moreover, compared with a poor profile (0-2 metrics), an intermediate (3-4 metrics) (OR = 0.221 95% CI, 0.024-0.911) and ideal CVH profile (5-7 metrics) (OR = 0.106 95% CI, 0.013-0.864) reduced the likelihood of cognitive impairment. We found that intermediate and ideal profiles were associated with a similarly low prevalence of cognitive impairment in Chilean older adults. PMID- 28895469 TI - Trends in aggressive play and refereeing among the top five European soccer leagues. AB - Current trends suggest professional soccer is becoming less aggressive, with England often argued to have the most aggressive of the top European leagues. The purpose of this study was to investigate differences in fouls and cards as indicators of aggressive play in the first divisions of England, France, Germany, Italy, and Spain over the past decade. Number of fouls per match and per yellow card has decreased in all leagues since 2007/08, though attempted tackles per foul has not changed or has increased. A lack of substantial rule changes suggests players have become less aggressive in tackling as opposed to referees becoming more lenient. Total number of fouls and cards per match were consistently lower in the English Premier League, however attempted tackles per foul was higher. The data also demonstrate the notions of home advantage and potentially referee bias, since referees tended to call more fouls and award more cards to away teams. Lastly, number of attempted tackles per foul and yellow cards received exhibited the strongest correlations with final league position across the leagues. In conclusion, our data support that elite European soccer has become less aggressive and the English Premier League is the most aggressive league. PMID- 28895470 TI - Generation of a Close-to-Native In Vitro System to Study Lung Cells-Extracellular Matrix Crosstalk. AB - Extracellular matrix (ECM) is an essential component of the tissue microenvironment, actively shaping cellular behavior. In vitro culture systems are often poor in ECM constituents, thus not allowing for naturally occurring cell-ECM interactions. This study reports on a straightforward and efficient method for the generation of ECM scaffolds from lung tissue and its subsequent in vitro application using primary lung cells. Mouse lung tissue was subjected to decellularization with 0.2% sodium dodecyl sulfate, hypotonic solutions, and DNase. Resultant ECM scaffolds were devoid of cells and DNA, whereas lung ECM architecture of alveolar region and blood and airway networks were preserved. Scaffolds were predominantly composed of core ECM and ECM-associated proteins such as collagens I-IV, nephronectin, heparan sulfate proteoglycan core protein, and lysyl oxidase homolog 1, among others. When homogenized and applied as coating substrate, ECM supported the attachment of lung fibroblasts (LFs) in a dose-dependent manner. After ECM characterization and biocompatibility tests, a novel in vitro platform for three-dimensional (3D) matrix repopulation that permits live imaging of cell-ECM interactions was established. Using this system, LFs colonized the ECM scaffolds, displaying a close-to-native morphology in intimate interaction with the ECM fibers, and showed nuclear translocation of the mechanosensor yes-associated protein (YAP), when compared with cells cultured in two dimensions. In conclusion, we developed a 3D-like culture system, by combining an efficient decellularization method with a live-imaging culture platform, to replicate in vitro native lung cell-ECM crosstalk. This is a valuable system that can be easily applied to other organs for ECM-related drug screening, disease modeling, and basic mechanistic studies. PMID- 28895471 TI - The indirect costs of palliative care in end-stage cancer: A real-life longitudinal register- and questionnaire-based study. AB - BACKGROUND: Palliative care needs are increasing as more people are dying from incurable diseases. Healthcare costs have been reported to be highest during the last year of life, but studies on the actual costs of palliative care are scarce. AIM: To explore the resource use and costs of palliative care among end-stage breast, colorectal and prostate cancer patients after termination of life prolonging oncological treatments, that is, during the palliative care period. DESIGN: A real-life longitudinal register- and questionnaire-based study of cancer patients' resource use and costs. PARTICIPANTS: In total, 70 patients in palliative care with no ongoing oncological treatments were recruited from the Helsinki University Hospital or from the local hospice. Healthcare costs, productivity costs and informal care costs were included. RESULTS: The mean duration of the palliative care period was 179 days. The healthcare cost accounted for 55%, informal care for 27% and productivity costs for 18% of the total costs. The last 2 weeks of life contributed to 37% of the healthcare cost. The costs of the palliative care period were higher in patients living alone, which was mostly caused by inpatient care ( p = 0.018). CONCLUSION: The 45% share of indirect costs is substantial in end-of-life care. The healthcare costs increase towards death, which is especially true of patients living alone. This highlights the significant role of caregivers. More attention should be paid to home care and caregiver support to reduce inpatient care needs and control the costs of end-of-life care. PMID- 28895473 TI - Neuroinflammation in Amyotrophic Lateral Sclerosis: Role of Redox (dys)Regulation. AB - SIGNIFICANCE: Amyotrophic lateral sclerosis (ALS) is due to degeneration of upper and lower motor neurons in the anterior horn of the spinal cord and in the motor cortex. Mechanisms leading to motor neuron death are complex and currently the disease is untreatable. Recent Advances: Work in genetic models of ALS indicates that an imbalance in the cross talk that physiologically exists between motor neurons and the surrounding cells is eventually detrimental to motor neurons. In particular, the cascade of events collectively known as neuroinflammation and mainly characterized by a reactive phenotype of astrocytes and microglia, moderate infiltration of peripheral immune cells, and elevated levels of inflammatory mediators has been consistently observed in motor regions of the central nervous system (CNS) in sporadic and familial ALS, constituting a hallmark of the disease. Resident glial cells and infiltrated immune cells are considered among the major producers of reactive species of oxygen and nitrogen in pathological conditions of the CNS, including motor neuron diseases. CRITICAL ISSUES: The timing and exact role of oxidative stress-mediated neuroinflammation and damage to motor neurons in ALS are still not fully elucidated. FUTURE DIRECTIONS: It is clear that a major challenge in the next future will be to envisage effective strategies to modulate the neuroinflammatory response in the symptomatic stage of disease, to prevent progression of neurodegeneration through the propagation of oxidative damage. Antioxid. Redox Signal. 29, 15-36. PMID- 28895472 TI - Aldo-Keto Reductase (AKR) 1C3 inhibitors: a patent review. AB - INTRODUCTION: AKR1C3 is a drug target in hormonal and hormonal independent malignancies and acts as a major peripheral 17beta-hydroxysteroid dehydrogenase to yield the potent androgens testosterone and dihydrotestosterone, and as a prostaglandin (PG) F synthase to produce proliferative ligands for the PG FP receptor. AKR1C3 inhibitors may have distinct advantages over existing therapeutics for the treatment of castration resistant prostate cancer, breast cancer and acute myeloid leukemia. Area covered: This article reviews the patent literature on AKR1C3 inhibitors using SciFinder which identified inhibitors in the following chemical classes: N-phenylsulfonyl-indoles, N (benzimidazoylylcarbonyl)- N-(indoylylcarbonyl)- and N-(pyridinepyrrolyl)- piperidines, N-benzimidazoles and N-benzindoles, repurposed nonsteroidal antiinflammatory drugs (indole acetic acids, N-phenylanthranilates and aryl propionic acids), isoquinolines, and nitrogen and sulfur substituted estrenes. The article evaluates inhibitor AKR potency, specificity, efficacy in cell-based and xenograft models and clinical utility. The advantage of bifunctional compounds that either competitively inhibit AKR1C3 and block its androgen receptor (AR) coactivator function or act as AKR1C3 inhibitors and direct acting AR antagonists are discussed. Expert opinion: A large number of potent and selective inhibitors of AKR1C3 have been described however, preclinical optimization, is required before their benefit in human disease can be assessed. PMID- 28895474 TI - Temporal Profile of Microtubule-Associated Protein 2: A Novel Indicator of Diffuse Brain Injury Severity and Early Mortality after Brain Trauma. AB - This study compared cerebrospinal fluid (CSF) levels of microtubule-associated protein 2 (MAP-2) from adult patients with severe traumatic brain injury (TBI) with uninjured controls over 10 days, and examined the relationship between MAP-2 concentrations and acute clinical and radiologic measures of injury severity along with mortality at 2 weeks and over 6 months. This prospective study, conducted at two Level 1 trauma centers, enrolled adults with severe TBI (Glasgow Coma Scale [GCS] score <=8) requiring a ventriculostomy, as well as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 h following TBI and analyzed via enzyme-linked immunosorbent assay for MAP-2 (ng/mL). Injury severity was assessed by the GCS score, Marshall Classification on computed tomography (CT), Rotterdam CT score, and mortality. There were 151 patients enrolled-130 TBI and 21 control patients. MAP-2 was detectable within 6 h of injury and was significantly elevated compared with controls (p < 0.001) at each time-point. MAP-2 was highest within 72 h of injury and decreased gradually over 10 days. The area under the receiver operating characteristic curve for deciphering TBI versus controls at the earliest time-point CSF was obtained was 0.96 (95% CI 0.93-0.99) and for the maximal 24-h level was 0.98 (95% CI 0.97-1.00). The area under the curve for initial MAP-2 levels predicting 2-week mortality was 0.80 at 6 h, 0.81 at 12 h, 0.75 at 18 h, 0.75 at 24 h, and 0.80 at 48 h. Those with Diffuse Injury III-IV had much higher initial (p = 0.033) and maximal (p = 0.003) MAP-2 levels than those with Diffuse Injury I-II. There was a graded increase in the overall levels and peaks of MAP-2 as the degree of diffuse injury increased within the first 120 h post-injury. These data suggest that early levels of MAP-2 reflect severity of diffuse brain injury and predict 2-week mortality in TBI patients. These findings have implications for counseling families and improving clinical decision making early after injury and guiding multidisciplinary care. Further studies are needed to validate these findings in a larger sample. PMID- 28895475 TI - Delayed intranasal infusion of human amnion epithelial cells improves white matter maturation after asphyxia in preterm fetal sheep. AB - Perinatal hypoxic-ischemic (HI) brain injury remains highly associated with neurodevelopmental disability after preterm birth. There is increasing evidence that disability is linked with impaired white matter maturation, but there is no specific treatment. In this study, we evaluated whether, in preterm fetal sheep, delayed intranasal infusion of human amnion epithelial cells (hAECs) given 1, 3 and 10 days after severe HI, induced by umbilical cord occlusion for 25 min, can restore white matter maturation or reduce delayed cell loss. After 21 days recovery, asphyxia was associated with reduced electroencephalographic (EEG) maturation, brain weight and cortical area, impaired maturation of oligodendrocytes (OLs), no significant loss of total OLs but a marked reduction in immature/mature OLs and reduced myelination. Intranasal infusion of hAECs was associated with improved brain weight and restoration of immature/mature OLs and fractional area of myelin basic protein, with reduced microglia and astrogliosis. Cortical EEG frequency distribution was partially improved, with reduced loss of cortical area, and attenuated cleaved-caspase-3 expression and microgliosis. Neuronal survival in deep grey matter nuclei was improved, with reduced microglia, astrogliosis and cleaved-caspase-3-positive apoptosis. These findings suggest that delayed intranasal hAEC administration has potential to alleviate chronic dysmaturation after perinatal HI. PMID- 28895476 TI - Editor's presentation. PMID- 28895479 TI - Letters to the Editor. PMID- 28895480 TI - The Distribution of the Superficial Peroneal Nerve on the Dorsum of the Foot and its Clinical Importance in Flap Surgery. AB - BACKGROUND: The superficial peroneal nerve (SPN) and its branches are at risk during surgical exposures. Our study aimed to demonstrate the distribution of the SPN on the dorsum of the foot to aid in surgical procedures close to this nerve. METHODS: The SPN was dissected in 30 cadaver lower limbs (13 male and two female). RESULTS: The variations in the distribution of the nerve were classified into seven types. CONCLUSION: A detailed knowledge of the branching patterns of the SPN may help to decrease iatrogenic injury to this nerve. PMID- 28895477 TI - Prospective Comparative Study of the Efficacy and Safety of New-Generation Versus First-Generation System for Super-Mini-Percutaneous Nephrolithotomy: A Revolutionary Approach to Improve Endoscopic Vision and Stone Removal. AB - PURPOSE: The study sought to compare the procedural and clinical results of super mini-percutaneous nephrolithotomy (SMP) with the use of first- and new-generation devices. METHODS: A prospective, comparative cohort study was carried out between February 2013 and January 2017. Patients who underwent either first- or new generation SMP were eligible for the study. Inclusion criteria were adult patients with renal stone <4 cm, or in pediatric patients with renal stone <2.5 cm with a history of failed extracorporeal shockwave lithotripsy. The primary outcome of the present study was the operating time, which was calculated from the starting of percutaneous puncture to the wound closure. Secondary outcomes were the stone-free rate (SFR), blood loss (hemoglobin decrease), hospital stay, and postoperative complications. RESULTS: One hundred fifty-six consecutive patients who underwent SMP for treatment of renal stones were eligible for the study, with the first 85 patients undergoing SMP with the first-generation device, and the remaining 71 consecutive patients being treated with the new generation SMP system. The two groups of patients had comparable demographic data, including age, BMI, stone size, Guy's score, stone location, comorbidities, grade of hydronephrosis, and history of urinary tract infection. The new generation SMP had a shorter operation time (39.3 vs 50.5 min, p = 0.016) and shorter postoperative hospitalization time (2.1 vs 3.0 days, p < 0.001) than the first-generation SMP. No significant difference existed between the two groups for SFR, hemoglobin decrease, and tubeless rate. The overall operative complication rates using the Clavien-Dindo grading system were similar between the two cohorts of patients. CONCLUSION: The clinical outcomes of the new generation SMP in patients with moderate-sized renal stone were comparable when compared with the first-generation SMP. New-generation SMP system using an irrigation/suction sheath improved intraoperative irrigation, a more efficient hydrodynamic mechanism for retrieval of fragments. This may account for the shorter operative time than the first-generation SMP system demonstrated in this study. PMID- 28895481 TI - Clinical Tip: A Novel Method of Cartilage Resection from the First Metatarsophalangeal Joint. PMID- 28895482 TI - Self-care and health-related quality of life in chronic heart failure: A longitudinal analysis. AB - BACKGROUND: Self-care is assumed to benefit health outcomes in patients with chronic heart failure (HF), but the evidence is conflicting for health-related quality of life (HRQOL). The aim of this study was to examine the association of (changes in) self-care with HRQOL while adjusting for psychological distress. METHODS: In total, 459 patients (mean age = 66.1 +/- 10.5 years, 73% male) with chronic HF completed questionnaires at baseline and at 6, 12 and 18 months of follow-up. Self-care and HF-specific HRQOL were quantified with the European Heart Failure Self-care Behaviour scale and the Minnesota Living with Heart Failure Questionnaire. RESULTS: Using general linear models, multivariable between-subject (estimate = -0.14, p = 0.005) and no within-subject effects of self-care were found for better HRQOL over time. Associations between self-care and HRQOL were fully explained by depression (estimate = 1.77, p < 0.001). Anxiety (estimate = 4.49, p < 0.001) and Type D personality (estimate = 13.3, p < 0.001) were associated with poor HRQOL, but only partially accounted for the relationship between self-care and emotional HRQOL. CONCLUSIONS: Self-care was prospectively associated with better disease-specific HRQOL in patients with HF, which was fully accounted for by depression, and partially accounted for by anxiety and Type D personality. Changes in self-care within a person did not affect HRQOL. Psychological distress should be considered in future efforts to address self-care and HRQOL. PMID- 28895483 TI - Investigating sexual problems, psychological distress and quality of life in female patients with Takotsubo cardiomyopathy: A prospective case-control study. AB - BACKGROUND: Takotsubo cardiomyopathy (TSCM) has detrimental effects on both physical and psychological health of sufferers. However, little is known whether TSCM also affects sexual functioning in female patients. AIM: The aim of this study was to investigate psychological distress (depression and anxiety), health related quality of life, and sexual functioning in women with TSCM and compare them with women with acute myocardial infarction and with healthy controls. METHODS: A three group prospective case-control design was used. Female patients with TSCM or acute myocardial infarction, as well as healthy controls (94 in each group), were recruited across eight Iranian university hospitals. Data were collected at baseline and after six and 18 months using the Hospital Anxiety and Depression Scale, the Short Form-12, the Female Sexual Function Index and the Female Sexual Distress Scale. Multilevel logistic regression was conducted. RESULTS: The TSCM group showed worst sexual functioning and the highest level of anxiety and depression at baseline ( p<0.01) compared with the two other groups. The TSCM and AMI groups showed comparable health-related quality of life at baseline, which was lower in both groups compared with the healthy controls ( p<0.01). Overall, depression, anxiety and health-related quality of life showed a significant change over time, especially in the TSCM group, with health-related quality of life decreasing, while anxiety and depression were increasing. Compared with the acute myocardial infarction and healthy control groups, the TSCM group showed a higher prevalence of sexual problems (odds ratios = 3.10 and 2.28, respectively) across time. Moreover, sexual functioning was found to be a mediator between anxiety and health-related quality of life in the TSCM group. CONCLUSION: Depression, anxiety, health-related quality of life, and sexual dysfunction tend to increase over time in female patients with TSCM; thus, healthcare providers should pay attention to these problems and provide appropriate treatment where necessary. PMID- 28895484 TI - Patterns, relevance and predictors of heart failure dyadic symptom appraisal. AB - BACKGROUND: Caregivers are thought to play a major role in helping patients first appraise and then respond to heart failure (HF) symptoms. AIMS: The aims of this study were to: (a) characterise distinct patterns of HF patient-caregiver dyads with respect to symptom appraisal; and (b) link dyadic symptom appraisal to contributions to self-care and caregiver strain. METHODS AND RESULTS: A cross sectional dyadic descriptive design was used to capture patient and caregiver appraisal of patient HF symptoms (i.e. dyspnoea, fatigue, pain and anxiety). Contributions to self-care were measured using patient and caregiver versions of the Self-Care of Heart Failure Index and the European Heart Failure Self-care Behaviour Scale. Caregiver strain was measured using the Multidimensional Caregiver Strain Index. Multilevel and latent class mixture modelling (LCMM) were used to examine distinct patterns of symptom appraisal. Two patterns of dyadic symptom appraisal were identified: one pattern ( n = 24; 38.7%) wherein caregivers appraised patients' symptoms as being significantly worse than did the patient (labelled as 'Caregiver > Patient'); and a second pattern ( n = 38; 61.3%) wherein patients appraised their symptoms similar to or worse than that as perceived by their caregiver (labelled as 'Patient ? Caregiver'). Dyads in the Caregiver > Patient pattern of symptom appraisal reported much better contributions to self-care (symptom response behaviours only), but also greater caregiver strain, compared with dyads in the Patient ? Caregiver pattern. Greater patient depression and older caregiver age were significant determinants of fitting the Patient ? Caregiver pattern. CONCLUSION: Differences in how HF patients and caregivers appraise symptoms together must be taken into consideration when examining contributions to HF care and caregiver outcomes. PMID- 28895485 TI - Efficacy of Adjuvant Magnesium for Posttonsillectomy Morbidity in Children: A Meta-analysis. AB - Objectives The perioperative administration of magnesium is known to reduce postoperative morbidities in adults, such as pain, agitation, and laryngospasm. The objective is to assess the effects of perioperative magnesium as the adjuvant to tonsillectomy as compared with tonsillectomy in children. Data Source Five databases (PubMed, SCOPUS, Embase, Web of Science, Cochrane). Method Two authors independently searched databases up to January 2017. We compared perioperative magnesium administration (magnesium groups) with no administration of magnesium (control group). The following outcomes were measured: postoperative pain intensity, analgesics administration, or other morbidities (laryngospasm, agitation, postoperative bleeding) in the postoperative 24 hours. Additionally, to evaluate the discrepancy of effects according to different administration routes, subgroup analyses regarding effects according to systemic or local administration of magnesium were performed. Results Nine prospective randomized controlled studies (n = 615) that evaluated the effect of magnesium in children having undergone tonsillectomy met inclusion criteria. Compared with control group, the time for first analgesic requirement was significantly delayed in magnesium groups (standardized mean difference = 0.75; 95% CI, 0.20-1.31; P = .0079). Laryngospasm (log odds ratio = -1.09; 95% CI,-2.11 to -0.07; P = .0362) and agitation score (standardized mean difference = -0.67; 95% CI, -0.97 to 0.36; P < .0001) in the recovery room also significantly decreased in magnesium groups. In subgroup analyses regarding pain and laryngospasm-related measurements, local administration of magnesium was shown to be more effective at reducing postoperative morbidities. Conclusions Perioperative magnesium regardless of route may offer pain, agitation, and laryngospasm relief without adverse effects in pediatric tonsillectomy. Based on the high heterogeneity of results within some parameters, further studies need to be performed to affirm these results. PMID- 28895486 TI - Iatrogenic Adrenal Insufficiency Secondary to Combination Therapy with Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Interlaminar Triamcinolone Injection in an AIDS Patient. AB - We report the first identified case of suspected iatrogenic adrenal insufficiency after an interlaminar injection of triamcinolone acetonide while on concomitant Stribild (elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg [EVG/c/TDF/FTC]). A 49-year-old female with HIV on EVG/c/TDF/FTC therapy presented to our endocrinology clinic to be evaluated for suspected Cushing syndrome. Prior to presentation, the patient had been given 2 interlaminar spinal injections of triamcinolone. Thereafter, she developed a swollen face, had unexplained weight gain, and fatigue. Cosyntropin stimulation test was positive for adrenal insufficiency. By applying the Naranjo Nomogram for Causality and the Drug Interaction Probability Scale to this drug-drug interaction, we calculated a score of 6 ( probable) and 5 ( probable), respectively. Symptoms resolved without further intervention. The EVG/c/TDF/FTC contains cobicistat, a strong cytochrome P450 3A4 (CYP3A4) inhibitor, which can potentiate drug interactions involving metabolizing of medications via this pathway. Clinicians are reminded to be vigilant while assessing the potential pharmacokinetic drug interactions not mentioned by the manufacturer. PMID- 28895487 TI - "...like because you are a grownup, you do not need help": Experiences of Transition from Pediatric to Adult Care among Youth with Perinatal HIV Infection, Their Caregivers, and Health Care Providers in the Dominican Republic. AB - With the introduction of combination antiretroviral therapy (ART) worldwide, youth with perinatal HIV infection are increasingly surviving childhood and transitioning to adult care. Although a normal life span is anticipated posttransition, successful transition to adult HIV care has proven difficult, with worse outcomes posttransition than in pediatric and adult care. This study is a qualitative analysis of data from 4 focus groups of pre- and posttransition patients, caregivers, and healthcare providers in the Dominican Republic at an institution that provides comprehensive treatment including ART for HIV-infected persons of all ages. All groups discussed the problems and challenges that patients, caregivers, and providers experience while living the transition process and beyond. Five major themes emerged: the trauma of transition itself, ART adherence, experience and impact of stigma, social supports and barriers, and recommendations for improving outcomes. Participants' insights offered approaches for a versatile structured transition process. PMID- 28895488 TI - A Systematic Review of Psychological Interventions for Sleep and Fatigue after Mild Traumatic Brain Injury. AB - This review evaluated the evidence for psychological interventions to improve sleep and reduce fatigue after mild traumatic brain injury (mTBI). Eight electronic databases were searched up until August 2016 for studies that: 1) included adults; 2) tested intervention effectiveness on sleep quality and fatigue post-acutely; and 3) applied a broadly-defined psychological intervention (e.g., cognitive behavioral therapy [CBT], counseling, or education). Only randomized controlled trials were eligible for inclusion. Of the 698 studies identified, four met the eligibility criteria and underwent data extraction. These studies were assessed for risk of bias by two independent reviewers using the Scottish Intercollegiate Guidelines Network Methodology Checklist 2 for randomized controlled trials. One study applied CBT and three studies used enhanced education to improve outcomes. Limited evidence and methodological bias prevents strong conclusions about the effectiveness of psychological interventions for sleep and fatigue after mTBI. All but one study targeted general post-concussion symptoms rather than sleep or fatigue specifically. This runs the risk that the potential benefits of a targeted approach are underestimated in this literature, and future sleep- and fatigue-focused interventions are recommended. It is tentatively concluded that compared with standard care or the provision of generic advice, small improvements in sleep and fatigue are observed through psychological intervention post-mTBI. PMID- 28895489 TI - Effects of mild running on substantia nigra during early neurodegeneration. AB - Moderate physical exercise acts at molecular and behavioural levels, such as interfering in neuroplasticity, cell death, neurogenesis, cognition and motor functions. Therefore, the aim of this study is to analyse the cellular effects of moderate treadmill running upon substantia nigra during early neurodegeneration. Aged male Lewis rats (9-month-old) were exposed to rotenone 1mg/kg/day (8 weeks) and 6 weeks of moderate treadmill running, beginning 4 weeks after rotenone exposure. Substantia nigra was extracted and submitted to proteasome and antioxidant enzymes activities, hydrogen peroxide levels and Western blot to evaluate tyrosine hydroxylase (TH), alpha-synuclein, Tom-20, PINK1, TrkB, SLP1, CRMP-2, Rab-27b, LC3II and Beclin-1 level. It was demonstrated that moderate treadmill running, practiced during early neurodegeneration, prevented the increase of alpha-synuclein and maintained the levels of TH unaltered in substantia nigra of aged rats. Physical exercise also stimulated autophagy and prevented impairment of mitophagy, but decreased proteasome activity in rotenone exposed aged rats. Physical activity also prevented H2O2 increase during early neurodegeneration, although the involved mechanism remains to be elucidated. TrkB levels and its anterograde trafficking seem not to be influenced by moderate treadmill running. In conclusion, moderate physical training could prevent early neurodegeneration in substantia nigra through the improvement of autophagy and mitophagy. PMID- 28895490 TI - The Association between Dual-Task Gait after Concussion and Prolonged Symptom Duration. AB - Quantitative gait measurements can identify persistent postconcussion impairments. However, their prognostic utility after injury to identify the likelihood of prolonged concussion symptoms remains unknown. Our objective was to examine if dual-task gait performance measures are independently associated with persistent (> 28 days) concussion symptoms among a sample of athletes. Sixty individuals diagnosed with a sport-related concussion were assessed within 10 days of their injury. Each participant completed a postconcussion symptom scale, an injury history questionnaire, and a single/dual-task gait examination. They were followed until they no longer reported symptoms, and the duration of time required for symptom resolution was calculated. A binary multivariable logistic regression model determined the independent association between dual-task gait and symptom duration (<= 28 days vs. >28 days) while controlling for the effect of gender, age, symptom severity, injury-to-examination time, and history of concussion. Seventeen (28%) participants reported a symptom duration >28 days. The dual-task cost for average gait speed (-25.9 +/- 9.5% vs. -19.8 +/- 8.9%; p = 0.027) and cadence (-18.0 +/- 2.9% vs. -12.0 +/- 7.7%; p = 0.029) was significantly greater among participants who experienced symptoms for >28 days. After adjusting for potential confounding variables, greater dual-task average gait speed costs were independently associated with prolonged symptom duration (aOR = 0.908; 95% CI = 0.835-0.987). Examinations of dual-task gait may provide useful information during multifaceted concussion examinations. Quantitative assessments that simultaneously test multiple domains, such as dual tasks, may be clinically valuable after a concussion to identify those more likely to experience symptoms for >28 days after injury. PMID- 28895491 TI - Preliminary Validation of the World Health Organization Disability Assessment Schedule 2.0 for Mild Traumatic Brain Injury. AB - The purpose of this study is to examine the reliability, factor structure, and validity of the World Health Organization Disability Assessment Schedule (WHODAS 2.0 12 item version) in a sample of patients who were slow to recover from a mild traumatic brain injury (mTBI). Participants were 79 adults with mTBI recruited from one of four specialty outpatient clinics in Vancouver, Canada. The WHODAS 2.0 12 item version is a disease-nonspecific measure of disability representing six International Classification of Disability, Functioning, and Health activity and participation domains including cognition, mobility, self-care, interpersonal functioning, life activities, and participation. Results of analyses showed that the WHODAS 2.0 had high internal consistency and adequate construct and concurrent validity. A three factor structure emerged in this sample. The scale differentiated between patients with good and those with poor outcomes based on post-concussion syndrome, psychiatric, and pain status. Participants with multiple comorbidities reported the most disability on the WHODAS. Concurrent validity was also supported by lower WHODAS scores in participants who had returned to work versus those who had not. To our knowledge, this is the first study to evaluate the psychometric properties of the WHODAS 2.0 in a sample of people with mTBI. In summary, the WHODAS was sensitive to post-concussion syndrome after mTBI, as well as to health conditions that commonly co-occur with mTBI (e.g., mental health problems and chronic pain). PMID- 28895492 TI - Low cardiac vagal tone index by heart rate variability differentiates bipolar from major depression. AB - OBJECTIVES: Major depressive disorder (MDD) and depression in bipolar disorder (BD) are often difficult to distinguish from each other. Autonomic nervous system (ANS) dysregulation is associated with various depressive symptoms and inflammatory response disinhibition. The beat-to-beat pattern of heart rate (heart rate variability, HRV) offers a non-invasive portal to ANS function and provides a reliable index of resting cardiac vagal tone. We quantified HRV and measured inflammatory biomarkers in MDD and BD patients in an effort to derive potential diagnostic criteria for MDD and BD. METHODS: Sixty-four MDD and 37 BD patients were enrolled. HRV was assessed and blood was drawn at baseline after antidepressant washout and prior to study initiation. HRV was quantified and corrected for artefacts. RESULTS: MDD subjects had significantly higher baseline respiratory sinus arrhythmia (P = 0.05) and LF-HRV (P < 0.01) in comparison to BD subjects. Compared to MDD subjects, BD subjects had significantly higher baseline levels of IL-10 (P < 0.01) and MCP-1 (P < 0.01). In the MDD group only, baseline LF-HRV was significantly positively correlated to baseline levels of IL-10 (r = 0.47, P < 0.01). CONCLUSIONS: Reduced vagal tone and higher levels of inflammatory biomarkers may distinguish BD from MDD and reveal an underlying pathophysiology of depression involving ANS dysfunction and chronic immune system dysregulation. PMID- 28895496 TI - Coherent care pathways for medically unexplained symptoms. PMID- 28895497 TI - Turning blue babies pink: Alfred Blalock's shunt for Fallot's Tetralogy. PMID- 28895493 TI - Comparative health system performance in six middle-income countries: cross sectional analysis using World Health Organization study of global ageing and health. AB - Objective To assess and compare health system performance across six middle income countries that are strengthening their health systems in pursuit of universal health coverage. Design Cross-sectional analysis from the World Health Organization Study on global AGEing and adult health, collected between 2007 and 2010. Setting Six middle-income countries: China, Ghana, India, Mexico, Russia and South Africa. Participants Nationally representative sample of adults aged 50 years and older. Main outcome measures We present achievement against key indicators of health system performance across effectiveness, cost, access, patient-centredness and equity domains. Results We found areas of poor performance in prevention and management of chronic conditions, such as hypertension control and cancer screening coverage. We also found that cost remains a barrier to healthcare access in spite of insurance schemes. Finally, we found evidence of disparities across many indicators, particularly in the effectiveness and patient centredness domains. Conclusions These findings identify important focus areas for action and shared learning as these countries move towards achieving universal health coverage. PMID- 28895499 TI - Why empathy is an upside-down concept. PMID- 28895500 TI - Anesthetic Management of a Patient With Tracheal Dehiscence Post-Tracheal Resection Surgery. AB - We present a case of a patient with complete tracheal dehiscence and multiple false passages after recent tracheal resection and anastomosis. Loss of tracheal continuity after disruption of anastomosis with distal stump retraction presents a unique anesthetic challenge given lack of access to the trachea and the need for adequate anesthesia and analgesia for surgical neck dissection. Traditional airway management, including awake fiberoptic intubation, intubation via direct laryngoscopy, needle cricothyrotomy, and awake tracheostomy are not viable options. Using total intravenous anesthesia with spontaneous ventilation, surgeons dissected the neck, retrieved the distal tracheal stump, repaired the trachea, and formalized the tracheostomy. We highlight the importance of recognizing the symptoms of a tracheal rupture, understanding the extreme limitation of securing the airway with traditional techniques, and discuss the alternative techniques including use of extracorporeal membrane oxygenation to avoid airway management. Awareness of increased mortality risk with tracheal reoperation and the significance of close communication between the anesthesiologists, the surgeons, and the patient is necessary for successful management. PMID- 28895501 TI - Nourishing the Spirit: Exploratory Research on Ayahuasca Experiences along the Continuum of Recovery from Eating Disorders. AB - Eating disorders (EDs) are serious health conditions that are among the most difficult to treat. Innovative treatments are needed and modalities from across cultures must be considered. Ayahuasca is a psychoactive plant-based tea originally used by Amazonian indigenous groups. A growing body of research points to its promise in the healing of various mental health issues. This study explored the potential therapeutic value of ayahuasca in the context of EDs, including the perceived impact of the preparatory diet and the ayahuasca purge. Sixteen individuals previously diagnosed with an ED participated in a semi structured interview relating to their experiences with ceremonial ayahuasca drinking. Interviews were analyzed using thematic analysis. Themes presented relate to the reduction or cessation of ED and mental health symptoms, shifts in body perception, and the importance of a ceremonial setting and after-care. For some, the preparatory diet resulted in familiar patterns of concern; however, none felt triggered by the purge in ayahuasca. Ceremonial ayahuasca drinking shows promise in the healing of EDs and warrants further research. PMID- 28895502 TI - Characterization of the Epicardial Adipose Tissue in Decellularized Human-Scaled Whole Hearts: Implications for the Whole-Heart Tissue Engineering. AB - Whole-organ engineering is an innovative field of regenerative medicine with growing translational perspectives. Recent reports suggest the feasibility of decellularization and repopulation of entire human size hearts. However, little is known about the susceptibility of epicardial adipose tissue (EAT) to decellularization. In this study, human size hearts of ovine donors were subjected to perfusion-based decellularization using detergent solutions. Upon basic histological evaluation and total DNA measurement myocardial regions prove largely decellularized while EAT demonstrated cellular remnants, further confirmed by transmission electron microscopy. Western blot analysis showed a significant reduction in lipid-associated and cardiac proteins. However, gas chromatography revealed unchanged proportional composition of fatty acids in EAT of decellularized whole hearts. Finally, cell culture medium conditioned with EAT from decellularized whole hearts had a significant deleterious effect on cardiac fibroblasts. These data suggest that perfusion decellularization of human size whole hearts provides inconsistent efficacy regarding donor material removal from myocardial regions as opposed to EAT. PMID- 28895503 TI - Needs assessment with elder Syrian refugees in Lebanon: Implications for services and interventions. AB - Currently, over 1 million Syrian and Palestinian refugees have fled Syria to take refuge in Lebanon. Among this vulnerable population, elder refugees warrant particular concern, as they shoulder a host of additional health and safety issues that require additional resources. However, the specific needs of elder refugees are often overlooked, especially during times of crisis. Our study used a semi-structured interview to survey the needs of elder refugees and understand their perceived support from Lebanese fieldworkers. Results indicate a high prevalence of depression and cognitive deficits in elder refugees, who expressed concerns surrounding illness, loneliness, war, and instability. Elders highlighted the importance of family connectedness in fostering security and normalcy and in building resilience during times of conflict. Elders spoke of their role akin that of the social workers with whom they interacted, in that they acted as a source of emotional support for their communities. Overall, this study clarifies steps to be taken to increase well-being in elder refugee populations and urges the response of humanitarian organisations to strengthen psychological support structures within refugee encampments. PMID- 28895504 TI - Understanding exercise hemodynamics. PMID- 28895505 TI - Pulmonary hypertension in chronic kidney disease: a hemodynamic characterization. PMID- 28895506 TI - Targeting L-arginine-nitric oxide-cGMP pathway in pulmonary arterial hypertension. PMID- 28895507 TI - Functional impact of exercise pulmonary hypertension in patients with borderline resting pulmonary arterial pressure. AB - Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP's in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure <=15 mmHg (n = 312) were stratified by mPAP < 13, 13-16, 17-20, and 21-24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13-16, 17-20, and 21-24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non PH (peak oxygen uptake 70 +/- 16% versus 92 +/- 19% predicted, P < 0.01; 72 +/- 13% versus 86 +/- 17% predicted, P < 0.05; and 64 +/- 15% versus 82 +/- 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 +/- 15% versus 68 +/- 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 +/- 599 mL/min versus 1756 +/- 720 mL/min versus 2482 +/- 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted. PMID- 28895509 TI - Mycoplasma tullyi sp. nov., isolated from penguins of the genus Spheniscus. AB - A mycoplasma isolated from the liver of a dead Humboldt penguin (Spheniscus humboldti) and designated strain 56A97T, was investigated to determine its taxonomic status. Complete 16S rRNA gene sequence analysis indicated that the organism was most closely related to Mycoplasma gallisepticum and Mycoplasma imitans(99.7 and 99.9 % similarity, respectively). The average DNA-DNA hybridization values between strain 56A97T and M. gallisepticum and M. imitans were 39.5 and 30 %, respectively and the Genome to Genome Distance Calculator gave results of 29.10 and 23.50 %, respectively. The 16S-23S rRNA intergenic spacer was 72-73 % similar to M. gallisepticum strains and 52.2 % to M. imitans. A partial sequence of rpoB was 91.1-92 % similar to M. gallisepticum strains and 84.7 % to M. imitans. Colonies possessed a typical fried-egg appearance and electron micrographs revealed the lack of a cell wall and a nearly spherical morphology, with an electron-dense tip-like structure on some flask-shaped cells. The isolate required sterol for growth, fermented glucose, adsorbed and haemolysed erythrocytes, but did not hydrolyse arginine or urea. The strain was compared serologically against 110 previously described Mycoplasma reference strains, showing that, except for M. gallisepticum, strain 56A97T is not related to any of the previously described species, although weak cross-reactions were evident. Genomic information, serological reactions and phenotypic properties demonstrate that this organism represents a novel species of the genus Mycoplasma, for which the name Mycoplasma tullyi sp. nov. is proposed; the type strain is 56A97T (ATCC BAA-1432T, DSM 21909T, NCTC 11747T). PMID- 28895508 TI - ESVM guidelines - the diagnosis and management of Raynaud's phenomenon. AB - Regarding the clinical diagnosis of Raynaud's phenomenon and its associated conditions, investigations and treatment are substantial, and yet no international consensus has been published regarding the medical management of patients presenting with this condition. Most knowledge on this topic derives from epidemiological surveys and observational studies; few randomized studies are available, almost all relating to drug treatment, and thus these guidelines were developed as an expert consensus document to aid in the diagnosis and management of Raynaud's phenomenon. This consensus document starts with a clarification about the definition and terminology of Raynaud's phenomenon and covers the differential and aetiological diagnoses as well as the symptomatic treatment. PMID- 28895510 TI - Catenovulum sediminis sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, strictly aerobic, rod-shaped and agar-hydrolysing bacterium, designated D2T, was isolated from a marine sediment sample collected from the coast of Weihai, China (37 degrees 31' 59" N 122 degrees 03' 47" E). The cells were motile by a lateral flagellum. Growth was observed at 10-42 degrees C, at pH 6.0-9.0 and with 0.5-8 % (w/v) NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain D2T belonged to the genus Catenovulum, appearing closely related to Catenovulum agarivorans YM01T (96.3 % 16S rRNA gene sequence similarity) and Catenovulum maritimumQ1T (93.9 %). The dominant fatty acids were summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2 OH), C16 : 0 and C10 : 0 3-OH. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, two phosphoaminolipids, two unknown lipids and three phospholipids. Ubiquinone 8 (Q-8) was found to be the major respiratory quinone. The DNA G+C content was 40.4 mol%. On the basis of genotypic, phenotypic and phylogenetic evidence, strain D2T is presented as a representative of a novel species of the genus Catenovulum, for which the name Catenovulum sediminis sp. nov. is proposed. The type strain is D2T (=KCTC 42869T=MCCC 1H00129T). An emended description of the genus Catenovulum is also provided. PMID- 28895511 TI - Croceivirga radicis gen. nov., sp. nov., isolated from a rotten tropical mangrove root. AB - A novel bacterial strain, designated HSG9T, was isolated from aisolated from a rotten tropical mangrove root. Cells of strain HSG9T were aerobic, Gram-stain negative, yellow, oxidase-negative and catalase-positive. Growth was observed in 0.5-9 % sea salt (optimum 3 %, w/v), at 10-42 degrees C (optimum 25-35 degrees C) and at pH 6.0-8.0 (optimum 7.0-8.0). Gelatin, esterase and Tweens 20, 40, 60 and 80 were hydrolysed, but starch, protein, cellulose and casein were not. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain HSG9T formed an independent lineage related to the family Flavobacteriaceae. The dominant fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The respiratory quinone was identified as MK-6 and the polar lipids were phosphatidylethanolamine, three unidentified phospholipids and an unidentified lipid. The DNA G+C content was 37.1 mol%. The combined genotypic and phenotypic data indicated that strain HSG9T represents a novel species of a new genus within the family Flavobacteriaceae, for which the name Croceivirgaradicis gen. nov., sp. nov. is proposed. The type strain is HSG9T (=MCCC 1A06690T=KCTC 52589T). PMID- 28895512 TI - Oryzisolibacter propanilivorax gen. nov., sp. nov., a propanil-degrading bacterium. AB - Strain EPL6T, a Gram-negative, motile, short rod was isolated from a propanil and 3,4-dichloroaniline enrichment culture produced from rice paddy soil. Based on the analyses of the 16S rRNA gene sequence, strain EPL6T was observed to be a member of the family Comamonadaceae, sharing the highest pairwise identity with type strains of the species Alicycliphilus denitrificans K601T (96.8 %) and Melaminivora alkalimesophila CY1T (96.8 %). Strain EPL6T was able to grow in a temperature range of 15-37 degrees C, pH 6-9 and in the presence of up to 4 % (w/v) NaCl and tested positive for catalase and oxidase reactions. The major respiratory quinone was Q8. The genomic DNA had a G+C content of 69.4+/-0.9 mol%. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol, and the major fatty acid methyl esters comprised C16 : 0, C18 : 1omega7c and summed feature 3 (C16 : 1omega7c/iso-C15 : 0 2-OH). Comparison of the genome sequence of strain EPL6T and of its closest neighbours, Melaminivora alkalimesophila CY1T and Alicycliphilus denitrificans K601T, yielded values of ANI <=84.1 % and of AAI <=80.3 %. Therefore, the genetic, phylogenetic, phenotypic and chemotaxonomic characteristics support the classification of this organism into a new taxon. Considering the genetic divergence of strain EPL6T from the type strains of the closest species, which belong to distinct genera, we propose a new genus within the family Comamonadaceae, named Oryzisolibacter propanilivorax gen. nov., sp. nov., represented by the isolate EPL6T as the type strain of the species (=LMG 28427T=CECT 8927T). PMID- 28895513 TI - Cadmium ion inhibition of quorum signalling in Chromobacterium violaceum. AB - Single-celled bacteria are capable of acting as a community by sensing and responding to population density via quorum signalling. Quorum signalling in Chromobacterium violaceum, mediated by the luxI/R homologue, cviI/R, regulates a variety of phenotypes including violacein pigmentation, virulence and biofilm formation. A number of biological and organic molecules have been described as quorum signalling inhibitors but, to date, metal-based inhibitors have not been widely tested. In this study, we show that quorum sensing is inhibited in C. violaceum in the presence of sub-lethal concentrations of cadmium salts. Notable Cd2+-inhibition was seen against pigmentation, motility, chitinase production and biofilm formation. Cd-inhibition of quorum-signalling genes occurred at the level of transcription. There was no direct inhibition of chitinase activity by Cd2+ at the concentrations tested. Addition of the cognate quorum signals, N-hexanoyl homoserine lactone or N-decanoyl homoserine lactone, even at concentrations in excess of physiological levels, did not reverse the inhibition, suggesting that Cd-inhibition of quorum signaling is irreversible. This study represents the first description of heavy metal-based quorum inhibition in C. violaceum. PMID- 28895514 TI - Lentibacillus sediminis sp. nov., isolated from a marine saltern. AB - A novel, Gram-stain-positive, moderately halophilic, endospore-forming, motile, facultatively anaerobic and rod-shaped strain, designated 0W14T, was isolated from a marine saltern of Wendeng, China. Optimal growth occurred at 37 degrees C, pH 7.5 and with 6.0 % (w/v) NaCl. MK-7 was the sole respiratory quinone and the peptidoglycan type of 0W14T was A4betal-Orn-d-Glu. The major cellular fatty acid (>10.0 %) in strain 0W14T was anteiso-C15 : 0. The polar lipid profile of strain 0W14T consisted of diphosphatidylglycerol, phosphatidylglycerol, two unknown glycolipids and four unknown phospholipids. The genomic DNA G+C content of the strain was 44.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 0W14T forms a phylogenetic lineage with members of the genus Lentibacillus within the family Bacillaceae. Based on data from the current polyphasic study, the isolate is proposed to represent a novel species of genus Lentibacillus, for which the name Lentibacillus sediminis sp. nov. is proposed. The type strain is 0W14T (=KCTC 33835T=MCCC 1H00171T). PMID- 28895515 TI - Escherichia coli type III secretion system 2 regulator EtrA promotes virulence of avian pathogenic Escherichia coli. AB - The Escherichia coli type III secretion system 2 (ETT2) is found in most E. coli strains, including pathogenic and commensal strains. Although many ETT2 gene clusters carry multiple genetic mutations or deletions, ETT2 is known to be involved in bacterial virulence. In enterohaemorrhagic E. coli (EHEC), ETT2 affects adhesion through the regulator EtrA, which regulates transcription and secretion of the type III secretion system (T3SS) encoded by the locus of enterocyte effacement (LEE). To date, no studies have been conducted on the role of EtrA in the virulence of avian pathogenic E. coli (APEC), which harbours only ETT2. Thus, we constructed etrA mutant and complemented strains of APEC and evaluated their phenotypes and pathogenicities. We found that the etrA gene deletion significantly reduced bacterial survival in macrophages, and proliferation and virulence in ducks. In addition, the etrA gene deletion reduced expression of the APEC fimbriae genes. Upregulation of genes encoding the pro inflammatory cytokines interleukin (IL)-1beta and IL-8 was also observed in HD-11 macrophages infected with the etrA gene mutant strain compared to the wild-type strain. Furthermore, the altered capacities of the mutant strain were restored by genetic complementation. Our observations demonstrate that the ETT2 regulator EtrA contributes to the virulence of APEC. PMID- 28895516 TI - Meyerozyma amylolytica sp. nov. from temperate deciduous trees and the transfer of five Candida species to the genus Meyerozyma. AB - In the course of two independent studies three yeasts have been isolated from temperate deciduous trees in Hungary and Germany. Analyses of nucleotide sequences of D1/D2 domains of the 26S rRNA gene (LSU) suggested that these strains belong to the Meyerozyma clade in Debaryomycetaceae (Saccharomycetales). The phylogenetic analysis of a concatenated alignment of the ITS region and LSU gene sequences confirmed the placement of the three strains in the Meyerozyma clade close to Candida elateridarum. If mixed in proper combinations, the strains formed one to two hat shaped ascospores in deliquescent asci. In addition to the ascospore formation, the three studied strains differed from Candida elateridarum and other members of the Meyerozyma clade in terms of ribosomal gene sequence and some physiological properties. To accommodate the above-noted strains, we describe the new species as Meyerozyma amylolytica sp. nov. (holotype: DSM 27310T; ex-type cultures: NCAIM Y.02140T=MUCL 56454T, allotype: NCAIM Y.01955A; ex-allotype culture: DSM 27468), MB 821663. Additionally, we propose the transfer of five non-ascosporic members of the Meyerozyma clade to the genus Meyerozyma as the following new taxonomic combinations Meyerozyma athensensis f.a., comb. nov. (MB 821664), Meyerozyma carpophila f.a., comb. nov. (MB 821665), Meyerozyma elateridarum f.a., comb. nov. (MB 821666), Meyerozyma neustonensis f.a., comb. nov. (MB 821667), and Meyerozyma smithsonii f.a., comb. nov. (MB 821668). PMID- 28895517 TI - Assessment of molecular and genetic evolution, antigenicity and virulence properties during the persistence of the infectious bronchitis virus in broiler breeders. AB - The infectious bronchitis virus (IBV) causes a highly contagious disease [infectious bronchitis (IB)] that results in substantial economic losses to the poultry industry worldwide. We conducted a molecular and phylogenetic analysis of the S1 gene of Brazilian (BR) IBV isolates from a routinely vaccinated commercial flock of broiler breeders, obtained from clinical IB episodes that occurred in 24 , 46- and 62-week-old chickens. We also characterized the antigenicity, pathogenesis, tissue tropism and spreading of three IBV isolates by experimental infection of specific pathogen-free (SPF) chickens and contact sentinel birds. The results reveal that the three IBV isolates mainly exhibited mutations in the hypervariable regions (HVRs) of the S1 gene and protein, but were phylogenetically and serologically closely related, belonging to lineage 11 of the GI genotype, the former BR genotype I. All three isolates caused persistent infection in broiler breeders reared in the field, despite high systemic anti-IBV antibody titres, and exhibited tropism and pathogenicity for the trachea and kidney after experimental infection in SPF chickens and contact birds. In conclusion, BR genotype I isolates of IBV evolve continuously during the productive cycle of persistently infected broiler breeders, causing outbreaks that are not impaired by the current vaccination programme with Massachusetts vaccine strains. In addition, the genetic alterations in the S1 gene of these isolates were not able to change their tissue tropism and pathogenicity, but did seem to negatively influence the effectiveness of the host immune responses against these viruses, and favour viral persistence. PMID- 28895518 TI - Lactobacillus curtus sp. nov., isolated from beer in Finland. AB - A Gram-stain-positive, catalase-negative and short-rod-shaped organism, designated VTT E-94560, was isolated from beer in Finland and deposited in the VTT culture collection as a strain of Lactobacillus rossiae. However, the results of 16S rRNA gene sequence analysis showed that VTT E-94560 was only related to Lactobacillus rossiae JCM 16176T with 97.0 % sequence similarity, lower than the 98.7 % regarded as the boundary for the species differentiation. Additional phylogenetic studies on the pheS gene, rpoA gene and 16S-23S rRNA internally transcribed spacer region further reinforced the taxonomically independent status of VTT E-94560 and its related Lactobacillus species including L. rossiae and Lactobacillus siliginis. Strain VTT E-94560 also exhibited several differences in its carbohydrate fermentation profiles from those related Lactobacillus species. In addition, DNA-DNA relatedness between VTT E-94560 and these two type strains was 4 % (L. rossiae JCM 16176T) and 12 % (L. siliginins JCM 16155T), respectively, which were lower than the 70 % cut-off for general species delineation, indicating that these three strains are not taxonomically identical at the species level. These studies revealed that VTT E-94560 represents a novel species, for which the name Lactobacillus curtus sp. nov. is proposed. The type strain is VTT E-94560T (=JCM 31185T). PMID- 28895519 TI - Parapedobacter lycopersici sp. nov., isolated from the rhizosphere soil of tomato plants (Solanum lycopersicum L.). AB - A novel Gram-stain-negative bacterial strain, designated T16R-256T, was isolated from the rhizosphere soil of tomato plants grown in a greenhouse in Yecheon-gun, Gyeongsangbuk-do, Republic of Korea and characterized using polyphasic taxonomy. Cells were aerobic, non-flagellated and rod-shaped. Colonies were light yellow, convex and round. The strain grew in the temperature range of 15-37 degrees C (optimally at 28-30 degrees C) and pH range of 7.0-9.0 (optimally at 7.0-8.0) and in 4 % NaCl (w/v). A comparison of 16S rRNA gene sequences showed that strain T16R-256T is a member of the genus Parapedobacter, exhibiting high sequence similarity with Parapedobacter pyrenivorans P-4T (94.2 %), Parapedobacter indicus RK1T (93.7 %), Parapedobacter koreensis Jip14T (93.7 %), Parapedobacter luteus 4M29T (93.6 %) and Parapedobacter soli DCY14T (93.4 %). The major polar lipids were phosphatidylethanolamine, sphingolipid, one aminophospholipid, two aminolipids and three unknown lipids. The major fatty acids (>10 % of the total fatty acids) were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 0 2-OH/C16 : 1omega7c. Strain T16R-256T contained MK-7 as the predominant respiratory quinone and homospermidine as the major polyamine. The genomic DNA G+C content of the type strain was 55.5 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain T16R-256T should be designated as representative of a novel species of the genus Parapedobacter, for which the name Parapedobacter lycopersici sp. nov. is proposed. The type strain is T16R-256T (=KACC 18788T=JCM 31602T). PMID- 28895520 TI - Three novel species of d-xylose-assimilating yeasts, Barnettozyma xylosiphila sp. nov., Barnettozyma xylosica sp. nov. and Wickerhamomyces xylosivorus f.a., sp. nov. AB - This study describes three novel xylose-assimilating yeasts, which were isolated from decayed wood collected from Bung Hatta Botanical Garden in West Sumatra and Cibodas Botanic Garden in West Java, or from litter from Eka Karya Bali Botanic Garden in Bali, Indonesia. Phylogenetic analysis was performed based on the sequences of the D1/D2 domains of the large ribosomal subunit (LSU), the small ribosomal subunit (SSU), the internal transcribed spacer (ITS) and elongation factor-1alpha (EF-1alpha), and the three strains were found to represent three novel species belonging to genera Barnettozyma or Wickerhamomyces. The morphological, biochemical and physiological characteristics indicated that the strains were distinct from other closely related species. Strains 13Y206T and 14Y196T belonging to the Barnettozyma clade are described as the type strains of Barnettozyma xylosiphila sp. nov. (type strain 13Y206T=NBRC 110202T=InaCC Y726T; MycoBank MB808598) and Barnettozyma xylosica sp. nov. (type strain 14Y196T=NBRC 111558T=InaCC Y1030T; MycoBank MB819485). Strain 14Y125T belonging to the Wickerhamomyces clade is described as the type strain of Wickerhamomyces xylosivorus f.a., sp. nov. (type strain 14Y125T=NBRC 111553T=InaCC Y1026T; MycoBank MB819484). PMID- 28895521 TI - Rhizobium esperanzae sp. nov., a N2-fixing root symbiont of Phaseolus vulgaris from Mexican soils. AB - Common bean (Phaseolus vulgaris L.) is the most important legume consumed worldwide; its genetic origins lie in the Mesoamerican (main centre) and Andean regions. It is promiscuous in establishing root-nodule symbioses; however, in the centres of origin/domestication, the predominant association is with Rhizobium etli. We have previously identified a new lineage (PEL-3) comprising three strains (CNPSo 661, CNPSo 666 and CNPSo 668T) isolated from root nodules of common bean in Mexico, and that have now been analysed in more detail. Sequences of the 16S rRNA gene positioned the three strains in a large clade including R. etli. Multilocus sequence analysis (MLSA) with four housekeeping genes (recA, glnII, gyrB and rpoA) positioned the three strains in a clade distinct from all other described species, with 100 % bootstrap support, and nucleotide identity (NI) of the four concatenated genes with the closest species R. etli was 95.0 %. Average nucleotide identity (ANI) values of the whole genome of CNPSo 668T and the closest species, R. etli, was 92.9 %. In the analyses of the symbiotic genes nifH and nodC, the strains comprised a cluster with other rhizobial symbionts of P. vulgaris. Other phenotypic and genotypic traits were determined for the new group and our data support the description of the three CNPSo strains as a novel species, for which the name Rhizobium esperanzae is proposed. The type strain is CNPSo 668T (=UMR 1320T=Z87-8T=LMG 30030 T=U 10001T), isolated from a common-bean nodule in Mexico. PMID- 28895522 TI - Flavobacterium quisquiliarum sp. nov., isolated from activated sludge. AB - A Gram-staining-negative, aerobic, rod-shaped bacterium, EA-12T, was isolated from activated sludge in Fujian Province, PR China. The results of phylogenetic analysis of the 16S rRNA gene sequences indicated that it was closely related to Flavobacterium pectinovorum DSM 6368T (97.5 %), Flavobacterium banpakuense 15F3T (97.0 %) and Flavobacterium arsenitoxidans S2-3HT (96.9 %). Cells grew at 15-37 degrees C (optimum, 25 degrees C), at pH 5.0-9.0 (optimum, pH 7.0) and in the presence of 0-1.0 % (w/v) NaCl. The strain contained MK-6 as the major menaquinone and the major cellular fatty acids were iso-C15 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and C16 : 0 3-OH. The polar lipids consisted of phosphatidylethanolamine and one unidentified phospholipid. The DNA G+C content was 36.1 mol% (Tm). The DNA-DNA relatedness between strain EA-12T and F. pectinovorum DSM 6368T was 38.6 %. On the basis of phenotypic, chemotaxonomic and phylogenetic comparisons with relatives and DNA-DNA relatedness values, it is concluded that EA-12T represents a novel species within the genus Flavobacterium, for which the name Flavobacterium quisquiliarum sp. nov. is proposed. The type strain is EA-12T (=CGMCC 1.15345T=NBRC 111769T). PMID- 28895523 TI - Characterisation of a newly isolated member of a candidatus lineage, Marispirochaeta aestuarii gen. nov., sp. nov. AB - Metagenome analysis of coastal marine habitats of Gujarat, India indicated the presence of twelve novel putative lineages of spirochaetes. Out of which a strain designated JC444T representing a novel putative lineage seven was isolated and characterized based on a polyphasic taxonomic approach. Strain JC444T was helical, Gram-stain-negative, obligate anaerobe, catalase and oxidase negative. Strain JC444T was able to grow at 15-45 degrees C (optimum at 30-35 degrees C), pH 6.5-8.6 (optimum at 7.5-8.0) and 0.6-5 % (optimum at 1.5-2.0 %) of NaCl concentration. The major end products of glucose fermentation were acetate, formate, hydrogen and carbon dioxide. C14 : 0, iso-C15 : 0, C16 : 0, C18 : 0, iso C15 : 1H/C13 : 03OH (summed feature 1), iso-C13 : 0, anteiso-C15 : 0 and iso-C17 : 0 were present as fatty acids. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and unidentified lipids (L1-4) were the polar lipids. G+C mol% of strain JC444T was 53.6 %. 16S rRNA gene sequence comparisons indicated that strain JC444T represents a member of the family Spirochaetaceae in the order Spirochaetales. Strain JC444T has a sequence similarity of 97.1 % with 'Candidatus Marispirochaeta associata' JC231 and <90.1 % with other members of the family Spirochaetaceae. Distinct morphological, physiological and genotypic differences from the previously described taxa support the classification of strain JC444T as a representative of a new genus and species in the family Spirochaetaceae, for which the name Marispirochaeta aestuarii gen. nov., sp. nov. is proposed. Type strain is JC444T (=KCTC 15554T=DSM 103365T). PMID- 28895524 TI - Nocardioides kandeliae sp. nov., an endophytic actinomycete isolated from leaves of Kandelia candel. AB - A Gram-stain-positive, aerobic, non-spore-forming, atrichous and short rod-shaped endophytic actinomycete, designated strain BGMRC 2075T, was isolated from the leaves of Kandelia candel, and was subjected to polyphasic characterization to unravel its taxonomic position. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain BGMRC 2075T belongs to the genus Nocardioides ,showing the highest 16S rRNA gene sequence similarity to Nocardioides aestuarii JC2056T (96.1 %), Nocardioides agariphilus MSL-28T (95.1 %) andNocardioides islandiensis MSL-26T (95.1 %). The predominant cellular fatty acids of strain BGMRC 2075T were iso-C16 : 0, C17 : 1omega8c and C17 : 0. The major menaquinone was MK-8(H4). The diagnostic diamino acid in the cell-wall peptidoglycan was ll 2,6-diaminopimelic acid. The predominant cell-wall sugars were composed of ribose and glucose. The polar lipid pattern contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylcholine, five unknown phospholipids, one phospholipid of unknown structure containing glucosamine, and an unknown polar lipid. The DNA G+C content was 70.8 mol%. All these data support the allocation of the novel strain to the genus Nocardioides. The results of physiological and biochemical characterization allow the phenotypic differentiation of strain BGMRC 2075T from N. aestuarii JC2056T, N. agariphilus MSL-28T and N. islandiensis MSL-26T. Strain BGMRC 2075T represents a novel species of the genus Nocardioides, for which we propose the name Nocardioides kandeliae sp. nov. The type strain is BGMRC 2075T (=KCTC 39886T=DSM 104480T). PMID- 28895525 TI - Description of Mycobacterium chelonae subsp. bovis subsp. nov., isolated from cattle (Bos taurus coreanae), emended description of Mycobacterium chelonae and creation of Mycobacterium chelonae subsp. chelonae subsp. nov. AB - Three rapidly growing mycobacterial strains, QIA-37T, QIA-40 and QIA-41, were isolated from the lymph nodes of three separate Korean native cattle, Hanwoo (Bos taurus coreanae). These strains were previously shown to be phylogenetically distinct but closely related to Mycobacterium chelonae ATCC 35752T by taxonomic approaches targeting three genes (16S rRNA, hsp6 and rpoB) and were further characterized using a polyphasic approach in this study. The 16S rRNA gene sequences of all three strains showed 99.7 % sequence similarity with that of the M. chelonae type strain. A multilocus sequence typing analysis targeting 10 housekeeping genes, including hsp65 and rpoB, revealed a phylogenetic cluster of these strains with M. chelonae. DNA-DNA hybridization values of 78.2 % between QIA-37T and M. chelonae indicated that it belongs to M. chelonae but is a novel subspecies distinct from M. chelonae. Phylogenetic analysis based on whole-genome sequences revealed a 95.44+/-0.06 % average nucleotide identity (ANI) value with M. chelonae, slightly higher than the 95.0 % ANI criterion for determining a novel species. In addition, distinct phenotypic characteristics such as positive growth at 37 degrees C, at which temperature M. chelonae does not grow, further support the taxonomic status of these strains as representatives of a novel subspecies of M. chelonae. Therefore, we propose an emended description of Mycobacterium chelonae, and descriptions of M. chelonae subsp. chelonae subsp. nov. and M. chelonae subsp. bovis subsp. nov. are presented; strains ATCC 35752T(=CCUG 47445T=CIP 104535T=DSM 43804T=JCM 6388T=NCTC 946T) and QIA-37T (=KCTC 39630T=JCM 30986T) are the type strains of the two novel subspecies. PMID- 28895526 TI - Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation. AB - BACKGROUND: Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. OBJECTIVES: To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. REVIEW METHODS: Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. RESULTS: Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of L20,000 per quality adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was L11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. LIMITATIONS: Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. CONCLUSIONS: Systematic review evidence suggests that MSI- and IHC based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016033879. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28895527 TI - Assessing the danger of self-sustained HIV epidemics in heterosexuals by population based phylogenetic cluster analysis. AB - Assessing the danger of transition of HIV transmission from a concentrated to a generalized epidemic is of major importance for public health. In this study, we develop a phylogeny-based statistical approach to address this question. As a case study, we use this to investigate the trends and determinants of HIV transmission among Swiss heterosexuals. We extract the corresponding transmission clusters from a phylogenetic tree. To capture the incomplete sampling, the delayed introduction of imported infections to Switzerland, and potential factors associated with basic reproductive number R0, we extend the branching process model to infer transmission parameters. Overall, the R0 is estimated to be 0.44 (95%-confidence interval 0.42-0.46) and it is decreasing by 11% per 10 years (4% 17%). Our findings indicate rather diminishing HIV transmission among Swiss heterosexuals far below the epidemic threshold. Generally, our approach allows to assess the danger of self-sustained epidemics from any viral sequence data. PMID- 28895528 TI - A synthetic biology approach to probing nucleosome symmetry. AB - The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this system for analysis of histone modification crosstalk, using mass spectrometry to separately identify modifications on each H3 molecule within asymmetric nucleosomes. The ability to generate asymmetric nucleosomes in vivo and in vitro provides a powerful and generalizable tool to probe the mechanisms by which H3 tails are read out by effector proteins in the cell. PMID- 28895529 TI - LARP4 mRNA codon-tRNA match contributes to LARP4 activity for ribosomal protein mRNA poly(A) tail length protection. AB - Messenger RNA function is controlled by the 3' poly(A) tail (PAT) and poly(A) binding protein (PABP). La-related protein-4 (LARP4) binds poly(A) and PABP. LARP4 mRNA contains a translation-dependent, coding region determinant (CRD) of instability that limits its expression. Although the CRD comprises <10% of LARP4 codons, the mRNA levels vary >20 fold with synonymous CRD substitutions that accommodate tRNA dynamics. Separately, overexpression of the most limiting tRNA increases LARP4 levels and reveals its functional activity, net lengthening of the PATs of heterologous mRNAs with concomitant stabilization, including ribosomal protein (RP) mRNAs. Genetic deletion of cellular LARP4 decreases PAT length and RPmRNA stability. This LARP4 activity requires its PABP-interaction domain and the RNA-binding module which we show is sensitive to poly(A) 3' termini, consistent with protection from deadenylation. The results indicate that LARP4 is a posttranscriptional regulator of ribosomal protein production in mammalian cells and suggest that this activity can be controlled by tRNA levels. PMID- 28895530 TI - Cell type boundaries organize plant development. AB - In plants the dorsoventral boundary of leaves defines an axis of symmetry through the centre of the organ separating the top (dorsal) and bottom (ventral) tissues. Although the positioning of this boundary is critical for leaf morphogenesis, how the boundary is established and how it influences development remains unclear. Using live-imaging and perturbation experiments we show that leaf orientation, morphology and position are pre-patterned by HD-ZIPIII and KAN gene expression in the shoot, leading to a model in which dorsoventral genes coordinate to regulate plant development by localizing auxin response between their expression domains. However we also find that auxin levels feedback on dorsoventral patterning by spatially organizing HD-ZIPIII and KAN expression in the shoot periphery. By demonstrating that the regulation of these genes by auxin also governs their response to wounds, our results also provide a parsimonious explanation for the influence of wounds on leaf dorsoventrality. PMID- 28895532 TI - A synaptotagmin suppressor screen indicates SNARE binding controls the timing and Ca2+ cooperativity of vesicle fusion. AB - The synaptic vesicle Ca2+ sensor Synaptotagmin binds Ca2+ through its two C2 domains to trigger membrane interactions. Beyond membrane insertion by the C2 domains, other requirements for Synaptotagmin activity are still being elucidated. To identify key residues within Synaptotagmin required for vesicle cycling, we took advantage of observations that mutations in the C2B domain Ca2+ binding pocket dominantly disrupt release from invertebrates to humans. We performed an intragenic screen for suppressors of lethality induced by expression of Synaptotagmin C2B Ca2+-binding mutants in Drosophila. This screen uncovered essential residues within Synaptotagmin that suggest a structural basis for several activities required for fusion, including a C2B surface implicated in SNARE complex interaction that is required for rapid synchronization and Ca2+ cooperativity of vesicle release. Using electrophysiological, morphological and computational characterization of these mutants, we propose a sequence of molecular interactions mediated by Synaptotagmin that promote Ca2+ activation of the synaptic vesicle fusion machinery. PMID- 28895531 TI - Genetic identification of a common collagen disease in puerto ricans via identity by-descent mapping in a health system. AB - Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease. PMID- 28895533 TI - What is a placental mammal anyway? AB - Many developmental functions in marsupials and eutherian mammals are accomplished by different tissues, but similar genes. PMID- 28895535 TI - An approach to screening for Cushing's syndrome in non-specialized health care settings. PMID- 28895534 TI - Molecular conservation of marsupial and eutherian placentation and lactation. AB - Eutherians are often mistakenly termed 'placental mammals', but marsupials also have a placenta to mediate early embryonic development. Lactation is necessary for both infant and fetal development in eutherians and marsupials, although marsupials have a far more complex milk repertoire that facilitates morphogenesis of developmentally immature young. In this study, we demonstrate that the anatomically simple tammar placenta expresses a dynamic molecular program that is reminiscent of eutherian placentation, including both fetal and maternal signals. Further, we provide evidence that genes facilitating fetal development and nutrient transport display convergent co-option by placental and mammary gland cell types to optimize offspring success. PMID- 28895536 TI - Impact of kitchen organization on oral intake of malnourished inpatients: A two center study. AB - AIM: To determine the impact of the type of hospital kitchen on the dietary intake of patients. METHODS: A cross-sectional, two-centre study, of cooking in a traditional kitchen (TK) and in a chilled kitchen (CK). Subjective global assessment (SGA) was used for nutritional diagnosis. Before study start, a dietician performed a nutritional assessment of the menus of each hospital. All dishes were weighed upon arrival to the ward and at the end of the meal. RESULTS: 201 and 41 patients from the centres with TK and CK respectively were evaluated. Prevalence of malnutrition risk was 50.2% at the hospital with TK and 48.8% at the hospital with CK (p=0.328). Forty-eight and 56 dishes were nutritionally evaluated at the hospitals with TK and CK respectively. Intake analysis consisted of 1993 and 846 evaluations in the hospitals with TK and CK respectively. Median food consumption was 76.83% at the hospital with TK (IQR 45.76%) and 83.43% (IQR 40.49%) at the hospital with CK (p<0.001). Based on the prevalence of malnutrition, a higher protein and energy intake was seen in malnourished patients from the CK as compared to the TK hospital, but differences were not significant after adjustment for other factors. CONCLUSIONS: Cooking in a chilled kitchen, as compared to a traditional kitchen, may increase energy and protein intake in hospitalized patients, which is particularly beneficial for malnourished patients. PMID- 28895537 TI - Definition of reference ranges for free T4, TSH, and thyroglobulin levels in healthy subjects of the Jaen Health District. AB - BACKGROUND AND OBJECTIVES: The treatment guidelines for thyroid dysfunction recommend defining reference ranges for thyroid hormones in each area through assessment of local population data considering the iodine nutritional status. The aim of this study was to define the reference ranges of free thyroxine (FT4), TSH, and thyroglobulin levels in a general population from Jaen, an area of southern Spain with an adequate iodine nutritional status, and whether they were associated with urinary iodine levels. PATIENTS AND METHODS: A cross-sectional study was conducted in 1,003 subjects of the general population of the Jaen Health District. Levels of urinary iodine, FT4, TSH, thyroglobulin, and thyroid peroxidase (TPO) antibodies were measured according to age and sex. RESULTS: Median and mean urinary iodine levels were 110.59MUg/L and 130.11MUg/L respectively. Median TSH level was 1.83MUIU/mL (p2.5=0.56MUIU/mL, p97.5=4.66MUIU/mL). Median FT4 level was 0.84ng/dL (p2.5=0.62ng/dL, p97.5=1.18ng/dL). TPO antibodies were detected in 5.7% of subjects. There was no correlation between urinary iodine levels and FT4, TSH or TPO antibodies. Subjects with positive TPO antibodies had higher TSH levels (3.34MUIU/L versus 2.14MUIU/mL, P=.001; odds ratio=2.42). CONCLUSIONS: Urinary iodine levels in Jaen are optimal according to World Health Organization standards. Reference ranges of FT4, TSH, and thyroglobulin do not differ from those reported in the literature and are no associated to urinary iodine levels. The prevalence of positive TPO antibodies was similar to that reported in other Spanish areas. PMID- 28895538 TI - Body composition in a population of school adolescents: a comparison of simple anthropometric methods and bioelectrical impedance. AB - OBJECTIVES: To report the anthropometric characteristics and body composition and to analyze the potential sex-based differences in Spanish schoolchildren and adolescents living in Granada and Ceuta. To estimate body fat percentage using regression equations and bioelectrical impedance to check for sex differences. An additional objective was to see whether the body fat percentages obtained by these two methods were similar. METHODS: A cross-sectional study including 1,518 children and adolescents (aged 9-16) from 12 primary and secondary schools in Ceuta and Granada. The nutritional status of the subjects was assessed and their body fat percentage was calculated. RESULTS: There was a strong sexual dimorphism, with higher prevalence rates of overweight in boys and obesity in girls. Girls had higher mean body fat levels regardless of the measuring method used (p<.001). Correlation between bioelectrical impedance analysis and regression equations was high (r=0.830), as was the internal correlation coefficient (ICC>0.75). A Bland-Altman comparison showed a high agreement between bioelectrical impedance and Behnke and Lohman equations. CONCLUSIONS: Specific equations considering subject sex and age should be used to estimate body density. Regardless of the method used, girls had higher body fat percentages. The Behnke and Lohman equations, combined with BIA, were found to be the most accurate methods for measuring body density in the study population. PMID- 28895539 TI - Frequency and clinical and molecular aspects of familial hypercholesterolemia in an endocrinology unit in Ciudad Bolivar, Venezuela. AB - OBJECTIVE: To assess the frequency and the clinical, biochemical, and molecular aspects of familial hypercholesterolemia (FH) in subjects attending an endocrinology unit. METHODS: An observational, descriptive study evaluating 3,140 subjects attending the endocrinology unit of Centro Medico Orinoco in Ciudad Bolivar, Venezuela, from 7 January 2013 to 9 December 2016. The index cases were selected using the Dutch Lipid Clinic Network criteria. Plasma lipid levels were measured, and a molecular analysis was performed by DNA sequencing of the LDLR and APOB genes. RESULTS: Ten (0.32%) of the 3,140 study patients had clinical and biochemical characteristics consistent with FH. All but one were female. Three had first-degree relatives with prior premature coronary artery; and none had a personal history of this condition. Three patients were obese; three had high blood pressure; and no one suffered from diabetes. Three patients had a history of tendon xanthomas, and one of corneal arcus. LDL-C levels ranged from 191 to 486mg/dL. Two patients were on statin therapy. The genetic causes of FH were identified in four patients, and were LDLR gene mutations in three of them and an APOB gene mutation in exon 26 in the other. CONCLUSION: Approximately, one out of every 300 people attending this endocrinology unit in those four years had FH, and LDLR gene mutations were the most prevalent cause. PMID- 28895540 TI - Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects. AB - BACKGROUND: Few studies assessing the relationship between single nucleotide polymorphisms in CNR2 and obesity or its related metabolic parameters are available. OBJECTIVE: To investigate the influence of polymorphism rs3123554 in the CNR2 receptor gene on obesity anthropometric parameters, insulin resistance, and adipokines in subjects with obesity. DESIGN: The study population consisted of 1027 obese subjects, who were performed bioelectrical impedance analyses, blood pressure measurements, serial assessments of dietary intake during three days, and biochemical tests. RESULTS: Genotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, HOMA-IR, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers. No differences were seen in these parameters between the GA and AA genotypes. There were no statistical differences in dietary intake. CONCLUSION: The main study finding was the association of the minor allele of the SNP rs3123554 in the CNR2 gene with body weight and triglyceride, HOMA-IR, insulin, and leptin levels. PMID- 28895541 TI - Financial impact of disease-related malnutrition at the San Pedro de Alcantara hospital. Estimated cost savings associated to a specialized nutritional survey. AB - INTRODUCTION AND OBJECTIVES: DRM is a highly prevalent condition in Spanish hospitals and is associated to increased healthcare costs. Costs associated to DRM were calculated using the methods of the PREDyCES study. The potential savings derived from specialized nutritional treatment were calculated by extrapolating the results of the SNAQ strategy. RESULTS: Median cost per procedure in patients with DRM was ?9,679.85, with a final cost of ?28,700,775.2. The cost of each patient with DRM was 2.63 times higher than the cost of patients with no DRM. The potential cost saving associated to specialized nutritional treatment was estimated at ?1,682,317.28 (5.86% of total cost associated to DRM). CONCLUSIONS: Patients with DRM showed a higher consumption of financial resources as compared to well-nourished patients. Specialized nutritional treatment is a potential cost-saving procedure. PMID- 28895542 TI - Selective sentinel lymph node biopsy in papillary thyroid carcinoma in patients with no preoperative evidence of lymph node metastasis. AB - INTRODUCTION: Lymphadenectomy is recommended during surgery for papillary thyroid carcinoma when there is evidence of cervical lymph node metastasis (therapeutic) or in high-risk patients (prophylactic) such as those with T3 and T4 tumors of the TNM classification. Selective sentinel lymph node biopsy may improve preoperative diagnosis of nodal metastases. OBJECTIVE: To analyze the results of selective sentinel lymph node biopsy in a group of patients with papillary thyroid carcinoma and no evidence of nodal involvement before surgery. PATIENTS AND METHOD: A retrospective, single-center study in patients with papillary thyroid carcinoma and no clinical evidence of lymph node involvement who underwent surgery between 2011 and 2013. The sentinel node was identified by scintigraphy. When the sentinel node was positive, the affected compartment was removed, and when sentinel node was negative, central lymph node dissection was performed. RESULTS: Forty-three patients, 34 females, with a mean age of 52.3 (+/ 17) years, were enrolled. Forty-six (27%) of the 170 SNs resected from 24 (55.8%) patients were positive for metastasis. In addition, 94 (15.6%) out of the 612 lymph nodes removed in the lymphadenectomies were positive for metastases. Twelve of the 30 (40%) low risk patients (cT1N0 and cT2N0) changed their stage to pN1, whereas 12 of 13 (92%) high risk patients (cT3N0 and cT4N0) changed to pN1 stage. CONCLUSIONS: Selective sentinel lymph node biopsy changes the stage of more than 50% of patients from cN0 to pN1. This confirms the need for lymph node resection in T3 and T4 tumors, but reveals the presence of lymph node metastases in 40% of T1-T2 tumors. PMID- 28895543 TI - Alcohol: are we enjoying responsibly? PMID- 28895544 TI - The subjective decision of cessation of colorectal cancer screening. PMID- 28895545 TI - Hepatitis C and the absence of genomic data in low-income countries: a barrier on the road to elimination? PMID- 28895551 TI - Indocyanine green fluorescence imaging in colorectal surgery: overview, applications, and future directions. AB - Indocyanine green fluorescence imaging is a surgical tool with increasing applications in colorectal surgery. This tool has received acceptance in various surgical disciplines as a potential method to enhance surgical field visualisation, improve lymph node retrieval, and decrease the incidence of anastomotic leaks. In colorectal surgery specifically, small studies have shown that intraoperative fluorescence imaging is a safe and feasible method to assess anastomotic perfusion, and its use might affect the incidence of anastomotic leaks. Controlled trials are ongoing to validate these conclusions. The number of new indications for indocyanine green continues to increase, including innovative options for detecting and guiding management of colorectal metastasis to the liver. These advances could offer great value for surgeons and patients, by improving the accuracy and outcomes of oncological resections. PMID- 28895552 TI - Measurement of track structure parameters of low and medium energy helium and carbon ions in nanometric volumes. AB - Ionization cluster size distributions produced in the sensitive volume of an ion counting wall-less nanodosimeter by monoenergetic carbon ions with energies between 45 MeV and 150 MeV were measured at the TANDEM-ALPI ion accelerator facility complex of the LNL-INFN in Legnaro. Those produced by monoenergetic helium ions with energies between 2 MeV and 20 MeV were measured at the accelerator facilities of PTB and with a 241Am alpha particle source. C3H8 was used as the target gas. The ionization cluster size distributions were measured in narrow beam geometry with the primary beam passing the target volume at specified distances from its centre, and in broad beam geometry with a fan-like primary beam. By applying a suitable drift time window, the effective size of the target volume was adjusted to match the size of a DNA segment. The measured data were compared with the results of simulations obtained with the PTB Monte Carlo code PTra. Before the comparison, the simulated cluster size distributions were corrected with respect to the background of additional ionizations produced in the transport system of the ionized target gas molecules. Measured and simulated characteristics of the particle track structure are in good agreement for both types of primary particles and for both types of the irradiation geometry. As the range in tissue of the ions investigated is within the typical extension of a spread-out Bragg peak, these data are useful for benchmarking not only 'general purpose' track structure simulation codes, but also treatment planning codes used in hadron therapy. Additionally, these data sets may serve as a data base for codes modelling the induction of radiation damages at the DNA-level as they almost completely characterize the ionization component of the nanometric track structure. PMID- 28895553 TI - Nanowire decorated, ultra-thin, single crystalline silicon for photovoltaic devices. AB - Reducing silicon (Si) wafer thickness in the photovoltaic industry has always been demanded for lowering the overall cost. Further benefits such as short collection lengths and improved open circuit voltages can also be achieved by Si thickness reduction. However, the problem with thin films is poor light absorption. One way to decrease optical losses in photovoltaic devices is to minimize the front side reflection. This approach can be applied to front contacted ultra-thin crystalline Si solar cells to increase the light absorption. In this work, homojunction solar cells were fabricated using ultra-thin and flexible single crystal Si wafers. A metal assisted chemical etching method was used for the nanowire (NW) texturization of ultra-thin Si wafers to compensate weak light absorption. A relative improvement of 56% in the reflectivity was observed for ultra-thin Si wafers with the thickness of 20 +/- 0.2 MUm upon NW texturization. NW length and top contact optimization resulted in a relative enhancement of 23% +/- 5% in photovoltaic conversion efficiency. PMID- 28895554 TI - Anomalous cyclotron mass dependence on the magnetic field and Berry's phase in (Cd1-x-y Zn x Mn y )3As2 solid solutions. AB - Shubnikov-de Haas (SdH) effect and magnetoresistance measurements of single crystals of diluted II-V magnetic semiconductors (Cd1-x-y Zn x Mn y )3As2 (x + y = 0.4, y = 0.04 and 0.08) are investigated in the temperature range T = 4.2 / 300 K and in transverse magnetic field B = 0 / 25 T. The values of the cyclotron mass m c, the effective g-factor g*, and the Dingle temperature T D are defined. In one of the samples (y = 0.04) a strong dependence of the cyclotron mass on the magnetic field m c(B) = m c(0) + alphaB is observed. The value of a phase shift close to beta = 0.5 indicates the presence of Berry phase and 3D Dirac fermions in a single crystals of (Cd1-x-y Zn x Mn y )3As2 in one of the samples (y = 0.08). PMID- 28895555 TI - Photonics surface waves on metamaterials interfaces. AB - A surface wave (SW) in optics is a light wave, which is supported at an interface of two dissimilar media and propagates along the interface with its field amplitude exponentially decaying away from the boundary. The research on surface waves has been flourishing in last few decades thanks to their unique properties of surface sensitivity and field localization. These features have resulted in applications in nano-guiding, sensing, light-trapping and imaging based on the near-field techniques, contributing to the establishment of the nanophotonics as a field of research. Up to present, a wide variety of surface waves has been investigated in numerous material and structure settings. This paper reviews the recent progress and development in the physics of SWs localized at metamaterial interfaces, as well as bulk media in order to provide broader perspectives on optical surface waves in general. For each type of the surface waves, we discuss material and structural platforms. We mainly focus on experimental realizations in the visible and near-infrared wavelength ranges. We also address existing and potential application of SWs in chemical and biological sensing, and experimental excitation and characterization methods. PMID- 28895556 TI - Challenges in computational evaluation of redox and magnetic properties of Fe based sulfate cathode materials of Li- and Na-ion batteries [J. Phys.: Condens. Matter 29 (2017) 215701]. AB - submitted as Erratum. PMID- 28895557 TI - Multi-level storage and ultra-high speed of superlattice-like Ge50Te50/Ge8Sb92 thin film for phase-change memory application. AB - Superlattice-like Ge50Te50/Ge8Sb92 (SLL GT/GS) thin film was systematically investigated for multi-level storage and ultra-fast switching phase-change memory application. In situ resistance measurement indicates that SLL GT/GS thin film exhibits two distinct resistance steps with elevated temperature. The thermal stability of the amorphous state and intermediate state were evaluated with the Kissinger and Arrhenius plots. The phase-structure evolution revealed that the amorphous SLL GT/GS thin film crystallized into rhombohedral Sb phase first, then the rhombohedral GeTe phase. The microstructure, layered structure, and interface stability of SLL GT/GS thin film was confirmed by using transmission electron microscopy. The transition speed of crystallization and amorphization was measured by the picosecond laser pump-probe system. The volume variation during the crystallization was obtained from x-ray reflectivity. Phase-change memory (PCM) cells based on SLL GT/GS thin film were fabricated to verify the multi level switching under an electrical pulse as short as 30 ns. These results illustrate that the SLL GT/GS thin film has great potentiality in high-density and high-speed PCM applications. PMID- 28895558 TI - Combination photo and electron beam lithography with polymethyl methacrylate (PMMA) resist. AB - We describe techniques for performing photolithography and electron beam lithography in succession on the same resist-covered substrate. Larger openings are defined in the resist film through photolithography whereas smaller openings are defined through conventional electron beam lithography. The two processes are carried out one after the other and without an intermediate wet development step. At the conclusion of the two exposures, the resist film is developed once to reveal both large and small openings. Interestingly, these techniques are applicable to both positive and negative tone lithographies with both optical and electron beam exposure. Polymethyl methacrylate, by itself or mixed with a photocatalytic cross-linking agent, is used for this purpose. We demonstrate that such resists are sensitive to both ultraviolet and electron beam irradiation. All four possible combinations, consisting of optical and electron beam lithographies, carried out in positive and negative tone modes have been described. Demonstration grating structures have been shown and process conditions have been described for all four cases. PMID- 28895559 TI - Sustained releasing sponge-like 3D scaffolds for bone tissue engineering applications. AB - Tissue engineering (TE) is envisaged to play a vital role in improving quality of life by restoring, maintaining or enhancing tissue and organ functions. TE scaffolds that are two-dimensional in structure suffer from undesirable issues, such as pore blockage, and do not closely mimic the native extra-cellular matrix in tissues. Significant efforts have therefore been channeled to fabricate three dimensional (3D) scaffolds using various techniques, especially electrospinning. In this study, we propose a modified one-step electrospinning process to arrive at a 3D scaffold with highly interconnected pores. Using a blend of poly (L lactide)/polycaprolactone/poly (ethylene oxide), this mechanically viable, sponge like 3D scaffold exhibited sufficiently large pores and enabled cell penetration beyond 500 MUm. Dexamethasone (Dex) was loaded into the fibers and a sustained drug release was achieved. Further, the potential of this Dex-loaded 3D scaffold was evaluated for upregulation of osteogenic genes with mesenchymal stem cells. The as-produced Dex-loaded 3D scaffold possesses a unique intertwined sub-micron fibrous morphology that can be tailored for use in bone tissue engineering and beyond. PMID- 28895561 TI - Sexual medicine: Transdermal oestrogen is effective. PMID- 28895560 TI - Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia. AB - The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3 D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 * CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients. PMID- 28895562 TI - Focal ablation therapy for renal cancer in the era of active surveillance and minimally invasive partial nephrectomy. AB - Partial nephrectomy is the optimal surgical approach in the management of small renal masses (SRMs). Focal ablation therapy has an established role in the modern management of SRMs, especially in elderly patients and those with comorbidities. Percutaneous ablation avoids general anaesthesia and laparoscopic ablation can avoid excessive dissection; hence, these techniques can be suitable for patients who are not ideal surgical candidates. Several ablation modalities exist, of which radiofrequency ablation and cryoablation are most widely applied and for which safety and oncological efficacy approach equivalency to partial nephrectomy. Data supporting efficacy and safety of ablation techniques continue to mature, but they originate in institutional case series that are confounded by cohort heterogeneity, selection bias, and lack of long-term follow-up periods. Image guidance and surveillance protocols after ablation vary and no consensus has been established. The importance of SRM biopsy, its optimal timing, the type of biopsy used, and its role in treatment selection continue to be debated. As safety data for active surveillance and experience with minimally invasive partial nephrectomy are expanding, the role of focal ablation therapy in the treatment of patients with SRMs requires continued evaluation. PMID- 28895565 TI - Prostate cancer: CTC phenotype informs treatment type. PMID- 28895563 TI - Characteristics and clinical significance of histological variants of bladder cancer. AB - In the past 10 years evidence for the clinical relevance of variant histology in urinary bladder cancer has been increasing. This increase has resulted in new classifications of urothelial cancers by the WHO in 2016, highlighting the importance of an accurate morphological description of pathological specimens for the therapeutic management of patients with bladder cancer. The rising awareness of the importance of an accurate pathological report manifests itself in the increasing prevalence of reporting of variant histology in daily practice. Histological variants can generally be divided into urothelial and nonurothelial. Urothelial variants often have similar features that also have specific morphological phenotypes, whereas nonurothelial variants have independent features. Overall, histological variants follow a more aggressive clinical course than conventional urothelial carcinoma, but conclusive data on their effect on survival are currently lacking. The clinical relevance of variant histology can manifest at three different levels: diagnostic, as identification is challenging and misinterpretation is not uncommon; prognostic, for patient risk stratification and outcome estimation; and therapeutic, as particular variants could be responsive to specific treatment strategies. An accurate morphological description of histological variants is necessary for patient consultation and therapy planning. Moreover, the association of variant histology with specific mutation patterns promises to be helpful in discovering targeted therapeutic approaches based on specific molecular pathways. PMID- 28895564 TI - Frontiers in robot-assisted retroperitoneal oncological surgery. AB - Robot assistance has been rapidly adopted by urological surgeons and has become particularly popular for oncological procedures involving the retroperitoneal space. The wide dissemination of robot assistance probably reflects the limited amount of operating space available within the retroperitoneum and the advantages provided by robot-assisted approaches, including 3D imaging, wristed instrumentation and the shorter learning curve compared with that associated with the equivalent laparoscopic techniques. Surgical procedures that have traditionally been performed using an open or laparoscopic approach, such as partial nephrectomy, radical nephrectomy, retroperitoneal lymph node dissection, nephroureterectomy and adrenalectomy, are now often being performed using robot assistance. The frontiers of robot-assisted retroperitoneal oncological surgery are constantly expanding, with an emphasis on maintaining oncological and functional outcomes, while minimizing the level of surgical invasiveness. PMID- 28895567 TI - Bladder cancer: IFNalpha-2b gene transfer: a new approach for BCG-resistant disease. PMID- 28895568 TI - Response to Targeted Cognitive Training Correlates with Change in Thalamic Volume in a Randomized Trial for Early Schizophrenia. AB - Reduced thalamic volume is consistently observed in schizophrenia, and correlates with cognitive impairment. Targeted cognitive training (TCT) of auditory processing in schizophrenia drives improvements in cognition that are believed to result from functional neuroplasticity in prefrontal and auditory cortices. In this study, we sought to determine whether response to TCT is also associated with structural neuroplastic changes in thalamic volume in patients with early schizophrenia (ESZ). Additionally, we examined baseline clinical, cognitive, and neural characteristics predictive of a positive response to TCT. ESZ patients were randomly assigned to undergo either 40 h of TCT (N=22) or a computer games control condition (CG; N=22 s). Participants underwent MRI, clinical, and neurocognitive assessments before and after training (4-month interval). Freesurfer automated segmentation of the subcortical surface was carried out to measure thalamic volume at both time points. Left thalamic volume at baseline correlated with baseline global cognition, while a similar trend was observed in the right thalamus. The relationship between change in cognition and change in left thalamus volume differed between groups, with a significant positive correlation in the TCT group and a negative trend in the CG group. Lower baseline symptoms were related to improvements in cognition and left thalamic volume preservation following TCT. These findings suggest that the cognitive gains induced by TCT in ESZ are associated with structural neuroplasticity in the thalamus. Greater symptom severity at baseline reduced the likelihood of response to TCT both with respect to improved cognition and change in thalamic volume. PMID- 28895566 TI - WNT signalling in prostate cancer. AB - Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours - particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-beta-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of beta-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer. PMID- 28895570 TI - Immunotherapy: Cancer vaccines on the move. PMID- 28895569 TI - The Effects of the Monoamine Stabilizer (-)-OSU6162 on Binge-Like Eating and Cue Controlled Food-Seeking Behavior in Rats. AB - Binge-eating disorder (BED) is characterized by recurring episodes of excessive consumption of palatable food and an increased sensitivity to food cues. Patients with BED display an addiction-like symptomatology and the dopamine system might be a potential treatment target. The clinically safe monoamine stabilizer (-) OSU6162 (OSU6162) restores dopaminergic dysfunction in long-term alcohol-drinking rats and shows promise as a novel treatment for alcohol use disorder. Here, the effects of OSU6162 on consummatory (binge-like eating) and appetitive (cue controlled seeking) behavior motivated by chocolate-flavored sucrose pellets were evaluated in non-food-restricted male Lister Hooded rats. OSU6162 significantly reduced binge-like intake of chocolate-flavored sucrose pellets without affecting prior chow intake. Furthermore, OSU6162 significantly reduced the cue-controlled seeking of chocolate-flavored sucrose pellets under a second-order schedule of reinforcement before, but not after, the delivery and ingestion of reward, indicating a selective effect on incentive motivational processes. In contrast, the dopamine D2/D3 receptor antagonist raclopride reduced the seeking of chocolate-flavored sucrose pellets both pre- and post reward ingestion and also reduced responding under simpler schedules of seeking behavior. The D1/5 receptor antagonist SCH23390 had no effect on instrumental behavior under any reinforcement schedule tested. Finally, local administration of OSU6162 into the nucleus accumbens core, but not dorsolateral striatum, selectively reduced cue controlled sucrose seeking. In conclusion, the present results show that OSU6162 reduces binge-like eating behavior and attenuates the impact of cues on seeking of palatable food. This indicates that OSU6162 might serve as a novel BED medication. PMID- 28895571 TI - Corrigendum: Can we deliver randomized trials of focal therapy in prostate cancer? AB - This corrects the article DOI: 10.1038/nrclinonc.2014.44. PMID- 28895572 TI - Manifesto for global women's health. PMID- 28895573 TI - Radiotherapy: Importantly, less is effective. PMID- 28895574 TI - Generating Rasch-based activity of daily living measures from the Spinal Cord Injury Longitudinal Aging Study. AB - STUDY DESIGN: Retrospective Longitudinal Study. OBJECTIVES: (1) To determine whether the Spinal Cord Injury Activities of Daily Living (SCI_ADL) measure shows adequate item-level and precision psychometrics; (2) to investigate whether the SCI_ADL measure effectively detects ADL changes across time; (3) to describe self care task(s) participants can and cannot do across time. SETTING: Two Midwestern hospitals and 1 Southeastern specialty hospital in 1993. METHODS: All participants were adults with traumatic SCI of at least 1-year duration at enrollment. We used 20-year (1993-2013) retrospective longitudinal data and categorized participants into three injury levels: C1-C4 (cervical; n=50), C5-C8 (n=126) and T1-S5 (thoracic, lumbar and sacral; n=168). We first examined psychometrics of the SCI_ADL with factor and Rasch analyses; then we investigated longitudinal change of SCI_ADL scores at three time points over 20 years (1993, 2003 and 2013) using generalized linear mixed modeling and post hoc analyses. RESULTS: The SCI_ADL measure demonstrated unidimensionality, person strata of 2.9, high Cronbach's alpha (0.93) and fair person reliability (0.76). T1-S5 had the highest measures, following C5-C8 and C1-C4 at three time points (P<0.05). The C1-C4 and T1-S5 groups showed significant decreases from 2003 to 2013; however, none of the three groups showed significant differences from 1993 to 2003 (P<0.05). CONCLUSIONS: The SCI_ADL measure could detect longitudinal ADL changes of the population with SCI across time. The C1-C4 group decreased the most in ADLs, indicating higher need of long-term services and rehabilitation. PMID- 28895575 TI - Predictors of pressure ulcer incidence following traumatic spinal cord injury: a secondary analysis of a prospective longitudinal study. AB - STUDY DESIGN: Secondary analysis of data from a prospective cohort study. OBJECTIVES: The objective of this study was to identify the medical and demographic factors associated with the development of pressure ulcers during acute-care hospitalization and inpatient rehabilitation following acute spinal cord injury. SETTING: The study was carried out at acute hospitalization, inpatient rehabilitation and outpatient rehabilitation sites at a university medical center in the United States. METHODS: Adults with acute traumatic spinal cord injury (n=104) were recruited within 24-72 h of admission to the hospital. Pressure ulcer incidence was recorded. RESULTS: Thirty-nine participants out of 104 (37.5%) developed at least one pressure ulcer during acute-care hospitalization and inpatient rehabilitation. Univariate logistic regression analyses revealed significant association of pressure ulcer incidence for those with pneumonia and mechanical ventilation (P=0.01) and higher injury severity (ASIA A) (P=0.01). Multiple logistic regression showed that the odds of formation of a first pressure ulcer in participants with ASIA A was 4.5 times greater than that for participants with ASIA B, CI (1-20.65), P=0.05, and 4.6 times greater than that for participants with ASIA C, CI (1.3-16.63), P=0.01. CONCLUSION: Among individuals with acute traumatic SCI, those with high-injury severity were at an increased risk to develop pressure ulcers. Pneumonia was noted to be associated with the formation of pressure ulcers. PMID- 28895576 TI - SCIM III (Spinal Cord Independence Measure version III): reliability of assessment by interview and comparison with assessment by observation. AB - STUDY DESIGN: Psychometric study. OBJECTIVES: The objective of this study was to examine the reliability of the Spinal Cord Independence Measure III (SCIM III) by interview and compare the findings with those of assessment by observation. SETTING: This study was conducted at Loewenstein Rehabilitation Hospital, Israel. METHODS: Thirty-five spinal cord lesion (SCL) patients who underwent rehabilitation at Loewenstein Rehabilitation Hospital in Israel were assessed during the last week before discharge with SCIM III by observation and by interview. Nineteen of the patients were also assessed by interview by a third rater to examine inter-rater reliability. Total agreement, kappa, Bland-Altman plots and intraclass correlation (ICC) were used for comparison between interviewers and between interviews and observations. RESULTS: Total agreement between the interviewers' scores and between interviews and observations was low to moderate (kappa coefficient 0.11-0.80). Bland-Altman analysis revealed good agreement, with low mean difference for almost all SCIM III subscales and total scores, between pairs of interviewers (bias -4.15, limits of agreement -22.51 to 14.19, for total score) and between interviews and observations (bias 1.62, limits of agreement -20.55 to 23.81, for total score). ICC coefficients for the SCIM III subscales and total scores were high (0.637-0.916). CONCLUSION: The findings of this study support the reliability and validity of SCIM III by interview, which appears to be useful for research of SCL patient groups. Individual scoring of SCIM III by interview, however, varied prominently between raters. Therefore, SCIM III by interview should be used with caution for clinical purposes, probably by raters whose scoring deviation, in relation to observation scores, is known. PMID- 28895577 TI - A study of predictors for hyponatraemia in patients with cervical spinal cord injury. AB - STUDY DESIGN: A retrospective study. OBJECTIVES: The objectives of the study were to investigate the predictors for hyponatraemia in patients with cervical spinal cord injuries (CSCIs) and to define the relationship between magnetic resonance imaging (MRI) scans and hyponatraemia. SETTING: The study was carried out at The First Affiliated Hospital of Anhui Medical University. METHODS: A total of 292 patients with CSCIs were retrospectively reviewed to determine the predictors of hyponatraemia. Fourteen variables were extracted from the medical records: age, sex, blood pressure (BP), tracheostomy, serum potassium, serum chloride, serum bicarbonate, serum albumin, intravenous fluid intake and urine volume for 24 h, haematocrit, haemoglobin, neurological assessment and four MRI signal patterns. Univariate and multivariate analyses were used to determine the effect of each variable on hyponatraemia. RESULTS: Eighty-two of the 270 patients (30%) developed hyponatraemia. Univariate analyses indicated that the following variables were significant predictors of hyponatraemia: tracheostomy; the initial American Spinal Injury Association (ASIA) Impairment Scale (AIS) A assessment; and haemorrhage changes on T2-weighted MRI scans, and low BP. Multivariate regression analyses revealed two variables were significant predictors of hyponatraemia: haemorrhage changes on T2-weighted MRI scans and low BP. CONCLUSIONS: Haemorrhage changes on MRI scans were closely associated with the onset of hyponatremia and could provide objective data for forecasting hyponatraemia in CSCI patients. Low BP was also a reasonable predictor of hyponatremia. PMID- 28895578 TI - Challenges in comprehensive management of spinal cord injury in India and in the Asian Spinal Cord network region: findings of a survey of experts, patients and consumers. AB - STUDY DESIGN: Online survey. OBJECTIVES: To understand the prevailing scenario of the comprehensive management of spinal cord injuries (SCI) in India and in the Asian Spinal Cord Network (ASCoN) region, especially with a view to document the challenges faced and its impact. SETTING: Indian Spinal Injuries Centre. METHODS: A questionnaire was designed which covered various aspects of SCI management. Patients, consumers (spinal injured patients discharged since at least 1 year) and experts in SCI management from different parts of India and the ASCoN region were approached to complete the survey. RESULTS: Sixty patients, 66 consumers and 34 experts completed the survey. Difference of opinion was noticed among the three groups. Disposable Nelaton catheters were used by 57% consumers and 47% patients. For reusable catheter, 31% experts recommended processing with soap and running water and 45% recommended clean cotton cloth bag for storage. Pre hospital care and community inclusion pose the biggest challenges in management of SCI. More than 75% of SCI faced problems of access and mobility in the community. Awareness about SCI, illiteracy and inadequate patient education are the most important factors hindering pre- and in-hospital care. Inadequate physical as well as vocational rehabilitation and financial barriers are thought to be the major factors hindering integration of spinal injured into mainstream society. Strong family support helped in rehabilitation. CONCLUSIONS: Our study brought out that SCI in India and ASCoN region face numerous challenges that affect access to almost all aspects of comprehensive management of SCI. PMID- 28895579 TI - A sexually dimorphic peptidergic system in the lower spinal cord controlling penile function in non-human primates. AB - STUDY DESIGN: Experimental animal study. OBJECTIVES: Although a population of gastrin-releasing peptide (GRP) neurons in the lumbar spinal cord has an important role in erection and ejaculation in rats, little information exists on this GRP system in primates. To identify the male-specific GRP system in the primate spinal cord, we studied the lumbosacral cord in macaque monkeys as a non human primate model. SETTING: University laboratory in Japan. METHODS: To determine the gene sequence of GRP precursors, the rhesus macaque monkey genomic sequence data were searched, followed by phylogenetic analysis. Subsequently, immunocytochemical analysis for GRP was performed in the monkey spinal cord. RESULTS: We have used bioinformatics to identify the ortholog gene for GRP precursor in macaque monkeys. Phylogenetic analysis suggested that primate prepro GRP is separated from that of other mammalian species and clustered to an independent branch as primates. Immunocytochemistry for GRP further demonstrated that male-dominant sexual dimorphism was found in the spinal GRP system in monkeys as in rodents. CONCLUSION: We have demonstrated in macaque monkeys that the GRP system in the lower spinal cord shows male-specific dimorphism and may have an important role in penile functions not only in rodents but also in primates. SPONSORSHIP: Tissues of Nihonzaru (Japanese macaque monkeys) were provided in part by National Institutes of Natural Sciences (NINS) through the National Bio-Resource Project (NBRP) of the MEXT, Japan. This work was supported in part by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (to KT; 15KK0343, 15J40220 and HS; 15K15202, 15KK0257, 15H05724). PMID- 28895580 TI - New path towards a better rice architecture. AB - New plant type (NPT) or ideal plant architecture (IPA) is an attractive way of increasing yield potential by promoting high resource use efficiency combined with better lodging resistance. In a recent paper in Cell Research, Wang et al. describe how a QTL they identified could bring about the desired NPT architecture by elucidating the role of its encoded gene in controlling the stability of IPA1/OsSPL14, a previously reported NPT protein, in the context of ubiquitination. PMID- 28895581 TI - Corrigendum: Improvement of Liver Fibrosis after Long-Term Antiviral Therapy Assessed by Fibroscan in Chronic Hepatitis B Patients With Advanced Fibrosis. PMID- 28895582 TI - Gastric Motor Dysfunction in Patients With Functional Gastroduodenal Symptoms. AB - OBJECTIVES: The pathophysiology of dyspeptic symptoms is complex. The aim of this study was to evaluate the association of gastric emptying (GE), gastric accommodation (GA), and respiratory sinus arrhythmia (RSA, to assess vagal dysfunction) in a large cohort with functional gastroduodenal symptoms. METHODS: We reviewed demographic, clinical features, and results of gastric motor and vagal function studies of 1,287 patients (74.0% females, mean age 43.1+/-15.4 years) who had undergone both single photon emission computed tomography GA and scintigraphic GE. Accommodation was based on postprandial to fasting gastric volume ratio (VR). Electrocardiograms were available and analyzed for RSA in 300 patients. RESULTS: There were 29.8% patients with normal GE and GA, 21.9% with abnormal GA only, 27.1% with abnormal GE only, and 21.1% with abnormal GA and GE. There were numerical differences in GA among patients with normal, accelerated, and delayed GE (P=0.062, by chi2). Increased GA (VR >3.85) was more prevalent in patients with delayed GE compared to accelerated GE (14.0% vs. 6.8%, P=0.004). Decreased VRs (median 2.9) were observed with accelerated GE compared to normal GE (median 3.1, P<0.05). Nausea and vomiting were more prevalent (in contrast to the less prevalent bloating) in patients with delayed compared to accelerated or normal GE (all P<0.05). In patients with diminished RSA, there was higher prevalence of reduced GA (41.5%) compared to those with preserved RSA (29.2%, P=0.031). Multivariable analysis showed associations of the main abdominal symptoms with gender, body mass index, gastric emptying, diabetes, and prior abdominal surgery. CONCLUSIONS: Patients with symptoms of functional gastroduodenal disorders may have one or more gastric motor dysfunctions and reduced RSA; among the patients with abnormal gastric motor functions, vomiting suggests delayed GE, whereas reduced RSA is associated with reduced GA. PMID- 28895583 TI - Psychosocial Distress and Quality of Life Impairment Are Associated With Symptom Severity in PPI Non-Responders With Normal Impedance-pH Profiles. AB - OBJECTIVES: Up to 50% of patients with reflux symptoms do not manifest a satisfactory symptom response to proton pump inhibitor (PPI) therapy. Our primary aim in this study was to identify factors associated with symptom perception among PPI non-responder phenotypes. METHODS: This prospective observational cohort study was performed from September 2014 to January 2017 at a single academic medical center and included PPI non-responders who underwent 24-h impedance-pH monitoring and completed a questionnaire set measuring patient reported symptom severity, quality of life (QOL), and psychosocial distress. Participants were separated into cohorts based on impedance-pH results: on PPI: acid exposure time (AET)/-symptom-reflux association (SRA), +AET, and -AET/+SRA; off PPI: functional (-AET/-SRA), gastroesophageal reflux disease (GERD) (+AET), and reflux hypersensitivity (RHS) (-AET/+SRA). The primary outcome was abnormal GERD symptom severity defined by GerdQ>=8. RESULTS: One hundred and ninety-two participants were included. Impedance-pH on PPI was performed on 125: 72 (58%) AET/-SRA, 42 (34%) +AET, and 11 (9%) -AET/+SRA. Among the -AET/-SRA group, younger age, higher dysphagia scores, QOL impairment, and higher brief symptom index were associated with GerdQ>=8. Among the +AET group, higher number of reflux-associated symptoms and lower distal contractile integral was associated with GerdQ>=8. Impedance-pH off PPI was performed on 67 participants: 39 (58%) functional, 16 (24%) GERD, and 12 (18%) RHS. Among the functional group, higher QOL impairment and dysphagia scores were seen with GerdQ>=8. CONCLUSIONS: Perceptions of reflux symptoms are associated with psychosocial distress, reduced QOL, and sensation of dysphagia among PPI non-responders with normal impedance pH. Among PPI refractory GERD patients, patient-reported symptom severity is associated with physiological differences, as opposed to psychosocial factors. PMID- 28895584 TI - Effects of lobeglitazone, a novel thiazolidinedione, on adipose tissue remodeling and brown and beige adipose tissue development in db/db mice. AB - BACKGROUND/OBJECTIVES: We investigated the effect of long-term treatment with lobeglitazone, a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, on adipose tissue (AT), focusing on its effects on insulin resistance in obese db/db mice. METHODS: Seven-week-old male db/db mice were assigned to either a vehicle-treated (n=8) or lobeglitazone treated (n=8) group. Lobeglitazone (1 mg kg-1 daily) was injected intraperitoneally for 20 weeks. RESULTS: Lobeglitazone treatment for 20 weeks resulted in a remarkably improved glycemic index, including significantly decreased glucose levels, enhanced insulin sensitivity and preserved pancreatic beta cells. Both whole body and subcutaneous AT weight increased in the lobeglitazone-treated group. However, lobeglitazone induced an increase in the number of small adipocyte in both epididymal and subcutaneous AT, with a significant weight decrease in the epididymal AT of db/db mice. Using flow cytometry, the CD11c-positive M1 macrophages and CD206-positive M2 macrophages in the epididymal AT were observed to exhibit a decreased M1-to-M2 ratio in lobeglitazone-treated db/db mice. Furthermore, in the lobeglitazone-treated group, interscapular brown AT was clearly visualized by 18F-fluoro-2-deoxy-D glucose positron emission tomography combined with computed tomography (18F-FDG PET/CT) and its mass was significantly greater than that of the vehicle-treated group. In the lobeglitazone-treated group, beige-specific gene expression and the number of mitochondria in white AT were upregulated. Lobeglitazone, with upregulating interferon regulatory factor-4 (a key transcriptional regulator of thermogenesis), promoted the development of brown adipocytes and the differentiation of white adipocytes into beige adipocytes. CONCLUSIONS: Long-term lobeglitazone treatment has a beneficial role in remodeling and ameliorating inflammation in white AT and in glycemic control, in relation to insulin sensitivity in obese db/db mice. Moreover, lobeglitazone induced the differentiation of brown and beige adipocytes. Collectively, our data suggest that lobeglitazone treatment provides promising effects on white and brown AT as well as great improvement in glycemic control, as a potent insulin sensitizer. PMID- 28895585 TI - Habitual sleep duration and sleep duration variation are independently associated with body mass index. AB - BACKGROUND: Sleep plays a vital role in maintaining homeostasis and promoting health. Previous studies show that shorter sleep duration is associated with elevated body mass index (BMI) and other cardiovascular risk factors. The goal of this study was to investigate the effects of habitual sleep duration and nightly sleep duration variation based on daily device-recorded data on BMI and obesity related biomarkers. METHODS: In all, 748 individuals (50.6% females, 85.4% European-Americans, average age: 49.7 years old) participated in a commercial lifestyle coaching program beginning in July 2015. Daily sleep data were recorded by Fitbit Charge HR wristbands. Clinical laboratory blood tests were measured up to three times over a 12-month period. Linear regression models were used for cross-sectional analyses, and generalized estimating equations for longitudinal analyses. All models were adjusted for age, sex, geographic location, season, genetic ancestry inferred from whole genome sequencing data, and BMI (if applicable). Multiple testing issues were corrected by false discovery rate. RESULTS: We calculated habitual sleep duration and nightly sleep duration variation. In general, females slept 15-min longer on average than males. A negative correlation was found between habitual sleep duration and BMI (beta= 1.12, standard error=0.25, P<0.001). Moreover, we identified a positive correlation between sleep duration variation and BMI (beta=2.97, standard error=0.79, P<0.001) while controlling for sleep duration, indicating that larger sleep duration variation is significantly and independently associated with increased BMI. CONCLUSIONS: We explored the impact of habitual sleep duration and sleep duration variation, and identified that shorter habitual sleep duration and larger duration variation were independently associated with increased BMI. PMID- 28895586 TI - Maresin 1 mitigates liver steatosis in ob/ob and diet-induced obese mice. AB - BACKGROUND/OBJECTIVES: The aim of this study was to characterize the effects of Maresin 1 (MaR1) in obesity-related liver steatosis and the mechanisms involved. METHODS: MaR1 effects on fatty liver disease were tested in ob/ob (2-10 MUg kg-1 i.p., 20 days) and in diet-induced obese (DIO) mice (2 MUg kg-1, i.p., or 50 MUg kg-1, oral gavage for 10 days), as well as in cultured hepatocytes. RESULTS: In ob/ob mice, MaR1 reduced liver triglycerides (TG) content, fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 protein expression, while increased acetyl CoA carboxylase (ACC) phosphorylation and LC3II protein expression, in parallel with a drop in p62 levels. Similar effects on hepatic TG, ACC phosphorylation, p62 and LC3II were observed in DIO mice after MaR1 i.p. injection. Interestingly, oral gavage of MaR1 also decreased serum transaminases, reduced liver weight and TG content. MaR1-treated mice exhibited reduced hepatic lipogenic enzymes content (FAS) or activation (by phosphorylation of ACC), accompanied by upregulation of carnitine palmitoyltransferase (Cpt1a), acyl-coenzyme A oxidase (Acox1) and autophagy-related proteins 5 and 7 (Atg5-7) gene expression, along with increased number of autophagic vacuoles and reduced p62 protein levels. MaR1 also induced AMP-activated protein kinase (AMPK) phosphorylation in DIO mice and in primary hepatocytes, and AMPK inhibition completely blocked MaR1 effects on Cpt1a, Acox1, Atg5 and Atg7 expression. CONCLUSIONS: MaR1 ameliorates liver steatosis by decreasing lipogenic enzymes, while inducing fatty acid oxidation genes and autophagy, which could be related to AMPK activation. Thus, MaR1 may be a new therapeutic candidate for reducing fatty liver in obesity. PMID- 28895587 TI - A new animal diet based on human Western diet is a robust diet-induced obesity model: comparison to high-fat and cafeteria diets in term of metabolic and gut microbiota disruption. AB - BACKGROUND/OBJECTIVES: Obesity is a metabolic disorder that predisposes patients to numerous diseases and has become a major global public-health concern. Animal models of diet-induced obesity (DIO) are frequently used to study obesity, but which DIO model most accurately reflects the pathology of human obesity remains unclear. In this study, we designed a diet based on the human Western diet (WD) and compared it with the cafeteria diet (CAF) and high-fat diet (HFD) in order to evaluate which diet most closely mirrors human obesity. METHODS: Wistar rats were fed four different diets (WD, CAF, HFD and a low-fat diet) for 18 weeks. Metabolic parameters and gut microbiota changes were then characterized. RESULTS: Rats fed the four different diets exhibited completely different phenotypes, highlighting the importance of diet selection. This study also revealed that WD most effectively induced obesity and obesity-related disorders, and thus proved to be a robust model of human obesity. Moreover, WD-fed rats developed obesity and obesity-related comorbidities independent of major alterations in gut microbiota composition (dysbiosis), whereas CAF-fed rats developed the greatest dysbiosis independent of obesity. We also characterized gut microbiota after feeding on these four different diets and identified five genera that might be involved in the pathogenesis of obesity. CONCLUSIONS: These data suggest that diet, and not the obese state, was the major driving force behind gut microbiota changes. Moreover, the marked dysbiosis observed in CAF-fed rats might have resulted from the presence of several additives present in the CAF diet, or even a lack of essential vitamins and minerals. Based on our findings, we recommend the use of the prototypic WD (designed here) in DIO models. Conversely, CAF could be used to investigate the effects of excessive consumption of industrially produced and highly processed foods, which are characteristic of Western society. PMID- 28895588 TI - Immunology &Cell Biology Publication of the Year Awards 2016. PMID- 28895589 TI - Instant on-paper protein digestion during blood spot sampling. AB - A concept integrating sampling and protein digestion is introduced here combining fast and simple fabrication by wax printing on filter paper with trypsin immobilized polymer beads. The paper reactors showed promising results with a high degree of protein digestion within fifty minutes in model protein mixtures as well as in human blood. The model protein mixture was used for the evaluation of performance both with and without a reduction and alkylation step. The paper reactors without reduction and alkylation showed between 46% and 75% protein sequence coverage and between five and 20 high confidence peptides (one and five zero missed cleavage peptides, respectively). Compared to a conventional in solution approach, the paper reactor showed 10% less protein sequence coverage, 29% fewer high confidence peptides and 19% fewer high confidence peptides with zero missed cleavages. Placement of the protein reduction and alkylation step (before or after protein digestion) was shown to be of low importance. The storage stability of the paper reactors with (six weeks) and without (twelve weeks) tryptic peptides was satisfactory. The ability of the paper reactors to digest complex biological samples was investigated by comparison with human whole blood samples prepared using a conventional dried blood spot (DBS) procedure with overnight digestion in non-targeted analysis. The reactors showed a comparable performance with 75 +/- 25 for the protein groups compared to 76 +/- 5 for the DBS samples. Additionally, 267 +/- 72 and 335 +/- 11 unique peptides (high confidence) were identified for on-paper digestion and DBS, respectively. PMID- 28895590 TI - Correction: Microchip in situ electrosynthesis of silver metallic oxide clusters for ultra-FAST detection of galactose in galactosemic newborns' urine samples. AB - Correction for 'Microchip in situ electrosynthesis of silver metallic oxide clusters for ultra-FAST detection of galactose in galactosemic newborns' urine samples by Laura Garcia-Carmona et al., Analyst, 2016, 141, 6002-6007. PMID- 28895591 TI - Development of drug-loaded polymer microcapsules for treatment of epilepsy. AB - Despite significant progress in developing new drugs for seizure control, epilepsy still affects 1% of the global population and is drug-resistant in more than 30% of cases. To improve the therapeutic efficacy of epilepsy medication, a promising approach is to deliver anti-epilepsy drugs directly to affected brain areas using local drug delivery systems. The drug delivery systems must meet a number of criteria, including high drug loading efficiency, biodegradability, neuro-cytocompatibility and predictable drug release profiles. Here we report the development of fibre- and sphere-based microcapsules that exhibit controllable uniform morphologies and drug release profiles as predicted by mathematical modelling. Importantly, both forms of fabricated microcapsules are compatible with human brain derived neural stem cells and differentiated neurons and neuroglia, indicating clinical compliance for neural implantation and therapeutic drug delivery. PMID- 28895594 TI - Determination of spectral markers of cytotoxicity and genotoxicity using in vitro Raman microspectroscopy: cellular responses to polyamidoamine dendrimer exposure. AB - Although consumer exposure to nanomaterials is ever increasing, with potential increased applications in areas such as drug and/or gene delivery, contrast agents and diagnosis, the determination of the cyto- and geno-toxic effects of nanomaterials on human health and the environment still remains challenging. Although many techniques have been established and adapted to determine the cytotoxicity and genotoxicity of nano-sized materials, these techniques remain limited by the number of assays required, total cost, and use of labels and they struggle to explain the underlying interaction mechanisms. In this study, Raman microspectroscopy is employed as an in vitro label-free, high content screening technique to observe toxicological changes within the cell in a multi-parametric fashion. The evolution of spectral markers as a function of time and applied dose has been used to elucidate the mechanism of action of polyamidoamine (PAMAM) dendrimers associated with cytotoxicity and their impact on nuclear biochemistry. PAMAM dendrimers are chosen as a model nanomaterial due to their widely studied cytotoxic and genotoxic properties and commercial availability. Point spectra were acquired from the cytoplasm to monitor the cascade of toxic events occurring in the cytoplasm upon nanoparticle exposure, whereas the spectra acquired from the nucleus and the nucleolus were used to explore PAMAM-nuclear material interaction as well as genotoxic responses. PMID- 28895596 TI - Electrochemical estimation of the active site density on metal-free nitrogen doped carbon using catechol as an adsorbate. AB - Carbon is heat-treated with a nitrogen-containing precursor (ammonia) to obtain nitrogen-doped carbon and the composition is estimated using CHN and XPS analysis. The active site density of the carbon and nitrogen-doped carbon is quantified using 1,2-dihydroxybenzene (catechol) molecules as an adsorbate in phosphate buffer (pH 7) solution. The features of the voltammograms of the catechol-adsorbed high surface area carbon and nitrogen-doped carbon are similar to that of the polished nitrogen-grafted glassy carbon electrode (GCE) reported in the literature. At the same time, the polished GCE does not show any well defined catechol adsorption features. It is found that the adsorption charge (obtained by integrating the peak area, after subtracting the background) is in the order of N/C 900 > N/C 1000 > N/C 800 > N/C 700 > C. A similar trend is observed in their oxygen reduction reaction (ORR) activity in 0.1 M KOH. Moreover, the turnover frequency (ToF) of the catalysts is calculated and it is comparable to that reported in the literature using other methods for non precious catalysts. Therefore, the adsorption charge can be correlated with the active site density of the carbon and nitrogen-doped carbon samples. PMID- 28895597 TI - Fragmentation of KrN+ clusters after electron impact ionization II. Long-time dynamics simulations of Kr7+ evolution and the role of initial electronic excitation. AB - Long time simulations, up to 100 ns, have been performed for the fragmentation of Kr7+ clusters after electron impact ionization. They rely on DIM approaches and hybrid non-adiabatic dynamics combining mean field and decoherence driven either by Tully fewest switches (TFS) algorithm or through electronic amplitude (AMP) calculations. With both methods, for the first time, when the initial electronic excited state belongs to group II correlating to P1/2 atomic ions, the fragmentation ratio in mainly monomer and dimer ions agrees very well with known experimental results. A complex non-adiabatic dynamics is found where initial neutral monomer evaporations due to gradual deexcitation over electronic states of group II are followed by a non-adiabatic transition across a wide energy gap of the spin-orbit origin to electronic states of group I. The resulting excess of kinetic energy causes the final fragmentation of charged intermediate fragments to stable ionic monomers or dimers. Characteristic times of these processes have been estimated. The kinetic energy distribution of the neutral and ionic monomers (the dominating final fragments) has been analyzed in detail. Interestingly they exhibit some signature of the initial excited electronic state which could allow for an experimental identification. PMID- 28895598 TI - Measurement of reaction kinetics of [177Lu]Lu-DOTA-TATE using a microfluidic system. AB - Microfluidic synthesis techniques can offer improvement over batch syntheses which are currently used for radiopharmaceutical production. These improvements are, for example, better mixing of reactants, more efficient energy transfer, less radiolysis, faster reaction optimization, and overall improved reaction control. However, scale-up challenges hinder the routine clinical use, so the main advantage is currently the ability to optimize reactions rapidly and with low reactant consumption. Translating those results to clinical systems could be done based on calculations, if kinetic constants and diffusion coefficients were known. This study describes a microfluidic system with which it was possible to determine the kinetic association rate constants for the formation of [177Lu]Lu DOTA-TATE under conditions currently used for clinical production. The kinetic rate constants showed a temperature dependence that followed the Arrhenius equation, allowing the determination of Arrhenius parameters for a Lu-DOTA conjugate (A = 1.24 +/- 0.05 * 1019 M-1 s-1, EA = 109.5 +/- 0.1 * 103 J mol-1) for the first time. The required reaction time for the formation of [177Lu]Lu DOTA-TATE (99% yield) at 80 degrees C was 44 s in a microfluidic channel (100 MUm). Simulations done with COMSOL Multiphysics(r) indicated that processing clinical amounts (3 mL reaction solution) in less than 12 min is possible in a micro- or milli-fluidic system, if the diameter of the reaction channel is increased to over 500 MUm. These results show that a continuous, microfluidic system can become a viable alternative to the conventional, batch-wise radiolabelling technique. PMID- 28895600 TI - Synthesis and characterisation of new Bi(iii)-containing apatite-type oxide ion conductors: the influence of lone pairs. AB - Lone-pair cations are known to enhance oxide ion conductivity in fluorite- and Aurivillius-type materials. Among the apatite-type phases, the opposite trend is found for the more widely studied silicate oxide ion conductors, which exhibit a dramatic decrease in conductivity on Bi(iii) incorporation. In this work, the influence of lone-pair cations on the properties of apatite-type germanate oxide ion conductors has been investigated by preparing and characterising seven related compositions with varying Bi(iii) content, by X-ray and neutron powder diffraction and impedance spectroscopy. All materials are very good oxide ion conductors (with conductivities of up to 1.29 * 10-2 S cm-1 at 775 degrees C). Increasing Bi(iii) content leads to increases in conductivity by up to an order of magnitude, suggesting significant differences in the oxide-ion conduction mechanisms between lone-pair-containing apatite-type germanate and silicate solid electrolytes. PMID- 28895601 TI - N,N-Diethyl-diaminopropane-copper(ii) oxalate self-reducible complex for the solution-based synthesis of copper nanocrystals. AB - Metal oxalates (C2O42-, ox) have been explored as promising precursors for the direct transformation of their oxalate moieties into metallic or metal oxide crystals via thermal decomposition without the formation of any byproducts due to releasing CO2 gas. The copper(ii) oxalate (Cu(ox)) crystal is a coordination polymer composed of an infinite coordination network with a thermal decomposition temperature around 300 degrees C; however, their insoluble nature in any solvents and relatively high decomposition temperature do not allow the solution based syntheses of surface-modified metallic Cu nanocrystals (NCs) in the presence of various surfactants such as long-chain alkylamines and alkylcarboxylates which have been used for increasing the dispersibility of NCs in organic solvents. In this study, the insoluble nature of Cu(ox) is overcome by mixing Cu(ox) crystals and N,N-diethyl-1,3-diaminopropane (dedap) to form a discrete complex, [Cu(ox)(dedap)2], whose structure is determined by X-ray crystallographic analysis. The obtained complex is well soluble in polar solvents and miscible with surfactants. Furthermore, it is decomposed at a moderate temperature of <170 degrees C with the evolution of CO2 gas; as a result, Cu NCs dispersible in organic solvents have been synthesized in suitable surfactants, such as the mixture of oleic acid, dodecylamine, and octylamine utilized as a reaction solvent. In addition, their potential application of the surface modified Cu NCs as a conductive-ink has been preliminarily tested. The Cu film sintered at 280 degrees C exhibits a resistivity of 40 MUOmega cm. PMID- 28895604 TI - Microwave-assisted synthesis of novel hetero[5]helicene-like molecules and coumarin derivatives. AB - A concise and efficient approach to design and synthesize hetero[5]helicene-like molecules and coumarin derivatives is reported. Intriguingly, using the same catalyst (silica sulfuric acid), and a different solvent and reaction temperature, the reaction selectively afforded hetero[5]helicene-like molecules 3 or coumarin derivatives 4. Product 4 has a highly planar geometry, and product 3 can be regarded as hetero[5]helicene-like because of its helical conformation. PMID- 28895607 TI - Rubber-elasticity and electrochemical activity of iron(ii) tris(bipyridine) crosslinked poly(dimethylsiloxane) networks. AB - 2,2'-Bipyridine-terminated poly(dimethylsiloxane)s (bpyPDMS) with number average molecular weights, MN, of 3300, 6100, 26 200, and 50 000 g mol-1 were synthesized. When mixed with Fe(BF4)2 at low concentrations, red solutions formed with UV-vis spectra that match those of iron(ii) tris(2,2'-bipyridine) (Fe(bpy)32+). Upon solvent evaporation, Fe(bpy)32+ crosslinked PDMS networks (bpyPDMS/Fe(ii)) formed, and were studied using oscillating shear rheometry. The shear storage moduli (0.084 to 2.6 MPa) were found to be inversely proportional to the MN of the PDMS, though the storage moduli at low molecular weights greatly exceeded the storage moduli of comparable covalently crosslinked PDMS networks. The shear storage moduli exhibited the characteristic rubbery plateau up to ~135 degrees C. Films of bpyPDMS/Fe(ii) coated onto electrodes were found to be electrochemically active, especially so when the PDMS MN is low. The Fe(bpy)32+ crosslinks can be reversibly oxidized over ~500 nm away from the electrode surface in the presence of a suitable electrolyte. PMID- 28895608 TI - Surfactant effects on droplet dynamics and deposition patterns: a lattice gas model. AB - A coarse-grained lattice gas model is developed to study pattern forming processes in drying drops containing surfactant. By performing Monte Carlo simulations of the model, the coupled dynamics of surfactant and liquid evaporation and the resulting oscillatory dynamics at the contact line are elucidated. We show that the coupled drop dynamics and the resulting final deposition patterns can be altered by adsorption kinetics. For slow adsorption rates, surfactant molecules recirculate along with colloidal particles and the area covered by the surfactant on the surface grows from the contact line as the initial concentration of the surfactant increases. This leads to coffee-ring patterns with wide rim areas upon drying or to multi-ring patterns depending on the surfactant concentration. For fast adsorption rates, a surfactant skin covers the entire surface area during the early phase of evaporation. This suppresses the coffee ring effect, and uniform patterns are obtained independent of surfactant concentration. The results suggest that the distribution of surfactant on the surface is critical in determining final deposition patterns and that understanding of the skin-forming process of the surfactant on the surface can help in manipulating the delicate pattern forming process of particles in evaporating drops. PMID- 28895610 TI - Cancer vaccines using supramolecular hydrogels of NSAID-modified peptides as adjuvants abolish tumorigenesis. AB - Inflammatory responses play crucial roles in the development and progression of tumors. Tumor-associated inflammation not only promotes tumor growth but also induces the suppression of immune responses against tumors. We demonstrate in this study that hydrogels of nonsteroidal anti-inflammatory drug (NSAID) modified D-tetrapeptides (GDFDFDY) are promising cancer vaccine adjuvants, especially for Fbp-gel and Car-gel. The hydrogels allow easy incorporation of a protein OVA antigen by vortexing. Our results indicate that vaccines based on Fbp-gel and Car gel increase IgG production by 1476- and 929-fold, compared with the OVA group, respectively. They exhibit higher IgG2a antibody titers and stimulate the production of IFN-gamma and IL-6 cytokines. Their higher antibody and cytokine eliciting properties in combination with their anti-inflammatory properties endow them with excellent tumor elimination properties in vivo. In a preventive immune assay against B16-OVA tumors, they totally prevent tumorigenesis. In a therapeutic immune assay against EG7-OVA tumors, they inhibit tumor growth by 75%, compared with the PBS group. Our results suggest the great potential of our hydrogels in the development of vaccines to treat cancers. PMID- 28895611 TI - Velocity amplification in pressure-driven flows between superhydrophobic gratings of small solid fraction. AB - With diminishing fraction of their solid portion, compound gas-solid superhydrophobic surfaces exhibit a large amount of slip which allows for appreciable velocity amplification in pressure-driven microchannel flows. We address this small solid-fraction limit in the context of a grating-like configuration, where superhydrophobicity is provided by a periodic array of flat meniscus bubbles which are trapped in a Cassie state within the grooved channel walls. Asymptotic analysis for both longitudinal and transverse flows reveals a logarithmic scaling of the effective slip length in the solid fraction of the compound boundaries, thus refuting earlier claims of an algebraic singularity. The logarithmic scaling in the longitudinal problem is explained using an analogy between the unidirectional velocity and the velocity potential in two-dimensional irrotational flows. In the transverse problem it has to do with the Stokes paradox. The mechanisms identified herein explain the absence of slip-length singularity in the comparable asymmetric configuration, where only one of the channel walls is superhydrophobic. PMID- 28895612 TI - Achiral flexible liquid crystal trimers exhibiting gyroid-like surfaces in chiral conglomerate phases. AB - Chiral conglomerate phases have attracted much attention not only for the spontaneous mirror symmetry breaking but also for their nanostructures. We investigated both surface and bulk structures of a homologues series of an achiral liquid crystal trimer I-(n,m) exhibiting soft crystalline chiral conglomerate phases by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The trimers were found to form bicontinuous networks. In particular, trimer I-(9,9) exhibited a single gyroid-like surface accompanying periodic distribution of dimples with a size of about 100 nm. It showed a sponge like structure in the bulk of the material. The twist conformation of the flexible trimer I-(n,m) can cause layer deformation, which produces bicontinuous networks exhibiting optical activity. PMID- 28895613 TI - [The G-Score - a Short Questionnaire for the Measurement of Subjective Physical Health]. AB - AIM: The measurement of subjective physical health is important in clinical settings as well as for research purposes. In the present paper, the psychometric properties of the G-Score, a 4 item screening questionnaire for the self assessment of one's physical health, is explored. METHODS: The Objectivity, validity and reliability were estimated. Moreover, an item analysis and a suitable cut-off-value for the differentiation between healthy and presumably ill subjects were conducted. Data from the Saxony Longitudinal Study ("Sachsische Langsschnittstudie") 1998-2013 were analysed (N=324-417 healthy individuals). RESULTS: The objectivity of the G-Score is estimated as very good. As a cut off for the differentiation between healthy and presumably ill subjects, a G-Score of 4 is suggested. The content validity is slightly lacking. Correlations with associated and non-associated constructs hint an interaction of physical with psychological discomfort. A good predictive validity of the instrument is assessed. Reliability estimates show acceptably good results. This indicates a high sensitivity for changes in the measured construct. CONCLUSION: Putting all results into consideration, a use of the G-Score as a screening questionnaire in research is recommended. However, more psychometric investigations with representative samples and objective comparative data should be carried out. PMID- 28895614 TI - [Negative Effects of Psychotherapy: Prevalence and Correlates in a Clinical Sample]. AB - INTRODUCTION: So far, the prevalence of negative effects of psychotherapy and their correlates have rarely been investigated in a systematic manner. The prevalence of negative effects varied between 3 studies with the Inventory for Assessing Negative Effects of Psychotherapy (INEP) with 20, 84, and 93.8% substantially. Thereby, the impact of bias effects remains unclear. In addition, reported correlates of the number of negative effects were examined and augmented with further correlates. MATERIAL AND METHODS: For the study, a clinical sample of inpatients and day-patients (N=200) evaluated their previous psychotherapy retrospectively before their current admission with the Inventory for Assessing Negative Effects of Psychotherapy (INEP). Sociodemographic and clinical data of both patients and therapists as well as time-related and methodical aspects of the evaluated psychotherapy were examined as possible correlates. RESULTS: 70.5% (n=141) of the patients reported at least one negative effect (M=2.11, SD=2.23). The most common negative effects were "longer periods of negative mood" (39.9%) and "being offended by statements of the therapist" (28%). Higher symptom severity, lower subjective success of the evaluated therapy, as well as unfulfilled expectations regarding therapy outcome but not the quality of the therapeutic relationship were associated with a higher number of negative effects. Also female gender of patient and therapist and a younger age of the therapist were significantly associated with more negative therapy effects. CONCLUSION: The prevalence of negative effects was not negligible. In line with previous studies, the highest rates of negative effects were reported for "symptoms" and aspects of the "therapeutic relationship". The study confirms several correlates for the number of retrospectively assessed negative effects. Patients need to be informed about negative effects prior to psychotherapeutic treatment. PMID- 28895615 TI - [Methamphetamine Use in Central Germany: A Qualitative Study on Consumer Groups and Motives from the Experts' Perspective]. AB - BACKGROUND: Methamphetamine is one of the most consumed illegal drugs worldwide. In Germany, Methamphetamine shows the highest rates of growth in comparison to other illegal substances in recent years. Particularly Central Germany has been struck by a high rise in consumption. International studies indicate that there is no specific group of people that can be identified as Methamphetamine users. Different consumption patterns in terms of Methamphetamine use can be identified within various social groups. This qualitative study will explore different consumer groups among methamphetamine users, their motives, and how they differ by drug addiction type. METHODS: The empirical data collection was carried out in a consecutive 2-stage process. Initially, 39 semi-structured individual interviews with experts from different clinical areas were carried out about their experience and perspectives on Methamphetamine use. The results of the individual interviews were subsequently discussed and validated within 2 interdisciplinary focus groups. All interviews and focus groups were digitally recorded, transcribed and analyzed according to the method of Meuser & Nagel. RESULTS: Altogether, 3 consumer groups were identified: (1) Young parents, women and pregnant women, (2) young drug users and early adapters and (3) older drug users or late entrants. The guiding motive in terms of Methamphetamine use described by the experts was improved efficiency. Further motives are for instance overcoming stressful situations, enablement and improvement of sexual experiences, self-esteem enhancement, coping with crisis or trauma, curiosity and drug use as leisure time activity. DISCUSSION/CONCLUSION: The results in terms of consumer groups and consumption motives are consistent with international findings and we were able to verify and expand them for Central Germany. The outcomes illustrated that there are different consumer groups among methamphetamine users that differ from consumer groups of other drug addiction types. Treatment and consultation have to anticipate these challenges and adapt their strategies to different needs. Finally, further improvement of accessibility for those affected persons is an imperative to the German healthcare system. PMID- 28895616 TI - ? PMID- 28895617 TI - Timing of Maternal Tobacco Exposure, Hypertension, and Risk of Singleton Small For-Gestational Age Infants. AB - OBJECTIVE: Small-for-gestational age infants are at an increased risk for disabilities and chronic health problems. Smoking and hypertension during pregnancy pose significant risks for fetal growth restriction. The study aims to identify whether (1) the timing of tobacco use modifies the risk of small-for gestational age, (2) there are differences in association by percentile of small for-gestational age (3rd, 5th, and 10th percentile), and (3) the effect of tobacco exposure on small-for-gestational age outcome is mediated by hypertension. MATERIALS AND METHODS: Data were obtained from the 2009 Natality public use file available through the National Center for Health Statistics. Women were categorized into 11 groups depending on the trimester of tobacco exposure, the number of daily cigarettes smoked, and presence of hypertension. Multivariable log-linear regression models were performed to determine the association between percentile of singleton small-for-gestational age outcome (3rd, 5th, and 10th), trimester and degree of tobacco exposure, and hypertension. RESULTS: Hypertension and smoking worked synergistically to restrict fetal growth. Hypertensive women who smoked heavily in all three trimesters were 4.34 times more likely to give birth to a 3rd percentile small-for-gestational age infant compared with nonsmoking normotensive women. CONCLUSION: The timing and duration of tobacco exposure mediates the risk and severity of fetal growth restriction. PMID- 28895618 TI - Acute Respiratory Distress in a Child with H3N2 Infection. PMID- 28895619 TI - Symptoms Of Common Mental Disorders In Professional Rugby: An International Observational Descriptive Study. AB - The aim of the study was to determine the prevalence of symptoms of common mental disorders among professional rugby players across countries. A cross-sectional analysis of the baseline questionnaires from an ongoing prospective cohort study was conducted. Nine national players' associations and three rugby unions distributed questionnaires based on validated scales for assessing symptoms of common mental disorders. Among the whole study sample (N=990; overall response rate of 28%), prevalence (4-week) of symptoms of common mental disorders ranged from 15% for adverse alcohol use to 30% for anxiety/depression. These findings support the prevalence rates of symptoms of common mental disorders found in previous studies among professional (i. e., elite) athletes across other sports, and suggestions can be made that the prevalence of symptoms of anxiety/depression seems slightly higher in professional rugby than in other general/occupational populations. Awareness of the prevalence of symptoms of common mental disorders should be improved in international rugby, and an interdisciplinary approach including psychological attention should be fostered in the medical care of professional rugby players. Adequate supportive measures to enhance awareness and psychological resilience would lead not only to improved health and quality of life among rugby players but arguably to enhanced performance in rugby. PMID- 28895620 TI - Epidemiology of Overuse Injuries in Youth Team Sports: A 3-year Prospective Study. AB - Prospective studies on overuse injuries and their impact on athletic training among youth team sports are scarce. The purpose of this study was to investigate the incidence, severity and player related risk factors of overuse injuries among young (12-20 years) basketball and floorball players. A total of 387 players participated in a 3-year prospective study. Each player completed a baseline questionnaire regarding their background information. Overuse injuries that prevented players to fully or partly participate in their regular training were collected. In all, 204 overuse injuries were registered (injury incidence 1.51 injuries/1 000 h of exposure; 95% CI 1.35-1.78). Most of the injuries involved the knee (35%) and lower back (21%), and were classified as severe (44%). Injury incidence was 1.51 (95% CI 1.2-1.82) and 1.61 (95% CI 1.32-1.91) in basketball and floorball, respectively. Incidence was significantly higher among female compared with male players (incidence rate ratio 1.58; 95% CI 1.20-2.09). Previous injury and playing at adult level were the strongest factors associated with occurrence of an overuse injury. In conclusion, overuse injuries of the knee and low back are relatively common in youth basketball and floorball. Effective prevention strategies as well as training load monitoring is needed in youth team sports. PMID- 28895621 TI - Optimum Drop Jump Height in Division III Athletes: Under 75% of Vertical Jump Height. AB - Our purpose was to evaluate the vertical ground reaction force, impulse, moments and powers of hip, knee and ankle joints, contact time, and jump height when performing a drop jump from different drop heights based on the percentage of a performer's maximum vertical jump height (MVJH). Fifteen male Division III athletes participated voluntarily. Eleven synchronized cameras and two force platforms were used to collect data. One-way repeated-measures analysis of variance tests were used to examine the differences between drop heights. The maximum hip, knee and ankle power absorption during 125%MVJH and 150%MVJH were greater than those during 75%MVJH. The impulse during landing at 100%MVJH, 125%MVJH and 150%MVJH were greater than 75%MVJH. The vertical ground reaction force during 150%MVJH was greater than 50%MVJH, 75%MVJH and 100%MVJH. Drop height below 75%MVJH had the most merits for increasing joint power output while having a lower impact force, impulse and joint power absorption. Drop height of 150%MVJH may not be desirable as a high-intensity stimulus due to the much greater impact force, increasing the risk of injury, without increasing jump height performance. PMID- 28895622 TI - Sciatic Nerve Conductivity is Impaired by Hamstring Strain Injuries. AB - The aim of this study was to assess sciatic nerve conductivity in athletes with a history of hamstring strain injuries. Twenty-seven athletes with a history of hamstring strain injuries were included in the injured group. The control group consisted of 16 uninjured participants. We measured the proximal and distal latencies and calculated the sciatic nerve conduction velocity to evaluate neuronal conductivity. The results were expressed as median values and interquartile ranges. Both proximal latency and distal latency of the injured limb in the injured group were significantly longer than those of the uninjured limb (p<0.05). The nerve conduction velocity of the injured limb in the injured group was significantly lower than that of the uninjured limb (p<0.05). There were no significant side-to-side differences in the control group. Sciatic nerve conductivity impairments may exist in athletes with a history of hamstring strain injuries. PMID- 28895623 TI - Comprehensive Analytics of Actovegin(r) and Its Effect on Muscle Cells. AB - The ingredients of Actovegin(r) were analyzed and its effects on the muscle cell proliferation were investigated. C2C12 myoblasts were cultured in medium. Actovegin(r) was added in five different concentrations (1, 5, 25, 125, and 250 ug) to the differentiation medium. The formations of proliferation factor Ki67 and myosin heavy chains were measured by immunofluorescence. The first primary antibody was anti-Ki67 and anti-Mf20. Cells were washed and treated with the second fluorochrome. Thirty-one Actovegin(r) ingredients were found to contain significantly higher concentrations and twenty-nine ingredients were found to contain significantly lower concentrations, compared to the mean ranges as described in the literature for the normal physiological concentrations in human adult serum/plasma. A significant increase in the formation of Ki67 was observed in Actovegin(r) groups, compared to controls. The mean area of myotubes was significantly increased in Actovegin(r) groups. A significant decrease in the number of myotubes was observed. An increased myotube size (fusion) was observed. The intensity of Mf20 was significantly increased in Actovegin(r) groups. It could be demonstrated that Actovegin(r) contains many physiological substances in significantly higher and some in lower concentrations compared to human adult serum. Furthermore, it could be shown that Actovegin(r) improves muscle cell proliferation. PMID- 28895624 TI - Development of an Incremental Sit-to-Stand Exercise for Aerobic Fitness Evaluation. AB - Incremental sit-to-stand exercise (ISTS) is an incremental exercise test using external signals to control the sit-to-stand rate in a given time frame. This study aimed to investigate the concurrent validity and reproducibility of the ISTS in aerobic fitness evaluation among healthy elderly women. Sixteen elderly women performed the ISTS and cycle ergometer test at 3-day to 2-week intervals, and six of the participants performed the ISTS twice. Peak oxygen uptake (VO2), peak heart rate and completion time on the ISTS and cycle ergometer test were determined. Measured peak VO2 on the cycle ergometer test was significantly related to the peak VO2 (r=0.80, P<0.05) and the completion time (r=0.65, P<0.05) on the ISTS. The intraclass correlation coefficients were 0.96 for peak VO2 values and 0.91 for the completion time values during the two ISTSs. In conclusion, the ISTS is a valid, reproducible and safe test for aerobic fitness evaluation in healthy elderly women. PMID- 28895625 TI - [Hot Topic: OCT-Angiography]. PMID- 28895626 TI - [Learning from Mistakes]. PMID- 28895627 TI - [Vitreous Substitute in Retinal Detachment Surgery - Why We Need a New Tamponade Strategy]. AB - Pars plana vitrectomy combined with an endotamponade is the most important concept in retinal detachment surgery. Numerous advances in techniques and tamponade materials have been made, but the general problems of retinal detachment surgery are still unsolved: The primary success rate is not adequate, and there is no adequate strategy to address proliferative vitreoretinopathy, multiple retinal breaks or persistent hypotony. The story of tamponades is full of myths and misunderstandings. A critical review shows that tamponades have only a minor role in the history of retinal detachment surgery. One might assume that the value of tamponades is overestimated. This may be because the underlying concept is limited: All available tamponades are hydrophobic, so they act by buoyant force and surface tension. This narrow focus on the hydraulic function allows only one tamponade vector and makes complete filling of the vitreous body space impossible. The hydrophobic character of the materials has fundamental disadvantages that tend to increase the risk of new breaks or PVR formation. Thus, a critical revaluation of the value of current tamponades is necessary. One solution might be to develop hydrogels as vitreous body substitute. Such a hydrophilic vitreous body substitute fits the natural and complex function of a juvenile, healthy vitreous much better than gas or silicone oil. PMID- 28895628 TI - [Exudative AMD in OCT Angiography]. AB - OCT angiography provides a combination of vascular and structural information. In contrast to conventional fluorescein angiography, there is no need for dye injection to give an image of choroidal neovascularisation. Although there is currently no classification of OCT angiography, different neovascular patterns can be observed, with criteria for activity. In the future, OCT angiography may help us to understand pathophysiological mechanisms and to develop therapeutic strategies. PMID- 28895629 TI - [Novel Examination Procedures for the Assessment of Retinal Artery Occlusion by OCT Angiography]. AB - Background Retinal artery occlusion (RAO) is the most common primary angiopathy of the retina. With an incidence of 0.01 - 0.15%, this it is a rather rare disease, but is associated with irreversible damage to the retina and a poor prognosis for visual acuity. Since the 1960s - when fluorescence angiography (FA) was developed -, there has been little change in diagnostic investigations. FA is still the standard procedure for the assessment of retinal artery occlusions. With the development of OCT angiography (OCT-A), new multimodal imaging procedures have become possible. Patients/Methods We used Zeiss AngioPlex(r)-OCT A technology in combination with the CIRRUSTM HD-OCT 5000 (Carl Zeiss Meditec, Inc., Dublin, USA) to create 6 * 6 mm and 3 * 3 mm volume scans of the area of non-perfusion in patients with RAO. Qualitative OCT-A analysis was performed on retinal images segmented into the superficial and deep retinal capillary plexus. In addition to this, volumetric scans can be segmented to any specific depth of the retina. On the basis of 4 cases, we demonstrate that OCT-A can be used to evaluate RAO. We present typical OCT-A findings. Results OCT-A images allow the detection of non-perfused areas in patients with acute and chronic RAO. The zones of reduced vascular perfusion are differently distributed in the superficial and deep retinal capillary plexus. In both acute and chronic cases of RAO, OCT-A offers important information on retinal vascular perfusion. Conclusion OCT-A can be used in the diagnosis and monitoring of acute and chronic cases of RAO. The advantages of OCT-A are that this technique is non-invasive and allows three dimensional microvascular visualisation within seconds. Although artefacts and the currently limited field of view can make it difficult to interpret OCT-A images reliably, these findings suggest that OCT-A may in future replace FA in the assessment of RAO in most patients. PMID- 28895630 TI - [Changes in OCT Angiography of Type 2 CNV in Neovascular AMD during Anti-VEGF Treatment]. AB - Purpose OCT-A is a new method to visualise the 2D and 3D structures of neovascular complexes in exudative AMD. The aim of the present study was to characterise type 2 CNV in different 2D segmentations and in 3D imaging and to investigate changes during anti-VEGF treatment. Methods 12 patients with type 2 CNV in FA and SD-OCT were selected. OCT-A (Avanti, Optovue) was obtained initially and after the first three injections and thereafter, if "new activity" (increase in sub- or intraretinal fluid) occurred. The characteristics of the type 2 CNV were classified initially and during follow-up in different segmentations (outer retina, RPE, CC, choroidea), in respect to the size of the CNV, the flow area within the CNV and flow index (% of flow area within the total lesion). Results Comparison of the vessel characteristics before and after anti VEGF treatment showed a significant reduction in the size of CNV at every level (p < 0.05). This was most significant at the RPE level (p < 0.005). After new activity, a significant increase in size was only recognised at the CC level (p < 0.05). Similarly, the most significant changes in the flow area were measured at the RPE level before and after treatment (p < 0.01) and at the CC level after new activity (p < 0.05). Demarcation from type 2 CNV of the bordering tissue was much better when activity occurred. Conclusions OCT-A provides a new opportunity for the assessment of vascular characteristics of type 2 CNV, and quantifies CNV size and vascularisation under anti-VEGF therapy. This may be used in further studies in combination with SD-OCT scans to describe characteristics of this type of CNV under treatment. OCT-A is an additional medical imaging procedure to SD-OCT and FA, but more experience is needed in distinguishing CNV in the active and non active stages. PMID- 28895631 TI - [OCT Angiography of RPE Tears in Exudative AMD: Morpohological Analysis of the Choriocapillaris and the RPE]. AB - Background Retinal pigment epithelium (RPE) tears are a typical complication of vascular pigment epithelium detachment in age-related macular degeneration (AMD). During proactive intense anti-VEGF therapy, stabilisation or improvement of function may occur. With the new method of OCT angiography (OCT-A), retinal vessels and flow density can be quantified. This pilot study investigates changes in the choriocapillars (CC) in areas with increasing FAF in OCT following an RPE tear. Methods In six eyes with an RPE-tear, prospectively initially and every three months thereafter, multimodal imaging was performed, including fundus autofluorescence (FAF) (HRA2, Heidelberg Engineering, Heidelberg, Deutschland) and OCT-A (RTVue XR Avanti, SSDA-Modus, Angiovue, Optovue, Freemont, CA, USA). With interactive MATLAB-software (MATLAB, MathWorks, Natick, MA, USA), FAF and OCT were geometrically superimposed. With the help of the Fiji software (National Institutes of Health, Bethesda, MD, USA), areas with increasing FAF flow intensity in OCT-A with CC-segmentation were measured during an average follow-up period of 12 months. Results We measured a reduction in the RPE-free area - due to an increase in autofluorescence tissue - of an average of 2.94 mm2 (SD 2.1 mm2; 42.1% of initial RPE-free area) in the boundary area of RPE-tears. At the end of the different follow-ups, some patients exhibited lower flow density in areas of regenerated autofluorescence than the initial findings. On the other hand, in some follow-ups, the same or increased flow density was seen. Conclusion In this pilot study, OCT-A was tested to analyse the structure of CC in areas of regenerated FAF after RPE-tears. Using external image editing software, FAF and OCT-A were compared during the follow-up. Thus apparent initial regression of the CC in the area mentioned above could be observed. During the follow-up and development of autofluorescent SHT, CC also regenerates up to the level of the initial findings of CC. PMID- 28895632 TI - [OCT Angiography in Exudative AMD with Detachment of Vascularised Retinal Pigment Epithelium]. AB - Background The aim of the following extended case study was to analyse whether choroidal neovascularisation (CNV) in vascularised epithelial detachments (PED) in OCT angiography (OCT-A) can be better visualised in OCT-A than in the established angiographic methods during the course of anti-VEGF therapy and if possible used to quantify the CNV size and flow area. These findings were compared with other SD-OCT characteristics of the lesion (PED height, retinal thickness). Patients and Methods 8 patients with PED and associated CNV were diagnosed with multimodal imaging and additionally OCT angiography was performed. The CNV region in the B-scan of the OCT-A was detected with a fine segmentation setting (20 um) parallel and just below the retinal pigment epithelium (RPE). The CNV area was manually marked, and the size of the CNV and the vessel section (flow area) were analysed with the evaluation tool of the device. This measurement was performed both initially and after anti-VEGF therapy (3 injections). At the same time, the visual acuity (logMAR) and the SD-OCT parameters of PED height and retinal thickness were determined before and after therapy and also statistically compared. Results Initially, the size of CNV in OCT-A showed a large phenotypic range of variation (0.33 - 1.35 mm2, mean 0.71 mm2). This decreased significantly under therapy (after therapy 0.44 - 0.84 mm2, mean 0.57 mm2, p = 0.02). The proportion of the vessels analysed within the CNV (flow area) varied as well (0.21 - 0.88 mm2, mean 0.45) and decreased under therapy (0.08 - 0.44 mm2 after therapy), mean 0.27 mm2, p = 0.07). The height of PED in SD-OCT was initially different (initially 274 - 1459 um, mean 607 um), but showed only small changes (132 - 1317 um, mean 524 um, p = 0.09) under therapy. This also applied to the mean retinal thickness (before therapy 315 um, after therapy 294 um, p = 0.5). Mean visual acuity also improved only slightly (p = 0.7) after therapy. from initially 0.51 to 0.45 logMAR. Conclusions The combination of SD-OCT and OCT-A offers significantly improved visualisation and quantification of CNV in a vascularised PED. With the help of OCT-A imaging, changes in the perfusion/size of the CNV can be quantified. Together with the retinal activity signs, this allows a second activity assessment of the CNV under anti-VEGF therapy. Due to its three-dimensional structure, especially for this subtype of the exudative AMD, it is of the utmost importance to develop three dimensional imaging for both structural SD-OCT and the OCT-A. PMID- 28895633 TI - Letter to the Editor: Free ILM Autograft for Macular Hole. PMID- 28895635 TI - ? PMID- 28895634 TI - Reply: Letter to the Editor - Free ILM Autograft for Macular Hole. PMID- 28895636 TI - [Minimally invasive Therapy of lacrimal Drainage System Stenosis]. AB - Epiphora is one of the most common symptoms for clinical ophthalmological consultation. This symptom is mostly caused by stenosis of the lacrimal drainage system. Over a century, external dacryocystostomy according to Toti was the treatment of choice. Today, new very encouraging minimally invasive techniques for recanalisation of the lacrimal drainage system, such as microdrilldacryoplasty or laserdacryoplasty, as well as bypass-based techniques, such as transcanalicular laser-assisted dacryocystorhinostomy, become more important in the treatment of dacryostenosis. PMID- 28895637 TI - Eating Frequency and Carbohydrate Intake in Adolescents with Type 1 Diabetes Differ from Those in Their Peers and are Associated with Glycemic Control. AB - AIM: The diet of people with type 1 diabetes may differ from that of healthy peers due to disease-related factors that may affect the course of diabetes. This cross-sectional study sought to compare meal and snacking frequency and corresponding carbohydrate intake among adolescents with intensively-treated type 1 diabetes and healthy peers and to analyze their association with glycemic control among diabetes patients. METHODS: Nutritional data of 712 11- to <19-year olds from a nationwide population-based survey on early-onset type 1 diabetes (52.7% boys/men, mean age 15.6 years) were compared with 949 food records of 296 healthy participants in the DONALD cohort study (49.7% boys, mean age 14.4 years) using linear mixed models. Furthermore, the association between eating frequency and/or carbohydrate intake with glycemic control (HbA1c) was analyzed with multiple linear regression models. RESULTS: After comprehensive adjustment, diabetes patients had, on average, 4.6 [95% confidence interval 3.6, 5.5] more meals or snacks/week but consumed 75.9 [64.5, 87.3] fewer grams of carbohydrates/day than the comparison group. Diabetes subjects also consumed breakfast, lunch, dinner, and snacks more frequently but ate fewer carbohydrates at all eating occasions. Total carbohydrate intake and carbohydrate intake at breakfast were associated with higher HbA1c levels, while increased breakfast frequency was associated with lower HbA1c levels. CONCLUSION: Eating frequency and carbohydrate intake differed between adolescents with early-onset type 1 diabetes and non-diabetic peers. The observed associations with glycemic control challenge the concept of a completely unregulated eating frequency and carbohydrate intake for people on intensified insulin therapy. PMID- 28895638 TI - Gender and Age Differences in Lipid Profile Among Chinese Adults in Nanjing: a Retrospective Study of Over 230,000 Individuals from 2009 to 2015. AB - BACKGROUND: Previous national survey suggested that dyslipidemia is an increasing burden in China and more severe in urban population. In this study, we retrospectively analyzed the gender and age differences in lipids and lipoproteins in a large Chinese urban population in Nanjing city. METHODS: A total of 236, 945 adults (age >=20 years old) who undertook a health check between 2009 and 2015 in our medical examination center were involved in the analysis. Fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride (TG) were measured by standard methods. RESULTS: The age-standardized estimates of serum total cholesterol, HDL cholesterol, LDL cholesterol and triglyceride were 4.77 (4.76 4.79), 1.19 (1.18-1.19), 2.53 (2.52-2.54) and 1.74 (1.72-1.76) mmol/L in males (n=130954), and 4.79 (4.78-4.80), 1.46 (1.45-1.46), 2.44 (2.43-2.45) and 1.21 (1.19-1.22) mmol/L in females (n=105991), respectively. The prevalence of dyslipidemia was significantly elevated in females above 50 years old, and the peak prevalence of dyslipidemia in males was in the age group of 40-59 years, earlier as compared to females (peaked at 60-69 years old). In addition, an increasing secular trend was observed in LDL cholesterol levels from 2009 to 2015 in both males and females. CONCLUSIONS: Dyslipidemia is an increasing epidemic in China, characterized by a rising trend of LDL cholesterol. The gender and age differences in serum levels of lipid profile as well as prevalence of dyslipidemia suggested that the middle-age men and postmenopausal women should be the prioritized target for better control of dyslipidemia and early prevention of cardiovascular disease. PMID- 28895639 TI - The PI3K/Akt1-FoxO1 Translocation Pathway Mediates EXf Effects on NIT-1 Cell Survival. AB - EXf, a glucagon-like peptide 1 (GLP-1) receptor agonist, stimulates beta-cell proliferation and reduces apoptosis in diabetic animal models, but the underlying mechanisms are not fully understood. We constructed a FoxO1-GFP fusion protein expression plasmid and transiently transfected it into NIT-1 cells to investigate whether FoxO1 mediates EXf effects on NIT-1 cell survival. Our results showed that EXf could increase cell viability by inhibiting apoptosis and stimulating proliferation, and it could also promote the translocation of the FoxO1-GFP fusion protein from the nucleus to the cytoplasm in NIT-1 cells. However, the above effects of EXf were suppressed by the inhibitor of PI3K. Comparative transcription analysis showed up-regulation of igf-1r, irs-2, pI3k, akt1 and pdx 1 in NIT-1 cells after EXf treatment. Moreover, the up-regulation of PI3K and phosphorylation of Akt1 upon EXf treatment was confirmed by Western blot, both phenomena were abrogated by wortmannin, an inhibitor of PI3K. In summary, FoxO1 may mediate the effects of EXf on NIT-1 cell survival by activating the PI3K/Akt1 pathway. PMID- 28895640 TI - The Application of SUDOSCAN for Screening Diabetic Peripheral Neuropathy in Chinese Population. AB - PURPOSE: Diabetic peripheral neuropathies are the common chronic complications of diabetes, but the diagnosis is insensitive by physical examination in busy outpatients. Here we evaluated the performance of SUDOSCAN in screening diabetic peripheral neuropathies in Chinese type 2 diabetic patients. METHODS: The study enrolled 180 patients for annually screening. All patients underwent neurological symptoms assessment, clinical examination, nerve conduction studies and cardiovascular autonomic reflex tests. SUDOSCAN was tested and evaluated with electrochemical skin conductance in hands and feet, asymmetry ratio in hands and feet and predicted cardiac neuropathy. RESULTS: Patients enrolled had an average age of 56.1 years, 9.8 years of diabetic duration. Patients with diabetic sensorimotor polyneuropathy showed significantly lower electrochemical skin conductance in feet and higher asymmetry ratio in feet compared with those without. Sensitivity and specificity of asymmetry ratio in feet for diagnosing diabetic sensorimotor polyneuropathy were 88.2% and 46.9% and area under ROC curve was 0.713. Patients with cardiovascular autonomic neuropathy showed significantly lower electrochemical skin conductance in hands and feet, and higher asymmetry ratio in feet and predicted cardiac neuropathy compared with those without. Sensitivity and specificity of electrochemical skin conductance in feet in diagnosing cardiovascular autonomic neuropathy were 85.6% and 76.1% with an area under ROC curve of 0.859. CONCLUSIONS: SUDOSCAN is a sensitive test to detect diabetic peripheral neuropathy in China and could be an effective screening tool in in busy outpatients and primary health care. PMID- 28895641 TI - Relationship between Oxidative Stress, Inflammation and Dyslipidemia with Fatty Liver Index in Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION/AIM: Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in individuals with type 2 diabetes mellitus (DM2), we aimed to investigate the potential benefit of determining markers of oxidative stress, inflammation and dyslipidemia for prediction of NAFLD, as estimated with fatty liver index (FLI) in individuals with DM2. METHODS: A total of 139 individuals with DM2 (of them 49.9% females) were enrolled in cross-sectional study. Anthropometric and biochemical parameters, as well as blood pressure were obtained. A FLI was calculated. RESULTS: Multivariate logistic regression analysis showed that high density lipoprotein cholesterol (HDL-c) and malondialdehyde (MDA) were independent predictors of higher FLI [Odds ratio (OR)=0.056, p=0.029; and OR=1.105, p=0.016, respectively]. In Receiver Operating Characteristic curve analysis, the addition of fatty liver risk factors (e. g., age, gender, body height, smoking status, diabetes duration and drugs metabolized in liver) to each analysed biochemical parameter [HDL-c, non-HDL-c, high sensitivity C-reactive protein (hsCRP), MDA and advanced oxidant protein products (AOPP)] in Model 1, increased the ability to discriminate patients with and without fatty liver [Area under the curve (AUC)=0.832, AUC=0.808, AUC=0.798, AUC=0.824 and AUC=0.743, respectively]. Model 2 (which included all five examined predictors, e. g., HDL-c, non-HDL-c, hsCRP, MDA, AOPP, and fatty liver risk factors) improved discriminative abilities for fatty liver status (AUC=0.909). Even more, Model 2 had the highest sensitivity and specificity (89.3% and 87.5%, respectively) together than each predictor in Model 1. CONCLUSION: Multimarker approach, including biomarkers of oxidative stress, dyslipidemia and inflammation, could be of benefit in identifying patients with diabetes being at high risk of fatty liver disease. PMID- 28895642 TI - Initiation of Basal Insulin Analog Treatment for Type 2 Diabetes and Reasons Behind Patients' Treatment Persistence Behavior: Real-World Data from Germany. AB - BACKGROUND: Poor treatment persistence can affect the real-world effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. METHODS: Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from market-research panels, participated in the survey. Patients were asked if they had >=7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" (>=1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. RESULTS: The 131 participants from Germany included 55 (42.0%) continuers, 50 (38.2%) interrupters and 26 (19.9%) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2%) and expectation to improve glycemic control (42.0%). More than 95% of participants received training before and during insulin initiation (considered as helpful by 81.7%); most (67.2%) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7%), improved physical well-being (49.1%), and instruction by physician or other HCP (45.5%). The most common reasons contributing to interruption/discontinuation were perceived weight gain (52.0%/50.0%), hypoglycemia (22.0%/38.5%), and potential adverse effects (30.0%/26.9%). CONCLUSIONS: Quality interactions between physicians or other HCPs and their patients before and during the initiation of basal insulin may help to manage patient expectations and to improve persistence to insulin therapy. PMID- 28895643 TI - Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, beta-Klotho, and FRS2alpha in Relation to FGF21-AMPK Signaling. AB - Thyroid hormone (3,3',5-triiodothyronine, T3) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T3 on the expression of the scaffold proteins beta-Klotho, fibroblast growth factor receptor substrate 2alpha (FRS2alpha), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T3/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic beta-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2alpha, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2. Also, protein levels of FGF21, FGFR1 (ELISA), and ERK1/2 (Western blot) were measured. T3 elicited a calorigenic response with higher hepatic mRNA expression of beta-Klotho, FRS2alpha, and FGF21, increased serum FGF21, without changes in liver FGFR1 mRNA and its plasma levels. In addition, T3 enhanced ERK1/2 phosphorylation and the mRNA expression of ERK1/2, RSK1, LKB1, AMPK, and Sestrin2. T3 administration enhances liver FGF21-AMPK signaling involving upregulation of the scaffold proteins beta-Klotho, FRS2alpha, and Sestrin2. beta-Klotho and FRS2 induction favours the operation of the FGF21-FGFR1-beta-Klotho complex as evidenced by the enhancement in ERK1/2 phosphorylation, whereas that of Sestrin2 recruits LKB1 to achieved AMPK activation, thus supporting a higher energy expenditure condition that may be desirable in some metabolic disorders. PMID- 28895644 TI - Relaxin Inhibits Cardiac Fibrosis in Diabetic Rats: Roles of Protein Kinase Cdelta. AB - Relaxin (Rlx) is known to antagonize diabetic cardiac fibrosis. However, its mechanism is poorly understood. Protein kinase Cdelta (PKCdelta) plays a crucial role in diabetic cardiomyopathy (DCM). This study explored the involvement of PKCdelta in Rlx's capacity of suppressing cardiac fibrosis in a rat model of type 2 diabetes mellitus (DM). Type 2 DM of 8-week-old male Sprague-Dawley (SD) rats was induced by a high-fat diet and the injection of streptozocin (STZ, 40 mg/kg). Fourteen-week-old rats with DM and rats in control group which were pre-treated for 1 week with human recombinant relaxin (rhRlx, 30 MUg/kg.d), were assessed to detect cardiac fibrosis and PKCdelta expression with Western blot. Cardiac fibroblasts of neonatal rats were treated for 72 h with rhRlx (100 ng/ml) under high glucose (HG). Western blot was utilized for detecting the membranous and cytoplasmic protein expressions of PKCdelta. The effects of rhRlx and PKCdelta inhibitor (rottlerin) were assessed either alone or in combination on the HG induced proliferation and differentiation of cardiac fibroblasts and the release of collagen I.Rlx treatment inhibited the differentiation of cardiac fibroblasts and the expression of collagen I. The expression of PKCdelta was regulated by Rlx in diabetic rats and cardiac fibroblasts under HG condition. The effects of Rlx upon the proliferation and differentiation of cardiac fibroblasts and the excretion of collagen I under HG were blunted by rottlerin. Rlx suppressed cardiac fibrosis in type 2 diabetic rats. This beneficial effect was associated with its ability of modulating the expression of PKCdelta. PMID- 28895645 TI - Most Effective Regimen of Tranexamic Acid for Reducing Bleeding and Transfusions in Primary Total Knee Arthroplasty: A Meta-Analysis of Randomized Controlled Trials. AB - The use of tranexamic acid (TXA) during primary total knee arthroplasty (TKA) is well documented. However, considering the potential side effects, including deep vein thrombosis (DVT) and pulmonary embolism (PE), the ideal route of administration remains controversial. Therefore, we performed a meta-analysis to compare the efficacy of topical versus intravenous TXA and explore the most effective regimen in patients undergoing primary TKA. We conducted a systematic literature search in PubMed, Embase, and the Cochrane database through July 2016 to identify randomized controlled trials (RCTs) evaluating the efficacy and safety of topical and intravenous TXA in primary TKA. We assessed the risk of bias using the Cochrane Collaboration's tool. We assessed the quality of evidence using the GRADE profiler software. A total of 15 RCTs including 1,240 participants met the inclusion criteria. We found no statistically significant difference between topical and intravenous TXA in terms of transfusion rate (p = 0.75), total blood loss (p = 0.51), total drain output (p = 0.60), maximum hemoglobin drop (p = 0.24), length of stay (p = 0.08), and thromboembolic complications (p = 0.73). Subgroup analyses showed that compared with 1 g topical TXA, 2 g topical TXA was more effective to reduce blood transfusion rate and total blood loss, and did not increase thromboembolic complications. We also found three times intravenous TXA was more effective than one time of intravenous TXA to reduce blood transfusion rate and total blood loss without increasing of thromboembolic complications. Topical TXA had a similar efficacy to intravenous TXA in reducing blood transfusion and blood loss, and did not increase the risk of thromboembolic complications in primary TKA. Besides, the current meta analysis suggested that three times of intravenous TXA is efficient and safe. We also recommended 2 g topical TXA instead of 1 g topical TXA because it was more efficient to reduce blood transfusion rate and total blood loss and did not increase thromboembolic complications. PMID- 28895647 TI - Sliding doors: heteromeric, volume-sensitive osmolyte channels. PMID- 28895646 TI - Transfusion Approaches and Mortality in Trauma Patients: A Narrative Review. PMID- 28895648 TI - Collateral impact: a dual role for climbing fibre collaterals to the cerebellar nuclei? PMID- 28895649 TI - Enhanced Trace Carbon Dioxide Capture on Heteroatom-Substituted RHO Zeolites under Humid Conditions. AB - Boron and copper heteroatoms were successfully incorporated into the frameworks of high-silica RHO zeolite by adopting a bulky alkali-metal-crown ether (AMCE) complex as the template. These heteroatom-doped zeolites show both larger micropore surface areas and volumes than those of their aluminosilicate analogue. Proton-type RHO zeolites were then applied for the separation of CO2 /CH4 /N2 mixtures, as these zeolites have weaker electric fields and, thus, lower heats of adsorption. The adsorption results showed that a balance between working capacity and adsorption heat could be achieved for these heteroatom-doped zeolites. Ideal adsorbed solution theory predictions indicate that these zeolites should have high selectivities even for remarkably dilute sources of CO2 . Finally, the heteroatom-substituted zeolites, especially the boron-substituted one, could be thermally regenerated rapidly at 150 degrees C after full hydration and maintained high regenerability for up to 30 cycles; therefore, they are potential candidates for trace CO2 removal under humid conditions. PMID- 28895650 TI - Vestibular vertical: a balancing act between the upper and lower limbs. PMID- 28895651 TI - Modulating the Physical and Electronic Properties over Positional Isomerism: The Dispirofluorene-Dihydroindacenodithiophene (DSF-IDT) Family. AB - We report the first studies on the intrinsic properties of a meta-substituted dihydroindacenodithienyl fragment and more generally the strong impact of positional isomerism on dihydroindacenodithiophene derivatives. The influence of the para and meta linkages has notably been highlighted not only for the electronic properties in solution (electrochemical properties, anodic polymerization, HOMO/LUMO energy levels, optical transitions, fluorescence spectra) but also on the physical properties in the solid state (molecular organization, crystallinity, and phase transitions). The positional isomerism hence appears to be a very efficient tool to drastically tune the properties of dihydroindacenodithiophene derivatives. PMID- 28895652 TI - Quantitative Proteomics and Targeted Fatty Acids Analysis Reveal the Damage of Triptolide in Liver and Kidney. AB - Triptolide (TP), the major active component in Tripterygium wilfordii Hook. f., is widely used for the treatment of rheumatoid arthritis and autoimmune diseases. However, organ toxicity, especially hepatotoxicity and nephrotoxicity, limits its clinical application. To fully understand the mechanism underlying TP toxicity, iTRAQ-based 2D-LC-MS/MS proteomics is used to detect differentially expressed proteins in the livers and kidneys of mice administered the LD50 dose of TP. Functional annotation revealed that multiple pathways are involved in TP toxicity, including acute-phase response signaling, the antigen presentation pathway, FXR/RXR activation, LPS/IL-1-mediated inhibition of RXR function, and EIF2 signaling. Members of the cytochrome P450 protein family that are involved in fatty acid (FA) metabolism, such as CYP2E1, show significant differences in expression among groups. Additionally, the proteomics data suggested that FAs are involved in TP-induced toxicity. FA analysis is conducted using HPLC-MRM to characterize the differences among various groups exposed to TP for different times. It has been found that 20 FAs in the liver show significant differences in abundance among groups, whereas in the kidneys, six FAs show significant differences in abundance. By integrating the proteomic and targeted FA analyses, it has been found that differently expressed proteins and FAs both participate in pathways including cellular lipolytic activity, peroxisomal fatty acid beta oxidation, and so on. Our data contribute to understanding the mechanisms underlying TP-induced organ toxicity. The results may help to improve the clinical efficacy and safety of TP in the future. PMID- 28895653 TI - Clinical interventions for Takayasu arteritis: A systematic review. AB - INTRODUCTION: Takayasu arteritis (TA) is a rare systemic vasculitis that affects large vessels often resistant to treatment and associated with high morbidity and mortality. Treatment is defied by the relapsing nature of the disease and frequent adverse effects of corticosteroids and immunosuppressors, rendering failure of treatment in a significant portion of patients. Considering the low quantity and quality of published studies focusing on treatment of TA, synthesis and critical assessment of the available evidence is fundamental to establish recommendations for clinical practice. OBJECTIVE: To evaluate the effectiveness and safety of clinical interventions for TA. METHODS: Systematic review conducted in accordance to recommendations stated in the Cochrane Handbook, with inclusion of all comparative studies focusing on any type of clinical intervention for TA. RESULTS: Five comparative studies were included (one randomised clinical trial, two non-randomised clinical trials, and two historical cohorts) totalling 342 patients, aiming at the assessment of effectiveness of corticosteroids, immunosuppressors, biologics and other types of pharmacological treatment for distinct clinical presentations of TA. The quality of studies, assessed by the use of instruments developed specifically for each study design, was considered low. Data scarcity and clinical heterogeneity prevented quantitative synthesis (meta-analysis). CONCLUSION: Despite an extensive literature search, few comparative studies with small sample sizes were retrieved. The quality of these studies was considered low, preventing recommendations on effectiveness and safety of the studied interventions for clinical practice. Until new comparative studies with more robust sample sizes are conducted, treatment of TA should be guided individually taking into account the severity of disease and the availability of treatment options. PMID- 28895654 TI - Graft-accelerated virus-induced gene silencing facilitates functional genomics in rose flowers. AB - Rose has emerged as a model ornamental plant for studies of flower development, senescence, and morphology, as well as the metabolism of floral fragrances and colors. Virus-induced gene silencing (VIGS) has long been used in functional genomics studies of rose by vacuum infiltration of cuttings or seedlings with an Agrobacterium suspension carrying TRV-derived vectors. However, VIGS in rose flowers remains a challenge because of its low efficiency and long time to establish silencing. Here we present a novel and rapid VIGS method that can be used to analyze gene function in rose, called 'graft-accelerated VIGS', where axillary sprouts are cut from the rose plant and vacuum infiltrated with Agrobacterium. The inoculated scions are then grafted back onto the plants to flower and silencing phenotypes can be observed within 5 weeks, post infiltration. Using this new method, we successfully silenced expression of the RhDFR1, RhAG, and RhNUDX1 in rose flowers, and affected their color, petal number, as well as fragrance, respectively. This grafting method will facilitate high-throughput functional analysis of genes in rose flowers. Importantly, it may also be applied to other woody species that are not currently amenable to VIGS by conventional leaf or plantlet/seedling infiltration methods. PMID- 28895656 TI - CsB4 O6 F: A Congruent-Melting Deep-Ultraviolet Nonlinear Optical Material by Combining Superior Functional Units. AB - The discovery of new nonlinear optical (NLO) materials for coherent light generation in the deep-ultraviolet (DUV, wavelength below 200 nm) region is essential for the development of laser technologies. Herein, we report a new material CsB4 O6 F (CBF), which combines the superior structural properties of two well-known NLO materials, beta-BaB2 O4 (BBO) and KBe2 BO3 F2 (KBBF). CBF exhibits excellent DUV optical properties including a short cutoff edge (155 nm), a large SHG response (~1.9*KDP), and a suitable birefringence that enables frequency doubling down to 171.6 nm. Remarkably, CBF melts congruently and shows an improved growth habit. In addition, our rational design strategy will contribute to the discovery of DUV NLO materials. PMID- 28895655 TI - Insulin resistance and cardiovascular outcomes in the ORIGIN trial. AB - AIMS: In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (Clinicaltrials.gov: NCT000069784), titrated doses of basal insulin glargine targeting fasting normoglycaemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycaemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes. MATERIALS AND METHODS: Self-titration of insulin doses targeting a fasting plasma glucose <=5.3 mmoL/L (95 mg/dL) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose-lowering oral agent at randomization. Normoglycaemia was defined as a fasting plasma glucose <5.6 mmol/L and HbA1c <6% at the 2-year visit. The median of the natural logarithm of insulin doses (expressed per kg of fat-free mass), recorded at every visit from randomization until either the penultimate visit or the first occurrence of a cardiovascular outcome, was analysed. RESULTS: Higher median insulin doses did not reflect incident cardiovascular events overall or in the subset that achieved normoglycaemia. When the dose taken before a cardiovascular event or the penultimate visit was analysed, the adjusted hazard of the composite of cardiovascular death, myocardial infarction or stroke was 0.94 (95% CI 0.88, 1.00) per unit higher dose overall, and 0.91 (95% CI 0.81, 1.01) in the normoglycaemic subset. CONCLUSIONS: Insulin resistance may not promote cardiovascular outcomes in individuals with dysglycaemia. PMID- 28895657 TI - Identifying psychogenic seizures through comorbidities and medication history. AB - OBJECTIVE: Low-cost evidence-based tools are needed to facilitate the early identification of patients with possible psychogenic nonepileptic seizures (PNES). Prior to accurate diagnosis, patients with PNES do not receive interventions that address the cause of their seizures and therefore incur high medical costs and disability due to an uncontrolled seizure disorder. Both seizures and comorbidities may contribute to this high cost. METHODS: Based on data from 1,365 adult patients with video-electroencephalography-confirmed diagnoses from a single center, we used logistic and Poisson regression to compare the total number of comorbidities, number of medications, and presence of specific comorbidities in five mutually exclusive groups of diagnoses: epileptic seizures (ES) only, PNES only, mixed PNES and ES, physiologic nonepileptic seizurelike events, and inconclusive monitoring. To determine the diagnostic utility of comorbid diagnoses and medication history to differentiate PNES only from ES only, we used multivariate logistic regression, controlling for sex and age, trained using a retrospective database and validated using a prospective database. RESULTS: Our model differentiated PNES only from ES only with a prospective accuracy of 78% (95% confidence interval =72-84%) and area under the curve of 79%. With a few exceptions, the number of comorbidities and medications was more predictive than a specific comorbidity. Comorbidities associated with PNES were asthma, chronic pain, and migraines (p < 0.01). Comorbidities associated with ES were diabetes mellitus and nonmetastatic neoplasm (p < 0.01). The population-level analysis suggested that patients with mixed PNES and ES may be a population distinct from patients with either condition alone. SIGNIFICANCE: An accurate patient-reported medical history and medication history can be useful when screening for possible PNES. Our prospectively validated and objective score may assist in the interpretation of the medication and medical history in the context of the seizure description and history. PMID- 28895658 TI - Laparoscopic and robotic-assisted versus open radical prostatectomy for the treatment of localised prostate cancer. AB - BACKGROUND: Prostate cancer is commonly diagnosed in men worldwide. Surgery, in the form of radical prostatectomy, is one of the main forms of treatment for men with localised prostate cancer. Prostatectomy has traditionally been performed as open surgery, typically via a retropubic approach. The advent of laparoscopic approaches, including robotic-assisted, provides a minimally invasive alternative to open radical prostatectomy (ORP). OBJECTIVES: To assess the effects of laparoscopic radical prostatectomy or robotic-assisted radical prostatectomy compared to open radical prostatectomy in men with localised prostate cancer. SEARCH METHODS: We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE) and abstract proceedings with no restrictions on the language of publication or publication status, up until 9 June 2017. We also searched bibliographies of included studies and conference proceedings. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) with a direct comparison of laparoscopic radical prostatectomy (LRP) and robotic-assisted radical prostatectomy (RARP) to ORP, including pseudo-RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data. The primary outcomes were prostate cancer-specific survival, urinary quality of life and sexual quality of life. Secondary outcomes were biochemical recurrence-free survival, overall survival, overall surgical complications, serious postoperative surgical complications, postoperative pain, hospital stay and blood transfusions. We performed statistical analyses using a random-effects model and assessed the quality of the evidence according to GRADE. MAIN RESULTS: We included two unique studies with 446 randomised participants with clinically localised prostate cancer. The mean age, prostate volume, and prostate-specific antigen (PSA) of the participants were 61.3 years, 49.78 mL, and 7.09 ng/mL, respectively. Primary outcomes We found no study that addressed the outcome of prostate cancer-specific survival. Based on data from one trial, RARP likely results in little to no difference in urinary quality of life (MD -1.30, 95% CI 4.65 to 2.05) and sexual quality of life (MD 3.90, 95% CI -1.84 to 9.64). We rated the quality of evidence as moderate for both quality of life outcomes, downgrading for study limitations. Secondary outcomes We found no study that addressed the outcomes of biochemical recurrence-free survival or overall survival.Based on one trial, RARP may result in little to no difference in overall surgical complications (RR 0.41, 95% CI 0.16 to 1.04) or serious postoperative complications (RR 0.16, 95% CI 0.02 to 1.32). We rated the quality of evidence as low for both surgical complications, downgrading for study limitations and imprecision.Based on two studies, LRP or RARP may result in a small, possibly unimportant improvement in postoperative pain at one day (MD 1.05, 95% CI -1.42 to -0.68 ) and up to one week (MD -0.78, 95% CI -1.40 to 0.17). We rated the quality of evidence for both time-points as low, downgrading for study limitations and imprecision. Based on one study, RARP likely results in little to no difference in postoperative pain at 12 weeks (MD 0.01, 95% CI -0.32 to 0.34). We rated the quality of evidence as moderate, downgrading for study limitations.Based on one study, RARP likely reduces the length of hospital stay (MD -1.72, 95% CI -2.19 to -1.25). We rated the quality of evidence as moderate, downgrading for study limitations.Based on two study, LRP or RARP may reduce the frequency of blood transfusions (RR 0.24, 95% CI 0.12 to 0.46). Assuming a baseline risk for a blood transfusion to be 8.9%, LRP or RARP would result in 68 fewer blood transfusions per 1000 men (95% CI 78 fewer to 48 fewer). We rated the quality of evidence as low, downgrading for study limitations and indirectness.We were unable to perform any of the prespecified secondary analyses based on the available evidence. All available outcome data were short-term and we were unable to account for surgeon volume or experience. AUTHORS' CONCLUSIONS: There is no high-quality evidence to inform the comparative effectiveness of LRP or RARP compared to ORP for oncological outcomes. Urinary and sexual quality of life related outcomes appear similar.Overall and serious postoperative complication rates appear similar. The difference in postoperative pain may be minimal. Men undergoing LRP or RARP may have a shorter hospital stay and receive fewer blood transfusions. All available outcome data were short-term, and this study was unable to account for surgeon volume or experience. PMID- 28895660 TI - Epidemiology, molecular classification and WHO grading of ependymoma. AB - Ependymoma can arise throughout all compartments of the central nervous system with prevalence for intracranial and spinal location in children and adults, respectively. The current histopathology based WHO grading system distinguishes grade I, II 'classic', and III 'anaplastic' ependymoma. However, analysis of multiple cohorts of intracranial ependymoma demonstrate a wide variance in the utility of the grade II versus grade III distinction as a prognostic marker that may additionally be confounded by the anatomic compartment. Recent (epi)genomic profiling efforts have identified molecularly distinct groups of ependymoma arising from all three anatomic compartments of the central nervous system that outperform the current histopathological classification regarding clinical associations. These advances have led to the cognition that molecular classification should be part of all future clinical trials in ependymoma patients. Clinical management of intracranial ependymomas (WHO Grade II/III) is challenging and molecular classification based risk stratification may help to intensify treatment and surveillance in high-risk patients but to de-escalate therapy in certain patient groups at low risk for recurrence. Finally, experience of neurosurgeons, and other disciplines, as well as intensified co-operation between all stakeholders involved hold promise to finally improve outcome of patients affected with ependymoma. PMID- 28895661 TI - The role of endoscopy in anterior skull base surgery. PMID- 28895662 TI - A case of Zoon Balanitis in an immune-competent teenager. PMID- 28895659 TI - Implementation strategies for health systems in low-income countries: an overview of systematic reviews. AB - BACKGROUND: A key function of health systems is implementing interventions to improve health, but coverage of essential health interventions remains low in low income countries. Implementing interventions can be challenging, particularly if it entails complex changes in clinical routines; in collaborative patterns among different healthcare providers and disciplines; in the behaviour of providers, patients or other stakeholders; or in the organisation of care. Decision-makers may use a range of strategies to implement health interventions, and these choices should be based on evidence of the strategies' effectiveness. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of implementation strategies for health systems in low income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on alternative implementation strategies and informing refinements of the framework for implementation strategies presented in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ-Evidence up to December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of implementation strategies on professional practice and patient outcomes and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the review findings. Two overview authors independently screened reviews, extracted data and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence) and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 39 of them in this overview. An additional four reviews provided supplementary information. Of the 39 reviews, 32 had only minor limitations and 7 had important methodological limitations. Most studies in the reviews were from high-income countries. There were no studies from low-income countries in eight reviews.Implementation strategies addressed in the reviews were grouped into four categories - strategies targeting:1. healthcare organisations (e.g. strategies to change organisational culture; 1 review);2. healthcare workers by type of intervention (e.g. printed educational materials; 14 reviews);3. healthcare workers to address a specific problem (e.g. unnecessary antibiotic prescription; 9 reviews);4. healthcare recipients (e.g. medication adherence; 15 reviews).Overall, we found the following interventions to have desirable effects on at least one outcome with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects.1.Strategies targeted at healthcare workers: educational meetings, nutrition training of health workers, educational outreach, practice facilitation, local opinion leaders, audit and feedback, and tailored interventions.2.Strategies targeted at healthcare workers for specific types of problems: training healthcare workers to be more patient-centred in clinical consultations, use of birth kits, strategies such as clinician education and patient education to reduce antibiotic prescribing in ambulatory care settings, and in-service neonatal emergency care training.3. Strategies targeted at healthcare recipients: mass media interventions to increase uptake of HIV testing; intensive self-management and adherence, intensive disease management programmes to improve health literacy; behavioural interventions and mobile phone text messages for adherence to antiretroviral therapy; a one time incentive to start or continue tuberculosis prophylaxis; default reminders for patients being treated for active tuberculosis; use of sectioned polythene bags for adherence to malaria medication; community-based health education, and reminders and recall strategies to increase vaccination uptake; interventions to increase uptake of cervical screening (invitations, education, counselling, access to health promotion nurse and intensive recruitment); health insurance information and application support. AUTHORS' CONCLUSIONS: Reliable systematic reviews have evaluated a wide range of strategies for implementing evidence-based interventions in low-income countries. Most of the available evidence is focused on strategies targeted at healthcare workers and healthcare recipients and relates to process-based outcomes. Evidence of the effects of strategies targeting healthcare organisations is scarce. PMID- 28895663 TI - Dermoscopy and reflectance confocal microscopy of osteoclastic deep benign fibrous histiocytoma. PMID- 28895664 TI - Severe and acute complications of biologics in psoriasis. AB - Biologic therapies have revolutionized the approach to immune-mediated diseases such as psoriasis. Due to their favorable safety profiles and excellent efficacy, biologic agents are considered the gold standard for moderate-to-severe psoriasis. The aim of this paper is to saliently review the severe and acute complications of the Food and Drug Administration (FDA) approved biologic agents for psoriasis. Reviewed agents include tumor necrosis factor alpha inhibitors (etanercept, infliximab, and adalimumab), interleukin 12/23 inhibitors (ustekinumab), and interleukin 17 (IL-17) inhibitors (secukinumab and ixekizumab). While malignancies, serious infections, and major adverse cardiovascular events have been reported, their association with biologic therapy are not hypothesized as causal. However, IL-17 inhibitors appear to cause exacerbations and new cases of inflammatory bowel disease. While more long-term studies are warranted in understanding the biologic's long-term side effect profile, short-term studies have confirmed that the biologics are some of the safest treatment options for psoriasis. Nevertheless, certain populations yield higher risk to acute complications with the biologics than others - physicians must use their judgement and vigilance when monitoring and treating patients undergoing therapy with biological agents. PMID- 28895665 TI - Clinical challenges faced in real-world management of moderate-to-severe psoriasis: a personal view. PMID- 28895666 TI - Current standards of surgical management in primary melanoma. AB - Melanoma accounts for the majority of skin cancer-related deaths, and its incidence continues to rise worldwide. While advanced disease has historically been associated with poor long-term survival, early-stage disease has a favorable prognosis and therefore, early diagnosis is paramount. Resection of primary melanoma requires a balance of maximizing oncological outcome while minimizing morbidity. Wide excision with 1-2 cm margins, depending on depth of the tumor, is the standard of care for surgical treatment of primary, invasive melanoma. Sentinel lymph node biopsy is indicated for patients with clinically node negative, intermediate-thickness primary melanomas but should also be considered in selected patients with thin and thick primaries. In this article, historical perspectives and key clinical trials regarding the current guidelines for the surgical management of primary melanoma are discussed. PMID- 28895667 TI - A review through the looking glass: new advances in dermoscopy. AB - Dermoscopy is a non-invasive diagnostic technique that facilitates the visualization of surface and subsurface structures of the skin. It has been proven to be an essential tool in the diagnosis of both malignant and benign cutaneous lesions. In this article, we review some of the most recent and noteworthy advances in dermoscopy. In addition, we discuss Reflectance Confocal Microscopy (RCM) and Optical Coherence Topography (OCT), two non-invasive imaging devices that may be used alongside dermoscopy to improve diagnostic accuracy. PMID- 28895668 TI - Concepts and controversies in the treatment of cutaneous lichen planus. AB - Cutaneous lichen planus (CLP) is a chronic autoimmune disease classically associated with severely pruritic, polygonal, violaceous, flat-topped papules and plaques. Subtypes such as hypertrophic and bullous lichen planus and lichen planus pigmentosus have been described. Treatment can be challenging, and prospective controlled studies are lacking. Corticosteroids remain the major options for topical and systemic treatment, although some non-steroidal options exist. Phototherapy, especially with narrow band ultraviolet B (NB-UVB), is effective, but caution must be taken because of the risk of keobnerization. Methotrexate and retinoids are an option for extensive disease, and are relatively well tolerated. Other treatments that have been investigated include sulfasalazine, low molecular weight heparin, griseofulvin, hydroxychloroquine, metronidazole and dapsone. PMID- 28895669 TI - Glycemic load and carbohydrates content in the diets of cancer patients AB - Background: Glycemic load (GL) is used to evaluate how various food products affect blood sugar level. According to some studies, high dietary GL may increase the risk of cancer development and recurrence. Objective: The aim of the study was to assess dietary glycemic load and intake of carbohydrates derived from various food products by patients staying on an oncological ward. Material and methods: The study group included 100 cancer patients aged 19-83 years (59.6 +/- 11.3 years). GL, energy and nutrient intake was estimated based on the data from the Food Frequency Questionnaire (FFQ). The correlations between dietary GL and consumption of 18 groups of products were assessed. Results: The average GL per 1000 kcal was 61.0 +/- 8.6 g in the diets of men and 56.2 +/- 9.5 g in the diets of women. High GL (>120 g) was observed in 76% of analyzed diets. The diets of men had higher GL, energy and sucrose content than the diets of women. Men, in comparison to women, consumed more refined grain products (144.1 +/- 78.2 g vs. 95.5 +/- 67.8 g), beverages (236.4 +/- 344.7 g vs. 69.2 +/- 173.0 g), honey and sugar (28.0 +/- 22.2 g vs. 16.7 +/- 18.0 g), dark chocolate (4.5 +/- 4.5 g vs. 3.9 +/- 6.7 g), sweets (66.1 +/- 56.6 g vs. 38.8 +/- 39.5 g) and soups (313.3 +/- 105.3 g vs. 260.8 +/- 160.3 g). Conclusions: Analyzed diets were characterized by high GL and simple sugars content. Men consumed more refined and sweetened products than women. The improvement of knowledge about proper nutrition is needed in studied group of cancer patients. PMID- 28895670 TI - Health risk assessment and dietary exposure of polycyclic aromatic hydrocarbons (PAHs), lead and cadmium from bread consumed in Nigeria. AB - Objective: A risk assessment and dietary exposure to polycyclic aromatic hydrocarbons (PAHs), lead and cadmium from bread, a common food consumed in Nigeria. Material and Methods: Sixty samples of bread were collected from different types of bakeries where the heat is generated by wood (42 samples) or by electricity (18 samples) from twenty bakeries located in Gusau Zamfara (B1- B14) and Port Harcourt Rivers States (B15-B20) in Nigeria. PAHs in bread were determined by gas chromatography. Lead and cadmium were determined using atomic absorption spectrophotometry. Results: Non-carcinogenic PAHs pyrene (13.72 MUg/kg) and genotoxic PAHs (PAH8), benzo[a]anthracene (9.13 MUg/ kg) were at the highest concentrations. Total benzo[a]pyrene concentration of 6.7 MUg/kg was detected in 100% of tested samples. Dietary intake of total PAHs ranged between 0.004-0.063 MUg/kg bw. day-1 (children), 0.002-0.028 MUg/kg day-1 (adolescents), 0.01-0.017 MUg/kg day-1 (male), 0.002-0.027 MUg/kg day-1 (female), and 0.002 0.025 MUg/kg day-1 (seniors). The Target Hazard Quotient (THQ) for Pb and Cd were below 1. Lead ranged from 0.01-0.071 mg/kg with 10.85 and 100% of bread samples violating the permissible limit set by USEPA, WHO and EU respectively. Cadmium ranged from 0.01-0.03 mg/kg, with all bread samples below the permissible limits as set by US EPA, JECFA and EU. The daily intake of Pb and Cd ranged from 0.03 0.23 MUg/kg bw day-1 and 0.033-0.36 MUg/kg bw day-1 respectively. Incremental lifetime cancer risk (ILCR) was 3.8 x 10-7. Conclusions: The levels of these contaminants in bread if not controlled might present a possible route of exposure to heavy metals and PAHs additional to the body burden from other sources. PMID- 28895671 TI - Quantitative evaluation of 1,3,1,6 beta-D-glucan contents in wild-growing species of edible Polish mushrooms AB - Background: Macrofungal beta-glucans are mainly represented by compounds with beta-1,3- and beta-1,6 glycosidic bonds. They have been shown to have immunomodulatory, anticancer, and antioxidant properties. Although there are many reports on the bioactivity and structure of fungal glucans, studies on the quantitative assessment of these compounds are sparse. Objective: The aim of the study was to determine total beta-glucans and 1,3-1,6-beta-D-glucan contents in selected species of wild-growing edible Polish mushrooms. Material and methods: Eight species of wild-growing edible mushrooms Boletus pinophilus, Hydnum repandum, Craterellus cornucopioides, Suillus variegatus, Suillus granulatus, Gyroporus cyanescens, Tricholomopsis rutilans, and Auricularia auricula-judae and one species of cultivated mushroom for comparison purposes Agaricus bisporus, were analyzed. Quantitative analysis of 1,3-1,6-beta-D-glucans was done using a colorimetric method in accordance with Nitschke et al. Result: Mean total beta glucan content varied from 13.5 g/100 g dry mass in A. bisporus (portobello variety) to 40.9 g/100 g dry mass in T. rutilans. Mean 1,3-1,6-beta-D-glucan content in the analyzed fruiting bodies ranged from 3.9 g/100 g dry mass in Agaricus bisporus (cremini) to 16.8 g/100 g dry mass in Auricularia auricula judae (wood ear). The following mushrooms demonstrated the greatest percentage of 1,3-1,6-beta-D-glucan contents in relation to the total beta-glucan content: Gyroporus cyanescens (54%), Suillus granulatus (49.8%), Auricularia auricula judae (47.9%), and Suillus variegatus (40.6%). Conclusions: Among the analyzed species, wild-growing mushrooms had a generally higher average 1,3-1,6-beta Dglucan content compared with cultivated mushrooms such as A. bisporus. The highest average content of these polysaccharides was observed in medicinal mushroom Auricularia auricula-judae. Comparable 1,3-1,6-beta-D-glucan content, in relation to this mushroom species, was found in Gyroporus cyanescens, Suillus granulatus and Suillus variegatus, which points to the possibility of the use of these species of mushrooms as medicinal foods. PMID- 28895672 TI - Meat and meat products - analysis of the most common threats in the years 2011 2015 in Rapid Alert System for Food and Feed (RASFF) AB - Background: The key tool used in the European Union in order to eliminate the risks associated with the consumption of potentially hazardous food is RASFF - Rapid Alert System for Food and Feed Safety. The RASFF was established to increase accountability and strengthening cooperation between states of the European Union in the field of food safety control. Objective: The aim of this study was to explore the trends and temporal and spatial distribution of notifications on food safety hazards between January 2011 and December 2015 with a special emphasis on meat and meat products on the basis of notification from RASFF. Material and methods: The study analyzed notifications on the annual reports of the RASFF published by the European Commission and requests added to the portal RASFF in the period 01.01.2011 - 31.12.2015 on the category of "meat and meat products (other than poultry) and "poultry meat and poultry meat products". Analysis included detailed information on each notification, such as the classification and date, hazard category, notifying country, country origin. Results: The most common classifications of notification were 'alert' and 'border rejection'. Generally, basis of this notifications were 'company's own check' and 'official control on the market'. Pathogenic microorganisms were the most often hazard of category in which the higher number of notifications concerned with Salmonella spp. Conclusion: Alert notification which is the most dangerous for consumers were the most common type of classification for notifications on 'meat and meat product' category. The most of notifications in category 'poultry meat and poultry meat products' were the result of border control. Pathogenic microorganisms were the reason for the huge number of notifications in studied product categories. Many of notifications were associated with products which origin countries were outside RASFF member states. PMID- 28895673 TI - The effect of interferential current therapy on patients with subacromial impingement syndrome: a randomized, double-blind, sham-controlled study. AB - BACKGROUND: Although interferential current (IFC) is a common electrotherapeutic modality used to treat musculoskeletal pain, there is not any randomized controlled trial investigating its clinical efficacy in subacromial impingement syndrome (SAIS). AIM: Investigation of effectiveness of IFC treatment in patients with SAIS. DESIGN: Randomized, double-blind, sham-controlled study. SETTING: Physical medicine and rehabilitation outpatient clinic. POPULATION: Patients (N.=65) between 25 and 65 years of age, with a diagnosis of SAIS according to clinical evaluation and subacromial injection test. METHODS: Patients were randomly distributed into two groups: 1) active IFC group (N.=33); 2) sham IFC group (N.=32). Exercise, cryotherapy, and a non-steroidal anti-inflammatory drug (NSAID) were given to both groups. Ten sessions of IFC with bipolar method were applied to the active IFC group daily 20 minutes per session, 5 days per week, for 2 weeks while sham IFC was applied to the sham IFC group with the same protocol. Visual Analog Scale (VAS), Constant scores, and Shoulder Disability Questionnaire (SDQ) were used for evaluation at baseline, immediately post treatment, and 1 month post-treatment. Both the patients and the researcher who assessed the outcomes were blinded to the treatment protocol throughout the study period. RESULTS: Sixty of the 65 patients (active IFC group N.=30, sham IFC group N.=30) completed the study, 3 patients from active IFC, 2 from sham IFC group dropped during the follow up period. Statistically significant improvement was observed in all parameters of both groups immediately and 1 month post-treatment (P<0.01). There were no statistical differences between the active IFC group and sham IFC group in all outcome parameters (P>0.05). CONCLUSIONS: Our results demonstrated that IFC therapy does not provide additional benefit to NSAID, cryotherapy, and exercise program in treatment of SAIS. CLINICAL REHABILITATION IMPACT: Our study responds to the needs of the lack of evidence in the field of rehabilitation. IFC therapy does not provide additional benefit for the treatment of SAIS. PMID- 28895674 TI - Activity of cesium 137Cs and potassium content in new potatoes imported to Poland AB - Background: Potatoes are an important component of the human diet. In addition to components which determine the nutrition and dietary values, potato tubers also contain anti-nutritional substances, inter alia radioactive elements. Natural and artifical radionuclides are released to the environment as a result of antropogenic activity, in a controlled or uncontrolled manner, and they are transferred to the human body through the food chain. Objective: The aim of the study was to determine the activity of radioactive cesium 137Cs isotope and potassium content, including the activity of 40K isotope, in new potatoes imported to Poland during the winter period from Mediterranean countries. Material and methods: The study material included new potatoes imported from Cyprus, Egypt and Israel, purchased in the city of Siedlce from the beginning of February to the end of March 2015. The activity of 137Cs and 40K isotopes in potato tubers was determined. Analyses were performed by gamma-spectrometric method. Laboratory tests were performed on a total of 18 samples. Based on the activity of 40K isotope, the total potassium content of potato tubers was calculated, with the assumption that 31.00 Bq 40K is equivalent to 1 g potassium. Results: The activity of 137Cs in most tested potato samples was below 0.2 Bq kg 1 (limit of quantification), and in other samles it was from 0.3 Bq kg-1 to 5.4 Bq kg-1. Potatoes of the same variety, originating from the same country, differed in terms of the activity of 137Cs. The highest activity of 137C, determined in potatoes imported from Cyprus, was seven times higher than the lowest value. The activity of 40K changed from 93.3 Bq kg-1 to 259.1 Bq kg-1. The average activity of 40K in potatoes imported from Cyprus, Egypt and Israel was at a similar level. The ratio of the activity of 137Cs determined in the tested potatoes to the activity of 40K changed from 0.00242 to 0.04163. The calculated potassium content in imported new potatoes was on average 4.376 g K kg-1 of the fresh weight of tubers and ranged from 3.010 g K kg-1 to 8.358 g K kg-1. Conclusions: The activity of the 137Cs cesium isotope in imported new potatoes in most tested samples was at a very low level (below the limit of quantification) and in other samples it did not exceed 5.5 Bq kg-1 and posed no threat to human lives. Potatoes originating from the same country differed in terms of the activity of 137Cs. The average activity of 40K in potatoes imported from Cyprus, Egypt and Israel was at a similar level and did not differ from the activity of 40K in domestically produced potatoes. The potassium content in imported new potatoes was determined by the variety. PMID- 28895675 TI - Estrogenic activity of commercial milk as revealed in immature hamster uterotrophic assay - pilot study AB - Background: The risk for public health posed by endocrine disruptors present in food is relatively new issue. Our current understanding of human exposure is mainly based on the residue analysis of selected compounds. With such approach potential, effects of mixtures, including so-far unidentified compounds are not taken into consideration. Therefore, the knowledge of overall hormonal activity in food samples is of big importance. Objective: Milk and dairy products are a rich source of estrogens but very rarely undergo testing for estrogenic activity. For this reason the rodent uterotrophic bioassay is one of the most useful tool. This preliminary study was conducted in immature hamsters to assess commercially available milk. The endpoint measured was uterine weight increase. Material and methods: Fifteen-day old females received ad libitum throughout 7 days commercially available milk i.e. raw goat's, raw cow's, processed 3.2% UHT, and for comparison soy milk. The animals of negative control group received water but positive control group got 17beta - estradiol (E2) at the concentration of 100 ng/ml. Results: All samples of milk showed estrogenic activity as follow: goat's >cow's >soy >processed milk. Significant increase of uteri weights were recorded in goat's (p<0.001) and cow's milk (p<0.01). However, the activity was approximately 5-fold lower than induced by 17beta-estradiol. The ratio uterine weight/body weight (%) in negative control was 0.096%, in milk experimental groups ranged from 0.112% to 0.153% and in positive control this value was 0.493%. Conclusion: The results suggest that commercially available milk has a weak uterotrophic activity. Further in vivo and in vitro studies are warranted to gain more insight into the estrogenic risk from milk and other dairy products. PMID- 28895676 TI - Maria Sklodowska-Curie, her life and work - the 150 anniversary of her birthday AB - Maria Sklodowska was born on November 7, 1867 in Warsaw (Poland). Her parents were teachers. Maria's mother has died in 1878 of tuberculosis. In 1893 and 1894, respectively, Maria was awarded master's degrees in physics and in mathematics from the Sorbonne University. In 1895 Maria married Pierre Curie. In 1897 their daughter Irene was born. Maria investigated rays emitted by uranium salts. She hypothesized that the radiation come from atom and called this phenomenon "radioactivity". In 1898, Maria and Pierre discovered new radioactive elements polonium and radium. In 1902 she isolated pure radium chloride and defined radium atomic mass. In June 1903, Maria supervised by Professor Lippmann was awarded her doctorate in physics from the Sorbonne University of Paris after presentation of the thesis "Investigation of radioactive bodies". In December 1903, Maria was awarded the Nobel Prize in Physics, along with her husband Pierre and Henri Becquerel, for their work on radioactivity. In 1904, the daughter Eve was born. On 19 April 1906, Pierre was killed in a road accident in Paris. In 1910 Maria isolated radium as a pure metal. She also defined an international standard for radioactive emissions (curie), published her fundamental results on radioactivity and textbook of radiology. She also defined the international pattern of radium. In 1911, she won her second Nobel Prize, this time in Chemistry, for her discovery of radium and polonium. In 1914 she was appointed director in the Radium Institute in Paris. During World War I, Maria became the director of the Red Cross Radiology Service and set up France's first military radiology centre. In May 1932 she has attended the official opening ceremony of the Radium Institute in Warsaw. On 4 July 1934, Maria Sklodowska-Curie has died aged 66 years in Sancellemoz sanatorium (France) of aplastic anemia. PMID- 28895677 TI - Can babies oral wipes with fluoride and/or calcium glycerophosphate prevent cariogenic demineralization? An in-vitro study. AB - BACKGROUND: The difficulties in reaching a good level of oral hygiene in young babies can be partly overcome with the use of baby oral wipes, which have been shown to effectively remove plaque from deciduous teeth. The presence of fluoride and calcium in these wipes could also prevent further demineralization of the teeth, as well as promote remineralization. The aim of this study is, therefore, was to analyze the preventive effect of OW containing F and CaGP on cariogenic demineralization in vitro. METHODS: For this, seventy enamel samples were treated with OW soaked in solutions containing different F concentrations (250 ppm; 500 ppm and 1500 ppm) with or not with 0.13% CaGP and distilled water for the control group. The samples were submitted to an 8-day cariogenic pH cycling. The experimental solutions were applied twice per cycle, by immersing a dry inert oral tissue into 4 mL of the solution and rubbing it over the enamel surface. Enamel microhardness was measured initially and after the experimental cycles. Environmental scanning electron microscope was taken to visualize and quantify elements on the enamel surface. RESULTS: No significant difference was observed (P=0.694), but when the groups containing CaGP were compared to the negative control solution, a significant difference was found. CONCLUSIONS: The presence of 0.13% CaGP and fluoride in concentrations greater than 500 ppm were able to provide protection of dental enamel against demineralization. PMID- 28895678 TI - Prognosis and cost-effectiveness of IVF in poor responders according to the Bologna Criteria. AB - Poor ovarian response (POR) to controlled ovarian hyperstimulation for in vitro fertilization (IVF) is one of the most challenging issue in the field of reproductive medicine. However, even if improving IVF outcome in poor responders (PORs) represents a main priority, the lack of a unique definition of POR has hampered research in this area. In order to overcome this impediment, an ESHRE Campus Workshop was organized in Bologna in 2010 and reached a consensus on the criteria for the diagnosis of POR ("Bologna Criteria"). In this review we aimed to estimate the prognostic potential of the ESHRE definition, to elucidate its possible weaknesses and to analyze the economic aspects of IVF in a population of poor responders (PORs). Available evidence confirmed that the Bologna criteria are able to select a population with a poor IVF prognosis thus supporting their validity. Nonetheless, different aspects of the definition have been criticized. The main points of debate concern the homogeneity of the population identified, the cut-off values chosen for the ovarian reserve tests and the risks factors other than age associated with POR. Data concerning the economic profile of IVF in PORs are scanty. The only published study on the argument showed that IVF in these cases is not cost-effective. However, considering the potential substantial impact of cost-effectiveness analyses on public health policies, there is the need for further and independent validations. PMID- 28895679 TI - A modern approach to the management of candidates for assisted reproductive technology procedures. AB - The growing use of assisted reproductive technologies (ART) and the incorrect information from mass media, determined in the public the wrong idea that the right moment of life for programming a pregnancy can be delayed well beyond the physiological fertile age. Spare and insufficient health authorities' interventions are driven to explain to the general population the reduction of the fertility potential of couples and particularly of women with advancing age. This situation, characterized by more and more women seeking for pregnancy after age 38-40 imposes to specialists in Reproductive Medicine an honest and transparent counselling. Today, more than ever, it is pertinent to talk about the need of an "ethic approach" to ART, by which the specialist takes care of all the aspects inherent to infertility, such as the strong motivations of the couples in searching a child, the wrong perception of ART infallibility, the incorrect advertising in the mass media about the pregnancy of elderly actresses and show girls, and finally, the enormous amount of commercial interests revolving around the "business" of in-vitro fertilization. In this context, the ideal policy that an ART center should adopt entails the correct and rapid identification of the characteristics of the couple, the exploitation of women ovarian reserve to obtain the right number of high quality oocytes, the protection of patients' health, the identification of the embryos with the highest chances of implantation and the reduction of the time to pregnancy. Here we analyse how to obtain each of these goals, through a literature review and expert clinical opinion. PMID- 28895680 TI - Optimizing preconception health in women of reproductive age. AB - There is a growing realization that efforts to optimize the health of women and reduce the risk of adverse maternal, perinatal and neonatal outcomes during pregnancy should commence in the preconception period. The preconception period (prior to or between pregnancies) provides an opportune time to address reproductive intentions and promote and support wellbeing and healthy behavior change regardless of pregnancy intention. Research over the last 30 years has explored the influence of a range of preconception risk factors and determinants of health on pregnancy and maternal and neonatal outcomes including: pregnancy planning, diet and micronutrient supplementation, physical activity, weight, smoking, recreational drug and alcohol use, mental health, oral hygiene, and chronic health and medical conditions. Preconception health messages, recommendations and guidelines originated in the USA and the preconception movement has gained momentum internationally with a variety of strategies developed and tested for improving preconception health, and related outcomes. The shift to integrate preconception health promotion into the continuum of women's healthcare requires a diverse multilevel and multistrategic approach involving a range of sectors and health professionals to address the determinants of health. This includes a system-wide effort to raise awareness of the importance of women's health prior to pregnancy, creating supportive environments as well as optimizing clinical practice, policy and programs informed by high quality research and longitudinal studies. While preconception health is relevant to both women and men globally, this review summarizes the predominant areas of preconception health for women in developed countries including the emergence of preconception health, the current health messages and evidence, the state of international guidelines and evidence-based interventions in preconception. PMID- 28895681 TI - How to complete gastroduodenal protection in patients with bleeding risk? PMID- 28895682 TI - Composite tissue flap transplantation for limb-salvage surgery in cases of severe lower limb burns. PMID- 28895683 TI - Clinical outcomes of two techniques in repairing rotator cuff tear: traditional double row vs. suture bridge. PMID- 28895684 TI - Changes in the definition of term infants and their implications in perinatal care: Are they being accomplished? PMID- 28895685 TI - Sharenting... should children's lives be disclosed on social media? PMID- 28895686 TI - Breastfeeding as a biological dialogue. PMID- 28895687 TI - Perceived health and its relation with macrosocial and individual factors in children from two departments of Tucuman, Argentina. AB - INTRODUCTION: The assessment of health-related quality of life (HRQoL) during childhood favors the identification of factors that affect growth and development. The objectives of this study were: a) to describe the HRQoL in children between 8.0 and 11.9 years old living in the Province of Tucuman; and b) to assess whether the HRQoL varies in relation to macrosocial (quality of life in the department, urban/rural household, socioeconomic status) and individual (age and sex) factors. POPULATION AND METHODS: Quantitative and cross-sectional study among students from the departments of Yerba Buena and Simoca. The KIDSCREEN-52 questionnaire was administered to measure the HRQoL dimensions, and Student" s t tests, analysis of variance and multivariate logistic regression analysis to evaluate the data according to macrosocial and individual factors. RESULTS: A total of 1647 surveys were analyzed. Younger students and of male sex, in general, had a better perception of their health. Yerba Buena residents had mean scores that were significantly lower in the financial resources dimension, as compared to residents of Simoca (45.3 vs. 46.7, p: 0.01). There was no association between the socioeconomic status and the HRQoL. Children from rural areas had the lowest scores in most dimensions, with significant differences in selfperception (51.3 vs. 53.0, p: 0.01) and mood (43.2 vs. 44.5, p: 0.03). CONCLUSIONS: Perceived health of children from Yerba Buena and Simoca varied in relation to macrosocial and individual factors. In Yerba Buena, the perception of financial resources was worse than in Simoca. In general, the opinion of children from urban areas was more favorable than that of children from rural areas. Younger students and of male sex had a better perception of their health status. PMID- 28895688 TI - Breakfast, nutritional status, and socioeconomic outcome measures among primary school students from the City of Salta: A cross-sectional study. AB - INTRODUCTION: Socioeconomic context and family dynamics are determining factors when considering eating habits and nutritional status among students. It has been demonstrated that skipping breakfast or having a light breakfast has an unfavorable impact on nutritional status. OBJETIVE: To establish a relationship among breakfast, sociodemographic outcome measures, and nutritional status among students attending public schools in the urban and peri-urban areas of the City of Salta. POPULATION AND METHODS: Descriptive, crosssectional study. Purposive, non-probability sampling of students attending urban and periurban primary schools (aged 9-13, boys and girls). Outcome measures: breakfast at home (habit, "enKid" breakfast quality, frequency, duration), nutritional status (body mass index, Z-score, World Health Organization), and sociodemographic outcome measures (family type, level of education, employment, parents' breakfast habit, commensality). Analysis of frequency, associations, logistic regression, odds ratio, confidence interval, p < 0.05, WHO AnthroPlus and SPSS v18 software. RESULTS: Two hundred and eighty-three students were assessed; 49.8% attended urban schools. Overweight or obesity was observed in 46.0%. Also, 55.1% skipped breakfast at home on the day of the assessment; among those who did have breakfast, 79.5% had a poor or very-poor quality meal. Among those who skipped breakfast, 40.7% of the girls and 54.7% of the boys were overweight or obese. A greater socioeconomic vulnerability and a higher percentage of students who attended school without having breakfast were observed in peri-urban schools. CONCLUSIONS: Eventually, the probability of skipping breakfast was associated with having a large family, absence of parental breakfast habit, a low level of maternal education, having breakfast alone, and being obese. PMID- 28895689 TI - A cost-benefit analysis of varicella vaccination in Aragon. AB - BACKGROUND: Varicella, a contagious and infectious disease that is usually benign in children, may become complicated among adults and vulnerable children and may even be life-threatening. There are effective vaccines. A retrospective study was conducted about costs and resulting hospitalizations related to this disease in the population of Aragon in the 2004-2014 period. Costs were compared to the expenses that would have been incurred if those people had received the vaccine and also to the expenses of vaccinating the 1-year-old population over the entire period. A cost-benefit analysis was done to assess the economic impact of varicella vaccination. METHOD: Data for the 11-year period were provided by the Autonomous Community of Aragon (Spain) and included annual varicella incidence, hospital discharges of varicella cases, costs of primary health care visits and hospitalizations for each year, costs of each workday as per the minimum annual salary and of drugs used). Capitalized costs were estimated and compared to capitalized expenses of vaccination, and a sensitivity analysis was performed. RESULTS: A benefit-cost ratio of 1.6 was obtained considering that all children who had varicella had been vaccinated and had received a booster dose. A benefit cost ratio of 1.24 was obtained considering that the vaccine had been administered to every 1-year-old individual at a price of EUR 28.59 per vaccine. Over the 11-year period, 53% of hospitalizations corresponded to children younger than 5 years old. CONCLUSIONS: Public campaigns for the immunization of children younger than 4 years old with 2 doses lead to cost savings and are cost-effective because the vaccine price results in a benefit-cost ratio greater than 1. A major reduction is expected in the number of hospitalizations among children aged 3-4 years. PMID- 28895690 TI - Instrument to assess educational programs for parents of children with congenital heart disease undergoing cardiac surgery. AB - OBJETIVE: To design and validate an instrument to assess the relevance of educational programs for parents of children with congenital heart disease (CHD) undergoing cardiac surgery. MATERIAL AND METHOD: In October 2011, an instrument was designed based on Kaufman's model and on the bibliography, and a survey was developed in the form of a checklist with 32 close-ended questions about received education and desired education, categorized into 5 items: educator, time, place, means, and content. The survey was reviewed by 4 academic professionals and 9 experts in the care of children with CHD, and the checklist was extended to include 42 close-ended questions and 5 open questions. The instrument was administered on the day before discharge to the parents of children with CHD undergoing cardiac surgery at the Department of Pediatrics between February and August 2013. The survey was self-administered by the first participants and administered by the investigator among the remaining participants. RESULTS: Fifty five children met inclusion criteria; a total of 60 parents took part in the study. Agreement was observed between received education and desired education, which was statistically significant only in terms of education provided by a cardiologist (p= 0.000, K= 0.659) and in the hall (p= 0.000, K= 0.655). Statistically significant differences were observed between the 19 self administered surveys and the 41 surveys administered by the investigator. Among the latter, a greater level of completion was observed for all items. CONCLUSION: A validated instrument was developed to assess the relevance of educational programs for parents of children with CHD undergoing cardiac surgery. This survey should be administered by a health care provider for a better understanding of information. PMID- 28895691 TI - Implementation of a checklist to increase adherence to evidence-based practices in a single pediatric intensive care unit. AB - INTRODUCTION: The use of checklists to increase adherence to evidence-based practices is not yet widespread in pediatric intensive care units. The objective of this study was to achieve 90% compliance with studied practices using an ad hoc checklist. POPULATION AND METHDOS: Time series quasiexperimental study conducted in ventilated children hospitalized in the pediatric intensive care unit. Studied practices included sedation breaks, plateau pressure <= 30 cm H 2O, fraction of inspired oxygen <= 60%, maintenance of headboard at > 30 degrees , chlorhexidine mouthwash, weekly ventilator circuit changes, preference for enteral feeding, reduction in the threshold for blood transfusions (hemoglobin: 7 g/dL), daily consideration of spontaneous breathing trials and central venous catheter removal. The checklist was used during ward rounds by the staff physicians in charge of the pediatric intensive care unit as part of an intervention to increase adherence and as a tracking tool. Each form completed on a daily basis was considered an observation. Observations were classified as defective in the case of non-compliance with one or more items. Adherence (the rate of nondefective units of observation) is summarized in the control chart. RESULTS: The study period lasted 420 days. A total of 732 patients were hospitalized; 218 underwent mechanical ventilation; 1201 observations were made, and 1191 were included in the study. The control chart with a 14-month time horizon showed increased adherence, a special cause variation pattern in the last 3 months of the study period, and > 90% compliance over the last 2 months. CONCLUSIONS: The implementation of a checklist increased adherence to studied practices and achieved more than 90% compliance over the last 2 months of the study period. PMID- 28895692 TI - Development of equations and proposed reference values to estimate body fat mass among Chilean children and adolescents. AB - INTRODUCTION: The assessment of body composition is relevant to establish nutritional status and identify potential health risks. OBJETIVE: a) To develop regression equations to predict fat mass (FM) using a dual-energy X-ray absorptiometry as reference method; b) to propose reference FM values based on chronological and biological age for Chilean children and adolescents. METHODOLOGY: Cross-sectional study in children and adolescents aged 5.0 to 18.9 years from the Maule Region (Chile). The sample was made up of 3593 subjects in a probabilistic fashion (stratified). Subjects' weight, standing height, sitting height, and waist circumference were assessed. Body mass index and age at peak development velocity (APGV) were estimated. Body composition (FM, fat-free mass, bone mass, and fat percentage) were established based on a dual-energy X-ray absorptiometry scan. RESULTS: APGV (biological age) was 14.9 +/- 0.9 years among boys and 11.5 +/- 0.7 among girls. Equations were developed to estimate FM among boys and girls using chronological age, APGV, and waist circumference as predictors. Percentiles were estimated to assess FM by dual-energy X-ray absorptiometry and regression equations. CONCLUSION: Equations were acceptable to establish FM; in addition, reference values were proposed to assess FM based on chronological and biological age. PMID- 28895693 TI - Relationship between infant mortality and altitude in the Northwest region of Argentina. AB - INTRODUCTION: Given its location on the Andes, the Northwest region of Argentina is geographically, socioeconomically, culturally, and biologically heterogeneous, and this is reflected on an infant mortality rate (IMR) that is higher than in any other Argentine region. OBJETIVE: To estimate IMR, neonatal mortality rate (NMR), and post-neonatal mortality rate (PNMR), and to analyze their spatial and temporal variations using secular trends and the relative risk based on altitudinal zones. POPULATION AND METHOD: This was a retrospective, descriptive, correlational study based on birth and death data recorded in the Northwest region of Argentina (1998-2010); IMR, NMR, PNMR, secular trends, and the relative risk of death were calculated by district and altitudinal zone (districts at < 2000 meters above sea level, lowlands; at > 2000 meters above sea level, highlands) by means of a cluster analysis. RESULTS AND CONCLUSIONS: Rates were higher in the highlands; IMR was 29.8%o (versus 15.6%o in the lowlands); PNMR was 17.7% in the highlands (versus 5.2% in the lowlands). In the highlands, there was an annual average reduction of 3.9% in IMR and of 4.1% in PNMR; in the lowlands, such reduction was of 7.0% in IMR and of 9.3% in PNMR. The relative risk of IMR and PNMR was significantly higher at high-altitude zones. NMR, its secular trend, and the relative risk did not show statistically significant differences between both altitudinal zones. PMID- 28895694 TI - Linezolid-related adverse effects in clinical practice in children. AB - INTRODUCTION: Linezolid may cause adverse effects such as thrombocytopenia, which were found to be dependent on receiving linezolid for longer than 2 weeks. There are limited studies concerning the safety and timing of linezolid-related adverse effects in children. Objective of this study was to evaluate the incidence of adverse effects associated with linezolid, with especially focusing on the time of occurrence. POPULATION AND METHODS: All children (<18 years of age) who received >3 days of linezolid therapy were included in this study. Adverse effects attributed to linezolid and time of occurrence of side effects was evaluated. RESULTS: A total of 179 children were enrolled to the study. The patients' median age was 4 years (6 days to 17 years). During linezolid treatment, 36 (20.1%) patients experienced adverse effects. The most common adverse effect was thrombocytopenia that was detected in 26 patients (14.5%). Other adverse effects were as following; elevated liver enzymes in 4 patients, leucopenia and anemia in 2 patients, renal function impairment in one patient, and serious skin reactions in 3 patients. Adverse effects were detected within median 7.5 days of therapy (ranging from 4 to 18 days). Among 36 patients, 26 (72.2%) patients had adverse effect on the first 10 days of therapy. CONCLUSION: Transient adverse effects were detected in 20.1% of the patients during linezolid therapy. These adverse effects may be detected earlier than ten days of treatment. Linezolid should be prescribed safely in children with monitoring adverse effects especially platelet count and level of liver enzymes. PMID- 28895695 TI - Bronchopulmonary dysplasia: incidence and risk factors. AB - INTRODUCTION: Bronchopulmonary dysplasia is the most common chronic pulmonary sequela among very low birth weight infants. The objective of this study was to estimate its incidence in our Neonatal Unit over the past 5 years and analyze associated risk factors. POPULATION AND METHODS: An observational and analytical study was conducted in a retrospective cohort, using data obtained from a prospective database of infants born at Hospital Italiano de Buenos Aires with a birth weight of less than 1500 grams between January 2010 and December 2014. The incidence of bronchopulmonary dysplasia and its association with several secondary outcome measures were studied. RESULTS: Two hundred and forty-five patients were included. The incidence of moderate/severe bronchopulmonary dysplasia was 22%, and it was associated with a younger gestational age and lower birth weight. A significant association was observed with surfactant use, mechanical ventilation requirement, and length of mechanical ventilation. Patients with moderate/severe bronchopulmonary dysplasia had a higher incidence of patent ductus arteriosus and late-onset sepsis. A lower birth weight (adjusted odds ratio |-#91;aOR|-#93;: 0.99, 95% confidence interval |-#91;CI|-#93;: 0.991 0.997, p< 0.001) and the length of mechanical ventilation (aOR: 1.08, 95% CI: 1.01-1.15, p < 0.01) remained associated following adjustment for other outcome measures. In addition, an association was observed among patients with intrauterine growth restriction born at less than 32 weeks of gestational age (OR: 4.71, 95% CI: 1.68-13.2). CONCLUSIONS: The incidence ofbronchopulmonary dysplasia in our unit was associated with a lower birth weight and the length of mechanical ventilation. Among infants born at less than 32 weeks of gestation, intrauterine growth restriction accounted for an additional risk. PMID- 28895696 TI - B-type natriuretic peptide: Usefulness in the management of critically-ill neonates. AB - INTRODUCTION: B-type natriuretic peptide (BNP) is responsible for changes in the heart organogenesis and is associated with transition to extrauterine life. In the first week of life, BNP levels are high and return to normal with the physiological loss in weight. High BNP levels are associated with different conditions. OBJETIVE: To establish the relationship between BNP levels and criticality and the short-term clinical course among patients hospitalized in the neonatal intensive care unit. METHOD: Observational and analytical study conducted in a prospective cohort. Criticality was defined as a requirement for assisted mechanical ventilation with a fraction of inspired oxygen of more than 50% and/or inotropes. Two blood samples were collected 72 hours apart. RESULTS: Seventy-three patients were included in the study. Depending on their clinical course on day 7, they were divided into 2 groups: patients with a good clinical course or a persistent, severe clinical course. The median baseline BNP level was similar in both groups (p: 0.15). The median BNP level at 72 hours was higher among patients with a persistent, severe clinical course (p: 0.005). The difference between both BNP values was calculated (DeltaBNP: BNP level at 72 hours - BNP level at 0 hours). The DeltaBNP was positive among patients with a persistent, severe clinical course (X= 1260 pg/mL; range: 426-2094) and negative in the group with a good clinical course (X= -967 pg/mL; range: -1656/-278) (p: 0.0002); sensitivity: 87%; specificity: 86%; positive predictive value: 74%; and negative predictive value: 93%. CONCLUSION: In this group of patients, the delta BNP value reflected the short-term clinical course. PMID- 28895697 TI - What is the value of neonatal autopsy? Pathological and clinical correlation in 135 cases. AB - INTRODUCTION: Neonatal autopsy is a valuable, critical diagnostic method to provide genetic counseling for future pregnancies. POPULATION AND METHODS: Retrospective study including all neonatal autopsies performed on deceased neonates at Clinica y Maternidad Suizo Argentina between January 1998 and December 2006. The rate of autopsies was established; the diagnosis indicated in the medical record was compared to autopsy findings. RESULTS: Out of 227 deceased infants, 135 autopsies were performed (rate: 59.5%). Concordance was complete in 25% of autopsies. New information was found in 26%, which had significant implications for genetic counseling. CONCLUSIONS: The rate of autopsies was 59.5%. Pathological and clinical correlation and unsuspected findings with implications for genetic counseling demonstrate the relevance of performing neonatal autopsies systematically. PMID- 28895698 TI - Serum prolactin levels in atopic dermatitis and the relationship with disease severity. AB - BACKGROUND: Prolactin performs as a neuroendocrine modulator of skin epithelial cell proliferation and the skin immune system. OBJETIVE: The aim was to assess the serum prolactin levels in patients with atopic dermatitis and the relationship with disease severity. METHODS: The study was performed on 46 patients with atopic dermatitis and 100 healthy controls aged between 0.5 years and 19.5 years. The diagnosis of atopic dermatitis was based on clinical findings and the severity of the disease was documented. Venous blood sampling was performed in order to measure prolactin levels. RESULTS: Prolactin levels in atopic dermatitis were not different from controls and there was no relationship between the severity of atopic dermatitis and serum prolactin levels. Prolactin may not have a role in the pathogenesis of atopic dermatitis. Further studies with larger sample sizes and measurement of prolactin levels in the skin may help to understand the role of prolactin in the pathogenesis of atopic dermatitis. PMID- 28895699 TI - Association between sleep-related breathing disorders and academic performance among children from Concepcion, Chile. AB - The objective of this study was to establish an association between academic performance in Math, Language Arts, and Science and the presence of sleep-related breathing disorders (SRBDs) among healthy schoolchildren from the city of Concepcion, Chile. Healthy children were defined as those without comorbidities. Outcome measures of interest included the analysis of academic performance in Math, Language Arts, and Science and the presence of SRBD assessed using the Pediatric Sleep Questionnaire. Two-hundred and fifty-six children were included in the study (59.8% were boys). In the studied sample, SRBD prevalence was 24.6%. A significant association was observed between SRBD and a low performance in Math (odds ratio |-#91;OR|-#93;: 3.1, 1.5-6.8), Language Arts (OR:2.5, 1.1-5.5), and Science (OR: 4.2, 1.7-10.0). To conclude, in the studied sample, the presence of SRBD was associated with a low academic performance in Language Arts, Math, and Science. PMID- 28895700 TI - Conflict of interest: Nuances between principles and the aim. AB - A conflict of interest exists when a health care provider's primary interest is at risk of being biased by a secondary interest that would cause harm. This concerns the different fields of professional practice. Based on a supplement of the Journal of the American Medical Association (JAMA) about conflicts of interest inviting to analyze the situation under the "Do No Harm" ethical principle, diverse scenarios are described, showing the intricacy and controversy of this topic. Elimination of conflict is not always possible, and there is consensus that science-based interactions among private organizations, health care providers and health institutions can be beneficial to patients. However, it is clear that such interaction requires transparent regulations to both manage conflict of interest and minimize bias. PMID- 28895701 TI - Management of cirrhotic ascites in children: Review and recommendations. Part 2: Electrolyte disturbances, nonelectrolyte disturbances, therapeutic options. AB - Ascites is a major complication of cirrhosis. There are several evidence-based articles and guidelines for the management of adults, but few data have been published in relation to children. In the case of a pediatric patient with cirrhotic ascites (PPCA), the following questions are raised: How are the clinical assessment and ancillary tests performed? When is ascites considered refractory? How is it treated? Should fresh plasma and platelets be infused before abdominal paracentesis to prevent bleeding? What are the hospitalization criteria? What are the indicated treatments? What complications can patients develop? When and how should hyponatremia be treated? What are the diagnostic criteria for spontaneous bacterial peritonitis? How is it treated? What is hepatorenal syndrome? How is it treated? When should albumin be infused? When should fluid intake be restricted? The recommendations made here are based on pathophysiology and suggest the preferred approach to diagnostic and therapeutic aspects, and preventive care. PMID- 28895703 TI - [Double aneuploidy: Klinefelter and Edwards syndromes (48,XXY,+18). Case report]. AB - The co-existence of a double chromosomal abnormality in one individual is a rare event, even more the simultaneous presence of Klinefelter (XXY) and Edwards (trisomy 18) syndrome. The aim of this article is to report the case of a newborn with a double aneuploidy, which consists in the coexistence of Edwards and Klinefelter syndrome. The patient's phenotype correlates mainly with Edwards syndrome. The diagnosis is made by performing the cytogenetics (karyotype) of peripheral blood lymphocytes. Only 15 cases of patients with Klinefelter and Edwards syndromes had been reported in literature so far. PMID- 28895702 TI - [X-linked adrenoleukodystrophy: a report of three cases. The importance of early diagnosis]. AB - X-linked adrenoleukodystrophy is the most common peroxisomal disorder. This disease is caused by a defect in the ABCD1 gen. Saturated very long chain fatty acids are accumulated in serum, adrenal cortex and central nervous system white matter. The clinical spectrum is characterized by progressive neurological dysfunction and adrenal insufficiency with a devastating prognosis. We report a first case of X-linked adrenoleukodystrophy with fatal evolution which identified two asymptomatic family members and established a preventive treatment. Although there is no definitive cure, we stress the importance of family study and evaluation of the individual in situation of risk to establish an early preventive treatment and to give in each particular situation suitable professional advice. PMID- 28895704 TI - [Novel mutation in TSC2 gene in pediatric patient with clinical diagnosis of tuberous sclerosis]. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins. This mutation is considered as a pathogenic variant and allows to broaden the spectrum of variants of TSC2 gene as a cause of TSC. PMID- 28895705 TI - [Complete heart block and asystole in a child with ataxia-telangiectasia]. AB - Ataxia-telangiectasia is a disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased predisposition to cancer susceptibility. Mutations in the ataxia telangiectasia mutated gene seem to play an important role in normal cell function and in cardiovascular remodeling. We report a case of a 14-year-old boy with ataxia-telangiectasia and high-grade B non-Hodgkin lymphoma who remained in continuous complete remission after chemotherapy and who was admitted into our Emergency Room presenting with episodes of presyncope. At admission he presented a complete atrioventricular block that evolved into asystole and required placement of a pacemaker. Cumulative cardiotoxic drugs received were at low risk. However, it is possible that this chronic degenerative disease may affect the cardiac conduction system over time. In the reviewed literature there are no or unknown reports of ataxia telangiectasia with malignant cardiac arrhythmias. PMID- 28895706 TI - [Neonatal renal abscess: a diagnostic and therapeutic challenge. A clinical case]. AB - Renal abscess is a rare disease in newborn, but severe consequences can occur: sepsis with high mortality, renal scar formation and risk of chronic renal failure. A neonate with unilateral renal abscess due to Staphylococcus aureus is reported, with septicemia, with no other suppurative focus, nor with urinary malformation, with good clinical evolution with intravenous antibiotics and without surgical treatment, but with renal scars sequel. From this case, the strategies of diagnosis, treatment and followup of the renal abscess in a neonate are analyzed, emphasizing the early diagnosis to avoid renal scars. PMID- 28895707 TI - [Juvenile form of Sandhoff disease: first case reported in Argentina]. AB - Sandhoff disease is a neurodegenerative, lysosomal and autosomal recessive disease caused by mutations in the HEXB gene. Three forms are recognized: infantile, juvenile and adult. Previously, an endogamous population in Cordoba, Argentina, was identified with a high incidence of Sandhoff disease, all reported cases were of the infantile type. In this work, we describe a child with the juvenile form of Sandhoff disease, the first case reported in Argentina. The patient is a 7-year-old boy presenting with ataxia, speech disturbances and global developmental delay, symptoms starting at the age of 2 years. Diagnosis was based on the hexosaminidase deficiency. Sequencing of genomic DNA revealed compound heterozygosity for two HEXB gene mutations: c.796T>G (p.Y266D) and c.1615C>T (p.R539C), both already reported. PMID- 28895708 TI - [Deep neck infections: Report of three pediatric cases]. AB - Retropharyngeal and parapharyngeal abscesses are rare but associated with significant morbidity and potential mortality. In recent years, there has been an increase in the incidence of these infections, mainly due to a greater availability of computed tomography scan and a greater virulence of the germs (Group A b-hemolytic Streptococcus and methicillin-resistant Staphylococcus aureus). They predominate in children younger than 5 years. Treatment of retropharyngeal and parapharyngeal abscesses consists of an intravenous antibiotic and eventually surgical drainage. Surgical treatment is indicated in patients with abscesses greater than 2 cm 3, with respiratory difficulty or poor response to initial antibiotic treatment. The aim of this study is to describe clinical features and treatment of three cases of deep neck abscesses presented at Hospital de Ninos Pedro de Elizalde, Otorhinolaryngology Department in the period of one year. PMID- 28895709 TI - Recombinant tissue plasminogen activator treatment for intracardiac vegetation in a very low birth weight infant. AB - Developing treatment options have resulted in prolonged admission and increased bacterial and fungal nosocomial infections as well as improved survival in neonatal intensive care unit. Invasive fungal infections in newborns are associated with significant morbidity and mortality and can cause endorgan dissemination such as endocarditis, endophthalmitis, septic arthritis, obstructive nephropathy and meningitis. Endocarditis requires aggressive systemic antifungal therapy and sometimes surgical intervention in neonates. We report a low birth weight premature infant with intracardiac vegetation that is rare and a life-threatening complication of invasive fungal infections. He was treated with caspofungin and recombinant tissue plasminogen activator in stead of surgical intervention. PMID- 28895710 TI - [Trichosporon asahii sepsis associated with urinary catheter in a pediatric burn unit: 2 case reports]. AB - Trichosporon asahii is a ubiquitous fungus that has been isolated as part of human microbiota. There has been an emergence of this pathogen in recent years, causing superficial and deep seated infections. There are scarce reports of urinary tract infections in pediatric intensive care burn units caused by this agent. We describe the cases of 2 pediatric patients with prolonged hospitalization due to severe burns that had received several antibiotic courses for previous infections. Both presented sepsis secondary to catheter related urinary tract infection by Trichosporon asahii. Both patients underwent urinary catheter replacement and were treated effectively with voriconazole for 10 days. In the cases presented, sepsis was assumed to be due to Trichosporon asahii since no other microorganism was identified and the patients showed favorable outcome with the prescribed treatment with voriconazole and replacement of the urinary catheter. PMID- 28895711 TI - [Post-intubation laryngeal granuloma: a rare complication of tracheal intubation in pediatrics. Case report]. AB - Laryngeal granulomas are benign lesions located in the posterior third of the glottis, mainly at the level of the vocal apophysis of the arytenoid cartilage. They are typically associated with three etiological factors: endotracheal intubation, inappropriate voice use and/or gastroesophageal reflux. The formation of a post-intubation laryngeal granuloma is a late complication related to intubation injury. It is uncommon in the child, especially if the period of intubation is short. It is usually unilateral and produces dysphonia, pharyngeal foreign body sensation and cough. Treatment consists of surgical removal when the lesion is pediculated or causes respiratory compromise. We present a 14-year-old girl who developed a pediculated laryngeal granuloma after orotracheal intubation of less than 24 hours, which was evidenced 3 months after cardiac surgery. We describe the pathogenesis, clinical manifestations, diagnosis and treatment of this pathology. PMID- 28895713 TI - [Hypochromic microcytic Anemias: Guideline for diagnosis. PMID- 28895712 TI - [Recommendations for the prevention of organic foreign bodies aspiration]. AB - Foreign body aspiration remains a common and potentially serious pediatric problem. Most aspirated foreign bodies are food. The education of parents and caregivers about choking hazards and how to avoid them is critical to reduce the incidence of these events. The pediatricians play a key role in promoting injury prevention. We indicate the main characteristics of hazardous food and we present recommendations on age-appropriate meals, adequate forms of food preparation and behavioral rules at mealtimes in order to reduce food choking. PMID- 28895714 TI - Controllable Interface Junction, In-Plane Heterostructures Capable of Mechanically Mediating On-Demand Asymmetry of Thermal Transports. AB - Designing structures with thermal rectification performance that can be regulated by or adapted to mechanical deformation is in great demand in wearable electronics. Herein, using nonequilibrium molecular dynamics simulation, we present an in-plane graphene-boron nitride heterostructure with a controlled interface junction and demonstrate that its thermal transport ability is asymmetric when reversing the direction of heat flow. Such thermal rectification performance can be further regulated by applying an external tensile loading due to the mitigation of stress concentration, phonon resonance, and phonon localization. The analyses on heat flow distribution, vibrational spectra, and phonon participation suggest that the out-of-plane phonon modes dominate thermal rectification at a small tensile strain, while the mechanical stress plays a dominant role in regulation at a large tensile strain due to the weakened localization of out-of-plane phonon modes. The effect of tensile loading on the thermal rectification is demonstrated by selective interface junction-enabled heterostructures, and the results indicate that both asymmetry and direction of thermal transport can be controlled by introducing defects to the interface junction and/or applying mechanical tensile strain. These findings and models are expected to provide an immediate guidance for designing and manufacturing 2D material-based devices with mechanically tunable thermal management capabilities. PMID- 28895715 TI - Pompon-like RuNPs-Based Theranostic Nanocarrier System with Stable Photoacoustic Imaging Characteristic for Accurate Tumor Detection and Efficient Phototherapy Guidance. AB - Even though numerous therapeutic methods exist for cancer treatment, many fail to achieve ideal outcomes or have severe side effects. Here, we describe a theranostic nanocarrier system with improved tumor vasculature detection and tumor margin quantification that increases the accuracy and guidance efficiency of phototherapy. Novel pompon-like RuNPs with superb photothermal properties and high encapsulation efficiency were first synthesized via the polyol reducing method. Based on these RuNPs, we then developed a multifunctional theranostic system, pRu-pNIPAM@RBT, composed of poly(N-isopropylacrylamide) as the thermal response switch and of [Ru(bpy)2(tip)]2+ as the photosensitizer of PDT and the contrast agent of biomedical imaging. We demonstrate that the pRu-pNIPAM@RBT can generate intracellular hyperthermia and reactive oxygen species (ROS) for simultaneous photothermal therapy (PTT) and photodynamic therapy (PDT) by laser activation. In contrast to other studies, our work highlights the integration of quantitative analysis of infrared thermal imaging and PA imaging data, which can distinguish between tumor and healthy tissues and guide the destructive but precise phototherapy and decrease nonspecific tissue injury. Considering the excellent in vivo antitumor phototherapeutic effects, this strategy may help preclinical researchers gain insight into theoretical as well as practical aspects of precision cancer therapy. PMID- 28895716 TI - Synthesis-Free Phase-Selective Gelator for Oil-Spill Remediation. AB - A new deep eutectic solvent (DES) was developed as a phase-selective gelator for oil-spill remediation. The newly designed nonionic DES is based on a combination of an amide (N-methylacetamide) and a long chain carboxylic acid (lauric acid) and does not require any synthetic procedure besides mixing. Our studies show that the DES works as gelator by forming a gel between lauric acid and the hydrocarbon, whereas the amide serves to form the DES and dissolves in water during the gelation process. In addition, the DES material has gelation properties comparable to those considered as state-of-the-art. Overall, the newly developed material shows a promising future in oil recovery methodologies. PMID- 28895717 TI - Backbone Circularization Coupled with Optimization of Connecting Segment in Effectively Improving the Stability of Granulocyte-Colony Stimulating Factor. AB - Backbone circularization of protein is a powerful method to improve its structural stability. In this paper, we presumed that a tight connection leads to much higher stability. Therefore, we designed circularized variants of a granulocyte-colony stimulating factor (G-CSF) with a structurally optimized terminal connection. To estimate the appropriate length of the connection, we surveyed the Protein Data Bank to find local structures as a model for the connecting segment. We set the library of local structures composed of "helix loop-helix," subsequently selected entries similar to the G-CSF terminus, and finally sorted the hit structures according to the loop length. Two, five, or nine loop residues were frequently observed; thus, three circularized variants (C163, C166, and C170) were constructed, prepared, and evaluated. All circularized variants demonstrated a higher thermal stability than linear G-CSF (L175). In particular, C166 that retained five connecting residues demonstrated apparent Tm values of 69.4 degrees C, which is 8.7 degrees C higher than that of the circularized variant with no truncation (C177), indicating that the optimization of the connecting segment is effective for enhancing the overall structural stability. C166 also showed higher proteolytic stability against both endoprotease and exopeptidase than L175. We anticipate that the present study will contribute to the improvement in the general design of circularized protein and development of G-CSF biobetters. PMID- 28895718 TI - Cold Crystallization of Glassy Polylactide during Solvent Crazing. AB - Uniaxial tension accompanied by the orientation and crystallization of polymer chains is one of the powerful methods for the improvement of mechanical properties. Crystallization of amorphous isotropic polylactide (PLA) at room temperature is studied for the first time during the drawing of films in the presence of liquid adsorption-active media (ethanol, water-ethanol mixtures, and n-heptane) by the solvent crazing mechanism. The crystalline structure arises only under simultaneous actions of a liquid medium and a tensile stress and does not depend on the nature of the environment. The degree of polymer crystallinity increases nearly linearly with the growth in the fraction of the fibrillar material and reaches a maximum value of 42-45%. It has been stated that polymer crystallization happens in crazes involving nanofibrils with a diameter of about 10-20 nm without affecting the bulk polymer parts. Wide-angle X-ray scattering has been used to confirm that the crazing-induced crystallization is accompanied by the formation of the alpha'-crystalline phase with crystallite sizes (X-ray coherent scattering region) of 3-5 nm, depending on the nature of the liquid medium. After stretching in liquid media to a high tensile strain, the strength of a PLA film has increased to 200 MPa. PMID- 28895720 TI - Temperature-Insensitive Piezoelectric Performance in Pb(Zr0.52Ti0.42Sn0.02Nb0.04)O3 Ceramics Prepared by Spark Plasma Sintering. AB - Dense Pb(Zr0.52Ti0.42Sn0.02Nb0.04)O3 high-performance piezoceramics were prepared by spark plasma sintering. Phase structure, domain structure, and temperature dependent electrical properties were systematically investigated. The spark plasma-sintered ceramics possess a pure perovskite structure with rhombohedral tetragonal (R-T) phase boundaries and a high Curie temperature of 347 degrees C. Reliable performance against temperature was observed. First, high strain behavior with a normalized strain d33* of 640 and 710 pm/V occurred at 25 and 150 degrees C, respectively, varying less than 11%. Besides, a large remnant polarization Pr of 36.9 MUC/cm2 is observed at room temperature and varies less than 18% within the temperature range of 25-150 degrees C. In addition, an enhanced piezoelectric coefficient d33 of ~460 pm/V was attained at a high temperature of 150 degrees C, manifesting a 40% enhancement with respect to the d33 value (330 pm/V) obtained at room temperature. PMID- 28895719 TI - Radical S-Adenosylmethionine Enzymes Involved in RiPP Biosynthesis. AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, acting as broad and narrow spectrum growth suppressors, antidiabetics, and antinociception and anticancer agents. Because of these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied. RiPP biosynthesis often involves enzymes that perform unique chemistry with intriguing reaction mechanisms, which attract chemists and biochemists alike to study and re-engineer these pathways. One particular type of RiPP biosynthetic enzyme is the so-called radical S adenosylmethionine (rSAM) enzyme, which utilizes radical-based chemistry to install several distinct PTMs. Here, we describe the rSAM enzymes characterized over the past decade that catalyze six reaction types from several RiPP biosynthetic pathways. We present the current state of mechanistic understanding and conclude with possible directions for future characterization of this enzyme family. PMID- 28895721 TI - Eukaryotic Ribosomal Expansion Segments as Antimicrobial Targets. AB - Diversity in eukaryotic rRNA structure and function offers possibilities of therapeutic targets. Unlike ribosomes of prokaryotes, eukaryotic ribosomes contain species-specific rRNA expansion segments (ESs) with idiosyncratic structures and functions that are essential and specific to some organisms. Here we investigate expansion segment 7 (ES7), one of the largest and most variable expansions of the eukaryotic ribosome. We hypothesize that ES7 of the pathogenic fungi Candida albicans (ES7CA) could be a prototypic drug target. We show that isolated ES7CA folds reversibly to a native-like state. We developed a fluorescence displacement assay using an RNA binding fluorescent probe, F-neo. F neo binds tightly to ES7CA with a Kd of 2.5 * 10-9 M but binds weakly to ES7 of humans (ES7HS) with a Kd estimated to be greater than 7 MUM. The fluorescence displacement assay was used to investigate the affinities of a library of peptidic aminosugar conjugates (PAs) for ES7CA. For conjugates with highest affinities for ES7CA (NeoRH, NeoFH, and NeoYH), the lowest dose needed to induce mortality in C. albicans (minimum inhibitory concentration, MIC) was determined. PAs with the lowest MIC values were tested for cytotoxicity in HEK293T cells. Molecules with high affinity for ES7CA in vitro induce mortality in C. albicans but not in HEK293T cells. The results are consistent with the hypothesis that ESs represent useful targets for chemotherapeutics directed against eukaryotic pathogens. PMID- 28895722 TI - Dielectric Sphere Clusters as a Model to Understand Infrared Spectroscopic Imaging Data Recorded from Complex Samples. AB - Understanding the infrared (IR) spectral response of materials as a function of their morphology is not only of fundamental importance but also of contemporary practical need in the analysis of biological and synthetic materials. While significant work has recently been reported in understanding the spectra of particles with well-defined geometries, we report here on samples that consist of collections of particles. First, we theoretically model the importance of multiple scattering effects and computationally predict the impact of local particles' environment on the recorded IR spectra. Both monodisperse and polydisperse particles are considered in clusters with various degrees of packing. We show that recorded spectra are highly dependent on the cluster morphology and size of particles but the origin of this dependence is largely due to the scattering that depends on morphology and not absorbance that largely depends on the volume of material. The effect of polydispersity is to reduce the fine scattering features in the spectrum, resulting in a closer resemblance to bulk spectra. Fourier transform-IR (FT-IR) spectra of clusters of electromagnetically coupled poly(methyl methacrylate) (PMMA) spheres with wavelength-scale diameters were recorded and compared to simulated results. Measured spectra agreed well with those predicted. Of note, when PMMA spheres occupy a volume greater than 18% of the focal volume, the recorded IR spectrum becomes almost independent of the cluster's morphological changes. This threshold, where absorbance starts to dominate the signal, exactly matches the percolation threshold for hard spheres and quantifies the transition between the single particle and bulk behavior. Our finding enables an understanding of the spectral response of structured samples and points to appropriate models for recovering accurate chemical information from in IR microspectroscopy data. PMID- 28895723 TI - High-Efficiency Co/CoxSy@S,N-Codoped Porous Carbon Electrocatalysts Fabricated from Controllably Grown Sulfur- and Nitrogen-Including Cobalt-Based MOFs for Rechargeable Zinc-Air Batteries. AB - Developing bifunctional oxygen electrocatalysts with superior catalytic activities of oxygen reduction reaction (ORR) and oxygen revolution reaction (OER) is crucial to their practical energy storage and conversion applications. In this work, we report the fabrication of Co/CoxSy@S,N-codoped porous carbon structures with various morphologies, specific surface areas, and pore structures, derived from controllably grown Co-based metal-organic frameworks with S- and N-containing organic ligands (thiophene-2,5-dicarboxylate, Tdc; and 4,4'-bipyridine, bpy) utilizing solvent effect (e.g., water and methanol) under room temperature and hydrothermal conditions. The results demonstrate that Co/CoxSy@S,N-codoped carbon fibers fabricated at a pyrolytic temperature of 800 degrees C (Co/CoxSy@SNCF-800) from Co-MOFs fibers fabricated in methanol under hydrothermal conditions as electrocatalysts exhibit superior bifunctional ORR and OER activities in alkaline media, endowing them as air cathodic catalysts in rechargeable zinc-air batteries with high power density and good durability. PMID- 28895724 TI - Investigation of Charge Transfer Kinetics at Carbon/Hydroquinone Interfaces for Redox-Active-Electrolyte Supercapacitors. AB - The redox-active electrolyte supercapacitor (RAES) is a relatively new type of energy storage device. Simple addition of selected redox species in the electrolyte can greatly enhance the energy density of supercapacitors relative to traditional electric double layer capacitors (EDLCs) owing to redox reactions. Studies on the kinetics at the interface of the electrode and redox mediator are important when developing RAESs. In this work, we employ highly accurate scanning electrochemical microscopy (SECM) to extract the kinetic constants at carbon/hydroquinone interfaces. The charge transfer rate constants are 1.2 * 10-2 and 1.3 * 10-2 cm s-1 for the carbon nanotube/hydroquinone and reduced graphene oxide/hydroquinone interfaces, respectively. These values are higher than those obtained by the conventional cyclic voltammetry method, approximately by an order of magnitude. The evaluation of heterogeneous rate constants with SECM would be the cornerstone for understanding and developing high performance RAESs. PMID- 28895725 TI - Luminescent and Photoconductive Layered Lead Halide Perovskite Compounds Comprising Mixtures of Cesium and Guanidinium Cations. AB - Interest in hybrid organic-inorganic lead halide compounds with perovskite-like two-dimensional crystal structures is growing due to the unique electronic and optoelectronic properties of these compounds. Herein, we demonstrate the synthesis, thermal and optical properties, and calculations of the electronic band structures for one- and two-layer compounds comprising both cesium and guanidinium cations: Cs[C(NH2)3]PbI4 (I), Cs[C(NH2)3]PbBr4 (II), and Cs2[C(NH2)3]Pb2Br7 (III). Compounds I and II exhibit intense photoluminescence at low temperatures, whereas compound III is emissive at room temperature. All of the obtained substances are stable in air and do not thermally decompose until 300 degrees C. Since Cs+ and C(NH2)3+ are increasingly utilized in precursor solutions for depositing polycrystalline lead halide perovskite thin films for photovoltaics, exploring possible compounds within this compositional space is of high practical relevance to understanding the photophysics and atomistic chemical nature of such films. PMID- 28895726 TI - Susceptibility of Goethite to Fe2+-Catalyzed Recrystallization over Time. AB - Recent work has shown that iron oxides, such as goethite and hematite, may recrystallize in the presence of aqueous Fe2+ under anoxic conditions. This process, referred to as Fe2+-catalyzed recrystallization, can influence water quality by causing the incorporation/release of environmental contaminants and biological nutrients. Accounting for the effects of Fe2+-catalyzed recrystallization on water quality requires knowing the time scale over which recrystallization occurs. Here, we tested the hypothesis that nanoparticulate goethite becomes less susceptible to Fe2+-catalyzed recrystallization over time. We set up two batches of reactors in which 55Fe2+ tracer was added at two different time points and tracked the 55Fe partitioning in the aqueous and goethite phases over 60 days. Less 55Fe uptake occurred between 30 and 60 days than between 0 and 30 days, suggesting goethite recrystallization slowed with time. Fitting the data with a box model indicated that 17% of the goethite recrystallized after 30 days of reaction, and an additional 2% recrystallized between 30 and 60 days. The decreasing susceptibility of goethite to recrystallize as it reacted with aqueous Fe2+ suggested that recrystallization is likely only an important process over short time scales. PMID- 28895727 TI - Multifrequency Optomechanical Stiffness Measurement of Single Adherent Cells on a Solid Substrate with High Throughput. AB - Mechanical properties of a cell reflect its biological and pathological conditions and there have been active research efforts to develop high-throughput platforms to mechanically characterize single cells. Yet, many of these research efforts are focused on suspended cells and use a flow-through configuration. In this paper, the stiffness of single adherent cells are optomechanically characterized using the vibration-induced phase shift (VIPS) without detaching them from the substrate. With the VIPS measurements, the frequency and amplitude dependency of the cell stiffness is investigated and statistically significant difference in the cell stiffness is confirmed after exposure to various drugs affecting cytoskeleton network. Furthermore, a 3-dimensional finite element model of a cell on a vibrating substrate is developed to extract the mechanical property from the measured VIPS. The developed technique can characterize the mechanical properties of single adherent cells at multiple frequencies with high throughput and will provide valuable clues in understanding cell mechanics. PMID- 28895728 TI - Polycaprolactone Nanocomposites Reinforced with Cellulose Nanocrystals Surface Modified via Covalent Grafting or Physisorption: A Comparative Study. AB - In the present work, cellulose nanocrystals (CNCs) have been surface-modified either via covalent grafting or through physisorption of poly(n-butyl methacrylate) (PBMA) and employed as reinforcement in PCL. Covalent grafting was achieved by surface-initiated atom transfer radical polymerization (SI-ATRP). Two approaches were utilized for the physisorption: using either micelles of poly(dimethyl aminoethyl methacrylate)-block-poly(n-butyl methacrylate) (PDMAEMA b-PBMA) or latex nanoparticles of poly(dimethyl aminoethyl methacrylate-co methacrylic acid)-block-poly(n-butyl methacrylate) (P(DMAEMA-co-MAA)-b-PBMA). Block copolymers (PDMAEMA-b-PBMA)s were obtained by ATRP and subsequently micellized. Latex nanoparticles were produced via reversible addition fragmentation chain-transfer (RAFT) mediated surfactant-free emulsion polymerization, employing polymer-induced self-assembly (PISA) for the particle formation. For a reliable comparison, the amounts of micelles/latex particles adsorbed and the amount of polymer grafted onto the CNCs were kept similar. Two different chain lengths of PBMA were targeted, below and above the critical molecular weight for chain entanglement of PBMA (Mn,c ~ 56 000 g mol-1). Poly(epsilon-caprolactone) (PCL) nanocomposites reinforced with unmodified and modified CNCs in different weight percentages (0.5, 1, and 3 wt %) were prepared via melt extrusion. The resulting composites were evaluated by UV-vis, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and tensile testing. All materials resulted in higher transparency, greater thermal stability, and stronger mechanical properties than unfilled PCL and nanocomposites containing unmodified CNCs. The degradation temperature of PCL reinforced with grafted CNCs was higher than that of micelle-modified CNCs, and the latter was higher than that of latex-adsorbed CNCs with a long PBMA chain length. The results clearly indicate that covalent grafting is superior to physisorption with regard to thermal and mechanical properties of the final nanocomposite. This unique study is of great value for the future design of CNC based nanocomposites with tailored properties. PMID- 28895729 TI - Effect of Non-fullerene Acceptors' Side Chains on the Morphology and Photovoltaic Performance of Organic Solar Cells. AB - Three indacenodithieno[3,2-b]thiophene (IT) cored small molecular acceptors (ITIC SC6, ITIC-SC8, and ITIC-SC2C6) were synthesized, and the influence of side chains on their performances in solar cells was systematically probed. Our investigations have demonstrated the variation of side chains greatly affects the charge dissociation, charge mobility, and morphology of the donor:acceptor blend films. ITIC-SC2C6 with four branched side chains showed improved solubility, which can ensure the polymer donor to form favorable fibrous nanostructure during the drying of the blend film. Consequently, devices based on PBDB-ST:ITIC-SC2C6 demonstrated higher charge mobility, more effective exciton dissociation, and the optimal power conversion efficiency up to 9.16% with an FF of 0.63, a Jsc of 15.81 mA cm-2, and a Voc of 0.92 V. These results reveal that the side chain engineering is a valid way of tuning the morphology of blend films and further improving PCE in polymer solar cells. PMID- 28895730 TI - Rheostatic Control of Cas9-Mediated DNA Double Strand Break (DSB) Generation and Genome Editing. AB - We recently reported two novel tools for precisely controlling and quantifying Cas9 activity: a chemically inducible Cas9 variant (ciCas9) that can be rapidly activated by small molecules and a ddPCR assay for time-resolved measurement of DNA double strand breaks (DSB-ddPCR). Here, we further demonstrate the potential of ciCas9 to function as a tunable rheostat for Cas9 function. We show that a new highly potent and selective small molecule activator paired with a more tightly regulated ciCas9 variant expands the range of accessible Cas9 activity levels. We subsequently demonstrate that ciCas9 activity levels can be dose-dependently tuned with a small molecule activator, facilitating rheostatic time-course experiments. These studies provide the first insight into how Cas9-mediated DSB levels correlate with overall editing efficiency. Thus, we demonstrate that ciCas9 and our DSB-ddPCR assay permit the time-resolved study of Cas9 DSB generation and genome editing kinetics at a wide range of Cas9 activity levels. PMID- 28895731 TI - Ba5Zn4(BO3)6: A Nonlinear-Optical Material with Reinforced Interlayer Connections and Large Second-Harmonic-Generation Response. AB - A nonlinear-optical crystal Ba5Zn4(BO3)6 (BZBO) is obtained that is constructed with [Zn4(BO3)4O6]infinity units bridged by planar BO3 groups along the a axis based on the flexibility of the BO3 and ZnO4 groups. The distance between adjacent [Zn4(BO3)4O6]infinity layers in BZBO is 5.07 A, which is much shorter than those of KBe2BO3F2, Ba2Zn(BO3)2, and Na2CsBe6B5O15. The smaller interlayer spacing and stronger bond between neighboring layers of BZBO contribute to a better growth habit than those of the other three. Also, with the cooperation of two kinds of nonlinear-optical active groups, BO3 and ZnO4, BZBO exhibits a large second-harmonic-generation response of about 2.6 times that of KDP. PMID- 28895732 TI - A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin. AB - Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers. This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin. Owing to the failure of the present pharmaceutical options, such as carboplatin a metallodrug based on Pt coordination chemistry, these species may help to overcome the problem of lethal resistance. Currently, ferrociphenolic entities generally operate via apoptotic and senescence pathways. We present here our first results in this new cyclic-imide series. PMID- 28895733 TI - Evidence for a Double Well in the First Triplet Excited State of 2-Thiouracil. AB - The computationally predicted presence of two structurally distinct minima in the first triplet excited (T1) state of 2-thiouracil (2TU) is substantiated by sub picosecond transient vibrational absorption spectroscopy (TVAS) in deuterated acetonitrile solution. Following 300 nm ultraviolet excitation to the second singlet excited state of 2TU, a transient infrared absorption band centered at 1643 cm-1 is observed within our minimum time resolution of 0.3 ps. It is assigned either to 2TU molecules in the S1 state or to vibrationally hot T1-state molecules, with the latter assignment more consistent with recent computational and experimental studies. The 1643 cm-1 band decays with a time constant of 7.2 +/- 0.8 ps, and there is corresponding growth of several further bands centered at 1234, 1410, 1424, 1443, 1511, 1626, and 1660 cm-1 which show no decline in intensity over the 1 ns time limit of our measurements. These spectral features are assigned to two different conformations of 2TU, corresponding to separate energy minima on the T1-state potential energy surface, on the basis of their extended lifetimes, computed infrared frequencies, and the observed quenching of the bands by addition of styrene. Corresponding measurements for the 4-thiouracil (4TU) isomer show sub-picosecond population of the T1 state, which vibrationally cools with a time constant of 5.2 +/- 0.6 ps. However, TVAS measurements in the carbonyl stretching region do not distinguish the two computed T1-state conformers of 4TU because of the similarity of their vibrational frequencies. PMID- 28895734 TI - Generalized Optimized Effective Potential for Orbital Functionals and Self Consistent Calculation of Random Phase Approximations. AB - A new self-consistent procedure for calculating the total energy with an orbital dependent density functional approximation (DFA), the generalized optimized effective potential (GOEP), is developed in the present work. The GOEP is a nonlocal Hermitian potential that delivers the sets of occupied and virtual orbitals and minimizes the total energy. The GOEP optimization leads to the same minimum as does the orbital optimization. The GOEP method is promising as an effective optimization approach for orbital-dependent functionals, as demonstrated for the self-consistent calculations of the random phase approximation (RPA) to the correlation functionals in the particle-hole (ph) and particle-particle (pp) channels. The results show that the accuracy in describing the weakly interacting van der Waals systems is significantly improved in the self-consistent calculations. In particular, the important single excitations contribution in non-self-consistent RPA calculations can be captured self consistently through the GOEP optimization, leading to orbital renormalization, without using the single excitations in the energy functional. PMID- 28895737 TI - Migration of Phospholipid Vesicles Can Be Selectively Driven by Concentration Gradients of Metal Chloride Solutions. AB - We have investigated the migrations of phospholipid vesicles under the concentration gradients of metal ions. We microinjected metal chloride solutions, monovalent (NaCl and KCl), divalent (CaCl2 and MgCl2), and trivalent (LaCl3) salts, toward phospholipid giant vesicles (GVs) composed of 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC). For NaCl, CaCl2, and MgCl2 solutions, the GVs migrated straight toward the tip of the micropipette in response to the concentration gradients, whereas for KCl and LaCl3, GVs moved to the opposite direction. Our motion tracking of lipid domains in a vesicle membrane showed no unidirectional flow in the membrane during the vesicle migration, indicating that the Marangoni mechanism is not responsible for the observed vesicle migration. We calculated the diffusiophoretic velocities for symmetric and asymmetrical electrolytes by solving the Stokes' equation numerically. The theoretical diffusiophoretic velocities described the observed migration velocities well. Thus, we can control the migration of vesicle in response to the concentration gradient by adapting the electrolytes and the lipids. PMID- 28895735 TI - Reduction-sensitive Paclitaxel Prodrug Self-assembled Nanoparticles with Tetrandrine Effectively Promote Synergistic Therapy Against Drug-sensitive and Multidrug-resistant Breast Cancer. AB - Codelivery of multiple drugs with complementary anticancer mechanisms by nanocarriers offers an effective strategy to treat cancers. Herein, conjugation (PTX-SS-VE) of paclitaxel (PTX) to vitamin E succinate (VE) self-assembled nanoparticles were used to load tetrandrine (TET) for combinational treatment against breast carcinoma. The ratio of PTX-SS-VE and TET was optimized. Compared with PTX, the TET/PTX-SS-VE coloaded nanoparticles (TPNPs) demonstrated superior cytotoxicity against both MCF-7 cells and MCF-7/Adr cells. TPNPs were facilitated to release PTX and TET under a highly reductive environment in tumor cells through the in vitro simulative release study. Cell apoptosis study and Western blotting analysis exhibited TPNPs could significantly increase cell apoptosis via modulating the levels of Bcl-2 protein and Caspase-3, which might be triggered by excess cellular reactive oxygen species (ROS) production through an intracellular ROS detection test. Cellular uptake study showed that TET could increase PTX accumulation in MCF-7/Adr cells but not in MCF-7 cells, which explained stronger synergetic efficacy of TPNPs on MCF-7/Adr cells. Overall, encapsulation of hydrophobic drugs, such as TET, in reduction-sensitive PTX-SS-VE nanoparticles provides a prospective strategy to effectively overcome the multidrug resistance of tumor cells in a synergistic manner. Such a uniquely small molecular weight prodrug-nanocarrier opens up new perspectives for the development of nanomedicines. PMID- 28895736 TI - InP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker Detection. AB - Electrically active field-effect transistors (FET) based biosensors are of paramount importance in life science applications, as they offer direct, fast, and highly sensitive label-free detection capabilities of several biomolecules of specific interest. In this work, we report a detailed investigation on surface functionalization and covalent immobilization of biomarkers using biocompatible ethanolamine and poly(ethylene glycol) derivate coatings, as compared to the conventional approaches using silica monoliths, in order to substantially increase both the sensitivity and molecular selectivity of nanowire-based FET biosensor platforms. Quantitative fluorescence, atomic and Kelvin probe force microscopy allowed detailed investigation of the homogeneity and density of immobilized biomarkers on different biofunctionalized surfaces. Significantly enhanced binding specificity, biomarker density, and target biomolecule capture efficiency were thus achieved for DNA as well as for proteins from pathogens. This optimized functionalization methodology was applied to InP nanowires that due to their low surface recombination rates were used as new active transducers for biosensors. The developed devices provide ultrahigh label-free detection sensitivities ~1 fM for specific DNA sequences, measured via the net change in device electrical resistance. Similar levels of ultrasensitive detection of ~6 fM were achieved for a Chagas Disease protein marker (IBMP8-1). The developed InP nanowire biosensor provides thus a qualified tool for detection of the chronic infection stage of this disease, leading to improved diagnosis and control of spread. These methodological developments are expected to substantially enhance the chemical robustness, diagnostic reliability, detection sensitivity, and biomarker selectivity for current and future biosensing devices. PMID- 28895738 TI - Tailoring Ink-Substrate Interactions via Thin Polymeric Layers for High Resolution Printing. AB - The surface properties of a substrate are among the most important parameters in the printing technology of functional materials, determining not only the printing resolution but also the stability of the printed features. This paper addresses the wetting difficulties encountered during inkjet printing on homogeneous substrates as a result of improper surface properties. We show that the wetting of a substrate and, consequently, the quality of the printed pattern, can be mediated through the deposition of polymeric layers that are a few nanometers thick. The chemical nature of the polymers determines the surface energy and polarity of the thin layer. Some applications, however, require a rigorous adjustment of the surface properties. We propose a simple and precise method of surface-energy tailoring based on the thermal decomposition of poly(methyl methacrylate) (PMMA) layers. A smooth transition in the wetting occurs when the thickness of the PMMA layer approaches zero, probably due to percolation of the underlying surface of the substrate, which enables the inkjet printing of complex structures with a high resolution. In particular, the wetting of three substrate-ink systems was successfully adjusted using the thin polymeric layer: (i) a tantalum-oxide-based ink on indium-tin-oxide-coated glass, (ii) a ferroelectric lead zirconate titanate ink on a platinized silicon substrate, and (iii) a silver nanoparticle ink on an alumina substrate. PMID- 28895739 TI - Metrics for Molecular Electronic Excitations: A Comparison between Orbital- and Density-Based Descriptors. AB - This study proposes a quantitative and qualitative comparison of two popular metrics used for time-dependent density functional simulations of chromophores when describing absorption and emission processes, with high discrimination power between short- and long-range character of involved electronic excitations and functional performances. To this end, a total of 160 absorption and emission electronic excitations of 80 molecular systems belonging to the "Real-Life Molecules" data set, recently introduced in literature, have been considered a relevant data set. The two selected indexes are based on density (the DCT one) and natural transition orbitals (the DeltarNTO one), respectively. For comparison purposes, an extension of the DCT index, in line with what exists for DeltarNTO, enabling to discriminate electronic transitions occurring in symmetric systems is also proposed. The results show that, independently of the exchange and correlation functional used, a good correlation between the natural transition orbital and density based descriptors is found, thus cross validating their use for the quantification of a large variety of transitions in chemically relevant molecular systems. PMID- 28895740 TI - Fluorine Functionalized Graphene Nano Platelets for Highly Stable Inverted Perovskite Solar Cells. AB - Edged-selectively fluorine (F) functionalized graphene nanoplatelets (EFGnPs-F) with a p-i-n structure of perovskite solar cells achieved 82% stability relative to initial performance over 30 days of air exposure without encapsulation. The enhanced stability stems from F-substitution on EFGnPs; fluorocarbons such as polytetrafluoroethylene are well-known for their superhydrophobic properties and being impervious to chemical degradation. These hydrophobic moieties tightly protect perovskite layers from air degradation. To directly compare the effect of similar hydrophilic graphene layers, edge-selectively hydrogen functionalized graphene nanoplatelet (EFGnPs-H) treated devices were tested under the same conditions. Like the pristine MAPbI3 perovskite devices, EFGnPs-H treated devices were completely degraded after 10 days. The hydrophobic properties of EFGnPs-F were characterized by contact angle measurement. The test results showed great water repellency compared to pristine perovskite films or EFGnPs-H coated films. This resulted in highly air-stable p-i-n perovskite solar cells. PMID- 28895741 TI - Minority Carrier Transport in Lead Sulfide Quantum Dot Photovoltaics. AB - Lead sulfide quantum dots (PbS QDs) are an attractive material system for the development of low-cost photovoltaics (PV) due to their ease of processing and stability in air, with certified power conversion efficiencies exceeding 11%. However, even the best PbS QD PV devices are limited by diffusive transport, as the optical absorption length exceeds the minority carrier diffusion length. Understanding minority carrier transport in these devices will therefore be critical for future efficiency improvement. We utilize cross-sectional electron beam-induced current (EBIC) microscopy and develop methodology to quantify minority carrier diffusion length in PbS QD PV devices. We show that holes are the minority carriers in tetrabutylammonium iodide (TBAI)-treated PbS QD films due to the formation of a p-n junction with an ethanedithiol (EDT)-treated QD layer, whereas a heterojunction with n-type ZnO forms a weaker n+-n junction. This indicates that modifying the standard device architecture to include a p type window layer would further boost the performance of PbS QD PV devices. Furthermore, quantitative EBIC measurements yield a lower bound of 110 nm for the hole diffusion length in TBAI-treated PbS QD films, which informs design rules for planar and ordered bulk heterojunction PV devices. Finally, the low-energy EBIC approach developed in our work is generally applicable to other emerging thin-film PV absorber materials with nanoscale diffusion lengths. PMID- 28895742 TI - Human Prestin: A Candidate PE1 Protein Lacking Stringent Mass Spectrometric Evidence? AB - The evidence that any protein exists in the Human Proteome Project (HPP; protein evidence 1 or PE1) has revolved primarily (although not exclusively) around mass spectrometry (MS) (93% of PE1 proteins have MS evidence in the latest neXtProt release), with robust and stringent, well-curated metrics that have served the community well. This has led to a significant number of proteins still considered "missing" (i.e., PE2-4). Many PE2-4 proteins have MS evidence of unacceptable quality (small or not enough unitypic peptides and unacceptably high protein/peptide FDRs), transcriptomic, or antibody evidence. Here we use a Chromosome 7 PE2 example called Prestin to demonstrate that clear and robust criteria/metrics need to be developed for proteins that may not or cannot produce clear-cut MS evidence while possessing significant non-MS evidence, including disease-association data. Many of the PE2-4 proteins are inaccessible, spatiotemporally expressed in a limited way, or expressed at such a very low copy number as to be unable to be detected by current MS methodologies. We propose that the HPP community consider and lead a communal initiative to accelerate the discovery and characterization of these types of "missing" proteins. PMID- 28895743 TI - Influence of Water on the Oxidation of Dimethyl Sulfide by the .OH Radical. AB - Oxidative stress of sulfur-containing biological molecules in aqueous environments may lead to the formation of adduct intermediates that are too short lived to be experimentally detectable. In this study we have modeled the simplest of such oxidative reactions: the attack of dimethyl sulfide (DMS) by a hydroxyl radical (.OH) to form a radical adduct, whose subsequent heterolytic dissociation leads to a radical cation (DMS+) that is important for further reactions. We have modeled the aqueous environment with a limited number of discrete water molecules, selected after an original multistep procedure, and further embedded in a polarizable continuum model, to observe the impact of the water configuration on the heterolytic dissociation of the radical adduct. Molecular dynamics and quantum chemical methods (DFT, MP2, and CCSD) were used to elucidate the lowest energy structures resulting from the .OH attack on DMS. Subsequent high level ab initio valence bond (BOVB) calculations revealed the possibility for the occurrence of subsequent heterolytic dissociation. PMID- 28895744 TI - Palladium-Catalyzed Aerobic Oxidative Hydroamination of Vinylarenes Using Anilines: A Wacker-Type Amination Pathway. AB - A palladium-catalyzed intermolecular hydroamination of vinylarene derivatives using anilines has been developed for the first time under aerobic conditions, where the regioselective formation of N-arylketimines is accomplished. The current aerobic oxidative hydroamination pathway of anilines is distinct from that of palladium-catalyzed hydroamination reactions that proceed to give sec arylethylamine and arylethylamine derivatives, identifying a longstanding missing reaction pathway, Wacker-type amination, to N-arylketimines using anilines. The ready availability of both starting materials, vinylarenes and anilines, offers an attractive and facile synthetic route to N-arylketimines in good to excellent yields. PMID- 28895745 TI - Probing the Interlayer Exciton Physics in a MoS2/MoSe2/MoS2 van der Waals Heterostructure. AB - Stacking atomic monolayers of semiconducting transition metal dichalcogenides (TMDs) has emerged as an effective way to engineer their properties. In principle, the staggered band alignment of TMD heterostructures should result in the formation of interlayer excitons with long lifetimes and robust valley polarization. However, these features have been observed simultaneously only in MoSe2/WSe2 heterostructures. Here we report on the observation of long-lived interlayer exciton emission in a MoS2/MoSe2/MoS2 trilayer van der Waals heterostructure. The interlayer nature of the observed transition is confirmed by photoluminescence spectroscopy, as well as by analyzing the temporal, excitation power, and temperature dependence of the interlayer emission peak. The observed complex photoluminescence dynamics suggests the presence of quasi-degenerate momentum-direct and momentum-indirect bandgaps. We show that circularly polarized optical pumping results in long-lived valley polarization of interlayer exciton. Intriguingly, the interlayer exciton photoluminescence has helicity opposite to the excitation. Our results show that through a careful choice of the TMDs forming the van der Waals heterostructure it is possible to control the circular polarization of the interlayer exciton emission. PMID- 28895746 TI - Growth of InAs Wurtzite Nanocrosses from Hexagonal and Cubic Basis. AB - Epitaxially connected nanowires allow for the design of electron transport experiments and applications beyond the standard two terminal device geometries. In this Letter, we present growth methods of three distinct types of wurtzite structured InAs nanocrosses via the vapor-liquid-solid mechanism. Two methods use conventional wurtzite nanowire arrays as a 6-fold hexagonal basis for growing single crystal wurtzite nanocrosses. A third method uses the 2-fold cubic symmetry of (100) substrates to form well-defined coherent inclusions of zinc blende in the center of the nanocrosses. We show that all three types of nanocrosses can be transferred undamaged to arbitrary substrates, which allows for structural, compositional, and electrical characterization. We further demonstrate the potential for synthesis of as-grown nanowire networks and for using nanowires as shadow masks for in situ fabricated junctions in radial nanowire heterostructures. PMID- 28895747 TI - Probing Intrawire, Interwire, and Diameter-Dependent Variations in Silicon Nanowire Surface Trap Density with Pump-Probe Microscopy. AB - Surface trap density in silicon nanowires (NWs) plays a key role in the performance of many semiconductor NW-based devices. We use pump-probe microscopy to characterize the surface recombination dynamics on a point-by-point basis in 301 silicon NWs grown using the vapor-liquid-solid (VLS) method. The surface recombination velocity (S), a metric of the surface quality that is directly proportional to trap density, is determined by the relationship S = d/4tau from measurements of the recombination lifetime (tau) and NW diameter (d) at distinct spatial locations in individual NWs. We find that S varies by as much as 2 orders of magnitude between NWs grown at the same time but varies only by a factor of 2 or three within an individual NW. Although we find that, as expected, smaller diameter NWs exhibit shorter tau, we also find that smaller wires exhibit higher values of S; this indicates that tau is shorter both because of the geometrical effect of smaller d and because of a poorer quality surface. These results highlight the need to consider interwire heterogeneity as well as diameter dependent surface effects when fabricating NW-based devices. PMID- 28895748 TI - Multiple sclerosis among service members of the active and reserve components of the U.S. Armed Forces and among other beneficiaries of the Military Health System, 2007-2016. AB - During 2007-2016, a total of 2,031 active component service members received incident diagnoses of multiple sclerosis (MS), for an overall unadjusted incidence rate of 14.9 cases per 100,000 p-yrs. The average overall unadjusted rate among reserve/guard members during this surveillance period was 6.9 cases per 100,000 persons. In both components, women had a higher overall incidence of MS than men across all race/ethnicity groups. Overall rates of MS were highest among non-Hispanic black service members. Crude annual incidence rates among active component members decreased slightly during 2007-2016, while rates among reserve/guard members were relatively stable. Among active component members, the annual female-to-male incidence ratios decreased during the 10-year period (3.7:1 in 2007 to 2.5:1 in 2016). Annual numbers of incident cases of MS decreased among non-service member Military Health System beneficiaries during this period. The median age at MS case-defining diagnosis was 32 years among active component members, 37 years among reserve/guard members, and 48 years among non-service member beneficiaries. The median time intervals between initial presentation and case-defining MS-related encounter ranged from 15 days among reserve/guard component members to 20 days among active component service members. This study makes a useful contribution to the literature on temporal changes in the incidence of MS by sex and race/ethnicity. PMID- 28895749 TI - Challenges with diagnosing and investigating suspected active tuberculosis disease in military trainees. AB - Between 1 January 2010 and 31 December 2016, a total of 14 U.S. and international military personnel in training at Joint Base San Antonio-Lackland, TX, were hospitalized due to suspected pulmonary tuberculosis (TB); of these, five personnel were diagnosed with active TB disease. Only one TB case had pulmonary symptoms, but these symptoms were not suggestive of TB. The incidence rate in the training population was 1.89 per 100,000 population (95% CI: 0.81, 4.42), with a higher rate when restricted to international military students attending the Defense Language Institute English Language Center. No instances of TB transmission were identified. The variety of atypical presentations and their resulting diagnostic and public health challenges prompted this retrospective review of all hospitalized cases. This case series highlights both the importance of a high index of clinical suspicion when TB is being considered in close congregate settings as well as the risk of overreliance on acid-fast bacilli staining and nucleic acid amplification testing for ruling out active pulmonary disease in young, otherwise healthy trainees. Practical solutions are suggested. PMID- 28895750 TI - Brief report: Mid-season influenza vaccine effectiveness estimates for the 2016 2017 influenza season. PMID- 28895751 TI - Extreme skeletal open bite correction with vertical elastics. AB - Severe skeletal open bites may be ideally treated with a combined surgical orthodontic approach. Alternatively, compensations may be planned to camouflage the malocclusion with orthodontics alone. This case report describes the treatment of an 18-year-old man who presented with a severe open bite involving the anterior and posterior teeth up to the first molars, increased vertical dimension, bilateral Class III molar relationship, bilateral posterior crossbite, dental midline deviation, and absence of the maxillary right canine and the mandibular left first premolar. A treatment plan including the extraction of the mandibular right first premolar and based on uprighting and vertical control of the posterior teeth, combined with extrusion of the anterior teeth using multiloop edgewise archwire mechanics and elastics was chosen. After 6 months of alignment and 2 months of multiloop edgewise archwire mechanics, the open bite was significantly reduced. After 24 months of treatment, anterior teeth extrusion, posterior teeth intrusion, and counterclockwise mandibular rotation were accomplished. Satisfactory improvement of the overbite, overjet, sagittal malocclusion, and facial appearance were achieved. The mechanics used in this clinical case demonstrated good and stable results for open-bite correction at the 2-year posttreatment follow-up. PMID- 28895753 TI - Thermal Breakdown Kinetics of 1-Ethyl-3-Methylimidazolium Ethylsulfate Measured Using Quantitative Infrared Spectroscopy. AB - In this work, the thermal stability of the room temperature ionic liquid (RTIL) 1 ethyl-3-methylimidazolium ethylsulfate ([EMIM][EtSO4]) is investigated using infrared (IR) spectroscopy. Quantitative IR absorption spectral data are measured for heated [EMIM][EtSO4]. Spectra have been collected between 25 C and 100 C using a heated optical cell. Multiple samples and cell pathlengths are used to determine quantitative values for the molar absorptivity of [EMIM][EtSO4]. These results are compared to previous computational models of the ion pair. These quantitative spectra are used to measure the rate of thermal decomposition of [EMIM][EtSO4] at elevated temperatures. The spectroscopic measurements of the rate of decomposition show that thermogravimetric methods overestimate the thermal stability of [EMIM][EtSO4]. PMID- 28895752 TI - Airflow Obstruction and Use of Solid Fuels for Cooking or Heating: BOLD Results. AB - RATIONALE: Evidence supporting the association of COPD or airflow obstruction with use of solid fuels is conflicting and inconsistent. OBJECTIVE: To assess the association of airflow obstruction with self-reported use of solid fuels for cooking or heating. METHODS: We analysed 18,554 adults from the BOLD study, who had provided acceptable post-bronchodilator spirometry measurements and information on use of solid fuels. The association of airflow obstruction with use of solid fuels for cooking or heating was assessed by sex, within each site, using regression analysis. Estimates were stratified by national income and meta analysed. We carried out similar analyses for spirometric restriction, chronic cough and chronic phlegm. MEASUREMENTS AND MAIN RESULTS: We found no association between airflow obstruction and use of solid fuels for cooking or heating (ORmen=1.20, 95%CI 0.94-1.53; ORwomen=0.88, 95%CI 0.67-1.15). This was true for low/middle and high income sites. Among never smokers there was also no evidence of an association of airflow obstruction with use of solid fuels (ORmen=1.00, 95%CI 0.57-1.76; ORwomen=1.00, 95%CI 0.76-1.32). Overall, we found no association of spirometric restriction, chronic cough or chronic phlegm with the use of solid fuels. However, we found that chronic phlegm was more likely to be reported among female never smokers and those who had been exposed for >=20 years. CONCLUSION: Airflow obstruction assessed from post-bronchodilator spirometry was not associated with use of solid fuels for cooking or heating. PMID- 28895754 TI - Coenzyme Q10 and retinaldehyde co-loaded nanostructured lipid carriers for efficacy evaluation in wrinkles. AB - This study depicts coenzyme Q10 (CoQ10) and retinaldehyde (RAL) co-loaded nanostructured lipid carriers (NLCs); having activity on different targets of photoageing, which can overcome deficits of conventional topical dosage forms. The developed NLCs were characterised for particle size, polydispersity index and percent entrapment efficiency (%EE), followed by their incorporation into Carbopol(r) 934 P-NF gel. In vitro cellular uptake and cytotoxicity assay was performed to evaluate NLCs and in vivo study on ultraviolet- (UV) induced wrinkle model to determine efficacy of NLCs. The developed stable, homogenous and spherical NLCs with size range of 200-230 nm and more than 80 %EE, showed prolonged, biphasic in vitro release pattern for CoQ10 and RAL. Ex vivo study portrayed negligible permeation through skin but appreciable penetration and distribution in skin layers. This has shown good uptake of both drugs with least cytotoxicity in cell culture studies. In vivo irritation study on Sprague Dawley (SD) rats and pharmacodynamic study on female Swiss albino mice proved it less irritant and efficacious. The developed NLCs thus hold promise in the efficient management of wrinkle and their reduction as indicated by the data obtained. PMID- 28895755 TI - Hemodynamic characterization of hypertensive patients with an exaggerated orthostatic blood pressure variation. AB - : Exaggerated orthostatic blood pressure variation (EOV) is a poorly understood phenomenon related to high cardiovascular risk. We aimed to determine whether hypertensive patients with EOV have a distinct hemodynamic pattern, assessed through impedance cardiography. METHODS: In treated hypertensive patients, we measured the cardiac index (CI), systemic vascular resistance index (SVRI), blood pressure (BP), and heart rate (HR) in the supine and standing (after 3 minutes) positions, defining three groups according to BP variation: 1) Normal orthostatic BP variation (NOV): standing systolic BP (stSBP)-supine systolic BP (suSBP) between -20 and 20 mmHg and standing diastolic BP (stDBP)-supine diastolic BP (suDBP) between -10 and 10 mmHg; 2) orthostatic hypotension (OHypo): stSBP suSBP<=-20 or stDBP-suDBP<=-10 mmHg; 3) orthostatic hypertension (OHyper): stSBP suSBP>=20 or stDBP-suDBP>=10 mmHg. We performed multivariable analyses to determine the association of hemodynamic variables with EOV. RESULTS: We included 186 patients. Those with OHyper had lower suDBP and higher orthostatic SVRI variation compared to NOV. In multivariable analyses, orthostatic HR variation (OR = 1.06 (95%CI 1.01-1.13), p = 0.03) and orthostatic SVRI variation (OR = 1.16 (95%CI 1.06-1.28), p = 0.002) were independently related to OHyper. No variables were independently associated with OHypo. CONCLUSION: Patients with OHyper have a distinct hemodynamic pattern, with an exaggerated increase in SVRI and HR when standing. PMID- 28895756 TI - Early treatment using fractional CO2 laser before skin suture during scar revision surgery in Asians. AB - Fractional CO2 laser is one of the most effective treatment options used to resurface scars. However, most previous studies have been performed on mature scars at least 2 months after surgery. Recent studies have emphasized the importance of early treatment to reduce scar formation. In the present study, we described our experience with fractional CO2 laser intervention before skin suture during scar revision surgery in Asians, and found the treatment was safe and effective. PMID- 28895757 TI - Intoxications in the STRIDA project involving a panorama of psychostimulant pyrovalerone derivatives, MDPV copycats. AB - CONTEXT: An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in intoxications involving 11 stimulant pyrovalerone NPS derivatives over a 5-year period. STUDY DESIGN: Case series of consecutive patients with admitted or suspected intake of NPS presenting to Swedish hospitals for emergency treatment from January 2011 to March 2016. PATIENTS AND METHOD: Blood and urine samples were collected from intoxicated patients presenting to hospitals all over Sweden. Analyses of NPS and other drugs of abuse were performed by immunochemical and liquid chromatography-mass spectrometry multi-component methods. Clinical data were collected during consultation with the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The study involved analytically confirmed cases with 11 pyrovalerone drugs. RESULTS: During the study period, 114 intoxications were detected that involved any of 11 new pyrovalerone drugs. In addition to these new pyrovalerone derivatives, 3,4-methylenedioxypyrovalerone (MDPV) was detected in 17 of the cases and alpha-pyrrolidinovalerophenone (alpha-PVP) in 45 cases. Identification was made according to forensic standards and comprised the following substances: 4F-alpha-PVP, alpha-PHP, PV8, 4Me-PPP, alpha-PBP, 4F-PV8, alpha-PPP, MDPHP, alpha-PVT, 4Cl-alpha-PVP, and 4F-alpha-PHP. The three most frequently detected drugs were alpha-PBP, MDPHP, and 4F-alpha-PVP. The age range of patients was 16-66 (median 30) years and 84% were males. The substance concentrations in urine and serum were highly variable, ranging from 1 ng/mL to 300 ug/mL. Poly-drug use was common with only 8 of 114 cases (7%) involving one pyrovalerone drug. The additional substances comprised other NPS and classical psychoactive drugs. The patients showed a variety of clinical signs; agitation, delirium, hallucinations, excessive motor activity, seizures, tachycardia, hypertension, and/or hyperthermia. CONCLUSIONS: In analytically confirmed NPS related intoxications, 11 new pyrovalerone derivatives in addition to MDPV and alpha-PVP were found. The clinical features were consistent with a sympathomimetic toxidrome, but the urine and serum concentrations were highly variable. The results demonstrated that many novel pyrovalerone stimulants were introduced on the recreational NPS drugs market. Analytical investigations were necessary to obtain this information. PMID- 28895759 TI - Validation of plantar pressure simulations using finite and discrete element modelling in healthy and diabetic subjects. AB - Plantar pressure simulation driven by integrated 3D motion capture data, using both a finite element and a discrete element model, is compared for ten healthy and ten diabetic neuropathic subjects. The simulated peak pressure deviated on average between 16.7 and 34.2% from the measured peak pressure. The error in the position of the peak pressure was on average smaller than 4.2 cm. No method was more accurate than the other although statistical differences were found between them. Both techniques are thus complementary and useful tools to better understand the alteration of diabetic foot biomechanics during gait. PMID- 28895758 TI - Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder. AB - AIMS: To examine medication adherence and discontinuation in two separate groups of patients with schizophrenia or bipolar disorder (BD), who began receiving a long-acting injectable antipsychotic (LAI) versus those who changed to a different oral antipsychotic monotherapy. MATERIALS AND METHODS: The Truven Health Analytics MarketScan Multi-State Medicaid claims database was used to identify patients with schizophrenia; Truven Health Analytics MarketScan Commercial and Medicaid claims databases were used to identify patients with BD. The analyses included adult patients (>=18 years) who either began receiving an LAI (no prior LAI therapy) or changed to a different oral antipsychotic (monotherapy). The first day of initiating an LAI or changing to a new oral antipsychotic was the index date. Linear and Cox regression models were conducted to estimate medication adherence (proportion of days covered [PDC]) and time to medication discontinuation (continuous medication gap >=60 days), respectively. Models adjusted for patient demographic and clinical characteristics, baseline medication use, and baseline ED or hospitalizations. RESULTS: Patients with schizophrenia (N = 5638) who began receiving LAIs had better medication adherence (5% higher adjusted mean adherence) during the 1 year post-index period and were 20% less likely to discontinue their medication during the entire follow-up period than patients who changed to a different oral antipsychotic monotherapy, adjusting for differences between LAI users and oral users. Similarly, patients with BD (N = 11,344) who began receiving LAIs also had 5% better medication adherence and were 19% less likely to discontinue their medication than those using oral antipsychotics. LIMITATIONS: Clinical differences unmeasurable in this database may have been responsible for the choice of LAI versus oral antipsychotics, and these differences may be responsible for some of the adherence advantages observed. CONCLUSIONS: This real-world study suggests that patients with schizophrenia or BD who began receiving LAIs had better medication adherence and lower discontinuation risk than those who changed to a different oral antipsychotic monotherapy. PMID- 28895760 TI - Application of a semi-automatic cartilage segmentation method for biomechanical modeling of the knee joint. AB - Manual segmentation of articular cartilage from knee joint 3D magnetic resonance images (MRI) is a time consuming and laborious task. Thus, automatic methods are needed for faster and reproducible segmentations. In the present study, we developed a semi-automatic segmentation method based on radial intensity profiles to generate 3D geometries of knee joint cartilage which were then used in computational biomechanical models of the knee joint. Six healthy volunteers were imaged with a 3T MRI device and their knee cartilages were segmented both manually and semi-automatically. The values of cartilage thicknesses and volumes produced by these two methods were compared. Furthermore, the influences of possible geometrical differences on cartilage stresses and strains in the knee were evaluated with finite element modeling. The semi-automatic segmentation and 3D geometry construction of one knee joint (menisci, femoral and tibial cartilages) was approximately two times faster than with manual segmentation. Differences in cartilage thicknesses, volumes, contact pressures, stresses, and strains between segmentation methods in femoral and tibial cartilage were mostly insignificant (p > 0.05) and random, i.e. there were no systematic differences between the methods. In conclusion, the devised semi-automatic segmentation method is a quick and accurate way to determine cartilage geometries; it may become a valuable tool for biomechanical modeling applications with large patient groups. PMID- 28895763 TI - Relationship of Eating Behaviors with Age, Anthropometric Measurements, and Body Composition Parameters among Professional Indian Women. AB - One hundred volunteer female college teachers were selected from Jalandhar, Punjab, India. General obesity was found in 56.6%, 76.9%, and 76.2%, abdominal obesity in 56.6%, 57.7%, and 81.0%, of 30- to 39-year-old (Group I), 40- to 49 year-old, (Group II) and 50- to 59-year-old (Group III) participants, respectively. A significantly (p <= .05) lower mean value of uncontrolled eating domain was observed in the participants belonging to Group I in comparison to Groups II and III. The cognitive restraint was less in Group III (13.71%), followed by Group II (14.04%) and I (13.71%). The mean values of emotional eating domain revealed not much difference in Group I (12.19%), Group II (12.65%), and Group III (12.00%). Adiposity showed a significant (p <= .10, .05) relationship with age and eating behaviors. In conclusion, lesser cognitive dietary restraint and emotional eating were the variables associated with adiposity in the participants. PMID- 28895764 TI - Group A streptococcal brain abscess in children: two case reports and a review of the literature. AB - Brain abscesses caused by group A Streptococcus (GAS) are infrequently encountered in children. We present two cases of brain abscess (one cerebellar and one located in the temporal lobe) due to GAS infection occurring in close temporal proximity in previously healthy young children living in different geographic areas of southern Israel. The relevant literature since 2000, in the context of recent epidemiological data reporting an increase in the incidence of invasive GAS infections, is reviewed. PMID- 28895765 TI - Prevalence and Incidence of Optic Neuritis in Patients with Different Types of Uveitis. AB - PURPOSE: This database study aims to investigate the incidence and prevalence of optic neuritis (ON) among patients with different types of uveitis. METHODS: A retrospective analysis of the Truven Health MarketScan(r) database from 2000 to 2014 was conducted. Patients with uveitis were followed until diagnosis of ON or until they were censored. Diagnosis of uveitis and demyelinating diseases of the central nervous system (DD) including ON were based on ICD-9 codes. Patients with a diagnosis of DD at or before the index date of diagnosis of uveitis were excluded from incidence calculation. In the prevalence analysis, any diagnoses of DD during continuous enrollment were counted. RESULTS: Among the 103,867 uveitis patients, 974 had ever been diagnosed with ON and 2121 with DD including ON during the continuous enrollment. Prevalence rates of ON in patients with intermediate, posterior and pan uveitis are approximately 2.0-2.5% while a lower prevalence (0.6%) of ON was observed in anterior uveitis. During a median follow up period of 2.2 years, 463 new cases of ON were diagnosed. The incidence rates of ON per 100 person-years (95% CI) were 0.12 (0.11-0.13), 0.28 (0.18-0.41), 0.29 (0.23-0.35) and 0.38 (0.24-0.56), respectively, for anterior, intermediate, posterior and pan uveitis. CONCLUSION: Incidence and prevalence of ON among patients with intermediate, posterior and pan uveitis were comparable and higher than the rates in patients with anterior uveitis. PMID- 28895766 TI - Adherence, persistence, and inpatient utilization among adult schizophrenia patients using once-monthly versus twice-monthly long-acting atypical antipsychotics. AB - AIMS: This study compared healthcare resource utilization (HRU), healthcare costs, adherence, and persistence among adult patients with schizophrenia using once-monthly (OM) vs twice-monthly (TM) atypical long-acting injectable (LAI) antipsychotic (AP) therapy. MATERIALS AND METHODS: A longitudinal retrospective cohort study was conducted using Medicaid claims data from six states. Patients initiated on aripiprazole or paliperidone palmitate were assigned to the OM cohort; risperidone-treated patients were assigned to the TM cohort. HRU and healthcare costs were assessed during the first 12 months following stabilization on the medication. Adherence was measured using the proportion of days covered (PDC) during the first year of follow-up. Persistence to the index medication was measured during the first 2 years following the index date. Comparison between the cohorts was achieved using multivariable generalized linear models, adjusting for demographic and clinical characteristics. RESULTS: Patients in the OM LAI cohort had lower inpatient HRU and medical costs when compared with patients in the TM cohort. Higher medical costs in the TM LAI cohort offset the higher pharmacy costs in the OM LAI cohort. Mean PDC during the first 12 months of follow-up was higher in the OM cohort than in the TM cohort (0.56 vs 0.50, p < .01). Median persistence was longer in the OM cohort than in the TM cohort (7.5 months vs 5.5 months), as was the hazard of discontinuing the index medication (hazard ratio = 0.83, p = .01). Kaplan-Meier rates of persistence at 1 year were higher for OM patients than for TM patients (37.6% vs 29.6%, p < .01). LIMITATIONS: This was a Medicaid sample with few aripiprazole LAI patients (5.4% of OM cohort). Medication use was inferred from pharmacy claims. CONCLUSIONS: Among Medicaid patients in these six states, OM AP treatment was associated with lower HRU, better adherence and persistence, and similar total costs compared to patients on TM treatment. PMID- 28895767 TI - Promising galactose-decorated biodegradable poloxamer 188-PLGA diblock copolymer nanoparticles of resibufogenin for enhancing liver cancer therapy. AB - Liver cancer is one of the major diseases affecting human health. Modified drug delivery systems through the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, have become a research focus for the treatment of liver cancer. Resibufogenin (RBG) is a popular traditional Chinese medicine and natural anti-cancer drug that was isolated from Chansu, but its cardiotoxicity and hydrophobicity have limited its clinical applications. Galactosyl-succinyl-poloxamer 188 and galactosyl-succinyl-poloxamer 188 polylactide-co-glycolide (Gal-SP188-PLGA) were synthesized using galactose, P188, and PLGA to achieve active liver-targeting properties. RBG-loaded Gal-SP188-PLGA nanoparticles (RGPPNs) and coumarin-6-loaded Gal-SP188-PLGA nanoparticles (CGPPNs) were prepared. The in vitro cellular uptake, cytotoxicity, and apoptosis of nanoparticles in HepG2 cells were analyzed. The in vivo therapeutic effects of nanoparticles were assessed in a hepatocarcinogenic mouse model. The results showed that Gal-SP188-PLGA was successfully synthesized. The cellular uptake assay demonstrated that CGPPNs had superior active liver-targeting properties. The ratio of apoptotic cells was increased in the RGPPN group. In comparison to the other groups, RGPPNs showed superior in vivo therapeutic effects and anticancer efficacy. Thus, the active liver-targeting RGPPNs, which can enhance the pharmacological effects and decrease the toxicity of RBG, are expected to become a promising and effective treatment for liver cancer. PMID- 28895768 TI - Protective effects of taurine against renal ischemia/reperfusion injury in rats by inhibition of gelatinases, MMP-2 and MMP-9, and p38 mitogen-activated protein kinase signaling. AB - Dysregulated expression of matrix metalloproteinases (MMPs) is closely associated with the pathogenesis of renal ischemia/reperfusion injury (I/R). The production of excessive reactive oxygen species (ROS) causes tissue damage. Increased ROS production causes activation of p38 mitogen-activated protein kinase (MAPK) signaling, which participates in gene regulation of MMPs, especially MMP-2 and MMP-9 (gelatinases). Taurine (2-aminoethanesulfonic acid) in mammalian cells functions in bile acid conjugation, maintenance of calcium homeostasis, osmoregulation, membrane stabilization, and antioxidation, antiinflammatory, and antiapoptotic action. We investigated the effects of taurine and the possible role of p38 MAPK signaling on regulation of MMP-2 and MMP-9 in a renal I/R injury model in rats. Rats were divided into three groups: sham, I/R, and I/R + taurine treated. After a right nephrectomy, I/R was induced by clamping the left renal pedicle for 1 h followed by 6 h reperfusion. Taurine was administered 45 min prior to induction of ischemia. Renal function was assessed by serum creatinine and blood urea nitrogen (BUN) levels. Tubule injury and structural changes were evaluated by light microscopy. Malondialdehyde (MDA) levels were analyzed by high performance liquid chromatography (HPLC). Superoxide dismutase (SOD) activity levels were measured using a colorimetric kit. mRNA expression of MMP-2 and MMP-9 was determined by real-time polymerase chain reaction. MMP-2 and MMP-9 activities were measured using a fluorimetric kit. Phosphorylated p38 (p-p38) and total p38 MAPK protein expressions were evaluated by western blot. Taurine pretreatment significantly attenuated renal dysfunction and histologic damage, such as renal tubule dilation and loss of brush borders. The pretreatment also decreased the MDA level and attenuated the reduction of SOD activity in the kidney during I/R. Taurine pretreatment also decreased significantly both MMP-2 and MMP-9 mRNA expression and MMP-9 activity induced by I/R. In addition, the activity of p38 MAPK signaling was down-regulated significantly by taurine administration. Inhibition of MMP-2 and MMP-9 expression and MMP-9 activity caused by taurine may be associated with suppression of p38 MAPK activation during I/R induced renal injury in rats. Therefore, taurine administration may prove to be a strategy for attenuating renal I/R injury. PMID- 28895769 TI - The cost-effectiveness of levodopa/carbidopa intestinal gel compared to standard care in advanced Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is an incurable, progressive neurological condition, with symptoms impacting movement, walking, and posture that eventually become severely disabling. Advanced PD (aPD) has a significant impact on quality of-life (QoL) for patients and their caregivers/families. Levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of advanced levodopa responsive PD with severe motor fluctuations and hyper-/dyskinesia when available combinations of therapy have not given satisfactory results. AIMS: To determine the cost-effectiveness of LCIG vs standard of care (SoC) for the treatment of aPD patients. METHODS: A Markov model was used to evaluate LCIG vs SoC in a hypothetical cohort of 100 aPD patients with severe motor fluctuations from an Irish healthcare perspective. Model health states were defined by Hoehn & Yahr (H&Y) scale-combined with amount of time in OFF-time-and death. SoC comprised of standard oral therapy +/- subcutaneous apomorphine infusion and standard follow up visits. Clinical efficacy, utilities, and transition probabilities were derived from published studies. Resource use was estimated from individual patient-level data from Adelphi 2012 UK dataset, using Irish costs, where possible. Time horizon was 20 years. Costs and outcomes were discounted at 4%. Both one-way and probabilistic sensitivity analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for LCIG vs SOC was ?26,944/quality adjusted life year (QALY) (total costs and QALYs for LCIG vs SoC: ?537,687 vs ?514,037 and 4.37 vs 3.49, respectively). LCIG is cost-effective at a payer threshold of ?45,000. The model was most sensitive to health state costs. CONCLUSION: LCIG is a cost-effective treatment option compared with SoC in patients with aPD. PMID- 28895771 TI - Platelet reactivity-adjusted antiplatelet therapy in patients with percutaneous coronary intervention: a meta-analysis of randomized controlled trials. AB - Numerous number of evidences show that high on-treatment platelet reactivity is a well-known risk factor for adverse events in patients after percutaneous coronary intervention (PCI). Controversial situations still exist regarding the effectiveness of tailoring antiplatelet therapy according to platelet function monitoring. The PubMed, Embase, and Cochrane Central databases were searched for randomized trials comparing platelet reactivity-adjusted antiplatelet therapy with conventional antiplatelet therapy in patients undergoing PCI. The primary end point was all-cause mortality, major adverse cardiac events (MACE) including cardiovascular (CV) death, nonfatal myocardial infarction (MI), definite/probable stent thrombosis (ST), revascularization, and stroke or transient ischemic attack (TIA). The safety end point was defined as major bleeding events. We derived pooled risk ratios (RRs) with fixed-effect models. Six studies enrolling 6347 patients were included. Compared with conventional treatment, tailoring antiplatelet failed to reduce all-cause mortality (RR: 0.89, 95% confidence interval [CI]: 0.63-1.24, P = 0.48), MACE (RR: 1.02, 95% CI: 0.92-1.14, P = 0.69), MI (RR: 1.07, 95% CI: 0.95-1.21, P = 0.24), CV death (RR: 0.69, 95% CI: 0.40-1.19, P = 0.09), ST (RR: 0.83, 95% CI: 0.50-1.38, P = 0.23), stroke or TIA (RR: 1.08, 95% CI: 0.55-2.12, P = 0.83), revascularization (RR: 0.96, 95% CI: 0.69-1.33, P = 0.79), and major bleeding events (RR: 0.79, 95% CI: 0.53-1.17, P = 0.24). Compared with traditional antiplatelet treatment, tailoring antiplatelet therapy according to platelet reactivity testing failed to reduce all-cause mortality, MACE, and major bleeding events in patients undergoing PCI. PMID- 28895770 TI - The use of platelet-rich plasma (PRP) in the treatment of gastrocnemius strains: a retrospective observational study. AB - The aim of the present retrospective observational study was to evaluate the time of functional recovery following a specific combined therapeutic approach characterized by an active exercise therapy carried out immediately after Platelet-rich plasma (PRP) injections for the treatment of the muscular lesion of the distal musculotendinous junction of the gastrocnemius medial head.Medical records of 31 subjects treated with three PRP intra-lesional ultrasound guided injections and 30 patients treated with the standard therapeutic approach (control group) were analyzed. Both groups followed the same rehabilitation therapy. Patients in the control group were able to start active exercise with a significant delay when compared to the PRP treated subjects: 17 +/- 7.2 days and 9 +/- 3.8 days (p = 0.0001), respectively. This delay was mainly due to the persistence of pain in the subjects in the control group. The time necessary to return to walk without pain was significantly shorter in the PRP treated group: 24.27 +/- 12.36 days versus 52.4 +/- 20.03 days in the control group (p < 0.001) as well as the time needed to fully return to practice the previous sport activity: 53.33 +/- 27.74 days versus 119.3 +/- 43.87 days in the control group (p < 0.001).The present study showed that ultrasound guided delivery of PRP into the site of muscle injury has to be considered a valid therapeutic approach with the potentiality of significantly reduce time and costs for reaching a complete functional recovery. PMID- 28895772 TI - Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders. AB - Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis. PMID- 28895773 TI - GATA1 gene variants associated with thrombocytopenia and anemia. PMID- 28895774 TI - Reduced platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. AB - Results from previous studies regarding platelet function in liver cirrhosis are discordant. The aim was to investigate platelet activation and platelet aggregation in patients with alcoholic liver cirrhosis. We included 27 patients with alcoholic liver cirrhosis and 22 healthy individuals. A recently established flow cytometric approach was used to measure platelet activation and platelet aggregation independent of sample platelet count. Platelet aggregation was further investigated using light transmission aggregometry (LTA) (for platelet count >100 * 109/L). Platelet agonists were adenosine diphosphate, thrombin receptor-activating peptide, arachidonic acid, collagen, and collagen-related peptide. Patients had lower median platelet count than healthy individuals, 125 * 109/L (interquartile range [IQR] 90-185) versus 240 * 109 (IQR 204-285), p < 0.001. Platelet activation levels in stimulated samples were lower in patients versus healthy individuals, e.g., after collagen-related peptide stimulation, the median percentage of platelets positive for activated glycoprotein IIb/IIIa was 85% (IQR 70-94) in patients versus 97% (IQR 94-99) in healthy individuals, p < 0.001; lower platelet activation capacity being associated with low platelet count and Child-Pugh class B/C cirrhosis. Flow cytometric platelet aggregation was reduced in patients for collagen-related peptide and for adenosine diphosphate, e.g., platelet aggregation (mean +/- standard deviation) was 57% +/- 4 in patients versus 70% +/- 1 in healthy individuals for collagen-related peptide, p = 0.01. Light LTA showed reduced collagen-induced platelet aggregation in some patients compared with healthy individuals. In conclusion, platelet function was reduced in some patients with alcoholic liver cirrhosis and the severity was associated with platelet count and severity of liver cirrhosis. PMID- 28895775 TI - The Prevalence of Corneal Opacity in Rural Areas in Iran: A Population-based Study. AB - PURPOSE: To determine the prevalence of corneal opacity in rural areas in Iran: a population-based study Methods: This was a cross-sectional population-based study using multi-stage cluster sampling from rural-dwellers of villages in the north and southwest of Iran. All participants underwent vision testing including measurement of visual acuity and refraction followed by slit lamp examination by an ophthalmologist through which the presence of corneal opacity was determined. RESULTS: The participants were 3314 people (response rate = 86.5%), and 56.3% were female. The prevalence of corneal opacity in at least one eye in the studied subjects was 1.68% (95% CI: 1.08-2.27%); 1.07% (95% CI: 0.04-3.43%) and 2.47% (95% CI: 1.49-3.43%) in women and men, respectively, and 1.45% (95% CI: 0.4 2.45%) and 1.97% (95% CI: 1.3-2.94%) in the southwest and north of the country, respectively. The prevalence of corneal opacity was related to male gender (OR = 2.06, 95% CI: 1.13-3.74) and age (OR = 1.06, 95% CI: 1.04- 1.09) but not with education level. The prevalence of visual impairment and blindness among cases with corneal opacity was 46.2% and 19.2%, respectively. CONCLUSION: Given the high prevalence of corneal opacity in rural areas in Iran, it is essential to prioritize rural areas for allocation of resources and facilities for the diagnosis, screening, and necessary treatment measures. PMID- 28895776 TI - Evaluation of analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease. AB - Objectives The objective of this study was to evaluate the analgesic effect and absorption of buprenorphine after buccal administration in cats with oral disease. Methods Six adult client-owned cats with chronic gingivostomatitis (weighing 5.1 +/- 1.1 kg) were recruited for a randomised, prospective, blinded, saline-controlled, crossover study. Pain scores, dental examination, stomatitis score and buccal pH measurement were conducted on day 1 under sedation in all cats. On day 2, animals were randomised into two groups and administered one of the two treatments buccally (group A received buprenorphine 0.02 mg/kg and group B received 0.9% saline) and vice versa on day 3. Pain scores and food consumption were measured at 30, 90 and 360 mins after the administration of buprenorphine. Blood samples were taken at the same time and plasma buprenorphine concentration was measured by liquid chromatography-mass spectrometry. Data were statistically analysed as non-parametric and the level of significance was set as P <0.05. Results There were no major side effects after buprenorphine administration. Buccal pH values ranged between 8.5 and 9.1 and the stomatitis disease activity index between 10 and 22 (17.8 +/- 4.5), with the scale ranging from 0-30. The maximum buprenorphine plasma concentration (14.8 ng/ml) was observed 30 mins after administration and there was low inter-individual variability. There was a significant difference between baseline pain scores compared with pain scores after buprenorphine ( P <0.05), and between the saline and buprenorphine group at 30 mins ( P = 0.04) and 90 mins ( P = 0.04). There was also a significant effect of the stomatitis index on the pain score. Regarding the pharmacokinetic parameters, cats with stomatitis showed lower bioavailability and shorter absorption half-life after buccal administration of buprenorphine compared with normal cats in previous studies. Conclusions and relevance Buccal administration of buprenorphine in cats with gingivostomatitis produces an analgesic effect and low inter-individual variability in plasma concentration, and it can be incorporated in their multimodal analgesia plan. PMID- 28895777 TI - Effects of Kinesio tape in individuals with lateral epicondylitis: A deceptive crossover trial. AB - OBJECTIVES: To determine the true and immediate effect of applying Kinesio tape (KT) on the pain intensity, pain-free grip strength, maximal grip strength, and electromyographic activity with facilitatory KT, inhibitory KT, sham KT, and untaped condition in patients with lateral epicondylitis (LE) who were ignorant about KT. DESIGN: Deceptive crossover trial. PARTICIPANTS: Thirty-three patients with unilateral chronic LE who were ignorant about KT, 30 of them were successfully deceived in this study. INTERVENTIONS: Patients were randomly allocated into different sequences of four taping conditions: facilitatory KT, inhibitory KT, sham KT, and untaped condition. OUTCOME MEASURES: Pain intensity, pain-free grip strength, maximal grip strength, and electromyographic activity of wrist extensor muscles were assessed immediately after each tape application. RESULTS: No significant differences in the pain intensity (p = 0.321, eta2 = 0.04); pain-free grip strength (p = 0.312, eta 2 = 0.04); maximal grip strength (p = 0.499, eta2 = 0.03); and electromyographic activity (maximal grip: p = 0.774, eta2 = 0.01; and pain-free grip: p = 0.618, eta2 = 0.02) were recorded among various taping conditions. CONCLUSIONS: Neither facilitatory nor inhibitory effects were observed between different application techniques of KT in patients with LE. Hence, alternative intervention should be used to manage LE. PMID- 28895778 TI - Eosinophil Cationic Protein and Histamine Production by Neutrophils from Periodontitis Patients. AB - BACKGROUND: Periodontitis develops through an inflammatory process caused by an infection at the microbial biofilm, followed by tissue destruction mediated by leucocytes which clinically cause significant destruction of connective tissue and bone. Several elements derived from the bacteria cause the inflammatory response and the release of mediators involved in the destruction of the periodontium. There are number of inflammatory mediators released by leukocytes, mainly neutrophils, upon bacterial challenge. However, neutrophil-derived histamine and Eosinophil Cationin Protein production and their role has not been characterized in periodontal inflammation. We previously found that neutrophils produce and release Eosinophil Cationic Protein and histamine, two important inflammatory mediators previously described in the periodontitis disease. Thus, the purpose of this study is to investigate whether neutrophils from periodontitis patients are able to produce Eosinophil Cationic protein and histamine in response to Lipopolysaccharides. MATERIALS AND METHODS: We analyzed ECP and histamine production in response to LPS by ELISA. We also analyzed the expression of the Histidine decarboxylase and ECP by flow cytometry and fluorescence microscopy in neutrophils from periodontitis patients in response to LPS. RESULTS: We found that neutrophils from periodontitis patients express higher levels of histidine decarboxylase and ECP than those from healthy volunteers, and they also release higher levels of histamine. CONCLUSIONS: The findings described could represent new knowledge of neutrophils as source of histamine and ECP in the progression of the periodontitis disease. PMID- 28895779 TI - Combination of Bone Graft and Resorbable Membrane for Alveolar Ridge Preservation: a Systematic Review, Meta-analysis and Trial Sequential Analysis. AB - INTRODUCTION: Alveolar ridge preservation (ARP) techniques are aimed to reduce the resorption after tooth extraction. The combination of a graft material covered with a resorbable membrane represent one of the most common strategies performed in the clinical practice. The aim of this systematic review was to analyse evidence regarding potential benefits of ARP procedures performed with allogenic/xenogenic grafts in combination with a resorbable membrane coverage in comparison to a spontaneous healing. MATERIALS AND METHODS: Electronic databases were screened independently by two authors in order to select studies suitable for inclusion in this revision. Horizontal Ridge Width Reduction (HRWR) and Vertical Ridge Height Reduction (VRHR) were investigated as primary outcomes and Volume Changes (VC) as secondary outcome. Meta-analysis was performed using the inverse of variance test with a random effect model. Adjustment for type I and II errors and analysis of the power of evidence was performed with Trial Sequential analysis (TSA). RESULTS: 7 studies met the inclusion criteria and were included in the quantitative synthesis. Meta-analysis revealed that the combination therapy resulted in a lower rate of resorption for both HRWR (-2.19 mm with 95% Confidence Interval (CI) [-2.67, -1.71]) and VRHR (-1.72 mm with 95% CI [-2.14, 1.30]). For VC no meta-analysis was performed due to insufficient data. Analysis of the power of the evidence performed with TSA, showed that the number of both studies and sockets analyzed is sufficient to validate such findings, despite the high rate of heterogeneity. CONCLUSIONS: The use of bone graft covered by a resorbable membrane is able to decrease the rate of alveolar ridge horizontal and vertical resorption after tooth extraction. The power and reliability of the evidences are strong enough to confirm the above-mentioned findings, despite the high rate of heterogeneity of included studies. PMID- 28895780 TI - miR-300 regulates cellular radiosensitivity through targeting p53 and apaf1 in human lung cancer cells. AB - microRNAs (miRNAs) play a crucial role in mediation of the cellular sensitivity to ionizing radiation (IR). Previous studies revealed that miR-300 was involved in the cellular response to IR or chemotherapy drug. However, whether miR-300 could regulate the DNA damage responses induced by extrinsic genotoxic stress in human lung cancer and the underlying mechanism remain unknown. In this study, the expression of miR-300 was examined in lung cancer cells treated with IR, and the effects of miR-300 on DNA damage repair, cell cycle arrest, apoptosis and senescence induced by IR were investigated. It was found that IR induced upregulation of endogenous miR-300, and ectopic expression of miR-300 by transfected with miR-300 mimics not only greatly enhanced the cellular DNA damage repair ability but also substantially abrogated the G2 cell cycle arrest and apoptosis induced by IR. Bioinformatic analysis predicted that p53 and apaf1 were potential targets of miR-300, and the luciferase reporter assay showed that miR 300 significantly suppressed the luciferase activity through binding to the 3' UTR of p53 or apaf1 mRNA. In addition, overexpression of miR-300 significantly reduced p53/apaf1 and/or IR-induced p53/apaf1 protein expression levels. Flow cytomertry analysis and colony formation assay showed that miR-300 desensitized lung cancer cells to IR by suppressing p53-dependent G2 cell cycle arrest, apoptosis and senescence. These data demonstrate that miR-300 regulates the cellular sensitivity to IR through targeting p53 and apaf1 in lung cancer cells. PMID- 28895781 TI - Selective nitration of PsbO1, PsbO2, and PsbP1 decreases PSII oxygen evolution and photochemical efficiency in intact leaves of Arabidopsis. AB - Exposure of intact Arabidopsis leaves to 40 ppm nitrogen dioxide (NO2) in light resulted almost exclusively in nitration of PsbO1, PsbO2, and PsbP1 of photosystem II (PSII), with minor nitration of four non-PS II proteins, including peroxiredoxin II E, as reported previously. Our previous findings that light triggered selective nitration of PsbO1 decreased oxygen evolution and that inhibition of photoelectric electron transport inhibited nitration of PsbO1 implied that the nitratable tyrosine residue of PsbO1 is redox-active. However, whether the nitratable tyrosine residues of PsbO2 and PsbP1 are redox-active is unknown. In this study, we determined the oxygen evolution and maximal photochemical efficiency of PSII in intact Arabidopsis leaves following exposure to 40 ppm NO2 in light and found that these parameters were decreased to 60 and 70% of the non-exposed control, respectively. Because PsbO1, PsbO2, and PsbP1 accounted for > 80% of anti-3-nitrotyrosine antibody signal intensities, observed decreases in the oxygen evolution and maximal photochemical efficiency of PSII were mainly attributable to nitration of the tyrosine residues of these PSII proteins. Thus, it is postulated that nitratable tyrosine residues of PsbO2 and PsbP1 are redox-active, as in the case of PsbO1. A new hypothetical model is proposed. PMID- 28895783 TI - The relationship between autobiographical memory, cognition, and emotion in older adults: a review. AB - Over the past 30 years, the concept of "autobiographical memory" has been highlighted in numerous behavioral and neuroanatomical studies. Importantly, episodic autobiographical memory, an aspect of autobiographical memory, has been shown to decrease with age but can be improved by training. Autobiographical memory is deeply associated with the default mode network (especially posterior cingulate cortex and medial prefrontal cortex), which is particularly interesting in the context of better understanding the relationship between autobiographical memory, cognition, and emotion in older adults. This article provides an overview of the behavioral and neuroanatomical characteristics of autobiographical memory, as well as its relationship with the default mode network, cognition, emotion, and aging. This article also provides an overall review of autobiographical memory training. PMID- 28895782 TI - Dendritic cells as natural latency reversing agent: A wake-up call for HIV-1. PMID- 28895784 TI - Immunotherapy for IgE-mediated wheat allergy. AB - Among various routes of immunotherapy for food allergy, oral immunotherapy (OIT) appears to have a promising result due to its ability to modify abnormal immunologic mechanism of IgE-mediated food allergy. Other methods for immunomodulation such as sublingual (SLIT) or epicutaneous (EPIT) immunotherapy which carry lower rates of systemic reactions, may have less efficacy. Wheat has recently been recognized as a more common cause of food-induced anaphylaxis than previously recognized, especially among young children, around the world. In wheat allergic patients, avoidance recommended as standard recommendation is not easy to follow, because wheat has been used as a common constituents in various kinds of consumed foods in every day's life. Therefore, wheat OIT may be considered as an alternative treatments of those in which wheat avoidance is not sufficient to avert frequent events of anaphylaxis resulting from inadvertent exposure to small amount of wheat among this population. Currently, only few clinical trials about wheat OIT are available. In this review, we discuss available protocols of wheat OIT, initial starting dose, maintenance dose, and the strategies to minimize the side effects during the treatment. PMID- 28895787 TI - Internet-based acceptance and commitment therapy for psychological distress experienced by people with hearing problems: a pilot randomized controlled trial. AB - Psychological distress is common among people with hearing problems, but treatments that specifically target this aspect have been almost non-existent. In this pilot randomized controlled trial, an eight-week long Internet-based treatment, informed by Acceptance and Commitment Therapy, was administered to explore the feasibility and efficacy of such a treatment. Included participants were randomized to either treatment (n = 31) or wait-list control (n = 30) condition. All participants were measured prior to randomization and immediately after treatment ended using standardized self-report instruments measuring hearing-related emotional and social adjustment (Hearing Handicap Inventory for the Elderly - S, HHIE-S), quality of life (Quality of Life Inventory, QOLI), and symptoms of depression and anxiety (Patient health Questionnaire, PHQ-9 and Generalized Anxiety Disorder scale, GAD-7). Linear mixed effects regression analysis using the full intention-to-treat sample demonstrated that the treatment had superior outcomes on the main outcome measure as compared with the control group, Cohen's d = 0.93, 95% CI [0.24, 1.63]. The benefits of treatment over control were also evident in scores of depression, Cohen's d = 0.61, 95% CI [0.04, 1.19], and quality of life, Cohen's d = 0.88, 95% CI [0.14, 1.61]. The results provide preliminary support for Internet-delivered acceptance and commitment therapy as a potentially effective treatment of psychological symptoms associated with hearing problems. PMID- 28895785 TI - Preclinical pharmacokinetic characterization of an adipose tissue-targeting monoclonal antibody in obese and non-obese animals. AB - Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and betaKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/betaKlotho. To understand the PK/PD relationship in non-obese and obese animals, we evaluated the adipose tissue distribution of the antibody, serum exposures, and an associated PD marker (high-molecular-weight adiponectin), in both non-obese and obese mice and monkeys. Antibody uptake into fat tissue was found to be higher on a per gram basis in non-obese animals compared to obese animals. Since obesity has been reported to be associated with reduced expression of FGFR1 and betaKlotho receptor in white adipose tissues in mice, our results suggest that the distribution in adipose tissues was influenced by target expression levels. Even so, the overall dose-normalized serum exposures were comparable between non-obese and obese mice and monkeys, suggesting that adipose tissue uptake plays a limited role in overall systemic PK determination. It remains to be determined if and how obesity and receptor expression in humans influence the PK and PD profile of this novel therapeutic candidate. PMID- 28895789 TI - Future Doctors' Perceptions about Incorporating Nutrition into Standard Care Practice. AB - OBJECTIVE: The increasing prevalence of chronic disease has been largely attributed to long-term poor nutrition and lifestyle choices. This study investigates the attitudes of our future physicians toward nutrition and the likelihood of incorporating nutrition principles into current treatment protocols. METHODS: Setting: The setting of this study was an Australian university medical school. SUBJECTS: Subjects including year 1-4 students (n = 928) in a 4-year medical bachelor, bachelor of surgery (MBBS) degree program. Students were invited to participate in a questionnaire based on an existing instrument, the Nutrition in Patient Care Attitude (NIPC) Questionnaire, to investigate their attitudes toward nutrition in health care practices. RESULTS: Respondents indicated that "high risk patients should be routinely counseled on nutrition" (87%), "nutrition counseling should be routine practice" (70%), and "routine nutritional assessment and counseling should occur in general practice" (57%). However, despite overall student support of nutritional counseling (70%) and assessment (86%), students were reluctant to perform actual dietary assessments, with only 38% indicating that asking for a food diary or other measure of dietary intake was important. CONCLUSION: These findings demonstrate that future physicians are aware of the importance of considering nutrition counseling and assessment. However, students are unlikely to adequately integrate relevant nutritional information into their treatment protocols, evidenced by their limited use of a basic nutritional assessment. This is potentially the result of a lack of formal nutrition education within their basic training. PMID- 28895788 TI - Association between Serum Unmetabolized Folic Acid Concentrations and Folic Acid from Fortified Foods. AB - OBJECTIVE: To investigate the association between serum unmetabolized folic acid (UMFA) concentrations and folic acid from fortified foods and nutrients known as dietary methyl-group donors (folate, methionine, choline, betaine and vitamins B2, B6 and B12) in participants exposed to mandatory fortification of wheat and maize flours with folic acid. METHODS: Cross-sectional study carried out with 144 healthy Brazilian participants, both sexes, supplement nonusers. Serum folate, UMFA, vitamin B12 and total plasma homocysteine (tHcy) were biochemically measured. Dietary intake was assessed by 2 non-consecutive 24-hour dietary recalls (24-HRs) and deattenuated energy-adjusted nutrient data were used for statistical analysis. RESULTS: Ninety eight (68.1%) participants were women. Median (interquartile range) age was 35.5 (28.0-52.0) years. Elevated serum folate concentrations (>45 nmol/L) were found in 17 (11.8%), while folate deficiency (<7 nmol/L) in 10 (6.9%) participants. No one had vitamin B12 deficiency (<148 pmol/L). An elevated serum UMFA concentration was defined as > 1 nmol/L (90th percentile). UMFA concentrations were positively correlated with folic acid intake and negatively correlated to choline, methionine and vitamin B6 intakes. Participants in the lowest quartile of UMFA concentrations had lower dietary intake of total folate (DFEs) and folic acid, and higher dietary intake of methionine, choline and vitamin B6 than participants in the highest quartile of UMFA. Folic acid intake (OR [95% CI] = 1.02 [1.01-1.04)] and being a male (OR [95% CI] = 0.40 [0.19-0.87) were associated with increased and reduced odds for UMFA concentrations > 0.55 nmol/L (median values), respectively. CONCLUSION: UMFA concentrations were directly influenced by folic acid intake from fortified foods in a healthy convenience sample of adult Brazilians exposed to mandatory flour fortification with folic acid. PMID- 28895790 TI - Experiential Avoidance and Bulimic Symptoms among Men in Residential Treatment for Substance Use Disorders: A Preliminary Examination. AB - There has been a growing focus on identifying factors that underlie and maintain bulimic symptoms and substance use disorders (SUDs), as both are associated with high mortality and poor clinical outcomes. Experiential avoidance has been an area of interest within both the eating disorder and SUD fields, as it is a robust risk factor for both disorders. No known research has examined the relationship between experiential avoidance and bulimic symptoms in a SUD treatment-seeking sample. Moreover, the extant literature has focused exclusively on female samples. The purpose of this exploratory study was to examine the relationship between bulimic symptoms and experiential avoidance within an understudied population: men in treatment for a SUD. Three separate hierarchical regression analyses were conducted to examine the following relationships: (1) experiential avoidance and bulimic symptoms; (2) experiential avoidance and alcohol use and problems; and (3) experiential avoidance and drug use and problems. Results demonstrated that, controlling for alcohol and drug use and problems, experiential avoidance was significantly associated with bulimic symptoms. Experiential avoidance was also significantly associated with alcohol use and problems and drug use and problems. These findings are preliminary and future research is needed to further examine this relationship. PMID- 28895791 TI - General Lack of Correlations between Age and Signs of the Metabolic Syndrome in Subjects with Non-diabetic Fasting Glucose Values. AB - BACKGROUND: Insulin resistance and advancing age are well-recognized risk factors for metabolic syndrome. Recent reports indicate that fasting glucose levels in non-diabetic patients correlate appropriately with the development of certain elements in metabolic syndrome, which suggest a cause-effect relationship with insulin resistance. OBJECTIVE: The present investigation assessed whether a significant association exists between chronological age and various elements of metabolic syndrome in this same group of subjects possessing non-diabetic fasting glucose levels. METHODS: Baseline data were taken from 288 subjects (age 17-87 years) with fasting glucose levels <= 125 mg/dl. Correlations between chronological age and different metabolic parameters were assessed to determine any statistically significant relationships and compare these with previously demonstrated metabolic parameters. RESULTS: With the exception of systolic blood pressure, the following correlations between age and components of metabolic syndrome were not significant or even significant in the opposite direction compared to those found in the same population using fasting glucose as the independent variable: body weight, body fat, diastolic blood pressure, white blood cell count (WBC)/neutrophil count, and circulating levels of insulin, high density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Although systolic blood pressure still increased, it was to a lesser extent than might be expected. CONCLUSIONS: In the present investigation, a cross sectional analysis was carried out over a wide age range of subjects. It is noteworthy that fasting glucose levels and the other major elements of metabolic syndrome did not change significantly with advancing age. These results demonstrate that decreasing insulin resistance and fasting glucose levels may be an important way to overcome the adverse effects and perturbations of advancing age-induced consequences of metabolic syndrome. PMID- 28895792 TI - Rash Impulsiveness and Negative Mood, but not Alexithymia or Reward Sensitivity, Differentiate Young to Middle-Aged Chronic Daily Smokers from Never-Smokers. AB - Given the well-established associations of the personality traits alexithymia, impulsivity, and reward sensitivity with problematic use of a variety of substances, including alcohol and cannabis, the present study sought to determine whether daily tobacco smoking is similarly linked to these traits. Male and female adults aged 18 to 40 years were recruited from the local Australian community, allowing comparison of demographically similar samples of current daily smokers (n = 47) to never-smokers (n = 59) on the relevant self-report measures. Multivariate analysis of covariance revealed that current smokers scored significantly higher than never-smokers on indices of negative mood, impulsiveness, and risky alcohol use, after controlling for social desirability. No significant group differences were found on indices of alexithymia, reward sensitivity, or punishment sensitivity. Results suggest that chronic daily cigarette smoking may be an exception to the maladaptive behaviors associated with alexithymia, and is driven primarily by mood regulation and poor impulse control. PMID- 28895793 TI - Food Stabilizing Antioxidants Increase Nutrient Bioavailability in the in Vitro Model. AB - OBJECTIVE: We investigated whether antioxidants may enhance bioavailability of lipids and carbohydrates and therefore increase the risk of obesity development. METHODS: We tested how supplementation with antioxidants (0.01% butylated hydroxytoluene [BHT], alpha-tocopherol, and green tea catechins) of a diet containing butter and wheat bread affects bioavailability of fats and carbohydrates. The absorption of the in vitro digested diet was estimated in the intestinal epithelia model of the Caco-2 cells cultured in Transwell chambers. RESULTS: In the case of the antioxidant-supplemented diets, we observed increased bioavailability of glucose, cholesterol, and lipids, as well as elevated secretion of the main chylomicron protein apoB-48 to the basal compartment. Importantly, we did not detect any rise in the concentrations of lipid peroxidation products (malondialdehyde, MDA) in the control samples prepared without antioxidants. CONCLUSIONS: Addition of antioxidants (in particular BHT) to the diet increases bioavailability of lipids and carbohydrates, which consequently may increase the risk of obesity development. The dose of antioxidants is a factor of fundamental importance, particularly for catechins: low doses increase absorption of lipids, whereas high doses exert the opposite effect. PMID- 28895794 TI - Effect of a Short-Course Treatment with Synbiotics on Plasma p-Cresol Concentration in Kidney Transplant Recipients. AB - OBJECTIVE: We evaluated whether a short-term course with synbiotics may lower plasma p-Cresol concentrations in kidney transplant patients (KTRs) who accumulate this uremic toxin both because of increased production by their dysbiotic gut microbiome and because of reduced elimination by the transplanted kidneys. METHODS: Thirty-six KTRs (29 males, mean age 49.6 +/- 9.1 years) with transplant vintage > 12 months, stable graft function, and no episode of acute rejection or infection in the last 3 months were enrolled in this single-center, parallel-group, double-blinded, randomized (2:1 synbiotic to placebo) study. Synbiotic (Probinul Neutro, CadiGroup, Rome, Italy) or placebo was taken at home for 30 days, as 5 g powder packets dissolved in water three times a day far from meals. The main outcome measure was the decrease in total plasma p-Cresol measured by high-performance liquid chromatography at baseline and after 15 and 30 days of placebo or synbiotic treatment. RESULTS: After 15 and 30 days of treatment, plasma p-Cresol decreased by 40% and 33% from baseline (both p < 0.05), respectively, in the synbiotic group, whereas it remained stable in the placebo group. After 30 days of treatment, no significant change was observed in either group in renal function, glycemia, plasma lipids, or albumin concentration. Treatment was well tolerated and did not induce any change in stool characteristics. CONCLUSION: The results of this pilot study suggest that treatment with synbiotics may be effective to lower plasma p-Cresol concentrations in KTRs. Prospective larger scale, longer term studies are needed to establish whether cardiovascular prognosis could also be improved with this nutritional intervention. PMID- 28895795 TI - Glycan characterization of the NIST RM monoclonal antibody using a total analytical solution: From sample preparation to data analysis. AB - Glycosylation is an important attribute of biopharmaceutical products to monitor from development through production. However, glycosylation analysis has traditionally been a time-consuming process with long sample preparation protocols and manual interpretation of the data. To address the challenges associated with glycan analysis, we developed a streamlined analytical solution that covers the entire process from sample preparation to data analysis. In this communication, we describe the complete analytical solution that begins with a simplified and fast N-linked glycan sample preparation protocol that can be completed in less than 1 hr. The sample preparation includes labelling with RapiFluor-MS tag to improve both fluorescence (FLR) and mass spectral (MS) sensitivities. Following HILIC-UPLC/FLR/MS analyses, the data are processed and a library search based on glucose units has been included to expedite the task of structural assignment. We then applied this total analytical solution to characterize the glycosylation of the NIST Reference Material mAb 8761. For this glycoprotein, we confidently identified 35 N-linked glycans and all three major classes, high mannose, complex, and hybrid, were present. The majority of the glycans were neutral and fucosylated; glycans featuring N-glycolylneuraminic acid and those with two galactoses connected via an alpha1,3-linkage were also identified. PMID- 28895796 TI - Prevalence and severity of fatigue in adolescents and young adults with acquired brain injury: A nationwide study. AB - OBJECTIVE: To investigate the prevalence and severity of fatigue in adolescents and young adults with acquired brain injury (ABI) compared with healthy controls (HCs) and to examine associations between fatigue and gender, age and level of education. METHODS: This cross-sectional study included 15-30 year old patients with ABI and a convenience sample of 15-30 year old HCs. All participants completed the 20-item Multidimensional Fatigue Inventory (MFI-20). Pathological fatigue was defined as "General Fatigue" >=12. Adjusted mean differences between groups were calculated using multivariate analysis of covariance (MANCOVA). The adjusted prevalence proportion ratio (PPRadj) of pathological fatigue was calculated using Poisson regression. RESULTS: The patients (n = 334) had higher scores than the HCs (n = 168) on all MFI-20 subscales with adjusted mean differences ranging from 1.7 to 4.7 and a higher prevalence of pathological fatigue (73% versus 29%), PPRadj 2.7 (95% confidence interval 2.1-3.5). Female patients experienced more fatigue than males on the "General Fatigue" and "Reduced Activity" subscales, while no gender differences were found in the HC group. Patients and HCs with elementary education had elevated scores on the "Reduced Activity" and "Mental Fatigue" subscales. Age was not associated with any of the subscale scores. CONCLUSION: Young patients with ABI had markedly higher prevalence and severity of fatigue than HCs. Age (15-30 years) was not associated with fatigue. No clear patterns of associations were evident with gender and level of education. ABBREVIATIONS: ABI: acquired brain injury; CI: confidence interval; GF: general fatigue; GOSE: Glasgow Outcome Scale Extended; HC: healthy control; MANCOVA: multivariate analysis of covariance; MF: mental fatigue; MFI-20: Multidimensional Fatigue Inventory-20; PF: physical fatigue; RA: reduced activity; RM: reduced motivation; TBI: traumatic brain injury. PMID- 28895799 TI - Protective effects of bellidifolin in hypoxia-induced in pheochromocytoma cells (PC12) and underlying mechanisms. AB - Bellidifolin, a xanthone compound derived from plants of Gentiana species, is known to exert a variety of pharmacological activities including anti-oxidation, anti-inflammatory and antitumor actions as well as a protective effect on cerebral ischemic nerve injury. The aim of this study was to examine the protective effects of bellidifolin on nerve injury produced by hypoxia and possible underlying mechanisms using pheochromocytoma cells (PC12). Data showed that the viability of PC12 cells subjected to hypoxia resulted in a significant decrease; however; pretreatment with certain concentrations of bellidifolin (20 or 40 MUmol/L) prior to hypoxia significantly increased the survival rate. The results of immunohistochemical staining analysis revealed that there were no marked alterations in the expression of pERK protein between all bellidifolin groups while the expression of p-p38MAPK protein was significantly enhanced by hypoxia. Pretreatment with different concentrations of bellidifolin followed by hypoxia significantly decreased the expression of p-p38MAPK protein. The results of western blot analysis showed that hypoxia induced the expression of the MAPK signaling pathway downstream of the key apoptosis factor caspase-3. Compared to hypoxia, the expression of caspase-3 in the presence of belliidifolin was significantly lower. Data suggest that bellidifolin may contribute to the protective effects associated with nerve injury initiated by hypoxia by mechanisms related to inhibition of cell apoptosis independent of the ERK pathway, but may involve blockade of p38MAPK signaling pathway activation and downstream caspase-3 expression. PMID- 28895798 TI - Nonmedical Opioid Use in Relation to Recency of Heroin Use in a Nationally Representative Sample of Adults in the United States. AB - Nonmedical opioid use has been linked to lifetime heroin use; however, research is needed to examine associations between nonmedical opioid use and current or recent heroin use, as current users appear to be at highest risk for harm. Data were from a nationally representative sample of non-institutionalized adults (age 18-64) in households participating in the National Survey of Drug Use and Health who reported lifetime heroin use (2005-2014, N = 7,111). We examined associations between frequency and recency of nonmedical opioid use and recency of heroin use. Most (86.7%) lifetime heroin users reported no heroin use in the last 12 months, while 6.1% reported current use (use in the last 30 days). The majority of the sample (69.3%) reported lifetime nonmedical opioid use; 14.3% reported nonmedical use in the last 30 days. Adjusted odds for current heroin use increased as frequency of past-year nonmedical opioid use increased, with a quarter (24.7%) of current heroin users reporting nonmedical opioid use on 157-365 days in the last year. Over half (54.7%) of current heroin users reported current nonmedical opioid use. Prevention efforts should consider that high-frequency and current nonmedical opioid use is a robust correlate of continued heroin use. PMID- 28895800 TI - Perpetrators of late life polyvictimization. AB - Most available data about perpetrators of elder abuse are included as part of the description of abuse experienced by older adults. Embedded within this literature is some evidence that perpetrators of elder abuse are involved in polyvictimization. Drawing upon prior empirical research of apparent cases of polyvictimization, this article focuses on what is known about the personal characteristics of perpetrators of polyvictimization, highlights the context of the relationship between perpetrators of polyvictimization and their older adult victims, addresses the potential consequences for perpetrators of polyvictimization, and provides recommendations for future research and practice. Findings elucidate characteristics of and potential outcomes for perpetrators of late life polyvictimization. PMID- 28895801 TI - Prevalence of Sexual Assault Victimization Among College Men, Aged 18-24: A Review. AB - PURPOSE: The current review provides summary and evaluation of prevalence data for the sexual victimization of college men ages 18 - 24. METHODS: Potential studies were selected by searching electronic bibliographic databases. Studies were initially selected for inclusion if they (1) assessed prevalence rates of sexual victimization on college campuses and (2) were published in a scholarly journal (3) in the English language. Utilizing this strategy, 3,973 studies were initially identified, of which 5 underwent complete review. RESULTS: All 5 studies returned results for sexual victimization of men on college campuses. However, identified prevalence data varies widely from 3.2% - 28.7% of the males surveyed. When incapacitation as a form of victimization was included in the study, college men as a whole appear to be most vulnerable to this form of sexual violence, though sexual minority males may have more heterogeneous experiences of victimization. CONCLUSIONS: Conceptualization of sexual victimization and wording of items attempting to assess prevalence rates likely lead to underestimation of true prevalence. Even with an incomplete understanding of prevalence, results suggest that continuing to assess prevalence may not be the most pressing need at this time. Research into the kinds of victimization college men face as well as education, prevention, and intervention within these areas may likely do more to positively advance the knowledge base. PMID- 28895802 TI - Slip and Trip Perturbations During an Object Transport Task Requiring a Lateral Change in Support. AB - The ability to counteract destabilizing external forces while simultaneously executing a complex task presents a novel way to ascertain one's ability to generate adaptive postural control responses to avoid a potential fall. In this study, participants performed an upper limb object transport task requiring a lateral change in support on a robotic platform that could remain fixed in space or translated (mimicking a slip or trip perturbation). No significant stability differences were observed at initial recovery step between slip and trip perturbations. Variability measures were greatest during the trip perturbations; though stability was at its greatest level preceding these perturbations. These results will aid in the design of future studies that will investigate adaptive postural control responses generated by older adults when executing similar, ongoing complex upper body tasks interrupted by a destabilizing support surface perturbation. PMID- 28895803 TI - "Otis": A Case Study of an Online Attempt to Purchase Children for Sex. AB - The researchers analyzed court documents to develop a case study of an individual convicted of buying sexual services from exploited children. Findings indicate that the subject deviates from preexisting victim selection processes and demonstrates characteristics inconsistent with existing sexual offender typologies that likens offender behaviors to the hunting techniques and behaviors of predatory animals. As evidenced in the case study, the individual perceived the victims solely as a means of deviant sexual satiation and did not participate in traditionally established victim acquisition techniques. In addition, the researchers propose adopting terminology that adheres to the term consumer rather than buyer as it better represents some offenders' disconnect and lack of empathy in the victim acquisition process. PMID- 28895797 TI - Neuroendocrine disruption of organizational and activational hormone programming in poikilothermic vertebrates. AB - In vertebrates, sexual differentiation of the reproductive system and brain is tightly orchestrated by organizational and activational effects of endogenous hormones. In mammals and birds, the organizational period is typified by a surge of sex hormones during differentiation of specific neural circuits; whereas activational effects are dependent upon later increases in these same hormones at sexual maturation. Depending on the reproductive organ or brain region, initial programming events may be modulated by androgens or require conversion of androgens to estrogens. The prevailing notion based upon findings in mammalian models is that male brain is sculpted to undergo masculinization and defeminization. In absence of these responses, the female brain develops. While timing of organizational and activational events vary across taxa, there are shared features. Further, exposure of different animal models to environmental chemicals such as xenoestrogens such as bisphenol A-BPA and ethinylestradiol-EE2, gestagens, and thyroid hormone disruptors, broadly classified as neuroendocrine disrupting chemicals (NED), during these critical periods may result in similar alterations in brain structure, function, and consequently, behaviors. Organizational effects of neuroendocrine systems in mammals and birds appear to be permanent, whereas teleost fish neuroendocrine systems exhibit plasticity. While there are fewer NED studies in amphibians and reptiles, data suggest that NED disrupt normal organizational-activational effects of endogenous hormones, although it remains to be determined if these disturbances are reversible. The aim of this review is to examine how various environmental chemicals may interrupt normal organizational and activational events in poikilothermic vertebrates. By altering such processes, these chemicals may affect reproductive health of an animal and result in compromised populations and ecosystem-level effects. PMID- 28895808 TI - Shared decision making after severe stroke-How can we improve patient and family involvement in treatment decisions? AB - People who are well may regard survival with disability as being worse than death. However, this is often not the case when those surviving with disability (e.g. stroke survivors) are asked the same question. Many routine treatments provided after an acute stroke (e.g. feeding via a tube) increase survival, but with disability. Therefore, clinicians need to support patients and families in making informed decisions about the use of these treatments, in a process termed shared decision making. This is challenging after acute stroke: there is prognostic uncertainty, patients are often too unwell to participate in decision making, and proxies may not know the patients' expressed wishes (i.e. values). Patients' values also change over time and in different situations. There is limited evidence on successful methods to facilitate this process. Changes targeted at components of shared decision making (e.g. decision aids to provide information and discussing patient values) increase patient satisfaction. How this influences decision making is unclear. Presumably, a "shared decision-making tool" that introduces effective changes at various stages in this process might be helpful after acute stroke. For example, by complementing professional judgement with predictions from prognostic models, clinicians could provide information that is more accurate. Decision aids that are personalized may be helpful. Further qualitative research can provide clinicians with a better understanding of patient values and factors influencing this at different time points after a stroke. The evaluation of this tool in its success to achieve outcomes consistent with patients' values may require more than one clinical trial. PMID- 28895809 TI - Screening, brief intervention, and referral to treatment (SBIRT) curriculum integration and sustainability: Social work and nursing faculty perspectives. AB - BACKGROUND: The Substance Abuse and Mental Health Services Administration (SAMHSA) has funded grants to universities to provide training and conduct research on the dissemination of Screening, Brief Intervention, and Referral to Treatment (SBIRT) to health care professionals. However, when it comes to integrating SBIRT content into an existing curriculum, difficulties can arise. When there is so much content already in the curriculum, adding more can be challenging. Additionally, some faculty believe that course curricula should be driven by the expertise and knowledge of faculty, not by opportunities afforded because of grant funding. METHODS: Using qualitative semi-structured faculty interviews and thematic data analysis, this study explored the process and content issues surrounding the integration of SBIRT content into the Masters of Social Work (MSW) and Masters of Science in Nursing (MSN) curricula at one university. RESULTS: Guidelines for the successful integration of SBIRT content into MSW and MSN curricula fall into two thematic areas: 1. Encourage buy-in and ownership of SBIRT curriculum development by current faculty. 2. Use a scaffolded approach. SBIRT includes several unique content areas which should be integrated per competencies addressed in each course. SBIRT content areas lend themselves to integration into a range of courses, employing an array of learning techniques and teaching materials. Scaffolding content requires creativity, which serves as the basis of the six subthemes that guide a scaffolded SBIRT integration approach. CONCLUSIONS: SBIRT offers an evidence based intervention that uses a public health approach to reduce harm from substance use. As such, professional nursing and social work education programs should teach SBIRT to their master's level practitioners. This paper proposes guidelines for integrating that content into existing curricula. PMID- 28895807 TI - Global stroke statistics: An update of mortality data from countries using a broad code of "cerebrovascular diseases". AB - Background Current information on mortality attributed to stroke among different countries is important for policy development and monitoring prevention strategies. Unfortunately, mortality data reported to the World Health Organization by different countries are inconsistent. Aims and/or hypothesis To update the repository of the most recent country-specific data on mortality from stroke for countries that provide data using a broad code for "cerebrovascular disease." Methods Data on mortality from stroke were obtained from the World Health Organization mortality database. We searched for countries that provided data, since 1999, on a combined category of "cerebrovascular disease" (code 1609) that incorporated International Classification of Diseases (10th edition) codes I60-I69. Using population denominators provided by the World Health Organization for the same year when available, or alternatively estimates obtained from the United Nations, we calculated crude mortality from "cerebrovascular disease" and mortality adjusted to the World Health Organization world population. We used the most recent year reported to the World Health Organization, as well as comparing changes over time. Results Since 1999, seven countries have provided these mortality data. Among these countries, crude mortality was greatest in the Russian Federation (in 2011), Ukraine (2012), and Belarus (2011) and was greater in women than men in these countries. Crude mortality was positively correlated with the proportion of the population aged >=65 years but not with time. Age adjusted mortality was greatest in the Russian Federation and Turkmenistan, and greater in men than women. Over time, mortality declined, with the greatest decline per annum evident in Kazakhstan (8.7%) and the Russian Federation (7.0%). Conclusions Among countries that provided data to the World Health Organization using a broad category of "cerebrovascular disease," there was a decline in mortality in two of the countries that previously had some of the largest mortality rates for stroke. PMID- 28895810 TI - 10 Notables From Behind the Scenes of the Health Care Reform Debate. AB - This is not meant to be "the 10 most important" people in health care policy. It's a sample from a larger group, and a different group of 10 might have been selected and would have been just as worthy-kind of like admission to a selective college. PMID- 28895811 TI - Outcomes-based Pricing Program Puts Money in Beneficiaries' Pockets. AB - Harvard Pilgrim's program gives rebates to beneficiaries if Repatha doesn't help them avoid a heart attack or stroke. It's just the latest in a growing number of outcomes-based pricing agreements in which an insurer can get a discount from a drugmaker if a drug doesn't help patients as much as expected. PMID- 28895812 TI - Tom Price, the ACA's Ardent Foe, Pushes For Repeal and Replace-With a Smile. AB - Price, 62, with pure white hair, rimless glasses, and an easy, slightly cherubic smile, comes across like a friendly, family doctor, not the ambitious, politically-minded orthopedic surgeon that he is. He calls the ACA "useless" because of the high deductibles. PMID- 28895813 TI - Mark Bertolini Wants To Take the 'Nasty' Out of Insurance. AB - The CEO and chairman of Aetna has a penchant for pulling headline-grabbing moves lately, including a high-profile departure from the industry's leading trade association, America's Health Insurance Plans, and an attempt to acquire another big-five insurer, Humana, then pulling out when the Justice Department opposed it. PMID- 28895814 TI - Scott Gottlieb Believes a Nimbler, Speedier FDA Can Spur Competition, Lower Prices. AB - The new head of the FDA might as well be starring alongside Tom Cruise in the latest installment of Mission Impossible. Since being named commissioner in May, Gottlieb has said he wants the FDA to speed the approval process for generic drugs, introduce competition to drive down prices, and get the opioid crisis under control. PMID- 28895816 TI - Bernard Tyson Preaches Gospel of Tech-and Change. AB - Kaiser Permanente's CEO says that if he were redesigning Kaiser from the ground up, he would begin with a technology platform, not with hospitals, and that "telehealth is going to be our future." He sees a future in which consumers know their bodies at least as well as they know their cars. PMID- 28895815 TI - Seema Verma Does Her Homework, Pushes for Beneficiaries To Have More Skin in the Game. AB - The new head of CMS recently wrote the nation's governors urging that Medicaid recipients be required to pay premiums, be charged for ER visits, and be encouraged to get jobs or job training. This "skin in the game" approach appeals to conservatives, though critics say it can depress participation among the poor. PMID- 28895817 TI - Elizabeth Rosenthal, a Storyteller Who Hopes Her Telling Will Make a Difference. AB - As editor-in-chief of the increasingly influential Kaiser Health News, she hopes to push back against a health care system in which every sector seems rigged against the patient. She leads a staff of 25 editors and reporters that includes two deep-digging data whizzes. PMID- 28895818 TI - James Capretta, a Conservative Health Care Policy Expert, Is Suddenly a Hot Ticket. AB - The conservative voice of reason on American health care policy and a fellow at the American Enterprise Institute says that "It would be far preferable for the country to reach some stability around health policy that both parties bought into." PMID- 28895819 TI - Paula Steiner Brings Her Blues Back Into the Black. AB - The president and CEO of Chicago-based Health Care Service Corp. made tough decisions to raise premiums and narrow networks. But, at least for now, HCSC plans to stay in the ACA exchanges while other insurers are jumping ship. PMID- 28895820 TI - Bob Kocher Believes (With Missionary Zeal) That Venture Capital Can Start To Cure What Ails American Health Care. AB - This upbeat doctor-policymaker-entrepreneur sees opportunity where others see a federal policy train wreck these days. For instance, he's pleased that both political parties seem to endorse a shift from fee-for-service to value-based care. However, continuing uncertainty about the individual market may chill new investment in that area for a while. PMID- 28895821 TI - ACOs Sit Like Gibraltar in Rough Seas of Change. AB - The ACO, a creature of the ACA that often gets confused with its progenitor, seems like it will survive-and maybe even thrive-in whatever healthscape emerges from the Republican anti-ACA push. But just what will happen to the various forms of the ACO that are now in place? PMID- 28895823 TI - Medical Travel Helps Unions, Employers Improve Cost and Quality of Care. AB - Not all medical travel programs are created equal, so employers should shop with a discerning eye. Most programs use a "proprietary" method to evaluate and select high-quality providers for their networks. It is important to ask questions. PMID- 28895822 TI - Navigating the Changing Tides of Health Care: 5 Areas for Leaders To Watch. AB - Questions abound. Which trends will take hold-and which will fizzle? What will market conditions be like six, 12, or 18 months from now? Are there moves to make without compromising what you've worked so hard to achieve? Here's what to look for. PMID- 28895824 TI - Value-based Care Will Flop Without Clinical Integration. AB - Value-based payment is gaining traction and proving to be a major factor in health care reform. But the success of those value-based models will depend on true clinical integration of providers-not just lip service to coordination. PMID- 28895825 TI - Management of a Rare Disease Population: A Model for Identifying a Patient Population With Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex (TSC) is a rare genetic disorder affecting the brain and other vital organs with varying symptoms and severity among patients. This study developed and validated a risk model to identify patients with TSC using large databases of medical and pharmacy claims. PMID- 28895826 TI - Trying for Association Health Plans Again and Again and Again. AB - Business groups like the U.S. Chamber of Commerce and the National Federation of Independent Business endorse association health plans (AHPs) as a way to give employers more options beyond the strictures of the Affordable Care Act. PMID- 28895827 TI - After a Big Entrance, It's Just So-So for Entresto. AB - Some industry observers wonder why the wunderkind hasn't done more wonderfully on the market. As a brand name drug, Entresto costs substantially more than the generic ACE inhibitors and ARBs. GoodRx reports the average cash price for uninsured patients for Entresto is $504 per month, compared with $44 for enalapril. PMID- 28895828 TI - New Caution About Risk Adjustment After United Whistleblower Lawsuit. AB - Did UnitedHealthcare's risk adjustment department actually "turn on the gas," as one executive put it, in an illegal effort to increase revenue? That's the claim at the heart of two cases the federal Department of Justice brought this spring against the nation's largest health insurer. The industry is watching closely. PMID- 28895829 TI - In Utah, Process Measures Are Winning Friends, Influencing Outcomes. AB - Choosing the right blend of quality metrics for each DRG is one of the many intricacies of Value-Driven Outcomes (VDOs), Utah's answer to the challenge of how to "do" value-based care. An initiative five years in the making, VDO matches indicators of quality to DRGs with substantial variation in cost within Utah's own system. PMID- 28895830 TI - California Dreamin', But Will It Stay That Way? AB - Medicaid expansion and Covered California's $100 million marketing plan makes the individual insurance market viable. This, even though premiums have gone up in the past few years (4.2% in 2015, 4% in 2016, 13.3% in 2017), and a movement to install a single-payer system would blow up the private insurance market. PMID- 28895831 TI - Texas: A Health Insurance Two-Step. AB - The Lone Star State continues to lead the country in the percentage of its residents without health insurance, although a dent has been made. As of 2015, 17% of Texans were uninsured, compared with 22% two years before, according to the most recent census bureau data. PMID- 28895832 TI - Sunny for Florida Blue, but It's Partly Cloudy in Sunshine State. AB - The ACA drove down the uninsured rate despite the lack of Medicare expansion, but major insurers have left the market. In some rural areas, Florida Blue is the only health plan in the game. Also in the mix: Consumers here usually pick the lowest-cost plan available. PMID- 28895833 TI - Tennessee: Individual Market Just Barely Viable-For Now. AB - Those who say the ACA is collapsing often point to Tennessee as evidence. And Gov. Bill Haslam has called it "ground zero" for plans pulling out of the ACA marketplaces. To give just one example, UnitedHealthcare left the individual market in the state at the end of 2016. PMID- 28895834 TI - Pennsylvania's Individual Market Seems To Be Slowly Stabilizing. AB - After premiums for 2017 increased, on average, by 32.5% over premiums for coverage in 2016, rate filings by insurers for 2018 show rates going up by only 8.8% over 2017 rates. But it could take at least five years for the ACA exchanges to shake all the bugs out. PMID- 28895835 TI - Massachusetts: What Universal Coverage Could Look Like. AB - The lowest rate of uninsured, but costs are a concern. That's due, in part, to the clout of the state's large prestigious health care systems, especially Partners Healthcare in Boston, which includes Harvard-affiliated Massachusetts General Hospital, and Brigham and Women's hospitals. PMID- 28895836 TI - Demographics, Geography Make for an Uphill Battle. AB - Maine presents some daunting challenges when it comes to insurance coverage and health care costs because it's both the most rural state in the country and the one with the highest median age, two factors that drive up health spending. PMID- 28895837 TI - Minnesota: A Health Care Island Scrambles To Stay Afloat. AB - The Democratic governor and the Republican legislature have moved to shore up the individual market, but Minnesotans are leaving it in droves. About 167,000 residents bought individual coverage this year, compared with 270,000 in 2016. Premium hikes have been caused, in part, by the consolidation of providers. PMID- 28895838 TI - Why a Strong Consumer-Centered Strategy Will Never Go Out of Style. AB - The awakening of the health care consumer is powerfully good news for the mission of providers and payers. In other industries, the same forces have led to innovation, cost reduction, and heightened value. We should expect health care to be no different. PMID- 28895839 TI - Ocrevus's Role in MS Battle May Signal Promising Trend. AB - With a list price that is 25% less than a competing drug, better outcomes, and less frequent dosing, maybe Ocrevus will start a new trend: better outcomes, easier administration-and a lower price. That trifecta is great news for people managing the cost and quality of MS care. PMID- 28895841 TI - From the Editor. PMID- 28895840 TI - Crucial role for T cell-intrinsic IL-18R-MyD88 signaling in cognate immune response to intracellular parasite infection. AB - MyD88 is the main adaptor molecule for TLR and IL-1R family members. Here, we demonstrated that T-cell intrinsic MyD88 signaling is required for proliferation, protection from apoptosis and expression of activation/memory genes during infection with the intracellular parasite Trypanosoma cruzi, as evidenced by transcriptome and cytometry analyses in mixed bone-marrow (BM) chimeras. The lack of direct IL-18R signaling in T cells, but not of IL-1R, phenocopied the absence of the MyD88 pathway, indicating that IL-18R is a critical MyD88-upstream pathway involved in the establishment of the Th1 response against an in vivo infection, a presently controvert subject. Accordingly, Il18r1-/- mice display lower levels of Th1 cells and are highly susceptible to infection, but can be rescued from mortality by the adoptive transfer of WT CD4+ T cells. Our findings establish the T-cell intrinsic IL-18R/MyD88 pathway as a crucial element for induction of cognate Th1 responses against an important human pathogen. PMID- 28895843 TI - Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy. AB - Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials. PMID- 28895842 TI - Adherence to antihypertensive medications and associations with blood pressure among African Americans with hypertension in the Jackson Heart Study. AB - The purpose of this study was to test the association between a self-report measure of 24-hour adherence to antihypertensive medication and blood pressure (BP) among African Americans. The primary analysis included 3558 Jackson Heart Study participants taking antihypertensive medication who had adherence data for at least one study examination. Nonadherence was defined by self-report of not taking one or more prescribed antihypertensive medications, identified during pill bottle review, in the past 24 hours. Nonadherence and clinic BP were assessed at Exam 1 (2000-2004), Exam 2 (2005-2008), and Exam 3 (2009-2013). Associations of nonadherence with clinic BP and uncontrolled BP (systolic BP >= 140 mm Hg or diastolic BP >= 90 mm Hg) were evaluated using unadjusted and adjusted linear and Poisson repeated measures regression models. The prevalence of nonadherence to antihypertensive medications was 25.4% at Exam 1, 28.7% at Exam 2, and 28.5% at Exam 3. Nonadherence was associated with higher systolic BP (3.38 mm Hg) and diastolic BP (1.47 mm Hg) in fully adjusted repeated measures analysis. Nonadherence was also associated with uncontrolled BP (prevalence ratio = 1.26; 95% confidence interval = 1.16-1.37). This new self-report measure may be useful for identifying nonadherence to antihypertensive medication in future epidemiologic studies. PMID- 28895844 TI - Integrating Vectors for Gene Therapy and Clonal Tracking of Engineered Hematopoiesis. AB - Gene therapy using autologous or allogeneic cells offers promising possibilities to treat inherited and acquired diseases, ideally leading to a long-lasting therapeutic correction. This article summarizes efforts that use integrating vectors derived from retroviruses and transposons, and briefly explains integrating vector biology and integration site analysis and recent successful application of this technology in clinical trials. Moreover, outlined is how these vectors can be used for cancer gene discovery and clonal tracking of benign and malignant hematopoiesis to gain insights into the dynamics of hematopoiesis. PMID- 28895845 TI - Nonintegrating Gene Therapy Vectors. AB - Gene delivery vectors that do not rely on host cell genome integration offer several advantages for gene transfer, chiefly the avoidance of insertional mutagenesis and position effect variegation. However, unless engineered for replication and segregation, nonintegrating vectors will dilute progressively in proliferating cells, and are not exempt of epigenetic effects. This article provides an overview of the main nonintegrating viral (adenoviral, adeno associated viral, integration-deficient retro-lentiviral, poxviral), and nonviral (plasmid vectors, artificial chromosomes) vectors used for preclinical and clinical cell and gene therapy applications. Particular emphasis is placed on their use in hematologic disease. PMID- 28895847 TI - Therapeutic Gene Editing Safety and Specificity. AB - Therapeutic gene editing is significant for medical advancement. Safety is intricately linked to the specificity of the editing tools used to cut at precise genomic targets. Improvements can be achieved by thoughtful design of nucleases and repair templates, analysis of off-target editing, and careful utilization of viral vectors. Advancements in DNA repair mechanisms and development of new generations of tools improve targeting of specific sequences while minimizing risks. It is important to plot a safe course for future clinical trials. This article reviews safety and specificity for therapeutic gene editing to spur dialogue and advancement. PMID- 28895846 TI - In Vivo Hematopoietic Stem Cell Transduction. AB - Current protocols for hematopoietic stem cell (HSC) gene therapy, involving the transplantation of ex vivo lentivirus vector-transduced HSCs into myeloablated recipients, are complex and not without risk for the patient. In vivo HSC gene therapy can be achieved by the direct modification of HSCs in the bone marrow after intraosseous injection of gene delivery vectors. A recently developed approach involves the mobilization of HSCs from the bone marrow into peripheral the blood circulation, intravenous vector injection, and re-engraftment of genetically modified HSCs in the bone marrow. We provide examples for in vivo HSC gene therapy and discuss advantages and disadvantages. PMID- 28895848 TI - Gene Editing: Regulatory and Translation to Clinic. AB - The clinical application and regulatory strategy of genome editing for ex vivo cell therapy is derived from the intersection of two fields of study: viral vector gene therapy trials; and clinical trials with ex vivo purification and engraftment of CD34+ hematopoietic stem cells, T cells, and tumor cell vaccines. This article covers the regulatory and translational preclinical activities needed for a genome editing clinical trial modifying hematopoietic stem cells and the genesis of this current strategy based on previous clinical trials using genome-edited T cells. The SB-728 zinc finger nuclease platform is discussed because this is the most clinically advanced genome editing technology. PMID- 28895849 TI - Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy. AB - Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old. Thus, pharmacokinetic monitoring is needed to achieve the targeted exposure goal for busulfan. PMID- 28895850 TI - Gene Therapy Approaches to Immunodeficiency. AB - Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes. This review reflects the progresses made in specific disorders, including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. PMID- 28895852 TI - Gene Therapy for Hemophilia. AB - The best currently available treatments for hemophilia A and B (factor VIII or factor IX deficiency, respectively) require frequent intravenous infusion of highly expensive proteins that have short half-lives. Factor levels follow a saw tooth pattern that is seldom in the normal range and falls so low that breakthrough bleeding occurs. Most hemophiliacs worldwide do not have access to even this level of care. In stark contrast, gene therapy holds out the hope of a cure by inducing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the hemophilic patient's own defective gene. PMID- 28895851 TI - Gene Therapy Approaches to Hemoglobinopathies. AB - Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with a lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Preclinical and early clinical studies showed the safety and potential efficacy of this therapeutic approach as well as the hurdles still limiting its general application. In addition, for both beta-thalassemia and sickle cell disease, an altered bone marrow microenvironment reduces the efficiency of stem cell harvesting as well as engraftment. These hurdles need be addressed for gene therapy for hemoglobinopathies to become a clinical reality. PMID- 28895853 TI - Hematopoietic Gene Therapies for Metabolic and Neurologic Diseases. AB - Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. PMID- 28895854 TI - Gene Therapy Approaches to Human Immunodeficiency Virus and Other Infectious Diseases. AB - Advances in gene therapy technologies, particularly in gene editing, are suggesting new avenues for the treatment of human immunodeficiency virus and other infectious diseases. This article outlines recent developments in antiviral gene therapies, including those based on the disruption of entry receptors or that target viral genomes using targeted nucleases, such as the CRISPR/Cas9 system. In addition, new ways to express circulating antiviral factors, such as antibodies, and approaches to harness and engineer the immune system to provide an antiviral effect that is not naturally achieved are described. PMID- 28895855 TI - Hematopoietic Stem Cell Approaches to Cancer. AB - Hematopoietic stem cells (HSCs) are unique in their ability to self-renew and generate all blood lineages for the entire life. HSC modification affects red blood cells, platelets, lymphocytes, and myeloid cells. Chemotherapy can result in myelosuppression, limiting effective chemotherapy administration. For diseases like glioblastoma, high expression of methlylguanine methyltransferase can inactivate alkylating agent chemotherapy. Here we discuss how HSCs can be modified to overcome this resistance, permitting sensitization of tumors to chemotherapy while simultaneously protecting the hematopoietic system. We also discuss how HSCs can be harnessed to produce powerful tumor killing T cells, potentially benefitting and complementing T-cell-based immunotherapies. PMID- 28895856 TI - Gene Modified T Cell Therapies for Hematological Malignancies. AB - This article focuses on clinical applications of T cells transduced to express recombinant T cell receptor and chimeric antigen receptor constructs directed toward hematological malignancies, and considers newer strategies incorporating gene-editing technologies to address GvHD and host-mediated rejection. Recent data from clinical trials are reviewed, and an overview is provided of current and emerging manufacturing processes; consideration is also given to new developments in the pipeline. PMID- 28895858 TI - Getting the Right Answer: Four Statistical Principles. PMID- 28895857 TI - Gene Therapy. PMID- 28895859 TI - Evidence Supporting the Effectiveness of Transition Programs for Youth With Special Health Care Needs. AB - More than 90% of adolescents and young adults with chronic medical conditions will survive into adulthood. Transitioning from pediatric to adult health care services for these individuals has often times been associated with deterioration of their health and Quality of Life. Separation from their pediatric provider and lack of preparedness of the adult health care system has been identified as major barriers in preventing the successful transition of these individuals. The purpose of this review is to summarize the available data related to transitioning adolescents and young adults (AYA) with special health care needs into the adult health care system. PMID- 28895860 TI - A rapid IL-17 response to Cryptosporidium parvum in the bovine intestine. AB - Cryptosporidium parvum causes diarrhoea, due to villi damage, in livestock and humans globally. Immunity develops after repeated infections but initial infections can be severe, highlighting the importance of early infection dynamics. We have modelled early C. parvum infection in bovine jejunum biopsies. IL-17A accumulated over time peaking at 9h post-infection, with no effect of infection on IL-1beta; antibiotics positively influenced IL-17A as higher levels were found in cultures with antibiotics. Infection of primary fibroblasts resulted in lower plaque formation when fibroblasts were primed with IL-17A. Our results indicate a role for IL-17A in reducing C. parvum-dependent host cell damage. PMID- 28895861 TI - Integrated effect of seasons and lactation stages on the plasma inflammatory cytokines, function and receptor expression of milk neutrophils in Sahiwal (Bos indicus) cows. AB - Mastitis is a highly prevalent and one of the costliest diseases of dairy cows affecting the mammary gland. Milk neutrophils present in the mammary gland serve as an integral part of the mammary immunity, and their performance is influenced by different environmental conditions and lactation stages. To investigate the combined effects of seasons and lactation stages on the mammary immunity, milk and blood samples were collected from three groups of high producing indigenous Sahiwal cows. Function and receptor expression of milk neutrophils together with cortisol and inflammatory interleukins concentration in blood were studied. The first group of cows started their lactation in winter and completed their lactation in hot-humid season; the second group started their lactation in hot dry season and completed it in winter. The third group started their lactation in hot-humid and completed by the hot-dry season. Plasma cortisol levels were very high during early lactation in all seasons. An inverse relationship was observed between cortisol levels and glucocorticoid receptor. Elevated phagocytic activity and plasma interleukin-2 levels were seen in winter and during mid lactation of all seasons. A positive correlation was noticed between plasma IL-8, the percentage of milk neutrophils and expression of chemokine receptors (CXCR1 and CXCR2). The highest expression of toll-like receptors (TLR2 and TLR4) and chemokine receptors was in hot-humid season. Reduction in the phagocytic activity of neutrophils, pro-inflammatory cytokines and elevated levels of cortisol in cows which started their lactation and attained peak lactation during hot-humid season indicated more stress in them. Integrated influence of both seasons and lactation stages on the activity of milk neutrophils along with plasma interleukins and cortisol levels may be used to develop suitable managemental strategies to improve mammary health and increase milk production in indigenous dairy breeds experiencing harsh environmental conditions. PMID- 28895862 TI - Immunomodulatory effects of soluble factors secreted by feline adipose tissue derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have immunomodulatory functions and differentiation capacity, and their clinical use is increasing in veterinary species. Although MSCs have been applied in the treatment in various inflammatory diseases, mechanistic research on feline MSCs is lacking. Accordingly, in this study, we aimed to investigate the immunomodulatory mechanisms of MSCs isolated from feline adipose tissue (fATMSCs). fATMSCs from healthy cats were cultured in an appropriate manner and cocultured with transwell-separated allogeneic feline peripheral blood mononuclear cells (fPBMCs) and RAW264.7 murine macrophages. After 48h of coculture, RNA was extracted from RAW264.7 cells and fPBMCs. Cytokine expression in these cells was measured using quantitative real-time polymerase chain reaction (qRT-PCR) and compared according to the presence of fATMSCs. The mRNA levels of pro-inflammatory cytokines, e.g., tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase, and interleukin (IL) 1beta, were significantly decreased in cocultures of mitogen-stimulated RAW264.7 cells with fATMSCs compared with that in the RAW264.7 cells control group. Additionally, changes in the expression of mRNAs extracted from fPBMCs were as follows: pro-inflammatory TNF-alpha, interferon-gamma, and IL-6 were decreased, and anti-inflammatory IL-10 was increased during coculture of mitogen-stimulated allogeneic fPBMCs with fATMSCs. We also extracted RNA and collected supernatants from fATMSCs during transwell culture for measurement of the expression and secretion of soluble factors by qRT-PCR and enzyme-linked immunosorbent assays, respectively. The mRNA expression of immunomodulatory factors from fATMSCs, including cyclooxygenase-2 (COX-2), transforming growth factor (TGF)-beta, indoleamine-2,3-dioxygenase (IDO) and hepatocyte growth factor, increased in the presence of RAW264.7 cells. Similarly, TGF-beta, COX-2, and IDO mRNA expression and prostaglandin E2 (PGE2) secretion from fATMSCs increased in the presence of allogeneic fPBMCs. Finally, we measured the viability of fPBMCs under various conditions. Cell viability decreased in fPBMCs suspended in fATMSC-derived conditioned medium, and this reduction was alleviated in the group supplemented with NS-398 a PGE2 inhibitor. Our data suggested that soluble factors, including PGE2, secreted by fATMSCs played an important role in the immunomodulatory effects of these cells. These findings may be helpful in the application of fATMSCs to feline patients with immune-related diseases. PMID- 28895863 TI - A monoclonal antibody for detection of intracellular and secreted interleukin-2 in horses. AB - Interleukin-2 (IL-2) is a T cell growth factor and major modulator of T helper (Th) cell differentiation. Here, we have developed and characterized a monoclonal antibody to equine IL-2 (anti-IL-2 mAb, clone 158-1). The IL-2 mAb detected rIL-2 by ELISA, intracellular staining and flow cytometry analysis and Western blotting. The IL-2 mAb was also paired with a polyclonal IL-2 detection antibody in both ELISA and a fluorescent bead-based assay. When these two assays were compared using identical reagents there was an improved analytical sensitivity (46pg/ml) and wider linear quantification range (46-100,000pg/ml) of IL-2 quantification using the fluorescent bead assay. Equine rIL-2 standards were expressed in both yeast and mammalian cells but the mammalian cell-expressed rIL 2 standard was found to be most accurate for native IL-2 quantification. Using this system we found that stimulation of equine peripheral blood mononuclear cells (PBMC) with phorbol 12-myristate 13-acetate (PMA) and ionomycin induced IL 2 secretion most potently. Pokeweed mitogen (PWM) consistently resulted in low amounts of IL-2 from PBMC, while concanavalin A (ConA), phytohemagglutinin-L (PHA L) and lipopolysaccharide (LPS) either marginally stimulated or failed to stimulate IL-2 secretion from equine PBMC. After stimulation of equine PBMC with PMA and ionomycin, IL-2 production was detected in 13.0% (range 7.5-16.8%) of the lymphocytes by flow cytometric analysis. IL-2 expression was mainly stimulated in CD4+ cells, in a sub-population of CD8+ cells, and also in CD4-/CD8- cell population. In addition, both IFN-gamma+/IL-2+ and IL-4+/IL-2+ producing cells were observed. Testing of serum and colostrum samples from 15 healthy horses showed that IL-2 was not detectable in these samples (<46pg/ml). In summary, the equine IL-2 mAb provides a new tool for the characterization of IL-2 producing equine cells and the quantification of secreted equine IL-2 in sensitive assays. PMID- 28895864 TI - Immunomodulatory potential of beta-glucan as supportive treatment in porcine rotavirus enteritis. AB - A non-blinded randomized clinical trial was conducted to assess the immunomodulatory potential of beta-glucan (BG) in piglet diarrhoea associated with type A rotavirus infection. A total of 12 rotavirus-infected diarrheic piglets were randomly divided into two groups: wherein six rotavirus-infected piglets were treated with supportive treatment (ST) and other six rotavirus infected piglets were treated with BG along with ST (ST-BG). Simultaneously, six healthy piglets were also included in the study which served as control. In rotavirus-infected piglets, marked increase of Intestinal Fatty Acid Binding Protein-2 (I-FABP2), nitric oxide (NOx), Interferon-gamma (IFN-gamma) concentrations and decrease of immunoglobulin G (IgG) were noticed compared to healthy piglets. The faecal consistency and dehydration scores were significantly higher in rotavirus-infected piglets than healthy piglets. The ST-BG treatment progressively reduced the I-FABP2 and increased the IgG concentrations over the time in rotavirus-infected piglets compared to piglets received only ST. A pronounced enhancement of NOx and IFN-gamma concentrations was observed initially on day 3 and thereafter the values reduced on day 5 in ST-BG treated piglets in comparison to piglets which received only ST. Additionally, ST-BG treatment significantly reduced faecal consistency and dehydration scores on day 3 compared to ST in rotavirus-infected piglets. These findings point that BG represents a potential additional therapeutic option to improve the health condition and reduce the piglet mortality from rotavirus associated diarrhoea where porcine rotavirus vaccine is not available. PMID- 28895865 TI - Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells. AB - Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92+/-6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37+/-0.8%, 40+/-8%, 41+/-4%, 23+/-3% and 19+/-5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell cultures were successfully established and characterized and they supported the proliferation of red bone marrow hematopoietic cells, which finally differentiated into monocytic cells and CD4+ and CD8+ cells. PMID- 28895866 TI - Specific immunotypes of canine T cell lymphoma are associated with different outcomes. AB - Canine lymphoma is a heterogeneous disease with many different subtypes. Lymphoma of T cell type in particular is variable in outcome, and includes subtypes with non-progressive, slowly- and rapidly-progressive disease course. Association of immunotype with disease course is incompletely defined. Here, results of flow cytometric immunotyping of 127 canine T cell lymphomas were analyzed in relation to survival and progression free interval. Samples originated from 101 multicentric, 8 mediastinal, 6 cutaneous, 5 hepatosplenic, 5 gastrointestinal and 2 other anatomic subtypes of T cell lymphoma. Compared to multicentric T cell lymphoma, gastrointestinal lymphoma had shorter survival and progression free interval, and hepatosplenic lymphoma had shorter survival. Among dogs with multicentric T cell lymphoma, immunotypes of CD4+/CD8-/MHCII+, CD4-/CD8+/MHCII+ and CD4-/CD8+/MHCII- were associated with longer survival times than the immunotype of CD4+/CD8-/MHCII-, and immunotypes of CD4+/CD8-/MHCII+, CD4 /CD8+/MHCII-, and CD4-/CD8-/MHCII+ were associated with longer progression free intervals. Dogs with multicentric T cell lymphoma and concurrent leukemia had shorter survival but similar progression free interval compared to those without leukemia. Body weight, sex, hypercalcemia, cell size, expression of CD3 and use of combination or single agent chemotherapy did not significantly affect outcome of multicentric TCL. PMID- 28895867 TI - Markedly different immune responses and virus kinetics in littermates infected with porcine circovirus type 2 or porcine parvovirus type 1. AB - Porcine parvovirus type 1 (PPV1) and porcine circovirus type 2 (PCV2) are small single-stranded DNA viruses with high prevalence in the global pig population. The aim of this study was to compare and contrast PCV2 and PPV1 infections in high-health status pigs and to describe PCV2 long-term infection dynamics. Six caesarian-derived colostrum-deprived pigs were randomly divided into two groups and were experimentally infected with PCV2 or PPV1 at 5 weeks of age. All pigs had detectable viremia by day (D) 3 post-infection. Pigs infected with PPV1 had a detectable INF-alpha response by D3 followed by a high IFN-gamma response by D6. The PPV1 pigs developed antibodies against PPV1 by D6 resulting in decreasing virus titers until PPV1 DNA became undetectable from D28 until D42. In contrast, PCV2-infected pigs had no detectable INF-alpha or IFN-gamma response after PCV2 infection. PCV2-infected pigs had no detectable anti-PCV2 humoral response until D49 and had a sustained high level of PCV2 DNA for the duration of the study. While PPV1-infected pigs were clinically normal, PCV2-infected pigs developed severe clinical illness including fatal systemic porcine circovirus associated disease (PCVAD) by D28, fatal enteric PCVAD by D56 and chronic PCVAD manifested as decreased weight gain and periods of diarrhea. Microscopically, all three PCV2 infected pigs had lymphoid lesions consistent with PCVAD and associated with low (chronic disease) to high (acute disease) levels of PCV2 antigen. Under the study conditions, there was a lack of early IFN-gamma and INF-alpha activation followed by a delayed and low humoral immune response and persisting viremia with PCV2 infection. In contrast, PPV1-infected pigs had IFN-gamma and INF-alpha activation and an effective immune response to the PPV1 infection. PMID- 28895868 TI - Identification of novel biomarkers for treatment monitoring in canine leishmaniosis by high-resolution quantitative proteomic analysis. AB - The objective of this study was to use the Tandem Mass Tag (TMT) isobaric label based proteomic approach, in order to identify new potential biomarkers for the treatment monitoring of canine leishmaniosis that could not be identified by the use of gel-based techniques. For this purpose serum samples were obtained from 5 clinically diseased dogs before and one month after the treatment of canine leishmaniosis. The non-depleted serum samples were subjected to reduction, alkylation and trypsin digestion, and the resulting peptides were labeled using 6 plex TMT reagents. To obtain information about protein identities and relative quantification, liquid chromatography-MS analysis of multiplexed TMT-labeled peptides was employed. This gel-free, label-based quantitative proteomic approach enabled identification of 117 canine proteins. Among these, 23 showed significant difference (p<0.05) in expression (two downregulated and 21 upregulated ranging from 1.25 to 2.5 fold change). Comparison of gel-free TMT-based quantification and a gel-based approach previously applied to the same samples resulted in the identification of some common markers (Apo-A1, vitamin D binding protein and RBP4). However, 20 additional differentially represented proteins were highlighted by the gel-free approach, 13 of which have not been previously reported in canine leishmaniosis. In conclusion, the TMT-based proteomic approach allowed identification of new serum proteins that significantly change in concentration after canine leishmaniosis treatment. These proteins are involved in various physiopathological processes such as inflammatory, coagulation or defense mechanisms, and could potentially be suitable biomarkers for treatment monitoring of this parasitic disease. PMID- 28895869 TI - Amiloride interferes with platelet- activating factor-induced respiratory burst and MMP-9 release in bovine neutrophils independent of Na+/H+ exchanger 1. AB - Cytoplasmic pH homeostasis is required for an appropriate response in polymorphonuclear neutrophils (PMNs). In these cells, chemotaxis and reactive oxygen species (ROS) production are reduced by the use of Na+/H+ exchanger (NHE 1) inhibitors, but these results are mainly obtained using amiloride, a non selective NHE-1 inhibitor. In bovine PMNs, the role of NHE-1 in functional responses has not been confirmed yet. The aim of this study was to determine the role of NHE-1 using amiloride and zoniporide in pH regulation, ROS production, matrix metalloproteinase 9 (MMP-9) release and calcium flux in bovine PMNs induced by the platelet activation factor (PAF), additionally we evaluated the presence of NHE-1 and NHE-2 mRNA Our data show the presence only of NHE-1 but not NHE-2 in bovine PMNs. Amiloride or zoniporide inhibited the intracellular alkalization induced by PAF without affecting calcium flux. Amiloride diminished ROS production and MMP-9 release, while zoniporide enhanced ROS production without change the MMP-9 release induced by PAF. Our work led us to conclude that changes in intracellular pH induced by PAF are regulated by NHE-1 in bovine neutrophils, but the effects of amiloride on ROS production and MMP-9 release induced by PAF are not NHE-1 dependent. PMID- 28895870 TI - Protection of commercial turkeys following inactivated or recombinant H5 vaccine application against the 2015U.S. H5N2 clade 2.3.4.4 highly pathogenic avian influenza virus. AB - Between December 2014 and June 2015, North America experienced the largest recorded foreign animal disease outbreak with over 47 million poultry dead or euthanized from viral exposure to a clade 2.3.4.4 H5 highly pathogenic avian influenza (HPAI) epizootic. Soon after the epizootic began, the U.S. Department of Agriculture (USDA) began testing the efficacy of different vaccines as a possible future control strategy. The aim of these studies were to evaluate the efficacy three H5 vaccines to aid in control of HPAI in commercial turkeys. Three different vaccine technologies were evaluated for efficacy: 1) inactivated reverse genetic laboratory-generated virus encoding a clade 2.3.4.4 H5 hemagglutinin (HA) gene (rgH5), 2) recombinant turkey herpesvirus encoding a clade 2.2. H5 HA (rHVT-AI), and 3) recombinant replication-deficient alphavirus RNA particle vaccine encoding a clade 2.3.4.4 H5 HA (RP-H5). All vaccines tested significantly (P<0.01) increased survival rates between vaccinated and sham vaccinated groups of poults challenged with A/turkey/Minnesota/12582/2015 clade 2.3.4.4 H5N2 HPAI. The rgH5 vaccine had detectable serum hemagglutination inhibition (HI) antibody against the challenge virus, and significantly reduced the frequency and level of viral shedding from oropharyngeal and cloacal swabs at days 2 and 4 post-challenge. Vaccination with only rHVT-AI or RP-H5 was not 100% protective, and failed to significantly reduce viral shedding post-challenge. A combined prime and boost strategy with the rHVT-AI and RP-H5, or rHVT-AI and rgH5, was 100% protective against lethal H5N2 HPAI challenge. Results of these studies led to USDA conditional approval of commercially available recombinant vaccines for use in turkeys as a control measure for clade 2.3.4.4 H5 HPAI epizootics. PMID- 28895871 TI - Type I interferons in the pathogenesis and treatment of canine diseases. AB - Type I interferons (IFNs) such as IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, and IFN-omega represent cytokines, which are deeply involved in the regulation and activation of innate and adaptive immune responses. They possess strong antiviral, antiproliferative, and immunomodulatory activities allowing their use in the therapy of different viral diseases, neoplasms, and immune-mediated disorders, respectively. Initially, treatment strategies were based on nonspecific inducers of type I IFNs, which were soon replaced by different recombinant proteins. Drugs with type I IFNs as active agents are currently used in the treatment of hepatitis B and C virus infection, lymphoma, myeloid leukemia, renal carcinoma, malignant melanoma, and multiple sclerosis in humans. In addition, recombinant feline IFN-omega has been approved for the treatment of canine parvovirus, feline leukemia virus, and feline immunodeficiency virus infections. However, the role of type I IFNs in the pathogenesis of canine diseases remains largely undetermined so far, even though some share pathogenic mechanisms and clinical features with their human counterparts. This review summarizes the present knowledge of type I IFNs and down-stream targets such as Mx and 2',5'-oligoadenylate synthetase proteins in the pathogenesis of infectious and immune-mediated canine diseases. Moreover, studies investigating the potential use of type I IFNs in the treatment of canine lymphomas, melanomas, sarcomas, and carcinomas, canine distemper virus, parvovirus, and papillomavirus infections as well as immune-mediated keratoconjunctivitis sicca and atopic dermatitis are presented. A separate chapter is dedicated to the therapeutic potential of IFN-lambda, a type III IFN, in canine diseases. However, further future studies are still needed to unravel the exact functions of the different subtypes of type I IFNs and their target genes in healthy and diseased dogs and the full potential action of type I IFNs as treatment strategy. PMID- 28895872 TI - Highlights from the 19th Workshop on Vitamin D in Boston, March 29-31, 2016. PMID- 28895874 TI - Charge transport by inverse micelles in non-polar media. AB - Charged inverse micelles play an important role in the electrical charging and the electrodynamics of nonpolar colloidal dispersions relevant for applications such as electronic ink displays and liquid toner printing. This review examines the properties and the behavior of charged inverse micelles in microscale devices in the absence of colloidal particles. It is discussed how charge in nonpolar liquids is stabilized in inverse micelles and how conductivity depends on the inverse micelle size, water content and ionic impurities. Frequently used nonpolar surfactant systems are investigated with emphasis on aerosol-OT (AOT) and poly-isobutylene succinimide (PIBS) in dodecane. Charge generation in the bulk by disproportionation is studied from measurements of conductivity as a function of surfactant concentration and from generation currents in quasi steady state. When a potential difference is applied, the steady-state situation can show electric field screening or complete charge separation. Different regimes of charge transport are identified when a voltage step is applied. It is shown how the transient and steady-state currents depend on the rate of bulk generation, on insulating layers and on the sticking or non-sticking behavior of charged inverse micelles at interfaces. For the cases of AOT and PIBS in dodecane, the magnitude of the generation rate and the type of interaction at the interface are very different. PMID- 28895875 TI - Strong second harmonic generation in two-dimensional ferroelectric IV monochalcogenides. AB - The two-dimensional ferroelectrics GeS, GeSe, SnS and SnSe are expected to have large spontaneous in-plane electric polarization and enhanced shift-current response. Using density functional methods, we show that these materials also exhibit the largest effective second harmonic generation reported so far. It can reach magnitudes up to [Formula: see text] which is about an order of magnitude larger than that of prototypical GaAs. To rationalize this result we model the optical response with a simple one-dimensional two-band model along the spontaneous polarization direction. Within this model the second-harmonic generation tensor is proportional to the shift-current response tensor. The large shift current and second harmonic responses of GeS, GeSe, SnS and SnSe make them promising non-linear materials for optoelectronic applications. PMID- 28895873 TI - Prenatal Serum Concentrations of Brominated Flame Retardants and Autism Spectrum Disorder and Intellectual Disability in the Early Markers of Autism Study: A Population-Based Case-Control Study in California. AB - BACKGROUND: Prior studies suggest neurodevelopmental impacts of polybrominated diphenyl ethers (PBDEs), but few have examined diagnosed developmental disorders. OBJECTIVES: Our aim was to determine whether prenatal exposure to brominated flame retardants (BFRs) is associated with autism spectrum disorder (ASD) or intellectual disability without autism (ID). METHODS: We conducted a population based case-control study including children with ASD (n=545) and ID (n=181) identified from the California Department of Developmental Services and general population (GP) controls (n=418) from state birth certificates. ASD cases were matched to controls by sex, birth month, and birth year. Concentrations of 10 BFRs were measured in maternal second trimester serum samples stored from routine screening. Logistic regression was used to calculate crude and adjusted odds ratios (AOR) for associations with ASD, and separately for ID, compared with GP controls, by quartiles of analyte concentrations in primary analyses. RESULTS: Geometric mean concentrations of five of the six congeners with >=55% of samples above the limit of detection were lower in mothers of children with ASD or ID than in controls. In adjusted analyses, inverse associations with several congeners were found for ASD relative to GP (e.g., quartile 4 vs. 1, BDE-153: AOR=0.56, 95% CI: 0.38, 0.84). When stratified by child sex (including 99 females with ASD, 77 with ID, and 73 with GP), estimates were consistent with overall analyses in boys, but in the opposite direction among girls, particularly for BDE 28 and -47 (AOR=2.58, 95% CI: 0.86, 7.79 and AOR=2.64, 95% CI: 0.97, 7.19, respectively). Similar patterns overall and by sex were observed for ID. CONCLUSIONS: Contrary to expectation, higher PBDE concentrations were associated with decreased odds of ASD and ID, though not in girls. These findings require confirmation but suggest potential sexual dimorphism in associations with prenatal exposure to BFRs. https://doi.org/10.1289/EHP1079. PMID- 28895876 TI - Drilling High Precision Holes in Ti6Al4V Using Rotary Ultrasonic Machining and Uncertainties Underlying Cutting Force, Tool Wear, and Production Inaccuracies. AB - Ti6Al4V alloys are difficult-to-cut materials that have extensive applications in the automotive and aerospace industry. A great deal of effort has been made to develop and improve the machining operations of Ti6Al4V alloys. This paper presents an experimental study that systematically analyzes the effects of the machining conditions (ultrasonic power, feed rate, spindle speed, and tool diameter) on the performance parameters (cutting force, tool wear, overcut error, and cylindricity error), while drilling high precision holes on the workpiece made of Ti6Al4V alloys using rotary ultrasonic machining (RUM). Numerical results were obtained by conducting experiments following the design of an experiment procedure. The effects of the machining conditions on each performance parameter have been determined by constructing a set of possibility distributions (i.e., trapezoidal fuzzy numbers) from the experimental data. A possibility distribution is a probability-distribution-neural representation of uncertainty, and is effective in quantifying the uncertainty underlying physical quantities when there is a limited number of data points which is the case here. Lastly, the optimal machining conditions have been identified using these possibility distributions. PMID- 28895877 TI - Recent Developments of Graphene Oxide-Based Membranes: A Review. AB - Membrane-based separation technology has attracted great interest in many separation fields due to its advantages of easy-operation, energy-efficiency, easy scale-up, and environmental friendliness. The development of novel membrane materials and membrane structures is an urgent demand to promote membrane-based separation technology. Graphene oxide (GO), as an emerging star nano-building material, has showed great potential in the membrane-based separation field. In this review paper, the latest research progress in GO-based membranes focused on adjusting membrane structure and enhancing their mechanical strength as well as structural stability in aqueous environment is highlighted and discussed in detail. First, we briefly reviewed the preparation and characterization of GO. Then, the preparation method, characterization, and type of GO-based membrane are summarized. Finally, the advancements of GO-based membrane in adjusting membrane structure and enhancing their mechanical strength, as well as structural stability in aqueous environment, are particularly discussed. This review hopefully provides a new avenue for the innovative developments of GO-based membrane in various membrane applications. PMID- 28895878 TI - Effect of Oral Pre-Meal Administration of Betaglucans on Glycaemic Control and Variability in Subjects with Type 1 Diabetes. AB - We conducted a double-blind placebo-controlled crossover pilot study to investigate the effect of oat betaglucans (beta-glucan) on glycaemic control and variability in adults with type 1 diabetes (T1D; n = 14). Stomacol(r) tablets (1.53 g of beta-glucan) or placebo (Plac) were administered three times daily before meals for two weeks. Glucose levels were monitored during the second week by continuous glucose monitoring (CGM). There was an increase in basic measures of glycaemic control (maximal glucose value 341 +/- 15 vs. 378 +/- 13 mg/dL for Plac and beta-glucan, p = 0.004), and average daily risk range (62 +/- 5 vs. 79 +/- 4 mg/dL for Plac and beta-glucan, p = 0.003) favouring Plac over beta-glucan, but no increase in the M-value (the weighted average of the glucose values) or other more complex measures. Basic measures of glucose variability were also slightly increased during beta-glucan treatment, with no difference in more complex measures. However, glycaemic variability increased between the first and last two CGM days on Plac, but remained unchanged on beta-glucan. In conclusion, in this pilot study we were unable to demonstrate a general positive effect of beta-glucan before meals on glucose control or variability in T1D. PMID- 28895879 TI - Wireless Technology Recognition Based on RSSI Distribution at Sub-Nyquist Sampling Rate for Constrained Devices. AB - Driven by the fast growth of wireless communication, the trend of sharing spectrum among heterogeneous technologies becomes increasingly dominant. Identifying concurrent technologies is an important step towards efficient spectrum sharing. However, due to the complexity of recognition algorithms and the strict condition of sampling speed, communication systems capable of recognizing signals other than their own type are extremely rare. This work proves that multi-model distribution of the received signal strength indicator (RSSI) is related to the signals' modulation schemes and medium access mechanisms, and RSSI from different technologies may exhibit highly distinctive features. A distinction is made between technologies with a streaming or a non streaming property, and appropriate feature spaces can be established either by deriving parameters such as packet duration from RSSI or directly using RSSI's probability distribution. An experimental study shows that even RSSI acquired at a sub-Nyquist sampling rate is able to provide sufficient features to differentiate technologies such as Wi-Fi, Long Term Evolution (LTE), Digital Video Broadcasting-Terrestrial (DVB-T) and Bluetooth. The usage of the RSSI distribution-based feature space is illustrated via a sample algorithm. Experimental evaluation indicates that more than 92% accuracy is achieved with the appropriate configuration. As the analysis of RSSI distribution is straightforward and less demanding in terms of system requirements, we believe it is highly valuable for recognition of wideband technologies on constrained devices in the context of dynamic spectrum access. PMID- 28895880 TI - The Role of Vitamin D in Thyroid Diseases. AB - The main role of vitamin D is regulating bone metabolism and calcium and phosphorus homeostasis. Over the past few decades, the importance of vitamin D in non-skeletal actions has been studied, including the role of vitamin D in autoimmune diseases, metabolic syndromes, cardiovascular disease, cancers, and all-cause mortality. Recent evidence has demonstrated an association between low vitamin D status and autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease, and impaired vitamin D signaling has been reported in thyroid cancers. This review will focus on recent data on the possible role of vitamin D in thyroid diseases, including autoimmune thyroid diseases and thyroid cancers. PMID- 28895881 TI - De Novo Assembly and Analysis of Polygonatum sibiricum Transcriptome and Identification of Genes Involved in Polysaccharide Biosynthesis. AB - Polygonatum sibiricum polysaccharides (PSPs) are used to improve immunity, alleviate dryness, promote the secretion of fluids, and quench thirst. However, the PSP biosynthetic pathway is largely unknown. Understanding the genetic background will help delineate that pathway at the molecular level so that researchers can develop better conservation strategies. After comparing the PSP contents among several different P. sibiricum germplasms, we selected two groups with the largest contrasts in contents and subjected them to HiSeq2500 transcriptome sequencing to identify the candidate genes involved in PSP biosynthesis. In all, 20 kinds of enzyme-encoding genes were related to PSP biosynthesis. The polysaccharide content was positively correlated with the expression patterns of beta-fructofuranosidase (sacA), fructokinase (scrK), UDP glucose 4-epimerase (GALE), Mannose-1-phosphate guanylyltransferase (GMPP), and UDP-glucose 6-dehydrogenase (UGDH), but negatively correlated with the expression of Hexokinase (HK). Through qRT-PCR validation and comprehensive analysis, we determined that sacA, HK, and GMPP are key genes for enzymes within the PSP metabolic pathway in P. sibiricum. Our results provide a public transcriptome dataset for this species and an outline of pathways for the production of polysaccharides in medicinal plants. They also present more information about the PSP biosynthesis pathway at the molecular level in P. sibiricum and lay the foundation for subsequent research of gene functions. PMID- 28895882 TI - Physiological and Transcriptomic Responses of Chinese Cabbage (Brassica rapa L. ssp. Pekinensis) to Salt Stress. AB - Salt stress is one of the major abiotic stresses that severely impact plant growth and development. In this study, we investigated the physiological and transcriptomic responses of Chinese cabbage "Qingmaye" to salt stress, a main variety in North China. Our results showed that the growth and photosynthesis of Chinese cabbage were significantly inhibited by salt treatment. However, as a glycophyte, Chinese cabbage could cope with high salinity; it could complete an entire life cycle at 100 mM NaCl. The high salt tolerance of Chinese cabbage was achieved by accumulating osmoprotectants and by maintaining higher activity of antioxidant enzymes. Transcriptomic responses were analyzed using the digital gene expression profiling (DGE) technique after 12 h of treatment by 200 mM NaCl. A total of 1235 differentially expressed genes (DEGs) including 740 up- and 495 down-regulated genes were identified. Functional annotation analyses showed that the DEGs were related to signal transduction, osmolyte synthesis, transcription factors, and antioxidant proteins. Taken together, this study contributes to our understanding of the mechanism of salt tolerance in Chinese cabbage and provides valuable information for further improvement of salt tolerance in Chinese cabbage breeding programs. PMID- 28895883 TI - The Effects of Resveratrol on Inflammation and Oxidative Stress in a Rat Model of Chronic Obstructive Pulmonary Disease. AB - Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans 3,5,4'-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1alpha in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1alpha expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1alpha signaling pathways. Thus resveratrol might be a therapeutic modality in COPD. PMID- 28895884 TI - Interaction of Recombinant Gallus gallus SEPT5 and Brain Proteins of H5N1-Avian Influenza Virus-Infected Chickens. AB - Septin forms a conserved family of cytoskeletal guanosine triphosphate (GTP) binding proteins that have diverse roles in protein scaffolding, vesicle trafficking, and cytokinesis. The involvement of septins in infectious viral disease pathogenesis has been demonstrated by the upregulation of SEPT5 protein and its mRNA in brain tissues of H5N1-infected chickens, thus, providing evidence for the potential importance of this protein in the pathogenesis of neurovirulence caused by the avian influenza virus. In this study, cloning, expression, and purification of Gallus gallus SEPT5 protein was performed in Escherichia coli. The SEPT5 gene was inserted into the pRSETB expression vector, transformed in the E. coli BL21 (DE3) strain and the expression of SEPT5 protein was induced by IPTG. The SEPT5 protein was shown to be authentic as it was able to be pulled down by a commercial anti-SEPT5 antibody in a co-immunoprecipitation assay. In vivo aggregation of the recombinant protein was limited by cultivation at a reduced temperature of 16 degrees C. Using co-immunoprecipitation techniques, the purified recombinant SEPT5 protein was used to pull down host's interacting or binding proteins, i.e., proteins of brains of chickens infected with the H5N1 influenza virus. Interacting proteins, such as CRMP2, tubulin proteins, heat-shock proteins and other classes of septins were identified using LCMS/MS. Results from this study suggest that the codon-optimized SEPT5 gene can be efficiently expressed in the E. coli bacterial system producing authentic SEPT5 protein, thus, enabling multiple host's proteins to interact with the SEPT5 protein. PMID- 28895885 TI - Anaplastic Lymphoma Kinase in Cutaneous Malignancies. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been implicated in the pathogenesis of a variety of neoplasms. As suggested by its name, ALK was first described as part of a translocation product in cases of anaplastic large-cell lymphoma, with other genetic and cytogenetic ALK mutations subsequently coming to attention in the development of many other hematologic and solid organ malignancies. ALK has now been shown to play a role in the pathogenesis of several cutaneous malignancies, including secondary cutaneous systemic anaplastic large-cell lymphoma (ALCL) and primary cutaneous ALCL, melanoma, spitzoid tumors, epithelioid fibrous histiocytoma, Merkel cell carcinoma, and basal cell carcinoma. The characterization of ALK-positivity in these cutaneous malignancies presents exciting opportunities for utilizing ALK targeted inhibitors in the treatment of these diseases. PMID- 28895887 TI - A Micronutrient Fortified Beverage Given at Different Dosing Frequencies Had Limited Impact on Anemia and Micronutrient Status in Filipino Schoolchildren. AB - This study evaluated the effects of a multi-micronutrient fortified juice drink given in different frequencies of consumption on hemoglobin (Hb) concentration of schoolchildren. Hb was measured in 2423 schoolchildren aged 6- to 9-years-old at baseline. All anemic children (n = 246) were randomly allocated into groups: Daily dose (HD: high dose), 5X/week (MD: Moderate Dose), 3X/week (LD: Low Dose) and unfortified (Control). Pre- and post-study measurements of micronutrients were collected from 228 children. At the endpoint, significant Hb increases were observed in all groups, but there was no significant difference between groups. There was a significant reduction in anemia prevalence in all groups from 100% to 36% (Control), 30% (LD), 23% (MD) and 26% (HD). No dose-response effect was observed in Hb in this population. Most likely, this resulted from better than expected micronutrient status and lower than expected severity of anemia and micronutrient deficiencies in this cohort. It is unlikely that the addition of a fortified beverage to school feeding programs in this population would have a positive impact. Whether such an intervention would be cost-effective as a preventative approach needs to be assessed. This study demonstrates the importance of targeting such interventions to appropriate populations. PMID- 28895886 TI - Immunopathogenesis of HPV-Associated Cancers and Prospects for Immunotherapy. AB - Human papillomavirus (HPV) infection is a causative factor for various cancers of the anogenital region and oropharynx, and is supposed to play an important cofactor role for skin carcinogenesis. Evasion from immunosurveillance favors viral persistence. However, there is evidence that the mere presence of oncogenic HPV is not sufficient for malignant progression and that additional tumor promoting steps are required. Recent studies have demonstrated that HPV transformed cells actively promote chronic stromal inflammation and conspire with cells in the local microenvironment to promote carcinogenesis. This review highlights the complex interplay between HPV-infected cells and the local immune microenvironment during oncogenic HPV infection, persistence, and malignant progression, and discusses new prospects for diagnosis and immunotherapy of HPV associated cancers. PMID- 28895888 TI - Health Effects of Ambient Air Pollution in Developing Countries. AB - The deleterious effects of ambient air pollution on human health have been consistently documented by many epidemiologic studies worldwide, and it has been calculated that globally at least seven million deaths are annually attributable to the effects of air pollution. The major air pollutants emitted into the atmosphere by a number of natural processes and human activities include nitrogen oxides, volatile organic compounds, and particulate matter. In addition to the poor ambient air quality, there is increasing evidence that indoor air pollution also poses a serious threat to human health, especially in low-income countries that still use biomass fuels as an energy resource. This review summarizes the current knowledge on ambient air pollution in financially deprived populations. PMID- 28895889 TI - The Skin Bacterium Propionibacterium acnes Employs Two Variants of Hyaluronate Lyase with Distinct Properties. AB - Hyaluronic acid (HA) and other glycosaminoglycans are extracellular matrix components in the human epidermis and dermis. One of the most prevalent skin microorganisms, Propionibacterium acnes, possesses HA-degrading activity, possibly conferred by the enzyme hyaluronate lyase (HYL). In this study, we identified the HYL of P. acnes and investigated the genotypic and phenotypic characteristics. Investigations include the generation of a P. acneshyl knockout mutant and HYL activity assays to determine the substrate range and formed products. We found that P. acnes employs two distinct variants of HYL. One variant, HYL-IB/II, is highly active, resulting in complete HA degradation; it is present in strains of the phylotypes IB and II. The other variant, HYL-IA, has low activity, resulting in incomplete HA degradation; it is present in type IA strains. Our findings could explain some of the observed differences between P. acnes phylotype IA and IB/II strains. Whereas type IA strains are primarily found on the skin surface and associated with acne vulgaris, type IB/II strains are more often associated with soft and deep tissue infections, which would require elaborate tissue invasion strategies, possibly accomplished by a highly active HYL-IB/II. PMID- 28895890 TI - Skin Penetration Enhancement by Natural Oils for Dihydroquercetin Delivery. AB - Natural oils are commonly used in topical pharmaceutical formulations as emulsifiers, stabilizers or solubility enhancers. They are presented as safe and inert components, mainly used for formulation purposes. It is confirmed that natural oils can affect the skin penetration of various substances. Fatty acids are mainly responsible for this effect. Current understanding lacks reliable scientific data on penetration of natural oils into the skin and their skin penetration enhancement potential. In the current study, fatty acid content analysis was used to determine the principal fatty acids in soybean, olive, avocado, sea-buckthorn pulp, raspberry seed and coconut oils. Time of flight secondary ion mass spectrometry bioimaging was used to determine the distribution of these fatty acids in human skin ex vivo after application of the oils. Skin penetration enhancement ratios were determined for a perspective antioxidant compound dihydroquercetin. The results demonstrated skin penetration of fatty acids from all oils tested. Only soybean and olive oils significantly increased the skin distribution of dihydroquercetin and can be used as skin penetration enhancers. However, no correlation can be determined between the fatty acids' composition and skin penetration enhancement using currently available methodological approaches. This indicates that potential chemical penetration enhancement should be evaluated during formulation of topically applied products containing natural oils. PMID- 28895892 TI - A Robotic Platform for Corn Seedling Morphological Traits Characterization. AB - Crop breeding plays an important role in modern agriculture, improving plant performance, and increasing yield. Identifying the genes that are responsible for beneficial traits greatly facilitates plant breeding efforts for increasing crop production. However, associating genes and their functions with agronomic traits requires researchers to observe, measure, record, and analyze phenotypes of large numbers of plants, a repetitive and error-prone job if performed manually. An automated seedling phenotyping system aimed at replacing manual measurement, reducing sampling time, and increasing the allowable work time is thus highly valuable. Toward this goal, we developed an automated corn seedling phenotyping platform based on a time-of-flight of light (ToF) camera and an industrial robot arm. A ToF camera is mounted on the end effector of the robot arm. The arm positions the ToF camera at different viewpoints for acquiring 3D point cloud data. A camera-to-arm transformation matrix was calculated using a hand-eye calibration procedure and applied to transfer different viewpoints into an arm based coordinate frame. Point cloud data filters were developed to remove the noise in the background and in the merged seedling point clouds. A 3D-to-2D projection and an x-axis pixel density distribution method were used to segment the stem and leaves. Finally, separated leaves were fitted with 3D curves for morphological traits characterization. This platform was tested on a sample of 60 corn plants at their early growth stages with between two to five leaves. The error ratios of the stem height and leave length measurements are 13.7% and 13.1%, respectively, demonstrating the feasibility of this robotic system for automated corn seedling phenotyping. PMID- 28895891 TI - Alignment of Mitotic Chromosomes in Human Cells Involves SR-Like Splicing Factors Btf and TRAP150. AB - Serine-arginine-rich (SR) or SR-like splicing factors interact with exon junction complex proteins during pre-mRNA processing to promote mRNA packaging into mature messenger ribonucleoproteins (mRNPs) and to dictate mRNA stability, nuclear export, and translation. The SR protein family is complex, and while many classical SR proteins have well-defined mRNA processing functions, those of other SR-like proteins is unclear. Here, we show that depletion of the homologous non classical serine-arginine-rich (SR) splicing factors Bcl2-associated transcription factor (Btf or BCLAF) and thyroid hormone receptor-associated protein of 150 kDa (TRAP150) causes mitotic defects. We hypothesized that the depletion of these SR-like factors affects mitosis indirectly through an altered expression of mitotic checkpoint regulator transcripts. We observed an altered abundance of transcripts that encode mitotic regulators and mitotic chromosome misalignment defects following Btf and/or TRAP150 depletion. We propose that, in addition to their previously reported roles in maintaining mRNA distribution, Btf and TRAP150 control the abundance of transcripts encoding mitotic regulators, thereby affecting mitotic progression in human cells. PMID- 28895893 TI - Applying Nonparametric Methods to Analyses of Short-Term Fine Particulate Matter Exposure and Hospital Admissions for Cardiovascular Diseases among Older Adults. AB - Short-term exposure to fine particulate matter (PM2.5) has been associated with increased risks of cardiovascular diseases (CVDs), but whether such associations are supportive of a causal relationship is unclear, and few studies have employed formal causal analysis methods to address this. We employed nonparametric methods to examine the associations between daily concentrations of PM2.5 and hospital admissions (HAs) for CVD among adults aged 75 years and older in Texas, USA. We first quantified the associations in partial dependence plots generated using the random forest approach. We next used a Bayesian network learning algorithm to identify conditional dependencies between CVD HAs of older men and women and several predictor variables. We found that geographic location (county), time (e.g., month and year), and temperature satisfied necessary information conditions for being causes of CVD HAs among older men and women, but daily PM2.5 concentrations did not. We also found that CVD HAs of disjoint subpopulations were strongly predictive of CVD HAs among older men and women, indicating the presence of unmeasured confounders. Our findings from nonparametric analyses do not support PM2.5 as a direct cause of CVD HAs among older adults. PMID- 28895894 TI - An Insight into T-DNA Integration Events in Medicago sativa. AB - The molecular mechanisms of transferred DNA (T-DNA) integration into the plant genome are still not completely understood. A large number of integration events have been analyzed in different species, shedding light on the molecular mechanisms involved, and on the frequent transfer of vector sequences outside the T-DNA borders, the so-called vector backbone (VB) sequences. In this work, we characterized 46 transgenic alfalfa (Medicago sativa L.) plants (events), generated in previous works, for the presence of VB tracts, and sequenced several T-DNA/genomic DNA (gDNA) junctions. We observed that about 29% of the transgenic events contained VB sequences, within the range reported in other species. Sequence analysis of the T-DNA/gDNA junctions evidenced larger deletions at LBs compared to RBs and insertions probably originated by different integration mechanisms. Overall, our findings in alfalfa are consistent with those in other plant species. This work extends the knowledge on the molecular events of T-DNA integration and can help to design better transformation protocols for alfalfa. PMID- 28895895 TI - Effects of Sleep Quality on Melatonin Levels and Inflammatory Response after Major Abdominal Surgery in an Intensive Care Unit. AB - Disruption of nocturnal sleep in an intensive care unit may remarkably affect production of melatonin, which is also known to have anti-inflammatory properties. In the present study, we aimed to investigate the effect of sleep quality on melatonin levels and inflammation after surgery. Thus, we compared the patients, who were screened in the side-rooms where the lights were dimmed and noise levels were reduced, with the patients who received usual care. Preoperative and postoperative urine 6-sulphatoxymelatonin, serum interleukin-1 (IL-1), interleukin-6 (IL-6), and c-reactive protein (CRP) levels were measured and data on sleep quality was collected using the Richards-Campbell Sleep Questionnaire. Postoperative CRP and IL-6 levels were greater in the control group than in the experimental group, whereas postoperative 24 h melatonin levels were greater than preoperative levels and the difference was steeper in the experimental group in concordance with sleep quality scores. Thus, the regulation of light and noise in ICUs may help the recovery after major surgeries in patients, potentially by increasing melatonin production, which has anti inflammatory properties. PMID- 28895897 TI - Accuracy of Base of Support Using an Inertial Sensor Based Motion Capture System. AB - The potential of miniature inertial sensors for human balance and gait analysis appears promising. Base of support (BOS), together with its interaction with center of mass, is a critical indicator in above mentioned research fields. This study aims to evaluate the accuracy of Xsens MVN BIOMECH, a commercial widely used inertial sensor-based motion capture system, for measuring static BOS and examine the effect of different task complexity on the accuracy. Eleven young males participated in this study and went through eleven different experimental tasks. Results showed there were considerable errors in estimating BOS area (error ranged from -12.6% to +64.6%) from Xsens MVN and a large error in foot separation distance when there was knee flexion. The estimated BOS area from MVN was smaller than the ground truth from footprint when there was no knee flexion, and larger when there was knee flexion, and it increased monotonically along with the knee flexion angles. Wrongly estimated foot separations, mainly caused by knee flexion, and the initial system estimation error on BOS, were two major reasons for error and instability of BOS estimation. The findings suggested that caution should be taken when using Xsens MVN BIOMECH to estimate BOS and foot position-related measurements, especially for postures/motions with knee flexion. PMID- 28895896 TI - Does the Host Contribute to Modulation of Mycotoxin Production by Fruit Pathogens? AB - Storage of freshly harvested fruit is a key factor in modulating their supply for several months after harvest; however, their quality can be reduced by pathogen attack. Fruit pathogens may infect their host through damaged surfaces, such as mechanical injuries occurring during growing, harvesting, and packing, leading to increased colonization as the fruit ripens. Of particular concern are fungal pathogens that not only macerate the host tissue but also secrete significant amounts of mycotoxins. Many studies have described the importance of physiological factors, including stage of fruit development, biochemical factors (ripening, C and N content), and environmental factors (humidity, temperature, water deficit) on the occurrence of mycotoxins. However, those factors usually show a correlative effect on fungal growth and mycotoxin accumulation. Recent reports have suggested that host factors can induce fungal metabolism, leading to the synthesis and accumulation of mycotoxins. This review describes the new vision of host-factor impact on the regulation of mycotoxin biosynthetic gene clusters underlying the complex regulation of mycotoxin accumulation in ripening fruit. PMID- 28895898 TI - Reducing the Shared Burden of Chronic Conditions among Persons Aging with Disability and Older Adults in the United States through Bridging Aging and Disability. AB - Persons aging with long-term disabilities such as spinal cord injury or multiple sclerosis and older adults share similar chronic conditions in mid and later life in the United States. The rising general interest and more prevalent federal requirements for use of evidence-based practices (EBP) in health promotion and chronic condition interventions highlight the gap between demand and the availability of EBPs for persons aging with disability in particular. Addressing this gap will require focused efforts that will benefit substantially by bridging the fields of aging and disability/rehabilitation to develop new EBPs, translate existing EBPs across populations, and borrow best practices across fields where there are few current EBPs. Understanding distinctions between disability-related secondary conditions and age-related chronic conditions is a first step in identifying shared conditions that are important to address for both mid-life and older adults with disabilities. This review articulates these distinctions, describes shared conditions, and discusses the current lack of EBPs for both populations. It also provides recommendations for bridging activities in the United States by researchers, professionals, and consumer advocates. We argue that these can more efficiently move research and practice than if activities were undertaken separately in each field (aging and disability/rehabilitation). PMID- 28895899 TI - Effects of Heat Stress on Construction Labor Productivity in Hong Kong: A Case Study of Rebar Workers. AB - Global warming is bringing more frequent and severe heat waves, and the result will be serious for vulnerable populations such as construction workers. Excessive heat stress has profound effects on physiological responses, which cause occupational injuries, fatalities and low productivity. Construction workers are particularly affected by heat stress, because of the body heat production caused by physically demanding tasks, and hot and humid working conditions. Field studies were conducted between August and September 2016 at two construction training grounds in Hong Kong. Onsite wet-bulb globe temperature (WBGT), workers' heart rate (HR), and labor productivity were measured and monitored. Based on the 378 data sets of synchronized environmental, physiological, construction labor productivity (CLP), and personal variables, a CLP-heat stress model was established. It was found that WBGT, percentage of maximum HR, age, work duration, and alcohol drinking habits were determining factors for predicting the CLP (adjusted R2 = 0.68, p < 0.05). The model revealed that heat stress reduces CLP, with the percentage of direct work time decreasing by 0.33% when the WBGT increased by 1 degrees C. The findings in this study extend the existing practice notes by providing scientific data that may be of benefit to the industry in producing solid guidelines for working in hot weather. PMID- 28895900 TI - Laser Indirect Shock Welding of Fine Wire to Metal Sheet. AB - The purpose of this paper is to present an advanced method for welding fine wire to metal sheet, namely laser indirect shock welding (LISW). This process uses silica gel as driver sheet to accelerate the metal sheet toward the wire to obtain metallurgical bonding. A series of experiments were implemented to validate the welding ability of Al sheet/Cu wire and Al sheet/Ag wire. It was found that the use of a driver sheet can maintain high surface quality of the metal sheet. With the increase of laser pulse energy, the bonding area of the sheet/wire increased and the welding interfaces were nearly flat. Energy dispersive spectroscopy (EDS) results show that the intermetallic phases were absent and a short element diffusion layer which would limit the formation of the intermetallic phases emerging at the welding interface. A tensile shear test was used to measure the mechanical strength of the welding joints. The influence of laser pulse energy on the tensile failure modes was investigated, and two failure modes, including interfacial failure and failure through the wire, were observed. The nanoindentation test results indicate that as the distance to the welding interface decreased, the microhardness increased due to the plastic deformation becoming more violent. PMID- 28895901 TI - Delayed Activation Kinetics of Th2- and Th17 Cells Compared to Th1 Cells. AB - During immune responses, different classes of T cells arise: Th1, Th2, and Th17. Mobilizing the right class plays a critical role in successful host defense and therefore defining the ratios of Th1/Th2/Th17 cells within the antigen-specific T cell repertoire is critical for immune monitoring purposes. Antigen-specific Th1, Th2, and Th17 cells can be detected by challenging peripheral blood mononuclear cells (PBMC) with antigen, and establishing the numbers of T cells producing the respective lead cytokine, IFN-gamma and IL-2 for Th1 cells, IL-4 and IL-5 for Th2, and IL-17 for Th-17 cells, respectively. Traditionally, these cytokines are measured within 6 h in flow cytometry. We show here that 6 h of stimulation is sufficient to detect peptide-induced production of IFN-gamma, but 24 h are required to reveal the full frequency of protein antigen-specific Th1 cells. Also the detection of IL-2 producing Th1 cells requires 24 h stimulation cultures. Measurements of IL-4 producing Th2 cells requires 48-h cultures and 96 h are required for frequency measurements of IL-5 and IL-17 secreting T cells. Therefore, accounting for the differential secretion kinetics of these cytokines is critical for the accurate determination of the frequencies and ratios of antigen-specific Th1, Th2, and Th17 cells. PMID- 28895902 TI - Millimeter Scale Track Irregularity Surveying Based on ZUPT-Aided INS with Sub Decimeter Scale Landmarks. AB - Railway track irregularity surveying is important for the construction and the maintenance of railway lines. With the development of inertial devices, systems based on Inertial Navigation System (INS) have become feasible and popular approaches in track surveying applications. In order to overcome the requirement of high precision control points, this paper proposes a railway track irregularity measurement approach using the INS combined with the Zero Velocity Updates (ZUPT) technique and sub-decimeter scale landmarks. The equations for calculating track irregularity parameters from absolute position errors are deduced. Based on covariance analysis, the analytical relationships among the track irregularity measurements with the drifts of inertial sensors, the initial attitude errors and the observations of velocity and position are established. Simulations and experimental results show that the relative accuracy for 30 m chord of the proposed approach for track irregularity surveying can reach approximately 1 mm (1sigma) with gyro bias instability of 0.01 degrees /h, random walk noise of 0.005 degrees / h , and accelerometer bias instability of 50 MU g , random noise of 10 MU g / Hz , while velocity observations are provided by the ZUPT technique at about every 60 m intervals. This accuracy can meet the most stringent requirements of millimeter scale medium wavelength track irregularity surveying for railway lines. Furthermore, this approach reduces the requirement of high precision landmarks which can lighten the maintenance burden of control points and improve the work efficiency of railway track irregularity measurements. PMID- 28895903 TI - Performable Case Studies in Ethics Education. AB - Bioethics education often includes the study of short stories, novels, plays, and films, because such materials present case examples that can highlight relevant issues and questions especially vividly for a wide range of students. In addition, creative writing is widely used in the education of health professional students and in continuing education settings for health professionals. There are very few academic or professional disciplines that do not use case studies, but the case study in dialogic form has not been standard practice for thousands of years. Dramatic arts casuistry-the creation and performance of short case studies designed specifically to raise bioethics issues for discussion-represents an application of literature and the medical humanities that is both unique and uniquely valuable. This essay describes the development and history of a course that has been successfully taught to medical students and graduate bioethics students, in which the class researches, writes, and performs a case study designed to elicit reflection and discussion about a topic and set of bioethics issues of current interest to both academic and general audiences. The model is also suited to the presentation and discussion of existing case studies, both live and via on-demand audio. PMID- 28895905 TI - Fuzzy Risk Evaluation in Failure Mode and Effects Analysis Using a D Numbers Based Multi-Sensor Information Fusion Method. AB - Failure mode and effect analysis (FMEA) is a useful tool to define, identify, and eliminate potential failures or errors so as to improve the reliability of systems, designs, and products. Risk evaluation is an important issue in FMEA to determine the risk priorities of failure modes. There are some shortcomings in the traditional risk priority number (RPN) approach for risk evaluation in FMEA, and fuzzy risk evaluation has become an important research direction that attracts increasing attention. In this paper, the fuzzy risk evaluation in FMEA is studied from a perspective of multi-sensor information fusion. By considering the non-exclusiveness between the evaluations of fuzzy linguistic variables to failure modes, a novel model called D numbers is used to model the non-exclusive fuzzy evaluations. A D numbers based multi-sensor information fusion method is proposed to establish a new model for fuzzy risk evaluation in FMEA. An illustrative example is provided and examined using the proposed model and other existing method to show the effectiveness of the proposed model. PMID- 28895904 TI - Effect of Sex and Body Mass Index on Children's Physical Activity Intensity during Free Play at an Indoor Soft Play Center: An Exploratory Study. AB - Background: Indoor soft play can provide a safe but exciting physical activity opportunity regardless of environmental conditions. Relatively little is known about the quality or quantity of physical activity engaged in by children during indoor free soft play. The aim of this study was to evaluate the contribution indoor free soft play can make in enabling children to meet physical activity guidelines and to evaluate the effects of sex and body mass index category. Methods: Seventy-two boys and girls aged five to 10 years engaged in un controlled indoor free soft play with a mean duration of 120.7 (27.1) min, during which physical activity was monitored using Actigraph accelerometers. Results: Children spent an average of 61.7 (24.2) min engaging in moderate to vigorous physical activity (MVPA) and 51.4% (n = 37) achieved the recommended 60 min of MVPA through the single visit to the indoor soft play center. Boys (68.3 (25.7) min) engaged in significantly (p < 0.05) more MVPA than girls (55.8 (21.4) min). Normal weight (65.7 (23.3) min) children engaged in significantly more MVPA than overweight children (48.0 (18.9) min). Conclusions: Attendance at a soft play indoor center has the potential to support children to engage in sufficient MVPA and overcome environmental factors that can restrict physical activity opportunities. PMID- 28895906 TI - Silicon Nitride Photonic Integration Platforms for Visible, Near-Infrared and Mid Infrared Applications. AB - Silicon nitride photonics is on the rise owing to the broadband nature of the material, allowing applications of biophotonics, tele/datacom, optical signal processing and sensing, from visible, through near to mid-infrared wavelengths. In this paper, a review of the state of the art of silicon nitride strip waveguide platforms is provided, alongside the experimental results on the development of a versatile 300 nm guiding film height silicon nitride platform. PMID- 28895907 TI - The Anti-Proliferation Activity and Mechanism of Action of K12[V18O42(H2O)]?6H2O on Breast Cancer Cell Lines. AB - Polyoxometalates (POMs) are inorganic clusters that possess potential anti bacterial, anti-viral, and anti-tumor activities. Herein, the in vitro anti proliferation activities of K12[V18O42(H2O)]?6H2O (V18) have been investigated on the MCF-7 and MDA-MB-231 cell lines. The results indicated that V18 could inhibit the proliferation of MCF-7 (IC50, 11.95 MUM at 48 h) in a dose-dependent manner compared to the positive control, 5-fluorouracil (5-Fu, p < 0.05). The anti proliferation activity of V18 might be mediated by arrest of the MCF-7 cells in the G2/M phase and induction of apoptosis and necrosis. Moreover, V18 can effectively quench the fluorescence of ctDNA. The binding mode between them may be groove or outside stacking binding. V18 can also effectively quench the intrinsic fluorescence of bovine serum albumin (BSA) and human serum albumin (HSA) via static quenching, and changed the conformation of BSA and HSA. PMID- 28895908 TI - A Robust Sparse Representation Model for Hyperspectral Image Classification. AB - Sparse representation has been extensively investigated for hyperspectral image (HSI) classification and led to substantial improvements in the performance over the traditional methods, such as support vector machine (SVM). However, the existing sparsity-based classification methods typically assume Gaussian noise, neglecting the fact that HSIs are often corrupted by different types of noise in practice. In this paper, we develop a robust classification model that admits realistic mixed noise, which includes Gaussian noise and sparse noise. We combine a model for mixed noise with a prior on the representation coefficients of input data within a unified framework, which produces three kinds of robust classification methods based on sparse representation classification (SRC), joint SRC and joint SRC on a super-pixels level. Experimental results on simulated and real data demonstrate the effectiveness of the proposed method and clear benefits from the introduced mixed-noise model. PMID- 28895909 TI - Measurement of Walking Ground Reactions in Real-Life Environments: A Systematic Review of Techniques and Technologies. AB - Monitoring natural human gait in real-life environments is essential in many applications, including quantification of disease progression, monitoring the effects of treatment, and monitoring alteration of performance biomarkers in professional sports. Nevertheless, developing reliable and practical techniques and technologies necessary for continuous real-life monitoring of gait is still an open challenge. A systematic review of English-language articles from scientific databases including Scopus, ScienceDirect, Pubmed, IEEE Xplore, EBSCO and MEDLINE were carried out to analyse the 'accuracy' and 'practicality' of the current techniques and technologies for quantitative measurement of the tri-axial walking ground reactions outside the laboratory environment, and to highlight their strengths and shortcomings. In total, 679 relevant abstracts were identified, 54 full-text papers were included in the paper and the quantitative results of 17 papers were used for meta-analysis and comparison. Three classes of methods were reviewed: (1) methods based on measured kinematic data; (2) methods based on measured plantar pressure; and (3) methods based on direct measurement of ground reactions. It was found that all three classes of methods have competitive accuracy levels with methods based on direct measurement of the ground reactions showing highest accuracy while being least practical for long term real-life measurement. On the other hand, methods that estimate ground reactions using measured body kinematics show highest practicality of the three classes of methods reviewed. Among the most prominent technical and technological challenges are: (1) reducing the size and price of tri-axial load-cells; (2) improving the accuracy of orientation measurement using IMUs; (3) minimizing the number and optimizing the location of required IMUs for kinematic measurement; (4) increasing the durability of pressure insole sensors, and (5) enhancing the robustness and versatility of the ground reactions estimation methods to include pathological gaits and natural variability of gait in real-life physical environment. PMID- 28895910 TI - A False Alarm Reduction Method for a Gas Sensor Based Electronic Nose. AB - Electronic noses (E-Noses) are becoming popular for food and fruit quality assessment due to their robustness and repeated usability without fatigue, unlike human experts. An E-Nose equipped with classification algorithms and having open ended classification boundaries such as the k-nearest neighbor (k-NN), support vector machine (SVM), and multilayer perceptron neural network (MLPNN), are found to suffer from false classification errors of irrelevant odor data. To reduce false classification and misclassification errors, and to improve correct rejection performance; algorithms with a hyperspheric boundary, such as a radial basis function neural network (RBFNN) and generalized regression neural network (GRNN) with a Gaussian activation function in the hidden layer should be used. The simulation results presented in this paper show that GRNN has more correct classification efficiency and false alarm reduction capability compared to RBFNN. As the design of a GRNN and RBFNN is complex and expensive due to large numbers of neuron requirements, a simple hyperspheric classification method based on minimum, maximum, and mean (MMM) values of each class of the training dataset was presented. The MMM algorithm was simple and found to be fast and efficient in correctly classifying data of training classes, and correctly rejecting data of extraneous odors, and thereby reduced false alarms. PMID- 28895912 TI - CD64: An Attractive Immunotherapeutic Target for M1-type Macrophage Mediated Chronic Inflammatory Diseases. AB - To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc gamma receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammation driven by M1-type dysregulated macrophages. This subpopulation plays a key role in the initiation and maintenance of a series of chronic diseases. The novel recombinant M1-specific immunotherapeutics offer the prospect of highly effective treatment strategies as they have been shown to selectively eliminate the disease-causing macrophage subpopulations. In this review, we provide a detailed summary of the data generated, together with the advantages and the clinical potential of CD64-based targeted therapies for the treatment of chronic inflammatory diseases. PMID- 28895913 TI - Dietary Factors Modulate Iron Uptake in Caco-2 Cells from an Iron Ingot Used as a Home Fortificant to Prevent Iron Deficiency. AB - Iron deficiency is a major public health concern and nutritional approaches are required to reduce its prevalence. The aim of this study was to examine the iron bioavailability of a novel home fortificant, the "Lucky Iron FishTM" (LIF) (www.luckyironfish.com/shop, Guelph, Canada) and the impact of dietary factors and a food matrix on iron uptake from LIF in Caco-2 cells. LIF released a substantial quantity of iron (about 1.2 mM) at pH 2 but this iron was only slightly soluble at pH 7 and not taken up by cells. The addition of ascorbic acid (AA) maintained the solubility of iron released from LIF (LIF-iron) at pH 7 and facilitated iron uptake by the cells in a concentration-dependent manner. In vitro digestion of LIF-iron in the presence of peas increased iron uptake 10 fold. However, the addition of tannic acid to the digestion reduced the cellular iron uptake 7.5-fold. Additionally, LIF-iron induced an overproduction of reactive oxygen species (ROS), similar to ferrous sulfate, but this effect was counteracted by the addition of AA. Overall, our data illustrate the major influence of dietary factors on iron solubility and bioavailability from LIF, and demonstrate that the addition of AA enhances iron uptake and reduces ROS in the intestinal lumen. PMID- 28895911 TI - Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer. AB - Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases. PMID- 28895914 TI - A 24-GHz Front-End Integrated on a Multilayer Cellulose-Based Substrate for Doppler Radar Sensors. AB - This paper presents a miniaturized Doppler radar that can be used as a motion sensor for low-cost Internet of things (IoT) applications. For the first time, a radar front-end and its antenna are integrated on a multilayer cellulose-based substrate, built-up by alternating paper, glue and metal layers. The circuit exploits a distributed microstrip structure that is realized using a copper adhesive laminate, so as to obtain a low-loss conductor. The radar operates at 24 GHz and transmits 5 mW of power. The antenna has a gain of 7.4 dBi and features a half power beam-width of 48 degrees. The sensor, that is just the size of a stamp, is able to detect the movement of a walking person up to 10 m in distance, while a minimum speed of 50 mm/s up to 3 m is clearly measured. Beyond this specific result, the present paper demonstrates that the attractive features of cellulose, including ultra-low cost and eco-friendliness (i.e., recyclability and biodegradability), can even be exploited for the realization of future high frequency hardware. This opens opens the door to the implementation on cellulose of devices and systems which make up the "sensing layer" at the base of the IoT ecosystem. PMID- 28895917 TI - UWB Monitoring System for AAL Applications. AB - Independent living of elderly persons in their homes requires support that can be provided with modern assistive technologies. Monitoring of elderly persons behaviour delivers valuable information that can be used for diagnosis and detection of health problems as well as triggering alerts in emergency situations. The paper includes a description of the ultra wideband system developed within Networked InfrasTructure for Innovative home Care Solutions (NITICS) Active and Assisted Living (AAL) project. The system can be used as a component of AAL platforms. It delivers data on users localization and has a fall detector functionality. The system also provides access to raw measurement results from Microelectromechanical Systems (MEMS) sensors embedded in the device worn by the monitored person. These data can be used in solutions intended for elderly person's behaviour investigation. The system was investigated under laboratory conditions as well as in home environment. The detailed system description and results of performed tests are included in the article. PMID- 28895915 TI - "Autoimmune(-Like)" Drug and Herb Induced Liver Injury: New Insights into Molecular Pathogenesis. AB - Idiosyncratic drug-induced liver injury (DILI) and hepatic injury due to herbal and dietary supplements (HDS) can adapt clinical characteristics of autoimmune hepatitis (AIH), such as the appearance of autoantibodies and infiltration of the liver by immune competent cells. To describe these cases of DILI/HDS, the poorly defined term "autoimmune(-like)" DILI/HDS came up. It is uncertain if these cases represent a subgroup of DILI/HDS with distinct pathomechanistic and prognostic features different from "classical" DILI/HDS. Besides, due to the overlap of clinical characteristics of "immune-mediated" DILI/HDS and AIH, both entities are not easy to differentiate. However, the demarcation is important, especially with regard to treatment: AIH requires long-term, mostly lifelong immunosuppression, whereas DILI/HDS does not. Only through exact diagnostic evaluation, exclusion of differential diagnoses and prolonged follow-up can the correct diagnosis reliably be made. Molecular mechanisms have not been analysed for the subgroup of "autoimmune(-like)" DILI/HDS yet. However, several pathogenetic checkpoints of DILI/HDS in general and AIH are shared. An analysis of these shared mechanisms might hint at relevant molecular processes of "autoimmune(-like)" DILI/HDS. PMID- 28895918 TI - Trauma Affecting Asian-Pacific Islanders in the San Francisco Bay Area. AB - Trauma is a transgenerational process that overwhelms the community and the ability of family members to cope with life stressors. An anthropologist trained in ethnographic methods observed three focus groups from a non-profit agency providing trauma and mental health services to Asian Americans living in the San Francisco Bay Area of United States. Supplemental information also was collected from staff interviews and notes. Many of the clients were immigrants, refugees, or adult children of these groups. This report consisted of authentic observations and rich qualitative information to characterize the impact of trauma on refugees and immigrants. Observations suggest that collective trauma, direct or indirect, can impede the success and survivability of a population, even after many generations. PMID- 28895916 TI - MicroRNAs in Different Histologies of Soft Tissue Sarcoma: A Comprehensive Review. AB - Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3'-untranslated region of messenger RNAs. They are involved in a variety of human diseases, including malignancies, such as endometrial cancer, osteosarcoma, bronchial carcinoma and breast cancer. In STS, various miRNAs are differentially expressed, thus contributing to development, progression and invasion. Therefore, the aim of the present review is to summarise current knowledge on the role of miRNAs in STS. Furthermore, the potential role of miRNAs as diagnostic, prognostic and predictive biomarkers is discussed. PMID- 28895919 TI - NAFLD: Is There Anything New under the Sun? AB - Nonalcoholic fatty liver disease (NAFLD) is an "umbrella" definition that encompasses a spectrum of histological liver changes ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with/without fibrosis, "cryptogenic" cirrhosis, and hepatocellular carcinoma (HCC), occurring in a dysmetabolic milieu, though in the absence of excessive alcohol consumption and other competing etiologies of chronic liver disease [1].[...]. PMID- 28895920 TI - EMT and Treatment Resistance in Pancreatic Cancer. AB - Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance. PMID- 28895921 TI - Food and Beverage Marketing in Schools: A Review of the Evidence. AB - Despite growing interest from government agencies, non-governmental organizations and school boards in restricting or regulating unhealthy food and beverage marketing to children, limited research has examined the emerging knowledge base regarding school-based food and beverage marketing in high-income countries. This review examined current approaches for measuring school food and beverage marketing practices, and evidence regarding the extent of exposure and hypothesized associations with children's diet-related outcomes. Five databases (MEDLINE, Web of Science, CINAHL, Embase, and PsycINFO) and six grey literature sources were searched for papers that explicitly examined school-based food and beverage marketing policies or practices. Twenty-seven papers, across four high income countries including Canada (n = 2), Ireland (n = 1), Poland (n = 1) and United States (n = 23) were identified and reviewed. Results showed that three main methodological approaches have been used: direct observation, self-report surveys, and in-person/telephone interviews, but few studies reported on the validity or reliability of measures. Findings suggest that students in the U.S. are commonly exposed to a broad array of food and beverage marketing approaches including direct and indirect advertising, although the extent of exposure varies widely across studies. More pervasive marketing exposure was found among secondary or high schools compared with elementary/middle schools and among schools with lower compared with higher socio-economic status. Three of five studies examining diet-related outcomes found that exposure to school-based food and beverage marketing was associated with food purchasing or consumption, particularly for minimally nutritious items. There remains a need for a core set of standard and universal measures that are sufficiently rigorous and comprehensive to assess the totality of school food and beverage marketing practices that can be used to compare exposure between study contexts and over time. Future research should examine the validity of school food and beverage marketing assessments and the impacts of exposure (and emerging policies that reduce exposure) on children's purchasing and diet-related knowledge, attitudes and behaviors in school settings. PMID- 28895922 TI - The Effect of Nutrition Therapy and Exercise on Cancer-Related Fatigue and Quality of Life in Men with Prostate Cancer: A Systematic Review. AB - BACKGROUND: Improvements in diet and/or exercise are often advocated during prostate cancer treatment, yet the efficacy of, and optimal nutrition and exercise prescription for managing cancer-related fatigue and quality of life remains elusive. The aim of this study is to systematically review the effects of nutrition and/or exercise on cancer-related fatigue and/or quality of life. METHODS: A literature search was conducted in six electronic databases. The Delphi quality assessment list was used to evaluate the methodological quality of the literature. The study characteristics and results were summarized in accordance with the review's Population, Intervention, Control, Outcome (PICO) criteria. RESULTS: A total of 20 articles (one diet only, two combined diet and exercise, and seventeen exercise only studies) were included in the review. Soy supplementation improved quality of life, but resulted in several adverse effects. Prescribing healthy eating guidelines with combined resistance training and aerobic exercise improved cancer-related fatigue, yet its effect on quality of life was inconclusive. Combined resistance training with aerobic exercise showed improvements in cancer-related fatigue and quality of life. In isolation, resistance training appears to be more effective in improving cancer-related fatigue and quality of life than aerobic exercise. Studies that utilised an exercise professional to supervise the exercise sessions were more likely to report improvements in both cancer-related fatigue and quality of life than those prescribing unsupervised or partially supervised sessions. Neither exercise frequency nor duration appeared to influence cancer-related fatigue or quality of life, with further research required to explore the potential dose-response effect of exercise intensity. CONCLUSION: Supervised moderate-hard resistance training with or without moderate-vigorous aerobic exercise appears to improve cancer-related fatigue and quality of life. Targeted physiological pathways suggest dietary intervention may alleviate cancer-related fatigue and improve quality of life, however the efficacy of nutrition management with or without exercise prescription requires further exploration. PMID- 28895923 TI - ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice. AB - There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents. PMID- 28895924 TI - Artificial Turf: Contested Terrains for Precautionary Public Health with Particular Reference to Europe? AB - Millions of adults, children and teenagers use artificial sports pitches and playgrounds globally. Pitches are artificial grass and bases may be made up of crumb rubber from recycled tires or new rubber and sand. Player injury on pitches was a major concern. Now, debates about health focus on possible exposure and uptake of chemicals within pitch and base materials. Research has looked at potential risks to users from hazardous substances such as metals, volatile organic compounds, polycyclic aromatic hydrocarbons including benzo (a) (e) pyrenes and phthalates: some are carcinogens and others may be endocrine disruptors and have developmental reproductive effects. Small environmental monitoring and modelling studies, often with significant data gaps about exposure, range of substances monitored, occupational exposures, types of surfaces monitored and study length across seasons, indicated little risk to sports people and children but some risk to installation workers. A few, again often small, studies indicated potentially harmful human effects relating to skin, respiration and cancers. Only one widely cited biomonitoring study has been done and no rigorous cancer epidemiological studies exist. Unravelling exposures and uptake over decades may prove complex. European regulators have strengthened controls over crumb rubber chemicals, set different standards for toys and crumb rubber pitches. Bigger US studies now underway attempting to fill some of the data gaps will report between 2017 and 2019. Public health professionals in the meantime may draw on established principles to support greater caution in setting crumb rubber exposure limits and controls. PMID- 28895926 TI - Influence of Hot Rolling and Heat Treatment on the Microstructural Evolution of beta20C Titanium Alloy. AB - The microstructural evolution and underlying mechanism of a new high strength, high toughness near beta titanium alloy, beta20C, during hot deformation, and heat treatment were studied qualitatively and quantitatively. It was found that dynamic recovery occurs mainly in beta phase, while alpha phase undergoes both a dynamic recovery and continuous incomplete dynamic recrystallization with a fraction of high-angle grain boundaries (>=15 degrees ) of 21.1% under hot rolling. Subsequently, alpha phase undergoes static recrystallization with an increasing fraction of high-angle grain boundaries (21.1%->60.7%) under annealing, while the grains are equiaxed with refined grain sizes of 1.63 um observed from the rolling direction (RD) and 1.66 um observed from the transverse direction (TD). Moreover, the average aspect ratio of the lamellar alpha phase was 2.44 observed from the RD and 3.12 observed from the TD after hot rolling, but decreased to 2.20 observed from the RD, and 2.53 observed from the TD after annealing. Furthermore, the strict Burgers' relationship between alpha and beta phases changed after hot-rolling and remains the distortion, even after the static recrystallization process of alpha phase during annealing. PMID- 28895925 TI - Bovine Lactoferrin Inhibits Dengue Virus Infectivity by Interacting with Heparan Sulfate, Low-Density Lipoprotein Receptor, and DC-SIGN. AB - Bovine lactoferrin (bLF) presents in milk and has been shown to inhibit several viral infections. Effective drugs are unavailable for the treatment of dengue virus (DENV) infection. In this study, we evaluated the antiviral effect of bLF against DENV infection in vivo and in vitro. Bovine LF significantly inhibited the infection of the four serotypes of DENV in Vero cells. In the time-of-drug addition test, DENV-2 infection was remarkably inhibited when bLF was added during or prior to the occurrence of virus attachment. We also revealed that bovine LF blocks binding between DENV-2 and the cellular membrane by interacting with heparan sulfate (HS), dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), and low-density lipoprotein receptors (LDLR). In addition, bLF inhibits DENV-2 infection and decreases morbidity in a suckling mouse challenge model. This study supports the finding that bLF may inhibit DENV infection by binding to the potential DENV receptors. PMID- 28895927 TI - Association between Childhood Diarrhoeal Incidence and Climatic Factors in Urban and Rural Settings in the Health District of Mbour, Senegal. AB - We assessed the association between childhood diarrhoeal incidence and climatic factors in rural and urban settings in the health district of Mbour in western Senegal. We used monthly diarrhoeal case records among children under five years registered in 24 health facilities over a four-year period (2011-2014). Climatic data (i.e., daily temperature, night temperature and rainfall) for the same four year period were obtained. We performed a negative binomial regression model to establish the relationship between monthly diarrhoeal incidence and climatic factors of the same and the previous month. There were two annual peaks in diarrhoeal incidence: one during the cold dry season and one during the rainy season. We observed a positive association between diarrhoeal incidence and high average temperature of 36 degrees C and above and high cumulative monthly rainfall at 57 mm and above. The association between diarrhoeal incidence and temperature was stronger in rural compared to urban settings, while higher rainfall was associated with higher diarrhoeal incidence in the urban settings. Concluding, this study identified significant health-climate interactions and calls for effective preventive measures in the health district of Mbour. Particular attention should be paid to urban settings where diarrhoea was most common in order to reduce the high incidence in the context of climatic variability, which is expected to increase in urban areas in the face of global warming. PMID- 28895928 TI - Collaborative Visual Analytics: A Health Analytics Approach to Injury Prevention. AB - Background: Accurate understanding of complex health data is critical in order to deal with wicked health problems and make timely decisions. Wicked problems refer to ill-structured and dynamic problems that combine multidimensional elements, which often preclude the conventional problem solving approach. This pilot study introduces visual analytics (VA) methods to multi-stakeholder decision-making sessions about child injury prevention; Methods: Inspired by the Delphi method, we introduced a novel methodology-group analytics (GA). GA was pilot-tested to evaluate the impact of collaborative visual analytics on facilitating problem solving and supporting decision-making. We conducted two GA sessions. Collected data included stakeholders' observations, audio and video recordings, questionnaires, and follow up interviews. The GA sessions were analyzed using the Joint Activity Theory protocol analysis methods; Results: The GA methodology triggered the emergence of 'common ground' among stakeholders. This common ground evolved throughout the sessions to enhance stakeholders' verbal and non-verbal communication, as well as coordination of joint activities and ultimately collaboration on problem solving and decision-making; Conclusions: Understanding complex health data is necessary for informed decisions. Equally important, in this case, is the use of the group analytics methodology to achieve 'common ground' among diverse stakeholders about health data and their implications. PMID- 28895930 TI - Dynamic Reconstruction Algorithm of Three-Dimensional Temperature Field Measurement by Acoustic Tomography. AB - Accuracy and speed of algorithms play an important role in the reconstruction of temperature field measurements by acoustic tomography. Existing algorithms are based on static models which only consider the measurement information. A dynamic model of three-dimensional temperature reconstruction by acoustic tomography is established in this paper. A dynamic algorithm is proposed considering both acoustic measurement information and the dynamic evolution information of the temperature field. An objective function is built which fuses measurement information and the space constraint of the temperature field with its dynamic evolution information. Robust estimation is used to extend the objective function. The method combines a tunneling algorithm and a local minimization technique to solve the objective function. Numerical simulations show that the image quality and noise immunity of the dynamic reconstruction algorithm are better when compared with static algorithms such as least square method, algebraic reconstruction technique and standard Tikhonov regularization algorithms. An effective method is provided for temperature field reconstruction by acoustic tomography. PMID- 28895929 TI - Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non alcoholic Steatohepatitis. AB - The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH. PMID- 28895931 TI - Wet-Chemical Synthesis of 3D Stacked Thin Film Metal-Oxides for All-Solid-State Li-Ion Batteries. AB - By ultrasonic spray deposition of precursors, conformal deposition on 3D surfaces of tungsten oxide (WO3) negative electrode and amorphous lithium lanthanum titanium oxide (LLT) solid-electrolyte has been achieved as well as an all-solid state half-cell. Electrochemical activity was achieved of the WO3 layers, annealed at temperatures of 500 degrees C. Galvanostatic measurements show a volumetric capacity (415 mAh.cm-3) of the deposited electrode material. In addition, electrochemical activity was shown for half-cells, created by coating WO3 with LLT as the solid-state electrolyte. The electron blocking properties of the LLT solid-electrolyte was shown by ferrocene reduction. 3D depositions were done on various micro-sized Si template structures, showing fully covering coatings of both WO3 and LLT. Finally, the thermal budget required for WO3 layer deposition was minimized, which enabled attaining active WO3 on 3D TiN/Si micro cylinders. A 2.6-fold capacity increase for the 3D-structured WO3 was shown, with the same current density per coated area. PMID- 28895932 TI - Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters. AB - A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, Gibberella zeae,Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 ug/mL. The target compounds exhibited best antifungal activity against P. piricola, in which compounds (Z)-4r (R = beta-pyridyl), (Z)-4q (R = alpha thienyl), (E)-4f' (R = p-F Ph), (Z)-4i (R = m-Me Ph), (Z)-4j (R = p-Me Ph), and (Z)-4p (R = alpha-furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound (Z)-4r (R = beta-pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the E-Z isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents. PMID- 28895934 TI - Elimination of Coptotermes lacteus (Froggatt) (Blattodea: Rhinotemitidae) Colonies Using Bistrifluron Bait Applied through In-Ground Bait Stations Surrounding Mounds. AB - The efficacy of bistrifluron termite bait was evaluated using in-ground bait stations placed around Coptotermes lacteus mounds in south-eastern Australia during late summer and autumn (late February to late May 2012). Four in-ground bait stations containing timber billets were placed around each of twenty mounds. Once sufficient numbers of in-ground stations were infested by termites, mounds were assigned to one of four groups (one, two, three or four 120 g bait canisters or 120 to 480 g bait in total per mound) and bait canisters installed. One mound, nominally assigned treatment with two canisters ultimately had no termite interception in any of the four in-ground stations and not treated. Eighteen of the remaining 19 colonies were eliminated by 12 weeks after bait placement, irrespective of bait quantity removed (range 43 to 480 g). Measures of colony decline-mound repair capability and internal core temperature-did not accurately reflect the colony decline, as untreated colonies showed a similar pattern of decline in both repair capability and internal mound core temperature. However, during the ensuing spring-summer period, capacity to repair the mound was restored in untreated colonies and the internal core temperature profile was similar to the previous spring-summer period which indicated that these untreated colonies remained healthy. PMID- 28895933 TI - Higher Protein Intake Does Not Improve Lean Mass Gain When Compared with RDA Recommendation in Postmenopausal Women Following Resistance Exercise Protocol: A Randomized Clinical Trial. AB - The aim of this study was to evaluate the effect of a higher protein intake on lean body mass (LBM) gain in postmenopausal women practicing resistance exercise and compare it to the Recommended Dietary Allowance (RDA) recommendation. Twenty three postmenopausal women (63.2 +/- 7.8 years) were randomized into two groups. The group with higher protein intake (n = 11) (HP) received a dietary plan with ~1.2 g.kg-1.day-1 of protein, while the normal protein (NP) group (n = 12) was instructed to ingest ~0.8 g.kg-1.day-1 of protein (RDA recommendation). Both groups performed the same resistance training protocol, 3 times a week, with progression of the number of sets (from 1 to 6 sets) and 8-12 repetitions. The intervention occurred over 10 weeks. Body composition evaluation was performed by dual-energy X-ray absorptiometry. The diet was evaluated by nine 24-h food recall summaries over the course of the study. During the intervention period, the HP group presented a higher protein (1.18 +/- 0.3 vs. 0.87 +/- 0.2 g.kg-1.day-1, p = 0.008) and leucine (6.0 +/- 1.4 vs. 4.3 +/- 0.9 g/day, p < 0.001) intake than the NP group, respectively. At the end of the intervention, there were increases in LBM both in HP (37.1 +/- 6.2 to 38.4 +/- 6.5 kg, p = 0.004) and in NP (37.6 +/- 6.2 to 38.8 +/- 6.4 kg, p < 0.001), with no differences between the groups (p = 0.572). In conclusion, increased protein intake did not promote higher LBM gain when compared to RDA recommendation in postmenopausal women performing resistance exercise during 10 weeks. This trial was registered at ClinicalTrials.gov as NCT03024125. PMID- 28895936 TI - Rapid and Highly Sensitive Non-Competitive Immunoassay for Specific Detection of Nodularin. AB - Nodularin (NOD) is a cyclic penta-peptide hepatotoxin mainly produced by Nodularia spumigena, reported from the brackish water bodies of various parts of the world. It can accumulate in the food chain and, for safety reasons, levels of NOD not only in water bodies but also in food matrices are of interest. Here, we report on a non-competitive immunoassay for the specific detection of NOD. A phage display technique was utilized to interrogate a synthetic antibody phage library for binders recognizing NOD bound to an anti-ADDA (3-Amino-9-methoxy 2,6,8-trimethyl-10-phenyldeca-4(E),6(E)-dienoic acid) monoclonal antibody (Mab). One of the obtained immunocomplex binders, designated SA32C11, showed very high specificity towards nodularin-R (NOD-R) over to the tested 10 different microcystins (microcystin-LR, -dmLR, -RR, -dmRR, -YR, -LY, -LF, -LW, -LA, -WR). It was expressed in Escherichia coli as a single chain antibody fragment (scFv) fusion protein and used to establish a time-resolved fluorometry-based assay in combination with the anti-ADDA Mab. The detection limit (blank + 3SD) of the immunoassay, with a total assay time of 1 h 10 min, is 0.03 ug/L of NOD-R. This represents the most sensitive immunoassay method for the specific detection of NOD reported so far. The assay was tested for its performance to detect NOD using spiked (0.1 to 3 ug/L of NOD-R) water samples including brackish sea and coastal water and the recovery ranged from 79 to 127%. Furthermore, a panel of environmental samples, including water from different sources, fish and other marine tissue specimens, were analyzed for NOD using the assay. The assay has potential as a rapid screening tool for the analysis of a large number of water samples for the presence of NOD. It can also find applications in the analysis of the bioaccumulation of NOD in marine organisms and in the food chain. PMID- 28895935 TI - Evaluation of the Molecular Structural Parameters of Normal Rice Starch and Their Relationships with Its Thermal and Digestion Properties. AB - The molecular structural parameters of six normal rice starches with different amylose contents were investigated through their iodine absorption spectra and gel permeation chromatography of fully branched and debranched starches. The thermal and digestion properties of starches were also determined and their relationships with molecular structural parameters were analyzed. Results showed that the molecular structural parameters of maximum absorption wavelength, blue value (BV), optical density 620 nm/550 nm (OD 620/550), amylose, intermediate component, and amylopectin, including its short branch-chains, long branch chains, and branching degree, had high correlation in different determining methods. The intermediate component of starch was significantly positively related to amylose and negatively related to amylopectin, and the amylopectin branching degree was significantly positively related to amylopectin content and negatively related to amylose content. The gelatinization temperatures and enthalpy of native starch were significantly positively related to BV, OD 620/550, and amylose content and negatively related to amylopectin short branch chains. The gelatinization temperatures and enthalpy of retrograded starch were significantly negatively related to amylopectin branching degree. The digestions of gelatinized and retrograded starches were significantly negatively related to the BV, OD 620/550, amylose, and intermediate component and positively related to amylopectin and its short branch-chains and branching degree. PMID- 28895937 TI - A Facile Oxidative Opening of the C-Ring in Luotonin A and Derivatives. AB - An oxidative ring opening reaction of the central ring C in the alkaloid Luotonin A and two of its derivatives was found to occur upon heating with an excess amine and potassium carbonate in dimethylsulfoxide (DMSO) solution in the presence of air oxygen. The structure of the novel amide-type products was elucidated and a possible mechanism for this reaction is proposed. Four of the new compounds show moderate in vitro anticancer activity towards human colon adenocarcinoma cells. PMID- 28895938 TI - Functional Amyloid Protection in the Eye Lens: Retention of alpha-Crystallin Molecular Chaperone Activity after Modification into Amyloid Fibrils. AB - Amyloid fibril formation occurs from a wide range of peptides and proteins and is typically associated with a loss of protein function and/or a gain of toxic function, as the native structure of the protein undergoes major alteration to form a cross beta-sheet array. It is now well recognised that some amyloid fibrils have a biological function, which has led to increased interest in the potential that these so-called functional amyloids may either retain the function of the native protein, or gain function upon adopting a fibrillar structure. Herein, we investigate the molecular chaperone ability of alpha-crystallin, the predominant eye lens protein which is composed of two related subunits alphaA- and alphaB-crystallin, and its capacity to retain and even enhance its chaperone activity after forming aggregate structures under conditions of thermal and chemical stress. We demonstrate that both eye lens alpha-crystallin and alphaB crystallin (which is also found extensively outside the lens) retain, to a significant degree, their molecular chaperone activity under conditions of structural change, including after formation into amyloid fibrils and amorphous aggregates. The results can be related directly to the effects of aging on the structure and chaperone function of alpha-crystallin in the eye lens, particularly its ability to prevent crystallin protein aggregation and hence lens opacification associated with cataract formation. PMID- 28895940 TI - Genotoype-by-sequencing of three geographically distinct populations of Olympia oysters, Ostrea lurida. AB - Olympia oysters are found along the west coast of North America and as the only native oyster species in the region, receive considerable attention with regard to restoration and conservation. Knowledge of genetic structure of this species is essential for resource managers. Here we provide genetic data for three distinct populations of Olympia oysters in Puget Sound, Washington, USA in the form of genotype-by-sequencing data (GBS). Specifically, this includes description of sequence data and a derived table that provides single nucleotide polymorphism (SNP) information for 10,363 loci. These data are valuable not only for resource managers responsible for restoration aquaculture practices, but can provide insight into ecological drivers of selection and diversity. PMID- 28895939 TI - Sleep Disorders in Childhood Neurogenetic Disorders. AB - enetic advances in the past three decades have transformed our understanding and treatment of many human diseases including neurogenetic disorders. Most neurogenetic disorders can be classified as "rare disease," but collectively neurogenetic disorders are not rare and are commonly encountered in general pediatric practice. The authors decided to select eight relatively well-known neurogenetic disorders including Down syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, congenital central hypoventilation syndrome, achondroplasia, mucopolysaccharidoses, and Duchenne muscular dystrophy. Each disorder is presented in the following format: overview, clinical characteristics, developmental aspects, associated sleep disorders, management and research/future directions. PMID- 28895941 TI - Outcome reporting bias in randomized-controlled trials investigating antipsychotic drugs. AB - Recent literature hints that outcomes of clinical trials in medicine are selectively reported. If applicable to psychotic disorders, such bias would jeopardize the reliability of randomized clinical trials (RCTs) investigating antipsychotics and thus their extrapolation to clinical practice. We therefore comprehensively examined outcome reporting bias in RCTs of antipsychotic drugs by a systematic review of prespecified outcomes on ClinicalTrials.gov records of RCTs investigating antipsychotic drugs in schizophrenia and schizoaffective disorder between 1 January 2006 and 31 December 2013. These outcomes were compared with outcomes published in scientific journals. Our primary outcome measure was concordance between prespecified and published outcomes; secondary outcome measures included outcome modifications on ClinicalTrials.gov after trial inception and the effects of funding source and directionality of results on record adherence. Of the 48 RCTs, 85% did not fully adhere to the prespecified outcomes. Discrepancies between prespecified and published outcomes were found in 23% of RCTs for primary outcomes, whereas 81% of RCTs had at least one secondary outcome non-reported, newly introduced, or changed to a primary outcome in the respective publication. In total, 14% of primary and 44% of secondary prespecified outcomes were modified after trial initiation. Neither funding source (P=0.60) nor directionality of the RCT results (P=0.10) impacted ClinicalTrials.gov record adherence. Finally, the number of published safety endpoints (N=335) exceeded the number of prespecified safety outcomes by 5.5 fold. We conclude that RCTs investigating antipsychotic drugs suffer from substantial outcome reporting bias and offer suggestions to both monitor and limit such bias in the future. PMID- 28895943 TI - Machine-learned and codified synthesis parameters of oxide materials. AB - Predictive materials design has rapidly accelerated in recent years with the advent of large-scale resources, such as materials structure and property databases generated by ab initio computations. In the absence of analogous ab initio frameworks for materials synthesis, high-throughput and machine learning techniques have recently been harnessed to generate synthesis strategies for select materials of interest. Still, a community-accessible, autonomously compiled synthesis planning resource which spans across materials systems has not yet been developed. In this work, we present a collection of aggregated synthesis parameters computed using the text contained within over 640,000 journal articles using state-of-the-art natural language processing and machine learning techniques. We provide a dataset of synthesis parameters, compiled autonomously across 30 different oxide systems, in a format optimized for planning novel syntheses of materials. PMID- 28895942 TI - Disrupted cortical brain network in post-traumatic stress disorder patients: a resting-state electroencephalographic study. AB - This study aimed to examine the source-level cortical brain networks of post traumatic stress disorder (PTSD) based on the graph theory using electroencephalography (EEG). Sixty-six cortical source signals were estimated from 78 PTSD and 58 healthy controls (HCs) of resting-state EEG. Four global indices (strength, clustering coefficient (CC), path length (PL) and efficiency) and one nodal index (CC) were evaluated in six frequency bands (delta, theta, alpha, low beta, high beta and gamma). PTSD showed decreased global strength, CC and efficiency, in delta, theta, and low beta band and enhanced PL in theta and low beta band. In low beta band, the strength and CC correlated positively with the anxiety scores, while PL had a negative correlation. In addition, nodal CCs were reduced in PTSD in delta, theta and low beta band. Nodal CCs of theta band correlated negatively with rumination and re-experience symptom scores; while, nodal CCs in low beta band correlated positively with anxiety and pain severity. Inefficiently altered and symptom-dependent changes in cortical networks were seen in PTSD. Our source-level cortical network indices might be promising biomarkers for evaluating PTSD. PMID- 28895944 TI - Genome wide in vivo mouse screen data from studies to assess host regulation of metastatic colonisation. AB - The process of metastasis is a multi-stage cascade with prior studies suggesting that the colonisation of the secondary site is the rate limiting step. This process involves contributions from the tumour cells and also non-tumour intrinsic factors such as the stroma and the haematopoietic system. In this study, we present data from screening 810 genetically-modified mouse lines with the experimental metastasis assay where intravenous delivery of murine metastatic melanoma B16-F10 cells was used to assess the formation of pulmonary metastasic foci. To date, these data have been studied with a two-step process cumulating in an integrative data analysis to identify genes controlling metastatic colonisation. We present the raw data, and a description to support fresh analyses where researchers can look both within and across gene sets to further elucidate process that regulate metastatic colonisation. PMID- 28895946 TI - DNA-SIP based genome-centric metagenomics identifies key long-chain fatty acid degrading populations in anaerobic digesters with different feeding frequencies. AB - Fats, oils and greases (FOG) are energy-dense wastes that can be added to anaerobic digesters to substantially increase biomethane recovery via their conversion through long-chain fatty acids (LCFAs). However, a better understanding of the ecophysiology of syntrophic LCFA-degrading microbial communities in anaerobic digesters is needed to develop operating strategies that mitigate inhibitory LCFA accumulation from FOG. In this research, DNA stable isotope probing (SIP) was coupled with metagenomic sequencing for a genome centric comparison of oleate (C18:1)-degrading populations in two anaerobic codigesters operated with either a pulse feeding or continuous-feeding strategy. The pulse-fed codigester microcosms converted oleate into methane at over 20% higher rates than the continuous-fed codigester microcosms. Differential coverage binning was demonstrated for the first time to recover population genome bins (GBs) from DNA-SIP metagenomes. About 70% of the 13C-enriched GBs were taxonomically assigned to the Syntrophomonas genus, thus substantiating the importance of Syntrophomonas species to LCFA degradation in anaerobic digesters. Phylogenetic comparisons of 13C-enriched GBs showed that phylogenetically distinct Syntrophomonas GBs were unique to each codigester. Overall, these results suggest that syntrophic populations in anaerobic digesters can have different adaptive capacities, and that selection for divergent populations may be achieved by adjusting reactor operating conditions to maximize biomethane recovery. PMID- 28895945 TI - Excess labile carbon promotes the expression of virulence factors in coral reef bacterioplankton. AB - Coastal pollution and algal cover are increasing on many coral reefs, resulting in higher dissolved organic carbon (DOC) concentrations. High DOC concentrations strongly affect microbial activity in reef waters and select for copiotrophic, often potentially virulent microbial populations. High DOC concentrations on coral reefs are also hypothesized to be a determinant for switching microbial lifestyles from commensal to pathogenic, thereby contributing to coral reef degradation, but evidence is missing. In this study, we conducted ex situ incubations to assess gene expression of planktonic microbial populations under elevated concentrations of naturally abundant monosaccharides (glucose, galactose, mannose, and xylose) in algal exudates and sewage inflows. We assembled 27 near-complete (>70%) microbial genomes through metagenomic sequencing and determined associated expression patterns through metatranscriptomic sequencing. Differential gene expression analysis revealed a shift in the central carbohydrate metabolism and the induction of metalloproteases, siderophores, and toxins in Alteromonas, Erythrobacter, Oceanicola, and Alcanivorax populations. Sugar-specific induction of virulence factors suggests a mechanistic link for the switch from a commensal to a pathogenic lifestyle, particularly relevant during increased algal cover and human-derived pollution on coral reefs. Although an explicit test remains to be performed, our data support the hypothesis that increased availability of specific sugars changes net microbial community activity in ways that increase the emergence and abundance of opportunistic pathogens, potentially contributing to coral reef degradation. PMID- 28895947 TI - Database of multi-parametric geophysical data from the TOMO-DEC experiment on Deception Island, Antarctica. AB - Deception Island volcano (Antarctica) is one of the most closely monitored and studied volcanoes on the region. In January 2005, a multi-parametric international experiment was conducted that encompassed both Deception Island and its surrounding waters. We performed this experiment from aboard the Spanish oceanographic vessel 'Hesperides', and from five land-based locations on Deception Island (the Spanish scientific Antarctic base 'Gabriel de Castilla' and four temporary camps). This experiment allowed us to record active seismic signals using a large network of seismic stations that were deployed both on land and on the seafloor. In addition, other geophysical data were acquired, including bathymetric high precision multi-beam data, and gravimetric and magnetic profiles. To date, the seismic and bathymetric data have been analysed but the magnetic and gravimetric data have not. We provide P-wave arrival-time picks and seismic tomography results in velocity and attenuation. In this manuscript, we describe the main characteristics of the experiment, the instruments, the data, and the repositories from which data and information can be obtained. PMID- 28895948 TI - Underwater recordings of the whistles of bottlenose dolphins in Fremantle Inner Harbour, Western Australia. AB - Dolphins use frequency-modulated whistles for a variety of social functions. Whistles vary in their characteristics according to context, such as activity state, group size, group composition, geographic location, and ambient noise levels. Therefore, comparison of whistle characteristics can be used to address numerous research questions regarding dolphin populations and behaviour. However, logistical and economic constraints on dolphin research have resulted in data collection biases, inconsistent analytical approaches, and knowledge gaps. This Data Descriptor presents an acoustic dataset of bottlenose dolphin (Tursiops aduncus) whistles recorded in the Fremantle Inner Harbour, Western Australia. Data were collected using an autonomous recorder and analysed using a range of acoustic measurements. Acoustic data review identified 336 whistles, which were subsequently measured for six key characteristics using Raven Pro software. Of these, 164 'high-quality' whistles were manually measured to provide an additional five acoustic characteristics. Digital files of individual whistles and corresponding measurements make this dataset available to researchers to address future questions regarding variations within and between dolphin communities. PMID- 28895950 TI - Diabetes: Cardiovascular benefits of metformin in T1DM. PMID- 28895951 TI - Diabetes: The diabetic brain. PMID- 28895949 TI - Fish and fishery historical data since the 19th century in the Adriatic Sea, Mediterranean. AB - Historic data on biodiversity provide the context for present observations and allow studying long-term changes in marine populations. Here we present multiple datasets on fish and fisheries of the Adriatic Sea covering the last two centuries encompassing from qualitative observations to standardised scientific monitoring. The datasets consist of three groups: (1) early naturalists' descriptions of fish fauna, including information (e.g., presence, perceived abundance, size) on 255 fish species for the period 1818-1936; (2) historical landings from major Northern Adriatic fish markets (Venice, Trieste, Rijeka) for the period 1902-1968, Italian official landings for the Northern and Central Adriatic (1953-2012) and landings from the Lagoon of Venice (1945-2001); (3) trawl-survey data from seven surveys spanning the period 1948-1991 and including Catch per Unit of Effort data (kgh-1 and/or nh-1) for 956 hauls performed at 301 stations. The integration of these datasets has already demonstrated to be useful to analyse historical marine community changes over time, and its availability through open-source data portal will facilitate analyses in the framework of marine historical ecology. PMID- 28895952 TI - [Socioeconomic inequalities in mortality due to all causes in the working age population of Poland in 2002 and 2011]. AB - BACKGROUND: The aim of the study was to evaluate the influence of education, marital status, employment status and place of residence on mortality in the working age population of Poland in 2002 and 2011. MATERIAL AND METHODS: All deaths of Poland's inhabitants aged 25-64, in 2002 (N = 97 004) and 2011 (N = 104 598) were analyzed. For individual socio-economic groups standardized mortality rates (SDR) per 100 000 and rate ratio (RR) were calculated. RESULTS: In the group of economically inactive men SDR decreased from 2244.3 in 2002 to 1781.9 in 2011, while in the group of economically active population increased from 253.8 to 298.9 (RR drop from 8.8 to 6). In the group of economically inactive women SDR decreased from 579.5 to 495.2, and among the economically active women population it increased from 78.8 to 90.9 (RR drop from 7.4 to 5.4). In the group of men with higher education SDR decreased from 285.7 to 246, while among men with primary education it increased from 1141 to 1183 (RR increase from 4 to 4.8). In the group of women with higher education SDR decreased from 127.2 to 115.6 and among women with primary education it increased from 375.8 to 423.1 (RR increase from 3 to 3.7). In the group of divorced/separated SDR also increased - from 1521.4 to 1729.8 among men and from 365.5 to 410.8 among women. CONCLUSIONS: Future prevention and educational programs should be addressed primarily to the population economically inactive, with primary education and those divorced/separated. Med Pr 2017;68(6):771-778. PMID- 28895953 TI - Curriculum United for Better Eczema Care: why, how, and what? AB - While various medical specialties treat eczema patients, care for these patients is largely fragmented and disorganized. Moreover, standardized treatment protocols that incorporate upcoming eczema therapies and emerging guidelines have yet to be established. Thus, there is both a need and an opportunity to equip clinicians to succeed in this novel and changing era of eczema care. The National Eczema Association's (NEA) strategic plan-developed through extensive discussions with patients who have atopic dermatitis and their caregivers, industry, and providers representing different specialties-called for the creation of an interdisciplinary coalition to steer this initiative. The Coalition United for Better Eczema Care (CUBE-C) is a network of cross-specialty leaders working to help construct an educational curriculum based on standards of effective treatment and disease management. PMID- 28895954 TI - Diagnosis, comorbidity, and psychosocial impact of atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease, with a remitting relapsing course. The central diagnostic features of AD include pruritus, xerosis, eczematous lesions with a characteristic morphology and distribution, and a personal or family history of atopic disease. Several clinical studies have emphasized the link between AD and other atopic disorders including asthma, allergic rhinitis, and food allergies. More recent studies indicate possible links between AD and other nonatopic disorders, including ADHD, sleep disturbance, and mental health disorders, suggesting an even more profound impact of this disease. Furthermore, the social, emotional, and personal impact of AD for patients and their caregivers is substantial. Understanding both the clinical characteristics and implications of AD is critical to lessening the psychosocial, clinical, and economic burden of this disease. PMID- 28895955 TI - Atopic dermatitis: pathogenesis. AB - Atopic Dermatitis (AD) is a complex inflammatory cutaneous disorder characterized by immune mediated inflammation and epidermal barrier dysfunction. Arising from a complex interplay between environmental and genetic factors, the definitive etiology of AD is perplexing and controversial. Advances in molecular medicine are radically transforming our understanding of AD pathogenesis. Increasing knowledge on the pathogenesis of AD results in novel therapeutic targets and pathways. This article details the pathogenesis section of the Curriculum United for Better Eczema Care (CUBE-C), facilitating primary care and sub-specialist education on the scientific advances driving recent AD therapeutic innovations. PMID- 28895956 TI - Atopic dermatitis: skin care and topical therapies. AB - Atopic dermatitis (AD) pathogenesis is strongly influenced by Type 2 innate lymphoid cell and T-helper cell type 2 lymphocyte-driven inflammation and skin barrier dysfunction. AD therapies attempt to correct this pathology, and guidelines suggest suggest basics of AD therapy, which include repair of the skin barrier through bathing practices and moisturizers, infection control, and further lifestyle modifications to avoid and reduce AD triggers.While some patients' AD may be controlled using these measures, inflammatory eczema including acute flares and maintenance therapy in more severe patients are treated with topical pharmacologic agents such as topical corticosteroids, topical calcineurin inhibitors, and, more recently, topical PDE-4 inhibitors. This model of basic skin therapy and, as needed, topical pharmacologic agents may be used to treat the vast majority of patients with AD and remains the staple of AD therapy. PMID- 28895957 TI - Atopic dermatitis: addressing allergy, infection, itch and complementary therapies. AB - Atopic dermatitis (AD) is a complex condition that results from the dynamic interplay between genetic predisposition, skin barrier defects, environmental factors, and a dysfunctional immune system. As a result, AD can be complicated by irritant and allergic contact dermatitis and imbalances in the skin microbiome, which can subsequently exacerbate the severity and complicate the course of preexisting atopic disease. Itch is an important symptom of AD, as it plays a large role in the quality of life of patients and their families. Since AD is a chronic, inflammatory disease that recrudesces throughout life, many have utilized alternative and/or complementary therapies, as monotherapy or in conjunction with conventional therapies, as a form of management. PMID- 28895958 TI - Atopic dermatitis: phototherapy and systemic therapy. AB - The majority of atopic dermatitis (AD) patients respond satisfactorily to gentle bathing, frequent moisturizing, and topical medications. Second-line therapies for AD should be used in recalcitrant cases or in patients with uncontrolled disease despite compliance with first-line measures and avoidance of allergens. Recommended advanced therapies include phototherapy, especially narrowband ultraviolet B, systemic immunosuppressants, and a new biologic agent. Few studies have compared head-to-head efficacy of the different immunosuppressant therapies such as cyclosporine, methotrexate, azathioprine and mycophenolate mofetil. Therefore, the agent used is based on provider and patient preferences and can be decided on a case-by-case basis. PMID- 28895959 TI - Atopic dermatitis: emerging therapies. AB - Crisaborole and dupilumab represent the first 2 Food and Drug Administration (FDA)-approved therapies for atopic dermatitis (AD) in more than 15 years, and there are many promising drugs currently in development. This new wave of therapeutics capitalizes on the large body of work clarifying the pathogenesis of AD over the last several decades. In particular, type 2 cytokine-driven inflammation and skin barrier dysfunction are key processes underlying AD pathogenesis. PMID- 28895960 TI - Atopic dermatitis: therapeutic care delivery: therapeutic education, shared decision-making, and access to care. AB - Atopic dermatitis (AD) is a chronic skin condition affecting children and adults, with a significant negative impact on patient and caregiver quality of life (QOL). Although effective treatments for AD are available, outcomes are often limited by poor adherence to treatment plans. Effective patient and caregiver education about the disease and its management is a necessary and important component of AD care. Therapeutic patient education (TPE) is a patient-centered process that aims to transfer information and skills necessary to manage and cope with a disease from health care professionals to patients and caregivers. Shared decision making between the health care provider and the patient/caregiver is an integral component of the TPE process and recognizes the importance of both the medical provider's clinical expertise, as well as the patient/caregiver's preferences and experiences regarding their own medical condition and its treatment. TPE programs for patients with AD and their caregivers are typically provided by multidisciplinary teams and utilize a number of different methods and tools to facilitate the transfer of knowledge and skills through both individual care and group-based educational sessions. TPE has been demonstrated to improve outcomes such as AD disease severity, treatment adherence, QOL, and coping with itch. It is important to consider strategies to reduce barriers to cost-effective accessible AD education and treatment. PMID- 28895961 TI - Microporous organic polymers involving thiadiazolopyridine for high and selective uptake of greenhouse gases at low pressure. AB - A new core of [1,2,5]-thiadiazolo-[3,4-c]-pyridine was employed for the fabrication of microporous organic polymers exhibiting a very high CO2 uptake of 5.8 mmol g-1 (25.5 wt%) at 273 K and 1 bar. The presence of CO2-philic active sites and microporosity confer the high uptake and superior selectivity (61) towards CO2 over N2. PMID- 28895962 TI - How functional groups influence the ROS generation and cytotoxicity of graphene quantum dots. AB - Herein we selectively deactivate the ketonic carbonyl, carboxylic, or hydroxyl groups on GQDs and compare the ROS generation ability of different GQD derivatives. The results indicate that the ROS generation ability of GQDs is closely related to the ketonic carbonyl groups. Removal of the oxygen functional groups on GQDs can increase the photostability and lower the photoinduced cytotoxicity. PMID- 28895963 TI - Small-angle neutron scattering study of a dense microemulsion system formed with an ionic liquid. AB - Mixtures of water, octane and 1-octanol with 1-tetradecyl-3-methylimidazolium chloride (C14MIM.Cl), often referred to as a surface active ionic liquid (SAIL), form water-in-oil microemulsions that have potential application as extraction media for various metal ions. Here, we present a structural study by small-angle neutron scattering (SANS) of dense microemulsions formed by surfactant-rich mixtures of these four compounds to understand how the SAIL can be used to tune the structures and properties of the microemulsions. The SANS experiments revealed that the microemulsions formed are composed of two phases, a water-in oil microemulsion and a bicontinuous microemulsion, which becomes the dominant phase at high surfactant concentration. In this concentration regime, the surfactant film becomes more rigid, having a higher bending modulus that results from the parallel stacking of the imidazolium ring of the SAIL. At lower surfactant concentrations, the molecular packing of the SAIL does not change with the water content of the microemulsion. The results presented here correlate well with previously observed changes in the interaction between the IL cation and metal ions (Y. Tong, L. Han and Y. Yang, Ind. Eng. Chem. Res., 2012, 51, 16438 16443), while the capacity of the microemulsion system for water remains high enough for using the system as an extraction medium. PMID- 28895964 TI - Dynamic SERS nanosensor for neurotransmitter sensing near neurons. AB - Current electrophysiology and electrochemistry techniques have provided unprecedented understanding of neuronal activity. However, these techniques are suited to a small, albeit important, panel of neurotransmitters such as glutamate, GABA and dopamine, and these constitute only a subset of the broader range of neurotransmitters involved in brain chemistry. Surface-enhanced Raman scattering (SERS) provides a unique opportunity to detect a broader range of neurotransmitters in close proximity to neurons. Dynamic SERS (D-SERS) nanosensors based on patch-clamp-like nanopipettes decorated with gold nanoraspberries can be located accurately under a microscope using techniques analogous to those used in current electrophysiology or electrochemistry experiments. In this manuscript, we demonstrate that D-SERS can measure in a single experiment ATP, glutamate (glu), acetylcholine (ACh), GABA and dopamine (DA), among other neurotransmitters, with the potential for detecting a greater number of neurotransmitters. The SERS spectra of these neurotransmitters were identified with a barcoding data processing method and time series of the neurotransmitter levels were constructed. The D-SERS nanosensor was then located near cultured mouse dopaminergic neurons. The detection of neurotransmitters was performed in response to a series of K+ depolarisations, and allowed the detection of elevated levels of both ATP and dopamine. Control experiments were also performed near glial cells, showing only very low basal detection neurotransmitter events. This paper demonstrates the potential of D-SERS to detect neurotransmitter secretion events near living neurons, but also constitutes a strong proof-of-concept for the broad application of SERS to the detection of secretion events by neurons or other cell types in order to study normal or pathological cell functions. PMID- 28895965 TI - Propagation of a thermo-mechanical perturbation on a lipid membrane. AB - The propagation of sound waves on lipid monolayers supported on water has been previously studied during the melting transition. Since changes in volume, area, and compressibility in lipid membranes have biological relevance, the observed sound propagation is of paramount importance. However, it is unknown what would occur on a lipid bilayer, which is a more approximate model of a cell membrane. With the aim to answer this relevant question, we built an experimental setup to assemble long artificial lipid membranes. We found that if these membranes are heated in order to force local melting, a thermo-mechanical perturbation propagates a long distance. Our findings may support the existence of solitary waves, postulated to explain the propagation of isentropic signals together with the action potential in neurons. PMID- 28895966 TI - Pd-PEPPSI: a general Pd-NHC precatalyst for Buchwald-Hartwig cross-coupling of esters and amides (transamidation) under the same reaction conditions. AB - Amides are of fundamental interest in many fields of chemistry involving organic synthesis, chemical biology and biochemistry. Here, we report the first catalytic Buchwald-Hartwig coupling of both common esters and amides by highly selective C(acyl)-X (X = O, N) cleavage to rapidly access aryl amide functionality via a cross-coupling strategy. Reactions are promoted by versatile, easily prepared, well-defined Pd-PEPPSI type precatalysts, and proceed in good to excellent yields and with excellent chemoselectivity for the acyl bond cleavage. The method is user friendly because it employs commercially-available, moisture- and air-stable precatalysts. Notably, for the first time we demonstrate selective C(acyl)-N and C(acyl)-O cleavage/Buchwald-Hartwig amination under the same reaction conditions, which allows for streamlining amide synthesis by avoiding restriction to a particular acyl metal precursor. Of broad interest, this study opens the door to using a family of well-defined Pd(ii)-NHC precatalysts bearing pyridine "throw away" ligands for the selective C(acyl)-amination of bench-stable carboxylic acid derivatives. PMID- 28895967 TI - Scavenging activity of Magneli phases as a function of Ti4+/Ti3+ ratios. AB - TiO2 is able to scavenge reactive oxygen and nitrogen species (ROS and RNS) in the absence of light. The scavenging mechanism has been related to the chemistry of defects (oxygen vacancy reduced oxidation states of Ti) but it is still unknown. This study describes the ROS scavenging activity of different titanium oxide phases and relates their scavenging activities with the Ti4+/Ti3+ molar ratio as well as the band gap value. The Ti5O9 phase, with a mixture of both oxidation states, presented a substantially higher percentage of 2,2-diphenyl-1 picrylhydracyl radicals (DPPH) eliminated per m2 of specific surface area in comparison to phases with predominant oxidation states Ti4+ or Ti3+ such as TiO2 and Ti2O3, respectively. The obtained results indicate that the DPPH scavenging mechanism corresponds to a catalytic process on the Ti5O9 surface which is facilitated by the presence of charges that can easily move through the material. The mobility of charges and electrons in the semiconductor surface, related to the presence of oxidation states Ti4+ and Ti3+ and a small band gap, could create an attractive surface for radical species such as DPPH. This puts forward Ti5O9 as a promising candidate coating for implantable biomedical devices, as an electrode, since it can cushion inflammatory processes which could lead to device encapsulation and, consequently, failure. PMID- 28895968 TI - Multiscale crack initiator promoted super-low ice adhesion surfaces. AB - Preventing icing on exposed surfaces is important for life and technology. While suppressing ice nucleation by surface structuring and local confinement is highly desirable and yet to be achieved, a realistic roadmap of icephobicity is to live with ice, but with lowest possible ice adhesion. According to fracture mechanics, the key to lower ice adhesion is to maximize crack driving forces at the ice substrate interface. Herein, we present a novel integrated macro-crack initiator mechanism combining nano-crack and micro-crack initiators, and demonstrate a new approach to designing super-low ice adhesion surfaces by introducing sub structures into smooth polydimethylsiloxane coatings. Our design promotes the initiation of macro-cracks and enables the reduction of ice adhesion by at least ~50% regardless of the curing temperature, weight ratio and size of internal holes, reaching a lowest ice adhesion of 5.7 kPa. The multiscale crack initiator mechanisms provide an unprecedented and versatile strategy towards designing super-low ice adhesion surfaces. PMID- 28895969 TI - Correction: Gold-loaded nanoporous iron oxide nanocubes: a novel dispersible capture agent for tumor-associated autoantibody analysis in serum. AB - Correction for 'Gold-loaded nanoporous iron oxide nanocubes: a novel dispersible capture agent for tumor-associated autoantibody analysis in serum' by Sharda Yadav et al., Nanoscale, 2017, 9, 8805-8814. PMID- 28895970 TI - Mechanisms and applications of terahertz metamaterial sensing: a review. AB - Terahertz (THz) technology has attracted great worldwide interest and novel high intensity THz sources and plasmonics are two of the most active fields of recent research. Being situated between infrared light and microwave radiation, the absorption of THz rays in molecular and biomolecular systems is dominated by the excitation of intramolecular and intermolecular vibrations. This indicates that THz technology is an effective tool for sensing applications. However, the low sensitivity of free-space THz detection limits the sensing applications, which gives a great opportunity to metamaterials. Metamaterials are periodic artificial electromagnetic media structured with a size scale smaller than the wavelength of external stimuli. They present localized electric field enhancement and large values of quality factor (Q factor) and show high sensitivity to minor environment changes. In the present work, the mechanism of THz metamaterial sensing and dry sample and microfluidic sensing applications based on metamaterials are introduced. Moreover, new directions of THz metamaterial sensing advancement and introduction of two-dimensional materials and nanoparticles for future THz applications are summarized and discussed. PMID- 28895971 TI - May-Thurner syndrome: missed diagnosis and missed early treatment? PMID- 28895972 TI - Motivators and Barriers to Walking in Older Adults With Peripheral Artery Disease. AB - The purpose of the current review is to provide, within the context of social cognitive theory, a current description of behavioral, personal, and environmental factors that motivate or prevent an individual with peripheral artery disease (PAD) from participating in activity. A comprehensive review to explore motivators and barriers to walking in older adults with PAD was performed to help guide development of interventions to increase activity. Several databases were used for the literature review, with inclusion criteria being all study designs with samples of older adults with PAD. From the initial yield of 22 abstracts, and additional hand search, eight publications were used for this review. Social cognitive theory provided a context for understanding barriers and motivators to walking experienced by older adults with PAD. Nurses may contribute to walking self-efficacy with support and motivation. [Journal of Gerontological Nursing, 44(1), 43-50.]. PMID- 28895974 TI - Intergenerational Program for Nursing Home Residents and Adolescents in Korea. AB - Structural changes in the Korean population, such as a growing trend toward nuclear families and urbanization, have given rise to a generational gap between older adults and the younger generation. The current study developed a 6-week intergenerational program to facilitate interactions between nursing home residents and high school students. The effects of the program were examined in 120 participants (60 nursing home residents and 60 high school students) in the southern area of South Korea. The intergenerational program helped nursing home residents rediscover the value of their lives, have positive feelings about their lives, and adapt to circumstances through the sustained positive interactions with the younger generation. Adolescents obtained wisdom from older adults' experiences, understanding of the value of life, and positive perceptions of older adults through in-depth communication. The current findings suggest that the intergenerational program for nursing home residents and adolescents is a valuable nursing intervention in Korea to overcome the generational gap and achieve developmental tasks. [Journal of Gerontological Nursing, 44(1), 32-41.]. PMID- 28895973 TI - Development and Testing of a Neuropsychiatric Symptoms Model in Mild Cognitive Impairment. AB - Neuropsychiatric symptoms are prevalent in individuals with mild cognitive impairment (MCI) and have a significant detrimental effect on health and quality of life. Identifying factors that contribute to their occurrence may enable prompt treatment and intervention. The current study entails the development and testing of a biopsychosocially based model to assist nurses in the identification of individuals with MCI who are most likely to experience symptoms of depression, apathy, and/or anxiety. Factors within the biological and sociodemographic domains of the Neuropsychiatric Symptoms in MCI (NPSMCI) model were tested using multivariate logistic regression analyses. Findings suggest that age, presence of an e4 allele of the apolipoprotein E gene, living situation, and degree of comorbid illness were associated with the occurrence of symptoms of depression and apathy. Further testing and refinement are necessary, but the findings provide guidance to nurses and alert them to assess individuals most likely to experience these symptoms. [Journal of Gerontological Nursing, 44(1), 21-30.]. PMID- 28895975 TI - ? PMID- 28895976 TI - ? PMID- 28895977 TI - ? PMID- 28895978 TI - ? PMID- 28895979 TI - ? PMID- 28895980 TI - Coping with the pain of elderly pain patients: Nursing approach. AB - OBJECTIVES: This study was designed to examine methods used by elderly patients to cope with pain and serve as a guide for nurses. METHODS: This descriptive survey was carried out with geriatric patients (n=100) aged 60 years or more in inpatient Algology Unit of a university hospital between November 28, 2014 and January 28, 2015. Data were collected using descriptive characteristics questionnaire prepared based on review of the literature and via one-on-one interviews using Pain Coping Questionnaire (PCQ). Data were evaluated using descriptive statistical methods, Independent sample t-test, one-way analysis of variance test, and Pearson correlation coefficient. RESULTS: Duration of pain experienced by the patients ranged from 1 month to 40 years, with mean duration of 63.57+/-82.65 months. Mean subscale scores of PCQ were: self-management, 19.22+/-6.54; helplessness, 13.45+/-3.86; conscious coping efforts, 11.90+/-3.97; and medical remedies, 12.62+/-3.98. Score of the patients who reported that they could manage their pain on their own (p<0.05), and of those who relied on medical remedies, believing that pain control is in the hands of nurses (p<0.05), were significantly higher. CONCLUSION: Means of coping with pain vary in geriatric patients and it is recommended that these differences be taken into account in nursing interventions. PMID- 28895982 TI - Prevalence of and risk factors for low back pain among healthcare workers in Denizli. AB - OBJECTIVES: The purpose of this study was to examine personal, occupational, and psychosocial risk factors affecting prevalence of low back pain in healthcare workers. METHODS: Study included total of 1682 participants (1010 female, 672 male) working at Denizli State Hospital. Low back pain section of Standardized Nordic Musculoskeletal Questionnaire (SNMA) was used to evaluate recent occurrence, pain experienced within previous year, and over lifetime. Perceived Stress Scale and Job Satisfaction Scale were also administered. RESULTS: Prevalence of lifetime low back pain in healthcare workers was determined to be 53% based on SNMA. It was observed that low back pain was most common among medical secretaries (56.9%). Advanced age, female gender, high body mass index (p=0.002), being married (p=0.0001), lack of regular exercise (p=0.009), working for more than 4 hours while standing (p=0.012) or sitting at desk (p=0.021), using computer for more than 4 hours (p=0.0001), greater number of years of service (p=0.001), and low job satisfaction (p=0.001) were found to be factors increasing low back pain risk. CONCLUSION: Our study demonstrated that healthcare workers are among group with high risk of low back pain. PMID- 28895981 TI - Radiofrequency thermocoagulation for the treatment of lower extremity ischemic pain: Comparison of monopolar and bipolar modes. AB - OBJECTIVES: Radiofrequency thermocoagulation (RFT) has been reported to be used safely to treat ischemic lower extremity pain. The objective of the present study was to evaluate efficiency of RFT for treatment of lower extremity ischemic pain and to compare effectiveness of monopolar RFT and bipolar RFT modes. METHODS: Following ethics committee approval, 30 American Society of Anesthesiologists classification I-III patients with ischemic lower extremity pain aged between 18 and 65 years were recruited. Patients were randomly allocated into 2 groups: MRT group (n=15) received monopolar RFT (80 degrees C) for 2 minutes at L2-3 level, and BRT group (n=15) received bipolar RFT (80 degrees C) for 2 minutes at L2-3 level. Systolic and diastolic blood pressure, heart rate, pain score, and supplemental analgesic requirements were recorded at 24 hours after application and at 7, 30, and 90 days. RESULTS: Numerical rating scale values in both groups decreased significantly over time and it was found to be significantly lower in BRT group after first and third months (p<0.05). Supplemental analgesic requirements were similar with no significant difference between the 2 groups at any point of study period (p>0.05). No adverse event or complication related to procedure or treatment was reported. CONCLUSION: In patients with ischemic lower extremity pain, both monopolar and bipolar RFT treatment modalities were found to significantly decrease pain levels. However, bipolar mode led to lower pain scores at 30 and 90 days, and longer duration of analgesia than monopolar mode. PMID- 28895983 TI - Primary headache associated with sexual activity: A case report. AB - Headaches provoked by triggering factors have been recognized for many decades. In many cases, the development of such headaches is secondary to an underlying pathology. However, in some cases, no abnormality can be identified. Primary headache associated with sexual activity (PHASA) is one of the subgroups of primary headaches. PHASA is a benign form of headache and lifetime prevalence is estimated to be 1% to 1.6% in the general population. A 38-year-old man was admitted to outpatient clinic reporting history of severe headaches during sexual intercourse for the last 2 months. Headaches occurred bilaterally in occipital area just after orgasm and lasted for about 2 hours. Propranolol 40 mg/ day was initiated and on followup, patient reported dramatic improvement in 2 weeks. Treatment was maintained for 6 months. Patient has been on regular follow-up for a year and had no recurrence of headache. This is a rare case PHASA. In this patient, prophylactic treatment with low dosage of propranolol was successful. PMID- 28895985 TI - [Antihistaminik kullanimi ile tetiklenen tekrarlayici bas agrisi ve reversible serebral vazokonstriksiyon sendromu]. AB - Reversible cerebral vasoconstriction syndrome (RCVS), also known as Call-Fleming syndrome, is one of the rare causes of thunderclap headaches, which are most often seen in females aged 20-40 years and which can cause neurological deficits. The cause of RCVS is thought to be multifocal arterial constriction and dilatation caused by transient disregulation of cerebral vascular tonus. Presently described is case of 63-year-old female patient who presented with complaint of sudden onset of recurrent headaches located on the left side. Physical and neurological examinations were normal. Cranial magnetic resonance imaging (MRI) angiography examination showed vasoconstrictions in the distal, particularly in middle cerebral arteries and posterior cerebral arteries. Primary angitis of central nervous system (CNS), first considered in differential diagnosis, was excluded because no parenchymal lesion was seen in cranial MRI and no protein increase was observed in cerebrospinal fluid. Dexamethasone sodium phosphate 4 mg/mL (4 mg/day) and nimodipine 90 mg/day treatment was initiated. Nimodipine dose was gradually increased to 120 mg/day. Headache resolved significantly after discontinuation of antihistaminic agents. The most important feature of RCVS to be highlighted is that clinical signs are reversible, unlike subarachnoid hemorrhage or primary angitis of CNS, which have similar clinical presentations. Although clinical signs of RCVS usually resolve, it should be considered that permanent neurological deficits may occur. PMID- 28895984 TI - [A rare cause of analgesic-resistant chronic headache: Isolated aspergilloma of the sphenoid sinus]. AB - The diagnosis of sphenoid sinus diseases is difficult due to nonspecific history and physical examination findings. Sphenoid sinus is a rare localization for aspergilloma. Delay in diagnosis and treatment can result in serious complications. Presently described is case of sphenoid sinus aspergilloma. Patient had been treated by department of psychiatry for many years due to sleep disturbances and headache. Clinical and radiological features of rare case of sphenoid sinus aspergilloma are discussed. PMID- 28895986 TI - An unusual complication of anesthesia: Unilateral spinal myoclonus. PMID- 28895987 TI - Sonoanatomic variation of the vasculature at infraclavicular region. PMID- 28895988 TI - Pain in women. AB - Men and women are different in response to experimental painful stimulation, in pain attitude such as reporting pain and pain coping behavior, in symptoms and signs of painful disorders and in response to pain treatment. Both acute and chronic pain conditions have diverse prevalence among the sexes. Overall, women have more than twice higher prevalence in painful disorders compared to men. Here I review putative mechanisms underlying sex differences in pain, including genetic factors that have sex-specific or sex-biased effects controlling pain and analgesia. PMID- 28895989 TI - Transcatheter aortic valve implantation. PMID- 28895990 TI - Cardiac fibroma in a neonate. PMID- 28895991 TI - Difficult diagnosis of Kawasaki disease in a patient with giant coronary artery aneurysms. PMID- 28895992 TI - Mass in a pacemaker pocket. PMID- 28895993 TI - Intramyocardial haemorrhage as a rare complication of myocardial infarction - the diagnostic value of cardiovascular magnetic resonance imaging. PMID- 28895994 TI - Asymptomatic course of arrhythmogenic right ventricular cardiomyopathy. PMID- 28895995 TI - Complete thrombosis of the ductus arteriosus could be the option to be alive in the seventh decade of life without specific symptoms. PMID- 28895996 TI - Transcatheter aortic valve implantation. Expert Consensus of the Association of Cardiovascular Interventions of the Polish Cardiac Society and the Polish Society of Cardio-Thoracic Surgeons, approved by the Board of the Polish Cardiac Society.... AB - Patients with severe symptomatic aortic stenosis have a poor prognosis with medical management alone, and surgical aortic valve replacement can improve symptoms and survival. In recent years, transcatheter aortic valve implantation (TAVI) has been demonstrated to improve survival in inoperable patients and to be an alternative treatment in patients in whom the risk of surgical morbidity or mortality is high or intermediate. A representative expert committee, summoned by the Association of Cardiovascular Interventions of the Polish Cardiac Society (ACVI) and the Polish Society of Cardio-Thoracic Surgeons, devel-oped this Consensus Statement in transcatheter aortic valve implantation. It endorses the important role of a multi-disciplinary "TAVI team" in selecting patients for TAVI and defines operator and institutional requirements fundamental to the establish ment of a successful TAVI programme. The article summarises current evidence and provides specific recommendations on organisation and conduct of transcatheter treatment of patients with aortic valve disease in Poland. PMID- 28895997 TI - [Elevated incidence of cognitive impairment in patients with asymptomatic carotid stenosis]. AB - INTRODUCTION: Stroke is one of the main causes of mortality and functional disability in developed countries. Carotid stenosis (CS) is considered the reason for 20-30% of strokes. However, the studies that have gone into depth on the cognitive status of these patients are limited. AIM: To investigate the cognitive performance of CS patients and its relationship with clinical variables (carotid obstruction, lifestyle). PATIENTS AND METHODS: 33 CS patients were evaluated using a broad neuropsychological protocol, and were divided into two groups: symptomatic CS and asymptomatic CS. RESULTS: 50-57% of CS patients showed deficits in processing speed and visual memory (immediate recall). 41.9% showed altered performance in semantic fluency, whereas the percentage was 30% in digits subtest. The percentage of altered performance was 20-27% in verbal memory (learning curve, delayed recall) and visual memory (delayed recall). No significant differences were found between the symptomatic CS and asymptomatic CS groups. Cognitive performance correlated significantly with lifestyle scale factors, but not with the percentage of carotid obstruction. CONCLUSION: A high percentage of CS patients showed a clinically altered performance in different cognitive domains, regardless of suffering vascular neurological symptoms (symptomatic vs asymptomatic CS). A close relationship was found between lifestyle and cognitive status of CS patients. PMID- 28895998 TI - [Effects of an intensive thalassotherapy and aquatic therapy program in stroke patients. A pilot study]. AB - INTRODUCTION: Stroke remains the leading cause of acquired disability. Health and social planning and management may vary and although prevention is crucial, having better treatments and strategies to reduce disability is needed. AIM: To determine the effect of an intensive program of thalassotherapy and aquatic therapy in stroke patients, valuing clinical parameters and functional validated scales. PATIENTS AND METHODS: A quasi-experimental prospective study consisting of a specific program assessed pre- and post- 3 weeks treatment to 26 stroke patients with a mild-moderate disability. The outcomes measured were: Berg Balance scale, Timed Up and Go test, 10-meter walking test, 6-minute walking test and pain Visual Analogue Scale. RESULTS: After intervention, participants had a significant improvement in all outcomes measured. CONCLUSIONS: Our results suggest that an intensive program of thalassotherapy and aquatic therapy could be useful during stroke rehabilitation to improve balance, gait and pain. PMID- 28895999 TI - [Quality of life and associated characteristics of restless legs syndrome in the adult population of Burgos, Spain]. AB - INTRODUCTION: Restless legs syndrome (RLS) is a neurological disorder with a prevalence of up to 15%, although little is known about its impact upon quality of life. AIM: To analyse the impact of RLS on health-related quality of life. SUBJECTS AND METHODS: A descriptive cross-sectional study. A random sample of 1,275 subjects over 18 years old, stratified by age, was taken from the urban area of Burgos, with an estimated prevalence, 10%; alpha, 5%; accuracy, 3%; and losses, 70%, using a two-phase study (screening and diagnosis of cases of RLS and non-cases confirmed by a doctor). The clinical and sociodemographic data were collected by means of semi-structured questionnaires, the European Quality of Life-5 Dimensions, the Restless Legs Syndrome Quality of Life Questionnaire, the Epworth Scale, the Goldberg Scale, the Sleep Scale and the International Restless Legs Syndrome Rating Scale. RESULTS: The prevalence of RLS was 5.6% (CI 95%: 2.5 8.7%). Of the total number of cases, 79.4% were women and only 7% had been previously diagnosed with RLS. Intense pain, insomnia and depression-anxiety were more frequent among the cases of RLS than in the controls (p < 0.001 in the three cases). The quality of life among the cases of RLS, especially in women, was poorer than among the controls (p < 0.001). For 11.7% of the cases, RLS made it difficult for the patients to work. CONCLUSIONS: RLS is associated with depression-anxiety, with a significant impact on sleep, on social and work relationships, and on the health-related quality of life. PMID- 28896000 TI - [Symptomatic absence seizures, the least known causation of absence seizures]. AB - INTRODUCTION: According to the 1981 International League Against Epilepsy classification, absence seizures are the paradigm of idiopathic generalised seizures of childhood. Although absences are mainly of an idiopathic origin, there are also symptomatic absences, which account for 10% of all cases of absences. It is thought that a structural pathology can favour the appearance of absences in genetically predisposed individuals. CASE REPORTS: We report the cases of two patients with symptomatic absence seizures of childhood onset. The first presented thalamic damage of a perinatal origin and the second had glucose transporter deficiency in the brain. CONCLUSION: A percentage of absence seizures in childhood are of a symptomatic origin. This occurs more frequently in children who present other types of epilepsy, focal or diffuse brain damage, and in early onset absences. PMID- 28896002 TI - [Intracerebral pial arteriovenous fistula with giant venous varix]. PMID- 28896001 TI - [Barriers impeding access to epilepsy surgery: a review of the literature]. AB - Drug-resistant epilepsy, a chronic condition with long-term consequences can be treated with surgery. The efficacy and safety of surgery for temporal lobe epilepsy have been established through a large number of retrospective and prospective cohort studies and two randomized controlled clinical trials. Despite the excellent outcomes reported after surgery, the literature suggests that this procedure is an underutilized treatment. While evidence is lacking as to why epilepsy surgery is underused, cited reasons include: failure of primary care physicians and neurologists to provide information and identify patients who could be referred for surgery; different levels of technology at various centers, resulting in different candidate selection strategies; the belief that epilepsy surgery is a risky procedure and that it should be only viewed as the last option; patient preference to avoid surgery; parents wanting to wait until their child is old enough to participate in the decision-making process regarding surgery; unwillingness of insurers to cover the expenses associated with presurgical evaluations or lack of insurance; racial and social disparities, among others. In this paper we review the available epidemiological data about lack of utilization of epilepsy surgery. PMID- 28896003 TI - [XVI Reunion de la Sociedad Castellano-Manchega de Neurologia. Communications]. PMID- 28896004 TI - [Trigeminal-autonomic cephalgia secondary to a spontaneous intra-orbital haematoma]. PMID- 28896005 TI - [Miller Fisher syndrome following treatment with certolizumab in a patient with rheumatoid arthritis]. PMID- 28896006 TI - [Kleine-Levin syndrome: immunogenetic hypothesis]. PMID- 28896007 TI - Further Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan: Response. PMID- 28896010 TI - Index to Subjects. PMID- 28896012 TI - Erratum: Addendum. AB - [This corrects the article on p. 33 in vol. 50.]. PMID- 28896013 TI - Clinical Evidence against the Contagiousness of Phthisis. PMID- 28896014 TI - Cystic Neuroma of the Posterior Tibial Nerve. PMID- 28896015 TI - A Case of Purulent Sub-Arachnitis, Probably Metastatic. PMID- 28896016 TI - Case of Very Large Meningocele. PMID- 28896017 TI - Three Cases of Puerperal Convulsions Treated by Venesection. PMID- 28896018 TI - Two Cases of Compression of the Spinal Cord by Sarcomatous Growths from the Soft Membranes. PMID- 28896019 TI - Gastrostomy for Malignant Stricture of the AEsophagus. Hydatid Cyst of Liver. PMID- 28896020 TI - Ulcerative Endocarditis of the Tricuspid Valve. Extensive Fibrinous Deposits. PMID- 28896021 TI - The Proofs of the Existence of a Phthisical Contagion. PMID- 28896023 TI - Congenital Deformity of Right Leg and Left Hand. PMID- 28896022 TI - Surgical Out-Patient Notes. PMID- 28896024 TI - Primary Scirrhus of the Upper Jaw in a Child Two Years Old. PMID- 28896025 TI - Recurrent Pendulous Fatty Tumour of Thigh. PMID- 28896026 TI - The Cardiograph in Medicine. PMID- 28896027 TI - A Study of "Medical Posture". PMID- 28896028 TI - Retinoscopy. PMID- 28896029 TI - Successful Termination of a Large Aneurism, without Surgical Interference. PMID- 28896030 TI - University College, Bristol. Medical School: Prize List. PMID- 28896031 TI - Malarial Poisoning: Inaugural Address. PMID- 28896032 TI - Cases of Muscular Atropy and Degeneration. PMID- 28896033 TI - Two Cases-One of Gouty Inflammation of the Testis, and Another the Testicle of Mumps. PMID- 28896034 TI - An Epidemic of Tetanus. PMID- 28896035 TI - Minute Haemorrhages in the Pia Mater. PMID- 28896036 TI - Note on the Utility of Iodoform in the Treatment of Phthisis, and Its Occasional Toxic Effects. PMID- 28896037 TI - A Case of Priapism. PMID- 28896038 TI - A Record of Twenty-One Cases of Placenta Praevia. PMID- 28896039 TI - Abdominal Section in Perforating-Ulcer of the Stomach. A Suggestion. PMID- 28896040 TI - Case of Spontaneous Cure of Spina Bifida, Followed by Hydrocephalus. PMID- 28896041 TI - On Giving Rest to the Digestive Organs by the Use of Peptonised Food. PMID- 28896042 TI - On Flat-Foot and Its Cure by Operation. PMID- 28896043 TI - Case of Death from Fat Embolism after Bone-Setting. PMID- 28896044 TI - Case of Diphtheria Treated by Tracheotomy, Peptonised Enemata and Iodoform. PMID- 28896045 TI - The Effects of Certain Anatomical Relations: A Lecture Delivered before the Medical Society, Charing Cross Hospital. PMID- 28896046 TI - Two Cases of Gastric Ulcer Treated by Peptonised Enemata. PMID- 28896047 TI - Case of Rupture of the Right Auricle of the Heart. PMID- 28896048 TI - Case of Successful Immediate Suturing of the Olecranon for Simple Fracture. PMID- 28896049 TI - Ingrowing Toe-Nail. PMID- 28896050 TI - The Nature and Treatment of Chorea. PMID- 28896051 TI - Case of Malignant Pustule. PMID- 28896052 TI - Case of Tumour (Columnar Papilloma) in Fourth Ventricle of Brain, with Hydrocephalus. PMID- 28896053 TI - Short Reports of Twelve Cases of Ligature of Some of the Main Arteries Occurring during the Past Few Months at the Bristol Royal Infirmary. PMID- 28896054 TI - Case of Cerebral Abscess Following Slight Injury. PMID- 28896055 TI - Sudden Death from Asphyxia in a Phthisical Boy. PMID- 28896056 TI - Case of Subacute Poliomyelitis Anterior, with Commencing Phthisis. PMID- 28896057 TI - An Undescribed Form of Stricture at the Orifice of the Male Urethra. PMID- 28896058 TI - Notes of Cases of Diphtheritic Paralysis, with Remarks. PMID- 28896059 TI - Case of Subdiaphragmatic Abscess of the Left Side. PMID- 28896060 TI - Glaucoma. PMID- 28896061 TI - A New Neurosis. (Thomsen's Disease). PMID- 28896062 TI - Three Cases of Intestinal Obstruction. PMID- 28896063 TI - Note on the after Treatment of Scarlet Fever by Scalded Oatmeal. PMID- 28896064 TI - The Etiology of Catarrh: Inaugural Address. PMID- 28896065 TI - A Case of Laryngeal Phthisis, in Which the Windpipe Was Opened on Account of Dyspnoea. PMID- 28896067 TI - Two Cases of Haemophilia. PMID- 28896066 TI - On the Diagnosis of Abscess of the Liver. PMID- 28896068 TI - Lateral Sclerosis of the Spinal Cord. PMID- 28896070 TI - Discussion on Intestinal Obstruction at the Bristol Meeting of the Bath and Bristol Branch of the British Medical Association. PMID- 28896069 TI - Some Points in the Pathology of General Paralysis of the Insane. PMID- 28896072 TI - Retention and Accumulation of Faeces. PMID- 28896071 TI - Mangana Water. PMID- 28896073 TI - Compound Comminuted Fracture of the Left Femur, with Much Laceration of the Soft Parts and the Knee Joint Freely Opened. PMID- 28896074 TI - Pendulous Fatty Tumour of Thigh. PMID- 28896075 TI - A Case of Sudden Pulmonary Congestion Relieved by Aspiration of the Aorta. PMID- 28896076 TI - Five Cases Illustrating the Action of Intra-Pulmonary Injections. PMID- 28896077 TI - Two Cases of Intestinal Polypus. PMID- 28896078 TI - Case of Rupture of Aorta. PMID- 28896079 TI - A Method of Expressing Ear-Power in Degrees of a Fixed Scale. PMID- 28896080 TI - Case of Lumbar Spinal Caries, Psoas Abscess, Suppurative Cerebro-Spinal Meningitis, Suicidal Tendencies. Death, Necropsy. PMID- 28896081 TI - Enlargement of the Spleen. PMID- 28896082 TI - Rupture of the Aorta. PMID- 28896083 TI - Wounds of the Fingers, and How to Treat Them. PMID- 28896084 TI - A Case of Hyperpyrexia Following Measles, Treated Successfully by the Wet-Pack and Cold Douche. PMID- 28896085 TI - Case of Attempted Suicide, by Precipitation from Clifton Suspension Bridge. PMID- 28896086 TI - The Border-Land of Insanity. PMID- 28896087 TI - Case of Ruptured Aorta. PMID- 28896089 TI - A Few Remarks upon Aachen (Aix-La-Chapelle). PMID- 28896088 TI - On Diphtheria: With Cases. PMID- 28896090 TI - Cremation. PMID- 28896092 TI - A Case of Addison's Disease. PMID- 28896091 TI - Notes on Some Morbid Appearances in the Brain and Spinal Cord of a Lioness. PMID- 28896093 TI - History of a Case of Lymphadenosis. PMID- 28896094 TI - The Relations Existing between Facial Neuralgia, Frontal Headache and Dental Caries. PMID- 28896095 TI - Pyrexia: A Retrospect, a Review, and a Forecast: Inaugural Address at the Annual Meeting of the Bristol Medico-Chirurgical Society. PMID- 28896096 TI - Periscope. PMID- 28896097 TI - Hoarseness and Loss of Voice. PMID- 28896098 TI - Latent Rheumatism. PMID- 28896100 TI - Scraps. PMID- 28896099 TI - A Case of Tumour in the Orbit. PMID- 28896101 TI - Some Interesting Cases of Stone in the Bladder. PMID- 28896102 TI - Notes on Preparations for the Sick. PMID- 28896103 TI - Periscope. PMID- 28896105 TI - Scraps. PMID- 28896104 TI - Ought Craniotomy to Be Abolished? PMID- 28896106 TI - Notes on Preparations for the Sick. PMID- 28896107 TI - On Graves's Disease, with a Case: Read before the Bristol Medico-Chirurgical Society. PMID- 28896108 TI - Ill Effects of a Small Aneurism of the Aortic Arch Illustrated. PMID- 28896109 TI - A Case of Suppurating Middle Ear, Thrombosis and Phlebitis of Lateral Sinus, Death. PMID- 28896110 TI - Observations on Some of the New Hypnotics. PMID- 28896111 TI - Case of Aneurism of Orbit. PMID- 28896112 TI - The Treatment of Warts by Internal Administration of Arsenic. PMID- 28896113 TI - On a Case of Cystic Goitre Treated by "Shelling out". PMID- 28896114 TI - Shakspere and the Medical Sciences: The Presidential Address at the Opening, on October 12th, 1887, of the 14th Session of the Bristol Medico-Chirurgical Society. PMID- 28896116 TI - Scraps. PMID- 28896115 TI - Notes on Preparations for the Sick. PMID- 28896117 TI - Periscope. PMID- 28896118 TI - Peripheral Neuritis: Read before the Bristol Medico-Chirurgical Society. PMID- 28896119 TI - On Rhinitis. PMID- 28896121 TI - Scraps. PMID- 28896120 TI - On a Case of Progressive Muscular Atrophy: Demonstrating the Nervous Origin and Nature of the Disease, and Its Amenability to Nervine Tonics. PMID- 28896122 TI - Periscope. PMID- 28896123 TI - Notes on Preparations for the Sick. PMID- 28896124 TI - A Case of Caesarean Section for Obstruction of Labour by a Pelvic Tumour. PMID- 28896125 TI - A Case of AEstivo-Autumnal Malarial Fever with Parasites of an Unusual Type. PMID- 28896126 TI - Editorial Notes. PMID- 28896127 TI - Meetings of Societies. PMID- 28896128 TI - Forms of Joint Disease Met with in Medical Practice. PMID- 28896129 TI - Notes on a Case of Blackwater Fever. PMID- 28896130 TI - Surgery. PMID- 28896131 TI - Notes on Some Cases from an Electrical Department. PMID- 28896133 TI - Notes on Preparations for the Sick. PMID- 28896132 TI - Medicine. PMID- 28896134 TI - A Case of Congenital Hypertrophic Stenosis of the Pylorus. PMID- 28896135 TI - Obstetrics. PMID- 28896136 TI - The Long Fox Lecture: The First Annual Lecture Arranged by the Committee of the Long Fox Memorial, Delivered in the Medical Library, University College, Bristol on November 4th, 1904. The Right Hon. Lewis Fry in the Chair. PMID- 28896137 TI - Surgery. PMID- 28896138 TI - Dermatology. PMID- 28896139 TI - Editorial Notes. PMID- 28896141 TI - Notes on Preparations for the Sick. PMID- 28896140 TI - Case of Mesenteric Cyst. PMID- 28896143 TI - Medicine. PMID- 28896142 TI - Problems in Psychology: The Presidential Address, Delivered on October 12th, 1904, at the Opening of the Thirty-first Session of the Bristol Medico Chirurgical Society. PMID- 28896144 TI - Meetings of Societies. PMID- 28896145 TI - On Torsion of the Spermatic Cord, with the Report of a Recent Case. PMID- 28896146 TI - A Case of Laryngeal Tuberculosis. PMID- 28896147 TI - Scraps. PMID- 28896148 TI - Royal College of Physicians of Edinburgh. PMID- 28896150 TI - Progress of the Medical Sciences. PMID- 28896149 TI - Puerperal Eclampsia. PMID- 28896151 TI - Case of Poisoning by Rhus Venenata. PMID- 28896153 TI - Notes on Preparations for the Sick. PMID- 28896155 TI - Virchow Testimonial Fund. PMID- 28896157 TI - Case of Septic Endocarditis with Cerebral Embolism. PMID- 28896156 TI - Health-Resorts in the West of England and South Wales: V. Malvern. PMID- 28896158 TI - Scraps. PMID- 28896159 TI - Epilepsy Treated by Sulphonal. PMID- 28896160 TI - Medical Progress, Local and General: The Presidential Address, Delivered on October 14th, 1891, at the Opening of the 18th Session of the Bristol Medico Chirurgical Society. PMID- 28896161 TI - Scraps. PMID- 28896163 TI - Progress of the Medical Sciences. PMID- 28896162 TI - On Modern Methods of Diagnosis in Gastric Affections. PMID- 28896165 TI - Notes on Preparations for the Sick. PMID- 28896164 TI - Notes on Preparations for the Sick. PMID- 28896167 TI - Progress of the Medical Sciences. PMID- 28896168 TI - Notes on Preparations for the Sick. PMID- 28896169 TI - Buxton: Its Baths and Climate. PMID- 28896170 TI - Chloroform versus Ether. PMID- 28896171 TI - Case of Tumour of the Pons. PMID- 28896173 TI - Progress of the Medical Sciences. PMID- 28896172 TI - Cases of Septic Thrombosis of the Lateral Sinus. PMID- 28896174 TI - Scraps. PMID- 28896175 TI - Subungual Exostosis. PMID- 28896176 TI - Notes on Preparations for the Sick. PMID- 28896177 TI - A Case of Tubal Gestation Producing Severe Hemorrhage without Rupture, Associated with the Presence of an Accessory Fallopian Tube. PMID- 28896178 TI - The Vagaries of Abdominal Tuberculosis: A Clinical Study. PMID- 28896179 TI - Meetings of Societies. PMID- 28896180 TI - Mortality and Sickness in the City of Bristol for the Year 1903. PMID- 28896181 TI - Editorial Notes. PMID- 28896182 TI - Ethyl Chloride as a General Anaesthetic. PMID- 28896183 TI - The Present Position of Radiotherapy in Therapeutics. PMID- 28896184 TI - Note on the Subsequent History of a Case of Pylorectomy. PMID- 28896185 TI - Aneurysm of the Ascending Aorta. PMID- 28896186 TI - Surgery. PMID- 28896187 TI - Leprosy in Jamaica. PMID- 28896188 TI - Medicine. PMID- 28896189 TI - On Surgical Analgesia by Spinal Cocainisation. PMID- 28896190 TI - Surgery. PMID- 28896191 TI - The Relationship of Chorea and Rheumatism. PMID- 28896192 TI - Lac Vinum Infantum: A Review of the Work of Infant Milk Depots. PMID- 28896193 TI - On the Throat as the Source of Systemic Infection in Acute Rheumatism. PMID- 28896194 TI - Some Observations on Tuberculous Disease of the Hip-Joint in Childhood and Youth: With Special Reference to Excision of the Joint. PMID- 28896195 TI - The Indications for Operation in Myo-Fibroma of the Uterus. PMID- 28896197 TI - Medicine. PMID- 28896196 TI - The Induction of General Anaesthesia by Intra-Spinal Injections of Cocaine. PMID- 28896198 TI - Editorial Notes. PMID- 28896199 TI - Haematemesis Associated with Small White Kidneys. PMID- 28896200 TI - Notes on a Case of Infantilism. PMID- 28896202 TI - Notes on Preparations for the Sick. PMID- 28896201 TI - Ethyl Chloride: A Few Practical Remarks. PMID- 28896203 TI - The Recuperative Power of Old Age. PMID- 28896204 TI - Periscope of Medical and Surgical Progress. PMID- 28896205 TI - Cases of Vesical Calculi. PMID- 28896206 TI - Heart-Lesions in Relation to Mental Symptoms. PMID- 28896207 TI - A Case of Masked Epilepsy. PMID- 28896208 TI - A Case of Intestinal Intussusception. PMID- 28896210 TI - Scraps. PMID- 28896209 TI - The Laryngoscope in Medicine. PMID- 28896211 TI - A Case of Emphysematous Abscess of Thigh, from Intestinal Injury. PMID- 28896213 TI - Scraps. PMID- 28896212 TI - Some Remarks on the Surgery of the Upper Eyelid. PMID- 28896214 TI - Notes on Two Hundred and Twelve Consecutive Operations in Four Thousand Six Hundred and Ten Cases among the Medical Patients, Bristol Royal Infirmary. PMID- 28896215 TI - Notes on Preparations for the Sick. PMID- 28896216 TI - Editorial Notes. PMID- 28896217 TI - Progress of the Medical Sciences. PMID- 28896218 TI - On Some of the Hemorrhages of Pregnancy. PMID- 28896219 TI - A Case of Paralysis of the Right Vocal Cord, Due to Thoracic Aneurysm. PMID- 28896220 TI - Some Cases of Displacement of Abdominal Viscera. PMID- 28896221 TI - The Fourteenth International Congress of Medicine. PMID- 28896222 TI - The Tuberculin Test in Cattle. PMID- 28896223 TI - The Clinical Significance of Chronic Hoarseness and Loss of Voice. PMID- 28896224 TI - Periscope of Medical and Surgical Progress. PMID- 28896225 TI - The Use of the Aspirator in Retention of Urine. PMID- 28896226 TI - The Treatment of Empyema by Incision and Drainage, as Illustrated by Forty Cases. PMID- 28896227 TI - Case of Aneurism of Aorta-Treatment by Galvano-Punctures: Result Encouraging. PMID- 28896228 TI - Case of Pernicious Anaemia. PMID- 28896229 TI - Scraps. PMID- 28896230 TI - Presidential Address: Delivered before the Bristol Medico-Chirurgical Society, Session 1886-7. PMID- 28896231 TI - Some Recent Additions to the Dietary of the Sick. PMID- 28896232 TI - Excoriationes Narium. PMID- 28896233 TI - A Case of Dislocation of the Ulna Backwards and the Radius Forwards. PMID- 28896235 TI - Scraps. PMID- 28896234 TI - Calculus on Foreign Body in Bladder; Perforation of Bladder. No Symptoms. PMID- 28896237 TI - Tonic Contraction of the Lower Extremities, or Tetany. PMID- 28896236 TI - Relation between Facial Neuralgia and Dental Irritation. PMID- 28896238 TI - Notes on Medical Therapeutics. PMID- 28896239 TI - Removal of the Uterine Appendages. PMID- 28896240 TI - Some Unusual Symptoms in a Case of Hydrocephalus. PMID- 28896241 TI - Notes on Practical Surgery. PMID- 28896242 TI - Notes on Ocular Therapeutics. PMID- 28896243 TI - Removal of the Uterine Appendages. PMID- 28896244 TI - Notes on a Case of Bronchial Croup. PMID- 28896245 TI - Case of Typhlitis. PMID- 28896246 TI - Microzymes in Nutrition. PMID- 28896248 TI - The Vomiting of Pregnancy. PMID- 28896247 TI - Scraps. PMID- 28896250 TI - Notes on Preparations for the Sick. PMID- 28896249 TI - Dermatology. PMID- 28896251 TI - Scraps. PMID- 28896252 TI - Surgery. PMID- 28896254 TI - The Bristol Meeting of the British Medical Association, 1894: Part 1. PMID- 28896253 TI - Two Cysts of Unusual Origin. PMID- 28896255 TI - Ergot of Rye as an Oxytocic. PMID- 28896257 TI - The Bristol Meeting of the British Medical Association, 1894: Part 2. PMID- 28896256 TI - Case of Myxoedema. PMID- 28896258 TI - Medicine. PMID- 28896259 TI - Medicine. PMID- 28896260 TI - Laryngology. PMID- 28896261 TI - Surgery. PMID- 28896262 TI - Notes on Preparations for the Sick. PMID- 28896263 TI - Scraps. PMID- 28896264 TI - Meetings of Societies. PMID- 28896265 TI - Cases of Senile Nerve Degeneration Resembling General Paralysis. PMID- 28896266 TI - Comparative Pathology: The Presidential Address, Delivered on October 10th, 1894, at the Opening of the 21st Session of the Bristol Medico-Chirurgical Society. PMID- 28896267 TI - Meetings of Societies. PMID- 28896268 TI - Medicine. PMID- 28896269 TI - Scraps. PMID- 28896270 TI - Appendicitis. PMID- 28896271 TI - Intussusception. PMID- 28896274 TI - Notes on Preparations for the Sick. PMID- 28896273 TI - Surgery. PMID- 28896272 TI - So-Called "Duct Cancer" of the Breast, with the Account of a Case of Large Recurrent Duct Papilloma. PMID- 28896276 TI - Scraps. PMID- 28896275 TI - Otology. PMID- 28896277 TI - Editorial Notes. PMID- 28896278 TI - Statistics Concerning Consumption and Other Preventable Diseases. PMID- 28896279 TI - Notes on Preparations for the Sick. PMID- 28896280 TI - Meetings of Societies. PMID- 28896281 TI - The Uses of Sanatoria for the Treatment of Tuberculosis. PMID- 28896282 TI - Two Cases of Sarcoma of the Intestine, with Secondary Infection in One by a Gas Forming Bacillus. PMID- 28896283 TI - On the Question of the Advisability of Ligaturing the Jugular Vein in the Treatment of Sigmoid-Sinus Thrombosis. PMID- 28896285 TI - A Retrospect of a Third Series of Fifty Consecutive Intra-Abdominal Operations. PMID- 28896284 TI - Progress of the Medical Sciences. PMID- 28896286 TI - Craniotomy, with the Implantation of Egg-Shell Membrane, for Jacksonian Epilepsy. PMID- 28896287 TI - Six Cases of Cerebro-Spinal Meningitis. PMID- 28896288 TI - On the Advantages of Enucleation of the Tonsils over Their Removal by the Guillotine. PMID- 28896289 TI - Nephropexy by Means of the Application of Strong Carbolic Acid and Temporary Support, with Report of Eight Cases. PMID- 28896291 TI - Meetings of Societies. PMID- 28896290 TI - Surgery. PMID- 28896292 TI - Editorial Notes. PMID- 28896293 TI - Notes on Preparations for the Sick. PMID- 28896295 TI - Some Notes on Examinations for Life Assurance. PMID- 28896294 TI - The Prevention of Apoplexy. PMID- 28896296 TI - Laryngology and Rhinology. PMID- 28896297 TI - Medicine. PMID- 28896298 TI - Three Cases of Ovarian Tumour Complicating Pregnancy, Labour and the Puerperium Respectively. PMID- 28896299 TI - Somnambulism. PMID- 28896300 TI - Notes on Preparations for the Sick. PMID- 28896301 TI - Pigmentation in Amenorrhoea. PMID- 28896303 TI - Scraps. PMID- 28896302 TI - Adherent Pericardium in Children. PMID- 28896304 TI - Surgery. PMID- 28896305 TI - The International Congress of Hygiene and Demography. PMID- 28896306 TI - A Case of Syringomyelia. PMID- 28896308 TI - Meetings of Societies. PMID- 28896307 TI - The William F. Jenks Memorial Prize. PMID- 28896309 TI - Medicine. PMID- 28896310 TI - Obstetrics. PMID- 28896311 TI - Notes on Preparations for the Sick. PMID- 28896312 TI - A Retrospect of a Third Series of Fifty Consecutive Intra-Abdominal Operations. PMID- 28896313 TI - Meetings of Societies. PMID- 28896314 TI - Scraps. PMID- 28896315 TI - Editorial Notes. PMID- 28896316 TI - A Case of Muscular Atrophy Due to Lead. PMID- 28896317 TI - X-Ray Photographs as Pictures: With Two Diagrams. PMID- 28896318 TI - A Case of Presentation of the Axilla at Full Term: Spontaneous Delivery of the Foetus. PMID- 28896319 TI - Case of Abscess in the Left Lateral Lobe of the Cerebellum, Successfully Evacuated: With Some Remarks on the Method of Operation Employed. PMID- 28896321 TI - A Case of Artificial Anus Following Herniotomy. PMID- 28896320 TI - The Origin of Gastric Ulcer. PMID- 28896323 TI - Meetings of Societies. PMID- 28896322 TI - Progress of the Medical Sciences. PMID- 28896324 TI - Backache, Sciatica and Ruptured Discs. PMID- 28896325 TI - The Effects of the Explosion. PMID- 28896327 TI - Editorial. PMID- 28896326 TI - Reiter's Syndrome. PMID- 28896328 TI - The Release of Atomic Energy and the Pathological Effects of Radiation. PMID- 28896329 TI - The Progress of Pharmacy and Pharmaceutical Chemistry. PMID- 28896330 TI - Surgery. PMID- 28896331 TI - On Some Symptoms of Cerebellar Tumours. PMID- 28896332 TI - Obstetrics. PMID- 28896333 TI - The Causes and Treatment of Baldness. PMID- 28896334 TI - A New Scheme for Infant Milk Depots. PMID- 28896335 TI - Acne Vulgaris and Its Treatment. PMID- 28896336 TI - Sprue. PMID- 28896337 TI - Editorial Notes. PMID- 28896338 TI - Medicine. PMID- 28896339 TI - Inebriety and the So-Called Cures. PMID- 28896340 TI - Notes on Preparations for the Sick. PMID- 28896341 TI - Cases of Joint Swellings Simulating Gout and Rheumatism. PMID- 28896342 TI - Meetings of Societies. PMID- 28896343 TI - Ophthalmology. PMID- 28896344 TI - A Note on Congenital Dilatation of the Ureters with Hydronephrosis. PMID- 28896346 TI - Surgery. PMID- 28896345 TI - Twin X-Ray Representation and the Reflecting Stereoscope. PMID- 28896347 TI - A Study of the Records of One Hundred and Fifty-Five Cases of Operation for Appendicitis. PMID- 28896349 TI - Notes on Preparations for the Sick. PMID- 28896348 TI - The Surgical Aspect of Cholelithiasis. PMID- 28896350 TI - On Some Anomalous Cases of Locomotor Ataxy. PMID- 28896351 TI - Medicine. PMID- 28896352 TI - Editorial Notes. PMID- 28896353 TI - The Relation of Medicine to the Natural Sciences: Presidential Address at the Annual Meeting of the Bath and Bristol Branch of the British Medical Association, June 28th, 1905. PMID- 28896354 TI - Notes on the Voluntary Notification of Phthisis, and on the Municipal Attitude in Bristol in Regard to the Disease. PMID- 28896355 TI - Meetings of Societies. PMID- 28896356 TI - A Study of the Records of One Hundred and Fifty-Five Cases of Operation for Appendicitis. PMID- 28896357 TI - On Two Cases of Myasthenia Gravis. PMID- 28896359 TI - Notes on Preparations for the Sick. PMID- 28896358 TI - The Long Fox Lecture: The Pathology and Treatment of Graves's Disease. PMID- 28896360 TI - Medicine. PMID- 28896361 TI - Surgery. PMID- 28896362 TI - The Family Doctor: The Presidential Address, Delivered on October 11th, 1905, at the Opening of the Thirty-Second Session of the Bristol Medico-Chirurgical Society. PMID- 28896363 TI - Editorial Notes. PMID- 28896364 TI - Cretinism and the Puerperium: Sequel to a Recorded History. PMID- 28896365 TI - Editorial Notes. PMID- 28896366 TI - Small-Pox in Bristol and Neighbourhood (1908-9). PMID- 28896367 TI - A Family with a Congenital Deformity of the Nose, and the Results of Subcutaneous Injection of Wax. PMID- 28896368 TI - The Indications for Gastro-Enterostomy. PMID- 28896369 TI - Electricity in General Practice. PMID- 28896370 TI - Surgery. PMID- 28896371 TI - A Case of Lead Encephalopathy. PMID- 28896372 TI - Meetings of Societies. PMID- 28896373 TI - Notes on Preparations for the Sick. PMID- 28896374 TI - A Discussion on "Treatment by Ionisation or Cataphoresis". PMID- 28896375 TI - Dermatology. PMID- 28896376 TI - Medicine. PMID- 28896377 TI - Referred Cardiac Pain. PMID- 28896378 TI - Surgery. PMID- 28896379 TI - Notes on Preparations for the Sick. PMID- 28896380 TI - The Safety of the Patient in Anaesthesia. PMID- 28896381 TI - Theoretical Considerations of Pulmonary Percussion Notes. PMID- 28896383 TI - Sleep and the Modern Hypnotics. PMID- 28896382 TI - Tuberculosis of the Colon. PMID- 28896384 TI - Editorial Notes. PMID- 28896386 TI - Medicine. PMID- 28896385 TI - Some Points in the Technique of the Radical Operation for Chronic Otitis Media Purulenta. PMID- 28896387 TI - The Adulteration of Milk in Bristol. PMID- 28896388 TI - Vomiting Connected with Anaesthesia. PMID- 28896389 TI - The Value of Some Lactic Acid Ferments. PMID- 28896390 TI - The Causes of Transient Cerebral Paralyses. PMID- 28896391 TI - Laryngology and Otology. PMID- 28896392 TI - Surgery. PMID- 28896393 TI - Editorial Notes. PMID- 28896394 TI - Precautions to Be Observed in Administration of Milk in Disease. PMID- 28896395 TI - Meetings of Societies. PMID- 28896396 TI - Some Impurities of Vended Milks. PMID- 28896397 TI - Notes on Preparations for the Sick. PMID- 28896398 TI - Thomas Dover: Physician and Merchant Adventurer. PMID- 28896399 TI - The Physique of Boys. PMID- 28896400 TI - The Long Fox Lecture: Metastatic Inflammations of the Eye. PMID- 28896402 TI - Progress of the Medical Sciences. PMID- 28896401 TI - Milk from a Public Health Standpoint-City of Bristol. PMID- 28896403 TI - The Fourteenth International Congress of Medicine. PMID- 28896404 TI - Some Surgical Aspects of Meckel's Diverticulum. PMID- 28896405 TI - Editorial Notes. PMID- 28896407 TI - Notes on New Drugs and Preparations for the Sick. PMID- 28896406 TI - Cystoscopy and Ureteral Catheterization: Observations on Twenty Examinations for Obscure Urinary and Abdominal Affections. PMID- 28896408 TI - The Progress in the Diagnosis and Treatment of Affections of the Throat, Nose, and Ear during the past Twenty Years: The Presidential Address, Delivered on October 9th, 1901, at the Opening of the Twenty-Eighth Session of the Bristol Medico-Chirurgical Society. PMID- 28896409 TI - The Quiet Production of Anaesthesia: A Clinical Lecture. PMID- 28896410 TI - Notes on Two Hundred and Twelve Consecutive Operations in Four Thousand Six Hundred and Ten Cases among the Medical Patients, Bristol Royal Infirmary. PMID- 28896411 TI - Meetings of Societies. PMID- 28896412 TI - Scraps. PMID- 28896413 TI - On Nephropexy. PMID- 28896414 TI - Medicine. PMID- 28896415 TI - Intermittent Swelling of the Parotid Glands. PMID- 28896416 TI - Mixed Infections. PMID- 28896418 TI - Hypernephroma or Mesothelioma of the Kidney. PMID- 28896419 TI - Surgery. PMID- 28896420 TI - A Case of Cervical Rib. PMID- 28896421 TI - Ophthalmology. PMID- 28896423 TI - Notes on Preparations for the Sick. PMID- 28896422 TI - The Ethical Aspects of Physical Research. PMID- 28896424 TI - Medicine and Its Practitioners during the Earlier Years of the History of Bath. PMID- 28896425 TI - Three Cases of Ataxia. PMID- 28896426 TI - On Hemorrhagic Diseases of the New-Born, with Report of a Case Due to Duodenal Ulcer. PMID- 28896428 TI - Editorial. PMID- 28896427 TI - Maternity Service in Bristol. PMID- 28896429 TI - Bristol's New Health Centre: In Leinster Avenue, Knowle West. PMID- 28896431 TI - Notes and News. PMID- 28896430 TI - Maternity Service in Bristol. PMID- 28896432 TI - Views Ancient and Modern on Placenta Praevia. PMID- 28896433 TI - The Prevention and Treatment of Postpartum Haemorrhage in Domiciliary Practice. PMID- 28896434 TI - The Symptoms and Clinical Diagnosis of Hiatus Hernia. PMID- 28896435 TI - Contact Dermatitis. PMID- 28896436 TI - Annotations. PMID- 28896437 TI - Reports of Meetings. PMID- 28896439 TI - Unexplained Pyrexia in a Child: Clinico-Pathological Report. PMID- 28896438 TI - On Reactions with the Newer Antibiotics. PMID- 28896440 TI - Maternity Service in Bristol. PMID- 28896441 TI - War Surgery in an Indian General Hospital in Mesopotamia. PMID- 28896443 TI - Meetings of Societies. PMID- 28896442 TI - The Journal: A Swan-Song. PMID- 28896444 TI - Animal Disease in Relation to Man. PMID- 28896445 TI - Editorial. PMID- 28896446 TI - Diagnosis and Medical Treatment. PMID- 28896447 TI - Surgical Treatment. PMID- 28896448 TI - Tuberculous Meningitis. PMID- 28896449 TI - The William Budd Health Centre. PMID- 28896450 TI - Argyria from the Use of Nasal Drops. PMID- 28896451 TI - The Results in 178 Cases of Prefrontal Leucotomy at the Bristol Mental Hospitals. PMID- 28896452 TI - Notes and News. PMID- 28896453 TI - Life for the Premature Baby. PMID- 28896455 TI - Reports of Meetings. PMID- 28896454 TI - Recent Trends in Blood Transfusion and Resuscitation. PMID- 28896456 TI - The Surgical Treatment of Bronchiectasis. PMID- 28896457 TI - Visit of Dr. Alfred Blalock. PMID- 28896458 TI - Editorial. PMID- 28896459 TI - The Diagnosis of Abdominal Emergencies in Children. PMID- 28896460 TI - Gargoylism. PMID- 28896461 TI - Unilateral Papillary Necrosis of Kidney in a Diabetic : A Rare Complication of Enlargement of the Prostate Gland. PMID- 28896462 TI - Notes and News. PMID- 28896463 TI - Maternity Service in Bristol. PMID- 28896464 TI - Unexplained Increase of Fatal Pulmonary Embolus at the Bristol Royal Infirmary in 1950. PMID- 28896466 TI - Reports of Meetings. PMID- 28896465 TI - The Relation between Hypertension and the Kidney: A Review. PMID- 28896467 TI - On the Excision of Strictures of the Urethra. PMID- 28896468 TI - Hyoscine and the Mydriatic Alkaloids. PMID- 28896469 TI - Obstetrics. PMID- 28896470 TI - The Medical Aspect of Boswell's "Life of Johnson," with Some Account of the Medical Men Mentioned in That Book: The Presidential Address, Delivered on October 12th, 1910, at the Opening of the Thirty=Seventh Session of the Bristol Medico=Chirurgical Society. PMID- 28896471 TI - Remarks on the Surgical Aspect of Glycosuria, and on Diabetic Gangrene, with the Record of Three Cases in Which Amputation Was Performed for Gangrene in Diabetics under Spinal Anaesthesia. PMID- 28896472 TI - Notes on Preparations for the Sick. PMID- 28896473 TI - Medicine. PMID- 28896474 TI - Meetings of Societies. PMID- 28896476 TI - Editorial Notes. PMID- 28896475 TI - Surgery. PMID- 28896478 TI - University College, Bristol. Faculty of Medicine. PMID- 28896477 TI - An Old-Time Syphilidiater. PMID- 28896479 TI - Scraps. PMID- 28896480 TI - Health-Resorts in the West of England and South Wales. Cheltenham. PMID- 28896481 TI - Surgery. PMID- 28896482 TI - Modern Medical Journalism: The Presidential Address, Delivered on October 11th, 1893, at the Opening of the 20th Session of the Bristol Medico-Chirurgical Society. PMID- 28896483 TI - Three Cases of Umbilical Hemorrhage Occurring in the Same Family. PMID- 28896484 TI - Meetings of Societies. PMID- 28896485 TI - Compression of the Umbilical Cord during Forceps Delivery. PMID- 28896486 TI - Notes on Preparations for the Sick. PMID- 28896487 TI - A Case of Double Empyema. PMID- 28896488 TI - Medicine. PMID- 28896489 TI - Ophthalmology. PMID- 28896490 TI - The XXXIX Long Fox Memorial Lecture: Some Food Infection Problems. PMID- 28896491 TI - Streptomycin. PMID- 28896492 TI - Blood Transfusion. PMID- 28896493 TI - Some Surgical Milestones: The Presidential Address, Delivered on Wednesday, 11th October, 1950 at the Opening of the Seventy-Second Session of the Bristol Medico Chirurgical Society. PMID- 28896494 TI - Meetings of Societies. PMID- 28896495 TI - Keratosis Pharyngis. PMID- 28896497 TI - Meetings of Societies. PMID- 28896496 TI - The Presidency. PMID- 28896499 TI - Modern Developments. PMID- 28896498 TI - The Local Problem. PMID- 28896500 TI - Surgical Neurology. PMID- 28896501 TI - The Medical Problem of To-Day. PMID- 28896502 TI - Liver Function Tests. PMID- 28896503 TI - Notes and News. PMID- 28896504 TI - Maternity Service in Bristol: Some Aspects of Integration and Possible Development. PMID- 28896505 TI - Eczema of the Colon: A New Conception of Ulcerative Colitis. PMID- 28896506 TI - Reports of Meetings. PMID- 28896507 TI - Poliomyelitis in Bristol, 1950. PMID- 28896508 TI - The Medical Witness for the Prosecution and the Defence. PMID- 28896509 TI - Society and Post-Graduate Programmes. PMID- 28896510 TI - Robbing Peter to Pay Paul. PMID- 28896511 TI - Annotations. PMID- 28896512 TI - Editorial Comment. PMID- 28896513 TI - Cases of Pneumonia. PMID- 28896514 TI - Vis Medicatrix Naturae: Inaugural Address at the Annual Meeting of the Bath and Bristol Branch of the British Medical Association, May 26th, 1909. PMID- 28896515 TI - Editorial Notes. PMID- 28896517 TI - Meetings of Societies. PMID- 28896516 TI - The Mercurial Treatment of Tabes Dorsalis. PMID- 28896519 TI - Surgery. PMID- 28896518 TI - Obstetrics. PMID- 28896520 TI - Notes on Preparations for the Sick. PMID- 28896521 TI - The History and Practice of Surgery in Ancient and Mediaeval Times: The President's Address, Delivered on October 13th, 1909, at the Opening of the Thirty-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28896522 TI - Medicine. PMID- 28896523 TI - Medicine. PMID- 28896524 TI - Ophthalmology. PMID- 28896526 TI - Editorial Notes. PMID- 28896525 TI - Infection of the Urinary Tract with Bacillus Coli. PMID- 28896527 TI - Diffuse Destructive Changes in the Liver Associated with Jaundice. PMID- 28896529 TI - Meetings of Societies. PMID- 28896528 TI - Radium and Some of Its Physical and Therapeutic Properties. PMID- 28896531 TI - Notes on Preparations for the Sick. PMID- 28896530 TI - Hypnotism. PMID- 28896533 TI - Oriental Medicine-Stray Jottings. PMID- 28896532 TI - Surgery. PMID- 28896534 TI - A Brief Account of Splenectomy with a Case of Simple Hypertrophy of the Spleen Treated by Operation. PMID- 28896536 TI - Editorial Notes. PMID- 28896535 TI - Radiographic Estimation of Simple Enlargement by Means of Visible Shadows. PMID- 28896538 TI - Notes on Preparations for the Sick. PMID- 28896537 TI - Medicine. PMID- 28896539 TI - Surgery. PMID- 28896540 TI - Post-Graduate Study: The Inaugural Address at the Annual Meeting of the Bath and Bristol Branch of the British Medical Association, 25th May, 1910. PMID- 28896541 TI - A Case of Anomalous Cutaneous Eruption Showing a Bacillus Morphologically Corresponding with the Klebs-Loeffler, and Clearing up under Diphtheritic Antitoxin. PMID- 28896542 TI - Dermatology. PMID- 28896543 TI - Cases of Leukaemia Treated by X-Rays. PMID- 28896544 TI - Notes on Preparations for the Sick. PMID- 28896546 TI - Meetings of Societies. PMID- 28896545 TI - On the Occurrence of Serous Pleurisy Due to Pneumococci and Tubercle Bacilli. PMID- 28896547 TI - What Is an Accident? PMID- 28896548 TI - Methods of Diagnosis in Gastric Cancer. PMID- 28896549 TI - Pathology. PMID- 28896550 TI - Notes on Two Cases of Urinary Calculus. PMID- 28896551 TI - Urinary Products of Intestinal Intoxication. PMID- 28896552 TI - The Third South Midland Field Ambulance. PMID- 28896553 TI - Paroxysmal OEdema of the Lungs. PMID- 28896554 TI - On the Course of Pernicious Anaemia in Older Persons. PMID- 28896555 TI - Some Recent Cases of Epidemic Cerebro-Spinal Meningitis. PMID- 28896557 TI - Surgery. PMID- 28896556 TI - The Tuberculosis Officer and His Work. PMID- 28896558 TI - A Case in Which a Stone Formed in the Urethra around a Piece of Wood Introduced into the Urethra Twenty-Six Years before the Removal of the Stone. PMID- 28896560 TI - Editorial Notes. PMID- 28896559 TI - Iodoform and Thyroidism. PMID- 28896561 TI - Notes on Biliary and Intestinal Sand. PMID- 28896562 TI - Diseases of the Ear, Nose and Throat. PMID- 28896563 TI - Bromoform Poisoning. PMID- 28896564 TI - Medicine. PMID- 28896565 TI - Notes on Preparations for the Sick. PMID- 28896567 TI - Notes on a Case of Oxycephaly. PMID- 28896566 TI - Meetings of Societies. PMID- 28896568 TI - Surgery. PMID- 28896569 TI - The Long Fox Lecture: The Development of the Human Skull. PMID- 28896570 TI - The Alleged Increase of Insanity. PMID- 28896571 TI - Scraps. PMID- 28896572 TI - Medicine. PMID- 28896574 TI - Notes on Preparations for the Sick. PMID- 28896573 TI - Laryngology. PMID- 28896575 TI - Surgery. PMID- 28896576 TI - Lesion of the Cauda Equina: Operation-Relief of Symptoms. PMID- 28896577 TI - The Combination of Syphilis and Tuberculosis, Especially in Regard to Laryngeal Affections. PMID- 28896579 TI - Surgery. PMID- 28896578 TI - Rotheln: A Summary. PMID- 28896581 TI - Laryngology and Rhinology. PMID- 28896580 TI - Notes on Preparations for the Sick. PMID- 28896582 TI - Society Meetings. PMID- 28896583 TI - Pleural Effusions: Their Diagnosis and Treatment. PMID- 28896584 TI - A Case of Extra-Uterine Gestation. PMID- 28896586 TI - Scraps. PMID- 28896585 TI - Medicine. PMID- 28896587 TI - Acute Inflammation around the Upper Cervical Vertebrae: A Subjective Clinical Study. PMID- 28896589 TI - New Drugs and Preparations for the Sick. PMID- 28896588 TI - Chronic Appendicitis in Its Relation to Dyspepsia. PMID- 28896590 TI - Introduction to a Discussion on the Diagnosis of Tuberculosis. PMID- 28896591 TI - Editorial Notes. PMID- 28896592 TI - Notes on Plague in Bristol in 1916. PMID- 28896593 TI - Splenectomy for Splenomegaly. PMID- 28896594 TI - Specialism and the Medical Curriculum, Mainly in Reference to Otology, Rhinology and Laryngology: The Presidential Address, Delivered on October 8th, 1913, at the Opening of the Fortieth Session of the Bristol Medico-Chirurgical Society. PMID- 28896595 TI - Pericolitis. PMID- 28896596 TI - Splenectomy in Banti's Disease. PMID- 28896598 TI - Medical Observations in the Clifton Zoological Gardens, with Notes on the Birth of Two Russian Bear Cubs in Captivity. PMID- 28896597 TI - Protective Ferments. PMID- 28896599 TI - A Simple Apparatus for Intratracheal Anaesthesia. PMID- 28896601 TI - Editorial Note. PMID- 28896600 TI - Surgery. PMID- 28896602 TI - Medicine. PMID- 28896603 TI - An Apparatus for the Intratracheal Administration of Ether. PMID- 28896605 TI - Meetings of Societies. PMID- 28896606 TI - Otology and Rhinology. PMID- 28896607 TI - On the Cerebral Symptoms of Lobar Pneumonia in Children. PMID- 28896609 TI - Notes on Preparations for the Sick. PMID- 28896608 TI - A Combined Manometer and Safety Valve for Intratracheal Anaesthesia. PMID- 28896610 TI - The Treatment of Chronic Constipation: A Discussion at the Bristol Medico Chirurgical Society, February 12th, 1913. PMID- 28896611 TI - An Example of the Stokes-Adams Syndrome. PMID- 28896612 TI - Medicine. PMID- 28896614 TI - Robert Shingleton Smith, M.D., B.Sc., F.R.C.P.: Editor, 1892-1912. PMID- 28896613 TI - Notes on a Case of Alternating Oxaluria and Phosphaturia. PMID- 28896615 TI - The Intravenous Administration of Neo-Salvarsan in Syphilis. PMID- 28896616 TI - Meetings of Societies. PMID- 28896617 TI - A Case of Acute Septicaemia Due to the B. Pyocyaneus. PMID- 28896618 TI - Aleucocythaemic Leukaemia. PMID- 28896619 TI - A Case of Alternating Oxaluria and Phosphaturia. PMID- 28896620 TI - Surgery. PMID- 28896621 TI - The End-Results of Cases Operated on for Gallstones. PMID- 28896623 TI - Acute Pancreatitis, with Special Reference to Its Treatment, and a Record of Three Cases Presenting Unusual Features. PMID- 28896622 TI - Gunshot Wounds of Peripheral Nerves. PMID- 28896624 TI - The Prevention of Sepsis in War Wounds, with Special Reference to the Carrel Dakin Method. PMID- 28896625 TI - Editorial Notes. PMID- 28896626 TI - Rectal Diverticula as a Causative Factor in Pelvic Inflammation in Women. PMID- 28896628 TI - The Hodgkins Fund Prizes. PMID- 28896627 TI - Fatigue Induced by Labour. PMID- 28896629 TI - Medicine. PMID- 28896630 TI - Obstetrics. PMID- 28896631 TI - Scraps. PMID- 28896633 TI - Notes on Preparations for the Sick. PMID- 28896632 TI - A Case of Thrombosis of the Femoral Artery Leading to Gangrene. PMID- 28896634 TI - Health-Resorts in the West of England and South Wales. Torquay. PMID- 28896636 TI - Meetings of the Bristol Medico-Chirurgical Society. PMID- 28896635 TI - One View of Heredity. PMID- 28896637 TI - The Bristol Eye Hospital. PMID- 28896638 TI - Surgery. PMID- 28896639 TI - Asthenopia and Ocular Headache. PMID- 28896640 TI - Two Cases of Branchial Fistulae. PMID- 28896641 TI - Note on the Technique of Sphenoidal Sinus Exploration for Meningococcal and Other Infections. PMID- 28896643 TI - Editorial Notes. PMID- 28896642 TI - Notes on the Enteric Group of Diseases as Seen in an Isolation Hospital in France. PMID- 28896644 TI - Meetings of Societies. PMID- 28896645 TI - The Reduction of Disabilities from Wounds in War. PMID- 28896646 TI - Some Neuroses of the War. PMID- 28896647 TI - Forensic Examination of Blood-Stains in the Tropics. PMID- 28896648 TI - On the Work of a Military General Hospital in Egypt. PMID- 28896649 TI - Experiences of an Ear, Nose and Throat Specialist at One of the Bases. PMID- 28896650 TI - Some Aspects of British Surgery in France. PMID- 28896651 TI - Medicine and Surgery in Mesopotamia. PMID- 28896652 TI - The Art of Medicine in the Age of Homer: The Presidential Address, Delivered on November 8th, 1916, at the Opening of the Forty-Third Session of the Bristol Medico-Chirurgical Society. PMID- 28896653 TI - Dermatology. PMID- 28896654 TI - Ten Months in France with a Field-Service X-Ray Outfit. PMID- 28896655 TI - The Effect of General Conditions on the Quality of the Teeth: The Presidential Address, Delivered on June 30th, 1915, at the Opening of the Session of the Bath and Bristol Branch of the British Medical Association. PMID- 28896656 TI - Notes on the Operation for Drainage of the Sphenoidal Sinus. PMID- 28896658 TI - Paralysis of the Accommodation-an a Posteriori View of Diphtheria. PMID- 28896657 TI - Editorial Notes. PMID- 28896659 TI - Meetings of Societies. PMID- 28896660 TI - On the Use of Morphia in Uraemia. PMID- 28896661 TI - Editorial Notes. PMID- 28896662 TI - A Case of Ascites Due to Thrombosis of the Hepatic Veins. PMID- 28896663 TI - The Treatment of Certain Deformities, More Especially of the Nose, by the Subcutaneous Injection of Paraffin. PMID- 28896664 TI - Dermatology. PMID- 28896665 TI - Notes on Three Pathological Specimens. PMID- 28896666 TI - Medicine. PMID- 28896667 TI - The Reputation of the Hotwells (Bristol) as a Health-Resort. PMID- 28896668 TI - The Unreliability of the Microscope in the Diagnosis of Malignant Disease. PMID- 28896669 TI - Notes on New Drugs and Preparations for the Sick. PMID- 28896670 TI - Surgery. PMID- 28896671 TI - Stereoscopic X-Ray Representation, with an Example. PMID- 28896672 TI - Editorial Notes. PMID- 28896673 TI - Obstetrics. PMID- 28896675 TI - Meetings of Societies. PMID- 28896674 TI - The Diagnosis of Oriental or Bubonic Plague. PMID- 28896676 TI - Surgery. PMID- 28896677 TI - Diplococcal Bronchitis. PMID- 28896679 TI - Notes on New Drugs and Preparations for the Sick. PMID- 28896678 TI - The Reputation of the Hotwells (Bristol) as a Health-Resort. PMID- 28896680 TI - Two Cases of Localised Necrosis of the Lung, with Recovery. PMID- 28896682 TI - Medicine. PMID- 28896681 TI - Some Cases of Ptosis. PMID- 28896683 TI - The Long Fox Lecture: Dermatitis from without and Dermatitis from Within. PMID- 28896684 TI - The Preservation of the Limb in the Treatment of Sarcoma of Bone: With the Account of a Case in Which the Upper Half of the Fibula was Excised for Periosteal Sarcoma. PMID- 28896685 TI - Medicine. PMID- 28896686 TI - Notes on Preparations for the Sick. PMID- 28896688 TI - Meetings of Societies. PMID- 28896687 TI - Fibroma of the Abdominal Wall. PMID- 28896689 TI - Dermatology. PMID- 28896690 TI - X-Ray Therapeutics: The Presidential Address, Delivered on October 10th, 1906, at the Opening of the Thirty-Third Session of the Bristol Medico-Chirurgical Society. PMID- 28896691 TI - Proteins and Protein Metabolism. PMID- 28896692 TI - Editorial Notes. PMID- 28896693 TI - Surgery. PMID- 28896694 TI - Problems in the Treatment of Haemoptysis. PMID- 28896695 TI - Some Developments in Dermatology during the Last Thirty Years: Presidential Address, Delivered on 12th October, 1927, at the Opening of the Fifty-Fifth Session of the Bristol Medico-Chirurgical Society. PMID- 28896696 TI - The Long Fox Memorial Lecture: The Reality of Delusions. PMID- 28896697 TI - Meetings of Societies. PMID- 28896698 TI - Recent Experiences of Intussusception. PMID- 28896699 TI - Editorial Notes. PMID- 28896700 TI - Some Remarks upon the Finsen Light Treatment of Lupus. PMID- 28896701 TI - Meetings of Societies. PMID- 28896702 TI - Notes on Preparations for the Sick. PMID- 28896703 TI - Editorial Notes. PMID- 28896704 TI - Missing Links in Joint Disease. PMID- 28896705 TI - Mobility. PMID- 28896707 TI - Surgery. PMID- 28896706 TI - Medicine. PMID- 28896708 TI - Obstetrics and Gynaecology. PMID- 28896709 TI - The Influence of the Auricles on the Percussion of the Heart. PMID- 28896710 TI - On the Diagnosis of Malignant Disease of the Body of the Uterus, with Notes of a Case Treated Twice by Curettage, and Finally by Hysterectomy. PMID- 28896711 TI - Meningococcal Septicaemia with a Report of a Case. PMID- 28896712 TI - The Value of the Chloride Content of the Cerebro-Spinal Fluid in Diagnosis and Prognosis. PMID- 28896713 TI - Indications for Manipulative Surgery. PMID- 28896714 TI - Editorial Note. PMID- 28896716 TI - Meetings of Societies. PMID- 28896715 TI - The Lymphocytosis of Infection. PMID- 28896717 TI - Redundant Colon: A Group of Cases Exhibiting Symptoms Traceable to This Condition. PMID- 28896718 TI - Chemotherapeutic Researches on Cancer. A Review. PMID- 28896719 TI - The Colloidal State of Matter. PMID- 28896720 TI - The Symptoms and Signs of Duodenal Ulcer. PMID- 28896721 TI - Peri-Arterial Sympathectomy. PMID- 28896722 TI - The Long Fox Memorial Lecture: The Relationship of Erythema Nodosum to Tuberculosis. PMID- 28896723 TI - Editorial Notes. PMID- 28896724 TI - Meetings of Societies. PMID- 28896725 TI - The Early Diagnosis and Treatment of Insanity. PMID- 28896727 TI - The Medical Treatment of Duodenal Ulcer. PMID- 28896726 TI - Treatment of Infantile Paralysis of the Lower Limb. PMID- 28896728 TI - Sugar Tolerance Tests. PMID- 28896729 TI - The Evidences of Heart Failure, and the Signs and Symptoms of Three Cases Personally Examined. PMID- 28896730 TI - The Comparative Value of Radiation Therapy in Dermatology. PMID- 28896732 TI - Meetings of Societies. PMID- 28896731 TI - A Note on the Pathology of Erythema Nodosum. PMID- 28896733 TI - Editorial Notes. PMID- 28896734 TI - Ocular Manifestations Following Encephalitis Lethargica. PMID- 28896735 TI - A Case of Mitral Stenosis with Auricular Fibrillation, Treated with Digitalis by the Cary Eggleston Method. PMID- 28896736 TI - The Reputation of the Hotwells (Bristol) as a Health-Resort. PMID- 28896737 TI - A Case of Gastro-Jejunostomy for Cancer of the Pylorus. PMID- 28896738 TI - Surgery. PMID- 28896740 TI - Editorial Notes. PMID- 28896739 TI - Notes on Ethyl Chloride as a General Anaesthetic. PMID- 28896742 TI - Meetings of Societies. PMID- 28896741 TI - On Some Urinary Infections, with Especial Reference to Their Treatment by Urotropin. PMID- 28896743 TI - Notes on a Case of Variola Nigra. (Malignant or Black Smallpox.). PMID- 28896744 TI - A Retrospect of a Further Series of Intra-Abdominal Operations. PMID- 28896745 TI - The Use of X-Rays in the Diagnosis of Renal Calculi. PMID- 28896747 TI - Notes on New Drugs and Preparations for the Sick. PMID- 28896746 TI - Medicine. PMID- 28896748 TI - Why Defective Nasal Respiration Impedes Growth and Development. PMID- 28896749 TI - Medicine. PMID- 28896750 TI - Clinical Note on a Case of Epithelioma of Tongue in a Young Woman. PMID- 28896751 TI - Surgery. PMID- 28896752 TI - Some Effects of Fright in Medicine. PMID- 28896753 TI - The Prognosis of Pulmonary Tuberculosis. PMID- 28896755 TI - Colitis Polyposa. PMID- 28896754 TI - Notes of a Case of Acute Yellow Atrophy of the Liver. PMID- 28896756 TI - Dermatology. PMID- 28896757 TI - Editorial Notes. PMID- 28896758 TI - A Case of Acute Yellow Atrophy of the Liver in a Child. PMID- 28896759 TI - Notes on Preparations for the Sick. PMID- 28896760 TI - Notes on a Case of Splenomegalic Biliary Cirrhosis, in a Boy Aged Six Years. PMID- 28896761 TI - Meetings of Societies. PMID- 28896762 TI - Anti-Tuberculous Vaccines and Sera. PMID- 28896763 TI - Obstetrics. PMID- 28896764 TI - Eighty Cases of Lupus Vulgaris. PMID- 28896765 TI - The Value of Compression of the Aorta in the Treatment of Post-Partum Hemorrhage. PMID- 28896766 TI - Meetings of Societies. PMID- 28896767 TI - Editorial Notes. PMID- 28896768 TI - A Case of Narcolepsy. PMID- 28896769 TI - Surgery. PMID- 28896770 TI - Medicine. PMID- 28896771 TI - Tumours and Tubercle in Monkeys. PMID- 28896772 TI - Notes on Preparations for the Sick. PMID- 28896773 TI - Cases Illustrating the More Unusual Complications of Pneumonia. PMID- 28896774 TI - Medicine. PMID- 28896775 TI - Lumbago. PMID- 28896776 TI - Meetings of Societies. PMID- 28896777 TI - Tubal Pregnancy-Its Diagnosis and Treatment. PMID- 28896778 TI - Surgery. PMID- 28896779 TI - Difficulties in the Surgical Diagnosis and Treatment of Cases Associated with Vomiting in Children. PMID- 28896780 TI - New Methods of Clinical Pathology. PMID- 28896781 TI - Health Notes in Bristol, 1905. PMID- 28896782 TI - The New Theory and Prophylaxis of Puerperal Eclampsia. PMID- 28896783 TI - Editorial Notes. PMID- 28896784 TI - Notes on Preparations for the Sick. PMID- 28896785 TI - The Relation of the Pelvic Floor to Pelvic Displacements and Pain in the Female. PMID- 28896786 TI - Obstetrics. PMID- 28896787 TI - Ophthalmology. PMID- 28896788 TI - Notes on Preparations for the Sick. PMID- 28896789 TI - The Uses of Static Electricity as an Aid to Recovery. PMID- 28896790 TI - Surgery. PMID- 28896792 TI - On the Treatment of Diabetes with Secretin. PMID- 28896791 TI - The Adaptation of Means in the Prevention of Disease: An Essay to Illustrate the Importance Towards Prevention of a Careful Study of the Life History of Individual Diseases. PMID- 28896793 TI - Editorial Notes. PMID- 28896794 TI - A Case of Mesenteric Thrombosis. PMID- 28896795 TI - The Treatment of Tabetic Ataxia by Methodical Exercises. PMID- 28896796 TI - Medicine. PMID- 28896797 TI - The Explanation of Alveolar Cleft Palate. PMID- 28896798 TI - The Doctor as Expert and Pioneer. PMID- 28896799 TI - On Some of the Initial Signs of Pleurisy. PMID- 28896800 TI - A Case of Banti's Disease, with Autopsy. PMID- 28896801 TI - Meetings of Societies. PMID- 28896802 TI - Surgery. PMID- 28896803 TI - Remarks on the "Light Treatment" of Lupus, Vulgaris and Erythematosus, and Rodent Ulcer, &c.: As Carried out at the Bristol General Hospital Since Dec. 9th, 1901, to the End of Dec., 1902. PMID- 28896804 TI - Two Cases of Ruptured Tubal Pregnancy. PMID- 28896805 TI - Perforated Typhoid Ulcer. PMID- 28896806 TI - On the Probable Rhythmical Contraction of the Bronchial Muscular Coat as a Factor in Pulmonary Disease. PMID- 28896807 TI - Editorial Notes. PMID- 28896808 TI - Therapeutics of a Sea Voyage. PMID- 28896809 TI - Medicine. PMID- 28896810 TI - Notes on Preparations for the Sick. PMID- 28896811 TI - Medicine. PMID- 28896812 TI - Electro-Therapeutics. PMID- 28896813 TI - A Contribution to the Conservative Surgery of the Uterine Appendages. PMID- 28896814 TI - Surgery. PMID- 28896815 TI - Round the World : A Medical Traveller's Notes. PMID- 28896816 TI - Notes on Preparations for the Sick. PMID- 28896818 TI - A Case of Perforated Duodenal Ulcer, with Remarks. PMID- 28896817 TI - A Granuloma of the Nose, Due to Iodide of Potassium. PMID- 28896819 TI - The Practical Value of Blood-Counts. PMID- 28896821 TI - Editorial Notes. PMID- 28896820 TI - The Antibodies in Disease. PMID- 28896822 TI - Four Cases of Renal Calculi Treated Successfully by Lumbar Nephro-Lithotomy. PMID- 28896823 TI - Laryngology and Rhinology. PMID- 28896824 TI - Editorial Notes. PMID- 28896825 TI - The Indications for Treatment in Nephroptosis. PMID- 28896826 TI - Otology. PMID- 28896827 TI - Notes on New Drugs and Preparations for the Sick. PMID- 28896828 TI - Medicine. PMID- 28896829 TI - Tubal Abortion. PMID- 28896830 TI - Vasomotor and Ocular Phenomena in Relation to Rheumatoid Arthritis. PMID- 28896831 TI - Surgery. PMID- 28896832 TI - Meetings of Societies. PMID- 28896833 TI - The Results of Operation in Fifty-Four Cases of Cancer of the Breast. PMID- 28896834 TI - The Medical Life: The Presidential Address, Delivered on October 8th 1902, at the Opening of the Twenty=Ninth Session of the Bristol Medico=Chirurgical Society. PMID- 28896836 TI - Surgery. PMID- 28896835 TI - Observations on Cases of Appendicitis. PMID- 28896838 TI - Editorial Notes. PMID- 28896837 TI - A Case of Generalised Sarcoma, with Blood Changes. PMID- 28896839 TI - Syphilis: The Presidential Address, Delivered on October 9th, 1907, at the Opening of the Thirty-Fourth Session of the Bristol Medico-Chirurgical Society. PMID- 28896840 TI - Medicine. PMID- 28896841 TI - Psychiatry. PMID- 28896842 TI - Notes on Preparations for the Sick. PMID- 28896843 TI - Proportional Representation and the Comparison of Radiographs. PMID- 28896844 TI - The Value of Compression of the Aorta in the Treatment of Post-Partum Hemorrhage. PMID- 28896846 TI - Meetings of Societies. PMID- 28896845 TI - Public Health in Bristol, 1906-7. PMID- 28896847 TI - Some Remarks on Spinal Anaesthesia as Based upon the Personal Observation of Thirty Cases. PMID- 28896848 TI - Muscular Atrophy and Sclerodermia. PMID- 28896849 TI - Otology. PMID- 28896850 TI - Note on Scurvy as a Cause of Haematuria in the Infant and in Old Age. PMID- 28896851 TI - Meetings of Societies. PMID- 28896853 TI - Notes on Preparations for the Sick. PMID- 28896852 TI - Editorial Notes. PMID- 28896854 TI - Laryngology. PMID- 28896855 TI - Surgery. PMID- 28896856 TI - A Case of Infantile Scurvy. PMID- 28896857 TI - Some Surprises in My Professional Career: The Presidential Address Deliverd on October 14th, 1903, at the Opening of the Thirtieth Session of the Bristol Medico Chirurgical Society. PMID- 28896859 TI - Medicine. PMID- 28896858 TI - Collargol: A Review of Some of Its Clinical Applications, with Experiments on Its Antiseptic Action. PMID- 28896860 TI - A Case of Infantile Scurvy or Scurvy-Rickets. PMID- 28896861 TI - Light Treatment. PMID- 28896862 TI - The Dangers of Delay in Ovariotomy. PMID- 28896863 TI - Trypanosomiasis. PMID- 28896864 TI - Dental Infections: Their Diagnosis and Treatment. PMID- 28896865 TI - Stokes-Adams Syndrome Produced by Digitalis in a Case of Auricular Fibrillation. PMID- 28896866 TI - Clinics from the Brain Physiologist's Viewpoint. PMID- 28896868 TI - Work in Great Britain. PMID- 28896867 TI - Acute Intestinal Obstruction. PMID- 28896869 TI - Meetings of Societies. PMID- 28896870 TI - Editorial Notes. PMID- 28896872 TI - Work in New York. PMID- 28896871 TI - Recent Dental Research. PMID- 28896874 TI - Editorial Notes. PMID- 28896873 TI - Changes in the Spleen in Acute Pyogenic Infections. PMID- 28896875 TI - Observations on Epilepsy. PMID- 28896877 TI - Five Years' Experience of Surgery in Exophthalmic Goitre. PMID- 28896876 TI - The Origin and Significance of Tuberculosis of the Tracheo-Bronchial Lymph Nodes of the Lung. PMID- 28896878 TI - A Case of Von Recklinghausen's Disease (Multiple Neurofibromata) with Spontaneous Fractures. PMID- 28896880 TI - Surgery. PMID- 28896879 TI - The Treatment of Graves' Disease. PMID- 28896881 TI - Medicine. PMID- 28896883 TI - Editorial Notes. PMID- 28896882 TI - The Sanatorium Treatment of Pulmonary Tuberculosis-Is It a Success? PMID- 28896884 TI - Notes on Preparations for the Sick. PMID- 28896885 TI - Prognosis. PMID- 28896886 TI - Meetings of Societies. PMID- 28896887 TI - Acquired Angioma of the Liver. PMID- 28896888 TI - Concluding Notes on a Case of Splenomegalic Cirrhosis in a Child Aged Seven Years. PMID- 28896889 TI - Some Notes on Styracol. PMID- 28896890 TI - Two Cases of Ruptured Intestine. PMID- 28896891 TI - Operations for Deflections and Spurs of the Nasal Septum, with Special Reference to Sub-Mucous Resection. PMID- 28896893 TI - Pathology. PMID- 28896892 TI - Cerebro-Spinal Fever (Epidemic Cerebro-Spinal Meningitis). PMID- 28896894 TI - The Infective Factor in Thrombosis and Embolism. PMID- 28896896 TI - Meetings of Societies. PMID- 28896895 TI - The Duty of Medicine to the Race: The Presidential Address, Delivered on 9th October, 1929, at the Opening of the Fifty-Seventh Session of the Bristol Medico Chirurgical Society. PMID- 28896897 TI - Editorial Notes. PMID- 28896898 TI - Hospitals-Voluntary or Self-Supporting? PMID- 28896899 TI - Ophthalmology. PMID- 28896900 TI - A Suggested Treatment for Functional Aphonia. PMID- 28896901 TI - A Case of Filariasis: Removal of Lymphatic Varix by Operation. PMID- 28896902 TI - Medicine. PMID- 28896903 TI - Notes on Preparations for the Sick. PMID- 28896904 TI - Rheumatic Carditis in Childhood. PMID- 28896905 TI - Treatment of Graves's Disease by Anti-Thyreoid Serum and by X-Rays. PMID- 28896906 TI - Editorial Notes. PMID- 28896907 TI - Cerebral Lesions in Pregnancy and Parturition. PMID- 28896909 TI - The Medical Reading Society, Bristol. PMID- 28896908 TI - Surgery. PMID- 28896910 TI - Meetings of Societies. PMID- 28896912 TI - Five Cases of Injury to Main Vessels Occurring in Civil Practice. PMID- 28896913 TI - Meetings of Societies. PMID- 28896911 TI - A Case of Typhoid Fever with Co-Existent Bacillus Coli Infection. PMID- 28896914 TI - The Beddoe Memorial Lecture: Anthropology: Old and New: Being an Account of What Dr. John Beddoe, a Physician of Bristol, Did for British Anthropology, Together with a Proposal for the Foundation of a Chair of Anthropology in the University of Bristol. PMID- 28896915 TI - Notes on the Treatment of Eclampsia. PMID- 28896916 TI - Editorial Notes. PMID- 28896917 TI - Perforation in Paratyphoid B. PMID- 28896918 TI - The Long Fox Memorial Lecture: The Influence of Food on the Production and Prevention of Disease. PMID- 28896920 TI - Periscope. PMID- 28896919 TI - Inebriety. PMID- 28896921 TI - A Case of Myxoedema. Congenital Heart Disease. Disseminated Sclerosis. PMID- 28896923 TI - Notes on Preparations for the Sick. PMID- 28896922 TI - Some Surgical Aspects of Carcinoma: The Presidential Address, Delivered Oct. 9th, 1889, at the Opening of the 16th Session of the Bristol Medico-Chirurgical Society. PMID- 28896924 TI - Scraps. PMID- 28896925 TI - Dilatation of the Stomach. PMID- 28896926 TI - Scraps. PMID- 28896927 TI - On the Treatment of Acute Inflammations of the Middle Ear. PMID- 28896928 TI - Bournemouth. PMID- 28896930 TI - Notes on Preparations for the Sick. PMID- 28896929 TI - Periscope. PMID- 28896931 TI - Hydrate of Chloral: A Therapeutic Study. PMID- 28896932 TI - On "Birth Palsy," with Illustrative Cases. PMID- 28896933 TI - Cases of Oral Surgery. PMID- 28896935 TI - On the Treatment of Laryngeal Growths. PMID- 28896934 TI - Periscope. PMID- 28896936 TI - Scraps. PMID- 28896937 TI - Notes on Preparations for the Sick. PMID- 28896938 TI - Observations on the Normal Diet. PMID- 28896939 TI - Clifton. PMID- 28896940 TI - Periscope. PMID- 28896941 TI - Tubercle of Medulla Oblongata. PMID- 28896942 TI - Reminiscences of an Army Surgeon: An Address Delivered at the Annual Meeting of the Bath and Bristol Branch of the British Medical Association, June 26th, 1889. PMID- 28896943 TI - Accidental Haemorrhage. PMID- 28896945 TI - Scraps. PMID- 28896944 TI - Chronic Pharyngitis with Elongated Uvula. PMID- 28896946 TI - Notes on Preparations for the Sick. PMID- 28896947 TI - Weston-Super-Mare. PMID- 28896948 TI - Personality-A Review. PMID- 28896949 TI - Uveo-Parotitic Paralysis. A Report of a Case and Some Account of Previous Instances. PMID- 28896950 TI - Editorial Notes. PMID- 28896952 TI - Meetings of Societies. PMID- 28896951 TI - The Operative Treatment of Meningitis. PMID- 28896953 TI - Polyneuritis Preceded by Inflammation of the Parotid, Lachrymal and Mammary Glands. PMID- 28896955 TI - Meetings of Societies. PMID- 28896954 TI - Rigid Rest in Rheumatic Carditis. PMID- 28896956 TI - The Treatment of Repressed Memories by Hypnotism. PMID- 28896957 TI - The Use of Insulin in Surgery. PMID- 28896958 TI - The Treatment of Lachrymal Obstruction. PMID- 28896959 TI - Kala Azar. Notes on the Disease and Its Treatment. PMID- 28896960 TI - Editorial Notes. PMID- 28896961 TI - Women Doctors with the Army in the Field. PMID- 28896962 TI - Medicine. PMID- 28896963 TI - Neuritis: Its Definition and Successful Treatment. PMID- 28896964 TI - Cotton-Seed Dermatitis and Its Cause, Pediculoides Ventricosus. PMID- 28896965 TI - The Clinical Examination of Stools. PMID- 28896966 TI - The Relation of the Autonomic Nervous System to Clinical Medicine: Presidential Address, Delivered on June 30th, 1926, to the Bath and Bristol Branch of the British Medical Association. PMID- 28896967 TI - A Case of Severe Herpes Zoster and Varicella Occurring Simultaneously in an Aged Patient. PMID- 28896968 TI - The Treatment of Cervical Erosion, with Special Reference to the "Pre-Cancerous" Cervix. PMID- 28896969 TI - The Investigation of Surgical Cases of Renal Disease. PMID- 28896970 TI - The Pathology of Cervical Erosion. PMID- 28896971 TI - Editorial Note. PMID- 28896972 TI - The Health of the Nation-A Review. PMID- 28896974 TI - Meetings of Societies. PMID- 28896973 TI - Acute Suffocative OEdema of the Lungs. PMID- 28896975 TI - Editorial Notes. PMID- 28896976 TI - The Hospitals of Madrid: a "Busman's Holiday". PMID- 28896977 TI - Two Cases of Angina Pectoris Following Sepsis. PMID- 28896978 TI - The Pathology of Coronary Occlusion. PMID- 28896980 TI - Meetings of Societies. PMID- 28896979 TI - Coronary Obstruction. PMID- 28896981 TI - Observations on Pellagra: With an Account of a Case. PMID- 28896983 TI - Editorial Notes. PMID- 28896982 TI - The Recommendations of the Royal Commission on Lunacy and Mental Disorder. PMID- 28896984 TI - Anaesthesia: Presidential Address, Delivered on 13th October, 1926, at the Opening of the Fifty-Fourth Session of the Bristol Medico-Chirurgical Society. PMID- 28896985 TI - The Central Nervous System in Addisonian Anaemia. PMID- 28896986 TI - Some Clinical Aspects of Sterility. PMID- 28896987 TI - Obstetrics. PMID- 28896988 TI - The Paralysis of Osteo-Arthritis. PMID- 28896990 TI - Meetings of Societies. PMID- 28896989 TI - Scraps. PMID- 28896991 TI - Buccal Glandular Tumours. PMID- 28896992 TI - Alcoholic Disease of the Heart. PMID- 28896994 TI - Medicine. PMID- 28896993 TI - Sarcomatous Tumour of the Shoulder-Centre in the Cortex of the Right Hemisphere: Operation, Improvement, Death. PMID- 28896996 TI - Notes on Preparations for the Sick. PMID- 28896995 TI - Four Cases of Blood-Poisoning in Brothers. PMID- 28896997 TI - Pneumococci in the Urine. PMID- 28896998 TI - Surgery. PMID- 28896999 TI - Editorial Notes. PMID- 28897000 TI - Suprarenal Virilism. With an Account of a Case. PMID- 28897001 TI - Meetings of Societies. PMID- 28897002 TI - The Ocular Signs of Migraine. PMID- 28897003 TI - The Long Fox Memorial Lecture: The AEtiology of Cardiac Disease. PMID- 28897004 TI - The Endometriomata. PMID- 28897005 TI - Early Medical Teaching in Bristol: The Bristol Medical School and Its Association with The University College. PMID- 28897006 TI - Editorial Notes. PMID- 28897007 TI - The Prophylaxis of Ophthalmia Neonatorum. PMID- 28897008 TI - Meetings of Societies. PMID- 28897009 TI - The Significance of Vertigo. PMID- 28897010 TI - Editorial Note. PMID- 28897011 TI - Meetings of Societies. PMID- 28897012 TI - A Visit to the near East. PMID- 28897013 TI - The Long Fox Memorial Lecture: Some Considerations on the Cells and Liquids of the Body and the Oxygen-Content of These. PMID- 28897014 TI - Some Clinical Aspects of Dysmenorrhoea. PMID- 28897015 TI - Six Cases of Cancer Arising in Tissues within the Duodenal Loop. PMID- 28897016 TI - Editorial Note. PMID- 28897017 TI - An Outbreak of Institutional Dysentery Due to the Y. Bacillus. PMID- 28897018 TI - ? PMID- 28897020 TI - Surgery. PMID- 28897019 TI - Medicine. PMID- 28897022 TI - Intestinal Stasis. PMID- 28897023 TI - On Toxic Polyneuritis of the Motor Type. PMID- 28897024 TI - Diseases of Children. PMID- 28897026 TI - Meetings of Societies. PMID- 28897025 TI - On the Pernasal Operation for Frontal Sinus Suppuration. PMID- 28897027 TI - Medicine. PMID- 28897028 TI - The Administration of Ether. PMID- 28897029 TI - On the Localisation of the Foramina at the Base of the Skull. PMID- 28897030 TI - Dermatology. PMID- 28897031 TI - The Progress of Surgery in the Last Twenty-Five Years: The Presidential Address, Delivered on July 12th, 1895, at the Annual Meeting of the Oxfordshire Branch of the British Medical Association. PMID- 28897032 TI - Notes on Preparations for the Sick. PMID- 28897033 TI - Surgery. PMID- 28897034 TI - On the Diagnosis of Cancer and of Simple Dilatation of the Stomach. PMID- 28897035 TI - The William F. Jenks Memorial Prize. PMID- 28897036 TI - Scraps. PMID- 28897037 TI - Medical Organisation and the Growth of the Medical Sciences in the Seventeenth Century, Illustrated by the Lives of Local Worthies. PMID- 28897038 TI - Editorial Notes. PMID- 28897039 TI - The End-Results of Operations on the Stomach and Duodenum. PMID- 28897041 TI - Surgery. PMID- 28897040 TI - Notes on Preparations for the Sick. PMID- 28897042 TI - Bristol Medico-Chirurgical Society. PMID- 28897043 TI - A Case of Hysterectomy for Fibroid Tumour of Uterus, with Intra-Abdominal Treatment of Pedicle. PMID- 28897044 TI - Medicine. PMID- 28897046 TI - Notes on Preparations for the Sick. PMID- 28897045 TI - Achondroplasia. PMID- 28897047 TI - A Case of Acute Ulcerative Endocarditis. PMID- 28897048 TI - Ophthalmology. PMID- 28897049 TI - Tablets of Anatomy. PMID- 28897050 TI - The Surgical Treatment of Myoma of the Uterus. PMID- 28897051 TI - Scraps. PMID- 28897052 TI - Congress of Gynaecology and Obstetrics. PMID- 28897053 TI - The Bacteriology of Some Suppurations Complicating Pulmonary Disease. PMID- 28897054 TI - Symphysiotomy. PMID- 28897055 TI - Surgery. PMID- 28897057 TI - Notes on Preparations for the Sick. PMID- 28897056 TI - Herpes and Brachial Neuritis. PMID- 28897058 TI - Editorial Notes. PMID- 28897060 TI - Household Syphilis (Syphilis OEconomica), with Observations on Acquired Syphilis in Infants. PMID- 28897059 TI - The Bristol Medical Library. PMID- 28897061 TI - Medicine. PMID- 28897062 TI - The Present Position of the Surgery of Malignant Growths: The Presidential Address, Delivered on October 11th, 1911, at the Opening of the Thirty-Eight Session of the Bristol Medico-Chirurgical Society. PMID- 28897063 TI - Meetings of Societies. PMID- 28897065 TI - Some Observations on Tea-Poisoning. PMID- 28897064 TI - Cardiac Arrhythmia: Five Cases. PMID- 28897066 TI - Otology. PMID- 28897068 TI - Surgery. PMID- 28897067 TI - School Surgery: The Presidential Address, delivered on October 9th, 1895, at the Opening of the 22nd Session of the Bristol Medico-Chirurgical Society. PMID- 28897069 TI - Two Cases of Fibroid Degeneration of the Myocardium. PMID- 28897070 TI - Laryngology. PMID- 28897071 TI - Medicine. PMID- 28897072 TI - Notes on Preparations for the Sick. PMID- 28897073 TI - Scraps. PMID- 28897074 TI - Bristol Medico-Chirurgical Society. PMID- 28897075 TI - Notes on Egypt as a Health-Resort. PMID- 28897076 TI - Four Cases of Cysts in the Neck of Similar Character, and Possibly Developed in Connection with Branchial Clefts. PMID- 28897078 TI - Surgery. PMID- 28897077 TI - Some Observations on School Hygiene. PMID- 28897079 TI - Furunculosis. PMID- 28897081 TI - Meetings of Societies. PMID- 28897080 TI - The Medical Aspect of Boswell's "Life of Johnson," with Some Account of the Medical Men Mentioned in That Book: The Presidential Address, Delivered on October 12th, 1910, at the Opening of the Thirty-Seventh Session of the Bristol Medico-Chirurgical Society. PMID- 28897082 TI - Medicine. PMID- 28897083 TI - On the Resection of the Posterior Spinal Nerve Roots. PMID- 28897084 TI - Auricular Fibrillation. PMID- 28897086 TI - Editorial Notes. PMID- 28897085 TI - Design for an Elementary Radiographic Camera. PMID- 28897088 TI - Notes on Preparations for the Sick. PMID- 28897087 TI - A Case of Ataxia in a Child Aged Three and a Half Years. PMID- 28897089 TI - Notes on Preparations for the Sick. PMID- 28897090 TI - The Nature and Treatment of Chorea. PMID- 28897091 TI - Defects in the Visual Field. PMID- 28897092 TI - The Long Fox Lecture: Cerebro-Spinal Syphilis. PMID- 28897093 TI - Meetings of Societies. PMID- 28897094 TI - Ophthalmology. PMID- 28897095 TI - Editorial Notes. PMID- 28897096 TI - Surgery. PMID- 28897097 TI - Medicine. PMID- 28897098 TI - Removal of Bullets and Other Metallic Foreign Bodies. PMID- 28897099 TI - Editorial Notes. PMID- 28897100 TI - Meetings of Societies. PMID- 28897101 TI - Gunshot Injuries to the Eyes. PMID- 28897102 TI - The Long Fox Lecture: The Evolution of the Sense of Sight. PMID- 28897103 TI - Cardiac Diseases and Disorders in Warfare. PMID- 28897104 TI - Surgery. PMID- 28897105 TI - The Foundation of the Medico-Chirurgical Society and The History of Military Medicine in England: The Presidential Address, Delivered on October 13th, 1915, at the Opening of the Forty-Second Session of the Bristol Medico-Chirurgical Society. PMID- 28897106 TI - Notes on Preparations for the Sick. PMID- 28897107 TI - Dermatology. PMID- 28897108 TI - The Antiseptic and Disinfectant Properties of Soap. PMID- 28897110 TI - A Simple Form of Influence Machine for X-Ray Work. PMID- 28897109 TI - Surgery. PMID- 28897111 TI - The College of Physicians of Philadelphia. PMID- 28897113 TI - Scraps. PMID- 28897112 TI - Some Groups of Interesting Cases of Abdominal Surgery. PMID- 28897114 TI - Medicine. PMID- 28897115 TI - On the Treatment of Subacute Bronchitis. PMID- 28897116 TI - Congres International de Medecine. PMID- 28897117 TI - Some Unusual Operations on Lunatics and Their Results. PMID- 28897118 TI - Notes on Preparations for the Sick. PMID- 28897119 TI - Surgery. PMID- 28897120 TI - On the Temperature in Cases of Apoplexy, and on the Occurrence (1) of OEdema and (2) of Loss of the Knee-Jerk in the Paralysed Limbs in Hemiplegia. PMID- 28897121 TI - A Case of Dislocation of the Hand and Carpus Backwards. PMID- 28897122 TI - Fracture of the Patella. PMID- 28897123 TI - Bristol Medico-Chirurgical Society. PMID- 28897124 TI - Scraps. PMID- 28897125 TI - Idiopathic Thrombosis of the Portal and Contributory Veins. PMID- 28897127 TI - Obstetrics and Gynaecology. PMID- 28897126 TI - Devon and Exeter Medical Society. PMID- 28897128 TI - A Case of Extreme Bradycardia: With Notes on the Eye-Symptoms. PMID- 28897130 TI - Medicine. PMID- 28897129 TI - Medicine. PMID- 28897131 TI - Notes on Preparations for the Sick. PMID- 28897132 TI - The Varieties of Uterine Neoplasms and Their Relative Frequency. PMID- 28897133 TI - Medical Bristol in the Eighteenth Century: The Presidential Address, Delivered on October 11th, 1899, at the Opening of the Twenty-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28897134 TI - Meetings of Societies. PMID- 28897135 TI - A Case of Neuritic Muscular Atrophy ("Peroneal" Type). PMID- 28897137 TI - Laryngology and Rhinology. PMID- 28897136 TI - Surgery. PMID- 28897138 TI - Scraps. PMID- 28897139 TI - The College of Physicians of Philadelphia. PMID- 28897140 TI - Therapeutics. PMID- 28897141 TI - Irreducible Intussusception: With Notes on a Fatal Case. PMID- 28897142 TI - The Bacterioscopic Diagnosis of Diphtheria. PMID- 28897143 TI - Meetings of Societies. PMID- 28897144 TI - Presentation to Dr. J. G. Swayne. PMID- 28897145 TI - Scraps. PMID- 28897146 TI - Medicine. PMID- 28897147 TI - Notes on Preparations for the Sick. PMID- 28897148 TI - Cystotomy for Bladder Tumours of Doubtful Malignancy. PMID- 28897149 TI - Surgery. PMID- 28897150 TI - Extra-Peritoneal Closure of Artificial Anus and Faecal Fistula. PMID- 28897151 TI - The Administration of Nitrous Oxide as a Preliminary to Ether Anaesthesia. PMID- 28897152 TI - Some Clinical Notes on Membranous Enteritis. PMID- 28897153 TI - Ophthalmology. PMID- 28897154 TI - Menorrhagia, Etc., and Hygienics. PMID- 28897156 TI - Scraps. PMID- 28897155 TI - Periscope. PMID- 28897157 TI - Notes on Preparations for the Sick. PMID- 28897158 TI - A Case of Gouty Peripheral Neuritis. PMID- 28897159 TI - Significance of Hoarseness and Aphonia in Cases of Pulmonary Phthisis. PMID- 28897160 TI - Notes from the Out-Patient Department. PMID- 28897161 TI - Droitwich and Its Brine Baths. PMID- 28897162 TI - The Treatment of Incomplete Abortion. PMID- 28897163 TI - Notes on a Rare Case of Morbus Caeruleus. PMID- 28897165 TI - Periscope. PMID- 28897164 TI - Two Cases of Phthisis Treated by Means of Subcutaneous and Intrapulmonary Injections of Carbolate of Camphor. PMID- 28897167 TI - Progressive Muscular Atrophy with Recovery. PMID- 28897166 TI - The Hour of Delivery. PMID- 28897168 TI - Notes on Preparations for the Sick. PMID- 28897169 TI - The Medical Certificate of the Cause of Death. PMID- 28897171 TI - Periscope. PMID- 28897170 TI - Scraps. PMID- 28897172 TI - Menorrhagia, Etc., and Hygienics. PMID- 28897173 TI - Scraps. PMID- 28897174 TI - Notes on Preparations for the Sick. PMID- 28897175 TI - Intubation of the Larynx: Read Before the Bristol Medico-Chirurgical Society. PMID- 28897176 TI - A Case of Suicidal Perforation of the Stomach by a Red-Hot Iron, with Remarks. PMID- 28897177 TI - Notes on Disinfection. PMID- 28897178 TI - Notes of Out-Patient Cases. PMID- 28897180 TI - Scraps. PMID- 28897179 TI - Some Recent Developments of the Germ Theory, More Particularly in Relation to the Treatment of Phthisis: The Presidential Address, Delivered on October 10th, 1888, at the Opening of the 15th Session of the Bristol Medico-Chirurgical Society. PMID- 28897181 TI - Cases Illustrating the Surgery of the Thyroid Body. PMID- 28897182 TI - A Case of Raynaud's Disease. PMID- 28897183 TI - Periscope. PMID- 28897184 TI - Notes on Preparations for the Sick. PMID- 28897186 TI - Scraps. PMID- 28897185 TI - Epidemic Influenza. PMID- 28897187 TI - Notes on Preparations for the Sick. PMID- 28897188 TI - The Bristol Infirmary in My Student Days, 1822-1828. PMID- 28897189 TI - Clinical Studies of Disease in Children. PMID- 28897191 TI - Periscope. PMID- 28897190 TI - A Case of Congenital Heart-Disease. PMID- 28897192 TI - Case of "Orbital Aneurism" Treated by Ligature of the Carotid. PMID- 28897194 TI - Periscope. PMID- 28897193 TI - The Sequelae of Suppurative Otitis Media. PMID- 28897195 TI - Scraps. PMID- 28897196 TI - The Symptoms and Treatment of Outgrowths from the Back of the Tongue. PMID- 28897197 TI - Case of Epithelioma of the Body of the Uterus. PMID- 28897198 TI - Notes on Preparations for the Sick. PMID- 28897199 TI - Post-Partum Complications. PMID- 28897200 TI - On Some Points in the Surgical Physiology of the Abdomen and Pelvis. PMID- 28897201 TI - A Case of Acute Ascending Paralysis (Landry's Paralysis). PMID- 28897202 TI - Factitious Urticaria. PMID- 28897203 TI - Notes on Preparations for the Sick. PMID- 28897204 TI - The International Medical Congress. PMID- 28897205 TI - Scraps. PMID- 28897206 TI - A Case of Factitious Urticaria. PMID- 28897207 TI - Personal Methods Employed in the Radical Cure of Hernia-Inguinal, Femoral and Umbilical. PMID- 28897209 TI - Periscope. PMID- 28897208 TI - The Sequelae of Suppurative Otitis Media. PMID- 28897211 TI - Periscope. PMID- 28897210 TI - On Some Varieties of Paraplegia with Lateral Sclerosis, with Cases. PMID- 28897212 TI - Multiple Cancellous Exostoses. PMID- 28897213 TI - Scraps. PMID- 28897214 TI - Notes on Preparations for the Sick. PMID- 28897216 TI - Some Cases of Peripheral Neuritis. PMID- 28897215 TI - Health-Resorts in the West of England and South Wales: IV. Ilfracombe. PMID- 28897217 TI - Some Points in Lunacy Practice in Relation to the General Practitioner: Abstract of the Presidential Address Delivered on October 13th, 1897, at the Opening of the 24th Session of the Bristol Medico-Chirurgical Society. PMID- 28897218 TI - Notes on Preparations for the Sick. PMID- 28897219 TI - Meetings of Societies. PMID- 28897220 TI - Cases of Hepatic and Intestinal Surgery. PMID- 28897221 TI - Surgery. PMID- 28897222 TI - Scraps. PMID- 28897223 TI - The Morphology and Pathology of the Pharyngeal Pouch of Rathke. PMID- 28897224 TI - Otology. PMID- 28897226 TI - Medicine. PMID- 28897225 TI - Laryngology and Rhinology. PMID- 28897227 TI - Notes on Preparations for the Sick. PMID- 28897228 TI - A Case of Hystero-Epilepsy. PMID- 28897229 TI - Surgery. PMID- 28897230 TI - Medicine. PMID- 28897231 TI - On the Use of Oxygen in the Treatment of Anaemia, with a Case Treated by Transfusion of Blood. PMID- 28897232 TI - Scraps. PMID- 28897233 TI - A Case of Needle in Foot Revealed by the X Rays. PMID- 28897234 TI - Dermatology. PMID- 28897235 TI - The Causation and Treatment of Sudden Dyspnoea in Goitre: With Report of a Case in Which the Middle Lobe of the Thyroid Was Excised for Such a Condition. PMID- 28897236 TI - Surgery. PMID- 28897237 TI - A Case of Hysterical Disease of Both Hips and Both Knees, with Extreme Distortion of the Lower Limbs. PMID- 28897238 TI - Medicine. PMID- 28897239 TI - Three Cases of Vaginal Hysterectomy for Malignant Disease. PMID- 28897240 TI - The Effect of the Rontgen Rays on Calculi: With the Report of a Case of Renal Calculus in Which the Diagnosis Was Confirmed by Skiagraphy. PMID- 28897241 TI - The Symptoms and Treatment of Chronic Suppuration of the Maxillary Antrum. PMID- 28897242 TI - Meetings of Societies. PMID- 28897243 TI - Secondary Rashes in Scarlet Fever. PMID- 28897244 TI - Ophthalmology. PMID- 28897246 TI - Scraps. PMID- 28897245 TI - Two Cases of Compound Depressed Fracture of Frontal Bone. PMID- 28897247 TI - Notes on Preparations for the Sick. PMID- 28897248 TI - Otology. PMID- 28897249 TI - A Case of Double Spasmodic Torticollis: Excision of Both Spinal Accessory Nerves. PMID- 28897250 TI - Surgery. PMID- 28897251 TI - Notes on Self-Poisoning and Its Treatment, with Special Reference to Some Physical Methods. PMID- 28897252 TI - Meetings of Societies. PMID- 28897253 TI - The Diagnosis and Treatment of Lumbago. PMID- 28897254 TI - The Evils of Marriage and Pregnancy in Women Who Do Not Possess Sound Pelvic Organs: The Presidential Address, Delivered on October 14th, 1896, at the Opening of the 23rd Session of the Bristol Medico-Chirurgical Society. PMID- 28897255 TI - Notes on Preparations for the Sick. PMID- 28897256 TI - Medicine. PMID- 28897257 TI - Laryngology. PMID- 28897258 TI - Scraps. PMID- 28897259 TI - Dermatology. PMID- 28897260 TI - The Causes of Death in Five Cases in a Colliery Explosion. PMID- 28897261 TI - Fifteen Years' Experience of Infectious Diseases in a Public School. PMID- 28897262 TI - Medicine. PMID- 28897263 TI - Two Cases of Intubation in Adults. PMID- 28897265 TI - Surgery. PMID- 28897264 TI - Scraps. PMID- 28897267 TI - A Case of Haemophilia with Joint Lesions. PMID- 28897266 TI - Notes on Preparations for the Sick. PMID- 28897268 TI - Meetings of Societies. PMID- 28897269 TI - Notes on Preparations for the Sick. PMID- 28897270 TI - Surgery. PMID- 28897272 TI - Dermoid Cyst of a Branchial Cleft. PMID- 28897271 TI - Induced Premature Labour in Certain Diseases of the Mother Not Obstructing Delivery. PMID- 28897274 TI - International Congress of Dermatology. PMID- 28897273 TI - The Clinical Significance of the Human Hand. PMID- 28897275 TI - Scraps. PMID- 28897276 TI - Medicine. PMID- 28897277 TI - Chloroform or Ether? PMID- 28897278 TI - International Congress of Gynaecology and Obstetrics. PMID- 28897279 TI - A Case of Ligature and Division of the Vasa Deferentia for Prostatic Hypertrophy. PMID- 28897280 TI - Obstetrics. PMID- 28897282 TI - Two Cases of Abdominal Section. PMID- 28897281 TI - A Case of Acute Miliary Tuberculosis: Treated with Antistreptococcic Serum on Account of the Presence in the Blood of the Streptococcus Pyogenes Albus. PMID- 28897283 TI - Medicine. PMID- 28897284 TI - Paralysis of the Respiratory Centre from Intracranial Pressure. PMID- 28897285 TI - Bristol Medico-Chirurgical Society. PMID- 28897286 TI - Notes on Preparations for the Sick. PMID- 28897288 TI - Scraps. PMID- 28897287 TI - Gynaecology and Obstetrics. PMID- 28897289 TI - Surgery. PMID- 28897291 TI - International Congress of Forensic Medicine. PMID- 28897290 TI - Paroxysmal Tachycardia. PMID- 28897293 TI - The Use of Alcohol from a Medical Standpoint. PMID- 28897292 TI - A Case of Ruptured Tubal Pregnancy. PMID- 28897294 TI - Induced Premature Labour in Certain Diseases of the Mother Not Obstructing Delivery. PMID- 28897295 TI - Editorial Note. PMID- 28897296 TI - Scraps. PMID- 28897298 TI - Surgery. PMID- 28897297 TI - Ophthalmology. PMID- 28897299 TI - Meetings of Societies. PMID- 28897300 TI - Medicine. PMID- 28897301 TI - Notes on Preparations for the Sick. PMID- 28897302 TI - Notes on a Case of Exophthalmic Goitre. PMID- 28897303 TI - Extra-Peritoneal Suppuration in Perforating Appendicitis. PMID- 28897305 TI - Editorial Notes. PMID- 28897304 TI - Two Years' Experience of the Operation for Strangulated Hernia at the Bristol General Hospital: And Its Lessons. PMID- 28897306 TI - Meetings of Societies. PMID- 28897307 TI - Medical Treatment of Hyperthyroidism. PMID- 28897308 TI - Eczema and Dermatitis. PMID- 28897309 TI - Men-Midwives of the past. PMID- 28897310 TI - The Clinical Importance of the Intervertebral Discs, with Special Reference to Nuclear Prolapses. PMID- 28897311 TI - The Place of Surgery in Hyperthyroidism. PMID- 28897312 TI - Editorial Notes. PMID- 28897313 TI - Medical Practice in Palestine. PMID- 28897314 TI - Thomas Marryat, M.D.: A Memoir. PMID- 28897316 TI - Meetings of Societies. PMID- 28897315 TI - The Evolution of British Orthopaedics. PMID- 28897317 TI - Editorial Notes. PMID- 28897318 TI - Treatment of Lachrymal Obstruction. PMID- 28897320 TI - Meetings of Societies. PMID- 28897319 TI - Diseases of the Lachrymal Sac. PMID- 28897321 TI - Silicosis: I.-Administrative and Clinical. PMID- 28897322 TI - Cyanosis in the Fatal Broncho-Pneumonia of Influenza. PMID- 28897323 TI - Silicosis: II.-Radiology and Pathology. PMID- 28897324 TI - The Long Fox Memorial Lecture: The Partnership between Anaesthesia and Surgery. PMID- 28897326 TI - Haematuria in the Pre-Eruptive Stage of Measles. PMID- 28897325 TI - Editorial Notes. PMID- 28897328 TI - Editorial Notes. PMID- 28897327 TI - Congenital Abnormalities of the External Ear. PMID- 28897329 TI - The Relation of Gynaecology to the Glands of Internal Secretion: The Presidential Address, Delivered on 8th October, 1930, at the Opening of the Fifty-Eighth Session of the Bristol Medico-Chirurgical Society. PMID- 28897330 TI - Necrosis of the Myocardium. PMID- 28897331 TI - Ectopic Pregnancy. PMID- 28897332 TI - Congenital Heart Disease as Seen in Elementary School Children. PMID- 28897333 TI - Meetings of Societies. PMID- 28897335 TI - Meetings of Societies. PMID- 28897334 TI - The Differential Diagnosis of Primary Iritis in the Early Stages. PMID- 28897336 TI - Editorial Note. PMID- 28897337 TI - Focal Infection. PMID- 28897338 TI - The Diagnosis of Swellings of the Long Bones, with a Case of Periosteal Sarcoma of the Femur. PMID- 28897339 TI - The Association between Goitre and Atrophic Rhinitis. PMID- 28897340 TI - The Expulsion of Bile. PMID- 28897341 TI - A Case of Congenital Obstruction of the Bile-Duct. PMID- 28897343 TI - Editorial Notes. PMID- 28897342 TI - The Work of the University Centre of Cardiac Research, 1927-31. PMID- 28897344 TI - Tetany Following Thyroid Operations. PMID- 28897345 TI - Sterilization of the Unfit. PMID- 28897346 TI - A Review of Seven Hundred Cases of Acute Appendicitis. PMID- 28897347 TI - Editorial Notes. PMID- 28897348 TI - Abscess of the Brain: With Reports of Two Cases. PMID- 28897349 TI - Reform of the Medical Curriculum. PMID- 28897350 TI - The Twenty-Third Long Fox Memorial Lecture: Some Aspects of Heart Disease in Childhood. PMID- 28897352 TI - Meetings of Societies. PMID- 28897351 TI - Cerebral Dermoid. PMID- 28897354 TI - Editorial Notes. PMID- 28897353 TI - Meetings of Societies. PMID- 28897356 TI - Nervous Disorders in General Practice. PMID- 28897355 TI - Vaginal Discharge. PMID- 28897357 TI - Congenital Word-Blindness. PMID- 28897359 TI - Editorial Notes. PMID- 28897358 TI - Looking Back: The Presidential Address, Delivered on 11th October, 1933, at the Opening of the Sixty-First Session of the Bristol Medico-Chirurgical Society. PMID- 28897360 TI - Meetings of Societies. PMID- 28897361 TI - Results of the Treatment of Mental Conditions. PMID- 28897362 TI - The Twenty-Fourth Long Fox Memorial Lecture: Observations on Pain. PMID- 28897364 TI - Meetings of Societies. PMID- 28897363 TI - Clinical Record: A Case of Pulmonary Consolidation of Doubtful Origin. PMID- 28897365 TI - Strangulated Hernia. PMID- 28897366 TI - Editorial Notes. PMID- 28897367 TI - Some Disorders of Movement and Their Mechanism. PMID- 28897368 TI - Some Intestinal Malformations and Their Clinical Significance. PMID- 28897369 TI - The Modern Outlook on Mental Health. PMID- 28897370 TI - Licence to Practise and Liberty to Teach Medicine in the English Provinces. PMID- 28897371 TI - The Problem of Man's Origin: The Presidential Address, Delivered on 10th October, 1934, at the Opening of the Sixty-Second Session of the Bristol Medico Chirurgical Society. PMID- 28897372 TI - Editorial Notes. PMID- 28897373 TI - Meetings of Societies. PMID- 28897374 TI - Habit and Illness. PMID- 28897375 TI - Light Ether Anaesthesia. PMID- 28897376 TI - Intracranial Tumours and the Occurrence of Papilloedema. PMID- 28897378 TI - Editorial Notes. PMID- 28897377 TI - Unsuccessful Tonsil and Adenoid Operations. PMID- 28897379 TI - Psychiatry. PMID- 28897380 TI - The Diagnosis of Peptic Ulcer and Its Bearings on Treatment. PMID- 28897381 TI - On the Diagnosis and Treatment of Diabetes Mellitus, with Special Reference to the Usages of Insulin. PMID- 28897382 TI - Editorial Notes. PMID- 28897383 TI - A Film Method for Determining the Reaction of the Liquids of the Body by Indicators. PMID- 28897384 TI - Disorders of Deglutition. PMID- 28897386 TI - Editorial Notes. PMID- 28897385 TI - Some Developments in Abdominal Surgery: The Presidential Address, Delivered on 12th December, 1917, at the Opening of the Forty-Fourth Session of the Bristol Medico-Chirurgical Society. PMID- 28897387 TI - The Operative Findings in Thirty Cases of Gunshot Injury of Nerves, with Remarks on Diagnosis, Localisation, and the Technique of Operation. PMID- 28897388 TI - The Systematic Examination of the Abdomen: The Presidential Address, Delivered on December 11th, 1918, at the Opening of the Forty-Fifth Session of the Bristol Medico-Chirurgical Society. PMID- 28897390 TI - Meetings of Societies. PMID- 28897389 TI - Postgraduate Study. PMID- 28897391 TI - Editorial Notes. PMID- 28897392 TI - The Long Fox Lecture: The Relation between Chemistry and Medicine. PMID- 28897393 TI - Hoarseness: The Importance of Early Laryngoscopy. PMID- 28897395 TI - Editorial Notes. PMID- 28897394 TI - Injuries to the Head Illustrating Functions of the Cortex. PMID- 28897396 TI - Meetings of Societies. PMID- 28897397 TI - Laryngology and Rhinology. PMID- 28897399 TI - Meetings of the Bristol Medico-Chirurgical Society. PMID- 28897398 TI - Medicine. PMID- 28897400 TI - Presentation to Sir George Buchanan. PMID- 28897401 TI - Obstetrics. PMID- 28897402 TI - Health Resorts in the West of England and South Wales. VI.-Tenby. PMID- 28897404 TI - Jefferson Medical College. PMID- 28897403 TI - Extra-Uterine Pregnancy. PMID- 28897406 TI - Notes on Preparations for the Sick. PMID- 28897405 TI - Scraps. PMID- 28897408 TI - Surgery. PMID- 28897407 TI - Hay Fever and Hay Asthma. PMID- 28897409 TI - Anaesthetics. PMID- 28897410 TI - The Association between Angioma of the Cerebellum, Polycystic Pancreas and Renal Adenoma (Lindau's Syndrome). PMID- 28897411 TI - Senile Arterial Changes in a Child Aged Seven Weeks. PMID- 28897412 TI - Editorial Notes. PMID- 28897413 TI - The Significance of Sleep Disorders. PMID- 28897414 TI - The Borderland between Surgery and Gynaecology. PMID- 28897415 TI - The Principles of Surgical Treatment of Infections of the Peritoneum. PMID- 28897416 TI - Editorial Notes. PMID- 28897417 TI - The Debt of Medicine to the Fine Arts: The Presidential Address, Delivered on October 11th, 1922, at the Opening of the Fiftieth Session of the Bristol Medico Chirurgical Society. PMID- 28897419 TI - The Physiology of Diet and Hygiene at the North Pole. PMID- 28897418 TI - Meetings of Societies. PMID- 28897420 TI - Acquired Resistance to Tuberculosis: A Factor in Clinical Type and Prognosis. PMID- 28897421 TI - A Physiological Conception of Prolonged Hysterical Conditions. PMID- 28897423 TI - Robert Shingleton Smith. PMID- 28897422 TI - Discussion on Renal Efficiency: A Discussion Held at a Meeting of the Bristol Medico-Chirurgical Society on November 9th, 1921. PMID- 28897425 TI - Editorial Notes. PMID- 28897424 TI - Medicine and Psychology. PMID- 28897426 TI - A Case of Primary Sarcoma of the Spleen. PMID- 28897427 TI - Clinical Diagnosis of Primary Syphilis. PMID- 28897428 TI - Portal Pyaemia Following Diverticulitis, with Report of a Case. PMID- 28897430 TI - Editorial Notes. PMID- 28897429 TI - The Histology of the Aortic Wall in Acute Rheumatism. PMID- 28897431 TI - Foreign Bodies in the Gullet. PMID- 28897432 TI - Meetings of Societies. PMID- 28897433 TI - An Epidemic of Virulent Diphtheria. PMID- 28897434 TI - Editorial Notes. PMID- 28897435 TI - The Early Treatment and Diagnosis of Anterior Poliomyelitis. PMID- 28897436 TI - The Treatment of Parenchymatous Goitre. PMID- 28897438 TI - Meetings of Societies. PMID- 28897437 TI - Three Cases of Sino-Auricular Block. PMID- 28897439 TI - The Long Fox Memorial Lecture: Ten Years' Progress in Surgical Treatment. PMID- 28897440 TI - Editorial Note. PMID- 28897441 TI - A Recent Outbreak of Rotheln. PMID- 28897442 TI - Progress of the Medical Sciences. PMID- 28897443 TI - International Congress of Gynaecology and Obstetrics. PMID- 28897444 TI - Scraps. PMID- 28897445 TI - The Quantitative Estimation of the Knee-Jerk. PMID- 28897446 TI - On a Rare Form of Spina Bifida (Syringo-Myelocele). PMID- 28897448 TI - Notes on Preparations for the Sick. PMID- 28897447 TI - Alvarenga Prize of the College of Physicians of Philadelphia. PMID- 28897450 TI - Scraps. PMID- 28897451 TI - Medicine. PMID- 28897453 TI - Ophthalmology. PMID- 28897452 TI - Notes on Preparations for the Sick. PMID- 28897454 TI - A Case of Multiple Symmetrical Joint Lesions. PMID- 28897456 TI - Forceps Delivery during the Last Fifty Years. PMID- 28897455 TI - A Case of Large Ovarian Tumour in a Young Girl. PMID- 28897457 TI - Surgery. PMID- 28897458 TI - The Role of Dilute Acids in Infection. PMID- 28897459 TI - The Long Fox Lecture: The Repair of Bone Injuries. PMID- 28897460 TI - Some Phases of Quackery in Relation to Diseases of the Eye: The Presidential Address, Delivered on October 12th, 1921, at the Opening of the Forty-Eight Session of the Bristol Medico-Chirurgical Society. PMID- 28897461 TI - Editorial Notes. PMID- 28897462 TI - Tuberculosis: The Inaugural Address at the Annual Meeting of the Bath and Bristol Branch of the British Medical Association, 19th June, 1912. PMID- 28897463 TI - Medicine. PMID- 28897464 TI - The Relationship between Toxicity and Chemical Reactivity in Certain Benzene Derivatives. PMID- 28897466 TI - Editorial Note. PMID- 28897465 TI - Raynaud's Disease. PMID- 28897467 TI - The Right and the Wrong Side of the X-Ray Picture; Has a Mistake Been Made? PMID- 28897468 TI - Surgery. PMID- 28897469 TI - Meetings of Societies. PMID- 28897470 TI - Ophthalmology. PMID- 28897471 TI - Some Remarks on Insanity; Its Classification and Nomenclature. PMID- 28897472 TI - Notes on Preparations for the Sick. PMID- 28897473 TI - Surgery. PMID- 28897474 TI - Editorial Notes. PMID- 28897475 TI - The Present Position of Psychotherapy. PMID- 28897476 TI - The Teething Myth. PMID- 28897477 TI - Meetings of Societies. PMID- 28897478 TI - Medicine. PMID- 28897480 TI - Gynaecology. PMID- 28897479 TI - Some Problems in Surgical Treatment of Abdominal Conditions. PMID- 28897481 TI - Surgery. PMID- 28897483 TI - Scraps. PMID- 28897482 TI - The Teachings of Failure: The Presidential Address, Delivered on October 12th. 1892, at the Opening of the 19th Session of the Bristol Medico-Chirurgical Society. PMID- 28897484 TI - Two Cases of Locomotor Ataxy with Charcot's Joint Disease. PMID- 28897485 TI - Obstetrics. PMID- 28897486 TI - Meetings of Societies. PMID- 28897487 TI - The Early History of the Bristol Medical School. PMID- 28897488 TI - Health-Resorts in the West of England and South Wales. Bath. PMID- 28897490 TI - Notes on Preparations for the Sick. PMID- 28897489 TI - Medicine. PMID- 28897492 TI - Meetings of Societies. PMID- 28897491 TI - Otology. PMID- 28897493 TI - Progress of the Medical Sciences. PMID- 28897495 TI - Disease in Mesopotamia. PMID- 28897494 TI - Contemporary Medicine from the Standpoint of Pathology: The Presidential Address, Delivered on October 8th, 1919, at the Opening of the Forty-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28897496 TI - Stammering as It Occurred in the War. PMID- 28897497 TI - On the Treatment of Ununited Fractures, with Especial Reference to the Use of Bone Grafts. PMID- 28897498 TI - The Therapeutic Uses of Radium. PMID- 28897499 TI - Meetings of Societies. PMID- 28897500 TI - Recovery after Mechanical Obstruction Due to the Passage of a Gallstone through the Intestine, with Septic Peritonitis. PMID- 28897501 TI - Labyrinthitis: Remarks, with Special Reference to Treatment, on Cases Shown to the Bristol Medico-Chirurgical Society, May 14th, 1924. PMID- 28897502 TI - Editorial Notes. PMID- 28897503 TI - Diverticulitis of the Pelvic Colon. PMID- 28897504 TI - Lachrymal Obstruction: Its Results, Dangers and Treatment. PMID- 28897505 TI - Notes on Preparations for the Sick. PMID- 28897506 TI - Meetings of Societies. PMID- 28897507 TI - Is Opsonic Treatment Useful in Phthisis? PMID- 28897508 TI - Some Notes on the Treatment of Haemoptysis in Pulmonary Tuberculosis. PMID- 28897509 TI - Medicine. PMID- 28897510 TI - Dermatology. PMID- 28897511 TI - Some Clinical Points in the Early Diagnosis of Pulmonary Tuberculosis. PMID- 28897512 TI - Surgery. PMID- 28897513 TI - Case of Filariasis with Abscess. PMID- 28897514 TI - Editorial Notes. PMID- 28897515 TI - Calmette's Ophthalmic Reaction in Tuberculosis. PMID- 28897516 TI - Radium and Its Surgical Applications. PMID- 28897517 TI - Some Points on the Care and Treatment of Mental Defectives: The Presidential Address, Delivered on 10th October, 1928, at the Opening of the Fifty-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28897518 TI - The Distal Phenomena That Accompany High Arterial Tension. PMID- 28897519 TI - A Case of Rectal Prolapse. PMID- 28897520 TI - Meetings of Societies. PMID- 28897521 TI - Editorial Notes. PMID- 28897522 TI - The Role of Pyelography in Renal Disorders. PMID- 28897524 TI - Editorial Notes. PMID- 28897523 TI - The Management of the Normal Puerperium. PMID- 28897525 TI - The Long Fox Lecture: The Conditioned Response. PMID- 28897526 TI - Auricular Failure. PMID- 28897527 TI - A Few Suggestions in General Surgery. PMID- 28897528 TI - Editorial Notes. PMID- 28897529 TI - The Effects of the War on the Mental Condition of the Citizens of Bristol. PMID- 28897530 TI - On the Causes of Death in Lobar Pneumonia. PMID- 28897531 TI - An Operation for the Cure of Prolapse and Cystocele. PMID- 28897532 TI - Irritable Heart. PMID- 28897533 TI - Medicine. PMID- 28897534 TI - Meetings of Societies. PMID- 28897535 TI - A Case of Erythraemia or Splenic Polycythaemia. PMID- 28897536 TI - Editorial Notes. PMID- 28897537 TI - The Diagnosis of Torsion of the Great Omentum, Illustrated by Two Case-Histories. PMID- 28897538 TI - Tuberculosis and Consumption in Relation to Public Health. PMID- 28897539 TI - The Clinical Significance of Adsorption Phenomena. PMID- 28897540 TI - Medicine and Surgery: The Presidential Address, Delivered on October 13th, 1920, at the Opening of the Forty-Seventh Session of the Bristol Medico-Chirurgical Society. PMID- 28897542 TI - Editorial Notes. PMID- 28897541 TI - Meetings of Societies. PMID- 28897543 TI - The Practical Importance of Posture in the Physical Examination of the Heart, with Some Remarks on Stethoscopes. PMID- 28897544 TI - Some Problems in Pulmonary Disease, with Special Reference to Radiography. PMID- 28897545 TI - Continuity and Change: The Presidential Address, Delivered on October 14th, 1925, at the Opening of the Fifty-Third Session of the Bristol Medico-Chirurgical Society. PMID- 28897546 TI - Remarks on Sinus Phlebitis and Thrombosis Complicating Suppurative Middle Ear Disease: With Notes of Nine Illustrative Cases. PMID- 28897547 TI - Editorial Notes. PMID- 28897548 TI - Progress in the Treatment of Empyema. PMID- 28897549 TI - A Case of Multiple Serositis (Pick's Disease) of Unusual Distribution. PMID- 28897550 TI - Editorial Notes. PMID- 28897551 TI - The Diagnosis of Scarlet Fever. PMID- 28897552 TI - The Comparative Efficiency of Local Anaesthetics. PMID- 28897554 TI - Meetings of Societies. PMID- 28897553 TI - The Evolutionary History of Renal Surgery and of Temporal Bone Surgery: The Presidential Address, Delivered on October 10th, 1923, at the Opening of the Fifty-First Session of the Bristol Medico-Chirurgical Society. PMID- 28897555 TI - Cancer of the Breast. PMID- 28897557 TI - Editorial Notes. PMID- 28897556 TI - Grave Cardiac Symptoms Due to Multiple Dental Abscess. PMID- 28897558 TI - Editorial Notes. PMID- 28897559 TI - Presidential Address : Postgraduate Medical Education: The Presidential Address, Delivered on October 8th, 1924, at the Opening of the Fifty-Second Session of the Bristol Medico-Chirurgical Society. PMID- 28897560 TI - A Comparative Review of Spinal and Peripheral Nerve Injuries. PMID- 28897562 TI - Meetings of Societies. PMID- 28897561 TI - Appendicitis as a Cause of Intestinal Obstruction. PMID- 28897563 TI - Vesical Calculus in a Urinary Typhoid Carrier. PMID- 28897564 TI - Poisoning by "Mustard" Gas. PMID- 28897566 TI - Editorial Notes. PMID- 28897565 TI - Famine-Dropsy as a Food-Deficiency Disease. PMID- 28897567 TI - Medicine. PMID- 28897568 TI - Surgery. PMID- 28897570 TI - Editorial Notes. PMID- 28897569 TI - A Note on Asthma. PMID- 28897571 TI - University of Bristol: Royal Opening of the New Buildings. PMID- 28897572 TI - Diagnosis of the Dyspepsias. PMID- 28897573 TI - A Case of Intrathecal Extramedullary Spinal Tumour: Confirmatory Localisation by Lipiodol, Relief by Operation. PMID- 28897574 TI - Some Points in the Differential Diagnosis of Focal Infection in the Nasal Sinuses Causing Ocular and Other Systemic Infections. PMID- 28897575 TI - Meetings of Societies. PMID- 28897576 TI - The Present Position of Surgery of the Nervous System. PMID- 28897577 TI - Some Considerations on the Applications of Physiology to Medicine. PMID- 28897578 TI - On Cases of Encephalitis Lethargica in Bristol. PMID- 28897579 TI - The Modern Treatment of Tuberculosis of the Spine. PMID- 28897581 TI - Editorial Notes. PMID- 28897580 TI - Surgery. PMID- 28897583 TI - Case of Lymphosarcoma of the Tonsil and Palate. PMID- 28897582 TI - Medicine. PMID- 28897584 TI - Malaria: A Discussion at a Meeting of the Bristol Medico-Chirurgical Society on December 10th, 1919. PMID- 28897586 TI - Meetings of Societies. PMID- 28897585 TI - Queene Elizabethes Achademy: (British Museum, Lansdowne MS. 98.) A Sixteenth Century Scheme for a London University. PMID- 28897588 TI - Editorial Notes. PMID- 28897587 TI - Meetings of Societies. PMID- 28897590 TI - The Leprosy Problem and Its Bearing on Tuberculosis: An Abstract of a Postgraduate Lecture at the University of Bristol. PMID- 28897589 TI - The Parkinsonian Syndrome : Some Points in Diagnosis and Treatment. PMID- 28897591 TI - The Evolutionary History of Renal Surgery and of Temporal Bone Surgery: The Presidential Address, Delivered on October 10th, 1923, at the Opening of the Fifty-First Session of the Btistol Medico-Chirurgical Society. PMID- 28897593 TI - Abdominal Fibroma Simulating Splenomegaly. PMID- 28897592 TI - Duodenal Ulcers : Their Detection by Photography. PMID- 28897594 TI - Operative Interference in Carcinoma of the Pancreas. PMID- 28897595 TI - Case of Rupture of Middle Meningeal Artery: Operation; Recovery. PMID- 28897596 TI - Medicine. PMID- 28897597 TI - Typhoid Fever and Typhoid Carriers. PMID- 28897599 TI - Meetings of Societies. PMID- 28897598 TI - The Treatment of Spreading Peritonitis by Drainage, the Fowler Position, and Rectal Instillation of Saline Solution, with Notes of a Second Successful Case. PMID- 28897600 TI - Editorial Notes. PMID- 28897601 TI - Notes on Preparations for the Sick. PMID- 28897602 TI - The Long Fox Lecture: Suppurative Disease in the Nose and Ear: With Special Reference to Some Newer Methods of Treatment. PMID- 28897603 TI - Surgery. PMID- 28897604 TI - The Bristol Medical Library. PMID- 28897605 TI - The Barber Surgeons. PMID- 28897606 TI - Surgery. PMID- 28897607 TI - Medicine. PMID- 28897609 TI - Editorial Notes. PMID- 28897608 TI - Tuberculin and Immunity. PMID- 28897610 TI - Meetings of Societies. PMID- 28897611 TI - Notes on Preparations for the Sick. PMID- 28897612 TI - The Problem of Medical Education: The Presidential Address, Delivered on October 9th, 1912, at the Opening of the Thirty-Ninth Session of the Bristol Medico Chirurgical Society. PMID- 28897613 TI - On Some Diseases Bearing Names of Saints. PMID- 28897614 TI - A Medical Naval Volunteer on Duty at Quebec, July, 1908. PMID- 28897615 TI - Recent Work on Leukaemia and Some Allied Affections: The President's Address, Delivered on October 14th, 1908, at the Opening of the Thirty-Fifth Session of the Bristol Medico-Chirurgical Society. PMID- 28897617 TI - Editorial Notes. PMID- 28897616 TI - Dilatation of Posterior Cerebral Vessels with Basal Hemorrhage in a Girl Aged Sixteen. PMID- 28897619 TI - Meetings of Societies. PMID- 28897618 TI - Medicine. PMID- 28897621 TI - The Causation of Certain Mid-Diastolic Murmurs. PMID- 28897620 TI - Notes on Cases. PMID- 28897622 TI - Surgery. PMID- 28897623 TI - Notes on Preparations for the Sick. PMID- 28897624 TI - The Management of the Ear, Nose and Throat in Influenza. PMID- 28897625 TI - Insomnia. PMID- 28897627 TI - Suprarenal Hypertrophy. PMID- 28897626 TI - Suprarenal Virilism. PMID- 28897629 TI - Meetings of Societies. PMID- 28897628 TI - Notes on the Treatment of Some Common Ocular Affections. PMID- 28897630 TI - Editorial Notes. PMID- 28897632 TI - Editorial Notes. PMID- 28897631 TI - Notes on Surgical Jaundice. PMID- 28897633 TI - Sex Hormones and Blood Pressure. PMID- 28897634 TI - The Importance of the First Year of War in Mental Disease. PMID- 28897635 TI - Thyrotoxicosis. PMID- 28897636 TI - Meetings of Societies. PMID- 28897637 TI - An Enemy of the People-Tuberculosis and Natural Selection. PMID- 28897639 TI - Notes on "Some Dreams and Their Significance". PMID- 28897638 TI - Notes on Preparations for the Sick. PMID- 28897640 TI - Intra-Cranial Complications of Ear Disease: A Discussion at the Bristol Medico Chirurgical Society, March 13th, 1912. PMID- 28897641 TI - The Differential Diagnosis of Swelling in the Breast. PMID- 28897642 TI - The Artificial Production of Pneumothorax in Pathisis by Injection of Nitrogen. PMID- 28897644 TI - Editorial Notes. PMID- 28897643 TI - A Case of the Heroin Habit. PMID- 28897645 TI - Notes on an Unusual Case of Hodgkin's Disease. PMID- 28897646 TI - The Casualty Surgery of Air Raids. PMID- 28897647 TI - Editorial Notes. PMID- 28897648 TI - Medicine from Ancient Greece to Soviet Russia. PMID- 28897649 TI - Meetings of Societies. PMID- 28897650 TI - Experiences of First Aid in Air Raids. PMID- 28897651 TI - Meetings of Societies. PMID- 28897652 TI - Editorial Notes. PMID- 28897653 TI - Trigeminal Neuralgia. PMID- 28897654 TI - Some Observations on the Relative Efficacy of the Various Treatments of Pernicious Anaemia. PMID- 28897655 TI - Some Observations on the Relationship between Structure and Function: The Presidential Address, Delivered on 14th October, 1931, at the Opening of the Fifty-Ninth Session of the Bristol Medico-Chirurgical Society. PMID- 28897656 TI - Human Improvability. PMID- 28897657 TI - Editorial Notes. PMID- 28897658 TI - The Fundamental Principles of Fracture Treatment. PMID- 28897659 TI - The Bristol Scheme for Dealing with an Outbreak of Typhus. PMID- 28897660 TI - Experiences of Typhus Fever. PMID- 28897661 TI - Inunction of Testosterone in Mental Disease. PMID- 28897662 TI - Anaesthesia. PMID- 28897663 TI - Some Gall-Bladder Cases Presenting Features of Interest. PMID- 28897664 TI - Direct Laryngoscopy, Bronchoscopy and OEsophagoscopy. PMID- 28897665 TI - Notes on Preparations for the Sick. PMID- 28897666 TI - Obstetrics. PMID- 28897667 TI - The End-Results of Forty-One Operations for Internal Derangements of the Knee Joint. PMID- 28897668 TI - Medicine. PMID- 28897669 TI - Lister: An Appreciation. PMID- 28897671 TI - Meetings of Societies. PMID- 28897670 TI - Surgery. PMID- 28897672 TI - Some Cases Illustrating the Difficulty and Importance of Early Diagnosis in Acute Intestinal Obstruction. PMID- 28897673 TI - Editorial Note. PMID- 28897674 TI - Operations on the Uterus and Appendages during Pregnancy. PMID- 28897675 TI - Some Observations on Tuberculosis of the Nose and Pharynx. PMID- 28897676 TI - A Case of Chronic Interstitial Pancreatitis of Uncertain Origin. PMID- 28897677 TI - Some Complications of Ruptured Liver. PMID- 28897678 TI - On the Renal Changes in a Case of Hemorrhage into the Pons with Consequent High Blood Pressure. PMID- 28897679 TI - Notes on Preparations for the Sick. PMID- 28897680 TI - Ophthalmology. PMID- 28897682 TI - The Aural Complications of Influenza and Their Treatment. PMID- 28897681 TI - Medicine. PMID- 28897683 TI - Early History of the Bristol Royal Infirmary. PMID- 28897685 TI - Editorial Notes. PMID- 28897684 TI - A Study of Ten Cases of Operation for Perforated Gastric Ulcer. PMID- 28897686 TI - A Case of Severe Trigeminal Neuralgia Successfully Treated by Excision of the Gasserian Ganglion. PMID- 28897688 TI - Surgery. PMID- 28897687 TI - Surgical Aid in Chronic Ulcer of the Stomach. PMID- 28897689 TI - Editorial Notes. PMID- 28897690 TI - Midwifery in Bristol. PMID- 28897691 TI - The Bombing of Bristol. PMID- 28897692 TI - Meetings of Societies. PMID- 28897693 TI - The Shelter Problem. PMID- 28897694 TI - The Twenty-Ninth Long Fox Memorial Lecture: Popular Misconceptions in Medical Matters. PMID- 28897695 TI - Induction of Labour by High Puncture of the Membranes: A Survey of Eighty-Seven Consecutive Cases Personally Induced during One Year-November, 1938-October, 1939. PMID- 28897696 TI - Traumatic Extradural Haemorrhage. Part I. PMID- 28897698 TI - Editorial Note. PMID- 28897697 TI - Cerebro-Spinal Meningitis in Bristol. PMID- 28897699 TI - Head Injuries in Wartime. PMID- 28897701 TI - University of Bristol Dental Hospital and School. PMID- 28897700 TI - Traumatic Extradural Haemorrhage. Part II: The Clinical Application of Electro Encephalograpy. PMID- 28897702 TI - Malum Immedicabile Cancer. PMID- 28897704 TI - Meetings of Societies. PMID- 28897705 TI - Editorial Notes. PMID- 28897703 TI - Electro-Encephalography: An Aid to Diagnosis. PMID- 28897706 TI - Provincial Medical Journals. PMID- 28897707 TI - Note on a Case of Ponto-Cerebellar Tumour in a Girl of Six Years. PMID- 28897708 TI - Editorial Notes. PMID- 28897709 TI - The Long Fox Lecture: The Problem of Deafness. PMID- 28897710 TI - The Effects of Lightning: With Special Reference to the Nervous System. PMID- 28897711 TI - Meetings of Societies. PMID- 28897712 TI - The Care and Management of Premature Infants. PMID- 28897713 TI - Prognosis in Coronary Thrombosis. PMID- 28897714 TI - The Thirty-First Long Fox Memorial Lecture: The Experimental Study of Development. PMID- 28897715 TI - Editorial Notes. PMID- 28897717 TI - The Story of the Bristol Hospitals. PMID- 28897716 TI - Hospital Re-Organization. PMID- 28897718 TI - Albuminuria in Pregnancy. PMID- 28897719 TI - Medical Education. PMID- 28897720 TI - Dysphagia with Anaemia, with Reports on Five Cases. PMID- 28897721 TI - The British Pharmacopoeia, 1932. PMID- 28897723 TI - Notes on Female Circumcision as Practised by the Ameru. PMID- 28897722 TI - Mental Deficiency: An Analysis of the Mental, Physical and Medical Characteristics of a Group of One Hundred and Sixty-Two Adult Feeble-Minded Women. PMID- 28897725 TI - Editorial Note. PMID- 28897724 TI - Albuminuria in Pregnancy. PMID- 28897726 TI - Social and Economic Conditions and the Incidence of Rheumatic Heart Disease. PMID- 28897728 TI - Editorial Notes. PMID- 28897727 TI - The Future of Health and Hospital Services from an Architect's Point of View. PMID- 28897729 TI - Editorial Note. PMID- 28897730 TI - Bristol's Contributions to Medical Progress. PMID- 28897731 TI - The History of the Bristol Medico-Chirurgical Journal. PMID- 28897732 TI - The Centenary of the Foundation of the Bristol Medical School. PMID- 28897733 TI - Thirty Years' Progress in the Study of Rheumatic Heart Disease. PMID- 28897734 TI - Meetings of Societies. PMID- 28897735 TI - Editorial Notes. PMID- 28897736 TI - Familial Multiple Telangiectases of the Skin and Mucous Membranes. PMID- 28897737 TI - Surgery for Pain. PMID- 28897738 TI - The Need for a Standard Method of Estimating the Blood-Pressure. PMID- 28897740 TI - Meetings of Societies. PMID- 28897739 TI - Anterior Poliomyelitis, or Infantile Paralysis. PMID- 28897742 TI - Editorial Notes. PMID- 28897741 TI - Enlarged Prostate. PMID- 28897743 TI - A Surgical Adventure: An Autobiographical Sketch: The Presidential Address, Delivered on 12th October, 1932, at the Opening of the Sixtieth Session of the Bristol Medico-Chirurgical Society. PMID- 28897745 TI - The Twenty-Second Long Fox Memorial Lecture: Recent Advances in the AEtiology, Diagnosis and Treatment of Cancer. PMID- 28897744 TI - The Use of the Ventral Position in the Treatment of Tuberculous Disease of the Spine in Children. PMID- 28897746 TI - Bristol University: Department of Preventive Medicine : Opening by the Minister of Health. PMID- 28897748 TI - Meetings of Societies. PMID- 28897747 TI - Bacillus Coli Infections of the Female Urinary Tract. PMID- 28897750 TI - Scraps. PMID- 28897749 TI - The Present Position of Radium Therapy. PMID- 28897751 TI - A Case of Laparotomy in Which a Large Pyosalpinx Simulating a Suppurating Tubo Ovarian Cyst Was Removed. PMID- 28897752 TI - Notes on Preparations for the Sick. PMID- 28897753 TI - Surgery. PMID- 28897754 TI - Melancholia. PMID- 28897755 TI - Fifty Consecutive Intra-Abdominal Operations. PMID- 28897756 TI - Hysterical Paroxysmal OEdema. PMID- 28897758 TI - Medicine. PMID- 28897757 TI - Dermatology. PMID- 28897759 TI - Notes on Preparations for the Sick. PMID- 28897760 TI - On Some Diseases Occurring in Men Who Worked in a Sewer. PMID- 28897761 TI - Meetings of Societies. PMID- 28897762 TI - Scraps. PMID- 28897763 TI - The Treatment of Enteric Fever. PMID- 28897764 TI - Surgery. PMID- 28897765 TI - Medicine. PMID- 28897766 TI - Ophthalmology. PMID- 28897767 TI - Obstetrics. PMID- 28897768 TI - Notes on Preparations for the Sick. PMID- 28897769 TI - Surgery. PMID- 28897771 TI - Meetings of Societies. PMID- 28897770 TI - On Occipital Presentations. PMID- 28897772 TI - Medicine. PMID- 28897773 TI - A Suggestion for the Treatment of Graves's Disease. PMID- 28897774 TI - A Case Resembling in Many Respects the Condition Known as Mucous Colitis. PMID- 28897775 TI - Scraps. PMID- 28897776 TI - Isolation after Diphtheria. PMID- 28897777 TI - Thot: An Exalted Surgeon and Physician. PMID- 28897778 TI - A Case of Cholecystotomy. PMID- 28897779 TI - Medicine. PMID- 28897780 TI - Progress and Practice: The Presidential Address, Delivered on October 12th, 1898, at the Opening of the Twenty-Fifth Session of the Bristol Medico-Chirurgical Society. PMID- 28897781 TI - Operation Rooms, past and Present. PMID- 28897782 TI - Notes on Preparations for the Sick. PMID- 28897783 TI - Scraps. PMID- 28897784 TI - Bristol Medico-Chirurgical Society. PMID- 28897785 TI - Surgery. PMID- 28897786 TI - Laryngology and Rhinology. PMID- 28897787 TI - A Suggested Method of Copying Sphygmograms. PMID- 28897788 TI - Otology. PMID- 28897789 TI - The Radical Cure of Reducible Hernia by Kocher's Method of Invagination, with Lateral Displacement of the Neck, of the Sac. PMID- 28897791 TI - Meetings of Societies. PMID- 28897790 TI - The Use of Protamine Insulin. PMID- 28897792 TI - Cerebral Malformations and Their Clinical Consequences. PMID- 28897794 TI - Editorial Notes. PMID- 28897793 TI - Psychological Factors in Disease. PMID- 28897795 TI - Meetings of Societies. PMID- 28897796 TI - Some Recent Advances in Ophthalmology. PMID- 28897797 TI - Some Medical Considerations of Sports and Games. PMID- 28897798 TI - Spasmodic Rhinorrhoea. PMID- 28897799 TI - The Seborrhoeic Dermatoses. PMID- 28897800 TI - Editorial Notes. PMID- 28897801 TI - Editorial Notes. PMID- 28897802 TI - The Twenty-Eighth Long Fox Memorial Lecture: Forest Folk: Modern Medicine in the Congo. PMID- 28897803 TI - Acute Appendicitis. PMID- 28897804 TI - War Surgery in Spain. PMID- 28897805 TI - The Prevention and Treatment of Prolapse. PMID- 28897807 TI - Meetings of Societies. PMID- 28897806 TI - An Investigation into the Mental State of the Parents and Sibs of 1,050 Mentally Defective Persons. PMID- 28897808 TI - Basal Narcosis. PMID- 28897810 TI - Editorial Notes. PMID- 28897809 TI - Diet in Pregnancy. PMID- 28897811 TI - Some Clinical Applications of the Male and Female Sex Hormones. PMID- 28897812 TI - Thoracic Surgery. PMID- 28897813 TI - Meetings of Societies. PMID- 28897814 TI - A Case of Lobectomy for Bronchiectasis. PMID- 28897815 TI - Editorial Notes. PMID- 28897816 TI - Medical Defence: The Presidential Address, Delivered on 13th October, 1937, at the Opening of the Sixty-Fifth Session of the Bristol Medico-Chirurgical Society. PMID- 28897817 TI - Some Problems in the Diagnosis and Treatment of Intra-Cranial Tumours. PMID- 28897818 TI - The Vitamin B Complex. PMID- 28897819 TI - The Medicinal Waters at Burnham-On-Sea. PMID- 28897820 TI - Editorial Notes. PMID- 28897821 TI - Some Tuberculous Conditions. PMID- 28897822 TI - Medicine and the Drama: The Presidential Address, Delivered on 12th October, 1938, at the Opening of the Sixty-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28897824 TI - Recent Advances in Surgery. PMID- 28897823 TI - The Management of Some Obstetric Emergencies. PMID- 28897825 TI - The Twenty-Seventh Long Fox Memorial Lecture: Air as a Conductor of Electricity. PMID- 28897826 TI - Syphilis in the Tropics. PMID- 28897827 TI - A Guide Dog for the Blind. PMID- 28897828 TI - Editorial Notes. PMID- 28897829 TI - Drinker's "Iron Lung" and Other Artificial Respirators. PMID- 28897830 TI - Meetings of Societies. PMID- 28897831 TI - Scraps. PMID- 28897833 TI - Notes on Preparations for the Sick. PMID- 28897832 TI - Surgery. PMID- 28897834 TI - Medicine. PMID- 28897836 TI - Notes on Some Thermal, Hydro-Thermal, Electric and Hydro-Electric Procedures, and the Indications for Their Use. PMID- 28897835 TI - Vascular Caruncle of the Urethra. PMID- 28897838 TI - Non-Bacillary Croup. PMID- 28897837 TI - Ophthalmology. PMID- 28897839 TI - The Spontaneous Disappearance of a Sarcomatous Tumour. PMID- 28897840 TI - Meetings of Societies. PMID- 28897841 TI - Rheumatic Disease of the Cardiac Muscle. PMID- 28897842 TI - Notes on Preparations for the Sick. PMID- 28897843 TI - Note on a Pre-Exanthematous Sign of Measles. PMID- 28897844 TI - Surgery. PMID- 28897846 TI - Medicine. PMID- 28897845 TI - Obstetrics. PMID- 28897847 TI - Abdominal Hysterectomy for Fibroids of the Uterus, with Retro-Peritoneal Treatment of the Stump, and Notes of Two Cases. PMID- 28897848 TI - Swedish Medical Gymnastics in Chronic Diseases of the Heart. PMID- 28897849 TI - Two Cases of the Sporadic Form of Epidemic Cerebro-Spinal Meningitis. PMID- 28897850 TI - Scraps. PMID- 28897851 TI - A Retrospect of a Second Series of Fifty Consecutive Intra-Abdominal Operations. PMID- 28897852 TI - Cases of Acute Intestinal Obstruction Treated by Operation. PMID- 28897853 TI - Presentation to Mr. L. M. Griffiths. PMID- 28897854 TI - Meetings of Societies. PMID- 28897855 TI - Scraps. PMID- 28897856 TI - The Inebriates' Acts, 1879-1899. PMID- 28897857 TI - One Thousand Consecutive Inductions of General Anaesthesia. PMID- 28897859 TI - The X-Ray History of a Fracture. PMID- 28897858 TI - Notes on Preparations for the Sick. PMID- 28897860 TI - Surgery. PMID- 28897861 TI - Medicine. PMID- 28897862 TI - Abdominal Incisions. PMID- 28897864 TI - The Dietetic Treatment of Zymotic Enteritis, Especially with Regard to the Use of Raw Meat Juice. PMID- 28897863 TI - Dermatology. PMID- 28897866 TI - Scraps. PMID- 28897865 TI - Reminiscences of the Bristol Royal Infirmary. PMID- 28897867 TI - The Technique of Halsted's Operation for Cancer of the Breast. PMID- 28897868 TI - Notes on Preparations for the Sick. PMID- 28897869 TI - Forty Cases for Operation for Appendicitis. PMID- 28897871 TI - Meetings of Societies. PMID- 28897870 TI - A Case of Diffuse Leontiasis Ossea. PMID- 28897872 TI - Laryngology and Rhinology. PMID- 28897873 TI - Otology. PMID- 28897874 TI - Some Modern Aspects of Preventive Medicine: The Presidential Address, Delivered on October 10th, 1900, at the Opening of the Twenty-Seventh Session of the Bristol Medico-Chirurgical Society. PMID- 28897876 TI - Five Cases of Pelvic Disease Treated by Laparotomy. PMID- 28897875 TI - Medicine. PMID- 28897877 TI - A Plea for Sanatoria for the Poorer Consumptives. PMID- 28897879 TI - Three Abdominal Cases Presenting Some Unusual Features. PMID- 28897878 TI - Surgery. PMID- 28897880 TI - The Differential Diagnosis of Malignant Disease of the Caecum from Chronic and Subacute Appendicitis. PMID- 28897881 TI - The Bristol Medical Officer of Health. PMID- 28897882 TI - Oral Sepsis as a Source of Systemic Infections. PMID- 28897883 TI - Editorial Notes. PMID- 28897884 TI - Meetings of Societies. PMID- 28897885 TI - The Clinical Manifestations and Treatment of Coliuria in Children. PMID- 28897887 TI - Editorial Notes. PMID- 28897886 TI - Notes on Some Bristol Medical Societies. PMID- 28897889 TI - Progress of the Medical Sciences. PMID- 28897888 TI - Some Impressions of the 1914 British Pharmacopoeia. PMID- 28897890 TI - The Evolution of Gynaecology: The Presidential Address, Delivered on October 14th, 1914, at the Opening of the Forty-First Session of the Bristol Medico Chirurgical Society. PMID- 28897891 TI - Editorial Notes. PMID- 28897892 TI - Progress of the Medical Sciences. PMID- 28897893 TI - Therapeutic Notes: Animal Extracts in Therapeutics. PMID- 28897894 TI - The Radiographic Centroscope and the Radiographic Episcope. PMID- 28897895 TI - A Case of Richter's Strangulated Hernia. PMID- 28897896 TI - Spiritual Healing: A Review. PMID- 28897898 TI - Meetings of Societies. PMID- 28897897 TI - Local Analgesia in Surgical Operations. PMID- 28897899 TI - Therapeutic Notes: Cell Proliferants. PMID- 28897900 TI - Editorial Notes. PMID- 28897901 TI - Mixed Infections in Pulmonary Tuberculosis, and Some General Observations on Treatment with Tuberculin. PMID- 28897902 TI - Notes on a Case of Lymphatic Leukaemia in a Child Aged Three Years. PMID- 28897904 TI - Progress of the Medical Sciences. PMID- 28897903 TI - The Secondary Infections of Pulmonary Tuberculosis and Their Treatment by Vaccines. PMID- 28897905 TI - On the Occurrence of Tachycardia in Association with Parenchymatous Goitre. PMID- 28897907 TI - Note on the Treatment of Laryngeal Tuberculosis by Tuberculin. PMID- 28897906 TI - Auto-Plastic Intra-Medullary Bone Pegging as a Method of Operative Treatment for Fractures. PMID- 28897908 TI - Fibroid Uterus. PMID- 28897910 TI - Progress of the Medical Sciences. PMID- 28897909 TI - Diseases of the Lungs Associated with the Presence of Friedlander's Bacillus. PMID- 28897912 TI - Meetings of Societies. PMID- 28897911 TI - Hyperpiesis and Arterio-Sclerosis. PMID- 28897914 TI - Therapeutic Notes: Colloid Metals. PMID- 28897913 TI - The Simulation of Aortic Aneurysm by Some Other Aortic and Cardiac Diseases. PMID- 28897915 TI - Notes on the Electrical Reactions in Facial Paralysis, Especially in Reference to the Prognosis in Post-Operative Cases. PMID- 28897916 TI - On Digital Percussion and the Cardiac Sign in Carcinoma. PMID- 28897918 TI - Meetings of Societies. PMID- 28897917 TI - Some Unusual Conditions Found in Operating for the Radical Cure of Hernia. PMID- 28897919 TI - Meetings of Societies. PMID- 28897920 TI - Editorial Note. PMID- 28897921 TI - Edward Tyson, M.D., F.R.S., 1650-1708: Anatomist and Anthropologist. PMID- 28897922 TI - "Look and See," Foreign Bodies in Air and Food Passages. PMID- 28897923 TI - Editorial Notes. PMID- 28897924 TI - The Goodenough Report on Medical Education: A Summary. PMID- 28897925 TI - The Thirty-Second Long Fox Memorial Lecture: The Social Aspects of Acute Rheumatism. PMID- 28897926 TI - Meetings of Societies. PMID- 28897927 TI - Editorial Notes. PMID- 28897929 TI - Meetings of Societies. PMID- 28897928 TI - Selection of Medical Students. PMID- 28897930 TI - Editorial Notes. PMID- 28897931 TI - Ham Green Hospital Extensions: The Opening Address Delivered. PMID- 28897932 TI - The Burden Mental Research Trust: Its Present and Future. PMID- 28897934 TI - Editorial Notes. PMID- 28897933 TI - Sulphanilamide in Treatment. PMID- 28897935 TI - Prontosil in Obstetrics. PMID- 28897937 TI - Meetings of Societies. PMID- 28897936 TI - Nutrition and Tuberculosis. PMID- 28897938 TI - Joseph Williams. PMID- 28897939 TI - A Treatment for Sciatica. PMID- 28897941 TI - Corneal Transplantation: Its History, Development and Practice. PMID- 28897940 TI - Editorial Note. PMID- 28897943 TI - Meetings of Societies. PMID- 28897942 TI - Bristol Eye Hospital. PMID- 28897944 TI - Photography and Medicine: The Presidential Address, Delivered on 9th October, 1935, at the Opening of the Sixty-Third Session of the Bristol Medico-Chirurgical Society. PMID- 28897946 TI - Editorial Notes. PMID- 28897945 TI - The Position of the Voluntary Hospitals in the National Health Services. PMID- 28897948 TI - Meetings of Societies. PMID- 28897947 TI - Ultra-Microscopic Examination of the Blood-Serum in Disease. PMID- 28897949 TI - Editorial Notes. PMID- 28897950 TI - Some Reflections on Research in Medicine. PMID- 28897951 TI - How Bristol Royal Infirmary Has Watched the World Change. PMID- 28897952 TI - The Carey Coombs Memorial Lecture on the Pathology and Surgical Treatment of Cardiac Ischaemia. PMID- 28897954 TI - The Evolution of a Casualty Clearing Station on the Western Front: The Presidential Address, Delivered on 14th October, 1936, at the Opening of the Sixty-Fourth Session of the Bristol Medico-Chirurgical Society. PMID- 28897953 TI - Spinal Anaesthesia. PMID- 28897955 TI - The Bristol Medical Dramatic Club. PMID- 28897957 TI - Editorial Notes. PMID- 28897956 TI - The Enlarged Prostate from the Point of View of Practitioner and Surgeon. PMID- 28897958 TI - Meetings of Societies. PMID- 28897959 TI - The Therapeutic Value of Altitude. PMID- 28897960 TI - The Role of the Central Nervous System in Disease: Recent Experimental Work in the U.S.S.R. PMID- 28897961 TI - Primary Carcinoma of the Lung Radiologically Considered. PMID- 28897962 TI - Editorial Notes. PMID- 28897963 TI - A Fatal Case of Meningitis Due to Infection of the Sphenoidal Sinus by Pfeiffer's Bacillus, with a Short Review of Methods of Treatment. PMID- 28897964 TI - The Treatment of Carcinoma of the Lung. PMID- 28897965 TI - Surgical Clinics in Scandinavia. PMID- 28897966 TI - The Pathological Aspect. PMID- 28897968 TI - Meetings of Societies. PMID- 28897967 TI - Clinical Features. PMID- 28897969 TI - Report of the Committee on the Scottish Health Services. PMID- 28897970 TI - A Lump in the Throat. PMID- 28897971 TI - Child Guidance. PMID- 28897973 TI - Editorial Notes. PMID- 28897972 TI - Meeting of Societies. PMID- 28897974 TI - The Bristol Royal Infirmary Bicentenary. PMID- 28897975 TI - The Twenty-Sixth Long Fox Memorial Lecture: The Debt of Western Medicine to the East. PMID- 28897976 TI - The Twenty-Fifth Long Fox Memorial Lecture: Somerset Lake Villages. PMID- 28897978 TI - Meetings of Societies. PMID- 28897977 TI - The Treatment of Tobacco Amblyopia by Acetyl-Choline. PMID- 28897979 TI - Abdominal Pain in Childhood. PMID- 28897980 TI - The History of the Bristol Medical Dramatic Club. PMID- 28897981 TI - Editorial Notes. PMID- 28897982 TI - House of John Wright: (John Wright & Sons Limited) Medical Printers and Publishers. PMID- 28897983 TI - Correction. AB - [This corrects the article on p. 61 in vol. 64.]. PMID- 28897984 TI - Clinical Note-Folic Acid. PMID- 28897985 TI - Meetings of Societies. PMID- 28897986 TI - Editorial Notes. PMID- 28897987 TI - Surgical Treatment in Hypertension. PMID- 28897988 TI - Editorial Note. PMID- 28897989 TI - Back to Work: The Presidential Address, Delivered on Wednesday, 9th October, 1946, at the Opening of the Sixty-Eighth Session of the Bristol Medico Chirurgical Society. PMID- 28897990 TI - Meetings of Societies. PMID- 28897991 TI - Meetings of Societies. PMID- 28897992 TI - Editorial Notes. PMID- 28897993 TI - Meetings of Societies. PMID- 28897994 TI - Thiouracil in Thyrotoxicosis. PMID- 28897995 TI - Non-Editorial Note. PMID- 28897996 TI - Editorial Notes. PMID- 28897997 TI - Meetings of Societies. PMID- 28897998 TI - Editor's Report. PMID- 28897999 TI - Alfred, the Zoo Gorilla. PMID- 28898000 TI - Edward Jenner: The Presidential Address, Delivered on Wednesday, 8th October, 1947, at the Opening of the Sixty-Ninth Session of the Bristol Medico-Chirurgical Society. PMID- 28898001 TI - Meetings of Societies. PMID- 28898002 TI - Editorial Notes. PMID- 28898003 TI - Editorial Note. PMID- 28898004 TI - Meetings of Societies. PMID- 28898005 TI - Meetings of Societies. PMID- 28898006 TI - Editorial Notes. PMID- 28898008 TI - Meetings of Societies. PMID- 28898007 TI - Corrigenda. AB - [This corrects the article on p. 7 in vol. 66.][This corrects the article on p. 14 in vol. 66.][This corrects the article on p. 51 in vol. 66.][This corrects the article on p. 74 in vol. 66.]. PMID- 28898009 TI - Editor's Report. PMID- 28898010 TI - Editorial Notes. PMID- 28898011 TI - Meetings of Societies. PMID- 28898012 TI - Some Recent Advances in Paediatrics. PMID- 28898013 TI - Gastric Ulcer with Perforation Into the Lesser Sac: Report of a Case. PMID- 28898015 TI - Epidemic Myalgia-Bornholm Disease. PMID- 28898014 TI - Poliomyelitis in Bristol, 1949. PMID- 28898016 TI - Congenital Atresia of the Oesophagus: Reports of Three Cases. PMID- 28898018 TI - Editorial Note. PMID- 28898017 TI - The Surgical Treatment of Hypertension-II. PMID- 28898020 TI - Meetings of Societies. PMID- 28898019 TI - The Prognosis in Hypertension. PMID- 28898021 TI - The Surgical Treatment of Hypertension-I. PMID- 28898023 TI - Meetings of Societies. PMID- 28898022 TI - Some Post-Mortem Surprises: The Presidential Address to the Cornwall Clinical Society, June 6th, 1949. PMID- 28898024 TI - Editorial Notes. PMID- 28898025 TI - Medicine in Eighteenth-Century Bristol: The Presidential Address, Delivered on Wednesday, 12th October, 1949, at the Opening of the Seventy-First Session of the Bristol Medico-Chirurgical Society. PMID- 28898026 TI - Some Medical Problems in China To-Day. PMID- 28898027 TI - The XXXVIII Long Fox Memorial Lecture: The Use of Tracer Elements in Biology and Medicine. PMID- 28898028 TI - The General Use of Histamine Antagonists: With Special Reference to Therapy in Dermatological Disorders. PMID- 28898029 TI - The Value of X-Ray Therapy for Metastases in Bone from Carcinoma of the Breast. PMID- 28898030 TI - Meetings of Societies. PMID- 28898031 TI - Impressions of American Rheumatology and Recent Advances in "Rheumocrinology". PMID- 28898032 TI - Editorial Note. PMID- 28898033 TI - The Work of a Department of Industrial Health. PMID- 28898035 TI - Meetings of Societies. PMID- 28898034 TI - Meetings of Societies. PMID- 28898036 TI - Editorial Notes. PMID- 28898037 TI - Jenner. PMID- 28898038 TI - Some Reminiscences and a Forecast. PMID- 28898040 TI - Bronchoscopic Diagnosis of Carcinoma of the Lung. PMID- 28898039 TI - Spindle-Celled Sarcoma of the Hard Palate. PMID- 28898041 TI - Resilient Energy Storage under High-Temperature with In-Situ-Synthesized MnOx@Graphene as Anode. AB - An novel exfoliation strategy to few-layered graphene (FLG) combined with in situ synthesized amorphous MnOx has been established via a facile and robust ball milling route in the presence of KMnO4. The facile synthesis approach has the features of low cost, environmentally friendly nature and scalable capability. As an anode for lithium-ion batteries, amorphous MnOx@FLG delivered a wonderful electrochemical performance under extremely operational conditions, that is, an excellent reversible capacity of 856 mAh g-1 at a high current density of 1 A g-1 after 75 cycles under a high temperature of 85 degrees C. Those excellent electrochemical performances could be ascribed to elaborately designed three dimensional nanostructure, the well-chosen electrolyte, significant incorporation of in situ Mn(IV) nanocrystal and few-layered graphene, and the contribution of pseudocapacitance. Remarkable electrochemical performance under a widely operational temperature window makes the amorphous MnOx@FLG composites promising anode of Li-ion batteries for heavy-duty application. PMID- 28898042 TI - Scalable Synthesis of Highly Crystalline MoSe2 and Its Ambipolar Behavior. AB - Atomically thin, two-dimensional material molybdenum diselenide (MoSe2) has been shown to exhibit significant potential for diverse applications. The intrinsic band gap of MoSe2 allows it to overcome the shortcomings of the zero-band-gap graphene, while its higher electron mobilities when compared to molybdenum disulfide (MoS2) make it more appropriate for practical devices in electronics and optoelectronics. However, its controlled growth has been an ongoing challenge for investigations and practical applications of the material. Here, we present an atmospheric pressure chemical vapor deposition (CVD) method to achieve highly crystalline, single- and few-layered MoSe2 using a SiO2/Si substrate. Our findings suggested that careful optimization of the flow rate can result in the controlled growth of large-area MoSe2 with desired layer numbers due to the adjustment of gaseous MoSe2 partial pressure and nucleation density. The FETs fabricated on such as-synthesized MoSe2 displayed different transport behaviors depending on the layer numbers, which can be attributed to the formation of Se vacancies generated during low flow rates. Monolayer MoSe2 showed n-type characteristics with an Ion/Ioff ratio of ~106 and a carrier mobility of ~19 cm2 V-1 s-1, whereas bilayer MoSe2 showed n-type-dominant ambipolar behavior with an Ion/Ioff ratio of ~105 and a higher mobility of ~65 cm2 V-1 s-1 for electrons as well as ~9 cm2 V-1 s-1 for holes. Our results provide a foundation for property controlled synthesis of MoSe2 and offer insight on the potential applications of our synthesized MoSe2 in electronics and optoelectronics. PMID- 28898043 TI - Orthogonally Functionalized Donor/Acceptor Homo- and Heterodimeric Dyes for Dye Sensitized Solar Cells: An Approach to Introduce Panchromaticity and Control the Charge Recombination. AB - Organic dyes possessing conjugated pi-framework forms closely packed monolayers on photoanode in dye-sensitized solar cell (DSSC), because of the limitation to control the orientation and the extend of intermolecular pi-pi interaction, self aggregation of dyes leads to reduced cell performance. In this report, a series of homodimeric (D1-D1 and D2-D2) and heterodimeric (D1-D2 and D2-D4) donor/acceptor (D/A) dyes containing spiroBiProDOT pi-spacer were designed and synthesized by utilizing Pd-catalyzed direct arylation reaction and correlates the device performance with monomeric dyes (D1 and D2). Both the thiophenes (pi spacer) of spiroBiProDOT were functionalized with same or different donor groups which led to homodimeric and heterodimeric chromophores in a single sensitizer. The homodimeric spiro-dye D1-D1 showed higher power conversion efficiency (PCE), of 7.6% with a Voc and Jsc of 0.672 V and 16.16 mA/cm2, respectively. On the other hand, the monomeric D1 exhibited a PCE of 3.2% (Voc of 0.64 V and Jsc of 7.2 mA/cm2), which is lower by 2.4 fold compared to dimeric analogue. The spiro unit provides flexibility between the incorporated chromophores to orient on TiO2 due to four sp3-centers, which arrest the molecular motions after chemisorption. This study shows a new molecular approach to incorporate two chromophores in the dimeric dye possessing complementary absorption characteristics toward panchromatic absorption. The attenuated charge recombination at TiO2/Dye/redox couple interface in case of D1-D1, owing to better passivation of TiO2 surface, was elucidated through impedance analysis. The FT-IR spectrum of D1-D1 adsorbed on TiO2 film indicated both the carboxylic units were involved in chemisorption which makes strong coupling between dye and TiO2. PMID- 28898044 TI - Uric Acid as an Electrochemically Active Compound for Sodium-Ion Batteries: Stepwise Na+-Storage Mechanisms of pi-Conjugation and Stabilized Carbon Anion. AB - Developing efficient sodium-ion-storage mechanisms to increase the energy capacity in organic electrodes is a critical issue even after this period of prolonged effort. Uric acid (UA), a simple organic compound with three carbonyl groups is demonstrated to be electrochemically active in the insertion/extraction of Na ions. Theoretical calculations and experimental characterizations reveal that the sodium-ion storage by UA is a result of the stepwise mechanisms of p-pi conjugation and the carbon anion. Aside from C?O, the functional group C?C(NH-)2 also provides an efficient Na-storage activated site in which the lone-pair electrons is stabilized through the planar-to-tetrahedral structural transition and low-energy orbital hybridization of N atoms. For further improvement of the electrochemical performance, a uric acid and carbon nanotube (UA@CNT) composite is prepared via a vacuum solution impregnation method. When employed as an anode material for sodium-ion batteries, the UA@CNT composite exhibits high specific capacity, excellent rate capability, and long cycling life even at high current densities. A reversible capacity of over 163 mA h g-1 is maintained even after 150 cycles at a current density of 200 mA g-1. The present study paves a way to develop reversible high-capacity organic electrode materials for sodium-ion batteries by a carbon-anion stabilization mechanism. PMID- 28898045 TI - Impact of Heterointerfaces in Solar Cells Using ZnSnP2 Bulk Crystals. AB - We report on the optimization of interface structure in ZnSnP2 solar cells. The effects of back electrode materials and related interface on photovoltaic performance were investigated. It was clarified that a conventional structure Mo/ZnSnP2 showed a Schottky-behavior, while an ohmic-behavior was observed in the Cu/ZnSnP2 structure annealed at 300 degrees C. STEM-EDX analysis suggested that Cu-Sn-P ternary compound was formed at the interface. This compound is considered to play an important role to obtain the ohmic contact between ZnSnP2 and Cu. In addition, it was clarified that the aqua regia etching of ZnSnP2 bulk crystals before chemical bath deposition process for the preparation of buffer layer was effective to remove the layer including lattice defects introduced by mechanical polishing, which was supported by TEM observations and photoluminescence measurements. This means that the carrier transport across the interface was improved because of the reduced defect at the interface. Consequently, the conversion efficiency of approximately 2% was achieved with the structure of Al/ZnO;Al/ZnO/CdS/ZnSnP2/Cu, where the values of short circuit current density, JSC, open circuit voltage, VOC, and fill factor, FF, were 8.2 mA cm-2, 0.452 V, and 0.533, respectively. However, the value of VOC was largely low considering the bandgap value of ZnSnP2. To improve the conversion efficiency, the optimization of buffer layer material is considered to be essential in the viewpoint of band alignment. PMID- 28898046 TI - Linking Catalyst-Coated Isotropic Colloids into "Active" Flexible Chains Enhances Their Diffusivity. AB - Active colloids are not constrained by equilibrium: ballistic propulsion, superdiffusive behavior, or enhanced diffusivities have been reported for active Janus particles. At high concentrations, interactions between active colloids give rise to complex emergent behavior. Their collective dynamics result in the formation of several hundred particle-strong flocks or swarms. Here, we demonstrate significant diffusivity enhancement for colloidal objects that neither have a Janus architecture nor are at high concentrations. We employ uniformly catalyst-coated, viz. chemo-mechanically, isotropic colloids and link them into a chain to enforce proximity. Activity arises from hydrodynamic interactions between enchained colloidal beads due to reaction-induced phoretic flows catalyzed by platinum nanoparticles on the colloid surface. This results in diffusivity enhancements of up to 60% for individual chains in dilute solution. Chains with increasing flexibility exhibit higher diffusivities. Simulations accounting for hydrodynamic interactions between enchained colloids due to active phoretic flows accurately capture the experimental diffusivity. These simulations reveal that the enhancement in diffusivity can be attributed to the interplay between chain conformational fluctuations and activity. Our results show that activity can be used to systematically modulate the mobility of soft slender bodies. PMID- 28898047 TI - Transglutaminase-Catalyzed Bioconjugation Using One-Pot Metal-Free Bioorthogonal Chemistry. AB - General approaches for controlled protein modification are increasingly sought after in the arena of chemical biology. Here, using bioorthogonal reactions, we present combinatorial chemoenzymatic strategies to effectuate protein labeling. A total of three metal-free conjugations were simultaneously or sequentially incorporated in a one-pot format with microbial transglutaminase (MTG) to effectuate protein labeling. MTG offers the particularity of conjugating residues within a protein sequence rather than at its extremities, providing a route to labeling the native protein. The reactions are rapid and circumvent the incompatibility posed by metal catalysts. We identify the tetrazine ligation as most-reactive for this purpose, as demonstrated by the fluorescent labeling of two proteins. The Staudinger ligation and strain-promoted azide-alkyne cycloaddition are alternatives. Owing to the breadth of labels that MTG can use as a substrate, our results demonstrate the versatility of this system, with the researcher being able to combine specific protein substrates with a variety of labels. PMID- 28898048 TI - Dielectric Meta-Holograms Enabled with Dual Magnetic Resonances in Visible Light. AB - Efficient transmission-type meta-holograms have been demonstrated using high index dielectric nanostructures based on Huygens' principle. It is crucial that the geometry size of building blocks be judiciously optimized individually for spectral overlap of electric and magnetic dipoles. In contrast, reflection-type meta-holograms using the metal/insulator/metal scheme and geometric phase can be readily achieved with high efficiency and small thickness. Here, we demonstrate a general platform for design of dual magnetic resonance based meta-holograms based on the geometric phase using silicon nanostructures that are quarter wavelength thick for visible light. Significantly, the projected holographic image can be unambiguously observed without a receiving screen even under the illumination of natural light. Within the well-developed semiconductor industry, our ultrathin magnetic resonance-based meta-holograms may have promising applications in anticounterfeiting and information security. PMID- 28898049 TI - Analysis of Plasmodium vivax Chloroquine Resistance Transporter Mutant Isoforms. AB - Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum malaria is widespread and has limited the use of CQ in many regions of the globe. Malaria caused by the related human parasite P. vivax is as widespread as is P. falciparum malaria and has been treated with CQ as extensively as has P. falciparum, suggesting that P. vivax parasites have been selected with CQ as profoundly as have P. falciparum parasites. Indeed, a growing number of clinical reports have presented data suggesting increased P. vivax CQR. Cytostatic (growth inhibitory) CQR for P. falciparum is caused by Plasmodium falciparum chloroquine resistance transporter (PfCRT) mutations, and it has been proposed that mutations in the PvCRT orthologue may simliarly cause P. vivax CQR via increasing CQ transport from the P. vivax digestive vacuole. Here we report the first quantitative analysis of drug transport mediated by all known mutant isoforms of Plasmodium vivax chloroquine resistance transporter (PvCRT) in order to test the protein's potential link to growing P. vivax CQR phenomena. Small, but statistically significant, differences in the transport of CQ and other quinoline antimalarial drugs were found for multiple PvCRT isoforms, relative to wild type PvCRT, suggesting that mutations in PvCRT can contribute to P. vivax CQR and other examples of quinoline antimalarial drug resistance. PMID- 28898050 TI - Direct Analysis of Aerosolized Chemical Warfare Simulants Captured on a Modified Glass-Based Substrate by "Paper-Spray" Ionization. AB - Paper spray ionization mass spectrometry offers a rapid alternative platform requiring no sample preparation. Aerosolized chemical warfare agent (CWA) simulants trimethyl phosphate, dimethyl methylphosphonate, and diisopropyl methylphosphonate were captured by passing air through a glass fiber filter disk within a disposable paper spray cartridge. CWA simulants were aerosolized at varying concentrations using an in-house built aerosol chamber. A custom 3D printed holder was designed and built to facilitate the aerosol capture onto the paper spray cartridges. The air flow through each of the collection devices was maintained equally to ensure the same volume of air sampled across methods. Each approach yielded linear calibration curves with R2 values between 0.98-0.99 for each compound and similar limits of detection in terms of disbursed aerosol concentration. While the glass fiber filter disk has a higher capture efficiency (~40%), the paper spray method produces analogous results even with a lower capture efficiency (~1%). Improvements were made to include glass fiber filters as the substrate within the paper spray cartridge consumable. Glass fiber filters were then treated with ammonium sulfate to decrease chemical interaction with the simulants. This allowed for improved direct aerosol capture efficiency (>40%). Ultimately, the limits of detection were reduced to levels comparable to current worker population limits of 1 * 10-6 mg/m3. PMID- 28898051 TI - Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the beta region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid beta fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the 11C-Pittsburgh Compound B (11C PIB). However, for in vitro conditions, significant binding of 3H-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid beta fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties. PMID- 28898052 TI - Heterogeneous Bimetallic Phosphide/Sulfide Nanocomposite for Efficient Solar Energy-Driven Overall Water Splitting. AB - Solar-driven overall water splitting is highly desirable for hydrogen generation with sustainable energy sources, which need efficient, earth-abundant, robust, and bifunctional electrocatalysts for both oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Herein, we propose a heterogeneous bimetallic phosphide/sulfide nanocomposite electrocatalyst of NiFeSP on nickel foam (NiFeSP/NF), which shows superior electrocatalytic activity of low overpotentials of 91 mV at -10 mA cm-2 for HER and of 240 mV at 50 mA cm-2 for OER in 1 M KOH solution. In addition, the NiFeSP/NF presents excellent overall water splitting performance with a cell voltage as low as 1.58 V at a current density of 10 mA cm 2. Combining with a photovoltaic device of a Si solar cell or integrating into photoelectrochemical (PEC) systems, the bifunctional NiFeSP/NF electrocatalyst implements unassisted solar-driven water splitting with a solar-to-hydrogen conversion efficiency of ~9.2% and significantly enhanced PEC performance, respectively. PMID- 28898053 TI - Graphene Oxide: An All-in-One Processing Additive for 3D Printing. AB - Many 3D printing technologies are based on the development of inks and pastes to build objects through droplet or filament deposition (the latter also known as continuous extrusion, robocasting, or direct ink writing). Controlling and tuning rheological behavior is key for successful manufacturing using these techniques. Different formulations have been proposed, but the search continues for approaches that are clean, flexible, robust and that can be adapted to a wide range of materials. Here, we show how graphene oxide (GO) enables the formulation of water-based pastes to print a wide variety of materials (polymers, ceramics, and steel) using robocasting. This work combines flow and oscillatory rheology to provide further insights into the rheological behavior of suspensions combining GO with other materials. Graphene oxide can be used to manipulate the viscoelastic response, enabling the formulation of pastes with excellent printing behavior that combine shear thinning flow and a fast recovery of their elastic properties. These inks do not contain other additives, only GO and the material of interest. As a proof of concept, we demonstrate the 3D printing of additive free graphene oxide structures as well as polymers, ceramics, and steel. Due to its amphiphilic nature and 2D structure, graphene oxide plays multiple roles, behaving as a dispersant, viscosifier, and binder. It stabilizes suspensions of different powders, modifies the flow and viscoelasticity of materials with different chemistries, particle sizes and shapes, and binds the particles together, providing green strength for manual handling. This approach enables printing complex 3D ceramic structures using robocasting with similar properties to alternative formulations, thus demonstrating the potential of using 2D colloids in materials manufacturing. PMID- 28898054 TI - Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals. AB - The development of (radio)pharmaceuticals with favorable pharmacokinetic profiles is crucial for allowing the optimization of the imaging or therapeutic potential and the minimization of undesired side effects. The aim of this study was, therefore, to evaluate and compare three different plasma protein binders (PPB 01, PPB-02, and PPB-03) that are potentially useful in combination with (radio)pharmaceuticals to enhance their half-life in the blood. The entities were functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator via a l-lysine and beta-alanine linker moiety using solid-phase peptide chemistry and labeled with 177Lu (T1/2 = 6.65 days), a clinically established radiometal. The binding capacities of these radioligands and 177Lu DOTA were evaluated using human plasma and solutions of human serum albumin (HSA), human alpha1-acid glycoprotein (alpha1-AGP), and human transthyretin (hTTR) by applying an ultrafiltration assay. 177Lu-DOTA-PPB-01 and 177Lu-DOTA-PPB 02 bound to a high and moderate extent to human plasma proteins (>90% and ~70%, respectively), whereas the binding to hTTR was considered negligible (<10%). 177Lu-DOTA-PPB-03 showed almost complete binding to human plasma proteins (>90%) with a high fraction bound to hTTR (~50%). Plasma protein binding of the 177Lu DOTA complex, which was used as a control, was not observed (<1%). 177Lu-DOTA-PPB 01 and 177Lu-DOTA-PPB-02 were both displaced (>80%) from HSA by ibuprofen, specific for Sudlow's binding site II and coherent with the aromatic structures, and >80% by their respective binding entities. 177Lu-DOTA-PPB-03 was displaced from hTTR by the site-marker l-thyroxine (>60%) and by its binding entity PPB-03* (>80%). All three radioligands were investigated with regard to the in vivo blood clearance in normal mice. 177Lu-DOTA-PPB-01 showed the slowest blood clearance (T1/2,beta: >15 h) followed by 177Lu-DOTA-PPB-03 (T1/2,beta: ~2.33 h) and 177Lu DOTA-PPB-02 (T1/2,beta: ~1.14 h), which was excreted relatively fast. Our results confirmed the high affinity of the 4-(4-iodophenyl)-butyric acid entity (PPB-01) to plasma proteins, while replacement of the halogen by an ethynyl entity (PPB 02) reduced the plasma protein binding significantly. An attractive approach is the application of the transthyretin binder (PPB-03), which shows high affinity to hTTR. Future studies in our laboratory will be focused on the application of these binding entities in combination with clinically relevant targeting agents for diagnostic and therapeutic purposes in nuclear medicine. PMID- 28898056 TI - Pressure-Stabilized Semiconducting Electrides in Alkaline-Earth-Metal Subnitrides. AB - High pressure is able to modify profoundly the chemical bonding and generate new phase structures of materials with chemical and physical properties not accessible at ambient conditions. We here report an unprecedented phenomenon on the pressure-induced formation of semiconducting electrides via compression of layered alkaline-earth subnitrides Ca2N, Sr2N, and Ba2N that are conducting electrides with loosely confined electrons in the interlayer voids at ambient pressure. Our extensive first-principles swarm structure searches identified the high-pressure semiconducting electride phases of a tetragonal I42d structure for Ca2N and a monoclinic Cc structure shared by Sr2N and Ba2N, both of which contain atomic-size cavities with paring electrons distributed within. These electride structures are validated by the excellent agreement between the simulated X-ray diffraction patterns and the experimental data available. We attribute the emergence of the semiconducting electride phases to the p-d hybridization on alkaline-earth-metal atoms under compression as well as the filling of the p-d hybridized band due to the interaction between Ca and N. Our work provides a unique example of pressure-induced metal-to-semiconductor transition in compound materials and reveals unambiguously the electron-confinement topology change between different types of electrides. PMID- 28898055 TI - A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux. AB - Lipid accumulation within the lumen of endolysosomal vesicles is observed in various pathologies including atherosclerosis, liver disease, neurological disorders, lysosomal storage disorders, and cancer. Current methods cannot measure lipid flux specifically within the lysosomal lumen of live cells. We developed an optical reporter, composed of a photoluminescent carbon nanotube of a single chirality, that responds to lipid accumulation via modulation of the nanotube's optical band gap. The engineered nanomaterial, composed of short, single-stranded DNA and a single nanotube chirality, localizes exclusively to the lumen of endolysosomal organelles without adversely affecting cell viability or proliferation or organelle morphology, integrity, or function. The emission wavelength of the reporter can be spatially resolved from within the endolysosomal lumen to generate quantitative maps of lipid content in live cells. Endolysosomal lipid accumulation in cell lines, an example of drug-induced phospholipidosis, was observed for multiple drugs in macrophages, and measurements of patient-derived Niemann-Pick type C fibroblasts identified lipid accumulation and phenotypic reversal of this lysosomal storage disease. Single cell measurements using the reporter discerned subcellular differences in equilibrium lipid content, illuminating significant intracellular heterogeneity among endolysosomal organelles of differentiating bone-marrow-derived monocytes. Single-cell kinetics of lipoprotein-derived cholesterol accumulation within macrophages revealed rates that differed among cells by an order of magnitude. This carbon nanotube optical reporter of endolysosomal lipid content in live cells confers additional capabilities for drug development processes and the investigation of lipid-linked diseases. PMID- 28898057 TI - The Too Many Faces of PD-L1: A Comprehensive Conformational Analysis Study. AB - In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the molecular dynamics trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in detail from a computational perspective. We hope that the data presented here support the ongoing efforts to discover effective therapies targeting the PD-1 immune checkpoint pathway. PMID- 28898058 TI - Mechanoregulation of SM22alpha/Transgelin. AB - SM22alpha, also named transgelin, is an actin filament-associated protein in smooth muscle and fibroblasts. Three decades after its discovery, the biological function of SM22alpha remains under investigation. Here we report a novel finding that the expression and degradation of SM22alpha/transgelin are regulated by mechanical tension. Following a mass spectrometry identification of SM22alpha degradation in isolated and tension-unloaded mouse aorta, we developed specific monoclonal antibodies to study the regulation of SM22alpha in human fetal lung myofibroblast line MRC-5 and primary cultures of neonatal mouse skin fibroblasts. The level of SM22alpha is positively related to the mechanical tension in the cytoskeleton produced by the myosin II motor in response to the stiffness of the culture matrix. Quantitative reverse transcription polymerase chain reaction demonstrated that the expression of SM22alpha is regulated at the transcriptional level. This mechanical regulation resembles that of calponin 2, another actin filament-associated protein. Immunofluorescent staining co-localized SM22alpha with F-actin, myosin, and calponin 2 in mouse skin fibroblasts. The close phylogenetic relationship between SM22alpha and the calponin family supports that SM22alpha is a calponin-like regulatory protein. The level of SM22alpha is decreased in skin fibroblasts isolated from calponin 2 knockout mice, suggesting interrelated regulation and function of the two proteins. On the other hand, SM22alpha expression was maximized at a matrix stiffness higher than that for calponin 2 in the same cell type, indicating differentiated regulation and tension responsiveness. The novel mechanoregulation of SM22alpha/transgelin lays the groundwork for understanding its cellular functions. PMID- 28898059 TI - Helix Propensities of Amino Acid Residues via Thioester Exchange. AB - We describe the use of thioester exchange equilibria to measure the propensities of amino acid residues to participate in helical secondary structure at room temperature in the absence of denaturants. Thermally or chemically induced unfolding has previously been employed to measure alpha-helix propensities among proteinogenic alpha-amino acid residues, and quantitative comparison with precedents indicates that the thioester exchange system is reliable for residues that lack side chain charge. This system allows the measurement of alpha-helix propensities for d-alpha-amino acid residues and propensities of residues with nonproteinogenic backbones, such as those derived from a beta-amino acid, to participate in an alpha-helix-like secondary structure. PMID- 28898060 TI - A Stable Neutral Compound with an Aluminum-Aluminum Double Bond. AB - Homodinuclear multiple-bonded neutral Al compounds, aluminum analogues of alkenes, have been a notoriously difficult synthetic target over the past several decades. Herein, we report the isolation of a stable neutral compound featuring an Al?Al double bond stabilized by N-heterocyclic carbenes. X-ray crystallographic and spectroscopic analyses demonstrate that the dialuminum entity possesses trans-planar geometry and an Al-Al bond length of 2.3943(16) A, which is the shortest distance reported for a molecular dialuminum species. This new species reacts with ethylene and phenyl acetylene to give the [2+2] cycloaddition products. The structure and bonding were also investigated by detailed density functional theory calculations. These results clearly demonstrate the presence of an Al?Al double bond in this molecule. PMID- 28898062 TI - Atomically Resolved Short-Range Order at the Nanoscale in the Ca-Mn-O System. AB - The elucidation of the reaction mechanisms involving redox processes in functional transition-metal oxides, which usually start in areas of very few nanometers in size, is yet a challenge to be satisfactorily achieved. Atomically resolved HAADF and EELS have provided both chemical and structural information at the nanoscale, which reveal the preservation of short-range cationic order in areas of 2-3 nm length as the driving force behind the reversibility of the Ca2Mn3O8-Ca2Mn3O5 redox process. Oxygen evolution is accommodated by cationic diffusion along the Ca and Mn layers of the cation-deficient Ca2Mn3O8 delafossite related structure, whereas Mn remains octahedrally coordinated. PMID- 28898061 TI - Postsynthetic Modification of Bacterial Peptidoglycan Using Bioorthogonal N Acetylcysteamine Analogs and Peptidoglycan O-Acetyltransferase B. AB - Bacteria have the natural ability to install protective postsynthetic modifications onto its bacterial peptidoglycan (PG), the coat woven into bacterial cell wall. Peptidoglycan O-acetyltransferase B (PatB) catalyzes the O acetylation of PG in Gram (-) bacteria, which aids in bacterial survival, as it prevents autolysins such as lysozyme from cleaving the PG. We explored the mechanistic details of PatB's acetylation function and determined that PatB has substrate specificity for bioorthgonal short N-acetyl cysteamine (SNAc) donors. A variety of functionality including azides and alkynes were installed on tri-N acetylglucosamine (NAG)3, a PG mimic, as well as PG isolated from various Gram (+) and Gram (-) bacterial species. The bioorthogonal modifications protect the isolated PG against lysozyme degradation in vitro. We further demonstrate that this postsynthetic modification of PG can be extended to use click chemistry to fluorescently label the mature PG in whole bacterial cells of Bacillus subtilis. Modifying PG postsynthetically can aid in the development of antibiotics and immune modulators by expanding the understanding of how PG is processed by lytic enzymes. PMID- 28898063 TI - Catalytic C(sp3)-H Alkylation via an Iron Carbene Intermediate. AB - The catalytic transformation of a C(sp3)-H bond to a C(sp3)-C bond via an iron carbene intermediate represents a long-standing challenge. Despite the success of enzymatic and small molecule iron catalysts mediating challenging C(sp3)-H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp3)-H alkylations via isoelectronic iron carbene intermediates have thus far been unsuccessful. Iron carbenes have been inert, or shown to favor olefin cyclopropanation and heteroatom-hydrogen insertion. Herein we report an iron phthalocyanine-catalyzed alkylation of allylic and benzylic C(sp3)-H bonds. Mechanistic investigations support that an electrophilic iron carbene mediates homolytic C-H cleavage and rebounds from the resulting organoiron intermediate to form the C-C bond; both steps are tunable via catalyst modifications. These studies suggest that for iron carbenes, distinct from other late metal carbenes, C-H cleavage is partially rate-determining and must be promoted to effect reactivity. PMID- 28898064 TI - Correction to Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States. PMID- 28898065 TI - Synergistic Coupling between Li6.75La3Zr1.75Ta0.25O12 and Poly(vinylidene fluoride) Induces High Ionic Conductivity, Mechanical Strength, and Thermal Stability of Solid Composite Electrolytes. AB - Easy processing and flexibility of polymer electrolytes make them very promising in developing all-solid-state lithium batteries. However, their low room temperature conductivity and poor mechanical and thermal properties still hinder their applications. Here, we use Li6.75La3Zr1.75Ta0.25O12 (LLZTO) ceramics to trigger structural modification of poly(vinylidene fluoride) (PVDF) polymer electrolyte. By combining experiments and first-principle calculations, we find that La atom of LLZTO could complex with the N atom and C?O group of solvent molecules such as N,N-dimethylformamide along with electrons enriching at the N atom, which behaves like a Lewis base and induces the chemical dehydrofluorination of the PVDF skeleton. Partially modified PVDF chains activate the interactions between the PVDF matrix, lithium salt, and LLZTO fillers, hence leading to significantly improved performance of the flexible electrolyte membrane (e.g., a high ionic conductivity of about 5 * 10-4 S cm-1 at 25 degrees C, high mechanical strength, and good thermal stability). For further illustration, a solid-state lithium battery of LiCoO2|PVDF-based membrane|Li is fabricated and delivers satisfactory rate capability and cycling stability at room temperature. Our study indicates that the LLZTO modifying PVDF membrane is a promising electrolyte used for all-solid-state lithium batteries. PMID- 28898066 TI - A Bimetallic Nickel-Gallium Complex Catalyzes CO2 Hydrogenation via the Intermediacy of an Anionic d10 Nickel Hydride. AB - Large-scale CO2 hydrogenation could offer a renewable stream of industrially important C1 chemicals while reducing CO2 emissions. Critical to this opportunity is the requirement for inexpensive catalysts based on earth-abundant metals instead of precious metals. We report a nickel-gallium complex featuring a Ni(0) >Ga(III) bond that shows remarkable catalytic activity for hydrogenating CO2 to formate at ambient temperature (3150 turnovers, turnover frequency = 9700 h-1), compared with prior homogeneous Ni-centered catalysts. The Lewis acidic Ga(III) ion plays a pivotal role in stabilizing catalytic intermediates, including a rare anionic d10 Ni hydride. Structural and in situ characterization of this reactive intermediate support a terminal Ni-H moiety, for which the thermodynamic hydride donor strength rivals those of precious metal hydrides. Collectively, our experimental and computational results demonstrate that modulating a transition metal center via a direct interaction with a Lewis acidic support can be a powerful strategy for promoting new reactivity paradigms in base-metal catalysis. PMID- 28898067 TI - Ligand-Targeted Drug Delivery. AB - Safety and efficacy constitute the major criteria governing regulatory approval of any new drug. The best method to maximize safety and efficacy is to deliver a proven therapeutic agent with a targeting ligand that exhibits little affinity for healthy cells but high affinity for pathologic cells. The probability of regulatory approval can conceivably be further enhanced by exploiting the same targeting ligand, conjugated to an imaging agent, to select patients whose diseased tissues display sufficient targeted receptors for therapeutic efficacy. The focus of this Review is to summarize criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity. Because most LTDs are composed of a targeting ligand (e.g., organic molecule, aptamer, protein scaffold, or antibody), spacer, cleavable linker, and therapeutic warhead, criteria for successful design of each component will be described. Moreover, because obstacles to successful drug design can differ among human pathologies, limitations to drug delivery imposed by the unique characteristics of different diseases will be considered. With the explosion of genomic and transcriptomic data providing an ever-expanding selection of disease-specific targets, and with tools for high-throughput chemistry offering an escalating diversity of warheads, opportunities for innovating safe and effective LTDs has never been greater. PMID- 28898068 TI - Protein-Mediated Colloidal Assembly. AB - Programmable colloidal assembly enables the creation of mesoscale materials in a bottom-up manner. Although DNA oligonucleotides have been used extensively as the programmable units in this paradigm, proteins, which exhibit more diverse modes of association and function, have not been widely used to direct colloidal assembly. Here we use protein-protein interactions to drive controlled aggregation of polystyrene microparticles, either through reversible coiled-coil interactions or through intermolecular isopeptide linkages. The sizes of the resulting aggregates are tunable and can be controlled by the concentration of immobilized surface proteins. Moreover, particles coated with different protein pairs undergo orthogonal assembly. We demonstrate that aggregates formed by association of coiled-coil proteins, in contrast to those linked by isopeptide bonds, are dispersed by treatment with chemical denaturants or soluble competing proteins. Finally, we show that protein-protein interactions can be used to assemble complex core-shell aggregates. This work illustrates a versatile strategy for engineering colloidal systems for use in materials science and biotechnology. PMID- 28898069 TI - Correction to Covalent Co-O-V and Sb-N Bonds Enable Polyoxovanadate Charge Control. PMID- 28898070 TI - Multivariate Metal-Organic Frameworks for Dialing-in the Binding and Programming the Release of Drug Molecules. AB - We report the control of guest release profiles by dialing-in desirable interactions between guest molecules and pores in metal-organic frameworks (MOFs). The interactions can be derived by the rate constants that were quantitatively correlated with the type of functional group and its proportion in the porous structure; thus the release of guest molecules can be predicted and programmed. Specifically, three probe molecules (ibuprofen, rhodamine B, and doxorubicin) were studied in a series of robust and mesoporous MOFs with multiple functional groups [MIL-101(Fe)-(NH2)x, MIL-101(Fe)-(C4H4)x, and MIL-101(Fe) (C4H4)x(NH2)1-x]. The release rate can be adjusted by 32-fold [rhodamine from MIL 101(Fe)-(NH2)x], and the time of release peak can be shifted by up to 12 days over a 40-day release period [doxorubicin from MIL-101(Fe)-(C4H4)x(NH2)1-x], which was not obtained in the physical mixture of the single component MOF counterparts nor in other porous materials. The corelease of two pro-drug molecules (ibuprofen and doxorubicin) was also achieved. PMID- 28898071 TI - Enhanced Catalytic Activity of Iridium(III) Complexes by Facile Modification of C,N-Bidentate Chelating Pyridylideneamide Ligands. AB - A set of aryl-substituted pyridylideneamide (PYA) ligands with variable donor properties owing to a pronounced zwitterionic and a neutral diene-type resonance structure were used as electronically flexible ligands at a pentamethylcyclopentadienyl (Cp*) iridium center. The straightforward synthesis of this type of ligand allows for an easy incorporation of donor substituents such as methoxy groups in different positions of the phenyl ring of the C,N bidentate chelating PYA. These modifications considerably enhance the catalytic activity of the coordinated iridium center toward the catalytic aerobic transfer hydrogenation of carbonyls and imines as well as the hydrosilylation of phenylacetylene. Moreover, these PYA iridium complexes catalyze the base-free transfer hydrogenation of aldehydes, and to a lesser extent also of ketones. Under standard transfer hydrogenation conditions including base, aldehydes are rapidly oxidized to carboxylic acids rather than reduced to the corresponding alcohol, as is observed under base-free conditions. PMID- 28898072 TI - Does Urban Form Affect Urban NO2? Satellite-Based Evidence for More than 1200 Cities. AB - Modifying urban form may be a strategy to mitigate urban air pollution. For example, evidence suggests that urban form can affect motor vehicle usage, a major contributor to urban air pollution. We use satellite-based measurements of urban form and nitrogen dioxide (NO2) to explore relationships between urban form and air pollution for a global data set of 1274 cities. Three of the urban form metrics studied (contiguity, circularity, and vegetation) have a statistically significant relationship with urban NO2; their combined effect could be substantial. As illustration, if findings presented here are causal, that would suggest that if Christchurch, New Zealand (a city at the 75th percentile for all three urban-form metrics, and with a network of buses, trams, and bicycle facilities) was transformed to match the urban form of Indio - Cathedral City, California, United States (a city at the 25th percentile for those same metrics, and exhibiting sprawl-like suburban development), our models suggest that Christchurch's NO2 concentrations would be ~60% higher than its current level. We also find that the combined effect of urban form on NO2 is larger for small cities (beta * IQR = -0.46 for cities < ~300 000 people, versus -0.22 for all cities), an important finding given that cities less than 500 000 people contain a majority of the urban population and are where much of the future urban growth is expected to occur. This work highlights the need for future study of how changes in urban form and related land use and transportation policies impact urban air pollution, especially for small cities. PMID- 28898074 TI - Bistable Dithienylethene-Based Metal-Organic Framework Illustrating Optically Induced Changes in Chemical Separations. AB - Dithienylethene-containing molecules have been examined due to their photoswitching capabilities. We have prepared a bistable, optically triggered, metal-organic framework (MOF) containing a dithienylethene moiety that was synthesized and characterized. The advantage of this material is that, unlike other dithienylethene-containing MOFs, the properties of the pore can be changed via an optical trigger without the potential risk of structural damage to the framework. We illustrate the application of this MOF to chemical separations. With this class of materials, optically triggered conductivity, chemical storage and release, and sensing are possible. PMID- 28898073 TI - Immobilizing Arsenic and Copper Ions in Manure Using a Nanocomposite. AB - Livestock manure (Man) commonly contains a certain quantity of heavy metal ions, such as arsenic (As) and copper (Cu) ions, resulting in a high risk on soil contamination. To solve this problem, heavy metal of manure was immobilized into sodium carbonate/biosilica/attapulgite composite (Na2CO3/BioSi/Attp), which was developed using a nanocomposite consisting of anhydrous sodium carbonate (Na2CO3), straw ash-based biochar and biosilica (BioSi), and attapulgite (Attp). When Na2CO3/BioSi/Attp was mixed with Man/AsCu, the obtained nanocomposite (Na2CO3/BioSi/Attp/Man/AsCu) with a porous nano-network structure could effectively control the release of As and Cu ions from manure through adsorption and chemical reaction. Meanwhile, a pot experiment indicated that Na2CO3/BioSi/Attp/Man/AsCu could increase the pH value of acid soil, promote the growth of rice, and significantly decrease the uptake of As and Cu ions by rice. Therefore, this work provides a promising approach to immobilize heavy metal ions in manure and, thus, lower the contamination risk to the environment. Na2CO3, BioSi, and Attp powders were mixed evenly with a weight ratio of WNa2CO3/WBioSi/WAttp = 3:1:2. PMID- 28898076 TI - Acetylcholinesterase Inhibitory Alkaloids from the Whole Plants of Zephyranthes carinata. AB - Eleven new alkaloids (1-11), classified as the 12-acetylplicamine (1), N-deformyl seco-plicamine (2), plicamine (3-6), 4a-epi-plicamine (7), seco-plicamine (8), and lycorine (9-11) framework types, along with 15 known alkaloids (12-26) were isolated from the whole plants of Zephyranthes carinata. The structures of the new alkaloids 1-11 were established by extensive spectroscopic data interpretation. The absolute configurations of 9 and 10 were defined by single crystal X-ray diffraction analysis. Zephycarinatines A (1), B (2), and G (7) represent the first examples of 12-acetylplicamine, N-deformyl-seco-plicamine, and 4a-epi-plicamine alkaloids, respectively. Alkaloids 6, 11, 17, and 20-23 exhibited AChE inhibitory activities with IC50 values ranging from 1.21 to 184.05 MUM, and a preliminary structure-activity relationship is discussed. PMID- 28898075 TI - Incorporation of Phosphorylated Tyrosine into Proteins: In Vitro Translation and Study of Phosphorylated IkappaB-alpha and Its Interaction with NF-kappaB. AB - Phosphorylated proteins play important roles in the regulation of many different cell networks. However, unlike the preparation of proteins containing unmodified proteinogenic amino acids, which can be altered readily by site-directed mutagenesis and expressed in vitro and in vivo, the preparation of proteins phosphorylated at predetermined sites cannot be done easily and in acceptable yields. To enable the synthesis of phosphorylated proteins for in vitro studies, we have explored the use of phosphorylated amino acids in which the phosphate moiety bears a chemical protecting group, thus eliminating the negative charges that have been shown to have a negative effect on protein translation. Bis-o nitrobenzyl protection of tyrosine phosphate enabled its incorporation into DHFR and IkappaB-alpha using wild-type ribosomes, and the elaborated proteins could subsequently be deprotected by photolysis. Also investigated in parallel was the re-engineering of the 23S rRNA of Escherichia coli, guided by the use of a phosphorylated puromycin, to identify modified ribosomes capable of incorporating unprotected phosphotyrosine into proteins from a phosphotyrosyl-tRNACUA by UAG codon suppression during in vitro translation. Selection of a library of modified ribosomal clones with phosphorylated puromycin identified six modified ribosome variants having mutations in nucleotides 2600-2605 of 23S rRNA; these had enhanced sensitivity to the phosphorylated puromycin. The six clones demonstrated some sequence homology in the region 2600-2605 and incorporated unprotected phosphotyrosine into IkappaB-alpha using a modified gene having a TAG codon in the position corresponding to amino acid 42 of the protein. The purified phosphorylated protein bound to a phosphotyrosine specific antibody and permitted NF-kappaB binding to a DNA duplex sequence corresponding to its binding site in the IL-2 gene promoter. Unexpectedly, phosphorylated IkappaB-alpha also mediated the exchange of exogenous DNA into an NF-kappaB-cellular DNA complex isolated from the nucleus of activated Jurkat cells. PMID- 28898077 TI - Simulation of Reversible Protein-Protein Binding and Calculation of Binding Free Energies Using Perturbed Distance Restraints. AB - Virtually all biological processes depend on the interaction between proteins at some point. The correct prediction of biomolecular binding free-energies has many interesting applications in both basic and applied pharmaceutical research. While recent advances in the field of molecular dynamics (MD) simulations have proven the feasibility of the calculation of protein-protein binding free energies, the large conformational freedom of proteins and complex free energy landscapes of binding processes make such calculations a difficult task. Moreover, convergence and reversibility of resulting free-energy values remain poorly described. In this work, an easy-to-use, yet robust approach for the calculation of standard state protein-protein binding free energies using perturbed distance restraints is described. In the binding process the conformations of the proteins were restrained, as suggested earlier. Two approaches to avoid end-state problems upon release of the conformational restraints were compared. The method was evaluated by practical application to a small model complex of ubiquitin and the very flexible ubiquitin-binding domain of human DNA polymerase iota (UBM2). All computed free energy differences were closely monitored for convergence, and the calculated binding free energies had a mean unsigned deviation of only 1.4 or 2.5 kJ.mol-1 from experimental values. Statistical error estimates were in the order of thermal noise. We conclude that the presented method has promising potential for broad applicability to quantitatively describe protein-protein and various other kinds of complex formation. PMID- 28898079 TI - A General Route to Include Pauli Repulsion and Quantum Dispersion Effects in QM/MM Approaches. AB - A methodology to account for nonelectrostatic interactions in Quantum Mechanical (QM)/Molecular Mechanics (MM) approaches is developed. Formulations for Pauli repulsion and dispersion energy, explicitly depending on the QM density, are derived. Such expressions are based on the definition of an auxiliary density on the MM portion and the Tkatchenko-Scheffler (TS) approach, respectively. The developed method is general enough to be applied to any QM/MM method and partition, provided an accurate tuning of a small number of parameters is obtained. The coupling of the method with both nonpolarizable and fully polarizable QM/fluctuating charge (FQ) approaches is reported and applied. A suitable parametrization for the aqueous solution, so that its most representative features are well reproduced, is outlined. Then, the obtained parametrization and method are applied to calculate the nonelectrostatic (repulsion and dispersion) interaction energy of nicotine in aqueous solution. PMID- 28898080 TI - Efficient Reconstruction of CAS-CI-Type Wave Functions for a DMRG State Using Quantum Information Theory and a Genetic Algorithm. AB - We improve the methodology to construct a complete active space-configuration interaction (CAS-CI) expansion for density-matrix renormalization group (DMRG) wave functions using a matrix-product state representation, inspired by the sampling-reconstructed CAS [SR-CAS; Boguslawski , K. ; J. Chem. Phys. 2011 , 134 , 224101 ] algorithm. In our scheme, the genetic algorithm, in which the "crossover" and "mutation" processes can be optimized based on quantum information theory, is employed when reconstructing a CAS-CI-type wave function in the Hilbert space. Analysis of results for ground and excited state wave functions of conjugated molecules, transition metal compounds, and a lanthanide complex illustrate that our scheme is very efficient for searching the most important CI expansions in large active spaces. PMID- 28898081 TI - Scalable Electron Correlation Methods. 4. Parallel Explicitly Correlated Local Coupled Cluster with Pair Natural Orbitals (PNO-LCCSD-F12). AB - We present an efficient explicitly correlated pair natural orbital local coupled cluster (PNO-LCCSD-F12) method. The method is an extension of our previously reported PNO-LCCSD approach ( Schwilk et al., J. Chem. Theory Comput. 2017 , 13 , 3650 - 3675 ). Near linear scaling with the molecular size is achieved by using pair, domain, and projection approximations, local density fitting and local resolution of the identity, and by exploiting the sparsity of the local molecular orbitals as well as of the projected atomic orbitals. The effect of the various domain approximations is tested for a wide range of chemical reactions and intermolecular interactions. In accordance with previous findings, it is demonstrated that the F12 terms significantly reduce the domain errors. The convergence of the reaction and interaction energies with respect to the parameters that determine the domain sizes and pair approximations is extensively tested. The results obtained with our default thresholds agree within a few tenths of a kcal mol-1 with the ones computed with very tight options. For cases where canonical calculations are still feasible, the relative energies of local and canonical calculations agree within similar error bounds. The PNO-LCCSD-F12 method needs only 25-40% more computer time than a corresponding PNO-LCCSD calculation while greatly improving the accuracy. Our program is well parallelized and capable of computing accurate correlation energies for molecules with more than 150 atoms using augmented triple-zeta basis sets and more than 5000 basis functions. Using several nodes of a small computer cluster, such calculations can be carried out within a few hours. PMID- 28898082 TI - Meroterpenoids from a Medicinal Fungus Antrodia cinnamomea. AB - Antrodia cinnamomea, a medicinal fungus indigenous to Taiwan, has been shown to exhibit a broad spectrum of bioactivities for the treatments of alcoholic intoxication, diarrhea, abdominal pain, and fatigue, and a number of active principles have been identified. Among the bioactive entities, clinical trials of antroquinonol and 4-acetyl antroquinonol B are being carried out for curing cancer, hypercholesterolemia, and hyperlipidemia. The total synthesis of antroquinonol has been achieved; however, investigating the structure-activity relationship of this class of compounds remained difficult due to the lack of available analogues. Twenty antroquinonols isolated from A. cinnamomea IFS006 are reported herein. Their structures were elucidated using spectral analysis and by comparison with literature values. Of these, 11 antroquinonol analogues, namely, antroquinonols N-X (1-11), were previously unreported. The growth inhibitory activity of all the antroquinonol analogues was evaluated against human A549 and PC-3 cancer cell lines, and antroquinonol A exhibited the most potent activity, with GI50 values of 5.7 +/- 0.2 and 13.5 +/- 0.2 MUM, respectively. Antroquinonols V (9) and W (10) also showed growth inhibitory activity against A549 cells with GI50 values of 8.2 +/- 0.8 and 7.1 +/- 2.1 MUM, respectively, compared to 5-fluorouracil (GI50 = 4.2 +/- 0.2 MUM). PMID- 28898083 TI - The Direct C-H Difluoromethylation of Heteroarenes Based on the Photolysis of Hypervalent Iodine(III) Reagents That Contain Difluoroacetoxy Ligands. AB - In this letter, an efficient method for the photolytic generation of difluoromethyl radicals from [bis(difluoroacetoxy)iodo]benzene reagents is described. The present approach enables the introduction of difluoromethyl groups into various heteroarenes under mild conditions in the absence of any additional reagents or catalysts. PMID- 28898084 TI - Asymmetric Nanoantennas for Ultrahigh Angle Broadband Visible Light Bending. AB - Wavefront manipulation in metasurfaces typically relies on phase mapping with a finite number of elements. In particular, a discretized linear phase profile may be used to obtain a beam bending functionality. However, discretization limits the applicability of this approach for high angle bending due to the drastic efficiency drop when the phase is mapped by a small number of elements. In this work, we discuss a novel concept for energy redistribution in diffraction gratings and its application in the visible spectrum range, which helps overcome the constraints of ultrahigh angle (above 80 degrees ) beam bending. Arranging asymmetric dielectric nanoantennas into diffractive gratings, we show that one can efficiently redistribute the power between the grating orders at will. This is achieved by precise engineering of the scattering pattern of the nanoantennas. The concept is numerically and experimentally demonstrated at visible frequencies using several designs of TiO2 (titanium dioxide) nanoantennas for medium (~55 degrees ) and high (~80 degrees ) angle light bending. Results show efficient broadband visible-light operation (blue and green range) of transmissive devices, reaching efficiencies of ~90% and 50%, respectively, at the optimized wavelength. The presented design concept is general and can be applied for both transmission and reflection operation at any desired wavelength and polarization. PMID- 28898085 TI - Gelsekoumidines A and B: Two Pairs of Atropisomeric Bisindole Alkaloids from the Roots of Gelsemium elegans. AB - Two pairs of atropisomeric bisindole alkaloids, gelsekoumidines A (1) and B (2), with a new carbon skeleton, were isolated from the roots of Gelsemium elegans. Compounds 1 and 2 represent the first examples of seco-koumine-gelsedine type alkaloids, which feature an unprecedented 20,21-seco-koumine scaffold fused with a gelsedine framework via a double bond. Their structures including absolute stereochemistry were elucidated by spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism (ECD) calculation. A plausible biogenetic pathway for the new compounds is also proposed. Compound 2 exhibited a moderate inhibitory effect against nitric oxide (NO) production. PMID- 28898086 TI - Theoretical Discovery of a Superconducting Two-Dimensional Metal-Organic Framework. AB - Superconductivity is a fascinating quantum phenomenon characterized by zero electrical resistance and the Meissner effect. To date, several distinct families of superconductors (SCs) have been discovered. These include three-dimensional (3D) bulk SCs in both inorganic and organic materials as well as two-dimensional (2D) thin film SCs but only in inorganic materials. Here we predict superconductivity in 2D and 3D organic metal-organic frameworks by using first principles calculations. We show that the highly conductive and recently synthesized Cu-benzenehexathial (BHT) is a Bardeen-Cooper-Schrieffer SC. Remarkably, the monolayer Cu-BHT has a critical temperature (Tc) of 4.43 K, while Tc of bulk Cu-BHT is 1.58 K. Different from the enhanced Tc in 2D inorganic SCs which is induced by interfacial effects, the Tc enhancement in this 2D organic SC is revealed to be the out-of-plane soft-mode vibrations, analogous to surface mode enhancement originally proposed by Ginzburg. Our findings not only shed new light on better understanding 2D superconductivity but also open a new direction to search for SCs by interface engineering with organic materials. PMID- 28898087 TI - Phosphine-Catalyzed Diastereo- and Enantioselective Michael Addition of beta Carbonyl Esters to beta-Trifluoromethyl and beta-Ester Enones: Enhanced Reactivity by Inorganic Base. AB - A novel chiral biamide-phosphine multifunctional catalyst has been developed that mediates the asymmetric intermolecular Michael addition of beta-carbonyl esters to beta-trifluoromethyl enones and 3-aroyl acrylates in the presence of competing methyl acrylate and the inorganic base. This method provides a facile access to structurally diverse trifluoromethyl and quaternary stereogenic centers with excellent enantioselectivity (up to 99% ee) and good diastereoselectivity (up to 13:1 dr). The addition of the inorganic base (K3PO4) does not cause the background racemic reaction and enhances the reactivity by serving as a co catalyst. PMID- 28898088 TI - Probing Single-Molecule Adhesion of a Stimuli Responsive Oligo(ethylene glycol) Methacrylate Copolymer on a Molecularly Smooth Hydrophobic MoS2 Basal Plane Surface. AB - Molybdenum disulfide (MoS2) has been receiving increasing attention in scientific research due to its unique properties. Up to now, several techniques have been developed to prepare exfoliated nanosize MoS2 dispersions to facilitate its applications. To improve its desired performance, as-prepared MoS2 dispersion needs further appropriate modification by polymers. Thus, understanding polymer MoS2 interaction is of great scientific importance and practical interest. Here, we report our results on molecular interactions of a biocompatible stimuli responsive copolymer with the basal plane surface of MoS2 determined using single molecule force spectroscopy (SMFS). Under isothermal conditions, the single molecule adhesion force of oligo(ethylene glycol) methacrylate copolymer was found to increase from 50 to 75 pN with increasing NaCl concentration from 1 mM to 2 M, as a result of increasing hydrophobicity of the polymers. The theoretical analysis demonstrated that single-molecule adhesion force is determined by two contributions: the adhesion energy per monomer and the entropic free energy of the stretched polymer chain. Further data analysis revealed a significant increase in the adhesion energy per monomer with a negligible change in the other contribution with increasing salt concentration. The hydrophobic attraction (HA) was found to be the main contribution for the higher adhesion energy in electrolyte solutions of higher NaCl concentrations where the zero-frequency of van der Waals interaction were effectively screened. The results illustrate that oligo(ethylene glycol) methacrylate copolymer is a promising polymer for functionalizing MoS2 and that one can simply change the salt concentration to modulate the single-molecule interactions for desired applications. PMID- 28898089 TI - A Novel Intrinsic Interface State Controlled by Atomic Stacking Sequence at Interfaces of SiC/SiO2. AB - On the basis of ab initio total-energy electronic-structure calculations, we find that electron states localized at the SiC/SiO2 interface emerge in the energy region between 0.3 eV below and 1.2 eV above the bulk conduction-band minimum (CBM) of SiC, being sensitive to the sequence of atomic bilayers in SiC near the interface. These new interface states unrecognized in the past are due to the peculiar characteristics of the CBM states that are distributed along the crystallographic channels. We also find that the electron doping modifies the energetics among the different stacking structures. Implication for performance of electron devices fabricated on different SiC surfaces is discussed. PMID- 28898090 TI - Tandem [3 + 2] Cycloaddition/1,4-Addition Reaction of Azomethine Ylides and Aza-o quinone Methides for Asymmetric Synthesis of Imidazolidines. AB - An enantioselective synthesis of biologically important imidazolidines has been achieved via a tandem [3 + 2] cycloaddition/1,4-addition reaction of azomethine ylide and aza-o-quinone methides. With the use of this tool, various imidazolidine derivatives are obtained in good yields with excellent diastereoselectivities and enantioselectivities. PMID- 28898091 TI - Directed Two-Photon Absorption in CdSe Nanoplatelets Revealed by k-Space Spectroscopy. AB - We show that two-photon absorption (TPA) is highly anisotropic in CdSe nanoplatelets, thus promoting them as a new class of directional two-photon absorbers with large cross sections. Comparing two-dimensional k-space spectroscopic measurements of the one-photon and two-photon excitation of an oriented monolayer of platelets, it is revealed that TPA into the continuum is a directional phenomenon. This is in contrast to one-photon absorption. The observed directional TPA is shown to be related to fundamental band anisotropies of zincblende CdSe and the ultrastrong anisotropic confinement. We recover the internal transition dipole distribution and find that this directionality arises from the intrinsic directionality of the underlying Bloch and envelope functions of the states involved. We note that the photoemission from the CdSe platelets is highly anisotropic following either one- or two-photon excitation. Given the directionality and high TPA cross-section of these platelets, they may, for example, find employment as efficient logic AND elements in integrated photonic devices, or directional photon converters. PMID- 28898092 TI - General Synthesis of the Nitropyrrolin Family of Natural Products via Regioselective CO2-Mediated Alkyne Hydration. AB - The total synthesis of the 2-nitropyrrole natural products nitropyrrolins A and B and the formal synthesis of nitropyrrolin D are reported. The key 2-nitro-4 alkylpyrrole core was efficiently assembled by Sonogashira cross-coupling, with complete control of regioselectivity. An unusual carboxylative cyclization, sulfonylcarbamate formation, and base-promoted cleavage sequence enabled access to the key hydroxy ketone without affecting the protected 2-nitropyrrole unit. The total synthesis provides a general approach for preparation of the bioactive nitropyrrolin family of natural products. PMID- 28898093 TI - Synthesis of Stable Citrate-Capped Silver Nanoprisms. AB - Citrate-stabilized silver nanoprisms (AgNPrs) can be easily functionalized using well-developed thiol based surface chemistry that is an important requirement for biosensor applications utilizing localized surface plasmon resonance (LSPR) and surface-enhanced Raman Scattering (SERS). Unfortunately, currently available protocols for synthesis of citrate-coated AgNPrs do not produce stable nanoparticles thus limiting their usefulness in biosensing applications. Here we address this problem by carrying out a systematic study of citrate-stabilized, peroxide-based synthesis of AgNPrs to optimize reaction conditions for production of stable and reproducible nanoprisms. Our analysis showed that concentration of secondary reducing agent, l-ascorbic acid, is critical to AgNPr stability. Furthermore, we demonstrated that optimization of other synthesis conditions such as stabilizer concentration, rate of silver nitrate addition, and seed dilution result in highly stable nanoprisms with narrow absorbance peaks ranging from 450 nm into near-IR. In addition, the optimized reaction conditions can be used to produce AgNPrs in a one-pot synthesis instead of a previously described two-step reaction. The resulting nanoprisms can readily interact with thiols for easy surface functionalization. These studies provide an optimized set of parameters for precise control of citrate stabilized AgNPr synthesis for biomedical applications. PMID- 28898094 TI - Low-Temperature Solid-State Synthesis of High-Purity BiFeO3 Ceramic for Ferroic Thin-Film Deposition. AB - The synthesis of high-purity BiFeO3 (BFO) ceramic by solid-state reaction is known to be very difficult due to inevitable formation of the secondary phases, mostly mullite-type Bi2Fe4O9 and sillenite-type Bi25FeO39. In particular, it is very difficult to completely remove the Bi-deficient Bi2Fe4O9 phase from sintered ceramic BFO targets. This problem consequently leads to the difficulty of fabricating high-quality BFO thin films using these sintered targets. Herein, we introduce a simple but effective low-temperature processing scheme for removing impurity phases in which optimized processing conditions are obtained by chemically correlating the first calcination step with the subsequent leaching and sintering steps. More specifically, we suitably avoid the formation of the high-temperature-stable Bi2Fe4O9 phase by performing the calcination at significantly low temperatures (between 650 and 675 degrees C) with Bi-excess starting powders. We have then fabricated epitaxially grown BFO thin films using these phase-pure ceramic targets and consequently achieved high-quality ferroelectricity and switchable photovoltaic responses. On the basis of the present experimental observations, we suggest that a low impurity concentration in the sintered BFO ceramic target, even with a low relative density, is advantageous for high-quality thin-film fabrication. PMID- 28898096 TI - Base-Promoted Cascade C-C Coupling/N-alpha-sp3C-H Hydroxylation for the Regiospecific Synthesis of 3-Hydroxyisoindolinones. AB - A base-promoted cascade reaction for the regiospecific synthesis of substituted 3 hydroxyisoindolinones under transition-metal-free conditions is developed. The base-mediated C-C bond coupling and N-alpha-sp3C-H bond hydroxylation are involved in this procedure, which features high regioselectivity, efficiency, and environmental friendliness. Various substituted 3-hydroxyisoindolinones, including some bioactive molecules, were provided in up to 93% yield for 28 examples. PMID- 28898095 TI - Activation of a Cryptic Gene Cluster in Lysobacter enzymogenes Reveals a Module/Domain Portable Mechanism of Nonribosomal Peptide Synthetases in the Biosynthesis of Pyrrolopyrazines. AB - Lysobacter are considered "peptide specialists". However, many of the nonribosomal peptide synthetase genes are silent. Three new compounds were identified from L. enzymogenes upon activating the six-module-containing led cluster by the strong promoter PHSAF. Although ledD was the first gene under PHSAF control, the second gene ledE was expressed the highest. Targeted gene inactivation showed that the two-module LedE and the one-module LedF were selectively used in pyrrolopyrazine biosynthesis, revealing a module/domain portable mechanism. PMID- 28898097 TI - Synthesis of Dihydropyrazoles via Ligand-Free Pd-Catalyzed Alkene Aminoarylation of Unsaturated Hydrazones with Diaryliodonium Salts. AB - A ligand-free, palladium-catalyzed aminoarylation reaction of the unactivated alkenes in beta,gamma-unsaturated hydrazones is described. This protocol enables efficient and simultaneous formation of C(sp3)-N and C(sp3)-C(sp2) bonds under mild conditions, providing a practical and general approach to various diversely substituted dihydropyrazoles in generally good yields, without the use of any stoichiometric external oxidant. PMID- 28898098 TI - Substituent Effects on the Coordination Chemistry of Metal-Binding Pharmacophores. AB - A combination of XAS, UV-vis, NMR, and EPR was used to examine the binding of a series of alpha-hydroxythiones to CoCA. All three appear to bind preferentially in their neutral, protonated forms. Two of the three clearly bind in a monodentate fashion, through the thione sulfur alone. Thiomaltol (TM) appears to show some orientational preference, on the basis of the NMR, while it appears that thiopyromeconic acid (TPMA) retains rotational freedom. In contrast, allothiomaltol (ATM), after initially binding in its neutral form, presumably through the thione sulfur, forms a final complex that is five-coordinate via bidentate coordination of ATM. On the basis of optical titrations, we speculate that this may be due to the lower initial pKa of ATM (8.3) relative to those of TM (9.0) and TPMA (9.5). Binding through the thione is shown to reduce the hydroxyl pKa by ~0.7 pH unit on metal binding, bringing only ATM's pKa close to the pH of the experiment, facilitating deprotonation and subsequent coordination of the hydroxyl. The data predict the presence of a solvent-exchangeable proton on TM and TPMA, and Q-band 2-pulse ESEEM experiments on CoCA + TM suggest that the proton is present. ESE-detected EPR also showed a surprising frequency dependence, giving only a subset of the expected resonances at X-band. PMID- 28898099 TI - Palladium-Catalyzed Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl Chlorides and Triflates. AB - The direct C3-arylation of N-unsubstituted indoles with aryl chlorides and triflates has been realized using a palladium-dihydroxyterphenylphosphine (DHTP) catalyst. The site selectivity is different from that obtained with other structurally related ligands. This unique feature of the DHTP ligand is attributed to complex formation between the lithium salts of the ligand and the indole. The method was applied to the late-stage derivatization of pharmaceuticals having a chloro group. PMID- 28898100 TI - Reactivity of Fe and Ru Complexes of Picolyl-Substituted N-Heterocyclic Carbene Ligand: Diverse Coordination Modes and Small Molecule Binding. AB - Complexes [MClCp*(HL)] (1[Fe]/1[Ru]) (where HL = 1-mesityl-3-(pyridin-2 ylmethyl)imidazol-2-ylidene) were synthesized from the reaction of in situ generated HL ligand and [FeClCp*(TMEDA)] (where TMEDA is N,N,N',N' tetramethylethylenediamine) or [RuClCp*]4, respectively. The deprotonation of 1[Fe]/1[Ru] with 1 equiv of LiHMDS led to cyclometalation through the o-Me of the mesityl group, forming [MCp*(L-kappaC,kappaC',kappaN)] 2[Fe]/2[Ru]. The coordinatively unsaturated compounds [MCp*(HL)]BPh4 3[Fe]/3[Ru] were prepared from 1[Fe]/1[Ru] and halide scavenger NaBPh4. Complex 3[Ru] showed agostic interactions between the o-Me group of the mesityl moiety and the metal center in solution and the solid state. When the vacant coordination site of 3[Fe]/3[Ru] is occupied by CO, the resulting [MCp*(CO)(HL)]BPh4 4[Fe]/4[Ru] can be deprotonated with 1 equiv of KHMDS at the pyridylic position to afford complexes [MCp*L'(CO)] 5[Fe]/5[Ru], where the L'- ligand chelates to the metal center through the nitrogen donor atom of the dearomatized pyridine ring and the carbene carbon. Complex 2[Fe] reacted rapidly with CO to afford the simple ligand substitution product [FeCp*(L-kappaC,kappaC')(CO)] 6[Fe], where the L- acts as a bidentate chelating ligand through the carbene carbon and benzylic carbon. Under the same condition, the reaction of 2[Ru] with CO forms [RuCp*L"(CO)] 7[Ru], where the L"- ligand (an isomer of L- and L'-) chelates to the metal center through the carbene carbon and a pyridyl carbon. Complexes 3[Fe]/3[Ru] reversibly bind dinitrogen to form [MCp*(HL)(N2)]BPh4 8[Fe]/8[Ru]. 3[Ru] reversibly binds dihydrogen to give [MCp*(H2)(HL)]BPh4 9[Ru], while no reaction was observed between 3[Fe] and H2. The reaction of 3[Ru] with dioxygen led to the isolation of a stable side-on O2 complex [RuCp*(HL)(O2)]BPh4 10[Ru], while the reaction of 3[Fe] with dioxygen led to an intractable mixture of products. PMID- 28898101 TI - Ph3P/I2-Mediated Synthesis of N,N',N"-Substituted Guanidines and 2 Iminoimidazolin-4-ones from Aryl Isothiocyanates. AB - A convenient one-pot procedure for the synthesis of acyclic and cyclic guanidines mediated by the Ph3P/I2 system is described. Sequential condensation of aryl isothiocyanates with amines followed by dehydrosulfurization and guanylation could lead to both symmetric and unsymmetric N,N',N"-substituted derivatives. Through a tandem guanylation-cyclization, a series of 2-iminoimidazolin-4-ones could also be prepared in good yields from the reaction of aryl isothiocyanates with amino acid methyl esters. PMID- 28898102 TI - Site-Selective TiO2 Coating on Asymmetric Patchy Particles. AB - The successful fabrication of TiO2-faced asymmetric patchy particles consisting of polystyrene and a Fe3O4/SiO2/TiO2 part is described. Such particles can be of large interest for photochemistry. The used site-selective coating approach demonstrates a modification strategy for a special patchy particle family which may have a general character. The stability of the coating has been tested under several conditions with no sign of disruption. The influence of the prepared asymmetric particles on oil/water phase mixing behavior was tested and turned out to be very diverse. Oils with low polarity (e.g., hexadecane, cyclohexane, octadecane) can form Pickering emulsions by the help of these particles; oils with high polarity (e.g., 1-octanol) form monodisperse macrodroplet systems with unusual stability. PMID- 28898103 TI - Comparative Study of Secondary Structure and Interactions of the R5 Peptide in Silicon Oxide and Titanium Oxide Coprecipitates Using Solid-State NMR Spectroscopy. AB - A biomimetic, peptide-mediated approach to inorganic nanostructure formation is of great interest as an alternative to industrial production methods. To investigate the role of peptide structure on silica (SiO2) and titania (TiO2) morphologies, we use the R5 peptide domain derived from the silaffin protein to produce uniform SiO2 and TiO2 nanostructures from the precursor silicic acid and titanium bis(ammonium lactato)dihydroxide, respectively. The resulting biosilica and biotitania nanostructures are characterized using scanning electron microscopy. To investigate the process of R5-mediated SiO2 and TiO2 formation, we carry out 1D and 2D solid-state NMR (ssNMR) studies on R5 samples with uniformly 13C- and 15N-labeled residues to determine the backbone and side-chain chemical shifts. 13C chemical shift data are in turn used to determine peptide backbone torsion angles and secondary structure for the R5 peptide neat, in silica, and in titania. We are thus able to assess the impact of the different mineral environments on peptide structure, and we can further elucidate from 13C chemical shifts change the degree to which various side chains are in close proximity to the mineral phases. These comparisons add to the understanding of the role of R5 and its structure in both SiO2 and TiO2 formation. PMID- 28898104 TI - Rotator Cuff Calcific Tendinitis: Ultrasound-Guided Needling and Lavage Versus Subacromial Corticosteroids: Five-Year Outcomes of a Randomized Controlled Trial. AB - BACKGROUND: Barbotage (needling and lavage) is often applied in the treatment of calcific tendinitis of the rotator cuff (RCCT). In a previously published randomized controlled trial, we reported superior clinical and radiological 1 year outcomes for barbotage combined with a corticosteroid injection in the subacromial bursa (SAIC) compared with an isolated SAIC. There are no trials with a midterm or long-term follow-up of barbotage available. PURPOSE: To compare the 5-year results of 2 regularly applied treatments of RCCT: ultrasound (US)-guided barbotage combined with a SAIC (group 1) versus an isolated US-guided SAIC (group 2). STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients were randomly assigned to group 1 or 2 and evaluated before and after treatment at regular time points until 12 months and also at 5 years using the Constant score (CS), the Western Ontario Rotator Cuff Index (WORC), and the Disabilities of the Arm, Shoulder and Hand (DASH). The calcification location and size and Gartner classification were assessed on radiographs. The rotator cuff condition was evaluated with US. Results were analyzed using t tests, linear regression, and a mixed model for repeated measures. RESULTS: Forty-eight patients were included (mean age, 52.0 +/- 7.3 years; 25 [52%] female) with a mean baseline CS of 68.7 +/- 11.9. After a mean follow-up of 5.1 +/- 0.5 years, the mean CS was 90 (95% CI, 83.0-95.9) in group 1 versus 87 (95% CI, 80.5-93.5) in group 2 ( P = .58). The mean improvement in the CS in group 1 was 18 (95% CI, 12.3-23.0) versus 21 (95% CI, 16.2-26.2) in group 2 ( P = .32). There was total resorption in 62% of group 1 and 73% of group 2 ( P = .45). The US evaluation of the rotator cuff condition showed no significant differences between the groups. With the mixed model for repeated measures, taking into account the baseline CS and Gartner classification, the mean treatment effect for barbotage was 6 (95% CI, -8.9 to 21.5), but without statistical significance. Follow-up scores were significantly associated with baseline scores and the duration of follow-up. Results for the DASH and WORC were similar. There were no significant complications, but 4 patients in group 1 and 16 in group 2 underwent additional treatment during the follow-up period ( P < .001). CONCLUSION: No more significant differences were found in the clinical and radiological outcomes between barbotage combined with a SAIC versus an isolated SAIC after 5 years of follow-up. Registration: NTR2282 (Dutch Trial Registry). PMID- 28898106 TI - Anterolateral Tenodesis or Anterolateral Ligament Complex Reconstruction: Effect of Flexion Angle at Graft Fixation When Combined With ACL Reconstruction. AB - BACKGROUND: Despite numerous technical descriptions of anterolateral procedures, knowledge is limited regarding the effect of knee flexion angle during graft fixation. PURPOSE: To determine the effect of knee flexion angle during graft fixation on tibiofemoral joint kinematics for a modified Lemaire tenodesis or an anterolateral ligament (ALL) complex reconstruction combined with anterior cruciate ligament (ACL) reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Twelve cadaveric knees were mounted in a test rig with kinematics recorded from 0 degrees to 90 degrees flexion. Loads applied to the tibia were 90-N anterior translation, 5-N.m internal tibial rotation, and combined 90-N anterior force and 5-N.m internal rotation. Intact, ACL-deficient, and combined ACL plus anterolateral-deficient states were tested, and then ACL reconstruction was performed and testing was repeated. Thereafter, modified Lemaire tenodeses and ALL procedures with graft fixation at 0 degrees , 30 degrees , and 60 degrees of knee flexion and 20-N graft tension were performed combined with the ACL reconstruction, and repeat testing was performed throughout. Repeated-measures analysis of variance and Bonferroni-adjusted t tests were used for statistical analysis. RESULTS: In combined ACL and anterolateral deficiency, isolated ACL reconstruction left residual laxity for both anterior translation and internal rotation. Anterior translation was restored for all combinations of ACL and anterolateral procedures. The combined ACL reconstruction and ALL procedure restored intact knee kinematics when the graft was fixed in full extension, but when the graft was fixed in 30 degrees and 60 degrees , the combined procedure left residual laxity in internal rotation ( P = .043). The combined ACL reconstruction and modified Lemaire procedure restored internal rotation regardless of knee flexion angle at graft fixation. When the combined ACL reconstruction and lateral procedure states were compared with the ACL-only reconstructed state, a significant reduction in internal rotation laxity was seen with the modified Lemaire tenodesis but not with the ALL procedure. CONCLUSION: In a knee with combined ACL and anterolateral ligament injuries, the modified Lemaire tenodesis combined with ACL reconstruction restored normal laxities at all angles of flexion for graft fixation (0 degrees , 30 degrees , or 60 degrees ), with 20 N of tension. The combined ACL and ALL procedure restored intact knee kinematics when tensioned in full extension. CLINICAL RELEVANCE: In combined anterolateral procedure plus intra-articular ACL reconstruction, the knee flexion angle is important when fixing the graft. A modified Lemaire procedure restored intact knee laxities when fixation was performed at 0 degrees , 30 degrees , or 60 degrees of flexion. The ALL procedure restored normal laxities only when fixation occurred in full extension. PMID- 28898105 TI - Gait Characteristics Associated With a Greater Increase in Medial Knee Cartilage T1rho and T2 Relaxation Times in Patients Undergoing Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Osteoarthritis of the medial tibiofemoral joint (MTFJ) is prevalent among patients undergoing anterior cruciate ligament reconstruction (ACLR). Magnetic resonance T1rho and T2 relaxation times provide noninvasive methods to quantify early cartilage degeneration. Altered sagittal-plane gait biomechanics have been observed after ACLR, but their associations with longitudinal changes in MTFJ cartilage T1rho and T2 remain unclear. Hypothesis/Purpose: To examine whether the peak knee flexion moment (KFM), knee flexion angle (KFA), and vertical ground-reaction force (vGRF) during gait are associated with prospective changes in medial tibiofemoral cartilage T1rho and T2 in ACL-reconstructed knees and to compare these gait characteristics between patients undergoing ACLR and healthy control participants. We hypothesized that a higher KFM, KFA, and vGRF would be associated with greater increases in cartilage relaxation times and that patients undergoing ACLR would demonstrate altered gait characteristics compared with healthy controls. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty three patients undergoing ACLR underwent gait analysis before and 6 months and 1 year after ACLR and knee magnetic resonance imaging (MRI) before and 6 months, 1 year, and 2 years after ACLR. Twelve healthy controls underwent knee MRI and gait analysis at baseline and 1 year. Cartilage T1rho and T2 were calculated for the medial tibia and medial femoral condyle. Linear regressions were used to evaluate associations between gait characteristics and changes in cartilage relaxation times from before ACLR to follow-up time points. Independent t tests were used to compare differences in gait between patients undergoing ACLR and control participants. RESULTS: A higher KFM and KFA before ACLR were related to greater increases in medial femoral condyle T1rho and T2 at 6 months after ACLR. Similarly, a higher KFM, KFA, and vGRF at 6 months were associated with greater increases in medial tibia and medial femoral condyle T1rho and T2 at 1 and 2 years after ACLR. Gait characteristics at 1 year were not associated with changes in cartilage relaxation times at 2 years after ACLR. Compared with healthy controls, patients undergoing ACLR demonstrated a lower KFM at 6 months after ACLR. CONCLUSION/CLINICAL RELEVANCE: The findings of this study revealed that a higher KFM, KFA, and vGRF during gait, especially at 6 months after ACLR, were associated with greater deterioration of MTFJ cartilage health at later time points. PMID- 28898108 TI - The safety of simultaneous cranioplasty and shunt implantation. AB - BACKGROUND: A large cranial defect combined with hydrocephalus is a frequent sequela of decompressive craniectomy (DC) performed to treat malignant intracranial hypertension. Currently, many neurosurgeons perform simultaneous cranioplasty and shunt implantation on such patients, but the safety of this combined procedure remains controversial. METHODS: We retrospectively evaluated 58 patients treated via cranioplasty and shunt implantation after DC. Twenty patients underwent simultaneous procedures (simultaneous operation group) and 38 underwent staged procedures (staged operation group). We collected and analysed demographic data, information on disease histories, and clinical findings. RESULTS: The overall complication rate was 19%. The two groups did not significantly differ regarding the all-complication (30% vs. 13%), bleeding complication (0% vs. 5%), or treatment failure (15% vs. 3%) rates. However, the rate of surgical site infection/incision healing problems (25% vs. 3%) and the re operation rate (20% vs. 3%) were significantly higher in the simultaneous operation group. CONCLUSION: Patients undergoing simultaneous cranioplasty/shunt implantation may be at a higher risk of infectious complications than those undergoing staged operations. PMID- 28898109 TI - Factors associated with Type II trauma in occupational groups working with traumatised children: a systematic review. AB - BACKGROUND: There is evidence that "Type II trauma" (TTT) - repeated exposure to traumatic events - can lead to the development of post-traumatic stress disorder (PTSD). TTT frequently occurs in occupational groups working with children who are themselves victims of trauma. AIM: To conduct a systematic review identifying risk factors for/protective factors against TTT-associated mental ill-health in employees working with traumatised children and explore how this type of work impacts upon social functioning. METHOD: Databases were searched for relevant studies and supplemented by hand searches. RESULTS: 836 papers were found and 13 were included in the review. The key themes identified were coping mechanisms; social support; personality; demographics; occupational support; work-related stressors; traumatic exposure; organisational satisfaction; training/experience and impact on life. CONCLUSION: Unhelpful coping strategies (e.g. denial) appeared to increase the risk of TTT. Training and strong support may be protective and work-related stressors (e.g. excessive workload) appeared detrimental. Despite some positive impacts of the work (e.g. becoming more appreciative of life) many negative impacts were identified, demonstrating the importance of minimising risk factors and maximising protective factors for staff at risk of TTT. PMID- 28898110 TI - The perception of Malaysian pedestrians toward the use of footbridges. AB - OBJECTIVE: The footbridge is a vital structure in the road network and a cornerstone among crossing facilities. Yet, it suffers from low usage by pedestrians as they try to cross the street on the level. This study aims to analyze the perceptions of Malaysian pedestrians toward the use of footbridges with the consideration of different factors. METHOD: The study was carried out by collecting data from field observation and questionnaire distribution on the street among the public. The data were statistically analyzed by applying multiple linear regression models and a series of chi-square tests. RESULTS: The study found that the most influential factor cited by pedestrians in decision making regarding using a footbridge is the existence of an escalator. Being in a hurry and the fear of heights were significantly associated with choosing not to use a footbridge. Zebra crossing was chosen as the most favorable type of crossing facility by the majority of respondents. In addition, installation of a fence and barriers was proposed as an effective procedure to prevent jaywalking. To construct new and efficient footbridges in the future, the study suggests consideration of traffic volume, posted speed limit, and the number of lanes, because these are the most influential factors to predict the usage rate. CONCLUSIONS: The study encourages decision makers and stakeholders to consider providing escalators for new footbridges to enhance the safety of pedestrians. PMID- 28898111 TI - Complications of Scleral-Fixated Intraocular Lenses. AB - INTRODUCTION: Understanding the evolution of complications after scleral-fixated lens placement demonstrates advantageous surgical techniques and suitable candidates. MATERIALS/METHODS: A literature search in PubMed for several terms, including "scleral intraocular lens complication," yielded 17 relevant articles. RESULTS: Reviewing complication trends over time, lens tilt and suture erosion have decreased, cystoid macular edema has increased, and retinal detachment has remained the same after scleral-fixated lens placement. The successful reduction in complications are attributed to several alterations in technique, including positioning sclerotomy sites 180 degrees apart and using scleral flaps or pockets to bury sutures. Possible reduction in retinal risks have been proposed by performing an anterior vitrectomy prior to lens placement in certain settings. DISCUSSION: Complications after scleral-fixated lens placement should assist patient selection. Elderly patients with a history of hypertension should be counseled regarding risk of suprachoroidal hemorrhage, while young patients and postocular trauma patients should be considered for concurrent anterior vitrectomy. PMID- 28898112 TI - Functional Odontoblastic-Like Cells Derived from Human iPSCs. AB - The induced pluripotent stem cells (iPSCs) have an intrinsic capability for indefinite self-renewal and large-scale expansion and can differentiate into all types of cells. Here, we tested the potential of iPSCs from dental pulp stem cells (DPSCs) to differentiate into functional odontoblasts. DPSCs were reprogrammed into iPSCs via electroporation of reprogramming factors OCT-4, SOX2, KLF4, LIN28, and L-MYC. The iPSCs presented overexpression of the reprogramming genes and high protein expressions of alkaline phosphatase, OCT4, and TRA-1-60 in vitro and generated tissues from 3 germ layers in vivo. Dentin discs with poly-L lactic acid scaffolds containing iPSCs were implanted subcutaneously into immunodeficient mice. After 28 d from implantation, the iPSCs generated a pulp like tissue with the presence of tubular dentin in vivo. The differentiation potential after long-term expansion was assessed in vitro. iPSCs and DPSCs of passages 4 and 14 were treated with either odontogenic medium or extract of bioactive cement for 28 d. Regardless of the passage tested, iPSCs expressed putative markers of odontoblastic differentiation and kept the same mineralization potential, while DPSC P14 failed to do the same. Analysis of these data collectively demonstrates that human iPSCs can be a source to derive human odontoblasts for dental pulp research and test bioactivity of materials. PMID- 28898113 TI - Interferon Regulatory Factor 6 Is Necessary for Salivary Glands and Pancreas Development. AB - Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis. This study aims to identify the role of IRF6 in development of exocrine glands, specifically the major salivary glands. Our transgenic mouse model that expresses LacZ reporter under the control of the human IRF6 enhancer element showed high expression of IRF6 in major and minor salivary glands and ducts. Immunostaining data also confirmed the endogenous expression of IRF6 in the developing ductal, serous, and mucous acinar cells of salivary glands. As such, we hypothesized that Irf6 is important for proper development of salivary glands and potentially other exocrine glands. Loss of Irf6 in mice causes an increase in the proliferation level of salivary cells, disorganized branching morphogenesis, and a lack of differentiated mucous acinar cells in submandibular and sublingual glands. Expression and localization of the acinar differentiation marker MIST1 were altered in Irf6-null salivary gland and pancreas. The RNA-Seq analysis demonstrated that 168 genes are differentially expressed and confer functions associated with transmembrane transporter activity, spliceosome, and transcriptional regulation. Furthermore, expression of genes involved in the EGF pathway-that is, Ereg, Ltbp4, Matn1, Matn3, and Tpo-was decreased at embryonic day 14.5, while levels of apoptotic proteins were elevated at postnatal day 0. In conclusion, our data report a novel role of Irf6 in exocrine gland development and support a rationale for performing exocrine functional tests for patients with IRF6-damaging mutations. PMID- 28898114 TI - Diagnostic challenges of kidney diseases in HIV-infected patients. AB - INTRODUCTION: Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH. Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on PubMed to identify reviews and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the following key words: 'HIV AND kidney', 'HIV AND Kidney biomarkers', 'CKD AND Kidney biomarkers'. Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio (uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack sensitivity. Different biomarkers of kidney diseases like N acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1 microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviral-induced tubulopathy, or predict cardiovascular events. More studies are needed to validate the routine use of these types of biomarkers. PMID- 28898117 TI - What Is a Joint Torque for Joints Spanned by Multiarticular Muscles? PMID- 28898115 TI - Mannose-binding lectin deficiency and miscarriages in rheumatoid arthritis. AB - OBJECTIVE: To investigate the association between mannose-binding lectin (MBL) serum level and MBL2 polymorphisms, and the frequency of spontaneous miscarriages in rheumatoid arthritis (RA) patients. METHODS: One hundred seventy seven women (mean age 50 years) with RA from Southern Brazil were studied and 4.5% had a history of abortion (8/177). The MBL levels were determined by ELISA. MBL2 polymorphisms in the promoter (-550H/L, -221X/Y), 5' untranslated region (4 P/Q) and exon 1 (p.Gly54Asp: B allele, p.Arg52Cys: D allele and p.Gly57Glu: C allele; collectively labelled O) were genotyped by sequencing. RESULTS: Mannose-binding lectin levels of RA patients ranged from <=100 ng/mL to 6640 ng/mL (median 541.5 ng/mL). There was a significant difference in MBL median levels (100 ng/mL vs. 625 ng/mL, respectively, p = .001) and frequency of MBL deficiency (75.0% vs. 24.1%, p = .007, OR = 10.3, 95%CI = 1.9-55.4), in patients with a history of miscarriage vs those without it. Patients with RA and miscarriage had more frequently haplotypes related with low MBL levels (p = .007, OR = 10.5, 95%CI = 1.3-84) than high producers. Moreover, LYPB haplotype and O allele were significantly associated with the occurrence of miscarriage (p = .001, OR = 9.7, 95%CI = 2.4-39.1 and p = .009, OR = 5.9, 95%CI = 1.4-23.4, respectively). CONCLUSIONS: The results suggest that MBL deficiency and the presence of MBL2 gene polymorphisms that lead to MBL deficiency are risk factors for the occurrence of miscarriage in patients with RA. PMID- 28898118 TI - High Bar Release in Triple Somersault Dismounts. AB - The release from the high bar was analyzed for six performances of triple backward somersaults. All 6 gymnasts released the bar with their mass centers below the level of the bar. The mean horizontal velocity of the mass center away from the bar was 1.2 m . s-1. This horizontal velocity was partitioned into contributions from the tangential and radial motions of the mass center relative to the bar and the movement of the bar relative to its neutral position. It was found that the tangential motion was the major contributor although the radial motion produced substantial positive contributions and the bar movement gave large negative contributions in two cases. PMID- 28898116 TI - Adaptive response criteria in road hazard detection among older drivers. AB - OBJECTIVES: The majority of existing investigations on attention, aging, and driving have focused on the negative impacts of age-related declines in attention on hazard detection and driver performance. However, driving skills and behavioral compensation may accommodate for the negative effects that age-related attentional decline places on driving performance. In this study, we examined an important question that had been largely neglected in the literature linking attention, aging, and driving: can top-down factors such as behavioral compensation, specifically adaptive response criteria, accommodate the negative impacts from age-related attention declines on hazard detection during driving? METHODS: In the experiment, we used the Drive Aware Task, a task combining the driving context with well-controlled laboratory procedures measuring attention. We compared younger (n = 16, age 21-30) and older (n = 21, age 65-79) drivers on their attentional processing of hazards in driving scenes, indexed by percentage of correct responses and reaction time of hazard detection, as well as sensitivity and response criteria using signal detection analysis. RESULTS: Older drivers, in general, were less accurate and slower on the task than younger drivers. However, results from this experiment revealed that older, but not younger, drivers adapted their response criteria when the traffic condition changed in the driving scenes. When there was more traffic in the driving scene, older drivers became more liberal in their responses, meaning that they were more likely to report that a driving hazard was detected. CONCLUSIONS: Older drivers adopt compensatory strategies for hazard detection during driving. Our findings showed that, in the driving context, even at an older age our attentional functions are still adaptive according to environmental conditions. This leads to considerations on potential training methods to promote adaptive strategies that may help older drivers maintain performance in road hazard detection. PMID- 28898119 TI - A New Method of Measuring 3-D Ground Reaction Forces under the Ski during Skiing on Snow. AB - A new method was developed for measuring the distribution of real time ground reaction forces under the snow ski. A platform composed of 20 separate beams was buried in snow under the ski track. Vertical, cross horizontal, and longitudinal horizontal force components were measured with strain gauge bridges separately on each beam, and the results were recorded with a data logger at 90 Hz. The test results for two types of skating skis are described. Anomalous behavior was observed in horizontal force components, where negative force values were recorded on some sections of the ski at the end of the initial kick phase. This suggests that some parts of the ski edge pushed in the opposite direction from the kicking force. This is interpreted to be due to a sharp bending along the bottom edge of the ski. It is concluded that the method could be used to measure 3-D dynamic forces under snow. PMID- 28898120 TI - Body Segment Moments of Inertia of the Elderly. AB - The segment principal moments of inertia of a sample of 7 elderly males and 12 elderly females were estimated using a model based on stacked elliptical cylinders at 2-cm intervals. Apart from the thigh, all male parameters were larger than female parameters. The largest differences were for the lower trunk and hand and for the forearm. The inertia parameters of the thigh for the males were about 12% smaller than the females. Nonlinear estimations of segment principal moments were then determined. The effect of the differences was tested by cross validating cadaver results against the elliptical model results. The regressions were then cross validated using an independent sample of 6 subjects. The standard errors of fit given as a percentage of the mean, Sf, were smaller than the cross validation results for the cadaver regressions and the differences were attributed to differences between cadavers and living subjects. PMID- 28898121 TI - Anterior Cruciate Ligament Forces in Alpine Skiing. AB - The purpose of this study was to estimate cruciate ligament forces in Alpine skiing during a movement that has been associated with anterior cruciate ligament (ACL) tears. Resultant knee joint forces and moments were obtained from two skiers during a World Cup Downhill race using an inverse dynamics approach and a 2-D bilaterally symmetric system model. It was found that ACL forces were typically small for both skiers throughout the movement analyzed because quadriceps forces prevented anterior displacement of the tibia relative to the femur at the knee joint angles observed. However, for about 10 ms, loading conditions in the knee joint of Subject 2 (who displayed poor form) were such that large ACL forces may have been present. These particular loading conditions were never observed in Subject 1, who displayed good form. Since neither of the skiers was injured, it is not possible to draw firm conclusions about isolated ACL tears in Alpine skiing from the data at hand. PMID- 28898124 TI - Editorial. PMID- 28898122 TI - Use of Ground Reaction Force Parameters in Predicting Peak Tibial Accelerations in Running. AB - Ground reaction force data and tibial accelerations from a skin-mounted transducer were collected during rearfoot running at 3.3 m/s across a force platform. Five repetitive trials from 27 subjects in each of 19 different footwear conditions were evaluated. Ground reaction force as well as tibial acceleration parameters were found to be useful for the evaluation of the cushioning properties of different athletic footwear. The good prediction of tibial accelerations by the maximum vertical force rate toward the initial force peak (r2 = .95) suggests that the use of a force platform is sufficient for the estimation of shock-absorbing properties of sport shoes. If an even higher prediction accuracy is required a regression equation with two variables (maximum force rate, median power frequency) may be used (r2 = .97). To evaluate the influence of footwear on the shock traveling through the body, a good prediction of peak tibial accelerations can be achieved from force platform measurements. PMID- 28898125 TI - JOURNAL CLUB: Diagnostic Utility of MRI After Negative or Inconclusive Mammography for the Evaluation of Pathologic Nipple Discharge. AB - OBJECTIVE: The purpose of this study is to determine the diagnostic utility of MRI after negative or inconclusive mammography for the evaluation of pathologic nipple discharge. MATERIALS AND METHODS: We conducted a retrospective review of breast MRI examinations from January 1, 2006, through December 31, 2015, that were performed after negative or inconclusive mammography for the evaluation of nipple discharge. Clinical notes, imaging findings, and pathology outcomes were reviewed. RESULTS: One hundred eighteen women (mean age, 49 years; range, 23-82 years) underwent MRI for evaluation of nipple discharge, 105 (89.0%) of whom had surgical excision or at least 2-year imaging follow-up. A total of six patients (6/105; 5.7%) were diagnosed with malignancy (ductal carcinoma in situ [DCIS] or invasive malignancy). Of 27 patients with positive MRI findings (final assessment of BI-RADS category 4), three (11.1%) were diagnosed with malignancy: DCIS grade 2-3, DCIS with focus of microinvasive ductal carcinoma, and invasive papillary carcinoma. An additional three patients (without suspicious findings at MRI) were diagnosed with malignancy at surgical excision, all of which were grade 1 DCIS. For patients with negative MRI findings (BI-RADS category 1, 2, or 3), the negative predictive value of MRI for malignancy was 96.2% (75/78). CONCLUSION: In women with nipple discharge and negative or inconclusive mammography findings, the risk of malignancy is low, at 5.7%. With negative MRI findings (BI-RADS category 1, 2, or 3), the risk of malignancy is less than 4%. Surveillance rather than surgical excision may be a reasonable option for patients without suspicious findings at MRI. PMID- 28898126 TI - Computerized Bone Age Estimation Using Deep Learning Based Program: Evaluation of the Accuracy and Efficiency. AB - OBJECTIVE: The purpose of this study is to evaluate the accuracy and efficiency of a new automatic software system for bone age assessment and to validate its feasibility in clinical practice. MATERIALS AND METHODS: A Greulich-Pyle method based deep-learning technique was used to develop the automatic software system for bone age determination. Using this software, bone age was estimated from left hand radiographs of 200 patients (3-17 years old) using first-rank bone age (software only), computer-assisted bone age (two radiologists with software assistance), and Greulich-Pyle atlas-assisted bone age (two radiologists with Greulich-Pyle atlas assistance only). The reference bone age was determined by the consensus of two experienced radiologists. RESULTS: First-rank bone ages determined by the automatic software system showed a 69.5% concordance rate and significant correlations with the reference bone age (r = 0.992; p < 0.001). Concordance rates increased with the use of the automatic software system for both reviewer 1 (63.0% for Greulich-Pyle atlas-assisted bone age vs 72.5% for computer-assisted bone age) and reviewer 2 (49.5% for Greulich-Pyle atlas assisted bone age vs 57.5% for computer-assisted bone age). Reading times were reduced by 18.0% and 40.0% for reviewers 1 and 2, respectively. CONCLUSION: Automatic software system showed reliably accurate bone age estimations and appeared to enhance efficiency by reducing reading times without compromising the diagnostic accuracy. PMID- 28898127 TI - Acute Pulmonary Embolism: Retrospective Cohort Study of the Predictive Value of Perfusion Defect Volume Measured With Dual-Energy CT. AB - OBJECTIVE: The purposes of this study were to investigate dual-energy CT findings predictive of clinical outcome and to determine the incremental risk stratification benefit of dual-energy CT findings compared with CT ventricular diameter ratio in patients with acute pulmonary embolism. MATERIALS AND METHODS: A retrospective evaluation was conducted of the cases of 172 patients with acute pulmonary embolism who underwent dual-energy CT. Ventricular diameter ratio and relative perfusion defect volume were measured. The primary endpoints were death within 30 days and pulmonary embolism-related death. RESULTS: A ventricular diameter ratio of 1 or greater was associated with increased risk of death within 30 days (hazard ratio, 3.822; p = 0.002) and pulmonary embolism-related death (hazard ratio, 18.051; p < 0.001). Relative perfusion defect volume was also associated with increased risk of death of any cause within 30 days (hazard ratio, 1.044; p = 0.014) and pulmonary embolism-related death (hazard ratio, 1.046; p = 0.017). However, the addition of relative perfusion defect volume to ventricular diameter ratio had no added benefit for prediction of death of any cause within 30 days (concordance statistic, 0.833 vs 0.815; p = 0.187) or pulmonary embolism-related death (concordance statistic, 0.873 vs 0.874; p = 0.866). CONCLUSION: Compared with ventricular diameter ratio alone, lung perfusion defect volume had no statistically significant added benefit for prediction of death of any cause within 30 days or of pulmonary embolism-related death among patients with acute PE. PMID- 28898128 TI - Technologist-Directed Repeat Musculoskeletal and Chest Radiographs: How Often Do They Impact Diagnosis? AB - OBJECTIVE: Radiologic technologists may repeat images within a radiographic examination because of perceived suboptimal image quality, excluding these original images from submission to a PACS. This study assesses the appropriateness of technologists' decisions to repeat musculoskeletal and chest radiographs as well as the utility of repeat radiographs in addressing examinations' clinical indication. MATERIALS AND METHODS: We included 95 musculoskeletal and 87 chest radiographic examinations in which the technologist repeated one or more images because of perceived image quality issues, rejecting original images from PACS submission. Rejected images were retrieved from the radiograph unit and uploaded for viewing on a dedicated server. Musculoskeletal and chest radiologists reviewed rejected and repeat images in their timed sequence, in addition to the studies' remaining images. Radiologists answered questions regarding the added value of repeat images. RESULTS: The reviewing radiologist agreed with the reason for rejection for 64.2% of musculoskeletal and 60.9% of chest radiographs. For 77.9% and 93.1% of rejected radiographs, the clinical inquiry could have been satisfied without repeating the image. For 75.8% and 64.4%, the repeated images showed improved image quality. Only 28.4% and 3.4% of repeated images were considered to provide additional information that was helpful in addressing the clinical question. CONCLUSION: Most repeated radiographs (chest more so than musculoskeletal radiographs) did not add significant clinical information or alter diagnosis, although they did increase radiation exposure. The decision to repeat images should be made after viewing the questionable image in context with all images in a study and might best be made by a radiologist rather than the performing technologist. PMID- 28898129 TI - Transatlantic Comparison of CT Radiation Doses in the Era of Radiation Dose Tracking Software. AB - OBJECTIVE: The purpose of this study is to compare diagnostic reference levels from a local European CT dose registry, using radiation-tracking software from a large patient sample, with preexisting European and North American diagnostic reference levels. MATERIALS AND METHODS: Data (n = 43,761 CT scans obtained over the course of 2 years) for the European local CT dose registry were obtained from eight CT scanners at six institutions. Means, medians, and interquartile ranges of volumetric CT dose index (CTDIvol), dose-length product (DLP), size-specific dose estimate, and effective dose values for CT examinations of the head, paranasal sinuses, thorax, pulmonary angiogram, abdomen-pelvis, renal-colic, thorax-abdomen-pelvis, and thoracoabdominal angiogram were obtained using radiation-tracking software. Metrics from this registry were compared with diagnostic reference levels from Canada and California (published in 2015), the American College of Radiology (ACR) dose index registry (2015), and national diagnostic reference levels from local CT dose registries in Switzerland (2010), the United Kingdom (2011), and Portugal (2015). RESULTS: Our local registry had a lower 75th percentile CTDIvol for all protocols than did the individual internationally sourced data. Compared with our study, the ACR dose index registry had higher 75th percentile CTDIvol values by 55% for head, 240% for thorax, 28% for abdomen-pelvis, 42% for thorax-abdomen-pelvis, 128% for pulmonary angiogram, 138% for renal-colic, and 58% for paranasal sinus studies. CONCLUSION: Our local registry had lower diagnostic reference level values than did existing European and North American diagnostic reference levels. Automated radiation tracking software could be used to establish and update existing diagnostic reference levels because they are capable of analyzing large datasets meaningfully. PMID- 28898130 TI - Imaging of Children With Nontraumatic Headaches. AB - OBJECTIVE: Headache in children is a common symptom and often is worrisome for clinicians and parents because of the breadth of possible underlying significant abnormalities, including meningitis, brain neoplasms, and intracranial hemorrhage. For this reason, many children with headaches undergo neuroimaging. Most neuroimaging studies performed of children with headaches have normal findings but may lead to significant downstream effects, including unnecessary exposure to ionizing radiation or sedation, as well as unnecessary cost to the health care system. In this article, we review the current evidence and discuss the role of neuroimaging in the diagnosis and management of pediatric headaches, with a special focus on tools that may aid in increasing the rate of positive findings, such as classification systems, algorithms, and red flag criteria. CONCLUSION: Many tools exist that can help in improving the appropriateness of neuroimaging in pediatric headache. The main issues that remain to be addressed include scientific proof of safety and validity of these tools and clarity regarding the risks, benefits, and cost-effectiveness of CT versus MRI in various clinical settings and scenarios. PMID- 28898131 TI - Lung Cancer Risk Associated With New Solid Nodules in the National Lung Screening Trial. AB - OBJECTIVE: As low-dose CT (LDCT) lung cancer screening moves into routine clinical practice, evaluation of nodules identified as new becomes critical. We examine the frequency and clinical outcomes of new lung nodules reported at the two postbaseline annual screening examinations (hereafter referred to as postbaseline time 1 [T1] and time 2 [T2]), compared with those detected at baseline in the National Lung Screening Trial. MATERIALS AND METHODS: Radiologists classified nodules detected at T1 and T2 as new or preexisting on the basis of comparison with findings from prior LDCT screening examinations. Subjects were tracked for lung cancer incidence and mortality. We examined the incidence of new nodules and their associated lung cancer risk by nodule size (i.e., mean diameter). RESULTS: A total of 25,002 subjects underwent the baseline LDCT screening examination and either a T1 or T2 LDCT screen. At both T1 and T2, 2.6% of subjects had new solid nodules. Of the new solid nodules, 53.0% were < 6 mm, 29.5% were 6 to < 10 mm, and 17.1% were >= 10 mm. Lung cancer risk (defined as diagnosis within 2 years of baseline) increased from 1.1% for nodules < 4 mm to 24.0% for those >= 20 mm. Compared with solid nodules detected at baseline, the cancer risk was higher for new solid nodules that were 4 to < 6 mm (p < 0.001) and 6 to < 8 mm (p < 0.001) but lower for new nodules >= 20 mm (p = 0.03). Cancers associated with new nodules had significantly poorer survival than did those associated with baseline nodules and were significantly less likely to be adenocarcinoma. CONCLUSION: The incidence of new nodules was 2-3% annually, with the cancer risk increasing by nodule size. New nodules may convey differential lung cancer risks by size, compared with baseline nodules. PMID- 28898133 TI - Differential impact of treadmill training on stroke-induced neurological disorders. AB - OBJECTIVE: Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the effects of continuous endurance training (CET) and high-intensity interval training (HIT) on stroke-associated anxiety, locomotion, neurological assessments and P70S6 Kinase (P70S6K) activation as well. To do this, rats were trained according to HIT and CET protocols for 2 months prior to being subject to middle cerebral artery occlusion surgery. METHODS: Twenty-four hours later behavioural examination was performed by elevated plus maze (EPM) testing, open field and neurological scoring followed by cortical and hippocampal P70S6Ks immunoblotting. RESULTS: According to the obtained data pre-ischaemic HIT and CET similarly improved neurological performance, anxiety levels and locomotion in EPM and open field tests following ischaemic stroke while there was a remarkable rise in hippocampal and cortical P70S6K activation in the HIT group compared to the CET counterparts. CONCLUSION: Behavioral and molecular data suggest that interval training is more beneficial rather than CET, but the distinct mechanisms of CET and HIT on memory are still topics to be discovered. PMID- 28898132 TI - Staged residential post-acute rehabilitation for adults following acquired brain injury: A comparison of functional gains rated on the UK Functional Assessment Measure (UK FIM+FAM) and the Mayo-Portland Adaptability Inventory (MPAI-4). AB - OBJECTIVE: To compare the UK Functional Assessment Measure (UK FIM+FAM) and Mayo Portland Adaptability Inventory (MPAI-4) as measures of functional change in patients with brain injury receiving a staged residential post-acute community based rehabilitation programme. RESEARCH DESIGN: Longitudinal cohort study of consecutive admissions (N = 42) over 3 years. METHODS: Patients were assessed at admission and discharge/annual review. We examined groups according to stage of independence on admission: Maximum support (stages 1 and 2: N = 17); moderate/maximum self-care/household support (stage 3: N = 15); minimal self-care and moderate household/community support (stages 4-6: N = 10). RESULTS: Median (IQR) age: 50 (37-56) years. Male:female ratio: (71%:29%). Aetiology: stroke (50%), traumatic (36%) and other brain injuries (14%). Both tools demonstrated significant gains in overall scores and all subscales (p < 0.01). However, the UK FIM+FAM provides more detailed evaluation of personal activities of daily living and mobility, which were most relevant in clients admitted in graduation stages 1 and 2 of the programme, whereas the MPAI-4 was more sensitive to changes in adjustment and participation for clients admitted in the later stages (4-6). CONCLUSIONS: The UK FIM+FAM and MPAI-4 provide complementary evaluation across functional tasks ranging from self-care to participation. This study supports their use for longitudinal outcome evaluation in community residential rehabilitation services that take patients at different stages of recovery. PMID- 28898134 TI - The Management of Complex Pain in Children Referred to a Pain Clinic at a Tertiary Children's Hospital in Australia. AB - Synopsis One of the key aspects of good health care for children and young people is the prevention and management of pain. The experience of persistent pain in children and adolescents not only has a major impact on physical, emotional, social, and developmental well-being, but also impacts the broader world, which includes family, school, and social networks. The multidisciplinary pediatric pain clinic adopts a holistic approach to care through a biopsychosocial model. One outcome of an initial pediatric pain clinic review is the creation of a pain management plan that addresses the pharmacological, physical, psychological, and other domains of care. Pediatric pain clinics are improving access by embracing technology through tele-health and internet-based treatment options. Outcome measurement will guide the development of models of care in the future. J Orthop Sports Phys Ther 2017;47(10):806-813. Epub 12 Sep 2017. doi:10.2519/jospt.2017.7355. PMID- 28898135 TI - Understanding Adolescent Low Back Pain From a Multidimensional Perspective: Implications for Management. AB - Synopsis Low back pain (LBP) is the leading cause of disability worldwide. It often begins in adolescence, setting a course for later in life. We have tracked the course of LBP in the Raine Study cohort from the age of 14 years into early adulthood. Our work has found that LBP is already prevalent in individuals at 14 years of age and increases throughout adolescence and into early adulthood. It is often comorbid with other musculoskeletal pain. For some adolescents, LBP has little impact; for others, its impact includes care seeking, taking medication, taking time off from school and work, as well as modifying physical and functional activity. Of concern is the increasing prevalence of LBP with impact across adolescence, reaching adult rates by 22 years of age. The predictors of disabling LBP in adolescence are multidimensional. They include female sex, negative back pain beliefs, poor mental health status, somatic complaints, involvement in sports, and altered stress responses. Genetics also plays a role. Ironically, the factors that we have historically thought to be important predictors of LBP, such as "poor" spinal posture, scoliosis, carrying school bags, joint hypermobility, and poor back muscle endurance, are not strong predictors. This challenges our clinical beliefs and highlights that adolescent LBP needs a flexible and targeted multidimensional approach to assessment and management. In most cases, we recommend a cognitive functional approach that challenges negative LBP beliefs, educates adolescents regarding factors associated with their LBP, restores functional capacity where it is impaired, and encourages healthy lifestyle habits. J Orthop Sports Phys Ther 2017;47(10):741 751. Epub 12 Sep 2017. doi:10.2519/jospt.2017.7376. PMID- 28898137 TI - Pain-Related Fear and Its Disabling Impact in Hypermobile Adolescents With Chronic Musculoskeletal Pain. AB - Study Design Cross-sectional study. Background Chronic musculoskeletal pain (CMP) has a negative impact on physical functioning. During adolescence, joint hypermobility is a potential risk factor for developing CMP, and pain-related fear contributes to the persistence of CMP. Whether pain-related fear and hypermobility are related, and even reinforce each other, resulting in a stronger association with perceived level of disability, is still unknown. Objectives To evaluate whether pain-related fear has a stronger association with disability in hypermobile compared to nonhypermobile adolescents with CMP. Methods The study included 116 adolescents with CMP. The presence of hypermobility was assessed using the Beighton score. Measures of pain intensity, age, sex, and pain-related fear were collected and included in the multivariable model. Hierarchical regression analysis, with disability as the dependent variable, was used to examine the interaction between hypermobility and pain-related fear. Results Hypermobile adolescents with CMP do not have more pain-related fear compared to nonhypermobile adolescents with CMP. There was no interaction effect between hypermobility and pain-related fear in explaining disability (beta = .20, P = .42). Similarly, perceived harmfulness of balance-related activities was not more strongly associated with disability in hypermobile adolescents with CMP. Conclusion The association of pain-related fear with the perceived level of disability is not more pronounced in hypermobile compared to nonhypermobile adolescents with CMP. J Orthop Sports Phys Ther 2017;47(10):775-781. Epub 12 Sep 2017. doi:10.2519/jospt.2017.7282. PMID- 28898136 TI - Accelerometer-Determined Physical Activity and Clinical Low Back Pain Measures in Adolescents With Chronic or Subacute Recurrent Low Back Pain. AB - Study Design Cross-sectional. Background Although low back pain (LBP) occurs commonly in adolescence, little is known about the relationship between objectively measured physical activity and chronic LBP. Objectives To assess the relationship between an objective physical activity measure (accelerometer) and standard clinical measures (pain intensity, disability, and quality of life) in a sample of adolescents with recurrent or chronic LBP. Methods The study included a subsample of 143 adolescents, 12 to 18 years of age, from a randomized clinical trial. Pearson correlations (r) and bivariate linear regression were used to assess the relationship between baseline measures of sedentary, light, and moderate-to-vigorous physical activity using accelerometers and clinical measures of LBP (pain intensity, disability, and quality of life). Results Participants spent an average of 610.5 minutes in sedentary activity, 97.6 minutes in light physical activity, and 35.6 minutes in moderate-to-vigorous physical activity per day. Physical activity was very weakly associated with clinical measures of LBP (r<0.13). None of the assessed correlations were statistically significant, and bivariate regression models showed that physical activity measures explained very little of the variability for clinical measures of LBP (R2<0.02). Conclusion We found no important relationship between objectively measured physical activity and self-reported LBP intensity, disability, or quality of life in adolescents with recurrent or chronic LBP. The parent randomized clinical trial was registered at ClinicalTrials.gov (NCT01096628). J Orthop Sports Phys Ther 2017;47(10):769-774. Epub 12 Sep 2017. doi:10.2519/jospt.2017.7345. PMID- 28898139 TI - Point-of-care ultrasound: its growing application in hospital medicine. AB - Point-of-care ultrasound is emerging as an important adjunct to the clinical examination. Ultrasonography has long been seen as a modality for experts but this is changing and it is hoped that, with appropriate training, point-of-care ultrasound will become a modern-day diagnostic necessity. PMID- 28898138 TI - Redox-sensitive transcription factors play a significant role in the development of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease which is associated with significant morbidity. Redox sensitive transcription factors including NF kappaB, HIF, AP-1, and Nrf2 are intimately involved in the pathogenesis of RA. The treatment of this disease is limited by the elusive nature of the pathogenesis of RA. NF-kappaB is crucial for the maturation of immune cells as well as production of TNFalpha and MMPs, which escalate RA. HIF is essential for activation of inflammatory cells, angiogenesis and pannus formation in RA. AP-1 regulates cytokine and MMP production as well as synovial hyperplasia which are key processes in RA. Nrf2 is involved with chondrogenesis, osteoblastogenesis, prostaglandin secretion and ROS production in RA. Targeting two or more of these transcription factors may result in increased efficacy than either therapy in isolation. This review will highlight the control specific mediators on these transcription factors, the subsequent effect of these transcription factors once activated, and then mesh this with the pathogenesis of RA. The elucidation of key transcription factor regulation in the pathogenesis of RA may highlight the novel therapy interventions which may prove to have a greater efficacy than those therapies currently available. PMID- 28898140 TI - Pneumocephalus after endoscopic sinus surgery. PMID- 28898141 TI - Documentation standards and clinical coding. PMID- 28898142 TI - Constructive criticism of critical psychiatry. PMID- 28898143 TI - James Learmonth: distinguished academic surgeon who operated on King George VI. PMID- 28898144 TI - The changing face of an epidemic: healthy old age with HIV. AB - The demographics of the HIV epidemic in the UK have changed significantly. Owing to a steady rate of new diagnoses and improved survival, the population of individuals living with HIV continues to increase. HIV is now widely considered to be a chronic condition and HIV-positive individuals are expected to live into old age. Increasing rates of age-related comorbidities challenge HIV care providers to deliver durable viral suppression, ensure long-term adherence to antiretroviral treatment and promote wellbeing into old age. High rates of mental health disorders and social stigma continue to have a negative impact on the quality of life of people living with HIV. Models of care must adapt to this evolving epidemic. PMID- 28898145 TI - Where is the optimum placement of an interscalene brachial plexus nerve block? PMID- 28898147 TI - How to improve psychiatric services: a perspective from critical psychiatry. AB - Concern has been expressed from both within and outwith psychiatry about the relative lack of improvement of mental health services. Critical psychiatry is an emerging school of thought, mainly the product of practicing clinicians, which could be useful in remedying this situation. This article outlines, for psychiatrists and doctors of other specialities, practices which could be improved, and the competencies required to achieve this, in terms of knowledge, skills and attitudes. PMID- 28898148 TI - IgG4-related disease as the differential diagnosis of hypophysitis. PMID- 28898149 TI - What do doctors and nurses think about development of clinical leadership? AB - Leadership development for health-care professionals is a priority within the NHS. Training is generally targeted at individual staff groups in isolation, even though contemporary leadership thinking recognizes the benefits of collaborative leadership between different clinical disciplines. Focussing on the attitudes and perceived training needs of undergraduate and qualified medical and nursing professionals, this article highlights the similarities and differences and will help to inform the design of existing and future leadership programmes. PMID- 28898150 TI - Fat 'fracture': a subcutaneous fat injury following a blunt trauma. PMID- 28898151 TI - Postoperative analgesia for shoulder surgery. AB - Both arthroscopic and open surgery of the shoulder are associated with significant postoperative pain. Use of opioids can result in adverse systemic effects, so a multi-modal analgesic approach and complementary analgesic techniques should be considered to minimize the postoperative opioid requirement. Single shot interscalene block provides effective pain control of early and limited duration which can be extended with a catheter. Continuous interscalene block should be considered for more invasive shoulder procedures. However, interscalene block is associated with hemidiaphragmatic paresis which is a substantial risk in patients with serious pulmonary pathology who could otherwise benefit most from a regional technique and the avoidance of opioids. Local infiltration analgesia, and suprascapular nerve block with or without axillary nerve block, have not been consistently shown to be superior to or as effective as interscalene block and there is insufficient evidence to support the use of supraclavicular block over interscalene block. PMID- 28898152 TI - Clinical News. PMID- 28898154 TI - Systemic anti-cancer therapy-induced diarrhoea. PMID- 28898153 TI - Diverticular disease of the terminal ileum mimics cancer. PMID- 28898155 TI - The value and challenges of collegiality in practice. PMID- 28898156 TI - Inspiring Change: a report on acute non-invasive ventilation. AB - The British Thoracic Society audit of non-invasive ventilation has shown that mortality rates are higher than expected and increasing. The National Confidential Enquiry into Patient Outcome and Death undertook a detailed analysis of data from 432 patients treated with acute non-invasive ventilation to identify how clinical aspects of non-invasive ventilation treatment could be improved. The study 'Inspiring Change' was published in July 2017. This review summarizes some of the important findings and associated recommendations that will improve treatment of patients and help to reduce mortality rates. PMID- 28898157 TI - Intravenous immunoglobulin as adjunctive treatment for Fournier's gangrene. PMID- 28898158 TI - Non-invasive ventilation: initiation and initial management. PMID- 28898159 TI - Clinical negligence costs: can we create a system that is reasonable and affordable? PMID- 28898160 TI - The role of opioid analgesia in treating chronic pain. PMID- 28898161 TI - Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma. AB - Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression-based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography-guided response assessment and the evolving cHL treatment landscape. PMID- 28898163 TI - Incorporating Interpersonal Skills into Otolaryngology Resident Selection and Training. AB - Increasing attention has been paid to the selection of otolaryngology residents, a highly competitive process but one with room for improvement. A recent commentary in this journal recommended that residency programs more thoroughly incorporate theory and evidence from personnel psychology (part of the broader field of organizational science) in the resident selection process. However, the focus of this recommendation was limited to applicants' cognitive abilities and independent work-oriented traits (eg, conscientiousness). We broaden this perspective to consider critical interpersonal skills and traits that enhance resident effectiveness in interdependent health care organizations and we expand beyond the emphasis on selection to consider how these skills can be honed during residency. We advocate for greater use of standardized team-based care simulations, which can aid in assessing and developing the key interpersonal leadership skills necessary for success as an otolaryngology resident. PMID- 28898162 TI - Modulation of protein A binding allows single-step purification of mouse bispecific antibodies that retain FcRn binding. AB - The increased number of bispecific antibodies (BsAb) under therapeutic development has resulted in a need for mouse surrogate BsAbs. Here, we describe a one-step method for generating highly pure mouse BsAbs suitable for in vitro and in vivo studies. We identify two mutations in the mouse IgG2a and IgG2b Fc region: one that eliminates protein A binding and one that enhances protein A binding by 8-fold. We show that BsAbs harboring these mutations can be purified from the residual parental monoclonal antibodies in one step using protein A affinity chromatography. The structural basis for the effects of these mutations was analyzed by X-ray crystallography. While the mutation that disrupted protein A binding also inhibited FcRn interaction, a bispecific mutant in which one subunit retained the ability to bind protein A could still interact with FcRn. Pharmacokinetic analysis of the serum half-lives of the mutants showed that the mutant BsAb had a serum half-life comparable to a wild-type Ab. The results describe a rapid method for generating panels of mouse BsAbs that could be used in mouse studies. PMID- 28898164 TI - Gossiping About Deviance: Evidence That Deviance Spurs the Gossip That Builds Bonds. AB - We propose that the gossip that is triggered when people witness behaviors that deviate from social norms builds social bonds. To test this possibility, we showed dyads of unacquainted students a short video of everyday campus life that either did or did not include an incident of negative or positive deviance (dropping or cleaning up litter). Study 1 showed that participants in the deviance conditions reported having a greater understanding of campus social norms than those in the control condition; they also expressed a greater desire to gossip about the video. Study 2 found that when given the opportunity, participants did gossip about the deviance, and this gossip was associated with increased norm clarification and (indirectly) social cohesion. These findings suggest that gossip may be a mechanism through which deviance can have positive downstream social consequences. PMID- 28898165 TI - Internalized stigma among patients with substance use disorders at a tertiary care center in India. AB - Internalized stigma among individuals with substance use disorders is a major barrier for accessing mental health services. This study aimed to assess internalized stigma among individuals with substance use disorders and to assess the relationship of internalized stigma with the quality of life. This cross sectional study recruited 201 patients with a clinical diagnosis of at least opioid or alcohol use disorder according to Diagnostic and Statistical Manual 5 at a public-funded tertiary care center in India. The study participants were interviewed using a sociodemographic questionnaire, the Internalized Stigma of Mental Illness Scale (ISMIS), and the World Health Organization's Quality of Life (WHOQOL-Bref) questionnaire. Seven participants (3.5% of the sample) had mild stigma according to ISMI scores, 62 (30.8%) had moderate stigma, and 132 (65.7%) had severe stigma. The various quality-of-life domains generally had a negative correlation with the internalized stigma scores. Participants using opioids as the primary substance of use were more likely to have severe internalized stigma. The experience of internalized stigma and dissatisfaction with quality of life is quite high among people suffering with substance use disorders in India. These results emphasize the need for interventions to reduce internal perception of stigma and improve the quality of life of individuals with substance use disorders. PMID- 28898167 TI - Praising Young Children for Being Smart Promotes Cheating. PMID- 28898166 TI - Transport of oxytetracycline, chlortetracycline, and ivermectin in surface runoff from irrigated pasture. AB - The transport of oxytetracycline, chlortetracycline, and ivermectin from manure was assessed via surface runoff on irrigated pasture. Surface runoff plots in the Sierra Foothills of Northern California were used to evaluate the effects of irrigation water application rates, pharmaceutical application conditions, vegetative cover, and vegetative filter strip length on the pharmaceutical discharge in surface runoff. Experiments were designed to permit the maximum potential transport of pharmaceuticals to surface runoff water, which included pre-irrigation to saturate soil, trimming grass where manure was applied, and laying a continuous manure strip perpendicular to the flow of water. However, due to high sorption of the pharmaceuticals to manure and soil, less than 0.1% of applied pharmaceuticals were detected in runoff water. Results demonstrated an increase of pharmaceutical transport in surface runoff with increased pharmaceutical concentration in manure, the concentration of pharmaceuticals in runoff water remained constant with increased irrigation flow rate, and no appreciable decrease in pharmaceutical runoff was produced with the vegetative filter strip length increased from 30.5 to 91.5 cm. Most of the applied pharmaceuticals were retained in the manure or within the upper 5 cm of soil directly beneath the manure application sites. As this study evaluated conditions for high transport potential, the data suggest that the risk for significant chlortetracycline, oxytetracycline, and ivermectin transport to surface water from cattle manure on irrigated pasture is low. PMID- 28898168 TI - Practice Evaluation Strategies Among Social Workers: Why an Evidence-Informed Dual-Process Theory Still Matters. AB - Practice evaluation strategies range in style from the formal-analytic tools of single-subject designs, rapid assessment instruments, algorithmic steps in evidence-informed practice, and computer software applications, to the informal interactive tools of clinical supervision, consultation with colleagues, use of client feedback, and clinical experience. The purpose of this article is to provide practice researchers in social work with an evidence-informed theory that is capable of explaining both how and why social workers use practice evaluation strategies to self-monitor the effectiveness of their interventions in terms of client change. The author delineates the theoretical contours and consequences of what is called dual-process theory. Drawing on evidence-informed advances in the cognitive and social neurosciences, the author identifies among everyday social workers a theoretically stable, informal-interactive tool preference that is a cognitively necessary, sufficient, and stand-alone preference that requires neither the supplementation nor balance of formal-analytic tools. The author's delineation of dual-process theory represents a theoretical contribution in the century-old attempt to understand how and why social workers evaluate their practice the way they do. PMID- 28898170 TI - Review of "Neuromuscular Disorders: Treatment and Management," by Tulio E. Bertorini. PMID- 28898169 TI - MiR-26b reverses temozolomide resistance via targeting Wee1 in glioma cells. AB - Emerging evidence has demonstrated that microRNAs (miRNA) play a critical role in chemotherapy-induced epithelial-mesenchymal transition (EMT) in glioma. However, the underlying mechanism of chemotherapy-triggered EMT has not been fully understood. In the current study, we determined the role of miR-26b in regulation of EMT in stable temozolomide (TMZ)-resistant (TR) glioma cells, which have displayed mesenchymal features. Our results illustrated that miR-26b was significantly downregulated in TR cells. Moreover, ectopic expression of miR-26b by its mimics reversed the phenotype of EMT in TR cells. Furthermore, we found that miR-26b governed TR-mediate EMT partly due to governing its target Wee1. Notably, overexpression of miR-26b sensitized TR cells to TMZ. These findings suggest that upregulation of miR-26b or targeting Wee1 could serve as novel approaches to reverse chemotherapy resistance in glioma. PMID- 28898171 TI - Febrile Infection-Related Epilepsy Syndrome (FIRES): A Literature Review and Case Study. AB - Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic syndrome that strikes previously healthy children aged 3-15 years and has an unknown pathogenesis and few treatments. These children experience a nonspecific febrile illness that is followed by prolonged refractory status epilepticus. Although the etiology is unknown, FIRES has a biphasic presentation, with the acute phase beginning as seizure activity lasting 1-12 weeks, then followed by the chronic phase, which is characterized by refractory seizures that cluster every 2-4 weeks, and may continue to be multifocal and independent. Treatment of FIRES is difficult, typically unresponsive to antiepileptic drugs. Some children resolve temporarily with drug-induced burst suppression comas. Other therapies such as a ketogenic diet have limited benefit. The outcome varies with the length of the acute phase and is usually poor, with up to 30% of cases ending in death and 66-100% of survivors having intellectual disability. The authors present a case of a 6-year-old child presenting with FIRES and refractory status epilepticus, which continued despite multidrug therapy. The patient underwent immunomodulatory therapy with the eventual resolution of status, but she developed a chronic, moderately severe encephalopathy, including intractable epilepsy. This case highlights the challenges of FIRES and the potential of immunomodulatory therapies for children with this disorder. PMID- 28898172 TI - No Further Yield of Ambulatory EEG for Epileptiform Discharges Beyond 13 Hours. AB - INTRODUCTION: This study aimed at evaluating the value added by 24-hour ambulatory EEG (AEEG) by comparing the presence of epileptiform discharges (EDs) between the first 30 minutes of recording versus the following 23.5 hours. MATERIALS AND METHODS: A retrospective review of AEEGs of subjects divided into two groups, epilepsy and undiagnosed episodes of loss of consciousness, was conducted. AEEGs were divided into early EEG (E-EEG) (first 30 minutes) and extended EEG (remaining 23.5 hours). Extended EEGs were further divided into segments (S): 31st minute to 8th hour (SI), 9th to 16th hours (SII) and 17th to 24th hours (SIII). Each consecutive segment was reviewed to identify new EDs not seen previously. RESULTS: Fifty-seven AEEGs were included, the median age being 36.3 years, the range being 18.7 to 78.6 years. There were 38 (66.6%) females. The collective yield of AEEG for detecting EDs was 19/57 (33.4%). The yield of E EEG of new EDs was 5/57 (9%). During extended EEG, the distribution of EDs was as follows: SI, 5/57 (9%); SII, 13/55 (24%); and SIII, 1/32 (3%). The yield, however, did not increase beyond the 13th hour. In undiagnosed episodes of loss of consciousness group (11), yield was 0/11 in all segments. CONCLUSIONS: (1) There was no value added for yield of EDs by extending the EEG recording beyond 13 hours in epilepsy group. (2) The probability of capturing EDs is negligible if the clinical history does not clearly support the diagnosis of seizure or epilepsy. PMID- 28898173 TI - Utility of Stereoelectroencephalography in Children with Dysembryoplastic Neuroepithelial Tumor and Cortical Malformation. AB - BACKGROUND: Uncontrolled seizures in children can contribute to irreversible cognitive impairment and developmental delay, in addition to placing them at risk for sudden unexplained death in epileptic patients (SUDEP). Since its introduction at Saint Ann Hospital in Paris in the 1960s, stereoelectroencephalography (SEEG) is increasingly being utilized at epilepsy centers in the United States as an invasive tool to help localize the seizure focus in drug-resistant focal epilepsy. INDICATIONS: Children with symptomatic epilepsy, commonly due to cortical dysplasia and dysembryoplastic neuroepithelial tumor (DNET), may benefit from SEEG investigation. The arrangement of SEEG electrodes is individually tailored based on the suspected location of the epileptogenic zone (EZ). The implanted depth electrodes are used to electrically stimulate the corresponding cortices to obtain information about the topography of eloquent cortex and EZ. Morbidity: Surgical morbidity in these children undergoing SEEG investigation is low, but not negligible. The number of electrodes directly correlates with the risk of intraoperative complication. Thus a risk and benefit analysis needs to be carefully considered for each patient. Neurodiagnostic technology: Both during and after the SEEG electrode implantation, the intraoperative monitoring and EEG technologists play a vital role in the successful monitoring of the patient. CONCLUSION: SEEG is an important tool in the process of epilepsy surgery in children with symptomatic epilepsy, commonly due to cortical dysplasia and DNET. PMID- 28898174 TI - Waveform Window #41: Fact or Artifact, 3rd Edition. PMID- 28898177 TI - Credentialing Organizations. PMID- 28898175 TI - An Unusual Presentation of Creutzfeldt-Jakob Disease and an Example of How Hickam's Dictum and Ockham's Razor Can Both Be Right. AB - Patients can have more than one neurological problem, and sorting out acute from chronic disease can be challenging. The authors report a middle-aged patient who presented with ataxia, right hemiparesis, and abnormal nystagmus. Magnetic resonance imaging (MRI) showed a Chiari and an arachnoid cyst with brainstem compression that appeared to explain his abnormal examination. Shortly after admission, he was noted to have intermittent abnormal behavior and confusion. History from family revealed significant acute and chronic psychiatric problems that appeared to explain his abnormal mental status; this delayed the diagnosis of intermittent complex partial seizures. The multitude of various symptoms resulted in a delay of the final diagnosis of Creutzfeldt-Jakob disease (CJD), which in retrospect explained the entire new physical examination, seizures, and mental status changes. PMID- 28898178 TI - ASET-CEU Quiz. PMID- 28898179 TI - Renal Medullary Carcinoma Associated with Sickle Cell Trait. PMID- 28898180 TI - Invited Commentary on "Molecular Breast Imaging in Breast Cancer Screening and Problem Solving". PMID- 28898181 TI - Subfertility: What the Radiologist Needs to Know. AB - The role of imaging in subfertility is well established but is changing. In addition to traditional fertility assessments, there is an emerging role for the radiologist. The role of imaging in fertility-restoring procedures in benign disease and congenital malformations is evolving, and there is a growing need for accurate identification of young candidates suitable for fertility-preserving surgery in the oncologic setting. To facilitate this developing role, knowledge of the key imaging modalities used and potential therapeutic applications is important for accurate diagnosis and interpretation by the radiologist. (c)RSNA, 2017. PMID- 28898182 TI - Invited Commentary on "CT Texture Analysis". PMID- 28898183 TI - Bronchiolitis: A Practical Approach for the General Radiologist-Erratum. PMID- 28898184 TI - Congratulations to the 2017 Editorial Fellows. PMID- 28898186 TI - Imaging of Breast Implant-associated Complications and Pathologic Conditions: Breast Imaging. PMID- 28898187 TI - Mature Cystic Teratoma: AIRP Best Cases in Radiologic-Pathologic Correlation. AB - Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). PMID- 28898188 TI - Contrast-enhanced US Approach to the Diagnosis of Focal Liver Masses. AB - Focal liver lesions are commonly encountered and often demonstrate nonspecific findings at initial imaging. Although most incidentally discovered liver lesions are benign, their noninvasive diagnosis is necessary, especially if they are large or atypical. Imaging characterization of focal liver lesions and exclusion of malignancy are of prime importance, particularly in high-risk populations. Contrast agent-enhanced ultrasonography of liver lesions is both accurate and reproducible for evaluation of benign and malignant liver tumors. Use of an imaging algorithm and a controlled sonographic technique, including dedicated arterial phase cine imaging and imaging every 30 seconds in the portal venous phase and the delayed (or late) phase, is essential for accurate characterization. This algorithmic analysis of focal liver lesions focuses first on the determination of malignancy by imaging the portal venous phase and the late phase; washout in these phases correlates with a malignant tumor, and sustained enhancement in these phases is suggestive that a lesion is benign. In addition, the timing and the intensity of washout differentiate hepatocellular malignancies from nonhepatocellular malignancies. Nonhepatocellular tumors demonstrate early and strong washout, whereas hepatocellular malignancies show delayed and weak washout. Subsequent analysis of dynamic real-time enhancement patterns in the arterial phase demonstrates specific enhancement patterns of common benign and malignant focal liver lesions. Hemangiomas show classic peripheral nodular enhancement, and spoke-wheel centrifugal enhancement is suggestive of focal nodular hyperplasia. Hepatic adenomas may show centripetal filling. However, arterial phase enhancement in malignancy has less specificity. Online supplemental material is available for this article. (c)RSNA, 2017 *. PMID- 28898185 TI - Thoracic Complications of Precision Cancer Therapies: A Practical Guide for Radiologists in the New Era of Cancer Care. AB - Recent advances in understanding the molecular mechanisms of cancer have opened a new era of precision medicine for cancer treatment. Precision cancer therapies target specific molecules that are responsible for cancer development and progression, and they achieve marked treatment benefits in specific cohorts of patients. However, these therapies are also associated with a variety of complications that are often unique to specific groups of anticancer agents. The rapidly increasing use of immune checkpoint inhibitors in the treatment of various advanced malignancies has brought new challenges in diagnosing and monitoring a unique set of toxic effects termed immune-related adverse events. Familiarity with cutting-edge cancer treatment approaches and awareness of the emerging complications from novel therapies are essential for radiologists, who play a key role in the care of patients with cancer. This article provides a comprehensive review of the thoracic complications of precision cancer therapies, describes their imaging features and clinical characteristics, and discusses the role of radiologists in the diagnosis and monitoring of these entities. The authors also address the molecular mechanisms of anticancer agents that relate to thoracic complications and emphasize emerging challenges in novel cancer therapies. This article is designed to serve as a practical reference guide for day-to-day practice for radiologists in the era of precision cancer medicine. (c)RSNA, 2017. PMID- 28898189 TI - CT Texture Analysis: Definitions, Applications, Biologic Correlates, and Challenges. AB - This review discusses potential oncologic and nononcologic applications of CT texture analysis ( CTTA CT texture analysis ), an emerging area of "radiomics" that extracts, analyzes, and interprets quantitative imaging features. CTTA CT texture analysis allows objective assessment of lesion and organ heterogeneity beyond what is possible with subjective visual interpretation and may reflect information about the tissue microenvironment. CTTA CT texture analysis has shown promise in lesion characterization, such as differentiating benign from malignant or more biologically aggressive lesions. Pretreatment CT texture features are associated with histopathologic correlates such as tumor grade, tumor cellular processes such as hypoxia or angiogenesis, and genetic features such as KRAS or epidermal growth factor receptor (EGFR) mutation status. In addition, and likely as a result, these CT texture features have been linked to prognosis and clinical outcomes in some tumor types. CTTA CT texture analysis has also been used to assess response to therapy, with decreases in tumor heterogeneity generally associated with pathologic response and improved outcomes. A variety of nononcologic applications of CTTA CT texture analysis are emerging, particularly quantifying fibrosis in the liver and lung. Although CTTA CT texture analysis seems to be a promising imaging biomarker, there is marked variability in methods, parameters reported, and strength of associations with biologic correlates. Before CTTA CT texture analysis can be considered for widespread clinical implementation, standardization of tumor segmentation and measurement techniques, image filtration and postprocessing techniques, and methods for mathematically handling multiple tumors and time points is needed, in addition to identification of key texture parameters among hundreds of potential candidates, continued investigation and external validation of histopathologic correlates, and structured reporting of findings. (c)RSNA, 2017. PMID- 28898191 TI - Imaging Scales and Techniques Used in the 2015 Endovascular Stroke Trials and AHA/ASA Revised Guidelines for Acute Intervention: Neurologic/Head and Neck Imaging. PMID- 28898190 TI - Renal Tumors of Childhood: Radiologic-Pathologic Correlation Part 2. The 2nd Decade: From the Radiologic Pathology Archives. AB - Malignant renal tumors account for 7% of childhood cancers, and Wilms tumors are by far the most common-but not in older children and adolescents. Among individuals in the latter half of their 2nd decade of life, renal cell carcinoma (RCC) is more common than Wilms tumor. The histopathologic spectrum of RCCs in children differs from that in adults. The most common subtype of RCC in children and adolescents is Xp11.2 translocation RCC, which is distinguished by hyperattenuation at nonenhanced computed tomography, a defined capsule, and associated retroperitoneal lymphadenopathy. Papillary RCC is the second most common histologic subtype. It enhances less intensely compared with the adjacent renal parenchyma and has a propensity for calcification. Clear cell RCC is seen in patients with von Hippel-Lindau disease and is distinguished by its relatively hypervascular nature. Medullary carcinoma affects adolescents with the sickle cell trait and is characterized by an infiltrative growth pattern and extensive metastasis at presentation. Angiomyolipoma is seen in children with tuberous sclerosis complex and is often multifocal and hypervascular, with macroscopic fat. Metanephric tumors are central, circumscribed, and typically calcified. Lymphoma usually manifests as multifocal masses, but it may involve a solitary mass or infiltrative pattern. Extensive adenopathy and involvement of the gastrointestinal tract or other organs also may be seen. Primitive neuroectodermal tumor is an aggressive neoplasm that is typically quite large at diagnosis. Knowledge of the clinical, biologic, and histopathologic features of renal tumors in older children and adolescents and their effects on the imaging appearance can help the radiologist offer a useful preoperative differential diagnosis. PMID- 28898192 TI - Intracranial Teratoma: Imaging, Intraoperative, and Pathologic Features: AIRP Best Cases in Radiologic-Pathologic Correlation. AB - Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). Online supplemental material is available for this article. PMID- 28898193 TI - Molecular Breast Imaging in Breast Cancer Screening and Problem Solving. AB - In the United States, legislative actions in over 28 states require radiologists to notify women who undergo breast screening mammography of their breast density. This has led to increased public interest in supplemental screening, but radiologists have not come to a consensus on a supplemental screening modality. In choosing between the most common options, whole-breast ultrasonography (US) and magnetic resonance (MR) imaging, one must weigh the benefits and drawbacks of each modality, as increased cancer detection may be accompanied by increased examination costs and biopsy rates. There has been recent interest in molecular breast imaging (MBI) for supplemental screening because of its high sensitivity, as well as its high specificity. This article describes how MBI fits into clinical practice alongside digital breast tomosynthesis (DBT), targeted US, and MR imaging. The authors describe their approach to breast cancer screening, which uses DBT as the primary imaging modality. DBT is complemented by automated density calculations and supplemented with functional imaging techniques, including MR imaging or MBI, for women with dense breasts. An algorithm based on the patient's breast cancer risk is used to determine if either MR imaging or MBI for supplemental screening is appropriate. MBI is also used as a problem-solving tool for the evaluation of clinical indications following complex mammography or US, or for unexplained physical findings. This article describes aspects related to implementing MBI in clinical practice, including the clinical workflow, patient management, radioactive tracer administration, and procedure reimbursement. (c) RSNA, 2017. PMID- 28898194 TI - Correlate: A PACS- and EHR-integrated Tool Leveraging Natural Language Processing to Provide Automated Clinical Follow-up. AB - A major challenge for radiologists is obtaining meaningful clinical follow-up information for even a small percentage of cases encountered and dictated. Traditional methods, such as keeping medical record number follow-up lists, discussing cases with rounding clinical teams, and discussing cases at tumor boards, are effective at keeping radiologists informed of clinical outcomes but are time intensive and provide follow-up for a small subset of cases. To this end, the authors developed a picture archiving and communication system accessible electronic health record (EHR)-integrated program called Correlate, which allows the user to easily enter free-text search queries regarding desired clinical follow-up information, with minimal interruption to the workflow. The program uses natural language processing (NLP) to process the query and parse relevant future clinical data from the EHR. Results are ordered in terms of clinical relevance, and the user is e-mailed a link to results when these are available for viewing. A customizable personal database of queries and results is also maintained for convenient future access. Correlate aids radiologists in efficiently obtaining useful clinical follow-up information that can improve patient care, help keep radiologists integrated with other specialties and referring physicians, and provide valuable experiential learning. The authors briefly review the history of automated clinical follow-up tools and discuss the design and function of the Correlate program, which uses NLP to perform intelligent prospective searches of the EHR. (c) RSNA, 2017. PMID- 28898196 TI - Teens and Technology Transforming Acne Treatment. AB - INTRODUCTION: Although the Internet contains many health Web sites with valid information, it also contains sites with false information. OBJECTIVE: To learn whether high school students searching health care information believe they are using evidence-based sites and to understand their topics of interest, frequently navigated sites, and trust/confidence in the credibility of information found. DESIGN: Cross-sectional. MAIN OUTCOME MEASURES: Students at a private high school answered an anonymous survey inquiring about their belief that they were using evidence-based sites, topics of interest, search engines of choice, and their trust in information obtained. Descriptive statistics and multivariate analysis of variance were used to compare trends across grade levels. RESULTS: Of 705 students enrolled, 24.7% were absent or declined to participate. For the remaining students, 497 completed the surveys, representing a response rate of 70.5% (497/705) and a participation rate of 93.6% (497/531). Overall, 82% of students communicated that they believed they were using evidence-based sources when searching for health information (p < 0.0006). Findings showed that 42% searched general health information, and 43% investigated specific medical conditions; topics related to skin and acne were researched significantly more often (p < 0.05). Overall, most students (80%) reported using Google as their number 1 search engine (p < 0.004), 38% reported using WebMD Search (p < 0.0002), and 50% of students used Wikipedia (not significant). CONCLUSION: Most students trust health information they learn from the Internet. We found it chilling that less than half of students obtained their information from a Web site with health care professionals' oversight. PMID- 28898195 TI - User-Centered Design for Developing Interventions to Improve Clinician Recommendation of Human Papillomavirus Vaccination. AB - INTRODUCTION: Human papillomavirus (HPV) is the most common sexually transmitted infection in the US and is associated with multiple types of cancer. Although effective HPV vaccines have been available since 2006, coverage rates in the US remain much lower than with other adolescent vaccinations. Prior research has shown that a strong recommendation from a clinician is a critical determinant in HPV vaccine uptake and coverage. However, few published studies to date have specifically addressed the issue of helping clinicians communicate more effectively with their patients about the HPV vaccine. OBJECTIVE: To develop one or more novel interventions for helping clinicians make strong and effective recommendations for HPV vaccination. METHODS: Using principles of user-centered design, we conducted qualitative interviews, interviews with persons from analogous industries, and a data synthesis workshop with multiple stakeholders. RESULTS: Five potential intervention strategies targeted at health care clinicians, youth, and their parents were developed. The two most popular choices to pursue were a values-based communication strategy and a puberty education workbook. CONCLUSION: User-centered design is a useful strategy for developing potential interventions to improve the rate and success of clinicians recommending the HPV vaccine. Further research is needed to test the effectiveness and acceptability of these interventions in clinical settings. PMID- 28898197 TI - Urgent Need for Improved Mental Health Care and a More Collaborative Model of Care. AB - Current treatments and the dominant model of mental health care do not adequately address the complex challenges of mental illness, which accounts for roughly one third of adult disability globally. These circumstances call for radical change in the paradigm and practices of mental health care, including improving standards of clinician training, developing new research methods, and re envisioning current models of mental health care delivery. Because of its dominant position in the US health care marketplace and its commitment to research and innovation, Kaiser Permanente (KP) is strategically positioned to make important contributions that will shape the future of mental health care nationally and globally.This article reviews challenges facing mental health care and proposes an agenda for developing a collaborative care model in primary care settings that incorporates conventional biomedical therapies and complementary and alternative medicine approaches. By moving beyond treatment delivery via telephone and secure video and providing earlier interventions through primary care clinics, KP is shifting the paradigm of mental health care to a collaborative care model focusing on prevention. Recommendations are to expand current practices to include integrative treatment strategies incorporating evidence-based biomedical and complementary and alternative medicine modalities that can be provided to patients using a collaborative care model. Recommendations also are made for an internal research program aimed at investigating the efficacy and cost-effectiveness of promising complementary and alternative medicine and integrative treatments addressing the complex needs of patients with severe psychiatric disorders, many of whom respond poorly to treatments available in KP mental health clinics. PMID- 28898198 TI - Appropriate Interval for Imaging Follow-up of Small Simple Pancreatic Cysts. AB - CONTEXT: The frequency at which patients should undergo follow-up imaging of small pancreatic cysts is problematic because different medical societies have different follow-up guidelines. OBJECTIVE: To determine whether short-term follow up of small pancreatic cysts is necessary to detect pancreatic cancer or cystic neoplasia. DESIGN: We retrospectively reviewed all abdominal magnetic resonance imaging (MRI) studies obtained in a geographically isolated health maintenance organization between January 1, 2012, and December 31, 2014, looking for pancreatic cysts. For each patient with one or more simple cysts, we recorded the size of the largest cyst. For patients with cysts, all their other computed tomography and MRI studies were reviewed to determine any change in size or morphology. The electronic medical record of every patient who underwent MRI was reviewed to determine development of pancreatic cancer. MAIN OUTCOME MEASURES: Change in cyst size on images. RESULTS: Of 1946 patients, 342 were found to have at least 1 pancreatic cyst. A total of 228 patients had additional imaging from which to determine rates of change. The mean rate (standard deviation) of change for these cysts was 0.1 +/- 2.0 mm/y. None of those cysts measuring 2 cm or smaller on MRI grew more than 5 mm in 2 years. CONCLUSION: Our data validate the clinical efficacy of obtaining follow-up imaging no sooner than 24 months after the initial detection of a simple pancreatic cyst 2 cm or smaller. Patients with cysts are more likely to have pancreatic cancer, but earlier follow-up imaging would not change their diagnosis of pancreatic cancer. PMID- 28898200 TI - Non-coding transcriptome in brain aging. PMID- 28898201 TI - AURKA inhibition mimics BRCAness. PMID- 28898199 TI - A druggable secretory protein maturase of Toxoplasma essential for invasion and egress. AB - Micronemes and rhoptries are specialized secretory organelles that deploy their contents at the apical tip of apicomplexan parasites in a regulated manner. The secretory proteins participate in motility, invasion, and egress and are subjected to proteolytic maturation prior to organellar storage and discharge. Here we establish that Toxoplasma gondii aspartyl protease 3 (ASP3) resides in the endosomal-like compartment and is crucially associated to rhoptry discharge during invasion and to host cell plasma membrane lysis during egress. A comparison of the N-terminome, by terminal amine isotopic labelling of substrates between wild type and ASP3 depleted parasites identified microneme and rhoptry proteins as repertoire of ASP3 substrates. The role of ASP3 as a maturase for previously described and newly identified secretory proteins is confirmed in vivo and in vitro. An antimalarial compound based on a hydroxyethylamine scaffold interrupts the lytic cycle of T. gondii at submicromolar concentration by targeting ASP3. PMID- 28898202 TI - Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging. AB - Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA) mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4 deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4 deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation. PMID- 28898203 TI - Structure of electric double layers in capacitive systems and to what extent (classical) density functional theory describes it. AB - Ongoing scientific interest is aimed at the properties and structure of electric double layers (EDLs), which are crucial for capacitive energy storage, water treatment, and energy harvesting technologies like supercapacitors, desalination devices, blue engines, and thermocapacitive heat-to-current converters. A promising tool to describe their physics on a microscopic level is (classical) density functional theory (DFT), which can be applied in order to analyze pair correlations and charge ordering in the primitive model of charged hard spheres. This simple model captures the main properties of ionic liquids and solutions and it predicts many of the phenomena that occur in EDLs. The latter often lead to anomalous response in the differential capacitance of EDLs. This work constructively reviews the powerful theoretical framework of DFT and its recent developments regarding the description of EDLs. It explains to what extent current approaches in DFT describe structural ordering and in-plane transitions in EDLs, which occur when the corresponding electrodes are charged. Further, the review briefly summarizes the history of modeling EDLs, presents applications, and points out limitations and strengths in present theoretical approaches. It concludes that DFT as a sophisticated microscopic theory for ionic systems is expecting a challenging but promising future in both fundamental research and applications in supercapacitive technologies. PMID- 28898204 TI - Beneficial Effect of Beraprost Sodium Plus Aspirin in the Treatment of Acute Ischemic Stroke. AB - BACKGROUND To investigate the combination of beraprost sodium (BPS) and aspirin in the treatment of acute ischemic stroke (AIS). MATERIAL AND METHODS 308 patients with acute cerebral infarction were randomly divided into two groups: experimental group (n=154), treated with BPS (40 MUg, tid) and aspirin (100 mg, qd); control group (n=154), treated with 100 mg of aspirin, qd). The antiplatelet therapy remained unchangeable until six months after hospital discharge. RESULTS Initially, no significant differences were found between the two groups. After six months, the relapse-free survival rate was similar between the treatment group (98.1%) and the control group (97.4%). One patient died from AIS in the control group. However, glomerular filtration rate was significantly higher; neurological function and functional ability of patients were better in patients treated with BPS plus aspirin (experimental group) than that in aspirin alone group. No significant difference was found in the function of the coagulation system, suggesting that BPS plus aspirin treatment did not increase the risk of bleeding. Serious adverse events did not occur in both groups. Facial flushing (one case) and mild gastrointestinal reaction (one case) were found in the treatment group without influencing treatment. CONCLUSIONS In our trial involving patients with acute cerebral infarction, BPS plus aspirin was not found to be superior to aspirin in reducing the recurrence of cerebral infarction or death. However, BPS plus aspirin treatment could improve renal function and neurological function without increasing the risk of bleeding. PMID- 28898205 TI - Tagging activated neurons with light. PMID- 28898206 TI - Reply: Greener revolutions for all require transparency and diversity, not secrecy. PMID- 28898208 TI - Interpreting the T-cell receptor repertoire. PMID- 28898209 TI - Neoantigen prediction and the need for validation. PMID- 28898210 TI - What's app? Helix wants you to quiz your genome-some of it for fun. PMID- 28898212 TI - Precision editing in the human embryo. PMID- 28898213 TI - 2Q17-Biotech stages a recovery. PMID- 28898214 TI - Blood feud erupts over Roche's bispecific antibody for hemophilia. PMID- 28898215 TI - Mouse phenotyping sheds light on rare disease. PMID- 28898207 TI - Shotgun metagenomics, from sampling to analysis. AB - Diverse microbial communities of bacteria, archaea, viruses and single-celled eukaryotes have crucial roles in the environment and in human health. However, microbes are frequently difficult to culture in the laboratory, which can confound cataloging of members and understanding of how communities function. High-throughput sequencing technologies and a suite of computational pipelines have been combined into shotgun metagenomics methods that have transformed microbiology. Still, computational approaches to overcome the challenges that affect both assembly-based and mapping-based metagenomic profiling, particularly of high-complexity samples or environments containing organisms with limited similarity to sequenced genomes, are needed. Understanding the functions and characterizing specific strains of these communities offers biotechnological promise in therapeutic discovery and innovative ways to synthesize products using microbial factories and can pinpoint the contributions of microorganisms to planetary, animal and human health. PMID- 28898216 TI - CRISPR patent estate splinters. PMID- 28898218 TI - Greener revolutions for all require transparency and diversity, not secrecy. PMID- 28898220 TI - Podcast: First rounders: Greg Winter. PMID- 28898219 TI - Nestle moves into gut microbiome tests. PMID- 28898221 TI - Go-ahead for first anti-IL-23 mAb to treat psoriasis. PMID- 28898223 TI - Recent patents related to clinical applications of sequencing. PMID- 28898222 TI - Around the world in a month. PMID- 28898224 TI - Buying time for transplants. PMID- 28898225 TI - Adenosine checkpoint agent blazes a trail, joins immunotherapy roster. PMID- 28898226 TI - After Myriad, what makes a gene patent claim 'markedly different' from nature? PMID- 28898227 TI - Challenges in the gene therapy commercial ecosystem. PMID- 28898228 TI - Vertex CF data wow Wall Street. PMID- 28898229 TI - What faculty hiring committees want. PMID- 28898230 TI - Massachusetts injects more cash into jobs. PMID- 28898231 TI - Albumin, bilirubin, uric acid and cancer risk: results from a prospective population-based study. AB - BACKGROUND: It has long been proposed that albumin, bilirubin and uric acid may inhibit cancer development due to their anti-oxidative properties. However, there is a lack of population-based studies on blood levels of these molecules and cancer risk. METHODS: Associations between pre-diagnostic serum albumin, bilirubin and uric acid and the risks of common cancers as well as cancer death in the EPIC-Heidelberg cohort were evaluated by multivariable Cox regression analyses. A case-cohort sample including a random subcohort (n=2739) and all incident cases of breast (n=627), prostate (n=554), colorectal (n=256), and lung cancer (n=195) as well as cancer death (n=761) that occurred between baseline (1994-1998) and 2009 was used. RESULTS: Albumin levels were inversely associated with breast cancer risk (hazard ratioQuartile 4 vs Quartile 1 (95% CI): 0.71 (0.51, 0.99), Plinear trend=0.004) and overall cancer mortality (HRQ4 vs Q1 (95% CI): 0.64 (0.48, 0.86), Plinear trend<0.001) after multivariable adjustment. Uric acid levels were also inversely associated with breast cancer risk (HRQ4 vs Q1 (95% CI): 0.72 (0.53, 0.99), Plinear trend=0.043) and cancer mortality (HRQ4 vs Q1 (95% CI): 0.75 (0.58, 0.98), Plinear trend=0.09). There were no significant associations between albumin or uric acid and prostate, lung and colorectal cancer. Serum bilirubin was not associated with any cancer end point. CONCLUSIONS: The present findings indicate that higher levels of albumin and uric acid are related to lower risks of breast cancer and cancer mortality. Further studies are needed to assess whether the observed associations are causal. PMID- 28898232 TI - Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC. PMID- 28898233 TI - Estimating the impact of a cancer diagnosis on life expectancy by socio-economic group for a range of cancer types in England. AB - BACKGROUND: Differences in cancer survival exist across socio-economic groups for many cancer types. Standard metrics fail to show the overall impact for patients and the population. METHODS: The available data consist of a population of ~2.5 million patients and include all patients recorded as being diagnosed with melanoma, prostate, bladder, breast, colon, rectum, lung, ovarian and stomach cancers in England between 1998 and 2013. We estimated the average loss in expectation of life per patient in years and the proportion of life lost for a range of cancer types, separately by deprivation group. In addition, estimates for the total number of years lost due to each cancer were also obtained. RESULTS: Lung and stomach cancers result in the highest overall loss for males and females in all deprivation groups in terms of both absolute life years lost and loss as a proportion of expected life remaining. Female lung cancer patients in the least- and most-deprived group lose 14.4 and 13.8 years on average, respectively, that is translated as 86.1% and 87.3% of their average expected life years remaining. Melanoma, prostate and breast cancers have the lowest overall loss. On the basis of the number of patients diagnosed in 2013, lung cancer results in the most life years lost in total followed by breast cancer. Melanoma and bladder cancer account for the lowest total life years lost. CONCLUSIONS: There are wide differences in the impact of cancer on life expectancy across deprivation groups, and for most cancers the most affluent lose less years. PMID- 28898234 TI - Circulating cytokines and small molecules follow distinct expression patterns in acute myeloid leukaemia. AB - BACKGROUND: Although aberrant expression of cytokines and small molecules (analytes) is well documented in acute myeloid leukaemia (AML), their co expression patterns are not yet identified. In addition, plasma baselines for some analytes that are biomarkers for other cancers have not been previously reported in AML. METHODS: We used multiplex array technology to simultaneously detect and quantify 32 plasma analyte (22 reported analytes and 10 novel analytes) levels in 38 patients. RESULTS: In our study, 16 analytes are found to be significantly deregulated (13 higher, 3 lower, Mann-Whitney U-test, P-value <0.005), where 5 of them have never been reported before in AML. We predicted a seven-analyte-containing multiplex panel for diagnosis of AML and, among them, MIF could be a possible therapeutic target. In addition, we observed that circulating analytes show five co-expression signatures. CONCLUSIONS: Circulating analyte expression in AML significantly differs from normal, and follow distinct expression patterns. PMID- 28898235 TI - Associations of Helicobacter pylori infection and chronic atrophic gastritis with accelerated epigenetic ageing in older adults. AB - BACKGROUND: Helicobacter pylori (HP) infection and chronic atrophic gastritis (CAG) have shown strong associations with the development of gastric cancer. This study aimed to examine whether both risk factors are associated with accelerated epigenetic ageing, as determined by the 'DNA methylation age', in a population based study of older adults (n=1477). METHODS: Serological measurements of HP antibodies and pepsinogen I and II for CAG definition were obtained by ELISA kits. Whole blood DNA methylation profiles were measured by Illumina Human Methylation450K Beadchip. DNA methylation ages were calculated by two algorithms proposed by Horvath and Hannum et al. RESULTS: After adjusting for potential covariates in linear regression models, we found that HP infection, infection with virulent HP strains (CagA+) and severe CAG were significantly associated with an increase in DNA methylation age by ~0.4, 0.6 and 1 year (all P-values <0.05), respectively. CONCLUSIONS: Our study indicates that both CagA+ HP infection and CAG go along with accelerated epigenetic ageing. PMID- 28898237 TI - Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients. AB - BACKGROUND: Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes. METHODS: We examined the potential role of tumour associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-beta1, which is upregulated in lung cancer. RESULTS: Nintedanib dose-dependently inhibited the TGF-beta1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-beta signalling and aberrant TAF-carcinoma cross-talk is regulated by different mechanisms in ADC and SCC. CONCLUSIONS: These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours. PMID- 28898236 TI - Smoking cessation and survival in lung, upper aero-digestive tract and bladder cancer: cohort study. AB - BACKGROUND: The aim was to examine the association between smoking cessation and prognosis in smoking-related cancer as it is unclear that cessation reduces mortality. METHODS: In this retrospective cohort study from 1999 to 2013, we assessed the association between cessation during the first year after diagnosis and all-cause and cancer-specific mortality. RESULTS: Of 2882 lung, 757 upper aero-digestive tract (UAT) and 1733 bladder cancer patients 27%, 29% and 21% of lung, UAT and bladder cancer patients quit smoking. In lung cancer patients that quit, all-cause mortality was significantly lower (HR: 0.82 (0.74-0.92), while cancer-specific mortality (HR: 0.89 (0.76-1.04) and death due to index cancer (HR: 0.90 (0.77-1.05) were non-significantly lower. In UAT cancer, all-cause mortality (HR: 0.81 (0.58-1.14), cancer-specific mortality (HR: 0.84 (0.48-1.45), and death due to index cancer (HR: 0.75 (0.42-1.34) were non-significantly lower. There was no evidence of an association between quitting and mortality in bladder cancer. The HRs were 1.02 (0.81-1.30) for all-cause, 1.23 (0.81-1.86) for cancer specific, and 1.25 (0.71-2.20) for death due to index cancer. These showed a non significantly lower risk in sensitivity analyses. CONCLUSIONS: People with lung and possibly UAT cancer who quit smoking have a lower risk of mortality than people who continue smoking. PMID- 28898238 TI - Glucosamine stimulates pheromone-independent dimorphic transition in Cryptococcus neoformans by promoting Crz1 nuclear translocation. AB - Morphotype switch is a cellular response to external and internal cues. The Cryptococcus neoformans species complex can undergo morphological transitions between the yeast and the hypha form, and such morphological changes profoundly affect cryptococcal interaction with various hosts. Filamentation in Cryptococcus was historically considered a mating response towards pheromone. Recent studies indicate the existence of pheromone-independent signaling pathways but their identity or the effectors remain unknown. Here, we demonstrated that glucosamine stimulated the C. neoformans species complex to undergo self-filamentation. Glucosamine-stimulated filamentation was independent of the key components of the pheromone pathway, which is distinct from pheromone-elicited filamentation. Glucosamine stimulated self-filamentation in H99, a highly virulent serotype A clinical isolate and a widely used reference strain. Through a genetic screen of the deletion sets made in the H99 background, we found that Crz1, a transcription factor downstream of calcineurin, was essential for glucosamine-stimulated filamentation despite its dispensability for pheromone-mediated filamentation. Glucosamine promoted Crz1 translocation from the cytoplasm to the nucleus. Interestingly, multiple components of the high osmolality glycerol response (HOG) pathway, consisting of the phosphorelay system and some of the Hog1 MAPK module, acted as repressors of glucosamine-elicited filamentation through their calcineurin-opposing effect on Crz1's nuclear translocation. Surprisingly, glucosamine-stimulated filamentation did not require Hog1 itself and was distinct from the conventional general stress response. The results demonstrate that Cryptococcus can resort to multiple genetic pathways for morphological transition in response to different stimuli. Given that the filamentous form attenuates cryptococcal virulence and is immune-stimulatory in mammalian models, the findings suggest that morphogenesis is a fertile ground for future investigation into novel means to compromise cryptococcal pathogenesis. PMID- 28898240 TI - Prevalence of signs of trachoma, ocular Chlamydia trachomatis infection and antibodies to Pgp3 in residents of Kiritimati Island, Kiribati. AB - OBJECTIVE: In some Pacific Island countries, such as Solomon Islands and Fiji, active trachoma is common, but ocular Chlamydia trachomatis (Ct) infection and trachomatous trichiasis (TT) are rare. On Tarawa, the most populous Kiribati island, both the active trachoma sign "trachomatous inflammation-follicular" (TF) and TT are present at prevalences warranting intervention. We sought to estimate prevalences of TF, TT, ocular Ct infection, and anti-Ct antibodies on Kiritimati Island, Kiribati, to assess local relationships between these parameters, and to help determine the need for interventions against trachoma on Kiribati islands other than Tarawa. METHODS: As part of the Global Trachoma Mapping Project (GTMP), on Kiritimati, we examined 406 children aged 1-9 years for active trachoma. We collected conjunctival swabs (for droplet digital PCR against Ct plasmid targets) from 1-9-year-olds with active trachoma, and a systematic selection of 1-9-year-olds without active trachoma. We collected dried blood spots (for anti-Pgp3 ELISA) from all 1-9-year-old children. We also examined 416 adults aged >=15 years for TT. Prevalence of TF and TT was adjusted for age (TF) or age and gender (TT) in five-year age bands. RESULTS: The age-adjusted prevalence of TF in 1-9-year-olds was 28% (95% confidence interval [CI]: 24-35). The age- and gender-adjusted prevalence of TT in those aged >=15 years was 0.2% (95% CI: 0.1-0.3%). Twenty-six (13.5%) of 193 swabs from children without active trachoma, and 58 (49.2%) of 118 swabs from children with active trachoma were positive for Ct DNA. Two hundred and ten (53%) of 397 children had anti-Pgp3 antibodies. Both infection (p<0.0001) and seropositivity (p<0.0001) were strongly associated with active trachoma. In 1-9-year-olds, the prevalence of anti-Pgp3 antibodies rose steeply with age. CONCLUSION: Trachoma presents a public health problem on Kiritimati, where the high prevalence of ocular Ct infection and rapid increase in seropositivity with age suggest intense Ct transmission amongst young children. Interventions are required here to prevent future blindness. PMID- 28898239 TI - Sustained effectiveness and cost-effectiveness of Counselling for Alcohol Problems, a brief psychological treatment for harmful drinking in men, delivered by lay counsellors in primary care: 12-month follow-up of a randomised controlled trial. AB - BACKGROUND: Counselling for Alcohol Problems (CAP), a brief intervention delivered by lay counsellors, enhanced remission and abstinence over 3 months among male primary care attendees with harmful drinking in a setting in India. We evaluated the sustainability of the effects after treatment termination, the cost effectiveness of CAP over 12 months, and the effects of the hypothesized mediator 'readiness to change' on clinical outcomes. METHODS AND FINDINGS: Male primary care attendees aged 18-65 years screening with harmful drinking on the Alcohol Use Disorders Identification Test (AUDIT) were randomised to either CAP plus enhanced usual care (EUC) (n = 188) or EUC alone (n = 189), of whom 89% completed assessments at 3 months, and 84% at 12 months. Primary outcomes were remission and mean standard ethanol consumed in the past 14 days, and the proposed mediating variable was readiness to change at 3 months. CAP participants maintained the gains they showed at the end of treatment through the 12-month follow-up, with the proportion with remission (AUDIT score < 8: 54.3% versus 31.9%; adjusted prevalence ratio [aPR] 1.71 [95% CI 1.32, 2.22]; p < 0.001) and abstinence in the past 14 days (45.1% versus 26.4%; adjusted odds ratio 1.92 [95% CI 1.19, 3.10]; p = 0.008) being significantly higher in the CAP plus EUC arm than in the EUC alone arm. CAP participants also fared better on secondary outcomes including recovery (AUDIT score < 8 at 3 and 12 months: 27.4% versus 15.1%; aPR 1.90 [95% CI 1.21, 3.00]; p = 0.006) and percent of days abstinent (mean percent [SD] 71.0% [38.2] versus 55.0% [39.8]; adjusted mean difference 16.1 [95% CI 7.1, 25.0]; p = 0.001). The intervention effect for remission was higher at 12 months than at 3 months (aPR 1.50 [95% CI 1.09, 2.07]). There was no evidence of an intervention effect on Patient Health Questionnaire 9 score, suicidal behaviour, percentage of days of heavy drinking, Short Inventory of Problems score, WHO Disability Assessment Schedule 2.0 score, days unable to work, or perpetration of intimate partner violence. Economic analyses indicated that CAP plus EUC was dominant over EUC alone, with lower costs and better outcomes; uncertainty analysis showed a 99% chance of CAP being cost-effective per remission achieved from a health system perspective, using a willingness to pay threshold equivalent to 1 month's wages for an unskilled manual worker in Goa. Readiness to change level at 3 months mediated the effect of CAP on mean standard ethanol consumption at 12 months (indirect effect -6.014 [95% CI -13.99, -0.046]). Serious adverse events were infrequent, and prevalence was similar by arm. The methodological limitations of this trial are the susceptibility of self reported drinking to social desirability bias, the modest participation rates of eligible patients, and the examination of mediation effects of only 1 mediator and in only half of our sample. CONCLUSIONS: CAP's superiority over EUC at the end of treatment was largely stable over time and was mediated by readiness to change. CAP provides better outcomes at lower costs from a societal perspective. TRIAL REGISTRATION: ISRCTN registry ISRCTN76465238. PMID- 28898241 TI - Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs. AB - OBJECTIVES: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life. STUDY DESIGN: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC MS. RESULTS: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI. DISCUSSION/CONCLUSION: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level. PMID- 28898242 TI - An iterative approach for the global estimation of sentence similarity. AB - Measuring the similarity between two sentences is often difficult due to their small lexical overlap. Instead of focusing on the sets of features in two given sentences between which we must measure similarity, we propose a sentence similarity method that considers two types of constraints that must be satisfied by all pairs of sentences in a given corpus. Namely, (a) if two sentences share many features in common, then it is likely that the remaining features in each sentence are also related, and (b) if two sentences contain many related features, then those two sentences are themselves similar. The two constraints are utilized in an iterative bootstrapping procedure that simultaneously updates both word and sentence similarity scores. Experimental results on SemEval 2015 Task 2 dataset show that the proposed iterative approach for measuring sentence semantic similarity is significantly better than the non-iterative counterparts. PMID- 28898244 TI - NeuroPlace: Categorizing urban places according to mental states. AB - Urban spaces have a great impact on how people's emotion and behaviour. There are number of factors that impact our brain responses to a space. This paper presents a novel urban place recommendation approach, that is based on modelling in-situ EEG data. The research investigations leverages on newly affordable Electroencephalogram (EEG) headsets, which has the capability to sense mental states such as meditation and attention levels. These emerging devices have been utilized in understanding how human brains are affected by the surrounding built environments and natural spaces. In this paper, mobile EEG headsets have been used to detect mental states at different types of urban places. By analysing and modelling brain activity data, we were able to classify three different places according to the mental state signature of the users, and create an association map to guide and recommend people to therapeutic places that lessen brain fatigue and increase mental rejuvenation. Our mental states classifier has achieved accuracy of (%90.8). NeuroPlace breaks new ground not only as a mobile ubiquitous brain monitoring system for urban computing, but also as a system that can advise urban planners on the impact of specific urban planning policies and structures. We present and discuss the challenges in making our initial prototype more practical, robust, and reliable as part of our on-going research. In addition, we present some enabling applications using the proposed architecture. PMID- 28898243 TI - Neoatherosclerosis development following bioresorbable vascular scaffold implantation in diabetic and non-diabetic swine. AB - BACKGROUND: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. AIM: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. METHODS: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. RESULTS: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. CONCLUSION: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes. PMID- 28898245 TI - Improving data sharing in research with context-free encoded missing data. AB - Lack of attention to missing data in research may result in biased results, loss of power and reduced generalizability. Registering reasons for missing values at the time of data collection, or-in the case of sharing existing data-before making data available to other teams, can save time and efforts, improve scientific value and help to prevent erroneous assumptions and biased results. To ensure that encoding of missing data is sufficient to understand the reason why data are missing, it should ideally be context-free. Therefore, 11 context-free codes of missing data were carefully designed based on three completed randomized controlled clinical trials and tested in a new randomized controlled clinical trial by an international team consisting of clinical researchers and epidemiologists with extended experience in designing and conducting trials and an Information System expert. These codes can be divided into missing due to participant and/or participation characteristics (n = 6), missing by design (n = 4), and due to a procedural error (n = 1). Broad implementation of context-free missing data encoding may enhance the possibilities of data sharing and pooling, thus allowing more powerful analyses using existing data. PMID- 28898246 TI - Cytotoxicity and anti-tumor effects of new ruthenium complexes on triple negative breast cancer cells. AB - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment. PMID- 28898247 TI - Prevalence of acromegaly in patients with symptoms of sleep apnea. AB - Acromegaly is a rare disease with nonspecific symptoms with acral enlargement being almost universally present at diagnosis. The estimated prevalence is 40-125 cases/million but targeted universal screening studies have found a higher prevalence (about 10 fold). The aim of the ACROSAHS study was to investigate the prevalence of acromegaly and acromegaly comorbidities in patients with sleep apnea symptoms and acral enlargement. ACROSAHS was a Spanish prospective non interventional epidemiological study in 13 Hospital sleep referral units. Facial and acral enlargement symptoms including: ring size and shoe size increase, tongue, lips and jaws enlargement, paresthesia or carpal tunnel syndrome and widening of tooth spaces, as well as other typical acromegaly comorbidities were recorded with a self-administered questionnaire of patients who attended a first visit for sleep apnea symptoms between 09/2013 and 07/2014. Serum insulin-like growth factor type 1 (IGF1) was measured in patients with >=1 acral symptom to determine the prevalence of acromegaly. Of the 1557 patients enrolled, 1477 with complete data (72% male) were analyzed. 530 patients (36%) reported at least 1 acral enlargement symptom and were tested for IGF-1, 41 were above range, persisted in 7, and among those, 2 cases of acromegaly were diagnosed (prevalence of at least 1.35 cases/1000). Overall, 1019 patients (69%) had >=2 acromegaly symptoms and should have been screened according to guidelines; moreover 373 patients (25%) had >=1 symptom of acral enlargement plus >=3 other acromegaly symptoms. In conclusion, in patients with sleep apnea symptoms and acral enlargement, we found an acromegaly prevalence of at least 1.35 cases per 1000 and a high prevalence of typical acromegaly symptoms. It is important that sleep specialists are aware of acromegaly symptoms to aid with acromegaly diagnosis. PMID- 28898249 TI - Projecting social contact matrices in 152 countries using contact surveys and demographic data. AB - Heterogeneities in contact networks have a major effect in determining whether a pathogen can become epidemic or persist at endemic levels. Epidemic models that determine which interventions can successfully prevent an outbreak need to account for social structure and mixing patterns. Contact patterns vary across age and locations (e.g. home, work, and school), and including them as predictors in transmission dynamic models of pathogens that spread socially will improve the models' realism. Data from population-based contact diaries in eight European countries from the POLYMOD study were projected to 144 other countries using a Bayesian hierarchical model that estimated the proclivity of age-and-location specific contact patterns for the countries, using Markov chain Monte Carlo simulation. Household level data from the Demographic and Health Surveys for nine lower-income countries and socio-demographic factors from several on-line databases for 152 countries were used to quantify similarity of countries to estimate contact patterns in the home, work, school and other locations for countries for which no contact data are available, accounting for demographic structure, household structure where known, and a variety of metrics including workforce participation and school enrolment. Contacts are highly assortative with age across all countries considered, but pronounced regional differences in the age-specific contacts at home were noticeable, with more inter-generational contacts in Asian countries than in other settings. Moreover, there were variations in contact patterns by location, with work-place contacts being least assortative. These variations led to differences in the effect of social distancing measures in an age structured epidemic model. Contacts have an important role in transmission dynamic models that use contact rates to characterize the spread of contact-transmissible diseases. This study provides estimates of mixing patterns for societies for which contact data such as POLYMOD are not yet available. PMID- 28898248 TI - Place field assembly distribution encodes preferred locations. AB - The hippocampus is the main locus of episodic memory formation and the neurons there encode the spatial map of the environment. Hippocampal place cells represent location, but their role in the learning of preferential location remains unclear. The hippocampus may encode locations independently from the stimuli and events that are associated with these locations. We have discovered a unique population code for the experience-dependent value of the context. The degree of reward-driven navigation preference highly correlates with the spatial distribution of the place fields recorded in the CA1 region of the hippocampus. We show place field clustering towards rewarded locations. Optogenetic manipulation of the ventral tegmental area demonstrates that the experience dependent place field assembly distribution is directed by tegmental dopaminergic activity. The ability of the place cells to remap parallels the acquisition of reward context. Our findings present key evidence that the hippocampal neurons are not merely mapping the static environment but also store the concurrent context reward value, enabling episodic memory for past experience to support future adaptive behavior. PMID- 28898251 TI - HbA1c for type 2 diabetes diagnosis in Africans and African Americans: Personalized medicine NOW! AB - Andrew Paterson discusses findings from a new study that shows HbA1c screening for diabetes will leave 2% of African Americans undiagnosed and how personalised medicine is needed. PMID- 28898250 TI - Effects of proteasome inhibitor MG-132 on the parasite Schistosoma mansoni. AB - Proteasome is a proteolytic complex responsible for intracellular protein turnover in eukaryotes, archaea and in some actinobacteria species. Previous work has demonstrated that in Schistosoma mansoni parasites, the proteasome inhibitor MG-132 affects parasite development. However, the molecular targets affected by MG-132 in S. mansoni are not entirely known. Here, we used expression microarrays to measure the genome-wide changes in gene expression of S. mansoni adult worms exposed in vitro to MG-132, followed by in silico functional analyses of the affected genes using Ingenuity Pathway Analysis (IPA). Scanning electron microscopy was used to document changes in the parasites' tegument. We identified 1,919 genes with a statistically significant (q-value <= 0.025) differential expression in parasites treated for 24 h with MG-132, when compared with control. Of these, a total of 1,130 genes were up-regulated and 790 genes were down regulated. A functional gene interaction network comprised of MG-132 and its target genes, known from the literature to be affected by the compound in humans, was identified here as affected by MG-132. While MG-132 activated the expression of the 26S proteasome genes, it also decreased the expression of 19S chaperones assembly, 20S proteasome maturation, ubiquitin-like NEDD8 and its partner cullin 3 ubiquitin ligase genes. Interestingly, genes that encode proteins related to potassium ion binding, integral membrane component, ATPase and potassium channel activities were significantly down-regulated, whereas genes encoding proteins related to actin binding and microtubule motor activity were significantly up regulated. MG-132 caused important changes in the worm tegument; peeling, outbreaks and swelling in the tegument tubercles could be observed, which is consistent with interference on the ionic homeostasis in S. mansoni. Finally, we showed the down-regulation of Bax pro-apoptotic gene, as well as up-regulation of two apoptosis inhibitor genes, IAP1 and BRE1, and in contrast, down-regulation of Apaf-1 apoptotic activator, thus suggesting that apoptosis is deregulated in S. mansoni exposed to MG-132. A considerable insight has been gained concerning the potential of MG-132 as a gene expression modulator, and overall the data suggest that the proteasome might be an important molecular target for the design of new drugs against schistosomiasis. PMID- 28898253 TI - Engineering human cell spheroids to model embryonic tissue fusion in vitro. AB - Epithelial-mesenchymal interactions drive embryonic fusion events during development, and perturbations of these interactions can result in birth defects. Cleft palate and neural tube defects can result from genetic defects or environmental exposures during development, yet very little is known about the effect of chemical exposures on fusion events during human development because of a lack of relevant and robust human in vitro assays of developmental fusion behavior. Given the etiology and prevalence of cleft palate and the relatively simple architecture and composition of the embryonic palate, we sought to develop a three-dimensional culture system that mimics the embryonic palate and could be used to study fusion behavior in vitro using human cells. We engineered size controlled human Wharton's Jelly stromal cell (HWJSC) spheroids and established that 7 days of culture in osteogenesis differentiation medium was sufficient to promote an osteogenic phenotype consistent with embryonic palatal mesenchyme. HWJSC spheroids supported the attachment of human epidermal keratinocyte progenitor cells (HPEKp) on the outer spheroid surface likely through deposition of collagens I and IV, fibronectin, and laminin by mesenchymal spheroids. HWJSC spheroids coated in HPEKp cells exhibited fusion behavior in culture, as indicated by the removal of epithelial cells from the seams between spheroids, that was dependent on epidermal growth factor signaling and fibroblast growth factor signaling in agreement with palate fusion literature. The method described here may broadly apply to the generation of three-dimensional epithelial mesenchymal co-cultures to study developmental fusion events in a format that is amenable to predictive toxicology applications. PMID- 28898254 TI - Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis. AB - INTRODUCTION: There are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis. OBJECTIVE: The aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN). METHODS: In a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN. RESULTS: We found higher adiponectin levels in the LN group compared with the no LN group (20.4 +/- 10.3 vs 15.6 +/- 7.8 MUg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 +/- 31.4 vs 22.5 +/- 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01-1.12; p = 0.02). Instead, leptin was not associated with LN. CONCLUSION: These findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse. PMID- 28898255 TI - Molecular and biochemical characterization of a potato collection with contrasting tuber carotenoid content. AB - After wheat and rice, potato is the third most important staple food worldwide. A collection of ten tetraploid (Solanum tuberosum) and diploid (S. phureja and S. chacoense) genotypes with contrasting carotenoid content was subjected to molecular characterization with respect to candidate carotenoid loci and metabolic profiling using LC-HRMS. Irrespective of ploidy and taxonomy, tubers of these genotypes fell into three groups: yellow-fleshed, characterized by high levels of epoxy-xanthophylls and xanthophyll esters and by the presence of at least one copy of a dominant allele of the beta-Carotene Hydroxylase 2 (CHY2) gene; white-fleshed, characterized by low carotenoid levels and by the presence of recessive chy2 alleles; and orange-fleshed, characterized by high levels of zeaxanthin but low levels of xanthophyll esters, and homozygosity for a Zeaxanthin Epoxidase (ZEP) recessive allele. Novel CHY2 and ZEP alleles were identified in the collection. Multivariate analysis identified several groups of co-regulated non-polar compounds, and resulted in the grouping of the genotypes according to flesh color, suggesting that extensive cross-talk exists between the carotenoid pathway and other metabolite pathways in tubers. Postharvest traits like tuber dormancy and weight loss during storage showed little correlation with tuber carotenoid content, with the exception of zeaxanthin and its esters. Other tuber metabolites, such as glucose, monogalactosyldiacyglycerol (a glycolipid), or suberin precursors, showed instead significant correlations with both traits. PMID- 28898256 TI - Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity. AB - Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson's Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies. PMID- 28898257 TI - Transiency of retinal ganglion cell action potential responses determined by PSTH time constant. AB - Retinal ganglion cells (RGC) have been described to react to light stimuli either by producing short bursts of spikes or by maintaining a longer, continuous train of action potentials. Fast, quickly decaying responses are considered to be transient in nature and encode information about movement and direction, while cell responses that show a slow, drawn-out response fall into the sustained category and are thought to be responsible for carrying information related to color and contrast. Multiple approaches have been introduced thus far to measure and determine response transiency. In this study, we adopted and slightly modified a method described by Zeck and Masland to characterize RGC response transiency values and compare them to those obtained by alternative methods. As the first step, RGC spike responses were elicited by light stimulation and peristimulus time histograms (PSTHs) were generated. PSTHs then were used to calculate the time constant (PSTHtau approach). We show that this method is comparable to or more reliable than alternative approaches to describe the temporal characteristics of RGC light responses. In addition, we also show that PSTHtau-s are compatible with time constants measured on RGC and/or bipolar cell graded potentials; thus they are suitable for studying signaling through parallel retinal pathways. PMID- 28898258 TI - Antioxidant and cytotoxic activity of propolis of Plebeia droryana and Apis mellifera (Hymenoptera, Apidae) from the Brazilian Cerrado biome. AB - Propolis is a complex bioactive mixture produced by bees, known to have different biological activities, especially in countries where there is a rich biodiversity of plant species. The objective of this study was to determine the chemical composition and evaluate the antioxidant and cytotoxic properties of Brazilian propolis from the species Plebeia droryana and Apis mellifera found in Mato Grosso do Sul, Brazil. In the ethanolic extracts of P. droryana propolis (ExEP-P) and A. mellifera (ExEP-A) acids, phenolic compounds, terpenes and tocopherol were identified as major compounds. Both extracts presented antioxidant activity against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical, the maximum activities being 500 MUg/mL (ExEP-P) and 300 MUg/mL (ExEP-A). However, only ExEP A was able to inhibit lipid peroxidation induced by the oxidizing agent 2,2' azobis(2-amidinopropane) dihydrochloride (AAPH), which inhibited oxidative hemolysis and reduced the levels of malondialdehyde (MDA) in human erythrocytes for 4 h of incubation. The extracts also reduced the cell viability of the K562 erythroleukemia tumour line, with a predominance of necrotic death. Thus, it is concluded that the propolis produced by P. droryana and A. mellifera contain important compounds capable of minimizing the action of oxidizing substances in the organism and reducing the viability of erythroleukemia cells. PMID- 28898259 TI - Association between retinal vein occlusion and an increased risk of acute myocardial infarction: A nationwide population-based follow-up study. AB - OBJECTIVE: To investigate a possible association between retinal vein occlusion (RVO) and an increased risk of developing acute myocardial infarction (AMI). DESIGN: A population-based retrospective cohort study using the entire population of the Taiwan National Health Insurance Research Database (NHIRD) from 1st January, 2001 to 31st December, 2013. METHODS: A total of 37921 subjects with RVO were enrolled in the RVO group, and 113763 subjects without RVO were enrolled in the comparison group. The comparison group consisted of randomly selected individuals who were propensity score (PS)-matched with the RVO group at a ratio of 1:3, based on age, gender, obesity, stroke, hyperviscosity syndrome, glaucoma, and the use of antithrombotic drugs. A log-rank test was used to compare the cumulative hazard of AMI between the two groups. A multivariate Cox regression analysis was used to estimate the adjusted hazard ratios (HRs) of AMI, adjusted for PS, diabetes, hypertension, hyperlipidemia, congestive heart failure, and chronic renal failure. RESULTS: The mean age of the cohort was 62.4+/-13.2 years. RVO patients had significantly higher proportions of diabetes, hypertension, hyperlipidemia, congestive heart failure, and chronic renal failure than the comparisons. The mean follow-up period was 5.52 years in the RVO group and 5.55 years in the comparison group (p = 0.16). A log-rank test comparing the cumulative hazard curves of AMI for the two groups revealed a significant difference (p<0.0001). In the multivariate Cox regression after adjustment for PS and confounders, the RVO group had a significantly higher risk of AMI (adjusted HR = 1.21; 95% CI: 1.13 to 1.30). When the RVO group was divided into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) and analyzed separately, both groups had significantly higher adjusted HRs for developing AMI than the comparison group. Moreover, the CRVO group had a significantly higher risk of AMI than the BRVO group. CONCLUSIONS: People with RVO are at significantly greater risk of developing AMI than individuals without RVO. PMID- 28898260 TI - Hyperglycemia-related advanced glycation end-products is associated with the altered phosphatidylcholine metabolism in osteoarthritis patients with diabetes. AB - To test whether type 2 diabetic patients have an elevated level of advanced glycation end-products (AGEs) and responsible for altered phosphatidylcholine metabolism, which we recently found to be associated with osteoarthritis (OA) and diabetes mellitus (DM), synovial fluid (SF) and plasma samples were collected from OA patients with and without DM. Hyperglycemia-related AGEs including methylglyoxal (MG), free methylglyoxal-derived hydroimidazolone (MG-H1), and protein bound N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL) levels were measured in both SF and plasma samples using liquid chromatography coupled tandem mass spectrometry methodology. The correlation between these AGEs and phosphatidylcholine acyl-alkyl C34:3 (PC ae C34:3) and C36:3 (PC ae C36:3) were examined. Eighty four patients with knee OA, including 46 with DM and 38 without DM, were included in the study. There was no significant difference in plasma levels of MG, MG-H1, CML, and CEL between OA patients with and without DM. However, the levels of MG and MG-H1, but not CML and CEL in SF were significantly higher in OA patients with DM than in those without (all p <=0.04). This association strengthened after adjustment for age, body mass index (BMI), sex and hexose level (p<0.02). Moreover, the levels of MG-H1 in SF was negatively and significantly correlated with PC ae C34:3 (rho = -0.34; p = 0.02) and PC ae C36:3 (rho = -0.39; P = 0.03) after the adjustment of age, BMI, sex and hexose level. Our data indicated that the production of non-protein bound AGEs was increased within the OA-affected joint of DM patients. This is associated with changes in phosphatidylcholine metabolism and might be responsible for the observed epidemiological association between OA and DM. PMID- 28898252 TI - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta analysis. AB - BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 * 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68% units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses. PMID- 28898261 TI - Aged blood factors decrease cellular responses associated with delayed gingival wound repair. AB - Aging is a gradual biological process characterized by a decrease in cell and organism functions. Gingival wound healing is one of the impaired processes found in old rats. Here, we studied the in vivo wound healing process using a gingival repair rat model and an in vitro model using human gingival fibroblast for cellular responses associated to wound healing. To do that, we evaluated cell proliferation of both epithelial and connective tissue cells in gingival wounds and found decreased of Ki67 nuclear staining in old rats when compared to their young counterparts. We next evaluated cellular responses of primary gingival fibroblast obtained from young subjects in the presence human blood serum of individuals of different ages. Eighteen to sixty five years old masculine donors were classified into 3 groups: "young" from 18 to 22 years old, "middle-aged" from 30 to 48 years old and "aged" over 50 years old. Cell proliferation, measured through immunofluorescence for Ki67 and flow cytometry for DNA content, was decreased when middle-aged and aged serum was added to gingival fibroblast compared to young serum. Myofibroblastic differentiation, measured through alpha smooth muscle actin (alpha-SMA), was stimulated with young but not middle-aged or aged serum both the protein levels and incorporation of alpha-SMA into actin stress fibers. High levels of PDGF, VEGF, IL-6R were detected in blood serum from young subjects when compared to middle-aged and aged donors. In addition, the pro inflammatory cytokines MCP-1 and TNF were increased in the serum of aged donors. In old rat wound there is an increased of staining for TNF compared to young wound. Moreover, healthy gingiva (non injury) shows less staining compared to a wound site, suggesting a role in wound healing. Moreover, serum from middle-aged and aged donors was able to stimulate cellular senescence in young cells as determined by the expression of senescence associated beta-galactosidase and histone H2A.X phosphorylated at Ser139. Moreover, we detected an increased frequency of gamma-H2A.X-positive cells in aged rat gingival tissues. The present study suggests that serum factors present in middle-aged and aged individuals may be responsible, at least in part, for the altered responses observed during wound healing in aging. PMID- 28898262 TI - Climate and air pollution impacts on habitat suitability of Austrian forest ecosystems. AB - Climate change and excess deposition of airborne nitrogen (N) are among the main stressors to floristic biodiversity. One particular concern is the deterioration of valuable habitats such as those protected under the European Habitat Directive. In future, climate-driven shifts (and losses) in the species potential distribution, but also N driven nutrient enrichment may threaten these habitats. We applied a dynamic geochemical soil model (VSD+) together with a novel niche based plant response model (PROPS) to 5 forest habitat types (18 forest sites) protected under the EU Directive in Austria. We assessed how future climate change and N deposition might affect habitat suitability, defined as the capacity of a site to host its typical plant species. Our evaluation indicates that climate change will be the main driver of a decrease in habitat suitability in the future in Austria. The expected climate change will increase the occurrence of thermophilic plant species while decreasing cold-tolerant species. In addition to these direct impacts, climate change scenarios caused an increase of the occurrence probability of oligotrophic species due to a higher N immobilisation in woody biomass leading to soil N depletion. As a consequence, climate change did offset eutrophication from N deposition, even when no further reduction in N emissions was assumed. Our results show that climate change may have positive side-effects in forest habitats when multiple drivers of change are considered. PMID- 28898264 TI - Assessment of Listeria monocytogenes virulence in the Galleria mellonella insect larvae model. AB - Several animal models have been used to understand the molecular basis of the pathogenicity, infectious dose and strain to strain variation of Listeria monocytogenes. The greater wax worm Galleria mellonella, as an alternative model, provides some useful advantages not available with other models and has already been described as suitable for the virulence assessment of various pathogens including L. monocytogenes. The objectives of this study are: 1) confirming the usefulness of this model with a wide panel of Listeria spp. including non pathogenic L. innocua, L. seeligeri, L. welshimeri and animal pathogen L. ivanovii; 2) assessment of virulence of several isogenic in-frame deletion mutants in virulence and stress related genes of L. monocytogenes and 3) virulence assessment of paired food and clinical isolates of L. monocytogenes from 14 major listeriosis outbreaks occurred worldwide between 1980 and 2015. Larvae injected with different concentrations of Listeria were incubated at 37 degrees C and monitored over seven days for time needed to kill 50% of larvae (LT50) and to determine change of bacterial population in G. mellonella, 2 and 24 hours post-inoculation. Non-pathogenic members of Listeria and L. ivanovii showed significantly (P < 0.05) higher LT50 (lower virulence) than the wild type L. monocytogenes strains. Isogenic mutants of L. monocytogenes with the deletions in prfA, plcA, hly, actA and virR genes, also showed significantly (P < 0.05) higher LT50 than the wild type strain at the inoculum of 106CFU/larva. Food isolates had significantly (P < 0.05) lower virulence than the paired clinical isolates, at all three inoculum concentrations. L. monocytogenes strains related to non invasive (gastroenteritis) outbreaks of listeriosis showed significantly (P < 0.05) lower virulence than isolates of the same serotype obtained from outbreaks with invasive symptoms. The difference, however, was dose and strain- dependent. No significant differences in virulence were observed among the serotype tested in this study. PMID- 28898263 TI - Genome-wide analysis of parent-of-origin interaction effects with environmental exposure (PoOxE): An application to European and Asian cleft palate trios. AB - Cleft palate only is a common birth defect with high heritability. Only a small fraction of this heritability is explained by the genetic variants identified so far, underscoring the need to investigate other disease mechanisms, such as gene environment (GxE) interactions and parent-of-origin (PoO) effects. Furthermore, PoO effects may vary across exposure levels (PoOxE effects). Such variation is the focus of this study. We upgraded the R-package Haplin to enable direct tests of PoOxE effects at the genome-wide level. From a previous GWAS, we had genotypes for 550 case-parent trios, of mainly European and Asian ancestry, and data on three maternal exposures (smoking, alcohol, and vitamins). Data were analyzed for Europeans and Asians separately, and also for all ethnicities combined. To account for multiple testing, a false discovery rate method was used, where q values were generated from the p-values. In the Europeans-only analyses, interactions with maternal smoking yielded the lowest q-values. Two SNPs in the 'Interactor of little elongation complex ELL subunit 1' (ICE1) gene had a q-value of 0.14, and five of the 20 most significant SNPs were in the 'N-acetylated alpha linked acidic dipeptidase-like 2' (NAALADL2) gene. No evidence of PoOxE effects was found in the other analyses. The connections to ICE1 and NAALADL2 are novel and warrant further investigation. More generally, the new methodology presented here is easily applicable to other traits and exposures in which a family-based study design has been implemented. PMID- 28898265 TI - Sigma 1 receptor regulates ERK activation and promotes survival of optic nerve head astrocytes. AB - The sigma 1 receptor (S1R) is a unique transmembrane protein that has been shown to regulate neuronal differentiation and cellular survival. It is expressed within several cell types throughout the nervous system and visceral organs, including neurons and glia within the eye. S1R ligands are therapeutic targets for diseases ranging from neurodegenerative conditions to neoplastic disorders. However, effects of S1R activation and inhibition within glia cells are not well characterized. Within the eye, the astrocytes at the optic nerve head are crucial to the health and survival of the neurons that send visual information to the brain. In this study, we used the S1R-specific agonist, (+)-pentazocine, to evaluate S1R activation within optic nerve head-derived astrocytes (ONHAs). Treatment of ONHAs with (+)-pentazocine attenuated the level and duration of stress-induced ERK phosphorylation following oxidative stress exposure and promoted survival of ONHAs. These effects were specific to S1R activation because they were not observed in ONHAs that were depleted of S1R using siRNA-mediated knockdown. Collectively, our results suggest that S1R activation suppresses ERK1/2 phosphorylation and protects ONHAs from oxidative stress-induced death. PMID- 28898267 TI - Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation. AB - E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors. We measured ionic currents and gating currents at pH 7.4 and pH 6.0 in Xenopus laevis oocytes. Contrary to our expectation, the movement of gating charges is shifted to more hyperpolarized membrane potentials by E1784K. Voltage-clamp fluorimetry experiments show that this gating charge shift is due to the movement of the DIVS4 voltage-sensor being shifted to more hyperpolarized membrane potentials. Using a model and experiments on fast inactivation-deficient channels, we show that changes to the rate and voltage dependence of fast inactivation are sufficient to shift the conductance curve in E1784K. Our results localize the effects of E1784K to DIVS4, and provide novel insight into the role of the DIV-VSD in regulating the voltage-dependencies of activation and fast inactivation. PMID- 28898266 TI - Translating natural genetic variation to gene expression in a computational model of the Drosophila gap gene regulatory network. AB - Annotating the genotype-phenotype relationship, and developing a proper quantitative description of the relationship, requires understanding the impact of natural genomic variation on gene expression. We apply a sequence-level model of gap gene expression in the early development of Drosophila to analyze single nucleotide polymorphisms (SNPs) in a panel of natural sequenced D. melanogaster lines. Using a thermodynamic modeling framework, we provide both analytical and computational descriptions of how single-nucleotide variants affect gene expression. The analysis reveals that the sequence variants increase (decrease) gene expression if located within binding sites of repressors (activators). We show that the sign of SNP influence (activation or repression) may change in time and space and elucidate the origin of this change in specific examples. The thermodynamic modeling approach predicts non-local and non-linear effects arising from SNPs, and combinations of SNPs, in individual fly genotypes. Simulation of individual fly genotypes using our model reveals that this non-linearity reduces to almost additive inputs from multiple SNPs. Further, we see signatures of the action of purifying selection in the gap gene regulatory regions. To infer the specific targets of purifying selection, we analyze the patterns of polymorphism in the data at two phenotypic levels: the strengths of binding and expression. We find that combinations of SNPs show evidence of being under selective pressure, while individual SNPs do not. The model predicts that SNPs appear to accumulate in the genotypes of the natural population in a way biased towards small increases in activating action on the expression pattern. Taken together, these results provide a systems-level view of how genetic variation translates to the level of gene regulatory networks via combinatorial SNP effects. PMID- 28898268 TI - Diet of bottlenose dolphins (Tursiops truncatus) from the Gulf of Cadiz: Insights from stomach content and stable isotope analyses. AB - The ecological role of species can vary among populations depending on local and regional differences in diet. This is particularly true for top predators such as the bottlenose dolphin (Tursiops truncatus), which exhibits a highly varied diet throughout its distribution range. Local dietary assessments are therefore critical to fully understand the role of this species within marine ecosystems, as well as its interaction with important ecosystem services such as fisheries. Here, we combined stomach content analyses (SCA) and stable isotope analyses (SIA) to describe bottlenose dolphins diet in the Gulf of Cadiz (North Atlantic Ocean). Prey items identified using SCA included European conger (Conger conger) and European hake (Merluccius merluccius) as the most important ingested prey. However, mass-balance isotopic mixing model (MixSIAR), using delta13C and delta15N, indicated that the assimilated diet consisted mainly on Sparidae species (e.g. seabream, Diplodus annularis and D. bellottii, rubberlip grunt, Plectorhinchus mediterraneus, and common pandora, Pagellus erythrinus) and a mixture of other species including European hake, mackerels (Scomber colias, S. japonicus and S. scombrus), European conger, red bandfish (Cepola macrophthalma) and European pilchard (Sardina pilchardus). These contrasting results highlight differences in the temporal and taxonomic resolution of each approach, but also point to potential differences between ingested (SCA) and assimilated (SIA) diets. Both approaches provide different insights, e.g. determination of consumed fish biomass for the management of fish stocks (SCA) or identification of important assimilated prey species to the consumer (SIA). PMID- 28898269 TI - Faecal carriage of CTX-M extended-spectrum beta-lactamase-producing Enterobacteriaceae among street children dwelling in Mwanza city, Tanzania. AB - BACKGROUND: Data on ESBL carriage of healthy people including children are scarce especially in developing countries. We analyzed the prevalence and genotypes of ESBL-producing Enterobacteriaceae (EPE) in Tanzanian street children with rare contact to healthcare facilities but significant interactions with the environment, animals and other people. METHODOLOGY/ PRINCIPLE FINDINGS: Between April and July 2015, stool samples of 107 street children, who live in urban Mwanza were analyzed for EPE. Intestinal carriage of EPE was found in 34 (31.8%, 95% CI; 22.7-40.3) children. Of the 36 isolates from 34 children, 30 (83.3%) were Escherichia coli (E. coli) and six Klebsiella pneumoniae (K. pneumoniae). Out of 36 isolates, 36 (100%), 35 (97%), 25 (69%) and 16 (44%) were resistant to tetracycline, trimethoprim-sulfamethoxazole, ciprofloxacin and gentamicin, respectively. Beta-lactamase genes and the multilocus sequence types of E. coli and K. pneumoniae were characterized. ESBL gene blaCTX-M-15 was detected in 75% (27/36) of ESBL isolates. Sequence types (STs) 131, 10, 448 and 617 were the most prevalent in E. coli. Use of local herbs (OR: 3.5, 95% CI: 1.51-8.08, P = 0.003) and spending day and night on streets (OR: 3.6, 95% CI: 1.44-8.97, P = 0.005) were independent predictors of ESBL carriage. CONCLUSIONS/ SIGNIFICANCE: We observed a high prevalence of blaCTX-M-15 in EPE collected from street children in Tanzania. Detection of E. coli STs 131, 10, 38 and 648, which have been observed worldwide in animals and people, highlights the need for multidisciplinary approaches to understand the epidemiology and drivers of antimicrobial resistance in low-income countries. PMID- 28898270 TI - Cyclic stretch induced IL-33 production through HMGB1/TLR-4 signaling pathway in murine respiratory epithelial cells. AB - Interleukin 33 (IL-33), an inflammatory and mechanically responsive cytokine, is an important component of a TLR4-dependent innate immune process in mucosal epithelium. Although TLR4 also plays a role in sensing biomechanical stretch, a pathway of stretch-induced TLR4-dependent IL-33 biosynthesis has not been revealed. In the current study, we show that short term (6 h) cyclic stretch (CS) of cultured murine respiratory epithelial cells (MLE-12) increased intracellular IL-33 expression in a TLR4 dependent fashion. There was no detectable IL-33 in conditioned media in this interval. CS, however, increased release of the notable alarmin, HMGB1, and a neutralizing antibody (2G7) to HMGB1 completely abolished the CS mediated increase in IL-33. rHMGB1 increased IL-33 synthesis and this was partially abrogated by silencing TLR4 suggesting additional receptors for HMGB1 are involved in its regulation of IL-33. Collectively, these data reveal a HMGB1/TLR4/IL-33 pathway in the response of respiratory epithelium to mechanical stretch. PMID- 28898271 TI - A neural network based computational model to predict the output power of different types of photovoltaic cells. AB - In this article, we introduced an artificial neural network (ANN) based computational model to predict the output power of three types of photovoltaic cells, mono-crystalline (mono-), multi-crystalline (multi-), and amorphous (amor ) crystalline. The prediction results are very close to the experimental data, and were also influenced by numbers of hidden neurons. The order of the solar generation power output influenced by the external conditions from smallest to biggest is: multi-, mono-, and amor- crystalline silicon cells. In addition, the dependences of power prediction on the number of hidden neurons were studied. For multi- and amorphous crystalline cell, three or four hidden layer units resulted in the high correlation coefficient and low MSEs. For mono-crystalline cell, the best results were achieved at the hidden layer unit of 8. PMID- 28898272 TI - Iron deficiency was not the major cause of anemia in rural women of reproductive age in Sidama zone, southern Ethiopia: A cross-sectional study. AB - BACKGROUND: Anemia, which has many etiologies, is a moderate/severe public health problem in young children and women of reproductive age in many developing countries. The aim of this study was to investigate prevalence of iron deficiency, anemia, and iron deficiency anemia using multiple biomarkers and to evaluate their association with food insecurity and food consumption patterns in non-pregnant women from a rural area of southern Ethiopia. METHODS: A cross sectional study was conducted in 202 rural women of reproductive age in southern Ethiopia. Anthropometrics and socio-demographic data were collected. A venipuncture blood sample was analyzed for hemoglobin (Hb) and for biomarkers of iron status. Biomarkers were skewed and were log transformed before analysis. Mean, median, Pearson's correlations and ordinary least-squares regressions were calculated. RESULTS: Median (IQR) Hb was 138 (127, 151) g/L. Based on an altitude adjusted (1708 m) cutoff of 125 g/L for Hb, 21.3% were anemic. Plasma ferritin was <15 MUg/L in 18.6% of the women. Only one woman had alpha-1-acid glycoprotein (AGP) >1.0 g/L; four women (2%) had > 5 mg/L of C-reactive protein (CRP). Of the 43 women who were anemic, 23.3% (10 women) had depleted iron stores based on plasma ferritin. Three of these had elevated soluble transferrin receptors (sTfR). Hemoglobin (Hb) concentration was negatively correlated with sTfR (r = 0.24, p = 0.001), and positively correlated with ferritin (r = 0.17, p = 0.018), plasma iron (r = 0.15, p = 0.046), transferrin saturation (TfS) (r = 0.15, p = 0.04) and body iron (r = 0.14, p = 0.05). Overall prevalence of iron deficiency anemia was only 5%. CONCLUSION: Iron deficiency anemia was not prevalent in the study population, despite the fact that anemia would be classified as a moderate public health problem. PMID- 28898273 TI - The association of dietary pattern and breast cancer in Jiangsu, China: A population-based case-control study. AB - This study aims to examine the association of breast cancer with dietary patterns among Chinese women. A population-based case-control study was conducted in Jiangsu, China. Newly diagnosed primary breast cancer patients were recruited as cases (n = 818). Controls (n = 935), selected from the general population, were frequency matched to cases. A validated food frequency questionnaire was used to assess dietary intake. Dietary patterns were identified by factor analysis and multivariable odds ratios (OR) and 95% confidence intervals (CI) were estimated. Four dietary patterns were identified: salty, vegetarian, sweet and traditional Chinese. The traditional Chinese pattern was found to be robustly associated with a lower risk of breast cancer among both pre- and post-menopausal women (4th vs. 1st quartile: OR for pre- and post-menopausal women was 0.47 and 0.68, respectively). Women with high factor scores of the sweet pattern also showed a decreased risk of breast cancer (4th vs. 1st quartile: OR for pre- and post menopausal women was 0.47 and 0.68, respectively). No marked association was observed between a vegetarian pattern or a salty pattern and breast cancer. These findings indicate that dietary patterns of the traditional Chinese and the sweet may favorably associate with the risk of breast cancer among Chinese women. PMID- 28898274 TI - Periplasmic flagella in Borrelia burgdoferi function to maintain cellular integrity upon external stress. AB - Tapping mode atomic force microscopy (AFM) in solution was used to analyze the role of the internally located periplasmic flagella (PFs) of the Lyme disease spirochete Borrelia burgdorferi in withstanding externally applied cellular stresses. By systematically imaging immobilized spirochetes with increasing tapping forces, we found that mutants that lack PFs are more readily compressed and damaged by the imaging process compared to wild-type cells. This finding suggest that the PFs, aside from being essential for motility and involved in cell shape, play a cytoskeletal role in dissipating energy and maintaining cellular integrity in the presence of external stress. PMID- 28898275 TI - The early onset of peripheral neuropathy might be a robust predictor for time to treatment failure in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel. AB - BACKGROUND: Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel therapy for patients with metastatic breast cancer. We performed a retrospective analysis assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel. PATIENTS AND METHODS: Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively. RESULTS: Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD >= 6 months) was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the EPN group (median 11.2 months, 95% CI: 9.5 12.9) was significantly longer than that of the non-EPN group (5.7 months, 95% CI: 4.6-6.8) (p<0.001). Multivariate analysis demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for TTF. CONCLUSION: The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel. PMID- 28898276 TI - Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants. AB - Liver myofibroblasts are specialized effector cells that drive hepatic fibrosis, a hallmark process of chronic liver diseases, leading to progressive scar formation and organ failure. Liver myofibroblasts are increasingly recognized as heterogeneous with regards to their origin, phenotype, and functions. For instance, liver myofibroblasts express cell markers that are universally represented such as, ItgalphaV and Pdgfrbeta, or restricted to a given subpopulation such as, Lrat exclusively expressed in hepatic stellate cells, and Gpm6a in mesothelial cells. To study liver myofibroblasts in vitro, we have previously generated and characterized a SV40-immortalized polyclonal rat activated portal fibroblast cell line called RGF-N2 expressing multiple mesothelin mRNA transcripts. Mesothelin, a cell-surface molecule expressed in normal mesothelial cells and overexpressed in several cancers such as, mesothelioma and cholangiocarcinoma, was recently identified as a key regulator of portal myofibroblast proliferation, and fibrosis progression in the setting of chronic cholestatic liver disease. Here, we identify novel mesothelin splice variants expressed in rat activated portal fibroblasts. RGF-N2 portal fibroblast cDNA was used as template for insertion of hemagglutinin tag consensus sequence into the complete open reading frame of rat mesothelin variant coding sequences by extension PCR. Purified amplicons were subsequently cloned into an expression vector for in vitro translation and transfection in monkey COS7 fibroblasts, before characterization of fusion proteins by immunoblot and immunofluorescence. We show that rat activated portal fibroblasts, hepatic stellate cells, and cholangiocarcinoma cells express wild-type mesothelin and additional splice variants, while mouse activated hepatic stellate cells appear to only express wild-type mesothelin. Notably, rat mesothelin splice variants differ from the wild-type isoform by their protein properties and cellular distribution in transfected COS7 fibroblasts. We conclude that mesothelin is a marker of activated murine liver myofibroblasts. Mesothelin gene expression and regulation may be critical in liver myofibroblasts functions and fibrosis progression. PMID- 28898277 TI - Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer. AB - Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis associated macrophages is not known. Here we mapped and quantified hemosiderin laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer. PMID- 28898278 TI - Transcriptome analysis of Phytolacca americana L. in response to cadmium stress. AB - Phytolacca americana L. (pokeweed) has metal phytoremediation potential, but little is known about its metal accumulation-related genes. In this study, the de novo sequencing of total RNA produced 53.15 million reads covering 10.63 gigabases of transcriptome raw data in cadmium (Cd)-treated and untreated pokeweed. Of the 97,502 assembled unigenes, 42,197 had significant matches in a public database and were annotated accordingly. An expression level comparison between the samples revealed 1515 differentially expressed genes (DEGs), 923 down and 592 up-regulated under Cd treatment. A KEGG pathway enrichment analysis of DEGs revealed that they were involved in 72 metabolism pathways, with photosynthesis, phenylalanine metabolism, ribosome, phenylpropanoid biosynthesis, flavonoid biosynthesis and carbon fixation in photosynthetic organisms containing 24, 18, 72, 14, 7 and 15 genes, respectively. Genes related to heavy metal tolerance, absorption, transport and accumulation were also identified, including 11 expansins, 8 nicotianamine synthases, 6 aquaporins, 4 ZRT/IRT-like proteins, 3 ABC transporters and 3 metallothioneins. The gene expression results of 12 randomly selected DEGs were validated using quantitative real-time PCR, and showed different response patterns to Cd in their roots, stems and leaves. These results may be helpful in increasing our understanding of heavy metal hyperaccumulators and in future phytoremediation applications. PMID- 28898279 TI - Lifestyle factors and oncogenic papillomavirus infection in a high-risk male population. AB - BACKGROUND: High risk human papillomavirus (HR-HPV) infection in males is a health issue with implications for HPV-related lesions in their partners. The identification of risk factors for male infection may improve our understanding of HR-HPV transmission and prevention. The aim of this study was to evaluate the relationships between lifestyle, genital warts and HR-HPV infection. The study was focused on men with an increased risk of HR-HPV infection: male sexual partners of women diagnosed with high-grade squamous intraepithelial cervical lesions. METHODS: Men were enrolled and prospectively recruited within the first six months after diagnosis of cervical lesions in their female partners (n = 175, 2013-2016). Epidemiological and sexual behaviour data were obtained. The presence of genital warts was established by visual inspection. Detection and genotyping of HR-HPV infection in genital samples were performed with a Linear Array HPV Genotyping Test. All HR-HPV positive men were offered a follow-up exam at 12 months. SPSS version 19 was used for statistical analysis. RESULTS AND DISCUSSION: The prevalence of HR-HPV infection in men was 45.1% (79/175). Genital warts were observed in 10.3% (18/175) of the subjects. Detection of genital warts (OR 3.5, p = 0.015), smoking habits (OR 2.3, p = 0.006) and sexual debut before 16 years old (OR 2, p = 0.035) were associated with an increased risk for HR-HPV infection (univariate analysis). This association was also observed for genital warts and smoking status in a multivariate analysis. The same genotype was found after one year in 71.4% (20/28) of subjects. CONCLUSIONS: The presence of genital warts and smoking habits seem to be associated with a higher risk of HR-HPV infection in males. Earlier sexual debut may increase this risk. Extensive knowledge of the natural history of HR-HPV infection in males is an absolute requirement for the design and implementation of prevention strategies for the general population as well as for specific populations such as couples after treatment for high-grade cervical lesions. PMID- 28898280 TI - ILC2s activated by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of Trichinella spiralis infection. AB - IL-25, an IL-17 family cytokine, derived from epithelial cells was shown to regulate Th2- and Th9-type immune responses. We previously reported that IL-25 was important in promoting efficient protective immunity against T. spiralis infection; however, the cellular targets of IL-25 to elicit type-2 immunity during infection have not yet been addressed. Here, we investigated IL-25 responding cells and their involvement in mediating type-2 immune response during T. spiralis infection. ILC2 and CD4+ Th2 cells residing in the gastrointestinal tract of T. spiralis infected mice were found to express high levels of surface interleukin-17 receptor B (IL-17RB), a component of the IL-25 receptor. Following T. spiralis infection, activated ILC2s upregulated surface MHCII expression and enhanced capacity of effector T helper cell in producing antigen-specific Th2 and Th9 cytokines through MHCII-dependent interactions. Reciprocally, lack of CD4+ T helper cells impaired ILC2 function to produce type 2-associated cytokines in responding to IL-25 during T. spiralis infection. Furthermore, mice deficient in IL-17RB showed markedly reduced ILC2 numbers and antigen-specific Th2 and Th9 cytokine production during T. spiralis infection. The Il17rb-/- mice failed to mount effective antigen specific Th2 and Th9 functions resulting in diminished goblet cell and mast cell responses, leading to delayed worm expulsion in the intestines and muscles. Thus, our data indicated that ILC2s and CD4+ Th2 cells are the predominant cellular targets of IL-25 following T. spiralis infection and their collaborative interactions may play a key role in mounting effective antigen-specific Th2 and Th9 cytokine responses against T. spiralis infection. PMID- 28898282 TI - P2X3 receptor involvement in endometriosis pain via ERK signaling pathway. AB - The purinergic receptor P2X ligand-gated ion channel 3 (P2X3) is crucially involved in peripheral nociceptive processes of somatic and visceral pain. Endometriosis pain is considered as a kind of inflammatory and neuropathic pain. However, whether P2X3 is involved in endometriosis pain has not been reported up to date. Here, we aimed to determine whether P2X3 expression in endometriotic lesions is involved in endometriosis pain, which is regulated by inflammatory mediators through extracellular regulated protein kinases (ERK) signalling pathway. We found that P2X3 expressions in endometriosis endometrium and endometriotic lesions were both significantly higher as compared with control endometrium (P<0.05), and both positively correlated with pain (P<0.05). The expression levels of phosphorylated -ERK (p-ERK), phosphorylated-cAMP-response element binding protein (p-CREB), and P2X3 in endometriotic stromal cells (ESCs) were all significantly increased in comparison to the initial levels after treated with interleukin (IL)-1beta (P<0.05) or adenosine triphosphate (ATP) (P<0.05), respectively, and did not increase after the ESCs were pre-treated with ERK1/2 inhibitor. Additionally, P2X3 and calcitonin gene related peptide (CGRP) were co-expressed in endometriotic lesions. These obtained results suggest that P2X3 might be involved in endometriosis pain signal transduction via ERK signal pathway. PMID- 28898281 TI - Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: The Preblin study. AB - BACKGROUND: Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection (HBsAg negative, antiHBc positive) is uncommon, but potentially fatal. The role of HBV prophylaxis in this setting is uncertain. The aim of this study was to compare the efficacy of tenofovir disoproxil fumarate (TDF) prophylaxis versus close monitoring in antiHBc-positive, HBsAg-negative patients under treatment with rituximab (RTX)-based regimens for hematologic malignancy. METHODS: PREBLIN is a phase IV, randomized, prospective, open-label, multicenter, parallel-group trial conducted in 17 hospitals throughout Spain. Anti-HBc positive, HBsAg-negative patients with undetectable HBV DNA were randomized to receive TDF 300 mg once daily (Group I) or observation (Group II). The primary endpoint was the percentage of patients showing HBV reactivation during 18 months following initiation of RTX treatment. Patients with detectable HBV DNA (Group III) received the same dose of TDF and were analyzed together with Group I to investigate TDF safety. RESULTS: Sixty-one patients were enrolled in the study, 33 in the TDF treatment group and 28 in the observation group. By ITT analysis, HBV reactivation was 0% (0/33) in the study group and 10.7% (3/28) in the observation group (p = 0.091). None of the patients in either group showed significant differences in liver function parameters between baseline and the last follow-up sample. TDF was generally well tolerated and there were no severe treatment-related adverse events. CONCLUSION: In patients with hematological malignancy and resolved hepatitis B infection receiving RTX-based regimens, HBV reactivation did not occur in patients given TDF prophylaxis. PMID- 28898283 TI - Sustained effectiveness and cost-effectiveness of the Healthy Activity Programme, a brief psychological treatment for depression delivered by lay counsellors in primary care: 12-month follow-up of a randomised controlled trial. AB - BACKGROUND: The Healthy Activity Programme (HAP), a brief behavioural intervention delivered by lay counsellors, enhanced remission over 3 months among primary care attendees with depression in peri-urban and rural settings in India. We evaluated the sustainability of the effects after treatment termination, the cost-effectiveness of HAP over 12 months, and the effects of the hypothesized mediator of activation on clinical outcomes. METHODS AND FINDINGS: Primary care attendees aged 18-65 years screened with moderately severe to severe depression on the Patient Health Questionnaire 9 (PHQ-9) were randomised to either HAP plus enhanced usual care (EUC) (n = 247) or EUC alone (n = 248), of whom 95% completed assessments at 3 months, and 91% at 12 months. Primary outcomes were severity on the Beck Depression Inventory-II (BDI-II) and remission on the PHQ-9. HAP participants maintained the gains they showed at the end of treatment through the 12-month follow-up (difference in mean BDI-II score between 3 and 12 months = 0.34; 95% CI -2.37, 1.69; p = 0.74), with lower symptom severity scores than participants who received EUC alone (adjusted mean difference in BDI-II score = 4.45; 95% CI -7.26, -1.63; p = 0.002) and higher rates of remission (adjusted prevalence ratio [aPR] = 1.36; 95% CI 1.15, 1.61; p < 0.009). They also fared better on most secondary outcomes, including recovery (aPR = 1.98; 95% CI 1.29, 3.03; p = 0.002), any response over time (aPR = 1.45; 95% CI 1.27, 1.66; p < 0.001), higher likelihood of reporting a minimal clinically important difference (aPR = 1.42; 95% CI 1.17, 1.71; p < 0.001), and lower likelihood of reporting suicidal behaviour (aPR = 0.71; 95% CI 0.51, 1.01; p = 0.06). HAP plus EUC also had a marginal effect on WHO Disability Assessment Schedule score at 12 months (aPR = -1.58; 95% CI -3.33, 0.17; p = 0.08); other outcomes (days unable to work, intimate partner violence toward females) did not statistically significantly differ between the two arms. Economic analyses indicated that HAP plus EUC was dominant over EUC alone, with lower costs and better outcomes; uncertainty analysis showed that from this health system perspective there was a 95% chance of HAP being cost-effective, given a willingness to pay threshold of Intl$16,060 equivalent to GDP per capita in Goa-per quality-adjusted life year gained. Patient-reported behavioural activation level at 3 months mediated the effect of the HAP intervention on the 12-month depression score (beta = -2.62; 95% CI 3.28, -1.97; p < 0.001). Serious adverse events were infrequent, and prevalence was similar by arm. We were unable to assess possible episodes of remission and relapse that may have occurred between our outcome assessment time points of 3 and 12 months after randomisation. We did not account for or evaluate the effect of mediators other than behavioural activation. CONCLUSIONS: HAP's superiority over EUC at the end of treatment was largely stable over time and was mediated by patient activation. HAP provides better outcomes at lower costs from a perspective covering publicly funded healthcare services and productivity impacts on patients and their families. TRIAL REGISTRATION: ISRCTN registry ISRCTN95149997. PMID- 28898285 TI - Improving the community-temperature index as a climate change indicator. AB - Climate change indicators are tools to assess, visualize and communicate the impacts of climate change on species and communities. Indicators that can be applied to different taxa are particularly useful because they allow comparative analysis to identify which kinds of species are being more affected. A general prediction, supported by empirical data, is that the abundance of warm-adapted species should increase over time, relative to the cool-adapted ones within communities, under increasing ambient temperatures. The community temperature index (CTI) is a community weighted mean of species' temperature preferences and has been used as an indicator to summarize this temporal shift. The CTI has the advantages of being a simple and generalizable indicator; however, a core problem is that temporal trends in the CTI may not only reflect changes in temperature. This is because species' temperature preferences often covary with other species attributes, and these other attributes may affect species response to other environmental drivers. Here, we propose a novel model-based approach that separates the effects of temperature preference from the effects of other species attributes on species' abundances and subsequently on the CTI. Using long-term population data of breeding birds in Denmark and demersal marine fish in the southeastern North Sea, we find differences in CTI trends with the original approach and our model-based approach, which may affect interpretation of climate change impacts. We suggest that our method can be used to test the robustness of CTI trends to the possible effects of other drivers of change, apart from climate change. PMID- 28898284 TI - Optic nerve head and retinal blood flow regulation during isometric exercise as assessed with laser speckle flowgraphy. AB - : The aim of the present study was to investigate regulation of blood flow (BF) in the optic nerve head (ONH) and a peripapillary region (PPR) during an isometric exercise-induced increase in ocular perfusion pressure (OPP) using laser speckle flowgraphy (LSFG) in healthy subjects. For this purpose, a total of 27 subjects was included in this study. Mean blur rate in tissue (MT) was measured in the ONH and in a PPR as well as relative flow volume (RFV) in retinal arteries (ART) and veins (VEIN) using LSFG. All participants performed isometric exercise for 6 minutes during which MT and mean arterial pressure were measured every minute. From these data OPP and pressure/flow curves were calculated. Isometric exercise increased OPP, MTONH and MTPRR. The relative increase in OPP (78.5 +/- 19.8%) was more pronounced than the increase in BF parameters (MTONH: 18.1 +/- 7.7%, MTPRR: 21.1 +/- 8.3%, RFVART: 16.5 +/-12.0%, RFVVEIN: 17.7 +/- 12.4%) indicating for an autoregulatory response of the vasculature. The pressure/flow curves show that MTONH, MTPRR, RFVART, RFVVEIN started to increase at OPP levels of 51.2 +/- 2.0%, 58.1 +/- 2.4%, 45.6 +/- 1.9% and 45.6 +/- 1.9% above baseline. These data indicate that ONHBF starts to increase at levels of approx. 50% increase in OPP: This is slightly lower than the values we previously reported from LDF data. Signals from the PPR may have input from both, the retina and the choroid, but the relative contribution is unknown. In addition, retinal BF appears to increase at slightly lower OPP values of approximately 45%. LSFG may be used to study ONH autoregulation in diseases such as glaucoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT02102880. PMID- 28898287 TI - Multimodal cues provide redundant information for bumblebees when the stimulus is visually salient, but facilitate red target detection in a naturalistic background. AB - Our understanding of how floral visitors integrate visual and olfactory cues when seeking food, and how background complexity affects flower detection is limited. Here, we aimed to understand the use of visual and olfactory information for bumblebees (Bombus terrestris terrestris L.) when seeking flowers in a visually complex background. To explore this issue, we first evaluated the effect of flower colour (red and blue), size (8, 16 and 32 mm), scent (presence or absence) and the amount of training on the foraging strategy of bumblebees (accuracy, search time and flight behaviour), considering the visual complexity of our background, to later explore whether experienced bumblebees, previously trained in the presence of scent, can recall and make use of odour information when foraging in the presence of novel visual stimuli carrying a familiar scent. Of all the variables analysed, flower colour had the strongest effect on the foraging strategy. Bumblebees searching for blue flowers were more accurate, flew faster, followed more direct paths between flowers and needed less time to find them, than bumblebees searching for red flowers. In turn, training and the presence of odour helped bees to find inconspicuous (red) flowers. When bees foraged on red flowers, search time increased with flower size; but search time was independent of flower size when bees foraged on blue flowers. Previous experience with floral scent enhances the capacity of detection of a novel colour carrying a familiar scent, probably by elemental association influencing attention. PMID- 28898286 TI - Structural investigation of C6/36 and Vero cell cultures infected with a Brazilian Zika virus. AB - Zika virus (ZIKV) is a member of the flavivirus genus, and its genome is approximately 10.8 kilobases of positive-strand RNA enclosed in a capsid and surrounded by a membrane. Studies on the replication dynamics of ZIKV are scarce, which limits the development of antiviral agents and vaccines directed against ZIKV. In this study, Aedes albopictus mosquito lineage cells (C6/36 cells) and African green monkey kidney epithelial cells (Vero cells) were inoculated with a ZIKV sample isolated from a Brazilian patient, and the infection was characterized by immunofluorescence staining, phase contrast light microscopy, transmission electron microscopy and real-time RT-PCR. The infection was observed in both cell lineages, and ZIKV particles were observed inside lysosomes, the rough endoplasmic reticulum and viroplasm-like structures. The susceptibility of C6/36 and Vero cells to ZIKV infection was demonstrated. Moreover, this study showed that part of the replicative cycle may occur within viroplasm-like structures, which has not been previously demonstrated in other flaviviruses. PMID- 28898288 TI - Long-term no-till: A major driver of fungal communities in dryland wheat cropping systems. AB - In the dryland Pacific Northwest wheat cropping systems, no-till is becoming more prevalent as a way to reduce soil erosion and fuel inputs. Tillage can have a profound effect on microbial communities and soilborne fungal pathogens, such as Rhizoctonia. We compared the fungal communities in long-term no-till (NT) plots adjacent to conventionally tilled (CT) plots, over three years at two locations in Washington state and one location in Idaho, US. We used pyrosequencing of the fungal ITS gene and identified 422 OTUs after rarefication. Fungal richness was higher in NT compared to CT, in two of the locations. Humicola nigrescens, Cryptococcus terreus, Cadophora spp. Hydnodontaceae spp., and Exophiala spp. were more abundant in NT, while species of Glarea, Coniochaetales, Mycosphaerella tassiana, Cryptococcus bhutanensis, Chaetomium perlucidum, and Ulocladium chartarum were more abundant in CT in most locations. Other abundant groups that did not show any trends were Fusarium, Mortierella, Penicillium, Aspergillus, and Macroventuria. Plant pathogens such as Rhizoctonia (Ceratobasidiaceae) were not abundant enough to see tillage differences, but Microdochium bolleyi, a weak root pathogen, was more abundant in NT. Our results suggest that NT fungi are better adapted at utilizing intact, decaying roots as a food source and may exist as root endophytes. CT fungi can utilize mature plant residues that are turned into the soil with tillage as pioneer colonizers, and then produce large numbers of conidia. But a larger proportion of the fungal community is not affected by tillage and may be niche generalists. PMID- 28898291 TI - Correction: Mucosal fluid glycoprotein DMBT1 suppresses twitching motility and virulence of the opportunistic pathogen Pseudomonas aeruginosa. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006392.]. PMID- 28898290 TI - Comparative effectiveness and tolerance of immunosuppressive treatments for idiopathic membranous nephropathy: A network meta-analysis. AB - BACKGROUND: Immunosuppressive agents in general are shown to prevent renal progression and all-cause mortality in idiopathic membranous nephropathy (IMN) patients with nephrotic syndrome. However, the efficacy and safety of different immunosuppressive treatments have not been systematic assessed and compared. A network meta-analysis was performed to compare different immunosuppressive treatment in IMN. METHODS: Cochrane library, MEDLINE, EMBASE and trial register system were searched for randomized controlled trials reporting the treatments for IMN to May 3, 2016. Composite endpoint of mortality or end-stage kidney disease (ESKD), complete or partial proteinuria remission and withdrawal because of treatment adverse events were compared combing direct and indirect comparison using network meta-analysis. Ranking different immunosuppressive treatments in the outcomes were analyzed by using surface under the cumulative ranking curve (SUCRA). RESULTS: Total 36 randomized controlled trials (n = 2018) covering 11 kinds of treatments were included. Compared with non-immunosuppressive treatment, only cyclophosphamide (CTX) and chlorambucil significantly reduced the risk of composite outcome of mortality or ESKD while combining the direct and indirect comparison (OR = 0.31, 95%CI: 0.12-0.81 and OR = 0.33, 95%CI: 0.12-0.92). CTX increased the composite outcome of complete remission (CR) or partial remission (PR) (OR = 4.29, 95%CI: 2.30-8.00) but chlorambucil did not (OR = 1.58, 95%CI: 0.80-3.12) as compared with non-immunosuppressive treatment. Chlorambucil also significantly increased the withdrawal risk (OR = 3.34, 95%CI: 1.37-8.17) as compared to CTX. Both tacrolimus (OR = 3.10, 95%CI: 1.36-7.09) and cyclosporine (CsA) (OR = 2.81, 95%CI: 1.08-7.32) also significantly increased the rate of CR or PR as compared with non-immunosuppressive treatment (without significant difference as compared with CTX), while ranking results showed that cyclosporine or tacrolimus was with less possibility of drug withdrawal as compared to CTX. CONCLUSIONS: Cyclophosphamide and chlorambucil reduce risk of ESKD or death in IMN with nephrotic range proteinuria, but carry substantial toxicity that may be lower for cyclophosphamide. Tacrolimus and cyclosporine increase the possibility of proteinuria remission with less drug withdrawal, but the effects on kidney failure remain uncertain. PMID- 28898289 TI - TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses. AB - Toll-like receptor (TLR)-mediated signaling are critical for host defense against pathogen invasion. However, excessive responses would cause harmful damages to the host. Here we show that deficiency of the E3 ubiquitin ligase TRIM32 increases poly(I:C)- and LPS-induced transcription of downstream genes such as type I interferons (IFNs) and proinflammatory cytokines in both primary mouse immune cells and in mice. Trim32-/- mice produced higher levels of serum inflammatory cytokines and were more sensitive to loss of body weight and inflammatory death upon Salmonella typhimurium infection. TRIM32 interacts with and mediates the degradation of TRIF, a critical adaptor protein for TLR3/4, in an E3 activity-independent manner. TRIM32-mediated as well as poly(I:C)- and LPS induced degradation of TRIF is inhibited by deficiency of TAX1BP1, a receptor for selective autophagy. Furthermore, TRIM32 links TRIF and TAX1BP1 through distinct domains. These findings suggest that TRIM32 negatively regulates TLR3/4-mediated immune responses by targeting TRIF to TAX1BP1-mediated selective autophagic degradation. PMID- 28898292 TI - The effect of age on the intestinal mucus thickness, microbiota composition and immunity in relation to sex in mice. AB - A mucus layer covers and protects the intestinal epithelial cells from direct contact with microbes. This mucus layer not only prevents inflammation but also plays an essential role in microbiota colonization, indicating the complex interplay between mucus composition-microbiota and intestinal health. However, it is unknown whether the mucus layer is influenced by age or sex and whether this contributes to reported differences in intestinal diseases in males and females or with ageing. Therefore, in this study we investigated the effect of age on mucus thickness, intestinal microbiota composition and immune composition in relation to sex. The ageing induced shrinkage of the colonic mucus layer was associated with bacterial penetration and direct contact of bacteria with the epithelium in both sexes. Additionally, several genes involved in the biosynthesis of mucus were downregulated in old mice, especially in males, and this was accompanied by a decrease in abundances of various Lactobacillus species and unclassified Clostridiales type IV and XIV and increase in abundance of the potential pathobiont Bacteroides vulgatus. The changes in mucus and microbiota in old mice were associated with enhanced activation of the immune system as illustrated by a higher percentage of effector T cells in old mice. Our data contribute to a better understanding of the interplay between mucus-microbiota and immune responses and ultimately may lead to more tailored design of strategies to modulate mucus production in targeted groups. PMID- 28898293 TI - The Vibrio cholerae var regulon encodes a metallo-beta-lactamase and an antibiotic efflux pump, which are regulated by VarR, a LysR-type transcription factor. AB - The genome sequence of V. cholerae O1 Biovar Eltor strain N16961 has revealed a putative antibiotic resistance (var) regulon that is predicted to encode a transcriptional activator (VarR), which is divergently transcribed relative to the putative resistance genes for both a metallo-beta-lactamase (VarG) and an antibiotic efflux-pump (VarABCDEF). We sought to test whether these genes could confer antibiotic resistance and are organised as a regulon under the control of VarR. VarG was overexpressed and purified and shown to have beta-lactamase activity against penicillins, cephalosporins and carbapenems, having the highest activity against meropenem. The expression of VarABCDEF in the Escherichia coli (DeltaacrAB) strain KAM3 conferred resistance to a range of drugs, but most significant resistance was to the macrolide spiramycin. A gel-shift analysis was used to determine if VarR bound to the promoter regions of the resistance genes. Consistent with the regulation of these resistance genes, VarR binds to three distinct intergenic regions, varRG, varGA and varBC located upstream and adjacent to varG, varA and varC, respectively. VarR can act as a repressor at the varRG promoter region; whilst this repression was relieved upon addition of beta lactams, these did not dissociate the VarR/varRG-DNA complex, indicating that the de-repression of varR by beta-lactams is indirect. Considering that the genomic arrangement of VarR-VarG is strikingly similar to that of AmpR-AmpC system, it is possible that V. cholerae has evolved a system for resistance to the newer beta lactams that would prove more beneficial to the bacterium in light of current selective pressures. PMID- 28898294 TI - Causal illusions in children when the outcome is frequent. AB - Causal illusions occur when people perceive a causal relation between two events that are actually unrelated. One factor that has been shown to promote these mistaken beliefs is the outcome probability. Thus, people tend to overestimate the strength of a causal relation when the potential consequence (i.e. the outcome) occurs with a high probability (outcome-density bias). Given that children and adults differ in several important features involved in causal judgment, including prior knowledge and basic cognitive skills, developmental studies can be considered an outstanding approach to detect and further explore the psychological processes and mechanisms underlying this bias. However, the outcome density bias has been mainly explored in adulthood, and no previous evidence for this bias has been reported in children. Thus, the purpose of this study was to extend outcome-density bias research to childhood. In two experiments, children between 6 and 8 years old were exposed to two similar setups, both showing a non-contingent relation between the potential cause and the outcome. These two scenarios differed only in the probability of the outcome, which could either be high or low. Children judged the relation between the two events to be stronger in the high probability of the outcome setting, revealing that, like adults, they develop causal illusions when the outcome is frequent. PMID- 28898295 TI - Relationships between sleep duration, physical activity and body mass index in young New Zealanders: An isotemporal substitution analysis. AB - BACKGROUND: The evidence regarding the unique effect of sedentary behaviour on obesity among children is unclear. Moreover, the effect of substituting sedentary behaviour with physical activity of different intensities on the body composition of children has received limited empirical study. OBJECTIVE: To examine the mathematical effects on Body Mass Index (BMI) of substituting sedentary behaviours with physical activities of different intensities on children and youth aged 5-14 years old in New Zealand. METHODS: Secondary analysis of accelerometer data from the National Survey of Children and Young People's Physical Activity and Dietary Behaviours in New Zealand (2008/09) was conducted. A total of 1812 children and youth aged 5-24 years provided accelerometer-derived data on daily sedentary time (SB), light intensity physical activity (LPA) and moderate to vigorous physical activity (MVPA). Sleep time was assessed with a validated computerised use-of-time tool. BMI was assessed using anthropometric measurements. Multiple linear regression models were used to examine the independent associations of SB, Sleep time, LPA, and MVPA on BMI. The isotemporal substitution approach was used to ascertain the mathematical effect of substituting each of the other behaviours on BMI. Analyses were stratified by age groups. RESULTS: SB showed a unique (inverse) association with BMI across all age groups (p<0.05) but 20-24 years (p>0.05). Similarly, MVPA was positively associated (p<0.001) across all age groups. Among age groups 5-9 years, 10-14 years and 15-19 years, the estimated impact of replacing 60 min/day of SB with the same amount of MVPA time resulted in decreased BMI for all age groups (p<0.001), ranging from -1.26 (5-9 years) to -1.43 units (15-19 years). Similar results were achieved when SB was replaced with LPA or sleeping time for children (5-19 years). In young people (age group 20-24), the impact of replacing 30 min/day of SB with MVPA resulted in an estimated -1 BMI units decrease (p<0.001). CONCLUSION: MVPA and SB have a unique effect on BMI. Further, substituting SB with LPA or MVPA was associated with a favourable effect on BMI across all age groups; with MVPA having the strongest association. PMID- 28898296 TI - Characterizing the interaction between physicians, pharmacists and pharmaceutical representatives in a middle-income country: A qualitative study. AB - BACKGROUND: Studies around the world have shown that interactions between pharmaceutical companies, pharmacists and physicians have a great influence on prescribing and drug dispensing practices. In middle-income countries, the nature and extent of these interactions have not been well researched. Our objectives were to qualitatively explore the nature of the interactions between pharmaceutical companies, physicians and pharmacists, their impact on drug prescription and dispensing practices in Lebanon. METHODS AND FINDINGS: We used grounded theory approach as well as the known sponsor, purposive, and snowballing sampling strategies to identify interviewees from the three respective groups: physicians, pharmacists, and pharmaceutical representatives. We conducted semi structured and analyzed transcripts thematically. This study encompassed 6 pharmaceutical representatives, 13 physicians and 13 pharmacists. The following themes emerged: purpose and driver for the interactions, nature of the interactions, incentives, impact on prescription practices, ethical considerations, and suggestions for managing the interactions. The main purposes for the interaction were educational, promotional, and monitoring prescription practices and dispensing, while the main drivers for these interactions were market potential and neighborhood socio-economic status. Physicians, pharmacists and pharmaceutical representatives who engage in these interactions benefit from a variety of incentives, some of which were characterized as unethical. It appears that pharmaceutical companies give prominence to selected physicians within their communities. Although members of the three interviewed groups refer to some of the interactions as being problematic, they described a culture of acceptance of gift giving. We developed a framework that depicts the prevailing politico-cultural environment, the interactions between the three professional groups, and their impact on drug prescription. Underreporting is the main limitation of this study. CONCLUSION: Interactions between physicians, pharmacists and pharmaceutical representatives are frequent. Although these interactions can be beneficial, they still have a substantial effect on drug prescription and dispensing practices. Hence, the need for new policies that regulate these interactions and penalize any misconduct. PMID- 28898298 TI - [Evaluation of Significant Autobiographical Memories Scale: Design and structural validation at an exploratory level]. AB - Personal memories are multimodal cognitive representations. Nowadays, psychometric instruments which aim to assess signifcant memories phenomenological features are scarce. Consequently, the Evaluation of Signifcant Autobiographical Memories Scale was constructed and structural validated at an exploratory level. A total of 404 individuals from Buenos Aires city (Argentina) participated in the research. Initially, an expert judgment and a pilot study administration were carried out. Next, a homogeneity and a principal components analysis were implemented. To assess the scale reliability, Cronbach's alphas coefficients were analyzed. The fnal version has 30 Likert response items gathered in 8 dimensions. Satisfactory psychometric proprieties were obtained - internal consistency of .892 and a total explained variance of 65.78%. The scale provides two main scores regarding the total quantity and intensity of the phenomenological components as well as a partial score per each dimension. It is stated that the test will prove to be useful in the research feld as well as in the clinical area. PMID- 28898297 TI - Effects and safety of oral tolvaptan in patients with congestive heart failure: A systematic review and network meta-analysis. AB - AIMS: Several studies reported treatment benefits of tolvaptan in patients with congestive heart failure (CHF). However, the optimal dosage remains unclear. We aimed to compare different dosage of tolvaptan to determine the optimal dosage in terms of the efficacy and safety. METHODS: We searched MEDLINE, PubMed, EMBASE, Cochrane CENTRAL and ClinicalTrials.gov through Aug 31, 2016. Randomized controlled trials (RCTs) comparing tolvaptan of different dosages or to placebo in patients with CHF were included. We used network meta-analysis to look for the optimal dosage in terms of effectiveness and safety. Urine output, body weight change and change in serum sodium were the main outcomes of efficacy. Adverse effects were the secondary outcomes. Quality was assessed by Cochrane risk-of bias tool. RESULTS: Twelve RCTs reporting 14 articles with 5793 patients (mean age, 65.7 +/- 11.9 years; 73.7% man) were included. Compared with placebo, the tolvaptan 30 mg had similar effects to tolvaptan 45-90 mg in terms of urine output (mean difference [MD] 2.03 liter; 95% confidence interval [CI] 1.3 to 2.71), body weight change (MD -1.12 kg; 95% CI -1.37 to -0.88) and change in serum sodium (MD 3.06 meq/L; 95% CI 2.43 to 3.68). Compared with placebo, tolvaptan of different dosage showed a non-significant higher risk of adverse effects. CONCLUSIONS: These findings suggest that tolvaptan 30 mg and 45 mg may be the optimum dosage for CHF patients, because of its ability to provide favourable clinical results without greater adverse effects. However, tolvaptan is not beneficial for reducing all-cause mortality in CHF patients. PMID- 28898299 TI - [Marijuana]. PMID- 28898300 TI - [Marijuana: A toxicological approach]. AB - From an adult perspective, both marijuana and alcohol consumption are becoming natural. Among illegal substances, marijuana has disseminated all over the word and specially in Argentina. Thus, a scientifc approach towards this issue must be developed and we should spread what we know about toxicity and adverse effects, particularly among adolescents. The impact of this kind of toxic during the neurodevelopmental period, both in cognitive and impulse control areas, may involve negative consequences for users at a later age. PMID- 28898301 TI - [Notes for a science of cannabis]. AB - The therapeutic and recreational use of cannabis and its derived products has been known since ancient times. The debate regarding its properties and legal status, which has recently changed in several states, has grown in recent years. However, scientifc evidence for or against its use, as well as for potential toxic effects in the short or long term, is scarce. In spite of the promising perspectives for its therapeutic use, in particular for neurological diseases such as refractory epilepsy or multiple sclerosis, which certainly aim for a controlled administration, this opinion article advocates for a greater incidence of basic and clinical scientifc research that may take this debate further away from matters of belief or prejudice and put it where it belongs, together with evidence and rationality. PMID- 28898302 TI - [Belief system regarding Cannabis, its use and consequences: Users versus non users in colombian university students]. AB - Descriptive and comparative study of cross-sectional that had as objective to evaluate and compare the beliefs about cannabis, its use and potential consequences between two groups of Colombian university students, matched by gender and age. The frst group consisted of ordinary consumers of cannabis (n=35) the second group consisted of students that have never tried cannabis (n=35). The results showed that the group of consumers presents a moderate risk of abuse and only the 20% fulflled dependence criteria. Furthermore, the non-consumers group was mostly agree about that the marijuana use: damages the memory, deteriorates the cognitive functions, creates dependency, can affect the neurons and mental health. Also, it can lead to legal problems, it is a harmful drug for the health, it affects the academic performance, it creates problems with the family, friends, couple and the like, it reduces the driving ability, and, that the marijuana that is sold in the street is always pure. The consumer group, instead, agreed that smoking tobacco affects the lungs more than smoking marijuana. Marijuana has a positive in?uence on the brain, it increases the creativity, and it is less damaging than alcohol and tobacco. Smart people smoke marijuana and it has medicinal effects. In conclusion, according to the kind of beliefs that they have about this drug, the cannabis consumers would have a decreased perception of risk in relation to the potential risk that the consumption brings from two points of view: a. They minimize the real risks of consuming and, b. They attribute some benefts and virtues to the cannabis. The kind of beliefs that the consumer have are maybe in?uenced, at least, in part, for experiences of family and other consumers and, furthermore, the reinforcement of the same consume. PMID- 28898303 TI - [Legal, illegal and legitimate in the use and misuse of substances]. AB - his article attempts to establish a dialogue between existing laws, their effectiveness and the controversy within the context of the popularization of substance use in the country. To this end, the origin of the criminalization of substance use and the contradictory positions that have been adopted in laws and court rulings are tracked. All this is confronted with the growing habit of psychoactive substance use among general population, which no laws and rulings have yet managed to in?uence. PMID- 28898304 TI - [Use of Cannabis and incidence of psychotic symptoms: Evidence from Buenos Aires]. AB - OBJECTIVES: Cannabis use has been frequently associated to the experience of psychotic symptoms in the research literature. The objective was to investigate the association between cannabis use and psychotic like experiences in the city of Buenos Aires. METHODS: A sample of 862 respondents of the metropolitan area of Buenos Aires, aged =18 years, was interviewed regarding their cannabis use, and presence of psychotic like experiences. RESULTS: Cannabis use was associated to psychotic like experiences, in particular to perceptual abnormalities (visual and auditory hallucinations). No association was found, however, between frequency of use and number of PLEs. CONCLUSIONS: Cannabis use could be related to the presence of PLEs. These results are pertinent regarding prevention, and could contribute to the analysis of the safety of cannabis use in the population studied. PMID- 28898305 TI - [Cannabis and its association with psychosis: What do we know?] AB - Psychoses are a group of diseases that cause enormous health and emotional burden for the patient and their families. In recent decades, the need for early intervention to improve their prognosis has been highlighted. It has long been postulated that cannabis use is a risk factor added to other factors such as genetics and developmental abnormalities. For this reason, and in the light of a growing movement for legalization of its use, it is vitally important to have reliable information to understand the details of the relationship between cannabis abuse and the development of psychosis. The purpose of this paper is to review the available information on the subject. Beyond some methodological criticisms, epidemiological fndings provide strong evidence that cannabis use may increase the risk of psychotic disorders, a public health message that should be spread. PMID- 28898306 TI - [Cannabis use in Epilepsy. Current situation in Argentina and abroad]. AB - Although at present we have over 20 different types of drugs for epilepsy, 30 to 40% of patients continue to have seizures. Preliminary data from human studies suggest that cannabis, cannabidiol in particular, is effective in the treatment of some patients with epilepsy. However, the available data are limited and do not allow defnitive conclusions. Only randomized clinical trials with controlled double-blind, placebo-controlled utilizing secure preparations and one or more cannabinoids, will provide comprehensive information on the effcacy and safety of use. In order to perform these trials it is necessary to have legislation authorizing the use of cannabis on epilepsy. PMID- 28898307 TI - ["Every use of cannabis is therapeutic"]. PMID- 28898308 TI - [The treatment of cannabis dependence: Clinical work, psychotherapy and evidence]. AB - Identifying compulsive consumption of marijuana in association with another mental disorder (attentional defcit disorder, bipolar disorder, depression or psychosis) presents the challenge of clarifying validated therapeutic strategies, especially within the teen population, in which it shows the highest prevalence. The ever-increasing prevalence and the need for regional treatments, demand that we approach this health matter as a public health issue. The ideological con?icts related to the necessary decriminalization of consumption and the current debate on the medical use of marijuana often confuse the urgent need to establish effective therapeutic strategies for the population affected by this mental disorder. Family therapy and community reinforcement are one of the most effcient interventions, other than the traditional individual and group therapies. Contingent, motivational and cognitive-behavioral tailored interventions appear to be most effcient and recommendable. Aerobic exercise and the use of mobile technology also show effectiveness. The administration of medications such as gabepentin, the aminoacid n-acetyl cysteine (NAC) and the cannabinoid cannabidiol (CBD) appear to be very promising. Usual medications, such as valproic acid, quetiapine and bupropion, increase craving, therefore intensifying the need for consumption and thus yielding overall negative results. PMID- 28898309 TI - [Psychiatric complications of cannabis use]. AB - atural and synthetic cannabinoids modify the modulatory activity of the endocannabinoid system. Psychiatric complications induced by cannabis are analyzed, i.e. those that start with intoxication but persist beyond the removal of the drug (cognitive, psychotic and anxiety disorders) and the development of addictive behavior. Adolescence is the period of greatest vulnerability to cognitive impact. Cannabis-induced psychosis has been linked to consumption of high concentration of tetrahydrocannabinol and personality traits of anxiety and somatization. The incidence of anxiety is related to the cannabinoid effect but even more with neurobiological changes of addiction. PMID- 28898310 TI - [Tuberculosis in children in Chile]. PMID- 28898311 TI - [Breastfeeding, gross motor development and obesity, is there any causal association?] AB - Childhood obesity is the main nutritional and public health problem in Chile, being the principal causes, the increase in energy dense foods and the decline of physical activity. Interventions to prevent obesity at infancy are focused mainly in improving quality and quantity of dietary intake, without taking into account physical activity, which is expressed under two years of age, mainly by motor development. Some studies have proven that motor development at early age, may influence the ability to perform physical activity. Thus, infants scoring a lower motor development may have a greater risk of becoming obese. It isn?t know if childhood obesity causes lower motor development (given that children may have greater difficulty to move), or on the contrary, it is the lower ability to move, which increases the obesity risk. The objective of this manuscriptis analize the evidence regards the relation between breastfeeding, motor development and obesity in the childhood.To be able to understand this asocation and casual mecanism, it is important to develop stategys focused in early infancy to promote breastfeeding, healthy eating and early stimulation, starting in pediatric office. PMID- 28898312 TI - [Analysis of risk factors for neonatal death in Chile, 2010-2014]. AB - AIM: To analyze socio-demographic as maternal and newborn factors associated with neonatal mortality in a tertiary hospital in Chile. PATIENTS AND METHOD: A retrospective analysis of case (neonatal death) and control (live births) was performed. A match 1:2 proportion considering year, month of birth and gender was made. By reviewing medical records and existing databases, we analyzed sociodemographic and pathophysiological variables of the mother and their newborn in a period between 2010 and 2014. RESULTS: During the period of study 81 neonatal deaths occurred in the hospital, with an estimated rate of 5.8 per thousand live births. Sixty-five cases were recruted, who were compared with 130 controls. The main causes of death were prematurity and congenital malformations. It was found that the presence of preterm birth (OR: 3; 95% CI 1.1-8.7), newborn small for gestational age (OR: 4; 95% CI 1.7-12.1) Apgar score at minute 4-7 (OR: 4; 95% CI 1.8-10.5), maternal activity outside the household (OR: 4; 95% CI 2.3 8.7), and cesarean delivery (OR: 3; 95% CI 1.5-5.6) were the most prevalent risk factors. CONCLUSION: Neonatal mortality is associated with prematurity. Therefore it is of relevance to continue promoting efforts to prevent preterm birth. PMID- 28898313 TI - [Death from external causes in infants in Colombia 2005-2013]. AB - : Latin America has shown a significant reduction in infant mortality in recent years. The objective of this study was to analyze official data for children under five years of age in Colombia, emphasizing external causes of death, which have been less studied. PATIENTS AND METHOD: Descriptive cross-sectional design using secondary information from death records reported by the National Administrative Department of Statistics (DANE) and information dynamic tables of vital statistics, taken from the official information system of the Ministry of Health and Social Protection (SISPRO), between 2005 and 2013 were reviewed. The information was organized in tables for descriptive analysis of variables such as age, sex, and specific cause of death, by departments. RESULTS: In this period 106,339 children under 5 years died; 85,897 of them (81%) in the first year of life. The number of deaths decreased from 14.266 in 2005, to 9.499 in 2013. The main external cause of death was drowning, responsible for 1749 deaths, followed by traffic accidents, 1.282. Homicides were responsible for 692 deaths. In all the causes of death analyzed there was a decline over the decade. DISCUSSION: Colombia is accomplishing the fourth millennium goal, ?reduce the mortality of children under 5 years.? Progress has been made in deaths from external causes, but there is still some way to go. PMID- 28898314 TI - [Associated factors to non-operative management failure of hepatic and splenic lesions secondary to blunt abdominal trauma in children]. AB - INTRODUCTION: The non operative management (NOM) is the standard management of splenic and liver blunt trauma in pediatric patients.Hemodynamic instability and massive transfusions have been identified as management failures. Few studies evaluate whether there exist factors allowing anticipation of these events. The objective was to identify factors associated with the failure of NOM in splenic and liver injuries for blunt abdominal trauma. PATIENTS AND METHOD: Retrospective analysis between 2007-2015 of patients admitted to the pediatric surgery at University Hospital Saint Vincent Foundation with liver trauma and/or closed Spleen. RESULTS: 70 patients were admitted with blunt abdominal trauma, 3 were excluded for immediate surgery (2 hemodynamic instability, 1 peritoneal irritation). Of 67 patients who received NOM, 58 were successful and 9 showed failure (8 hemodynamic instability, 1 hollow viscera injury). We found 3 factors associated with failure NOM: blood pressure (BP) < 90 mmHg at admission (p = 0.0126; RR = 5.19), drop in hemoglobin (Hb) > 2 g/dl in the first 24 hours (p = 0.0009; RR = 15.3), and transfusion of 3 or more units of red blood cells (RBC) (0.00001; RR = 17.1). Mechanism and severity of trauma and Pediatric Trauma Index were not associated with failure NOM. CONCLUSIONS: Children with blunted hepatic or splenic trauma respond to NOM. Factors such as BP < 90 mmHg at admission, an Hb fall > 2 g/dl in the first 24 hours and transfusion of 3 or more units of RBC were associated with the failure in NOM. PMID- 28898315 TI - [Morbimortality associated to nutritional status and feeding path in children with cerebral palsy]. AB - INTRODUCTION: Children and adolescents with cerebral palsy (CP) have a high prevalence of malnutrition associated to poor prognosis. For an adequate nutritional assessment, new growth curves (Brooks, 2011) are available, in which precise cut-off points in Weight/Age index correlate to increased morbidity and mortality rate. OBJECTIVE: To evaluate risk of hospitalization and death in patients with CP, according to nutritional risk (NR). PATIENTS AND METHOD: Observational and prospective cohort study of patients with CP in an outpatient referral center. We registered demographic, socioeconomic data and nutritional assessment. During a one-year follow-up, hospitalizations and mortality were recorded. The correspondent committee extended an ethical approval. RESULTS: 81 CP patients were recruit, age 131.6 +/- 60.4 months (25-313), 60 % male, 77.5 % without independent mobility. The 23 NR patients (28.4%) had lower muscle and fat mass (p = 0.000). During the follow-up, 29/81 patients required hospitalization (35.8%) and 4/81 died (4.9%). There was not an increased risk of hospitalization and/or mortality in NR group, but both were significantly higher in gastrostomy fed children (RR: 2,98 CI 95%: 1.32-6.75 combining both variables). CONCLUSIONS: In this study, children and adolescents with severe CP and nutritional risk had similar morbidity and mortality during a one-year follow-up, compared to those with acceptable nutritional status. Both risks were higher in gastrostomy-fed than the orally fed children. PMID- 28898316 TI - [Risk factors and biochemical markers in metabolic bone disease of premature newborns]. AB - BACKGROUND: Metabolic bone disease (MBD) of prematurity is a complication of multifactorial aetiology, which has been increasing, due to progressive decrease in mortality of preterm newborns. The aim of the study was to analyze risk factors of severe MBD and its analytical markers. PATIENTS AND METHOD: Retrospective study involving preterm infants less than 32 weeks gestational age and/or weight less tan 1,500 g born between january 2012 and december 2014. Comparison was made according to the presence of severe MBD. RESULTS: 139 patients were recruited. Mean value of 25(OH)D3 was 70.68 +/- 25.20 nmol/L, being higher in patients born in spring-summer than in autumn-winter (80.94 +/- 25.33 vs 61.13 +/- 21.07; p = 0.000). Levels of 25(OH)D3 were similar in patients with severe MBD compared with the rest of patients (65.61 +/- 26.49 vs 72.07 +/- 24.89, P = 0.283). Higher levels of alkaline phosphatase (AP, IU/L ) (1314.19 +/- 506.67 vs 476.56 +/- 188.85; p = 0.000) were found in these patients. Cutoff point of AP 796.5 IU/L (S 95.2%, specificity 92.4%) was calculated by ROC curve. The risk factors most associated to severe EMO were restricted fetal growth, birth weight, duration of ventilation therapy and parenteral nutrition. CONCLUSIONS: AP levels were the best marker of severe MBD development. EMO risk increases with the number of risk factors and lower levels of 25(OH)D3. Levels of 25(OH)D3 higher than 70nmol/L appear to protect from the development of severe MBD, even in patients with multiple risk factors. PMID- 28898317 TI - [Recommendations from parents of obese children in treatment to the health-care team: qualitative study]. AB - INTRODUCTION: The family plays an essential role in the adherence and effectiveness in the treatment of childhood obesity. Caregivers? experience is fundamental for proper guidance. AIM: To describe the recommendations for the health-care team made by parents of children that are being treated for obesity. PATIENTS AND METHOD: Cross-sectional and descriptive study with a qualitative approach and purposeful sampling. In the first semester of 2015, interviews were conducted with nine parents of children from 4 to 10 years old that were being treated for obesity ad who had at least three medical appointments in the previous year. The data analysis was based on the Grounded Theory Approach through open coding. The study was ethically approved and informed parental consent was obtained. RESULTS: The results were grouped in the following main categories: a) Health-care team-caregiver relationship, b) Health-care team-child relationship, c) Encouraging family participation, d) Encouraging therapeutic adherence in the child and e) Frequency of medical appointments. CONCLUSION: From the perspective of this group of parents of obese children, the health-care team should establish a close therapeutic bond with the children and their parents during the treatment process, in addition to encouraging family participation. The importance of developing therapeutic interventions that consider the perspective of the patient?s system is emphasized. PMID- 28898318 TI - [Chronic recurrent multifocal osteomyelitis in a pediatric patient, a case report]. AB - INTRODUCTION: Chronic recurrent multifocal osteomyelitis (CRMO) is a very rare disease, of unknown origin that affects primarily the metaphysis of long bones. It is characterized by an insidious onset of symptoms and multiple remissions. The chronicity of symptoms, the diagnostic imaging and the lack of response to first line antibiotic treatment, should be helpful for diagnostic. OBJECTIVE: Present a clinical case, based on clinical, laboratory, radiologic imaging and histopathological results, that ultimately led to the diagnostic of CRMO. CASE REPORT: 9 year old, female patient, with one month of bilateral knee and left ankle arthralgia. Bone Gammagraphy and full body MRI, showed multifocal bone inflammation. These findings led to a biopsy, that turned negative for malignancy and infection. Given all the information available from the laboratory test results, radiologic imaging and histopathological findings, CRMO diagnosis was made. NSAID treatment was order, with good results. CONCLUSIONS: CRMO is a rare disease that even to date and with cutting edge technology, still represents a diagnostic challenge that primarily relies on a high level of suspicion, for a timely and correct treatment. PMID- 28898319 TI - [Tetanus, a current disease in pediatric population: Case report]. AB - INTRODUCTION: Tetanus is an acute disease caused by a toxin produced by Clostridium tetanii. The disease can affect people of any age, and the fatality rate is high. Thanks to immunization the number of cases of the disease has decreased, although they are still present in isolation in countries with social and economic backwardness. OBJECTIVE: To describe a case of a pediatric patient with generalized tetanus to reinforce the relevance of prophylaxis and early detection. CASE REPORT: 6 years old female patient, with only one dose of pentavalent vaccine, 10 days after sharps injury by wood chips, starts with fever, muscle pain and generalized contractions, Tetanus was diagnosed by clinical symptoms and history. The management was based on the latest recommendations of the World Health Organization (WHO): Penicillin-Metronidazole antibiotic regimen, tetanus toxoid and tetanus high-dose gammaglobulin. After 2 years of follow-up under physiotherapy support, slight motor sequelae were observed. CONCLUSION: Tetanus is still presented in the pediatric population, associated with lack of vaccination. It is necessary to know the disease to provide proper diagnosis and management according to international lineaments. PMID- 28898320 TI - [Peroxisomal disorder, rhizomelyc chondrodysplasia punctata type 1: case report]. AB - INTRODUCTION: Peroxisomal diseases are a group of monogenic disorders that include defects in peroxisome biogenesis or enzyme dificiencies. Rhizomelic chondrodysplasia punctata type 1 (RCDP1) belongs to the first group, caused by autosomal recessive mutations on PEX7 gene, encoding for PTS2 receptor. The aims of this report are to describe a genetic disease of low prevalence, explaining its main characteristics and the importance of the diagnostic approach and genetic counseling. CASE REPORT: 13-month-old male infant with no medical history, family or consanguinity, demonstrate at birth upper limbs shortening. Surgery intervention at seven months old for bilateral cataract. Growth retardation, psychomotor retardation, minor craniofacial anomalies, rhyzomelic shortened upper limbs and lower limbs lesser degree. Punctata calcifications in patella cartilage. Also fatty acid phytanic and pristanic increased levels. Patient dead at age of 3 years. DISCUSSION: RCDP1 is a rare disease, with a prevalence of 1/100,000. Different mutations of PEX7 gene have been described, with variations in phenotype. The treatment is basically symptomatic and depends on the severity of clinical manifestations. The rhizomelic type has poor prognosis, most patients do not survive before the first decade of live. Genetic counseling is essential because it is consider a 25% risk of recurrence. PMID- 28898321 TI - [Cleidocranial dysplasia: a case report]. AB - INTRODUCTION: Cleidocraneal dysplasia (CCD) is a rare skeletal autosomal dominant syndrome characterized by dental anomalies and bone abnormalities. These clinical manifestations do not require treatment in most cases. The disease is caused by mutation in the gene RUNX2 (CBAF1), located on the short arm of chromosome 6. OBJECTIVE: To report a case of CCD and perform a literature review focused on clinical manifestations and diagnosis. CASE REPORT: A 3 year old patient, who was clinically diagnosed with CCD since birth. The patient showed incomplete development of cranial bones, bell-shaped thorax, adequate dentition and presence of clavicles. Molecular analysis reported that the patient is carrying the pathogenic variant c.674G>A in the RUNX2 gene, confirming the diagnosis. CONCLUSIONS: The CCD is a rare condition, with special clinical features. It is important to establish early diagnosis in these patients in order to offer a better quality of life, and if necessary, appropriate treatment. PMID- 28898322 TI - [New mutation in ATM gen in patient whith Ataxia Telangiectasia: Clinical case]. AB - INTRODUCTION: The ataxia telangiectasia syndrome (AT) is a genetic disease with an autosomal recessive inheritance pattern, with multisystem involvement and a broad clinical spectrum. It is caused by the mutation of the ATM gene, causing reduction or absence of the ATM proteinkinase, altering processes in the cell cycle, DNA repair and apoptosis. The objective of this article is to report the case of a patient with ataxia telangiectasia syndrome, caused by a mutation not previously reported in the literature. CASE REPORT: A 14 year-old patient native to Colombia, with classic clinical and phenotypical manifestations of AT syndrome, which started at 6 years of age with pondostatural alteration, recurrent respiratory infections, oculocutaneus telangiectasias and progressive neurological disorder that included: regression in her psychomotor development, ataxia and oculomotor apraxia. ATM gene sequencing is performed evidencing a homozygous mutation not reported in literature. DISCUSSION: In Latin America are sparse the number of reports of patients with ataxia telangiectasia and only few of these describe their molecular findings. Molecular studies allow the diagnosis and a better orientation in the management and prognosis of patients with neurodegenerative diseases. The report of undescribed molecular variants is of great importance to establish the etiology of such diseases in diverse population groups, such as the countries of Latin America. PMID- 28898324 TI - [Probiotics: innocuousness, prevention and risks]. AB - Probiotics have been defined as live microorganisms which, when ingested in adequate numbers, confer health benefits to the host. They are currently consumed without any age restrictions and adverse effects such as sepsis, a marker of the risk of invasion of the bloodstream, are extremely infrequent. However, some health professionals express doubts about probiotics being truly innocuous. This review discusses the incidence of sepsis secondary to probiotics use, mainly lactobacilli and bifidobacteria, evaluated through molecular biology or classic culture techniques, showing that sepsis in large numbers of individuals along decennia is extremely low, of the order of 0,02% en some centers or as low as 1 case/million population in France. These data are important considering the use different species and strains of these microorganisms. Few studies which have reported other adverse effects but many of these have problems with their design that cast doubt about the validity of their results. On the contrary, it has been shown that probiotic microorganisms exert positive stimulatory effects on innate and acquired immunity, with decrease of the manifestations of atopy and eczema. These positive effects are further evidenced by the beneficial effects of many species of probiotics in preventing necrotizing enterocolitis in patients as functionally labile as premature-born babies. PMID- 28898323 TI - [Pontocerebellar hypoplasia secondary to CASK gene deletion: Case report]. AB - INTRODUCTION: Pontocerebellar hypoplasia (PCH) is a reduction of the size of the cerebellum and pons secondary to an alteration in its development, and can be caused by neurodegenerative diseases of genetic origin, of which there are known 10 subtypes (PCH 1-10), cortical malformations, metabolic and genetic diseases. OBJECTIVE: To present the case of a child with microcephaly, PCH and West syndrome, in which the genetic study allowed to make the diagnosis of a deletion on chromosome X. CASE REPORT: This is a female infant of 7-month at diagnosis, without family or obstetric history of interest, head circumference at birth -1.5 standard deviations (SD). She had little weight and growth in head circumference progression. In addition, physical examination revealed no fixating gaze, hypotonia with preserved deep tendon reflexes. Progressively developed refractary seizures. Brainsteam Auditory Evoked Potential demonstrated involvement of pontomesencefphalic ways and neuroimaging Pontocerebellar hypoplasia. The genetic study (aCGH) showed heterozygous deletion on the X chromosome, affecting the CASK gene. CONCLUSIONS: Given the wide differential diagnosis proposed at the PCH, new cytogenetic techniques have improved the classification of HPC and in some cases establish their etiology, so in these cases can provide appropriate genetic counseling to families. PMID- 28898325 TI - [Life needs to be thought]. PMID- 28898326 TI - [Comparative study of growth and morbid incidence among a group of infants born to mother with tuberculosis and a control group: Revista chilena de Pediatria 1948]. PMID- 28898327 TI - [Transition from pediatric to adult health care services for adolescents with chronic diseases: Recommendations from the Adolescent Branch from Sociedad Chilena de Pediatria]. AB - The Adolescent Branch from Sociedad Chilena de Pediatria supports the implementation of planned programs for transition from child to adult health centers, oriented to adolescents with chronic diseases, in order to ensure an appropriate follow-up and a high-quality health care. Recommendations for care are set out in the FONIS and VRI PUC project carried out by the Division of Pediatrics of the Universidad Catolica de Chile: ?Transition process from pediatric to adult services: perspectives of adolescents with chronic diseases, caregivers and health professionals?, whose goal was to describe the experience, barriers, critical points, and facilitators in the transition process. Critical points detected in this study were: existence of a strong bond between adolescents, caregivers and the pediatric team, resistance to transition, difficulty developing autonomy and self-management among adolescents; invisibility of the process of adolescence; and lack of communication between pediatric and adult team during the transfer. According to these needs, barriers and critical points, and based on published international experiences, recommendations are made for implementation of gradual and planned transition processes, with emphasis on the design and implementation of transition policies, establishment of multidisciplinary teams and transition planning. We discuss aspects related to coordination of teams, transfer timing, self-care and autonomy, transition records, adolescent and family participation, need for emotional support, ethical aspects involved, importance of confidentiality, need for professional training, and the need for evaluation and further research on the subject. PMID- 28898328 TI - Afebrile dengue. PMID- 28898330 TI - [Analysis of Crowding in an Adult Emergency Department of a tertiary university hospital]. AB - BACKGROUND: Crowding in Emergency Departments (ED), results from the imbalance between the simultaneous demand for health care and the ability of the system to respond. The NEDOCS scale (National Emergency Department Crowding Scale) measures the degree of crowding in an ED. AIM: To describe ED Crowding characteristics, using the NEDOCS scale, in an Argentinean hospital. MATERIAL AND METHODS: A retrospective cohort study was conducted with all adult patient consultations between July 2013 and July 2014 at the ED of Hospital Italiano de Buenos Aires. We included all hours in the analysis period (365 days x 24 h = 8,760). The NEDOCS value was calculated for each hour using an automatic algorithm and was quantified in a six points score. Levels 4 (overcrowded), 5 (severely overcrowded) and 6 (dangerously overcrowded) were defined as overcrowding. Contour plots analysis was applied to identify patterns. RESULTS: During the study period, 124,758 visits to the ED were registered. Overcrowding was present in 57.7% (5,055) of the analyzed hours. A predominance of scores between four and five was observed between 10:00 and 24:00 hours. The months with predominance of overcrowding were June, July and August (southern winter). CONCLUSIONS: The calculation of the NEDOCS score and the analysis of its temporal distribution are highly relevant to identify opportunities for improvement and to develop mechanisms to prevent the highest categories of overcrowding. PMID- 28898331 TI - [Coverage of a screening program and prevalence of diabetic retinopathy in primary carec]. AB - BACKGROUND: Diabetic retinopathy is the first cause of blindness during working years. AIM: Provide knowledge of screening coverage, prevalence and level of diabetic retinopathy in patients that belong to the Cardiovascular Health Program in primary care. MATERIAL AND METHODS: Analysis of retinographies performed to 9076 diabetic patients aged 61 +/- 13 years (61% women) adscribed to a Cardiovascular Health program in primary care centers of South-East Metropolitan Santiago. The examination was carried out by the evaluation of retinographies by trained optometrists. RESULTS: The coverage of the screening program was 21%. The prevalence of sight threatening diabetic retinopathy was 3,1%. The prevalence of these entities was 45% higher in people aged between 18 and 44 years than in older people. Their prevalence in urban communities was 32% higher than in rural locations. CONCLUSIONS: The coverage of the screening program is low. Diabetic patients aged 18 to 44 years and those coming from urban communities have a higher prevalence of severe non-proliferative and proliferative diabetic retinopathy. PMID- 28898332 TI - [Prediction of hospital mortality of ST elevation myocardial infarction using TIMI score]. AB - BACKGROUND: Thrombolysis in myocardial infarction risk score (TIMI-RS) was designed to predict early mortality in patients with a ST elevation acute myocardial infarction (STEAMI). AIM: To evaluate the predictive capacity for hospital mortality of TIMI-RS. MATERIAL AND METHODS: Patients with <= 12-hour evolution STEAMI were selected from a prospective registry of all patients hospitalized in our coronary unity within January 1988 and December 2005. Observed mortality was analyzed according to TIMI-RS and its predictive capacity was estimated. RESULTS: We analyzed 1125 consecutive patients aged 61 +/- 13 years (76% men). Fifty one percent were smokers, 47% hypertensive and 40% had a history of angina. Fifty eight percent of patients underwent reperfusion therapy. Most patients had TIMI-RS scores <= 5 points and only 3.6% had scores >= 10 points. Overall mortality was 14.8% and there was an 80% concordance between observed mortality and that predicted with the TIMI-RS score. The area under the curve for the receiver operating characteristic (ROC) curve was 0.7. CONCLUSIONS: TIMI-RS was acceptably useful to predict in-hospital mortality in this group of patients with STEAMI. Differences between the observed and originally predicted mortality are explained by the clinical profile and therapeutic protocols applied to patients in different studies. Thus, caution needs to be taken when interpreting the risk associated to a specific score, particularly within non reperfused patients whose risk might be underestimated. PMID- 28898333 TI - [Usefulness of imaging studies in prostate cancer: Analysis of 241 patients]. AB - BACKGROUND: The role of staging studies in patients with prostate cancer (PCa) is a topic of discussion. AIM: To evaluate the usefulness of imaging studies in patients with prostate cancer. MATERIAL AND METHODS: We reviewed the pathology service records to identify patients with prostate cancer diagnosed between 2003 and 2013. We reviewed the electronic medical records of those patients identified as having a prostate cancer. Patients were grouped according D?amico?s classification of cancer dissemination risk. We analized the frequency of imaging studies requested and their efficacy to detect metastases in each risk group. RESULTS: We identified 241 patients with a mean age of 67 years. Fifty two percent of patients were classified as low-risk, 32% as intermediate-risk and 16% as high risk. At least one imaging study was requested to 64% of patients (49, 78 and 87% of patients with low, intermediate and high risk respectively). Among the 155 patients in whom an imaging study was requested, no metastases were found in the low risk group. On the other hand, dissemination was found in 7% of the intermediate-risk group and 62% of the high-risk group. CONCLUSIONS: Half of patients with prostate cancer were classified as low risk. In half of this group of low risk patients, staging studies were requested and the probability of detecting metastases was low or nil. The odds of detecting metastases increased in higher risk groups. PMID- 28898334 TI - [Effects of a lower body weight or waist circumference on cardiovascular risk]. AB - BACKGROUND: Overall and central obesity are important risk factors for cardiovascular disease. AIM: To investigate the association of body weight, body mass index (BMI) and waist circumference (WC) with cardiovascular risk factors in Chile. MATERIAL AND METHODS: We included 5,157 participants from the National Health Survey 2009-2010. Prevalence of type 2 diabetes, hypertension, metabolic syndrome and dyslipidemia (high total cholesterol and triglyceride levels and low HDL-cholesterol) were defined using international recommendations. BMI and WC were measured using standardized protocols. RESULTS: A five percent lower body weight, BMI and WC were associated with a significant reduction in cardiovascular risk factors. For each 5% reduction in body weight, the risk for hypertension decreased by 8 and 9% in women and men respectively. Similar risk reductions were observed for diabetes (9 and 11% respectively), metabolic syndrome (23 and 30% respectively), low HDL cholesterol (13 and 13% respectively), high triglyceride levels (16 and 18% respectively) and total cholesterol (8 and 10% respectively). Similar findings were observed for BMI and WC. CONCLUSIONS: Lower body weight, BMI or WC are associated with important reductions in cardiovascular risk factors. A 5% reduction in these adiposity markers could be a perfectly feasible goal for lifestyle interventions. PMID- 28898335 TI - [The impact of a self-directed teaching approach on academic performance of medical students]. AB - BACKGROUND: Students should be encouraged to become reflexive and develop autonomous, lifelong learning habits. Therefore, teachers should focus on learning strategies which stimulate autonomous learning. AIM: To assess the impact of a self-directed teaching methodology on the academic performance of medical students in cellular biology and biochemistry. MATERIALS AND METHODS: During 2013, 85 students received a traditional teaching methodology and during 2014, 85 students received a self-directed learning methodology. The grades obtained and the number of failures in the courses of cellular biology and biochemistry were compared in both groups. RESULTS: The percentages of students approved at the end of the courses during 2013 and 2014 were 64 and 96% respectively (p < 0.01). The grades obtained by the 2014 students were also significantly higher than those obtained by 2013 students. CONCLUSIONS: This study confirms that academic performance improves with a self-directed teaching approach. PMID- 28898336 TI - [Analysis of human cyst echinococcosis in a northern Chilean region from 2008 to 2012]. AB - BACKGROUND: The Coquimbo Region in Chile has the highest incidence of hydatidosis in central and northern Chile. AIM: To analyze the incidence of human cystic echinococcosis (CE) in the Coquimbo Region between 2008 and 2012. MATERIAL AND METHODS: Official records of reported cases were analyzed. The association of the location, age and sex with the presence/absence of CE was analyzed by means of logistic regressions. The incidence was reported as cases per 100,000 inhabitants. RESULTS: The mean annual incidence was 2.6 cases per 100,000 inhabitants, which ranged from 3.1 (2010) to 1.9 (2012) cases. The districts with higher incidence were Punitaqui (21.2 cases), Paihuano (9 cases), Rio Hurtado (8 cases), Canela (8.1 cases), Monte Patria (7.9 cases), Vicuna (6.9 cases) and Combarbala (6.9 cases). The incidence in these locations was significantly higher than elsewhere in the region. Males had a significantly higher incidence than females (3.3 and 1.8 respectively). Incidence increased significantly with age, notably increasing after 45 years of age. CONCLUSIONS: Rural locations had the highest incidences of CE in the Coquimbo Region. The disease was reported more commonly in adults and mainly in men. PMID- 28898337 TI - [The influence of pedagogic and discipline training on the teaching quality of university professors]. AB - BACKGROUND: University teachers prioritize acquiring knowledge about their disciplines over pedagogic training. However, the latter is becoming increasingly important in the present teaching scenario. AIM: To relate pedagogic practices with pedagogic training of teachers from health care careers of public and private universities. MATERIAL AND METHODS: Pedagogic practice and training activities participation questionnaires were answered by 296 teachers of undergraduate students from Chilean public and private universities. RESULTS: There was a direct correlation between discipline training and all pedagogic practice factors. However, pedagogic training correlated with all the factors with the exception of teacher centered learning. Teachers with a master degree had higher scores in factors related to teaching planning and process assessment. Having a doctor degree had no impact on these factors. A multiple regression analysis showed that both discipline and pedagogic training and having a master degree were associated with pedagogic practices of teachers. CONCLUSIONS: Both pedagogic and discipline training influence the quality of teaching provided by undergraduate teachers. PMID- 28898338 TI - [Response to ABVD chemotherapeutic protocol in patients with early stage Hodgkin?s lymphoma]. AB - BACKGROUND: Recent trials show that > 90% of patients with early stage Hodgkin's Lymphoma (ESHL) can be cured, especially when using the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapeutic (CT) protocol. The use of radiotherapy (RT) is variable and can be selected according to the presence of specific risk factors, including PET-CT, as recently reported. AIM: To report the experience in the treatment of ESHL. MATERIAL AND METHODS: Retrospective and descriptive analysis of patients with ESHL treated at the Red de Salud UC Christus between 2011-2015. RESULTS: Twenty-two patients were treated. In 73%, the tumor was of nodular sclerosis histologic type. Most patients (95%) were in stage II, and 78% had a favorable prognosis according to the Deutsche Hodgkin Studiengruppe (GHSG) criteria. All patients were stratified using PET-CT and treated using the ABVD CT protocol, for 4-6 cycles. Only 5 patients received RT. There was no change of conduct after interim-PET-CT results. Ninety one percent of patients achieved complete response and there were two cases of refractory disease. Both cases underwent hematopoietic stem cell transplantation. After 17 months of median follow-up, 91% of patients are relapse-free, and only one patient died (5%). CONCLUSIONS: ABVD offers excellent results for ESHL patients. The benefit of PET-CT should be evaluated with prospective protocols, aiming to select patients needing RT or to reduce the number of CT cycles. PMID- 28898339 TI - [Young woman, daughter of a father with Alport?s syndrome, debuts with a impure nephrotic syndrome]. PMID- 28898340 TI - [From insulin pump and continuous glucose monitoring to the artificial pancreas]. AB - Technology for diabetes care has undergone major development during recent decades. These technological advances include continuous subcutaneous insulin infusion (CSII), also known as insulin pumps, and real-time continuous glucose monitoring system (RT-CGMS). The integration of CSII and RT-CGMS into a single device has led to sensor-augmented pump therapy and more recently, a technology that has automated delivery of basal insulin therapy, known as hybrid system. These new technologies have led to benefits in attaining better metabolic control and decreasing the incidence of severe hypoglycemia, especially in patients with type 1 diabetes. This review describes the types of technologies currently available or under investigation for these purposes, their benefits and disadvantages, recommendations and the appropriate patient selection for their use. The clinical use of the hybrid system and artificial pancreas seem to be possible in the near future. PMID- 28898341 TI - [Shared decision making in patients with diabetes mellitus]. AB - Patients with diabetes mellitus often have several medical problems and carry a burden imposed by their illness and treatment. Health care often ignores the values, preferences and context of patients, leading to treatments that do not fit into patients? overwhelmed lives. Shared Decision Making (SDM) emerges as a way to answer the question: ?What?s best for the patient??. SDM promotes an empathic conversation between patients and clinicians that integrates the best evidence available with their values, preferences and context. We discuss three SDM approaches for patients with diabetes: one focused on sharing information, another on making choices, and a third one on helping patients and clinicians to talk about how to address the problems of living with diabetes and its comorbidities. Despite the benefits demonstrated in studies conducted in the U.S. and Europe, the implementation of SDM continues to be a challenge. In Latin America, healthcare and socio-economic conditions render the implementation of SDM more challenging. Research aimed to respond to this challenge is necessary. Meanwhile, clinicians can practice SDM by sharing evidence-based information, giving voice to patients? values and preferences in making choices, and creating empathic conversations aimed at decisions aligned with patients? context, dreams, goals, and life expectations. PMID- 28898342 TI - [An update on inpatient treatment of anorexia nervosa: practical recommendations]. AB - Anorexia Nervosa (AN) is the psychiatric illness with the highest mortality, especially if it is associated with psychiatric and somatic comorbidity. Medical complications can be multiple and jeopardize the normal development of children and adolescents, even permanently. Although its prevalence is lower compared with other psychiatric disorders, its tendency to chronicity and the severity of its consequences are remarkable. Although outpatient treatment of anorexia is privileged as far as possible, the risks associated with poor response to treatment or lack of adherence of the patient or family, require the possibility of hospitalization at any time of the disease. We searched and analyzed the national and international literature available (especially clinical guidelines) about the indication for hospital treatment in AN and the interventions recognized as necessary and effective during hospitalization. Despite the lack of standardized criteria for hospitalization, the available information converge on the need for a multidisciplinary work by a specialist team, to make family interventions especially in adolescents and tailor treatment according to the individual physical, psychological and social needs. PMID- 28898343 TI - [Differential diagnosis of bone marrow and lung granulomas: Report of one case]. AB - The differential diagnosis of pulmonary tuberculosis and lymphoma with pulmonary infiltration is very difficult, given their similar clinical characteristics. We report a 59 year old female with weight loss, fever, dyspnea and cough of several months of duration. She had a cavitated mass in lung imaging. A positive conventional PCR lead to the diagnosis of tuberculosis, but she had negative smears and cultures for Mycobacterium tuberculosis. The patient did not respond to treatment and her clinical condition worsened. A peripheral lymph node biopsy confirmed the presence of a diffuse large B cell non-Hodgkin lymphoma. Bone marrow pathology showed non caseating granulomas, again with negative microbiological tests for M. tuberculosis. Findings in the bone marrow were interpreted as a secondary sarcoid reaction to cancer and PCR results as a false positive. The lymphoma was treated, achieving complete remission. This case highlights the importance of the differential diagnosis between these two entities. PMID- 28898344 TI - [Lung epithelioid hemangioendothelioma: Report of one case]. AB - Epithelioid hemangioendothelioma is a multifocal tumor that rarely metastasizes. It is difficult to diagnose, most often it is an incidental finding in young asymptomatic women. The radiologic pattern is heterogeneous. Histologic confirmation of Weibel-Palade bodies or immunohistochemistry based on specific tumor markers such as factor VIII and CD34 are the most important finding to confirm the diagnosis. We report a 21 years old woman Presenting with cough and dyspnea. A chest X ray was suggestive of tuberculosis. Sputum smears were negative for acid fat bacilli and the tuberculin test was negative. A chest CAT scan showed multiple nodular lesions. A surgical biopsy of the lesions confirmed the presence of a hemangioendothelioma. The patient was initially treated with prednisone and azathioprine without response. Thereafter, the patient is without treatment and without evidence of disease progression. PMID- 28898345 TI - [Endoscopic lung volume reduction in advanced pulmonary emphysema: initial experience in Chile]. AB - Chronic obstructive pulmonary disease (COPD) has no curative treatment, and in moderate to advanced stages, functional parameters and quality of life are affected. Lung volume reduction improves respiratory parameters and quality of life of these patients. Endoscopic lung volume reduction is a minimally invasive procedure that uses endobronchial valves or coils. Valves are unidirectional, blocking the air from entering the target lobe during inspiration, allowing the exit of air and secretions during expiration. Complete fissure and absence of collateral ventilation are needed for an adequate functioning of endobronchial valves. Endobronchial coils cause mechanical retraction of the lung parenchyma. We report two patients who underwent endoscopic lung volume reduction by endobronchial valves. One patient was on continuous positive pressure non invasive ventilation due to his severe emphysema. PMID- 28898346 TI - [Treatment of hyperthyroidism with radioiodine during hemodialysis: Report of one case]. AB - Although radioiodine (131-I) can be used as treatment of hyperthyroidism for patients in hemodialysis, its use is limited and the experience is mainly related to differentiated thyroid carcinoma. We report a 58 years old female on hemodialysis with recurrent hyperthyroidism after propylthiouracil treatment. She was successfully treated with 131-I and four months after the intervention her euthyroid state was confirmed. We measured 131-I activity in blood, dialysate liquid and other waste products, as well as patient radiation exposure rates. We found that 131-I elimination was prolonged through time with no major dependence on hemodialysis, as opposed to the elimination of 131-I in patients with thyroid carcinoma. This was probably due to high radiotracer uptake in hyper functioning thyroid tissue. Conversely, radiation content in dialysate wastes or equipment was minimal. Furthermore, the rate of both environmental exposure and exposure of nursing staff in charge of hemodialysis sessions, was minimal and met international security standards. In conclusion, I-131 therapy showed both appropriate effectiveness and safety in this case and may be considered as a suitable treatment alternative to thyroidectomy when antithyroid drugs are unsuccessful. PMID- 28898347 TI - [The problem of medical approach to disability: An interdisciplinary challenge between health, education and law]. PMID- 28898348 TI - [Feedback: Cornerstone of clinical teaching]. PMID- 28898349 TI - [Teaching blindly: Need for surveys and evaluations in medical students and physicians from Peru]. PMID- 28898350 TI - [Julio Nazer M.D. (1926-2016)]. PMID- 28898351 TI - [CORRECTION]. PMID- 28898352 TI - Approaches for in silico finishing of microbial genome sequences. AB - The introduction of next-generation sequencing (NGS) had a significant effect on the availability of genomic information, leading to an increase in the number of sequenced genomes from a large spectrum of organisms. Unfortunately, due to the limitations implied by the short-read sequencing platforms, most of these newly sequenced genomes remained as "drafts", incomplete representations of the whole genetic content. The previous genome sequencing studies indicated that finishing a genome sequenced by NGS, even bacteria, may require additional sequencing to fill the gaps, making the entire process very expensive. As such, several in silico approaches have been developed to optimize the genome assemblies and facilitate the finishing process. The present review aims to explore some free (open source, in many cases) tools that are available to facilitate genome finishing. PMID- 28898353 TI - In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation. AB - Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3 substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs. PMID- 28898354 TI - Comparative genome-wide polymorphic microsatellite markers in Antarctic penguins through next generation sequencing. AB - Microsatellites are valuable molecular markers for evolutionary and ecological studies. Next generation sequencing is responsible for the increasing number of microsatellites for non-model species. Penguins of the Pygoscelis genus are comprised of three species: Adelie (P. adeliae), Chinstrap (P. antarcticus) and Gentoo penguin (P. papua), all distributed around Antarctica and the sub Antarctic. The species have been affected differently by climate change, and the use of microsatellite markers will be crucial to monitor population dynamics. We characterized a large set of genome-wide microsatellites and evaluated polymorphisms in all three species. SOLiD reads were generated from the libraries of each species, identifying a large amount of microsatellite loci: 33,677, 35,265 and 42,057 for P. adeliae, P. antarcticus and P. papua, respectively. A large number of dinucleotide (66,139), trinucleotide (29,490) and tetranucleotide (11,849) microsatellites are described. Microsatellite abundance, diversity and orthology were characterized in penguin genomes. We evaluated polymorphisms in 170 tetranucleotide loci, obtaining 34 polymorphic loci in at least one species and 15 polymorphic loci in all three species, which allow to perform comparative studies. Polymorphic markers presented here enable a number of ecological, population, individual identification, parentage and evolutionary studies of Pygoscelis, with potential use in other penguin species. PMID- 28898355 TI - Topical Cross-Linked HA-Based Hydrogel Accelerates Closure of Corneal Epithelial Defects and Repair of Stromal Ulceration in Companion Animals. AB - Purpose: The purpose of this study was to determine the safety of topical ocular administration of a cross-linked, modified hyaluronic acid (xCMHA-S) hydrogel, and its effectiveness in accelerating repair and closure of acute and nonhealing corneal ulcers in companion animals as a veterinary treatment and its utility as a model for therapy in human corneal ulceration. Methods: Two concentrations of xCMHA-S (0.33% and 0.75%) were topically administered to the eyes of rabbits six times daily for 28 days to assess safety. Then, 30 dogs and 30 cats with spontaneous acute corneal ulcers were treated with either xCMHA-S (0.75%) or a non-cross-linked hyaluronic acid (HA) solution (n = 15 per group for each species), three times daily until the ulcer had healed. Finally, 25 dogs with persistent nonhealing corneal ulcers were treated with xCMHA-S (0.75%) twice daily until the ulcer had healed. Results: Both concentrations of the xCMHA-S hydrogel were well tolerated, safe, and nontoxic in the 28-day exaggerated dosing study in healthy rabbits. Topically applied xCMHA-S significantly accelerated closure of acute corneal stromal ulcers in dogs and cats compared with a non cross-linked HA solution. Further, topical administration of the xCMHA-S aided in closure of nonhealing corneal stromal ulcers in dogs. Conclusions: Hyaluronic acid has previously been shown to aid in corneal wound repair. This study demonstrates that a cross-linked, modified HA hydrogel provides further benefit by accelerating time to corneal wound closure compared to a non-cross-linked HA solution in companion animals, and therefore may be beneficial in fulfilling an unmet need in humans. PMID- 28898356 TI - Structure-Function Relationships in Perimetric Glaucoma: Comparison of Minimum Rim Width and Retinal Nerve Fiber Layer Parameters. AB - Purpose: To test the hypotheses that: (1) structure-function (SF) relationships between visual fields (VF) and Bruch's membrane opening-based minimum rim width (BMO-MRW) measurements are superior to those for peripapillary retinal nerve fiber layer (pRNFL) in perimetric glaucoma; (2) BMO-MRW measurements may extend the utility of structural measurement across the range of glaucoma severity; and (3) to estimate the influence of Bruch's membrane opening (BMO) size on BMO-MRW measurements. Methods: One hundred eight perimetric glaucoma eyes (68 patients) with good quality spectral-domain optical coherence tomography images of the optic disc and pRNFL, and reliable VF within 6 months were recruited. Relationship of global and sectoral BMO-MRW and pRNFL thickness with corresponding VF parameters and the influence of normalizing BMO-MRW (on BMO circumference, nBMO-MRW) on SF relationships were investigated. Broken-stick models were used to compare the point at which pRNFL and BMO-MRW parameters reached their measurement floor. Results: The median (interquartile range) of VF mean deviation was -5.9 (-12.6 to -3.6) dB. Spearman correlation coefficients between pRNFL, BMO-MRW, and nBMO-MRW measures and corresponding VF cluster average deviations ranged between 0.55 to 0.80, 0.35 to 0.66, and 0.38 to 0.65, respectively. Bruch's membrane opening-MRW parameters demonstrated weaker SF relationships compared with pRNFL globally and in temporal, temporal-superior, and nasal-inferior sectors (P < 0.03). Normalization of BMO-MRW did not significantly influence SF relationships. Conclusions: Structure-function relationships were somewhat weaker with BMO-MRW parameters compared with pRNFL in eyes with perimetric glaucoma. Bruch's membrane opening-MRW normalization did not significantly change SF relationships in this group of eyes with mild departures from average BMO size. PMID- 28898358 TI - Relevance of the Implementation of Teeth in Three-Dimensional Vocal Tract Models. AB - Purpose: Recently, efforts have been made to investigate the vocal tract using magnetic resonance imaging (MRI). Due to technical limitations, teeth were omitted in many previous studies on vocal tract acoustics. However, the knowledge of how teeth influence vocal tract acoustics might be important in order to estimate the necessity of implementing teeth in vocal tract models. The aim of this study was therefore to estimate the effect of teeth on vocal tract acoustics. Method: The acoustic properties of 18 solid (3-dimensional printed) vocal tract models without teeth were compared to the same 18 models including teeth in terms of resonance frequencies (fRn). The fRn were obtained from the transfer functions of these models excited by white noise at the glottis level. The models were derived from MRI data of 2 trained singers performing 3 different vowel conditions (/i/, /a/, and /u/) in speech and low-pitched and high-pitched singing. Results: Depending on the oral configuration, models exhibiting side cavities or side branches were characterized by major changes in the transfer function when teeth were implemented via the introduction of pole-zero pairs. Conclusions: To avoid errors in modeling, teeth should be included in 3 dimensional vocal tract models for acoustic evaluation. Supplemental Material: https://doi.org/10.23641/asha.5386771. PMID- 28898359 TI - Nanochip Turns Skin Into a Bioreactor. PMID- 28898360 TI - Lightweight Exosuit Could Help Patients Walk After Stroke. PMID- 28898357 TI - Photoreceptor Layer Thickness Changes During Dark Adaptation Observed With Ultrahigh-Resolution Optical Coherence Tomography. AB - Purpose: To examine outer retinal band changes after flash stimulus and subsequent dark adaptation with ultrahigh-resolution optical coherence tomography (UHR-OCT). Methods: Five dark-adapted left eyes of five normal subjects were imaged with 3-MUm axial-resolution UHR-OCT during 30 minutes of dark adaptation following 96%, 54%, 23%, and 0% full-field and 54% half-field rhodopsin bleach. We identified the ellipsoid zone inner segment/outer segment (EZ[IS/OS]), cone interdigitation zone (CIZ), rod interdigitation zone (RIZ), retinal pigment epithelium (RPE), and Bruch's membrane (BM) axial positions and generated two dimensional thickness maps of the EZ(IS/OS) to the four bands. The average thickness over an area of the thickness map was compared against that of the dark adapted baselines. The time-dependent thickness changes (photoresponses) were statistically compared against 0% bleach. Dark adaptometry was performed with the same bleaching protocol. Results: The EZ(IS/OS)-CIZ photoresponse was significantly different at 96% (P < 0.0001) and 54% (P = 0.006) bleach. At all three bleaching levels, the EZ(IS/OS)-RIZ, -RPE, and -BM responses were significantly different (P < 0.0001). The EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ time courses were similar to the recovery of rod- and cone-mediated sensitivity, respectively, measured with dark adaptometry. The maximal EZ(IS/OS)-CIZ and EZ(IS/OS)-RIZ response magnitudes doubled from 54% to 96% bleach. Both EZ(IS/OS) RPE and EZ(IS/OS)-BM responses resembled dampened oscillations that were graded in amplitude and duration with bleaching intensity. Half-field photoresponses were localized to the stimulated retina. Conclusions: With noninvasive, near infrared UHR-OCT, we characterized three distinct, spatially localized photoresponses in the outer retinal bands. These photoresponses have potential value as physical correlates of photoreceptor function. PMID- 28898361 TI - Expanded Tissue Samples Poised to Assist Pathologists. PMID- 28898362 TI - Antiphospholipid Antibodies. PMID- 28898363 TI - The Durability of Antireflux Surgery. PMID- 28898364 TI - Menopausal Hormone Therapy: Understanding Long-term Risks and Benefits. PMID- 28898365 TI - Breast Cancer Surgery: Less Is More. PMID- 28898366 TI - Acute Diarrheal Infections in Adults. PMID- 28898368 TI - "America's Health First": A Misnomer. PMID- 28898369 TI - Progress in Teaching Psychiatry: Adolf Meyer, M.D., Baltimore. PMID- 28898370 TI - Association Between Ruptured Distal Biceps Tendon and Wild-Type Transthyretin Cardiac Amyloidosis. PMID- 28898371 TI - Behavioral Economics and Health Insurance Reform. PMID- 28898372 TI - Medication Reconciliation vs Medication Review. PMID- 28898373 TI - Guideline Recommendations for Statin Therapy. PMID- 28898374 TI - Behavioral Economics and Health Insurance Reform-Reply. PMID- 28898375 TI - Medication Reconciliation vs Medication Review-Reply. PMID- 28898376 TI - Guideline Recommendations for Statin Therapy-Reply. PMID- 28898377 TI - Association Between Laparoscopic Antireflux Surgery and Recurrence of Gastroesophageal Reflux. AB - Importance: Cohort studies, mainly based on questionnaires and interviews, have reported high rates of reflux recurrence after antireflux surgery, which may have contributed to a decline in its use. Reflux recurrence after laparoscopic antireflux surgery has not been assessed in a long-term population-based study of unselected patients. Objectives: To determine the risk of reflux recurrence after laparoscopic antireflux surgery and to identify risk factors for recurrence. Design and Setting: Nationwide population-based retrospective cohort study in Sweden between January 1, 2005, and December 31, 2014, based on all Swedish health care and including 2655 patients who underwent laparoscopic antireflux surgery according to the Swedish Patient Registry. Their records were linked to the Swedish Causes of Death Registry and Prescribed Drug Registry. Exposures: Primary laparoscopic antireflux surgery due to gastroesophageal reflux disease in adults (>18 years). Main Outcomes and Measures: The outcome was recurrence of reflux, defined as use of antireflux medication (proton pump inhibitors or histamine2 receptor antagonists for >6 months) or secondary antireflux surgery. Multivariable Cox regression was used to assess risk factors for reflux recurrence. Results: Among all 2655 patients who underwent antireflux surgery (median age, 51.0 years; interquartile range, 40.0-61.0 years; 1354 men [51.0%]) and were followed up for a median of 5.6 years, 470 patients (17.7%) had reflux recurrence; 393 (83.6%) received long-term antireflux medication and 77 (16.4%) underwent secondary antireflux surgery. Risk factors for reflux recurrence included female sex (hazard ratio [HR], 1.57 [95% CI, 1.29-1.90]; 286 of 1301 women [22.0%] and 184 of 1354 men [13.6%] had recurrence of reflux), older age (HR, 1.41 [95% CI, 1.10-1.81] for age >=61 years compared with <=45 years; recurrence among 156 of 715 patients and 133 of 989 patients, respectively), and comorbidity (HR, 1.36 [95% CI, 1.13-1.65] for Charlson comorbidity index score >=1 compared with 0; recurrence among 180 of 804 patients and 290 of 1851 patients, respectively). Hospital volume of antireflux surgery was not associated with risk of reflux recurrence (HR, 1.09 [95% CI, 0.77-1.53] for hospital volume <=24 surgeries compared with >=76 surgeries; recurrence among 38 of 266 patients [14.3%] and 271 of 1526 patients [17.8%], respectively). Conclusions and Relevance: Among patients who underwent primary laparoscopic antireflux surgery, 17.7% experienced recurrent gastroesophageal reflux requiring long-term medication use or secondary antireflux surgery. Risk factors for recurrence were older age, female sex, and comorbidity. Laparoscopic antireflux surgery was associated with a relatively high rate of recurrent gastroesophageal reflux disease requiring treatment, diminishing some of the benefits of the operation. PMID- 28898378 TI - Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. AB - Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96 1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration: clinicaltrials.gov Identifier: NCT00000611. PMID- 28898380 TI - Pneumothorax. PMID- 28898379 TI - Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. AB - Importance: The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor-positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective: To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants: The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions: All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures: The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results: Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance: Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10 year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00003855. PMID- 28898382 TI - What Should I Do When I Hear the Call for Medical Assistance in a Plane? PMID- 28898384 TI - Lax Infection Control Consequences. PMID- 28898385 TI - Challenges in HCV Elimination. PMID- 28898386 TI - Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction for the prevention of postoperative pancreatic fistula following pancreaticoduodenectomy. AB - BACKGROUND: Pancreatoduodenectomy is a surgical procedure used to treat diseases of the pancreatic head and, less often, the duodenum. The most common disease treated is cancer, but pancreatoduodenectomy is also used for people with traumatic lesions and chronic pancreatitis. Following pancreatoduodenectomy, the pancreatic stump must be connected with the small bowel where pancreatic juice can play its role in food digestion. Pancreatojejunostomy (PJ) and pancreatogastrostomy (PG) are surgical procedures commonly used to reconstruct the pancreatic stump after pancreatoduodenectomy. Both of these procedures have a non-negligible rate of postoperative complications. Since it is unclear which procedure is better, there are currently no international guidelines on how to reconstruct the pancreatic stump after pancreatoduodenectomy, and the choice is based on the surgeon's personal preference. OBJECTIVES: To assess the effects of pancreaticogastrostomy compared to pancreaticojejunostomy on postoperative pancreatic fistula in participants undergoing pancreaticoduodenectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 9), Ovid MEDLINE (1946 to 30 September 2016), Ovid Embase (1974 to 30 September 2016) and CINAHL (1982 to 30 September 2016). We also searched clinical trials registers (ClinicalTrials.gov and WHO ICTRP) and screened references of eligible articles and systematic reviews on this subject. There were no language or publication date restrictions. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) assessing the clinical outcomes of PJ compared to PG in people undergoing pancreatoduodenectomy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We performed descriptive analyses of the included RCTs for the primary (rate of postoperative pancreatic fistula and mortality) and secondary outcomes (length of hospital stay, rate of surgical re-intervention, overall rate of surgical complications, rate of postoperative bleeding, rate of intra-abdominal abscess, quality of life, cost analysis). We used a random-effects model for all analyses. We calculated the risk ratio (RR) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes (using PG as the reference) with 95% confidence intervals (CI) as a measure of variability. MAIN RESULTS: We included 10 RCTs that enrolled a total of 1629 participants. The characteristics of all studies matched the requirements to compare the two types of surgical reconstruction following pancreatoduodenectomy. All studies reported incidence of postoperative pancreatic fistula (the main complication) and postoperative mortality.Overall, the risk of bias in included studies was high; only one included study was assessed at low risk of bias.There was little or no difference between PJ and PG in overall risk of postoperative pancreatic fistula (PJ 24.3%; PG 21.4%; RR 1.19, 95% CI 0.88 to 1.62; 7 studies; low-quality evidence). Inclusion of studies that clearly distinguished clinically significant pancreatic fistula resulted in us being uncertain whether PJ improved the risk of pancreatic fistula when compared with PG (19.3% versus 12.8%; RR 1.51, 95% CI 0.92 to 2.47; very low-quality evidence). PJ probably has little or no difference from PG in risk of postoperative mortality (3.9% versus 4.8%; RR 0.84, 95% CI 0.53 to 1.34; moderate-quality evidence).We found low-quality evidence that PJ may differ little from PG in length of hospital stay (MD 1.04 days, 95% CI -1.18 to 3.27; 4 studies, N = 502) or risk of surgical re-intervention (11.6% versus 10.3%; RR 1.18, 95% CI 0.86 to 1.61; 7 studies, N = 1263). We found moderate-quality evidence suggesting little difference between PJ and PG in terms of risk of any surgical complication (46.5% versus 44.5%; RR 1.03, 95% CI 0.90 to 1.18; 9 studies, N = 1513). PJ may slightly improve the risk of postoperative bleeding (9.3% versus 13.8%; RR 0.69, 95% CI: 0.51 to 0.93; low-quality evidence; 8 studies, N = 1386), but may slightly worsen the risk of developing intra abdominal abscess (14.7% versus 8.0%; RR 1.77, 95% CI 1.11 to 2.81; 7 studies, N = 1121; low quality evidence). Only one study reported quality of life (N = 320); PG may improve some quality of life parameters over PJ (low-quality evidence). No studies reported cost analysis data. AUTHORS' CONCLUSIONS: There is no reliable evidence to support the use of pancreatojejunostomy over pancreatogastrostomy. Future large international studies may shed new light on this field of investigation. PMID- 28898387 TI - Prevalence and Correlates of Elder Abuse in Sao Paulo and Rio de Janeiro. AB - OBJECTIVES: To assess the prevalence of elder abuse and to investigate potential sociodemographic, health behavior, and medical correlates. DESIGN: Cross sectional data were collected in face-to-face assessments. SETTING: Sao Paulo and Rio de Janeiro, Brazil. PARTICIPANTS: Individuals aged 60 to 75. MEASUREMENTS: Information on elder abuse was obtained using the Brazil-adapted, nine-item Hwalek-Sengstock Elder Abuse Screening Test. Sampling design-adjusted descriptive statistics and logistic regression were used in analyses. RESULTS: The overall prevalence of abuse was 14.4% (n = 46/259, 95% confidence interval (CI) = 9.82 20.61) in Sao Paulo and 13.3% (n = 27/197, 95% CI = 8.76-19.74) in Rio de Janeiro. Unadjusted analyses indicated that poor education, low physical activity, unemployment, heart disease, and psychiatric problems were associated with abuse, but in adjusted analyses, self-reported elder abuse was significantly associated only with psychiatric problems (Sao Paulo: OR = 4.48, 95% CI = 1.75 11.45; Rio de Janeiro: OR = 21.61, 95% CI = 6.39-73.14). CONCLUSION: Elder abuse is prevalent in Sao Paulo and Rio de Janeiro, but whether concomitants of abuse are cause, effect, or both is unclear because this was a cross-sectional study. These findings highlight the importance of the problem, as well as the need to develop measures to increase awareness, facilitate prevention, and fight against abuse of elderly adults. PMID- 28898388 TI - Memory and Executive Functioning in 12-Year-Old Children With a History of Institutional Rearing. AB - We examined visual recognition memory and executive functioning (spatial working memory [SWM], spatial planning, rule learning, and attention shifting) in 12-year olds (n = 150) who participated in the Bucharest Early Intervention Project, a randomized controlled trial of foster care for institutionally reared children. Similar to prior reports at 8 years of age, institutionally reared children showed significant deficits in visual recognition memory and SWM. Deficits in attention shifting and rule learning were also apparent at this time point. These data suggest that early experiences continue to shape the development of memory, learning, and executive functioning processes in preadolescence, which may explain broader cognitive and learning difficulties commonly associated with severe early life neglect. PMID- 28898389 TI - Racial Differences in the Association Between Apolipoprotein E Risk Alleles and Overall and Total Cardiovascular Mortality Over 18 Years. AB - OBJECTIVES: To examine the difference in the association between apolipoprotein (APO)E allele and overall and cardiovascular mortality between African Americans (AAs) and European Americans (EAs). DESIGN: Longitudinal, cohort study of 18 years. SETTING: Biracial urban US population sample. PARTICIPANTS: 4,917, 68% AA and 32% EA. MEASUREMENTS: APOE genotype and mortality based on National Death Index. RESULTS: A higher proportion of AAs than of EAs had an APOE epsilon2 allele (epsilon2epsilon2/epsilon2epsilon3/epsilon2epsilon4; 22% vs 13%) and an APOE epsilon4 allele (epsilon3epsilon4/epsilon4epsilon4; 33% vs 24%). After adjusting for known risk factors, the risk of mortality was 19% less with the APOE epsilon2 allele (hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.76-0.87), and the risk of cardiovascular mortality was 35% less (HR = 0.65, 95% CI = 0.58-0.76) than with the epsilon3epsilon3 allele. The risk of mortality was 10% greater with the APOE epsilon4 allele (HR = 1.10, 95% CI = 1.04-1.16), and the risk of cardiovascular mortality was 20% greater (HR = 1.20, 95% CI = 1.07 1.29) than with the epsilon3epsilon3 allele. No difference in the association between APOE allele and mortality was observed between AAs and EAs. CONCLUSION: The APOE epsilon4 allele increased the risk of overall and cardiovascular mortality, whereas the APOE epsilon2 allele decreased the risk of overall and cardiovascular mortality. There was no racial difference in the association between these alleles and mortality. PMID- 28898390 TI - Comprehensive geriatric assessment for older adults admitted to hospital. AB - BACKGROUND: Comprehensive geriatric assessment (CGA) is a multi-dimensional, multi-disciplinary diagnostic and therapeutic process conducted to determine the medical, mental, and functional problems of older people with frailty so that a co-ordinated and integrated plan for treatment and follow-up can be developed. This is an update of a previously published Cochrane review. OBJECTIVES: We sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to use these data to estimate its cost-effectiveness. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 5 October 2016; we also checked reference lists and contacted study authors. SELECTION CRITERIA: We included randomised trials that compared inpatient CGA (delivered on geriatric wards or by mobile teams) versus usual care on a general medical ward or on a ward for older people, usually admitted to hospital for acute care or for inpatient rehabilitation after an acute admission. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures expected by Cochrane and Effective Practice and Organisation of Care (EPOC). We used the GRADE approach to assess the certainty of evidence for the most important outcomes. For this update, we requested individual patient data (IPD) from trialists, and we conducted a survey of trialists to obtain details of delivery of CGA. We calculated risk ratios (RRs), mean differences (MDs), or standardised mean differences (SMDs), and combined data using fixed-effect meta-analysis. We estimated cost-effectiveness by comparing inpatient CGA versus hospital admission without CGA in terms of cost per quality-adjusted life year (QALY) gained, cost per life year (LY) gained, and cost per life year living at home (LYLAH) gained. MAIN RESULTS: We included 29 trials recruiting 13,766 participants across nine, mostly high-income countries. CGA increases the likelihood that patients will be alive and in their own homes at 3 to 12 months' follow-up (risk ratio (RR) 1.06, 95% confidence interval (CI) 1.01 to 1.10; 16 trials, 6799 participants; high-certainty evidence), results in little or no difference in mortality at 3 to 12 months' follow-up (RR 1.00, 95% CI 0.93 to 1.07; 21 trials, 10,023 participants; high-certainty evidence), decreases the likelihood that patients will be admitted to a nursing home at 3 to 12 months follow-up (RR 0.80, 95% CI 0.72 to 0.89; 14 trials, 6285 participants; high-certainty evidence) and results in little or no difference in dependence (RR 0.97, 95% CI 0.89 to 1.04; 14 trials, 6551 participants; high-certainty evidence). CGA may make little or no difference to cognitive function (SMD ranged from -0.22 to 0.35 (5 trials, 3534 participants; low-certainty evidence)). Mean length of stay ranged from 1.63 days to 40.7 days in the intervention group, and ranged from 1.8 days to 42.8 days in the comparison group. Healthcare costs per participant in the CGA group were on average GBP 234 (95% CI GBP -144 to GBP 605) higher than in the usual care group (17 trials, 5303 participants; low-certainty evidence). CGA may lead to a slight increase in QALYs of 0.012 (95% CI -0.024 to 0.048) at GBP 19,802 per QALY gained (3 trials; low-certainty evidence), a slight increase in LYs of 0.037 (95% CI 0.001 to 0.073), at GBP 6305 per LY gained (4 trials; low-certainty evidence), and a slight increase in LYLAH of 0.019 (95% CI 0.019 to 0.155) at GBP 12,568 per LYLAH gained (2 trials; low-certainty evidence). The probability that CGA would be cost-effective at a GBP 20,000 ceiling ratio for QALY, LY, and LYLAH was 0.50, 0.89, and 0.47, respectively (17 trials, 5303 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Older patients are more likely to be alive and in their own homes at follow-up if they received CGA on admission to hospital. We are uncertain whether data show a difference in effect between wards and teams, as this analysis was underpowered. CGA may lead to a small increase in costs, and evidence for cost-effectiveness is of low-certainty due to imprecision and inconsistency among studies. Further research that reports cost estimates that are setting-specific across different sectors of care are required. PMID- 28898391 TI - Recoding of synonymous genes to expand evolutionary landscapes requires control of secondary structure affecting translation. AB - Synthetic DNA design needs to harness the many information layers embedded in a DNA string. We previously developed the Evolutionary Landscape Painter (ELP), an algorithm that exploits the degeneracy of the code to increase protein evolvability. Here, we have used ELP to recode the integron integrase gene (intI1) in two alternative alleles. Although synonymous, both alleles yielded less IntI1 protein and were less active in recombination assays than intI1. We spliced the three alleles and mapped the activity decrease to the beginning of alternative sequences. Mfold predicted the presence of more stable secondary structures in the alternative genes. Using synonymous mutations, we decreased their stability and recovered full activity. Following a design-build-test approach, we have now updated ELP to consider such structures and provide streamlined alternative sequences. Our results support the possibility of modulating gene activity through the ad hoc design of 5' secondary structures in synthetic genes. PMID- 28898392 TI - Black Adolescent Males: Intersections Among Their Gender Role Identity and Racial Identity and Associations With Self-Concept (Global and School). AB - Intersectional approaches for understanding identity have gained momentum in the social sciences. Black adolescent males are often perceived as threatening, underachieving, and hypermasculine, which is reinforced through media outlets and psychological research that portray them as a monolith rather than a heterogeneous group with multiple intersecting identities. This cross-sectional study of 70 Black adolescent males between 14 and 18 years old simultaneously explores their race and gender identities and associations with self-concept (global and school). Results demonstrated that participants reported a combination of feminine and masculine gender roles, rather than hypermasculine. A canonical correlation analysis found that Black racial identity attitudes (RIAS L) and gender roles simultaneously contributed to significant relationships with total and school self-concept. Study limitations and future directions for research and practice are discussed. PMID- 28898393 TI - Is Behcet's disease a 'class 1-opathy'? The role of HLA-B*51 in the pathogenesis of Behcet's disease. AB - The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behcet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies. PMID- 28898394 TI - Diagnostic accuracy of serum antibodies to human papillomavirus type 16 early antigens in the detection of human papillomavirus-related oropharyngeal cancer. AB - BACKGROUND: Because of the current epidemic of human papillomavirus (HPV)-related oropharyngeal cancer (OPC), a screening strategy is urgently needed. The presence of serum antibodies to HPV-16 early (E) antigens is associated with an increased risk for OPC. The purpose of this study was to evaluate the diagnostic accuracy of antibodies to a panel of HPV-16 E antigens in screening for OPC. METHODS: This case-control study included 378 patients with OPC, 153 patients with nonoropharyngeal head and neck cancer (non-OPC), and 782 healthy control subjects. The tumor HPV status was determined with p16 immunohistochemistry and HPV in situ hybridization. HPV-16 E antibody levels in serum were identified with an enzyme-linked immunosorbent assay. A trained binary logistic regression model based on the combination of all E antigens was predefined and applied to the data set. The sensitivity and specificity of the assay for distinguishing HPV-related OPC from controls were calculated. Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for the association of head and neck cancer with the antibody status. RESULTS: Of the 378 patients with OPC, 348 had p16-positive OPC. HPV-16 E antibody levels were significantly higher among patients with p16-positive OPC but not among patients with non-OPC or among controls. Serology showed high sensitivity and specificity for HPV-related OPC (binary classifier: 83% sensitivity and 99% specificity for p16-positive OPC). CONCLUSIONS: A trained binary classification algorithm that incorporates information about multiple E antibodies has high sensitivity and specificity and may be advantageous for risk stratification in future screening trials. Cancer 2017;123:4886-94. (c) 2017 American Cancer Society. PMID- 28898396 TI - Biodiversity maintenance may be lower under partial niche differentiation than under neutrality. AB - Niche differentiation is normally regarded as a key promoter of species coexistence in competitive systems. One might therefore expect that relative to neutral assemblages, niche-differentiated communities should support more species with longer persistence and lower probability of extinction. Here we compare stochastic niche and neutral dynamics in simulated assemblages, and find that when local dynamics combine with immigration from a regional pool, the effect of niches can be more complex. Trait variation that lessens competition between species will not necessarily give all immigrating species their own niche to occupy. Such partial niche differentiation protects certain species from local extinction, but precipitates exclusion of others. Differences in regional abundances and intrinsic growth rates have similar impacts on persistence times as niche differentiation, and therefore blur the distinction between niche and neutral dynamical patterns-although niche dynamics will influence which species persist longer. Ultimately, unless the number of niches available to species is sufficiently high, niches may actually heighten extinction rates and lower species richness and local persistence times. Our results help make sense of recent observations of community dynamics, and point to the dynamical observations needed to discern the influence of niche differentiation. PMID- 28898395 TI - Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis. AB - The global obesity epidemic and its associated co-morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their 'classical' function in energy storage and release, adipocytes interact with adipose-tissue-resident immune cells, among which are lipid-responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen-presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non-professional antigen presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with 'environmental factors' such as tissue/organ environment and co-stimulatory signals, are able to influence the fate of adipose-tissue resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies. PMID- 28898397 TI - Genome-wide DNA methylation analysis of senescence in repetitively infected memory cytotoxic T lymphocytes. AB - The immune system including antigen-specific CD8 T cells, which are cytotoxic T lymphocytes (CTLs), can acquire the potential for more effective elimination of the pathogen at re-infection. As memory CTLs could exert protective immunity after the next response, we aimed to elucidate the substantial change of repetitively infected memory CTLs. Currently, DNA methylation status in repetitively infected memory CTLs is unknown, so we performed next-generation sequencing to evaluate methylation status and transcriptional regulation of naive, primary and secondary memory CD8 T cells on the basis of transcription start sites (TSS). Notably, total CpG sites in the entire regions of all genes were significantly unmethylated in primary memory CTLs (young memory CTLs) and even more unmethylated in secondary memory CTLs (old memory CTLs). However, total proximal regions from TSS, which cover transcriptional promoters, were steadily methylated with repeated infections. In contrast, distal regions from TSS, which are the majority of entire regions and include transcriptional enhancers, were extensively unmethylated by infections. In association between transcriptional and methylation changes, accompanied by genes characteristic of the immune response, natural killer cell signature genes, known to be expressed in senescent CD8 T cells, were transcriptionally up-regulated and unmethylated in young memory CTLs, and more so in old memory CTLs, whereas ribosomal proteins were transcriptionally down-regulated and methylated in proximal region from the TSS by infections. Our results suggest that epigenetically augmented enhancers and suppressed promoters, which could consequently lead to global decline of transcription and translation, could represent the senescence of memory CTLs. PMID- 28898399 TI - Bias-corrected estimation of the Rudas-Clogg-Lindsay mixture index of fit. AB - Rudas, Clogg, and Lindsay (1994, J. R Stat Soc. Ser. B, 56, 623) introduced the so-called mixture index of fit, also known as pi-star (pi*), for quantifying the goodness of fit of a model. It is the lowest proportion of 'contamination' which, if removed from the population or from the sample, makes the fit of the model perfect. The mixture index of fit has been widely used in psychometric studies. We show that the asymptotic confidence limits proposed by Rudas et al. (1994, J. R Stat Soc. Ser. B, 56, 623) as well as the jackknife confidence interval by Dayton (, Br. J. Math. Stat. Psychol., 56, 1) perform poorly, and propose a new bias-corrected point estimate, a bootstrap test and confidence limits for pi star. The proposed confidence limits have coverage probability much closer to the nominal level than the other methods do. We illustrate the usefulness of the proposed method in practice by presenting some practical applications to log linear models for contingency tables. PMID- 28898398 TI - Integrating high-throughput screening and sequencing for monoclonal antibody discovery and engineering. AB - Monoclonal antibody discovery and engineering is a field that has traditionally been dominated by high-throughput screening platforms (e.g. hybridomas and surface display). In recent years the emergence of high-throughput sequencing has made it possible to obtain large-scale information on antibody repertoire diversity. Additionally, it has now become more routine to perform high throughput sequencing on antibody repertoires to also directly discover antibodies. In this review, we provide an overview of the progress in this field to date and show how high-throughput screening and sequencing are converging to deliver powerful new workflows for monoclonal antibody discovery and engineering. PMID- 28898400 TI - Intravesical electromotive drug administration for non-muscle invasive bladder cancer. AB - BACKGROUND: Electromotive drug administration (EMDA) is the use of electrical current to improve the delivery of intravesical agents to reduce the risk of recurrence in people with non-muscle invasive bladder cancer (NMIBC). It is unclear how effective this is in comparison to other forms of intravesical therapy. OBJECTIVES: To assess the effects of intravesical EMDA for the treatment of NMIBC. SEARCH METHODS: We performed a comprehensive search using multiple databases (CENTRAL, MEDLINE, EMBASE), two clinical trial registries and a grey literature repository. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The last search was February 2017. SELECTION CRITERIA: We searched for randomised studies comparing EMDA of any intravesical agent used to reduce bladder cancer recurrence in conjunction with transurethral resection of bladder tumour (TURBT). DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated quality of evidence (QoE) according to GRADE on a per outcome basis. MAIN RESULTS: We included three trials with 672 participants that described five distinct comparisons. The same principal investigator conducted all three trials. All studies used mitomycin C (MMC) as the chemotherapeutic agent for EMDA. 1. Postoperative MMC-EMDA induction versus postoperative Bacillus Calmette-Guerin (BCG) induction: based on one study with 72 participants with carcinoma in situ (CIS) and concurrent pT1 urothelial carcinoma, we are uncertain (very low QoE) about the effect of MMC-EMDA on time to recurrence (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.64 to 1.76; corresponding to 30 more per 1000 participants, 95% CI 180 fewer to 380 more). There was no disease progression in either treatment arm at three months' follow up. We are uncertain (very low QoE) about serious adverse events (RR 0.75, 95% CI 0.18 to 3.11). 2. Postoperative MMC-EMDA induction versus MMC-passive diffusion (PD) induction: based on one study with 72 participants with CIS and concurrent pT1 urothelial carcinoma, postoperative MMC-EMDA may (low QoE) reduce disease recurrence (RR 0.65, 95% CI 0.44 to 0.98; corresponding to 147 fewer per 1000 participants, 95% CI 235 fewer to 8 fewer). There was no disease progression in either treatment arm at three months' follow-up. We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.50, 95% CI 0.27 to 8.45). 3. Postoperative MMC-EMDA with sequential BCG induction and maintenance versus postoperative BCG induction and maintenance: based on one study with 212 participants with pT1 urothelial carcinoma of the bladder with or without CIS, postoperative MMC-EMDA with sequential BCG may result (low QoE) in a longer time to recurrence (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77; corresponding to 181 fewer per 1000 participants, 95% CI 256 fewer to 79 fewer) and time to progression (HR 0.36, 95% CI 0.17 to 0.75; corresponding to 63 fewer per 1000 participants, 95% CI 82 fewer to 24 fewer). We are uncertain (very low QoE) about the effect of MMC-EMDA on serious adverse events (RR 1.02, 95% CI 0.21 to 4.94). 4. Single-dose, preoperative MMC-EMDA versus single-dose, postoperative MMC-PD: based on one study with 236 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.47, 95% CI 0.32 to 0.69; corresponding to 247 fewer per 1000 participants, 95% CI 341 fewer to 130 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.81, 95% CI 0.00 to 259.93; corresponding to 34 fewer per 1000 participants, 95% CI 193 fewer to 807 more) and serious adverse events (RR 0.79, 95% CI 0.30 to 2.05). 5. Single-dose, preoperative MMC-EMDA versus TURBT alone: based on one study with 233 participants with primary pTa and pT1 urothelial carcinoma, preoperative MMC-EMDA likely (moderate QoE) results in a longer time to recurrence (HR 0.40, 95% CI 0.28 to 0.57; corresponding to 304 fewer per 1000 participants, 95% CI 390 fewer to 198 fewer) for a median follow-up of 86 months. We are uncertain (very low QoE) about the effect of MMC-EMDA on time to progression (HR 0.74, 95% CI 0.00 to 247.93; corresponding to 49 fewer per 1000 participants, 95% CI 207 fewer to 793 more) or serious adverse events (HR 1.74, 95% CI 0.52 to 5.77). AUTHORS' CONCLUSIONS: While the use of EMDA to administer intravesical MMC may result in a delay in time to recurrence in select patient populations, we are uncertain about its impact on serious adverse events in all settings. Common reasons for downgrading the QoE were study limitations and imprecision. A potential role for EMDA-based administration of MMC may lie in settings where more established agents (such as BCG) are not available. In the setting of low or very low QoE for most comparisons, our confidence in the effect estimates is limited and the true effect sizes may be substantially different from those reported here. PMID- 28898401 TI - Testing autocorrelation and partial autocorrelation: Asymptotic methods versus resampling techniques. AB - Autocorrelation and partial autocorrelation, which provide a mathematical tool to understand repeating patterns in time series data, are often used to facilitate the identification of model orders of time series models (e.g., moving average and autoregressive models). Asymptotic methods for testing autocorrelation and partial autocorrelation such as the 1/T approximation method and the Bartlett's formula method may fail in finite samples and are vulnerable to non-normality. Resampling techniques such as the moving block bootstrap and the surrogate data method are competitive alternatives. In this study, we use a Monte Carlo simulation study and a real data example to compare asymptotic methods with the aforementioned resampling techniques. For each resampling technique, we consider both the percentile method and the bias-corrected and accelerated method for interval construction. Simulation results show that the surrogate data method with percentile intervals yields better performance than the other methods. An R package pautocorr is used to carry out tests evaluated in this study. PMID- 28898402 TI - Interventions for obtaining and maintaining employment in adults with severe mental illness, a network meta-analysis. AB - BACKGROUND: People with severe mental illness show high rates of unemployment and work disability, however, they often have a desire to participate in employment. People with severe mental illness used to be placed in sheltered employment or were enrolled in prevocational training to facilitate transition to a competitive job. Now, there are also interventions focusing on rapid search for a competitive job, with ongoing support to keep the job, known as supported employment. Recently, there has been a growing interest in combining supported employment with other prevocational or psychiatric interventions. OBJECTIVES: To assess the comparative effectiveness of various types of vocational rehabilitation interventions and to rank these interventions according to their effectiveness to facilitate competitive employment in adults with severe mental illness. SEARCH METHODS: In November 2016 we searched CENTRAL, MEDLINE, Embase, PsychINFO, and CINAHL, and reference lists of articles for randomised controlled trials and systematic reviews. We identified systematic reviews from which to extract randomised controlled trials. SELECTION CRITERIA: We included randomised controlled trials and cluster-randomised controlled trials evaluating the effect of interventions on obtaining competitive employment for adults with severe mental illness. We included trials with competitive employment outcomes. The main intervention groups were prevocational training programmes, transitional employment interventions, supported employment, supported employment augmented with other specific interventions, and psychiatric care only. DATA COLLECTION AND ANALYSIS: Two authors independently identified trials, performed data extraction, including adverse events, and assessed trial quality. We performed direct meta analyses and a network meta-analysis including measurements of the surface under the cumulative ranking curve (SUCRA). We assessed the quality of the evidence for outcomes within the network meta-analysis according to GRADE. MAIN RESULTS: We included 48 randomised controlled trials involving 8743 participants. Of these, 30 studied supported employment, 13 augmented supported employment, 17 prevocational training, and 6 transitional employment. Psychiatric care only was the control condition in 13 studies. Direct comparison meta-analysis of obtaining competitive employmentWe could include 18 trials with short-term follow-up in a direct meta-analysis (N = 2291) of the following comparisons. Supported employment was more effective than prevocational training (RR 2.52, 95% CI 1.21 to 5.24) and transitional employment (RR 3.49, 95% CI 1.77 to 6.89) and prevocational training was more effective than psychiatric care only (RR 8.96, 95% CI 1.77 to 45.51) in obtaining competitive employment.For the long-term follow-up direct meta-analysis, we could include 22 trials (N = 5233). Augmented supported employment (RR 4.32, 95% CI 1.49 to 12.48), supported employment (RR 1.51, 95% CI 1.36 to 1.68) and prevocational training (RR 2.19, 95% CI 1.07 to 4.46) were more effective than psychiatric care only. Augmented supported employment was more effective than supported employment (RR 1.94, 95% CI 1.03 to 3.65), transitional employment (RR 2.45, 95% CI 1.69 to 3.55) and prevocational training (RR 5.42, 95% CI 1.08 to 27.11). Supported employment was more effective than transitional employment (RR 3.28, 95% CI 2.13 to 5.04) and prevocational training (RR 2.31, 95% CI 1.85 to 2.89). Network meta-analysis of obtaining competitive employmentWe could include 22 trials with long-term follow-up in a network meta-analysis.Augmented supported employment was the most effective intervention versus psychiatric care only in obtaining competitive employment (RR 3.81, 95% CI 1.99 to 7.31, SUCRA 98.5, moderate-quality evidence), followed by supported employment (RR 2.72 95% CI 1.55 to 4.76; SUCRA 76.5, low-quality evidence).Prevocational training (RR 1.26, 95% CI 0.73 to 2.19; SUCRA 40.3, very low-quality evidence) and transitional employment were not considerably different from psychiatric care only (RR 1.00,95% CI 0.51 to 1.96; SUCRA 17.2, low-quality evidence) in achieving competitive employment, but prevocational training stood out in the SUCRA value and rank.Augmented supported employment was slightly better than supported employment, but not significantly (RR 1.40, 95% CI 0.92 to 2.14). The SUCRA value and mean rank were higher for augmented supported employment.The results of the network meta-analysis of the intervention subgroups favoured augmented supported employment interventions, but also cognitive training. However, supported employment augmented with symptom-related skills training showed the best results (RR compared to psychiatric care only 3.61 with 95% CI 1.03 to 12.63, SUCRA 80.3).We graded the quality of the evidence of the network ranking as very low because of potential risk of bias in the included studies, inconsistency and publication bias. Direct meta-analysis of maintaining competitive employment Based on the direct meta-analysis of the short-term follow up of maintaining employment, supported employment was more effective than: psychiatric care only, transitional employment, prevocational training, and augmented supported employment.In the long-term follow-up direct meta-analysis, augmented supported employment was more effective than prevocational training (MD 22.79 weeks, 95% CI 15.96 to 29.62) and supported employment (MD 10.09, 95% CI 0.32 to 19.85) in maintaining competitive employment. Participants receiving supported employment worked more weeks than those receiving transitional employment (MD 17.36, 95% CI 11.53 to 23.18) or prevocational training (MD 11.56, 95% CI 5.99 to 17.13).We did not find differences between interventions in the risk of dropouts or hospital admissions. AUTHORS' CONCLUSIONS: Supported employment and augmented supported employment were the most effective interventions for people with severe mental illness in terms of obtaining and maintaining employment, based on both the direct comparison analysis and the network meta-analysis, without increasing the risk of adverse events. These results are based on moderate- to low-quality evidence, meaning that future studies with lower risk of bias could change these results. Augmented supported employment may be slightly more effective compared to supported employment alone. However, this difference was small, based on the direct comparison analysis, and further decreased with the network meta-analysis meaning that this difference should be interpreted cautiously. More studies on maintaining competitive employment are needed to get a better understanding of whether the costs and efforts are worthwhile in the long term for both the individual and society. PMID- 28898403 TI - Healthcare financing systems for increasing the use of tobacco dependence treatment. AB - BACKGROUND: Tobacco smoking is the leading preventable cause of death worldwide, which makes it essential to stimulate smoking cessation. The financial cost of smoking cessation treatment can act as a barrier to those seeking support. We hypothesised that provision of financial assistance for people trying to quit smoking, or reimbursement of their care providers, could lead to an increased rate of successful quit attempts. This is an update of the original 2005 review. OBJECTIVES: The primary objective of this review was to assess the impact of reducing the costs for tobacco smokers or healthcare providers for using or providing smoking cessation treatment through healthcare financing interventions on abstinence from smoking. The secondary objectives were to examine the effects of different levels of financial support on the use or prescription of smoking cessation treatment, or both, and on the number of smokers making a quit attempt (quitting smoking for at least 24 hours). We also assessed the cost effectiveness of different financial interventions, and analysed the costs per additional quitter, or per quality-adjusted life year (QALY) gained. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register in September 2016. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled trials and interrupted time series studies involving financial benefit interventions to smokers or their healthcare providers, or both. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed the quality of the included studies. We calculated risk ratios (RR) for individual studies on an intention-to-treat basis and performed meta-analysis using a random-effects model. MAIN RESULTS: In the current update, we have added six new relevant studies, resulting in a total of 17 studies included in this review involving financial interventions directed at smokers or healthcare providers, or both.Full financial interventions directed at smokers had a favourable effect on abstinence at six months or longer when compared to no intervention (RR 1.77, 95% CI 1.37 to 2.28, I2 = 33%, 9333 participants). There was no evidence that full coverage interventions increased smoking abstinence compared to partial coverage interventions (RR 1.02, 95% CI 0.71 to 1.48, I2 = 64%, 5914 participants), but partial coverage interventions were more effective in increasing abstinence than no intervention (RR 1.27 95% CI 1.02 to 1.59, I2 = 21%, 7108 participants). The economic evaluation showed costs per additional quitter ranging from USD 97 to USD 7646 for the comparison of full coverage with partial or no coverage.There was no clear evidence of an effect on smoking cessation when we pooled two trials of financial incentives directed at healthcare providers (RR 1.16, CI 0.98 to 1.37, I2 = 0%, 2311 participants).Full financial interventions increased the number of participants making a quit attempt when compared to no interventions (RR 1.11, 95% CI 1.04 to 1.17, I2 = 15%, 9065 participants). There was insufficient evidence to show whether partial financial interventions increased quit attempts compared to no interventions (RR 1.13, 95% CI 0.98 to 1.31, I2 = 88%, 6944 participants).Full financial interventions increased the use of smoking cessation treatment compared to no interventions with regard to various pharmacological and behavioural treatments: nicotine replacement therapy (NRT): RR 1.79, 95% CI 1.54 to 2.09, I2 = 35%, 9455 participants; bupropion: RR 3.22, 95% CI 1.41 to 7.34, I2 = 71%, 6321 participants; behavioural therapy: RR 1.77, 95% CI 1.19 to 2.65, I2 = 75%, 9215 participants.There was evidence that partial coverage compared to no coverage reported a small positive effect on the use of bupropion (RR 1.15, 95% CI 1.03 to 1.29, I2 = 0%, 6765 participants). Interventions directed at healthcare providers increased the use of behavioural therapy (RR 1.69, 95% CI 1.01 to 2.86, I2 = 85%, 25820 participants), but not the use of NRT and/or bupropion (RR 0.94, 95% CI 0.76 to 1.18, I2 = 6%, 2311 participants).We assessed the quality of the evidence for the main outcome, abstinence from smoking, as moderate. In most studies participants were not blinded to the different study arms and researchers were not blinded to the allocated interventions. Furthermore, there was not always sufficient information on attrition rates. We detected some imprecision but we judged this to be of minor consequence on the outcomes of this study. AUTHORS' CONCLUSIONS: Full financial interventions directed at smokers when compared to no financial interventions increase the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting. There was no clear and consistent evidence of an effect on smoking cessation from financial incentives directed at healthcare providers. We are only moderately confident in the effect estimate because there was some risk of bias due to a lack of blinding in participants and researchers, and insufficient information on attrition rates. PMID- 28898404 TI - High versus standard volume enteral feeds to promote growth in preterm or low birth weight infants. AB - BACKGROUND: Breast milk alone, given at standard recommended volumes (150 to 180 mL/kg/d), is not adequate to meet the protein, energy, and other nutrient requirements of growing preterm or low birth weight infants. One strategy that may be used to address these potential nutrient deficits is to give infants enteral feeds in excess of 200 mL/kg/d ('high-volume' feeds). This approach may increase nutrient uptake and growth rates, but concerns include that high-volume enteral feeds may cause feed intolerance, gastro-oesophageal reflux, aspiration pneumonia, necrotising enterocolitis, or complications related to fluid overload, including patent ductus arteriosus and bronchopulmonary dysplasia. OBJECTIVES: To assess the effect on growth and safety of feeding preterm or low birth weight infants with high (> 200 mL/kg/d) versus standard (<= 200 mL/kg/d) volume of enteral feeds. Infants in intervention and control groups should have received the same type of milk (breast milk, formula, or both), the same fortification or micronutrient supplements, and the same enteral feeding regimen (bolus, continuous) and rate of feed volume advancement.To conduct subgroup analyses based on type of milk (breast milk vs formula), gestational age or birth weight category of included infants (very preterm or VLBW vs preterm or LBW), presence of intrauterine growth restriction (using birth weight relative to the reference population as a surrogate), and income level of the country in which the trial was conducted (low or middle income vs high income) (see 'Subgroup analysis and investigation of heterogeneity'). SEARCH METHODS: We used the Cochrane Neonatal standard search strategy, which included searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) in the Cochrane Library; MEDLINE (1946 to November 2016); Embase (1974 to November 2016); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to November 2016), as well as conference proceedings, previous reviews, and trial registries. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared high-volume versus standard-volume enteral feeds for preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported the risk ratio and risk difference for dichotomous data, and the mean difference for continuous data, with respective 95% confidence intervals. . We assessed the quality of evidence at the outcome level via the GRADE approach. MAIN RESULTS: We found one eligible trial that included 64 infants. This trial was not blinded. Analysis showed a higher rate of weight gain in the high-volume feeds group: mean difference 6.20 g/kg/d (95% confidence interval 2.71 to 9.69). There was no increase in the risk of feed intolerance or necrotising enterocolitis with high-volume feeds, but 95% confidence intervals around these estimates were wide. We assessed the quality of evidence for these outcomes as 'low' or 'very low' because of imprecision of the estimates of effect and concern about risk of bias due to lack of blinding in the included trial. Trial authors provided no data on other outcomes, including gastro-oesophageal reflux, aspiration pneumonia, necrotising enterocolitis, patent ductus arteriosus, bronchopulmonary dysplasia, or long-term growth and neurodevelopment. AUTHORS' CONCLUSIONS: We found only very limited data from one small unblinded trial on the effects of high-volume feeds on important outcomes for preterm or low birth weight infants. The quality of evidence is low to very low. Hence, available evidence is insufficient to support or refute high-volume enteral feeds in preterm or low birth weight infants. A large, pragmatic randomised controlled trial is needed to provide data of sufficient quality and precision to inform policy and practice. PMID- 28898405 TI - Phosphorylation of bacterial L9 and its functional implication in response to starvation stress. AB - The bacterial L9 (bL9) protein expressed and purified from Escherichia coli is stably phosphorylated. We mapped seven Ser/Thr phosphorylation sites, all of which but one are located at the carboxyl-terminal domain (CTD). When a histidine tag is fused to the C-terminus, bL9 is no longer phosphorylated. Phosphorylation of bL9 causes complete disordering of its CTD and helps cell survival under nutrient-limiting conditions. Previous structural studies of the ribosome have shown that bL9 exhibits two distinct conformations, one of which competes with binding of RelA to the 30s rRNA and prevents RelA activation. Taken together, we suggest that the flexibility of the bL9 CTD enabled by phosphorylation would remove the steric hindrance, serving as a previously unknown mechanism to regulate RelA function and help cell survival under starvation stress. PMID- 28898406 TI - DC-SIGN reacts with TLR-4 and regulates inflammatory cytokine expression via NF kappaB activation in renal tubular epithelial cells during acute renal injury. AB - In the pathological process of acute kidney injury (AKI), innate immune receptors are essential in inflammatory response modulation; however, the precise molecular mechanisms are still unclear. Our study sought to demonstrate the inflammatory response mechanisms in renal tubular epithelial cells via Toll-like receptor-4 (TLR-4) and dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin 1 (DC-SIGN) signalling. We found that DC-SIGN exhibited strong expression in renal tubular epithelial cells of human acute renal injury tissues. DC-SIGN protein expression was increased significantly when renal tubular epithelial cells were exposed to lipopolysaccharide (LPS) for a short period. Furthermore, DC-SIGN was involved in the activation of p65 by TLR-4, which excluded p38 and c-Jun N-terminal kinases (JNK). Interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha expression was decreased after DC-SIGN knock-down, and LPS induced endogenous interactions and plasma membrane co-expression between TLR-4 and DC-SIGN. These results show that DC-SIGN and TLR-4 interactions regulate inflammatory responses in renal tubular epithelial cells and participate in AKI pathogenesis. PMID- 28898407 TI - Compassionate and self-image goals as interpersonal maintenance factors in clinical depression and anxiety. AB - OBJECTIVE: Interpersonal models of depression and anxiety have not examined the role of interpersonal goals in shaping relationships and symptoms. Striving to promote/protect desired self-images (self-image goals) may undermine relationships and increase symptoms, whereas striving to support others (compassionate goals) may be protective, but clinical relevance is unknown. METHOD: We tested effects of compassionate versus self-image goals on interpersonal functioning and symptoms in clinically depressed and/or anxious participants (N = 47) during 10 days of experience sampling, over a 6-week follow up, and in a dyadic relationship. RESULTS: Participants reported higher conflict and symptoms on days that they most pursued self-image goals, but noted higher perceived support and lower symptoms when pursuing compassionate goals. Goals prospectively predicted symptom changes 6 weeks later. Lastly, informant-rated interpersonal goals predicted relationship satisfaction of both patients and significant others. CONCLUSION: Results suggest the relevance of self-image and compassionate goals for the interpersonal maintenance of depression and anxiety. PMID- 28898408 TI - Emotion-related impulsivity and rumination predict the perimenstrual severity and trajectory of symptoms in women with a menstrually related mood disorder. AB - OBJECTIVE: Women with menstrually related mood disorders (MRMDs) demonstrate clinically significant distress during the premenstrual week that remits with the onset of menses. Relatively little is known about psychosocial mechanisms of MRMDs. Given the core affective and behavioral symptoms of MRMDs, dysfunctional responses to emotion (e.g., difficulties with awareness and regulation of emotion; rumination and impulsive or maladaptive behavior in response to emotion) may be important factors to explore as cognitive and behavioral mechanisms in MRMDs. The purpose of the present study was to examine the associations of various dysfunctional responses to emotion (as measured using the Difficulties in Emotion Regulation Scale [DERS] and brooding on the Ruminative Responses Scale [RRS]) with premenstrual symptom severity and trajectory. METHOD: A total of 54 women (mean age = 38.11; 65% Caucasian) with prospectively confirmed MRMDs completed the DERS and RRS, and provided 2-4 menstrual cycles of daily symptom reports. RESULTS: Only the emotion-related impulsivity subscale of the DERS was robustly associated with premenstrual symptom severity. Brooding rumination predicted a more rapid premenstrual increase and slower postmenstrual remission of some symptoms. CONCLUSION: Both rumination and emotion-related impulsivity may be important treatment targets in cognitive behavioral interventions aimed at reducing symptom severity and cyclicity in MRMDs. PMID- 28898409 TI - Combined Effect of Ultrasound and Mild Temperatures on the Inactivation of E. coli in Fresh Carrot Juice and Changes on its Physicochemical Characteristics. AB - : The combination of ultrasound and mild temperatures to process fruits and vegetables juices is a novel approach that is showing promising results for microbial inactivation and preservation of bioactive compounds and sensory attributes. This study centers on investigating the inactivation of Escherichia coli (ATCC 11755) in carrot juice as a result of the combined effect of ultrasound (24 kHz frequency, 120 MUm, and 400 W) with temperature (50, 54, and 58 degrees C) and processing time (0 to 10 min). In addition, the possible changes in physicochemical properties and the retention of bioactive compounds after processing were analyzed. Microbial inactivation with ultrasound treatment at 50 degrees C resulted in 3.5 log reduction after 10 min, whereas at 54 degrees C almost 5 log reduction was attained in the same period of time; meanwhile, for treatment at 58 degrees C, no viable cells were detected (>5 log reduction) after 2 min. There was no significant difference (P > 0.05) on pH (6.80 to 6.82), degrees Brix (8.0 to 8.5), titratable acidity (0.29% to 0.30%), total carotenoid (1774 to 1835 MUg/100 mL), phenolic compounds (20.19 to 20.63 MUg/mL), ascorbic acid (4.8 mg/100 mL), and color parameters between fresh and ultrasound treated samples at the studied temperatures. To predict the inactivation patterns, observed values were tested using 3 different general models: first-order, Weibull distribution, and biphasic. The Weibull and biphasic models show good correlation for inactivation under all processing conditions. Results show ultrasound in combination with mild temperature could be effectively used to process fresh carrot juice providing a safe product without affecting physicochemical characteristics. PRACTICAL APPLICATIONS: The combination of ultrasound and mild temperatures is effective in reducing microbial load in carrot juice to safe levels. This combination would be beneficial in the industrial processing of carrot juice without altering the quality attributes or bioactive compounds. PMID- 28898410 TI - The client's perspective on (experiences of) psychotherapy: A practice friendly review. AB - Recent decades have seen a significant increase in the number of studies exploring client perspectives on, and experiences of, psychotherapy. The present article provides a practice friendly overview of this research, identifying common domains of inquiry, and providing examples of findings relevant to practitioners. Research in this area can be categorized in terms of the client's perspective pertaining to theoretical constructs, studies of client satisfaction, and qualitative studies that are either open-ended or explore specific aspects of client experiences. Examples of this latter category include studies looking at distinct processes (e.g., self-disclosure), particular theoretical constructs (e.g., therapeutic alliance), helpful versus unhelpful aspects of therapy, and significant events. Research suggests that therapist willingness to seek client perspectives, openness to hear what clients have to say, nondefensiveness in the face of negative feedback, and ability to modulate actions accordingly are all likely to contribute to stronger relationships with clients and stronger collaboration, correspondingly contributing to stronger therapeutic outcomes. PMID- 28898411 TI - 50 years of rational-emotive and cognitive-behavioral therapy: A systematic review and meta-analysis. AB - OBJECTIVE: Rational emotive behavior therapy (REBT), introduced by Albert Ellis in the late 1950s, is one of the main pillars of cognitive-behavioral therapy. Existing reviews on REBT are overdue by 10 years or more. We aimed to summarize the effectiveness and efficacy of REBT since its beginnings and investigate the alleged mechanisms of change. METHOD: Systematic search identified 84 articles, out of which 68 provided data for between-group analyses and 39 for within-group analyses. RESULTS: We found a medium effect size of REBT compared to other interventions on outcomes (d = 0.58) and on irrational beliefs (d = 0.70), at posttest. For the within-group analyses, we obtained medium effects for both outcomes (d = 0.56) and irrational beliefs (d = 0.61). Several significant moderators emerged. CONCLUSION: REBT is a sound psychological intervention. Directions for future studies are outlined, stemming from the limitations of existing ones. PMID- 28898412 TI - Antioxidant Activity of Chinese Shanxi Aged Vinegar and Its Correlation with Polyphenols and Flavonoids During the Brewing Process. AB - : One of the most famous Chinese vinegars, Shanxi aged vinegar (SAV), is produced with solid-state fermentation technology. Total antioxidant activity (TAC) is a special property for SAV. In this study, we investigate correlations between total antioxidant activity (TAC) and total polyphenol (TP) and total flavonoid (TF) contents of SAV, especially during the brewing process. For SAV, TAC, TP, and TF increased with the increase of aging time. The correlation coefficients between TAC and TP were 0.869 and 0.934, respectively, when analyzed with the method of ABTS and FRAP. They were 0.828 (ABTS) and 0.877 (FRAP) between the TAC and TF. In smoking pei stage that is a special technique for SAV different from other Chinese cereal vinegars, TAC increased by 120% (ABTS) and 111% (FRAP) mainly due to the increase of TP (89%) and TF (75%), which was more obvious than that during alcohol fermentation and acetic acid fermentation stages. Moreover, variation during brewing process of 8 main polyphenol compounds that were proved responsible for the TAC of SAV was analyzed. In addition to catechins and chlorogenic acid, gallic acid serves as one of the principal antioxidant ingredients in SAV. PRACTICAL APPLICATION: Total antioxidant activity (TAC) of Shanxi aged vinegar (SAV), which is highly correlated with total polyphenol and total flavonoid, increased with aging time, however, there is a little loss of total antioxidant after more than 8 y. During the brewing process smoking pei technique is important for enhancing the TAC of SAV suggesting critical controlled and thoroughly study of smoking pei stage are needed to improve the quality of SAV. PMID- 28898413 TI - Corrigendum. PMID- 28898414 TI - BMP signaling regulates the skeletal and connective tissue differentiation during caudal fin regeneration in sailfin molly (Poecilia latipinna). AB - Caudal fin regeneration in sailfin molly, Poecilia latipinna (Lesueur 1821) involves an initial wound healing stage, followed by blastema that is formed of fast proliferating cells. In order to replicate the lost fin, correct differentiation of the blastemal cells into various tissues is the prime essence. Among the molecular signals governing proper differentiation of blastemal cells, members of the bone morphogenetic protein (BMP) family are crucial. Herein, we investigated the specific effects of inhibition of BMP signaling using LDN193189 on skeletal and connective tissue formation in the regenerating tail fin of P. latipinna during early differentiation phase. It was observed that BMP inhibition leads to reduction in the length of regeneration, which can be correlated with compromised proliferation of blastemal cells. Decreased expression of cell proliferation marker like pcna together with reduced BrdU positive cells consolidate the above observation. Further, histological analysis revealed stunted progression of skeletal tissues and this correlated with the reduced expression of sox9, runx2 and dlx5, Osc and Osn genes in response to BMP inhibition. Also, defective bone patterning was observed due to BMP inhibition, which was associated with diminished levels of shh, ptc-1, gli2 and other BMP ligands. Moreover, histochemical analysis revealed that collagen, one of the most prominent components of connective tissue, was formed below par in treated fin tissues which was subsequently confirmed by biochemical and transcript level analyses. Overall our results highlight the importance of the BMP pathway in proper differentiation of skeletal and connective tissues during the differentiation stage of regenerating caudal fin. PMID- 28898415 TI - Co-occurrence of citrinin and ochratoxin A in rice in Asia and its implications for human health. AB - Citrinin (CIT) and ochratoxin A (OTA) are nephrotoxic mycotoxins, produced by several Aspergillus and Penicillium species and their co-occurrence in rice may cause health effects in humans. Rice is an important food crop worldwide and is a major staple food in Asia which may be invaded by CIT and OTA producing fungal spores in the field, during harvest and storage. Humans are exposed to these mycotoxins through ingestion of contaminated rice and other food commodities. Yet, data on the combined presence to these food contaminants are still insufficient to estimate human exposure in Asia. This review describes the prevalence of CIT and OTA in rice in Asia and its implications on human health, which may help in establishing and carrying out proper management strategies against mould development on rice. From the health point of view, combined exposition of CIT and OTA should be a public concern as both are nephrotoxic and long-term exposure can pose detrimental health effects. Thus, it is necessary for local farmers and food factories to implement strict measures and to improve methods for rice preservation during the distribution to consumers, particularly in the markets. Moreover, regular surveys for CIT and OTA occurrence in rice and human biomonitoring are recommended to reduce the health effects in Asian population. (c) 2017 Society of Chemical Industry. PMID- 28898416 TI - Reporting and identifying child physical abuse: How well are we doing? AB - Entry into the child protection system in the US begins with a child maltreatment report. Some evidence suggests that report source and child age are related to report outcomes, but there has been no national study of these relationships. The purpose of this secondary data analysis was to describe the distribution of report sources for child physical abuse (CPA), and examine whether (a) the source of a report and (b) child age contribute to the likelihood of substantiation of the reported abuse. Multilevel logistic regressions were conducted using a US national sample of 204,414 children investigated for CPA in 2013 in a dataset obtained from the National Child Abuse and Neglect Data System. Results showed that fewer than one in seven children reported for CPA were confirmed victims of abuse. Professionally mandated reporters initiated the majority of CPA reports, and their reports were more likely to be substantiated compared with nonprofessionals. However, reports made by even the most accurate professional group (legal/law enforcement) had only a 26% chance of substantiation, and some professional groups had a lower likelihood of substantiation than nonprofessionals. Reports made by professionals were less likely to be substantiated as child age increased. More research is warranted to develop and test the effectiveness of training programs to improve CPA reporting and identification. PMID- 28898417 TI - Exploring how viruses enhance plants' resilience to drought and the limits to this form of viral payback. AB - This article comments on: Virulence determines beneficial trade-offs in the response of virus-infected plants to drought via induction of salicylic acid. PMID- 28898418 TI - Matrix metalloproteinase-8 levels in periodontal disease patients: A systematic review. AB - Periodontal disease is characterized as a disorder of the oral microbiota resulting in an immune response which, in turn, leads to the destruction of periodontal tissue. Matrix metalloproteinase-8 (MMP-8) has been reported as the major metalloproteinase involved in periodontal disease, being present at high levels in gingival crevicular fluid and salivary fluid (SF). The aim of this systematic review was to evaluate the scientific literature regarding the expression of MMP-8 in gingival crevicular fluid and SF in patients with periodontal disease, analyzing its validity as a possible biomarker in the diagnosis of periodontal disease. A systematic review of the literature was performed using the PubMed/Medline, CENTRAL and Science Direct databases. Studies concerning the use of MMP-8 in the diagnosis of periodontal disease that evaluated its effectiveness as a biomarker for periodontal disease were selected. The search strategy provided a total of 6483 studies. After selection, six articles met all the inclusion criteria and were included in the present systematic review. The studies demonstrated significantly higher concentrations of MMP-8 in patients with periodontal disease compared with controls, as well as in patients presenting more advanced stages of periodontal disease. The findings on higher MMP-8 concentrations in patients with periodontal disease compared with controls imply the potential adjunctive use of MMP-8 in the diagnosis of periodontal disease. PMID- 28898419 TI - A block matching based approach with multiple simultaneous templates for the real time 2D ultrasound tracking of liver vessels. AB - PURPOSE: The implementation of motion management techniques in radiation therapy can aid in mitigating uncertainties and reducing margins. For motion management to be effective, it is necessary to track key structures both accurately and at a real-time speed. Therefore, the focus of this work was to develop a 2D algorithm for the real-time tracking of ultrasound features to aid in radiation therapy motion management. MATERIALS AND METHODS: The developed algorithm utilized a similarity measure-based block matching algorithm incorporating training methods and multiple simultaneous templates. The algorithm is broken down into three primary components, all of which use normalized cross-correlation (NCC) as a similarity metric. First, a global feature shift to account for gross displacements from the previous frame is determined using large block sizes which encompass the entirety of the feature. Second, the most similar reference frame is chosen from a series of training images that are accumulated during the first K frames of tracking to aid in contour consistency and provide a starting point for the localized template initialization. Finally, localized block matching is performed through the simultaneous use of both a training frame and the previous frame. The localized block matching utilizes a series of templates positioned at the boundary points of the training and previous contours. The weighted final boundary points from both the previous and the training frame are ultimately combined and used to determine an affine transformation from the previous frame to the current frame. RESULTS: A mean tracking error of 0.72 +/- 1.25 mm was observed for 85 point-landmarks across 39 ultrasound sequences relative to manual ground truth annotations. The image processing speed per landmark with the GPU implementation was between 41 and 165 frames per second (fps) during the training set accumulation, and between 73 and 234 fps after training set accumulation. Relative to a comparable multithreaded CPU approach using OpenMP, the GPU implementation resulted in speedups between -30% and 355% during training set accumulation, and between -37% and 639% postaccumulation. CONCLUSIONS: Initial implementations indicated an accuracy that was comparable to or exceeding those achieved by alternative 2D tracking methods, with a computational speed that is more than sufficient for real-time applications in a radiation therapy environment. While the overall performance reached levels suitable for implementation in radiation therapy, the observed increase in failures for smaller features, as well as the algorithm's inability to be applied to nonconvex features warrants additional investigation to address the shortcomings observed. PMID- 28898420 TI - Characterization of hyperbranched core-multishell nanocarriers as an innovative drug delivery system for the application at the oral mucosa. AB - BACKGROUND AND OBJECTIVES: In the oral cavity, the mucosal tissues may develop a number of different pathological conditions, such as inflammatory diseases (gingivitis, periodontitis) and autoimmune disorders (eg, oral lichen planus) that require therapy. The application of topical drugs is one common therapeutic approach. However, their efficacy is limited. Dilution effects due to saliva hinder the adherence and the penetration of drug formulations. Therefore, the bioavailability of oral topical drugs is insufficient, and patients may suffer from disease over years, if not life-long. MATERIAL AND METHODS: In the present study, we characterized core-multishell (CMS) nanocarriers for their potential use as drug delivery systems at oral mucosal tissues. For this purpose, we prepared porcine masticatory as well as buccal mucosa and performed Franz cell diffusion experiments. Penetration of fluorescently labeled CMS nanocarriers into the mucosal tissue was analyzed using confocal laser scanning microscopy. Upon exposure to CMS nanocarriers, the metabolic and proliferative activity of gingival epithelial cells was determined by MTT and sulforhodamine B assays, respectively. RESULTS: Here, we could show that the carriers penetrate into both mucosal tissues, while particles penetrate deeper into the masticatory mucosa. Electron paramagnetic resonance spectroscopy revealed that the 3-carboxy-2,2,5,5 tetramethyl-1-pyrrolidinyloxy-labeled glucocorticoid dexamethasone loaded on to the CMS nanocarriers was released from the carriers in both mucosal tissues but with a higher efficiency in the buccal mucosa. The release from the nanocarriers is in both cases superior compared to the release from a conventional cream, which is normally used for the treatment of inflammatory conditions in the oral cavity. The CMS nanocarriers exhibited neither cytotoxic nor proliferative effects in vitro. CONCLUSION: These findings suggested that CMS nanocarriers might be an innovative approach for topical drug delivery in the treatment of oral inflammatory diseases. PMID- 28898421 TI - Tooth bleaching with low-temperature plasma lowers surface roughness and Streptococcus mutans adhesion. AB - AIM: To evaluate the structural-morphological changes in enamel surface roughness and Streptococcus mutans adhesion after tooth bleaching using plasma in combination with a low concentration of 15% carbamide peroxide (CP). METHODOLOGY: Sixty pairs of premolars were randomly assigned to the treatment groups (n = 30; buccal surface, groups 1A/2A) or controls (n = 30; palatal surface, Groups 1B/2B). Group 1A received a low concentration of 15% CP and low-temperature plasma. Premolars in group 1B were placed in phosphate-buffered saline and served as controls. The buccal surface of Groups 2A was subjected to 15% CP alone, whilst the palatal surface was subsequently immersed in PBS (group 2B). After bleaching, all teeth were soaked for 1 h in artificial saliva at 37 degrees C. Subsequently, teeth were placed in brain-heart infusion with S. mutans at 37 degrees C for 24 h. The assessment of the structural-morphological changes was carried out using a biofilm assay, scanning electron microscopy and atomic force microscopy. Statistical analysis of the data was performed with the SPSS (SPSS Inc., Version 18.0, Chicago, IL, USA). The Student's t-test was used to determine whether there was a significant difference in the structural-morphological effects with and without plasma. RESULTS: Significantly less S. mutans adhesion was observed in group 1A compared with the other groups (P < 0.05). Moreover, the surface roughness was significantly greater in group 2A compared with the other groups (P < 0.05). CONCLUSIONS: The application of plasma did not result in any structural-morphological and topographic changes in the enamel. The combined bleaching method using plasma and a low concentration of 15% CP was less destructive, particularly with respect to tooth surface changes. PMID- 28898422 TI - Dynamic gastric digestion of a commercial whey protein concentrate?. AB - BACKGROUND: A dynamic gastrointestinal simulator, simgi(r) , has been applied to assess the gastric digestion of a whey protein concentrate. Samples collected from the outlet of the stomach have been compared to those resulting from the static digestion protocol INFOGEST developed on the basis of physiologically inferred conditions. RESULTS: Progress of digestion was followed by SDS-PAGE and LC-MS/MS. By SDS-PAGE, serum albumin and alpha-lactalbumin were no longer detectable at 30 and 60 min, respectively. On the contrary, beta-lactoglobulin was visible up to 120 min, although in decreasing concentrations in the dynamic model due to the gastric emptying and the addition of gastric fluids. Moreover, beta-lactoglobulin was partly hydrolysed by pepsin probably due to the presence of heat-denatured forms and the peptides released using both digestion models were similar. Under dynamic conditions, a stepwise increase in number of peptides over time was observed, while the static protocol generated a high number of peptides from the beginning of digestion. CONCLUSION: Whey protein digestion products using a dynamic stomach are consistent with those generated with the static protocol but the kinetic behaviour of the peptide profile emphasises the effect of the sequential pepsin addition, peristaltic shaking, and gastric emptying on protein digestibility. (c) 2017 Society of Chemical Industry. PMID- 28898423 TI - Iterative volume of interest based 4D cone-beam CT. AB - PURPOSE: 4D cone-beam CT (CBCT) has potential applications in soft tissue alignment and tumor motion verification at the time of radiation treatment. However, prominent streak artifacts with conventional image reconstructions have limited its clinical use and alternative reconstructions are generally too computationally expensive for the time available. We propose an iterative volume of interest based (I4D VOI) reconstruction technique, where 4D reconstruction is only performed within a VOI, to limit streak artifacts with limited added computation time. METHODS: The I4D VOI technique is compared to standard cone beam filtered back projection (FDK), an FDK VOI technique, and unconstrained total variation (TV) minimization by comparing tumor motion quantification errors and image quality. 14 long CBCT scans (6.5 to 12 min) of patients receiving radiation treatment for lung cancer were used for the comparison. Rigid registration between phase images of FDK reconstructions using all projections were used to quantify the gold standard motion. Projections were removed to simulate 2 minute scans and these new projection sets were used for each of the test reconstructions. RESULTS: Excluding two patients where registration failed, the average root mean square (RMS) error for each method was as follows: 1.5 +/- 0.2 mm for FDK, 1.4 +/- 0.2 mm for FDK VOI, 1.3 +/- 0.2 mm for I4D VOI, 1.7 +/- 0.4 mm for low regularization TV minimization, and 1.1 +/- 0.2 mm for high regularization TV minimization. No significant difference was observed between RMS error for I4D VOI and the other methods, except for unsmoothed FDK VOI (P = 0.02). An increase in RMS error difference between I4D VOI and smoothed FDK VOI was observed going from 2 min to 1 min scans (0.1 mm to 0.3 mm, P = 0.20 to P = 0.09). CONCLUSIONS: I4D VOI and FDK VOI reconstruction measured tumor trajectories with equivalent accuracy as TV minimization with improved bony anatomy image quality and computation time (I4D VOI was approximately 15 and 95 times faster than low and high regularization TV minimization, respectively). Within the VOI, streak artifact reduction compared to FDK VOI may be beneficial for tumor visualization and motion measurement, but requires further study. PMID- 28898424 TI - Relationship Between Consumer Acceptability and Pungency-Related Flavor Compounds of Vidalia Onions. AB - : A consumer study was conducted to evaluate preferences in Vidalia onions, and define consumer acceptability thresholds for commonly analyzed flavor compounds associated with pungency. Two varieties of Vidalia onions (Plethora and Sapelo Sweet) were grown at 3 fertilizer application rates (37.5 and 0; 134.5 and 59.4; and 190 and 118.8 kg/ha of nitrogen and sulfur, respectively), creating 6 treatments with various flavor attributes to use in the study. Bulb soluble solids, sugars, pyruvic acid, lachrymatory factor (LF; propanethial S-oxide), and methyl thiosulfinate (MT) content were determined and compared to sensory responses for overall liking, intensity of the sharp/pungent/burning sensation (SPB), and intent to buy provided by 142 consumers. Onion pyruvate, LF, MT, and sugar content increased as fertilization rate increased, regardless of onion variety. Consumer responses showed participants preferred onions with low SPB, which correlated positively to lower pyruvate, LF and MT concentrations, but showed no relationship to total sugars in the onion bulb. Regression analyses revealed that the majority of consumers (>=55%) found the flavor of Vidalia onions acceptable when the concentrations of LF, pyruvic acid, and MT within the bulbs were below 2.21, 4.83, and 0.43 nmol/mL, respectively. These values will support future studies aimed at identifying the optimal cultivation practices for production of sweet Vidalia onions, and can serve as an industry benchmark for quality control, thus ensuring the flavor of Vidalia onions will be acceptable to the majority of consumers. PRACTICAL APPLICATION: This study identified the relationship between consumer preferences and commonly analyzed flavor compounds in Vidalia onions, and established thresholds for these compounds at concentrations which the majority of consumers will find desirable. These relationships and thresholds will support future research investigating how cultural practices impact onion quality, and can be used to assist growers in variety selection decisions. In addition, this information will provide a benchmark to Vidalia onion producers for quality control of the sweet onions produced, ensuring that the onions are consistently of a desired quality, thereby increasing consumer's reliability in the Vidalia onion brand. PMID- 28898425 TI - Response of porcine epithelial rests of Malassez to stimulation by interleukin-6. AB - AIM: To investigate the proliferation and migration of epithelial cell rests of Malassez (ERM) after stimulation with IL-6. METHODOLOGY: Porcine-derived ERM were seeded on Dulbecco's modified Eagle's Medium, and IL-6 (100 pg mL-1 ) was incorporated into the culture medium. The WST-1 assay was performed to evaluate cell proliferation, and absorption was measured at 450 nm. A wound-healing assay and immunofluorescence assay for integrin alpha3 were conducted to investigate migration. The Kruskal-Wallis test and the Mann-Whitney U-test with Bonferroni correction were used to analyse data of WST-1 and wound-healing assays. RESULTS: Cell proliferation following the stimulation by IL-6 increased over time, with a significant increase being observed at 6 h (P < 0.05), but not in a concentration dependent manner. Cell proliferation was significantly greater in IL-6-treated ERM than in nontreated ERM (P < 0.05). The results of the wound-healing assay revealed earlier closure in IL-6-treated ERM (P < 0.05). In the immunofluorescence assay, integrin alpha3 was detected at the edge of cell processes adjacent to the wound area. A neutralized antibody abrogated the effects of the IL-6 stimulation in cell proliferation and migration. CONCLUSION: IL-6 promoted the proliferation and migration of porcine ERM in vitro. PMID- 28898426 TI - Differences between inflammatory and catabolic mediators of peri-implantitis and periodontitis lesions following initial mechanical therapy: An exploratory study. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to analyze the differences in inflammatory and catabolic mediators expressed in peri-implantitis compared to periodontitis lesions after non-surgical therapy. Peri-implantitis is associated with a faster rate of bone loss when compared with periodontitis, and peri implant non-surgical therapy is ineffective to cure peri-implantitis. This may be due to persistent inflammation in peri-implantitis tissues after initial mechanical treatment. MATERIAL AND METHODS: Eleven patients with peri-implantitis and 10 with severe chronic periodontitis received non-surgical therapy. They were included at re-evaluation (8 weeks) if they presented pocket depth >=6 mm with bleeding on probing, and the indication for open flap debridement surgery. Connective tissues were harvested during surgery from diseased sites. Healthy gingiva were harvested during third molar extraction in a third group of healthy patients (n=10). Explants were incubated for 24 hours in media culture and the release of cytokines, chemokines, growth factors, osteoprotegerin, receptor activator of nuclear factor kappa-B ligand (RANKL), matrix metalloproteinase and tissue inhibitors of matrix metalloproteinase (TIMP) in the conditioned media was analyzed by an exploratory multiplex immunoassay. When difference was found in the conditioned media, an immunohistochemistry was performed to compare expression in the tissues. RESULTS: Connective tissues from non-stabilized peri implantitis exhibited a distinct cytokine profile compared to periodontitis lesions that did not respond to initial therapy. Indeed, TIMP-2 was significantly increased in media from peri-implantitis (P<=.05). In addition, the in situ expression of TIMP-2, interleukin-10 and RANKL was also significantly increased in peri-implantitis tissues (P<=.05). However, the ratio of RANKL/osteoprotegerin positive cells did not vary (P>=.05). CONCLUSION: This study suggests that peri implantitis and periodontitis connective tissues exhibit differences in response to non-surgical treatment, which may contribute to a different pattern of disease evolution. PMID- 28898427 TI - The dental therapist movement in the United States: A critique of current trends. AB - Dental therapists are members of the oral health workforce in over 50 countries in the world typically caring for children in publically funded school-based programs. A movement has developed in the United States to introduce dental therapists to the oral health workforce in an attempt to improve access to care and to reduce disparities in oral health. This article critiques trends in the United States movement in the context of the history and success of dental therapists practicing internationally. While supporting the dental therapist movement, we challenge: a) the use of dental therapists treating adults, versus focusing on children; b) the use of dental therapists in the private versus the public/not-for-profit sector; and c) requirements that a dental therapist must also be credentialed as a dental hygienist. PMID- 28898428 TI - Soil CO2 venting as one of the mechanisms for tolerance of Zn deficiency by rice in flooded soils. AB - We sought to explain rice (Oryza sativa) genotype differences in tolerance of zinc (Zn) deficiency in flooded paddy soils and the counter-intuitive observation, made in earlier field experiments, that Zn uptake per plant increases with increasing planting density. We grew tolerant and intolerant genotypes in a Zn-deficient flooded soil at high and low planting densities and found (a) plant Zn concentrations and growth increased with planting density and more so in the tolerant genotype, whereas the concentrations of other nutrients decreased, indicating a specific effect on Zn uptake; (b) the effects of planting density and genotype on Zn uptake could only be explained if the plants induced changes in the soil to make Zn more soluble; and (c) the genotype and planting density effects were both associated with decreases in dissolved CO2 in the rhizosphere soil solution and resulting increases in pH. We suggest that the increases in pH caused solubilization of soil Zn by dissolution of alkali soluble, Zn-complexing organic ligands from soil organic matter. We conclude that differences in venting of soil CO2 through root aerenchyma were responsible for the genotype and planting density effects. PMID- 28898429 TI - TGACG-BINDING FACTOR 1 (TGA1) and TGA4 regulate salicylic acid and pipecolic acid biosynthesis by modulating the expression of SYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1 (SARD1) and CALMODULIN-BINDING PROTEIN 60g (CBP60g). AB - Salicylic acid (SA) and pipecolic acid (Pip) play important roles in plant immunity. Here we analyzed the roles of transcription factors TGACG-BINDING FACTOR 1 (TGA1) and TGA4 in regulating SA and Pip biosynthesis in Arabidopsis thaliana. We quantified the expression levels of SYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1 (SARD1) and CALMODULIN-BINDING PROTEIN 60g (CBP60g), which encode two master transcription factors of plant immunity, and the accumulation of SA and Pip in tga1-1 tga4-1 mutant plants. We tested whether SARD1 and CBP60g are direct targets of TGA1 by chromatin immunoprecipitation-polymerase chain reaction (ChIP PCR). In addition to promoting pathogen-induced SA biosynthesis, we found that SARD1 and CBP60g also positively regulated Pip biosynthesis by targeting genes encoding key biosynthesis enzymes of Pip. TGA1/TGA4 were required for full induction of SARD1 and CBP60g in plant defense. ChIP-PCR analysis showed that SARD1 was a direct target of TGA1. In tga1-1 tga4-1 mutant plants, the expression levels of SARD1 and CBP60g along with SA and Pip accumulation following pathogen infection were dramatically reduced compared with those in wild-type plants. Consistent with reduced expression of SARD1 and CBP60g, pathogen-associated molecular pattern (PAMP)-induced pathogen resistance and systemic acquired resistance were compromised in tga1-1 tga4-1. Our study showed that TGA1 and TGA4 regulate Pip and SA biosynthesis by modulating the expression of SARD1 and CBP60g. PMID- 28898430 TI - Effect of drying methods on the structure, thermo and functional properties of fenugreek (Trigonella foenum graecum) protein isolate. AB - BACKGROUND: Different drying methods due to protein denaturation could alter the functional properties of proteins, as well as their structure. So, this study focused on the effect of different drying methods on amino acid content, thermo and functional properties, and protein structure of fenugreek protein isolate. RESULTS: Freeze and spray drying methods resulted in comparable protein solubility, dynamic surface and interfacial tensions, foaming and emulsifying properties except for emulsion stability. Vacuum oven drying promoted emulsion stability, surface hydrophobicity and viscosity of fenugreek protein isolate at the expanse of its protein solubility. Vacuum oven process caused a higher level of Maillard reaction followed by the spray drying process, which was confirmed by the lower amount of lysine content and less lightness, also more browning intensity. DeltaH of fenugreek protein isolates was higher than soy protein isolate, which confirmed the presence of more ordered structures. Also, the bands which are attributed to the alpha-helix structures in the FTIR spectrum were in the shorter wave number region for freeze and spray dried fenugreek protein isolates that show more possibility of such structures. CONCLUSION: This research suggests that any drying method must be conducted in its gentle state in order to sustain native structure of proteins and promote their functionalities. (c) 2017 Society of Chemical Industry. PMID- 28898431 TI - Anti-inflammatory and antioxidant properties of Schisandrin C promote mitochondrial biogenesis in human dental pulp cells. AB - AIM: To examine the properties of Schisandrin C as an anti-inflammatory and antioxidant compound, and whether its characteristics promote mitochondrial biogenesis in human dental pulp cells (HDPCs). METHODOLOGY: HDPCs were extracted from fresh third molars and cultured for experiments. Reactive oxidative stress (ROS) and nitric oxide (NO) formation were analysed by a Muse cell analyser. Western blotting and gelatin zymography were used to identify the presence of antioxidants, as well as anti-inflammatory and mitochondrial biogenesis with specific antibody. An unpaired Student's t-test was used for statistical analysis. RESULTS: Schisandrin C inhibited lipopolysaccharide-stimulated inflammatory molecules; interleukin 1 beta, tumour necrosis factor alpha, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, matrix metalloproteinase-2 and -9, NO production, ROS formation, nuclear factor kappa B translocation (P < 0.05) through the mitogen-activated protein kinase pathway. Schisandrin C increased the expression of superoxide dismutase enzymes as well as haem oxygenase-1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha through the phosphorylated-protein kinase B (p-Akt) and nuclear factor erythroid 2-related factor-2 pathways (P < 0.05). The anti-inflammatory and antioxidant properties of Schisandrin C promoted mitochondrial biogenesis. CONCLUSIONS: Schisandrin C has the potential to reduce inflammation and oxidation and to promote mitochondrial biogenesis. Therefore, Schisandrin C may be considered for use as an anti-inflammatory compound for oral inflammation through mitochondrial biogenesis. PMID- 28898432 TI - Hyperglycemia on admission and hospitalization outcomes in patients with atrial fibrillation. AB - BACKGROUND: We evaluated the association of admission blood glucose (ABG) and mortality in patients with and without diabetes mellitus (DM) hospitalized for atrial fibrillation (AF). HYPOTHESIS: Hyperglycemia on admission is a bad prognostic marker in patients with AF. METHODS: Observational data were collected from electronic records of patients age >= 18 years hospitalized for AF in 2011 2013. Twelve-month data were available in all cases. ABG levels were classified as follows: 70 to 110 mg/dL, normal; 111 to 140 mg/dL, mildly elevated; 141 to 199 mg/dL, moderately elevated; >=200 mg/dL, markedly elevated. Cox proportional hazards model was used to assess overall survival by ABG categories, adjusted for study variables. Primary outcome measure was mortality at end of follow-up. RESULTS: The cohort included 1127 patients (45% male; median age, 75 +/- 13 years), of whom 331 had DM. Mortality rates by ABG levels were 19% (77/407 patients), normal ABG; 26% (92/353 patients), mildly elevated ABG; 28% (69/244 patients), moderately elevated ABG; and 41% (50/123 patients), markedly elevated ABG. Data were analyzed for the entire cohort following adjustment for age, sex, CHADS2 score, ischemic heart disease, smoking, and alcohol consumption. Compared with normal ABG, the adjusted hazard ratio for mortality was higher in patients with moderately elevated ABG (2.1, 95% confidence interval: 1.19-7.94, P < 0.05) and markedly elevated ABG (1.6, 95% confidence interval: 1.02-5.31, P < 0.05). CONCLUSIONS: In patients with and without DM hospitalized for AF, moderately to markedly elevated ABG levels are associated with increased mortality. PMID- 28898433 TI - Changes in parameters of right ventricular function with cardiac resynchronization therapy. AB - BACKGROUND: Studies have shown that cardiac resynchronization therapy (CRT) significantly improves right ventricle (RV) size and function in patients with heart failure (HF). HYPOTHESIS: CRT does not lead to improvement in RV function independent of baseline clinical variables. METHODS: A systematic search of studies published between 1966 to August 31, 2015 was conducted using Pub Med, CINAHL, Cochrane CENTRAL and the Web of Science databases. Studies reporting tricuspid annular plane systolic excursion (TAPSE) or RV basal strain or RV long axis diameter or RV short axis diameter or RV fractional area change (FAC), before and after CRT, were identified. A meta-analysis was performed using random effects with inverse variance method to determine the pooled mean difference in various parameters of RV function after CRT. Meta-regression analysis was performed to test the relationship between change in various parameters of RV functions after CRT and covariates- age, QRS duration, and left ventricular ejection fraction (LVEF). RESULTS: Thirteen studies (N=1541) were selected for final analysis. CRT therapy led to statistically significant increases in TAPSE [1.21 (95% CI 0.55-1.86; p<0.001)], RV FAC [2.26 (95% CI 0.50-4.01; p<0.001)] and basal strain [2.82 (95% CI 0.59-5.05; p<0.001)] and statistically significant decreases in mean RV long axis diameter [-2.94 (95% CI -5.07- -0.82; p=0.005)] and short axis diameter [-1.39 (95% CI -2.10- -0.67; p=0.876)] after a mean follow up period of 9 months. However, after meta-regression analysis for age, QRS duration, and baseline LVEF as covariates, there was no significant improvement in any of the parameters of RV function after CRT. CONCLUSION: There was a statistically significant improvement in TAPSE, RV basal strain, RV fractional area, RV long axis and short axis with CRT. However, improvement in these echocardiographic parameters of RV function after CRT was not independent of baseline clinical variables but statistically dependent on age, QRS duration and baseline LVEF. PMID- 28898434 TI - Cold sensing in grapevine-Which signals are upstream of the microtubular "thermometer". AB - Plants can acquire freezing tolerance in response to cold but non-freezing temperatures. To efficiently activate this cold acclimation, low temperature has to be sensed and processed swiftly, a process that is linked with a transient elimination of microtubules. Here, we address cold-induced microtubules elimination in a grapevine cell line stably expressing a green fluorescent protein fusion of Arabidopsis TuB6, which allows to follow their response in vivo and to quantify this response by quantitative image analysis. We use time-course studies with several specific pharmacological inhibitors and activators to dissect the signalling events acting upstream of microtubules elimination. We find that microtubules disappear within 30 min after the onset of cold stress. We provide evidence for roles of calcium influx, membrane rigidification, and activation of NAD(P)H oxidase as factors in signal susception and amplification. We further conclude that a G-protein in concert with a phospholipase D convey the signal towards microtubules, whereas calmodulin seems to be not involved. Moreover, activation of jasmonate pathway in response to cold is required for an efficient microtubule response. We summarize our findings in a working model on a complex signalling hub at the membrane-cytoskeleton interphase that assembles the susception, perception and early transduction of cold signals. PMID- 28898435 TI - Wearable slot antenna at 2.45 GHz for off-body radiation: Analysis of efficiency, frequency shift, and body absorption. AB - The interaction of body-worn antennas with the human body causes a significant decrease in antenna efficiency and a shift in resonant frequency. A resonant slot in a small conductive box placed on the body has been shown to reduce these effects. The specific absorption rate is less than international health standards for most wearable antennas due to small transmitter power. This paper reports the linear relationship between power absorbed by biological tissues at different locations on the body and radiation efficiency based on numerical modeling (r = 0.99). While the -10 dB bandwidth of the antenna remained constant and equal to 12.5%, the maximum frequency shift occurred when the antenna was close to the elbow (6.61%) and on the thigh (5.86%). The smallest change was found on the torso (4.21%). Participants with body-mass index (BMI) between 17 and 29 kg/m2 took part in experimental measurements, where the maximum frequency shift was 2.51%. Measurements showed better agreement with simulations on the upper arm. These experimental results demonstrate that the BMI for each individual had little effect on the performance of the antenna. Bioelectromagnetics. 39:25-34, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28898436 TI - Letter to Liu et al.'s "Efficacy of Exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome". PMID- 28898438 TI - Collagen XI mutation lowers susceptibility to load-induced cartilage damage in mice. AB - Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018. PMID- 28898437 TI - Regulation of fibroblast growth factor 8 (FGF8) in chicken embryonic stem cells differentiation into spermatogonial stem cells. AB - Fibroblast growth factors (FGFs) are essential in regulating the formation of spermatogonial stem cells (SSCs). Here, we explored the effect of FGF8 on chicken SSCs formation by knockdown or overexpression of FGF8 in chicken embryonic stem cells (ESCs) both in vitro and in vivo. Our results showed that knockdown of FGF8 could facilitate the differentiation of ESCs into SSCs, overexpression of FGF8 could promote PGCs self-renewal, inhibit SSCs formation. This study further revealed the positive correlation between the expression level of FGF8 and MAPK/ERK signal. In the absence of FGF8, the expression of downstream genes such as FGFR2, GRB2, RAS, BRAF, RAF1, and MEK2 was not maintained, while overexpressing FGF8 enhances them. Thus, our study demonstrated that FGF8 can regulate germ cell fate by modulating the dynamic equilibrium between differentiation and self-renewal, which provides a new idea for the study of germ cell regulatory network. PMID- 28898439 TI - Evaluation of the use of midazolam as a co-induction agent with ketamine for anaesthesia in sedated ponies undergoing field castration. AB - BACKGROUND: There are limited investigations comparing ketamine to a ketamine midazolam co-induction. OBJECTIVES: To compare quality and safety of general anaesthesia induced using ketamine alone with anaesthesia co-induced using ketamine and midazolam. STUDY DESIGN: Randomised, double blinded, placebo controlled trial. METHODS: After i.v. detomidine (20 MUg/kg) thirty-eight ponies undergoing field castration received either 0.06 mg/kg (0.6 mL/50 kg) midazolam (group M) or 0.6 mL/50 kg placebo (group P) with 2.2 mg/kg ketamine i.v. for anaesthetic induction. Quality of anaesthetic induction, endotracheal intubation, surgical relaxation and recovery were scored using combinations of simple descriptive and visual analogue scales. Time of sedation, induction, start of endotracheal intubation, first movement, sternal recumbency and standing were recorded, as were time, number and total quantity of additional i.v. detomidine and ketamine injections. Cardiorespiratory variables were assessed every 5 min. Adverse effects were documented. Data were tested for normality and analysed with a mixed model ANOVA, Fisher's exact test, unpaired Students' t test and Wilcoxon Rank-sum as appropriate; P<0.05 was considered significant. RESULTS: Group M had better scores for induction (P = 0.005), intubation (P<0.001) and surgical relaxation (P<0.001) and required fewer additional injections of detomidine and ketamine (P = 0.04). Time (minutes) from induction to first movement (P<0.001), sternal recumbency (P =< 0.001) and standing was longer (P = 0.05) in group M. Recoveries were uneventful with no difference in quality between groups (P = 0.78). MAIN LIMITATIONS: Clinical study with noninvasive monitoring undertaken in field conditions. CONCLUSIONS: Ketamine-midazolam co-induction compared to ketamine alone improved quality of induction, ease of intubation and muscle relaxation without impacting recovery quality. PMID- 28898441 TI - Three-dimensional reconstruction of the pharyngeal gland cells in the predatory nematode Pristionchus pacificus. AB - Pristionchus pacificus is a model system in evolutionary biology and for comparison to Caenorhabditis elegans. As a necromenic nematode often found in association with scarab beetles, P. pacificus exhibits omnivorous feeding that is characterized by a mouth-form dimorphism, an example of phenotypic plasticity. Eurystomatous animals have a dorsal and a sub-ventral tooth enabling predatory feeding on other nematodes whereas stenostomatous animals have only a dorsal tooth and are microbivorous. Both mouth forms of P. pacificus, like all members of the Diplogastridae family, lack the grinder in the terminal bulb of the pharynx resulting in a fundamentally different organization of several pharynx associated structures. Here, we describe the three-dimensional reconstruction of the pharyngeal gland cells in P. pacificus based on serial transmission electron microscopical analysis of 2527 sections of 50 nm thickness. In comparison to C. elegans, P. pacificus lacks two gland cells (g2) usually associated with grinder function, whereas the three gland cells of g1 (g1D, g1VL, and g1VR) are very prominent. The largest expansion is seen for g1D, which has an anterior process that opens into the buccal cavity through a canal in the dorsal tooth. We provide the morphological description and fine structural analysis of the P. pacificus gland cells, the behavior of the pharynx and preliminary insight into exocytosis of gland cell vesicles in P. pacificus. PMID- 28898440 TI - Low Lactobacilli abundance and polymicrobial diversity in the lower reproductive tract of female rhesus monkeys do not compromise their reproductive success. AB - The lower reproductive tract of nonhuman primates is colonized with a diverse microbiota, resembling bacterial vaginosis (BV), a gynecological condition associated with negative reproductive outcomes in women. Our 4 aims were to: (i) assess the prevalence of low Lactobacilli and a BV-like profile in female rhesus monkeys; (ii) quantify cytokines in their cervicovaginal fluid (CVF); (iii) examine the composition and structure of their mucosal microbiota with culture independent sequencing methods; and (iv) evaluate the potential influence on reproductive success. CVF specimens were obtained from 27 female rhesus monkeys for Gram's staining, and to determine acidity (pH), and quantify proinflammatory cytokines. Based on Nugent's classification, 40% had a score of 7 or higher, which would be indicative of BV in women. Nugent scores were significantly correlated with the pH of the CVF. Interleukin-1beta was present at high concentrations, but not further elevated by high Nugent scores. Vaginal swabs were obtained from eight additional females to determine microbial diversity by rRNA gene amplicon sequencing. At the phylum level, the Firmicutes/Bacteroidetes ratio was low. The relative abundance of Lactobacilli was also low (between 3% and 17%), and 11 other genera were present at >1%. However, neither the microbial diversity in the community structure, nor high Nugent scores, was associated with reduced fecundity. Female monkeys provide an opportunity to understand how reproductive success can be sustained in the presence of a diverse polymicrobial community in the reproductive tract. PMID- 28898442 TI - Bayesian estimation of multivariate normal mixtures with covariate-dependent mixing weights, with an application in antimicrobial resistance monitoring. AB - Bacteria with a reduced susceptibility against antimicrobials pose a major threat to public health. Therefore, large programs have been set up to collect minimum inhibition concentration (MIC) values. These values can be used to monitor the distribution of the nonsusceptible isolates in the general population. Data are collected within several countries and over a number of years. In addition, the sampled bacterial isolates were not tested for susceptibility against one antimicrobial, but rather against an entire range of substances. Interest is therefore in the analysis of the joint distribution of MIC data on two or more antimicrobials, while accounting for a possible effect of covariates. In this regard, we present a Bayesian semiparametric density estimation routine, based on multivariate Gaussian mixtures. The mixing weights are allowed to depend on certain covariates, thereby allowing the user to detect certain changes over, for example, time. The new approach was applied to data collected in Europe in 2010, 2012, and 2013. We investigated the susceptibility of Escherichia coli isolates against ampicillin and trimethoprim, where we found that there seems to be a significant increase in the proportion of nonsusceptible isolates. In addition, a simulation study was carried out, showing the promising behavior of the proposed method in the field of antimicrobial resistance. PMID- 28898443 TI - Re-evaluation of 33 'unclassified' eosinophilic renal cell carcinomas in young patients. AB - AIMS: We sought to determine if some unclassified renal cell carcinomas (RCCs) in children and young adults that are characterised by predominantly eosinophilic cytoplasm are related to the recently described succinate dehydrogenase (SDH) deficient RCC, fumarate hydratase (FH)-deficient RCC or eosinophilic solid and cystic (ESC) RCC. METHODS AND RESULTS: We reviewed 33 unclassified RCCs with predominantly eosinophilic cytoplasm in patients aged 35 years or younger. Immunohistochemistry (IHC) for SDHB, FH and CK20 (a marker of ESC) was performed in all cases. IHC for 2-succinocysteine (2SC) was performed on RCC with loss of FH labelling. Four RCC (12%) (median age 18 years) demonstrated loss of FH labelling as well as aberrant 2SC labelling, and were thus classified as FH deficient RCCs. Importantly, none of these cases demonstrated the characteristic macronucleoli typical of FH-deficient RCC. Eight RCC (24%) (median age 20.5 years) demonstrated loss of SDHB and were reclassified as SDH-deficient RCCs. Importantly, only four of eight SDH-deficient RCC demonstrated the characteristic cytoplasmic vacuoles and inclusions of typical SDH-deficient RCC. Ten RCC (30%) (median age 27 years) were reclassified as ESC RCCs. Four of 10 ESC RCC were multifocal (one bilateral), four of 10 ESC RCC occurred in males and one patient presented with liver and lung metastases, all not described previously in ESC. Eleven RCC (33%) remained unclassified. CONCLUSIONS: Pathologists should have a low threshold for performing FH, SDHB and CK20 IHC when confronted with unclassified eosinophilic RCC or 'oncocytoma' in young patients. PMID- 28898444 TI - A sequential test for assessing observed agreement between raters. AB - Assessing the agreement between two or more raters is an important topic in medical practice. Existing techniques, which deal with categorical data, are based on contingency tables. This is often an obstacle in practice as we have to wait for a long time to collect the appropriate sample size of subjects to construct the contingency table. In this paper, we introduce a nonparametric sequential test for assessing agreement, which can be applied as data accrues, does not require a contingency table, facilitating a rapid assessment of the agreement. The proposed test is based on the cumulative sum of the number of disagreements between the two raters and a suitable statistic representing the waiting time until the cumulative sum exceeds a predefined threshold. We treat the cases of testing two raters' agreement with respect to one or more characteristics and using two or more classification categories, the case where the two raters extremely disagree, and finally the case of testing more than two raters' agreement. The numerical investigation shows that the proposed test has excellent performance. Compared to the existing methods, the proposed method appears to require significantly smaller sample size with equivalent power. Moreover, the proposed method is easily generalizable and brings the problem of assessing the agreement between two or more raters and one or more characteristics under a unified framework, thus providing an easy to use tool to medical practitioners. PMID- 28898446 TI - Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice. AB - : Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, antioxidants may still play a role in cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. CONCLUSION: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. (Hepatology 2018). PMID- 28898445 TI - Characterizing adults with Type 2 diabetes mellitus and intellectual disability: outcomes of a case-finding study. AB - AIMS: To report the results of a case-finding study conducted during a feasibility trial of a supported self-management intervention for adults with mild to moderate intellectual disability and Type 2 diabetes mellitus, and to characterize the study sample in terms of diabetes control, health, and access to diabetes management services and support. METHODS: We conducted a cross-sectional case-finding study in the UK (March 2013 to June 2015), which recruited participants mainly through primary care settings. Data were obtained from medical records and during home visits. RESULTS: Of the 325 referrals, 147 eligible individuals participated. The participants' mean (sd) HbA1c concentration was 55 (15) mmol/mol [7.1 (1.4)%] and the mean (sd) BMI was 32.9 (7.9) kg/m2 , with 20% of participants having a BMI >40 kg/m2 . Self-reported frequency of physical activity was low and 79% of participants reported comorbidity, for example, cardiovascular disease, in addition to Type 2 diabetes. The majority of participants (88%) had a formal or informal supporter involved in their diabetes care, but level and consistency of support varied greatly. Post hoc exploratory analyses showed a significant association between BMI and self reported mood, satisfaction with diet and weight. CONCLUSIONS: We found high obesity and low physical activity levels in people with intellectual disability and Type 2 diabetes. Glycaemic control was no worse than in the general Type 2 diabetes population. Increased risk of morbidity in this population is less likely to be attributable to poor glycaemic control and is probably related, at least in part, to greater prevalence of obesity and inactivity. More research, focused on weight management and increasing activity in this population, is warranted. PMID- 28898447 TI - Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events. AB - : The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. CONCLUSION: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2017). PMID- 28898448 TI - Neutral glenoid alignment in reverse shoulder arthroplasty does not guarantee decreased risk of impingement. AB - Reverse Shoulder Arthroplasty (RSA) has gained popularity over the recent years, but impingement concerns are still present. Surgeons aim to correct pre-operative glenoid deformities to reduce impingement but it can be challenging without assistance like patient specific guides. However, it is unclear how accurate glenoid correction affects the impingement. The main objective of this study was to determine whether accurate glenoid correction to neutral version and tilt can reduce the risk of impingement. Two types of virtual surgeries were performed on 22 pre-operative arthritic shoulders: (i) "Interactive," the glenoid baseplate could be placed with accuracy, and (ii) "Blind," surgeons placed the RSA baseplate while they could only visualize the glenoid. The virtual models were then used in an RSA biomechanical model which recorded impingement for (i) four Range of Motion (ROM) tasks, (ii) ten Activities of Daily Living (ADL). The "Blind" method resulted in more variable glenoid placement (version and tilt) than the "Interactive" method (p = 0.001). However, both methods showed similar ROM and impingement occurrence in ADLs. The results suggest it is challenging for surgeons to accurately correct version and tilt on arthritic glenoids when only referencing off of the face of the glenoid. However, the variable glenosphere placement observed in the "Blind" method did not result in worse impingement compared to the accurate "Interactive" method. This was because both methods had similar inferior baseplate positioning which is more important than correcting version or tilt. Implantation accuracy remains important in RSA, but pre operative planning should not just target at correcting version and tilt. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1213-1219, 2018. PMID- 28898449 TI - In reply to Hynes et al.: 'Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stages II/III colon cancer in a large population-based study'. PMID- 28898450 TI - Why do you not call the condition takotsubo syndrome triggered by acute coronary ischemia? PMID- 28898451 TI - Comparative ultrastructure of coxal glands in unfed larvae of Leptotrombidium orientale (Schluger, 1948) (Trombiculidae) and Hydryphantes ruber (de Geer, 1778) (Hydryphantidae). AB - Coxal glands of unfed larvae Leptotrombidium orientale (Schluger, 1948) (Trombiculidae), a terrestrial mite parasitizing vertebrates, and Hydryphantes ruber (de Geer, 1778) (Hydryphantidae), a water mite parasitizing insects were studied using transmission electron microscopy. In both species, the coxal glands are represented by a paired tubular organ extending on the sides of the brain from the mouthparts to the frontal midgut wall and are formed of the cells arranged around the central lumen. As in other Parasitengona, the coxal glands are devoid of a proximal sacculus. The excretory duct, joining with ducts of the prosomal salivary glands constitutes the common podocephalic duct, opening into the subcheliceral space. The coxal glands of L. orientale are composed of a distal tubule with a basal labyrinth, an intermediate segment without labyrinth, and a proximal tubule bearing tight microvilli on the apical cell surface and coiled around the intermediate segment. The coxal glands of H. ruber mainly consist of the uniformly organized proximal tubule with apical microvilli of the cells lacking the basal labyrinth. This tubule shows several loops running backward and forward in a vertical plane on the side of the brain. In contrast to L. orientale, larvae of H. ruber reveal a terminal cuticular sac/bladder for accumulation of secreted fluids. Organization of the coxal glands depends on the ecological conditions of mites. Larvae of terrestrial L. orientale possess distal tubule functioning in re-absorption of ions and water. Conversely, water mite larvae H. ruber need to evacuate of the water excess, so the filtrating proximal tubule is prominent. PMID- 28898452 TI - Distinct histomorphology for growth arrest and digitate outgrowth in cultivated Haliclona sp. (Porifera: Demospongiae). AB - The use of sponges in biotechnological processes is limited by the supply problem, and sponge biomass production is becoming a current topic of research. The distinction between characteristics for growth and growth arrest is also important for environmental monitoring. In this study, we analyze the morphology of the digitate outgrowths from the sponge Haliclona sp. The sponge Haliclona sp. was successfully cultivated for 14 months in a closed system. The morphological characterization of growth arrest was performed after submitting explants to starvation-stress for approximately 2 weeks, to correlate morphology with growth and growth arrest. The digitate outgrowth showed three distinct regions: mature (MR), transition (TR) and immature (IR). Our data suggest a growth developmental program, with collagen fascicles guiding axial growth in IR, followed by progressive development of choanocyte chambers and large aquiferous systems at the more mature proximal region (choanosome). The intercalation of choanocyte chambers and small aquiferous systems inside collagen fascicles previously originated at the IR region can be responsible for thickening expansion and conversion of the collagen fascicles into columnar choanosome in MR. The growth arrest after starvation-stress assay showed morphological changes in the IR corroborating collagen in the extreme tip of the digitate outgrowth as an important role in guiding of axial growth of Haliclona sp. The identification of distinct morphologies for growth and growth arrest suggest a growth developmental program, and these data could be useful for further investigations addressing sponge biomass gain and environmental monitoring. PMID- 28898453 TI - Echocardiographic guidance and monitoring of left atrial appendage closure with AtriClip during open-chest cardiac surgery. AB - Left atrial appendage (LAA) closure prevents thromboembolic risk and avoids lifelong anticoagulation due to atrial fibrillation (AF). Nowadays, AtriClip, a modern epicardial device approved in June 2010, allows external and safe closure of LAA in patients undergoing cardiac surgery during other open-chest cardiac surgical procedures. Such a surgical approach and its epicardial deployment differentiates LAA closure with AtriClip from percutaneous closure techniques such as Watchman (Boston Scientific, Marlborough, MA, USA), Lariat (SentreHEART Inc., Redwood City, CA, USA), and Amplatzer Amulet (St. Jude Medical, St. Paul, MN, USA) device procedures. AtriClip positioning must consider perioperative transesophageal echocardiography (TEE) to confirm LAA anatomical features, to explore the links with neighboring structures, and finally to assess its successful closure. We report a sequence of images to document the role of intraoperative TEE during an elective aortic valve replacement and LAA external closure with AtriClip. PMID- 28898454 TI - Reverberation and multiple shadow artifacts recorded from patients with intra pericardial centrifugal continuous-flow left ventricular assist devices. AB - Artifacts are by-products of ultrasound imaging that may cause confusion or misdiagnosis if not interpreted correctly. There are, however, several disorders where a specific pattern of artifacts can aid in diagnosis, especially when the object in question cannot be visualized directly. In this manuscript, we report two patients with reverberation and shadow artifacts originating from the housing and the propeller of a continuous-flow intra-pericardial left ventricular assist device. Visualization of the artifacts required modified transthoracic views, so these artifacts should not pose a diagnostic challenge during a routine echocardiographic evaluation. However, we consider that shadow artifacts might be used to evaluate pump thrombosis in patients with intra-pericardial assist devices. PMID- 28898455 TI - Coronary-pulmonary arterial fistula in a neonate with pulmonary atresia ventricular septal defect and single coronary artery. AB - In cases of pulmonary atresia with ventricular septal defect (PA-VSD), coronary pulmonary arterial fistula (CPAF) as the main source of pulmonary blood supply is extremely rare. These fistulae may arise from the left coronary artery, right coronary artery, or a single coronary artery. Fistulae from a single coronary artery are unusual. We are reporting a case of PA-VSD with single coronary artery and CPAF as the main source of pulmonary supply in addition to two major aortopulmonary collateral arteries (MAPCAS). Successful surgical correction with VSD closure and right ventricle (RV) to the pulmonary artery (PA) conduit was made. PMID- 28898456 TI - Urinary prostaglandin D2 metabolite excretion during the first six months of life was significantly lower in breast-fed than formula-fed infants. AB - AIM: The metabolic changes that occur during the postnatal weaning period appear to be particularly important for future health, and breast milk is considered to provide the optimal source of infant nutrition. This pilot study from September 2013 to May 2015 examined the effect of breastfeeding on prostaglandin metabolism in healthy term infants. METHODS: Urine samples were collected from 19 infants at one month of age in the Juntendo University Hospital, Tokyo, Japan. The 13 infants in the breast-fed group received less than 540 mL/week of their intake from formula, and the other six were exclusively fed on formula. At six months, we sampled 14 infants: nine breast-fed and five receiving formula. The infants were from normal single pregnancies and free from perinatal complications. We analysed urinary prostaglandin metabolites-tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM)-using liquid chromatography tandem-mass spectrometry. RESULTS: Urinary t-PGDM excretion at one and six months was significantly lower in breast-fed infants than formula-fed infants. However, urinary t-PGEM excretion at one and six months was not significantly different between the groups. CONCLUSION: Our study showed that the type of feeding in early infancy affected prostaglandin metabolism in healthy term infants. PMID- 28898457 TI - Organic solute transporter-beta (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis. AB - : Primary bile acid malabsorption is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2) can cause primary bile acid malabsorption but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric organic solute transporter alpha-beta (OSTalpha-OSTbeta; SLC51A-SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTbeta deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma-glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTalpha partner protein. CONCLUSION: The findings identify OSTbeta deficiency as a cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTalpha-OSTbeta's key role in the enterohepatic circulation of bile acids in humans. (Hepatology 2017). PMID- 28898458 TI - Different and Often Opposing Forces Drive the Encapsulation and Multiple Exterior Binding of Charged Guests to a M4 L6 Supramolecular Vessel in Water. AB - The supramolecular assembly [Ga4 L6 ]12- acts as a nanoscale flask to mediate the reactivity of encapsulated reactive guests and also functions as a catalyst to carry out enzyme-like chemical transformations. The guest binding to the interior cavity and exterior of this host is difficult to untangle because multiple equilibria occur in solution, and only when refining simultaneously data obtained from different techniques, such as NMR, UV/Vis, and calorimetry, can the accurate solution thermodynamics of these host-guest systems be determined. This study reports the driving forces for the inclusion and stepwise exterior guest binding of different aliphatic quaternary ammonium guests to the [Ga4 L6 ]12- assembly. Encapsulation into the host cavity was found to be an entropy-driven process, whereas exterior ion association is driven either by enthalpically favorable attractive forces or by the entropy gain due to desolvation, depending on guest size and character. The analysis of the energetics of reaction may help predicting and understanding the intimate role and contribution of the transition state in those rate-accelerated reactions involving this supramolecular assembly as an enzyme-like molecular flask. PMID- 28898459 TI - Transgastric: A forgotten view for atrial septal defect device closure procedures? AB - Percutaneous closure of an atrial septal defect in the cardiac catheterization laboratory requires noninvasive imaging to assist in characterization of the atrial septal defect and deployment of the device. Transesophageal echocardiography is the modality most often used in these circumstances. Transesophageal echocardiographic guidelines exist for the assessment and guidance for atrial septal defect closures, but these guidelines do not mention transgastric views. In this case, we demonstrate that transgastric views are helpful in describing the atrial septal defect, especially as it concerns the inferior vena cava rim. PMID- 28898460 TI - Burden of chronic urticaria relative to psoriasis in five European countries. AB - BACKGROUND: Quantification of burden of chronic spontaneous urticaria (CSU) vs. psoriasis (PsO) is limited. OBJECTIVE: To evaluate the burden associated with CSU vs. PsO of all severities (overall PsO), mild and moderate/severe PsO. METHODS: This retrospective cross-sectional analysis compared data from adult patients with chronic urticaria (CU), used as a proxy for CSU, and PsO from the National Health and Wellness Survey in France, Germany, Italy, Spain and the United Kingdom. Outcomes included mental and physical component summary scores (MCS and PCS) calculated from the Short Form (SF)-36v2 or SF-12v2, SF-6D health utility scores, self-reported psychological complaints (anxiety, depression and sleep difficulties), work productivity and activity impairment, and self-reported healthcare resource utilization. Bivariate and multivariate analyses for each outcome and comparative groups were conducted. RESULTS: This analysis included 769 CU and 7857 PsO (26.9% moderate/severe) patients. Following adjustment for covariates, CU patients showed a greater health-related quality of life (HRQoL) impairment vs. overall PsO (MCS: -2.4, PCS: -1.6, SF-6D: -0.03; all P < 0.001). CU patients showed a higher risk of anxiety, depression and sleep difficulties [odds ratio (OR): 1.63, 1.34 and 1.56, respectively; all P < 0.01] and greater healthcare resource use vs. overall PsO. The overall activity impairment was significantly greater in CU patients than in overall PsO patients (P = 0.001), while the impact on work was not significantly different. The results vs. moderate/severe PsO group showed no significant differences on all outcomes. CONCLUSION: Burden of illness in CU is higher than PsO of all severities but similar to that observed in moderate/severe PsO. Both diseases have a similar negative impact on work productivity. PMID- 28898461 TI - Risks of different skin tumour combinations after a first melanoma, squamous cell carcinoma and basal cell carcinoma in Dutch population-based cohorts: 1989-2009. AB - BACKGROUND: Skin cancer patients are primarily at increased risk of developing subsequent skin cancers of the same type. Shared risk factors might also increase the occurrence of a different type of subsequent skin cancer. OBJECTIVE: To investigate risks of different skin tumour combinations after a first melanoma, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). METHODS: All melanoma and SCC patients included in the national Netherlands Cancer Registry (NCR) and all BCC patients included in the regional Eindhoven Cancer Registry (ECR) between 1989 and 2009 were followed until diagnosis of a subsequent different skin cancer (melanoma, SCC or BCC), date of death or end of study. Cumulative risks, standardized incidence ratios (SIR) and absolute excess risks (AER) of subsequent skin cancers were calculated. RESULTS: A total of 50 510 melanoma patients and 64 054 patients with a SCC of the skin were included (national data NCR). The regional data of the ECR consisted of 5776 melanoma patients, 5749 SCC patients and 41 485 BCC patients. The 21-year cumulative risk for a subsequent melanoma after a first SCC or BCC was respectively 1.7% and 1.3% for males and 1.3% and 1.2% for females; SCC after melanoma or BCC was 4.6% and 9.3% (males) and 2.6% and 4.1% (females); BCC after melanoma or SCC was respectively 13.2% and 27.8% (males) and 14.9% and 21.1% (females). SIRs and AERs remained elevated up to 21 years after the first melanoma, SCC or BCC. CONCLUSION: This large population-based study investigating risks of developing a different subsequent cutaneous malignancy showed high-cumulative risks of mainly KC and markedly increased relative and absolute risks of all tumour combinations. These estimates confirm a common carcinogenesis and can serve as a base for follow-up guidelines and patient education aiming for an early detection of the subsequent cancers. PMID- 28898462 TI - p0071 interacts with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of non-small cell lung cancer. AB - As a member of the p120-catenin (p120ctn) subfamily, the p0071 study in tumor is very limited. We demonstrated the clinicopathological significance of p0071 in non-small cell lung cancer (NSCLC), as well as E-cadherin. Co-immunoprecipitation was used to detect the interaction of p0071 with E-cadherin in A549 and SPC cells (E-cadherin is mainly expressed in the cytoplasm of these cells). p0071 cytoplasmic expression was knocked down by siRNA in these cells and this effect on the RhoA activity and cell invasion and migration ability were measured. p0071 overexpression in the cytoplasm of tumor cell was correlated with lymphatic metastase and poor prognosis of NSCLC. The patients with both abnormal expression of p0071 and E-cadherin (cytoplasmic expression) had a statistically significant shorter survival than the patients without both abnormal expression (P < 0.05). There is a significant correlation between cytoplasmic overexpression of p0071 and E-cadherin in NSCLC tissues. p0071 interacted with E-cadherin in the cytoplasm of A549 and SPC cell lines. Treatment with siRNA-p0071 inhibited the invasion and migration ability of NSCLC cells. Above results confirmed that p0071 interacted with E-cadherin in the cytoplasm so as to promote the invasion and metastasis of NSCLC. PMID- 28898463 TI - Update on the potential significance of psammoma bodies in lung adenocarcinoma from a modern perspective. AB - AIMS: Psammoma bodies are concentrically lamellated microscopic structures made of calcium. They are commonly observed in papillary carcinomas of the thyroid gland and serous papillary adenocarcinomas of the ovary, but are also occasionally detected in lung adenocarcinomas. Only one study, published in 1972, has systematically described the significance of psammoma bodies in lung adenocarcinomas. The aim of this study was to update the significance of psammoma bodies in lung adenocarcinomas from a modern perspective. METHODS AND RESULTS: Psammoma bodies were detected in 7.2% (59/822) of the adenocarcinomas examined, among which the papillary (20.3%, 12/59) and acinar (44.1%, 26/59) histological subtypes, with the feature of a terminal respiratory unit (91.5%, 54/59), were dominant. Malignant potential (cell growth activity measured by Ki67 labelling, lymph node metastasis, and postoperative survival) did not significantly differ between adenocarcinomas with and without psammoma bodies. On the basis of cytogenetic features, adenocarcinomas with psammoma bodies were preferentially affected by tyrosine kinase inhibitor (TKI)-targetable driver mutations [EGFR (69.8%, 37/53), ALK (13.2%, 7/53), and ROS1 (1.9%, 1/53)]. Multivariate analyses confirmed that psammoma bodies may constitute an independent predictor for these mutations, particularly EGFR and ALK mutations. CONCLUSIONS: Psammoma bodies may predict a favourable response of lung adenocarcinomas to TKIs. PMID- 28898464 TI - Functionalized Ultrasmall Fluorinated Graphene with High NIR Absorbance for Controlled Delivery of Mixed Anticancer Drugs. AB - Fluorinated graphene (FG) possess distinctively novel properties different from graphene and is suitable for many biomedical applications. However, the hydrophobic nature and inert properties of FG limit its further application as a biological material. Here we show the preparation of nano-sized FG (ca. 60 nm) that exhibits high NIR absorbance for photothermal therapy. In order to make it stable in physiological solutions, the FG is enriched with oxygen and followed by covalent binding with chitosan as a novel pH-responsive nanocarrier. Furthermore, controlled loading of two anticancer drugs, doxorubicin (DOX) and camptothecin (CPT) has been realized and the functionalized ultrasmall FG shows remarkably high cytotoxicity toward Hela cancer cells compared to that loaded with either CPT or DOX only. This work established nano-sized FG as a novel photothermal agent due to its small size and can be used a stimulus-responsive nanocarrier for mixed drug delivery and combined therapy. PMID- 28898465 TI - Polar-Electrode-Bridged Electroluminescent Displays: 2D Sensors Remotely Communicating Optically. AB - A novel geometry for electroluminescent devices, which does not require transparent electrodes for electrical input, is demonstrated, theoretically analyzed, and experimentally characterized. Instead of emitting light through a conventional electrode, light emission occurs through a polar liquid or solid and input electrical electrodes are coplanar, rather than stacked in a sandwich configuration. This new device concept is scalable and easily deployed for a range of modular alternating-current-powered electroluminescent light sources and light-emitting sensing devices. The polar-electrode-bridged electroluminescent displays can be used as remotely readable, spatially responsive sensors that emit light in response to the accumulation and distribution of materials on the device surface. Using this device structure, various types of alternating current devices are demonstrated. These include an umbrella that automatically lights up when it rains, a display that emits light from regions touched by human fingers (or painted upon using a mixture of oil and water), and a sensor that lights up differently in different areas to indicate the presence of water and its freezing. This study extends the dual-stack, coplanar-electrode device geometry to provide displays that emit light from a figure drawn on an electroluminescent panel using a graphite pencil. PMID- 28898466 TI - An overview of genetically modified crop governance, issues and challenges in Malaysia. AB - The application of agricultural biotechnology attracts the interest of many stakeholders. Genetically modified (GM) crops, for example, have been rapidly increasing in production for the last 20 years. Despite their known benefits, GM crops also pose many concerns not only to human and animal health but also to the environment. Malaysia, in general, allows the use of GM technology applications but it has to come with precautionary and safety measures consistent with the international obligations and domestic legal frameworks. This paper provides an overview of GM crop technology from international and national context and explores the governance and issues surrounding this technology application in Malaysia. Basically, GM research activities in Malaysia are still at an early stage of research and development and most of the GM crops approved for release are limited for food, feed and processing purposes. Even though Malaysia has not planted any GM crops commercially, actions toward such a direction seem promising. Several issues concerning GM crops as discussed in this paper will become more complex as the number of GM crops and varieties commercialised globally increase and Malaysia starts to plant GM crops. (c) 2017 Society of Chemical Industry. PMID- 28898468 TI - Nanodroplet-Containing Polymers for Efficient Low-Power Light Upconversion. AB - Sensitized triplet-triplet-annihilation-based photon upconversion (TTA-UC) permits the conversion of light into radiation of higher energy and involves a sequence of photophysical processes between two dyes. In contrast to other upconversion schemes, TTA-UC allows the frequency shifting of low-intensity light, which makes it particularly suitable for solar-energy harvesting technologies. High upconversion yields can be observed for low viscosity solutions of dyes; but, in solid materials, which are better suited for integration in devices, the process is usually less efficient. Here, it is shown that this problem can be solved by using transparent nanodroplet-containing polymers that consist of a continuous polymer matrix and a dispersed liquid phase containing the upconverting dyes. These materials can be accessed by a simple one step procedure that involves the free-radical polymerization of a microemulsion of hydrophilic monomers, a lipophilic solvent, the upconverting dyes, and a surfactant. Several glassy and rubbery materials are explored and a range of dyes that enable TTA-UC in different spectral regions are utilized. The materials display upconversion efficiencies of up to ~15%, approaching the performance of optimized oxygen-free reference solutions. The data suggest that the matrix not only serves as mechanically coherent carrier for the upconverting liquid phase, but also provides good protection from atmospheric oxygen. PMID- 28898467 TI - Mohs micrographic surgery in the elderly: comparison of tumours, surgery and first-year follow-up in patients younger and older than 80 years old in REGESMOHS. AB - BACKGROUND: The elderly population is increasing and more patients in this group undergo Mohs micrographic surgery (MMS). The few publications investigating MMS in elderly people conclude that it is a safe procedure; however, these are single centre studies without a comparison group. OBJECTIVE: To compare the characteristics of patients, tumours, MMS and 1-year follow-up in patients younger than 80 years, with patients older than 80 years at the time of surgery. METHODS: Data was analysed from REGESMOHS, a prospective cohort study of patients treated with MMS. The participating centres were 19 Spanish hospitals where at least one MMS is performed per week. Data on characteristics of the patient, tumour and surgery were recorded. Follow-up data were collected from two visits; the first within 1 month postsurgery and the second within the first year. RESULTS: From July 2013 to October 2016, 2575 patients that underwent MMS were included in the registry. Of them, 1942 (75.4%) were aged <80 years and 633 (24.6%) were >=80 years old. In the elderly, the tumour size was significantly higher with a higher proportion of squamous cell carcinoma. Regarding surgery, elderly more commonly had tumours with deeper invasion and required a higher number of Mohs surgery stages, leaving larger defects and requiring more time in the operating room. Despite this, the incidence of postoperative complications was the same in both groups (7%) and there were no significant differences in proportion of relapses in the first-year follow-up. CONCLUSION: The risk of short term complications and relapses were similar in elderly and younger groups. MMS is a safe procedure in the elderly. PMID- 28898469 TI - Establishing a regional paediatric registry improved the overview and detection of side effects in children on anticoagulants. PMID- 28898470 TI - Dichloro-Cycloazatriphosphane: The Missing Link between N2 P2 and P4 Ring Systems in the Systematic Development of NP Chemistry. AB - A dichloro-cycloazatriphosphane that incorporates a cyclic NP3 backbone could be synthesized using knowledge gained from the chemistry of N2 P2 and P4 ring systems. It fills the gap between the congeneric compounds [ClP(MU-NR)]2 and [ClP(MU-PR)]2 (R=sterically demanding substituent), and thus contributes to the systematic development of nitrogen-phosphorus chemistry in general. The title compound was studied with respect to its formation via a labile aminodiphosphene, which readily underwent different rearrangement reactions depending on the solvent. All compounds were fully characterized by experimental and computational methods. PMID- 28898471 TI - Response to 'Let's change the conversation'. PMID- 28898472 TI - Theoretical Evidence for the Utilization of Low-Valent Main-Group Complexes as Rare-Synthon Equivalents. AB - We examine by the means of computational chemistry the ability of two phosphasilenes to transfer the phosphinidene moiety to four double bonded organic functional groups (>C=C<, -N=N-, >C=O, and >C=S) in the presence of different bulky ligands. We show that large bulky groups in the reactants can sterically prohibit the otherwise favored association of reactants and phosphasilenes and instead a new phosphinidene transfer reaction can occur. We find that the transfer reaction mechanism is generally present independent from the functional group and by introducing large enough trimethylsilyl or tert-butyl-dimethylsilyl ligands it can be used to transfer phosphinidene to organic functional groups such as thioformaldehydes or diazenes, respectively. We propose that by exploiting the complex bonding nature of low-valent main group complexes they can act as synthetic equivalents of hitherto unknown very reactive synthons. We encourage experimentalists to explore the reactivity of their main-group complexes by varying the size of the bulky substituents on the reactants that can result in new unexpected chemistry. PMID- 28898473 TI - Influence of prucalopride on esophageal secondary peristalsis in reflux patients with ineffective motility. AB - BACKGROUND AND AIM: Ineffective esophageal motility (IEM) is associated with gastroesophageal reflux disease. Secondary peristalsis contributes to esophageal clearance. Prucalopride promotes secondary peristalsis by stimulating 5 hydroxytrypatamine 4 receptors in the esophagus. We aimed to determine whether prucalopride would augment secondary peristalsis in gastroesophageal reflux disease patients with IEM. METHODS: After a baseline recording of primary peristalsis, secondary peristalsis was stimulated by slow and rapid mid esophageal injections of air in 15 patients with IEM. Two separate sessions with 4-mg oral prucalopride or placebo were randomly performed. RESULTS: Prucalopride significantly increased primary peristaltic wave amplitude (68.1 +/- 10.0 vs 55.5 +/- 8.8 mmHg, P = 0.02). The threshold volume for triggering secondary peristalsis was significantly decreased by prucalopride during slow (9.3 +/- 0.8 vs 12.0 +/- 0.8 mL; P = 0.04) and rapid air injection (4.9 +/- 0.3 vs 7.1 +/- 0.1 mL; P = 0.01). Secondary peristalsis was triggered more frequently after application of prucalopride (55% [43-70%]) than placebo (45% [33-50%]) (P = 0.008). Prucalopride did not change pressure wave amplitudes during slow air injection (84.6 +/- 8.1 vs 57.4 +/- 13.8 mmHg; P = 0.19) or pressure wave amplitudes during rapid air injection (84.2 +/- 8.6 vs 69.5 +/- 12.9 mmHg; P = 0.09). CONCLUSIONS: Prucalopride enhances primary peristalsis and mechanosensitivity of secondary peristalsis with limited impact on secondary peristaltic activities in IEM patients. Our study suggests that prucalopride appears to be useful in augmenting secondary peristalsis in patients with IEM only via sensory modulation of esophageal secondary peristalsis. PMID- 28898475 TI - Skin-to-skin back transfers provide a feasible, safe and low-stress alternative to conventional neonatal transport. PMID- 28898474 TI - Quality of life measurement in acne. Position Paper of the European Academy of Dermatology and Venereology Task Forces on Quality of Life and Patient Oriented Outcomes and Acne, Rosacea and Hidradenitis Suppurativa. AB - Acne causes profound negative psychological and social effects on the quality of life (QoL) of patients. The European Dermatology Forum S3-Guideline for the Treatment of Acne recommended adopting a QoL measure as an integral part of acne management. Because of constantly growing interest in health-related QoL assessment in acne and because of the high impact of acne on patients' lives, the European Academy of Dermatology and Venereology Task Force on QoL and Patient Oriented Outcomes and the Task Force on Acne, Rosacea and Hidradenitis Suppurativa have documented the QoL instruments that have been used in acne patients, with information on validation, purposes of their usage, description of common limitations and mistakes in their usage and overall recommendations. PMID- 28898477 TI - Removing the Australian tax exemption on healthy food adds food stress to families vulnerable to poor nutrition. AB - OBJECTIVE: To assess the impact of changing the Australian Goods and Services Tax (GST) on household food stress, which occurs when >25% of disposable income needs to be spent on food. METHODS: Weekly healthy meal plan costs for average-income (AI), low-income (LI) and welfare-dependent (WDI) families were calculated using the 2013 Western Australian (WA) Food Access and Costs Survey. Four GST scenarios were compared: 1) status quo; 2) increasing GST to 15%; 3) expanding base to include exempt foods at 10% GST; and 4) expanding base to include exempt foods and increasing the tax to 15%. RESULTS: Single-parent families risk food stress regardless of their income or the GST scenario (requiring 24-42% of disposable income). The probability of food stress in Scenario 1 is 100% for WDI two-parent families and 36% for LI earners. In Scenarios 3 and 4, food stress probability is 60-72% for two-parent LI families and AI single-parent families, increasing to 88 94% if residing in very remote areas. CONCLUSION: There is food stress risk among single-parent, LI and WDI families, particularly those residing in very remote areas. Implications for public health: Expanding GST places an additional burden on people who are already vulnerable to poor nutrition and chronic disease due to their socioeconomic circumstances. PMID- 28898476 TI - Proceeding report of the Symposium on Hidradenitis Suppurativa Advances (SHSA). AB - Hidradenitis Suppurativa (HS) is a chronic debilitating skin condition that impairs the productivity and the quality of patients' lives. HS has recently drawn lots of attention among scholars to further expand their knowledge but it still loads with uncertainties and gaps to be explored. This publication addresses these uncertainties, and provides a road-map for researchers, scholars and clinicians from different disciplines for their future studies about HS. This is a proceeding report of the first Symposium on Hidradenitis Suppurativa Advances (SHSA), and it reviews the scientific sessions about the epidemiology, pathophysiology, presentations, and management of HS. This symposium was a great opportunity for experts in the HS field to exchange their knowledge, and improve their mutual understanding of this disease. PMID- 28898479 TI - Synthesis of Coordination Polymer Nanoparticles using Self-Assembled Block Copolymers as Template. AB - Nowadays there is a high demand in specialized functional materials, for example, for applications as sensors in biomedicine. For the realization of such applications, nanostructures and the integration in a composite matrix are indispensable. Coordination polymers and networks, for example, with spin crossover properties, are a highly promising family of switchable materials in which the switching process can be triggered by various external stimuli. An overview over different strategies for the synthesis of nanoparticles of such systems is given. A special focus is set on the use of block copolymer micelles as templates for the synthesis of nanocomposites. The block copolymer defines the final size and shape of the nanoparticle core. Additionally it allows a further functionalization of the obtained nanoparticles by variation of the polymer blocks and an easy deposition of the composite material on surfaces. PMID- 28898478 TI - Electrocatalytic Azide Oxidation Mediated by a Rh(PNP) Pincer Complex. AB - One-electron oxidation of the rhodium(I) azido complex [Rh(N3 )(PNP)] (5), bearing the neutral, pyridine-based PNP ligand 2,6-bis(di-tert butylphosphinomethyl)pyridine, leads to instantaneous and selective formation of the mononuclear rhodium(I) dinitrogen complex [Rh(N2 )(PNP)]+ (9+ ). Interestingly, complex 5 also acts as a catalyst for electrochemical N3- oxidation (Ep ~-0.23 V vs. Fc+/0 ) in the presence of excess azide. This is of potential relevance for the design of azide-based and direct ammonia fuel cells, expelling only harmless dinitrogen as an exhaust gas. PMID- 28898480 TI - eta1 -Arene Complexes as Intermediates in the Preparation of Molecular Phosphorescent Iridium(III) Complexes. AB - Molecular phosphorescent heteroleptic bis-tridentate iridium(III) emitters have been prepared via eta1 -arene intermediates. In the presence of 4.0 mol of AgOTf, the complex [(IrCl{kappa3 -N,C,N-(pyC6 HMe2 py)})(MU-Cl)]2 (1; pyC6 H2 Me2 py=1,3 di(2-pyridyl)-4,6-dimethylbenzene) reacted with 9-(6-phenylpyridin-2-yl)-9H carbazole (PhpyCzH) and 2-phenoxy-6-phenylpyridine (PhpyOPh) to give [Ir{kappa3 N,C,N-(pyC6 HMe2 py)}{kappa3 -C,N,C'-(C6 H4 pyCzH)}]OTf (2) and [Ir{kappa3 -N,C,N (pyC6 HMe2 py)}{kappa3 -C,N,C'-(C6 H4 pyOPh)}]OTf (3). The X-ray diffraction structures of 2 and 3 reveal that the carbazolyl and phenoxy substituents of the C,N,C' ligand coordinate to the metal center to form an eta1 -arene pi bond. Treatment of 2 and 3 with KOtBu led to the deprotonation of the coordinated carbon atom of the eta1 -arene group to afford the molecular phosphorescent [5t+4t'] heteroleptic iridium(III) complexes [Ir{kappa3 -N,C,N-(pyC6 HMe2 py)}{kappa3 -C,N,C'-(C6 H4 pyCz)}] (4) and [Ir{kappa3 -N,C,N-(pyC6 HMe2 py)}{kappa3 -C,N,C'-(C6 H4 pyOC6 H4 )}] (5). These complexes are green emitters that display short lifetimes and high quantum yields of 0.73 (4) and 0.87 (5) in the solid state. PMID- 28898481 TI - Escape from predators and genetic variance in birds. AB - Predation is a common cause of death in numerous organisms, and a host of antipredator defences have evolved. Such defences often have a genetic background as shown by significant heritability and microevolutionary responses towards weaker defences in the absence of predators. Flight initiation distance (FID) is the distance at which an individual animal takes flight when approached by a human, and hence, it reflects the life-history compromise between risk of predation and the benefits of foraging. Here, we analysed FID in 128 species of birds in relation to three measures of genetic variation, band sharing coefficient for minisatellites, observed heterozygosity and inbreeding coefficient for microsatellites in order to test whether FID was positively correlated with genetic variation. We found consistently shorter FID for a given body size in the presence of high band sharing coefficients, low heterozygosity and high inbreeding coefficients in phylogenetic analyses after controlling statistically for potentially confounding variables. These findings imply that antipredator behaviour is related to genetic variance. We predict that many threatened species with low genetic variability will show reduced antipredator behaviour and that subsequent predator-induced reductions in abundance may contribute to unfavourable population trends for such species. PMID- 28898482 TI - Impact of renal replacement therapy on survival in patients with KDIGO stage 3 acute kidney injury: A propensity score matched analysis. AB - AIM: To investigate the impact of renal replacement therapy (RRT) on 90-day mortality in critically ill patients suffering from KDIGO stage 3 acute kidney injury (AKI) with or without life-threatening complications using propensity score matching analysis. METHODS: We conducted a retrospective analysis of critically ill adult patients with KDIGO Stage 3 AKI with or without RRT during ICU stay between 1/1/2011-31/12/2013. Cox regression analysis and propensity score matching methods were used to determine predictors for 90-day mortality. RESULTS: Among 661 patients, 50.5% received RRT. The unadjusted 90-day mortality rate was 42.5% and 54.1% in patients who had or had not received RRT, respectively. After adjustment with propensity score based on the probability of receiving RRT, the cox regression analysis showed that RRT was associated with a lower 90-day mortality (p<0.001). Among 322 propensity-matched pairs, RRT was associated with lower ICU (23.6% vs. 39.8%, p=0.002), hospital (33.5% vs. 55.9%, p<0.001) and 90-day mortality (34.2% vs. 58.4%, p<0.001), and a higher 90-day renal recovery rate (57.8% vs. 45.3% full recovery, p=0.026) compared with no RRT. When an alternate propensity model was used, the benefits associated with RRT were very similar, except 90-day renal recovery became insignificant. CONCLUSION: Our observational study found that in critically ill patients with KDIGO Stage 3 AKI, RRT may be associated with lower 90-day mortality. The benefit of RRT on renal recovery was less prominent. Medical futility and practice variations may complicate study interpretation. To avoid these limitations, large scale multicenter, non-observational study is recommended. PMID- 28898483 TI - Functionalization of 3-Iridacyclopentenes. AB - Members of a series of iridacyclopentenes of composition [TpMe2 Ir(k2 -C,C-CH2 CR'=CRCH2 )(CO)] (TpMe2 =hydrotris(3,5-dimethylpyrazolyl)borate; R=R'=H, 1; R=Me, R'=H, 2; R=R'=Me, 3) have been subjected to common organic chemistry procedures for hydrogenation, cyclopropanation, epoxidation, water addition through hydroboration, cis-dihydroxylation, and ozonolysis. The stability of metallacycles 1-3, imparted by the presence of the co-ligands TpMe2 and CO, directs the reactivity towards the C=C double bonds, and furthermore the stereochemistry of the products formed is strongly dictated by the steric demands of the TpMe2 ligand. While the products obtained in some of the above-mentioned reactions are the expected ones from an organic chemistry point of view, in other cases the results differ from the outcomes of similar reactions carried out with the all-carbon counterparts. PMID- 28898484 TI - Prehospital Supraglottic Airway Was Associated With Good Neurologic Outcome in Cardiac Arrest Victims Especially Those Who Received Prolonged Cardiopulmonary Resuscitation. AB - OBJECTIVES: We performed this study to investigate the association of prehospital supraglottic airway (SGA) on neurologic outcome in cardiac arrest victims with adjustment of postresuscitation variables as well as prehospital and resuscitation variables. METHODS: This study was a retrospective study based on a multicenter prospective cohort registry from December 2013 to April 2016. According to the 28-day cerebral performance categories (CPCs) scale, patients were divided into the good-outcome group (CPC 1-2) and the poor-outcome group (CPC 3-5). We compared the two groups with respect to demographic variables, prehospital and in-hospital resuscitation variables, and postresuscitation variables. RESULTS: A total of 869 cardiac arrest victims who received in progress cardiopulmonary resuscitation (CPR) were delivered to the emergency department of three hospitals, and 310 patients were admitted to the intensive care unit. The use of a prehospital SGA was independently associated with 28-day good neurologic outcome (odds ratio [OR] = 7.88; 95% confidence interval [CI] = 1.33-46.53; p = 0.023] when postresuscitation variables were adjusted, although there were no significant association with the acquisition of sustained return of spontaneous circulation (OR = 0.992; 95% CI = 0.591-1.666; p = 0.976). Furthermore, a prehospital SGA was significantly associated with good neurologic outcome, especially in patients who received prolonged CPR (low flow time > 15 minutes; OR = 3.41; 95% CI = 1.23-9.45; p = 0.018) rather than in patients with nonprolonged CPR (OR = 4.50; 95% CI = 0.75-27.13; p = 0.101). CONCLUSIONS: When postresuscitation variables were adjusted, the prehospital SGA was independently associated with 28-day good neurologic outcome in cardiac arrest victims. PMID- 28898486 TI - High-Pressure Chemistry and the Mechanochemical Polymerization of [5]-Cyclo-p phenylene. AB - Evidence for the surprising formation of polymeric phases under high pressure for conjugated nanohoop molecules was found. This paper represents one of the unique cases, in which the molecular-level effects of pressure in crystalline organic solids is addressed, and provides a general approach based on vibrational Raman spectroscopy combining experiments and computations. In particular, we studied the structural and supramolecular chemistry of the cyclic conjugated nanohoop molecule [5]cyclo-para-phenylene ([5]CPP) under high pressures up to 10 GPa experimentally and up to 20 GPa computationally. The theoretical modeling for periodic crystals predicts good agreements with the experimentally obtained Raman spectra in the molecular phase. In addition, we have discovered two stable polymeric phases that arise in the simulation. The critical pressures in the simulation are too high, but the formation of polymeric phases at high pressures provides a natural explanation for the observed irreversibility of the Raman spectra upon pressure release between 6 and 7 GPa. The geometric parameters show a deformation toward quinonoid structures at high pressures accompanied by other deformations of the [5]CPP nanohoops. The quinonoidization of the benzene rings is linked to the systematic change of the bond length alternation as a function of the pressure, providing a qualitative interpretation of the observed spectral shifts of the molecular phase. PMID- 28898485 TI - Transcranial magnetic stimulation of the dorsal lateral prefrontal cortex inhibits medial orbitofrontal activity in smokers. AB - BACKGROUND AND OBJECTIVE: Several studies have shown that repetitive transcranial magnetic stimulation (rTMS), applied to the dorsolateral prefrontal cortex (DLPFC), can reduce cue-elicited craving in smokers. Currently, the mechanism of this effect is unknown. We used functional magnetic resonance imaging (fMRI) to explore the effect of a single treatment of rTMS on cortical and sub-cortical neural activity in non-treatment seeking nicotine-dependent participants. METHODS: We conducted a randomized, counterbalanced, crossover trial in which participants attended two experimental visits separated by at least 1 week. On the first visit, participants received either active, or sham rTMS (10 Hz, 5 s on, 10 s-off, 100% motor threshold, 3,000 pulses) over the left DLPFC, and on the second visit they received the opposite condition (active or sham). Cue craving fMRI scans were completed before and after each rTMS session. RESULTS: A total of 11 non-treatment seeking nicotine-dependent cigarette smokers were enrolled in the study [six female, average age 39.7 +/- 13.2, average cigarettes per day 17.3 +/- 5.9]. Active rTMS decreased activity in the contralateral medial orbitofrontal cortex (mOFC) and ipsilateral nucleus accumbens (NAc) compared to sham rTMS. CONCLUSIONS: This preliminary data suggests that one session of rTMS applied to the DLPFC decreases brain activity in the NAc and mOFC in smokers. SCIENTIFIC SIGNIFICANCE: rTMS may exert its anti-craving effect by decreasing activity in the NAc and mOFC in smokers. Despite a small sample size, these findings warrant future rTMS/fMRI studies in addictions. (Am J Addict 2017;26:788 794). PMID- 28898487 TI - Structural and thermodynamic characterization of metal binding in Vps29 from Entamoeba histolytica: implication in retromer function. AB - Vps29 is the smallest subunit of retromer complex with metallo-phosphatase fold. Although the role of metal in Vps29 is in quest, its metal binding mutants has been reported to affect the localization of the retromer complex in human cells. In this study, we report the structural and thermodynamic consequences of these mutations in Vps29 from the protozoan parasite, Entamoeba histolytica (EhVps29). EhVps29 is a zinc binding protein as revealed by X-ray crystallography and isothermal titration calorimetry. The metal binding pocket of EhVps29 exhibits marked differences in its 3-dimensional architecture and metal coordination in comparison to its human homologs and other metallo-phosphatases. Alanine substitutions of the metal-coordinating residues showed significant alteration in the binding affinity of EhVps29 for zinc. We also determined the crystal structures of metal binding defective mutants (D62A and D62A/H86A) of EhVps29. Based on our results, we propose that the metal atoms or the bound water molecules in the metal binding site are important for maintaining the structural integrity of the protein. Further cellular studies in the amoebic trophozoites showed that the overexpression of wild type EhVps29 leads to reduction in intracellular cysteine protease activity suggesting its crucial role in secretion of the proteases. PMID- 28898488 TI - Prevention of total thyroidectomy in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) based on combined interpretation of ultrasonographic and cytopathologic results. AB - OBJECTIVE: To explore the potential preoperative ultrasonography (US) and cytopathological features to avoid total thyroidectomy in NIFTP. CONTEXT: Recently, it has been proposed that that noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) be classified as tumours, rather than cancer. PATIENTS: A total of 142 surgically proven follicular variant papillary thyroid carcinomas (FVPTCs; 45 NIFTP, 97 non-NIFTP; mean size: 20.4+/ 11.0 mm, range: 10.0-65.0 mm) from 142 patients were included in this study. MEASUREMENTS: Three preoperative features of thyroid nodules (each US finding, US and Bethesda category) were compared in NIFTP and non-NIFTP groups. The preoperative decision-making process to avoid total thyroidectomy in NIFTP was evaluated based on combination of those features. RESULTS: In each US finding, there was only significantly less macrocalcification in the NIFTP group than in the non-NIFTP group (8.8% [4/45] vs 32.0% [31/97], P = .006). In US category, all of the NIFTP nodules were a low or intermediate suspicion (100% [45/45]). In Bethesda category, 26.7% [12/45] of the NIFTP was diagnosed as either suspicious malignancy or malignant, which increased the risk of a total thyroidectomy. In our study, a total thyroidectomy might be avoided in all of the NIFTP cases if lobectomy was selected for the nodules classified as a low or intermediate suspicion in US, despite being classified as a suspicious malignancy or malignant by cytopathology. CONCLUSIONS: Combining the US and cytopathological results could sensitively reduce total thyroidectomy in cases of NIFTP. PMID- 28898489 TI - Let's change the conversation. PMID- 28898490 TI - Inclusion of equity in economic analyses of public health policies: systematic review and future directions. AB - OBJECTIVES: To assess current approaches to inclusion of equity in economic analysis of public health interventions and to recommend best approaches and future directions. METHODS: We conducted a systematic review of studies that have used socioeconomic position (SEP) in cost-effectiveness analyses. Studies were identified using MedLine, EconLit and HEED and were evaluated based on their SEP specific inputs and methods of quantification of the health and financial inequalities. RESULTS: Twenty-nine relevant studies were identified. The majority of studies comparing two or more interventions left interpretation of the size of the health and financial inequality differences to the reader. Newer approaches include: i) use of health inequality measures to quantify health inequalities; ii) inclusion of financial impacts, such as out-of-pocket expenditures; and iii) use of equity weights. The challenge with these approaches is presenting results that policy makers can easily interpret. CONCLUSIONS: Using CEA techniques to generate new information about the health equity implications of alternative policy options has not been widely used, but should be considered to inform future decision making. Implications for public health: Inclusion of equity in economic analysis would facilitate a more nuanced comparison of interventions in relation to efficiency, equity and financial impact. PMID- 28898492 TI - Immunisation for refugees in Australia: a policy review and analysis across all States and Territories. AB - OBJECTIVE: Although people of refugee background are likely to be under-immunised before and after resettlement, no study to date has evaluated refugee specific immunisation policies in Australia. We developed a framework to analyse immunisation policies across Australia to highlight the strengths and gaps so as to inform development of more effective refugee specific immunisation policies. METHODS: We sourced publicly available immunisation policy documents from state and territory government websites. Content analysis of seven policy documents was undertaken using a developed framework comprising crucial policy determinants. RESULTS: Immunisation policy differed substantially across the jurisdictions. While most policies did not highlight the importance of data collection on immunisation for refugees and the public funding of vaccines for refugees, policy determinants such as accessibility and obligations were fulfilled by most jurisdictions. CONCLUSION: Our findings indicate stark differences in immunisation policy for people of refugee background across Australia. Highlighted gaps demonstrate the need to revise current policies so that they are aligned with their intended outcome of enhancing uptake of vaccines and improving immunisation coverage among resettled refugees in Australia. Implications for public health: Immunisation policy development for refugees needs to be robust enough to ensure equitable health services to this group. PMID- 28898491 TI - Skin denervation does not alter cortical potentials to surface concentric electrode stimulation: A comparison with laser evoked potentials and contact heat evoked potentials. AB - BACKGROUND: In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. METHODS: In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. RESULTS: We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. CONCLUSION: The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. SIGNIFICANCE: Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system. PMID- 28898493 TI - Egg shape mimicry in parasitic cuckoos. AB - Parasitic cuckoos lay their eggs in nests of host species. Rejection of cuckoo eggs by hosts has led to the evolution of egg mimicry by cuckoos, whereby their eggs mimic the colour and pattern of their host eggs to avoid egg recognition and rejection. There is also evidence of mimicry in egg size in some cuckoo-host systems, but currently it is unknown whether cuckoos can also mimic the egg shape of their hosts. In this study, we test whether there is evidence of mimicry in egg form (shape and size) in three species of Australian cuckoos: the fan-tailed cuckoo Cacomantis flabelliformis, which exploits dome nesting hosts, the brush cuckoo Cacomantis variolosus, which exploits both dome and cup nesting hosts, and the pallid cuckoo Cuculus pallidus, which exploits cup nesting hosts. We found evidence of size mimicry and, for the first time, evidence of egg shape mimicry in two Australian cuckoo species (pallid cuckoo and brush cuckoo). Moreover, cuckoo-host egg similarity was higher for hosts with open nests than for hosts with closed nests. This finding fits well with theory, as it has been suggested that hosts with closed nests have more difficulty recognizing parasitic eggs than open nests, have lower rejection rates and thus exert lower selection for mimicry in cuckoos. This is the first evidence of mimicry in egg shape in a cuckoo-host system, suggesting that mimicry at different levels (size, shape, colour pattern) is evolving in concert. We also confirm the existence of egg size mimicry in cuckoo-host systems. PMID- 28898494 TI - N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Recent neurobiological evidences along with clinical observations justify the use of N-acetylcysteine (NAC) as a medication for craving. The objective of our study was to assess the evidence of efficacy of NAC for craving in substance use disorders in randomized clinical trials (RCTs). METHODS: Systematic review of the RCTs literature (PROSPERO number 56698) until February, 2017, using MEDLINE, Cochrane Library and clinicaltrials.gov. We included seven RCTs (n = 245); most with small-to-moderate sample sizes. The main outcome was the Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I2 and the chi2 test. Publication bias was evaluated using the Begg's funnel plot and the Egger's test. Meta-regression was performed using the random-effects model. RESULTS: Comparing NAC versus placebo, NAC was significantly superior for craving symptoms (Hedges' g = 0.94; 95%CI 0.55 1.33). The funnel plot showed the risk of publication bias was low and between study heterogeneity was not significant (I2 = 44.4%, p = 0.07 for the chi2 test). A subgroup analysis performed using meta-regression showed no particular influence. DISCUSSION AND CONCLUSIONS: NAC was superior to placebo for craving reduction in SUDs. The relatively small number of trials and their heterogeneous methodology were possible limitations; however, these positive thrilling results stimulate further studies for clarifying the potential impact of NAC for craving symptoms in SUDs. SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and favorable tolerability, in addition to being an over-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and its favorable tolerability, in addition to being anover-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. (Am J Addict 2017;26:660-666). PMID- 28898496 TI - Cumulative incidence of admission to permanent residential aged care for Australian women - A competing risk analysis. AB - OBJECTIVE: To provide a direct estimate of the risk of admission to permanent residential aged care among older women while accounting for death, according to housing type and other variables. METHODS: A competing risk analysis from 8,867 Australian women born 1921-26, using linked data from the Australian Longitudinal Study on Women's Health (ALSWH), Residential Aged Care (RAC), and the Australian National Death Index. RESULTS: After accounting for deaths, around 35% of women will be admitted to RAC between ages 73 and 90. The conditional cumulative incidence of admission to RAC was 26.9% if living in a house, compared to 36.0% from an apartment, 43.6% within a retirement village, and 37.1% if living in a mobile home. Each one-year increase in age was associated with a relative 17% increased risk of RAC. CONCLUSIONS: Around one-third of women will enter RAC between age 73 and 90. Living in a house had the lowest risk of entering residential aged care over time. Implications for public health: These findings have important implications for planning for aged care services, including the role of housing in delaying admission to residential aged care, and the need for residential care by a high proportion of women towards the end of life. PMID- 28898495 TI - Clinical features of cystatin A expression in patients with pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy known, with an extremely poor prognosis due to the lack of an efficient diagnostic scheme and no radical treatment option, except surgery. Therefore, understanding the pathophysiology of, and finding a novel biomarker to detect, PDAC should be prioritized. We observed an increase in mRNA expression of the cysteine protease inhibitor cystatin A (CSTA) in CD4+ T cells in peripheral blood cells of nine patients with PDAC, compared with the expression in seven healthy volunteers. Moreover, we confirmed significantly higher CSTA mRNA expression in a larger cohort of 41 patients with PDAC compared with that in 20 healthy volunteers. Correspondingly, the serum CSTA concentrations in 36 patients with PDAC were higher than those in 37 healthy volunteers, and this increase was correlated with PDAC clinical stage. Furthermore, the expression of CSTA and cathepsin B, which is a lysosomal cysteine protease inhibited by CSTA, was observed in tumor tissues and tumor-infiltrating immune cells in 20 surgically resected PDAC tissues by immunohistochemical staining. Expression of CSTA was detected in some tumor tissues and many tumor-infiltrating immune cells. Cathepsin B expression was also observed in most tumor tissues and tumor-infiltrating immune cells. In conclusion, CSTA and its substrate cathepsin B are involved in PDAC-related inflammation. The increment of CSTA expression in peripheral blood of patients with PDAC may have a potential role as a PDAC immunopathologic biomarker. PMID- 28898498 TI - Recent Advances in Processing of Stereocomplex-Type Polylactide. AB - Over the past two decades, biomass-derived and biodegradable polylactide (PLA) has sparked tremendous attention as a sustainable alternative to traditional petroleum-derived polymers for diverse applications. Unfortunately, the current applications of PLA have been mainly limited to biomedical and commodity fields, mostly because the poor heat resistance (resulting from low melting temperature) and hydrolysis stability make it hard to use as an engineering plastic. Stereocomplexation between enantiomeric poly(l-lactide) (PLLA) and poly(d lactide) (PDLA) opens a new avenue toward PLA-based engineering plastics with improved properties. The formation, crystal structure, properties, and potential applications of stereocomplex-type PLA (SC-PLA) are summarized by some research groups. However, since it is challenging to achieve full stereocomplexation from high-molecular-weight PLLA/PDLA blends and to avoid serious thermal degradation of the PLAs after complete melting, the advances and progress in the processing of SC-PLA into useful products are quite rare in open publication. In this review, some important strategies for enhancing stereocomplex crystallization in practical processing operations are presented and recently developed processing technologies for SC-PLA are highlighted, such as low-temperature sintering. Furthermore, major challenges and future developments are briefly discussed. This review is expected to potentially open up new research activities in the processing of SC-PLA. PMID- 28898497 TI - A pediatric structural MRI analysis of healthy brain development from newborns to young adults. AB - Assessment of healthy brain maturation can be useful toward better understanding natural patterns of brain growth and toward the characterization of a variety of neurodevelopmental disorders as deviations from normal growth trajectories. Structural magnetic resonance imaging (MRI) provides excellent soft-tissue contrast, which allows for the assessment of gray and white matter in the developing brain. We performed a large-scale retrospective analysis of 993 pediatric structural brain MRI examinations of healthy subjects (n = 988, aged 0 32 years) imaged clinically at 3 T, and extracted a wide variety of measurements such as white matter volumes, cortical thickness, and gyral curvature localized to subregions of the brain. All extracted structural biomarkers were tested for their correlation with subject age at time of imaging, providing measurements that may assist in the assessment of neurological maturation. Additional analyses were also performed to assess gender-based differences in the brain at a variety of developmental stages, and to assess hemispheric asymmetries. Results add to the literature by analyzing a realistic distribution of healthy participants imaged clinically, a useful cohort toward the investigation and creation of diagnostic tests for a variety of pathologies as aberrations from healthy growth trajectories. The next generation of diagnostic tests will be responsible for identifying pathological conditions from populations of healthy clinically imaged individuals. Hum Brain Mapp 38:5931-5942, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28898499 TI - Pacific Islands Families (PIF) Study: housing and psychological distress among Pacific mothers. AB - OBJECTIVE: In a sample of Pacific mothers living in New Zealand, we examined: 1) maternal reports about seven specific major housing problems (too small, difficult to get to from the street, in poor condition, damp, cold, presence of pests, too expensive); and 2) associations between these housing problems and maternal psychological distress, adjusting for some maternal sociodemographic characteristics. METHODS: The Pacific Islands Families longitudinal study follows a cohort of Pacific children born in Auckland, New Zealand, in 2000 and their parents. At the 14-year phase, mothers (n=844) were asked about housing conditions and psychological distress. RESULTS: Mothers who reported having any major housing problem, particularly the presence of pests and poor housing conditions, were significantly more likely to report psychological distress after adjusting for sociodemographic confounders. CONCLUSIONS: The impact of housing on mental health is complex and may be influenced by social, health and sociodemographic characteristics of Pacific mothers. Implications for public health: The finding that housing problems are significantly associated with psychological distress among Pacific mothers in New Zealand is an important finding. However, more in-depth qualitative research is needed to provide a clearer understanding of the way housing problems affect mental health and to guide strategies that minimise this outcome for Pacific mothers. PMID- 28898500 TI - Offset analgesia: The role of peripheral and central mechanisms. AB - BACKGROUND: Offset Analgesia (OA) can be evoked by a three-heat-stimulus train (T1-T2-T3), with T1 (5 s) and T3 (20 s) having the same temperature (e.g. 48 degrees C) and T2 (5 s) being slightly higher (1-3 degrees C). OA is defined as a disproportional pain reduction caused by the slight temperature decrease from T2 to T3. As the pain modulatory mechanisms behind OA are still poorly understood, the current study aimed to investigate the role of peripheral and central mechanisms by applying heat stimuli to the same location and to different unilateral and bilateral locations. METHOD: Young healthy volunteers participated in the study. A 'standard-OA' paradigm (48-49-48 degrees C) was applied to the non-dominant volar forearm (T1-T2-T3 applied on the same location). 'Unilateral OA' trials were applied on three different locations of the non-dominant volar forearm (the same dermatome). 'Bilateral-OA' trials were applied by shifting T1 T2-T3 between dominant and non-dominant volar forearms. A constant stimulus of 48 degrees C was applied as control for the evoked pain. The pain intensities were continuously recorded using an electronic visual analogue scale. RESULTS: The largest pain intensity reduction was reported for the 'standard-OA' paradigm (p < 0.001) compared with the control stimulus. Both 'Unilateral-OA' and 'Bilateral OA' trials caused a significant pain reduction (p < 0.05) compared with the control; however, the pain reduction was less than that evoked by 'standard-OA' (p < 0.05). CONCLUSION: This study showed that OA could be elicited when the stimuli were applied both to the same and to different locations (ipsi- and contralateral) indicating that peripheral as well as central mechanisms are involved in mediating OA. SIGNIFICANCE: This study investigated offset analgesia by applying thermal painful stimuli to the ipsi- and bilateral forearms in healthy subjects and found that both peripheral and central mechanisms seem to mediate offset analgesia. PMID- 28898501 TI - Growth of Pseudomonas aeruginosa in zinc poor environments is promoted by a nicotianamine-related metallophore. AB - Previous studies have suggested that P. aeruginosa possesses redundant zinc uptake systems. To identify uncharacterized zinc transporters, we analyzed the genome-wide transcriptional responses of P. aeruginosa PA14 to zinc restriction. This approach led to the identification of an operon (zrmABCD) regulated by the zinc uptake regulator Zur, that encodes for a metallophore-mediated zinc import system. This operon includes the genes for an uncharacterized TonB-dependent Outer Membrane Protein (ZrmA) and for a putative nicotianamine synthase (ZrmB). The simultaneous inactivation of the ZnuABC transporter and of one of these two genes markedly decreases the ability of P. aeruginosa to grow in zinc-poor media and compromises intracellular zinc accumulation. Our data demonstrate that ZrmB is involved in the synthesis of a metallophore which is released outside the cell and mediates zinc uptake through the ZrmA receptor. We also show that alterations in zinc homeostasis severely affect the ability of P. aeruginosa to cause acute lung and systemic infections in C57BL/6 mice, likely due to the involvement of zinc in the expression of several virulence traits. These findings disclose a hitherto unappreciated role of zinc in P. aeruginosa pathogenicity and reveal that this microorganism can obtain zinc through a strategy resembling siderophore mediated iron uptake. PMID- 28898502 TI - Reduced range of the endangered crested capuchin monkey (Sapajus robustus) and a possible hybrid zone with Sapajus nigritus. AB - The crested capuchin monkey (Sapajus robustus) is an endangered species endemic to the highly fragmented Atlantic Forest of Brazil. Surveys for S. robustus were carried out over a 25-month period (2003-2005) to obtain more precise geographical limits for the western range of the species. Previously published localities for S. robustus were mapped, and each point was given a 25-km radius "buffer zone." The largest forest remnants in the buffer zones (>300 ha) in Minas Gerais were visited in order to interview the local people and/or survey the forests directly using playback recordings of S. robustus. Camera traps were used in key localities if interviews suggested the presence of capuchins but no animals were sighted during the surveys. Of 127 valid interviews, only 39 people reported the presence of Sapajus in nearby forest fragments. We confirmed the presence of Sapajus in only 19 of these. S. robustus occurred in four, and S. libidinosus, S. nigritus, S. xanthosternos, or S. robustus * S. nigritus (hybrids?) occurred in the remaining 15. Based on our study, the estimated geographical distribution of S. robustus is 119,654 km2 , which represents a reduction of more than 70,000 km2 when compared to its formerly described range. The geographical limits as defined in this study are: northeast-the Jequitinhonha River; northwest and west-the Jequitinhonha River; southwest-the Suacui Grande River and the Espinhaco mountains; southeast-the Doce River; east-the Atlantic Ocean. A probable hybrid zone where capuchin monkeys have morphological features of both S. nigritus and S. robustus was found between the Santo Antonio and the Suacui Grande rivers. The elucidation of the geographical distribution of S. robustus is important for its conservation, facilitating the delineation of priority areas for the creation of reserves and the initiation of studies of the species' ecology and behavior. PMID- 28898503 TI - Using appreciative inquiry methodology to develop a weight management program for obese children in New Zealand. AB - OBJECTIVES: Paediatric obesity predicts adult obesity, and alarming new data in New Zealand reveals that obesity among the young continues to rise. In this study, we used a novel solution-focused paradigm, or appreciative inquiry perspective, to explore the factors that influence not just obese but non-obese states (that is, healthy weight as well as obesity), in Pacific adolescents (aged 13-17) living in socioeconomically deprived neighbourhoods. METHODS: Sixty-eight parents and adolescents from 30 families were recruited and interviewed, resulting in 15 obese and 15 healthy weight adolescents participating in the study. RESULTS: Our findings showed that, despite living in low socioeconomic circumstances, parents were able to alter their micro-environments to prevent obesity in their children. Parents with healthy weight adolescents had food rules in the home and monitored their children's eating and television viewing time. CONCLUSIONS: An appreciative inquiry approach to obesity research can uncover resiliency factors within families that can be applied to obesity prevention and treatment programs. Implications for public health: Appreciative inquiry methodology is a promising alternative qualitative research strategy for developing health interventions for low-income ethnic minority communities. PMID- 28898504 TI - Reversible DNA-Protein Cross-Linking at Epigenetic DNA Marks. AB - 5-Formylcytosine (5fC) is an endogenous DNA modification frequently found within regulatory elements of mammalian genes. Although 5fC is an oxidation product of 5 methylcytosine (5mC), the two epigenetic marks show distinct genome-wide distributions and protein affinities, suggesting that they perform different functions in epigenetic signaling. A unique feature of 5fC is the presence of a potentially reactive aldehyde group in its structure. Herein, we show that 5fC bases in DNA readily form Schiff-base conjugates with Lys side chains of nuclear proteins in vitro and in vivo. These covalent protein-DNA complexes are reversible (t1/2 =1.8 h), suggesting that they contribute to transcriptional regulation and chromatin remodeling. On the other hand, 5fC-mediated DNA-protein cross-links, if present at replication forks or actively transcribed regions, may interfere with DNA replication and transcription. PMID- 28898505 TI - In Situ Synthesis of Imidazolium-Crosslinked Ionogels via Debus-Radziszewski Reaction Based on PAMAM Dendrimers in Imidazolium Ionic liquid. AB - This study reports a remarkably facile method to synthesize novel ionogels with imidazolium cycle crosslinks based on polyamidoamine (PAMAM) dendrimers via one pot, modified Debus-Radziszewski reaction in ionic liquid 1-ethyl-3 methylimidazolium acetate ([EMIM][OAc]). High room temperature ionic conductivity (up to 6.8 mS cm-1 ) is achieved, and more remarkably, it can still exceed 1 mS cm-1 when the dendrimer content reached 70% because PAMAM dendrimers are completely amorphous with many cavities and the newly formed imidazolium crosslinks contains ions. The elastic modulus of these ionogels can exceed 106 Pa due to the newly-formed rigid imidazolium crosslinks. Crucially, these ionogels are robust gels even at temperatures up to 160 degrees C. Such novel ionogels with high ionic conductivity, tunable modulus, and flexibility are desirable for use in high-temperature flexible electrochemical devices. PMID- 28898506 TI - Physical activity may decrease the likelihood of children developing constipation. AB - AIM: Childhood constipation is common. We evaluated children diagnosed with constipation, who were referred to an Icelandic paediatric emergency department, and determined the effect of lifestyle factors on its aetiology. METHODS: The parents of children who were diagnosed with constipation and participated in a phase IIB clinical trial on laxative suppositories answered an online questionnaire about their children's lifestyle and constipation in March-April 2013. The parents of nonconstipated children that visited the paediatric department of Landspitali University Hospital or an Icelandic outpatient clinic answered the same questionnaire. RESULTS: We analysed responses regarding 190 children aged one year to 18 years: 60 with constipation and 130 without. We found that 40% of the constipated children had recurrent symptoms, 27% had to seek medical attention more than once and 33% received medication per rectum. The 47 of 130 control group subjects aged 10-18 were much more likely to exercise more than three times a week (72%) and for more than a hour (62%) than the 26 of 60 constipated children of the same age (42% and 35%, respectively). CONCLUSION: Constipation risk factors varied with age and many children diagnosed with constipation had recurrent symptoms. Physical activity may affect the likelihood of developing constipation in older children. PMID- 28898507 TI - Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non-alcoholic fatty liver disease (NAFLD) independent of insulin resistance. METHODS: In a biopsy-proven NAFLD cohort, we measured serum GDF15 levels using enzyme-linked immunosorbent assays. RESULTS: Among 190 subjects (mean age, 53 +/- 14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy-proven non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = .010) or NAFL patients (P = .001). Subjects with advanced fibrosis (>=F3) also showed higher GDF15 levels compared to the others (F0-2; P < .001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04-17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's rho, .525; P < .001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX-2 cells, GDF15 treatment resulted in enhanced expression of alpha-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. CONCLUSIONS: Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti-fibrotic pharmacotherapy. PMID- 28898508 TI - Hepatitis C virus core protein induces hepatic steatosis via Sirt1-dependent pathway. AB - BACKGROUND & AIMS: Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. METHODS: To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied. RESULTS: Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARgamma2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARgamma2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARgamma2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARgamma2 expression. CONCLUSIONS: Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARgamma2 expression. PMID- 28898509 TI - What do we know about the diets of Aboriginal and Torres Strait Islander peoples in Australia? A systematic literature review. AB - OBJECTIVE: To provide an overview of published research on the dietary intake of Aboriginal and Torres Strait Islander peoples. METHODS: Peer-reviewed literature from 1990 to October 2016 was searched to identify studies that measured the dietary intake of Australian Aboriginal and Torres Strait Islander populations. Study quality was assessed using a purposely devised quality appraisal tool. Meta analysis was not possible due to the heterogeneity in dietary intake assessment methods. A narrative synthesis of study findings, where key themes were compared and contrasted was completed. RESULTS: Twenty-five articles from twenty studies with outcome measures related to dietary intake were included. Dietary intake was assessed by electronic store sales, store turnover method, 24-hour dietary recall, food frequency questionnaire and short questions. Consistent findings were low reported intakes of fruit and vegetables and high intakes of total sugar and energy-dense, nutrient-poor food and beverages. CONCLUSIONS: While differences between studies and study quality limit the generalisability of the findings, most studies suggest that the diets of Aboriginal and Torres Strait Islander peoples are inadequate. Implications for public health: A more concerted approach to understanding dietary patterns of Aboriginal and Torres Strait Islander peoples is required to inform policy and practice to improve diet and nutrition. PMID- 28898510 TI - Multi-Photon Absorption in Metal-Organic Frameworks. AB - Multi-photon absorption (MPA) is among the most prominent nonlinear optical (NLO) effects and has applications, for example in telecommunications, defense, photonics, and bio-medicines. Established MPA materials include dyes, quantum dots, organometallics and conjugated polymers, most often dispersed in solution. We demonstrate how metal-organic frameworks (MOFs), a novel NLO solid-state materials class, can be designed for exceptionally strong MPA behavior. MOFs consisting of zirconium- and hafnium-oxo-clusters and featuring a chromophore linker based on the tetraphenylethene (TPE) molecule exhibit record high two photon absorption (2PA) cross-section values, up to 3600 GM. The unique modular building-block principle of MOFs allows enhancing and optimizing their MPA properties in a theory-guided approach by combining tailored charge polarization, conformational strain, three-dimensional arrangement, and alignment of the chromophore linkers in the crystal. PMID- 28898511 TI - Mutations in the major gas vesicle protein GvpA and impacts on gas vesicle formation in Haloferax volcanii. AB - Gas vesicles are proteinaceous, gas-filled nanostructures produced by some bacteria and archaea. The hydrophobic major structural protein GvpA forms the ribbed gas vesicle wall. An in-silico 3D-model of GvpA of the predicted coil alpha1-beta1-beta2-alpha2-coil structure is available and implies that the two beta-chains constitute the hydrophobic interior surface of the gas vesicle wall. To test the importance of individual amino acids in GvpA we performed 85 single substitutions and analyzed these variants in Haloferax volcanii DeltaA + Amut transformants for their ability to form gas vesicles (Vac+ phenotype). In most cases, an alanine substitution of a non-polar residue did not abolish gas vesicle formation, but the replacement of single non-polar by charged residues in beta1 or beta2 resulted in Vac- transformants. A replacement of residues near the beta turn altered the spindle-shape to a cylindrical morphology of the gas vesicles. Vac- transformants were also obtained with alanine substitutions of charged residues of helix alpha1 suggesting that these amino acids form salt-bridges with another GvpA monomer. In helix alpha2, only the alanine substitution of His53 or Tyr54, led to Vac- transformants, whereas most other substitutions had no effect. We discuss our results in respect to the GvpA structure and data available from solid-state NMR. PMID- 28898512 TI - Knowledge, attitudes and opinions towards measles and the MMR vaccine across two NSW cohorts. AB - OBJECTIVE: Although the number of national measles cases has greatly decreased since 1980s, there has been resurgence in disease incidence in recent years. While parental knowledge and attitudes toward both disease and vaccinations are known to influence vaccine uptake, the contribution of these factors toward vaccination rates in NSW populations has not been studied. The aim of this study was to investigate the knowledge and opinions on measles and MMR vaccine in NSW Central and North Coast regions. METHODS: Parents (n=201) of children <12 years were surveyed with a purpose design survey at public beaches at the Central Coast and community markets at the North Coast. RESULTS: Eight per cent of respondents reported not immunising their child with MMR vaccine. Most respondents recognised that measles is a highly contagious disease. Non-immunisers were found to be older, had a lower perceived severity of measles, were less likely to agree with the efficacy and safety of the vaccine, and were more likely to have encountered someone who had suffered side-effects of the vaccine. CONCLUSIONS: There is considerable concern over safety of MMR vaccine among non-immunisers. Implications for public health: Improving confidence in MMR vaccine should be a target of future public health interventions. PMID- 28898513 TI - Characterisation of a sucrose-independent in vitro biofilm model of supragingival plaque. AB - OBJECTIVES: Sugar consumption has been decreasing in Japan, suggesting higher rates of sucrose-independent supragingival plaque formation. For developing an in vitro biofilm model of sucrose-independent supragingival plaque, this study aimed to investigate the compositions and functions on contributing to cariogenicity in comparison with sucrose-dependent biofilm. MATERIALS AND METHODS: An in vitro multispecies biofilm containing Actinomyces naeslundii, Streptococcus gordonii, S. mutans, Veillonella parvula and Fusobacterium nucleatum was formed on 24-well plates in the absence or presence of 1% sucrose. Compositions were assessed by plate culture, scanning electron microscopy and confocal laser scanning microscopy after fluorescent in situ hybridisation or labelling of extracellular polymeric substances (EPS). Functions were assessed by acidogenicity, adherence strength and sensitivities to anticaries agents. RESULTS: Although both biofilms exhibited a Streptococcus predominant bacterial composition, there were differences in bacterial and EPS compositions; in particular, little glucan EPS was observed in sucrose-independent biofilm. Compared with sucrose-dependent biofilm, acidogenicity, adherence strength and antimicrobial resistance of sucrose-independent biofilm were only slightly lower. However, dextranase degradation was substantially lower in sucrose-independent biofilm. CONCLUSION: Our findings suggest that sucrose-independent biofilm may have cariogenicity as with sucrose-dependent biofilm. These in vitro models can help further elucidate plaque-induced caries aetiology and develop new anticaries agents. PMID- 28898514 TI - Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. AB - AIMS: To examine the incidence of amputation in patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose co-transporter 2 (SGLT2) inhibitors overall, and canagliflozin specifically, compared with non-SGLT2 inhibitor antihyperglycaemic agents (AHAs). MATERIALS AND METHODS: Patients with T2DM newly exposed to SGLT2 inhibitors or non-SGLT2 inhibitor AHAs were identified using the Truven MarketScan database. The incidence of below-knee lower extremity (BKLE) amputation was calculated for patients treated with SGLT2 inhibitors, canagliflozin, or non-SGLT2 inhibitor AHAs. Patients newly exposed to canagliflozin and non-SGLT2 inhibitor AHAs were matched 1:1 on propensity scores, and a Cox proportional hazards model was used for comparative analysis. Negative controls (outcomes not believed to be associated with any AHA) were used to calibrate P values. RESULTS: Between April 1, 2013 and October 31, 2016, 118 018 new users of SGLT2 inhibitors, including 73 024 of canagliflozin, and 226 623 new users of non-SGLT2 inhibitor AHAs were identified. The crude incidence rates of BKLE amputation were 1.22, 1.26 and 1.87 events per 1000 person-years with SGLT2 inhibitors, canagliflozin and non-SGLT2 inhibitor AHAs, respectively. For the comparative analysis, 63 845 new users of canagliflozin were matched with 63 845 new users of non-SGLT2 inhibitor AHAs, resulting in well-balanced baseline covariates. The incidence rates of BKLE amputation were 1.18 and 1.12 events per 1000 person-years with canagliflozin and non-SGLT2 inhibitor AHAs, respectively; the hazard ratio was 0.98 (95% confidence interval 0.68-1.41; P = .92, calibrated P = .95). CONCLUSIONS: This real-world study observed no evidence of increased risk of BKLE amputation for new users of canagliflozin compared with non-SGLT2 inhibitor AHAs in a broad population of patients with T2DM. PMID- 28898515 TI - Age-related changes in and determinants of macular ganglion cell-inner plexiform layer thickness in normal Chinese adults. AB - IMPORTANCE: Consideration of age-related changes in macular ganglion cell-inner plexiform layer (mGCIPL) thickness are important for glaucoma progression analysis. BACKGROUND: To report age-related changes in and the determinants of high-definition optical coherence tomography (HD-OCT) measurements of mGCIPL thickness. DESIGN: Cross-sectional study. PARTICIPANTS: 326 healthy adults. METHODS: All subjects underwent Cirrus HD-OCT measurements of mGCIPL. One-way analysis of variance (ANOVA) was used to compare mGCIPL thickness between 7 decades based age groups and macular sectors. Multiple regression analysis determined the association between mGCIPL thickness and age, gender, intraocular pressure (IOP), peripapillary retinal nerve fibre layer thickness (pRNFL) and spherical equivalent. MAIN OUTCOME MEASURES: Change in mGCIPL thickness and determinants of thickness. RESULTS: Mean mGCIPL thickness in 295 subjects was 80.80 +/- 6.42 MUm. Mean mGCIPL decreased by 0.12 MUm (95% CI [confidence interval], 0.09-0.16) with every year of age; 1.61 MUm (95% CI, 0.08-2.41) per decade. It showed two steep declines with age, first in the fifth and next in the seventh decade with relative stability between them. mGCIPL thickness was associated with pRNFL thickness (beta = 0.30, P < 0.001) and IOP (beta = -0.19, P = 0.03) but not with gender (beta = -1.09, P = 0.116) or spherical equivalent (beta = -0. 24, P = 0.145). CONCLUSIONS AND RELEVANCE: Mean mGCIPL thickness showed a small age-related linear decrease with two steep drops in the fifth and seventh decades. Thinner mGCIPL was independently associated with age, thinner pRNFL and higher IOP. These factors should be considered if using mGCIPL to detect progression of glaucoma and other optic neuropathies characterized by the loss of retinal ganglion cells. PMID- 28898516 TI - Structural and functional imaging of aqueous humour outflow: a review. AB - Maintaining healthy aqueous humour outflow (AHO) is important for intraocular cellular health and stable vision. Impairment of AHO can lead to increased intraocular pressure, optic nerve damage and concomitant glaucoma. An improved understanding of AHO will lead to improved glaucoma surgeries that enhance native AHO as well as facilitate the development of AHO-targeted pharmaceuticals. Recent AHO imaging has evolved to live human assessment and has focused on the structural evaluation of AHO pathways and the functional documentation of fluid flow. Structural AHO evaluation is predominantly driven by optical coherence tomography, and functional evaluation of flow is performed using various methods, including aqueous angiography. Advances in structural and functional evaluation of AHO are reviewed with discussion of strengths, weaknesses and potential future directions. PMID- 28898517 TI - Characterization of the functional activity of botulinum neurotoxin subtype B6. AB - Clostridium botulinum produces the highly potent neurotoxin, botulinum neurotoxin (BoNT), which is classified into seven serotypes (A-G); the subtype classification is confirmed by the diversity of amino acid sequences among the serotypes. BoNT from the Osaka05 strain is associated with type B infant botulism and has been classified as BoNT/B subtype B6 (BoNT/B6) by phylogenetic analysis and the antigenicity of its C-terminal heavy chain (HC ) domain. However, the molecular bases for its properties, including its potency, are poorly understood. In this study, BoNT/B6 holotoxin was purified and the biological activity and receptor binding activity of BoNT/B6 compared with those of the previously characterized BoNT/B1 and BoNT/B2 subtypes. The derivative BoNT/B6 was found to be already nicked and in an activated form, indicating that endogenous protease production may be higher in this strain than in the other two strains. BoNT/B1 exhibited the greatest lethal activity in mice, followed by BoNT/B6, which is consistent with the sensitivity of PC12 cells. No significant differences were seen in the enzymatic activities of the BoNT/Bs against their substrate. HC /B1 and HC /B6 exhibited similar binding affinities to synaptotagmin II (SytII), which is a specific protein receptor for BoNT/B. Binding to the SytII/ganglioside complex is functionally related to the toxic action; however, the receptor recognition sites are conserved. These results suggest that the distinct characteristics and differences in biological sensitivity of BoNT/B6 may be attributable to the function of its Hc .domain. PMID- 28898518 TI - Interaction of Ester-Functionalized Ionic Liquids with Atomically-Defined Cobalt Oxides Surfaces: Adsorption, Reaction and Thermal Stability. AB - Hybrid materials consisting of ionic liquid (ILs) films on supported oxides hold a great potential for applications in electronic and energy materials. In this work, we have performed surface science model studies scrutinizing the interaction of ester-functionalized ILs with atomically defined Co3 O4 (111) and CoO(100) surfaces. Both supports are prepared under ultra-high vacuum (UHV) conditions in form of thin films on Ir(100) single crystals. Subsequently, thin films of three ILs, 3-butyl-1-methyl imidazolium bis(trifluoromethyl-sulfonyl) imide ([BMIM][NTf2 ]), 3-(4-methoxyl-4-oxobutyl)-1-methylimidazolium bis(trifluoromethyl-sulfonyl) imide ([MBMIM][NTf2 ]), and 3-(4-isopropoxy-4 oxobutyl)-1-methylimidazolium bis(trifluoromethyl-sulfonyl) imide ([IPBMIM][NTf2 ]), were deposited on these surfaces by physical vapor deposition (PVD). Time resolved and temperature-programmed infrared reflection absorption spectroscopy (TR-IRAS, TP-IRAS) were applied to monitor in situ the adsorption, film growth, and thermally induced desorption. By TP-IRAS, we determined the multilayer desorption temperature of [BMIM][NTf2 ] (360+/-5 K), [MBMIM][NTf2 ] (380 K) and [IPBMIM][NTf2 ] (380 K). Upon deposition below the multilayer desorption temperature, all three ILs physisorb on both cobalt oxide surfaces. However, strong orientation effects are observed in the first monolayer, where the [NTf2 ] ion interacts with the surface through the SO2 groups and the CF3 groups point towards the vacuum. For the two functionalized ILs, the [MBMIM]+ and [IPBMIM]+ interact with the surface Co2+ ions of both surfaces via the CO group of their ester function. A very different behavior is found, if the ILs are deposited above the multilayer desorption temperature (400 K). While for [BMIM][NTf2 ] and [MBMIM][NTf2 ] a molecularly adsorbed monolayer film is formed, [IPBMIM][NTf2 ] undergoes a chemical transformation on the CoO(100) surface. Here, the ester group is cleaved and the cation is chemically linked to the surface by formation of a surface carboxylate. The IL-derived species in the monolayer desorb at temperatures around 500 to 550 K. PMID- 28898519 TI - Near-Infrared Free-Radical and Free-Radical-Promoted Cationic Photopolymerizations by In-Source Lighting Using Upconverting Glass. AB - A method is presented for the initiation of free-radical and free-radical promoted cationic photopolymerizations by in-source lighting in the near-infrared (NIR) region using upconverting glass (UCG). This approach utilizes laser irradiation of UCG at 975 nm in the presence of fluorescein (FL) and pentamethyldiethylene triamine (PMDETA). FL excited by light emitted from the UCG undergoes electron-transfer reactions with PMDETA to form free radicals capable of initiating polymerization of methyl methacrylate. To execute the corresponding free-radical-promoted cationic polymerization of cyclohexene oxide, isobutyl vinyl ether, and N-vinyl carbazole, it was necessary to use FL, dimethyl aniline (DMA), and diphenyliodonium hexafluorophosphate as sensitizer, coinitiator, and oxidant, respectively. Iodonium ions promptly oxidize DMA radicals formed to the corresponding cations. Thus, cationic polymerization with efficiency comparable to the conventional irradiation source was achieved. PMID- 28898520 TI - Sugars and beyond. The role of sugars and the other nutrients and their potential impact on caries. AB - The traditional concept of caries as a multifactorial transmittable and infectious disease has been challenged. Novel conceptual ideas have come to add to the complexity of this highly prevalent disease worldwide. Current etiological understanding of the disease has emphasized the pivotal role of sugars in caries. In fact, current definition points toward an ecological disease caused by the commensal microbiota that under ecological imbalances, mainly due to high and or frequent sugars consumption, creates a state of dysbiosis in the dental biofilm. This modern conceptual idea, however, tends to underrate a key issue. As humans are omnivore and consume a mix diet composed by a multitude of substances, the role of the diet in caries must not be restricted only to the presence of fermentable sugars. This review explores the contribution of other food components, ubiquitous to the diet, mostly as potentially protective factors. Anticaries nutrients might determine an environmental change, affecting the ecology of the oral microbiome and partially mitigating the effect of sugars. Understanding the function of the food usually consumed by the people will contribute new knowledge on the mechanisms associated with the onset of caries, on new caries risk variables and on potential novel strategies for the prevention and treatment of the disease. PMID- 28898521 TI - Design and methodology of the Shanghai child and adolescent large-scale eye study (SCALE). AB - IMPORTANCE: Nearly half of children suffering vision impairment reside in China with myopia accounting for the vast majority. BACKGROUND: To describe the design and methodology of the Shanghai Child and Adolescent Large-scale Eye Study (SCALE). DESIGN: The SCALE was a city wide, school-based, prospective survey. PARTICIPANTS: Children and adolescents aged 4-14 years from kindergarten (middle and senior), primary schools and junior high schools of all 17 districts and counties of the city of Shanghai, China were examined in 2012-2013. METHODS: Each enrolled child underwent vision assessment (distance visual acuity; uncorrected and with corrective device if worn) and their parent/carer completed a questionnaire designed to elicit risk factors associated with myopia. Additionally, non-cycloplegic autorefraction and ocular axial length was measured in a subset of the larger sample. MAIN OUTCOME MEASURES: Prevalence and the associated factors of vision impairment, myopia and high myopia in Shanghai. RESULTS: In 2012-2013, a total of 910 245 of the eligible 1 196 763 children and adolescents identified from census (76%, mean age 9.0 +/- 2.7 years [4-14 years]) were enrolled with visual acuity screened in the city of Shanghai. Of these, 610 952 children (67% of the entire sample) underwent non-cycloplegic autorefraction and 219 188 (24% of the entire sample) had both non-cycloplegic autorefraction and axial length measurements. CONCLUSIONS AND RELEVANCE: The study results will provide insights on the burden of vision impairment, myopia and high myopia in children and adolescents in a metropolitan area of China, and contribute to the policies and strategies to address and limit the burden. PMID- 28898522 TI - Insecticide susceptibilities of the two rice planthoppers Nilaparvata lugens and Sogatella furcifera in East Asia, the Red River Delta, and the Mekong Delta. AB - BACKGROUND: The two rice planthoppers, Nilaparvata lugens and Sogatella furcifera, have different life cycles in the regions of East Asia, the Red River Delta, and the Mekong Delta. The susceptibilities of these species to a range of insecticides have not previously been compared among the three regions over multiple years. Here, we describe the differences and similarities in insecticide susceptibilities of the two species among the three regions in 2006-2011. RESULTS: In all three regions in 2006 - 2011, N. lugens developed high and moderate levels of resistance to imidacloprid and thiamethoxam, respectively, but this species did not develop resistance to fipronil. In contrast, S. furcifera developed a high level of resistance to fipronil. The ranges in 50% lethal dose (LD50 ) values for N. lugens treated with both imidacloprid and thiamethoxam were similar over time between East Asia and the Red River Delta, and were different in the Mekong Delta. CONCLUSION: The results support the idea that resistant populations migrate from the Red River Delta region to East Asia. Therefore, continuous monitoring of the susceptibility of N. lugens to insecticides in the Red River Delta is very important for insecticide resistance management in East Asia. (c) 2017 Society of Chemical Industry. PMID- 28898523 TI - "Yubi-wakka" (finger-ring) test: A practical self-screening method for sarcopenia, and a predictor of disability and mortality among Japanese community dwelling older adults. AB - AIM: We developed a simple self-screening method, the "Yubi-wakka (finger-ring)" test to assess sarcopenia swiftly. This prospective cohort study aimed to examine the validity of this test as a practical method among community-dwelling older adults for identifying sarcopenia, and for predicting disability and mortality. METHODS: We followed 1904 older adults, and analyzed associations between this "Yubi-wakka" test result at baseline in 2012 and sarcopenia at baseline, new onset sarcopenia followed until 2014, and new-certification for the long-term care insurance and mortality followed until 2016. The "Yubi-wakka" test checks whether the maximum non-dominant calf circumference is bigger than the individual's own finger-ring circumference, which is formed by the thumb and forefinger of both hands. We divided participants into three groups, "bigger," "just fits" and "smaller" based on a comparison between the calf and finger-ring circumference. RESULTS: Of 1904 participants (mean age 72.8 +/- 5.4 years), 53% were grouped as "bigger," 33% were in "just fits" and 14% were in "smaller." Relative to "bigger," the test results statistically associated with sarcopenia ("just fits" OR 2.4, 95% CI 1.4-4.1 and "smaller" OR 6.6, 95% CI 3.5-13), by multivariate analyses. The test results also increased the risk of new-onset sarcopenia ("just fits" HR 2.1, 95% CI 1.2-3.8 and "smaller" HR 3.4, 95% CI 1.8 6.4). Furthermore, the "smaller" had 2.0- and 3.2-fold increased risks for needing long-term care insurance services and mortality, respectively. CONCLUSIONS: The "Yubi-wakka" test is an extremely practical method to identify older adults at risk of sarcopenia, disability and mortality. This test might contribute to increased primary prevention for sarcopenia by serving as an early wake-up call for older adults against becoming sarcopenic. Geriatr Gerontol Int 2018; 18: 224-232. PMID- 28898524 TI - Enzymatic Addition of Alcohols to Terpenes by Squalene Hopene Cyclase Variants. AB - Squalene-hopene cyclases (SHCs) catalyze the polycyclization of squalene into a mixture of hopene and hopanol. Recently, amino-acid residues lining the catalytic cavity of the SHC from Alicyclobacillus acidocaldarius were replaced by small and large hydrophobic amino acids. The alteration of leucine 607 to phenylalanine resulted in increased enzymatic activity towards the formation of an intermolecular farnesyl-farnesyl ether product from farnesol. Furthermore, the addition of small-chain alcohols acting as nucleophiles led to the formation of non-natural ether-linked terpenoids and, thus, to significant alteration of the product pattern relative to that obtained with the wild type. It is proposed that the mutation of leucine at position 607 may facilitate premature quenching of the intermediate by small alcohol nucleophiles. This mutagenesis-based study opens the field for further intermolecular bond-forming reactions and the generation of non-natural products. PMID- 28898526 TI - Spin-State-Controlled Photodissociation of Iron(III) Azide to an Iron(V) Nitride Complex. AB - The generation of iron(V) nitride complexes, which are targets of biomimetic chemistry, is reported. Temperature-dependent ion spectroscopy shows that this reaction is governed by the spin-state population of their iron(III) azide precursors and can be tuned by temperature. The complex [(MePy2 TACN)Fe(N3 )]2+ (MePy2 TACN=N-methyl-N,N-bis(2-picolyl)-1,4,7-triazacyclononane) exists as a mixture of sextet and doublet spin states at 300 K, whereas only the doublet state is populated at 3 K. Photofragmentation of the sextet state complex leads to the reduction of the iron center. The doublet state complex photodissociates to the desired iron(V) nitride complex. To generalize these findings, we show results for complexes with cyclam-based ligands. PMID- 28898525 TI - Analyses of N-linked glycans of PrPSc revealed predominantly 2,6-linked sialic acid residues. AB - Mammalian prions (PrPSc ) consist of misfolded, conformationally altered, self replicating states of the sialoglycoprotein called prion protein or PrPC . Recent studies revealed that the sialylation status of PrPSc plays a major role in evading innate immunity and infecting a host. Establishing the type of linkage by which sialic acid residues are attached to galactose is important, as it helps to identify the sialyltransferases responsible for sialylating PrPC and outline strategies for manipulating the sialyation status of PrPSc . Using enzymatic treatment with sialidases and lectin blots, this study demonstrated that in N linked glycans of PrPSc , the sialic acid residues are predominantly alpha 2,6 linked. High percentages of alpha 2,6-linked sialic acids were observed in PrPSc of three prion strains 22L, RML, and ME7, as well as PrPSc from brain, spleen, or N2a cells cultured in vitro. Moreover, the variation in the percentage of alpha 2,3- versus 2,6-linked sialic acid was found to be relatively minor between brain , spleen-, or cell-derived PrPSc , suggesting that the type of linkage is independent of tissue type. Based on the current results, we propose that sialyltransferases of St6Gal family, which is responsible for attaching sialic acids via alpha 2,6-linkages to N-linked glycans, controls sialylation of PrPC and PrPSc . PMID- 28898527 TI - Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study. AB - This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269. PMID- 28898528 TI - Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: A promising clinical alternative to the conventional intrahepatic site. AB - Subcutaneous tissue is a promising site for islet transplantation, due to its large area and accessibility, which allows minimally invasive procedures for transplantation, graft monitoring, and removal of malignancies as needed. However, relative to the conventional intrahepatic transplantation site, the subcutaneous site requires a large number of islets to achieve engraftment success and diabetes reversal, due to hypoxia and low vascularity. We report that the efficiency of subcutaneous islet transplantation in a Lewis rat model is significantly improved by treating recipients with inhaled 50% oxygen, in conjunction with prevascularization of the graft bed by agarose-basic fibroblast growth factor. Administration of 50% oxygen increased oxygen tension in the subcutaneous site to 140 mm Hg, compared to 45 mm Hg under ambient air. In vitro, islets cultured under 140 mm Hg oxygen showed reduced central necrosis and increased insulin release, compared to those maintained in 45 mm Hg oxygen. Six hundred syngeneic islets subcutaneously transplanted into the prevascularized graft bed reversed diabetes when combined with postoperative 50% oxygen inhalation for 3 days, a number comparable to that required for intrahepatic transplantation; in the absence of oxygen treatment, diabetes was not reversed. Thus, we show oxygen inhalation to be a simple and promising approach to successfully establishing subcutaneous islet transplantation. PMID- 28898529 TI - The Design, Development, and Evaluation of a Qualitative Data Collection Application for Pregnant Women. AB - PURPOSE: This article explores the development and evaluation of a smartphone mobile software application (app) to collect qualitative data. The app was specifically designed to capture real-time qualitative data from women planning a vaginal birth after caesarean delivery. This article outlines the design and development of the app to include funding, ethics, and the recruitment of an app developer, as well as the evaluation of using the app by seven participants. ORGANIZING CONSTRUCT: Data collection methods used in qualitative research include interviews and focus groups (either online, face-to-face, or by phone), participant diaries, or observations of interactions. This article identifies an alternative data collection methodology using a smartphone app to collect real time data. CONCLUSIONS: The app provides real-time data and instant access to data alongside the ability to access participants from a variety of locations. This allows the researcher to gain insight into the experiences of participants through audio or video recordings in longitudinal studies without the need for constant interactions or interviews with participants. CLINICAL RELEVANCE: Using smartphone applications can allow researchers to access participants who are traditionally hard to reach and access their data in real time. Evaluating these apps before use in research is invaluable. PMID- 28898530 TI - A Cost-Effectiveness Analysis of Intradiscal Electrothermal Therapy Compared with Circumferential Lumbar Fusion. AB - STUDY DESIGN: Cost-effectiveness analysis. OBJECTIVE: To evaluate the cost effectiveness of intradiscal electrothermal therapy (IDET) relative to circumferential lumbar fusion with femoral ring allograft (FRA) in the United Kingdom. SUMMARY OF BACKGROUND DATA: Circumferential lumbar fusion is an established treatment for discogenic low back pain. However, IDET could be a cost effective treatment alternative as it can be carried out as a day case. METHODS: Patient-level data were available for patients with discogenic low back pain treated with FRA (n = 37) in a randomized trial of FRA vs. titanium cage, and for patients recruited to a separate study evaluating the use of IDET (n = 85). Both studies were carried out at a single institution in the United Kingdom. Patients were followed-up for 24 months, with data collected on low back disability (Oswestry Disability Index), back and leg pain (visual analog scale), quality of life (Short Form 36), radiographic evaluations, and U.K. National Health Service (NHS) resource use. Cost-effectiveness was measured by the incremental cost per quality-adjusted life year (QALY) gained. RESULTS: Both treatments produced statistically significant improvements in outcome at 24-month follow-up. NHS costs were significantly lower with IDET due to a shorter mean procedure time (377.4 minutes vs. 49.9 minutes) and length of stay (7 days vs. 1.2 days). At a threshold of L20,000 per QALY, the probability that IDET is cost effective is high. CONCLUSIONS: Both treatments led to significant improvements in patient outcomes that were sustained for at least 24 months. Costs were lower with IDET, and for appropriate patients IDET is an effective and cost-effective treatment alternative. PMID- 28898531 TI - Synergistic Hepatoprotective and Antioxidant Effect of Artichoke, Fig, Blackberry Herbal Mixture on HepG2 Cells and Their Metabolic Profiling Using NMR Coupled with Chemometrics. AB - The edible plants have long been reported to possess a lot of biological activities. Herein, the hepatoprotective and the antioxidant activities of the aqueous infusion of the edible parts of Cynara cardunculus, Ficus carica, and Morus nigra and their herbal mixture (CFM) was investigated in vitro using CCl4 induced damage in HepG2 cells. The highest amelioration was observed via the consumption of CFM at 1 mg/ml showing 47.00% and 37.09% decline in aspartate transaminase and alanine transaminase and 77.32% and 101.02% increase in reduced glutathione and superoxide dismutase comparable to CCl4 treated cells. Metabolic profiling of their aqueous infusions was done using nuclear magnetic resonance spectroscopic experiments coupled with chemometrics particularly hierarchical cluster analysis (HCA) and principal component analysis (PCA). The structural closeness of the various metabolites existing in black berry and the mixture as reflected in the PCA score plot and HCA processed from the 1 H-NMR spectral data could eventually explained the close values in their biological behavior. For fig and artichoke, the existence of different phenolic metabolites that act synergistically could greatly interpret their potent biological behavior. Thus, it can be concluded that a herbal mixture composed of black berry, artichoke, and fig could afford an excellent natural candidate to combat oxidative stress and counteract hepatic toxins owing to its phenolic compounds. PMID- 28898532 TI - Immunological efficacy of herbal medicines in prostate cancer patients treated by personalized peptide vaccine. AB - This randomized phase II study investigated the immunological efficacy of herbal medicines (HM) using Hochu-ekki-to and Keishi-bukuryo-gan in combination with personalized peptide vaccination (PPV) for castration-resistant prostate cancer (CRPC). Seventy patients with CRPC were assigned to two arms; PPV plus HM or PPV alone. Two to four peptides were chosen from 31 peptides derived from cancer antigens for a s.c. injection of PPV given eight times according to the patient's human leukocyte antigen type and levels of antigen-specific IgG titer before PPV treatment. Peptide-specific CTL, IgG, regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (Mo-MDSC), and interleukin-6 (IL-6) responses were measured before and at the eighth vaccination. Clinical outcomes were also analyzed. Combination therapy of PPV with HM was well tolerated without severe adverse events. There was no significant change in antigen-specific IgG, CTL, Treg or clinical outcomes. Combination therapy of PPV with HM stabilized the frequency of Mo-MDSC (1.91%-1.92%, P = 0.96) and serum levels of IL-6 (19.2 pg/mL to 16.1 pg/mL, P = 0.63) during the treatment. In contrast, the frequency of Mo MDSC and levels of IL-6 in the PPV-alone group were significantly increased (0.91%-1.49% for Mo-MDSC and 9.2 pg/mL to 19.4 pg/mL for IL-6, respectively). These results suggest that the combined use of HM has the potential to prevent the immunosuppression induced by Mo-MDSC or IL-6 during immunotherapy. More research is needed to validate the findings of the present study. PMID- 28898533 TI - Optimization of the ultrasound-assisted extraction of antioxidant phloridzin from Lithocarpus polystachyus Rehd. using response surface methodology. AB - The purpose of this study was to optimize the extraction process of phloridzin from Lithocarpus polystachyus Rehd. leaves using response surface methodology and to determine the antioxidant capacity of the extract. A Box-Behnken design was used to analyze the effects of ethanol concentration, liquid-solid ratio, soak time and extraction time on the extraction yield of phloridzin. The content of phloridzin was determined by high-performance liquid chromatography. To assess the antioxidant capacity of the extract, three in vitro test systems were used (1,1-,diphenyl-2-picrylhydrazyl, hydroxyl radical scavenging test and reduction force). The optimal parameters obtained by response surface methodology were a volume fraction of ethanol of 64%, a liquid-solid ratio of 37:1, a soaking time of 35 h and a sonication time of 38 min. The proportion of the extraction of phloridzin from L. polystachyus under these industrial process conditions was 3.83%. According to the obtained results, response surface methodology could be suggested as an adequate model for optimizing the extraction process of phloridzin from L. polystachyus. Ultrasound extraction significantly increased the extraction rate of phloridzin, which could be used as an antioxidant in pharmaceutical and food products. PMID- 28898534 TI - Proteomic Analysis of the Secretome of Porcine Alveolar Macrophages Infected with Porcine Reproductive and Respiratory Syndrome Virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes porcine reproductive and respiratory syndrome (PRRS), which is characterized by reproductive failure and respiratory disorders. The secretome of PRRSV-infected porcine alveolar macrophages (PAMs), which are the primary target cells of PRRSV, was analyzed by label-free quantitative proteomics to gain a profile of proteins secreted during PRRSV infection. A total of 95 secreted proteins with differentially expressed levels between PRRSV- and mock-infected PAMs was screened. Among these, the expression levels of 49 and 46 proteins were up regulated and down-regulated, respectively, in PRRSV-infected cell supernatants, as compared with mock-infected cell supernatants. Bioinformatic analysis revealed that the differentially expressed proteins were enriched in several signaling pathways related to the immune and inflammatory responses, such as the Toll-like receptor signaling pathway and NF-kappa B signaling pathway, and involved in a great diversity of biological processes, such as protein binding and localization, as well as immune effector processes. In addition, PRRSV-infected cell supernatants induced significant expression of inflammatory cytokines in vascular endothelial cells. These findings suggest that the secreted proteins play potential roles in the host immune and inflammatory responses as well as PRRSV replication, thereby providing new insights into cell-to-cell communication during PRRSV infection. PMID- 28898536 TI - Treatment with Naloxegol Versus Placebo: Pain Assessment in Patients with Noncancer Pain and Opioid-Induced Constipation. AB - OBJECTIVE: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain. METHODS: Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11 point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures. RESULTS: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean +/- SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 +/- 1.07, -0.3 +/- 1.05 (P = 0.773 vs. placebo), and 0.2 +/- 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 +/- 0.94, -0.1 +/- 0.87 (P = 0.744), and 0.0 +/- 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean +/- SD changes from baseline dose were -1.8 +/- 30.19, -2.3 +/- 20.52 (P = 0.724 vs. placebo), and 0.4 +/- 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 +/- 17.14, -1.3 +/- 17.11 (P = 0.669 vs. placebo), and 0.1 +/- 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. CONCLUSION: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC. PMID- 28898535 TI - Characterization of social cognition impairment in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) has been associated with deficits in social cognition. However, little is known about which domains of social cognition are predominantly affected and what other factors are associated with it. The aim was (i) to characterize social cognition deficit in a group of MS outpatients and (ii) to relate impairment in social cognition to overall cognitive status, depression and fatigue. METHODS: Thirty-five MS patients (mean disease duration 12.9 years, median Expanded Disability Status Scale (EDSS) 3 and 34 healthy controls (HCs) were examined using the German version of the Geneva Social Cognition Scale to measure different domains of social cognition. Standard neuropsychological testing was applied to all patients and to 20 HCs. Patient reported outcomes included questionnaires for fatigue, depression, anxiety and executive-behavioural disturbances. RESULTS: The mean social cognition raw score was lower in the MS patients compared to the HCs (86.5 +/- 8.7 vs. 91.2 +/- 5.9, P = 0.005; d = 0.6) and did not correlate with EDSS or disease duration. The difference was driven by facial affect recognition and the understanding of complex social situations (14% and 23% of patients respectively under the cut off). The impairment in these two tasks did not correlate with general cognitive performance or depression but with fatigue. CONCLUSIONS: The impairment in our group was restricted to high order and affective social cognition tasks and independent of general cognitive performance, EDSS, disease duration and depression. Fatigue correlated with social cognition performance, which might be due to common underlying neuronal networks. PMID- 28898537 TI - Stabilizing an amyloidogenic lambda6 light chain variable domain. AB - : Light chain amyloidosis is a lethal disease where vital organs are damaged by the fibrillar aggregation of monoclonal light chains. lambda6a is an immunoglobulin light chain encoded by the germ-line gene segment implicated in this disease. AR is a patient-derived germ-line variant with a markedly low thermodynamic stability and prone to form fibrils in vitro in less than an hour. Here, we sought to stabilize this domain by mutating some residues back to the germ-line sequence, and the most stabilizing mutations were the single-mutant AR F21I and the double-mutant AR-F21/IV104L, both located in the hydrophobic core. While mutation Arg25Gly in 6aJL2 destabilized the domain, mutating Gly25 back to arginine in AR did not contribute to stabilization as expected. Crystallographic structures of AR and 6a-R25G were generated to explain this discrepancy. Finally, 6a-R25G crystals revealed an octameric assembly which was emulated into 6aJL2 and AR crystals by replicating their structural parameters and suggesting a common assembly pattern. DATABASE: The atomic coordinates and structure factors have been deposited in the Protein Data Bank under the accession numbers 5IR3 and 5C9K. PMID- 28898538 TI - Longitudinal slit procedure combined with negative-pressure wound therapy for exposed Achilles tendons. PMID- 28898539 TI - Plant Proteogenomics: Improvements to the Grapevine Genome Annotation. AB - Grapevine is an important perennial fruit to the wine industry, and has implications for the health industry with some causative agents proven to reduce heart disease. Since the sequencing and assembly of grapevine cultivar Pinot Noir, several studies have contributed to its genome annotation. This new study further contributes toward genome annotation efforts by conducting a proteogenomics analysis using the latest genome annotation from CRIBI, legacy proteomics dataset from cultivar Cabernet Sauvignon and a large RNA-seq dataset. A total of 341 novel annotation events are identified consisting of five frame shifts, 37 translated UTRs, 15 exon boundaries, one novel splice, nine novel exons, 159 gene boundaries, 112 reverse strands, and one novel gene event in 213 genes and 323 proteins. From this proteogenomics evidence, the Augustus gene prediction tool predicted 52 novel and revised genes (54 protein isoforms), 11 genes of which are associated with key traits such as stress tolerance and floral and fruity wine characteristics. This study also highlights a likely over assembly with the genome, particularly on chromosome 7. PMID- 28898540 TI - Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy. AB - TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development. PMID- 28898541 TI - Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries. AB - BACKGROUND: Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes. OBJECTIVE: To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice. METHODS: We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries. RESULTS: Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively. CONCLUSION: Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy. PMID- 28898542 TI - Maximizing donor allocation: A review of UNOS region 9 donor heart turn-downs. AB - This study was performed to determine if organ selection practices for heart utilization by Region 9 transplant programs were optimal, and to identify opportunities to increase local organ recovery. A retrospective review of de identified region-wide donor data January 1, 2010 through December 31, 2013 was performed. Over the study period 537 heart donors were identified, of which 321 (60%) were transplanted. Two hundred-sixteen consented hearts were not used; 190 of these were not recovered, and 26 were recovered but not transplanted. Of these, 245/321 (76%) hearts were transplanted at one of 5 regional programs, 15 (5%) were transplanted out of region as primary offers, and 61 (19%) were turned down in region and exported. Of the 61 exported hearts, 43 were turned down in region for donor-related "quality" codes (UNOS 830, 833-837) by at least one program, the remaining 18 hearts were turned down for non-"quality" reasons, primarily histocompatibility and size. Only 5/43 exported were turned down for "quality" reasons by all regional programs offered the organ. A review of consented, not recovered donor offers suggested an additional 28 organs were possibly appropriate for transplant. Our review of regional turn-downs suggests transplant centers could potentially identify additional usable organs without compromising short-term outcomes. PMID- 28898543 TI - Follicular and cystic regression of locally advanced basal cell carcinoma following short-term neoadjuvant vismodegib therapy. PMID- 28898544 TI - Direct preparation of a graphene oxide modified monolith in a glass syringe as a solid-phase extraction cartridge for the extraction of quaternary ammonium alkaloids from Chinese patent medicine. AB - Packed cartridges have been widely used in solid-phase extraction. However, there are still some drawbacks, such as they are blocked easily and the method is time consuming. In view of the advantages of monoliths, a monolithic extraction material has been directly synthesized in a glass syringe without any gap between the monolith and syringe inner wall. The monolithic syringe was modified with graphene oxide by loading graphene oxide dispersion onto it. The content of graphene oxide and the surface topography of the monolith have been evaluated by elemental analysis and scanning electron microscopy, respectively, which confirmed the successful modification. This prepared graphene oxide-modified monolithic syringe was directly used as a traditional solid-phase extraction cartridge. As expected, it shows good permeability and excellent capability for the extraction of quaternary ammonium alkaloids. The sample loading velocity (1-6 mL/min) does not affect the recovery. Under the optimal conditions, good linearities (R = 0.9992-0.9998) were obtained for five quaternary ammonium alkaloids, and the limits of detection and quantification were 0.5-1 and 1-2 MUg/L, respectively. The proposed method was successfully applied for the analysis of quaternary ammonium alkaloids in Chinese patent medicine. PMID- 28898545 TI - Attitudes towards mental illness among medical students in China: Impact of medical education on stigma. AB - INTRODUCTION: Stigma towards people with mental illness impedes effective treatment. A recent study found that Chinese students were less socially accepting of people with mental illness than counterparts from other countries. The current study examined stigma among Chinese medical students at different levels of training. METHODS: Medical students (N = 1372 from 12 Chinese schools) were surveyed with a questionnaire addressing attitudes and beliefs about people with mental illness. Analysis of variance was used to compare responses from students: (1) with no psychiatry training; (2) who had only taken a didactic course; and (3) who had completed both a course and a clinical rotation. Specific attitudes were identified through factor analysis. Interest in further training and other personal experience were also examined. RESULTS: Factor analysis revealed attitudes favoring: (1) social acceptance of people with mental illness, (2) not believing in supernatural causes of mental illness, (3) bio-psycho-social causation, (4) rehabilitation, and (5) social integration. The absence of consistent trends across training levels suggested that education did not increase nonstigmatized attitudes. Areas of most stigmatization were low social acceptance and little favor for social integration. Measures most strongly correlated with nonstigmatized attitudes were as follows: interest in clinical psychiatry, belief that psychiatry should be more valued, and having friends with mental illness. DISCUSSION: Although medical school education showed little effect on attitudes, students with more individual experiences such as planning to continue clinical psychiatric training, believing psychiatry should be more valued, and having friends with mental illness had less stigmatized attitudes than others. PMID- 28898546 TI - Taking the challenge: A protocolized approach to optimize Pneumocystis pneumonia prophylaxis in renal transplant recipients. AB - While trimethoprim-sulfamethoxazole is considered first-line therapy for Pneumocystis pneumonia prevention in renal transplant recipients, reported adverse drug reactions may limit use and increase reliance on costly and less effective alternatives, often aerosolized pentamidine. We report our experience implementing a protocolized approach to trimethoprim-sulfamethoxazole adverse drug reaction assessment and rechallenge to optimize prophylaxis in this patient cohort. We retrospectively reviewed 119 patients receiving Pneumocystis pneumonia prophylaxis prior to and after protocol implementation. Forty-two patients (35%) had 48 trimethoprim-sulfamethoxazole adverse drug reactions documented either at baseline or during the prophylaxis period, of which 83% were non-immune-mediated and 17% were immune-mediated. Significantly more patients underwent trimethoprim sulfamethoxazole rechallenge after protocol implementation (4/22 vs 23/27; P = .0001), with no recurrence of adverse drug reactions in 74%. In those who experienced a new or recurrent reaction (26%), all were mild and self-limiting with only 1 recurrence of an immune-mediated reaction. After protocol implementation, aerosolized pentamidine-associated costs were reduced. The introduction of a standard approach to trimethoprim-sulfamethoxazole rechallenge in the context of both prior immune and non-immune-mediated reactions was safe and successful in improving the uptake of first-line Pneumocystis pneumonia prophylaxis in renal transplant recipients. PMID- 28898547 TI - HLX is a candidate gene for a pattern of anomalies associated with congenital diaphragmatic hernia, short bowel, and asplenia. AB - Isolated congenital diaphragmatic hernia is often a sporadic event with a low recurrence risk. However, underlying genetic etiologies, such as chromosome anomalies or single gene disorders, are identified in a small number of individuals. We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first-cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20-Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could explain the fetal findings. PMID- 28898548 TI - Plasma Catechols After Eating Olives. AB - Olives contain 3,4-dihydroxyphenyl compounds (catechols)-especially 3,4 dihydroxyphenylethanol (DOPET)-that have therapeutic potential as nutraceuticals. Whether olive ingestion affects plasma levels of free (unconjugated) catechols has been unknown. Arm venous blood was sampled before and 15, 30, 45, 60, 120, 180, and 240 min after six healthy volunteers ate 10 Kalamata olives. Catechols were assayed by alumina extraction followed by liquid chromatography with series electrochemical detection. Plasma DOPET increased to 18.5 times baseline at 30 min (area under the curve (AUC) 39.2 +/- 9.2 pmol-min/mL, P = 0.008). 3,4 Dihydroxyphenylacetic acid (DOPAC) increased markedly (peak 37.4 times baseline, AUC 23,490 +/- 4,151 pmol-min/mL, P = 0.002). The sum of 10 catechols increased 12-fold (P < 0.0001). Eating olives produces large-magnitude increases in plasma levels of catechols, mainly DOPAC. DOPET seems to go undergo extensive hepatic metabolism to DOPAC. PMID- 28898549 TI - Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification. AB - AIM: Interstitial lung disease (ILD) in infants represents a rare and heterogenous group of disorders, distinct from those occurring in adults. In recent years a new entity within this category is being recognized, namely filamin A (FLNA) mutation related lung disease. Our aims are to describe the clinical and radiological course of patients with this disease entity to aid clinicians in the prognostic counseling and management of similar patients they may encounter. METHOD: A retrospective case note review was conducted of all patients treated at our institution (a specialist tertiary referral childrens' center) for genetically confirmed FLNA mutation related lung disease. The clinical presentation, evolution, management and radiological features were recorded and a medical literature review of Medline indexed articles was conducted. RESULTS: We present a case series of four patients with interstitial lung disease and genetically confirmed abnormalities within the FLNA gene. Their imaging findings all reveal a pattern of predominantly upper lobe overinflation, coarse pulmonary lobular septal thickening and diffuse patchy atelectasis. The clinical outcomes of our patients have been variable ranging from infant death, lobar resection and need for supplemental oxygen and bronchodilators. CONCLUSION: The progressive nature of the pulmonary aspect of this disorder and need for early aggressive supportive treatment make identification crucial to patient management and prognostic counseling. PMID- 28898550 TI - Rare, yet relevant tumor cells - A new twist to melanoma cell plasticity. PMID- 28898551 TI - Elucidation of GlcNAc-binding properties of type III intermediate filament proteins, using GlcNAc-bearing polymers. AB - Vimentin, desmin, glial fibrillary acidic protein (GFAP) and peripherin belong to type III intermediate filament family and are expressed in mesenchymal cells, skeletal muscle cells, astrocytes and peripheral neurons, respectively. Vimentin and desmin possess N-acetyl-d-glucosamine (GlcNAc)-binding properties on cell surfaces. The rod II domain of these proteins is a GlcNAc-binding site, which also exists in GFAP and peripherin. However, the GlcNAc-binding activities and behaviors of these proteins remain unclear. Here, we characterized the interaction and binding behaviors of these proteins, using various well-defined GlcNAc-bearing polymers synthesized by radical polymerization with a reversible addition-fragmentation chain transfer reagent. The small GlcNAc-bearing polymers strongly interacted with HeLa cells through vimentin expressed on the cell surface and interacted with vimentin-, desmin-, GFAP- and peripherin-transfected vimentin-deficient HeLa cells. These proteins present high affinity to GlcNAc bearing polymers, as shown by surface plasmon resonance. These results show that type III intermediate filament proteins possess GlcNAc-binding activities on cell surfaces. These findings provide important insights into novel cellular functions and physiological significance of type III intermediate filaments. PMID- 28898552 TI - A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP5. AB - : The ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family of proteins mediates purinergic signaling by degrading extracellular nucleotides and also participates in phospholipid metabolism. NPP5 (ENPP5) is the least characterized member of this group and its specific role is unknown. This enzyme does not display activity on certain nucleotides and on other typical NPP substrates. In order to gain insights into its function, we determined the crystal structure of human and murine NPP5. Structural comparison with close homologs revealed a key phenylalanine to tyrosine substitution that prevents efficient hydrolysis of nucleotide diphosphates and triphosphates; reversal of this mutation enabled degradation of these molecules. Interestingly, NPP5 is able to cleave nicotinamide adenine dinucleotide (NAD), suggesting a potential role of this enzyme in NAD-based neurotransmission. An NPP5-specific metal binding motif is found adjacent to the active site, although its significance is unclear. These findings expand our understanding of substrate specificity within the NPP family. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 5VEM, 5VEN, and 5VEO. PMID- 28898554 TI - Pulmonary blastoma in a child: Report of a case with cytological findings. AB - Pulmonary blastoma is an uncommon tumour. It constitutes <0.1% of all resected lung cancers. It is even more rare in children with only a few case reports describing this entity in them. Pulmonary blastoma should not be confused with pleuropulmonary blastoma which is a paediatric lung tumour with different morphology and better outcome. Here we take the opportunity of describing pulmonary blastoma in a 3 years old child along with its cytological findings. PMID- 28898553 TI - Rational Development of Neutral Aqueous Electrolytes for Zinc-Air Batteries. AB - Neutral aqueous electrolytes have been shown to extend both the calendar life and cycling stability of secondary zinc-air batteries (ZABs). Despite this promise, there are currently no modeling studies investigating the performance of neutral ZABs. Traditional continuum models are numerically insufficient to simulate the dynamic behavior of these complex systems because of the rapid, orders-of magnitude concentration shifts that occur. In this work, we present a novel framework for modeling the cell-level performance of pH-buffered aqueous electrolytes. We apply our model to conduct the first continuum-scale simulation of secondary ZABs using aqueous ZnCl2 -NH4 Cl as electrolyte. We first use our model to interpret the results of two recent experimental studies of neutral ZABs, showing that the stability of the pH value is a significant factor in cell performance. We then optimize the composition of the electrolyte and the design of the cell considering factors including pH stability, final discharge product, and overall energy density. Our simulations predict that the effectiveness of the pH buffer is limited by slow mass transport and that chlorine-containing solids may precipitate in addition to ZnO. PMID- 28898555 TI - Complementary and alternative medicine in US adults with diabetes: Reasons for use and perceived benefits. AB - BACKGROUND: Although complementary and alternative medicine (CAM) is increasingly used, little is known about the reasons for CAM use (treatment, wellness, or both), or the self-reported perceived benefits among US adults with diabetes. In this study we estimated prevalence rates of overall and specific types of CAM, as well as the perceived benefits of CAM, by reason for use among US diabetic adults. METHODS: Cross-sectional data from the 2012 National Health Interview Survey, which represents non-institutionalized adults with diabetes (n = 3386 unweighted), were used to estimate prevalence rates of CAM use by reason. Multivariate logistic regression analyses were used to investigate the odds of perceived benefits of CAM by reason for use after controlling for covariates. RESULTS: Of US diabetic adults, 26.2% reported using some form of CAM in the past year. Of these, 56.7% used CAM for both treatment and wellness, 28.3% used CAM for wellness only, and 15.0% used CAM for treatment only. Regardless of reasons for use, most commonly used CAM were herbal therapies (56.9%), followed by chiropractic (25.3%) and massage (20.2%). Those using CAM for a combination of both treatment and wellness had a higher likelihood of self-reporting a "better sense of control over their health" (P = 0.011) and "improved overall health and feeling better" (P = 0.014) than those using CAM for treatment only. CONCLUSION: Although CAM may be a promising approach to improving health-related quality of life, future research should address efficacy and patient safety. PMID- 28898556 TI - Critical Appraisal Tools and Reporting Guidelines for Evidence-Based Practice. AB - BACKGROUND: Nurses engaged in evidence-based practice (EBP) have two important sets of tools: Critical appraisal tools and reporting guidelines. Critical appraisal tools facilitate the appraisal process and guide a consumer of evidence through an objective, analytical, evaluation process. Reporting guidelines, checklists of items that should be included in a publication or report, ensure that the project or guidelines are reported on with clarity, completeness, and transparency. PURPOSE: The primary purpose of this paper is to help nurses understand the difference between critical appraisal tools and reporting guidelines. A secondary purpose is to help nurses locate the appropriate tool for the appraisal or reporting of evidence. METHODS: A systematic search was conducted to find commonly used critical appraisal tools and reporting guidelines for EBP in nursing. RATIONALE: This article serves as a resource to help nurse navigate the often-overwhelming terrain of critical appraisal tools and reporting guidelines, and will help both novice and experienced consumers of evidence more easily select the appropriate tool(s) to use for critical appraisal and reporting of evidence. Having the skills to select the appropriate tool or guideline is an essential part of meeting EBP competencies for both practicing registered nurses and advanced practice nurses (Melnyk & Gallagher-Ford, 2015; Melnyk, Gallagher Ford, & Fineout-Overholt, 2017). RESULTS: Nine commonly used critical appraisal tools and eight reporting guidelines were found and are described in this manuscript. Specific steps for selecting an appropriate tool as well as examples of each tool's use in a publication are provided. LINKING EVIDENCE TO ACTION: Practicing registered nurses and advance practice nurses must be able to critically appraise and disseminate evidence in order to meet EBP competencies. This article is a resource for understanding the difference between critical appraisal tools and reporting guidelines, and identifying and accessing appropriate tools or guidelines. PMID- 28898557 TI - Improved Survival for Rural Trauma Patients Transported by Helicopter to a Verified Trauma Center: A Propensity Score Analysis. AB - OBJECTIVES: Recent studies using advanced statistical methods to control for confounders have demonstrated an association between helicopter transport (HT) versus ground ambulance transport (GT) in terms of improved survival for adult trauma patients. The aim of this study was to apply a methodologically vigorous approach to determine if HT is associated with a survival benefit for when trauma patients are transported to a verified trauma center in a rural setting. METHODS: The ascertainment of trauma patients age >= 15 years (n = 469 cases) by HT and (n = 580 cases) by GT between 1999 and 2012 was restricted to the scene of injury in a rural area of 10 to 35 miles from the trauma center. The propensity score (PS) was determined using data including demographics, prehospital physiology, intubation, total prehospital time, and injury severity. The PS matching was performed with different calipers to select a higher percentage of matches of HT compared to GT patients. The outcome of interest was survival to discharge from hospital. Identical logistic regression analysis was done taking into account for each matched design to select an appropriate effect estimate and confidence interval (CI) controlling for initial vital signs in the emergency department, the need for urgent surgery, intensive care unit admission, and mechanical ventilation. RESULTS: Unadjusted mortalities for HT compared to GT were 7.7 and 5.3%, respectively (p > 0.05). The adjusted rates were 4.0% for HT and 7.6% for GT (p < 0.05). In a PS well-matched data set, HT was associated with a 2.69-fold increase in odds of survival compared to GT patients (adjusted odds ratio = 2.69; 95% CI = 1.21-5.97). CONCLUSIONS: In a rural setting, we demonstrated improved survival associated with HT compared to GT for scene transportation of adult trauma patients to a verified Level II trauma center using an advanced methodologic approach, which included adjustment for transport distance. The implication of survival benefit to rural population is discussed. We recommend larger studies with multiple trauma systems need to be repeated using similar study methodology to substantiate our findings. PMID- 28898558 TI - Combination of Capillaroscopic and Ultrasonographic Evaluations in Systemic Sclerosis: Results of a Cross-Sectional Study. AB - OBJECTIVE: To compare microvascular damages on nailfold capillaroscopy (NFC) with macrovascular manifestations evaluated by hand power Doppler ultrasonography (PDUS) in systemic sclerosis (SSc) patients, and to assess the associations of these damages with the main digital manifestations of the disease: digital ulcers, acroosteolysis, and calcinosis. METHODS: NFC, hand radiographs, and PDUS were systematically performed in 64 unselected SSc patients. PDUS evaluation with assessment of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were performed blinded for the results of radiographs and NFC. RESULTS: UAO and pathologic FPBF were associated with severe capillary loss (<4 capillaries/mm) on NFC (odds ratio [OR] 4.04 [95% confidence interval (95% CI) 1.23-13.29]; P < 0.05, and OR 3.38 [95% CI 1.03-11.05]; P < 0.05, respectively). Digital ulcer history was associated with UAO (OR 10.71 [95% CI 3.36-34.13]; P < 0.0001), pathologic FPBF (OR 7.67 [95% CI 2.52-23.28]; P < 0.0001), late NFC pattern (OR 6.33 [95% CI 2.03-19.68]; P = 0.001), and severe capillary loss (OR 8.52 [95% CI 2.15-33.78]; P = 0.001). Acroosteolysis was also associated with UAO (OR 15.83 [95% CI 3.95-63.54]; P < 0.0001), pathologic FPBF (OR 5.52 [95% CI 1.71-17.90]; P = 0.003), late NFC pattern (OR 6.86 [95% CI 2.18-21.53]; P = 0.001), and severe capillary loss (OR 7.20 [95% CI 2.16-24.02]; P = 0.001). Calcinosis on radiographs was associated with late NFC pattern (OR 5.41 [95% CI 1.82-16.12]; P = 0.002), severe capillary loss (OR 12.69 [95% CI 3.14-51.26]; P < 0.0001), and UAO (OR 3.19 [95% CI 1.14-8.92]; P = 0.025). Combination of UAO and severe capillary loss in the same patient was especially associated with digital ulcer history (OR 18.60 [95% CI 2.24-154.34]; P = 0.001) and acroosteolysis (OR 10.83 [95% CI 2.56-45.88]; P = 0.001). CONCLUSION: Microvascular damages evaluated by NFC and macrovascular features like UAO assessed by PDUS show concordant associations with the main digital manifestations of the disease. PMID- 28898559 TI - Changes in Physical Activity After Total Hip or Knee Arthroplasty: A Systematic Review and Meta-Analysis of Six- and Twelve-Month Outcomes. AB - OBJECTIVE: Little is known about the extent to which physical activity (PA) levels change following total knee or hip joint replacement relative to pain, physical function, and quality of life. Our objective was to conduct a systematic review and meta-analysis on changes in PA relative to pain, quality of life, and physical function after total knee or hip joint replacement. METHODS: We searched the PubMed (Medline), Embase, and CINAHL databases for peer-reviewed, English language cohort studies measuring PA with an accelerometer from presurgery to postsurgery. Random-effects models were used to produce standardized mean differences (SMDs) for PA, quality of life, pain, and physical function outcomes. Heterogeneity was assessed using I2 . RESULTS: Seven studies (336 participants) met the eligibility criteria. No significant increase in PA was found at 6 months (SMD 0.14 [95% confidence interval (95% CI) -0.05, 0.34]; I2 = 0%) and a small to moderately significant effect was found for increasing PA at 12 months (SMD 0.43 [95% CI 0.22, 0.64]; I2 = 0%). Large improvements were found at 6 months in physical function (SMD 0.97 [95% CI 0.12, 1.82]; I2 = 92.3%), pain (SMD -1.47 [95% CI -2.28, -0.65]; I2 = 91.6%), and quality of life (SMD 1.02 [95% CI 0.30, 1.74]; I2 = 83.2%). CONCLUSION: Physical activity did not change at 6 months, and a small to moderate improvement was found at 12 months postsurgery, despite large improvements in quality of life, pain, and physical function. Reasons for the lack of increased PA are unknown but may be behavioral in nature, as a sedentary lifestyle is difficult to change. Changing sedentary behavior should be a future focus of research in this subgroup. PMID- 28898560 TI - Off the beaten path: A case of mediastinal ectopic thyroid tissue. PMID- 28898561 TI - Haptic simulation of tissue tearing during surgery. AB - We present a method for the real-time, interactive simulation of tissue tearing during laparoscopic surgery. The method is designed to work at haptic feedback rates (ie, around 1 kHz). Tissue tearing is simulated under the general framework of continuum damage mechanics. The problem is stated as a general, multidimensional parametric problem, which is solved by means of proper generalized decomposition methods. One of the main novelties is the reduction of history-dependent problems, such as damage mechanics, by resorting to an approach in which a reduced-order field of initial damage values is considered as a parameter of the formulation. We focus on the laparoscopic cholecystectomy procedure as a general example of the performance of the method. PMID- 28898562 TI - Skipping breakfast among Australian children and adolescents; findings from the 2011-12 National Nutrition and Physical Activity Survey. AB - OBJECTIVE: Skipping breakfast has been linked with poor diet quality, higher BMI and adverse cardiometabolic outcomes. This study aimed to determine the prevalence and correlates of skipping breakfast among Australian children and adolescents. METHODS: A total of 1,592 2-17-year-olds completed two 24-hour recalls, collected via face-to-face and telephone interview, in the 2011-12 National Nutrition and Physical Activity Survey. Breakfast was an eating occasion of >=210kJ named as 'breakfast' by the participant. Child, household and adult correlates of skipping breakfast were reported. Odds ratios were calculated using ordinal regression. Linear regression was used to examine differences in dietary intake. Survey weights were applied to give nationally representative estimates. RESULTS: Most (86.8% of boys, 81.4% of girls) ate breakfast on both days, 11.8% of boys and 14.8% girls skipped on one day and 1.4% boys and 3.8% girls skipped on both days. Characteristics associated with skipping breakfast were being female, being older, being underweight or overweight/obese, poorer diet, lower physical activity, inadequate sleep, lower household income, greater socioeconomic disadvantage, and being from a single-parent home. CONCLUSION: Skipping breakfast was common among Australian adolescents but few consistently skipped. Implications for public health: Interventions to increase breakfast should target adolescents, particularly girls, and low SEP households. PMID- 28898564 TI - Pseudoexfoliation syndrome and pseudoexfoliation glaucoma in New Zealand Maori. PMID- 28898563 TI - Direct-acting antiviral agent-based regimen for HCV recurrence after combined liver-kidney transplantation: Results from the ANRS CO23 CUPILT study. AB - Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver-kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second-generation direct-acting antivirals (DAAs) in this difficult-to-treat population. The ANRS CO23 "Compassionate use of Protease Inhibitors in Viral C Liver Transplantation" (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety-six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow-up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA-based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT. PMID- 28898565 TI - Projected Burden of Osteoarthritis and Rheumatoid Arthritis in Australia: A Population-Level Analysis. AB - OBJECTIVE: To forecast the prevalence and direct health care costs of osteoarthritis (OA) and rheumatoid arthritis (RA) in Australia to the year 2030. METHODS: An epidemiologic model of the Australian population was developed. Data on the national prevalence of OA and RA were obtained from the Australian Bureau of Statistics (ABS) 2014-2015 National Health Survey. Future prevalence was estimated using ABS population projections for 2020, 2025, and 2030. Available government data on direct health care expenditure for OA and RA were modeled to forecast costs (in Australian $) for the years 2020, 2025, and 2030, from the perspective of the Australian public health care system. RESULTS: The number of people with OA is expected to increase nationally from almost 2.2 million in 2015 to almost 3.1 million Australians in 2030. The number of people with RA is projected to increase from 422,309 in 2015 to 579,915 in 2030. Health care costs for OA were estimated to be over $2.1 billion in 2015; by the year 2030, these are forecast to exceed $2.9 billion ($970 for every person with the condition). Health care costs for RA were estimated to be over $550 million in 2015, including $273 million spent on biologic disease-modifying antirheumatic drugs. Health care costs for RA are projected to rise to over $755 million by the year 2030. CONCLUSION: OA and RA are costly conditions that will impose an increasing health care burden at the population level. These projections provide tangible data that can be used to map future health service provision to expected need. PMID- 28898566 TI - Comparison of a new air-assisted sprayer and two conventional sprayers in terms of deposition, loss to the soil and residue of azoxystrobin and tebuconazole applied to sunlit greenhouse tomato and field cucumber. AB - BACKGROUND: Plant protection products (PPPs) are applied in China and many other developing countries with knapsack sprayers at high volumes with coarse spray quality, resulting in a high percentage of pesticide losses. In this study, a new air-assisted electric knapsack sprayer and two conventional knapsack sprayers were evaluated in terms of pesticide deposition, residues and loss into the soil. Artificial targets fixed to the upper side and underside of the leaf surface in six zones (at two depths and three heights) were used to collect the deposition, which were analyzed by liquid chromatography triple-quadrupole mass spectrometry. RESULTS: The air-assisted electric knapsack sprayer produced more deposition and better penetrability and uniformity than the two traditional spraying methods. In particular, the air-assisted electric knapsack sprayer reduced pesticide losses to the soil by roughly 37% to 75% and deposited 1.18 and 1.24 times more pesticide than the manual air-pressure and battery-powered knapsack sprayers, respectively. The residues of azoxystrobin and tebuconazole in tomato and cucumber were below the maximum residue limits (MRLs). CONCLUSION: In general, use of the the air-assisted electric knapsack sprayer in tomato and cucumber crops could improve the effectiveness of PPPs, reduce the risk of contamination and protect food safety. (c) 2017 Society of Chemical Industry. PMID- 28898567 TI - Multicolor Photo-Crosslinkable AIEgens toward Compact Nanodots for Subcellular Imaging and STED Nanoscopy. AB - Aggregation induced emission (AIE) has attracted considerable interest for the development of fluorescence probes. However, controlling the bioconjugation and cellular labeling of AIE dots is a challenging problem. Here, this study reports a general approach for preparing small and bioconjugated AIE dots for specific labeling of cellular targets. The strategy is based on the synthesis of oxetane substituted AIEgens to generate compact and ultrastable AIE dots via photo crosslinking. A small amount of polymer enriched with oxetane groups is cocondensed with most of the AIEgens to functionalize the nanodot surface for subsequent streptavidin bioconjugation. Due to their small sizes, good stability, and surface functionalization, the cell-surface markers and subcellular structures are specifically labeled by the AIE dot bioconjugates. Remarkably, stimulated emission depletion imaging with AIE dots is achieved for the first time, and the spatial resolution is significantly enhanced to ~95 nm. This study provides a general approach for small functional molecules for preparing small sized and ultrastable nanodots. PMID- 28898568 TI - Application of Pulse Radiolysis to Mechanistic Investigations of Catalysis Relevant to Artificial Photosynthesis. AB - Taking inspiration from natural photosystems, the goal of artificial photosynthesis is to harness solar energy to convert abundant materials, such as CO2 and H2 O, into solar fuels. Catalysts are required to ensure that the necessary redox half-reactions proceed in the most energy-efficient manner. It is therefore critical to gain a detailed mechanistic understanding of these catalytic reactions to develop new and improved catalysts. Many of the key catalytic intermediates are short-lived transient species, requiring time resolved spectroscopic techniques for their observation. The two main methods for rapidly generating such species on the sub-microsecond timescale are laser flash photolysis and pulse radiolysis. These methods complement one another, and both provide important spectroscopic and kinetic information. However, pulse radiolysis proves to be superior in systems with significant spectroscopic overlap between the photosensitizer and other species present during the reaction. Herein, the pulse radiolysis technique and how it has been applied to mechanistic investigations of halfreactions relevant to artificial photosynthesis are reviewed. PMID- 28898570 TI - Efficient Photocatalytic Hydrogen Evolution via Band Alignment Tailoring: Controllable Transition from Type-I to Type-II. AB - Considering the sizable band gap and wide spectrum response of tin disulfide (SnS2 ), ultrathin SnS2 nanosheets are utilized as solar-driven photocatalyst for water splitting. Designing a heterostructure based on SnS2 is believed to boost their catalytic performance. Unfortunately, it has been quite challenging to explore a material with suitable band alignment using SnS2 nanomaterials for photocatalytic hydrogen generation. Herein, a new strategy is used to systematically tailor the band alignment in SnS2 based heterostructure to realize efficient H2 production under sunlight. A Type-I to Type-II band alignment transition is demonstrated via introducing an interlayer of Ce2 S3 , a potential photocatalyst for H2 evolution, between SnS2 and CeO2 . Subsequently, this heterostructure demonstrates tunability in light absorption, charge transfer kinetics, and material stability. The optimized heterostructure (SnS2 -Ce2 S3 CeO2 ) exhibits an incredibly strong light absorption ranging from deep UV to infrared light. Significantly, it also shows superior hydrogen generation with the rate of 240 umol g-1 h-1 under the illumination of simulated sunlight with a very good stability. PMID- 28898571 TI - Risk factors of post- endoscopic retrograde cholangiopancreatography pancreatitis in biliary type sphincter of Oddi dysfunction in Japanese patients. AB - OBJECTIVE: Suspected sphincter of Oddi dysfunction (SOD) is a well-known risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The indication of ERCP for suspected SOD patients was very low in Japan compared to other countries. Therefore, the risk of PEP may be different in Japanese SOD patients. The objective of this study was to evaluate the risk of PEP in suspected biliary type SOD in Japan. METHODS: From December 1996 to January 2017, 72 patients were suspected as having biliary type SOD, by questionnaire, liver function tests, hepatobiliary scintigraphy, abdominal ultrasonography, upper gastrointestinal endoscopy, endoscopic ultrasonography and magnetic resonance cholangiopancreatography. Finally, 60 patients who underwent ERCP were included in this study, and the factors associated with PEP were evaluated. RESULTS: The overall PEP rate was 23.3% (n = 14). Diagnostic ERCP alone for SOD did not increase the risk of PEP. The correlation of PEP incidence with pancreatic duct guidewire (PGW) technique and endoscopic sphincterotomy (EST) was indicated in univariate and multivariate analysis. Pancreatic stent placement was a risk in univariate analysis but not in multivariate analysis. CONCLUSIONS: PGW technique and EST for biliary type SOD were important risk factors for PEP. Pancreatic stenting was ineffective for prevention of PEP. PMID- 28898569 TI - Altered task-related modulation of long-range connectivity in children with autism. AB - : Functional connectivity differences between children with autism spectrum disorder (ASD) and typically developing children have been described in multiple datasets. However, few studies examine the task-related changes in connectivity in disorder-relevant behavioral paradigms. In this paper, we examined the task related changes in functional connectivity using EEG and a movement-based paradigm that has behavioral relevance to ASD. Resting-state studies motivated our hypothesis that children with ASD would show a decreased magnitude of functional connectivity during the performance of a motor-control task. Contrary to our initial hypothesis, however, we observed that task-related modulation of functional connectivity in children with ASD was in the direction opposite to that of TDs. The task-related connectivity changes were correlated with clinical symptom scores. Our results suggest that children with ASD may have differences in cortical segregation/integration during the performance of a task, and that part of the differences in connectivity modulation may serve as a compensatory mechanism. Autism Res 2018, 11: 245-257. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Decreased connectivity between brain regions is thought to cause the symptoms of autism. Because most of our knowledge comes from data in which children are at rest, we do not know how connectivity changes directly lead to autistic behaviors, such as impaired gestures. When typically developing children produced complex movements, connectivity decreased between brain regions. In children with autism, connectivity increased. It may be that behavior-related changes in brain connectivity are more important than absolute differences in connectivity in autism. PMID- 28898572 TI - Editorial: Ratiometric Optical Imaging of Subclinical Inflammation With a Thrombin-Cleavable Probe: A Future Tool for the In Vivo Visualization of Clinically Silent Synovitis? PMID- 28898573 TI - Alternatives to Autopsy for Fetal and Early Neonatal (Perinatal) Deaths: Insights from the Wisconsin Stillbirth Service Program. AB - BACKGROUND: Although autopsy is a key component of the etiologic evaluation following fetal and early neonatal death, and traditionally has been the preferred method to determine the cause of death, an alternative may be suitable when traditional autopsy by a perinatal pathologist is not available or declined. METHODS: Among 3137 cases evaluated through the Wisconsin Stillbirth Service Program (WiSSP), a community-based program for etiologic evaluation of second trimester miscarriage, stillbirth, and early neonatal death, most diagnoses are based on multiple types of data including placental pathology, clinical examination, photographs, maternal records, radiographs, and laboratory testing. RESULTS: Cases in the WiSSP cohort without autopsy have nearly the same overall rate of diagnosis as those with traditional autopsy (56% vs. 58%). Review of the literature shows that although recent systematic protocols including autopsy, placental pathology and genetic studies yield a definite or probable diagnosis in 70% or more, both healthcare providers and families desire less invasive options. Several minimally invasive protocols substituting imaging, primarily MRI, for traditional autopsy have been proposed, but the numbers of deaths evaluated are still very small. CONCLUSION: We join others who have promoted the benefits of a targeted or less invasive protocol to study perinatal deaths, and emphasize integration of clinical data, selective imaging, genetic testing, and parental counseling. Birth Defects Research 109:1430-1441, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28898574 TI - Integrating kidney transplantation into value-based care for people with renal failure. AB - Healthcare reimbursement is increasingly tied to value instead of volume, with special attention paid to resource-intensive populations such as patients with renal disease. To this end, Medicare has sponsored pilot projects to encourage providers to develop care coordination and population health management strategies to provide quality care while reducing resource utilization. In this Personal Viewpoint essay, we argue in favor of expanding one such pilot project the Comprehensive ESRD Care (CEC) initiative-to include patients with advanced chronic kidney disease and kidney transplant recipients. The implementation of the Medicare Access and CHIP Reauthorization Act (MACRA) offers a time-sensitive incentive for transplant centers in particular to align with extant CECs. An "expanded" CEC model proffers opportunity for robust cooperation between general nephrology practices, dialysis providers, and transplant centers to develop care coordination strategies for all patients with renal disease, realign incentives for all clinical stakeholders to increase kidney transplantation rates, and reduce total costs of care. PMID- 28898576 TI - Low-Temperature Solution Processed Random Silver Nanowire as a Promising Replacement for Indium Tin Oxide. AB - A low-temperature solution-based process for depositing silver nanowire (AgNW) networks for use as transparent conductive top electrode is demonstrated. These AgNWs when applied to Cu2ZnSnS4 solar cells outperformed indium tin oxide as the top electrode. Thinner nanowires allow the use of lower temperatures during processing, while longer wires allow lowered sheet resistance for the same surface coverage of NWs, enhancing the transmittance/conductance trade-off. Conductive atomic force microscopy and percolation theory were used to study the quality of the NW network at the microscale. Our optimized network yielded a sheet resistance of 18 Omega/? and ~95% transmission across the entire wavelength range of interest for a deposition temperature as low as of 60 degrees C. Our results show that AgNWs can be used for low-temperature cell fabrication using cheap solution-based processes that could also be promising for other solar cells constrained to low processing temperatures such as organic and perovskite solar cells. PMID- 28898575 TI - A Green and Sustainable Route to Carbohydrate Vinyl Ethers for Accessing Bioinspired Materials with a Unique Microspherical Morphology. AB - Synthesizing chemicals and materials from renewable sources is one of the main aims of modern science. Carbohydrates represent excellent renewable natural raw materials that are ecofriendly, inexpensive, and biologically compatible. A green procedure has been developed for the vinylation of carbohydrates by using readily available calcium carbide. Various carbohydrates were utilized as starting materials, resulting in mono-, di-, and tetravinyl ethers in high to excellent yields (81-92 %). The synthesized biobased vinyl ethers were utilized as monomers in free radical and cationic polymerizations. A unique combination of a smooth surface and intrinsic microcompartments was achieved in the synthesized materials. Two types of biobased materials were prepared involving microspheres and intrinsic hollow compartments in polymers. Scanning electron microscopy with built-in ion beam cutting was applied to reveal the spatial hierarchical structures in 3D space. PMID- 28898577 TI - Regio- and Diastereoselective Construction of Spirocyclopenteneoxindoles through Phosphine-Catalyzed [3 + 2] Annulation of Methyleneindolinone with Alkynoate Derivatives. AB - A phosphine-catalyzed [3 + 2] annulation of isatin-derived alpha,beta-unsaturated ketones with alkynoates for the synthesis of cyclopentene spiro-oxindole skeletons has been developed. This reaction afforded the desired products in high to excellent yields (up to 99%) with high regioselectivity and moderate to high diastereoselectivities (up to 20:1). This strategy allows facile diastereoselective preparation of biologically important spiro-(cyclopentene) oxindoles containing three contiguous stereocenters, including the quaternary stereogenic center joining the two rings. PMID- 28898578 TI - An Alternatively Packed Dry Molten Globule-like Intermediate in the Native State Ensemble of a Multidomain Protein. AB - It has been difficult to quantify the degree of side-chain conformational heterogeneity in the native (N) state ensemble of proteins and the relative energetic contributions of the side-chain packing and the hydrophobic effect in protein stability. Here, we show using multiple site-specific spectroscopic probes and tools of thermodynamics that the N state ensemble of a multidomain protein contains an equilibrium intermediate (I) whose interdomain region resembles a dry molten globule. In the I state, a tryptophan residue in the interdomain region is alternatively packed, but its secondary structure and intradomain packing are N-like. The I state also has a larger interdomain distance, but the domain-domain interface is dry and molten. Our results indicate that hydrophobic desolvation and side-chain packing are decoupled during protein folding and that interdomain packing interactions have an important energetic contribution in protein stability. Dynamic interconversion between alternatively packed N-like states could be important for multiple allosteric and ligand binding functions of this protein. PMID- 28898579 TI - Identifying the Oscillatory Mechanism of the Glucose Oxidase-Catalase Coupled Enzyme System. AB - We provide experimental evidence of periodic and aperiodic oscillations in an enzymatic system of glucose oxidase-catalase in a continuous-flow stirred reactor coupled by a membrane with a continuous-flow reservoir supplied with hydrogen peroxide. To describe such dynamics, we formulate a detailed mechanism based on partial results in the literature. Finally, we introduce a novel method for estimation of unknown kinetic parameters. The method is based on matching experimental data at an oscillatory instability with stoichiometric constraints of the mechanism formulated by applying the stability theory of reaction networks. This approach has been used to estimate rate coefficients in the catalase part of the mechanism. Remarkably, model simulations show good agreement with the observed oscillatory dynamics, including apparently chaotic intermittent behavior. Our method can be applied to any reaction system with an experimentally observable dynamical instability. PMID- 28898580 TI - Self-Assembled Cu-Sn-S Nanotubes with High (De)Lithiation Performance. AB - Through a gelation-solvothermal method without heteroadditives, Cu-Sn-S composites self-assemble to form nanotubes, sub-nanotubes, and nanoparticles. The nanotubes with a Cu3-4SnS4 core and Cu2SnS3 shell can tolerate long cycles of expansion/contraction upon lithiation/delithiation, retaining a charge capacity of 774 mAh g-1 after 200 cycles with a high initial Coulombic efficiency of 82.5%. The importance of the Cu component for mitigation of the volume expansion and structural evolution upon lithiation is informed by density functional theory calculations. The self-generated template and calculated results can inspire the design of analogous Cu-M-S (M = metal) nanotubes for lithium batteries or other energy storage systems. PMID- 28898581 TI - Trapping and Structural Characterization of the XNO2.NO3- (X = Cl, Br, I) Exit Channel Complexes in the Water-Mediated X- + N2O5 Reactions with Cryogenic Vibrational Spectroscopy. AB - The heterogeneous reaction of N2O5 with sea spray aerosols yields the ClNO2 molecule, which is postulated to occur through water-mediated charge separation into NO3- and NO2+ ions followed by association with Cl-. Here we address an alternative mechanism where the attack by a halide ion can yield XNO2 by direct insertion in the presence of water. This was accomplished by reacting X-(D2O)n (X = Cl, Br, I) cluster ions with N2O5 to produce ions with stoichiometry [XN2O5]-. These species were cooled in a 20 K ion trap and structurally characterized by vibrational spectroscopy using the D2 messenger tagging technique. Analysis of the resulting band patterns with DFT calculations indicates that they all correspond to exit channel ion-molecule complexes based on the association of NO3 with XNO2, with the NO3- constituent increasingly perturbed in the order I > Br > Cl. These results establish that XNO2 can be generated even when more exoergic reaction pathways involving hydrolysis are available and demonstrate the role of the intermediate [XN2O5]- in the formation of XNO2. PMID- 28898582 TI - Spatiotemporal Distribution and Alpine Behavior of Short Chain Chlorinated Paraffins in Air at Shergyla Mountain and Lhasa on the Tibetan Plateau of China. AB - Pristine high-altitude mountains are ideal areas for studying the potential mechanism behind the long-range transport and environmental behavior of persistent organic pollutants in remote areas. Short chain chlorinated paraffins (SCCPs) are the most complex halogenated contaminants in the environment, and have attracted extensive worldwide interest in recent years. In this study, the spatiotemporal concentrations and distributions of SCCPs in air collected from Shergyla Mountain (located in the southeast of the Tibetan Plateau) and Lhasa were investigated during 2012-2015. Generally, the total SCCP levels at Shergyla Mountain and Lhasa were between 130 and 1300 pg/m3 and 1100-14440 pg/m3, respectively. C10 and C11 components were the most abundant homologue groups, indicating that lighter SCCP homologue groups are capable of relatively long range atmospheric transport. Relatively high but insignificant atmospheric SCCP concentrations at Shergyla Mountain area and Lhasa were observed from 2013 to 2015 compared with 2012. At Shergyla Mountain, SCCP concentrations on the eastern and western slopes increased with altitude, implying that "mountain cold trapping" might occur for SCCPs. A back-trajectory model showed that SCCP sources at Shergyla Mountain and Lhasa were primarily influenced by the tropical monsoon from Southwest and South Asia. PMID- 28898583 TI - Electronic Structures of Small (RuO2)n (n = 1-4) Nanoclusters and Their Anions and the Hydrolysis Reactions with Water. AB - Group 8 (RuO2)n (n = 1-4) nanoclusters, their anions, and the hydrolysis reactions of the neutral clusters have been studied with the density functional theory (DFT) as well as coupled cluster CCSD(T) theory. The ground state is predicted to be a singlet and a doublet for the neutral RuO2 clusters and anionic clusters, respectively. The CCSD(T) method is required to predict the correct ground state. The calculated singlet-triplet gaps (<15 kcal/mol) and fluoride affinities (<95 kcal/mol) are smaller than those of the group 4 (MO2)n and group 6 (MO3)n metal oxide clusters. The electron affinities range from 2.2 to 3.4 eV, showing that the RuO2 clusters are quite reducible. Clustering energies and heats of formation are calculated. The water physisorption energies are predicted to be -10 to -20 kcal/mol with the adsorption energy for the singlet being generally more exothermic than that for the triplet. The hydrolysis reactions are exothermic for the monomer and dimer clusters and are slightly endothermic or neutral for the trimer and tetramer. H2O is readily dissociated on the monomer and dimer but not on the trimer and tetramer. The physisorption and chemisorption energies are less exothermic, and the barriers for the hydrolysis reactions are larger for RuO2 nanoclusters than for the corresponding group 4 ZrO2 nanoclusters. PMID- 28898584 TI - In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance. AB - Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir oral products including the tablet, powder, and solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of liquid-liquid phase separation (LLPS) in biorelevant dissolution media. Higher, stable apparent RTV concentrations were observed in the FeSSIF-V2 as compared to those in the FaSSIF-V2, which suggested a food effect with higher exposure in the fed state. This is inconsistent with the evaluation in vivo. The biphasic test revealed significantly lower degrees of supersaturation of RTV in the aqueous media from these dosage forms as compared to results of the two-stage dissolution test. RTV concentrations in octanol at 6 h obtained from the tablet and powder with the use of the biorelevant media are consistent with corresponding in vivo AUC and Cmax under the fasting and moderate fat fed (MFF) states and predict the food effect. The underlying mechanisms responsible for the food effect are also proposed. Fractional partition profiles of RTV obtained in octanol from these three Norvir oral products are in agreement with the corresponding fractional absorption profiles in vivo under both the fasting and MFF states. This study reveals a complex interplay among the dissolution, precipitation, and partition processes from these formulations that dictate the oral exposure of RTV. PMID- 28898585 TI - Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors. AB - Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum-associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators. PMID- 28898587 TI - The antioxidant and antiapoptotic effect of boric acid on hepatoxicity in chronic alcohol-fed rats. AB - The harmful use of alcohol is a worldwide problem involving all ages. This study aims to investigate chronic alcohol exposure related hepatotoxicity on the rat liver and possible hepatoprotective effects of boric acid. Rats were separated into 4 different groups: control, ethanol, ethanol+boric acid, and boric acid. We measured (i) malondialdehyde (MDA), total sialic acid (TSA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels, which are known to be the markers of alcohol damage; and also (ii) caspase-3, tumor necrosis factor-alpha (TNF-alpha), and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) as the markers of apoptosis. In the ethanol group, MDA, TSA, and TNF-alpha levels increased whereas SOD and CAT levels decreased compared with the control group. Ethanol+boric acid group MDA, TSA, caspase-3, and TNF-alpha levels decreased whereas SOD and CAT levels increased compared with the ethanol group. Using histopathological evaluation of light microscope images, immunohistochemical caspase-3 and TNF-alpha activity in the ethanol+boric acid group were shown to be decreased compared with that in the ethanol group. Our results revealed that ethanol is capable of triggering oxidative stress and apoptosis in the rat liver. We propose that boric acid is an effective compound in protecting the rat liver against ethanol. PMID- 28898586 TI - Transcerebral net exchange of vasoactive peptides and catecholamines during lipopolysaccharide-induced systemic inflammation in healthy humans. AB - The systemic inflammatory response triggered by lipopolysaccharide (LPS) is associated with cerebral vasoconstriction, but the underlying mechanisms are unknown. We therefore examined whether a 4-hour intravenous LPS infusion (0.3 ng.kg-1) induces any changes in the transcerebral net exchange of the vasoactive peptides endothelin-1 (ET-1) and calcitonin-gene related peptide (CGRP) and catecholamines in human volunteers. Cerebral blood flow was measured by the Kety Schmidt technique, and paired arterial-to-jugular venous blood samples were obtained for estimating the transcerebral exchange of ET-1, CGRP, and catecholamines by the Fick principle in 12 volunteers before and after LPS infusion. The cerebrovascular release of ET-1 was enhanced, whereas the transcerebral net exchange of CGRP and catecholamines was unaffected. Our findings thus point towards locally produced ET-1 within the cerebrovasculature as a contributor to cerebral vasoconstriction after LPS infusion. PMID- 28898588 TI - MicroRNAs in the pathogenesis of type 2 diabetes: new research progress and future direction. AB - miRNA is a short non-coding RNA that can influence mRNA processing at the post transcriptional level. A large number of miRNAs have been found in virtually all species so far, and these small molecules play an important role in many different physiological processes and various pathologic conditions, such as cell metabolism, cancer, autoimmune disease, and diabetes mellitus. T2D arises from a dysregulated response to the elevated glucose level in the circulation. The prevalence of T2D has increased dramatically in all age groups, and T2D in older adults is associated with more T2D complications and higher mortality. Despite the existing findings describing the pathological mechanism, T2D pathology is more complex and the pathophysiology of the disease is still not fully elucidated. In this review, we summarize the current understanding of miRNA mediated modulation of gene expression in T2D pathogenesis, as well as related signaling pathways, and insight into the important role of miRNA in various T2D complications. Furthermore, the potential therapeutic value of miRNA for T2D patients is also discussed in detail. PMID- 28898589 TI - Science of Biosimilars. AB - Biosimilar therapeutic proteins in oncology offer the potential to decrease costs while providing safety and efficacy profiles consistent with their respective reference or originator products. Biosimilars have a number of important differences from generic small-molecule drugs, including manufacturing processes that are unique from their reference products. These differences may affect biosimilars through posttranslational modifications that can occur in specific cellular production lines, and these modifications have potential effects on protein structure, function, clinical pharmacology, and immunogenicity. Regulatory agencies expect these differences to be identified, analyzed, and minimized through iterative processes and extensive preclinical efforts. Generic naming of biosimilars reflects the nonproprietary reference product name along with a meaningless four-letter suffix to ensure that each product can be uniquely identified for prescribing and pharmacovigilance purposes. Labeling information for biosimilars reflects a greater detail of comparisons to reference products than conventional generic drugs, which ensures that prescribers can understand the source of information and have a complete understanding of the therapeutic profile of each biosimilar agent. Postmarketing surveillance programs will be required to evolve and ensure optimal pharmacovigilance reporting, because the potential for unexpected adverse events with biosimilars is higher than with conventional generic agents as a result of different manufacturing processes and different clinical trial designs and durations. The existing filgrastim biosimilars are likely to be joined soon by therapeutic monoclonal antibodies, including rituximab, trastuzumab, and bevacizumab, on the basis of patent expiration dates and clinical trial results. PMID- 28898591 TI - Emerging Opportunities and Challenges of Biosimilars in Oncology Practice. PMID- 28898590 TI - Biosimilars: Reimbursement Issues in Your Oncology Practice. PMID- 28898592 TI - When One Is a Hammer, Everything Looks Like a Nail. PMID- 28898593 TI - Biosimilars: Implications for Clinical Practice. AB - In 2015, the United States Food and Drug Administration (FDA) approved the first biosimilar, filgrastim-sndz, a biosimilar of the granulocyte colony-stimulating factor filgrastim. Since that time, the FDA has approved four additional biosimilar tumor necrosis factor alpha inhibitors, and, in May 2017, the Oncology Drug Advisory Committee voted in favor of approval of an epoetin alfa biosimilar. The patents of several widely used biologic cancer therapies (including trastuzumab, rituximab, bevacizumab, cetuximab, and pegfilgrastim) are recently expired or due to expire in the near future, so the introduction of biosimilars into the oncology treatment armamentarium is imminent. However, their arrival also will introduce challenges, including pharmacy and supply chain management and the need for education of clinicians and patients about the efficacy and safety of these agents. These considerations, along with an overview of biosimilars in the oncology pipeline, will be discussed in this review. PMID- 28898594 TI - European Perspective on Biosimilars. PMID- 28898595 TI - Hematological Analysis of the Ascidian Botrylloides leachii (Savigny, 1816) During Whole-Body Regeneration. AB - Whole-body regeneration (WBR)-the formation of an entire adult from only a small fragment of its own tissue-is extremely rare among chordates. Exceptionally, in the colonial ascidian Botrylloides leachii (Savigny, 1816) a fully functional adult is formed from their common vascular system after ablation of all adults from the colony in just 10 d, thanks to their high blastogenetic potential. While previous studies have identified key genetic markers and morphological changes, no study has yet focused on the hematological aspects of regeneration despite the major involvement of the remaining vascular system and the contained hemocytes in this process. To dissect this process, we analyzed colony blood flow patterns using time-lapse microscopy to obtain a quantitative description of the velocity, reversal pattern, and average distance traveled by hemocytes. We also observed that flows present during regeneration are powered by temporally and spatially synchronized contractions of the terminal ampullae. In addition, we revised previous studies of B. leachii hematology as well as asexual development using histological sectioning and compared the role played by hemocytes during WBR. We found that regeneration starts with a rapid healing response characterized by hemocyte aggregation and infiltration of immunocytes, followed by increased activity of hemoblasts, recruitment of macrophage-like cells for clearing the tissues of debris, and their subsequent disappearance from the circulation concomitant with the maturation of a single regenerated adult. Overall, we provide a detailed account of the hematological properties of regenerating B. leachii colonies, providing novel lines of inquiry toward the decipherment of regeneration in chordates. PMID- 28898596 TI - Erratum: The Biological Bulletin, Volume 232, Number 1, pp. 19-29. PMID- 28898598 TI - Crossing the Divide: Admixture Across the Antarctic Polar Front Revealed by the Brittle Star Astrotoma agassizii. AB - The Antarctic Polar Front (APF) is one of the most well-defined and persistent oceanographic features on the planet and serves as a barrier to dispersal between the Southern Ocean and lower latitudes. High levels of endemism in the Southern Ocean have been attributed to this barrier, whereas the accompanying Antarctic Circumpolar Current (ACC) likely promotes west-to-east dispersal. Previous phylogeographic work on the brittle star Astrotoma agassizii Lyman, 1875 based on mitochondrial genes suggested isolation across the APF, even though populations in both South American waters and the Southern Ocean are morphologically indistinguishable. Here, we revisit this finding using a high-resolution 2b-RAD (restriction-site-associated DNA) single-nucleotide polymorphism (SNP)-based approach, in addition to enlarged mitochondrial DNA data sets (16S rDNA, COI, and COII), for comparison to previous work. In total, 955 biallelic SNP loci confirmed the existence of strongly divergent populations on either side of the Drake Passage. Interestingly, genetic admixture was detected between South America and the Southern Ocean in five individuals on both sides of the APF, revealing evidence of recent or ongoing genetic contact. We also identified two differentiated populations on the Patagonian Shelf with six admixed individuals from these two populations. These findings suggest that the APF is a strong but imperfect barrier. Fluctuations in location and strength of the APF and ACC due to climate shifts may have profound consequences for levels of admixture or endemism in this region of the world. PMID- 28898599 TI - Transcriptomic Basis of Metamorphic Competence in the Salt-Marsh-Dwelling Polychaete Capitella teleta. AB - Marine invertebrate larvae typically take hours to weeks after being released into the plankton before becoming "competent" to metamorphose. The mechanisms that govern this transition between the precompetent and metamorphically competent states are unknown. We studied gene expression patterns in precompetent and competent larvae of the salt-marsh-dwelling polychaete worm Capitella teleta (Blake, Grassle & Eckelbarger, 2009)-a species in which precompetent larvae are unusually easy to distinguish from competent larvae-to determine differences in gene expression associated with the onset of metamorphic competence. More than 1530 genes were more highly expressed in precompetent larvae, while more than 1060 genes were more highly expressed in competent larvae. Competent larvae downregulated the expression of genes belonging to gene ontologies relating to growth and development and upregulated those associated with ligand-binding transmembrane channels with possible chemo- and mechanosensory functions. Most of these channels were annotated as being from the degenerin/epithelial sodium channel family or the G-protein-coupled receptor family; proteins from these families can have chemosensory functions. Serotonin and GABA (gamma-aminobutyric acid) receptors are among the genes that were upregulated in competent larvae; both have been shown to induce larvae of C. teleta and other marine invertebrates to metamorphose and are thought to be components of the signal transduction pathway that leads to metamorphosis. Overall, it appears that once larvae of C. teleta have completed development of the internal structures and physiology required for juvenile life during the precompetent period, they then upregulate the expression of chemosensory proteins and neurotransmitter receptors that will enable them to detect and transduce a settlement cue signal. PMID- 28898600 TI - Rapid Associative Learning and Stable Long-Term Memory in the Squid Euprymna scolopes. AB - Learning and memory in cephalopod molluscs have received intensive study because of cephalopods' complex behavioral repertoire and relatively accessible nervous systems. While most of this research has been conducted using octopus and cuttlefish species, there has been relatively little work on squid. Euprymna scolopes Berry, 1913, a sepiolid squid, is a promising model for further exploration of cephalopod cognition. These small squid have been studied in detail for their symbiotic relationship with bioluminescent bacteria, and their short generation time and successful captive breeding through multiple generations make them appealing models for neurobiological research. However, little is known about their behavior or cognitive ability. Using the well established "prawn-in-the-tube" assay of learning and memory, we show that within a single 10-min trial E. scolopes learns to inhibit its predatory behavior, and after three trials it can retain this memory for at least 12 d. Rapid learning and very long-term retention were apparent under two different training schedules. To our knowledge, this study is the first demonstration of learning and memory in this species as well as the first demonstration of associative learning in any squid. PMID- 28898601 TI - Characterization of the Gray Whale Eschrichtius robustus Genome and a Genotyping Array Based on Single-Nucleotide Polymorphisms in Candidate Genes. AB - Genetic and genomic approaches have much to offer in terms of ecology, evolution, and conservation. To better understand the biology of the gray whale Eschrichtius robustus (Lilljeborg, 1861), we sequenced the genome and produced an assembly that contains ~95% of the genes known to be highly conserved among eukaryotes. From this assembly, we annotated 22,711 genes and identified 2,057,254 single nucleotide polymorphisms (SNPs). Using this assembly, we generated a curated list of candidate genes potentially subject to strong natural selection, including genes associated with osmoregulation, oxygen binding and delivery, and other aspects of marine life. From these candidate genes, we queried 92 autosomal protein-coding markers with a panel of 96 SNPs that also included 2 sexing and 2 mitochondrial markers. Genotyping error rates, calculated across loci and across 69 intentional replicate samples, were low (0.021%), and observed heterozygosity was 0.33 averaged over all autosomal markers. This level of variability provides substantial discriminatory power across loci (mean probability of identity of 1.6 * 10-25 and mean probability of exclusion >0.999 with neither parent known), indicating that these markers provide a powerful means to assess parentage and relatedness in gray whales. We found 29 unique multilocus genotypes represented among our 36 biopsies (indicating that we inadvertently sampled 7 whales twice). In total, we compiled an individual data set of 28 western gray whales (WGSs) and 1 presumptive eastern gray whale (EGW). The lone EGW we sampled was no more or less related to the WGWs than expected by chance alone. The gray whale genomes reported here will enable comparative studies of natural selection in cetaceans, and the SNP markers should be highly informative for future studies of gray whale evolution, population structure, demography, and relatedness. PMID- 28898602 TI - Parallel Patterns of Host-Specific Morphology and Genetic Admixture in Sister Lineages of a Commensal Barnacle. AB - Symbiotic relationships are often species specific, allowing symbionts to adapt to their host environments. Host generalists, on the other hand, have to cope with diverse environments. One coping strategy is phenotypic plasticity, defined by the presence of host-specific phenotypes in the absence of genetic differentiation. Recent work indicates that such host-specific phenotypic plasticity is present in the West Pacific lineage of the commensal barnacle Chelonibia testudinaria (Linnaeus, 1758). We investigated genetic and morphological host-specific structure in the genetically distinct Atlantic sister lineage of C. testudinaria. We collected adult C. testudinaria from loggerhead sea turtles, horseshoe crabs, and blue crabs along the eastern U.S. coast between Delaware and Florida and in the Gulf of Mexico off Mississippi. We find that shell morphology, especially shell thickness, is host specific and comparable in similar host species between the Atlantic and West Pacific lineages. We did not detect significant genetic differentiation related to host species when analyzing data from 11 nuclear microsatellite loci and mitochondrial sequence data, which is comparable to findings for the Pacific lineage. The most parsimonious explanation for these parallel patterns between distinct lineages of C. testudinaria is that C. testudinaria maintained phenotypic plasticity since the lineages diverged 4-5 mya. PMID- 28898603 TI - Strange Bedfellows No More: How Integrated Stem-Cell Transplantation and Palliative Care Programs Can Together Improve End-of-Life Care. AB - In the intense, cure-oriented setting of hematopoietic stem-cell transplantation (HSCT), delivery of high-quality palliative and end-of-life care is a unique challenge. Although HSCT affords patients a chance for cure, it carries a significant risk of morbidity and mortality. During HSCT, patients usually experience high symptom burden and a significant decrease in quality of life that can persist for long periods. When morbidity is high and the chance of cure remote, the tendency after HSCT is to continue intensive medical interventions with curative intent. The nature of the complications and overall condition of some patients may render survival an unrealistic goal and, as such, continuation of artificial life-sustaining measures in these patients may prolong suffering and preclude patient and family preparation for end of life. Palliative care focuses on the well-being of patients with life-threatening conditions and their families, irrespective of the goals of care or anticipated outcome. Although not inherently at odds with HSCT, palliative care historically has been rarely offered to HSCT recipients. Recent evidence suggests that HSCT recipients would benefit from collaborative efforts between HSCT and palliative care services, particularly when initiated early in the transplantation course. We review palliative and end-of-life care in HSCT and present models for integrating palliative care into HSCT care. With open communication, respect for roles, and a spirit of collaboration, HSCT and palliative care can effectively join forces to provide high-quality, multidisciplinary care for these highly vulnerable patients and their families. PMID- 28898604 TI - The TEAM Approach: Mistaking Artifact for Art? PMID- 28898605 TI - The TEAM Approach to Improving Oncology Outcomes by Incorporating Palliative Care in Practice. AB - Palliative care (PC) concurrent with usual oncology care is now the standard of care that is recommended for any patient with advanced cancer to begin within 8 weeks of diagnosis on the basis of evidence-driven national clinical practice guidelines; however, there are not enough interdisciplinary palliative care teams to provide such care. How and what can an oncology office incorporate into usual care, borrowing the tools used in PC randomized clinical trials (RCTs), to improve care for patients and their caregivers? We reviewed the multiple RCTs for common practical elements and identified methods and techniques that oncologists can use to deliver some parts of concurrent interdisciplinary PC. We recommend the standardized assessment of patient-reported outcomes, including the evaluation of symptoms with such tools as the Edmonton or Memorial Symptom Assessment Scales, spirituality with the FICA Spiritual History Tool or similar questions, and psychosocial distress with the Distress Thermometer. All patients should be assessed for how they prefer to receive information, their current understanding of their situation, and if they have considered some advance care planning. Approximately 1 hour of additional time with the patient is required each month. If the oncologist does not have established ties with spiritual care and social work, he or she should establish these relationships for counseling as required. Caregivers should be asked about coping and support needs. Oncologists can adapt PC techniques to achieve results that are similar to those in the RCTs of PC plus usual care compared with usual care alone. This is comparable to using data from RCTs of trastuzamab or placebo, adopting what was used in the RCTs without modification or dilution. PMID- 28898606 TI - Palliative Care Integration in Hematopoietic Stem-Cell Transplantation: The Need for Additional Research. PMID- 28898607 TI - [Diabetes in Coronary Disease: The Risk of Non-Diagnosis]. PMID- 28898608 TI - [Health Governance and Proximity Management: The Need for Autonomy in Management in Primary Health Care Systems]. PMID- 28898609 TI - [Diabetes Screening in Patients with Macrovascular Coronary Disease: Are the New European Guidelines a Step Backwards?] AB - BACKGROUND: The new European guidelines on diabetes mellitus and cardiovascular diseases propose that the FINnish Diabetes RIsk SCore should be used to evaluate the risk of diabetes mellitus and that diabetes mellitus screening in coronary artery disease patients should be based on fasting glucose and HbA1c. The 2 hour oral glucose tolerance test, recommended for all pts in the previous guidelines, is now only recommended for 'inconclusive' cases. We aimed to evaluate this new strategy. MATERIAL AND METHODS: Fasting glucose, HbA1c and glucose tolerance test (75 g, 2h) were prospectively evaluated in a consecutive group of pts with coronary artery disease. ADA criteria (both glucose tolerance test and HbA1c) were used to define diabetes mellitus and pre-diabetes mellitus. Diabetes mellitus risk was evaluated according to the FINnish Diabetes RIsk SCore. RESULTS: A total of 135 patients were included (mean age 62.3 +/- 13.1 years, 99 males). Glucose tolerance test and HbA1c together diagnosed 18 (13.3%) new cases of diabetes mellitus and 77 (57.0%) patients with pre-diabetes mellitus. Fasting glucose + HbA1c (guidelines strategy) identified 12/18 patients with diabetes mellitus (Sens 66.7%; negative predictive value 95.1%; Kappa 0.78; p < 0.0001) and 83/95 patients with glucose anomalies (pre- diabetes mellitus + diabetes mellitus) (Sens 87.4%; negative predictive value 76.9%). Performing glucose tolerance test in the 29 patients with an elevated FINnish Diabetes RIsk SCore would allow identifying 15/18 patients with diabetes mellitus (Sens 83.3%; negative predictive value 97.5%; Kappa 0.85; p < 0.0001) and 86/95 patients with glucose anomalies (Sens 90.5%; negative predictive value 81.6%). DISCUSSION: Although this strategy improved the screening accuracy, one in each six patients with diabetes mellitus would still remain undiagnosed, as compared to measuring HbA1c and performing an glucose tolerance test in all patients. CONCLUSION: Using the FINnish Diabetes RIsk SCore to select candidates to additional glucose tolerance test improves the accuracy for identifying diabetic patients, as compared with fasting glucose + HbA1c alone. However, 1/6 patients diabetes mellitus is still left undiagnosed with this strategy proposed by the current guidelines. PMID- 28898610 TI - [Visceral Leishmaniasis in HIV-Infected Patients: The Challenge of Relapse and Treatment Failure]. AB - INTRODUCTION: Visceral leishmaniasis is an endemic disseminated infection, considered to be the third most frequent opportunistic parasitic infection in Europe. It is especially prevalent in patients co-infected with human immunodeficiency virus, in whom it poses a great therapeutic challenge due to increased risk of relapse. The goal of this study is to characterize a population of co-infected patients, as well as the efficiency of the adopted treatment strategies. MATERIAL AND METHODS: Retrospective study with a sample composed of all patients with visceral leishmaniasis and human immunodeficiency virus admitted in an Infectious Diseases ward over a period of 10 years. RESULTS: Of the 23 enrolled patients, two were female (8.7%). The mean TCD4+ cell count was 104.4 cells/uL (+/- 120.3cells/uL), only two patients had undetectable viral load (< 20 copies/mL) and 16 (69.6%) were not under antiretroviral therapy at the time of diagnosis. Treatment-wise, liposomal amphotericin B was used in 18 patients, meglumine antimoniate in four and miltefosine in one. Fourteen (60.9%) were adherent to secondary prophylaxis protocol. A relapse rate of 26.1% was observed (six patients). DISCUSSION: Co-infection is responsible for higher treatment failure rates and more relapses. TCD4+ cell count is the main predictive factor of relapse, and strict adherence to chemoprophylaxis protocols unequivocally results in a reduction of relapse rate. Combined treatment strategies using liposomal amphotericin B and miltefosine yield fewer therapeutic failures than the classic approach. CONCLUSION: We therefore conclude that alternative, combined therapeutic protocols seem to be a viable solution for these patients. PMID- 28898611 TI - A Retrospective Analysis of the Real-Life Utilization of Ranibizumab in Patients with Wet Age-Related Macular Degeneration from Portugal. AB - INTRODUCTION: Anti-vascular endothelial growth factor therapy has revolutionized the treatment of wet age-related macular degeneration; however, it is important to monitor actual use of ranibizumab and related treatment outcomes in routine practice. MATERIAL AND METHODS: This was a retrospective, observational study to monitor the 2-year outcomes following ranibizumab treatment for wet age-related macular degeneration in Portugal. Patients treated between January 2009 and December 2009 were retrospectively evaluated. All decisions were made by the treating physician in accordance with their usual routine clinical practice. The primary assessment was mean change in visual acuity score using Early Treatment Diabetic Retinopathy Study or Snellen equivalent. RESULTS: A total of 128 patients with wet age-related macular degeneration were analyzed (mean age 79.4 years; mean visual acuity score 54.2 letters). Mean change in visual acuity score from baseline was -1.6 letters (n = 82) at year one and -5.1 letters (n = 72) at year two. The mean number of ranibizumab injections was 3.8 (year one) and 1.6 (year two). On average, patients attended 8.6 and 5.0 visits and optical coherence tomography was used in 75.0% of patients in year one and in 56.3% of patients in year two, respectively. DISCUSSION: Despite a relatively high number of visits, including monitoring visits and use of optical coherence tomography - guided therapy, few injections were administered and visual acuity was not improved. CONCLUSION: These findings indicate that as-needed treatment resulted in under-dosing in a real-life setting in Portugal. Such limitations may also be related to increasing numbers of patients, resulting in clinic saturation. PMID- 28898612 TI - [Paediatric Invasive Pneumococcal Disease Before Universal Vaccination: 1995 - 2015]. AB - INTRODUCTION: Pneumococcal conjugate vaccine was introduced in the private market in Portugal in 2001, reaching over the years a moderately high coverage. In July 2015, it was included in the National Immunisation Program. The aim of this study was to characterize invasive pneumococcal disease in a pediatric hospital before universal use of the vaccine. MATERIAL AND METHODS: Retrospective analysis of medical records of all children with Streptococcus pneumoniae identified by culture and/or molecular biology (available since 2008), in products obtained from sterile sites, from January 1995 to June 2015. We evaluated demographic, clinical and microbiological data. Serotype results are available since 2004. RESULTS: Over those 20 years, 112 invasive pneumococcal disease cases were identified, with a median age of 15 months (1 month - 15 years). The median number of cases /year was 4, the highest between 2001 - 2002 (8/year) and 2007 - 2012 (7 - 11/year). The identification occurred mostly in blood culture (72), cerebrospinal fluid (24), pleural fluid (11) an others (5). The most frequent diagnoses were pneumonia (38%), occult bacteraemia (34%) and meningitis (21%). Over the period under review, there was an increase of pneumonia and slight increase of OB, with meningitis cases remaining relatively unchanged. DISCUSSION: In the last two decades, there was no reduction in the number of cases of invasive pneumococcal disease. There was an increase in isolates from pneumonia and occult bacteraemia that might be due to the introduction of molecular biological methods for Streptococcus pneumoniae detection. Vaccine serotypes were predominant. CONCLUSION: This retrospective analysis before universal vaccination will contribute to evaluate the impact of vaccination in the Portuguese pediatric population. PMID- 28898613 TI - Functional, Sensorial, Mobility and Communication Difficulties in the Portuguese Oldest Old (80+). AB - INTRODUCTION: The ageing of populations is evident in most developed countries, and the oldest old group is one of the segments with the fastest growing. The aim of this paper is to examine sociodemographic and health related characteristics of the portuguese oldest old, using a census-based approach. MATERIAL AND METHODS: A descriptive study considering all residents aged 80 years and older at the time of the 2011 Census (n = 532 219) was conducted. Information on sociodemographic characteristics, sensory functions (seeing, hearing), functional status (walking/climbing stairs, bathing/dressing alone), cognition (memory/concentration), and communication (understanding others/being understood) as assessed by the Portuguese census official questionnaires were analyzed. RESULTS: Findings revealed that most of the oldest old are women (64.5%), widowed (53.9%), illiterate (46.1%) and live in private households (88.8%). Walking/climbing stairs (57.1%), vision (39.1%) and hearing (35.1%) were the dimensions where the oldest old presented major constrains. In parallel, understanding others/being understood (25.9%) and memory/concentration (34.4%) were the dimensions with lower percentages of difficulties. Significant differences were found between octogenarians/nonagenarians and centenarians for vision, walk/climb stairs, and bathing/dressing alone, with centenarians presenting a higher percentage of difficulties. DISCUSSION: Portuguese oldest old showed significant difficulties in activities of daily living, nevertheless cognitive and communication capacities seem to be commonly maintained. Taken together, these findings suggest the need for functional assistance, which can be ultimately managed by the older person him/herself. CONCLUSION: Based on the observed differences between centenarians and younger oldest old, specific interventions should be equated to better respond to their potentially distinctive needs. PMID- 28898614 TI - [Fine-needle Aspiration of Thyroid Nodules: Is it Worth Repeating?] AB - INTRODUCTION: The fine-needle aspiration has a significant role in assessing the malignancy risk of thyroid nodules. There is uncertainty regarding the value of repeat fine-needle aspiration in benign nodules. This study aims to evaluate the concordance of results in consecutive fine-needle aspiration and to study the relevance of repetition in benign results. MATERIAL AND METHODS: Retrospective study of the 4800 thyroid nodules fine-needle aspiration held in Instituto de Patologia e Imunologia Molecular da Universidade do Porto between January 1, 2014 and May 2, 2016. Of the initial sample, we selected the repeated fine-needle aspiration on the same nodule. RESULTS: The first fine-needle aspiration result of the 309 nodules underwent revaluation was non-diagnostic in 103 (33.3%), benign in 120 (38.8%) and atypia/follicular lesion of undetermined significance in 86 (27.8%). The agreement between the first and second fine-needle aspiration was significantly higher in cases with an initial benign result (benign: 85.8%, non-diagnostic: 27.2% and atypia/follicular lesion of undetermined significance: 17.4%, p < 0.005). The fine-needle aspiration repeating motifs in initially benign nodules (n = 78) were repetition suggestion in 58, nodule growth in 17 and suspicious ultrasonographic features in 3. DISCUSSION: The fine-needle aspiration repetition in nodules with initial non-diagnostic and atypia/follicular lesion of undetermined significance result changed the initial diagnosis in a significant proportion of patients, modifying their therapeutic approach. The high concordance of results in initially benign nodules makes fine-needle aspiration repetition not cost-effective in most cases. CONCLUSION: The fine-needle aspiration should be repeated when the initial cytology result is non-diagnostic or atypia/follicular lesion of undetermined significance. PMID- 28898615 TI - Breech Presentation: Vaginal Versus Cesarean Delivery, Which Intervention Leads to the Best Outcomes? AB - INTRODUCTION: The best route of delivery for the term breech fetus is still controversial. We aim to compare maternal and neonatal outcomes between vaginal and cesarean term breech deliveries. MATERIAL AND METHODS: Multicentric retrospective cohort study of singleton term breech fetuses delivered vaginally or by elective cesarean section from January 2012 - October 2014. Primary outcomes were maternal and neonatal morbidity or mortality. RESULTS: Sixty five breech fetuses delivered vaginally were compared to 1262 delivered by elective cesarean. Nulliparous women were more common in the elective cesarean group (69.3% vs 24.6%; p < 0.0001). Gestational age at birth was significantly lower in the vaginal delivery group (38 +/- 1 weeks vs 39 +/- 0.8 weeks; p = 0.0029) as was birth weight (2928 +/- 48.4 g vs 3168 +/- 11.3 g; p < 0.0001). Apgar scores below seven on the first and fifth minutes were more likely in the vaginal delivery group (1st minute: 18.5% vs 5.9%; p = 0.0006; OR 3.6 [1.9 - 7.0]; 5th minute: 3.1% vs 0.2%; p = 0.0133; OR 20.0 [2.8 - 144.4]), as was fetal trauma (3.1% vs 0.3%: p = 0.031; OR 9.9 [1.8-55.6]). Neither group had cases of fetal acidemia. Admission to the Neonatal Intensive Care Unit, maternal postpartum hemorrhage and the incidence of other obstetric complications were similar between groups. DISCUSSION: Although vaginal breech delivery was associated with lower Apgar scores and higher incidence of fetal trauma, overall rates of such events were low. Admission to the neonatal intensive care unit and maternal outcomes were similar. CONCLUSION: Both delivery routes seem equally valid, neither posing high maternal or neonatal complications' incidence. PMID- 28898616 TI - The Calcium/Phosphorus Homeostasis in Chronic Kidney Disease: From Clinical Epidemiology to Pathophysiology. AB - INTRODUCTION: A simple data filtering process together with some basic concepts of control theory applied to electronically stored clinical data were used to identify some of the pathophysiological mechanisms underlying the perturbations of the calcium/phosphorus homeostasis in chronic kidney disease. MATERIAL AND METHODS: Retrospective data (a set per patient of serum single value concentrations of creatinine, calcium, phosphorus, parathormone, 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D) from 2507 patients with stable chronic kidney disease not on renal replacement therapy were studied. The variables were paired and subjected sequentially to a moving average and partioned into frequency classes. The plots were interpreted using the concept of a feedback loop comprising two branches of opposite sign and of set point of the loop. The set point for each pair of variables is displaced in the course of the disease and this displacement indicates which of the two factors involved (the serum concentrations of calcium or parathormone, for example) is primarily affected. RESULTS: This analysis showed that in the course of the development of chronic kidney disease the relationships between the observed variables progressed following a monotonous, a biphasic or a triphasic pattern. DISCUSSION: As chronic kidney disease progresses, calcium/phosphorus metabolism regulation evolves through different phases. Later, there is a progressive loss of the parathyroid gland sensitivity to the control by the serum concentrations of calcium and phosphorus. The sensitivity to the inhibitory action of 1,25 dihydroxyvitamin D decreases monotonously but never releases the gland. CONCLUSION: The clinical data analysis used permits to illustrate the underlying pathophysiological mechanisms. PMID- 28898617 TI - [Secondary Arterial Hypertension: Uncertainties in Diagnosis]. AB - Arterial hypertension is regarded today as a global public health problem, and the prevalence rate in Portugal is 26.9%. According to the etiology, is classified into primary or secondary arterial hypertension. In about 90% of cases it is not possible to establish a cause, so is called primary arterial hypertension. In the remaining 5 to 10%, it can be identified secondary causes, which are potentially treatable. For secondary arterial hypertension study to be cost-effective, it is essential to understand which patients investigate, and evaluate the best strategy to adopt. The main causes identified as responsible for secondary arterial hypertension are: kidney disease; endocrine and vascular diseases and obstructive sleep apnea. Among these some are consensual, and others more controversial in the literature. In this regard we present two cases of arterial hypertension, which are potentially secondary in etiology, but still focus of debate. PMID- 28898618 TI - [Klebsiella pneumoniae from K1 and Hypervirulent Clone ST23: First Documented Case in Portugal]. AB - The hypervirulent K1 serotype Klebsiella pneumoniae is responsible for a new invasive syndrome, typically associated to hepatic abscesses with extra-hepatic complications. Initially described in Taiwan, it has significantly spread to several Asian countries and more recently to Europe and North America, thus constituting an emerging and global problem. The authors describe a case report of a 64-years-old portuguese caucasian woman without any previous diseases or epidemiological risk factors such as trips or contact with Asian products or population, diagnosed with a pyogenic liver abscess with pleural effusion caused by this hyper-virulent strain. A successful clinical cure was achieved after the etiological identification and treatment with antimicrobial therapy combined with catheter drainage. This is the first identification of hypervirulent Klebsiella pneumonia ST 23 clone in Portugal in the context of an invasive syndrome. PMID- 28898619 TI - Target Sign: Endoscopic Sign of the Colonic Perforation. PMID- 28898620 TI - [Fatal Hemoptysis]. PMID- 28898622 TI - Tensin-4-Dependent MET Stabilization Is Essential for Survival and Proliferation in Carcinoma Cells. PMID- 28898621 TI - [Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar Sao Joao, Portugal]. AB - In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar Sao Joao, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality. PMID- 28898623 TI - The Stimulus Selectivity and Connectivity of Layer Six Principal Cells Reveals Cortical Microcircuits Underlying Visual Processing. PMID- 28898624 TI - Effects of Cortical Microstimulation on Confidence in a Perceptual Decision. PMID- 28898626 TI - Molecular Architecture of the 40S?eIF1?eIF3 Translation Initiation Complex. PMID- 28898625 TI - Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS. PMID- 28898627 TI - ATRX Directs Binding of PRC2 to Xist RNA and Polycomb Targets. PMID- 28898628 TI - The Genetics of Major Depression. PMID- 28898629 TI - Cingulate-Hippocampus Coherence and Trajectory Coding in a Sequential Choice Task. PMID- 28898631 TI - Neuronal Machinery of Sleep Homeostasis in Drosophila. PMID- 28898630 TI - Retraction Notice to: Dystroglycan and Perlecan Provide a Basal Cue Required for Epithelial Polarity during Energetic Stress. PMID- 28898632 TI - Astrocyte-Derived Endothelin-1 Inhibits Remyelination through Notch Activation. PMID- 28898633 TI - Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn. PMID- 28898634 TI - Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits. PMID- 28898635 TI - The Breast Cancer Oncogene EMSY Represses Transcription of Antimetastatic microRNA miR-31. PMID- 28898636 TI - Coexistence of Two Forms of LTP in ACC Provides a Synaptic Mechanism for the Interactions between Anxiety and Chronic Pain. PMID- 28898637 TI - Interspecies Systems Biology Uncovers Metabolites Affecting C. elegans Gene Expression and Life History Traits. PMID- 28898638 TI - The Cell-Cycle State of Stem Cells Determines Cell Fate Propensity. PMID- 28898639 TI - VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses through the Polarity Protein LGN. PMID- 28898640 TI - Capsaspora owczarzaki. AB - Capsaspora owczarzaki is a unicellular eukaryote that is becoming pivotal to understanding the origin of animal multicellularity. PMID- 28898641 TI - Twitter as a means to study temporal behaviour. AB - Biomedical research has exploited vital and other statistics (e.g., birth or death rates) for almost 200 years [1]. The Internet has become a rich source of digital databases, which are being used for many lines of research (e.g., circadian and seasonal [2] or metabolism [3,4]). Internet-based studies generally investigate large populations while individual social media accounts are rarely used to analyse, for example, individual sleep-wake behaviour (e.g., youtu.be/wBNcP-LkpfA). I therefore applied time series analyses, commonly used in circadian and sleep research, to approximately 12,000 tweets sent from a single Twitter account (@realdonaldtrump; December, 2014 to March, 2017). The account was clearly used by different individuals/groups launching tweets from various devices. Among these, the Android phone was the most consistent over the years. Its tweet activity peaked twice a day (early morning and late night), and both peaks showed a strong seasonality by tracking dawn. PMID- 28898642 TI - Animal Navigation: A Novel Map Strategy. AB - Elegant new experiments show that migrant birds at high European latitudes can use magnetic declination to infer longitude. PMID- 28898643 TI - Place Cells: Knowing Where You Are Depends on Knowing Where You're Heading. AB - Knowing where you are and knowing where you are heading are both necessary for navigation. Does knowing where you are depend on knowing where you are heading, or is it the other way around? A new study suggests that knowing where you are heading allows you to know where you are. PMID- 28898644 TI - Centrosome Biology: Polymer-Based Centrosome Maturation. AB - The molecular mechanisms that control how the centrosome increases in size and microtubule nucleation capacity during mitosis have remained elusive. Recent work using in vitro assays provide exciting clues as to how this may occur. PMID- 28898645 TI - Sensory Neurobiology: Wet Fly Fishing. AB - A neuron responding to moist air and its ionotropic receptor have been identified in Drosophila melanogaster. Moreover, second-order neurons integrate temperature and humidity information before reaching higher brain centres. PMID- 28898646 TI - Plant Vasculature: Selective Membrane-to-Microtubule Tethering Patterns the Xylem Cell Wall. AB - To introduce pits into a cell wall, plants depolymerize cortical microtubules, which prevents subsequent secondary cell wall thickening. A newly identified protein tethers microtubules to the plasma membrane and contains this breakdown to defined regions, thereby shaping these holes. PMID- 28898647 TI - Genetics: Master Regulator or Master of Disguise? AB - The pha-1 gene of Caenorhabditis elegans was originally heralded as a master regulator of organ differentiation. A new study suggests instead that pha-1 actually serves no role in development and instead is a component of a selfish genetic element. PMID- 28898648 TI - Motor Control: CRF Regulates Coordination and Gait. AB - The function of the olivo-cerebellar tract is not restricted to the supervision of plasticity in the cerebellar cortex. There is growing evidence that the climbing fibers also tune motor commands. A novel study unravels a role of corticotropin-releasing factor (CRF) in motor coordination and gait control. PMID- 28898649 TI - Morphogenesis: Shaping Tissues through Extracellular Force Gradients. AB - Organ sculpting requires directed physical force generation. Force imbalances are primarily thought to arise from within cells. A new study, however, demonstrates that an extracellular-matrix-based stiffness gradient in the Drosophila egg chamber instructs tissue elongation. PMID- 28898650 TI - Wilhelm Hofmeister and the foundations of plant science. AB - On January 12th 1877, the Grim Reaper visited Wilhelm Hofmeister (Figure 1) for the last time. Having recently witnessed the death of a wife, two daughters, and two sons (only two of his nine children survived him), the German botanist, perhaps succumbing to the weight of his own grief, suffered a series of strokes and then promptly died at the age of 52 in Lindenau, Germany. He has since faded into the dusty annals of 19th century botany, his contributions to our knowledge about plants, how they come into being, develop and interact with their environment, mostly forgotten. In an ode to Hofmeister marking 100 years since his birth, Douglas Haughton Campbell of Stanford University, referring to Hofmeister's studies in comparative morphology, wrote, "...there is no question that Hofmeister's work will remain as probably the most brilliant contribution ever made to this fundamental department of botany" [1]. And in an essay published in Plant Physiology, Donald Kaplan and Todd Cooke went further still, writing, "Frederich Wilhelm Benedikt Hofmeister stands as one of the most remarkable figures in the history of botany and one who made fundamental contributions to all areas of plant biology" [2]. If that wasn't enough, Kaplan and Cooke added "In terms of native genius, he is certainly the peer of both Darwin and Mendel and may have even exceeded them in the breadth and depth of his talents." PMID- 28898651 TI - From early farmers to Norman Borlaug - the making of modern wheat. AB - If we wander through the countryside, passing fields of wheat, it is apparent that this crop is reasonably short in stature and that the stems carry large ears. However, this was not always the case. If we take a look at depictions of wheat throughout history, we observe that wheat used to be fairly tall. It was not until the second half of the 20th century that dwarf wheat varieties started to dominate the agricultural landscape. Underlying this short stature are the Reduced height (Rht) genes, which encode DELLA proteins and which formed the cornerstone of the Green Revolution. PMID- 28898652 TI - Thigmomorphogenesis. AB - Braam and Chehab introduce thigmomorphogenesis - the phenomenon of touch-induced changes in plant growth and development. PMID- 28898653 TI - Apical dominance. AB - Barbier et al. give a quick guide to apical dominance, whereby a plant's main shoot dominates and inhibits the outgrowth of other shoots. PMID- 28898655 TI - Plant embryogenesis. AB - Land plants are called 'embryophytes' and thus, their collective name is defined by their ability to form embryos. Indeed, embryogenesis is a widespread phenomenon in plants, and much of our diet is composed of embryos (just think of grains, beans or nuts; Figure 1). However, in addition to embryos as a source of nutrition, they are also a fascinating study object. Some of the most fundamental decisions on fate and identity, as well as patterning and morphogenesis, are taken during the first days of plant life. Yet, embryos are diverse in structure and function, and embryogenesis in plants is by no means restricted to the zygote - the product of fertilization. In this Primer, we discuss the adventures of the young plant. We will consider what it means to be a plant embryo and how to become one. We will next highlight how the study of early embryogenesis can reveal principles underlying oriented cell division and developmental pattern formation in plants. PMID- 28898654 TI - Plant cell walls. AB - Plants are able to generate large leaf surfaces that act as two-dimensional solar panels with a minimum investment in building material, thanks to a hydrostatic skeleton. This requires high intracellular pressures (up to 1 MPa), which depend on the presence of strong cell walls. The walls of growing cells (also called primary walls), are remarkably able to reconcile extreme tensile strength (up to 100 MPa) with the extensibility necessary for growth. All walled organisms are confronted with this dilemma - the need to balance strength and extensibility - and bacteria, fungi and plants have evolved independent solutions to cope. In this Primer, we discuss how plant cells have solved this problem, allowing them to support often very large increases in volume and to develop a broad variety of shapes (Figure 1A,B,D). This shape variation reflects the targeted deposition of wall material combined with local variations in cell-wall extensibility, processes that remain incompletely understood. Once the cell has reached its final size, it can lay down secondary wall layers, the composition and architecture of which are optimized to exert specific functions in different cell types (Figure 1E-G). Such functions include: providing mechanical support, for instance, for fibre cells in tree trunks or grass internodes; impermeabilising and strengthening vascular tissue to resist the negative pressure of the transpiration stream; increasing the surface area of the plasma membrane to facilitate solute exchange between cells (Figure 1C); or allowing important elastic deformation, for instance, to support the opening and closing of stomates. Specialized secondary walls, such as those constituting seed mucilage, are stored in a dehydrated form in seedcoat epidermis cells and show rapid swelling upon hydration of the seed. Other walls, in particular in reserve tissues, can accommodate large amounts of storage polysaccharides, which can be easily mobilized as a carbon source. Here we will discuss some general principles underlying wall architecture and wall growth that have emerged from recent studies, as well as future questions for investigation (Box 1). PMID- 28898656 TI - Seed dormancy and germination. AB - Reproduction is a critical time in plant life history. Therefore, genes affecting seed dormancy and germination are among those under strongest selection in natural plant populations. Germination terminates seed dispersal and thus influences the location and timing of plant growth. After seed shedding, germination can be prevented by a property known as seed dormancy. In practise, seeds are rarely either dormant or non-dormant, but seeds whose dormancy-inducing pathways are activated to higher levels will germinate in an ever-narrower range of environments. Thus, measurements of dormancy must always be accompanied by analysis of environmental contexts in which phenotypes or behaviours are described. At its simplest, dormancy can be imposed by the formation of a simple physical barrier around the seed through which gas exchange and the passage of water are prevented. Seeds featuring this so-called 'physical dormancy' often require either scarification or passage through an animal gut (replete with its associated digestive enzymes) to disrupt the barrier and permit germination. In other types of seeds with 'morphological dormancy' the embryo remains under developed at maturity and a dormant phase exists as the embryo continues its growth post-shedding, eventually breaking through the surrounding tissues. By far, the majority of seeds exhibit 'physiological dormancy' - a quiescence program initiated by either the embryo or the surrounding endosperm tissues. Physiological dormancy uses germination-inhibiting hormones to prevent germination in the absence of the specific environmental triggers that promote germination. During and after germination, early seedling growth is supported by catabolism of stored reserves of protein, oil or starch accumulated during seed maturation. These reserves support cell expansion, chloroplast development and root growth until photoauxotrophic growth can be resumed. PMID- 28898657 TI - Radial plant growth. AB - One of the extraordinary features of plants is their growth capacity. Depending on the species and the environment, body forms are manifold and, at the same time, constantly reshaped. An important basis of this plastic variation and life long accumulation of biomass is radial growth. Here, we use this term to describe the ability to grow in girth by the formation of wood, bast and cork. The more technical term for radial growth is secondary growth, which distinguishes the process from primary growth taking place at the tips of stems and roots during plant elongation. PMID- 28898659 TI - The ABC model of floral development. AB - Flowers are organized into concentric whorls of sepals, petals, stamens and carpels, with each of these floral organ types having a unique role in reproduction (Figure 1). Sepals enclose and protect the flower bud, while petals can be large and showy so as to attract pollinators (or people!). Stamens produce pollen grains that contain male gametes, while the carpels contain the ovules that when fertilized will produce the seeds. While the size, shape, number and elaboration of each of these organ types can be quite different, the same general organization of four floral organ types arranged in concentric whorls exists across all flowering plant (angiosperm) species. As I shall explain in this Primer, the 'ABC model' is a simple and satisfying explanation for how this conserved floral architecture is genetically specified. PMID- 28898658 TI - Phyllotaxis. AB - Leaves and flowers are arranged in regular patterns around the stem of a plant, a phenomenon known as phyllotaxis. Different arrangements occur, such as distichous, decussate or spiral (Figure 1). Most prevalent in nature are spirals in which the average divergence angles between successive organs are close to 137.5 degrees , the so-called 'golden angle'. It is this exact number that has given phyllotaxis its special flavor as a quantitative developmental problem, and over the centuries, it has enjoyed the attention of scientists far beyond botany. In the 1830s mathematicians described the spirals as they related to the Fibonacci numbers, and in the 1860s improved microscopes made it possible for botanists to observe the initiation of leaf and flower primordia in a diversity of plants. This descriptive work led to the conclusion that new organ primordia form in the first available space between existing primordia, a conclusion still valid today. But how does it work? Ideas from the early 20th century suggested that an inhibitor produced by existing primordia diffuses towards the shoot apical meristem: where the concentration of the inhibitor falls below a threshold value, an organ is initiated. Other models dating back to the 1870s have tried to explain phyllotactic patterning by applying the laws of mechanics. Such models went through a long period of marginal interest, but have experienced a remarkable renaissance over the past 20 years. In this Primer I will give a broad overview of phyllotaxis, its emergence from the shoot apical meristem, how auxin and its transporter function as a 'pattern generator', and the role of tissue mechanics and computational modeling. PMID- 28898660 TI - Succulent plants. AB - The peculiar morphologies of succulent plants have been variously considered as grotesque monstrosities and exotic curiosities, but succulents have always been perceived as unique. The succulent syndrome is considered to be one of the most remarkable examples of convergent evolution across the plant kingdom. Common to all succulents is the presence of large cells for water storage. However, cellular succulence can occur in any vegetative plant organ, with the level of succulence in roots, stems, and leaves being subject to a certain degree of evolutionary coordination. Furthermore, cellular succulence scales up to morphological succulence according to various anatomical schemes that confer contrasting functional characteristics. This means that succulence is associated with a broad range of ecophysiological strategies and occurs in plants that have evolved in many different environments. PMID- 28898661 TI - How to make a domesticate. AB - The Neolithic Revolution brought about the transition from hunting and gathering to sedentary societies, laying the foundation for the development of modern civilizations. The primary innovation that facilitated these changes was the domestication of plants and animals. In the case of plants, this involved the cultivation and selection of individuals with larger edible parts, easier harvesting, and decreased defenses, traits that allowed for the production of a food surplus and occupational specialization. Plant domestication is a process which started approximately 10,000 years ago and has thereafter been repeated independently in many locales around the world. Here, we offer a perspective that seeks to predict what factors influence the success of domestication, how many genes contributed to the process, where these genes originated and the implications for de novo domestication. PMID- 28898662 TI - Size-dependent variation in plant form. AB - The study of organic form has a long and distinguished history going at least as far back as Aristotle's Historia Anima-lium, wherein he identified five basic biological processes that define the forms of animals (metabolism, temperature regulation, information processing, embryo development, and inheritance). Unfortunately, all of Aristotle's writings about plant forms are lost. We know of them only indirectly from his student Theophrastus's companion books, collectively called Historia Plantarum, wherein plant forms are categorized into annual herbs, herbaceous perennials, shrubs, and trees. The study of plant forms did not truly begin until the romantic poet and naturalist Goethe proposed the concept of a hypothetical 'Plant Archetype', declared "Alles ist Blatt", and first coined the word morphologie, which inspired the French anatomist Cuvier (who established the field of comparative morphology), the English naturalist Darwin (who saw his theory of evolution reinforced by it), and the Scottish mathematician D'Arcy Thompson (who attempted to quantify it). PMID- 28898663 TI - Late Palaeozoic plants. AB - Land plants are one of the major constituents of terrestrial ecosystems on Earth, and play an irreplaceable role in human activities today. If we are to understand the extant plants, it is imperative that we have some understanding of the fossil plants from the deep geological past, particularly those that occurred during their early evolutionary history, in the late Palaeozoic. PMID- 28898664 TI - Growth and Development of Three-Dimensional Plant Form. AB - Plants can generate a spectacular array of complex shapes, many of which exhibit elaborate curvature in three dimensions, illustrated for example by orchid flowers and pitcher-plant traps. All of these structures arise through differential growth. Recent findings provide fresh mechanistic insights into how regional cell behaviours may lead to tissue deformations, including anisotropies and curvatures, which shape growing volumes and sheets of cells. Here were review our current understanding of how genes, growth, mechanics, and evolution interact to generate diverse structures. We illustrate problems and approaches with the complex three-dimensional trap of the bladderwort, Utricularia gibba, to show how a multidisciplinary approach can be extended to new model systems to understand how diverse plant shapes can develop and evolve. PMID- 28898665 TI - Shaping 3D Root System Architecture. AB - Plants are sessile organisms rooted in one place. The soil resources that plants require are often distributed in a highly heterogeneous pattern. To aid foraging, plants have evolved roots whose growth and development are highly responsive to soil signals. As a result, 3D root architecture is shaped by myriad environmental signals to ensure resource capture is optimised and unfavourable environments are avoided. The first signals sensed by newly germinating seeds - gravity and light direct root growth into the soil to aid seedling establishment. Heterogeneous soil resources, such as water, nitrogen and phosphate, also act as signals that shape 3D root growth to optimise uptake. Root architecture is also modified through biotic interactions that include soil fungi and neighbouring plants. This developmental plasticity results in a 'custom-made' 3D root system that is best adapted to forage for resources in each soil environment that a plant colonises. PMID- 28898666 TI - Plant Strategies for Enhancing Access to Sunlight. AB - Light is a vital resource for plants, which compete for it particularly in dense communities. Plants have multiple photosensory receptors to detect the presence of competitors and thereby adjust their growth and developmental strategies accordingly. Broadly speaking, plants fall into two categories depending on their response to shading by leaves: shade tolerant or shade avoiding. Here, we describe the photoperception mechanisms and the growth responses elicited by the neighboring vegetation in shade-avoiding plants, focusing on Arabidopsis thaliana, where these responses are best understood. The type of response depends on plant density, ranging from neighbor detection modulating growth in anticipation of future shading to the response to canopy shade where light resources are limiting. These diverse environments are sensed by various photoreceptors, and we will describe our current understanding of signal integration triggered by distinct light cues in diverse light conditions. PMID- 28898667 TI - The Evolution of Diverse Floral Morphologies. AB - The angiosperm flower develops through a modular programme which, although ancient and conserved, provides the flexibility that has allowed an almost infinite variety of floral forms to emerge. In this review, we explore the evolution of floral diversity, focusing on our recent understanding of the mechanistic basis of evolutionary change. We discuss the various ways in which flower size and floral organ size can be modified, the means by which flower shape and symmetry can change, and the ways in which floral organ position can be varied. We conclude that many challenges remain before we fully understand the ecological and molecular processes that facilitate the diversification of flower structure. PMID- 28898668 TI - Understanding the Arbuscule at the Heart of Endomycorrhizal Symbioses in Plants. AB - Arbuscular mycorrhizal fungi form associations with most land plants and facilitate nutrient uptake from the soil, with the plant receiving mineral nutrients from the fungus and in return providing the fungus with fixed carbon. This nutrient exchange takes place through highly branched fungal structures called arbuscules that are formed in cortical cells of the host root. Recent discoveries have highlighted the importance of fatty acids, in addition to sugars, acting as the form of fixed carbon transferred from the plant to the fungus and several studies have begun to elucidate the mechanisms that control the plant processes necessary for fungal colonisation and arbuscule development. In this review, we analyse the mechanisms that allow arbuscule development and the processes necessary for nutrient exchange between the plant and the fungus. PMID- 28898669 TI - Molecular Mechanisms of Root Gravitropism. AB - Plant shoots typically grow against the gravity vector to access light, whereas roots grow downward into the soil to take up water and nutrients. These gravitropic responses can be altered by developmental and environmental cues. In this review, we discuss the molecular mechanisms that govern the gravitropism of angiosperm roots, where a physical separation between sites for gravity sensing and curvature response has facilitated discovery. Gravity sensing takes place in the columella cells of the root cap, where sedimentation of starch-filled plastids (amyloplasts) triggers a pathway that results in a relocalization to the lower side of the cell of PIN proteins, which facilitate efflux of the plant hormone auxin efflux. Consequently, auxin accumulates in the lower half of the root, triggering bending of the root tip at the elongation zone. We review our understanding of the molecular mechanisms that control this process in primary roots, and discuss recent insights into the regulation of oblique growth in lateral roots and its impact on root-system architecture and soil exploration. PMID- 28898670 TI - Shoot-Root Communication in Flowering Plants. AB - As sessile organisms, terrestrial plants have evolved sophisticated mechanisms to coordinate the growth and development of two distinct systems, the shoot and the root, in response to environmental fluctuations. Adaptive systemic responses are accomplished by shoot-root communication, which involves diverse long-distance signalling molecules. During the last few decades, various genetic, biochemical, molecular, and grafting studies have identified multiple long-distance signalling molecules which are crucial for plants to adapt to external changes. In this minireview, the long-distance signals implicated in systemic responses to various environmental cues are discussed. PMID- 28898671 TI - Preterm newborn pain research review. AB - This narrative review is based on a literature search of PubMed and PsycINFO for research on preterm newborn pain published during the last ten years. The high prevalence of painful procedures being performed with preterm newborns without analgesia (79%), with a median of 75 painful procedures being received during hospitalization and as many as 51 painful procedures per day highlights the importance of this problem. This review covers the pain assessments that have been developed, the short-term effects of the painful procedures, the longer-term developmental outcomes and the pharmacological and alternative therapies that have been researched. The most immediate effects reported for repeated painful procedures include increased heart rate, oxidative stress and cortisol as well as decreased vagal activity. Lower body weight and head circumference have been noted at 32 weeks gestation. Blunted cortisol reactivity to stressors has been reported for three-month-olds and thinner gray matter in 21 of 66 cerebral regions and motor and cognitive developmental delays have been noted as early as eight months. Longer-term outcomes have been reported at school age including less cortical thickness, lower vagal activity, delayed visual- perceptual development, lower IQs and internalizing behavior. Pharmacological interventions and their side effects and non-pharmacological therapies are also reviewed including sucrose, milk and nonnutritive sucking which have been effective but thought to negatively affect breast-feeding. Full-body interventions have included tucking, swaddling, kangaroo care and massage therapy. Although these have been effective for alleviating immediate pain during invasive procedures, research is lacking on the routine use of these therapies for reducing long-term pain effects. Further, additional randomized controlled replication studies are needed. PMID- 28898672 TI - A BMPy Road for Venous Development. AB - Detailed molecular pathways for the specific growth of arteries and lymphatic vessels have been identified, but the mechanisms controlling venous vessel growth have been obscure. Tischfield and colleagues (2017) shed new light on this problem by identifying a role for BMP signaling in development of the cerebral venous system. PMID- 28898673 TI - Arp2/3: Not Absolutely Required After All? AB - The Arp2/3 complex nucleates branched actin networks and is thought to be essential for macrophage migration and phagocytosis. In this issue of Developmental Cell, Rotty et al. (2017) show that there is only a surprisingly specific requirement for Arp2/3 in integrin-dependent macrophage functions, including CR3 phagocytosis and haptotaxis on fibronectin. PMID- 28898674 TI - mRNAs on the Move after Lunch. AB - mRNA localization often contributes to translational control. Reporting in Science, Moor et al. (2017) now show that many mRNAs and ribosomes are asymmetrically distributed along the apical-basal axis of enterocytes. Remarkably, when starved mice are fed, mRNAs encoding ribosomal proteins rapidly move to the ribosome-rich apical side to activate translation. PMID- 28898675 TI - A DNA Crosslinker Collects Mitotic Chromosomes. AB - Incorporating each set of daughter chromosomes into a single nucleus at the end of mitosis is essential for genome stability. In a recent Cell paper, Samwer et al. (2017) show that by non-covalently crosslinking DNA, BAF promotes chromosome coalescence, preventing nuclear membranes from enwrapping individual chromosomes to form micronuclei. PMID- 28898676 TI - Developmental ERK Signaling Goes Digital. AB - Reporting in Developmental Cell, de la Cova et al. (2017) present a biosensor to measure ERK activity dynamics in C. elegans larvae. They find that fate decision signaling involves frequency-modulated, digital ERK activity pulses. These findings may explain how graded morphogen signals are converted into precise and robust cell fate patterns. PMID- 28898677 TI - Difference in Dachsous Levels between Migrating Cells Coordinates the Direction of Collective Cell Migration. AB - In contrast to extracellular chemotactic gradients, how cell-adhesion molecules contribute to directing cell migration remains more elusive. Here we studied the collective migration of Drosophila larval epidermal cells (LECs) along the anterior-posterior axis and propose a migrating cell group-autonomous mechanism in which an atypical cadherin Dachsous (Ds) plays a pivotal role. In each abdominal segment, the amount of Ds in each LEC varied along the axis of migration (Ds imbalance), which polarized Ds localization at cell boundaries. This Ds polarity was necessary for coordinating the migratory direction. Another atypical cadherin, Fat (Ft), and an unconventional myosin Dachs, both of which bind to Ds, also showed biased cell-boundary localizations, and both were required for the migration. Altogether, we propose that the Ds imbalance within the migrating tissue provides the directional cue and that this is decoded by Ds Ft-mediated cell-cell contacts, which restricts lamellipodia formation to the posterior end of the cell. PMID- 28898678 TI - Using language to get ready: Familiar labels help children engage proactive control. AB - A key developmental transition is the ability to engage executive functions proactively in advance of needing them. We tested the potential role of linguistic processes in proactive control. Children completed a task in which they could proactively track a novel (target) shape on a screen as it moved unpredictably amid novel distractors and needed to identify where it disappeared. Children almost always remembered which shape to track, but those who learned familiar labels for the target shapes before the task had nearly twice the odds of tracking the target compared with those who received experience with the targets but no labels. Children who learned labels were also more likely to spontaneously vocalize labels when the target appeared. These findings provide the first evidence of a causal role for linguistic processes in proactive control and suggest new ideas about how proactive control develops, why language supports a variety of executive functions, and how interventions might best be targeted. PMID- 28898679 TI - Systemic treatment of renal cell cancer: A comprehensive review. AB - Kidney cancer represents about 5% of all new cancer diagnoses. The most common form of kidney cancer arises from renal epithelium, named renal cell carcinoma (RCC). This entity comprises different histological and molecular subtypes. Unraveling the molecular biology and cytogenetic of RCC has enabled the development of several targeted agents that have improved treatment outcomes of these patients. This article reviews all the agents currently approved for the treatment of RCC, and discuss upcoming molecules. Mechanism of action, preclinical and clinical development and ongoing trials, are presented for each agent, providing a broad vision of the current state of targeted therapy in RCC and possible future developments. PMID- 28898680 TI - Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen Presenting Cells Critical for T Cell Immunity. PMID- 28898681 TI - Cancer-Selective Targeting of the NF-kappaB Survival Pathway with GADD45beta/MKK7 Inhibitors. PMID- 28898682 TI - Global Reprogramming of the Cellular Translational Landscape Facilitates Cytomegalovirus Replication. PMID- 28898683 TI - Microcephaly-Associated Protein WDR62 Regulates Neurogenesis through JNK1 in the Developing Neocortex. PMID- 28898684 TI - Highly Efficient Targeted Mutagenesis of Drosophila with the CRISPR/Cas9 System. PMID- 28898685 TI - Avoidance of the vaginal incision site for mesh placement in vaginal wall prolapse surgery: A prospective study. AB - OBJECTIVE: To evaluate efficacy of a minimal surface area, vaginally-installed polypropylene tape (VPT), avoiding insertion on the incision line to treat an anterior, posterior or anteroposterior vaginal wall prolapse. STUDY DESIGN: Patients with an anterior, posterior or anteroposterior vaginal wall prolapse waiting for surgical treatment were included in the study. Primary outcome was the incidence of prolapse recurrence reported with combined outcome measures and was reported with Kaplan-Meier cumulative incidence. Secondary outcomes were operative complications, adverse events, urinary, colorectal and sexual functions as well as quality of life. Participation in the study involved up to 8 visits over 5 years. At each visit, patients used a self-reported questionnaire to report symptoms related to pain, urinary, colorectal, sexual functions, and quality of life. A physical examination was also performed. Paired t-tests were used to investigate change in POP-Q and quality of life measurements since baseline. RESULTS: 71 patients underwent the procedure and were followed-up for an average (standard deviation) of 32.5 (18.7) months. Only 2 (2.8%) women experienced a recurrence of their pelvic organ prolapse. Only one case of erosion and no case of persistent pain have been recorded up to 5 years post-surgery. Quality of life was improved and then sustained throughout the follow-up period (p<0.01). CONCLUSION: This VPT surgical procedure is safe and has a high level of efficacy to treat anterior, posterior or anteroposterior vaginal wall prolapse. It is also associated with improvements in quality of life of patients which are sustained for many years. PMID- 28898686 TI - The impact of ovulation induction and ovarian stimulation on the risk of pregnancy-induced hypertension and on neonatal outcomes: A case/control study. AB - OBJECTIVES: To study the role of ovarian stimulation procedures on the risk of pregnancy-induced hypertension, gestational diabetes mellitus and neonatal outcomes according to women's characteristics and the causes of infertility. DESIGN: Retrospective, observational, case/control study. PATIENTS: Spontaneous pregnancies (group A, n=8107), pregnancies achieved after mild ovarian ovulation induction without other Assisted Reproductive Technology (ART) procedures (group B, n=44), pregnancies after mild ovarian stimulation and ART procedures (group C, n=53) or pregnancies after multi (>2) follicular stimulation with gonadotrophin therapy and ART procedures (group D, n=133); all of the groups had identical protocols for prenatal care. MAIN OUTCOME MEASUREMENTS: Pregnancy-induced hypertension (PIH), fetal macrosomia (estimated fetal weight >90th percentile), gestational diabetes mellitus, caesarean section, and neonatal outcomes. RESULTS: The incidence rates of PIH (2.7, 11.6, 4.2, and 2.5%) in groups A, B, C and D, respectively, (p=0.004), fetal macrosomia (4.7, 7.0, 20.8, and 7.6%, respectively, p<0.001), caesarean section (21.8, 37.2, 21.7, and 17.6%, respectively, p=0.048), differed among the groups. The high incidence of PIH in pregnancies following ovulation induction was driven by polycystic ovarian syndrome (PCOS) per se. CONCLUSION: PCOS per se was associated with more PIH, and ART procedures after mild mono/bi follicular ovarian stimulation were associated with more fetal macrosomia. PMID- 28898688 TI - Improving non-technical skills (teamwork) in post-partum haemorrhage: A grouped randomised trial. AB - OBJECTIVE: To determine the effect of a decision support technology on teamwork and associated non-technical (NTS) and technical skills when teams manage post partum haemorrhage (PPH) in the simulated environment. METHODS: Multidisciplinary (MDT) maternity teams were taught how to manage post partum haemorrhage. They were randomised to the intervention: using a decision support mobile digital platform or a control group. Each team managed a post-partum simulation, which was recorded and reviewed by assessors. Primary outcome measures to assess teams NTS were the validated Global Assessment of Obstetric Team Performance (GAOTP) and Clinical Teamwork Scale (CTS). Secondary outcome measures were the 'friends and family test', technical skills, and the System Usability Scale (SUS). Sample size estimation was calculated by using 80% power 5% significance two tailed test (p1=85% p2=40%) n=34. RESULTS: 38 teams from August 2014-February 2016, were recruited, technical issues with failure of recording equipment meant 4 teams were excluded from teamwork analysis (1 intervention 3 control). Teamwork improved across all domains with the intervention (using a decision support mobile digital platform) p <0.01. CTS improved between 6.7-16.8% (average 14.2%) and GAOTP between 8.6-17.1% (average 13.5%) for all domains. Using the control group as baseline, the intervention improved teamwork by 25% using CTS and 22% using GAOTP. Fewer technical skills were missed with the intervention (p<0.01). There was no statistical difference in the time technical skills were achieved. Assessors were more likely to recommend intervention teams 87.5% (77/88) than control teams 63.6% (56/88) p<0.01 to their friends or family. The SUS was 'Good' (69) becoming excellently 'Usable' (81.6) over the study period. CONCLUSION: We report a decision support system, which improved NTS when managing PPH. Lack of teamwork is often cited as the cause of failures in care and we report a usable technology that assists with and improves teamwork during an emergency. PMID- 28898687 TI - Outcomes of mifepristone usage for cervical ripening and induction of labour in full-term pregnancy. Randomized controlled trial. AB - OBJECTIVE: The most commonly used approved indications for mifepristone in obstetrics include: termination of early pregnancy, cervical dilatation prior to abortion, labour induction in case of fetal death in utero. Fewer studies have been conducted on the effect of mifepristone on cervical ripening and induction of labour in term pregnancy with a live fetus. The aim of our study was to evaluate efficacy and safety of mifepristone use for cervical ripening and induction of labour versus expectant management in full-term pregnancy. STUDY DESIGN: Randomized controlled trial. 149 women were randomized, 74 for cervical ripening and induction with mifepristone (200mg orally at the moment of enrollment and, if applicable, second dose after 24h), 75 - expectant management. Primary outcomes: gain in Bishop Score within 24 and 48-h of mifepristone; number of women going into spontaneous labor within 24, 48 and 72-h of mifepristone; rate of failed induction or expectant management. SECONDARY OUTCOMES: enrollment induction to delivery interval; mode of delivery; requirement of oxytocin augmentation, neonatal outcomes. RESULTS: After 48h from enrollment mean gain in Bishop score was 2.58+/-1.33 in the induction group and 1.15+/-0.97 in the expectant group (<0.001). Failed management rate was 5.41% and 2.67%, respectively. Significantly more mifepristone treated women had labour within 24, 48 and 72h from enrollment (RR 15.20 CI 95% 2.06-112.18; RR 6.08 CI 95% 2.73 13.57; RR 2.14 CI 95% 1.04-4.42) (p<0.05). Enrollment-induction to delivery interval was significantly shorter in mifepristone group: 2.69+/-2.06 vs 3.77+/ 1.86days (p<0.001). Premature rupture of membranes, meconium-stained amniotic fluid were more common in expectant management, but regional analgesia and cephalopelvic disproportion - in induction group. There were no differences in mode of delivery, requirement of oxytocin augmentation and main neonatal outcomes. CONCLUSION: Mifepristone was efficient on inducing cervical ripening and labour in full-term pregnancy. There were no significant difference in main maternal and neonatal outcomes between mifepristone use and expectant management. There were no serious adverse side effects of mifepristone, but there were some features of the course of labor, like more painful uterine contractions and trend of higher rate of cephalopelvic disproportion, that might be directly related to the mifepristone action. PMID- 28898689 TI - Scratching the Surface of Immunotherapeutic Targets in Neuroblastoma. AB - In this issue of Cancer Cell, Bosse et al. report GPC2 as a therapeutic target in neuroblastoma. They show that GPC2 is selectively expressed on the cell surface of neuroblastoma and is a dependency in this disease. Moreover, they demonstrate the therapeutic potential of an antibody-drug conjugate targeting GPC2. PMID- 28898690 TI - When LMO1 Meets MYCN, Neuroblastoma Is Metastatic. AB - LMO1 is a high-risk neuroblastoma susceptibility gene, but how LMO1 cooperates with MYCN in neuroblastoma tumorigenesis is unclear. In this issue of Cancer Cell, Zhu et al. develop a novel zebrafish model that elucidates a mechanism by which LMO1 and MYCN synergistically initiate neuroblastoma and contribute to metastatic disease progression. PMID- 28898691 TI - Leukemic Cells "Gas Up" Leaky Bone Marrow Blood Vessels. AB - In this issue of Cancer Cell, Passaro et al. demonstrate how leukemia through aberrant induction of reactive oxygen species and nitric oxide production trigger marrow vessel leakiness, instigating pro-leukemic function. Disrupted tumor blood vessels promote exhaustion of non-malignant stem and progenitor cells and may facilitate leukemia relapse following chemotherapeutic treatment. PMID- 28898692 TI - Smoke-Induced Changes to the Epigenome Provide Fertile Ground for Oncogenic Mutation. AB - How genetic and epigenetic events synergize to generate the oncogenic state is not well understood. In this issue of Cancer Cell, Vaz et al. provide compelling evidence that exposure to chronic cigarette smoke causes progressive epigenetic alterations that prime for key genetic events to drive the development of lung cancer. PMID- 28898693 TI - No Oxygen? No Glucose? No Problem: Fatty Acid Catabolism Enhances Effector CD8+ TILs. AB - The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8+ TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy. PMID- 28898694 TI - Intravascular Survival and Extravasation of Tumor Cells. AB - Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research. PMID- 28898695 TI - Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma. AB - We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target. PMID- 28898696 TI - A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development. AB - Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX. PMID- 28898699 TI - Redefining Hormonal Therapy for Advanced Prostate Cancer: Results from the LATITUDE and STAMPEDE Studies. PMID- 28898697 TI - Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. AB - We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation. PMID- 28898700 TI - MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. PMID- 28898698 TI - Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. AB - How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8+ TILs enhance peroxisome proliferator activated receptor (PPAR)-alpha signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8+ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8+ TILs' antigen specificity. Further promoting FA catabolism improves the CD8+ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures. PMID- 28898701 TI - Target virus log10 reduction values determined for two reclaimed wastewater irrigation scenarios in Japan based on tolerable annual disease burden. AB - Multiple-barriers are widely employed for managing microbial risks in water reuse, in which different types of wastewater treatment units (biological treatment, disinfection, etc.) and health protection measures (use of personal protective gear, vegetable washing, etc.) are combined to achieve a performance target value of log10 reduction (LR) of viruses. The LR virus target value needs to be calculated based on the data obtained from monitoring the viruses of concern and the water reuse scheme in the context of the countries/regions where water reuse is implemented. In this study, we calculated the virus LR target values under two exposure scenarios for reclaimed wastewater irrigation in Japan, using the concentrations of indigenous viruses in untreated wastewater and a defined tolerable annual disease burden (10-4 or 10-6 disability-adjusted life years per person per year (DALYpppy)). Three genogroups of norovirus (norovirus genogroup I (NoV GI), geogroup II (NoV GII), and genogroup IV (NoV GIV)) in untreated wastewater were quantified as model viruses using reverse transcription microfluidic quantitative PCR, and only NoV GII was present in quantifiable concentration. The probabilistic distribution of NoV GII concentration in untreated wastewater was then estimated from its concentration dataset, and used to calculate the LR target values of NoV GII for wastewater treatment. When an accidental ingestion of reclaimed wastewater by Japanese farmers was assumed, the NoV GII LR target values corresponding to the tolerable annual disease burden of 10-6 DALYpppy were 3.2, 4.4, and 5.7 at 95, 99, and 99.9%tile, respectively. These percentile values, defined as "reliability," represent the cumulative probability of NoV GII concentration distribution in untreated wastewater below the corresponding tolerable annual disease burden after wastewater reclamation. An approximate 1-log10 difference of LR target values was observed between 10-4 and 10-6 DALYpppy. The LR target values were influenced mostly by the change in the logarithmic standard deviation (SD) values of NoV GII concentration in untreated wastewater and the reliability values, which highlights the importance of accurately determining the probabilistic distribution of reference virus concentrations in source water for water reuse. PMID- 28898702 TI - Climate warming and cyanobacteria blooms: Looks at their relationships from a new perspective. AB - Climate warming and eutrophication are regarded as two important contributors to the occurrence of cyanobacteria blooms in aquatic ecosystems. However, the feedback of cyanobacteria blooms to climate warming and eutrophication is not fully clear. In this study, a microcosm system was established to simulate the decomposition processes of cyanobacteria blooms. It was observed that a large amount of nitrogen and phosphorus was released into the overlying water, and the concentrations of nitrogen and phosphorus were increased with the amount of added cyanobacteria bloom biomass addition. Subsequently, these released nutrients became available for primary production and intensified the eutrophic state of freshwater lakes. During the decomposition of cyanobacteria blooms, the microenvironment acquired low DO, low pH, and reductive conditions. Together with abundant organic matter in the water column and sediment, a large amount of CH4 and CO2 produced through organic matter mineralization, in which CH4 was the dominant fraction, occupied 50%-92% in mass of emitted carbon. Furthermore, a certain amount of N2O, probably underestimated, was produced with a strong greenhouse effect, even though its magnitude was small. These observations clarify that the feedbacks among cyanobacteria blooms formation and climate warming as well as the eutrophication of freshwater lakes are not unidirectional, but bidirectional. Given that climate warming enhanced the occurrence of cyanobacteria blooms, it was proposed that there are two vicious loops between cyanobacteria blooms, lake eutrophication and climate warming, which should be considered in the future management of aquatic ecosystems. PMID- 28898703 TI - Investigation of the impact of trace elements on anaerobic volatile fatty acid degradation using a fractional factorial experimental design. AB - The requirement of trace elements (TE) in anaerobic digestion process is widely documented. However, little is understood regarding the specific requirement of elements and their critical concentrations under different operating conditions such as substrate characterisation and temperature. In this study, a flask batch trial using fractional factorial design is conducted to investigate volatile fatty acids (VFA) anaerobic degradation rate under the influence of the individual and combined effect of six TEs (Co, Ni, Mo, Se, Fe and W). The experiment inoculated with food waste digestate, spiked with sodium acetate and sodium propionate both to 10 g/l. This is followed by the addition of a selection of the six elements in accordance with a 26-2 fractional factorial principle. The experiment is conducted in duplicate and the degradation of VFA is regularly monitored. Factorial effect analysis on the experimental results reveals that within these experimental conditions, Se has a key role in promoting the degradation rates of both acetic and propionic acids; Mo and Co are found to have a modest effect on increasing propionic acid degradation rate. It is also revealed that Ni shows some inhibitory effects on VFA degradation, possibly due to its toxicity. Additionally, regression coefficients for the main and second order effects are calculated to establish regression models for VFA degradation. PMID- 28898704 TI - Interpretation of indeterminate HIV-1 PCR results are influenced by changing vertical transmission prevention regimens. AB - BACKGROUND: Suppression of HIV by antiretroviral drugs may be one of the reasons that indeterminate HIV-1 PCR results are obtained from testing HIV-exposed infants. This complicates the early identification of infected infants, potentially delaying initiating treatment early. There is uncertainty as to how different vertical HIV transmission prevention regimens (VTP) affect the rate and predictive value of indeterminate PCR results. OBJECTIVES: To investigate rates of indeterminate PCR results, outcomes of subsequent samples and the predictive value of an indeterminate PCR for a later positive result in the setting of intensifying VTP in the Western Cape province of South Africa. STUDY DESIGN: Retrospective laboratory data analysis. Diagnostic PCR data of a public health laboratory from June 2009 to October 2014 was analysed and categorised by South African VTP regimens. First indeterminate HIV-1 PCRs in patients younger than 12 months were linked with follow-up HIV-1 PCRs and/or serological tests. Linked results sets were analysed by PCR amplification characteristics and subsequent patient outcome. RESULTS: Over intensified VTP regimens, the rate of indeterminate and positive PCRs decreased significantly (5.6-3.2% and 2.4-0.4%, respectively; both p<0.001). Most notably, significantly more patients with indeterminate results had positive PCRs on subsequent samples during WHO Option B+ use compared to older regimens (64.1% vs. 14.7%, p<0.001) at a median 28days later. CONCLUSIONS: Indeterminate HIV PCRs, although decreasing in frequency with Option B+, should be regarded with a high index of suspicion for being representative of true HIV-1 infections. Additional virological testing is required to arrive at a definitive diagnosis. PMID- 28898705 TI - Relationships of bullying involvement with intelligence, attention, and executive function in children and adolescents with attention-deficit/hyperactivity disorder. AB - This study investigated the relationship of bullying victimization and perpetration with the levels of intelligence, attention, and executive function in children who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD). The experiences of bullying involvement in 105 children with ADHD were assessed using the Chinese version of the School Bullying Experience Questionnaire. Their scores for four intelligence indexes on the Wechsler Intelligence Scale for Children 4th Edition-Chinese version were determined. Their levels of attention and executive function were assessed using the Comprehensive Nonverbal Attention Test Battery. The results of logistic regression analyses indicated that a high Perceptual Reasoning Index was significantly associated with a decreased risk of being victims of bullying. A high level of executive function was significantly associated with a decreased risk of being victims and perpetrators of bullying. Bullying victimization and perpetration in children with ADHD having a low PRI and low executive function should be routinely surveyed. PMID- 28898706 TI - Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide. AB - Large number of studies was published about predictive value of cytokines for graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Recently, there has been a growing interest in GVHD prophylaxis with post transplant cyclophosphamide (PTCy). Clinical data on the dynamics of proinflammatory cytokines with this prophylaxis is lacking. In this study, we have measured the levels of IL-17, IL-6, IL-8, IFN-gamma and TNF-alpha in plasma on days -7, 0, +7, +14 and after engraftment in 20 patients with acute GVHD and 40 matched control patients with PTCy-based prophylaxis. Low levels of IL-8 (p=0.04) on day +7 and IFN-gamma (p=0.03) after engraftment were associated with grade II-IV acute GVHD. The same pattern was observed for severe acute GVHD. Low IFN-gamma after engraftment was also associated with increased non-relapse mortality (p=0.014). No impact of cytokine levels on overall survival and relapse incidence was observed (p>0.05). In conclusion, the dynamics of IL-8 and IFN gamma in GVHD patients after PTCy was different from previously reported after conventional prophylaxis. PMID- 28898707 TI - The effect of prenatal substance use and maternal contingent responsiveness on infant affect. AB - BACKGROUND: The effects of prenatal substance exposure on neurobehavioral outcomes are inherently confounded by the effects of the postnatal environment, making it difficult to disentangle their influence. The goal of this study was to examine the contributing effects of prenatal substance use and parenting style (operationalized as contingent responding during the play episodes of the Still face paradigm [SFP]) on infant affect. METHODS: A prospective cohort design was utilized with repeated assessment of substance use during pregnancy and the administration of the SFP, which measures infant response to a social stressor, at approximately 6months of age. Subjects included 91 dyads classified into four groups: 1) Control (n=34); 2) Medication assisted therapy for opioid dependence (MAT; n=19); 3) Alcohol (n=15); 4) Alcohol+MAT (n=23). Mean % of positive infant affect and mean % of maternal responsiveness (watching, attention seeking, and contingent responding) was compared among the five SFP episodes across the four study groups by MANOVA. Mixed effects modelling was used to estimate the contributing effects of the study groups and maternal responsiveness on infant affect. RESULTS: Maternal contingent responding was associated with increase (beta=0.84; p<0.0001) and attention seeking with decrease (beta=-0.78; p<0.0001) in infant positive affect. The combined effect of prenatal exposures and covariates explained 15.8% of the variability in infant positive affect, while the model including contingent responding and covariates explained 67.1% of the variability. CONCLUSIONS: Higher maternal responsiveness was a much stronger predictor of infant behavior than prenatal exposures, providing the basis for future intervention studies focusing on specific parenting strategies. PMID- 28898708 TI - Cue exposure therapy reduces overeating of exposed and non-exposed foods in obese adolescents. AB - BACKGROUND AND OBJECTIVES: This study tested whether two sessions of food cue exposure therapy reduced eating in the absence of hunger (EAH), specified for exposed and non-exposed food, in overweight and obese adolescents, and whether habituation of food cue reactivity and reduced CS-US expectancies predicted a decrease in EAH. METHODS: 41 overweight adolescents (aged 12-18 years) were randomly assigned to a cue exposure intervention or a lifestyle intervention (control condition). Habituation of food cue reactivity (self-reported desire to eat and salivation) and CS-US expectancy were measured during both sessions, and EAH was measured at the end of session two. RESULTS: Compared to the control condition, the cue exposure condition showed less EAH for the exposed food item as well as for the non-exposed food items. Larger within-session (WSH) and between-session habituation (BSH) of cue reactivity were not related to less EAH, change in CS-US expectancy was unrelated to EAH. LIMITATIONS: The study was underpowered, and compliance to homework instructions between sessions was poor, intervention effects might have been larger when participants adhered to daily homework exercises. CONCLUSIONS: Food cue exposure was effective to reduce EAH of exposed and non-exposed food items, indicating generalisability of the exposure effect. In line with exposure effects in anxiety disorders, habituation was not found to benefit outcome, though the present data do also not provide evidence that CS-US expectancy violation predicts EAH. PMID- 28898709 TI - Pragmatic skills after childhood traumatic brain injury: Parents' perspectives. AB - The purpose of this study was to characterize pragmatic deficits after childhood traumatic brain injury (TBI) within the home environment social contexts where they occur. We used a descriptive qualitative approach to describe parents' experiences in communicating with their child with TBI. Participants were ten mothers of children ages 6-12 years who had sustained a moderate to severe TBI more than one year prior to the study. Mothers' experiences were collected through semi-structured interviews and questionnaires. Interviews were analyzed using a deductive framework to develop social contexts and pragmatic deficit themes for communication in the home. Overall, mothers primarily described their children with TBI as exhibiting average or near average pragmatic skills at home, but nine observed some pragmatic deficits and/or social behavior problems. There were four in-home social contexts in which pragmatic deficits were observed. Emergent themes also included outside-of-the home social contexts and social behavior problems. There was some overlap of pragmatic deficit and social behavior problem themes among contexts, but many deficits were context specific. This study's pragmatic deficit themes expanded on prior childhood TBI pragmatic investigations by identifying contexts in and outside of the home in which pragmatic deficits may occur after TBI. Learning Outcomes Readers will be able to describe the day-to-day social contexts that may be impacted by pragmatic deficits after childhood TBI. Readers will be able to compare the pragmatic deficit themes identified as occurring in the home to those occurring outside of the home. PMID- 28898710 TI - Effects of semantic weight on verb retrieval in individuals with aphasia: A different perspective. AB - The majority of people with aphasia have word retrieval difficulty and effective treatment remains elusive. There have been a few studies that have explored the effects of semantic complexity on verb retrieval in individuals with aphasia; each used a variation of Breedin et al.'s (1998) delayed repetition/story completion task. Although each subsequent investigator worked to address potential confounds in order to achieve more valid results that would give rise to a clearer understanding of these deficits, findings and their interpretations have varied. In our replication, groups of individuals with aphasia (9 agrammatic and 9 anomic) plus 12 age-matched controls participated in a story completion task that included novel distracter stories to prevent rehearsal. Additionally, stimuli were developed in strict adherence to novel semantic and syntactic templates to control for relevant factors, and stimuli were prerecorded to ensure uniform delivery. We calculated the number of target verbs produced and overall production of light and heavy verbs, and error analysis was performed with special attention to semantically appropriate substitutions. In contrast to previous studies, we found no significant performance differences on these measures within or between groups. Exploratory analyses were performed. Results are discussed in terms of relevant factors of verb retrieval and implications for future experimental design. Application to much-needed verb retrieval treatment is also considered. PMID- 28898711 TI - SJL bone marrow-derived macrophages do not have IRF3 mutations and are highly susceptible to Theiler's virus infection. AB - It is well known that SJL mice are susceptible to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease while C57BL6 (B6) and B10 mice are resistant, and H-2s on a B10 background (B10.S) contributes modestly to susceptibility. A recent study linked two IRF3 non-conservative mutations in SJL compared to B10.S mice to resistance to TMEV infection of SJL peritoneal-derived macrophages, an observation of practical interest in light of the central role of IRF3 transcription factor in the type I interferon (IFN) response. However, we did not find these non-conservative mutations among SJL, B10.S, B6 and B10 mice in the IRF3 amino acid sequence, and show SJL bone marrow derived macrophages infected with TMEV exhibit increased virus RNA replication and infectious virus yields as well as greater IL-6 production than C57Bl strain (including B10.S) cultures. PMID- 28898713 TI - Longitudinal trends in HbA1c and associations with comorbidity and all-cause mortality in Asian patients with type 2 diabetes: A cohort study. AB - AIMS: This study examined longitudinal trends in HbA1c in a multi-ethnic Asian cohort of diabetes patients, and the associations of these trends with future risk of acute myocardial infarction (AMI), stroke, end stage renal failure (ESRD) and all-cause mortality. METHODS: 6079 participants with type 2 diabetes mellitus in Singapore were included. HbA1c measurements for the five years previous to recruitment were used to identify patterns of HbA1c trends. Outcomes were recorded through linkage with the National Disease Registry. The median follow-up for longitudinal trends in HbA1c was 4.1years and for outcomes was between 7.0 and 8.3years. HbA1c patterns were identified using latent class growth modeling, and associations with outcomes were analyzed using Cox proportional hazards models. RESULTS: Four distinct HbA1c patterns were observed; "low-stable" (72.2%), "moderate-stable" (22.0%), "moderate-increase" (2.9%), and "high decrease" (2.8%). The risk of comorbidities and death was significantly higher in moderate-increase and high-decrease groups compared to the low-stable group; the hazard ratios for stroke, ESRD, and death for moderate increase group were 3.22 (95%CI 1.27-8.15), 4.76 (95%CI 1.92-11.83), and 1.88 (95%CI 1.15-3.07), respectively, and for high-decrease group were 2.16 (95%CI 1.02-4.57), 3.05 (95%CI 1.54-6.07), and 2.79 (95%CI 1.97-3.95), respectively. Individuals in the moderate-increase group were significantly younger, with longer diabetes duration, and greater proportions of Malays and Indians. CONCLUSIONS: Deteriorating HbA1c pattern and extremely high initial HbA1c are associated with increased risk of long-term comorbidities and death. Therapeutic interventions to alter longitudinal HbA1c trends may be helpful in reducing this risk. PMID- 28898712 TI - Inhibition of the lytic cycle of Kaposi's sarcoma-associated herpesvirus by cohesin factors following de novo infection. AB - Establishment of Kaposi's sarcoma-associated herpesvirus (KSHV) latency following infection is a multistep process, during which polycomb proteins are recruited onto the KSHV genome, which is crucial for the genome-wide repression of lytic genes during latency. Strikingly, only a subset of lytic genes are expressed transiently in the early phase of infection prior to the binding of polycomb proteins onto the KSHV genome, which raises the question what restricts lytic gene expression in the first hours of infection. Here, we demonstrate that both CTCF and cohesin chromatin organizing factors are rapidly recruited to the viral genome prior to the binding of polycombs during de novo infection, but only cohesin is required for the genome-wide inhibition of lytic genes. We propose that cohesin is required for the establishment of KSHV latency by initiating the repression of lytic genes following infection, which is an essential step in persistent infection of humans. PMID- 28898714 TI - Effect of follow-up by a hospital diabetes care team on diabetes control at one year after discharge from the hospital. AB - AIM: This study was conducted to evaluate the effect of continued follow-up by a hospital diabetes team on HbA1c at 1-year after discharge. METHODS: Adults with HbA1c >=8% (64mmol/mol), undergoing an elective surgery, were treated in the perioperative period and randomized to continued care (CC) or the usual care (UC) after discharge. Patients in the CC group received weekly to monthly phone calls from a diabetes specialist nurse practitioner (NP) to review their home blood glucose values, diet, exercise, and medications. Patients in the UC group followed with their diabetes care providers. RESULTS: Out of 151 patients, 77 were randomized to the CC group and 74 to the UC group. HbA1c (%) at 1-year was 8.2+/-1.4 in the CC group and 8.5+/-1.5 in the UC group (p=NS). Change in HbA1c from baseline was similar between the groups; -0.7+/-1.4 in the CC versus -0.7+/ 1.5 in the UC group (p=NS). A higher number of calls was not associated with lower HbA1c or reduction in HbA1c. There were 41 insulin-treated patients in the CC group and 53 in the UC group and among them, HbA1c reduction was 0.5+/-1.5 and 0.6+/-1.3 respectively (p=NS). CONCLUSIONS: Optimal perioperative treatment of diabetes is associated with an improvement in HbA1c but continued follow-up by a hospital diabetes team after discharge does not have an additional impact on long term glycemic control. ClinicalTrials.gov identifier NCT02065050. PMID- 28898715 TI - Cortisol and salivary alpha-amylase trajectories following a group social evaluative stressor with adolescents. AB - Intraindividual variability in stress responsivity and the interrelationship of multiple neuroendocrine systems make a multisystem analytic approach to examining the human stress response challenging. The present study makes use of an efficient social-evaluative stress paradigm - the Group Public Speaking Task for Adolescents (GPST-A) - to examine the hypothalamic-pituitary-adrenocortical (HPA) axis and Autonomic Nervous System (ANS) reactivity profiles of 54 adolescents with salivary cortisol and salivary alpha-amylase (sAA). First, we account for individuals' time latency of hormone concentrations between individuals. Second, we use a two-piece multilevel growth curve model with landmark registration to examine the reactivity and recovery periods of the stress response separately. This analytic approach increases the models' sensitivity to detecting trajectory differences in the reactivity and recovery phases of the stress response and allows for interindividual variation in the timing of participants' peak response following a social-evaluative stressor. The GPST-A evoked typical cortisol and sAA responses in both males and females. Males' cortisol concentrations were significantly higher than females' during each phase of the response. We found no gender difference in the sAA response. However, the rate of increase in sAA as well as overall sAA secretion across the study were associated with steeper rates of cortisol reactivity and recovery. This study demonstrates a way to model the response trajectories of salivary biomarkers of the HPA-axis and ANS when taking a multisystem approach to neuroendocrine research that enables researchers to make conclusions about the reactivity and recovery phases of the HPA-axis and ANS responses. As the study of the human stress response progresses toward a multisystem analytic approach, it is critical that individual variability in peak latency be taken into consideration and that accurate modeling techniques capture individual variability in the stress response so that accurate conclusions can be made about separate phases of the response. PMID- 28898716 TI - Celebrity over science? An analysis of Lyme disease video content on YouTube. AB - Lyme disease has been a subject of medical controversy for several decades. In this study we looked at the availability and type of content represented in a (n = 700) selection of YouTube videos on the subject of Lyme disease. We classified video content into a small number of content areas, and studied the relationship between these content areas and 1) video views and 2) video likeability. We found very little content uploaded by government or academic institutions; the vast majority of content was uploaded by independent users. The most viewed videos tend to contain celebrity content and personal stories; videos with prevention information tend to be of less interest, and videos with science and medical information tend to be less liked. Our results suggest that important public health information on YouTube is very likely to be ignored unless it is made more appealing to modern consumers of online video content. PMID- 28898717 TI - Targeting dendritic cells through gold nanoparticles: A review on the cellular uptake and subsequent immunological properties. AB - Gold nanoparticles (NPs) have been proposed as a highly potential tool in immunotherapies due to its advantageous properties including customizable size and shapes, surface functionality and biocompatibility. Dendritic cells (DCs), the sentinels of immune response, have been of interest to be manipulated by using gold NPs for targeted delivery of immunotherapeutic agent. Researches done especially in human DCs showed a variation of gold NPs effects on cellular uptake and internalization, DC maturation and subsequent T cells priming as well as cytotoxicity. In this review, we describe the synthesis and physiochemical properties of gold NPs as well as the importance of gold NPs in immunotherapies through their actions on human DCs. PMID- 28898718 TI - Interleukin 17 regulates SHP-2 and IL-17RA/STAT-3 dependent Cyr61, IL-23 and GM CSF expression and RANKL mediated osteoclastogenesis by fibroblast-like synoviocytes in rheumatoid arthritis. AB - Interleukin (IL)-17 predominately produced by the Th17 cells, plays a crucial role in the fibroblast-like synoviocytes (FLS) mediated disease process of rheumatoid arthritis (RA). IL-17 exerts its pathogenic effects in RA-FLS by IL 17/IL-17RA/STAT-3 signaling. Recent studies have shown that RA-FLS produces SHP 2, Cyr61, IL-23, GM-CSF and RANKL which results in worsening of the disease. However, whether IL-17/IL-17RA/STAT-3 signaling regulates SHP-2, Cyr61, IL-23, GM CSF and RANKL expressions in RA-FLS remains unknown. In this study, IL-17 treatment dramatically induced the production of Cyr61, IL-23 and GM-CSF in FLS isolated from adjuvant induced arthritis (AA) rats. Conversely, IL-17 mediated production of Cyr61, IL-23 and GM-CSF was abrogated by knockdown of IL-17RA using a small interfering RNA or blockade of STAT-3 activation with S3I-201 in AA-FLS. Interestingly, IL-17 treatment noticeably increased the expression of IL-17RA and SHP-2 in AA-FLS. However, silencing of IL-17RA reversed the effect of IL-17 on the expression of IL-17RA and SHP-2 in AA-FLS. In addition, an increased number of TRAP-positive multinucleated cells were observed in a coculture system consisting of IL-17 treated AA-FLS and rat bone marrow derived monocytes/macrophages. Further, mechanistically we found that IL-17 upregulated RANKL expression in AA-FLS that was dependent on the IL-17/IL-17RA/STAT-3 signaling cascade. Knockdown of IL-17RA or inhibition of STAT-3 activation decreased the IL- 17 induced RANKL expression by AA-FLS and their osteoclastogenic potential. Taken together, our findings demonstrate that IL-17 regulates SHP-2 expression and IL-17RA/STAT-3 dependent production of Cyr61, IL 23, GM-CSF and RANKL in AA-FLS and may reveal a new insight into the pathogenesis of RA. PMID- 28898719 TI - A cost-effective LC-MS/MS method for identification and quantification of alpha amanitin in rat plasma: Application to toxicokinetic study. AB - alpha-Amanitin is the main lethal component of amanita mushrooms, and data on its toxicokinetics are few. The aim of this study was to develop a sensitive and cost effective method to identify alpha-amanitin and investigate its toxicokinetic parameters using liquid chromatography-triple quadrupole tandem mass spectrometry. The colchicine was used as the internal standard (IS). The compounds were extracted from plasma samples by protein precipitation with acetonitrile (containing 1% formic acid). The analysis was performed through multiple reactions monitoring. The molecular ions and fragment ions of alpha amanitin could be used as characteristic ions to perform qualitative analysis of alpha-amanitin. The assay was successfully validated by selectivity, linearity, matrix effect, precision and accuracy, recovery and stability according to the U.S. Food and Drug Administration Guidance, and applied to study the toxicokinetic profile of alpha-amanitin in rats after a single intraperitoneal administration. PMID- 28898721 TI - Multifunctional zirconium nitride/copper multilayer coatings on medical grade 316L SS and titanium substrates for biomedical applications. AB - Protecting from wear and corrosion of many medical devices in the biomedical field is an existing scientific challenge. Surface modification with multilayer ZrN/Cu coating was deposited on medical grade stainless steel (SS) and titanium substrates to enhance their surface properties. Structural results revealed that the ZrN/Cu coatings are highly crystalline and uniform microstructure on both the substrates. Dry and wet tribological measurements of the coated titanium substrate exhibit enhanced wear resistance and low friction coefficient due to the improved microstructure. Similarly, the corrosion resistance was exceptionally improved on titanium substrates, resulting from the high inertness of coating to the SBF electrolyte solution. Antibacterial activity and epifluorescence results signify the effective killing of pathogens by means of ion release killing as well as contact killing mechanisms. PMID- 28898722 TI - Influence of gamma and electron beam sterilization on the stability of a premixed injectable calcium phosphate cement for trauma indications. AB - Premixed calcium phosphate cements (CPC's) are becoming the material of choice for injectable cements as a result of their effective delivery to the target implantation site. For orthopaedic use, it is of vital importance that the attributes of these CPC's are not compromised by irradiation sterilization. Therefore, the aim of this study is to determine the influence of irradiation sterilization on a range of premixed CPC's, with an emphasis on improving product shelf life through the use of optimal packaging configurations and annealing steps. Electron spin resonance (ESR) confirmed the presence of free radicals in the inorganic phase of the CPC paste following irradiation. The inclusion of a 24 h annealing step was the only successful method in reducing the degree of free radical formation. Based on the results of injectability force testing, it was revealed that an annealing step greater than 24-h significantly altered the viscosity, however; at 24-h the key attributes of the CPC paste were minimally effected. Overall, it was established that vacuum packing the CPC paste, placing the contents into a foil pouch, gamma irradiating at the minimal dose required and using an annealing step of <= 24-h, has the potential to extend the shelf life of the cement. PMID- 28898720 TI - Not so secret agents: Event-related potentials to semantic roles in visual event comprehension. AB - Research across domains has suggested that agents, the doers of actions, have a processing advantage over patients, the receivers of actions. We hypothesized that agents as "event builders" for discrete actions (e.g., throwing a ball, punching) build on cues embedded in their preparatory postures (e.g., reaching back an arm to throw or punch) that lead to (predictable) culminating actions, and that these cues afford frontloading of event structure processing. To test this hypothesis, we compared event-related brain potentials (ERPs) to averbal comic panels depicting preparatory agents (ex. reaching back an arm to punch) that cued specific actions with those to non-preparatory agents (ex. arm to the side) and patients that did not cue any specific actions. We also compared subsequent completed action panels (ex. agent punching patient) across conditions, where we expected an inverse pattern of ERPs indexing the differential costs of processing completed actions asa function of preparatory cues. Preparatory agents evoked a greater frontal positivity (600-900ms) relative to non-preparatory agents and patients, while subsequent completed actions panels following non-preparatory agents elicited a smaller frontal positivity (600 900ms). These results suggest that preparatory (vs. non-) postures may differentially impact the processing of agents and subsequent actions in real time. PMID- 28898723 TI - Experimental and modeling investigation on the rheological behavior of collagen solution as a function of acetic acid concentration. AB - Systematic analysis of the rheological behavior of collagen solution (10mg/mL) as a function of acetic acid (AA) concentration (0.1-10M) was performed to achieve a deeper understanding about the interaction between collagen molecules and acidic solvent. Steady shear tests showed that all samples exhibited pseudo-plasticity with shear-thinning behavior. Viscosity decreased from 236.448 to 0.792Pa.s at 0.1s-1 suggesting the flow ability of collagen solution improved with increasing AA concentration. Dynamic frequency sweep analysis revealed that the storage modulus, loss modulus, and complex viscosity decreased with the increased AA concentration due to the disentanglement of collagen molecules, while the loss tangent increased. Hysteresis loop areas of collagen solutions were determined by thixotropic measurement, which demonstrated that weaker thixotropic behavior was associated with higher AA concentrations. Furthermore, the ability to resist deformation and elasticity was lower at higher AA concentration. Maximum compliance values increased from 0.042 to 376.407Pa-1, and the recovery percentage decreased from 97.670% to 0.315%. Finally, corresponding mathematical models were employed to simulate and quantitatively assess the experimental data. PMID- 28898724 TI - Flexural strength of fiber reinforced posts after mechanical aging by simulated chewing forces. AB - This study evaluated the effect of simulated chewing forces on the flexural strength of fiber reinforced posts (FRPs). Four different brands of FRPs were selected as main group for the study: RelyX Fiber Post (RX), IceLight (ICE), Unicore Posts (UC), FlouroPost (FP). Ten posts in each main group didn't receive any aging process and tested as baseline (BL), other ten posts were subjected to simulated chewing forces/mechanical aging (MA) as follows: Post spaces were prepared in acrylic with drill. Depth of preparation was adjusted to leave 4-mm coronal part of posts protruding from canals. Coronal parts were incrementally restored with resin-composite (Clearfil Majesty Posterior A2, Kuraray, Osaka, Japan). Prepared samples were subjected to chewing cycles in a chewing simulator (Chewing Simulator CS-4, Mechatronik, Germany). Flexural strengths of all groups were measured with three-point bending test. Data were analyzed by two-way ANOVA and Tukey's test (alpha = 0.05). After MA, flexural strengths of all posts were significantly decreased when compared with BL for all FRPs tested (p < 0.05). At BL, highest flexural strength values were obtained for ICE. After MA, similar to BL, highest flexural strength values were obtained for ICE. Only RX showed statistically significant difference when compared with ICE (p < 0.05). UC and FP showed similar flexural strength values with ICE (p > 0.05). It may be concluded that chewing forces on post-core systems may reduce the flexural strengths of FRPs. PMID- 28898725 TI - Maximum insertion torque of a novel implant-abutment-interface design for PEEK dental implants. AB - Frequent reports attest to the various advantages of tapered implant/abutment interfaces (IAIs) compared to other types of interfaces. For this reason, a conical IAI was designed as part of the development of a PEEK (polyetheretherketone)-based dental implant. This IAI is equipped with an apically displaced anti-rotation lock with minimal space requirements in the form of an internal spline. The objective of this study was the determination of the average insertion torque (IT) at failure of this design, so as to determine its suitability for immediate loading, which requires a minimum IT of 32Ncm. 10 implants each made of unfilled PEEK, carbon fiber reinforced ("CFR") PEEK (> 50vol% continuous axially parallel fibers) as well as of titanium were produced and tested in a torque test bench. The average IT values at failure of the unfilled PEEK implants were measured at 22.6 +/- 0.5Ncm and were significantly higher than those of the CFR-Implants (20.2 +/- 2.5Ncm). The average IT values at failure of the titanium specimens were significantly higher (92.6 +/- 2.3Ncm) than those of the two PEEK variants. PEEK- and CFR-PEEK-implants in the present form cannot adequately withstand the insertion force needed to achieve primary stability for immediate loading. Nevertheless, the achievable torque resilience of the two PEEK-variants may be sufficient for a two-stage implantation procedure. To improve the torque resistance of the PEEK implant material the development of a new manufacturing procedure is necessary which reinforces the PEEK base with continuous multi-directional carbon fibers as opposed to the axially parallel fibers of the tested PEEK compound. PMID- 28898726 TI - Bioinspired surface functionalization of metallic biomaterials. AB - Metallic biomaterials are widely used for clinical applications because of their excellent mechanical properties and good durability. In order to provide essential biofunctionalities, surface functionalization is of particular interest and requirement in the development of high-performance metallic implants. Inspired by the functional surface of natural biological systems, many new designs and conceptions have recently emerged to create multifunctional surfaces with great potential for biomedical applications. This review firstly introduces the metallic biomaterials, important surface properties, and then elaborates some strategies on achieving the bioinspired surface functionalization for metallic biomaterials. PMID- 28898727 TI - Reconciling professional identity: A grounded theory of nurse academics' role modelling for undergraduate students. AB - Role modelling by experienced nurses, including nurse academics, is a key factor in the process of preparing undergraduate nursing students for practice, and may contribute to longevity in the workforce. A grounded theory study was undertaken to investigate the phenomenon of nurse academics' role modelling for undergraduate students. The study sought to answer the research question: how do nurse academics role model positive professional behaviours for undergraduate students? The aims of this study were to: theorise a process of nurse academic role modelling for undergraduate students; describe the elements that support positive role modelling by nurse academics; and explain the factors that influence the implementation of academic role modelling. The study sample included five second year nursing students and sixteen nurse academics from Australia and the United Kingdom. Data was collected from observation, focus groups and individual interviews. This study found that in order for nurse academics to role model professional behaviours for nursing students, they must reconcile their own professional identity. This paper introduces the theory of reconciling professional identity and discusses the three categories that comprise the theory, creating a context for learning, creating a context for authentic rehearsal and mirroring identity. PMID- 28898728 TI - Nursing students collaborating to develop multiple-choice exam revision questions: A student engagement study. AB - BACKGROUND: Nursing students find bioscience subjects challenging. Bioscience exams pose particular concerns for these students, which may lead to students adopting a surface-approach to learning. OBJECTIVES: To promote student collective understanding of bioscience, improve their confidence for the final exam, and improve deeper understanding of bioscience. DESIGN: In order to address exam anxiety, and improve student understanding of content, this student engagement project involved nursing students collaborating in small groups to develop multiple-choice questions and answers, which became available to the entire student cohort. SETTINGS: This study was conducted at two campuses of an Australian university, within a first year bioscience subject as part of the undergraduate nursing programme. PARTICIPANTS: All students enrolled in the subject were encouraged to attend face-to-face workshops, and collaborate in revision question writing. Online anonymous questionnaires were used to invite student feedback on this initiative; 79 respondents completed this feedback. METHODS: Students collaborated in groups to write revision questions as part of in-class activities. These questions were made available on the student online learning site for revision. An online feedback survey was deployed at the conclusion of all workshops for this subject, with questions rated using a Likert scale. RESULTS: Participants indicated that they enjoyed the opportunity to collaborate in this activity, and almost all of these respondents used these questions in their exam preparation. There was strong agreement that this activity improved their confidence for the final exam. Importantly, almost two thirds of respondents agreed that writing questions improved their understanding of content, and assisted in their active reflection of content. CONCLUSIONS: Overall, this initiative revealed various potential benefits for the students, including promoting bioscience understanding and confidence. This may improve their long-term understanding of bioscience for nursing practice, as registered nurses' bioscience knowledge can impact on patient outcomes. PMID- 28898729 TI - Evaluation of the multi-slice computed tomography outcomes in diaphragmatic injuries related to penetrating and blunt trauma. AB - PURPOSE: Traumatic diaphragmatic rupture is a diagnostic challenge for both surgeons and radiologists and generally occurs secondary to blunt and penetrating trauma of thoracoabdominal region. MATERIAL AND METHODS: 56 patients who underwent surgical procedure due to blunt or penetrating trauma were included to the study. RESULTS: There were 37 diaphragmatic ruptures in the left side and 19 patients in the right side. The most common radiological finding was "the direct monitoring of defect" (54,3%). CONCLUSION: Findings suggestive of diaphragmatic rupture must be carefully evaluated in patients with blunt or penetrating thoracoabdominal trauma. PMID- 28898730 TI - Immunogenicity of ORFV-based vectors expressing the rabies virus glycoprotein in livestock species. AB - The parapoxvirus Orf virus (ORFV) encodes several immunomodulatory proteins (IMPs) that modulate host-innate and pro-inflammatory responses and has been proposed as a vaccine delivery vector for use in animal species. Here we describe the construction and characterization of two recombinant ORFV vectors expressing the rabies virus (RABV) glycoprotein (G). The RABV-G gene was inserted in the ORFV024 or ORFV121 gene loci, which encode for IMPs that are unique to parapoxviruses and inhibit activation of the NF-kappaB signaling pathway. The immunogenicity of the resultant recombinant viruses (ORFV?024RABV-G or ORFV?121RABV-G, respectively) was evaluated in pigs and cattle. Immunization of the target species with ORFV?024RABV-G and ORFV?121RABV-G elicited robust neutralizing antibody responses against RABV. Notably, neutralizing antibody titers induced in ORFV?121RABV-G-immunized pigs and cattle were significantly higher than those detected in ORFV?024RABV-G-immunized animals, indicating a higher immunogenicity of ORFVDelta121-based vectors in these animal species. PMID- 28898731 TI - Ferroelectric spontaneous polarization steering charge carriers migration for promoting photocatalysis and molecular oxygen activation. AB - Introducing a polarization electric field in photocatalyst system is regarded asa new concept for photocatalytic activity enhancement. In this work, we first unearth that the spontaneous polarization of ferroelectric BaTiO3 promotes the photocatalytic and molecular oxygen activation performance of the narrow-band-gap semiconductor BiOI. Ferroelectric tetragonal-phase BaTiO3 (T-BaTiO3) were prepared via calcination of nonferroelectric cubic-phase BaTiO3 (C-BaTiO3), and their polarization ability was verified via ultrasonication-assisted piezoelectric catalytic degradation. Then, the C-BaTiO3/BiOI and T-BaTiO3/BiOI heterostructures are fabricated by a soft-chemical method. To disclose the influence of ferroelectric spontaneous polarization on charge movement behavior, the photocatalytic and molecular oxygen activation properties are monitored by degradation of methyl orange (MO) and superoxide radical (O2-) evolution under visible light irradiation (lambda>420nm), respectively. The results demonstrated that T-BaTiO3/BiOI far outperforms C-BaTiO3/BiOI and pristine BiOI. The ferroelectric spontaneous polarization of T-BaTiO3 can steer the migration of photogenerated charge carriers and induce efficient separation, accounting for the strengthened photodegradation and reactive oxygen species O2- production rate (11.02*10-7molL-1h-1). The study may furnish a new reference for developing efficient tactics to advance the photocatalytic and molecular oxygen activation ability for environmental chemistry and biochemistry applications. PMID- 28898732 TI - Poly(N-isopropylacrylamide)-hydroxyapatite nanocomposites as thermoresponsive filling materials on dentinal surface and tubules. AB - HYPOTHESIS: Dental decay, asa consequence of exposure to acidic foods and drinks, represents one of the most important tooth pathologies. Recently, enamel and dentinal surface remineralization using hydroxyapatite nano- and microparticles has been proposed; however, commercial remineralizing toothpastes are quite expensive, mostly due to the high costs of hydroxyapatite. Hence, we propose a thermoresponsive hybrid nanocomposite material as filler for tooth defects. The use of thermoresponsive composite particles aims at filling exposed dentinal tubules in response to a change of temperature in the oral cavity. In addition, the presence of the organic matrix contributes to the occlusion of the dentinal tubules, therefore reducing the needed amount of hydroxyapatite. EXPERIMENTS: Poly-N-isopropylacrylamide microgels containing different amounts of hydroxyapatite nanoparticles were prepared via radical polymerization in the presence of N-N'-methylenebisacrylamide as cross-linker followed by mechanical grinding. The nano- and microstructure of the hydrogels and their thermal behavior were studied via small-angle X-ray scattering (SAXS), scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Defected teeth were treated with a dispersion of nanocomposite microparticles to simulate toothpaste action. FINDINGS: The hydrogels maintain their structure and thermal responsiveness when loaded with an amount of hydroxyapatite nanoparticles up to 2.3%w/w. In addition, the lower critical solution temperature is not affected by the presence of the mineral particles. Exposed dentinal tubules on the surface of test tooth samples were successfully occluded after 15 cycles of treatment with a dispersion of nanocomposite microparticles alternated with washing steps. PMID- 28898733 TI - Manipulation of Pickering emulsion rheology using hydrophilically modified silica nanoparticles in brine. AB - HYPOTHESIS: Previous work on Pickering emulsions has shown that bromohexadecane in-water emulsions (50% oil) stabilized with fumed and spherical particles modified with hexadecyl groups develop a noticeable zero shear elastic storage modulus (G'0) of 200Pa and 9Pa, respectively, while in just 50mM NaCl. This high G'0 can be problematic for subsurface applications where brine salinities are higher and on the order of 600mM NaCl. High reservoir salinity coupled with low formation pressure drops could prevent an emulsion with a high G'0 from propagating deep into formation. It is hypothesized that G'0 of an emulsion can be minimized by using sterically stabilized silica nanoparticles modified with the hydrophilic silane (3-glycidyloxypropyl)trimethoxysilane (glymo). EXPERIMENTS: Bromohexadecane-in-water emulsions were stabilized with low and high coverage glymo nanoparticles. Oscillatory rheology was used to monitor G'0 asa function of nanoparticle concentration, oil volume fraction, salinity, and pH. Cryogenic scanning electron microscopy was used to make observations on the emulsion microstructure. FINDINGS: G'0 of bromohexadecane-in-water emulsions were minimized by using particles with a high coverage of glymo on the particle surface, which reduced the Ca2+/silanol site interactions. Emulsions that were stabilized with low surface coverage particles had noticeably higher G'0, however, their G'0 could be reduced by a factor of 3.3 by simply lowering the solution pH to 3. Cryo-SEM images showed that nanoparticle bridging was more pronounced with nanoparticles that had low glymo coverage as opposed to high coverage. PMID- 28898734 TI - A facile, bio-based, novel approach for synthesis of covalently functionalized graphene nanoplatelet nano-coolants toward improved thermo-physical and heat transfer properties. AB - In this study, we synthesized covalently functionalized graphene nanoplatelet (GNP) aqueous suspensions that are highly stable and environmentally friendly for use as coolants in heat transfer systems. We evaluated the heat transfer and hydrodynamic properties of these nano-coolants flowing through a horizontal stainless steel tube subjected to a uniform heat flux at its outer surface. The GNPs functionalized with clove buds using the one-pot technique. We characterized the clove-treated GNPs (CGNPs) using X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). We then dispersed the CGNPs in distilled water at three particle concentrations (0.025, 0.075 and 0.1wt%) in order to prepare the CGNP-water nanofluids (nano-coolants). We used ultraviolet-visible (UV-vis) spectroscopy to examine the stability and solubility of the CGNPs in the distilled water. There is significant enhancement in thermo-physical properties of CGNPs nanofluids relative those for distilled water. We validated our experimental set-up by comparing the friction factor and Nusselt number for distilled water obtained from experiments with those determined from empirical correlations, indeed, our experimental set-up is reliable and produces results with reasonable accuracy. We conducted heat transfer experiments for the CGNP water nano-coolants flowing through the horizontal heated tube in fully developed turbulent condition. Our results are indeed promising since there is a significant enhancement in the Nusselt number and convective heat transfer coefficient for the CGNP-water nanofluids, with only a negligible increase in the friction factor and pumping power. More importantly, we found that there is a significant increase in the performance index, which is a positive indicator that our nanofluids have potential to substitute conventional coolants in heat transfer systems because of their overall thermal performance and energy savings benefits. PMID- 28898735 TI - Electrochemical co-preparation of cobalt sulfide/reduced graphene oxide composite for electrocatalytic activity and determination of H2O2 in biological samples. AB - In this work, we describe a simple approach for the preparation of cobalt sulfide/reduced graphene oxide (CoS/RGO) nanohybrids via single step electrochemical method. The electrocatalytic activity of the CoS/RGO nanohybrids was evaluated towards the detection hydrogen peroxide (H2O2). The physiochemical properties of the prepared composite was characterized by means of field emission scanning electron microscopy, high-resolution transmission electron microscopy, X ray photoelectron spectroscopy, Raman spectroscopy and X-ray powder diffraction patterns. The CoS/RGO modified electrode showed superior electrocatalytic activity towards the detection of H2O2. The amperometric (i-t) studies revealed that the CoS/RGO performed well by attaining a wide linear response range of H2O2 from 0.1 to 2542.4MUM with a lower detection limit 42nM and the sensitivity of 2.519MUAMUM-1cm-2. Meanwhile, the CoS/RGO nanohybrids exhibited good selectivity, rapid and stable response towards H2O2. The practical applicability of the sensor was successfully evaluated in human serum and urine samples with satisfactory recoveries. PMID- 28898736 TI - Freestanding two-dimensional Ni(OH)2 thin sheets assembled by 3D nanoflake array as basic building units for supercapacitor electrode materials. AB - Freestanding two dimensional (2D) porous nanostructures have great potential in electrical energy storage. In the present work, we reported the first synthesis of two-dimensional (2D) beta-Ni(OH)2 thin sheets (CQU-Chen-Ni-O-H-1) assembled by 3D nanoflake array as basic building units under acid condition by direct hydrothermal decomposition of the mixed solution of nickel nitrate (Ni(NO3)2) and acetic acid (CH3COOH, AA). The unique 3D nanoflake array assembled mesoporous 2D structures endow the thin sheets with a high specific capacitance of 1.78Fcm-2 (1747.5Fg-1) at the current density of 1.02mAcm-2 and good rate capability of 67.4% retain from 1.02 to 10.2mAcm-2. The corresponding assembled asymmetric supercapacitor (ASC) achieves (CQU-Chen-Ni-O-H-1//active carbon (AC)) a high voltage of 1.8V and an energy density of 23.45Whkg-1 with a maximum power density of 9kWkg-1, as well as cycability with 93.6% capacitance retention after 10,000 cycles. These results show the mesoporous thin sheets have great potential for SCs and other energy storage devices. PMID- 28898737 TI - Light illumination intensity dependence of photovoltaic parameter in polymer solar cells with ammonium heptamolybdate as hole extraction layer. AB - A low-temperature, solution-processed molybdenum oxide (MoOX) layer and a facile method for polymer solar cells (PSCs) is developed. The PSCs based on a MoOX layer as the hole extraction layer (HEL) is a significant advance for achieving higher photovoltaic performance, especially under weaker light illumination intensity. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) measurements show that the (NH4)6Mo7O24 molecule decomposes and forms the molybdenum oxide (MoOX) molecule when undergoing thermal annealing treatment. In this study, PSCs with the MoOX layer as the HEL exhibited better photovoltaic performance, especially under weak light illumination intensity (from 100 to 10mWcm-2) compared to poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)-based PSCs. Analysis of the current density-voltage (J-V) characteristics at various light intensities provides information on the different recombination mechanisms in the PSCs with a MoOX and PEDOT:PSS layer as the HEL. That the slopes of the open-circuit voltage (VOC) versus light illumination intensity plots are close to 1 unity (kT/q) reveals that bimolecular recombination is the dominant and weaker monomolecular recombination mechanism in open-circuit conditions. That the slopes of the short-circuit current density (JSC) versus light illumination intensity plots are close to 1 reveals that the effective charge carrier transport and collection mechanism of the MoOX/indium tin oxide (ITO) anode is the weaker bimolecular recombination in short-circuit conditions. Our results indicate that MoOX is an alternative candidate for high performance PSCs, especially under weak light illumination intensity. PMID- 28898738 TI - Different magnesium release profiles from W/O/W emulsions based on crystallized oils. AB - Water-in-oil-in-water (W/O/W) double emulsions based on crystallized oils were prepared and the release kinetics of magnesium ions from the internal to the external aqueous phase was investigated at T=4 degrees C, for different crystallized lipophilic matrices. All the emulsions were formulated using the same surface-active species, namely polyglycerol polyricinoleate (oil-soluble) and sodium caseinate (water-soluble). The external aqueous phase was a lactose or glucose solution at approximately the same osmotic pressure as that of the inner droplets, in order to avoid osmotic water transfer phenomena. We investigated two types of crystallized lipophilic systems: one based on blends of cocoa butter and miglyol oil, exploring a solid fat content from 0 to 90% and the other system based on milk fat fractions for which the solid fat content varies between 54 and 86%. For double emulsions based on cocoa butter/miglyol oil, the rate of magnesium release was gradually lowered by increasing the % of fat crystals i.e. cocoa butter, in agreement with a diffusion/permeation mechanism. However for double emulsions based on milk fat fractions, the rate of magnesium release was independent of the % of fat crystals and remains the one at t=0. This difference in diffusion patterns, although the solid content is of the same order, suggests a different distribution of fat crystals within the double globules: a continuous fat network acting as a physical barrier for the diffusion of magnesium for double emulsions based on cocoa butter/miglyol oil and double globule/water interfacial distribution for milk fat fractions based double emulsions, through the formation of a crystalline shell allowing an effective protection of the double globules against diffusion of magnesium to the external aqueous phase. PMID- 28898739 TI - P-type conductive polymer/zeolitic imidazolate framework-67 (ZIF-67) nanocomposite film: Synthesis, characterization, and electrochemical performance as efficient electrode materials in pseudocapacitors. AB - In the present work, zeolitic imidazolate framework (ZIF-67) was synthesized via chemical routes. For improving the electrochemical performance of the conductive polymer, POAP/ /ZIF-67 composite films were fabricated by POAP electropolymerization in the presence of ZIF-67 as active electrodes for electrochemical supercapacitors. The structural and the valance states of the prepared samples were characterized by X-ray diffraction (XRD) and field emission scanning electron microscopy (FESEM). Different electrochemical methods, including galvanostatic charge discharge experiments, cyclic voltammetry, and electrochemical impedance spectroscopy, have been applied to study the system performance. The supercapacitive behavior of the composite film was attributed to the (i) high active surface area of the composite, the (ii) charge transfer along the polymer chain due to the conjugation form of the polymer, and finally, the (iii) synergism effect between the conductive polymer and ZIF-67. PMID- 28898740 TI - Transition from children's to adult services for young adults with life-limiting conditions: A realist review of the literature. AB - BACKGROUND: Improvements in care and treatment have led to more young adults with life-limiting conditions living beyond childhood, which means they must make the transition from children's to adult services. This has proved a challenging process for both young adults and service providers, with complex transition interventions interacting in unpredictable ways with local contexts. OBJECTIVES: To explain how intervention processes interact with contextual factors to help transition from children's to adult services for young adults with life-limiting conditions. DESIGN: Systematic realist review of the literature. DATA SOURCES: Literature was sourced from four electronic databases: Embase, MEDLINE, Science Direct and Cochrane Library from January 1995 to April 2016. This was supplemented with a search in Google Scholar and articles sourced from reference lists of included papers. REVIEW METHODS: Data were extracted using an adapted standardised data extraction tool which included identifying information related to interventions, mechanisms, contextual influences and outcomes. Two reviewers assessed the relevance of papers based on the inclusion criteria. Methodological rigor was assessed using the relevant Critical Appraisal Skills Programme tools. RESULTS: 78 articles were included in the review. Six interventions were identified related to an effective transition to adult services. Contextual factors include the need for children's service providers to collaborate with adult service providers to prepare an environment with knowledgeable staff and adequate resources. Mechanisms triggered by the interventions include a sense of empowerment and agency amongst all stakeholders. CONCLUSIONS: Early planning, collaboration between children's and adult service providers, and a focus on increasing the young adults' confidence in decision-making and engaging with adult services, are vital to a successful transition. Interventions should be tailored to their context and focused not only on organisational procedures but on equipping young adults, parents/carers and staff to engage with each other effectively. PMID- 28898741 TI - Comparative studies of cutins from lime (Citrus aurantifolia) and grapefruit (Citrus paradisi) after TFA hydrolysis. AB - Grapefruit and lime cutins were analyzed and compared in order to obtain information about their cutin architecture. This was performed using a sequential hydrolysis, first with trifluoroacetic acid to remove most of the polysaccharides present in the cutins, followed by an alkaline hydrolysis in order to obtain the main aliphatic compounds. Analysis by CPMAS 13C NMR and ATR FT-IR of the cutins after 2.0 M TFA revealed that grapefruit cutin has independent aliphatic and polysaccharide domains while in the lime cutin these components could be homogeneously distributed. These observations were in agreement with an AFM analysis of the cutins obtained in the hydrolysis reactions. The main aliphatic compounds were detected and characterized as 16-hydroxy-10-oxo-hexadecanoic acid and 10,16-dihydroxyhexadecanoic acid. These were present in grapefruit cutin at 35.80% and 21.86% and in lime cutin at 20.44% and 40.36% respectively. PMID- 28898742 TI - Neutrophil CD64, C-reactive protein, and procalcitonin in the identification of sepsis in the ICU - Post-test probabilities. AB - PURPOSE: We were interested in whether C-reactive protein (CRP) and procalcitonin (PCT) distinguish sepsis from non-septic controls and whether a combination of CRP, PCT, and neutrophil CD64 improves identification of sepsis in the intensive care unit (ICU). MATERIALS AND METHODS: We analyzed the CRP and PCT concentrations from 27 patients with sepsis and 15 ICU controls. In addition, CD64 on neutrophils was measured using quantitative flow cytometry. We present a multiple marker analysis for sepsis diagnostics combining neutrophil CD64, CRP, and PCT using post-test analysis. RESULTS: The CRP and PCT values separated sepsis and non-septic ICU patients. In post-test analysis, CRP provided a positive probability of 0.48 and a negative probability of 0.053 for sepsis in the ICU; while, the corresponding values were 0.35 and 0.0059, respectively, for PCT and 0.62 and 0.0013, respectively, for neutrophil CD64. When neutrophil CD64 was analyzed with PCT and CRP, the probabilities were 0.98 and <0.001, respectively. CONCLUSIONS: Neutrophil CD64 expression was superior to PCT and CRP for the identification of sepsis in ICU. Positive post-test probability for any combinations of simultaneously analyzed CRP, PCT and CD64 showed improved diagnostic accuracy for sepsis. This approach may be useful for guiding antibiotic treatment in ICU. PMID- 28898743 TI - qSOFA score: Predictive validity in Enterobacteriaceae bloodstream infections. AB - PURPOSE: To determine whether the quick Sequential Organ Failure Assessment (qSOFA) retains predictive validity in patients with Enterobacteriaceae sepsis that all received appropriate initial antimicrobial therapy. MATERIALS AND METHODS: Retrospective cohort at Barnes-Jewish Hospital including individuals with Enterobacteriaceae sepsis receiving appropriate initial antimicrobial therapy between 6/2009-12/2013. Outcomes were compared according to qSOFA score and sepsis classification. RESULTS: We identified 510 patients with Enterobacteriaceae sepsis; 67 (13.1%) died. Mortality was higher in patients with qSOFA scores of 2 or 3 than those with scores of 0 or 1 (13.3% and 42.4% versus 5.1% and 1.8%). In multivariate logistic regression analysis, altered mental status (AMS) alone or qSOFA score>=2 were both predictors of mortality with odds ratios of 8.01 and 5.39, respectively. Regardless of sepsis severity, non survivors were significantly more likely to have AMS than survivors. Sepsis severity, qSOFA, and AMS had comparable predictive validity for mortality. CONCLUSIONS: Our results support qSOFA score, AMS, and sepsis severity as acceptable bedside tools for prognostication during initial clinical assessment in patients with sepsis. qSOFA retained its predictive validity in this cohort, suggesting that appropriate initial antimicrobial therapy is not an effect modifier for mortality when using qSOFA for prognostication. PMID- 28898744 TI - The ability of intensive care unit physicians to estimate long-term prognosis in survivors of critical illness. AB - PURPOSE: To assess the reliability of physicians' prognoses for intensive care unit (ICU) survivors with respect to long-term survival and health related quality of life (HRQoL). METHODS: We performed an observational cohort-study in a single mixed tertiary ICU in The Netherlands. ICU survivors with a length of stay >48h were included. At ICU discharge, one-year prognosis was estimated by physicians using the four-option Sabadell score to record their expectations. The outcome of interest was poor outcome, which was defined as dying within one-year follow-up, or surviving with an EuroQoL5D-3L index <0.4. RESULTS: Among 1399 ICU survivors, 1068 (76%) subjects were expected to have a good outcome; 243 (18%) a poor long-term prognosis; 43 (3%) a poor short-term prognosis, and 45 (3%) to die in hospital (i.e. Sabadell score levels). Poor outcome was observed in 38%, 55%, 86%, and 100% of these groups respectively (concomitant c-index: 0.61). The expected prognosis did not match observed outcome in 365 (36%) patients. This was almost exclusively (99%) due to overoptimism. Physician experience did not affect results. CONCLUSIONS: Prognoses estimated by physicians incorrectly predicted long-term survival and HRQoL in one-third of ICU survivors. Moreover, inaccurate prognoses were generally the result of overoptimistic expectations of outcome. PMID- 28898745 TI - Glycosylation is important for FcXTH1 activity as judged by its structural and biochemical characterization. AB - Xyloglucan endotransglycosylase/hydrolases (XTH) may have endotransglycosylase (XET) and/or hydrolase (XEH) activities. Previous studies suggest that XTHs might play a key role in ripening of Fragaria chiloensis fruit as FcXTH1 transcripts increase as fruit softens. FcXTH1 protein sequence contains a conserved N glycosylation site adjacent to catalytic residues. The FcXTH1 structure was built through comparative modeling methodology, the structure displays a beta-jellyroll type folding with a curvature generated by eight antiparallel beta-sheets that holds the catalytic motif that is oriented towards the central cavity of the protein. Through Molecular Dynamic Simulations (MDS) analyses the protein-ligand interactions of FcXTH1 were explored, finding a better interaction with xyloglucans than cellulose. Nevertheless, the stability of the protein-ligand complex depends on the glycosylation state of FcXTH1: better energy interactions were determined for the glycosylated protein. As a complement, the molecular cloning and heterologous expression of FcXTH1 in Pichia pastoris was performed, and the recombinant protein was active and displayed strict XET activity. A KM value of 17.0 MUM was determined for xyloglucan oligomer. The deglycosylation of FcXTH1 by PNGase-F treatment affects its biochemical properties (increase KM and reduce kcat/KM ratio) and reduces its stability. As a conclusion, glycosylation of FcXTH1 is important for its biological function. PMID- 28898746 TI - Plant growth-promoting endophyte Piriformospora indica alleviates salinity stress in Medicago truncatula. AB - Piriformospora indica, a cultivable root endophytic fungus, induces growth promotion as well as biotic stress resistance and tolerance to abiotic stress in a broad range of host plants. In this study, the potential protection for M Medicago truncatula plants from salinity stress by P. indica was explored. The improved plant growth under severe saline condition was exhibited in P. indica colonized lines. Moreover, the antioxidant enzymes activities and hyphae density in roots were increased by the endophyte under high salt concentration. Conversely, reduced malondialdehyde (MDA) activity, Na+ content and relative electrolyte conductivity (REC) were observed in P. indica colonized plants. Especially, osmoprotectant proline accumulated and the expression of Delta 1 Pyrroline-5-carboxylate synthetase gene (P5CS2) was induced. The defense related genes PR1 and PR10 and the transcription factors MtAlfin1-like and C2H2-type zinc finger protein MtZfp-c2h2 were induced by P. indica colonization as well. Further work indicated that salinity resistance was increased in overexpressing P5CS2, MtAlfin1-like and MtZfp-c2h2 transgenic M. truncatula plants. Interestingly, our data showed that the transcription factors MtAlfin1-like and MtZfp-c2h2 were positively contributed to P. indica colonization. These results demonstrate that tolerance to salinity stress was conferred by P. indica in M. truncatula via accumulation of osmoprotectant, stimulating antioxidant enzymes and the expression of defense-related genes. This work revealed the potential application of P. indica's as a plant growth-promoting fungus for the target improvement either in crop protection or in the salinized soil improvement indirectly. PMID- 28898747 TI - Contraction of the transverse abdominal muscle in pelvic girdle pain is enhanced by pain provocation during the task. AB - BACKGROUND: Understanding of the pathogenesis of pain in the lumbopelvic region remains a challenge. It is suggested that lumbopelvic pain is related to decreased contraction of the transverse abdominal muscles (TrA). OBJECTIVE: To investigate how pain provoked by a task influences TrA contraction during that task. DESIGN: A case-control cross-sectional study. METHOD: We recruited 40 non pregnant women with persistent pregnancy-related posterior pelvic girdle pain (PGP) and 33 parous women (healthy controls) without PGP. TrA thickness was measured by ultrasound at various levels of bilateral hip adduction, with increments of 20 N from 0 to 140 N. Pain during the tests was registered. RESULTS: After correction for the level of adduction force, TrA thickness increase during pain-provoking tests of participants with PGP was 6.3 percentage points higher than in their pain-free tests (p = 0.01) and 0.91 percentage points higher than in the pain-free tests of healthy controls (p < 0.01). CONCLUSION: TrA contraction in PGP is enhanced when a task provokes pain. These results may have consequences for the treatment of persistent pregnancy-related posterior pelvic girdle pain. PMID- 28898748 TI - Behaviour change: Trialling a novel approach to reduce industrial stormwater pollution. AB - The evidence base for the performance and effectiveness of non-structural measures to manage stormwater pollution in industrial areas is relatively underdeveloped, despite their increased use in practice. This study aims to advance stormwater management practice and research by presenting a detailed case study of the development, implementation and evaluation of a targeted behaviour change trial that engaged small to medium industrial businesses in stormwater pollution prevention. Utilising a combination of different behaviour change strategies - including capacity building, social norms and commitment - a number of preventative stormwater pollution behaviours were changed in participating businesses. Our study provides a practice model for tackling stormwater pollution from a behavioural perspective that can be further developed by both practitioners and researchers to create effective and long-lasting change. PMID- 28898749 TI - Time-lagged response of carabid species richness and composition to past management practices and landscape context of semi-natural field margins. AB - Field margins are key features for the maintenance of biodiversity and associated ecosystem services in agricultural landscapes. Little is known about the effects of management practices of old semi-natural field margins, and their historical dimension regarding past management practices and landscape context is rarely considered. In this paper, the relative influence of recent and past management practices and landscape context (during the last five years) were assessed on the local biodiversity (species richness and composition) of carabid assemblages of field margins in agricultural landscapes of northwestern France. The results showed that recent patterns of carabid species richness and composition were best explained by management practices and landscape context measured four or five years ago. It suggests the existence of a time lag in the response of carabid assemblages to past environmental conditions of field margins. The relative contribution of past management practices and past landscape context varied depending on the spatial scale at which landscape context was taken into account. Carabid species richness was higher in grazed or sprayed field margins probably due to increased heterogeneity in habitat conditions. Field margins surrounded by grasslands and crops harbored species associated with open habitats whilst forest species dominated field margins surrounded by woodland. Landscape effect was higher at fine spatial scale, within 50 m around field margins. The present study highlights the importance of considering time-lagged responses of biodiversity when managing environment. It also suggests that old semi-natural field margins should not be considered as undisturbed habitats but more as management units being part of farming activities in agricultural landscapes, as for arable fields. PMID- 28898750 TI - Assessment of the effectiveness of onsite exsitu remediation by enhanced natural attenuation in the Niger Delta region, Nigeria. AB - This study was conducted to quantify and rank the effectiveness of onsite exsitu remediation by enhanced natural attenuation using soil quality index. The investigation was conducted at three oil spill sites in the Niger Delta (5.317 degrees N, 6.467 degrees E), Nigeria with a predominance of Oxisols. Baseline assessment and a two-step post-remediation monitoring of the sites were conducted. Target contaminants including total petroleum hydrocarbon (TPH) and BTEX (benzene, toluene, ethylbenzene, and xylene) were analyzed by gas chromatography-mass spectrometry. Results of the baseline assessment showed that TPH concentrations across the study sites averaged between 5113 and 7640 mg/kg at 0- to 1-m depth, which was higher than the local regulatory value of 5000 mg/kg. The soil quality index across the sites ranged between 68 and 45, suggesting medium to high potential ecological health risks with medium to high priority for remediation. BTEX concentrations followed a similar trend. However, after remediation TPH degraded rapidly initially and then slowly but asymptotically during the post-remediation monitoring period. Then, soil quality index across the study sites ranged between 100 and 58, indicating very low to medium potential ecological health risks. This demonstrates the effectiveness of onsite exsitu remediation by enhanced natural attenuation as a remediation strategy for petroleum-contaminated soils, which holds great promise for the Niger Delta province. PMID- 28898751 TI - Treatment of model solutions and wastewater containing selected hazardous metal ions using a chitin/lignin hybrid material as an effective sorbent. AB - A chitin/lignin material with defined physicochemical and morphological properties was used as an effective adsorbent of environmentally toxic metals from model systems. Particularly significant is its use in the neutralization of real industrial wastes. The ions Ni2+, Cu2+, Zn2+ and Pb2+ were adsorbed on the functional sorbent, confirming the high sorption capacity of the newly obtained product, primarily due to the presence on its surface of numerous active functional groups from the component biopolymers. The kinetics of the process of ion adsorption from model solution were investigated, and the experimental data were found to fit significantly better to a type 1 pseudo-second-order kinetic model, as confirmed by the high correlation coefficient of 0.999 for adsorption of both nickel(II) copper(II) zinc(II) and lead(II) ions. The experimental data obtained on the basis of adsorption isotherms corresponded to the Langmuir model. The sorption capacity of the chitin/lignin material was measured at 70.41 mg(Ni2+)/g, 75.70 mg(Cu2+)/g, 82.41 mg(Zn2+)/g and 91.74 mg(Pb2+)/g. Analysis of thermodynamic parameters confirmed the endothermic nature of the process. It was also shown that nitric acid is a very effective desorbing (regenerating) agent, enabling the chitin/lignin material to be reused as an effective sorbent of metal ions. The sorption abilities of the chitin/lignin system with respect to particular metal ions can be ordered in the sequence Ni2+water>acetone. In all complexes, the pi+-pi+ stacking interactions increase with the electron-donating substituents (EDSs) and decrease with the electron-withdrawing substituents (EWSs). Excellent correlations were found between the DeltaEpi+?pi+ values of the complexes and a combination of Hammett substituent constants. The results obtained from the atoms in molecules (AIM) and natural bond orbital (NBO) analysis show that the sum of electron densities calculated at BCPs and CCPs between the rings (?rBCP and ?rhoCCP) and the sum of donor-acceptor interaction energies (?E2) from one ring to other can be used as useful descriptors in the prediction of DeltaEpi+?pi+ values in the complexes. PMID- 28898789 TI - Transcriptome-wide identification and competitive disruption of sacum-binding partners in human colorectal cancer. AB - Human sacum is regulatory adaptor protein involved in cellular signaling network of colorectal cancer. Molecular evidence suggests that the protein is integrated into oncogenic signaling network by binding to SH3-containing proteins through its proline-rich motifs. In this study, we have performed a transcriptome-wide analysis and identification of sacum-binding partners in the genome profile of human colorectal cancer. The sacum-binding potency of SH3-containing proteins found in colorectal cancer was investigated by using bioinformatics modeling and intermolecular binding analysis. With the protocol we were able to predict those high-affinity domain binders of the proline-rich peptides of human sacum in a high-throughput manner, and to analyze sequence-specific interaction in the domain-peptide recognition at molecular level. Consequently, a number of putative domain binders with both high affinity and specificity were identified, from which the Src SH3 domain was selected as a case study and tested for its binding activity towards the sacum peptides. We also designed two peptide variants that may have potent capability to competitively disrupt sacum interaction with its partners. PMID- 28898790 TI - Cytotoxicity and potential anti-inflammatory activity of velutin on RAW 264.7 cell line differentiation: Implications in periodontal bone loss. AB - OBJECTIVES: Hypoxia-inducible factor-1alpha (HIF-1alpha) has been implicated in periodontal tissue inflammation and possibly in osteoclast differentiation, while polyphenols are known to be anti-inflammatory natural compounds that are capable of regulating the NF-kappaB protein complex pathway. The objective of this study was to investigate cytotoxicity and HIF-1alpha expression through the NF-kappaB pathway by polyphenol velutin (Euterpe oleracea Mart.), found in the pulp of acai fruit, during inflammatory RAW 264.7 differentiation. DESIGN: RAW 264.7 mouse monocyte macrophage cells were stimulated with RANKL (30ng/mL) and Porphyromonas gingivalis lipopolysaccharide (1MUg/mL). Cells were treated with various concentrations of velutin (0.5-2MUM) to check for viability, morphology, osteoclast differentiation, and HIF-1alpha expression (Western blot). RESULTS: Alamar blue cell viability assay showed no toxicity to RAW cells with the use of velutin in all concentrations tested (p>0.05). Velutin did not induce cell apoptosis based on caspase 3/7 assay (p>0.05). Fluorescence images stained by DAPI showed no alteration in the morphology of RAW cell nuclei (p>0.05) treated with velutin. TRAP assays demonstrated a dose-dependent reduction in osteoclast formation by velutin when compared with control (p<0.05). Velutin showed a reduction in HIF-1alpha expression related to IkappaB phosphorylation when compared with control (p<0.001). CONCLUSIONS: At the tested concentrations, velutin was not cytotoxic to RAW 264.7 and differentiated cells. Velutin reduced osteoclast differentiation and downregulated HIF-1alpha through the NF-kappaB pathway. PMID- 28898791 TI - Overlooked complication of anticoagulant therapy: The intramural small bowel hematoma-A case report. AB - INTRODUCTION: Intramural small bowel hematoma is a rare, and often overlooked consequence of anticoagulant therapy. In this report we present such a case in order to bring forth awareness to this entity, and its management. PRESENTATION OF CASE: We report a 81-year old male who presented with abdominal pain for 2days. He had been under anticoagulant therapy with warfarin for 9 years, presenting with an elevated INR of 6,2. Intramural small bowel hematoma was confirmed with abdominal ultrasound and CT scan. The patient was treated conservatively with anticoagulant suspension and administration of antidote, and was subsequently discharged after 6days. DISCUSSION: Abdominal complaints and an elevated INR value point to the possible diagnosis of intramural small bowel hematoma, however these abdominal symptoms can vary between a mild pain and an established acute abdomen. CT scan showing symmetric bowel thickening associated with some luminal narrowing confirms the diagnosis. In terms of management, there are not sufficient papers to support a standardized treatment; currently the most accepted approach seems to be conservative treatment after the exclusion of complications that would call for surgery. CONCLUSION: Anticoagulant therapy is becoming a widespread prescription as the population ages, and intramural small bowel hematoma is one consequence in need of consideration. PMID- 28898792 TI - Laparoscopic management for spontaneous jejunal perforation caused by nonspecific ulcer: A case report. AB - INTRODUCTION: Nonspecific small bowel ulcers are rare and there have been limited reports. We applied laparoscopic surgery successfully for the perforation caused by this disease of jejunum. PRESENTATION OF CASE: A 70-year-old man visited to our hospital with complaint of abdominal pain and fever. He was diagnosed abdominal peritonitis with findings of intraperitoneal gas and fluid. Emergency laparoscopic surgery was performed. A perforation 5mm in diameter was recognized in jejunum opposite side of mesentery. Partial resection of jejunum with end-to end anastomosis and peritoneal lavage were performed. Pathologically, an ulcer was recognized around the blowout perforation without specific inflammation. He was discharged uneventfully 12days after surgery. CONCLUSION: Laparoscopic surgery has diagnostic and therapeutic advantages because of its lower invasion with a good operation view, and in case of the small bowel, it is easy to shift extra-corporeal maneuver. PMID- 28898793 TI - Displaced acromion fracture: A rare injury, case report. AB - INTRODUCTION: Acromion fractures are extremely rare. There are no common accepted treatment schemes and fixation methods We aimed to present a case which may contribute to the diagnosis and treatment of acromion fracture in a patient with polytrauma. PRESENTATION OF CASE: Acromion fracture associated with scapula and clavicle fractures was diagnosed in 40 years old patient and treated with open reduction and cannulated screw fixation. The fracture healing was completed without causing subacromial impingement. DISCUSSION: In patients with polytrauma, diagnosis and treatment of acromion fractures can be delayed or overlooked. In improperly treated acromion fractures; pain, movement restriction, subacromial impingement, rotator cuff injury and symptomatic nonunion can occur. CONCLUSION: We recommend early surgical treatment for displaced acromion fractures, reduction of subacromial space and disruption of the superior shoulder suspensory complex. PMID- 28898794 TI - Surgical management of late bullet embolization from the abdomen to the right ventricle: Case report. AB - INTRODUCTION: Secondary embolus from gun projectile is a rare entity, it represents a clinical and therapeutic dilemma because the potential complications involving central and peripheral circulation. Each case reported in the literature represents a challenge because their unique and different clinical scenarios. PRESENTATION OF CASE: We present the management of a 33-year-old man with past history of a gunshot wound on left flank with no evidence of any exit wounds, treated with exploratory laparotomy without removing the gunshot bullet from the abdomen. The patient presents 6 years later with non-productive cough and retrosternal pain with no other symptoms; the patient underwent a chest x ray, electrocardiogram, thoracoabdominal CT, echocardiogram and cardiac catheterization and showed a bullet in the right ventricular floor. The projectile was extracted by sternotomy with extracorporeal circulation through the right atrium, without any complications. DISCUSSION: In 1834, Thomas David reported for the first time a wood-fragment embolization. There have been reported less than 200 cases including embolization of other materials; most of the gunshot bullet embolization cases reported on literature were reported after war. Clinical manifestations are associated with the anatomical site of embolism and mortality rate for a retained bullet is 6% associated with complication in 25% of cases. Mortality rate decreases to 1-2% if the bullet is removed. CONCLUSION: There are no established guidelines about the management of migrating foreign bodies or bullets, however, conservative, endovascular and surgical management have been proposed. In the cases of bullet embolization to the thoracic cavity, surgery represents a safe, low risk approach with high success rates. PMID- 28898795 TI - Intestinal perforation that developed after chemotherapy in a patient diagnosed with non-Hodgkin lymphoma: A case report and review of literature. AB - INTRODUCTION: Non-Hodgkin Lymphomas (NHL) appear with the malign transformation of mature lymphocytes. Intestinal perforations are one of the most well-known complications of NHLs. In this review, a 29-year-old male patient who was diagnosed with NHL with gastrointestinal involvement that developed intestinal perforation after chemotherapy is presented. PRESENTATION OF CASE: A 29-year-old male patient who received systemic chemotherapy in another healthcare center due to Major B-Cell Lymphoma was examined because he had stomachache after the treatment. The patient was urgently taken to operation. In the exploration, there were partly mass lesions in all small intestine segments. It was determined that one of the lesion was perforated. Small intestine resection was applied. The pathology report on resection material was reported as High Grade Major B-Cell Lymphoma. DISCUSSION: In the treatment of Lymphoma with intestinal B-Cells, there is no consensus because this disease is rarely observed. Perforation may appear as a complication of the chemotherapy. Depending on the steroids given to the patient, perforation may develop, and the clinical symptoms may be masked. CONCLUSION: It must be born in mind that there may be intestinal involvement in patients diagnosed with NHL, and intestinal perforation may develop due to chemotherapy. PMID- 28898796 TI - Transjugular biopsy case report of inferior vena cava hepatocellular carcinoma with intracardiac extension. AB - BACKGROUND: Diagnosis of hepatocellular carcinoma (HCC) can be established with near certainty by correlating radiological imaging with clinical presentation. However, in the absence of diagnostic certainty, biopsy of liver tissue is mandatory for optimal management. We present our management of a patient with advanced liver disease who presented with an IVC mass extending into the right atrium, with co-existing liver lesions not meeting criteria for an imaging diagnosis of HCC. CASE PRESENTATION: A 62-year-old male with Child-Pugh C liver cirrhosis presented with decompensated liver failure. Multiple imaging modalities demonstrated an inferior vena cava (IVC) mass extending into the right atrium with co-existing liver lesions not meeting radiological criteria for an imaging diagnosis of HCC. There was no contiguous evidence of HCC in the liver, yet there was extensive tumour burden in the IVC representing a separate metastatic lesion without any indication of direct tumour spread. Under fluoroscopic and angiographic guidance, a biopsy catheter was advanced through the right atrium into the IVC. Histology from the biopsy demonstrated fragments of malignant tumour with features consistent with moderately differentiated HCC without thrombus. Given the poor prognosis associated with metastatic HCC with IVC and intracardiac involvement, a multidisciplinary decision was made with the patient's family for palliation care. CONCLUSION: Transjugular biopsy of IVC masses can be performed effectively, in an awake patient, without the need for sedation or anaesthesia. Where multiple imaging modalities fail to confirm a diagnosis for liver or IVC pathology, transluminal biopsy can assist with definitive diagnosis and treatment planning. PMID- 28898797 TI - Scarless surgery for a huge liver cyst: A case report. AB - INTRODUCTION: Symptomatic or complicated liver cysts sometimes require surgical intervention and laparoscopic fenestration is the definitive treatment for these cysts. We performed minimally invasive surgery, hybrid natural orifice transluminal endoscopic surgery (NOTES) without scarring, for a huge liver cyst. PRESENTATION OF CASE: An 82-year-old female presented with a month-long history of right upper abdominal pain. We diagnosed her condition as a huge liver cyst by morphological studies. She denied any history of abdominal trauma. Her serum CEA and CA19-9 were normal and a serum echinococcus serologic test was negative. Laparoscopic fenestration, using a hybrid NOTES procedure via a transvaginal approach, was performed for a huge liver cyst because we anticipated difficulty with an umbilical approach, such as single incision laparoscopic surgery (SILS). Her post-operative course was uneventful and she was discharged from our hospital three days after surgery. Pain killers were not required during and after hospitalization. No recurrence of the liver cyst or bulging was detected by clinical examination two years later. DISCUSSION: A recent trend of laparoscopic procedure has been towards minimizing the number of incisions to achieve less invasiveness. This hybrid NOTES, with a small incision for abdominal access, along with vaginal access, enabled painless operation for a huge liver cyst. CONCLUSION: We report a huge liver cyst treated by hybrid NOTES. This approach is safe, less invasive, and may be the first choice for a huge liver cyst. PMID- 28898798 TI - Free disease long-term survival in primary thoracic spine leiomyosarcoma after total en bloc spondylectomy: A case report. AB - INTRODUCTION: To describe an unusual primary vertebral leiomyosarcoma in thoracic spine. PRESENTATION OF CASE: An isolated lesion of the T11 vertebra in a 62-year old woman with no neurologic deficit is reported. Imaging findings indicated a nonspecific high-grade malignant lesion. TC-guided biopsy failed thus open incisional biopsy was needed. A diagnosis of low-intermediate mesenchymal sarcoma was made. A total en bloc spondylectomy of T11 was performed with three-column reconstruction. The histology and immunostaining showed the appearance of leiomyosarcoma. After diagnosis, post-operative radiation therapy was performed. Metastatic lesion was ruled out by CT scans of the chest, abdomen and pelvis, in addition to total body radionuclide scanning and 18-F-FDG-PET. After five years of follow-up, no signs of local recurrence, metastasis or distant lesions suggesting a primary lesion were observed. DISCUSSION: Vertebral primary leiomyosarcoma is exceedingly rare. Primary vertebral leiomyosarcoma diagnosis must be performed when the metastatic origin is excluded. For the treatment of primary tumors, total en bloc spondylectomy (TES) is the technique of choice to achieve marginal or wide tumor resection, decrease the risk of local recurrence and remote lesions and increase survival. CONCLUSIONS: A well-planned pre operative study and a wide surgical excision can result in local tumor control and long-term survival. This case presents the longest disease-free survival period of a primary leiomyosarcoma in spinal location after total en bloc spondylectomy. PMID- 28898799 TI - Rare diagnosis of intestinal lipomatosis complicated by intussusception in an adult: A case report. AB - INTRODUCTION: Intestinal Lipomatosis consists of diffuse lipomas in various regions from the small to large bowel. They can remain asymptomatic or present with complications such as Intussusception. DISCUSSION: Intestinal lipomatosis complicated by Intussusception is a rare occurrence that has not been well documented. Rare condition management is difficult to approach because of the customizability each scenario requires. We hope through sharing our approach this can serve as a rough template to physicians who find themselves in a similar scenario. Overtime, as more case reports and surgical approaches are recorded we can establish future advancements in surgery. PRESENTATION OF CASE: We present the case of a 47 year-old male who arrived at the Emergency Department with a chief complaint of abdominal pain. A CT scan revealed ileocolic intussusception. An intramural lipoma of the terminal ileum served as the lead point. Exploratory laparotomy confirmed the Intussusception and a right hemicolectomy was performed to repair the affected area. Examination of the resected large bowel showed diffuse thickening of the mucosa in the area of the cecum confirmed to be submucosal lipomatosis on histological examination. Patient was discharged on the fifth post-operative day. CONCLUSION: This case confirmed previous treatment modalities in the management of intussusception. It also corroborates the complication of intussusception with Intestinal lipomatosis. It teaches us the importance of keeping a wide differential when considering a diagnosis of bowel obstruction. Through imaging, surgical exploration, and pathological interpretation, this case, which began as a complaint of abdominal pain, concluded as a rare clinical entity. PMID- 28898800 TI - Texting during stair negotiation and implications for fall risk. AB - BACKGROUND/AIM: Walking requires the integration of the sensory and motor systems. Cognitive distractions have been shown to interfere with negotiation of complex walking environments, especially in populations at greater risk for falls (e.g. the elderly). With the pervasiveness of mobile messaging and the recent introduction of augmented reality mobile gaming, it is increasingly important to understand how distraction associated with the simultaneous use of a mobile device impacts navigation of the complex walking environments experienced in daily life. In this study, we investigated how gait kinematics were altered when participants performed a texting task during step negotiation. METHODS: Twenty participants (13 female, 7 males) performed a series of walking trials involving a step-deck obstacle, consisting of at least 3 texting trials and 3 non-texting trials. RESULTS: When texting, participants ascended more slowly and demonstrated reduced dual-step foot toe clearance. Participants similarly descended more slowly when texting and demonstrated reduced single-step foot heel clearance as well as reduced dual-step foot fore-aft heel clearance. CONCLUSION: These data support the conclusion that texting during stair negotiation results in changes to gait kinematics that may increase the potential for gait disruptions, falls, and injury. Further research should examine the effect texting has on performing other common complex locomotor tasks, actual fall risk, and the patterns of resulting injury rate and severity when negotiating complex environments. PMID- 28898801 TI - The free moment is associated with torsion between the pelvis and the foot during gait. AB - BACKGROUND: During walking, the friction between the foot and the ground surface causes a free moment (FM), which influences the torsional stress on the lower extremity. However, few studies have investigated the FM during natural walking. The main aim of this study was to examine the relationship between the FM and the absolute and relative rotation angles of the foot and pelvis. METHODS: The rotation angles of foot and pelvic were measured in 18 healthy men using a motion capture system. Rotation angles were measured in absolute and relative coordinates as well as in reference to the line connecting the center of pressure (CoP) line under the right and left feet to evaluate the effects of the opposite lower limb on the FM. The absolute and relative rotation angles of the foot and pelvis were entered into forced-entry linear regression models to evaluate the influence on the FM. FINDINGS: Only the relative angle of rotation between the foot and pelvis could explain the prediction equations significantly. In the Pearson's product-moment correlation coefficient, the rotation angles of the foot and pelvis defined using the bilateral CoP points had not significantly correlated with FM. No joint rotation movement was correlated with FM. INTERPRETATION: The torsion of the entire lower extremity should be performed principally through hip internal rotation. When evaluating the FM as a torsional stress, focusing on the rotation of the entire lower extremity, rather than on one segment, is beneficial. PMID- 28898802 TI - Nucleases activities during French bean leaf aging and dark-induced senescence. AB - During leaf senescence resources are managed, with nutrients mobilized from older leaves to new sink tissues. The latter implies a dilemma in terms of resource utilization, the leaf senescence should increase seed quality whereas delay in senescence should improve the seed yield. Increased knowledge about nutrient recycling during leaf senescence could lead to advances in agriculture and improved seed quality. Macromolecules mobilized during leaf senescence include proteins and nucleic acids. Although nucleic acids have been less well studied than protein degradation, they are possible reservoirs of nitrogen and phosphorous. The present study investigated nuclease activities and gene expression patterns of five members of the S1/P1 family in French bean (Phaseolus vulgaris L. cv.)Page: 2 during leaf senescence. An in-gel assay was used to detect nuclease activity during natural and dark-induced senescence, with single stranded DNA (ssDNA) used as a substrate. The results revealed two nucleases (glycoproteins), with molecular masses of 34 and 39kDa in the senescent leaves. The nuclease activities were higher at a neutral than at an acidic pH. EDTA treatment inhibited the activities of the nucleases, and the addition of zinc resulted in the recovery of these activities. Both the 34 and 39kDa nucleases were able to use RNA and double-stranded DNA (dsDNA) as substrates, although their activities were low when dsDNA was used as a substrate. In addition, two ribonucleases with molecular masses of 14 and 16kDa, both of which could only utilize RNA as a substrate, were detected in the senescent leaves. Two members of the S1/P1 family, PVN2 and PVN5, were expressed under the experimental conditions, suggesting that these two genes were involved in senescence. The nuclease activity of the glycoproteins and gene expression were similar under both natural senescence and dark-induced senescence conditions. PMID- 28898803 TI - Cytotoxic effects of commonly used nanomaterials and microplastics on cerebral and epithelial human cells. AB - Plastic wastes are among the major inputs of detritus into aquatic ecosystems. Also, during recent years the increasing use of new materials such as nanomaterials (NMs) in industrial and household applications has contributed to the complexity of waste mixtures in aquatic systems. The current effects and the synergism and antagonisms of mixtures of microplastics (MPLs), NMs and organic compounds on the environment and in human health have, to date, not been well understood but instead they are a cause for general concern. The aim of this work is to contribute to a better understanding of the cytotoxicity of NMs and microplastics/nanoplastics (MPLs/NPLs), at cell level in terms of oxidative stress (evaluating Reactive Oxygen Species effect) and cell viability. Firstly, the individual cytotoxicity of metal nanoparticles (NPs) (AgNPs and AuNPs), of metal oxide NPs (ZrO2NPs, CeO2NPs, TiO2NPs, and Al2O3NPs), carbon nanomaterials (C60fullerene, graphene), and MPLs of polyethylene (PE) and polystyrene (PS) has been evaluated in vitro. Two different cellular lines T98G and HeLa, cerebral and epithelial human cells, respectively, were employed. The cells were exposed during 24-48h to different levels of contaminants, from 10ng/mL to 10ug/mL, under the same conditions. Secondly, the synergistic and antagonistic relationships between fullerenes and other organic contaminants, including an organophosphate insecticide (malathion), a surfactant (sodium dodecylbenzenesulfonate) and a plasticiser (diethyl phthalate) were assessed. The obtained results confirm that oxidative stress is one of the mechanisms of cytotoxicity at cell level, as has been observed for both cell lines and contributes to the current knowledge of the effects of NMs and MPLs-NPLs. PMID- 28898804 TI - Application of manure containing tetracyclines slowed down the dissipation of tet resistance genes and caused changes in the composition of soil bacteria. AB - Manure application contributes to the increased environmental burden of antibiotic resistance genes (ARGs). We investigated the response of tetracycline (tet) resistance genes and bacterial taxa to manure application amended with tetracyclines over two months. Representative tetracyclines (oxytetracycline, chlorotetracycline and doxycycline), tet resistance genes (tet(M), tet(O), tet(W), tet(S), tet(Q) and tet(X)) and bacterial taxa in the untreated soil, +manure, and +manure+tetracyclines groups were analyzed. The abundances of all tet resistance genes in the +manure group were significantly higher than those in the untreated soil group on day 1. The abundances of all tet resistance genes (except tet(Q) and tet(X)) were significantly lower in the +manure group than those in the +manure+tetracyclines group on day 30 and 60. The dissipation rates were higher in the +manure group than those in the +manure+tetracyclines group. Disturbance of soil bacterial community composition imposed by tetracyclines was also observed. The results indicated that tetracyclines slowed down the dissipation of tet resistance genes in arable soil after manure application. Application of manure amended with tetracyclines may provide a significant selective advantage for species affiliated to the taxonomical families of Micromonosporaceae, Propionibacteriaceae, Streptomycetaceae, Nitrospiraceae and Clostridiaceae. PMID- 28898805 TI - Molecular changes in vitellogenin gene of Spodoptera exigua after long-time exposure to cadmium - Toxic side effect or microevolution? AB - The reproduction of pest insects is a continuously ongoing issue, especially in the environmental pollution context. Natural or artificial stressing factors enforce a kind of trade-off, most often between growth/survival and reproduction, which improves fitness of the organism. Harmful factors, such as cadmium, can affect the vitellogenesis leading to reduction of yolk synthesis and egg production. The aim of this study was to assess whether 130-generational selection to cadmium in food might have induced change in vitellogenesis of Spodoptera exigua. We analyzed the level of Vg gene expression in S. exigua from the control and the cadmium strain at regular time intervals within 48h after eclosion. The full sequence of Vg gene was also compared between strains. The vitellogenin gene expression in both strains was time-dependent. This dependence was more visible in the control strain. In the cadmium strain the vitellogenin expression was significantly lower, comparing with the control strain in the first day after eclosion but increased significantly in the second day. The sequenced CDS (5286bp long) of the control and the cadmium strains were translated into protein sequences containing both 1761 aa. The protein sequences comparison revealed that there is one amino acid change at aa position 1282. Multiple alignments of six orthologous proteins from different species showed that amino acid change is located in the conserved position. Long-lasting exposure to cadmium resulted in permanent mutation in vitellogenin gene. We do not know yet if the mutation can improve fitness of the cadmium-selected insects. However, we can suppose that the mutation is neutral or even beneficial. The mutation and most probably additional effects of cadmium exposure have an influence on the vitellogenin expression. Some modification in the expression of the vitellogenin receptor are also likely to be important. PMID- 28898806 TI - Benefits of switching to suvorexant for mild primary insomnia when sleepwalking episodes occur during zolpidem treatment. PMID- 28898807 TI - Social functioning in individuals with first episode psychosis: One-year follow up study. AB - BACKGROUND: Improvement in social functioning is important for recovery in first episode psychosis (FEP). METHODOLOGY: 51 individuals diagnosed with first episode psychosis were assessed for social functioning at baseline and one year follow up. RESULTS: Significant improvement was seen in certain domains of social functioning measured by LSP scale such as communication and non-turbulence while no significant changes were observed in self-care and social contact. CONCLUSION: At one year follow-up, partial improvement in social functioning is observed in individuals with first episode psychosis. This warrants inclusion of specific interventions to improve social functioning in the management plan of individuals with FEP. PMID- 28898808 TI - Associations between statewide prescription drug monitoring program (PDMP) requirement and physician patterns of prescribing opioid analgesics for patients with non-cancer chronic pain. AB - OBJECTIVE: State-level prescription drug monitoring programs (PDMPs) have been implemented in most states. PDMPs enable registered prescribers to obtain real time information on patients' prescription history to reduce non-medical use of controlled drugs. This study examined whether PDMP implementation and different levels of PDMP requirements were associated with physicians' patterns of prescribing opioid analgesics for patients with non-cancer chronic pain. METHODS: This is a secondary analysis study using cross-sectional national data. Patients with non-cancer chronic pain from the 2012 National Ambulatory Medical Care Survey were included (weighted N=81,018,131; unweighted N=3295). Heckman two-step selection procedure employing two logistic regressions was used to explore the associations between PDMP requirements and physicians' prescribing behaviors, controlling for physician characteristics, patient characteristics, physician healthcare system interaction, and physician-patient relationship, guided by the Eisenberg's model of physician decision making. RESULTS: State PDMP implementation status and requirement levels were not associated with physician opioid prescribing for non-cancer chronic pain treatment (p's ranged 0.30-0.32). Patients with Medicare coverage were more likely to be prescribed opioid analgesics than those with private health insurance (OR=1.55, p<0.01). Hispanic patients were less likely to be prescribed opioid analgesics than non-Hispanic white patients (OR=0.61, p<0.05). CONCLUSIONS: Findings indicated that the effectiveness of PDMPs on physicians' opioid prescribing tendency for non-cancer chronic pain treatment could not be supported. Policy makers should be aware of the need for redesigning PDMPs regarding requirements and enforcement for prescribers and related stakeholders. Future studies also are needed to identify characteristics contributing to PDMP effectiveness in reducing non-medical use of prescription opioids. PMID- 28898809 TI - Occurrence of nitro- and oxy-PAHs in agricultural soils in eastern China and excess lifetime cancer risks from human exposure through soil ingestion. AB - The quality of agricultural soil is vital to human health, however soil contamination is a severe problem in China. Polycyclic aromatic hydrocarbons (PAHs) have been found to be among the major soil contaminants in China. PAH derivatives could be more toxic but their measurements in soils are extremely limited. This study reports levels, spatial distributions and compositions of 11 nitrated (nPAHs) and 4 oxygenated PAHs (oPAHs) in agricultural soils covering 26 provinces in eastern China to fill the data gap. The excess lifetime cancer risk (ELCR) from the exposure to them in addition to 21 parent PAHs (pPAHs) via soil ingestion has been estimated. The mean concentration of ?nPAHs and ?oPAHs in agricultural soils is 50+/-45MUg/kg and 9+/-8MUg/kg respectively. Both ?nPAHs and ?oPAHs follow a similar spatial distribution pattern with elevated concentrations found in Liaoning, Shanxi, Henan and Guizhou. However if taking account of pPAHs, the high ELCR by soil ingestion is estimated for Shanxi, Zhejiang, Liaoning, Jiangsu and Hubei. The maximum ELCR is estimated at ca.10-5 by both deterministic and probabilistic studies with moderate toxic equivalent factors (TEFs). If maximum TEFs available are applied, there is a 0.2% probability that the ELCR will exceed 10-4 in the areas covered. There is a great chance to underestimate the ELCR via soil ingestion for some regions if only the 16 priority PAHs in agricultural soils are considered. The early life exposure and burden are considered extremely important to ELCR. Emission sources are qualitatively predicted and for areas with higher ELCR such as Shanxi and Liaoning, new loadings of PAHs and derivatives are identified. This is the first large scale study on nPAHs and oPAHs contamination levels in agricultural soils in China. The risk assessment based on this underpins the policy making and is valuable for both scientists and policy makers. PMID- 28898810 TI - The European water-based environmental quality standard for pentachlorophenol is NOT protective of benthic organisms. AB - Risk management of toxic substances is often based on Environmental Quality Standards (EQS) set for the water compartment, assuming they will also protect benthic organisms. In the absence of experimental data, EQS for sediments can be estimated by the equilibrium partitioning approach. The present study investigates whether this approach is protective of benthic organisms against pentachlorophenol (PCP), a legacy contaminant and EU priority substance still used in some parts of the world. Three freshwater species of invertebrates with different life cycles and feeding behaviors (the oligochaetes Lumbriculus variegatus, Tubifex tubifex and the dipteran insect Chironomus riparius) were exposed to PCP spiked sediments (2.10-46.03mgPCP/kg d.w. plus controls) in laboratory standard tests. Exposure duration was 28days for T. tubifex and L. variegatus and 10 and 28days for C. riparius; according to the corresponding OECD guidelines. For each investigated end-point, dose-response data were normalized to the mean control and fitted to a four-parameter log-logistic model for calculating the corresponding EC50 and EC10. The ranges for EC50 and EC10 estimates were 4.39 (Chironomus riparius-emergence)-27.50 (Tubifex tubifex cocoon) and 0.30 (T. tubifex-young worms) -16.70 (T. tubifex-cocoon) mg/kg d.w., respectively. The EC50 and the EC10 values of L. variegatus were within these ranges. Following the EU Technical Guidance for deriving EQS, the lowest EC10 value of 0.30mg/kg (T. tubifex-young worms) resulted in a PCP quality standard (QS) for sediments of 30ng/g, about one fourth of the tentative QS of 119ng/g estimated by the equilibrium partitioning (EqP) approach. The response of benthic biota to PCP varied across organisms and across end-points for the same organism, so that the use of sediment PCP-QS calculated using the EqP-approach may be under protective of the most sensitive organisms. Information on the possible effects of PCP on resident organisms must therefore be collected for appropriately managing aquatic systems. PMID- 28898811 TI - Modelling the correlations of e-waste quantity with economic increase. AB - Waste from Electrical and Electronic Equipment (WEEE or e-waste) is regarded as one of the fastest growing waste streams in the world and is becoming an emerging issue owing to adverse consequences on the natural environment and the human health. This research article reveals the presence of a strong linear correlation among global e-waste generation and Gross Domestic Product. The obtained results indicate that the best fit for data can be reached by comparing e-waste collected volumes and GDP PPS. More in detail, an increase of 1000 GDP PPS means an additional 0.27kg of e-waste collected and 0.22kg of e-waste reused/recycled. Furthermore, for each additional citizen, there will be an increase of 7.7kg of e waste collected and 6.2kg of e-waste reused/recycled. The better collection of e waste acts an important role concerning the circular economy, and it can be an advantageous approach. Therefore, e-waste could be considered as an opportunity for recycling or recovery of valuable metals (e.g., copper, gold, silver, and palladium), given their significant content in precious metals than in mineral ores. PMID- 28898812 TI - Formation of hydroxylated and methoxylated polychlorinated biphenyls by Bacillus subtilis: New insights into microbial metabolism. AB - The detoxification and degradation of polychlorinated biphenyls (PCBs) have been studied. However, little information is available about the biological mechanisms involved in the metabolism of hydroxylated polychlorinated biphenyls (OH-PCBs) and methoxylated polychlorinated biphenyls (MeO-PCBs) by specific microorganism. In this study, the simultaneous formation of OH-PCB (major metabolite) and MeO PCB (minor metabolite) was found in Bacillus subtilis after exposure to PCB. Interconversion between MeO-PCB and OH-PCB was also observed and the demethylation ratio of MeO-PCB was higher than the methylation ratio of OH-PCB. The high-throughput RNA-sequencing (RNA-Seq) was conducted to analyze the genes involved in the metabolism processes. The potential metabolism pathways of PCB by Bacillus subtilis were proposed. PCB can be transformed to OH-PCB by Cytochrome P450 encoded by the genes bioI and cypA. The genes ycgJ and ycgI that are related with methyltransferase are potentially involved in the subsequent biotransformation from OH-PCB to MeO-PCB. MeO-PCB was prone to be transformed to OH-PCB by a group of hydrolases. This is the first study considering the mechanism involved in the interconversion between OH-PCBs and MeO-PCBs by microorganism. These findings broaden our insights into the biotransformation mechanism of PCBs in the environment. PMID- 28898813 TI - Insight into the modulation of intestinal proteome of juvenile common carp (Cyprinus carpio L.) after dietary exposure to ZnO nanoparticles. AB - ZnO nanoparticles (NPs) are widely used in industrial and consumer products. Therefore understanding their interaction with biological systems is key to their safe application. Proteomics was applied to assess the sub-lethal effects of dietary ZnO NPs on two parts of carp intestine, the intestinal folds and the muscular parts. A commercial carp feed containing 500mgkg-1 of ZnO NPs was fed to fish for six weeks. The abundances of 32 proteins in the treated intestinal folds were significantly changed and in addition, 28 proteins were significantly changed in the muscular parts. Pathways analysis revealed downregulation of pathways attributed to protein synthesis in both parts of the treated intestine. Remodelling of actin cytoskeleton pathways were regulated positively and negatively in intestinal folds and muscular parts, respectively, albeit via different mechanisms. Apoptosis response was indicated in exposed intestinal folds, whereas elevated levels of protein associated with cancerous cell survival were observed in the muscular parts. Results showed that ZnO NPs affected the protein abundances associated with cell motility, immune system response, oxidative stress response, as well as cell metabolism. Data are available via ProteomeXchange with identifier PXD006867. PMID- 28898814 TI - The distribution of lumbar intervertebral angles in upright standing and extension is related to low back pain developed during standing. AB - BACKGROUND: Lumbar lordosis measures are poorly related to clinical low back pain, however using a controlled exposure such as prolonged standing to identify pain groups may clarify this relationship. The purpose of this study was to determine the distribution of lumbar intervertebral angles in asymptomatic persons who do (pain developers) and do not (non-pain developers) develop low back pain during standing. METHODS: Sagittal plane lumbar spine radiographs of eight pain developers and eight non-pain developers were taken in three poses: upright standing, full extension and full flexion. Measures of vertebral end plate orientations from L1 to S1 were taken in each pose to compute: intervertebral angles, contribution of each level to the total curve, total lordosis, ranges of motion, relative pose positioning within the range of motion, vertebral shape, and lumbar spine recurve. Measures were compared between pain groups and lumbar levels. FINDINGS: Pain group differences in intervertebral angles and level contributions were greatest in the full extension pose, with pain developers having greater contributions from higher lumbar levels and fewer contributions from lower levels than non-pain developers. Pain group differences in intervertebral angle distributions were less pronounced in upright standing and non-existent in full flexion. No other measures differentiated pain groups. INTERPRETATIONS: Although participants had similar gross-lumbar spine curvature characteristics, non-pain developers have more curvature at lower levels in upright standing and full extension. These differences in regional vertebral kinematics may partially be responsible for standing-induced low back pain. PMID- 28898815 TI - Biomechanical evaluation of different surgical procedures in single-level transforaminal lumbar interbody fusion in vitro. AB - BACKGROUNDS: A variety of improved surgical methods were adopted in the transforaminal lumbar interbody fusion. A mechanical stability provides an ideal environment for the formation of a fusion mass and is the basis of their good outcomes. The object of this study is to evaluate the initial similarities and differences of four commonly-used posterior surgical procedures biomechanically. METHODS: Biomechanical testing was performed at L3-4 motion segment in 6 fresh frozen human cadaveric lumbar spines (L2-L5), including the following sequentially tested configurations: 1) intact motion segment; 2) bilateral pedicle screw fixation; 3) unilateral pedicle screw fixation; 4) unilateral pedicle screw plus contralateral translaminar facet joint screw fixation according to the Magerl technique; and 5) bilateral pedicle screw fixation with bilateral facetectomies. The range of motion, neutral zone and stiffness of each method and intact segment were collected and compared. FINDINGS: All of four methods reduce the range of motion significantly in flexion and extension and lateral bending but not in axial torsion compared with the native segment. There is no significant difference among four procedures about the range of motion in all loading modes. All of methods increase the stiffness of segmental motion compared with intact segment in all loading modes, but only bilateral pedicle screw fixation showed significant increases in stiffness in flexion and extension(p=0.02) and lateral bending(p=0.023). The stiffness offered by instrumented constructs in different methods showed no significant difference in all loading modes. INTERPRETATION: The stiffness offered by four different posterior fixations in single segmental transforaminal lumbar interbody fusion is not significantly different. PMID- 28898816 TI - Impaired heel to toe progression during gait is related to reduced ankle range of motion in people with Multiple Sclerosis. AB - BACKGROUND: Gait impairment in people with Multiple Sclerosis results from neurological impairment, muscle weakness and reduced range of motion. Restrictions in passive ankle range of motion can result in abnormal heel-to-toe progression (weight transfer) and inefficient gait patterns in people with Multiple Sclerosis. The purpose of this study was to determine the associations between gait impairment, heel-to-toe progression and ankle range of motion in people with Multiple Sclerosis. METHODS: Twelve participants with Multiple Sclerosis and twelve healthy age-matched participants were assessed. Spatiotemporal parameters of gait and individual footprint data were used to investigate group differences. A pressure sensitive walkway was used to divide each footprint into three phases (contact, mid-stance, propulsive) and calculate the heel-to-toe progression during the stance phase of gait. FINDINGS: Compared to healthy controls, people with Multiple Sclerosis spent relatively less time in contact phase (7.8% vs 25.1%) and more time in the mid stance phase of gait (57.3% vs 33.7%). Inter-limb differences were observed in people with Multiple Sclerosis between the affected and non-affected sides for contact (7.8% vs 15.3%) and mid stance (57.3% and 47.1%) phases. Differences in heel-to-toe progression remained significant after adjusting for walking speed and were correlated with walking distance and ankle range of motion. INTERPRETATION: Impaired heel-to-toe progression was related to poor ankle range of motion in people with Multiple Sclerosis. Heel-to-toe progression provided a sensitive measure for assessing gait impairments that were not detectable using standard spatiotemporal gait parameters. PMID- 28898817 TI - Long-term trends in incidence and survival of penile cancer in France. AB - BACKGROUND: Penile cancer is rare, and few population-based studies have described changes in time trend. This study aims to determine whether there has been an evolution in incidence and survival of penile cancer over time in France. METHODS: Rates of age world-standardized incidence (ASRW) and net survival (NS) between 1989 and 2011 were calculated using data from 16 French cancer registries. Time trend incidence and survival analysis were confined to the eight registries operating throughout the full period. Log-linear Poisson regression analysis was used to estimate the average annual percentage change (AAPC) in incidence rates. The incidence rate for the most recent period was also calculated from all 16 cancer registries operating during 2009-2011. Human papillomavirus (HPV) exposure was deduced from the morphological code. NS was estimated using the Pohar-Perme estimator of the net cumulative rate. RESULTS: No significant change in incidence was observed between 1989 and 2011 (AAPC: 0.08%; 95%CI: -1.01%; +1.17%). The incidence increased with age. The ASRW in 16 registries operating in 2009-2011 was 0.59 per 100,000 (95%CI: 0.50-0.68). The proportion of cases potentially linked to HPV was nearly 11% and did not change significantly over time. NS decreased with age but did not change over time (around 65% at 5 years). CONCLUSION: Penile cancer remains rare in France, but survival is still low - probably because of delays in diagnosis and limited improvements in care. International clinical trials are needed to develop care recommendations based on an adequate level of evidence. PMID- 28898818 TI - The impact of demographic factors, behaviors and environmental exposure to mercury content in the hair of the population living in the region of Lodz (central Poland). AB - The aim of this work was to access the influence of different factors such as sex, age, fish consumption, hair dyeing or smoking habit on the content of mercury in human hair samples. The research was carried on 444 samples (102 males and 342 females) collected from the population of people living in the region of Lodz (central Poland). The content of mercury in human hair samples was determined using the Mercury Analyzer MA 3000 (Nippon Instruments, Japan). The obtained results were elaborated using Statistica ver. 10.0 software. The mean value of mercury in investigated human hair samples was found to be 0.174+/ 0.137mg/kg. We observed the statistically significant correlations (p<0.05) between the content of Hg in hair of the studied population and factors such as gender, age, and fish consumption. However, no statistically significant differences were found in relation to cosmetic treatment such as hair dyeing or smoking. PMID- 28898819 TI - Characterization of UF foulants and fouling mechanisms when applying low in-line coagulant pre-treatment. AB - Fluorescence spectroscopy was used as a characterization method to examine organic fouling of single ultrafiltration (UF) fibres at bench-scale. Low doses of coagulant were applied to modify organic properties, without significant formation of precipitates. This approach compliments previous studies investigating coagulation as a pre-treatment method for UF fouling control, which have principally focused on reduction of foulant concentrations. Using a continuous system, short time-scale fluorescence results demonstrated significant adsorption of humic components to virgin membrane fibres. Following an initial adsorption phase, protein-like material was the only organic component to be significantly removed by UF. Low doses of coagulant (<1 mg/L as alum; < 0.043 mg/L as Al3+) were observed to significantly reduce irreversible fouling rates for two different surface waters. Paralleling reduced irreversible fouling, surface tryptophan fluorescence resulting from material adsorbed to the fouled membrane increased, as measured using a fibre optic probe. Analysis of peak shifts in the protein-like component revealed a red-shift at low coagulant dose, possibly indicative of greater exposure of tryptophan residues resulting from conformational changes in the protein structure. It is hypothesized that low coagulant doses modified membrane-foulant interactions, resulting in increased adsorption of protein-like matter to the surface. Subsequent interactions of bulk foulants with the adsorbed organic monolayer discouraged further adsorption and reduced irreversible fouling potential. PMID- 28898820 TI - Terahertz spectroscopic investigation of gallic acid and its monohydrate. AB - The low-frequency spectra of gallic acid (GA) and its monohydrate were investigated by terahertz time-domain spectroscopy (THz-TDS) in the range of 0.5 to 4.5THz. The dehydration process of GA monohydrate was monitored on-line. The kinetic mechanism of the dehydration process was analyzed depending on the THz spectral change at different temperatures. The results indicate that the diffusion of water molecule dominates the speed of the entire dehydration process. Solid-state density functional theory (DFT) calculations of the vibrational modes of both GA and its monohydrate were performed based on their crystalline structures for better interpreting the experimental THz spectra. The results demonstrate that the characterized features of GA mainly originate from the collective vibrations of molecules. And the interactions between GA and water molecules are responsible for THz fingerprint of GA monohydrate. Multi-techniques including differential scanning calorimetry and thermogravimetry (DSC-TG) and powder X-ray diffraction (PXRD) were also carried out to further investigate GA and its monohydrate. PMID- 28898821 TI - Topological analysis (BCP) of vibrational spectroscopic studies, docking, RDG, DSSC, Fukui functions and chemical reactivity of 2-methylphenylacetic acid. AB - Experimental FT-IR and FT-Raman spectra of 2-methylphenylacetic acid (MPA) were recorded and theoretical values are also analyzed. The non-linear optical (NLO) properties were evaluated by determination of first (5.5053*10-30 e.s.u.) and second hyper-polarizabilities (7.6833*10-36 e.s.u.) of the title compound. The Multiwfn package is used to find the weak non-covalent interaction (Van der Wall interaction) and strong repulsion (steric effect) of the molecule and examined by reduced density gradient. The molecular electrostatic potential (MEP) analysis used to find the most reactive sites for the electrophilic and nucleophilic attack. The chemical activity (electronegativity, hardness, chemical softness and chemical potential) of the title compound was predicted with the help of HOMO LUMO energy values. The natural bond orbital (NBO) has been analyzed the stability of the molecule arising from the hyper-conjugative interaction. DSSCs were discussed in structural modifications that improve the electron injection efficiency of the title compound (MPA). The Fukui functions are calculated in order to get information associated with the local reactivity properties of the title compound. The binding sites of the two receptors were reported by molecular docking field and active site bond distance is same 1.9A. The inhibitor of the title compound forms a stable complex with 1QYV and 2H1K proteins at the binding energies are -5.38 and -5.85 (?G in kcal/mol). PMID- 28898822 TI - Enhanced enzymatic hydrolysis of eucalyptus by synergy of zinc chloride hydrate pretreatment and bovine serum albumin. AB - Enhancement of eucalyptus enzymatic saccharification by synergy of ZnCl2 hydrate pretreatment and bovine serum albumin (BSA) was investigated in this study. The result showed that the ZnCl2 hydrate pretreatment could not only selectively extract up to ~100% of the hemicellulose from eucalyptus, but also convert portion of high crystalline cellulose I into low crystalline cellulose II, which both beneficial for enhancing subsequent pretreated solids enzymatic saccharification. The addition of BSA into enzymatic hydrolysis step could significantly promote the glucose release from pretreated solids, especially, under the low enzyme loading. Furthermore, the material balance indicated that the highest glucose yield of this study was 35.5g/100g raw material, which representing 90.3% of glucose in raw eucalyptus, combined with the xylose yield, 13.9g/100g eucalyptus, it can be concluded that ZnCl2 hydrate pretreatment offered the potential to co-produce xylose and glucose from eucalyptus. PMID- 28898824 TI - Comparison of biochar, zeolite and their mixture amendment for aiding organic matter transformation and nitrogen conservation during pig manure composting. AB - The aim of this work was to compare the impact of biochar, zeolite and their mixture on nitrogen conservation and organic matter transformation during pig manure (PM) composting. Four treatments were set-up from PM mixed with wheat straw and then applied 10% biochar (B), 10% zeolite (Z) and 10% biochar+10% zeolite (B+Z) into composting mixtures (dry weight basis), while treatment without additives applied used as control. Results indicated that adding B, Z and B+Z could obviously (p<0.05) improve the organic matter degradation and decrease the nitrogen loss. And combined addition of B and Z further promoted the organic matter humification and reduced the heavy metals mobility. Meanwhile the highest mitigation of ammonia (63.40%) and nitrogen dioxide (78.13%) emissions was observed in B+Z added treatment. Comparison of organic matter transformation, nitrogen conservation and compost quality indicated that the combined use of biochar and zeolite could be more useful for PM composting. PMID- 28898823 TI - Highly porous carbon from a natural cellulose fiber as high efficiency sorbent for lead in waste water. AB - The persistence of hollow centre in the carbon obtained from milkweed floss provides exceptional sorption characteristics, not seen in common biomasses or their derivatives. A considerably high sorption of 320mg of lead per gram of milkweed carbon was achieved without any chemical modification to the biomass. In this research, we have carbonized milkweed floss and used the carbon as a sorbent for lead in waste water. A high surface area of 170m2g-1 and pore volume of 1.07cm3g-1 was seen in the carbon. Almost complete removal (>99% efficiency) of lead could be achieved within 5min when the concentration of lead in the solution was 100ppm, close to that prevailing in industrial waste water. SEM images showed that the carbon was hollow and confocal images confirmed that the sorbate could penetrate inside the hollow tube. PMID- 28898825 TI - Evaluation of biochar powder on oxygen supply efficiency and global warming potential during mainstream large-scale aerobic composting. AB - This study investigated the effects of biochar powder on oxygen supply efficiency and global warming potential (GWP) in the large-scale aerobic composting pattern which includes cyclical forced-turning with aeration at the bottom of composting tanks in China. A 55-day large-scale aerobic composting experiment was conducted in two different groups without and with 10% biochar powder addition (by weight). The results show that biochar powder improves the holding ability of oxygen, and the duration time (O2>5%) is around 80%. The composting process with above pattern significantly reduce CH4 and N2O emissions compared to the static or turning-only styles. Considering the average GWP of the BC group was 19.82% lower than that of the CK group, it suggests that rational addition of biochar powder has the potential to reduce the energy consumption of turning, improve effectiveness of the oxygen supply, and reduce comprehensive greenhouse effects. PMID- 28898826 TI - Identification of hotspots for NO and N2O production and consumption in counter- and co-diffusion biofilms for simultaneous nitrification and denitrification. AB - A membrane-aerated biofilm reactor (MABR) provides a counter-current substrate diffusion geometry in which oxygen is supplied from a gas-permeable membrane on which a biofilm is grown. This study hypothesized that an MABR would mitigate NO and N2O emissions compared with those from a conventional biofilm reactor (CBR). Two laboratory-scale reactors, representing an MABR and CBR, were operated by feeding synthetic industrial wastewater. The surficial nitrogen removal rate for the MABR [4.51+/-0.52g-N/(m2day)] was higher than that for the CBR [3.56+/-0.81g N/(m2day)] (p<0.05). The abundance of beta-proteobacterial ammonia-oxidizing bacteria in the MABR biofilm aerobic zone was high. The NO and N2O concentrations at the biofilm-liquid interface in the MABR were 0.0066+/-0.0014 and 0.01+/ 0.0009mg-N/L, respectively, two and 28 times lower than those in the CBR. The NO and N2O production hotspots were closely located in the MABR aerobic zone. PMID- 28898827 TI - Purification and antioxidant activity of phycocyanin from Synechococcus sp. R42DM isolated from industrially polluted site. AB - The cyanobacterium Synechococcus sp. R42DM, isolated from an industrially polluted site Vatva, Gujarat, India was recognized to produce phycocyanin (PC) as major phycobiliprotein. In present study, the combinatorial approach of chemical and physical methods i.e. Triton-X 100 treatment and ultra-sonication was designed for extraction of PC. From cell extract, the intact and functional-PC was purified up to purity 4.03 by ammonium sulphate fractionation and ion exchange chromatography. The PC displayed considerable in vitro antioxidant and radical-scavenging activity. This PC was further noticed to scavenge intracellular-ROS and to increase tolerance against thermal and oxidative stress in Caenorhabditis elegans. Moreover, the PC was noticed to improve the physiological behaviour and longevity of C. elegans. In addition, the PC showed remarkable stability under physico-chemical stressors, which is desirable for their use in biomedical applications. In conclusion, present paper added up evidence in support of the prospective use of PC as an antioxidant nutraceutical. PMID- 28898828 TI - In-situ biogas upgrading process: Modeling and simulations aspects. AB - Biogas upgrading processes by in-situ hydrogen (H2) injection are still challenging and could benefit from a mathematical model to predict system performance. Therefore, a previous model on anaerobic digestion was updated and expanded to include the effect of H2 injection into the liquid phase of a fermenter with the aim of modeling and simulating these processes. This was done by including hydrogenotrophic methanogen kinetics for H2 consumption and inhibition effect on the acetogenic steps. Special attention was paid to gas to liquid transfer of H2. The final model was successfully validated considering a set of Case Studies. Biogas composition and H2 utilization were correctly predicted, with overall deviation below 10% compared to experimental measurements. Parameter sensitivity analysis revealed that the model is highly sensitive to the H2 injection rate and mass transfer coefficient. The model developed is an effective tool for predicting process performance in scenarios with biogas upgrading. PMID- 28898829 TI - Sugarcane vinasse treatment by two-stage anaerobic membrane bioreactor: Effect of hydraulic retention time on changes in efficiency, biogas production and membrane fouling. AB - This research investigated the effect of hydraulic retention time (HRT) on two stage anaerobic membrane bioreactor (2-SAnMBR) performance treating sugarcane vinasse. The experimental setup consisted of an upflow acidogenic reactor and a continuous stirred methanogenic reactor, fitted with submersed microfiltration hollow-fiber membranes. The results indicated excellent performance and robustness of 2-SAnMBR. The reduction in HRT of 5.3-3.1days did not cause loss of its performance. The 2-SAnMBR showed high capacity of removing organic matter (97%), producing biogas (6.3Nm3 of CH4 per m3 of treated vinasse) and did not completely remove important nutrients to fertigation. Reducing the HRT, the average mass of soluble microbial products (SMP) and extracellular polymeric substances (EPS) per mass of mixed liquor volatile suspended solids (MLVSS) increased. Consequently, the transmembrane pressure (TPM) rate and fouling resistance rise. Despite the fouling effect, physical and chemical cleaning processes were able to recover operational permeability. PMID- 28898830 TI - Sugar and ethanol production from woody biomass via supercritical water hydrolysis in a continuous pilot-scale system using acid catalyst. AB - The aim of this study were to efficiently produce fermentable sugars by continuous type supercritical water hydrolysis (SCWH) of Quercus mongolica at the pilot scale with varying acid catalyst loading and to use the obtained sugars for ethanol production. The SCWH of biomass was achieved in under one second (380 degrees C, 230bar) using 0.01-0.1% H2SO4. With 0.05% H2SO4, 49.8% of sugars, including glucose (16.5% based on biomass) and xylose monomers (10.8%), were liberated from biomass. The hydrolysates were fermented with S. cerevisiae DXSP and D452-2 to estimate ethanol production. To prepare the fermentation medium, the hydrolysates were detoxified using activated charcoal and then concentrated. The ethanol yield of fermentation with S. cerevisiae DXSP was 14.1% (based on biomass). The proposed system has potential for improvement in yield through process optimization. After further development, it is expected to be a competitive alternative to traditional systems for ethanol production from woody biomass. PMID- 28898831 TI - Improving nitrogen utilization efficiency of aquaponics by introducing algal bacterial consortia. AB - Aquaponics is a promising technology combining aquaculture with hydroponics. In this study, algal-bacterial consortia were introduced into aquaponics, i.e., algal-bacterial based aquaponics (AA), to improve the nitrogen utilization efficiency (NUE) of aquaponics. The results showed that the NUE of AA was 13.79% higher than that of media-based aquaponics (MA). In addition, higher NO3- removal by microalgae assimilation led to better water quality in AA, which made up for the deficiencies of poor aquaponic management of nitrate. As a result of lower NO3- concentrations and dramatically higher dissolved oxygen (DO) concentrations caused by microalgae photosynthesis in the photobioreactor, the N2O emission of AA was 89.89% lower than that of MA, although nosZ gene abundance in MA's hydroponic bed was approximately 30 times over that in AA. Considering the factors mentioned above, AA would improve the sustainability of aquaponics and have a good application foreground. PMID- 28898832 TI - Evaluation of integrated ammonia recovery technology and nutrient status with an in-vessel composting process for swine manure. AB - The study investigated the effect of different initial moisture (IM) content (55, 60, 65, and 70%) of composting mixtures (swine manure and sawdust) for the production of nutrient rich manure, and the recovery of ammonia through a condensation process using a vertical cylindrical in-vessel composter for 56days. The composting resulted in a significant reduction in C:N ratio and electrical conductivity (EC), with a slight increase in pH in all products. The NH3 were emitted notably, and at the same time the NO3--N concentration gradually increased with the reduction of NH4+-N in the composting mixtures. The overall results confirmed, the 65% IM showed the maximum nutritional yield, maturity and non-phytotoxic effects (Lycopersicon esculentum L.), with the results of ideal compost product in the following order of IM: 65%>60%>70%>55%. Finally, the recovered condensed ammonia contained considerable ammonium nitrogen concentrations and could be used as fertilizer. PMID- 28898833 TI - Bioelectricity generation, contaminant removal and bacterial community distribution as affected by substrate material size and aquatic macrophyte in constructed wetland-microbial fuel cell. AB - Integrating microbial fuel cell with constructed wetland (CW-MFC) is a novel way to harvest bioelectricity during wastewater treatment. In this study, the bioelectricity generation, containment removal and microbial community distribution in CW-MFC as affected by substrate material sizes and aquatic macrophyte were investigated. The planted CW-MFC with larger filler size showed a significant promotion of the relative abundance of electrochemically active bacteria (beta-Proteobacteria), which might result in the increase of bioelectricity generation in CW-MFC (8.91mWm-2). Additionally, a sharp decrease of voltage was observed in unplanted CW-MFC with smaller filler size in Cycle eight. However, the peak COD (86.7%) and NO3-N (87.1%) removal efficiencies were observed in planted CW-MFC with smaller filler size, which was strongly related to the biodiversity of microorganisms. Generally, the acclimation of exoelectrogens as dominant microbes in the anode chamber of planted CW-MFC with larger filler size could promote the bioelectricity generation during wastewater treatment. PMID- 28898834 TI - Cometabolic degradation of low-strength coking wastewater and the bacterial community revealed by high-throughput sequencing. AB - Cometabolism technology was employed to degrade low-strength coking wastewater (CWW) in Sequencing Batch Reactor (SBR). The bacterial community compositions were monitored by high-throughput sequencing. Cometabolic substrate effectively improved the chemical oxygen demand (COD) removal efficiency in glucose-added system (A1) compared to glucose-free system (A0). Meanwhile, A1 exhibited larger biomass, better settlement performance, and higher dehydrogenase activity (DHA). More importantly, high-throughput sequencing revealed that dominant populations in A1 were quite different with A0. Thauera (9.27%), Thermogutta (7.58%), and Defluviimonas (4.6%) began to enrich in A1 after cometabolic substrate supplement. Especially, Thauera, as the most dominant populations in Al, could degrade a wide spectrum of aromatic compounds, which may contribute to the better system performance. This work would provide a novel option to treat low-strength CWW, discern the relationship between bacterial community and CWW quality, and further explore the cometabolic degradation through bacterial community structures. PMID- 28898835 TI - Assessment upon heterotrophic microalgae screened from wastewater microbiota for concurrent pollutants removal and biofuel production. AB - Heterotrophic microalgae, capable of converting organic carbons to biofuel, as well as assimilating nutrients, have a great prospective in wastewater treatment. Meanwhile, the knowledge about heterotrophic microalgae is still far less than the autotrophic conterpart. Hence, in this study, 20 heterotrophic microalgal strains were isolated from a domestic wastewater treatment plant, and identified according to morphology and partial 18S and 23S rRNA gene sequences. Further, their biological traits were assessed in terms of N, P, TOC removal efficiencies, growth parameters, self-settleability and lipids production, expressed through a comprehensive selection index. By such, the optimal strains were chosen and applied back to treat the real wastewater, with or without pretreatment of sterilization. An organic-adaptable strain, i.e., Botryococcus sp. NJD-1, was ultimately recommended to achieve the concurrent biofuel production (up to 61.7% lipid content) and pollutants removal (up to 64.5%, 89.8% and 67.9% for N, P and TOC) in pristine wastewater. PMID- 28898837 TI - Phase separation and microbial distribution in the hyperthermophilic-mesophilic type temperature-phased anaerobic digestion (TPAD) of waste activated sludge (WAS). AB - In order to investigate the phase separation and microbial distribution in the TPAD, the conventional thermophilic-mesophilic type (TM-TPAD) and the hyperthermophilic-mesophilic type (HM-TPAD) were operated with a single-stage mesophilic anaerobic digestion (MAD) as control. HM-TPAD accomplished the volatile solids destruction 14.5% higher than MAD. Calculating conversion efficiencies distinguished the separation of acidogenic and methanogenic phases in HM-TPAD, which was not found in TM-TPAD. The differences on microbial distributions also reflected the phase separation in HM-TPAD. The protein degraders, Coprothermobacter had higher abundance in the first stage than the second stage of HM-TPAD but it had similar abundance between the two stages of TM TPAD. Also, the archaeal communities from the two stages of HM-TPAD shared the least similarity but those from the two stages of TM-TPAD were closely similar. PMID- 28898836 TI - Ozonolysis of straw from Secale cereale L. for anaerobic digestion. AB - The effect of different ozonation conditions on straw from Secale cereale (rye straw) pretreatment has been investigated. Using the Taguchi method, this study analyzed the optimum conditions for pretreatment of rye straw by ozonation. After 60min of rye straw ozonation the concentration of reducing sugars (RS) and volatile fatty acid (VFA), chemical oxygen demand (COD) were 7.4, 32.3 and 11.7 times higher, respectively compared to samples raw rye straw. The most effective rye straw ozonation occurred while using the highest amount of the rye straw (15g) treated with lower ozone dose (100gO3/m3) in the longest period of time (60min). For this variant of experiment the increment of methane production was 291.71dm3CH4/kgVS. Moreover, co-digestion of sewage sludge with addition of 20% ozonated rye straw allowed to obtain 269.1dm3CH4/kgVS. The positive effect of ozone on changes in the rye straw structure has been confirmed by SEM and FTIR analysis. PMID- 28898838 TI - Speciation of heavy metals and bacteria in cow dung after vermicomposting by the earthworm, Eisenia fetida. AB - This work was conducted to evaluate the total concentration and speciation of heavy metals (Cd, Pb and Cr) in vermicompost product (EFCD) by Eisenia fetida (EF) with cow dung (FCD). Meanwhile, the bacterial community and diversity of the three were compared by high-throughput sequencing. Results showed that heavy metal concentrations were declined significantly in EFCD. Sequential extraction indicated that the exchangeable fraction of Cd and Pb decreased markedly and the residual fractions increased in EFCD. Though the exchangeable fraction of Cr increased, the total concentration reduced greatly. Furthermore, the speciation of Cd, Pb and Cr bioaccumulated in EF were different. Besides, the bacterial diversity was highest in EFCD, and twelve genera with species having heavy metal resistance/tolerance were found from the genus of different abundance of the three. Vermicomposting effectively reduced the total concentration and toxicity for heavy metals, and the bacterial composition and diversity were changed greatly during vermicomposting. PMID- 28898839 TI - Bacteria-enhanced dilute acid pretreatment of lignocellulosic biomass. AB - Pretreatment is indispensable for the large-scale and low-cost bio-products production from lignocellulosic biomass. Herein, a new bacteria-enhanced dilute acid pretreatment (BE-DAP) strategy was introduced. Cupriavidus basilensis B-8 as a potential bacterium for lignin degradation was employed. Multi-scale characterizations on the physicochemical structure of rice straw indicated that Cupriavidus basilensis B-8 could act on the lignin droplets formed in dilute acid pretreatment (DAP), and dig out these droplets to recover cracks and holes on rice straw surface, leaving an opened and porous structure for the easy access of enzyme to inner cellulose. Eventually, the enzymatic digestibility of RS was increased by 35-70% and 173-244% in BE-DAP compared to DAP pretreated and untreated RS, respectively. The BE-DAP strategy, as well as its physicochemical mechanism, opened new perspectives for lignocellulose pretreatment. PMID- 28898840 TI - Enhancement of solvent production by overexpressing key genes of the acetone butanol-ethanol fermentation pathway in Clostridium saccharoperbutylacetonicum N1 4. AB - Clostridium saccharoperbutylacetonicum N1-4 is well known as a hyper-butanol producing strain. However, little information is available concerning its butanol production mechanism and the development of more robust strains. In this study, key biosynthetic genes (either endogenous or exogenous) including the sol operon (bld-ctfA-ctfB-adc), adhE1, adhE1D485G, thl, thlA1V5A, thlAV5A and the expression cassette EC (thl-hbd-crt-bcd) were overexpressed in C. saccharoperbutylacetonicum N1-4 to evaluate their potential in enhancement of butanol production. The overexpression of sol operon increased ethanol production by 400%. The overexpression of adhE1 and adhED485G resulted in a 5.6- and 4.9-fold higher ethanol production, respectively, producing final acetone-butanol-ethanol (ABE) titers (30.6 and 30.1gL-1) of among the highest as ever reported for solventogenic clostridia. The most significant increase of butanol production (by 13.7%) and selectivity (73.7%) was achieved by the overexpression of EC. These results provides a solid foundation and essential references for the further development of more robust strains. PMID- 28898841 TI - Impact of mild alkali dosage on immobilized Exiguobacterium spp. mediated cost and energy efficient sludge disintegration. AB - Approaches to (extracellular polymeric substance) EPS removal were studied with major aim to enhance the biodegradability and sludge solubilization. In this study, a novel approach of entrapment of bacterial strain was carried out to achieve long term activity of protease secreting bacteria Exiguobacterium sp. A mild treatment of potassium hydroxide (KOH) was applied to remove EPS which was followed by entrapment under the biological pretreatment. The efficiency of Exiguobacterium was predicted through dissolvable organic and suspended solids (SS) reduction. The maximum dissolvable organic matter released was 2300mg/L with the solubilization of 23% which was obtained for sludge without EPS (SWOE). For dissolvable organic release, SWOE showed higher final methane production of 232mL/g COD at the production rate of 16.2mL/g COD.d. The SWOE pretreatment was found to be cost effective and less energy intensive beneficial in terms of energy and cost (43.9KWh and -8.2USD) when compared to sludge with EPS (SWE) pretreatment (-177.6KWh and -91.23USD). PMID- 28898842 TI - Catalytic production of 1,4-pentanediol from corn stover. AB - A novel strategy of large-scale 1,4-pentanediol (1,4-PDO) production derived from corn stover is presented based on catalytic conversion experiments. In this strategy, cellulose and hemicellulose of corn stover are catalytically converted to GVL by using corn stover derived GVL asa reaction solvent, and GVL asa reaction intermediate is then upgraded to 1,4-PDO. In the strategy, three possible designs consisting of conversion and separation subsystems are developed in terms of biomass residues as electricity or fuel sources (A: electricity source, B: electricity and fuel sources, and C: fuel source). The economic feasibility of the process designs was demonstrated taking into account the minimum selling price (MSP; US$/kg) of 1,4-PDO with a comparison with the petro based process. Design C was the best MSP (US$ 1.25/kg) of those assessed because of its higher energy efficiency (69-82%) while meeting lower total annualized costs (4.7-6.5%) than Designs A and B. PMID- 28898843 TI - Co-pyrolysis behavior of fermentation residues with woody sawdust by thermogravimetric analysis and a vacuum reactor. AB - This study aimed at cost-effective utilization of fermentation residues (FR) from biogas project for bio-energy via co-pyrolysis of FR and woody sawdust (WS). In this study, a vacuum reactor was used to study the pyrolysis behaviors of individual and blend samples of FR and WS. Obvious synergistic effects were observed, resulting in a lower char yield but a higher gas yield. The presence of woody sawdust promoted the devolatilization of FR, and improved the syngas (H2 and CO) content in the gaseous products. Compared to those of the char from pyrolysis of individual feedstock, co-pyrolysis of FR and WS in the vacuum reactor promoted the cracking reactions of large aromatic rings, enlarged the surface area and reduced the oxygenated groups of the resulted char. PMID- 28898844 TI - Polar aprotic solvent-water mixture as the medium for catalytic production of hydroxymethylfurfural (HMF) from bread waste. AB - Valorisation of bread waste for hydroxymethylfurfural (HMF) synthesis was examined in dimethyl sulfoxide (DMSO)-, tetrahydrofuran (THF)-, acetonitrile (ACN)-, and acetone-water (1:1v/v), under heating at 140 degrees C with SnCl4 as the catalyst. The overall rate of the process was the fastest in ACN/H2O and acetone/H2O, followed by DMSO/H2O and THF/H2O due to the rate-limiting glucose isomerisation. However, the formation of levulinic acid (via rehydration) and humins (via polymerisation) was more significant in ACN/H2O and acetone/H2O. The constant HMF maxima (26-27mol%) in ACN/H2O, acetone/H2O, and DMSO/H2O indicated that the rates of desirable reactions (starch hydrolysis, glucose isomerisation, and fructose dehydration) relative to undesirable pathways (HMF rehydration and polymerisation) were comparable among these mediums. They also demonstrated higher selectivity towards HMF production over the side reactions than THF/H2O. This study differentiated the effects of polar aprotic solvent-water mediums on simultaneous pathways during biomass conversion. PMID- 28898845 TI - The transformation pathways of nitrogen in sewage sludge during hydrothermal treatment. AB - Hydrothermal treatment (HT) has been proved as a significant pretreatment in decreasing emissions of NOX pollutants from thermochemical utilization of sewage sludge (SS) derived solid fuel. This study aims to investigate the denitrification of HT and the redistribution of nitrogen (N) in different products so as to speculate the comprehensive pathway of N transformation during hydrothermal process. Results found that only 20% of N remained in hydrochar, whereas the rest of N (nearly 80%) was transformed into other phase. A majority of amino-N in SS was enriched in liquid phase in the form of Org-N at first, then further decomposed to NH4+-N. The remaining amino-N converted to pyrrole-N, pyridine-N and quaternary-N as temperature progresses. Meanwhile, amine-N derived from protein-N formed heterocyclic-N in oil phase via Diels-Alder reaction. NH3, the major nitrogenous gas, was dissolved in liquid as NH4+-N immediately after producing, but increased with prolonged reaction time. PMID- 28898846 TI - Synthesis of a novel magnetic nano-scale biosorbent using extracellular polymeric substances from Klebsiella sp. J1 for tetracycline adsorption. AB - The magnetic nano-scale biosorbent (Fe3O4/MFX) was synthesized by the chelation and cross-linking procedure with extracellular polymeric substances (MFX) and Fe3O4. Fe3O4/MFX possessed the porous structure and numerous functional groups (i.e., amino, carboxyl, and hydroxyl), and its core region had a typical size of ~11nm. The maximum adsorption capacity was 56.04mgg-1 at pH 6.0, 10mgL-1 of tetracycline, and 160mgL-1 of Fe3O4/MFX. The data is properly fitted by the Langmuir, Freundlich, and pseudo-second-order kinetics models. As elucidated by the model parameters and FTIR analysis, chemical ion exchange and COOH could mainly contribute to the adsorption. Meanwhile, the desorption and regeneration experiments implied the adsorption efficiency decreased by only 3.37-8.37% after five adsorption-desorption cycles, and the detection of iron leaching by ICP-OES showed a fine stability of Fe3O4/MFX. Therefore, this technically facile, easily recyclable, and environmentally friendly biosorbent has potential for practical applications in antibiotic removal. PMID- 28898847 TI - Environmentally-friendly strategy for separation of 1,3-propanediol using biocatalytic conversion. AB - Glycerol waste from the biodiesel production can be used as a carbon source in the production of 1,3-propanediol (1,3-PD) through microbial fermentation. However, downstream processing is a major bottleneck that restricts its biological production. Here, we investigated an environmentally-friendly method to enzymatically separate 1,3-PD. The transformation of 1,3-PD to an ester was achieved by exploiting the esterification reaction with fatty acids under lipase catalysis. The reaction efficiency was optimized using different poly-alcohols that were existed in the fermentation broth reacted with a fatty acid. Whereas the 1,3-PD conversion reached 62%, only a 0.06% and 0.08% conversion was reached for 2,3-butanediol and glycerol, illustrating the former's more efficient separation. The recovery efficiency of 1,3-PD was 96%. Finally, 1,3-PD was obtained by lipase-directed ester hydrolysis. Taken together, the bio-catalyzed separation process presented here is a novel and promising method for recovering 1,3-PD. PMID- 28898848 TI - Comparative evaluation of piggery wastewater treatment in algal-bacterial photobioreactors under indoor and outdoor conditions. AB - This work evaluated the performance of four open algal-bacterial photobioreactors operated at ~26days of hydraulic retention time during the treatment of 10 (*10) and 20 (*20) times diluted piggery wastewater (PWW) under indoor (I) and outdoor (O) conditions for four months. The removal efficiencies (REs) of organic matter, nutrients and zinc from PWW, along with the dynamics of biomass concentration and structure of algal-bacterial population were assessed. The highest TOC-RE, TP-RE and Zn-RE (94+/-1%, 100% and 83+/-2%, respectively) were achieved indoors in *10 PWW, while the highest TN-RE (72+/-8%) was recorded outdoors in *10 PWW. Chlorella vulgaris was the dominant species regardless of the ambient conditions and PWW dilution. Finally, DGGE-sequencing of the bacterial community revealed the occurrence of four phyla, Proteobacteria being the dominant phylum with 15 out of the 23 most intense bands. PMID- 28898849 TI - Pyrolysis, kinetics analysis, thermodynamics parameters and reaction mechanism of Typha latifolia to evaluate its bioenergy potential. AB - This work was focused on understanding the pyrolysis of Typha latifolia. Kinetics, thermodynamics parameters and pyrolysis reaction mechanism were studied using thermogravimetric data. Based on activation energies and conversion points, two regions of pyrolysis were established. Region-I occurred between the conversion rate 0.1-0.4 with peak temperatures 538K, 555K, 556K at the heating rates of 10Kmin-1, 30Kmin-1, and 50Kmin-1, respectively. Similarly, the Region-II occurred between 0.4 and 0.8 with peak temperatures of 606K, 621K, 623K at same heating rates. The best model was diffusion mechanism in Region-I. In Region-II, the reaction order was shown to be 2nd and 3rd. The values of activation energy calculated using FWO and KAS methods (134-204kJmol-1) remained same in both regions reflecting that the best reaction mechanism was predicted. Kinetics and thermodynamic parameters including E, DeltaH, DeltaS, DeltaG shown that T. latifolia biomass is a remarkable feedstock for bioenergy. PMID- 28898850 TI - Impact of temperatures on microbial community structures of sewage sludge biological hydrolysis. AB - This study investigated the biological hydrolysis performance at 35 degrees C (BH35), 42 degrees C (BH42), and 55 degrees C (BH55) and the effect of temperatures on microbial communities of the hydrolyzed sludge. The results showed that the suspended solid reduction, volatile fatty acids (VFA) production, and biogas production increased with the BH temperatures. VFAs produced in the sludge BH included acetic acid, propionic acid, isobutyric acid, butyric acid, and isovaleric acid with the fractions of acetic acid increased with BH temperatures. The Illumina MiSeq sequencing analysis showed that the microbial taxonomic structures of the BH systems varied with BH temperatures. It was found that Acidaminobacter at 35 degrees C, Proteiniphilum and Lutispor at 42 degrees C, and Gelria at 55 degrees C were the main protein fermenting bacteria genera, while the carbohydrate fermenting bacteria might belong to the genera of Macellibacteroides and Paludibacter at 35 degrees C, Fronticella at 42 degrees C, and Tepidimicrobium at 55 degrees C. PMID- 28898851 TI - Cellulose conversion of corn pericarp without pretreatment. AB - We report enzyme hydrolysis of cellulose in unpretreated pericarp at a cellulase loading of 0.25FPU/g pericarp solids using a phenol tolerant Aspergillus niger pectinase preparation. The overall protein added was 5mg/g and gave 98% cellulose conversion in 72h. However, for double the amount of enzyme from Trichoderma reesei, which is significantly less tolerant to phenols, conversion was only 16%. The key to achieving high conversion without pretreatment is combining phenol inhibition-resistant enzymes (such as from A. niger) with unground pericarp from which release of phenols is minimal. Size reduction of the pericarp, which is typically carried out in a corn-to-ethanol process, where corn is first ground to a fine powder, causes release of highly inhibitory phenols that interfere with cellulase enzyme activity. This work demonstrates hydrolysis without pretreatment of large particulate pericarp is a viable pathway for directly producing cellulose ethanol in corn ethanol plants. PMID- 28898852 TI - Enhanced production of astaxanthin by Chromochloris zofingiensis in a microplate based culture system under high light irradiation. AB - The green microalga Chromochloris zofingiensis is a promising producer of natural astaxanthin. In the present study, C. zofingiensis was first cultivated in shake flasks under low light irradiation and then subjected to continuous high light irradiation, which effectively promoted astaxanthin production. In addition, a microplate-based culture system in concert with high light irradiation from blue light and white light above 150MUmolm-2s-1 was constructed and applied to improve astaxanthin production. Blue light exerted more positive influences on astaxanthin accumulation, but when the light intensity was increased to 300MUmolm 2s-1, astaxanthin biosynthesis was substantially inhibited. Conversely, in a nitrogen-deprived culture under white light, the highest astaxanthin content for C. zofingiensis, 7.1mg/g, was obtained. The highest astaxanthin yield achieved was 38.9mg/L in a culture with 0.1g/L nitrate under the same culture conditions. This study demonstrates that C. zofingiensis has great potential for natural astaxanthin production. PMID- 28898853 TI - Partially consolidated bioprocessing of mixed lignocellulosic feedstocks for ethanol production. AB - Rapid urbanization and industrialization have accelerated the energy demand which cannot be met by decreasing fossil fuels thereby substantiate the need for lignocellulosic ethanol. The present study is one such attempt towards bioethanol production in an eco-friendly manner using enzymes in which a mixture of lignocellulosic biomass namely, Ricinus communis, Saccharum officinarum (tops) and Saccharum spontaneum were taken as a substrate. The mixed biomass was processed through partially consolidated bioprocessing (PCBP) approach which involves a non-isothermal simultaneous pretreatment and saccharification step where a concoction of laccase (Pleurotus djamor) and holocellulase (Trichoderma reseei RUT C30) was used followed by co-fermentation within the same reactor. The process parameters influencing PCBP were optimized using feed-forward ANN model which resulted in a maximum ethanol concentration of 7.86% (v/v) (62.01g/L) at pentose to hexose strain ratio of 0.696 (v/v), substrate loading of 27.54% (w/v) and incubation time of 21.96h. PMID- 28898854 TI - Factors affecting seawater-based pretreatment of lignocellulosic date palm residues. AB - Seawater-based pretreatment of lignocellulosic biomass is an innovative process at research stage. With respect to process optimization, factors affecting seawater-based pretreatment of lignocellulosic date palm residues were studied for the first time in this paper. Pretreatment temperature (180 degrees C-210 degrees C), salinity of seawater (0ppt-50ppt), and catalysts (H2SO4, Na2CO3, and NaOH) were investigated. The results showed that pretreatment temperature exerted the largest influence on seawater-based pretreatment in terms of the enzymatic digestibility and fermentability of pretreated solids, and the inhibition of pretreatment liquids to Saccharomyces cerevisiae. Salinity showed the least impact to seawater-based pretreatment, which widens the application spectrum of saline water sources such as brines discharged in desalination plant. Sulfuric acid was the most effective catalyst for seawater-based pretreatment compared with Na2CO3 and NaOH. PMID- 28898855 TI - Cost effective dry anaerobic digestion in textile bioreactors: Experimental and economic evaluation. AB - The aim of this work was to study dry anaerobic digestion (dry-AD) of manure bedded with straw using textile-based bioreactor in repeated batches. The 90-L reactor filled with the feedstocks (22-30% total solid) and inoculum without any further treatment, while the biogas produced were collected and analyzed. The digestate residue was also analyzed to check its suitability as bio-fertilizer. Methane yield after acclimatization increased from 183 to 290NmlCH4/gVS, degradation time decreased from 136 to 92days and the digestate composition point to suitable bio-fertilizer. The results then used to carry out economical evaluation, which shows dry-AD in textile bioreactors is a profitable method of handling the waste with maximum payback period of 5years, net present value from $7,000 to $9,800,000 (small to large bioreactors) with internal rate of return from 56.6 to 19.3%. PMID- 28898856 TI - Acetate-assisted increase of butyrate production by Eubacterium limosum KIST612 during carbon monoxide fermentation. AB - The acetate-assisted cultivation of Eubacterium limosum KIST612 was found to provide a way for enhancing cell mass, the carbon monoxide (CO) consumption rate, and butyrate production using CO as an electron and energy source. Cell growth (146%), MUmax (121%), and CO consumption rates (151%) increased significantly upon the addition of 30mM acetate to microbial cultures. The main product of CO fermentation by E. limosum KIST612 shifted from acetate to butyrate in the presence of acetate, and 5.72mM butyrate was produced at the end of the reaction. The resting cell experimental conditions indicated acetate uptake and an increase in the butyrate concentration. Three routes to acetate assimilation and energy conservation were suggested based on given experimental results and previously genome sequencing data. Acetate assimilation via propionate CoA-transferase (PCT) was expected to produce 1.5mol ATP/mol butyrate, and was thus anticipated to be the most preferred route. PMID- 28898857 TI - Production of eicosapentaenoic acid by high cell density cultivation of the marine oleaginous diatom Fistulifera solaris. AB - Polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), have attracted attention owing to their health benefits for humans, as well as their importance in aquaculture and animal husbandry. Establishing a sustainable PUFA supply based on fish oils has been difficult due to their increasing demand. Therefore, alternative sources of PUFAs are required. In this research, we examined the potential of the marine oleaginous diatom Fistulifera solaris as an alternative producer of PUFAs. Optimization of culture conditions was carried out for high cell density cultivation, and a maximal biomass productivity of 1.32+/ 0.13g/(L.day) was achieved. By slightly adjusting the culture conditions for EPA production, the maximal EPA productivity reached 135.7+/-10.0mg/(L.day). To the best of our knowledge, this is the highest EPA productivity among microalgae cultured under photoautotrophic conditions. This result indicates that F. solaris is a promising candidate host for sustainable PUFA production. PMID- 28898858 TI - Microbial community structure in aerobic and fluffy granules formed in a sequencing batch reactor supplied with 4-chlorophenol at different settling times. AB - Toxic compounds, such as 4-chlorophenol (4-CP), which is a common pollutant in wastewater, are removed efficiently from sequencing batch reactors (SBRs) by microorganisms. The bacterial community in aerobic granules formed during the removal of 4-CP in a SBR was monitored for 63days. The SBR reactor was operated with a constant filling and withdrawal time of 7 and 8min and decreasing settling time (30, 5, 3 and 2min) to induce the formation of aerobic granules. During the acclimation period lasting 15days (30min settling time) had a strong effect on the bacterial community. From day 18 onwards, Sphingobium and Comamonadaceae were detected. Rhizobiaceae were dominant from day 24 to day 28 when stable aerobic granules were formed. At day 35, fluffy granules were formed, but the bacterial community structure did not change, despite the changes in the reactor operation to inhibit filamentous bacteria growth. This is the first report on changes in the bacterial community structure of aerobic and fluffy granules during granulation process in a reactor fed with 4-CP and the prediction of its metabolic pathways. PMID- 28898860 TI - Direct detection of the triphenylpyrylium-derived short-lived intermediates in the photocatalyzed degradation of acetaminophen, acetamiprid, caffeine and carbamazepine. AB - Advanced oxidation processes are useful methodologies to accomplish abatement of contaminants; however, elucidation of the reaction mechanisms is hampered by the difficult detection of the short-lived primary key species involved in the photocatalytic processes. Nevertheless, herein the combined use of an organic photocatalyst such as triphenylpyrylium (TPP+) and photophysical techniques based on emission and absorption spectroscopy allowed monitoring the photocatalyst derived short-lived intermediates. This methodology has been applied to the photocatalyzed degradation of different pollutants, such as acetaminophen, acetamiprid, caffeine and carbamazepine. First, photocatalytic degradation of a mixture of the pollutants showed that acetaminophen was the most easily photodegraded, followed by carbamazepine and caffeine, being the abatement of acetamiprid almost negligible. This process was accompanied by mineralization, as demonstrated by trapping of carbon dioxide using barium hydroxide. Then, emission spectroscopy measurements (steady-state and time-resolved fluorescence) allowed demonstrating quenching of the singlet excited state of TPP+. Laser flash photolysis experiments with absorption detection showed that oxidation of contaminants is accompanied by TPP+ reduction, with formation of a pyranyl radical (TPP), that constituted a fingerprint of the redox nature of the occurring process. The relative amounts of TPP detected was also correlated with the efficiency of the photodegradation process. PMID- 28898859 TI - Antibacterial clay against gram-negative antibiotic resistant bacteria. AB - Antibiotic resistant bacteria persist throughout the world because they have evolved the ability to express various defense mechanisms to cope with antibiotics and the immune system; thus, low-cost strategies for the treatment of these bacteria are needed, such as the usage of environmental minerals. This paper reports the antimicrobial properties of a clay collected from Brunnenberg, Germany, that is composed of ferroan saponite with admixtures of quartz, feldspar and calcite as well as exposed or hidden (layered at inner regions) nano Fe(0). Based on the growth curves (log phase) of six antibiotic resistant bacteria (4 gram-negative and 2 gram-positive), we concluded that the clay acted as a bacteriostat; however, the clay was only active against the gram-negative bacteria (except for resilient Klebsiella pneumonia). The bacteriostatic mode of action was evidenced by the initial lack of Colony Forming Units on agar plates with growth registered afterward, certainly after 24h, and can be explained because interactions between membrane lipopolysaccharides and the siloxane surfaces of the clay. Labile or bioavailable Fe in the clay (extracted by EDTA or DFO-B) induced the quantitative production of HO as well as oxidative stress, which, nevertheless, did not account for by its bacteriostatic activity. PMID- 28898861 TI - Removal and metabolism of triclosan by three different microalgal species in aquatic environment. AB - Triclosan, an antimicrobial additive widely used in personal care products, has caused the contamination of various aquatic environment. Biodegradation was proved to play a vital role in the treatment of triclosan in wastewater. However, there is limited information about the metabolic pathway. In this study, three common freshwater microalgae including Chlorella pyrenoidosa (C. pyrenoidosa), Desmodesmus sp., and Scenedesmus obliquus (S. obliquus) were applied to remove and biodegrade triclosan in aqueous culture medium. High removal rate up to 99.7% was observed during the treatment of 400MUgL-1 triclosan by the three microalgae for 1day. The removal of triclosan attributed to cellular uptake by C. pyrenoidosa, and biotransformation by Desmodesmus sp. and S. obliquus. Simultaneously, triclosan metabolites resulted from hydroxylation, reductive dechlorination, or ether bond cleavage and their conjugates produced through glucosylation and/or methylation were detected in the biodegradation samples. Metabolic pathway of triclosan by algae were firstly proposed in this work, shedding light on the environmental fate of triclosan. PMID- 28898862 TI - Degradation and intermediates of diclofenac as instructive example for decomposition of recalcitrant pharmaceuticals by hydroxyl radicals generated with pulsed corona plasma in water. AB - Seven recalcitrant pharmaceutical residues (diclofenac, 17alpha-ethinylestradiol, carbamazepine, ibuprofen, trimethoprim, diazepam, diatrizoate) were decomposed by pulsed corona plasma generated directly in water. The detailed degradation pathway was investigated for diclofenac and 21 intermediates could be identified in the degradation cascade. Hydroxyl radicals have been found primarily responsible for decomposition steps. By spin trap enhanced electron paramagnetic resonance spectroscopy (EPR), OH-adducts and superoxide anion radical adducts were detected and could be distinguished applying BMPO as a spin trap. The increase of concentrations of adducts follows qualitatively the increase of hydrogen peroxide concentrations. Hydrogen peroxide is eventually consumed in Fenton-like processes but the concentration is continuously increasing to about 2mM for a plasma treatment of 70min. Degradation of diclofenac is inversely following hydrogen peroxide concentrations. No qualitative differences between byproducts formed during plasma treatment or due to degradation via Fenton induced processes were observed. Findings on degradation kinetics of diclofenac provide an instructive understanding of decomposition rates for recalcitrant pharmaceuticals with respect to their chemical structure. Accordingly, conclusions can be drawn for further development and a first risk assessment of the method which can also be applied towards other AOPs that rely on the generation of hydroxyl radicals. PMID- 28898863 TI - Efficient promotion of charge transfer and separation in hydrogenated TiO2/WO3 with rich surface-oxygen-vacancies for photodecomposition of gaseous toluene. AB - Oxygen-deficient TiO2/WO3 constructed via the controllable temperature of hydrogen annealing is designed in view of combining the broad visible spectrum absorption with the prominent coupled semiconductor properties. Surface lattice disorder of TiO2/WO3 arises at hydrogen annealing temperature of 200 and 300 degrees C, while critical phase transition from TiO2/WO3 to TiO2/WO2.9 occurs at 400 degrees C, both of which can introduce oxygen vacancies. The hydrogenated TiO2/WO3 with rich surface-oxygen-vacancies exhibits much higher photocatalytic activity for decomposition of gaseous toluene than pristine TiO2/WO3 under visible-light illumination (lambda>420nm). The photoelectrochemical analysis shows that the improved electronic properties of oxygen-deficient TiO2/WO3 enable dramatically efficient promotion of photoinduced charge transfer and separation, which is the key factor for the improved photocatalytic activity. It is hoped that the present work could boost ongoing interest for preparing various hydrogenated coupled semiconductors with enhanced activity for diverse photocatalytic applications. PMID- 28898864 TI - What happens with organic micropollutants during UV disinfection in WWTPs? A global perspective from laboratory to full-scale. AB - The phototransformation of 18 organic micropollutants (OMPs) commonly detected in wastewater treatment plant (WWTP) effluents was examined attempting to explain their fate during UV disinfection in WWTPs. For this purpose, a lab-scale UV reactor (lamp emitting at 254nm) was used to study the influence of the operational conditions (UV dose, temperature and water matrix) on OMPs abatement and disinfection efficiency. Chemical properties of OMPs and the quality of treated effluent were identified as key factors affecting the phototransformation rate of these compounds. Sampling campaigns were carried out at the inlet and outlet of UV systems of three WWTPs, and the results evidenced that only the most photosensitive compounds, such as sulfamethoxazole and diclofenac, are eliminated. Therefore, despite UV treatment is an effective technology to phototransform OMPs, the UV doses typically applied for disinfection (10 50mJ/cm2) are not sufficient to remove them. Consequently, small modifications (increase of UV dose, use of catalysts) should be applied in WWTPs to enhance the abatement of OMPs in UV systems. PMID- 28898865 TI - Automatic Measurement of Fetal Brain Development from Magnetic Resonance Imaging: New Reference Data. AB - BACKGROUND: Accurate fetal brain volume estimation is of paramount importance in evaluating fetal development. The aim of this study was to develop an automatic method for fetal brain segmentation from magnetic resonance imaging (MRI) data, and to create for the first time a normal volumetric growth chart based on a large cohort. SUBJECTS AND METHODS: A semi-automatic segmentation method based on Seeded Region Growing algorithm was developed and applied to MRI data of 199 typically developed fetuses between 18 and 37 weeks' gestation. The accuracy of the algorithm was tested against a sub-cohort of ground truth manual segmentations. A quadratic regression analysis was used to create normal growth charts. The sensitivity of the method to identify developmental disorders was demonstrated on 9 fetuses with intrauterine growth restriction (IUGR). RESULTS: The developed method showed high correlation with manual segmentation (r2 = 0.9183, p < 0.001) as well as mean volume and volume overlap differences of 4.77 and 18.13%, respectively. New reference data on 199 normal fetuses were created, and all 9 IUGR fetuses were at or below the third percentile of the normal growth chart. DISCUSSION: The proposed method is fast, accurate, reproducible, user independent, applicable with retrospective data, and is suggested for use in routine clinical practice. PMID- 28898866 TI - ENETS Newsletter Summer 2017. PMID- 28898867 TI - Cerebral Fat Embolism: Clinical Presentation, Diagnostic Steps and Long-Term Follow-Up. AB - OBJECTIVE: Symptomatic cerebral fat embolism (CFE) is a rare complication that occurs after a traumatic injury or orthopaedic surgery and is diagnostically challenging. No data is currently available concerning long-term follow-up. METHODS: We identified from medical records 9 patients with CFE and revised the clinical signs and the diagnostic process. We then analysed long-term follow-up data, targeting clinical course after discharge, neurological impairment, and current quality of life, using the Barthel index and the modified Rankin Scale. RESULTS: All 9 patients initially showed severe neurological deficits, including disturbance of consciousness ranging from somnolence to coma. During the follow up period for 3-58 months after the insult 2 patients had died. The 7 patients who remained alive had either recovered completely or showed only minor neurological deficits after rehabilitation. They were nearly independent in daily life and needed only minimal assistance. We performed the first brain biopsy in a patient with CFE. CONCLUSION: Most patients had a good outcome after long-term follow-up. In patients with an unexplained altered state of consciousness after a traumatic injury or an orthopaedic surgery, an MRI with diffusion-weighted imaging must be performed to uncover the characteristic pattern of disseminated hyperintense lesions in the white matter that are associated with CFE. PMID- 28898868 TI - Euflammation Attenuates Central and Peripheral Inflammation and Cognitive Consequences of an Immune Challenge after Tumor Development. AB - OBJECTIVE: Repeated subthreshold bacterial exposures in rodents cause novel euflammation that attenuates neuroinflammation and sickness behaviors upon subsequent infectious challenges to the host without eliciting illness behavior. The investigation of bacterial exposure effects on brain and behavior is clinically relevant because bacterial-based antitumor treatments are used successfully, but are suboptimal due to their illness side effects. In addition, behavioral consequences (depression, cognitive impairments) to homeostatic challenges that are associated with inflammation are prevalent and reduce the quality of life in cancer patients and survivors. Therefore, this study tested the potential for euflammation to attenuate behavioral consequences of an immune challenge in tumor-bearing mice. METHODS: Mice with and without oral tumors in their flank underwent the established peripheral euflammatory protocol or vehicle treatment, followed by an acute peripheral immune challenge (lipopolysaccharide [LPS] injection) or PBS. Cognitive function and sickness behavior were assessed after the challenge, and peripheral and central inflammatory responses were measured. RESULTS: Euflammation reduced LPS-induced peripheral and central inflammation in all mice; however, neuroinflammation was less attenuated in tumor bearing mice compared with tumor-free controls. LPS-induced lethargy and cognitive impairments were more pronounced among tumor-bearing mice and were effectively attenuated with euflammation. Cognitive changes were independent of brain-derived growth factor gene expression in the hippocampus. CONCLUSION: These results suggest that induction of euflammation may be useful in alleviating the negative side effects of bacterial-based tumor treatments and in potentially attenuating common behavioral comorbidities associated with cancer or other chronic diseases. PMID- 28898869 TI - Disrupted Brain Network Hubs in Subtype-Specific Parkinson's Disease. AB - BACKGROUND/AIMS: The topological organization of brain functional networks is impaired in Parkinson's disease (PD). However, the altered patterns of functional network hubs in different subtypes of PD are not completely understood. METHODS: 3T resting-state functional MRI and voxel-based graph-theory analysis were employed to systematically investigate the intrinsic functional connectivity patterns of whole-brain networks. We enrolled 31 patients with PD (12 tremor dominant [TD] and 19 with postural instability/gait difficulty [PIGD]) and 22 matched healthy controls. Whole-brain voxel-wise functional networks were constructed by measuring the temporal correlations of each pair of brain voxels. Functional connectivity strength was calculated to explore the brain network hubs. RESULTS: We found that both the TD and PIGD subtypes had comprehensive disrupted regions. These mainly involved the basal ganglia, cerebellum, superior temporal gyrus, pre- and postcentral gyri, inferior frontal gyrus, middle temporal gyrus, lingual gyrus, insula, and parahippocampal gyrus. Furthermore, the PIGD subgroup had more disrupted hubs in the cerebellum than the TD subgroup. These disruptions of hub connectivity were not correlated with the HY stage or disease duration. CONCLUSION: Our results emphasize the subtype-specific PD related degeneration of brain hubs, providing novel insights into the pathophysiological mechanisms of connectivity dysfunction in different PD subgroups. PMID- 28898870 TI - Short-Term Vitamin D3 Supplementation in Children with Neurodisabilities: Comparison of Two Delivery Methods. AB - BACKGROUND/AIMS: Vitamin D deficiency is common in children with neurodisabilities. Oral vitamin D3 may not be absorbed appropriately due to dysphagia and tube feeding. The aim of this study was to compare efficacy of vitamin D3 buccal spray with that of oral drops. METHODS: Twenty-four children with neurodisabilities (5-17 years) and vitamin D deficiency (25(OH)D <=20 ng/mL) were randomized to receive vitamin D3 buccal spray 800 IU/daily (n = 12) or oral drops 750 IU/daily (n = 12) for 3 months during winter. RESULTS: Both groups had a significant increase in 25(OH)D (z = 150; p < 0.0001). The differences between baseline and final parathyroid hormone measurements did not reach significance in both groups. Markers of bone formation and resorption did not change significantly in both groups. The satisfaction with the formulation was significantly higher in the patients using spray. CONCLUSION: Vitamin D3 supplementation with buccal spray and oral drops are equally effective in short term treatment of vitamin D deficiency in children with neurodisabilities. Buccal spray may be more acceptable by the patients. PMID- 28898871 TI - Placental Component and Pregnancy Outcome in Singleton versus Twin Pregnancies Complicated by Preeclampsia. AB - OBJECTIVE: To compare placental histopathological lesions and pregnancy outcomes in singleton and twin pregnancies complicated by preeclampsia (PE). METHODS: Maternal characteristics, neonatal outcomes, and placental histopathology reports of pregnancies complicated by PE between January 2008 and October 2016 were reviewed. Results were compared between singletons (singleton group) and dichorionic-diamniotic twins (twin group). Placental lesions were classified into maternal and fetal vascular supply lesions. Small for gestational age (SGA) was defined as birth weight <=10th percentile. Composite adverse neonatal outcome was defined as one or more early neonatal complications. RESULTS: Compared to the twin group (n = 67), the singleton group (n = 275) was characterized by lower maternal age (p = 0.003), higher gestational age (p < 0.001), higher rates of previous PE (p = 0.017), chronic hypertension (p = 0.036), and severe features (p < 0.001). Placentas from the singleton group were characterized by higher rates of maternal vascular malperfusion lesions (p < 0.001) and fetal vascular supply lesions (p = 0.002). Using multivariable regression analysis, composite maternal and fetal vascular malperfusion lesions were independently associated with singletons (aOR = 2.7, 95% CI = 1.2-7.8, p < 0.001, and aOR = 1.2, 95% CI = 1.2 5.6, p = 0.025, respectively). SGA was more common in the singleton group (p = 0.002). Neonatal outcome did not differ between the groups. CONCLUSION: Placentas from singleton pregnancies complicated by PE were characterized by higher rates of maternal and fetal vascular lesions compared to those from twin pregnancies, suggesting that different mechanisms participate in the development of PE in these two groups. PMID- 28898872 TI - Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression? AB - INTRODUCTION: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. METHODS: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1alpha, MIP-1beta, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. RESULTS: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. DISCUSSION: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD. PMID- 28898873 TI - Two-Year Outcomes of a Treat-and-Extend Regimen Using Intravitreal Aflibercept Injections for Typical Age-Related Macular Degeneration. AB - PURPOSE: The aim of this study was to evaluate the efficacy of a treat-and-extend (TAE) regimen using intravitreal injection of aflibercept (IVA) for typical age related macular degeneration (tAMD). METHODS: We retrospectively studied 61 treatment-naive eyes with tAMD. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), number of injections, and complications during 2 years were evaluated. RESULTS: BCVA significantly improved by on average 0.13 logMAR units, and CMT and CCT significantly decreased after 2 years. The number of injections was on average 13.6. In the second year, eyes with classic choroidal neovascularization (CNV) needed significantly fewer treatments than eyes with occult CNV. Fourteen eyes, which developed subfoveal fibrosis, showed significantly poorer BCVA after 2 years. Subfoveal fibrosis was significantly common in classic CNV. CONCLUSION: A TAE regimen using IVA for tAMD might be effective for improving BCVA and exudative changes. The exudation may be suppressed with fewer treatments in classic CNV compared to occult CNV. PMID- 28898874 TI - Associations between Liver Enzyme Levels and Parameters of the Metabolic Syndrome in Obese Children. AB - BACKGROUND: Obesity is strongly associated with insulin resistance, hypertension, dyslipidemia, and therefore risk for metabolic syndrome (MetS), which is an increasing problem in youth. The potential role of elevated liver enzyme levels in this context needs to be further investigated. METHODS: This paper provides a post hoc analysis of a cross-sectional study of 77 obese nondiabetic children (51% female; median age 11.7 years; BMI >97th percentile) enrolled at the University of Bonn, Bonn, Germany. Anthropometric parameters, lipid profiles, glycemic control, and liver enzyme levels were evaluated. Glucose and insulin levels were determined during an oral glucose tolerance test (OGTT). Gender- and age-specific cutoff values were used to assess MetS. RESULTS: A high prevalence of hypertension (51%), dyslipidemia (52%), elevated liver enzyme levels (51%), and hyperglycemia (24%) was found. There was considerable overlap between the presence of different MetS risk factors in individuals, and 40% of the participants had >=3 of a maximum of 5 MetS risk factors. Elevated liver enzyme levels were significantly associated with reduced insulin sensitivity, as the OGTT-insulin response was significantly higher in participants with elevated transaminases (p = 0.01). This association was independent of hyperglycemia and dyslipidemia (p = 0.03). CONCLUSIONS: We conclude that liver enzyme levels are related to insulin sensitivity in obese children and could therefore be an indirect indicator for MetS. Testing for disturbed glucose metabolism should be considered for obese children with elevated liver enzymes. PMID- 28898875 TI - Enteroendocrine Cells: Metabolic Relays between Microbes and Their Host. AB - Gut bacteria exert a variety of metabolic functions unavailable to the host and are increasingly seen as a virtual organ located inside our gastrointestinal tract. Scattered in our intestinal epithelium, enteroendocrine cells (EECs) regulate several aspects of the host's physiology and translate signals coming from the gut microbiota through their hormonal secretions. In this chapter, we will assess the interplay between the gut microbiota and EEC and its consequences for the physiology of the host. We will first describe alterations of different populations of EEC in germ-free animals. The role of mediators of this interaction, such as microbial metabolites and their receptors will also be discussed. Finally, different strategies harnessing host-microbe crosstalk for therapeutic purposes will be presented with an emphasis on obesity and related disorders. PMID- 28898876 TI - Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS). AB - BACKGROUND: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. METHODS: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. RESULTS: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. CONCLUSION: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor. PMID- 28898877 TI - Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays. AB - Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. There is an urgent need to develop tools to identify individuals at high risk of developing SCLC. We have previously reported that the cytokinesis-blocked micronucleus (CBMN) assay is a strong predictor of non-small cell lung cancer (NSCLC). Here, we investigate the sensitivity of the CBMN endpoints as predictors of SCLC risk. We conducted the CBMN assay on SCLC patients (n = 216), NSCLC patients (n = 173), and healthy controls (n = 204). Per sample, 1,000 binucleated cells (BN) were scored, and 3 endpoints, micronuclei (BN-MN), nucleoplasmic bridges (BN-NPB), and nuclear buds(BN-BUD), were recorded. Spectral karyotyping was also conducted on SCLC patients (n = 116) and NSCLC patients (n = 137) to identify genomic regions unique to each disease. Significantly higher levels of CBMN endpoints were observed in both cancer groups compared to controls. BN-NPBs were significantly higher among SCLC patients compared to NSCLC patients (p < 0.001). Chromosomes 5 and 17 were associated with BN-MN, and chromosomes 5, 18, 20, and 22 were associated with BN-NPBs in SCLC patients. Given the high frequency of chromosome aberrations observed in SCLC, events such as reinsertion of the micronucleus and chromothripsis may be potential mechanisms for the genetic instability in these patients. PMID- 28898878 TI - Development of Laboratory Investigations in Disorders of Sex Development. AB - Scientific knowledge to understand the biological basis of sex development was prompted by the observation of variants different from the 2 most frequent body types, and this became one of the fields first studied by modern pediatric endocrinology. The clinical observation was supported by professionals working in different areas of laboratory sciences which led to the description of adrenal and gonadal steroidogenesis, the enzymes involved, and the different deficiencies. Steroid hormone measurements evolved from colorimetry to radioimmunoassay (RIA) and automated immunoassays, although gas and liquid chromatography coupled to mass spectrometry are now the gold standard techniques for steroid measurements. Peptide hormones and growth factors were purified, and their measurement evolved from RIA to automated immunoassays. Hormone action mechanisms were described, and their specific receptors were characterized and assayed in experimental materials and in patient tissues and cell cultures. The discovery of the genetic basis for variant sex developments began with the description of the sex chromosomes. Molecular technology allowed cloning of genes coding for the different proteins involved in sex determination and development. Experimental animal models aided in verifying the roles of proteins and also suggested new genes to be investigated. New candidate genes continue to be described based on experimental models and on next-generation sequencing of patient DNAs. PMID- 28898879 TI - Comparison of Clomethiazole and Diazepam in the Treatment of Alcohol Withdrawal Syndrome in Clinical Practice. AB - BACKGROUND: The objective of this retrospective study was to compare the effectivity and tolerability of diazepam and clomethiazole in the treatment of alcohol withdrawal syndrome (AWS) in a large clinical sample. METHODS: The data of 566 patients admitted to an intensive care psychiatric unit in Germany (2010 2014) were evaluated. The course of withdrawal was analyzed on a matched sample (n = 152) consisting of a diazepam group (n = 76) and a clomethiazole group (n = 76). Medical assessment was based on a standardized point-based symptom rating scale called AESB (Alkoholentzugssymptom-Bogen), a German modified version of the Revised Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar). RESULTS: Although the mean daily symptom reduction did not differ significantly, patients treated with clomethiazole were treated significantly shorter and needed less concomitant antipsychotic medication. Numbers of complications and adverse events did not show significant differences. CONCLUSION: Both clomethiazole and diazepam were effective and equally safe in the treatment of AWS. Clomethiazole provided a faster withdrawal and required less concomitant antipsychotic medication and therefore might be the more favorable option for patients and physicians. Taken into account the methodological limitations of the study (retrospective design, secondary matching, missing randomization, use of clomethiazole as drug of first choice), further studies are needed to confirm this result. PMID- 28898880 TI - Personalized Management of Cardiovascular Disorders. AB - Personalized management of cardiovascular disorders (CVD), also referred to as personalized or precision cardiology in accordance with general principles of personalized medicine, is selection of the best treatment for an individual patient. It involves the integration of various "omics" technologies such as genomics and proteomics as well as other new technologies such as nanobiotechnology. Molecular diagnostics and biomarkers are important for linking diagnosis with therapy and monitoring therapy. Because CVD involve perturbations of large complex biological networks, a systems biology approach to CVD risk stratification may be used for improving risk-estimating algorithms, and modeling of personalized benefit of treatment may be helpful for guiding the choice of intervention. Bioinformatics tools are helpful in analyzing and integrating large amounts of data from various sources. Personalized therapy is considered during drug development, including methods of targeted drug delivery and clinical trials. Individualized recommendations consider multiple factors - genetic as well as epigenetic - for patients' risk of heart disease. Examples of personalized treatment are those of chronic myocardial ischemia, heart failure, and hypertension. Similar approaches can be used for the management of atrial fibrillation and hypercholesterolemia, as well as the use of anticoagulants. Personalized management includes pharmacotherapy, surgery, lifestyle modifications, and combinations thereof. Further progress in understanding the pathomechanism of complex cardiovascular diseases and identification of causative factors at the individual patient level will provide opportunities for the development of personalized cardiology. Application of principles of personalized medicine will improve the care of the patients with CVD. PMID- 28898881 TI - Performance of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Isolated Mediastinal and Hilar Lymphadenopathy. AB - BACKGROUND: Although many studies have assessed the diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the context of a specific disease, few studies have assessed the overall diagnostic yield, sensitivity, and negative predictive value in patients with isolated mediastinal and hilar lymphadenopathy (IMHL). OBJECTIVE: We evaluated the performance of EBUS-TBNA for diagnosing IMHL in a population with a high prevalence of concurrent or preexisting non-pulmonary malignancy. METHODS: A retrospective chart review of patients who underwent EBUS-TBNA from October 2008 to April 2014 was performed to identify patients with IMHL. Patients with known or suspected primary pulmonary malignancy were excluded. When available, EBUS TBNA results were cross-referenced with further diagnostic investigation or clinical diagnosis based on follow-up. RESULTS: EBUS-TBNA was used to sample 765 lymph nodes from 350 patients. One hundred and fourteen (33.3%) patients had a concurrent or preexisting non-pulmonary malignancy. The overall yield of EBUS TBNA for specific diagnosis was 300/350 (86%). The diagnostic yield for sarcoidosis, lymphoproliferative disease, metastatic lymphadenopathy from extrathoracic malignancy, and necrotizing granuloma was 123/149 (83%), 27/33 (82%), 20/25 (80%), and 13/19 (68%), respectively. Amongst 50 patients with non diagnostic EBUS-TBNA, 25 yielded an insufficient sample and another 25 yielded only benign lymphoid material which was not representative of the underlying pathology. Overall, EBUS-TBNA had a sensitivity of 89%, a diagnostic yield of 86%, and a negative predictive value of 79%. CONCLUSION: For patients with isolated hilar or mediastinal lymphadenopathy and a high background prevalence of concurrent and preexisting non-pulmonary malignancy, EBUS-TBNA is a reliable first-line diagnostic investigation. PMID- 28898882 TI - Hospitalisation in Children with Adrenal Insufficiency and Hypopituitarism: Is There a Differential Burden between Boys and Girls and between Age Groups? AB - BACKGROUND/AIMS: To determine the burden of hospitalisation in children with adrenal insufficiency (AI)/hypopituitarism in Australia. METHODS: A retrospective study of Australian hospitalisation data. All admissions between 2001 and 2014 for patients aged 0-19 years with a principal diagnosis of AI/hypopituitarism were included. Denominator populations were extracted from national statistics datasets. RESULTS: There were 3,779 admissions for treatment of AI/hypopituitarism in patients aged 0-19 years, corresponding to an average admission rate of 48.7 admissions/million/year. There were 470 (12.4%) admissions for an adrenal crisis (AC). Overall, admission for AI/hypopituitarism was comparable between the sexes. Admission rates for all AI, hypopituitarism, congenital adrenal hyperplasia (CAH), and "other and unspecified causes" of AI were highest among infants and decreased with age. Admissions for primary AI increased with age in both sexes. Males had significantly higher rates of admission for hypopituitarism. AC rates differed by both sex and age group. CONCLUSION: This nationwide study of the epidemiology of hospital admissions for a principal diagnosis of AI/hypopituitarism shows that admissions generally decreased with age; males had higher rates of admission for hypopituitarism; females had higher rates of admission for CAH and "other and unspecified causes" of AI; and AC incidence varied by age and sex. Increased awareness of AI and AC prevention strategies may reduce some of these admissions. PMID- 28898883 TI - Anti-Inflammatory Nutrition and Successful Ageing in Elderly Individuals: The Multinational MEDIS Study. AB - BACKGROUND: The role of diet and inflammation in successful ageing is not transparent, and as such, is still being investigated. The aim of the present work was to evaluate the inflammatory potential of dietary habits in the successful ageing of a random sample of older adults living in the Mediterranean basin and who participated in the MEDIS (MEDiterranean ISlands) study. METHODS: During 2005-2016, 3,128 older adults (aged 65-100 years) from 24 Mediterranean islands and the rural Mani region (Peloponnesus) of Greece were enrolled in the study. A multidimensional successful ageing index consisting of 10 components was employed. A validated and reproducible Food Frequency Questionnaire (FFQ) was used to evaluate the dietary habits of the older adults. A nutrition anti inflammatory (NAI) score based on the participants' specific dietary habits was assessed. RESULTS: Participants with high NAI scores (proinflammatory nutrition) had a higher prevalence of hypercholesterolemia and lower levels of successful ageing. After adjusting for several confounders, the NAI score was associated with successful ageing (-0.03, 95% CI -0.5 to -0.006). Stratified analysis by gender and advanced age revealed heterogeneity in the NAI score, predicting successful ageing. CONCLUSIONS: The inflammatory potential of nutrition was reported as an important factor for successful ageing, suggesting that further research is needed on the role of anti- and proinflammatory dietary habits in healthy and successful ageing. PMID- 28898884 TI - Effects of Mucuna pruriens on Free Fatty Acid Levels and Histopathological Changes in the Brains of Rats Fed a High Fructose Diet. AB - OBJECTIVE: To investigate free fatty acid levels and histopathological changes in the brain of rats fed a high fructose diet (HFrD) and to evaluate the effects of Mucuna pruriens, known to have antidiabetic activity, on these changes. MATERIALS AND METHODS: The study comprised 28 mature female Wistar rats. The rats were divided into 4 groups, each included 7 rats. Group 1: control; group 2: fed an HFrD; group 3: fed normal rat chow and M. pruriens; group 4: fed an HFrD and M. pruriens for 6 weeks. At the end of 6 weeks, the rats were decapitated, blood and brain tissues were obtained. Serum glucose and triglyceride levels were measured. Free fatty acid levels were measured in 1 cerebral hemisphere of each rat and histopathological changes in the other. The Mann-Whitney U test was used to compare quantitative continuous data between 2 independent groups, and the Kruskal-Wallis test was used to compare quantitative continuous data between more than 2 independent groups. RESULTS: Arachidonic acid and docosahexaenoic acid levels were significantly higher in group 2 than in group 1 (p < 0.05). Free arachidonic acid and docosahexaenoic acid levels in group 4 were significantly less than in group 2 (p < 0.05). Histopathological examination of group 2 revealed extensive gliosis, neuronal hydropic degeneration, and edema. In group 4, gliosis was much lighter than in group 2, and edema was not observed. Neuronal structures in group 4 were similar to those in group 1. CONCLUSIONS: The HFrD increased the levels of free arachidonic acid and docosahexaenoic acid probably due to membrane degradation resulting from possible oxidative stress and inflammation in the brain. The HFrD also caused extensive gliosis, neuronal hydropic degeneration, and edema. Hence, M. pruriens could have therapeutic effects on free fatty acid metabolism and local inflammatory responses in the brains of rats fed an HFrD. PMID- 28898885 TI - Pilot Neonatal Screening Program for Central Congenital Hypothyroidism: Evidence of Significant Detection. AB - BACKGROUND/AIM: Congenital hypothyroidism (CH) is a heterogeneous entity. Neonatal screening programs based on thyrotropin (TSH) determination allow primary CH diagnosis but miss central CH (CCH). CCH causes morbidity, alerts to other pituitary deficiencies, and is more prevalent than previously thought. We aimed at developing a pilot neonatal screening program for CCH detection. PATIENTS AND METHODS: A prospective 2-year pilot neonatal screening study based on simultaneous dried blood specimen TSH and thyroxine (T4) measurements was implemented in term newborns aged 2-7 days. Those with T4 <=4.5 ug/dL (-2.3 SDS) and TSH <10 mIU/L were recalled (suspicious of CCH) and underwent clinical and biochemical assessment performed by expert pediatric endocrinologists. RESULTS: A total of 67,719 newborns were screened. Primary CH was confirmed in 24 (1: 2,821). Forty-four newborns with potential CCH were recalled (recall rate 0.07%) at a mean age of 12.6 +/- 4.8 days. In this group, permanent CCH was confirmed in 3 (1: 22,573), starting L-T4 treatment at a mean age of 12.3 +/- 6.6 days; 14 boys showed T4-binding globulin deficiency (1: 4,837); 24 had transient hypothyroxinemia (21 non-thyroidal illness and 3 healthy); and 3 died before the confirmation stage. According to initial free T4 measurements, CCH patients had moderate hypothyroidism. CONCLUSIONS: Adding T4 to TSH measurements enabled the identification of CCH as a prevalent condition and contributed to improving the care of newborns with congenital hypopituitarism and recognizing other thyroidal disorders. PMID- 28898886 TI - The Role of Dr. Francis Willis in the Madness of George III. AB - In the well-known story of the illness of King George III, what is often overlooked is the part played by Dr. Francis Willis, an inconspicuous doctor who with great success ran an asylum in Lincolnshire. In November 1788, he was called to attend the King whose mania was becoming uncontrollable. Because of his interventions there was a slow but marked improvement. The King's recovery in 1789 increased Willis' reputation and expanded his practice. PMID- 28898887 TI - Angelman Syndrome due to a Maternally Inherited Intragenic Deletion Encompassing Exons 7 and 8 of the UBE3A Gene. AB - Angelman syndrome (AS) is characterised by developmental delay, lack of speech, seizures, a characteristic behavioural profile with a happy demeanour, microcephaly, and ataxia. More than two-thirds of cases are due to an approximately 5-Mb interstitial deletion of the imprinted region 15q11.2q13, which is usually de novo. The rest are associated with point mutations in the UBE3A gene, imprinting defects, and paternal uniparental disomy. Small intragenic UBE3A deletions have rarely been described. They are usually maternally inherited, increasing the recurrence risk to 50%, and may be missed by conventional testing (methylation studies and UBE3A gene sequencing). We describe a boy with AS due to an 11.7-kb intragenic deletion. The deletion was identified by array-CGH and was subsequently detected in his affected first cousin and unaffected maternal grandfather, mother, and aunt, confirming the silencing of the paternal allele. The patient had developmental delay, speech impairment, a happy demeanour, microcephaly, and an abnormal EEG, but no seizures by the age of 4 years. Delineation of the underlying genetic mechanism is of utmost importance for reasons of genetic counselling, as well as appropriate management and prognosis. Alternative techniques, such as array-CGH and MLPA, are necessary when conventional testing for AS has failed to identify the underlying genetic mechanism. PMID- 28898888 TI - Outcome of Bronchopulmonary Sequestration with Massive Pleural Effusion after Intrafetal Vascular Laser Ablation. AB - OBJECTIVE: To assess the outcome of 12 fetuses with bronchopulmonary sequestration (BPS) and massive pleural effusion after intrafetal vascular laser ablation (VLA). METHODS: All fetuses with BPS and massive pleural effusion that were treated with intrafetal VLA during a 5-year period (2012-2016) were reviewed for safety, intrauterine course, and postnatal outcome. RESULTS: In the study period, 12 fetuses with BPS were treated with VLA. In 7 (58.3%) fetuses, complete cessation of blood flow was achieved after the first VLA, while in 5 (41.7%) fetuses, residual perfusion of the feeding vessel was demonstrated at follow-up. A second intervention was successful in 4 of 5 (80%) fetuses. Overall, in 11 of 12 (91.7%) fetuses, complete coagulation of the feeding vessel could be achieved, followed by a reduction in size or complete resolution of the BPS. All 11 fetuses with successful prenatal intervention were live-born at a median gestational age of 39+1 (range, 37+5-41+2) weeks. Postnatally, 2 (18.2%) of the 11 newborns underwent sequestrectomy, as well as the preterm newborn on which a second fetal intervention was not feasible. CONCLUSION: VLA is an effective and safe treatment of BPS that appears to be of benefit in improving prognosis and decreasing the need for postnatal sequestrectomy. PMID- 28898889 TI - Chrysotile Causes Human Bronchial Epithelial Cell Apoptosis in Response to the Fas-Mediated Apoptosis Pathway. AB - AIMS: Asbestos is harmful to human health. However, the pathogenicity of chrysotile is a controversial matter. This study aimed to investigate the apoptosis of a human bronchial epithelial cell line (BEAS-2B) exposed to chrysotile that may function in part through the Fas death receptor pathway. METHODS: Cultured human BEAS-2B cells were treated with chrysotile and cell viability was evaluated by CCK-8 assay. The induction of cell apoptosis was evaluated by FACS analysis. mRNA expression levels of Fas, caspase-3, and caspase 8 were evaluated quantitatively by real-time PCR. The expression of Fas, caspase 3, and caspase-8 proteins were evaluated by Western blot. Meanwhile, cells were preincubated with various concentrations of anti-Fas antibody (CH11) and antagonistic anti-Fas antibody (ZB4). RESULTS: Chrysotile inhibits proliferation, induces apoptosis, and upregulates the expression of Fas, caspase-3, and caspase 8. The role of Fas as a regulator of chrysotile-induced apoptosis in BEAS-2B cells was tested by the prominent increase in and partial blockade of the apoptotic rate with CH11 and ZB4. When CH11 was pretreated, a synergistic effect was apparent on chrysotile-induced apoptosis and the mRNA and protein expression levels of Fas and cleaved caspase-3. CONCLUSION: Chrysotile causes the apoptosis of BEAS-2B cells via the Fas death receptor pathway. The Fas-mediated apoptosis pathway plays an important role in chrysotile-induced apoptosis of BEAS-2B cells in vitro. PMID- 28898890 TI - An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP). AB - BACKGROUND: RECAP (NCT00662038) was an open-label extension study in patients with idiopathic pulmonary fibrosis (IPF) who completed either the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) 016 phase 3 trial or the Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY) 004/006 phase 3 trials. OBJECTIVE: To obtain long-term safety data for pirfenidone in patients with IPF in RECAP. METHODS: Of the 1,334 patients who participated in the phase 3 trials, 1,058 entered RECAP. The final analysis from enrollment (September 2008) to June 2015 is presented. RESULTS: Mean (SD) and median (range) pirfenidone exposures in RECAP were 122 (98) weeks and 88 (>0 to 349) weeks, respectively, with a mean daily dose of 2,091.1 mg. Cumulative total exposure was 2,482 patient exposure years (PEY). The treatment-emergent adverse event (TEAE) rate was 701.9 per 100 PEY. The serious TEAE rate was 53.5 per 100 PEY, with the most common serious TEAE being IPF (11.1 per 100 PEY). Of the 231 deaths (9.3 per 100 PEY), the most common cause was IPF (5.4 per 100 PEY). The treatment discontinuation rate due to a TEAE was 17.9 per 100 PEY; discontinuations were due to IPF (7.2 per 100 PEY), pneumonia, respiratory failure, acute respiratory failure, rash (0.5 per 100 PEY each), and nausea (0.4 per 100 PEY). For patients from CAPACITY 004/006 who entered RECAP, the mean change in percent predicted forced vital capacity from RECAP baseline at 180 weeks was -9.6%. Median on-treatment survival from the first pirfenidone dose in RECAP was 77.2 months. CONCLUSIONS: RECAP provides long-term follow-up and safety data for pirfenidone that were consistent with the known profile, with no new safety signals observed. PMID- 28898891 TI - New Insights into the Natural History of Congenital Zika Virus Syndrome. AB - We describe the prenatal evolution of the brain findings in a patient with proved Zika virus infection at 8 weeks of gestation showing the very early appearance at 17 weeks of ventriculomegaly and signs of brain parenchymal involvement without microcephaly. The involvement of the brain becomes more evident at 22 and 27 weeks with the apparition of calcifications and microcephaly. Interestingly, the postnatal findings failed to show significant worsening when compared to these prenatal findings. PMID- 28898892 TI - Posterior Hemi-/Laminectomy and Facetectomy Approach for the Treatment of Dumbbell-Shaped Schwannomas in the Subaxial Cervical Spine: A Retrospective Study of 26 Cases. AB - OBJECTIVE: It is difficult to completely and safely remove a tumor that is located in the subaxial cervical spine by using the posterior approach because of the anatomical characteristics. Previous reports regarding the total removal of subaxial schwannomas using the one-stage posterior approach are still limited. This study was to evaluate the feasibility and efficacy of treating the dumbbell shaped schwannomas in the subaxial cervical spine using the one-stage posterior approach. METHODS: Patients with dumbbell-shaped schwannomas in the subaxial cervical spine were treated using the one-stage posterior approach. Surgical profile, clinical outcomes, MRI and X-ray images, and complications were investigated. Japanese Orthopaedic Association (JOA) score and McCormick functional schema score were obtained. RESULTS: The average follow-up was 21.5 +/ 5.1 months, with a range of 12-31 months. Twenty-six patients were enrolled in the study. Total resection was achieved in all patients using the one-stage posterior approach with hemi- or laminectomy and facetectomy. All cases underwent lateral mass screw fixation and fusion. JOA improved significantly (p < 0.01). The McCormick score improved significantly (p < 0.05) after the surgery. No mortality, morbidity, or tumor recurrence was observed during the follow-up period. CONCLUSION: Our technique was feasible and effective for the treatment of dumbbell schwannomas in the subaxial cervical spine. The tumor could be totally removed in most cases safely. PMID- 28898893 TI - Effects of Artesunate on the Expressions of Insulin-Like Growth Factor-1, Osteopontin and C-Telopeptides of Type II Collagen in a Rat Model of Osteoarthritis. AB - OBJECTIVE: The study aims to explore the effects of artesunate on insulin-like growth factor-1 (IGF-1), Osteopontin (OPN), and C-telopeptides of type II collagen (CTX-II) in serum, synovial fluid (SF), and cartilage tissues of rats with osteoarthritis (OA). METHODS: OA models were established. Normal model, artesunate, and Viatril-S groups (20 rats respectively) were set. Enzyme-linked immunosorbent assay, IHC staining, and quantitative real-time polymerase chain reaction were conducted to calculate IGF-1, OPN, and CTX-II levels in serum, SF, and cartilage tissues of rats. The pathological changes in cartilage tissues were evaluated with Mankin score and Hematoxylin-Eosin staining. RESULTS: Compared with the normal group, the model group showed increased IGF-1 level; decreased OPN, CTX-II levels in the serum and SF; and contrary results were seen in the cartilage tissues. A gradual ascending IGF-1 level and descending OPN and CTX-II levels existed in the serum and SF in the artesunate and Viatril-S groups after 2 weeks. The model group showed the most obvious pathological changes and highest Mankin score compared with the other groups. Higher IGF-1 level and lower OPN, CTX-II levels were exhibited in the cartilage tissue in the artesunate and Viatril-S groups but not in the model group. CONCLUSION: Artesunate and Viatril-S inhibit OA development by elevating IGF-1 level and reducing OPN and CTX-II levels. PMID- 28898894 TI - Editorial to Driving Ability and Psychotropic Drugs. PMID- 28898895 TI - Erratum: International Reports of Unexpected Low Plasma Concentrations of Dabigatran Suggest That More Frequent Measurements Will Add Value. PMID- 28898896 TI - Intracranial Hemorrhage: A Devastating Outcome of Congenital Bleeding Disorders Prevalence, Diagnosis, and Management, with a Special Focus on Congenital Factor XIII Deficiency. AB - Intracranial hemorrhage (ICH) is a medical emergency. In congenital bleeding disorders, ICH is a devastating presentation accompanied with a high rate of morbidity and mortality. The prevalence of ICH is highly variable among congenital bleeding disorders, with the highest incidence observed in factor (F) XIII deficiency (FXIIID) (~30%). This life-threatening presentation is less common in afibrinogenemia, FVIII, FIX, FVII, and FX deficiencies, and is rare in severe FV and FII deficiencies, type 3 von Willebrand disease and inherited platelet function disorders (IPFDs). In FXIIID, this diathesis most often occurs after trauma in children, whereas spontaneous ICH is more frequent in adults. About 15% of patients with FXIIID and ICH die; the bleeding causes 80% of deaths in this coagulopathy. Although in FXIIID, the bleed most commonly is intraparenchymal (> 90%), epidural, subdural, and subarachnoid hemorrhages also have been reported, albeit rarely. As this life-threatening bleeding causes neurological complications, early diagnosis can prevent further expansion of the hematoma and secondary damage. Neuroimaging plays a crucial role in the diagnosis of ICH, but signs and symptoms in patients with severe FXIIID should trigger replacement therapy even before establishment of the diagnosis. Although a high dose of FXIII concentrate can reduce the rate of morbidity and mortality of ICH in FXIIID, it may occasionally trigger inhibitor development, thus complicating ICH management and future prophylaxis. Nevertheless, replacement therapy is the mainstay of treatment for ICH in FXIIID. Neurosurgery is performed in patients with FXIIID and epidural hematoma and a hemorrhage diameter exceeding 2 cm or a volume of ICH is more than 30 cm3. Contact sports are not recommended in people with FXIIID as they can elicit ICH. However, a considerable number of safe sports and activities have been suggested to have more benefits than dangers for patients with congenital bleeding disorders, and are hence suitable for these patients. PMID- 28898897 TI - von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications. AB - Venous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications. PMID- 28898898 TI - Mechanisms of Platelet Dysfunction in Patients with Implantable Devices. AB - As treatment options in modern medicine continue to expand, physicians globally have witnessed a veritable explosion in the utility of therapeutic devices. Particularly within the spheres of cardiology and critical care medicine, a plethora of devices are now available with an ever-increasing range of clinical indications. Additionally, the advent of transcatheter-mounted devices has enabled patients unsuitable for more invasive procedures to benefit from intervention, thereby greatly expanding the cohort of device-eligible patients. However, despite advances in design and materials, as well as pharmacological prophylaxis, hemostatic complications continue to plague device recipients, contributing to morbidity and mortality. Elucidating the complex interplay between components of the hemostatic system and cardiac devices has been the subject of much recent research, with greater focus on the coagulation cascade and device-induced perturbations. However, less is known about impact of mechanical surfaces on platelets and the resultant clinical complications, both hemorrhagic and thrombotic. This review will focus on exploring the pathobiology of platelet-surface interactions, contextualized within the wider hemostatic system, with a focus on the increasingly utilized technologies of transcatheter aortic-valve implantation, ventricular assist devices, and extracorporeal membrane oxygenation. PMID- 28898900 TI - The Complications of Vascular Access in Hemodialysis. AB - Complications related to hemodialysis vascular access continue to have a major impact on morbidity and mortality. Vascular access dysfunction is the single most important factor that determines the quality of dialysis treatment. Vascular access stenosis is a common complication that develops in a great majority of patients with an arteriovenous access and leads to access dysfunction. By restricting luminal diameter, this complication leads to a reduction in blood flow and places the access at risk for thrombosis. Similarly, the development of catheter-related fibroepithelial sheath also causes catheter dysfunction with its detrimental effects on blood flow. In this article, we discuss the most common complications associated with dialysis access and provide therapeutic options to manage these problems. PMID- 28898901 TI - The Lupus Anticoagulant Paradox. AB - Lupus anticoagulant (LA) represents the most enigmatic antibody population in patients with antiphospholipid syndrome and represents a paradox that is still unsolved. This class of antiphospholipid antibody causes a phospholipid-dependent prolongation of the clotting time but is associated with an increased risk of thrombosis and pregnancy morbidity. In this review, we will provide an overview of the different antibodies that have been associated with LA activity, their importance based on clinical studies, and address the question why this prolongation of the clotting time is associated with thrombosis rather than a bleeding tendency. PMID- 28898899 TI - Platelets as Modulators of Liver Diseases. AB - Platelets are key players in thrombosis and hemostasis. Alterations in platelet count and function are common in liver disease, and may contribute to bleeding or thrombotic complications in liver diseases and during liver surgery. In addition to their hemostatic function, platelets may modulate liver diseases by mechanisms that are incompletely understood. Here, we present clinical evidence for a role of platelets in the progression of chronic and acute liver diseases, including cirrhosis, acute liver failure, and hepatocellular carcinoma. We also present clinical evidence that platelets promote liver regeneration following partial liver resection. Subsequently, we summarize studies in experimental animal models that support these clinical observations, and also highlight studies that are in contrast with clinical observations. The combined results of clinical and experimental studies suggest that platelets may be a therapeutic target in the treatment of liver injury and repair, but the gaps in our understanding of mechanisms involved in platelet-mediated modulation of liver diseases call for caution in clinical application of these findings. PMID- 28898902 TI - Bleeding and Thrombotic Complications in the Use of Extracorporeal Membrane Oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) has been used for >40 years to support lung and heart failure; however, bleeding and thrombosis remain serious complications. The known etiologies of bleeding include heparin effect or overdose, coagulopathy, thrombocytopenia, platelet dysfunction, acquired von Willebrand syndrome, and hyperfibrinolysis. Bleeding sites may include cannula insertion sites, recent surgical incisions, vascular access sites, lung, gastrointestinal tract, mouth, nose, thoracic cavity, abdominal cavity, and brain. Massive bleeding in the brain, the most feared bleeding complication, can be rapidly fatal because it occurs in a rigid closed space, is difficult to drain, and cannot be stopped with direct pressure to the bleeding site. Pulmonary hemorrhage may cause irreversible lung damage. Management should be swift and precise to prevent fatal bleeding. In contrast, etiologies of thrombosis include high fibrinogen and factor VIII levels, heparin resistance, and platelet activation. Achieving the optimal anticoagulation balance to prevent bleeding and thrombosis in ECMO patients is extremely complex. Experts in hemostasis should be a part of an institutional ECMO team and continuously available for immediate management. PMID- 28898904 TI - The Protective Effect of the Ethanol Leaf Extract of Andrographis Paniculata on Cisplatin-Induced Acute Kidney Injury in Rats Through nrf2/KIM-1 Signalling Pathway. AB - The ethanol leaf extract of Andrographis paniculata was used to ameliorate the renal toxicity induced by cisplatin in 28 rats divided into four groups of seven rats per group. Group A received normal saline for the duration of the experiment. Group B animals were treated with cisplatin (10 mg/kg i.p) on day 1 and 3 days after received normal saline for the next 7 days while groups C and D animals also received 10 mg/kg dose of cisplatin on day 1 but after 3 days were then respectively treated with 200 and 400 mg/kg doses of the extract of Andrographis paniculata for the remaining 7 days through oral administration. Serum chemistry was used for the determination of markers of oxidative stress, anti-oxidant enzymes, serum biomarkers etc. Histopathology and immunohistochemistry were also carried out. Results showed that all oxidative stress markers assayed were significantly increased in group B animals but reverse is the case for groups C and D. On the other hand, antioxidant enzymes assayed experienced significant increase for groups C and D while these parameters experienced significant decrease for group B animals. Histopathology showed severe infiltration of inflammatory cells into renal tissues of group B animals whereas for groups C and D animals, only moderate glomerular degeneration was noted. In immunohistochemistry, while there is higher expression of KIM-1 for group B, there was a lower expression in groups C and D. Again, there was lower expression of Nrf2 for group B but higher expressions in groups C and D animals. PMID- 28898905 TI - Taguchi Experimental Design for Optimization of Recombinant Human Growth Hormone Production in CHO Cell Lines and Comparing its Biological Activity with Prokaryotic Growth Hormone. AB - Growth hormone deficiency results in growth retardation in children and the GH deficiency syndrome in adults and they need to receive recombinant-GH in order to rectify the GH deficiency symptoms. Mammalian cells have become the favorite system for production of recombinant proteins for clinical application compared to prokaryotic systems because of their capability for appropriate protein folding, assembly, post-translational modification and proper signal. However, production level in mammalian cells is generally low compared to prokaryotic hosts. Taguchi has established orthogonal arrays to describe a large number of experimental situations mainly to reduce experimental errors and to enhance the efficiency and reproducibility of laboratory experiments.In the present study, rhGH was produced in CHO cells and production of rhGH was assessed using Dot blotting, western blotting and Elisa assay. For optimization of rhGH production in CHO cells using Taguchi method An M16 orthogonal experimental design was used to investigate four different culture components. The biological activity of rhGH was assessed using LHRE-TK-Luciferase reporter gene system in HEK-293 and compared to the biological activity of prokaryotic rhGH.A maximal productivity of rhGH was reached in the conditions of 1%DMSO, 1%glycerol, 25 uM ZnSO4 and 0 mM NaBu. Our findings indicate that control of culture conditions such as the addition of chemical components helps to develop an efficient large-scale and industrial process for the production of rhGH in CHO cells. Results of bioassay indicated that rhGH produced by CHO cells is able to induce GH-mediated intracellular cell signaling and showed higher bioactivity when compared to prokaryotic GH at the same concentrations. PMID- 28898903 TI - Inhibition of Factors XI and XII for Prevention of Thrombosis Induced by Artificial Surfaces. AB - Exposure of blood to a variety of artificial surface induces contact activation, a process that contributes to the host innate response to foreign substances. On the foreign surface, the contact factors, factor XII (FXII), and plasma prekallikrein undergo reciprocal conversion to their fully active protease forms (FXIIa and alpha-kallikrein, respectively) by a process supported by the cofactor high-molecular-weight kininogen. Contact activation can trigger blood coagulation by conversion of factor XI (FXI) to the protease FXIa. There is interest in developing therapeutic inhibitors to FXIa and FXIIa because these activated factors can contribute to thrombosis in certain situations. Drugs targeting these proteases may be particularly effective in thrombosis triggered by exposure of blood to the surfaces of implantable medical devices. Here, we review clinical data supporting roles for FXII and FXI in thrombosis induced by medical devices, and preclinical data suggesting that therapeutic targeting of these proteins may limit surface-induced thrombosis. PMID- 28898906 TI - Application of Spray Drying Technique for Flowability enhancement of Divalproex Sodium. AB - BACKGROUND: Tablets and capsules are the most accepted and widely used solid dosage forms in the medical therapy. Flow property of the powders is playing a key role in the various pharmaceutical fields especially in the fomulation of tablets and capsules. The high hygroscopic crystalline structure of anhydrous Divalproex sodium (DVX) makes it to be appear as waxy white flakes with almost no powder flowability which cause serious problems during the tabletting and capsule filling procedures. PURPOSE: The main objective of this study was to improve the flowability of DVX powder. METHODS: DVX was mixed with mannitol or lactos in different ratios, dissolved in water and differet binary mixtures of ethanol:water, and finally spray dried with different spray drying conditions. Particle size and powders morphology were assessed by Scanning Electron Microscopy (SEM). The poweder flowability was assessed by measurmet of Hausner ratio (HR), Carr's index (CI) and angle of repose (AOR) indexes. Furthermore, the content uniformity of DVX in spray-dried powders was determined by using a validated HPLC technique. RESULTS: The results showed that spray drying technique improved DVX flowability by forming spherical particles with narrow size distribution AOR value of DVX was decrease from not flowable to 36.1 degrees in spray dried solid dispersion indicating the improvmet of powder flowability from very poor to fair/good condition. CONCLUSION: Findings suggest that the spray drying technique improves DVX flowability and may pave the way for improvement in the tabletting procedure of DVX. PMID- 28898907 TI - Effects of Cobalamin (Vitamin B12) on Gentamicin Induced Nephrotoxicity in Rat. AB - Background The main side effect of gentamicin is nephrotoxicity. The effect of cobalamin (Cob) was investigated on gentamicin nephrotoxicity in rats. Methods Renal injury induced by i.p. injection of gentamicin (100 mg/kg) for 8 consecutive days. Cobalamin (6 mg/kg/day, i.p) treatment was done for 8 consecutive days as co-treatment and post-treatment protocol. Results Cobalamin significantly increased creatinine clearance levels and renal blood flow which were reduced by gentamicin. Also, cobalamin significantly improved serum electrolytes (sodium and potassium) levels which were disturbed by gentamicin. Cobalamin significantly compensated deficits in the antioxidant defense mechanisms, suppressed lipid per oxidation and ameliorated renal tissue damage mediated by gentamicin. Conclusion The results of the current study indicated that cobalamin effectively protected the kidney tissue against gentamicin induced acute nephrotoxicity in rats. The antioxidant and anti-inflammatory activities can be supposed the main factors responsible for the nephroprotective effect of cobalamin. PMID- 28898908 TI - Influence of High-Dose Folic Acid on Methotrexate Efficacies and Safety in Japanese Rheumatoid Arthritis Patients. AB - Backgrounds Folic acid dose at ?5 mg/week has been recommended for rheumatoid arthritis (RA) patients to decrease risk of methotrexate adverse effects. However, higher doses of folic acid is used in some cases. We examined the influence of high-dose folic acid on methotrexate efficacies and safety in Japanese RA patients. Methods 502 RA patients of four hospitals prescribed methotrexate and folic acid were included. These patients were divided into two subgroups according to the threshold of folic acid dose by 5 mg/week. Basic patient characteristics, methotrexate doses, and the efficacies or adverse effects of methotrexate were retrospectively compared between the two patient subgroups. Results The frequency of folic acid use at doses higher than 5 mg/week was significantly different between the four hospitals (P<0.001). The prevalence of methotrexate adverse effects was not significantly different between the patients taking folic acid less and more than 5 mg/week. However, in the lower dose methotrexate subgroup (?8 mg/week), the prevalence of patients exhibiting abnormal serum ALT concentrations in the patients using higher (>5 mg/week) dose of folic acid was significantly higher than that in the lower (?5 mg/week) folic acid-treated subgroup (P=0.029). Folic acid dose between patients taking methotrexate less and more than 8 mg/week was not significantly different. Major conclusion Folic acid dose was dependent on the hospitals, while efficacies and hepatotoxicity of methotrexate was not basically different between patients taking less and more than 5 mg/week of folic acid. PMID- 28898909 TI - Anti-Hyperglycaemic Effect of Cleome Rutidosperma in Alloxan-Induced Diabetic Albino Rats. AB - The hypoglycaemic and antihyperglycaemic effects of methanol extract of leaves of Cleome rutidosperma (Cr) DC (Family: Capparidaceae) was investigated in Wistar rats. Fifty normoglycaemic male rats (120 g-200 g) were divided into groups A (hypoglycaemic study; n=20) and B (antihyperglycaemic study; n=30). Each experiment had one control group and three groups administered with Cr (100, 200 or 400 mg/kg) respectively. Group B had two additional groups of diabetic untreated rats and glibenclamide-treated diabetic rats. Diabetes was induced in Group B rats (except control) fasted overnight for 12 h by intraperitoneal injection of Alloxan (100 mg/kg). Fasting blood glucose levels (FBGL) were determined and alloxan-treated rats with BGL >200 mg/dl 48 h post-induction were considered diabetic. Data obtained were analyzed using One-way ANOVA and Duncan Multiple Range Test (p<0.05). Cr-treated rats showed significant decline in BGL with noteworthy decline by day 3 post-treatment at the dose of 200 mg/kg (236.40+/-14.72 mg/dl) from 336.40+/-21.06 mg/dl. Cr at the dose of 200 mg/kg (72.20+/-6.18 mg/dl, 69.20+/-7.81 mg/dl, 137.80+/-7.15 mg/dl and 70.60+/-10.66 mg/dl) showed better glycemic control compared to glibenclamide (194.50+/-7.75 mg/dl, 253.75+/-7.20 mg/dl, 284.25+/-10.56 mg/dl and 156.00+/-10.80 mg/dl). Cr treated rats also showed progressive weight gain through the course of the study. This study demonstrated Cr has antihyperglycemic effect with more rapid onset of action and better glycemic control compared to glibenclamide. PMID- 28898910 TI - Balanced Coagonist of GLP-1 and Glucagon Receptors Corrects Dyslipidemia by Improving FGF21 Sensitivity in Hamster Model. AB - Hyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC). Antagonists of GLP-1, glucagon, and FGF21 receptors were coadministered, and FGF21 sensitivity was determined in liver and adipose tissue. Repeated dose treatment of coagonist reduced cholesterol and increased FGF21 in blood and liver. Coagonist treatment reduced hepatic triglyceride secretion, increased lipolysis and reduced body weight. Antagonism of GLP-1 and glucagon receptors partially blocked the effect of the coagonist on lipid metabolism in circulation and liver, while FGF21 receptor antagonist completely abolished it. Glucagon and GLP-1 receptors antagonists blocked the action of coagonist on cholesterol excretion and bile flow in liver, but FGF21 antagonist was not effective. Treatment with the coagonist increased expression of FGF21, FGF21R and cofactor betaKlotho in liver and adipose. In conclusion, coagonist of GLP-1 and glucagon receptors improved lipid metabolism in liver of dyslipidemic hamsters. This effect is partially mediated by GLP-1 and glucagon receptors, and the improved FGF21 sensitivity could be the mechanism of hypolipidemic action of the coagonist of GLP-1/glucagon receptors. PMID- 28898911 TI - Lactobacilus Delbrueckii subsp. Bulgaricus Modulates the Secretion of Th1/Th2 and Treg Cell-Related Cytokines by PBMCs from Patients with Atopic Dermatitis. AB - Background Atopic dermatitis (AD) is an inflammatory skin disease which may be due to the imbalance between Th1-, Th2 and Treg cell-related immune responses. Evidences suggest that appropriate stimulation with probiotics may correct the skewed immune response in children with AD. The aim was to determine the effects of the yogurt culture lactobacillus Bulgaricus on the secretion of Th1/Th2/Treg type cytokines by PBMCs from children with AD. MethodsL. Bulgaricus was cultivated on MRS broth. The PBMCs from 20 children with AD were separated by Ficoll-Hypaque centrifugation and co-cultured with different concentrations of UV killed bacteria in RPMI-1640 plus 10% FCS for 48/72 h. The levels of IL-10, IL-4, IL-12 and IFN-gamma were measured in supernatant of PBMCs by ELISA. ResultsL. Bulgaricus significantly up-regulated the secretion of IL-10, IL-12 and IFN gamma, whereas decreased the secretion of IL-4 by PBMCs at both incubation times 48 h/72 h and both bacteria:PBMCs ratios 100:1/50:1, compared to control (p<0.05). There were no significant differences between incubation times 48 h and 72 h regarding the secretion levels of IL-12, IFN-gamma and IL-4. However, the secretion of IL-10 by L. Bulgaricus-stimulated PBMCs at incubation time 72 h and in the presence of bacteria:PBMCs ratio 100:1 was significantly higher than in incubation time 48 h and in the presence of bacteria:PBMCs ratio 50:1 (P<0.000 and P<0.00, respectively). Conclusion These data show that L. Bulgaricus may modulate the secretion of Th1-, Th2-Treg-related cytokines in AD patients. Therefore, the possible potential therapeutic of L. Bulgaricus for treatment of AD should be consider in further investigation. PMID- 28898912 TI - Application of Graphene and its Derivatives in Cancer Diagnosis and Treatment. AB - Although chemotherapies are successful in some cases, systemic toxicity could be simultaneously observed due to the lack of drugs selectivity to cancerous tissues, leading to the failure of the chemotherapies. Furthermore, the therapeutic effects will be significantly improved if the anticancer drugs could be delivered to cancer cells with high selectivity. In recent years, there have been many advances in the field of diagnosis and treatment of cancer as a result of the development of novel materials with noticeable and often unique properties. Nanoparticles have unique biological properties, owing to their small size and large surface area-to-volume ratio, which allow them to bind, absorb, and carry compounds such as small molecule drugs, DNA, RNA, proteins, and probes with high efficiency. In the course of the last decade, Graphene and its derivatives have attracted growing interest in medicinal and pharmaceutical sciences, and many studies have focused on the potential of Graphene and its derivatives as carriers for targeted drug delivery intended for cancer diagnosis and therapies. In the present study, we will review the characteistics and application of Graphene and its different derivatives and finally discuss the opportunities, limitations, and challenges in this encouraging field. PMID- 28898913 TI - [Tuberculosis]. PMID- 28898914 TI - [Neuroanatomy of the Oculomotor System]. AB - After just a clinical examination, the experienced neurologist can assign specific symptoms quite precisely to distinct lesions within the brain and other parts of the nervous system, on the basis of his neuroanatomical knowledge. This also holds true for lesions affecting the oculomotor system. The aim of this article is to give a comprehensive overview of the neuroanatomical basis of the oculomotor system, in order to facilitate the precise spatial assignment of potential lesions affecting the control of eye movements. After a brief introduction, the components of the system are discussed, including the extraocular muscles and their innervating nerves. The following section will then cover the control of eye movements and will specifically address distinct patterns of eye movements and areas within the central nervous system controlling these. This article also gives a brief overview of the intraocular muscles and their control. PMID- 28898915 TI - [Current Therapies in Superficial Malignant Tumors]. AB - This article is a review of diagnostic and therapeutic possibilities in common epibulbar malignant tumors, such as basal cell carcinoma, conjunctival lymphoma, squamous cell carcinoma and conjunctival melanoma. Most importantly, for every tumor patient there is a detailed anamnesis, split lamp examination and photo documentation. Further regular controls after therapy are required due to the risk of recurrences.Basal cell carcinoma is the most common tumor of the periocular skin, divided into three subtypes (nodular, superficial and morphea). The treatment consists of total excision with a sufficient safety margin.The most common tumor of the orbital and ocular adnexa are lymphoma. They can appear primary or secondary, as lymphatic system disease. The gold standard therapy is a percutaneous irradiation.Squamous cell carcinoma and its precancerous stages (CIN I - III) are frequently diagnosed on the conjunctiva. A complete tumor excision is required, but sometimes it is not possible due to large tumor growth. Therefore, an adjuvant therapy with mitomycin C eyedrops, brachytherapy with ruthenium plaque or proton radiotherapy is required.Conjunctival melanoma is a rare, but life-threatening disease. Melanosis with atypia has a high risk for degeneration and requires further treatment with mitomycin C eyedrops. In cases of malignant tumor growth, an excision with a non-touch technique and adjuvant therapy with brachy or proton irradiation should be applied. PMID- 28898916 TI - [Rehabilitation Following Limbal Stem Cell Deficiency: Current Treatment Options and Future Developments]. AB - Limbal stem cell deficiency (LSCD) is a condition caused by the loss of corneal epithelial regenerative potential. The treatment of this condition is still a challenge. It results from various conditions both intrinsic as well as extrinsic. LSCD can be either uni- or bilateral and either partial or total. Today treatment options include a variety of techniques including transplantation of amniotic membrane and limbal tissue or tissue engineered cell sheets. This article summarizes the current techniques to treat LSCD and upcoming developments. PMID- 28898917 TI - Technical aspects of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Technical Guideline - March 2017. AB - For routine EUS-guided sampling of solid masses and lymph nodes (LNs) ESGE recommends 25G or 22G needles (high quality evidence, strong recommendation); fine needle aspiration (FNA) and fine needle biopsy (FNB) needles are equally recommended (high quality evidence, strong recommendation).When the primary aim of sampling is to obtain a core tissue specimen, ESGE suggests using 19G FNA or FNB needles or 22G FNB needles (low quality evidence, weak recommendation).ESGE recommends using 10-mL syringe suction for EUS-guided sampling of solid masses and LNs with 25G or 22G FNA needles (high quality evidence, strong recommendation) and other types of needles (low quality evidence, weak recommendation). ESGE suggests neutralizing residual negative pressure in the needle before withdrawing the needle from the target lesion (moderate quality evidence, weak recommendation).ESGE does not recommend for or against using the needle stylet for EUS-guided sampling of solid masses and LNs with FNA needles (high quality evidence, strong recommendation) and suggests using the needle stylet for EUS-guided sampling with FNB needles (low quality evidence, weak recommendation).ESGE suggests fanning the needle throughout the lesion when sampling solid masses and LNs (moderate quality evidence, weak recommendation).ESGE equally recommends EUS-guided sampling with or without on site cytologic evaluation (moderate quality evidence, strong recommendation). When on-site cytologic evaluation is unavailable, ESGE suggests performance of three to four needle passes with an FNA needle or two to three passes with an FNB needle (low quality evidence, weak recommendation).For diagnostic sampling of pancreatic cystic lesions without a solid component, ESGE suggests emptying the cyst with a single pass of a 22G or 19G needle (low quality evidence, weak recommendation). For pancreatic cystic lesions with a solid component, ESGE suggests sampling of the solid component using the same technique as in the case of other solid lesions (low quality evidence, weak recommendation).ESGE does not recommend antibiotic prophylaxis for EUS-guided sampling of solid masses or LNs (low quality evidence, strong recommendation), and suggests antibiotic prophylaxis with fluoroquinolones or beta-lactam antibiotics for EUS-guided sampling of cystic lesions (low quality evidence, weak recommendation). ESGE suggests that evaluation of tissue obtained by EUS-guided sampling should include histologic preparations (e. g., cell blocks and/or formalin-fixed and paraffin embedded tissue fragments) and should not be limited to smear cytology (low quality evidence, weak recommendation). PMID- 28898918 TI - Insertion of percutaneous endoscopic gastrostomy tubes with jejunal extensions using the "wedge" technique: a novel method to prevent retrograde tube migration into the stomach. AB - Background and study aim In percutaneous endoscopic gastrostomy (PEG) with jejunal extension (PEGJ) procedures, retrograde migration of the jejunal extension tube into the stomach during endoscope withdrawal is a frustrating problem. We describe the novel "wedge" technique for inserting the jejunal extension tube, utilizing single-balloon enteroscopy to anchor it in place. Patients and methods Prospective 1-year study of consecutive patients undergoing PEGJ insertion at a single tertiary care center. The primary outcome was number of pyloric intubations required to place the jejunal extension tube. Secondary outcomes included success rate, time, and complications related to jejunal extension tube insertion. Results 17 patients underwent the procedure. The jejunal extension tube was inserted at the first attempt in 15 patients (88.2 %) and 2 required another pyloric intubation. Abdominal X-ray showed that all PEGJ tubes were successfully seated in the proximal jejunum. The mean (SD) time required for jejunal extension insertion was 16.9 (8.6) minutes. Two adverse events occurred due to PEG insertion although none were related to the jejunal extension insertion itself. Conclusions: The "wedge" technique is an effective and easy method for inserting a jejunal extension tube after PEG insertion. PMID- 28898919 TI - Comparison of two fluoroscopic images to ensure efficient scope insertion for biliary intervention in patients with Roux-en-Y hepaticojejunostomy. AB - Background and study aims No standard procedure for endoscopic retrograde cholangiopancreatography is available for patients with Roux-en-Y hepaticojejunostomy (RYHJ) with side-to-end hepaticojejunostomy. We therefore explored methods of efficient scope insertion at a hepaticojejunostomy site. Patients and methods Patients with suspected biliary disease were prospectively enrolled. Based on two fluoroscopic images obtained on scope insertion into each lumen of a two-pronged Roux-en-Y anastomosis, we selected the lumen in which the distal end of the scope progressed toward the patient's liver or head. The accuracy of this method for selecting the correct lumen leading to the hepaticojejunostomy site was investigated. Results Of the 33 included patients, successful insertion to the hepaticojejunostomy site was achieved in 32 (97 %), 26 (81 %) of whom had undergone the imaging method. The accuracy of the method was 88 % (23/26). The time required for insertion between the anastomotic site and the hepaticojejunostomy site was shorter when the lumen selection had been correct (13 minutes [7 - 30] (n = 23) vs. 18 minutes [8 - 28] (n = 9); P = 0.95). Conclusion This method based on two fluoroscopic images was useful for achieving efficient scope insertion in patients with RYHJ.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000014183). PMID- 28898920 TI - Higher adenoma detection rate with the endocuff: a randomized trial. AB - Background and study aim Different techniques have been introduced to improve the endoscopist's view and enhance the detection of polyps. The endocuff is a polymer sleeve cap that is connected to the tip of the colonoscope in order to improve visualization of the mucosa during colonoscopy. The aim of the study was to compare adenoma detection rates (ADR) of endocuff-assisted colonoscopy and conventional colonoscopy. Patients and methods Patients 50 years or older were randomized into two groups: an endocuff-assisted colonoscopy group and a conventional colonoscopy group without the endocuff. Results A total of 337 patients were included: 174 in the endocuff group and 163 in the conventional group. The median age was 61 years (interquartile range 55 - 70 years), and 74 % were women. The ADR was higher in the endocuff group than in the conventional group (22.4 % vs. 13.5 %; P = 0.02). The mean number of adenomas was 0.30 (SD 0.25) in the endocuff group and 0.21 (SD 0.26) in the conventional group (P = 0.02). The rate of ileal intubation was lower in the endocuff group (73 % vs. 87 %; P < 0.001). No serious adverse events occurred with the use of the endocuff. Conclusions Endocuff colonoscopy achieved a greater ADR than conventional colonoscopy.Trial registered at ClinicalTrials.gov (NTC02387593). PMID- 28898921 TI - Long-term quality of life after peroral endoscopic myotomy remains compromised in patients with achalasia type III. AB - Background and study aims Peroral endoscopic myotomy (POEM) is an excellent endoscopic treatment for achalasia. Clinical and manometric parameters are used for evaluation and follow-up. However, clinical success does not guarantee high quality of life (QoL) scores, generating doubts about their direct relationship. We aimed to evaluate QoL scores before and after POEM at medium and long term, to evaluate differences between achalasia subtypes and find which factors related to low QoL scores. Patients and methods Achalasia-confirmed patients undergoing POEM between February 2012 and November 2016. and completing at least 1 year of follow up, were included. Assessment before and at 1, 6, 12, 24, 36 and 48 months after POEM employed manometry, barium series, Eckardt score, and the AE-18 health related QoL scale. Demographic, clinical, and procedure characteristics were documented, with comparisons between subgroups. Multiple logistic regression analysis was done. Results 65 of 88 patients were included (38 women, 27 men; median age 47 years, interquartile range [IQR] 20 - 81), and 50 (76.9 %) completed 4 years of follow-up. Eckardt score improved (median, preprocedure 10 vs. post-procedure 2; P = 0.002) and this persisted. There was initial improvement in median integrated relaxation pressure (IRP) (29.4 mmHg [16 - 55] vs. 10.3 mmHg [3 - 18]; P = 0.000) and median QoL scores (40 vs. 68 at 1 month; P = 0.002); however IRP increased and QoL scores decreased. Men with confirmed type III achalasia had low QoL scores. Conclusions All patients had significant clinical improvement after POEM, with medium- to long-term persistence. Though quality of life and IRP initially improved, they deteriorated in the long term. Male sex and type III achalasia seem to be associated with low QoL scores. PMID- 28898922 TI - Cold versus hot endoscopic mucosal resection for nonpedunculated colorectal polyps sized 6-10 mm: a randomized trial. AB - BACKGROUND AND STUDY AIMS: Cold snare polypectomy is an established method for the resection of small colorectal polyps; however, significant incomplete resection rates still leave room for improvement. We aimed to assess the efficacy of cold snare endoscopic mucosal resection (CS-EMR), compared with hot snare endoscopic mucosal resection (HS-EMR), for nonpedunculated polyps sized 6 - 10 mm. PATIENTS AND METHODS: This study was a dual-center, randomized, noninferiority trial. Consecutive adult patients with at least one nonpedunculated polyp sized 6 - 10 mm were enrolled. Eligible polyps were randomized (1:1) to be treated with either CS-EMR or HS-EMR. Both methods involved submucosal injection of a methylene blue-tinted normal saline solution. The primary noninferiority end point was histological eradication evaluated by postpolypectomy biopsies (noninferiority margin - 10 %). Secondary outcomes included occurrence of intraprocedural bleeding, clinically significant postprocedural bleeding, and perforation. RESULTS: Among 689 patients screened, 155 patients with 164 eligible polyps were included (CS-EMR n = 83, HS-EMR n = 81). The overall rate of histological complete resection was 92.8 % in the CS-EMR group and 96.3 % in the HS-EMR group (difference 3.5 %; 95 % confidence interval [CI] - 4.15 to 11.56), showing noninferiority of CS-EMR compared with HS-EMR. CS EMR was shown to be noninferior both for polyps measuring 6 - 7 mm (CS-EMR 93.3 %; HS-EMR 100 %; 95 %CI - 7.95 to 21.3) and those of 8 - 10 mm (92.5 % vs. 94.7 %, respectively; 95 %CI - 7.91 to 13.16). Rates of intraprocedural bleeding were similar between the two groups (CS-EMR 3.6 %, HS-EMR 1.2 %; P = 0.30). No clinically significant postprocedural bleeding or perforation occurred in either group. CONCLUSIONS: CS-EMR appears to be a valuable modification of the standard cold snare technique, obviating the need to use diathermy for nonpedunculated colorectal polyps sized 6 - 10 mm. PMID- 28898926 TI - Hybrid cell-centred/vertex model for multicellular systems with equilibrium preserving remodelling. AB - We present a hybrid cell-centred/vertex model for mechanically simulating planar cellular monolayers undergoing cell reorganisation. Cell centres are represented by a triangular nodal network, while the cell boundaries are formed by an associated vertex network. The two networks are coupled through a kinematic constraint which we allow to relax progressively. Special attention is paid to the change of cell-cell connectivity due to cell reorganisation or remodelling events. We handle these situations by using a variable resting length and applying an Equilibrium-Preserving Mapping on the new connectivity, which computes a new set of resting lengths that preserve nodal and vertex equilibrium. We illustrate the properties of the model by simulating monolayers subjected to imposed extension and during a wound healing process. The evolution of forces and the Equilibrium-Preserving Mapping are analysed during the remodelling events. As a by-product, the proposed technique enables to recover fully vertex or fully cell-centred models in a seamless manner by modifying a numerical parameter of the model. PMID- 28898923 TI - Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism. AB - BACKGROUND AND PURPOSE: Human parathyroid hormone (PTH) is critical for maintaining physiological calcium homeostasis and plays an important role in the formation and maintenance of the bone. Full-length PTH and a truncated peptide form are approved for treatment of hypoparathyroidism and osteoporosis respectively. Our initial goal was to develop an improved PTH therapy for osteoporosis, but clinical development was halted. The novel compound was then repurposed as an improved therapy for hypoparathyroidism. EXPERIMENTAL APPROACH: A longer-acting form of PTH was synthesised by altering the peptide to increase cell surface residence time of the bound ligand to its receptor. In vitro screening identified a compound, which was tested in an animal model of osteoporosis before entering human trials. This compound was subsequently tested in two independent animal models of hypoparathyroidism. KEY RESULTS: The peptide identified, LY627-2K, exhibited delayed internalization kinetics. In an ovariectomy-induced bone loss rat model, LY627-2K demonstrated improved vertebral bone mineral density and biomechanical properties at skeletal sites and a modest increase in serum calcium. In a Phase I clinical study, dose-dependent increases in serum calcium were reproduced. These observations prompted us to explore a second indication, hypoparathyroidism. In animal models of this disease, LY627-2K restored serum calcium, comparing favourably to treatment with wild-type PTH. CONCLUSIONS AND IMPLICATIONS: We summarize the repositioning of a therapeutic candidate with substantial preclinical and clinical data. Our results support its repurposing and continued development, from a common indication (osteoporosis) to a rare disease (hypoparathyroidism) by exploiting a shared molecular target. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc. PMID- 28898924 TI - Prevalence of Autism Spectrum Disorders with and without Intellectual Disability by Gestational Age at Birth in the Stockholm Youth Cohort: a Register Linkage Study. AB - BACKGROUND: Preterm birth has been linked to increased risk of autism spectrum disorders (ASD), but how this risk changes with gestational age at birth has not been well characterised, especially with regard to co-occurring intellectual disability (ID). METHODS: Register-based cohort study of singleton births in 1984 2007 in Stockholm County, Sweden (N total: 480 728; n ASD: 10 025). We assessed overall and sex-specific, gestational week-specific prevalence estimates and risk ratios of ASD with and without ID. RESULTS: Preterm and postterm births were associated with elevated risk of ASD, and the relationship between gestational age at birth and ASD with and without ID differed in males and females. Risk of ASD without ID was higher in preterm births among both sexes and decreased continuously with increasing length of gestation. Risk of ASD with ID was higher in both preterm and postterm births among both sexes, with postterm birth in females being more highly associated with ASD with ID than that in males. CONCLUSIONS: The relationship between gestational age at birth and ASD differs by the presence/absence of co-occurring ID and fetal sex. Both preterm and postterm birth are associated with increased risk of ASD. Risk of ASD is not constant within conventionally defined gestational age at birth periods. Further research on mechanism underlying these associations is needed. PMID- 28898927 TI - In-hospital 'CODE STEMI' improves door-to-balloon time in patients undergoing primary percutaneous coronary intervention. AB - OBJECTIVE: Reducing time to reperfusion for ST-segment elevation myocardial infarction (STEMI) is essential in improving outcomes. Consequently, numerous strategies have been employed to reduce median door-to-balloon time (DTBT). METHODS: CODE STEMI is an ED physician-activated STEMI notification system. On activation, an announcement is made over the hospital's public announcement (PA) system. We prospectively analysed all in-hours STEMI patients who had primary percutaneous coronary intervention (PPCI) Pre-CODE STEMI (2014) and after CODE STEMI was implemented (2015). The primary end-points were median DTBT and the proportion of STEMI patients achieving a DTBT <=90 min. The secondary end-points were in-hospital outcomes, and a composite of major adverse cardiac events (MACE) and hospital readmission rates at 30 days and 12 months. RESULTS: There were 41 and 42 patients in Pre-CODE STEMI and CODE STEMI groups respectively. Baseline characteristics were similar. DTBT was significantly reduced by 22.1 min from 67.1 +/- 34.9 min Pre-CODE STEMI to 45.0 +/- 22.7 min (P = 0.001) in the CODE STEMI group. Door-to-door time (DTDT) was also reduced from 46.3 +/- 30.9 min to 29.4 +/- 23.3 min (P = 0.006). A greater proportion of CODE STEMI patients achieved the target DTBT <=90 min (95.2% vs 73.2%, P = 0.007). CODE STEMI patients had less systolic dysfunction measured by a left ventricle ejection fraction of <=40% (10.0% vs 27.8%, P = 0.07). There were trends to lower in hospital mortality rates (4.8% vs 9.8%, P = 0.43), MACE at 30 days and 12 months (4.8% vs 9.8%, P = 0.43; 11.9% vs 22.0%, P = 0.25). CONCLUSION: The novel in hospital in-hours CODE STEMI notification system significantly reduced DTBT in patients undergoing PPCI. PMID- 28898929 TI - Dental management for patients undergoing heart valve surgery. AB - This study sought to review current guidelines and the most optimal dental management for patients undergoing cardiac valve surgery. PMID- 28898928 TI - Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50. AB - BACKGROUND AND PURPOSE: Recent crystal structures of GPCRs have emphasized the previously unappreciated role of the second extracellular (E2) loop in ligand binding and gating and receptor activation. Here, we have assessed the role of the E2 loop in the activation of the melatonin MT1 receptor and in the inactivation of the closely related orphan receptor GPR50. EXPERIMENTAL APPROACH: Chimeric MT1 -GPR50 receptors were generated and functionally analysed in terms of 2-[125 I]iodomelatonin binding, Gi /cAMP signalling and beta-arrestin2 recruitment. We also used computational molecular dynamics (MD) simulations. KEY RESULTS: MD simulations of 300 ns revealed (i) the tight hairpin structure of the E2 loop of the MT1 receptor (ii) the most suitable features for melatonin binding in MT1 receptors and (iii) major predicted rearrangements upon MT1 receptor activation, stabilizing interaction networks between Phe179 or Gln181 in the E2 loop and transmembrane helixes 5 and 6. Functional assays confirmed these predictions, because reciprocal replacement of MT1 and GPR50 residues/domains led to the predicted loss- and gain-of-melatonin action of MT1 receptors and GPR50 respectively. CONCLUSIONS AND IMPLICATIONS: Our work demonstrated the crucial role of the E2 loop for MT1 receptor and GPR50 function by proposing a model in which the E2 loop is important in stabilizing active MT1 receptor conformations and by showing how evolutionary processes appear to have selected for modifications in the E2 loop in order to make GPR50 unresponsive to melatonin. PMID- 28898930 TI - Impact and experiences of delayed discharge: A mixed-studies systematic review. AB - BACKGROUND: The impact of delayed discharge on patients, health-care staff and hospital costs has been incompletely characterized. AIM: To systematically review experiences of delay from the perspectives of patients, health professionals and hospitals, and its impact on patients' outcomes and costs. METHODS: Four of the main biomedical databases were searched for the period 2000-2016 (February). Quantitative, qualitative and health economic studies conducted in OECD countries were included. RESULTS: Thirty-seven papers reporting data on 35 studies were identified: 10 quantitative, 8 qualitative and 19 exploring costs. Seven of ten quantitative studies were at moderate/low methodological quality; 6 qualitative studies were deemed reliable; and the 19 studies on costs were of moderate quality. Delayed discharge was associated with mortality, infections, depression, reductions in patients' mobility and their daily activities. The qualitative studies highlighted the pressure to reduce discharge delays on staff stress and interprofessional relationships, with implications for patient care and well being. Extra bed-days could account for up to 30.7% of total costs and cause cancellations of elective operations, treatment delay and repercussions for subsequent services, especially for elderly patients. CONCLUSIONS: The poor quality of the majority of the research means that implications for practice should be cautiously made. However, the results suggest that the adverse effects of delayed discharge are both direct (through increased opportunities for patients to acquire avoidable ill health) and indirect, secondary to the pressures placed on staff. These findings provide impetus to take a more holistic perspective to addressing delayed discharge. PMID- 28898931 TI - What Kind of Policies for Fertility Treatment would Improve Affordability and Outcomes for Individuals and the Public? PMID- 28898932 TI - Effects of thermopeaking on the thermal response of alpine river systems to heatwaves. AB - Within the past 30years there have been two major heatwave events (in 2003 and 2006) that broke 500-year-old temperature records in Europe. Owing to the growing concern of rising temperatures, we analyzed the potential response in a number of river sections that are subject to hydropeaking and thermopeaking through the intermittent release of water from hydropower stations. Thermopeaking in alpine streams is known to intermittently cool down the river water in summer and to warm it up in winter. We analyzed the response of river water temperature to air temperature during heatwaves at 19 gauging stations across Switzerland, using a 30-yr dataset at a 10-min resolution. Stations were either classified into "unpeaked" or "peaked" groups according to four statistical indicators related to hydropeaking and thermopeaking pressure. Peaked stations were exposed to reduced temporal variability in river water temperature, and it was determined that correlations between river water and air temperature were weaker for peaked stations compared with unpeaked stations. Similarly, peaked stations showed a much weaker response to heatwaves compared with unpeaked stations. It is important to note that this "cooling effect" created by hydro-thermopeaking was most pronounced during the two major heatwave events that took place in 2003 and 2006. Furthermore, results from thermal stress events on the growth of a typical cold eurythermic fish species (brown trout) increased continuously in rivers subject to peaked station water release during heatwaves. While hydropower operations that take place high up on mountains releasing hypolimnetic water may mitigate the adverse effects of heatwaves on downstream alpine river ecosystems locally, our results show the complexity of an artificial physical template associated with flow regime regulation in alpine streams. PMID- 28898933 TI - Inside the guts of the city: Urban-induced alterations of the gut microbiota in a wild passerine. AB - Urbanisation represents one of the most radical forms of terrestrial land use change and has been shown to lead to alterations in ecosystem functioning and community dynamics and changes in individual phenotypic traits. While the recent surge in microbiome studies has brought about a paradigm shift by which individuals cannot truly be considered independently of the bacterial communities they host, the role of gut microbiota in organismal response to human-induced environmental change is still scarcely studied. Here, we applied a metabarcoding approach to examine the impact of urbanisation on the gut microbiota of Passer domesticus. We found urbanisation to be associated to lower microbiota species diversity, modifications in taxonomic composition and community structure, and changes in functional composition. The strength of these relationships, however, depended on the spatial scale and season at which they were considered. Such spatio-temporal effect suggests that urbanisation may dampen the natural seasonal variation of the gut microbiota observed in more pristine habitats, potentially influencing the fitness of urban organisms. Our results hence shed light on a hitherto little considered perspective, i.e. that the negative effects of urbanisation on city-dwelling organisms may extend to their microbiomes, causing potential dysbioses. PMID- 28898934 TI - The associations between phthalate exposure and insulin resistance, beta-cell function and blood glucose control in a population-based sample. AB - In developed countries, phthalate exposure is ubiquitous. Previous studies have shown an association between phthalate levels and health effects. To test associations between phthalate exposures, estimated from urinary phthalate metabolites, and insulin resistance, beta-cell function and glucose control. Data were obtained from a cross-sectional, nationally representative study; the Canadian Health Measures Survey (CHMS, 2009-2011). Participants under the age of 12, those with diabetes, who were pregnant or who had not fasted overnight were excluded. Fasting blood glucose, insulin, and glycosylated hemoglobin (HbA1C) levels were measured in a subset of participants, and urine was collected for creatinine and phthalate metabolites. We tested associations between these variables using linear regression analysis. Of 4437 participants (12-79years old), 2119 had fasting glucose measurements and at least one phthalate metabolite above detection limits. MBzP, MCPP, MEHP, MEHHP, MiBP, and the sum of DEHP metabolites were positively associated with increased HbA1C (p<0.05). DEHP metabolites were positively associated with increased fasting glucose, insulin, HOMA-IR and HOMA-beta. An interquartile increase in the sum of log transformed DEHP metabolites was associated with increases in HOMA-IR and HOMA-beta of 0.15 (95% CI 0.04, 0.26) and 10.24 (95% CI 3.71, 16.77) respectively. Increased concentrations of all measured phthalate metabolites were associated with reduced blood glucose control. DEHP metabolites were also associated with increased glucose concentrations, and indicators of beta-cell function and insulin resistance. Our results suggest that exposure to phthalates may possibly impair control of blood glucose and thereby predispose to pre-diabetes. PMID- 28898935 TI - Monitoring hand, foot and mouth disease by combining search engine query data and meteorological factors. AB - Hand, foot and mouth disease (HFMD) has been recognized as a significant public health threat and poses a tremendous challenge to disease control departments. To date, the relationship between meteorological factors and HFMD has been documented, and public interest of disease has been proven to be trackable from the Internet. However, no study has explored the combination of these two factors in the monitoring of HFMD. Therefore, the main aim of this study was to develop an effective monitoring model of HFMD in Guangzhou, China by utilizing historical HFMD cases, Internet-based search engine query data and meteorological factors. To this end, a case study was conducted in Guangzhou, using a network-based generalized additive model (GAM) including all factors related to HFMD. Three other models were also constructed using some of the variables for comparison. The results suggested that the model showed the best estimating ability when considering all of the related factors. PMID- 28898936 TI - Aerobic composting reduces antibiotic resistance genes in cattle manure and the resistome dissemination in agricultural soils. AB - Composting has been suggested as a potential strategy to eliminate antibiotic residues and pathogens in livestock manure before its application as an organic fertilizer in agro-ecosystems. However, the impacts of composting on antibiotic resistance genes (ARGs) in livestock manure and their temporal succession following the application of compost to land are not well understood. We examined how aerobic composting affected the resistome profiles of cattle manure, and by constructing laboratory microcosms we compared the effects of manure and compost application to agricultural soils on the temporal succession of a wide spectrum of ARGs. The high-throughput quantitative PCR array detected a total of 144 ARGs across all the soil, manure and compost samples, with Macrolide-Lincosamide Streptogramin B, aminoglycoside, multidrug, tetracycline, and beta-lactam resistance as the most dominant types. Composting significantly reduced the diversity and relative abundance of ARGs and mobile genetic elements (MGEs) in the cattle manure. In the 120-day microcosm incubation, the diversity and abundance of ARGs in manure-treated soils were significantly higher than those in compost-treated soils at the beginning of the experiment. The level of antibiotic resistance rapidly declined over time in all manure- and compost-treated soils, coupled with similar temporal patterns of manure- and compost-derived bacterial communities as revealed by SourceTracker analysis. The network analysis revealed more intensive interactions/associations among ARGs and MGEs in manure-treated soils than in compost-treated soils, suggesting that mobility potential of ARGs was lower in soils amended with compost. Our results provide evidence that aerobic composting of cattle manure may be an effective approach to mitigate the risk of antibiotic resistance propagation associated with land application of organic wastes. PMID- 28898937 TI - Species- and habitat-specific bioaccumulation of total mercury and methylmercury in the food web of a deep oligotrophic lake. AB - Niche segregation between introduced and native fish in Lake Nahuel Huapi, a deep oligotrophic lake in Northwest Patagonia (Argentina), occurs through the consumption of different prey. Therefore, in this work we analyzed total mercury [THg] and methylmercury [MeHg] concentrations in top predator fish and in their main prey to test whether their feeding habits influence [Hg]. Results indicate that [THg] and [MeHg] varied by foraging habitat and they increased with greater percentage of benthic diet and decreased with pelagic diet in Lake Nahuel Huapi. This is consistent with the fact that the native creole perch, a mostly benthivorous feeder, which shares the highest trophic level of the food web with introduced salmonids, had higher [THg] and [MeHg] than the more pelagic feeder rainbow trout and bentho-pelagic feeder brown trout. This differential THg and MeHg bioaccumulation observed in native and introduced fish provides evidence to the hypothesis that there are two main Hg transfer pathways from the base of the food web to top predators: a pelagic pathway where Hg is transferred from water, through plankton (with Hg in inorganic species mostly), forage fish to salmonids, and a benthic pathway, as Hg is transferred from the sediments (where Hg methylation occurs mostly), through crayfish (with higher [MeHg] than plankton), to native fish, leading to one fold higher [Hg]. PMID- 28898938 TI - Characterization of wash-off from urban impervious surfaces and SuDS design criteria for source control under semi-arid conditions. AB - Knowledge about pollutant wash-off from urban impervious surfaces is a key feature for developing effective management strategies. Accordingly, further information is required about urban areas under semi-arid climate conditions at the sub-catchment scale. This is important for designing source control systems for pollution. In this study, a characterization of pollutant wash-off has been performed over sixteen months, at the sub-catchment scale for urban roads as impervious surfaces. The study was conducted in Valencia, Spain, a city with a Mediterranean climate. The results show high event mean concentrations for suspended solids (98mg/l), organic matter (142mgCOD/l, 25mgBOD5/l), nutrients (3.7mgTN/l, 0.4mgTP/l), and metals (0.23, 0.32, 0.62 and 0.17mg/l for Cu, Ni, Pb, and Zn, respectively). The results of the runoff characterization highlight the need to control this pollution at its source, separately from wastewater because of their different characteristics. The wash-off, defined in terms of mobilized mass (g/m2) fits well with both process-based and statistical models, with the runoff volume and rainfall depth being the main explanatory variables. Based on these results and using information collected from hydrographs and pollutographs, an approach for sizing sustainable urban drainage systems (SuDS), focusing on water quality and quantity variables, has been proposed. By setting a concentration-based target (TSS discharged to receiving waters <35mg/l), the results indicate that for a SuDS type detention basin (DB), an off-line configuration performs better than an on-line configuration. The resulting design criterion, expressed as SuDS volume per unit catchment area, assuming a DB type SuDS, varies between 7 and 10l/m2. PMID- 28898939 TI - The effective mitigation of greenhouse gas emissions from rice paddies without compromising yield by early-season drainage. AB - Global rice production systems face two opposing challenges: the need to increase production to accommodate the world's growing population while simultaneously reducing greenhouse gas (GHG) emissions. Adaptations to drainage regimes are one of the most promising options for methane mitigation in rice production. Whereas several studies have focused on mid-season drainage (MD) to mitigate GHG emissions, early-season drainage (ED) varying in timing and duration has not been extensively studied. However, such ED periods could potentially be very effective since initial available C levels (and thereby the potential for methanogenesis) can be very high in paddy systems with rice straw incorporation. This study tested the effectiveness of seven drainage regimes varying in their timing and duration (combinations of ED and MD) to mitigate CH4 and N2O emissions in a 101 day growth chamber experiment. Emissions were considerably reduced by early season drainage compared to both conventional continuous flooding (CF) and the MD drainage regime. The results suggest that ED+MD drainage may have the potential to reduce CH4 emissions and yield-scaled GWP by 85-90% compared to CF and by 75 77% compared to MD only. A combination of (short or long) ED drainage and one MD drainage episode was found to be the most effective in mitigating CH4 emissions without negatively affecting yield. In particular, compared with CF, the long early-season drainage treatments LE+SM and LE+LM significantly (p<0.01) decreased yield-scaled GWP by 85% and 87% respectively. This was associated with carbon being stabilised early in the season, thereby reducing available C for methanogenesis. Overall N2O emissions were small and not significantly affected by ED. It is concluded that ED+MD drainage might be an effective low-tech option for small-scale farmers to reduce GHG emissions and save water while maintaining yield. PMID- 28898940 TI - Levels and spatial distributions of levoglucosan and dissolved organic carbon in snowpits over the Tibetan Plateau glaciers. AB - In this study, we collected 60 snowpit samples in nine glaciers from the northern to the southern Tibetan Plateau (TP), to study the levels and spatial distributions of levoglucosan and dissolved organic carbon (DOC). The lowest concentration of levoglucosan was found in the Yuzhufeng (YZF) glacier with a mean value of 0.24+/-0.08ngmL-1, while the highest concentration of levoglucosan was detected in the Gurenhekou (GRHK) glacier with a mean value of 11.72+/ 15.61ngmL-1. However, the average DOC concentration in TP glaciers were comparable, without significant regional differences. The levoglucosan/DOC ratio ranged from 0.02 to 6.03% in the Tibetan Plateau glaciers. This ratios and the correlations between levoglucosan and DOC suggested that biomass burning products contributed only marginally to DOC levels in the TP glaciers. Moreover, the analysis of air mass backward trajectories suggested that levoglucosan and DOC in TP glaciers should be transported from the northwestern TP, internal TP, Central Asia, South and East Asia regions. PMID- 28898941 TI - Facilitated transport of titanium dioxide nanoparticles via hydrochars in the presence of ammonium in saturated sands: Effects of pH, ionic strength, and ionic composition. AB - The widespread use of nanoparticles (NPs) has led to their inevitable introduction into environmental systems. How the existence of hydrochars in crop soils will affect the mobility of nanoparticle titanium dioxide (nTiO2), especially in the presence of ammonium (NH4+), remains unknown. Research is needed to study the effects of hydrochars on the transport and retention of nTiO2 and to uncover the mechanisms of these effects on nTiO2 transport. Column experiments with nTiO2 and hydrochars were performed in various electrolyte (NaCl, NH4Cl, and CaCl2) solutions under a controlled pH (6.0 and 8.0). Additionally, the size distributions and scanning electron microscope (SEM) and transmission electron microscope (TEM) images of the NPs were observed. The experimental results suggested that the mobility of the hydrochars was much better than that of nTiO2. Thus, the mobility of nTiO2 was improved upon their attachment to the hydrochars. The facilitated transport of nTiO2 in the presence of hydrochars was stronger at pH8.0 than at pH6.0, and facilitated transport was nearly independent of the electrolyte cation at pH8.0. However, at pH6.0, the facilitated transport in various electrolytes had the following order: NaCl>NH4Cl>CaCl2. The conversion from a completely reversible to a partially irreversible deposition of nTiO2 in sand was induced by the partially irreversible retention of hydrochars, and this phenomenon was more pronounced in the presence of NH4+ than in the presence of Na+. In particular, the irreversible deposition of nTiO2-hydrochars was enhanced as the cation concentration increased. The increased irreversible retention of nTiO2 was related to the greater k2 value (irreversible attachment coefficients) on site 2 for hydrochars based on two-site kinetic retention modeling. Thus, there is a potential risk of contaminating crops, soil, and underground water when nTiO2 exists in a hydrochar amended environment, especially when associated with NH4-N fertilizer. PMID- 28898942 TI - Exposure of stone marten (Martes foina) and polecat (Mustela putorius) to anticoagulant rodenticides: Effects of regulatory restrictions of rodenticide use. AB - When anticoagulant rodenticides (ARs) are used to control rodent populations there is also a widespread secondary exposure of non-target predators to ARs. To reduce secondary exposure, regulatory restrictions in AR usage were tightened in Denmark in 2011. The restrictions included the cessation of AR use for plant protection and any use away from buildings, as well as limitations in private consumers' access to ARs. To quantify and evaluate the efficiency of the regulatory measures to reduce secondary exposure, we analysed ARs in liver tissue from 40 stone martens (Martes foina) and 40 polecats (Mustela putorius) collected before and 31 stone martens and 29 polecats collected after the restrictions were imposed. No declines in the prevalence ARs were detected following the regulatory restrictions in either stone marten (Before: 98%, After: 100%) or polecat (Before: 93%, After: 97%). The total AR concentration was higher in stone martens than in polecats in both sampling periods. Between the two sampling periods, the total AR concentrations in the mustelids increased (P<0.001). The increase was significant for stone marten (Before: 419ng/g ww, After: 1116ng/g ww, P<0.001), but not for polecat (Before: 170ng/g ww, After: 339ng/g ww). Overall, the total AR concentration was positively correlated to the urban area and the area used for Christmas tree production in which ARs were regularly used before 2011. The regulatory restrictions in AR usage did not reduce exposure of non-target stone martens and polecats. The temporal and spatial patterns of AR concentrations in predators indicate that chemical rodent control in and around buildings is the dominant source for the exposure of non-target predators in intensively human dominated landscapes in Denmark. The results suggest that non-chemical methods for rodents control at buildings are necessary to prevent widespread secondary AR exposure of predators in human modified landscapes. PMID- 28898943 TI - Physiographical variability in arsenic dynamics in Bangladeshi soils. AB - Rice plants grown on soils with elevated arsenic have been shown to have increased arsenic content in their grains. To gain a better understanding of the likelihood of high grain arsenic in rice grown in different soils, it is important to understand the factors affecting the bioavailability and mobility of arsenic. Paddy soils from six different physiographic regions of Bangladesh were collected, and diffusive gradients in thin-films (DGT) were used to assess the porewater and solid phase arsenic. While significant differences were identified in total soil arsenic (1.4-9.8mg/kg), porewater arsenic (AsCsoln) (5.6 64.7MUg/l), labile arsenic (AsCDGT) (6.3-77.6MUg/l), and solid phase pool of arsenic (AsKd) (52-1057l/kg), importantly arsenic resupply capacity was not different between the physiographic regions. All soils had a high ratio of DGT to porewater arsenic (~1), this in conjunction with the porewater arsenic values and the high AsKd values suggesting a large solid phase pool of arsenic capable of contributing towards the resupply/transport of the labile pool of arsenic in the soil porewater. This indicates that there is less difference in soil arsenic availability than might be predicted based solely on total soil arsenic content between the physiographic regions. PMID- 28898944 TI - Associations between urinary total arsenic levels, fetal development, and neonatal birth outcomes: A cohort study in Taiwan. AB - BACKGROUND: Arsenic exposure is a global health concern. Several studies have focused on chronic arsenic exposure in adults; however, limited data are available regarding the potential adverse effects of prenatal exposure on fetuses and neonates. OBJECTIVES: To assess which time point maternal arsenic exposure may influence the fetus during pregnancy and birth outcomes. METHODS: In this study, total arsenic concentrations were analyzed in urine samples collected from 130 women with singleton pregnancies (22-45years old) in Taiwan from March to December of 2010. All fetal biometric measurements in each trimester period and birth outcomes at delivery were obtained. We applied a generalized estimating equation model and multivariate regression models to evaluate the associations between maternal urinary total arsenic (UtAs) exposure during pregnancy, fetal biometric measurements, and neonatal birth outcomes. RESULTS: We observed statistically significant correlations between maternal UtAs levels and the fetal biparietal diameter over all three trimesters (beta=-1.046mm, p<0.05). Multiple regression analyses showed a negative association between maternal UtAs levels and chest circumference in the first trimester (beta=-0.721cm, p<0.05), and second-trimester UtAs exposure was associated with decreases in birth weight (beta=-173.26g, p<0.01), head circumference (beta=-0.611cm, p<0.05), and chest circumference (beta=-0.654cm, p<0.05). Dose-response relationships were also observed for maternal UtAs exposure and birth outcomes. CONCLUSIONS: We identified a negative relationship between maternal UtAs levels during pregnancy, fetal development, and neonatal birth outcomes. These findings should be confirmed in future studies with large sample sizes. PMID- 28898945 TI - Microplastic and mesoplastic contamination in canned sardines and sprats. AB - No report was found on the occurrence of microplastics in processed seafood products that are manufactured for direct human consumption. This study investigates the potential presence of micro- and mesoplastics in 20 brands of canned sardines and sprats originating from 13 countries over 4 continents followed by their chemical composition determination using micro-Raman spectroscopy. The particles were further inspected for their inorganic composition through energy-dispersive X-ray spectroscopy (EDX). Plastic particles were absent in 16 brands while between 1 and 3 plastic particles per brand were found in the other 4 brands. The most abundant plastic polymers were polypropylene (PP) and polyethylene terephthalate (PET). The presence of micro- and mesoplastics in the canned sardines and sprats might be due to the translocation of these particles into the edible tissues, improper gutting, or the result of contamination from the canneries. The low prevalence of micro- and mesoplastics sized >149MUm, and the absence of potentially hazardous inorganic elements on them, might indicate the limited health risks associated with their presence in canned sardines and sprats. Due to the possible increase in micro- and mesoplastic loads in seafood products over time, the findings of this study suggest their quantification to be included as one of the components of food safety management systems. PMID- 28898946 TI - Towards the understanding of antibiotic occurrence and transport in groundwater: Findings from the Baix Fluvia alluvial aquifer (NE Catalonia, Spain). AB - Antibiotics are an increasing focus of interest due to their high detection frequency in the environment. However, their presence in water bodies is not regulated by environmental policies. This field study investigates, for the first time, the occurrence, behavior and fate of a selection of 53 antibiotics, including up to 10 chemical groups, in an alluvial aquifer originated from manure application in an agricultural region using hydrogeological, hydrochemical and isotopic approaches. Up to 11 antibiotics were found in groundwater corresponding to 4 different chemical groups: fluoroquinolones, macrolides, quinolones and sulfonamides. In surface water, only 5 different antibiotics from 2 chemical groups: fluoroquinolones and sulfonamides, were quantified. The most frequent antibiotics were sulfamethoxazole and ciprofloxacin. Concentrations of antibiotics were in the order of ng/L, with maximum concentrations of 300ng/L in groundwater. Hydrochemistry and isotopic data and geostatistics confirmed the spatial trend observed for nitrates, where nitrate concentrations tend to be higher in the margin areas of the study area, and lower concentrations are found nearby the river. On the other hand, no clear continuous spatial concentration trend of antibiotics was observed in the aquifer, supported by the short spatial correlation found in the variograms. This indicates that the physical-chemical properties and processes of each antibiotic (mainly, sorption and degradation), and other environmental issues, such as a patchy diffuse input and the manure antibiotic content itself, play an important role in their spatial distribution in groundwater. A discussion on the estimation of the antibiotic sorption parameter reveals the difficulties of describing such phenomena. Furthermore, retardation factors will extend over several orders of magnitude, which highly affects the movement of individual antibiotics within the aquifer. To summarize, this study points out the difficulties associated with antibiotic research in groundwater in order to define water resources quality management strategies and environmental regulations. PMID- 28898947 TI - Soil enzyme dynamics in chlorpyrifos-treated soils under the influence of earthworms. AB - Earthworms contribute, directly and indirectly, to contaminant biodegradation. However, most of bioremediation studies using these annelids focus on pollutant dissipation, thus disregarding the health status of the organism implied in bioremediation as well as the recovery of indicators of soil quality. A microcosm study was performed using Lumbricus terrestris to determine whether earthworm density (2 or 4individuals/kg wet soil) and the time of exposure (1, 2, 6, 12, and 18wk) could affect chlorpyrifos persistence in soil initially treated with 20mg active ingredientkg-1 wet soil. Additionally, selected earthworm biomarkers and soil enzyme activities were measured as indicators of earthworm health and soil quality, respectively. After an 18-wk incubation period, no earthworm was killed by the pesticide, but clear signs of severe intoxication were detected, i.e., 90% inhibition in muscle acetylcholinesterase and carboxylesterase (CbE) activities. Unexpectedly, the earthworm density had no significant impact on chlorpyrifos dissipation rate, for which the measured half-life ranged between 30.3d (control soils) and 44.5d (low earthworm density) or 36.7d (high earthworm density). The dynamic response of several soil enzymes to chlorpyrifos exposure was examined calculating the geometric mean and the treated-soil quality index, which are common enzyme-based indexes of microbial functional diversity. Both indexes showed a significant and linear increase of the global enzyme response after 6wk of chlorpyrifos treatment in the presence of earthworms. Examination of individual enzymes revealed that soil CbE activity could decrease chlorpyrifos oxon impact upon the rest of enzyme activities. Although L. terrestris was found not to accelerate chlorpyrifos dissipation, a significant increase in the activity of soil enzyme activities was achieved compared with earthworm-free, chlorpyrifos-treated soils. Therefore, the inoculation of organophosphorus contaminated soils with L. terrestris arises as a complementary bioremediation strategy in terms of recovery of soil biochemical performance and quality. PMID- 28898948 TI - Long-term characteristics of satellite-based PM2.5 over East China. AB - With the explosive economic development of China over the past few decades, air pollution has become a serious environmental problem and has attracted increasing global concern. Using satellite-based PM2.5 data from 2000 to 2015, we found that the temporal-spatial variation of PM2.5 in East China is characterized by high concentrations in the northern part and low concentrations in the southern part of East China, and by being seasonally high in autumn and winter but low in spring and summer. We also found that the regional average PM2.5 concentration shows an approximative peak pattern over the last 16years, with the highest, 60.13MUgm-3, and the lowest, 46.18MUgm-3, occurring in 2007 and 2000, respectively. Despite obviously diminishing heavy polluted regions with a PM2.5 of >80MUgm-3 after 2011, those cells dominated by natural background have still not recovered back to the clean level of 2000. These characteristics are valuable information to analyze the relative contributions of anthropogenic emissions and atmospheric conditions to the temporal-spatial variation characteristics of PM2.5. PMID- 28898949 TI - Efficiencies and mechanisms of ZSM5 zeolites loaded with cerium, iron, or manganese oxides for catalytic ozonation of nitrobenzene in water. AB - Discharge of industrial wastewater causes water pollution. It is therefore necessary to treat wastewater prior to discharge. Catalytic ozonation processes (COP) using ZSM5 zeolites loaded with metallic (Ce, Fe, or Mn) oxides to remove nitrobenzene from water were investigated. The total organic carbon (TOC) removal by the COP treatment with NaZSM5-38, HZSM5-38, and NaZSM5-100 were increased by 6.7%, 23.1%, and 19.8%, respectively, in comparison with single ozonation efficiency (39.2%). The loadings of Ce, Fe, or Mn oxides increased the catalytic activity relative to ZSM5 zeolites alone. The Ce loaded material (Ce/NaZSM5-38) had the highest TOC removal (86.3%). The different-metallic-oxides loaded zeolites exhibited different chemical processes during the removal of nitrobenzene from water. During COP treatment, NaZSM5-38 zeolites removed nitrobenzene mainly via OH mediated oxidation. HZSM5-38 and NaZSM5-100 zeolites showed powerful adsorption toward nitrobenzene. Both adsorption and direct ozonation contribute the TOC removal in their early uses. The OH mediated oxidation dominates the TOC removal process as the adsorption became saturated after multiple uses. Surface SiO bonds and/or SiO(H)Al structures are the active sites for ZSM5 zeolites. Efficient surface dispersion of the metallic oxides enhances the catalytic activity. This study shows the high potentials of ZSM5 zeolites as catalysts in COP to efficiently treat refractory wastewaters. PMID- 28898950 TI - Prenatal Bisphenol-A exposure affects fetal length growth by maternal glutathione transferase polymorphisms, and neonatal exposure affects child volume growth by sex: From multiregional prospective birth cohort MOCEH study. AB - We aimed to evaluate the effects of Bisphenol-A (BPA) exposure on fetal/child growth from the fetal period to 72months after birth. The MOCEH study is a prospective birth cohort study in Korea. A total of 788 mother-child pairs in the third trimester and 366 pairs in the neonatal period who completed BPA assessment and fetal/children growth outcomes were included. BPA assessments were conducted twice in the third trimester using maternal urines and the neonatal period using neonatal urines. Fetal femur length was measured with ultrasound, and estimated fetal-weight was calculated. Child growth outcomes including three z-scores for age-specific length, weight-for-length (WFL) and weight were calculated. Analysis was performed according to infant sex and maternal glutathione transferases (GSTs) polymorphisms. When maternal urinary BPA concentration in the third trimester increased by 1 log-transformed unit of BPA/Cr, the third trimester femur length decreased 0.03(0.01)cm in the whole and 0.06(0.02)cm in the GSTM1/GSTT1 either null group. Then, maternal urinary BPA levels and birth outcomes were positively correlated. When the prenatal BPA concentration is increased by 1 log-transformed unit of BPA/Cr, the z-score for weight at birth increased 0.05(0.02) in whole and 0.06(0.03) in boys and the z-score for WFL at birth increased 0.05(0.02) in whole and 0.07(0.03) in girls. In linear mixed models, significant positive effects of the neonatal urinary BPA were found on WFL over the 72months period. When the neonatal BPA concentration is increased by 1 log-transformed unit of BPA concentration, the z-score for weight through 6 72months increased 0.09(0.03) in whole and 0.12(0.05) in girls. Our study suggests BPA exposure is negatively associated with intrauterine linear growth, but has a positive association with volume growth during childhood. Furthermore, intrauterine growth was affected by maternal GSTs polymorphism, and child growth was affected by sex. PMID- 28898951 TI - Biocompatible hollow polymeric particles produced by a mild solvent- and template free strategy. AB - Macroscopic hollow polymeric particles are attractive materials for various applications such as surgery, food industry, agriculture, etc. However, protocols reporting their synthesis have hitherto made use of organic solvents and/or sacrificial templates, compromising the encapsulation of different bioactive compounds and the process yield. Here, millimeter-size, hollow polymeric particles were synthesized, for the first time, in a solvent- and template free manner onto superhydrophobic surfaces (SHS). The particles were produced upon assembly and double superficial crosslinking of liquid droplets of DNA and methacrylamide chitosan aqueous solutions (CH:MA), leading to liquid-core particles with a hardened hydrogel shell. The particles displayed appealing physical and biological properties. The millimeter-size hydrogel shell, resulting from the double ionic/covalent crosslinking of CH:MA, endowed the hollow particles with softness to the touch and an outstanding structural stability against manipulation by hand and with forceps. Meanwhile, the liquid DNA core guaranteed a biocompatible cell encapsulation followed by a superior release and proliferation of viable cells, as compared to solid CH:MA particles prepared as a blank. Particles with these characteristics show promise for surgical protocols practiced in Tissue Engineering and Regenerative Medicine, where manipulable and biocompatible synthetic implants are often needed to supply living cells and other sensitive bioactive compounds. PMID- 28898952 TI - Temperature responsive fluorescent polymer nanoparticles (TRFNPs) for cellular imaging and controlled releasing of drug to living cells. AB - Recent studies have demonstrated that drug delivery by using functional nanomaterials with imaging capability could afford plenty of insightful information for the better control of the delivery process. In this work, we developed temperature responsive fluorescent nanoparticles (TRFNPs) for drug delivery and cellular imaging. The TRFNP was fabricated by one-pot co precipitation of thermal sensitive amphiphilic block copolymers polystyrene-b poly(N-isopropyl acrylamide) (PS-b-PNIPAM) and fluorescent conjugated polymer poly [(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(1,4-benzo(2,1',3)-thiadiazole)] (PFBT) in the presence of desired small guest molecules. The dynamic light scattering (DLS) measurements verified that this functional nanoparticle exhibited temperature dependent size variation, which could therefore regulate the releasing rate of loaded guest molecules (e.g. drugs) inside the polymer core. Besides, the TRFNPs displayed good photostability in terms of optical characterization. The cellular cytotoxicity characterization demonstrated that this nanoparticle exhibited good biocompatibility even under the mass concentration of 10MUg/mL. By using Nile Red as a model molecule, the temperature controlled releasing process from TRFNPs in solution as well as inside living cells was monitored directly according to the spectroscopic and microscopic characterizations. Furthermore, anti-cancer drug was successfully delivered into living cells via TRFNPs and released in a temperature dependent manner. As a consequence, owing the attractive merits as mentioned above, this nanostructure would find broad applications in nanomedicine in the future. PMID- 28898953 TI - Transfer of mercury and phenol derivatives across the placenta of Baltic grey seals (Halichoerus grypus grypus). AB - The placenta is an intermediary organ between the female and the developing foetus. Some chemical substances, including the most harmful ones, exhibit the ability to accumulate in or penetrate through the placenta. The aim of the study was to determine the role of the placenta of the Baltic grey seal (Halichoerus grypus grypus) in the transfer of endocrine disrupting compounds (EDCs) - (bisphenol A, 4-tert- octylphenol, 4- nonylphenol), as well as total and organic mercury. 30 placentas were collected from grey seals pupping under human care at the Hel Marine Station in the years 2007-2016. The assays were conducted using the technique of high-preformance liquid chromatography (phenol derivatives) and atomic absorption spectrometry (mercury and selenium). A measurable level of EDCs was indicated in the placentas of grey seals. It was established that the inorganic Hg form was accumulated in the placenta, and that its concentrations were an order of magnitude higher than the concentrations of the organic form, which penetrated to the foetus. Similar observations were made for phenol derivatives - bisphenol A, 4-tert- octylphenol and 4-nonylphenol. For this compound group the placenta was a barrier, but the properties of phenol derivatives suggest the possibility of their penetration through this organ. PMID- 28898954 TI - Degradation of 2,4,6-trichlorophenol with peroxymonosulfate catalyzed by soluble and supported iron porphyrins. AB - Degradation of 2,4,6-trichloropenol (TCP) with peroxymonosulfate (PMS) catalyzed by iron porphyrin tetrasulfonate ([FePTS)] was investigated in an 8-to-1 (v/v) CH3OH-H2O mixture. Typical reaction medium contained a 4.00 mL methanol solution of TCP (0.100 mmol), a 0.50 mL aqueous solution of catalyst (5.0 * 10-4 mmol), and 0.100 mmol PMS (as 0.031 g of Oxone). The reaction was performed at ambient temperature. The conversion of TCP was 74% in 30 min and 80% in 6 h when the catalyst was [FePTS]. Amberlite IRA-900 supported [FePTS] catalyst was also prepared. In the recycling experiments the homogeneous [FePTS] lost its activity after the first cycle, while [FePTS]-Amberlite IRA 900 maintained its activity for the first 2 cycles. After the second cycle, the conversion of TCP dropped to <10% for Amberlite IRA-900 supported [FePTS] catalyst. The degradation of TCP with PMS was also attempted using cobalt, copper, nickel and palladium porphyrin tetrasulfonate catalysts, however, no catalytic activity was observed with these structures. PMID- 28898956 TI - Long short-term memory neural network for air pollutant concentration predictions: Method development and evaluation. AB - Air pollutant concentration forecasting is an effective method of protecting public health by providing an early warning against harmful air pollutants. However, existing methods of air pollutant concentration prediction fail to effectively model long-term dependencies, and most neglect spatial correlations. In this paper, a novel long short-term memory neural network extended (LSTME) model that inherently considers spatiotemporal correlations is proposed for air pollutant concentration prediction. Long short-term memory (LSTM) layers were used to automatically extract inherent useful features from historical air pollutant data, and auxiliary data, including meteorological data and time stamp data, were merged into the proposed model to enhance the performance. Hourly PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 2.5 MUm) concentration data collected at 12 air quality monitoring stations in Beijing City from Jan/01/2014 to May/28/2016 were used to validate the effectiveness of the proposed LSTME model. Experiments were performed using the spatiotemporal deep learning (STDL) model, the time delay neural network (TDNN) model, the autoregressive moving average (ARMA) model, the support vector regression (SVR) model, and the traditional LSTM NN model, and a comparison of the results demonstrated that the LSTME model is superior to the other statistics based models. Additionally, the use of auxiliary data improved model performance. For the one-hour prediction tasks, the proposed model performed well and exhibited a mean absolute percentage error (MAPE) of 11.93%. In addition, we conducted multiscale predictions over different time spans and achieved satisfactory performance, even for 13-24 h prediction tasks (MAPE = 31.47%). PMID- 28898955 TI - Aging of microplastics promotes their ingestion by marine zooplankton. AB - Microplastics (<5 mm) are ubiquitous in the marine environment and are ingested by zooplankton with possible negative effects on survival, feeding, and fecundity. The majority of laboratory studies has used new and pristine microplastics to test their impacts, while aging processes such as weathering and biofouling alter the characteristics of plastic particles in the marine environment. We investigated zooplankton ingestion of polystyrene beads (15 and 30 MUm) and fragments (<=30 MUm), and tested the hypothesis that microplastics previously exposed to marine conditions (aged) are ingested at higher rates than pristine microplastics. Polystyrene beads were aged by soaking in natural local seawater for three weeks. Three zooplankton taxa ingested microplastics, excluding the copepod Pseudocalanus spp., but the proportions of individuals ingesting plastic and the number of particles ingested were taxon and life stage specific and dependent on plastic size. All stages of Calanus finmarchicus ingested polystyrene fragments. Aged microbeads were preferred over pristine ones by females of Acartia longiremis as well as juvenile copepodites CV and adults of Calanus finmarchicus. The preference for aged microplastics may be attributed to the formation of a biofilm. Such a coating, made up of natural microbes, may contain similar prey as the copepods feed on in the water column and secrete chemical exudates that aid chemodetection and thus increase the attractiveness of the particles as food items. Much of the ingested plastic was, however, egested within a short time period (2-4 h) and the survival of adult Calanus females was not affected in an 11-day exposure. Negative effects of microplastics ingestion were thus limited. Our findings emphasize, however, that aging plays an important role in the transformation of microplastics at sea and ingestion by grazers, and should thus be considered in future microplastics ingestion studies and estimates of microplastics transfer into the marine food web. PMID- 28898957 TI - Persistent organic pollutants in krill from the Bellingshausen, South Scotia, and Weddell Seas. AB - Persistent organic pollutants (POPs) reach Antarctica through atmospheric transport, oceanic currents, and to minor extent, by migratory animals. The Southern Ocean is a net sink for many POPs, with a key contribution of the settling fluxes of POPs bound to organic matter (biological pump). However, little is known about POP transfer through the food web in the Southern Ocean and Antarctic waters, where krill is an important ecological node. In this study, we assessed the occurrence of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) in Antarctic krill (Euphausia superba) from the Bellingshausen, South Scotia and Weddell Seas around the Antarctic Peninsula. The concentrations of PCDD/Fs, PBDEs and PCBs in krill showed a large variability and the average were higher (generally within a factor 3) than those previously reported for eastern Antarctica. This result highlights regional differences related to atmospheric transport and deposition, and also probable regional sources due to human activities. Bioaccumulation and biomagnification factors for PCBs in krill were estimated using previously reported phytoplankton and seawater concentrations for this region. These suggested a near water-krill equilibrium for PCBs, which was not observed for water-phytoplankton partitioning. The estimated removal settling fluxes of PCBs due to the biological pump were several orders of magnitude higher than the estimated fluxes of PCBs transferred from phytoplankton to krill. PMID- 28898958 TI - Radiotherapy for laryngeal cancer-technical aspects and alternate fractionation. AB - Early laryngeal, especially glottic, cancer is a good candidate for radiotherapy because obvious early symptoms (e.g. hoarseness) make earlier treatment possible and with highly successful localized control. This type of cancer is also a good model for exploring the basic principles of radiation oncology and several key findings (e.g. dose, fractionation, field size, patient fixation, and overall treatment time) have been noted. For example, unintended poor outcomes have been reported during transition from 60Cobalt to linear accelerator installation in the 1960s, with usage of higher energy photons causing poor dose distribution. In addition, shell fixation made precise dose delivery possible, but simultaneously elevated toxicity if a larger treatment field was necessary. Of particular interest to the radiation therapy community was altered fractionation gain as a way to improve local tumor control and survival rate. Unfortunately, this interest ceased with advancements in chemotherapeutic agents because alternate fractionation could not improve outcomes in chemoradiotherapy settings. At present, no form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy. In addition, the substantial workload associated with this technique made it difficult to add extra fractionation routinely in busy clinical hospitals. Hypofractionation, on the other hand, uses a larger single fractionation dose (2-3 Gy), making it a reasonable and attractive option for T1 T2 early glottic cancer because it can improve local control without the additional workload. Recently, Japan Clinical Oncology Group study 0701 reprised its role in early T1-T2 glottic cancer research, demonstrating that this strategy could be an optional standard therapy. Herein, we review radiotherapy history from 60Cobalt to modern linear accelerator, with special focus on the role of alternate fractionation. PMID- 28898960 TI - Corrigendum. PMID- 28898959 TI - Cognitive Training Using a Novel Memory Game on an iPad in Patients with Amnestic Mild Cognitive Impairment (aMCI). AB - Background: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties. Methods: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of amnestic mild cognitive impairment assigned to either the cognitive training (n=21; 8 hours of gameplay over 4 weeks) or control (n=21; clinic visits as usual) groups. Results: Significant time-by-pattern-by-group interactions were found for cognitive performance in terms of the number of errors made and trials needed on the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task (P=.044; P=.027). Significant time-by-group interactions were also found for the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning first trial memory score (P=.002), Mini-Mental State Examination (P=.036), the Brief Visuospatial Memory Test (P=.032), and the Apathy Evaluation Scale (P=.026). Within-group comparisons revealed highly specific effects of cognitive training on episodic memory. The cognitive training group maintained high levels of enjoyment and motivation to continue after each hour of gameplay, with self confidence and self-rated memory ability improving over time. Conclusions: Episodic memory robustly improved in the cognitive training group. "Gamified" cognitive training may also enhance visuospatial abilities in patients with amnestic mild cognitive impairment. Gamification maximizes engagement with cognitive training by increasing motivation and could complement pharmacological treatments for amnestic mild cognitive impairment and mild Alzheimer's disease. Larger, more controlled trials are needed to replicate and extend these findings. PMID- 28898961 TI - The economic impact of workplace wellness programmes in Canada. AB - Background: The economic benefits of workplace wellness programmes (WWPs) are commonly cited as a reason for employers to implement such programmes; however, there is limited evidence outside of the US context exploring their economic impact. US evidence is less relevant in countries such as Canada with universal publicly funded health systems because of the lower potential employer savings from WWPs. Aims: To conduct a systematic review of the Canadian literature investigating the economic impact of WWPs from an employer perspective. The quality of that evidence was also assessed. Methods: We reviewed literature which included analyses of four economic outcomes: return on investment calculations; cost-effectiveness or cost-benefit analyses; valuations of productivity, turnover, absenteeism and/or presenteeism costs; and valuations of health care utilization costs. We applied the British Medical Journal (BMJ) Economic Evaluation Working Party Checklist to evaluate the quality of this evidence. Results: Eight studies met the inclusion criteria. Although the studies showed that WWPs generated economic benefits from an employer perspective (largely from productivity changes), none of the reviewed studies were in the high-quality category (i.e. fulfilled at least 75% of the checklist criteria) and most had severe methodological issues. Conclusions: Though the Canadian literature pertaining to the economic impact of WWPs spans over three decades, robust evidence on this topic remains sparse. Future research should include a comparable control group, a time horizon of over a year, both direct and indirect costs, and researchers should apply analytical techniques that account for potential selection bias. PMID- 28898962 TI - Occupational rhinoconjunctivitis caused by the common indoor plant, Hoya compacta. AB - Background: Allergic reactions to the common house plant Hoya compacta (HC) have not previously been described. Aims: To confirm HC as the cause of rhinoconjunctivitis in three horticultural workers. Methods: Greenhouse working conditions were reproduced in our challenge chamber. Results: All three cases developed rhinoconjunctivitis when working with HC plants. A control challenge was performed in two cases with iceberg lettuce causing no symptoms. Nasal volume measured by acoustic rhinometry (AR) fell after all three active challenges, but also after one of the control challenges. Conclusions: Our study confirms that HC may cause occupational rhinoconjunctivitis and asthma through a Type I hypersensitivity reaction. Specific inhalation challenges, nasal nitric oxide measurement and AR may be useful additional tools in supporting such diagnoses for occupational physicians to consider. PMID- 28898963 TI - Job demands, resources and mental health in UK prison officers. AB - Background: Research findings indicate that working as a prison officer can be highly stressful, but the aspects of work that predict their mental health status are largely unknown. Aims: To examine, using elements of the demands-resources model, the extent to which work pressure and several potential resources (i.e. control, support from managers and co-workers, role clarity, effective working relationships and positive change management) predict mental health in a sample of UK prison officers. Methods: The Health and Safety Executive Management Standards Indicator Tool was used to measure job demands and resources. Mental health was assessed by the General Health Questionnaire-28. The effects of demands and resources on mental health were examined via linear regression analysis with GHQ score as the outcome. Results: The study sample comprised 1267 prison officers (86% male). Seventy-four per cent met 'caseness' criteria for mental health problems. Job demands, poor interpersonal relationships, role ambiguity and, to a lesser extent, low job control and poor management of change were key predictors of mental health status. Conclusions: The findings of this study can help occupational health practitioners and psychologists develop structured interventions to improve well-being among prison officers. PMID- 28898964 TI - Comparison of clinic models for patients with work-related asthma. AB - Background: Work-related asthma (WRA) is a prevalent occupational lung disease that is associated with undesirable effects on psychological status, quality of life (QoL), workplace activity and socioeconomic status. Previous studies have also indicated that clinic structure may impact outcomes among patients with asthma. Aims: To identify the impact of clinic structure on psychological status, QoL, workplace limitations and socioeconomic status of patients with WRA among two different tertiary clinic models. Methods: We performed a cross-sectional analysis between two tertiary clinics: clinic 1 had a traditional referral base and clinical staffing while clinic 2 entirely comprised Worker's Compensation System referrals and included an occupational hygienist and a return-to-work coordinator. Beck Anxiety and Depression II Inventories (BAI and BDI-II), Marks' Asthma Quality of Life Questionnaire (M-AQLQ) and Work Limitation Questionnaire (WLQ) were used to assess outcomes for patients with WRA. Results: Clinic 2 participants had a better psychological status across the four instruments compared with clinic 1 (for Beck 'Anxiety': P < 0.001 and 'Depression': P < 0.01, 'Mood' domain of M-AQLQ: NS and 'Mental Demands' domain of WLQ: P < 0.01). Clinic 2 had a greater proportion of participants with reduced income. Conclusions: Our study indicates that clinic structure may play a role in outcomes. Future research should examine this in larger sample sizes. PMID- 28898966 TI - Employment characteristics of a complex adult congenital heart disease cohort. AB - Background: Due to advances in surgical techniques and subsequent management, there have been remarkable improvements in the survival of patients with congenital heart disease. In particular, larger numbers of patients with complex disease are now living into adulthood and are entering the workforce. Aims: To establish the types of employment complex adult congenital heart disease (ACHD) patients are engaged in, based on the largest cohort of patients with a single ventricle circulation in the UK. Methods: Records of all patients with a univentricular (Fontan) circulation at the Queen Elizabeth Hospital were reviewed. Employment status was categorized according to the Standard Occupational Classification criteria (2010). Results: A total of 210 patient records were reviewed. There was the same proportion of professionals in our cohort compared to the rest of the UK (20% versus 20%). There were greater proportions working in the caring, leisure and other service occupations (15% versus 9%), the elementary occupations (17% versus 11%), sales and customer service occupations (14% versus 8%) and administrative and secretarial occupations (12% versus 11%). The reverse trend was observed for associate professions and technical occupations (7% versus 14%), skilled trades (10% versus 11%), process, plant and machine operatives (3% versus 6%) and managers, directors and senior officials (2% versus 10%). Conclusions: The data show that ACHD patients with a single ventricle are engaged in a diverse range of occupations. It is essential that early education and employment advice are given to this cohort to maximize future employment potential. PMID- 28898965 TI - Late boosting phenomenon in TST conversion among health care workers. AB - Background: Available information is insufficient to guide determination of whether tuberculin skin test (TST) conversions of health care workers (HCWs) within 2 years of two-step testing are related to occupational exposures or to other causes, including late boosting. Aims: To describe the epidemiologic factors of TST conversion in HCWs, comparing early TST conversion (<=2 years after two-step testing) with late conversion to possibly distinguish late boosting phenomenon from occupational TST conversion. Methods: Retrospective analysis of a database of TSTs of HCWs from 1 January 1998, through 31 May 2014, in the United States Midwest. Results: In total, 40142 HCWs had 197932 tests over the 16 years, with 123 conversions (conversion rate: 0.3%; 95% CI 0.3-0.4%). Among 61 HCWs with a negative two-step TST, 30 (49%) were found to have early TST conversion within 2 years; 31 (51%) had late conversion, with likely occupational exposure but no identifiable community risks. Persons with early conversion were more likely to be born outside the USA (89% versus 57%; P < 0.05), had a higher rate of prior bacille Calmette-Guerin (BCG) vaccination (89% versus 52%; P < 0.05) and had no identifiable risk factors for conversion (63% versus 58%; P < 0.05). Conclusions: Early conversions among HCWs after negative two-step TST are associated with various nonoccupational factors, including international birth and BCG vaccination history. Therefore, conversion is not a reliable indicator of recent tuberculosis contact in this population, and two-step TST is insufficient to discount a delayed boosting response for HCWs. PMID- 28898967 TI - Systematic review: Lost-time injuries in the US mining industry. AB - Background: The mining industry is associated with high levels of accidents, injuries and illnesses. Lost-time injuries are useful measures of health and safety in mines, and the effectiveness of its safety programmes. Aims: To identify the type of lost-time injuries in the US mining workforce and to examine predictors of these occupational injuries. Methods: Primary papers on lost-time injuries in the US mining sector were identified through a literature search in eight health, geology and mining databases, using a systematic review protocol tailored to each database. The Critical Appraisal Skills Programme (CASP), Framework of Quality Assurance for Administrative Data Source and the Cochrane Collaboration 'Risk of bias' assessment tools were used to assess study quality. Results: A total of 1736 articles were retrieved before duplicates were removed. Fifteen articles were ultimately included with a CASP mean score of 6.33 (SD 0.62) out of 10. Predictors of lost-time injuries included slips and falls, electric injuries, use of mining equipment, working in underground mining, worker's age and occupational experience. Conclusions: This is the first systematic review of lost-time injuries in the US mining sector. The results support the need for further research on factors that contribute to workplace lost-time injuries as there is limited literature on the topic. Safety analytics should also be applied to uncover new trends and predict the likelihood of future incidents before they occur. New insights will allow employers to prevent injuries and foster a safer workplace environment by implementing successful occupational health and safety programmes. PMID- 28898968 TI - Systematic review: Factors associated with return to work in burnout. AB - Background: Professional burnout predicts sick leave and even permanent withdrawal from the labour force. However, knowledge of the barriers to and facilitators of return to work (RTW) in such burnout is limited. Aims: To identify factors associated with RTW of burned-out individuals to inform occupational health care (OHC) RTW policy. Methods: A systematic search of peer reviewed quantitative and mixed-method studies published from January 2005 to July 2016 in English and Finnish in ARTO, CINAHL (EBSCO), Medic, PsycINFO (ProQuest), PubMed, Scopus and Web of Science databases, followed by a manual search. We included studies that identify burnout with valid burnout measures and measure the degree of RTW or sick leave as outcomes. We excluded studies with heterogeneous samples without subgroup analyses of RTW in burnout cases. Results: We included 10 studies (three experimental and seven observational) of the initial 1345 identified. The studies reported work-related factors; enhanced communication (positive association) and low control at work (negative association) and individual-related factors; male gender (positive association), covert coping (negative association), high over-commitment to work (positive association) and burnout-related factors; unimpaired sleep (positive association), duration of sick leave over 6 months (negative association) and part-time sick leave (positive association) associated with RTW in burnout. Associations between burnout rehabilitation and RTW, and the level of symptoms and cognitive impairment and RTW remained unclear. Conclusions: Few quantitative studies, of varied methodological quality, explore factors associated with RTW in burnout. Further research is needed to build an evidence base and develop guidelines for supportive OHC actions. PMID- 28898970 TI - Occupational metal exposures, smoking and diabetes. PMID- 28898969 TI - Job-specific mandatory medical examinations for the police force. AB - Background: Mandatory medical examinations (MMEs) of workers should be based on the health and safety requirements that are needed for effectively performing the relevant work. For police personnel in the Netherlands, no job-specific MME exists that takes the specific tasks and duties into account. Aims: To provide the Dutch National Police with a knowledge base for job-specific MMEs for police personnel that will lead to equitable decisions from an occupational health perspective about who can perform police duties. Methods: We used a stepwise mixed-methods approach in which we included interviews with employees and experts and a review of the national and international literature. We determined the job demands for the various police jobs, determined which were regarded as specific job demands and formulated the matching health requirements as specific as possible for each occupation. Results: A total of 21 specific job demands were considered relevant in different police jobs. These included biomechanical, physiological, physical, emotional, psychological/cognitive and sensory job demands. We formulated both police-generic and job-specific health requirements based on the specific job demands. Two examples are presented: bike patrol and criminal investigation. Conclusions: Our study substantiated the need for job specific MMEs for police personnel. We found specific job demands that differed substantially for various police jobs. The corresponding health requirements were partly police-generic, and partly job-specific. PMID- 28898971 TI - Organizational occupational health interventions: what works for whom in which circumstances? PMID- 28898972 TI - Revalidation, appraisal and multisource feedback for occupational physicians. PMID- 28898973 TI - Occupational medicine in the Middle East. PMID- 28898974 TI - Reply. PMID- 28898975 TI - The MRC breathlessness scale. PMID- 28898976 TI - Regulation of immune and neural function via leukocyte Ig-like receptors. AB - Leukocyte Ig-like receptors (LILRs)/Ig-like transcripts (ILTs) are expressed on innate and adaptive immune cells and maintain immune homeostasis. LILRs consist of activating and inhibitory-type receptors that regulate adequate cellular functions. LILRs were firstly identified as MHC class I receptors, therefore expression and/or polymorphisms of LILRs are reported to associate with autoimmune disorders and transplant rejection; however, recent accumulating evidences have revealed that LILRs recognize with diverse ligands including bacteria and virus. In addition, inhibitory LILRB2 (ILT4) and murine relative paired Ig-like receptor (PIR)-B are expressed on neuron and is involved in the dysregulation of central nervous system via interaction with neuronal ligands including amyloid beta-protein. In this review, we summarize recent discoveries on the functions of inhibitory MHC class I receptors, and discuss their regulatory roles in immune responses and neural functions. PMID- 28898977 TI - From the Cover: Metabolomics Reveals a Role of Betaine in Prenatal DBP Exposure Induced Epigenetic Transgenerational Failure of Spermatogenesis in Rats. AB - There is increasing concern that early-life exposure to endocrine disruptors affects male offspring reproduction. However, whether di-n-butyl phthalate (DBP), a widely used endocrine disruptor, has transgenerational effects and, if so, the exact underlying molecular mechanisms involved remain unknown. In our study, 5 of time-mated pregnant SD rats were exposed to 0 and 500 mg/kg DBP with corn oil as the vehicle via oral gavage from embryonic days (E8-E14). Epigenetic and metabolomic of testis were analyzed after post-natal 60 days. Sperm and testicular cell functions were examined to confirm the transgenerational effects. DBP exposure significantly decreased the sperm counts in F1 through F3 generation. We found distinct metabolic changes in the testis of both F1 and F3 generation offspring, specifically, a significantly increased level of betaine, which is an important methyl donor. In contrast, the expression of betaine homocysteine S-methyltransferase (BHMT), which catalyzes the transfer of methyl moiety from betaine to homocysteine, significantly decreased. There was accompanying global DNA hypomethylation, along with a reduction in follistatin like 3 (Fstl3) promoter hypomethylation, which is a known modulator of Sertoli cell number and spermatogenesis. In summary, we conclude that metabolomic and epigenetic changes induced by the aberrant expression of BHMT represent a novel mechanism linking in utero DBP exposure to transgenerational spermatogenesis failure. PMID- 28898980 TI - Free Testosterone: Pumping up the Tires or Ending the Free Ride? PMID- 28898981 TI - Performance of the cobas MRSA/SA Test for Simultaneous Detection of Methicillin Susceptible and Methicillin-Resistant Staphylococcus aureus From Nasal Swabs. AB - Objectives: Health care-associated methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (SA) infections are continuing problems. Rapidly determining the MRSA colonization status of a patient facilitates practice to reduce spread of MRSA clinical disease. Sensitive detection of all SA prior to surgery, followed by decolonization, can significantly reduce postoperative infection from this pathogen. Our goal was to validate a new automated assay for this testing. Methods: We compared performance of the cobas MRSA/SA Test on the cobas 4800 System to direct and enriched chromogenic culture using nasal swabs collected from patients at six United States sites. Results: Compared to direct and enriched culture, the sensitivity for MRSA and SA was 93.1% and 93.9%, and the specificity was 97.5% and 94.2%, respectively. After discrepancy analysis, the sensitivity for MRSA and SA was 97.1% and 98.6%, and the specificity was 98.3% and 95.5%, respectively. Compared to direct culture, sensitivity for detecting any SA was 99.6%. Conclusions: The cobas MRSA/SA Test is an effective tool to simultaneously perform surveillance testing for nasal colonization of both MRSA and MSSA. PMID- 28898982 TI - Prevalence of Anal Human Papillomavirus (HPV) and Performance of Cepheid Xpert and Hybrid Capture 2 (hc2) HPV Assays in South African HIV-Infected Women. AB - Objectives: This study investigated anal high-risk HPV (HR-HPV) prevalence in HIV infected women using the Cepheid Xpert HPV assay and compares its performance with that of Hybrid Capture-2 (hc2). Methods: A total of 199 HIV-infected women were recruited from Helen Joseph Hospital, Johannesburg. Stored ThinPrep anal swabs that had previously been tested using hc2 were tested for HPV using Xpert. Results: The HR-HPV prevalence by Xpert was 40.8% and similar to hc2 (41.8%) with overall agreement of 86.7%; Cohen's kappa 0.73 (95% CI 0.63-0.82). High grade squamous intraepithelial lesions (HSIL) was associated with increasing number of multiple HPV infection (P < .001). Xpert and hc2 were similarly sensitive (77.4% and 77.4%, respectively) and specific (66.1% and 64.8% respectively) for HSIL detection. HPV16 (OR: 14.0, 95% CI: 3.9-48.0, P < .0001), HPV39/68/56/66 (OR: 4.1, 95% CI: 1.4-12, P = .01) and HPV51/59 (OR: 2.8, 95% CI: 1.1-7.6, P = .04) were independently associated with anal HSIL. Conclusions: Xpert HPV typing is a promising anal screening test in HIV-infected women that performs similarly to hc2. PMID- 28898983 TI - Ki-67 Expression in Breast Cancer Tissue Microarrays: Assessing Tumor Heterogeneity, Concordance With Full Section, and Scoring Methods. AB - Objectives: Ki-67 has been proposed to be used as a surrogate marker to differentiate luminal breast carcinomas (BCs). The purpose of this study was to determine the utility of and best approaches for using tissue microarrays (TMAs) and Ki-67 staining to distinguish luminal subtypes in large epidemiology studies of luminal/human epidermal growth factor receptor 2 (HER2)-negative BC. Methods: Full-section and TMA (three 0.6-mm cores and two 1.0-mm cores) slides of 109 cases were stained with Ki-67 antibody. We assessed two ways of collapsing TMA cores: a weighted approach and mitotically active approach. Results: For cases with at least a single 0.6-mm TMA core (n = 107), 16% were misclassified using a mitotically active approach and 11% using a weighted approach. For cases with at least a single 1.0-mm TMA core (n = 101), 5% were misclassified using either approach. For the 0.6-mm core group, there were 33.3% discordant cases. The number of discordant cases increased from 18% in the group of two cores to 40% in the group of three cores (P = .039). Conclusions: Ki-67 tumor heterogeneity was common in luminal/HER2- BC. Using a weighted approach was better than using a mitotically active approach for core to case collapsing. At least a single 1.0-mm core or three 0.6-mm cores are required when designing a study using TMA. PMID- 28898984 TI - Analysis of Daily Laboratory Orders at a Large Urban Academic Center: A Multifaceted Approach to Changing Test Ordering Patterns. AB - Objectives: We sought to address concerns regarding recurring inpatient laboratory test order practices (daily laboratory tests) through a multifaceted approach to changing ordering patterns. Methods: We engaged in an interdepartmental collaboration to foster mindful test ordering through clinical policy creation, electronic clinical decision support, and continuous auditing and feedback. Results: Annualized daily order volumes decreased from approximately 25,000 to 10,000 during a 33-month postintervention review. This represented a significant change from preintervention order volumes (95% confidence interval, 0.61-0.64; P < 10-16). Total inpatient test volumes were not affected. Conclusions: Durable changes to inpatient order practices can be achieved through a collaborative approach to utilization management that includes shared responsibility for establishing clinical guidelines and electronic decision support. Our experience suggests auditing and continued feedback are additional crucial components to changing ordering behavior. Curtailing daily orders alone may not be a sufficient strategy to reduce in-laboratory costs. PMID- 28898985 TI - Lineage Switch Between B-Lymphoblastic Leukemia and Acute Myeloid Leukemia Intermediated by "Occult" Myelodysplastic Neoplasm: Two Cases of Adult Patients With Evidence of Genomic Instability and Clonal Selection by Chemotherapy. AB - Objectives: Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML). Methods: Retrospective review of clinical and laboratory data. Results: Complex cytogenetic abnormalities were detected in B ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered "occult" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse. Conclusions: Lineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome. PMID- 28898986 TI - Building a New Transfusion Service. AB - Objectives: For over 60 years, Harborview Medical Center (HMC) in Seattle has received its blood components and pretransfusion testing from a centralized transfusion service operated by the regional blood supplier. In 2011, a hospital based transfusion service (HBTS) was activated. Methods: After 5 years of operation, we evaluated the effects of the HBTS by reviewing records of hospital blood use, quality system events, blood product delivery times, and costs. Furthermore, the effects of in-house expertise on laboratory medicine resident and medical laboratory scientist student training, as well as regulatory and accrediting agency concerns, were reviewed. Results: Blood use records from 2003 to 2015 demonstrated large reductions in blood component procurement, allocation, transfusion, and wastage with decreases in costs temporally related to the change in service. The turnaround time for thawed plasma for trauma patients decreased from 90 to 3 minutes. Transfusion medicine education metrics for residents and laboratory technology students improved significantly. HMC researchers brought in $2 million in transfusion research funding. Conclusions: HMC successfully transitioned to an HBTS, providing world-class primary transfusion support to a level 1 trauma center. Near-term benefits in patient care, education, and research resulted. Blood support became faster, safer, and cheaper. PMID- 28898987 TI - Typical and Atypical Granular Cell Tumors of Soft Tissue: A Clinicopathologic Study of 50 Patients. AB - Objectives: Granular cell tumors are rare neoplasms of neural origin. Despite the mesenchymal nature of these tumors, they rarely occur in the soft tissue, and as a result, this subset is not well characterized. We present the largest case series to date comprising 50 patients with benign and atypical soft tissue granular cell tumors in an effort to better define the pathologic features in this subset of lesions. Methods: All cases of soft tissue granular cell tumors from the Ohio State Medical Center and the Medical College of Wisconsin over a 10 year period were reviewed for histologic and clinical findings. Results: The most common location was the upper extremity. The mean age was 38.6 years, and the mean size of the tumor was 2.1 cm. An infiltrative growth pattern was seen in 58.8% of cases, and positive margins were found in 68.2%. Eleven (21.6%) cases showed evidence of cytologic atypia and fulfilled the criteria for a diagnosis of atypical giant cell tumor. Two of 11 patients with long-term follow-up experienced local recurrence. Conclusions: Compared with granular cell tumors overall, the soft tissue subset shows a larger average size and higher propensity for incomplete resections, with atypical features being relatively common. Our findings suggest that soft tissue granular cell tumors may be slightly more aggressive than their dermal or organ-confined counterparts. PMID- 28898979 TI - Obesity Pathogenesis: An Endocrine Society Scientific Statement. AB - Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this "upward setting" or "resetting" of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences. PMID- 28898988 TI - Comparison of Oncotype DX With Modified Magee Equation Recurrence Scores in Low Grade Invasive Carcinoma of Breast. AB - Objectives: Several specific histologic types of invasive carcinoma of breast, including invasive tubular carcinoma (ITC), invasive mucinous carcinoma (IMC), and classical invasive lobular carcinoma (CILC), are considered low-grade carcinomas with favorable outcomes. We aimed to investigate the utility of Oncotype DX test in these tumors by comparing its recurrence score (RS) with the modified Magee equation RS. Methods: Oncotype DX RSs were collected and modified Magee equation RSs were calculated in 163 low-grade invasive breast carcinomas, including 105 CILCs, 41 ITCs, and 17 IMCs. Results: In total, 105 (64.4%) cases had an Oncotype DX RS less than 18, 56 (34.4%) were between 18 and 30, and two (1.2%) were more than 30. Of the cases, 124 (76.1%) had a modified Magee RS less than 18, 39 (23.9%) were between 18 and 30, and no case was more than 30. The overall agreement between Oncotype DX RS and modified Magee RS risk categories was 68.7%. Two CILCs with an Oncotype DX RS more than 30 had modified Magee equation RSs of 20.3 and 20.0, respectively, and both had not shown recurrent disease. Conclusions: Performing Oncotype DX on low-grade invasive carcinomas is unlikely to provide additional useful information beyond Magee equation RS, and eliminating Oncotype DX from these cases could lead to substantial cost savings. PMID- 28898989 TI - Role of Histone H3K27 Trimethylation Loss as a Marker for Malignant Peripheral Nerve Sheath Tumor in Fine-Needle Aspiration and Small Biopsy Specimens. AB - Objectives: Accurate diagnosis of malignant peripheral nerve sheath tumor (MPNST) is often challenging on fine-needle aspiration (FNA) or core needle biopsy. Recurrent mutations in EED and SUZ12, which encode subunits of polycomb repressive complex 2 (PRC2), have been identified in 70% to 92% of MPNSTs; PRC2 inactivation leads to loss of trimethylation of lysine 27 of histone H3 (H3K27me3). We evaluated the utility of H3K27me3 immunohistochemistry for distinguishing MPNST from its cytomorphologic mimics. Methods: H3K27me3 immunohistochemistry was performed on 180 cases of spindle cell neoplasms sampled by FNA (n = 66) and needle biopsy (n = 114), and loss of nuclear staining was scored. Tumor types included MPNST, dedifferentiated liposarcoma, schwannoma, solitary fibrous tumor, leiomyosarcoma, melanoma, synovial sarcoma, sarcomatoid carcinoma, gastrointestinal stromal tumor, desmoid fibromatosis, low-grade fibromyxoid sarcoma, and unclassified spindle cell sarcoma/undifferentiated pleomorphic sarcoma. Results: Complete loss of H3K27me3 was observed in 54% (13/24) of MPNSTs. In contrast, only two (of 156) histologic mimics showed complete loss of H3K27me3. Partial loss of H3K27me3 was present in a subset of cases (26/180), including both MPNST and non-MPNSTs. Conclusions: Complete loss of H3K27me3 is a highly specific (98.7%) marker of MPNST that can distinguish MPNST from cytomorphologic mimics in FNA cell block and small biopsy specimens. PMID- 28898990 TI - Real-Time Clinical Decision Support Decreases Inappropriate Plasma Transfusion. AB - Objectives: To curtail inappropriate plasma transfusions, we instituted clinical decision support as an alert upon order entry if the patient's recent international normalized ratio (INR) was 1.7 or less. Methods: The alert was suppressed for massive transfusion and within operative or apheresis settings. The plasma order was automatically removed upon alert acceptance while clinical exception reasons allowed for continued transfusion. Alert impact was studied comparing a 7-month control period with a 4-month intervention period. Results: Monthly plasma utilization decreased 17.4%, from a mean +/- SD of 3.40 +/- 0.48 to 2.82 +/- 0.6 plasma units per hundred patient days (95% confidence interval [CI] of difference, -0.1 to 1.3). Plasma transfused below an INR of 1.7 or less decreased from 47.6% to 41.6% (P = .0002; odds ratio, 0.78; 95% CI, 0.69-0.89). The alert recommendation was accepted 33% of the time while clinical exceptions were chosen in the remaining cases (active bleeding, 31%; other clinical indication, 33%; and apheresis, 2%). Alert acceptance rate varied significantly among different provider specialties. Conclusions: Clinical decision support can help curtail inappropriate plasma use but needs to be part of a comprehensive strategy including audit and feedback for comprehensive, long-term changes. PMID- 28898991 TI - Defining Papillary Carcinoma of the Thyroid: A Short Review and Analysis. AB - Objectives: To review how changes in the pathologic definitions for papillary tumors of the thyroid during recent decades have affected outcomes for patients with these tumors. Methods: Forty-nine previous reports or studies involving collectively 53,606 patients were reviewed, and new analyses were performed on the data to include analyses of agreement, incidence, survival, and diagnostic categories. Results: The past emphasis on cytologic features to define papillary tumors has not resulted in ideal pairwise agreement between pathologists and has produced incidence and survival data suggesting overdetection and overdiagnosis. Most recently, tissue patterns have been reemphasized. Conclusions: With the recent reemphasis on diagnostic tissue patterns (over cytologic criteria), agreements between pathologists for the diagnosis of papillary tumors should improve, and the incidence of papillary carcinoma should decline. Nevertheless, updated survival analyses demonstrate excellent long-term survival for most of those diagnosed with papillary carcinomas. PMID- 28898992 TI - Amphistomatic leaf surfaces independently regulate gas exchange in response to variations in evaporative demand. AB - The occurrence of amphistomatic leaves (stomata on both surfaces) versus hypostomatic leaves (stomata limited to the lower or abaxial surface) has strong associations with environment. Amphistomy provides the advantage of higher conductance of CO2 for photosynthesis, however, unless the stomata on both leaf surfaces can be independently controlled in response to environmental cues, amphistomy may lead to inefficient gas exchange. While previous studies have found evidence that stomata can operate independently across and between surfaces of dorsiventral leaves, we investigate whether an independent stomatal response can be induced for isobilateral leaves by largely natural conditions. Here, we exposed surfaces of isobilateral, amphistomatic Eucalyptus globulus Labill. leaves to natural diurnal variation in differential evaporative demand, using leaf orientation to drive differences in irradiance and heat load on leaf surfaces. We identified preferential closure of stomata on the surface exposed to higher irradiation (and therefore evaporative demand) during the afternoon under natural conditions and similarly induced differential stomatal closure under experimental conditions in the laboratory. The differential response confirms that sufficient hydraulic isolation exists for independent stomatal response to occur between surfaces of amphistomatic, isobilateral leaves, and importantly, we show that natural conditions can induce surface-specific stomatal closure. PMID- 28898993 TI - The phloem-xylem consortium: until death do them part. PMID- 28898994 TI - How well do growing season dynamics of photosynthetic capacity correlate with leaf biochemistry and climate fluctuations? AB - Accurate values of photosynthetic capacity are needed in Earth System Models to predict gross primary productivity. Seasonal changes in photosynthetic capacity in these models are primarily driven by temperature, but recent work has suggested that photoperiod may be a better predictor of seasonal photosynthetic capacity. Using field-grown kudzu (Pueraria lobata (Willd.) Ohwi), a nitrogen fixing vine species, we took weekly measurements of photosynthetic capacity, leaf nitrogen, and pigment and photosynthetic protein concentrations and correlated these with temperature, irradiance and photoperiod over the growing season. Photosynthetic capacity was more strongly correlated with photoperiod than with temperature or daily irradiance, while the growing season pattern in photosynthetic capacity was uncoupled from changes in leaf nitrogen, chlorophyll and Rubisco. Daily estimates of the maximum carboxylation rate of Rubisco (Vcmax) based on either photoperiod or temperature were correlated in a non-linear manner, but Vcmax estimates from both approaches that also accounted for diurnal temperature fluctuations were similar, indicating that differences between these models depend on the relevant time step. We advocate for considering photoperiod, and not just temperature, when estimating photosynthetic capacity across the year, particularly as climate change alters temperatures but not photoperiod. We also caution that the use of leaf biochemical traits as proxies for estimating photosynthetic capacity may be unreliable when the underlying relationships between proxy leaf traits and photosynthetic capacity are established outside of a seasonal framework. PMID- 28898995 TI - Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL 1 cells using novel recording and numerical approaches. AB - Aims: Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Methods and results: Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca2+ (apparent Kd = ~500 nM) were enough to activate this channel. Similar submicromolar Ca2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo Rudy) incorporating the Ca2+- and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (>= six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. Conclusions: These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue. PMID- 28898996 TI - The expression of the rare caveolin-3 variant T78M alters cardiac ion channels function and membrane excitability. AB - Aims: Caveolinopathies are a family of genetic disorders arising from alterations of the caveolin-3 (cav-3) gene. The T78M cav-3 variant has been associated with both skeletal and cardiac muscle pathologies but its functional contribution, especially to cardiac diseases, is still controversial. Here, we evaluated the effect of the T78M cav-3 variant on cardiac ion channel function and membrane excitability. Methods and results: We transfected either the wild type (WT) or T78M cav-3 in caveolin-1 knock-out mouse embryonic fibroblasts and found by immunofluorescence and electron microscopy that both are expressed at the plasma membrane and form caveolae. Two ion channels known to interact and co immunoprecipitate with the cav-3, hKv1.5 and hHCN4, interact also with T78M cav-3 and reside in lipid rafts. Electrophysiological analysis showed that the T78M cav 3 causes hKv1.5 channels to activate and inactivate at more hyperpolarized potentials and the hHCN4 channels to activate at more depolarized potentials, in a dominant way. In spontaneously beating neonatal cardiomyocytes, the expression of the T78M cav-3 significantly increased action potential peak-to-peak variability without altering neither the mean rate nor the maximum diastolic potential. We also found that in a small cohort of patients with supraventricular arrhythmias, the T78M cav-3 variant is more frequent than in the general population. Finally, in silico analysis of both sinoatrial and atrial cell models confirmed that the T78M-dependent changes are compatible with a pro-arrhythmic effect. Conclusion: This study demonstrates that the T78M cav-3 induces complex modifications in ion channel function that ultimately alter membrane excitability. The presence of the T78M cav-3 can thus generate a susceptible substrate that, in concert with other structural alterations and/or genetic mutations, may become arrhythmogenic. PMID- 28898998 TI - Sirtuin 1 steers anti-inflammatory effects in vascular smooth muscle cells: protection without burden? PMID- 28898997 TI - Angiotensin II infusion into ApoE-/- mice: a model for aortic dissection rather than abdominal aortic aneurysm? AB - Aims: Angiotensin II-infused ApoE-/- mice are a popular mouse model for preclinical aneurysm research. Here, we provide insight in the often-reported but seldom-explained variability in shape of dissecting aneurysms in these mice. Methods and results: N = 45 excised aortas were scanned ex vivo with phase contrast X-ray tomographic microscopy. Micro-ruptures were detected near the ostium of celiac and mesenteric arteries in 8/11 mice that were sacrificed after 3 days of angiotensin II-infusion. At later time points (after 10, 18, and 28 days) the variability in shape of thoraco-abdominal lesions (occurring in 31/34 mice) was classified into 7 different categories based on the presence or absence of a medial tear (31/31), an intramural hematoma (23/31) or a false channel (11/23). Medial tears were detected both in the thoracic and the abdominal aorta and were most prevalent at the left and ventral aspects of celiac and mesenteric arteries. The axial length of the hematoma strongly correlated to the total number of ruptured branch ostia (r2 = 0.78) and in 22/23 mice with a hematoma the ostium of the left suprarenal artery had ruptured. Supraceliac diameters at baseline were significantly lower for mice that did not develop an intramural hematoma, and the formation of a false channel within that intramural hematoma depended on the location, rather than the length, of the medial tear. Conclusion: Based on our observations we propose an elaborate hypothesis that explains how aortic side branches (i) affect the initiation and propagation of medial tears and the subsequent adventitial dissection and (ii) affect the variability in shape of dissecting aneurysms. This hypothesis was partially validated through the live visualization of a dissecting aneurysm that formed during micro-CT imaging, and led us to the conclusion that angiotensin II-infused mice are more clinically relevant for the study of aortic dissections than for the study of abdominal aortic aneurysms. PMID- 28898999 TI - Tweak up-regulates endothelin-1 system in mouse and human endothelial cells. PMID- 28899000 TI - RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node. AB - Aims: RHOA-ROCK signalling regulates cell migration, proliferation, differentiation, and transcription. RHOA is expressed in the developing cardiac conduction system in chicken and mice. In early development, the entire sinus venosus myocardium, including both the transient left-sided and the definitive sinoatrial node (SAN), has pacemaker potential. Later, pacemaker potential is restricted to the right-sided SAN. Disruption of RHOA expression in adult mice causes arrhythmias including bradycardia and atrial fibrillation, the mechanism of which is unknown but presumed to affect the SAN. The aim of this study is to assess the role of RHOA-ROCK signalling in SAN development in the chicken heart. Methods and results: ROCK signalling was inhibited chemically in embryonic chicken hearts using Y-27632. This prolonged the immature state of the sinus venosus myocardium, evidenced by up-regulation of the transcription factor ISL1, wide distribution of pacemaker potential, and significantly reduced heart rate. Furthermore ROCK inhibition caused aberrant expression of typical SAN genes: ROCK1, ROCK2, SHOX2, TBX3, TBX5, ISL1, HCN4, CX40, CAV3.1, and NKX2.5 and left right asymmetry genes: PITX2C and NODAL. Anatomical abnormalities in pulmonary vein development were also observed. Patch clamp electrophysiology confirmed the immature phenotype of the SAN cells and a residual left-sided sinus venosus myocardium pacemaker-like potential. Conclusions: RHOA-ROCK signalling is involved in establishing the right-sided SAN as the definitive pacemaker of the heart and restricts typical pacemaker gene expression to the right side of the sinus venosus myocardium. PMID- 28899002 TI - The unexpected intelligence: what is the naked mole-rat's secret to surviving oxygen deprivation? PMID- 28899001 TI - A role for autoantibodies in atherogenesis. AB - An increased risk of cardiovascular disease (CVD) has long been recognized amongst people with autoimmune disease. It has been unclear whether this is due mainly to the ensuing treatment, particularly steroids, or whether some of this risk is due to the autoimmune process itself with subsequent inflammation. Indeed, a large body of evidence supports a role for chronic inflammation in atherogenesis, and autoantibodies have been identified as mediators in this complex inflammatory environment. Our aim is to carry out a systematic review of existing literature in order to formally establish the strength of the association between autoantibodies and atherosclerosis, amongst individuals without clinical autoimmune disease. An electronic search of five databases to June 2016 was performed by two independent reviewers. Inclusion criteria were analytical studies of adults, with at least two studies per autoantibody. Quality analysis was carried out using the Newcastle-Ottawa scale and the Cochrane Risk of Bias Quality Assessment Tool where appropriate. Where possible, studies were pooled using random effects models. Raised levels of anti-cardiolipin (odds ratio [OR] = 1.30; 95% CI: 1.15-1.49) and anti-oxidized low-density lipoprotein Immunoglobulin (Ig) G (OR = 1.25; 95% CI: 1.11-1.41), unspecified anti-cyclic citrullinated protein (OR = 3.09; 95% CI: 1.49-6.41) and anti-human heat shock protein 60 IgA (OR = 1.57; 95% CI: 1.15-2.16) were observed to increase the risk of cardiovascular outcomes. Alternatively, Anti-phosphorylcholine IgM (OR = 1.31; 95% CI: 1.14-1.50) conferred protection against CVD. Our results support an important role for autoantibodies in mediating cardiovascular events, independent of therapeutic treatments. Future research may focus on the presence of autoantibodies as markers of immune dysregulation and CVD risk. PMID- 28899003 TI - The science of stents: angioplasty turns 40. PMID- 28899004 TI - Improving the outcome of primary PCI: protection from reperfusion injury. PMID- 28899005 TI - Young researchers enjoying great science and good company in the south of France in summer! PMID- 28899006 TI - Network medicine: a new paradigm for cardiovascular disease research and beyond. PMID- 28899007 TI - The spectrum of structural and functional network alterations in malformations of cortical development. AB - Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory. PMID- 28899009 TI - In and out of control: brain mechanisms linking fluency of action selection to self-agency in patients with schizophrenia. AB - Sense of agency refers to the feeling of control over one's actions, and their consequences. It involves both predictive processes linked to action control, and retrospective 'sense-making' causal inferences. Schizophrenia has been associated with impaired predictive processing, but the underlying mechanisms that impair patients' sense of agency remain unclear. We introduce a new 'prospective' aspect of agency and show that subliminally priming an action not only influences response times, but also influences reported sense of agency over subsequent action outcomes. This effect of priming was associated with altered connectivity between frontal areas and the angular gyrus. The effects on response times and on frontal action selection mechanisms were similar in patients with schizophrenia and in healthy volunteers. However, patients showed no effects of priming on sense of agency, no priming-related activation of angular gyrus, and no priming related changes in fronto-parietal connectivity. We suggest angular gyrus activation reflects the experiences of agency, or non-agency, in part by processing action selection signals generated in the frontal lobes. The altered action awareness that characterizes schizophrenia may be due to impaired communication between these areas. PMID- 28899008 TI - Phenotypic analysis of 303 multiplex families with common epilepsies. AB - Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and inter-relationships of the common epilepsy syndromes. PMID- 28899010 TI - Modelling APOE E3/4 allele-associated sporadic Alzheimer's disease in an induced neuron. AB - The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) E3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE E3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-beta42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE E3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE E3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE E3/4 patient induced neurons reveals a strong interaction between APOE E3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE E3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE E3/4 and another Alzheimer's disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer's disease for therapeutic discovery. PMID- 28899011 TI - Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. PMID- 28899012 TI - Reply: Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. PMID- 28899013 TI - The fatigue conundrum. PMID- 28899016 TI - Reply: The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders. PMID- 28899015 TI - The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders. PMID- 28899014 TI - Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. AB - See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-beta, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-beta or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-beta, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-beta40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-beta, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-beta levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep. PMID- 28899017 TI - Cortical functional hyperconnectivity in a mouse model of depression and selective network effects of ketamine. AB - See Huang and Liston (doi:10.1093/awx166) for a scientific commentary on this article.Human depression is associated with glutamatergic dysfunction and alterations in resting state network activity. However, the indirect nature of human in vivo glutamate and activity assessments obscures mechanistic details. Using the chronic social defeat mouse model of depression, we determine how mesoscale glutamatergic networks are altered after chronic stress, and in response to the rapid acting antidepressant, ketamine. Transgenic mice (Ai85) expressing iGluSnFR (a recombinant protein sensor) permitted real-time in vivo selective characterization of extracellular glutamate and longitudinal imaging of mesoscale cortical glutamatergic functional circuits. Mice underwent chronic social defeat or a control condition, while spontaneous cortical activity was longitudinally sampled. After chronic social defeat, we observed network-wide glutamate functional hyperconnectivity in defeated animals, which was confirmed with voltage sensitive dye imaging in an independent cohort. Subanaesthetic ketamine has unique effects in defeated animals. Acutely, subanaesthetic ketamine induces large global cortical glutamate transients in defeated animals, and an elevated subanaesthetic dose resulted in sustained global increase in cortical glutamate. Local cortical inhibition of glutamate transporters in naive mice given ketamine produced a similar extracellular glutamate phenotype, with both glutamate transients and a dose-dependent accumulation of glutamate. Twenty-four hours after ketamine, normalization of depressive-like behaviour in defeated animals was accompanied by reduced glutamate functional connectivity strength. Altered glutamate functional connectivity in this animal model confirms the central role of glutamate dynamics as well as network-wide changes after chronic stress and in response to ketamine. PMID- 28899018 TI - Encephalitis lethargica: 100 years after the epidemic. PMID- 28899019 TI - Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. AB - See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-beta by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid beta to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-beta load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-beta positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [beta(standard error) = -0.169 (0.034), P = 9.2 * 10-7], executive function [beta(standard error) = -0.139 (0.048), P = 0.004), and attention [beta(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [beta(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [beta(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-beta to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-beta positron emission tomography to stratify individuals at risk of decline. PMID- 28899021 TI - Cortex-wide optical imaging and network analysis of antidepressant effects. PMID- 28899020 TI - Progression marker of Parkinson's disease: a 4-year multi-site imaging study. AB - Progression markers of Parkinson's disease are crucial for successful therapeutic development. Recently, a diffusion magnetic resonance imaging analysis technique using a bitensor model was introduced allowing the estimation of the fractional volume of free water within a voxel, which is expected to increase in neurodegenerative disorders such as Parkinson's disease. Prior work demonstrated that free water in the posterior substantia nigra was elevated in Parkinson's disease compared to controls across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in controls at a single site. Here, the goal was to validate free water in the posterior substantia nigra as a progression marker in Parkinson's disease, and describe the pattern of progression of free water in patients with a 4-year follow-up tested in a multicentre international longitudinal study of de novo Parkinson's disease (http://www.ppmi-info.org/). The analyses examined: (i) 1-year changes in free water in 103 de novo patients with Parkinson's disease and 49 controls; (ii) 2- and 4-year changes in free water in a subset of 46 patients with Parkinson's disease imaged at baseline, 12, 24, and 48 months; (iii) whether 1- and 2-year changes in free water predict 4-year changes in the Hoehn and Yahr scale; and (iv) the relationship between 4-year changes in free water and striatal binding ratio in a subgroup of Parkinson's disease who had undergone both diffusion and dopamine transporter imaging. Results demonstrated that: (i) free water level in the posterior substantia nigra increased over 1 year in de novo Parkinson's disease but not in controls; (ii) free water kept increasing over 4 years in Parkinson's disease; (iii) sex and baseline free water predicted 4-year changes in free water; (iv) free water increases over 1 and 2 years were related to worsening on the Hoehn and Yahr scale over 4 years; and (v) the 4-year increase in free water was associated with the 4-year decrease in striatal binding ratio in the putamen. Importantly, all longitudinal results were consistent across sites. In summary, this study demonstrates an increase over 1 year in free water in the posterior substantia nigra in a large cohort of de novo patients with Parkinson's disease from a multi-site cohort study and no change in healthy controls, and further demonstrates an increase of free water in Parkinson's disease over the course of 4 years. A key finding was that results are consistent across sites and the 1-year and 2-year increase in free water in the posterior substantia nigra predicts subsequent long-term progression on the Hoehn and Yahr staging system. Collectively, these findings demonstrate that free water in the posterior substantia nigra is a valid, progression imaging marker of Parkinson's disease, which may be used in clinical trials of disease-modifying therapies. PMID- 28899022 TI - Correlating quantitative susceptibility mapping with cognitive decline in Alzheimer's disease. PMID- 28899023 TI - The circadian profile of epilepsy improves seizure forecasting. AB - It is now established that epilepsy is characterized by periodic dynamics that increase seizure likelihood at certain times of day, and which are highly patient specific. However, these dynamics are not typically incorporated into seizure prediction algorithms due to the difficulty of estimating patient-specific rhythms from relatively short-term or unreliable data sources. This work outlines a novel framework to develop and assess seizure forecasts, and demonstrates that the predictive power of forecasting models is improved by circadian information. The analyses used long-term, continuous electrocorticography from nine subjects, recorded for an average of 320 days each. We used a large amount of out-of-sample data (a total of 900 days for algorithm training, and 2879 days for testing), enabling the most extensive post hoc investigation into seizure forecasting. We compared the results of an electrocorticography-based logistic regression model, a circadian probability, and a combined electrocorticography and circadian model. For all subjects, clinically relevant seizure prediction results were significant, and the addition of circadian information (combined model) maximized performance across a range of outcome measures. These results represent a proof of-concept for implementing a circadian forecasting framework, and provide insight into new approaches for improving seizure prediction algorithms. The circadian framework adds very little computational complexity to existing prediction algorithms, and can be implemented using current-generation implant devices, or even non-invasively via surface electrodes using a wearable application. The ability to improve seizure prediction algorithms through straightforward, patient-specific modifications provides promise for increased quality of life and improved safety for patients with epilepsy. PMID- 28899024 TI - A restless night makes for a rising tide of amyloid. PMID- 28899025 TI - The nociferous influence of interictal discharges on memory. PMID- 28899026 TI - Dead salmon and voodoo correlations: should we be sceptical about functional MRI? PMID- 28899027 TI - Editorial. PMID- 28899028 TI - Street Audits to Measure Neighborhood Disorder: Virtual or In-Person? AB - Neighborhood conditions may influence a broad range of health indicators, including obesity, injury, and psychopathology. In particular, neighborhood physical disorder-a measure of urban deterioration-is thought to encourage crime and high-risk behaviors, leading to poor mental and physical health. In studies to assess neighborhood physical disorder, investigators typically rely on time consuming and expensive in-person systematic neighborhood audits. We compared 2 audit-based measures of neighborhood physical disorder in the city of Detroit, Michigan: One used Google Street View imagery from 2009 and the other used an in person survey conducted in 2008. Each measure used spatial interpolation to estimate disorder at unobserved locations. In total, the virtual audit required approximately 3% of the time required by the in-person audit. However, the final physical disorder measures were significantly positively correlated at census block centroids (r = 0.52), identified the same regions as highly disordered, and displayed comparable leave-one-out cross-validation accuracy. The measures resulted in very similar convergent validity characteristics (correlation coefficients within 0.03 of each other). The virtual audit-based physical disorder measure could substitute for the in-person one with little to no loss of precision. Virtual audits appear to be a viable and much less expensive alternative to in-person audits for assessing neighborhood conditions. PMID- 28899029 TI - Invited Commentary: Observing Neighborhood Physical Disorder in an Age of Technological Innovation. AB - Researchers across several disciplines have argued that the characteristics of neighborhood environments can affect a variety of individual- and neighborhood level outcomes. Physical disorder is one feature of neighborhoods that scholars have argued is important, but data that capture physical disorder have been limited because of the time and resources required for in-person audits. The advent of Google Street View, which provides publicly available street-level imagery with nearly complete coverage of the United States, opens new possibilities for researchers. In this issue of the Journal, Mooney et al. (Am J Epidemiol. 2017;186(3):265-273) compare in-person and virtual audits in Detroit, Michigan, and demonstrate that virtual audits offer key advantages to measuring neighborhood physical disorder over in-person audits, including substantial reductions in time and resources with little to no loss of measurement precision. In this invited commentary, I welcome the use of virtual audits for advancing the study of neighborhoods and outline areas in which they can advance understanding of neighborhood effects. I also describe areas of caution in their implementation and outline how new innovations can advance the use of virtual audits for furthering understanding of neighborhood environments. PMID- 28899030 TI - Mooney et al. Respond to "Observing Neighborhood Physical Disorder". PMID- 28899032 TI - Mating response and construction of heterothallic strains of the fission yeast Schizosaccharomyces octosporus. AB - The fission yeast Schizosaccharomyces octosporus is one of four species in the genus Schizosaccharomyces. Recently released genome sequence data provide useful information for comparative studies. However, Sz. octosporus has not yet been genetically characterized because there have been no heterothallic strains of this species. Here we report the construction of stable heterothallic strains of Sz. octosporus for genetic crosses. First, we continuously observed the mating process of a homothallic strain, yFS286, and determined the mating frequency of Sz. octosporus on various sporulation media. It showed, on average, 30% zygote formation on mating, and a higher frequency of zygotes (43.8 +/- 4.7%) on PMG medium. Regardless of sporulation, the number of spores within an ascus was variable. Schizosaccharomyces octosporus forms eight-spored asci, but preferentially produced four-spored asci on MEA or YMoA medium. To obtain heterothallic strains essential for genetic analyses, we isolated spontaneous mutants showing heterothallic-like phenotypes. We also constructed stable heterothallic strains by deleting the silent mat region. As a result, we established the following heterothallic strains, TS162 as h+ and TS150/TS161 as h , which successfully mated with each other. These genetic tools will be useful for yeast genetics such as molecular cloning, gene complementation tests and tetrad (octad) analysis. PMID- 28899033 TI - Recombination sites on hybrid chromosomes in Saccharomyces pastorianus share common sequence motifs and define a complex evolutionary relationship between group I and II lager yeasts. AB - Saccharomyces pastorianus, referred to as lager yeasts, are hybrids of S. cerevisiae and S. eubayanus. Isolates within the species are divided into two groups (I and II) based on chromosome structure and composition. Following the hybridisation, the parental chromosomes underwent homeologous recombination, generating a set of hybrid chromosomes unique to the species. Here, we assessed the recombination events in seven lager yeast genomes to more clearly define the evolutionary route of lager yeasts. Meta-analysis of the recombination epicentres, as well as a detailed analysis of recombination events at the MAT locus, reveals a more complex evolutionary relationship between the group I and II lager yeasts than previously considered and identifies several divergent routes of evolution leading to the current S. pastorianus strains. We show that recombination epicentres contain sequential runs of pyrimidines, often flanked by purines, on one strand of the DNA, and identify two common sequence motifs present in >80% of the recombination epicentres, indicating that a common mechanism might account for the recombination events. Taken together, the data support a sequential hybridisation model of evolution for the two types of lager yeasts and suggest that the genomes of this newly emerged species are highly dynamic and continually evolving. PMID- 28899035 TI - Advance, Adapt, Achieve: The 2016 Congress of Neurological Surgeons Presidential Address. PMID- 28899036 TI - Overlapping Surgery: A Review of the Controversy, the Evidence, and Future Directions. PMID- 28899037 TI - New Clinical-Pathological Classification of Intraspinal Injury Following Traumatic Acute Complete Thoracic Spinal Cord Injury: Postdurotomy/Myelotomy Observations From the INSPIRE Trial. PMID- 28899038 TI - Achieving Optimal Outcome for Degenerative Lumbar Spondylolisthesis: Randomized Controlled Trial Results. PMID- 28899034 TI - Genome-scale modeling of yeast: chronology, applications and critical perspectives. AB - Over the last 15 years, several genome-scale metabolic models (GSMMs) were developed for different yeast species, aiding both the elucidation of new biological processes and the shift toward a bio-based economy, through the design of in silico inspired cell factories. Here, an historical perspective of the GSMMs built over time for several yeast species is presented and the main inheritance patterns among the metabolic reconstructions are highlighted. We additionally provide a critical perspective on the overall genome-scale modeling procedure, underlining incomplete model validation and evaluation approaches and the quest for the integration of regulatory and kinetic information into yeast GSMMs. A summary of experimentally validated model-based metabolic engineering applications of yeast species is further emphasized, while the main challenges and future perspectives for the field are finally addressed. PMID- 28899039 TI - The Utility of Thromboelastography for Predicting The Risk of Progression of Intracranial Hemorrhage in Traumatic Brain Injury Patients. PMID- 28899040 TI - The Future of Cranial Neurosurgery-Adapting New Approaches. PMID- 28899031 TI - Saccharomyces cerevisiae strains for second-generation ethanol production: from academic exploration to industrial implementation. AB - The recent start-up of several full-scale 'second generation' ethanol plants marks a major milestone in the development of Saccharomyces cerevisiae strains for fermentation of lignocellulosic hydrolysates of agricultural residues and energy crops. After a discussion of the challenges that these novel industrial contexts impose on yeast strains, this minireview describes key metabolic engineering strategies that have been developed to address these challenges. Additionally, it outlines how proof-of-concept studies, often developed in academic settings, can be used for the development of robust strain platforms that meet the requirements for industrial application. Fermentation performance of current engineered industrial S. cerevisiae strains is no longer a bottleneck in efforts to achieve the projected outputs of the first large-scale second generation ethanol plants. Academic and industrial yeast research will continue to strengthen the economic value position of second-generation ethanol production by further improving fermentation kinetics, product yield and cellular robustness under process conditions. PMID- 28899041 TI - Translational Advances in the Management of Acute Spinal Cord Injury: What is New? What is Hot? PMID- 28899042 TI - Stereotactic Radiosurgery: The Revolutionary Advance in the Treatment of Spine Metastases. PMID- 28899044 TI - Japanese Congress of Neurological Surgeons Presidential Address-Treatment of Carotid Artery Stenosis Based on Plaque Imaging. PMID- 28899043 TI - GPR133 Promotes Glioblastoma Growth in Hypoxia. PMID- 28899045 TI - Recent Advances in Epilepsy Surgery and Achieving Best Outcomes Using High Frequency Oscillations, Diffusion Tensor Imaging, Magnetoencephalography, Intraoperative Neuromonitoring, Focal Cortical Dysplasia, and Bottom of Sulcus Dysplasia. PMID- 28899046 TI - Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury: Functional Outcomes at 12 Months in a Phase II Clinical Trial. PMID- 28899047 TI - Quantification of Cordotomy Lesion Using Spinal Cord Diffusion Tensor Imaging. PMID- 28899048 TI - Growing Brains: How Adapting to Africa Advanced the Treatment of Infant Hydrocephalus. PMID- 28899049 TI - IDH1 Mutation and World Health Organization 2016 Diagnostic Criteria for Adult Diffuse Gliomas: Advances in Surgical Strategy. PMID- 28899050 TI - Advances in Genomics Explain Medulloblastoma Behavior at the Bedside. PMID- 28899051 TI - Neuroendoscopy to Achieve Superior Glioma Resection Outcomes. PMID- 28899052 TI - Preface to Clinical Neurosurgery Volume 64, Proceedings of the Congress of Neurological Surgeons 2016 Annual Meeting. PMID- 28899053 TI - Intracranial Meningiomas in the Era of Human Immunodeficiency Virus Infection and Antiretroviral Therapies in KwaZulu-Natal, South Africa: An Observational Case Control Study. PMID- 28899054 TI - Privademics: The Best of Both Worlds. PMID- 28899055 TI - Factors Associated With Playing Through a Sport-Related Concussion. PMID- 28899056 TI - Aspirin for the Prevention of Intracranial Aneurysm Rupture. PMID- 28899057 TI - Adapting Findings From Rare Peripheral Nerve Disorders Can Lead to Broad Applications in Neurosurgery. PMID- 28899058 TI - Distinct Radiomic Phenotypes Define Glioblastoma TP53-PTEN-EGFR Mutational Landscape. PMID- 28899059 TI - Targeting Neoantigens in Glioblastoma: An Overview of Cancer Immunogenomics and Translational Implications. PMID- 28899061 TI - Transsulcal Parafascicular Surgery Using Brain Path(r) for Subcortical Lesions. PMID- 28899060 TI - Scanning Fiber Angioscopy: A Multimodal Intravascular Imaging Platform for Carotid Atherosclerosis. PMID- 28899062 TI - A Focused Review of Clinical and Preclinical Studies of Cell-Based Therapies in Stroke. PMID- 28899063 TI - Disruptive Innovation in Neurovascular Disease. PMID- 28899064 TI - Effect of Complications within 90 Days on Cost Per Quality-Adjusted Life Year Gained Following Elective Surgery for Degenerative Lumbar Spine Disease. PMID- 28899065 TI - Strategies for Autonomous Sensor-Brain Interfaces for Closed-Loop Sensory Reanimation of Paralyzed Limbs. PMID- 28899066 TI - Pathogenesis of Chiari I - Pathophysiology of Syringomyelia: Implications for Therapy: A Summary of 3 Decades of Clinical Research. PMID- 28899071 TI - Honored Guest of the Congress of Neurological Surgeons 2016 Annual Meeting: Edward H. Oldfield, MD, FACS. PMID- 28899067 TI - Cushing's Disease: Lessons Learned From 1500 Cases. PMID- 28899074 TI - Thyroid-Specific T Cells in Patients With Differentiated Thyroid Cancer: Implications for Immune-Based Therapies? PMID- 28899075 TI - Letter to the Editor: "Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study". PMID- 28899076 TI - Letter to the Editor: The Effect of Genetic Factors on the Response to Vitamin D Supplementation May Be Mediated by Vitamin D-Binding Protein Concentrations. PMID- 28899077 TI - Cushing Disease: Are We Making Progress? PMID- 28899078 TI - Response to Letter: "Normal Pubertal Development in Daughters of Women With PCOS: A Controlled Study". PMID- 28899079 TI - Challenges for Zika prevention in Myanmar. PMID- 28899080 TI - Pulmonary fibrosis in connective tissue disease (CTD): urgent challenges and opportunities. PMID- 28899081 TI - 'Bending' models of halotropism: incorporating protein phosphatase 2A, ABCB transporters, and auxin metabolism. AB - Salt stress causes worldwide reductions in agricultural yields, a problem that is exacerbated by the depletion of global freshwater reserves and the use of contaminated or recycled water (i.e. effluent water). Additionally, salt stress can occur as cultivated areas are subjected to frequent rounds of irrigation followed by periods of moderate to severe evapotranspiration, which can result in the heterogeneous aggregation of salts in agricultural soils. Our understanding of the later stages of salt stress and the mechanisms by which salt is transported out of cells and roots has greatly improved over the last decade. The precise mechanisms by which plant roots perceive salt stress and translate this perception into adaptive, directional growth away from increased salt concentrations (i.e. halotropism), however, are not well understood. Here, we provide a review of the current knowledge surrounding the early responses to salt stress and the initiation of halotropism, including lipid signaling, protein phosphorylation cascades, and changes in auxin metabolism and/or transport. Current models of halotropism have focused on the role of PIN2- and PIN1-mediated auxin efflux in initiating and controlling halotropism. Recent studies, however, suggest that additional factors such as ABCB transporters, protein phosphatase 2A activity, and auxin metabolism should be included in the model of halotropic growth. PMID- 28899082 TI - Pollen tube vs CHUKNORRIS: the action is pulsatile. PMID- 28899083 TI - Plant membranes and border control. PMID- 28899084 TI - Comparison of liquid-based cytology (CellPrepPlus) and conventional smears in pancreaticobiliary disease. AB - BACKGROUND/AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUSFNA) and brushing cytology are used worldwide to diagnose pancreatic and biliary malignant tumors. Liquid-based cytology (LBC) has been developed and it is currently used to overcome the limitations of conventional smears (CS). In this study, the authors aimed to compare the diagnostic value of the CellPrepPlus (CP; Biodyne) LBC method with CS in samples obtained using EUS-FNA and brushing cytology. METHODS: This study prospectively enrolled 75 patients with pancreatic or biliary lesions from June 2012 to October 2013. For cytological analyses, including inadequate specimens, benign and atypical were further classified into benign, and suspicious and malignant were subcategorized as malignant. Sensitivity, specificity, accuracy, and positive predictive values (PPV) and negative predictive values (NPV) were evaluated. RESULTS: In the EUS-FNA based cytological analysis of pancreatic specimens, CP had a sensitivity of 60.7%; specificity, 100%; accuracy, 77.1%; PPV, 100%; and NPV, 64.5%. CS had a sensitivity of 85.7%; specificity, 100%; accuracy, 91.7%; PPV, 100%; and NPV, 83.3%. In the brushing cytology based analysis of biliary specimens, CP had sensitivity of 53.1%; specificity, 100%; accuracy, 54.5%; PPV, 100%; and NPV, 6.3%. CS had a sensitivity of 78.1%; specificity, 100%; accuracy, 78.8%; PPV, 100%; and NPV, 12.5%. CONCLUSION: Our study found that CP had a lower sensitivity because of low cellularity compared with CS. Therefore, CP (LBC) has a lower diagnostic accuracy for pancreatic EUS-FNA based and biliary brush cytology based analyses compared with CS. PMID- 28899085 TI - Correlation between NADPH oxidase-mediated oxidative stress and dysfunction of endothelial progenitor cell in hyperlipidemic patients. AB - BACKGROUND/AIMS: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (NOX)-mediated oxidative stress plays a key role in promotion of oxidative injury in the cardiovascular system. The aim of this study is to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic patients and to assess the correlation between NOX activity and the functions EPCs. METHODS: A total of 30 hyperlipidemic patients were enrolled for this study and 30 age matched volunteers with normal level of plasma lipids served as controls. After the circulating EPCs were isolated, the EPC functions (migration, adhesion and tube formation) were evaluated and the status of NOX (expression and activity) was examined. RESULTS: Compared to the controls, hyperlipidemic patients showed an increase in plasma lipids and a reduction in EPC functions including the attenuated abilities in adhesion, migration and tube formation, concomitant with an increase in NOX expression (NOX2 and NOX4), NOX activity, and reactive oxygen species production. The data analysis showed negative correlations between NOX activity and EPC functions. CONCLUSIONS: There is a positive correlation between the NOX-mediated oxidative stress and the dysfunctions of circulating EPCs in hyperlipidemic patients, and suppression of NOX might offer a novel strategy to improve EPCs functions in hyperlipidemia. PMID- 28899086 TI - Copper-Catalyzed Enantioselective Hydroboration of Unactivated 1,1-Disubstituted Alkenes. AB - We report an efficient and highly enantioselective hydroboration of aliphatic 1,1 disubstituted alkenes with pinacolborane using a phosphine-Cu catalyst. The method allows facile preparation of enantiomerically enriched beta-chiral alkyl pinacolboronates from a range of 1,1-disubstituted alkenes with high enantioselectivity up to 99% ee. Unprecedented enantiodiscrimination between the geminal alkyl substituents was observed with functional group compatibility in the hydroboration. Furthermore, a catalyst loading as low as 1 mol % furnished the desired product without a decrease in yield or selectivity, demonstrating its efficiency in gram scale synthesis. PMID- 28899087 TI - Molecular Ion Formation by Photoinduced Electron Transfer at the Tetracyanoquinodimethane/Au(111) Interface. AB - Optically induced processes in organic materials are essential for light harvesting, switching, and sensor technologies. Here we studied the electronic properties of the tetracyanoquinodimethane(TCNQ)/Au(111) interface by using two photon photoemission spectroscopy. For this interface we demonstrated the lack of charge-transfer interactions, but we found a significant increase in the sample work function due to UV-light illumination, while the electronic structure of the TCNQ-derived states remain unaffected. Thereby the work function of the interface can be tuned over a wide range via the photon dose. We assigned this to a photoinduced metal-to-molecule electron transfer creating negative ions. The electrons are bound by a small potential barrier. Thus thermal activation reverses the process resulting in the original work function value. The presented photoinduced charge transfer at the TCNQ/Au(111) interface can be used for continuous work function tuning across the substrate's work function, which can be applied in device-adapted hole-injection layers or organic UV-light sensors. PMID- 28899088 TI - Identification of Siglec Ligands Using a Proximity Labeling Method. AB - Siglecs are a family of receptor-type glycan recognition proteins (lectins) involved in self-nonself discrimination by the immune system. Identification of Siglec ligands is necessary to understand how Siglec-ligand interaction translates into biological outcomes. However, this is challenging because the interaction is weak. To facilitate identification of Siglec ligands, we adopted a proximity labeling method based on the tyramide radicalization principle. Cells that express Siglec ligands were labeled with Siglec-peroxidase complexes and incubated with biotin tyramide and hydrogen peroxide to generate short-lived tyramide radicals that covalently label the proteins near the Siglec-peroxidase complex. A proof-of-principle experiment using CD22 (Siglec-2) probe identified its known ligands on B cells, including CD22 itself, CD45, and IgM, among others, demonstrating the validity of this method. The specificity of labeling was confirmed by sialidase treatment of target cells and using glycan recognition deficient mutant CD22 probes. Moreover, possible interactions between biotin labeled proteins were revealed by literature-based protein-protein interaction network analysis, implying the presence of a molecular cluster comprising CD22 ligands. Further application of this method identified CD44 as a hitherto unknown Siglec-15 ligand on RAW264.7-derived osteoclasts. These results demonstrated the utility of proximity labeling for the identification of Siglec ligands, which may extend to other lectins. PMID- 28899089 TI - Highly Active Multimetallic Palladium Nanoalloys Embedded in Conducting Polymer as Anode Catalyst for Electrooxidation of Ethanol. AB - Fabrication of multimetallic nanocatalysts with controllable composition remains a challenge for the development of low-cost electrocatalysts, and incorporating metal-based catalysts into active carbon nanoarchitectures represents an emerging strategy to improve the catalytic performance of electrocatalysts. Herein, a facile method developed for Pd nanoparticle (NP)-based multimetallic alloys incorporated on polypyrrole (Ppy) nanofibers by in situ nucleation and growth of NPs using colloidal radiolytic technique is described. Electrochemical measurement suggests that the as-prepared catalysts demonstrate dramatically enhanced electrocatalytic activity for ethanol oxidation in alkaline medium. The ultrasmall Pd30Pt29Au41/Ppy nanohybrids (~8 nm) exhibit excellent electrocatalytic activity, which is ~5.5 times higher than that of its monometallic counterparts (12 A/mg Pd, 5 times higher activity compared to that of Pd/C catalyst). Most importantly, the ternary nanocatalyst shows no obvious change in chemical structure and long-term stability, reflected in the 2% loss in forward current density during 1000 cycles. The superior catalytic activity and durability of the nanohybrids have been achieved due to the formation of Pt-Pd-Au heterojunctions with cooperative action of the three metals in the alloy composition, and the strong interactions between the Ppy nanofiber support with the metal NPs. The facile synthetic approach provides a new generation of polymer supported metal alloy hybrid nanostructures as potential electrocatalysts with superior catalytic activity for fuel cell applications. PMID- 28899090 TI - Synthesis and Sensory Characteristics of Kokumi gamma-[Glu]n-Phe in the Presence of Glutamine and Phenylalanine: Glutaminase from Bacillus amyloliquefaciens or Aspergillus oryzae as the Catalyst. AB - The transpeptidase activity of glutaminase from Bacillus amyloliquefaciens (GBA) and Aspergillus oryzae (GAO) to yield gamma-[Glu]n-Phe peptides were verified for the first time. In the presence of Gln and Phe, gamma-Glu-Phe and gamma-Glu-gamma Glu-Phe were synthesized by GAO, and gamma-Glu-Phe, gamma-Glu-gamma-Glu-Phe, gamma-Glu-gamma-Glu-gamma-Glu-Phe, gamma-Glu-gamma-Glu-gamma-Glu-gamma-Glu-Phe, and gamma-Glu-gamma-Glu-gamma-Glu-gamma-Glu-gamma-Glu-Phe were synthesized by GBA. The Km values for the transpeptidation catalyzed by GBA and GAO were 47.88 and 153.92 mM (Phe as the acceptor), 84.89 and 236.47 mM (gamma-Glu-Phe as the acceptor), indicating that GBA had a greater affinity than GAO for Phe and gamma Glu-Phe in the transpeptidation reaction. The Km values for the transpeptidation catalyzed by GBA against acceptors, Phe and gamma-[Glu](1<=n<5)-Phe (47.88-206.47 mM), increased with an elevated number of gamma-glutamyl residue within the acceptor. The optimal conditions for gamma-[Glu]n-Phe synthesis were pH 10 and 37 degrees C for 3 h, 300 mM Gln, 100 mM Phe, 0.05 U/mL GBA. All the gamma [Glu](1<=n<=5)-Phe exhibited astringency in water and imparted a kokumi taste to commercial soy sauce and model chicken broth. The astringent threshold values (2.5-3.92 mM) were approximately 3-fold of the kokumi threshold concentrations (0.78-1.53 mM). gamma-[Glu]n-Phe or the post-enzymatic reaction mixture enhanced the umami intensity of commercial soy sauce and model chicken broth. PMID- 28899091 TI - Thermodynamic Origin of Multilayer Structures in Langmuir Polymer Films. AB - The emergence of polymer-free water surface in a Langmuir polymer film at conditions where a homogeneous coverage has been expected previously is explained on the basis of the surface tensions of polymer and water, gammapv and gammawv, respectively, as well as the interfacial tension between the two materials, gammapw. The polymer molecules considered are 22-residue poly(gamma-benzyl-l glutamate) (PBLG) peptides in alpha-helical conformation. Values for gammapv and gammapw derived from MD simulations are consistent with values inferred from experiments considering the emergence of polymer-free surface area for ultrathin films studied using the surface forces apparatus in earlier work. Based on these surface properties, the behavior of individual PBLG peptides at the air-water interface, the dimerization of PBLG peptides, the equilibrium height and width of fibers with given cross section, and the lateral fusion of fibers are described. We show that a prerequisite for the emergence of multilayer structures, which appear locally in domains of sizes of tens to hundreds of micrometers in the considered Langmuir polymer film, is that the condition gammapv + gammapw - gammawv > 0 holds true. PMID- 28899092 TI - Spatiotemporal Organization of Catalysts Driven by Enhanced Diffusion. AB - Recently, both microfluidic and fluorescence correlation spectroscopy experiments have revealed that diffusion coefficients of active biological catalysts (enzymes) rise proportionately to their catalytic rate. Similar effects have also been observed for active material catalysts, such as platinum nanocatalysts in hydrogen peroxide solution. While differences in diffusion coefficients have recently been cleverly exploited to spatially separate active from inactive catalysts, here we investigate the consequences of these novel findings on the spatiotemporal organization of catalysts. In particular, we show that chemical reactions-such as coupled catalytic reactions-may drive effective attraction or repulsion between catalysts which in turn drives their spatiotemporal organization. This, we argue, may have implications for internal cell signaling. PMID- 28899093 TI - Investigation of Dioscorea bulbifera Rhizome-Induced Hepatotoxicity in Rats by a Multisample Integrated Metabolomics Approach. AB - The use of herbal medicines continues to expand globally, meanwhile, herb associated hepatotoxicity is becoming a safety issue. As a conventional Chinese medicinal herb, Dioscorea bulbifera rhizome (DBR) has been documented to cause hepatic toxicity. However, the exact underlying mechanism remains largely unexplored. In the present study, we aimed to profile entire endogenous metabolites in a biological system using a multisample integrated metabolomics strategy. Our findings offered additional insights into the molecular mechanism of the DBR-induced hepatotoxicity. We identified different metabolites from rat plasma, urine, and feces by employing gas chromatography-mass spectrometry in combination with multivariate analysis. In total, 55 metabolites distributed in 33 metabolic pathways were identified as being significantly altered in DBR treated rats. Correlation network analysis revealed that the hub metabolites of hepatotoxicity were mainly associated with amino acid, bile acid, purine, pyrimidine, lipid, and energy metabolism. As such, DBR affected the physiological and biological functions of liver via the regulation of multiple metabolic pathways to an abnormal state. Notably, our findings also demonstrated that the multisample integrated metabolomics strategy has a great potential to identify more biomarkers and pathways in order to elucidate the mechanistic complexity of toxicity of traditional Chinese medicine. PMID- 28899094 TI - Solvent Entropy Contributions to Catalytic Activity in Designed and Optimized Kemp Eliminases. AB - We analyze the role of solvation for enzymatic catalysis in two distinct, artificially designed Kemp Eliminases, KE07 and KE70, and mutated variants that were optimized by laboratory directed evolution. Using a spatially resolved analysis of hydration patterns, intermolecular vibrations, and local solvent entropies, we identify distinct classes of hydration water and follow their changes upon substrate binding and transition state formation for the designed KE07 and KE70 enzymes and their evolved variants. We observe that differences in hydration of the enzymatic systems are concentrated in the active site and undergo significant changes during substrate recruitment. For KE07, directed evolution reduces variations in the hydration of the polar catalytic center upon substrate binding, preserving strong protein-water interactions, while the evolved enzyme variant of KE70 features a more hydrophobic reaction center for which the expulsion of low-entropy water molecules upon substrate binding is substantially enhanced. While our analysis indicates a system-dependent role of solvation for the substrate binding process, we identify more subtle changes in solvation for the transition state formation, which are less affected by directed evolution. PMID- 28899095 TI - Nanodrops of Discotic Liquid Crystals: A Monte Carlo Study. AB - We study the morphologies of nematic nanodrops in a vapor of a discotic nematogen by Monte Carlo simulations. The fluid interactions are modeled by a Gay-Berne model with molecular elongations of kappa = 0.3 and 0.5 and different values of the energy anisotropy parameter kappa' in the range of temperature T in which the nematic coexists with a vapor phase. We considered nanodrops of N = 4000 and 32 000 particles. For kappa > kappa', we observe that nanodrops are quite spherical (even for N = 4000 nanodrops), with a homogeneous director field for kappa = 0.3 and a bipolar nematic configuration with tangential anchoring for kappa = 0.5. By increasing the value of kappa', nanodrops change from spherical to lens-shaped for kappa = 0.3, and for kappa = 0.5, spherical nanodrops with homeotropic anchoring and a disclination ring located on its equatorial plane are observed. Although no radial nanodrops are observed, isotropic liquid nanodrops with a paranematic shell and radial texture are observed for temperatures slightly above the vapor-isotropic-nematic triple point when the vapor-isotropic interface is completely wet by the nematic phase. PMID- 28899096 TI - Physical, Rheological, Functional, and Film Properties of a Novel Emulsifier: Frost Grape Polysaccharide from Vitis riparia Michx. AB - A novel emulsifier, Frost grape polysaccharide (FGP), isolated from natural exudate of the species Vitis riparia Michx, was physically and rheologically characterized. The determination of the physical, structural, thermodynamic, emulsification, film, and rheological properties of FGP provide essential details for the commercial adoption of this novel plant polysaccharide. FGP is capable of producing exceptionally stable emulsions when compared with the industrially ubiquitous gum arabic (GA). The FGP isolate contained a negligible amount of nitrogen (0.03%), indicating that it does not contain an associated glycoprotein, unlike GA. Solutions of FGP have a high degree of thermostability, displaying no loss in viscosity with temperature cycling and no thermal degradation when held at 90 degrees C. FGP is an excellent film former, producing high tensile strength films which remain intact at temperatures up to 200 degrees C. This work identified a number of potential food and pharmaceutical applications where FGP is significantly superior to GA. PMID- 28899097 TI - Optically Assisted Surface Functionalization for Protein Arraying in Aqueous Media. AB - Protein surface patterning is employed in a broad spectrum of applications ranging from protein microarray analysis to 2D cell organization. However, limitations arise because of the highly sensitive nature of proteins requiring careful handling to ensure their structural and functional integrity during the grafting process. Here, we describe a patterning protocol that keeps proteins in an aqueous environment during their immobilization, avoiding the loss of their biological activity. The procedure is based on the UV-mediated removal of polyethylene glycol self-assembled monolayers in a transparent microfluidic chamber, giving access to micrometric motifs of predefined geometries. Afterward, modified proteins can be grafted on the photopatterned domains. We also studied the influence of reactive oxygen species for a better understanding of the chemical mechanism involved in this process. Finally, as a proof of concept, a protein microarray was created with this process using cell-capturing antibodies to immobilize human blood cells, confirming the functionality of the arrayed proteins. PMID- 28899098 TI - Heterodimers Made of Upconversion Nanoparticles and Metal-Organic Frameworks. AB - Creating nanoparticle dimers has attracted extensive interest. However, it still remains a great challenge to synthesize heterodimers with asymmetric compositions and synergistically enhanced functions. In this work, we report the synthesis of high quality heterodimers composed of porphyrinic nanoscale metal-organic frameworks (nMOF) and lanthanide-doped upconversion nanoparticles (UCNPs). Due to the dual optical properties inherited from individual nanoparticles and their interactions, absorption of low energy photons by the UCNPs is followed by energy transfer to the nMOFs, which then undergo activation of porphyrins to generate singlet oxygen. Furthermore, the strategy enables the synthesis of heterodimers with tunable UCNP size and dual NIR light harvesting functionality. We demonstrated that the hybrid architectures represent a promising platform to combine NIR-induced photodynamic therapy and chemotherapy for efficient cancer treatment. We believe that such heterodimers are capable of expanding their potential for applications in solar cells, photocatalysis, and nanomedicine. PMID- 28899099 TI - Accurately Modeling the Conformational Preferences of Nucleosides. AB - Sugar puckering of nucleosides impacts nucleic acid structures; hence their biological function. Similarly, nucleoside-based therapeutics may adopt different conformations affecting their binding affinity, DNA incorporation, and excision rates. As a result, significant efforts have been made to develop nucleoside analogues adopting specific conformations to improve bioactivity and pharmacokinetic profiles of the corresponding nucleoside-containing drugs. Understanding and ultimately predicting these conformational preferences would significantly help in the design of more effective structures. We report herein a computational study based on hybrid QM/MM umbrella sampling simulations that allow the accurate prediction of the sugar conformational preferences of chemically modified nucleosides in solution. Moreover, we pair these simulations with natural bond orbital (NBO) analysis to gain key insights into the role of substituents in the conformational preferences of these nucleosides. PMID- 28899100 TI - Rust and Thinning Management Effect on Cup Quality and Plant Performance for Two Cultivars of Coffea arabica L. AB - Beverage quality is a complex attribute of coffee ( Coffea arabica L.). Genotype (G), environment (E), management (M), postharvest processing, and roasting are all involved. However, little is known about how G * M interactions influence beverage quality. We investigated how yield and coffee leaf rust (CLR) disease (caused by Hemileia vastatrix Berk. et Br.) management affect cup quality and plant performance, in two coffee cultivars. Sensory and chemical analyses revealed that 10 of 70 attributes and 18 of 154 chemical volatile compounds were significantly affected by G and M. Remarkably, acetaminophen was found for the first time in roasted coffee and in higher concentrations under more stressful conditions. A principal component analysis described 87% of the variation in quality and plant overall performance. This study is a first step in understanding the complexity of the physiological, metabolic, and molecular changes in coffee production, which will be useful for the improvement of coffee cultivars. PMID- 28899101 TI - Retention of qualified healthcare workers in rural Senegal: lessons learned from a qualitative study. AB - INTRODUCTION: Deployment and retention of a sufficient number of skilled and motivated human resources for health (HRH) at the right place and at the right time are critical to ensure people's right to access a universal quality of health care. Vision Tokyo 2010 Network, an international network of HRH managers at the ministry of health (MoH) level in nine Francophone African countries, identified maldistribution of a limited number of healthcare personnel and their retention in rural areas as overarching problems in the member countries. The network conducted this study in Senegal to identify the determining factors for the retention of qualified HRH in rural areas, and to explore an effective and feasible policy that the MoH could implement in the member countries. METHODS: Doctors, nurses, midwives and superior technicians in anesthesiology who were currently working (1) in a rural area and had been for more than 2 years, (2) in Dakar with experience of working in a rural area or (3) in Dakar without any prior experience working in a rural area were interviewed about their willingness and reasons for accepting work or continuing to work in a rural area and their suggested policies for deployment and retention of healthcare workers in rural areas. In-depth interviews were conducted with policy makers in MoH, asking for their perceptions on human resource management in health and about their suggested policies for deployment and retention. RESULTS: A total of 176 healthcare workers and eight policy makers were interviewed. The willingness to face challenges in a new place was one of the main reasons for accepting work in rural areas. The identified factors to motivate or demotivate healthcare workers in rural areas were related to pre-service and in-service education, regulatory systems, financial and non-financial incentive schemes and environmental support. Factors not included in WHO's global recommendation but highly valued in this study were (1) the fairness, transparency and predictability of human resource management by the MoH and (2) employment status, ie permanent government staff versus contract staff. Financial incentive schemes were less commonly suggested. Family bonding and religious-related non-financial incentive schemes were found to be specific factors in Senegal, but would also be applicable in countries where family and religion play important roles in the values of healthcare workers. CONCLUSIONS: Improved HRH management, eg the transparency of human resource management by the MoH, was identified as a pre-condition of any policy implementation related to HRH. This factor can be considered in other countries struggling to retain healthcare workers in rural areas. The Vision Tokyo 2010 Network or HRH managers' network in Francophone Africa, Senegal MoH and the research team plan to conduct a quantitative survey to confirm the generalizability of the results of this qualitative survey, and to identify the most effective combination of policies to improve the retention of qualified healthcare workers and seek their implementation in other countries in the region as network activities. PMID- 28899102 TI - Community Based Antiretroviral Treatment in Rural Zimbabwe. AB - Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance. PMID- 28899103 TI - drFrnE Represents a Hitherto Unknown Class of Eubacterial Cytoplasmic Disulfide Oxido-Reductases. AB - AIMS: Living cells employ thioredoxin and glutaredoxin disulfide oxido-reductases to protect thiol groups in intracellular proteins. FrnE protein of Deinococcus radiodurans (drFrnE) is a disulfide oxido-reductase that is induced in response to Cd2+ exposure and is involved in cadmium and radiation tolerance. The aim of this study is to probe structure, function, and cellular localization of FrnE class of proteins. RESULTS: Here, we show drFrnE as a novel cytoplasmic oxido reductase that could be functional in eubacteria under conditions where thioredoxin/glutaredoxin systems are inhibited or absent. Crystal structure analysis of drFrnE reveals thioredoxin fold with an alpha helical insertion domain and a unique, flexible, and functionally important C-terminal tail. The C tail harbors a novel 239-CX4C-244 motif that interacts with the active site 22 CXXC-25 motif. Crystal structures with different active site redox states, including mixed disulfide (Cys22-Cys244), are reported here. The biochemical data show that 239-CX4C-244 motif channels electrons to the active site cysteines. drFrnE is more stable in the oxidized form, compared with the reduced form, supporting its role as a disulfide reductase. Using bioinformatics analysis and fluorescence microscopy, we show cytoplasmic localization of drFrnE. We have found "true" orthologs of drFrnE in several eubacterial phyla and, interestingly, all these groups apparently lack a functional glutaredoxin system. Innovation and Conclusion: We show that drFrnE represents a new class of hitherto unknown intracellular oxido-reductases that are abundantly present in eubacteria. Unlike other well-known oxido-reductases, FrnE harbors an additional dithiol motif that acts as a conduit to channel electrons to the active site during catalytic turnover. Antioxid. Redox Signal. 28, 296-310. PMID- 28899104 TI - Therapeutic Vaccine Against HIV, Viral Variability, Cytotoxic T Lymphocyte Epitopes, and Genetics of Patients. AB - The scientific and medical community is seeking to cure HIV. Several pathways have been or are being explored including therapeutic vaccination. Viroimmunological studies on primary infection as well as on elite controllers have demonstrated the importance of the cytotoxic CD8 response and have mainly oriented research on vaccine constructs toward this type of response. The results of these trials are clearly not commensurate with the hope placed in them. Might there be one or more uncontrolled variables? The genetics of patients need to be taken into consideration, especially their human lymphocyte antigen (HLA) alleles. There is a need to find a balance between the conservation of cytotoxic T lymphocyte (CTL) epitopes and presentation by HLA alleles. The pathway is a narrow one between adaptation of the virus to HLA I restriction and the definition of conserved proviral CTL epitopes presentable by HLA I alleles. It is likely that the genetics of patients will need to be considered for HIV-1 vaccine studies and that multidisciplinary collaboration will be essential in this field of infectious diseases. PMID- 28899107 TI - It's About Time: Temporality in Analysis. PMID- 28899110 TI - Unpleasant Business: Rat, Jew, Payment, and Covenant in Freud's RAT Man. AB - Freud's repression of Judaism and its cultural markers from the published "Rat Man" case history has been noted but never satisfactorily explained. This elision can be interpreted using Freud's suggestion that the paradigmatic "rat" represents (among other things) a circumcised penis marking an intergenerational, covenantal exchange. When read against the case study as originally published, Freud's process notes for the Rat Man's treatment (the only set of such notes on a published case that Freud didn't destroy) suggest that Freud chose to sanitize the published version of explicitly Jewish content, thus repeating a pattern of absence as a marker of debt. This debt only grows more tortuous and powerful the longer it remains unpaid. This system of elision in the Rat Man suggests that Freud understood deferral and denial to be built into the Jewish system of piety. Thus, it would seem that Freud used the Rat Man case history to explore Judaism through its repression; Freud's relation to and interpretation of Jewish values are revealed as a primary, if unconscious, subject of the text. PMID- 28899105 TI - A Summary of the Second Annual HIV Microbiome Workshop. AB - Commensal organisms appear to play significant roles in normal homeostasis as well as in the pathogenesis of HIV infection in a number of different organ systems. On November 17th and 18th, 2016, leading researchers from around the world met to discuss their insights on advances in our understanding of HIV and the microbiome at the National Institutes of Health (NIH) in Bethesda. Dr. Elhanan Borenstein of the University of Washington gave a keynote address where he discussed new developments in systems biology which hold the promise of illuminating the pathways by which these organisms interact with human physiology. He suggested that we need to get past correlations in microbiome research by using models and informatics which incorporate metagenomics to predict functional changes in the microbiome. PMID- 28899111 TI - Reconstruction in A Two-Person World May Be More About The Present Than The Past: Freud and The Wolf Man, an Illustration. AB - The psychoanalytic process of reconstruction has yet to be examined from the perspective of today's two-person psychologies. Earlier writers on the subject have implicated the analyst and his emotional involvement as influences that may distort the valid recovery of memories, while others have written that the transference and the reconstructed past are interdependent. By contrast with both views, it is suggested here that the reconstructed product itself may reflect the transference-countertransference engagement of the dyad: in some instances, and to some extent in all instances, the scene or story of the presumed past will be a version of the current analytic relationship. In certain cases consideration of the conscious and unconscious emotional entanglements of the dyad will reveal that the reconstruction says more about the analytic present than about the past. Freud's Wolf Man case provides a good illustration of this point. While a broad consensus exists that its famous primal scene reconstruction cannot be veridical, it has most often been dismissed as distorted by Freud's theoretical commitments. A closer examination of the relationship between Freud and Pankejeff reveals that the reconstruction is an accurate rendering of warded-off aspects of the dyad's way of being together. The potential clinical utility of adopting this perspective is that it encourages the analyst to reflect on his clinical reconstructions, interrogating them for clues to otherwise elusive aspects of the current clinical relationship. PMID- 28899112 TI - Response To Commentaries. PMID- 28899113 TI - Open-mouthed and Wide-eyed: Psychoanalytic Reflections on Curiosity. PMID- 28899121 TI - Unconscious Fantasy and The Priming Phenomenon. AB - This paper is the third in a series of investigations into (1) the nature and development of unconscious fantasy, (2) its place in a contemporary model of mind that, parenthetically, suggests a possible solution to the problem of theoretical pluralism, and (3) its mode of operation in the mind. The aim of these investigations is to update the notion of unconscious fantasy, an indispensable construct in psychoanalytic theories that assume out-of-awareness mentation, and to situate that construct within contemporary views of mental functioning in disciplines such as philosophy of mind, cognitive science, and developmental psychology. At the same time, data accessible only through psychoanalytic work challenge these fields with findings that indicate the need for further investigation. This paper argues that experimental evidence on the phenomenon of "priming" lends support to one of the seminal claims in our field, one frequently attacked as an outmoded shibboleth: that is, that the past matters, whether encoded in declarative or in procedural memory. In common parlance, we are "primed" to respond to some situations in predetermined ways; the past primes us to experience the present in often unique and personal ways. There is evidence too that the priming mechanism and the encoding of subjective experience in declarative and procedural memory operate from very early in life. PMID- 28899122 TI - The Primitive Edge of Creativity: Destruction and Reparation in Louise Bourgeois's Art. AB - Viewed within the psychic geography of Thomas Ogden's modes of generating and organizing experience, in particular the autistic-contiguous mode, Louise Bourgeois's creative imagination can be seen as originating on what Ogden (1989) has called the primitive edge of experience. This mode, dominated by the sensory, is characterized by chaos, fragmentation, and a loss of boundaries. In dynamic movements between the depressive and the autistic-contiguous positions, between destructive and reparative impulses, Bourgeois transforms experiences of chaos, as well as destructive aggression, into aesthetic order and form, into works of art. She is able to delve into the most elemental and presymbolic modes of psychic experience and artistically harness raw feelings and sensations on what can be called the primitive edge of creativity. PMID- 28899123 TI - Subchondral bone microarchitecture analysis in the proximal tibia at 7-T MRI. AB - Background Bone remodels in response to mechanical loads and osteoporosis results from impaired ability of bone to remodel. Bone microarchitecture analysis provides information on bone quality beyond bone mineral density (BMD). Purpose To compare subchondral bone microarchitecture parameters in the medial and lateral tibia plateau in individuals with and without fragility fractures. Material and Methods Twelve female patients (mean age = 58 +/- 15 years; six with and six without previous fragility fractures) were examined with dual-energy X ray absorptiometry (DXA) and 7-T magnetic resonance imaging (MRI) of the proximal tibia. A transverse high-resolution three-dimensional fast low-angle shot sequence was acquired (0.234 * 0.234 * 1 mm). Digital topological analysis (DTA) was applied to the medial and lateral subchondral bone of the proximal tibia. The following DTA-based bone microarchitecture parameters were assessed: apparent bone volume; trabecular thickness; profile-edge-density (trabecular bone erosion parameter); profile-interior-density (intact trabecular rods parameter); plate-to rod ratio; and erosion index. We compared femoral neck T-scores and bone microarchitecture parameters between patients with and without fragility fracture. Results There was no statistical significant difference in femoral neck T-scores between individuals with and without fracture (-2.4 +/- 0.9 vs. -1.8 +/- 0.7, P = 0.282). Apparent bone volume in the medial compartment was lower in patients with previous fragility fracture (0.295 +/- 0.022 vs. 0.317 +/- 0.009; P = 0.016). Profile-edge-density, a trabecular bone erosion parameter, was higher in patients with previous fragility fracture in the medial (0.008 +/- 0.003 vs. 0.005 +/- 0.001) and lateral compartment (0.008 +/- 0.002 vs. 0.005 +/- 0.001); both P = 0.025. Other DTA parameters did not differ between groups. Conclusion 7 T MRI and DTA permit detection of subtle changes in subchondral bone quality when differences in BMD are not evident. PMID- 28899124 TI - Apparent diffusion coefficient (ADC) does not correlate with different serological parameters in myositis and myopathy. AB - Background Magnetic resonance imaging (MRI) is widely used in several muscle disorders. Diffusion-weighted imaging (DWI) is an imaging modality, which can reflect microstructural tissue composition. The apparent diffusion coefficient (ADC) is used to quantify the random motion of water molecules in tissue. Purpose To investigate ADC values in patients with myositis and non-inflammatory myopathy and to analyze possible associations between ADC and laboratory parameters in these patients. Material and Methods Overall, 17 patients with several myositis entities, eight patients with non-inflammatory myopathies, and nine patients without muscle disorder as a control group were included in the study (mean age = 55.3 +/- 14.3 years). The diagnosis was confirmed by histopathology in every case. DWI was obtained in a 1.5-T scanner using two b-values: 0 and 1000 s/mm2. In all patients, the blood sample was acquired within three days to the MRI. The following serological parameters were estimated: C-reactive protein, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and myoglobine. Results The estimated mean ADC value for the myositis group was 1.89 +/- 0.37 * 10-3 mm2/s and for the non-inflammatory myopathy group was 1.79 +/- 0.33 * 10-3 mm2/s, respectively. The mean ADC values (1.15 +/- 0.37 * 10-3 mm2/s) were significantly higher to unaffected muscles (vs. myositis P = 0.0002 and vs. myopathy P = 0.0021). There were no significant correlations between serological parameters and ADC values. Conclusion Affected muscles showed statistically significantly higher ADC values than normal muscles. No linear correlations between ADC and serological parameters were identified. PMID- 28899125 TI - Reduction of metal artifacts from unilateral hip arthroplasty on dual-energy CT with metal artifact reduction software. AB - Background The evaluation of hip arthroplasty is a challenge in computed tomography (CT). The virtual monochromatic spectral (VMS) images with metal artifact reduction software (MARs) in spectral CT can reduce the artifacts and improve the image quality. Purpose To evaluate the effects of VMS images and MARs for metal artifact reduction in patients with unilateral hip arthroplasty. Material and Methods Thirty-five patients underwent dual-energy CT. Four sets of VMS images without MARs and four sets of VMS images with MARs were obtained. Artifact index (AI), CT number, and SD value were assessed at the periprosthetic region and the pelvic organs. The scores of two observers for different images and the inter-observer agreement were evaluated. Results The AIs in 120 and 140 keV images were significantly lower than those in 80 and 100 keV images. The AIs of the periprosthetic region in VMS images with MARs were significantly lower than those in VMS images without MARs, while the AIs of pelvic organs were not significantly different. VMS images with MARs improved the accuracy of CT numbers for the periprosthetic region. The inter-observer agreements were good for all the images. VMS images with MARs at 120 and 140 keV had higher subjective scores and could improve the image quality, leading to reliable diagnosis of prosthesis related problems. Conclusion VMS images with MARs at 120 and 140 keV could significantly reduce the artifacts from hip arthroplasty and improve the image quality at the periprosthetic region but had no obvious advantage for pelvic organs. PMID- 28899127 TI - Invited Readers 2016. PMID- 28899126 TI - Impact of region of interest (ROI) size on the diagnostic performance of shear wave elastography in differentiating solid breast lesions. AB - Background Shear wave elastography (SWE) using a region of interest (ROI) can demonstrate the quantitative elasticity of breast lesions. Purpose To prospectively evaluate the impact of two different ROI sizes on the diagnostic performance of SWE for differentiating benign and malignant breast lesions. Material and Methods A total of 154 breast lesions were included. Two types of ROIs were investigated: one involving an approximately 2-mm diameter, small round ROIs placed over the stiffest area of the lesion, as determined by SWE (ROI-S); and another ROI drawn along the margin of the lesion using a touch pen or track ball to encompass the entire lesion (ROI-M). Maximum elasticity (Emax), mean elasticity (Emean), minimum elasticity (Emin), and standard deviation (SD) were measured for the two ROIs. The area under the receiver operating characteristic curve (AUC) as well as the sensitivity and specificity of each elasticity value were determined. Results The AUCs for ROI-S were higher than those for ROI-M when differentiating benign and malignant breast solid lesions. The Emax, Emean, Emin, and SD of the elasticity values for ROI-S were 0.865, 0.857, 0.816, and 0.849, respectively, and for ROI-M were 0.820, 0.780, 0.724, and 0.837, respectively. However, only Emax ( P = 0.0024) and Emean ( P = 0.0015) showed statistically significant differences. For ROI-S, the sensitivity and specificity of Emax were 78.8% and 84.3%, respectively, and those for Emean were 80.8% and 81.4%, respectively. Conclusion Using ROI-S with Emax and Emean has better diagnostic performance than ROI-M for differentiating between benign and malignant breast lesions. PMID- 28899129 TI - JAPA New Author Prize. PMID- 28899131 TI - How Psychoanalysis Lost the Birthing Body: Commentary on Balsam. PMID- 28899135 TI - Freud, The Birthing Body, and Modern Life. AB - Freud early on had an astute sense of the psychic impact of the bodily power of females' biological sex and childbearing potential. His early appreciation of the biological femaleness of a body, however, became gradually obscured after 1908, distorted by an exaggerated male view that was challenged in the 1920s and 1930s but then became fixed in stone by his followers. This strange but hegemonic view was once again challenged, especially in the U.S., in the 1970s. In spite of sporadic efforts after that, however, the impact of the female body qua female, in analysis and for the mind's functioning, has never been acknowledged in general in psychoanalytic thought (except as marked as an infantile archaic fantasy or sequestered into a special adult "women's issues" category). Given the vibrant culture of enacted gender multiplicities that we encounter clinically today, where does this confused lag in understanding leave us regarding psychoanalytic ideas about natally sexed procreative female (or male) bodies as they articulate with gender? PMID- 28899136 TI - Comings and Goings. PMID- 28899138 TI - Un Homme Manque: Freud's Engagement with Alfred Adler's Masculine Protest: Commentary on Balsam. PMID- 28899137 TI - Reply to Kravis. PMID- 28899139 TI - Moving from Within The Maternal: The Choreography of Analytic Eroticism. AB - With Kristeva's concept of maternal eroticism (2014) as starting point, the "multiverse" of mother/child erotic sensibilities-the dance of the semiotic chora is explored and a parallel engagement proposed within the analytic dyad. The dance of psychoanalysis is not the creative product of the patient's mind alone. Clinical work invites, requires, a choreographic engagement by the clinician in interplay with the patient. The clinician's analytic activity is thus akin to choreography: the structuring of a dance, or of a session, expresses an inner impulse brought into narrative form. The embodied art of dance parallels the clinician's creative vitality in contributing to the shaping of the movement of a session. Through formulation of an analytic eroticism, the terrain of what traditionally has been viewed as erotic transference and countertransference can be expanded to clinical benefit. PMID- 28899141 TI - ????? ?? ??? ?? ??(The Fundamental Rule and Fundamental Value of Psychoanalysis). PMID- 28899140 TI - Exploring Freud's Resistance to The Oceanic Feeling. AB - This paper takes up Romain Rolland's description of a nearly universal "oceanic feeling" and considers Freud's avowed disinterest in this concept. Herman Melville elaborates and expands the concept of the oceanic in the text of Moby Dick, juxtaposing Ishmael's oceanic reverie while up high on the masthead with Ahab's focused determination to destroy Moby Dick. Melville's extension of the concept recasts the oceanic as an aspect of Freud's recommendations about the necessary conditions for psychoanalytic process, inviting a comparison of going to sea with going into analysis. Freud's Civilization and Its Discontents allows for further thoughts about the danger Freud recognizes in this feeling, a way that the oceanic feeling may be an expression of the death instinct. Together, these explorations point in the direction both of a centrality of an oceanic experience in psychoanalysis and a recognition of the risks that the oceanic entails, deepening our understanding of the many reasons Freud might have wished to avoid it. PMID- 28899145 TI - Nathan Kravis on Shulman's "The Analyst's Pleasure". PMID- 28899146 TI - The Critique of Regression: The Person, The Field, The Lifespan. AB - The term regression refers to the idea that a person can return to earlier phases of mental development and the primitive modes of functioning associated with them. A core concept in both conflict and deficit models of development, the idea has nonetheless come under increasing scrutiny from critics who argue that it misleads us into a genetic fallacy whereby we reduce the issues of adolescent and adult development to their childhood precursors. Inderbitzen and Levy (2000) suggest that we focus on transformations, or shifts, in mental organization, instead of on regressions. But discarding the concept of regression has theoretical implications: to adopt instead a focus on shifts in mental organization we must (1) consider our object of study to be the meaning-making person, not isolated instincts or needs; (2) understand conscious and unconscious mental life to be embedded in the here-and-now relational field; and (3) adopt a lifespan model of development. The aim here is to outline a theoretical framework in which we can more fully explore the possibility of discarding "regression" in favor of a focus on transformations in the developmental present. PMID- 28899147 TI - Acknowledging the "Analyst as Person": A Developmental Achievement. PMID- 28899150 TI - Will This Case Count? The Influence of Training on Treatment. AB - Mandated use of the couch-whether specifically stated or tacitly communicated by supervisors and colleagues-to fulfill requirements for graduation or certification is a significant disservice to candidates and their patients. In its training standards, it is argued, APsaA and its member institutes should state explicitly that a treatment can qualify as a psychoanalysis, regardless of whether the patient is using the couch, as long as the process is analytic and the candidate's thinking is demonstrably analytic. The mandate, however conveyed, that one must use the couch interferes with candidates' optimal analytic functioning, jeopardizing their patients' analyses. Data from infant observation, neuroscience, and facial expression studies-unavailable to earlier generations of analysts-support a more nuanced view of use of the couch. Each analysis is unique, and some analyses might well benefit from use of both the couch and the chair at different phases of treatment, but unless this is spelled out by ApsaA and its member institutes, candidates and junior analysts will be prevented from freely contemplating the clinical benefits or detriments of their use in specific cases. PMID- 28899152 TI - Me Here, You There-Now What? Commentary on Kite, Morris, Wilson, and Kattlove. PMID- 28899154 TI - The Analyst's Offer. PMID- 28899157 TI - Don't Fence Me In: What is American About American Psychoanalysis? PMID- 28899155 TI - The Fundamental Ethical Ambiguity of the Analyst as Person. PMID- 28899161 TI - The Ethical Foundation of Analytic Action. PMID- 28899167 TI - University Forum: Revitalizing The South Side of Chicago. PMID- 28899162 TI - High levels of viral suppression among East African HIV-infected women and men in serodiscordant partnerships initiating antiretroviral therapy with high CD4 counts and during pregnancy. AB - BACKGROUND: People who are asymptomatic and feel healthy, including pregnant women, may be less motivated to initiate ART or achieve high adherence. We assessed whether ART initiation, and viral suppression 6, 12 and 24-months after ART initiation, were lower in HIV-infected members of serodiscordant couples who initiated during pregnancy or with higher CD4 counts. METHODS: We used data from the Partners Demonstration Project, an open-label study of the delivery of integrated PrEP and ART (at any CD4 count) for HIV prevention among high-risk HIV serodiscordant couples in Kenya and Uganda. Differences in viral suppression (HIV RNA <400 copies/ml) among people initiating ART at different CD4 count levels (<=350, 351-500, and >500 cells/mm3) and during pregnancy were estimated using Poisson regression. RESULTS: Of 865 HIV-infected participants retained after becoming eligible for ART during study follow-up, 95% initiated ART. Viral suppression 24-months after ART initiation was high overall (97%), and comparable among those initiating ART at CD4 counts >500, 351-500 and <=350 cells/mm3 (96% vs 97% vs 97%; relative risk [RR] 0.98; 95% CI: 0.93-1.03 for CD4 >500 vs <350 and RR 0.99; 95% CI: (0.93-1.06) for CD4 351-500 vs <=350). Viral suppression was as likely among women initiating ART primarily to prevent perinatal transmission as ART initiation for other reasons (p=0.9 at 6 months and p=0.5 at 12 months). CONCLUSIONS: Nearly all HIV-infected partners initiating ART were virally suppressed by 24 months, irrespective of CD4 count or pregnancy status. These findings suggest that people initiating ART at high CD4 counts or due to pregnancy can adhere to ART as well as those starting treatment with symptomatic HIV disease or low CD4 counts. PMID- 28899168 TI - Patients' Illnesses: How They Affect Analysts and The Analytic Work. PMID- 28899170 TI - Freud as an Existential Humanistic Psychotherapist: The Case of Margarethe. PMID- 28899171 TI - Reflections On Mortality: A Patient Faces Death. PMID- 28899173 TI - The Presence of The Analyst in Lacanian Treatment. AB - Transference implies the actualization of the analyst in the analytic encounter. Lacan developed this idea through the syntagm presence of the analyst. In the course of his seminars, however, two completely different presences emerge, with major implications for how the treatment is directed. In the light of Lacan's idea that the transference is constituted in Real, Symbolic, and Imaginary dimensions, it can be seen how in his early work the analyst's presence is a phenomenon at the crossroads between signifiers and images. From the 1960s onward, however, the analyst's presence comes to necessarily involve the Real. This means it points to the moment at which symbolization reaches its limits. The clinical implications of this later interpretation of the presence of the analyst as incorporating the Real are manifold and affect psychoanalytic practice with regard to the position and the interventions of the analyst. Specifically, interventions targeted at provoking changes in defenses against experiences of excess or senselessness are discussed and illustrated with case vignettes and a published case. With transference considered "the navel of the treatment," the necessity that traumatic material will emerge in relation to the analyst becomes clear. PMID- 28899175 TI - Bion's Agony in The Long Week-End. AB - In The Long Week-End Wilfred Bion focuses on his emotional distress during the first twenty-one years of his life. Rarely employing psychoanalytic terminology, he attempts to explore his emotional experience directly, struggling to find a language that could capture the complexity of inner life. Central to The Long Week-End is his desire to communicate how easily he could feel unintelligent, inept, weak, ashamed, guilty, angry, frightened, and cowardly in various settings. This self-criticism at times undermines his theoretical stance in this work, as he emphasizes the importance of doubt and uncertainty when attempting to comprehend most dimensions of experience. PMID- 28899177 TI - ??????? ??? ?????? ???? "??? ??" ??? ????? ?? ?? (Reflections on the Analyst's "Good Enough" Capacity to Bear Disappointment, with Special Attention to Repetition). PMID- 28899180 TI - An Inclusive Psychoanalyst: Sidney Blatt's Contribution In Perspective. AB - Sidney Blatt personified in many ways the striving toward an inclusive, broad minded, nonsectarian, and nondogmatic psychoanalysis. Intrigued and inspired by many trends in psychoanalytic thought and neighboring disciplines, he believed deeply in the coexistence and mutual contributions of a psychoanalytic clinical practice and of systematic empirical research on development and its disruptions, evolving personality traits, and the ways psychoanalytic treatment becomes effective. Carl Rogers, David Rapaport, and John Bowlby were among the figures who played a significant role in the development of his rich and complex thinking and productive work. PMID- 28899182 TI - Cognitive-Humanistic Psychodynamics: Sidney Blatt's Theoretical-Philosophical Legacy. AB - A number of broad-based, theoretical-philosophical tenets are to be gleaned from Sidney Blatt's voluminous, extensive, and unique scholarly work. Dominant themes in Blatt's life and work include (1) his fascination with cognition, particularly mental maps, or representations, of reality; (2) the influence of humanistic values (e.g., agency, need for growth, gestalts, need for balance, and an optimistic focus on resilience); and (3) a steadfast adherence to Freud's revolutionary discovery of the dynamic unconscious. Philosophically speaking, Blatt has left a unique, integrative, and vibrant legacy for the field, one that might be called cognitive-humanistic psychodynamics. PMID- 28899188 TI - Commentary On Brown. PMID- 28899184 TI - The Broken Self: Injured States in The Transference-Countertransference Matrix. AB - Themes of injury and injuredness reverberate throughout the treatment of patients categorized as having disorders of the self. Aspects of the various identifications that these patients may make with clinicians who are visibly physically handicapped from the outset of treatment are explored. Vignettes from psychoanalytically informed psychotherapies conducted at frequencies of up to three times weekly reveal how these identifications are used to externalize a sense of internal psychic impairment and to shed defective introjects in an attempt to preserve a faltering self. Themes of injury and defectiveness resonate throughout the transference-countertransference matrix, leading either to a working through of the injured state or, in unfortunate cases, to the disabling of the treatment itself. Particular attention is paid to patients who reveal during treatment that they were raised by a physically ill or handicapped parent and are therefore particularly vulnerable to castrative or disintegrative anxiety. Implications for the use of the able-bodied clinician by such patients are also considered, as well as the use of the clinician's injuredness by less primitively organized patients. The limitations of these treatments are also addressed. PMID- 28899190 TI - Sidney Blatt's Psychoanalytic Legacy: An Introduction. PMID- 28899191 TI - Mental Representation in The Thought of Sidney Blatt: Developmental Processes. AB - Mental representation was a central construct in Sidney Blatt's contributions to psychology and psychoanalysis. This brief review demonstrates that Blatt's understanding of representation was always informed by basic psychoanalytic concepts like the centrality of early caregiver-infant relationships and of unconscious mental processes. Although Blatt's earlier writings were informed by psychoanalytic ego psychology and Piagetian cognitive developmental psychology, they focused nonetheless on how an individual uses bodily and relational experiences to construct an object world; they also consistently presented object representations as having significant unconscious dimensions. From the mid-1980s onward, Blatt's contributions, in dialogue with his many students, moved in an even more experiential/relational direction and manifested the influence of attachment theory, parent-infant interaction research, and intersubjectivity theory. They also incorporated contemporary cognitive psychology, with its emphasis on implicit or procedural, rather than explicit, dimensions as a means of accounting for aspects of object representations that are not in conscious awareness. Throughout his career, however, Blatt regarded mental representation as the construct that mediates between the child's earliest bodily and relational experiences and the mature adult's symbolic, most emotionally profound capacities. PMID- 28899194 TI - JAPA Prizes for 2016. PMID- 28899196 TI - On Psychic Determinism. AB - A confusion persists in the psychoanalytic literature regarding the concept of psychic determinism. Two authors are cited in whose works the concept is identified as foundational to psychoanalysis, in the one case as a "fundamental hypothesis" (Charles Brenner) and in the other as an "underlying presupposition" or assumption (Linda A.W. Brakel). Both claims are based on a conflation of the concept Freud had in mind with a philosophical doctrine going by the same name but meaning something quite different. The philosophical doctrine has no place in psychoanalysis at all, and Freud's concept does not play a foundational role there. In a second section a restricted concept of psychic determinism is critically examined. A third section deals with the impact of that restricted concept on clinical theory and contemporary controversies about clinical practice. Finally, some possible reasons for this confusion are suggested. PMID- 28899193 TI - Maternal Self-Critical and Dependent Personality Styles and Mother-Infant Communication. AB - This study investigated mother-infant communication in relation to Blatt's measures of adult personality organization, namely, interpersonal relatedness and self-definition, defining the higher ends of these two measures as dependency and self-criticism, respectively. A nonclinical sample of 126 mother-infant dyads provided the data. An evaluation of maternal self-criticism and dependency was made six weeks postpartum; four months postpartum, mother-infant self- and interactive contingencies during face-to-face play were studied and analyzed in conjunction with the earlier evaluation. Self- and interactive contingencies were defined by the predictability within, and between, the behaviors of each partner. This approach assesses the process of relating from moment to moment within a dyad. Self-contingency measures the degree of stability/variability of one person's ongoing rhythms of behavior; interactive contingency measures the likelihood that one person's behavior is influenced by the behavior of the partner. Infant and mother facial affect, gaze, and touch, and infant vocal affect, were coded second by second from split-screen videotape. Maternal self criticism and dependency had strikingly different effects on mother-infant communication. Self-critical mothers showed lowered attention and emotion coordination, staying more "separate" from infants in these realms, compromising infant interactive efficacy. This finding is consistent with Blatt and colleagues' descriptions of self-critical individuals as preoccupied with self definition, compromising relatedness. Dependent mothers and their infants showed reciprocal emotional vigilance, consistent with Blatt and colleague's description of dependent individuals as "empty" and "needy" of emotional supplies from their partner. The study documents that the influence of the mother's personality organization operates through both infant and maternal contributions, a co created process rather than a direct unilateral transmission from mother to infant. PMID- 28899197 TI - Personality, Psychopathology, and Health Through the Lens of Interpersonal Relatedness and Self-Definition. AB - Sidney Blatt's seminal contributions in the domain of personality development, psychopathology, and health rank among the best researched and most empirically supported theories in psychoanalysis. Blatt is known primarily for his two polarities model of personality development, which he viewed as evolving through a dialectical, synergistic interaction between two fundamental processes across the lifespan: the development of interpersonal relatedness on the one hand, and of self-definition on the other. In this model, psychopathology is viewed as an attempt to find a balance, however distorted, between relatedness and self definition. Neurobiological research has confirmed the intrinsic dialectical relationship between these two processes in the development of the neural circuits subserving these capacities, a finding with important implications for physical health. Research relevant to these ideas is reviewed, and the influence that Blatt's approach has had in reintroducing psychodynamic factors into contemporary psychology and psychiatry, as reflected in DSM-5, is discussed. PMID- 28899198 TI - Adaptive immune constraints on C. difficile vaccination. PMID- 28899201 TI - Cross-cultural adaptation, reliability, and validation of the Korean version of the identification functional ankle instability (IdFAI). AB - PURPOSE: To cross-culturally adapt the Identification Functional Ankle Instability for use with Korean-speaking participants. METHODS: The English version of the IdFAI was cross-culturally adapted into Korean based on the guidelines. The psychometric properties in the Korean version of the IdFAI were measured for test-retest reliability, internal consistency, criterion-related validity, discriminative validity, and measurement error 181 native Korean speakers. RESULTS: Intra-class correlation coefficients (ICC2,1) between the English and Korean versions of the IdFAI for test-retest reliability was 0.98 (standard error of measurement = 1.41). The Cronbach's alpha coefficient was 0.89 for the Korean versions of IdFAI. The Korean versions of the IdFAI had a strong correlation with the SF-36 (rs = -0.69, p < .001) and the Korean version of the Cumberland Ankle Instability Tool (rs = -0.65, p < .001). The cutoff score of >10 was the optimal cutoff score to distinguish between the group memberships. The minimally detectable change of the Korean versions of the IdFAI score was 3.91. CONCLUSION: The Korean versions of the IdFAI have shown to be an excellent, reliable, and valid instrument. The Korean versions of the IdFAI can be utilized to assess the presence of Chronic Ankle Instability by researchers and clinicians working among Korean-speaking populations. Implications for rehabilitation The high recurrence rate of sprains may result into Chronic Ankle Instability (CAI). The Identification of Functional Ankle Instability Tool (IdFAI) has been validated and recommended to identify patients with Chronic Ankle Instability (CAI). The Korean version of the Identification of Functional Ankle Instability Tool (IdFAI) may be also recommend to researchers and clinicians for assessing the presence of Chronic Ankle Instability (CAI) in Korean-speaking population. PMID- 28899200 TI - Spoken language and everyday functioning in 5-year-old children using hearing aids or cochlear implants. AB - OBJECTIVE: This study investigated the factors influencing 5-year language, speech and everyday functioning of children with congenital hearing loss. DESIGN: Standardised tests including PLS-4, PPVT-4 and DEAP were directly administered to children. Parent reports on language (CDI) and everyday functioning (PEACH) were collected. Regression analyses were conducted to examine the influence of a range of demographic variables on outcomes. STUDY SAMPLE: Participants were 339 children enrolled in the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study. RESULTS: Children's average receptive and expressive language scores were approximately 1 SD below the mean of typically developing children, and scores on speech production and everyday functioning were more than 1 SD below. Regression models accounted for 70-23% of variance in scores across different tests. Earlier CI switch-on and higher non-verbal ability were associated with better outcomes in most domains. Earlier HA fitting and use of oral communication were associated with better outcomes on directly administered language assessments. Severity of hearing loss and maternal education influenced outcomes of children with HAs. The presence of additional disabilities affected outcomes of children with CIs. CONCLUSIONS: The findings provide strong evidence for the benefits of early HA fitting and early CI for improving children's outcomes. PMID- 28899202 TI - A serial mediation model of workplace social support on work productivity: the role of self-stigma and job tenure self-efficacy in people with severe mental disorders. AB - PURPOSE: Compared to groups with other disabilities, people with a severe mental illness face the greatest stigma and barriers to employment opportunities. This study contributes to the understanding of the relationship between workplace social support and work productivity in people with severe mental illness working in Social Enterprises by taking into account the mediating role of self-stigma and job tenure self-efficacy. METHOD: A total of 170 individuals with a severe mental disorder employed in a Social Enterprise filled out questionnaires assessing personal and work-related variables at Phase-1 (baseline) and Phase-2 (6-month follow-up). Process modeling was used to test for serial mediation. RESULTS: In the Social Enterprise workplace, social support yields better perceptions of work productivity through lower levels of internalized stigma and higher confidence in facing job-related problems. When testing serial multiple mediations, the specific indirect effect of high workplace social support on work productivity through both low internalized stigma and high job tenure self efficacy was significant with a point estimate of 1.01 (95% CI = 0.42, 2.28). CONCLUSIONS: Continued work in this area can provide guidance for organizations in the open labor market addressing the challenges posed by the work integration of people with severe mental illness. Implications for Rehabilitation: Work integration of people with severe mental disorders is difficult because of limited access to supportive and nondiscriminatory workplaces. Social enterprise represents an effective model for supporting people with severe mental disorders to integrate the labor market. In the social enterprise workplace, social support yields better perceptions of work productivity through lower levels of internalized stigma and higher confidence in facing job-related problems. PMID- 28899203 TI - An Overview of the Advantages of KEAP1-NRF2 System Activation During Inflammatory Disease Treatment. AB - SIGNIFICANCE: Inflammation can be defined as a protective immune response against harmful exogenous and endogenous stimuli. Nevertheless, prolonged or autoimmune inflammatory responses are likely to cause pathological states that are associated with a production of inflammation-associated molecules along with reactive oxygen species (ROS). Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) signaling provides a cell protection mechanism against oxidative insults when endogenous stress defense mechanisms are imbalanced. Understanding the roles of the KEAP1-NRF2 system in inflammation caused by various types of stimuli may aid in the development of new therapies. Recent Advances: There have been tremendous advances in understanding the mechanism by which the KEAP1-NRF2 pathway abrogates inflammation. In addition to the well-established ROS-dependent pathway, recent studies have provided evidence of the direct repression of the transcription of pro-inflammatory cytokine genes, such as IL1b and IL6 (encoding Interleukin-1beta and Interleukin-6, respectively). Further, the expanding functions of NRF2 have elicited interest in the development of therapeutic modalities for inflammatory diseases, including multiple sclerosis and sickle cell disease. Critical Issues and Future Directions: Despite progress in the understanding of molecular mechanisms supporting the roles that NRF2 plays during inflammation, the relationship between NRF2 and other transcription factors and mediators of inflammation still remains ambiguous. Further studies are required to address the effects of functional polymorphisms in KEAP1 and NRF2 that modify susceptibility to specific disease-related inflammation. Comprehensive analyses in the future should explore tissue- or cell-type specific NRF2 activation to elaborate effects of NRF2 induction. Antioxid. Redox Signal. 00, 000-000. PMID- 28899199 TI - Transcriptional Regulation by Nrf2. AB - SIGNIFICANCE: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Understanding the regulation of Nrf2 activity and downstream pathways has major implications for human health. Recent Advances: Nrf2 regulates the transcription of components of the glutathione and thioredoxin antioxidant systems, as well as enzymes involved in phase I and phase II detoxification of exogenous and endogenous products, NADPH regeneration, and heme metabolism. It therefore represents a crucial regulator of the cellular defense mechanisms against xenobiotic and oxidative stress. In addition to antioxidant responses, Nrf2 is involved in other cellular processes, such as autophagy, intermediary metabolism, stem cell quiescence, and unfolded protein response. Given the wide range of processes that Nrf2 controls, its activity is tightly regulated at multiple levels. Here, we review the different modes of regulation of Nrf2 activity and the current knowledge of Nrf2-mediated transcriptional control. CRITICAL ISSUES: It is now clear that Nrf2 lies at the center of a complex regulatory network. A full comprehension of the Nrf2 program will require an integrated consideration of all the different factors determining Nrf2 activity. FUTURE DIRECTIONS: Additional computational and experimental studies are needed to obtain a more dynamic global view of Nrf2-mediated gene regulation. In particular, studies comparing how the Nrf2-dependent network changes from a physiological to a pathological condition can provide insight into mechanisms of disease and instruct new treatment strategies. PMID- 28899204 TI - Physical and functional properties of spray-dried powders from blackcurrant juice and extracts obtained from the waste of juice processing. AB - Blackcurrants contain high levels of polyphenolics, particularly flavonols and anthocyanins, which contribute to their high antioxidant activity. The aims of this work were the recovery of bioactive compounds from the remaining solid (waste) after processing blackcurrant juice and to obtain spray-dried powders from the blackcurrant juice and extracts. The extraction of bioactive compounds from the fruit pulp was performed by ultrasound-assisted extraction. Experiments were conducted to select the more suitable solvent, and citric acid was chosen. Then, to optimize the extraction conditions (time, solvent concentration, and amplitude) an experimental design using a Box-Behnken Design was done. Comparing the optimized extract with the fruit, 31% total monomeric anthocyanins, 19% total phenolic compounds, and 10% antioxidant capacity were obtained. The optimized extract and the juice were mixed and spray dried, using maltodextrin as carrier matrix. A blackcurrant powder with low hygroscopicity 14.46 +/- 0.13 (g a.w./100 g d.m) and high solubility 94.25 +/- 4% was obtained. High concentration of bioactive compounds and antioxidant capacity was recorded: Total monomeric anthocyanins 63.01 +/- 1 (mg cyn-3-glu/100 g.d.m), total phenolic content 116.87 +/- 5 (mg gallic acid/100 g d.m.), and antioxidant capacity 144.40 +/- 0.11 (mg eq Trolox/100 g.d.m.). PMID- 28899205 TI - Non-invasive vagus nerve stimulation for the management of refractory primary chronic headaches: A real-world experience. AB - Background Non-invasive vagus nerve stimulation has initial evidence of efficacy in migraine and cluster headache. However, little is known about its role in the management of refractory chronic headaches. Methods We evaluated the preventive and abortive effects of non-invasive vagus nerve stimulation in 41 consecutive patients with refractory primary chronic headaches in an open-label prospective clinical audit. Headache diaries were used to collect clinical information. Those who obtained at least 30% reduction in headache days/episodes after three months of treatment were considered responders and were offered treatment continuation. Results Twenty-three patients with chronic migraine, 12 with chronic cluster headache, four with hemicrania continua and two with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) were treated. Two of 23 chronic migraine patients, one of 12 chronic cluster headache patients, and two of four hemicrania continua patients were considered responders. None of the patients with SUNA benefited from the therapy. Two chronic migraine patients were able to reduce the pain severity of moderate migraines with non-invasive vagus nerve stimulation. Conclusion Non-invasive vagus nerve stimulation may not constitute an effective acute nor preventive treatment in refractory chronic primary headaches. The encouraging effect in hemicrania continua warrants further evaluation in larger studies. PMID- 28899206 TI - Randomized single-blind multicenter trial comparing the effects of standard and augmented acupuncture protocols on sleep quality and depressive symptoms in patients with depression. AB - The study was aimed to compare the effects of standard and augmented acupuncture on depressive symptoms and sleep disturbances in patients with depression. This is a randomized, single-blind, multicenter trial. 140 subjects with clinical insomnia (score of >= 7 on the Pittsburgh Sleep Quality Index (PSQI)) were randomized to the standard (LI4, LIV3, EX-HN3, and GV20) or augmented (LI4, LIV3, EX-HN3, GV20, LU7, and KID6, including intradermal needles for sustained treatment) acupuncture groups. Participants received two sessions weekly for six weeks. In trial, The primary outcomes were improvements in PSQI and the Hamilton Rating Scale (HAMD). Secondary outcomes were treatment credibility and adverse events. Outcomes were assessed at baseline, week 3, end of treatment, and 4-week follow-up. From the 105 randomized patients, 89 completed the trial and were included in the final analyses. Better efficacy was observed in the augmented group compared with the standard acupuncture to improve the PSQI and HAMD at week 3, end of treatment, and 4-week follow-up (all p < .05). The HAMD scores improved with time, except between end of treatment and 4-week follow-up, while in the standard group, HAMD scored improved from baseline to week 3, and stopped improving thereafter. The PSQI scores improved with time in the two groups, except between end of treatment and 4-week follow-up. Compared with the standard protocol, the augmented acupuncture protocol had a better efficacy to treat depression and to improve sleep quality of patients with depression. PMID- 28899207 TI - Anti-Fragmentation of Resting-State Functional Magnetic Resonance Imaging Connectivity Networks with Node-Wise Thresholding. AB - Functional magnetic resonance imaging (fMRI)-based functional connectivity networks are often constructed by thresholding a correlation matrix of nodal time courses. In a typical thresholding approach known as hard thresholding, a single threshold is applied to the entire correlation matrix to identify edges representing superthreshold correlations. However, hard thresholding is known to produce a network with uneven allocation of edges, resulting in a fragmented network with a large number of disconnected nodes. It is suggested that an alternative network thresholding approach, node-wise thresholding, is able to overcome these problems. To examine this, various network characteristics were compared between networks constructed by hard thresholding and node-wise thresholding, with publicly available resting-state fMRI data from 123 healthy young subjects. It was found that networks constructed with hard thresholding included a large number of disconnected nodes, while such network fragmentation was not observed in networks formed with node-wise thresholding. Moreover, in hard thresholding networks, fragmentized modular organization was observed, characterized by a large number of small modules. On the contrary, such modular fragmentation was not observed in node-wise thresholding networks, producing modules that were robust at any threshold and highly consistent across subjects. These results indicate that node-wise thresholding may lead to less fragmented networks. Moreover, node-wise thresholding enables robust characterization of network properties without much influence by the selection of a threshold. PMID- 28899208 TI - The Regulation of NRF2 by Nutrient-Responsive Signaling and Its Role in Anabolic Cancer Metabolism. AB - SIGNIFICANCE: The stress responsive transcription factor nuclear factor erythroid 2 p45-related factor 2, or NRF2, regulates the expression of many cytoprotective enzymes to mitigate oxidative stress under physiological conditions. NRF2 is activated in response to oxidative stress, growth factor signaling, and changes in nutrient status. In addition, somatic mutations that disrupt the interaction between NRF2 and its negative regulator Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated 1 (KEAP1) commonly occur in cancer and are thought to promote tumorigenesis. Recent Advances: While it is well established that aberrant NRF2 activation results in enhanced antioxidant capacity in cancer cells, recent exciting findings demonstrate a role for NRF2-mediated metabolic deregulation that supports cancer cell proliferation. CRITICAL ISSUES: In this review, we describe how the NRF2-KEAP1 signaling pathway is altered in cancer, how NRF2 is regulated by changes in cellular metabolism, and how NRF2 reprograms cellular metabolism to support proliferation. FUTURE DIRECTIONS: Future studies will delineate the NRF2-regulated processes critical for metabolic adaptation to nutrient availability, cellular proliferation, and tumorigenesis. Antioxid. Redox Signal. 00, 000-000. PMID- 28899209 TI - Microneedle-mediated transdermal delivery of nanostructured lipid carriers for alkaloids from Aconitum sinomontanum. AB - A combination method using microneedle (MN) pretreatment and nanostructured lipid carriers (NLCs) was developed to improve the transdermal delivery of therapeutics. The MN treatment of the skin and co-administration of NLCs loaded with total alkaloids isolated from Aconitum sinomontanum (AAS-NLCs) significantly increased the skin permeation of the drugs. Fluorescence imaging confirmed that MNs could provide microchannels penetrating the stratum corneum, and delivery of NLCs through the channels led to their deeper permeation. In vivo studies showed that combination of AAS-NLCs with MNs (AAS-NLCs-MN) in transdermal delivery could improve the bioavailability and maintain stable drug concentrations in the blood. Moreover, AAS-NLCs-MN showed benefits in eliminating paw swelling, decreasing inflammation and pain, and regulating immune function in adjuvant arthritis rats. After administration of AAS-NLCs-MN, no skin irritation was observed in rabbits, and electrocardiograms of rats showed improved arrhythmia. These results indicated that the dual approach combining MN insertion and NLCs has the potential to provide safe transdermal delivery and to improve the therapeutic efficacy through sustained release of AAS. PMID- 28899210 TI - Competitive action video game players display rightward error bias during on-line video game play. AB - Research in asymmetrical visuospatial attention has identified a leftward bias in the general population across a variety of measures including visual attention and line-bisection tasks. In addition, increases in rightward collisions, or bumping, during visuospatial navigation tasks have been demonstrated in real world and virtual environments. However, little research has investigated these biases beyond the laboratory. The present study uses a semi-naturalistic approach and the online video game streaming service Twitch to examine navigational errors and assaults as skilled action video game players (n = 60) compete in Counter Strike: Global Offensive. This study showed a significant rightward bias in both fatal assaults and navigational errors. Analysis using the in-game ranking system as a measure of skill failed to show a relationship between bias and skill. These results suggest that a leftward visuospatial bias may exist in skilled players during online video game play. However, the present study was unable to account for some factors such as environmental symmetry and player handedness. In conclusion, video game streaming is a promising method for behavioural research in the future, however further study is required before one can determine whether these results are an artefact of the method applied, or representative of a genuine rightward bias. PMID- 28899211 TI - Factorial Validity of the Movement Assessment Battery for Children-2nd Edition (MABC-2) in 7-16-Year-Olds. AB - The Movement Assessment Battery for Children-2nd Edition (MABC-2) is a test of motor development, widely used in clinical and research settings. To address which motor abilities are actually captured by the motor tasks in the two age versions of the MABC-2, the AB2 for 7- 10-year-olds and the AB3 for 11- 16-year olds, we examined AB2 and AB3 factorial validity. We conducted confirmatory factor analysis (SPSS AMOS 22.0) on data from the test's standardization samples of children aged 7-10, n = 483, and 11-16, n = 674, in order to find the best fitting models. The covariance matrix of AB2 and AB3 fit a three-factor model that included tasks of manual dexterity, aiming and catching, and balance. However, factor analytic models fitting AB2 and AB3 did not involve the dynamic balance tasks of hopping with the better leg and hopping with the other leg; and the drawing trail showed very low factor validity. In sum, both AB2 and AB3 of the MABC-2 test are able to discriminate between the three specific motor abilities; but due to questionable psychometric quality, the drawing trail and hopping tasks should be modified to improve the construct validity for both age versions of the MABC-2. PMID- 28899212 TI - This Issue Has Titles and Abstracts in English and French. PMID- 28899213 TI - Serum paraoxonase activity in patients with ischaemic and nonischaemic dilated cardiomyopathy. AB - BACKGROUND: This study examined whether the serum PON1 activity is different in patients with ischaemic dilated cardiomyopathy (IDCM) and nonischaemic dilated cardiomyopathy (NDCM) and the relation between the serum PON1 activity and serum pro-BNP levels. METHODS AND RESULTS: In this study, we enrolled 60 patients with left ventricular systolic failure (New York Heart Association [NYHA] class III IV) and a left ventricular ejection fraction (EF) < 40% as determined by echocardiography and 30 healthy subjects. The patients with systolic heart failure were divided into two groups: patients with IDCM and patients with NDCM. Blood samples were obtained to measure the serum PON1 activity and the serum pro BNP levels. The median serum PON1 activities were lower among the patients with IDCM or with NDCM compared with the control subjects (p < .001, p = .043, respectively). Compared with the control subjects, the patients with IDCM or with NDCM had higher serum pro-BNP levels (p < .001, p < .001, respectively). The serum PON1 activity was negatively correlated with the serum pro-BNP levels in patients with IDCM (r = -0.548, p < .001). The area under the ROC curve of the serum PON1 activity was 0.798. Using a serum PON1 activity of 201.3 U/L as a cut off value, the sensitivity was 86.84% and specificity was 66.67% for the diagnosis of IDCM. CONCLUSIONS: In this study, the serum PON1 activity was significantly reduced in the patients with IDCM or with NDCM compared with the control subjects. The serum PON1 activity of the patients with IDCM was negatively correlated with the serum pro-BNP levels. PMID- 28899214 TI - Assaulted and Unheard: Violence Against Healthcare Staff. AB - Healthcare workers regularly face the risk of violent physical, sexual, and verbal assault from their patients. To explore this phenomenon, a collaborative descriptive qualitative study was undertaken by university-affiliated researchers and a union council representing registered practical nurses, personal support workers, and other healthcare staff in Ontario, Canada. A total of fifty-four healthcare workers from diverse communities were consulted about their experiences and ideas. They described violence-related physical, psychological, interpersonal, and financial effects. They put forward such ideas for prevention strategies as increased staffing, enhanced security, personal alarms, building design changes, "zero tolerance" policies, simplified reporting, using the criminal justice system, better training, and flagging. They reported such barriers to eliminating risks as the normalization of violence; underreporting; lack of respect from patients, visitors, higher status professionals, and supervisors; poor communication; and the threat of reprisal for speaking publicly. Inadequate postincident psychological and financial support compounded their distress. PMID- 28899215 TI - Effect of lysine succinylation on the regulation of 2-oxoglutarate dehydrogenase inhibitor, OdhI, involved in glutamate production in Corynebacterium glutamicum. AB - In Corynebacterium glutamicum, the activity of the 2-oxoglutarate dehydrogenase (ODH) complex is negatively regulated by the unphosphorylated form of OdhI protein, which is critical for L-glutamate overproduction. We examined the potential impact of protein acylation at lysine (K)-132 of OdhI in C. glutamicum ATCC13032. The K132E succinylation-mimic mutation reduced the ability of OdhI to bind OdhA, the catalytic subunit of the ODH complex, which reduced the inhibition of ODH activity. In vitro succinylation of OdhI protein also reduced the ability to inhibit ODH, and the K132R mutation blocked the effect. These results suggest that succinylation at K132 may attenuate the OdhI function. Consistent with these results, the C. glutamicum mutant strain with OdhI-K132E showed decreased L glutamate production. Our results indicated that not only phosphorylation but also succinylation of OdhI protein may regulate L-glutamate production in C. glutamicum. PMID- 28899216 TI - A little bit of science. PMID- 28899217 TI - 'The psychological problem is looking at you, are you looking for it?': psychological associations with symptomatic musculoskeletal referrals. AB - It is important that paediatric orthopaedic surgeons recognise that psychological conditions may present with musculoskeletal symptoms. Identification through careful and sensitive history taking is vital. There is a lack of training in this regard in paediatric orthopaedics. We present a series of cases initially referred for a musculoskeletal complaint. Further probing revealed an underlying psychological problem which was neither picked up by the referring physician nor volunteered by the patient. In our opinion, it is important that this training omission is addressed as such psychological problems may be devastating for these individuals and their families. PMID- 28899218 TI - Relationship between serum 25-hydroxy vitamin D levels and retinopathy of prematurity. AB - Aim To evaluate the relationship between serum 25-hydroxy vitamin D, 25 (OH) D, levels and retinopathy of prematurity. Methods and Results Serum 25 (OH) D levels were measured in 97 very low birth weight infants, prior to vitamin D supplementation. The development of retinopathy of prematurity and its treatment requirement were evaluated. At follow-up, retinopathy of prematurity developed in 71 (73.2%) infants. Serum 25 (OH) D levels were significantly lower in infants with retinopathy of prematurity than ones without retinopathy of prematurity ( P < 0.001). The infants who required treatment had lower 25 (OH) D levels compared with the infants who did not required treatment (7.1 +/- 5.2 ng/ml vs. 11.9 +/- 6.5 ng/ml; P = 0.003). Multivariate analysis showed that lower serum 25 (OH) D levels may be a risk factor for retinopathy of prematurity development [OR: 1.14, 95% CI (1.02-1.27), P = 0.02]. Conclusion Lower 25 (OH) D levels in the first days of life may be related to retinopathy of prematurity development and treatment requirement in premature infants. PMID- 28899219 TI - Adjunctive Treatments for Type 1 Diabetes. PMID- 28899220 TI - Diagnosis of mesial temporal sclerosis: sensitivity, specificity and predictive values of the quantitative analysis of magnetic resonance imaging. AB - In the diagnosis of mesial temporal sclerosis (MTS), sensitivity, specificity and predictive values of qualitative assessment using conventional magnetic resonance imaging are low, mainly in mild or bilateral atrophy. Quantitative analysis may improve this performance. We evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of quantitative analysis using the hippocampal volumetric index (HVI) and hippocampal asymmetry index (HAI) compared with qualitative assessment in the MTS diagnosis. Twenty five patients diagnosed with MTS, and 25 healthy subjects underwent conventional magnetic resonance imaging. Hippocampal volumes were obtained using an automated software (FreeSurfer); HVI and HAI were calculated. Receiver operating characteristic curve analysis was performed to obtain the optimal threshold values. Sensitivity, specificity and predictive values were calculated. Sensitivity, specificity, PPV and NPV for qualitative analysis were 44.00%, 96.00%, 91.67% and 63.16%, respectively. In the quantitative analysis, a threshold value of K = 0.22 for HVI provided a sensitivity value of 76.00%, specificity value of 96.00%, PPV of 95.00% and NPV of 80.00%. A threshold value of K = 0.06 for HAI provided the minimum C1 and C2 errors, with a sensitivity value of 88.00%, specificity value of 100%, PPV of 100% and NPV of 89.30%. A statistically significant difference was observed for HAI ( P < 0.0001), and ipsilateral HVI (left MTS, P = 0.0152; right MTS, P < 0.0001), between MTS and healthy groups. The HVI and HAI, both individually and in conjunction, improved the sensitivity, specificity and predictive values of magnetic resonance imaging in the diagnosis of MTS compared to the qualitative analysis and other quantitative techniques. The HAI is highly accurate in the diagnosis of unilateral MTS, whereas the HVI may be better for bilateral MTS cases. PMID- 28899221 TI - Predictors of prolongation in radiation treatment time in a veteran population treated with chemoradiation for oropharyngeal cancer. AB - BACKGROUND: Prolonged radiation treatment time (RTT) is associated with worse tumor control. Here we identify and determine the implications of factors that predict treatment prolongation in Veterans Affairs (VA) patients undergoing chemoradiation. METHODS: Chart review from July 2000 to October 2013. 81 patients with advanced stage oropharyngeal cancer treated with chemoradiation. RESULTS: Twenty-nine patients (35.8%) had RTT prolonged by >=10 days. Prolongation mainly resulted from acute treatment toxicity (n = 22, 76%). There was no significant difference in RTT for patients treated with concurrent cisplatin versus cetuximab, or in patients treated with or without induction chemotherapy. One /three-year locoregional control and overall survival rates of 83.4%/76.3% and 83.5%/63.6% for patients without prolonged RTT versus 61.8%/61.8% and 82.8%/73.8% for those with prolongation (p >.05). CONCLUSIONS: Prolonged RTT is a significant predictor of worse locoregional control and predominantly resulted from treatment side effects. More aggressive regimens with induction and concurrent chemotherapy did not predispose to prolonged RTT. PMID- 28899223 TI - Triggers for attempted suicide in Istanbul youth, with special reference to their socio-demographic background. AB - OBJECTIVE: Suicidal behavior of young people is a topic of utmost importance because suicide is irreversible, and should be prevented. Knowing about the psychosocial background and the triggering events could help in preventing suicidal behavior. We therefore aimed at identifying psychosocial factors that may trigger suicidal behavior in youth. METHODS: We analyzed retrospectively the standardized records of 2232 youths aged <=25 years, who were treated after a suicide attempt at emergency units of public hospitals in Istanbul, Turkey during a period of 1 year. We describe this population according to sex and socio economic conditions, like educational, occupational, relationship status and link them with their reported reasons for suicide attempts. RESULTS: The majority of patients were female (81.6%, N = 1822 females, 18.4%, N = 410 males). Independent of their educational and occupational background, patients indicated most frequently intra-familial problems (females 45.8%, males 30.5%), intrapersonal problems (females 19.9%, males 18.5%), and relationship problems (females 11.3%, males 23.9%) as triggering reasons. CONCLUSIONS: Because intra-familial problems were the most frequently reported triggers of suicide attempts, preventive measures should focus on handling intra-familial conflicts. As sex differences were observed for the second-most common trigger-reasons, prevention should also focus on differentially handling intrapersonal and relationship conflicts better. PMID- 28899222 TI - Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. AB - BACKGROUND: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. METHODS: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. RESULTS: A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P<=0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). CONCLUSIONS: Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035 .). PMID- 28899224 TI - Photo-cross-linked biodegradable hydrogels based on n-arm-poly(ethylene glycol), poly(epsilon-caprolactone) and/or methacrylic acid for controlled drug release. AB - In this paper, a novel kind of photo-cross-linked biodegradable hydrogels based on n-arm-poly(ethylene glycol) ( n = 2, 3, and 4) and poly(E-caprolactone) was prepared by ultraviolet-initiated free radical polymerization. The resulting n arm-poly(ethylene glycol)-poly(E-caprolactone) and n-arm-poly(ethylene glycol) poly(E-caprolactone) acrylate (n-arm-PEG-PCL-AC, macromer) were characterized by proton nuclear magnetic resonance and fourier transform infrared spectra. The influences of arm numbers and concentration of macromer on the properties of hydrogel were researched systematically, and the results showed that the gelation time, equilibrium swelling ratio, in vitro degradation, and drug release rate decreased with the increase of arm numbers and concentration of macromer. The degradation and drug release rate could be controlled by varying the cross linking density of hydrogel, indicating a potential application as controlled drug delivery system. Cytotoxicity test of hydrogel extracts was conducted using L929 mouse fibroblasts, and the relative growth rate exceeded 75% (cytotoxicity type: class 1) after incubation for 24 h, showing excellent cytocompatibility. In addition, the paper presented a pH-sensitive hydrogel (G4pH) based on 4-arm-PEG PCL-AC and acrylic acid, and the influences of pH value on swelling behaviors and in vitro drug release of the pH-sensitive hydrogel were examined. The hydrogels shrank under acidic condition and would swell in neutral or basic medium. The pH dependent drug release behaviors indicated a promising application of the materials as oral drug delivery vehicles. PMID- 28899225 TI - International teleconsultation on conjoined twins leading to a successful separation: a case report. AB - Conjoined twins are identical twins that have incompletely separated in utero. The prognosis for conjoined twins is poor and management in a skilled tertiary care centre is paramount for definitive care. We describe our experience with a telemedical consultation on conjoined twins in The Dominican Republic from our eHealth centre in Valhalla, NY. The patients were two month old, female, pygopagus conjoined twins. A multidisciplinary teleconference was initiated with the patients, their family, the referring paediatrician and our team. Based on this teleconsultation, the team felt as though the twins may be amenable to a surgical separation. They presented to our centre in Valhalla, NY, for a detailed physical examination and series of imaging studies. Soon after, the patients underwent a successful 21 h separation procedure and were discharged 12 weeks later. To our knowledge, this is one of the first reports of an international teleconsultation leading to a successful conjoined twin separation procedure. PMID- 28899226 TI - Adenoid cystic carcinoma of the head and neck: a retrospective multicenter study. AB - BACKGROUND: Adenoid cystic carcinoma of the head and neck (ACCHN) is rare and difficult to study effective treatment at one institute. Our aim is to identify prognostic factors for this disease by conducting a multicenter study at 11 institutions in Japan. METHODS: A retrospective multicenter study of ACCHN was performed. One hundred and three patients were identified between 2006 and 2015. The overall survival (OS) rate for all patients was calculated, and OS, locoregional control (LRC) rate, or no distant metastasis (NDM) rate was calculated for patients in that the surgery was performed without distant metastasis (DM). Statistical analyses were performed. RESULTS: A significant difference with multivariate analysis was observed in patients in sublingual glands, stage IV and the use of radiation therapy >=60Gy (sufficient RT) in OS for all patients. A significant difference was observed in the use of sufficient postoperative RT in the OS and the LRC rate, and in pathological surgical margins in the NDM rate. CONCLUSION: Sublingual glands or stage IV was a poorer, and sufficient RT was a better prognostic factor for ACCHN. Sufficient RT was effective to prevent local recurrence after surgical resection. Positive surgical margins caused an increase in DM. PMID- 28899227 TI - Phenethyl isothiocyanate protects against H2O2-induced insulin resistance in 3T3 L1 adipocytes. AB - Obesity is associated with systemic oxidative stress and leads to insulin resistance. Phenethyl isothiocyanate (PEITC), a natural dietary isothiocyanate, has been shown to have beneficial effects in improving cellular defense activities against oxidative stress through activation of nuclear factor erythroid-2 related factor 2 (Nrf2) pathway. However, little evidence exists if the antioxidative activity has beneficial effects on glucose metabolism. Here, we tested the preventive potential of PEITC for impaired insulin-induced glucose uptake by oxidative stress in 3T3-L1 adipocytes. Treatment with PEITC increased the expression of antioxidative enzymes regulated by Nrf2 such as gamma glutamylcysteine-synthetase, heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1 and glutathione S-transferase, and reduced oxidative stress induced by H2O2. Furthermore, PEITC restored impaired insulin-stimulated glucose uptake, translocation of glucose transporter 4 and insulin signaling by H2O2. These results indicate that PEITC protected insulin-regulated glucose metabolism impaired by oxidative stress through the antioxidative activity in 3T3-L1 adipocytes. PMID- 28899228 TI - Intraoperative venoplasty to facilitate placement of tunneled catheters for hemodialysis. AB - Objective With the implementation of the K-DOQI guidelines, more patients are in need of long-term dialysis catheters until maturation of the arteriovenous fistula. However, on occasion, when placing a tunneled cuffed catheter for hemodialysis, we have encountered difficulty with passing the guidewire in spite of demonstration of a patent cervical portion of the internal jugular vein on duplex. Herein, we review our experience with intraoperative venoplasty for placement of TesioTM catheters (Medcomp Harleysville, PA). Methods Of the 1147 TesioTM catheters placed since 1997 by our service, 35 venograms were performed due to difficulty encountered with placement of the guidewire. Patent veins were all crossed with the use of angle-guiding catheters, angled glidewires, and a torque vise. If chronically occluded intrathoracic veins were identified, an alternate site was selected for the placement of the TesioTM catheter. Results Of the 35 cases with difficulty in catheter placement, venogram demonstrated a patent but tortuous vein in 9, chronically occluded intrathoracic veins in 6, and severe stenosis of the intrathoracic veins in 20. In 19 cases with severe stenosis of the intrathoracic veins, balloon angioplasty with an 8-mm balloon was successfully performed, which allowed successful placement of a functional TesioTM catheter. In the additional one case, the catheter was not able to be placed despite angioplasty. Seven lesions that underwent balloon angioplasty were in the innominate vein, 11 were in the proximal internal jugular vein, and two were in the superior vena cava. Conclusion Venous balloon angioplasty can be used to maintain options for the site of access for tunneled cuffed catheters and may be necessary to assist with placement of long term cuffed dialysis catheters. PMID- 28899229 TI - Thyroid Storm: A Japanese Perspective. AB - BACKGROUND: Thyroid storm (TS) is life threatening. In the mid-2000s, its incidence was poorly defined, peer-reviewed diagnostic criteria were not available, and management and treatment did not seem to be verified based upon evidence and latest advances in medicine. METHODS: First, diagnostic criteria were developed based on 99 patients in the literature and seven patients in this study. Then, initial and follow-up surveys were conducted from 2004 through 2008, targeting all hospitals in Japan to obtain and verify information on patients who met diagnostic criteria for TS. Based on these data, the diagnostic criteria were revised, and management and treatment guidelines were created. RESULTS: The incidence of TS in hospitalized patients in Japan was estimated to be 0.20 per 100,000 per year and 0.22% of all thyrotoxic patients. The mortality rate was 10.7%. Multiple organ failure was the most common cause of death, followed by congestive heart failure, respiratory failure, and arrhythmia. In the final diagnostic criteria for TS, the definition of jaundice as serum bilirubin concentration >3 mg/dL was added. Based upon nationwide surveys and the latest information, guidelines for the management and treatment for TS were extensively revised and algorithms were developed. CONCLUSIONS: TS remains a life-threatening disorder, with >10% mortality in Japan. New peer-reviewed diagnostic criteria for TS are presented and its clinical features, prognosis, and incidence are clarified based on nationwide surveys. Furthermore, this information helped to establish detailed guidelines for the management and treatment of TS. A prospective prognostic study to validate the guidelines is eagerly anticipated. PMID- 28899230 TI - Research on the alliance: Knowledge in search of a theory. AB - OBJECTIVES: The aim of this review paper is to summarize the challenges facing research on the alliance now and going forward. The review begins with a brief overview of the development of the concept of the alliance in historical context. METHOD: A summary of what has been accomplished both within the psychotherapy research community and in other professions is presented. Current challenges facing this line of research are identified, including the existence of a wide range of operational definitions that results in a diffusion of the identity of the alliance concept. It is argued that the current situation generates risks to incremental growth in several lines of research. CONCLUSIONS: A case is made that a lack of clarity regarding how several variables within the broader category of therapeutic relationships fit together, overlap, or complement each other is also potentially problematic. Efforts to resolve the lack of a consensual definition are reviewed, and in conclusion, it is argued that a resumption of a conversation about the relationship in the helping context in general, and the alliance in particular, should be resumed. PMID- 28899231 TI - Neuron-Type-Specific Utility in a Brain-Machine Interface: a Pilot Study. AB - CONTEXT: Firing rates of single cortical neurons can be volitionally modulated through biofeedback (i.e. operant conditioning), and this information can be transformed to control external devices (i.e. brain-machine interfaces; BMIs). However, not all neurons respond to operant conditioning in BMI implementation. Establishing criteria that predict neuron utility will assist translation of BMI research to clinical applications. FINDINGS: Single cortical neurons (n=7) were recorded extracellularly from primary motor cortex of a Long-Evans rat. Recordings were incorporated into a BMI involving up-regulation of firing rate to control the brightness of a light-emitting-diode and subsequent reward. Neurons were classified as 'fast-spiking', 'bursting' or 'regular-spiking' according to waveform-width and intrinsic firing patterns. Fast-spiking and bursting neurons were found to up-regulate firing rate by a factor of 2.43+/-1.16, demonstrating high utility, while regular-spiking neurons decreased firing rates on average by a factor of 0.73+/-0.23, demonstrating low utility. CONCLUSION/CLINICAL RELEVANCE: The ability to select neurons with high utility will be important to minimize training times and maximize information yield in future clinical BMI applications. The highly contrasting utility observed between fast-spiking and bursting neurons versus regular-spiking neurons allows for the hypothesis to be advanced that intrinsic electrophysiological properties may be useful criteria that predict neuron utility in BMI implementation. PMID- 28899232 TI - RNA-Seq reveals a central role for lectin, C1q and von Willebrand factor A domains in the defensive glue of a terrestrial slug. AB - The tough, hydrogel glue produced by the slug Arion subfuscus achieves impressive performance through metal-based, protein cross-links. The primary sequence of these proteins was determined through transcriptome sequencing and proteome analysis by tandem mass spectrometry. The main proteins that correlate with adhesive function are a group of 11 small, highly abundant lectin-like proteins. These proteins matched the ligand-binding C-lectin, C1q or H-lectin domains. The variety of different lectin-like proteins and their potential for oligomerization suggests that they function as versatile and potent cross-linkers. In addition, the glue contains five matrilin-like proteins that are rich in von Willebrand factor A (VWA) and EGF domains. Both C-lectins and VWA domains are known to bind to ligands using divalent cations. These findings are consistent with the double network mechanism proposed for slug glue, with divalent ions serving as sacrificial bonds to dissipate energy. PMID- 28899233 TI - Differences in utility elicitation methods in cardiovascular disease: a systematic review. AB - AIMS: Utility values inform estimates of the cost-effectiveness of treatment for cardiovascular disease (CVD), but values can vary depending on the method used. The aim of this systematic literature review (SLR) was to explore how methods of elicitation impact utility values for CVD. MATERIALS AND METHODS: This review identified English-language articles in Embase, MEDLINE, and the gray literature published between September 1992 and August 2015 using keywords for "utilities" and "stroke", "heart failure", "myocardial infarction", or "angina". Variability in utility values based on the method of elicitation, tariff, or type of respondent was then reported. RESULTS: This review screened 4,341 citations; 290 of these articles qualified for inclusion in the SLR because they reported utility values for one or more of the cardiovascular conditions of interest listed above. Of these 290, the 41 articles that provided head-to-head comparisons of utility methods for CVD were reviewed. In this sub-set, it was found that methodological differences contributed to variation in utility values. Direct methods often yielded higher scores than did indirect methods. Within direct methods, there were no clear trends in head-to-head studies (standard gamble [SG] vs time trade-off); but general population respondents often provided lower scores than did patients with the disease when evaluating the same health states with SG methods. When comparing indirect methods, the EQ-5D typically yielded higher values than the SF-6D, but also showed more sensitivity to differences in health states. CONCLUSIONS: When selecting CVD utility values for an economic model, consideration of the utility elicitation method is important, as this review demonstrates that methodology of choice impacts utility values in CVD. PMID- 28899234 TI - A Youth-Leader Program in Baltimore City Recreation Centers: Lessons Learned and Applications. AB - Peer-led interventions may be an effective means of addressing the childhood obesity epidemic; however, few studies have looked at the long-term sustainability of such programs. As part of a multilevel obesity prevention intervention, B'More Healthy Communities for Kids, 16 Baltimore college students were trained as youth-leaders (YLs) to deliver a skill-based nutrition curriculum to low-income African American children (10-14 years old). In April 2015, formative research was used to inform sustainability of the YL program in recreation centers. In-depth interviews were conducted with recreation center directors ( n = 4) and the YLs ( n = 16). Two focus groups were conducted with YLs ( n = 7) and community youth-advocates ( n = 10). Barriers to this program included difficulties with transportation, time constraints, and recruiting youth. Lessons learned indicated that improving trainings and incentives to youth were identified as essential strategies to foster continuity of the youth-led program and capacity building. High school students living close to the centers were identified as potential candidates to lead the program. Based on our findings, the initial intervention will be expanded into a sustainable model for implementation, using a train-the-trainer approach to empower community youth to be change agents of the food environment and role models. PMID- 28899235 TI - Oxidative status and reduced glutathione levels in premature coronary artery disease and coronary artery disease. AB - Identifying patients at risk of developing premature coronary artery disease (PCAD) which occurs at age below 45 years old and constitutes approximately 7-10% of coronary artery disease (CAD) worldwide remains a problem. Oxidative stress has been proposed as a crucial step in the early development of PCAD. This study was conducted to determine the oxidative status of PCAD in comparison to CAD patients. PCAD (<45 years old) and CAD (>60 years old) patients were recruited with age-matched controls (n = 30, each group). DNA damage score, plasma malondialdehyde (MDA) and protein carbonyl content were measured for oxidative damage markers. Antioxidants such as erythrocyte glutathione (GSH), oxidised glutathione (GSSG), and glutathione peroxidase activity (GPx), superoxide dismutase (SOD) and catalase (CAT) were also determined. DNA damage score and protein carbonyl content were significantly higher in both PCAD and CAD when compared to age-matched controls while MDA level was increased only in PCAD (p<.05). In contrast, GSH, GSH/GSSG ratio, alpha-tocotrienol isomer, and GPx activity were significantly decreased, but only in PCAD when compared to age matched controls. The decrease in GSH was associated with PCAD (OR = 0.569 95%CI [0.375 - 0.864], p = .008) and cut-off values of 6.69 MUM with areas under the ROC curves (AUROC) 95%CI: 0.88 [0.80-0.96] (sensitivity of 83.3%; specificity of 80%). However, there were no significant differences in SOD and CAT activities in all groups. A higher level of oxidative stress indicated by elevated MDA levels and low levels of GSH, alpha-tocotrienol and GPx activity in patients below 45 years old may play a role in the development of PCAD and has potential as biomarkers for PCAD. PMID- 28899236 TI - Looking forward: the effects of photographs on the qualities of future thinking. AB - Future episodic thinking relies on the reconstruction of remembered experiences. Photographs provide one means of remembering, acting as a "cognitive springboard" for generating related memory qualities. We wondered whether photographs would also invite embellishment of future thought qualities, particularly in the presence (or absence) of associated memories. In two studies participants generated future events in familiar (associated memories) and novel (no associated memories) locations. Half of the participants viewed scene location photographs during event generation. All participants then imagined the events for one minute and completed a self-report measure of content qualities. Results of the current set of studies suggested that for novel locations, no differences in qualities emerged; however, for familiar locations, photographs did not enhance qualities and, in some cases, actually constrained perceptual (Experiments 1 and 2) and sensory (Experiment 1) detail ratings of future thoughts. Thus, photographs did not invite embellishment of future thought details. PMID- 28899237 TI - Prisms Transform Perspectives. AB - In the following article, Lila Ortuno and Dr. Kristine Florczak describe the personal and professional growth gained by a graduate student undertaking a knowledge based personal reflection of practice. PMID- 28899238 TI - The Paradox of Transformational Learning in Academe. PMID- 28899239 TI - The Chains Around Academic Freedom in Teaching-Learning. AB - Freedom as a concept has been much debated. Is freedom an innate part of being, or does freedom even truly exists? These are questions that have gleaned countless hours of discourse over the years. Two components of freedom that can influence nurse higher education are freedom of speech, in the form of media, and academic freedom. The author of this column first introduces three views of freedom to demonstrate the differences surrounding it. A discussion of the media's use or misuse of freedom of speech and its influence on nursing education is then presented, followed by an examination of current threats to academic freedom in today's institutes of higher learning and specifically in the nursing education arena. The author concludes with suggestions on being a nurse educator through living as a humanbecoming professional while navigating issues surrounding nursing education. PMID- 28899240 TI - What Do I Do Now? AB - The author in this article reports a literature review on the core concepts of a Parse inquiry on the lived experience of feeling sad: unrelenting misery, pondering the irreplaceable (remembering), and persevering with adversity. New conceptualizations of sadness are presented and the question for health professionals is posed: What do we do now? PMID- 28899241 TI - The Syrian Refugee Crisis: What Nurses Need to Know. AB - The civil war in Syria that began in 2011 has displaced millions of Syrians of all ages. While the number that have arrived in the United States is small in comparison to many other countries, it is important that nurses and other healthcare workers here understand that many of them have faced considerable trauma and endured stresses. Most of them are Muslims. Muslims in the United States and elsewhere represent a heterogeneous group of people with a long intellectual and cultural history. Islamic cultural patterns do pose unique barriers to a primarily Anglo-Saxon medical system that medical practitioners need to consider in order to avoid misunderstanding and provide culturally sensitive care. The authors discuss the Syrian refugee crisis and the experience of being a Muslim or Arab American patient in U.S. healthcare settings. PMID- 28899242 TI - Transforming Nursing Education and the Formation of Students: Using the Humanbecoming Paradigm. AB - Transforming nursing education is a current focus across the country, the result of recent national reports that have made significant contributions for evaluating and changing curricula and ways students are taught. However, the need to ground these strategies for change within our discipline's ontological foundation through nursing theory must be addressed. The purpose of this article is to use Parse's Humanbecoming Paradigm to provide educators with exemplars of discipline-specific theory-based changes across educational levels. The exemplars are situated within the important tensions that educators face today in undergraduate, advanced practice, and doctoral programs. Conclusions are drawn regarding continuing efforts to ensure that nurse educators incorporate discipline-relevant theories when transforming nursing education. PMID- 28899243 TI - Understanding by Looking Through Prisms. AB - The authors of this column explore the transformational journey of a nursing student pursuing a graduate degree through the prisms of ethics, aesthetics, and nursing theory. The wisdom and insights gained contribute to an ever-changing worldview of humans and living experiences. PMID- 28899244 TI - Transformational Leadership in Nursing Education: Making the Case. AB - Transformational leadership is a trending style and competency that has been embraced by many industries and nursing practice settings. Similar positive influence on follower engagement, teamwork, and solidarity might be experienced if transformational leadership is employed by administration and faculty as a guiding framework for nursing education. The impact of embedding a teamwork culture in basic nursing education could be significant on students and ultimately on the nursing profession. Further research is needed to develop and test application of the transformational leadership framework in nursing education. PMID- 28899245 TI - Evaluation of Healthy Living Wellness Program With Minority Underserved Economically Disadvantaged Older Adults. AB - The purpose of this Roy adaptation model-guided study was to test the effectiveness of a student registered nurse intern-led nursing intervention entitled the Healthy Living Wellness Program. A one-group pretest/posttest preexperimental design was used. The intervention was imparted to minority, underserved, economically disadvantaged older adults ( N = 30). Significant findings pre- and postintervention were reported for body mass index, waist circumference, self-reported blood glucose, and weight. The findings supported the effectiveness of the nursing intervention, the Healthy Living Wellness Program, guided by the Roy adaptation model. PMID- 28899246 TI - What Families Want From Nurses. PMID- 28899247 TI - "Oh, the Places" Nurses "Go!": Leading-Following Within Rural Nursing. AB - It is interesting to imagine the many diverse places and settings that nurses "go" to serve individuals, families, and communities with their unique knowledge base. Nurses working in rural areas have many challenges and opportunities, since they work in isolated areas "in the wide open air" where there is limited access to healthcare. PMID- 28899248 TI - Shedding Light for Future Generations. PMID- 28899249 TI - Ethics With Mentoring. AB - The concept of mentoring is a phenomenon critical to teaching-learning in coming to know in the performing art of leadership. The author of this article discusses the mentoring relationship from an alternative view through the humanbecoming lens of understanding. Possibilities of ethical nurse practice with the art of mentoring from the humanbecoming perspective are illuminated. PMID- 28899250 TI - Again, What Is Nursing Science? AB - This article again asks, What is nursing science? Who knows? Who cares? The author describes the threat to the survival of nursing science grounded in nursing frameworks and theories. This threat is magnified by the proposal of the Council for the Advancement of Nursing Science (CANS) to change the curricula of PhD education. The aim of CANS is to prepare nurse scientists for lifelong competitive careers in interdisciplinary research, often focused on funding priorities of the National Institute of Nursing Research (NINR). Curricula would include preparation for conducting research in topics such as omics, e-science, translation science, biobehavioral science, symptom science, and team science. How can this be nursing science? It is argued that this focus might obliterate nursing's discipline-specific phenomenon of concern, the human-universe-health process. PMID- 28899251 TI - Leading-Following in the Context of Rural Nursing. AB - Leading-following, as defined by Parse, is "deliberately innovating with potent engaging in persistently pursuing excellence. It is an indivisible, unpredictable, ever changing cocreation." Parse noted that processes forming the essence of leading-following require commitment, risk-taking, acknowledging ambiguity, respecting others, and vigilance. There is a bond between members of society and nurses-an expectation that nurses will provide care to individuals, families, and communities. Nursing is a profession where the potential to create meaning in healthcare has not yet been fully realized. PMID- 28899252 TI - Thoughts About Created Environment: A Neuman Systems Model Concept. AB - This essay is about the Neuman systems model concept of the created environment. The essay, based on work by Frans Verberk, a Neuman systems model scholar from the Netherlands, extends understanding of the created environment by explaining how this distinctive perspective of environment represents an elaboration of the physiological, psychological, sociocultural, developmental, and spiritual variables, which are other central concepts of the Neuman Systems Model. PMID- 28899255 TI - Mentoring: An Evolving Relationship. AB - The column concerns itself with mentoring as an evolving relationship between mentor and mentee. The collegiate mentoring model, the transformational transcendence model, and the humanbecoming mentoring model are considered in light of a dialogue with mentors at a Midwest university and conclusions are drawn. PMID- 28899256 TI - The Experience of Feeling Disrespected: A Humanbecoming Perspective. AB - The concept of feeling disrespected was explored using the Parse research method. Ten women living with embodied largeness were asked, "What is the experience of feeling disrespected?" The structure of the living experience was feeling disrespected is mortifying disheartenment arising with disquieting irreverence, as distancing affiliations surface while enduring hardship. The findings provided new knowledge of living quality, advanced nursing practice, and presented future direction for research. PMID- 28899257 TI - Peplau's Theory of Interpersonal Relations: An Alternate Factor Structure for Patient Experience Data? AB - A confirmatory factor analysis of data from the responses of 12,436 patients to 16 items on the Consumer Assessment of Healthcare Providers and Systems-Hospital survey was used to test a latent factor structure based on Peplau's middle-range theory of interpersonal relations. A two-factor model based on Peplau's theory fit these data well, whereas a three-factor model also based on Peplau's theory fit them excellently and provided a suitable alternate factor structure for the data. Though neither the two- nor three-factor model fit as well as the original factor structure, these results support using Peplau's theory to demonstrate nursing's extensive contribution to the experiences of hospitalized patients. PMID- 28899258 TI - Do Persons Living with HIV Continue to Fill Prescriptions for Antiretroviral Drugs during a Gap in Care? Analysis of a Large Commercial Claims Database. AB - The significance of a gap in HIV care depends, at least partially, on whether patients continue to fill prescriptions for antiretroviral (ARV) drugs during the gap in care. We used a billing claims database to determine the proportion of persons who filled >=1 prescription for ARV drugs during a gap in care (no clinic visit in >6 months). Persons were stratified into 3 groups: "never" (prescriptions never filled), "sometimes" (prescriptions filled >0%-<100% of months), and "always" (prescriptions filled monthly). Logistic regression analyses were conducted to determine factors associated with "never" filling ARV drugs. Of 14 308 persons, 69% (n = 9817), 13% (n = 1928), and 18% (n = 2563) "never," "sometimes," and "always" filled ARV drugs during the gap in care. Persons aged 18 to 29 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 1.39-1.74), women (OR = 1.67, CI 1.52-1.83), and persons from the Northeast region of the United States (OR = 1.86, CI 1.69-2.03) were more likely to never fill ARV drugs than persons aged >=30 years, men, and persons outside the Northeast, respectively. Efforts should be made to minimize gaps in care, emphasize importance of therapy, and provide adherence support. PMID- 28899260 TI - Reduction in electrocardiographic lateral precordial voltage after subcutaneous implantable cardioverter-defibrillator implantation. PMID- 28899259 TI - Delivery of HIV Antiretroviral Therapy Adherence Support Services by HIV Care Providers in the United States, 2013 to 2014. AB - BACKGROUND: Little is known about clinicians' adoption of recommendations of the International Association of Providers of AIDS Care and others for supporting adherence to antiretroviral therapy (ART). METHODS: We surveyed a probability sample of US HIV care providers to estimate the percentage offering 3 ART adherence support services to most or all patients and assessed the characteristics of providers offering all 3 services (comprehensive support) to most or all patients. RESULTS: Almost all providers (95.5%) discussed ART adherence at every visit, 60.1% offered advice about tools to increase adherence, 53.5% referred nonadherent patients for supportive services, and 42.8% provided comprehensive support. Nurse practitioners were more likely to offer comprehensive support as were providers who practiced at Ryan White HIV/AIDS Program-funded facilities, provided primary care, or started caring for HIV infected patients within 10 years. CONCLUSION: Less than half of HIV care providers offered comprehensive ART adherence support. Certain subgroups may benefit from interventions to increase delivery of adherence support. PMID- 28899261 TI - Nursing Home Referral Within the Veterans Health Administration: Practice Variation by Payment Source and Facility Type. AB - Veterans enrolled within the Veterans Health Administration (VHA) of the U.S. Department of Veterans Affairs (VA) may receive nursing home (NH) care in VHA operated Community Living Centers (CLCs), State Veterans Homes (SVHs), or community NHs, which may or may not be under contract with the VHA. This study examined VHA staff perceptions of how Veterans' eligibility for VA and other payment impacts NH referrals within VA Medical Centers (VAMCs). Thirty-five semistructured interviews were performed with discharge planning and contracting staff from 12 VAMCs from around the country. VA staff highlights the preeminent role that VA priority status played in determining placement in VA-paid NH care. VHA staff reported that Veterans' placement in a CLC, community NH, or SVH was contingent, in part, on potential payment source (VA, Medicare, Medicaid, and other) and anticipated length of stay. They also reported that variation in Veteran referral to VA-paid NH care across VAMCs derived, in part, from differences in local and regional policies and markets. Implications for NH referral within the VHA are drawn. PMID- 28899262 TI - Discrepancy detection in the retrieval-enhanced suggestibility paradigm. AB - Retrieval-enhanced suggestibility (RES) refers to the finding that immediately recalling the details of a witnessed event can increase susceptibility to later misinformation. In three experiments, we sought to gain a deeper understanding of the role that retrieval plays in the RES paradigm. Consistent with past research, initial testing did increase susceptibility to misinformation - but only for those who failed to detect discrepancies between the original event and the post event misinformation. In all three experiments, subjects who retrospectively detected discrepancies in the post-event narratives were more resistant to misinformation than those who did not. In Experiments 2 and 3, having subjects concurrently assess the consistency of the misinformation narratives negated the RES effect. Interestingly, in Experiments 2 and 3, subjects who had retrieval practice and detected discrepancies were more likely to endorse misinformation than control subjects who detected discrepancies. These results call attention to limiting conditions of the RES effect and highlight the complex relationship between retrieval practice, discrepancy detection, and misinformation endorsement. PMID- 28899263 TI - Seeing Beyond the At-Hand. PMID- 28899264 TI - Ubiquitous Technology in Healthcare and Teaching-Learning: Scourge or Blessing? AB - The author in this article introduces a discussion of one school of nursing's efforts integrating telehealth education into undergraduate and graduate curricula using King's theory of goal attainment as a guide. The introduction shares a story of loss in a rural setting without access to quality healthcare to highlight the blessing technology may be. However, challenges are discussed that arise through the ubiquitous use of technology in person-to-person communication and relationships. PMID- 28899265 TI - Enhancing Telehealth Education in Nursing: Applying King's Conceptual Framework and Theory of Goal Attainment. AB - Telehealth technologies are increasingly used in the provision of nursing care to clients and populations. The education of nurses must include content and practice with telehealth technologies. The authors of this article discuss how one school of nursing has infused telehealth content and resources into undergraduate and graduate curricula using King's conceptual system and theory of goal attainment as a guide. PMID- 28899266 TI - Graduate Students' Reflections on Elder and End-of-Life Care for Prisoners. AB - The focus of this report was graduate nursing students' reflections on elder and end-of-life care for prisoners. The personal reflections of 21 graduate nursing students who attended a presentation by Susan J. Loeb on October 26, 2016 were included in this report. The title of the presentation was "Enhancing End-of-Life Care for Prisoners Through Partnering With the Prison Community." The student essays were synthesized to construct a summary essay, from which four themes were identified: aging in prison, dying in prison, ethical and professional issues in the elder and end-of-life care of prisoners, and ethical and professional issues in research involving elderly and end-of-life care of prisoners. These findings were interpreted from a global perspective in light of two different nursing perspectives: the humanbecoming tradition and the science of unitary human beings. PMID- 28899267 TI - Benner's Novice to Expert Model: An Application for Simulation Facilitators. AB - This paper details the application of Benner's Novice to Expert Model to simulation educator knowledge, skills, and attitude for academic and practice settings. Facilitator development in the use of simulation methods is gaining more attention and support. If simulation is to continue to advance as a discipline, a theoretical basis is needed. The Novice to Expert Model provides the necessary conceptual structure to guide simulation facilitator development and assist in understanding learning trajectory. This theory-based approach that defines and operationalizes the five stages of development provides guidance for development resources, educational programs, and infrastructure needed at various program levels. PMID- 28899268 TI - Linking the Unitary Paradigm to Policy through a Synthesis of Caring Science and Integrative Nursing. AB - The principles of integrative nursing and caring science align with the unitary paradigm in a way that can inform and shape nursing knowledge, patient care delivery across populations and settings, and new healthcare policy. The proposed policies may transform the healthcare system in a way that supports nursing praxis and honors the discipline's unitary paradigm. This call to action provides a distinct and hopeful vision of a healthcare system that is accessible, equitable, safe, patient-centered, and affordable. In these challenging times, it is the unitary paradigm and nursing wisdom that offer a clear path forward. PMID- 28899269 TI - New Rogerian Theoretical Thinking About Unitary Science. AB - A theory of pandimensional awareness-integral presence is presented. The relation of wellbecoming and integral presence contributes to the theory, as well as discussion of human field image and human field hugs. Unitary patterning processes offer ways to participate in wellbecoming. New ways are suggested for education, practice, and research in a unitary science perspective. PMID- 28899270 TI - Liberating Discoveries. AB - The author in this article identifies two liberating discoveries that foster human flourishing: the potential of new knowledge and the importance of living gratitude. These two liberating discoveries are explored from the humanbecoming perspective and cite important inquiries that expand understanding of the phenomena of new knowledge and feeling grateful. PMID- 28899271 TI - Fit for Practice: Analysis and Evaluation of Watson's Theory of Human Caring. AB - The aim of the authors of this paper is to analyze Watson's theory of human caring for its usefulness and worth in education, practice, and research. The reason for undertaking this analysis is to evaluate if Watson's theory would be useful for nursing in those countries where such theories were not an established part of the nursing curriculum. Furthermore, in some European countries, their political past or cultural influences led to an unquestioned adoption of the biomedical model. As their political culture changes, many social structures have had to be revisited, and for nursing, this has meant the introduction of theoretical reasoning, teaching, and practice. PMID- 28899272 TI - The Living Experience of Feeling Playful. AB - The purpose of this study was to investigate the living experience of feeling playful. Parse's research method was used to answer the question: What is the structure of the living experience of feeling playful? The participants were 10 persons, ages 9 to 83, living in the United States. The central finding of the study is the living experience of feeling playful is entertaining amusements amid burdens with uplifting endeavors strengthening affiliations with blissful moments of unfettered unfolding. The living experience of feeling playful is discussed in relation to the principles of the humanbecoming paradigm and in relation to how it can inform further research. PMID- 28899273 TI - Translating Nursing Philosophy for Practice and Healthcare Policy. AB - This article introduces the feature article on policy implications of integrative nursing. It describes unitary ontology in nursing, highlighting the Rogerian view of holism. The importance of linking philosophy to practice policy is emphasized. PMID- 28899274 TI - Kritek's Ethical Perspective for Nursing: Moral Courage. PMID- 28899275 TI - How Do Nurses Practice? AB - Understanding how nurses align theory with practice is key to the wellbeing of patients. In these times, there is a lack of regard for what patients want and need in living their quality of life. Since nurses are the facilitators of patient care, they must define how they are with patients and advocate for all people. PMID- 28899276 TI - The Dichotomy: How to Resolve. PMID- 28899279 TI - More Questions. PMID- 28899277 TI - Reflections on Moral Courage. AB - The author presents her reflections on the concept of moral courage that have evolved from her life's work in the area of conflict and conflict resolution. Her profound analysis uncovers issues behind nursing's collective silence when action may be needed. PMID- 28899280 TI - Ethics and Discovering New Meanings With Metaphors. AB - Metaphors are widely understood concepts or structures of human understanding undergirded with transformational creativity. The usages of metaphors are ubiquitous; they are used to convey unique meaning messages in healthcare disciplines. This article begins an ethical straight-thinking discussion of the defining aspects of metaphors and their usage in the discipline of nursing. The humanbecoming paradigm is used to discover new meanings of the metaphor hands-on and its ethical implications for understanding in the discipline of nursing. PMID- 28899281 TI - The Value of Developing a Mixed-Methods Program of Research. AB - This article contributes to the discussion of the value of utilizing mixed methodological approaches to conduct nursing research. To this end, the author of this article proposes creating a mixed-methods program of research over time, where both quantitative and qualitative data are collected and analyzed simultaneously, rather than focusing efforts on designing singular mixed-methods studies. A mixed-methods program of research would allow for the best of both worlds: precision through focus on one method at a time, and the benefits of creating a robust understanding of a phenomenon over the trajectory of one's career through examination from various methodological approaches. PMID- 28899283 TI - Optimal Aging: A Neuman Systems Model Perspective. AB - The purpose of this paper is to describe aspects of optimal aging from the perspective of the Neuman systems model. An overview of the model is presented followed by a discussion of usual stressors encountered as people age and their common responses to these stressors. The position taken is that optimal aging for an individual is not necessarily equated with high-level wellness but rather is the best possible aging for that individual. A Neuman systems model practice methodology tool is used to illustrate how to apply the model to determine the optimal level of aging for individuals with and without chronic illnesses. PMID- 28899284 TI - Identifying and addressing the governance accountability problem. AB - Successive global health crises - from HIV and AIDS to SARS and H5N1 to Ebola - highlight one of the most pressing challenges to global health security: the GAP the governance accountability problem. Introduced in 2014 in the book entitled, HIV/AIDS and the South African state: The responsibility to respond, this article takes up Alan Whiteside's challenges, in a book review in these pages, to offer a more comprehensive analysis of the GAP. The GAP [Sehovic, A. B. (2014). HIV/AIDS and the South African state: The responsibility to respond. Ashgate Global Health.] posits that there is a disconnect between ad hoc, state and non-state interventions to respond to an epidemic crisis, and the ultimate guarantee for health (security), which remains legally vested with the state. The existence and expansion of such ad hoc solutions result in a negligence: a failure of re ordering of health rights and responsibilities for health between such actors and the accountable state. The GAP aims to highlight this disjunction. This article first defines the GAP. Second, it asks two questions: First, what is the contribution of the GAP thesis to understanding the emerging health security landscape? Second, what can the GAP offer in terms of practical insight into viable solutions to the re-ordering of state/non-state-based responsibility and accountability for global health security? PMID- 28899285 TI - Predicting rehabilitation length of stay in Canada: It's not just about impairment. AB - INTRODUCTION: Current tertiary Spinal Cord Injury (SCI) rehabilitation funding and rehabilitation length of stay (R-LOS) in most North American jurisdictions are linked to an individual's impairment. Our objectives were to: 1) describe the impact of relevant demographic, impairment and medical complexity variables at rehabilitation admission on R-LOS among adult Canadians with traumatic SCI; and 2) identify factors which extend R-LOS. METHODS: Data from 1,376 adults with traumatic SCI were obtained via chart abstraction and administrative data linkage from 15 Rick Hansen SCI Registry sites (2004-2014). Variables included age, sex, neurological impairment (level, severity), rehabilitation onset days, R-LOS, Glasgow Coma Score (GCS) at admission, prior ventilation or endotracheal tube (Vent/ETT), or indwelling bladder catheter at acute discharge, pain interference score, intensive care unit (ICU) length of stay (LOS), and lower extremity motor scores (LEMS) at rehabilitation admission. Variables related to R-LOS in bivariate analysis were included in multivariate analysis to determine their impact on R-LOS. RESULTS: Prior Vent/ETT tube, indwelling bladder catheter, GCS, LEMS, and neurological impairment were related to R-LOS in bivariate analysis. Multivariate linear regression analyses identified five variables as significant predictors: age, Vent/ETT for >24 hours in acute care, indwelling bladder catheter at acute discharge, LEMS, and NLI/AIS subgroup at rehabilitation admission explained 32% of the variation in R-LOS (p<0.001). CONCLUSIONS: Based on the enclosed formula, and knowledge of an individual's age at injury, spinal cord impairment (level and severity), prior Vent/ETT, presence of an indwelling bladder catheter, and LEMS at admission, administrators and clinicians may readily identify patients for whom an extended R-LOS beyond conventional LOS targets is likely. PMID- 28899287 TI - Pedagogical Approaches to Teaching-Learning Theory. PMID- 28899286 TI - Restless legs syndrome related to hemorrhage of a thoracic spinal cord cavernoma. AB - CONTEXT: Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the lower limbs often accompanied by unpleasant sensations in the legs, worsened at rest and in the evening. Symptoms are improved by movement. Its pathophysiology remains poorly understood. Lesion-related RLS has been reported, mainly in cases of stroke-related RLS involving the brainstem and lenticulostriate nuclei. Only few data of RLS in a context of spinal cord injury have been reported. FINDINGS: We report the case of a woman with secondary RLS due to hemorrhage of a spinal cord cavernoma located at T9-T10. Following recovery from the acute phase of the hemorrhage, the patient began to complain about restlessness in her legs causing impaired sleep and daytime somnolence. Polysomnographic investigations found a high index of periodic leg movements during sleep (71/hour), but no sleep disordered breathing. Iron stores were normal. Relief of symptom's severity was obtained with gabapentin 600mg in the evening. CONCLUSION/CLINICAL RELEVANCE: We hypothesize a possible involvement of the diencephalospinal pathway in the patient's RLS pathophysiology. A systematic study of focal lesions associated with RLS may contribute to improving our understanding of the pathophysiological mechanisms underlying this condition. The frequency of RLS associated with lesions of the spinal cord might be underestimated. Clinicians should be aware of spinal cord lesion-related RLS, especially as efficient treatments are available. PMID- 28899288 TI - Transitions and Transformations in Nursing Leadership. AB - The dialogue with Dr. Melanie Dreher focuses on a time of transition and her reflections on her career as a dean. Dr. Dreher shares from a personal and professional perspective. PMID- 28899289 TI - Pregnant With Promise for Far Too Long: Time to Deliver! AB - The meaning of the terms nursing science and science of nursing are briefly explored from an historical perspective than from a Rogerian nursing science perspective. Seminal ideas from Martha Rogers' writings, including an editorial from the inaugural issue of the journal Nursing Science, are noted. The author concludes with a Rogerian nursing science perspective of the unitary rhythm of dying-grieving with examples from participants of a qualitative study of the experience of relating to a loved one who has died. PMID- 28899291 TI - Ethics and Reverence for the Discipline of Nursing. AB - Healthcare disciplines, including nursing, are emerging sciences that contain discipline-specific theories that guide the activities of research, practice, and education. The term nursing science calls forth meaning that has long been accepted and referred to as the extant nursing theories undergirded with philosophy of science. Recent writings dispute the purposes and future usage of nursing theoretical frameworks in the science of nursing. The author of this article proposes new thinking about the importance of reverence and ethical implications for the future of formal inquiry in nursing science. PMID- 28899292 TI - Evidence or Clinicians or the Person: Who Should Be at the Center? AB - In this column, the issue of who should drive healthcare decision-making will be considered. To that end, evidence-based practice and evidence-informed practice models of care will be discussed. Problems with the use of each of these models will be brought to light followed by a presentation of a proposed model of care that puts the person at the center of healthcare decision- making. PMID- 28899293 TI - Feeling Comfortable: A Humanbecoming Perspective. AB - Feeling comfortable is a universal living experience. From the worldview of the humanbecoming paradigm, concept inventing is an appropriate method to expand understanding and knowledge of universal experiences. The purpose of this article is to provide a synthetic definition of feeling comfortable using the concept inventing process. Through concept inventing, a synthetic definition of feeling comfortable emerged as penetrating quietude amid potential upheaval arising with opportunities and restrictions with envisioning the familiar anew. Further development of the concept through qualitative research is recommended. PMID- 28899294 TI - Thoughts About Nursing Conceptual Models and the "Medical Model". AB - This essay, written to celebrate the 30th anniversary of Nursing Science Quarterly, focuses on the distinctions between the discipline of nursology and the trade of medicine. The distinctions are drawn from content found in nursing conceptual models and from literature about the elusive content of the so-called "medical model." PMID- 28899295 TI - Benner's Framework and Clinical Decision-Making in the Critical Care Environment. AB - Completed as part of a larger dissertational study, the purpose of this portion of this descriptive correlational study was to examine the relationships among registered nurses' clinical experiences and clinical decision-making processes in the critical care environment. The results indicated that there is no strong correlation between clinical experience in general and clinical experience in critical care and clinical decision-making. There were no differences found in any of the Benner stages of clinical experience in relation to the overall clinical decision-making process. PMID- 28899296 TI - Caring Science Conscious Dying: An Emerging Metaparadigm. AB - Caring science is an extant theory of human relationship, guiding the profession of nursing with the understanding and application of a moral-ethical praxis that promotes, protects, and provides human dignity throughout the life continuum. Over the past 30 or more years, caring science has transformed nursing by calling for a heightened ethical perspective of human dignity in how nurses practice, educate, research, and evolve the profession. Conscious dying is a framework rooted in a human caring ontology, which strives to deepen the nurse healer's awareness in tending to a patient's dying and death, returning death to its sacred place in the cycle of life. Reflective inventories are self-reflection tools that have been used to encourage nurses' personal growth and development and may be utilized in individual or group settings. The purpose herein is to introduce an emerging metaparadigm that links self to system, interweaving and integrating the teachings of caring science and conscious dying through the use of reflective inventories for both the individual nurse and collective of nursing. PMID- 28899297 TI - Thirty Years: Still Keeping the Dream Alive. PMID- 28899299 TI - Seeking Comfort. AB - This article introduces a concept inventing paper on feeling comfortable. The introduction describes a personal experience of seeking comfort, which includes serene calm amid distracting unrest. PMID- 28899300 TI - A Living Science, A Living Journal. PMID- 28899301 TI - Engaging and Honoring Older Adults in Research. AB - Research involving persons with cognitive changes associated with aging, including dementia, has increased dramatically in the past two decades, motivated in large part by an increasing number of older adults with such issues. Velzke in the paper that follows this introduction discusses why it is important and how to include older adults as participants in research. While focused primarily on elders and their caregivers in Scotland, the topic is a globally important one. PMID- 28899302 TI - Healthcare Crisis: Do Nurses Help or Hurt? AB - Healthcare is becoming a tangled web of dead ends, refusal of treatments by insurance companies who continue to report incredible profits, leaving many of the middle class and underserved without benefits, treatment, and care. The nursing profession must rise to this catastrophic state and strive for both in unison and individually so patients receive the care they need and deserve. PMID- 28899303 TI - Philosophical Clarity and Justifying the Scope of Advanced Practice Nursing. AB - The United States (US) Department of Veterans Affairs proposed a policy change for nursing practice that would grant full practice authority to advanced practice registered nurses (APRNs) nationwide. In this article, the author briefly explains this proposed policy and explores the relevance and implications of bringing philosophy into policy debates and discussions about the nature and scope of practice. PMID- 28899304 TI - Including the Voice of Older Adults in Research. AB - The authors of this paper discuss the use of participatory and visual research methods with older adults with daily care needs in the United Kingdom. The comments made by older adults and their caregivers in focus groups provided the narrative for this paper. The authors also discuss how to engage older adults in participatory research. Nursing research and practice both involve evaluating processes to gain a holistic understanding of patients through multiple means of data collection. In other words, how do nurses give voice to otherwise silent older adults, even in cases when their strength and recall is failing? PMID- 28899305 TI - Writing From the Edge. AB - On the 30th Anniversary of Nursing Science Quarterly, the 17-year journey of conceiving, launching, and guiding the "Teaching-Learning Column" was explored in this dialogue with Dr. Sandra Schmidt Bunkers, adjunct professor of nursing, South Dakota State University Brookings, South Dakota, founding contributing editor of the column, and Dr. Barbara Backer Condon, Professor of Nursing, Briar Cliff University, Sioux City, Iowa, contributing editor, 2012-2016. Reflecting on the shared stories, the challenge is offered to continue the tradition of the column in reading, writing, and thinking from the edge, to bravely consider what might be, daring to go beyond the confinements of mainstream thinking, and to vision as yet unimagined possibilities in teaching-learning in nursing. PMID- 28899306 TI - The Living Experience of Feeling Surprised. AB - The purpose of this article is to report the finding of a Parse research method study on the universal living experience of feeling surprised. In dialogical engagement with the researcher, eight participants described the experience. The structure of the living experience of feeling surprised was found to be: Feeling surprised is stunning amazement arising with shifting fortunes, as delight amid despair surfaces with diverse involvements. PMID- 28899307 TI - Atypical outbreak of Q fever affecting low-risk residents of a remote rural town in New South Wales. AB - We investigated an outbreak of Q fever in a remote rural town in New South Wales, Australia. Cases identified through active and passive case finding activities, and retrospective laboratory record review were interviewed using a standard questionnaire. Two sets of case-case analyses were completed to generate hypotheses regarding clinical, epidemiological and exposure risk factors associated with infection during the outbreak. Laboratory-confirmed outbreak cases (n=14) were compared with an excluded case group (n=16) and a group of historic Q fever cases from the region (n=106). In comparison with the historic case group, outbreak cases were significantly more likely to be female (43% vs. 18% males, P = 0.04) and identify as Aboriginal (29% vs. 7% non-Aboriginal, P = 0.03). Similarly, very few cases worked in high-risk occupations (21% vs. 84%, P < 0.01). Most outbreak cases (64%) reported no high-risk exposure activities in the month prior to onset. In comparison with the excluded case group, a significantly increased proportion of outbreak cases had contact with dogs (100% vs. 63%, P = 0.02) or sighted kangaroos on their residential property (100% vs. 60%, P = 0.02). High rates of tick exposure (92%) were also reported, although this was not significantly different from the excluded case group. While a source of this outbreak could not be confirmed, our findings suggest infections likely occurred via inhalation of aerosols or dust contaminated by Coxiella burnetii, dispersed through the town from either an unidentified animal facility or from excreta of native wildlife or feral animals. Alternatively transmission may have occurred via companion animals or tick vectors. PMID- 28899308 TI - Demographic and geographical risk factors for gonorrhoea and chlamydia in greater Western Sydney, 2003-2013. AB - INTRODUCTION: Notification rates of sexually transmitted infections (STIs) have increased in New South Wales as elsewhere in Australia. Understanding trends in chlamydia and gonorrhoea notifications at smaller geographical areas may assist public health efforts to deliver targeted STI interventions. METHODS: Routinely collected disease notification data from 2 local health districts within the greater Western Sydney area were analysed. De-identified notifications of gonorrhoea and chlamydia were extracted for people aged over 15 years during the period 1 January 2003 to 31 December 2013. Sex-specific and age-specific population notification rates for each infection were calculated. Incidence rate ratios were also calculated with age group, sex, year and local government area (LGA) of residence as explanatory variables. RESULTS: Rates of gonorrhoea and chlamydia increased among males and females over the period. Males had a 4-fold increased risk of gonorrhoea (P<0.0001). Compared with the 30-44 years age group, young people aged 15-29 years had a 70% increased risk of gonorrhoea and a 4-fold increased risk of chlamydia (P values < 0.0001). Chlamydia notifications demonstrated smaller and more uniform annual increases across LGAs compared with gonorrhoea notifications, which appeared more highly clustered. CONCLUSION: Analysis of notification rates of chlamydia and gonorrhoea in the greater Western Sydney area suggest that young people aged 15-29 years and residents of particular LGAs are at greater risk of infection. A limitation was the unknown effect of patterns of testing. Nevertheless, these results can support the planning of local sexual health clinical services as well as the design of targeted health promotion interventions. PMID- 28899309 TI - Waterparks are high risk for cryptosporidiosis: A case-control study in Victoria, 2015. AB - BACKGROUND: An increase in notifications of cryptosporidiosis was observed in Victoria between March and April 2015. Cases mostly resided in one metropolitan region and hypothesis-generating interviews identified common exposures to aquatic facilities. We conducted a case-control study to determine exposure source(s) and facilitate control measures. METHODS: Laboratory-confirmed cases of cryptosporidiosis from the region of interest notified between 1 March and 23 April 2015 were included. Controls residing in the same region were recruited from participants in a population health survey and frequency matched (2 per case) by age group. Details of exposure to potential risk factors were collected using a standardised telephone questionnaire for the 14-days prior to illness for cases, and an analogous exposure period for controls. Univariable and multivariable logistic regression were used to determine risk factors associated with illness using STATA SE 13.1. RESULTS: Thirty cases and 66 controls were included in the study. Half the cases were less than 12 years of age and 62% were female. Illness was most strongly associated with recreational water exposure at any waterpark (adjusted odds ratio (aOR)=73.5; 95% confidence interval (CI):6.74 802), and specifically at Victorian waterparks (aOR=45.6; 95% CI:5.20-399). Cases were linked with attendance at either a waterpark in the region or an adjacent region. As a result of this investigation, hyperchlorination was completed at identified facilities and swim hygiene information distributed. CONCLUSION: This study reinforces the potential for recreational water facilities, particularly waterparks, to act as a transmission source of Cryptosporidium infections. Continued communication to patrons is required to ensure healthy swimming practice in Victorian aquatic facilities. PMID- 28899311 TI - Australian National Enterovirus Reference Laboratory annual report, 2014. AB - Following the World Health Organization (WHO) recommendation, Australia conducts surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years of age as the main method to monitor its polio-free status. Cases of AFP in children are notified to the Australian Paediatric Surveillance Unit or the Paediatric Active Enhanced Disease Surveillance System and faecal specimens are referred for virological investigation to the National Enterovirus Reference Laboratory. In 2014, no cases of poliomyelitis were reported from clinical surveillance and Australia reported 1.4 non-polio AFP cases per 100,000 children, meeting the WHO performance criterion for a sensitive surveillance system. Non polio enteroviruses can also be associated with AFP and enterovirus A71 and echovirus types 6 and 7 were identified from clinical specimens from cases of AFP. Globally, 359 cases of polio were reported in 2014, with the 3 endemic countries, Afghanistan, Nigeria and Pakistan, accounting for 95% of the cases. In May 2014, the WHO declared the international spread of wild poliovirus to be a public health emergency of international concern and has since maintained recommendations for polio vaccination of travellers from countries reporting cases of wild polio. PMID- 28899310 TI - Influenza viruses received and tested by the Melbourne WHO Collaborating Centre for Reference and Research on Influenza annual report, 2015. AB - As part of its role in the World Health Organization's (WHO) Global Influenza Surveillance and Response System, the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received a total of 5,557 influenza positive samples during 2015. Viruses were analysed for their antigenic, genetic and antiviral susceptibility properties. In 2015, influenza B viruses predominated over influenza A(H1)pdm09 and A(H3) viruses, accounting for a total of 58% of all viruses analysed. The vast majority of A(H1)pdm09, A(H3) and influenza B viruses analysed at the Centre were found to be antigenically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2015. However, phylogenetic analysis of a selection of viruses indicated that the majority of circulating A(H3) viruses were genetically distinct from the WHO recommended strain for 2015, resulting in an update to the recommended vaccine strain for the Southern Hemisphere for 2016. With an increasing predominance of B/Victoria lineage viruses over B/Yamagata lineage viruses through the course of 2015, WHO also updated the recommended influenza B strain in the trivalent influenza vaccine for 2016. Of more than 3,300 samples tested for resistance to the neuraminidase inhibitors oseltamivir and zanamivir, only 1 A(H1)pdm09 virus showed highly reduced inhibition by oseltamivir. The Centre undertook primary isolation of candidate vaccine viruses directly into eggs, and in 2015 a total of 45 viruses were successfully isolated in eggs. PMID- 28899312 TI - Australian Paediatric Surveillance Unit annual report, 2015. PMID- 28899313 TI - OzFoodNet quarterly report, 1 January to 31 March 2015. PMID- 28899314 TI - National Notifiable Diseases Surveillance System, 1 January to 31 March 2017. PMID- 28899315 TI - Australian Meningococcal Surveillance Programme, 1 January to 31 March 2017. PMID- 28899316 TI - Road safety: serious injuries remain a major unsolved problem. AB - OBJECTIVE: To investigate temporal trends in the incidence, mortality, disability adjusted life-years (DALYs), and costs of health loss caused by serious road traffic injury. DESIGN, SETTING AND PARTICIPANTS: A retrospective review of data from the population-based Victorian State Trauma Registry and the National Coronial Information System on road traffic-related deaths (pre- and in-hospital) and major trauma (Injury Severity Score > 12) during 2007-2015.Main outcomes and measures: Temporal trends in the incidence of road traffic-related major trauma, mortality, DALYs, and costs of health loss, by road user type. RESULTS: There were 8066 hospitalised road traffic major trauma cases and 2588 road traffic fatalities in Victoria over the 9-year study period. There was no change in the incidence of hospitalised major trauma for motor vehicle occupants (incidence rate ratio [IRR] per year, 1.00; 95% CI, 0.99-1.01; P = 0.70), motorcyclists (IRR, 0.99; 95% CI, 0.97-1.01; P = 0.45) or pedestrians (IRR, 1.00; 95% CI, 0.97 1.02; P = 0.73), but the incidence for pedal cyclists increased 8% per year (IRR, 1.08; 95% CI; 1.05-1.10; P < 0.001). While DALYs declined for motor vehicle occupants (by 13% between 2007 and 2015), motorcyclists (32%), and pedestrians (5%), there was a 56% increase in DALYs for pedal cyclists. The estimated costs of health loss associated with road traffic injuries exceeded $14 billion during 2007-2015, although the cost per patient declined for all road user groups. CONCLUSIONS: As serious injury rates have not declined, current road safety targets will be difficult to meet. Greater attention to preventing serious injury is needed, as is further investment in road safety, particularly for pedal cyclists. PMID- 28899318 TI - Understanding and managing the health impacts of poor air quality from landscape fires. PMID- 28899319 TI - Public reporting of clinician-level data. PMID- 28899320 TI - Extreme heat threatens the health of Australians. PMID- 28899321 TI - Thunderstorm asthma outbreak of November 2016: a natural disaster requiring planning. PMID- 28899323 TI - Insights into the origin and identity of the discipline of public health. PMID- 28899322 TI - Von Meyenburg complexes in a patient with obstructive jaundice. PMID- 28899326 TI - Is inpatient rehabilitation after a routine total knee replacement justified? PMID- 28899327 TI - Reducing the rate of serious injuries to cyclists. PMID- 28899328 TI - The value of inpatient rehabilitation after uncomplicated knee arthroplasty: a propensity score analysis. AB - OBJECTIVE: To compare the effectiveness of rehabilitation after total knee arthroplasty (TKA) in models with or without an inpatient rehabilitation component. DESIGN, SETTING AND PARTICIPANTS: A propensity score-matched cohort of privately insured patients with osteoarthritis who underwent primary, unilateral TKA in one of 12 Australian hospitals between August 2013 and January 2015 were included. Those discharged to an inpatient facility because of poor progress or who experienced significant complications within 90 days of surgery were excluded. INTERVENTION: Discharge after surgery to an inpatient rehabilitation facility or home. MAIN OUTCOME MEASURES: Patient-reported knee pain and function (Oxford Knee Score; at 90 and 365 days after surgery) and health rating (EuroQol "today" health scale; at 35, 90 and 365 days). Inpatient and community-based rehabilitation provider charges were also assessed. RESULTS: 258 patients (129 pairs) from a sample of 332 were matched according to their propensity scores for receiving inpatient rehabilitation; covariates used in the matching included age, sex, body mass index, and markers of health and impairment. The only significant difference in outcomes was that EuroQol health scores were better on Day 35 for patients not undergoing inpatient rehabilitation (median difference, 5; IQR, -10 to 19; P = 0.01). Median rehabilitation provider charges were significantly higher for those discharged to inpatient therapy (total costs: median difference, $9500; IQR, $7000-11 497; P < 0.001; community therapy costs: median difference, $749; IQR, $0-1980; P < 0.001). CONCLUSIONS: Rehabilitation pathways incorporating inpatient rehabilitation did not achieve better joint-specific outcomes or health scores than alternatives not including inpatient rehabilitation. Given the substantial cost differences, better value alternatives should be considered for patients after uncomplicated TKA. PMID- 28899329 TI - Cataract surgery coverage rates for Indigenous and non-Indigenous Australians: the National Eye Health Survey. AB - OBJECTIVE: To determine cataract surgery coverage rates for Indigenous and non Indigenous Australians. DESIGN: National cross-sectional population-based survey. SETTING: Thirty randomly selected Australian geographic sites, stratified by remoteness. PARTICIPANTS: 3098 non-Indigenous Australians aged 50 years or more and 1738 Indigenous Australians aged 40 years or more, recruited and examined in the National Eye Health Survey (NEHS) between March 2015 and April 2016. METHODS: Participants underwent an interviewer-administered questionnaire that collected socio-demographic information and past ocular care history, including cataract surgery. For those with visual acuity worse than 6/12, anterior segment photography and slit lamp examinations were conducted. MAIN OUTCOME MEASURES: Cataract surgery coverage rates according to WHO and NEHS definitions; associated risk factors. RESULTS: Cataract surgery coverage rates calculated with the NEHS definition 1 of vision impairment (visual acuity worse than 6/12) were lower for Indigenous than non-Indigenous participants (58.5% v 88.0%; odds ratio [OR], 0.32; P < 0.001). According to the World Health Organization definition (eligibility criterion: best-corrected visual acuity worse than 6/18), coverage rates were 92.5% and 98.9% for Indigenous and non-Indigenous Australians respectively. Greater age was significantly associated with higher cataract surgery coverage in Indigenous (OR, 1.41 per 10 years; P = 0.048) and non Indigenous Australians (OR, 1.58 per 10 years; P = 0.004). CONCLUSIONS: The cataract surgery coverage rate was higher for non-Indigenous than Indigenous Australians, indicating the need to improve cataract surgery services for Indigenous Australians. The WHO definition of the coverage rate may overestimate the cataract surgery coverage rate in developed nations and should be applied with caution. PMID- 28899330 TI - REM sleep behaviour disorder: not just a bad dream. AB - Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of the normal atonia during the REM stage of sleep, resulting in overt motor behaviours that usually represent the enactment of dreams. Patients will seek medical attention due to sleep-related injuries or unpleasant dream content. Idiopathic RBD which occurs independently of any other disease occurs in up to 2% of the older population. Meanwhile, secondary RBD is very common in association with certain neurodegenerative conditions. RBD can also occur in the context of antidepressant use, obstructive sleep apnoea and narcolepsy. RBD can be diagnosed with a simple screening question followed by confirmation with polysomnography to exclude potential mimics. Treatment for RBD is effective and involves treatment of underlying causes, modification of the sleep environment, and pharmacotherapy with either clonazepam or melatonin. An important finding in the past decade is the recognition that almost all patients with idiopathic RBD will ultimately go on to develop Parkinson disease or dementia with Lewy bodies. This suggests that idiopathic RBD represents a prodromal phase of these conditions. Physicians should be aware of the risk of phenoconversion. They should educate idiopathic RBD patients to recognise the symptoms of these conditions and refer as appropriate for further testing and enrolment into research trials focused on neuroprotective measures. PMID- 28899331 TI - Influence of birth month on the probability of Western Australian children being treated for ADHD. PMID- 28899332 TI - Influence of birth month on the probability of Western Australian children being treated for ADHD. PMID- 28899333 TI - Invasive Neisseria gonorrhoeae producing pre-septal cellulitis and keratoconjunctivitis: diagnosis and management. PMID- 28899334 TI - The obesity epidemic and sugar-sweetened beverages: a taxing time. PMID- 28899335 TI - Family violence: an illustrated guide to the terminology. PMID- 28899336 TI - Around the universities and research institutes. PMID- 28899338 TI - Incidence and severity of postoperative sore throat: a randomized comparison of Glidescope with Macintosh laryngoscope. AB - BACKGROUND: Postoperative sore throat (POST) is a common problem following endotracheal (ET) intubation during general anesthesia. The objective was to compare the incidence and severity of POST during routine intubation with Glidescope (GL) and Macintosh laryngoscope (MCL). METHODS: One hundred forty adult patients ASA I and II with normal airway, scheduled to undergo elective surgery under GA requiring ET intubation were enrolled in this prospective randomized study and were randomly divided in two groups, GL and MCL. Incidence and severity of POST was evaluated at 0, 6, 12 and 24 h after surgery. RESULTS: At 0 h, the incidence of POST was more in MCL than GL (n = 41 v.s n = 22, P = 0.001), and also at 6 h after surgery (n = 37 v.s n = 23, P = 0.017). Severity of POST was more at 0, 6 and 12 h after surgery in MCL (P < 0.001, P = 0.001, P = 0.004 respectively). CONCLUSIONS: Routine use of GL for ET tube placement results in reduction in the incidence and severity of POST compared to MCL. TRIAL REGISRATION: ClinicalTrials.gov NCT02848365 . Retrospectively Registered (Date of registration: July, 2016). PMID- 28899339 TI - Ciliate diversity and distribution patterns in the sediments of a seamount and adjacent abyssal plains in the tropical Western Pacific Ocean. AB - BACKGROUND: Benthic ciliates and the environmental factors shaping their distribution are far from being completely understood. Likewise, deep-sea systems are amongst the least understood ecosystems on Earth. In this study, using high throughput DNA sequencing, we investigated the diversity and community composition of benthic ciliates in different sediment layers of a seamount and an adjacent abyssal plain in the tropical Western Pacific Ocean with water depths ranging between 813 m and 4566 m. Statistical analyses were used to assess shifts in ciliate communities across vertical sediment gradients and water depth. RESULTS: Nine out of 12 ciliate classes were detected in the different sediment samples, with Litostomatea accounting for the most diverse group, followed by Plagiopylea and Oligohymenophorea. The novelty of ciliate genetic diversity was extremely high, with a mean similarity of 93.25% to previously described sequences. On a sediment depth gradient, ciliate community structure was more similar within the upper sediment layers (0-1 and 9-10 cm) compared to the lower sediment layers (19-20 and 29-30 cm) at each site. Some unknown ciliate taxa which were absent from the surface sediments were found in deeper sediments layers. On a water depth gradient, the proportion of unique OTUs was between 42.2% and 54.3%, and that of OTUs shared by all sites around 14%. However, alpha diversity of the different ciliate communities was relatively stable in the surface layers along the water depth gradient, and about 78% of the ciliate OTUs retrieved from the surface layer of the shallowest site were shared with the surface layers of sites deeper than 3800 m. Correlation analyses did not reveal any significant effects of measured environmental factors on ciliate community composition and structure. CONCLUSIONS: We revealed an obvious variation in ciliate community along a sediment depth gradient in the seamount and the adjacent abyssal plain and showed that water depth is a less important factor shaping ciliate distribution in deep-sea sediments unlike observed for benthic ciliates in shallow seafloors. Additionally, an extremely high genetic novelty of ciliate diversity was found in these habitats, which points to a hot spot for the discovery of new ciliate species. PMID- 28899340 TI - Regulatory network changes between cell lines and their tissues of origin. AB - BACKGROUND: Cell lines are an indispensable tool in biomedical research and often used as surrogates for tissues. Although there are recognized important cellular and transcriptomic differences between cell lines and tissues, a systematic overview of the differences between the regulatory processes of a cell line and those of its tissue of origin has not been conducted. The RNA-Seq data generated by the GTEx project is the first available data resource in which it is possible to perform a large-scale transcriptional and regulatory network analysis comparing cell lines with their tissues of origin. RESULTS: We compared 127 paired Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs) and whole blood samples, and 244 paired primary fibroblast cell lines and skin samples. While gene expression analysis confirms that these cell lines carry the expression signatures of their primary tissues, albeit at reduced levels, network analysis indicates that expression changes are the cumulative result of many previously unreported alterations in transcription factor (TF) regulation. More specifically, cell cycle genes are over-expressed in cell lines compared to primary tissues, and this alteration in expression is a result of less repressive TF targeting. We confirmed these regulatory changes for four TFs, including SMAD5, using independent ChIP-seq data from ENCODE. CONCLUSIONS: Our results provide novel insights into the regulatory mechanisms controlling the expression differences between cell lines and tissues. The strong changes in TF regulation that we observe suggest that network changes, in addition to transcriptional levels, should be considered when using cell lines as models for tissues. PMID- 28899341 TI - Development of a home-based training program for post-ward geriatric rehabilitation patients with cognitive impairment: study protocol of a randomized controlled trail. AB - BACKGROUND: Geriatric patients with cognitive impairment (CI) show an increased risk for a negative rehabilitation outcome and reduced functional recovery following inpatient rehabilitation. Despite this obvious demand, evidence-based training programs at the transition from rehabilitation to the home environments are lacking. The aim of this study is to evaluate the efficacy of a feasible and cost-effective home-based training program to improve motor performance and to promote physical activity, specifically-tailored for post-ward geriatric patients with CI. METHODS: A sample of 101 geriatric patients with mild to moderate stage CI following ward-based rehabilitation will be recruited for a blinded, randomized controlled trial with two arms. The intervention group will conduct a 12 week home-based training, consisting of (1) Exercises to improve strength/power, and postural control; (2) Individual walking trails to enhance physical activity; (3) Implementation of patient-specific motivational strategies to promote behavioral changes. The control group will conduct 12 weeks of unspecific flexibility exercise. Both groups will complete a baseline measurement before starting the program, at the end of the intervention, and after 24 weeks for follow-up. Sensor-based as well as questionnaire-based measures will be applied to comprehensively assess intervention effects. Primary outcomes document motor performance, assessed by the Short Physical Performance Battery, and level of physical activity (PA), as assessed by duration of active episodes (i.e., sum of standing and walking). Secondary outcomes include various medical, psycho social, various PA and motor outcomes, including sensor-based assessment as well as cost effectiveness. DISCUSSION: Our study is among the first to provide home based training in geriatric patients with CI at the transition from a rehabilitation unit to the home environment. The program offers several unique approaches, e.g., a comprehensive and innovative assessment strategy and the integration of individually-tailored motivational strategies. We expect the program to be safe and feasible in geriatric patients with CI with the potential to enhance the sustainability of geriatric rehabilitation programs in patients with CI. TRIAL REGISTRATION: International Standard Randomized Controlled Trial (# ISRCTN82378327 ). Registered: August 10, 2015. PMID- 28899342 TI - Measuring the burden of treatment for chronic disease: implications of a scoping review of the literature. AB - BACKGROUND: Although there has been growing research on the burden of treatment, the current state of evidence on measuring this concept is unknown. This scoping review aimed to provide an overview of the current state of knowledge as well as clear recommendations for future research, within the context of chronic disease. METHODS: Four health-based databases, Scopus, CINAHL, Medline, and PsychInfo, were comprehensively searched for peer-reviewed articles published between the periods of 2000-2016. Titles and abstracts were independently read by two authors. All discrepancies between the authors were resolved by a third author. Data was extracted using a standardized proforma and a comparison analysis was used in order to explore the key treatment burden measures and categorize them into three groups. RESULTS: Database searching identified 1458 potential papers. After removal of duplications, and irrelevant articles by title, 1102 abstracts remained. An additional 22 papers were added via snowball searching. In the end, 101 full papers were included in the review. A large number of the studies involved quantitative measures and conceptualizations of treatment burden (n = 64; 63.4%), and were conducted in North America (n = 49; 48.5%). There was significant variation in how the treatment burden experienced by those with chronic disease was operationalized and measured. CONCLUSION: Despite significant work, there is still much ground to cover to comprehensively measure treatment burden for chronic disease. Greater qualitative focus, more research with cultural and minority populations, a larger emphasis on longitudinal studies and the consideration of the potential effects of "identity" on treatment burden, should be considered. PMID- 28899343 TI - Genome-wide gene expression analysis in the placenta from fetus with trisomy 21. AB - BACKGROUND: We performed whole human genome expression analysis in placenta tissue (normal and T21) samples in order to investigate gene expression into the pathogenesis of trisomy 21 (T21) placenta. We profiled the whole human genome expression of placental samples from normal and T21 fetuses using the GeneChip Human Genome U133 plus 2.0 array. Based on these data, we predicted the functions of differentially expressed genes using bioinformatics tools. RESULTS: A total of 110 genes had different expression patterns in the T21 placentas than they did in the normal placentas. Among them, 77 genes were up-regulated in the T21 placenta and 33 genes were down-regulated compared to their respective levels in normal placentas. Over half of the up-regulated genes (59.7%, n = 46) were located on HSA21. Up-regulated genes in the T21 placentas were significantly associated with T21 and its complications including mental retardation and neurobehavioral manifestations, whereas down-regulated genes were significantly associated with diseases, such as cystitis, metaplasia, pathologic neovascularization, airway obstruction, and diabetes mellitus. The interactive signaling network showed that 53 genes (40 up-regulated genes and 13 down-regulated genes) were an essential component of the dynamic complex of signaling (P < 1.39e-08). CONCLUSIONS: Our findings provide a broad overview of whole human genome expression in the placentas of fetuses with T21 and a possibility that these genes regulate biological pathways that have been involved in T21 and T21 complications. Therefore, these results could contribute to future research efforts concerning gene involvement in the disease's pathogenesis. PMID- 28899344 TI - Bacteriophages are the major drivers of Shigella flexneri serotype 1c genome plasticity: a complete genome analysis. AB - BACKGROUND: Shigella flexneri is the primary cause of bacillary dysentery in the developing countries. S. flexneri serotype 1c is a novel serotype, which is found to be endemic in many developing countries, but little is known about its genomic architecture and virulence signatures. We have sequenced for the first time, the complete genome of S. flexneri serotype 1c strain Y394, to provide insights into its diversity and evolution. RESULTS: We generated a high-quality reference genome of S. flexneri serotype 1c using the hybrid methods of long-read single molecule real-time (SMRT) sequencing technology and short-read MiSeq (Illumina) sequencing technology. The Y394 chromosome is 4.58 Mb in size and shares the basic genomic features with other S. flexneri complete genomes. However, it possesses unique and highly modified O-antigen structure comprising of three distinct O-antigen modifying gene clusters that potentially came from three different bacteriophages. It also possesses a large number of hypothetical unique genes compared to other S. flexneri genomes. CONCLUSIONS: Despite a high level of structural and functional similarities of Y394 genome with other S. flexneri genomes, there are marked differences in the pathogenic islands. The diversity in the pathogenic islands suggests that these bacterial pathogens are well adapted to respond to the selection pressures during their evolution, which might contribute to the differences in their virulence potential. PMID- 28899346 TI - One symptom, two arrhythmias: the rare and the even rarer. AB - BACKGROUND: Wolff-Parkinson-White (WPW) syndrome and idiopathic left ventricular tachycardia (ILVT) are rare and up to now the coexistence of both entities has rarely been reported. In patients with ventricular preexcitation the underlying mechanism of paroxysmal tachycardia most likely is atrioventricular reentrant tachycardia (AVRT). However, without ECG documentation of the tachycardia diagnosis of the underlying mechanism cannot be made due to similar clinical presentation of AVRT and ILVT. CASE PRESENTATION: We report a case of a two staged occurrence of two rare arrhythmias in a young adult, who was admitted to our hospital twice within 6 months because of paroxysmal tachycardia. WPW syndrome and ILVT as underlying arrhythmias have been diagnosed and were ablated successfully. CONCLUSIONS: This case highlights the diagnostic defiance of rare tachycardia entities and the paramount importance of ECG documentation and analysis of all available tachycardia ECGs. PMID- 28899345 TI - Phylogeographic structure, cryptic speciation and demographic history of the sharpbelly (Hemiculter leucisculus), a freshwater habitat generalist from southern China. AB - BACKGROUND: Species with broad distributions frequently divide into multiple genetic forms and may therefore be viewed as "cryptic species". Here, we used the mitochondrial cytochrome b (Cytb) and 12 nuclear DNA loci to investigate phylogeographic structures of the sharpbelly (Hemiculter leucisculus) in rivers in southern China and explored how the geological and climatic factors have shaped the genetic diversity and evolutionary history of this species. RESULTS: Our mitochondrial phylogenetic analysis identified three major lineages (lineages A, B, and C). Lineages B and C showed a relatively narrower geographic distribution, whereas lineage A was widely distributed in numerous drainages. Divergence dates suggested that H. leucisculus populations diverged between 1.61 2.38 Ma. Bayesian species delimitation analysis using 12 nuclear DNA loci indicated the three lineages probably represented three valid taxa. Isolation with-migration (IM) analysis found substantial gene flow has occurred among the three lineages. Demographic analyses showed that lineages B and C have experienced rapid demographic expansion at 0.03 Ma and 0.08 Ma, respectively. CONCLUSIONS: Hemiculter leucisculus populations in drainages in southern China comprise three mtDNA lineages, and each of which may represent a separate species. Intense uplift of the Qinghai-Tibetan Plateau, evolution of Asian monsoons, changes in paleo-drainages, and poor dispersal ability may have driven the divergence of the three putative species. However, gene flow occurs among the three lineages. Climatic fluctuations have a prominent impact on the populations from the lineages B and C, but exerted little influence on the lineage A. PMID- 28899347 TI - Case report of hyperglycemic nonketotic chorea with rapid radiological resolution. AB - BACKGROUND: Hemichorea is a rare manifestation of nonketotic hyperglycemia that usually affects elderly Asian women with poor glycemic control. Non-contrast computerized Tomography and T1- weighted Magnetic Resonance Imaging shows characteristic hyperintense basal ganglia lesions. CASE PRESENTATION: A Fifty seven year old Sri Lankan female presented with a two-day history of right upper limb chorea. She had been diagnosed with diabetes mellitus one year ago, but was not on any treatment and did not have any micro vascular or macro vascular complications. Random blood sugar was 420 mg/dl and full blood count, liver function tests, renal function tests, inflammatory markers, thyroid function tests, Urine protein / creatinine ratio, electrocardiogram and 2D Echo were normal. Arterial blood gas did not show acidosis and ketone bodies were not detected in urine. Non-contrast computerized Tomography brain on day 1 showed left side hyperdense lentiform and caudate nuclei and MRI on day 3 showed slightly high signal intensity of left side basal ganglia on T1- weighted images and low signal intensity on T2-weighted and Fluid-attenuated inversion recovery images. She was started on insulin and a low dose of clonazepam and glycemic control was achieved on day 3. Two days later, the chorea completely disappeared. CT brain was repeated 4 days and 10 days following glycemic control, which showed rapid resolution of CT changes. Clonazepam was stopped in 2 weeks and chorea did not recur. CONCLUSION: This is a rare manifestation of diabetes in Sri lanka and diagnosing this rare entity will direct clinicians to achieve optimum glycemic control as the treatment which will lead to rapid clinical response without any other medications. In this case report we high light that with the clinical improvement, repeating a CT scan even after a very short period like 2 weeks will show rapid radiological resolution. This repeat imaging can also be useful to confirm the diagnosis, which will minimize unnecessary investigations and treatments. Further cases of hyperglycemic nonketotic chorea with brain imaging performed within short intervals is needed to evaluate the nature of rapid radiological changes, which will be useful to understand the pathology of this condition. PMID- 28899348 TI - Cesarean section to prevent mother-to-child transmission of hepatitis B virus in China: A meta-analysis. AB - BACKGROUND: Hepatitis B virus (HBV) is predominantly transmitted through mother to-child transmission (MTCT). To date, it remains unclear whether the method of parturition affects MTCT of HBV. In order to clarify whether cesarean section, when compared with vaginal delivery, could reduce the risk of MTCT of HBV in China, we conducted this meta-analysis. METHODS: A systematic literature search was performed of the PubMed (Medline), Embase, ISI Web of Science, China Biological Medicine Database, China National Knowledge Infrastructure, and VIP Database for Chinese Technical Periodicals databases for articles written in English or Chinese through July 2015.The reference lists of relevant articles were also scrutinized for additional papers. Randomized controlled trials, cohort studies, or case-control studies investigating the effect of delivery mode on MTCT of HBV were included. RESULTS: This analysis involved 28 articles containing 30 datasets. The data encompassed 9906 participants. The MTCT rate of HBV was 6.76% (670 of 9906) overall, with individual rates of 4.37% (223 of 5105) for mothers who underwent cesarean section and 9.31% (447 of 4801) for those who underwent vaginal delivery. The summary relative risk (RR) was 0.51 (95%CI: 0.44 0.60, P < 0.001), indicating a statistically significant decrease in HBV vertical transmission via cesarean section compared with vaginal delivery. The heterogeneity among studies was moderate with an I 2 of29.3%.Publication bias was not detected by the Egger's and Begg's tests, and the funnel plot was symmetric. In the subgroup analyses, maternal hepatitis B e antigen status and follow-up time did not affect the significance of the results, but hepatitis B immune globulin (HBIG) administration to mother and infant did. CONCLUSIONS: Cesarean section could reduce the risk of MTCT of HBV in comparison to vaginal delivery in China. However, owing to several limitations of our meta-analysis, future well designed randomized controlled trials with adequate statistical power, might be a more appropriate next step. PMID- 28899349 TI - The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma. AB - BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) are recommended therapies for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear. METHODS: Between August 2004 and November 2014, 104 patients with BCLC stage B/C HCC were enrolled at the Affiliated Tumor Hospital of Guangxi Medical University, China. Forty-eight patients were treated with sorafenib alone (sorafenib group) and 56 with TACE plus sorafenib (TACE + sorafenib group). Baseline demographic/clinical data were collected. The primary outcomes were median overall survival (OS) and progression-free survival (PFS). Secondary outcomes were overall response rate (ORR) and sorafenib-related adverse events (AEs). Baseline characteristics associated with disease prognosis were identified using multivariate Cox hazards regression. RESULTS: The mean age of the 104 patients (94 males; 90.38%) was 49.02 +/- 12.29 years. Of the baseline data, only albumin level (P = 0.028) and Child-Pugh class (P = 0.017) differed significantly between groups. Median OS did not differ significantly between the sorafenib and TACE + sorafenib groups (18.0 vs. 22.0 months, P = 0.223). Median PFS was significantly shorter in the sorafenib group than that in the TACE + sorafenib group (6.0 vs. 8.0 months, P = 0.004). Six months after treatments, the ORRs were similar between the sorafenib and TACE + sorafenib groups (12.50% vs. 18.75%, P = 0.425). The rates of grade III-IV adverse events in sorafenib and TACE + sorafenib groups were 29.2% vs. 23.2%, respectively. TACE plus sorafenib treatment (HR = 0.498, 95% CI = 0.278-0.892), no vascular invasion (HR = 0.354, 95% CI = 0.183-0.685) and Child-Pugh class A (HR = 0.308, 95% CI = 0.141-0.674) were significantly associated with better OS, while a larger tumor number was predictive of poorer OS (HR = 1.286, 95% CI = 1.031-1.604). TACE plus sorafenib treatment (HR = 0.461, 95% CI = 0.273-0.780) and no vascular invasion (HR = 0.557, 95% CI = 0.314-0.988) were significantly associated with better PFS. CONCLUSIONS: Compared with sorafenib alone, combining TACE with sorafenib might prolong survival and delay disease progression in patients with advanced HCC. PMID- 28899350 TI - Epidemiological profile and obstetric outcomes of patients with peripartum congestive heart failure in Taiwan: a retrospective nationwide study. AB - BACKGROUND: During pregnancy, the hyperdynamic physiology of circulation can exacerbate many cardiovascular disorders. Congestive heart failure (CHF) usually occurs during late pregnancy, which is significantly associated with a high level of maternal and neonatal morbidities and mortalities. The profile of women who develop peripartum CHF (PCHF) is unknown. We investigated the epidemiological profiles of PCHF. METHODS: In this retrospective cohort study, PCHF patients were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in Taiwan's National Health Insurance Research Database. Risk factors and obstetric outcomes were compared in women with and without PCHF. RESULTS: From 2,115,873 birth-mothers in Taiwan between 1997 and 2013, we identified 512 with PCHF (incidence: 24.20/105). More women with than without PCHF were older (>= 35, 18.16% vs. 9.62%), and had more multifetal gestations (7.42% vs. 1.40%), gestational hypertension (HTN) (19.2% vs. 1.31%), and gestational diabetes mellitus (4.10% vs. 0.67%). After the analysis had been adjusted for confounders, the leading comorbidities associated with PCHF were structural heart diseases (adjusted odds ratio [aOR]: 67.21; 95% confidence interval [CI]: 54.29-83.22), pulmonary diseases (aOR: 13.12; 95% CI: 10.28-16.75), chronic HTN (aOR: 11.27; 95% CI: 6.94-18.28), thyroid disease (aOR: 9.53; 95% CI: 5.27-17.23), and gestational HTN (aOR: 5.16; 95% CI: 3.89-6.85). PCHF patients also had a higher rate of cesarean sections (66.41% vs. 34.46%; p < 0.0001). CONCLUSION: Maternal structural heart diseases, pulmonary diseases, thyroid disorders, and preexisting or gestational HTN are associated with a higher risk of developing PCHF. Birth-mothers with PCHF also had a higher risk of caesarean section and adverse outcomes, including maternal death. Our findings should benefit healthcare providers, and government and health insurance policy makers. PMID- 28899351 TI - Association of plasma potassium with mortality and end-stage kidney disease in patients with chronic kidney disease under nephrologist care - The NephroTest study. AB - BACKGROUND: Low and high blood potassium levels are common and were both associated with poor outcomes in patients with chronic kidney disease (CKD). Whether such relationships may be altered in CKD patients receiving optimized nephrologist care is unknown. METHODS: NephroTest is a hospital-based prospective cohort study that enrolled 2078 nondialysis patients (mean age: 59 +/- 15 years, 66% men) in CKD stages 1 to 5 who underwent repeated extensive renal tests including plasma potassium (PK) and glomerular filtration rate (GFR) measured (mGFR) by 51Cr-EDTA renal clearance. Test reports included a reminder of recommended targets for each abnormal value to guide treatment adjustment. Main outcomes were cardiovascular (CV) and all-cause mortality before end-stage kidney disease (ESKD), and ESKD. RESULTS: At baseline, median mGFR was 38.4 mL/min/1.73m2; prevalence of low PK (<4 mmol/L) was 26.5%, and of high PK (>5 mmol/L) 6.4%; 74.4% of patients used angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). After excluding 137 patients with baseline GFR < 10 mL/min/1.73m2 or lost to follow-up, 459 ESKD events and 236 deaths before ESKD (83 CV deaths) occurred during a median follow-up of 5 years. Compared to patients with PK within [4, 5] mmol/L at baseline, those with low PK had hazard ratios (HRs) [95% CI] for all-cause and CV mortality before ESKD, and for ESKD of 0.82 [0.58-1.16], 1.01 [0.52-1.95], and 1.14 [0.89-1.47], respectively, with corresponding figures for those with high PK of 0.79 [0.48 1.32], 1.5 [0.69-3.3], and 0.92 [0.70-1.21]. Considering time-varying PK did not materially change these findings, except for the HR of ESKD associated with high PK, 1.39 [1.09-1.78]. Among 1190 patients with at least two visits, PK had normalized at the second visit in 39.9 and 54.1% respectively of those with baseline low and high PK. Among those with low PK that normalized, ARB or ACEi use increased between the visits (68.3% vs 81.8%, P < .0001), and among those with high PK that normalized, potassium-binding resin and bicarbonate use increased (13.0% vs 37.0%, P < .001, and 4.4% vs 17.4%, P = 0.01, respectively) without decreased ACEi or ARB use. CONCLUSION: In these patients under nephrology care, neither low nor high PK was associated with excess mortality. PMID- 28899352 TI - Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker. AB - BACKGROUND: Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). METHODS: First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. RESULTS: Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/beta-catenin signalling pathway. CONCLUSION: The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients. PMID- 28899354 TI - Conducting a team-based multi-sited focused ethnography in primary care. AB - Focused ethnography is an applied and pragmatic form of ethnography that explores a specific social phenomenon as it occurs in everyday life. Based on the literature a problem-focused research question is formulated before the data collection. The data generation process targets key informants and situations so that relevant results on the pre-defined topic can be obtained within a relatively short time-span. As part of a theory based evaluation of alternative forms of consultation (such as video, phone and email) in primary care we used the focused ethnographic method in a multisite study in general practice across the UK. To date there is a gap in the literature on using focused ethnography in healthcare research.The aim of the paper is to build on the various methodological approaches in health services research by presenting the challenges and benefits we encountered whilst conducing a focused ethnography in British primary care. Our considerations are clustered under three headings: constructing a shared understanding, dividing the tasks within the team, and the functioning of the focused ethnographers within the broader multi-disciplinary team.As a result of using this approach we experienced several advantages, like the ability to collect focused data in several settings simultaneously within in a short time-span. Also, the sharing of experiences and interpretations between the researchers contributed to a more holistic understanding of the research topic. However, mechanisms need to be in place to facilitate and synthesise the observations, guide the analysis, and to ensure that all researchers feel engaged. Reflection, trust and flexibility among the team members were crucial to successfully adopt a team focused ethnographic approach. When used for policy focussed applied healthcare research a team-based multi-sited focused ethnography can uncover practices and understandings that would not be apparent through surveys or interviews alone. If conducted with care, it can provide timely findings within the fast moving context of healthcare policy and research. PMID- 28899353 TI - Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation. AB - BACKGROUND: Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns. RESULTS: Using a comparative epigenomics approach, we identified and compared the tissue-specific DNA methylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors. CONCLUSIONS: Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites. PMID- 28899355 TI - Genetic tests for estimating dairy breed proportion and parentage assignment in East African crossbred cattle. AB - BACKGROUND: Smallholder dairy farming in much of the developing world is based on the use of crossbred cows that combine local adaptation traits of indigenous breeds with high milk yield potential of exotic dairy breeds. Pedigree recording is rare in such systems which means that it is impossible to make informed breeding decisions. High-density single nucleotide polymorphism (SNP) assays allow accurate estimation of breed composition and parentage assignment but are too expensive for routine application. Our aim was to determine the level of accuracy achieved with low-density SNP assays. METHODS: We constructed subsets of 100 to 1500 SNPs from the 735k-SNP Illumina panel by selecting: (a) on high minor allele frequencies (MAF) in a crossbred population; (b) on large differences in allele frequency between ancestral breeds; (c) at random; or (d) with a differential evolution algorithm. These panels were tested on a dataset of 1933 crossbred dairy cattle from Kenya/Uganda and on crossbred populations from Ethiopia (N = 545) and Tanzania (N = 462). Dairy breed proportions were estimated by using the ADMIXTURE program, a regression approach, and SNP-best linear unbiased prediction, and tested against estimates obtained by ADMIXTURE based on the 735k-SNP panel. Performance for parentage assignment was based on opposing homozygotes which were used to calculate the separation value (sv) between true and false assignments. RESULTS: Panels of SNPs based on the largest differences in allele frequency between European dairy breeds and a combined Nelore/N'Dama population gave the best predictions of dairy breed proportion (r2 = 0.962 to 0.994 for 100 to 1500 SNPs) with an average absolute bias of 0.026. Panels of SNPs based on the highest MAF in the crossbred population (Kenya/Uganda) gave the most accurate parentage assignments (sv = -1 to 15 for 100 to 1500 SNPs). CONCLUSIONS: Due to the different required properties of SNPs, panels that did well for breed composition did poorly for parentage assignment and vice versa. A combined panel of 400 SNPs was not able to assign parentages correctly, thus we recommend the use of 200 SNPs either for breed proportion prediction or parentage assignment, independently. PMID- 28899356 TI - Barriers to lifestyle changes for prevention of cardiovascular disease - a survey among 40-60-year old Danes. AB - BACKGROUND: Elimination of modifiable risk factors including unhealthy lifestyle has the potential for prevention of 80% of cardiovascular disease cases. The present study focuses on disclosing barriers for maintaining specific lifestyle changes by exploring associations between perceiving these barriers and various sociodemographic and health-related characteristics. METHODS: Data were collected through a web-based questionnaire survey and included 962 respondents who initially accepted treatment for a hypothetical cardiovascular risk, and who subsequently stated that they preferred lifestyle changes to medication. Logistic regression was used to analyse associations between barriers to lifestyle changes and relevant covariates. RESULTS: A total of 45% of respondents were identified with at least one barrier to introducing 30 min extra exercise daily, 30% of respondents reported at least one barrier to dietary change, and among smokers at least one barrier to smoking cessation was reported by 62% of the respondents. The perception of specific barriers to lifestyle change depended on sociodemographic and health-related characteristics. CONCLUSION: We observed a considerable heterogeneity between different social groups in the population regarding a number of barriers to lifestyle change. Our study demonstrates that social inequality exists in the ability to take appropriate preventive measures through lifestyle changes to stay healthy. This finding underlines the challenge of social inequality even in populations with equal and cost-free access to health care. Our study suggests supplementing traditional public campaigns to counter cardiovascular disease by using individualized and targeted initiatives. PMID- 28899358 TI - Visualization of chromosome condensation in plants with large chromosomes. AB - BACKGROUND: Most data concerning chromosome organization have been acquired from studies of a small number of model organisms, the majority of which are mammals. In plants with large genomes, the chromosomes are significantly larger than the animal chromosomes that have been studied to date, and it is possible that chromosome condensation in such plants was modified during evolution. Here, we analyzed chromosome condensation and decondensation processes in order to find structural mechanisms that allowed for an increase in chromosome size. RESULTS: We found that anaphase and telophase chromosomes of plants with large chromosomes (average 2C DNA content exceeded 0.8 pg per chromosome) contained chromatin-free cavities in their axial regions in contrast to well-characterized animal chromosomes, which have high chromatin density in the axial regions. Similar to animal chromosomes, two intermediates of chromatin folding were visible inside condensing (during prophase) and decondensing (during telophase) chromosomes of Nigella damascena: approximately 150 nm chromonemata and approximately 300 nm fibers. The spatial folding of the latter fibers occurs in a fundamentally different way than in animal chromosomes, which leads to the formation of chromosomes with axial chromatin-free cavities. CONCLUSION: Different compaction topology, but not the number of compaction levels, allowed for the evolution of increased chromosome size in plants. PMID- 28899357 TI - Comparative transcriptome analysis provides clues to molecular mechanisms underlying blue-green eggshell color in the Jinding duck (Anas platyrhynchos). AB - BACKGROUND: In birds, blue-green eggshell color (BGEC) is caused by biliverdin, a bile pigment derived from the degradation of heme and secreted in the eggshell by the shell gland. Functionally, BGEC might promote the paternal investment of males in the nest and eggs. However, little is known about its formation mechanisms. Jinding ducks (Anas platyrhynchos) are an ideal breed for research into the mechanisms, in which major birds lay BGEC eggs with minor individuals laying white eggs. Using this breed, this study aimed to provide insight into the mechanisms via comparative transcriptome analysis. RESULTS: Blue-shelled ducks (BSD) and white-shelled ducks (WSD) were selected from two populations, forming 4 groups (3 ducks/group): BSD1 and WSD1 from population 1 and BSD2 and WSD2 from population 2. Twelve libraries from shell glands were sequenced using the Illumina RNA-seq platform, generating an average of 41 million clean reads per library, of which 55.9% were mapped to the duck reference genome and assembled into 31,542 transcripts. Expression levels of 11,698 genes were successfully compared between all pairs of 4 groups. Of these, 464 candidate genes were differentially expressed between cross-phenotype groups, but not for between same phenotype groups. Gene Ontology (GO) annotation showed that 390 candidate genes were annotated with 2234 GO terms. No candidate genes were directly involved in biosynthesis or transport of biliverdin. However, the integral components of membrane, metal ion transport, cholesterol biosynthesis, signal transduction, skeletal system development, and chemotaxis were significantly (P < 0.05) overrepresented by candidate genes. CONCLUSIONS: This study identified 464 candidate genes associated with duck BGEC, providing valuable information for a better understanding of the mechanisms underlying this trait. Given the involvement of membrane cholesterol contents, ions and ATP levels in modulating the transport activity of bile pigment transporters, the data suggest a potential association between duck BGEC and the transport activity of the related transporters. PMID- 28899359 TI - Transcript profiling of the immunological interactions between Actinobacillus pleuropneumoniae serotype 7 and the host by dual RNA-seq. AB - BACKGROUND: The complexity of the pathogenic mechanism underlying the host immune response to Actinobacillus pleuropneumonia (App) makes the use of preventive measures difficult, and a more global view of the host-pathogen interactions and new insights into this process are urgently needed to reveal the pathogenic and immune mechanisms underlying App infection. Here, we infected specific pathogen free Mus musculus with App serotype 7 by intranasal inoculation to construct an acute hemorrhagic pneumonia infection model and isolated the infected lungs for analysis of the interactions by dual RNA-seq. RESULTS: Four cDNA libraries were constructed, and 2428 differentially expressed genes (DEGs) of the host and 333 DEGs of App were detected. The host DEGs were mainly enriched in inflammatory signaling pathways, such as the TLR, NLR, RLR, BCR and TCR signaling pathways, resulting in large-scale cytokine up-regulation and thereby yielding a cytokine cascade for anti-infection and lung damage. The majority of the up-regulated cytokines are involved in the IL-23/IL-17 cytokine-regulated network, which is crucial for host defense against bacterial infection. The DEGs of App were mainly related to the transport and metabolism of energy and materials. Most of these genes are metabolic genes involved in anaerobic metabolism and important for challenging the host and adapting to the anaerobic stress conditions observed in acute hemorrhagic pneumonia. Some of these genes, such as adhE, dmsA, and aspA, might be potential virulence genes. In addition, the up-regulation of genes associated with peptidoglycan and urease synthesis and the restriction of major virulence genes might be immune evasion strategies of App. The regulation of metabolic genes and major virulence genes indicate that the dominant antigens might differ during the infection process and that vaccines based on these antigens might allow establishment of a precise and targeted immune response during the early phase of infection. CONCLUSION: Through an analysis of transcriptional data by dual RNA-seq, our study presents a novel global view of the interactions of App with its host and provides a basis for further study. PMID- 28899360 TI - Biological networks in Parkinson's disease: an insight into the epigenetic mechanisms associated with this disease. AB - BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorders in the world. Studying PD from systems biology perspective involving genes and their regulators might provide deeper insights into the complex molecular interactions associated with this disease. RESULT: We have studied gene co-expression network obtained from a PD-specific microarray data. The co-expression network identified 11 hub genes, of which eight genes are not previously known to be associated with PD. Further study on the functionality of these eight novel hub genes revealed that these genes play important roles in several neurodegenerative diseases. Furthermore, we have studied the tissue specific expression and histone modification patterns of the novel hub genes. Most of these genes possess several histone modification sites those are already known to be associated with neurodegenerative diseases. Regulatory network namely mTF-miRNA-gene-gTF involves microRNA Transcription Factor (mTF), microRNA (miRNA), gene and gene Transcription Factor (gTF). Whereas long noncoding RNA (lncRNA) mediated regulatory network involves miRNA, gene, mTF and lncRNA. mTF miRNA-gene-gTF regulatory network identified a novel feed-forward loop. lncRNA mediated regulatory network identified novel lncRNAs of PD and revealed the two way regulatory pattern of PD-specific miRNAs where miRNAs can be regulated by both the TFs and lncRNAs. SNP analysis of the most significant genes of the co expression network identified 20 SNPs. These SNPs are present in the 3' UTR of known PD genes and are controlled by those miRNAs which are also involved in PD. CONCLUSION: Our study identified eight novel hub genes which can be considered as possible candidates for future biomarker identification studies for PD. The two regulatory networks studied in our work provide a detailed overview of the cellular regulatory mechanisms where the non-coding RNAs namely miRNA and lncRNA, can act as epigenetic regulators of PD. SNPs identified in our study can be helpful for identifying PD at an earlier stage. Overall, this study may impart a better comprehension of the complex molecular interactions associated with PD from systems biology perspective. PMID- 28899361 TI - Interactive visual exploration and refinement of cluster assignments. AB - BACKGROUND: With ever-increasing amounts of data produced in biology research, scientists are in need of efficient data analysis methods. Cluster analysis, combined with visualization of the results, is one such method that can be used to make sense of large data volumes. At the same time, cluster analysis is known to be imperfect and depends on the choice of algorithms, parameters, and distance measures. Most clustering algorithms don't properly account for ambiguity in the source data, as records are often assigned to discrete clusters, even if an assignment is unclear. While there are metrics and visualization techniques that allow analysts to compare clusterings or to judge cluster quality, there is no comprehensive method that allows analysts to evaluate, compare, and refine cluster assignments based on the source data, derived scores, and contextual data. RESULTS: In this paper, we introduce a method that explicitly visualizes the quality of cluster assignments, allows comparisons of clustering results and enables analysts to manually curate and refine cluster assignments. Our methods are applicable to matrix data clustered with partitional, hierarchical, and fuzzy clustering algorithms. Furthermore, we enable analysts to explore clustering results in context of other data, for example, to observe whether a clustering of genomic data results in a meaningful differentiation in phenotypes. CONCLUSIONS: Our methods are integrated into Caleydo StratomeX, a popular, web-based, disease subtype analysis tool. We show in a usage scenario that our approach can reveal ambiguities in cluster assignments and produce improved clusterings that better differentiate genotypes and phenotypes. PMID- 28899362 TI - Nationwide cross-sectional survey of schistosomiasis and soil-transmitted helminthiasis in Sudan: study protocol. AB - BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis (STHs) are target neglected tropical diseases (NTDs) of preventive chemotherapy, but the control and elimination of these diseases have been impeded due to resource constraints. Few reports have described study protocol to draw on when conducting a nationwide survey. We present a detailed methodological description of the integrated mapping of schistosomiasis and STHs on the basis of our experiences, hoping that this protocol can be applied to future surveys in similar settings. In addition to determining the ecological zones requiring mass drug administration interventions, we aim to provide precise estimates of the prevalence of these diseases. METHODS: A school-based cross-sectional design will be applied for the nationwide survey across Sudan. The survey is designed to cover all districts in every state. We have divided each district into 3 different ecological zones depending on proximity to bodies of water. We will employ a probability proportional-to-size sampling method for schools and systematic sampling for student selection to provide adequate data regarding the prevalence for schistosomiasis and STHs in Sudan at the state level. A total of 108,660 students will be selected from 1811 schools across Sudan. After the survey is completed, 391 ecological zones will be mapped out. To carry out the survey, 655 staff members were recruited. The feces and urine samples are microscopically examined by the Kato-Katz method and the sediment smears for helminth eggs respectively. For quality control, a minimum of 10% of the slides will be rechecked by the federal supervisors in each state and also 5% of the smears are validated again within one day by independent supervisors. DISCUSSION: This nationwide mapping is expected to generate important epidemiological information and indicators about schistosomiasis and STHs that will be useful for monitoring and evaluating the control program. The mapping data will also be used for overviewing the status and policy formulation and updates to the control strategies. This paper, which describes a feasible and practical study protocol, is to be shared with the global health community, especially those who are planning to perform nationwide mapping of NTDs by feces or urine sampling. PMID- 28899363 TI - A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer. AB - BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. METHODS: This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2 overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. RESULTS: Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. CONCLUSIONS: LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012). PMID- 28899364 TI - Determination of risk factors affecting the in-hospital prognosis of patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention. AB - BACKGROUND: To determine the factors affecting the in-hospital prognosis of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI), and to establish its prognostic discriminant model. METHODS: A total of 701 consecutive STEMI patients undergoing PCI were enrolled in this study. The patients were divided into two groups, good prognosis and poor prognosis, based on whether the patient had adverse outcomes (death or heart function >= grade III) at discharge. Demographic and basic clinical characteristics, diagnosis at admission (e.g., ventricular function, complications, or hyperlipidemia), and biomedical indicators (e.g., blood count, basal metabolism and biochemical composition, blood lipid and glucose levels, myocardial biomarkers, and coagulation) were collected and analyzed. RESULTS: We determined 22 factors as risk factors for the in-hospital prognosis of STEMI patients after PCI: age, cardiac function during hospitalization, complications, history of diabetes mellitus, et al., among which the history of diabetes, uric acid, urea nitrogen, and activated partial thromboplastin time (APTT) were independent risk factors. CONCLUSION: We identified four independent risk factors for the in-hospital prognosis of STEMI patients after PCI and generated a prognostic model to predict the adverse outcomes of these patients. PMID- 28899365 TI - Implementation of internet-delivered cognitive behavior therapy within community mental health clinics: a process evaluation using the consolidated framework for implementation research. AB - BACKGROUND: Depression and anxiety are prevalent and under treated conditions that create enormous burden for the patient and the health system. Internet delivered cognitive behavior therapy (ICBT) improves patient access to treatment by providing therapeutic information via the Internet, presented in sequential lessons, accompanied by brief weekly therapist support. While there is growing research supporting ICBT, use of ICBT within community mental health clinics is limited. In a recent trial, an external unit specializing in ICBT facilitated use of ICBT in community mental health clinics in one Canadian province (ISRCTN42729166; registered November 5, 2013). Patient outcomes were very promising and uptake was encouraging. This paper reports on a parallel process evaluation designed to understand facilitators and barriers impacting the uptake and implementation of ICBT. METHODS: Therapists (n = 22) and managers (n = 11) from seven community mental health clinics dispersed across one Canadian province who were involved in implementing ICBT over ~2 years completed an online survey (including open and closed-ended questions) about ICBT experiences. The questions were based on the Consolidated Framework for Implementation Research (CFIR), which outlines diverse constructs that have the potential to impact program implementation. RESULTS: Analyses suggested ICBT implementation was perceived to be most prominently facilitated by intervention characteristics (namely the relative advantages of ICBT compared to face-to-face therapy, the quality of the ICBT program that was delivered, and evidence supporting ICBT) and implementation processes (namely the use of an external facilitation unit that aided with engaging patients, therapists, and managers and ICBT implementation). The inner setting was identified as the most significant barrier to implementation as a result of limited resources for ICBT combined with greater priority given to face to-face care. CONCLUSIONS: The results contribute to understanding facilitators and barriers to using ICBT within community mental health clinics and serve to identify recommendations for improving uptake and implementation of ICBT in clinic settings. PMID- 28899366 TI - Effects of physical activity calorie expenditure (PACE) labeling: study design and baseline sample characteristics. AB - BACKGROUND: Obesity and physical inactivity are responsible for more than 365,000 deaths per year and contribute substantially to rising healthcare costs in the US, making clear the need for effective public health interventions. Calorie labeling on menus has been implemented to guide consumer ordering behaviors, but effects on calories purchased has been minimal. METHODS: In this project, we tested the effect of physical activity calorie expenditure (PACE) food labels on actual point-of-decision food purchasing behavior as well as physical activity. Using a two-group interrupted time series cohort study design in three worksite cafeterias, one cafeteria was assigned to the intervention condition, and the other two served as controls. Calories from food purchased in the cafeteria were assessed by photographs of meals (accompanied by notes made on-site) using a standardized calorie database and portion size-estimation protocol. Primary outcomes will be average calories purchased and minutes of moderate to vigorous physical activity (MVPA) by individuals in the cohorts. We will compare pre-post changes in study outcomes between study groups using piecewise generalized linear mixed model regressions (segmented regressions) with a single change point in our interrupted time-series study. The results of this project will provide evidence of the effectiveness of worksite cafeteria menu labeling, which could potentially inform policy intervention approaches. DISCUSSION: Labels that convey information in a more readily understandable manner may be more effective at motivating behavior change. Strengths of this study include its cohort design and its robust data capture methods using food photographs and accelerometry. PMID- 28899367 TI - Is economic environment associated with the physical activity levels and obesity in Chinese adults? A cross-sectional study of 30 regions in China. AB - BACKGROUND: Based on the 2014 survey of physical activity and physical fitness data of 20 - 69 year old Chinese, this study aims to investigate the relationship between economic development and people's physical activity in China. METHODS: A total of 43,389 adults from 30 different regions in mainland China were recruited. The GDP per capita of the 30 regions were determined based on the 2013 annual statistical report released by the national bureau of statistics of China and provincial level statistics bureaus. A questionnaire was used to determine the participants' exercise frequency, duration, and intensity. RESULTS: For the 30 regions surveyed, the correlation coefficients between GDP per capita and weekly activity were 0.23 for men and 0.15 for women. The correlation coefficients between GDP per capita and obesity rates were 0.52 for men and 0.39 for women. CONCLUSIONS: Although people in economically advanced regions in China currently engage in more physical activities than those in less economically developed regions, overweight and obesity persist as serious problems. PMID- 28899368 TI - Neighborhood-resources for the development of a strong SOC and the importance of understanding why and how resources work: a grounded theory approach. AB - BACKGROUND: Providing individuals with psychosocial resources such as sense of coherence (SOC) seems a beneficial strategy for health promotion in the neighborhood. In order to become a supporting theory for health promotion, Salutogenesis should renew its focus on resources for health, and explore how the development of a strong SOC can be facilitated. METHODS: Relevant issues were explored using a Grounded Theory- approach. Three focus-group-sessions and three in-depth interviews were conducted with strategically sampled participants. The transcripts of the focus groups were initially analyzed line-by-line to ensure that insights emerged from the data. We then applied focused and systemic analyses to achieve axial coding, and to include insights into how social interactions during focus groups may reveal social processes in real-life neighborhoods. The data from the in-depth interviews were used to validate and fill emerging categories, as well as to ensure data-saturation. RESULTS: Findings indicate the importance of repeated experiences with resources and every-day challenges to develop a strong SOC. Active engagement with resources is a favorable condition for significant experiences, which enhance the internalization of resources. Core experiences are characterized by a re organization of resources. Participation in intellectual meaning-making through equal power dialogue seems to broaden perspectives and promote the strengthening of SOC. A strong SOC can also be described as a deeper understanding of how and why resources work, which allows for a more flexible use of resources, including replacing missing resources. CONCLUSION: A new understanding of SOC as an intuitive understanding of how, why and under which circumstances resources work, as well as a new focus on everyday life and repeated experiences might facilitate new approaches to a purposeful strengthening of SOC through the planning and implementation of public measures. PMID- 28899369 TI - Nursing care needs and services utilised by home-dwelling elderly with complex health problems: observational study. AB - BACKGROUND: In Norway, as in many Western countries, a shift from institutional care to home care is taking place. Our knowledge is limited regarding which needs for nursing interventions patients being cared for in their home have, and how they are met. We aimed at assessing aspects of health and function in a representative sample of the most vulnerable home-dwelling elderly, to identify their needs for nursing interventions and how these needs were met. METHODS: In this observational study we included patients aged 75+ living in their own homes in Oslo, who received daily home care, had three or more chronic diagnoses, received daily medication, and had been hospitalized during the last year. Focused attention and cognitive processing speed were assessed with the Trail Making Test A (TMT-A), handgrip strength was used as a measure of sarcopenia, mobility was assessed with the "Timed Up-and-Go" test, and independence in primary activities of daily living by the Barthel Index. Diagnoses and medication were collected from electronic medical records. For each diagnosis, medication and functional impairment, a consensus group defined which nursing service that the particular condition necessitated. We then assessed whether these needs were fulfilled for each participant. RESULTS: Of 150 eligible patients, 83 were included (mean age 87 years, 25% men). They had on average 6 diagnoses and used 9 daily medications. Of the 83 patients, 61 (75%) had grip strength indicating sarcopenia, 27 (33%) impaired mobility, and 69 (83%) an impaired TMT-A score. Median amount of home nursing per week was 3.6 h (interquartile range 2.6 to 23.4). Fulfilment of pre-specified needs was >60% for skin and wound care in patients with skin diseases, observation of blood glucose in patients taking antidiabetic drugs, and in supporting food intake in patients with eating difficulties. Most other needs as defined by the consensus group were fulfilled in <10% of the patients. CONCLUSIONS: We identified a very frail group of home dwelling patients. For this group, resources for home nursing should probably be used in a more flexible and pro-active way to aim for preserving functional status, minimize symptom burden, and prevent avoidable hospitalisations. PMID- 28899370 TI - Resource utilization and costs associated with the addition of an antimuscarinic in patients treated with an alpha-blocker for the treatment of urinary symptoms linked to benign prostatic hyperplasia. PMID- 28899371 TI - Simultaneous detection of alpha-Lactoalbumin, beta-Lactoglobulin and Lactoferrin in milk by Visualized Microarray. AB - BACKGROUND: alpha-Lactalbumin (a-LA), beta-lactoglobulin (beta-LG) and lactoferrin (LF) are of high nutritional value which have made ingredients of choice in the formulation of modern foods and beverages. There remains an urgent need to develop novel biosensing methods for quantification featuring reduced cost, improved sensitivity, selectivity and more rapid response, especially for simultaneous detection of multiple whey proteins. RESULTS: A novel visualized microarray method was developed for the determination of a-LA, beta-LG and LF in milk samples without the need for complex or time-consuming pre-treatment steps. The measurement principle was based on the competitive immunological reaction and silver enhancement technique. In this case, a visible array dots as the detectable signals were further amplified and developed by the silver enhancement reagents. The microarray could be assayed by the microarray scanner. The detection limits (S/N = 3) were estimated to be 40 ng/mL (alpha-LA), 50 ng/mL (beta-LG), 30 ng/mL (LF) (n = 6). CONCLUSIONS: The method could be used to simultaneously analyze the whey protein contents of various raw milk samples and ultra-high temperature treated (UHT) milk samples including skimmed milk and high calcium milk. The analytical results were in good agreement with that of the high performance liquid chromatography. The presented visualized microarray has showed its advantages such as high-throughput, specificity, sensitivity and cost effective for analysis of various milk samples. PMID- 28899372 TI - The combination of recombinant and non-recombinant Bacillus subtilis spore display technology for presentation of antigen and adjuvant on single spore. AB - BACKGROUND: Bacillus subtilis spores can be used for presentation of heterologous proteins. Two main approaches have been developed, the recombinant one, requiring modification of bacterial genome to express a protein of interest as a fusion with spore-coat protein, and non-recombinant, based on the adsorption of a heterologous protein onto the spore. So far only single proteins have been displayed on the spore surface. RESULTS: We have used a combined approach to adsorb and display FliD protein of Clostridium difficile on the surface of recombinant IL-2-presenting spores. Such spores presented FliD protein with efficiency comparable to FliD-adsorbed spores produced by wild-type 168 strain and elicited FliD-specific immune response in intranasally immunized mice. CONCLUSIONS: Our results indicate that such dual display technology may be useful in creation of spores simultaneously presenting adjuvant and antigen molecules. Regarding the characteristics of elicited immune response it seems plausible that such recombinant IL-2-presenting spores with adsorbed FliD protein might be an interesting candidate for vaccine against infections with Clostridium difficile. PMID- 28899373 TI - Maximizing the impact of malaria funding through allocative efficiency: using the right interventions in the right locations. AB - BACKGROUND: The high burden of malaria and limited funding means there is a necessity to maximize the allocative efficiency of malaria control programmes. Quantitative tools are urgently needed to guide budget allocation decisions. METHODS: A geospatial epidemic model was coupled with costing data and an optimization algorithm to estimate the optimal allocation of budgeted and projected funds across all malaria intervention approaches. Interventions included long-lasting insecticide-treated nets (LLINs), indoor residual spraying (IRS), intermittent presumptive treatment during pregnancy (IPTp), seasonal mass chemoprevention in children (SMC), larval source management (LSM), mass drug administration (MDA), and behavioural change communication (BCC). The model was applied to six geopolitical regions of Nigeria in isolation and also the nation as a whole to minimize incidence and malaria-attributable mortality. RESULTS: Allocative efficiency gains could avert approximately 84,000 deaths or 15.7 million cases of malaria in Nigeria over 5 years. With an additional US$300 million available, approximately 134,000 deaths or 37.3 million cases of malaria could be prevented over 5 years. Priority funding should go to LLINs, IPTp and BCC programmes, and SMC should be expanded in seasonal areas. To minimize mortality, treatment expansion is critical and prioritized over some LLIN funding, while to minimize incidence, LLIN funding remained a priority. For areas with lower rainfall, LSM is prioritized over IRS but MDA is not recommended unless all other programmes are established. CONCLUSIONS: Substantial reductions in malaria morbidity and mortality can be made by optimal targeting of investments to the right malaria interventions in the right areas. PMID- 28899375 TI - Erratum to: development and testing of a mobile application to support diabetes self-management for people with newly diagnosed type 2 diabetes: a design thinking case study. PMID- 28899374 TI - Determinants of internal migrant health and the healthy migrant effect in South India: a mixed methods study. AB - BACKGROUND: Internal labour migration is an important and necessary livelihood strategy for millions of individuals and households in India. However, the precarious position of migrant workers within Indian society may have consequences for the health of these individuals. Previous research on the connections between health and labour mobility within India have primarily focused on the negative health outcomes associated with this practice. Thus, there is a need to better identify the determinants of internal migrant health and how these determinants shape migrant health outcomes. METHODS: An exploratory mixed methods study was conducted in 26 villages in the Krishnagiri district of Tamil Nadu. Sixty-six semi-structured interviews were completed using snowball sampling, followed by 300 household surveys using multi-stage random sampling. For qualitative data, an analysis of themes and content was completed. For quantitative data, information on current participation in internal labour migration, in addition to self-reported morbidity and determinants of internal migrant health, was collected. Morbidity categories were compared between migrant and non-migrant adults (age 14-65 years) using a Fisher's exact test. RESULTS: Of the 300 households surveyed, 137 households (45.7%) had at least one current migrant member, with 205 migrant and 1012 non-migrant adults (age 14-65 years) included in this study. The health profile of migrant and non-migrants was similar in this setting, with 53 migrants (25.9%) currently suffering from a health problem compared to 273 non-migrants (27.0%). Migrant households identified both occupational and livelihood factors that contributed to changes in the health of their migrant members. These determinants of internal migrant health were corroborated and further expanded on through the semi-structured interviews. CONCLUSIONS: Internal labour migration in and of itself is not a determinant of health, as participation in labour mobility can contribute to an improvement in health, a decline in health, or no change in health among migrant workers. Targeted public health interventions should focus on addressing the determinants of internal migrant health to enhance the contributions these individuals can make to their households and villages of origin. PMID- 28899376 TI - Perceptions about Iranian-Kurds' ethnic-inequality in health. AB - BACKGROUND: Evidence shows ethnic-inequality is a very effective variable in the Community and individual health associated outcomes. This study focused on gaining a deeper understanding of people's perception on inequality of health in Iranian-Kurds and its determinants. METHODS: The study was conducted in the three cities of Marivan, Sanandaj (capital of Kurdistan province in Iran) and Tehran (capital of the country). The study was conducted through 34 in-depth interviews and ten focus group discussions with health services users, academic graduates and health delivery service personnel. RESULTS: Consensus on social, mental and physical health inequality did not exist within the study participants. However, there were concerns about differences in healthcare access and utilization. Several participants believed that access to health services and socio-cultural differences of Kurds affected the healthcare utilization. CONCLUSIONS: Since, people perceived ethnic-inequality in healthcare access and utilization, ethnicity must be considered as a mandatory stratifier in monitoring health status and a concern during planning health interventions. People's awareness, resources management and allocation are factors requiring more consideration when choosing policy options. PMID- 28899377 TI - Quantitative magnetic resonance imaging (MRI) analysis of anterior talofibular ligament in lateral chronic ankle instability ankles pre- and postoperatively. AB - BACKGROUND: The aim of this study was to quantitatively evaluate and characterize the dimension and signal intensity of anterior talofibular ligament (ATFL) using 3.0 T MRI in the mechanical ankle instability group pre- and postoperatively. METHODS: A total of 97 participants were recruited retrospectively in this study, including 56 with mechanical chronic ankle instability (CAI group) and 41 without ankle instability (Control group). All the subjects accepted MRI preoperatively. Among the 56 CAI patients, 25 patients, who accepted modified Brostrom repair of ATFL, underwent a MRI scan at follow-up. The ATFL dimension (length and width) and signal/noise ratio (SNR) were measured based on MRI images. The results of the MRI studies were then compared between groups. RESULTS: The CAI group had a significantly higher ATFL length (p = 0.03) or ATFL width (p < 0.001) compared with the control group. The mean SNR value of the CAI group was significantly higher than that of the control group (p = 0.006). Furthermore, the mean SNR value of the ATFL after repair surgery (8.4 +/- 2.4) was significantly lower than that of the ATFL before surgery (11.2 +/- 3.4) (p < 0.001). However, no significant change of ATFL length or ATFL width were observed after repair surgery. CONCLUSIONS: CAI ankles had a higher ATFL length or width as well as higher signal intensity compared with stable ankles. After repair surgery, the mean SNR value of the ATFL decreased, indicating the relaxed ATFL becomes tight postoperatively. PMID- 28899378 TI - Prevalence rates of childhood trauma in medical students: a systematic review. AB - BACKGROUND: It is known that medical students suffer from high rates of mental health difficulties. In recent years there has been an increasing focus on the need to improve support and treatment services for those in difficulty. In order to meet these needs it is important to clarify the relevant aetiological factors. There is robust evidence from general population studies that a history of childhood trauma (including physical and sexual abuse and emotional neglect) predisposes to the subsequent development of mental health difficulties in adult life. It has previously been speculated that students with a history of such trauma might preferentially apply to study medicine. METHODS: This systematic review seeks to examine the existing evidence base with regard to rates of childhood trauma in medical student populations. Articles were identified through a literature search of psychINFO, web of science, Embase and medline. RESULTS: This search generated 11 articles which were deemed to meet criteria for inclusion in this review. There is a wide range of results given for rates of childhood trauma in these studies. CONCLUSIONS: The published research which examines rates of childhood trauma affecting medical students is limited and difficult to generalise from, or to use to draw firm conclusions. Given the possible negative outcomes of a history of childhood trauma in medical students, including that such a history may be associated with difficulties in a student progressing in their undergraduate and postgraduate examinations, well-organised prospective studies are required. PMID- 28899379 TI - Spatial models for the rational allocation of routinely distributed bed nets to public health facilities in Western Kenya. AB - BACKGROUND: In high to moderate malaria transmission areas of Kenya, long-lasting insecticidal nets (LLINs) are provided free of charge to pregnant women and infants during routine antenatal care (ANC) and immunization respectively. Quantities of LLINs distributed to clinics are quantified based on a combination of monthly consumption data and population size of target counties. However, this approach has been shown to lead to stock-outs in targeted clinics. In this study, a novel LLINs need quantification approach for clinics in the routine distribution system was developed. The estimated need was then compared to the actual allocation to identify potential areas of LLIN over- or under-allocation in the high malaria transmission areas of Western Kenya. METHODS: A geocoded database of public health facilities was developed and linked to monthly LLIN allocation. A network analysis approach was implemented using the location of all public clinics and topographic layers to model travel time. Estimated travel time, socio-economic and ANC attendance data were used to model clinic catchment areas and the probability of ANC service use within these catchments. These were used to define the number of catchment population who were likely to use these clinics for the year 2015 equivalent to LLIN need. Actual LLIN allocation was compared with the estimated need. Clinics were then classified based on whether allocation matched with the need, and if not, whether they were over or under allocated. RESULTS: 888 (70%) public health facilities were allocated 591,880 LLINs in 2015. Approximately 682,377 (93%) pregnant women and infants were likely to have attended an LLIN clinic. 36% of the clinics had more LLIN than was needed (over-allocated) while 43% had received less (under-allocated). Increasing efficiency of allocation by diverting over supply of LLIN to clinics with less stock and fully covering 43 clinics that did not receive nets in 2015 would allow for complete matching of need with distribution. CONCLUSION: The proposed spatial modelling framework presents a rationale for equitable allocation of routine LLINs and could be used for quantification of other maternal and child health commodities applicable in different settings. Western Kenya region received adequate LLINs for routine distribution in line with government of Kenya targets, however, the model shows important inefficiencies in the allocation of the LLINs at clinic level. PMID- 28899380 TI - Hotspots in research on the measurement of medical students' clinical competence from 2012-2016 based on co-word analysis. AB - BACKGROUND: This study aimed to identify hotspots in research on clinical competence measurements from 2012 to 2016. METHODS: The authors retrieved literature published between 2012 and 2016 from PubMed using selected medical subject headings (MeSH) terms. They used BibExcel software to generate high frequency MeSH terms and identified hotspots by co-word analysis and cluster analysis. RESULTS: The authors searched 588 related articles and identified 31 high-frequency MeSH terms. In addition, they obtained 6 groups of high-frequency MeSH terms that reflected the domain hotspots. CONCLUSIONS: This study identified 6 hotspots of domain research, including studies on influencing factors and perception evaluation, improving and developing measurement tools, feedback measurement, measurement approaches based on computer simulation, the measurement of specific students in different learning phases, and the measurement of students' communication ability. All of these research topics could provide useful information for educators and researchers to continually conduct in-depth studies. PMID- 28899381 TI - Ned-19 inhibition of parasite growth and multiplication suggests a role for NAADP mediated signalling in the asexual development of Plasmodium falciparum. AB - BACKGROUND: Although malaria is a preventable and curable human disease, millions of people risk to be infected by the Plasmodium parasites and to develop this illness. Therefore, there is an urgent need to identify new anti-malarial drugs. Ca2+ signalling regulates different processes in the life cycle of Plasmodium falciparum, representing a suitable target for the development of new drugs. RESULTS: This study investigated for the first time the effect of a highly specific inhibitor of nicotinic acid adenine dinucleotide phosphate (NAADP) induced Ca2+ release (Ned-19) on P. falciparum, revealing the inhibitory effect of this compound on the blood stage development of this parasite. Ned-19 inhibits both the transition of the parasite from the early to the late trophozoite stage and the ability of the late trophozoite to develop to the multinucleated schizont stage. In addition, Ned-19 affects spontaneous intracellular Ca2+ oscillations in ring and trophozoite stage parasites, suggesting that the observed inhibitory effects may be associated to regulation of intracellular Ca2+ levels. CONCLUSIONS: This study highlights the inhibitory effect of Ned-19 on progression of the asexual life cycle of P. falciparum. The observation that Ned-19 inhibits spontaneous Ca2+ oscillations suggests a potential role of NAADP in regulating Ca2+ signalling of P. falciparum. PMID- 28899382 TI - Carrion crows (Corvus corone) of southwest Germany: important hosts for haemosporidian parasites. AB - BACKGROUND: Avian malaria parasites (Plasmodium spp.) and other Haemosporida (Haemoproteus and Leucocytozoon spp.) form a diverse group of vector-transmitted blood parasites that are abundant in many bird families. Recent studies have suggested that corvids may be an important host for Plasmodium spp. and Leucocytozoon spp. METHODS: To investigate the diversity of Haemosporida of resident carrion crows (Corvus corone) and Eurasian Magpies (Pica pica) in southwest Germany, 100 liver samples of corvids were examined using a nested PCR method to amplify a 1063 bp fragment of the haemosporidian mitochondrial cytochrome b gene. The phylogenetic relationship of parasite lineages obtained from these birds was inferred. RESULTS: Haemosporidian DNA was detected in 85 carrion crows (89.5%) and in all five Eurasian Magpies. The most abundant parasite genus was Leucocytozoon with a prevalence of 85.3% (n = 95). 65.3% of the samples (n = 62) contained multiple infections. Thirteen haemosporidian lineages were isolated from the corvid samples. Female carrion crows were more likely infected with haemosporidian parasites than males. DISCUSSION: This study provides the first insight into the diversity of haemosporidian parasites of corvids in Germany. Very high prevalences were found and based on the applied diagnostic method also a high amount of multiple infections could be detected. Due to the high diversity of haemosporidian parasites found in corvids, they seem to be excellent model organisms to test species deliminations in haemosporidian parasites. PMID- 28899383 TI - Paediatric cardiopulmonary resuscitation training program in Latin-America: the RIBEPCI experience. AB - BACKGROUND: To describe the design and to present the results of a paediatric and neonatal cardiopulmonary resuscitation (CPR) training program adapted to Latin America. METHODS: A paediatric CPR coordinated training project was set up in several Latin-American countries with the instructional and scientific support of the Spanish Group for Paediatric and Neonatal CPR. The program was divided into four phases: CPR training and preparation of instructors; training for instructors; supervised teaching; and independent teaching. Instructors from each country participated in the development of the next group in the following country. Paediatric Basic Life Support (BLS), Paediatric Intermediate (ILS) and Paediatric Advanced (ALS) courses were organized in each country adapted to local characteristics. RESULTS: Five Paediatric Resuscitation groups were created sequentially in Honduras (2), Guatemala, Dominican Republican and Mexico. During 5 years, 6 instructors courses (94 students), 64 Paediatric BLS Courses (1409 students), 29 Paediatrics ILS courses (626 students) and 89 Paediatric ALS courses (1804 students) were given. At the end of the program all five groups are autonomous and organize their own instructor courses. CONCLUSIONS: Training of autonomous Paediatric CPR groups with the collaboration and scientific assessment of an expert group is a good model program to develop Paediatric CPR training in low- and middle income countries. Participation of groups of different countries in the educational activities is an important method to establish a cooperation network. PMID- 28899385 TI - Coronary artery calcium score plays an important role for cardiovascular risk stratification in the statin benefit groups of asymptomatic individuals. AB - BACKGROUND: The purpose of this study was to describe and analyze the relationship between statin benefit groups based on statin-intensity class of drugs and coronary artery calcium score (CACS) using multidetector computed tomography (MDCT) in an asymptomatic Korean population. METHODS: A total of 3914 asymptomatic individuals (mean age: 55 +/- 10 years; male: female = 2649: 1265) who underwent MDCT for health examination between January 2009 and December 2012 were retrospectively enrolled. They were categorized into three groups based on statin-intensity class of drugs (high-intensity (n = 1284, 32.8%); moderate intensity (n = 1602, 40.9%) and low-intensity (n = 931, 23.8%) statin therapy groups) according to the American College of Cardiology (ACC)/American heart Association (AHA) 2013 guideline and the relationship between CACS and statin benefit group was analyzed. The statin benefit group was defined as individuals who should be considered moderate- and high-intensity statin therapy. RESULTS: Ten-year atherosclerotic cardiovascular disease (ASCVD; 12.6 +/- 5.3% vs. 2.9 +/- 1.9%, p < 0.001) and CACS (98 +/- 270 vs. 3 +/- 2, p < 0.001) were significantly higher in the high-intensity group compared to the moderate-intensity statin therapy group. In the high-intensity statin therapy group, age [odds ratio: 1.299 (1.137-1.483), p < 0.001], male gender [odds ratio: 44.252 (1.959-999.784), p = 0.001], and fasting blood glucose [odds ratio: 1.046 (1.007-1.087), p = 0.021] were independent risk factors associated with CACS >=300 on multivariate logistic regression analysis. CONCLUSIONS: CACS on MDCT might be an important complementary tool for cardiovascular disease risk stratification. This study indicates that individualization of statin therapy as well as lifestyle modification will be useful in asymptomatic individuals, especially those in whom high-intensity statin therapy is required. PMID- 28899386 TI - Improved clinical outcome measures of knee pain and function with concurrent resolution of subchondral Bone Marrow Edema Lesion and joint effusion in an osteoarthritic patient following Pentosan Polysulphate Sodium treatment: a case report. AB - BACKGROUND: At present, there are no registered products for the treatment of subchondral Bone Marrow Edema Lesion (BML) and associated knee pain. Patients who do not respond to current anti-inflammatory therapies are left with limited treatment options, and may resort to operative management with Total Knee Arthroplasty (TKA). We report the use of Pentosan Polysulphate Sodium (PPS) for the treatment of BMLs of the knee. CASE PRESENTATION: We report the case of a 70 year-old female with knee osteoarthritis presenting with a high level of knee pain, scoring 8 on the Numerical Rating Scale (NRS), and functional limitation demonstrating a poor Lysholm Knee Score of 37. MRI scans of the knee revealed subchondral BML in the medial femoral condyle and medial tibial plateau. The patient was administered a course of Pentosan Polysulphate Sodium (PPS) intramuscularly twice weekly, for 3 weeks. MRI scans 2 weeks post-treatment showed complete resolution of the bone marrow edema at the medial femoral condyle and medial tibial plateau with concomitant recovery from pain (NRS pain score of 0), and a 43% improvement of the Lysholm Knee Score. In addition, marked reduction in joint effusion was also demonstrated in the MRI scan post PPS therapy. CONCLUSION: The MRI interpretations demonstrate improved clinical outcome measures ensuing therapeutic intervention with PPS, and warranting further investigation into the efficacy of PPS in the treatment of BML associated pain and dysfunction in the osteoarthritic population via randomized controlled trial, or equivalent rigorous methodological technique. PMID- 28899384 TI - Systematic review of quantitative imaging biomarkers for neck and shoulder musculoskeletal disorders. AB - BACKGROUND: This study systematically summarizes quantitative imaging biomarker research in non-traumatic neck and shoulder musculoskeletal disorders (MSDs). There were two research questions: 1) Are there quantitative imaging biomarkers associated with the presence of neck and shoulder MSDs?, 2) Are there quantitative imaging biomarkers associated with the severity of neck and shoulder MSDs? METHODS: PubMed and SCOPUS were used for the literature search. One hundred and twenty-five studies met primary inclusion criteria. Data were extracted from 49 sufficient quality studies. RESULTS: Most of the 125 studies were cross sectional and utilized convenience samples of patients as both cases and controls. Only half controlled for potential confounders via exclusion or in the analysis. Approximately one-third reported response rates. In sufficient quality articles, 82% demonstrated at least one statistically significant association between the MSD(s) and biomarker(s) studied. The literature synthesis suggested that neck muscle size may be decreased in neck pain, and trapezius myalgia and neck/shoulder pain may be associated with reduced vascularity in the trapezius and reduced trapezius oxygen saturation at rest and in response to upper extremity tasks. Reduced vascularity in the supraspinatus tendon may also be a feature in rotator cuff tears. Five of eight studies showed an association between a quantitative imaging marker and MSD severity. CONCLUSIONS: Although research on quantitative imaging biomarkers is still in a nascent stage, some MSD biomarkers were identified. There are limitations in the articles examined, including possible selection bias and inattention to potentially confounding factors. Recommendations for future studies are provided. PMID- 28899387 TI - Cognitive performance of children living in endemic areas for Plasmodium vivax. AB - BACKGROUND: The role of repeated episodes of malaria on the cognitive development of children is a relevant issue in endemic areas since it can have a long-lasting impact on individual lifespan. The aim of the current paper was to investigate whether the history of malaria can impair the verbal and performance skills of children living in an endemic area with low transmission of Plasmodium vivax malaria. METHODS: A cross-sectional study was conducted with children living in an endemic area of P. vivax malaria in Brazilian Amazon basin. The history of episodes of malaria was used as criteria for inclusion of children in the groups. The cognitive performance was assessed by the Wechsler intelligence scale for children-III edition (WISC-III), which was applied to the participants of study by two trained psychologists. RESULTS: A total of 17 cases and 26 controls was included in the study. A significant low score of verbal quotient was found in the cases (p = 0.005), however, the performance IQ was similar in both groups (p = 0.304). The full-scale IQ was significantly lower in the cases when compared to the controls (p = 0.042). The factorials index showed significant difference only in the subtest of verbal comprehension with the lower values in the cases (p = 0.0382), compared to the controls. The perceptual organization (p = 0.363), freedom from distractability (p = 0.180) and processing speed (p = 0.132) were similar in both groups. CONCLUSIONS: Children with a history of vivax malaria has a significant impairment of verbal and full-scale quotients as well as a significant low index of verbal comprehension. These findings are likely due to the absenteeism caused by malaria and by the low parental education, which impairs an adequate response to the environmental stimulus. PMID- 28899388 TI - A review of Grey and academic literature of evaluation guidance relevant to public health interventions. AB - BACKGROUND: Public Health evaluation is essential to understanding what does and does not work, and robust demonstration of effectiveness may be crucial to securing future funding. Despite this, programs are often implemented with poor, incomplete or no evaluation. Public health practitioners are frequently required to provide evidence for the effectiveness of their services; thus, there is a growing need for evaluation guidance on how to evaluate public health programs. The aim of this study is to identify accessible high-quality, evaluation guidance, available to researchers and practitioners and to catalogue, summarise and categorise the content of a subset of accessible, quality guides to evaluation. METHODS: We systematically reviewed grey and academic literature for documents providing support for evaluation of complex health interventions. Searches were conducted January to March 2015, and included academic databases, internet search engines, and consultations with academic and practicing public health experts. Data were extracted by two authors and sent to the authors of the guidance documents for comments. RESULTS: Our initial search identified 402 unique documents that were screened to identify those that were (1) developed by or for a national or international organization (2) freely available to all (3) published during or after 2000 (4) specific to public health. This yielded 98 documents from 43 organisations. Of these, 48 were reviewed in detail. This generated a detailed catalogue of quality evaluation guidance. The content included in documents covers 37 facets of evaluation. CONCLUSIONS: A wide range of guidance on evaluation of public health initiatives is available. Time and knowledge constraints may mean that busy practitioners find it challenging to access the most, up-to-date, relevant and useful guidance. This review presents links to and reviews of 48 quality guides to evaluation as well as categorising their content. This facilitates quick and each access to multiple selected sources of specific guidance. PMID- 28899389 TI - The utilization of formal and informal home care by older patients with cancer: a Belgian cohort study with two control groups. AB - BACKGROUND: The purpose of this paper is to analyse the utilization of formal and informal home care among older patients with cancer (OCP) and to compare this with middle-aged patients with cancer (MCP) and older patients without cancer (ONC). Additionally, we examined predictors of transitions towards formal care one year after a cancer diagnosis. METHODS: OCP and MCP had to be recruited within three months after a cancer diagnosis and have an estimated life expectancy over six months. ONC consisted of patients without known cancer, seen by the general practitioner. Formal and informal care were compared between the patient groups at baseline, i.e. shortly after a cancer diagnosis and changes in care were studied after one year. RESULTS: A total of 844 patients were evaluable for formal care at baseline and 469 patients (56%) at follow-up. At baseline, about half of older adults and 18% of MCP used formal care, while about 85% of cancer patients and 57% ONC used informal care. Formal care increased for all groups after one year though not significantly in OCP. The amount of informal care only changed in MCP which decreased after one year. Cancer-related factors and changes in need factors predict a transition towards formal care after a cancer diagnosis. CONCLUSIONS: A cancer diagnosis has a different impact on the use of formal and informal care than ageing as such. The first year after a cancer diagnosis is an important time to follow-up on the patients' needs for home care. PMID- 28899390 TI - 'If it's a medical issue I would have covered it by now': learning about fibromyalgia through the hidden curriculum: a qualitative study. AB - BACKGROUND: Fibromyalgia syndrome (FMS) is a long-term condition that affects between 1 and 5% of the general population and lies within the spectrum of medically unexplained symptoms (MUS). FMS can be difficult to diagnose and is usually done so as a diagnosis of exclusion. There is continuing debate regarding its legitimacy excluding other causes of symptoms. It is known that the diagnosis and management of MUS, including FMS, receives little attention in medical curricula and attitudes towards patients with FMS amongst medical professionals and trainees can be negative. The purpose of this study was to investigate how attitudes and perspectives of undergraduate medical students towards FMS are acquired during their training. METHODS: Qualitative interviews with 21 medical students were conducted to explore their views on FMS, encounters with patients with FMS, and where learning about FMS occurs. Participants were recruited from two English medical schools and the study was approved by two University Ethics committees. Interviews were digitally recorded with consent and data analysed thematically, using principles of constant comparison. RESULTS: The data were organised within three themes: i) FMS is a complex, poorly understood condition; ii) multiple sources for learning about FMS; and iii) consequences of negative attitudes for patients with FMS. CONCLUSION: Undergraduate medical students have limited understanding of, and are sceptical over the existence of FMS. These attitudes are influenced by the 'hidden curriculum' and witnessing attitudes and actions of their clinical teachers. Students interpret a lack of formal curriculum teaching around FMS to mean that it is not serious and hence a low priority. Encountering a patient, friend or family member with FMS can increase knowledge and lead to altered perceptions of the condition. Teaching and learning about FMS needs to be consistent to improve knowledge and attitudes of clinicians. Undergraduate students should be exposed to patients with FMS so that they better understand patients with FMS. PMID- 28899391 TI - Mixomics analysis of Bacillus subtilis: effect of oxygen availability on riboflavin production. AB - BACKGROUND: Riboflavin, an intermediate of primary metabolism, is one kind of important food additive with high economic value. The microbial cell factory Bacillus subtilis has already been proven to possess significant importance for the food industry and have become one of the most widely used riboflavin producing strains. In the practical fermentation processes, a sharp decrease in riboflavin production is encountered along with a decrease in the dissolved oxygen (DO) tension. Influence of this oxygen availability on riboflavin biosynthesis through carbon central metabolic pathways in B. subtilis is unknown so far. Therefore the unveiled effective metabolic pathways were still an unaccomplished task till present research work. RESULTS: In this paper, the microscopic regulation mechanisms of B. subtilis grown under different dissolved oxygen tensions were studied by integrating 13C metabolic flux analysis, metabolomics and transcriptomics. It was revealed that the glucose metabolic flux through pentose phosphate (PP) pathway was lower as being confirmed by smaller pool sizes of metabolites in PP pathway and lower expression amount of ykgB at transcriptional level. The latter encodes 6-phosphogluconolactonase (6-PGL) under low DO tension. In response to low DO tension in broth, the glucose metabolic flux through Embden-Meyerhof-Parnas (EMP) pathway was higher and the gene, alsS, encoding for acetolactate synthase was significantly activated that may result due to lower ATP concentration and higher NADH/NAD+ ratio. Moreover, ResE, a membrane-anchored protein that is capable of oxygen regulated phosphorylase activity, and ResD, a regulatory protein that can be phosphorylated and dephosphorylated by ResE, were considered as DO tension sensor and transcriptional regulator respectively. CONCLUSIONS: This study shows that integration of transcriptomics, 13C metabolic flux analysis and metabolomics analysis provides a comprehensive understanding of biosynthesized riboflavin's regulatory mechanisms in B. subtilis grown under different dissolved oxygen tension conditions. The two-component system, ResD-ResE, was considered as the signal receiver of DO tension and gene regulator that led to differences between biomass and riboflavin production after triggering the shifts in gene expression, metabolic flux distributions and metabolite pool sizes. PMID- 28899393 TI - The mixed benefit of low lipoprotein(a) in type 2 diabetes. AB - BACKGROUND: Lipoprotein(a) (Lp(a)), a variant low-density lipoprotein (LDL), is a major genetic risk factor for cardiovascular disease. It is unknown whether an inverse relationship exists between Lp(a) and beta-cell function (BCF), as for LDL-cholesterol (LDL-C) lowering by statins. We therefore assessedthe cardiometabolic phenotype of 340 men with type 2 diabetes mellitus (T2DM) in relation to Lp(a), focusing on BCF and hyperbolic product [BxS], which adjusts BCF to insulin sensitivity and secretion. METHODS: Two groups were analyzed according to Lp(a) quartiles (Q): a (very-)low Lp(a) (Q1;n = 85) vs a normal-to high Lp(a) group (Q2-Q4;n = 255). RESULTS: In the overall cohort, mean Lp(a) was 52 nmol.L-1. Median Lp(a) was 6 nmol.L-1 (Q1) vs 38 nmol.L-1 (Q2-Q4). There were no differences between groups regarding age; education; diabetes duration; body mass index; body composition and smoking. Q1 had significantly worse glycemic control, higher systolic blood pressure, more severe metabolic syndrome, and more frequent hepatic steatosis. Insulin sensitivity was significantly lower (- 37%) in Q1, who also had lesser hyperbolic product (- 27%), and higher [BxS] loss rate (+ 15%). Q1 also had higher frequency (+31%) and severity (+20%) of atherogenic dyslipidemia. Microangiopathy and neuropathy were higher in Q1 (+ 34% and + 48%, respectively), whereas Q2-Q4 patients had increased macroangiopathy (+ 51%) and coronary artery disease (CAD; + 94%). CONCLUSIONS: Low Lp(a) appears both beneficial and unhealthy in T2DM. It is associated with unfavourable cardiometabolic phenotype, lesser BCF, poorer glycemic control, and increased microvascular damage despite being linked to markedly reduced CAD, suggesting that Lp(a)-related vascular risk) follows a J-shaped curve. PMID- 28899392 TI - Care beyond the hospital ward: understanding the socio-medical trajectory of herpes simplex virus encephalitis. AB - BACKGROUND: Herpes simplex virus (HSV) encephalitis is a life-threatening infection of the brain, which has significant physical, cognitive and social consequences for survivors. Despite increasing recognition of the long-term effects of encephalitis, research and policy remains largely focused on its acute management, meaning there is little understanding of the difficulties people face after discharge from acute care. This paper aims to chart the problems and challenges which people encounter when they return home after treatment for HSV encephalitis. METHODS: The paper reports on data from 30 narrative interviews with 45 people affected by HSV encephalitis and their significant others. The study was conducted as part of the ENCEPH-UK programme grant on Understanding and Improving the Outcome of Encephalitis. RESULTS: The findings show the diverse challenges which are experienced by people after treatment for HSV encephalitis. We first chart how peoples' everyday lives are fragmented following their discharge from hospital. Second, we document the social consequences which result from the longer-term effects of encephalitis. Finally, we show how the above struggles are exacerbated by the lack of support systems for the post-acute effects of encephalitis, and describe how people are consequently forced to devise their own care routines and strategies for managing their problems. CONCLUSION: The paper argues that in order to improve long-term outcomes in encephalitis, it is vital that we develop pathways of support for the condition beyond the acute hospital setting. We conclude by making recommendations to enhance communication and care for the post-acute consequences of encephalitis, to ensure those affected are fully supported through the chronic effects of this devastating disease. PMID- 28899394 TI - A two-state comparative implementation of peer-support intervention to link veterans to health-related services after incarceration: a study protocol. AB - BACKGROUND: Approximately 600,000 persons are released from prison annually in the United States. Relatively few receive sufficient re-entry services and are at risk for unemployment, homelessness, poverty, substance abuse relapse and recidivism. Persons leaving prison who have a mental illness and/or a substance use disorder are particularly challenged. This project aims to create a peer mentor program to extend the reach and effectiveness of reentry services provided by the Department of Veterans' Affairs (VA). We will implement a peer support for reentry veterans sequentially in two states. Our outcome measures are 1) fidelity of the intervention, 2) linkage to VA health care and, 3) continued engagement in health care. The aims for this project are as follows: (1) Conduct contextual analysis to identify VA and community reentry resources, and describe how reentry veterans use them. (2) Implement peer-support, in one state, to link reentry veterans to Veterans' Health Administration (VHA) primary care, mental health, and SUD services. (3) Port the peer-support intervention to another, geographically, and contextually different state. DESIGN: This intervention involves a 2-state sequential implementation study (Massachusetts, followed by Pennsylvania) using a Facilitation Implementation strategy. We will conduct formative and summative analyses, including assessment of fidelity, and a matched comparison group to evaluate the intervention's outcomes of veteran linkage and engagement in VHA health care (using health care utilization measures). The study proceeds in 3 phases. DISCUSSION: We anticipate that a peer support program will be effective at improving the reentry process for veterans, particularly in linking them to health, mental health, and SUD services and helping them to stay engaged in those services. It will fill a gap by providing veterans with access to a trusted individual, who understands their experience as a veteran and who has experienced justice involvement. The outputs from this project, including training materials, peer guidebooks, and implementation strategies can be adapted by other states and regions that wish to enhance services for veterans (or other populations) leaving incarceration. A larger cluster-randomized implementation effectiveness study is planned. TRIAL REGISTRATION: This protocol is registered with clinicaltrials.gov on November 4, 2016 and was assigned the number NCT02964897 . PMID- 28899395 TI - Role of Rab5 in the formation of macrophage-derived foam cell. AB - BACKGROUND: Foam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell. METHODS: Immunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL). RESULTS: Rab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5 Q79L. CONCLUSIONS: Rab5 plays an important role in modulating the intracellular cholesterol of macrophages and consequently mediating the formation of foam cells. PMID- 28899396 TI - Transcriptomic meta-analysis identifies gene expression characteristics in various samples of HIV-infected patients with nonprogressive disease. AB - BACKGROUND: A small proportion of HIV-infected patients remain clinically and/or immunologically stable for years, including elite controllers (ECs) who have undetectable viremia (<50 copies/ml) and long-term nonprogressors (LTNPs) who maintain normal CD4+ T cell counts for prolonged periods (>10 years). However, the mechanism of nonprogression needs to be further resolved. In this study, a transcriptome meta-analysis was performed on nonprogressor and progressor microarray data to identify differential transcriptome pathways and potential biomarkers. METHODS: Using the INMEX (integrative meta-analysis of expression data) program, we performed the meta-analysis to identify consistently differentially expressed genes (DEGs) in nonprogressors and further performed functional interpretation (gene ontology analysis and pathway analysis) of the DEGs identified in the meta-analysis. Five microarray datasets (81 cases and 98 controls in total), including whole blood, CD4+ and CD8+ T cells, were collected for meta-analysis. RESULTS: We determined that nonprogressors have reduced expression of important interferon-stimulated genes (ISGs), CD38, lymphocyte activation gene 3 (LAG-3) in whole blood, CD4+ and CD8+ T cells. Gene ontology (GO) analysis showed a significant enrichment in DEGs that function in the type I interferon signaling pathway. Upregulated pathways, including the PI3K-Akt signaling pathway in whole blood, cytokine-cytokine receptor interaction in CD4+ T cells and the MAPK signaling pathway in CD8+ T cells, were identified in nonprogressors compared with progressors. In each metabolic functional category, the number of downregulated DEGs was more than the upregulated DEGs, and almost all genes were downregulated DEGs in the oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle in the three types of samples. CONCLUSIONS: Our transcriptomic meta-analysis provides a comprehensive evaluation of the gene expression profiles in major blood types of nonprogressors, providing new insights in the understanding of HIV pathogenesis and developing strategies to delay HIV disease progression. PMID- 28899397 TI - Splatter: simulation of single-cell RNA sequencing data. AB - As single-cell RNA sequencing (scRNA-seq) technologies have rapidly developed, so have analysis methods. Many methods have been tested, developed, and validated using simulated datasets. Unfortunately, current simulations are often poorly documented, their similarity to real data is not demonstrated, or reproducible code is not available. Here, we present the Splatter Bioconductor package for simple, reproducible, and well-documented simulation of scRNA-seq data. Splatter provides an interface to multiple simulation methods including Splat, our own simulation, based on a gamma-Poisson distribution. Splat can simulate single populations of cells, populations with multiple cell types, or differentiation paths. PMID- 28899398 TI - Associations of two-pore domain potassium channels and triple negative breast cancer subtype in The Cancer Genome Atlas: systematic evaluation of gene expression and methylation. AB - OBJECTIVES: It is unclear whether 2-pore domain potassium channels are novel molecular markers with differential expression related to biologically aggressive triple-negative type breast tumors. Our objective was to systematically evaluate associations of 2-pore domain potassium channel gene expression and DNA methylation with triple-negative subtype in The Cancer Genome Atlas invasive breast cancer dataset. Methylation and expression data for all fifteen 2-pore domain potassium family genes were examined for 1040 women, and associations with triple-negative subtype (vs. luminal A) were evaluated using age/race adjusted generalized-linear models, with Bonferroni-corrected significance thresholds. Subtype associated CpG loci were evaluated for functionality related to expression using Spearman's correlation. RESULTS: Overexpression of KCNK5, KCNK9 and KCNK12, and underexpression of KCNK6 and KCNK15, were significantly associated with triple-negative subtype (Bonferroni-corrected p < 0.0033). A total of 195 (114 hypomethylated and 81 hypermethylated) CpG loci were found to be significantly associated with triple-negative subtype (Bonferroni-corrected p < 8.22 * 10-8). Significantly negatively correlated expression patterns that were differentially observed in triple-negative vs. luminal A subtype were demonstrated for: KCNK2 (gene body: cg04923840, cg13916421), KCNK5 (gene body: cg05255811, cg18705155, cg09130674, cg21388745, cg00859574) and KCNK9 (TSS1500: cg21415530, cg12175729; KCNK9/TRAPPC9 intergenic region: cg17336929, cg25900813, cg03919980). CpG loci listed for KCNK5 and KCNK9 all showed relative hypomethylation for probability of triple-negative vs. luminal A subtype. Triple negative subtype was associated with distinct 2-pore domain potassium channel expression patterns. Both KCNK5 and KCNK9 overexpression appeared to be functionally related to CpG loci hypomethylation. PMID- 28899399 TI - A comparison of blood stream infections with extended spectrum beta-lactamase producing and non-producing Klebsiella pneumoniae in pediatric patients. AB - BACKGROUND: Rapid development and global spread of multidrug resistant Klebsiella pneumonia (K. pneumoniae) as a major cause of nosocomial infections is really remarkable. The aim of this study was to explore risk factors for health care associated blood stream infections (BSI) caused by ESBL-producing K. pneumoniae in children and analyze clinical outcomes. METHODS: A retrospective review of patients younger than 18 years-old with blood stream infection caused by K. pneumoniae was performed. Patients with ESBL-producing K. pneumoniae isolates were compared with ESBL-non-producing isolates in terms of risk factors, outcome and mortality. RESULTS: Among 111 K. pneumoniae isolates 62% (n = 69) were ESBL producing K. pneumoniae. The median total length of hospitalization and median length of stay in hospital before infection was significantly higher in patients with ESBL-producing isolates than ESBL-non-producing. Use of combined antimicrobial treatment was significantly different between ESBL-producing and ESBL-non-producing groups, 75.4% and 24.6%, respectively (p = 0.001). Previous aminoglycoside use was higher in cases with ESBL -producing isolates (p = 0.001). Logistic regression analysis showed a significant correlation between mortality and use of combined antibiotics (OR 4.22; p = 0.01). CONCLUSION: ESBL production in K. pneumoniae isolates has a significant impact on clinical course of BSIs. Total length of hospitalization, length of hospital stay before infection, prior combined antibiotic use and use of aminoglycosides were significant risk factors for development of ESBL-producing K. pneumoniae related BSI. PMID- 28899400 TI - Impact of combined sodium chloride and saturated long-chain fatty acid challenge on the differentiation of T helper cells in neuroinflammation. AB - BACKGROUND: There has been a marked increase in the incidence of autoimmune diseases like multiple sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Here, growing evidence suggests that ingredients of a Western diet like high intake of sodium chloride (NaCl) or saturated fatty acids may impact systemic immune responses, thus increasing disease susceptibility. Recently, we have shown that high dietary salt or long chain fatty acid (LCFA) intake indeed aggravates T helper (Th) cell responses and neuroinflammation. METHODS: Naive CD4+ T cells were treated with an excess of 40 mM NaCl and/or 250 MUM lauric acid (LA) in vitro to analyze effects on Th cell differentiation, cytokine secretion, and gene expression. We employed ex vivo analyses of the model disease murine experimental autoimmune encephalomyelitis (EAE) to investigate whether salt and LCFA may affect disease severity and T cell activation in vivo. RESULTS: LCFA, like LA, together with NaCl enhance the differentiation of Th1 and Th17 cells as well as pro-inflammatory cytokine and gene expression in vitro. In cell culture, we observed an additive effect of LA and hypertonic extracellular NaCl (NaCl + LA) in Th17 differentiation assays as well as on IL-17, GM-CSF, and IL-2 gene expression. In contrast, NaCl + LA reduced Th2 frequencies. We employed EAE as a model of Th1/Th17 cell-mediated autoimmunity and show that the combination of a NaCl- and LA-rich diet aggravated the disease course and increased T cell infiltration into the central nervous system (CNS) to the same extent as dietary NaCl. CONCLUSIONS: Our findings demonstrate a partially additive effect of NaCl and LA on Th cell polarization in vitro and on Th cell responses in autoimmune neuroinflammation. These data may help to better understand the pathophysiology of autoimmune diseases such as MS. PMID- 28899401 TI - The impact of preload on 3-dimensional deformation parameters: principal strain, twist and torsion. AB - BACKGROUND: Strain analysis is feasible using three-dimensional (3D) echocardiography. This approach provides various parameters based on speckle tracking analysis from one full-volume image of the left ventricle; however, evidence for its volume independence is still lacking. METHODS: Fifty-eight subjects who were examined by transthoracic echocardiography immediately before and after hemodialysis (HD) were enrolled. Real-time full-volume 3D echocardiographic images were acquired and analyzed using dedicated software. Two dimensional (2D) longitudinal strain (LS) was also measured for comparison with 3D strain values. RESULTS: Longitudinal (pre-HD: -24.57 +/- 2.51, post-HD: -21.42 +/- 2.15, P < 0.001); circumferential (pre-HD: -33.35 +/- 3.50, post-HD: -30.90 +/- 3.22, P < 0.001); and radial strain (pre-HD: 46.47 +/- 4.27, post-HD: 42.90 +/- 3.61, P < 0.001) values were significantly decreased after HD. The values of 3D principal strain (PS), a unique parameter of 3D images, were affected by acute preload changes (pre-HD: -38.10 +/- 3.71, post-HD: -35.33 +/- 3.22, P < 0.001). Twist and torsion values were decreased after HD (pre-HD: 17.69 +/- 7.80, post HD: 13.34 +/- 6.92, P < 0.001; and pre-HD: 2.04 +/- 0.86, post-HD:1.59 +/- 0.80, respectively, P < 0.001). The 2D LS values correlated with the 3D LS and PS values. CONCLUSION: Various parameters representing left ventricular mechanics were easily acquired from 3D echocardiographic images; however, like conventional parameters, they were affected by acute preload changes. Therefore, strain values from 3D echocardiography should be interpreted with caution while considering the preload conditions of the patients. PMID- 28899402 TI - The international food unit: a new measurement aid that can improve portion size estimation. AB - BACKGROUND: Portion size education tools, aids and interventions can be effective in helping prevent weight gain. However consumers have difficulties in estimating food portion sizes and are confused by inconsistencies in measurement units and terminologies currently used. Visual cues are an important mediator of portion size estimation, but standardized measurement units are required. In the current study, we present a new food volume estimation tool and test the ability of young adults to accurately quantify food volumes. The International Food UnitTM (IFUTM) is a 4x4x4 cm cube (64cm3), subdivided into eight 2 cm sub-cubes for estimating smaller food volumes. Compared with currently used measures such as cups and spoons, the IFUTM standardizes estimation of food volumes with metric measures. The IFUTM design is based on binary dimensional increments and the cubic shape facilitates portion size education and training, memory and recall, and computer processing which is binary in nature. METHODS: The performance of the IFUTM was tested in a randomized between-subject experiment (n = 128 adults, 66 men) that estimated volumes of 17 foods using four methods; the IFUTM cube, a deformable modelling clay cube, a household measuring cup or no aid (weight estimation). Estimation errors were compared between groups using Kruskall-Wallis tests and post-hoc comparisons. RESULTS: Estimation errors differed significantly between groups (H(3) = 28.48, p < .001). The volume estimations were most accurate in the group using the IFUTM cube (Mdn = 18.9%, IQR = 50.2) and least accurate using the measuring cup (Mdn = 87.7%, IQR = 56.1). The modelling clay cube led to a median error of 44.8% (IQR = 41.9). Compared with the measuring cup, the estimation errors using the IFUTM were significantly smaller for 12 food portions and similar for 5 food portions. Weight estimation was associated with a median error of 23.5% (IQR = 79.8). CONCLUSIONS: The IFUTM improves volume estimation accuracy compared to other methods. The cubic shape was perceived as favourable, with subdivision and multiplication facilitating volume estimation. Further studies should investigate whether the IFUTM can facilitate portion size training and whether portion size education using the IFUTM is effective and sustainable without the aid. A 3-dimensional IFUTM could serve as a reference object for estimating food volume. PMID- 28899403 TI - Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still's disease. AB - BACKGROUND: HLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still's disease (AOSD) in a Japanese population by determining the DRB1 allele distributions. METHODS: DRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing. RESULTS: In Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 * 10-6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91-4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49 3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18-0.66) with AOSD, and amino acid residues 86 and 98 of the DRbeta chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy. CONCLUSION: The DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD. PMID- 28899405 TI - Neonatal hemolytic anemia does not always indicate thalassemia: a case report. AB - BACKGROUND: Congenital erythropoietic porphyria is a rare autosomal recessive disorder that affects heme-porphyrin synthesis. This disorder is due to the genetic defect of uroporphyrinogen III cosynthase. This defect results in the accumulation of high amounts of uroporphyrin I in all tissues, leading to clinical manifestations ranging from mild to severe chronic damage of the skin, cartilage and bone. Hypertrichosis, erythrodontia and reddish-colored urine are often present, as well as hemolytic anemia accompanied by hepatosplenomegaly. CASE PRESENTATION: Here, we present a case of a 5-year-old male child of Middle Eastern origin who had been diagnosed as having alpha thalassemia and was undergoing chronic blood transfusions. He later presented with hypopigmented skin lesions and atrophy post-photosensitivity, persistent red-colored urine and hepatosplenomegaly. Laboratory investigations showed a high level of porphyrin metabolites in his plasma and erythrocytes. As a result, he was diagnosed as having Congenital erythropoietic porphyria. CONCLUSION: Here, we diagnose a case of congenital erythropoietic porphyria which was initially missed, although the clinical features were clear (red-colored urine, hepatosplenomegaly and hemolytic anemia were present since birth, and skin manifestations appeared at the age of 22 months after being exposed to sunlight). After a DNA test was performed, the patient was initially diagnosed as having alpha thalassemia. We identified two causes of hemolytic anemia (congenital erythropoietic porphyria and alpha thalassemia) in this patient. The diagnosis of congenital erythropoietic porphyria was missed up until the child turned 5 years old. To our knowledge, this is the first case of hemolytic anemia to be reported with a diagnosis of both congenital erythropoietic porphyria and alpha thalassemia. PMID- 28899406 TI - Forecasting the regional distribution and sufficiency of physicians in Japan with a coupled system dynamics-geographic information system model. AB - BACKGROUND: In Japan, the shortage of physicians has been recognized as a major medical issue. In our previous study, we reported that the absolute shortage will be resolved in the long term, but maldistribution among specialties will persist. To address regional shortage, several Japanese medical schools increased existing quota and established "regional quotas." This study aims to assist policy makers in designing effective policies; we built a model for forecasting physician numbers by region to evaluate future physician supply-demand balances. METHODS: For our case study, we selected Hokkaido Prefecture in Japan, a region displaying disparities in healthcare services availability between urban and rural areas. We combined a system dynamics (SD) model with geographic information system (GIS) technology to analyze the dynamic change in spatial distribution of indicators. For Hokkaido overall and for each secondary medical service area (SMSA) within the prefecture, we analyzed the total number of practicing physicians. For evaluating absolute shortage and maldistribution, we calculated sufficiency levels and Gini coefficient. Our study covered the period 2010-2030 in 5-year increments. RESULTS: According to our forecast, physician shortage in Hokkaido Prefecture will largely be resolved by 2020. Based on current policies, we forecast that four SMSAs in Hokkaido will continue to experience physician shortages past that date, but only one SMSA would still be understaffed in 2030. CONCLUSION: The results show the possibility that diminishing imbalances between SMSAs would not necessarily mean that regional maldistribution would be eliminated, as seen from the sufficiency levels of the various SMSAs. Urgent steps should be taken to place doctors in areas where our forecasting model predicts that physician shortages could occur in the future. PMID- 28899404 TI - Extracellular vesicle-packaged miRNA release after short-term exposure to particulate matter is associated with increased coagulation. AB - BACKGROUND: Exposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter <= 10 MUm (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study. RESULTS: Short-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudioTM 12 K Flex Real Time PCR System and the top 40 EV miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR 106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels. CONCLUSIONS: Research on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development. PMID- 28899407 TI - Association of medial meniscal extrusion with medial tibial osteophyte distance detected by T2 mapping MRI in patients with early-stage knee osteoarthritis. AB - BACKGROUND: Medial meniscal extrusion (MME) is associated with progression of medial knee osteoarthritis (OA), but no or little information is available for relationships between MME and osteophytes, which are found in cartilage and bone parts. Because of the limitation in detectability of the cartilage part of osteophytes by radiography or conventional magnetic resonance imaging (MRI), the rate of development and size of osteophytes appear to have been underestimated. Because T2 mapping MRI may enable us to evaluate the cartilage part of osteophytes, we aimed to examine the association between MME and OA-related changes, including osteophytes, by using conventional and T2 mapping MRI. METHODS: Patients with early-stage knee OA (n = 50) were examined. MRI-detected OA-related changes, in addition to MME, were evaluated according to the Whole Organ Magnetic Resonance Imaging Score. T2 values of the medial meniscus and osteophytes were measured on T2 mapping images. Osteophytes surgically removed from patients with end-stage knee OA were histologically analyzed and compared with findings derived by radiography and MRI. RESULTS: Medial side osteophytes were detected by T2 mapping MRI in 98% of patients with early-stage knee OA, although the detection rate was 48% by conventional MRI and 40% by radiography. Among the OA-related changes, medial tibial osteophyte distance was most closely associated with MME, as determined by multiple logistic regression analysis, in the patients with early-stage knee OA (beta = 0.711, p < 0.001). T2 values of the medial meniscus were directly correlated with MME in patients with early-stage knee OA, who showed >= 3 mm of MME (r = 0.58, p = 0.003). The accuracy of osteophyte evaluation by T2 mapping MRI was confirmed by histological analysis of the osteophytes removed from patients with end-stage knee OA. CONCLUSIONS: Our study demonstrates that medial tibial osteophyte evaluated by T2 mapping MRI is frequently observed in the patients with early-stage knee OA, showing close association with MME, and that MME is positively correlated with the meniscal degeneration. PMID- 28899408 TI - Respiratory support in patients with acute respiratory distress syndrome: an expert opinion. AB - Acute respiratory distress syndrome (ARDS) is a common condition in intensive care unit patients and remains a major concern, with mortality rates of around 30 45% and considerable long-term morbidity. Respiratory support in these patients must be optimized to ensure adequate gas exchange while minimizing the risks of ventilator-induced lung injury. The aim of this expert opinion document is to review the available clinical evidence related to ventilator support and adjuvant therapies in order to provide evidence-based and experience-based clinical recommendations for the management of patients with ARDS. PMID- 28899409 TI - Alcohol consumption and breast tumor gene expression. AB - BACKGROUND: Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER) positive tumors. However, the biological mechanisms underlying this association are not completely understood. METHODS: We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses' Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR) <0.1 identified in tumors were validated in RNA sequencing data of invasive breast tumors (N = 166) from The Cancer Genome Atlas. RESULTS: No individual genes were significantly differentially expressed by alcohol consumption in the NHS/NHSII. However, GSEA identified 33 and 68 pathway-defined gene sets at FDR <0.1 among 471 ER+ and 127 ER- tumors, respectively, all of which were validated. Among ER+ tumors, consuming 10+ grams of alcohol per day (vs. 0) was associated with upregulation in RNA metabolism and transport, cell cycle regulation, and DNA repair, and downregulation in lipid metabolism. Among ER- tumors, in addition to upregulation in RNA processing and cell cycle, alcohol intake was linked to overexpression of genes involved in cytokine signaling, including interferon and transforming growth factor (TGF)-beta signaling pathways, and translation and post-translational modifications. Lower lipid metabolism was observed in both ER+ tumors and ER+ tumor-adjacent normal samples. Most of the significantly enriched gene sets identified in ER- tumors showed a similar enrichment pattern among ER- tumor-adjacent normal tissues. CONCLUSIONS: Our data suggest that moderate alcohol consumption (i.e. 10+ grams/day, equivalent to one or more drinks/day) is associated with several specific and reproducible biological processes and pathways, which adds potential new insight into alcohol-related breast carcinogenesis. PMID- 28899410 TI - Nucleolar and spindle associated protein 1 promotes the aggressiveness of astrocytoma by activating the Hedgehog signaling pathway. AB - BACKGROUND: The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown. METHODS: The expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway. RESULTS: NUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway. CONCLUSION: These findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma. PMID- 28899411 TI - Non-polio enteroviruses in faeces of children diagnosed with acute flaccid paralysis in Nigeria. AB - BACKGROUND: The need to investigate the contribution of non-polio enteroviruses to acute flaccid paralysis (AFP) cannot be over emphasized as we move towards a poliovirus free world. Hence, we aim to identify non-polio enteroviruses recovered from the faeces of children diagnosed with AFP in Nigeria. METHODS: Ninety-six isolates, (95 unidentified and one previously confirmed Sabin poliovirus 3) recovered on RD cell culture from the stool of children <15 years old diagnosed with AFP in 2014 were analyzed. All isolates were subjected to RNA extraction, cDNA synthesis and three different PCR reactions (one panenterovirus 5'-UTR and two different VP1 amplification assays). VP1 amplicons were then sequenced and isolates identified. RESULTS: 92.71% (89/96) of the isolates were detected by at least one of the three assays as an enterovirus. Precisely, 79.17% (76/96), 6.25% (6/96), 7.30% (7/96) and 7.30% (7/96) of the isolates were positive for both, positive and negative, negative and positive, as well as negative for both the 5'-UTR and VP1 assays, respectively. In this study, sixty nine (69) of the 83 VP1 amplicons sequenced were identified as 27 different enterovirus types. The most commonly detected were CV-B3 (10 isolates) and EV-B75 (5 isolates). Specifically, one, twenty-four and two of the enterovirus types identified in this study belong to EV-A, EV-B and EV-C respectively. CONCLUSIONS: This study reports the circulating strains of 27 non-polio enterovirus types in Nigerian children with AFP in 2014 and Nigerian strains of CV-B2, CV-B4, E17, EV B80, EV-B73, EV-B97, EV-B93, EV-C99 and EV-A120 were reported for the first time. Furthermore, it shows that being positive for the 5'-UTR assay should not be the basis for subjecting isolates to the VP1 assays. PMID- 28899413 TI - Evolution and genome specialization of Brucella suis biovar 2 Iberian lineages. AB - BACKGROUND: Swine brucellosis caused by B. suis biovar 2 is an emergent disease in domestic pigs in Europe. The emergence of this pathogen has been linked to the increase of extensive pig farms and the high density of infected wild boars (Sus scrofa). In Portugal and Spain, the majority of strains share specific molecular characteristics, which allowed establishing an Iberian clonal lineage. However, several strains isolated from wild boars in the North-East region of Spain are similar to strains isolated in different Central European countries. RESULTS: Comparative analysis of five newly fully sequenced B. suis biovar 2 strains belonging to the main circulating clones in Iberian Peninsula, with publicly available Brucella spp. genomes, revealed that strains from Iberian clonal lineage share 74% similarity with those reference genomes. Besides the 210 kb translocation event present in all biovar 2 strains, an inversion with 944 kb was presented in chromosome I of strains from the Iberian clone. At left and right crossover points, the inversion disrupted a TRAP dicarboxylate transporter, DctM subunit, and an integral membrane protein TerC. The gene dctM is well conserved in Brucella spp. except in strains from the Iberian clonal lineage. Intraspecies comparative analysis also exposed a number of biovar-, haplotype- and strain specific insertion-deletion (INDELs) events and single nucleotide polymorphisms (SNPs) that could explain differences in virulence and host specificities. Most discriminative mutations were associated to membrane related molecules (29%) and enzymes involved in catabolism processes (20%). Molecular identification of both B. suis biovar 2 clonal lineages could be easily achieved using the target-PCR procedures established in this work for the evaluated INDELs. CONCLUSION: Whole genome analyses supports that the B. suis biovar 2 Iberian clonal lineage evolved from the Central-European lineage and suggests that the genomic specialization of this pathogen in the Iberian Peninsula is independent of a specific genomic event(s), but instead driven by allopatric speciation, resulting in the establishment of a new ecovar. PMID- 28899414 TI - The Zamvar pericardial fold. AB - This paper describes a pericardial fold that has not yet been mentioned in the Anatomy or Surgery literature.The "Zamvar" pericardial fold is formed by the parietal pericardium and the overlying fibrous pericardium folding back onto themselves over the left-sided pulmonary veins; it is 1 to 3 mm wide, and runs from the inferior edge of the left inferior pulmonary vein, to the superior edge of the left superior pulmonary vein. A similar fold is not seen on the right side.The presence of this fold allows for the safe placement of the deep pericardial retraction suture used during off-pump coronary artery surgery. PMID- 28899412 TI - The effect of information about the benefits and harms of mammography on women's decision-making: study protocol for a randomized controlled trial. AB - BACKGROUND: The decision to participate or not in breast cancer screening is complex due to the trade-off between the expected benefit of breast cancer mortality reduction and the major harm of overdiagnosis. It seems ethically necessary to inform women so that they can actively participate in decision making and make an informed choice based on their values and preferences. The objective of this study is to assess the effects of receiving information about the benefits and harms of screening on decision-making, in women approaching the age of invitation to mammography screening. METHODS: A two-stage, randomized controlled trial (RCT). In the first stage, 40 Basic Health Areas (BHAs) will be selected and randomized to intervention or control. In the second stage, women within each BHA will be randomly selected (n = 400). Four breast cancer screening programs (BCSPs) of the Spanish public health system, three in Catalonia and one in the Canary Islands will participate in the study. Women in the intervention arm will receive a leaflet with detailed information on the benefits and harms of screening using mammography. Women in the control arm will receive a standard leaflet that does not mention harms and recommends accepting the invitation to participate in the biennial examinations of the BCSP. The primary outcome is informed choice, a dichotomous variable that combines knowledge, attitudes, and intentions. Secondary outcomes include decisional conflict; confidence in the decision made; anxiety about screening participation; worry about breast cancer; anticipated regret; time perspective; perceived importance of benefits/harms of screening; perceived risk of breast cancer; and leaflet acceptability. Primary and secondary outcomes are assessed 2-3 weeks after the intervention. DISCUSSION: This is the first RCT that assesses the effect of informing about the benefits and harms of breast cancer screening in Spain in women facing the decision to be screened using mammography. It aims to assess the impact of information on several decisional outcomes and to contribute to paving the road towards shared decision-making in breast cancer screening in our country. TRIAL REGISTRATION: ClinicalTrials.gov registry, ID: NCT03046004 . Retrospectively registered on 4 February 2017. Trial name: InforMa study. PMID- 28899415 TI - The experiences of caregivers of children living with HIV and AIDS in Uganda: a qualitative study. AB - BACKGROUND: Home-based care for HIV patients is popular in contexts severely affected by the epidemic and exacts a heavy toll on caregivers. This study aimed at understanding the experiences of caregivers and their survival strategies. METHODS: A total of 18 caregivers (3 males and 15 females) were interviewed using a semi-structured interview guide, and thematic analysis was used to analyse the data. RESULTS: Analysis suggests that the caregivers are burdened with insecure provisions for food and difficulties in accessing health care. They however survived these strains through managing their relationships, sharing burden with care-recipients, social networks and instrumental spirituality. These findings are discussed under two major themes: 1). Labour of caregiving and 2). Survivalism. CONCLUSIONS: Home-based care presents huge opportunities for community response to the HIV/AIDS epidemic in African settings. It is however burdensome and thus should not be left for families alone to shoulder. There is therefore an urgent need for protecting home-based care for HIV children in Uganda. Implications for improving and strengthening social interventions in home based care of HIV/AIDS in the Ugandan context are addressed. PMID- 28899416 TI - Alzheimer's disease prevention: from risk factors to early intervention. AB - Due to the progressive aging of the population, Alzheimer's disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild-moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant.In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies. Secondly, we review the development of public-private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD related cognitive impairment.The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer's dementia for only a few years, would have a huge impact on public health. PMID- 28899418 TI - The effect of a national web course "Help-Brain-Heart" as a supplemental learning tool before CPR training: a cluster randomised trial. AB - BACKGROUND: The effectiveness of cardiopulmonary resuscitation (CPR) learning methods is unclear. Our aim was to evaluate whether a web course before CPR training, teaching the importance of recognition of symptoms of stroke and acute myocardial infarction (AMI) and a healthy lifestyle, could influence not only theoretical knowledge but also practical CPR skills or willingness to act in a cardiac arrest situation. METHODS: Classes with 13-year-old students were randomised to CPR training only (control) or a web course plus CPR training (intervention). Data were collected (practical test and a questionnaire) directly after training and at 6 months. CPR skills were evaluated using a modified Cardiff test (12-48 points). Knowledge on stroke symptoms (0-7 points), AMI symptoms (0-9 points) and lifestyle factors (0-6 points), and willingness to act were assessed by the questionnaire. The primary endpoint was CPR skills at 6 months. CPR skills directly after training, willingness to act and theoretical knowledge were secondary endpoints. Training and measurements were performed from December 2013 to October 2014. RESULTS: Four hundred and thirty-two students were included in the analysis of practical skills and self-reported confidence. The mean score for CPR skills was 34 points after training (control, standard deviation [SD] 4.4; intervention, SD 4.0; not significant [NS]); and 32 points at 6 months for controls (SD 3.9) and 33 points for intervention (SD 4.2; NS). At 6 months, 73% (control) versus 80% (intervention; P = 0.05) stated they would do compressions and ventilation if a friend had a cardiac arrest, whereas 31% versus 34% (NS) would perform both if the victim was a stranger. One thousand, two hundred and thirty-two students were included in the analysis of theoretical knowledge; the mean scores at 6 months for the control and intervention groups were 2.8 (SD 1.6) and 3.2 (SD 1.4) points (P < 0.001) for stroke symptoms, 2.6 (SD 2.0) and 2.9 (SD 1.9) points (P = 0.008) for AMI symptoms and 3.2 (SD 1.2) and 3.4 (SD 1.0) points (P < 0.001) for lifestyle factors, respectively. DISCUSSION: Use of online learning platforms is a fast growing technology that increases the flexibility of learning in terms of location, time and is available before and after practical training. CONCLUSIONS: A web course before CPR training did not influence practical CPR skills or willingness to act, but improved the students' theoretical knowledge of AMI, stroke and lifestyle factors. PMID- 28899417 TI - Serotonin augmentation therapy by escitalopram has minimal effects on amyloid beta levels in early-stage Alzheimer's-like disease in mice. AB - BACKGROUND: Dysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer's disease (AD). Accumulation of toxic amyloid-beta (Abeta) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Abeta pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Abeta pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Abeta pathology in the APPswe/PS1DeltaE9 (APP/PS1) mouse model of AD. METHODS: We administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 +/- 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis. RESULTS: Amyloid-beta-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Abeta42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Abeta40 increased in the neocortex of SSRI treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Abeta42 and Abeta40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein alpha were reduced in the neocortex after 5-HTergic deafferentation. CONCLUSIONS: Because this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Abeta42 and Abeta40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Abeta pathology. PMID- 28899420 TI - Prognostic value of systemic immune-inflammation index in patients with gastric cancer. AB - BACKGROUND: Inflammation-based indexes have been used to predict survival and recurrence in cancer patients. Systemic immune-inflammation index (SII) was reported to be associated with prognosis in some malignant tumors. In the present study, we aimed to explore the association between SII and the prognosis of patients with gastric cancer. METHODS: We retrospectively analyzed data from 444 gastric cancer patients who underwent gastrectomy at the First Affiliated Hospital of Sun Yat-sen University between January 1994 and December 2005. Preoperative SII was calculated. The Chi square test or Fisher's exact test was used to determine the relationship between preoperative SII and clinicopathologic characteristics. Overall survival (OS) rates were estimated using the Kaplan Meier method, and the effect of SII on OS was analyzed using the Cox proportional hazards model. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of SII, NLR, and PLR. RESULTS: SII equal to or higher than 660 was significantly associated with old age, large tumor size, unfavorable Borrmann classification, advanced tumor invasion, lymph node metastasis, distant metastasis, advanced TNM stage, and high carcino-embryonic antigen level, high neutrophil-lymphocyte ratio, and high platelet-lymphocyte ratio (all P < 0.05). High SII was significantly associated with unfavorable prognosis (P < 0.001) and SII was an independent predictor for OS (P = 0.015). Subgroups analysis further showed significant associations between high SII and short OS in stage I, II, III subgroups (all P < 0.05). SII was superior to NLR and PLR for predicting OS in patients with gastric cancer. CONCLUSION: Preoperative SII level is an independent prognostic factor for OS in patients with gastric cancer. PMID- 28899421 TI - Scrotoschisis: a case report. AB - BACKGROUND: Scrotoschisis is a rare congenital anomaly of the scrotal wall with idiopathic etiology and unknown prevalence. This pathology is extremely rare. We report a new case and review the literature for relevant data. CASE PRESENTATION: A 3-day-old full-term baby boy of African ethnicity, who had a homebirth, with birth weight of 2.7 kg presented to our emergency department with exteriorization of left testis; after clinical examination and proper investigations the diagnosis was scrotoschisis. Surgical treatment was performed by primary closure with excellent follow-up. We reviewed the literature to elaborate on the etiology of this pathology and its management. CONCLUSIONS: Scrotoschisis is a rare congenital anomaly affecting healthy babies. Early management is substantial. Further studies are recommended to learn more about the etiology and long-term results, including the effect on the fertility. PMID- 28899419 TI - Increased plasma lipid levels exacerbate muscle pathology in the mdx mouse model of Duchenne muscular dystrophy. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin expression and leads to severe ambulatory and cardiac function decline. However, the dystrophin-deficient mdx murine model of DMD only develops a very mild form of the disease. Our group and others have shown vascular abnormalities in animal models of MD, a likely consequence of the fact that blood vessels express the same dystrophin-associated glycoprotein complex (DGC) proteins as skeletal muscles. METHODS: To test the blood vessel contribution to muscle damage in DMD, mdx 4cv mice were given elevated lipid levels via apolipoprotein E (ApoE) gene knockout combined with normal chow or lipid-rich Western diets. Ambulatory function and heart function (via echocardiogram) were assessed at 4 and 7 months of age. After sacrifice, muscle histology and aortic staining were used to assess muscle pathology and atherosclerosis development, respectively. Plasma levels of total cholesterol, high-density lipoprotein (HDL), triglycerides, and creatine kinase (CK) were also measured. RESULTS: Although there was an increase in left ventricular heart volume in mdx-ApoE mice compared to that in mdx mice, parameters of heart function were not affected. Compared with wild-type and ApoE null, only mdx-ApoE KO mice showed significant ambulatory dysfunction. Despite no significant difference in plasma CK, histological analyses revealed that elevated plasma lipids in chow- and Western diet-fed mdx-ApoE mice was associated with severe exacerbation of muscle pathology compared to mdx mice: significant increase in myofiber damage and fibrofatty replacement in the gastrocnemius and triceps brachii muscles, more reminiscent of human DMD pathology. Finally, although both ApoE and mdx-ApoE groups displayed increased plasma lipids, mdx ApoE exhibited atherosclerotic plaque deposition equal to or less than that of ApoE mice. CONCLUSIONS: Since others have shown that lipid abnormalities correlate with DMD severity, our data suggest that plasma lipids could be primary contributors to human DMD severity and that the notoriously mild phenotype of mdx mice might be attributable in part to their endogenously low plasma lipid profiles. Hence, DMD patients may benefit from lipid-lowering and vascular targeted therapies. PMID- 28899423 TI - Comparative study on alkaloids and their anti-proliferative activities from three Zanthoxylum species. AB - BACKGROUND: Alkaloids have been considered as the most promising bioactive ingredients in plant species from the genus Zanthoxylum. This study reports on the compositions and contents of the Zanthoxylum alkaloids (ZAs) from three Zanthoxylum species, and their potential anti-proliferation activities. METHODS: An HPLC-UV/ESI-MS/MS method was established and employed to analyze the alkaloids in different Zanthoxylum extracts. The common and unique peaks and their relative contents were summarized and compared to evaluate the similarity and dissimilarity of the three Zanthoxylum species. Meanwhile, inhibitory activity tests to four carcinoma cell lines, i.e., stomach tumor cells (SGC-7901), cervical tumor cells (Hela), colon tumor cells (HT-29) and Hepatic tumor cells (Hep G2), were carried out in vitro to evaluate the bioactivities of the ZAs. RESULTS: Seventy peaks were detected in the crude total alkaloid samples, and 58 of them were identified. As a result, 13 common peaks were found in the extracts of all the three Zanthoxylum species, while some unique peaks were also observed in specific species, with 17 peaks in Z. simulans, 15 peaks in Z. ailanthoides and 11 peaks in Z. chalybeum, respectively. The comparison of the composition and relative contents indicated that alkaloids of benzophenanthridine type commonly present in all the three Zanthoxylum species with high relative contents among the others, which are 60.52% in Z. ailanthoides, 30.52% in Z. simulans and 13.84% in Z. chalybeum, respectively. In terms of activity test, Most of the crude alkaloids extracts showed remarkable inhibitory activities against various tumor cells, and the inhibitory rates ranged from 60.71 to 93.63% at a concentration of 200 MUg/mL. However, SGC-7901 cells seemed to be more sensitive to the ZAs than the other three cancer cells. CONCLUSION: The alkaloid profiles detected in this work revealed significant differences in both structures and contents among Zanthoxylum species. The inhibitory rates for different cancer cells in this study indicated that the potential anti-cancer activity should be attributed to quaternary alkaloids in these three species, which will provide great guidance for further exploring this traditional medicinal resource as new healthcare products. PMID- 28899422 TI - Moderating effects of sex on the impact of diagnosis and amyloid positivity on verbal memory and hippocampal volume. AB - BACKGROUND: Alzheimer's disease (AD) impacts men and women differently, but the effect of sex on predementia stages is unclear. The objective of this study was to examine whether sex moderates the impact of florbetapir positron emission tomography (PET) amyloid positivity (A+) on verbal learning and memory performance and hippocampal volume (HV) in normal cognition (NC) and early mild cognitive impairment (eMCI). METHODS: Seven hundred forty-two participants with NC and participants with eMCI from the Alzheimer's Disease Neuroimaging Initiative (second cohort [ADNI2] and Grand Opportunity Cohort [ADNI-GO]) were included. All had baseline florbetapir PET measured, and 526 had screening visit HV measured. Regression moderation models were used to examine whether A+ effects on Rey Auditory Verbal Learning Test learning and delayed recall and right and left HV (adjusted for total intracranial volume) were moderated by diagnosis and sex. Age, cognition at screening, education, and apolipoprotein E epsilon4 carrier status were controlled. RESULTS: Women with A+, but not those with florbetapir PET amyloid negative (A-),eMCI showed poorer learning. For women with NC, there was no relationship of A+ with learning. In contrast, A+ men trended toward poorer learning regardless of diagnosis. A similar trend was found for verbal delayed recall: Women with A+, but not A-, eMCI trended toward reduced delayed recall; no effects were observed for women with NC or for men. Hippocampal analyses indicated that women with A+, but not those with A-, eMCI, trended toward smaller right HV; no significant A+ effects were observed for women with NC. Men showed similar, though nonsignificant, patterns of smaller right HV in A+ eMCI, but not in men with A- eMCI or NC. No interactive effects of sex were noted for left HV. CONCLUSIONS: Women with NC showed verbal learning and memory scores robust to A+, and women with A+ eMCI lost this advantage. In contrast, A+ impacted men's scores less significantly or not at all, and comparably across those with NC and eMCI. Sex marginally moderated the relationship of A+ and diagnosis with right HV, such that women with NC showed no A+ effect and women with A+ eMCI lost that advantage in neural integrity; the pattern in men was less clear. These findings show that women with A+ eMCI (i.e., prodromal AD) have differential neural and cognitive decline, which has implications for considering sex in early detection of AD and development of therapeutics. PMID- 28899424 TI - Clade homogeneity and low rate of delta virus despite hyperendemicity of hepatitis B virus in Ethiopia. AB - BACKGROUND: Although hepatitis B virus (HBV) is hyperendemic and heterogeneous in its genetic diversity in Ethiopia, little is known about hepatitis D virus (HDV) circulating genotypes and molecular diversity. METHODS: A total of 321 hepatitis B surface antigen (HBsAg) positives (125 HIV co-infected, 102 liver disease patients and 94 blood donors) were screened for anti-HDV antibody. The anti-HDV positive sera were subjected to Real time PCR for HDV-RNA confirmation. The non coding genome region (spanning from 467 to 834 nucleotides) commonly used for HDV genotyping as well as complete HDV genome were sequenced for genotyping and molecular analysis. RESULTS: The anti-HDV antibody was found to be 3.2% (3) in blood donors, 8.0% (10) in HIV co-infected individuals and 12.7% (13) in liver disease patients. None of the HIV co-infected patients who revealed HBV lamivudine (3TC) resistance at tyrosine-methionine/isoleucine-aspartate-aspartate (YM(I)DD) reverse transcriptase (RT) motif with concomitant vaccine escape gene mutants was positive for anti-HDV antibody. The HDV viremia rate was 33.3%, 30.0% and 23.1% in respect to the above study groups. All the six isolates sequenced were phylogenetically classified as HDV genotype 1 (HDV-1) and grouped into two monophyletic clusters. Amino acid (aa) residues analysis of clathrin heavy chain (CHC) domain and the isoprenylation signal site (Py) at 19 carboxyl (C)-terminal amino acids (aa 196-214) and the HDV RNA binding domain (aa 79-107) were highly conserved and showed a very little nucleotide variations. All the sequenced isolates showed serine at amino acid position 202. The RNA editing targets of the anti-genomic HDV RNA (nt1012) and its corresponding genomic RNA (nt 580) showed nucleotides A and C, respectively. CONCLUSIONS: The low seroprevalence and viraemic rates of HDV in particular during HIV-confection might be highly affected by HBV drug resistance selected HBsAg mutant variants in this setting, although HDV-1 sequences analysis revealed clade homogeneity and highly conserved structural and functional domains. Thus, the potential role of HBV drug resistance associated polymerase mutations and concomitant HBsAg protein variability on HDV viral assembly, secretion and infectivity needs further investigation. PMID- 28899425 TI - The physiological determinants of low-level urine cadmium: an assessment in a cross-sectional study among schoolchildren. AB - BACKGROUND: Recent studies in children have reported associations of urinary cadmium (U-Cd), used as biomarker of Cd body burden, with renal dysfunction, retarded growth and impaired cognitive development in children. Little is known, however, about factors influencing U-Cd in children and likely to act as confounders. METHODS: In a cross-sectional study involving 249 schoolchildren (mean age, 5.72 years; 138 boys), we measured the urine concentrations of cadmium, zinc, lead, albumin, alpha1-microglobulin (A1M), retinol-binding protein, beta2-microglobulin and club cell protein (CC16). Determinants of U-Cd expressed per creatinine or adjusted to specific gravity were identified by multiple regression analyses. RESULTS: Girls and boys had similar median concentrations of U-Cd (0.22 and 0.24 MUg/L, 0.33 and 0.35 MUg/g creatinine, respectively). When models were run without including creatinine or specific gravity among independent variables, urinary zinc, urinary A1M and age emerged as the strongest predictors of U-Cd expressed per g creatinine or adjusted to SG. When adding creatinine among predictors, urinary creatinine emerged as an additional strong predictor correlating negatively with U-Cd per g creatinine. This strong residual influence of diuresis, not seen when adding specific gravity among predictors, linked U-Cd to U-A1M or U-CC16 through secondary associations mimicking those induced by Cd nephrotoxity. CONCLUSIONS: In young children U-Cd largely varies with diuresis, zinc metabolism and urinary A1M. These physiological determinants, unrelated to Cd body burden, may confound the child renal and developmental outcomes associated with low-level U-Cd. PMID- 28899426 TI - Benign metastasizing leiomyoma presenting as multiple cystic pulmonary nodules: a case report. AB - BACKGROUND: Benign metastatic leiomyoma (BML) is an extremely rare disease. Although uterine leiomyomas are benign histologically, they can metastasize to distant sites. While the incidence is very low, the lung is the organ most frequently affected by BML. Pulmonary BML usually presents as numerous well defined nodules of various sizes, while the cavitary or cystic features in the nodules are rarely observed on radiologic images. CASE PRESENTATION: A 52-year old woman complained of cough and dyspnea for one month. She had been previously diagnosed with uterine leiomyoma and had undergone total hysterectomy about 14 years prior. High-resolution computed tomography (CT) images showed that there were multiple cystic nodules of various sizes in both lungs. Pathologic examination revealed that the pulmonary nodule had complex branching glandular structures lined by a single layer of simple cuboidal to columnar epithelium that was surrounded by abundant spindle cells. Additional immunohistochemistry data suggested that pulmonary nodule diagnosis was BML-associated uterine leiomyoma. CONCLUSION: In this report, we introduce an interesting case of pulmonary BML that presented as a combination of various kinds of nodules including simple round nodules, simple cysts, and cysts with a solid portion, which are very rare radiologic features of BML in lung. In addition, when the patient is a woman of reproductive age, physicians should meticulously review the gynecological history and suspect BML when there are various cystic pulmonary lesions. PMID- 28899427 TI - Activation of dorsal horn cannabinoid CB2 receptor suppresses the expression of P2Y12 and P2Y13 receptors in neuropathic pain rats. AB - BACKGROUND: More evidence suggests that dorsal spinal cord microglia is an important site contributing to CB2 receptor-mediated analgesia. The upregulation of P2Y12 and P2Y13 purinoceptors in spinal dorsal horn microglia is involved in the development of pain behavior caused by peripheral nerve injury. However, it is not known whether the expression of P2Y12 and P2Y13 receptors at spinal dorsal horn will be influenced after CB2 receptor activation in neuropathic pain rats. METHODS: Chronic constriction injury (CCI) and intrathecal ADPbetaS injection were performed in rats to induce neuropathic pain. The paw withdrawal latency (PWL) was used to evaluate thermal hyperalgesia in neuropathic rats. The expression of P2Y12 and P2Y13 receptors, p-p38MAPK, and NF-kappaBp65 was detected with RT-PCR and western blotting analysis. RESULTS: Treatment with AM1241 produces a pronounced inhibition of CCI-induced thermal hyperalgesia and significantly inhibited the increased expression of P2Y12 and P2Y13 receptors at the mRNA and protein levels, which open up the possibility that P2Y12 and P2Y13 receptor expression are downregulated by CB2 receptor agonist AM1241 in CCI rats. Western blot analysis demonstrated that AM1241 reduced the elevated expression of p-p38MAPK and NF-kappaBp65 in the dorsal spinal cord induced by CCI. After administration with either SB203580 (p38MAPK inhibitor) or PDTC (NF-kappaB inhibitor), the levels of P2Y13 receptor expression in the dorsal spinal cord were lower than those in the CCI group. However, in CCI rats, the increased expression of P2Y12 receptor was prevented by intrathecal administration of PDTC but not by SB203580. In addition, minocycline significantly decreased the increased expression of P2Y12 and P2Y13 receptors. The similar results can be observed in ADPbetaS-treated rats. Intrathecal injection of ADPbataS causes thermal hyperalgesia and increased expression of P2Y12 and P2Y13 receptors in the dorsal spinal cord of naive rats. Moreover, intrathecal injection of AM1241 alleviates pain response and reduces the elevated expression of P2Y12 and P2Y13 receptors, p-p38MAPK, and NF-kappaBp65 in the dorsal spinal cord of ADPbetaS treated rats. Intrathecal injection of SB203580 significantly inhibited the ADPbetaS-induced P2Y13 receptor expression, without affecting P2Y12 receptor expression. However, treatment with either SB203580 or PDTC effectively inhibited P2Y13 receptor expression compared to ADPbetaS-treated rats. CONCLUSIONS: In CCI- and ADPbetaS-treated rats, AM1241 pretreatment could efficiently activate CB2 receptor, while inhibiting p38MAPK and NF-kappaB activation in the dorsal spinal cord. CB2 receptor stimulation decreased P2Y13 receptor expression via p38MAPK/NF kappaB signaling. On the other hand, CB2 receptor activation decreased P2Y12 receptor expression via p38MAPK-independent NF-kappaB signaling pathway. PMID- 28899428 TI - Proximal tibial trabecular bone mineral density is related to pain in patients with osteoarthritis. AB - BACKGROUND: Our objective was to examine the relationships between proximal tibial trabecular (epiphyseal and metaphyseal) bone mineral density (BMD) and osteoarthritis (OA)-related pain in patients with severe knee OA. METHODS: The knee was scanned preoperatively using quantitative computed tomography (QCT) in 42 patients undergoing knee arthroplasty. OA severity was classified using radiographic Kellgren-Lawrence scoring and pain was measured using the pain subsection of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). We used three-dimensional image processing techniques to assess tibial epiphyseal trabecular BMD between the epiphyseal line and 7.5 mm from the subchondral surface and tibial metaphyseal trabecular BMD 10 mm distal from the epiphyseal line. Regional analysis included the total epiphyseal and metaphyseal region, and the medial and lateral epiphyseal compartments. The association between total WOMAC pain scores and BMD measurements was assessed using hierarchical multiple regression with age, sex, and body mass index (BMI) as covariates. Statistical significance was set at p < 0.05. RESULTS: Total WOMAC pain was associated with total epiphyseal BMD adjusted for age, sex, and BMI (p = 0.013) and total metaphyseal BMD (p = 0.017). Regionally, total WOMAC pain was associated with medial epiphyseal BMD adjusted for age, sex, and BMI (p = 0.006). CONCLUSION: These findings suggest that low proximal tibial trabecular BMD may have a role in OA-related pain pathogenesis. PMID- 28899429 TI - Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment. AB - BACKGROUND: Amyloid pathology in subjects with mild cognitive impairment (MCI) is an important risk factor for progression to dementia due to Alzheimer's disease. Predicting the onset of dementia is challenging even in the presence of amyloid, as time to progression varies considerably among patients and depends on the onset of neurodegeneration. Survival analysis can account for variability in time to event, but has not often been applied to MRI measurements beyond singular predefined brain regions such as the hippocampus. Here we used a voxel-wise survival analysis to identify in an unbiased fashion brain regions where decreased gray matter volume is associated with time to dementia, and assessed the effects of amyloid on these associations. METHODS: We included 276 subjects with MCI (mean age 67 +/- 8, 41% female, mean Mini-Mental State Examination 26.6 +/- 2.4), baseline 3D T1-weighted structural MRI, baseline cerebrospinal fluid (CSF) biomarkers, and prospective clinical follow-up. We fitted for each voxel a proportional Cox hazards regression model to study whether decreased gray matter volume predicted progression to dementia in the total sample, and stratified for baseline amyloid status. RESULTS: Dementia at follow-up occurred in 122 (44%) subjects over an average follow-up period of 2.5 +/- 1.5 years. Baseline amyloid positivity was associated with progression to dementia (hazard ratio 2.4, p < 0.001). Within amyloid-positive subjects, decreased gray matter volume in the hippocampal, temporal, parietal, and frontal regions was associated with more rapid progression to dementia (median (interquartile range) hazard ratio across significant voxels 1.35 (1.32-1.40)). Repeating the analysis in amyloid-negative subjects revealed similar patterns (median (interquartile range) hazard ratio 1.76 (1.66-1.91)). CONCLUSIONS: In subjects with MCI, both abnormal amyloid CSF and decreased gray matter volume were associated with future progression to dementia. The spatial pattern of decreased gray matter volume associated with progression to dementia was consistent for amyloid-positive and amyloid-negative subjects. PMID- 28899430 TI - The aberrant upstream pathway regulations of CDK1 protein were implicated in the proliferation and apoptosis of ovarian cancer cells. AB - BACKGROUND: Upregulation of Cyclin dependent kinase 1 (CDK1) protein is closely related with the prognosis of several malignant tumors. Chk1-CDC25C-CDK1 signaling and P53-P21WAF1-CDK1 signaling pathways are closely related with the cell cycle G2/M phase regulation. The present study aimed to analyze the relationship between CDK1 and the proliferation and apoptosis of ovarian cancer cells, investigate its molecular mechanism preliminarily. METHODS: The specific short-hair RNA (shRNA) plasmids and negative control plasmid of CDK1, checkpoint kinase 1 (CHK1) and p53 genes were transfected into ovarian cancer SK-OV-3 and OVCAR-3 cells respectively. The expressions of CDK1, CHK1 and p53 mRNA and CDK1, Chk1 and P53 protein were detected by sqRT-PCR and Western blot, levels of phospho-CDK1(Thr14/Tyr15), CyclinB1, phospho-Chk1(ser345), cell division cycle 25C (CDC25C), phospho-CDC25C(ser216), P21WAF1, phospho-P53(ser15), proliferating cell nuclear antigen (PCNA), Ki-67, Bcl-2, Bax, Caspase8, Cleaved-caspase3 and Cytochrome C were examined by Western blot. The cell proliferation was measured by MTT and Trypan blue exclusion assay respectively, the cell cycle phase distribution and cell apoptosis rate were detected by flow cytometry (FCM) assay. RESULTS: As results of CDK1 inhibition by shRNA, the cell proliferation was repressed, the cell numbers of G2/M phase and cell apoptosis rate were increased in both SK-OV-3 and OVCAR-3 cells. After knockdown of CDK1, expressions of PCNA, Ki-67 and Bcl-2 protein were downregulated, expressions of Bax, Caspase8, Cleaved caspase3 and Cytochrome C were upregulated. While knockdown the CHK1 and p53 by shRNA respectively, the similar effects were observed on the cell proliferation, cell cycle phase distribution and apoptosis in both SK-OV-3 and OVCAR-3 cells, as well as the expressions of the proliferation and apoptosis related proteins mentioned above. Moreover, the levels of p-CDK1(Thr14/Tyr15) were increased after either CHK1 inhibition or p53 inhibition. CONCLUSIONS: Abnormal activation of CDK1 was implicated in the proliferation and apoptosis regulation of ovarian cancer cells, which might be due to the aberrant regulations of the upstream Chk1 CDC25C and P53-P21WAF1 signaling pathway. PMID- 28899431 TI - The role of perfusion and diffusion MRI in the assessment of patients affected by probable idiopathic normal pressure hydrocephalus. A cohort-prospective preliminary study. AB - BACKGROUND: Invasive tests measuring resistance to cerebral spinal fluid (CSF) outflow and the effect of temporary drainage of CSF are used to select candidates affected by idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery. Neither test, however, completely excludes patients from treatment. Perfusion and diffusion magnetic resonance imaging (MRI) are non-invasive techniques that might be of value in selecting patients for surgical treatment and understanding brain changes in iNPH patients. The aim of this study was to understand the role of perfusion and diffusion MRI in selecting candidates for shunt surgery and to investigate the relationship between cerebral perfusion and possible microstructural changes in brain tissue before and after invasive tests, and after ventricular-peritoneal (VP) shunt implantation, to better clarify pathophysiological mechanisms underlying iNPH. METHODS: Twenty-three consecutive patients with probable iNPH were included in this study. Patients underwent a clinical and neuroradiological evaluation before and after invasive tests, and after surgery. Only patients who showed a positive result in at least one of the invasive tests were submitted for VP shunt implantation. Perfusion and diffusion magnetic resonance imaging (MRI) was performed before and after invasive tests and after shunt surgery. RESULTS: Thirteen patients underwent surgery and all showed clinical improvement after VP shunt implantation and a significant increase in perfusion in both periventricular white matter (PVWM) and basal ganglia (BG) regions. The 10 patients that did not have surgery showed after invasive tests, a significant reduction in perfusion in both PVWM and BG regions. Comparing the changes in perfusion with those of diffusion in positive patients we found a significant positive correlation in BG and a significant inverse correlation in PVWM area. CONCLUSIONS: Perfusion MRI is a non-invasive technique that could be useful together with invasive tests in selecting patients for surgical treatment. Furthermore, the relationship between perfusion and diffusion data could better clarify pathophysiological mechanisms underlying iNPH. In PVWM area we suggest that interstitial edema could reduce microvascular blood flow and interfere with the blood supply to these regions. In BG regions we suggest that a chronic hypoxic insult caused by blood hypo-perfusion produces a chronic cytotoxic edema. Both in PVWM and in BG regions, pathophysiological mechanisms could be modified after VP-shunt implantation. PMID- 28899432 TI - Prevalence and associations of microalbuminuria in proteinuria-negative patients with type 2 diabetes in two regional hospitals in Cameroon: a cross-sectional study. AB - BACKGROUND: Microalbuminuria (MA) is the earliest clinical evidence of diabetic nephropathy, but most patients in sub-Saharan Africa (SSA) only have access to much cheaper dipstick proteinuria as a means to screen for diabetic nephropathy. The aim of this study was to determine the prevalence and associations of MA among proteinuria-negative type 2 diabetic patients in a SSA setting. METHODS: In this cross-sectional study, patients with type 2 diabetes screened negative for dipstick proteinuria in a primary healthcare hospital were assessed. Detection of microalbuminuria was carried out in two steps: qualitative detection using special microalbumin urine strip, and quantitative laboratory measurement and calculation of urinary albumin-to-creatinine ratio (UACR). Microalbuminuria was defined as UACR of 30-300 mg/g. RESULTS: A total of 162 type 2 diabetic patients were included. Using quantitative assessment, the prevalence of microalbuminuria was 14.2% (95% CI 8.8-19.6) whereas 26.5% (95% CI 19.8-34.0) had microalbuminuria with urine strip. The mean systolic blood pressure (p = 0.032), diastolic blood pressure (p = 0.032) and serum creatinine concentration (p < 0.001) were higher in people with microalbuminuria as compared to those with normoalbuminuria, whereas the mean body mass index (p = 0.046) and mean eGFR (p < 0.001) were lower in the albuminuria group. In multiple linear regression, eGFR (p = 0.001) and serum creatinine concentration (p = 0.003) were independently associated with increased UACR. CONCLUSIONS: One in every seven proteinuria-negative type 2 diabetic patients has microalbuminuria in primary care setting in Cameroon; microalbuminuria is associated with higher systolic and diastolic blood pressure, and declining kidney function. Our results emphasize the urgent need to increase the accessibility to microalbuminuria testing to ensure that all diabetic patients with negative dipstick proteinuria can benefit. PMID- 28899433 TI - Wearable sensors to predict improvement following an exercise intervention in patients with knee osteoarthritis. AB - BACKGROUND: Muscle strengthening exercises consistently demonstrate improvements in the pain and function of adults with knee osteoarthritis, but individual response rates can vary greatly. Identifying individuals who are more likely to respond is important in developing more efficient rehabilitation programs for knee osteoarthritis. Therefore, the purpose of this study was to determine if pre intervention multi-sensor accelerometer data (e.g., back, thigh, shank, foot accelerometers) and patient reported outcome measures (e.g., pain, symptoms, function, quality of life) can retrospectively predict post-intervention response to a 6-week hip strengthening exercise intervention in a knee OA cohort. METHODS: Thirty-nine adults with knee osteoarthritis completed a 6-week hip strengthening exercise intervention and were sub-grouped as Non-Responders, Low-Responders, or High-Responders following the intervention based on their change in patient reported outcome measures. Pre-intervention multi-sensor accelerometer data recorded at the back, thigh, shank, and foot and Knee Injury and Osteoarthritis Outcome Score subscale data were used as potential predictors of response in a discriminant analysis of principal components. RESULTS: The thigh was the single best placement for classifying responder sub-groups (74.4%). Overall, the best combination of sensors was the back, thigh, and shank (81.7%), but a simplified two sensor solution using the back and thigh was not significantly different (80.0%; p = 0.27). CONCLUSIONS: While three sensors were best able to identify responders, a simplified two sensor array at the back and thigh may be the most ideal configuration to provide clinicians with an efficient and relatively unobtrusive way to use to optimize treatment. PMID- 28899434 TI - Effective delivery of social and behavior change communication through a Care Group model in a supplementary feeding program. AB - BACKGROUND: In 2014, an intervention aimed at increasing the oil in corn soy blend (CSB) porridge prepared by caregivers of children with moderate acute malnutrition was implemented in Southern Malawi. This analysis describes the flow of key messages delivered through the Care Group model during this intervention. METHODS: The intervention provided a supplementary food ration of CSB and oil and used a Care Group model in which healthcare workers were trained to deliver social and behavior change communication (SBCC) to care group volunteers who then delivered messages to caregivers of beneficiary children. Healthcare workers also delivered messages to caregivers directly. Interviews and focus groups were conducted with all three groups in order to determine the exchange of key messages about ingredient use, storage, and purpose, which were analyzed descriptively. RESULTS: Analysis of SBCC flow and information exchange showed that 100% of caregivers reported learning about the amounts of oil and CSB to use while preparing porridge and over 90% of caregivers, healthcare workers, and care group volunteers reported talking about it. Focus groups confirmed an effective flow of communication among these three groups. CONCLUSION: This analysis evaluated the flow of key SBCC messages through multiple, overlapping lines of communication among healthcare workers, care group volunteers, and caregivers; the effective transmission of these SBCC messages through this model may contribute to the success of a supplementary feeding intervention program. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT01873196 ). PMID- 28899435 TI - Optimizing Visits to the Site of Death for Bereaved Families After Disasters and Terrorist Events. AB - In recent years it has been common after disasters and terrorist events to offer bereaved families the opportunity to visit the place where their loved ones died. Many report that such visits are beneficial in processing their loss. Various factors, both cognitive (eg, counteracting disbelief) and existential or emotional (eg, achieving a sense of closeness to the deceased), are associated with the experienced benefit. Nonetheless, exacerbations of trauma and grief reactions (eg, re-enactment fantasies) are common, with some of the bereaved also reporting adverse reactions after the visit. Subsequently, proper preparations are a prerequisite before such visits take place. This article describes how to optimize collective visits to the site of death after disasters or terrorist events for bereaved families. Important questions-for example, concerning those who should be responsible for organizing a visit and those who should be invited, the timing of the visit, what can be done at the site, the need for support personnel, and other practical issues-are discussed and general guidelines are recommended. (Disaster Med Public Health Preparedness. 2018;12:523-527). PMID- 28899436 TI - Educational level and employment status in adults with congenital heart disease. AB - : Purpose Through this study we aimed to assess the educational level and employment status of adults with CHD in Germany. METHODS: Data were acquired from an online survey carried out in 2015 by the German National Register for Congenital Heart Defects. A total of 1458 adults with CHD participated in the survey (response rate: 37.6%). For 1198 participants, detailed medical information, such as main cardiac diagnosis and information from medical reports, was available. RESULTS: Of the participants surveyed (n=1198), 54.5% (n=653) were female, and the mean age was 30 years. The majority of respondents (59.4%) stated that they had high education levels and that they were currently employed (51.1%). Patients with simple CHD had significantly higher levels of education (p<0.001) and were more likely to be employed (p=0.01) than were patients with complex CHD. CONCLUSIONS: More than half of the participants had high education levels and the majority were employed. The association between CHD and its severity and individuals' educational attainment should be investigated more closely in future studies. PMID- 28899437 TI - Novel Method for Preparing Transmission Electron Microscopy Samples of Micrometer Sized Powder Particles by Using Focused Ion Beam. AB - The preparation of transmission electron microscopy (TEM) samples from powders is quite difficult and challenging. For powders with particles in the 1-5 MUm size range, it is especially difficult to select an adequate sample preparation technique. Epoxy is commonly used to bind powder, but drawbacks, such as differential milling originating from unequal milling rates between the epoxy and powder, remain. We propose a new, simple method for preparing TEM samples. This method is especially useful for powders with particles in the 1-5 MUm size range that are vulnerable to oxidation. The method uses solder as an embedding agent together with focused ion beam (FIB) milling. The powder was embedded in low temperature solder using a conventional hot-mounting instrument. Subsequently, FIB was used to fabricate thin TEM samples via the lift-out technique. The solder proved to be more effective than epoxy in producing thin TEM samples with large areas. The problem of differential milling was mitigated, and the solder binder was more stable than epoxy under an electron beam. This methodology can be applied for preparing TEM samples from various powders that are either vulnerable to oxidation or composed of high atomic number elements. PMID- 28899438 TI - Facilitators and Barriers to Preparedness Partnerships: A Veterans Affairs Medical Center Perspective. AB - OBJECTIVE: This study sought to understand facilitators and barriers faced by local US Department of Veterans Affairs Medical Center (VAMC) emergency managers (EMs) when collaborating with non-VA entities. METHODS: Twelve EMs participated in semi-structured interviews lasting 60 to 90 minutes discussing their collaboration with non-VAMC organizations. Sections of the interview transcripts concerning facilitators and barriers to collaboration were coded and analyzed. Common themes were organized into 2 categories: (1) internal (ie, factors affecting collaboration from within VAMCs or by VA policy) and (2) external (ie, interagency or interpersonal factors). RESULTS: Respondents reported a range of facilitators and barriers to collaboration with community-based agencies. Internal factors facilitating collaboration included items such as leadership support. An internal barrier example included lack of clarity surrounding the VAMC's role in community disaster response. External factors noted as facilitators included a shared goal across organizations while a noted barrier was a perception that potential partners viewed a VAMC partnership with skepticism. CONCLUSION: Federal institutions are important partners for the success of community disaster preparedness and response. Understanding the barriers that VAMCs confront, as well as potential facilitators to collaboration, should enhance the development of VAMC-community partnerships and improve community health resilience. (Disaster Med Public Health Preparedness. 2018;12:431-436). PMID- 28899439 TI - Psychological morbidity and parenting stress in mothers of primary school children by timing of acquisition of HIV infection: a longitudinal cohort study in rural South Africa. AB - Longitudinal maternal mental health data are needed from high HIV prevalence settings. The Siyakhula Cohort (SC) is a population-based cohort of HIV-positive and negative mothers (n=1506) with HIV-negative children (n=1536) from rural South Africa. SC includes 767 HIV-negative mothers; 465 HIV-positive in pregnancy; 272 HIV-positive since pregnancy (n=2 missing HIV status). A subgroup (n=890) participated in a non-randomized breastfeeding intervention [Vertical Transmission Study (VTS)]; the remaining (n=616) were resident in the same area and received antenatal care at the time of the VTS, but were not part of the VTS, instead receiving the standard of care Prevention of Mother-to-Child Transmission (PMTCT) Programme. In secondary analysis we investigated the prevalence of, and factors associated with, psychological morbidity amongst mothers who were still the primary caregiver of the child (1265 out of 1506) at follow-up (7-11 years post-birth). We measured maternal depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder Scale-7) and parenting stress (Parenting Stress Index-36), using standardized cut-offs and algorithms. In total, 75 (5.9%) mothers met criteria for depression, 37 (2.9%) anxiety and 134 (10.6%) parenting stress. Using complete case logistic regression (n=1206 out of 1265 mothers) as compared to being HIV-negative, testing HIV-positive in pregnancy doubled odds of depression [adjusted odd ratios (aOR)=1.96 [1.0-3.7] P=0.039]. Parenting stress was positively associated with acquisition of HIV after pregnancy (aOR=3.11 [1.9 5.2] P<0.001) and exposure to household crime (aOR=2.02 [1.3-3.2] P=0.003); negatively associated with higher maternal education (aOR=0.29 [0.1-0.8] P=0.014), maternal employment (aOR=0.55 [0.3-0.9] P=0.024). Compared with the standard of care PMTCT, VTS mothers had reduced odds of parenting stress (aOR=0.61 [0.4-0.9] P=0.016). Integrating parental support into mostly bio medical treatment programmes, during and beyond pregnancy, is important. PMID- 28899440 TI - The impact of social media promotion with infographics and podcasts on research dissemination and readership. AB - OBJECTIVE: In 2015 and 2016, the Canadian Journal of Emergency Medicine (CJEM) Social Media (SoMe) Team collaborated with established medical websites to promote CJEM articles using podcasts and infographics while tracking dissemination and readership. METHODS: CJEM publications in the "Original Research" and "State of the Art" sections were selected by the SoMe Team for podcast and infographic promotion based on their perceived interest to emergency physicians. A control group was composed retrospectively of articles from the 2015 and 2016 issues with the highest Altmetric score that received standard Facebook and Twitter promotions. Studies on SoMe topics were excluded. Dissemination was quantified by January 1, 2017 Altmetric scores. Readership was measured by abstract and full-text views over a 3-month period. The number needed to view (NNV) was calculated by dividing abstract views by full-text views. RESULTS: Twenty-nine of 88 articles that met inclusion were included in the podcast (6), infographic (11), and control (12) groups. Descriptive statistics (mean, 95% confidence interval) were calculated for podcast (Altmetric: 61, 42 80; Abstract: 1795, 1135-2455; Full-text: 431, 0-1031), infographic (Altmetric: 31.5, 19-43; Abstract: 590, 361-819; Full-text: 65, 33-98), and control (Altmetric: 12, 8-15; Abstract: 257, 159-354; Full-Text: 73, 38-109) articles. The NNV was 4.2 for podcast, 9.0 for infographic, and 3.5 for control articles. Discussion Limitations included selection bias, the influence of SoMe promotion on the Altmetric scores, and a lack of generalizability to other journals. CONCLUSION: Collaboration with established SoMe websites using podcasts and infographics was associated with increased Altmetric scores and abstract views but not full-text article views. PMID- 28899441 TI - Use of proton-pump inhibitors is associated with depression: a population-based study. AB - Treatment with proton-pump inhibitors (PPIs) might be associated with neuropsychological side effects. We examined the association between use of PPIs and depressive symptoms in an elderly population. Mood was assessed by the 30 item Geriatric Depression Scale (GDS) in all 344 inhabitants of Tuscania (Italy) aged 75 years and over, without exclusion criteria; depression was defined by a GDS score >=11. Use of PPIs was associated with a higher GDS score in linear regression analysis (B = 2.43; 95% CI = 0.49-4.38; p = 0.014) after adjusting; also, use of PPIs was associated with increased adjusted probability of depression in logistic regression (OR = 2.38; 95% CI = 1.02-5.58; p = 0.045). Higher PPIs dosages were associated with increased probability of depression (p for trend = 0.014). This association was independent of the diagnosis of peptic disease, as well as the use of antidepressant medications. No association was found between use of H2-blockers or antacids and the GDS score. Calculation of the population attributable risk indicated that 14% of depression cases could be avoided by withdrawal of PPIs. Use of PPIs might represent a frequent cause of depression in older populations; thus, mood should be routinely assessed in elderly patients on PPIs. PMID- 28899442 TI - Applications of 256-Slice, Spiral Computed Tomography Perfusion Scanning in Limb Salvage After High-Voltage Electrical Injury. AB - OBJECTIVE: This study aimed to investigate the applications of intelligent 256 slice computed tomography (iCT) perfusion imaging in high-voltage electrical injuries (HVEIs). METHODS: 256-slice iCT was used to perform perfusion scanning for 48 patients with HVEI to detect the perfusion parameters. RESULTS: The blood flow (BF) and peak enhancement intensity (PEI) values of the plane lower than the amputation level of the diseased side (ALD) were smaller than those of the corresponding healthy side (P<0.05); therefore, the differences were statistically significant. The BF value of the plane beyond the ALD was bigger than that of the ALD (t=2.99 and P=0.042); therefore, the difference was statistically significant. The BF, PEI, and blood volume values of the plane below the ALD were smaller than those of the ALD (P<0.05); therefore, the differences were statistically significant. CONCLUSIONS: The technique of 256 slice iCT perfusion imaging could provide richer and more comprehensive imaging data for the clinical treatment of HVEIs, thus exhibiting its benefit in reducing the disability of patients with HVEIs. (Disaster Med Public Health Preparedness. 2018;12:478-485). PMID- 28899443 TI - Geriatric gambling disorder: challenges in clinical assessment. AB - To the Editor: The gaming industry is growing rapidly, as is the proportion of older adults aged 65 years or older who participate in gambling (Tse et al., 2012). With casinos tailoring their venues and providing incentives to attract older adults, and with the increasing popularity of "pleasure trips" to casinos organized by retirement homes, plus active promotion of government-operated lotteries in many countries, this trend is likely to continue. Gambling disorder (GD) or "pathological" or "problem" gambling presents a public health concern in the geriatric population. However, ascertainment of its prevalence and diagnostic accuracy have proven challenging. This is largely due to the absence of diagnostic criteria specific to the geriatric age and rating scales validated for use in this population. PMID- 28899444 TI - Use of Implementation Science for a Sustained Reduction of Central-Line Associated Bloodstream Infections in a High-Volume, Regional Burn Unit. AB - OBJECTIVE We describe the use of implementation science at the unit level and organizational level to guide an intervention to reduce central-line-associated bloodstream infections (CLABSIs) in a high-volume, regional, burn intensive care unit (BICU). DESIGN A single center observational quasi-experimental study. SETTING A regional BICU in Maryland serving 300-400 burn patients annually. INTERVENTIONS In 2011, an organizational-level and unit-level intervention was implemented to reduce the rates of CLABSI in a high-risk patient population in the BICU. At the organization level, leaders declared a goal of zero infections, created an infrastructure to support improvement efforts by creating a coordinating team, and engaged bedside staff. Performance data were transparently shared. At the unit level, the Comprehensive Unit-based Safety Program (CUSP)/ Translating Research Into Practice (TRIP) model was used. A series of interventions were implemented: development of new blood culture procurement criteria, implementation of chlorhexidine bathing and chlorhexidine dressings, use of alcohol impregnated caps, routine performance of root-cause analysis with executive engagement, and routine central venous catheter changes. RESULTS The use of an implementation science framework to guide multiple interventions resulted in the reduction of CLABSI rates from 15.5 per 1,000 central-line days to zero with a sustained rate of zero CLABSIs over 3 years (rate difference, 15.5; 95% confidence interval, 8.54-22.48). CONCLUSIONS CLABSIs in high-risk units may be preventable with the a use a structured organizational and unit level paradigm. Infect Control Hosp Epidemiol 2017;38:1306-1311. PMID- 28899446 TI - Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria. AB - BACKGROUND: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. METHODS: Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: "mild cognitive impairment," "dementia," "prodromal dementia," "preclinical dementia," "Alzheimer's," "depression," "dysphoria," "mania," "euphoria," "bipolar disorder," and "irritability." RESULTS: Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. CONCLUSION: Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies. PMID- 28899445 TI - Microbial Disruption Indices to Detect Colonization With Multidrug-Resistant Organisms. AB - OBJECTIVE To characterize the microbial disruption indices of hospitalized patients to predict colonization with multidrug-resistant organisms (MDROs). DESIGN A cross-sectional survey of the fecal microbiome was conducted in a tertiary referral, acute-care hospital in Boston, Massachusetts. PARTICIPANTS The study population consisted of adult patients hospitalized in general medical/surgical wards. METHODS Rectal swabs were obtained from patients within 48 hours of hospital admission and screened for MDRO colonization using conventional culture techniques. The V4 region of the 16S rRNA gene was sequenced to assess the fecal microbiome. Microbial diversity and composition, as well as the functional potential of the microbial communities present in fecal samples, were compared between patients with and without MDRO colonization. RESULTS A total of 44 patients were included in the study, of whom 11 (25%) were colonized with at least 1 MDRO. Reduced microbial diversity and high abundance of metabolic pathways associated with multidrug-resistance mechanisms characterized the fecal microbiome of patients colonized with MDRO at hospital admission. CONCLUSIONS Our data suggest that microbial disruption indices may be key to predicting MDRO colonization and could provide novel infection control approaches. Infect Control Hosp Epidemiol 2017;38:1312-1318. PMID- 28899447 TI - Shifting care from community hospitals to intensive community support: a mixed method study. AB - : Aim To examine how the introduction of intensive community support (ICS) affected admissions to community hospital (CH) and to explore the views of patients, carers and health professionals on this transition. BACKGROUND: ICS was introduced to provide an alternative to CH provision for patients (mostly very elderly) requiring general rehabilitation. METHOD: Routine data from both services were analysed to identify the number of admissions and length of stay between September 2012 and September 2014. In total, 10 patients took part in qualitative interviews. Qualitative interviews and focus groups were undertaken with 19 staff members, including managers and clinicians. Findings There were 5653 admissions to CH and 1710 to ICS between September 2012 and September 2014. In the five months before the introduction of ICS, admission rates to CH were on average 217/month; in the final five months of the study, when both services were fully operational, average numbers of patients admitted were: CH 162 (a 25% reduction), ICS 97, total 259 (a 19% increase). Patients and carers rated both ICS and CH favourably compared with acute hospital care. Those who had experienced both services felt each to be appropriate at the time; they appreciated the 24 h availability of staff in CH when they were more dependent, and the convenience of being at home after they had improved. In general, staff welcomed the introduction of ICS and appreciated the advantages of home-based rehabilitation. Managers had a clearer vision of ICS than staff on the ground, some of whom felt underprepared to work in the community. There was a consensus that ICS was managing less complex and dependent patients than had been envisaged. CONCLUSION: ICS can provide a feasible adjunct to CH that is acceptable to patients. More work is needed to promote the vision of ICS amongst staff in both community and acute sectors. PMID- 28899448 TI - Is it possible to register the ideas, concerns and expectations behind the reason for encounter as a means of classifying patient preferences with ICPC-2? AB - BACKGROUND: Family practice aims to recognize the health problems and needs expressed by the person rather than only focusing on the disease. Documenting person-related information will facilitate both the understanding and delivery of person-focused care. Aim To explore if the patients' ideas, concerns and expectations (ICE) behind the reason for encounter (RFE) can be coded with the International Classification of Primary Care, version 2 (ICPC-2) and what kinds of codes are missing to be able to do so. METHODS: In total, 613 consultations were observed, and patients' expressions of ICE were narratively recorded. These descriptions were consequently translated to ICPC codes by two researchers. Descriptions that could not be translated were qualitatively analysed in order to identify gaps in ICPC-2. RESULTS: In all, 613 consultations yielded 672 ICE expressions. Within the 123 that could not be coded with ICPC-2, eight categories could be defined: concern about the duration/time frame; concern about the evolution/severity; concern of being contagious or a danger to others; patient has no concern, but others do; expects a confirmation of something; expects a solution for the symptoms without specification of what it should be; expects a specific procedure; and expects that something is not done. Discussion Although many ICE can be registered with ICPC-2, adding eight new categories would capture almost all ICE. PMID- 28899449 TI - The provider perspective: investigating the effect of the Electronic Patient Reported Outcome (ePRO) mobile application and portal on primary care provider workflow. AB - : Aim This qualitative study investigates how the Electronic Patient-Reported Outcome (ePRO) mobile application and portal system, designed to capture patient reported measures to support self-management, affected primary care provider workflows. BACKGROUND: The Canadian health system is facing an ageing population that is living with chronic disease. Disruptive innovations like mobile health technologies can help to support health system transformation needed to better meet the multifaceted needs of the complex care patient. However, there are challenges with implementing these technologies in primary care settings, in particular the effect on primary care provider workflows. METHODS: Over a six week period interdisciplinary primary care providers (n=6) and their complex care patients (n=12), used the ePRO mobile application and portal to collaboratively goal-set, manage care plans, and support self-management using patient-reported measures. Secondary thematic analysis of focus groups, training sessions, and issue tracker reports captured user experiences at a Toronto area Family Health Team from October 2014 to January 2015. Findings Key issues raised by providers included: liability concerns associated with remote monitoring, increased documentation activities due to a lack of interoperability between the app and the electronic patient record, increased provider anxiety with regard to the potential for the app to disrupt and infringe upon appointment time, and increased demands for patient engagement. Primary care providers reported the app helped to focus care plans and to begin a collaborative conversation on goal setting. However, throughout our investigation we found a high level of provider resistance evidenced by consistent attempts to shift the app towards fitting with existing workflows rather than adapting much of their behaviour. As health systems seek innovative and disruptive models to better serve this complex patient population, provider change resistance will need to be addressed. New models and technologies cannot be disruptive in an environment that is resisting change. PMID- 28899450 TI - Joining forces to prevent dementia: The International Research Network On Dementia Prevention (IRNDP). AB - Dementia is a neurodegenerative disorder with global impact, with the largest proportion of cases occurring in low- and middle-income countries. It is estimated that there are 46.8 million cases globally with approximately 10 million new cases each year or a new case occurring every 3 sec (Prince et al., 2015). For comparison there are 36.7 million HIV cases with an estimated 2 million new cases each year (WHO, 2017). The rise in dementia prevalence is largely due to population ageing, with the oldest being at highest risk. To date there are no diseases modifying medications for Alzheimer's disease or the other causes of dementia. Academics and research groups are increasingly focused on prevention or delay of dementia (Brayne and Miller, 2017) and a number of organizations now prioritize dementia, indicating a strong and coherent international effort to address this problem. Examples include the World Health Organisation (WHO), which has established a Global Dementia Observatory; the World Dementia Council; the Organisation for Economic Co-operation and Development (OECD); the U.S. National Alzheimer's Project Act (NAPA); and the Global Council on Brain Health. PMID- 28899451 TI - Hand Hygiene Improvement and Sustainability: Assessing a Breakthrough Collaborative in Western Switzerland. AB - OBJECTIVE To assess hand hygiene improvement and sustainability associated with a Breakthrough Collaborative. DESIGN Multicenter analysis of hand hygiene compliance through direct observation by trained observers. SETTING A total of 5 publicly funded hospitals in 14 locations, with a total of 1,152 beds, in the County of Vaud, Switzerland. PARTICIPANTS Clinical staff. INTERVENTIONS In total, 59,272 opportunities for hand hygiene were monitored for the duration of the study, for an average of 5,921 per audit (range, 5,449-6,852). An 18-month Hand Hygiene Breakthrough Collaborative was conducted to implement the WHO multimodal promotional strategy including improved access to alcohol-based hand rub, education, performance measurement and feedback, reminders and communication, leadership engagement, and safety culture. RESULTS Overall hand hygiene compliance improved from 61.9% to 88.3% (P<.001) over 18 months and was sustained at 88.9% (P=.248) 12 months after the intervention. Hand hygiene compliance among physicians increased from 62% to 85% (P<.001) and finally 86% at follow-up (P=.492); for nursing staff, compliance improved from 64% to 90% (P<.001) and finally 90% at follow-up (P=.464); for physiotherapists compliance improved from 50% to 90% (P<.001) and finally 91% at follow-up (P=.619); for X-ray technicians compliance improved from 45% to 80% (P<.001) and finally 81% at follow-up (P=.686). Hand hygiene compliance also significantly increased with sustained improvement across all hand hygiene indications and all hospitals. CONCLUSIONS A rigorously conducted multicenter project combining the Breakthrough Collaborative method for its structure and the WHO multimodal strategy for content and measurement was associated with significant and substantial improvement in compliance across all professions, all hand hygiene indications, and all participating hospitals. Infect Control Hosp Epidemiol 2017;38:1420-1427. PMID- 28899452 TI - LC-HRMS for Characterizing Durum Wheat Pasta Production Variability and Consumer Overall Liking. AB - Semolina pasta represents one of the most important dishes in Italian cuisine worldwide. Italy is the leader in its production and, recently, the worldwide diffusion of its production has begun to grow tremendously. The perceived quality of a food product, such as pasta, is a key feature that allows a company to increase and maintain the competitive advantage of a specific brand. The overall flavor perception of the consumer, therefore, has become as important as other key quality factors such as texture and color; thus, the food industry needs to meet consumer expectations and needs the tools to objectively "measure" the quality of food products. Untargeted fingerprinting by means of coupling LC with high-resolution MS (HRMS) has been well received within the analytical community, and different studies exploiting this approach for the characterization of high value food products have recently been reported in the literature. In the present work, a tentative application of the sensomics approach to cluster analysis of semolina pasta obtained using different production conditions was developed to objectively define target molecules that correlate with consumer overall liking of an industrial standard product. Principal component analysis of chemical and physical testing, GC-MS, LC-HRMS, and sensory data were performed with the aim of identifying the main parameters to discern similarities and differences among samples and clustering them according to these features. The correlation between analytical data and compounds related to sensory data was further investigated, and lastly, a partial least-squares regression model for the prediction of consumer overall liking was reported. PMID- 28899453 TI - Application of MALDI-TOF MS Systems in the Rapid Identification of Campylobacter spp. of Public Health Importance. AB - Campylobacteriosis is an infectious gastrointestinal disease caused by Campylobacter spp. In most cases, it is either underdiagnosed or underreported due to poor diagnostics and limited databases. Several DNA-based molecular diagnostic techniques, including 16S ribosomal RNA (rRNA) sequence typing, have been widely used in the species identification of Campylobacter. Nevertheless, these assays are time-consuming and require a high quality of bacterial DNA. Matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF) MS is an emerging diagnostic technology that can provide the rapid identification of microorganisms by using their intact cells without extraction or purification. In this study, we analyzed 24 American Type Culture Collection reference isolates of 16 Campylobacter spp. and five unknown clinical bacterial isolates for rapid identification utilizing two commercially available MADI-TOF MS platforms, namely the bioMerieux VITEK(r) MS and Bruker Biotyper systems. In addition, 16S rRNA sequencing was performed to confirm the species-level identification of the unknown clinical isolates. Both MALDI-TOF MS systems identified the isolates of C. jejuni, C. coli, C. lari, and C. fetus. The results of this study suggest that the MALDI-TOF MS technique can be used in the identification of Campylobacter spp. of public health importance. PMID- 28899454 TI - Determination of Carotenoids in Infant, Pediatric, and Adult Nutritionals by HPLC with UV-Visible Detection: Single-Laboratory Validation, First Action 2017.04. AB - This reversed-phase HPLC method uses C30 chromatography and UV-Vis spectroscopy to determine cis and trans isomers of lutein, beta-carotene, and lycopene in infant, pediatric, and adult nutritionals. Samples are saponified with a mixture of potassium hydroxide, tetrahydrofuran, and methanol, and carotenoids are extracted from saponified samples with 75 + 25 hexane-methyl tertiary butyl ether (MtBE). After extraction, a portion of the organic layer is evaporated to dryness, and the residue is dissolved in 75 + 25 10% butylated hydroxytoluene in methanol-MtBE. Prepared samples are injected into a C30 HPLC column where cis and trans isomers of lutein, beta-carotene, and lycopene are separated with a methanol-MtBE gradient and detected with UV-Vis spectroscopy at 445 nm. Total carotenoid concentrations are calculated by comparison of sample peak areas with the areas of trans carotenoid standards of known concentration. During a single laboratory validation of this method, total lutein repeatability and intermediate precision ranged from 1.89 to 14.9 and 1.93 to 14.0%, respectively, in infant and adult nutritional matrixes with concentrations >1 MUg/100 g. Total beta-carotene repeatability and intermediate precision ranged from 1.81 to 6.77 and 3.07 to 16.2%, respectively, in infant and adult nutritional matrixes with concentrations >1 MUg/100 g, and total lycopene repeatability and intermediate precision ranged from 3.01 to 6.37 and 4.29 to 10.3%, respectively, in infant and adult nutritional matrixes with concentrations >1 MUg/100 g. Mean overspike recoveries ranged from 90.3 to 95.3, 89.3 to 108, and 97.3 to 109% for lutein, beta carotene, and lycopene, respectively. The method also demonstrated good linearity. For lutein, r averaged 0.99991 over a standard range of approximately 10-250 ug/L trans-lutein. with average calibration errors of <1%. For beta carotene and lycopene, r averaged 0.99993 and 0.9998 over standard ranges of approximately 25-500 and 5-100 ug/L with calibration errors of <1 and <1.5%, respectively. Lutein, beta-carotene, and lycopene LOQs in ready-to-feed nutritionals were estimated to be 0.4, 0.1, and 0.3 ug/100 g, respectively. This method met AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals Standard Method Performance Requirements and was approved as a First Action Official Method at the AOAC INTERNATIONAL 2017 midyear meeting. PMID- 28899455 TI - Mitotic Arrest-Deficient Protein 2B Overexpressed in Lung Cancer Promotes Proliferation, EMT, and Metastasis. AB - As the non-catalytic subunit of mammalian DNA polymerase, mitotic arrest deficient protein 2B (MAD2B) has been reportedto play a role in cell-cycle regulation, DNA damage tolerance, gene expression and carcinogenesis. Although its expression is known to be associated with poor prognosis in several types of human cancers, the significance of MAD2B expression in lung malignancies is still unclear. Our study showed that MAD2B expression significantly increased in lung cancer, especially in the metastatic tissues. We also found that knockdown of MAD2B inhibited the migration, invasion and epithelialmesenchymal transitions of lung cancer cells in vitro and the metastasis in vivo, while over-expression of MAD2B had the opposite effect. Microarray and western blotting data indicated that slug might be its downstream target since knockdown of MAD2B inhibited the expression while over-expression increased the expression of slug. Moreover, the expression of MAD2B was found positively correlated with slug in lung cancer tissues, as well. Collectively, these findings indicate an oncogenic role of MAD2B in lung cancer, and slug might be involved in the process. PMID- 28899456 TI - ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy. AB - Resistance to bortezomib (BZ) is the major problem that largely limits its clinical application in multiple myeloma treatment. In the current study, we investigated whether ClC5, a member of the chloride channel family, is involved in this process. The MTT assay showed that BZ treatment decreased cell viability in three multiple myeloma cell lines (ARH77, U266, and SKO-007), with IC50 values of 2.83, 4.37, and 1.91 nM, respectively. Moreover, BZ increased the conversion of LC3B-I to LC3B-II and expressions of beclin-1 and ATG5, concomitantly with a decreased p62 expression. Pharmacological inhibition of autophagy with 3-MA facilitated cell death in response to BZ treatment. Additionally, BZ increased ClC5 protein expression in ARH77, U266, and SKO-007 cells. Knockdown of ClC5 with small interfering RNA sensitized cells to BZ treatment, and upregulation of ClC5 induced chemoresistance to BZ. Furthermore, ClC5 downregulation promoted BZ induced LC3B-I to LC3B-II conversion and beclin-1 expression, whereas overexpression of ClC5 showed the opposite results in ARH77 cells. Finally, BZ induced dephosphorylation of AKT and mTOR, which was significantly attenuated by ClC5 inhibition. However, ClC5 upregulation further enhanced AKT and mTOR dephosphorylation induced by BZ. Our study demonstrates that ClC5 induces chemoresistance of multiple myeloma cells to BZ via increasing prosurvival autophagy by inhibiting the AKT-mTOR pathway. These data suggest that ClC5 may play a critical role in future multiple myeloma treatment strategies. PMID- 28899458 TI - Long Noncoding RNA MALAT1 Functions as a Sponge of MiR-200c in Ovarian Cancer. AB - Previous researches have revealed that alteration of non-coding RNAs expression level in malignancies can significantlymodify the course of diseases. Current study was aimed to investigate the biological functions of lncRNA MALAT1 and miR 200c, as well as the interaction between them. Quantitative real-time polymerase chain reaction (qRT-PCR) showed that lncRNA MALAT1 was overexpressed in ovarian cancer tissues and cell lines in compare to adjacent normal tissue and normal human ovarian surface epithelial cells (HOSEPiCs). Contrarily, miR-200c expression was significantly decreased in ovarian cancer, which is negatively correlated with MALAT1 expression. In addition, overexpression of lncRNA MALAT1 appeared to be related to worse prognosis and higher metastasis. In consistent with clinical outcomes, down-regulation of lncRNA MALAT1 suppressed the cell viability, migration and invasion abilities of ovarian cancer cell lines. Moreover, bioinformatics analysis suggested that3'-UTR of lncRNA MALAT1 and miR 200c have a complementarity region. Rescue experiments confirmed that miR-200c could reverse the tumor-suppressive effect of knock-down of lncRNA MALAT1 on ovarian cancer cells. Nevertheless, luciferase assays verified the existence of direct binding between miR-200c and lncRNA MALAT1. In general, results of this study indicated that lncRNA MALAT1 is a oncogene in ovarian cancer, involved in the regulation of cell viability, migration and invasion abilities of ovarian cancer cells, which achieved its biological function by regulating miR-200c expression. Therefore, lncRNA MALAT1 could be a promising prognostic biomarker and therapeutic target for ovarian cancer and its relation with miR-200c might be a starting point for future researches. PMID- 28899457 TI - Swainsonine Inhibits Invasion and the EMT Process in Esophageal Carcinoma Cells by Targeting Twist1. AB - Esophageal cancer is a common gastrointestinal cancer, with a very high mortality rate in patients with metastasis. Swainsonine, a cytotoxic fungal alkaloid, has been shown to inhibit cell growth in esophageal cancer. In the present study, we explored the effects of swainsonine on cell invasion and metastasis in esophageal cancer cells. Human esophageal carcinoma cells were treated with different doses of swainsonine, and then cell viability, invasion, and apoptosis were measured. The mRNA and protein expressions of Twist1, apoptosis- and EMT-related factors, and PI3K/AKT pathway factors were detected by qRT-PCR and Western blot. Swainsonine had no effect on esophageal cancer cell viability and apoptosis, but it significantly decreased cell invasion in a dose-dependent manner. Swainsonine increased the expression of E-cadherin but decreased the expression of N cadherin, vimentin, ZEB1, and snail in a dose-dependent manner, thereby inhibiting EMT. Last, we found that swainsonine inhibits cell invasion and EMT in the esophageal carcinoma cells by downregulation of Twist1 and deactivation of the PI3K/AKT signaling pathway. PMID- 28899459 TI - [Ring 14 chromosome syndrome in a boy mainly manifesting as drug-resistant epilepsy]. PMID- 28899460 TI - [Genetic variations and epilepsy]. PMID- 28899461 TI - [Alternating hemiplegia of childhood and epilepsy in an infant]. PMID- 28899462 TI - [Diagnosis of alternating hemiplegia of childhood]. PMID- 28899463 TI - [Bone metabolism disorders caused by sodium valproate therapy in children with epilepsy and the prevention of the disorders by supplementation of calcium and vitamin D]. PMID- 28899464 TI - [Effect of sodium valproate therapy on bone metabolism]. PMID- 28899465 TI - [Clinical features and MYO5B mutations of a family affected by microvillus inclusion disease]. AB - Microvillus inclusion disease (MVID) is an autosomal recessive disorder caused by biallelic mutations in the MYO5B or STX3 gene. Refractory diarrhea and malabsorption are the main clinical manifestations. The aim of this study was to investigate the clinical features and MYO5B gene mutations of an infant with MVID. A 21-day-old female infant was referred to the hospital with the complaint of diarrhea for 20 days. On physical examination, growth retardation of the body weight and length was found along with moderately jaundiced skin and sclera. Breath sounds were clear in the two lungs and the heart sounds were normal. The abdomen was distended and the veins in the abdominal wall were observed. The liver and spleen were not palpable. Biochemical analysis revealed raised serum total bile acids, bilirubin, transaminases and gamma-glutamyl transpeptidase while decreased levels of serum sodium, chloride, phosphate and magnesium. Blood gas analysis indicated metabolic acidosis. The preliminary diagnosis was congenital diarrhea, and thus parenteral nutrition was given along with other symptomatic and supportive measures. However, diarrhea, metabolic acidosis and electrolyte disturbance were intractable, and the cholestatic indices, including transaminases, gamma-glutamyl transpeptidase, bilirubin and total bile acids, remained at increased levels. One month later, the patient was discharged and then lost contact. On genetic analysis, the infant was proved to be a compound heterozygote of the c.310+2Tdup and c.1966C>T(p.R656C) variants of the gene MYO5B, with c.310+2Tdup being a novel splice-site mutation. MVID was thus definitely diagnosed. PMID- 28899466 TI - [Clinical features and ETFDH mutations of children with late-onset glutaric aciduria type II: a report of two cases]. AB - OBJECTIVE: To investigate the clinical and genetic features of two families with late-onset glutaric aciduria type II caused by ETFDH mutations. METHODS: Target gene sequence capture and next generation sequencing were used for sequencing of suspected patients and their family members. The patients' clinical features were retrospectively analyzed and literature review was performed. RESULTS: The probands of the two families had a clinical onset at the ages of 10 years and 5.5 years respectively, with the clinical manifestations of muscle weakness and muscle pain. Laboratory examinations revealed significant increases in the serum levels of creatine kinase, creatine kinase-MB, and lactate dehydrogenase. Tandem mass spectrometry showed increases in various types of acylcarnitines. The analysis of urine organic acids showed an increase in glutaric acid. Electromyography showed myogenic damage in both patients. Gene detection showed two novel mutations in the ETFDH gene (c.1331T>C from the mother and c.824C>T from the father) in patient 1, and the patient's younger brother carried the c.1331T>C mutation but had a normal phenotype. In patient 2, there was a novel mutation (c.177insT from the father) and a known mutation (c.1474T>C from the mother) in the ETFDH gene. Several family members carried such mutations. Both patients were diagnosed with glutaric aciduria type II. Their symptoms were improved after high-dose vitamin B2 treatment. CONCLUSIONS: For patients with unexplained muscle weakness and pain, serum creatine kinase, acylcarnitines, and urinary organic acids should be measured, and the possibility of glutaric aciduria type II should be considered. Genetic detection is helpful to make a confirmed diagnosis. PMID- 28899467 TI - [Clinical significance of fractional exhaled nitric oxide combined with in vitro allergen test in identifying children at a high risk of asthma among those with recurrent wheezing]. AB - OBJECTIVE: To investigate the clinical value of combined determination of in vitro allergens and fractional exhaled nitric oxide (FeNO) in indentifying children at a high risk of asthma among those with recurrent wheezing. METHODS: A total of 148 children with recurrent wheezing (0.5-6 years old) were enrolled as study subjects, and 80 healthy children who underwent physical examination were enrolled as the control group. Pharmacia UniCAP immunoassay analyzer was used to measure specific immunoglobulin E (sIgE). Nano Coulomb Nitric Oxide Analyzer was used to measure FeNO. The asthma predictive index (API) was evaluated. RESULTS: The recurrent wheezing group had a significantly higher proportion of children with positive sIgE than the control group [68.9% (102/148) vs 11.3% (9/80); P<0.05]. The recurrent wheezing group also had significantly higher levels and positive rate of FeNO than the control group (P<0.05). The overall positive rate of API in children with wheezing was 32.4%, and the API-positive children had a significantly higher FeNO value than the API-negative children (51+/-6 ppb vs 13+/-5 ppb; P<0.05). The detection rate of API was 40.2% (41/102) in positive sIgE children and 50.1% (38/73) in FeNO-positive children, and there was no significant difference between these two groups. The children with positive sIgE and FeNO had a significantly higher detection rate of API (81.4%) than those with positive sIgE or FeNO (P<0.05). CONCLUSIONS: Combined determination of FeNO and in vitro allergens is more sensitive in detecting children at a high risk of asthma than FeNO or in vitro allergens determination alone and provides a good method for early identification, diagnosis, and intervention of asthma in children. PMID- 28899468 TI - [Pathogen distribution and bacterial resistance in children with severe community acquired pneumonia]. AB - OBJECTIVE: To investigate the distribution of pathogens and bacterial resistance in children with severe community-acquired pneumonia (CAP). METHODS: A total of 522 children with severe CAP who were hospitalized in 2016 were enrolled as study subjects. According to their age, they were divided into infant group (402 infants aged 28 days to 1 year), young children group (73 children aged 1 to 3 years), preschool children group (35 children aged 3 to 6 years), and school-aged children group (12 children aged >=6 years). According to the onset season, all children were divided into spring group (March to May, 120 children), summer group (June to August, 93 children), autumn group (September to November, 105 children), and winter group (December to February, 204 children). Sputum specimens from the deep airway were collected from all patients. The phoenix-100 automatic bacterial identification system was used for bacterial identification and drug sensitivity test. The direct immunofluorescence assay was used to detect seven common respiratory viruses. The quantitative real-time PCR was used to detect Mycoplasma pneumoniae (MP) and Chlamydia trachomatis (CT). RESULTS: Of all the 522 children with severe CAP, 419 (80.3%) were found to have pathogens, among whom 190 (45.3%) had mixed infection. A total of 681 strains of pathogens were identified, including 371 bacterial strains (54.5%), 259 viral strains (38.0%), 12 fungal strains (1.8%), 15 MP strains (2.2%), and 24 CT strains (3.5%). There were significant differences in the distribution of bacterial, viral, MP, and fungal infections between different age groups (P<0.05). There were significant differences in the incidence rate of viral infection between different season groups (P<0.05), with the highest incidence rate in winter. The drug-resistance rates of Streptococcus pneumoniae to erythromycin, tetracycline, and clindamycin reached above 85%, and the drug-resistance rates of Staphylococcus aureus to penicillin, erythromycin, and clindamycin were above 50%; they were all sensitive to vancomycin and linezolid. The drug-resistance rates of Haemophilus influenzae to cefaclor and cefuroxime were above 60%, but it was sensitive to cefotaxime. The drug-resistance rates of Escherichia coli and Klebsiella pneumoniae to ampicillin, cefotaxime, and ceftriaxone were above 60%, but they were sensitive to carbapenems and compound preparation of enzyme inhibitors. CONCLUSIONS: Bacteria are the main pathogens in children with severe CAP and mixed infection is prevalent. The drug-resistance rates of these pathogenic bacteria are high. PMID- 28899469 TI - [Association between family environment and developmental coordination disorder in preschool children]. AB - OBJECTIVE: To investigate the influence of family environment on developmental coordination disorder (DCD) in preschool children. METHODS: Stratified random cluster sampling was used to select 1 727 children (4-6 years old). The Movement Assessment Battery for Children was used to screen out the children with DCD. The Family Environment Scale on Motor Development for Preschool Urban Children and a self-designed questionnaire were used to assess family environment. RESULTS: A total of 117 children were confirmed with DCD. There were significant differences in mother's education level and family structure between the DCD and normal control groups. There were also significant differences in the scores of "Let children manage their daily items" and "Arrange all affairs" between the DCD and normal control groups. The multivariate logistic regression analysis indicated that when children's age and gender were controlled, mother's education level, family structure, "Let children manage their daily items", and "Arrange all affairs" were main factors influencing the development of DCD in children (P<0.05). CONCLUSIONS: Family environment may affect the development of DCD in preschool children. Therefore, parents should not arrange all affairs for children and should provide more opportunities for children to manage their daily life, in order to promote the development of early motor coordination and prevent the development of DCD. PMID- 28899470 TI - [Association between depression during pregnancy and low birth weight in neonates: a Meta analysis]. AB - OBJECTIVE: To study the association between depression during pregnancy and low birth weight in neonates, and to provide a scientific basis for the prevention of low birth weight. METHODS: Cohort studies on the association between depression during pregnancy and low birth weight were collected and a Meta analysis was performed. Data were extracted independently by two investigators, and quality assessment was performed according to Newcastle-Ottawa Scale. The Egger's test was used to evaluate publication bias. RESULTS: A total of 12 cohort studies with 37 192 samples were included. The results of the Meta analysis showed that depression during pregnancy was associated with low birth weight (Z=2.08, P=0.038), and the neonates whose mothers had depression during pregnancy tended to have a high risk of low birth weight (RR=1.303, 95%CI: 1.015-1.672). The sensitivity analysis showed that the results of this Meta analysis were stable and reliable, and the Egger's test showed no publication bias. CONCLUSIONS: Depression during pregnancy may be a risk factor for low birth weight in neonates. PMID- 28899471 TI - [A report of two children with fever, headache, and purpura]. AB - In this study, two school-aged children had an acute onset in spring and had the manifestations of fever, headache, vomiting, disturbance of consciousness, purpura and ecchymosis, and positive meningeal irritation sign. There were increases in peripheral white blood cells and neutrophils, but reductions in the hemoglobin level and platelet count in the two children. They had a significant increase in C-reactive protein. There were hundreds or thousands of white blood cells in the cerebrospinal fluid, mainly neutrophils. Increased protein contents but normal levels of glucose and chloride in the cerebrospinal fluid were found. Head CT scan showed multiple hematomas in the right cerebellum and both hemispheres in one child. Bone marrow cytology indicated infection in the bone marrow, and both blood culture and bone marrow culture showed methicillin resistant Staphylococcus aureus (MRSA). Both patients had cardiac murmurs and progressive reductions in the hemoglobin level and platelet count during treatment, and echocardiography showed the formation of vegetation in the aortic valve. Therefore, the patients were diagnosed with infectious endocarditis (IE). Vancomycin was used as the anti-infective therapy based on the results of drug sensitivity test. One child was cured after 6 weeks, and the other child was withdrawn from the treatment and then died. Dynamic monitoring of cardiac murmurs should be performed for children with unexplained fever, and echocardiography should be performed in time to exclude IE. IE should also be considered for children with purulent meningitis and skin and mucosal bleeding which cannot be explained by the reduction in platelet count. PMID- 28899472 TI - [Long-term effect of oligodendrocyte precursor cell transplantation on a rat model of white matter injury in the preterm infant]. AB - OBJECTIVE: To investigate the long-term effect of oligodendrocyte precursor cell (OPC) transplantation on a rat model of white matter injury (WMI) in the preterm infant. METHODS: A total of 80 Sprague-Dawley rats aged 3 days were randomly divided into sham-operation group, model control group, 5-day ventricular/white matter transplantation group, 9-day ventricular/white matter transplantation group, 14-day ventricular/white matter transplantation group (n=10 each). All groups except the sham-operation group were treated with right common carotid artery ligation and hypoxia for 80 minutes to establish a rat model of WMI in the preterm infant. OPCs were prepared from the human fetal brain tissue (10-12 gestational weeks). At 5, 9, and 14 days after modeling, 3*105 OPCs were injected into the right lateral ventricle or white matter in each transplantation group, and myelin sheath and neurological function were evaluated under an electron microscope at ages of 60 and 90 days. RESULTS: Electron microscopy showed that at an age of 60 days, each transplantation group had a slight improvement in myelin sheath injury compared with the model control group; at an age of 90 days, each transplantation group had significantly thickened myelin sheath and reduced structural damage compared with the model control group, and the 14-day transplantation groups had the most significant changes. There were no significant differences in the degree of myelin sheath injury between the ventricular and white matter transplantation groups at different time points. At an age of 60 or 90 days, the transplantation groups had a significantly higher modified neurological severity score (mNSS) than the sham-operation group and a significantly lower mNSS than the model control group (P<0.05). CONCLUSIONS: OPC transplantation may have a long-term effect in the treatment of WMI in the preterm infant, and delayed transplantation may enhance its therapeutic effect. PMID- 28899473 TI - [Effect of corticosterone on lissencephaly 1 expression in developing cerebral cortical neurons of fetal rats cultured in vitro]. AB - OBJECTIVE: To investigate the effect of corticosterone on the expression of the neuronal migration protein lissencephaly 1 (LIS1) in developing cerebral cortical neurons of fetal rats. METHODS: The primary cultured cerebral cortical neurons of fetal Wistar rats were divided into control group, low-dose group, and high-dose group. The neurons were exposed to the medium containing different concentrations of corticosterone (0 MUmol/L for the control group, 0.1 MUmol/L for the low-dose group, and 1.0 MUmol/L for the high-dose group). The neurons were collected at 1, 4, and 7 days after intervention. Western blot and immunocytochemical staining were used to observe the change in LIS1 expression in neurons. RESULTS: Western blot showed that at 7 days after intervention, the low- and high-dose groups had significantly higher expression of LIS1 in the cytoplasm and nucleus of cerebral cortical neurons than the control group (P<0.05), and the high-dose group had significantly lower expression of LIS1 in the cytoplasm of cerebral cortical neurons than the low-dose group (P<0.05). Immunocytochemical staining showed that at 1, 4, and 7 days after corticosterone intervention, the high-dose group had a significantly lower mean optical density of LIS1 than the control group and the low-dose group (P<0.05). At 7 days after intervention, the low-dose group had a significantly lower mean optical density of LIS1 than the control group (P<0.05). CONCLUSIONS: Corticosterone downregulates the expression of the neuronal migration protein LIS1 in developing cerebral cortical neurons of fetal rats cultured in vitro, and such effect depends on the concentration of corticosterone and duration of corticosterone intervention. PMID- 28899474 TI - [Effect of glutaryl-CoA dehydrogenase gene silencing and high-concentration lysine on the viability of BRL hepatocytes]. AB - OBJECTIVE: To investigate the effect of glutaryl-CoA dehydrogenase (GCDH) gene silencing and accumulation of lysine metabolites on the viability of hepatocytes. METHODS: BRL cells were divided into normal control group, negative control group, and GCDH silencing group. The shRNA lentiviral vector for silencing GCDH gene was constructed, and the BRL hepatocytes in the GCDH silencing group and the negative control group were infected with this lentivirus and negative control virus respectively, and then cultured in a medium containing 5 mmol/L lysine. Immunofluorescence assay was used to measure the infection efficiency of lentivirus. Western blot was used to measure the expression of GCDH protein. MTT assay was used to evaluate cell viability. Hoechest33342 staining was used to measure cell apoptosis. Western blot was used to measure the expression of Caspase-3, an index of cell apoptosis. RESULTS: The lentivirus constructed effectively silenced the GCDH gene in hepatocytes (P<0.01). MTT assay and Hoechest 33342 staining showed no significant differences in cell viability and apoptosis between groups (P>0.05). There was also no significant difference in the expression of Caspase-3 protein between groups (P>0.05). CONCLUSIONS: GCDH gene silencing and accumulation of lysine metabolites may not cause marked hepatocyte injury. PMID- 28899475 TI - [Gene mutations in a newborn infant with hypermethioninemia]. PMID- 28899476 TI - [Advances in genetic research of cerebral palsy]. AB - Cerebral palsy is a group of syndromes caused by non-progressive brain injury in the fetus or infant and can cause disabilities in childhood. Etiology of cerebral palsy has always been a hot topic for clinical scientists. More and more studies have shown that genetic factors are closely associated with the development of cerebral palsy. With the development and application of various molecular and biological techniques such as chromosome microarray analysis, genome-wide association study, and whole exome sequencing, new achievements have been made in the genetic research of cerebral palsy. Chromosome abnormalities, copy number variations, susceptibility genes, and single gene mutation associated with the development of cerebral palsy have been identified, which provides new opportunities for the research on the pathogenesis of cerebral palsy. This article reviews the advances in the genetic research on cerebral palsy in recent years. PMID- 28899477 TI - [Research advances in pharmacogenomics of mercaptopurine]. AB - Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine. PMID- 28899478 TI - Clinically-diagnosed Susac syndrome in a 50-year-old. PMID- 28899479 TI - Olfactory ensheathing cell tumor: a case presentation. PMID- 28899480 TI - Variability in hemoglobin levels in hemodialysis patients in the current era: a retrospective cohort study. AB - BACKGROUND: Given regulatory and reimbursement changes in anemia management, we examined hemoglobin variability in a contemporary cohort of maintenance hemodialysis patients. MATERIALS AND METHODS: The study population included > 200,000 hemodialysis patients with Medicare parts A and B as primary payer on October 1, 2012. Based on 25th and 75th percentiles, monthly hemoglobin values were categorized as low, intermediate, or high. Six variability categories were created by patterns during the 6-month observation period. Stable categories were: always-low, alwaysintermediate, always-high; variable patterns were: varying between low and intermediate, intermediate and high, low and high (mostvariable). Cox proportional hazard models were used to assess the association between hemoglobin variability and all-cause mortality or major adverse cardiac events (MACE). RESULTS: The 25th and 75th hemoglobin percentiles were 10.2 and 11.5 g/dL, respectively, in 2012, vs. 11 and 12.5 g/dL in 2004. ESA doses were lower in all categories in 2012 and transfusion rates higher, particularly for always-low patients. Hemoglobin variability decreased modestly: in 2004, 6.0% were always-intermediate, vs. 9.5% in 2012. In 2012, more patients were always-high and fewer were most-variable. Mortality hazard ratios (HRs) were higher for patients with any low hemoglobin: always-low (HR, 95% CI: 2.07, 1.84 - 2.31), varying between low and intermediate (1.37, 1.29 - 1.45), and most-variable (1.23, 1.16 - 1.31); the pattern was similar for MACE. CONCLUSIONS: In 2012 vs. 2004, hemoglobin levels decreased, the range of levels narrowed, and variability decreased modestly; transfusions increased. The highest risk of mortality and MACE appeared to occur in patients with persistently low, rather than highly variable, hemoglobin levels. PMID- 28899481 TI - CAL-B-Catalyzed deacylation of benzylic acetates: Effect of amines addition. Comparison of several approaches. AB - Herein, we report an efficient enantioselective cleavage of the acyl-moity of some secondary benzylic acetate derivatives catalyzed by lipase B from Candida antarctica (CAL-B) in the presence of triethylamine, as additive, in non aqueous media. The influence of the hydrophobicity of two solvent, the basicity of three amines and the amount of CAL-B were studied in the presence/absence of molecular sieves 4A. The best results in term of selectivity are achieved using the triethylamine as basic additive and in that case, the reactivity is only best at low conversion. To establish the effect of the parallel and/or competitive hydrolysis and its impact on the reactivity and selectivity of the enzymatic resolution, the kinetic profiles of three CAL-B-deacylation approaches of phenylethylacetate have been compared, using different nucleophiles in competition with the internal water mediated by: Na2CO3, EtOH and by using the Et3N as additive. Furthermore, a comparison between these deacylations with the acylation of 1-phenylethanol with isopropenylacetate, has been made. The appropriate modulation of some crucial parameters allows an optimal conversion and a high selectivity depending on the acetate structure and the introduced base. In the majority of cases, the (R)-alcohols are obtained with ee>99% and selectivities E>200 under mild conditions. PMID- 28899482 TI - Enzymatic synthesis of chlorogenic acid glucoside using dextransucrase and its physical and functional properties. AB - Chlorogenic acid, a major polyphenol in edible plants, possesses strong antioxidant activity, anti-lipid peroxidation and anticancer effects. It used for industrial applications; however, this is limited by its instability to heat or light. In this study, we for the first time synthesized chlorogenic acid glucoside (CHG) via transglycosylation using dextransucrase from Leuconostoc mesenteroides and sucrose. CHG was purified and its structure determined by nuclear magnetic resonance and matrix-associated laser desorption ionization-time of-flight mass spectroscopy. The production yield of CHG was 44.0% or 141mM, as determined by response surface methodology. CHG possessed a 65% increased water solubility and 2-fold browning resistance while it displayed stronger inhibition of lipid peroxidation and of colon cancer cell growth by MTT assay, compared to chlorogenic acid. Therefore, this study may expand the industrial applications of chlorogenic acid as water-soluble or browning resistant compound (CHG) through enzymatic glycosylation. PMID- 28899483 TI - Preparation, activity and structure of cross-linked enzyme aggregates (CLEAs) with nanoparticle. AB - Cross-linked enzyme aggregates (CLEAs) have emerged as an interesting biocatalyst design for enzyme immobilization. However, the commercialization of CLEAs is often hampered by their shortcomings, such as poor-controlled particle size, low activity and sticky characteristic. In order to overcome these drawbacks, five nanoparticles (NPs) (nano-TiO2, nano-MgO, nano-Ni, nano-Cu and nano-Fe3O4) were used to improve CLEAs activity and structure in this study. Results showed that moderate dosage of nano-TiO2 addition increased CLEAs activity, and the most increment was 15.2% relative to CLEAs without NPs. This was possibly due to more channels and smaller size particle of CLEAs after nano-TiO2 addition. Moreover, nano-TiO2 addition not only decreased fluorescence intensity but also caused the red shift in tryptophan (Trp) and tyrosine (Typ) residues. Nano-TiO2 addition decreased Km and increased Vmax of CLEAs. These changes were benefit to the activity and structure of CLEAs. However, addition of other four NPs (nano-MgO, nano-Ni, nano-Cu and nano-Fe3O4) did not increase CLEAs activity and even decrease CLEAs activity due to less amorphous cavities and larger or discrete particle size than CLEAs without NPs. In addition, FT-IR results showed that NPs addition increases the content of regular structure of CLEAs, and causes a partial transformation of beta-turn into beta-sheet. This study showed that it was potential to improve CLEAs performance by nano-TiO2 addition. PMID- 28899484 TI - Rational design of Kluyveromyces marxianus ZJB14056 aldo-keto reductase KmAKR to enhance diastereoselectivity and activity. AB - t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-1b) is a valuable chiral synthon of atorvastatin calcium. A novel NADPH-specific aldo-keto reductase (AKR) was identified from a thermotolerant yeast Kluyveromyces marxianus ZJB14056 by genome database mining, displaying t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1a) reducing activity and moderate diastereoselectivity (dep~80.5%). Molecular homology modeling and docking studies demonstrated that the side chain of Trp297 blocks binding of (5R)-1a to KmAKR. The mutation of Trp297 to His led to dramatic conformational changes and significant improvement in both diastereoselectivity and activity. In comparison with KmAKR, KmAKR-W297H displayed strict diastereoselectivity, and 2.8-fold, 3.9-fold improvement in kcat and kcat/Km toward (5R)-1a, which were 10.36s-1 and 6.56s-1.mM-1 respectively. Coupling KmAKR-W297H with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for coenzyme regeneration, 100mM (5R)-1a was completely reduced to (3R,5R)-1b within 12h, in a dep >99.5%. PMID- 28899485 TI - Fluorescent CdSe QDs containing Bacillus licheniformis bioprobes for Copper (II) detection in water. AB - Quantum dots (QDs) are semiconductor nanoparticles (NPs) that offer valuable functionality for cellular labeling, drug delivery, solar cells and quantum computation. In this study, we reported that CdSe QDs could be bio-synthesized in Bacillus licheniformis. After optimization, the obtained CdSe QDs exhibited a uniform particle size of 3.71+/-0.04nm with a maximum fluorescence emission wavelength at 550nm and the synthetical positive ratio can reach up to 87%. Spectral properties, constitution, particle sizes and crystalline phases of the CdSe QDs were systematically and integrally investigated. The CdSe QD-containing Bacillus licheniformis cells were further used as whole fluorescent bio-probes to detect copper (II) (Cu2+) in water, which demonstrated a low limit of detection (0.91MUM). The assay also showed a good selectivity for Cu2+ over other ions including Al3+, Cd2+, Mg2+, K+, Na+, NH4+, Zn2+, CH3COO+, Pb2+ and I-. Our study suggests the fluorescent CdSe QDs-containing Bacillus licheniformis bio-probes as a promising approach for detection of Cu2+ in complex solution environment. PMID- 28899486 TI - Immobilization on graphene oxide improves the thermal stability and bioconversion efficiency of D-psicose 3-epimerase for rare sugar production. AB - D-Psicose (D-ribo-2-hexulose or D-allulose), an epimer of D-fructose is considered as a rare low-calorie sugar displaying important physiological functions. Enzymatic production using ketose 3-epimerases is the feasible process for the production of D-Psicose. However, major drawbacks in application of ketose 3-epimerases are bioconversion efficiency and reusability of the enzyme. We have attempted immobilization of ketose 3-epimerases from Agrobacterium tumefaciens (agtu) D-psicose 3-epimerase (DPEase) on graphene oxide. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and Thermo gravimetric analysis (TGA) showed that the enzyme was successfully immobilized on the graphene oxide. Graphene oxide immobilized agtu-DPEase (GO agtu-DPEase) shows pH optima at 7.5 and 60 degrees C as higher working temperature. Significant improvement in thermal stability was observed which showed half-life of 720min at 60 degrees C whereas Agrobacterium tumefaciens (agtu) DPEase displayed 3.99min. At equilibrium, 40:60 (D-psicose: D-fructose) the bioconversion efficiency was accounted for Graphene oxide immobilized DPEase which is higher than the agtu-DPEase. Graphene oxide immobilized DPEase showed bioconversion efficiency up to 10 cycles of reusability. PMID- 28899488 TI - Investigating the structural and functional features of representative recombinants of chondroitinase ABC I. AB - Chondroitin Sulfate Proteoglycans (CSPGs) are the main inhibitors for axon regeneration after damaging of Central Nervous System (CNS). Chondroitinase ABC I (cABC I) can degrade CSPGs by removing chondroitin and dermatan sulfate side chains from proteoglycans. Hence, it may be considered as an attractive candidate in biomedicine. For practical applications of this enzyme, increasing the effective circulating level and reducing the number and volume of injections for patients is one of the main concerns which is directly related to conformational stability and catalytic efficiency of the enzyme. Structural examination of C terminal domain of cABC I reveals that there are a few numbers of residues in helical conformation which are positioned at the context of a cohesive structural organization of beta-strands. In line with our previous studies on C-terminal domain of cABC I and regarding the residues in alpha-helix conformation; we designed and constructs some representative mutants including M889K, M889L, L679D/M889K and L679S/M889K. According to structural and functional characterization of protein variants and regarding the wide range of variability in determining parameters for beta-sheet conformation, we proposed a model in which the structural integrity of beta-strands at C-terminal domain can be manipulated and directed toward a new patterns of organization, some of them may have positive effects on the structural and functional features of the enzyme. Using this strategy it may be possible to improve functional and structural features of the enzyme by engineering the intra-molecular interactions in positions far from the active site of the enzyme. PMID- 28899487 TI - Discovery, cloning and characterisation of proline specific prolyl endopeptidase, a gluten degrading thermo-stable enzyme from Sphaerobacter thermophiles. AB - Gluten free products have emerged during the last decades, as a result of a growing public concern and technological advancements allowing gluten reduction in food products. One approach is to use gluten degrading enzymes, typically at low or ambient temperatures, whereas many food production processes occur at elevated temperature. We present in this paper, the discovery, cloning and characterisation of a novel recombinant thermostable gluten degrading enzyme, a proline specific prolyl endoprotease (PEP) from Sphaerobacter thermophiles. The molecular mass of the prolyl endopeptidase was estimated to be 77kDa by using SDS PAGE. Enzyme activity assays with a synthetic dipeptide Z-Gly-Pro-p-nitroanilide as the substrate revealed that the enzyme had optimal activity at pH 6.6 and was most active from pH 5.0-8.0. The optimum temperature was 63 degrees C and residual activity after one hour incubation at 63 degrees C was higher than 75 %. The enzyme was activated and stabilized by Co2+ and inhibited by Mg2+, K+ and Ca2+ followed by Zn2+, Na+, Mn2+, Al3+, and Cu2+. The Km and kcat values of the purified enzyme for different substrates were evaluated. The ability to degrade immunogenic gluten peptides (PQPQLPYPQPQLPY (a-gliadin) and SQQQFPQPQQPFPQQP (gamma-hordein)) was also confirmed by enzymatic assays and mass spectrometric analysis of cleavage fragments. Addition of the enzyme during small scale mashing of barley malt reduced the gluten content. The findings here demonstrate the potential of enzyme use during mashing to produce gluten free beer, and provide new insights into the effects of proline specific proteases on gluten degradation. PMID- 28899489 TI - Enhanced production of xylitol from xylose by expression of Bacillus subtilis arabinose:H+ symporter and Scheffersomyces stipitis xylose reductase in recombinant Saccharomyces cerevisiae. AB - Inefficient transport of xylose into Saccharomyces cerevisiae is a major hurdle for production of xylitol, a natural sweetener with five carbons. To facilitate the xylose transport and hence increase xylose conversion to xylitol, the araE gene encoding an arabinose:H+ symporter (AraE) from Bacillus subtilis and the XYL1 gene from Scheffersomyces stipitis were expressed in Saccharomyces cerevisiae EBY.VW4000, a hxt null mutant. The resulting strain of EXHA exhibited 4.1 fold increases in xylose consumption rate and xylitol productivity, relative to the control strain without AraE. Also, overexpression of AraE in wild type S. cerevisiae D452-2 having all hexose transporters and the XYL1 gene increased both xylose consumption and xylitol production considerably. In a glucose-limited fed batch culture with intermittent addition of xylose, the DXXA strain with multiple copies of araE and XYL1 produced 177.8g/L xylitol with 2.47g/L-h productivity, which were 26.9 and 17.6 times higher than those for a batch culture of the DX strain expressing the XYL1 gene only, respectively. It was concluded that B. subtilis AraE might be a potent xylose transporter and conferred much higher xylose-consuming and xylitol-producing abilities to S. cerevisiae. PMID- 28899490 TI - A new pH indicator dye-based method for rapid and efficient screening of l asparaginase producing microorganisms. AB - l-asparaginase is a pharmaceutically and industrially important enzyme as it has potential to treat different cancers and inhibit acrylamide formation in fried and baked food products. In the present study, an attempt was made to screen for new and novel l-asparaginase producers using a widely applied phenol red and bromothymol blue (BTB)1 dye-based plate assay. Screening of four different soil samples for l-asparaginase producers resulted in the isolation of three new potential l-asparaginase producing bacteria. These three strains identified (by 16S rRNA sequencing) as a Pseudomonas resinovorans strain IGS-131, a Bacillus safensis strain IGS-81, and a Glutamicibacter arilaitensis strain ICS-13 with enzyme activities of 10.91 IU/ml, 6.65 IU/ml, and 1.47 IU/ml, respectively. These three strains of bacteria have not been reported as l-asparaginase producers previously. Also, we developed a new pH indicator dye-based plate assay for the screening of l-asparaginase producers after testing eight different pH indicator dyes. This cresol red dye-based method gave a better differentiable zone of hydrolysis and consistent results as compared to previously reported phenol red and BTB-based plate assay. It was also found to be efficient in comparison to all other dyes studied. It produced a bright yellow color at acidic pH (5.5) and turned into a dark red or maroon color when pH was increased (above 7.5). This finding is expected to make screening of all kinds of l-asparaginases more comfortable, rapid, and efficient. PMID- 28899491 TI - Association between selenium and lycopene supplementation and incidence of prostate cancer: Results from the post-hoc analysis of the procomb trial. AB - BACKGROUND: Many potential chemopreventive agents have been used in PCa prevention, including selenium (Se) and lycopene (Ly). However, their role has been matter of debate over the years, due to potential of promotion of PCa. PURPOSE: In this study we aimed at evaluating the incidence risk of prostate cancer (PCa) in a cohort of patients treated with Se and Ly. METHODS: The Procomb trial design has been previously published (ISRCTN78639965). From April 2012 to April 2014 209 patients were followed and underwent prostate biopsy when PSA >=4 ng/ml and/or suspicion of PCa. The all cohort was composed by patients treated with Se and Ly (Group A = 134 patients) and control (Group B = 75 patients). RESULTS: During the follow-up time of 2 years, a total of 24 patients (11.5%) underwent prostate biopsy, of which 9 (4.3%) where diagnosed with PCa and 15 (7.2%) where diagnosed with benign prostatic hyperplasia. We did not observe statistical differences in terms of mean changes of PSA between the two groups (p value for trend = 0.33). The relative risk (RR) for PCa was 1.07 and 0.89 in group A and B, respectively (p = 0.95). At the multivariate Cox regression analysis supplementation with Se and Ly was not associated with greater risk of PCa (hazard ratio: 1.38; p = 0.67). CONCLUSION: In this analysis we did not show evidences supporting a detrimental role of Selenium and Lycopene supplementation in increasing PCa after 2 years of therapy, nor supporting a protective role. PMID- 28899492 TI - Tilianin pretreatment prevents myocardial ischemia-reperfusion injury via preservation of mitochondrial function in rat heart. AB - BACKGROUND: Tilianin has been demonstrated to exert protective effects on the heart against ischemia-reperfusion (I/R) injury, yet whether it is beneficial to the mitochondria during myocardial I/R is unclear. METHODS: In this study, we demonstrated that pretreatment with Tilianin dose-dependently raised the levels of ATP of the myocardium, and protected the microstructures and functions of mitochondria in rats. Furthermore, the cytoprotective effect of Tilianin has been confirmed in vivo and in the H9c2 cardiomyoblast cell line with enhancing activities of the mitochondria, controlling the levels of Ca2+ and reactive oxygen species (ROS), and inhibiting the expression of caspase-3 and AIF in cytoplasm. CONCLUSIONS: In conclusion, the study suggests that Tilianin may be of clinical value for the protective effects of cardiomyocytes and mitochondria by inhibiting myocardium energy metabolism and apoptosis during myocardial ischemia reperfusion injury (MIRI). PMID- 28899493 TI - Protective effects of Paeoniflorin against AOPP-induced oxidative injury in HUVECs by blocking the ROS-HIF-1alpha/VEGF pathway. AB - BACKGROUND: Paeoniflorin, a monoterpene glycoside, exerts protective vascular effects, showing good antioxidant properties. However, whether Paeoniflorin has protective effect against the oxidative damage induced by advanced oxidation protein products (AOPPs) in Human umbilical vein endothelial cells (HUVECs) is unknown, as is the underlying mechanism. PURPOSE: The present study was designed to investigate the effect of Paeoniflorin on oxidative damage of HUVECs and elucidate its underlying molecular mechanisms. METHODS: The fluorescence intensity of 2', 7'-dichlorofluorescein-diacetate (DCFH-DA) staining was detected for intracellular reactive oxygen species (ROS) production. The increases mitochondrial membrane potential (MMP) was measured via flow cytometry and confocal microscopy using MitoTracker(r) Deep Red/ MitoTracker(r) Green staining. The intracellular adenosine triphosphate (ATP) was measured by ATP Determination Kit according to the manufacturer's protocol. Nox2, Nox4, hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and nuclear factor-kappaB (NF-kappaB) p65 expressions were detected by western blot. RESULTS: Our results showed that Paeoniflorin increases MMP and ATP levels of HUVECs induced by AOPPs, and attenuates NF-kappaB p65 expression on HUVECs might mainly result from its antioxidant capability by suppressing ROS production. Moreover, we also found that Paeoniflorin can suppress HIF-1alpha and VEGF protein expression through a decrease of ROS production via down-regulation of Nox2/Nox4 expression in HUVECs. AOPP-induced RAGE mRNA up-regulation was blocked by Paeoniflorin treatment in HUVECs. CONCLUSION: Our results provided the first experimental that Paeoniflorin protects against AOPP-induced oxidative damage in HUVECs, mainly through a mechanism involving a decrease in ROS production by the inhibition of Nox2/Nox4 and RAGE expression; restored ATP depletion and mitochondria dysfunction via ROS suppression; and down-regulated HIF-1alpha/VEGF, possibly via the ROS-NF-kappaB axis. PMID- 28899494 TI - Intranasal co-administration of 1,8-cineole with influenza vaccine provide cross protection against influenza virus infection. AB - BACKGROUND: Vaccination is the most efficient means for protection against influenza. However, the various vaccines have low efficacy to protect against pandemic strains because of antigenic drift and recombination of influenza virus. Adjuvant therapy is one of the attempts to improve influenza vaccine effective cross-protection against influenza virus infection. Our previous study confirmed that 1,8-cineole inhibits the NF-kappaB, reduces pro-inflammatory cytokines, and relieves the pathological changes of viral pneumonia in mice infected with influenza virus. HYPOTHESIS/PURPOSE: 1,8-cineole, administered via intranasal (i.n.) route, may also have the capacity to be an adjuvant of the influenza vaccine. This study was designed to investigate the potential use of i.n. co administration of 1,8-cineole, a major component of the Eucalyptus essential oils, with influenza vaccine and whether could provide cross-protection against influenza virus infection in a mouse model. STUDY DESIGN: I.n. co-administration of 1,8-cineole in two doses (6.25 and 12.5 mg/kg) with influenza vaccine was investigated in a mouse model in order to see whether it could provide cross protection against influenza virus infection. METHODS: The mice were intranasally immunized three times at the 0, 7 and 14 day with vaccine containing 0.2 ug hemagglutinin (HA) and/or without 1,8-cineole. Seven days after the 3rd immunization dose, the mice were infected with 50 ul of 15 LD50 (50% mouse lethal dose) influenza virus A/FM/1/47 (H1N1). On day 6 post-infection, 10 mice per group were sacrificed to collect samples, to take the body weight and lung, and detect the viral load, pathological changes in the lungs and antibody, etc. The collected samples included blood serum and nasal lavage fluids. In addition, the survival experiments were carried out to investigate the survival of mice. RESULTS: Mice i.n. inoculated with influenza vaccine and 12.5 mg/kg 1,8-cineole increased the production of influenza-specific serum immunoglobulin (Ig) G2a antibodies, stimulated mucosal secretive IgA (s-IgA) responses at the nasal cavity, improved the expression of respiratory tract intraepithelial lymphocytes (IELs) in the upper respiratory tract, and promoted dendritic cell (DC) maturation and the expression of co-stimulatory molecules cluster of differentiation (CD)40, CD80 and CD86 in peripheral blood. Importantly, mice that had received 1,8-cineole-supplemented influenza vaccine showed longer survival time, milder inflammation, less weight loss and mortality rate and lower lung index and viral titers compared to that of mice immunized a non-1,8-cineole adjuvanted split vaccine. Thus, i.n. immunization with 1,8-cineole-adjuvanted vaccine induces a superior cross-protective immunity against infection with influenza than an inactivated vaccine only. CONCLUSION: These results suggest that 1,8-cineole (12.5 mg/kg) has a cross-protection against influenza virus, co administered with inactivated influenza viral antigen in a mouse model. PMID- 28899495 TI - Cytotoxic activities of Telectadium dongnaiense and its constituents by inhibition of the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Wnt/beta-catenin signaling pathway is a potential target for the treatment of human colon cancer. Thus, the inhibitory effects of various plant extracts on cell proliferation and Wnt signal transduction were evaluated to discover a Wnt signaling inhibitor. PURPOSE: The present study aimed to investigate the cytotoxicity involved in Wnt pathway of the MeOH extract from Telectadium dongnaiense bark (TDB) and to identify its bioactive constituents by bioassay-guided fractionation. METHODS: The sulforhodamine B-based proliferation assay and the beta-catenin/TCF-responsive reporter gene assay were employed as screening systems. The isolation and identification of compounds were elucidated on the basis of spectroscopic methods. Inhibitory effects on the expression levels of Wnt target genes were determined by real-time PCR and western blotting. RESULTS: The extract of TDB most strongly inhibited cell proliferation and TOPflash activity (IC50 = 1.5 and 2.0 ug/ml), which was correlated with its inhibitory effects on the expression of Wnt target genes. Three major compounds were isolated from bioactive fractions and were identified as 1,4 dicaffeoylquinic acid (1), quercetin 3-rutinoside (2), and periplocin (3). Only compound 3 showed anti-proliferative activity (IC50 = 0.06 uM) and exhibited Wnt signaling inhibitory effects in HCT116 colon cancer cells. CONCLUSIONS: This study contributes to understanding the cytotoxic properties of TDB extract and its constituents and provides a potent strategy for its further application. PMID- 28899496 TI - Neem (Azadirachta indica): An indian traditional panacea with modern molecular basis. AB - BACKGROUND: For centuries, agents derived from natural sources (mother nature), especially plants have been the primary source of medicine. Neem, also referred to as Azadirachta indica is one such plant that has been so named because it provides freedom from all diseases, and used for thousands of years in Indian and African continents. Different parts of the plant including flowers, leaves, seeds and bark have been used to treat both acute and chronic human diseases; and used as insecticide; antimicrobial, larvicidal, antimalarial, antibacterial, antiviral, and spermicidal. PURPOSE: What is there in neem and how it manifests its wide variety of effects is the focus of this review. How neem and its constituents modulate various cellular pathways is discussed. The animal and human studies carried out with neem and its constituents is also discussed. CONCLUSION: Over 1000 research articles published on neem has uncovered over 300 structurally diverse constituents, one third of which are limonoids including nimbolide, azadarachtin, and gedunin. These agents manifest their effects by modulating multiple cell signaling pathways. PMID- 28899497 TI - Molecular targets and anticancer potential of sanguinarine-a benzophenanthridine alkaloid. AB - BACKGROUND: Cancer is an enormous global health burden, and should be effectively addressed with better therapeutic strategies. Currently, over 60% of the clinically approved anticancer agents are either directly isolated from natural sources or are modified from natural lead molecules. Sanguinarine (SNG), a quaternary benzophenanthridine alkaloid has gained increasing attention in recent years as a potential anticancer agent. PURPOSE: There is a large untapped source of phytochemical-based anticancer agents remaining to be explored. This review article aims to recapitulate different anticancer properties of SNG, and describes some of the molecular targets involved in exerting its effect. It also depicts the pharmacokinetic and toxicological properties of SNG, two parameters important in determining the druggability of a molecule. METHODS: Numerous in vivo and in vitro published studies have signified the anticancer properties of SNG. In order to collate and decipher these properties, an extensive literature search was conducted in PubMed, ScienceDirect, and Scopus using keywords followed by the evaluation of the relevant articles where the relevant reports are integrated and analyzed. RESULTS: Apart from inducing cell death, SNG inhibits pro-tumorigenic processes such as invasion, angiogenesis, and metastasis in different cancers. Moreover, SNG has been shown to synergistically enhance the sensitivity of several chemotherapeutic agents and is effective against a variety of multi-drug resistant cancers. PMID- 28899498 TI - Galangin ameliorates cisplatin induced nephrotoxicity in vivo by modulation of oxidative stress, apoptosis and inflammation through interplay of MAPK signaling cascade. AB - BACKGROUND AND PURPOSE: Cisplatin is a widely used chemotherapeutic agent but now a-days its usage is limited in clinical chemotherapy because of its severe nephrotoxic effect on renal tissues. Galangin, a flavonoid obtained from ginger family has been demonstrated to have antioxidant, anti-apoptotic and anti inflammatory properties. This study is aimed to investigate the possible ameliorative effect of galangin in a rodent model of cisplatin-induced nephrotoxicity. MATERIAL AND METHODS: Adult male albino wistar rats were divided into six groups (n=6) viz normal, cisplatin-control, galangin (25, 50 and 100mg/kg p.o.) and per se (100mg/kg galangin, p.o.). Galangin was administrated orally to the rats for a period of 10 days. On the 7th day of the treatment, nephrotoxicity was induced in all the groups by a single dose of cisplatin (8mg/kg, i.p.) (except normal and per se group). On the 11th day, the rats were anaesthetized and blood was withdrawn via direct heart puncture for biochemical estimation. Rats were sacrificed and kidneys were isolated and preserved for evaluation of histopathological, ultra structural immunohistochemical studies and western blot analysis. RESULTS: Cisplatin significantly impaired renal function and increased oxidative stress and inflammation. It also increased expression of pro-apoptotic proteins Bax and caspase-3 and decreased the expression of the anti apoptotic protein Bcl-2. Histological and ultrastructural findings were also supportive of renal tubular damage. Pretreatment with galangin (100mg/kg p.o.) preserved renal function, morphology, suppressed oxidative stress, inflammation and the activation of apoptotic pathways. TUNEL assay showed decreased DNA fragmentation on galangin pre-treatment. Furthermore, galangin (100mg/kg) pre treatment also reduced the expression of NFkappaB along with proteins MAPK pathway i.e. p38, JNK and ERK1/2. CONCLUSION: In conclusion, Galangin (100mg/kg, p.o.) significantly ameliorated cisplatin induced nephrotoxicity by suppressing MAPK induced inflammation and apoptosis. PMID- 28899499 TI - Mechanisms underlying antiatherosclerotic properties of an enriched fraction obtained from Ilex paraguariensis A. St.-Hil. AB - BACKGROUND: Ilex paraguariensis A. St. Hil. var. paraguariensis (Aquifoliaceae) popularly known as 'mate' is an important species native to South America. Despite numerous studies showing significant antioxidant and lipid lowering properties, the antiatherosclerotic mechanisms of this species remain unknown. PURPOSE: To evaluate the possible antiatherosclerotic effects of a butanolic fraction (n-BFIP) obtained from I. paraguariensis and to investigate the molecular mechanisms involved in this activity. METHODS: First, n-BFIP was obtained from the hydroalcoholic extract and a detailed phytochemical investigation about its main secondary metabolites was performed. Then, during 8 experimental weeks, rabbits received diet supplemented with 1% cholesterol (CRD). After 4 weeks of CDR, animals were redistributed into five groups (n = 6) and treated (p.o.) with n-BFIP (10, 30 and 100 mg/kg), simvastatin (5 mg/kg), or vehicle (filtered water, 1 ml/kg) once daily for 4 weeks. An additional group was fed with cholesterol-free diet and treated with vehicle. At the end of 8 weeks, serum samples were obtained for the measurement of serum lipids, lipid and protein oxidation and indirect nitric oxide levels. In addition, serum IL-1beta, IL-6, sICAM-1, sVCAM-1, and intracellular cGMP levels in rabbit aortic rings were measured. Samples from the aortic arch and thoracic segment were collected for histopathological analysis. RESULTS: CRD induced oxidative and nitrosative stress and increased serum lipids, IL-1beta, IL-6, sICAM-1, and sVCAM-1 levels. In addition, structural changes in the intima layers of different arterial branches were also found. Although it did not change serum lipids, n-BFIP reverted oxidative and nitrosative stress and reduced IL-1beta, IL-6, sICAM-1, and sVCAM-1 levels, besides to increasing intracellular levels of cGMP in vitro. In addition, the formation of atherosclerotic plaques was reduced to values close to those of animals fed with cholesterol-free diet. CONCLUSIONS: A 4-week n-FBIP treatment reduces the progression of the atherosclerotic disease in New Zealand rabbits. These effects are associated with an attenuation of oxidative and nitrosative stress, affecting IL-1beta, IL-6, sICAM-1 and sVCAM-1 levels. PMID- 28899500 TI - Calebin A, a novel component of turmeric, suppresses NF-kappaB regulated cell survival and inflammatory gene products leading to inhibition of cell growth and chemosensitization. AB - BACKGROUND: While the anti-inflammatory and anticancer potential of curcumin, which is derived from turmeric (Curcuma longa), has been studied extensively, very little is known about Calebin A, another novel compound from the same source. PURPOSE: To determine whether Calebin A exhibits anti-inflammatory and anticancer potential. METHODS: We examined the anti-inflammatory potential of Calebin A by DNA binding of NF-kappaB. Anticancer properties of Calebin were determined by MTT and FACS analysis and NF-kappaB regulated expression of proteins was assessed by western blotting. RESULTS: Calebin A suppressed NF kappaB activation induced by various stimuli. This inhibition of NF-kappaB activation was mediated through the suppression of direct binding of NF kappaB/p65 to the DNA. This inhibitory effect was reversed by a reducing agent, and mutation of the Cys38 of p65 to serine abolished the effect of Calebin A on this binding. Suppression of NF-kappaB activation by Calebin A resulted in the down-regulation of the expression of proteins involved in tumor cell survival, proliferation, inflammation, and metastasis. Furthermore, Calebin A inhibited proliferation and induced apoptosis in a wide variety of tumor cells, as examined by various assays. It enhanced apoptosis induced by chemotherapeutic agents. CONCLUSION: Our results demonstrate that Calebin A inhibits NF-kappaB activation pathway through interaction with p65 and potentiates apoptosis in cancer cells; thus, it has potential in the treatment of cancer. However, further in vivo studies are warranted to define its anti-inflammatory and anticancer potential. PMID- 28899501 TI - Modulation of P-glycoprotein by Stemona alkaloids in human multidrug resistance leukemic cells and structural relationships. AB - BACKGROUND: Multidrug resistance (MDR) is a major reason for the failure of chemotherapy in the treatment of cancer patients. P-gp over-expression in MDR cancer cells is a multifactorial phenomenon with biochemical resistance mechanisms. Stemofoline (STF), isolated from Stemona bukillii, has been reported to be an MDR reversing compound. PURPOSE: This study investigated whether other Stemona alkaloids that had been purified from Stemonaceae plants exerted MDR modulation activity. METHODS: MTT assay was performed to determine the MDR reversing property of the alkaloids. Modulation of P-gp function by these compounds was investigated using cell cycle analysis and P-gp fluorescent substrate accumulation assays. P-gp expression was determined by Western blot analysis. We preliminarily examined the safety of these compounds in normal human fibroblasts and human peripheral blood mononuclear cells (PBMCs) using the MTT assay, and in red blood cells (human and rat) through in vitro hemolysis assays. RESULTS: Three of the eight alkaloids tested, isostemofoline (ISTF), 11Z didehydrostemofoline (11Z-DSTF) and 11E-didehydrostemofoline (11E-DSTF), enhanced the chemotherapeutic sensitivity of MDR leukemic K562/Adr cells, which overexpressed P-gp. The P-gp functional studies showed that these three alkaloids increased the accumulation of P-gp substrates, calcein-AM (C-AM) and rhodamine123 (Rho 123) in K562/Adr cells, while this effect was not seen in drug sensitive parental K562 cells. Whereas, the alkaloids did not alter P-gp expression as was determined by Western blotting analysis. CONCLUSION: The alkaloids reversed MDR via the inhibition of P-gp function. For pharmaceutical safety testing, the alkaloids were found to be not toxic to normal human fibroblasts and PBMCs. Moreover, the effective compounds did not induce hemolysis in either human or rat erythrocytes. These compounds may be introduced as potential candidate molecules for treating cancers exhibiting P-gp-mediated MDR. PMID- 28899502 TI - Melaleuca quinquenervia essential oil inhibits alpha-melanocyte-stimulating hormone-induced melanin production and oxidative stress in B16 melanoma cells. AB - BACKGROUND: Essential oils are odorous, volatile products of plant secondary metabolism, which are found in many leaves and stems. They show important biological activities, which account for the development of aromatherapy used in complementary and alternative medicine. The essential oil extracted from Melaleuca quinquenervia (Cav.) S.T. Blake (paperbark) (MQ-EO) has various functional properties. PURPOSE: The aim of this study is to investigate the chemical composition of MQ-EO by using gas chromatography-mass spectrometry (GC MS) and evaluate its tyrosinase inhibitory activity. METHODS: Gas chromatography mass spectrometry (GC-MS)-based metabolomics was used to identify 18 components in MQ-EO. The main components identified were 1,8-cineole (21.60%), alpha-pinene (15.93%), viridiflorol (14.55%), and alpha-terpineol (13.73%). B16 melanoma cells were treated with alpha-melanocyte-stimulating hormone (alpha-MSH) in the presence of various concentrations of MQ-EO or its major compounds. Cell viability was accessed by MTT assay and cellular tyrosinase activity and melanin content were determined by using spectrophotographic methods. The antioxidant mechanism of MQ-EO in alpha-MSH stimulated B16 cells was also investigated. RESULTS: In alpha-melanocyte-stimulating hormone (alpha-MSH)-stimulated murine B16 melanoma cells, MQ-EO, 1,8-cineole, alpha-pinene, and alpha-terpineol significantly reduced melanin content and tyrosinase activity. Moreover, MQ-EO, 1,8-cineole, alpha-pinene, and alpha-terpineol decreased malondialdehyde (MDA) levels. In addition, restored glutathione (GSH) levels, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activities were increased in alpha-MSH-stimulated B16 cells. MQ-EO not only decreased apoptosis but also reduced DNA damage in alpha-MSH stimulated B16 cells. These results showed that MQ-EO and its main components, 1,8-cineole, alpha-pinene, and alpha-terpineol, possessed potent anti-tyrosinase and anti-melanogenic activities besides the antioxidant properties. CONCLUSIONS: The active functional components of MQ-EO were found to be 1,8-cineole, alpha-pinene, and alpha-terpineol. Consequently, the results of present study suggest that MQ-EO is non-cytotoxic and can be used as a skin-whitening agent, both medically and cosmetically. PMID- 28899503 TI - Salicylate-based phytopharmaceuticals induce adaptive cytokine and chemokine network responses in human fibroblast cultures. AB - BACKGROUND: Cytokines and chemokines (CC) play a central role in immunoregulatory and inflammatory processes. Neutralising antibodies for single proinflammatory cytokines have developed into a powerful, though expensive and not always curative therapeutic strategy for severe diseases. Considering the redundancy of CC functions, network (N) rather than single target approaches are essential. Phytopharmaceuticals, common adjuvant therapies, are known modulators of a broad spectrum of CCs, but as complex mixtures with multiple targets they have not been systematically investigated. We investigated the effect of clinically established salicylate-based phytopharmaceuticals alone or in combination on CCNs under non inflammatory and inflammatory conditions, using fibroblasts being a major source of cytokines in connective tissue diseases. METHODS: Synchronised human skin fibroblasts (HSKF) were treated for 6 h with standardised fluid plant extracts (E) of Populus tremula L. [end concentration: 0.06%, 0.1%], Solidago virgaurea L. [0.02%, 0.1%], Fraxinus excelsior L. [0.02%, 0.1%], an established combination of the three extracts-STW1 [0.05, 0.1%] and acetyl salicylic acid (ASA) [30 ug/ml], individually or in the presence of lipopolysaccharides (LPS) [10 ug/ml]. Cell lysates were profiled for 23 cytokines. Supernatants were investigated for IL-6 and IL-8 release (ELISA). Total RNA was isolated for gene-expression profiling. RESULTS: Under non-inflammatory conditions P. tremula E and ASA increased cellular proteins (P) IL-8 and IL-10; S. virgaurea E modulated IL-1alpha, IL-10, IL-15 and Groalpha (P). F. excelsior decreased IL-1alpha and IL-15 (P). The combination of the three extracts (STW1) modulated IL-1alpha, IL-3 and TNF-beta (P). LPS stimulation increased cellular IL-8, Groalpha, MCP-1 and RANTES (P) and increased the secretion of IL-6 and IL-8 into the medium. Under these inflammatory conditions F. excelsior reduced GMCSF, GCSF and RANTES. STW1 reduced IL-1alpha, IL-8, Groalpha, and MCP-1(P). Secretion of IL-8 and IL-6 was reduced by STW1 and ASA. Gene expression profiles supported non-additive CCN profiles. CONCLUSION: Salicylate based phytopharmaceuticals provoke cellular pro-and anti inflammatory CCN responses under non-stress conditions, which adapt to anti inflammatory responses after LPS-stimulation. CCN-profiles of the single extracts are not additives in combination. A simultaneous activation of cellular pro- and anti-inflammatory cytokines might heighten the immunological reactivity status of a cell. PMID- 28899504 TI - Horizontal natural product transfer: A potential source of alkaloidal contaminants in phytopharmaceuticals. AB - BACKGROUND: It was recently shown that nicotine and pyrrolizidine alkaloids that leach out from decomposing plant material (donor plants) are subsequently taken up by the roots of acceptor plants and translocated into their leaves. Furthermore, it is well established that plant roots take up xenobiotics, generally by simple diffusion, and that this passive import depends on the physico-chemical properties of the substances. HYPOTHESIS: Based on the well known uptake of xenobiotics, we assumed that in analogy, the uptake of alkaloids, which are leached out from plant material (donor plants) represents a quite general feature of plant biology. METHODS: Using barley as a model plant, we analyzed the uptake of alkaloids by applying them to Hordeum vulgare seedlings. Based on HPLC analyses, the presence of the particular alkaloids in the acceptor plants was determined. RESULTS: We demonstrated that numerous alkaloids of different structural types are able to diffuse through biomembranes and are taken up by acceptor plants. In contrast, an uptake of quaternary alkaloids, with a permanent positive charge, could not be detected. CONCLUSION: As most alkaloidal plants generally die back afield, and the corresponding natural products are leached out into the soil. Our findings have substantial relevance for all plant derived commodities, especially for the production of phytopharmaceuticals and the related safety issues. Moreover, the evidence that plants are inherently able to take up alkaloids from the soil, which are derived from other plants, will alter our appraisal of plant-plant interactions. In this context, the classical definition of xenobiotics, which are considered as "non-natural" substances, might be also extended by including natural products leached out into the soil. PMID- 28899505 TI - An alkaloid extract obtained from Phlegmariurus Saururus induces neuroprotection after status epilepticus. AB - BACKGROUND: The brain is exposed to many excitotoxic insults that can lead to neuronal damage. Among these, Epilepsy is a neurological disease that affects a large percentage of world population and is commonly associated with cognitive disorders and excitotoxic neuronal death. Most experimental strategies are focused on preventing Status Epilepticus (SE), but once it has already occurred, the key question is whether it is possible to save neurons. PURPOSE: The aim of this study was to determine if a purified alkaloid extract (AE) obtained from Phlegmariurus saururus, a genus of Lycophyte plants (sometimes known as firmossesor fir club mosses) could induce neuroprotection following SE. METHODS: In vitro and in vivo techniques were applied for this purpose. Protein levels were measured by western blotting procedures. Neuronal death analysis was performed by calcein-ethidium staining and the presence of the NeuN protein as a marker for presence or absence of cells (in vitro experiments) and by Fluoro Jade B staining for the in vivo experiments. RESULTS: The effect of AE in the hippocampal neurons culture was the first determination, where we found an increase in neuronal survival and in the level of pErk and TrkB activation, 24 h after the addition of AE. In a well-established in vitro model of SE, we found that 24 h after being added to the hippocampal neuron-astrocyte co-culture, the AE induces a significant increase in neuronal survival. In addition to this, in the in vivo Li-pilocarpine model of SE, the AE induced a remarkable neuroprotection in areas such as the entorhinal cortex and hippocampal CA1 area. CONCLUSION: These results make the AE an excellent candidate for potential clinical use in neurological disorders where memory impairment and neuronal death occurs. PMID- 28899506 TI - Green tea effects on cognition, mood and human brain function: A systematic review. AB - BACKGROUND: Green tea (Camellia sinensis) is a beverage consumed for thousands of years. Numerous claims about the benefits of its consumption were stated and investigated. As green tea is experiencing a surge in popularity in Western culture and as millions of people all over the world drink it every day, it is relevant to understand its effects on the human brain. PURPOSE: To assess the current state of knowledge in the literature regarding the effects of green tea or green tea extracts, l-theanine and epigallocatechin gallate both components of green tea-on general neuropsychology, on the sub-category cognition and on brain functions in humans. METHODS: We systematically searched on PubMed database and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. We structured our effort according to the PRISMA statement. OUTCOME: We reviewed and assessed 21 studies, 4 of which were randomised controlled trials, 12 cross-over studies (both assessed with an adapted version of the DELPHI-list), 4 were cross-sectional studies and one was a cohort study (both assessed with an adapted version of the Newcastle-Ottawa assessment scale). The average study quality as appraised by means of the DELPHI list was good (8.06/9); the studies evaluated with the Newcastle-Ottawa-scale were also good (6.7/9). CONCLUSIONS: The reviewed studies presented evidence that green tea influences psychopathological symptoms (e.g. reduction of anxiety), cognition (e.g. benefits in memory and attention) and brain function (e.g. activation of working memory seen in functional MRI). The effects of green tea cannot be attributed to a single constituent of the beverage. This is exemplified in the finding that beneficial green tea effects on cognition are observed under the combined influence of both caffeine and l-theanine, whereas separate administration of either substance was found to have a lesser impact. PMID- 28899507 TI - Ziziphus spinosa seeds for insomnia: A review of chemistry and psychopharmacology. AB - BACKGROUND: In Chinese medicine, Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou is widely used for the treatment of insomnia. PURPOSE/SECTIONS: This paper summarises the chemistry, psychopharmacology, and compares the pharmaceutical effects of the seeds of Ziziphus jujuba plant, Ziziphus spinosa (ZS) seeds, with benzodiazepines. Whole extracts and constituent compounds have been evaluated in preclinical and clinical studies. CONCLUSIONS: ZS secondary metabolites modulate GABAergic activity and the serotonergic system. The actual therapeutic agents require further confirmation/identification so that new insomnia phytomedicines can be discovered. PMID- 28899508 TI - Pellitorine, an extract of Tetradium daniellii, is an antagonist of the ion channel TRPV1. AB - BACKGROUND: Transient Receptor Potential Vanilloid 1 (TRPV1) confers noxious heat and inflammatory pain signals in the peripheral nervous system. Clinical trial of resiniferatoxin from Euphorbia species is successfully aimed at TRPV1 in cancer pain management and heading toward new selective painkiller status that further validates this target for drug discovery efforts. Evodia species, used in traditional medicine for hundreds of years, are a recognised source of different TRPV1 agonists, but no antagonist has yet been reported. HYPOTHESIS/PURPOSE: In a search for painkiller leads, we noted for the first time a TRPV1 antagonist activity in the fresh fruits of Tetradium daniellii (Benn.) T.G. Hartley (syn. Evodia hupehensis Dode). METHODS: Through a combination of extraction and purification methods with functional TRPV1-specific Ca2+ uptake assays (bioactivity-guided fractionation/isolation/purification); we isolated a new painkiller candidate that is a distant structural homologue of capsiate exovanilloids and endovanilloids such as anandamide, but a putative competitive inhibitor of the TRPV1. Four additional inactive compounds (N-isobutyl-4,5-epoxy 2E-decadienamide, geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol) were also co-purified with pellitorine. Their structures were established by extensive 1D- and 2D-NMR spectroscopic analysis. RESULTS: 1H- and 13C NMR determination of the chemical structure revealed it to be pellitorine, (2E,4E)-N-(2-methylpropyl)deca-2,4-dienamide, which can compete structurally with algesics released in inflammation. In contrast to previous isolates from Evodia species, pellitorine blocked capsaicin-evoked Ca2+ uptake with an IC50 of 154 ug/ml (0.69 mM/l). N-Isobutyl-4,5-epoxy-2E-decadienamide and geranylpsoralen, 8 (7',8'-epoxygeranyloxy)psoralen, and xanthotoxol did not affect the TRPV1. CONCLUSION: This is the first evidence that pellitorine, an aliphatic alkylamide analogue of capsaicin, can serve as an antagonist of the TRPV1 and may inhibit exovanilloid-induced pain. PMID- 28899509 TI - A standardized Humulus lupulus (L.) ethanol extract partially prevents ovariectomy-induced bone loss in the rat without induction of adverse effects in the uterus. AB - BACKGROUND: Hops (Humulus lupulus (L.)) dietary supplements are of interest as herbal remedies to alleviate menopausal symptoms, such as hot flushes, depression and anxiety. So far, the evidence regarding estrogenic and related properties of hops preparations has been considered insufficient for a market authorization for menopausal indications. PURPOSE: The study aims to investigate a chemically standardized hops extract regarding its safety in the uterus, as wells as its efficacy to prevent bone loss in the ovariectomized rat model. STUDY DESIGN/METHODS: Female Wistar rats were ovariectomized and divided into a control group receiving phytoestrogen-free diet, a group treated with E2benzoate (0.93 mg/kg body weight/d) and a group treated with the standardized hops extract (60 mg/kg body weight/d) for 8 weeks. Micro-computed tomography of the tibiae and vertebrae, as wells as histological changes in the uterus and tibia were analyzed. RESULTS: Neither uterotrophic nor proliferative effects were observed in the endometrium in response to the oral 8-week administration of the hops extract. However, site-dependent skeletal effects were observed. The hops extract significantly decreased the number of osteoclasts in the tibial metaphysis and prevented reduction of the trabecular thickness that resulted from estradiol depletion. In contrast, the hops extract did not prevent the ovariectomy-induced micro-architectural changes in the lumbar vertebra. Certain parameters (e.g. thickness and number of trabeculae) were even found to be below the values determined in the ovariectomized control group. CONCLUSION: Taken together, the results provide evidence for the safety of the standardized hops extract and point to a weak bone type-specific, protective effect on bone loss following estradiol depletion. PMID- 28899510 TI - Screening of hepatoprotective compounds from licorice against carbon tetrachloride and acetaminophen induced HepG2 cells injury. AB - BACKGROUND: Licorice and its constituents, especially licorice flavonoids have been reported to possess significant hepatoprotective activities. However, previous studies mainly focus on the extract and major compounds, and few reports are available on other licorice compounds. PURPOSE: This work aims to evaluate the in vitro hepatoprotective activities of licorice compounds and screen active compounds, and to establish the structure-activity relationship. METHODS: A compound library consisting of 180 compounds from three medicinal licorice species, Glycyrrhiza uralensis, G. glabra and G. inflata was established. HepG2 cells were incubated with the compounds, together with the treatment of 0.35% CCl4 for 6 h and 14 mM APAP for 24 h, respectively. RESULTS: A total of 62 compounds at 10 uM showed protective effects against CCl4 to improve cell viability from 52.5% to >60%, and compounds 5 (licoflavone A), 104 (3,4 didehydroglabridin), 107 (isoliquiritigenin), 108 (3,4,3',4' tetrahydroxychalcone), and 111 (licochalcone B) showed the most potent activities, improving cell viability to >80%. And 64 compounds showed protective effects against APAP to improve cell viability from 52.0% to >60%, and compounds 47 (derrone), 76 (xambioona), 77 ((2S)-abyssinone I), 107 (isoliquiritigenin), 118 (licoagrochalcone A), and 144 (2'-O-demethybidwillol B) showed the most potent activities, improving cell viability to >80%. Preliminary structure activity analysis indicated that free phenolics compounds especially chalcones showed relatively stronger protective activities than other types of compounds. CONCLUSION: Compounds 5, 76, 104, 107, 111, 118 and 144 possess potent activities against both CCl4 and APAP, and 5, 76 and 118 were reported for the first time. They could be the major active compounds of licorice for the treatment of liver injury. PMID- 28899511 TI - Safflower bud inhibits RANKL-induced osteoclast differentiation and prevents bone loss in ovariectomized mice. AB - BACKGROUND: The powder and extract of safflower seeds are known to be effective in the prevention of bone loss in ovariectomized animals. However, the inhibitory effect and molecular mechanisms of safflower bud (SB), the germinated safflower, on bone destruction is unclear. PURPOSE: The present study was designed to investigate the inhibitory effect and molecular mechanism of SB on osteoclastic differentiation and on bone loss in ovarietomized (OVX) mice. METHODS: Osteoclastogenesis was determined by TRAP staining, F-actin ring formation, and bone resorption assay. NF-kappaB and MAPKs activation was analyzed by transfection assay and Western blot, respectively. Real-time PCR was performed to examine the expression of osteoclastogenesis-related genes. Histological changes, increases in TRAP-positive cells, and cathepsin K expression were examined in the metaphysis of OVX mice. Density of bone marrow was evaluated by uCT. RESULTS: SB inhibited the RANKL-induced differentiation of BMDMs into osteoclasts in a dose dependent manner. F-actin ring formation and bone resorption were also reduced by SB in RANKL-treated BMDMs. In addition, SB decreased the activation of NF-kappaB and MAPKs and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. Feeding of SB-included diet prevented bone loss in OVX mice. The number of TRAP-positive cells and level of protein expression of cathepsin K was reduced and bone mineral density was increased in the metaphysis of mice fed SB compared with OVX mice. CONCLUSION: These findings suggest that SB can be a preventive and therapeutic candidate for destructive bone diseases. PMID- 28899512 TI - Nepeta deflersiana attenuates isoproterenol-induced myocardial injuries in rats: Possible involvement of oxidative stress, apoptosis, inflammation through nuclear factor (NF)-kappaB downregulation. AB - BACKGROUND: Nepeta deflersiana (Lamiaceae) is a perennial herb used in the Saudi and Yemeni folk medicine as an anti-inflammatory, carminative, and antirheumatic agent. PURPOSE: This study explores the phytochemistry of the plant and the cardioprotective effect of N. deflersiana ethanolic extract (NDEE) against isoproterenol (ISP)-induced myocardial injury in rats. DESIGN/METHODS: Cardiac function, serum cardiac enzymes, myocardial antioxidants, inflammatory, and apoptotic biomarkers, and histopathological parameters were studied in ISP injured Wistar rat heart tissues. RESULTS: To the best of our knowledge, this is the first study to report the isolation of nine secondary metabolites from this plant: 1alpha-hydroxy-7alpha,14alpha,18-triacetoxy-isopimara-8,15-diene (1), beta sitosterol (2), lupeol (3), ursolic acid (4), 2,3-dihydroxy ursolic acid (5), caffeic acid (6), methyl rosmarinate (7), rosmarinic acid (8), and an irridoid glucoside 8-epi-7-deoxyloganic acid (9). To explain the mechanisms underlying the cardioprotective effect of NDEE, we evaluated the redox-sensitivity of NDEE in ISP-induced cardiac injury. The oral administration of NDEE (50 and 100 mg/kg b.w) prevented the depletion of endogenous antioxidants (CAT, SOD, NP-SH, and NO) and myocyte injury marker enzymes and inhibited lipid peroxidation (MDA, MPO). Moreover, NDEE downregulated the expression of pro-inflammatory cytokines (TNFalpha, IL-6, and IL-10) and apoptotic markers (caspase-3 and Bax) and upregulated the anti-apoptotic protein Bcl2. Furthermore, NDEE pretreatment significantly downregulated cardiac NF-kappaB (p65) expression, NF-kappaB-DNA binding activity, and MPO activity. Histological data showed that NDEE pretreatment reduced myonecrosis, edema, and infiltration of inflammatory cells and restored the architecture of cardiomyocytes. CONCLUSION: NDEE demonstrated strong antioxidant, cardioprotective, anti-inflammatory, and anti-apoptotic potential against myocardial damage. This further endorses the use of N. deflersiana in Yemeni folk medicine against cardiovascular diseases. PMID- 28899513 TI - Mechanisms underlying the wound healing potential of propolis based on its in vitro antioxidant activity. AB - BACKGROUND: Propolis is a resinous substance collected by honeybees, Apis mellifera, from various plant sources. Having various pharmacological and biological activities, it has been used in folk medicine and complementary therapies since ancient times. PURPOSE: To evaluate the effects and underlying mechanism of the protective effects of the ethanol extract of Chinese propolis (EECP) on L929 cells injured by hydrogen peroxide (H2O2). STUDY DESIGN: The wound healing activities of EECP in L929 cells with H2O2-induced damage were investigated. METHODS: The main components of EECP were analyzed by RP-HPLC, and the free radical scavenging capacity and reducing power were also measured. The effects of EECP on the expression of antioxidant-related genes in fibroblast L929 cells were determined using qRT-PCR and western blotting. RESULTS: EECP had significant protective effects against cell death induced by H2O2 and significantly inhibited the decline of collagen mRNA expression caused by H2O2 in L929 cells. CONCLUSION: EECP induced the expression of antioxidant-related genes, such as HO-1, GCLM, and GCLC, which has great implications for the potential of propolis to alleviate oxidative stress in wound tissues. The protective effects of propolis have great implications for using propolis as a wound healing regent. PMID- 28899514 TI - Citral, a monoterpenoid aldehyde interacts synergistically with norfloxacin against methicillin resistant Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus (SA), is a major human pathogen causing wide range of clinical infections, which has been further complicated by drug resistance like methicillin resistant S. aureus (MRSA), vancomycin intermediate S. aureus (VISA)/vancomycin resistant S. aureus (VRSA), etc. The present study was aimed at determining anti-staphylococcal potential of citral against drug resistant clinical isolates alone and in combination with antibiotics. PURPOSE: To assess the potential of citral in combination with norfloxacin in treating drug resistant infections of SA. STUDY DESIGN: In the present study, synergistic interaction of citral and norfloxacin against drug resistant SA strains was evaluated. Further the efficacy and possible mechanism of action of the combination was also evaluated using in vitro and in vivo assays. METHOD: The anti-staphylococcal activity of each of the monoterpene and the antibiotic was determined in terms of MIC and the effective concentration of both compounds in combination was obtained by checkerboard assay. In vivo efficacy and oral acute toxicity was evaluated in Swiss albino mice model. To understand the mechanism of action, time-kill curve, bacteriolysis, leakage, membrane depolarization, salt tolerance and ethidium bromide efflux assays were performed. RESULTS: Citral was found effective against clinical isolates of SA with MIC values ranging from 75 to 150 ug ml-1 exhibiting bacteriostatic activity. Citral interacted synergistically, reducing MIC of norfloxacin up to 32-folds with FICI <= 0.50. Citral did not affect cell wall, but could damage cell membrane, inhibit efflux pump and affect the membrane potential. Citral could reduce the staphylococcal load of spleen and liver tissues in a dose-dependent manner which was further reduced when used in combination with norfloxacin. Citral did not exhibit any mortality or morbidity up to 500 mg kg-1 body weight and found to prolong the post-antibiotic effect of norfloxacin. CONCLUSION: Based on these observations, citral could be a lead candidate phytomolecule for further developing it into an anti-staphylococcal agent. The observations of combination study will help in reducing the burden of antibiotics leading to delayed resistance development. PMID- 28899515 TI - The water extract of Liuwei dihuang possesses multi-protective properties on neurons and muscle tissue against deficiency of survival motor neuron protein. AB - BACKGROUND: Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease. PURPOSE: This study aimed to investigate the potential protection of LWDH-WE on SMN deficiency induced neurodegeneration and muscle weakness. STUDY DESIGN: The effects of LWDH WE on SMN deficiency-induced neurotoxicity and muscle atrophy were examined by using SMN-deficient NSC34 motor neuron-like cells and SMA-like mice, respectively. METHODS: Inducible SMN-knockdown NSC34 motor neuron-like cells were used to mimic SMN-deficient condition. Doxycycline (1 ug/ml) was used to induce SMN deficiency in stable NSC34 cell line carrying SMN-specific shRNA. SMADelta7 mice were used as a severe type of SMA mouse model. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Apoptotic cells and neurite length were observed by inverted microscope. Protein expressions were examined by western blots. Muscle strength of animals was evaluated by hind-limb suspension test. RESULTS: LWDH-WE significantly increased SMN protein level, mitochondrial membrane potential and cell viability of SMN-deficient NSC34 cells. LWDH-WE attenuated SMN deficiency-induced down-regulation of B-cell lymphoma-2 (Bcl-2) and up-regulation of cytosolic cytochrome c and cleaved caspase-3. Moreover, LWDH WE prevented SMN deficiency-induced inhibition of neurite outgrowth and activation of Ras homolog gene family, member A (RhoA)/ Rho-associated protein kinase (ROCK2)/ phospho-LIM kinase (p-LIMK)/ phospho-cofilin (p-cofilin) pathway. Furthermore, in SMA-like mice, LWDH-WE improved muscle strength and body weight accompanied with up-regulation of SMN protein in spinal cord, brain, and gastrocnemius muscle tissues. CONCLUSION: The present study demonstrated that LWDH-WE protects motor neurons against SMN deficiency-induced neurodegeneration, and it also improves the muscle strength of SMA-like mice, suggesting the potential benefits of LWDH-WE as a complementary prescription for SMN deficiency related diseases. PMID- 28899516 TI - Erratum to "Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms" [Biochim. Biophys. Acta 1854/9 (2015) 1078-1089]. PMID- 28899517 TI - Metabolic biomarkers in community obese children: effect of obstructive sleep apnea and its treatment. AB - OBJECTIVE: Obesity and obstructive sleep apnea in children have been associated with metabolic morbidities. The present study aimed to evaluate the presence of metabolic alterations among obese children recruited from the community, with and without obstructive sleep apnea syndrome (OSAS), and the impact of treatment of OSAS on metabolic profiles. METHODS: A cross-sectional, prospective, multicenter study of Spanish children aged 3-14 years with a body mass index (BMI) >=95th percentile for age and sex were randomly selected in the first phase. Four groups emerged for follow-up: (1) no treatment; (2) dietary intervention; (3) surgical treatment of OSA; and (4) continuous positive airway pressure (CPAP) treatment of OSA. Fasting blood tests were performed at baseline (T0) and approximately one year after the intervention (T1). RESULTS: A total of 113 obese children with a mean age of 11.3 +/- 2.9 years completed T0 and T1 assessments. Their mean BMI z score at T1 was 1.34 +/- 0.59, and mean Respiratory Disturbance Index was 8.6 +/- 13.0 at T0 and 3.3 +/- 4.0/hour total sleep time at T1. Only glucose fasting levels differed among metabolic parameters in obese children with OSAS and without OSAS at baseline (T0) (p = 0.018). There were statistically significant differences between surgically treated OSAS (p = 0.002), and CPAP-treated OSAS (p = 0.024) versus the non-OSAS group in the glucose levels between baseline (T0) and follow-up (T1) after controlling for age and change in BMI. Significant univariate associations between BMI and C-reactive protein, insulin, and homeostasis model assessment of insulin resistance emerged at both T0 and T1. CONCLUSIONS: Concurrent obesity and OSAS could promote metabolic and inflammatory alterations, and the latter appeared to be sensitive to OSAS treatment outcomes. ClinicalTrials.gov Identifier: NCT01322763. PMID- 28899518 TI - Relationship between obstructive sleep apnea and neuroimaging signatures of cerebral small vessel disease in community-dwelling older adults. The Atahualpa Project. AB - BACKGROUND/OBJECTIVES: Evidence of a relationship between obstructive sleep apnea (OSA) and neuroimaging signatures of cerebral small vessel disease (SVD) is limited. The present study aimed to evaluate this association in older adults living in rural Ecuador, where small vessel disease is a major pathogenetic mechanism underlying stroke. METHODS: A representative random sample of Atahualpa residents aged >=60 years enrolled in the Atahualpa Project neuroimaging substudy underwent a single-night diagnostic polysomnography. We evaluated whether OSA associates with severity of white matter hyperintensities (WMH), silent lacunar infarctions and deep cerebral microbleeds, using multivariate models adjusted for relevant confounders. RESULTS: Of 351 candidates, 104 (30%) were randomly selected. Of these, 97 individuals (mean age 72.3 +/- 7 years, 65% women) had adequate recordings and were included. Mean apnea/hypopnea index was 13.8 +/- 14.1 episodes per hour; 27 persons (28%) had >=15 episodes per hour and were considered to have moderate-to-severe OSA. Moderate-to-severe WMH were noticed in 25 individuals (25.8%), silent lacunar infarctions in 22 (22.7%) and deep cerebral microbleeds in 12 (12.4%). In multivariate models, OSA was associated with moderate-to-severe WMH (OR: 3.94; 95% C.I.: 1.09-14.97; p = 0.037), but not with silent lacunar infarctions (p = 0.195) or deep cerebral microbleeds (p = 0.405). A linear regression model confirmed the independent association between the apnea/hypopnea index and moderate-to-severe WMH (beta: -7.14; 95% C.I.: -13.6 to -0.69; p = 0.031). CONCLUSIONS: Individuals with moderate-to-severe OSA are almost four times more likely to have diffuse subcortical damage of vascular origin than those with none-to-mild OSA, independently of demographics and cardiovascular risk factors. PMID- 28899519 TI - The association between daytime napping and risk of diabetes: a systematic review and meta-analysis of observational studies. AB - OBJECTIVE: To investigate the association between daytime napping and prevalent/incident diabetes mellitus (DM) based on systematic review and meta analytic data. METHODS: The electronic databases of Embase, Medline, Pubmed and Web of Science were searched. Relevant studies were extracted by two reviewers independently. The associations between daytime napping (irrespective of duration), long nap (>=1 h/day) and short nap (<1 h/day), and risk of DM were assessed according to study types. Overall estimates were pooled using either fixed- or random-effect with inverse variance meta-analysis. Heterogeneity of included studies was assessed using the I2 test and possible cause of the heterogeneity was examined by meta-regression analyses. RESULTS: Ten studies (four cross-sectional and six longitudinal cohort) comprising a total of 304,885 individuals and 20,857 cases of DM were included in the systematic review, with an average napping prevalence of 47%. Nappers were found to have increased risk of DM in both cross-sectional and cohort studies. However, significant heterogeneity was present. Long nap (>=1 h/day) was associated with both prevalent and incident DM; in particular, those with a daily nap over 1 h had a 31% increased risk of developing DM during follow-up (95% confidence interval: 2 67%). Conversely, no such association was found in individuals with short naps (<1 h/day) in cohort studies. CONCLUSIONS: Long daytime napping over 1 h per day was associated with increased risk of both prevalent and incident DM. Further studies are needed to confirm the findings. PMID- 28899520 TI - Cholinergic neurotransmission and olfactory function in obstructive sleep apnea syndrome: a TMS study. AB - BACKGROUND/OBJECTIVE: Odor identification and discrimination are reduced in subjects with obstructive sleep apnea syndrome (OSAS), but the pathophysiology of the olfactory dysfunction in OSAS is still poorly understood. Experimental evidence suggests that olfactory impairment could be related to central cholinergic dysfunction. Short latency afferent inhibition (SAI) is a paired pulse transcranial magnetic stimulation (TMS) protocol that gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. The objective of the study was to assess the cholinergic function, as measured by SAI, in OSAS patients with olfactory impairment. METHODS: We applied SAI technique in 20 patients with OSAS and in 20 healthy control subjects; SAI values were correlated with the Sniffin' Sticks olfactory test results. RESULTS: SAI was reduced in OSAS patients when compared with control subjects. We also found a strong negative correlation between olfactory parameters and SAI. CONCLUSIONS: These findings suggest that cholinergic dysfunction is a robust determinant of hyposmia also in OSAS patients. Reduced SAI values and presence of olfactory impairment might indicate an increased risk of cognitive decline in patients with OSAS. PMID- 28899521 TI - Summertime blues? A re-examination of the seasonality of web searches for restless legs and leg cramps. AB - OBJECTIVE: Studies that examined Internet searches for restless legs and leg cramps have found a strong seasonal effect with peaks in summer and troughs in winter months. The present study used an econometric approach to examine the seasonality of such searches in greater detail. METHODS: Monthly relative search volumes for 'restless legs' and 'leg cramps' from 2004 to March 2017 in the United Kingdom (UK) and Australia were obtained from Google Trends. Average percentage change from winter to summer months was examined. The TRAMO-SEATS procedure from the DEMETRA statistical software was used to decompose the data into trend, seasonal and noise components and to determine whether a combined seasonality test was positive. RESULTS: There were substantial percentage increases in Google Trends searches between winter and summer months regarding restless legs in the UK (median increase 46%) and Australia (33%) and regarding leg cramps in the UK (95%) and Australia (50%). However, the combined seasonality test was positive only for leg cramps and not for restless legs in both countries: although there was significant stable seasonality in restless legs searches, this was outweighed by substantial moving seasonality and noise components. CONCLUSIONS: Examination of average percentage increase in search volume from winter to summer exaggerates the degree of seasonality. Seasonal effects for restless legs searches are non-significant when the trend and noise components of the data are considered, although this does not exclude a clinical significance for the identified stable seasonality. Significant seasonality, with a summer peak, is present for leg cramps searches and suggests an increase in the incidence or severity of leg cramps in summer. PMID- 28899523 TI - Validation of the screening tool ApneaLink(r) in comparison to polysomnography for the diagnosis of sleep-disordered breathing in children and adolescents. AB - OBJECTIVE: While out-of-center testing was introduced as an alternative for the diagnosis of obstructive sleep apnea in adults, polysomnography (PSG) is still considered mandatory in the diagnosis of sleep-disordered breathing (SDB) in children. The purpose of this study was to validate the outpatient screening device ApneaLink(r) in comparison to PSG in children and adolescents for the diagnosis of SDB. METHODS: Sixty consecutive children and adolescents (10.4 +/- 6.2, 0-22 years) with suspected SDB admitted to the sleep laboratory underwent simultaneous recording with full PSG and the screening device ApneaLink(r) based on flow measurement and oxygen saturation. RESULTS: The mean apnea-hypopnea index (AHI) was 11.8 +/- 19.7 in PSG and 10.3 +/- 12.0 in ApneaLink(r). When the AHI threshold was set to 5/h to diagnose SDB, the overall sensitivity for ApneaLink(r) was 79% and the specificity was 63%. After reducing the AHI threshold to 1/h, the sensitivity and specificity were 94% and 29%. In children older than 10 years, the performance of ApneaLink(r) improved (AHI 5/h: sensitivity 80%, specificity 64%; AHI 1/h: sensitivity 100%, specificity 50%). CONCLUSION: These results show that the outpatient screening device ApneaLink(r) reliably identifies SDB in preselected children older than 10 years. In contrast, it may not be used for the exclusion of SDB. PMID- 28899522 TI - Actigraphy scoring for sleep outcome measures in chronic obstructive pulmonary disease. AB - BACKGROUND: Actigraphy is commonly used to measure sleep outcomes so that sleep can be measured conveniently at home over multiple nights. Actigraphy has been validated in people with sleep disturbances; however, the validity of scoring settings in people with chronic medical illnesses such as chronic obstructive pulmonary disease remains unclear. The purpose of this secondary analysis was to compare actigraphy-customized scoring settings with polysomnography (PSG) for the measurement of sleep outcomes in people with chronic obstructive pulmonary disease who have insomnia. METHODS: Participants underwent overnight sleep assessment simultaneously by PSG and actigraphy at the University of Illinois of Chicago Sleep Science Center. Fifty participants (35 men and 15 women) with mild to-severe chronic obstructive pulmonary disease and co-existing insomnia were included in the analysis. Sleep onset latency, total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) were calculated independently from data derived from PSG and actigraphy. Actigraphy sleep outcome scores obtained at the default setting and several customized actigraphy settings were compared to the scored PSG results. RESULTS: Although no single setting was optimal for all sleep outcomes, the combination of 10 consecutive immobile minutes for sleep onset or end and an activity threshold of 10 worked well. Actigraphy overestimated TST and SE and underestimated WASO, but there was no difference in variance between PSG and actigraphy in TST and SE when the 10 * 10 combination was used. As the average TST and SE increased, the agreement between PSG and actigraphy appeared to increase, and as the average WASO decreased, the agreement between PSG and actigraphy appeared to increase. CONCLUSION: Results support the conclusion that the default actigraphy settings may not be optimal for people with chronic obstructive pulmonary disease and co-existing insomnia. PMID- 28899524 TI - Adherence to continuous positive airway pressure improves attention/psychomotor function and sleepiness: a bias-reduction method with further assessment of APPLES. AB - OBJECTIVE/BACKGROUND: Variable adherence to prescribed therapies for sleep disorders is commonplace. This study was designed to integrate three available statistical technologies (instrumental variables, residual inclusion, and shrinkage) to allow sleep investigators to employ data on variable adherence in the estimation of the causal effect of treatment as received on clinical outcomes. PATIENTS/METHODS: Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), regression adjustment for observed and unobserved confounders was applied to two primary neurocognitive outcomes, plus two measures of sleepiness. We demonstrate how to obtain estimates of reduced uncertainty for the causal effect of treatment as received for continuous positive airway pressure (CPAP) within clinical subpopulations (defined by baseline disease severity) of sleep apnea patients. RESULTS AND CONCLUSIONS: Following six months of treatment, statistically significant improvements caused by device adherence were detected for subjective sleepiness in mild, moderate, and severe disease, objective sleepiness in severe disease, and attention and psychomotor function in moderate disease. Some evidence for worsening of learning and memory due to increased adherence in moderate disease was also detected. Application to APPLES illustrates that this method can yield bias corrections for unobserved confounders that are substantial-revealing new clinical findings. Use of this fully general method throughout sleep research could sharpen understanding of the true efficacy of pharmacotherapies, medical devices, and behavioral interventions. Extensive technical appendices are provided to facilitate application of this general method. Clinicaltrials.gov identifier NCT00051363. PMID- 28899525 TI - Restless legs syndrome after high-risk TIA and minor stroke: association with reduced quality of life. AB - BACKGROUND: Restless legs syndrome (RLS) is a movement disorder that is associated with poor quality of life and depressive symptoms in the general population. Emerging evidence suggests that RLS is closely associated with cerebrovascular disease. We assessed the effect of RLS on quality of life after stroke and transient ischemic attack (TIA). METHODS: In this single-center prospective study, we recruited patients within 14 days of high-risk TIA or minor stroke. Patients were diagnosed with RLS using a questionnaire based on the 2003 International RLS Study Group criteria, and diagnoses were confirmed by a sleep neurologist. Follow-up assessments were conducted within 2-6 months of recruitment. The outcome of quality of life was measured using the Stroke specific Quality of Life (SS-QoL). RESULTS: Of the 94 patients recruited into the study, 23 (24.4%) were diagnosed with RLS: 11 were newly diagnosed with RLS and 12 had RLS preceding the index stroke/TIA. There were no significant differences in baseline characteristics between those with or without RLS. Median SS-QoL in patients with RLS was lower at baseline (p = 0.008) and at follow-up (p = 0.002). RLS patients had more depressive symptoms at follow-up (p = 0.007). Ordinal logistic regression demonstrated that RLS was negatively associated with quality of life at baseline (OR = 0.28; p = 0.010) and at follow-up (OR = 0.14; p = 0.029), independent of functional outcome and depressive symptoms. CONCLUSIONS: RLS is common after stroke or TIA and negatively affects the quality of life. Screening for RLS after cerebrovascular events may be warranted, and future research should assess whether treatment of RLS can improve post-stroke quality of life. PMID- 28899526 TI - Association between severity of untreated sleep apnoea and postoperative complications following major cardiac surgery: a prospective observational cohort study. AB - OBJECTIVE: To examine whether untreated sleep apnoea is associated with prolonged Intensive Care Unit (ICU) stay and increased frequency of postoperative ICU complications, in patients undergoing major cardiac surgery. PATIENTS/METHODS: Adult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery, between March 2013 and July 2014, were considered. We excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, required emergency surgery or were due to be admitted on the day of surgery. Patients underwent inpatient overnight oximetry on the night prior to their surgery to assess for the presence of sleep apnoea. Since oximetry alone cannot differentiate obstructive from central apnoea, the results are reported as sleep apnoea which was diagnosed in patients with an arterial oxygen desaturation index (ODI) >= 5/h. RESULTS: The primary outcome measure was length of stay (LoS) in ICU in days. The secondary outcome was a composite measure of postoperative complications in ICU. Multivariate models were developed to assess associations between ODI and the primary and secondary outcome measures, adjusting for preselected predictor variables, relative to primary and secondary outcomes. There was no significant association between ODI and ICU LoS, HR 1.0, 95% CI 0.99-1.02; p = 0.12. However we did find a significant association between ODI and postoperative complications in the ICU, OR = 1.1; 95% CI 1.02-1.17; p = 0.014. The probability of developing complications rose with higher ODI, reflecting sleep apnoea severity. CONCLUSIONS: Acknowledging the limitations of this prospective study, untreated sleep apnoea did not predict an increased length of stay in ICU but we do report an association with postoperative complications in patients undergoing major cardiac surgery. PMID- 28899527 TI - Restless legs syndrome is highly prevalent in patients with post-polio syndrome. AB - OBJECTIVE: Few studies have quantified the prevalence of restless legs syndrome (RLS) in patients with post-polio syndrome (PPS). Our objective was to assess the prevalence and severity of RLS in patients with PPS and to examine the demographic characteristics of this population. METHOD: This was a cross sectional study conducted from April 2010 to May 2012 at the outpatient Neuromuscular Disorders clinic of Universidade Federal de Sao Paulo, Sao Paulo, Brazil. We evaluated 119 patients with PPS, consecutively recruited, and investigated for RLS based on the diagnostic criteria established by the International Restless Legs Syndrome Study Group (IRLSSG). Patients were evaluated with the Brazilian version of the IRLSSG severity scale. RESULTS: The prevalence of RLS was 36% (n = 43; 32 women and 11 men). The ages at onset of RLS (median = 41 years) and PPS (median = 41 years) were concurrent, and the correlation between onset of symptoms of RLS and onset of symptoms of PPS was positive and very strong (Spearman r = 0.93, p = 0.01). The median RLS severity was 23 (range, 20-28). Low educational achievement and depression were predictive of RLS development. CONCLUSION: In the largest population of patients with PPS studied to date, our results indicate a high prevalence of RLS, marked disease severity, and concomitant onset of both conditions in many patients with PPS. Further studies are needed to elucidate a possible pathophysiologic mechanism linking these two conditions. We suggest that all post-polio patients with sensory and motor complaints in the legs be investigated for RLS. PMID- 28899528 TI - Back to sleep or not: the effect of the supine position on pediatric OSA: Sleeping position in children with OSA. AB - BACKGROUND: In both adults and children, obstructive sleep apnea (OSA) has significant adverse cardiovascular consequences. In adults, sleeping position has a marked effect on the severity of OSA; however, the limited number of studies conducted in children have reported conflicting findings. We aimed to evaluate the effect of sleeping position on OSA severity and the cardiovascular consequences in preschool-aged children. METHODS: This was a retrospective analysis of children (3-5 years of age) diagnosed with OSA (n = 75) and nonsnoring controls (n = 25). Sleeping position was classified as supine, semi supine, left lateral, right lateral, prone, and semi-prone by using video recordings during one night of attended polysomnography. OSA severity and cardiovascular parameters were compared between the positions. RESULTS: All children spent significantly more sleep time in the supine position than in any other position. The obstructive apnea-hypopnea index was higher in the supine position than in the other sleeping positions during NREM (p < 0.05), higher in the moderate/severe OSA group when sleeping in the supine position than when sleeping in the left and right lateral positions (p < 0.05 for both) and prone position (p = 0.007) during REM. Sympathovagal balance was decreased in children with OSA in the supine and lateral positions (p < 0.05). CONCLUSIONS: This study identified that preschool-aged children, whether nonsnoring controls or children with OSA, predominately sleep in the supine position, and OSA was more severe in the supine position. We suggest that to avoid the supine sleep position, positional therapy has the potential to ameliorate OSA severity, and the known cardiovascular consequences. PMID- 28899529 TI - QT interval variability index and QT interval duration during different sleep stages in patients with obstructive sleep apnea. AB - OBJECTIVES: The aim of the study was to investigate the impact of obstructive sleep apnea (OSA) on the QT interval variability and duration in patients during different sleep stages. METHODS: Polysomnographic recordings of 28 (13 male, 15 female) patients with OSA and 30 (15 male, 15 female) patients without OSA were analyzed. The QT interval variability index (QTVI) and the corrected QT interval (QTc) analyses were performed using two awake, 3-4 non-rapid eye movement (NREM) and three rapid eye movement (REM) sleep episodes (each 300 s). The Bazett formula, linear, and parabolic heart rate correction formulas with two separate alpha values were used. RESULTS: QTVI was statistically higher in OSA than in non OSA patients for males while awake (awake -0.7 +/- 0.3 vs -1.2 +/- 0.2, p = 0.001; NREM -0.9 +/- 0.4 vs -1.1 +/- 0.3, p = 0.110; REM -1.1 +/- 0.3 vs -1.3 +/- 0.2, p = 0.667) and for females in all wake-sleep stages (awake -0.3 +/- 0.7 vs 0.9 +/- 0.5, p = 0.001; NREM -0.3 +/- 0.5 vs -0.8 +/- 0.4, p = 0.002; REM -0.3 +/ 0.5 vs -1.0 +/- 0.4, p < 0.001). QTVI was significantly higher during awake compared to sleep stages in OSA males (p < 0.05); no difference between wake sleep stages was found in females (p > 0.05). Significant gender differences in QTVI existed in OSA patients during sleep (p < 0.05) but not while awake. No significant differences in QTc between patients groups were observed. CONCLUSIONS: OSA is associated with increased QT variability. REM sleep per se does not increase QTVI. In OSA patients, QTVI might be a more useful measure to detect ventricular repolarization abnormality than measures of QTc. PMID- 28899530 TI - Associations between sleep duration and physical activity and dietary behaviors in Chinese adolescents: results from the Youth Behavioral Risk Factor Surveys of 2015. AB - OBJECTIVE: To assess the association between sleep duration and physical activity and dietary behaviors among adolescents in a representative sample. METHODS: The analysis was performed using data from the 2015 Ningbo Youth Risk Behavior Survey. Associations between physical activity and dietary behaviors and sleep duration were examined on weighted data using logistic regression. RESULTS: Of the 10726 students, roughly 40% reported sleep duration <8 h. Longer sleep duration was associated with higher likelihood of milk intake, fruit consumption, vegetable consumption, water consumption, moderate physical activity, and muscle strengthening physical activity, and with a lower likelihood of cigarette use, alcohol use, sweets intake, Western fast food intake, and breakfast skipping. CONCLUSION: Insufficient sleep may be common among Chinese adolescents. Sleep duration was associated with dietary behaviors, physical activity, and other health-related behaviors. These findings suggest that sleep duration could be a potential target for many health-risk behaviors in young adolescents. PMID- 28899531 TI - Sleep disorders and allergic diseases in Chinese toddlers. AB - OBJECTIVE: Optimal sleep is important for child growth, development, and immune function. We aimed to explore whether sleep disorders were associated with the risk of allergic diseases in Chinese toddlers. METHODS: This study included 566 children (aged 23.9 +/- 0.7 months; 51.1% boys) in Shanghai, China. Sleep parameters (total sleep time, sleep onset latency, nocturnal awaking and snoring) were assessed by an expanded version of the Brief Infant Sleep Questionnaire (BISQ-expanded). Information on four allergic diseases (wheeze, eczema, food allergy, and allergic rhinitis) in the past year was collected via standard questionnaire and judged by pediatricians. We used logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) for having any/and each of the four allergic diseases, based on sleep parameters, adjusting for children's age and gender, mode of delivery, any breastfeeding duration, children's body mass index (BMI), children's exposure to passive smoking, maternal education, family income, family allergic history, and children's antibiotic use. RESULTS: There were 23.3% of children with at least one of the four allergic diseases. Snoring was significantly associated with increased odds of having any allergy (adjusted OR = 1.95; 95% CI: 1.17, 3.26), eczema (OR = 1.83, 95% CI: 1.03, 3.23) and food allergy (OR = 4.31, 95% CI: 1.23, 15.14), after adjustment for potential confounders. Nocturnal awaking >=2 times per night was associated with higher risk of food allergy (OR = 3.92, 95% CI: 1.00, 15.35) and wheeze (OR = 6.16, 95% CI: 1.28, 29.74). CONCLUSION: In this study, presence of certain sleep disorders was associated with higher risk of having allergic diseases in Chinese toddlers. PMID- 28899532 TI - The association between Disruptive Mood Dysregulation Disorder symptoms and sleep problems in children with and without ADHD. AB - BACKGROUND: Many youth experience persistent irritability and recurrent temper outbursts, conceptualized by DSM-5 as Disruptive Mood Dysregulation Disorder (DMDD). Sleep deprivation impairs emotion regulation which could increase rates of DMDD symptoms, especially in those with preexisting regulatory impairments, as seen with ADHD. However, there has been little examination of the relationship between chronic sleep problems and DMDD symptoms. METHODS: Associations between DMDD symptoms and sleep parameters in children were assessed using parent-report and objective measures of sleep in a general population sample (N = 665) and an ADHD sample (N = 784). Irritability, temper outbursts, sleep problems and other psychological problems were assessed with the Pediatric Behavior Scale. The general population study also completed overnight polysomnography (PSG). RESULTS: DMDD symptoms were reported in 9.2% of the community sample and 31.4% of the ADHD sample. In both samples, children with DMDD symptoms had significantly higher parent-reported sleep problems than children without DMDD symptoms. Children with sleep problems had significantly higher DMDD scores than children without sleep problems. However, DMDD symptoms were most strongly associated with oppositional behavior. Sleep problems were not a significant contributor. Hyperactivity impulsivity was most strongly associated with sleep problems, and DMDD was not a significant contributor. Children with and without DMDD symptoms did not differ significantly on any PSG parameter. CONCLUSIONS: Associations between parent reported sleep problems and DMDD symptoms were due to their shared relationship with other behavioral problems. Therefore, chronic sleep problems do not appear to be a primary source of DMDD symptoms in children with or without ADHD. PMID- 28899533 TI - The increased risk of stroke in early insomnia following traumatic brain injury: a population-based cohort study. AB - OBJECTIVE: Insomnia, a common symptom after traumatic brain injury (TBI), may be a pre-symptom for developing stroke. This study aims to investigate whether insomnia is a potential risk factor for stroke after TBI, especially early insomnia. METHODS: Taiwan's Longitudinal Health Insurance Database 2000 from 1999 to 2013 was used in this cohort study. TBI patients with insomnia were selected based on the ICD-9-CM code (TBI: 801-804 and 850-854; insomnia: 307.4, 327, and 780.5). The outcome we were interested in was stroke (ICD-9-CM: 430-438). The incidence rate ratio of stroke between TBI with insomnia and the general population with insomnia was calculated by Poisson regression. The relative risk adjusted for potential confounding variables was estimated by Cox regression. RESULTS: For 1174 TBI patients with insomnia and 5870 general patients with insomnia, TBI patients have 209.85 incidence risk of new-onset stroke if they have insomnia. TBI patients have 2.28-fold (95% CI: 1.70-3.06) risk of new-onset stroke compared with the general population, even when controlling for age, gender, socioeconomic status, and comorbidities. The hazard ratio of new-onset stroke among different phases of new-onset insomnia after TBI surgery is 1.95 fold (95% CI: 1.05-3.62), 2.75-fold (95% CI: 1.73-4.37), and 2.66-fold (95% CI: 1.68-4.21) at <=3, 3-12, and 12-24 months, compared with the general population with insomnia, respectively. CONCLUSION: TBI patients with insomnia have a higher risk of stroke compared with the general population with insomnia. Early new onset insomnias after TBI will have higher risk of stroke. Therefore, we consider that insomnia could be a signal of the development of new-onset stroke in TBI patients. PMID- 28899534 TI - Gene-by-environment interactions of the CLOCK, PEMT, and GHRELIN loci with average sleep duration in relation to obesity traits using a cohort of 643 New Zealand European children. AB - OBJECTIVES: Modern technology may have desensitised the 'biological clock' to environmental cues, disrupting the appropriate co-ordination of metabolic processes. Susceptibility to misalignment of circadian rhythms may be partly genetically influenced and effects on sleep quality and duration could predispose to poorer health outcomes. Shorter sleep duration is associated with obesity traits, which are brought on by an increased opportunity to eat and/or a shift of hormonal profile promoting hunger. We hypothesised that increased sleep duration will offset susceptible genetic effects, resulting in reduced obesity risk. METHODS: We recruited 643 (male: 338; female: 305) European children born to participants in the New Zealand centre of the International Screening for Pregnancy Endpoints sleep study. Ten genes directly involved in the circadian rhythm machinery and a further 20 genes hypothesised to be driven by cyclic oscillations were evaluated by Sequenom assay. Multivariable regression was performed to test the interaction between gene variants and average sleep length (derived from actigraphy), in relation to obesity traits (body mass index (BMI) z scores and percentage body fat (PBF)). RESULTS: No association was found between average sleep length and BMI z-scores (p = 0.056) or PBF (p = 0.609). Uncorrected genotype associations were detected between STAT-rs8069645 (p = 0.0052) and ADIPOQ-rs266729 (p = 0.019) with differences in average sleep duration. Evidence for uncorrected gene-by-sleep interactions of the CLOCK-rs4864548 (p = 0.0039), PEMT-936108 (p = 0.016) and GHRELIN-rs696217 (p = 0.046) were found in relation to BMI z-scores but not for PBF. CONCLUSION: Our results indicate that children may have different genetic susceptibility to the effects of sleep duration on obesity. Further confirmatory studies are required in other population cohorts of different age groups. PMID- 28899535 TI - Efficacy and safety of acupuncture treatment on primary insomnia: a randomized controlled trial. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of acupuncture treatment for primary insomnia. METHODS: We conducted a single center, single-blinded, and randomized controlled clinical trial. Seventy-two patients with primary insomnia were randomly assigned into two groups - the acupuncture group, who received acupuncture treatment, and the control group, who received sham acupuncture treatment. The treatment was given three times a week for four weeks. Patients were asked to wear sleep monitors and complete questionnaires every two weeks for a total of eight weeks. The primary outcome was the Insomnia Severity Index (ISI). The secondary outcomes were sleep parameters including sleep efficiency (SE), sleep awakenings (SA) and total sleep time (TST) recorded by the Actigraphy, as well as scores of the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). RESULTS: Compared with pretreatment baseline, patients in both groups had varying degrees of improvements in their sleep conditions. Paired t-test showed that there was a significant difference in all indicators in the acupuncture group before and after acupuncture treatment. One-way analysis of covariance adjusted for baseline scores indicated that the ISI improved dramatically in the acupuncture group at two weeks post-treatment (F = 11.3, p = 0.001), four weeks post-treatment (F = 33.6, p < 0.001), 2 weeks follow-up (F = 39.4, p < 0.001) and four weeks follow up (F = 34.1, p < 0.001). Similar significant improvements can also be observed in the SE, TST and SDS scores. Although no differences in SA and SAS were shown between the two groups until the end of the treatment, remarkable decrements in SA and SAS were found in the acupuncture treatment group after the two-week and four-week follow-ups. CONCLUSION: Acupuncture treatment is more effective than sham acupuncture treatment in increasing insomnia patients' sleep quality and improving their psychological health. TRIAL REGISTRATION: Chinese Clinical Trial Registry: Chi CTR-TRC-14004859. PMID- 28899536 TI - Utility of new-generation pacemakers in sleep apnea screening. AB - OBJECTIVE: Patients with cardiac pacemakers present a high prevalence of undiagnosed sleep apnea syndrome (SAS). New-generation pacemakers have algorithms that identify sleep respiratory events. Our aim was to evaluate their accuracy in the diagnosis of SAS. METHODS: We performed a prospective study that included patients with new-generation pacemakers (Reply 200 pacemakers). All patients underwent a polysomnography (PSG). On the same night, the respiratory disturbance index of the PSG (RDI-PSG) and of the pacemaker (RDI-PM) were recorded. The agreement between methods was assessed using the kappa coefficient, Bland and Altman statistics and receiver operating characteristic (ROC) curves. RESULTS: Sixty patients were recruited but the RDI-PM for the PSG night was not available in six patients. PSG diagnosed SAS in 74% of patients (20% severe, 19% moderate, 35% mild). Besides snoring (63%), most patients had no SAS symptoms. There was a strong positive correlation between RDI-PSG and RDI-PM (r = 0.522, p < 0.001), but the level of agreement between methods regarding SA diagnosis/severity was poor (k = 0.167). ROC curves identified a RDI-PM of 10 events/h as the optimal cut-off point for diagnosing SAS (area under the curve (AUC): 0.81, sensitivity: 80%, specificity: 79%, positive predictive value: 91%, negative predictive value: 58%). The best cut-off for identifying moderate/severe SAS was at 13 events/h (AUC: 0.86, sensitivity: 100%, specificity: 70%, positive predictive value: 68%, negative predictive value: 100%). CONCLUSIONS: SAS prevalence in patients with pacemakers is high (74%). Most are asymptomatic, which could delay the diagnosis. Patients with clinical indication for a pacemaker may benefit from a device with sleep apnea monitoring. PMID- 28899537 TI - Severity of individual obstruction events increases with age in patients with obstructive sleep apnea. AB - BACKGROUND: Age is a risk factor of obstructive sleep apnea (OSA). It has been shown that OSA progresses over time, although conflicting results have been reported. However, the effect of age on the severity of OSA and individual obstruction events has not been investigated within different OSA severity categories by taking the most prominent confounding factors (i.e., body mass index, gender, smoking, daytime sleepiness, snoring, hypertension, heart failure, and proportion of supine sleep) into account. METHODS: Polygraphic data of 1090 patients with apnea-hypopnea index (AHI) >=5 were retrospectively reanalyzed. The effect of age on the severity of OSA and obstruction events was investigated in general, within different OSA severity categories, and in different age groups (age <40, 40<= age <50, 50<= age <60, and age >=60 years). RESULTS: In the whole population, AHI and durations of apneas, hypopneas, and desaturations increased with increasing age (B >= 0.108, p <= 0.010). In more detailed analysis, AHI increased with age only in the moderate OSA category (B = 0.075, p = 0.022), although durations of apneas increased in mild and severe OSA categories (B >= 0.076, p <= 0.038). Furthermore, durations of hypopneas increased with age in mild and moderate OSA categories (B >= 0.105, p <= 0.038), and durations of desaturations (B >= 0.120, p <= 0.013) in all OSA severity categories. AHI was not statistically significantly different between the age groups, although durations of obstruction events tended to increase towards older age groups. CONCLUSION: As obstruction event severity was more strongly dependent on the age than it was dependent on AHI, considering the severity of obstruction events could be beneficial while estimating the long-term effects of the treatments and prognosticating the disease progression. PMID- 28899538 TI - Relationship between stress coping and sleep disorders among the general Japanese population: a nationwide representative survey. AB - OBJECTIVE: To clarify the prevalence of stress, and examine the relationship between sleep disorders and stress coping strategies among highly stressed individuals in the general Japanese population. METHODS: A cross-sectional nationwide survey was undertaken in November 2007. Men and women were randomly selected from 300 districts throughout Japan. Data from 7671 (3532 men (average age 53.5 +/- 17.0 years) and 4139 women (average age 53.9 +/- 17.7 years)) were analyzed. Participants completed a self-reported questionnaire on stress, sleep disorders, and stress coping strategies in the previous month. RESULTS: Highly stressed individuals comprised 16.6% (95% confidence interval 15.8-17.5%) of the total sample, and most were aged 20-49 years. In multiple logistic regression, symptoms of insomnia (ie, difficulty initiating sleep, difficulty maintaining sleep, and early morning awakening), excessive daytime sleepiness, nightmares, daytime malfunction, and lack of rest due to sleep deprivation were more prone to occur in highly stressed individuals. In addition, logistic regression analysis controlling for other adjustment factors revealed that stress coping strategies such as 'giving up on problem-solving', 'enduring problems patiently', 'smoking' and 'drinking alcohol' were positively associated with the above-mentioned sleep disorders. On the other hand, stress coping strategies such as 'exercising', 'enjoying hobbies', and 'sharing worries' were inversely associated with the above-mentioned sleep disorders. CONCLUSIONS: Distraction-based stress coping (eg, hobbies, exercise, and optimistic thinking) was found to be preferable to problem-based stress coping in a highly stressed Japanese general population. PMID- 28899539 TI - Can the analysis of built-in software of CPAP devices replace polygraphy in children? AB - OBJECTIVES: Polysomnography (PSG) is the gold standard for the scoring of residual respiratory events during continuous positive airway pressure (CPAP). Studies comparing PSG scoring with automatic scoring by the built-in software of CPAP devices have reported acceptable agreements except for the hypopnea index (HI) in adult patients, but no study has yet been conducted in children. The aim of the present study was to compare the automatic scoring by CPAP device and manual scoring using the software tracings of the CPAP device integrating pulse oximetry (SpO2) with in-lab polygraphy (PG). METHODS: Consecutive clinically stable children treated with constant CPAP (ResMed) for at least one month and scheduled for a nocturnal PG were recruited. A pulse oximeter was connected to the CPAP device. The PG apnea-hypopnea index (AHIPG), scored according to modified AASM guidelines, was compared with the automatic AHI reported by the CPAP device (AHIA CPAP) and the manual scoring of the AHI on the CPAP software (AHIM CPAP). RESULTS: Fifteen children (1.5-18.6 years) were included. Mean residual AHIPG was 0.9 +/- 1.2/hour (0.0-4.6/hour) vs. AHIA CPAP of 3.6 +/- 3.6/hour (0.5-14.7/hour) (p < 0.001), and AHIM CPAP of 1.2 +/- 1.6/hour (0.0 5.1/hour) (p = 0.01). Correlation between AHIPG and AHIA CPAP was good (r = 0.667; p = 0.007), and improved when considering AHIM CPAP (r = 0.933; p < 0.001). Strong correlations were also observed between the PG apnea index (AI) and HI, and the manually scored AI and HI on CPAP, respectively. CONCLUSIONS: Manual scoring of respiratory events on the built-in software tracings of CPAP devices integrating SpO2 signal may be helpful. These results have to be confirmed in patients with higher AHI. PMID- 28899540 TI - Moving into poverty during childhood is associated with later sleep problems. AB - OBJECTIVE: A social gradient in sleep has been demonstrated across the life span, but previous studies have been cross-sectional and used self-reported socioeconomic status (SES) indicators. Using registry-based data on family income trajectories, the current study examined the association between relative poverty in childhood and subsequent sleep in adolescence. METHODS: Data on family income during 2004-2010 was obtained from the National Income Registry. Poverty was defined as household income <60% of the mean national income. Information on self reported sleep was based the youth@hordaland-survey (n = 8873) conducted in 2012 when the adolescents were 16-19 years old. Latent class analysis (LCA) was used to identify trajectories of family household poverty, and analysis of variance and general linear models were used to examine associations between income trajectories and sleep, adjusting for confounders. RESULTS: LCA identified four classes: 'never poor', two classes characterized by moving in or out of poverty, and 'chronically poor'. Compared to the 'never poor' group, adolescents from families in the 'moving into poverty' group displayed worse sleep across most sleep measures, including shorter sleep, lower sleep efficiency, and more nocturnal wake time (but not sleep onset latency). Neither adolescents from families who had moved out of poverty by increasing family income, nor the 'chronically poor' group differed significantly from the reference group. CONCLUSIONS: The study found that downward socioeconomic mobility was associated with increased adolescent sleep problems. More studies are required on the mechanisms that may account for the association, to find targeted and effective strategies to prevent short sleep duration in adolescents from families with unstable financial circumstances. PMID- 28899541 TI - Sleep problems, short sleep and a combination of both increase the risk of depressive symptoms in older people: a 6-year follow-up investigation from the English Longitudinal Study of Ageing. AB - STUDY OBJECTIVES: This study investigated whether sleep problems, sleep duration and a combination of short or long sleep with sleep problems were predictive of depressive symptoms six years later. METHODS: Participants were 4545 men and women aged 50 years or older from the English Longitudinal Study of Ageing. Sleep problems were indexed through self-report enquiring about the most frequent insomnia symptoms including difficulties falling asleep, waking up several times a night and waking up in the morning feeling tired. Sleep duration was ascertained by asking about average sleep in the weeknight. Depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale. RESULTS: Sleep problems were predictive of elevated depressive symptoms at follow up (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.19-1.56). When explored separately, waking up in the morning feeling tired (OR = 1.71, 95% CI = 1.24-2.37) followed by difficulties falling asleep (OR = 1.49, 95% CI = 1.06 2.11) were also predictors of future depressive symptoms. Compared to optimal duration, short (OR = 1.90, 95% CI = 1.34-2.71) but not long sleep hours were also linked to elevated depressive symptoms. Participants reporting short sleep hours combined with high sleep problems also had an elevated risk of depressive symptoms six years later (OR = 1.85, 95% CI = 1.15-3.00). Long sleep combined with high sleep problems was not predictive of depressive symptoms. CONCLUSIONS: Short and disturbed sleep and their combination increase the risk of future depressive symptoms in older adults. PMID- 28899542 TI - Predominant obstructive or central sleep apnea in patients with atrial fibrillation: influence of characterizing apneas versus apneas and hypopneas. AB - OBJECTIVE/BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with atrial fibrillation (Afib). Although a high proportion of respiratory events are hypopneas, previous studies have only used apneas to differentiate obstructive (OSA) from central (CSA) sleep apnea. This study investigated the impact of using apneas and hypopneas versus apneas only to define the predominant type of SDB in Afib patients with preserved ejection fraction. PATIENTS/METHODS: This retrospective analysis was based on high-quality cardiorespiratory polygraphy (PG) recordings (07/2007-03/2016) that were re-analyzed using 2012 American Academy of Sleep Medicine criteria, with differentiation of apneas and hypopneas as obstructive or central. Classification of predominant (>50% of events) OSA and CSA was defined based on apneas only (OSAAI and CSAAI) or apneas and hypopneas (OSAAHI and CSAAHI). SDB was defined as an apnea-hypopnea index >=5/h. RESULTS: A total of 211 patients were included (146 male, age 68.7 +/- 8.5 y). Hypopneas accounted for >50% of all respiratory events. Based on apneas only, 46% of patients had predominant OSA and 44% had predominant CSA. Based on apneas and hypopneas, the proportion of patients with OSA was higher (56%) and that with CSA was lower (36%). In the subgroup of patients with moderate to severe SDB (AHI >= 15/h), the proportion with predominant CSA was 55.2% based on apneas only versus 42.1% with apneas and hypopneas. CONCLUSIONS: In hospitalized patients with Afib and SDB, use of apneas and hypopneas versus apneas alone had an important influence on the proportion of patients classified as having predominant OSA or CSA. PMID- 28899543 TI - Autocannibalism induced by obstructive sleep apnea. PMID- 28899544 TI - Periorbital integrated potentials: useful phasic REM sleep markers. PMID- 28899545 TI - A different rhythm of life: sleep patterns in the first 4 years of life and associated sociodemographic characteristics in a large Brazilian birth cohort. AB - OBJECTIVE: Sleep is an important marker of healthy development and has been associated with emotional, behavioral, and cognitive development. There is limited longitudinal data on children's sleep with only a few reports from low- and middle-income countries (LMICs). We investigate sleep parameters and associated sociodemographic characteristics in a population-based longitudinal study in Pelotas, Brazil. METHODS: Data from the Pelotas 2004 Birth Cohort were used (N = 3842). Infant sleep was collected through maternal report at 3, 12, 24, and 48 months: sleep duration, bed and wake time, nighttime awakenings, co sleeping and sleep disturbances (24 and 48 months). RESULTS: Compared to children in high-income countries (HICs), children in Brazil showed a substantial shift in rhythms with later bed and wake times by approximately 2 hours. These remain stable throughout the first 4 years of life. This population also shows high levels of co-sleeping which remain stable throughout (49.0-52.2%). Later bedtime was associated with higher maternal education and family income. Higher rates of co-sleeping were seen in families with lower income and maternal education and for children who were breastfed. All other sleep parameters were broadly similar to data previously reported from HICs. CONCLUSION: The shift in biological rhythms in this representative community sample of children in Brazil challenges our understanding of optimal sleep routine and recommendations. PMID- 28899547 TI - Linear dimensions of normal upper airway structure by magnetic resonance imaging in Chinese Han infants and preschool children. AB - OBJECTIVES: To establish normative data of upper airway structure in Chinese Han infants and preschool children. METHODS: Magnetic resonance imaging (MRI) scans of 521 Chinese Han infants and preschool children (225 girls, 296 boys) aged from 1 day to 72 months were selected from the children who underwent head MRI at the Capital Institute of Pediatrics Affiliated Children Hospital, Beijing, China. No subjects had sleep-disordered breathing or associated conditions that may have affected the upper airway anatomy. The upper airway dimensions and surrounding soft tissue sizes were measured along the mid-sagittal and axial images. RESULTS: On images from the mid-sagittal image, the normative values of the following were obtained for all age group: thickness of the adenoid and nasopharyngeal area, length and thickness of the soft palate, length and height of the tongue, length of upper airway, distance between the mental spine and clivus, and the adenoid oblique width, soft palate oblique width, and tongue oblique width along the mental spine-clivus line. Normative values of the mean tonsillar width and intertonsillar space on the axial images were also obtained. There were no differences in any measurements between boys and girls in either infants or preschool children. Older children had larger airway dimensions, as expected. CONCLUSION: Normative values for upper airway structure in Chinese Han infants and preschool children assessed by MRI were established. The upper airway dimension and surrounding soft tissues size, including soft palate, adenoid, tongue, and tonsils, were increased with age. There were no gender differences during the first six years of life. These data may prove useful when studying airway disease in Chinese Han children. PMID- 28899546 TI - Exploring the nap paradox: are mid-day sleep bouts a friend or foe? AB - The mid-day nap, sometimes called a siesta, is a ubiquitous occurrence across the lifespan. It is well established that in addition to reducing sleepiness, mid-day naps offer a variety of benefits: memory consolidation, preparation for subsequent learning, executive functioning enhancement, and a boost in emotional stability. These benefits are present even if a sufficient amount of sleep is obtained during the night prior. However, we present a paradox: in spite of these reported benefits of naps, frequent napping has also been associated with numerous negative outcomes (eg, cognitive decline, hypertension, diabetes), particularly in older populations. This association exists even when statistically controlling for relevant health- and sleep-affecting determinants. An emerging hypothesis suggests inflammation is a mediator between mid-day naps and poor health outcomes, yet further research is necessary. Given this, it may be premature to 'prescribe' naps as a health enhancer. Herein, we aggregate findings from several branches of sleep research (eg, developmental neuroscience, cognitive neuroscience, sleep medicine) to critically examine the paradoxical role of naps in cognitive and somatic health. This review uncovers gaps in the literature to guide research opportunities in the field. PMID- 28899548 TI - Magnet foreign body ingestion: rare occurrence but big consequences. AB - PURPOSE: To review the outcomes of magnet ingestions from two children's hospitals and develop a clinical management pathway. METHODS: Children <18years old who ingested a magnet were reviewed from 1/2011 to 6/2016 from two tertiary center children's hospitals. Demographics, symptoms, management and outcomes were analyzed. RESULTS: From 2011 to 2016, there were 89 magnet ingestions (50 from hospital 1 and 39 from hospital 2); 50 (56%) were males. Median age was 7.9 (4.0 12.0) years; 60 (67%) presented with multiple magnets or a magnet and a second metallic co-ingestion. Suspected locations found on imaging were: stomach (53%), small bowel (38%), colon (23%) and esophagus (3%). Only 35 patients (39%) presented with symptoms and the most common symptom was abdominal pain (33%). 42 (47%) patients underwent an intervention, in which 20 (23%) had an abdominal operation. For those undergoing abdominal surgery, an exact logistic regression model identified multiple magnets or a magnet and a second metallic object co ingestion (OR 12.9; 95% CI, 2.4 - Infinity) and abdominal pain (OR 13.0; 95% CI, 3.2-67.8) as independent risk factors. CONCLUSION: Magnets have a high risk of requiring surgical intervention for removal. Therefore, we developed a management algorithm for magnet ingestion. LEVEL OF EVIDENCE: Level III. PMID- 28899549 TI - Following the Deepwater Horizon oil spill: What we know about the effects of oil on birds? PMID- 28899550 TI - Geometric effects on OO bond scission of copper(II)-alkylperoxide complexes. AB - Copper(II) complexes supported by N3-tridentate ligands, consisting of a rigid cyclic diamine (8-membered cyclic-diamine; L8 or 7-membered cyclic-diamine; L7) and a 2-(2-pyridyl)ethyl (-CH2CH2Py) group, were synthesized and structurally characterized. Reaction of the copper(II) complexes and cumene hydroperoxide (CmOOH) in the presence of triethylamine in CH3CN gave the corresponding cumylperoxide complexes L8CuIIOOCm and L7CuIIOOCm. The UV-vis and EPR spectra suggested that L8CuIIOOCm takes a tetrahedrally distorted structure, whereas L7CuIIOOCm has a planar geometry in solution. Resonance Raman spectra of these alkylperoxide complexes indicated that the O-O stretching vibration energy of L8CuIIOOCm (nuO-O=878cm-1) is somewhat lower than that of L7CuIIOOCm (nuO-O=881cm 1). Such a difference in O-O bond strength is reflected to the reactivity difference of these two alkylperoxide complexes. Namely, the reactivity L8CuIIOOCm toward CHD (1,4-cyclohexadiene) as well as solvent molecule (CH3CN) is higher than that of L7CuIIOOCm due to the weaker O-O bond of the former complex as compared to that of the latter complex. Geometric effects on the reactivity induced by the supporting ligands are discussed. PMID- 28899551 TI - Relationship between neuronal network architecture and naming performance in temporal lobe epilepsy: A connectome based approach using machine learning. AB - Impaired confrontation naming is a common symptom of temporal lobe epilepsy (TLE). The neurobiological mechanisms underlying this impairment are poorly understood but may indicate a structural disorganization of broadly distributed neuronal networks that support naming ability. Importantly, naming is frequently impaired in other neurological disorders and by contrasting the neuronal structures supporting naming in TLE with other diseases, it will become possible to elucidate the common systems supporting naming. We aimed to evaluate the neuronal networks that support naming in TLE by using a machine learning algorithm intended to predict naming performance in subjects with medication refractory TLE using only the structural brain connectome reconstructed from diffusion tensor imaging. A connectome-based prediction framework was developed using network properties from anatomically defined brain regions across the entire brain, which were used in a multi-task machine learning algorithm followed by support vector regression. Nodal eigenvector centrality, a measure of regional network integration, predicted approximately 60% of the variance in naming. The nodes with the highest regression weight were bilaterally distributed among perilimbic sub-networks involving mainly the medial and lateral temporal lobe regions. In the context of emerging evidence regarding the role of large structural networks that support language processing, our results suggest intact naming relies on the integration of sub-networks, as opposed to being dependent on isolated brain areas. In the case of TLE, these sub-networks may be disproportionately indicative naming processes that are dependent semantic integration from memory and lexical retrieval, as opposed to multi-modal perception or motor speech production. PMID- 28899552 TI - The use of dissolvable layered double hydroxide components in an in situ solid phase extraction for chromatographic determination of tetracyclines in water and milk samples. AB - This research presents a simple and green in situ solid phase extraction (is-SPE) combined with high-performance liquid chromatography (HPLC) for the simultaneous analysis of tetracyclines (TCs) including tetracycline, oxytetracycline, and chlortetracycline. In is-SPE, TCs were efficiently extracted through the precipitation formation of dissolvable layered double hydroxides (LDHs) by mixing the LDH components such as magnesium and aluminum ions (both in metal chloride salts) thoroughly in an alkaline sample solution. After the centrifugation, the precipitate was completely dissolved with trifluoroacetic acid to release the enriched TCs, and then analyzed by HPLC. Under optimized conditions, this method gave good enrichment factors (EFs) of 41-93 with low limits of detection (LODs) of 0.7-6MUg/L and limits of quantitation (LOQs) of 3-15MUg/L. Also, the proposed method was successfully applied for the determination of TCs in water and milk samples with the recoveries ranging from 81.7-108.1% for water and 55.7-88.7% for milk. PMID- 28899553 TI - Hollow mesoporous carbon spheres-based fiber coating for solid-phase microextraction of polycyclic aromatic hydrocarbons. AB - In this study, a novel hollow mesoporous carbon spheres-based fiber (HMCSs-F) was fabricated to immobilize HMCSs onto a stainless steel wire for solid-phase microextraction (SPME). Characterization results showed that the HMCSs-F possessed a large specific surface area, high porosity and uniform pore size. To demonstrate the extraction performance, a series of polycyclic aromatic hydrocarbons (PAHs) was chosen as target analytes. The experimental parameters including extraction and desorption conditions were optimized. Compared to commercial fibers, the HMCSs-F exhibited better extraction efficiency for PAHs. More interestingly, a good extraction selectivity for PAHs from the complex matrix was observed in these HMCSs-F. The enhanced SPME performance was attributed to the unique pore structure and special surface properties of the HMCSs. Furthermore, under the optimum conditions, the limits of detection (LODs) for the HMCSs-F were in the range of 0.20-1.15ngL-1 with a corresponding relative standard deviation that was below 8.6%. The method was successfully applied for the analysis of PAHs in actual environmental water samples with recoveries ranging from 85.9% to 112.2%. These results imply that the novel HMCSs-F have potential application in environmental water analysis. PMID- 28899554 TI - Construction of a hydrazone-linked chiral covalent organic framework-silica composite as the stationary phase for high performance liquid chromatography. AB - Covalent organic frameworks (COFs), as an emerging class of crystalline porous organic polymers, have great potential for applications in chromatographic separation owning to their fascinating crystalline structures and outstanding properties. However, development of COF materials as novel stationary phases in high performance liquid chromatography (HPLC) is just in its infancy. Herein, we report the design and construction of a new hydrazone-linked chiral COF, termed BtaMth COF, from a chiral hydrazide building block (Mth) and present a one-pot synthetic method for the fabrication of BtaMth@SiO2 composite for HPLC separation of isomers. The as-synthesized BtaMth chiral COF displays good crystallinity, high porosity, as well as excellent chemical stability. Meanwhile, the fabricated HPLC column by using BtaMth@SiO2 composite as the new stationary phase exhibits high resolution performances for the separation of positional isomers including nitrotoluene and nitrochlorobenzene, as well as cis-trans isomers including beta cypermethrin and metconazole. Additionally, some effects such as the composition of the mobile phase and column temperature for HPLC separations on the BtaMth@SiO2 packed column also have been studied in detail. The successful applications indicate the great potentials of hydrazone-linked chiral COF-silica composite as novel stationary phase for the efficient HPLC separation. PMID- 28899555 TI - Comprehensive two dimensional liquid chromatography as analytical strategy for pharmaceutical analysis. AB - Comprehensive on-line two-dimensional liquid chromatography (LCxLC) is expected to generate impressive peak capacities, which makes it a method of choice for the analysis of complex samples such as pharmaceuticals. A comparative study of different sets of chromatographic conditions including stationary phase, pH additive and organic modifier was carried out with two real pharmaceutical samples in order to find out the best analytical conditions for implementation of one or several generic on-line LCxLC separations. Our choice was based on the evaluation of both degree of orthogonality and practical sample peak capacity under linear gradient conditions. The potential of 190 combinations of chromatographic systems was compared. A set of 3 RPLCxRPLC configurations was found to be very attractive for both samples and in good agreement with the findings of a previous study carried out with 17 model compounds, thereby supporting the idea of using generic LCxLC conditions in the pharmaceutical area. The three selected 2D-systems were implemented for the on-line RPLCxRPLC-UV/MS analysis of two pharmaceutical samples. It was shown, for each sample, that these 2D-systems were able to generate an effective peak capacity close to 1000 in less than 50min. For each sample, baseline separation was obtained for every known compound and furthermore a large number of unknown impurities could also be separated and identified. Finally, in the proposed conditions, the total number of compounds detected was significantly improved from one RPLC separation to one RPLCxRPLC separation. Only a small additional gain was observed by performing a second RPLCxRPLC separation or even a third one. PMID- 28899556 TI - A Multi-institutional Comparison of SBRT and IMRT for Definitive Reirradiation of Recurrent or Second Primary Head and Neck Cancer. AB - PURPOSE: Two modern methods of reirradiation, intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are established for patients with recurrent or second primary squamous cell carcinoma of the head and neck (rSCCHN). We performed a retrospective multi-institutional analysis to compare methods. METHODS AND MATERIALS: Data from patients with unresectable rSCCHN previously irradiated to >=40 Gy who underwent reirradiation with IMRT or SBRT were collected from 8 institutions. First, the prognostic value of our IMRT based recursive partitioning analysis (RPA) separating those patients with unresectable tumors with an intertreatment interval >2 years or those with <=2 years and without feeding tube or tracheostomy dependence (class II) from other patients with unresected tumors (class III) was investigated among SBRT patients. Overall survival (OS) and locoregional failure were then compared between IMRT and SBRT by use of 2 methods to control for baseline differences: Cox regression weighted by the inverse probability of treatment and subset analysis by RPA classification. RESULTS: The study included 414 patients with unresectable rSCCHN: 217 with IMRT and 197 with SBRT. The unadjusted 2-year OS rate was 35.4% for IMRT and 16.3% for SBRT (P<.01). Among SBRT patients, RPA classification retained an independent association with OS. On Cox regression weighted by the inverse probability of treatment, no significant differences in OS or locoregional failure between IMRT and SBRT were demonstrated. Analysis by RPA class showed similar OS between IMRT and SBRT for class III patients. In all class II patients, IMRT was associated with improved OS (P<.001). Further subset analysis demonstrated comparable OS when >=35 Gy was delivered with SBRT to small tumor volumes. Acute grade >=4 toxicity was greater in the IMRT group than in the SBRT group (5.1% vs 0.5%, P<.01), with no significant difference in late toxicity. CONCLUSIONS: Reirradiation both with SBRT and with IMRT appear relatively safe with favorable toxicity compared with historical studies. Outcomes vary by RPA class, which informs clinical trial design. Survival is poor in class III patients, and alternative strategies are needed. PMID- 28899557 TI - Can the recovery of lower limb fractures be achieved by use of 3D printing mirror model? AB - INTRODUCTION: The mirror imaging 3D printing model can be used a as a reference for anatomical reduction in unilateral lower limb fractures. However, the premise of using mirror technology is that the bilateral lower limb bones are similar enough. Because one side had a fracture, it was impossible to compare this directly to the other side. Usually, surgeons think that the bilateral bones are symmetrical and use mirror technology without judging their symmetry. METHODS: In patients with a unilateral lower limb bone fracture, we measured the long axis and short axis of the three selected transverse sections of the bilateral long bone for comparison to judge the symmetry of the bilateral long bones on CT images. Then, we printed a life-size normal mirror image of the long bone that is similar to the affected side. The model was used as a reference for the anatomical reduction of fractures and preoperative practice. RESULTS: Seventy eight patients with lower limb bone fracture were included in this study. 24 groups of data were generated according to the same level and same axis. There were significant differences between the short axis of the left and right femoral condyle 5cm from the intercondylar keel (p=0.011), and the short axis of the distal tibia 15cm from the ankle dome (p=0.026). There was no significant difference between the left and right sides in the other 22 groups. Of all of the patients in our research, 3 patients decided to forego the surgical treatment and the operation was performed on the model instead, and the lengths of 2 patients showed deviation in actual operations, preventing anatomical reduction. The remaining 73 patients used the pre-bended plates and screws from preoperative practice in the actual operations, and postoperative X-ray examinations showed that the length of the deviation was within the permissible range. CONCLUSION: The "Comparison of long axis and short axis of three equidistant transverse sections" method makes it easy to judge the symmetry of the bilateral long bones, and prevents the blindness of preoperative planning using the contralateral mirror model directly. PMID- 28899558 TI - Arthroscopically measured syndesmotic stability after screw vs. suture button fixation in a cadaveric model. AB - BACKGROUND: Appropriate management of ankle syndesmotic instability is needed to prevent the development of complications. Previous biomechanical studies have evaluated movement of the fibula after screw or suture button fixations with different results, most likely being caused by variations in experimental setups that did not mirror the in vivo clinical setting. This study aimed to arthroscopically compare in a cadaveric model the stability of syndesmotic fixation with either a suture button or syndesmotic screw. METHODS: Eight fresh matched pairs of human ankle cadaver specimens (above knee) underwent arthroscopic assessment with (1) intact ligaments, (2) after complete disruption, and (3) after repair with either a quadracortical syndesmotic screw or suture button construct. In every stage, four loading conditions were considered under 100N of direct force: 1) unstressed, 2) lateral hook test, 3) anterior to posterior (AP) translation test, and 4) posterior to anterior (PA) translation test. Coronal plane tibiofibular diastasis, as well as sagittal plane tibiofibular translation, were arthroscopically measured. RESULTS: Coronal plane anterior and posterior tibiofibular diastasis and sagittal plane tibiofibular translation were measured using probes of increasing diameters. Following screw fixation, syndesmotic stability was similar to the uninjured syndesmosis in the coronal plane (anterior, median 0.0mm [IQR 0.0-0.3] vs. 0.3mm [IQR 0.2-0.3]; p=0.57; posterior, median 0.1mm [IQR 0.0-0.4] vs. 0.2mm [IQR 0.1-0.3]; p=1.0) but more rigid in the sagittal plane (median 0.0mm [IQR 0.0-0.1] vs. 1.0mm [IQR 0.4 1.5]; p=0.012). Repairing the unstable syndesmosis with a suture button construct resulted in coronal plane stability similar to the uninjured syndesmosis (anterior, median 0.2mm [IQR 0.1-0.3] vs. 0.2mm [IQR 0.1-0.3]; p=0.48; posterior, median 0.2mm [IQR 0.1-0.3] vs. 0.3mm [IQR 0.1-0.5]; p=0.44). However, sagittal plane fibular motion remained unstable as compared to the uninjured syndesmosis (median 2.2mm [IQR 1.6-2.6] vs. 0.8mm [IQR 0.4-1.3]; p=0.012). CONCLUSION: Current fixation methods for syndesmotic disruption maintain coronal plane fibular stability. Screw and suture button constructs, however, respectively resulted in greater or insufficient constraint to fibular motion in the sagittal plane as compared to the intact syndesmotic ligament. These findings suggest that neither traditional screw nor suture button fixations optimally stabilize the syndesmosis, which may have implications for postoperative care and clinical outcomes. PMID- 28899559 TI - Emergency general surgery and trauma: Outcomes from the first consultant-led service in Singapore. AB - INTRODUCTION: There is a significant burden on public health systems from emergency surgical and trauma (ESAT) patients. In Western countries, the response has been to separate acute and elective surgery with the creation of a new sub specialty: acute care surgery. Dedicated acute units have shown improvements in efficiency and clinical outcomes for patients. The aim of this study was to assess the results of the first such unit in Singapore. MATERIALS AND METHODS: A retrospective analysis was performed of a 12-month period of acute admissions between May 2014 and April 2015, with comparison of 6-months before and after the creation of the ESAT service. The ESAT service was a consultant led dedicated team managing all daily acute and trauma patients. Demographic, efficiency and clinical outcome key performance indicators were compared. RESULTS: There were 2527 acute admissions split between the two time periods. The ESAT service (N=1279) managed soft tissue infections (257, 20%), appendicitis (199, 16%) and biliary disease (175, 14%) most commonly. The most common of the 573 procedures performed were incision and drainage (242, 42%), appendicectomy (188, 33%) and laparotomy (84, 16%). Clinical outcome during the ESAT service included reduction in overall mean length of stay (4.5d to 3.5d, P<0.01) and mortality (24/1248 (1.9%) to 11/1279 (0.9%), P=0.03). Efficiency gains in theatre booking time, ED surgical review and overall costs were also noted. CONCLUSION: The creation of an ESAT service has led to improved efficiency of care with no worsening of clinical outcomes for acute general surgical and trauma patients. PMID- 28899560 TI - Nerve injuries to the volar aspect of the hand: A comparison of the reliability of the Weber static test versus the gauze test. AB - When examining lacerations to the volar aspect of the hand a gauze test may usually be performed to detect nerve injuries. However, published literature suggests that its sensitivity and specificity are lower than 100%. The aim of this study was to determine whether a Weber static (main hypothesis) and dynamic test or a Semmes-Weinstein test (secondary hypotheses) could be a more reliable test than the gauze test to rule out any nerve injury and avoid unnecessary wound explorations. Our case series included a total of 102 patients presenting with 123 palmar lacerations and 158 nerve injuries. On arrival at the emergency department, every patient was tested for epicritic sensation at the pulp of the injured and contralateral fingers with the Weber static and dynamic tests and the Semmes-Weinstein monofilament test. All lacerations underwent exploration under anesthetic to rule out nerve injury. The sensitivities of the gauze test, the Weber static test, the Weber dynamic test and the Semmes Weinstein monofilament test were proven to be 82.5%, 98.6%, 97.9% and 86.7% respectively. The specificities of the gauze test, the Weber static test, the Weber dynamic test and the Semmes Weinstein monofilament test were 79%, 79%, 79% and 78.9% respectively. Examination of lacerations to the volar aspect of the hand to rule out any nerve injuries should include a Weber static test instead of a gauze test. A negative Weber static test should not however discourage a surgical exploration of the laceration to rule out tendinous or vascular injury. PMID- 28899561 TI - Letter to Editor regarding "Can intermittent pneumatic compression (IPC) reduce time to surgery for malleolar fractures?" by K.B. Arndt et al. PMID- 28899562 TI - The design, production and clinical application of 3D patient-specific implants with drilling guides for acetabular surgery. AB - An innovative procedure for the development of 3D patient-specific implants with drilling guides for acetabular fracture surgery is presented. By using CT data and 3D surgical planning software, a virtual model of the fractured pelvis was created. During this process the fracture was virtually reduced. Based on the reduced fracture model, patient-specific titanium plates including polyamide drilling guides were designed, 3D printed and milled for intra-operative use. One of the advantages of this procedure is that the personalised plates could be tailored to both the shape of the pelvis and the type of fracture. The optimal screw directions and sizes were predetermined in the 3D model. The virtual plan was translated towards the surgical procedure by using the surgical guides and patient-specific osteosynthesis. Besides the description of the newly developed multi-disciplinary workflow, a clinical case example is presented to demonstrate that this technique is feasible and promising for the operative treatment of complex acetabular fractures. PMID- 28899563 TI - Treating osteomyelitis of major limb amputations with a modified Lautenbach technique. AB - INTRODUCTION: Major lower limb amputation significantly increases the energy cost of walking for patients. Complications such as osteomyelitis may require further surgery, and can lead to shortening of the stump. In these cases, the aim should be to treat infection without shortening the limb further. We present a series of patients with established osteomyelitis of the amputation stump, managed using a modified Lautenbach technique. METHOD: Six patients with either above or below knee amputations, in the practice of a single orthopaedic surgeon, were studied. Ages range from 39 to 64 years, and reasons for amputation included infection, pain, and necrosis. All patients had osteomyelitis in the amputation stump confirmed on MRI. RESULTS: At a mean follow-up of 3.75 years (range 7 months to 6 years) all six patients had no clinical or haematological evidence of infection, and had returned to independent living. Stump length was preserved in all cases, including in one patient who underwent two procedures to ensure complete debridement. CONCLUSIONS: We believe that this case series is the largest so far published regarding this modification of the Lautenbach Procedure. This operation treats infection effectively without further loss of bone length, and no patients so far have developed significant complications. PMID- 28899564 TI - Avoiding delayed diagnosis of significant blunt bowel and mesenteric injuries: Can a scoring tool make the difference? A 7-year retrospective cohort study. AB - INTRODUCTION: Significant blunt bowel and mesenteric injuries (sBBMI) are frequently missed despite the widespread use of computed tomography (CT). Early treatment improves the outcome related to these injuries. The aim of this study was to assess the prevalence of sBBMI, the incidence of delayed diagnosis and to test the performance of the Bowel Injury Prediction Score (BIPS), determined by the white blood cell (WBC) count, presence or absence of abdominal tenderness and CT grade of mesenteric injury. PATIENTS AND METHODS: Single-centre, registry based retrospective cohort study, screening all consecutive trauma patients admitted to Lausanne University Hospital Trauma Centre from 2008 to 2015 after a road traffic accident. All patients with reliable information about the presence or absence of sBBMI who underwent abdominal CT and for whom calculation of the BIPS was possible were included for analysis. The incidence of delayed (>24h after admission) diagnosis in the patient group with sBBMI was determined and the diagnostic performance of the BIPS for sBBMI was assessed. RESULTS: For analysis, 766 patients with reliable information about the presence or absence of sBBMI were included. The prevalence of sBBMI was 3.1% (24/766). In 24% (5/21) of stable trauma patients undergoing CT, a diagnostic delay of more than 24h occurred. Abdominal tenderness (p<0.0001) and CT grade >=4 (p<0.0001) were associated with sBBMI, whereas CT grade 4 alone (p=0.93) and WBC count >=17G/l (p=0.30) were not. A BIPS >=2 had a sensitivity of 89% (95% CI, 67-99), specificity of 89% (95% CI, 86-91), positive likelihood ratio of 8 (95% CI, 6.1-10), negative likelihood ratio of 0.12 (95% CI, 0.03-0.44), positive predictive value (PPV) of 19% (95% CI, 15-24) and negative predictive value (NPV) of 99.7% (95% CI, 98.7-99.9). CT alone identified 79% (15/19) and the BIPS 89% (17/19) of patients with sBBMI (p=0.66). CONCLUSIONS: Diagnostic delays in patients with sBBMI are common (24%), despite the routine use of abdominal CT. Application of the BIPS on the present cohort would have led to a high number of non-therapeutic abdominal explorations without identifying significantly more sBBMI early than CT alone. PMID- 28899565 TI - Local neighbors as positives, regional neighbors as negatives: Competing channels in the relationship between others' income, health, and happiness. AB - That well-being is decreasing in others' income is termed the "relative income hypothesis" (RIH) by scholars of subjective well-being (SWB) and has substantial empirical support. Some studies, however, present evidence of both positive and negative explanatory channels in the relationship between others' income and SWB. We develop a theoretical framework integrating four distinct channels through which neighbors' income can affect utility: public goods, cost of living, expectations of future income, and direct effects (RIH or altruism). We estimate the relationship with SWB data from the U.S. Gallup-Healthways Well-Being Index and median-income data from the American Community Survey for ZIP codes and MSAs. The relationship is proximity-dependent: positive (negative) when using ZIP-code (MSA) median income as reference income, suggesting that positive (negative) channels dominate locally (regionally) and reconciling the literature's seemingly divergent results. These findings are consistent across SWB measures and many health-related indices. Additional analyses support the public-goods and cost-of living channels. PMID- 28899566 TI - Unemployment, drugs and attitudes among European youth. AB - This paper studies changes in the patterns of drug consumption and attitudes towards drugs in relation to sky-high (youth) unemployment rates brought about by the Great Recession. Our analysis is based on data for 28 European countries that refer to young people. We find that the consumption of cannabis and 'new substances' is positively related to increasing unemployment rates. An increase of 1% in the regional unemployment rate is associated with an increase of 0.7 percentage points in the ratio of young people who state that they have consumed cannabis at some point in time. Our findings also indicate that higher unemployment may be associated with more young people perceiving that access to drugs has become more difficult, particularly access to ecstasy, cocaine and heroin. According to young Europeans, when the economy worsens, anti-drug policies should focus on the reduction of poverty and unemployment, and not on implementing tougher measures against users. PMID- 28899567 TI - Spontaneous uterine rupture due to pyometra, a case report. PMID- 28899568 TI - Long-term survival after acute kidney injury following ruptured abdominal aortic aneurysm repair. AB - OBJECTIVE: Acute kidney injury (AKI) is a major complication of ruptured abdominal aortic aneurysm (RAAA). Severe AKI is associated with high morbidity and mortality in the short term. The objective of this study was to determine the association between AKI after RAAA repair and long-term survival. METHODS: We conducted a retrospective cohort study of all patients undergoing RAAA repair in three hospitals between 2004 and 2011. Outcomes were long-term survival after RAAA repair, incidence of postoperative AKI, and chronic dialysis rates. Survival rates were compared between different AKI groups (no AKI, Risk, Injury, Failure) with Kaplan-Meier survival analyses and log-rank tests. Univariable and multivariable Cox regression analyses were carried out to assess the association of survival with AKI, preoperative shock, postoperative shock, and sex. The main analysis focused on the group of patients surviving initial hospital stay. RESULTS: Our study encompassed 362 patients with RAAA. AKI occurred in 267 of 362 patients (74%). At discharge, 267 patients were alive (74%). Median survival in this group was 7.2 years. Survival was not significantly different between the four AKI groups (P = .07). However, the univariable Cox regression analysis demonstrated a significant association between Failure and reduced long-term survival compared with having no AKI (hazard ratio, 1.85; 95% confidence interval, 1.15-2.97). This association did not remain significant after multivariable adjustment. Four patients were discharged with chronic dialysis, and four other patients needed chronic dialysis later after discharge. CONCLUSIONS: This study demonstrates no significant independent association between AKI after RAAA repair and long-term survival. Only a small proportion of patients developed end-stage renal disease at a later stage in life. PMID- 28899569 TI - On the influence of wall calcification and intraluminal thrombus on prediction of abdominal aortic aneurysm rupture. AB - OBJECTIVE: Parameters other than maximum diameter that predict rupture of abdominal aortic aneurysms (AAAs) may be helpful for risk-benefit analysis in individual patients. The aim of this study was to characterize the biomechanical structural characteristics associated with AAA walls to better identify the related mechanistic variables required for an accurate prediction of rupture risk. METHODS: Anterior AAA wall (n = 40) and intraluminal thrombus (ILT; n = 114) samples were acquired from 18 patients undergoing open surgical repair. Biomechanical characterization was performed using controlled circumferential stretching tests combined with a speckle-strain tracking technique to quantify the spatial heterogeneity in deformation and localized strains in the AAA walls containing calcification. After mechanical testing, the accompanying microstructural characteristics of the AAA wall and ILT types were examined using electron microscopy. RESULTS: No significant correlation was found between the AAA diameter and the wall mechanical properties in terms of Cauchy stress (rs = 0.139; P = .596) or stiffness (rs = -0.451; P = .069). Quantification of significant localized peak strains, which were concentrated in the tissue regions surrounding calcification, reveals that peak strains increased by a mean of 174% as a result of calcification and corresponding peak stresses by 18.2%. Four ILT types characteristic of diverse stages in the evolving tissue microstructure were directly associated with distinct mechanical stiffness properties of the ILT and underlying AAA wall. ILT types were independent of geometric factors, including ILT volume and AAA diameter measures (ILT stiffness and AAA diameter [rs = 0.511; P = .074]; ILT stiffness and ILT volume [rs = -0.245; P = .467]). CONCLUSIONS: AAA wall stiffness properties are controlled by the load-bearing capacity of the noncalcified tissue portion, and low stiffness properties represent a highly degraded vulnerable wall. The presence of calcification that is contiguous with the inner wall causes severe tissue overstretching in surrounding tissue areas. The results highlight the use of additional biomechanical measures, detailing the biomechanical-structural characteristics of AAA tissue, that may be a helpful adjunct to improve the accuracy of rupture prediction. PMID- 28899570 TI - Prevalence of iron deficiency without anaemia in inflammatory bowel disease and impact on health-related quality of life. AB - INTRODUCTION: Iron deficiency without anaemia (IDWA) is commonly found in outpatients with inflammatory bowel disease (IBD) in an even higher proportion than anaemia. However, its true prevalence and possible impact on health-related quality of life (HRQoL) are unknown. The objectives of this study were: to establish the prevalence of IDWA, identify possible associated factors and measure their impact on HRQoL. MATERIAL AND METHODS: 127 patients with IBD in an outpatient setting were consecutively included in an observational, descriptive, cross-sectional study. IDWA was defined as ferritin levels of <100 ng/ml with inflammatory activity or <=30 ng/ml without it, with transferrin saturation of <=16%, and with normal haemoglobin levels. HRQoL was assessed using two questionnaires: the IBDQ-9 for symptoms related to IBD and the FACIT-F to measure the presence of fatigue. Fatigue was considered extreme with a score of <=30 points. RESULTS: The prevalence of IDWA was 37%. Variables associated with its occurrence were female gender (OR=2.9; p=.015) and the presence of inflammatory activity (OR=9.4; p=.001). Patients with IDWA presented HRQoL questionnaires with lower overall scores; decreases of 6.6 (p<.001) and 4.3 (p=.037) points in the IBDQ-9 and the FACIT-F were recorded, respectively. In addition, an increase of 29.4% in the presence of extreme fatigue was observed. CONCLUSION: The prevalence of IDWA is considerable in outpatients with IBD. IDWA is associated with female gender and inflammatory activity. It has a clear negative impact on HRQoL. A more active approach is needed to treat this complication. PMID- 28899571 TI - Simultaneous recovery of calcium phosphate granules and methane in anaerobic treatment of black water: Effect of bicarbonate and calcium fluctuations. AB - Calcium phosphate (CaP) granules were discovered in the anaerobic treatment of vacuum collected black water (BW), using upflow anaerobic sludge blanket (UASB) technology. This allows simultaneous recovery of CaP granules and methane in the UASB reactor. However, the role of BW composition on CaP granulation is not yet understood. Moreover, CaP granulation was not observed in previous research on anaerobic treatment of BW, although similar treatment conditions were applied. Therefore, this study shows specifically the influence of bicarbonate and calcium fluctuations in BW on the phosphorus accumulation in the UASB reactor, which directly affects CaP granulation. Without calcium addition, 5% of the total phosphorus (P) fed was found as CaP granules in the reactor (61 mgP g-1dried matter), after 260 days of operation. Simultaneously, 65% of the COD in BW was efficiently converted into methane at 25 degrees C. Variations of bicarbonate and calcium concentrations in raw BW showed a significant influence on phosphorus accumulation in the UASB reactor. Geochemical modelling showed that the increase of soluble calcium from 39 to 54 mg L-1 in BW triggers supersaturation for calcium phosphate precursors (Cax(PO4)y). Concurrently, bicarbonate decreased from 2.7 to 1.2 g L-1, increasing further the ionic activity of calcium. Formation and accumulation of seed particles possibly enhanced CaP granulation. Preliminary results showed that addition of calcium (Ca2+/PO43- molar ratio of 3) increased the accumulation of total P in the UASB reactor to more than 85%. This further increases the granulation rate and consequently, the process feasibility. PMID- 28899572 TI - Hypoglossal nerve palsy in the course of dissection of the internal carotid arteries - Case reports. AB - : Internal carotid artery dissection (ICAD) has become an increasingly recognized cause of cerebrovascular accidents in young and middle-aged patients. We report 2 cases of hypoglossal nerve palsy in the course of dissection of the internal carotid arteries. The first patient was admitted to the Department of Neurology due to swallowing difficulty, speech articulation disorders and numbness of the right half of the tongue for 4 weeks. Extracranial vessel ultrasound (US) and transcranial colour Doppler (TCD) visualized thrombus causing occlusion of the right internal carotid artery (RICA). Angio-CT revealed a compression on right XII nerve and a dissection of the RICA. The second patient was referred to the Department of Neurology due to articulation disorders and swallowing difficulties. On admission, neurological examination revealed tongue deviation towards the right side with evidence of atrophy of the right half of the tongue, deviation of the uvula to the right side, absence of palatal and pharyngeal reflexes, rhinolalia and dysphagia. Vessel imaging was taken using angio-MR showing mural thrombus of the RICA. CONCLUSION: The diagnosis of spontaneous non traumatic dissection of the carotid arteries is a major challenge for clinicians. ICAD must be considered for young and middle-aged patients when severe headache is preceded by the co-existence of focal neurological symptoms. The probability of ICAD increases in the presence of predisposing diseases. The final diagnosis is based on imaging studies: color duplex ultrasound, CT angiography or MR angiography. PMID- 28899573 TI - Split-spectrum processing technique for SNR enhancement of ultrasonic guided wave. AB - Ultrasonic guided wave (UGW) systems are broadly used in several branches of industry where the structural integrity is of concern. In those systems, signal interpretation can often be challenging due to the multi-modal and dispersive propagation of UGWs. This results in degradation of the signals in terms of signal-to-noise ratio (SNR) and spatial resolution. This paper employs the split spectrum processing (SSP) technique in order to enhance the SNR and spatial resolution of UGW signals using the optimized filter bank parameters in real time scenario for pipe inspection. SSP technique has already been developed for other applications such as conventional ultrasonic testing for SNR enhancement. In this work, an investigation is provided to clarify the sensitivity of SSP performance to the filter bank parameter values for UGWs such as processing bandwidth, filter bandwidth, filter separation and a number of filters. As a result, the optimum values are estimated to significantly improve the SNR and spatial resolution of UGWs. The proposed method is synthetically and experimentally compared with conventional approaches employing different SSP recombination algorithms. The Polarity Thresholding (PT) and PT with Minimization (PTM) algorithms were found to be the best recombination algorithms. They substantially improved the SNR up to 36.9dB and 38.9dB respectively. The outcome of the work presented in this paper paves the way to enhance the reliability of UGW inspections. PMID- 28899574 TI - Orbital Implants in Enucleation Surgery: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To compare the motility and complication rates of porous and nonporous implants after enucleation surgery. METHODS: Literature searches of the PubMed and Cochrane Library databases were last performed in February 2017 to identify studies published between 2003 and 2017 on outcomes after enucleation surgeries in which a variety implants were used. The searches were limited to the English language with abstracts and yielded 43 articles, which the Ophthalmic Technology Assessment Committee Oculoplastics and Orbit Panel reviewed for relevancy. Twenty five articles were considered to have met the search strategy, and the panel methodologist assigned ratings to them according to the level of evidence. RESULTS: Only 2 of the 25 articles identified met the criteria for level I evidence. Eighteen of the studies did not assess motility after enucleation surgery, and the 7 that did evaluate this metric involved porous implants. The studies that analyzed this outcome reported favorable results, but the results were not uniformly based on objective analysis. Both porous and nonporous implants were well tolerated, and complication rates were generally low for both types. CONCLUSIONS: In keeping with increasing surgeon preference for porous implants, most studies identified in this literature search involved the use of this type of implant. These implants resulted in excellent motility after enucleation surgery, although many studies did not assess this outcome. Regardless of implant type, major complications were rare, and infection was exceptionally uncommon after enucleation. Given the paucity of data on motility and the absence of direct, objective comparisons of porous and nonporous implants, definitive conclusions about the impact of implant material on motility cannot be made. Since few studies evaluated nonporous implants, direct comparisons cannot be made definitively between implant types, and future investigations are needed to enable a critical assessment. PMID- 28899575 TI - eHealth in integrated care programs for people with multimorbidity in Europe: Insights from the ICARE4EU project. AB - INTRODUCTION: Care for people with multimorbidity requires an integrated approach in order to adequately meet their complex needs. In this respect eHealth could be of help. This paper aims to describe the implementation, as well as benefits and barriers of eHealth applications in integrated care programs targeting people with multimorbidity in European countries, including insights on older people 65+. METHODS: Within the framework of the ICARE4EU project, in 2014, expert organizations in 24 European countries identified 101 integrated care programs based on selected inclusion criteria. Managers of these programs completed a related on-line questionnaire addressing various aspects including the use of eHealth. In this paper we analyze data from this questionnaire, in addition to qualitative information from six programs which were selected as 'high potential' for their innovative approach and studied in depth through site visits. RESULTS: Out of 101 programs, 85 adopted eHealth applications, of which 42 focused explicitly on older people. In most cases Electronic Health Records (EHRs), registration databases with patients' data and tools for communication between care providers were implemented. Percentages were slightly higher for programs addressing older people. eHealth improves care integration and management processes. Inadequate funding mechanisms, interoperability and technical support represent major barriers. CONCLUSION: Findings seems to suggest that eHealth could support integrated care for (older) people with multimorbidity. PMID- 28899576 TI - Neuroscience and everyday life: Facing the translation problem. AB - To enable the impact of neuroscientific insights on our daily lives, careful translation of research findings is required. However, neuroscientific terminology and common-sense concepts are often hard to square. For example, when neuroscientists study lying to allow the use of brain scans for lie-detection purposes, the concept of lying in the scientific case differs considerably from the concept in court. Furthermore, lying and other cognitive concepts are used unsystematically and have an indirect and divergent mapping onto brain activity. Therefore, scientific findings cannot inform our practical concerns in a straightforward way. How then can neuroscience ultimately help determine if a defendant is legally responsible, or help someone understand their addiction better? Since the above-mentioned problems provide serious obstacles to move from science to common-sense, we call this the 'translation problem'. Here, we describe three promising approaches for neuroscience to face this translation problem. First, neuroscience could propose new 'folk-neuroscience' concepts, beyond the traditional folk-psychological array, which might inform and alter our phenomenology. Second, neuroscience can modify our current array of common-sense concepts by refining and validating scientific concepts. Third, neuroscience can change our views on the application criteria of concepts such as responsibility and consciousness. We believe that these strategies to deal with the translation problem should guide the practice of neuroscientific research to be able to contribute to our day-to-day life more effectively. PMID- 28899577 TI - Real-time discrete suboptimal control for systems with input and state delays: Experimental tests on a dehydration process. AB - This article presents a suboptimal control strategy with finite horizon for affine nonlinear discrete systems with both state and input delays. The Dynamic Programming Approach is used to obtain the suboptimal control sequence, but in order to avoid the computation of the Bellman functional, a numerical approximation of this function is proposed in every step. The feasibility of our proposal is demonstrated via an experimental test on a dehydration process and the obtained results show a good performance and behavior of this process. Then in order to demonstrate the benefits of using this kind of control strategy, the results are compared with a non optimal control strategy, particularly with respect to results produced by an industrial Proportional Integral Derivative (PID) Honeywell controller, which is tuned using the Ziegler-Nichols method. PMID- 28899578 TI - Fault detection for piecewise affine systems with application to ship propulsion systems. AB - In this paper, the design approach of non-synchronized diagnostic observer-based fault detection (FD) systems is investigated for piecewise affine processes via continuous piecewise Lyapunov functions. Considering that the dynamics of piecewise affine systems in different regions can be considerably different, the weighting matrices are used to weight the residual of each region, so as to optimize the fault detectability. A numerical example and a case study on a ship propulsion system are presented in the end to demonstrate the effectiveness of the proposed results. PMID- 28899579 TI - CXCL4-induced macrophages in human atherosclerosis. AB - Atherosclerosis is considered an inflammatory disease of the arterial wall. Monocytes and monocyte-derived cells (most often termed macrophages) play an essential role in the formation of atherosclerotic lesions, as they take up lipids leading to subsequent foam cell formation accompanied by release of pro inflammatory cytokines. Similarly, platelets have been discovered to represent an important cell type mediating inflammatory and immune processes in atherogenesis, mainly by secreting chemokines, which are stored in the platelets' alpha granules, upon platelet activation. Therefore, the interaction between monocyte derived cells and platelets is of exceptional importance. In this review, we specifically focus on the chemokine (platelet factor-4, PF4) and its effects on monocytes and monocyte-derived cells. By formation of heterodimers dimers and oligomers with CCL5, CXCL4 induces binding of monocytes cells to endothelial cell and thereby promotes diapedesis of monocytes into the subendothelial space. CXCL4 also affects the differentiation of monocytes as it induces a specific macrophage phenotype, which we suggested to term "M4". For example, CXCL4-induced macrophages irreversibly lose the hemoglobin-haptoglobin scavenger receptor CD163. The combination of CD68, S100A8, and MMP7 turned out to reliably identify M4 macrophages both in vitro and in vivo within atherosclerotic lesions. In human atherosclerotic plaques, M4 macrophages are predominantly present in the adventitia and the intima and their prevalence is associated with plaque instability suggesting that they are a marker of pro-inflammatory activity. Overall, CXCL4-induced M4 macrophages may represent a target for diagnostic and therapeutic interventions in human atherosclerotic disease. PMID- 28899580 TI - The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis. AB - The kynurenine pathway (KP) is the major metabolic route of tryptophan (Trp) metabolism. Indoleamine 2,3-dioxygenase (IDO1), the enzyme responsible for the first and rate-limiting step in the pathway, as well as other enzymes in the pathway, have been shown to be highly regulated by cytokines. Hence, the KP has been implicated in several pathologic conditions, including infectious diseases, psychiatric disorders, malignancies, and autoimmune and chronic inflammatory diseases. Additionally, recent studies have linked the KP with atherosclerosis, suggesting that Trp metabolism could play an essential role in the maintenance of immune homeostasis in the vascular wall. This review summarizes experimental and clinical evidence of the interplay between cytokines and the KP and the potential role of the KP in cardiovascular diseases. PMID- 28899581 TI - Deconstructing Superorganisms and Societies to Address Big Questions in Biology. AB - Social insect societies are long-standing models for understanding social behaviour and evolution. Unlike other advanced biological societies (such as the multicellular body), the component parts of social insect societies can be easily deconstructed and manipulated. Recent methodological and theoretical innovations have exploited this trait to address an expanded range of biological questions. We illustrate the broadening range of biological insight coming from social insect biology with four examples. These new frontiers promote open-minded, interdisciplinary exploration of one of the richest and most complex of biological phenomena: sociality. PMID- 28899583 TI - What could be learned from a decade with standardized remission criteria in schizophrenia spectrum disorders: An exploratory follow-up study. AB - A decade has passed since the standardized remission criteria of schizophrenia spectrum disorders-the Andreasen Criteria-were defined. Over 2000 studies have been published, but only a few describe symptomatic remission over time. In this prospective study we followed patients for 3 and 5years, respectively. The aim was to investigate how different symptoms affect the occurrence of remission and how the remission cut-off level affects remission sustainability. The participants were patients diagnosed with schizophrenia spectrum disorders (DSM IV). First, the importance of each core symptom for remission was examined using the Positive and Negative Syndrome Scale (n=274). Second, we investigated which items affect patients to either go in and out of remission or never achieve remission (n=154). Third, we investigated how the sustainability of remission is affected by a cut-off set to 2 (minimal) and 3 (mild) points, respectively (n=154). All core symptoms affected the occurence of remission, to a higher or lesser extent. Delusions and Hallucinatory behavior contributed the strongest to fluctuation between remission and non-remission, while the contribution of Mannerism and posturing was very marginal. Negative symptoms were enhanced when remission was never achieved. Moreover, the study found that remission duration was significantly longer for the cut-off score 2 rather than 3. The study shows that, over time, remission criteria discriminate between being stable, unstable, or never in remission. Patients with only a minimal occurrence of symptom intensity exhibit a significantly longer remission duration compared to patients with mild symptom intensity, indicating that the treatment goal should be minimal symptom intensity. PMID- 28899582 TI - FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts. AB - BACKGROUND: Previous human and animal studies have demonstrated the ability of exogenously administered basic fibroblast growth factor (FGF2) to act as an antifibrotic agent in the skin. Though the activity of FGF2 as an anti-scarring agent is well-established for fibrotic skin wounds, the mechanisms by which FGF2 exerts these actions are not entirely understood. Canonical FGF2 signaling proceeds in part via FGFR/MAPK pathways in human dermal fibroblasts, and FGF2 has been described to prevent or reverse the fibroblast-to-myofibroblast transition, which is driven by TGFbeta signaling and understood to be an important step in the formation of a fibrotic scar in vivo. Thus, we set out to investigate the antagonistic effects of FGF2 on TGFbeta signaling as well as the broader effects of MAPK inhibition on the TGFbeta-mediated induction of myofibroblast gene expression. OBJECTIVE: To better understand the effects of FGF2 signaling pathways on myofibroblastic gene expression and cell phenotypes. METHODS: Human dermal fibroblasts were cultured in vitro in the presence of FGF2, TGFbeta, and/or MAPK inhibitors, and the effects of these agents were investigated by molecular biology techniques including qRT-PCR, immunofluorescence, Western blot, and flow cytometry. RESULTS: FGF2 inhibited TGFbeta-mediated fibroblast activation, resulting in more rapidly proliferating, spindle-shaped cells, compared to the more slowly proliferating, flatter TGFbeta-treated cells. Treatment with FGF2 also attenuated TGFbeta-mediated increase in expression of myofibroblast markers smooth muscle alpha-actin, calponin, transgelin, connective tissue growth factor, ED-A fibronectin, and collagen I. FGF2-mediated antagonism of the TGFbeta-mediated fibroblast-to-myofibroblast transition was reversed by small molecule inhibition of ERK or JNK, and it was potentiated by inhibition of p38. MAPK inhibition was demonstrated to have qualitatively similar effects even in the absence of exogenous FGF2, and small molecule inhibition of p38 MAPK was sufficient to attenuate TGFbeta-mediated fibroblast activation. CONCLUSIONS: Inhibition of select MAPK signaling pathways can reverse or potentiate anti fibrotic FGF2 effects on human dermal fibroblasts, as well as exert their effects independently of exogenous FGF2 supplementation. PMID- 28899584 TI - Evaluating the past to improve the future - A qualitative study of ICU patients' experiences. AB - BACKGROUND: The recovery period for patients who have been in an intensive care unitis often prolonged and suboptimal. Anxiety, depression and post-traumatic stress disorder are common psychological problems. Intensive care staff offer various types of intensive aftercare. Intensive care follow-up aftercare services are not standard clinical practice in Norway. OBJECTIVE: The overall aim of this study is to investigate how adult patients experience theirintensive care stay their recovery period, and the usefulness of an information pamphlet. METHOD: A qualitative, exploratory research with semi-structured interviews of 29 survivors after discharge from intensive care and three months after discharge from the hospital. RESULTS: Two main themes emerged: "Being on an unreal, strange journey" and "Balancing between who I was and who I am" Patients' recollection of their intensive care stay differed greatly. Continuity of care and the nurse's ability to see and value individual differences was highlighted. The information pamphlet helped intensive care survivors understand that what they went through was normal. CONCLUSIONS: Continuity of care and an individual approach is crucial to meet patients' uniqueness and different coping mechanisms. Intensive care survivors and their families must be included when information material and rehabilitation programs are designed and evaluated. PMID- 28899585 TI - Response to "Re: A Systematic Review and Meta-analysis of the Association Between C-reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease". PMID- 28899586 TI - Dissociative sensibility disorders - A retrospective case series and systematic literature review. AB - CONTEXT: Dissociative disorders present a huge challenge in clinical settings. In contrast to other dissociative symptoms, dissociative sensibility disorders are rarely focused on. OBJECTIVE: To identify the clinical characteristics and outcomes of dissociative sensibility disorders in children and adolescents, and to review the use of diagnostic procedures. DATA SOURCES: For the review, a literature search used Pubmed, Embase, Web of Science, and PubPsych (to 02/2015) and the reference lists of the studies identified. STUDY SELECTION: Screening of titles and abstracts; full-text assessment by two reviewers. DATA SELECTION: The original case series was identified by using the local data register. DATA EXTRACTION: Two reviewers independently reviewed the data and, if they agreed on the relevance, extracted the data. In the original case series, data were extracted retrospectively from the records. RESULTS: Sixteen studies and seven case reports were identified, including 931 cases with dissociative disorders. In 210 cases the patient suffered either from a single sensibility disorder or predominantly from sensibility disorders. We identified thirteen further cases in our cohort. In both groups there was female predominance; the mean age of manifestation was early adolescence. The timing of admissions was variable. In approximately 50% of cases a premorbid stressful life event could be identified. Over 75% of cases had a good prognosis with complete resolution. LIMITATIONS: Retrospective character of our own data collection, partially missing differentiation between the subgroups of dissociative disorders in the reviewed studies. CONCLUSIONS: There is no uniform procedure for diagnostic work-up. The overall short-term prognosis is good. PMID- 28899587 TI - Gradual Onset Diseases: Misperception of Disease Onset. AB - PURPOSE: Gradual onset diseases (eg, carpal tunnel syndrome, cubital tunnel syndrome, and trapeziometacarpal arthrosis) tend to go unnoticed for years. When a slowly progressive disease transitions from asymptomatic to symptomatic, it may seem like an acute event. The primary aim of this study was to determine the percentage of patients who perceive the slowly progressive disease as having started within 1 year. We also hypothesized that (1) there would be no factors associated with perception of an onset of disease within 1 year, more specifically among patients with advanced disease; and (2) there would be no difference in a decision to pursue operative treatment between patients who perceived the onset of the disease to be recent and those who perceived it to be long-standing. METHODS: In this retrospective study, we reviewed the medical records of 732 patients newly diagnosed with carpal tunnel syndrome (n = 114), cubital tunnel syndrome (n = 276), or trapeziometacarpal arthrosis (n = 342), for the onset of symptoms. Multiple factors were assessed for (1) association with perception of disease onset within 1 year, and (2) choice for operative treatment in bivariate and multivariable analyses. RESULTS: A total of 69% of all subjects and 68% of patients with advanced disease perceived the disease as having started within 1 year. A perceived provocation (such as an injury or surgery) was associated with a perception of recent onset. A decision to pursue operative treatment was not different between the 2 groups. CONCLUSIONS: Slowly progressive diseases are often misperceived as relatively new. CLINICAL RELEVANCE: Effective communication strategies are important to ensure that people make choices consistent with their values and not based on misconceptions. PMID- 28899588 TI - Costs Associated With Single-Use and Conventional Sets for Distal Radius Plating. AB - PURPOSE: Volar plating of distal radius fractures is an increasingly common procedure. Presterilized, single-use volar plate fixation sets have been purported to increase operating room efficiency and decrease cost. The purpose of this study was to compare the actual cost of using a conventional set compared with the projected cost of using its single-use counterpart. METHODS: We retrospectively analyzed 30 consecutive cases of volar plate fixation in which conventional instrument sets were used. Hardware and processing costs were calculated for the conventional sets and compared with the projected cost of using single-use sets. RESULTS: The mean total cost of hardware and processing for the conventional sets was $2,728, whereas the projected cost for the single use sets was slightly higher at $2,868. Twenty-three of the 30 cases would have required additional screws not available in the single-use set. The cost of the additional screws needed to supplement the single-use set would have added an average of $282/case. Overall, the combined hardware and processing cost was lower for conventional sets in 25 of the 30 cases. CONCLUSIONS: Although the price of the single-use set is less than the mean charge for use of a conventional set, additional screws not available in the single-use set were required in 77% of cases and consequently rendered the conventional set cheaper in 83% of cases. Stocking the single-use sets with additional screws to reflect the most commonly used screw lengths could make these sets more cost effective in the future. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analysis IV. PMID- 28899589 TI - Trapeziectomy With Suspension-Interposition Arthroplasty for Thumb Carpometacarpal Osteoarthritis: A Randomized Controlled Trial Comparing the Use of Allograft Versus Flexor Carpi Radialis Tendon. AB - PURPOSE: The objective of this randomized controlled trial was to compare the 12 month postoperative Michigan Hand Outcomes Questionnaire (MHQ) total score between patients with osteoarthritis (OA) at the first carpometacarpal (CMC I) joint who underwent trapeziectomy with suspension-interposition arthroplasty using the flexor carpi radialis (FCR) tendon and those receiving a human dermal collagen template (allograft). METHODS: We included 60 patients with CMC I OA who met the indications for surgery. They were randomized into 1 of 2 groups: trapeziectomy using the FCR tendon or trapeziectomy with the allograft for suspension-interposition. Patients completed a set of questionnaires including the MHQ and were clinically assessed at baseline, 6 weeks, and 3, 6, and 12 months after surgery. Complications were recorded. RESULTS: We operated on 29 patients using the FCR tendon; 31 patients received an allograft. Baseline MHQ total scores significantly increased from 51 (95% confidence interval [CI], 46 56) to 83 (95% CI, 78-87) and 53 (95% CI, 47-58) to 76 (95% CI, 69-84) by 12 months in the FCR and allograft groups, respectively. We found similar outcomes for both groups at all follow-up assessments. Five complications occurred in the FCR group, and 10 in the allograft group. Revision surgery was required for one allograft patient. CONCLUSIONS: The use of the FCR tendon or allograft for trapeziectomy with suspension-interposition arthroplasty in patients with CMC I OA leads to similar outcomes with more complications, mainly tendon irritations, associated with the latter. Therefore, we only use the allograft in cases of severe instability requiring a larger amount of suspension-interposition material or for revision procedures after failed suspension-interposition with the FCR tendon. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I. PMID- 28899590 TI - An investigation of co-combustion municipal sewage sludge with biomass in a 20kW BFB combustor under air-fired and oxygen-enriched condition. AB - The behavior of municipal sewage sludge (MSS) with biomass (Guar stalks (GS), Mustard Husk (MH), Prosopis Juliflora Wood (PJW)) has been investigated in a 20kW bubbling fluidized bed (BFB) combustor under both air-fired (A-F) and oxygen enriched (O-E) conditions. The work presented is divided into three parts, first part cover the thermogravimetric analysis (TGA), second part cover the experimental investigation of BFB combustor, and third part covers the ash analysis. TGA was performed with a ratio of 50%MSS/50%biomass (GS, MH, PJW) and results show that 50%MSS/50%GS has highest combustion characteristic factor (CCF). The experimental investigation of BFB combustor was performed for two different ratios of MSS/biomass (50%/50% and 25%/75%) and the combustion characteristics of blends were distinctive under both A-F and O-E condition. Despite 50%MSS/50%GS showing the highest combustion performance in TGA analysis, it formed agglomerates during burning in BFB. Due to this formation of large amount of agglomerates, de-fluidization was observed in the combustor bed after 65-75min in A-F conditions. The rate of de-fluidization increased under O-E condition. The de-fluidization problem disappeared when the share of MSS was reduced to 25%, but small amounts of the agglomerate were still present in the bed. With oxygen enhancement, the combustion efficiency of BFB combustor was improved and flue gasses were found within permissible limit. The maximum conceivable combustion efficiency (97.1%) for BFB combustor was accomplished by using 50% MSS/50%PJW under O-E condition. Results show that a ratio of 25%MSS/75%biomass combusted successfully inside the BFB combustor and extensive work is required for efficient utilization of significant share of MSS with biomass. SEM/EDS analyses were performed for agglomerate produced and for the damaged heater to study the surface morphology and compositions. The elemental heterogeneity of fly ash generated during MSS/biomass combustion was analyzed using Microwave Plasma-Atomic Emission Spectroscopy (MP-AES). PMID- 28899591 TI - Robust assessment of both biochemical methane potential and degradation kinetics of solid residues in successive batches. AB - The well-known batch assay test is used worldwide to determine the biochemical methane potential (BMP) of solid substrates in a single batch but its use to estimate the degradation kinetics may lead to underestimations. To overcome this problem, a different approach was carried out to characterize simultaneously both BMP of solid substrates and their degradation kinetics in successive batches, i.e. after an acclimation period. In a second step, a simple model was developed based on the methane production curve in batch mode for dividing the organic matter of the substrate into three sub-fractions according to their degradation rates (rapid, moderate and slow). The protocol developed was applied to 50 different substrates and a database was built. This database includes: the overall BMP (mL CH4/g VS) and the degradation kinetics for each substrate, i.e. the global specific organic degradation rate (g VS/g VSS.d) along with the 3 sub fractions and their specific degradation rates. The comparison with the BMP from the literature did not highlight significant difference with the BMP measured in this study. Furthermore, the degradation rates seem to be specific characteristics for each substrate and no clear correlation was found between the degradation kinetics and the kind of substrates. The information available in the database will be useful for the design and operation of anaerobic digesters: Optimization of the mix of co-substrates, choice of the applied OLR, simulation of methane production and of the rate of substrate degradation. PMID- 28899592 TI - The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator Has a Role in Predicting Discharge to Post-Acute Care in Total Joint Arthroplasty. AB - BACKGROUND: Patient demand and increasing cost awareness have led to the creation of surgical risk calculators that attempt to predict the likelihood of adverse events and to facilitate risk mitigation. The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator is an online tool available for a wide variety of surgical procedures, and has not yet been fully evaluated in total joint arthroplasty. METHODS: A single-center, retrospective review was performed on 909 patients receiving a unilateral primary total knee (496) or hip (413) arthroplasty between January 2012 and December 2014. Patient characteristics were entered into the risk calculator, and predicted outcomes were compared with observed results. Discrimination was evaluated using the receiver-operator area under the curve (AUC) for 90-day readmission, return to operating room (OR), discharge to skilled nursing facility (SNF)/rehab, deep venous thrombosis (DVT), and periprosthetic joint infection (PJI). RESULTS: The risk calculator demonstrated adequate performance in predicting discharge to SNF/rehab (AUC 0.72). Discrimination was relatively limited for DVT (AUC 0.70, P = .2), 90-day readmission (AUC 0.63), PJI (AUC 0.67), and return to OR (AUC 0.59). Risk score differences between those who did and did not experience discharge to SNF/rehab, 90-day readmission, and PJI reached significance (P < .01). Predicted length of stay performed adequately, only overestimating by 0.2 days on average (rho = 0.25, P < .001). CONCLUSION: The American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator has fair utility in predicting discharge to SNF/rehab, but limited usefulness for 90-day readmission, return to OR, DVT, and PJI. Although length of stay predictions are similar to actual outcomes, statistical correlation remains relatively weak. PMID- 28899593 TI - Radiographic Findings in Patients With Catastrophic Varus Collapse After Total Knee Arthroplasty. AB - BACKGROUND: Catastrophic varus collapse is an uncommon mechanism of failure in primary total knee arthroplasty (TKA). Varus collapse has been associated with obesity and smaller implant sizes. However, to our knowledge, preoperative radiographic characterization of this cohort has not been performed. Therefore, the following study evaluated preoperative alignment and how this correlates with the degree of eventual varus collapse identified in this patient population prior to revision. METHODS: Utilizing our institutional database, 1106 revision TKAs were performed from 2004 to 2017. Of these, 35 patients were revised secondary to tibial varus collapse. Twenty-seven patients had their primary TKA performed at our institution. Coronal alignment of the knee was recorded from anteroposterior knee radiographs. Medial tibial bone loss was recorded at final follow-up. RESULTS: The average body mass index was 38 kg/m2. Twenty-six of 27 patients had a preoperative varus deformity (4.2 degrees varus) and all were corrected to a valgus coronal alignment immediately postoperatively (5.2 degrees valgus, P = .0001). Twenty-four of 27 patients' coronal alignment after varus collapse was within 2 degrees of their preoperative alignment (5.8 degrees varus). Twenty five of 27 patients had radiographic medial tibial bone loss prior to varus collapse. CONCLUSION: Tibial varus collapse in an uncommon cause of failure after primary TKA. Preoperative varus deformity, postoperative medial tibial bone loss, and obesity were common findings in this series of patients. Therefore, increased tibial stem lengths should be considered in patients with a preoperative varus deformity, small tibial implant size, and a body mass index >=35 kg/m2 undergoing primary TKA. PMID- 28899594 TI - Delayed Detection of Spontaneous Bilateral Tubal Ectopic Pregnancies After Methotrexate Treatment. AB - BACKGROUND: Bilateral tubal ectopic pregnancies are a rare subset of ectopic pregnancy that can pose a diagnostic dilemma for clinicians. There is no distinct clinical presentation for bilateral tubal ectopic pregnancies, although they are typically associated with assistive reproductive techniques. In addition, there is no single diagnostic feature to help clinicians delineate bilateral tubal ectopic pregnancies from other types of ectopic pregnancy prior to passing the discriminatory zone (such as heterotopic pregnancy or twin ectopic [two gestational sacs in one tube]). Diagnosis is typically made via direct visualization intraoperatively and therefore treatment is usually surgical. CASE REPORT: We present a case of spontaneous bilateral tubal ectopic pregnancies diagnosed 7 days apart via transvaginal ultrasound. The patient presented to the emergency department with pelvic pain on the contralateral side of her previously diagnosed ectopic pregnancy and vaginal spotting. Bilateral adnexal masses were visualized on ultrasound and her serum beta-human chorionic gonadotropin level had a 5.9% decline from day 4 to day 7 after methotrexate administration 7 days prior; gynecology was consulted. The patient was successfully treated with an additional dose of intramuscular methotrexate without any complications. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The implications of this case suggest that diagnosis of bilateral tubal ectopic pregnancies requires clinicians to have a high level of suspicion in any pregnant female with a suspected or known ectopic pregnancy who presents with pelvic pain regardless of prior diagnosis or treatment. PMID- 28899595 TI - Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1. AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period. PMID- 28899596 TI - FRAX vs CAROC for the Canadian Imaging Physician: An Existential Dilemma. PMID- 28899598 TI - Polycyclic aromatic hydrocarbons (PAHs) in sediment and sea urchin (Echinometra mathaei) from the intertidal ecosystem of the northern Persian Gulf: Distribution, sources, and bioavailability. AB - The distribution, sources and bioavailability of polycyclic aromatic hydrocarbons (PAHs) in sediment and sea urchin (Echinometra mathaei) from the intertidal zone of the northern Persian Gulf were investigated. Total PAH concentrations varied from 12.8 to 81.25 and from 16.7 to 35 MUgKg-1 dry weight in sediment and Echinometra mathaei, respectively. The PAH concentrations can be classified as low. Source identification and apportionment using diagnostic ratios and principal component analysis demonstrate that the combustion of fossil fuels, road traffic, combustion of natural gas and biomass, and oil spill could be considered as the main sources of PAH contamination. The first PAH biota-sediment accumulation factors (BSAF) data from sediment to Echinometra mathaei in the intertidal zone of the northern Persian Gulf were calculated, indicating accumulation of both lower and higher molecular weight PAHs, with a preferential accumulation of lower molecular weight PAHs. PMID- 28899597 TI - Playing Well with Others: Extrinsic Cues Regulate Neural Progenitor Temporal Identity to Generate Neuronal Diversity. AB - During neurogenesis, vertebrate and Drosophila progenitors change over time as they generate a diverse population of neurons and glia. Vertebrate neural progenitors have long been known to use both progenitor-intrinsic and progenitor extrinsic cues to regulate temporal patterning. In contrast, virtually all temporal patterning mechanisms discovered in Drosophila neural progenitors (neuroblasts) involve progenitor-intrinsic temporal transcription factor cascades. Recent results, however, have revealed several extrinsic pathways that regulate Drosophila neuroblast temporal patterning: nutritional cues regulate the timing of neuroblast proliferation/quiescence and a steroid hormone cue that is required for temporal transcription factor expression. Here, we discuss newly discovered extrinsic cues regulating neural progenitor temporal identity in Drosophila, highlight conserved mechanisms, and raise open questions for the future. PMID- 28899599 TI - Naturally Occurring Radioactive Material (NORM) in seawater of the northern Arabian Gulf - Baseline measurements. AB - This study focuses on creating baseline for 238U, 235U, 234U, 210Pb, 210Po and 40K concentrations in the northern Arabian Gulf. The respective concentration ranges were 0.047-0.050, 0.00186-0.00198, 0.054-0.057, 0.00085-0.00092, 0.00051 0.00062 and 18.6-19.1Bql-1. These results suggest that the levels are generally comparable to other marine waters in the northern hemisphere. There were no hot spots observed from oil and gas industry. These data will serve as a baseline to gauge possible future inputs of TENORMs in the northern Gulf. A positive and linear correlation was observed between 238,234U, 40K isotopes and seawater salinity. The results also suggest significant fractionation between 210Po and 210Pb, attributed to rapid removal of 210Po by biota compared to 210Pb. The mean residence time for 210Po in the study area was 371days. The 234U/238U and 238U/235U activity ratios in seawater samples vary between 1.14-1.15, and 0.038 0.040. The 234U/238U and 235U/238U ratio is similar to the expected composition of seawater (1.148+/-0.002) and 0.0462. PMID- 28899601 TI - Baclofen Toxicity in Kidney Disease. AB - Baclofen, a commonly prescribed muscle relaxant, is primarily excreted via the kidneys; toxicity is a potentially serious adverse outcome in patients with decreased kidney function. We describe a patient with end-stage kidney disease receiving hemodialysis who developed neurotoxicity and hemodynamic instability after receiving baclofen for muscle spasms. In this case, prompt recognition of baclofen toxicity and urgent hemodialysis were effective in reversing this toxicity. This case is used to examine the pharmacokinetics and pathophysiology of baclofen toxicity and discuss appropriate diagnosis and management of baclofen toxicity. We recommend reducing the baclofen dose in patients who have moderately reduced kidney function (estimated glomerular filtration rate, 30 60mL/min/1.73m2) and avoiding use in patients with severely reduced kidney function (estimated glomerular filtration rate < 30mL/min/1.73m2) or on renal replacement therapy. PMID- 28899602 TI - An Increasingly Complex Relationship Between Salt and Water. PMID- 28899600 TI - Rebuilding Chromosomes After Catastrophe: Emerging Mechanisms of Chromothripsis. AB - Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase. Chromothripsis scars the cancer genome with localized DNA rearrangements that frequently generate extensive copy number alterations, oncogenic gene fusion products, and/or tumor suppressor gene inactivation. Here we review emerging mechanisms underlying chromothripsis with a focus on the contribution of cell division errors caused by centromere dysfunction. PMID- 28899603 TI - Anaemia, but not iron deficiency, is associated with clinical symptoms and quality of life in patients with severe heart failure and palliative home care: A substudy of the PREFER trial. AB - BACKGROUND: To explore the relationships between anaemia or iron deficiency (ID) and symptoms, quality of life (QoL), morbidity, and mortality. METHODS: A post hoc, non-prespecified, explorative substudy of the prospective randomized PREFER trial. One centre study of outpatients with severe HF and palliative need managed with advanced home care. Associations between anaemia, ID, and the Edmonton Symptom Assessment Scale (ESAS), Euro QoL (EQ-5D), Kansas City Cardiomyopathy Questions (KCCQ) were examined only at baseline but at 6months for morbidity and mortality. RESULTS: Seventy-two patients (51 males, 21 females), aged 79.2+/ 9.1years. Thirty-nine patients (54%) had anaemia and 34 had ID (47%). Anaemia was correlated to depression (r=0.37; p=0.001), anxiety (r=0.25; p=0.04), and reduced well-being (r=0.26; p=0.03) in the ESAS; mobility (r=0.33; p=0.005), pain/discomfort (r=0.27; p=0.02), and visual analogue scale of health state (r= 0.28; p=0.02) in the EQ-5D; and physical limitation (r=-0.27; p=0.02), symptom stability; (r=-0.43; p<0.001); (r=-0.25; p=0.033), social limitation;(r=-0.26; p=0.03), overall summary score; (r=-0.24, p=0.046) and clinical summary score; (r=-0.27; p=0.02) in the KCCQ. ID did not correlate to any assessment item. Anaemia was univariably associated with any hospitalization (OR: 3.0; CI: 1.05 8.50, p=0.04), but not to mortality. ID was not significantly associated with any hospitalization or mortality. CONCLUSION: Anaemia, but not ID, was associated although weakly with symptoms and QoL in patients with advanced HF and palliative home care. PMID- 28899605 TI - World Apheresis Association Registry Update. PMID- 28899604 TI - Clinical and epidemiological use of nested PCR targeting the repetitive element IS1111 associated with the transposase gene from Coxiella burnetii. AB - Q fever is a worldwide zoonosis caused by Coxiella burnetii-a small obligate intracellular Gram-negative bacterium found in a variety of animals. It is transmitted to humans by inhalation of contaminated aerosols from urine, feces, milk, amniotic fluid, placenta, abortion products, wool, and rarely by ingestion of raw milk from infected animals. Nested PCR can improve the sensitivity and specificity of testing while offering a suitable amplicon size for sequencing. Serial dilutions were performed tenfold to test the limit of detection, and the result was 10* detection of C. burnetti DNA with internal nested PCR primers relative to trans-PCR. Different biological samples were tested and identified only in nested PCR. This demonstrates the efficiency and effectiveness of the primers. Of the 19 samples, which amplify the partial sequence of C. burnetii, 12 were positive by conventional PCR and nested PCR. Seven samples-five spleen tissue samples from rodents and two tick samples-were only positive in nested PCR. With these new internal primers for trans-PCR, we demonstrate that our nested PCR assay for C. burnetii can achieve better results than conventional PCR. PMID- 28899606 TI - Is tissue engineering of patient-specific oral mucosa grafts the future of urethral reconstruction? PMID- 28899607 TI - The scholarly productivity and work environments of academic pharmacists. AB - BACKGROUND: Productive faculty are key to generating new knowledge and advancing pharmacy practice. The work environments of academic pharmacists are critical to their vitality, commitment, and longevity. OBJECTIVES: To (1) identify correlates of faculty scholarly productivity and teaching effectiveness, considering personal and environmental characteristics; (2) determine the relationship between a faculty's perception of organizational citizenship behaviors they witness with the organizational culture of their employing college/school of pharmacy; and (3) describe the relationship between organizational climate, job satisfaction, and commitment of academic pharmacists. METHODS: A self administered survey was disseminated to a random sample of U.S. academic pharmacists acquired from AACP list-servs. The survey measured perceptions of their organization's culture, the organizational citizenship behaviors they witness at their institution, their job satisfaction, teaching load and productivity, and scholarly productivity based upon peer-reviewed scholarly papers accepted. Both bivariate and multivariate (regression) procedures were employed to identify factors most responsible for explaining academic pharmacist's work environment. RESULTS: Responses were received from 177 of 600 survey recipients. Faculty reported having had accepted 10.9 +/- 13.6 papers in peer-reviewed journals during the previous 5 years, with most of those in journals with relatively low Impact Factor scores. Faculty productivity was related to type of academic institution employed, teaching effectiveness, job satisfaction, and other factors. Organizational citizenship behaviors and organizational culture was seen similarly by faculty of varied ranks and experience levels. Commitment to remain at the current college/school of pharmacy was highly associated with culture, climate, and job satisfaction conditions. CONCLUSIONS: The results provided evidence for a strong connection or nexus between teaching and research effectiveness. Organizational culture of academic pharmacy programs is highly important for faculty vitality and commitment. The findings should be helpful for academic leaders in devising programs for mentoring, development, and retention of faculty. PMID- 28899608 TI - [The new AEP: innvoation, investigation, union and indepenence. Leadership and generational handover]. PMID- 28899610 TI - Nosocomial-acquired and community-onset Clostridium difficile infection at an academic hospital in Italy: Epidemiology, recurrences and toxin genes distribution. AB - Toxinogenic Clostridium difficile infection (CDI) is a leading cause of infectious diarrhea. In this retrospective cohort study the molecular epidemiology of hospital-acquired and community-associated CDI was investigated in patients admitted to a tertiary care hospital. CD in stools samples was revealed by a two steps diagnostic algorithm, firstly screening for positivity to GDH antigen and thereafter RT-PCR analysis. Increased CDI incidence was observed ranging from 1.70episodes/10000patient-days in the 1st year, to 2.62 in the 2nd year, mostly hospitalized in the medicine wards, followed by outpatients (5.74 and 5.12episodes/10.000patient-days respectively). CDI positive were older than CDI negative patients and presented increased trend of diarrhea episodes as the patients' age increased. RT-PCR positive patients (n degrees = 314) were classified according to the CD toxin producing genes in three groups (1-3, carrying tcdB, both tcdB and cdt, and the two genes plus the deletion Delta117 of tcdC, respectively). The incidence of the group 2 and 3 increased statistically with the age of the patients showing correlation with the gender. Higher frequency of patients belonging to group 1 and group 3 was observed in the medical wards. Of note was the high incidence of group 3 in outpatients. Interestingly, patients with previous health care contacts had higher risk (RR = 1.88) of being infected by CD strains with higher toxicity than community patients. Recurrence rate was 15.9%. In conclusion the knowledge of the toxigenic profiles and of their relationships to gender, age and wards distribution may help the clinicians in the clinical management of the disease. PMID- 28899611 TI - Normal uric acid levels in nascent metabolic syndrome patients residing in northern California. PMID- 28899609 TI - Constructing Experience: Event Models from Perception to Action. AB - Mental representations of everyday experience are rich, structured, and multimodal. In this article we consider the adaptive pressures that led to human construction of such representations, arguing that structured event representations enable cognitive systems to more effectively predict the trajectory of naturalistic everyday activity. We propose an account of how cortical systems and the hippocampus (HPC) interact to construct, maintain, and update event representations. This analysis throws light on recent research on story comprehension, event segmentation, episodic memory, and action planning. It also suggests how the growing science base can be deployed to diagnose impairments in event perception and memory, and to improve memory for everyday events. PMID- 28899612 TI - The Schizotypal Personality Questionnaire-Brief lacks measurement invariance across three countries. AB - The Schizotypal Personality Questionnaire-Brief (SPQ-B) is a commonly-used tool for measuring schizotypal personality traits and due to its wide application, its cross-cultural validity is of interest. Previous studies suggest that the SPQ-B either has a three- or four-factor structure, but the majority of studies have been conducted in Western contexts and little is known about the psychometric properties of the scale in other populations. In this study factorial invariance testing across three cultural contexts-Australia, China and Chile was conducted. In total, 729 young adults (Mean age = 23.99 years, SD = 9.87 years) participated. Invariance testing did not support the four-factor model across three countries. Confirmatory Factor Analyses revealed that neither the four- nor three-factor model had strong fit in any of the settings. However, in comparison with other competing models, the four-factor model showed the best for the Australian sample, while the three-factor model was the most reasonable for both Chinese and Chilean samples. The reliability of the SPQ-B scores, estimated with Omega, ranged from 0.86 to 0.91. These findings suggest that the SPQ-B factors are not consistent across different cultural groups. We suggest that these differences could be attributed to potential confounding cultural and translation issues. PMID- 28899613 TI - Psychiatric comorbidity pattern in treatment-seeking veterans. AB - This study investigated comorbidity patterns in treatment-seeking veterans and currently-serving Canadian Forces members of an outpatient mental health clinic from September 2006-September 2014. Using a retrospective cohort design, latent class analysis was conducted to determine latent classes of comorbidity (including posttraumatic stress disorder [PTSD], major depressive disorder [MDD], generalized anxiety disorder, panic disorder, and alcohol use disorder [AUD]). Multiple logistic regression was used to determine which covariates (age, gender, number of deployments, and service duration) were predictors of latent class membership. Among the 486 participants, 79.2% had more than one probable mental health condition. The most common comorbidity was PTSD and MDD (61.5%), followed by PTSD and GAD (52.3%). Among those with PTSD, almost all (95%) had a subsequent condition, predominantly MDD (82.6% of those with PTSD had MDD). A two-class model was the best fitting model with a high comorbidity and a low comorbidity class. Older age and shorter service duration significantly increased the probability of being in the high comorbidity class when not controlling for member status. Results showed that treatment-seeking veterans and military personnel have high rates of comorbidity, particularly alongside PTSD. Therefore, it is critical for clinicians to be able to assess and treat comorbidity. PMID- 28899614 TI - Measuring pathology using the PANSS across diagnoses: Inconsistency of the positive symptom domain across schizophrenia, schizoaffective, and bipolar disorder. AB - Although the Positive and Negative Syndrome Scale (PANSS) was developed for use in schizophrenia (SZ), antipsychotic drug trials use the PANSS to measure symptom change also for bipolar (BP) and schizoaffective (SA) disorder, extending beyond its original indications. If the dimensions measured by the PANSS are different across diagnoses, then the same score change for the same drug condition may have different meanings depending on which group is being studied. Here, we evaluated whether the factor structure in the PANSS was consistent across schizophrenia (n = 3647), bipolar disorder (n = 858), and schizoaffective disorder (n = 592). Along with congruency coefficients, Hancock's H, and Jaccard indices, we used target rotations and statistical tests of invariance based on confirmatory factor models. We found the five symptom dimensions measured by the 30-item PANSS did not generalize well to schizoaffective and bipolar disorders. A model based on an 18-item version of the PANSS generalized better across SZ and BP groups, but significant problems remained in generalizing some of the factors to the SA sample. Schizophrenia and bipolar disorder showed greater similarity in factor structure than did schizophrenia and schizoaffective disorder. The Anxiety/Depression factor was the most consistent across disorders, while the Positive factor was the least consistent. PMID- 28899615 TI - Metrology for decommissioning nuclear facilities: Partial outcomes of joint research project within the European Metrology Research Program. AB - Decommissioning of nuclear facilities incurs high costs regarding the accurate characterisation and correct disposal of the decommissioned materials. Therefore, there is a need for the implementation of new and traceable measurement technologies to select the appropriate release or disposal route of radioactive wastes. This paper addresses some of the innovative outcomes of the project "Metrology for Decommissioning Nuclear Facilities" related to mapping of contamination inside nuclear facilities, waste clearance measurement, Raman distributed temperature sensing for long term repository integrity monitoring and validation of radiochemical procedures. PMID- 28899616 TI - Risk factors for dental problems: Recommendations for oral health in infancy. AB - Primary care providers, gynaecologists and paediatricians have to be aware of the importance of oral health in infancy and possible consequences for child's development, growth, health and quality of life. Oral diseases, particularly dental caries, developmental defects of the dental tissues and periodontal or orthodontic issues have a complex and interrelated aetiology with common, primarily behavioral based risk factors. A sugar-rich diet is the key risk factor with detrimental consequences for general and oral health, particularly in combination with an insufficient oral hygiene. Therefore, daily tooth brushing with fluoride toothpaste and reducing of sugar intake are the key pillars to prevent oral diseases, including a positive effect on numerous chronic diseases. Future preventive approaches should focus on pregnant women and mothers of infants with a common vision of health and a shared responsibility for children's oral health care to promote healthy lifestyles and self-care practices in families. PMID- 28899617 TI - Better medicines for neonates: Improving medicine development, testing, and prescribing. AB - Pharmacotherapy is a powerful tool to improve the outcome of neonates. Unfortunately, the potential health impact of pharmacotherapy in neonates remains underexplored. This necessitates a structured approach to go beyond the current practice of trial and error, reflected in off-label prescription. The existing regulatory framework hereby provides a structure to reflect about aspects like pharmacokinetic models for dose selection and outcome assessment, including long term safety. Future medicine development should also be driven by neonatal needs, diseases and pathophysiology, since surfactant is the latest product developed for preterm neonates. The potential impact is illustrated by ongoing repurposing (propranolol, allopurinol, erythropoietin, Insulin-like Growth Factor-1) projects. Clinical researchers will be crucial to close the knowledge gap by developing dose selection tools and outcome assessment tools and by exploring pathophysiological mechanisms. The final step of such a structured approach cycle is the subsequent translation of accumulated knowledge into improved prescribing. PMID- 28899618 TI - Smell and taste in the preterm infant. AB - Olfaction and gustation are critical for the enjoyment of food but also have important metabolic roles, initiating the cephalic phase response that sets in train secretion of hormones important for metabolism and digestion before any food is actually ingested. Smell and taste receptors are functional in the fetus and there is evidence for antenatal learning of odours. Despite enteral nutrition and metabolism being major issues in the care of very preterm infants, often little consideration is given to the potential role of smell and taste in supporting these processes, or in the role they may have in encoding hypothalamic circuitry in a way that promotes healthy metabolism in the post-neonatal period. This review will discuss the evidence for the role of smell and taste in the newborn infant. PMID- 28899619 TI - First do the experiment: Do computerised interpretation of cardiotocography and other widely used interventions improve newborn outcomes? AB - The introduction of continuous electronic fetal heart rate monitoring (EFM) in labour has coincided with a steady and remarkable fall in perinatal mortality. Whether this is cause or coincidence remains unclear because randomised trials have been underpowered. Attempts to improve the sensitivity and specificity of fetal compromise detection using fetal blood sampling and pH measurement, pulse oximetry, and fetal electrocardiogram analysis have failed to provide evidence of additional value in randomised trials. Recently, litigation to obtain compensation for obstetric and midwifery error, often reported to be failure to recognise abnormal EFM traces, has escalated. The hypothesis that computerised heart rate pattern recognition could reduce adverse outcomes was tested in a randomised controlled trial of 46,000 labours but showed no benefit. It seems that complicating risk factors such as fetal growth restriction, meconium liquor, pyrexia in labour, and excessive use of oxytocin, are more important than previously realised. PMID- 28899620 TI - The Action Radius of Oxytocin Release in the Mammalian CNS: From Single Vesicles to Behavior. AB - The hypothalamic neuropeptide oxytocin (OT) has attracted the attention both of the scientific community and a general audience because of its prosocial effects in mammals, and OT is now seen as a facilitator of mammalian species propagation. Furthermore, OT is a candidate for the treatment of social deficits in several neuropsychiatric and neurodevelopmental conditions. Despite such possibilities and a long history of studies on OT behavioral effects, the mechanisms of OT actions in the brain remain poorly understood. In the present review, based on anatomical, biochemical, electrophysiological, and behavioral studies, we propose a novel model of local OT actions in the central nervous system (CNS) via focused axonal release, which initiates intracellular signaling cascades in specific OT sensitive neuronal populations and coordinated brain region-specific behaviors. PMID- 28899621 TI - Hepatocellular carcinoma metastasis to sphenoid and cavernous sinus: An unexpected cause of ptosis. PMID- 28899622 TI - E-health in inflammatory bowel diseases: More challenges than opportunities? AB - Patients with inflammatory bowel disease need close monitoring for an optimal disease management. For this, e-health technologies are promising tools. But the current evidence for the implementation of e-health in inflammatory bowel disease is weak. For this a critical evaluation of the existing evidence is presented. Furthermore some essential conditions need to be full-filled. We need a robust digital infrastructure that is workable for the patient and the healthcare provider. Important legal issues need to be solved to protect the patient. And the e-health technologies will have to proof their durability, feasibility and acceptance for the patient on the long term. PMID- 28899623 TI - TYMS Gene Polymorphisms in Breast Cancer Patients Receiving 5-Fluorouracil-Based Chemotherapy. PMID- 28899624 TI - Desiring assemblages: A case for desire over pleasure in critical drug studies. AB - While critical drug researchers have long pushed for an acknowledgement of pleasure in discourses of drug use, few have explored the alternative possibilities offered by Deleuze and Guattari's concept of desire. In this paper I map out some of the conceptual differences between pleasure and desire and explore the opportunities opened up by attending more closely to desire in critical drug studies. I suggest that while discourses of pleasure do make an important intervention into and against dominant narratives of risk, harm, and addiction, they may inadvertently be working to keep in place the very binaries and forms of neoliberal western subjectivity that support those narratives. I argue that a Deleuzo-Guattarian ontology of desire is a better tool with which to make sense of the complex relations that form between drugs and bodies, challenge medical and criminal responses to drug use, and bring forth assemblages that enhance, rather than diminish, bodily capacities. PMID- 28899625 TI - Cost-effectiveness of HPV vaccination in the context of high cervical cancer incidence and low screening coverage. AB - BACKGROUND: Estonia has high cervical cancer incidence and low screening coverage. We modelled the impact of population-based bivalent, quadrivalent or nonavalent HPV vaccination alongside cervical cancer screening. METHODS: A Markov cohort model of the natural history of HPV infection was used to assess the cost effectiveness of vaccinating a cohort of 12-year-old girls with bivalent, quadrivalent or nonavalent vaccine in two doses in a national, school-based vaccination programme. The model followed the natural progression of HPV infection into subsequent genital warts (GW); premalignant lesions (CIN1-3); cervical, oropharyngeal, vulvar, vaginal and anal cancer. Vaccine coverage was assumed to be 70%. A time horizon of 88years (up to 100years of age) was used to capture all lifetime vaccination costs and benefits. Costs and utilities were discounted using an annual discount rate of 5%. RESULTS: Vaccination of 12-year old girls alongside screening compared to screening alone had an incremental cost effectiveness ratio (ICER) of ?14,007 (bivalent), ?14,067 (quadrivalent) and ?11,633 (nonavalent) per quality-adjusted life-year (QALY) in the base-case scenario and ranged between ?5367-21,711, ?5142-21,800 and ?4563-18,142, respectively, in sensitivity analysis. The results were most sensitive to changes in discount rate, vaccination regimen, vaccine prices and cervical cancer screening coverage. CONCLUSION: Vaccination of 12-year-old girls alongside current cervical cancer screening can be considered a cost-effective intervention in Estonia. Adding HPV vaccination to the national immunisation schedule is expected to prevent a considerable number of HPV infections, genital warts, premalignant lesions, HPV related cancers and deaths. Although in our model ICERs varied slightly depending on the vaccine used, they generally fell within the same range. Cost-effectiveness of HPV vaccination was found to be most dependent on vaccine cost and duration of vaccine immunity, but not on the type of vaccine used. PMID- 28899626 TI - Influenza A haemagglutinin specific IgG responses in children and adults after seasonal trivalent live attenuated influenza vaccination. AB - Influenza is a major respiratory pathogen and vaccination is the main method of prophylaxis. In 2012, the trivalent live attenuated influenza vaccine (LAIV3) was licensed in Europe for use in children. Vaccine-induced antibodies directed against the main viral surface glycoprotein, haemagglutinin (HA), play an important role in virus neutralization through different mechanism. The objective of this study was to dissect the HA specific antibody responses induced after LAIV3 immunization to the influenza A viruses in children and adults. Plasma was collected from 20 children and 20 adults pre- and post-LAIV3 vaccination (up to ayear) and analysed by the haemagglutination inhibition (HI) and ELISA assays. We found that LAIV3 boosted the HA specific IgG response against the head and the full-length of H3N2 in children, but not adults. Adults had higher levels of pre existing stalk antibodies (towards H3N2 and H1N1), but these were not boosted by LAIV3. Importantly, we observed a trend in boosting of H1N1 HA stalk specific antibodies in children after LAIV3. Whereas, heterosubtypic H5 and H7 full-length HA specific antibodies were not boosted in either children or adults. In conclusion, LAIV3 elicited H3-head and low levels of H1 stalk specific antibody responses in children, supporting the prophylactic use of LAIV in children. PMID- 28899627 TI - Passive, health center-based assessment of adverse events following oral cholera immunization in Nampula city, Mozambique. PMID- 28899629 TI - What is 'confidence' and what could affect it?: A qualitative study of mothers who are hesitant about vaccines. AB - BACKGROUND: Public confidence in immunization is critical to maintaining high vaccine-coverage rates needed to protect individuals and communities from vaccine preventable diseases. Recent attention has been placed on factors influencing confidence in vaccination in the US and globally, but comprehensive understanding of what drives or hinders confidence in childhood vaccination is yet to be reached. As such, assessing parents' confidence in childhood vaccination and the ways in which educational materials affect confidence is needed. OBJECTIVE: We sought to (1) learn how mothers who are hesitant about vaccination characterize confidence in health-related products for young children, including the recommended vaccines; (2) gain insights on what influences vaccine confidence beliefs; and (3) assess whether short, education materials affect parental confidence in childhood vaccinations. METHODS: Eight moderator-lead focus groups (n=61), stratified by socioeconomic status, were undertaken with mothers of children 5years of age of less who are hesitant about vaccines. Four of the groups were held in the Philadelphia, PA area and four were held in the San Francisco/Oakland, CA area. Three educational material pairs, each consisting of a 2-3min video and an infographic poster about an immunization-related topic, were reviewed and assessed for influence on confidence. RESULTS: Qualitative data analysis was used to identify overarching themes across the focus groups. Themes, insights, and illustrative quotes were identified and provided for each of the major discussion areas: primary health concerns for young children; confidence beliefs and perceptions, including for recommended vaccines; facilitators and barriers to confidence; and reactions to the educational materials. CONCLUSIONS: Results provide helpful insights into how mothers who are hesitant about vaccines perceive confidence in childhood vaccines and health-related products, suggestions for how to improve confidence, and support for the value and use of short videos as part of vaccination education efforts. Findings can aid those developing vaccination education materials and resources designed to foster vaccine confidence. PMID- 28899628 TI - A novel approach to a rabies vaccine based on a recombinant single-cycle flavivirus vector. AB - The RepliVax(r) vaccine (RV) platform is based on flavivirus genomes that are rationally attenuated by deletion. These single-cycle RV vaccine candidates targeting flavivirus pathogens have been demonstrated to be safe, highly immunogenic, and efficacious in animal models, including non-human primates. Here we show utility of the technology for delivery of a non-flavivirus immunogen by engineering several West Nile-based RV vectors to express full-length rabies virus G protein. The rabies virus G protein gene was incorporated in place of different West Nile structural protein gene deletions. The resulting RV-RabG constructs were demonstrated to replicate to high titers (8 log10 infectious particles/ml) in complementing helper cells. Following infection of normal cells, they provided efficient rabies virus G protein expression, but did not spread to surrounding cells. Expression of rabies virus G protein was stable and maintained through multiple rounds of in vitro passaging. A sensitive neurovirulence test in 2-3 day old neonatal mice demonstrated that RV-RabG candidates were completely avirulent indicative of high safety. We evaluated the RV-RabG variants in several animal models (mice, dogs, and pigs) and demonstrated that a single dose elicited high titers of rabies virus-neutralizing antibodies and protected animals from live rabies virus challenge (mice and dogs). Importantly, dogs were protected at both one and two years post-immunization, demonstrating durable protective immunity. The data demonstrates the potential of the RepliVax(r) technology as a potent vector delivery platform for developing vaccine candidates against non flavivirus targets. PMID- 28899630 TI - Protection against infectious bronchitis virus by spike ectodomain subunit vaccine. AB - The avian coronavirus infectious bronchitis virus (IBV) S1 subunit of the spike (S) glycoprotein mediates viral attachment to host cells and the S2 subunit is responsible for membrane fusion. Using IBV Arkansas-type (Ark) S protein histochemistry, we show that extension of S1 with the S2 ectodomain improves binding to chicken tissues. Although the S1 subunit is the major inducer of neutralizing antibodies, vaccination with S1 protein has been shown to confer inadequate protection against challenge. The demonstrated contribution of S2 ectodomain to binding to chicken tissues suggests that vaccination with the ectodomain might improve protection compared to vaccination with S1 alone. Therefore, we immunized chickens with recombinant trimeric soluble IBV Ark-type S1 or S-ectodomain protein produced from codon-optimized constructs in mammalian cells. Chickens were primed at 12days of age with water-in-oil emulsified S1 or S ectodomain proteins, and then boosted 21days later. Challenge was performed with virulent Ark IBV 21days after boost. Chickens immunized with recombinant S ectodomain protein showed statistically significantly (P<0.05) reduced viral loads 5days post-challenge in both tears and tracheas compared to chickens immunized with recombinant S1 protein. Consistent with viral loads, significantly reduced (P<0.05) tracheal mucosal thickness and tracheal lesion scores revealed that recombinant S-ectodomain protein provided improved protection of tracheal integrity compared to S1 protein. These results indicate that the S2 domain has an important role in inducing protective immunity. Thus, including the S2 domain with S1 might be promising for better viral vectored and/or subunit vaccine strategies. PMID- 28899631 TI - Biochemical differences in the mass and activity tests of lipoprotein-associated phospholipase A2 explain the discordance in results between the two assay methods. AB - OBJECTIVES: There are two platforms for the detection of Lp-PLA2 in sera or plasmas: by its enzymatic activity (PLAC(r) activity test) and by its mass concentration (PLAC(r) mass test). It has been long recognized that these two platforms are not correlated well. The underlying cause for this is therefore investigated by the biochemical characterization of the two PLAC tests. DESIGN & METHODS: Human sera with and without the treatment by detergent were fractionated by using a Superose-6 column in phosphate buffered saline and the phospholipid associated Lp-PLA2 was assessed by both PLAC mass and activity tests. The Lp-PLA2 values of the two PLAC tests were compared under such conditions. RESULTS: Fractionation of sera and plasmas indicates that the association of Lp-PLA2 with phospholipids, especially LDL and other large size phospholipid vesicles, may block the detection of the enzyme by antibodies in the immunoassay format under the conditions of the PLAC mass test. Inclusion of high concentration (>CMC, critical micelle concentration) of detergents in the assay buffer of PLAC mass test dissociates Lp-PLA2 from phospholipid vesicles and results in the full detection of all Lp-PLA2 in sera or plasmas for concentration. Such assay modification significantly improves the correlation between the PLAC mass and PLAC activity tests. CONCLUSIONS: PLAC mass test only detects a small portion of the total Lp-PLA2, mainly the Lp-PLA2 associated with HDL. This is the main cause of the discordance and poor correlation between the PLAC mass and activity tests. Our results demonstrate the PLAC activity test is more accurate in assessing the total level of circulating Lp-PLA2. PMID- 28899632 TI - The deposition of anti-DNA IgG contributes to the development of cutaneous lupus erythematosus. AB - Anti-DNA IgG is a hallmark of systemic lupus erythematosus and induces internal injuries in patients. It is known that cutaneous lupus erythematosus (CLE) involves the deposition of autoantibodies in the dermoepidermal junction of the skin and that anti-DNA IgG binds specifically to keratinocytes. However, the definite role of anti-DNA IgG in CLE remains unclear. The purpose of this study was to elucidate the effect of anti-DNA IgG on keratinocytes in CLE. Skin tissues were collected from patients with CLE and healthy controls. Also, murine anti-DNA IgG was incubated with frozen sections of murine skin or PAM212 keratinocytes. The chemotaxis of J774.2 macrophages was evaluated in special chambers with keratinocytes under anti-DNA IgG stimulation. Enzyme-linked immunosorbent assay, flow cytometry, Western blot, and surface plasmon resonance were used to quantitate the interaction between anti-DNA IgG and keratinocyte-related self antigens. The results showed that anti-DNA IgG could be eluted from the lesional tissues of CLE patients, depending on the serum positivity. Murine anti-DNA IgG bound preferably to the dermoepidermal zones of normal skin and specifically to collagen III and the suppressor of cytokine signalling 1 (SOCS1) but not to Ro52. Moreover, the chemotaxis of macrophages was promoted by the incubation of anti DNA IgG with keratinocytes. Interestingly, anti-DNA IgG exaggerated both the expression and the activation of fibroblast growth factor inducible 14 (Fn14) in keratinocytes and regulated SOCS1 signals in a time-dependent manner. In conclusion, anti-DNA IgG may contribute to the development of CLE through binding to keratinocyte-related antigens, exacerbating inflammatory infiltration, and modulating Fn14 and SOCS1 pathways. PMID- 28899633 TI - Intussusception in a preterm newborn. PMID- 28899634 TI - Corrigendum to "Early erythropoietin administration does not increase the risk of retinopathy in preterm infants" [PEDN 58 (2017) 48-56]. PMID- 28899635 TI - Fast technique for the identification of Gilbertella persicaria via optical microscopy. AB - Gilbertella persicaria is an important phytopathogen that is confused with Mucor spp. and Rhizopus spp. The main distinguishing characteristic of G. persicaria is the presence of appendages in sporangiospores, and their observation by conventional staining techniques generally fails. A technique is described using light microscopy for fast and reliable diagnosis. PMID- 28899636 TI - Target and distractor processing and the influence of load on the allocation of attention to task-irrelevant threat. AB - This study investigated the characteristics of two distinct mechanisms of attention - stimulus enhancement and stimulus suppression - using an event related potential (ERP) approach. Across three experiments, participants viewed sparse visual search arrays containing one target and one distractor. The main results of Experiments 1 and 2 revealed that whereas neural signals for stimuli that are not inherently salient could be directly suppressed without prior attentional enhancement, this was not the case for stimuli with motivational relevance (human faces). Experiment 3 showed that as task difficulty increased, so did the need for suppression of distractor stimuli. It also showed the preferential attentional enhancement of angry over neutral distractor faces, but only under conditions of high task difficulty, suggesting that the effects of distractor valence on attention are greatest when there are fewer available resources for distractor processing. The implications of these findings are considered in relation to contemporary theories of attention. PMID- 28899637 TI - Predictors of emergency department discharge following pediatric drowning. PMID- 28899638 TI - Subpectoral Biceps Tenodesis for Treatment of Isolated Type II SLAP Lesions in a Young and Active Population. AB - PURPOSE: The purpose of this study was to evaluate outcomes following open subpectoral biceps tenodesis for the treatment of isolated type II SLAP lesions in patients 45 years of age or younger and evaluate the rate of return to sport. METHODS: All patients included in the study were at least 2 years out from open subpectoral biceps tenodesis for treatment of an isolated type II SLAP lesion and were treated between December 2007 and March 2015. All patients older than 45, those who had prior surgery on the index shoulder, and those who had any concomitant reconstructive shoulder procedures were excluded. American Shoulder and Elbow Surgeons (ASES), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Single Assessment Numeric Evaluation (SANE), and Short-Form 12 Physical Component Summary (SF-12 PCS) scores were collected pre- and postoperatively along with postoperative patient satisfaction. Patient return to sport was evaluated by questionnaire. RESULTS: Twenty patients with a mean age of 38 years (range 21-45) were included, of which 16 were available for follow-up. There was significant improvement in median pre- to postoperative outcome scores (ASES, 66-94 points, P = .001; QuickDASH, 31-8, P = .003; SANE, 60-92, P = .001, SF-12 PCS, 41-52 points, P = .002), with a median patient satisfaction of 8.5 points (range 1-10) at a mean follow-up of 3.4 years (range, 2.0-6.3 years). At final follow-up, all patients had returned to sport, with 73% of patients indicating a return to their previous or comparable level of sports. Subgroup analysis showed 80% of overhead athletes returned to the same or a comparable level postoperatively. CONCLUSIONS: This study suggests that young patients around their 30s participating in sport at a recreational level may benefit from open subpectoral biceps tenodesis for a primary isolated SLAP II tear and would experience excellent outcomes, high satisfaction, and a high rate of return to sport. LEVEL OF EVIDENCE: Level IV, therapeutic case study. PMID- 28899639 TI - Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region. AB - BACKGROUND: It is being increasingly reported that some of the youth onset diabetes patients cannot be classified clearly as type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) based on usual criteria and the term double diabetes (DD) coined for these cases. AIM: The objective of the study was to find out the prevalence of DD in youth onset diabetes patients from east Delhi and neighboring NCR region. METHODS: A total of 200 patients with youth onset diabetes below 25 years of age were recruited from a tertiary care hospital in East Delhi. Clinical history, family history of diabetes and anthropometry of patients were recorded. Fasting serum C-peptide, Anti-IA2-antibody and Anti-GAD antibody were measured in all patients. Patients positive for Anti-GAD-antibody (>1.05U/ml) and C-peptide level >0.3nmol/l were characterized as DD patients. Patients negative for Anti-GAD-antibody and C-peptide >0.3nmol/l were kept under the category of T2DM. Patients with low C-peptide level along with one of the following, positive Anti-GAD-antibody, positive Anti-IA2-antibody and diabetic ketoacidosis (DKA) were considered as T1DM. Remaining patients were kept under the unknown category. RESULTS: Mean age of study subjects was 18.2+/-7.1years. Seven percent (7%) of the subjects were classified as DD, 51% as T1DM, 13% as T2DM and 29% were kept under the unknown category. Mean age of subjects with 22.2+/-9.7, 16.9+/-6.7, 20.6+/-7.7 and 19.4+/-7.4 years in DD, T1DM, T2DM and unknown category respectively. Mean BMI of subjects with DD, T1DM, T2DM and unknown category was 19.8+/-5.7, 16.6+/-3.7, 19.3+/-4.1 and 18.0+/-4.6 kg/m2 respectively. CONCLUSION: Double diabetes is an important occurrence among youth onset diabetes subjects. Only half of the subjects with youth onset of diabetes had T1DM. PMID- 28899640 TI - Status epilepticus in pregnancy: Etiology, management, and clinical outcomes. AB - BACKGROUND: Status epilepticus (SE) in pregnancy carries significant risk to both mother and fetus. There is limited literature available on SE occurring in pregnancy world-over, with majority being from obstetric centers. METHODS: All women who developed SE related to pregnancy (gestation, labor, or puerperium) between January 2000 and December 2016 were included in the study. Data were collected from our SE registry, maintained, and archived in the institute. The variables influencing the maternal and fetal outcome were compared using Student's t-test for continuous variables and Fisher's exact test for discrete variables. RESULTS: During the 16-year study period, a total of 348 SE events were recorded in 294 patients. Among these, there were 138 women, of which 17 had SE related to pregnancy. The etiology of SE was remote symptomatic in two and acute symptomatic in 15 patients. The various causes detected after initial evaluation for acute symptomatic SE were eclampsia (n=4), posterior reversible encephalopathy syndrome due to various causes other than eclampsia (n=6), cortical venous thrombosis (n=3), subarachnoid hemorrhage (n=1), and NMDA receptor antibody-mediated encephalitis (n=1).13 of 17 women with SE (76%) had good outcome. Majority of the fetuses had good outcomes, i.e., Category 1 (n=9, 57%). Duration of intensive care unit stay (p=0.029) and Status Epilepticus Severity Score (p=0.0324) at admission, were found to be significantly associated with poor outcomes. CONCLUSION: In any patient presenting with SE occurring in pregnancy, though eclampsia is presumed to be the most common overall cause; it is relevant to consider other etiologies such as posterior reversible encephalopathy syndrome, cortical venous thrombosis, and autoimmune encephalitis especially in cases presenting with refractory SE. Posterior reversible encephalopathy may occur in pregnancy due to diverse etiologies other than eclampsia. PMID- 28899641 TI - Attention-Deficit/Hyperactivity Disorder Medication Use in Adolescents: The Patient's Perspective. AB - PURPOSE: The purpose of the study was to gain more insight into the attitudes of adolescents using medication for attention-deficit/hyperactivity disorder (ADHD). METHODS: A cross-sectional study among adolescents (aged 12-18 years) who filled at least two prescriptions for ADHD medication in the preceding year was conducted. Adolescents were invited to fill in an online questionnaire containing questions on sociodemographics, health status, illness perceptions, medication adherence, and medication beliefs. RESULTS: We invited 1,200 adolescents of whom 181 adolescents (122 males, mean age 14.2 +/- 1.7 years) completed the online questionnaire. They mostly used methylphenidate (n = 167; 92%) as a pharmacological treatment for ADHD. Half of the study population (n = 93; 51%) experienced side effects, such as decreased appetite and sleep problems. Most participants (n = 150; 83%) had an indifferent attitude (perceived low necessity and low concerns) toward their ADHD medication. More than half of the study population (n = 111; 61%) reported to be nonadherent based on the Medication Adherence Report Scale. The highest score of the Brief Illness Perception Questionnaire was on "treatment control," suggesting that adolescents do think their medication is effective, despite their indifferent drug attitude. CONCLUSIONS: Most adolescents using ADHD medication had an indifferent attitude toward their medication and reported low adherence rates. These findings should be taken into account when treating adolescents with ADHD; regular counseling and monitoring of the pharmacological treatment might be useful to optimize treatment. PMID- 28899642 TI - Evaluation of Myocardial Function According to Early Diastolic Intraventricular Pressure Difference in Fetuses. AB - BACKGROUND: Intraventricular pressure difference (IVPD), the diastolic suction during early diastole, is known as a useful marker of myocardial diastolic function in adults with different heart diseases, but there are no studies of fetal IVPD. The aim of this study was to determine whether IVPD exists and changes prenatally and whether IVPD correlates with preexisting parameters to evaluate fetal cardiac diastolic function and ventricular dominance. METHODS: Cross-sectional study data (stroke volume, fetal cardiac output, E/A ratio, and myocardial performance index) from 117 healthy fetuses at 17 to 36 weeks of gestation were retrospectively evaluated. The total IVPD was calculated using Euler's equation with color M-mode data. Segmental IVPD was evaluated as apical, mid, and basal IVPDs. RESULTS: The total IVPD in the right ventricle and left ventricle significantly increased in late gestation compared with that in different fetuses studied at midgestation (right and left ventricles, rho = 0.813 and rho = 0.895, respectively; P < .001). In both ventricles, the apical IVPD percentage, but not basal or mid IVPD, significantly increased at late gestation compared with that in different fetuses studied at midgestation. Both stroke volumes were correlated with IVPD (right and left ventricles, rho = 0.796 and rho = 0.784, respectively; P < .001). Although myocardial performance index in the left ventricle did not show a significant correlation with IVPD, the E/A ratio had a very weak correlation with IVPD (right ventricle, rho = 0.576, P < .001; left ventricle, rho = 0.338, P < .01). CONCLUSIONS: IVPD has been proved to exist in both ventricles during the fetal stage. The total IVPD increased in late gestation, and the ventricular length increased because of increased apical IVPD in both ventricles. Furthermore, the increase of IVPD in both ventricles was correlated with stroke volume and, accordingly, cardiac output. Left ventricular dominance in IVPD from the fetal stage may offer interesting insight into fetal cardiac development. PMID- 28899643 TI - Towards semisynthetic natural compounds with a biaryl axis: Oxidative phenol coupling in Aspergillus niger. AB - Regio- and stereoselective phenol coupling is difficult to achieve using synthetic strategies. However, in nature, cytochrome P450 enzyme-mediated routes are employed to achieve complete axial stereo- and regiocontrol in the biosynthesis of compounds with potent bioactivity. Here, we report a synthetic biology approach whereby the bicoumarin metabolic pathway in Aspergillus niger was specifically tailored towards the formation of new coupling products. This strategy represents a manipulation of the bicoumarin pathway in A. niger via interchange of the phenol-coupling biocatalyst and could be applied to other components of the pathway to access a variety of atropisomeric natural product derivatives. PMID- 28899644 TI - Transcriptomics reveals tissue/organ-specific differences in gene expression in the starfish Patiria pectinifera. AB - Starfish (Phylum Echinodermata) are of interest from an evolutionary perspective because as deuterostomian invertebrates they occupy an "intermediate" phylogenetic position with respect to chordates (e.g. vertebrates) and protostomian invertebrates (e.g. Drosophila). Furthermore, starfish are model organisms for research on fertilization, embryonic development, innate immunity and tissue regeneration. However, large-scale molecular data for starfish tissues/organs are limited. To provide a comprehensive genetic resource for the starfish Patiria pectinifera, we report de novo transcriptome assemblies and global gene expression analysis for six P. pectinifera tissues/organs - body wall (BW), coelomic epithelium (CE), tube feet (TF), stomach (SM), pyloric caeca (PC) and gonad (GN). A total of 408 million high-quality reads obtained from six cDNA libraries were assembled de novo using Trinity, resulting in a total of 549,598 contigs with a mean length of 835 nucleotides (nt), an N50 of 1473nt, and GC ratio of 42.5%. A total of 126,136 contigs (22.9%) were obtained as predicted open reading frames (ORFs) by TransDecoder, of which 102,187 were annotated with NCBI non-redundant (NR) hits, and 51,075 and 10,963 were annotated with Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) using the Blast2GO program, respectively. Gene expression analysis revealed that tissues/organs are grouped into three clusters: BW/CE/TF, SM/PC, and GN, which likely reflect functional relationships. 2408, 8560, 2687, 1727, 3321, and 2667 specifically expressed genes were identified for BW, GN, PC, CE, SM and TF, respectively, using the ROKU method. This study provides a valuable transcriptome resource and novel molecular insights into the functional biology of different tissues/organs in starfish as a model organism. PMID- 28899645 TI - Transcriptome-based discovery of pathways and genes related to reproduction of the black tiger shrimp (Penaeus monodon). AB - The black tiger shrimp (Penaeus monodon) is an aquatic animal with considerable economic importance. Poor reproductive maturation in captivity impedes sustainable aquaculture production of this species. This study aims to provide transcriptomic information on reproductive organs using 454 pyrosequencing technology. The transcriptome analysis of ovaries and testes revealed 41,136 transcripts with 20,192 contigs. We found novel sets of transcripts completing several important reproductive pathways such as gonadotropin-releasing hormone (GnRH) signaling and progesterone-mediated oocyte maturation. In addition, we found transcripts encoding for receptors crucial for initiation of the maturation process, such as GnRH receptor (GnRHR), voltage-dependent calcium channel L type alpha-1C (CACNA1C) and epidermal growth factor receptor (EGFR). Moreover, we found a putative novel vigillin encoding for an estrogen-induced polysome associated protein, which has not been reported in penaeid shrimp. These results suggest that the regulatory mechanism of the pathways important to reproductive maturation might be similar to those in the vertebrate. The obtained data will consequently accelerate the study of reproductive biology of this important species to ensure a sustainable shrimp farming industry. PMID- 28899646 TI - Early life adversity potentiates expression of addiction-related traits. AB - Many individuals sporadically and circumstantially sample addictive drugs, yet few become addicted. The individual vulnerabilities underlying the development of addiction are not well understood. Correlational findings show that early life adversity is associated with a greater propensity to develop drug addiction. However, the mechanisms by which early life adversity increases addiction vulnerability are unknown. Separate lines of research have found that several traits are associated with addiction. Here, we examined the effects of early life adversity on addiction-related traits in adulthood. We weaned male and female Sprague-Dawley rats (postnatal day - PND21) and randomly assigned them to either a non-adversity group (N-ADV) or an adversity group (ADV). ADV rats experienced adversity from PND 21-35, they were: a) singly housed, b) food restricted for 12h/day, c) subjected to forced-swim sessions, and d) restrained and exposed to predator odour (1h). As adults, rats were tested for impulsivity, anxiety-like behaviour, novelty preference, and attribution of incentive salience to a reward cue. ADV rats showed enhanced novelty preference and attributed greater incentive value to a reward cue. Compared to N-ADV rats, a greater proportion of ADV rats expressed multiple addiction risk traits. Furthermore, fewer ADV rats expressed no addiction risk traits. This effect was most evident in female ADV rats. PMID- 28899647 TI - Improving gene transfer in Clostridium pasteurianum through the isolation of rare hypertransformable variants. AB - Effective microbial metabolic engineering is reliant on efficient gene transfer. Here we present a simple screening strategy that may be deployed to isolate rare, hypertransformable variants. The procedure was used to increase the frequency of transformation of the solvent producing organism Clostridium pasteurianum by three to four orders of magnitude. PMID- 28899649 TI - Small field characterization of a Nanochamber prototype under flattening filter free photon beams. AB - INTRODUCTION: Nanochambers present some advantages in terms of energy independence and absolute dose measurement for small field dosimetry in the SBRT scenario. Characterization of a micro-chamber prototype was carried out both under flattened and flattening-filter-free (FFF) beams with particular focus on stem effect. METHODS: The study included characterization of leakage and stem effects, dose rate and dose per pulse dependence, measurement of profiles, and percentage depth doses (PDDs). Ion collection efficiency and polarity effects were measured and evaluated against field size and dose per pulse. The 6_MV, 6_MV_FFF and 10_MV FFF beams of a Varian EDGE were used. Output factors were measured for field sizes ranging from 0.8*0.8cm2 to 20*20cm2 and were compared with other detectors. RESULTS: The 2mm diameter of this chamber guarantees a high spatial resolution with low penumbra values. In orthogonal configuration a strong stem (and cable) effect was observed for small fields. Dose rate and dose per pulse dependence were <0.3% and 0.6% respectively for the whole range of considered values. The Nanochamber exhibits a field size (FS) dependence of the polarity correction >2%. The OF values were compared with other small field detectors showing a good agreement for field sizes >2*2cm2. The large field over response was corrected applying kpol(FS). CONCLUSIONS: Nanochamber is an interesting option for small field measurements. The spherical shape of the active volume is an advantage in terms of reduced angular dependence. An interesting feature of the Nanochamber is its beam quality independence and, as a future development, the possibility to use it for small field absolute dosimetry. PMID- 28899648 TI - Italian folk plant-based remedies to heal headache (XIX-XX century). AB - BACKGROUND: Headache has been recognized since antiquity. From the late nineteenth to the early to mid-twentieth century, Italian folk remedies to treat headache were documented in a vast corpus of literature sources. AIM: The purpose of this paper is to bring to light the plant-based treatments utilized by Italian folk medicine to heal headache in an attempt to discuss these remedies from a modern pharmacological point of view. Moreover, we compare the medical applications described by Hippocrates, Pliny the Elder, Dioscorides, Galen and Serenus Sammonicus with those utilized by Italian folk medicine to check if they result from a sort of continuity of use by over two thousand years. RESULTS: A detailed search of the scientific data banks such as Medline and Scopus was undertaken to uncover recent results concerning the anti-inflammatory, anti nociceptive and analgesic activities of the plants. Fifty-eight (78.4%) plant based remedies have shown in vivo, in vitro or in human trials a large spectrum of anti-inflammatory, anti-nociceptive and analgesic activities. Moreover, thirty one of remedies (41.9%) were already included in the pharmacopoeia between the 5th century BC and the 2nd century AD. CONCLUSION: Italian folk medicine could be a promising source of knowledge and could provide evidences for active principles that have not as of yet been fully used for their potential. PMID- 28899650 TI - Micropatterned surface electrode for massive selective stimulation of intraepidermal nociceptive fibres. AB - BACKGROUND: No satisfactory neurophysiological test for nociceptive afferents is available to date. Laser stimuli present risks of skin damage, whilst electrical stimulation through specially designed electrodes is not selective enough. NEW METHOD: We present a new electrode designed according to critical issues identified in preliminary computer simulations concerning electric field gradient through the skin. To provide selective stimulation the activating electric field must be limited to intraepidermal free nerve endings. To this end, a new interdigitated electrode (IDE) was made of conductive rails arranged in a comb like micropattern, situated only 150MUm apart from each other (150 IDE) and alternately connected to the opposite poles of the stimulator. RESULTS: Evoked potentials recorded from the scalp were obtained after stimulation with the 150 IDE and with a similarly designed, but more widely spaced electrode (1000MUm, or 1000 IDE). Small amplitude early and medium latency components were recorded with the 1000 IDE, suggesting activation of Abeta fibres. On the other hand, the 150 IDE only evoked late responses, confirming sufficient selectivity in small fibre activation. COMPARISON WITH EXISTING METHOD(S): The main differences with existing electrodes are: 1) Microspaced interdigitated conductive rails. 2) The potentially unlimited surface of stimulation and high efficiency per surface unit, resulting in large numbers of activated nociceptors. CONCLUSIONS: A new electrode providing selective stimulation of nociceptive nerve free endings is presented. It is non-invasive, and its surface can be enlarged at will. It is expected that it may greatly help in neurophysiological assessment of conditions affecting the nociceptive pathway. PMID- 28899651 TI - Is higher formula intake and limited dietary diversity in Australian children at 14 months of age associated with dietary quality at 24 months? AB - A varied and diverse diet in childhood supports optimum long-term preferences and growth. Previous analysis from 14-month-old Australian children in the NOURISH and South Australian Infants Dietary Intake (SAIDI) studies found higher formula intake was associated with lower dietary diversity. This analysis investigated whether formula intake and dietary diversity at 14 months of age is associated with dietary quality at 24 months. This is a secondary analysis of intake data from NOURISH and SAIDI cohorts. Scores for dietary diversity, fruit variety, vegetable variety and meat/alternative variety were combined using structural equation modelling to form the latent variable 'Dietary quality' (DQ) at age 24 months. A longitudinal model examined influence of formula (grams), cow's milk (grams) and dietary diversity at 14 months and covariates, on DQ. At age 24 months (n = 337) 27% of children obtained a maximum dietary diversity score (5/5). Variety scores were relatively low - with mean variety scores (and possible range) being four for fruit (0-30); five for vegetables (0-36); and three for meat/alternatives (0-8). Dietary diversity at 14 months (beta = 0.19, p = 0.001), maternal age (beta = 0.24, p < 0.001) and education (beta = 0.22, p < 0.001) predicted DQ at 24 months while Child Food Neophobia Score was negatively associated with DQ (beta = -0.30, p < 0.001). Formula intake was negatively associated with diversity at 14 months, but not DQ at 24. Diversity and variety were limited despite sociodemographic advantage of the sample. Diversity at 14 months, degree of neophobia and sociodemographic factors predicted DQ at 24 months. There is an ongoing need to emphasise the importance of repeated early exposure to healthy foods, such that children have the opportunity to learn to like a range of tastes and texture, thereby maximising dietary diversity and quality in infancy and early toddlerhood. PMID- 28899652 TI - Predicting preschool children's eating in the absence of hunger from maternal pressure to eat: A longitudinal study of low-income, Latina mothers. AB - Early work by Klesges et al. (1983, 1986) suggested that mothers who frequently prompt their children to eat have children at greater risk for obesity. This is consistent with the hypothesis that controlling feeding practices override children's responsiveness to their internal fullness cues, increasing the risk of overeating and obesity (e.g., Johnson & Birch, 1994). Subsequent cross-sectional research on pressure to eat, however, has been inconsistent. Most studies have shown that maternal self-reports of pressure to eat are negatively associated with childhood obesity, and observational studies showed inconsistent relationships with child weight status. In the present study we examined the association between low-income, Latina mothers' pressure to eat and their preschool children's eating in the absence of hunger using both self-report and observational measures of feeding practices. A longitudinal design examined eating in the absence of hunger over 18 months; children's BMI at the initial timepoint was statistically controlled to address the tendency of mothers of underweight children to pressure their children to eat. At each timepoint, mothers completed the Child Feeding Questionnaire (Birch et al., 2001) and were observed feeding their child a meal in a laboratory setting. Eating in the absence of hunger (Fisher & Birch, 1999) was assessed at both timepoints as well. A cross-lagged panel model showed that observed maternal prompts to eat a different food at time one predicted kcal consumed in the absence of hunger at time two (controlling for kcal consumed in the absence of hunger at first timepoint: beta = 0.20, p < 0.05). Results suggest that pressure to eat alone may not be what contributes to eating in the absence of hunger, but that the nature of that pressure may be more important. PMID- 28899654 TI - Deciphering the loss of metal binding due to mutation D83G of human SOD1 protein causing FALS disease. AB - Mutations in Cu/Zn superoxide dismutase 1 (SOD1) protein are found to be the causative factor, behind the majority of familial amyotrophic later sclerosis (FALS) cases. The mutations particularly on the metal (Zn) binding residues are found to increase the disease onset in the individuals suffering from FALS, while the presence of the metal ion (Zn) is essential for the catalytic activity and retaining the protein stability. Thus in our study, we focused on one such metal binding mutant (D83G) and assessed the impact of the mutation on protein structure and function. The influence of mutation was examined dynamically, using discrete molecular dynamics on both the native and mutant SOD1 protein respectively. Accordingly, the variation in conformational stability, residual flexibility and protein compactness along with the change in conformational free energy were monitored over the entire dynamic period. Moreover, the motion of native and mutant SOD1 was also observed via the essential dynamics. Besides, the disparity in Zn ion binding was inspected through distance analysis and steered molecular dynamics, correspondingly. Therefore, the study provides a better understanding over the profound effect of mutation on SOD1, both structurally and functionally, using computational approaches. PMID- 28899653 TI - Role of autophagy in Zika virus infection and pathogenesis. AB - Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates. Autophagy can serve dual roles in virus infection with either pro- or antiviral functions depending on the virus and the stage of the viral replication cycle. Recent studies have suggested a role for autophagy in Zika virus (ZIKV) replication by demonstrating the accumulation of autophagic vesicles following ZIKV infection in both in vitro and in vivo models. In human fetal neural stem cells, ZIKV inhibits Akt-mTOR signaling to induce autophagy, increase virus replication and impede neurogenesis. However, autophagy also has the potential to limit ZIKV replication, with separate studies demonstrating antiviral roles for autophagy at the maternal-placental-fetal interface, and more specifically, at the endoplasmic reticulum where virus replication is established in an infected cell. Interestingly, ZIKV (and related flaviviruses) has evolved specific mechanisms to overcome autophagy at the ER, thus demonstrating important roles for these autophagic pathways in virus replication and host response. This review summarizes the known roles of autophagy in ZIKV replication and how they might influence virus tissue tropism and disease. PMID- 28899655 TI - Characteristics of physical activity interventions and effects on cardiorespiratory fitness in children aged 6-12 years-A systematic review. AB - OBJECTIVES: To examine the characteristics of physical activity (PA) interventions and the effects on cardiorespiratory fitness (CRF) in healthy children based on treatment theory. DESIGN: Systematic review. METHODS: PubMed and Embase were searched for studies published between 2003 and 2016. Inclusion criteria were: Participants: healthy children aged 6-12. INTERVENTIONS: interventions with activities to increase PA behaviour or physical fitness (PF) regardless of setting. CONTROL: no or alternative intervention. OUTCOME: exercise based CRF measure with appropriate analysis of CRF effects. STUDY DESIGN: randomized controlled trial. Effect size was calculated using dppc2 and the methodological quality of the studies was assessed using the PEDro scale. RESULTS: Of 1002 studies screened, 23 met the inclusion criteria. Thirteen of the 23 studies found statistically significant improvements in CRF and eight studies showed medium to high effect sizes. Interventions with medium to high effect sizes focused more often on PF than PA behaviour, had slightly higher frequencies of activities and had a shorter duration than the less effective interventions. CONCLUSIONS: The fact that thirteen studies demonstrated statistically significant improvements in CRF is promising but also emphasizes the need to keep improving research methods and the development and execution of interventions. Interventions with larger effect sizes appear to be more controlled, as they usually relied on smaller sample sizes and the components of these interventions encompassed protocolled training sessions which defined and monitored the relative training intensity intended. A duration of at least six weeks and a frequency of three to four times a week is recommended. PMID- 28899656 TI - Greater ankle strength, anaerobic and aerobic capacity, and agility predict Ground Combat Military Occupational School graduation in female Marines. AB - : Women can serve in all military occupational specialties (MOS); however, musculoskeletal and physiological characteristics that predict successful completion of ground combat MOS schools by female Marines are unknown. OBJECTIVES: To determine which demographic, musculoskeletal, and physiological characteristics predict graduation from infantry and vehicle ground combat MOS schools in female Marines. DESIGN: Prospective cohort study. METHODS: Prior to MOS school, the following were assessed in 62 female Marines (22.0+/-3.0yrs, 163.9+/-5.8cm, 63.4+/-7.2kg): isokinetic shoulder, trunk, and knee and isometric ankle strength; body composition; anaerobic power (AP)/capacity (AC); maximal oxygen uptake (VO2max); and field-based fitness tests (broad jump, medicine ball throw, pro-agility). Both absolute and normalized (%body mass: %BM) values were utilized for strength, AP, AC, and VO2max. Select tests from each Marine's most recent Physical Fitness Test (PFT: abdominal crunches, 3-mile run time) and Combat Fitness Test (CFT: Maneuver Under Fire, Movement to Contact) were recorded. Participants were classified as graduated (N=46) or did not graduate (N=16). Simple logistic regression was performed to determine predictors of MOS school graduation. Statistical significance was set a priori at alpha=0.05. RESULTS: Absolute and normalized ankle inversion and eversion strength, normalized anaerobic capacity, absolute and normalized VO2max, right pro-agility, and PFT 3-mile run time significantly predicted MOS school graduation (p<0.05). CONCLUSIONS: Greater ankle strength, better agility, and greater anaerobic and aerobic capacity are important for successful completion of ground combat MOS school in female Marines. Prior to entering ground combat MOS school, it is recommended that female Marines should train to optimize these mobility-centric characteristics. PMID- 28899657 TI - HIF-1alpha/Ascl2/miR-200b regulatory feedback circuit modulated the epithelial mesenchymal transition (EMT) in colorectal cancer cells. AB - We have reported that Achaete scute-like 2 (Ascl2) transcriptionally repressed miR-200 family members and affected the epithelial-mesenchymal transition (EMT) mesenchymal-epithelial transition (MET) plasticity in colorectal cancer (CRC) cells. However, little is known about the regulation of the Ascl2/miR-200 axis. Here, we found that hypoxia inducible factor-1alpha (HIF-1alpha) mRNA levels were positively correlated with Ascl2 mRNA levels and inversely correlated with miR 200b in CRC samples. Mechanistically, we showed that Ascl2 was a downstream target of HIF-1alpha and had a critical role in the EMT phenotype induced by hypoxia or HIF-1alpha over-expression. Hypoxia or HIF-1alpha over-expression activated Ascl2 expression in CRC cells in a direct transcriptional mechanism via binding with the hypoxia-response element (HRE) at the proximal Ascl2 promoter. HIF-1alpha-induced Ascl2 expression repressed miR-200b expression to induce EMT occurrence. Furthermore, we found HIF-1alpha was a direct target of miR-200b. MiR 200b bound with the 3'-UTR of HIF-1alpha in CRC cells. HIF-1alpha/Ascl2/miR-200b regulatory feedback circuit modulated the EMT-MET plasticity of CRC cells. Our results confirmed a novel HIF-1alpha/Ascl2/miR-200b regulatory feedback circuit in modulating EMT-MET plasticity of CRC cells, which could serve as a possible therapeutic target. PMID- 28899658 TI - Knockdown of LRP/LR induces apoptosis in pancreatic cancer and neuroblastoma cells through activation of caspases. AB - The 37kDa/67kDa laminin receptor (LRP/LR) serves various physiological and pathological roles such as enhancing tumour-related processes including metastasis, angiogenesis, cellular viability and telomerase activation in cancerous cell lines. The present study investigates the effect of siRNA mediated downregulation of LRP/LR on pancreatic cancer (AsPC-1) and neuroblastoma (IMR-32) cells. MTT and BrdU assays revealed that siRNA mediated downregulation of LRP resulted in a significant reduction in cell viability and cell proliferation. In addition, knock-down of LRP resulted in phosphatidylserine externalization, diminished nuclear integrity and significantly enhanced caspase-3 activity, which is indicative of apoptosis. LRP downregulation resulted in a significant increase in caspase-8 activity in IMR-32 cells and enhanced caspase-8 and 9 activity in AsPC-1 cells. These data recommend siRNA mediated knock-down of LRP as a potential therapeutic avenue for the treatment of pancreatic cancer and neuroblastoma. PMID- 28899660 TI - Effects of Legal Access to Cannabis on Scheduled II-V Drug Prescriptions. AB - BACKGROUND: Co-prescribing of scheduled drugs is endemic in the United Sates, increasing health risks to patients and the burden on healthcare systems. PURPOSE: We conducted a pragmatic historical cohort study to measure the effect of enrollment in a state-authorized United States' Medical Cannabis Program (MCP) on scheduled II-V drug prescription patterns. PROCEDURES: Eighty-three chronic pain patients, who enrolled in the New Mexico MCP between April 1, 2010 and October 3, 2015, were compared with 42 nonenrolled patients over a 24-month period (starting 6 months before enrollment for the MCP patients) using the Prescription Monitoring Program. The outcome variables include baseline levels and pre- and postenrollment monthly trends in the number of drug prescriptions, distinct drug classes, dates prescription drugs were filled, and prescribing providers. FINDINGS: Twenty-eight MCP patients (34%) and 1 comparison group patient (2%) ceased the use of all scheduled prescription medications by the last 6 months of the observation period. Age- and sex-adjusted regressions show that, although no statistically significant differences existed in pre-enrollment levels and trends, the postenrollment trend among MCP patients is statistically significantly negative for all 4 measures (decreases in counts of -0.02 to -0.04, P values between <.001 and .017), whereas the postenrollment trend is 0 among the comparison group. Controlling for time-invariant patient characteristics suggested that MCP patients showed statistically significantly lower levels across all 4 measures by 10 months postenrollment. CONCLUSIONS: Legal access to cannabis may reduce the use of multiple classes of dangerous prescription medications in certain patient populations. PMID- 28899659 TI - BRG1 promotes VEGF-A expression and angiogenesis in human colorectal cancer cells. AB - Angiogenesis plays an important role in tumor growth and progression in solid tumors. Vascular endothelial growth factor (VEGF) is one of the most critical and specific factors that stimulate both physiological and pathological angiogenesis. Here, we report a novel role of BRG1, the core subunit of SWI/SNF family complexes, in angiogenesis. In this study, we demonstrate that BRG1 is overexpressed in colorectal cancer and decreased expression of BRG1 not only blocks cell proliferation but remarkably inhibits the ability of HUVECs to form capillary-like structures. Moreover, our study shows that BRG1 can regulate the expression of VEGF-A by interacting with HIF-1alpha. Furthermore, we find VEGF-A is overexpressed in colorectal cancer and is positively correlated with BRG1 expression. Taken together, our study demonstrated that BRG1 can promote VEGF-A expression and angiogenesis in colorectal cancer and BRG1 may be a novel drug target for the treatment of colorectal cancer. PMID- 28899662 TI - Baseline Association of Motoric Cognitive Risk Syndrome With Sustained Attention, Memory, and Global Cognition. AB - OBJECTIVES: Slow gait has been shown to be a good predictor of declining cognitive function in healthy older adults. Motoric cognitive risk (MCR) syndrome is a new construct incorporating slow gait and subjective cognitive complaints in individuals without dementia who have preserved activities of daily living. This analysis investigated the prevalence of MCR and factors associated with MCR in a nationally representative population. In addition, cross-sectional associations between MCR and cognitive domains, an relationship yet to be fully elucidated in literature, was investigated. MEASUREMENTS: Participants completed a comprehensive neuropsychological assessment and gait analysis at a health assessment center. Logistic regression was employed to examine associated health factors. Composite scores reflecting global cognition, memory, sustained attention, executive function, and processing speed were constructed using neuropsychological test scores. Associations between MCR and these composites were quantified using multivariate generalized linear modelling. All analyses were weighted to be nationally representative. SETTING: Community-dwelling adults in The Irish Longitudinal Study on Aging (TILDA) completed an interview and a center-based health assessment. PARTICIPANTS: Participants aged 60 years and over (n = 2151, age; mean: 67.84 years, range: 60-93) were included. Participants with a Mini-Mental State Examination score of below 24, a diagnosis of serious memory impairment, Parkinson disease, dementia, or Alzheimer disease were excluded. RESULTS: MCR prevalence was estimated at 2.56% (95% confidence interval 1.97, 3.31). Significant risk factors for MCR were antidepressant use [odds ratio (OR) 4.46, P < .001], self-reported poor vision (OR 4.92, P < .05), and obesity (OR 2.29, P < .01). Individuals with MCR performed worse on tests that assess memory (B: -0.58, P < .001), global cognition (B: -0.42, P < .001), and sustained attention (B: -0.34, P < .05) with robust adjustment made for confounding demographic and health variables. CONCLUSIONS: MCR is characterized by strong negative associations with global cognition, attention, and memory. This may be indicative of the underlying pathology of MCR. The effect of antidepressant use on MCR is novel and may represent an important consideration in future studies. PMID- 28899661 TI - Frailty, Polypharmacy, and Health Outcomes in Older Adults: The Frailty and Dependence in Albacete Study. AB - BACKGROUND/OBJECTIVES: To investigate if polypharmacy modifies the association between frailty and health outcomes in older adults. DESIGN: Ongoing cohort study. SETTING: Albacete City, Spain. PARTICIPANTS: A total for 773 participants, 457 women (59.1%), over age 70 years from the FRADEA Study. MEASUREMENTS: Frailty phenotype, polypharmacy considered as the chronic use of 5 or more drugs, and comorbidity were collected at the baseline visit. Participants were categorized in 6 groups according to frailty and polypharmacy, and were followed up for 5.5 years (mean 1057 days, range 1-2007). Mortality or incident disability in basic activities of daily living was considered the main outcome variable. Hospitalization and visits to the emergency department were also recorded. The adjusted association between combined frailty status and polypharmacy with outcome variables was analyzed. RESULTS: The mean age of study population was 78.5 years. In this population, we identified a 15.3% (n = 118) of frail with polypharmacy, 3.4% (n = 26) of frail without polypharmacy, 35.3% (n = 273) of prefrail with polypharmacy, 20.3% (n = 157) of prefrail without polypharmacy, 10.3% (n = 80) of nonfrail with polypharmacy, and 15.4% (n = 119) of nonfrail participants without polypharmacy. Participants with frailty and polypharmacy had a higher adjusted risk of mortality or incident disability [odds ratio (OR) 5.3; 95% confidence interval (CI) 2.3-12.5] and hospitalization (OR 2.3; 95% CI 1.2 4.4), compared with those without frailty and polypharmacy. Frail and prefrail participants with polypharmacy had a higher adjusted mortality risk compared with the nonfrail without polypharmacy, hazard ratio 5.8 (95% CI 1.9-17.5) and hazard ratio 3.1 (95% CI 1.1-9.1), respectively. CONCLUSIONS: Polypharmacy is associated with mortality, incident disability, hospitalization, and emergency department visits in frail and prefrail older adults, but not in nonfrail adults. Polypharmacy should be monitored in these patient subgroups to optimize health outcomes. PMID- 28899663 TI - Prevalence of antibodies against severe fever with thrombocytopenia syndrome virus in shelter dogs in the Republic of Korea. AB - The purpose of this study was to investigate the seroprevalence of antibodies against severe fever with thrombocytopenia syndrome virus (SFTSV) in shelter dogs in the Republic of Korea (ROK) using an indirect immunofluorescence assay and virus neutralization test. Sera were collected from 426 dogs in 12 animal shelters throughout the ROK from March 2016 to November 2016. Overall, 59 of 426 (13.9%) samples were seropositive for antibodies against SFTSV. A significant difference was observed in accordance with the sampling region (p<0.001), but not according to the sex (p=0.279) or breed (p=0.729) of the dogs. The seroprevalence of SFTSV showed an inversely proportional trend to the latitude of the sampling regions: the highest rate was observed in the southern region followed by the Jeju-do region. This is the first report on the nationwide prevalence of antibodies against SFTSV in companion dogs in animal shelters throughout the ROK. PMID- 28899665 TI - Toxin composition of the 2016 Microcystis aeruginosa bloom in the St. Lucie Estuary, Florida. AB - A bloom of the cyanobacteria, Microcystis aeruginosa occurred in the St. Lucie Estuary during the summer of 2016, stimulated by the release of waters from Lake Okeechobee. This cyanobacterium produces the microcystins, a suite of heptapeptide hepatotoxins. The toxin composition of the bloom was analyzed and was compared to an archived bloom sample from 2005. Microcystin-LR was the most abundant toxin with lesser amounts of microcystin variants. Nodularin, cylindrospermopsin and anatoxin-a were not detected. PMID- 28899664 TI - Implant for autologous soft tissue reconstruction using an adipose-derived stem cell-colonized alginate scaffold. AB - BACKGROUND: Adipose-derived stem cells represent an interesting option for soft tissue replacement as they are easy to procure and can generate their own blood supply through the production of angiogenic factors. We seeded adipose-derived stem cells on a bioresorbable, biocompatible polymer alginate scaffold to generate autologous soft tissue constructs for repair. MATERIALS AND METHODS: We built and optimized an alginate scaffold and tested its biocompatibility using the MTT assay and its hydration capacity. We then isolated, characterized, and differentiated murine, porcine, and human adipose-derived stem cells. We characterized their angiogenic potential in vitro by VEGF ELISA and HUVEC tube formation assay in traditional cell culture substrate and in the actual three dimensional scaffold. We assessed the angiogenic potential of adipose-derived stem cell-colonized scaffolds in ovo by chorion allantois membrane angiogenesis assay. RESULTS: Adipose-derived stem cells differentiated into adipocytes within the alginate scaffolds and demonstrated angiogenic activity. VEGF secretion by adipose-derived stem cells decreased significantly over the 21-day course of adipocyte differentiation in traditional cell culture substrate, but not in scaffolds. Adipose-derived stem cells differentiated for 21 days in scaffolds led to the longest HUVEC tube formation. Scaffolds colonized with adipose-derived stem cells resulted in significantly improved vascularization in ovo. CONCLUSIONS: We demonstrate the feasibility of implant production based on adipose-derived stem cell-colonized alginate scaffolds. The implants demonstrate biocompatibility and promote angiogenesis in vitro and in ovo. Therefore, they provide a combination of essential properties for an implant intended for soft tissue replacement. PMID- 28899666 TI - Stem cells and the circadian clock. AB - The circadian timing system is a complex biological network of interacting circadian clocks that regulates 24h rhythms of behavioral and physiological processes. One intriguing observation is that stem cell homeostasis is subject to circadian clock regulation. Rhythmic oscillations have been observed in a variety of embryonic and adult stem cell dependent processes, such as hematopoietic progenitor cell migration, the hair follicle cycle, bone remodeling, regenerative myogenesis and neurogenesis. This review aims to discuss the nature of the circadian clock in embryonic stem cells and how it changes during differentiation. Furthermore, it will examine how the circadian clock contributes to adult stem cell function in different tissues of the body with an emphasis on the brain and adult neurogenesis. PMID- 28899668 TI - The sp7 gene is required for maturation of osteoblast-lineage cells in medaka (Oryzias latipes) vertebral column development. AB - Sp7 is a zinc finger transcription factor that is essential for osteoblast differentiation in mammals. To verify the characteristic features of osteoblast lineage cells in teleosts, we established medaka sp7 mutants using a transcription activator-like effector nuclease (TALEN) genome editing system. These mutants showed severe defects in the formation of skeletal structures. In particular, the neural and the hemal arches were not formed, although the chordal centra were formed. Analysis of the transgenic medaka revealed that sp7 mutant had normal distribution of type X collagen a1 a (col10a1a)-positive osteoblast like cells around the centrum and at the proximal region of the vertebral arch. The sp7 mutant phenotype could be rescued by exogenous sp7 expression in col10a1a positive cells, as well as in sp7-positive osteoblast cells. Furthermore, runx2 positive osteoblast progenitors were observed on the vertebral arches, but not on the centrum, during vertebral column development. In addition, these osteoblast progenitors differentiated into the col10a1a-positive cells. In sp7 mutant, the runx2-positive cells were normally distributed at the region of unformed vertebral arch but failed to differentiate into col10a1a-positive cells. These results indicate that osteoblast-lineage cells undergo two distinct differentiation processes during development of the vertebral arch and the centrum. Nevertheless, our results verified that sp7 gene expression in osteoblast-lineage cells is required for differentiation into mature osteoblasts to form the vertebral column and other skeletal structures. PMID- 28899669 TI - Successful Treatment of a Patient With Gastric Mucosa-Associated Lymphoma. PMID- 28899667 TI - bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression. AB - Balancing self-renewal and differentiation of stem cells requires differential expression of self-renewing factors in two daughter cells generated from the asymmetric division of the stem cells. In Drosophila type II neural stem cell (or neuroblast, NB) lineages, the expression of the basic helix-loop-helix-Orange (bHLH-O) family proteins, including Deadpan (Dpn) and E(spl) proteins, is required for maintaining the self-renewal and identity of type II NBs, whereas the absence of these self-renewing factors is essential for the differentiation of intermediate neural progenitors (INPs) generated from type II NBs. Here, we demonstrate that Dpn maintains type II NBs by suppressing the expression of Earmuff (Erm). We provide evidence that Dpn and E(spl) proteins suppress Erm by directly binding to C-sites and N-boxes in the cis-regulatory region of erm. Conversely, the absence of bHLH-O proteins in INPs allows activation of erm and Erm-mediated maturation of INPs. Our results further suggest that Pointed P1 (PntP1) mediates the dedifferentiation of INPs resulting from the loss of Erm or overexpression of Dpn or E(spl) proteins. Taken together, these findings reveal mechanisms underlying the regulation of the maintenance of type II NBs and differentiation of INPs through the differential expression of bHLH-O family proteins. PMID- 28899670 TI - Definition, Pathogenesis, and Management of That Cursed Dyspepsia. AB - Dyspepsia is an umbrella term used to encompass a number of symptoms thought to originate from the upper gastrointestinal tract. These symptoms are relatively nonspecific; not surprisingly, therefore, a myriad of conditions may present with any one or a combination of these symptoms. Therein lays the clinician's first challenge: detecting the minority who may have a potentially life-threatening disorder, such as gastric cancer, from a population whose symptoms are, for the most part, considered functional in origin. The second challenge lies in the definition and management of those individuals with functional dyspepsia (FD); the major focus of this review. The Rome process has addressed the issue of FD definition and a look back at the evolution of Rome criteria for this disorder illustrates the complexities that have so frustrated us. There has been no shortage of hypotheses to explain symptom pathogenesis in FD; initially focused on gastric sensorimotor dysfunction, these have now strayed well into the duodenum and have come to entertain such factors as immune responses and the microbiome. FD has proven to be an equally challenging area for therapeutics; while the staple approaches of acid suppression and eradication of Helicobacter pylori have some limited efficacy in select populations, strategies to ameliorate symptoms in the majority of sufferers based on presumed pathophysiology have largely foundered. Lacking a validated biomarker(s) FD continues to be an elusive target and is likely to remain so until we can better define the various phenotypes that it must surely contain. PMID- 28899671 TI - Obesity, but Not Physical Activity, Is Associated With Higher Prevalence of Asymptomatic Diverticulosis. PMID- 28899672 TI - Large Meckel's Diverticulum and Dilated Adjacent Small Intestine Presenting With Intestinal Obstruction. PMID- 28899673 TI - Detection of Arteriovenous Malformations on the Underside of the Duodenal Papilla. PMID- 28899674 TI - Pretreatment of agricultural biomass for anaerobic digestion: Current state and challenges. AB - The anaerobic digestion (AD) of agricultural biomass is an attractive second generation biofuel with potential environmental and economic benefits. Most agricultural biomass contains lignocellulose which requires pretreatment prior to AD. For optimization, the pretreatment methods need to be specific to the characteristics of the biomass feedstock. In this review, cereal residue, fruit and vegetable wastes, grasses and animal manure were selected as the agricultural biomass candidates, and the fundamentals and current state of various pretreatment methods used for AD of these feedstocks were investigated. Several nonconventional methods (electrical, ionic liquid-based chemicals, ruminant biological pretreatment) offer potential as targeted pretreatments of lignocellulosic biomass, but each comes with its own challenges. Pursuing an energy-intensive route, a combined bioethanol-biogas production could be a promising a second biofuel refinery option, further emphasizing the importance of pretreatment when lignocellulosic feedstock is used. PMID- 28899675 TI - Kraft lignin biorefinery: A perspective. AB - Lignin is a huge energy and carbon reserve but owing to its highly biologically recalcitrant nature it is commonly regarded as a waste in lignocellulosic biomass biorefinery. To realize the lignin biorefinery, it is proposed to use Kraft lignin, isolated from black liquor from Kraft pulping mills, as starting material to be fragmented by fast pyrolysis or selective catalysis to aromatic sub-units and to be post-refining with additional cleavage reaction and separation/purification as commodity aromatics pool in chemical industries. This Note calls for research efforts on detailed investigation of the feasibility of this proposed scenario. PMID- 28899676 TI - Self-recoverable voltage reversal in stacked microbial fuel cells due to biofilm capacitance. AB - In order to assess the effects of biofilm capacitance on self-recovering voltage reversals, the restored current is determined and compared with the measured biofilm capacitance by analyzing the results of electrochemical impedance spectroscopy. This comparison demonstrates that self-recovering voltage reversals are caused by temporary damage to, and the recovery of, biofilm capacitance which arises due to the ability of redox enzymes in the electron transfer system to temporarily store electrons. Thus, the development of procedures for voltage reversal control and for the maintenance of serially connected microbial fuel cells (MFCs) should take into account such temporary voltage reversal phenomenon. This discovery and characterization of self-recovering voltage reversals is expected to be practically useful to enhance the reliability of MFCs to be scaled up and implemented in practical systems. PMID- 28899677 TI - Evaluation of humic substances during co-composting of sewage sludge and corn stalk under different aeration rates. AB - Sewage sludge and corn stalk were co-composted under different aeration rates 0.12 (AR0.12), 0.24 (AR0.24), 0.36 (AR0.36)L.kg-1DMmin-1, respectively. Transformation of humic substance was evaluated by a series of chemical and spectroscopic methods to reveal compost humification. Results showed that aeration rate could significantly affect compost stability and humification process. Humic acid contents in AR0.24 were significantly higher than those in the other two treatments. The final humic acid/fulvic acid ratios in AR0.12, AR0.24 and AR0.36 treatment were 1.0, 1.9 and 0.8, respectively, corresponding to the final E4/E6 of 4.7, 3.2 and 5.5. Moreover, compost in AR0.24 treatment had a high stability degree due to the low C/N atom ratio and high C/H atom ratio. However, it is noteworthy that composting could not significantly affect the structure of HA in a 35-day period. These results indicate that composting with the aeration rate of 0.24L.kg-1DMmin-1 could accelerated the humification process. PMID- 28899678 TI - Behavior of nitrogen removal in an aerobic sponge based moving bed biofilm reactor. AB - This study aims to investigate the behavior of nitrogen removal in an aerobic sponge based moving bed biofilm reactor by evaluating nitrification and denitrification rates of sponge biocarriers from three aerobic moving bed biofilm reactors (MBBRs) with filling ratios of 10% (R-10), 20% (R-20) and 30% (R-30). Results showed that the highest removal efficiencies of total nitrogen in three reactors were 84.5% (R-10), 93.6% (R-20) and 95.3% (R-30). Correspondingly, simultaneous nitrification and denitrification rate (SND) was 90.9%, 97.6% and 100%, respectively. Although R-20 had the highest attached-growth biomass (AGB) per gram of sponge compared to the other two reactors, R-30 showed the maximum ammonium oxidation rate (AOR) (2.1826+/-0.0717mgNH4+-N/gAGB/h) and denitrification rate (DNR) (5.0852+/-0.0891mgNO3--N/gAGB/h), followed by R-20 and R-10. These results indicated AOR, DNR and AGB were affected by the filling ratio under the same operation mode. PMID- 28899679 TI - Anaerobic treatment of pharmaceutical wastewater: A critical review. AB - Pharmaceutical wastewaters are usually produced by chemical-synthetic process, and thus contain high levels of organic pollutants, biotoxicity and salinity. Anaerobic technology is a viable option for treating pharmaceutical wastewater owing to its advantages of withstanding high organic-loading, less sludge production and lower operating cost as compared with conventional activated sludge process. In this paper, several types of modern anaerobic or hybrid systems were reviewed on their pollutant reduction performance and operating conditions for treating pharmaceutical wastewater. Meanwhile, the typical predominant microbial populations found in anaerobic process treating pharmaceutical wastewater were summarized. Moreover, the environmental impact of antibiotic residues and health risk of spreading of antibiotic resistant genes (ARGs) were also assessed to offer an in-depth understanding of the growing concern on the discharge of treated pharmaceutical effluent. PMID- 28899681 TI - Comparative Degradomics of Porcine and Human Wound Exudates Unravels Biomarker Candidates for Assessment of Wound Healing Progression in Trauma Patients. AB - Impaired cutaneous wound healing is a major complication in elderly people and patients suffering from diabetes, the rate of which is rising in industrialized countries. Heterogeneity of clinical manifestations hampers effective molecular diagnostics and decisions for appropriate therapeutic regimens. Using a customized positional quantitative proteomics workflow, we have established a time-resolved proteome and N-terminome resource from wound exudates in a clinically relevant pig wound model that we exploited as a robust template to interpret a heterogeneous dataset from patients undergoing the same wound treatment. With zyxin, IQGA1, and HtrA1, this analysis and validation by targeted proteomics identified differential abundances and proteolytic processing of proteins of epidermal and dermal origin as prospective biomarker candidates for assessment of critical turning points in wound progression. Thus, we show the possibility of using a fine-tuned animal wound model to bridge the translational gap as a prerequisite for future extended clinical studies with large cohorts of individuals affected by healing impairments. Data are available via ProteomeXchange with identifier PXD006674. PMID- 28899682 TI - Caveolin-1 Controls Hyperresponsiveness to Mechanical Stimuli and Fibrogenesis Associated RUNX2 Activation in Keloid Fibroblasts. AB - Keloids are pathological scars characterized by excessive extracellular matrix production that are prone to form in body sites with increased skin tension. CAV1, the principal coat protein of caveolae, has been associated with the regulation of cell mechanics, including cell softening and loss of stiffness sensing ability in NIH3T3 fibroblasts. Although CAV1 is present in low amounts in keloid fibroblasts (KFs), the causal association between CAV1 down-regulation and its aberrant responses to mechanical stimuli remain unclear. In this study, atomic force microscopy showed that KFs were softer than normal fibroblasts with a loss of stiffness sensing. The decrease of CAV1 contributed to the hyperactivation of fibrogenesis-associated RUNX2, a transcription factor germane to osteogenesis/chondrogenesis, and increased migratory ability in KFs. Treatment of KFs with trichostatin A, which increased the acetylation level of histone H3, increased CAV1 and decreased RUNX2 and fibronectin. Trichostatin A treatment also resulted in cell stiffening and decreased migratory ability in KFs. Collectively, these results suggest a role for CAV1 down-regulation in linking the aberrant responsiveness to mechanical stimulation and extracellular matrix accumulation with the progression of keloids, findings that may lead to new developments in the prevention and treatment of keloid scarring. PMID- 28899680 TI - The cephalic phase insulin response to nutritive and low-calorie sweeteners in solid and beverage form. AB - The purpose of the study was to examine the role of the cephalic phase insulin response (CPIR) following exposure to nutritive and low-calorie sweeteners in solid and beverage form in overweight and obese adults. In addition, the role of learning on the CPIR to nutritive and low-calorie sweetener exposure was tested. Sixty-four overweight and obese adults (age: 18-50years, BMI: 24-37kg/m2, body fat percentage>25% for men and >32% for women) were sham-fed (at 2-minute intervals for 14min) a randomly assigned test load comprised of a nutritive (sucrose) or low-calorie sweetener (sucralose) in beverage or solid form in phase 1 of the study. A 2-3ml blood sample was collected before and 2, 6, 10, 14, 61, 91 and 121min after oral exposure for serum insulin and glucose analysis. During phase 2, participants underwent a 2-week training period to facilitate associative learning between the sensory properties of test loads and their post ingestive effects. In phase 3, participants were retested for their cephalic phase responses as in phase 1. Participants were classified as responders if they demonstrated a positive insulin response (rise of serum insulin above baseline i.e. Delta insulin) 2min post-stimulus in phase 1. Among responders exposed to the same sweetener in Phases 1 and 3, the proportion of participants that displayed a rise of insulin with oral exposure to sucralose was significantly greater when the stimulus was in the solid form compared to the beverage form. Sucralose and sucrose exposure elicited similarly significant increases in serum insulin 2min after exposure and significant decreases after 2min in responders in both food forms. The solid food form elicited greater CPIR over 2, 6 and 10min than the beverage form. There was no effect of learning on insulin responses after training. The results indicate the presence of a significant CPIR in a subset of individuals with overweight or obesity after oral exposure to sucralose, especially when present in solid food form. Future studies must confirm the reliability of this response. PMID- 28899683 TI - A Missense Mutation within the Helix Termination Motif of KRT25 Causes Autosomal Dominant Woolly Hair/Hypotrichosis. PMID- 28899684 TI - Glycoprotein Nonmelanoma Clone B Regulates the Crosstalk between Macrophages and Mesenchymal Stem Cells toward Wound Repair. AB - The process of wound repair requires the coordinated participation of multiple types of cells, which are sequentially recruited during the healing process. In response to tissue injury, both macrophages and mesenchymal stem cells (MSCs) are recruited to the site of injury, where they participate in the repair process. Despite considerable understanding of the role of each cell type in the process of wound repair, the nature of the dynamic interplay between these two cell types and how this interaction influences the process of wound repair are not well understood. Here, using an in vivo model of cutaneous wound healing in mice, we provide evidence that GPNMB is functionally important in promoting the recruitment of MSCs to the site of skin injury, which in turn modulates inflammatory responses by directing the M2 polarization of macrophages in acute wound healing. Furthermore, we show that GPNMB activity is impaired in a diabetic wound environment, which is associated with impaired MSC recruitment that is reversed by the topical administration of recombinant GPNMB protein to the wounds of diabetic mice. Our study provides important insight into the crosstalk between macrophages and endogenous MSCs toward wound repair. PMID- 28899685 TI - The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy. AB - TRIP4 was identified as having a proliferation promoting effect in melanoma cells based on small interfering RNA library screening, however, its precise function in melanoma progression is completely unknown. Here, we explored the carcinogenic role of TRIP4 in melanoma. The high expression of TRIP4 was observed in human melanoma cells and tissues. Its knockdown suppressed melanoma progression in vitro and in vivo, including melanoma cell proliferation, migration, and invasion inhibition and apoptosis induction. Further mechanistic analysis showed that TRIP4 promoted melanoma growth through modulation of COX-2 and iNOS expression partially by activating NF-kappaB signaling indirectly and partially by the direct anchoring of itself at COX-2 and iNOS promoter via synergy with p300. TRIP4 was confirmed to regulate the sensitivity to anti-BRAF targeted agents in BRAF-mutant human melanoma cells and xenografts. In addition, clinical data showed that high expression of TRIP4 was positively correlated with increased expression of COX-2 and iNOS and predicted poor prognosis in a cohort of 100 melanoma patients. Collectively, these results show a pro-tumorigenic role of TRIP4, provide an insight into the mechanism of TRIP4 as a candidate therapeutic target, and suggest the potential of TRIP4 and BRAF dual targeting as an effective therapeutic strategy for melanoma. PMID- 28899686 TI - The Anti-C1s Antibody TNT003 Prevents Complement Activation in the Skin Induced by Bullous Pemphigoid Autoantibodies. PMID- 28899687 TI - Proteomic Profiling of Sweat Exosome Suggests its Involvement in Skin Immunity. AB - Healthy human skin sustains an effective immune defense mechanism, formed by a complex physical and chemical epidermal barrier that coordinates with different cellular components of the skin immune system. However, the mechanism by which skin cells regulate local immune homeostasis in health and disease contexts is not well known. To investigate whether exosomes exist in sweat, sweat samples from healthy individuals were collected after aerobic exercise. Sweat exosome was isolated via differential ultracentrifugation, observed under transmission electron microscopy, measured by dynamic light scattering, and confirmed by immunoblot. Further, shotgun liquid chromatography (LC)-mass spectrometry (MS)/MS analysis was conducted to investigate the proteomic profiling of sweat exosome. Secreted exosome was detected in human sweat. A total of 1,062 proteins were identified in sweat exosome, including 997 different proteins compared with sweat proteomics and 896 unique proteins compared with urine, saliva, and plasma exosomes. Diverse antimicrobial peptides and immunological factors were found in sweat exosome, suggesting the involvement of exosome in skin immunity. This study provides direct evidence that secreted exosomes exist in human sweat. The proteomic profiling of sweat exosome provides insight into sweat features and the potential physiological significance of exosomes in immune homeostasis. PMID- 28899688 TI - Keratins Regulate the Adhesive Properties of Desmosomal Cadherins through Signaling. AB - Tightly controlled intercellular adhesion is crucial for the integrity and function of the epidermis. The keratin filament cytoskeleton anchors desmosomes, supramolecular complexes required for strong intercellular adhesion. We tested whether keratin filaments control cell adhesion by regulating the adhesive properties of desmosomal cadherins such as desmoglein (Dsg) 3. Atomic force microscopy and fluorescence recovery after photobleaching experiments showed reduced Dsg3 adhesive forces and membrane stability in murine keratinocytes lacking all keratin filaments. Impairment of the actin cytoskeleton also resulted in decreased Dsg3 immobilization but did not affect Dsg3 binding properties, indicating that the latter are exclusively controlled by keratins. Reduced binding forces were dependent on p38 mitogen-activated protein kinase activity, which was deregulated in keratin-deficient cells. In contrast, inhibition of protein kinase C signaling, which is known to be controlled by keratins, promoted and spatially stabilized Dsg3-mediated interactions in the membrane. These results show a previously unreported mechanism for how keratins stabilize intercellular adhesion on the level of single desmosomal adhesion molecules. PMID- 28899689 TI - Enhanced Expression of Genes Related to Xenobiotic Metabolism in the Skin of Patients with Atopic Dermatitis but Not with Ichthyosis Vulgaris. AB - Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and alpha-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism. PMID- 28899691 TI - Transcriptome modulation of bovine trophoblast cells in vitro by Neospora caninum. AB - Neospora caninum is one of the most efficient transplacentally transmitted pathogens in cattle and is a cause of abortion in this domestic species. The invasion and proliferation of Neospora caninum in the placenta and its dissemination to the foetus are crucial events in the outcome of an infection. In the bovine placenta, the placentomes are formed by maternal caruncles, which are delimited by a maternal epithelium and foetal cotyledons, which are delimited by an epithelial layer named the trophoblast. These epithelia form a physical barrier against foetal infection. Furthermore, trophoblast cells act as an innate immune defence at the foetal-maternal interface. Neospora caninum invades and proliferates in trophoblast cells in vitro, but it is unknown whether host cell modulation events, which affect the immune response and other processes in the trophoblast, occur. In this work, we investigated the transcriptomic modulation by Neospora caninum infection in the bovine trophoblast cell line F3. In addition, two Neospora caninum isolates with marked differences in virulence, Nc Spain1H and the Nc-Spain7, were used in this study to investigate the influence of these isolates in F3 modulation. The results showed a clear influence on extracellular matrix reorganisation, cholesterol biosynthesis and the transcription factor AP-1 network. Interestingly, although differences in the transcriptome profiles induced by each isolate were observed, specific isolate modulated processes were not identified, suggesting very similar regulation in both isolates. Differential expression of the N. caninum genes between both isolates was also investigated. Genes involved in host cell attachment and invasion (SAG-related and microneme proteins), glideosome, rhoptries, metabolic processes, cell cycle and stress response were differentially expressed between the isolates, which could explain their variability. This study provides a global view of Neospora caninum interactions with bovine trophoblast cells and of the intra-specific differences between two Neospora caninum isolates with biological differences. PMID- 28899690 TI - Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis. AB - Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans. PMID- 28899693 TI - Clinical efficacy of botulinum toxin in salivary duct stenosis: A preliminary study of six cases. AB - INTRODUCTION: Salivary duct stenosis is the second most common cause of obstructive pathology after lithiases, and it primarily affects the parotid gland. Salivary duct stenosis is treated with drug therapy and/or sialendoscopy. If unsuccessful, surgical removal of the gland is indicated, but it is associated with a high risk of facial morbidity. The aim of this study is to evaluate the clinical efficacy of an alternate treatment, botulinum toxin, in salivary duct stenosis. MATERIAL AND METHODS: In a preliminary retrospective study from January 2011 to December 2014, six patients with parotid duct stenosis received 50IU of botulinum toxin in three injections in the parotid gland. The frequency of relapses and the intensity of pain and swelling were recorded before and after treatment. The onset of action and duration of efficacy were also assessed. RESULTS: Four of six patients showed a decrease in the frequency of swelling episodes and greater pain relief during the first year of treatment, but to a lesser extent after 2years. The mean duration of efficacy was 3.5months with an interval between two injections of 5.7months. Only one parotidectomy had to be performed. No major side effects were observed, with only one case of local infection at the injection site. CONCLUSION: Botulinum toxin appears to be a viable alternative in treating salivary duct stenosis before resorting to surgical gland removal. PMID- 28899692 TI - In vitro efficacy of bumped kinase inhibitors against Besnoitia besnoiti tachyzoites. AB - Besnoitia besnoiti is an apicomplexan parasite responsible for bovine besnoitiosis, a chronic and debilitating disease that causes systemic and skin manifestations and sterility in bulls. Neither treatments nor vaccines are currently available. In the search for therapeutic candidates, calcium-dependent protein kinases have arisen as promising drug targets in other apicomplexans (e.g. Neospora caninum, Toxoplasma gondii, Plasmodium spp. and Eimeria spp.) and are effectively targeted by bumped kinase inhibitors. In this study, we identified and cloned the gene coding for BbCDPK1. The impact of a library of nine bumped kinase inhibitor analogues on the activity of recombinant BbCDPK1 was assessed by luciferase assay. Afterwards, those were further screened for efficacy against Besnoitiabesnoiti tachyzoites grown in Marc-145 cells. Primary tests at 5uM revealed that eight compounds exhibited more than 90% inhibition of invasion and proliferation. The compounds BKI 1294, 1517, 1553 and 1571 were further characterised, and EC99 (1294: 2.38uM; 1517: 2.20uM; 1553: 3.34uM; 1571: 2.78uM) were determined by quantitative real-time polymerase chain reaction in 3 day proliferation assays. Exposure of infected cultures with EC99 concentrations of these drugs for up to 48h was not parasiticidal. The lack of parasiticidal action was confirmed by transmission electron microscopy, which showed that bumped kinase inhibitor treatment interfered with cell cycle regulation and non disjunction of tachyzoites, resulting in the formation of large multi-nucleated complexes which co-existed with viable parasites within the parasitophorous vacuole. However, it is possible that, in the face of an active immune response, parasite clearance may occur. In summary, bumped kinase inhibitors may be effective drug candidates to control Besnoitiabesnoiti infection. Further in vivo experiments should be planned, as attainment and maintenance of therapeutic blood plasma levels in calves, without toxicity, has been demonstrated for BKIs 1294, 1517 and 1553. PMID- 28899694 TI - Anti-atherosclerotic effect of hesperidin in LDLr-/- mice and its possible mechanism. AB - Hesperidin, a citrus bioflavonoid, exerts numerous pharmacological activities. However, its protective effect against atherosclerosis in vivo remains poorly understood. In the present study, we aimed to observe the effects of hesperidin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr /-) mice. After 12 weeks of treatment, the animals were sacrificed. The blood samples were collected for further analysis. Mouse peritoneal macrophages were collected. Hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation, gene expressions were performed on liver and aorta samples. The data showed that hesperidin ameliorated HFD-induced weight gain, improved insulin resistance and ameliorated hyperlipidemia. Hesperidin suppressed HFD-induced hepatic steatosis, atherosclerotic plaque area and macrophage foam cell formation. Further study showed that hesperidin down regulated expressions of acetyl coenzyme A carboxylase alpha (ACCalpha) and fatty acid synthase (FAS) which are two key enzymes in fatty acid and triglyceride synthesis in liver; and upregulated expression of hepatic ATP-binding cassette transporters G8 (ABCG8), macrophage ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) which are transporters involved in the process of reverse cholesterol transport. Hesperidin also reduced oxidative stress by normalizing activities of antioxidant enzymes and inflammation in HFD-fed LDLr-/- mice. These findings suggest that hesperidin reduced atherosclerosis via its pleiotropic effects, including improvement of insulin resistance, amelioration of lipid profiles, inhibition of macrophage foam cell formation, anti-oxidative effect and anti-inflammatory action. PMID- 28899695 TI - Preeclampsia and coronary plaque erosion: Manifestations of endothelial dysfunction resulting in cardiovascular events in women. AB - Atherosclerosis is the major underlying pathology of cardiovascular disease (CVD). The risk for CVD is increased in women with a history of preeclampsia. Multiple studies have indicated that accelerated atherosclerosis underlies this increased CVD risk. Furthermore, it has been suggested that endothelial dysfunction and inflammation play an important role in the increased CVD risk of women with preeclampsia. Rupture or erosion of atherosclerotic plaques can induce the formation of thrombi that underlie the onset of acute clinical CVD such as myocardial infarction and stroke. In relatively young women, cardiovascular events are mainly due to plaque erosions. Eroded plaques have a distinct morphology compared to ruptured plaques, but have been understudied as a substrate for CVD. The currently available evidence points towards lesions with features of stability such as high collagen content and smooth muscle cells and with distinct mechanisms that further promote the pro-thrombotic environment such as Toll Like Receptor (TLR) signaling and endothelial apoptosis. These suggested mechanisms, that point to endothelial dysfunction and intimal thickening, may also play a role in preeclampsia. Pregnancy is considered a stress test for the cardiovascular system with preeclampsia as an additional pathological substrate for earlier manifestation of vascular disease. This review provides a summary of the possible common mechanisms involved in preeclampsia and accelerated atherosclerosis in young females and highlights plaque erosion as a likely substrate for CVD events in women with a history of preeclampsia. PMID- 28899696 TI - Serotonin 2A receptor disulfide bridge integrity is crucial for ligand binding to different signalling states but not for its homodimerization. AB - The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys148 (transmembrane helix 3, TM3) and Cys227 (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization. A DTT-induced decrease in the number of binding sites (1190 +/- 63.55 fmol/mg protein for control cells compared with 921.2 +/- 60.84 fmol/mg protein for DTT treated cells) as well as in the efficacy of both signalling pathways characterized was observed, although the affinity and potency were unchanged. Bioluminiscence resonance energy transfer (BRET) assays revealed the DTT treatment did not modify the homodimeric nature of serotonin 5-HT2A receptors. In molecular dynamic simulations, the ECL-2 of the receptor with a broken cysteine bond adopts a wider variety of conformations, some of which protrude deeper into the receptor orthosteric binding pocket leading to collapse of the pocket. A shrunken binding pocket would be incapable of accommodating lysergic acid diethylamide (LSD). Our findings suggest that the decrease of efficacy may be due to disruption of disulfide bridge between TM3 and ECL-2. This reveals the integrity of the ECL-2 epitope, which should be explored in the development of novel ligands acting as allosteric modulators of serotonin 5-HT2A receptors. PMID- 28899697 TI - Implementation of a human podocyte injury model of chronic kidney disease for profiling of renoprotective compounds. AB - Degradation of podocyte structural integrity and function are hallmarks of proteinuric chronic kidney disease. In vivo, injury of podocytes manifests itself in the form of disruption of foot process morphology and associated cytoskeletal architecture, de-differentiation, and loss of adhesion to the glomerular basement membrane. Given the critical role played by this highly specialized cell type in maintaining glomerular filtration, there is a need for improved physiologically relevant cellular models that enable detection of disease-relevant indicators of podocyte perturbation. We have addressed this need by evaluating a subclone of conditionally immortalized human podocytes through quantitative benchmarking against freshly isolated primary human podocytes. Benchmarking was performed by measuring key phenotypic parameters, expression of podocyte specific proteins and multiparametric responses to stressors that model different aspects of podocyte perturbation. We subsequently employed the subcloned cells to profile the protective activity of structurally distinct adenosine kinase inhibitors. Our results support the translatability of our cellular model and set the stage for broader screening of renoprotective compounds with a view to eventually treat proteinuric kidney disease. PMID- 28899698 TI - Betulinic acid derivative BA5, a dual NF-kB/calcineurin inhibitor, alleviates experimental shock and delayed hypersensitivity. AB - Betulinic acid (BA) is a naturally occurring triterpenoid with several biological properties already described, including immunomodulatory activity. Here we investigated the immunomodulatory activity of eight semi-synthetic amide derivatives of betulinic acid. Screening of derivatives BA1-BA8 led to the identification of compounds with superior immunomodulatory activity than BA on activated macrophages and lymphocytes. BA5, the most potent derivative, inhibited nitric oxide and TNFalpha production in a concentration-dependent manner, and decreased NF-kappaB activation in Raw 264.7 cells. Additionally, BA5 inhibited the proliferation of activated lymphocytes and the secretion of IL-2, IL-4 IL-6, IL-10, IL-17A and IFNgamma, in a concentration-dependent manner. Flow cytometry analysis in lymphocyte cultures showed that treatment with BA5 induces cell cycle arrest in pre-G1 phase followed by cell death by apoptosis. Moreover, BA5 also inhibited the activity of calcineurin, an enzyme that plays a critical role in the progression of cell cycle and T lymphocyte activation. BA5 has a synergistic inhibitory effect with dexamethasone on lymphoproliferation, showing a promising profile for drug combination. Finally, we observed immunosuppressive effects of BA5 in vivo in mouse models of lethal endotoxemia and delayed type hypersensitivity. Our results reinforce the potential use of betulinic acid and its derivatives in the search for potent immunomodulatory drugs. PMID- 28899699 TI - Factors associated with lumbar disc hernia recurrence after microdiscectomy. AB - INTRODUCTION: Lumbar disc hernias are a common cause of spinal surgery. Hernia recurrence is a prevalent complication. OBJECTIVE: To analyse the risk factors associated with hernia recurrence in patients undergoing surgery in our institution. MATERIALS AND METHODS: Lumbar microdiscectomies between 2010 and 2014 were analysed, patients with previous surgeries, extraforaminales and foraminal hernias were excluded. Patients with recurrent hernia were the case group and those who showed no recurrence were the control group. RESULTS: 177 patients with lumbar microdiscectomy, of whom 30 experienced recurrence (16%), and of these 27 were reoperated. Among the risk factors associated with recurrence, we observed a higher rate of disc height, higher percentage of spinal canal occupied by the hernia and presence of degenerative facet joint changes; we observed no differences in sex, body mass index or age. DISCUSSION: Previous studies show increased disc height and young patients as possible factors associated with recurrence. CONCLUSION: In our series we found that the higher rate of disc height, the percentage of spinal canal occupied by the hernia and degenerative facet joint changes were associated with hernia recurrence. PMID- 28899700 TI - The Agony of It All: Musculoskeletal Discomfort in the Reading Room. AB - PURPOSE: The purpose of this study was to determine the extent and severity of musculoskeletal discomfort in radiologists using a standardized tool, the Cornell Musculoskeletal Discomfort Questionnaire (CMDQ). In addition, we evaluated the influence of demographic factors on the frequency of symptoms, degree of discomfort, interference of symptoms with ability to work, and overall pain. METHODS: The CMDQ was distributed via an anonymous link to all radiology trainees and faculty at our institution. The questionnaire assessed frequency and location of pain, severity of symptoms, and degree to which discomfort interfered with work. In addition, demographic data were collected. RESULTS: The survey was completed by 99 radiologists (39% response rate). The majority (80%) of respondents spent greater than 7 hours per workday at a diagnostic workstation. The neck (66%), lower back (61%), upper back (43%), right shoulder (36%), and right wrist (33%) were the areas where radiologists most frequently reported ache, pain, or discomfort at least once per week. More than 7 hours per day at a computer workstation was significantly associated with higher total pain. CONCLUSIONS: Musculoskeletal discomfort in the week before the survey was reported by the majority of radiologists and was significantly influenced by demographic factors. Further investigation is needed to understand the causes of radiologists' discomfort at work and to evaluate interventions to ameliorate these symptoms. PMID- 28899701 TI - Evolution in Trainee Participation in Global Health. PMID- 28899702 TI - Giving, Taking, and Matching: Leveraging the Power of Diverse Collaborative Behaviors to Build a Successful Radiology Team. AB - Within a radiology team, members individually lean toward being givers or takers. Radiology leadership must recognize this characteristic and leverage the strengths of givers and takers to best assist the team and to provide effective motivation. Understanding the importance of balancing these qualities within a team improves productivity and morale and reduces burnout. PMID- 28899703 TI - Image Gently Have-A-Heart Campaign. PMID- 28899704 TI - 2017 ACR Annual Meeting Open-Microphone Session: Navigating the Landscape of Changing Practice Models: Private Practice, Corporate Radiology, and Enterprise Systems. AB - Many practice groups are considering adopting new practice models, primarily to secure their practices by adapting to new payment models, government compliance and regulation, and increasing IT and infrastructure costs. As we move toward value-based care and capitation, the value equation (value = quality/cost) will lead us to also compete on cost to improve value. No matter what payment models ultimately dominate, we need to be prepared to lead in a value-based care environment. Measures of value will either be defined by radiologists or imposed by outside entities. It is critical to our continued success that practices and practice leaders continue to fully and strongly support the ACR to avoid the possibility of a decline in membership that may accompany a lack of practice engagement. Consolidation appears inevitable, but with the help of the ACR, radiologists should have a vibrant future if investments are made now in determining appropriate radiology-specific value measures that are meaningful in consolidated health care environments. PMID- 28899705 TI - Disparities in Care Among Patients With Cardiac Implantable Electronic Devices Undergoing MRI. AB - IMPORTANCE: Abundant data now demonstrate safe use of MRI for patients with non MR conditional cardiac implantable electronic devices (CIEDs). However, CMS does not currently reimburse these examinations. OBJECTIVE: Determine whether differences in reimbursement between commercial insurance carriers and CMS are impacting the completion rates of MRI examinations ordered in patients with non MR conditional CIEDs. METHODS: This study retrospectively examined patients with non-MR conditional CIEDs for whom an MRI was ordered between January 1, 2015, and August 31, 2016. Completion rates of MRI in patients with Medicare or Medicaid insurance were compared with those in patients with commercial insurance. Before November 7, 2015, all patients with non-MR conditional CIEDs underwent MRI examinations at no charge to the patient regardless of insurance. After that date, outpatients with only Medicare or Medicaid insurance coverage received an Advanced Beneficiary Notice that informed them that they would have to pay out of pocket for the entire cost of their MRI examinations. RESULTS: Of 143 MRI examinations ordered, 127 met inclusion criteria for analysis. In the post Advanced Beneficiary Notice period, outpatients with commercial insurance were significantly more likely to complete their MRI examinations (19 of 22 patients, 86%) when compared with patients with Medicare or Medicaid insurance (1 of 36 patients, 3%; P <.0001). No significant difference was observed in the inpatient setting. CONCLUSIONS: Due to CMS coverage policies based on now outdated concepts about MRI safety, patients with non-MR conditional CIEDs and Medicare or Medicaid insurance are undergoing significantly fewer appropriate diagnostic MRI examinations than patients with commercial insurance. PMID- 28899706 TI - Big Data and Machine Learning: A Resident's Perspective of the 2016 Intersociety Conference. PMID- 28899707 TI - Collaborative Branding of Partnered Health Systems in Radiology. AB - In an effort to expand clinical reach and achieve economies of scale, academic radiology practices are strategically expanding into the community by establishing partnerships with existing community health systems. A challenge with this model is to effectively brand the collaboration in a way that underscores the strengths of both partners. In this article, the authors look at the benefits and risks of cobranding and review cobranding strategies for implementation by academic radiology practices considering partnership-based network expansion. PMID- 28899708 TI - The Reading Room Coordinator: Reducing Radiologist Burnout in the Digital Age. PMID- 28899709 TI - Phosphorylation of epidermal growth factor receptor at serine 1047 in cultured lung alveolar epithelial cells by bradykinin B2 receptor stimulation. AB - Accumulating evidence indicates that epidermal growth factor receptor (EGFR) is desensitized by phosphorylation of serine 1047 (Ser1047). We and other groups have reported that stimulation of a receptor of tumor-necrosis factor alpha (TNFalpha) and Toll-like receptor 5 (TLR5) induced the phosphorylation of Ser1047 through activation of p38 mitogen-activated protein kinase (p38 MAPK) in cultured lung alveolar epithelial A549 cells. However, phosphorylation of EGFR at Ser1047 by stimulation of any G-protein coupled receptors (GPCRs) has not been reported in any cultured cells. In the present study, we first confirmed that A549 cells expressed bradykinin (BK) B2 receptor, and then, we examined whether BK treatment of A549 cells activated MAPKs and induced the phosphorylation of EGFR at Ser1047. Immunoblotting analysis and reporter gene assays indicated that BK activated the pathways of extracellular signal-regulated kinase (ERK) and p38 MAPK. Inhibitor studies suggested that Gq/11 was mainly involved in the activation of ERK and p38 MAPK. We found that stimulation of the BK B2 receptor, but not the BK B1 receptor, induced phosphorylation of EGFR at Ser1047. Pharmacological experiments indicated that both ERK and p38 MAPK were involved in the phosphorylation of EGFR. These results strongly suggested that BK regulates EGFR functions in lung alveolar epithelial cells. In addition, we found that BK treatment increased the mRNA level of dual specificity MAPK phosphatase 5 (DUSP5) in an ERK-dependent manner, which suggested that a negative feedback mechanism of ERK existed in the cells. PMID- 28899710 TI - Health literacy and coronary artery disease: A systematic review. AB - OBJECTIVE: Identify health literacy (HL) screening instruments available to CAD patients; describe the prevalence of low HL; explore the predictors of low HL; and, identify the association between HL, health behaviors, and outcomes among these patients. METHODS: A literature search of electronic databases was conducted for published articles from database inception to February 2017. Eligible articles included the assessment of HL in CAD patients. Health behaviors and outcomes included diet, exercise, smoking, medication use, hospital readmission, knowledge, health-related quality of life (HRQoL), and psychosocial indicators. RESULTS: Overall, ten articles were included, of which two were RCTs, and seven were considered "good" quality. The most used screening instruments were REALM and TOFHLA. The average prevalence of low HL was 30.5%. Low HL participants were more likely to be older, male, from a non-white ethnic group, have many CVD comorbidities, lower educational level, disadvantaged socioeconomic position, and less likely to be employed. Low HL was consistently associated with hospital readmissions, low HRQoL, higher anxiety and lower social support. CONCLUSION: The literature on HL in CAD patients is very limited. PRACTICE IMPLICATIONS: Healthcare providers should start adopting strategies that can potentially mitigate the impact of low HL in the care of CAD patients. PMID- 28899711 TI - Colorectal cancer screening: Associations between information provision, attitudes and intended participation. AB - OBJECTIVE: Properly informing target audiences is crucial in population-based screening programs. We aimed to evaluate the impact of information about CRC screening on attitudes and intended participation in a screening-naive population. METHODS: 614 persons (aged 55-75 years) received a survey. Information on CRC and screening was provided piece by piece, and per piece its impact on attitudes and intended participation was assessed. All persons received the same information content, but the sequence of information differed per condition: information on the high mortality rate of colorectal cancer was presented in the first or the second piece. Educational levels, the extent people considered future consequences, and value concordance between attitudes and intentions were assessed. RESULTS: 436 persons (response 71%) completed the survey. Overall most respondents reported positive attitudes towards CRC screening (78%) and intentions to participate in CRC screening (83%), independent of sequence of information provision. Intentions about participation were value concordant in the majority (88%). Results were similar in low educated groups. CONCLUSION: Providing balanced information about CRC screening (also addressing negative effects) did not impede value concordance and high rates of intended participation. PRACTICE IMPLICATIONS: High rates of screening intentions are possible without omitting threatening health information in communication materials. PMID- 28899712 TI - An empirical test of the Health Empowerment Model: Does patient empowerment moderate the effect of health literacy on health status? AB - OBJECTIVE: The Health Empowerment Model (Schulz & Nakamoto, 2013) advocates that the effects of health literacy and empowerment are intertwined on health outcomes. This study aims to test this assumption in the context of health status as a patient outcome. METHODS: A cross-sectional study was conducted with a sample of 302 participants between June and December 2015. The participants' health literacy (using the NVS and S-TOFHLA tests), empowerment and self-reported health status were assessed. RESULTS: The participants having a high level of patient empowerment and concurrent adequate health literacy (the so-called 'effective self-managers') reported better health status compared to patients who had either lower health literacy and/or lower empowerment scores (P<0.05). Moreover, the meaningfulness (b=0.053, t(297)=2.29, P=0.02) and competence (b=0.07, t(297)=2.47, P=0.01) sub-dimensions of patient empowerment moderated the effect of the NVS on current health status. CONCLUSION: The study provides evidence for the independence of health literacy and empowerment and partial evidence for their interaction predicting health status. PRACTICE IMPLICATIONS: Our findings highlight that health literacy and patient empowerment (in particular its competence and meaningfulness sub-facets) are crucial patient related variables, to be taken into consideration simultaneously, during screening and health promotion campaigns fostering health status in the general population. PMID- 28899713 TI - Interrater reliability of the Patient Education Materials Assessment Tool (PEMAT). AB - OBJECTIVE: To assess the interrater reliability (IRR) and usability of the Patient Education Materials Assessment Tool (PEMAT) and the relationship between PEMAT scores and readability levels. METHODS: One hundred ten materials (80 print, 30 audiovisual) were evaluated, each by two raters, using the PEMAT. IRR was calculated using Gwet's AC1 and summarized across items in each PEMAT domain (understandability and actionability) and by material type. A survey was conducted to solicit raters' experience using the PEMAT. Readability of each material was assessed using the SMOG Index. RESULTS: The median IRR was 0.92 for understandability and 0.93 for actionability across all relevant items, indicating good IRR. Eight PEMAT items had Gwet's AC1 values less than 0.81. PEMAT and SMOG Index scores were inversely correlated, with a Spearman's rho of 0.20 (p=0.081) for understandability and -0.15 (p=0.194) for actionability. While 92% of raters agreed the PEMAT was easy to use, survey results suggested specific items for clarification. CONCLUSION: While the PEMAT demonstrates moderate to excellent IRR overall, amendments to items with lower IRR may increase the usefulness of the tool. PRACTICE IMPLICATIONS: The PEMAT is a useful supplement to reading level alone in the assessment of educational materials. PMID- 28899714 TI - Qualitative evaluation of a narrative reflection program to help medical trainees recognize and avoid overuse: "Am I doing what's right for the patient?" AB - OBJECTIVE: The Do No Harm Project is a novel reflective writing program that encourages medical trainees to reflect on and write up clinical narratives about instances of avoidable medical overuse. Our goal is to describe this program and to explore the effect of the program on those participating. METHODS: Semi structured interviews were conducted to explore how participating in the project influenced the thinking, attitudes, and behaviors of participating internal medicine residents. Interviews were conducted with 20 out of the 24 participants from the first 15 months of the program. RESULTS: The following themes emerged from our analysis: 1) learning through reflection (with three sub-themes: empathy for the patient perspective, a critical approach to one's own clinical practice, and awareness of the problem of overuse); 2) empowerment to discuss instances of overuse and act before it occurs; and 3) perceptions of enhanced evidence-based practice and shared decision-making. CONCLUSION: Trainees volunteering to complete a reflective writing exercise perceived improved ability to avoid overuse and improved self-efficacy to change clinical behaviors that do not align with optimal patient care. PRACTICE IMPLICATIONS: Reflective writing may help trainees recognize and avoid medical overuse. PMID- 28899715 TI - The relationship between 25-hydroxyvitamin D concentration and liver enzymes in overweight or obese adults: Cross-sectional and interventional outcomes. AB - Vitamin D deficiency is prevalent in individuals with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. However, there is limited and inconsistent data on the effect of vitamin D supplementation on liver function. Hepatic enzymes have been used as surrogate markers for NAFLD and have been associated with metabolic syndrome. We examined the relationships between 25 hydroxyvitamin D (25(OH)D) and gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP) in 120 drug-naive individuals with no history of liver disease. In addition, the effect of vitamin D supplementation (100,000 loading dose of cholecalciferol followed by 4000IU daily for 16 weeks) on hepatic enzymes was investigated in a subgroup of 54 vitamin D deficient overweight or obese individuals (28 randomised to cholecalciferol and 26 to placebo). Hepatic enzymes, anthropometric parameters, lipid profile, insulin sensitivity (hyperinsulinaemic-euglycaemic clamp, M value) and high sensitivity C-reactive protein (hs-CRP) were measured before and after the intervention. In the cross-sectional study, levels of GGT and ALT were higher in men compared to women (both p=0.001). There were no significant differences in GGT, ALT and ALP between vitamin D categories (25(OH)D<25nmol/L, 25-50nmol/L, and >50nmol/L) and no relationships were found between the three enzymes and 25(OH)D before and after adjustment for age, sex, BMI, WHR, and insulin sensitivity (all p>0.5). In the randomised trial, 25(OH)D concentrations increased in the vitamin D group (mean change 57.0+/-21.3nmol/L) compared to the placebo group (mean change 1.9+/-15.1nmol/L). Mean changes in GGT, ALT and ALP were not significantly different between vitamin D and placebo groups (all p>0.2). Change in 25(OH)D concentration was not correlated with changes in GGT, ALT and ALP before and after adjustments for age and sex (all p>0.1). In summary, 25(OH)D concentrations were not related to hepatic enzymes in drug-naive adults with no history of liver disease, and vitamin D supplementation had no effect on the serum levels of hepatic enzymes in vitamin D-deficient and overweight or obese, otherwise healthy individuals. Hence, vitamin D supplementation is unlikely to prevent incident NAFLD. PMID- 28899716 TI - From birth to death: A role for reactive oxygen species in neuronal development. AB - Historically, ROS have been considered toxic molecules, especially when their intracellular concentration reaches high values. However, physiological levels of ROS support crucial cellular processes, acting as second messengers able to regulate intrinsic signaling pathways. Specifically, both the central and peripheral nervous systems are especially susceptible to changes in the redox state, developing either a defense or adaptive response depending on the concentration, source and duration of the pro-oxidative stimuli. In this review, we summarize classical and modern concepts regarding ROS physiology, with an emphasis on the role of the NADPH oxidase (NOX) complex, the main enzymatic and regulated source of ROS in the nervous system. We discuss how ROS and redox state contribute to neurogenesis, polarization and maturation of neurons, providing a context for the spatio-temporal conditions in which ROS modulate neural fate, discriminating between "oxidative distress", and "oxidative eustress". Finally, we present a brief discussion about the "physiological range of ROS concentration", and suggest that these values depend on several parameters, including cell type, developmental stage, and the source and type of pro oxidative molecule. PMID- 28899717 TI - Early patterns of activity in the developing cortex: Focus on the sensorimotor system. AB - Early development of somatotopic cortical maps occurs during the fetal period in humans and during the postnatal period in rodents. During this period, the sensorimotor cortex expresses transient patterns of correlated neuronal activity including delta waves, gamma- and spindle-burst oscillations. These early activity patterns are largely driven by the thalamus and triggered, in a topographic manner, by sensory feedback resulting from spontaneous movements. Early cortical activities are instrumental for competitive interactions between sensory inputs for the cortical territories, they prevent cortical neurons from apoptosis and their alteration may lead to disturbances in cortical network development in a number of neurodevelopmental diseases. PMID- 28899718 TI - Molecular characterization of circulating tumor cells-from bench to bedside. AB - Circulating tumor cells (CTCs) are cancer cells discovered in cancer patients' peripheral blood that successfully escape from the primary tumor site and/or metastases, struggle to survive in the bloodstream, and have potential for seeding metastases. Numerous methods have been proposed to capture CTCs. The value of CTCs as a means of understanding cancer metastasis and a major form of 'liquid biopsy' has been widely demonstrated. Recently, single-cell molecular analyses of CTCs have provided profound biological insights into tumor heterogeneity, mechanism of metastasis and tumor evolution. In addition, because CTC analysis is non-invasive, CTCs exhibit great potential as biomarkers for assessment of cancer prognosis and therapy response. In this review, we summarize modern technologies for CTC detection and isolation, single-cell genomic/transcriptomic characterization of CTCs, and prospective clinical applications of CTCs. We expect that, after further technical improvements in methods of detection and sequencing, CTC analyses will shed new light on the mechanisms driving cancer metastasis and benefit many cancer patients. PMID- 28899719 TI - Hepatic Masses in a Patient With Inflammatory Bowel Disease. PMID- 28899720 TI - A 59-Year-Old Man With New Jaundice. PMID- 28899721 TI - Endoscopic Resection of Esophageal Mucosal Bridge. PMID- 28899722 TI - Effect of Nonurothelial Histologic Variants on the Outcomes of Radical Cystectomy for Nonmetastatic Muscle-invasive Urinary Bladder Cancer. AB - INTRODUCTION: Knowledge of the comparative oncologic outcomes of histologic variants after radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) relies on small case series. We compared the effect of pure squamous cell carcinoma, adenocarcinoma, and neuroendocrine carcinoma compared with pure urothelial carcinoma (PUC) on overall survival (OS) and pathologic tumor, lymph node, and surgical margin status after RC. PATIENTS AND METHODS: Using the National Cancer Database, we retrospectively examined patients undergoing RC for MIBC from 2003 to 2011. Our cohort was stratified according to histologic type and included only pure variants: squamous cell, adenocarcinoma, neuroendocrine, and PUC. Inverse probability weighting-adjusted and facility-clustered Cox and logistic regression analyses were used to assess the effect of histologic variants versus PUC on OS and pathologic outcomes. RESULTS: Overall, 475 (4.4%), 224 (2.1%), 155 (1.4%), and 10,033 (92.2%) patients underwent RC for MIBC with pure squamous cell carcinoma, adenocarcinoma, neuroendocrine carcinoma, and PUC, respectively. In inverse probability weighting-adjusted analyses, squamous cell (hazard ratio, 1.26; 95% confidence interval [CI], 1.07-1.49; P = .006) and neuroendocrine (hazard ratio, 1.53; 95% CI, 1.21-1.95; P < .001) types were associated with worse OS relative to PUC. Squamous cell carcinoma (odds ratio [OR], 1.58; 95% CI, 1.23-2.04; P < .001), adenocarcinoma (OR, 1.49; 95% CI, 1.04 2.14; P = .030), and neuroendocrine carcinoma (OR, 2.37; 95% CI, 1.58-3.55; P < .001) at diagnosis were associated with greater odds of >= pT3 disease. The squamous cell and neuroendocrine variants were associated with decreased (OR, 0.66; 95% CI, 0.48-0.91; P = .012) and increased (OR, 1.58; 95% CI, 1.06-2.37; P = .026) odds of pN+ disease, respectively. Adenocarcinoma was associated with greater odds of positive margins (OR, 2.14; 95% CI, 1.39-3.30; P = .001). CONCLUSION: Pure squamous cell and neuroendocrine carcinoma histologic types were associated with worse OS relative to PUC. However, no difference was found between adenocarcinoma and PUC. All histologic variants were associated with higher tumor stage at surgery compared with PUC. PMID- 28899723 TI - Characterization of Differences Between Prostate Cancer Patients Presenting With De Novo Versus Primary Progressive Metastatic Disease. AB - BACKGROUND: Men who present with metastatic disease can have de novo or primary progressive disease. We characterized and compared the outcomes between these 2 groups. PATIENTS AND METHODS: A retrospective cross-sectional analysis from a single institution of de novo versus primary progressive metastatic patients during a 2-year consecutive period was undertaken. Patient characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment were obtained. The t test, Mann-Whitney U test, and Fisher exact test were used to test differences in patient and disease characteristics between the de novo and primary progressive metastatic groups. Differences in the Kaplan-Meier survival curves were compared using the log-rank test. RESULTS: A total of 90 patients (n = 38 with de novo and 52 with primary progressive disease) were included. Statistically significant median differences were found for the prostate-specific antigen level at the development of metastases: de novo 63.1 ng/ml vs primary progressive 12.5 ng/ml, p= <.001; albumin and hemoglobin, P = .03 and P = .045, respectively). The median duration of hormone sensitivity was 372 days (range, 54-3753 days) in the de novo group versus 1613 days (range, 7 4314 days) in the primary progressive group (P = .00006). Overall survival was worse in the de novo arm, with a median survival of 6.2 years compared with a median survival in the primary progressive group of 11.6 years (P = .027). CONCLUSION: Although the reported samples were small, our data revealed a potential difference in disease aggressiveness in those presenting with de novo metastatic cancer with higher risk disease and shorter time to castration resistance and worse survival. These data could have implications for earlier and more aggressive treatment for men presenting with de novo metastatic prostate cancer. PMID- 28899724 TI - Neo-semiotics: Introducing zeroness into Peircean semiotics may bridge the knowable and the unknowable. PMID- 28899726 TI - Benefit-risk of corticosteroids in acute gout patients: An updated meta-analysis and economic evaluation. AB - The efficacy, safety and health-economic outcomes were compared between corticosteroid and non-corticosteroid treatments in acute gout patients. All electronic literatures comparing the curative effects or full economic evaluations of corticosteroids versus non-corticosteroids on acute pain in acute gout patients and published until June 30, 2017 in any language were searched through PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Pooled odds ratios with 95% confidence intervals and standard(or weighted) mean difference were calculated using random-or fixed effects models according to the I2 statistic test of heterogeneity. Economic elevations were combined through qualitative narrative synthesis. Finally, seven randomized controlled trials(RCTs) involving 929 patients were included here and suggested corticosteroids had comparable analgesic efficacy to non corticosteroids on day 5. As for inflammation and PGA, corticosteroids might outperform non-corticosteroids in reducing tenderness and swelling. Corticosteroids versus non-corticosteroids could significantly reduce incidence of only serious adverse advents, but not total adverse advents, with substantial heterogeneity. Qualitative narrative synthesis of economic elevation involving only one study shows corticosteroids are more cost-effective than indomethacin. The existing RCTs do not provide sufficient or precise evidence that corticosteroids are superior to non-corticosteroids in pain relief of acute gout patients. Therefore, studies on chronic use of corticosteroids or comparative studies with colchicine, tramadol and/or opiates may be needed in the future, as is patient satisfaction with analgesic control. PMID- 28899727 TI - The clinical profile of patients with cardiac arrest induced by hemorrhagic stroke. PMID- 28899725 TI - Nitric oxide donor [Ru(terpy)(bdq)NO]3+ induces uncoupling and phosphorylation of endothelial nitric oxide synthase promoting oxidant production. AB - [Ru(terpy)(bdq)NO]3+ (TERPY) is a nitric oxide (NO) donor that promotes relaxation of the mesenteric artery and aorta in rats. We sought to investigate whether it acts as both an NO donor and endothelial NO synthase (eNOS) activator, as shown previously for nitroglycerin. Human umbilical vein endothelial cells (HUVECs) and human embryonic kidney 293 cells transfected with empty vector (HEK) or eNOS cDNA (HEK-eNOS) were treated with TERPY (1uM) for different lengths of time. eNOS expression, dimerization, and Ser1177 phosphorylation, caveolin-1 (Cav 1) oligomerization, Cav-1 Tyr14 phosphorylation were evaluated by Western blotting. Studies also assessed the production of reactive oxygen/nitrogen species (ROS/RNS) in HUVECs and HEK-eNOS cells. In HEK cells devoid of eNOS, TERPY released NO without additional stimulus indicating that is an NO donor. Moreover, in HEK-eNOS cells, TERPY-induced NO production that was blocked by L NAME. In addition, TERPY increased ROS and ONOO- production which were blocked by more than 80% by BH4 (essential eNOS co-factor) and eNOS siRNA. These results suggest that TERPY-induced ROS and ONOO- production were originated from eNOS. HUVECs stimulated with TERPY showed increased eNOS Ser1177 and Cav-1 Tyr14 phosphorylation, and decreased eNOS dimerization, Cav-1 oligomerization, and Cav 1/eNOS interaction after 20min. It suggests that TERPY induces eNOS hyperactivation and uncoupling by disrupting Cav-1/eNOS interaction and depleting BH4. Endothelium-dependent vasodilation in response to NO donor TERPY is associated with eNOS activation and uncoupling, and thereby appears to be mediated, at least in part, via eNOS-dependent ROS/RNS production. PMID- 28899728 TI - Maslinic acid ameliorates NMDA receptor blockade-induced schizophrenia-like behaviors in mice. AB - Schizophrenia is a chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Primary treatments for schizophrenia relieve the positive symptoms but are less effective against the negative and cognitive symptoms. In the present study, we investigated whether maslinic acid, isolated from Syzygium aromaticum (clove), can ameliorate schizophrenia-like behaviors in mice induced by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. After maslinic acid treatment in the MK-801 model, we examined the behavioral alteration and signaling pathways in the prefrontal cortex. Mice were treated with maslinic acid (30 mg/kg), and their behaviors were evaluated through an array of behavioral tests. The effects of maslinic acid were also examined in the signaling pathways in the prefrontal cortex. A single administration of maslinic acid blocked the MK-801-induced hyperlocomotion and reversed the MK-801-induced sensorimotor gating deficit in the acoustic startle response test. In the social novelty preference test, maslinic acid ameliorated the social behavior deficits induced by MK-801. The MK-801-induced attention and recognition memory impairments were also alleviated by a single administration of maslinic acid. Furthermore, maslinic acid normalized the phosphorylation levels of Akt-GSK-3beta and ERK-CREB in the prefrontal cortex. Overall, maslinic acid ameliorated the schizophrenia-like symptoms induced by MK-801, and these effects may be partly mediated through Akt-GSK-3beta and ERK-CREB activation. These findings suggest that maslinic acid could be a candidate for the treatment of several symptoms of schizophrenia, including positive symptoms, sensorimotor gating disruption, social interaction deficits, and cognitive impairments. PMID- 28899729 TI - Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala. AB - The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5 HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors. PMID- 28899730 TI - A green tea polyphenol epigallocatechin-3-gallate enhances neuroregeneration after spinal cord injury by altering levels of inflammatory cytokines. AB - Spinal cord injury (SCI) is a debilitating condition which is characterized by an extended secondary injury due to the presence of inflammatory local milieu. Epigallocatechin gallate (EGCG) appears to possess strong neuroprotective properties. Here, we evaluated the beneficial effect of EGCG on recovery from SCI. Male Wistar rats were given either EGCG or saline directly to the injured spinal cord and thereafter a daily IP injection. Behavior recovery was monitored by BBB, plantar, rotarod and flat-beam tests. The levels of inflammatory cytokines were determined on days 1, 3, 7, 10 and 14 after SCI. Additionally, NF kappaB pathway activity was evaluated. The results demonstrated that EGCG-treated rats displayed a superior behavioral performance in a flat beam test, higher axonal sprouting and positive remodelation of glial scar. Cytokine analysis revealed a reduction in IL-6, IL2, MIP1alpha and RANTES levels on days 1 and 3, and an upregulation of IL-4, IL-12p70 and TNFalpha 1 day following SCI in EGCG treated rats. Treatment with EGCG was effective in decreasing the nuclear translocation of subunit p65 (RelA) of the NF-kappaB dimer, and therefore canonical NF-kappaB pathway attenuation. A significant increase in the gene expression of growth factors (FGF2 and VEGF), was noted in the spinal cord of EGCG-treated rats. Further, EGCG influenced expression of M1 and M2 macrophage markers. Our results have demonstrated a therapeutic value of EGCG in SCI, as observed by better behavioral performance measured by flat beam test, modulation of inflammatory cytokines and induction of higher axonal sprouting. PMID- 28899731 TI - Combined physical-cognitive training enhances postural performances during daily life tasks in older adults. AB - Physical-cognitive interventions seem promising to improve balance and gait performances and prevent falls in the elderly. Although these beneficial effects, it is still not clear whether these physical-cognitive training modalities leads to more general non-specific adaptations that can be transferred to some measures reflecting every day abilities. This randomized controlled trial examined postural (center of pressure oscillations), physical (lower body strength, gait speed, functional mobility, dynamic balance) and cognitive performances (reaction time) and postural performance during daily life tasks (walking while conversing on a phone and maintaining an upright standing posture while buttoning a shirt) in older adults (66.29+/-3.61years) pre- and post- 6-months physical and physical cognitive interventions. Results showed that both training modalities improve balance (p<0.001), physical functions (p<0.01) and attention (p<0.001) in older adults. Only simultaneous physical-cognitive training enhances performance in daily life tasks. Three months after the intervention, these improvements were generally maintained for physical functions and attention and were not maintained for the postural performances in daily life task. In conclusion, physical training improves postural balance, mobility, attention and physical functions in older adults. Only simultaneous physical-cognitive training modality enhances performance in some tasks relative to every day abilities. Nonetheless, these gains were lost after 3 months of detraining period suggesting a need for older people to participate regularly in such training for their daily life independence. PMID- 28899732 TI - Administration of tranexamic acid to reduce maternal mortality related to postpartum haemorrhage: comments on the WOMAN trial. PMID- 28899733 TI - Paralysis analysis - does choice of muscle relaxant for obstetric general anaesthesia influence neonatal outcomes? PMID- 28899734 TI - Anaesthetic management of pregnant patients with cardiac implantable electronic devices: case reports and review. AB - Heart disease is a leading cause of maternal mortality and morbidity. Pregnant women with structural, conduction or degenerative cardiac disease who require rhythm control or who are at high risk of sudden cardiac death may carry a cardiac implantable electronic device or may occasionally require the insertion of one during their pregnancy. These women are now encountered more frequently in clinical practice, and it is essential that a multidisciplinary approach, beginning from the early antenatal phase, be adopted in their counselling and management. Contemporary cardiac rhythm control devices are a constantly evolving technology with increasingly sophisticated features; anaesthetists should therefore have an adequate understanding of the principles of their operation and the special considerations for their use, in order to enable their safe management in the peripartum period. Of particular importance is the potential adverse effect of electromagnetic interference, which may cause device malfunction or damage, and the precautions required to reduce this risk. The ultimate goal in the management of this patient subgroup is to minimise the disruption to cardiovascular physiology that may occur near the time of labour and delivery and to control the factors that impact on device integrity and function. We present the ante- and peripartum management of two pregnant women with an implantable cardioverter-defibrillator, followed by a review and update of the anaesthetic management of parturients with cardiac implantable electronic devices. PMID- 28899735 TI - A randomised comparison of bolus phenylephrine and ephedrine for the management of spinal hypotension in patients with severe preeclampsia and fetal compromise. AB - BACKGROUND: Studies in healthy patients undergoing elective caesarean delivery show that, compared with phenylephrine, ephedrine used to treat spinal hypotension is associated with increased fetal acidosis. This has not been investigated prospectively in women with severe preeclampsia. METHODS: Patients with preeclampsia requiring caesarean delivery for a non-reassuring fetal heart tracing were randomised to receive either bolus ephedrine (7.5-15mg) or phenylephrine (50-100ug), to treat spinal hypotension. The primary outcome was umbilical arterial base excess. Secondary outcomes were umbilical arterial and venous pH and lactate concentration, venous base excess, and Apgar scores. RESULTS: Among 133 women, 64 who required vasopressor treatment were randomised into groups of 32 with similar patient characteristics. Pre-delivery blood pressure changes were similar. There was no difference in mean [standard deviation] umbilical artery base excess (-4.9 [3.7] vs -6.0 [4.6] mmol/L for ephedrine and phenylephrine respectively; P=0.29). Mean umbilical arterial and venous pH and lactate concentrations did not significantly differ between groups (7.25 [0.08] vs 7.22 [0.10], 7.28 [0.07] vs 7.27 [0.10], and 3.41 [2.18] vs 3.28 [2.44] mmol/L respectively). Umbilical venous oxygen tension was higher in the ephedrine group (2.8 [0.7] vs 2.4 [0.62]) kPa, P=0.02). There was no difference in 1- or 5-min Apgar scores, numbers of neonates with 1-min Apgar scores <7 or with a pH <7.2. CONCLUSIONS: In patients with severe preeclampsia and fetal compromise, fetal acid-base status is independent of the use of bolus ephedrine versus phenylephrine to treat spinal hypotension. PMID- 28899736 TI - Characterization of genome-wide copy number aberrations in colonic mixed adenoneuroendocrine carcinoma and neuroendocrine carcinoma reveals recurrent amplification of PTGER4 and MYC genes. AB - Colonic mixed adenoneuroendocrine carcinoma (MANEC) is an aggressive neoplasm with worse prognosis compared with adenocarcinoma. To gain a better understanding of the molecular features of colonic MANEC, we characterized the genome-wide copy number aberrations of 14 MANECs and 5 neuroendocrine carcinomas using the OncoScan FFPE (Affymetrix, Santa Clara, CA) assay. Compared with 269 colonic adenocarcinomas, 19 of 42 chromosomal arms of MANEC exhibited a similar frequency of major aberrant events as adenocarcinomas, and 13 chromosomal arms exhibited a higher frequency of copy number gains. Among them, the most significant chromosomal arms were 5p (77% versus 13%, P = .000012) and 8q (85% versus 33%, P = .0018). The Genomic Identification of Significant Targets in Cancers algorithm identified 7 peaks that drive the tumorgenesis of MANEC. For all except 5p13.1, the peaks largely overlapped with those of adenocarcinoma. Two tumors exhibited MYC amplification localized in 8q24.21, and 2 tumors exhibited PTGER4 amplification localized in 5p13.1. A total of 8 tumors exhibited high copy number gain of PTGER4 and/or MYC. Whereas the frequency of MYC amplification was similar to adenocarcinoma (10.5% versus 4%, P = .2), the frequency of PTGER4 amplification was higher than adenocarcinoma (10.5% versus 0.3%, P = .01). Our study demonstrates similar, but also distinct, copy number aberrations in MANEC compared with adenocarcinoma and suggests an important role for the MYC pathway of colonic carcinoma with neuroendocrine differentiation. The discovery of recurrent PTGER4 amplification implies a potential of exploring targeting therapy to the prostaglandin synthesis pathways in a subset of these tumors. PMID- 28899737 TI - Expression of YES-associated protein (YAP) and its clinical significance in breast cancer tissues. AB - The transcriptional co-activator YES-associated protein (YAP) has been reported to act as both an oncogene and tumor suppressor in breast cancers. In this study, we evaluated YAP expression immunohistochemically in 324 breast cancer tissues and correlated the expression with clinicopathological findings and patient survival data. Additionally, we reviewed the literature to clarify the role of YAP in breast cancer. We detected YAP, estrogen receptor, progesterone receptor (PR), and human epidermal growth receptor-2 (HER2) expression and a Ki67 labeling index >20% in 53.4%, 49.0%, 45.0%, 28.3%, and 57.4% of invasive ductal carcinoma tissues, respectively. YAP is mainly localized within the tumor cell nuclei, and its expression was associated with the PR status and luminal A subtype. YAP expression also inversely correlated with the HER2 and Ki67 levels and lymph node metastasis. Kaplan-Meier curves revealed associations of YAP expression with favorable disease-free survival (DFS) and overall survival in patients with luminal A breast cancer and with favorable DFS association among patients with invasive ductal carcinoma, luminal B (HER2-), and luminal B (HER2+) breast cancers. A multivariate Cox analysis revealed that YAP expression and PR status were independent favorable predictors of DFS and overall survival, respectively, among patients with breast cancer, whereas tumor-node-metastasis stage and an old age were independent predictors of a poor DFS. Our results, together with the literature review findings, suggest that YAP could be a prognostic marker in patients with breast cancer. PMID- 28899738 TI - Angiomyomatous hamartoma of lymph nodes, revisited: clinicopathologic study of 21 cases, emphasizing its distinction from lymphangioleiomyomatosis of lymph nodes. AB - Angiomyomatous hamartoma of lymph nodes (AMH-LN) is an uncommon benign proliferation of smooth muscle, blood vessels, collagenous stroma, and adipocytes, most commonly affecting inguinal LN. A similar constellation of cell types constitutes various members of the perivascular epithelioid cell tumor (PEComa) family, including lymphangioleiomyomatosis (LAM), which can involve LN in women. Because some LN-LAM patients have tuberous sclerosis complex and/or other PEComa family lesions, it is clinically relevant to distinguish LN-LAM from AMH-LN. Given their similar features, however, the possibility that AMH-LN is a morphologic variant of LN-LAM merits inquiry. The dual melanocytic and myoid immunophenotype distinguishes the PEComa family from its mimics. Cathepsin K has recently emerged as a more sensitive marker for the PEComa family than HMB-45, which can be weak and focal, but cathepsin K has not been studied in AMH-LN. This study evaluated 21 AMH-LNs for clinical, morphologic, and immunophenotypic features of LN-LAM. None (0/21) had tuberous sclerosis complex or PEComas. Thirteen (62%) were male, unlike LN-LAM, which is restricted to women. All cases exhibited intraparenchymal proliferation of variable-sized, thick-walled blood vessels within collagenous stroma containing a sparse to focally cellular population of haphazardly distributed smooth muscle cells. Admixed adipocytes were commonly present. None exhibited classical features of LN-LAM such as subcapsular localization, extranodal extension, intralymphatic growth, compact nests, branching lymphatic channels, plump cell shape, or foamy/clear cytoplasm. None exhibited any staining for cathepsin K, HMB-45, or microphthalmia transcription factor. There is no clinical, morphologic, or immunohistochemical evidence to suggest that AMH-LN is a variant of LN-LAM. PMID- 28899739 TI - Epithelial-mesenchymal transition of tumor budding in colorectal cancer: the mystery of CD44-positive stromal cells. PMID- 28899740 TI - Histone 3.3 mutations in giant cell tumor and giant cell-rich sarcomas of bone. AB - Mutually exclusive histone 3.3 gene mutations have been recognized in chondroblastoma and giant cell tumor of bone (GCTB), which may be useful for differential diagnostic purposes in morphologically ambiguous cases. Although more than 90% of GCTBs present histone 3.3 variants exclusively in the H3F3A gene, chondroblastoma is mutated mainly in H3F3B. In this study, we examined a series of giant cell-rich primary bone tumors, aiming to evaluate the possible diagnostic role of histone 3.3 mutations in the differential diagnosis between GCTB and giant cell-rich sarcomas. Sixteen cases of nonmetastatic GCTB, 9 GCTBs with lung metastases, and 35 giant cell-rich sarcomas were selected from our institutional archives. Eight chondroblastomas were used as controls. Direct sequencing for the presence of H3F3A and H3F3B variants in coding region between codons 1 and 42, including the hotspot codons (28, 35, and 37), was performed on DNA extracted from formalin-fixed, paraffin-embedded tissue using conventional polymerase chain reaction and fast coamplification at lower denaturation temperature-polymerase chain reaction. Overall, 24 GCTBs (96%) presented a mutation in the H3F3A gene (15 of 16 nonmetastatic and 9 of 9 metastatic). Five sarcomas harbored an H3F3A mutation (3 p.G35W, 1 p.G35L, and 1 p.G35E), and these were all secondary malignant GCTBs. In conclusion, we confirm that H3F3A mutational testing may be a useful adjunct to differentiate GCTB from giant cell rich sarcomas. Although the presence of H3F3A mutations does not exclude with certainty a diagnosis of sarcoma, the possibility of a malignant evolution of GCTB should also be considered. PMID- 28899741 TI - Small bowel stenosis: a manifestation of chronic graft-versus-host disease in children? AB - Digestive graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation, but small bowel obstruction is an extremely rare event. We present herein the first pediatric series of 4 cases of small bowel obstruction after bone marrow transplantation with detailed gross, histological data and their genetic status of the NOD2 gene. All patients had a history of severe acute GVHD treated by immunosuppressive agents and/or infliximab (in 3 cases). Acute or progressively worsening abdominal pain accompanied by small bowel occlusion occurred 5-16 months after graft, and computed tomographic scan revealed multiple small intestinal stenoses. Failure of intensive medical treatment led to surgical resection of affected loops. Stigmata of acute (apoptosis of crypts and satellitosis) and chronic GVHD features (submucosal fibrosis and serosae sclerolipomatosis), as well as extensive ulcerations, were observed in all ileal specimens. NOD2 mutation was found in only 1 patient. The follow-up showed successful outcome after surgery. PMID- 28899742 TI - ICN_Atlas: Automated description and quantification of functional MRI activation patterns in the framework of intrinsic connectivity networks. AB - Generally, the interpretation of functional MRI (fMRI) activation maps continues to rely on assessing their relationship to anatomical structures, mostly in a qualitative and often subjective way. Recently, the existence of persistent and stable brain networks of functional nature has been revealed; in particular these so-called intrinsic connectivity networks (ICNs) appear to link patterns of resting state and task-related state connectivity. These networks provide an opportunity of functionally-derived description and interpretation of fMRI maps, that may be especially important in cases where the maps are predominantly task unrelated, such as studies of spontaneous brain activity e.g. in the case of seizure-related fMRI maps in epilepsy patients or sleep states. Here we present a new toolbox (ICN_Atlas) aimed at facilitating the interpretation of fMRI data in the context of ICN. More specifically, the new methodology was designed to describe fMRI maps in function-oriented, objective and quantitative way using a set of 15 metrics conceived to quantify the degree of 'engagement' of ICNs for any given fMRI-derived statistical map of interest. We demonstrate that the proposed framework provides a highly reliable quantification of fMRI activation maps using a publicly available longitudinal (test-retest) resting-state fMRI dataset. The utility of the ICN_Atlas is also illustrated on a parametric task modulation fMRI dataset, and on a dataset of a patient who had repeated seizures during resting-state fMRI, confirmed on simultaneously recorded EEG. The proposed ICN_Atlas toolbox is freely available for download at http://icnatlas.com and at http://www.nitrc.org for researchers to use in their fMRI investigations. PMID- 28899743 TI - cTBS disruption of the supplementary motor area perturbs cortical sequence representation but not behavioural performance. AB - Neuroimaging studies have repeatedly emphasized the role of the supplementary motor area (SMA) in motor sequence learning, but interferential approaches have led to inconsistent findings. Here, we aimed to test the role of the SMA in motor skill learning by combining interferential and neuroimaging techniques. Sixteen subjects were trained on simple finger movement sequences for 4 days. Afterwards, they underwent two neuroimaging sessions, in which they executed both trained and novel sequences. Prior to entering the scanner, the subjects received inhibitory transcranial magnetic stimulation (TMS) over the SMA or a control site. Using multivariate fMRI analysis, we confirmed that motor training enhances the neural representation of motor sequences in the SMA, in accordance with previous findings. However, although SMA inhibition altered sequence representation (i.e. between-sequence decoding accuracy) in this area, behavioural performance remained unimpaired. Our findings question the causal link between the neuroimaging correlate of elementary motor sequence representation in the SMA and sequence generation, calling for a more thorough investigation of the role of this region in performance of learned motor sequences. PMID- 28899745 TI - Primatologist: A modular segmentation pipeline for macaque brain morphometry. AB - Because they bridge the genetic gap between rodents and humans, non-human primates (NHPs) play a major role in therapy development and evaluation for neurological disorders. However, translational research success from NHPs to patients requires an accurate phenotyping of the models. In patients, magnetic resonance imaging (MRI) combined with automated segmentation methods has offered the unique opportunity to assess in vivo brain morphological changes. Meanwhile, specific challenges caused by brain size and high field contrasts make existing algorithms hard to use routinely in NHPs. To tackle this issue, we propose a complete pipeline, Primatologist, for multi-region segmentation. Tissue segmentation is based on a modular statistical model that includes random field regularization, bias correction and denoising and is optimized by expectation maximization. To deal with the broad variety of structures with different relaxing times at 7 T, images are segmented into 17 anatomical classes, including subcortical regions. Pre-processing steps insure a good initialization of the parameters and thus the robustness of the pipeline. It is validated on 10 T2 weighted MRIs of healthy macaque brains. Classification scores are compared with those of a non-linear atlas registration, and the impact of each module on classification scores is thoroughly evaluated. PMID- 28899746 TI - Performance of five research-domain automated WM lesion segmentation methods in a multi-center MS study. AB - BACKGROUND AND PURPOSE: In vivoidentification of white matter lesions plays a key role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset. METHODS: 70 MS patients (median EDSS of 2.0 [range 0.0 6.5]) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on 'unseen' center. RESULTS: Compared to the reference mean lesion volume (4.85 +/- 7.29 mL), the methods displayed a mean difference of 1.60 +/- 4.83 (Cascade), 2.31 +/- 7.66 (LGA), 0.44 +/- 4.68 (LPA), 1.76 +/- 4.17 (Lesion-TOADS) and -1.39 +/- 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 +/- 0.23), Lesion TOADS (SI = 0.35 +/- 0.18) and kNN-TTP (SI = 0.44 +/- 0.14) than for Cascade (SI = 0.26 +/- 0.17) or LGA (SI = 0.31 +/- 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization. CONCLUSION: The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods. PMID- 28899747 TI - A neural signature of food semantics is associated with body-mass index. AB - Visual recognition of objects may rely on different features depending on the category to which they belong. Recognizing natural objects, such as fruits and plants, weighs more on their perceptual attributes, whereas recognizing man-made objects, such as tools or vehicles, weighs more upon the functions and actions they enable. Edible objects are perceptually rich but also prepared for specific functions, therefore it is unclear how perceptual and functional attributes affect their recognition. Two event-related potentials experiments investigated: (i) whether food categorization in the brain is differentially modulated by sensory and functional attributes, depending on whether the food is natural or transformed; (ii) whether these processes are modulated by participants' body mass index. In experiment 1, healthy normal-weight participants were presented with a sentence (prime) and a photograph of a food. Primes described either a sensory feature ('It tastes sweet') or a functional feature ('It is suitable for a wedding party') of the food, while photographs depicted either a natural (e.g., cherry) or a transformed food (e.g., pizza). Prime-feature pairs were either congruent or incongruent. This design aimed at modulating N400-like components elicited by semantic processing. In experiment 1, N400-like amplitude was significantly larger for transformed food than for natural food with sensory primes, and vice versa with functional primes. In experiment 2, underweight and obese women performed the same semantic task. We found that, while the N400-like component in obese participants was modulated by sensory-functional primes only for transformed food, the same modulation was found in underweight participants only for natural food. These findings suggest that the level of food transformation interacts with participants' body mass index in modulating food perception and the underlying brain processing. PMID- 28899748 TI - Biomonitoring of 2,4,6-trinitrotoluene and degradation products in the marine environment with transplanted blue mussels (M. edulis). AB - Since World War I considerable amounts of warfare material have been dumped at sea worldwide, but little is known about the fate of the explosive components in the marine environment. Sea dumped munitions are able to contaminate the surroundings because of the release of explosive chemicals due to corrosion and breaching or by detonation after blast-operations. This implies the risk of accumulation of toxic compounds in human and wildlife food chains. With the help of divers, we performed an active biomonitoring study with transplanted blue mussels (M. edulis) in a burdened area (Kolberger Heide, Germany) with explosive compounds near blast craters over an exposure time of 93days. With this biomonitoring system, we could show that blue mussels accumulate 2,4,6 trinitrotoluene (TNT) and its metabolites 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT) in their tissues. In all mussels deployed at the ground, we found a body burden with 2-ADNT of 103.75+/-12.77ng/g wet weight and with 4-ADNT of 131.31+/-9.53ng/g wet weight. TNT itself has been found in six mussels with an average concentration of 31.04+/-3.26ng/g mussel wet weight. In the mussels positioned at one meter above the ground no TNT nor 2-ADNT could be detected, but 4-ADNT was found in all samples with an average concentration of 8.71+/-2.88ng/g mussel wet weight. To the best of our knowledge, this is the first study using blue mussels M. edulis as an active biomonitoring system for TNT and its metabolites 2-ADNT and 4-ADNT in a free field experiment in a burdened area. Moreover, with this system, we unequivocally proved that these toxic explosives accumulate in the marine biota resp. in the marine food chain, thereby posing a possible risk to the marine ecosphere and human health. PMID- 28899744 TI - Neural and metabolic basis of dynamic resting state fMRI. AB - Resting state fMRI (rsfMRI) as a technique showed much initial promise for use in psychiatric and neurological diseases where diagnosis and treatment were difficult. To realize this promise, many groups have moved towards examining "dynamic rsfMRI," which relies on the assumption that rsfMRI measurements on short time scales remain relevant to the underlying neural and metabolic activity. Many dynamic rsfMRI studies have demonstrated differences between clinical or behavioral groups beyond what static rsfMRI measured, suggesting a neurometabolic basis. Correlative studies combining dynamic rsfMRI and other physiological measurements have supported this. However, they also indicate multiple mechanisms and, if using correlation alone, it is difficult to separate cause and effect. Hypothesis-driven studies are needed, a few of which have begun to illuminate the underlying neurometabolic mechanisms that shape observed differences in dynamic rsfMRI. While the number of potential noise sources, potential actual neurometabolic sources, and methodological considerations can seem overwhelming, dynamic rsfMRI provides a rich opportunity in systems neuroscience. Even an incrementally better understanding of the neurometabolic basis of dynamic rsfMRI would expand rsfMRI's research and clinical utility, and the studies described herein take the first steps on that path forward. PMID- 28899749 TI - CYP4A/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats. AB - The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days. Blood pressure (BP) was measured by tail-cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25mgkg-1day-1 for 7days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2mgkg-1day-1) or nifedipine (3mgkg-1day-1) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling. PMID- 28899750 TI - Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen treatment facilitates cell proliferation and slowing down of DNA damage response in GST-P expressing preneoplastic lesions. AB - We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and gammaH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or gammaH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARalpha agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis. PMID- 28899751 TI - Homeostatic and circadian mechanisms of bioluminescence regulation differ between a forest and a facultative cave species of glowworm, Arachnocampa. AB - Glowworms, members of the keroplatid fly genus, Arachnocampa, glow to attract prey. Here we describe substantial differences in the bioluminescence regulatory systems of two species; one is a troglophile with populations both in caves and outside of caves in wet forest (Arachnocampa tasmaniensis) and the other has no known cave populations (Arachnocampa flava). We find that A. tasmaniensis is ready to initiate bioluminescence at any time darkness is encountered. In contrast, A. flava shows a homeostatic control of bioluminescence; it is unlikely to initiate bioluminescence when exposed to dark pulses during the photophase and it does so with a long latency. Another difference between the two species is that A. tasmaniensis individuals synchronize their bioluminescence in the dark zone of caves under the control of the circadian system and A. flava individuals do not synchronize to each other, rather their circadian control system entrains to the light:dark cycle to promote nocturnal bioluminescence. Consequently, we produced a phase-response curve in response to photic entrainment under constant darkness for both species. The shape of the phase-response curves differs between the two species as does the overall sensitivity to the identical entrainment conditions. The phase-response curve of A. tasmaniensis facilitates synchronization whereas that of A. flava facilitates nocturnal glowing. The two species comparison highlights possible pathways of divergence of circadian control of physiological functions that could be associated with the extreme ecological differences experienced in cave and surface habitats. PMID- 28899752 TI - Are adult life history traits in oriental fruit moth affected by a mild pupal heat stress? AB - Thermal stress at one life stage can affect fitness at a later stage in ectotherms with complex life cycles. Most relevant studies have focused on extreme stress levels, but here we also show substantial fitness effects in a moth when pupae are exposed to a relatively mild and sublethal heat stress. We consider the impact of a 35 degrees C heat stress of 2h in three geographically separate populations of the oriental fruit moth (OFM, Grapholita molesta) from northern, middle and southern China. Heat stress negatively affected fecundity but increased adult heat resistance and adult longevity. Fitness effects were mostly consistent across populations but there were also some population differences. In the Shenyang population from northern China, there was a hormetic effect of heat on female longevity not evident in the other populations. Adults from all populations had higher LT50s due to heat stress after pupal exposure to the sublethal stress. These results highlight that the pupal stage is a particularly sensitive window for development and they have implications for seasonal adaptation in uncertain environments as well as changes in pest dynamics under climate warming. PMID- 28899753 TI - Precise gene editing of chicken Na+/H+ exchange type 1 (chNHE1) confers resistance to avian leukosis virus subgroup J (ALV-J). AB - Avian leukosis virus subgroup J (ALV-J), first isolated in the late 1980s, has caused economic losses to the poultry industry in many countries. As all chicken lines studied to date are susceptible to ALV infection, there is enormous interest in developing resistant chicken lines. The ALV-J receptor, chicken Na+/H+ exchange 1 (chNHE1) and the critical amino acid sequences involved in viral attachment and entry have already been characterized. However, there are no reported attempts to induce resistance to the virus by targeted genome modification of the receptor sequences. In an attempt to induce resistance to ALV J infection, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated (CRISPR/Cas9)-based genome editing approaches to modify critical residues of the chNHE1 receptor in chicken cells. The susceptibility of the modified cell lines to ALV-J infection was examined using enhanced green fluorescent protein (EGFP)-expressing marker viruses. We showed that modifying the chNHE1 receptor by artificially generating a premature stop codon induced absolute resistance to viral infection, with mutations of the tryptophan residue at position 38 (Trp38) being very critical. Single-stranded oligodeoxynucleotide (ssODN)-mediated targeted recombination of the Trp38 region revealed that deletions involving the Trp38 residue were most effective in conferring resistance to ALV-J. Moreover, protein structure analysis of the chNHE1 receptor sequence suggested that its intrinsically disordered region undergoes local conformational changes through genetic alteration. Collectively, these results demonstrate that targeted mutations on chNHE1 alter the susceptibility to ALV-J and the technique is expected to contribute to develop disease-resistant chicken lines. PMID- 28899754 TI - On the Whereabouts of HIV-1 Cellular Entry and Its Fusion Ports. AB - HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus-cell fusion in vitro may contribute to the development of future therapeutic interventions. Collectively, novel findings underline the need for potent, host-directed therapies that disrupt the earliest stages of the virus life cycle and preclude the emergence of resistant viral variants. PMID- 28899755 TI - NAD+ in Aging: Molecular Mechanisms and Translational Implications. AB - The coenzyme NAD+ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD+ levels is important for cells with high energy demands and for proficient neuronal function. NAD+ depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD+ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD+ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD+ biosynthesis, together with putative mechanisms of NAD+ action against aging, including recent preclinical and clinical trials. PMID- 28899756 TI - Stability-based sorting: The forgotten process behind (not only) biological evolution. AB - Natural selection is considered to be the main process that drives biological evolution. It requires selected entities to originate dependent upon one another by the means of reproduction or copying, and for the progeny to inherit the qualities of their ancestors. However, natural selection is a manifestation of a more general persistence principle, whose temporal consequences we propose to name "stability-based sorting" (SBS). Sorting based on static stability, i.e., SBS in its strict sense and usual conception, favours characters that increase the persistence of their holders and act on all material and immaterial entities. Sorted entities could originate independently from each other, are not required to propagate and need not exhibit heredity. Natural selection is a specific form of SBS-sorting based on dynamic stability. It requires some form of heredity and is based on competition for the largest difference between the speed of generating its own copies and their expiration. SBS in its strict sense and selection thus have markedly different evolutionary consequences that are stressed in this paper. In contrast to selection, which is opportunistic, SBS is able to accumulate even momentarily detrimental characters that are advantageous for the long-term persistence of sorted entities. However, it lacks the amplification effect based on the preferential propagation of holders of advantageous characters. Thus, it works slower than selection and normally is unable to create complex adaptations. From a long-term perspective, SBS is a decisive force in evolution-especially macroevolution. SBS offers a new explanation for numerous evolutionary phenomena, including broad distribution and persistence of sexuality, altruistic behaviour, horizontal gene transfer, patterns of evolutionary stasis, planetary homeostasis, increasing ecosystem resistance to disturbances, and the universal decline of disparity in the evolution of metazoan lineages. SBS acts on all levels in all biotic and abiotic systems. It could be the only truly universal evolutionary process, and an explanatory framework based on SBS could provide new insight into the evolution of complex abiotic and biotic systems. PMID- 28899757 TI - Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study. AB - The inferior longitudinal fascicle (ILF) is one of the major occipital-temporal association pathways. Several studies have mapped its hierarchical segmentation to specific functions. There is, however, no consensus regarding a detailed description of ILF fibre organisation. The aim of this study was to establish whether the ILF has a constant number of subcomponents. A secondary aim was to determine the quantitative diffusion proprieties of each subcomponent and assess their anatomical trajectories and connectivity patterns. A white matter dissection of 14 post-mortem normal human hemispheres was conducted to define the course of the ILF and its subcomponents. These anatomical results were then investigated in 24 right-handed, healthy volunteers using in vivo diffusion tensor imaging (DTI) and streamline tractography. Fractional anisotropy (FA), volume, fibre length and the symmetry coefficient of each fibre group were analysed. In order to show the connectivity pattern of the ILF, we also conducted an analysis of the cortical terminations of each segment. We confirmed that the main structure of the ILF is composed of three constant components reflecting the occipital terminations: the fusiform, the lingual and the dorsolateral-occipital. ILF volume was significantly lateralised to the right. The examined indices of ILF subcomponents did not show any significant difference in lateralisation. The connectivity pattern and the quantitative distribution of ILF subcomponents suggest a pivotal role for this bundle in integrating information from highly specialised modular visual areas with activity in anterior temporal territory, which has been previously shown to be important for memory and emotions. PMID- 28899758 TI - Chronic global analysis of vascular permeability and cerebral blood flow after bone marrow stromal cell treatment of traumatic brain injury in the rat: A long term MRI study. AB - Vascular permeability and hemodynamic alteration in response to the transplantation of human bone marrow stromal cells (hMSCs) after traumatic brain injury (TBI) were longitudinally investigated in non directly injured and normal appearing cerebral tissue using magnetic resonance imaging (MRI). Male Wistar rats (300-350g, n=30) subjected to controlled cortical impact TBI were intravenously injected with 1ml of saline (at 6-h or 1-week post-injury, n=5/group) or with hMSCs in suspension (~3*106 hMSCs, at 6-h or 1-week post injury, n=10/group). MRI measurements of T2-weighted imaging, cerebral blood flow (CBF) and blood-to-brain transfer constant (Ki) of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), and neurological behavioral estimates were performed on all animals at multiple time points up to 3-months post-injury. Our long-term imaging data show that blood-brain barrier (BBB) breakdown and hemodynamic disruption after TBI, as revealed by Ki and CBF, respectively, affect both hemispheres of the brain in a diffuse manner. Our data reveal a sensitive vascular permeability and hemodynamic reaction in response to the time-dependent transplantation of hMSCs. A more rapid reduction of Ki following cell treatment is associated with a higher level of CBF in the injured brain, and acute (6h) cell administration leads to enhanced therapeutic effects on both the recovery of vascular integrity and stabilization of cerebral perfusion compared to delayed (1w) cell engraftment. Our results indicate that cell-enhanced BBB reconstitution plays an important role in underlying the restoration of CBF in the injured brain, which in turn, contributes to the improvement of functional outcome. PMID- 28899759 TI - Hippocampal metabolism and prefrontal brain structure: A combined 1H-MR spectroscopy, neuropsychological, and voxel-based morphometry (VBM) study. AB - Hippocampal structural and functional integrity impacts on multiple remote areas of the brain, and this connectivity is central to multiple cognitive functions in healthy and disease. We studied associations of hippocampal metabolic markers N acetyl aspartate (NAA) and glutamate (Glu and Glx; assessed with 1H magnetic resonance spectroscopy) and brain grey matter (studied with voxel-based morphometry, VBM) in 20 healthy subjects. We found a significant correlation between right hippocampal NAA and left ventrolateral prefrontal cortical grey matter (TFCE, p<0.05, FWE-corrected), as well as verbal fluency markers, and right hippocampal Glx (glutamate/glutamine) and left cerebellar volume. Our studies demonstrate a structure-function correlation that might underlie the interaction of the hippocampus with prefrontal cortex and cerebellum, which might be central to several neurological and psychiatric disorders, including schizophrenia or depression. PMID- 28899760 TI - Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse. AB - It is suggested that altered neuroplasticity contributes to the pathophysiology of schizophrenia and antipsychotics may exhibit some of their therapeutic efficacies by improving neurogenesis and/or proliferation of neural progenitors. The aim of this study is to investigate whether chronic antipsychotics treatment affect neurogenesis in adult mouse hippocampus. Animals were administered olanzapine, quetiapine, clozapine, risperidone, aripiprazole, or haloperidol via the osmotic minipump for 21days and then injected with 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells. BrdU-positive cells in the hippocampus were quantified by stereology. Aripiprazole, quetiapine, clozapine, and olanzapine significantly increased density of BrdU-positive cells in the hippocampus. Interestingly, other antipsychotic drugs had tendency to increasing BrdU-positive cells, whereas haloperidol had propensity to decrease with a marginal significance. These results suggest that differences of neurogenesis among these drugs may, at least in part, account for their pharmacological profiles. PMID- 28899761 TI - Major contraindication to the endotoxemia activity assay in septic shock patients. PMID- 28899762 TI - The role of non-endothelial cells on the penetration of nanoparticles through the blood brain barrier. AB - The blood brain barrier (BBB) is a well-established cell-based membrane that circumvents the central nervous system (CNS), protecting it from harmful substances. Due to its robustness and cell integrity, it is also an outstanding opponent when it comes to the delivery of several therapeutic agents to the brain, which requires the crossing through its highly-organized structure. This regulation and cell-cell communications occur mostly between astrocytes, pericytes and endothelial cells. Therefore, alternative ways to deliver drugs to the CNS, overcoming the BBB are required, to improve the efficacy of brain target drugs. Nanoparticles emerge here as a promising drug delivery strategy, due to their ability of high drug loading and the capability to exploit specific delivery pathways that most drugs are unable to when administered freely, increasing their bioavailability in the CNS. Thus, further attempts to assess the possible influence of non-endothelial may have on the BBB translocation of nanoparticles are here revised. Furthermore, the use of macrophages and/or monocytes as nanoparticle delivery cells are also approached. Lastly, the temporarily disruption of the overall organization and normal structure of the BBB to promote the penetration of nanoparticles aimed at the CNS is described, as a synergistic path. PMID- 28899763 TI - Provoking an end-to-end continuous direct compression line with raw materials prone to segregation. AB - Continuous manufacturing of solid oral dosage forms is promising for increasing the efficiency and quality of pharmaceutical production and products. In this study a whole train continuous direct compression (CDC) line has been provoked using challenging formulations typically prone to segregation in batch powder processing. Industrial compositions including components with variable size, bulk density and cohesive nature were selected. An experimental design, including variables such as API/mannitol particle size, API amount, powder feed rate and mixer speed, enabled the output quality of the provoked process to be assessed. Contrary to previous studies, a broader range of finished tablet quality attributes were probed, including content, uniformity of content, tensile strength as well as release performance. Overall, the continuous direct compression line was found to be a capable and efficient manufacturing process for the challenging compositions studied and surprisingly tolerable to handle the materials susceptible to segregation in typical batch settings. As expected, and given the 'fixed' apparatus configuration used in this study, the particulate material properties were found to have the most significant impact on the finished tablet quality attributes. The results emphasize the importance for taking a holistic approach when developing the operational windows and the strategy for control, e.g. by integrating the appropriate material properties, the actual apparatus design, and the relevant formulation design. The CDC line's ability to handle cohesive materials also seem to be one of the key advantages, thus confirming the recent promising results from other continuous direct compression studies. PMID- 28899764 TI - Iron oxide core oil-in-water nanoemulsion as tracer for atherosclerosis MPI and MRI imaging. AB - PURPOSE: For early atherosclerosis imaging, magnetic oil-in-water nanoemulsion (NE) decorated with atheroma specific monoclonal antibody was designed for Magnetic Particle Imaging (MPI) and Magnetic Resonance Imaging (MRI). MPI is an emerging technique based on direct mapping of superparamagnetic nanoparticles which may advantageously complement MRI. METHODS: NE oily droplets were loaded with superparamagnetic iron oxide nanoparticles of 7, 11 and 18nm and biofunctionalized with atheroma specific scFv-Fc TEG4-2C antibody. RESULTS: Inclusion of nanoparticles inside NE did not change the hydrodynamic diameter of the oil droplets, close to 180nm, nor the polydispersity. The droplets were negatively charged (zeta=-30mV). In vitro MPI signal was assessed by Magnetic Particle Spectroscopy (MPS). NE displayed MRI and MPS signals confirming its potential as new contrast agent. NE MPS signal increase with NPs size close to the gold standard (Resovist). In MRI, NE displayed R2* transversal relaxivity of 45.45, 96.04 and 218.81mM-1s-1 for 7, 11 and 18nm respectively. NE selectively bind atheroma plaque both in vitro and ex vivo in animal models of atherosclerosis. CONCLUSION: Magnetic NE showed reasonable MRI/MPS signals and a significant labelling of the atheroma plaque. These preliminary results support that NE platform could selectively image atherosclerosis. PMID- 28899765 TI - Mechanical particle coating using polymethacrylate nanoparticle agglomerates for the preparation of controlled release fine particles: The relationship between coating performance and the characteristics of various polymethacrylates. AB - We aimed to understand the factors controlling mechanical particle coating using polymethacrylate. The relationship between coating performance and the characteristics of polymethacrylate powders was investigated. First, theophylline crystals were treated using a mechanical powder processor to obtain theophylline spheres (<100MUm). Second, five polymethacrylate latexes were powdered by spray freeze drying to produce colloidal agglomerates. Finally, mechanical particle coating was performed by mixing theophylline spheres and polymethacrylate agglomerates using the processor. The agglomerates were broken under mechanical stress to coat the spheres effectively. The coating performance of polymethacrylate agglomerates tended to increase as their pulverization progressed. Differences in the grindability of the agglomerates were attributed to differences in particle structure, resulting from consolidation between colloidal particles. High-grindability agglomerates exhibited higher pulverization as their glass transition temperature (Tg) increased and the further pulverization promoted coating. We therefore conclude that the minimization of polymethacrylate powder by pulverization is an important factor in mechanical particle coating using polymethacrylate with low deformability. Meanwhile, when product temperature during coating approaches Tg of polymer, polymethacrylate was soften to show high coating performance by plastic deformation. The effective coating by this mechanism may be accomplished by adjusting the temperature in the processor to the Tg. PMID- 28899766 TI - Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. AB - Ageing of the global population has become a public health concern with an important socio-economic dimension. Ageing is characterized by an increase in the concentration of inflammatory markers in the bloodstream, a phenomenon that has been termed "inflammageing". The inflammatory response is beneficial as an acute, transient reaction to harmful conditions, facilitating the defense, repair, turnover and adaptation of many tissues. However, chronic and low grade inflammation is likely to be detrimental for many tissues and for normal functions. We provide an overview of low grade inflammation (LGI) and determine the potential drivers and the effects of the "inflamed" phenotype observed in the elderly. We discuss the role of gut microbiota and immune system crosstalk and the gut-brain axis. Then, we focus on major health complications associated with LGI in the elderly, including mental health and wellbeing, metabolic abnormalities and infections. Finally, we discuss the possibility of manipulating LGI in the elderly by nutritional interventions. We provide an overview of the evidence that exists in the elderly for omega-3 fatty acid, probiotic, prebiotic, antioxidant and polyphenol interventions as a means to influence LGI. We conclude that slowing, controlling or reversing LGI is likely to be an important way to prevent, or reduce the severity of, age-related functional decline and the onset of conditions affecting health and well-being; that there is evidence to support specific dietary interventions as a strategy to control LGI; and that a continued research focus on this field is warranted. PMID- 28899767 TI - Effects of hexavalent chromium on mouse splenic T lymphocytes. AB - Hexavalent chromium [Cr(VI)] is widely used in various industrial processes and has been recognized as a carcinogen. As the first line of host defense system, the immune system can be a primary target of Cr(VI). T cell population represents a major arm of the immune system that plays a critical role in host anti-tumor immunity. Dysfunction of T cells, such as exhaustion under the persistent presence of tumor antigen, compromise host anti-tumor immunity resulting in oncogenesis. Previous studies have shown Cr(VI) exposure alters the phenotype of human peripheral blood lymphocytes. However, the mechanism of the alteration and whether such an alteration in immunity affects immunosurveillance and promotes carcinogenicity are not clear. Using a culture of mouse splenic T cells as an in vitro model system, the present study assessed the effects of Cr(VI) on T cells, as the first step in our investigation of the mechanism underlying Cr(VI) inhibited immunosurveillance and carcinogenesis. Our results showed that Cr(VI) decreased the viability of CD4+ and CD8+ T cells and inhibited their activation, proliferation, cytokine release and cytolytic function. PMID- 28899768 TI - Missed Opportunities to Decrease Radiation Exposure in Children with Renal Trauma. AB - PURPOSE: Efforts have been made to reduce use of computerized tomography in children with blunt abdominal injury. Computerized tomography may be overused in pediatric patients with renal trauma. MATERIALS AND METHODS: We performed a retrospective chart review of all renal trauma patients younger than 18 years old treated at 2 urban trauma centers from 2002 to 2016. We collected demographic and clinical characteristics, renal trauma grades, urological interventions, and timing and use of computerized tomography and renal ultrasound. RESULTS: During the study period 145 patients presented with blunt renal trauma. During hospitalization 46 patients (32%) underwent repeat computerized tomography. About 20% of repeat computerized tomograms were performed less than 48 hours after the first scan. After controlling for center, isolated injury (yes/no), stent placement, age and surgical interventions (yes/no) patients who underwent delayed imaging on their first scan had decreased odds of undergoing a second computerized tomogram (adjusted OR 0.2, 95% CI 0.05-0.9, p = 0.04). Number needed to treat to prevent 1 repeat scan in high grade renal trauma patients was 3 (95% CI 2-4). Estimated sensitivity and specificity for ultrasound monitoring to detect an abnormality requiring urological intervention are 50% and 94%, respectively. CONCLUSIONS: Repeat computerized tomography in pediatric patients with renal trauma is common. Obtaining delayed imaging on the initial scan in patients with high grade renal trauma may prevent repeat scans. Renal ultrasound provides diagnostic usefulness in monitoring kidney injuries and should be considered before repeating computerized tomography. PMID- 28899769 TI - Incidence and Predictors of Complications due to Urethral Stricture in Patients Awaiting Urethroplasty. AB - PURPOSE: We examined the incidence and predictors of complications due to urethral stricture in patients awaiting urethroplasty. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who underwent urethroplasty from 2009 to 2013. The primary outcome was complications, defined as any unplanned interaction with the health care system due to urethral stricture during the period between the decision to perform surgery and urethroplasty. RESULTS: A total of 276 patients were identified for analysis. Median stricture length was 4.0 cm and 67.4% of strictures were in the bulbar urethra. The most common stricture etiologies were idiopathic in 47.8% of cases and traumatic in 15.9%. Overall 15.9% of patients presented with a complication with a median time to complication of 43 days. Median surgical wait time was 151 days. Complications included urinary tract infections in 56.8% of patients, acute urinary retention in 20.5%, genitourinary pain in 5.8% and catheter related issues in 15.9%. Univariate analysis suggested that catheter dependent status, number of prior endoscopic treatments, a hypospadias and/or trauma etiology, and prior urethroplasty were potential significant predictors of complications. Multivariate analysis yielded only catheter dependent status (HR 5.2, 95% CI 2.4 11.3, p <0.0001) and prior failed urethroplasty (HR 1.6, 95% CI 1.1-2.3, p = 0.03) as significantly associated with complications. CONCLUSIONS: To our knowledge our study is the first to examine and quantify the morbidity of urethroplasty wait time. Approximately 16% of patients experienced a complication while awaiting urethroplasty. The optimal wait time should be less than 43 days. Patients with prior urethroplasty and catheters at the time of the surgical decision should be prioritized as they may be more likely to experience complications. PMID- 28899770 TI - Use of non-prescription analgesics and male reproductive function. AB - We studied the association between intake of non-prescription analgesics and semen quality and male reproductive hormone levels in a cross-sectional study among 1493 men. The men provided one semen (n=1493) and blood sample (n=1056) and filled in questionnaires on use of non-prescription analgesics (paracetamol, NSAIDs and combination drugs (yes/no)). Adjusting for age, study and other covariates, we observed no association between intake of non-prescription analgesics and markers of semen quality. Adjusting for age and time of day of blood sampling, users of non-prescription analgesics had a 10.4% (95% confidence interval (CI) 4.0-17.1%) higher testosterone level than non-users. When we stratified by medication type, the association between analgesics and higher testosterone was observed between users of non-steroidal anti-inflammatory drugs (NSAIDs) and combination drugs but not paracetamol. This study suggests that use of non-prescription analgesics is associated with slightly higher serum testosterone levels than non-use. PMID- 28899771 TI - Effectiveness of mechanical debridement with and without adjunct antimicrobial photodynamic therapy in the treatment of periodontal inflammation among patients with prediabetes. AB - AIM: The aim of the present study was to assess the effectiveness of mechanical debridement (MD) with and without adjunct antimicrobial photodynamic therapy (aPDT) in the treatment of periodontal inflammation among patients with prediabetes. METHODS: Demographic information was collected using a questionnaire. Hemoglobin A1c (HbA1c) levels were measured at baseline and at 3 and 6 months' follow-up. TREATMENT: Individuals were randomly divided into 2 groups as follows: (a) Group-1, participants underwent full-mouth MD; and Group 2: participants underwent full-mouth MD with adjunct aPDT. In groups 1 and 2, full-mouth plaque index (PI), bleeding on probing (BOP) and probing pocket depth (PPD) were measured at baseline and at 3 and 6 months' follow-up. In both groups, full-mouth digital intraoral radiographs were also taken. Sample-size was estimated and statistical analysis was performed with level of significance set as P<0.05. RESULTS: In total, 70 prediabetic male individuals (35 patients in group-1 and 35 in group-2) were included. At baseline, PI, BOP, number of sites with PPD >=4mm were comparable among individuals in groups 1 and 2. In groups 1 and 2, PI (P<0.05), BOP (P<0.05), number of sites with PPD >=4mm (P<0.05) were significantly higher at baseline compared with 3 months' follow-up. There was no statistically significant difference in PI, BOP, number of sites with PPD >=4mm at 3 and 6 months' follow-up. At 6 months' follow-up, PI, BOP, number of sites with PPD >=4mm were comparable to their respective baseline values. There was no statistically significant difference in CBL in both groups at 3 and 6 months' follow-up. There was no statistically significant difference in HbA1c levels among individuals in groups 1 and 2 at all-time intervals. CONCLUSION: In the short-term, MD is effective in reducing periodontal inflammation among patients with prediabetes. The contribution of adjunct aPDT in this regard is insignificant. PMID- 28899772 TI - Change in plasma membrane potential of rat thymocytes by tert-butylhydroquinone, a food additive: Possible risk on lymphocytes. AB - Tertiary butylhydroquinone (TBHQ) is a food additive and has various beneficial actions under in vitro and in vivo experimental conditions. Therefore, it is necessary to collect additional data on the toxicity of TBHQ in order to avoid adverse effects during clinical applications. Changes in plasma membrane potential are associated with changes in physiological functions even in non excitable cells such as lymphocytes. Thus, compounds that affect membrane potential may modify some lymphocytic functions. The effect of TBHQ on plasma membrane potential was examined in rat thymocytes using flow cytometric techniques. Treatment of rat thymocytes with TBHQ caused hyperpolarization and then depolarization. The TBHQ-induced hyperpolarization was due to the activation of Ca2+-dependent K+ channels. TBHQ elevated intracellular Ca2+ levels. The depolarization by TBHQ was caused by a nonspecific increase in membrane ionic permeability. Both the sustained depolarization and elevation of intracellular Ca2+ level by TBHQ are thought to be adverse for thymocytes because such changes disturb membrane and intracellular signaling. The thymus is most active during neonatal and pre-adolescent periods. If TBHQ exerts adverse actions on thymocytes, it may result in an immunotoxic effect in neonates and adolescents. PMID- 28899773 TI - Hepatoprotective effects of raspberry (Rubus coreanus Miq.) seed oil and its major constituents. AB - Raspberry seed is a massive byproduct of raspberry juice and wine but usually discarded. The present study employed a microwave-assisted method for extraction of raspberry seed oil (RSO). The results revealed that omega-6 fatty acids (linoleic acid and gamma-linolenic acid) were the major constituents in RSO. Cellular antioxidant enzyme activity such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were investigated in HepG2 cells treated with RSO. Induction of the synthesis of several antioxidants in H2O2 exposed HepG2 cells was found. RSO increased the enzyme activity of SOD, CAT, and GPx in H2O2-exposed HepG2. Furthermore, RSO inhibited the phosphorylation of upstream mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (c-JNK) and extracellular signal-regulated kinase (ERK). Taken together, the possible mechanisms to increase antioxidant enzyme activities in HepG2 may through the suppression of ERK and JNK phosphorylation. Raspberry seed oil exhibited good effects on the activities of the intracellular antioxidant enzymes and seems to protect the liver from oxidative stress through the inhibition of MAPKs. PMID- 28899774 TI - Further insights on tomato plant: Cytotoxic and antioxidant activity of leaf extracts in human gastric cells. AB - This study focused the toxicity against human gastric adenocarcinoma cells (AGS) and the antioxidant activity of hydromethanol (HME), acetone (AcE) and alkaloid (AE) extracts prepared from the leaves of tomato plant cultivars (Caramba, Valentine, Negro, Abuela, and Anairis). AE, HME and AcE extracts of all cultivars reduced cell viability, IC50 values ranging from 9 +/- 2 to 55 +/- 11, from 103 +/- 25 to 171 +/- 29 and from 291 +/- 26 to 459 +/- 14 MUg mL-1, respectively. Moreover, both HME and AcE extracts scavenged *NO (IC50 values ranged from 0.87 +/- 0.12 to 1.54 +/- 0.23 and from 0.90 +/- 0.01 to 2.23 +/- 0.14 mg mL-1, respectively), but only HMEs was able to scavenge O2*- showing IC50 values from 0.12 +/- <=0.01 to 0.43 +/- 0.08 mg mL-1. Our results demonstrate that tomato leaves, a by-product of tomato processing industry, are a valuable source of bioactive compounds, providing beneficial properties for human health. PMID- 28899775 TI - Unique phagocytic properties of hemocytes of Pacific oyster Crassostrea gigas against yeast and yeast cell-wall derivatives. AB - For a marine bivalve mollusk such as Pacific oyster Crassostrea gigas, the elimination of foreign particles via hemocyte phagocytosis plays an important role in host defense mechanisms. The hemocytes of C. gigas have a high phagocytic ability for baker's yeast (Saccharomyces cerevisiae) and its cell-wall product zymosan. C. gigas hemocytes might phagocytose yeast cells after binding to polysaccharides on the cell-wall surface, but it is unknown how and what kinds of polysaccharide molecules are recognized. We conducted experiments to determine differences in the phagocytic ability of C. gigas hemocytes against heat-killed yeast (HK yeast), zymosan and zymocel, which are similarly sized and shaped but differ in the polysaccharide composition of their particle surface. We found that both the agranulocytes and granulocytes exerted strong phagocytic ability on all tested particles. The phagocytic index (PI) of granulocytes for zymosan was 9.4 +/- 1.7, which significantly differed with that for HK yeast and zymocel (P < 0.05). To evaluate the PI for the three types of particles, and especially to understand the outcome of the much higher PI for zymosan, PI was gauged in increments of 5 (1-5, 6-10, 11-15, and >=16), and the phagocytic frequencies were compared according to these increments. The results show that a markedly high PI of >=16 was exhibited by 18.1% of granulocytes for zymosan, significantly higher than 1.7% and 3.9% shown for HK yeast and zymocel, respectively (P < 0.05). These findings indicate that the relatively high PI for zymosan could not be attributed to a situation wherein all phagocytic hemocytes shared a high mean PI, but rather to the ability of some hemocytes to phagocytose a larger portion of zymosan. To determine whether the phagocytosis of these respective particles depended on the recognition of specific polysaccharide receptors on the hemocyte surface, C. gigas hemocytes were pretreated with soluble alpha-mannan or beta-laminarin and then allowed to phagocytose the three types of the particles. The percentage of phagocytic cells of beta-laminarin-treated granulocytes decreased significantly for zymosan and zymocel, but not for yeast. These results suggest that C. gigas might possess at least two types of hemocytes, and that one type of the hemocytes (granulocytes) is more active for phagocytosis. The granulocytes were found to have multiple subtypes with different phagocytic abilities and multiple phagocytic receptors. Some of the granulocyte subtypes revealed a much stronger phagocytic ability, depending on the presence of beta-glucan receptors for phagocytosis. PMID- 28899776 TI - The effect of temperature on the mucosal IgM antibody response to DNP-KLH in channel catfish (Ictalurus punctatus). AB - Bath immersion remains a practical route for immunizing against disease in channel catfish; however research efforts in this area have revealed variable results when activating mucosal Ab responses with different antigens. This is likely due to a number of factors including the individual species, age of the fish, preparation of the immunogens, and differences in the overall dosage and the duration of exposure to vaccines. The current study sought to evaluate the effect of water temperature on the in vivo mucosal adaptive immune response in channel catfish to a protein-hapten antigen, DNP-KLH. Fish were bath immersed at different water temperatures and periodically evaluated over an eighteen week period for the development of serum and mucosal IgM antibodies to DNP-KLH using an indirect enzyme-linked immunosorbent assay. None of the temperature groups produced a serum antibody response; however there were detectable DNP-KLH specific IgM antibodies in the mucus starting at week eight. The extent of the mucosal antibody response and duration differed between the treatments. Our results show that there are intrinsic differences in the capacity to generate in vivo mucosal Ab responses in the skin at different water temperatures and the implications of these findings to channel catfish farming will be discussed. PMID- 28899777 TI - Jerusalem artichoke enriched diet on growth performance, immuno-hematological changes and disease resistance against Aeromonas hydrophila in Asian seabass (Lates calcarifer). AB - A 45 days feeding trial was conducted to study the effect of Jerusalem artichoke (JA) on growth performance, body composition, biochemical, immuno-hematological parameters and disease resistance in Asian seabass (Lates calcarifer) fingerlings against Aeromonas hydrophila. JA was supplemented at three different levels viz., control 0, 5, 10, and 20 g kg-1 in the commercial diet (403 g kg-1protein and 89 g kg -1lipid) in L. calcarifer. The results showed that there were no significant (P > 0.05) differences in various growth parameters, while the whole body composition showed significant differences (P < 0.05) between control and treatment groups. Hematological parameters showed that red blood cells (RBC), white blood cells (WBC), hemoglobin (Hb), pack cell volume (PCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were not significantly (P > 0.05) affected by dietary supplementation of JA at different concentration. However, the mean corpuscular volume (MCV) was significantly (P < 0.05) higher in the fish fed with 20 g kg-1 JA supplemented diet. Biochemical parameters revealed that glucose, urea, cholesterol, and triglyceride showed significant (P < 0.05) differences between control and treatments groups. Interestingly, 20 g kg-1 JA supplemented diet significantly modulates the innate immune response and disease resistance against Aeromonas hydrophila compared with control and other treatment groups. The results of the study revealed that 20 g kg-1 JA supplementation has a beneficial effect in the biochemical, immunological and disease resistance in L. calcarifer juveniles. PMID- 28899778 TI - Vma3p protects cells from programmed cell death through the regulation of Hxk2p expression. AB - In yeast, the vacuolar proton-pumping ATPase (V-ATPase) acidifies vacuoles to maintain pH of cytoplasm. Yeast cells lacking V-ATPase activity, due to a disruption of any VMA (vacuolar membrane ATPase) gene, remain viable but demonstrate growth defects. Although it has been suggested that VMA genes are critical for phospholipid biosynthesis, the link between VMA genes and phospholipid biosynthesis is still uncertain. Here, we found that cells lacking Vma3p, one of the major V-ATPase assembly genes, had a growth defect in the absence of inositol, suggesting that Vma3p is important in phospholipid biosynthesis. Through real-time PCR, we found that cells lacking Vma3p down regulated HXK2 expression. Furthermore, acetic acid sensitivity assay showed that cells lacking Vma3p were more sensitive to acetic acid than WT cells. HXK2 encodes hexokinase 2 which can phosphorylate glucose during phospholipid biosynthesis. Since cells lacking HXK2 are sensitive to acetic acid and this is an indicator of programmed cell death, our observations suggest that Vma3p plays an important role in programmed cell death. Taken together, we have proposed a working model to describe how Vma3p protects cells against apoptosis through the regulation of HXK2 expression. PMID- 28899779 TI - Eupatilin with PPARalpha agonistic effects inhibits TNFalpha-induced MMP signaling in HaCaT cells. AB - Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a flavonoid compound exhibiting several beneficial biological activities, including neuroprotection, anti-cancer, antinociception, chondroprotection, anti-oxidation, and anti inflammation. Our previous study demonstrated that eupatilin specifically activates peroxisome proliferator-activated receptor alpha (PPARalpha) through direct binding. The PPAR subfamily includes ligand-dependent transcription factors that consist of three isotypes: PPARalpha, PPARbeta/delta, and PPARgamma. All isotypes are involved in inflammation, epidermal proliferation/differentiation and skin barrier function. Among them, PPARalpha regulates lipid and glucose metabolism and skin homeostasis. In this study, we confirm that the ability of eupatilin as a PPARalpha activator significantly inhibited tumor necrosis factor-alpha (TNFalpha)-induced matrix metalloproteinase (MMP)-2/-9 expression and proteolytic activity in HaCaT human epidermal keratinocytes. Furthermore, we found that eupatilin subsequently suppressed IkappaBalpha phosphorylation, blocked NF-kappaB p65 nuclear translocation and down-regulated MAPK/AP-1 signaling via PPARalpha activation. Taken together, our data suggest that eupatilin inhibits TNFalpha-induced MMP-2/-9 expression by suppressing NF-kappaB and MAPK/AP-1 pathways via PPARalpha. Our findings suggest the usefulness of eupatilin for preventing skin aging. PMID- 28899780 TI - Hydrogen peroxide production is affected by oxygen levels in mammalian cell culture. AB - Although oxygen levels in the extracellular space of most mammalian tissues are just a few percent, under standard cell culture conditions they are not regulated and are often substantially higher. Some cellular sources of reactive oxygen species, like NADPH oxidase 4, are sensitive to oxygen levels in the range between 'normal' physiological (typically 1-5%) and standard cell culture (up to 18%). Hydrogen peroxide in particular participates in signal transduction pathways via protein redox modifications, so the potential increase in its production under standard cell culture conditions is important to understand. We measured the rates of cellular hydrogen peroxide production in some common cell lines, including C2C12, PC-3, HeLa, SH-SY5Y, MCF-7, and mouse embryonic fibroblasts (MEFs) maintained at 18% or 5% oxygen. In all instances the rate of hydrogen peroxide production by these cells was significantly greater at 18% oxygen than at 5%. The increase in hydrogen peroxide production at higher oxygen levels was either abolished or substantially reduced by treatment with GKT 137831, a selective inhibitor of NADPH oxidase subunits 1 and 4. These data indicate that oxygen levels experienced by cells in culture influence hydrogen peroxide production via NADPH oxidase 1/4, highlighting the importance of regulating oxygen levels in culture near physiological values. However, we measured pericellular oxygen levels adjacent to cell monolayers under a variety of conditions and with different cell lines and found that, particularly when growing at 5% incubator oxygen levels, pericellular oxygen was often lower and variable. Together, these observations indicate the importance, and difficulty, of regulating oxygen levels experienced by cells in culture. PMID- 28899781 TI - Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome. AB - Mitochondrial diseases are the result of aberrant mitochondrial function caused by mutations in either nuclear or mitochondrial DNA. Poor bone health has recently been suggested as a symptom of mitochondrial diseases; however, a direct link between decreased mitochondrial function and poor bone health in mitochondrial disease has not been demonstrated. In this study, stem cells from human exfoliated deciduous teeth (SHED) were isolated from a child with Leigh syndrome (LS), a mitochondrial disease, and the effects of decreased mitochondrial function on poor bone health were analyzed. Compared with control SHED, LS SHED displayed decreased osteoblastic differentiation and calcium mineralization. The intracellular and mitochondrial calcium levels were lower in LS SHED than in control SHED. Furthermore, the mitochondrial activity of LS SHED was decreased compared with control SHED both with and without osteoblastic differentiation. Our results indicate that decreased osteoblast differentiation potential and osteoblast function contribute to poor bone health in mitochondrial diseases. PMID- 28899782 TI - WITHDRAWN: The lncRNA-GAS5/miR-23a/Foxo3a axis regulates cardiac hypertrophy by Wnt/beta-catenin signal pathway. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28899783 TI - Induced sensitivity to EGFR inhibitors is mediated by palmitoylated cysteine 1025 of EGFR and requires oncogenic Kras. AB - Currently, there are no effective therapeutic strategies targeting Kras driven cancers, and therefore, identifying new targeted therapies and overcoming drug resistance have become paramount for effective long-term cancer therapy. We have found that reducing expression of the palmitoyl transferase DHHC20 increases cell death induced by the EGFR inhibitor gefitinib in Kras and EGFR mutant cell lines, but not MCF7 cells harboring wildtype Kras. We show that the increased gefitinib sensitivity in cancer cells induced by DHHC20 inhibition is mediated directly through loss of palmitoylation on a previously identified cysteine residue in the C-terminal tail of EGFR. We utilized an EGFR point mutant in which the palmitoylated cysteine 1025 is mutated to alanine (EGFRC1025A), that results in receptor activation. Expression of the EGFR mutant alone in NIH3T3 cells does not increase sensitivity to gefitinib-induced cell death. However, when EGFRC1025A is expressed in cells expressing activated KrasG12V, EGFR inhibitor induced cell death is increased. Surprisingly, lung cancer cells harboring the EGFR inhibitor resistant mutation, T790M, become sensitive to EGFR inhibitor treatment when DHHC20 is inhibited. Finally, the small molecule, 2-bromopalmitate, which has been shown to inhibit palmitoyl transferases, acts synergistically with gefitinib to induce cell death in the gefitinib resistant cell line NCI-H1975. PMID- 28899784 TI - MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1. AB - Non-alcoholic fatty liver diseases (NAFLD) is one of the leading cause of chronic liver diseases in the world. However, the pathogenesis of NAFLD is still unclear. Emerging studies have demonstrated that microRNAs (miRs) are profoundly involved in NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-181b influences NAFLD via direct targeting SIRT1. The expression of miR181b was up-regulated while SIRT1 was down-regulated in both human NAFLD patients and high fat diet (HFD) induced NAFDL mice model. And palmitic acid (PA) treatment increased the miR-181b expression while decreased SIRT1 expression in HepG2 cells. Further, we identified that SIRT1 is a direct downstream target of miR-181b. Ectopic expression of miR-181b significantly repressed the 3'-UTR reporter activities of SIRT1 in a dose-dependent manner, while the effect of miR 181b was interrupted when the binding site of miR-181b within the SIRT1 3'-UTR was mutated. And overexpression of miR-181b reduced both the mRNA and protein levels of SIRT1 in HepG2 cells. We also found that inhibition of miR-181b expression alleviates hepatic steatosis both in vitro and in vivo. And the effect of miR-181b on steatosis was blocked by SIRT1 overexpression. Taken together, our data indicated that increased expression of miR-181b potentially contributes to altered lipid metabolism in NAFLD. Downregulation of miR-34a may be a therapeutic strategy against NAFLD by regulating its target SIRT1. PMID- 28899785 TI - Capacity and tendency: A neuroscientific framework for the study of emotion regulation. AB - It is widely accepted that the ability to effectively regulate one's emotions is a cornerstone of physical and mental health. As such, it should come as no surprise that the number of neuroimaging studies focused on emotion regulation and associated processes has increased exponentially in the past decade. To date, neuroimaging research on this topic has examined two distinct but complementary features of emotion regulation - the capacity to effectively utilize a strategy to regulate emotion and to a lesser extent, the tendency to choose to regulate. However, theoretical accounts of emotion regulation have only recently begun to distinguish capacity from tendency. In the present review, we provide a novel framework for conceptualizing these two intertwined, yet distinct, facets of emotion regulation. First we characterize brain regions that support emotion generation and are thus targeted by emotion regulation. Next, we synthesize findings from the dozens of neuroimaging studies that have examined emotion regulation capacity, focusing in particular on the most commonly studied emotion regulation strategy - reappraisal. Finally, we discuss emerging neuroimaging research examining state and trait regulatory tendencies. We conclude by integrating findings from neuroimaging research on emotion regulation capacity and tendency and suggest ways that this integrated model can inform basic and translational neuroscientific research on emotion regulation. PMID- 28899786 TI - Artemin transiently increases iNOS expression in primary cultured trigeminal ganglion neurons. AB - Artemin, a member of the glial cell line-derived neurotrophic factor family, is an important cytokine and a critical participant in trigeminal pain disorders such as tongue pain and migraine. However, the mechanisms underlying artemin's activity are largely unknown. In the present study, we used primary cultured trigeminal ganglion neurons (TGNs) to determine the effect of artemin on the expression of the inducible form of nitric oxide synthase (iNOS), which is released in response to painful and inflammatory stimuli. Following artemin treatment, western blot analysis showed that the protein level of iNOS was transiently elevated after artemin treatment for 15min (p<0.05). Immunofluorescence revealed that both the expressions of iNOS and GFRalpha3 were significantly up-regulated after artemin treatment for 15min. In addition, iNOS expression induced by artemin was co-localized with GFRalpha3 and TUJ-1 in primary cultured TGNs, respectively. Our results indicate a previously unknown role of artemin in regulating iNOS expression in primary cultured TGNs, and regulation of iNOS might be involved in the mechanism through which artemin participates in the trigeminal pain pathway. PMID- 28899787 TI - Differential expression of ryanodine receptor isoforms after spinal cord injury. AB - Ryanodine receptors (RyRs) are highly conductive intracellular Ca2+ release channels and are widely expressed in many tissues, including the central nervous system. RyRs have been implicated in intracellular Ca2+ overload which can drive secondary damage following traumatic injury to the spinal cord (SCI), but the spatiotemporal expression of the three isoforms of RyRs (RyR1-3) after SCI remains unknown. Here, we analyzed the gene and protein expression of RyR isoforms in the murine lumbar dorsal root ganglion (DRG) and the spinal cord lesion site at 1, 2 and 7 d after a mild contusion SCI. Quantitative RT PCR analysis revealed that RyR3 was significantly increased in lumbar DRGs and at the lesion site at 1 and 2 d post contusion compared to sham (laminectomy only) controls. Additionally, RyR2 expression was increased at 1 d post injury within the lesion site. RyR2 and -3 protein expression was localized to lumbar DRG neurons and their spinal projections within the lesion site acutely after SCI. In contrast, RyR1 expression within the DRG and lesion site remained unaltered following trauma. Our study shows that SCI initiates acute differential expression of RyR isoforms in DRG and spinal cord. PMID- 28899788 TI - The translocator protein ligand XBD173 improves clinical symptoms and neuropathological markers in the SJL/J mouse model of multiple sclerosis. AB - Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory, demyelinating and neurodegenerative components causing motor, sensory, visual and/or cognitive symptoms. The relapsing-remitting MS affecting 85% of patients is reliably mimicked by the proteolipid-protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) SJL/J-mouse model. Significant progress was made for MS treatment but the development of effective therapies devoid of severe side-effects remains a great challenge. Here, we combine clinical, behavioral, histopathological, biochemical and molecular approaches to demonstrate that low and well tolerated doses (10-20mg/kg) of TSPO ligand XBD173 (Emapunil) efficiently ameliorate clinical signs and neuropathology of PLP-EAE mice. In addition to the conventional clinical scoring of symptoms, we applied the robust behavioral Catwalk-method to confirm that XBD173 (10mg/kg) increases the maximum contact area parameter at EAE-disease peak, indicating an improvement/recovery of motor functions. Consistently, histopathological studies coupled with microscope-cellSens quantification and RT-qPCR analyzes showed that XBD173 prevented demyelination by restoring normal protein and mRNA levels of myelin basic protein that was significantly repressed in PLP-EAE mice spinal cord and brain. Interestingly, ELISA-based measurement revealed that XBD173 increased allopregnanolone concentrations in PLP-EAE mice spinal and brain tissues. Furthermore, flow cytometry assessment demonstrated that XBD173 therapy decreased serum level of pro-inflammatory cytokines, including interleukin-17A, Interleukin 6 and tumor-necrosis-factor alpha in PLP-EAE mice. As the optimal XBD173 dosing exerting the maximal beneficial action in EAE mice is the lower 10mg/kg dose, the paper opens interesting perspectives for the development of efficient and safe therapies against MS with slight or no side-effects. PMID- 28899789 TI - The evolutionary logic of sepsis. AB - The recently proposed Microbiome Mutiny Hypothesis posits that members of the human microbiome obtain information about the host individuals' health status and, when host survival is compromised, switch to an intensive exploitation strategy to maximize residual transmission. In animals and humans, sepsis is an acute systemic reaction to microbes invading the normally sterile body compartments. When induced by formerly mutualistic or neutral microbes, possibly in response to declining host health, sepsis appears to fit the 'microbiome mutiny' scenario except for its apparent failure to enhance transmission of the causative organisms. We propose that the ability of certain species of the microbiome to induce sepsis is not a fortuitous side effect of within-host replication, but rather it might, in some cases, be the result of their adaptive evolution. Whenever host health declines, inducing sepsis can be adaptive for those members of the healthy human microbiome that are capable of colonizing the future cadaver and spread by cadaver-borne transmission. We hypothesize that such microbes might exhibit switches along the 'mutualist - lethal pathogen - decomposer - mutualist again' scenario, implicating a previously unsuspected, surprising level of phenotypic plasticity. This hypothesis predicts that those species of the healthy microbiome that are recurring causative agents of sepsis can participate in the decomposition of cadavers, and can be transmitted as soil borne or water-borne infections. Furthermore, in individual sepsis cases, the same microbial clones that dominate the systemic infection that precipitates sepsis, should also be present in high concentration during decomposition following death: this prediction is testable by molecular fingerprinting in experimentally induced animal models. Sepsis is a leading cause of human death worldwide. If further research confirms that some cases of sepsis indeed involve the 'mutiny' (facultative phenotypic switching) of normal members of the microbiome, then new strategies could be devised to prevent or treat sepsis by interfering with this process. PMID- 28899790 TI - Alisporivir rescues defective mitochondrial respiration in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a severe muscle disease of known etiology without effective, or generally applicable therapy. Mitochondria are affected by the disease in animal models but whether mitochondrial dysfunction is part of the pathogenesis in patients remains unclear. We show that primary cultures obtained from muscle biopsies of DMD patients display a decrease of the respiratory reserve, a consequence of inappropriate opening of the permeability transition pore (PTP). Treatment with the cyclophilin inhibitor alisporivir - a cyclosporin A derivative that desensitizes the PTP but does not inhibit calcineurin - largely restored the maximal respiratory capacity without affecting basal oxygen consumption in cells from patients, thus reinstating a normal respiratory reserve. Treatment with alisporivir, but not with cyclosporin A, led to a substantial recovery of respiratory function matching improved muscle ultrastructure and survival of sapje zebrafish, a severe model of DMD where muscle defects are close to those of DMD patients. Alisporivir was generally well tolerated in HCV patients and could be used for the treatment of DMD. PMID- 28899791 TI - Toward a hierarchical virtual screening and toxicity risk analysis for identifying novel CA XII inhibitors. AB - Carbonic anhydrase isoform XII (CA XII) is a potential target for cancer treatment. In this study, pharmacophore modeling, hierarchical virtual screening, and toxicity risk analysis were performed for identifying novel CA XII inhibitors. A pharmacophore model of two classes of CA XII inhibitors was generated. The pharmacophore model indicated the important features of inhibitors for the binding with the CA XII. The model was then utilized to screen the ZINC and CoCoCo databases for retrieving potential hit compounds of CA XII. For accurate conclusions about the selectivity of inhibitors, the retrieved molecules which obey of Lipinski's rule of five (RO5) and have no toxicity risk were docked in a CA XII 3D structure by smina. Finally, on the basis of binding affinity and the binding mode of the molecules, twelve molecules were prioritized as promising hits. It should be noted that two of hits H5 and H6 were previously reported in the CHEMBL database. This hierarchical method is worthy of reducing the time and using almost all information available. The final hits may be used as a lead to discovery novel CA XII inhibitors. PMID- 28899793 TI - Comprehensive assessment for serum treatment for single antigen test for detection of HLA antibodies. AB - The single antigen test is widely used in the field of transplantation to determine the specificity of HLA antibodies. It will be beneficial to standardize the procedure of the single antigen test among HLA laboratories. It is not uncommon that single antigen testing on native sera fails to detect antibodies with very high concentrations. It has been shown that cleavage products of activated complement components may mask strongly binding antibodies in single antigen testing. To overcome inhibition by the activated complement products, sera are pretreated with ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DTT), or heat inactivation before single antigen testing. However, no studies have been published to systemically compare the impact of these treatments on single antigen testing. The aim of this study is to understand the different effects these treatments may have on single antigen test results. We found that mean fluorescence intensity (MFI) obtained from sera treated with EDTA and heat inactivation were nearly identical, while DTT treatment was less potent to remove the inhibition. In addition, sera dilution did not further increase MFI of antibodies after EDTA treatment. Our results provide guidance to choose a pretreatment reagent for single antigen testing, and to compare studies obtained from laboratories using different treatments. PMID- 28899792 TI - Evidence for non-linear metabolism at low benzene exposures? A reanalysis of data. AB - The presence of a high-affinity metabolic pathway for low level benzene exposures of less than one part per million (ppm) has been proposed although a pathway has not been identified. The variation of metabolite molar fractions with increasing air benzene concentrations was suggested as evidence of significantly more efficient benzene metabolism at concentrations <0.1 ppm The evidence for this pathway is predicated on a rich data set from a study of Chinese shoe workers exposed to a wide range of benzene concentrations (not just "low level"). In this work we undertake a further independent re-analysis of this data with a focus on the evidence for an increase in the rate of metabolism of benzene exposures of less than 1 ppm. The analysis dataset consisted of measurements of benzene and toluene from personal air samplers, and measurements of unmetabolised benzene and toluene and five metabolites (phenol hydroquinone, catechol, trans, trans-muconic acid and s-phenylmercapturic acid) from post-shift urine samples for 213 workers with an occupational exposure to benzene (and toluene) and 139 controls. Measurements from control subjects were used to estimate metabolite concentrations resulting from non-occupational sources, including environmental sources of benzene. Data from occupationally exposed subjects were used to estimate metabolite concentrations as a function of benzene exposure. Correction for background (environmental exposure) sources of metabolites was achieved through a comparison of geometric means in occupationally exposed and control populations. The molar fractions of the five metabolites as a function of benzene exposure were computed. A supra-linear relationship between metabolite concentrations and benzene exposure was observed over the range 0.1-10 ppm benzene, however over the range benzene exposures of between 0.1 and 1 ppm only a modest departure from linearity was observed. The molar fractions estimated in this work were near constant over the range 0.1-10 ppm. No evidence of high affinity metabolism at these low level exposures was observed. Our reanalysis brings in to question the appropriateness of the dataset for commenting on low dose exposures and the use of a purely statistical approach to the analysis. PMID- 28899794 TI - Female rats exhibit less avoidance than male rats of a cocaine-, but not a morphine-paired, saccharin cue. AB - Rats avoid intake of an otherwise palatable taste cue when paired with drugs of abuse (Grigson and Twining, 2002). In male rats, avoidance of drug-paired taste cues is associated with conditioned blunting of dopamine in the nucleus accumbens (Grigson and Hajnal, 2007), conditioned elevation in circulating corticosterone (Gomez et al., 2000), and greater avoidance of the drug-paired cue predicts greater drug-taking (Grigson and Twining, 2002). While female rats generally are more responsive to drug than male rats, in this self-administration model, female rats consume more of a cocaine-paired saccharin cue and take less drug than males (Cason and Grigson, 2013). What is not known, however, is whether the same is true when a saccharin cue predicts availability of an opiate, particularly when the amount of drug experienced is held constant via passive administration by the experimenter. Here, avoidance of a saccharin cue was evaluated following pairings with experimenter delivered cocaine or morphine in male and female rats. Results showed that males and females avoided intake of a taste cue when paired with experimenter administered morphine or cocaine, and individual differences emerged whereby some male and female rats exhibited greater avoidance of the drug-paired cue than others. Female rats did not drink more of the saccharin cue than males when paired with morphine in Experiment 1, however, they did drink more of the saccharin cue than male rats when paired with cocaine in Experiment 2. While no pattern with estrous cycle emerged, avoidance of the cocaine-paired cue, like avoidance of a morphine-paired cue (Gomez et al., 2000), was associated with a conditioned elevation in corticosterone in both male and female rats. PMID- 28899795 TI - MicroRNA-137 and its downstream target LSD1 inversely regulate anesthetics induced neurotoxicity in dorsal root ganglion neurons. AB - PURPOSE: Anesthetic reagents, such as bupivacaine (Bv), induce significant neurotoxicity in dorsal root ganglion neurons (DRGNs). In this study, we investigated the expression, function and cross-association of microRNA-137-3p (miR-137-3p) and lysine (K)-specific demethylase 1A (LSD1) in a murine model of Bv-induced neural injury in DRGNs. METHODS: Murine DRGNs were culture in vitro and treated with Bv. QPCR was used to evaluate miR-137-3p expression in Bv injured DRGNs. MiR-137-3p was genetically downregulated to evaluate its rescuing effect on Bv-induced DRGN apoptosis and neurite retraction. The association of miR-137-3p on its downstream target, LSD1 coding gene KDM1A, was evaluated by dual-luciferase activity assay and qPCR. In miR-137-3p-downregulated DRGNs, KDM1A was inhibited to evaluate its involvement in miR-137-3p-mediated modulation on Bv induced DRGN neurotoxicity. Furthermore, KDM1A expression in Bv-injured DRGN was evaluated by qPCR, and LSD1 was overexpressed in DRGN to evaluate its direct effect on Bv-induced neurotoxicity. RESULTS: MiR-137-3p was upregulated in Bv injured DRGNs. MiR-137-3p downregulation rescued Bv-induced DRGN apoptosis and neurite retraction. LSD1 was demonstrated to be downstream to, and inversely modulated by miR-137-3p in DRGN. In Bv-injured DRGNs, LSD1 downregulation reversed miR-137-3p-downregualtion-induced neural protection. Furthermore, LSD1 upregulation directly rescued Bv-induced apoptosis and neurite retraction in DRGNs. CONCLUSIONS: MiR-137-3p and its downstream target LSD1 are inversely associated to regulate anesthetics-induced neurotoxicity in DRGN. This signaling pathway may be a therapeutic candidate to reduce anesthetics-induced neurological damage in human patients. PMID- 28899796 TI - Once is too much: Early development of the opponent process in taste reactivity behavior is associated with later escalation of cocaine self-administration in rats. AB - Evidence suggests that the addiction process may begin immediately in some vulnerable subjects. Specifically, some rats have been shown to exhibit aversive taste reactivity (gapes) following the intraoral delivery of a cocaine-predictive taste cue after as few as 1-2 taste-drug pairings. After only 3-4 trials, the number of gapes becomes a reliable predictor of later cocaine self administration. Given that escalation of drug-taking behavior over time is recognized as a key feature of substance use disorder (SUD) and addiction, the present study examined the relationship between early aversion to the cocaine predictive flavor cue and later escalation of cocaine self-administration in an extended-access paradigm. The data show that rats who exhibit the greatest conditioned aversion early in training to the intraorally delivered cocaine paired cue exhibit the greatest escalation of cocaine self-administration over 15 extended-access trials. This finding suggests that early onset of the conditioned opponent process (i.e., the near immediate shift from ingestion to rejection of the drug-paired cue) is a reliable predictor of future vulnerability and resilience to cocaine addiction-like behavior. Future studies must determine the underlying neural mechanisms associated with this early transition and, hence, with early vulnerability to the later development of SUD and addiction. In so doing, we shall be in position to discover novel diagnostics and novel avenues of prevention and treatment. PMID- 28899797 TI - Should we treat congenital heart block with fluorinated corticosteroids? PMID- 28899798 TI - Is ACPA positivity the main driver for rheumatoid arthritis treatment? Pros and cons. AB - Rheumatoid Arthritis (RA) is an autoimmune chronic disease that is characterized by the positivity of various antibodies, the most specific being autoantibodies against citrullinated antigens (ACPA). Despite ACPA are not arthritogenic by themselves, ACPA positive individuals have high risk of RA development and ACPA positivity is associated with severe erosive phenotype and higher mortality rate compared to seronegative RA. Moreover, ACPA status is associated with favorable response to biologics targeting pathways involving autoantibody producing cells as B lymphocytes. In the current review we have discussed the pros and cons on the available scientific evidences, regarding the diagnostic, prognostic and management implications of ACPAs in RA. PMID- 28899799 TI - Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review. AB - Neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membranes of activated neutrophils. NETs are found in a variety of conditions such as infection, malignancy, atherosclerosis, and autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. Studies suggest that an imbalance between "NETosis," which is a process by which NETs are formed, and NET degradation may be associated with autoimmune diseases. Neutrophils, interleukin-8, ANCA and other inflammatory molecules are considered to play a key role in NET formation. Prolonged exposure to NETs-related cascades is associated with autoimmunity and increases the chance of systemic organ damage. In this review, we discuss the roles of various inflammatory molecules in relation to NETs. We also describe the role of NETs in the pathogenesis of autoimmune diseases and discuss the possibility of using targeted therapies directed to NETs and associated molecules to treat autoimmune diseases. PMID- 28899800 TI - Bone mineral density and vitamin D status in systemic lupus erythematosus (SLE): A systematic review. AB - Despite the improvement in the quality of life of patients with SLE due to scientific and technological advances, SLE remains a disease that over the years may produce irreversible damage to patients. Osteoporosis and secondary bone fractures are two of the major causes of irreparable injury in patients with SLE. Vitamin D insufficiency may play a vital role both in reduced bone mineral density (BMD) and in the appearance of fractures, although its mechanisms of action are still unclear. We performed a systematic review of the literature in order to determine the prevalence and predictors of reduced vitamin D plasma levels, bone loss and the presence of fractures in SLE patients. Our review encompassed all English-language publications using Medline and EMBase electronic databases from their inception (1966 and 1980, respectively) to December 2016. We included all intervention studies and observational studies in which vitamin D plasma levels, BMD and bone loss were measured and applied to patients with SLE. Previous studies suggested an increase in bone loss and fracture in patients with SLE compared with general population and although there is a high prevalence of vitamin D insufficiency in the general population, previous studies had demonstrated lower vitamin D levels in patients with SLE compared to age-matched controls. The etiology of reduced bone mass and reduced vitamin D plasma levels in SLE is multifactorial and includes a variety of intrinsic factors related to the disease itself and treatment side effects. SLE patients are at risk for developing these two comorbidities (reduced vitamin D plasma levels and low BMD) and it is therefore essential to study, monitor, prevent and treat bone metabolism disorders in SLE patients. PMID- 28899801 TI - Is PET/CT essential in the diagnosis and follow-up of temporal arteritis? AB - The increasing availability and improvement of imaging techniques are deeply influencing diagnosis and work-up of patients affected with vasculitis, particularly those with large vessel vasculitis (LVV). Fluorodeoxyglucose (18F FDG) positron emission tomography (PET), especially when integrated with computed tomography (CT), is taking hold as a useful diagnostic technique to examine the aorta and the other large vessels in giant cell arteritis (GCA) with concomitant large vessel involvement (LV-GCA). In this paper we examined the progresses performed in this field in the last twenty years and the evidence available so far according to two different points of view ('pros' and 'cons'), in order to give a comprehensive answer to a still open question about the role of PET/CT in the diagnosis and follow-up of GCA. PMID- 28899802 TI - The new targeted therapy in systemic lupus erythematosus: Is the glass half-full or half-empty? AB - Biologic therapy is still limited in lupus, where chronic steroid exposure and wide-spectrum immunosuppression are major triggers of organ damage. In this viewpoint, the authors summarize their views for a "half-full or half-empty" glass on targeted therapy in SLE. The are several reasons for seeing the glass half-empty and in this section the authors propose a critical reflection on scarceness of novel targeted lupus therapies. They show how hard it is to identify suitable biological and clinical targets and to choose the patients that may best fit those targets, as well as to stratify patients according to disease subtype and response, all contributing to the final outcome. On the other hand, reasons are emerging to see the glass half-full, including the growing evidence that disease activity and damage can both be hindered by the proper use of novel drugs and that promising molecules are upcoming. In this section, the authors contextualize potentials and failures of new drugs, providing a critical reading of disappointing results and underlining the concrete benefits obtainable through a wise use of available treatments. Indeed, combining medications with new therapeutic strategies such as the treat-to-target seems the right approach to add some water to a filling glass. PMID- 28899803 TI - Humanistic and cost burden of systemic sclerosis: A review of the literature. AB - BACKGROUND: Systemic sclerosis (SSc), or systemic scleroderma, is a chronic multisystem autoimmune disease characterised by widespread vascular injury and progressive fibrosis of the skin and internal organs. Patients with SSc have decreased survival, with pulmonary involvement as the main cause of death. Current treatments for SSc manage a range of symptoms but not the cause of the disease. Our review describes the humanistic and cost burden of SSc. METHODS: A structured review of the literature was conducted, using predefined search strategies to search PubMed, Embase, and the Cochrane Library. Grey literature searches also were conducted. RESULTS: In total, 2226 articles were identified in the databases and 52 were included; an additional 10 sources were included from the grey literature. The review identified six studies reporting relevant cost estimates conducted in five different countries and four studies that assessed the humanistic burden of SSc. Total direct annual medical costs per patient for Europe varied from ?3544 to ?8452. For Canada, these costs were reported to be from Can$5038 to Can$10,673. In the United States, the total direct health care costs were reported to be US$17,365 to US$18,396. Different key drivers of direct costs were reported, including hospitalisations, outpatients, and medication. The total annual costs per patient were reported at Can$18,453 in Canada and varied from ?11,074 to ?22,459 in Europe. Indirect costs represented the largest component of the total costs. EQ-5D utility scores were lower for patients with SSc than those observed in the general population, with reported mean values of 0.49 and 0.68, respectively. The average value of the Health Assessment Questionnaire for patients with SSc was significantly higher than the control population (0.94), and the average value of the SF-36 was significantly lower than the control population: 49.99 for the physical dimension and 58.42 for the mental dimension. CONCLUSIONS: Overall, there is a paucity of information on the burden of SSc. Nonetheless, our review indicates that the quality of life of patients with SSc is considerably lower than that of the general population. In addition, SSc places a considerable economic burden on health care systems and society as a whole. PMID- 28899804 TI - Can we withdraw anticoagulation in patients with antiphospholipid syndrome after seroconvertion? AB - The current mainstay of treatment in patients with thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation, mainly with Vitamin K antagonist agents. Some recently available studies have created new ground for discussion about the possible discontinuation of anticoagulation therapy in patients with a history of thrombotic APS in whom antiphospholipid antibodies (aPL) are not detected any longer (i.e. aPL seroconversion). We report the main points discussed at the last CORA Meeting regarding the issue whether or not anticoagulation can be stopped after aPL seroconversion. In particular, we systematically reviewed the available evidence investigating the clinical outcome of APS patients with aPL seroconversion in whom anticoagulation was stopped when compared to those in whom therapy was continued regardless the aPL profile. Furthermore, the molecular basis for the aPL pathogenicity, the available evidence of non-criteria aPL and their association with thrombosis are addressed. To date, available evidence is still limited to support the indication to stop oral anticoagulation therapy in patients with a previous diagnosis of thrombotic APS who subsequently developed a negative aPL profile. The identification of the whole risk profile for cardiovascular manifestations and possibly of a second level aPL testing in selected patients with aPL might support the eventual clinical decision but further investigation is warranted. PMID- 28899805 TI - Performance of GenoType(r) MTBDRplus assay in the diagnosis of drug-resistant tuberculosis in Tangier, Morocco. AB - OBJECTIVES: In Morocco, tuberculosis (TB) is a major public health problem with high morbidity and mortality. The main problem faced by the national TB programme is the high rate of drug-resistant (DR), particularly multi-drug resistant (MDR) strains. Diagnosis of DR-TB is mainly performed by conventional techniques that are time consuming with limited efficacy. In 2014, the GenoType(r) MTBDRplus assay was introduced in Morocco for drug susceptibility testing (DST). In this regard, the present study was planned to assess the diagnostic accuracy of the GenoType(r) MTBDRplus assay. METHODS: A total of 70 samples from suspected TB cases in Tangier (Morocco) were analysed by conventional DST and GenoType(r) MTBDRplus assay. RESULTS: Among the 70 samples, 37.1% were MDR, whereas monoresistance to isoniazid (INH) and rifampicin (RIF) was detected in 186% and 17.1% of strains, respectively, by DST. Using the GenoType(r) MTBDRplus approach, 12 isolates (17.1%) were identified as INH monoresistant, 9 (12.9%) as RIF monoresistant and 26 (37.1%) as MDR. rpoB531 and katG315 mutations were the most common mutations associated with resistance to RIF and INH, respectively. Significantly, all phenotypically MDR strains were also MDR by GenoType(r) MTBDRplus. The sensitivity of GenoType(r) MTBDRplus was 92.1% for RIF resistance and 97.4% for INH resistance, whereas the specificity was 100% for the two tested drugs. CONCLUSIONS: GenoType(r) MTBDRplus assay is a rapid, reliable and accurate tool for the detection of DR-TB in clinical specimens. Its routine use will be of a great interest to prevent the dissemination of DR-TB in the community. PMID- 28899806 TI - First report of ceftriaxone-resistant Streptococcus pneumoniae meningitis in Belarus. PMID- 28899807 TI - Tn2008-driven carbapenem resistance in Acinetobacter baumannii isolates from a period of increased incidence of infections in a Southwest Virginia hospital (USA). AB - OBJECTIVES: The objectives of this study were (i) to determine the genetic basis for carbapenem resistance in multidrug-resistant (MDR) Acinetobacter baumannii strains isolated from patients affected by a sudden increase in the incidence of infections by such organisms in a tertiary care hospital in Virginia, USA, in 2009-2010 and (ii) to examine whether such strains are commonly encountered in the hospital setting. METHODS: The whole genomes of one outbreak strain as well as one carbapenem-resistant and one carbapenem-sensitive strain from sporadic infections in 2010-2012 were sequenced and analysed. Then, 5 outbreak isolates and 57 sporadic isolates (of which 39 were carbapenem-resistant) were screened by PCR for relevant DNA elements identified in the genomics investigation. RESULTS: All three strains for which whole-genome sequences were obtained carried resistance genes linked to MDR phenotypes and a ca. 111-kbp plasmid (pCMCVTAb1) without drug resistance genes. Of these, the two carbapenem-resistant strains possessed a ca. 74-kbp plasmid (pCMCVTAb2) carrying a Tn2008 transposon that provides high-level carbapenem resistance. PCR analysis showed that all of the outbreak isolates carried both plasmids and Tn2008, and of the sporadic isolates 88% carried pCMCVTAb1, 25% contained pCMCVTAb2 and 50% of the latter group carried Tn2008. CONCLUSIONS: Carbapenem resistance in outbreak strains and 12% of sporadic isolates was due to the pCMCVTAb2-borne Tn2008. This is the first report of a Tn2008-driven outbreak of carbapenem-resistant A. baumannii infections in the Commonwealth of Virginia, which followed similar cases in Pennsylvania and Ohio. PMID- 28899808 TI - Complete genome sequence of the nematicidal Bacillus thuringiensis MYBT18247. AB - The Gram-positive spore forming bacterium Bacillus thuringiensis MYBT18247 encodes three cry toxin genes, (cry6Ba2, cry6Ba3 and cry21-like) which are active against nematodes. For a better understanding of the evolution of virulence and cry toxins, we present here the complete genome sequence of Bacillus thuringiensis MYBT18247. Various additional virulence factors such as bacteriocins, proteases and hemolysins were identified. In addition, the methylome and the metabolic potential of the strain were analyzed and the strain phylogenetically classified. PMID- 28899809 TI - Estimation of Drug Particle Size in Intact Tablets by 2-Dimensional X-Ray Diffractometry. AB - The average grain size of a crystalline material can be determined from the gamma profile of Debye rings in 2-dimensional X-ray diffraction frames. Our objectives were to: (1) validate the method for organic powders and use it to determine the grain size in intact tablets, and (2) demonstrate the pharmaceutical application of this technique by determining the grain size of the active pharmaceutical ingredient in marketed formulations. Six sieve fractions of sucrose were prepared and the particle size distribution was confirmed by laser diffraction. Their average grain size was determined from the 2-dimensional X-ray diffraction frames by the gamma-profile method. For particles <90 MUm (based on sieving), the average particle size determined by the 3 methods were in good agreement. When these particles were compressed, there was no discernible change in the sucrose grain size in tablets. When the particles were >250 MUm, compression resulted in a mixture of large grains and fine powder. The grain size of acetaminophen in 11 marketed tablet formulations was determined to be either ~35 MUm or ~80 MUm. This nondestructive technique can therefore be potentially useful to estimate the grain size of crystalline formulation components in intact tablets. PMID- 28899810 TI - Quantity discrimination in canids: Dogs (Canis familiaris) and wolves (Canis lupus) compared. AB - Accumulating evidence indicates that animals are able to discriminate between quantities. Recent studies have shown that dogs' and coyotes' ability to discriminate between quantities of food items decreases with increasing numerical ratio. Conversely, wolves' performance is not affected by numerical ratio. Cross species comparisons are difficult because of differences in the methodologies employed, and hence it is still unclear whether domestication altered quantitative abilities in canids. Here we used the same procedure to compare pet dogs and wolves in a spontaneous food choice task. Subjects were presented with two quantities of food items and allowed to choose only one option. Four numerical contrasts of increasing difficulty (range 1-4) were used to assess the influence of numerical ratio on the performance of the two species. Dogs' accuracy was affected by numerical ratio, while no ratio effect was observed in wolves. These results align with previous findings and reinforce the idea of different quantitative competences in dogs and wolves. Although we cannot exclude that other variables might have played a role in shaping quantitative abilities in these two species, our results might suggest that the interspecific differences here reported may have arisen as a result of domestication. PMID- 28899811 TI - Group selection in behavioral evolution. AB - How may patterns of behavior change over an organism's lifetime? The answer is that they evolve (behavioral evolution) as species evolve over generations (biological evolution). In biological evolution, under certain conditions, groups of cooperative organisms would be selected over groups of non-cooperative organisms, even when cooperation imposes a cost to individuals. Analogously, in behavioral evolution, patterns of acts may be selected even when each individual act in the pattern is costly. Although there is considerable debate among biologists whether the conditions for group selection are met in biological evolution, it is argued here that they are met in behavioral evolution (as well as in cultural evolution). The article shows how selection of patterns can explain the learning of self-control and altruism. PMID- 28899812 TI - The starving brain: Overfed meets undernourished in the pathology of mild cognitive impairment (MCI) and Alzheimer's disease (AD). AB - Type II Diabetes affects 400 million people worldwide (IDF, 2013). The pathology is paradoxical: internal starvation activated by overfeeding. Hyperinsulinemic impairments of glucose homeostasis are treated with anti-hyperglycemics exacerbating cell starvation, inducing hypoglycemia and raising respiratory quotient. Reductions in hyperglycemia are achieved at the expense of glucose dependency and metabolic inflexibility (Gibas & Gibas, 2017). The brain is not immune from these cycles of starvation. The bioenergetic model characterizes propagation of late-onset, sporadic Alzheimer's disease as loss of molecular fidelity and compromised energy originating in brain networks with highest metabolic demand. Impaired networks function as hubs of connectivity with other "at risk" regions causing propagation of disease to neighboring cells and compensatory up-regulation in protein synthesis, including amyloid precursor protein (Demetrius et al., 2014). Impaired brain circuits are hypo-metabolic. Cerebral energy declines after stages of quasi-stable, hyper-metabolism. Elevated insulin with low bioavailable glucose cross the BBB hyper-activating neurons to preserve brain function, thereby overloading the astrocyte-neuron lactate shuttle. Sustained deficits reprogram the neural phenotype toward lactate driven, OXPHOS. Increased OXPHOS fosters competition between normal and "metabolically charged" neurons for limited fuel. Cerebral starvation causes apoptosis of healthy neurons due to selective disadvantage. The neuroenergetic model defines late-onset neural decline as symptomatic of "brain starvation" resulting from a physiological paradox, concurrent hyperinsulinemia and hypoglycemia, without an evolved cellular response. Catabolic degeneration occurs on a spectrum linear to energy deficit ranging from mild cognitive impairment (MCI) to Alzheimer's disease (AD); this pathology of cerebral starvation is known as Type III diabetes. PMID- 28899813 TI - Re-inventing drug development: A case study of the I-SPY 2 breast cancer clinical trials program. AB - BACKGROUND: In this case study, we profile the I-SPY 2 TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And molecular anaLysis 2), a unique breast cancer clinical trial led by researchers at 20 leading cancer centers across the US, and examine its potential to serve as a model of drug development for other disease areas. This multicenter collaboration launched in 2010 to reengineer the drug development process to be more efficient and patient-centered. METHODS: We conduct several interviews with the I-SPY leadership as well as a literature review of relevant publications to assess the I-SPY 2 initiative. RESULTS: To date, six drugs have graduated from I-SPY 2, identified as excellent candidates for phase 3 trials in their corresponding tumor subtype, and several others have been or are still being evaluated. These trials are also more efficient, typically involving fewer subjects and reaching conclusions more quickly, and candidates have more than twice the predicted likelihood of success in a smaller phase 3 setting compared to traditional trials. CONCLUSIONS: We observe that I-SPY 2 possesses several novel features that could be used as a template for more efficient and cost effective drug development, namely its adaptive trial design; precompetitive network of stakeholders; and flexible infrastructure to accommodate innovation. PMID- 28899814 TI - Single immunization with MF59-adjuvanted inactivated whole-virion H7N9 influenza vaccine provides early protection against H7N9 virus challenge in mice. AB - H7N9 influenza infection in humans would result in severe respiratory illness. Vaccination is the best way to prevent influenza virus. In this paper, we investigated the effect of early protection provided by inactivated whole-virion H7N9 influenza vaccine in a mouse model. Mice were immunized intramuscularly once with different doses of inactivated whole-virion H7N9 influenza vaccine alone or in combination with MF59 adjuvant. Specific IgM and IgG antibody titers in sera of mice were detected by ELISA 3, 5 and 7days after immunization. To evaluate the early protection provided by the vaccine, mice were challenged with lethal dose (40LD50) of homologous virus 3, 5 and 7 days after immunization respectively. The survival rate and body weight change of mice during 21 days after challenge and the residual lung virus titer on 3rd day after challenge were determined. The results demonstrated that mice could obtain effective protection 3 days after immunization with the vaccine at a high dose, and 5-7 days after immunization even at a low dose. Thus early immune responses induced by inactivated whole virion H7N9 vaccine could provide effective protection. PMID- 28899815 TI - Blockage of regulatory T cells augments induction of protective immune responses by influenza virus-like particles in aged mice. AB - Elderly humans over 65 years old are at great risk to pathogenesis by influenza virus infection. However, although influenza vaccines provide effective protection in healthy young adults, protection of elderly adults is substantially lower even with a good match between the vaccine and the circulating influenza virus. To gain insight of the underlying mechanism for the reduced immunogenicity of influenza vaccines in the aged population, we investigated immunogenicity of influenza virus-like particle vaccines in aged mice, which represent a useful model for studying aging associated impairment in immune responses. Specifically, we investigated the effect of inhibiting regulatory T cells in aged mice on induction of protective immune responses by influenza vaccines. Our results showed that injecting anti-CD25 antibodies could down-regulate CD25 on the surface of regulatory T cells and significantly increase the levels of antibody responses induced by VLP immunization in aged mice. Further, the profiles of antibody responses were also changed towards Th1 type by regulatory T cell blockage in aged mice. Moreover, aged mice that were treated by anti-CD25 antibodies prior to vaccination were more effectively protected against lethal influenza virus challenge. PMID- 28899816 TI - Enzyme-crosslinked gene-activated matrix for the induction of mesenchymal stem cells in osteochondral tissue regeneration. AB - : The development of osteochondral tissue engineering is an important issue for the treatment of traumatic injury or aging associated joint disease. However, the different compositions and mechanical properties of cartilage and subchondral bone show the complexity of this tissue interface, making it challenging for the design and fabrication of osteochondral graft substitute. In this study, a bilayer scaffold is developed to promote the regeneration of osteochondral tissue within a single integrated construct. It has the capacity to serve as a gene delivery platform to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. For the subchondral bone layer, the bone matrix with organic (type I collagen, Col) and inorganic (hydroxyapatite, Hap) composite scaffold has been developed through mineralization of hydroxyapatite nanocrystals oriented growth on collagen fibrils. We also prepare multi-shell nanoparticles in different layers with a calcium phosphate core and DNA/calcium phosphate shells conjugated with polyethyleneimine to act as non-viral vectors for delivery of plasmid DNA encoding BMP2 and TGF-beta3, respectively. Microbial transglutaminase is used as a cross-linking agent to crosslink the bilayer scaffold. The ability of this scaffold to act as a gene-activated matrix is demonstrated with successful transfection efficiency. The results show that the sustained release of plasmids from gene-activated matrix can promote prolonged transgene expression and stimulate hMSCs differentiation into osteogenic and chondrogenic lineages by spatial and temporal control within the bilayer composite scaffold. This improved delivery method may enhance the functionalized composite graft to accelerate healing process for osteochondral tissue regeneration. STATEMENT OF SIGNIFICANCE: In this study, a gene-activated matrix (GAM) to promote the growth of both cartilage and subchondral bone within a single integrated construct is developed. It has the capacity to promote transfection of human mesenchymal stem cells (hMSCs) and the functional osteochondral tissues formation. The results show that the sustained release of plasmids including TGF-beta and BMP-2 from GAM could promote prolonged transgene expression and stimulate hMSCs differentiation into the osteogenic and chondrogenic lineages by spatial control manner. This improved delivery method should enhance the functionalized composite graft to accelerate healing process in vitro and in vivo for osteochondral tissue regeneration. PMID- 28899817 TI - Acute oral toxicity study of magnesium oxide nanoparticles and microparticles in female albino Wistar rats. AB - Advancements in nanotechnology have led to the development of the nanomedicine, which involves nanodevices for diagnostic and therapeutic purposes. A key requirement for the successful use of the nanoparticles (NPs) in biomedical applications is their good dispensability, colloidal stability in biological media, internalization efficiency, and low toxicity. Therefore, toxicological profiling is necessary to understand the mechanism of NPs and microparticles (MPs). MgO NPs have attracted wide scientific interest due to ease of synthesis, chemical stability and unique properties. However, their toxic effects on humans should also be of concern with the increased applications of nano MgO. The present study was aimed to assess the toxicological potential of MgO NPs in comparison to their micron counterparts in female Wistar rats. Toxicity was evaluated using genotoxicity, histological, biochemical, antioxidant and biodistribution parameters post administration of MgO particles to rats through oral route. The results obtained from the investigation revealed that the acute exposure to the high doses of MgO NPs produced significant (p < 0.01) DNA damage and biochemical alterations. Antioxidant assays revealed prominent oxidative stress at the high dose level for both the particles. Toxicokinetic analysis showed significant levels of Mg accumulation in the liver and kidney tissues apart from urine and feces. Further, mechanistic investigational reports are warranted to document safe exposure levels and health implications post exposure to high levels of NPs. PMID- 28899818 TI - Familial 9q33q34 microduplication in siblings with developmental disorders and macrocephaly. AB - Because several genes responsible for epileptic encephalopathy are located on the 9q33q34 region, patients with chromosomal deletions of this region often show intractable epilepsy and neurodevelopmental disability. Contrary to these findings, chromosomal duplications of this region have never been reported previously. We identified a first case of 9q33q34 microduplications in siblings associated with developmental disorders and macrocephaly. Their mother was a mosaic carrier of this duplication. Duplicated regions involved STXBP1; the gene related to epileptic encephalopathy. Neurological features including developmental delay and macrocephaly observed in the present siblings may be derived from the extra-copy of STXBP1. PMID- 28899819 TI - Information content of dendritic spines after motor learning. AB - Dendritic spines, small protrusions emerging from the dendrites of most excitatory synapses in the mammalian brain, are highly dynamic structures and their shape and number is continuously modulated by memory formation and other adaptive changes of the brain. In this study, using a behavioral paradigm of motor learning, we applied the non-linear analysis of dendritic spines to study spine complexity along dendrites of cortical and subcortical neural systems, such as the basal ganglia, that sustain important motor learning processes. We show that, after learning, the spine organization has greater complexity, as indexed by the maximum Lyapunov exponent (LyE). The positive value of the exponent demonstrates that the system is chaotic, while recurrence plots show that the system is not simply composed by random noise, but displays quasi-periodic behavior. The increase in the maximum LyE and in the system entropy after learning was confirmed by the modification of the reconstructed trajectories in phase-space. Our results suggest that the remodeling of spines, as a result of a chaotic and non-random dynamical process along dendrites, may be a general feature associated with the structural plasticity underlying processes such as long-term memory maintenance. Furthermore, this work indicates that the non linear method is a very useful tool to allow the detection of subtle stimulus induced changes in dendritic spine dynamics, giving a key contribution to the study of the relationship between structure and function of spines. PMID- 28899820 TI - A facilitating role for the primary motor cortex in action sentence processing. AB - The involvement of the motor system in action language comprehension is a hotly debated topic in cognitive neuroscience and psychology. Recent studies suggest that primary motor cortex (M1) response to action language is context-sensitive rather than automatic and necessary. Specifically, semantic polarity (i.e. affirmative/negative valence) appears to modulate the intensity of this response, which is stronger for affirmative action sentences. The aim of our study was to examine further the context sensitivity of M1 response. More specifically, we aimed to determine whether M1 response follows semantic polarity or the core meaning of the sentence using two-part action sentences containing interacting polarities. Modulations of M1 activity were recorded using surface electromyography of the first dorsal interosseous muscle of the right hand in 22 healthy participants. Our results show an increase in M1 activity during the first part of the sentence, regardless of semantic polarity. This response was then modulated by the polarity of the second part of the sentence, which carried crucial information regarding the action. These observations suggest that M1 differentially responds to different aspects of action sentences, one response being automatic and the other following the core meaning of the sentence. Our results thus contribute to clarifying the nature of the motor response to action language, which is key to develop more comprehensive and plausible neurobiological models of language processing. PMID- 28899821 TI - Correlation between brain circuit segregation and obesity. AB - Obesity is a major public health problem. Herein, we aim to identify the correlation between brain circuit segregation and obesity using multimodal functional magnetic resonance imaging (fMRI) techniques and analysis. Twenty obese patients (BMI=37.66+/-5.07) and 30 healthy controls (BMI=22.64+/-3.45) were compared using neuroimaging and assessed for symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). All participants underwent resting-state fMRI (rs-fMRI) and T1-weighted imaging using a 1.5T MRI. Multimodal MRI techniques and analyses were used to assess obese patients, including the functional connectivity (FC), amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), graph theoretical analysis (GTA), and voxel-based morphometry (VBM). Correlations between brain circuit segregation and obesity were also calculated. In the VBM, obese patients showed altered gray matter volumes in the amygdala, thalamus and putamen. In the FC, the obesity group showed increased functional connectivity in the bilateral anterior cingulate cortex and decreased functional connectivity in the frontal gyrus of default mode network. The obesity group also exhibited altered ALFF and ReHo in the prefrontal cortex and precuneus. In the GTA, the obese patients showed a significant decrease in local segregation and a significant increase in global integration, suggesting a shift toward randomization in their functional networks. Our results may provide additional evidence for potential structural and functional imaging markers for clinical diagnosis and future research, and they may improve our understanding of the underlying pathophysiology of obesity. PMID- 28899822 TI - Early strength recovery after anterior cruciate ligament reconstruction using the fascia lata. AB - INTRODUCTION: After undergoing anterior cruciate ligament (ACL) reconstruction, patients must recover at least 80% of their hamstring and quadriceps strength to be able to return to sports without risk to the graft. Harvesting of the patellar tendon leads to large deficits in quadriceps strength, while harvesting the hamstring tendons leads to large deficits in hamstring strength. However, there are no published studies on the strength deficit after ACL reconstruction with the fascia lata. The objective of this study was to evaluate the results of isokinetic testing in patients who underwent ACL reconstruction with a fascia lata graft and to analyze the individual factors affecting these results. The hypothesis was that preserving the quadriceps and hamstrings would lead to satisfactory isokinetic testing results by preserving the physiological balance between the flexor and extensor mechanisms in the leg. MATERIALS AND METHODS: In this retrospective, single-center study, 53 patients had their quadriceps and hamstring strength recovery evaluated 6 months and 1 year post-ACL reconstruction by concentric isometric testing at a slow (90 degrees /s) and fast velocity (240 degrees /s). These results were analyzed as a function of individual characteristics such as age, sex, preinjury level and type of sports activity, and IKDC and Lysholm scores. RESULTS: The quadriceps strength deficit at the slow and fast velocities was 27.5% and 22.5% at 6 months and 15.5% and 11% at 1 year, respectively. The hamstring strength deficit at the slow and fast velocities was 12.1% and 7% at 6 months and 8% and 6.4% at 1 year, respectively. The quadriceps to hamstring ratio at the slow and fast velocities was 66.7+/-16.5 and 71.3+/ 15.5 at 6 months, and 61.1+/-14.9 and 67.6+/-12.5 at 1 year. Being less than 25 years of age, having a subjective IKDC grade or Lysholm score above 90, and being a professional athlete were significant predictors of better muscle strength recovery. DISCUSSION: Isokinetic testing at 6 months and 1 year after ACL reconstruction surgery using the fascia lata showed that the quadriceps to hamstring ratio is close to physiological standards. LEVEL OF EVIDENCE: IV retrospective study. PMID- 28899824 TI - Group- and Individual-Level Responsiveness of the 3-Point Berg Balance Scale and 3-Point Postural Assessment Scale for Stroke Patients. AB - OBJECTIVES: To examine both group- and individual-level responsiveness of the 3 point Berg Balance Scale (BBS-3P) and 3-point Postural Assessment Scale for Stroke Patients (PASS-3P) in patients with stroke, and to compare the responsiveness of both 3-point measures versus their original measures (Berg Balance Scale [BBS] and Postural Assessment Scale for Stroke Patients [PASS]) and their short forms (short-form Berg Balance Scale [SFBBS] and short-form Postural Assessment Scale for Stroke Patients [SFPASS]) and between the BBS-3P and PASS 3P. DESIGN: Data were retrieved from a previous study wherein 212 patients were assessed at 14 and 30 days after stroke with the BBS and PASS. SETTING: Medical center. PARTICIPANTS: Patients (N=212) with first onset of stroke within 14 days before hospitalization. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Group-level responsiveness was examined by the standardized response mean (SRM), and individual-level responsiveness was examined by the proportion of patients whose change scores exceeded the minimal detectable change of each measure. The responsiveness was compared using the bootstrap approach. RESULTS: The BBS-3P and PASS-3P had good group-level (SRM, .60 and SRM, .56, respectively) and individual level (48.1% and 44.8% of the patients with significant improvement, respectively) responsiveness. Bootstrap analyses showed that the BBS-3P generally had superior responsiveness to the BBS and SFBBS, and the PASS-3P had similar responsiveness to the PASS and SFPASS. The BBS-3P and PASS-3P were equally responsive to both group and individual change. CONCLUSIONS: The responsiveness of the BBS-3P and PASS-3P was comparable or superior to those of the original and short-form measures. We recommend the BBS-3P and PASS-3P as responsive outcome measures of balance for individuals with stroke. PMID- 28899823 TI - A predictive radiological analysis of short stems versus both shortened and long stems in primary hip replacement: A case-control study of 100 cases of Metha versus ABG II and Omnifit HA at 2-8years' follow-up. AB - INTRODUCTION: Short hip stems, intended to conserve bone stock and ensure a more physiological distribution of stress in the femur under loading, are meeting with renewed interest. Radiologic semiology is not known exactly, particularly in relation to conventional implants; we therefore conducted a case-control study of 3 types of implant differing only in stem length: short, shortened or long. The aim was: (1) to compare radiographic aspects, (2) to attempt to systematize medium-term radiologic status for the 3 types, and (3) to assess the impact of radiographic aspect on loosening and revision rates. HYPOTHESIS: The short Metha stem is better adapted to the recipient bone than longer stems, without sacrificing stability. MATERIAL AND METHODS: A prospective series comprising the first 100 selected cases of hip replacement using the short Metha stem was compared to two other series of 100 "long" (Omnifit HA) and 100 "shortened" (ABG II) stems at comparable follow-up: 4.05+/-1.44years (range: 2-8years) for Metha, 4.48+/-0.97years (range: 2-8years) for Omnifit, and 4.75+/-2.07years (range: 2 8years) for ABG II. Selection criteria in this initial phase were very strict: young age and/or high activity level, with good bone stock and femoral morphology suited to fitting a Metha stem (no "stovepipe" or "champagne-flute" femurs), for which 12.8% of primary hip replacements were selected. Matching was performed by sampling on criteria of age, gender, body-mass index and etiology. Radiographic parameters were compared between the short stem group and the two control groups and classified according to Engh-Massin score (10 points for fixation and 17 for stability). RESULTS: The short Metha stem provided excellent fixation scores: 7.65/10, versus 7.16 (P=0.003) and 5.92 (P=0.0001) for ABG II and Omnifit, respectively. Likewise, stability was scored 14.23/17 for Metha, vs. 14.51 (NS) and 11.83 (P=0.0001) respectively, and the total score was higher for Metha (21.88/27) than ABG II (21.67; P=0.03) or, more particularly, Omnifit (17.83; P=0.0001). The Metha stem was never associated with thigh pain or periprosthetic fracture. 8-year survival was 100%, without significant difference with respect to ABG II (100%; NS) or Omnifit (98.8%; 95% CI: 0.964-1; NS). DISCUSSION: The apparent radiologic superiority of the short Metha stem requires long-term confirmation in non-selected series. Meanwhile, Metha can be asserted to have demonstrated optimal compromise between lasting bone anchorage and respect of bone physiology under loading at medium term. LEVEL OF EVIDENCE: III, case control study. PMID- 28899826 TI - Comparative Efficacy of Intra-Articular Steroid Injection and Distension in Patients With Frozen Shoulder: A Systematic Review and Network Meta-Analysis. AB - OBJECTIVE: To compare the efficacy of intra-articular (IA) steroid injection and distension in patients with frozen shoulder. DATA SOURCES: Databases, including MEDLINE (via PubMed), Embase, Scopus, and Cochrane Library, were searched for studies published up to November 2016. STUDY SELECTION: We included all published randomized controlled trials (RCTs), quasi-experimental studies, and observational studies investigating the effectiveness of IA steroid injection, distension, and physiotherapy in patients with frozen shoulder. Sixteen RCTs and 1 observational study were enrolled in meta-analysis. DATA EXTRACTION: Full texts were independently reviewed, and quality of RCTs was assessed with The Cochrane Collaboration's tool. The primary outcome was functional improvement; the secondary outcomes included pain reduction and external rotation (ER) improvement. DATA SYNTHESIS: In pairwise meta-analysis, pooled standardized mean difference (SMD) of functional improvement and pain reduction revealed equal efficacy at 3 follow-up time points. With respect to ER improvement, distension has a superior effect compared with IA steroid injection in the short term [(2 4wk; SMD, -.36; 95% confidence interval [CI], -.68 to -.04) and medium term (6 16wk; SMD, -0.80; 95% CI, -1.32 to -0.29). The network meta-analysis indicated a better efficacy for distension than for IA steroid injection in ER improvement only in the medium term (6-16wk; SMD, -0.70; 95% CI, -1.19 to -0.21). CONCLUSIONS: IA steroid injection was as effective as distension in shoulder function improvement, pain reduction, and increasing ER of the shoulder. Distension yielded better ER improvement in the medium term but to a minor extent in the long term. For patients with predominant ER limitation, early distension could be considered the primary choice of treatment. PMID- 28899825 TI - Long-Term Performance and User Satisfaction With Implanted Neuroprostheses for Upright Mobility After Paraplegia: 2- to 14-Year Follow-Up. AB - OBJECTIVE: To quantify the long-term (>2y) effects of lower extremity (LE) neuroprostheses (NPs) for standing, transfers, stepping, and seated stability after spinal cord injury. DESIGN: Single-subject design case series with participants acting as their own concurrent controls, including retrospective data review. SETTING: Hospital-based clinical biomechanics laboratory with experienced (>20y in the field) research biomedical engineers, a physical therapist, and medical monitoring review. PARTICIPANTS: Long-term (6.2+/-2.7y) at home users (N=22; 19 men, 3 women) of implanted NPs for trunk and LE function with chronic (14.4+/-7.1y) spinal cord injury resulting in full or partial paralysis. INTERVENTIONS: Technical and clinical performance measurements, along with user satisfaction surveys. MAIN OUTCOME MEASURES: Knee extension moment, maximum standing time, body weight supported by lower extremities, 3 functional standing tasks, 2 satisfaction surveys, NP usage, and stability of implanted components. RESULTS: Stimulated knee extension strength and functional capabilities were maintained, with 94% of implant recipients reporting being very or moderately satisfied with their system. More than half (60%) of the participants were still using their implanted NPs for exercise and function for >10min/d on nearly half or more of the days monitored; however, maximum standing times and percentage body weight through LEs decreased slightly over the follow up interval. Stimulus thresholds were uniformly stable. Six-year survival rates for the first-generation implanted pulse generator (IPG) and epimysial electrodes were close to 90%, whereas those for the second-generation IPG along with the intramuscular and nerve cuff electrodes were >98%. CONCLUSIONS: Objective and subjective measures of the technical and clinical performances of implanted LE NPs generally remained consistent for 22 participants after an average of 6 years of unsupervised use at home. These findings suggest that implanted LE NPs can provide lasting benefits that recipients value. PMID- 28899827 TI - Randomized Trial of Clitoral Vacuum Suction Versus Vibratory Stimulation in Neurogenic Female Orgasmic Dysfunction. AB - OBJECTIVE: To examine the safety and efficacy of using a clitoral vacuum suction device (CVSD) versus vibratory stimulation (V) to treat orgasmic dysfunction in women with multiple sclerosis (MS) or spinal cord injury (SCI). DESIGN: Randomized clinical trial. SETTING: Two academic medical centers. PARTICIPANTS: Women (N=31) including 20 with MS and 11 with SCI. INTERVENTION: A 12-week trial of the use of a CVSD versus V. MAIN OUTCOME MEASURES: Female Sexual Function Inventory (FSFI) and Female Sexual Distress Scale (FSDS). RESULTS: Twenty-three women (18 MS, 5 SCI) completed the study including 13 of 16 randomized to CVSD and 10 of 15 randomized to V. There was a statistically significant increase in total FSFI score (P=.011), desire (P=.009), arousal (P=.009), lubrication (P=.008), orgasm (P=.012), and satisfaction (P=.049), and a significant decrease in distress as measured by FSDS (P=.020) in subjects using the CVSD. In subjects who used V, there was a statistically significant increase in the orgasm subscale of the FSFI (P=.028). Subjects using the CVSD maintained improvements 4 weeks after treatment. CONCLUSIONS: CVSD is safe and overall efficacious to treat female neurogenic sexual dysfunction related to MS and SCI. V is also safe and efficacious for female neurogenic orgasmic dysfunction; however, results were limited to the active treatment period. Because of ease of access and cost, clinicians can consider use of V for women with MS or SCI with orgasmic dysfunction. CVSD is recommended for women with multiple sexual dysfunctions or for whom V is ineffective. PMID- 28899828 TI - Borderline Ovarian Tumor in the Pediatric and Adolescent Population: A Case Series and Literature Review. AB - STUDY OBJECTIVE: To determine the diagnosis, management, and outcome for children and adolescents with borderline ovarian tumor (BOT), and to provide a review of the literature on BOT in children and adolescents. DESIGN: A retrospective cohort study of female adolescents younger than age 21 years diagnosed with BOT between January 2001 and May 2016. SETTING: Texas Children's Hospital, Houston, Texas. PARTICIPANTS: Fourteen patients (ages 12 to 18 years) diagnosed with BOT. MAIN OUTCOME MEASURES: Clinical presentation, preoperative characteristics, surgical technique, cancer stage, histology, treatment, and recurrence. RESULTS: Median age at diagnosis was 15.5 years, with most postmenarchal. Abdominal mass/pain were the most common presenting symptoms. Median tumor size was 16.6 cm (range, 4 32 cm). Preoperative cancer antigen 125 (CA 125) was elevated in 54% (7/13) of cases. All patients had fertility-preserving surgery, either cystectomy (CY) or unilateral salpingo-oophorectomy (USO): 5 via laparoscopy (LSC) and 9 via laparotomy. Most were stage I with 5 serous and 9 mucinous BOT histology. No one received adjuvant chemotherapy. Two patients had recurrence. One had ipsilateral recurrence 2 months after LSC CY for FIGO stage IC1 mucinous BOT. The second had contralateral recurrence 15 months after laparotomy, right USO for FIGO stage IIIC serous BOT treated with LSC CY, then a second recurrence treated with USO after oocyte cryopreservation for fertility preservation. All patients were alive at last follow-up, 1 with disease. CONCLUSIONS: BOT in children and adolescents can be treated conservatively with fertility-preserving techniques and surveillance with good outcome. The role of adjuvant therapy is not known. PMID- 28899829 TI - Multi-scale mechanical characterization of prostate cancer cell lines: Relevant biological markers to evaluate the cell metastatic potential. AB - BACKGROUND: Considering the importance of cellular mechanics in the birth and evolution of cancer towards increasingly aggressive stages, we compared nano mechanical properties of non-tumoral (WPMY-1) and highly aggressive metastatic (PC-3) prostate cell lines both on cell aggregates, single cells, and membrane lipids. METHODS: Cell aggregate rheological properties were analyzed during dynamic compression stress performed on a homemade rheometer. Single cell visco elasticity measurements were performed by Atomic Force Microscopy using a cantilever with round tip on surface-attached cells. At a molecular level, the lateral diffusion coefficient of total extracted lipids deposited as a Langmuir monolayer on an air-water interface was measured by the FRAP technique. RESULTS: At cellular pellet scale, and at single cell scale, PC-3 cells were less stiff, less viscous, and thus more prone to deformation than the WPMY-1 control. Interestingly, stress-relaxation curves indicated a two-step response, which we attributed to a differential response coming from two cell elements, successively stressed. Both responses are faster for PC-3 cells. At a molecular scale, the dynamics of the PC-3 lipid extracts are also faster than that of WPMY-1 lipid extracts. CONCLUSIONS: As the evolution of cancer towards increasingly aggressive stages is accompanied by alterations both in membrane composition and in cytoskeleton dynamical properties, we attribute differences in viscoelasticity between PC-3 and WPMY-1 cells to modifications of both elements. GENERAL SIGNIFICANCE: A decrease in stiffness and a less viscous behavior may be one of the diverse mechanisms that cancer cells adopt to cope with the various physiological conditions that they encounter. PMID- 28899830 TI - Simple Lateral Suboccipital Approach and Modification for Vertebral Artery Aneurysms: A Study of 52 Cases Over 10 Years. AB - INTRODUCTION: Complex skull base approaches are frequently used to treat intracranial vertebral artery (VA) and proximal posterior inferior cerebellar artery (PICA) aneurysms. These complex procedures are associated with higher risk of neurovascular injury. Hence, a less-invasive surgical approach is needed to improve the efficacy and safety of treatment. METHODS: A retrospective analysis was conducted on clinical and radiologic data from surgeries in which simple lateral suboccipital and "lateral-enough" approaches were used to clip VA aneurysms in the Department of Neurosurgery at Helsinki University Central Hospital from 2000 to 2009. RESULTS: Fifty-two VA or PICA aneurysms were treated using the simple lateral suboccipital approach. Sixteen patients (31%) presented with an unruptured aneurysm, 21 patients (40%) with World Federation of Neurosurgical Societies (WFNS) grade 1-3, and 15 patients (29%) with World Federation of Neurosurgical Societies grade 4-5. The aneurysms were saccular in 48 cases (92%), dissecting in 3 cases (6%), and fusiform in 1 case (2%). The most common aneurysm location was the VA-PICA junction (81%). The mean final modified Rankin Scale score was 2, and in unruptured cases, all patients had favorable clinical outcomes. The main causes of unfavorable outcome were poor preoperative clinical grade (P = 0.002), preoperative intraventricular hemorrhage (P = 0.008), postoperative hydrocephalus (P = 0.003), brain infarction (P = 0.005), and postoperative pneumonia (P < 0.001). CONCLUSIONS: We describe a 10-year experience using a simple lateral suboccipital approach and its modification by the senior author (J.H.) to treat VA and proximal PICA aneurysms. Unfavorable outcome was related to the poor preoperative clinical grade, preoperative intraventricular hemorrhage, and postoperative pneumonia. PMID- 28899831 TI - Acquired Chiari I Malformation with Syringomyelia Secondary to Colloid Cyst with Hydrocephalus-Case Report and Review of Literature. AB - INTRODUCTION: Acquired Chiari malformation and associated syringomyelia have been previously described following lumbar puncture/drainage, lumboperitoneal shunts, and spontaneous cerebrospinal fluid leakage. In addition to these etiologies, space-occupying lesions such as meningiomas, epidermoid cysts, medulloblastomas, and arachnoid cysts are rare causes of acquired Chiari malformation and syringomyelia. We report a rare case of colloid cyst with hydrocephalus causing secondary Chiari malformation with syringomyelia. CASE REPORT: A 58-year-old lady presented with neck pain and difficulty in walking and numbness of all 4 limbs of 1-year duration. Diagnostics with magnetic resonance imaging of the head and the cervical spine were done in the referring hospital. The patients was then referred with the diagnosis of colloid cyst with hydrocephalus and Chiari malformation 1 with cervicodorsal syringomyelia. She underwent colloid cyst excision through the transcallosal approach. Postoperatively the patient showed improvement in her symptomatology. Magnetic resonance imaging of the brain and cervical spine at 6 months' follow-up showed resolved Chiari malformation and resolving syrinx. CONCLUSIONS: Colloid cyst with hydrocephalus is a rare cause of secondary Chiari malformation with syringomyelia. Surgical management of the underlying lesion improves acquired Chiari malformation and associated syringomyelia. PMID- 28899832 TI - Radiologic Predictors for Extent of Resection in Pituitary Adenoma Surgery. A Single-Center Study. AB - BACKGROUND: Preoperative radiologic evaluation of pituitary adenomas is essential. Despite the efforts made to determine the achieved resection grade after pituitary adenoma surgery, there is a high level of disagreement among all the available classifications and measurement methods used. Our study aimed to determine pituitary adenoma imaging features, easily obtained from preoperative magnetic resonance, which could be used as resection predictor variables. Second, we analyzed the usefulness of the ellipsoid method in pituitary adenoma volume determination. METHODS: Two-hundred and ninety-four pituitary adenomas, which were surgically treated in our department, were retrospectively analyzed. Age, gender, surgical approach, hormonal status, greater tumor diameter, volume, cavernous sinus invasion, and extent of resection were evaluated. RESULTS: One hundred and forty-eight surgical procedures were conducted with a microsurgical transsphenoidal approach whereas 146 were conducted with an endoscopic endonasal approach. Gross total resection was achieved in 54.08% of cases. There were no significant differences in the extent of resection regarding the approach used, age, gender, or hormonal production by the tumor. Only Knosp grade (P < 0.001) and tumor volume (P < 0.05) had a statistically and independent significant relationship with the extent of resection. Furthermore, we found a high correlation between the calculated volume, using the ellipsoid method, and the volume measurement obtained with complex planimetry methods. CONCLUSIONS: Pituitary adenoma volume and cavernous sinus invasion, graded with the Knosp scale, are 2 pituitary tumor features that, when used in combination, predict the complexity of the surgery and the difficulty of achieving gross total resection in pituitary adenoma surgery. PMID- 28899833 TI - A Pilot Study of the Level of Evidence and Collaboration in Published Neurosurgical Research. AB - OBJECTIVE: Large-scale studies analyzing neurosurgical published research are lacking. This pilot study was designed to assess feasibility of an ongoing annual neurosurgical literature and research analysis of published articles in English language neurosurgery journals. METHODS: All scientific articles published during 2015 in the print version of 14 English-language neurosurgery journals were reviewed individually. RESULTS: During 2015, 4065 articles were published in 14 neurosurgical journals. Of these, 1116 (27.5%) were nonscientific articles and were excluded from the analysis, and 2949 scientific articles were analyzed. Of these, 2% and 8.5% of publications met criteria for levels of evidence 1 and 2, respectively. One third of published manuscripts (33.2%) were retrospective chart reviews. There were 1742 different centers (mean 1.95 centers per article; range, 1-19) represented in 2949 articles from 67 countries (mean 1.23 countries per article; range, 1-12). Multicenter collaboration was present in 47.5% of published articles, and international collaboration was present in 17.5%. The highest numbers of U.S. author international collaborations were with Canada (70 collaborations), China (33 collaborations) and Italy (25 collaborations). Data for levels of evidence, multicenter collaborations, and international collaborations are presented for each individual journal and subject within neurosurgery. CONCLUSIONS: This pilot analysis provides a descriptive assessment of levels of evidence and collaboration based on journal, general subject matter, and subcategories of subject allowing for comparison. This methodology may be used on an annual basis to establish neurosurgery publication trends and to identify underrepresented areas of research within the specialty. PMID- 28899834 TI - Hyponatremia in Traumatic Brain Injury: A Practical Management Protocol. AB - BACKGROUND: Hyponatremia (defined as serum sodium <135 mEq/L) is the most common electrolyte abnormality in traumatic brain injury (TBI) and is also an independent predictor of poor neurologic outcome. The reported incidence of hyponatremia varies widely in literature reports, and there is continuing difficulty in clearly differentiating between the 2 common causes of hyponatremia with natriuresis: the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral salt wasting (CSW). We encounter hyponatremia frequently in our practice, and we therefore decided to review data from our center to estimate the incidence of hyponatremia and the results of our management strategies, and attempt to formulate simple guidelines for the correction of hyponatremia in TBI. METHODS: A retrospective analysis of 1500 consecutively admitted patients with TBI was performed by the use of electronic records and radiographic review. Hyponatremia was defined as serum sodium <135 mEq/L, and natriuresis as a urine spot sodium of more than >40 mEq/L. The incidence of TBI, its management, and the effect of fludrocortisone were evaluated. RESULTS: The incidence of hyponatremia was 13.2%. Early therapy with fludrocortisone significantly reduced the duration of hospital stay (P < 0.05). Traumatic subarachnoid hemorrhage was the most common abnormality on the admission computed tomographic scan in patients who experienced hyponatremia. CONCLUSION: Early initiation of fludrocortisone in the setting of hyponatremia with natriuresis decreases the hospital stay. This protocol is probably safer in a tropical country where fluid restriction might be harmful. It also eliminates the need to differentiate between SIADH and CSW. PMID- 28899835 TI - Successful Treatment with Microvascular Decompression Surgery of a Patient with Hemiparesis Caused by Vertebral Artery Compression of the Medulla Oblongata: Case Report and Review of the Literature. AB - BACKGROUND: There are few reports on hemiparesis caused by vascular medullary compression, which can occur because of dolichoectasia of the vertebrobasilar arterial system. In this article, we report a case of vertebral artery compression of the medulla oblongata in a 67-year-old woman. CASE DESCRIPTION: The patient was hypertensive, and she developed hemiparesis and intermittent spasms over 5 years. These spasms had worsened during the last year. Cranial nerve magnetic resonance imaging showed compression of the medulla oblongata by the left vertebral artery. A motor evoked potential (MEP) examination showed abnormal conduction of MEPs of bilateral toe abductors. The patient underwent microvascular decompression surgery under general anesthesia through a retrosigmoid keyhole approach. This operation led to relief of vascular compression and symptomatic improvement. CONCLUSIONS: Our case suggests that detailed history, imaging studies, and electrophysiologic studies help lead to a correct and early diagnosis of hemiparesis caused by vascular compression of the rostral ventrolateral medulla. Microvascular decompression surgery improves patient symptoms, and intraoperative electrophysiologic monitoring helps to avoid injury to important adjacent nerves. PMID- 28899836 TI - Spinal Hydatid Cyst Disease. AB - OBJECTIVE: A hydatic cyst (HC) is a zoonotic infection affecting the liver and lungs, with rare spinal involvement. We discuss the long-term results in 8 patients with spinal HC who were monitored at our clinic for 7 to 15 years. METHODS: The demographic data and clinicopathologic characteristics of 8 patients with spinal HC diagnosed between 2000 and 2016 were evaluated for their contribution to recurrence, and the long-term follow-up results were examined. RESULTS: Four male and 4 female patients with a median age of 30.75 years (range, 17-45 years) at the first surgery were included. Infections were localized in the thoracic (3), thoracolumbar (1), lumbar (1), sacral (1), cervicothoracic (1), and lumbosacral (1) regions. Two patients had secondary HCs that spread from another organ (lung and kidney). Patients underwent 2 to 5 surgeries during the study period, with an average follow-up time of 8.5 years (range, 7-15 years) after the first surgery. The surgical treatments included an anterior corpectomy and anterior plate for a patient with cervical localization and cystectomy for a patient with sacral localization; the other patients underwent cystectomy with corpectomy and stabilization with an anterior approach, cyst excision and laminectomy with a posterior approach, or additional posterior transpedicular screw stabilization. The patients were prescribed albendazole. CONCLUSIONS: Spinal HC treatment is difficult, particularly in patients with vertebral and paraspinal involvement, spinal instability, and recurrence. Long-term follow-up is critical, and patients require medical and surgical treatment, with regular clinical, radiologic, and serologic examinations. The cysts must be removed without rupture during surgery, and the surgical area must be irrigated with hypertonic saline solution to reduce the risk of recurrence. PMID- 28899837 TI - An integrative taxonomic study of Pavanelliella spp. (Monogenoidea, Dactylogyridae) with the description of a new species from the nasal cavities of an Amazon pimelodid catfish. AB - The present study is an integrative taxonomic analysis of Pavanelliella spp. (Monogenoidea, Dactylogyridae), and describes a new species from the nasal cavities of the Amazonian pimelodid catfish Brachyplatystoma rousseauxii (Siluriformes Pimelodidae) from the Tapajos River (Amazon Basin, Para state, Brazil). Pavanelliella jarii sp. n. is characterized by the presence of 3-4 rings in the male copulatory organ, the absence of rings around the vaginal atrium and by its sinuous vaginal canal, which sometimes forms 0.5-1 rings in the distal portion. The sequencing of the small subunit ribosomal DNA (ssrDNA) and internal transcribed spacer 1 (ITS-1) of three species of Pavanelliella, Vancleaveus cicinnus, and an undetermined dactylogyrid allowed the phylogenetic reconstruction of these dactylogyrids. The analysis indicated that P. jarii sp. n. is closely related to Pavanelliella takemotoi and Pavanelliella pavanellii, which formed a sister clade to ancylodiscoidines parasites of siluriform fish from the Oriental and Afrotropical regions. The analysis also corroborated the non-monophyly of Ancyrocephalinae, revealing that ancylodiscoidines arose between ancyrocephalines lineages, in a sister relationship to pseudodactylogyrines+marine ancyrocephalines+ancyrocephalines parasites of afrotropical perciforms+dactylogyrines. Cladistical analysis indicates that the haptoral anchor/bar complex has been lost several times in the evolutionary history of Dactylogyridae. The analysis also indicated that Dactylogyrus is polyphyletic, as Acolpenteron ureteroecetes and Dactylogyroides longicirrus arose between the three lineages formed by Dactylogyrus spp. PMID- 28899838 TI - Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties. AB - C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B), are potent positive regulators of endochondral bone growth, making the CNP pathway one of the most promising therapeutic targets for the treatment of growth failure. However, the administration of exogenous CNP is not fully effective, due to its rapid clearance in vivo. Modification of CNP to potentially druggable derivatives may result in increased resistance to proteolytic degradation, longer plasma half-life (T1/2), and better distribution to target tissues. In the present study, we designed and evaluated CNP/ghrelin chimeric peptides as novel CNP derivatives. We have previously reported that the ghrelin C terminus increases peptide metabolic stability. Therefore, we combined the 17 membered, internal disulfide ring portion of CNP with the C-terminal portion of ghrelin. The resultant peptide displayed improved biokinetics compared to CNP, with increased metabolic stability and longer plasma T1/2. Repeated subcutaneous administration of the chimeric peptide to mice resulted in a significant acceleration in longitudinal growth, whereas CNP(1-22) did not. These results suggest that the ghrelin C-terminus improves the stability of CNP, and the chimeric peptide may be useful as a novel therapeutic agent for growth failure and short stature. PMID- 28899839 TI - No evidence for major adverse events related to suspicion of Ebola in France, 2014-2015. PMID- 28899840 TI - Estimation of seasonal influenza vaccine effectiveness using data collected in primary care in France: comparison of the test-negative design and the screening method. AB - OBJECTIVES: We discussed which method between the test-negative design (TND) and the screening method (SM) could provide more robust real-time and end-of-season vaccine effectiveness (VE) estimates using data collected from routine influenza surveillance in primary care. METHODS: We used data collected during two influenza seasons, 2014-15 and 2015-16. Using the SM, we estimated end-of-season VE in preventing medically attended influenza-like illness and laboratory confirmed influenza among the population at risk. Using the TND, we estimated end of-season VE in preventing influenza among both the general and the at-risk population. We estimated real-time VE using both methods. RESULTS: For the SM, the overall adjusted end-of-season VE was 24% (95% confidence interval (CI), 16 to 32) and 12% (95% CI, -16 to 33) during season 2014-15, and 53% (95% CI, 44 to 60) and 47% (95% CI, 23 to 64) during season 2015-16, in preventing influenza like illness and laboratory-confirmed influenza, respectively. For the TND, the overall adjusted end-of-season VE was -17% (95% CI, -79 to 24) and -38% (95% CI, 199 to 13) in 2014-15, and 10% (95% CI, -31 to 39) and 18% (95% CI, -33 to 50) in 2015-16, among the general and at-risk population, respectively. Real-time VE estimates obtained through the TND showed more variability across each season and lower precision than those estimated with the SM. CONCLUSIONS: Although the worldwide use of the TND allows for comparison of overall VE estimates among countries, the SM performs better in providing robust real-time VE estimates among the population at risk. PMID- 28899841 TI - Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis. AB - OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) virus has a variety of central nervous system (CNS) manifestations. However, there are limited data regarding SFTS-associated encephalopathy/encephalitis (SFTSAE) and its mechanism. METHODS: All patients with confirmed SFTS who underwent cerebrospinal fluid (CSF) examination due to suspected acute encephalopathy were enrolled in three referral hospitals between January 2013 and October 2016. Real time RT-PCR for SFTS virus and chemokine/cytokines levels from blood and CSF were analysed. RESULTS: Of 41 patients with confirmed SFTS by RT-PCR for SFTS virus using blood samples, 14 (34%) underwent CSF examination due to suspected SFTSAE. All 14 patients with SFTSE revealed normal protein and glucose levels in CSF, and CSF pleocytosis was uncommon (29%, 4/14). Of the eight patients whose CSF was available for further analysis, six (75%) yielded positive results for SFTS virus. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) level in CSF were significantly higher than those in serum (geometric mean 1889 pg/mL in CSF versus 264 pg/mL in serum for MCP-1, p = 0.01, and geometric mean 340 pg/mL in CSF versus 71 pg/mL in serum for IL-8, p = 0.004). CONCLUSIONS: The CNS manifestation of SFTS as acute encephalopathy/encephalitis is a common complication of SFTS. Although meningeal inflammation was infrequent in patients with SFTSAE, SFTS virus was frequently detected in CSF with elevated MCP-1 and IL 8. These findings indicate that possible direct invasion of the CNS by SFTS virus with the associated elevated cytokine levels in CSF may play an important role in the pathogenesis of SFTSAE. PMID- 28899842 TI - Identifying Which Urban Children With Asthma Benefit Most From Clinician Prompting: Subgroup Analyses From the Prompting Asthma Intervention in Rochester Uniting Parents and Providers (PAIR-UP) Trial. AB - OBJECTIVE: Clinician prompts increase the likelihood of guideline-recommended corrective actions (preventive medication prescription, dose change, and/or adherence promotion) for symptomatic children with poorly controlled or persistent asthma in the primary care setting, but it is unclear if all children equally benefit. The objectives of this study were to identify whether asthma severity, visit type, and current preventive medication use were predictive of corrective actions during visits for children with symptomatic asthma, and determine whether these factors modified the effect of a prompting intervention. METHODS: We conducted prespecified subgroup analyses of a cluster randomized controlled trial of physician prompting that promoted guideline-based asthma management for urban children with symptomatic asthma. We tested predictors of corrective actions with bivariate and multivariate multilevel logistic regressions, compared intervention effects across factor categories via stratified analyses, and characterized effect modification with interaction term analyses. RESULTS: Prompting intervention exposure, moderate/severe disease, asthma-focused visits, and current preventive medication use were predictive of corrective actions. The prompting intervention significantly increased the rate of corrective actions for children across categories of disease severity, visit type, and preventive medication use. However, the intervention effect was significantly smaller for children already using a preventive medication (adjusted odds ratio [OR], 2.01; 95% confidence interval [CI], 1.19-3.38) compared with children without preventive medication use (adjusted OR, 6.25; 95% CI, 3.39-11.54). CONCLUSIONS: Prompting increases the likelihood of corrective actions during clinic encounters; however, children already using preventive medication benefit less. It is critical for providers to recognize the need for corrective actions among these symptomatic children. PMID- 28899843 TI - A machine learning approach for the identification of new biomarkers for knee osteoarthritis development in overweight and obese women. AB - OBJECTIVE: Knee osteoarthritis (OA) is among the higher contributors to global disability. Despite its high prevalence, currently, there is no cure for this disease. Furthermore, the available diagnostic approaches have large precision errors and low sensitivity. Therefore, there is a need for new biomarkers to correctly identify early knee OA. METHOD: We have created an analytics pipeline based on machine learning to identify small models (having few variables) that predict the 30-months incidence of knee OA (using multiple clinical and structural OA outcome measures) in overweight middle-aged women without knee OA at baseline. The data included clinical variables, food and pain questionnaires, biochemical markers (BM) and imaging-based information. RESULTS: All the models showed high performance (AUC > 0.7) while using only a few variables. We identified both the importance of each variable within the models as well its direction. Finally, we compared the performance of two models with the state-of the-art approaches available in the literature. CONCLUSIONS: We showed the potential of applying machine learning to generate predictive models for the knee OA incidence. Imaging-based information were found particularly important in the proposed models. Furthermore, our analysis confirmed the relevance of known BM for knee OA. Overall, we propose five highly predictive small models that can be possibly adopted for an early prediction of knee OA. PMID- 28899844 TI - A new lipid formulation of low dose ibuprofen shows non-inferiority to high dose standard ibuprofen: the FLARE study (flaring arthralgia relief evaluation in episodic flaring knee pain) - a randomised double-blind study. AB - OBJECTIVE: To investigate short-term efficacy and safety of a novel lipid ibuprofen formulation 1200 mg/day compared with standard ibuprofen 1200 mg/day and 2400 mg/day in episodic knee arthralgia/flaring pain. DESIGN: Multicentre, randomised, double-blind, 3-arm, non-inferiority trial conducted at 27 primary care centres. Adults with >=1 knee flare episode within 12 months were recruited within 24 h of new flare with pain severity >=5 on a 0-10 numerical rating scale (NRS). Primary outcome was change from baseline in WOMAC pain subscale over 5 days. Main secondary outcome was Gastrointestinal Symptom Rating Scale (GSRS) change from baseline. Other endpoints included assessment of WOMAC total subscale scores and self-reported NRS for pain, subject nominated activity, stiffness and swelling. RESULTS: 462 patients were enrolled (58.9% males; mean age 52.2 years). Treatment allocation comprised 148 lipid 1200 mg, 155 soft-gel 1200 mg, 159 soft gel 2400 mg. WOMAC pain subscale scores decreased in all groups, with lipid 1200 mg being non-inferior to soft-gel 1200 mg (adjusted mean difference -0.26 [95% confidence interval [CI] -0.69, 0.17]) and to soft-gel 2400 mg (difference 0.19 [95% CI -0.24, 0.62]). No differences were seen in mean GSRS total scores. NRS secondary endpoints suggested greater improvements in the lipid 1200 mg group compared to soft-gel 1200 mg, with similar results to soft-gel 2400 mg. The most frequent drug-related adverse events (AEs) were gastrointestinal (GI) disorders, with statistically fewer events for lipid 1200 mg vs soft-gel 2400 mg (P = 0.01, post-hoc analysis). CONCLUSIONS: Ibuprofen 1200 mg/day lipid formulation was non inferior to standard ibuprofen soft-gel capsules 1200 mg and 2400 mg/day in relieving flaring knee pain. NRS endpoints showed lipid 1200 mg was numerically similar to soft-gel 2400 mg. TRIAL REGISTRATION NUMBER: EudraCT number: 2014 004254-33. PMID- 28899845 TI - Upwelling-derived oceanographic conditions impact growth performance and growth related gene expression in intertidal fish. AB - Growth is one of the main biological processes in aquatic organisms that is affected by environmental fluctuations such as upwelling (characterized by food rich waters). In fish, growth is directly related with skeletal muscle increase; which represents the largest tissue of body mass. However, the effects of upwelling on growth, at the physiological and molecular level, are unknown. This study used Girella laevifrons (one of the most abundant intertidal fish in Eastern South Pacific) as a biological model, considering animals from upwelling (U) and non-upwelling (NU) areas. Here, we evaluated the effect of nutritional composition and food availability on growth performance and expression of key growth-related genes (insulin-kike growth factor 1 (igf1) and myosin heavy-chain (myhc)) and atrophy-related genes (muscle ring-finger 1 (murf1), F-box only protein 32 (atrogin-1) and BCL2/adenovirus E1B 19kDa-interacting protein 3 (bnip3)). We reported that, among zones, U fish displayed higher growth performance in response to nutritional composition, specifically between protein- and fiber-rich diets (~1g). We also found in NU fish that atrophy-related genes were upregulated with fiber-rich diet and during fasting (~2-fold at minimum respect U). In conclusion, our results suggest that the growth potential of upwelling fish may be a consequence of differential muscle gene expression. Our data provide a preliminary approach contributing on how upwelling influence fish growth at the physiological and molecular levels. Future studies are required to gain further knowledge about molecular differences between U and NU animals, as well as the possible applications of this knowledge in the aquaculture industry. PMID- 28899846 TI - Quality of Patient Information Websites About Congenital Heart Defects: Mixed Methods Study of Perspectives Among Individuals With Experience of a Prenatal Diagnosis. AB - BACKGROUND: When a heart defect is prenatally diagnosed in the fetus, expectant parents experience a great need for information about various topics. After the diagnosis, the Web is used for supplemental information, and the scarcity of research calls attention to the need to explore patient information websites from the perspectives of the intended consumers. OBJECTIVE: The overarching aim of this study was to explore the quality of Swedish patient information websites about congenital heart defects, from the perspectives of individuals with experience of a prenatal diagnosis of congenital heart defect in the fetus. METHODS: This was a mixed-methods study of websites identified through systematic searches in the two most used Web-based search engines. Of the total 80 screened hits, 10 hits led to patient information websites about congenital heart defects. A quality assessment tool inspired by a previous study was used to evaluate each website's appearance, details, relevance, suitability, information about treatment choices, and overall quality. Answers were given on a 5-point Likert scale, ranging from 1, representing the lowest score, to 5, representing the highest score. Each website was assessed individually by persons with experience of continued (n=4) and terminated (n=5) pregnancy following a prenatal diagnosis. Assessments were analyzed with Kendall's coefficient of concordance W, Mann Whitney U test, Friedman's test, and a Wilcoxon-Nemenyi-McDonald-Thompson test. In addition, each assessor submitted written responses to open-ended questions in the quality assessment tool, and two joint focus group discussions were conducted with each group of assessors. The qualitative data were analyzed with inductive manifest content analysis. RESULTS: Assessments represented a low score (median=2.0) for treatment choices and moderate scores (median=3.0) for appearance, details, relevance, suitability, and overall quality. No website had a median of the highest achievable score for any of the questions in the quality assessment tool. Medians of the lowest achievable score were found in questions about treatment choices (n=4 websites), details (n=2 websites), suitability (n=1 website), and overall quality (n=1 website). Websites had significantly different scores for appearance (P=.01), details (P<.001), relevance (P<.001), suitability (P<.001), treatment choices (P=.04), and overall quality (P<.001). The content analysis of the qualitative data generated six categories: (1) advertisements, (2) comprehensiveness, (3) design, (4) illustrations and pictures, (5) language, and (6) trustworthiness. Various issues with the included websites were highlighted, including the use of inappropriate advertisements, biased information, poor illustrations, complex language, and poor trustworthiness. CONCLUSIONS: From the perspectives of the intended consumers, patient information websites about congenital heart defects are, to a large extent, inadequate tools for supplemental information following a prenatal diagnosis. Health professionals should initiate discussions with patients about their intentions to use the Web, inform them about the varied quality in the Web-based landscape, and offer recommendations for appropriate Web-based sources. PMID- 28899847 TI - Enhancing Seasonal Influenza Surveillance: Topic Analysis of Widely Used Medicinal Drugs Using Twitter Data. AB - BACKGROUND: Uptake of medicinal drugs (preventive or treatment) is among the approaches used to control disease outbreaks, and therefore, it is of vital importance to be aware of the counts or frequencies of most commonly used drugs and trending topics about these drugs from consumers for successful implementation of control measures. Traditional survey methods would have accomplished this study, but they are too costly in terms of resources needed, and they are subject to social desirability bias for topics discovery. Hence, there is a need to use alternative efficient means such as Twitter data and machine learning (ML) techniques. OBJECTIVE: Using Twitter data, the aim of the study was to (1) provide a methodological extension for efficiently extracting widely consumed drugs during seasonal influenza and (2) extract topics from the tweets of these drugs and to infer how the insights provided by these topics can enhance seasonal influenza surveillance. METHODS: From tweets collected during the 2012-13 flu season, we first identified tweets with mentions of drugs and then constructed an ML classifier using dependency words as features. The classifier was used to extract tweets that evidenced consumption of drugs, out of which we identified the mostly consumed drugs. Finally, we extracted trending topics from each of these widely used drugs' tweets using latent Dirichlet allocation (LDA). RESULTS: Our proposed classifier obtained an F1 score of 0.82, which significantly outperformed the two benchmark classifiers (ie, P<.001 with the lexicon-based and P=.048 with the 1-gram term frequency [TF]). The classifier extracted 40,428 tweets that evidenced consumption of drugs out of 50,828 tweets with mentions of drugs. The most widely consumed drugs were influenza virus vaccines that had around 76.95% (31,111/40,428) share of the total; other notable drugs were Theraflu, DayQuil, NyQuil, vitamins, acetaminophen, and oseltamivir. The topics of each of these drugs exhibited common themes or experiences from people who have consumed these drugs. Among these were the enabling and deterrent factors to influenza drugs uptake, which are keys to mitigating the severity of seasonal influenza outbreaks. CONCLUSIONS: The study results showed the feasibility of using tweets of widely consumed drugs to enhance seasonal influenza surveillance in lieu of the traditional or conventional surveillance approaches. Public health officials and other stakeholders can benefit from the findings of this study, especially in enhancing strategies for mitigating the severity of seasonal influenza outbreaks. The proposed methods can be extended to the outbreaks of other diseases. PMID- 28899849 TI - David Oliver: What GPs told me about how they see the future. PMID- 28899848 TI - A Multi-Level, Mobile-Enabled Intervention to Promote Physical Activity in Older Adults in the Primary Care Setting (iCanFit 2.0): Protocol for a Cluster Randomized Controlled Trial. AB - BACKGROUND: Most older adults do not adhere to the US Centers for Disease Control physical activity guidelines; their physical inactivity contributes to overweight and multiple chronic conditions. An urgent need exists for effective physical activity-promotion programs for the large number of older adults in the United States. OBJECTIVE: This study presents the development of the intervention and trial protocol of iCanFit 2.0, a multi-level, mobile-enabled, physical activity promotion program developed for overweight older adults in primary care settings. METHODS: The iCanFit 2.0 program was developed based on our prior mHealth intervention programs, qualitative interviews with older patients in a primary care clinic, and iterative discussions with key stakeholders. We will test the efficacy of iCanFit 2.0 through a cluster randomized controlled trial in six pairs of primary care clinics. RESULTS: The proposed protocol received a high score in a National Institutes of Health review, but was not funded due to limited funding sources. We are seeking other funding sources to conduct the project. CONCLUSIONS: The iCanFit 2.0 program is one of the first multi-level, mobile-enabled, physical activity-promotion programs for older adults in a primary care setting. The development process has actively involved older patients and other key stakeholders. The patients, primary care providers, health coaches, and family and friends were engaged in the program using a low-cost, off the-shelf mobile tool. Such low-cost, multi-level programs can potentially address the high prevalence of physical inactivity in older adults. PMID- 28899850 TI - Oral surgeon whose misconduct was "serious, persistent, and shocking" is struck off. PMID- 28899853 TI - The potential for chemotherapy-free strategies in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) may be 1 of the few cancers for which multiple chemotherapy and nonchemotherapy regimens are considered as standard. Despite the significant activity of chemotherapy in the first-line setting and beyond, its limitations are reflected in the relatively poor ultimate outcomes of patients with MCL treated in the real world. Patients with highly proliferative MCL and those with TP53 mutations tend to respond poorly despite intensive cytotoxic therapies. Patients with comorbidities and those who are geographically isolated may not have access to the regimens that may appear most promising in clinical trials. Thoughtfully directed, nonchemotherapy agents might overcome some of the factors associated with a poor prognosis, such at TP53 mutation, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens. Several clinical trials have already demonstrated that combinations of nonchemotherapy plus chemotherapy drugs can impact outcomes, whereas data with nonchemotherapy agents alone or in combination have suggested that some patients might be well suited to treatment without chemotherapy at all. However, challenges including chronic or unexpected toxicities, the rational vs practical development of combinations, and the financial acceptability of new strategies abound. The nonchemotherapy era is here: how it unfolds will depend on how we meet these challenges. PMID- 28899852 TI - Identification of extant vertebrate Myxine glutinosa VWF: evolutionary conservation of primary hemostasis. AB - Hemostasis in vertebrates involves both a cellular and a protein component. Previous studies in jawless vertebrates (cyclostomes) suggest that the protein response, which involves thrombin-catalyzed conversion of a soluble plasma protein, fibrinogen, into a polymeric fibrin clot, is conserved in all vertebrates. However, similar data are lacking for the cellular response, which in gnathostomes is regulated by von Willebrand factor (VWF), a glycoprotein that mediates the adhesion of platelets to the subendothelial matrix of injured blood vessels. To gain evolutionary insights into the cellular phase of coagulation, we asked whether a functional vwf gene is present in the Atlantic hagfish, Myxine glutinosa We found a single vwf transcript that encodes a simpler protein compared with higher vertebrates, the most striking difference being the absence of an A3 domain, which otherwise binds collagen under high-flow conditions. Immunohistochemical analyses of hagfish tissues and blood revealed Vwf expression in endothelial cells and thrombocytes. Electron microscopic studies of hagfish tissues demonstrated the presence of Weibel-Palade bodies in the endothelium. Hagfish Vwf formed high-molecular-weight multimers in hagfish plasma and in stably transfected CHO cells. In functional assays, botrocetin promoted VWF dependent thrombocyte aggregation. A search for vwf sequences in the genome of sea squirts, the closest invertebrate relatives of hagfish, failed to reveal evidence of an intact vwf gene. Together, our findings suggest that VWF evolved in the ancestral vertebrate following the divergence of the urochordates some 500 million years ago and that it acquired increasing complexity though sequential insertion of functional modules. PMID- 28899854 TI - Nonclassical FCGR2C haplotype is associated with protection from red blood cell alloimmunization in sickle cell disease. AB - Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is alloimmunization. The low-affinity Fcgamma receptors, expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and alloimmune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC alloimmunization in SCD. In this case-control study, DNA samples from 2 cohorts of transfused SCD patients were combined (France and The Netherlands). Cases had a positive history of alloimmunization, having received >=1 RBC unit. Controls had a negative history of alloimmunization, having received >=20 RBC units. Single nucleotide polymorphisms and copy number variation of the FCGR2/3 gene cluster were studied in a FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared using logistic regression. Two hundred seventy-two patients were included (130 controls, 142 cases). The nonclassical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased alloimmunization risk (odds ratio [OR] 0.26, 95% confidence [CI] 0.11-0.64). This association persisted when only including controls with exposure to >=100 units (OR 0.30, CI 0.11-0.85) and appeared even stronger when excluding cases with Rh or K antibodies only (OR 0.19, CI 0.06 0.59). In conclusion, SCD patients with the FCGR2Cnc-ORF polymorphism have over a 3-fold lower risk for RBC alloimmunization in comparison with patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens. PMID- 28899855 TI - A simple method of measuring the wear of explanted acetabular component inserts. AB - AIMS: The determination of the volumetric polyethylene wear on explanted material requires complicated equipment, which is not available in many research institutions. Our aim in this study was to present and validate a method that only requires a set of polyetheretherketone balls and a laboratory balance to determine wear. METHODS: The insert to be measured was placed on a balance, and a ball of the appropriate diameter was inserted. The cavity remaining between the ball and insert caused by wear was filled with contrast medium and the weight of the contrast medium was recorded. The volume was calculated from the known density of the liquid. The precision, inter- and intraobserver reliability, were determined by four investigators on four days using nine inserts with specified wear (0.094 ml to 1.626 ml), and the intra-class correlation coefficient was calculated. The feasibility of using this method in routine clinical practice and the time required for measurement were tested on 84 explanted inserts by one investigator. RESULTS: In order to get the mean for all investigators and determinations, the deviation between the measured and specified wear was -0.08 ml (sd 0.12; -0.21 to 0.11). The interobserver reliability was 0.989 ml (95% confidence interval (CI) 0.964 to 0.997) and the intraobserver reliability was 0.941 for observer 1 (95% CI 0.846 to 0.985), 0.983 for observer 2 (95% CI 0.956 to 0.995), 0.939 for observer 3 (95% CI 0.855 to 0.984), and 0.934 for observer 4 (95% CI 0.790 to 0.984). The mean time required to examine the samples was two minutes (sd 2; 1 to 5). CONCLUSION: The method presented here was shown to be sufficiently precise for many settings and is a cost-effective and quick method of determining the volumetric wear of explanted acetabular components. However, the measurement of wear for scientific purposes will probably continue to involve more accurate and dedicated laboratory equipment.Cite this article: Bone Joint Res 2017;6:530-534. PMID- 28899856 TI - Release of the tourniquet immediately after the implantation of the components reduces the incidence of deep vein thrombosis after primary total knee arthroplasty. AB - AIMS: The length of the tourniquet time during total knee arthroplasty (TKA) is related to the incidence of post-operative deep vein thrombosis (DVT). Our aim in this study was to investigate the effect of the early release of the tourniquet on the incidence of DVT in patients undergoing TKA. METHODS: A total of 200 patients who underwent TKA between November 2015 and November 2016 were prospectively enrolled. The tourniquet was inflated before surgery and released immediately after the introduction of the components (early release group). This group was compared with a retrospective cohort of 200 primary TKAs, in which the tourniquet was released after the dressings had been applied (late release group). The presence of a DVT was detected using bilateral lower limb ultrasonography. Peri-operative clinical and follow-up data were collected for analysis. RESULTS: The incidence of DVT in the early release group (9 of 196, 4.6%) was significantly lower compared with the late release group (24 of 200, 12%; odds ratio (OR) 0.35, 95% confidence interval (CI) 0.16 to 0.78, p = 0.008). The incidence of proximal DVT in the early release group (1 of 196 (0.5%)) was significantly lower than in the late release group (8 of 196, 4%; OR 0.12, 95% CI 0.02 to 0.99, p = 0.020). Although the mean intra-operative blood loss was higher in the early release group, the mean post-operative drainage, total blood loss, transfusion requirements and complications were not significantly different in the two groups. CONCLUSION: In patients who undergo TKA, releasing the tourniquet early is associated with a decreased incidence of DVT, without increasing the rate of complications.Cite this article: Bone Joint Res 2017;6:535-541. PMID- 28899859 TI - Development of a Surveillance System for Pediatric Hospital-Acquired Venous Thromboembolism. AB - BACKGROUND: Pediatric hospital-acquired (HA) venous thromboembolism (VTE) is a vexing problem with improvement efforts hampered by lack of robust surveillance methods to establish accurate rates of HA-VTE. METHODS: At a freestanding children's hospital, a multidisciplinary team worked to develop a comprehensive surveillance strategy for HA-VTE. Starting with diagnosis codes, we implemented complementary detection methods, including clinical and radiology data, to develop a robust surveillance system. HA-VTE events were tracked by using descriptive statistics and a statistical process control chart. Detection methods were evaluated via retrospective application of each method to every identified HA-VTE. Initial detection method was tracked. RESULTS: A total of 68 HA-VTE events were identified and the median number of events per 1000 patient days increased from 0.18 to 0.34. No single detection method would have identified all events. Each detection method initially identified HA-VTE events. CONCLUSIONS: Implementation of multiple detection methods has optimized timely detection of HA VTE. This allows the establishment of a reliable baseline rate, enabling quality improvement efforts to address HA-VTE. PMID- 28899860 TI - Getting Closer to Optimizing the Prevention and Detection of VTE in Hospitalized Children. PMID- 28899857 TI - High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. AB - Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population. PMID- 28899858 TI - REDD1 induction regulates the skeletal muscle gene expression signature following acute aerobic exercise. AB - The metabolic stress placed on skeletal muscle by aerobic exercise promotes acute and long-term health benefits in part through changes in gene expression. However, the transducers that mediate altered gene expression signatures have not been completely elucidated. Regulated in development and DNA damage 1 (REDD1) is a stress-induced protein whose expression is transiently increased in skeletal muscle following acute aerobic exercise. However, the role of this induction remains unclear. Because REDD1 altered gene expression in other model systems, we sought to determine whether REDD1 induction following acute exercise altered the gene expression signature in muscle. To do this, wild-type and REDD1-null mice were randomized to remain sedentary or undergo a bout of acute treadmill exercise. Exercised mice recovered for 1, 3, or 6 h before euthanization. Acute exercise induced a transient increase in REDD1 protein expression within the plantaris only at 1 h postexercise, and the induction occurred in both cytosolic and nuclear fractions. At this time point, global changes in gene expression were surveyed using microarray. REDD1 induction was required for the exercise-induced change in expression of 24 genes. Validation by RT-PCR confirmed that the exercise-mediated changes in genes related to exercise capacity, muscle protein metabolism, neuromuscular junction remodeling, and Metformin action were negated in REDD1-null mice. Finally, the exercise-mediated induction of REDD1 was partially dependent upon glucocorticoid receptor activation. In all, these data show that REDD1 induction regulates the exercise-mediated change in a distinct set of genes within skeletal muscle. PMID- 28899861 TI - Quality Initiative to Introduce Pediatric Venous Thromboembolism Risk Assessment for Orthopedic and Surgery Patients. AB - BACKGROUND AND OBJECTIVES: Pediatric hospital-acquired venous thromboembolism (VTE) is costly, has high morbidity, and is often preventable. The objective of this quality-improvement effort was to increase the percentage of general surgery and orthopedic patients >=10 years of age screened for VTE risk from 0% to 80%. METHODS: At a freestanding children's hospital, 2 teams worked to implement VTE risk screening for postoperative inpatients. The general surgery team used residents and nurse practitioners to perform screening whereas the orthopedic team initially used bedside nursing staff. Both groups employed multiple small tests of change. Shared key interventions included refinement of a screening tool, provider education, mitigation of failures, and embedding the risk assessment task into staff workflow. The primary outcome measure, the percentage of eligible patients with a completed VTE risk assessment, was plotted on run charts. Secondary outcome measures for screened patients included the level of risk, the use of appropriate prophylaxis, and VTE events. RESULTS: Median weekly percentage of general surgery patients screened for VTE risk increased from 0% to 86% within 12 months, and median weekly percentage of orthopedic patients screened for VTE risk increased from 0% to 46% within 8 months. Among screened patients, the majority were at low or moderate risk for VTE and received prophylaxis in accordance with or beyond guideline recommendations. No screened patients developed VTE. CONCLUSIONS: Quality-improvement methods were used to implement a VTE risk screening process for postoperative patients. Using providers as screeners, as opposed to bedside nurses, led to a greater percentage of patients screened. PMID- 28899862 TI - Challenges and opportunity in the era of quantitative echocardiography. AB - The advancement of echocardiography in the past two decades is more than downsizing of the machines and improvement of image quality, but introduction of new imaging modalities leading to the ability of performing quantitative analysis. This function is greatly facilitated by the integration of echo machines with high performance computers, software programming and establishment of workstation for offline analysis. Today, echo examination is more than estimation of ejection fraction (EF) and patterns of left ventricular (LV) diastolic dysfunction. Echosonographers are facing a large number of quantitative parameters for interpretation. In newer imaging modalities such as tissue Doppler imaging, speckle tracking, 3-dimensional echocardiography and 3D-transoesophageal echocardiography, quantitative echocardiographic assessment has important roles. These have brought many opportunities but also challenges in our echo practice. PMID- 28899865 TI - Lasker Awards Honor Three Researchers. AB - Three top cancer researchers were among recipients of the prestigious Albert and Mary Lasker Foundation awards. Douglas R. Lowy, MD, and John T. Schiller, PhD, were honored for research leading to the development of the first human papillomavirus vaccine. The prize for basic medical research went to Michael N. Hall, PhD, who discovered the TOR signaling pathway and its role in regulating cell growth and metabolism. PMID- 28899864 TI - Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. AB - Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest.Significance: This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. Cancer Discov; 7(12); 1394-403. (c)2017 AACR.See related commentary by Comino-Mendez and Turner, p. 1368This article is highlighted in the In This Issue feature, p. 1355. PMID- 28899863 TI - A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles. AB - Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266-83. (c)2017 AACR.See related commentary by Towers and Thorburn, p. 1218This article is highlighted in the In This Issue feature, p. 1201. PMID- 28899866 TI - Subacute endovascular recanalization of symptomatic cerebral artery occlusion: a propensity score-matched analysis. AB - BACKGROUND: The interval between the onset of cerebral vessel occlusion and recanalization has been shown to be an independent predictor of poor outcomes. However, endovascular recanalization of symptomatic cerebral vessel occlusion in the subacute period has not been well documented. We investigated the safety and efficacy of subacute recanalization of occluded cerebral vessels in patients with ischemic stroke or transient ischemic attacks (TIAs). METHODS: Between 2014 and 2015, 98 patients were admitted to the emergency room for ischemic stroke or TIA with a small infarct core, which was defined as modest early ischemic change on non-contrast CT or overt diffusion-perfusion mismatch. All patients underwent pre transfemoral cerebral angiography and post-endovascular treatment. The patients were classified according to acute (onset-to-groin puncture time <=6 hours) or subacute (onset-to-groin puncture time >6 hours) recanalization. Using propensity score analysis, recipients of acute and subacute recanalization underwent 1:1 matching. RESULTS: Following 1:1 propensity score matching, 32 patients who underwent acute and 32 who underwent subacute intra-arterial thrombolysis were matched. There were no significant differences in National Institutes of Health Stroke Scale at discharge, modified Rankin scale (mRS), the proportion of patients with an mRS value of 0-2, mortality at discharge, intracerebral bleeding, postprocedural infarct extension, newly detected infarction, and hyperintense acute reperfusion marker on follow-up images between the acute and subacute recanalization groups. CONCLUSIONS: In selected patients with clinically unstable cerebral artery occlusions, a diffusion-perfusion mismatch and small CT lesions, subacute and acute recanalization has comparable safety and efficacy rates. PMID- 28899867 TI - Epidural interlaminar injections in severe degenerative lumbar spine: fluoroscopy should not be a luxury. AB - OBJECTIVE: To assess technical efficacy, accuracy, and safety of epidural (interlaminar) injections performed blindly in patients with a severely degenerated lumbar spine. METHODS: Over 12 consecutive months, 138 patients with a severe degenerative lumbar spine underwent epidural (interlaminar) injection as therapy for low back pain and neuralgia. Patients had already undergone a blind epidural infiltration with minimum or no pain reduction. The session was repeated in the angiography suite. Patients were placed in the lateral decubitus position. The injection was performed without image guidance by an anaesthesiologist; the target level was defined before the beginning of the procedure. Once air resistance loss was felt it was presumed that the needle was inside the epidural space. Verification of needle position was performed by injection of 1-3 mL of iodinated contrast medium under fluoroscopy in a lateral projection. RESULTS: Correct needle position inside the epidural space was documented in 82/138 cases (59.4%); unexpected extraepidural location was seen in 56/138 cases (40.6%). Target level was reached in 96/138 cases (69.6%); in 42/138 cases (30.4%) the needle was positioned in a non-target level. In 5/138 (3.6%) cases, there was inadvertent intradural position of the needle. Image guidance was subsequently used for correct positioning of the needle, which was feasible in all cases. CONCLUSION: Blind interlaminar epidural injections lack the accuracy of exact needle location that imaging guidance offers in approximately 40% of cases, when there is difficult spine anatomy and the initial epidural approach has failed to provide pain relief. Image guidance for interlaminar epidural injection ensures accurate needle placement, enhancing the safety and efficacy of the procedure. PMID- 28899868 TI - B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity. AB - Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL 6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral autoimmunity, whether B cell-derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell-derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from systemic autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-gamma, consistent with the critical roles for B cell intrinsic IFN-gamma receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive autoimmunity via local IL-6 production required for TFH differentiation and autoimmune GC formation. PMID- 28899869 TI - Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation. AB - Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIalpha. Notably, TrkB stimulation with 7,8 dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD. PMID- 28899871 TI - Migration Experiences and Reported Sexual Behavior Among Young, Unmarried Female Migrants in Changzhou, China. AB - BACKGROUND: China has a large migrant population, including many young unmarried women. Little is known about their sexual behavior, contraceptive use, and risk of unintended pregnancy. METHODS: 475 unmarried female migrants aged 15-24, working in 1 of 6 factories in 2 districts of Changzhou city, completed an anonymous self-administered questionnaire in May 2012 on demographic characteristics, work and living situation, and health. We examined demographic and migration experience predictors of sexual and contraceptive behavior using bivariate and multivariate regressions. RESULTS: 30.1% of the respondents were sexually experienced, with the average age at first sex of 19 years (standard deviation=3). 37.8% reported using contraception at first sex, 58.0% reported using consistent contraception during the past year, and 28.0% reported having at least 1 unintended pregnancy with all unintended pregnancies resulting in abortion. Those who had had at least 1 abortion reported having on average 1.6 abortions [SD=1] in total. Migrating with a boyfriend and changing jobs fewer times were associated with being sexually experienced. Younger age, less education, and changing jobs more times were associated with inconsistent contraceptive use. CONCLUSION: These findings demonstrate there is an unmet need for reproductive health education and services where these women work as well as in their hometown communities. This education must begin early to reach young women before they migrate. PMID- 28899873 TI - Toxic multinodular goitre: a surprising finding. PMID- 28899870 TI - Mbd3/NuRD controls lymphoid cell fate and inhibits tumorigenesis by repressing a B cell transcriptional program. AB - Differentiation of lineage-committed cells from multipotent progenitors requires the establishment of accessible chromatin at lineage-specific transcriptional enhancers and promoters, which is mediated by pioneer transcription factors that recruit activating chromatin remodeling complexes. Here we show that the Mbd3/nucleosome remodeling and deacetylation (NuRD) chromatin remodeling complex opposes this transcriptional pioneering during B cell programming of multipotent lymphoid progenitors by restricting chromatin accessibility at B cell enhancers and promoters. Mbd3/NuRD-deficient lymphoid progenitors therefore prematurely activate a B cell transcriptional program and are biased toward overproduction of pro-B cells at the expense of T cell progenitors. The striking reduction in early thymic T cell progenitors results in compensatory hyperproliferation of immature thymocytes and development of T cell lymphoma. Our results reveal that Mbd3/NuRD can regulate multilineage differentiation by constraining the activation of dormant lineage-specific enhancers and promoters. In this way, Mbd3/NuRD protects the multipotency of lymphoid progenitors, preventing B cell-programming transcription factors from prematurely enacting lineage commitment. Mbd3/NuRD therefore controls the fate of lymphoid progenitors, ensuring appropriate production of lineage-committed progeny and suppressing tumor formation. PMID- 28899872 TI - Fever, bone pain and erectile dysfunction. Where is the cat? AB - Cat-scratch disease is due to Bartonella henselae and commonly presents as a localised papular lesion with regional lymphadenopathy. We report the case of a young man suffering general symptoms and dysautonomy characterised by an erectile dysfunction due to an invasive cat-scratch disease. He was successfully treated by tetracyclines during 3 weeks. PMID- 28899874 TI - Pulsus alternans: a visual clue to a grave disorder! PMID- 28899876 TI - Treatment and management of children with haemolytic uraemic syndrome. AB - Haemolytic uraemic syndrome (HUS), comprising microangiopathic haemolytic anaemia, thrombocytopaenia and acute kidney injury, remains the leading cause of paediatric intrinsic acute kidney injury, with peak incidence in children aged under 5 years. HUS most commonly occurs following infection with Shiga toxin producing Escherichia coli (STEC-HUS). Additionally, HUS can occur as a result of inherited or acquired dysregulation of the alternative complement cascade (atypical HUS or aHUS) and in the setting of invasive pneumococcal infection. The field of HUS has been transformed by the discovery of the central role of complement in aHUS and the dawn of therapeutic complement inhibition. Herein, we address these three major forms of HUS in children, review the latest evidence for their treatment and discuss the management of STEC infection from presentation with bloody diarrhoea, through to development of fulminant HUS. PMID- 28899875 TI - Stridor is not always croup: infantile haemangioma in the airway. PMID- 28899877 TI - Multiresistant E. coli urine infections in children: a case-control study. AB - OBJECTIVE: Urinary tract infections (UTIs) caused by resistant organisms are increasing which poses challenges when selecting empirical antimicrobial therapy. The aim of this study is to determine risk factors for multiresistant Escherichia coli UTIs in children. DESIGN: We included all reported urinary isolates from a children's hospital collected between January 2010 and June 2013. Patients who had multiresistant E. coli UTIs were identified and a retrospective review of medical records performed. Patient-specific clinical and demographic factors were compared with age-matched and gender-matched controls with non-multiresistant E. coli UTIs. Univariable and multivariable statistical analysis were performed to determine significant risk factors for multiresistant organism E.coli UTIs. RESULTS: In total, there were 2692 positive urine cultures, 1676 (62.3%) from 1169 patients were E. coli. Multiresistant E. coli was isolated from 139 (8.3% of all E. coli) cultures in 99 patients. Thirteen incomplete medical records were excluded, leaving 86 patients, matched with 86 controls. In multivariable regression, the only significant risk factor was antibiotic use in the previous month (adjusted OR 3.0, 95% CI 1.4 to 6.2), but not previous hospital admission (adjusted OR 1.4, 95% CI 0.6 to 2.9), being an inpatient at the time of diagnosis (adjusted OR 2.4, 95% CI 0.8 to 7.4) and previous instrumentation (adjusted OR 1.0, 95% CI 0.4 to 2.4). CONCLUSIONS: This is the first case-control study to examine multiresistant UTI in Australian children. Clinicians should be judicious in the use of antibiotics in treatment and prophylaxis of UTIs. In children presenting with UTI and recent antibiotic exposure, amoxicillin-clavulanic acid appears to be an appropriate empiric antibiotic choice in our population. PMID- 28899878 TI - Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. AB - Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs-when mixed with TNBC cells-could increase TNBC cell metastatic potency. After treatment with TGF beta to induce endothelial-mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stimulate the expression and secretion of the chemokine, CCL5, from ECs, which then acts in a paracrine fashion on TNBC cells to enhance their migration, invasion, and metastasis. CCL5, in turn, accelerates TNBC cell secretion of PAI-1 and promotes TNBC cell metastasis, thus forming a positive feedback loop. Moreover, this enhanced metastatic ability is reversible and dependent on CCL5 signaling via the chemokine receptor, CCR5. Of importance, key features of this pathway are manifested in patients with TNBC and in The Cancer Genome Atlas database. Taken together, our results suggest that ECs enhance EMT-induced TNBC cell metastasis via PAI-1 and CCL5 signaling and illustrate the potential of developing new PAI-1 and CCL5-targeting therapy for patients with TNBC.-Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. PMID- 28899879 TI - Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise. AB - Preservation of lean body mass (LBM) may be important during dietary energy restriction (ER) and requires equal rates of muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Currently, the relative contribution of MPS and MPB to the loss of LBM during ER in humans is unknown. We aimed to determine the impact of dietary protein intake and resistance exercise on MPS and MPB during a controlled short-term energy deficit. Adult men (body mass index, 28.6 +/- 0.6 kg/m2; age 22 +/- 1 yr) underwent 10 d of 40%-reduced energy intake while performing unilateral resistance exercise and consuming lower protein (1.2 g/kg/d, n = 12) or higher protein (2.4 g/kg/d, n = 12). Pre- and postintervention testing included dual-energy X-ray absorptiometry, primed constant infusion of ring-[13C6]phenylalanine, and 15[N]phenylalanine to measure acute postabsorptive MPS and MPB; D2O to measure integrated MPS; and gene and protein expression. There was a decrease in acute MPS after ER (higher protein, 0.059 +/- 0.006 to 0.051 +/- 0.009%/h; lower protein, 0.061 +/- 0.005 to 0.045 +/- 0.006%/h; P < 0.05) that was attenuated with resistance exercise (higher protein, 0.067 +/- 0.01%/h; lower protein, 0.061 +/- 0.006%/h), and integrated MPS followed a similar pattern. There was no change in MPB (energy balance, 0.080 +/- 0.01%/hr; ER rested legs, 0.078 +/- 0.008%/hr; ER exercised legs, 0.079 +/- 0.006%/hr). We conclude that a reduction in MPS is the main mechanism that underpins LBM loss early in ER in adult men.-Hector, A. J., McGlory, C., Damas, F., Mazara, N., Baker, S. K., Phillips, S. M. Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise. PMID- 28899880 TI - Effects of aging and resistance training in rat tendon remodeling. AB - In elderly persons, weak tendons contribute to functional limitations, injuries, and disability, but resistance training can attenuate this age-related decline. We evaluated the effects of resistance training on the extracellular matrix (ECM) of the calcaneal tendon (CT) in young and old rats and its effect on tendon remodeling. Wistar rats aged 3 mo (young, n = 30) and 20 mo (old, n = 30) were divided into 4 groups: young sedentary, young trained, old sedentary (OS), and old trained (OT). The training sessions were conducted over a 12-wk period. Aging in sedentary rats showed down-regulation in key genes that regulated ECM remodeling. Moreover, the OS group showed a calcification focus in the distal region of the CT, with reduced blood vessel volume density. In contrast, resistance training was effective in up-regulating connective tissue growth factor, VEGF, and decorin gene expression in old rats. Resistance training also increased proteoglycan content in young and old rats in special small leucine rich proteoglycans and blood vessels and prevented calcification in OT rats. These findings confirm that resistance training is a potential mechanism in the prevention of aging-related loss in ECM and that it attenuates the detrimental effects of aging in tendons, such as ruptures and tendinopathies.-Marqueti, R. C., Durigan, J. L. Q., Oliveira, A. J. S., Mekaro, M. S., Guzzoni, V., Aro, A. A., Pimentel, E. R., Selistre-de-Araujo, H. S. Effects of aging and resistance training in rat tendon remodeling. PMID- 28899881 TI - Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice. AB - Ten-eleven translocation methylcytosine dioxygenase 1 (Tet1) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5 hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as Egr1, c-fos, Arc, and Bdnf, followed by the activation of intracellular calcium signals (i.e., CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits (Gabra2 and Gabra4) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the Egr1 promoter in vitro Tet1 enhanced Egr1 expression, which may have led to alterations in Gabra2 and Gabra4 expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.-Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice. PMID- 28899884 TI - Supraventricular tachycardia diagnosed by smartphone ECG. AB - Diagnosis of paroxysmal supraventricular tachycardia (PSVT) may be difficult due to its episodic nature, which can be brief and self-limited, limiting the ability for clinicians to diagnose the specific rhythm disorder in a timely manner. We present a case of PSVT, which was unable to be diagnosed through typical evaluation with an event monitor despite several years of symptoms. The patient was ultimately diagnosed using the AliveCor Mobile ECG, a smartphone-based ECG device and application, which he purchased himself and captured a typical atrioventricular node re-entrant tachycardia. The patient was then able to email his cardiologist the tracing, which led to an electrophysiology study and successful slow pathway ablation procedure. Smartphone-based technology has the potential to push diagnostic evaluations outside of the healthcare system and empower patients. PMID- 28899882 TI - Chromosome 15 structural abnormalities: effect on IGF1R gene expression and function. AB - Insulin-like growth factor 1 receptor (IGF1R), mapping on the 15q26.3 chromosome, is required for normal embryonic and postnatal growth. The aim of the present study was to evaluate the IGF1R gene expression and function in three unrelated patients with chromosome 15 structural abnormalities. We report two male patients with the smallest 15q26.3 chromosome duplication described so far, and a female patient with ring chromosome 15 syndrome. Patient one, with a 568 kb pure duplication, had overgrowth, developmental delay, mental and psychomotor retardation, obesity, cryptorchidism, borderline low testis volume, severe oligoasthenoteratozoospermia and gynecomastia. We found a 1.8-fold increase in the IGF1R mRNA and a 1.3-fold increase in the IGF1R protein expression (P < 0.05). Patient two, with a 650 kb impure duplication, showed overgrowth, developmental delay, mild mental retardation, precocious puberty, low testicular volume and severe oligoasthenoteratozoospermia. The IGF1R mRNA and protein expression was similar to that of the control. Patient three, with a 46,XX r(15) (p10q26.2) karyotype, displayed intrauterine growth retardation, developmental delay, mental and psychomotor retardation. We found a <0.5-fold decrease in the IGF1R mRNA expression and an undetectable IGF1R activity. After reviewing the previously 96 published cases of chromosome 15q duplication, we found that neurological disorders, congenital cardiac defects, typical facial traits and gonadal abnormalities are the prominent features in patients with chromosome 15q duplication. Interestingly, patients with 15q deletion syndrome display similar features. We speculate that both the increased and decreased IGF1R gene expression may play a role in the etiology of neurological and gonadal disorders. PMID- 28899883 TI - MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice. AB - MicroRNA-146a (miR-146a) regulates multiple immune diseases. However, the role of miR-146a in diabetic peripheral neuropathy (DPN) has not been investigated. We found that mice (db/db) with type 2 diabetes exhibited substantial downregulation of miR-146a in sciatic nerve tissue. Systemic administration of miR-146a mimics to diabetic mice elevated miR-146a levels in plasma and sciatic nerve tissue and substantially increased motor and sensory nerve conduction velocities by 29 and 11%, respectively, and regional blood flow by 50% in sciatic nerve tissue. Treatment with miR-146a mimics also considerably decreased the response in db/db mice to thermal stimuli thresholds. Histopathological analysis showed that miR 146a mimics markedly augmented the density of fluorescein isothiocyanate-dextran perfused blood vessels and increased the number of intraepidermal nerve fibers, myelin thickness, and axonal diameters of sciatic nerves. In addition, miR-146a treatment reduced and increased classically and alternatively activated macrophage phenotype markers, respectively. Analysis of miRNA target array revealed that miR-146a mimics greatly suppressed expression of many proinflammatory genes and downstream related cytokines. Collectively, our data indicate that treatment of diabetic mice with miR-146a mimics robustly reduces DPN and that suppression of hyperglycemia-induced proinflammatory genes by miR 146a mimics may underlie its therapeutic effect. PMID- 28899885 TI - Dilation of epidural space and posterior soft tissue veins in Hirayama disease. PMID- 28899886 TI - Brainstem encephalitis and acute polyneuropathy associated with hepatitis E infection. AB - A 59-year-old man presented with feverish illness. His Glasgow Coma Scale was 15, had reduced visual acuity in the left eye with partial left ptosis and mild left hemiparesis with an extensor left plantar. Over 48 hours, he accrued multiple cranial nerves palsies and progressed to a flaccid paralysis necessitating admission to an intensive care unit.Cerebrospinal fluid (CSF) study showed 20 lymphocytes and raised protein. Viral and bacterial PCRs were negative. Samples for Lyme, blood-borne viruses, syphilis and autoantibodies were also negative. MRI brain showed T2 abnormalities within the brainstem. Nerve conduction studies revealed an acute motor and sensory axonal neuropathy pattern of Guillian Barre Syndrome (GBS). The patient was treated for both infective and inflammatory causes of brainstem encephalitis and GBS.Retrospective studies confirmed the presence of hepatitis E virus (HEV) RNA in CSF and serum studies showed positive HEV IgG and IgM prior to intravenous infusion. After 3 months of intensive rehabilitation, the patient was discharged home walking with a frame. PMID- 28899887 TI - Strategies for research engagement of clinicians in allied health (STRETCH): a mixed methods research protocol. AB - INTRODUCTION: Allied health professionals (AHPs) report positive attitudes to using research evidence in clinical practice, yet often lack time, confidence and skills to use, participate in and conduct research. A range of multifaceted strategies including education, mentoring and guidance have been implemented to increase AHPs' use of and participation in research. Emerging evidence suggests that knowledge brokering activities have the potential to support research engagement, but it is not clear which knowledge brokering strategies are most effective and in what contexts they work best to support and maintain clinicians' research engagement. METHODS AND ANALYSIS: This protocol describes an exploratory concurrent mixed methods study that is designed to understand how allied health research fellows use knowledge brokering strategies within tailored evidence based interventions, to facilitate research engagement by allied health clinicians. Simultaneously, a realist approach will guide a systematic process evaluation of the research fellows' pattern of use of knowledge brokering strategies within each case study to build a programme theory explaining which knowledge brokering strategies work best, in what contexts and why. Learning and behavioural theories will inform this critical explanation. ETHICS AND DISSEMINATION: An explanation of how locally tailored evidence-based interventions improve AHPs use of, participation in and leadership of research projects will be summarised and shared with all participating clinicians and within each case study. It is expected that local recommendations will be developed and shared with medical and nursing professionals in and beyond the health service, to facilitate building research capacity in a systematic and effective way. PMID- 28899888 TI - Protocol for a systematic review of instruments for the assessment of quality of life and well-being in children and adolescents with cerebral palsy. AB - INTRODUCTION: Cerebral palsy is the most common cause of physical disability in children and adolescents and is associated with impairments that may reduce the quality of life (QOL) of this population. Patient-reported outcome measures (PROMs) can facilitate the assessment of the effect of disease and treatment on QOL, from a patient viewpoint. The purpose of this systematic review is to identify PROMs that are used to measure QOL and subjective well-being (SWB) outcomes in young people with cerebral palsy and to evaluate the suitability of these PROMs for application in economic evaluations within this population. METHODS AND ANALYSIS: MEDLINE, Scopus, the Cochrane Library, Web of Science Core Collection, EconLit, PsycINFO, CINAHL, EMBASE and Informit will be systematically searched from inception to date of search. Published peer-reviewed, English language articles reporting PROMs measuring QOL or SWB outcomes in children and adolescents with cerebral palsy will be included. One reviewer will conduct the initial search and screen titles and abstracts for potentially eligible studies. The search will be performed in November 2017. To reduce the likelihood of reviewer selection bias, two other reviewers will independently screen a randomly selected subsample (10%) of the citations. Two reviewers will then retrieve full texts of potentially eligible studies and assess them against predefined inclusion criteria. The suitability of selected PROMs for use in economic evaluations of young people with cerebral palsy will be assessed using the International Society of Quality of Life Research recommended Minimum Standards and the Patient-Centered Outcomes and Comparative Effectiveness Research checklist. A narrative synthesis of extracted data will be presented including study descriptive data, PROMs measurement properties, settings in which they were applied and the valuation methods. Recommendations for practice on the selection of PROMs for use in economic evaluations of children and adolescents with cerebral palsy will be presented. ETHICS AND DISSEMINATION: Ethical approval is not required as the proposed systematic review will not use primary data. The results of this study will be widely disseminated through publication in a peer reviewed journal and conference presentation(s). SYSTEMATIC REVIEW REGISTRATION NUMBER: International Prospective Register of Systematic Reviews number: CRD42016049746. PMID- 28899889 TI - Neck circumference and clustered cardiovascular risk factors in children and adolescents: cross-sectional study. AB - OBJECTIVE: Early detection of cardiovascular disease (CVD) risk factors, such as obesity, is crucial to prevent adverse long-term effects on individuals' health. Therefore, the aims were: (1) to explore the robustness of neck circumference (NC) as a predictor of CVD and examine its association with numerous anthropometric and body composition indices and (2) to release sex and age specific NC cut-off values to classify youths as overweight/obese. DESIGN: Cross sectional study. SETTING: 23 primary schools and 17 secondary schools from Spain. PARTICIPANTS: 2198 students (1060 girls), grades 1-4 and 7-10. MEASURES: Pubertal development, anthropometric and body composition indices, systolic and diastolic blood pressure (SBP and DBP, respectively), cardiorespiratory fitness, blood sampling triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), glucose and inflammatory markers. Homoeostasis model assessment (HOMA-IR) and cluster of CVD risk factors were calculated. RESULTS: NC was negatively associated with maximum oxygen consumption (R2=0.231, P<0.001 for boys; R2=0.018, P<0.001 for girls) and adiponectin (R2=0.049, P<0.001 for boys; R2=0.036, P<0.001 for girls); and positively associated with SBP, DBP, TC/HDL-c, TG, HOMA, complement factors C-3 and C-4, leptin and clustered CVD risk factor in both sexes (R2 from 0.035 to 0.353, P<0.01 for boys; R2 from 0.024 to 0.215, P<0.001 for girls). Moreover, NC was positively associated with serum C reactive protein and LDL-c only in boys (R2 from 0.013 to 0.055, P<0.05). CONCLUSION: NC is a simple, low-cost and practical screening tool of excess of upper body obesity and CVD risk factors in children and adolescents. Paediatricians can easily use it as a screening tool for overweight/obesity in children and adolescents. For this purpose, sex and age specific thresholds to classify children and adolescents as normal weight or overweight/obese are provided. PMID- 28899890 TI - What is the impact of research champions on integrating research in mental health clinical practice? A quasiexperimental study in South London, UK. AB - OBJECTIVES: Key challenges for mental health healthcare professionals to implement research alongside clinical activity have been highlighted, such as insufficient time to apply research skills and lack of support and resources. We examined the impact of employing dedicated staff to promote research in community mental health clinical settings. DESIGN: Quasiexperiment before and after study. SETTING: South London and Maudsley National Health Service Foundation Trust. PARTICIPANTS: 4455 patients receiving care from 15 community mental health teams between 1 December 2013 and 31 December 2014. OUTCOME MEASURES: The proportion of patients approached for research participation in clinical services where research champions were present (intervention group), and where research champions were not present (comparison group). RESULTS: Patients in the intervention group were nearly six times more likely to be approached for research participation (Adj. OR=5.98; 95% CI 4.96 to 7.22). CONCLUSIONS: Investing in staff that promote and drive research in clinical services increases opportunities for patients to hear about and engage in clinical research studies. However, investment needs to move beyond employing short-term staff. PMID- 28899891 TI - Effect of anesthesia depth on postoperative clinical outcome in patients with supratentorial tumor (DEPTH): study protocol for a randomized controlled trial. AB - INTRODUCTION: Recent studies have shown that deep anaesthesia is associated with poor outcomes. However, no randomised controlled trials have been conducted to test the causality in patients undergoing brain tumour resection. METHODS AND ANALYSIS: DEPTH is a multicenter, randomised, parallel-group, blind trial. The depth of general anaesthesia will be monitored using the bispectral index (BIS). Patients elected for supratentorial tumour resection will be randomly allocated to the deep or the light anaesthesia group in which the target BIS value is 35 or 50, respectively. BIS will be maintained at the target value for more than 90% of the total anaesthesia period. The primary outcome is the disability-free survival rate at postoperative 30 days and 1 year. The secondary outcomes are the mortality and morbidity within 30 days after surgery. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been granted by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medicine University. The reference number is KY2016-059-02. The results of this study will be disseminated through presentations at scientific conferences and publication in scientific journals. TRIAL REGISTRATION: NCT03033693. PMID- 28899892 TI - Does internet-based cognitive behaviour therapy reduce healthcare costs and resource use in treatment of social anxiety disorder? A cost-minimisation analysis conducted alongside a randomised controlled trial. AB - OBJECTIVES: Social anxiety disorder (SAD) can be effectively treated with internet-delivered cognitive behavioural therapy (ICBT), but studies on long-term cost minimisation from a healthcare provider perspective in comparison to an evidence-based control treatment of therapeutic equivalence are lacking. The objective of the study was to determine whether ICBT reduces healthcare costs and use of healthcare resources compared with cognitive behavioural group therapy (CBGT). DESIGN: A cost-minimisation study alongside a randomised controlled trial where participants (n=126) with SAD were randomised to ICBT or to CBGT. Costs measured from a healthcare provider perspective were estimated using time-driven activity-based costing alongside health status over 4 years from baseline measured with EQ-5D. SETTING: A psychiatric outpatient clinic in Stockholm, Sweden. PARTICIPANTS: Participants were 126 individuals with SAD. PRIMARY OUTCOME MEASURES: Changes in EQ-5D and costs. INTERVENTIONS: Participants received either CBGT or ICBT for a duration of 15 weeks. RESULTS: ICBT minimised healthcare costs and demonstrated health improvements within the non-inferiority margin. Assuming a practical work capacity for personnel varying between 100%, 80% and 50% of theoretical full capacity, the cost for ICBT varied in the range between 400?, 463? and 654 ?, while the cost for CBGT varied between 699?, 806? and 1134?. Within-group effect size was -0.36 (95% CI -0.70 to -0.01) for ICBT and -0.25 (95% CI -0.60 to 0.10) for CBGT. Mean use of effective psychologist time in ICBT was 189.60 (SD=53.77) minutes compared with 499.78 (SD=30.91) in the CBGT group. CONCLUSIONS: In treatment of SAD, ICBT is equally effective but is associated with more efficient staff utilisation and less costs compared with CBGT. From a healthcare provider perspective, ICBT is an advantageous treatment option. TRIAL REGISTRATION NUMBER: PMID- 28899893 TI - Acute In Vivo Analysis of ATP Release in Rat Kidneys in Response to Changes of Renal Perfusion Pressure. AB - BACKGROUND: ATP and derivatives are recognized to be essential agents of paracrine signaling. It was reported that ATP is an important regulator of the pressure-natriuresis mechanism. Information on the sources of ATP, the mechanisms of its release, and its relationship to blood pressure has been limited by the inability to precisely measure dynamic changes in intrarenal ATP levels in vivo. METHODS AND RESULTS: Newly developed amperometric biosensors were used to assess alterations in cortical ATP concentrations in response to changes in renal perfusion pressure (RPP) in anesthetized Sprague-Dawley rats. RPP was monitored via the carotid artery; ligations around the celiac/superior mesenteric arteries and the distal aorta were used for manipulation of RPP. Biosensors were acutely implanted in the renal cortex for assessment of ATP. Rise of RPP activated diuresis/natriuresis processes, which were associated with elevated ATP. The increases in cortical ATP concentrations were in the physiological range (1-3 MUmol/L) and would be capable of activating most of the purinergic receptors. There was a linear correlation with every 1-mm Hg rise in RPP resulting in a 70 nmol/L increase in ATP. Furthermore, this elevation of RPP was accompanied by a 2.5-fold increase in urinary H2O2. CONCLUSIONS: Changes in RPP directly correlate with renal sodium excretion and the elevation of cortical ATP. Given the known effects of ATP on regulation of glomerular filtration and tubular transport, the data support a role for ATP release in the rapid natriuretic responses to acute increases in RPP. PMID- 28899894 TI - Variation in Management of Patients With Obstructive Coronary Artery Disease: Insights From the Veterans Affairs Clinical Assessment and Reporting Tool (VA CART) Program. AB - BACKGROUND: Little is known about facility-level variation in the use of revascularization procedures for the management of stable obstructive coronary artery disease. Furthermore, it is unknown if variation in the use of coronary revascularization is associated with use of other cardiovascular procedures. METHODS AND RESULTS: We evaluated all elective coronary angiograms performed in the Veterans Affairs system between September 1, 2007, and December 31, 2011, using the Clinical Assessment and Reporting Tool and identified patients with obstructive coronary artery disease. Patients were considered managed with revascularization if they received percutaneous coronary intervention (PCI) or coronary artery bypass grafting within 30 days of diagnosis. We calculated risk adjusted facility-level rates of overall revascularization, PCI, and coronary artery bypass grafting. In addition, we determined the association between facility-level rates of revascularization and post-PCI stress testing. Among 15 650 patients at 51 Veterans Affairs sites who met inclusion criteria, the median rate of revascularization was 59.6% (interquartile range, 55.7%-66.7%). Across all facilities, risk-adjusted rates of overall revascularization varied from 41.5% to 88.1%, rate of PCI varied from 23.2% to 80.6%, and rate of coronary artery bypass graftingvariedfrom 7.5% to 36.5%. Of 6179 patients who underwent elective PCI, the median rate of stress testing in the 2 years after PCI was 33.7% (interquartile range, 30.7%-47.1%). There was no evidence of correlation between facility-level rate of revascularization and follow-up stress testing. CONCLUSIONS: Within the Veterans Affairs system, we observed large facility-level variation in rates of revascularization for obstructive coronary artery disease, with variation driven primarily by PCI. There was no association between facility level use of revascularization and follow-up stress testing, suggesting use rates are specific to a particular procedure and not a marker of overall facility-level use. PMID- 28899895 TI - Biomechanical and Hemodynamic Measures of Right Ventricular Diastolic Function: Translating Tissue Biomechanics to Clinical Relevance. AB - BACKGROUND: Right ventricular (RV) diastolic function has been associated with outcomes for patients with pulmonary hypertension; however, the relationship between biomechanics and hemodynamics in the right ventricle has not been studied. METHODS AND RESULTS: Rat models of RV pressure overload were obtained via pulmonary artery banding (PAB; control, n=7; PAB, n=5). At 3 weeks after banding, RV hemodynamics were measured using a conductance catheter. Biaxial mechanical properties of the RV free wall myocardium were obtained to extrapolate longitudinal and circumferential elastic modulus in low and high strain regions (E1 and E2, respectively). Hemodynamic analysis revealed significantly increased end-diastolic elastance (Eed) in PAB (control: 55.1 mm Hg/mL [interquartile range: 44.7-85.4 mm Hg/mL]; PAB: 146.6 mm Hg/mL [interquartile range: 105.8-155.0 mm Hg/mL]; P=0.010). Longitudinal E1 was increased in PAB (control: 7.2 kPa [interquartile range: 6.7-18.1 kPa]; PAB: 34.2 kPa [interquartile range: 18.1 44.6 kPa]; P=0.018), whereas there were no significant changes in longitudinal E2 or circumferential E1 and E2. Last, wall stress was calculated from hemodynamic data by modeling the right ventricle as a sphere: stress=Pressure*radius2*thickness. CONCLUSIONS: RV pressure overload in PAB rats resulted in an increase in diastolic myocardial stiffness reflected both hemodynamically, by an increase in Eed, and biomechanically, by an increase in longitudinal E1. Modest increases in tissue biomechanical stiffness are associated with large increases in Eed. Hemodynamic measurements of RV diastolic function can be used to predict biomechanical changes in the myocardium. PMID- 28899896 TI - Impact of Worsened Metabolic Syndrome on the Risk of Dementia: A Nationwide Cohort Study. AB - BACKGROUND: The relationship of alteration of metabolic syndrome (MetS) with dementia remains unclear. The purpose of study was to evaluate the association between dynamic change in MetS status around a 5-year period and dementia. METHODS AND RESULTS: The cohort study was conducted from the Taiwanese Survey on Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia in 2002, with follow-up in 2007. The sample was subsequently linked to the National Health Insurance Research Database. Participants were divided into 3 groups: persistent MetS (MetS both in 2002 and 2007); nonpersistent MetS (MetS either in 2002 or 2007); and non-MetS (MetS neither in 2002 nor 2007). Furthermore, the individuals with nonpersistent MetS were categorized as improved MetS (MetS in 2002 but not in 2007) and worsened MetS (MetS not in 2002 but in 2007). Each participant was tracked until the end of 2011 to identify the development of dementia. In total, 3458 participants aged 40 to 80 years were included. Up to 10 years and 31 741 person-years of follow-up, 76 patients developed dementia. Only a relationship was found between the nonpersistent MetS and dementia (adjusted hazard ratio=1.93; 95% confidence interval =1.17-3.19; P=0.010). Moreover, a significantly higher dementia risk was observed in patients with worsened MetS (adjusted hazard ratio=2.22; 95% confidence interval=1.32-3.72; P=0.003), but not those with persistent (P=0.752) or improved (P=0.829) MetS. Similar results were detected in participants aged >=65 years. CONCLUSIONS: Patients with worsened MetS had an increased dementia risk during the 10-year follow-up period in a population-based sample. PMID- 28899897 TI - Transfusion of Polynitroxylated Pegylated Hemoglobin Stabilizes Pial Arterial Dilation and Decreases Infarct Volume After Transient Middle Cerebral Artery Occlusion. AB - BACKGROUND: Polynitroxylation of hemoglobin confers superoxide dismutase-mimetic and peroxidase activity and may protect from reperfusion injury in addition to facilitating oxygen transport. We determined whether transfusion of polynitroxylated PEGylated hemoglobin (PNPH) is protective in the rat filament model of 2 hours of middle cerebral artery occlusion (MCAO). METHODS AND RESULTS: Transfusion of 10 mL/kg of PNPH at 20 minutes of MCAO reduced infarct volume by over 70% (n=10). To determine whether PNPH might act by promoting vasodilation, pial arteriolar diameter in the distal MCA border region was measured in closed cranial windows. With no transfusion, MCAO induced an initial dilation (36+/-2% +/-SE) that subsided by 2 hours (5+/-4%; n=8). With PNPH transfusion at 20 minutes of MCAO, the initial dilation (31+/-3%) was better maintained at 2 hours (21+/-4%; n=7; P<0.02). Delaying PNPH transfusion until 90 minutes of MCAO increased perfusion in the border region from 48+/-6% of the preischemic baseline to 67+/-8% (n=8; P<0.005). The effect of PNPH transfusion after reperfusion was also tested. Compared with the control median hemispheric infarct volume of 22% (13% to 34% interquartiles; n=15), infarct volume was reduced to 7% (3% to 13%; n=14 P<0.05) when PNPH was transfused at 4 hours after MCAO (2 hours of reperfusion) but not significantly when transfused at 6 hours (8%; 3% to 35%; n=14) or at 8 hours (12%; 10% to 25%; n=14) after MCAO. CONCLUSIONS: PNPH transfusion has a significant therapeutic window for protection during and after transient MCAO and may act, in part, by stabilizing vascular function and improving collateral blood flow. PMID- 28899898 TI - Investigating the association of rs2910164 with cancer predisposition in an Irish cohort. AB - INTRODUCTION: MicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA-mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort. METHODS: The study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22. RESULTS: The total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98-1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18 2.14), P = 0.002). CONCLUSION: The rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort. PMID- 28899899 TI - Dual function of UPF3B in early and late translation termination. AB - Nonsense-mediated mRNA decay (NMD) is a cellular surveillance pathway that recognizes and degrades mRNAs with premature termination codons (PTCs). The mechanisms underlying translation termination are key to the understanding of RNA surveillance mechanisms such as NMD and crucial for the development of therapeutic strategies for NMD-related diseases. Here, we have used a fully reconstituted in vitro translation system to probe the NMD proteins for interaction with the termination apparatus. We discovered that UPF3B (i) interacts with the release factors, (ii) delays translation termination and (iii) dissociates post-termination ribosomal complexes that are devoid of the nascent peptide. Furthermore, we identified UPF1 and ribosomes as new interaction partners of UPF3B. These previously unknown functions of UPF3B during the early and late phases of translation termination suggest that UPF3B is involved in the crosstalk between the NMD machinery and the PTC-bound ribosome, a central mechanistic step of RNA surveillance. PMID- 28899901 TI - Do the stars align? Distribution of high-quality ratings of healthcare sectors across US markets. AB - BACKGROUND: The US government created five-star rating systems to evaluate hospital, nursing homes, home health agency and dialysis centre quality. The degree to which quality is a property of organisations versus geographical markets is unclear. OBJECTIVES: To determine whether high-quality healthcare service sectors are clustered within US healthcare markets. DESIGN: Using data from the Centers for Medicare and Medicaid Services' Hospital, Dialysis, Nursing Home and Home Health Compare databases, we calculated the mean star ratings of four healthcare sectors in 304 US hospital referral regions (HRRs). For each sector, we ranked HRRs into terciles by mean star rating. Within each HRR, we assessed concordance of tercile rank across sectors using a multirater kappa. Using t-tests, we compared characteristics of HRRs with three to four top-ranked sectors, one to two top-ranked sectors and zero top-ranked sectors. RESULTS: Six HRRs (2.0% of HRRs) had four top-ranked healthcare sectors, 38 (12.5%) had three top-ranked health sectors, 71 (23.4%) had two top-ranked sectors, 111 (36.5%) had one top-ranked sector and 78 (25.7%) HRRs had no top-ranked sectors. A multirater kappa across all sectors showed poor to slight agreement (K=0.055). Compared with HRRs with zero top-ranked sectors, those with three to four top-ranked sectors had higher median incomes, fewer black residents, lower mortality rates and were less impoverished. Results were similar for HRRs with one to two top-ranked sectors. CONCLUSIONS: Few US healthcare markets exhibit high-quality performance across four distinct healthcare service sectors, suggesting that high-quality care in one sector may not be dependent on or improve care quality in other sectors. Policies that promote accountability for quality across sectors (eg, bundled payments and shared quality metrics) may be needed to systematically improve quality across sectors. PMID- 28899902 TI - Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis. AB - Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR-/- mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR /- mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKalpha. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk. PMID- 28899900 TI - Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia. AB - Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss-of-function disorders such as Hirschsprung disease. PMID- 28899903 TI - SOCS3 expression in SF1 cells regulates adrenal differentiation and exercise performance. AB - Many hormones/cytokines are secreted in response to exercise and cytokine signaling may play a pivotal role in the training adaptations. To investigate the importance of cytokine signaling during vertical ladder climbing, a resistance exercise model, we produced mice lacking SOCS3 protein exclusively in steroidogenic factor-1 (SF1) cells (SF1 Socs3 KO mice). SF1 expression is found in steroidogenic cells of the adrenal cortex and gonads, as well as in neurons of the ventromedial nucleus of the hypothalamus. Histological markers of the fetal adrenal zone (or X-zone in rodents) were still present in adult males and postpartum SF1 Socs3 KO females, suggesting a previously unrecognized effect of SOCS3 on the terminal differentiation of the adrenal gland. This change led to a distinct distribution of lipid droplets along the adrenal cortex. Under basal conditions, adult SF1 Socs3 KO mice exhibited similar adrenal weight, and plasma ACTH and corticosterone concentrations. Nonetheless, SF1 Socs3 KO mice exhibited a blunted ACTH-induced corticosterone secretion. The overall metabolic responses induced by resistance training remained unaffected in SF1 Socs3 KO mice, including changes in body adiposity, glucose tolerance and energy expenditure. However, training performance and glucose control during intense resistance exercise were impaired in SF1 Socs3 KO mice. Furthermore, a reduced counter regulatory response to 2-deoxy-d-glucose was observed in mutant mice. These findings revealed a novel participation of SOCS3 regulating several endocrine and metabolic aspects. Therefore, cytokine signaling in SF1 cells exerts an important role to sustain training performance possibly by promoting the necessary metabolic adjustments during exercise. PMID- 28899904 TI - GP referrals under fire. PMID- 28899905 TI - On revalidation the GMC is listening to you. PMID- 28899906 TI - Does the doctrine of double effect apply to the prescription of barbiturates? Syme vs the Medical Board of Australia. AB - The doctrine of double effect (DDE) is a principle of crucial importance in law and medicine. In medicine, the principle is generally accepted to apply in cases where the treatment necessary to relieve pain and physical suffering runs the risk of hastening the patient's death. More controversially, it has also been used as a justification for withdrawal of treatment from living individuals and physician-assisted suicide. In this paper, I will critique the findings of the controversial Victorian Civil and Administrative Tribunal (VCAT) hearing Syme vs the Medical Board of Australia In that hearing, Dr Rodney Syme, a urologist and euthanasia advocate, was defending his practice of prescribing barbiturates to terminally ill patients. Syme claimed that he prescribed the drugs with the intention of relieving their existential suffering and not to assist in suicide; he argued that the DDE could be applied. Pace VCAT, I argue that this is an illegitimate application of DDE. I argue that a close scrutiny of Syme's actions reveals that, at the very least, he intended to give patients the option of suicide. He furthermore used what on a traditional definition of DDE would be considered a 'bad' means-the prescription of Nembutal-to achieve a 'good' end-the relief of suffering. The case demonstrates the crucial importance of analysing an agent's 'intention' and the 'effects' of their actions when applying DDE. Ethicists and, indeed, the judiciary need to attend to the ethical complexities of DDE when they assess the applicability of DDE to end of life care. If they fail to do this, the doctrine risks losing its legitimacy as an ethical principle. PMID- 28899907 TI - A novel function of CXCL10 in mediating monocyte production of proinflammatory cytokines. AB - IFN-gamma-inducible protein 10 (CXCL10), a chemokine that is abundantly secreted in response to inflammatory stimuli, has been implicated in the pathogenesis of multiple inflammatory diseases, such as inflammatory bowel disease. Whereas CXCL10 is traditionally recognized for recruiting pathogenic T cells to inflamed sites, its nonchemotactic role during inflammation remains poorly defined. In this report, we identified a novel function of CXCL10 in the regulation of the inflammatory potential of human monocytes to produce cytokines. We found that CXCL10 was necessary and sufficient for IFN-gamma-primed human monocytes to induce a robust production of proinflammatory cytokines, such as IL-12 and IL-23. CXCL10-induced monocyte production of these cytokines depended on CXCR3 receptor engagement as well as on the Ikappa B kinase and p38 MAPK signaling pathways. By using an innate-mediated murine colitis model, we demonstrated that anti-CXCL10 Ab treatment robustly suppressed the local production of myeloid-derived inflammatory cytokines and intestinal tissue damage. Together, our data unravel a previously unappreciated role of CXCL10 in the amplification of myeloid cell mediated inflammatory responses. Targeting CXCL10 is therefore an attractive approach to treating inflammatory diseases that are driven by innate and adaptive immunity. PMID- 28899908 TI - Activation of the "Splenocardiac Axis" by electronic and tobacco cigarettes in otherwise healthy young adults. AB - The "Splenocardiac Axis" describes an inflammatory signaling network underlying acute cardiac ischemia, characterized by sympathetic nerve stimulation of hematopoietic tissues, such as the bone marrow and spleen, which then release proinflammatory monocytes that populate atherosclerotic plaques, thereby promoting ischemic heart disease. Electronic (e) cigarettes, like tobacco cigarettes trigger sympathetic nerve activation, but virtually nothing is known about their influence on hematopoietic and vascular tissues and cardiovascular risks. The objective of this study was to determine if the Splenocardiac Axis is activated in young adults who habitually use either tobacco or e-cigarettes. In otherwise healthy humans who habitually use tobacco cigarettes or e-cigarettes (not both), we used 18F-flurorodeoxyglucose positron emission tomography/computer tomography (FDG-PET/CT) to test the hypothesis that tobacco or e-cigarettes increased metabolic activity of the hematopoietic and vascular tissues. FDG uptake in the spleen increased from nonuser controls (1.62 +/- 0.07), to the e cigarette users (1.73 +/- 0.04), and was highest in tobacco cigarette smokers (1.82 +/- 0.09; monotone P = 0.05). Similarly, FDG uptake in the aorta increased from the nonuser controls (1.87 +/- 0.07) to the e-cigarette users (1.98 +/- 0.07), and was highest in tobacco cigarette smokers (2.10 +/- 0.07; monotone P = 0.04). FDG uptake in the skeletal muscle, which served as a control tissue, was not different between the groups. In conclusion, these findings are consistent with activation of the Splenocardiac Axis by emissions from tobacco cigarettes and e-cigarettes. This activation suggests a mechanism by which tobacco cigarettes, and potentially e-cigarettes, may lead to increased risk of future cardiovascular events. PMID- 28899909 TI - Depletion of the mRNA translation initiation inhibitor, programmed cell death protein 4 (PDCD4), impairs L6 myotube formation. AB - The mechanistic (mammalian) target of rapamycin complex 1 (mTORC1) signaling is vital for optimal muscle mass and function. Although the significance of mTORC1 in stimulating muscle growth is unequivocal, evidence in support of its role during muscle regeneration is less clear. Here, we showed that the abundance (protein and mRNA) of the mTORC1/S6K1 substrate, programmed cell death protein 4 (PDCD4), is upregulated at the onset of differentiation of L6 and C2C12 cells. The increase in PDCD4 was not associated with any changes in S6K1 activation, but the abundance of beta transducing repeat-containing protein (beta-TrCP), the ubiquitin ligase that targets PDCD4 for degradation, increased. Myoblasts lacking PDCD4 showed impaired myotube formation and had markedly low levels of MHC-1. Analysis of poly (ADP-ribose) Polymerase (PARP), caspase 7 and caspase 3 indicated reduced apoptosis in PDCD4-deficient cells. Our data demonstrate a role for PDCD4 in muscle cell formation and suggest that interventions that target this protein may hold promise for managing conditions associated with impaired myotube formation. PMID- 28899910 TI - Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia. AB - Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia. PMID- 28899911 TI - Correlation of end tidal carbon dioxide, amplitude spectrum area, and coronary perfusion pressure in a porcine model of cardiac arrest. AB - Amplitude Spectrum Area (AMSA) values during ventricular fibrillation (VF) correlate with myocardial energy stores and predict defibrillation success. By contrast, end tidal CO2 (ETCO2) values provide a noninvasive assessment of coronary perfusion pressure and myocardial perfusion during cardiopulmonary resuscitation (CPR). Given the importance of the timing of defibrillation shock delivery on clinical outcome, we tested the hypothesis that AMSA and ETCO2 correlate with each other and can be used interchangably to correlate with myocardial perfusion in an animal laboratory preclinical, randomized, prospective investigation. After 6 min of untreated VF, 12 female pigs (32 +/- 1 Kg), isoflurane anesthetized pigs received sequentially 3 min periods of standard (S) CPR, S-CPR+ an impedance threshold device (ITD), and then active compression decompression (ACD) + ITD CPR Hemodynamic, AMSA, and ETCO2 measurements were made with each method of CPR The Spearman correlation and Friedman tests were used to compare hemodynamic parameters. ETCO2, AMSA, coronary perfusion pressure, cerebral perfusion pressure were lowest with STD CPR, increased with STD CPR + ITD and highest with ACD CPR + ITD Further analysis demonstrated a positive correlation between AMSA and ETCO2 (r = 0.37, P = 0.025) and between AMSA and key hemodynamic parameters (P < 0.05). This study established a moderate positive correlation between ETCO2 and AMSA These findings provide the physiological basis for developing and testing a novel noninvasive method that utilizes either ETCO2 alone or the combination of ETCO2 and AMSA to predict when defibrillation might be successful. PMID- 28899912 TI - Do nitric oxide synthase and cyclooxygenase contribute to sweating response during passive heating in endurance-trained athletes? AB - The aim of our study was to determine if habitual endurance training can influence the relative contribution of nitric oxide synthase (NOS) and cyclooxygenase (COX) in the regulation of sweating during a passive heat stress in young adults. Ten trained athletes and nine untrained counterparts were passively heated until oral temperature (as estimated by sublingual temperature, Tor) increased by 1.5 degrees C above baseline resting. Forearm sweat rate (ventilated capsule) was measured at three skin sites continuously perfused with either lactated Ringer's solution (Control), 10 mmol/L NG -nitro-L-arginine methyl ester (L-NAME, non-selective NOS inhibitor), or 10 mmol/L ketorolac (Ketorolac, non-selective COX inhibitor) via intradermal microdialysis. Sweat rate was averaged for each 0.3 degrees C increase in Tor Sweat rate at the L-NAME site was lower than Control following a 0.9 and 1.2 degrees C increase in Tor in both groups (all P <= 0.05). Relative to the Control site, NOS-inhibition reduced sweating similarly between the groups (P = 0.51). Sweat rate at the Ketorolac site was not different from the Control at any levels of Tor in both groups (P > 0.05). Nevertheless, a greater sweat rate was measured at the end of heating in the trained as compared to the untrained individuals (P <= 0.05). We show that NOS contributes similarly to sweating in both trained and untrained individuals during a passive heat stress. Further, no effect of COX on sweating was measured for either group. The greater sweat production observed in endurance-trained athletes is likely mediated by factors other than NOS- and COX-dependent mechanisms. PMID- 28899913 TI - Central chemoreflex activation induces sympatho-excitation without altering static or dynamic baroreflex function in normal rats. AB - Central chemoreflex activation induces sympatho-excitation. However, how central chemoreflex interacts with baroreflex function remains unknown. This study aimed to examine the impact of central chemoreflex on the dynamic as well as static baroreflex functions under open-loop conditions. In 15 anesthetized, vagotomized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled intra sinus pressure (CSP). We then recorded sympathetic nerve activity (SNA) at the celiac ganglia, and activated central chemoreflex by a gas mixture containing various concentrations of CO2 Under the baroreflex open-loop condition (CSP = 100 mmHg), central chemoreflex activation linearly increased SNA and arterial pressure (AP). To examine the static baroreflex function, we increased CSP stepwise from 60 to 170 mmHg and measured steady-state SNA responses to CSP (mechanoneural arc), and AP responses to SNA (neuromechanical arc). Central chemoreflex activation by inhaling 3% CO2 significantly increased SNA irrespective of CSP, indicating resetting of the mechanoneural arc, but did not change the neuromechanical arc. As a result, central chemoreflex activation did not change baroreflex maximum total loop gain significantly (-1.29 +/- 0.27 vs. 1.68 +/- 0.74, N.S.). To examine the dynamic baroreflex function, we randomly perturbed CSP and estimated transfer functions from 0.01 to 1.0 Hz. The transfer function of the mechanoneural arc approximated a high-pass filter, while those of the neuromechanical arc and total (CSP-AP relationship) arcs approximated a low pass filter. In conclusion, central chemoreflex activation did not alter the transfer function of the mechanoneural, neuromechanical, or total arcs. Central chemoreflex modifies hemodynamics via sympatho-excitation without compromising dynamic or static baroreflex AP buffering function. PMID- 28899914 TI - Military training elicits marked increases in plasma metabolomic signatures of energy metabolism, lipolysis, fatty acid oxidation, and ketogenesis. AB - Military training studies provide unique insight into metabolic responses to extreme physiologic stress induced by multiple stressor environments, and the impacts of nutrition in mediating these responses. Advances in metabolomics have provided new approaches for extending current understanding of factors modulating dynamic metabolic responses in these environments. In this study, whole-body metabolic responses to strenuous military training were explored in relation to energy balance and macronutrient intake by performing nontargeted global metabolite profiling on plasma collected from 25 male soldiers before and after completing a 4-day, 51-km cross-country ski march that produced high total daily energy expenditures (25.4 MJ/day [SD 2.3]) and severe energy deficits (13.6 MJ/day [SD 2.5]). Of 737 identified metabolites, 478 changed during the training. Increases in 88% of the free fatty acids and 91% of the acylcarnitines, and decreases in 88% of the mono- and diacylglycerols detected within lipid metabolism pathways were observed. Smaller increases in 75% of the tricarboxylic acid cycle intermediates, and 50% of the branched-chain amino acid metabolites detected were also observed. Changes in multiple metabolites related to lipid metabolism were correlated with body mass loss and energy balance, but not with energy and macronutrient intakes or energy expenditure. These findings are consistent with an increase in energy metabolism, lipolysis, fatty acid oxidation, ketogenesis, and branched-chain amino acid catabolism during strenuous military training. The magnitude of the energy deficit induced by undereating relative to high energy expenditure, rather than macronutrient intake, appeared to drive these changes, particularly within lipid metabolism pathways. PMID- 28899915 TI - Conditional Deletion of the L-Type Calcium Channel Cav1.2 in NG2-Positive Cells Impairs Remyelination in Mice. AB - Exploring the molecular mechanisms that drive the maturation of oligodendrocyte progenitor cells (OPCs) during the remyelination process is essential to developing new therapeutic tools to intervene in demyelinating diseases such as multiple sclerosis. To determine whether L-type voltage-gated calcium channels (L VGCCs) are required for OPC development during remyelination, we generated an inducible conditional knock-out mouse in which the L-VGCC isoform Cav1.2 was deleted in NG2-positive OPCs (Cav1.2KO). Using the cuprizone (CPZ) model of demyelination and mice of either sex, we establish that Cav1.2 deletion in OPCs leads to less efficient remyelination of the adult brain. Specifically, Cav1.2KO OPCs mature slower and produce less myelin than control oligodendrocytes during the recovery period after CPZ intoxication. This reduced remyelination was accompanied by an important decline in the number of myelinating oligodendrocytes and in the rate of OPC proliferation. Furthermore, during the remyelination phase of the CPZ model, the corpus callosum of Cav1.2KO animals presented a significant decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compared with controls. In addition, in a mouse line in which the Cav1.2KO OPCs were identified by a Cre reporter, we establish that Cav1.2KO OPCs display a reduced maturational rate through the entire remyelination process. These results suggest that Ca2+ influx mediated by L-VGCCs in oligodendroglial cells is necessary for normal remyelination and is an essential Ca2+ channel for OPC maturation during the remyelination of the adult brain.SIGNIFICANCE STATEMENT Ion channels implicated in oligodendrocyte differentiation and maturation may induce positive signals for myelin recovery. Voltage-gated Ca2+ channels (VGCCs) are important for normal myelination by acting at several critical steps during oligodendrocyte progenitor cell (OPC) development. To determine whether voltage Ca2+ entry is involved in oligodendrocyte differentiation and remyelination, we used a conditional knockout mouse for VGCCs in OPCs. Our results indicate that VGCCs can modulate oligodendrocyte maturation in the demyelinated brain and suggest that voltage gated Ca2+ influx in OPCs is critical for remyelination. These findings could lead to novel approaches for obtaining a better understanding of the factors that control OPC maturation in order to stimulate this pool of progenitors to replace myelin in demyelinating diseases. PMID- 28899916 TI - GD1a Overcomes Inhibition of Myelination by Fibronectin via Activation of Protein Kinase A: Implications for Multiple Sclerosis. AB - Remyelination failure by oligodendrocytes contributes to the functional impairment that characterizes the demyelinating disease multiple sclerosis (MS). Since incomplete remyelination will irreversibly damage axonal connections, treatments effectively promoting remyelination are pivotal in halting disease progression. Our previous findings suggest that fibronectin aggregates, as an environmental factor, contribute to remyelination failure by perturbing oligodendrocyte progenitor cell (OPC) maturation. Here, we aim at elucidating whether exogenously added gangliosides (i.e., cell surface lipids with a potential to modulate signaling pathways) could counteract fibronectin-mediated inhibition of OPC maturation. Exclusive exposure of rat oligodendrocytes to GD1a, but not other gangliosides, overcomes aggregated fibronectin-induced inhibition of myelin membrane formation, in vitro, and OPC differentiation in fibronectin aggregate containing cuprizone-induced demyelinated lesions in male mice. GD1a exerts its effect on OPCs by inducing their proliferation and, at a late stage, by modulating OPC maturation. Kinase activity profiling revealed that GD1a activated a protein kinase A (PKA)-dependent signaling pathway and increased phosphorylation of the transcription factor cAMP response element-binding protein. Consistently, the effect of GD1a in restoring myelin membrane formation in the presence of fibronectin aggregates was abolished by the PKA inhibitor H89, whereas the effect of GD1a was mimicked by the PKA activator dibutyryl-cAMP. Together, GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation by activating a PKA-dependent signaling pathway. Given the persistent presence of fibronectin aggregates in MS lesions, ganglioside GD1a might act as a potential novel therapeutic tool to selectively modulate the detrimental signaling environment that precludes remyelination.SIGNIFICANCE STATEMENT As an environmental factor, aggregates of the extracellular matrix protein fibronectin perturb the maturation of oligodendrocyte progenitor cells (OPCs), thereby impeding remyelination, in the demyelinating disease multiple sclerosis (MS). Here we demonstrate that exogenous addition of ganglioside GD1a overcomes the inhibiting effect of aggregated fibronectin on OPC maturation, both in vitro and in vivo, by activating a PKA-dependent signaling pathway. We propose that targeted delivery of GD1a to MS lesions may act as a potential novel molecular tool to boost maturation of resident OPCs to overcome remyelination failure and halt disease progression. PMID- 28899917 TI - Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome. AB - Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivoSIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients. PMID- 28899918 TI - Adaptation of Thalamic Neurons Provides Information about the Spatiotemporal Context of Stimulus History. AB - Adaptation of neural responses due to the history of sensory input has been observed across all sensory modalities. However, the computational role of adaptation is not fully understood, especially when one considers neural coding problems in which adaptation increases the ambiguity of the neural responses to simple stimuli. To address this, we quantified the impact of adaptation on the information conveyed by thalamic neurons about paired whisker stimuli in male rat. At the single neuron level, although paired-pulse adaptation reduces the information about the present stimulus, the information per spike increases. Moreover, the adapted response can convey significant amounts of information about whether, when and where a previous stimulus occurred. At the population level, ambiguity of the adapted responses about the present stimulus can be compensated for by large numbers of neurons. Therefore, paired-pulse adaptation does not reduce the discriminability of simple stimuli. It provides information about the spatiotemporal context of stimulus history.SIGNIFICANCE STATEMENT The present work provides a computational framework that demonstrates how adaptation allows neurons to encode spatiotemporal dynamics of stimulus history. PMID- 28899921 TI - Author's reply to Hawkins. PMID- 28899920 TI - The TRPM1 Channel Is Required for Development of the Rod ON Bipolar Cell-AII Amacrine Cell Pathway in the Retinal Circuit. AB - Neurotransmission plays an essential role in neural circuit formation in the central nervous system (CNS). Although neurotransmission has been recently clarified as a key modulator of retinal circuit development, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we investigated the role of neurotransmission from photoreceptor cells to ON bipolar cells in development using mutant mouse lines of both sexes in which this transmission is abrogated. We found that deletion of the ON bipolar cation channel TRPM1 results in the abnormal contraction of rod bipolar terminals and a decreased number of their synaptic connections with amacrine cells. In contrast, these histological alterations were not caused by a disruption of total glutamate transmission due to loss of the ON bipolar glutamate receptor mGluR6 or the photoreceptor glutamate transporter VGluT1. In addition, TRPM1 deficiency led to the reduction of total dendritic length, branch numbers, and cell body size in AII amacrine cells. Activated Goalpha, known to close the TRPM1 channel, interacted with TRPM1 and induced the contraction of rod bipolar terminals. Furthermore, overexpression of Channelrhodopsin-2 partially rescued rod bipolar cell development in the TRPM1-/- retina, whereas the rescue effect by a constitutively closed form of TRPM1 was lower than that by the native form. Our results suggest that TRPM1 channel opening is essential for rod bipolar pathway establishment in development.SIGNIFICANCE STATEMENT Neurotransmission has been recognized recently as a key modulator of retinal circuit development in the CNS. However, the roles of individual synaptic transmissions are not yet fully understood. In the current study, we focused on neurotransmission between rod photoreceptor cells and rod bipolar cells in the retina. We used genetically modified mouse models which abrogate each step of neurotransmission: presynaptic glutamate release, postsynaptic glutamate reception, or transduction channel function. We found that the TRPM1 transduction channel is required for the development of rod bipolar cells and their synaptic formation with subsequent neurons, independently of glutamate transmission. This study advances our understanding of neurotransmission-mediated retinal circuit refinement. PMID- 28899919 TI - Astrocyte-Mediated Neuronal Synchronization Properties Revealed by False Gliotransmitter Release. AB - Astrocytes spontaneously release glutamate (Glut) as a gliotransmitter (GT), resulting in the generation of extrasynaptic NMDAR-mediated slow inward currents (SICs) in neighboring neurons, which can increase local neuronal excitability. However, there is a deficit in our knowledge of the factors that control spontaneous astrocyte GT release and the extent of its influence. We found that, in rat brain slices, increasing the supply of the physiological transmitter Glut increased the frequency and signaling charge of SICs over an extended period. This phenomenon was replicated by exogenous preexposure to the amino acid D aspartate (D-Asp). Using D-Asp as a "false" GT, we determined the extent of local neuron excitation by GT release in ventrobasal thalamus, CA1 hippocampus, and somatosensory cortex. By analyzing synchronized neuronal NMDAR-mediated excitation, we found that the properties of the excitation were conserved in different brain areas. In the three areas, astrocyte-derived GT release synchronized groups of neurons at distances of >;200 MUm. Individual neurons participated in more than one synchronized population, indicating that individual neurons can be excited by more than one astrocyte and that individual astrocytes may determine a neuron's synchronized network. The results confirm that astrocytes can act as excitatory nodes that can influence neurons over a significant range in a number of brain regions. Our findings further suggest that chronic elevation of ambient Glut levels can lead to increased GT Glut release, which may be relevant in some pathological states.SIGNIFICANCE STATEMENT Astrocytes spontaneously release glutamate (Glut) and other gliotransmitters (GTs) that can modify neuronal activity. Exposing brain slices to Glut and D aspartate (D-Asp) before recording resulted in an increase in frequency of GT mediated astrocyte-neuron signaling. Using D-Asp, it was possible to investigate the effects of specific GT release at neuronal NMDARs. Calcium imaging showed synchronized activity in groups of neurons in cortex, hippocampus, and thalamus. The size of these populations was similar in all areas and some neurons were involved in more than one synchronous group. The findings show that GT release is supply dependent and that the properties of the signaling and activated networks are largely conserved between different brain areas. PMID- 28899922 TI - Changes in admission thresholds in English emergency departments. AB - BACKGROUND: The most common route to a hospital bed in an emergency is via an Emergency Department (ED). Many recent initiatives and interventions have the objective of reducing the number of unnecessary emergency admissions. We aimed to assess whether ED admission thresholds had changed over time taking account of the casemix of patients arriving at ED. METHODS: We conducted a retrospective cross-sectional analysis of more than 20 million attendances at 47 consultant-led EDs in England between April 2010 and March 2015. We used mixed-effects logistic regression to estimate the odds of a patient being admitted to hospital and the impact of a range of potential explanatory variables. Models were developed and validated for four attendance subgroups: ambulance-conveyed children, walk-in children, ambulance-conveyed adults and walk-in adults. RESULTS: 23.8% of attendances were for children aged under 18 years, 49.7% were female and 30.0% were conveyed by ambulance. The number of ED attendances increased by 1.8% per annum between April 2010-March 2011 (year 1) and April 2014-March 2015 (year 5). The proportion of these attendances that were admitted to hospital changed negligiblybetween year 1 (27.0%) and year 5 (27.5%). However, after adjusting for patient and attendance characteristics, the odds of admission over the 5-year period had reduced by 15.2% (95% CI 13.4% to 17.0%) for ambulance-conveyed children, 22.6% (95% CI 21.7% to 23.5%) for walk-in children, 20.9% (95% CI 20.4% to 21.5%) for ambulance conveyed adults and 22.9% (95% CI 22.4% to 23.5%) for walk-in adults. CONCLUSIONS: The casemix-adjusted odds of admission via ED to NHS hospitals in England have decreased since April 2010. EDs are admitting a similar proportion of patients to hospital despite increases in the complexity and acuity of presenting patients. Without these threshold changes, the number of emergency admissions would have been 11.9% higher than was the case in year 5. PMID- 28899923 TI - A retrospective analysis of 34 potentially missed cases of female genital mutilation in the emergency department. AB - OBJECTIVES: To discover if healthcare professionals working within an ED are able to make a diagnosis of female genital mutilation (FGM) in those patients who have previously undergone the procedure and report it as per UK law. DESIGN: A retrospective analysis of patients' notes who were assigned an FGM code during the period of May 2015 to August 2016. SETTING: Single-centre, large UK major trauma centre offering a tertiary FGM clinic. PARTICIPANTS: Any woman coded during the study period as having undergone FGM. PRIMARY OUTCOME: Number of FGM cases identified by the ED. SECONDARY OUTCOMES: Mean age, presenting complaint, discharge diagnosis, genitourinary exam and defibulation status. RESULTS: 34 patients were identified as having undergone FGM, 19 had previously attended ED and none had their FGM identified during their ED attendance. The age range of those identified was 23 to 40 years. None had undergone defibulation. CONCLUSION: This study demonstrates that the identification of FGM victims by an ED is very poor, and more work needs to be done to increase awareness of the subject by front-line staff. PMID- 28899924 TI - Relationship between UGT1A9 gene polymorphisms, efficacy, and safety of propofol in induced abortions amongst Chinese population: a population-based study. AB - The present study aimed to investigate the influence of UGT1A9 gene polymorphisms on the efficacy of propofol in patients undergoing the painless induced abortion method. A total of 156 women seeking voluntary pregnancy termination procedures were selected for the study, and subsequently underwent painless induced abortions, following anesthesia by means of propofol administration. PCR restriction fragment length polymorphism (PCR-RFLP) was performed to detect the polymorphisms of UGT1A9 gene at -440C/T, -1818C/T, and -1887T/G loci. The time, effect-site concentration, and bispectral index (BIS) for the Observer's Assessment of Alertness/Sedation (OAA/S) (up to 4 points) were observed and recorded in patients following discontinuation of propofol. The time and effect site concentration for BIS reaching 80 in patients following the discontinuation of propofol were observed and recorded. Postoperative observations of adverse reactions, such as nausea, vomiting, and respiratory depression were all made record of. In comparison with patients with UGT1A9 -440C/T CT and TT, those with UGT1A9 -440C/T CC displayed shorter durations of OAA/S by up to 4 points, shorter BIS times reaching 80, as well as higher corresponding effect-site concentrations. No significant differences were detected in the patients with 440C/T, -1818T/C, and -1887T/G in incidence of nausea, vomiting, and respiratory depression. The findings of the study highlighted correlation between UGT1A9 440C/T gene polymorphisms and positive propofol efficacy in patients undergoing painless induced pregnancy termination procedures. PMID- 28899925 TI - X-ray data processing. AB - The method of molecular structure determination by X-ray crystallography is a little over a century old. The history is described briefly, along with developments in X-ray sources and detectors. The fundamental processes involved in measuring diffraction patterns on area detectors, i.e. autoindexing, refining crystal and detector parameters, integrating the reflections themselves and putting the resultant measurements on to a common scale are discussed, with particular reference to the most commonly used software in the field. PMID- 28899926 TI - Peptides mediating DNA transport on microtubules and their impact on non-viral gene transfer efficiency. AB - Synthetic vectors such as cationic polymers and cationic lipids remain attractive tools for non-viral gene transfer which is a complex process whose effectiveness relies on the ability to deliver a plasmid DNA (pDNA) into the nucleus of non dividing cells. Once in the cytosol, the transport of pDNAs towards the nuclear envelope is strongly impaired by their very low cytosolic mobility due to their large size. To promote their movement towards the cell nucleus, few strategies have been implemented to exploit dynein, the microtubule's (MT's) motor protein, for propagation of cytosolic pDNA along the MTs towards the cell nucleus. In the first part of this review, an overview on MTs, dynein, dynein/virus interaction feature is presented followed by a summary of the results obtained by exploitation of LC8 and TCTEL1 dynein light chain association sequence (DLC-AS) for non-viral transfection. The second part dedicated to the adenoviral protein E3-14.7K, reports the transfection efficiency of polyplexes and lipoplexes containing the E3-14.7K-derived P79-98 peptide linked to pDNA. Here, several lines of evidence are given showing that dynein can be targeted to improve cytosolic pDNA mobility and accumulate pDNA near nuclear envelope in order to facilitate its transport through the nuclear pores. The linkage of various DLC-AS to pDNA carriers led to modest transfection improvements and their direct interaction with MTs was not demonstrated. In contrast, pDNA linked to the P79-98 peptide interacting with TCTEL1 via a cytosolic protein (fourteen seven K interacting protein-1 (FIP-1)), interaction with MTs is evidenced in cellulo and transfection efficiency is improved. PMID- 28899927 TI - MiR-138 protects cardiac cells against hypoxia through modulation of glucose metabolism by targetting pyruvate dehydrogenase kinase 1. AB - Dysfunction of cardiac cells under hypoxia has been identified as an essential event leading to myocytes functional failure. MiRNAs are importantly regulatory small-noncoding RNAs that negatively regulate gene expression through the direct binding of 3'-UTR region of their target mRNAs. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under pathological conditions.Pyruvate dehydrogenase kinase 1 (PDK1) is a kinase which phosphorylates pyruvate dehydrogenase to inactivate it, leading to elevated anaerobic glycolysis and decreased cellular respiration. In the present study, we report that miR-138 expressions were significantly suppressed under long exposure to hypoxia. In addition, overexpression of miR-138 protects human cardiac cells against hypoxia. We observed miR-138 inhibits glycolysis but promotes mitochondrial respiration through directly targetting PDK1. Moreover, we demonstrate that hypoxia induces cardiac cell death through increased glycolysis and decreased mitochondrial respiration. Inhibition of glycolysis by either glycolysis inhibitor or knockdown glycolysis enzymes, Glucose transportor 1 (Glut1) or PDK1 contributes to cardiac cells' survival. The cell sentivity to hypoxia was recovered when the PDK1 level was restored in miR-138 overexpressing cardiac cells. The present study leads to the intervention of novel therapeutic strategies against cardiac cells dysfunction during surgery or ischemia. PMID- 28899928 TI - Treatment of hypertension by increasing impaired endothelial TRPV4-KCa2.3 interaction. AB - The currently available antihypertensive agents have undesirable adverse effects due to systemically altering target activity including receptors, channels, and enzymes. These effects, such as loss of potassium ions induced by diuretics, bronchospasm by beta-blockers, constipation by Ca2+ channel blockers, and dry cough by ACEI, lead to non-compliance with therapies (Moser, 1990). Here, based on new hypertension mechanisms, we explored a new antihypertensive approach. We report that transient receptor potential vanilloid 4 (TRPV4) interacts with Ca2+ activated potassium channel 3 (KCa2.3) in endothelial cells (ECs) from small resistance arteries of normotensive humans, while ECs from hypertensive patients show a reduced interaction between TRPV4 and KCa2.3. Murine hypertension models, induced by high-salt diet, N(G)-nitro-l-arginine intake, or angiotensin II delivery, showed decreased TRPV4-KCa2.3 interaction in ECs. Perturbation of the TRPV4-KCa2.3 interaction in mouse ECs by overexpressing full-length KCa2.3 or defective KCa2.3 had hypotensive or hypertensive effects, respectively. Next, we developed a small-molecule drug, JNc-440, which showed affinity for both TRPV4 and KCa2.3. JNc-440 significantly strengthened the TRPV4-KCa2.3 interaction in ECs, enhanced vasodilation, and exerted antihypertensive effects in mice. Importantly, JNc-440 specifically targeted the impaired TRPV4-KCa2.3 interaction in ECs but did not systemically activate TRPV4 and KCa2.3. Together, our data highlight the importance of impaired endothelial TRPV4-KCa2.3 coupling in the progression of hypertension and suggest a novel approach for antihypertensive drug development. PMID- 28899929 TI - Pathogen-specific B-cell receptors drive chronic lymphocytic leukemia by light chain-dependent cross-reaction with autoantigens. AB - Several lines of evidence indirectly suggest that antigenic stimulation through the B-cell receptor (BCR) supports chronic lymphocytic leukemia (CLL) development. In addition to self-antigens, a number of microbial antigens have been proposed to contribute to the selection of the immunoglobulins expressed in CLL. How pathogen-specific BCRs drive CLL development remains, however, largely unexplored. Here, we utilized mouse models of CLL pathogenesis to equip B cells with virus-specific BCRs and study the effect of antigen recognition on leukemia growth. Our results show that BCR engagement is absolutely required for CLL development. Unexpectedly, however, neither acute nor chronic exposure to virus derived antigens influenced leukemia progression. Rather, CLL clones preferentially selected light chains that, when paired with virus-specific heavy chains, conferred B cells the ability to recognize a broad range of autoantigens. Taken together, our results suggest that pathogens may drive CLL pathogenesis by selecting and expanding pathogen-specific B cells that cross-react with one or more self-antigens. PMID- 28899931 TI - Social media and JNIS: expanding the digital clique. PMID- 28899930 TI - Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients. AB - Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34+ cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34+ cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells. PMID- 28899933 TI - Chemistry in a vesicle. PMID- 28899932 TI - Utility of perfusion imaging in acute stroke treatment: a systematic review and meta-analysis. AB - BACKGROUND: Variability in imaging protocols and techniques has resulted in a lack of consensus regarding the incorporation of perfusion imaging into stroke triage and treatment. The objective of our study was to evaluate the available scientific evidence regarding the utility of perfusion imaging in determining treatment eligibility in patients with acute stroke and in predicting their clinical outcome. METHODS: We performed a systematic review of the literature using PubMed, Web of Science, and Cochrane Library focusing on themes of medical imaging, stroke, treatment, and outcome (CRD42016037817). We included randomized controlled trials, cohort studies, and case-controlled studies published from 2011 to 2016. Two independent reviewers conducted the study appraisal, data abstraction, and quality assessments of the studies. RESULTS: Our literature search yielded 13 studies that met our inclusion criteria. In total, 994 patients were treated with the aid of perfusion imaging compared with 1819 patients treated with standard care. In the intervention group 51.1% of patients had a favorable outcome at 3 months compared with 45.6% of patients in the control group (p=0.06). Subgroup analysis of studies that used multimodal therapy (IV tissue plasminogen activator, endovascular thrombectomy) showed a significant benefit of perfusion imaging (OR 1.89, 95% CI 1.43 to 2.51, p<0.01). CONCLUSIONS: Perfusion imaging may represent a complementary tool to standard radiographic assessment in enhancing patient selection for reperfusion therapy, with a subset of patients having up to 1.9 times the odds of achieving independent functional status at 3 months. This is particularly important as patients selected based on perfusion status often included individuals who did not meet the current treatment eligibility criteria. PMID- 28899934 TI - Bronchial hyperresponsiveness and obesity in middle age: insights from an Australian cohort. AB - The association between obesity and bronchial hyperresponsiveness (BHR) is incompletely characterised. Using the 2006 follow-up of the Tasmanian Longitudinal Health Study, we measured the association between obesity and BHR and whether it was mediated by small airway closure or modified by asthma and sex of the patient.A methacholine challenge measured BHR. Multivariable logistic regression measured associations between body mass index (BMI) and BHR, adjusting for sex, asthma, smoking, corticosteroid use, family history and lung function. Mediation by airway closure was also measured.Each increase in BMI of 1 kg.m-2 was associated with a 5% increase in the odds of BHR (OR 1.05, 95% CI 1.01-1.09) and 43% of this association was mediated by airway closure. In a multivariable model, BMI (OR 1.06, 95% CI 1.00-1.16) was associated with BHR independent of female sex (OR 3.26, 95% CI 1.95-5.45), atopy (OR 2.30, 95% CI 1.34-3.94), current asthma (OR 5.74, 95% CI 2.79-11.82), remitted asthma (OR 2.35, 95% CI 1.27-4.35), low socioeconomic status (OR 2.11, 95% CI 1.03-4.31) and forced expiratory volume in 1 s/forced vital capacity (OR 0.86, 95% CI 0.82-0.91). Asthma modified the association with an increasing probability of BHR as BMI increased, only in those with no or remitted asthma.An important fraction of the BMI/BHR association was mediated via airway closure. Conflicting findings in previous studies could be explained by failure to consider this intermediate step. PMID- 28899935 TI - Macrophage dysfunction in the pathogenesis and treatment of asthma. AB - Asthma is a chronic respiratory condition frequently associated with aberrant airway and systemic inflammation. Various inflammatory phenotypes in asthmatic airways have been described that relate to clinical phenotypes and impact on responses to conventional and novel asthma therapies. Macrophages are abundant immunocytes in the lung, capable of mounting diverse responses required for homeostasis and defence against pathogens.Here, we summarise the clinical evidence regarding macrophage dysfunction in asthma. We also describe evidence supporting the role of macrophages as therapeutic targets in asthma. We conclude that macrophage dysfunction in asthma is highly prevalent and heterogeneous, and hypothesise that macrophages may play roles in promoting the discrete inflammatory phenotypes of asthma.These clinical findings, along with recent ground-breaking insights into the ontogeny, behavioural complexity and longevity of pulmonary macrophages, support continued research into the role of macrophages as disease modifiers, biomarkers and therapeutic targets in asthma. PMID- 28899936 TI - Bosutinib-related pneumonitis. PMID- 28899938 TI - Phase three studies of biologics for severe asthma: could do better? PMID- 28899937 TI - Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation. AB - Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology ("over-perception"). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy. PMID- 28899939 TI - Work productivity loss in mild to moderate COPD: lessons learned from the CanCOLD study. PMID- 28899940 TI - Treating anxious expectations can improve dyspnoea in patients with COPD. PMID- 28899941 TI - After the asthmas: Star Wars and Star Trek. PMID- 28899942 TI - Trz1, the long form RNase Z from yeast, forms a stable heterohexamer with endonuclease Nuc1 and mutarotase. AB - Proteomic studies have established that Trz1, Nuc1 and mutarotase form a complex in yeast. Trz1 is a beta-lactamase-type RNase composed of two beta-lactamase-type domains connected by a long linker that is responsible for the endonucleolytic cleavage at the 3'-end of tRNAs during the maturation process (RNase Z activity); Nuc1 is a dimeric mitochondrial nuclease involved in apoptosis, while mutarotase (encoded by YMR099C) catalyzes the conversion between the alpha- and beta configuration of glucose-6-phosphate. Using gel filtration, small angle X-ray scattering and electron microscopy, we demonstrated that Trz1, Nuc1 and mutarotase form a very stable heterohexamer, composed of two copies of each of the three subunits. A Nuc1 homodimer is at the center of the complex, creating a two-fold symmetry and interacting with both Trz1 and mutarotase. Enzymatic characterization of the ternary complex revealed that the activities of Trz1 and mutarotase are not affected by complex formation, but that the Nuc1 activity is completely inhibited by mutarotase and partially by Trz1. This suggests that mutarotase and Trz1 might be regulators of the Nuc1 apoptotic nuclease activity. PMID- 28899943 TI - The chromatin remodeling Isw1a complex is regulated by SUMOylation. AB - The ISWI class of proteins consists of a family of chromatin remodeling ATPases that is ubiquitous in eukaryotes and predominantly functions to slide nucleosomes laterally. The yeast Saccharomyces cerevisiae Isw1 partners with several non essential alternative subunits - Ioc2, Ioc3, or Ioc4 - to form two distinct complexes Isw1a and Isw1b. Besides its ATPase domain, Isw1 presents a C-terminal region formed by HAND, SANT, and SLIDE domains responsible for interaction with the Ioc proteins and optimal association of Isw1 to chromatin. Despite diverse studies on the functions of the Isw1-containing complexes, molecular evidence for a regulation of this chromatin remodeling ATPase is still elusive. Results presented here indicate that Isw1 is not only ubiquitylated but also strongly SUMOylated on multiple lysine residues by the redundant Siz1/Siz2 SUMO E3 ligases. However, Isw1 is a poor substrate of the Ulp1 and Ulp2 SUMO proteases, thus resulting in a high level of modification. Extensive site-directed mutagenesis allowed us to identify the major SUMOylation sites and develop a SUMO defective mutant of Isw1. Using this molecular tool, we show that SUMOylation of Isw1 specifically facilitates and/or stabilizes its interaction with its cofactor Ioc3 and consequently the efficient recruitment of the Isw1-Ioc3 complex onto chromatin. Together these data reveal a new regulatory mechanism for this fascinating remodeling factor. PMID- 28899945 TI - Bindings of NO, CO, and O2 to multifunctional globin type dehaloperoxidase follow the 'sliding scale rule'. AB - Dehaloperoxidase-hemoglobin (DHP), a multifunctional globin protein, not only functions as an oxygen carrier as typical globins such as myoglobin and hemoglobin, but also as a peroxidase, a mono- and dioxygenase, peroxygenase, and an oxidase. Kinetics of DHP binding to NO, CO, and O2 were characterized for wild type DHP A and B and the H55D and H55V DHP A mutants using stopped-flow methods. All three gaseous ligands bind to DHP significantly more weakly than sperm whale myoglobin (SWMb). Both CO and NO bind to DHP in a one-step process to form a stable six-coordinate complex. Multiple-step NO binding is not observed in DHP, which is similar to observations in SWMb, but in contrast with many heme sensor proteins. The weak affinity of DHP for O2 is mainly due to a fast O2 dissociation rate, in accordance with a longer epsilonN-Fe distance between the heme iron and distal histidine in DHP than that in Mb, and an open-distal pocket that permits ligand escape. Binding affinities in DHP show the same 3-4 orders separation between the pairs NO/CO and CO/O2, consistent with the 'sliding scale rule' hypothesis. Strong gaseous ligand discrimination by DHP is very different from that observed in typical peroxidases, which show poor gaseous ligand selectivity, correlating with a neutral proximal imidazole ligand rather than an imidazolate. The present study provides useful insights into the rationale for DHP to function both as mono-oxygenase and oxidase, and is the first example of a globin peroxidase shown to follow the 'sliding scale rule' hypothesis in gaseous ligand discrimination. PMID- 28899944 TI - Novel endogenous retrovirus-derived transcript expressed in the bovine placenta is regulated by WNT signaling. AB - Endogenous retroviruses (ERVs) are involved in placentation; perhaps, the most well-known ERVs are the syncytins, actively transcribed env genes involved in cell-cell fusion and possible morphological variations. However, ERVs other than syncytins that play an important role in placental development have not been well characterized. To identify ERV genes expressed during the onset of placentation in the bovine species, we characterized the expression profiles of bovine conceptus transcripts during the peri-attachment period using RNA-seq analysis, and confirming some candidates through real-time PCR. Using in silico and PCR analyses, we identified a novel ERV proviral sequence derived from a gag region, designated bovine endogenous retroviruses (BERV)-K3, containing Gag_p10 and Gag_p24, zinc finger domain. Initial expression of this ERV in bovine conceptuses was on day 20 (day 0 = day of estrus), soon after conceptus attachment to the endometrial epithelium, and its high placental expression was maintained up to the middle of pregnancy. The BERV-K3 transcript was also found in the uterine luminal and glandular epithelia, liver, kidney, intestine, and skin. BERV-K3 is located on chromosome 7 and integrated within LOC100848658, from which noncoding RNA could be transcribed. Furthermore, the expression of endogenous BERV-K3 in bovine trophoblast cell lines was induced by a WNT agonist, a signaling system common to genes expressed in placentas. These data support the argument that during the evolutionary process, mammals incorporated not only similar ERV sequences, but also ERVs unique to individual species. BERV-K3 is in the latter case, likely providing functions unique to ruminant gestation. PMID- 28899946 TI - Secondary prevention treatment after acute stroke in older South Asian, Chinese and other Canadians: a retrospective data analysis. AB - BACKGROUND: Little is known about whether there are differences in medication use between older patients of Chinese descent, those of South Asian descent and other Canadian patients after acute ischemic or primary intracerebral hemorrhagic stroke. The aim of this population-based study was to evaluate potential ethnic differences in secondary prevention pharmacotherapy after acute stroke. METHODS: Using health administrative data, we conducted a retrospective analysis of all patients aged 66 years or more admitted to hospital with acute stroke in Ontario (1997-2011) and British Columbia (1997-2009). We compared prescriptions filled for statins, warfarin, any antihypertensive agent, the recommended combination of angiotensin-converting-enzyme (ACE) inhibitor and diuretic, and the combination of ACE inhibitor, diuretic and statin within 1 year after ischemic or primary intracerebral hemorrhagic stroke. RESULTS: There were 118 362 patients with acute stroke (3430 Chinese, 2075 South Asian and 112 857 other Canadians). Among those with ischemic stroke (n = 108 699), Chinese patients were less likely than other Canadian patients to fill prescriptions for the combination of ACE inhibitor, diuretic and statin (adjusted odds ratio [OR] 0.64 [95% confidence interval (CI) 0.55-0.74]) and, in those with atrial fibrillation, for warfarin (adjusted OR 0.75 [95% CI 0.59-0.95]). There were no differences in filling of prescriptions for antihypertensive therapy overall between the 3 groups. Among patients with intracerebral hemorrhagic stroke (n = 9663), Chinese patients were less likely than other Canadian patients to fill prescriptions for the combination of ACE inhibitor and diuretic (adjusted OR 0.51 [95% CI 0.38-0.69]), and South Asians were more likely than other Canadian patients to fill prescriptions for any antihypertensive agent (adjusted OR 1.73 [95% CI 1.21-2.49]). INTERPRETATION: We identified ethnic differences in filling of prescriptions for several secondary prevention medications after acute stroke. The reasons underlying these differences need to be investigated. PMID- 28899947 TI - Is lobbying legislation chilling public debate on health? PMID- 28899948 TI - Happy 20th anniversary MEN1: from positional cloning to gene function restoration. PMID- 28899950 TI - Prevalence and Prognostic Significance of Left Ventricular Noncompaction in Patients Referred for Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: Presence of prominent left ventricular trabeculation satisfying criteria for left ventricular noncompaction (LVNC) on routine cardiac magnetic resonance examination is frequently encountered; however, the clinical and prognostic significance of these findings remain elusive. This registry aimed to assess LVNC prevalence by 4 current criteria and to prospectively evaluate an association between diagnosis of LVNC by these criteria and adverse events. METHODS AND RESULTS: There were 700 patients referred for cardiac magnetic resonance: 42% were women, median age was 70 years (range, 45-71 years), mean left ventricular ejection fraction was 51% (+/-17%), and 32% had late gadolinium enhancement on cardiac magnetic resonance. The cohort underwent diagnostic assessment for LVNC by 4 separate imaging criteria-referenced by their authors as Petersen, Stacey, Jacquier, and Captur, with LVNC prevalence of 39%, 23%, 25% and 3%, respectively. Primary clinical outcome was combined end point of time to death, ischemic stroke, ventricular tachycardia/ventricular fibrillation, and heart failure hospitalization. Secondary clinical outcomes were (1) all-cause mortality and (2) time to the first occurrence of any of the following events: cardiac death, ischemic stroke, ventricular tachycardia/ventricular fibrillation, or heart failure hospitalization. During a median follow-up of 7 years, there were no statistically significant differences in assessed outcomes noted between patients with and without LVNC irrespective of the applied criteria. CONCLUSIONS: Current criteria for the diagnosis of LVNC leads to highly variable disease prevalence in patients referred for cardiac magnetic resonance. The diagnosis of LVNC, by any current criteria, was not associated with adverse clinical events on nearly 7 years of follow-up. Limited conclusions can be made for Captur criteria due to low observed prevalence. PMID- 28899952 TI - Excessive Trabeculations and Prognosis: The Plot Thickens. PMID- 28899953 TI - Interleukin Antagonists: Have We Found the Right One to Block? Are Cardiovascular Effects of Biologic Therapies Similar? PMID- 28899951 TI - Lowering Interleukin-12 Activity Improves Myocardial and Vascular Function Compared With Tumor Necrosis Factor-a Antagonism or Cyclosporine in Psoriasis. AB - BACKGROUND: Interleukin (IL)-12 activity is involved in the pathogenesis of psoriasis and acute coronary syndromes. We investigated the effects of IL-12 inhibition on vascular and left ventricular (LV) function in psoriasis. METHODS AND RESULTS: One hundred fifty psoriasis patients were randomized to receive an anti-IL-12/23 (ustekinumab, n=50), anti-tumor necrosis factor-a (TNF-alpha; etanercept, n=50), or cyclosporine treatment (n=50). At baseline and 4 months post-treatment, we measured (1) LV global longitudinal strain, twisting, and percent difference between peak twisting and untwisting at mitral valve opening (%untwMVO) using speckle-tracking echocardiography, (2) coronary flow reserve, (3) pulse wave velocity and augmentation index, (4) circulating NT-proBNP (N terminal pro-B-type natriuretic peptide), TNF-alpha, IL-6, IL-12, IL-17, malondialdehyde, and fetuin-a. Compared with baseline, all patients had improved global longitudinal strain (median values: -17.7% versus -19.5%), LV twisting (12.4 degrees versus 14 degrees ), %untwMVO (27.8% versus 35%), and coronary flow reserve (2.8 versus 3.1) and reduced circulating NT-proBNP, IL-17, TNF alpha, and IL-6 post-treatment (P<0.05). Compared with anti-TNF-alpha and cyclosporine, anti-IL-12/23 treatment resulted in a greater improvement of global longitudinal strain (25% versus 17% versus 6%,), LV twist (27% versus 17% versus 1%), %untwMVO (31% versus 27% versus 17%), and coronary flow reserve (14% versus 11% versus 4%), as well as a greater reduction of IL-12 (-25% versus -4% versus 2%), malondialdehyde (-27% versus +5% versus +26%), and NT-proBNP(-26% versus 13.6% versus 9.1%) and increase of fetuin-a (P<0.01). Pulse wave velocity and augmentation index were improved only after anti-IL-12/23 treatment and correlated with changes in global longitudinal strain, LV twisting-untwisting (P<0.05). CONCLUSIONS: In psoriasis, IL-12/23 inhibition results in a greater improvement of coronary, arterial, and myocardial function than TNF-alpha inhibition or cyclosporine treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02144857. PMID- 28899949 TI - The future: genetics advances in MEN1 therapeutic approaches and management strategies. AB - The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come. PMID- 28899954 TI - Differentiating the QRS Morphology of Posterior Fascicular Ventricular Tachycardia From Right Bundle Branch Block and Left Anterior Hemiblock Aberrancy. AB - BACKGROUND: Left posterior fascicular ventricular tachycardia (LPF-VT) is frequently misdiagnosed as supraventricular tachycardia with aberrant right bundle branch block (RBBB) and left anterior hemiblock (LAHB). The purpose of the present study was to define the morphological ECG characteristics of LPF-VT and attempt to differentiate it from RBBB and LAHB aberrancy. METHODS AND RESULTS: A systematic Medline search was used to identify or locate ECG tracings from patients with LPF-VTs. ECGs with LPF-VT were also collected from patients who underwent ablation of this arrhythmia at the Tel Aviv and Sheba Medical Centers. These ECGs were compared with ECGs of consecutive patients with RBBB and LAHB and no obvious cardiac pathology by echocardiography. Overall, 183 ECGs of LPF-VT were compared with 61 ECGs showing RBBB and LAHB. Univariate analysis demonstrated differences in QRS axis, limb (I, aVr), and precordial (V1, V2, V6) ECG leads. On multivariate logistic regression analysis, LPF-VT was more often associated with atypical RBBB-like V1 morphology (odds ratio, 5.1; P=0.004), positive QRS in aVr (odds ratio, 19.2; P<0.001), V6 R/S ratio <=1 (odds ratio, 6.7; P=0.01), and QRS <=140 ms (odds ratio, 7.7; P<0.001). Using these 4 variables, a prediction model was developed that predicted LPF-VT with sensitivity and specificity of 82.1% and 78.3%, respectively. Patients with 3 of 4 positive variables had high probability of having LPF-VT, whereas patients with <=1 positive variable always had RBBB plus LAHB. CONCLUSIONS: The morphological ECG characteristics of LPF-VT were defined, and a high accurate tool for correctly differentiating LPF-VT from RBBB and LAHB aberrancy was developed. PMID- 28899955 TI - Natural History and Clinical Predictors of Atrial Tachycardia in Adults With Congenital Heart Disease. AB - BACKGROUND: Atrial tachycardias (ATs) are a significant source of morbidity in adults with congenital heart disease (CHD). This study evaluates the incidence and clinical predictors of AT in a cohort of patients with CHD. METHODS AND RESULTS: We included 3311 adults (median age at entry 22.6 years, 50.6% males) with CHD (49% simple, 39% moderate, and 12% complex) prospectively followed up in a tertiary center for 37 607 person-years. Predictors of AT were identified by multivariable Cox regression analysis accounting for left truncation. An external validation was performed in a contemporary cohort of 1432 patients. Overall, 153 (4.6%) patients presented AT. AT burden was highest in complex CHD, such as single ventricle (22.8%) and d-transposition of the great arteries (22.1%). Hazard rates of AT across lifetime, age at presentation, and the time lapse between surgery and the first AT episode varied among the most common CHD. Independent risk factors for developing AT were univentricular physiology, previous intracardiac repair, systemic right ventricle, pulmonary hypertension, pulmonary regurgitation, pulmonary atrioventricular valve regurgitation, pulmonary and systemic ventricular dysfunction. At the age of 40 years, AT-free survival in patients with 0, 1, 2, and >=3 risk factors was 100%, 94%, 76%, and 50%, respectively. These findings were confirmed in the validation cohort. CONCLUSIONS: Natural history of AT differed among the most common forms of CHD. Simple clinical parameters, easily obtained by noninvasive means, were independent predictors of AT in adults with CHD. Although risk was negligible in patients without any of these factors, their addition progressively increased AT burden. PMID- 28899956 TI - Atrial Tachyarrhythmia in Congenital Heart Disease: Beyond the Suture Lines. PMID- 28899957 TI - Electrocardiographic Findings of Fascicular Ventricular Tachycardia Versus Supraventricular Tachycardia With Aberrancy: Why the Difference? PMID- 28899958 TI - Serotonin transporter binding and anxiety symptoms in Parkinson's disease. AB - BACKGROUND: Anxiety is a common neuropsychiatric symptom in Parkinson's disease (PD), yet the neural mechanisms have been scarcely investigated. Disturbances in dopaminergic and serotonergic signalling may play a role in its pathophysiology. 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (123I FP-CIT) is a single-photon emission CT radiotracer, and its binding in striatal and extrastriatal subcortical brain areas represents predominant binding to the presynaptic dopamine transporter (DAT) and the serotonin transporter (SERT), respectively. Availability of DAT and SERT may thus provide an in vivo measure for the integrity of both dopamine and serotonin neurons. METHODS: We studied the association between anxiety symptoms, measured with an affective subscale of the Beck Anxiety Inventory, and (extra)striatal 123I-FP-CIT binding in 127 non demented patients with PD with a median disease duration of 2.55 (IQR 2.90) years. We conducted the analyses on patients currently on or not on dopamine replacement therapy (DRT). RESULTS: Severity of anxiety symptoms showed a significant negative association with 123I-FP-CIT binding ratios in the right thalamus (beta=-0.203, p=0.019; DeltaR2=0.040) (multiple testing pcorr <0.020). In the subgroup of patients not on DRT (n=81), we found a significant negative association between anxiety and thalamic 123I-FP-CIT binding ratios bilaterally (right: beta=-0.349, p=0.001, DeltaR2=0.119; left: beta=-0.269, p=0.017, DeltaR2=0.071) (pcorr <0.020). CONCLUSION: This study shows that higher levels of anxiety in patients with PD are associated with lower thalamic 123I-FP-CIT binding, pointing towards a contribution of serotonergic degeneration to anxiety symptoms in PD. PMID- 28899959 TI - Impaired Malate and Fumarate Accumulation Due to the Mutation of the Tonoplast Dicarboxylate Transporter Has Little Effects on Stomatal Behavior. AB - Malate is a central metabolite involved in a multiplicity of plant metabolic pathways, being associated with mitochondrial metabolism and playing significant roles in stomatal movements. Vacuolar malate transport has been characterized at the molecular level and is performed by at least one carrier protein and two channels in Arabidopsis (Arabidopsis thaliana) vacuoles. The absence of the Arabidopsis tonoplast Dicarboxylate Transporter (tDT) in the tdt knockout mutant was associated previously with an impaired accumulation of malate and fumarate in leaves. Here, we investigated the consequences of this lower accumulation on stomatal behavior and photosynthetic capacity as well as its putative metabolic impacts. Neither the stomatal conductance nor the kinetic responses to dark, light, or high CO2 were highly affected in tdt plants. In addition, we did not observe any impact on stomatal aperture following incubation with abscisic acid, malate, or citrate. Furthermore, an effect on photosynthetic capacity was not observed in the mutant lines. However, leaf mitochondrial metabolism was affected in the tdt plants. Levels of the intermediates of the tricarboxylic acid cycle were altered, and increases in both light and dark respiration were observed. We conclude that manipulation of the tonoplastic organic acid transporter impacted mitochondrial metabolism, while the overall stomatal and photosynthetic capacity were unaffected. PMID- 28899960 TI - Overexpression of RING Domain E3 Ligase ZmXerico1 Confers Drought Tolerance through Regulation of ABA Homeostasis. AB - Drought stress is one of the main environmental problems encountered by crop growers. Reduction in arable land area and reduced water availability make it paramount to identify and develop strategies to allow crops to be more resilient in water-limiting environments. The plant hormone abscisic acid (ABA) plays an important role in the plants' response to drought stress through its control of stomatal aperture and water transpiration, and transgenic modulation of ABA levels therefore represents an attractive avenue to improve the drought tolerance of crops. Several steps in the ABA-signaling pathway are controlled by ubiquitination involving really interesting new genes (RING) domain-containing proteins. We characterized the maize (Zea mays) RING protein family and identified two novel RING-H2 genes called ZmXerico1 and ZmXerico2 Expression of ZmXerico genes is induced by drought stress, and we show that overexpression of ZmXerico1 and ZmXerico2 in Arabidopsis and maize confers ABA hypersensitivity and improved water use efficiency, which can lead to enhanced maize yield performance in a controlled drought-stress environment. Overexpression of ZmXerico1 and ZmXerico2 in maize results in increased ABA levels and decreased levels of ABA degradation products diphaseic acid and phaseic acid. We show that ZmXerico1 is localized in the endoplasmic reticulum, where ABA 8'-hydroxylases have been shown to be localized, and that it functions as an E3 ubiquitin ligase. We demonstrate that ZmXerico1 plays a role in the control of ABA homeostasis through regulation of ABA 8'-hydroxylase protein stability, representing a novel control point in the regulation of the ABA pathway. PMID- 28899961 TI - Abscisic Acid Down-Regulates Hydraulic Conductance of Grapevine Leaves in Isohydric Genotypes Only. AB - Plants evolved different strategies to cope with water stress. While isohydric species maintain their midday leaf water potential (PsiM) under soil water deficit by closing their stomata, anisohydric species maintain higher stomatal aperture and exhibit substantial reductions in PsiM It was hypothesized that isohydry is related to a locally higher sensitivity of stomata to the drought hormone abscisic acid (ABA). Interestingly, recent lines of evidence in Arabidopsis (Arabidopsis thaliana) suggested that stomatal responsiveness is also controlled by an ABA action on leaf water supply upstream from stomata. Here, we tested the possibility in grapevine (Vitis vinifera) that different genotypes ranging from near isohydric to more anisohydric may have different sensitivities in these ABA responses. Measurements on whole plants in drought conditions were combined with assays on detached leaves fed with ABA. Two different methods consistently showed that leaf hydraulic conductance (Kleaf) was down-regulated by exogenous ABA, with strong variations depending on the genotype. Importantly, variation between isohydry and anisohydry correlated with Kleaf sensitivity to ABA, with Kleaf in the most anisohydric genotypes being unresponsive to the hormone. We propose that the observed response of Kleaf to ABA may be part of the overall ABA regulation of leaf water status. PMID- 28899962 TI - Pollen Aperture Factor INP1 Acts Late in Aperture Formation by Excluding Specific Membrane Domains from Exine Deposition. AB - Accurate placement of extracellular materials is a critical part of cellular development. To study how cells achieve this accuracy, we use formation of pollen apertures as a model. In Arabidopsis (Arabidopsis thaliana), three regions on the pollen surface lack deposition of pollen wall exine and develop into apertures. In developing pollen, Arabidopsis INAPERTURATE POLLEN1 (INP1) protein acts as a marker for the preaperture domains, assembling there into three punctate lines. To understand the mechanism of aperture formation, we studied the dynamics of INP1 expression and localization and its relationship with the membrane domains at which it assembles. We found that INP1 assembly occurs after meiotic cytokinesis at the interface between the plasma membrane and the overlying callose wall, and requires the normal callose wall formation. Sites of INP1 localization coincide with positions of protruding membrane ridges in proximity to the callose wall. Our data suggest that INP1 is a late-acting factor involved in keeping specific membrane domains next to the callose wall to prevent formation of exine at these sites. PMID- 28899964 TI - The Deepwater Horizon Oil Spill Coast Guard Cohort study. AB - OBJECTIVES: Long-term studies of oil spill responders are urgently needed as oil spills continue to occur. To this end, we established the prospective Deepwater Horizon (DWH) Oil Spill Coast Guard Cohort study. METHODS: DWH oil spill responders (n=8696) and non-responders (n=44 823) who were members of the US Coast Guard (20 April-17 December 2010) were included. This cohort uses both prospective, objective health data from military medical encounters and cross sectional survey data. Here, we describe the cohort, present adjusted prevalence ratios (PRs) estimating cross-sectional associations between crude oil exposure (none, low/medium, high) and acute physical symptoms, and present adjusted relative risks (RRs) based on longitudinal medical encounter data (2010-2012) for responders/non-responders and responders exposed/not exposed to crude oil. RESULTS: Responders and non-responders in this large cohort (n=53 519) have similar characteristics. Crude oil exposure was reported by >50% of responders. We found statistically significant associations for crude oil exposure with coughing (PRhigh=1.78), shortness of breath (PRhigh=2.30), wheezing (PRhigh=2.32), headaches (PRhigh=1.46), light-headedness/dizziness (PRhigh=1.96), skin rash/itching (PRhigh=1.87), diarrhoea (PRhigh=1.76), stomach pain (PRhigh=1.67), nausea/vomiting (PRhigh=1.48) and painful/burning urination (PRhigh=2.89) during deployment. Longitudinal analyses revealed that responders had elevated RRs for dermal conditions (RR=1.09), as did oil-exposed responders for chronic respiratory conditions (RR=1.32), asthma (RR=1.83) and dermal conditions (RR=1.21). CONCLUSIONS: We found positive associations between crude oil exposure and various acute physical symptoms among responders, as well as longer term health effects. This cohort is well positioned to evaluate both short term and long-term effects of oil spill exposures using both self-reported and clinical health data. PMID- 28899963 TI - S5H/DMR6 Encodes a Salicylic Acid 5-Hydroxylase That Fine-Tunes Salicylic Acid Homeostasis. AB - The phytohormone salicylic acid (SA) plays essential roles in biotic and abiotic responses, plant development, and leaf senescence. 2,5-Dihydroxybenzoic acid (2,5 DHBA or gentisic acid) is one of the most commonly occurring aromatic acids in green plants and is assumed to be generated from SA, but the enzymes involved in its production remain obscure. DMR6 (Downy Mildew Resistant6; At5g24530) has been proven essential in plant immunity of Arabidopsis (Arabidopsis thaliana), but its biochemical properties are not well understood. Here, we report the discovery and functional characterization of DMR6 as a salicylic acid 5-hydroxylase (S5H) that catalyzes the formation of 2,5-DHBA by hydroxylating SA at the C5 position of its phenyl ring in Arabidopsis. S5H/DMR6 specifically converts SA to 2,5-DHBA in vitro and displays higher catalytic efficiency (Kcat/Km = 4.96 * 104 m-1 s-1) than the previously reported S3H (Kcat/Km = 6.09 * 103 m-1 s-1) for SA. Interestingly, S5H/DMR6 displays a substrate inhibition property that may enable automatic control of its enzyme activities. The s5h mutant and s5hs3h double mutant overaccumulate SA and display phenotypes such as a smaller growth size, early senescence, and a loss of susceptibility to Pseudomonas syringae pv tomato DC3000. S5H/DMR6 is sensitively induced by SA/pathogen treatment and is expressed widely from young seedlings to senescing plants, whereas S3H is more specifically expressed at the mature and senescing stages. Collectively, our results disclose the identity of the enzyme required for 2,5-DHBA formation and reveal a mechanism by which plants fine-tune SA homeostasis by mediating SA 5-hydroxylation. PMID- 28899965 TI - Economic evaluation of occupational health services: necessary, challenging and promising. PMID- 28899966 TI - Factors associated with work productivity among people with COPD: Birmingham COPD Cohort. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are more likely to take time off work (absenteeism) and report poor performance at work (presenteeism) compared to those without COPD. Little is known about the modifiable factors associated with these work productivity outcomes. AIM: To assess the factors associated with work productivity among COPD patients. METHODS: Cross-sectional analysis of baseline data from a subsample (those in paid employment) of the Birmingham COPD Cohort study. Absenteeism was defined by self-report over the previous 12 months. Presenteeism was assessed using the Stanford Presenteeism Scale. Logistic regression analysis was used to assess the effects of sociodemographic, clinical and occupational characteristics on work productivity. RESULTS: Among 348 included participants, increasing dyspnoea was the only factor associated with both absenteeism and presenteeism (p for trend<0.01). Additionally, increasing history of occupational exposure to vapours, gases, dusts or fumes (VGDF) was independently associated with presenteeism (p for trend<0.01). CONCLUSIONS: This is the first study to identify important factors associated with poor work productivity among patients with COPD. Future studies should evaluate interventions aimed at managing breathlessness and reducing occupational exposures to VGDF on work productivity among patients with COPD. PMID- 28899967 TI - Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping, and Monitoring. AB - Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making.Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome.Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy.Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856-62. (c)2017 AACR. PMID- 28899968 TI - Multispectral Optoacoustic Tomography (MSOT) of Human Breast Cancer. AB - Purpose: In a pilot study, we introduce fast handheld multispectral optoacoustic tomography (MSOT) of the breast at 28 wavelengths, aiming to identify high resolution optoacoustic (photoacoustic) patterns of breast cancer and noncancerous breast tissue.Experimental Design: We imaged 10 female patients ages 48-81 years with malignant nonspecific breast cancer or invasive lobular carcinoma. Three healthy volunteers ages 31-36 years were also imaged. Fast-MSOT was based on unique single-frame-per-pulse (SFPP) image acquisition employed to improve the accuracy of spectral differentiation over using a small number of wavelengths. Breast tissue was illuminated at the 700-970 nm spectral range over 0.56 seconds total scan time. MSOT data were guided by ultrasonography and X-ray mammography or MRI.Results: The extended spectral range allowed the computation of oxygenated hemoglobin (HBO2), deoxygenated hemoglobin (HB), total blood volume (TBV), lipid, and water contributions, allowing first insights into in vivo high resolution breast tissue MSOT cancer patterns. TBV and Hb/HBO2 images resolved marked differences between cancer and control tissue, manifested as a vessel-rich tumor periphery with highly heterogeneous spatial appearance compared with healthy tissue. We observe significant TBV variations between different tumors and between tumors over healthy tissues. Water and fat lipid layers appear disrupted in cancer versus healthy tissue; however, offer weaker contrast compared with TBV images.Conclusions: In contrast to optical methods, MSOT resolves physiologic cancer features with high resolution and revealed patterns not offered by other radiologic modalities. The new features relate to personalized and precision medicine potential. Clin Cancer Res; 23(22); 6912-22. (c)2017 AACR. PMID- 28899969 TI - TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression. AB - Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation.Experimental Design: Combination of (i) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) in vivo studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples.Results: TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur.Conclusions: Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease. Clin Cancer Res; 23(23); 7324-32. (c)2017 AACR. PMID- 28899970 TI - Targeting Prostate Cancer Subtype 1 by Forkhead Box M1 Pathway Inhibition. AB - Purpose: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype, with no treatment options available in the clinic.Experimental Design: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1. The findings were evaluated in vitro and in the ENZR CRPC xenograft model in vivoResults: The results revealed that ENZR CRPC cells are enriched with PCS1 signature and that Forkhead box M1 (FOXM1) pathway is the central driver of this subtype. Notably, we identified Monensin as a novel FOXM1-binding agent that selectively targets FOXM1 to reverse the PCS1 signature and its associated stem-like features and reduces the growth of ENZR CRPC cells and xenograft tumors.Conclusions: Our preclinical data indicate FOXM1 pathway as a master regulator of PCS1 tumors, namely in ENZR CRPC, and targeting FOXM1 reduces cell growth and stemness in ENZR CRPC in vitro and in vivo These preclinical results may guide clinical evaluation of targeting FOXM1 to eradicate highly aggressive and lethal PCS1 prostate cancer tumors. Clin Cancer Res; 23(22); 6923-33. (c)2017 AACR. PMID- 28899971 TI - Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma. AB - Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301-11. (c)2017 AACR. PMID- 28899972 TI - Immunotherapy of Lymphoma and Myeloma: Facts and Hopes. AB - Immune checkpoint blockade has driven a revolution in modern oncology, and robust drug development of immune checkpoint inhibitors is underway in both solid tumors and hematologic malignancies. High response rates to programmed cell death 1 (PD 1) blockade using nivolumab or pembrolizumab in classical Hodgkin lymphoma (cHL) and several variants of non-Hodgkin lymphoma (NHL) revealed an intrinsic biological sensitivity to this approach, and work is ongoing exploring combinations with immune checkpoint inhibitors in both cHL and NHL. There are also preliminary data suggesting antitumor efficacy of PD-1 inhibitors used in combination with immunomodulatory drugs in multiple myeloma, and effects of novel monoclonal antibody therapies on the tumor microenvironment may lead to synergy with checkpoint blockade. Although immune checkpoint inhibitors are generally well tolerated, clinicians must use caution and remain vigilant when treating patients with these agents in order to identify immune-related toxicities and prevent treatment-related morbidity and mortality. Autologous stem cell transplant is a useful tool for treatment of hematologic malignancies and has potential as a platform for use of immune checkpoint inhibitors. An important safety signal has emerged surrounding the risk of graft-versus-host disease associated with use of PD-1 inhibitors before and after allogeneic stem cell transplant. We aim to discuss the facts known to date in the use of immune checkpoint inhibitors for patients with lymphoid malignancies and our hopes for expanding the benefits of immunotherapy to patients in the future. Clin Cancer Res; 24(5); 1002-10. (c)2017 AACR. PMID- 28899974 TI - Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance. AB - Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPV-negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P = 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV+, HPV-/p53wt, HPV /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV+, 16.3% for HPV-/p53wt and 22.6% for HPV /p53abn tumors (P = 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P = 0.020).Conclusions: HPV- and HPV+ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV-/p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV+ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC. Clin Cancer Res; 23(22); 6781-9. (c)2017 AACR. PMID- 28899973 TI - TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup. AB - Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines.Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. (c)2017 AACR. PMID- 28899975 TI - Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo. AB - Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (*5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130-40. (c)2017 AACR. PMID- 28899978 TI - New chapter in tackling antimicrobial resistance in Thailand. PMID- 28899976 TI - Core Concept: Human artificial chromosomes offer insights, therapeutic possibilities, and challenges. PMID- 28899979 TI - Clinical performance evaluation of the Idylla NRAS-BRAF mutation test on retrospectively collected formalin-fixed paraffin-embedded colorectal cancer tissue. AB - AIMS: Understanding the molecular mechanisms of underlying disease has led to a movement away from the one-drug-fits-all paradigm towards treatment tailored to the genetic profile of the patient. The Biocartis Idylla platform is a novel fully automated, real-time PCR-based in vitro diagnostic system. The Idylla NRAS BRAF mutation test has been developed for the qualitative detection of mutations in NRAS and BRAF oncogenes, facilitating genetic profiling of patients with cancer. The aim of this study was to carry out a formal clinical performance evaluation. METHODS: Two-hundred and forty-two formalin-fixed paraffin-embedded (FFPE) human malignant colorectal cancer (CRC) tissue samples were identified in departmental archives and tested with both the Idylla NRAS-BRAF mutation test and the Agena Bioscience MassARRAY test. RESULTS: The overall concordance between the Idylla NRAS-BRAF mutation test and the MassARRAY comparator reference test result was 241/242 (99.59%, lower bound of one-sided 95% CI=98.1%) for NRAS and 242/242 (lower bound of 95% one-sided 95% CI=98.89%) for BRAF. The Idylla NRAS-BRAF test detected one NRAS mutation that had not been reported by the MassARRAY comparator reference test. Reanalysis of this sample by droplet digital PCR confirmed that the mutation was present, but at an allelic frequency below the stated sensitivity level of the MassARRAY system. CONCLUSION: These results confirm that the Idylla NRAS-BRAF mutation test has high concordance with a widely used NRAS BRAF test, and is therefore suitable for use as an in vitro diagnostic device for this application. PMID- 28899980 TI - Standardisation of practice for Canadian pathologists' assistants. PMID- 28899982 TI - CORRECTION. PMID- 28899981 TI - Evidence for a Role of ANAC082 as a Ribosomal Stress Response Mediator Leading to Growth Defects and Developmental Alterations in Arabidopsis. AB - Ribosome-related mutants in Arabidopsis thaliana share several notable characteristics regarding growth and development, which implies the existence of a common pathway that responds to disorders in ribosome biogenesis. As a first step to explore this pathway genetically, we screened a mutagenized population of root initiation defective2 (rid2), a temperature-sensitive mutant that is impaired in pre-rRNA processing, and isolated suppressor of root initiation defective two1 (sriw1), a suppressor mutant in which the defects of cell proliferation observed in rid2 at the restrictive temperature was markedly rescued. sriw1 was identified as a missense mutation of the NAC transcription factor gene ANAC082 The sriw1 mutation greatly alleviated the developmental abnormalities of rid2 and four other tested ribosome-related mutants, including rid3 However, the impaired pre-rRNA processing in rid2 and rid3 was not relieved by sriw1 Expression of ANAC082 was localized to regions where phenotypic effects of ribosome-related mutations are readily evident and was elevated in rid2 and rid3 compared with the wild type. These findings suggest that ANAC082 acts downstream of perturbation of biogenesis of the ribosome and may mediate a set of stress responses leading to developmental alterations and cell proliferation defects. PMID- 28899984 TI - Non-invasive diagnosis of hepatocellular carcinoma revisited. PMID- 28899983 TI - Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection. AB - BACKGROUND AND AIMS: HBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells. METHODS: Monocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining. RESULTS: In chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-beta, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-beta expression via the MyD88/NFkappaB signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation. CONCLUSIONS: Our findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition. PMID- 28899985 TI - Young woman with segmental colitis. PMID- 28899986 TI - Perioperative Spending on Spinal Fusion for Scoliosis for Children With Medical Complexity. AB - BACKGROUND: Global payment is used with surgeries to optimize health, lower costs, and improve quality. We assessed perioperative spending on spinal fusion for scoliosis to inform how this might apply to children. METHODS: Retrospective analysis of 1249 children using Medicaid and aged >=5 years with a complex chronic condition undergoing spinal fusion in 2013 from 12 states. From perioperative health services measured 6 months before and 3 months after spinal fusion, we simulated a spending reallocation with increased preoperative care and decreased hospital care. RESULTS: Perioperative spending was $112 353 per patient, with 77.9% for hospitalization, 12.3% for preoperative care, and 9.8% for postdischarge care. Primary care accounted for 0.2% of total spending; 15.4% and 49.2% of children had no primary care visit before and after spinal fusion, respectively. Compared with having no preoperative primary care visit, 1 to 2 visits were associated with a 12% lower surgery hospitalization cost (P = .05) and a 9% shorter length of stay (LOS) (P = .1); >=3 visits were associated with a 21% lower hospitalization cost (P < .001) and a 14% shorter LOS (P = .01). Having >=3 preoperative primary care visits for all children would increase total perioperative spending by 0.07%. This increased cost could be underwritten by a 0.1% reduction in hospital LOS or a 1.0% reduction in 90-day hospital readmissions. CONCLUSIONS: Hospital care accounted for most perioperative spending in children undergoing spinal fusion. Multiple preoperative primary care visits were associated with lower hospital costs and shorter hospitalizations. Modestly less hospital resource use could underwrite substantial increases in children's preoperative primary care. PMID- 28899987 TI - Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo. AB - BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific alpha myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or beta-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88+/-8% of contractile function versus 35+/-15% in littermate controls and 28+/-8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. CONCLUSIONS: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI. PMID- 28899989 TI - Dipeptidyl Peptidase-4 Inhibitors and Risk of Heart Failure in Patients With Type 2 Diabetes Mellitus: A Population-Based Cohort Study. AB - BACKGROUND: The association between dipeptidyl-peptidase IV inhibitors (DPP-4i) and heart failure (HF) remains unclear. In 1 randomized controlled trial and some observational studies, DPP-4i reportedly increased the risk of HF, but 2 other randomized controlled trials and observational studies have shown no such risk. Here, we evaluated the risk of HF and cardiovascular outcomes of DPP-4i compared with sulfonylureas. METHODS AND RESULTS: A population-based retrospective cohort study was conducted using the Korean Health Insurance Review and Assessment Service database from January 1, 2009, to December 31, 2015. Incident users of sulfonylurea and DPP-4i who were not prescribed the comparator drug in the year before treatment initiation were included. DPP-4i-treated and sulfonylurea treated patients were matched on propensity score, calculated with >40 variables. The risk of hospitalization for HF was evaluated with a Cox proportional hazards model in 255 691 matched pairs. Analyses were conducted in the total patient population and in both strata divided by the presence of cardiovascular disease during the baseline period. The hazard ratios (HRs) of hospitalization for HF for DPP-4i-treated patients were 0.78 (95% confidence interval [CI], 0.67-0.86) in all of the patients, 0.77 (95% CI, 0.68-0.79) in patients with baseline cardiovascular disease, and 0.71 (95% CI, 0.56-0.90) in patients without baseline cardiovascular disease compared with HRs for sulfonylurea-treated patients. Sitagliptin and linagliptin showed statistically lower risk for hospitalization for HF (HR, 0.76; 95% CI, 0.67-0.86 for sitagliptin-prescribed patients; HR, 0.74; 95% CI, 0.59-0.92 for linagliptin-prescribed patients) than for sulfonylurea. The HRs for hospitalization for myocardial infarction and stroke with the use of a DPP-4i versus sulfonylurea were HR, 0.76 (95% CI, 0.67-0.87) and HR, 0.63 (95% CI, 0.60-0.67), respectively. CONCLUSIONS: Our findings suggest that DPP-4i use did not increase the risk of HF compared with sulfonylurea. In addition, the risks for cardiovascular outcomes were not elevated in DPP-4i treated patients compared with sulfonylurea-treated patients. PMID- 28899988 TI - Impact of Incident Heart Failure on Body Composition Over Time in the Health, Aging, and Body Composition Study Population. AB - BACKGROUND: Prevalence of heart failure (HF) increases significantly with age, coinciding with age-related changes in body composition that are common and consequential. Still, body composition is rarely factored in routine HF care. METHODS AND RESULTS: The Health, Aging, and Body Composition study is a prospective cohort study of nondisabled adults. Using yearly dual-energy x-ray absorptiometry, body composition was assessed in the Health, Aging, and Body Composition study over 6 years, comparing those who developed incident HF versus those who did not. Among 2815 Health, Aging, and Body Composition participants (48.5% men; 59.6% whites; mean age, 73.6+/-2.9 years), 111 developed incident HF over the 6-year study period. At entry into the Health, Aging, and Body Composition study, men and women who later developed HF had higher total body mass when compared with those versus those who did not develop HF (men, 80.9+/-10 versus 78.6+/-12.9 kg, P=0.05; women, 72.7+/-15.0 versus 68.2+/-14.2 kg, P=0.01, respectively). However, after developing HF, loss of total lean body mass was disproportionate; men with HF lost 654.6 versus 391.4 g/y in non-HF participants, P=0.02. Loss of appendicular lean mass was also greater with HF (-419.9 versus 318.2 g/y; P=0.02), even after accounting for total weight change. Among women with HF, loss of total and appendicular lean mass were also greater than in non HF participants but not to the extent seen among men. CONCLUSIONS: Incident HF in older adults was associated with disproportionate loss of lean mass, particularly among men. Prognostic implications are significant, with key sex-specific inferences on physical function, frailty, disability, and pharmacodynamics that all merit further investigation. PMID- 28899990 TI - Generalist physicians' challenges in understanding specialists' clinic notes. PMID- 28899992 TI - Depletion of Progranulin Reduces GluN2B-Containing NMDA Receptor Density, Tau Phosphorylation, and Dendritic Arborization in Mouse Primary Cortical Neurons. AB - Loss-of-function mutations in the progranulin (PGRN) gene are a common cause of familial frontotemporal lobar degeneration (FTLD). This age-related neurodegenerative disorder, characterized by brain atrophy in the frontal and temporal lobes and such typical symptoms as cognitive and memory impairment, profound behavioral abnormalities, and personality changes is thought to be related to connectome dysfunctions. Recently, PGRN reduction has been found to induce a behavioral phenotype reminiscent of FTLD symptoms in mice by affecting neuron spine density and morphology, suggesting that the protein can influence neuronal structural plasticity. Here, we evaluated whether a partial haploinsufficiency-like PGRN depletion, achieved by using RNA interference in primary mouse cortical neurons, could modulate GluN2B-containing N-methyl-d aspartate (NMDA) receptors and tau phosphorylation, which are crucially involved in the regulation of the structural plasticity of these cells. In addition, we studied the effect of PGRN decrease on neuronal cell arborization both in the presence and absence of GluN2B-containing NMDA receptor stimulation. We found that PGRN decline diminished GluN2B-containing NMDA receptor levels and density as well as NMDA-dependent tau phosphorylation. These alterations were accompanied by a marked drop in neuronal arborization that was prevented by an acute GluN2B containing NMDA receptor stimulation. Our findings support that PGRN decrease, resulting from pathogenic mutations, might compromise the trophism of cortical neurons by affecting GluN2B-contaning NMDA receptors. These mechanisms might be implicated in the pathogenesis of FTLD. PMID- 28899991 TI - Infographic: Consensus statement on concussion in sport. PMID- 28899993 TI - Sixty seconds on . . . upselling. PMID- 28899994 TI - Heterodimeric capping protein is required for stereocilia length and width regulation. AB - Control of the dimensions of actin-rich processes like filopodia, lamellipodia, microvilli, and stereocilia requires the coordinated activity of many proteins. Each of these actin structures relies on heterodimeric capping protein (CAPZ), which blocks actin polymerization at barbed ends. Because dimension control of the inner ear's stereocilia is particularly precise, we studied the CAPZB subunit in hair cells. CAPZB, present at ~100 copies per stereocilium, concentrated at stereocilia tips as hair cell development progressed, similar to the CAPZB interacting protein TWF2. We deleted Capzb specifically in hair cells using Atoh1 Cre, which eliminated auditory and vestibular function. Capzb-null stereocilia initially developed normally but later shortened and disappeared; surprisingly, stereocilia width decreased concomitantly with length. CAPZB2 expressed by in utero electroporation prevented normal elongation of vestibular stereocilia and irregularly widened them. Together, these results suggest that capping protein participates in stereocilia widening by preventing newly elongating actin filaments from depolymerizing. PMID- 28899995 TI - HIV seroconversion among Baltimore City residents tested at a mobile van programme. AB - BACKGROUND: Many individuals with HIV in the USA are unaware of their diagnosis, and therefore cannot be engaged in treatment services, have worse clinical outcomes and are more likely to transmit HIV to others. Mobile van testing may increase HIV testing and diagnosis. Our objective was to characterise risk factors for HIV seroconversion among individuals using mobile van testing. METHODS: A case cohort study (n=543) was conducted within an HIV surveillance dataset of mobile van testing users with at least two HIV tests between September 2004 and August 2009 in Baltimore, Maryland. A subcohort (n=423) was randomly selected; all additional cases were added from the parent cohort. Cases (n=122 total, two from random subcohort) had documented seroconversion at the follow-up visit. A unique aspect of the analysis was use of Department of Corrections data to document incarceration between the times of initial and subsequent testing. Multivariate Cox proportional hazards models were used to compare HIV transmission risk factors between individuals who seroconverted and those who did not. RESULTS: One hundred and twenty-two HIV seroconversions occurred among 8756 individuals (1.4%), a rate higher than that in Baltimore City Health Department's STD Clinic clients (1%). Increased HIV seroconversion risk was associated with men who have sex with men (MSM) (HR 32.76, 95% CI 5.62 to 191.12), sex with an HIV positive partner (HR 70.2, 95% CI 9.58 to 514.89), and intravenous drug use (IDU) (HR 5.65, 95% CI 2.41 to 13.23). CONCLUSIONS: HIV testing is a crucial first step in the HIV care continuum and an important HIV prevention tool. This study confirmed the need to reach high-risk populations (MSM, sex with HIV positive individuals, individuals with IDU) and to increase comprehensive prevention services so that high-risk individuals stay HIV uninfected. HIV testing in mobile vans may be an effective outreach strategy for identifying infection in certain populations at high risk for HIV. PMID- 28899996 TI - Prediction and Subtyping of Hypertension from Pan-Tissue Transcriptomic and Genetic Analyses. AB - Hypertension (HT) is a complex systemic disease involving transcriptional changes in multiple organs. Here we systematically investigate the pan-tissue transcriptional and genetic landscape of HT spanning dozens of tissues in hundreds of individuals. We find that in several tissues, previously identified HT-linked genes are dysregulated and the gene expression profile is predictive of HT. Importantly, many expression quantitative trait loci (eQTL) SNPs associated with the population variance of the dysregulated genes are linked with blood pressure in an independent genome-wide association study, suggesting that the functional effect of HT-associated SNPs may be mediated through tissue-specific transcriptional dysregulation. Analyses of pan-tissue transcriptional dysregulation profile, as well as eQTL SNPs underlying the dysregulated genes, reveals substantial heterogeneity among the HT patients, revealing two broad groupings - a Diffused group where several tissues exhibit HT-associated molecular alterations and a Localized group where such alterations are localized to very few tissues. These two patient subgroups differ in several clinical phenotypes including respiratory, cerebrovascular, diabetes, and heart disease. These findings suggest that the Diffused and Localized subgroups may be driven by different molecular mechanisms and have different genetic underpinning. PMID- 28899997 TI - Improving Disease Prediction by Incorporating Family Disease History in Risk Prediction Models with Large-Scale Genetic Data. AB - Despite the many successes of genome-wide association studies (GWAS), the known susceptibility variants identified by GWAS have modest effect sizes, leading to notable skepticism about the effectiveness of building a risk prediction model from large-scale genetic data. However, in contrast to genetic variants, the family history of diseases has been largely accepted as an important risk factor in clinical diagnosis and risk prediction. Nevertheless, the complicated structures of the family history of diseases have limited their application in clinical practice. Here, we developed a new method that enables incorporation of the general family history of diseases with a liability threshold model, and propose a new analysis strategy for risk prediction with penalized regression analysis that incorporates both large numbers of genetic variants and clinical risk factors. Application of our model to type 2 diabetes in the Korean population (1846 cases and 1846 controls) demonstrated that single-nucleotide polymorphisms accounted for 32.5% of the variation explained by the predicted risk scores in the test data set, and incorporation of family history led to an additional 6.3% improvement in prediction. Our results illustrate that family medical history provides valuable information on the variation of complex diseases and improves prediction performance. PMID- 28899998 TI - Correction for Wang et al., "Nucleophosmin, a Critical Bax Cofactor in Ischemia Induced Cell Death". PMID- 28899999 TI - Correction for Bagarova et al., "Constitutively Active ALK2 Receptor Mutants Require Type II Receptor Cooperation". PMID- 28900000 TI - Correction for Lecona et al., "USP7 Cooperates with SCML2 To Regulate the Activity of PRC1". PMID- 28900001 TI - Samd7 is a cell type-specific PRC1 component essential for establishing retinal rod photoreceptor identity. AB - Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity. PMID- 28900002 TI - Modeling Parkinson's disease pathology by combination of fibril seeds and alpha synuclein overexpression in the rat brain. AB - Although a causative role of alpha-synuclein (alpha-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human alpha-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human alpha-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human alpha-syn fibrils to trigger Lewy-like alpha-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human alpha-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like alpha-syn aggregates. alpha-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated alpha-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of alpha-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies. PMID- 28900003 TI - Local optical control of ferromagnetism and chemical potential in a topological insulator. AB - Many proposed experiments involving topological insulators (TIs) require spatial control over time-reversal symmetry and chemical potential. We demonstrate reconfigurable micron-scale optical control of both magnetization (which breaks time-reversal symmetry) and chemical potential in ferromagnetic thin films of Cr (Bi,Sb)2Te3 grown on SrTiO3 By optically modulating the coercivity of the films, we write and erase arbitrary patterns in their remanent magnetization, which we then image with Kerr microscopy. Additionally, by optically manipulating a space charge layer in the underlying SrTiO3 substrates, we control the local chemical potential of the films. This optical gating effect allows us to write and erase p n junctions in the films, which we study with photocurrent microscopy. Both effects are persistent and may be patterned and imaged independently on a few micron scale. Dynamic optical control over both magnetization and chemical potential of a TI may be useful in efforts to understand and control the edge states predicted at magnetic domain walls in quantum anomalous Hall insulators. PMID- 28900004 TI - Network of microbial and antibiotic interactions drive colonization and infection with multidrug-resistant organisms. AB - The emergence and spread of multidrug-resistant organisms (MDROs) across global healthcare networks poses a serious threat to hospitalized individuals. Strategies to limit the emergence and spread of MDROs include oversight to decrease selective pressure for MDROs by promoting appropriate antibiotic use via antibiotic stewardship programs. However, restricting the use of one antibiotic often requires a compensatory increase in the use of other antibiotics, which in turn selects for the emergence of different MDRO species. Further, the downstream effects of antibiotic treatment decisions may also be influenced by functional interactions among different MDRO species, with the potential clinical implications of such interactions remaining largely unexplored. Here, we attempt to decipher the influence network between antibiotic treatment, MDRO colonization, and infection by leveraging active surveillance and antibiotic treatment data for 234 nursing home residents. Our analysis revealed a complex network of interactions: antibiotic use was a risk factor for primary MDRO colonization, which in turn increased the likelihood of colonization and infection by other MDROs. When we focused on the risk of catheter-associated urinary tract infections (CAUTI) caused by Escherichia coli, Enterococcus, and Staphylococcus aureus we observed that cocolonization with specific pairs of MDROs increased the risk of CAUTI, signifying the involvement of microbial interactions in CAUTI pathogenesis. In summary, our work demonstrates the existence of an underappreciated healthcare-associated ecosystem and strongly suggests that effective control of overall MDRO burden will require stewardship interventions that take into account both primary and secondary impacts of antibiotic treatments. PMID- 28900006 TI - From understanding of color perception to dynamical systems by manifold learning. PMID- 28900005 TI - Shocking superantigens promote establishment of bacterial infection. PMID- 28900007 TI - E46K alpha-synuclein pathological mutation causes cell-autonomous toxicity without altering protein turnover or aggregation. AB - alpha-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as "synucleinopathies," but the mechanisms underlying this toxicity remain poorly understood. To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs. Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic. While E46K induced robust PLK2-dependent aSyn phosphorylation at serine 129, inhibiting this phosphorylation did not alleviate aSyn toxicity, strongly suggesting that this pathological hallmark of synucleinopathies is an epiphenomenon. Optical pulse-chase experiments with Dendra2-tagged aSyn versions indicated that the E46K mutation does not alter aSyn protein turnover. Moreover, since the mutation did not promote overt aSyn aggregation, we conclude that E46K toxicity was driven by soluble species. Finally, we developed an assay to assess whether neurons expressing E46K aSyn affect the survival of neighboring control neurons. Although we identified a minor non-cell-autonomous component spatially restricted to proximal neurons, most E46K aSyn toxicity was cell autonomous. Thus, we have been able to recapitulate the toxicity of soluble aSyn species at a stage preceding aggregation, detecting non-cell-autonomous toxicity and evaluating how some of the main aSyn hallmarks are related to neuronal survival. PMID- 28900009 TI - On the origin of shape fluctuations of the cell nucleus. AB - The nuclear envelope (NE) presents a physical boundary between the cytoplasm and the nucleoplasm, sandwiched in between two highly active systems inside the cell: cytoskeleton and chromatin. NE defines the shape and size of the cell nucleus, which increases during the cell cycle, accommodating for chromosome decondensation followed by genome duplication. In this work, we study nuclear shape fluctuations at short time scales of seconds in human cells. Using spinning disk confocal microscopy, we observe fast fluctuations of the NE, visualized by fluorescently labeled lamin A, and of the chromatin globule surface (CGS) underneath the NE, visualized by fluorescently labeled histone H2B. Our findings reveal that fluctuation amplitudes of both CGS and NE monotonously decrease during the cell cycle, serving as a reliable cell cycle stage indicator. Remarkably, we find that, while CGS and NE typically fluctuate in phase, they do exhibit localized regions of out-of-phase motion, which lead to separation of NE and CGS. To explore the mechanism behind these shape fluctuations, we use biochemical perturbations. We find the shape fluctuations of CGS and NE to be both thermally and actively driven, the latter caused by forces from chromatin and cytoskeleton. Such undulations might affect gene regulation as well as contribute to the anomalously high rates of nuclear transport by, e.g., stirring of molecules next to NE, or increasing flux of molecules through the nuclear pores. PMID- 28900008 TI - Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. AB - Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1-/- mice), Ly6Chigh monocytes (CCR2-/- mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2 induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2 induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies. PMID- 28900010 TI - Prior expectations induce prestimulus sensory templates. AB - Perception can be described as a process of inference, integrating bottom-up sensory inputs and top-down expectations. However, it is unclear how this process is neurally implemented. It has been proposed that expectations lead to prestimulus baseline increases in sensory neurons tuned to the expected stimulus, which in turn, affect the processing of subsequent stimuli. Recent fMRI studies have revealed stimulus-specific patterns of activation in sensory cortex as a result of expectation, but this method lacks the temporal resolution necessary to distinguish pre- from poststimulus processes. Here, we combined human magnetoencephalography (MEG) with multivariate decoding techniques to probe the representational content of neural signals in a time-resolved manner. We observed a representation of expected stimuli in the neural signal shortly before they were presented, showing that expectations indeed induce a preactivation of stimulus templates. The strength of these prestimulus expectation templates correlated with participants' behavioral improvement when the expected feature was task-relevant. These results suggest a mechanism for how predictive perception can be neurally implemented. PMID- 28900012 TI - Meta-analysis of field experiments shows no change in racial discrimination in hiring over time. AB - This study investigates change over time in the level of hiring discrimination in US labor markets. We perform a meta-analysis of every available field experiment of hiring discrimination against African Americans or Latinos (n = 28). Together, these studies represent 55,842 applications submitted for 26,326 positions. We focus on trends since 1989 (n = 24 studies), when field experiments became more common and improved methodologically. Since 1989, whites receive on average 36% more callbacks than African Americans, and 24% more callbacks than Latinos. We observe no change in the level of hiring discrimination against African Americans over the past 25 years, although we find modest evidence of a decline in discrimination against Latinos. Accounting for applicant education, applicant gender, study method, occupational groups, and local labor market conditions does little to alter this result. Contrary to claims of declining discrimination in American society, our estimates suggest that levels of discrimination remain largely unchanged, at least at the point of hire. PMID- 28900011 TI - Robust mechanobiological behavior emerges in heterogeneous myosin systems. AB - Biological complexity presents challenges for understanding natural phenomenon and engineering new technologies, particularly in systems with molecular heterogeneity. Such complexity is present in myosin motor protein systems, and computational modeling is essential for determining how collective myosin interactions produce emergent system behavior. We develop a computational approach for altering myosin isoform parameters and their collective organization, and support predictions with in vitro experiments of motility assays with alpha-actinins as molecular force sensors. The computational approach models variations in single myosin molecular structure, system organization, and force stimuli to predict system behavior for filament velocity, energy consumption, and robustness. Robustness is the range of forces where a filament is expected to have continuous velocity and depends on used myosin system energy. Myosin systems are shown to have highly nonlinear behavior across force conditions that may be exploited at a systems level by combining slow and fast myosin isoforms heterogeneously. Results suggest some heterogeneous systems have lower energy use near stall conditions and greater energy consumption when unloaded, therefore promoting robustness. These heterogeneous system capabilities are unique in comparison with homogenous systems and potentially advantageous for high performance bionanotechnologies. Findings open doors at the intersections of mechanics and biology, particularly for understanding and treating myosin-related diseases and developing approaches for motor molecule-based technologies. PMID- 28900013 TI - Optimal deployment of resources for maximizing impact in spreading processes. AB - The effective use of limited resources for controlling spreading processes on networks is of prime significance in diverse contexts, ranging from the identification of "influential spreaders" for maximizing information dissemination and targeted interventions in regulatory networks, to the development of mitigation policies for infectious diseases and financial contagion in economic systems. Solutions for these optimization tasks that are based purely on topological arguments are not fully satisfactory; in realistic settings, the problem is often characterized by heterogeneous interactions and requires interventions in a dynamic fashion over a finite time window via a restricted set of controllable nodes. The optimal distribution of available resources hence results from an interplay between network topology and spreading dynamics. We show how these problems can be addressed as particular instances of a universal analytical framework based on a scalable dynamic message-passing approach and demonstrate the efficacy of the method on a variety of real-world examples. PMID- 28900014 TI - Regulation of the cell cycle and centrosome biology by deubiquitylases. AB - Post-translational modification of proteins by ubiquitylation is increasingly recognised as a highly complex code that contributes to the regulation of diverse cellular processes. In humans, a family of almost 100 deubiquitylase enzymes (DUBs) are assigned to six subfamilies and many of these DUBs can remove ubiquitin from proteins to reverse signals. Roles for individual DUBs have been delineated within specific cellular processes, including many that are dysregulated in diseases, particularly cancer. As potentially druggable enzymes, disease-associated DUBs are of increasing interest as pharmaceutical targets. The biology, structure and regulation of DUBs have been extensively reviewed elsewhere, so here we focus specifically on roles of DUBs in regulating cell cycle processes in mammalian cells. Over a quarter of all DUBs, representing four different families, have been shown to play roles either in the unidirectional progression of the cell cycle through specific checkpoints, or in the DNA damage response and repair pathways. We catalogue these roles and discuss specific examples. Centrosomes are the major microtubule nucleating centres within a cell and play a key role in forming the bipolar mitotic spindle required to accurately divide genetic material between daughter cells during cell division. To enable this mitotic role, centrosomes undergo a complex replication cycle that is intimately linked to the cell division cycle. Here, we also catalogue and discuss DUBs that have been linked to centrosome replication or function, including centrosome clustering, a mitotic survival strategy unique to cancer cells with supernumerary centrosomes. PMID- 28900016 TI - Geometries of vasculature bifurcation can affect the level of trophic damage during formation of a brain ischemic lesion. AB - Ischemic lesion is a common cause of various diseases in humans. Brain tissue is especially sensitive to this type of damage. A common reason for the appearance of an ischemic area is a stop in blood flow in some branch of the vasculature system. Then, a decreasing concentration gradient results in a low mean level of oxygen in surrounding tissues. After that, the biochemical ischemic cascade spreads. In this review, we examine these well-known events from a new angle. It is stressed that there is essential evidence to predict the formation of an ischemic micro-area at the base of vascular bifurcation geometries. Potential applications to improve neuroprotection are also discussed. PMID- 28900017 TI - Omega-3 fatty acids and inflammatory processes: from molecules to man. AB - Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappaB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor gamma. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance. PMID- 28900015 TI - Structure and function of Pif1 helicase. AB - Pif1 family helicases have multiple roles in the maintenance of nuclear and mitochondrial DNA in eukaryotes. Saccharomyces cerevisiae Pif1 is involved in replication through barriers to replication, such as G-quadruplexes and protein blocks, and reduces genetic instability at these sites. Another Pif1 family helicase in S. cerevisiae, Rrm3, assists in fork progression through replication fork barriers at the rDNA locus and tRNA genes. ScPif1 (Saccharomyces cerevisiae Pif1) also negatively regulates telomerase, facilitates Okazaki fragment processing, and acts with polymerase delta in break-induced repair. Recent crystal structures of bacterial Pif1 helicases and the helicase domain of human PIF1 combined with several biochemical and biological studies on the activities of Pif1 helicases have increased our understanding of the function of these proteins. This review article focuses on these structures and the mechanism(s) proposed for Pif1's various activities on DNA. PMID- 28900018 TI - Distinct Spatiotemporal Dynamics of Peptidoglycan Synthesis between Mycobacterium smegmatis and Mycobacterium tuberculosis. AB - Peptidoglycan (PG), a polymer cross-linked by d-amino acid-containing peptides, is an essential component of the bacterial cell wall. We found that a fluorescent d-alanine analog (FDAA) incorporates chiefly at one of the two poles in Mycobacterium smegmatis but that polar dominance varies as a function of the cell cycle in Mycobacterium tuberculosis: immediately after cytokinesis, FDAAs are incorporated chiefly at one of the two poles, but just before cytokinesis, FDAAs are incorporated comparably at both. These observations suggest that mycobacterial PG-synthesizing enzymes are localized in functional compartments at the poles and septum and that the capacity for PG synthesis matures at the new pole in M. tuberculosis Deeper knowledge of the biology of mycobacterial PG synthesis may help in discovering drugs that disable previously unappreciated steps in the process.IMPORTANCE People are dying all over the world because of the rise of antimicrobial resistance to medicines that could previously treat bacterial infections, including tuberculosis. Here, we used fluorescent d-alanine analogs (FDAAs) that incorporate into peptidoglycan (PG)-the synthesis of which is an attractive drug target-combined with high- and super-resolution microscopy to investigate the spatiotemporal dynamics of PG synthesis in M. smegmatis and M. tuberculosis FDAA incorporation predominates at one of the two poles in M. smegmatis In contrast, while FDAA incorporation into M. tuberculosis is also polar, there are striking variations in polar dominance as a function of the cell cycle. This suggests that enzymes involved in PG synthesis are localized in functional compartments in mycobacteria and that M. tuberculosis possesses a mechanism for maturation of the capacity for PG synthesis at the new pole. This may help in discovering drugs that cripple previously unappreciated steps in the process. PMID- 28900019 TI - The Human Salivary Microbiome Is Shaped by Shared Environment Rather than Genetics: Evidence from a Large Family of Closely Related Individuals. AB - The human microbiome is affected by multiple factors, including the environment and host genetics. In this study, we analyzed the salivary microbiomes of an extended family of Ashkenazi Jewish individuals living in several cities and investigated associations with both shared household and host genetic similarities. We found that environmental effects dominated over genetic effects. While there was weak evidence of geographical structuring at the level of cities, we observed a large and significant effect of shared household on microbiome composition, supporting the role of the immediate shared environment in dictating the presence or absence of taxa. This effect was also seen when including adults who had grown up in the same household but moved out prior to the time of sampling, suggesting that the establishment of the salivary microbiome earlier in life may affect its long-term composition. We found weak associations between host genetic relatedness and microbiome dissimilarity when using family pedigrees as proxies for genetic similarity. However, this association disappeared when using more-accurate measures of kinship based on genome-wide genetic markers, indicating that the environment rather than host genetics is the dominant factor affecting the composition of the salivary microbiome in closely related individuals. Our results support the concept that there is a consistent core microbiome conserved across global scales but that small-scale effects due to a shared living environment significantly affect microbial community composition.IMPORTANCE Previous research shows that the salivary microbiomes of relatives are more similar than those of nonrelatives, but it remains difficult to distinguish the effects of relatedness and shared household environment. Furthermore, pedigree measures may not accurately measure host genetic similarity. In this study, we include genetic relatedness based on genome-wide single nucleotide polymorphisms (SNPs) (rather than pedigree measures) and shared environment in the same analysis. We quantify the relative importance of these factors by studying the salivary microbiomes in members of a large extended Ashkenazi Jewish family living in different locations. We find that host genetics plays no significant role and that the dominant factor is the shared environment at the household level. We also find that this effect appears to persist in individuals who have moved out of the parental household, suggesting that aspects of salivary microbiome composition established during upbringing can persist over a time scale of years. PMID- 28900020 TI - Petrobactin Is Exported from Bacillus anthracis by the RND-Type Exporter ApeX. AB - Bacillus anthracis-a Gram-positive, spore-forming bacterium-causes anthrax, a highly lethal disease with high bacteremia titers. Such rapid growth requires ample access to nutrients, including iron. However, access to this critical metal is heavily restricted in mammals, which requires B. anthracis to employ petrobactin, an iron-scavenging small molecule known as a siderophore. Petrobactin biosynthesis is mediated by asb gene products, and import of the iron bound (holo)-siderophore into the bacterium has been well studied. In contrast, little is known about the mechanism of petrobactin export following its production in B. anthracis cells. Using a combination of bioinformatics data, gene deletions, and laser ablation electrospray ionization mass spectrometry (LAESI-MS), we identified a resistance-nodulation-cell division (RND)-type transporter, termed ApeX, as a putative petrobactin exporter. Deletion of apeX abrogated export of intact petrobactin, which accumulated inside the cell. However, growth of DeltaapeX mutants in iron-depleted medium was not affected, and virulence in mice was not attenuated. Instead, petrobactin components were determined to be exported through a different protein, which enables iron transport sufficient for growth, albeit with a slightly lower affinity for iron. This is the first report to identify a functional siderophore exporter in B. anthracis and the in vivo functionality of siderophore components. Moreover, this is the first application of LAESI-MS to sample a virulence factor/metabolite directly from bacterial culture media and cell pellets of a human pathogen.IMPORTANCEBacillus anthracis requires iron for growth and employs the siderophore petrobactin to scavenge this trace metal during infections. While we understand much about petrobactin biosynthesis and ferric petrobactin import, how apo-petrobactin (iron free) is exported remains unknown. This study used a combination of bioinformatics, genetics, and mass spectrometry to identify the petrobactin exporter. After screening 17 mutants with mutations of candidate exporter genes, we identified the apo-petrobactin exporter (termed ApeX) as a member of the resistance-nodulation-cell division (RND) family of transporters. In the absence of ApeX, petrobactin accumulates inside the cell while continuing to export petrobactin components that are capable of transporting iron. Thus, the loss of ApeX does not affect the ability of B. anthracis to cause disease in mice. This has implications for treatment strategies designed to target and control pathogenicity of B. anthracis in humans. PMID- 28900021 TI - Another Brick in the Wall: a Rhamnan Polysaccharide Trapped inside Peptidoglycan of Lactococcus lactis. AB - Polysaccharides are ubiquitous components of the Gram-positive bacterial cell wall. In Lactococcus lactis, a polysaccharide pellicle (PSP) forms a layer at the cell surface. The PSP structure varies among lactococcal strains; in L. lactis MG1363, the PSP is composed of repeating hexasaccharide phosphate units. Here, we report the presence of an additional neutral polysaccharide in L. lactis MG1363 that is a rhamnan composed of alpha-l-Rha trisaccharide repeating units. This rhamnan is still present in mutants devoid of the PSP, indicating that its synthesis can occur independently of PSP synthesis. High-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) analysis of whole bacterial cells identified a PSP at the surface of wild-type cells. In contrast, rhamnan was detected only at the surface of PSP-negative mutant cells, indicating that rhamnan is located underneath the surface-exposed PSP and is trapped inside peptidoglycan. The genetic determinants of rhamnan biosynthesis appear to be within the same genetic locus that encodes the PSP biosynthetic machinery, except the gene tagO encoding the initiating glycosyltransferase. We present a model of rhamnan biosynthesis based on an ABC transporter-dependent pathway. Conditional mutants producing reduced amounts of rhamnan exhibit strong morphological defects and impaired division, indicating that rhamnan is essential for normal growth and division. Finally, a mutation leading to reduced expression of lcpA, encoding a protein of the LytR-CpsA-Psr (LCP) family, was shown to severely affect cell wall structure. In lcpA mutant cells, in contrast to wild-type cells, rhamnan was detected by HR-MAS NMR, suggesting that LcpA participates in the attachment of rhamnan to peptidoglycan.IMPORTANCE In the cell wall of Gram-positive bacteria, the peptidoglycan sacculus is considered the major structural component, maintaining cell shape and integrity. It is decorated with other glycopolymers, including polysaccharides, the roles of which are not fully elucidated. In the ovococcus Lactococcus lactis, a polysaccharide with a different structure between strains forms a layer at the bacterial surface and acts as the receptor for various bacteriophages that typically exhibit a narrow host range. The present report describes the identification of a novel polysaccharide in the L. lactis cell wall, a rhamnan that is trapped inside the peptidoglycan and covalently bound to it. We propose a model of rhamnan synthesis based on an ABC transporter dependent pathway. Rhamnan appears as a conserved component of the lactococcal cell wall playing an essential role in growth and division, thus highlighting the importance of polysaccharides in the cell wall integrity of Gram-positive ovococci. PMID- 28900022 TI - Binding of NAD+-Glycohydrolase to Streptolysin O Stabilizes Both Toxins and Promotes Virulence of Group A Streptococcus. AB - The globally dominant, invasive M1T1 strain of group A Streptococcus (GAS) harbors polymorphisms in the promoter region of an operon that contains the genes encoding streptolysin O (SLO) and NAD+-glycohydrolase (NADase), resulting in high level expression of these toxins. While both toxins have been shown experimentally to contribute to pathogenesis, many GAS isolates lack detectable NADase activity. DNA sequencing of such strains has revealed that reduced or absent enzymatic activity can be associated with a variety of point mutations in nga, the gene encoding NADase; a commonly observed polymorphism associated with near-complete abrogation of activity is a substitution of aspartic acid for glycine at position 330 (G330D). However, nga has not been observed to contain early termination codons or mutations that would result in a truncated protein, even when the gene product contains missense mutations that abrogate enzymatic activity. It has been suggested that NADase that lacks NAD-glycohydrolase activity retains an as-yet-unidentified inherent cytotoxicity to mammalian cells and thus is still a potent virulence factor. We now show that expression of NADase, either enzymatically active or inactive, augments SLO-mediated toxicity for keratinocytes. In culture supernatants, SLO and NADase are mutually interdependent for protein stability. We demonstrate that the two proteins interact in solution and that both the translocation domain and catalytic domain of NADase are required for maximal binding between the two toxins. We conclude that binding of NADase to SLO stabilizes both toxins, thereby enhancing GAS virulence.IMPORTANCE The global increase in invasive GAS infections in the 1980s was associated with the emergence of an M1T1 clone that harbors a 36-kb pathogenicity island, which codes for increased expression of toxins SLO and NADase. Polymorphisms in NADase that render it catalytically inactive can be detected in clinical isolates, including invasive strains. However, such isolates continue to produce full-length NADase. The rationale for this observation is not completely understood. This study characterizes the binding interaction between NADase and SLO and reports that the expression of each toxin is crucial for maximal expression and stability of the other. By this mechanism, the presence of both toxins increases toxicity to keratinocytes and is predicted to enhance GAS survival in the human host. These observations provide an explanation for conservation of full-length NADase expression even when it lacks enzymatic activity and suggest a critical role for binding of NADase to SLO in GAS pathogenesis. PMID- 28900023 TI - Gene Expression in Leishmania Is Regulated Predominantly by Gene Dosage. AB - Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal "somy" (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection.IMPORTANCELeishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy. PMID- 28900024 TI - Metabolic Roles of Uncultivated Bacterioplankton Lineages in the Northern Gulf of Mexico "Dead Zone". AB - Marine regions that have seasonal to long-term low dissolved oxygen (DO) concentrations, sometimes called "dead zones," are increasing in number and severity around the globe with deleterious effects on ecology and economics. One of the largest of these coastal dead zones occurs on the continental shelf of the northern Gulf of Mexico (nGOM), which results from eutrophication-enhanced bacterioplankton respiration and strong seasonal stratification. Previous research in this dead zone revealed the presence of multiple cosmopolitan bacterioplankton lineages that have eluded cultivation, and thus their metabolic roles in this ecosystem remain unknown. We used a coupled shotgun metagenomic and metatranscriptomic approach to determine the metabolic potential of Marine Group II Euryarchaeota, SAR406, and SAR202. We recovered multiple high-quality, nearly complete genomes from all three groups as well as candidate phyla usually associated with anoxic environments-Parcubacteria (OD1) and Peregrinibacteria Two additional groups with putative assignments to ACD39 and PAUC34f supplement the metabolic contributions by uncultivated taxa. Our results indicate active metabolism in all groups, including prevalent aerobic respiration, with concurrent expression of genes for nitrate reduction in SAR406 and SAR202, and dissimilatory nitrite reduction to ammonia and sulfur reduction by SAR406. We also report a variety of active heterotrophic carbon processing mechanisms, including degradation of complex carbohydrate compounds by SAR406, SAR202, ACD39, and PAUC34f. Together, these data help constrain the metabolic contributions from uncultivated groups in the nGOM during periods of low DO and suggest roles for these organisms in the breakdown of complex organic matter.IMPORTANCE Dead zones receive their name primarily from the reduction of eukaryotic macrobiota (demersal fish, shrimp, etc.) that are also key coastal fisheries. Excess nutrients contributed from anthropogenic activity such as fertilizer runoff result in algal blooms and therefore ample new carbon for aerobic microbial metabolism. Combined with strong stratification, microbial respiration reduces oxygen in shelf bottom waters to levels unfit for many animals (termed hypoxia). The nGOM shelf remains one of the largest eutrophication-driven hypoxic zones in the world, yet despite its potential as a model study system, the microbial metabolisms underlying and resulting from this phenomenon-many of which occur in bacterioplankton from poorly understood lineages-have received only preliminary study. Our work details the metabolic potential and gene expression activity for uncultivated lineages across several low DO sites in the nGOM, improving our understanding of the active biogeochemical cycling mediated by these "microbial dark matter" taxa during hypoxia. PMID- 28900025 TI - Psp Stress Response Proteins Form a Complex with Mislocalized Secretins in the Yersinia enterocolitica Cytoplasmic Membrane. AB - The bacterial phage shock protein system (Psp) is a conserved extracytoplasmic stress response that is essential for the virulence of some pathogens, including Yersinia enterocolitica It is induced by events that can compromise inner membrane (IM) integrity, including the mislocalization of outer membrane pore forming proteins called secretins. In the absence of the Psp system, secretin mislocalization permeabilizes the IM and causes rapid cell death. The Psp proteins PspB and PspC form an integral IM complex with two independent roles. First, the PspBC complex is required to activate the Psp response in response to some inducing triggers, including a mislocalized secretin. Second, PspBC are sufficient to counteract mislocalized secretin toxicity. Remarkably, secretin mislocalization into the IM induces psp gene expression without significantly affecting the expression of any other genes. Furthermore, psp null strains are killed by mislocalized secretins, whereas no other null mutants have been found to share this specific secretin sensitivity. This suggests an exquisitely specific relationship between secretins and the Psp system, but there has been no mechanism described to explain this. In this study, we addressed this deficiency by using a coimmunoprecipitation approach to show that the Psp proteins form a specific complex with mislocalized secretins in the Y. enterocolitica IM. Importantly, analysis of different secretin mutant proteins also revealed that this interaction is absolutely dependent on a secretin adopting a multimeric state. Therefore, the Psp system has evolved with the ability to detect and detoxify dangerous secretin multimers while ignoring the presence of innocuous monomers.IMPORTANCE The phage shock protein (Psp) response has been linked to important phenotypes in diverse bacteria, including those related to antibiotic resistance, biofilm formation, and virulence. This has generated widespread interest in understanding various aspects of its function. Outer membrane secretin proteins are essential components of export systems required for the virulence of many bacterial pathogens. However, secretins can mislocalize into the inner membrane, and this induces the Psp response in a highly specific manner and kills Psp-defective strains with similar specificity. There has been no mechanism described to explain this exquisitely specific relationship between secretins and the Psp system. Therefore, this study provides a critical advance by discovering that Psp effector proteins form a complex with secretins in the Yersinia enterocolitica inner membrane. Remarkably, this interaction is absolutely dependent on a secretin adopting its multimeric state. Therefore, the Psp system detects and detoxifies dangerous secretin multimers, while ignoring the presence of innocuous secretin monomers. PMID- 28900026 TI - Activity-Related Conformational Changes in d,d-Carboxypeptidases Revealed by In Vivo Periplasmic Forster Resonance Energy Transfer Assay in Escherichia coli. AB - One of the mechanisms of beta-lactam antibiotic resistance requires the activity of d,d-carboxypeptidases (d,d-CPases) involved in peptidoglycan (PG) synthesis, making them putative targets for new antibiotic development. The activity of PG synthesizing enzymes is often correlated with their association with other proteins. The PG layer is maintained in the periplasm between the two membranes of the Gram-negative cell envelope. Because no methods existed to detect in vivo interactions in this compartment, we have developed and validated a Forster resonance energy transfer assay. Using the fluorescent-protein donor-acceptor pair mNeonGreen-mCherry, periplasmic protein interactions were detected in fixed and in living bacteria, in single samples or in plate reader 96-well format. We show that the d,d-CPases PBP5, PBP6a, and PBP6b of Escherichia coli change dimer conformation between resting and active states. Complementation studies and changes in localization suggest that these d,d-CPases are not redundant but that their balanced activity is required for robust PG synthesis.IMPORTANCE The periplasmic space between the outer and the inner membrane of Gram-negative bacteria contains many essential regulatory, transport, and cell wall synthesizing and -hydrolyzing proteins. To date, no assay is available to determine protein interactions in this compartment. We have developed a periplasmic protein interaction assay for living and fixed bacteria in single samples or 96-well-plate format. Using this assay, we were able to demonstrate conformation changes related to the activity of proteins that could not have been detected by any other living-cell method available. The assay uniquely expands our toolbox for antibiotic screening and mode-of-action studies. PMID- 28900028 TI - Education and health and well-being: direct and indirect effects with multiple mediators and interactions with multiple imputed data in Stata. AB - BACKGROUND: Previous methods for assessing mediation assume no multiplicative interactions. The inverse odds weighting (IOW) approach has been presented as a method that can be used even when interactions exist. The substantive aim of this study was to assess the indirect effect of education on health and well-being via four indicators of adult socioeconomic status (SES): income, management position, occupational hierarchy position and subjective social status. METHODS: 8516 men and women from the Tromso Study (Norway) were followed for 17 years. Education was measured at age 25-74 years, while SES and health and well-being were measured at age 42-91 years. Natural direct and indirect effects (NIE) were estimated using weighted Poisson regression models with IOW. Stata code is provided that makes it easy to assess mediation in any multiple imputed dataset with multiple mediators and interactions. RESULTS: Low education was associated with lower SES. Consequently, low SES was associated with being unhealthy and having a low level of well-being. The effect (NIE) of education on health and well-being is mediated by income, management position, occupational hierarchy position and subjective social status. CONCLUSION: This study contributes to the literature on mediation analysis, as well as the literature on the importance of education for health-related quality of life and subjective well-being. The influence of education on health and well-being had different pathways in this Norwegian sample. PMID- 28900027 TI - Sirtuin Lipoamidase Activity Is Conserved in Bacteria as a Regulator of Metabolic Enzyme Complexes. AB - Lipoic acid is an essential metabolic cofactor added as a posttranslational modification on several multimeric enzyme complexes. These protein complexes, evolutionarily conserved from bacteria to humans, are core regulators of cellular metabolism. While the multistep enzymatic process of adding lipoyl modifications has been well characterized in Escherichia coli, the enzyme required for the removal of these lipoyl moieties (i.e., a lipoamidase or delipoylase) has not yet been identified. Here, we describe our discovery of sirtuins as lipoamidases in bacteria and establish their conserved substrates. Specifically, by using a series of knockout, overexpression, biochemical, in vitro, proteomic, and functional assays, we determined the substrates of sirtuin CobB in E. coli as components of the pyruvate dehydrogenase (PDH), alpha-ketoglutarate dehydrogenase (KDH), and glycine cleavage (GCV) complexes. In vitro assays provided direct evidence for this specific CobB activity and its NAD+ dependence, a signature of all sirtuins. By designing a targeted quantitative mass spectrometry method, we further measured sirtuin-dependent, site-specific lipoylation on these substrates. The biological significance of CobB-modulated lipoylation was next established by its inhibition of both PDH and KDH activities. By restricting the carbon sources available to E. coli, we demonstrated that CobB regulates PDH and KDH under several growth conditions. Additionally, we found that SrtN, the sirtuin homolog in Gram-positive Bacillus subtilis, can also act as a lipoamidase. By demonstrating the evolutionary conservation of lipoamidase activity across sirtuin homologs, along with the conservation of common substrates, this work emphasizes the significance of protein lipoylation in regulating central metabolic processes.IMPORTANCE Here, we demonstrate that sirtuin lipoamidase activity exists in both Gram-positive and Gram-negative bacteria and establishing its conservation from bacteria to humans. Specifically, we discovered that CobB and SrtN act as lipoamidases in E. coli and B. subtilis, respectively. Intriguingly, not only is this sirtuin enzymatic activity conserved, but also the lipoylated substrates and functions are conserved, as bacterial sirtuins negatively regulate the lipoylation levels and activities of PDH and KDH. Considering that PDH and KDH regulate two carbon entry points into the tricarboxylic acid cycle, our finding highlights lipoylation as a conserved molecular toggle that regulates central metabolic pathways. Indeed, our findings from tests in which we limited nutrient availability support this. Furthermore, this study illustrates how the integration of technologies from different disciplines provides avenues to uncover enzymatic activities at the core of cellular metabolism regulation. PMID- 28900029 TI - Young adulthood and adulthood adiposity in relation to incidence of pancreatic cancer: a prospective study of 0.5 million Chinese adults and a meta-analysis. AB - BACKGROUND: Adult adiposity is positively associated with pancreatic cancer in Western populations. Little is known, however, about the association in China where many have lower body mass index (BMI) or about the relevance of young adulthood adiposity for pancreatic cancer in both Western and East Asian populations. METHODS: The China Kadoorie Biobank (CKB) recruited 512 891 adults aged 30-79 years during 2004-2008, recording 595 incident cases of pancreatic cancer during 8-year follow-up. Cox regression yielded adjusted HRs for pancreatic cancer associated with self-reported young adulthood (mean ~25 years) BMI and with measured adulthood (mean ~52 years) BMI and other adiposity measures (eg, waist circumference (WC)). These were further meta-analysed with published prospective studies. RESULTS: Overall, the mean BMI (SD) was 21.9 (2.6) at age 25 years and 23.7 (3.3) kg/m2 at age 52 years. Young adulthood BMI was strongly positively associated with pancreatic cancer in CKB (adjusted HR=1.36, 95% CI 1.16 to 1.61, per 5 kg/m2 higher BMI) and in meta-analysis of CKB and four other studies (1.18, 1.12 to 1.24). In CKB, there was also a positive association of pancreatic cancer with adulthood BMI (1.11, 0.97 to 1.27, per 5 kg/m2), similar in magnitude to that in meta-analyses of East Asian studies using measured BMI (n=2; 1.08, 0.99 to 1.19) and of Western studies (n=25; 1.10, 1.06 to 1.12). Likewise, meta-analysis of four studies, including CKB, showed a positive association of adulthood WC with pancreatic cancer (1.10, 1.06 to 1.14, per 10 cm). CONCLUSIONS: In both East Asian and Western populations, adiposity was positively associated with risk of pancreatic cancer, with a somewhat stronger association for young than late-life adiposity. PMID- 28900030 TI - Multiple mechanisms contribute to increased neutral lipid accumulation in yeast producing recombinant variants of plant diacylglycerol acyltransferase 1. AB - The apparent bottleneck in the accumulation of oil during seed development in some oleaginous plant species is the formation of triacylglycerol (TAG) by the acyl-CoA-dependent acylation of sn-1,2-diacylglycerol catalyzed by diacylglycerol acyltransferase (DGAT, EC 2.3.1.20). Improving DGAT activity using protein engineering could lead to improvements in seed oil yield (e.g. in canola-type Brassica napus). Directed evolution of B. napus DGAT1 (BnaDGAT1) previously revealed that one of the regions where amino acid residue substitutions lead to higher performance in BnaDGAT1 is in the ninth predicted transmembrane domain (PTMD9). In this study, several BnaDGAT1 variants with amino acid residue substitutions in PTMD9 were characterized. Among these enzyme variants, the extent of yeast TAG production was affected by different mechanisms, including increased enzyme activity, increased polypeptide accumulation, and possibly reduced substrate inhibition. The kinetic properties of the BnaDGAT1 variants were affected by the amino acid residue substitutions, and a new kinetic model based on substrate inhibition and sigmoidicity was generated. Based on sequence alignment and further biochemical analysis, the amino acid residue substitutions that conferred increased TAG accumulation were shown to be present in the DGAT1 PTMD9 region of other higher plant species. When amino acid residue substitutions that increased BnaDGAT1 enzyme activity were introduced into recombinant Camelina sativa DGAT1, they also improved enzyme performance. Thus, the knowledge generated from directed evolution of DGAT1 in one plant species can be transferred to other plant species and has potentially broad applications in genetic engineering of oleaginous crops and microorganisms. PMID- 28900031 TI - The metal chaperone Atox1 regulates the activity of the human copper transporter ATP7B by modulating domain dynamics. AB - The human transporter ATP7B delivers copper to the biosynthetic pathways and maintains copper homeostasis in the liver. Mutations in ATP7B cause the potentially fatal hepatoneurological disorder Wilson disease. The activity and intracellular localization of ATP7B are regulated by copper, but the molecular mechanism of this regulation is largely unknown. We show that the copper chaperone Atox1, which delivers copper to ATP7B, and the group of the first three metal-binding domains (MBD1-3) are central to the activity regulation of ATP7B. Atox1-Cu binding to ATP7B changes domain dynamics and interactions within the MBD1-3 group and activates ATP hydrolysis. To understand the mechanism linking Atox1-MBD interactions and enzyme activity, we have determined the MBD1-3 conformational space using small angle X-ray scattering and identified changes in MBD dynamics caused by apo-Atox1 and Atox1-Cu by solution NMR. The results show that copper transfer from Atox1 decreases domain interactions within the MBD1-3 group and increases the mobility of the individual domains. The N-terminal segment of MBD1-3 was found to interact with the nucleotide-binding domain of ATP7B, thus physically coupling the domains involved in copper binding and those involved in ATP hydrolysis. Taken together, the data suggest a regulatory mechanism in which Atox1-mediated copper transfer activates ATP7B by releasing inhibitory constraints through increased freedom of MBD1-3 motions. PMID- 28900032 TI - Nucleolar and spindle-associated protein 1 (NUSAP1) interacts with a SUMO E3 ligase complex during chromosome segregation. AB - The mitotic spindle is composed of dynamic microtubules and associated proteins that together direct chromosome movement during mitosis. The spindle plays a vital role in accurate chromosome segregation fidelity and is a therapeutic target in cancer. Nevertheless, the molecular mechanisms by which many spindle associated proteins function remains unknown. The nucleolar and spindle associated protein NUSAP1 is a microtubule-binding protein implicated in spindle stability and chromosome segregation. We show here that NUSAP1 localizes to dynamic spindle microtubules in a unique chromosome-centric pattern, in the vicinity of overlapping microtubules, during metaphase and anaphase of mitosis. Mass spectrometry-based analysis of endogenous NUSAP1 interacting proteins uncovered a cell cycle-regulated interaction between the RanBP2-RanGAP1-UBC9 SUMO E3 ligase complex and NUSAP1. Like NUSAP1 depletion, RanBP2 depletion impaired the response of cells to the microtubule poison Taxol. NUSAP1 contains a conserved SAP domain (SAF-A/B, Acinus, and PIAS). SAP domains are common among many other SUMO E3s, and are implicated in substrate recognition and ligase activity. We speculate that NUSAP1 contributes to accurate chromosome segregation by acting as a co-factor for RanBP2-RanGAP1-UBC9 during cell division. PMID- 28900033 TI - High-resolution structure of a lytic polysaccharide monooxygenase from Hypocrea jecorina reveals a predicted linker as an integral part of the catalytic domain. AB - For decades, the enzymes of the fungus Hypocrea jecorina have served as a model system for the breakdown of cellulose. Three-dimensional structures for almost all H. jecorina cellulose-degrading enzymes are available, except for HjLPMO9A, belonging to the AA9 family of lytic polysaccharide monooxygenases (LPMOs). These enzymes enhance the hydrolytic activity of cellulases and are essential for cost efficient conversion of lignocellulosic biomass. Here, using structural and spectroscopic analyses, we found that native HjLPMO9A contains a catalytic domain and a family-1 carbohydrate-binding module (CBM1) connected via a linker sequence. A C terminally truncated variant of HjLPMO9A containing 21 residues of the predicted linker was expressed at levels sufficient for analysis. Here, using structural, spectroscopic, and biochemical analyses, we found that this truncated variant exhibited reduced binding to and activity on cellulose compared with the full-length enzyme. Importantly, a 0.95-A resolution X-ray structure of truncated HjLPMO9A revealed that the linker forms an integral part of the catalytic domain structure, covering a hydrophobic patch on the catalytic AA9 module. We noted that the oxidized catalytic center contains a Cu(II) coordinated by two His ligands, one of which has a His-brace in which the His-1 terminal amine group also coordinates to a copper. The final equatorial position of the Cu(II) is occupied by a water-derived ligand. The spectroscopic characteristics of the truncated variant were not measurably different from those of full-length HjLPMO9A, indicating that the presence of the CBM1 module increases the affinity of HjLPMO9A for cellulose binding, but does not affect the active site. PMID- 28900034 TI - beta-Catenin directs the transformation of testis Sertoli cells to ovarian granulosa-like cells by inducing Foxl2 expression. AB - Sertoli and granulosa cells are two major types of somatic cells in male and female gonads, respectively. Previous studies have shown that Sertoli and granulosa cells are derived from common progenitor cells and that differentiation of these two cell types is regulated by sex differentiation genes. The signaling pathway including the adhesion and transcription factor Ctnnb1 (cadherin associated protein, beta1, also known as beta-catenin) regulates differentiation of granulosa cells in the absence of the transcription factor Sry, and overactivation of beta-catenin in the presence of Sry leads to granulosa prior to sex determination. Surprisingly, our previous study found that beta-catenin overactivation in Sertoli cells after sex determination can also cause disruption of the testicular cord and aberrant testis development. However, the underlying molecular mechanism was unclear. In this study, we found that constitutive activation of Ctnnb1 in Sertoli cells led to ectopic expression of the granulosa cell-specific marker FOXL2 in testes. Co-staining experiments revealed that FOXL2 positive cells were derived from Sertoli cells, and Sertoli cells were transformed into granulosa-like cells after Ctnnb1 overactivation. Further studies demonstrated that CTNNB1 induced Foxl2 expression by directly binding to transcription factor Tcf/Lef-binding sites in the FOXL2 promoter region. We also found that direct overexpression of Foxl2 decreased the expression of Sertoli cell-specific genes in primary Sertoli cells. Taken together, these results demonstrate that repression of beta-catenin (CTNNB1) signaling is required for lineage maintenance of Sertoli cells. Our study provides a new mechanism for Sertoli cell lineage maintenance during gonad development. PMID- 28900035 TI - Prion protein is required for tumor necrosis factor alpha (TNFalpha)-triggered nuclear factor kappaB (NF-kappaB) signaling and cytokine production. AB - The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF) alpha-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFalpha up regulates the expression of p-IkappaB-kinase alpha/beta (p-IKKalpha/beta), p-p65, and p-JNK, but down-regulates the IkappaBalpha protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade. When PRNP is deleted in M2 cells, the effects of TNFalpha are no longer detectable. More importantly, p-p65 and p-JNK responses are restored when PRNP is reintroduced into the PRNP null cells. TNFalpha also activates NF-kappaB and increases TNFalpha production in wild-type M2 cells, but not in PrP-null M2 cells. Similar results are obtained in the BxPC-3 cells. Moreover, TNFalpha activation of NF-kappaB requires ubiquitination of receptor-interacting serine/threonine kinase 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). TNFalpha treatment increases the binding between PrP and the deubiquitinase tumor suppressor cylindromatosis (CYLD), in these treated cells, binding of CYLD to RIP1 and TRAF2 is reduced. We conclude that PrP traps CYLD, preventing it from binding and deubiquitinating RIP1 and TRAF2. Our findings reveal that PrP enhances the responses to TNFalpha, promoting proinflammatory cytokine production, which may contribute to inflammation and tumorigenesis. PMID- 28900036 TI - Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice. AB - Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently up-regulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 up-regulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine the role of Plk1 in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis. Surprisingly, Plk1 overexpression had no apparent phenotypes in the mice. Given that no malignant tumor formation was observed even after a long period of Plk1 overexpression, we reasoned that additional factors are required for tumorigenesis in Plk1-overexpressing mice. Because Plk1 can directly participate in the regulation of the DNA damage response (DDR) pathway, we challenged Plk1-overexpressing mice with ionizing radiation (IR) and found that Plk1-overexpressing mice are much more sensitive to IR than their wild-type littermates. Analysis of tumor development in the Plk1-overexpressing mice indicated a marked decrease in the time required for tumor emergence after IR. At the molecular level, Plk1 overexpression led to reduced phosphorylation of the serine/threonine kinases ATM and Chk2 and of histone H2AX after IR treatment both in vivo and in vitro Furthermore, RNA-Seq analysis suggested that Plk1 elevation decreases the expression of several DDR genes. We conclude that Plk1 overexpression may contribute to tumor formation by both inducing chromosomal instability and suppressing the DDR pathway. PMID- 28900037 TI - ZNF143 protein is an important regulator of the myeloid transcription factor C/EBPalpha. AB - The transcription factor C/EBPalpha is essential for myeloid differentiation and is frequently dysregulated in acute myeloid leukemia. Although studied extensively, the precise regulation of its gene by upstream factors has remained largely elusive. Here, we investigated its transcriptional activation during myeloid differentiation. We identified an evolutionarily conserved octameric sequence, CCCAGCAG, ~100 bases upstream of the CEBPA transcription start site, and demonstrated through mutational analysis that this sequence is crucial for C/EBPalpha expression. This sequence is present in the genes encoding C/EBPalpha in humans, rodents, chickens, and frogs and is also present in the promoters of other C/EBP family members. We identified that ZNF143, the human homolog of the Xenopus transcriptional activator STAF, specifically binds to this 8-bp sequence to activate C/EBPalpha expression in myeloid cells through a mechanism that is distinct from that observed in liver cells and adipocytes. Altogether, our data suggest that ZNF143 plays an important role in the expression of C/EBPalpha in myeloid cells. PMID- 28900038 TI - SOCS1 is an inducible negative regulator of interferon lambda (IFN-lambda) induced gene expression in vivo. AB - Type I (alpha and beta) and type III (lambda) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor kappaB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-alphas and IFN-lambdas. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signaling is controlled by the inducible negative regulators suppressor of cytokine signaling 1 (SOCS1), SOCS3, and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFN-gamma signaling has not been clarified. Here we used knockout cell lines and mice to show that IFN-lambda signaling is regulated by SOCS1 but not by SOCS3 or USP18. These differences were the basis for the distinct kinetic properties of type I and III IFNs. We found that IFN-alpha signaling is transient and becomes refractory after hours, whereas IFN-lambda provides a long-lasting IFN-stimulated gene induction. PMID- 28900039 TI - The Contributing Risk of Tobacco Use for ARDS Development in Burn-Injured Adults With Inhalation Injury. AB - BACKGROUND: This study aims to determine the relationship between tobacco use, inhalation injury, and ARDS in burn-injured adults. METHODS: This study was an observational cohort of 2,485 primary burn admissions to a referral burn center between January 1, 2008 and March 15, 2015. Subjects were evaluated by methods used to account for mediation and traditional approaches (multivariable logistic regression and propensity score analysis). Mediation analysis examined both the (1) indirect effect of tobacco use via inhalation injury as the mediator on ARDS development and (2) the direct effect of tobacco use alone on ARDS development. RESULTS: ARDS development occurred in 6.8% (n = 170) of the cohort. Inhalation injury occurred in 5.0% (n = 125) of the cohort, and ARDS developed in 48.8% (n = 83) of the subjects with inhalation injury. Tobacco use was 2-fold more common in subjects with ARDS. In the mediated model, the direct effect of tobacco use on ARDS, including interaction between tobacco use and inhalation injury, was not significant (odds ratio [OR] 1.63, 95% CI 0.91-2.92, P = .10). However, the indirect effect of tobacco use via inhalation injury as the mediator was significant (OR 1.61, 95% CI 1.25-2.07, P < .001), and the proportion of the total effect of tobacco use operating through the mediator was 55.6%. In the non mediation models (multivariable logistic regression and propensity score analysis), which controlled for inhalation injury and other covariables, the OR for the association between tobacco use and ARDS was 1.84 (95% CI 1.22-2.81, P < .001) and 1.69 (95% CI 1.04-2.75, P = .03), respectively. CONCLUSIONS: In mediation analysis, inhalation injury was the overwhelming predictor for ARDS development, whereas tobacco use has its strongest effect indirectly through inhalation injury. Patients with at least moderate inhalation injury are at greatest risk for ARDS development despite baseline risk factors like tobacco use. PMID- 28900040 TI - Reduced Diaphragm Excursion During Reflexive Citric Acid Cough Test in Subjects With Subacute Stroke. AB - BACKGROUND: Diaphragm excursion is limited during respiratory maneuvers after a stroke. How the diaphragm is limited during reflexive coughs and affects the effectiveness of cough in stroke patients is unclear. This study aimed to measure reflexive cough strength by cough peak flow (CPF) induced by citric acid nebulization (2.8 mol/L), record diaphragm excursions during reflexive coughs in stroke subjects at risk of silent aspiration, and compare these values with those of stroke subjects without risk of aspiration or dysphagia. METHODS: Twenty-one subjects with subacute stroke (mean stroke onset, 13.6 d) at risk of silent aspiration (penetration-aspiration scale, 8) and 21 stroke subjects without dysphagia or aspiration (controls) were included. Diaphragmatic excursions were assessed using real-time sonography in all subjects; the main outcome measure was reflexive CPF induced by citric acid nebulization. RESULTS: The median (interquartile range) values of citric acid-induced CPF values were significantly more reduced in the 21 subjects with silent aspiration (45 [0-83] L/min) than in the control subjects (97 [66-162] L/min) (P = .004). Diaphragmatic excursions during the reflexive coughs were also significantly reduced (P < .001), although both groups had a similar range in the initial National Institutes of Health Stroke Scale scores and level of disability, as measured by the modified Barthel index. Citric acid-induced CPF was significantly correlated with the number of generated coughs (rs = 0.69), voluntary cough CPF (rs = 0.85), and degree of diaphragm excursion on both sides (rs = 0.50 [hemiplegic] and rs = 0.55 [nonhemiplegic]) but not correlated with the degree of hemiparesis, National Institutes of Health Stroke Scale score, or modified Barthel index scores. The 6 month follow up revealed that 7 subjects in group A experienced aspiration pneumonia. CONCLUSIONS: Stroke subjects at risk of silent aspiration showed reduced CPF and more limited diaphragm excursion during the citric acid-induced reflexive cough test. (ClinicalTrials.gov registration NCT02080988.). PMID- 28900042 TI - Classic Spotlight, 2004 and 2005: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 28900041 TI - Predicting Extubation Outcome by Cough Peak Flow Measured Using a Built-in Ventilator Flow Meter. AB - BACKGROUND: Successful weaning from mechanical ventilation depends on the patient's ability to cough efficiently. Cough peak flow (CPF) could predict extubation success using a dedicated flow meter but required patient disconnection. We aimed to predict extubation outcome using an overall model, including cough performance assessed by a ventilator flow meter. METHODS: This was a prospective observational study conducted from November 2014 to October 2015. Before and after a spontaneous breathing trial, subjects were encouraged to cough as strongly as possible before freezing the ventilator screen to assess CPF and tidal volume (VT) in the preceding inspiration. Early extubation success rate was defined as the proportion of subjects not re-intubated 48 h after extubation. Diagnostic performance of CPF and VT was assessed by using the area under the curve of the receiver operating characteristic curve. Cut-off values for CPF and VT were defined according to median values and used to describe the performance of a predictive test combining them with risk factors of early extubation failure. RESULTS: Among 673 subjects admitted, 92 had a cough assessment before extubation. For the 81 subjects with early extubation success, the median CPF was -67.7 L/min, and median VT was 0.646 L. For the 11 subjects with early extubation failure, the median CPF was -57.3 L/min, and median VT was 0.448 L. Area under the curve was 0.61 (95% CI 0.37-0.83) for CPF and 0.64 (95% CI 0.42-0.84) for CPF/VT combined. After dichotomization (CPF < -60 L/min or VT > 0.55 L), there was a synergistic effect to predict early extubation success (P < .001). The predictive value of success reached 94.2% for CPF/VT combined. The overall model including pH before extubation < 7.45 reached a 66.7% predictive value of failure. CONCLUSIONS: CPF measured using the flow meter of an ICU ventilator was able to predict extubation success and to build a composite score to predict extubation failure. The results were close to that found in previous studies that used a dedicated flow meter. This could help to identify high-risk subjects to prevent extubation failure. (ClinicalTrials.gov registration NCT02847221.). PMID- 28900045 TI - GBCAs and Risk for Nephrogenic Systemic Fibrosis: A Literature Review. AB - PURPOSE: To examine the risks of using of gadolinium-based contrast agents (GBCAs) in magnetic resonance (MR) imaging and explore strategies to reduce the likeliness of adverse effects in patients who might be at risk for developing nephrogenic system fibrosis (NSF). METHODS: A search of 3 scholarly databases was performed to identify articles that discuss adverse reactions to GBCAs, specifically relating to kidney function, in MR examinations. A total of 20 peer reviewed articles were analyzed. DISCUSSION: Safety of contrast media is related to the stability of the chelate bond (ie, macrocyclic or linear). Patients who have decreased kidney function or chronic kidney disease are at higher risk for an adverse reaction to GBCAs; typically, macrocyclic contrast agents are considered safer than linear contrast agents for patients at risk for developing NSF because of their higher kinetic stability. Recommended doses of gadolinium should be adhered to carefully for all patients in conjunction with the glomerular filtration rate guidelines for contrast administration defined by the American College of Radiology. CONCLUSION: Although there are advantages to contrast use in MR examinations, technologists should work closely with referring physicians and radiologists to minimize risks for developing NSF in patients who have decreased kidney function. PMID- 28900046 TI - Student Incivility in Radiography Education. AB - PURPOSE: To examine student incivility in radiography classrooms by exploring the prevalence of uncivil behaviors along with the classroom management strategies educators use to manage and prevent classroom disruptions. METHODS: A survey was designed to collect data on the severity and frequency of uncivil student behaviors, classroom management strategies used to address minor and major behavioral issues, and techniques to prevent student incivility. The participants were educators in radiography programs accredited by the Joint Review Committee on Education in Radiologic Technology. RESULTS: Findings indicated that severe uncivil student behaviors in radiography classrooms do not occur as often as behaviors classified as less severe. Radiography educators in this study used a variety of strategies and techniques to manage and prevent student incivility; however, radiography educators who received formal training in classroom management reported fewer incidents of student incivility than those who had not received formal training. DISCUSSION: The participants in this study took a proactive approach to addressing severe behavioral issues in the classroom. Many radiography educators transition from the clinical environment to the classroom setting with little to no formal training in classroom management. Radiography educators are encouraged to attend formal training sessions to learn how to manage the higher education classroom effectively. CONCLUSION: Student incivility is present in radiography classrooms. This study provides a foundation for future research on incivility. PMID- 28900044 TI - Regulation of autophagy, NF-kappaB signaling, and cell viability by miR-124 in KRAS mutant mesenchymal-like NSCLC cells. AB - KRAS mutant non-small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Despite having the same "driver" mutation, mesenchymal NSCLCs are less responsive than are epithelial NSCLCs to inhibition of the RAS pathway. Identifying alternative networks that promote survival specifically in mesenchymal NSCLC may lead to more effective treatments for this subtype. Through their numerous targets in cellular signaling pathways, noncoding microRNAs (miRNAs) often function as tumor suppressors or oncogenes. In particular, some miRNAs regulate the epithelial-mesenchymal transition (EMT). We derived an EMT related miRNA signature by profiling the abundance of miRNAs in a panel of epithelial (KE) or mesenchymal (KM) KRAS mutant NSCLC cell lines. This signature revealed a number of suppressed miRNAs in KM cell lines, including members of the miR-200 family, which can suppress tumor progression by inhibiting EMT. Reconstituting KM cells with one of these miRNAs, miR-124, disrupted autophagy and decreased cell survival by reducing the abundance of p62, which is both an adaptor for selective autophagy and a regulator of the transcription factor nuclear factor kappaB (NF-kappaB). Suppression of p62 by miR-124 correlated with reduced abundance of the autophagy activator beclin 1 (BECN1), the ubiquitin ligase TRAF6, and the NF-kappaB subunit RELA/p65. The abundance of miR-124 inversely correlated with the expression of BECN1 and TRAF6 in patient NSCLC samples. These findings reveal how the loss of miR-124 promotes cell survival networks in the aggressive mesenchymal subtype of KRAS mutant NSCLC, which might lead to improved subtype-selective therapeutic strategies for patients. PMID- 28900043 TI - A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. AB - GPR15 is an orphan G protein-coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines. GPR15L was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, GPR15L was also abundant in the cervix. In skin, GPR15L was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from Gpr15l-deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis. PMID- 28900047 TI - Serving, Following, and Leading in Health Care. AB - Radiologic technologists often perform diverse roles throughout the workday, and they should have at least a minimal understanding of the responsibility and effects of these roles on the patient and organization. Although technologists can practice independently or as part of a work group, individuals should be prepared to improve patient care and to function as a servant, follower, and leader for the overall success of the organization. This article examines those roles, emphasizing servantship. PMID- 28900048 TI - Community-acquired Pneumonia. AB - The most commonly ordered radiologic examination is the chest radiograph, and it is considered the gold standard for diagnosing pneumonia. For this reason, it is essential that radiologic technologists understand the disease and how it affects patients. This article discusses the anatomy of the lungs, along with the epidemiology, pathophysiology, risk factors, signs and symptoms, diagnosis, treatment, and complications of community-acquired pneumonia. PMID- 28900049 TI - New Datasets Advance Visualization of the Pancreas. PMID- 28900050 TI - Transitioning From the Classroom to the Clinical Environment. PMID- 28900051 TI - Interpreting Statistics and the Language of Research. PMID- 28900053 TI - JRCERT Accreditation Standards: Focus on Safety. PMID- 28900054 TI - Whole-brain Volume Perfusion Computed Tomography: Acquisition Techniques and Radiation Dose. PMID- 28900055 TI - Enriching a Culture of Radiation Safety Excellence Using a Patient Radiation Dose Monitoring Program. PMID- 28900056 TI - A Qualitative Study of Minority Radiologic Science Students' Clinical Experiences. PMID- 28900057 TI - Exploring the Idea of a New Form of External-beam Therapy. PMID- 28900059 TI - Neuroimaging of Sports Concussions. AB - Concussions resulting from sports activities have received attention in recent years, and failure to prevent head injury has undergone scrutiny. Although many factors contribute to sports concussion incidence, determining when an athlete can return to play is crucial to minimizing long-term effects of concussion. To date, neuroimaging plays a limited role in concussion evaluation, but conventional and advanced neuroimaging techniques are contributing to the body of research on their future use in evaluation. PMID- 28900060 TI - [The Role of Microglia in Neuroinflammation]. AB - Microglia play a critical role in innate immunity in the central nervous system (CNS). The activation of these calls is also observed in various psycho neurological disorders. In this context, microglia may control the pathological processes to maintain the homeostasis of the CNS. However, microglia are also key players in neuroinflammation and induce chronic neuronal damage. Thus, microglial activation represents a potential therapeutic target in various neurological disorders. PMID- 28900061 TI - [Microglia in Brain Development]. AB - Microglia, traditionally known as resident immune cells in the brain, have been recently identified as one of the important cell types engaging in the formation and maintenance of neural circuitry, especially during the development. In this review, I describe the diversity of microglial functions revealed in different phases of development, ranging from neurogenesis to circuit formation. In particular, microglia possess dual functions in supporting the survival of neuronal structures or neural cells themselves, and removing excess neural components. Understanding these processes and underlying molecular mechanisms will provide important insights into the regulation of neural circuitry development. It further implicates the involvement of microglial dysfunction in neurodevelopmental disorders. PMID- 28900062 TI - [Roles of Microglia in Neurodegenerative Diseases]. AB - Recent advances in glial research have elucidated the roles of microglia under various contexts in health and disease. Microglial activation used to be considered only as a consequence of neuronal damage. However, a series of studies using mouse models of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease selectively affecting motor neurons, indicated that microglia actively influence the disease course. In this review, we summarize the growing evidence that microglia play a critical role in the survival and demise of motor neurons in ALS. These observations suggest microglia as a promising therapeutic target of neurodegenerative diseases. PMID- 28900063 TI - [Translational Research on Neuropsychiatric Disorders: Focusing on Microglia Hypothesis]. AB - Microglia-immune cells in the brain-have recently been highlighted to understand the pathophysiology of psychiatric disorders such as schizophrenia, depression, and autism. In this review paper, we introduce the microglia hypothesis for psychiatric disorders. In addition, we introduce our novel translational research approach to psychiatric disorders using microglia-like (iMG) cells directly induced from human blood, these iMG cells can be produced from peripheral monocytes within two weeks using two cytokines: granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-34 (IL-34). PMID- 28900064 TI - [Positron Emission Tomography Imaging of Microglia in Diagnosis of Dementia]. AB - Neuroinflammation which involves microglial activation is believed to be closely associated with the progression of neurodegeneration in Alzheimer's disease. The activation of microglia is receiving rising attention as a diagnostic and therapeutic target; however, it is important to distinguish its state and phenotype of the microglia. Positron emission tomography (PET) is a non-invasive method that can help visualize the changes of molecules associated with microglial activation in neurological disease under in vivo conditions. In this review, recent PET preclinical and clinical studies, and new molecular targets for the imaging of microglia are described. PMID- 28900065 TI - [Establishment and Maintenance of Adult Neural Stem Cells]. AB - Neural stem cells (NSCs) in the adult mammalian brain produce new neurons throughout life. Defects in adult neurogenesis can influence neurodegenerative and psychiatric disorders. Hence, understanding long-term maintenance of adult NSCs is crucial. Cell-intrinsic and -extrinsic factors contribute to long-term maintenance of adult NSCs, and we have previously reported that NSCs produce their own niches that send a feedback signal for their own maintenance. In addition, we have identified a slowly dividing subpopulation of embryonic neural progenitor cells that is set aside during development, and later becomes a substantial fraction of NSCs in the adult subventricular zone. Here, we review the mechanisms of long-term maintenance and embryonic origin of adult NSCs. We also discuss current topics on adult NSCs and future perspectives in this field of study. PMID- 28900066 TI - [To Test Glutamate Hypothesis for Schizophrenia Utilizing Proton Magnetic Resonance Spectroscopy]. AB - Recent advancement in magnetic resonance spectroscopy (MRS) has elucidated the pathophysiology of mental illness, including schizophrenia. MRS is a neuroimaging technique that non-invasively measures chemicals, using nuclear magnetic resonance. This narrative review explains proton MRS (1H-MRS) and introduces pivotal studies to examine a glutamate hypothesis for schizophrenia, employing 1H-MRS. PMID- 28900067 TI - [Dimethyl Fumarate in Multiple Sclerosis]. AB - At the end of 2016, dimethyl fumarate (DMF) was approved as the sixth disease modifying drug for multiple sclerosis by the Pharmaceuticals and Medical Devices Agency of Japan. Two randomized, placebo-controlled, phase III studies (DEFINE and CONFIRM) showed beneficial effects in patients in Western countries, with relapsing-remitting multiple sclerosis (RRMS). Some of the benefits included a decreased annual relapse rate, inhibition of disease activity (shown using brain magnetic resonance imaging), and a decreased proportion of patients with confirmed disease progression. The APEX study, which included Japanese patients with RRMS, also showed similar results, but reported some adverse effects. Flushing and gastrointestinal events (e.g., nausea, vomiting, abdominal pain, and diarrhea) occurring within 1 month of the initiation of DMF treatment are major causes of discontinuation of the drug. The most serious adverse event is progressive multifocal leukoencephalopathy (PML), which was reported in four patients with MS treated with DMF, worldwide. Grade 3 lymphopenia (less than 500/mm3) due to apoptosis occurs in some DMF-treated patients with MS and is more prevalent among older patients. A reduction in CD8+ T cells is more pronounced than that in CD4+ T cells. Patients with grade 3 lymphopenia, aged more than 50 years, are at a risk for PML development. Further studies are needed to determine the appropriate final dose and an acceptable dose-escalation method for DMF treatment, to prevent or decrease adverse effects in Japanese patients with MS. PMID- 28900068 TI - [Efficacy of Topical Agents for Symptomatic Treatment of Rotigotine Patch-Induced Skin Disorders]. AB - Since the effect of a percutaneous absorption-type dopamine agonist (DA) preparation, rotigotine patch, stably persists by once-a-day application, this dosage form is appropriate for Parkinson's disease patients showing levodopa induced wearing off phenomenon. On the other hand, skin disorders, mainly application site reaction, are characteristic problems associated with use of the patch. In this study, to clarify the influence of a topical agent used to prevent or treat rotigotine patch-induced skin disorder on continuation of the patch application, patients who started rotigotine patch application at our hospital were retrospectively surveyed. The one-year continuation rate of rotigotine patch application was 37.3% (53 of 142 cases). It was insufficient to prevent skin disorders, only by the pre-treatment of a moisturizing agent alone. Regarding the effective rate of topical agents used to treat skin disorders, that of very strong-class steroids was 89.5%, being significantly higher than those of weak steroids, moisturizing agents, and antihistamines. It was suggested that for countermeasures against rotigotine patch-induced skin disorders, treatment with very strong-class steroids for external use early after development of skin disorders is more effective than preventive treatment with topical agents regardless of the type. (Received March 30, 2017; Accepted May 16, 2017; Published September 1, 2017). PMID- 28900069 TI - Current issues and areas for improvement in the Korean Dental Hygienist National Licensing Examination: an expert Delphi survey among dental hygienists. AB - PURPOSE: This study aimed to investigate current issues and areas for improvement in the Korean Dental Hygienist National Licensing Examination (KDHNLE) through an expert Delphi survey. METHODS: A Delphi survey was conducted from May through August 2016 in Korea. This Delphi survey included 20 persons representing the field of dental hygiene (7 groups from various dental hygiene-related organizations). The Delphi survey was administered through e-mail as 3 rounds of questionnaire surveys regarding the issues facing the KDHNLE and potential solutions to those challenges. The primary Delphi survey was an open questionnaire. In each round, subjects' responses were categorized according to the detailed themes of their responses. The minimum value of the content validity ratio of the survey results was determined by the number of panels participating in the Delphi survey. RESULTS: Issues facing the KDHNLE were identified from the results of the Delphi survey. The following 4 items had an average importance score of 4.0 or higher and were considered as important by over 85% of the panels: the failure of the practical test to reflect actual clinical settings, the focus of the practical test on dental scaling, the gap between the items evaluated on the national examination and actual practical work, and insufficiency in strengthening the expertise of licensed dental hygienists. The following items were suggested for improvement: more rigorous rater training, adjustment of the difficulty of the licensing examination, the introduction of a specialized dental hygienist system, and more rigorous refresher training for licensed dental hygienists. CONCLUSION: Based on the above results, the KDHNLE should be improved according to the core competencies of dental hygienists, including on-site clinical practice experience. PMID- 28900070 TI - Item development process and analysis of 50 case-based items for implementation on the Korean Nursing Licensing Examination. AB - PURPOSE: The purpose of this study was to improve the quality of items on the Korean Nursing Licensing Examination by developing and evaluating case-based items that reflect integrated nursing knowledge. METHODS: We conducted a cross sectional observational study to develop new case-based items. The methods for developing test items included expert workshops, brainstorming, and verification of content validity. After a mock examination of undergraduate nursing students using the newly developed case-based items, we evaluated the appropriateness of the items through classical test theory and item response theory. RESULTS: A total of 50 case-based items were developed for the mock examination, and content validity was evaluated. The question items integrated 34 discrete elements of integrated nursing knowledge. The mock examination was taken by 741 baccalaureate students in their fourth year of study at 13 universities. Their average score on the mock examination was 57.4, and the examination showed a reliability of 0.40. According to classical test theory, the average level of item difficulty of the items was 57.4% (80%-100% for 12 items; 60%-80% for 13 items; and less than 60% for 25 items). The mean discrimination index was 0.19, and was above 0.30 for 11 items and 0.20 to 0.29 for 15 items. According to item response theory, the item discrimination parameter (in the logistic model) was none for 10 items (0.00), very low for 20 items (0.01 to 0.34), low for 12 items (0.35 to 0.64), moderate for 6 items (0.65 to 1.34), high for 1 item (1.35 to 1.69), and very high for 1 item (above 1.70). The item difficulty was very easy for 24 items (below -2.0), easy for 8 items (-2.0 to -0.5), medium for 6 items (-0.5 to 0.5), hard for 3 items (0.5 to 2.0), and very hard for 9 items (2.0 or above). The goodness-of-fit test in terms of the 2-parameter item response model between the range of 2.0 to 0.5 revealed that 12 items had an ideal correct answer rate. CONCLUSION: We surmised that the low reliability of the mock examination was influenced by the timing of the test for the examinees and the inappropriate difficulty of the items. Our study suggested a methodology for the development of future case-based items for the Korean Nursing Licensing Examination. PMID- 28900071 TI - A Case of Non-Islet Cell Tumor Hypoglycemia (NICTH) Associated with Gastrointestinal Stromal Tumor (GIST). AB - BACKGROUND Non-islet cell tumor hypoglycemia (NICTH) is a newly recognized, but uncommon, paraneoplastic syndrome that is associated with tumors of mesenchymal origin. We report a case of NICTH associated with a gastrointestinal stromal tumor (GIST). CASE REPORT A 60-year-old man presented to the emergency department of our hospital after being found unconscious in his home. His serum blood glucose on hospital admission was 40 mg/dL. He reported a three-month history of diffuse abdominal pain, fatigue, and blurred vision. Laboratory medicine investigations showed reduced levels of insulin, C-peptide, insulin-like growth factor binding protein (IGFBP)-3, and insulin-like growth factor (IGF)-1, but his IGFBP-2 was increased. Computed tomography (CT) scan of the chest and abdomen showed an abdominal mass that involved the small bowel, mesentery, and omentum, with lesions in the right lung and the left rib. Histopathology of a CT-guided biopsy of the abdominal mass showed a low-grade sarcomatous spindle cell neoplasm that was positive for CD117 using immunohistochemistry and with an exon 11 c-KIT mutation. These findings were consistent with a diagnosis of GIST and treatment with imatinib commenced. CONCLUSIONS This case report has shown that hypoglycemia in the setting of low levels of insulin, C-peptide, IGF-1, and IGFBP-3 is suggestive of a diagnosis of NICTH, which should be investigated for an underlying source, which in this case, was confirmed to be a malignant GIST. PMID- 28900072 TI - No Awakening in Supratentorial Intracerebral Hemorrhage Is Potentially Caused by Sepsis-Associated Encephalopathy. AB - BACKGROUND Acute supratentorial intracerebral hemorrhage (sICH) with secondary sepsis is increasing in frequency. We investigated whether no awakening (NA) after sICH with coma is potentially caused by sepsis-associated encephalopathy (SAE). MATERIAL AND METHODS A case-control study of 147 recruited sICH cases with NA and 198 sICH controls with subsequent awakening (SA) was performed at 2 centers in China. All patients underwent brain computed tomography (CT) scans on admission. The odds ratio (OR) of NA was calculated using logistic regression. RESULTS During the study period, 56.5% (83/147) of the patients with sICH with coma and NA had SAE, and 10% (20/198) with sICH with coma and SA had SAE; this difference between the 2 groups was significant (p<0.000). The sICH patients with coma and NA exhibited a longer median time from onset to coma (2.0 days vs. 0.5 days), more frequent confirmed infection (98.0% vs. 24.2%), and a higher Sequential Organ Failure Assessment (SOFA) score (6.3+/-1.5 vs. 3.4+/-0.8). These patients also exhibited lower hematoma volume (28.0+/-18.8 vs. 38.3+/-24), a lower initial National Institutes of Health Stroke Scale score (19.5+/-6.6 vs. 30.3+/-6.8), more frequent brain midline shift (59.2% vs. 27.8%), more frequent diffuse cerebral swelling (64.6% vs. 16.0%), and higher 30-day mortality (54.4% vs. 0.0%) than the patients who did awaken. Logistic multivariable regression analyses revealed that only a higher SOFA score (OR, 1.4; 95% CI, 1.079-1.767; p=0.010) and SAE (OR, 4.0; 95% CI, 1.359-6.775; p=0.001) were associated with NA events in patients with sICH. CONCLUSIONS NA in sICH patients with coma is potentially caused by secondary SAE. PMID- 28900073 TI - [Molecular Mechanisms of HIV-1 Genetic Diversity]. AB - High genetic diversity of HIV-1 is the main factor behind the fact that HIV infection is widespread and difficult to treat. Although a limited number (or only one) of virus particles enters the blood upon infection, the particles are replicated in infected cells and rapidly produce new genetic variants that are resistant to the host immune system and antiretroviral drugs. This circumstance hampers the development of anti-HIV-1 vaccines and requires new antiretroviral drugs to be designed. The cause of the high variation of HIV-1 is related to the properties of its reverse transcriptase, which is error prone and often makes mistakes when transcribing virus RNA. Moreover, host APOBEC3-family proteins deaminate cytosines in the resulting minus strand DNA copy, leading to C/G-T/A transitions. The review considers several mechanisms that generate HIV-1 variants, including multiple recombination events between two different RNA copies colocated within one capsid. To understand the mechanisms of high genetic diversity of HIV-1 is essential for designing basically new approaches to treatment of HIV infection and AIDS. PMID- 28900074 TI - [Regulation of microRNA Activity in Stress]. AB - Stressors substantially affect the physiology of cells. Depending on the severity and duration of stress exposure, cells either strive to maintain homeostasis or adapt by adjusting their gene expression patterns. One of the mechanisms to change gene expression is regulating the microRNA (miRNA) levels and activities of microRNA-protein complexes. A fine tuning of the interaction of miRNAs with their mRNA targets determines the specificity of protein synthesis and the quantitative composition of the protein pool in stress. The review considers the mechanisms that regulate miRNA biogenesis, miRNA-mediated mRNA repression, and activity of miRNA-protein complexes in animal cells exposed to various stress factors. PMID- 28900076 TI - [CRISPR/CAS9, the King of Genome Editing Tools]. AB - The discovery of CRISPR/Cas9 brought a hope for having an efficient, reliable, and readily available tool for genome editing. CRISPR/Cas9 is certainly easy to use, while its efficiency and reliability remain the focus of studies. The review describes the general principles of the organization and function of Cas nucleases and a number of important issues to be considered while planning genome editing experiments with CRISPR/Cas9. The issues include evaluation of the efficiency and specificity for Cas9, sgRNA selection, Cas9 variants designed artificially, and use of homologous recombination and nonhomologous end joining in DNA editing. PMID- 28900075 TI - [Circulating microRNAs in the Identification of Biological Fluids: A New Approach to Standardization of Expression-Based Diagnostics]. AB - Molecular profiling of normal tissues is a regular and necessary step when developing systems for expression analyses in biological samples, including diagnostic panels for various diseases and conditions. Yet there are still no rigorous criteria to allow precise typing of normal tissues. A main problem is that the methods employed in diagnostic expression testing are difficult to standardize. While various technologies, instruments, and reagents are available, universal protocols of handling biological material are lacking, thus impairing the reproducibility of data from independent studies. The review describes a new approach to standardizing circulating microRNA studies in forensic biology, which has relatively recently (7-8 years ago) come to employ RNA markers in molecular typing of tissues and biological fluids. Forensic biology is now one of the few disciplines where several panels of tissue mRNA markers have been developed within a short period of time and a number of specific microRNA markers have been established and validated for several biological fluids. To allow their successful use, new protocols have been combined with the available, rigidly standardized system of genetic personal identification. Although a ready diagnostic product has still not been obtained with this well-working approach, the apparent efficiency of the standardization methods clearly demonstrates that the problem is possible to solve in other biomedical fields, including those where RNA-based diagnostic protocols are still under development. PMID- 28900077 TI - [The Spectrum of Mutations in Genes Associated with Resistance to Rifampicin, Isoniazid, and Fluoroquinolones in the Clinical Strains of M. tuberculosis Reflects the Transmissibility of Mutant Clones]. AB - To study the transmissibility of drug resistant mutant clones, M. tuberculosis samples were isolated from the patients of the clinical department and the polyclinic of the Central TB Research Institute (n = 1455) for 2011-2014. A number of clones were phenotypically resistant to rifampicin (n = 829), isoniazid (n = 968), and fluoroquinolones (n = 220). We have detected 21 resistance associated variants in eight codons of rpoB, six variants in three codons of katG, three variants in two positions of inhA, four variants in four positions of ahpC, and nine variants in five codons of gyrA, which were represented in the analyzed samples with varied frequencies. Most common mutations were rpoB 531 Ser >Leu (77.93%), katG 315 (Ser->Thr) (94.11%), and gyrA 94 (Asp->Gly) (45.45%). We found that the mutations at position 15 of inhA (C->T) (frequency of 25.72%) are commonly associated with katG 315 (Ser->Thr). This association of two DNA variants may arise due to the double selection by coexposure of M. tuberculosis to isoniazid and ethionamide. The high transmissibility of mutated strains was observed, which may be explained by the minimal influence of the resistance determinants on strain viability. The high transmissibility of resistant variants may also explain the large populational prevalence of drug-resistant TB strains. PMID- 28900079 TI - [Hsp70 Genes of the Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae) Parasitic Wasp]. AB - Miniaturization is an evolutionary process that is widely represented in both invertebrates and vertebrates. Miniaturization frequently affects not only the size of the organism and its constituent cells, but also changes the genome structure and functioning. The structure of the main heat shock genes (hsp70 and hsp83) was studied in one of the smallest insects, the Megaphragma amalphitanum (Hymenoptera: Trichogrammatidae) parasitic wasp, which is comparable in size with unicellular organisms. An analysis of the sequenced genome has detected six genes that relate to the hsp70 family, some of which are apparently induced upon heat shock. Both induced and constitutively expressed hsp70 genes contain a large number of introns, which is not typical for the genes of this family. Moreover, none of the found genes form clusters, and they are all very heterogeneous (individual copies are only 75-85% identical), which indicates the absence of gene conversion, which provides the identity of genes of this family in Drosophila and other organisms. Two hsp83 genes, one of which contains an intron, have also been found in the M. amalphitanum genome. PMID- 28900078 TI - [Polymorphic Variants of Glutamate Receptor (GRIK5, GRIN2B) and Serotonin Receptor (HTR2A) Genes Are Associated with Chronic Obstructive Pulmonary Disease]. AB - Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system that affects primarily distal respiratory pathways and lung parenchyma. Smoking tobacco is a major risk factor for COPD. The relationship of HTR4 (rs3995090), HTR2A (rs6313), GRIK5 (rs8099939), GRIN2B (rs2268132), and CHRNB4 (rs1948) gene polymorphisms and COPD, as well as the contribution of these polymorphisms to the variations in quantitative characteristics that describe respiratory function, smoking behavior, and nicotine dependence was assessed in an ethnically homogeneous Tatar population. The polymorphisms of HTR2A (rs6313) (P = 0.026, OR = 1.42 for the CC genotype) and GRIN2B (rs2268132) (P = 0.0001, OR = 2.39 for the TT genotype) were significantly associated with increased risk of COPD. The AA genotype of GRIK5 (rs8099939) had a protective effect (P = 0.02, OR = 0.61). Importantly, the HTR2A (rs6313), GRIN2B (rs2268132), and GRIK5 (rs8099939) polymorphisms were only associated with COPD in smokers. Smoking index (pack-years) was significantly higher in carriers of the GRIK5 genotype AC (rs8099939) (P = 0.0027). The TT genotype of GRIN2B (rs2268132) was associated with COPD in subjects with high nicotine dependence according to the Fagerstrom test (P = 0.002, OR = 2.98). The TT genotype of HTR2A (rs6313) was associated with a reduced risk of the disease in the group with moderate nicotine dependence (P = 0.02, OR = 0.22). The CC genotype of HTR2A (rs6313) and the TT genotype of GRIN2B (rs2268132) were associated with higher levels of nicotine dependence according to the Fagerstrom test (P = 0.0011 and P = 0.037). Our results may provide insight into potential molecular mechanisms that involve the glutamate (GRIK5, GRIN2B) and serotonin (HTR2A) receptor genes in the pathogenesis of COPD. PMID- 28900080 TI - [Dynamics of LINE-1 Retrotransposon Methylation Levels in Circulating DNA from Lung Cancer Patients Undergoing Antitumor Therapy]. AB - Malignant cell transformation is accompanied with abnormal DNA methylation, such as the hypermethylation of certain gene promoters and hypomethylation of retrotransposons. In particular, the hypomethylation of the human-specific family of LINE-1 retrotransposons was observed in lung cancer tissues. It is also known that the circulating DNA (cirDNA) of blood plasma and cell-surface-bound circulating DNA (csb-cirDNA) of cancer patients accumulate tumor-specific aberrantly methylated DNA fragments, which are currently considered to be valuable cancer markers. This work compares LINE-1 retrotransposon methylation patterns in cirDNA of 16 lung cancer patients before and after treatment. CirDNA was isolated from blood plasma, and csb-cirDNA fractions were obtained by successive elution with EDTA-containing phosphate buffered saline and trypsin. Concentrations of methylated LINE-1 region 1 copies (LINE-1-met) were assayed by real-time methylation-specific PCR. LINE-1 methylation levels were normalized to the concentration of LINE-1 region 2, which was independent of the methylation status (LINE-1-Ind). The concentrations of LINE-1-met and LINE-1-Ind in csb cirDNA of lung cancer patients exhibited correlations before treatment (r = 0.54), after chemotherapy (r = 0.72), and after surgery (r = 0.83) (P < 0.05, Spearman rank test). In the total group of patients, the level of LINE-1 methylation (determined as the LINE-1-met/LINE-1-Ind ratio) was shown to increase significantly during the follow-up after chemotherapy (P < 0.05, paired t test) and after surgery compared to the level of methylation before treatment (P < 0.05, paired t test). The revealed association between the level of LINE-1 methylation and the effect of antitumor therapy was more pronounced in squamous cell lung cancer than in adenocarcinoma (P < 0.05 and P > 0.05, respectively). These results suggest a need for the further investigation of dynamic changes in levels of LINE-1 methylation depending on the antitumor therapy. PMID- 28900081 TI - [miR-218 Promoted the Apoptosis of Human Ovarian Carcinoma Cells via Suppression of the WNT/beta-Catenin Signaling Pathway]. AB - MicroRNA-218 (miR-218) is a short, noncoding RNA, with multiple biological functions. In this study, we aimed to investigate the potential effects of miR 218 on the apoptosis of human ovarian carcinoma cells and the underlying mechanisms by which miR-218 exerted its actions. After over-expressing miR-218 in human ovarian carcinoma (OVCAR3) cells, cell viability was determined by MTT method, cell apoptosis was observed by flow cytometry (FCM), mRNA expression of miR-218, Bcl2, Bax was measured by RT-PCR and protein expression levels of Wnt, tankyrase and beta-catenin were quantified by Western blots. Over-expression of miR-218 potently suppressed cell viability and promoted the apoptosis of human ovarian carcinoma cells in a time-dependent manner. In addition, the down regulation of tankyrase expression level was detected in miR-218-over-expressed cells. Following the block of the Wnt/beta-catenin signaling pathway using the inhibitor XAV-939, the effects of miR-218 on the proliferation and apoptosis of human ovarian carcinoma cells were significantly suppressed. Augmenting expression of miR-218 and/or miRNA-218 mimicking therapeutics may provide viable avenue for the treatment of ovarian cancer. PMID- 28900082 TI - [Inhibition of Invasive Properties of Murine Melanoma by Bovine Pancreatic DNase I In Vitro and In Vivo]. AB - After a long pause, the accumulation of data on the involvement of tumor-specific DNA and extracellular DNA in metastasis has again placed enzymes with deoxyribonuclease activity in the focus of the search for antitumor and antimetastatic drugs. In this work, the ability of bovine pancreatic DNase I to reduce the invasive potential of B16 melanoma has been investigated in vitro and in vivo. It was found that DNase I had a cytotoxic effect on B16 melanoma cells (IC50 ~ 10^(4) U/mL). At the same time, significantly lower doses of DNase I (10^(2)-10^(3) U/mL) inhibited the migratory activity of melanoma cells in vitro, causing a decrease in the distance of cell front migration and in the area of scratch healing 48 h after the enzyme addition, as well as reducing the rate of cell migration. In mice with B16 metastatic melanoma, intramuscular administration of DNase I in the dose range of 0.12-1.20 mg/kg resulted in a two- to threefold decrease in the number of surface lung metastases and caused nonspecific antigenic immune stimulation. PMID- 28900083 TI - [The Effects of Chronic Alcoholization on the Expression of Brain-Derived Neurotrophic Factor and Its Receptors in the Brains of Mice Genetically Predisposed to Depressive-Like Behavior]. AB - Brain-derived neurotropic factor (BDNF) plays an important role in mechanisms of depression. Precursor protein of this factor (proBDNF) can initiate apoptosis in the brain, while the mature form of BDNF is involved in neurogenesis. It is known that chronic alcoholization leads to the activation of apoptotic processes, neurodegeneration, brain injury, and cognitive dysfunction. In this work, we have studied the influence of long-term ethanol exposure on the proBDNF and BDNF protein levels, as well as on the expression of genes that encode these proteins in the brain structures of ASC mice with genetic predisposition to depressive like behavior and in mice from parental nondepressive CBA strain. It was shown that chronic alcoholization results in a reduction of the BDNF level in the hippocampus and an increase in the amount of TrkB and p75 receptors in the frontal cortex of nondepressive CBA mice. At the same time, the long-term alcoholization of depressive ASC mice results in an increase of the proBDNF level in the frontal cortex and a reduction in the p75 protein level in the hippocampus. It has also been shown that, in depressive ASC mice, proBDNF and BDNF levels are significantly lower in the hippocampus and the frontal cortex compared with nondepressive CBA strain. However, no significant differences in the expression of genes encoding the studied proteins were observed. Thus, changes in the expression patterns of proBDNF, BDNF, and their receptors under the influence of alcoholization in the depressive ASC strain and nondepressive CBA strain mice are different. PMID- 28900084 TI - [A Betasatellite-Encoded Protein Regulates Key Components of Gene Silencing System in Plants]. AB - Small circular single-stranded DNA satellites, called betasatellites, have been found in association with some monopartite begomovirus infections. The Cotton leaf curl Multan betasatellite (CLCuMuB) is known to influence symptom induction in cotton leaf curl disease. CLCuMuB contains a single gene, betaC1, whose product is a pathogenicity determinant and a suppressor of RNA silencing. Although induction of RNA silencing by RNA and DNA viruses has been well documented in plants, the interactions between betasatellites and the host's silencing machinery remain poorly understood. In this study, the transgenic expression of betaC1 from CLCuMuB in Arabidopsis thaliana plants produced severe developmental abnormalities, which resembled those produced by mutations in the key genes of the gene silencing pathway. Analysis of transgenic plants expressing CLCuMuB betaC1 using real-time PCR showed that the expression levels of both AGO1 and DCL1 genes were significantly increased. In contrast, the expression of HEN1 gene in the betaC1-expressing leaf tissues was similar to that of wild-type plants. The CLCuMuB betaC1 protein was found to physically interact with the AGO1 protein in a yeast two-hybrid system. It is possible that specific targeting of the gene silencing key components by the CLCuMuB betaC1 inhibits the RNA silencing-based host defence. PMID- 28900085 TI - [Expression of miR-21 and Its Acat1, Armcx1, and Pten Target Genes in Liver of Female Rats Treated with DDT and Benzo[a]pyrene]. AB - MiR-21 is the most studied cancer-promoting oncomiR, which target numerous tumor suppressor genes associated with proliferation, apoptosis, and invasion. Here we have studied the synthesis of miR-21 and quantified the mRNA and protein levels for miR-21 potential target genes, i.e., Acat1, Armcx1, and Pten, in the livers of female Wistar rats after their treatment with either 1,1-trichloro-2,2-di(4 chlorophenyl)ethane (DDT) or benzo[a]pyrene (BP). The most important finding appears to be the significant decrease in the miR-21 level the day after treatment with DDT with subsequent rebound. These changes are accompanied by an increase and subsequent drop in the levels of mRNAs and proteins of the Acat1, Armcx1, and Pten genes. These observations indicate the involvement of miR-21 in the posttranscriptional regulation of the Acat1, Armcx1, and Pten genes in response to xenobiotics. We hypothesize that the toxic effects of xenobiotics may be indirect and may manifest by inducing epigenetic changes, particularly through the regulation of miRNAs and their target genes. PMID- 28900086 TI - [Optimal Artificial Mini-Introns for Transgenic Expression in the Cells of Mice and Hamsters]. AB - Introns can frequently enhance transgene expression, and sometimes they are absolutely substantial. Based on an analysis of murine genes, in which mRNA does not have alternative splicing, a universal design of the efficiently spliced artificial introns of small sizes has been proposed. These introns are shown to be efficiently spliced in CHO cells from hamster ovaries. The proposed strategy can be used to include introns in cDNA, which would elevate the production of recombinant proteins in cell culture, as well as in transgenic animals. PMID- 28900087 TI - [Nascent Polypeptide-Associated Complex as Tissue-Specific Cofactor during Germinal Cell Differentiation in Drosophila Testes]. AB - During the process of spermatogenesis, the proliferation of spermatogonia (stem cell descendants) is replaced by their differentiation in growing spermatocytes responsible for the preparation to meiosis, which is accompanied by a cardinal change in transcriptional programs. We have demonstrated that, in drosophila, this process is accompanied by a splash of the expression of beta-subunit of nascent polypeptide-associated complex (NAC) associated by ribosomes. Nascent polypeptide-associated complex is known as a chaperone involved in co translational protein folding. This is the first case of the detection of tissue specific co-translational NAC cofactor in multicellular eukaryotes. It is proposed that spermatocyte specific NAC is involved in the modulation of the expression of the proteins that provide the functioning of subsequent stages of spermatogenesis. PMID- 28900088 TI - [Estimation of Time-Dependent microRNA Expression Patterns in Brain Tissue, Leukocytes, and Blood Plasma of Rats under Photochemically Induced Focal Cerebral Ischemia]. AB - miRNA expression over different time periods (24 and 48 h) using the quantitative RT-PCR and deep sequencing has been evaluated in a model of photochemically induced thrombosis. A combination of two approaches allowed us to determine the miRNA expression patterns caused by ischemia. Nine miRNAs, including let-7f-5p, miR-221-3p, miR-21-5p, miR-30c-5p, miR-30a-3p, miR-223-3p, miR-23a-3p, miR-22-5p, and miR-99a-5p, were differentially expressed in brain tissue and leukocytes of rats 48 h after onset of ischemia. In addition, six miRNAs were differentially expressed in the brain tissue and blood plasma of rats 24 h after exposure, among which miR-145-3p and miR-375-3p were downregulated and miR-19a-3p, miR-92a-3p, miR-188-5p, and miR-532-5p were upregulated. In our opinion, miR-188-5p and miR 532-5p may be considered to be new potential markers of ischemic injury. The level of miRNA expression tended to increase 48 h after the onset of ischemia in brain tissue and leukocytes, which reflects not only the local response in brain tissue due to inflammation, vascular endothelial dysfunction, and disorders of the permeability of the blood-brain barrier, but also the systemic response of the organism to multifactor molecular processes induced by ischemic injury. PMID- 28900089 TI - [High-Content siRNA Screen of the Kinome Identifies Kinases Involved in Git2 Induced Mesenchymal-Epithelial Transition]. AB - Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal epithelial transition (MET) programs are involced in the metastatic process. More and more evidence confirms that EMT is vital for the initiation and dissemination of cancer cells whereas MET is critical for successful metastatic colonization of a secondary organ. The regulating mechanism of EMT mediated cancer progression and metastasis has been deeply investigated. However, what processes are dependent on MET in metastatic cascades remains unclear. Here, we created a cell based high-content siRNA screen using the breast cancer cell line 4TO7 to search for kinases that were involved in Git2-induced MET. Our results revealed that 58 kinases including transferase, phosphorylation regulators, ATP/nucleotide partners potentially participate in Git2-induced MET. Our preliminary data is expected to facilitate elucidation of the mechanism on how MET is initiated during cancer metastasis. PMID- 28900090 TI - [Method for the Molecular Cytogenetic Visualization of Fragile Site FRAXA]. AB - Fragile X syndrome is one of the most common reasons for human hereditary mental retardation. It is associated with the expansion of CGG repeats in the 5' untranslated region of the FMR1 gene, which results in the suppression of its expression and the development of the disease. At present, methods based on PCR and Southern blot analysis are used for diagnostics of the fragile X syndrome. The presence of a fragile site FRAXA on the X chromosome is typical for patients with this pathology. We developed a method of visualizing this site in cell cultures obtained from patients using the fluorescent in situ hybridization (FISH) and the combination of two probes. The method allows one to detect five types of signals on the X chromosome, three of which are normal, while two are associated with the emergence of fragile site FRAXA. An analysis of the distribution of all signal types in cell lines from healthy individuals and patients with fragile X syndrome demonstrated that the method allows one to determine differences between lines with a high statistical significance and that it is applicable to detecting cells that are carriers of the syndrome. PMID- 28900091 TI - [Secondary Structure of Abeta(1-16) Complexes with Zinc: A Study in the Gas Phase Using Deuterium/Hydrogen Exchange and Ultra-High-Resolution Mass Spectrometry]. AB - Complexes of peptide fragment 1-16 of beta-amyloid with transition metals play an important role in the development of a broad class of neurodegenerative diseases, which determines the interest in investigating the structures of these complexes. In this work, we have applied the method of the deuterium/hydrogen exchange in combination with ultra-high-resolution mass spectrometry to study conformational changes in (1-16) beta-amyloid peptide induced by binding of zinc(II) atoms. The efficiency of the deuterium/hydrogen exchange depended on the number of zinc atoms bound to the peptide and on the temperature of the ionization source region. Deuterium/hydrogen exchange reactions have been performed directly in the ionization source. The number of exchanges decreased considerably with an increasing numbers of zinc atoms. The relationship has been described with a damped exponential curve, which indicated that the binding of zinc atoms altered the conformation of the peptide ion by making it less open, which limits the access to inner areas of the molecule. PMID- 28900092 TI - [Impact of Delivery Method on Antiviral Activity of Phosphodiester, Phosphorothioate, and Phosphoryl Guanidine Oligonucleotides in MDCK Cells Infected with H5N1 Bird Flu Virus]. AB - We have previously described nanocomposites containing conjugates or complexes of native oligodeoxyribonucleotides with poly-L-lysine and TiO2 nanoparticles. We have shown that these nanocomposites efficiently suppressed influenza A virus reproduction in MDCK cells. Here, we have synthesized previously undescribed nanocomposites that consist of TiO2 nanoparticles and polylysine conjugates with oligonucleotides that contain phosphoryl guanidine or phosphorothioate internucleotide groups. These nanocomposites have been shown to exhibit antiviral activity in MDCK cells infected with H5N1 influenza A virus. The nanocomposites containing phosphorothioate oligonucleotides inhibited virus replication ~130 fold. More potent inhibition, i.e., ~5000-fold or ~4600-fold, has been demonstrated by nanocomposites that contain phosphoryl guanidine or phosphodiester oligonucleotides, respectively. Free oligonucleotides have been nearly inactive. The antiviral activity of oligonucleotides of all three types, when delivered by Lipofectamine, has been significantly lower compared to the oligonucleotides delivered in the nanocomposites. In the former case, the phosphoryl guanidine oligonucleotide has appeared to be the most efficient; it has inhibited the virus replication by a factor of 400. The results make it possible to consider phosphoryl guanidine oligonucleotides, along with other oligonucleotide derivatives, as potential antiviral agents against H5N1 avian flu virus. PMID- 28900093 TI - [Synthesis of Circular DNA Templates with T4 RNA Ligase for Rolling Circle Amplification]. AB - Currently, isothermal methods of nucleic acid amplification have been well established; in particular, rolling circle amplification is of great interest. In this approach, circular ssDNA molecules have been used as a target that can be obtained by the intramolecular template-dependent ligation of an oligonucleotide C-probe. Here, a new method of synthesizing small circular DNA molecules via the cyclization of ssDNA based on T4 RNA ligase has been proposed. Circular ssDNA is further used as the template for the rolling circle amplification. The maximum yield of the cyclization products was observed in the presence of 5-10% polyethylene glycol 4000, and the optimum DNA length for the cyclization constituted 50 nucleotides. This highly sensitive method was shown to detect less than 10^(2) circular DNA molecules. The method reliability was proved based on artificially destroyed dsDNA, which suggests its implementation for analyzing any significantly fragmented dsDNA. PMID- 28900094 TI - [Protein-Protein Interactions of Huntingtin in the Hippocampus]. AB - Huntingtin (HTT) occurs in the neuronal cytoplasm and can interact with structural elements of synapses. Huntington's disease (HD) results from pathological expansion of a polyglutamine stretch in the HTT molecule, being probably associated with aberrant protein-protein interactions. The pathogenetic mechanism is still incompletely understood. Alterations of the synaptic structure and plasticity in the hippocampus are observed in early HD. The objective of the study was to theoretically evaluate the HTT contribution to changes in synaptic plasticity by integrating the available experimental data. HTT protein complexes are involved in maintaining the efficiency of synaptic transmission. A pathogenic HTT form (polyQ-HTT) probably disrupts the protein-protein interactions in distorts the dynamics of molecular processes in the synapsis. It was assumed that polyQ-HTT may compete with postsynaptic density proteins and proteins regulating cytoskeleton remodeling. PMID- 28900095 TI - Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella. AB - Bacterial flagella are cell locomotion and occasional adhesion organelles composed primarily of the polymeric protein flagellin, but to date have not been associated with any enzymatic function. Here, we report the bioinformatics-driven discovery of a class of enzymatic flagellins that assemble to form proteolytically active flagella. Originating by a metallopeptidase insertion into the central flagellin hypervariable region, this flagellin family has expanded to at least 74 bacterial species. In the pathogen, Clostridium haemolyticum, metallopeptidase-containing flagellin (which we termed flagellinolysin) is the second most abundant protein in the flagella and is localized to the extracellular flagellar surface. Purified flagellar filaments and recombinant flagellin exhibit proteolytic activity, cleaving nearly 1000 different peptides. With ~ 20,000 flagellin copies per ~ 10-MUm flagella this assembles the largest proteolytic complex known. Flagellum-mediated extracellular proteolysis expands our understanding of the functional plasticity of bacterial flagella, revealing this family as enzymatic biopolymers that mediate interactions with diverse peptide substrates.So far no enzymatic activity has been attributed to flagellin, the major component of bacterial flagella. Here the authors use bioinformatic analysis and identify a metallopeptidase insertion in flagellins from 74 bacterial species and show that recombinant flagellin and flagellar filaments have proteolytic activity. PMID- 28900098 TI - Preprints under peer review. PMID- 28900096 TI - Comparison of quality of life between Billroth-I and Roux-en-Y anastomosis after distal gastrectomy for gastric cancer: A randomized controlled trial. AB - Studies comparing Billroth-I (B-I) with Roux-en-Y (R-Y) anastomosis are still lacking and inconsistent. The aim of this trial was to compare the quality of life (QoL) of B-I with R-Y reconstruction after curative distal gastrectomy for gastric cancer. A total of 140 patients were randomly assigned to the B-I group (N = 70) and R-Y group (N = 70) with the comparable baseline characteristics. The overall postoperative morbidity rates were 18.6% and 25.7% in the B-I group and R Y group without significant difference. More estimated blood loss and longer surgical duration were found in the R-Y group. At the postoperative 1 year time point, the B-I group had a higher score in pain, but lower score in global health. However, the R-Y anastomosis was associated with lower incidence of reflux symptoms at postoperative 6 months (P = 0.002) and postoperative 9 months (P = 0.007). The multivariable analyses of variance did not show any interactions between the time trend and grouping. For the results of endoscopic examination, the degree and extent of remnant gastritis were milder significantly in the R-Y group. The stronger anti-reflux capability of R-Y anastomosis contributes to the higher QoL by reducing the reflux related gastritis and pain symptoms, and promotes a better global health. PMID- 28900097 TI - Electrical properties and thermal stability in stack structure of HfO2/Al2O3/InSb by atomic layer deposition. AB - Changes in the electrical properties and thermal stability of HfO2 grown on Al2O3 passivated InSb by atomic layer deposition (ALD) were investigated. The deposited HfO2 on InSb at a temperature of 200 degrees C was in an amorphous phase with low interfacial defect states. During post-deposition annealing (PDA) at 400 degrees C, In-Sb bonding was dissociated and diffusion through HfO2 occurred. The diffusion of indium atoms from the InSb substrate into the HfO2 increased during PDA at 400 degrees C. Most of the diffused atoms reacted with oxygen in the overall HfO2 layer, which degraded the capacitance equivalent thickness (CET). However, since a 1-nm-thick Al2O3 passivation layer on the InSb substrate effectively reduced the diffusion of indium atoms, we could significantly improve the thermal stability of the capacitor. In addition, we could dramatically reduce the gate leakage current by the Al2O3 passivation layer. Even if the border traps measured by C-V data were slightly larger than those of the as-grown sample without the passivation layer, the interface trap density was reduced by the Al2O3 passivation layer. As a result, the passivation layer effectively improved the thermal stability of the capacitor and reduced the interface trap density, compared with the sample without the passivation layer. PMID- 28900099 TI - Rapid global ocean-atmosphere response to Southern Ocean freshening during the last glacial. AB - Contrasting Greenland and Antarctic temperatures during the last glacial period (115,000 to 11,650 years ago) are thought to have been driven by imbalances in the rates of formation of North Atlantic and Antarctic Deep Water (the 'bipolar seesaw'). Here we exploit a bidecadally resolved 14C data set obtained from New Zealand kauri (Agathis australis) to undertake high-precision alignment of key climate data sets spanning iceberg-rafted debris event Heinrich 3 and Greenland Interstadial (GI) 5.1 in the North Atlantic (~30,400 to 28,400 years ago). We observe no divergence between the kauri and Atlantic marine sediment 14C data sets, implying limited changes in deep water formation. However, a Southern Ocean (Atlantic-sector) iceberg rafted debris event appears to have occurred synchronously with GI-5.1 warming and decreased precipitation over the western equatorial Pacific and Atlantic. An ensemble of transient meltwater simulations shows that Antarctic-sourced salinity anomalies can generate climate changes that are propagated globally via an atmospheric Rossby wave train.A challenge for testing mechanisms of past climate change is the precise correlation of palaeoclimate records. Here, through climate modelling and the alignment of terrestrial, ice and marine 14C and 10Be records, the authors show that Southern Ocean freshwater hosing can trigger global change. PMID- 28900100 TI - Oscillations of ultra-weak photon emission from cancer and non-cancer cells stressed by culture medium change and TNF-alpha. AB - Cells spontaneously emit photons in the UV to visible/near-infrared range (ultra weak photon emission, UPE). Perturbations of the cells' state cause changes in UPE (evoked UPE). The aim of the present study was to analyze the evoked UPE dynamics of cells caused by two types of cell perturbations (stressors): (i) a cell culture medium change, and (ii) application of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Four types of human cell lines were used (squamous cell carcinoma cells, A431; adenocarcinomic alveolar basal epithelial cells, A549; p53-deficient keratinocytes, HaCaT, and cervical cancer cells, HeLa). In addition to the medium change, TNF-alpha was applied at different concentrations (5, 10, 20, and 40 ng/mL) and UPE measurements were performed after incubation times of 0, 30, 60, 90 min, 2, 5, 12, 24, 48 h. It was observed that (i) the change of cell culture medium (without added TNF-alpha) induces a cell type-specific transient increase in UPE with the largest UPE increase observed in A549 cells, (ii) the addition of TNF-alpha induces a cell type specific and dose-dependent change in UPE, and (iii) stressed cell cultures in general exhibit oscillatory UPE changes. PMID- 28900101 TI - Impact of Comorbidity on Fatality Rate of Patients with Middle East Respiratory Syndrome. AB - To date, 1841 cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been reported worldwide, with 652 deaths. We used a publically available case line list to explore the effect of relevant factors, notably underlying comorbidities, on fatal outcome of Middle East respiratory syndrome (MERS) cases up to the end of October 2016. A Bayesian Weibull proportional hazards regression model was used to assess the effect of comorbidity, age, epidemic period and sex on the fatality rate of MERS cases and its variation across countries. The crude fatality rate of MERS cases was 32.1% (95% credibility interval (CI): 29.9%, 34.3%). Notably, the incremental change of daily death rate was most prominent during the first week since disease onset with an average increase of 13%, but then stabilized in the remaining two weeks when it only increased 3% on average. Neither sex, nor country of infection were found to have a significant impact on fatality rates after taking into account the age and comorbidity status of patients. After adjusting for age, epidemic period, MERS patients with comorbidity had around 4 times the risk for fatal infection than those without (adjusted hazard ratio of 3.74 (95% CI: 2.57, 5.67)). PMID- 28900102 TI - Photobleaching in STED nanoscopy and its dependence on the photon flux applied for reversible silencing of the fluorophore. AB - In STED (stimulated emission depletion) nanoscopy, the resolution and signal are limited by the fluorophore de-excitation efficiency and photobleaching. Here, we investigated their dependence on the pulse duration and power of the applied STED light for the popular 750 nm wavelength. In experiments with red- and orange emitting dyes, the pulse duration was varied from the sub-picosecond range up to continuous-wave conditions, with average powers up to 200 mW at 80 MHz repetition rate, i.e. peak powers up to 1 kW and pulse energies up to 2.5 nJ. We demonstrate the dependence of bleaching on pulse duration, which dictates the optimal parameters of how to deliver the photons required for transient fluorophore silencing. Measurements with the dye ATTO647N reveal that the bleaching of excited molecules scales with peak power with a single effective order ~1.4. This motivates peak power reduction while maintaining the number of STED-light photons, in line with the superior resolution commonly achieved for nanosecond STED pulses. Other dyes (ATTO590, STAR580, STAR635P) exhibit two distinctive bleaching regimes for constant pulse energy, one with strong dependence on peak power, one nearly independent. We interpret the results within a photobleaching model that guides quantitative predictions of resolution and bleaching. PMID- 28900104 TI - Geometrically-controlled polarisation processing in femtosecond-laser-written photonic circuits. AB - Polarisation of light is a powerful and widely used degree of freedom to encode information, both in classical and quantum applications. In particular, quantum information technologies based on photons are being revolutionised by the use of integrated photonic circuits. It is therefore very important to be able to manipulate the polarisation of photons in such circuits. We experimentally demonstrate the fabrication by femtosecond laser micromachining of components such as polarisation insensitive and polarising directional couplers, operating at 1550 nm wavelength, where the two opposite behaviours are achieved just by controlling the geometric layout of the photonic circuits, being the waveguides fabricated with the same irradiation recipe. We expect to employ this approach in complex integrated photonic devices, capable of a full control of the photons polarisation for quantum cryptography, quantum computation and quantum teleportation experiments. PMID- 28900103 TI - YeeJ is an inverse autotransporter from Escherichia coli that binds to peptidoglycan and promotes biofilm formation. AB - Escherichia coli is a commensal or pathogenic bacterium that can survive in diverse environments. Adhesion to surfaces is essential for E. coli colonization, and thus it is important to understand the molecular mechanisms that promote this process in different niches. Autotransporter proteins are a class of cell-surface factor used by E. coli for adherence. Here we characterized the regulation and function of YeeJ, a poorly studied but widespread representative from an emerging class of autotransporter proteins, the inverse autotransporters (IAT). We showed that the yeeJ gene is present in ~40% of 96 completely sequenced E. coli genomes and that YeeJ exists as two length variants, albeit with no detectable functional differences. We demonstrated that YeeJ promotes biofilm formation in different settings through exposition at the cell-surface. We also showed that YeeJ contains a LysM domain that interacts with peptidoglycan and thus assists its localization into the outer membrane. Additionally, we identified the Polynucleotide Phosphorylase PNPase as a repressor of yeeJ transcription. Overall, our work provides new insight into YeeJ as a member of the recently defined IAT class, and contributes to our understanding of how commensal and pathogenic E. coli colonise their environments. PMID- 28900106 TI - Practical passive decoy state measurement-device-independent quantum key distribution with unstable sources. AB - Measurement-device-independent quantum key distribution (MDI-QKD) with the active decoy state method can remove all detector loopholes, and resist the imperfections of sources. But it may lead to side channel attacks and break the security of QKD system. In this paper, we apply the passive decoy state method to the MDI-QKD based on polarization encoding mode. Not only all attacks on detectors can be removed, but also the side channel attacks on sources can be overcome. We get that the MDI-QKD with our passive decoy state method can have a performance comparable to the protocol with the active decoy state method. To fit for the demand of practical application, we discuss intensity fluctuation in the security analysis of MDI-QKD protocol using passive decoy state method, and derive the key generation rate for our protocol with intensity fluctuation. It shows that intensity fluctuation has an adverse effect on the key generation rate which is non-negligible, especially in the case of small data size of total transmitting signals and long distance transmission. We give specific simulations on the relationship between intensity fluctuation and the key generation rate. Furthermore, the statistical fluctuation due to the finite length of data is also taken into account. PMID- 28900105 TI - A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol. AB - Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy. However, some healthy individuals have pre-existing anti-PEG antibodies and certain patients develop anti-PEG antibody during treatment with PEGylated medicines, suggesting that genetics might play a role in PEG immunogenicity. Here we perform genome-wide association studies for anti-PEG IgM and IgG responses in Han Chinese with 177 and 140 individuals, defined as positive for anti-PEG IgM and IgG responses, respectively, and with 492 subjects without either anti-PEG IgM or IgG as controls. We validate the association results in the replication cohort, consisting of 211 and 192 subjects with anti-PEG IgM and anti-PEG IgG, respectively, and 596 controls. We identify the immunoglobulin heavy chain (IGH) locus to be associated with anti-PEG IgM response at genome-wide significance (P = 2.23 * 10-22). Our findings may provide novel genetic markers for predicting the immunogenicity of PEG and efficacy of PEGylated therapeutics.Some individuals develop antibodies against the polyethylene glycol that is commonly used in therapeutic preparations. Here the authors conduct a GWAS in Han Chinese and find the IGH locus is associated with anti-PEG IgM. PMID- 28900107 TI - Giant magnetoelectric effects achieved by tuning spin cone symmetry in Y-type hexaferrites. AB - Multiferroics materials, which exhibit coupled magnetic and ferroelectric properties, have attracted tremendous research interest because of their potential in constructing next-generation multifunctional devices. The application of single-phase multiferroics is currently limited by their usually small magnetoelectric effects. Here, we report the realization of giant magnetoelectric effects in a Y-type hexaferrite Ba0.4Sr1.6Mg2Fe12O22 single crystal, which exhibits record-breaking direct and converse magnetoelectric coefficients and a large electric-field-reversed magnetization. We have uncovered the origin of the giant magnetoelectric effects by a systematic study in the Ba2 x Sr x Mg2Fe12O22 family with magnetization, ferroelectricity and neutron diffraction measurements. With the transverse spin cone symmetry restricted to be two-fold, the one-step sharp magnetization reversal is realized and giant magnetoelectric coefficients are achieved. Our study reveals that tuning magnetic symmetry is an effective route to enhance the magnetoelectric effects also in multiferroic hexaferrites.Control of the electrical properties of materials by means of magnetic fields or vice versa may facilitate next-generation spintronic devices, but is still limited by their intrinsically weak magnetoelectric effect. Here, the authors report the existence of an enhanced magnetoelectric effect in a Y-type hexaferrite, and reveal its underlining mechanism. PMID- 28900108 TI - Nanograin size effects on the strength of biphase nanolayered composites. AB - In this work, we employ atomic-scale simulations to uncover the interface-driven deformation mechanisms in biphase nanolayered composites. Two internal boundaries persist in these materials, the interlayer crystalline boundaries and intralayer biphase interfaces, and both have nanoscale dimensions. These internal surfaces are known to control the activation and motion of dislocations, and despite the fact that most of these materials bear both types of interfaces. From our calculations, we find that the first defect event, signifying yield, is controlled by the intralayer spacing (grain size, d), and not the intralayer biphase spacing (layer thickness, h). The interplay of two internal sizes leads to a very broad transition region from grain boundary sliding dominated flow, where the material is weak and insensitive to changes in h, to grain boundary dislocation emission and glide dominated flow, where the material is strong and sensitive to changes in h. Such a rich set of states and size effects are not seen in idealized materials with one of these internal surfaces removed. These findings provide some insight into how changes in h and d resulting from different synthesis processes can affect the strength of nanolayered materials. PMID- 28900109 TI - Region-specific differential corneal and scleral mRNA expressions of MMP2, TIMP2, and TGFB2 in highly myopic-astigmatic chicks. AB - Myopia and astigmatism, two common refractive errors frequently co-exist, are affecting vision at all working distances in the affected populations worldwide. Eyeballs having these refractive errors are known to exhibit abnormal eye shape at the anterior and posterior eye segments, but whether the outer coats of these abnormal eyeballs, cornea anteriorly and sclera posteriorly, are regulated by region-specific molecular mechanism remains unclear. Here we presented the changes in mRNA expression levels of three genes (MMP2, TIMP2, and TGFB2), all known to participate in extracellular matrix organization, at five regions of the cornea and sclera in chickens developing high myopia and astigmatism induced by form deprivation. We found that, compared to normal chicks, the highly myopic astigmatic chicks had significantly higher expression of all three genes in the superior sclera (Mann-Whitney tests, all p <= 0.05), as well as higher TIMP2 expression in the central cornea and nasal sclera (Mann-Whitney tests, both p <= 0.05). Strikingly, the superior scleral region stood out as showing the strongest and most widespread correlations between mRNA expression and biometry parameters including axial and astigmatic components (r = + 0.52~ + 0.85, all p < 0.05). These results imply that local molecular mechanism may manipulate the eye shape remodeling across the globe during refractive-error development. PMID- 28900110 TI - Enhancement of Environmental Hazard Degradation in the Presence of Lignin: a Proteomics Study. AB - Proteomics studies of fungal systems have progressed dramatically based on the availability of more fungal genome sequences in recent years. Different proteomics strategies have been applied toward characterization of fungal proteome and revealed important gene functions and proteome dynamics. Presented here is the application of shot-gun proteomic technology to study the bio remediation of environmental hazards by white-rot fungus. Lignin, a naturally abundant component of the plant biomass, is discovered to promote the degradation of Azo dye by white-rot fungus Irpex lacteus CD2 in the lignin/dye/fungus system. Shotgun proteomics technique was used to understand degradation mechanism at the protein level for the lignin/dye/fungus system. Our proteomics study can identify about two thousand proteins (one third of the predicted white-rot fungal proteome) in a single experiment, as one of the most powerful proteomics platforms to study the fungal system to date. The study shows a significant enrichment of oxidoreduction functional category under the dye/lignin combined treatment. An in vitro validation is performed and supports our hypothesis that the synergy of Fenton reaction and manganese peroxidase might play an important role in DR5B dye degradation. The results could guide the development of effective bioremediation strategies and efficient lignocellulosic biomass conversion. PMID- 28900111 TI - Carrier re-sequencing reveals rare but benign variants in recessive deafness genes. AB - For recessive Mendelian disorders, determining the pathogenicity of rare, non synonymous variants in known causative genes can be challenging without expanded pedigrees and/or functional analysis. In this study, we proposed to establish a database of rare but benign variants in recessive deafness genes by systematic carrier re-sequencing. As a pilot study, 30 heterozygous carriers of pathogenic variants for deafness were identified from unaffected family members of 18 deaf probands. The entire coding regions of the corresponding genes were re-sequenced in those carriers by targeted next-generation sequencing or Sanger sequencing. A total of 32 non-synonymous variants were identified in the normal-hearing carriers in trans with the pathogenic variant and therefore were classified as benign. Among them were five rare (minor allele frequencies less than 0.005) variants that had previously undefined, disputable or even misclassified function: p.A434T (c.1300 G > A) in SLC26A4, p.R266Q (c.797 G > A) in LOXHD1, p.K96Q (c.286 A > C) in MYO15A, p.T123N (c.368 C > A) in GJB2 and p.V1299I (c.797 G > A) in CDH23. Our results suggested that large scale carrier re-sequencing may be warranted to establish a database of rare but benign variants in causative genes in order to reduce false positive genetic diagnosis of recessive Mendelian disorders. PMID- 28900112 TI - Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing. AB - Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC ); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus. PMID- 28900113 TI - Abnormalities of signal transduction networks in chronic schizophrenia. AB - : Schizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia. DISEASE MECHANISMS: A SIGNALING IMBALANCE: A study by US scientists indicates that changes in the activity of key signaling proteins may underlie core symptoms of schizophrenia. Protein kinases mediate the activation of intracellular signaling events and analyses of the kinome, the complete set of protein kinases encoded in the genome, previously revealed significant changes in phosphorylation patterns in postmortem brain tissue from patients with schizophrenia. Based on these findings, Jennifer McGuire at the University of Cincinnati and colleagues investigated the upstream regulation of these proteins. They identified both established and novel proteins associated with schizophrenia in the anterior cingulate cortex, with JNK and AKT activity being the most disrupted in schizophrenia patients. Their findings highlight how subtle changes in the activity of a small number of signaling proteins can propagate and have major consequences for mental health. PMID- 28900114 TI - Programmed Self-Assembly of a Biochemical and Magnetic Scaffold to Trigger and Manipulate Microtubule Structures. AB - Artificial bio-based scaffolds offer broad applications in bioinspired chemistry, nanomedicine, and material science. One current challenge is to understand how the programmed self-assembly of biomolecules at the nanometre level can dictate the emergence of new functional properties at the mesoscopic scale. Here we report a general approach to design genetically encoded protein-based scaffolds with modular biochemical and magnetic functions. By combining chemically induced dimerization strategies and biomineralisation, we engineered ferritin nanocages to nucleate and manipulate microtubule structures upon magnetic actuation. Triggering the self-assembly of engineered ferritins into micrometric scaffolds mimics the function of centrosomes, the microtubule organizing centres of cells, and provides unique magnetic and self-organizing properties. We anticipate that our approach could be transposed to control various biological processes and extend to broader applications in biotechnology or material chemistry. PMID- 28900115 TI - A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor Risk Acute Myeloid Leukemia Patients. AB - Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI PEG20&rank = 12 ). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to <=10 MUM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20. PMID- 28900116 TI - Response induced in Mycoplasma gallisepticum under heat shock might be relevant to infection process. AB - Despite the fact the term "proteome" was proposed to characterize a set of proteins in one of mycoplasma species, proteome response to various exposures in this bacteria are still obscure. Commonly, authors studying proteomic response on perturbation models in mycoplasmas use single approach and do not confirm their findings by alternative methods. Consequently, the results of proteomic analysis should be validated by complementary techniques. In this study we utilized three complementary approaches (SWATH, MRM, 2D-DIGE) to assess response of Mycoplasma gallisepticum under heat stress on proteomic level and combined these findings with metabolic response and the results of transcriptional profiling. We divide response into two modes - one is directly related to heat stress and other is triggered during heat stress, but not directly relevant to it. The latter includes accumulation of ATP and shedding of antigens. Both of these phenomena may be relevant to evasion of host's immune system and dissemination during mycoplasmosis in vivo. PMID- 28900117 TI - Dextromethorphan Exhibits Anti-inflammatory and Immunomodulatory Effects in a Murine Model of Collagen-Induced Arthritis and in Human Rheumatoid Arthritis. AB - Dextromethorphan (d-3-methoxy-17-methylmorphinan, DXM) is a commonly used antitussive with a favorable safety profile. Previous studies have demonstrated that DXM has anti-inflammatory and immunomodulatory properties; however, the effect of DXM in rheumatoid arthritis (RA) remains unknown. Herein, we found that DXM treatment attenuated arthritis severity and proinflammatory cytokine expression levels, including TNF-alpha, IL-6, and IL-17A, in paw tissues of CIA mice. DXM treatment also reduced serum TNF-alpha, IL-6, and IL-17A levels of CIA mice and patients with RA. DXM further decreased the production of anti-CII IgG, IFN-gamma, and IL-17A in collagen-reactive CD4+ T cells extracted from the lymph nodes of CIA mice. In vitro incubation of bone marrow-derived dendritic cells with DXM limited CD4+ T-cell proliferation and inflammatory cytokine secretion. In conclusion, our results showed that DXM attenuated arthritis symptoms in CIA mice and significantly reduced proinflammatory cytokines in patients with RA, suggesting that it can be used as an anti-arthritic agent. PMID- 28900118 TI - Arf6 in lymphatic endothelial cells regulates lymphangiogenesis by controlling directional cell migration. AB - The small GTPase Arf6 plays pivotal roles in a wide variety of cellular events such as endocytosis, exocytosis, and actin cytoskeleton reorganization. However, the physiological functions of Arf6 at the whole animal level have not yet been thoroughly understood. Here, we show that Arf6 regulates developmental and tumor lymphangiogenesis in mice. Lymphatic endothelial cell (LEC)-specific Arf6 conditional knockout (LEC-Arf6 cKO) mouse embryos exhibit severe skin edema and impairment in the formation of lymphatic vessel network at the mid-gestation stage. Knockdown of Arf6 in human LECs inhibits in vitro capillary tube formation and directed cell migration induced by vascular endothelial growth factor-C (VEGF C) by inhibiting VEGF-C-induced internalization of beta1 integrin. Finally, we found that LEC-Arf6 cKO mice transplanted with B16 melanoma cells attenuated tumor lymphangiogenesis and progression. Collectively, these results demonstrate that Arf6 in LECs plays a crucial role in physiological and pathological lymphangiogenesis. PMID- 28900119 TI - Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry. AB - Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 * 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease. PMID- 28900120 TI - Recurrent network dynamics reconciles visual motion segmentation and integration. AB - In sensory systems, a range of computational rules are presumed to be implemented by neuronal subpopulations with different tuning functions. For instance, in primate cortical area MT, different classes of direction-selective cells have been identified and related either to motion integration, segmentation or transparency. Still, how such different tuning properties are constructed is unclear. The dominant theoretical viewpoint based on a linear-nonlinear feed forward cascade does not account for their complex temporal dynamics and their versatility when facing different input statistics. Here, we demonstrate that a recurrent network model of visual motion processing can reconcile these different properties. Using a ring network, we show how excitatory and inhibitory interactions can implement different computational rules such as vector averaging, winner-take-all or superposition. The model also captures ordered temporal transitions between these behaviors. In particular, depending on the inhibition regime the network can switch from motion integration to segmentation, thus being able to compute either a single pattern motion or to superpose multiple inputs as in motion transparency. We thus demonstrate that recurrent architectures can adaptively give rise to different cortical computational regimes depending upon the input statistics, from sensory flow integration to segmentation. PMID- 28900121 TI - Dominance of the hypothalamus-pituitary-adrenal axis over the renin-angiotensin aldosterone system is a risk factor for decreased insulin secretion. AB - How the association between the hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin-aldosterone system (RAAS) affects glucose metabolism were not well examined in a general population. Participants of the population-based 2015 Iwaki study were enrolled (n: 1,016; age: 54.4 +/- 15.1 years). Principal component (PC) analysis identified two PCs: PC1 represented levels of the HPA axis (serum cortisol) and the RAAS (plasma aldosterone) as a whole, and PC2 represented the HPA axis relative to the RAAS (HPA axis dominance). We examined the association between these PCs and glucose metabolism using homeostasis model assessment indices of reduced insulin sensitivity (HOMA-R) and secretion (HOMA beta). Univariate linear regression analyses showed a correlation between PC2 and HOMA-beta (beta = -0.248, p < 0.0001), but not between PC1 and HOMA-beta (beta = 0.004, p = 0.9048). The correration between PC2 and HOMA-beta persisted after adjustment for multiple factors (beta = -0.101, p = 0.0003). No correlations were found between the PCs and HOMA-R. When subjects were tertiled based on PC2, the highest tertile was at greater risk of decreased insulin secretion (defined as the lower one third of HOMA-beta (<=68.9)) than the lowest tertile after adjustment for multiple factors (odds ratio, 2.00; 95% confidence interval, 1.35 2.97). The HPA axis dominance is associated with decreased insulin secretion in a Japanese population. PMID- 28900122 TI - Projection Stereolithographic Fabrication of BMP-2 Gene-activated Matrix for Bone Tissue Engineering. AB - Currently, sustained in vivo delivery of active bone morphogenetic protein-2 (BMP 2) protein to responsive target cells, such as bone marrow-derived mesenchymal stem cells (BMSCs), remains challenging. Ex vivo gene transfer method, while efficient, requires additional operation for cell culture and therefore, is not compatible with point-of-care treatment. In this study, two lentiviral gene constructs - (1) Lv-BMP/GFP, containing human BMP-2 and green fluorescent protein (GFP) gene (BMP group); or (2) Lv-GFP, containing GFP gene (GFP group) - were incorporated with human BMSCs into a solution of photocrosslinkable gelatin, which was then subjected to visible light-based projection stereolithographic printing to form a scaffold with desired architectures. Upon in vitro culture, compared to the GFP group, cells from BMP group showed >1,000-fold higher BMP-2 release, and the majority of them stained intensely for alkaline phosphatase activity. Real-time RT-PCR also showed dramatically increased expression of osteogenesis marker genes only in the BMP group. 3.5 months post-implantation into SCID mice, the micro-computed tomography imaging showed detectable mineralized areas only in the BMP group, which was restricted within the scaffolds. Alizarin red staining and immunohistochemistry of GFP and osteocalcin further indicated that the grafted hBMSCs, not host cells, contributed primarily to the newly formed bone. PMID- 28900123 TI - Effects of low intraperitoneal pressure and a warmed, humidified carbon dioxide gas in laparoscopic surgery: a randomized clinical trial. AB - Laparoscopic surgery technology continues to advance. However, much less attention has been focused on how alteration of the laparoscopic surgical environment might improve clinical outcomes. We conducted a randomized, 2 * 2 factorial trial to evaluate whether low intraperitoneal pressure (IPP) (8 mmHg) and/or warmed, humidified CO2 (WH) gas are better for minimizing the adverse impact of a CO2 pneumoperitoneum on the peritoneal environment during laparoscopic surgery and for improving clinical outcomes compared to the standard IPP (12 mmHg) and/or cool and dry CO2 (CD) gas. Herein we show that low IPP and WH gas may decrease inflammation in the laparoscopic surgical environment, resulting in better clinical outcomes. Low IPP and/or WH gas significantly lowered expression of inflammation-related genes in peritoneal tissues compared to the standard IPP and/or CD gas. The odds ratios of a visual analogue scale (VAS) pain score >30 in the ward was 0.18 (95% CI: 0.06, 0.52) at 12 hours and 0.06 (95% CI: 0.01, 0.26) at 24 hours in the low IPP group versus the standard IPP group, and 0.16 (95% CI: 0.05, 0.49) at 0 hours and 0.29 (95% CI: 0.10, 0.79) at 12 hours in the WH gas group versus the CD gas group. PMID- 28900124 TI - Using CRISPR/Cas9-mediated gene editing to further explore growth and trade-off effects in myostatin-mutated F4 medaka (Oryzias latipes). AB - Myostatin (MSTN) suppresses skeletal muscle development and growth in mammals, but its role in fish is less well understood. Here we used CRISPR/Cas9 to mutate the MSTN gene in medaka (Oryzias latipes) and evaluate subsequent growth performance. We produced mutant F0 fish that carried different frameshifts in the OlMSTN coding sequence and confirmed the heritability of the mutant genotypes to the F1 generation. Two F1 fish with the same heterozygous frame-shifted genomic mutations (a 22 bp insertion in one allele; a 32 bp insertion in the other) were then crossbred to produce subsequent generations (F2~F5). Body length and weight of the MSTN-/- F4 medaka were significantly higher than in the wild type fish, and muscle fiber density in the inner and outer compartments of the epaxial muscles was decreased, suggesting that MSTN null mutation induces muscle hypertrophy. From 3~4 weeks post hatching (wph), the expression of three major myogenic related factors (MRFs), MyoD, Myf5 and Myogenin, was also significantly upregulated. Some medaka had a spinal deformity, and we also observed a trade-off between growth and immunity in MSTN-/- F4 medaka. Reproduction was unimpaired in the fast-growth phenotypes. PMID- 28900125 TI - Mergeable nervous systems for robots. AB - Robots have the potential to display a higher degree of lifetime morphological adaptation than natural organisms. By adopting a modular approach, robots with different capabilities, shapes, and sizes could, in theory, construct and reconfigure themselves as required. However, current modular robots have only been able to display a limited range of hardwired behaviors because they rely solely on distributed control. Here, we present robots whose bodies and control systems can merge to form entirely new robots that retain full sensorimotor control. Our control paradigm enables robots to exhibit properties that go beyond those of any existing machine or of any biological organism: the robots we present can merge to form larger bodies with a single centralized controller, split into separate bodies with independent controllers, and self-heal by removing or replacing malfunctioning body parts. This work takes us closer to robots that can autonomously change their size, form and function.Robots that can self-assemble into different morphologies are desired to perform tasks that require different physical capabilities. Mathews et al. design robots whose bodies and control systems can merge and split to form new robots that retain full sensorimotor control and act as a single entity. PMID- 28900127 TI - Orbital bistatic radar observations of asteroid Vesta by the Dawn mission. AB - We present orbital bistatic radar observations of a small-body, acquired during occultation by the Dawn spacecraft at asteroid Vesta. The radar forward scattering properties of different reflection sites are used to assess the textural properties of Vesta's surface at centimeter-to-decimeter scales and are compared to subsurface hydrogen concentrations observed by Dawn's Gamma Ray and Neutron Detector to assess potential volatile occurrence in the surface and shallow subsurface. We observe significant differences in surface radar reflectivity, implying substantial spatial variations in centimeter-to-decimeter scale surface roughness. Our results suggest that unlike the Moon, Vesta's surface roughness variations cannot be explained by cratering processes only. In particular, the occurrence of heightened hydrogen concentrations within large smoother terrains (over hundreds of square kilometers) suggests that potential ground-ice presence may have contributed to the formation of Vesta's current surface texture. Our observations are consistent with geomorphological evidence of transient water flow from Dawn Framing Camera images.The Dawn spacecraft has provided orbital bistatic radar observations of a small body in the solar system. Here, the authors present results from Vesta suggesting that smooth terrains with heightened hydrogen concentrations indicate that ground-ice presence potentially helped shape Vesta's current surface texture. PMID- 28900126 TI - A new mild hyperthermia device to treat vascular involvement in cancer surgery. AB - Surgical margin status in cancer surgery represents an important oncologic parameter affecting overall prognosis. The risk of disease recurrence is minimized and survival often prolonged if margin-negative resection can be accomplished during cancer surgery. Unfortunately, negative margins are not always surgically achievable due to tumor invasion into adjacent tissues or involvement of critical vasculature. Herein, we present a novel intra-operative device created to facilitate a uniform and mild heating profile to cause hyperthermic destruction of vessel-encasing tumors while safeguarding the encased vessel. We use pancreatic ductal adenocarcinoma as an in vitro and an in vivo cancer model for these studies as it is a representative model of a tumor that commonly involves major mesenteric vessels. In vitro data suggests that mild hyperthermia (41-46 degrees C for ten minutes) is an optimal thermal dose to induce high levels of cancer cell death, alter cancer cell's proteomic profiles and eliminate cancer stem cells while preserving non-malignant cells. In vivo and in silico data supports the well-known phenomena of a vascular heat sink effect that causes high temperature differentials through tissues undergoing hyperthermia, however temperatures can be predicted and used as a tool for the surgeon to adjust thermal doses delivered for various tumor margins. PMID- 28900128 TI - The L-type Voltage-Gated Calcium Channel co-localizes with Syntaxin 1A in nano clusters at the plasma membrane. AB - The secretory signal elicited by membrane depolarization traverses from the Ca2+ bound alpha11.2 pore-forming subunit of the L-type Ca2+-channel (Cav1.2) to syntaxin 1 A (Sx1A) via an intra-membrane signaling mechanism. Here, we report the use of two-color Photo-Activated-Localization-Microscopy (PALM) to determine the relation between Cav1.2 and Sx1A in single-molecule detail. We observed nanoscale co-clusters of PAmCherry-tagged Sx1A and Dronpa-tagged alpha11.2 at a ~1:1 ratio. PAmCherry-tagged Sx1AC145A, or PAmCherry-tagged Sx2, an inactive Cav1.2 modulator, in which Cys145 is a Ser residue, showed no co-clustering. These results are consistent with the crucial role of the single cytosolic Sx1ACys145 in clustering with Cav1.2. Cav1.2 and the functionally inactive transmembrane-domain double mutant Sx1AC271V/C272V engendered clusters with a ~2:1 ratio. A higher extent of co-clustering, which coincides with compromised depolarization-evoked transmitter-release, was observed also by oxidation of Sx1ACys271 and Cys272. Our super-resolution-imaging results set the stage for studying co-clustering of the channel with other exocytotic proteins at a single molecule level. PMID- 28900129 TI - Multiple P450s and Variation in Neuronal Genes Underpins the Response to the Insecticide Imidacloprid in a Population of Drosophila melanogaster. AB - Insecticide resistance is an economically important example of evolution in response to intense selection pressure. Here, the genetics of resistance to the neonicotinoid insecticide imidacloprid is explored using the Drosophila Genetic Reference Panel, a collection of inbred Drosophila melanogaster genotypes derived from a single population in North Carolina. Imidacloprid resistance varied substantially among genotypes, and more resistant genotypes tended to show increased capacity to metabolize and excrete imidacloprid. Variation in resistance level was then associated with genomic and transcriptomic variation, implicating several candidate genes involved in central nervous system function and the cytochrome P450s Cyp6g1 and Cyp6g2. CRISPR-Cas9 mediated removal of Cyp6g1 suggested that it contributed to imidacloprid resistance only in backgrounds where it was already highly expressed. Cyp6g2, previously implicated in juvenile hormone synthesis via expression in the ring gland, was shown to be expressed in metabolically relevant tissues of resistant genotypes. Cyp6g2 overexpression was shown to both metabolize imidacloprid and confer resistance. These data collectively suggest that imidacloprid resistance is influenced by a variety of previously known and unknown genetic factors. PMID- 28900130 TI - Nectin-like molecule-4/cell adhesion molecule 4 inhibits the ligand-induced dimerization of ErbB3 with ErbB2. AB - The ligand-induced dimerization of cell surface single-transmembrane receptors is essential for their activation. However, physiological molecules that inhibit their dimerization and activation have not been identified. ErbB3 dimerizes with ErbB2 upon binding of heregulin (HRG) to ErbB3, causing the ErbB2-catalyzed tyrosine phosphorylation of ErbB3, which leads to the activation of the signalling pathways for cell movement and survival. Genetic disorders of this receptor cause tumorigenesis and metastasis of cancers. We show here that nectin like molecule-4/cell adhesion molecule 4, known to serve as a tumour suppressor, interacts with ErbB3 in the absence of HRG and inhibits the HRG-induced dimerization of ErbB3 with ErbB2 and its activation. The third immunoglobulin like domain of nectin-like molecule-4 cis-interacts with the extracellular domain 3 of ErbB3. We describe here a novel regulatory mechanism for the activation and signalling of cell surface single-transmembrane receptors. PMID- 28900131 TI - Partitioning the roles of CYP6G1 and gut microbes in the metabolism of the insecticide imidacloprid in Drosophila melanogaster. AB - Resistance to insecticides through enhanced metabolism is a worldwide problem. The Cyp6g1 gene of the vinegar fly, Drosophila melanogaster, is a paradigm for the study of metabolic resistance. Constitutive overexpression of this gene confers resistance to several classes of insecticides, including the neonicotinoid imidacloprid (IMI). The metabolism of IMI in this species has been previously shown to yield oxidative and nitro-reduced metabolites. While levels of the oxidative metabolites are correlated with CYP6G1 expression, nitro-reduced metabolites are not, raising the question of how these metabolites are produced. Some IMI metabolites are known to be toxic, making their fate within the insect a second question of interest. These questions have been addressed by coupling the genetic tools of gene overexpression and CRISPR gene knock-out with the mass spectrometric technique, the Twin-Ion Method (TIM). Analysing axenic larvae indicated that microbes living within D. melanogaster are largely responsible for the production of the nitro-reduced metabolites. Knock-out of Cyp6g1 revealed functional redundancy, with some metabolites produced by CYP6G1 still detected. IMI metabolism was shown to produce toxic products that are not further metabolized but readily excreted, even when produced in the Central Nervous System (CNS), highlighting the significance of transport and excretion in metabolic resistance. PMID- 28900132 TI - The lipid-sensor TREM2 aggravates disease in a model of LCMV-induced hepatitis. AB - Lipid metabolism is increasingly being appreciated to affect immunoregulation, inflammation and pathology. In this study we found that mice infected with lymphocytic choriomeningitis virus (LCMV) exhibit global perturbations of circulating serum lipids. Mice lacking the lipid-sensing surface receptor triggering receptor expressed on myeloid cells 2 (Trem2 -/-) were protected from LCMV-induced hepatitis and showed improved virus control despite comparable virus specific T cell responses. Non-hematopoietic expression of TREM2 was found to be responsible for aggravated hepatitis, indicating a novel role for TREM2 in the non-myeloid compartment. These results suggest a link between virus-perturbed lipids and TREM2 that modulates liver pathogenesis upon viral infection. Targeted interventions of this immunoregulatory axis may ameliorate tissue pathology in hepatitis. PMID- 28900133 TI - FCN1 (M-ficolin), which directly associates with immunoglobulin G1, is a molecular target of intravenous immunoglobulin therapy for Kawasaki disease. AB - Kawasaki disease (KD), an acute systemic vasculitis of early childhood, is of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is an effective treatment, but its molecular target remains elusive. DNA microarray analysis of peripheral blood mononuclear cells (PBMCs) revealed that at least 21 genes are drastically down-regulated after IVIG treatment in most KD patients. qRT-PCR analysis confirmed that the mRNA levels of five of these genes were considerably reduced in almost all KD patients after IVIG treatment. Western blot (Wb) of PBMC extracts revealed that levels of FCN1 (M-ficolin), a protein of the complement system that defends against infectious agents, were reduced after IVIG treatment in many KD patients. In another set of KD patients, Wb confirmed that levels of both FCN1 were greatly reduced after IVIG therapy. Wb revealed that the collagen like domain of FCN1 directly bound to IgG1 in vitro through a portion of the CH1 and CH3 domains, and synthetic peptides corresponding to these domains of IgG1 efficiently inhibited these associations. These results suggest that FCN1 is a molecular target of intravenous IVIG in KD patients. We propose that these peptides and a humanized monoclonal antibody against FCN1 could be useful in combination therapy with IVIG. PMID- 28900134 TI - Minimally Invasive Micro-Indentation: mapping tissue mechanics at the tip of an 18G needle. AB - Experiments regarding the mechanical properties of soft tissues mostly rely on data collected on specimens that are extracted from their native environment. During the extraction and in the time period between the extraction and the completion of the measurements, however, the specimen may undergo structural changes which could generate unwanted artifacts. To further investigate the role of mechanics in physiology and possibly use it in clinical practices, it is thus of paramount importance to develop instruments that could measure the viscoelastic response of a tissue without necessarily excising it. Tantalized by this opportunity, we have designed a minimally invasive micro-indenter that is able to probe the mechanical response of soft tissues, in situ, via an 18G needle. Here, we discuss its working principle and validate its usability by mapping the viscoelastic properties of a complex, confined sample, namely, the nucleus pulposus of the intervertebral disc. Our findings show that the mechanical properties of a biological tissue in its local environment may be indeed different than those that one would measure after excision, and thus confirm that, to better understand the role of mechanics in life sciences, one should always perform minimally invasive measurements like those that we have here introduced. PMID- 28900135 TI - Hedgehog signalling is required for cell survival in Drosophila wing pouch cells. AB - An appropriate balance between cell survival and cell death is essential for correct pattern formation in the animal tissues and organs. Previous studies have shown that the short-range signalling molecule Hedgehog (Hh) is required for cell proliferation and pattern formation in the Drosophila central wing discs. Signal transduction by one of the Hh targets, the morphogen Decapentaplegic (Dpp), is required for not only cell proliferation, but also cell survival in the pouch cells. However, Hh function in cell survival and cell death has not been revealed. Here, we found that loss of Hh signal activity induces considerable Caspase-dependent cell death in the wing pouch cells, and this process was independent of both Dpp signalling and Jun-N-terminal kinase (JNK) signalling. Loss of Hh induced activation of the pro-apoptotic gene hid and inhibition of diap1. Therefore, we identified an important role of Hh signalling in cell survival during Drosophila wing development. PMID- 28900136 TI - Differential effects of soluble and aggregating polyQ proteins on cytotoxicity and type-1 myosin-dependent endocytosis in yeast. AB - Huntington's disease develops when the polyglutamine (polyQ) repeat in the Huntingtin (Htt) protein is expanded to over 35 glutamines rendering it aggregation-prone. Here, using Htt exon-1 as a polyQ model protein in a genome wide screen in yeast, we show that the normal and soluble Htt exon-1 is toxic in cells with defects in type-1 myosin-dependent endocytosis. The toxicity of Htt is linked to physical interactions with type-1 myosins, which occur via the Htt proline-rich region, leading to a reduction in actin patch polarization and clathrin-dependent endocytosis. An expansion of the polyQ stretch from 25 to 103 glutamines, which causes Htt aggregation, alleviated Htt toxicity in cells lacking Myo5 or other components involved in early endocytosis. The data suggest that the proline-rich stretch of Htt interacts with type-1 myosin/clathrin dependent processes and demonstrate that a reduction in the activity of such processes may result in a positive selection for polyQ expansions. PMID- 28900137 TI - Tailoring Eigenmodes at Spectral Singularities in Graphene-based PT Systems. AB - The spectral singularity existing in PT-synthetic plasmonic system has been widely investigated. Only lasing-mode can be excited resulting from the passive characteristic of metallic materials. Here, we investigated the spectral singularity in the hybrid structure composed of the photoexcited graphene and one dimensional PT-diffractive grating. In this system, both lasing- and absorption modes can be excited with the surface conductivity of photoexcited graphene being loss and gain, respectively. Remarkably, the spectral singularity will disappear with the optically pumped graphene to be lossless. In particular, we find that spectral singularities can exhibit symmetry-modes, when the loss and gain of the grating is unbalanced. Meanwhile, by tuning the loss (gain) of graphene and non PT diffraction grating, lasing- and absorption-modes can also be excited. We hope that tunable optical modes at spectral singularities can have some applications in designing novel surface-enhanced spectroscopies and plasmon lasers. PMID- 28900138 TI - Adaptation of influenza A (H7N9) virus in primary human airway epithelial cells. AB - Influenza A (H7N9) is an emerging zoonotic pathogen with pandemic potential. To understand its adaptation capability, we examined the genetic changes and cellular responses following serial infections of A (H7N9) in primary human airway epithelial cells (hAECs). After 35 serial passages, six amino acid mutations were found, i.e. HA (R54G, T160A, Q226L, H3 numbering), NA (K289R, or K292R for N2 numbering), NP (V363V/I) and PB2 (L/R332R). The mutations in HA enabled A(H7N9) virus to bind with higher affinity (from 39.2% to 53.4%) to sialic acid alpha2,6-galactose (SAalpha2,6-Gal) linked receptors. A greater production of proinflammatory cytokines in hAECs was elicited at later passages together with earlier peaking at 24 hours post infection of IL-6, MIP-1alpha, and MCP-1 levels. Viral replication capacity in hAECs maintained at similar levels throughout the 35 passages. In conclusion, during the serial infections of hAECs by influenza A(H7N9) virus, enhanced binding of virion to cell receptors with subsequent stronger innate cell response were noted, but no enhancement of viral replication could be observed. This indicates the existence of possible evolutional hurdle for influenza A(H7N9) virus to transmit efficiently from human to human. PMID- 28900139 TI - Gene expression profiling of calcifications in breast cancer. AB - We investigated the gene expression profiles of calcifications in breast cancer. Gene expression analysis of surgical specimen was performed using Affymetrix GeneChip(r) Human Gene 2.0 ST arrays in 168 breast cancer patients. The mammographic calcifications were reviewed by three radiologists and classified into three groups according to malignancy probability: breast cancers without suspicious calcifications; breast cancers with low-to-intermediate suspicious calcifications; and breast cancers with highly suspicious calcifications. To identify differentially expressed genes (DEGs) between these three groups, a one way analysis of variance was performed with post hoc comparisons with Tukey's honest significant difference test. To explore the biological significance of DEGs, we used DAVID for gene ontology analysis and BioLattice for clustering analysis. A total of 2551 genes showed differential expression among the three groups. ERBB2 genes are up-regulated in breast cancers with highly suspicious calcifications (fold change 2.474, p < 0.001). Gene ontology analysis revealed that the immune, defense and inflammatory responses were decreased in breast cancers with highly suspicious calcifications compared to breast cancers without suspicious calcifications (p from 10-23 to 10-8). The clustering analysis also demonstrated that the immune system is associated with mammographic calcifications (p < 0.001). Our study showed calcifications in breast cancers are associated with high levels of mRNA expression of ERBB2 and decreased immune system activity. PMID- 28900140 TI - Seed germination of Caragana species from different regions is strongly driven by environmental cues and not phylogenetic signals. AB - Seed germination behavior is an important factor in the distribution of species. Many studies have shown that germination is controlled by phylogenetic constraints, however, it is not clear whether phylogenetic constraints or environmental cues explain seed germination of a genus from a common ancestor. In this study, seed germination under different temperature- and water-regimes [induced by different osmotic potentials of polyethylene glycol (PEG)] was investigated in the phylogenetically-related Caragana species that thrive in arid, semiarid, semihumid and humid environments. The results showed that the final percentage germination (FPG) decreased from 95% in species from arid habitats to 0% in species from humid habitats, but with no significant phylogenetic signal. Rather, the response of seed germination to temperature and PEG varied greatly with species from arid to humid habitats and was tightly linked to the ecological niche of the species, their seed coat structure and abscisic acid concentration. The findings are not consistent with the hypothesis that within a family or a genus, seed germination strategies can be a stable evolutionary trait, thus constraining interspecific variation, but the results clearly show that seed germination of Caragana species distributed across a range of habitats has adapted to the environment of that habitat. PMID- 28900141 TI - Dianxianning improved amyloid beta-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic C. elegans. AB - Dianxianning (DXN) is a traditional Chinese formula, and has been approved in China for treating epilepsy since 1996. Here anti-Alzheimer's disease activity of DXN has been reported. DXN improved AD-like symptoms of paralysis and 5-HT sensitivity of transgenic Abeta1-42 C. elegans. In worms, DXN significantly increased Abeta monomers and decreased the toxic Abeta oligomers, thus reducing Abeta toxicity. DXN significantly suppressed the expression of hsp-16.2 induced by juglone, and up-regulated sod-3 expression. These results indicated that DXN increased stress resistance and protected C. elegans against oxidative stress. Furthermore, DXN could significantly promote DAF-16 nuclear translocation, but it did not activate SKN-1. The inhibitory effect of DXN on the Abeta toxicity was significantly reverted by daf-16 RNAi, rather than skn-1 RNAi or hsf-1 RNAi. These results indicated that DAF-16 is at least partially required for the anti AD effect of DXN. In conclusion, DXN improved Abeta-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic worms. Together with our data obtained by Morris water maze test, the results showed that DXN markedly ameliorated cognitive performance impairment induced by scopolamine in mice. All the results support that DXN is a potential drug candidate to treat Alzheimer's diseases. PMID- 28900142 TI - Earth system feedback statistically extracted from the Indian Ocean deep-sea sediments recording Eocene hyperthermals. AB - Multiple transient global warming events occurred during the early Palaeogene. Although these events, called hyperthermals, have been reported from around the globe, geologic records for the Indian Ocean are limited. In addition, the recovery processes from relatively modest hyperthermals are less constrained than those from the severest and well-studied hothouse called the Palaeocene-Eocene Thermal Maximum. In this study, we constructed a new and high-resolution geochemical dataset of deep-sea sediments clearly recording multiple Eocene hyperthermals in the Indian Ocean. We then statistically analysed the high dimensional data matrix and extracted independent components corresponding to the biogeochemical responses to the hyperthermals. The productivity feedback commonly controls and efficiently sequesters the excess carbon in the recovery phases of the hyperthermals via an enhanced biological pump, regardless of the magnitude of the events. Meanwhile, this negative feedback is independent of nannoplankton assemblage changes generally recognised in relatively large environmental perturbations. PMID- 28900143 TI - A unique case of human Zika virus infection in association with severe liver injury and coagulation disorders. AB - ABSATRCT: Zika virus (ZIKV) has caused major concern globally due to its rapid dissemination and close association with microcephaly in children and Gullian Barr syndrome in adults. In this study, we identified a patient returned from Cambodia who experienced high fever, chill and myalgia. Lab tests discovered sign of severe liver injury including significantly elevated serum transaminases' level, decreased serum albumin level, and markedly increased levels of lactic dehydrogenase, alpha-hydroxybutyric dehydrogenase and creatine kinase in serum. Moreover, severe thrombocytopenia and altered blood levels of fibrinogen and fibrinogen degradation product were also observed, indicating the existence of clotting disorders. A ZIKV strain clustered into the Asian lineage was isolated from the patient's serum. When inoculated into suckling mice, this virus significantly retarded mouse body-weight gain and caused 70% mortality. Our results demonstrate a close association between ZIKV and severe liver injury and coagulation disorders and suggest that clinicians should be aware of compatible symptoms in patients and manage them accordingly. PMID- 28900144 TI - Structural and functional insights into the periplasmic detector domain of the GacS histidine kinase controlling biofilm formation in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic pathogenic bacterium responsible for both acute and chronic infections and has developed resistance mechanisms due to its ability to promote biofilm formation and evade host adaptive immune responses. Here, we investigate the functional role of the periplasmic detector domain (GacSPD) from the membrane-bound GacS histidine kinase, which is one of the key players for biofilm formation and coordination of bacterial lifestyles. A gacS mutant devoid of the periplasmic detector domain is severely defective in biofilm formation. Functional assays indicate that this effect is accompanied by concomitant changes in the expression of the two RsmY/Z small RNAs that control activation of GacA-regulated genes. The solution NMR structure of GacSPD reveals a distinct PDC/PAS alpha/beta fold characterized by a three-stranded beta-sheet flanked by alpha-helices and an atypical major loop. Point mutations in a putative ligand binding pocket lined by positively-charged residues originating primarily from the major loop impaired biofilm formation. These results demonstrate the functional role of GacSPD, evidence critical residues involved in GacS/GacA signal transduction system that regulates biofilm formation, and document the evolutionary diversity of the PDC/PAS domain fold in bacteria. PMID- 28900145 TI - Characterization of influenza A viruses with polymorphism in PB2 residues 701 and 702. AB - The 701 and 702 positions of influenza PB2 polymerase subunit are previously shown to have roles on host range. Limited polymorphisms at these two residues are identified in natural isolates, thereby limiting the study of their role in the polymerase. In this study, we generated 31 viable viruses by random mutagenesis at this region, indicating that these positions can tolerate a wide range of amino acids. These mutants demonstrated varying polymerase activities and viral replication rates in mammalian and avian cells. Notably, some mutants displayed enhanced polymerase activity, yet their replication kinetics were comparable to the wild-type virus. Surface electrostatic charge predication on the PB2 structural model revealed that the viral polymerase activity in mammalian cells generally increases as this region becomes more positively charged. One of the mutants (701A/702E) showed much reduced pathogenicity in mice while others had a pathogenicity similar to the wild-type level. Distinct tissue tropisms of the PB2-701/702 mutants were observed in infected chicken embryos. Overall, this study demonstrates that the PB2-701/702 region has a high degree of sequence plasticity and sequence changes in this region can alter virus phenotypes in vitro and in vivo. PMID- 28900146 TI - A bead-assisted flow cytometry method for the semi-quantitative analysis of Extracellular Vesicles. AB - Most experimental approaches commonly employed for the characterization and quantitation of EVs are time consuming, require of specialized instrumentation and often are rather inaccurate. To circumvent the caveats imposed by EV small size, we used general and specific membrane markers in bead assisted flow cytometry, to provide a semi-quantitative measure of EV content in a given sample. EVs were isolated from in vitro cultured cells-conditioned medium and biological fluids by size exclusion chromatography and coupled to latex beads to allow their detection by standard flow cytometers. Our analyses demonstrate a linear correlation between EV concentration and Mean Fluorescence Intensity values in samples cleared of protein contaminants. Comparison with one of the most widespread method such as NTA, suggests a similar linear range and reliable accuracy to detect saturation. However, although detection of the different biomarkers is feasible when tested on ultracentrifugation-enriched samples, protein contamination impairs quantitation of this type of samples by bead-based flow cytometry. Thus, we provide evidence that bead-assisted flow cytometry method is an accurate and reliable method for the semiquantitative bulk analysis of EVs, which could be easily implemented in most laboratories. PMID- 28900147 TI - Depletion of Cr(VI) from aqueous solution by heat dried biomass of a newly isolated fungus Arthrinium malaysianum: A mechanistic approach. AB - For the first time, the heat dried biomass of a newly isolated fungus Arthrinium malaysianum was studied for the toxic Cr(VI) adsorption, involving more than one mechanism like physisorption, chemisorption, oxidation-reduction and chelation. The process was best explained by the pseudo-second order kinetic model and Redlich-Peterson isotherm with maximum predicted biosorption capacity (Q m ) of 100.69 mg g-1. Film-diffusion was the rate-controlling step and the adsorption was spontaneous, endothermic and entropy-driven. The mode of interactions between Cr(VI) ions and fungal biomass were investigated by several methods [Fourier Transform-Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD) and Energy Dispersive X-ray spectroscopy (EDX)]. X-ray Photoelectron Spectroscopy (XPS) studies confirmed significant reduction of Cr(VI) into non-toxic Cr(III) species. Further, a modified methodology of Atomic Force Microscopy was successfully attempted to visualize the mycelial ultra-structure change after chromium adsorption. The influence of pH, biomass dose and contact time on Cr(VI) depletion were evaluated by Response Surface Model (RSM). FESEM-EDX analysis also exhibited arsenic (As) and lead (Pb) peaks on fungus surface upon treating with synthetic solutions of NaAsO2 and Pb(NO3)2 respectively. Additionally, the biomass could also remove chromium from industrial effluents, suggesting the fungal biomass as a promising adsorbent for toxic metals removal. PMID- 28900148 TI - Evaluation of Bleb Fluid After Baerveldt Glaucoma Implantation Using Magnetic Resonance Imaging. AB - We evaluated bleb fluid images taken after Baerveldt glaucoma implantation. T2 weighted images of bleb fluid were scanned with 3 Tesla magnetic resonance imaging in 52 patients who had undergone tube-shunt surgery using the 350-mm2 endplate Baerveldt glaucoma implant; three-dimensional images were constructed from these images. Bleb fluid images were classified into either a layer of bleb fluid on either side of the endplate (double bleb layer group; n = 24) or one layer outside the endplate (single bleb layer group; n = 28). Despite there being no correlation between the bleb volume and the postoperative IOP (r = -0.080; P = 0.57), the double bleb layer group had significantly lower postoperative IOPs than the single bleb layer group (12.3 +/- 3.8 mmHg vs. 14.7 +/- 4.1 mmHg, respectively; P = 0.033). The single bleb layer was significantly related to higher numbers of prior intraocular surgeries (relative risk = 2.85; P = 0.0014). Formation of a layer of bleb fluid on either side of the endplate may have resulted in the lower postoperative IOPs after Baerveldt glaucoma implantation. Repeated intraocular surgery adversely affects formation of the double bleb layer. PMID- 28900149 TI - Assessment of T-cell receptor repertoire and clonal expansion in peripheral T cell lymphoma using RNA-seq data. AB - T-cell clonality of peripheral T-cell lymphoma (PTCL) is routinely evaluated with a PCR-based method using genomic DNA. However, there are limitations with this approach. The purpose of this study was to determine the utility of RNA-seq for assessing T-cell clonality and T-cell antigen receptor (TCR) repertoire of the neoplastic T-cells in 108 PTCL samples. TCR transcripts, including complementarity-determining region 3 (CDR3) sequences, were assessed. In normal T cells, the CDR3 sequences were extremely diverse, without any clonotype representing more than 2% of the overall TCR population. Dominant clones could be identified in 65 out of 76 PTCL cases (86%) with adequate TCR transcript expression. In monoclonal cases, the dominant clone varied between 11% and 99% of TCRbeta transcripts. No unique Valpha or Vbeta usage was observed. Small T-cell clones were often observed in T- and NK-cell tumors in a percentage higher than observed in reactive conditions. gamma chain expression was very low in tumors expressing TCRalphabeta, but its expression level was high and clonality was detected in a TCRgammadelta expressing tumor. NK cell lymphoma (NKCL) did not express significant levels of TCR Vbeta or Vgamma genes. RNA-seq is a useful tool for detecting and characterizing clonal TCR rearrangements in PTCL. PMID- 28900150 TI - High throughput data analyses of the immune characteristics of Microtus fortis infected with Schistosoma japonicum. AB - Microtus fortis exhibits natural resistance against Schistosoma japonicum, and the parasite cannot grow and develop in M. fortis. Extensive research has been carried out, however, the associated mechanism remains unclear. In the present study, we analysed the combined data obtained from a cytokine chip assay, transcriptome, and metabolome. The cytokine profile from C57BL/6 and M. fortis mice was assessed before and after infection. Several cytokines increased during the second and third week post-infection. Some transcripts related to cytokine genes and associated proteins were also highly expressed (i.e., Hgf, C3, and Lbp). The liver metabolism of M. fortis following infection with S. japonicum was assessed. We identified 25 different metabolites between the uninfected and infected M. fortis, and 22 different metabolites between infected M. fortis and C57BL/6 mice. The metabolomic pathways of these differential metabolites were then analysed with MetPA, revealing that they were involved in histidine metabolism, valine, leucine, and isoleucine biosyntheses, and lysine degradation. Thus, the elevated expression of these metabolites and pathways may promote the phagocytic function of the neutrophils and natural killer cell activity following TLR activation. These results provide novel insight into the resistance mechanism of M. fortis against S. japonicum. PMID- 28900151 TI - In situ vocal fold properties and pitch prediction by dynamic actuation of the songbird syrinx. AB - The biomechanics of sound production forms an integral part of the neuromechanical control loop of avian vocal motor control. However, we critically lack quantification of basic biomechanical parameters describing the vocal organ, the syrinx, such as material properties of syringeal elements, forces and torques exerted on, and motion of the syringeal skeleton during song. Here, we present a novel marker-based 3D stereoscopic imaging technique to reconstruct 3D motion of servo-controlled actuation of syringeal muscle insertions sites in vitro and focus on two muscles controlling sound pitch. We furthermore combine kinematic analysis with force measurements to quantify elastic properties of sound producing medial labia (ML). The elastic modulus of the zebra finch ML is 18 kPa at 5% strain, which is comparable to elastic moduli of mammalian vocal folds. Additionally ML lengthening due to musculus syringealis ventralis (VS) shortening is intrinsically constraint at maximally 12% strain. Using these values we predict sound pitch to range from 350-800 Hz by VS modulation, corresponding well to previous observations. The presented methodology allows for quantification of syringeal skeleton motion and forces, acoustic effects of muscle recruitment, and calibration of computational birdsong models, enabling experimental access to the entire neuromechanical control loop of vocal motor control. PMID- 28900152 TI - A 3D magnetic tissue stretcher for remote mechanical control of embryonic stem cell differentiation. AB - The ability to create a 3D tissue structure from individual cells and then to stimulate it at will is a major goal for both the biophysics and regenerative medicine communities. Here we show an integrated set of magnetic techniques that meet this challenge using embryonic stem cells (ESCs). We assessed the impact of magnetic nanoparticles internalization on ESCs viability, proliferation, pluripotency and differentiation profiles. We developed magnetic attractors capable of aggregating the cells remotely into a 3D embryoid body. This magnetic approach to embryoid body formation has no discernible impact on ESC differentiation pathways, as compared to the hanging drop method. It is also the base of the final magnetic device, composed of opposing magnetic attractors in order to form embryoid bodies in situ, then stretch them, and mechanically stimulate them at will. These stretched and cyclic purely mechanical stimulations were sufficient to drive ESCs differentiation towards the mesodermal cardiac pathway.The development of embryoid bodies that are responsive to external stimuli is of great interest in tissue engineering. Here, the authors culture embryonic stem cells with magnetic nanoparticles and show that the presence of magnetic fields could affect their aggregation and differentiation. PMID- 28900153 TI - Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload. AB - Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy. PMID- 28900154 TI - Synthesis and Evaluation of GM2-Monophosphoryl Lipid A Conjugate as a Fully Synthetic Self-Adjuvant Cancer Vaccine. AB - An efficient method was developed for the synthesis of a GM2 derivative suitable for the conjugation with various biomolecules. This GM2 derivative was covalently linked to keyhole limpet hemocyanin (KLH) and monophosphoryl lipid A (MPLA) to form novel therapeutic cancer vaccines. Immunological evaluations of the resultant conjugates in mice revealed that they elicited robust GM2-specific overall and IgG antibody responses. Moreover, the GM2-MPLA conjugate was disclosed to elicit strong immune responses without the use of an adjuvant, proving its self-adjuvant property. The antisera of both conjugates showed strong binding and mediated similarly effective complement-dependent cytotoxicity to GM2 expressing cancer cell line MCF-7. Based on these results, it was concluded that both GM2-MPLA and GM2-KLH are promising candidates as therapeutic cancer vaccines, whereas fully synthetic GM2-MPLA, which has homogeneous and well defined structure and self-adjuvant property, deserves more attention and studies. PMID- 28900155 TI - Inflexible neurobiological signatures precede atypical development in infants at high risk for autism. AB - Variability in neurobiological signatures is ubiquitous in early life but the link to adverse developmental milestones in humans is unknown. We examined how levels of signal and noise in movement signatures during the 1st year of life constrain early development in 71 healthy typically developing infants, either at High or Low familial Risk (HR or LR, respectively) for developing Autism Spectrum Disorders (ASD). Delays in early learning developmental trajectories in HR infants (validated in an analysis of 1,445 infants from representative inf ant sibling studies) were predicted by worse stochastic patterns in their spontaneous head movements as early as 1-2 months after birth, relative to HR infants who showed more rapid developmental progress, as well as relative to all LR infants. While LR 1-2 mo-old infants' movements were significantly different during a language listening task compared to during sleep, HR infants' movements were more similar during both conditions, a striking lack of diversity that reveals context inflexible experience of ambient information. Contrary to expectation, it is not the level of variability per se that is particularly detrimental in early life. Rather, inflexible sensorimotor systems and/or atypical transition between behavioral states may interfere with the establishment of capacity to extract structure and important cues from sensory input at birth, preceding and contributing to an atypical brain developmental trajectory in toddlerhood. PMID- 28900156 TI - Dual Roles of Two Isoforms of Autophagy-related Gene ATG10 in HCV-Subgenomic replicon Mediated Autophagy Flux and Innate Immunity. AB - Autophagy and immune response are two defense systems that human-body uses against viral infection. Previous studies documented that some viral mechanisms circumvented host immunity mechanisms and hijacked autophagy for its replication and survival. Here, we focus on interactions between autophagy mechanism and innate-immune-response in HCV-subgenomic replicon cells to find a mechanism linking the two pathways. We report distinct effects of two autophagy-related protein ATG10s on HCV-subgenomic replication. ATG10, a canonical long isoform in autophagy process, can facilitate HCV-subgenomic replicon amplification by promoting autophagosome formation and by combining with and detaining autophagosomes in cellular periphery, causing impaired autophagy flux. ATG10S, a non-canonical short isoform of ATG10 proteins, can activate expression of IL28A/B and immunity genes related to viral ds-RNA including ddx-58, tlr-3, tlr-7, irf-3 and irf-7, and promote autophagolysosome formation by directly combining and driving autophagosomes to perinuclear region where lysosomes gather, leading to lysosomal degradation of HCV-subgenomic replicon in HepG2 cells. ATG10S also can suppress infectious HCV virion replication in Huh7.5 cells. Another finding is that IL28A protein directly conjugates ATG10S and helps autophagosome docking to lysosomes. ATG10S might be a new host factor against HCV replication, and as a target for screening chemicals with new anti-virus mechanisms. PMID- 28900157 TI - Synergy of two low-affinity NLSs determines the high avidity of influenza A virus nucleoprotein NP for human importin alpha isoforms. AB - The influenza A virus nucleoprotein (NP) is an essential multifunctional protein that encapsidates the viral genome and functions as an adapter between the virus and the host cell machinery. NPs from all strains of influenza A viruses contain two nuclear localization signals (NLSs): a well-studied monopartite NLS1 and a less-characterized NLS2, thought to be bipartite. Through site-directed mutagenesis and functional analysis, we found that NLS2 is also monopartite and is indispensable for viral infection. Atomic structures of importin alpha bound to two variants of NLS2 revealed NLS2 primarily binds the major-NLS binding site of importin alpha, unlike NLS1 that associates with the minor NLS-pocket. Though peptides corresponding to NLS1 and NLS2 bind weakly to importin alpha, the two NLSs synergize in the context of the full length NP to confer high avidity for importin alpha7, explaining why the virus efficiently replicates in the respiratory tract that exhibits high levels of this isoform. This study, the first to functionally characterize NLS2, demonstrates NLS2 plays an important and unexpected role in influenza A virus infection. We propose NLS1 and NLS2 form a bipartite NLS in trans, which ensures high avidity for importin alpha7 while preventing non-specific binding to viral RNA. PMID- 28900158 TI - Dynamic oropharyngeal and faecal microbiota during treatment in infants hospitalized for bronchiolitis compared with age-matched healthy subjects. AB - Bronchiolitis is one of the most severe diseases affecting infants worldwide. An imbalanced oropharynx (OP) microbiota has been reported in infants hospitalized with bronchiolitis; however, the microbiota dynamics in the OP and faeces during therapy remain unexplored. In total, 27 infants who were hospitalized with bronchiolitis were selected for this study, and sampling was conducted before therapy and after clinical recovery. We also recruited 22 age-matched healthy infants for this study. The faecal and OP microbiota diversity in the patients was lower than that in the healthy children. The faecal microbiota (FM) in the diseased children significantly differed from that in the healthy subjects and contained accumulated Bacteroides and Streptococcus. The OP microbiota in both the healthy and diseased infants was dominated by Streptococcus. After the treatment, the FM and OP microbiota in the patients was comparable to that before the treatment. This study may serve as an additional reference for future bronchiolitis studies, and the "risk microbiota model" of clinically recovered infants suggests an increased susceptibility to pathogen intrusion. PMID- 28900159 TI - Computational Cell Cycle Profiling of Cancer Cells for Prioritizing FDA-Approved Drugs with Repurposing Potential. AB - Discovery of first-in-class medicines for treating cancer is limited by concerns with their toxicity and safety profiles, while repurposing known drugs for new anticancer indications has become a viable alternative. Here, we have developed a new approach that utilizes cell cycle arresting patterns as unique molecular signatures for prioritizing FDA-approved drugs with repurposing potential. As proof-of-principle, we conducted large-scale cell cycle profiling of 884 FDA approved drugs. Using cell cycle indexes that measure changes in cell cycle profile patterns upon chemical perturbation, we identified 36 compounds that inhibited cancer cell viability including 6 compounds that were previously undescribed. Further cell cycle fingerprint analysis and 3D chemical structural similarity clustering identified unexpected FDA-approved drugs that induced DNA damage, including clinically relevant microtubule destabilizers, which was confirmed experimentally via cell-based assays. Our study shows that computational cell cycle profiling can be used as an approach for prioritizing FDA-approved drugs with repurposing potential, which could aid the development of cancer therapeutics. PMID- 28900160 TI - Induction of oxidative metabolism by the p38alpha/MK2 pathway. AB - Adequate responses to environmental stresses are essential for cell survival. The regulation of cellular energetics that involves mitochondrial energy production and oxidative stress is central in the process of stress adaptation and response. The p38alpha signalling pathway plays a key role in the response to stress stimuli by orchestrating multiple cellular processes. However, prolonged activation of the p38alpha pathway results in impaired cell proliferation and can lead to cell death. Here we use a system to specifically activate p38alpha signalling and show that sustained activation of this pathway suffices to induce important metabolic changes, including high dependence on glucose for cell survival, increased consumption of glutamine, enhanced respiration rate and elevated production of mitochondrial reactive oxygen species (ROS). Moreover, we provide evidence that increased production of mitochondrial superoxide as a consequence of elevated mitochondria activity, contributes to the p38alpha reduced cell survival triggered by sustained p38alpha activation. We also show that the p38alpha-activated kinase MAPKAPK2 (MK2) plays an important role orchestrating the observed metabolic changes. Our results illustrate a new function of p38alpha signalling in the regulation of cellular metabolism, which may lead to cell death upon persistent activation of the pathway. PMID- 28900161 TI - Acetyl-4'-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency. AB - Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency. PMID- 28900162 TI - New model for predicting preterm delivery during the second trimester of pregnancy. AB - In this study, a new model for predicting preterm delivery (PD) was proposed. The primary model was constructed using ten selected variables, as previously defined in seventeen different studies. The ability of the model to predict PD was evaluated using the combined measurement from these variables. Therefore, a prospective investigation was performed by enrolling 130 pregnant patients whose gestational ages varied from 17+0 to 28+6 weeks. The patients underwent epidemiological surveys and ultrasonographic measurements of their cervixes, and cervicovaginal fluid and serum were collected during a routine speculum examination performed by the managing gynecologist. The results showed eight significant variables were included in the present analysis, and combination of the positive variables indicated an increased probability of PD in pregnant patients. The accuracy for predicting PD were as follows: one positive - 42.9%; two positives - 75.0%; three positives - 81.8% and four positives - 100.0%. In particular, the combination of >=2* positives had the best predictive value, with a relatively high sensitivity (82.6%), specificity (88.1%) and accuracy rate (79.2%), and was considered the cut-off point for predicting PD. In conclusion, the new model provides a useful reference for evaluating the risk of PD in clinical cases. PMID- 28900163 TI - Spatio-temporal and dynamic regulation of neurofascin alternative splicing in mouse cerebellar neurons. AB - Alternative splicing is crucial for molecular diversification, which greatly contributes to the complexity and specificity of neural functions in the central nervous system (CNS). Neurofascin (NF) is a polymorphic cell surface protein that has a number of splicing isoforms. As the alternative splicing of the neurofascin gene (Nfasc) is developmentally regulated, NF isoforms have distinct functions in immature and mature brains. However, the molecular mechanisms underlying the alternative splicing of Nfasc in neurons are not yet understood. Here, we demonstrate that, alongside developmental regulation, Nfasc alternative splicing is spatially controlled in the mouse brain. We then identified distinct Nfasc splicing patterns at the cell-type level in the cerebellum, with Nfasc186 being expressed in Purkinje cells and absent from granule cells (GCs). Furthermore, we show that high K+-induced depolarization triggers a shift in splicing from Nfasc140 to Nfasc186 in cerebellar GCs. Finally, we identified a neural RNA binding protein, Rbfox, as a key player in neural NF isoform selection, specifically controlling splicing at exons 26-29. Together, our results show that Nfasc alternative splicing is spatio-temporally and dynamically regulated in cerebellar neurons. Our findings provide profound insight into the mechanisms underlying the functional diversity of neuronal cell-adhesive proteins in the mammalian CNS. PMID- 28900164 TI - Enhancing laser-driven proton acceleration by using micro-pillar arrays at high drive energy. AB - The interaction of micro- and nano-structured target surfaces with high-power laser pulses is being widely investigated for its unprecedented absorption efficiency. We have developed vertically aligned metallic micro-pillar arrays for laser-driven proton acceleration experiments. We demonstrate that such targets help strengthen interaction mechanisms when irradiated with high-energy-class laser pulses of intensities ~1017-18 W/cm2. In comparison with standard planar targets, we witness strongly enhanced hot-electron production and proton acceleration both in terms of maximum energies and particle numbers. Supporting our experimental results, two-dimensional particle-in-cell simulations show an increase in laser energy conversion into hot electrons, leading to stronger acceleration fields. This opens a window of opportunity for further improvements of laser-driven ion acceleration systems. PMID- 28900165 TI - GCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis. AB - The mitochondrial enriched GCN5-like 1 (GCN5L1) protein has been shown to modulate mitochondrial protein acetylation, mitochondrial content and mitochondrial retrograde signaling. Here we show that hepatic GCN5L1 ablation reduces fasting glucose levels and blunts hepatic gluconeogenesis without affecting systemic glucose tolerance. PEPCK and G6Pase transcript levels are downregulated in hepatocytes from GCN5L1 liver specific knockout mice and their upstream regulator, FoxO1 protein levels are decreased via proteasome-dependent degradation and via reactive oxygen species mediated ERK-1/2 phosphorylation. ERK inhibition restores FoxO1, gluconeogenic enzyme expression and glucose production. Reconstitution of mitochondrial-targeted GCN5L1 blunts mitochondrial ROS, ERK activation and increases FoxO1, gluconeogenic enzyme expression and hepatocyte glucose production. We suggest that mitochondrial GCN5L1 modulates post-translational control of FoxO1, regulates gluconeogenesis and controls metabolic pathways via mitochondrial ROS mediated ERK activation. Exploring mechanisms underpinning GCN5L1 mediated ROS signaling may expand our understanding of the role of mitochondria in gluconeogenesis control.Hepatic gluconeogenesis is tightly regulated at transcriptional level and is essential for survival during prolonged fasting. Here Wang et al. show that the mitochondrial enriched GCN5-like 1 protein controls hepatic glucose production by regulating FoxO1 protein levels via proteasome-dependent degradation and, in turn, gluconeogenic gene expression. PMID- 28900166 TI - Development of novel Meju starter culture using plant extracts with reduced Bacillus cereus counts and enhanced functional properties. AB - We developed a novel type of Meju starter culture using single and combined extracts of Allium sativum (garlic clove), Nelumbo nucifera (lotus leaves), and Ginkgo biloba (ginkgo leaves) to improve the quality and functionality of Meju based fermented products. Meju samples fermented with plant extracts (10 mg/ml) showed phenolic contents of 11.4-31.6 mg/g (gallic acid equivalents). Samples of extracts (garlic clove, lotus leaves, ginkgo leaves and their combination) fermented with Meju strongly inhibited tyrosinase, alpha-glucosidase, and elastase activities by 36.43-64.34%, 45.08-48.02%, and 4.52-10.90%, respectively. Specifically, ginkgo leaves extract added to fermented Meju samples at different concentrations (1% and 10%) strongly inhibited tyrosinase, alpha-glucosidase, and elastase activities and exhibited a potent antibacterial effect against Bacillus cereus with a significant reduction in bacterial counts compared with the effects observed for garlic clove and lotus leaf added to Meju samples. Scanning electron microscopy revealed severe morphological alterations of the B. cereus cell wall in response to ginkgo leaf extracts. Gas chromatographic mass spectroscopic analysis of plant extract-supplemented Meju samples and control Meju samples identified 113 bioactive compounds representing 98.44-99.98% total extract. The proposed approach may be useful for the development of various fermented functional foods at traditional and commercial levels. PMID- 28900167 TI - Unexpected viscoelastic deformation of tight sandstone: Insights and predictions from the fractional Maxwell model. AB - Tight gas is one important unconventional hydrocarbon resource that is stored in tight sandstone, whose mechanical property greatly influences the tight gas production process and is commonly believed to be simply elastic when designing the stimulation plan. However, the experimental evidence provided in this work surprisingly shows that tight sandstone can deform in a viscoelastic way. Such an unexpected observation poses a challenge in accurately modelling the deformation process. We solve this problem by adopting the fractional Maxwell model to successfully derive the constitutive equation of tight sandstone, based on which not only all the experimental data can be interpreted quantitatively, but also reasonable and consistent predictions as to tight sandstone's long-term deformation behaviour can be made. We then investigate the typicality of our results in China's Changqing oilfield, which is one major centre of tight gas production and where the rock samples for experiments are obtained. It is estimated that a non-negligible portion of 18% tight sandstone samples in this area will probably display viscoelasticity. Finally, our work implies that the mechanical properties of other materials may also need further scrutiny to possibly uncover any unexpected behaviour, overlooking which may result in misleading predictions. PMID- 28900168 TI - Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach. AB - Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl4-induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early prediction and to reveal significant fibrotic pathways and their dynamic changes in different stages of liver fibrosis. Finally, nine differential metabolites in urine and ten in serum were selected and identified involving the most relevant metabolic pathways. Perturbations of tryptophan, valine, leucine, isoleucine, and citrate (TCA) cycle metabolites, along with sphingolipid and glycerophospholipid metabolites, occurred from the onset of liver fibrosis. Furthermore, dysregulation of valine and bile acid biosynthesis metabolites occurred in the intermediate and advanced stages. More importantly, among these metabolites, urinary kynurenic acid, 5 hydroxyindoleacetyl glycine, 4-(2-amino-3-hydroxyphenyl)-2,4-dioxobutanoic acid and serum sphinganine, sphingomyelin, L-leucine, L-tryptophan, and LysoPC(17:0) changed at all time points and may serve as potential early biomarkers for the diagnosis of hepatic fibrosis and as therapeutic targets. Overall, this work evaluates the potential of these metabolites for the early detection of liver fibrosis. PMID- 28900169 TI - Negative Differential Conductance & Hot-Carrier Avalanching in Monolayer WS2 FETs. AB - The high field phenomena of inter-valley transfer and avalanching breakdown have long been exploited in devices based on conventional semiconductors. In this Article, we demonstrate the manifestation of these effects in atomically-thin WS2 field-effect transistors. The negative differential conductance exhibits all of the features familiar from discussions of this phenomenon in bulk semiconductors, including hysteresis in the transistor characteristics and increased noise that is indicative of travelling high-field domains. It is also found to be sensitive to thermal annealing, a result that we attribute to the influence of strain on the energy separation of the different valleys involved in hot-electron transfer. This idea is supported by the results of ensemble Monte Carlo simulations, which highlight the sensitivity of the negative differential conductance to the equilibrium populations of the different valleys. At high drain currents (>10 MUA/MUm) avalanching breakdown is also observed, and is attributed to trap assisted inverse Auger scattering. This mechanism is not normally relevant in conventional semiconductors, but is possible in WS2 due to the narrow width of its energy bands. The various results presented here suggest that WS2 exhibits strong potential for use in hot-electron devices, including compact high frequency sources and photonic detectors. PMID- 28900170 TI - Protein arginylation targets alpha synuclein, facilitates normal brain health, and prevents neurodegeneration. AB - Alpha synuclein (alpha-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that alpha-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased alpha-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways. In the mouse brain, lack of arginylation leads to an increase in alpha-syn's insoluble fraction, accompanied by behavioral changes characteristic for neurodegenerative pathology. Our data show that lack of arginylation in the brain leads to neurodegeneration, and suggests that alpha-syn arginylation can be a previously unknown factor that facilitates normal alpha-syn folding and function in vivo. PMID- 28900171 TI - Mechanistic insight into internal conversion process within Q-bands of chlorophyll a. AB - The non-radiative relaxation of the excitation energy from higher energy states to the lowest energy state in chlorophylls is a crucial preliminary step for the process of photosynthesis. Despite the continuous theoretical and experimental efforts to clarify the ultrafast dynamics of this process, it still represents the object of an intense investigation because the ultrafast timescale and the congestion of the involved states makes its characterization particularly challenging. Here we exploit 2D electronic spectroscopy and recently developed data analysis tools to provide more detailed insights into the mechanism of internal conversion within the Q-bands of chlorophyll a. The measurements confirmed the timescale of the overall internal conversion rate (170 fs) and captured the presence of a previously unidentified ultrafast (40 fs) intermediate step, involving vibronic levels of the lowest excited state. PMID- 28900172 TI - Cultural and Developmental Influences on Overt Visual Attention to Videos. AB - Top-down influences on observers' overt attention and how they interact with the features of the visual environment have been extensively investigated, but the cultural and developmental aspects of these modulations have been understudied. In this study we investigated these effects for US and Yucatec Mayan infants, children, and adults. Mayan and US participants viewed videos of two actors performing daily Mayan and US tasks in the foreground and the background while their eyes were tracked. Our region of interest analysis showed that viewers from the US looked significantly less at the foreground activity and spent more time attending to the 'contextual' information (static background) compared to Mayans. To investigate how and what visual features of videos were attended to in a comprehensive manner, we used multivariate methods which showed that visual features are attended to differentially by each culture. Additionally, we found that Mayan and US infants utilize the same eye-movement patterns in which fixation duration and saccade amplitude are altered in response to the visual stimuli independently. However, a bifurcation happens by age 6, at which US participants diverge and engage in eye-movement patterns where fixation durations and saccade amplitudes are altered simultaneously. PMID- 28900174 TI - A broadband photodetector based on Rhodamine B-sensitized ZnO nanowires film. AB - A broadband photodetector has been developed on the basis of ZnO nanowires (NWs)/Rhodamine B (RhB) hybrid system. The device is fabricated by spraying NWs on to gold interdigital electrodes followed by modifying the NWs via an RhB solution-casting process. Measurements show that the as-fabricated device demonstrates photoresponsivity ranging from 300 nm to 700 nm with a bandwidth as large as 400 nm. The role of the dye sensitizer adsorbed on the surface of NWs is modeled to alter the transportation path of photo-generated carriers. The calculations based on the measurements reveal that the device exhibits a prominent responsivity in the interested band with maximum responsivity of 5.5 A/W for ultraviolet (UV) light and 3 A/W for visible (VIS) light under 8 V bias, respectively. The sensitization not only widens the response spectrum with external quantum efficiency leaping up to 771% at VIS but also improves UV responsivity with maximum 51% enhancement. From the time-dependent photo-current measurement, it is found that the response time (rise and decay times in total) of the device largely reduced from 17.5 s to 3.3 s after sensitization. A comparison of the obtained photodetector with other ZnO-based photodetectors is summarized from the view point of responsivity and bandwidth. PMID- 28900173 TI - FGFR inhibitor, AZD4547, impedes the stemness of mammary epithelial cells in the premalignant tissues of MMTV-ErbB2 transgenic mice. AB - The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) regulates signaling pathways involved in cell proliferation and differentiation. Currently, the anti-tumor properties of FGFR inhibitors are being tested in preclinical and clinical studies. Nevertheless, reports on FGFR inhibitor-mediated breast cancer prevention are sparse. In this study, we investigated the anti-cancer benefits of AZD4547, an FGFR1-3 inhibitor, in ErbB2 overexpressing breast cancer models. AZD4547 (1-5 uM) demonstrated potent anti proliferative effects, inhibition of stemness, and suppression of FGFR/RTK signaling in ErbB2-overexpressing human breast cancer cells. To study the in vivo effects of AZD4547 on mammary development, mammary epithelial cell (MEC) populations, and oncogenic signaling, MMTV-ErbB2 transgenic mice were administered AZD4547 (2-6 mg/kg/day) for 10 weeks during the 'risk window' for mammary tumor development. AZD4547 significantly inhibited ductal branching and MEC proliferation in vivo, which corroborated the in vitro anti-proliferative properties. AZD4547 also depleted CD24/CD49f-sorted MEC populations, as well as the CD61highCD49fhigh tumor-initiating cell-enriched population. Importantly, AZD4547 impaired stem cell-like characteristics in primary MECs and spontaneous tumor cells. Moreover, AZD4547 downregulated RTK, mTOR, and Wnt/beta-catenin signaling pathways in premalignant mammary tissues. Collectively, our data provide critical preclinical evidence for AZD4547 as a potential breast cancer preventative and therapeutic agent. PMID- 28900177 TI - Comparison of soil analytical methods for estimating wheat potassium fertilizer requirements in response to contrasting plant K demand in the glasshouse. AB - The traditional soil potassium (K) testing methods fail to accurately predict K requirement by plants. The Diffusive Gradients in Thin-films (DGT) method is promising, but the relationship between the DGT-measured K pool and plant available K is not clear. Wheat (Triticum aestivum L., cv. Frame) was grown in 9 Australian broad acre agricultural soils in a glasshouse trial until the end of tillering growth stage (GS30) with different plant K demands generated by varying plant numbers and pot sizes. Different K concentrations in soils were varied by 4 rates of K fertilizer application. The relative dry matter and K uptake were plotted against the soil K test value (CaCl2, Colwell and NH4OAc and DGT K measurements). To obtain 90% of maximum relative dry matter at low root density (closest to field conditions), the critical value of the NH4OAc K method was 91 (R2 = 0.56) mg kg-1. The DGT K method was not able to accurately predict relative dry matter or K uptake due to a weak extraction force for K from soils with high CEC values. Further endeavor on increasing K extraction force of the DGT method is warranted to obtain accurate plant available K results. PMID- 28900175 TI - Dynamic and Kinetic Elements of u-Opioid Receptor Functional Selectivity. AB - While the therapeutic effect of opioids analgesics is mainly attributed to u opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to beta-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throughput molecular dynamics simulations of MOR bound to a classical opioid drug (morphine) or a potent G protein-biased agonist (TRV-130). Statistical analyses of Markov state models built using this large simulation dataset combined with information theory enabled, for the first time: a) Identification of four distinct metastable regions along the activation pathway, b) Kinetic evidence of a different dynamic behavior of the receptor bound to a classical or G protein-biased opioid agonist, c) Identification of kinetically distinct conformational states to be used for the rational design of functionally selective ligands that may eventually be developed into improved drugs; d) Characterization of multiple activation/deactivation pathways of MOR, and e) Suggestion from calculated transition timescales that MOR conformational changes are not the rate-limiting step in receptor activation. PMID- 28900176 TI - Network attributes underlying intellectual giftedness in the developing brain. AB - Brain network is organized to maximize the efficiency of both segregated and integrated information processing that may be related to human intelligence. However, there have been surprisingly few studies that focus on the topological characteristics of brain network underlying extremely high intelligence that is intellectual giftedness, particularly in adolescents. Here, we examined the network topology in 25 adolescents with superior intelligence (SI-Adol), 25 adolescents with average intelligence (AI-Adol), and 27 young adults with AI (AI Adult). We found that SI-Adol had network topological properties of high global efficiency as well as high clustering with a low wiring cost, relative to AI Adol. However, contrary to the suggested role that brain hub regions play in general intelligence, the network efficiency of rich club connection matrix, which represents connections among brain hubs, was low in SI-Adol in comparison to AI-Adol. Rather, a higher level of local connection density was observed in SI Adol than in AI-Adol. The highly intelligent brain may not follow this efficient yet somewhat stereotypical process of information integration entirely. Taken together, our results suggest that a highly intelligent brain may communicate more extensively, while being less dependent on rich club communications during adolescence. PMID- 28900178 TI - Uniformly dispersed platinum-cobalt alloy nanoparticles with stable compositions on carbon substrates for methanol oxidation reaction. AB - Alloying platinum (Pt) with suitable transition metals is effective way to enhance their catalytic performance for methanol oxidation reaction, and reduce their cost at mean time. Herein, we report our investigation on the synthesis of bimetallic platinum-cobalt (PtCo) alloy nanoparticles, their activation, as well as the catalytic evaluation for methanol oxidation reaction. The strategy starts with the synthesis of PtCo alloy nanoparticles in an organic medium, followed by loading on carbon substrates. We then remove the capping agent by refluxing the carbon-supported PtCo particles in acetic acid before electrochemical measurements. We emphasize the change in composition of the alloys during refluxing process, and the initial PtCo alloys with Pt/Co ratio of 1/2 turns into stable alloys with Pt/Co ratio of 3/1. The final Pt3Co particles have uniform distribution on carbon substrates, and exhibit activity with 2.4 and 1.5 times of that for commercial Pt/C and PtRu/C for methanol oxidation reaction. PMID- 28900179 TI - MicroRNA-28 potentially regulates the photoreceptor lineage commitment of Muller glia-derived progenitors. AB - Retinal degenerative diseases ultimately result into irreversible photoreceptor death or loss. At present, the most promising treatment for these diseases is cell replacement therapy. Muller glia are the major glia in the retina, displaying cardinal features of retinal progenitor cells, and can be candidate of seed cells for retinal degenerative diseases. Here, mouse retinal Muller glia dissociated and cultured in vitro amplified and were dedifferentiated into Muller glia-derived progenitors (MGDPs), demonstrating expression of stem/progenitor cell markers Nestin, Sox2 and self-renewal capacity. MicroRNAs (miRNAs) play unique roles in the retinogenesis, so we hypothesized miRNAs would contribute to photoreceptor lineage commitment of MGDPs. By TargetScan, Miranda, and Pictar bioinformatics, gain/loss-of-function models, dual luciferase assay, we identified and validated that miR-28 targeted the photoreceptor-specific CRX transcription factor. Anti-miR-28 could induce MGDPs to differentiate into neurons strongly expressing CRX and Rhodopsin, while miR-28 mimic suppressed CRX and Rhodopsin expression. Knockdown of CRX by siRNA blocked the expression of CRX and Rhodospin upregulated by anti-miR-28, indicating that anti-miR-28 potentially induced photoreceptor commitment of MGDPs by targeting CRX, but more experiments are necessary to confirm their role in differentiation. PMID- 28900180 TI - Emotion perception improvement following high frequency transcranial random noise stimulation of the inferior frontal cortex. AB - Facial emotion perception plays a key role in interpersonal communication and is a precursor for a variety of socio-cognitive abilities. One brain region thought to support emotion perception is the inferior frontal cortex (IFC). The current study aimed to examine whether modulating neural activity in the IFC using high frequency transcranial random noise stimulation (tRNS) could enhance emotion perception abilities. In Experiment 1, participants received either tRNS to IFC or sham stimulation prior to completing facial emotion and identity perception tasks. Those receiving tRNS significantly outperformed those receiving sham stimulation on facial emotion, but not identity, perception tasks. In Experiment 2, we examined whether baseline performance interacted with the effects of stimulation. Participants completed a facial emotion and identity discrimination task prior to and following tRNS to either IFC or an active control region (area V5/MT). Baseline performance was a significant predictor of emotion discrimination performance change following tRNS to IFC. This effect was not observed for tRNS targeted at V5/MT or for identity discrimination. Overall, the findings implicate the IFC in emotion processing and demonstrate that tRNS may be a useful tool to modulate emotion perception when accounting for individual differences in factors such as baseline task performance. PMID- 28900181 TI - Heterogeneity Aware Random Forest for Drug Sensitivity Prediction. AB - Samples collected in pharmacogenomics databases typically belong to various cancer types. For designing a drug sensitivity predictive model from such a database, a natural question arises whether a model trained on diverse inter tumor heterogeneous samples will perform similar to a predictive model that takes into consideration the heterogeneity of the samples in model training and prediction. We explore this hypothesis and observe that ensemble model predictions obtained when cancer type is known out-perform predictions when that information is withheld even when the samples sizes for the former is considerably lower than the combined sample size. To incorporate the heterogeneity idea in the commonly used ensemble based predictive model of Random Forests, we propose Heterogeneity Aware Random Forests (HARF) that assigns weights to the trees based on the category of the sample. We treat heterogeneity as a latent class allocation problem and present a covariate free class allocation approach based on the distribution of leaf nodes of the model ensemble. Applications on CCLE and GDSC databases show that HARF outperforms traditional Random Forest when the average drug responses of cancer types are different. PMID- 28900182 TI - Conservation performance of different conservation governance regimes in the Peruvian Amazon. AB - State-controlled protected areas (PAs) have dominated conservation strategies globally, yet their performance relative to other governance regimes is rarely assessed comprehensively. Furthermore, performance indicators of forest PAs are typically restricted to deforestation, although the extent of forest degradation is greater. We address these shortfalls through an empirical impact evaluation of state PAs, Indigenous Territories (ITs), and civil society and private Conservation Concessions (CCs) on deforestation and degradation throughout the Peruvian Amazon. We integrated remote-sensing data with environmental and socio economic datasets, and used propensity-score matching to assess: (i) how deforestation and degradation varied across governance regimes between 2006-2011; (ii) their proximate drivers; and (iii) whether state PAs, CCs and ITs avoided deforestation and degradation compared with logging and mining concessions, and the unprotected landscape. CCs, state PAs, and ITs all avoided deforestation and degradation compared to analogous areas in the unprotected landscape. CCs and ITs were on average more effective in this respect than state PAs, showing that local governance can be equally or more effective than centralized state regimes. However, there were no consistent differences between conservation governance regimes when matched to logging and mining concessions. Future impact assessments would therefore benefit from further disentangling governance regimes across unprotected land. PMID- 28900183 TI - A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model. AB - Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dye ucd6 model, we determined if treatment with HDACi can rescue cone photoreceptor mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue in our dataset. Co-treatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness. PMID- 28900184 TI - Survivin and XIAP - two potential biological targets in follicular thyroid carcinoma. AB - Follicular thyroid carcinoma's (FTC) overall good prognosis deteriorates if the tumour fails to retain radioactive iodine. Therefore, new druggable targets are in high demand for this subset of patients. Here, we investigated the prognostic and biological role of survivin and XIAP in FTC. Survivin and XIAP expression was investigated in 44 FTC and corresponding non-neoplastic thyroid specimens using tissue microarrays. Inhibition of both inhibitor of apoptosis proteins (IAP) was induced by shRNAs or specific small molecule antagonists and functional changes were investigated in vitro and in vivo. Survivin and XIAP were solely expressed in FTC tissue. Survivin expression correlated with an advanced tumour stage and recurrent disease. In addition, survivin proved to be an independent negative prognostic marker. Survivin or XIAP knockdown caused a significant reduction in cell viability and proliferation, activated caspase3/7 and was associated with a reduced tumour growth in vivo. IAP-targeting compounds induced a decrease of cell viability, proliferation and cell cycle activity accompanied by an increase in apoptosis. Additionally, YM155 a small molecule inhibitor of survivin expression significantly inhibited tumour growth in vivo. Both IAPs demonstrate significant functional implications in the oncogenesis of FTCs and thus prove to be viable targets in patients with advanced FTC. PMID- 28900185 TI - Anti-Abeta single-chain variable fragment antibodies restore memory acquisition in a Drosophila model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a prevalent neurodegenerative disorder triggered by the accumulation of soluble assemblies of the amyloid-beta42 (Abeta42) peptide. Despite remarkable advances in understanding the pathogenesis of AD, the development of palliative therapies is still lacking. Engineered anti-Abeta42 antibodies are a promising strategy to stall the progression of the disease. Single-chain variable fragment (scFv) antibodies increase brain penetration and offer flexible options for delivery while maintaining the epitope targeting of full antibodies. Here, we examined the ability of two anti-Abeta scFv antibodies targeting the N-terminal (scFv9) and C-terminal (scFv42.2) regions of Abeta42 to suppress the progressive memory decline induced by extracellular deposition of Abeta42 in Drosophila. Using olfactory classical conditioning, we observe that both scFv antibodies significantly improve memory performance in flies expressing Abeta42 in the mushroom body neurons, which are intimately involved in the coding and storage of olfactory memories. The scFvs effectively restore memory at all ages, from one-day post-eclosion to thirty-day-old flies, proving their ability to prevent the toxicity of different pathogenic assemblies. These data support the application of this paradigm of Abeta42-induced memory loss in Drosophila to investigate the protective activity of Abeta42-binding agents in an AD-relevant functional assay. PMID- 28900186 TI - Improvement of the glycoproteomic toolbox with the discovery of a unique C terminal cleavage specificity of flavastacin for N-glycosylated asparagine. AB - To determine all potential N-glycosylation sites of a glycoprotein, one central aspect of every bottom-up N-glycoproteomic strategy is to generate suitable N glycopeptides that can be detected and analyzed by mass spectrometry. Specific proteases, such as trypsin, bear the potential of generating N-glycopeptides that either carry more than one N-glycosylation site or are too long to be readily analyzed by mass spectrometry- both due to the lack of tryptic cleavage sites near the N-glycosylation site. Here, we present a newly identified cleavage specificity of flavastacin, a protease from Flavobacterium menigosepticum, which up to now - was only reported to cleave peptide bonds N-terminal to aspartic acid residues. In contrast to literature, we could not confirm this N-terminal specificity of flavastacin for aspartic acid. However, for the first time, we show a unique cleavage specificity of flavastacin towards the C-terminus of N glycosylated asparagine residues. Implemented in an N-glycoproteomic workflow the use of flavastacin can thus not only render data analysis much easier, it can also significantly increase the confidence of MS-based N-glycoproteomic analyses. We demonstrate this newly discovered specificity of flavastacin by in-depth LC MS(/MS) analysis of complex-type glycosylated human lactotransferrin and bovine serum albumin peptides and N-glycopeptides that were generated by trypsin and flavastacin digestion. Following to this work, further elucidation of the efficiency, specificity and mode of action of flavastacin is needed, but we believe that our discovery has great potential to facilitate and improve the characterization of N-glycoproteomes. PMID- 28900187 TI - Electrostatics of non-neutral biological microdomains. AB - Voltage and charge distributions in cellular microdomains regulate communications, excitability, and signal transduction. We report here new electrical laws in a biological cell, which follow from a nonlinear electro diffusion model. These newly discovered laws derive from the geometrical cell membrane properties, such as membrane curvature, volume, and surface area. The electro-diffusion laws can now be used to predict and interpret voltage distribution in cellular microdomains such as synapses, dendritic spine, cilia and more. PMID- 28900188 TI - Decoding finger movement in humans using synergy of EEG cortical current signals. AB - The synchronized activity of neuronal populations across multiple distant brain areas may reflect coordinated interactions of large-scale brain networks. Currently, there is no established method to investigate the temporal transitions between these large-scale networks that would allow, for example, to decode finger movements. Here we applied a matrix factorization method employing principal component and temporal independent component analyses to identify brain activity synchronizations. In accordance with previous studies investigating "muscle synergies", we refer to this activity as "brain activity synergy". Using electroencephalography (EEG), we first estimated cortical current sources (CSs) and then identified brain activity synergies within the estimated CS signals. A decoding analysis for finger movement in eight directions showed that such CS synergies provided more information for dissociating between movements than EEG sensor signals, EEG synergy, or CS signals, suggesting that temporal activation patterns of the synchronizing CSs may contain information related to motor control. A quantitative analysis of features selected by the decoders further revealed temporal transitions among the primary motor area, dorsal and ventral premotor areas, pre-supplementary motor area, and supplementary motor area, which may reflect transitions in motor planning and execution. These results provide a proof of concept for brain activity synergy estimation using CSs. PMID- 28900189 TI - Misalignment with the external light environment drives metabolic and cardiac dysfunction. AB - Most organisms use internal biological clocks to match behavioural and physiological processes to specific phases of the day-night cycle. Central to this is the synchronisation of internal processes across multiple organ systems. Environmental desynchrony (e.g. shift work) profoundly impacts human health, increasing cardiovascular disease and diabetes risk, yet the underlying mechanisms remain unclear. Here, we characterise the impact of desynchrony between the internal clock and the external light-dark (LD) cycle on mammalian physiology. We reveal that even under stable LD environments, phase misalignment has a profound effect, with decreased metabolic efficiency and disrupted cardiac function including prolonged QT interval duration. Importantly, physiological dysfunction is not driven by disrupted core clock function, nor by an internal desynchrony between organs, but rather the altered phase relationship between the internal clockwork and the external environment. We suggest phase misalignment as a major driver of pathologies associated with shift work, chronotype and social jetlag.The misalignment between internal circadian rhythm and the day-night cycle can be caused by genetic, behavioural and environmental factors, and may have a profound impact on human physiology. Here West et al. show that desynchrony between the internal clock and the external environment alter metabolic parameters and cardiac function in mice. PMID- 28900190 TI - Soil microbial carbon utilization, enzyme activities and nutrient availability responses to Bidens pilosa and a non-invasive congener under different irradiances. AB - Two Bidens species (Bidens pilosa and B. bipinnata) that originate from America have been introduced widely in pan-tropics, with the former regarded as a noxious invasive weed whereas the latter naturalized as a plant resource. Whether the two species exhibit different effects on the belowground system remains rarely studied. This study was conducted to investigate soil microbial carbon (C) utilization, enzyme activities and available nitrogen, phosphorus and potassium contents under the two species in a subtropical garden soil of southern China under different levels of light intensity. Results showed that the microbial C utilization and enzyme activities were not significantly different under the two species, implying that the strong invasiveness of B. pilosa could not be due to the plant-soil microbe interactions, at least plant-induced alterations of microbial community function to utilize C substrates. Alternatively, available soil nitrogen and potassium contents were significantly higher under B. pilosa than under B. bipinnata in full sun, indicating that the strong invasiveness of B. pilosa could result from rapid nutrient mobilizations by B. pilosa. However, the differences turned non-significant as light intensity decreased, suggesting that light availability could substantially alter the plant effects on soil nutrient mobilizations. PMID- 28900191 TI - Broadband biphoton generation and statistics of quantum light in the UV-visible range in an AlGaN microring resonator. AB - We present a physical investigation on the generation of correlated photon pairs that are broadly spaced in the ultraviolet (UV) and visible spectrum on a AlGaN/AlN integrated photonic platform which is optically transparent at these wavelengths. Using spontaneous four wave mixing (SFWM) in an AlGaN microring resonator, we show design techniques to satisfy the phase matching condition between the optical pump, the signal, and idler photon pairs, a condition which is essential and is a key hurdle when operating at short wavelength due to the strong normal dispersion of the material. Such UV-visible photon pairs are quite beneficial for interaction with qubit ions that are mostly in this wavelength range, and will enable heralding the photon-ion interaction. As a target application example, we present the systematic AlGaN microresonator design for generating signal and idler photon pairs using a blue wavelength pump, while the signal appears at the transition of ytterbium ion (171Yb+, 369.5 nm) and the idler appears in the far blue or green range. The photon pairs have minimal crosstalk to the pump power due to their broad spacing in spectral wavelength, thereby relaxing the design of on-chip integrated filters for separating pump, signal and idler. PMID- 28900192 TI - Comparative transcriptome analysis of axillary buds in response to the shoot branching regulators gibberellin A3 and 6-benzyladenine in Jatropha curcas. AB - Cytokinin (CK) is the primary hormone that positively regulates axillary bud outgrowth. However, in many woody plants, such as Jatropha curcas, gibberellin (GA) also promotes shoot branching. The molecular mechanisms underlying GA and CK interaction in the regulation of bud outgrowth in Jatropha remain unclear. To determine how young axillary buds respond to GA3 and 6-benzyladenine (BA), we performed a comparative transcriptome analysis of the young axillary buds of Jatropha seedlings treated with GA3 or BA. Two hundred and fifty genes were identified to be co-regulated in response to GA3 or BA. Seven NAC family members were down-regulated after treatment with both GA3 and BA, whereas these genes were up-regulated after treatment with the shoot branching inhibitor strigolactone. The expressions of the cell cycle genes CDC6, CDC45 and GRF5 were up-regulated after treatment with both GA3 and BA, suggesting they may promote bud outgrowth via regulation of the cell cycle machinery. In the axillary buds, BA significantly increased the expression of GA biosynthesis genes JcGA20oxs and JcGA3ox1, and down-regulated the expression of GA degradation genes JcGA2oxs. Overall, the comprehensive transcriptome data set provides novel insight into the responses of young axillary buds to GA and CK. PMID- 28900193 TI - Synchrotron-based nu-XRF mapping and MU-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin. AB - The increasing prevalence of tattoos provoked safety concerns with respect to particle distribution and effects inside the human body. We used skin and lymphatic tissues from human corpses to address local biokinetics by means of synchrotron X-ray fluorescence (XRF) techniques at both the micro (MU) and nano (nu) scale. Additional advanced mass spectrometry-based methodology enabled to demonstrate simultaneous transport of organic pigments, heavy metals and titanium dioxide from skin to regional lymph nodes. Among these compounds, organic pigments displayed the broadest size range with smallest species preferentially reaching the lymph nodes. Using synchrotron MU-FTIR analysis we were also able to detect ultrastructural changes of the tissue adjacent to tattoo particles through altered amide I alpha-helix to beta-sheet protein ratios and elevated lipid contents. Altogether we report strong evidence for both migration and long-term deposition of toxic elements and tattoo pigments as well as for conformational alterations of biomolecules that likely contribute to cutaneous inflammation and other adversities upon tattooing. PMID- 28900194 TI - Live imaging reveals the dynamics and regulation of mitochondrial nucleoids during the cell cycle in Fucci2-HeLa cells. AB - Mitochondrial DNA (mtDNA) is organized in nucleoprotein complexes called mitochondrial nucleoids (mt-nucleoids), which are critical units of mtDNA replication and transmission. In humans, several hundreds of mt-nucleoids exist in a cell. However, how numerous mt-nucleoids are maintained during the cell cycle remains elusive, because cell cycle synchronization procedures affect mtDNA replication. Here, we analyzed regulation of the maintenance of mt-nucleoids in the cell cycle, using a fluorescent cell cycle indicator, Fucci2. Live imaging of mt-nucleoids with higher temporal resolution showed frequent attachment and detachment of mt-nucleoids throughout the cell cycle. TFAM, an mtDNA packaging protein, was involved in the regulation of this dynamic process, which was important for maintaining proper mt-nucleoid number. Both an increase in mt nucleoid number and activation of mtDNA replication occurred during S phase. To increase mt-nucleoid number, mtDNA replication, but not nuclear DNA replication, was necessary. We propose that these dynamic and regulatory processes in the cell cycle maintain several hundred mt-nucleoids in proliferating cells. PMID- 28900196 TI - Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. AB - Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22 hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20 Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non genomic VDR site. Inhibition of RORalpha and RORgamma transactivation activities in a Tet-on CHO cell reporter system, RORalpha co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORalpha and RORgamma as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved. PMID- 28900197 TI - Structural insights into the Middle East respiratory syndrome coronavirus 4a protein and its dsRNA binding mechanism. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host's immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system. Multiple variants of p4a dsRNA were created and investigated through extensive molecular dynamics procedures to highlight crucial interfacial residues that may be used as potential pharmacophores for future drug development. The structural analysis revealed that p4a exhibits a typical alphabetabetabetaalpha fold structure, as found in other dsRNA-binding proteins. The alpha1 helix and the beta1-beta2 loop play a crucial role in recognizing and establishing contacts with the minor grooves of dsRNA. Further, mutational and binding free energy analyses suggested that in addition to K63 and K67, two other residues, K27 and W45, might also be crucial for p4a-dsRNA stability. PMID- 28900198 TI - Analysis and comparison of the wolf microbiome under different environmental factors using three different data of Next Generation Sequencing. AB - Next Generation Sequencing has been widely used to characterize the prevalence of fecal bacteria in many different species. In this study, we attempted to employ a low-cost and high-throughput sequencing model to discern information pertaining to the wolf microbiota. It is hoped that this model will allow researchers to elucidate potential protective factors in relation to endangered wolf species. We propose three high-throughput sequencing models to reveal information pertaining to the micro-ecology of the wolf. Our analyses advised that, among the three models, more than 100,000 sequences are more appropriate to retrieve the communities' richness and diversity of micro-ecology. In addition, the top five wolf microbiome OTUs (99%) were members of the following five phyla: Bacteroidetes, Fusobacteria, Firmicutes, Proteobacteria, and Actinobacteria. While Alloprevotella, Clostridium_sensu_stricto_1, Anaerobiospirillum, Faecalibactreium and Streptococcus were shared by all samples, their relative abundances were differentially represented between domestic dogs and other wolves. Our findings suggest that altitude, human interference, age, and climate all contribute towards the micro-ecology of the wolf. Specifically, we observed that genera Succinivibrio and Turicibacter are significantly related to altitude and human interference (including hunting practices). PMID- 28900195 TI - Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. AB - It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects <= 65 years of age than among those > 65 years (interaction p-value = 4.0 * 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 * 10-8). We observed one genome wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk. PMID- 28900199 TI - Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90. AB - Cancer stem cells (CSCs) are a pivotal target for eradicating hepatocellular carcinoma (HCC). We previously reported that distinctive CSCs regulating tumorigenicity (EpCAM+ CSCs) and metastasis (CD90+ CSCs) have different epithelial/mesenchymal gene expression signatures. Here, we examined the influence of sorafenib, a multiple-receptor tyrosine kinase inhibitor used as a first-line treatment for advanced HCC, on EpCAM+ and CD90+ CSCs. CD90+ cells showed higher c-Kit gene/protein expression than EpCAM+ cells. Sorafenib treatment reduced the number of CD90+ cells with attenuated c-Kit phosphorylation, whereas it enriched the EpCAM+ cell population. We evaluated the role of CD90+ and EpCAM+ CSCs in vivo by subcutaneously injecting these CSCs together in immune-deficient mice. We observed that sorafenib subtly affected the suppression of primary tumor growth maintained by EpCAM+ CSCs, but completely inhibited the lung metastasis mediated by CD90+ CSCs. We further evaluated the effect of sorafenib on extracellular vesicle (EV) production and found that sorafenib suppressed the production of EVs containing TGF-beta mRNA in CD90+ cells and inhibited the cell-cell communication and motility of EpCAM+ cells. Our data suggest the following novel effects of sorafenib: suppressing CD90+ CSCs and inhibiting the production of EVs regulating distant metastasis. PMID- 28900200 TI - Differential landscape of non-CpG methylation in embryonic stem cells and neurons caused by DNMT3s. AB - Methylated non-CpGs (mCpH; H means A, C, and T) have emerged as key epigenetic marks in mammalian embryonic stem cells (ESCs) and neurons, regulating cell type specific functions. In these two cell types, mCpHs show distinct motifs and correlations to transcription that could be a key in understanding the cell type specific regulations. Thus, we attempted to uncover the underlying mechanism of the differences in ESCs and neurons by conducting a comprehensive analysis of public whole genome bisulfite sequencing data. Remarkably, there were cell type specific mCpH patterns around methylated CpGs (mCpGs), resulted from preferential methylation at different contexts by DNA methyltransferase (DNMT) 3a and 3b. These DNMTs are differentially expressed in ESCs and brain tissues, resulting in distinct mCpH motifs in these two cell types. Furthermore, in ESCs, DNMT3b interacts with histone H3 tri-methylated at lysine 36 (H3K36me3), resulting in hyper-methylation at CpHs upon actively transcribed genes, including those involved in embryo development. Based on the results, we propose a model to explain the differential establishment of mCpHs in ESCs and neurons, providing insights into the mechanism underlying cell type-specific formation and function of mCpHs. PMID- 28900202 TI - Pixelated Checkerboard Metasurface for Ultra-Wideband Radar Cross Section Reduction. AB - In this paper we designed and fabricated a metasurface working as a radar cross section (RCS) reducer over an ultra wide band of frequency from 3.8 to 10.7 GHz. The designed metasurface is a chessboard-like surface made of alternating tiles, with each tile composed of identical unit cells. We develop a novel, simple, highly robust and fully automated approach for designing the unit cells. First, a topology optimization algorithm is used to engineer the shape of the two unit cells. The area of each unit cell is pixelated. A particle swarm optimization algorithm is applied wherein each pixel corresponds to a bit having a binary value of 1 or 0 indicating metallization or no metallization. With the objective of reducing the RCS over a specified frequency range, the optimization algorithm is then linked to a full wave three-dimensional electromagnetic simulator. To validate the design procedure, a surface was designed, fabricated and experimentally tested showing significantly enhanced performance than previous works. Additionally, angular analysis is also presented showing good stability and wide-angle behavior of the designed RCS reducer. The automated design procedure has a wide range of applications and can be easily extended to design surfaces for antennas, energy harvesters, noise mitigation in electronic circuit boards amongst others. PMID- 28900201 TI - Deep sequencing reveals the first fabavirus infecting peach. AB - A disease causing smaller and cracked fruit affects peach [Prunus persica (L.) Batsch], resulting in significant decreases in yield and quality. In this study, peach tree leaves showing typical symptoms were subjected to deep sequencing of small RNAs for a complete survey of presumed causal viral pathogens. The results revealed two known viroids (Hop stunt viroid and Peach latent mosaic viroid), two known viruses (Apple chlorotic leaf spot trichovirus and Plum bark necrosis stem pitting-associated virus) and a novel virus provisionally named Peach leaf pitting-associated virus (PLPaV). Phylogenetic analysis based on RNA-dependent RNA polymerase placed PLPaV into a separate cluster under the genus Fabavirus in the family Secoviridae. The genome consists of two positive-sense single-stranded RNAs, i.e., RNA1 [6,357 nt, with a 48-nt poly(A) tail] and RNA2 [3,862 nt, with a 25-nt poly(A) containing two cytosines]. Biological tests of GF305 peach indicator seedlings indicated a leaf-pitting symptom rather than the smaller and cracked fruit symptoms related to virus and viroid infection. To our knowledge, this is the first report of a fabavirus infecting peach. PLPaV presents several new molecular and biological features that are absent in other fabaviruses, contributing to an overall better understanding of fabaviruses. PMID- 28900203 TI - Metabolic engineering for recombinant major ampullate spidroin 2 (MaSp2) synthesis in Escherichia coli. AB - In this research, metabolic engineering was employed to synthesize the artificial major ampullate spidroin 2 (MaSp2) in the engineered Escherichia coli. An iterative seamless splicing strategy was used to assemble the MaSp2 gene, which could reach 10000 base pairs, and more than 100 kDa protein was expected. However, only 55 kDa recombinant MaSp2 was obtained. Because MaSp2 is rich in alanine and glycine residues, Glycyl/alanyl-tRNA pool and extra amino acids adding were adopted in order to supplement alanine and glycine in the protein translation process. With the supplementary alanine and glycine (0.05 wt%) in the medium, MaSp2 constructed in pET28a(+) and Gly/Ala-tRNA constructed in pET22b(+) were co-expressed in Escherichia coli BL21 (DE3). As results, the artificial MaSp2 with 110 kDa molecular weight was obtained in the present work. This work demonstrates a successful example of applying metabolic engineering approaches and provided a potential way with the enhanced Glycyl/alanyl-tRNA pool to achieve the expression of high molecular weight protein with the repeated motifs in the engineered Escherichia coli. PMID- 28900204 TI - Monovision by Implantation of Posterior Chamber Phakic Intraocular Lens with a Central Hole (Hole ICL) for Early Presbyopia. AB - This study was aimed to evaluate visual performance at near to far distances in early presbyopic patients undergoing monovision by implantation of an ICL with a central hole (hole ICL). This pilot study comprised thirty-four eyes of 17 early presbyopic patients (age, 40 to 53 years) who underwent hole ICL implantation, and whose targeted refraction was set at emmetropia for the dominant eye, and at slight myopia (-0.5 to -1.0 diopters (D)) for the non-dominant eye. Corrected distance visual acuity was significantly improved, from -0.11 +/- 0.07 preoperatively to -0.19 +/- 0.09 logMAR postoperatively (p < 0.001, Wilcoxon signed-rank test). Uncorrected distance visual acuity was also significantly improved from 1.43 +/- 0.35 preoperatively to -0.04 +/- 0.18 logMAR postoperatively (p < 0.001). The mean binocular visual acuity was 0.01 logMAR or better at all distances (5.0, 3.0, 2.0, 1.0, 0.7, 0.5, and 0.3 m). All eyes were within +/- 0.5 D of the targeted correction. All patients had within the normal range of near stereopsis. Neither cataract formation, significant intraocular pressure rise, nor vision-threatening complications occurred. Monovision by hole ICL implantation provided good binocular vision at near to far distances, without developing cataract, suggesting its feasibility as a new surgical presbyopic approach for early presbyopia. PMID- 28900206 TI - Hybrid organic-inorganic polariton laser. AB - Organic materials exhibit exceptional room temperature light emitting characteristics and enormous exciton oscillator strength, however, their low charge carrier mobility prevent their use in high-performance applications such as electrically pumped lasers. In this context, ultralow threshold polariton lasers, whose operation relies on Bose-Einstein condensation of polaritons - part light part-matter quasiparticles, are highly advantageous since the requirement for high carrier injection no longer holds. Polariton lasers have been successfully implemented using inorganic materials owing to their excellent electrical properties, however, in most cases their relatively small exciton binding energies limit their operation temperature. It has been suggested that combining organic and inorganic semiconductors in a hybrid microcavity, exploiting resonant interactions between these materials would permit to dramatically enhance optical nonlinearities and operation temperature. Here, we obtain cavity mediated hybridization of GaAs and J-aggregate excitons in the strong coupling regime under electrical injection of carriers as well as polariton lasing up to 200 K under non-resonant optical pumping. Our demonstration paves the way towards realization of hybrid organic-inorganic microcavities which utilise the organic component for sustaining high temperature polariton condensation and efficient electrical injection through inorganic structure. PMID- 28900205 TI - ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury. AB - The apolipoprotein E4 (ApoE4) genotype combines with traumatic brain injury (TBI) to increase the risk of developing Alzheimer's Disease (AD). However, the underlying mechanism(s) is not well-understood. We found that after exposure to repetitive blast-induced TBI, phosphoinositol biphosphate (PIP2) levels in hippocampal regions of young ApoE3 mice were elevated and associated with reduction in expression of a PIP2 degrading enzyme, synaptojanin 1 (synj1). In contrast, hippocampal PIP2 levels in ApoE4 mice did not increase after blast TBI. Following blast TBI, phospho-Tau (pTau) levels were unchanged in ApoE3 mice, whereas in ApoE4 mice, levels of pTau were significantly increased. To determine the causal relationship between changes in pTau and PIP2/synj1 levels after TBI, we tested if down-regulation of synj1 prevented blast-induced Tau hyper phosphorylation. Knockdown of synj1 decreased pTau levels in vitro, and abolished blast-induced elevation of pTau in vivo. Blast TBI increased glycogen synthase kinase (GSK)-3beta activities in ApoE4 mice, and synj1 knockdown inhibited GSK3beta phosphorylation of Tau. Together, these data suggest that ApoE proteins regulate brain phospholipid homeostasis in response to TBI and that the ApoE4 isoform is dysfunctional in this process. Down-regulation of synj1 rescues blast induced phospholipid dysregulation and prevents development of Tau hyper phosphorylation in ApoE4 carriers. PMID- 28900207 TI - Reevaluating the prognostic significance of male gender for papillary thyroid carcinoma and microcarcinoma: a SEER database analysis. AB - The prognostic significance of gender remains controversial for papillary thyroid carcinoma (PTC). In this study, we investigated the associations between gender and prognosis in a large cohort of patients with PTC or PTMC that was diagnosed in 2010-2013 and recorded in the Surveillance, Epidemiology, and End Results cancer registry. The mean +/- standard deviation duration of survival for all patients with PTC during the study period was 21.47 +/- 14.04 months. In Kaplan Meier analyses of the entire cohort of PTC patients, survival curves for all cause death and cancer-specific death declined more sharply for men than for women. Similar results were observed in analyses of patients with PTCs > 1 cm and PTMC. After adjusting for potential confounders, hazard rates indicated significantly elevated all-cause mortality for men in analyses of all PTCs, PTCs > 1 cm, and PTMCs. However, in a confounder-adjusted analysis of patients with PTMC, the hazard rate did not indicate significantly higher mortality for men than for women. Our study demonstrated that male gender is an independent poor prognostic factor for all PTCs and for PTCs > 1 cm. However, gender is not an independent prognostic factor for cause-specific survival in PTMC. PMID- 28900208 TI - Qualitative and quantitative responses to press perturbations in ecological networks. AB - Predicting the sign of press perturbation responses in ecological networks is challenging, due to the poor knowledge of the strength of the direct interactions among the species, and to the entangled coexistence of direct and indirect effects. We show in this paper that, for a class of networks that includes mutualistic and monotone networks, the sign of press perturbation responses can be qualitatively determined based only on the sign pattern of the community matrix, without any knowledge of parameter values. For other classes of networks, we show that a semi-qualitative approach yields sufficient conditions for community matrices with a given sign pattern to exhibit mutualistic responses to press perturbations; quantitative conditions can be provided as well for community matrices that are eventually nonnegative. We also present a computational test that can be applied to any class of networks so as to check whether the sign of the responses to press perturbations is constant in spite of parameter variations. PMID- 28900209 TI - Iron oxide nanoparticles can cross plasma membranes. AB - Iron deficiency is a major global public health problem despite decades of efforts with iron supplementation and fortification. The issue lies on the poor tolerability of the standard of care soluble iron salts, leading to non compliance and ineffective correction of iron-deficiency anaemia. Iron nanoformulations have been proposed to fortify food and feed to address these issues. Since it was just postulated that some nanoparticles (NPs) might cross the plasma membrane also by a non-endocytotic pathway gaining direct access to the cytoplasm, we have studied iron NP uptake under this perspective. To this aim, we have used a recently tested protocol that has proven to be capable of following the cytoplasmic changes of iron concentration dynamics and we have demonstrated that iron oxide NPs, but not zerovalent iron NPs nor iron oxide NPs that were surrounded by a protein corona, can cross plasma membranes. By electrophysiology, we have also shown that a small and transient increase of membrane conductance parallels NP crossing of plasma membrane. PMID- 28900211 TI - The controllable destabilization route for synthesis of low cytotoxic magnetic nanospheres with photonic response. AB - We present a new approach for obtaining magnetic nanospheres with tunable size and high magnetization. The method is implemented via controllable destabilization of a stable magnetite hydrosol with glycerol, leading to the formation of aggregates followed by their stabilization with the citrate shell. This inexpensive, simple and easily scalable approach required no special equipment. The obtained samples were characterized by high stability and magnetization over 80 emu/g. Effects of synthetic conditions on physicochemical properties of nanospheres were monitored by hydrodynamic size, zeta potential, and polydispersity of magnetite aggregates. The size of the resulting aggregates varied between 650 nm and 40 nm, and the zeta potential from +30 mV to -43 mV by changing the ratio of the reagents. Under optimal conditions the clusters with a diameter of 80 nm were produced with a narrow size distribution +/-3 nm. These characteristics allowed for optical response to the external magnetic field, thereby producing a magnetic photon liquid. Due to biocompatibility of the reagents used in the synthesis the nanospheres evoked a negligible cytotoxicity for human non-malignant and tumor cell lines. These results make new materials valuable in photonics and biomedicine. PMID- 28900212 TI - A nano-mechanical instability as primary contribution to rolling resistance. AB - Rolling resistance ranks among the top ten automobile megatrends, because it is directly linked to fuel efficiency and emissions reduction. The mechanisms controlling this phenomenon are hidden deeply inside the complexity of tire tread materials and do elude direct experimental observation. Here we use atomistic molecular modelling to identify a novel nano-mechanical mechanism for dissipative loss in silica filled elastomers when the latter are subjected to dynamic strain. The force-vs-particle separation curve of a single silica particle-to-silica particle contact, embedded inside a polyisoprene rubber matrix, is obtained, while the contact is opened and closed by a cyclic force. We confirm the occurrence of spontaneous relative displacements ('jolts') of the filler particles. These jolts give rise to energy dissipation in addition to the usual viscous loss in the polymer matrix. As the temperature is increased the new loss mechanism becomes dominant. This has important technical implications for the control and reduction of tire rolling resistance as well as for many other elastomer composite applications involving dynamic loading. PMID- 28900210 TI - Alterations of Brain Functional Architecture Associated with Psychopathic Traits in Male Adolescents with Conduct Disorder. AB - Psychopathic traits of conduct disorder (CD) have a core callous-unemotional (CU) component and an impulsive-antisocial component. Previous task-driven fMRI studies have suggested that psychopathic traits are associated with dysfunction of several brain areas involved in different cognitive functions (e.g., empathy, reward, and response inhibition etc.), but the relationship between psychopathic traits and intrinsic brain functional architecture has not yet been explored in CD. Using a holistic brain-wide functional connectivity analysis, this study delineated the alterations in brain functional networks in patients with conduct disorder. Compared with matched healthy controls, we found decreased anti synchronization between the fronto-parietal network (FPN) and default mode network (DMN), and increased intra-network synchronization within the frontothalamic-basal ganglia, right frontoparietal, and temporal/limbic/visual networks in CD patients. Correlation analysis showed that the weakened FPN-DMN interaction was associated with CU traits, while the heightened intra-network functional connectivity was related to impulsivity traits in CD patients. Our findings suggest that decoupling of cognitive control (FPN) with social understanding of others (DMN) is associated with the CU traits, and hyper functions of the reward and motor inhibition systems elevate impulsiveness in CD. PMID- 28900213 TI - Copine-7 binds to the cell surface receptor, nucleolin, and regulates ciliogenesis and Dspp expression during odontoblast differentiation. AB - Tooth development is a progressive process regulated by interactions between epithelial and mesenchymal tissues. Our previous studies showed that copine-7 (Cpne7), a dental epithelium-derived protein, is a signalling molecule that is secreted by preameloblasts and regulates the differentiation of preodontoblasts into odontoblasts. However, the mechanisms involved in the translocation of Cpne7 from preameloblasts to preodontoblasts and the functions of Cpne7 during odontogenesis are poorly understood. Here, we showed that the internalization of Cpne7 was mediated primarily by caveolae. This process was initiated by Cpne7 binding to the cell surface protein, nucleolin. Treatment with recombinant Cpne7 protein (rCpne7) in human dental pulp cells (hDPCs) caused an increase in the number of ciliated cells. The expression level of cilium components, Ift88 and Kif3a, and Dspp were increased by rCpne7. Treatment with Ift88 siRNA in hDPCs and MDPC-23 cells significantly down-regulated the expression of Dspp, an odontoblastic differentiation marker gene. Furthermore, the treatment with nucleolin siRNA in MDPC-23 cells decreased the expression of Dmp1, Dspp, and cilium components. Our findings suggested that the binding of Cpne7 with its receptor, nucleolin, has an important function involving Cpne7 internalization into preodontoblasts and regulation of Dspp expression through ciliogenesis during odontoblast differentiation. PMID- 28900215 TI - Highly Effective Broad Spectrum Chimeric Larvicide That Targets Vector Mosquitoes Using a Lipophilic Protein. AB - Two mosquitocidal bacteria, Bacillus thuringiensis subsp. israelensis (Bti) and Lysinibacillus sphaericus (Ls) are the active ingredients of commercial larvicides used widely to control vector mosquitoes. Bti's efficacy is due to synergistic interactions among four proteins, Cry4Aa, Cry4Ba, Cry11Aa, and Cyt1Aa, whereas Ls's activity is caused by Bin, a heterodimer consisting of BinA, the toxin, and BinB, a midgut-binding protein. Cyt1Aa is lipophilic and synergizes Bti Cry proteins by increasing midgut binding. We fused Bti's Cyt1Aa to Ls's BinA yielding a broad-spectrum chimeric protein highly mosquitocidal to important vector species including Anopheles gambiae, Culex quinquefasciatus, and Aedes aegypti, the latter an important Zika and Dengue virus vector insensitive to Ls Bin. Aside from its vector control potential, our bioassay data, in contrast to numerous other reports, provide strong evidence that BinA does not require conformational interactions with BinB or microvillar membrane lipids to bind to its intracellular target and kill mosquitoes. PMID- 28900216 TI - Elastic properties of single-walled carbon nanotube thin film by nanoindentation test. AB - This paper carries out a preliminary study for the elastic properties of single walled carbon nanotube (SWCNT) thin film. The SWCNT thin films (~250 nm) are prepared by a simple and cost effective method of spin-coating technology. Nanoindentation test with a Berkovich indenter is used to determine the hardness and elastic modulus of the SWCNT thin film. It is important to note that the elastic properties of SWCNT film are indirectly derived from the information of load and displacement of the indenter under certain assumptions, deviation of the 'test value' is inevitable. In this regard, uncertainty analysis is an effective process in guarantying the validity of the material properties. This paper carries out uncertainty estimation for the tested elastic properties of SWCNT film by nanoindentation. Experimental results and uncertainty analysis indicates that nanoindentation test could be an effective and reliable method in determine the elastic properties of SWCNT thin film. Moreover, the obtained values of hardness and elastic modulus can further benefit the design of SWCNT thin film based components. PMID- 28900214 TI - Structure-function correlations in Retinitis Pigmentosa patients with partially preserved vision: a voxel-based morphometry study. AB - Retinitis Pigmentosa is a group of hereditary retinal dystrophy disorders associated with progressive peripheral visual field loss. The impact of this retinal loss in cortical gray matter volume has not been addressed before in Retinitis Pigmentosa patients with low vision. Voxel-based morphometry was applied to study whole brain gray matter volume changes in 27 Retinitis Pigmentosa patients with partially preserved vision and 38 age- and gender matched normally sighted controls to determine whether peripheral visual loss can lead to changes in gray matter volume. We found significant reductions in gray matter volume that were restricted to the occipital cortex of patients. The anteromedial pattern of reduced gray matter volume in visual primary and association cortices was significantly correlated with the extent of the peripheral visual field deficit in this cohort. Moreover, this pattern was found to be associated with the extent of visual field loss. In summary, we found specific visual cortical gray matter loss in Retinitis Pigmentosa patients associated with their visual function profile. The spatial pattern of gray matter loss is consistent with disuse-driven neuronal atrophy which may have clinical implications for disease management, including prosthetic restoration strategies. PMID- 28900217 TI - Large strain synergetic material deformation enabled by hybrid nanolayer architectures. AB - Nanolayered metallic composites are much stronger than pure nanocrystalline metals due to their high density of hetero-interfaces. However, they are usually mechanically instable due to the deformation incompatibility among the soft and hard constituent layers promoting shear instability. Here we designed a hybrid material with a heterogeneous multi-nanolayer architecture. It consists of alternating 10 nm and 100 nm-thick Cu/Zr bilayers which deform compatibly in both stress and strain by utilizing the layers' intrinsic strength, strain hardening and thickness, an effect referred to as synergetic deformation. Micropillar tests show that the 6.4 GPa-hard 10 nm Cu/Zr bilayers and the 3.3 GPa 100 nm Cu layers deform in a compatible fashion up to 50% strain. Shear instabilities are entirely suppressed. Synergetic strengthening of 768 MPa (83% increase) compared to the rule of mixture is observed, reaching a total strength of 1.69 GPa. We present a model that serves as a design guideline for such synergetically deforming nano hybrid materials. PMID- 28900218 TI - Sources of Variation in the Gut Microbial Community of Lycaeides melissa Caterpillars. AB - Microbes can mediate insect-plant interactions and have been implicated in major evolutionary transitions to herbivory. Whether microbes also play a role in more modest host shifts or expansions in herbivorous insects is less clear. Here we evaluate the potential for gut microbial communities to constrain or facilitate host plant use in the Melissa blue butterfly (Lycaeides melissa). We conducted a larval rearing experiment where caterpillars from two populations were fed plant tissue from two hosts. We used 16S rRNA sequencing to quantify the relative effects of sample type (frass versus whole caterpillar), diet (plant species), butterfly population and development (caterpillar age) on the composition and diversity of the caterpillar gut microbial communities, and secondly, to test for a relationship between microbial community and larval performance. Gut microbial communities varied over time (that is, with caterpillar age) and differed between frass and whole caterpillar samples. Diet (host plant) and butterfly population had much more limited effects on microbial communities. We found no evidence that gut microbe community composition was associated with caterpillar weight, and thus, our results provide no support for the hypothesis that variation in microbial community affects performance in L. melissa. PMID- 28900219 TI - Rapid Staining of Circulating Tumor Cells in Three-Dimensional Microwell Dialysis (3D-MUDialysis) Chip. AB - The conventional techniques to detect circulating tumour cells (CTCs) are lengthy and the use of centrifugal forces in this technique may cause cell mortality. As the number of CTCs in patients is quite low, the present study aims towards a gentler diagnostic procedure so as not to lose too many CTCs during the sample preparation process. Hence, a Three-Dimensional Microwell dialysis (3D MUDialysis) chip was designed in this study to perform gentle fluorescence removal process by using dialysis-type flow processes without centrifuging. This leads to a minimum manual handling of CTCs obtained in our study without any contamination. In addition, a rapid staining process which necessitates only about half the time of conventional techniques (35 minutes instead of 90 minutes) is being illustrated by the employment of dialysis process (by dynamically removing water and waste at once) instead of only static diffusion (by statically removing only waste by diffusion). Staining efficiency of our technique is improved over conventional staining because of the flow rate in 3D-MUDialysis staining. Moreover, the staining process has been validated with clinical whole blood samples from three TNM stage IV colon cancer patients. The current technique may be termed as "miniature rapid staining and dialysing system". PMID- 28900220 TI - Diffusion kurtosis imaging evaluating epithelial-mesenchymal transition in colorectal carcinoma xenografts model: a preliminary study. AB - Epithelial-mesenchymal transition (EMT) plays an important role in aggravating invasiveness and metastatic behavior of colorectal cancer (CRC). Identification of EMT is important for structuring treatment strategy, but has not yet been studied by using noninvasive imaging modality. Diffusion kurtosis imaging (DKI) is an advanced diffusion weighted model that could reflect tissue microstructural changes in vivo. In this study, EMT was induced in CRC cells (HCT116) by overexpressing Snail1 gene. We aimed to investigate the value of DKI in identifying EMT in CRC and decipher the correlations between DKI-derived parameters and EMT biomarker E-cadherin and cell proliferative index Ki-67 expression. Our results revealed that HCT116/Snail1 cells presented changes consistent with EMT resulting in significant increase in migration and invasion capacities. DKI could identify CRC with EMT, in which the DKI-derived parameter diffusivity was significantly lower, and kurtosis was significantly higher than those in the CRC/Control. Diffusivity was negatively and kurtosis was positively correlated with Ki-67 expression, whereas diffusivity was positively and kurtosis was negatively correlated with E-cadherin expression. Therefore, our study concluded that DKI can identify EMT in CRC xenograft tumors. EMT-contained CRC tumors with high Ki-67 and low E-cadherin expression were vulnerable to have lower diffusivity and higher kurtosis coefficients. PMID- 28900221 TI - Lasing by driven atoms-cavity system in collective strong coupling regime. AB - The interaction of laser cooled atoms with resonant light is determined by the natural linewidth of the excited state. An optical cavity is another optically resonant system where the loss from the cavity determines the resonant optical response of the system. The near resonant combination of an optical Fabry-Perot cavity with laser cooled and trapped atoms couples two distinct optical resonators via light and has great potential for precision measurements and the creation of versatile quantum optics systems. Here we show how driven magneto optically trapped atoms in collective strong coupling regime with the cavity leads to lasing at a frequency red detuned from the atomic transition. Lasing is demonstrated experimentally by the observation of a lasing threshold accompanied by polarization and spatial mode purity, and line-narrowing in the outcoupled light. Spontaneous emission into the cavity mode by the driven atoms stimulates lasing action, which is capable of operating as a continuous wave laser in steady state, without a seed laser. The system is modeled theoretically, and qualitative agreement with experimentally observed lasing is seen. Our result opens up a range of new measurement possibilities with this system. PMID- 28900222 TI - A mesocosm study of oxygen and trace metal dynamics in sediment microniches of reactive organic material. AB - Deposition of particulate organic matter (POM) induces diagenetic hot spots at the sediment-water interface (SWI). Here we explore the effects of intensive POM degradation for metal mobilization at the SWI. By using a combined planar optode DGT (diffusive gradient in thin-films) sensor we obtained simultaneous measurements of dissolved O2 and trace metal dynamics around an aggregate of reactive organic matter placed on the SWI of a sediment mesocosm. The aggregate induced a rapid, highly localized, decrease in O2 concentration, resulting in an anoxic feature at the SWI. Co-located with this feature, we observed intense Fe and Mn mobilization, removal of Co, Ni and Zn and found evidence for the concurrent release and precipitation of Pb within a small confined volume. We also identified two small microniches in the anoxic sediment below the SWI, defined by elevated trace metal mobilization. Differences between the metal release rates in these two microniches indicate that they were formed by the mineralisation of different types of organic matter buried in the sediment. Our results provide direct empirical evidence for the potential importance of POM induced reactive microniches when considering the fluxes of metals from and within aquatic sediments, and suggest that other elements' cycles may also be affected. PMID- 28900223 TI - Accurate Design of Low Backscattering Metasurface Using Iterative Fourier Transform Algorithm. AB - An accurate method is proposed to design low-backscattering metasurfaces efficiently using an iterative Fourier transform algorithm, which avoids the large amount of time-consuming numerical simulations of complicated electromagnetic problems and provides satisfactory performance to reduce the backward scattering. As an example of the application, a broadband low backscattering metasurface is designed, fabricated, and characterized. Both full wave simulation and measured results reveal that the proposed method offers a rapid and efficient tool to manipulate the scattering behaviors of the metasurface, and thus realizes significant scattering reductions. PMID- 28900224 TI - Magnetoelectric oxide based stochastic spin device towards solving combinatorial optimization problems. AB - Solving combinatorial optimization problems is challenging. Mapping onto the ground-state search problem of the Ising Hamiltonian is a promising approach in this field, where the components of the optimization set are modeled as artificial spin units. The search for a suitable physical system to realize these spin units is an active area of research. In this work, we have demonstrated a scheme to model the Ising Hamiltonian with multiferroic oxide/nanomagnet units. Although nanomagnet-based implementation has been shown before, we have utilized the magnetoelectric effect of the multiferroics to make voltagecontrolled spin units with less current flow in the network. Moreover, we have proposed a unique approach of configuring the coupling network of the system directly from the Ising Hamiltonian of a traveling salesman problem (TSP). We have developed a coupled micromagnetic simulation framework and solved TSPs of size 26-city and 15 city with an accuracy of 100% for the latter. PMID- 28900225 TI - The neural basis of spatial vision losses in the dysfunctional visual system. AB - Human vision relies on correct information processing from the eye to various visual areas. Disturbances in the visual perception of simple features are believed to come from low-level network (e.g., V1) disruptions. In the present study, we modelled monocular losses in spatial vision through plausible multiple network modifications in early visual coding. We investigated perceptual deficits in anisometropic amblyopia and used the monocular tilt illusion as a probe of primary visual cortex orientation coding and inhibitory interactions. The psychophysical results showed that orientation misperception was higher in amblyopic eyes (AE) than in the fellow and neurotypical eyes and was correlated with the subject's AE peak contrast sensitivity. The model fitted to the experimental results allowed to split these observations between different network characteristics by showing that these observations were explained by broader orientation tuning widths in AEs and stronger lateral inhibition in abnormal amblyopic system that had strong contrast sensitivity losses. Through psychophysics measures and computational modelling of V1, our study links multiple perceptual changes with localized modifications in the primary visual cortex. PMID- 28900226 TI - A Controllable and Integrated Pump-enabled Microfluidic Chip and Its Application in Droplets Generating. AB - A microfluidic chip with a controllable and integrated piezoelectric pump was proposed and demonstrated, where the pump was designed as a micro-actuator based on polyvinylidene fluoride (PVDF) organic piezoelectric film. In this case, the pump should integrate with the microfluidics device very well into one chip. The flow rate can be precisely controlled in the range of 0-300 ul/min for water by tuning the Vpp and frequency of Alternating Current (AC) voltage applied on the diaphragm. To analyze the relationship between the flow rate and the deflection of diaphragm, the deformations of diaphragm at different voltages were researched. The displacement of diaphragm was defined as 17.2 um at the voltages of 3.5 kV, 5 Hz when the pump chamber was full of water. We have used the integrated microfluidic chip with two pumps for droplet generation to demonstrate its great potential for application in droplet-based microfluidic chip. PMID- 28900228 TI - Fabrication and characterisation of magnetic graphene oxide incorporated Fe3O4@polyaniline for the removal of bisphenol A, t-octyl-phenol, and alpha naphthol from water. AB - In this study, we fabricated a novel material composed of magnetic graphene oxide incorporated Fe3O4@polyaniline (Fe3O4@PANI-GO) using a modified Hummers' method, solvothermal, and two-step polymerisation method. The resulting products were characterised by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD). The results indicated that magnetic Fe3O4@PANI particles were successfully loaded onto the surface of the graphene oxide. Further Fe3O4@PANI-GO was investigated to remove bisphenol A(BPA), alpha-naphthol, and t-octyl-phenol (t-OP) from water samples by magnetic solid phase extraction. Under the optimal conditions, the Fe3O4@PANI-GO composite exhibited good adsorption capacity for t-OP, BPA, and alpha-naphthol, and the adsorption of these followed a pseudo-second-order kinetic model. Adsorption isotherms fit the Langmuir model, and the adsorption was an endothermic and spontaneous process. This work indicated that Fe3O4@PANI-GO earned great application prospect for removing phenolic contaminants from polluted water. PMID- 28900227 TI - Long noncoding RNAs in the model species Brachypodium distachyon. AB - Eukaryotic genomes are pervasively transcribed and only a small portion of the transcribed sequences belongs to protein coding genes. High-throughput sequencing technology contributed to consolidate this perspective, allowing the identification of numerous noncoding RNAs with key roles in biological processes. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nt with limited phylogenetic conservation, expressed at low levels and characterized by tissue/organ specific expression profiles. Although a large set of lncRNAs has been identified, the functional roles of lncRNAs are only beginning to be recognized and the molecular mechanism of lncRNA-mediated gene regulation remains largely unexplored, particularly in plants where their annotation and characterization are still incomplete. Using public and proprietary poly-(A)+ RNA seq data as well as a collection of full length ESTs from several organs, developmental stages and stress conditions in three Brachypodium distachyon inbred lines, we describe the identification and the main features of thousands lncRNAs. Here we provide a genome-wide characterization of lncRNAs, highlighting their intraspecies conservation and describing their expression patterns among several organs/tissues and stress conditions. This work represents a fundamental resource to deepen our knowledge on long noncoding RNAs in C3 cereals, allowing the Brachypodium community to exploit these results in future research programs. PMID- 28900229 TI - A Class II small heat shock protein OsHsp18.0 plays positive roles in both biotic and abiotic defense responses in rice. AB - Bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most devastating diseases of rice. However, the molecular mechanism underpinning the Xoo resistance of rice is still not fully understood. Here, we report that a class II small heat shock protein gene, OsHsp18.0, whose expression was differentially induced between a resistant and a susceptible variety in response to Xoo infection, plays positive roles in both biotic and abiotic resistance. The molecular chaperone activity of OsHsp18.0 was confirmed by a bacterium-expressed glutathione S-transferase fusion protein. Overexpression of OsHsp18.0 in a susceptible rice variety significantly enhanced its resistance to multiple Xoo strains, whereas silencing of OsHsp18.0 in a resistant variety drastically increased its susceptibility. The enhanced Xoo resistance in OsHsp18.0 overexpressing lines was positively correlated with the sensitized salicylic acid dependent defense responses. In addition to disease resistance, the OsHsp18.0 overexpressing and silencing lines exhibited enhanced and reduced tolerance, respectively, to heat and salt treatments. The subcellular localization study revealed that the green fluorescent protein-OsHsp18.0 was enriched on the nuclear envelope, suggesting a potential role of OsHsp18.0 in the nucleo-cytoplasmic trafficking. Together, our results reveal that the rice OsHsp18.0 is a positive regulator in both biotic and abiotic defense responses. PMID- 28900230 TI - The Influence of the Position of the Double Bond and Ring Size on the Stability of Hydrogen Bonded Complexes. AB - To study the influence of the position of the double bond and ring size on the stability of hydrogen bonded complexes, the 1:1 complexes formed between 2,2,2 trifluoroethanol (TFE) and three heterocyclic compounds including 2,3 dihydrofuran (2,3-DHF), 2,5-dihydrofuran (2,5-DHF) and 3,4-dihydropyran (3,4-DHP) were investigated systematically. The formation of hydrogen bonded TFE-2,3-DHF, TFE-2,5-DHF and TFE-3,4-DHP complexes were identified by gas phase FTIR spectroscopy at room temperature, and the OH-stretching fundamental transition of TFE was red shifted upon complexation. The competition between the O atom and pi electrons bonding sites within the complexes was studied, and the O-H...pi type hydrogen bond was found to be less stable than the O-H...O in all three cases. The observed red shifts of the OH-stretching fundamental transitions in the complexes were attributed to the formation of O-H...O hydrogen bond. Equilibrium constants of the complexation reactions were determined from measured and calculated OH-stretching fundamental intensities. Both theoretical calculations and experimental results reveal that the hydrogen bond strengths in the complexes follow the sequence: TFE-2,5-DHF > TFE-2,3-DHF ~ TFE-3,4-DHP, thus the position of the double bond exerts significantly larger influence than ring size on the stability of the selected hydrogen bonded complexes. PMID- 28900232 TI - Three novel structural phenomena in the cellular ontogeny of Oenococcus oeni from northern China. AB - Stress resistance and growth are important aspects to consider when engineering Oenococcus oeni strains for winemaking. We identified 3 previously unreported structural phenomena in the cell ontogeny of O. oeni sampled in northern China. We show that budding and binary fission (BBF) occur simultaneously in the growth process; that a novel 'pomegranate-shaped structure' (PSS) occurs mainly in the stationary and death phases; and that symbiosis and cyclical phenomena (SCP) occur throughout the various cell growth phases. These observations add to the current knowledge of the cell growth process of O. oeni. BBF, PSS, and SCP sufficiently describe the characteristics of the cellular ontogeny of O. oeni. We highlight a newly identified structure that explains the complex cell growth process. These findings will help understand the growth and development of O. oeni, supplementing the knowledge base of the established phases and providing new perspectives into its complex growth patterns. PMID- 28900231 TI - Functional neural changes associated with acquired amusia across different stages of recovery after stroke. AB - Brain damage causing acquired amusia disrupts the functional music processing system, creating a unique opportunity to investigate the critical neural architectures of musical processing in the brain. In this longitudinal fMRI study of stroke patients (N = 41) with a 6-month follow-up, we used natural vocal music (sung with lyrics) and instrumental music stimuli to uncover brain activation and functional network connectivity changes associated with acquired amusia and its recovery. In the acute stage, amusic patients exhibited decreased activation in right superior temporal areas compared to non-amusic patients during instrumental music listening. During the follow-up, the activation deficits expanded to comprise a wide-spread bilateral frontal, temporal, and parietal network. The amusics showed less activation deficits to vocal music, suggesting preserved processing of singing in the amusic brain. Compared to non-recovered amusics, recovered amusics showed increased activation to instrumental music in bilateral frontoparietal areas at 3 months and in right middle and inferior frontal areas at 6 months. Amusia recovery was also associated with increased functional connectivity in right and left frontoparietal attention networks to instrumental music. Overall, our findings reveal the dynamic nature of deficient activation and connectivity patterns in acquired amusia and highlight the role of dorsal networks in amusia recovery. PMID- 28900233 TI - COPT2, a plasma membrane located copper transporter, is involved in the uptake of Au in Arabidopsis. AB - The mechanism of gold nanoparticle formation and genes involved in such processes, especially Au transport in plants are not understood. Previous reports pointed to the probable role of COPT2 in Au transport based on the transcript accumulation of COPT2 under Au exposure. Here, we provide evidence revealing the additional role of COPT2 for Au mobilization in yeast and Arabidopsis. The COPT2 transcripts significantly accumulated in the root of Arabidopsis under Au exposure. The expression of COPT2 restores Cu uptake ability in ctr1Deltactr3Delta mutants and leads to Au sensitivity in yeast, which is comparable to Cu in growth kinetics experiments. The metal measurement data showed that the Au level was increased in COPT2, expressing yeast cells compared to vector transformed control. The copt2 mutant of Arabidopsis displayed a similar growth pattern to that of Col-0 under Au treatment. However, a notable phenotypic difference was noticed in three-week-old plants treated with and without Au. Consistent with yeast, Au uptake was reduced in the copt2 mutant of Arabidopsis. Together, these results clearly reveal the Au uptake capability of COPT2 in yeast and Arabidopsis. This is the first report showing the potential role of any transporter towards uptake and accumulation of Au in plants. PMID- 28900234 TI - Urea deep placement reduces yield-scaled greenhouse gas (CH4 and N2O) and NO emissions from a ground cover rice production system. AB - Ground cover rice production system (GCRPS), i.e., paddy soils being covered by thin plastic films with soil moisture being maintained nearly saturated status, is a promising technology as increased yields are achieved with less irrigation water. However, increased soil aeration and temperature under GCRPS may cause pollution swapping in greenhouse gas (GHG) from CH4 to N2O emissions. A 2-year experiment was performed, taking traditional rice cultivation as a reference, to assess the impacts of N-fertilizer placement methods on CH4, N2O and NO emissions and rice yields under GCRPS. Averaging across all rice seasons and N-fertilizer treatments, the GHG emissions for GCRPS were 1973 kg CO2-eq ha-1 (or 256 kg CO2 eq Mg-1), which is significantly lower than that of traditional cultivation (4186 kg CO2-eq ha-1or 646 kg CO2-eq Mg-1). Furthermore, if urea was placed at a 10-15 cm soil depth instead of broadcasting, the yield-scaled GHG emissions from GCRPS were further reduced from 377 to 222 kg CO2-eq Mg-1, as N2O emissions greatly decreased while yields increased. Urea deep placement also reduced yield-scaled NO emissions by 54%. Therefore, GCRPS with urea deep placement is a climate- and environment-smart management, which allows for maximal rice yields at minimal GHG and NO emissions. PMID- 28900235 TI - Neural correlates of ambient thermal sensation: An fMRI study. AB - An increasing number of biometeorological and psychological studies have demonstrated the importance and complexity of the processes involved in environmental thermal perception in humans. However, extant functional imaging data on thermal perception have yet to fully reveal the neural mechanisms underlying these processes because most studies were performed using local thermal stimulation and did not dissociate thermal sensation from comfort. Thus, for the first time, the present study employed functional magnetic resonance imaging (fMRI) and manipulated ambient temperature during brain measurement to independently explore the neural correlates of thermal sensation and comfort. There were significant correlations between the sensation of a lower temperature and activation in the left dorsal posterior insula, putamen, amygdala, and bilateral retrosplenial cortices but no significant correlations were observed between brain activation and thermal comfort. The dorsal posterior insula corresponds to the phylogenetically new thermosensory cortex whereas the limbic structures (i.e., amygdala and retrosplenial cortex) and dorsal striatum may be associated with supramodal emotional representations and the behavioral motivation to obtain heat, respectively. The co-involvement of these phylogenetically new and old systems may explain the psychological processes underlying the flexible psychological and behavioral thermo-environmental adaptations that are unique to humans. PMID- 28900236 TI - India plate angular velocity and contemporary deformation rates from continuous GPS measurements from 1996 to 2015. AB - We estimate a new angular velocity for the India plate and contemporary deformation rates in the plate interior and along its seismically active margins from Global Positioning System (GPS) measurements from 1996 to 2015 at 70 continuous and 3 episodic stations. A new India-ITRF2008 angular velocity is estimated from 30 GPS sites, which include stations from western and eastern regions of the plate interior that were unrepresented or only sparsely sampled in previous studies. Our newly estimated India-ITRF2008 Euler pole is located significantly closer to the plate with ~3% higher angular velocity than all previous estimates and thus predicts more rapid variations in rates and directions along the plate boundaries. The 30 India plate GPS site velocities are well fit by the new angular velocity, with north and east RMS misfits of only 0.8 and 0.9 mm/yr, respectively. India fixed velocities suggest an approximate of 1-2 mm/yr intra-plate deformation that might be concentrated along regional dislocations, faults in Peninsular India, Kachchh and Indo-Gangetic plain. Relative to our newly-defined India plate frame of reference, the newly estimated velocities for 43 other GPS sites along the plate margins give insights into active deformation along India's seismically active northern and eastern boundaries. PMID- 28900237 TI - Difference in gating and doping effects on the band gap in bilayer graphene. AB - A band gap is opened in bilayer graphene (BLG) by applying an electric field perpendicular to the layer, which offers versatility and controllability in graphene-based electronics. The presence of the band gap has been confirmed using double-gated BLG devices in which positive and negative gate voltages are applied to each side of BLG. An alternative method to induce the electric field is electron and hole doping of each side of BLG using electron-transfer adsorbates. However, the generation of the band gap by carrier doping is still under investigation. Here, we determined whether the electron/hole doping can produce the electric field required to open the band gap by measuring the temperature dependence of conductivity for BLG placed between electron-donor self-assembled monolayers (SAMs) and electron-acceptor molecules. We found that some devices exhibited a band gap and others did not. The potentially irregular and variable structure of SAMs may affect the configuration of the electric field, yielding variable electronic properties. This study demonstrates the essential differences between gating and doping. PMID- 28900238 TI - Limitations of Qdot labelling compared to directly-conjugated probes for single particle tracking of B cell receptor mobility. AB - Single-particle tracking (SPT) is a powerful method for exploring single-molecule dynamics in living cells with nanoscale spatiotemporal resolution. Photostability and bright fluorescence make quantum dots (Qdots) a popular choice for SPT. However, their large size could potentially alter the mobility of the molecule of interest. To test this, we labelled B cell receptors on the surface of B lymphocytes with monovalent Fab fragments of antibodies that were either linked to Qdots via streptavidin or directly conjugated to the small organic fluorophore Cy3. Imaging of receptor mobility by total internal reflection fluorescence microscopy (TIRFM), followed by quantitative single-molecule diffusion and confinement analysis, definitively showed that Qdots sterically hinder lateral mobility regardless of the substrate to which the cells were adhered. Qdot labelling also drastically altered the frequency with which receptors transitioned between apparent slow- and fast-moving states and reduced the size of apparent confinement zones. Although we show that Qdot-labelled probes can detect large differences in receptor mobility, they fail to resolve subtle differences in lateral diffusion that are readily detectable using Cy3-labelled Fabs. Our findings highlight the utility and limitations of using Qdots for TIRFM and wide-field-based SPT, and have significant implications for interpreting SPT data. PMID- 28900239 TI - Siglec-5 is a novel marker of critical limb ischemia in patients with diabetes. AB - Critical Limb Ischemia (CLI) is common but uncommonly diagnosed. Improved recognition and early diagnostic markers for CLI are needed. Therefore, the aim of our study was to identify plasma biomarkers of CLI in patients with type 2 diabetes mellitus (T2DM). In this study, antibody-coated glass slide arrays were used to determine the plasma levels of 274 human cytokines in four matched cases of diabetes with and without CLI. Potential biomarkers were confirmed in an independent cohort by ELISA. After adjusting for confounding risk factors, only plasma level of Siglec-5 remained significantly associated with an increased odds ratio (OR) for diabetes with CLI by binary logistic regression analysis. Receiver operating characteristic (ROC) curve analysis revealed the optimal cut-off points for Siglec-5 was 153.1 ng/ml. After entering Siglec-5, the AUC was 0.99, which was higher than that of confounding risk factors only (AUC = 0.97, P < 0.05). Siglec-5 was expressed in plaques, but not in healthy artery wall in T2DM patients. Elevated plasma Siglec-5 was independently associated with CLI in T2DM. Plasma Siglec-5 levels are implicated as an early diagnostic marker of CLI in T2DM patients and it may become a target for the prevention or treatment of CLI in diabetes. PMID- 28900240 TI - Gut microbiota: Microbial metabolites as mimickers of human molecules. PMID- 28900241 TI - Propolis envelope in Apis mellifera colonies supports honey bees against the pathogen, Paenibacillus larvae. AB - Honey bees have immune defenses both as individuals and as a colony (e.g., individual and social immunity). One form of honey bee social immunity is the collection of antimicrobial plant resins and the deposition of the resins as a propolis envelope within the nest. In this study, we tested the effects of the propolis envelope as a natural defense against Paenibacillus larvae, the causative agent of American foulbrood (AFB) disease. Using colonies with and without a propolis envelope, we quantified: 1) the antimicrobial activity of larval food fed to 1-2 day old larvae; and 2) clinical signs of AFB. Our results show that the antimicrobial activity of larval food was significantly higher when challenged colonies had a propolis envelope compared to colonies without the envelope. In addition, colonies with a propolis envelope had significantly reduced levels of AFB clinical signs two months following challenge. Our results indicate that the propolis envelope serves as an antimicrobial layer around the colony that helps protect the brood from bacterial pathogen infection, resulting in a lower colony-level infection load. PMID- 28900242 TI - Dietary docosahexaenoic acid (DHA) as lysophosphatidylcholine, but not as free acid, enriches brain DHA and improves memory in adult mice. AB - Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease. PMID- 28900243 TI - Normothermic Microwave Irradiation Induces Death of HL-60 Cells through Heat Independent Apoptosis. AB - Microwaves have been used in various cancer therapies to generate heat and increase tumor cell temperature; however, their use is limited by their side effects in normal cells and the acquisition of heat resistance. We previously developed a microwave irradiation method that kills cultured cancer cells, including a human promyelomonocytic leukemia (HL-60) cell line, by maintaining a cellular temperature of 37 degrees C during treatment. In the present study, we investigated the mechanisms underlying HL-60 cell death during this treatment. The microwave-irradiated HL-60 cells appear to undergo caspase-independent apoptosis, whereby DNA fragmentation was induced by mitochondrial dysfunction related expression of apoptosis-inducing factor (AIF). Caspase-dependent apoptosis was also interrupted by the loss of apoptotic protease-activating factor 1 (Apaf-1) and caspase 9. Moreover, these cells did not exhibit a heat stress response, as shown by the lack of heat shock protein 70 (HSP70) upregulation. Alternatively, in HL-60 cells heated at 42.5 degrees C, HSP70 expression was upregulated and a pathway resembling death receptor-induced apoptosis was activated while mitochondrial function was maintained. Collectively, these results suggest that the cell death pathway activated by our 37 degrees C microwave irradiation method differs from that induced during other heating methods and support the use of normothermic microwave irradiation in clinical cancer treatments. PMID- 28900244 TI - IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. AB - IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4+ T cells are being elucidated, with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Ralpha inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet+ cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4. PMID- 28900245 TI - The role of metronomic capecitabine for treatment of recurrent hepatocellular carcinoma after liver transplantation. AB - The management of recurrent hepatocellular carcinoma untreatable with surgical options is based on systemic therapy with sorafenib. Due to the high rates of adverse events connected to the therapy with sorafenib, metronomic capecitabine seems a promising strategy for these patients. We analyzed the data of 38 patients with hepatocellular carcinoma recurrent after liver transplantation performed at our center. We compared the outcome of 17 patients receiving metronomic capecitabine versus 20 patients experiencing best supportive care and versus the data of the literature about treatment with sorafenib. In the group treated with metronomic capecitabine we observed an increased survival after tumor recurrence at the univariate and multivariate analysis compared to the group of best supportive care (median 22 months vs. 7 months, p < 0.01). Data from the literature on the use of sorafenib showed outcomes like our study group, with similar patient and tumoral features. The episodes of acute rejection and the tumor stage at the recurrence showed a correlation with patient survival at the univariate analysis. The metronomic capecitabine for hepatocellular cancer recurrent after liver transplantation seems effective without important adverse events and comparable results to sorafenib. PMID- 28900246 TI - MALDI-TOF-MS based identification and molecular characterization of food associated methicillin-resistant Staphylococcus aureus. AB - Food-borne methicillin resistant Staphylococcus aureus (MRSA) is involved in two fold higher mortality rate compared to methicillin susceptible S. aureus (MSSA). Eventhough Mysuru recognized as cleanest city in the world, prevalence of food contamination is not detailed. The aim is to screen food samples from Mysuru area and to characterize MRSA strain, employing MALDI-Biotyper, multiplex PCR to distinguish between MRSA and MSSA by PCR-coupled single strand conformation polymorphism (PCR-SSCP). Of all the food-borne pathogens, S. aureus contamination accounts for 94.37 +/- 0.02% (P < 0.01), strains characterized by means of nuc genes, followed by species specific identification by Coa, Eap and SpA genes and multiplex PCR to confirm the presence of three methicillin resistant staphylococcal species simultaneously using nuc and phoP genes. Amplification of mecA gene in 159 isolates confirmed that all strains are methicillin resistant, except UOM160 (MSSA) and multi-drug resistant (MDR) in 159 isolates confirmed by 22 sets of beta-lactam antibiotics. MSSA and MDR-MRSA were discriminated by PCR SSCP using nuc gene for the first time. From the present studies, compared to conventional methods MALDI-Biotyper emerged as an effective, sensitive (>99%), robust (<2 min), and alternative tool for pathogen identification, and we developed a PCR-SSCP technique for rapid detection of MSSA and MRSA strains. PMID- 28900247 TI - Effects of protease-treated royal jelly on muscle strength in elderly nursing home residents: A randomized, double-blind, placebo-controlled, dose-response study. AB - Although we have found that protease-treated royal jelly (pRJ) benefit for the skeletal muscle mass and strength in the aged animals, the potential beneficial effects have not been evaluated in humans. The aim of this study was to determine whether pRJ intake had beneficial effects on muscle strength in elderly nursing home residents. One hundred and ninety-four subjects enrolled into this multicenter, randomized, double-blind, placebo-controlled study. Subjects received either placebo(Group 1), pRJ 1.2 g/d(Group 2), or 4.8 g/d(Group 3). Data through 1 year are reported for 163 subjects. The primary outcome measure is handgrip strength. Secondary outcomes include several physical performance tests (six-minute walk test, timed up and go test, and standing on one leg with eyes closed). The dropout rate was 16.0%. The means (95% confidence interval) of change in handgrip strength for placebo, low-dose, and high-dose groups are 0.98(-2.04,0.08), 0.50(-0.65,1.65) and 1.03(-0.37,2.44) kg (P = 0.06, P for trend = 0.02), respectively. No significant effects of the interventions were observed for physical performances. These findings suggest that pRJ treatment might not improve, but rather attenuate the progression of decrease in muscle strength in elderly people. In addition, we have not found that pRJ intervention can achieve improvement or attenuating the decrease in physical performance. PMID- 28900248 TI - High extinction ratio electromagnetically induced transparency analogue based on the radiation suppression of dark modes. AB - A high extinction ratio (ER) electromagnetically induced transparency (EIT) analogue based on single-layer metamaterial is designed and experimentally demonstrated in this paper. This design involves four mirror-like symmetrically coupled split ring resonators (SRRs) that exhibit a bright-dark-dark-bright mode configuration. The EIT-like effect is realized by coupling between the bright resonators and dark resonators. The high ER feature is achieved from the suppression of radiative losses, due to opposite directions of electric and magnetic dipoles of two dark modes in the unit cell. Classical coupled resonator model is used to theoretically analyze the device transmission performances and to characterize parameter influence of the ER. Both numerical simulation and experiment results demonstrate that the ER of this device can reach more than 21 dB, which is 11 dB higher than that of conventional bright-dark coupling SRR arrangement. Finally, the potential multi-channel sensing utility of this device is demonstrated to show the importance of high ER feature. PMID- 28900249 TI - Effect of efflux pump inhibition on Pseudomonas aeruginosa transcriptome and virulence. AB - Efflux pumps of the resistance-nodulation-cell-division (RND) family increase antibiotic resistance in many bacterial pathogens, representing candidate targets for the development of antibiotic adjuvants. RND pumps have also been proposed to contribute to bacterial infection, implying that efflux pump inhibitors (EPIs) could also act as anti-virulence drugs. Nevertheless, EPIs are usually investigated only for their properties as antibiotic adjuvants, while their potential anti-virulence activity is seldom taken into account. In this study it is shown that RND efflux pumps contribute to Pseudomonas aeruginosa PAO1 pathogenicity in an insect model of infection, and that the well-characterized EPI Phe-Arg-beta-naphthylamide (PAbetaN) is able to reduce in vivo virulence of the P. aeruginosa PAO1 laboratory strain, as well as of clinical isolates. The production of quorum sensing (QS) molecules and of QS-dependent virulence phenotypes is differentially affected by PAbetaN, depending on the strain. Transcriptomic and phenotypic analyses showed that the protection exerted by PAbetaN from P. aeruginosa PAO1 infection in vivo correlates with the down regulation of key virulence genes (e.g. genes involved in iron and phosphate starvation). Since PAbetaN impacts P. aeruginosa virulence, anti-virulence properties of EPIs are worthy to be explored, taking into account possible strain specificity of their activity. PMID- 28900250 TI - 5,7-Di-N-acetyl-8-epiacinetaminic acid: A new non-2-ulosonic acid found in the K73 capsule produced by an Acinetobacter baumannii isolate from Singapore. AB - Nonulosonic acids are found in the surface polysaccharides of many bacterial species and are often implicated in pathogenesis. Here, the structure of a novel 5,7-diacetamido-3,5,7,9-tetradeoxynon-2-ulosonic acid recovered from the capsular polysaccharide of a multiply antibiotic resistant Acinetobacter baumannii isolate was determined. The isolate carries a sugar synthesis module that differs by only a single gene from the module for the synthesis of 5,7-diacetamido-3,5,7,9 tetradeoxy-L-glycero-L-altro-non-2-ulosonic acid or 5,7-di-N-acetylacinetaminic acid, recently discovered in the capsule of another A. baumannii isolate. The new monosaccharide is the C8-epimer of acinetaminic acid (8eAci; 5,7-diacetamido 3,5,7,9-tetradeoxy-D-glycero-L-altro-non-2-ulosonic acid) and the C7-epimer of legionaminic acid. This monosaccharide had not previously been detected in a biological sample but had been synthesized chemically. PMID- 28900251 TI - Integration of c-axis oriented Bi3.15Nd0.85Ti2.95Hf0.05O12/La0.67Sr0.33MnO3 ferromagnetic-ferroelectric composite film on Si substrate. AB - A La0.67Sr0.33MnO3 (LSMO) ferromagnetic layer and a Nd3+/Hf4+ co-substituted Bi4Ti3O12 (Bi3.15Nd0.85Ti3-xHfxO12 (BNTHx, x = 0, 0.025, 0.05, 0.1 and 0.15)) ferroelectric layer were successively deposited onto the (00 l)-oriented LaNiO3 (LNO) layer buffered (001) Si substrate via all chemical solution deposition (CSD) method. As a result, the BNTHx/LSMO ferromagnetic-ferroelectric composite films integrated on Si substrate exhibit high c-axis orientation. The Nd3+/Hf4+ co-substituted BNTHx films have the lower leakage current and the better ferroelectric properties than the mono-substituted Bi4Ti3O12 (Bi3.15Nd0.85Ti3O12 and Bi4Ti2.95Hf0.05O12) films. In particular, the BNTH0.05/LSMO/LNO film has the lowest leakage current density of 2.5 * 10-7 A/cm2 at 200 kV/cm, and the highest remnant polarization (Pr) of 27.3 MUC/cm2. The BNTH0.05/LSMO/LNO composite film also exhibits the soft ferromagnetism characteristics with a high saturated magnetization of 258 emu/cm3 at 300 K, and the excellent magnetoelectric (ME) effect. The variations of ME voltage coefficient alpha E values with DC bias magnetic field H bias shows that the BNTH0.05/LSMO/LNO film has the high alpha E value at near zero H bias. Moreover, at H bias = 0 Oe, the alpha E value gradually increases from zero with the increasing of the AC magnetic field frequency, and eventually reaches about 18.9 V/cm.Oe at 100 kHz, suggesting the existence of self-biased ME effect. PMID- 28900253 TI - Leaf thermotolerance in tropical trees from a seasonally dry climate varies along the slow-fast resource acquisition spectrum. AB - Knowledge of the upper limits of temperature tolerance is essential to understand how tropical trees will respond to global warming. We quantified leaf thermotolerance in 41 tree species growing in a seasonally dry tropical region of the Indian subcontinent to examine: (1) differences between evergreen and deciduous species; (2) relationships with leaf mass per area (LMA) and leaf size; and, (3) seasonal variation in thermotolerance. Thermotolerance ranged from 45.5 degrees C to 50.5 degrees C among species, was higher for evergreen than deciduous species, and was negatively related to a continuous estimate of deciduousness. Species with higher LMA had higher thermotolerance, but we did not detect any relationship between leaf size and thermotolerance. Seasonal changes in thermotolerance varied among species implying that species' capacity to acclimate may differ. Thermal safety margins, the difference between thermotolerance and maximum habitat temperatures indicate that most species may be highly vulnerable to future warming. Overall our results show that deciduous, and fast growing species with low LMA are likely to be more negatively affected by global warming. This differential vulnerability may lead to directional changes in composition in dry tropical forests, and such changes could alter vegetation-atmosphere feedbacks and further exacerbate global warming. PMID- 28900252 TI - Profiling of the metabolic transcriptome via single molecule molecular inversion probes. AB - Cancer-specific metabolic alterations are of high interest as therapeutic targets. These alterations vary between tumor types, and to employ metabolic targeting to its fullest potential there is a need for robust methods that identify candidate targetable metabolic pathways in individual cancers. Currently, such methods include 13C-tracing studies and mass spectrometry/ magnetic resonance spectroscopic imaging. Due to high cost and complexity, such studies are restricted to a research setting. We here present the validation of a novel technique of metabolic profiling, based on multiplex targeted next generation sequencing of RNA with single molecule molecular inversion probes (smMIPs), designed to measure activity of and mutations in genes that encode metabolic enzymes. We here profiled an isogenic pair of cell lines, differing in expression of the Von Hippel Lindau protein, an important regulator of hypoxia inducible genes. We show that smMIP-profiling provides relevant information on active metabolic pathways. Because smMIP-based targeted RNAseq is cost-effective and can be applied in a medium high-throughput setting (200 samples can be profiled simultaneously in one next generation sequencing run) it is a highly interesting approach for profiling of the activity of genes of interest, including those regulating metabolism, in a routine patient care setting. PMID- 28900254 TI - Large manipulative experiments revealed variations of insect abundance and trophic levels in response to the cumulative effects of sheep grazing. AB - Livestock grazing can affect insects by altering habitat quality; however, the effects of grazing years and intensities on insect abundance and trophic level during manipulative sheep grazing are not well understood. Therefore, we investigated these effects in a large manipulative experiment from 2014 to 2016 in the eastern Eurasian steppe, China. Insect abundance decreased as sheep grazing intensities increased, with a significant cumulative effect occurring during grazing years. The largest families, Acrididae and Cicadellidae, were susceptible to sheep grazing, but Formicidae was tolerant. Trophic primary and secondary consumer insects were negatively impacted by increased grazing intensities, while secondary consumers were limited by the decreased primary consumers. Poor vegetation conditions caused by heavy sheep grazing were detrimental to the existence of Acrididae, Cicadellidae, primary and secondary consumer insects, but were beneficial to Formicidae. This study revealed variations in insect abundance and trophic level in response to continuous sheep grazing in steppe grasslands. Overall, our results indicate that continuous years of heavy- and over- sheep grazing should be eliminated. Moreover, our findings highlight the importance of more flexible sheep grazing management and will be useful for developing guidelines to optimize livestock production while maintaining species diversity and ecosystem health. PMID- 28900255 TI - Saturated mutagenesis of ketoisovalerate decarboxylase V461 enabled specific synthesis of 1-pentanol via the ketoacid elongation cycle. AB - Iterative ketoacid elongation has been an essential tool in engineering artificial metabolism, in particular the synthetic alcohols. However, precise control of product specificity is still greatly challenged by the substrate promiscuity of the ketoacid decarboxylase, which unselectively hijacks ketoacid intermediates from the elongation cycle along with the target ketoacid. In this work, preferential tuning of the Lactococcus lactis ketoisovalerate decarboxylase (Kivd) specificity toward 1-pentanol synthesis was achieved via saturated mutagenesis of the key residue V461 followed by screening of the resulting alcohol spectrum. Substitution of V461 with the small and polar amino acid glycine or serine significantly improved the Kivd selectivity toward the 1 pentanol precursor 2-ketocaproate by lowering its catalytic efficiency for the upstream ketoacid 2-ketobutyrate and 2-ketovalerate. Conversely, replacing V461 with bulky or charged side chains displayed severely adverse effect. Increasing supply of the iterative addition unit acetyl-CoA by acetate feeding further drove 2-ketoacid flux into the elongation cycle and enhanced 1-pentanol productivity. The Kivd V461G variant enabled a 1-pentanol production specificity around 90% of the total alcohol content with or without oleyl alcohol extraction. This work adds insight to the selectivity of Kivd active site. PMID- 28900256 TI - Genomic and transcriptomic analysis of the toluene degrading black yeast Cladophialophora immunda. AB - Cladophialophora immunda is an ascomycotal species belonging to the group of the black yeasts. These fungi have a thick and melanized cell wall and other physiological adaptations that allows them to cope with several extreme physical and chemical conditions. Member of the group can colonize some of the most extremophilic environments on Earth. Cladophialophora immunda together with a few other species of the order Chaetothyriales show a special association with hydrocarbon polluted environments. The finding that the fungus is able to completely mineralize toluene makes it an interesting candidate for bioremediation purposes. The present study is the first transcriptomic investigation of a fungus grown in presence of toluene as sole carbon and energy source. We could observe the activation of genes involved in toluene degradatation and several stress response mechanisms which allowed the fungus to survive the toluene exposure. The thorough comparative genomics analysis allowed us to identify several events of horizontal gene transfer between bacteria and Cladophialophora immunda and unveil toluene degradation steps that were previously reported in bacteria. The work presented here aims to give new insights into the ecology of Cladophialophora immunda and its adaptation strategies to hydrocarbon polluted environments. PMID- 28900257 TI - Subtle shifts in microbial communities occur alongside the release of carbon induced by drought and rewetting in contrasting peatland ecosystems. AB - Peat represents a globally significant pool of sequestered carbon. However, peatland carbon stocks are highly threatened by anthropogenic climate change, including drought, which leads to a large release of carbon dioxide. Although the enzymatic mechanisms underlying drought-driven carbon release are well documented, the effect of drought on peatland microbial communities has been little studied. Here, we carried out a replicated and controlled drought manipulation using intact peat 'mesocosm cores' taken from bog and fen habitats, and used a combination of community fingerprinting and sequencing of marker genes to identify community changes associated with drought. Community composition varied with habitat and depth. Moreover, community differences between mesocosm cores were stronger than the effect of the drought treatment, emphasising the importance of replication in microbial marker gene studies. While the effect of drought on the overall composition of prokaryotic and eukaryotic communities was weak, a subset of the microbial community did change in relative abundance, especially in the fen habitat at 5 cm depth. 'Drought-responsive' OTUs were disproportionately drawn from the phyla Bacteroidetes and Proteobacteria. Collectively, the data provide insights into the microbial community changes occurring alongside drought-driven carbon release from peatlands, and suggest a number of novel avenues for future research. PMID- 28900258 TI - Single Cell Oxygen Mapping (SCOM) by Scanning Electrochemical Microscopy Uncovers Heterogeneous Intracellular Oxygen Consumption. AB - We developed a highly sensitive oxygen consumption scanning microscopy system using platinized platinum disc microelectrodes. The system is capable of reliably detecting single-cell respiration, responding to classical regulators of mitochondrial oxygen consumption activity as expected. Comparisons with commercial multi-cell oxygen detection systems show that the system has comparable errors (if not smaller), with the advantage of being able to monitor inter and intra-cell heterogeneity in oxygen consumption characteristics. Our results uncover heterogeneous oxygen consumption characteristics between cells and within the same cell's microenvironments. Single Cell Oxygen Mapping (SCOM) is thus capable of reliably studying mitochondrial oxygen consumption characteristics and heterogeneity at a single-cell level. PMID- 28900259 TI - Selective tubular activation of hypoxia-inducible factor-2alpha has dual effects on renal fibrosis. AB - Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2alpha activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2alpha activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2alpha at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF 2alpha activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1alpha activation. In conclusion, late-stage renal tubular HIF-2alpha activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD. PMID- 28900260 TI - High sulfur-containing carbon polysulfide polymer as a novel cathode material for lithium-sulfur battery. AB - The lithium-sulfur battery, which offers a high energy density and is environmental friendly, is a promising next generation of rechargeable energy storage system. However, despite these attractive attributes, the commercialization of lithium-sulfur battery is primarily hindered by the parasitic reactions between the Li metal anode and dissolved polysulfide species from the cathode during the cycling process. Herein, we synthesize the sulfur rich carbon polysulfide polymer and demonstrate that it is a promising cathode material for high performance lithium-sulfur battery. The electrochemical studies reveal that the carbon polysulfide polymer exhibits superb reversibility and cycle stability. This is due to that the well-designed structure of the carbon polysulfide polymer has several advantages, especially, the strong chemical interaction between sulfur and the carbon framework (C-S bonds) inhibits the shuttle effect and the pi electrons of the carbon polysulfide compound enhance the transfer of electrons and Li+. Furthermore, as-prepared carbon polysulfide polymer-graphene hybrid cathode achieves outstanding cycle stability and relatively high capacity. This work highlights the potential promise of the carbon polysulfide polymer as the cathode material for high performance lithium sulfur battery. PMID- 28900261 TI - A Phytochemical Approach to Promotion of Self-renewal in Murine Spermatogonial Stem Cell by Using Sedum Sarmentosum Extract. AB - Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, which is dependent on the ability to self-renew and differentiation. Controlling self renewal and differentiation of SSCs could apply to treatment of disease such as male infertility. Recently, in the field of stem cell research, it was demonstrated that effective increase in stem cell activity can be achieved by using growth factors derived from plant extracts. In this study, our aim is to investigate components from natural plant to improve the self-renewal of SSCs. To find the components, germ cells were cultured with comprehensive natural plant extracts, and then the more pure fraction, and finally single compound at different concentrations. As a result, we found 5H-purin-6-amine at 1 ug/mL, originated from Sedum sarmentosum, was a very effective compound induced SSCs proliferation. Our data showed that germ cells cultured with 5H-purin-6-amine could maintain their stable characteristics. Furthermore, transplantation results demonstrated that 5H-purin-6-amine at 1 ug/mL increased the activity of SSCs, indicating the compound could increase true SSC concentration within germ cells to 1.96-fold. These findings would be contributed to improve further reproductive research and treat male infertility by using natural plant extracts. PMID- 28900262 TI - Microwave properties of the single-layer periodic structure composites composed of ethylene-vinyl acetate and polycrystalline iron fibers. AB - A single-layer microwave absorbing structure composed of the ethylene-vinyl acetate (EVA) powders and polycrystalline iron fibers (PIFs) with thickness of 2 mm, which has a periodic array of circular hole, is designed and fabricated using the mechanical method. We show that the reflection loss (RL) can be easily adjusted by changing the geometric parameters. The maximum RL is 18.7 dB at 15 GHz, and the effective absorption bandwidth of 1.7 GHz for the diameter of circular hole is 10 mm, and enhanced to be 23.7 dB at 15.1 GHz with the corresponding bandwidth of 7.2 GHz when the diameter decreases to 5 mm. The measured absorption of the composite is in good accordance with the simulation results. Furthermore, the possible absorption mechanism of the composite has been discussed. Our results illustrate that the integration of frequency selective surface (FSS) with traditional PIFs can achieve a wide frequency range of a strong absorption. PMID- 28900263 TI - Physicochemical stability and transfection efficiency of cationic amphiphilic copolymer/pDNA polyplexes for spinal cord injury repair. AB - Multiple age-related and injury-induced characteristics of the adult central nervous system (CNS) pose barriers to axonal regeneration and functional recovery following injury. In situ gene therapy is a promising approach to address the limited availability of growth-promoting biomolecules at CNS injury sites. The ultimate goal of our work is to develop, a cationic amphiphilic copolymer for simultaneous delivery of drug and therapeutic nucleic acids to promote axonal regeneration and plasticity after spinal cord injury. Previously, we reported the synthesis and characterization of a cationic amphiphilic copolymer, poly (lactide co-glycolide)-graft-polyethylenimine (PgP) and its ability to efficiently transfect cells with pDNA in the presence of serum. We also demonstrated the efficacy of PgP as a therapeutic siRhoA carrier in a rat compression spinal cord injury model. In this work, we show that PgP/pDNA polyplexes provide improved stability in the presence of competing polyanions and nuclease protection in serum relative to conventional branched polyethylenimine control. PgP/pDNA polyplexes maintain bioactivity for transfection after lyophilization/reconstitution and during storage at 4 degrees C for up to 5 months, important features for commercial and clinical application. We also demonstrate that PgP/pDNA polyplexes loaded with a hydrophobic fluorescent dye are retained in local neural tissue for up to 5 days and that PgP can efficiently deliver pbeta-Gal in a rat compression SCI model. PMID- 28900264 TI - Measuring Spectral Inconsistency of Multispectral Images for Detection and Segmentation of Retinal Degenerative Changes. AB - Multispectral imaging (MSI) creates a series of en-face fundus spectral sections by leveraging an extensive range of discrete monochromatic light sources and allows for an examination of the retina's early morphologic changes that are not generally visible with traditional fundus imaging modalities. An Ophthalmologist's interpretation of MSI images is commonly conducted by qualitatively analyzing the spectral consistency between degenerated areas and normal ones, which characterizes the image variation across different spectra. Unfortunately, an ophthalmologist's interpretation is practically difficult considering the fact that human perception is limited to the RGB color space, while an MSI sequence contains typically more than ten spectra. In this paper, we propose a method for measuring the spectral inconsistency of MSI images without supervision, which yields quantitative information indicating the pathological property of the tissue. Specifically, we define mathematically the spectral consistency as an existence of a pixel-specific latent feature vector and a spectrum-specific projection matrix, which can be used to reconstruct the representative features of pixels. The spectral inconsistency is then measured using the number of latent feature vectors required to reconstruct the representative features in practice. Experimental results from 54 MSI sequences show that our spectral inconsistency measurement is potentially invaluable for MSI-based ocular disease diagnosis. PMID- 28900265 TI - Urban heat island impacted by fine particles in Nanjing, China. AB - Atmospheric aerosol particles (especially particles with aerodynamic diameters equal to or less than 2.5 MUm, called PM2.5) can affect the surface energy balance and atmospheric heating rates and thus may impact the intensity of urban heat islands. In this paper, the effect of fine particles on the urban heat island intensity in Nanjing was investigated via the analysis of observational data and numerical modelling. The observations showed that higher PM2.5 concentrations over the urban area corresponded to lower urban heat island (UHI) intensities, especially during the day. Under heavily polluted conditions, the UHI intensity was reduced by up to 1 K. The numerical simulation results confirmed the weakening of the UHI intensity due to PM2.5 via the higher PM2.5 concentrations present in the urban region than those in the suburban areas. The effects of the fine particles on the UHI reduction were limited to the lowest 500 1000 m. The daily range of the surface air temperature was also reduced by up to 1.1 K due to the particles' radiative effects. In summary, PM2.5 noticeably impacts UHI intensity, which should be considered in future studies on air pollution and urban climates. PMID- 28900266 TI - CHA2DS2-VASc score as predictor of ischemic stroke in patients undergoing coronary artery bypass grafting and percutaneous coronary intervention. AB - Ischemic stroke following coronary revascularization procedures remains one of the most potentially devastating complications. CHA2DS2-VASc score has been widely used for stroke risk stratification in AF patients. The aim of this nationwide study was to examine the association between the CHA2DS2-VASc score and ischemic stroke following coronary revascularization procedures. We identified patients undergoing coronary revascularization procedures, coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), using the electronic Hospitalization Summary Reports. Logistic regression models were applied to evaluate the association of CHA2DS2-VASc score with the risk of post procedural ischemic stroke. We identified 54,714 patients undergoing CABG and 263,063 patients undergoing PCI from 2013 to 2015. The CHA2DS2-VASc score had a positive graded association with the risk of post-procedural ischemic stroke in both CABG and PCI (P for trend <0.001). The adjusted risk of post-procedural ischemic stroke increased by an estimated 122.4% (odds ratio [OR], 2.22; 95% confidence interval [CI], 2.11-2.35) and 34.7% (OR, 1.35; 95% CI, 1.31-1.39) for each additional 1 point in the CHA2DS2-VASc score in CABG and PCI, respectively. In conclusion, these findings suggested that CHA2DS2-VASc score was an independent predictor of the development of post-procedural ischemic stroke in patients undergoing CABG and PCI. PMID- 28900267 TI - Investigating the neural correlates of smoking: Feasibility and results of combining electronic cigarettes with fMRI. AB - Cigarette addiction is driven partly by the physiological effects of nicotine, but also by the distinctive sensory and behavioural aspects of smoking, and understanding the neural effects of such processes is vital. There are many practical difficulties associated with subjects smoking in the modern neuroscientific laboratory environment, however electronic cigarettes obviate many of these issues, and provide a close simulation of smoking tobacco cigarettes. We have examined the neural effects of 'smoking' electronic cigarettes with concurrent functional Magnetic Resonance Imaging (fMRI). The results demonstrate the feasibility of using these devices in the MRI environment, and show brain activation in a network of cortical (motor cortex, insula, cingulate, amygdala) and sub-cortical (putamen, thalamus, globus pallidus, cerebellum) regions. Concomitant relative deactivations were seen in the ventral striatum and orbitofrontal cortex. These results reveal the brain processes involved in (simulated) smoking for the first time, and validate a novel approach to the study of smoking, and addiction more generally. PMID- 28900268 TI - Interrogation of gamma-tubulin alleles using high-resolution fitness measurements reveals a distinct cytoplasmic function in spindle alignment. AB - gamma-Tubulin has a well-established role in nucleating the assembly of microtubules, yet how phosphorylation regulates its activity remains unclear. Here, we use a time-resolved, fitness-based SGA approach to compare two gamma tubulin alleles, and find that the genetic interaction profile of gammatub-Y362E is enriched in spindle positioning and cell polarity genes relative to that of gammatub-Y445D, which is enriched in genes involved in spindle assembly and stability. In gammatub-Y362E cells, we find a defect in spindle alignment and an increase in the number of astral microtubules at both spindle poles. Our results suggest that the gammatub-Y362E allele is a separation-of-function mutation that reveals a role for gamma-tubulin phospho-regulation in spindle alignment. We propose that phosphorylation of the evolutionarily conserved Y362 residue of budding yeast gamma-tubulin contributes to regulating the number of astral microtubules associated with spindle poles, and promoting efficient pre-anaphase spindle alignment. PMID- 28900269 TI - Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice. AB - The complex role of neutrophils in modulating the inflammatory response is increasingly appreciated. Our studies profiled the expression of mRNAs and microRNAs (miRs) in lung neutrophils in mice during S. pneumoniae pneumonia and performed in depth in silico analyses. Lung neutrophils were isolated 24 hours after intratracheal instillation of PBS or S. pneumoniae, and differentially expressed (DE) mRNAs and miRs were identified. Lung neutrophils from mice with S. pneumoniae pneumonia contained 4127 DE mRNAs, 36% of which were upregulated at least 2-fold. During pneumonia, lung neutrophils increase expression of pattern recognition receptors, receptors for inflammatory mediators, transcription factors including NF-kappaB and AP-1, Nrf2 targets, cytokines, chemokines and other inflammatory mediators. Interestingly, neutrophils responded to Type I interferons, whereas they both produced and responded to Type II interferon. Expression of regulators of the inflammatory and immune response was verified at the mRNA and protein level. Of approximately 1100 miRs queried, 31 increased and 67 decreased more than 2-fold in neutrophils from S. pneumoniae pneumonia. Network analyses of potential DE miR-target DE mRNA interactions revealed candidate key regulatory miRs. Thus, S. pneumoniae modulates mRNA and miR expression by lung neutrophils, increasing their ability to respond and facilitating host defense. PMID- 28900270 TI - Multiplex quantitative analysis of microRNA expression via exponential isothermal amplification and conformation-sensitive DNA separation. AB - Expression profiling of multiple microRNAs (miRNAs) generally provides valuable information for understanding various biological processes. Thus, it is necessary to develop a sensitive and accurate miRNA assay suitable for multiplexing. Isothermal exponential amplification reaction (EXPAR) has received significant interest as an miRNA analysis method because of high amplification efficiency. However, EXPAR cannot be used for a broader range of applications owing to limitations such as complexity of probe design and lack of proper detection method for multiplex analysis. Here, we developed a sensitive and accurate multiplex miRNA profiling method using modified isothermal EXPAR combined with high-resolution capillary electrophoresis-based single-strand conformation polymorphism (CE-SSCP). To increase target miRNA specificity, a stem-loop probe was introduced instead of a linear probe in isothermal EXPAR to allow specific amplification of multiple miRNAs with minimal background signals. CE-SSCP, a conformation-dependent separation method, was used for detection. Since CE-SSCP eliminates the need for probes to have different lengths, easier designing of probes with uniform amplification efficiency was possible. Eight small RNAs comprising six miRNAs involved in Caenorhabditis elegans development and two controls were analyzed. The expression patterns obtained using our method were concordant with those reported in previous studies, thereby supporting the proposed method's robustness and utility. PMID- 28900271 TI - Transgenerational exposure of North Atlantic bivalves to ocean acidification renders offspring more vulnerable to low pH and additional stressors. AB - While early life-stage marine bivalves are vulnerable to ocean acidification, effects over successive generations are poorly characterized. The objective of this work was to assess the transgenerational effects of ocean acidification on two species of North Atlantic bivalve shellfish, Mercenaria mercenaria and Argopecten irradians. Adults of both species were subjected to high and low pCO2 conditions during gametogenesis. Resultant larvae were exposed to low and ambient pH conditions in addition to multiple, additional stressors including thermal stress, food-limitation, and exposure to a harmful alga. There were no indications of transgenerational acclimation to ocean acidification during experiments. Offspring of elevated pCO2-treatment adults were significantly more vulnerable to acidification as well as the additional stressors. Our results suggest that clams and scallops are unlikely to acclimate to ocean acidification over short time scales and that as coastal oceans continue to acidify, negative effects on these populations may become compounded and more severe. PMID- 28900272 TI - From malaria to cancer: Computational drug repositioning of amodiaquine using PLIP interaction patterns. AB - Drug repositioning identifies new indications for known drugs. Here we report repositioning of the malaria drug amodiaquine as a potential anti-cancer agent. While most repositioning efforts emerge through serendipity, we have devised a computational approach, which exploits interaction patterns shared between compounds. As a test case, we took the anti-viral drug brivudine (BVDU), which also has anti-cancer activity, and defined ten interaction patterns using our tool PLIP. These patterns characterise BVDU's interaction with its target s. Using PLIP we performed an in silico screen of all structural data currently available and identified the FDA approved malaria drug amodiaquine as a promising repositioning candidate. We validated our prediction by showing that amodiaquine suppresses chemoresistance in a multiple myeloma cancer cell line by inhibiting the chaperone function of the cancer target Hsp27. This work proves that PLIP interaction patterns are viable tools for computational repositioning and can provide search query information from a given drug and its target to identify structurally unrelated candidates, including drugs approved by the FDA, with a known safety and pharmacology profile. This approach has the potential to reduce costs and risks in drug development by predicting novel indications for known drugs and drug candidates. PMID- 28900273 TI - Laminarinase from Flavobacterium sp. reveals the structural basis of thermostability and substrate specificity. AB - Laminarinase from Flavobacterium sp. strain UMI-01, a new member of the glycosyl hydrolase 16 family of a marine bacterium associated with seaweeds, mainly degrades beta-1,3-glucosyl linkages of beta-glucan (such as laminarin) through the hydrolysis of glycosidic bonds. We determined the crystal structure of ULam111 at 1.60-A resolution to understand the structural basis for its thermostability and substrate specificity. A calcium-binding motif located on the opposite side of the beta-sheet from catalytic cleft increased its degrading activity and thermostability. The disulfide bridge Cys31-Cys34, located on the beta2-beta3 loop near the substrate-binding site, is responsible for the thermostability of ULam111. The substrates of beta-1,3-linked laminarin and beta 1,3-1,4-linked glucan bound to the catalytic cleft in a completely different mode at subsite -3. Asn33 and Trp113, together with Phe212, formed hydrogen bonds with preferred substrates to degrade beta-1,3-linked laminarin based on the structural comparisons. Our structural information provides new insights concerning thermostability and substrate recognition that will enable the design of industrial biocatalysts. PMID- 28900275 TI - 87Sr/86Sr evidence from the epeiric Martin Ridge Basin for enhanced carbonate weathering during the Hirnantian. AB - A pronounced positive delta13C excursion in the Hirnantian Age has been documented globally, reflecting large perturbations of carbon cycling in the Late Ordovician oceans. Increased organic-carbon burial or enhanced carbonate weathering during glacioeustatic sea-level regression has been proposed to account for this anomalous C-isotope excursion. To test the two competing hypotheses, we measured 87Sr/86Sr and delta13C of carbonates from the Copenhagen Canyon section in Nevada, USA. Our data reveal two rapid negative 87Sr/86Sr shifts that coincide with two prominent positive delta13C excursions and glacial advances. Numerical model simulations suggest that enhanced weathering of carbonates driven by glacio-eustatically controlled sea-level fall is required to produce the observed drops of 87Sr/86Sr and the coeval large positive delta13C excursions, possibly with or without increased organic carbon burial. PMID- 28900276 TI - Highly variable lifespan in an annual reptile, Labord's chameleon (Furcifer labordi). AB - Among tetrapods, the current record holder for shortest lifespan is Labord's chameleon, Furcifer labordi. These reptiles from the arid southwest of Madagascar have a reported lifespan of 4-5 months during the annual rainy season and spend the majority of their life (8-9 months) as a developing embryo. This semelparous, annual life history is unique among tetrapods, but only one population (Ranobe) in the southernmost distribution range has been studied. We therefore investigated the potential for environmentally-dependent variability in lifespan in a population in Kirindy Forest, which has a much longer warm rainy season. While no adults were found after March in Ranobe, the disappearance of adults was delayed by several months in Kirindy. Our data also revealed sex-biased mortality, suggesting that females have a longevity advantage. Furthermore, we found that, after an unusually long previous rainy season, one female was capable of surviving until a second breeding season. Keeping F. labordi in cages under ambient conditions demonstrated that also males can also survive until the next season of activity under these conditions. Our study therefore revealed considerable variability in the extreme life history of this tetrapod that is linked to variation in ecological factors. PMID- 28900274 TI - Characterization and Identification of a woody lesion mimic mutant lmd, showing defence response and resistance to Alternaria alternate in birch. AB - Lesion mimic mutants (LMM) usually show spontaneous cell death and enhanced defence responses similar to hypersensitive response (HR) in plants. Many LMM have been reported in rice, wheat, maize, barley, Arabidopsis, etc., but little was reported in xylophyta. BpGH3.5 is an early auxin-response factor which regulates root elongation in birch. Here, we found a T-DNA insertion mutant in a BpGH3.5 transgenic line named lmd showing typical LMM characters and early leaf senescence in Betula platyphylla * B. pendula. lmd showed H2O2 accumulation, increased SA level and enhanced resistance to Alternaria alternate, compared with oe21 (another BpGH3.5 transgenic line) and NT (non-transgenic line). Cellular structure observation showed that programmed cell death occurred in lmd leaves. Stereomicroscope observation and Evans' blue staining indicated that lmd is a member of initiation class of LMM. Transcriptome analysis indicated that defence response-related pathways were enriched. Southern-blot indicated that there were two insertion sites in lmd genome. Genome re-sequencing and thermal asymmetric interlaced PCR (TAIL-PCR) confirmed the two insertion sites, one of which is a T DNA insertion in the promoter of BpEIL1 that may account for the lesion mimic phenotype. This study will benefit future research on programmed cell death, HR and disease resistance in woody plants. PMID- 28900277 TI - Nepenthes pitchers are CO2-enriched cavities, emit CO2 to attract preys. AB - Carnivorous plants of the genus Nepenthes supplement their nutrient deficiency by capturing arthropods or by mutualistic interactions, through their leaf-evolved biological traps (pitchers). Though there are numerous studies on these traps, mostly on their prey capture mechanisms, the gas composition inside them remains unknown. Here we show that, Nepenthes unopened pitchers are CO2-enriched 'cavities', when open they emit CO2, and the CO2 gradient around open pitchers acts as a cue attracting preys towards them. CO2 contents in near mature, unopened Nepenthes pitchers were in the range 2500-5000 ppm. Gas collected from inside open N. khasiana pitchers showed CO2 at 476.75 +/- 59.83 ppm. CO2-enriched air-streaming through N. khasiana pitchers (at 619.83 +/- 4.53 ppm) attracted (captured) substantially higher number of aerial preys compared to air-streamed pitchers (CO2 at 412.76 +/- 4.51 ppm). High levels of CO2 dissolved in acidic Nepenthes pitcher fluids were also detected. We demonstrate respiration as the source of elevated CO2 within Nepenthes pitchers. Most unique features of Nepenthes pitchers, viz., high growth rate, enhanced carbohydrate levels, declined protein levels, low photosynthetic capacity, high respiration rate and evolved stomata, are influenced by the CO2-enriched environment within them. PMID- 28900278 TI - Function Coupling Mechanism of PhuS and HemO in Heme Degradation. AB - Most bacteria possess only one heme-degrading enzyme for obtaining iron, however few bacteria such as Pseudomonas aeruginosa express two, namely PhuS and HemO. While HemO is a well-known heme oxygenase, previously we discovered that PhuS also possesses heme degradation activity and generates verdoheme, an intermediate of heme breakdown. To understand the coexistence of these two enzymes, using the DFT calculation we reveal that PhuS effectively enhances heme degradation through its participation in heme hydroxylation, the rate limiting reaction. Heme is converted to verdoheme in this reaction and the energy barrier for PhuS is substantially lower than for HemO. Thus, HemO is mainly involved in the ring opening reaction which converts verdoheme to biliverdin and free iron. Our kinetics experiments show that, in the presence of both PhuS and HemO, complete degradation of heme to biliverdin is enhanced. We further show that PhuS is more active than HemO using heme as a substrate and generates more CO. Combined experimental and theoretical results directly identify function coupling of this two-enzyme system, resulting in more efficient heme breakdown and utilization. PMID- 28900279 TI - Next Generation Sequencing Plus (NGS+) with Y-chromosomal Markers for Forensic Pedigree Searches. AB - There is high demand for forensic pedigree searches with Y-chromosome short tandem repeat (Y-STR) profiling in large-scale crime investigations. However, when two Y-STR haplotypes have a few mismatched loci, it is difficult to determine if they are from the same male lineage because of the high mutation rate of Y-STRs. Here we design a new strategy to handle cases in which none of pedigree samples shares identical Y-STR haplotype. We combine next generation sequencing (NGS), capillary electrophoresis and pyrosequencing under the term 'NGS+' for typing Y-STRs and Y-chromosomal single nucleotide polymorphisms (Y SNPs). The high-resolution Y-SNP haplogroup and Y-STR haplotype can be obtained with NGS+. We further developed a new data-driven decision rule, FSindex, for estimating the likelihood for each retrieved pedigree. Our approach enables positive identification of pedigree from mismatched Y-STR haplotypes. It is envisaged that NGS+ will revolutionize forensic pedigree searches, especially when the person of interest was not recorded in forensic DNA database. PMID- 28900280 TI - Metagenomic insight into the microbial networks and metabolic mechanism in anaerobic digesters for food waste by incorporating activated carbon. AB - Powdered activated carbon (AC) is commonly used as an effective additive to enhance anaerobic digestion (AD), but little is known about how the metabolic pathways resulting from adding AC change the microbial association network and enhance food waste treatment. In this work, the use of AC in an anaerobic digestion system for food waste was explored. Using bioinformatics analysis, taxonomic trees and the KEGG pathway analysis, changes in microbial network and biometabolic pathways were tracked. The overall effect of these changes were used to explain and validate improved digestion performance. The results showed that AC accelerated the decomposition of edible oil in food waste, enhancing the conversion of food waste to methane with the optimized dosage of 12 g AC per reactor. Specifically, when AC was added, the proponoate metabolic pathway that converts propanoic acid to acetic acid became more prominent, as measured by 16S rRNA in the microbial community. The other two metabolic pathways, Lipid Metabolism and Methane Metabolism, were also enhanced. Bioinformatics analysis revealed that AC promoted the proliferation of syntrophic microorganisms such as Methanosaeta and Geobacter, forming a highly intensive syntrophic microbial network. PMID- 28900281 TI - Oleic acid induces apoptosis and autophagy in the treatment of Tongue Squamous cell carcinomas. AB - Oleic acid (OA), a main ingredient of Brucea javanica oil (BJO), is widely known to have anticancer effects in many tumors. In this study, we investigated the anticancer effect of OA and its mechanism in tongue squamous cell carcinoma (TSCC). We found that OA effectively inhibited TSCC cell proliferation in a dose- and time-dependent manner. OA treatment in TSCC significantly induced cell cycle G0/G1 arrest, increased the proportion of apoptotic cells, decreased the expression of CyclinD1 and Bcl-2, and increased the expression of p53 and cleaved caspase-3. OA also obviously induced the formation of autolysosomes and decreased the expression of p62 and the ratio of LC3 I/LC3 II. The expression of p-Akt, p mTOR, p-S6K, p-4E-BP1 and p-ERK1/2 was significantly decreased in TSCC cells after treatment with OA. Moreover, tumor growth was significantly inhibited after OA treatment in a xenograft mouse model. The above results indicate that OA has a potent anticancer effect in TSCC by inducing apoptosis and autophagy via blocking the Akt/mTOR pathway. Thus, OA is a potential TSCC drug that is worthy of further research and development. PMID- 28900282 TI - A novel non prophage(-like) gene-intervening element within gerE that is reconstituted during sporulation in Bacillus cereus ATCC10987. AB - Gene rearrangement is a widely-shared phenomenon in spore forming bacteria, in which prophage(-like) elements interrupting sporulation-specific genes are excised from the host genome to reconstitute the intact gene. Here, we report a novel class of gene-intervening elements, named gin, inserted in the 225 bp gerE coding region of the B. cereus ATCC10987 genome, which generates a sporulation specific rearrangement. gin has no phage-related genes and possesses three site specific recombinase genes; girA, girB, and girC. We demonstrated that the gerE rearrangement occurs at the middle stage of sporulation, in which site-specific DNA recombination took place within the 9 bp consensus sequence flanking the disrupted gerE segments. Deletion analysis of gin uncovered that GirC and an additional factor, GirX, are responsible for gerE reconstitution. Involvement of GirC and GirX in DNA recombination was confirmed by an in vitro recombination assay. These results broaden the definition of the sporulation-specific gene rearrangement phenomenon: gene-intervening elements are not limited to phage DNA but may include non-viral genetic elements that carry a developmentally-regulated site-specific recombination system. PMID- 28900283 TI - A multiplex preclinical model for adenoid cystic carcinoma of the salivary gland identifies regorafenib as a potential therapeutic drug. AB - Adenoid cystic carcinomas (ACC) are rare salivary gland cancers with a high incidence of metastases. In order to study this tumor type, a reliable model system exhibiting the molecular features of this tumor is critical, but none exists, thereby inhibiting in-vitro studies and the analysis of metastatic behavior. To address this deficiency, we have coupled an efficient method to establish tumor cell cultures, conditional reprogramming (CR), with a rapid, reproducible and robust in-vivo zebrafish model. We have established cell cultures from two individual ACC PDX tumors that maintain the characteristic MYB translocation. Additional mutations found in one ACC culture also seen in the PDX tumor. Finally, the CR/zebrafish model mirrors the PDX mouse model and identifies regorafenib as a potential therapeutic drug to treat this cancer type that mimic the drug sensitivity profile in PDX model, further confirming the unique advantages of multiplex system. PMID- 28900284 TI - MiR-503 modulates epithelial-mesenchymal transition in silica-induced pulmonary fibrosis by targeting PI3K p85 and is sponged by lncRNA MALAT1. AB - Silicosis is a kind of chronic, progressive and incurable lung fibrotic diseases with largely unknown and complex pathogenesis and molecular mechanisms. Mounting evidence suggests that microRNAs (miRNAs, miRs) are involved in the pathogenesis of silicosis. Our previous study based on miRNA microarray had shown that the expression levels of miR-503 were down-regulated in mouse lung tissues of silica induced pulmonary fibrosis. Here, we validated the decreased expression of miR 503 in the fibrotic mouse lung tissues, human bronchial epithelial cells (HBE) and human lung adenocarcinoma A549 cells which were exposed to silica. In addition, overexpressed miR-503 inhibited silica-induced pulmonary fibrosis by attenuating the severity and the distribution of lesions in vivo and limiting the process of epithelial-mesenchymal transition (EMT) in vitro. Our molecular study further demonstrated that PI3K p85 is one of the target genes of miR-503 and the downstream molecules (Akt, mTOR and Snail) are tightly associated with EMT. Furthermore, the up-regulated lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), acted as a competing endogenous RNA (ceRNA), can directly bound to miR-503, which indicated that lncRNA MALAT1 may modulate the expression of miR-503 thus triggering the activation of downstream fibrotic signaling pathways. Taken together, our data suggested that MALAT1-miR-503 PI3K/Akt/mTOR/Snail pathway plays critical roles in silica-induced pulmonary fibrosis. PMID- 28900285 TI - Clinical characteristics and risk factors for developing bone metastases in patients with breast cancer. AB - The risk factors for predicting bone metastases in patients with breast cancer are still controversial. Here, a total of 2133 patients with breast cancer, including 327 with bone metastases (15.33%) and 1806 without bone metastases (84.67%) were retrospective reviewed from January 2005 to December 2015. The spine was found to be the most common site for bone metastases, followed by ribs (57.5%), pelvis (54.1%) and sternum (44.3%). The results indicated that axillary lymph node metastases and the concentrations of CA125, CA153, ALP and hemoglobin were the independent risk factors for bone metastases in patients with breast cancer. The receiver operating characteristics (ROC) curves showed that combined axillary lymph node metastases, high CA153 and ALP, with low hemoglobin were the most accurate biomarkers for predicting bone metastases in breast cancer [area under the curve = 0.900], and the sensitivity and specificity for the prediction were 78.5% and 87.8%, respectively. Therefore, breast cancer patients with more axillary lymph node metastases, high serum concentrations of CA125, CA153, ALP and low level of hemoglobin were closely related to bone metastases. Combined axillary lymph node metastases, CA153, ALP with hemoglobin have the highest predictive accuracy for bone metastases in breast cancer. PMID- 28900287 TI - Quantitative Characterization of Structural and Mechanical Properties of Boron Nitride Nanotubes in High Temperature Environments. AB - The structural stability and mechanical integrity of boron nitride nanotubes (BNNTs) in high temperature environments are of importance in pursuit of their applications that are involved with extreme thermal processing and/or working conditions, but remain not well understood. In this paper, we perform an extensive study of the impacts of high temperature exposure on the structural and mechanical properties of BNNTs with a full structural size spectrum from nano- to micro- to macro-scale by using a variety of in situ and ex situ material characterization techniques. Atomic force microscopy (AFM) and high resolution transmission electron microscopy measurements reveal that the structures of individual BNNTs can survive at up to 850 degrees C in air and capture the signs of their structural degradation at 900 degrees C or above. In situ Raman spectroscopy measurements reveal that the BN bonds in BNNT micro-fibrils undergo substantial softening at elevated temperatures of up to 900 degrees C. The AFM based nanomechanical compression measurements demonstrate that the mechanical integrity of individual BNNTs remain intact after being thermally baked at up to 850 degrees C in air. The studies reveal that BNNTs are structurally and mechanically stable materials in high temperature environments, which enables their usages in high temperature applications. PMID- 28900286 TI - Adolescent THC Exposure Causes Enduring Prefrontal Cortical Disruption of GABAergic Inhibition and Dysregulation of Sub-Cortical Dopamine Function. AB - Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases such as schizophrenia. GABAergic hypofunction in the prefrontal cortex (PFC) is a cardinal pathological feature of schizophrenia and may be a mechanism by which the PFC loses its ability to regulate sub-cortical dopamine (DA) resulting in schizophrenia-like neuropsychopathology. In the present study, we exposed adolescent rats to Delta-9-tetra-hydrocannabinol (THC), the psychoactive component in marijuana. At adulthood, we characterized the functionality of PFC GABAergic neurotransmission and its regulation of sub cortical DA function using molecular, behavioral and in-vivo electrophysiological analyses. Our findings revealed a persistent attenuation of PFC GABAergic function combined with a hyperactive neuronal state in PFC neurons and associated disruptions in cortical gamma oscillatory activity. These PFC abnormalities were accompanied by hyperactive DAergic neuronal activity in the ventral tegmental area (VTA) and behavioral and cognitive abnormalities similar to those observed in psychiatric disorders. Remarkably, these neuronal and behavioral effects were reversed by pharmacological activation of GABAA receptors in the PFC. Together, these results identify a mechanistic link between dysregulated frontal cortical GABAergic inhibition and sub-cortical DAergic dysregulation, characteristic of well-established neuropsychiatric endophenotypes. PMID- 28900288 TI - Optical source of individual pairs of colour-conjugated photons. AB - We theoretically demonstrate that Kerr nonlinearity in optical circuits can lead to both resonant four-wave mixing and photon blockade, which can be used for high yield generation of high-fidelity individual photon pairs with conjugated frequencies. We propose an optical circuit, which, in the optimal pulsed-drive regime, would produce photon pairs at the rate up to 5 * 105 s -1 (0.5 pairs per pulse) with [Formula: see text] for one of the conjugated frequencies. We show that such a scheme can be utilised to generate colour-entangled photons. PMID- 28900289 TI - Spatiotemporal brain dynamics of auditory temporal assimilation. AB - Time is a fundamental dimension, but millisecond-level judgments sometimes lead to perceptual illusions. We previously introduced a "time-shrinking illusion" using a psychological paradigm that induces auditory temporal assimilation (ATA). In ATA, the duration of two successive intervals (T1 and T2), marked by three auditory stimuli, can be perceived as equal when they are not. Here, we investigate the spatiotemporal profile of human temporal judgments using magnetoencephalography (MEG). Behavioural results showed typical ATA: participants judged T1 and T2 as equal when T2 - T1 <= +80 ms. MEG source localisation analysis demonstrated that regional activity differences between judgment and no-judgment conditions emerged in the temporoparietal junction (TPJ) during T2. This observation in the TPJ may indicate its involvement in the encoding process when T1 ? T2. Activation in the inferior frontal gyrus (IFG) was enhanced irrespective of the stimulus patterns when participants engaged in temporal judgment. Furthermore, just after the final marker, activity in the IFG was enhanced specifically for the time-shrinking pattern. This indicates that activity in the IFG is also related to the illusory perception of time-interval equality. Based on these observations, we propose neural signatures for judgments of temporal equality in the human brain. PMID- 28900290 TI - Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients. AB - Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD 1 axis inhibitors with CCRT. PMID- 28900291 TI - Assessing the expected response to genomic selection of individuals and families in Eucalyptus breeding with an additive-dominant model. AB - We report a genomic selection (GS) study of growth and wood quality traits in an outbred F2 hybrid Eucalyptus population (n=768) using high-density single nucleotide polymorphism (SNP) genotyping. Going beyond previous reports in forest trees, models were developed for different selection targets, namely, families, individuals within families and individuals across the entire population using a genomic model including dominance. To provide a more breeder-intelligible assessment of the performance of GS we calculated the expected response as the percentage gain over the population average expected genetic value (EGV) for different proportions of genomically selected individuals, using a rigorous cross validation (CV) scheme that removed relatedness between training and validation sets. Predictive abilities (PAs) were 0.40-0.57 for individual selection and 0.56 0.75 for family selection. PAs under an additive+dominance model improved predictions by 5 to 14% for growth depending on the selection target, but no improvement was seen for wood traits. The good performance of GS with no relatedness in CV suggested that our average SNP density (~25 kb) captured some short-range linkage disequilibrium. Truncation GS successfully selected individuals with an average EGV significantly higher than the population average. Response to GS on a per year basis was ~100% more efficient than by phenotypic selection and more so with higher selection intensities. These results contribute further experimental data supporting the positive prospects of GS in forest trees. Because generation times are long, traits are complex and costs of DNA genotyping are plummeting, genomic prediction has good perspectives of adoption in tree breeding practice. PMID- 28900292 TI - A Bayesian test for Hardy-Weinberg equilibrium of biallelic X-chromosomal markers. AB - The X chromosome is a relatively large chromosome, harboring a lot of genetic information. Much of the statistical analysis of X-chromosomal information is complicated by the fact that males only have one copy. Recently, frequentist statistical tests for Hardy-Weinberg equilibrium have been proposed specifically for dealing with markers on the X chromosome. Bayesian test procedures for Hardy Weinberg equilibrium for the autosomes have been described, but Bayesian work on the X chromosome in this context is lacking. This paper gives the first Bayesian approach for testing Hardy-Weinberg equilibrium with biallelic markers at the X chromosome. Marginal and joint posterior distributions for the inbreeding coefficient in females and the male to female allele frequency ratio are computed, and used for statistical inference. The paper gives a detailed account of the proposed Bayesian test, and illustrates it with data from the 1000 Genomes project. In that implementation, a novel approach to tackle multiple testing from a Bayesian perspective through posterior predictive checks is used. PMID- 28900293 TI - Dogs are not better than humans at detecting coherent motion. AB - The ability to perceive motion is one of the main properties of the visual system. Sensitivity in detecting coherent motion has been thoroughly investigated in humans, where thresholds for motion detection are well below 10% of coherence, i.e. of the proportion of dots coherently moving in the same direction, among a background of randomly moving dots. Equally low thresholds have been found in other species, including monkeys, cats and seals. Given the lack of data from the domestic dog, we tested 5 adult dogs on a conditioned discrimination task with random dot displays. In addition, five adult humans were tested in the same condition for comparative purposes. The mean threshold for motion detection in our dogs was 42% of coherence, while that of humans was as low as 5%. Therefore, dogs have a much higher threshold of coherent motion detection than humans, and possibly also than phylogenetically closer species that have been tested in similar experimental conditions. Various factors, including the relative role of global and local motion processing and experience with the experimental stimuli may have contributed to this result. Overall, this finding questions the general claim on dogs' high performance in detecting motion. PMID- 28900294 TI - Timing for Surgical Stabilization with K-wires after Open Fractures of Proximal and Middle Phalangeal Shaft. AB - The optimal timing for surgical stabilization after open fractures of proximal and middle phalangeal shaft remained unclear. Total 147 patients with single open fracture in proximal or middle phalangeal shaft (arrived within 8 hours) who received K-wire fixation from June 2012 to June 2015 were included for analysis. The timing for surgical stabilization of fractures (immediate or delayed) was decided according to the surgeons' preferences. The Michigan hand outcomes questionnaire (MHQ) scores, grip strength and total active motion (TAM) one year after the initial surgery were similar between the two groups. There was no significant difference in the incidence of tenosynovitis, bone nonunion. The overall infection rate in immediate fixation group was slightly but not significantly higher compared with the delayed fixation group (29.2% versus 20.7% P = 0.212). However, patients with both palmar and dorsal wounds who received immediate fixation had much higher infection rate compared with delayed fixation (52.6% versus 22.7%, P = 0.047). The immediate fixation could reduce costs and the period of hospitalization. Open fractures with both palmar and dorsal wounds should be treated with delayed fixation of K-wires otherwise stabilized immediately after injury. PMID- 28900295 TI - An autocrine purinergic signaling controls astrocyte-induced neuronal excitation. AB - Astrocyte-derived gliotransmitters glutamate and ATP modulate neuronal activity. It remains unclear, however, how astrocytes control the release and coordinate the actions of these gliotransmitters. Using transgenic expression of the light sensitive channelrhodopsin 2 (ChR2) in astrocytes, we observed that photostimulation reliably increases action potential firing of hippocampal pyramidal neurons. This excitation relies primarily on a calcium-dependent glutamate release by astrocytes that activates neuronal extra-synaptic NMDA receptors. Remarkably, our results show that ChR2-induced Ca2+ increase and subsequent glutamate release are amplified by ATP/ADP-mediated autocrine activation of P2Y1 receptors on astrocytes. Thus, neuronal excitation is promoted by a synergistic action of glutamatergic and autocrine purinergic signaling in astrocytes. This new mechanism may be particularly relevant for pathological conditions in which ATP extracellular concentration is increased and acts as a major danger signal. PMID- 28900296 TI - The causes and ecological correlates of head scale asymmetry and fragmentation in a tropical snake. AB - The challenge of identifying the proximate causes and ecological consequences of phenotypic variation can be facilitated by studying traits that are usually but not always bilaterally symmetrical; deviations from symmetry likely reflect disrupted embryogenesis. Based on a 19-year mark-recapture study of >1300 slatey grey snakes (Stegonotus cucullatus) in tropical Australia, and incubation of >700 eggs, we document developmental and ecological correlates of two morphological traits: asymmetry and fragmentation of head scales. Asymmetry was directional (more scales on the left side) and was higher in individuals with lower heterozygosity, but was not heritable. In contrast, fragmentation was heritable and was higher in females than males. Both scale asymmetry and fragmentation were increased by rapid embryogenesis but were not affected by hydric conditions during incubation. Snakes with asymmetry and fragmentation exhibited slightly lower survival and increased (sex-specific) movements, and females with more scale fragmentation produced smaller eggs. Counterintuitively, snakes with more asymmetry had higher growth rates (possibly reflecting trade-offs with other traits), and snakes with more fragmentation had fewer parasites (possibly due to lower feeding rates). Our data paint an unusually detailed picture of the complex genetic and environmental factors that, by disrupting early embryonic development, generate variations in morphology that have detectable correlations with ecological performance. PMID- 28900297 TI - Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach. AB - Extensive efforts have been undertaken in search of biomarkers for predicting the chemoradiotherapy response in rectal cancer. However, most attention on treatment efficiency prediction in carcinoma is addicted to single or limited molecules. Network biomarkers are considered to outperform single molecules in predictive power. In this study, candidate microRNAs (miRNAs) were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were obtained from four experimentally confirmed interactions and three computationally predicted databases. Functional enrichment analysis of all the targets revealed their associations with chemoradiotherapy response, indicating they could be promising biomarkers. Two lists of key target mRNAs of the candidate miRNAs were retrieved from protein-protein interaction (PPI) network and mRNA expression profiles, respectively. Pathway analysis and literature validation revealed that the mRNA lists were highly related to the ionizing radiation. The above miRNAs along with the key miRNA targets provide potential miRNA-mRNA regulatory pairs as network biomarkers in which all the network components may be used for predicting the chemoradiotherapy response. These results demonstrated that the network biomarkers could provide a useful model for predicting the chemoradiotherapy response and help in further understanding the molecular basis of response differences, which should be prioritized for further study. PMID- 28900298 TI - Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer. AB - Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Many patients suffer from bone metastasis. Sclerostin, a key regulator of normal bone remodeling, is critically involved in osteolytic bone diseases. However, its role in breast cancer bone metastasis remains unknown. Here, we found that sclerostin was overexpressed in breast cancer tumor tissues and cell lines. Inhibition of sclerostin by antibody (Scl-Ab) significantly reduced migration and invasion of MDA-MB-231 and MCF-7 cells in a time- and dose dependent manner. In xenograft model, sclerostin inhibition improved survival of nude mice and prevented osteolytic lesions resulting from tumor metastasis. Taken together, sclerostin promotes breast cancer cell migration, invasion and bone osteolysis. Inhibition of sclerostin may serve as an efficient strategy for interventions against breast cancer bone metastasis or osteolytic bone diseases. PMID- 28900299 TI - Social resource foraging is guided by the principles of the Marginal Value Theorem. AB - Optimality principles guide how animals adapt to changing environments. During foraging for nonsocial resources such as food and water, species across taxa obey a strategy that maximizes resource harvest rate. However, it remains unknown whether foraging for social resources also obeys such a strategic principle. We investigated how primates forage for social information conveyed by conspecific facial expressions using the framework of optimal foraging theory. We found that the canonical principle of Marginal Value Theorem (MVT) also applies to social resources. Consistent with MVT, rhesus macaques (Macaca mulatta) spent more time foraging for social information when alternative sources of information were farther away compared to when they were closer by. A comparison of four models of patch-leaving behavior confirmed that the MVT framework provided the best fit to the observed foraging behavior. This analysis further demonstrated that patch leaving decisions were not driven simply by the declining value of the images in the patch, but instead were dependent upon both the instantaneous social value intake rate and current time in the patch. PMID- 28900301 TI - Geometric Phase Generated Optical Illusion. AB - An optical illusion, such as "Rubin's vase", is caused by the information gathered by the eye, which is processed in the brain to give a perception that does not tally with a physical measurement of the stimulus source. Metasurfaces are metamaterials of reduced dimensionality which have opened up new avenues for flat optics. The recent advancement in spin-controlled metasurface holograms has attracted considerate attention, providing a new method to realize optical illusions. We propose and experimentally demonstrate a metasurface device to generate an optical illusion. The metasurface device is designed to display two asymmetrically distributed off-axis images of "Rubin faces" with high fidelity, high efficiency and broadband operation that are interchangeable by controlling the helicity of the incident light. Upon the illumination of a linearly polarized light beam, the optical illusion of a 'vase' is perceived. Our result provides an intuitive demonstration of the figure-ground distinction that our brains make during the visual perception. The alliance between geometric metasurface and the optical illusion opens a pathway for new applications related to encryption, optical patterning, and information processing. PMID- 28900300 TI - Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila. AB - Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS. PMID- 28900302 TI - Functional dissection of hematopoietic stem cell populations with a stemness monitoring system based on NS-GFP transgene expression. AB - Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFPhigh cells exhibited significantly higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34+ cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs. PMID- 28900303 TI - Exploring priming responses involved in peach fruit acclimation to cold stress. AB - Cold storage of fruit may induce the physiological disorder chilling injury (CI); however, the molecular basis of CI development remains largely unexplored. Simulated conditions of CI priming and suppression provided an interesting experimental system to study cold response in fruit. Peaches (cv. June Gold) at the commercial harvest (CH) or tree-ripe (TR) stages were immediately exposed to cold treatment (40 d, 0 degrees C) and an additional group of CH fruits were pre conditioned 48 h at 20 degrees C prior to low-temperature exposure (pre conditioning, PC). Following cold treatment, the ripening behaviour of the three groups of fruits was analysed (3 d, 20 degrees C). Parallel proteomic, metabolomic and targeted transcription comparisons were employed to characterize the response of fruit to CI expression. Physiological data indicated that PC suppressed CI symptoms and induced more ethylene biosynthesis than the other treatments. Differences in the protein and metabolic profiles were identified, both among treatments and before and after cold exposure. Transcriptional expression patterns of several genes were consistent with their protein abundance models. Interestingly, metabolomic and gene expression results revealed a possible role for valine and/or isoleucine in CI tolerance. Overall, this study provides new insights into molecular changes during fruit acclimation to cold environment. PMID- 28900304 TI - The campaign for a National Strategy for Gypsy site provision and the role of Public Health activism in the 1960-1970s. AB - We trace the post-war evolution of a national approach to providing caravan sites for Gypsies and Travellers-something essential to protect the health of that population in the United Kingdom (UK). Throughout the 1950s and 1960s, the late Norman Dodds MP championed in Parliament the plight of the UK's Gypsies and other nomads. He was instrumental in galvanising support for the 1968 Caravan Sites Act. The vision of influential individuals working in public and environmental health surmounted practical considerations and local opposition to implement the national programme of site provision envisioned by the Act. We detail this hitherto neglected aspect of Gypsy politics and policy development. In doing so, we highlight the transformative potential of public health and argue for a return to the comprehensive vision motivating these pioneers in the 1960s and 1970s. PMID- 28900305 TI - Berberine ameliorates fatty acid-induced oxidative stress in human hepatoma cells. AB - Oxidative stress is thought to be critical for the pathogenesis of hepatic steatosis and its progress to non-alcoholic steatohepatitis. Berberine (BBR) can improve hepatic steatosis. In this study, we investigated the role of BBR in ameliorating oxidative stress. Lipid accumulation was measured in the livers of C57BL/6 mice fed a high fat diet (HFD) or a normal diet for 8 weeks, then either received BBR or vehicle for the study duration. Nrf2 distribution was detected in male Sprague-Dawley rats' livers in vivo and in Huh7 cells in vitro. ROS generation and mitochondrial complex expression was measured in Huh7 cells. HepG2 cells were employed for the measurement of oxygen consumption rates. Our results showed that BBR reduced triglyceride accumulation in the liver of HFD-fed mice. The activation and nuclear distribution of Nrf2 was decreased in the hepatocytes of rats that received BBR treatment, while on a HFD. BBR also markedly reduced Nox2-dependent cytoplasmic ROS production and mitochondrial ROS production, which was mediated by the down-regulation of Complex I and III expression. In conclusion, BBR has a great potential to reduce the effects of oxidative stress, which likely contributes to its protective effect in inhibiting the progression of hepatic steatosis to steatohepatitis. PMID- 28900307 TI - Marine microbiology: Algal virus boosts nitrogen uptake in the ocean. PMID- 28900306 TI - Effect of HNO3 concentration on a novel silica-based adsorbent for separating Pd(II) from simulated high level liquid waste. AB - A new kind of silica-based (Crea + TODGA)/SiO2-P adsorbent with high selectivity adsorption for palladium (Pd) was synthesized to examined the applicability for partitioning process of high level liquid waste (HLLW). Adsorption behavior of Pd(II) towards (Crea + TODGA)/SiO2-P adsorbent and stability of adsorbent against HNO3 solution were investigated by batch method. The degradation parts of (Crea + TODGA)/SiO2-P dissolved in liquid phase were estimated by total organic carbon (TOC) analyzer. (Crea + TODGA)/SiO2-P adsorbent showed good selectivity adsorption for Pd(II) and reached equilibrium within 24 hr. The adsorption ability of (Crea + TODGA)/SiO2-P for Pd(II) and the content of TOC leaked decreased with the increasing of HNO3 concentration. In 3 M HNO3, the average of K d values were 85.03 cm3/g and 26.10 cm3/g after contact time one to 28 days at 298 K and 323 K, respectively. While the content of TOC leaked from the adsorbent after 28 days were 1095 ppm (298 K) and 2989 ppm (323 K), respectively. Therefore, the adsorbent showed good stability at 298 K after contact with nitric acid for a long time. All results indicated (Crea + TODGA)/SiO2-P can be proposed as an applicable and efficient absorbent for separation of Pd(II) in 3 M HNO3 at 298 K. PMID- 28900308 TI - Bacterial pathogenesis: Rewiring cellular dynamics and metabolism. PMID- 28900309 TI - Viral infection: A bacteriophage-like entry pathway in eukaryotes. PMID- 28900310 TI - Microbiome: Copy-catting host signalling molecules. PMID- 28900311 TI - Archaeal biology: Plasmid propagation by virus-like particles. PMID- 28900312 TI - Dynamic patterns of overexploitation in fisheries. AB - Understanding overfishing and regulating fishing quotas is a major global challenge for the 21st Century both in terms of providing food for humankind and to preserve the oceans' ecosystems. However, fishing is a complex economic activity, affected not just by overfishing but also by such factors as pollution, technology, financial factors and more. For this reason, it is often difficult to state with complete certainty that overfishing is the cause of the decline of a fishery. In this study, we developed a simple dynamic model specifically designed to isolate and to study the role of depletion on production. The model is based on the well-known Lotka-Volterra model, or Prey-Predator mechanism, assuming that the fish stock and the fishing industry are coupled variables that dynamically affect each other. In the model, the fishing industry acts as the "predator" and the fish stock as the "prey". If the model can fit historical data, in particular relative to the productive decline of specific fisheries, then we have a strong indication that the decline of the fish stock is driving the decline of the fishery production. The model doesn't pretend to be a general description of the fishing industry in all its varied forms; however, the data reported here show that the model can describe several historical cases of fisheries whose production decreased and collapsed, indicating that the overexploitation of the fish stocks is an important factor in the decline of fisheries. PMID- 28900314 TI - Evaluation of Metabolic Syndrome and Related Factors in Children Affected by Acute Lymphoblastic Leukemia. AB - INTRODUCTION: Obesity is among the medical problems in survivors of childhood acute lymphoblastic leukemia (ALL). These patients are at risk of metabolic syndrome (MS). The present study aimed to follow the patients with ALL regarding the incidence of MS. PATIENTS AND METHODS: This study was conducted on all patients who referred to the oncology clinic from July 2012 to July 2013. The exclusion criteria of the study were ALL relapse, secondary malignancy, hypothyroidism, Down syndrome, and below 2 years of age. ALL had to be diagnosed at least 12 months before enrollment into this study. MS was assessed by serum triglyceride, cholesterol, fasting blood sugar, leptin, and insulin levels. Besides, body mass index (BMI) and blood pressure (BP) were measured at diagnosis and at the last visit. RESULTS: This study was conducted on 53 patients (male = 35, female = 18). At the end of the study, 13 patients (24.53%) were overweight compared to 3 patients at diagnosis (P = 0.04). The mean blood leptin level was higher in overweight patients compared to the others (P = 0.001). MS was detected in 21 patients (39.6%), including 12 males and 9 females. In addition, the BMI Z score significantly increased over the study period (P = 0.001). CONCLUSIONS: Being overweight is a complication of ALL treatment, which is associated with elevated blood leptin level and BMI Z-score. Therefore, MS criteria, such as BP, weight, and serum triglyceride level, should be taken into account in each visit. PMID- 28900313 TI - Selective ATP-Binding Cassette Subfamily C Gene Expression and Proinflammatory Mediators Released by BEAS-2B after PM2.5, Budesonide, and Cotreated Exposures. AB - ATP-binding cassette subfamily C (ABCC) genes code for phase III metabolism proteins that translocate xenobiotic (e.g., particulate matter 2.5 (PM2.5)) and drug metabolites outside the cells. IL-6 secretion is related with the activation of the ABCC transporters. This study assesses ABCC1-4 gene expression changes and proinflammatory cytokine (IL-6, IL-8) release in human bronchial epithelial cells (BEAS-2B) exposed to PM2.5 organic extract, budesonide (BUD, used to control inflammation in asthmatic patients), and a cotreatment (Co-T: PM2.5 and BUD). A real-time PCR assay shows that ABCC1 was upregulated in BEAS-2B exposed after 6 and 7 hr to PM2.5 extract or BUD but downregulated after 6 hr of the Co-T. ABCC3 was downregulated after 6 hr of BUD and upregulated after 6 hr of the Co-T exposures. ABCC4 was upregulated after 5 hr of PM2.5 extract, BUD, and the Co-T exposures. The cytokine assay revealed an increase in IL-6 release by BEAS-2B exposed after 5 hr to PM2.5 extract, BUD, and the Co-T. At 7 hr, the Co-T decreases IL-6 release and IL-8 at 6 hr. In conclusion, the cotreatment showed an opposite effect on exposed BEAS-2B as compared with BUD. The results suggest an interference of the BUD therapeutic potential by PM2.5. PMID- 28900315 TI - Efficacy and Safety of Deferasirox in Pediatric Patients of Thalassemia at a Tertiary Care Teaching Hospital. AB - OBJECTIVE: To evaluate efficacy, safety and utilization pattern of deferasirox in paediatric patients of transfusion dependant beta Thalassemia Major at a tertiary care teaching hospital in Gujarat. MATERIALS AND METHODS: This observational, prospective-retrospective, single centre, continuous study was conducted in a tertiary care teaching hospital among paediatric patients of transfusion dependent beta Thalassemia Major. Patients treated with deferasirox for not more than 12 weeks were enrolled. Details of blood transfusions, relevant investigations performed every 3 weeks and 3 months and drugs used were recorded in a pretested case record form. Parents were provided with a diary to record the details of ADRs. Data were analyzed for demographic characteristics, number and mean volume of blood transfusions, changes in serum ferritin and iron levels, number and types of ADRs and progression, causality, severity and preventability of ADRs. RESULTS: Of the 60 patients enrolled, one patient was lost to follow up and four withdrew their consent. Of the remaining 55 patients, 36 were boys and 19 were girls (mean age: 6 +/- 3.14 years), including patients of 1-3 years (11), 4-6 years (24), 7-10 years (12) and 11-12 years (8). Thirty six patients were born of consanguineous marriages. Adherence to blood transfusion guidelines and deferasirox prescribing and administration guidelines was observed. A serial and significant decrease in mean serum ferritin and serum iron at 3 weeks and 3 months with deferasirox treatment was observed in all age groups except that of 11-12 years. A total of 117 ADRs were observed in 52 patients from 19498 doses, most common being diarrhea (24), raised serum creatinine (15), raised hepatic enzymes (14), abdominal pain (14) and rashes (14). A reduction in dose was required in 32 cases, while a temporary stoppage was indicated in 41 cases. Deferasirox was the possible and probable cause of 65 and 51 ADRs respectively as assessed by WHO-UMC scale. Majority of ADRs were definitely preventable and mild in nature. CONCLUSION: beta Thalassemia Major is more common in males. A rational prescribing of deferasirox was observed. Deferasirox effectively reduced serum ferritin and serum iron levels in these patients. PMID- 28900316 TI - Benson's Relaxation Effect in Comparing to Systematic Desensitization on Anxiety of Female Nurses: A Randomized Clinical Trial. AB - INTRODUCTION: Nursing staffs expose to a high level of anxiety. This study aimed to compare the effect of Benson's relaxation and systematic desensitization methods for decreasing the anxiety score of nurses. MATERIALS AND METHODS: In a randomized clinical trial, 72 female nurses were assigned randomly to three different groups. Benson's relaxation and systematic desensitization were used as intervention beside control group. After intervention, the Spielberger state trait anxiety inventory was used for measuring the anxiety score. Analysis of variance (ANOVA), Tukey test, and paired t-test were applied for comparing three group scores. RESULTS: The ANOVA test showed that a significant difference among three groups regarding scores of posttrait and poststate anxiety (P < 0.05). The Tukey test showed that both Benson's relaxation and systematic desensitization methods were effective in decreasing of the anxiety score of nurses. Moreover, the mean change in trait and state anxiety scores at Benson's relaxation and systematic desensitization groups was more than control group, respectively, and was statistically significant. CONCLUSION: Both Benson's relaxation and systematic desensitization methods are effective in improvement of the state and trait dimensions of anxiety. However, these methods could be applied in stressful situation among medical staffs of students. PMID- 28900317 TI - Evaluation of Cytotoxicity Effects of Oleo-Gum-Resin and Its Essential Oil of Ferula assa-foetida and Ferulic Acid on 4T1 Breast Cancer Cells. AB - BACKGROUND: Cancer causes significant morbidity and mortality and is a major public health problem worldwide. Breast cancer is a leading cause of cancer associated mortality in women, and the incidence is also on the rise in the entire world. Medicinal plants have been an important source of several clinically useful anticancer agents. AIM: In this study, we studied the growth inhibitory effect of asafoetida and its essential oil and ferulic acid on antitumor activity using mouse breast cancer cell line. MATERIALS AND METHODS: For this aim, cells were exposed to these components at different concentrations and for different time durations. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay was carried out to characterize the cytotoxicity of the constituents used. RESULTS: Our results showed that all three constituents could inhibit 4T1 cell proliferation. Our MTT assay results showed a significant cytotoxicity effect in a time- and concentration-dependent manner. It also demonstrated that essential oil of asafoetida has a stronger effect in decreasing viability breast cancer cells. Ferulic acid showed a significant effect only at a dose of 500 MUg/ml. CONCLUSIONS: Based on the results of cellular carried out in this study, we could demonstrate that asafoetida and its essential oil and ferulic acid have inhibitory effect on the growth of breast cancer cell line. As evidenced from these preliminary results, asafoetida and its derivative constituents may be considered as attractive alternatives to serve as lead compounds in drug development for breast cancer as an adjuvant therapy. However, much remains to be done before such agent could be introduced to the clinic. PMID- 28900318 TI - Normal Tissue Complications following Hypofractionated Chest Wall Radiotherapy in Breast Cancer Patients and Their Correlation with Patient, Tumor, and Treatment Characteristics. AB - INTRODUCTION: Normal tissue complications following chest wall radiotherapy (RT) are inevitable, and the long-term data on hypofractionation are still limited. To quantify the late effects of hypofractionated RT on cardiac, pulmonary, brachial plexus, and regional lymphatics and their correlation with patient, tumor, and treatment characteristics is the main objective of this study. MATERIALS AND METHODS: Two hundred and sixteen breast cancer patients following mastectomy were treated with hypofractionated schedules either 40 Gy in 15 fractions or 42.5 Gy in 16 fractions. Common Toxicity Criteria version 3.0 was utilized to quantify the late effects of hypofractionation on cardiac, pulmonary, brachial plexus, and lymphedema at a maximum follow-up of 5 years. RESULTS: Median follow-up was 42 months. Median age was 49 years. 14.8% developed >=Grade (Gr) 2 late cardiac toxicity. 10.2% developed >=Gr2 late pulmonary toxicity. There were 28.7% patients who developed >=Gr2 lymphedema. Sixty-seven out of 216 patients had symptomatic brachial plexopathy at 5-year follow-up. Variables found to increase the incidence of these adverse events included smoking, hypertension, diabetes mellitus, body mass index >=25, extent of axillary dissection, and use of supraclavicular field. CONCLUSION: Hypofractionation leads to increased risk of normal tissue complications partly influenced by some patient- and treatment related factors, but these were manageable and minimally disabling. PMID- 28900319 TI - Investigation of Vitamin D Receptor Gene Polymorphism in Pediatric Patients with Brain Cancer. AB - AIM: In recent years, it is believed that Vitamin D may play a protective role in some cancer types. Certain regions of the Vitamin D receptor (VDR) gene may show a genetic difference in structure. The most frequent polymorphisms in this gene are in Taq-1, Fok-1, and Bsm-1 regions. Some adult cancer types are associated with VDR gene polymorphism such as; colorectal carcinoma, breast carcinoma, and prostate carcinoma. Reviewing the medical literature, no such study had been done on children so far. MATERIALS AND METHODS: We investigated the association of the three most common gene polymorphisms (Taq-1, Fok-1, and Bsm-1 regions) in VDR gene in 32 children with brain tumors and forty control healthy volunteers. RESULTS: We could not find any relationship between childhood brain tumors and VDR gene polymorphism in these three regions. CONCLUSION: The present results suggest that the Taq-1, Fok-1, and Bsm-1 polymorphism in the VDR gene and pediatric brain cancers have no association. PMID- 28900320 TI - A Cross-sectional Survey Assessing Knowledge, Attitude, and Practice Regarding Oral Cancer among Private Medical and Dental Practitioners in Bhubaneswar City. AB - INTRODUCTION: Oral cancer is a public health problem giving rise to a great number of disabilities and deaths, but the possibility of survival is astonishingly higher when detected early. Health professionals therefore have an important role and responsibility in the prevention and early detection of oral cancer. They should be in a position to identify all suspicious lesions and to search for specialist opinion as promptly as possible when unsure, while also referring to the most appropriate discipline. AIM: This study aimed to assess the knowledge, attitude, and practices (KAPs) regarding oral cancer among private medical practitioners (MPs) and private dental practitioners (DPs). MATERIALS AND METHODS: A cross-sectional, questionnaire-based study was conducted among 334 MPs and 201 DPs in Bhubaneswar. A self-designed, close-ended questionnaire containing 28 items was delivered to the practitioners in their clinics. Correlation between KAP among MPs and DPs was done by Karl Pearson's correlation coefficient test. Student's t-test was used to compare the KAP among the practitioners. RESULTS: Of the 535 practitioners approached, 513 filled the questionnaire with a response rate of 95.88%. Significantly, the mean knowledge index was higher among DPs (10.96 +/- 1.85). The attitude index was higher in the MPs (6.89 +/- 1.11), and the practice index was higher among the DPs (4.95 +/- 0.91). CONCLUSION: The study puts forward the need of further training for both MPs and DPs to increase awareness and to strengthen their abilities to diagnose potentially cancerous intra-oral lesions. PMID- 28900321 TI - Pattern of Adverse Drug Reactions to Anticancer Drugs: A Quantitative and Qualitative Analysis. AB - INTRODUCTION: Anticancer drugs contribute significantly to the global burden of adverse drug reactions (ADRs). Any attempt to quantify their magnitude and provide upgraded knowledge would help oncologists in writing safer prescriptions. AIM: This observational follow-up study was conducted on newly diagnosed cancer patients receiving anticancer therapy with an aim to determine the frequency, severity, causality, predictability, and preventability of ADRs. SUBJECTS AND METHODS: The patients were followed up for 6 months for the appearance of adverse events. Data were analyzed using IBM SPSS Statistics for Windows, Version 22.0. (Armonk, NY) and presented in the form of descriptive statistics. RESULTS: Each patient was prescribed approximately 6.85 +/- 1.51 (mean +/- standard error) drugs on average. All the patients (100%) receiving anticancer chemotherapy had ADRs. Alopecia, nausea and vomiting, burning tingling, and numbness were the most frequently encountered ADRs. The incidence of alopecia (P < 0.0004), nausea (P < 0.03), and oral ulceration (P < 0.02) was higher in females. Maximum reactions were of Grade 2 (69.53%). Most of the reactions (75.80%) appeared within 10 days of receiving the first cycle. 99.58% reactions were not serious. According to the WHO - The Uppsala Monitoring Centre criteria, 99.47% ADRs fell in possible category. According to the Naranjo's algorithm, 100% ADRs fell in probable category. About 94.80% reactions were found to be predictable. About 56.47% reactions were probably preventable, and 43.53% reactions were not preventable. CONCLUSION: Multiple ADRs were seen in newly diagnosed cancer patients. Most of them were predictable, of mild-to-moderate severity, nonserious, and preventable. A majority of the ADRs recovered over time. PMID- 28900322 TI - Stigma Perceived by Women Following Surgery for Breast Cancer. AB - CONTEXT: Women undergoing treatment for breast cancer often have psychological morbidity and body image difficulties. The risk factors for increased levels of stigma in women with breast cancer have not been adequately studied. AIMS: This study aimed at investigating the associations of high levels of stigma in women with breast cancer. SETTINGS AND DESIGN: This cross-sectional study was conducted in a comprehensive cancer center in India and recruited women (n = 134) undergoing surgical treatment for breast cancer. METHODS: Body image difficulties, including stigma and affective symptoms, were quantified, alongside disease- and treatment-related variables using standardized questionnaires. STATISTICAL ANALYSIS USED: Univariate analysis followed by multivariate logistic regression was performed to find the risk factors of high levels of stigma related to body image. RESULTS: In the univariate analysis, high levels of stigma were associated with lesser educational attainment (odds ratio [OR] =2.92, confidence interval [CI] 1.25-6.8, P = 0.01), breast conservation surgery (BCS) as opposed to mastectomy (OR = 4.78, CI 2.07-11.03, P < 0.001), having an anxiety disorder (OR = 2.4, CI 1.09-5.33, P = 0.03), and depression (OR = 3.08, CI 1.37 6.89, P < 0.01). On multivariate logistic regression, with stigma as the dependent variable, being less educated (adjusted OR [AOR] 3.08, CI 1.18-8.04, P = 0.02) and opting for BCS (AOR 6.12, CI 2.41-15.5, P < 0.001) were associated with higher stigma. CONCLUSIONS: Women with breast cancer should be screened for distress and stigma. Women opting for BCS may still have unmet emotional needs on completion of surgery and should have access to psychological interventions to address stigma, affective symptoms, and body image problems. PMID- 28900323 TI - Detection and Significance of Human Epidermal Growth Factor Receptor 2 Expression in Gastric Adenocarcinoma. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis of several types of cancer, including gastric cancer. Overexpression of HER2 is noted in 10%-22.8% of gastric adenocarcinoma and its identification is of immense importance for management by targeted drugs. Detection of HER2 expression in gastric malignancies has not been undertaken previously in the local population. OBJECTIVE: To ascertain HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship with the anatomic location and histomorphology. MATERIALS AND METHODS: A total of 47 cases of gastric adenocarcinoma diagnosed over 2 years constituted the study group. Clinical history, type of operation, gross morphology, and hematoxylin and eosin (H and E) stained sections were reviewed. Two paraffin blocks were selected, immunostain was performed using rabbit monoclonal HER2 antibody and Hoffmann scoring system was applied. RESULTS: Most of gastric carcinomas occurred in male (42 cases), having a mean age of 53.6 years. A total of eight cases (17.1%) had expressed a score of 3+ HER2 positivity. All positivity was noted in intestinal type according to Lauren classification (25%) and none in diffuse type. All HER2 score of 3+ was noted in histological grade of well and moderately differentiated adenocarcinoma. Score 2+ was noted in seven cases, among them, only two were poorly differentiated gastric adenocarcinoma. CONCLUSION: HER2 overexpression was noticeably associated with an intestinal subtype, and well and moderately differentiated adenocarcinomas. Such cases of gastric adenocarcinoma are considered for targeted therapy with trastuzumab in the local population. PMID- 28900324 TI - A Significant Breakthrough in the Incidence of Childhood Cancers and Evaluation of its Risk Factors in Southern Iran. AB - BACKGROUND AND OBJECTIVE: This study investigates epidemiologic and practical information about the incidence and risk factors of childhood cancer in a population of Southern Iranian children. MATERIALS AND METHODS: A total number of 300 cancer patients along with 600 age- and gender-matched healthy control were interviewed by a trained physician regarding their demographic characteristics, and major family-associated risk factors, childhood malignancies. RESULTS: The average annual percentage change for cancers in the studied population is calculated as 45%. Our study indicated that possible risk factors which could contribute to the development of childhood cancer are maternal oral contraceptive pill use during pregnancy, exposure to radiation during pregnancy, parental smoking, residence near high voltage electricity lines, exposure to pesticides and fertilizers, patient allergy, contact with domestic animals and father's educational degree. Furthermore, new ecological risk factors such as air pollution due to nonstandard petroleum or toxic inhalant particles, nonhealthy food consumption, and satellite jamming are other predisposing factors. CONCLUSION: Our study reported a higher average annual percentage change of childhood cancers in our area, compared to the existing literature. In conclusion, detection and prevention of the consistent and possible new environmental risk factors such as nonstandard petroleum or satellite jamming from all around the country should be taking into consideration. PMID- 28900325 TI - Symptom Burden and Quality of Life Issues among Patients of Chronic Myeloid Leukemia on Long-term Imatinib Therapy. AB - BACKGROUND: Tyrosine kinase inhibitors such as imatinib have improved survival in chronic myeloid leukemia (CML). Imatinib can cause chronic side effects which are not considered serious but can impact the quality of life (QoL) of the patient. METHODS: The results of a detailed symptom burden analysis and its impact on QoL scores in a cohort of patients on long-term imatinib is presented in this study. Symptom burden was assessed using the M. D. Anderson Symptom Inventory specific for CML patients. An indigenously developed QoL questionnaire (Cancer Institute Quality of Life II) was administered simultaneously. RESULTS: Of 221 patients of CML (M:F = 133:88; median age: 39 years [18-65], median duration of imatinib: 4 years), QoL scores were high in 46%, average in 39%, and low in 14%. QoL scores were negatively correlated with general symptoms (r = -0.612, P < 0.001), CML specific symptoms (r = -0.513, P < 0.001), and interference of symptoms (r = 0.596, P < 0.001). CONCLUSIONS: Significant impairment of QoL was noted among patients with CML primarily due to the burden of symptom related to side effects of imatinib. This issue must be addressed both in the clinic as well as in all studies of CML. PMID- 28900326 TI - The Relationship between Serum Selenium and Zinc with Gastroesophageal Cancers in the Southeast of Iran. AB - BACKGROUND: Selenium (Se) and zinc (Zn) have antioxidant and anticancer properties. OBJECTIVE: The aim of this study was to evaluate the serum levels of Se and Zn and the correlation between the levels of these two elements with risk of incidence of esophageal cancer (EC) and gastric cancer (GC). MATERIALS AND METHODS: In a case-control study, we selected sixty patients with GC or EC as the intervention group and 120 age-matched individuals as the control group. Exclusion criteria were the individuals with kidney and liver failure and the consumer of dietary supplements such as Se and Zn. Measurement of serum Se was done in a graphite furnace system and atomic absorption device of Varian and of serum Zn was done by a flame photometer system (flame) and atomic absorption device of Varian. RESULTS: In thirty patients of ECs, 90% were squamous cell carcinoma and 10% adenocarcinoma, and out of thirty patients of GCs, 90% were intestinal type and 10% diffuse type. The level of two elements in cancer patients was lower than the control group (P < 0.05). There was no significant different between two cancer groups for level of Se and Zn, but there was a significant difference between the control group with two other groups. CONCLUSION: Our study confirmed the findings from previous prospective studies and randomized trials that reducing of lower levels of Se and Zn can effect on incidence of cancer. PMID- 28900327 TI - Metastatic Ewing's Sarcoma: Revisiting the "Evidence on the Fence". AB - Metastatic Ewing's sarcoma is a challenging disease for oncology care providers with wide spectrum of disease at presentation, widely varying approach to the treatment and varied outcomes. The paucity of randomized evidence is a barrier in developing a consensus. This perspective provides the evidence "for and against" the benefit of aggressive approach including local and systemic therapy in patients presenting with metastatic Ewing's sarcoma and provide general recommendations so as to help select patients who will benefit with definitive intent treatment and also, avoid aggressive approach in patients with dismal outcome. PMID- 28900328 TI - Immune Checkpoint Blockers and Ovarian Cancer. AB - Although the idea, called "cancer immunotherapy," is very appealing and has previously been shown to work in several mouse models of cancer, it has in general been very difficult to translate cancer immunotherapy approaches to humans. Because of this frustration, by the 1990s, many scientists and biotechnology companies had given up on the idea of cancer immunotherapy. After few years, first detection T-cell suppression of effect of cytotoxic T-lymphocyte antigen-4 (CTLA4) molecule was established. Antibody (Ab) to CTLA4 could increase T-cell starting a completely new age of tumor immunology. Immune checkpoints are new ways in manipulation of immunological control over malignant tumors. It has lent an important measure to manage, especially recurrent and refractory cancers and those cancer where there is an unmet need like recurrent melanoma, renal cell carcinoma, and recurrent ovarian cancer. As a new development, this subject is experiencing rapid progress, and multiple avenues are opening up. Although there are many hurdles to overcome this needs constant updating, especially for students of ovarian cancer who are looking at it with much hope. PMID- 28900329 TI - Cytotoxic Drug Dispersal, Cytotoxic Safety, and Cytotoxic Waste Management: Practices and Proposed India-specific Guidelines. AB - This article deals with practices related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management and attempts at India-specific guidelines for their dispersal and disposal. The articles related to cytotoxic drug dispersal, cytotoxic safety, and cytotoxic waste management were reviewed from PubMed and their applicability in Indian health-care facilities (HCFs) was also reviewed. All HCFs dealing with cytotoxic drugs should consider cytotoxic policy, patient safety and health-care worker safety, and environmental monitoring program as per the available international guidelines customized as per Indian conditions. Utmost care in handling cytotoxic waste is quintessential. The formation of India-specific cytotoxic guidelines requires the inputs from all stakeholders. Cytotoxic waste, cytotoxic safety, and cytotoxic waste management should be the subject of a national strategy with an infrastructure, cradle-to grave legislation, competent regulatory authority, and trained personnel. PMID- 28900331 TI - Solid Pseudopapillary Tumor of Pancreas: A Case Report and Review of Literature. AB - Solid pseudopapillary neoplasm of the pancreas is one of the rarest forms of pancreatic neoplasm. It was also known as Franz's tumor or Hamoudi tumor until WHO labeled it as solid pseudopapillary tumor (SPT) in 1996. It typically affects young non-Caucasian females in their second or third decade of life. Treatment involves complete excision of the tumor which results in complete cure in majority of the cases. We present here a report of 11-year-old girl with SPT and also do a review of literature for this rare tumor. PMID- 28900332 TI - A Case of Mature Cystic Teratoma in an 8-year-old Girl: A Rare Case Report. AB - Ovarian tumors are commonly seen in reproductive age group in women. However, when they occur at extremes of age, the suspicion of malignancy increases. The detection of dermoid cyst at 8 years of age is uncommon and hence is being reported to acquaint the doctors of this possibility. Awareness of benign tumors in small children can help in proper counseling of patient party and planning the surgical procedure. PMID- 28900330 TI - Role of Insulin-like Growth Factor, Insulin-like Growth Factor Receptors, and Insulin-like Growth Factor-binding Proteins in Ovarian Cancer. AB - Insulin and IGFs play an important role in cancer initiation and progression, including ovarian cancer (OC). Epithelial ovarian cancer (EOC) is the most frequent type of OC in women and it is the most lethal gynecological malignancy worldwide. Generally, insulin is associated with metabolism, whereas Insulin like growth factors (IGFs) are involved in cell proliferation. Hence, Insulin-like growth factor binding proteins (IGFBPs) determines the bioavailability of IGFs in circulation. The interplay between these molecules such as insulin, IGFs, IGFBPs and insulin-like growth factor receptor 1 (IGF1R) may be crucial for ovarian cancer cell biology and cancer progression. However, the IGF1R inhibitors exhibiting potent activity on IGF/IGF1R also demonstrated activity against OC cells. The combination therapy of drugs may prove to be beneficial in clinical management of OC. This review describes both molecular and clinical associations between insulin and IGF1 signaling pathways in ovarian cancer. The data was collected using PubMed search engine with the following key words such as ovarian cancer, IGFs, IGFBP, IGF1Rs and ovarian cancer. PMID- 28900333 TI - Ruptured Malignant Ovarian Tumor in an Adolescent Girl: A Rare Case Report. AB - Germ cell tumors which arise mainly in pediatric and adolescent age group, account for 30% of all ovarian tumors, but constitute only 5% of all malignant ovarian tumors. The presentation is usually insidious with the patient presenting with abdominal swelling and dull aching pain. We report a rare case of a malignant germ cell tumor in a 12-year-old girl who presented with acute abdomen due to spontaneous rupture of tumor resulting in hemoperitoneum. The patient was taken up for emergency laparotomy and left salpingo-opherectomy with omentectomy and drainage of hemoperitoneum was done. The authors conclude that ruptured malignant ovarian tumor should be considered in the differential diagnosis of any young girl presenting with abdominal mass and acute abdominal pain. PMID- 28900334 TI - Massive Hemoptysis: A Rare Presentation of Anterior Mediastinal Teratoma in an Adolescent. AB - Germ cell tumors are predominantly found in the gonads, and the most common extragonadal site is anterior mediastinum. Usual symptoms are cough, dyspnea, and fever, chest pain due to mass effect or intrapulmonary invasion but hemoptysis is rare and may result from either communication with tracheobronchial tree or may result from bronchial bleeding due to irritation by tumor. As in our case, patient presenting with massive hemoptysis and shock are the rarest presentation of a benign teratoma. PMID- 28900335 TI - Rhabdoid Meningioma of Brain - A Rare Aggressive Tumor. AB - Rhabdoid meningioma is a rare aggressive variant of meningioma, regarded as WHO Grade III type. Histologically and cytologically, it is distinctive type having abundant eosinophilic cytoplasm, cytoplasmic inclusion with eccentrically placed vesicular nuclei and prominent nucleoli. High recurrence rate and poor outcome are important features. Here, we are presenting a rare case of rhabdoid meningioma found in a recurrent meningioma of the posterior fossa in a middle aged female. We emphasized the squash cytology and histology finding of the rare neoplasm. PMID- 28900336 TI - Prosthetic Management of Hard Palate Perforation in a Child with Acute Lymphoblastic Leukemia. AB - Palatal perforation is an uncommon complication seen in children with acute lymphoblastic leukemia undergoing chemotherapy. This may impact basic functions, such as speech, swallowing, chewing, affecting the quality of life (QOL). Prosthetic rehabilitation of the palatal perforation with obturator can optimally restore function, thereby improving and enhancing the QOL of these patients. PMID- 28900337 TI - Mammary Myofibroblastoma with Unusual Morphological and Immunohistochemical Features. AB - Mammary myofibroblastoma (MFB) is a rare mesenchymal tumor, derived from mammary stromal fibro/myofibroblasts, which has various morphological features and characteristic immunohistochemical staining. The epithelioid morphologic variant is defined, accordingly, as a proliferation of exclusively or predominantly (>50%) epithelioid cells, variably embedded in a myxoid to fibrous stroma. These histological and cytological features may pose a diagnostic challenge mainly with metaplastic carcinoma and invasive lobular carcinoma of the breast. Thus, immunohistochemical staining by myofibroblastic markers is helpful for confirming diagnosis. Herein, we present a case of MFB in a 43-year-old female. This case report emphasizes the role of immunohistochemistry as gold standard in the diagnosis of MFB. This case is also being presented because of its unusual radiologic findings, its epithelioid histologic variant mimicking malignancy, and its uncommon immunohistochemical phenotype. PMID- 28900338 TI - Bulky Pelvic Hodgkin Lymphoma in a Prepubertal Girl. AB - Pure infra-diaphragmatic presentation is rare in pediatric Hodgkin lymphoma (HL). Isolated pelvic presentation is restricted to case reports in adults. We describe a unique presentation of HL as a primary pelvic disease in an 11-year-old prepubertal girl. She was treated based on the Euronet-Paediatric Hodgkin's Lymphoma Group protocol (EuroNet-PHL-C1) recommendations and assigned to treatment Group 2 (Stage IIB). The patient had bulky disease and a suboptimal response on interim 18-fluorodeoxyglucose positron emission tomography. The child was administered chemotherapy alone. Pelvic radiotherapy was consciously avoided due to the high risk of gonadal failure. She remains disease-free for 18 months now. Treatment of pediatric HL necessitates a delicate balance between achieving cure as well as avoiding serious late effects of therapy. PMID- 28900339 TI - Metastatic Primary Angiosarcoma of the Breast: Can We Tame It the Metronomic Way. AB - Primary angiosarcoma of the breast is a highly aggressive but rare malignant neoplasm. Palliative chemotherapy with different agents and combinations has been tried in the metastatic setting with poor results. We present the case of a young woman with this disease describing her aggressive course. We used a metronomic combination of oral drugs due to her poor general condition and achieved disease stabilization although not durable. PMID- 28900340 TI - Primary Intraosseous Malignant Peripheral Nerve Sheath Tumor of Metacarpal Bones of the Hand in a Patient Without Neurofibromatosis 1: Report of a Rare Case. AB - Malignant peripheral nerve sheath tumor (MPNST) usually arises in peripheral nerve sheath cells. The intraosseous location of MPNST is rare. Mandible is the most common site of bony involvement. Involvement of bones of the hand is quite unusual. We report a case of MPNST involving metacarpal bones of the left hand treated with surgery followed by adjuvant radiation and chemotherapy and review the pertinent literature. PMID- 28900341 TI - Hepatic Amyloidosis: Something That Can camouflage and Deceive our Perception! AB - Amyloidosis is a multi-systemic diffusely infiltrating disease due to extracellular deposition of protein-mucopolysaccharide complexes. The type of protein deposited determines the subgroup of amyloid. Hepatic amyloidosis is a rare infiltrating disease affecting the hepatic parenchyma. A wide range of clinical presentation and atypical imaging findings delay the diagnosis of amyloidosis, while tissue biopsy demonstrating amyloid deposits is vital for a definitive diagnosis. PMID- 28900342 TI - Incidence and Pattern of Childhood Cancers in India: Findings from Population based Cancer Registries. AB - Childhood cancers have different characteristics than those occurring among adults and described as cancers occurring below 15 years of age. In developed countries, its incidence is relatively rare but it's a leading cause of death. More than 80% of the childhood cancers are occurring in low and middle income countries. Based on data from population based cancer registries under National Cancer Registry Programme, in this commentary, we described the incidence and pattern of Childhood cancers in India and its implications. PMID- 28900343 TI - Two Cases of Acinic Cell Carcinoma of Parotid Gland - Rare Papillary Cystic Variant: One Unusual Presentation in Older Male Patient. PMID- 28900344 TI - Primary Diffuse Large B-cell Lymphoma of the Breast: A Rare Case and Review of Literature. PMID- 28900345 TI - Alternative Ketogenic Diet with Coconut Milk in a Case with Underlying Colorectal Cancer. PMID- 28900346 TI - Toxoplasmosis and Lymphoma: The Mimickers. PMID- 28900348 TI - Improvement in vaccination knowledge among health students following an integrated extra curricular intervention, an explorative study in the University of Palermo. AB - INTRODUCTION: Vaccination coverages threaten to decrease because of false beliefs in their unsafety and inefficacy. Therefore formation of future health-care workers on this topic is fundamental to deal with any doubt and to promote active immunization among general population. METHODS: In order to assess health-care students' knowledge about vaccination before an integrated seminar on this topic, and to evaluate their improvement after the educational intervention, an integrated educational intervention was held by a multidisciplinary team. Before and after the seminar, 118 students of medicine and biology schools at Palermo University were asked to answer 10 multiple-choice questions regarding vaccine history, mechanism of action, side effects, composition, use and nowadays issues (hesitancy). Two more questions investigating possible changes on students' attitudes towards vaccination and the usefulness of the formative intervention, were added at the post-test phase of the survey. RESULTS: Eighty-one out of 118 students (68.6%) answered to both pre- and post-test questions. 97.6% and 81.5% of the participating group also completed the two additional questions about their improvement in knowledge (question 11) and attitudes (question 12) towards vaccinations. The post-test results showed a significant improvement for all questions administered, except for number 3 (about a specific immunological content), with an overall percentage of correct answers increasing from 38.8% to 77.6% (p(c)< 0.001). CONCLUSIONS: The present explorative study put the basis for future studies, stronger in the methodology, and highlights the importance of educating health-care professions students by integrated extra-curricular intervention to be held early in their degree curricula and in order to improve knowledge and attitudes towards vaccinations and to prepare them to promote vaccines among the general population. PMID- 28900349 TI - Knowledge and behaviour of nursing students on the prevention of healthcare associated infections. AB - INTRODUCTION: Hospital infections, or "healthcare associated infections" (HAI) represent the most common and serious complications of healthcare. Adoption of safe care practices able to prevent or control the transmission of infections, both in hospitals and in other healthcare settings is crucial. The aim of the study is to assess the awareness about the risk factors and the most effective measures of prevention of HAI in the University of Ferrara nursing school students, giving particular attention to the hand hygiene practices and the use of standard precautions. METHODS: 339 students attending all the three years of course of the same academic year were enrolled. An anonymous questionnaire was administered in order to investigate the knowledge about three specific areas: infections associated with healthcare practices (HAI), standard precautions (SP) and hand hygiene (HH). RESULTS: A sufficient level of knowledge by all the three groups of students was observed only in the SP area. A barely sufficient score was reached only by the third year students with regard to the proper HH. The level of knowledge about HAI was inadequate. CONCLUSIONS: A periodically check of nursing students' knowledge would be advisable in order to fill any gaps, improve training, reduce HAI and increase prevention measures compliance. PMID- 28900350 TI - Influence of physical activity and interest for food and sciences versus weight disorders in children aged 8 to 18 years. AB - INTRODUCTION: Being overweight and obesity are a growing problem and are often related to a lack of physical activity among younger people. This study aims to describe the prevalence of weight disorders in Belgian schoolchildren. Secondly, this study examines the association between physical activity, weight disorders and the interest in food and sciences. METHODS: We examined 525 children aged between 8 and 18 years old, who attended the Brussels Food Fair or the Belgian Science Day in 2013. They completed a standardized questionnaire about lifestyle and physical activity. Their weight, height, blood pressure and waist circumference were measured. The physical condition of participants was estimated using the Ruffier test. RESULTS: The average age of all participants was 11.2 years (95% CI: 8.7-13.7), the prevalence of being overweight and obesity was 16.3% and 5.4%, respectively. For all participants in the representative group the affiliation to a sports club was associated with a normal weight (P < 0.05). According to this study, the kind of transportation to school (foot/bike or car/bus) had no effect on their body mass index (BMI). Neither was there a significant relationship between the physical activity of the children and the result of their Ruffier test. CONCLUSIONS: The prevalence of being overweight and obesity in children aged 8 to 18 years is alarming. Membership to a sports club was linked significantly to a normal weight and a lower prevalence of being overweight and obesity. PMID- 28900351 TI - An overview of different health indicators used in the European Health Systems. AB - INTRODUCTION: In the European Union three different health systems could be defined according to service delivery, financing, and economic policies: Beveridge, Bismarck and Mixed system. Although health systems are hardly to compare, various organizations are developing methods assessing performance. In the present work the performance of the three systems were evaluated using European Community Health Indicators according to Organization for Economic Cooperation and Development. METHODS: The study has been conducted among the 28 states of the European Union using the following indicators: Standardized death rate for diseases of the circulatory system, standardized death rate of malignant neoplasms, road traffic accidents with injury, life expectancy at birth, incidence of Human Immunodeficiency Virus (HIV), infant deaths, pure alcohol consumption, infants vaccinated against Diphtheria Tetanus Pertussis (DTP), public and total expenditure on health over the period 2001-2010. RESULTS: The variation of health indicators over the observational time shows similar trend of circulatory system diseases and malignant neoplasms death rates, road accidents with injury, infant deaths, life expectancy at birth, public and total health expenditure. Some differences in the trend of HIV incidence, alcohol intake and DTP vaccination rates arise among systems. Grouping countries by health system paradigm and geographical area, resulted in a relevant heterogeneity (I2 >= 90%, Pvalue < 0.0001). No clear superiority of a given health delivery system was found with respect to other paradigms. CONCLUSIONS: In accordance with the evidence of our study, it can be stated that best performances are more likely to be linked to country specific economic factors. In conclusion, it was not possible to identify the best health system model. PMID- 28900347 TI - Campylobacter: from microbiology to prevention. AB - In last years, Campylobacter spp has become one of the most important foodborne pathogens even in high-income countries. Particularly, in Europe, Campylobacteriosis is, since 2005, the foodborne disease most frequently notified and the second in USA, preceded by the infection due to Salmonella spp. Campylobacter spp is a commensal microorganism of the gastrointestinal tract of many wild animals (birds such as ducks and gulls), farm animals (cattle and pigs) and companion animals (such as dogs and cats) and it is responsible for zoonoses. The transmission occurs via the fecal-oral route through ingestion of contaminated food and water. The disease varied from a watery diarrhea to a severe inflammatory diarrhea with abdominal pain and fever and can be burdened by some complications. The main recognized sequelae are Guillain-Barre Syndrome (GBS), the Reactive Arthritis (REA) and irritable bowel syndrome (IBS). Recently, many cases of Campylobacter spp isolated from human infections, showed an important resistance to various antibiotics such as tetracyclines and fluoroquinolones. For these reasons, the prevention of this infection plays an essential role. Many preventive measures exist to limit the transmission of the pathogens and the subsequent disease such as the health surveillance, the vaccination of the poultry and the correct food hygiene throughout the entire production chain. A global surveillance of Campylobacteriosis is desirable and should include data from all countries, including notifications of cases and the microbiological data typing of strains isolated from both human and animal cases. PMID- 28900352 TI - Exploring patient safety culture in preventive medicine settings: an experience from Northern Italy. AB - INTRODUCTION: Patient safety and quality in healthcare are inseparable. Examining patient safety culture in staff members contributes to further develop quality in healthcare. In Italy there has been some experience in assessing patient safety culture in staff working in hospital. In this pilot study we explored patient safety culture in public health staff working in Italian Local Health Authorities. METHODS: We carried out a descriptive cross sectional study in four Italian territorial Prevention facilities in Northern Italy. We administrated an adapted Italian version of the US Hospital Survey of Patient Safety Culture to all the staff within these facilities. The survey consisted of 10 dimensions based on 33 items, according to the results of a previous psychometric validation. RESULTS: Seventy per cent of the staff responded to the survey (N = 479). Overall, six out of the 10 dimensions exhibited composite scores of positive response frequency for patient safety culture below 50%. While "communication openness" (65%) was the most developed factor, "teamwork across Units" (37%) was the least developed. The work areas with the highest composite scores were Management and the Public Health Laboratory, while in terms of professional categories, Physicians had the highest scores. Patient safety culture in the staff participating in this study was lower than in hospital staff. DISCUSSION: Our descriptive cross sectional study is the first to be carried out in Preventive medicine settings in Italy. It has clearly indicated the need of improvement. Consequently, several interventions with this aim have been implemented. PMID- 28900353 TI - Brain doping: stimulants use and misuse among a sample of Italian college students. AB - INTRODUCTION: The non-medical use of prescription stimulants (NMUPS) has become the subject of great interest for its diffusion among university students, who abuse these substances to cope with the increasing load of academic stress. NMUPS has been widely investigated in the U.S. due to its increasing trend; this behavior, however, has also been reported in Europe. The aim of this cross sectional study was to examine stimulants misuse in a Northern Italian geographic area, identifying possible developments of the phenomenon in Italy. METHODS: To evaluate academic and extra-academic NMUPS (Methylphenidate and Amphetamines), an anonymous multiplechoice questionnaire was administrated to a sample of Bachelor's and Master's degrees students attending a University North East of Italy. Data elaboration and CI 95% were performed with Excel software 2013. Fisher's exact tests were performed using Graph- Pad INSTAT software. RESULTS: Data from 899 correctly completed questionnaires were analyzed in this study. 11.3% of students reported NMUPS, with an apparent greater use by students aged 18-22 years (73.5%) and without any statistically significant gender predominance. Fifty-seven point eight percent of students used stimulants at most five times in six months, and the most frequent academic and extra-academic reasons to use them were respectively to improve concentration while studying (51.0%) and sports performance (25.5%). NMUPS was higher among working students than nonworking ones (p < 0.05), suggesting a use of stimulants to cope with stress by the first ones. CONCLUSIONS: These exploratory and preliminary data suggest that NMUPS is quite relevant in Northern Italy, suggesting a need for preventive and monitoring measures, as well as future analysis via a longitudinal multicenter study. PMID- 28900354 TI - Knowledge, attitudes, beliefs and practices of Occupational Physicians towards seasonal influenza vaccination: a cross-sectional study from North-Eastern Italy. AB - INTRODUCTION: The present study aims to characterize personal attitudes and knowledge of a sample of Italian Occupational Physicians (OPh) towards Seasonal Influenza Vaccine (SIV) in healthcare workers (HCWs). METHODS: In total, 92 OPh (42.4% males, 57.6% females, mean age of 47.3 +/- 10.4 years, 50 specialists in Occupational Medicine, 42 specialists in Hygiene and Public Health) were asked about their attitudes towards influenza vaccine, their general knowledge of vaccine practice, their propensity towards vaccines and, eventually, their risk perception about the influenza and influenza vaccine was investigated. A regression analysis was then performed in order to better characterize predictive factors for vaccine propensity. RESULTS: Influenza was recognized as a vaccination recommended for HCWs in 89/92 of the sampled OPh (96.7%). However, prevalence of misconceptions about vaccines was relatively high, with 26/92 (28.3%) and 24/92 (26.1%) referring vaccinations as eliciting allergic and autoimmune diseases, respectively and identifying lethargic encephalitis (18/92, 19.6%), autism (17/92, 18.5%), diabetes mellitus (15/92, 16.3%) and multiple sclerosis (13/92, 14.1%) as causatively vaccine-related. Propensity towards influenza vaccination found a significant predictor in the general knowledge (beta coefficient 0.213, p value = 0.043), risk perception (beta coefficient 0.252, p value = 0.018) and general propensity towards vaccinations (beta coefficient 0.384, p value = 0.002). DISCUSSION: In spite of a diffuse propensity towards SIV, adherence of OPh was still < 50% of the sample. Moreover, sharing of misbeliefs and misconceptions was significant. As knowledge and risk perceptions were identified as significant predictors of vaccine propensity, our results suggest that information and training programs for OPh should be appropriately designed. PMID- 28900355 TI - Distribution of blaTEM, blaSHV, and blaCTX-M genes among ESBL-producing P. aeruginosa isolated from Qazvin and Tehran hospitals, Iran. AB - INTRODUCTION: Pseudomonas aeruginosa is as an important opportunistic human pathogen, which is associated with several clinical infections that are usually difficult to treat because of resistance to multiple antimicrobials. The production of extendedspectrum beta-lactamases (ESBLs) is an important mechanism of beta-lactam resistance. The aims of this study were to determine the prevalence of ESBLs, antimicrobial susceptibility, and to detect the blaTEM, blaSHV, and blaCTX-M genes. METHODS: In this study, carried out from March 2013 to December 2014, 266 P. aeruginosa isolates were collected from patients admitted to teaching hospitals of Qazvin and Tehran, Iran. All isolates were initially screened for ESBL production by disk diffusion method and were further confirmed using a combined disk method. Antimicrobial susceptibility of ESBL producing isolates was determined by standard disk diffusion method. Polymerase Chain Reaction (PCR) and sequencing techniques were employed for detection of blaTEM, blaSHV, and blaCTX-M genes. RESULTS: In total, 262 (98.5%) P. aeruginosa isolates were nonsusceptible to the used extended spectrum cephalosporins, and, among these, 75 (28.6%) isolates were ESBL producers. Fifty-nine (78.7%) of ESBL producing isolates showed multidrug-resistance pattern. Of 75 ESBL-positive isolates, the blaTEM-1 (26.7%) was the most common gene, followed by blaCTX-M-15 (17.3%), blaSHV-1 (6.7%), and blaSHV-12 (4%), either alone or in combination. CONCLUSIONS: The results of this study showed the notable prevalence of ESBLs among the clinical isolates of P. aeruginosa in Iran, indicating the urgency for the implementation of appropriate follow-up measures for infection control and proper administration of antimicrobial agents in our medical settings. PMID- 28900356 TI - Humidifiers for oxygen therapy: what risk for reusable and disposable devices? AB - INTRODUCTION: Nosocomial pneumonia accounts for the vast majority of healthcare associated infections (HAI). Although numerous medical devices have been discussed as potential vehicles for microorganisms, very little is known about the role played by oxygen humidifiers as potential sources of nosocomial pathogens. The purpose of this research was to evaluate the safety of the reuse of humidifiers by analysing the rate of microbial contamination in reusable and disposable oxygen humidifiers used during therapy, and then discuss their potential role in the transmission of respiratory pathogens. METHODS: Water samples from reusable and disposable oxygen humidifiers were collected from different wards of the University Hospital of Messina, Italy, where nosocomial pneumonia has a higher incidence rate due to the "critical" clinical conditions of inpatients. In particular, we monitored the Internal Medicine and Pulmonology wards for the medical area; the General Surgery and Thoracic and Cardiovascular Surgery wards for the surgical area and the Intensive Care Unit and Neonatal Intensive Care Unit for the emergency area. The samples were always collected after a period of 5 days from initial use for both types of humidifiers. Samples were processed using standard bacteriological techniques and microbial colonies were identified using manual and automated methods. RESULTS: High rates of microbial contamination were observed in samples from reusable oxygen humidifiers employed in medical (83%), surgical (77%) and emergency (50%) areas. The most relevant pathogens were Pseudomonas aeruginosa, amongst the Gram-negative bacteria, and Staphylococcus aureus, amongst the Gram-positive bacteria. Other pathogens were detected in lower percentage. The disposable oxygen humidifier samples showed no contamination. CONCLUSIONS: This research presents evidence of the high rate and type of microbial contamination of reusable humidifiers employed for oxygen therapy. These devices may thus be involved in the transmission of potential pathogens. It could be important, for the prevention of nosocomial pneumonia, to replace them with singleuse humidifiers for which the absence of microbial contamination has been confirmed. PMID- 28900357 TI - Five-year microbiological monitoring of wards and operating theatres in southern Italy. AB - INTRODUCTION: Nosocomial infections are one of the greatest problems in public health. Several studies have highlighted the role played by the hospital environment as a possible source of transmission of nosocomial pathogens. METHODS: A five-year monitoring of bacterial contamination on healthcare workers hands, surfaces most closely in contact with inpatient wards, operating theatres and "at rest" and "in use" operating theatre air samples. For the samples, we used sterile swabs, contact slides, manual API, and automated VITEK systems for identification. RESULTS: In the five-year period, a total of 9396 samples were collected and analysed. In ward patients, 4398 samplings were carried out with 4.7%, 9.4%, 7%, 10.8% and 7.9% positive results respectively from 2010 to 2014. For hands, 648 samplings were carried out, with a positivity of 40.74%. In operating theatres, 4188 samples were taken, with a positivity of 11.9%. Regarding air in empty and full theatres, 1962 samplings were carried out with a positivity rate equal to 31.9%. The monitoring showed a low rate of contamination with a progressive decrease in the fiveyear period on operating theatres surfaces and hands, while there was an increase in the surgical site wards and in the air of operating rooms. CONCLUSIONS: Our investigation has revealed the presence of pathogens on the assessed surfaces and the need for environmental monitoring, which can be a valuable tool for reducing contamination. PMID- 28900358 TI - Risk assessment of legionellosis in cardiology units. AB - Infective Endocarditis (IE) is a disease with high morbidity and mortality. Nowadays, in addition to classic pathogens were isolated exigent Gram negative bacteria as A. baumannii, A. lwoffii, C. burnetii, Bartonella, Chlamydia and Legionella. We present our experience of Legionella isolations in environmental sample (water and air) collected from the Cardiology units belonging to two hospitals in Messina (Italy). A total of 80 samples were carried out, 30 and 50, respectively in the first and in the second structure: 55 of water and 25 of aerosol. The positivity of 30% of the water samples analyzed and 15% of those aerosol strengthens the conviction of the need for greater environmental monitoring, especially in the wards at high risk. PMID- 28900359 TI - Effectiveness of ATP bioluminescence to assess hospital cleaning: a review. AB - INTRODUCTION: Contamination of hospital surfaces plays an important role in the transmission of several healthcare-associated microorganisms, therefore methods for evaluating hospital surfaces' cleaning gain particular importance. Among these, there are visual inspection, quantitative microbiology, fluorescent markers and adenosine triphosphate (ATP) bioluminescence. The latter seems to provide interesting features, detecting the presence of ATP on surface (as Relative Light Units, RLU), a proxy of organic matter and microbial contamination. Several studies have investigated the effectiveness of this technology; with this research, we aim to summarize the most significant results. METHODS: A systematic review was conducted. The keywords (namely, "ATP", "bioluminescence", "hospital" and "surfaces") were searched in PubMed/MEDLINE and Scopus databases, in order to find relevant data, from January 2000 to October 2014. After the selection, we globally considered 27 articles. RESULTS: Most of the studies were conducted in United Kingdom and in USA. Different threshold RLU benchmark values were identified by analyzed studies. Fourteen of these researches compared the ATP bioluminescence with microbiological methods, 11 identified a significant correlation between the two methods, although poor or not complete for 5. DISCUSSION: ATP bioluminescence is not a standardized methodology: each tool has different benchmark values, not always clearly defined. At the moment, we can say that the technique could be used to assess, in real time, hospital surfaces where cleanliness is required, but not sterility. PMID- 28900360 TI - Resource allocation criteria in a hospital. AB - INTRODUCTION: Allocate fixed resources among competing users is a challenge in terms of hospital management in order to obtain the best performance considering strategic objectives. In order to address this need, a system of evaluation in an important research and teaching hospital was designed. This study describes resource allocation criteria in a hospital focusing on the evaluation system and its developed application methodology. METHODS: The indicator system allows the strategic management to rapidly detect the priorities in the evaluations of the Strategic, Organizational, Managerial, Economic, Research and Qualitative conditions of each unit. The chosen indicators are expressed with three numerical values, (1 indicating critical status, 2 acceptable conditions and 3 a good operational situation). RESULTS AND DISCUSSION: The adopted evaluation system considered different thematic areas: Strategic, Organizational, Managerial, Economic, Research and Qualitative. In order to define each area, 3 fields of evaluation have been chosen. The indicators have been structured according to a pyramid system allowing creating a single indicator for each area for each unit. Furthermore, a single indicator has been fixed in order to facilitate a first consideration on whether to carry out or not closer examinations of the most critical units. This manuscript describes an attempt to define objective criteria for the allocation of scarce resources in order to achieve the hospital's strategic objectives. The indicators identified allow to obtain an overall score for each unit, which allows the management to prioritize the needs. PMID- 28900361 TI - Developing a Stoma Acceptance Questionnaire to improve motivation to adhere to enterostoma self-care. AB - INTRODUCTION: In stoma care, patient education is often weak in terms of improving patients' level of acceptance of living with a stoma. Self-care educational interventions in enterostomal patients, which according to Orem's Theory should take into account these patients' specific needs, require instruments that measure patients' stoma acceptance to improve motivation based on the resumption of activities they used to carry out before having a stoma. The aim of the study was to develop an instrument that measures the level of stoma acceptance to improve motivation to adhere to enterostoma self-care. METHODS: Aspects that improve stoma acceptance and consequently motivation to adhere to enterostoma self-care were identified through 10 focus groups. In the focus groups, the motivation indicators were grouped, categorised and results entered into a Stoma Acceptance Questionnaire (SAQ). The SAQ was then piloted with 104 enterostomal patients from three general hospitals. To assess the construct validity of the SAQ, Mokken Scaling was used to explore the latent structure of the SAQ. Mokken scaling is a non-parametric method that falls under the umbrella of methods described as item response theories (IRT). RESULTS: The theme "Living with a stoma"; "Autonomy"; "Support"; "Ability to deal with stoma", plus a common underlying theme: "Stoma acceptance" were dissussed by the Focus Groups. The experts identified the items of the (SAQ) through these themes. Mokken Scaling identified the "resumption of enterostomal patients' normal activities" as a measure of stoma acceptance, thus confirming the construct validity of the SAQ. CONCLUSIONS: The tool proposed affords a pioneering example of how this gap can be bridged. Indeed, the SAQ could enable nurses adopting a standardized approach for the assessment of enterostomal patients' motivation to resume their normal activities and identify needs linked to this. The SAQ could also be used to measure the effectiveness of psychosocial and educational interventions aimed at improving stoma acceptance. PMID- 28900362 TI - Knowledge and training needs on built environment and indoor health of Italian public health residents: a national survey. AB - INTRODUCTION: The Working Group for Hygiene of Built Environment and the National Council of Residents of the Italian Society of Hygiene, Preventive Medicine and Public Health conducted a nation-wide survey to evaluate the knowledge and training needs on Built Environment and Indoor Health of Italian public health residents. RESULTS: The compliance was very high (52,4%), covering the totality of Italian postgraduate schools. The results underline a severe lack of theoretical formation and practical training, but also diffuse discrepancies across the country, and show a strong interest of residents on this topic. CONCLUSIONS: The authors propose to adopt a national core curriculum, and suggest some strategies to improve learning. PMID- 28900363 TI - Concerning the vitamin D reference range: pre-analytical and analytical variability of vitamin D measurement. AB - Unlike other vitamins, the vitamin D concentration in blood varies cyclically over the course of the year in relation to genetic (gender, ethnicity, polymorphisms) and environmental factors (sunlight exposure, diet, food-related or direct vitamin D supplementation, skin pigmentation). Although the major diagnostics manufacturers have recently developed improved automated 25-hydroxy vitamin D immunoassays, the intra- and inter-laboratory variability is still high (especially at low vitamin D concentrations) which might lead to incorrect vitamin D deficiency/insufficiency diagnosis. Moreover, despite recent efforts to standardize the assay and minimize its variability, the current bias for measured vitamin D concentrations is often still above the desirable +/- 10% criterion. Because the implications of low vitamin D concentrations in non-skeletal diseases are still partially unknown, international guideline recommendations for establishing meaningful ranges, at any time over the course of the year, irrespective not only of environmental and personal factors but also of instrumental variability, are needed. In this review, we discuss the main factors that influence the variability of vitamin D concentrations and whether a centile curve, individually calculated by a theoretical equation considering such factors, might be better suited than a fixed limit to assess abnormal vitamin D concentrations in otherwise healthy subjects. Vitamin D reference ranges during pregnancy, childhood, or diagnosed illnesses, which merit separate discussion, are beyond the scope of this review. PMID- 28900364 TI - Performance characteristics of lipoprotein-associated phospholipase A2 activity assay on the Dimension Vista analyser and preliminary study of a healthy Italian population. AB - INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a marker of vascular inflammation associated with coronary heart disease and stroke. We evaluated analytical performance of the PLAC(r) Activity Test on Siemens Dimension Vista(r) 1500 analyzer and measured Lp-PLA2 activity in Italian adults to establish reference intervals (RIs) and evaluate correlation with circulating lipids and age. MATERIALS AND METHODS: The evaluation protocol consisted of precision, linearity, sensitivity, method comparison, substrate depletion ("hook") effect and interference assessment. Inhibitor (Darapladib) effect was also evaluated. Lp-PLA2 activity was measured in 250 healthy donors (123 males, 127 females, aged 18-70 years). Central 95% RIs were established using nonparametric statistics. RESULTS: Intra-assay and inter-assay precision showed CVs of 0.6% - 1.4% and 0.9% - 2.0%, respectively. Linearity replicates showed R2 > 0.98. Limit of quantitation was 5.8 U/L (CV = 9.4%). Bland Altman plot showed bias - 0.9, 95% limits of agreement -6.5 - 4.72. Passing-Bablok regression showed excellent correlation (Slope = 1.02, 95% CI: 1.01 to 1.03; Intercept = - 1.86, 95% CI: - 3.08 to - 1.26; R2 = 0.999). No "hook effect" was observed at Lp-PLA2 activities <= 1000 U/L. Average Lp-PLA2 activity in 250 healthy donors was 182 +/ 44 U/L (mean +/- SD). Males showed statistically significant higher activities than females (P < 0.001). RIs were 107 - 265 U/L for males and 84 - 225 U/L for females. Moderate significant correlation (r = 0.29, P < 0.001) was found between Lp-PLA2 activity and total cholesterol. CONCLUSIONS: The PLAC(r) Activity Test shows very good performance characteristics on Dimension Vista(r) 1500. PMID- 28900365 TI - Changing reference intervals for haemoglobin in Denmark: Clinical and financial aspects. AB - INTRODUCTION: Based on international experiences and altering demography the reference intervals (RI) for haemoglobin (Hb) concentrations in blood were changed in Denmark in 2013 from 113 - 161 g/L to 117 - 153 g/L for women and from 129 - 177 g/L to 134 - 170 g/L for men. The aim of this study was to determine the derived change in prevalence of anaemia and the change in yearly health care costs of diagnostic investigations associated with the expected, as we hypothesized, increased prevalence and health care costs. MATERIALS AND METHODS: Data from 96,314 non-hospitalised patients (55,341 females and 40,973 males, aged 18 - 105 years) from general practitioners and community specialists of Funen, Denmark, were extracted from the laboratory information system. The prevalence of anaemia according to the new and the old RI were investigated, and additional costs were calculated based on estimated additional blood analyses and nationally recommended endoscopic procedures. RESULTS: Changing the Hb RI increased the number of anaemic patients by 52% (3450 patients) over a two-year period. With new RI the proportion of anaemic elderly above 80 years was 20.5% for females and 43.9% for males. Annual costs of derived additional assessments due to the altered RI were estimated to be 5.7 million ?, which equals the cost of 1214 knee replacement surgeries in Denmark. CONCLUSIONS: Changing the Hb RI has been expensive, despite the fact that no outcome studies have justified the alteration. The methodological approach for establishing new RI, here particularly for Hb, should be thoroughly considered. In general, physicians should use RI with caution. PMID- 28900366 TI - Tau protein as a possible marker of cerebrospinal fluid leakage in cerebrospinal fluid rhinorrhoea: A pilot study. AB - INTRODUCTION: The management of posttraumatic cerebrospinal fluid (CSF) rhinorrhoea remains a clinical challenge. Cerebrospinal fistula is a dural defect responsible for possible CSF leakage into the contiguous air-filled cavities located at the skull base. The risk of central nervous system infection in these conditions is severe and can be life threatening. Consequently, a specific CSF biomarker might be used in case of difficult diagnosis of CSF rhinorrhoea. CSF Tau protein is a neuronal protein, commonly assessed for diagnosis of Alzheimer Disease (AD). The aim of this study was to determine whether the Tau protein could be a relevant marker of CSF leakage. MATERIALS AND METHODS: Tau protein measurement was performed by enzyme-linked immunosorbent assay in 13 patients with CSF leakage (CSF rhinorrhoea group), and 8 patients with spontaneous aqueous rhinorrhoea (non-CSF leakage group). The serum concentration of Tau protein was measured by ELISA in both CSF rhinorrhoea group and non-CSF leakage group. RESULTS: In patients with CSF leakage, CSF Tau protein median concentration was 479 ng/L (197 - 2325 ng/L). On the other hand, the Tau protein concentration was below the lower limit of quantification (LLoQ) (< 87 ng/L) in non-CSF leakage group. Serum Tau protein concentration by ELISA was also below LLoQ (< 87 ng/L) for all subjects. CONCLUSION: ELISA measurement of Tau protein in rhinorrhoea fluid may be a reliable and relevant marker for detecting the presence of CSF in the nasal discharge and sign the existence of a CSF leakage. PMID- 28900367 TI - Measurement of HbA1c and HbA2 by Capillarys 2 Flex Piercing HbA1c programme for simultaneous management of diabetes and screening for thalassemia. AB - INTRODUCTION: Thalassemia could interfere with some assays for haemoglobin A1c (HbA1c) measurement, therefore, it is useful to be able to screen for thalassemia while measuring HbA1c. We used Capillarys 2 Flex Piercing (Capillarys 2FP) HbA1c programme to simultaneously measure HbA1c and screen for thalassemia. MATERIALS AND METHODS: Samples from 498 normal controls and 175 thalassemia patients were analysed by Capillarys 2FP HbA1c programme (Sebia, France). For method comparison, HbA1c was quantified by Premier Hb9210 (Trinity Biotech, Ireland) in 98 thalassaemia patients samples. For verification, HbA1c from eight thalassaemia patients was confirmed by IFCC reference method. RESULTS: Among 98 thalassaemia samples, Capillarys 2FP did not provide an HbA1c result in three samples with HbH due to the overlapping of HbBart's with HbA1c fraction; for the remaining 95 thalassaemia samples, Bland-Altman plot showed 0.00 +/- 0.35% absolute bias between two systems, and a significant positive bias above 7% was observed only in two HbH samples. The HbA1c values obtained by Capillarys 2FP were consistent with the IFCC targets (relative bias below +/- 6%) in all of the eight samples tested by both methods. For screening samples with alpha (alpha-) thalassaemia silent/trait or beta (beta-) thalassemia trait, the optimal HbA2 cut-off values were <= 2.2% and > 2.8%, respectively. CONCLUSIONS: Our results demonstrated the Capillarys 2FP HbA1c system could report an accurate HbA1c value in thalassemia silent/trait, and HbA2 value (<= 2.2% for alpha-thalassaemia silent/trait and > 2.8% for beta-thalassemia trait) and abnormal bands (HbH and/or HbBart's for HbH disease, HbF for beta-thalassemia) may provide valuable information for screening. PMID- 28900368 TI - Testing lupus anticoagulants in a real-life scenario - a retrospective cohort study. AB - INTRODUCTION: Lupus anticoagulant (LAC) testing is challenging. Most data are derived from a well-controlled study environment with potential alterations to daily routines. The aim of this retrospective cohort study was to assess the capacity of various LAC screening tests and derived mixing tests to predict a positive result in subsequent confirmation tests in a large cohort of patients. MATERIALS AND METHODS: In 5832 individuals, we retrospectively evaluated the accuracy of the aPTT-A, aPTT-LAscreen, aPTT-FS and dRVVTscreen and of their derived mixing tests in detecting a positive confirmation test result within the same blood specimen. The group differences, degree of correlation and the predictive accuracy of LAC coagulation tests were analysed using the Mann-Whitney U test, the Spearman-rank-correlation and by area under the receiver operating characteristic curve (ROC-AUC) analysis. ROC-AUCs were compared with the Venkatraman's permutation test. RESULTS: The pre-test probability of patients with clinically suspected LAC was 36% in patients without factor deficiency or anticoagulation therapy. The aPTT-LAscreen showed the best diagnostic accuracy with a ROC-AUC of 0.84 (95% CI: 0.82 - 0.86). No clear advantage of the dRVVT derived mixing test was detectable when compared to the dRVVTscreen (P = 0.829). Usage of the index of circulating anticoagulant (ICA) did not improve the diagnostic power of respective mixing tests. CONCLUSIONS: Among the parameters evaluated, aPTT-LAscreen and derived mixing test parameters were the most accurate tests. In our study cohort, neither other mixing test nor the ICA presented any further advantage in LAC diagnostics. PMID- 28900369 TI - The local clinical validation of a new lithium heparin tube with a barrier: BD Vacutainer(r) Barricor LH Plasma tube. AB - INTRODUCTION: Although serum-providing blood tubes with a barrier are still widely used due to their significant advantages, the use of blood tubes with a barrier to provide plasma is becoming widespread. We compared 22 analytes in a BD Vacutainer(r) Barricor LH Plasma tube for local clinical validation of this new lithium heparin tube with a barrier. MATERIALS AND METHODS: Samples from 44 volunteers were collected in different tubes (Becton Dickinson and Company): Z tube without additive (reference), clot-activator tube with gel (SST), lithium heparin tube without gel (LiH), and lithium heparin tube with barrier (Barricor). Analyte concentrations in different tubes were compared with the reference tube. All tubes were also evaluated according to additional testing (different centrifugation durations, blood-sampling techniques and individual differences). RESULTS: Aspartate aminotransferase (AST), glucose (Glc), potassium (K), lactate dehydrogenase (LD), sodium (Na), and total protein (TP) had a significant bias in Barricor (9.19%, - 3.24%, - 4.88%, 21.60%, - 0.40%, 5.03%, respectively) relative to the reference tube. There was no statistical difference between different centrifugation durations and individual differences for AST, K and LD in LiH and/or Barricor (P > 0.05). There was a significant bias for LD between LiH and Barricor in terms of blood-sampling techniques (21.2% and 12.4%, respectively). CONCLUSIONS: Recently, the use of plasma has become prominent due to some of its advantages. In this study, plasma AST, K, LD, Glc and TP levels in Barricor were clinically different in comparison to serum. The results of additional tests showed that higher levels of LD in Barricor did not result from haemolysis, and they might be related to other factors including number of platelets, cellular fragility, or functional environment. PMID- 28900370 TI - Utility of routine laboratory preoperative tests based on previous results: Time to give up. AB - INTRODUCTION: The usefulness and cost-effectiveness of routine laboratory preoperative tests (POTs) have been challenged recently. In fact, the American Society of Anesthesiologists (ASA) Task Force has stated that test results obtained from the medical record within 6 months of surgery generally are mostly acceptable. The aim of our study was to evaluate the degree of utility of POTs and their clinical benefit based on this recommendation. MATERIAL AND METHODS: We studied retrospectively every routine POT request from 8 randomly selected weeks in 2016. Every POT contained glucose, creatinine, haemoglobin and coagulation tests (PT-INR). Each pathological result for these tests was registered and classified as "expected" (if previous pathological result within 6 months existed for that test) or "unexpected" (if previous pathological result within 6 months did not exist for that test). Results of ASA physical status classification (a system for assessing the fitness of patients before surgery) and changes in patient management after POTs were retrieved from medical history as well. RESULTS: A total of 4516 tests (from 1129 patients) were analysed and 498 results were found pathological (11%). Of these, 403 were expected (8.9%) and 95 unexpected (2.1%). There was not any change in anaesthetic management for any patient due to these findings. CONCLUSIONS: Routine POTs are an inefficient and low-value service. POTs have to be always ordered selectively after a previous consideration of specific information obtained from several sources (medical records, interviews, examinations, type of surgery) and only if the information obtained will result in changes in the management of the patient. PMID- 28900372 TI - Psychological stress has a higher rate of developing addictive behaviors compared to physical stress in rat offspring. AB - Prenatal stress could have great influence on development of offspring and might alter cognitive function and other physiological processes of children. The current study was conducted to study the effect of physical or psychological prenatal stress on addictive and anxiety-like behavior of male and female offspring during their adolescence period (postnatal day (PND) 40). Adult female rats were exposed to physical (swimming) or psychological (observing another female rat swimming) stress from day six of gestation for 10 days. Male and female offspring were assayed for anxiety-like behavior, motor and balance function and morphine conditioned place preference using the open field, elevated plus maze (EPM), rotarod and wire grip assay and conditioned place preference. Offspring in both physical and psychological prenatal stress groups demonstrated significant increase in anxiety-like behavior in EPM paradigm, but no alterations were observed in motor and balance function of animals. Offspring in the psychological prenatal stress group had an increased preference for morphine in comparison to control and physical prenatal stress groups. Results of the current study demonstrated that animals exposed to psychological stress during fetal development are at a higher risk of developing addictive behaviors. Further research might elucidate the exact mechanisms involved to provide better preventive and therapeutic interventions. PMID- 28900371 TI - Biochemical Measurements of Free Opsin in Macular Degeneration Eyes: Examining the 11-CIS Retinal Deficiency Hypothesis of Delayed Dark Adaptation (An American Ophthalmological Society Thesis). AB - PURPOSE: To test the hypothesis that delayed dark adaptation in patients with macular degeneration is due to an excess of free unliganded opsin (apo-opsin) and a deficiency of the visual chromophore, 11-cis retinal, in rod outer segments. METHODS: A total of 50 human autopsy eyes were harvested from donors with and without macular degeneration within 2-24 hrs. postmortem. Protocols were developed which permitted dark adaptation of normal human eyes after death and enucleation. Biochemical methods of purifying rod outer segments were optimized and the concentration of rhodopsin and apo-opsin was measured with UV-visible scanning spectroscopy. The presence of apo-opsin was calculated by measuring the difference in the rhodopsin absorption spectra before and after the addition of 11-cis retinal. RESULTS: A total of 20 normal eyes and 16 eyes from donors with early, intermediate and advanced stages of macular degeneration were included in the final analysis. Dark adaptation was achieved by harvesting whole globes in low light, transferring into dark (light-proof) canisters and dissecting the globes using infrared light and image converters for visualization. Apo-opsin was readily detected in positive controls after the addition of 11-cis retinal. Normal autopsy eyes showed no evidence of apo-opsin. Eyes with macular degeneration also showed no evidence of apo-opsin, regardless of the severity of disease. CONCLUSIONS: Methods have been developed to study dark adaptation in human autopsy eyes. Eyes with age-related macular degeneration do not show a deficiency of 11-cis retinal or an excess of apo-opsin within rod outer segments. PMID- 28900373 TI - MafB silencing in macrophages does not influence the initiation and growth of lung cancer induced by urethane. AB - An increased number of tumor-associated macrophages (TAMs) that exhibit the M2 macrophage phenotype is related to poorer prognosis in cancer patients. MafB is a transcription factor regulating the differentiation of macrophages. However, involvement of MafB for the development of TAMs is unknown. This study was designed to investigate the role of MafB in a murine urethane-induced lung cancer model. Urethane was injected intraperitoneally into wild-type and dominant negative MafB transgenic mice. Twenty-four weeks later, mice were sacrificed and their lungs removed for pathological analysis. The numbers and mean areas of lung cancer were evaluated. In addition, the numbers of Mac-3-positive macrophages were evaluated in each tumor. The numbers and mean areas of lung cancer induced by urethane administration were not significantly different between wild-type and dominant-negative MafB transgenic mice. The numbers of TAMs in lung cancer tissue were not significantly different between the two groups. MafB silencing using dominant-negative MafB did not influence the initiation and growth of lung cancer in mice exposed to urethane. These data suggest that MafB may not be related to the development of TAMs. PMID- 28900374 TI - Association between polymorphisms in the promoter region of the apolipoprotein E (APOE) gene and Alzheimer's disease: A meta-analysis. AB - Several studies have evaluated the role of polymorphisms in the promoter region of APOE gene that encodes apolipoprotein E (APOE) and the susceptibility to Alzheimer's disease (AD). The aim of this literature review and meta-analysis was to investigate the relationship between the APOE promoter region single nucleotide polymorphisms (SNPs) (rs449647, -491A/T; rs769446, -427T/C and rs405509 -219T/G) and the risk of developing AD. Eligible controlled studies published up to November 2016 were retrieved from main online scientific and medical databases. Odds ratio (OR) and 95 % confidence interval (CI) were used to calculate the strength of the relationship. A total of 23 publications (19 for rs449647, ten for rs769446 and ten for rs405509) were retrieved that included 5,703 patients with AD and 5,692 controls. The C allele of the rs769446 variant of the promoter region of APOE gene was significantly associated with an increase of risk of AD (OR = 1.271, 95 % CI = 1.114-1.449, P < 0.0001), while other genetic models of this variant were not related with susceptibility to AD. Rs449647 and rs405509 polymorphisms of APOE gene were not associated with an increase of risk of AD. The findings of this literature review and meta-analysis have shown that rs769446 polymorphism in the promoter region of APOE gene could be a risk factor for AD. Future large-scale studies on the role of polymorphisms in the promoter region of APOE gene in AD are still awaited. PMID- 28900375 TI - Expression and purification of untagged GlnK proteins from actinobacteria. AB - The PII protein family constitutes one of the most conserved and well distributed family of signal transduction proteins in nature. These proteins play key roles in nitrogen and carbon metabolism. PII function has been well documented in Gram negative bacteria. However, there are very few reports describing the in vitro properties and function of PII derived from Gram-positive bacteria. Here we present the heterologous expression and efficient purification protocols for untagged PII from three Actinobacteria of medical and biotechnological interest namely: Mycobacterium tuberculosis, Rhodococcus jostii and Streptomyces coelicolor. Circular dichroism and gel filtration analysis supported that the purified proteins are correctly folded. The purification protocol described here will facilitate biochemical studies and help to uncover the biochemical functions of PII proteins in Actinobacteria. PMID- 28900377 TI - Serum soluble receptor of advanced glycation end products and risk of metabolic syndrome in Egyptian obese women. AB - Obesity is one of the diagnostic criteria of metabolic syndrome (MS). It is correlated with insulin resistance (IR) and high vascular risk as well. Advanced glycation end products (AGEs) and their receptor (RAGE) play an important role in abnormal metabolic components in obese women. This study aimed to explore the serum levels of sRAGE in Egyptian obese women and compare with healthy non-obese controls and investigate the relationship between serum sRAGE, metabolic parameters, and obesity complications. The soluble form of receptor for advanced glycation end products (sRAGE), anthropometry, metabolic and biochemical biomarkers were measured in 100 obese women and 100 age-matched healthy control non-obese women. The homeostasis model assessment estimate of insulin resistance (HOMA-IR) has been determined from serum insulin and glucose values. Serum sRAGE levels were significantly lower in obese cases than controls and inversely correlated with obesity and metabolic parameters. Results of univariate and multivariate analyses for determinants of serum sRAGE levels in obese cases showed that parameters statistically and significantly related were body mass index (BMI), waist circumference (WC), LDL-C, TG, BP, HOMA-IR, ALT and AST. sRAGE is a novel biomarker for metabolic dysfunction in Egyptian obese women and might predict the future cardio-metabolic events. PMID- 28900376 TI - Physical activity and beta-amyloid pathology in Alzheimer's disease: A sound mind in a sound body. AB - Alzheimer's disease (AD) is the most common type of dementia worldwide. Since curative treatment has not been established for AD yet and due to heavy financial and psychological costs of patients' care, special attention has been paid to preventive interventions such as physical activity. Evidence shows that physical activity has protective effects on cognitive function and memory in AD patients. Several pathologic factors are involved in AD-associated cognitive impairment some of which are preventable by physical activity. Also, various experimental and clinical studies are in progress to prove exercise role in the beta-amyloid (Abeta) pathology as a most prevailing hypothesis explaining AD pathogenesis. This study aims to review the role of physical activity in Abeta-related pathophysiology in AD. PMID- 28900378 TI - Steroid resistance and concomitant respiratory infections: A challenging battle in pulmonary clinic. PMID- 28900379 TI - Postmenopausal hormone and the risk of nephrolithiasis: A meta-analysis. AB - Menopause is reported to be associated with increased urinary calcium excretion, which may enhance the risk for the development of calcium kidney stones. However, it remains controversial about whether high level of postmenopausal hormone (PMH) is a risk factor for formation of nephrolithiasis. Several observational studies have shown that PMH is protective based on 24-hour urinary parameters. Recent clinical trials provided evidence to conclude that estrogen therapy increases the risk of nephrolithiasis in healthy postmenopausal women. Our study aimed to comprehensively assess clinical evidence on the relationship between postmenopausal hormone level and risk of nephrolithiasis. To conduct systematic review, we pooled total 98 potentially related articles in Cochrane library, Medline, and Embase. Three studies with a total of 71101 study participants that included two clinical trials, 4 stratified and potentially usable results by the status of menopause and type of PMH use derived from one prospective cohort study, and one case-control studies were selected to pool relative risk using random-effect model. How the difference in menopause status, whether naturally menopausal or surgically menopausal, influenced the pooled relative risk was included in the subgroup analysis. The study population aged from 45 to 70 years old. The follow-up year and adjusted confounders differed across different studies. The pooled relative risk for the 7 stratified studies was 0.91 (95 % confidence interval (CI): [0.72, 1.14]). In the menopausal status-specific analysis, the pooled relative risk for naturally menopausal women was 0.92 (95 % CI, [0.64, 1.27]; I2 = 82.74 %) whereas the pooled relative risk for surgically postmenopausal women is 0.90 (95 % CI, [0.63, 1.29]; I2 = 78.47 %). The above results suggested that there was no significant association between PMH and the risk of nephrolithiasis. The difference in menopausal status did not influence the relationship between PMH and the risk of kidney stone formation. PMID- 28900380 TI - Meta-analysis of neuron specific enolase in predicting pediatric brain injury outcomes. AB - A reliable biomarker has not been identified to predict the outcome of traumatic brain injury (TBI) in children. Therefore, the present systematic review and meta analysis aimed to assess the association between neuron specific enolase (NSE) and traumatic brain injury (TBI) in children. Two independent reviewers searched electronic databases of EMBASE, Cochrane library, Medline and Scopus and then they summarized the results and did a quality control check. At the end, standardized mean difference (SMD) with 95 % confidence interval (CI) and performance of NSE were assessed. 10 studies were included in the present meta analysis. Average serum (SMD=1.3; 95 % CI: 0.5 to 2.1; p=0.001) and CSF levels (SMD=2.45; 95 % CI: 1.04 to 3.8; p<0.0001) of NSE biomarker were significantly higher in children with TBI with unfavorable outcome compared with other children. Serum NSE had an area under the curve, sensitivity and specificity of 0.75 (95 % CI: 0.72 to 0.79), 0.74 (95 % CI: 0.64 to 0.82) and 0.69 (95 % CI: 0.59 to 0.77), respectively in prediction outcome of TBI. Positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of serum NSE were 2.4 (95 % CI: 1.7 to 3.3), 0.38 (95 % CI: 0.26 to 0.55) and 6.0 (95 % CI: 3.0 to 12.0), respectively. The results show that the performance of NSE is in a moderate level in prediction of unfavorable outcome in children with TBI. However, data in this aspect is not sufficient and more studies are needed. PMID- 28900381 TI - The association of vimentin and fibronectin gene expression with epithelial mesenchymal transition and tumor malignancy in colorectal carcinoma. AB - Colorectal cancer is the most common malignancy of the gastrointestinal tract with very high mortality. One of the most distinguishing features for the establishment of an epithelial-mesenchymal transition phenotype is the alteration of mesenchymal markers expression and structural adhesion proteins. We evaluated the significance of vimentin and fibronectin gene expression in relation to invasion and metastasis in CRC patients. Tissue specimens were collected consecutively from forty-five colorectal carcinoma patients during surgeries. Tissues were divided into two separate parts for pathological and molecular assays. In order to histological staging, tissue sections were prepared from formalin-fixed paraffin-embedded blocks and stained with Hematoxylin and Eosin. To quantify gene expression, specimens were dissected and homogenized. Moreover, SW480, SW48, SW948, Caco-2, HT-29 and LS174T as human colon cancer cell lines were obtained and cultured, then molecular analyzing was performed. As results the expression of VIM gene increased in SW480, SW48 and SW948 while it decreased in Caco-2, HT-29 and LS174T. Moreover, FN was up-regulated in Caco-2, HT-29 and SW948, while it was down-regulated in SW480, SW48 and LS174T. In tissues, vimentin and fibronectin expression significantly increased in stromal cells, whereas vimentin decreased in colonic epithelial cells and fibronectin had no significant change. Vimentin and fibronectin expression were changed in tumor tissues. It was found an association between vimentin expression with age and tumor size; over-expression in older age and decreasing in larger tumor size. Furthermore, fibronectin over-expression is correlated to older age and high tumor stages; up-regulation with increasing age and high tumor stages. PMID- 28900382 TI - Immunization enhances the natural antibody repertoire. AB - The role of immunization in the production of antibodies directed against immunogens is widely appreciated in laboratory animals and in humans. However, the role of immunization in the development of "natural antibodies" has not been investigated. Natural antibodies are those antibodies present without known history of infection or immunization, and react to a wide range of targets, including "cryptic" self-antigens that are exposed upon cell death. In this study, the ability of immunization to elicit the production of natural antibodies in laboratory rats was evaluated. Laboratory rats were immunized with a series of injections using peanut extracts (a common allergen), a high molecular weight protein conjugated to hapten (FITC-KLH), and a carbohydrate conjugated to hapten (DNP-Ficall). Significantly greater binding of antibodies from immunized animals compared to controls was observed to numerous autologous organ extracts (brain, kidney, liver, lung, prostate, and spleen) for both IgM and IgG, although the effect was more pronounced for IgM. These studies suggest that immunization may have at least one unforeseen benefit, enhancing networks of natural antibodies that may be important in such processes as wound repair and tumor surveillance. Such enhancement of natural antibody function may be particularly important in Western society, where decreased exposure to the environment may be associated with a weakened natural antibody repertoire. PMID- 28900383 TI - Effects of platelet rich plasma and chondrocyte co-culture on MSC chondrogenesis, hypertrophy and pathological responses. AB - Regarding the inadequate healing capability of cartilage tissue, cell-based therapy is making the future of cartilage repair and regeneration. Mesenchymal stem cells (MSC) have shown great promise in cartilage regeneration. However, a yet-unresolved issue is the emergence of hypertrophic and pathologic markers during in vitro MSC chondrogenesis. Articular chondrocytes (AC) can suppress the undesired hypertrophy when co-cultured with MSC. On the other hand, platelet rich plasma (PRP), is considered potentially effective for cartilage repair and in vitro chondrogenesis. We thus aimed to harness chondro-promotive effects of PRP and hypertrophic-suppressive effects of AC:MSC co-culture to achieve a more functional cartilage neo-tissue. We used PRP or conventional-differentiation chondrogenic media (ConvDiff) in MSC mono-cultures and AC:MSC co-cultures. We assessed gene expression of chondrogenic and hypertrophic markers using real-time RT-PCR and immunostaining. Alkaline-phosphatase activity (ALP) and calcium content of the pellets were quantified. We also measured VEGF and TNF-alpha secretion via ELISA. We showed PRP had higher chondrogenic potential (in mRNA and protein level) and hypertrophic-suppressive effects than Conv-Diff (mRNA level). Co-culturing reduced ALP while PRP increased calcium deposition. In all four groups, TNF-alpha was down-regulated compared to MSC controls, with co-cultures receiving ConvDiff media secreting the least. Meanwhile, the only group with increased VEGF secretion was PRP-mono-cultures. We observed synergistic effects for PRP and AC:MSC co-culture in enhancing chondrogenesis. Inclusion of AC reduced hypertrophic markers and angiogenic potential in PRP groups. We thus propose that combination of PRP and co-culture would favor chondrogenesis while alleviate but not totally eradicate undesired hypertrophic and pathologic responses. PMID- 28900384 TI - Cancer chemoprevention by oleaster (Elaeagnus angustifoli L.) fruit extract in a model of hepatocellular carcinoma induced by diethylnitrosamine in rats. AB - Hepatocellular carcinoma (HCC) is a frequent and fatal human cancer with poor diagnosis that accounts for over half a million deaths each year worldwide. Elaeagnus angustifolia L. known as oleaster has a wide range of pharmacological activities. This study aimed to investigate the chemopreventive effect of aqueous extract of E. angustifolia fruit (AEA) against diethylnitrosamine (DEN)-induced HCC in rats. HCC was induced in rats by a single injection of DEN (200 mg/kg) as an initiator. After two weeks, rats were orally administered 2 acetylaminofluorene or 2-AAF (30 mg/kg) as a promoter for two weeks. Oleaster treated rats were orally pretreated with the increasing doses of AEA two weeks prior to DEN injection that continued until the end of the experiment. In the current study, a significant decrease in serum biomarkers of liver damage and cancer, including alfa-fetoprotein (AFP), gamma glutamyl transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) was observed in AEA treated rats when compared to HCC rats. Furthermore, the oleaster extract exhibited in vivo antioxidant activity by elevating reduced glutathione (GSH) contents as well as preventing lipid peroxidation in the liver tissues of DEN treated rats. The relative weight of liver, a prognostic marker of HCC, was also reduced in oleaster-treated rats. To conclude, our results clearly demonstrated that oleaster fruit possesses a significant chemopreventive effect against primary liver cancer induced by DEN in rats. It can be suggested that the preventive activity of oleaster against hepatocarcinogenesis may be mediated through the antioxidant, anti-inflammation, and antimutagenic effects of the fruit. PMID- 28900385 TI - The impact of stress on body function: A review. AB - Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. The compensatory responses to these stresses are known as stress responses. Based on the type, timing and severity of the applied stimulus, stress can exert various actions on the body ranging from alterations in homeostasis to life-threatening effects and death. In many cases, the pathophysiological complications of disease arise from stress and the subjects exposed to stress, e.g. those that work or live in stressful environments, have a higher likelihood of many disorders. Stress can be either a triggering or aggravating factor for many diseases and pathological conditions. In this study, we have reviewed some of the major effects of stress on the primary physiological systems of humans. PMID- 28900386 TI - Altered Developmental Expression of the Astrocyte-Secreted Factors Hevin and SPARC in the Fragile X Mouse Model. AB - Astrocyte dysfunction has been indicated in many neurodevelopmental disorders, including Fragile X Syndrome (FXS). FXS is caused by a deficiency in fragile X mental retardation protein (FMRP). FMRP regulates the translation of numerous mRNAs and its loss disturbs the composition of proteins important for dendritic spine and synapse development. Here, we investigated whether the astrocyte derived factors hevin and SPARC, known to regulate excitatory synapse development, have altered expression in FXS. Specifically, we analyzed the expression of these factors in wild-type (WT) mice and in fragile X mental retardation 1 (Fmr1) knock-out (KO) mice that lack FMRP expression. Samples were collected from the developing cortex and hippocampus (regions of dendritic spine abnormalities in FXS) of Fmr1 KO and WT pups. Hevin and SPARC showed altered expression patterns in Fmr1 KO mice compared to WT, in a brain-region specific manner. In cortical tissue, we found a transient increase in the level of hevin in postnatal day (P)14 Fmr1 KO mice, compared to WT. Additionally, there were modest decreases in Fmr1 KO cortical levels of SPARC at P7 and P14. In the hippocampus, hevin expression was much lower in P7 Fmr1 KO mice than in WT. At P14, hippocampal hevin levels were similar between genotypes, and by P21 Fmr1 KO hevin expression surpassed WT levels. These findings imply aberrant astrocyte signaling in FXS and suggest that the altered expression of hevin and SPARC contributes to abnormal synaptic development in FXS. PMID- 28900387 TI - Social Isolation in Early versus Late Adolescent Mice Is Associated with Persistent Behavioral Deficits That Can Be Improved by Neurosteroid-Based Treatment. AB - Early trauma and stress exposure during a critical period of life may increase the risk of major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) in adulthood. The first-choice treatment for MDD and PTSD are selective serotonin reuptake inhibitor (SSRI) antidepressants. Unfortunately, half of MDD and PTSD patients show resistance to the therapeutic effects of these drugs and more efficient treatments are essential. Both MDD and PTSD patients present reduced levels of allopregnanolone (Allo), a potent endogenous positive allosteric modulator of GABA action at GABAA receptors which are normalized by SSRIs in treatment responders. Thus, Allo analogs or drugs that stimulate its levels may offer an alternative in treating SSRIs-non-responders. We tested several drugs on the aggressive behavior of early and late adolescent socially isolated (SI) mice, a model of PTSD. Isolation in early adolescence (PND 21) induced more severe aggression than mice isolated at PND 45. A single non sedating administration of S-fluoxetine (S-FLX; 0.375-1.5 mg/kg), or of the Allo analogs ganaxolone (GNX; 10 mg/kg), BR351 (1-5 mg/kg), or BR297 (0.3125-2.5 mg/kg), or of the endocannabinoid, N-palmitoylethanolamine (PEA; 5-20 mg/kg) all decreased aggression more effectively in late than early adolescent SI mice. Importantly, the number of drug non-responders was higher in early than late SI mice for all the drugs tested. The non-responder rate was more elevated (12-64%) after S-FLX treatment, while 100% of mice responded to a single administration of PEA at the dose range of 15-20 mg/kg. Moreover, GNX, BR351, and BR297's antiaggressive effect persisted longer than S-FLX in both late and early SI mice. All drugs tested failed to alter locomotor activity of SI mice. Our results show that drugs that mimic Allo's action or that induce Allo biosynthesis may be valuable for the treatment of "SSRIs non-responder" patients. PMID- 28900388 TI - DISC1 Regulates the Proliferation and Migration of Mouse Neural Stem/Progenitor Cells through Pax5, Sox2, Dll1 and Neurog2. AB - Background: Disrupted-in-schizophrenia 1 (DISC1) regulates neurogenesis and is a genetic risk factor for major psychiatric disorders. However, how DISC1 dysfunction affects neurogenesis and cell cycle progression at the molecular level is still unknown. Here, we investigated the role of DISC1 in regulating proliferation, migration, cell cycle progression and apoptosis in mouse neural stem/progenitor cells (MNSPCs) in vitro. Methods: MNSPCs were isolated and cultured from mouse fetal hippocampi. Retroviral vectors or siRNAs were used to manipulate DISC1 expression in MNSPCs. Proliferation, migration, cell cycle progression and apoptosis of altered MNSPCs were analyzed in cell proliferation assays (MTS), transwell system and flow cytometry. A neurogenesis specific polymerase chain reaction (PCR) array was used to identify genes downstream of DISC1, and functional analysis was performed through transfection of expression plasmids and siRNAs. Results: Loss of DISC1 reduced proliferation and migration of MNSPCs, while an increase in DISC1 led to increased proliferation and migration. Meanwhile, an increase in the proportion of cells in G0/G1 phase was concomitant with reduced levels of DISC1, but significant changes were not observed in the number MNSPCs undergoing apoptosis. Paired box gene 5 (Pax5), sex determining region Y-box 2 (Sox2), delta-like1 (Dll1) and Neurogenin2 (Neurog2) emerged as candidate molecules downstream of DISC1, and rescue experiments demonstrated that increased or decreased expression of either molecule regulated proliferation and migration in DISC1-altered MNSPCs. Conclusion: These results suggest that Pax5, Sox2, Dll1 and Neurog2 mediate DISC1 activity in MNSPC proliferation and migration. PMID- 28900389 TI - Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family. AB - Background: Immune mechanisms recently emerged as important contributors to migraine pathology with cytokines affecting neuronal excitation. Therefore, elucidating the profile of cytokines activated in various forms of migraine, including those with a known genetic cause, can help in diagnostic and therapeutic approaches. Methods: Here we (i) performed exome sequencing to identify the causal gene mutation and (ii) measured, using Bio-Plex technology, 22 cytokines in serum of patients with familial migraine (two with hemiplegic migraine and two with migraine with aura) from a Russian family that ethnically belongs to the Tatar population. MRI scanning was used to assess cerebellar atrophy associated with migraine in mutation carriers. Results: Whole-exome sequencing revealed the R583Q missense mutation in the CACNA1A gene in the two patients with hemiplegic migraine and cerebellar ataxia with atrophy, confirming a FHM1 disorder. Two further patients did not have the mutation and suffered from migraine with aura. Elevated serum levels of pro-inflammatory and pro-nociceptive IL-6 and IL-18 were found in all four patients (compared to a reference panel), whereas pro-apoptotic SCGF-beta and TRAIL were higher only in the patients with the FHM1 mutation. Also, cytokines CXCL1, HGF, LIF, and MIF were found particularly high in the two mutation carriers, suggesting a possible role of vascular impairment and neuroinflammation in disease pathogenesis. Notably, some "algesic" cytokines, such as beta-NGF and TNFbeta, remained unchanged or even were down-regulated. Conclusion: We present a detailed genetic, neurological, and biochemical characterization of a small Russian FHM1 family and revealed evidence for higher levels of specific cytokines in migraine patients that support migraine-associated neuroinflammation in the pathology of migraine. PMID- 28900391 TI - Quantitative Susceptibility Mapping Reveals an Association between Brain Iron Load and Depression Severity. AB - Previous studies have detected abnormal serum ferritin levels in patients with depression; however, the results have been inconsistent. This study used quantitative susceptibility mapping (QSM) for the first time to examine brain iron concentration in depressed patients and evaluated whether it is related to severity. We included three groups of age- and gender-matched participants: 30 patients with mild-moderate depression (MD), 14 patients with major depression disorder (MDD) and 20 control subjects. All participants underwent MR scans with a 3D gradient-echo sequence reconstructing for QSM and performed the 17-item Hamilton Depression Rating Scale (HDRS) test. In MDD, the susceptibility value in the bilateral putamen was significantly increased compared with MD or control subjects. In addition, a significant difference was also observed in the left thalamus in MDD patients compared with controls. However, the susceptibility values did not differ between MD patients and controls. The susceptibility values positively correlated with the severity of depression as indicated by the HDRS scores. Our results provide evidence that brain iron deposition may be associated with depression and may even be a biomarker for investigating the pathophysiological mechanism of depression. PMID- 28900392 TI - Corrigendum: The Impact of Aerobic Exercise on Fronto-Parietal Network Connectivity and Its Relation to Mobility: An Exploratory Analysis of a 6-Month Randomized Controlled Trial. AB - [This corrects the article on p. 344 in vol. 11, PMID: 28713255.]. PMID- 28900390 TI - Genetically-Driven Enhancement of Dopaminergic Transmission Affects Moral Acceptability in Females but Not in Males: A Pilot Study. AB - Moral behavior has been a key topic of debate for philosophy and psychology for a long time. In recent years, thanks to the development of novel methodologies in cognitive sciences, the question of how we make moral choices has expanded to the study of neurobiological correlates that subtend the mental processes involved in moral behavior. For instance, in vivo brain imaging studies have shown that distinct patterns of brain neural activity, associated with emotional response and cognitive processes, are involved in moral judgment. Moreover, while it is well-known that responses to the same moral dilemmas differ across individuals, to what extent this variability may be rooted in genetics still remains to be understood. As dopamine is a key modulator of neural processes underlying executive functions, we questioned whether genetic polymorphisms associated with decision-making and dopaminergic neurotransmission modulation would contribute to the observed variability in moral judgment. To this aim, we genotyped five genetic variants of the dopaminergic pathway [rs1800955 in the dopamine receptor D4 (DRD4) gene, DRD4 48 bp variable number of tandem repeat (VNTR), solute carrier family 6 member 3 (SLC6A3) 40 bp VNTR, rs4680 in the catechol-O-methyl transferase (COMT) gene, and rs1800497 in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene] in 200 subjects, who were requested to answer 56 moral dilemmas. As these variants are all located in genes belonging to the dopaminergic pathway, they were combined in multilocus genetic profiles for the association analysis. While no individual variant showed any significant effects on moral dilemma responses, the multilocus genetic profile analysis revealed a significant gender-specific influence on human moral acceptability. Specifically, those genotype combinations that improve dopaminergic signaling selectively increased moral acceptability in females, by making their responses to moral dilemmas more similar to those provided by males. As females usually give more emotionally-based answers and engage the "emotional brain" more than males, our results, though preliminary and therefore in need of replication in independent samples, suggest that this increase in dopamine availability enhances the cognitive and reduces the emotional components of moral decision-making in females, thus favoring a more rationally-driven decision process. PMID- 28900393 TI - Postural Hand Synergies during Environmental Constraint Exploitation. AB - Humans are able to intuitively exploit the shape of an object and environmental constraints to achieve stable grasps and perform dexterous manipulations. In doing that, a vast range of kinematic strategies can be observed. However, in this work we formulate the hypothesis that such ability can be described in terms of a synergistic behavior in the generation of hand postures, i.e., using a reduced set of commonly used kinematic patterns. This is in analogy with previous studies showing the presence of such behavior in different tasks, such as grasping. We investigated this hypothesis in experiments performed by six subjects, who were asked to grasp objects from a flat surface. We quantitatively characterized hand posture behavior from a kinematic perspective, i.e., the hand joint angles, in both pre-shaping and during the interaction with the environment. To determine the role of tactile feedback, we repeated the same experiments but with subjects wearing a rigid shell on the fingertips to reduce cutaneous afferent inputs. Results show the persistence of at least two postural synergies in all the considered experimental conditions and phases. Tactile impairment does not alter significantly the first two synergies, and contact with the environment generates a change only for higher order Principal Components. A good match also arises between the first synergy found in our analysis and the first synergy of grasping as quantified by previous work. The present study is motivated by the interest of learning from the human example, extracting lessons that can be applied in robot design and control. Thus, we conclude with a discussion on implications for robotics of our findings. PMID- 28900394 TI - Navigation and Self-Semantic Location of Drones in Indoor Environments by Combining the Visual Bug Algorithm and Entropy-Based Vision. AB - We introduce a hybrid algorithm for the self-semantic location and autonomous navigation of robots using entropy-based vision and visual topological maps. In visual topological maps the visual landmarks are considered as leave points for guiding the robot to reach a target point (robot homing) in indoor environments. These visual landmarks are defined from images of relevant objects or characteristic scenes in the environment. The entropy of an image is directly related to the presence of a unique object or the presence of several different objects inside it: the lower the entropy the higher the probability of containing a single object inside it and, conversely, the higher the entropy the higher the probability of containing several objects inside it. Consequently, we propose the use of the entropy of images captured by the robot not only for the landmark searching and detection but also for obstacle avoidance. If the detected object corresponds to a landmark, the robot uses the suggestions stored in the visual topological map to reach the next landmark or to finish the mission. Otherwise, the robot considers the object as an obstacle and starts a collision avoidance maneuver. In order to validate the proposal we have defined an experimental framework in which the visual bug algorithm is used by an Unmanned Aerial Vehicle (UAV) in typical indoor navigation tasks. PMID- 28900395 TI - Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs. AB - With the advent of highly active antiretroviral therapy (HAART) survival rates among patients infected by HIV have increased. However, even though survival has increased HIV-associated neurocognitive disorders (HAND) still persist, suggesting that HAART-drugs may play a role in the neurocognitive impairment observed in HIV-infected patients. Given previous data demonstrating that astrocyte senescence plays a role in neurocognitive disorders such as Alzheimer's disease (AD), we examined the role of HAART on markers of senescence in primary cultures of human astrocytes (HAs). Our results indicate HAART treatment induces cell cycle arrest, senescence-associated beta-galactosidase, and the cell cycle inhibitor p21. Highly active antiretroviral therapy treatment is also associated with the induction of reactive oxygen species and upregulation of mitochondrial oxygen consumption. These changes in mitochondria correlate with increased glycolysis in HAART drug treated astrocytes. Taken together these results indicate that HAART drugs induce the senescence program in HAs, which is associated with oxidative and metabolic changes that could play a role in the development of HAND. PMID- 28900397 TI - The Comparative Efficiency of Intraperitoneal and Intravitreous Injection of Hydrogen Rich Saline against N-Methyl-N-Nitrosourea Induced Retinal Degeneration: A Topographic Study. AB - Retinitis pigmentosa (RP) comprises a heterogeneous group of inherited retinal diseases leading to blindness. The present study explored the protective effects of hydrogen rich saline (HRS) against the photoreceptor degeneration in the N Methyl-N-nitrosourea (MNU) administrated rat, a pharmacologically induced RP model. The therapeutic effects of intraperitoneal (IP) and intravitreous (IV) injections of HRS on regional retina was quantified via topographic measurements. The MNU administrated rats received IV or IP injections of HRS, and then they were subjected to electroretinography, multi electrode array, histological and immunohistochemistry examinations. The concentrations of the retinal malondialdehyde (MDA), superoxide dismutase (SOD), as well as the mRNA levels of apoptotic-associated genes were quantified. The IP and IV delivery pathways of HRS were both effective to ameliorate MNU induced photoreceptor degeneration. Moreover, the IV acted as a more efficient delivery method than the IP in terms of therapeutic effects. Particularly, the topographic measurements suggested that the IV delivery of HRS could alleviate MNU induced photoreceptor degeneration in the posterior retina. The immunostaining experiments also verified the comparative efficiency between IV and IP delivery of HRS on regional cone photoreceptors. Focal cone photoreceptors showed different susceptibilities to HRS and exhibited as a distinct spatial disequilibrium: cone photoreceptors in the ST quadrant were preferentially rescued; meanwhile, HRS induced protection was feeblest in the IN quadrant. Furthermore, the HRS treatment increased the level of retinal SOD, while reduce the level of retinal MDA in MNU administered rats. The expression levels of sever apoptotic -associated genes were significantly altered by HRS treatment. Collectively, these findings suggest that the IV space is an excellent target for HRS delivery. The IV delivery of HRS can efficiently alleviate the photoreceptors (especially these locate at the posterior retina) from MNU toxicity and act as a candidate treatment for RP. PMID- 28900399 TI - Acacetin from Traditionally Used Saussurea involucrata Kar. et Kir. Suppressed Adipogenesis in 3T3-L1 Adipocytes and Attenuated Lipid Accumulation in Obese Mice. AB - Acacetin, a flavone that can be isolated from the Saussurea involucrata plant, has anti-tumor and anti-inflammatory properties that ameliorate airway hyperresponsiveness in asthmatic mice. This study investigated whether acacetin has anti-adipogenic effects in 3T3-L1 adipocytes and whether it regulates the inflammatory response in adipocytes and macrophages. It also investigated whether acacetin ameliorates lipid accumulation in high-fat diet- (HFD) induced obese mice. Differentiated 3T3-L1 cells were treated with acacetin. The glycerol levels in the culture medium were measured, and the expression of proteins and genes involved in adipogenesis and lipolysis were assayed by Western blot and real-time PCR, respectively. Inflammatory cytokine signaling pathway activity was assessed in macrophages that were treated with acacetin and cultured with differentiated medium from 3T3-L1 cells. Intraperitoneal injections of acacetin were administered to HFD-induced obese mice twice a week for 10 weeks. Acacetin significantly increased the levels of glycerol in the culture medium and significantly inhibited lipid accumulation in adipocytes. Acacetin reduced the expression of adipogenesis-related transcription factors, including the expression of the CCAAT/enhancer-binding protein; it also increased sirtuin 1 expression and AMPK phosphorylation in adipocytes. In macrophages cultured with differentiated media from 3T3-L1 adipocytes, acacetin reduced the levels of inflammatory mediators and the activity of the mitogen-activated protein kinase and NF-kappaB pathways. In obese mice, acacetin reduced both body weight and visceral adipose tissue weight. These results demonstrate that acacetin inhibited adipogenesis in adipocytes and in obese mice. Acacetin also reduced the inflammatory response of macrophages that were stimulated with differentiated media from 3T3-L1 cells. PMID- 28900398 TI - Role of Hydrogen Sulfide in Retinal Diseases. AB - As the third gasotransmitter, hydrogen sulfide (H2S) plays a crucial role in the physiology and pathophysiology of many systems in the body, such as the nervous, cardiovascular, respiratory, and gastrointestinal systems. The mechanisms for its effects, including inhibiting ischemic injury, reducing oxidative stress damage, regulating apoptosis, and reducing the inflammation reaction in different systems, have not been fully understood. Recently, H2S and its endogenous synthesis pathway were found in the mammalian retina. This review describes the production and the metabolism of H2S and the evidence of a role of H2S in the retina physiology and in the different retinal diseases, including retinal degenerative diseases and vascular diseases. In the retina, H2S is generated in the presence of cystathionine-beta-synthase, cystathionine-gamma-lyase, and 3 mercaptopyruvate sulfurtransferase from L-cysteine. The role of endogenous H2S and its physiologic effect in the retina are still elusive. However, strong evidence shows that retina-derived H2S might play protective or deleterious role in the pathogenesis of retinal diseases. For example, by regulating Ca2+ influx, H2S can protect retinal neurons against light-induced degeneration. H2S preconditioning can mediate the anti-apoptotic effect of retinal ganglion cells in retinal ischemia/reperfusion injury. Treatment with H2S in rats relieves diabetic retinopathy by suppressing oxidative stress and reducing inflammation. Further studies would greatly improve our understanding of the pathophysiologic mechanisms responsible for retinal diseases and the potential for the H2S-related therapy of the retinal diseases as well. PMID- 28900400 TI - Fractional Stability of Trunk Acceleration Dynamics of Daily-Life Walking: Toward a Unified Concept of Gait Stability. AB - Over the last decades, various measures have been introduced to assess stability during walking. All of these measures assume that gait stability may be equated with exponential stability, where dynamic stability is quantified by a Floquet multiplier or Lyapunov exponent. These specific constructs of dynamic stability assume that the gait dynamics are time independent and without phase transitions. In this case the temporal change in distance, d(t), between neighboring trajectories in state space is assumed to be an exponential function of time. However, results from walking models and empirical studies show that the assumptions of exponential stability break down in the vicinity of phase transitions that are present in each step cycle. Here we apply a general non exponential construct of gait stability, called fractional stability, which can define dynamic stability in the presence of phase transitions. Fractional stability employs the fractional indices, alpha and beta, of differential operator which allow modeling of singularities in d(t) that cannot be captured by exponential stability. The fractional stability provided an improved fit of d(t) compared to exponential stability when applied to trunk accelerations during daily-life walking in community-dwelling older adults. Moreover, using multivariate empirical mode decomposition surrogates, we found that the singularities in d(t), which were well modeled by fractional stability, are created by phase-dependent modulation of gait. The new construct of fractional stability may represent a physiologically more valid concept of stability in vicinity of phase transitions and may thus pave the way for a more unified concept of gait stability. PMID- 28900401 TI - Development and Testing of a Novel Arm Cranking-Powered Watercraft. AB - There is a lack of human-powered watercrafts for people with lower-body disabilities. The purpose of this study was therefore to develop a watercraft for disabled people and investigate the metabolic cost and efficiency when pedaling. The watercraft was designed by combining parts of a waterbike and a handbike. Nine able-bodied subjects pedaled the watercraft at different speeds on a lake to provide steady-state metabolic measurements, and a deceleration test was performed to measure the hydrodynamic resistance of the watercraft. The results showed a linear correlation between metabolic power and mechanical power (r2 = 0.93). Metabolic expenditure when pedaling the watercraft was similar to other physical activities performed by people with lower-body disabilities. Moreover, the efficiency of the watercraft showed to be comparable to other human-powered watercraft and could, as a result, be an alternative fitness tool especially for people with lower-body disabilities, who seek water activities. A number of suggestions are proposed however, to improve the efficiency and ergonomics of the watercraft. PMID- 28900402 TI - Shaving Bridges and Tuning Kitaraa: The Effect of Language Switching on Semantic Processing. AB - Language switching has been repeatedly found to be costly. Yet, there are reasons to believe that switches in language might benefit language comprehension in some groups of people, such as less proficient language learners. This study therefore investigated the interplay between language switching and semantic processing in groups with varying language proficiency. EEG was recorded while L2 learners of English with intermediate and high proficiency levels read semantically congruent or incongruent sentences in L2. Translations of congruent and incongruent target words were additionally presented in L1 to create intrasentential language switches. A control group of English native speakers was tested in order to compare responses to non-switched stimuli with those of L2 learners. An omnibus ANOVA including all groups revealed larger N400 responses for non-switched incongruent stimuli compared to congruent stimuli. Additionally, despite switches to L1 at target word position, semantic N400 responses were still elicited in both L2 learner groups. Further switching effects were reflected by an N400-like effect and a late positivity complex, pointing to possible parsing efforts after language switches. Our results therefore show that although language switches are associated with increased mental effort, switches may not necessarily be costly on the semantic level. This finding contributes to the ongoing discussion on language inhibition processes, and shows that, in these intermediate and high proficient L2 learners, semantic processes look similar to those of native speakers of English. PMID- 28900403 TI - (Bad) Feelings about Meeting Them? Episodic and Chronic Intergroup Emotions Associated with Positive and Negative Intergroup Contact As Predictors of Intergroup Behavior. AB - Based on two cross-sectional probability samples (Study 1: N = 1,382, Study 2: N = 1,587), we studied the interplay between positive and negative intergroup contact, different types of intergroup emotions (i.e., episodic intergroup emotions encountered during contact and more general chronic intergroup emotions), and outgroup behavior in the context of intergroup relations between non-immigrant Germans and foreigners living in Germany. In Study 1, we showed that positive and negative contact are related to specific episodic intergroup emotions (i.e., anger, fear and happiness). Results of Study 2 indicate an indirect effect of episodic intergroup emotions encountered during contact experiences on specific behavioral tendencies directed at outgroup members via more chronic situation-independent intergroup emotions. As expected, anger predicted approaching (discriminatory) behavioral tendencies (i.e., aggression) while fear predicted avoidance. The results extend the existing literature on intergroup contact and emotions by addressing positive and negative contact simultaneously and differentiating between situation-specific episodic and chronic intergroup emotions in predicting discriminatory behavioral tendencies. PMID- 28900404 TI - Cantonese-Speaking Children Do Not Acquire Tone Perception before Tone Production A Perceptual and Acoustic Study of Three-Year-Olds' Monosyllabic Tones. AB - Models of phonological development assume that speech perception precedes speech production and that children acquire suprasegmental features earlier than segmental features. Studies of Chinese-speaking children challenge these assumptions. For example, Chinese-speaking children can produce tones before two and-a-half years but are not able to discriminate the same tones until after 6 years of age. This study compared the perception and production of monosyllabic Cantonese tones directly in 3 -year-old children. Twenty children and their mothers identified Cantonese tones in a picture identification test and produced monosyllabic tones in a picture labeling task. To control for lexical biases on tone ratings, the mother- and child-productions were low-pass filtered to eliminate lexical information and were presented to five judges for tone classification. Detailed acoustic analysis was performed. Contrary to the view that children master lexical tones earlier than segmental phonemes, results showed that 3-year-old children could not perceive or produce any Cantonese tone with adult-like proficiency and incorrect tone productions were acoustically different from criterion. In contrast to previous findings that Cantonese speaking children mastered tone production before tone perception, we observed more accuracy during speech perception than production. Findings from Cantonese speaking children challenge some of the established tenets in theories of phonological development that have been tested mostly with native English speakers. PMID- 28900405 TI - The Minimal and Short-Lived Effects of Minority Language Exposure on the Executive Functions of Frisian-Dutch Bilingual Children. AB - Various studies have shown that bilingual children need a certain degree of proficiency in both languages before their bilingual experiences enhance their executive functioning (EF). In the current study, we investigated if degree of bilingualism in Frisian-Dutch children influenced EF and if this effect was sustained over a 3-year period. To this end, longitudinal data were analyzed from 120 Frisian-Dutch bilingual children who were 5- or 6-years-old at the first time of testing. EF was measured with two attention and two working memory tasks. Degree of bilingualism was defined as language balance based on receptive vocabulary and expressive morphology scores in both languages. In a context with a minority and a majority language, such as the Frisian-Dutch context, chances for becoming proficient in both languages are best for children who speak the minority language at home. Therefore, in a subsequent analysis, we examined whether minority language exposure predicted language balance and whether there was a relationship between minority language exposure and EF, mediated by language balance. The results showed that intensity of exposure to Frisian at home, mediated by language balance, had an impact on one of the attention tasks only. It predicted performance on this task at time 1, but not at time 2 and 3. This partially confirms previous evidence that the cognitive effects of bilingualism are moderated by degree of bilingualism and furthermore reveals that substantial minority language exposure at home indirectly affects bilingual children's cognitive development, namely through mediation with degree of bilingualism. However, the findings also demonstrate that the effect of bilingualism on EF is limited and unstable. PMID- 28900406 TI - Neural Representation. A Survey-Based Analysis of the Notion. AB - The word representation (as in "neural representation"), and many of its related terms, such as to represent, representational and the like, play a central explanatory role in neuroscience literature. For instance, in "place cell" literature, place cells are extensively associated with their role in "the representation of space." In spite of its extended use, we still lack a clear, universal and widely accepted view on what it means for a nervous system to represent something, on what makes a neural activity a representation, and on what is re-presented. The lack of a theoretical foundation and definition of the notion has not hindered actual research. My aim here is to identify how active scientists use the notion of neural representation, and eventually to list a set of criteria, based on actual use, that can help in distinguishing between genuine or non-genuine neural-representation candidates. In order to attain this objective, I present first the results of a survey of authors within two domains, place-cell and multivariate pattern analysis (MVPA) research. Based on the authors' replies, and on a review of neuroscientific research, I outline a set of common properties that an account of neural representation seems to require. I then apply these properties to assess the use of the notion in two domains of the survey, place-cell and MVPA studies. I conclude by exploring a shift in the notion of representation suggested by recent literature. PMID- 28900396 TI - Corrigendum: Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images. AB - [This corrects the article on p. 146 in vol. 9, PMID: 28572766.]. PMID- 28900407 TI - Psychometric Properties of a Multidimensional Scale of Sense of Community in the School. AB - Sense of community in the school has been associated with a range of important outcomes for students. However, there are currently no standard definitions of sense of community in the school with corresponding measures with established psychometric properties. To fill this gap, the main aim of the present study was to propose a model of sense of community in the school, its operationalization and to examine its key psychometric properties (factorial structure, reliability, differential item functioning, differential test functioning of the scale and discriminant, convergent, and criterion validity). Participants were 1,076 students from 22 public middle schools and 724 students from 22 public high schools located in the Italian city of Genoa and its province. To test the dimensionality of the scale, we conducted exploratory and confirmatory factor analysis under the Item Response Theory paradigm. Exploratory factor analysis confirmed three dimensions: Membership, Emotional connection, and Opportunities. A confirmatory factor analysis revealed that the bifactor model exhibited the largest improvement in fit. Cronbach's alpha, omega total, and omega hierarchical indicated a good reliability for the measure. Internal consistency was satisfactory, considering Cronbach's alpha and omega. Analysis of differential item/test functioning of the scale showed that girls and boys as well as students attending middle school and those attending high school responded in largely similar ways to the measure. Finally, the instrument demonstrated good discriminant, convergent, and criterion validity. Together, these findings indicate that our theory driven model of sense of community in the school is valid and that the instrument is a reliable measure for assessing sense of community in the school. PMID- 28900408 TI - Corrigendum: Two Sides of Emotion: Exploring Positivity and Negativity in Six Basic Emotions across Cultures. AB - [This corrects the article on p. 610 in vol. 8, PMID: 28473791.]. PMID- 28900410 TI - Human Connections and Their Roles in the Occupational Well-being of Healthcare Professionals: A Study on Loneliness and Empathy. AB - Human connections are key to the promotion of health and prevention of illness; moreover, illness can cause deterioration of human connections. Healthcare professional-patient relationships are key to ensuring the preservation of adequate human connections. It is important for healthcare professionals to develop their ability to foster satisfactory human connections because: (i) they represent social support for patients; and (ii) they prevent work-related stress. In this study we assessed the relationship between absence (loneliness) and presence (empathy) of human connections with the occupational well-being of healthcare professionals. The Scale of Collateral Effects, which measures somatization, exhaustion, and work alienation; the Jefferson Scale of Empathy; and the Social and Emotional Loneliness Scale for Adults, were mailed to 628 healthcare professionals working in Spanish public healthcare institutions. The following explanatory variables were used to evaluate work well-being: (a) empathy, as a professional competence; (b) loneliness, age, and family burden, as psychological indicators; and (c) professional experience, work dedication, and salary, as work indicators. Comparison, correlation, and regression analyses were performed to measure the relationships among these variables and occupational well-being. Of 628 surveys mailed, 433 (69% response rate) were returned fully completed. Adequate reliability was confirmed for all instruments. The entire sample was divided into four groups, based on the combined variable, "occupation by sex." Comparative analyses demonstrated differences among "occupation by sex" groups in collateral effects (p = 0.03) and empathy (p = 0.04), but not loneliness (p = 0.84). Inverse associations between empathy and collateral effects were confirmed for somatization (r = -0.16; p < 0.001), exhaustion (r = 0.14; p = 0.003), and work alienation (r = -0.16; p < 0.001). Furthermore, loneliness was positively associated with collateral effects (r = 0.22; p < 0.001). Neither family burden, nor work dedication to clinics or management activities were associated with the three collateral effects measured. These findings support an important role for empathy in the prevention of work stress in healthcare professionals. They also confirm that loneliness, as a multidimensional and domain specific experience, is detrimental to occupational well-being. PMID- 28900409 TI - Learning to Dislike Chocolate: Conditioning Negative Attitudes toward Chocolate and Its Effect on Chocolate Consumption. AB - Evaluative conditioning (EC) procedures can be used to form and change attitudes toward a wide variety of objects. The current study examined the effects of a negative EC procedure on attitudes toward chocolate, and whether it influenced chocolate evaluation and consumption. Participants were randomly assigned to the experimental condition in which chocolate images were paired with negative stimuli, or the control condition in which chocolate images were randomly paired with positive stimuli (50%) and negative stimuli (50%). Explicit and implicit attitudes toward chocolate images were collected. During an ostensible taste test, chocolate evaluation and consumption were assessed. Results revealed that compared to participants in the control condition, participants in the experimental condition showed more negative explicit and implicit attitudes toward chocolate images and evaluated chocolate more negatively during the taste test. However, chocolate consumption did not differ between experimental and control conditions. These findings suggest that pairing chocolate with negative stimuli can influence attitudes toward chocolate, though behavioral effects are absent. Intervention applications of EC provide avenues for future research and practices. PMID- 28900411 TI - Can We Retrieve the Information Which Was Intentionally Forgotten? Electrophysiological Correlates of Strategic Retrieval in Directed Forgetting. AB - Retrieval inhibition hypothesis of directed forgetting effects assumed TBF (to-be forgotten) items were not retrieved intentionally, while selective rehearsal hypothesis assumed the memory representation of retrieved TBF (to-be-forgotten) items was weaker than TBR (to-be-remembered) items. Previous studies indicated that directed forgetting effects of item-cueing method resulted from selective rehearsal at encoding, but the mechanism of retrieval inhibition that affected directed forgetting of TBF (to-be-forgotten) items was not clear. Strategic retrieval is a control process allowing the selective retrieval of target information, which includes retrieval orientation and strategic recollection. Retrieval orientation via the comparison of tasks refers to the specific form of processing resulted by retrieval efforts. Strategic recollection is the type of strategies to recollect studied items for the retrieval success of targets. Using a "directed forgetting" paradigm combined with a memory exclusion task, our investigation of strategic retrieval in directed forgetting assisted to explore how retrieval inhibition played a role on directed forgetting effects. When TBF items were targeted, retrieval orientation showed more positive ERPs to new items, indicating that TBF items demanded more retrieval efforts. The results of strategic recollection indicated that: (a) when TBR items were retrieval targets, late parietal old/new effects were only evoked by TBR items but not TBF items, indicating the retrieval inhibition of TBF items; (b) when TBF items were retrieval targets, the late parietal old/new effect were evoked by both TBR items and TBF items, indicating that strategic retrieval could overcome retrieval inhibition of TBF items. These findings suggested the modulation of strategic retrieval on retrieval inhibition of directed forgetting, supporting that directed forgetting effects were not only caused by selective rehearsal, but also retrieval inhibition. PMID- 28900412 TI - Corrigendum: Influence of Landmarks on Wayfinding and Brain Connectivity in Immersive Virtual Reality Environment. AB - [This corrects the article on p. 1220 in vol. 8, PMID: 28775698.]. PMID- 28900413 TI - Impaired Cerebellum to Primary Motor Cortex Associative Plasticity in Parkinson's Disease and Spinocerebellar Ataxia Type 3. AB - BACKGROUND: Functional perturbation of the cerebellum (CB)-motor cortex (M1) interactions may underlie pathophysiology of movement disorders, such as Parkinson's disease (PD) and spinocerebellar ataxia type 3 (SCA3). Recently, M1 motor excitability can be bidirectionally modulated in young subjects by corticocortical paired associative stimulation (PAS) on CB and contralateral M1 with transcranial magnetic stimulation (TMS), probably through the cerebello dentato-thalamo-cortical (CDTC) circuit. In this study, we investigated the CB to M1-associative plasticity in healthy elderly PD and SCA3. METHODS: Ten right handed PD patients, nine gene-confirmed SCA3 patients, and 10 age-matched healthy controls (HC) were studied. One hundred and twenty pairs of TMS of the left M1 preceded by right lateral CB TMS at an interstimulus interval of 2 (CB -> M1 PAS2ms) and 6 ms (CB -> M1 PAS6ms) were, respectively, applied with at least 1 week interval. M1 excitability was assessed by motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cerebellar inhibition (CBI) at the first dorsal interosseous muscle of the right hand before and after the CB -> M1 PAS. RESULTS: The M1 excitability represented by MEP amplitude was significantly facilitated and suppressed in the HC group by CB -> M1 PAS2ms and CB -> M1 PAS6ms, respectively. The bidirectional modulation on MEP amplitude was absent in the PD and SCA3 groups. SICI and the baseline CBI were significantly reduced in the SCA3 group compared to those of the HC group irrespective of the CB -> M1 PAS protocols. There was a significant reduction of CBI immediately and 60 min after the CB -> M1 PAS protocols in the HC group but not in the patient groups. No significant change of ICF was found. CONCLUSION: Corticocortical CB -> M1 PAS can induce bidirectional motor cortical plasticity in M1 for healthy aged subjects. The modulation may be independent of the inhibitory neurocircuits, such as SICI and CBI, and the facilitatory mechanism like ICF. Both patients with PD and SCA3 showed impairment of such plasticity, suggesting significant functional perturbation of the CDTC circuit. PMID- 28900414 TI - Alterations in Spectral Attributes of Surface Electromyograms after Utilization of a Foot Drop Stimulator during Post-Stroke Gait. AB - BACKGROUND: A foot drop stimulator (FDS) is a rehabilitation intervention that stimulates the common peroneal nerve to facilitate ankle dorsiflexion at the appropriate time during post-stroke hemiplegic gait. Time-frequency analysis (TFA) of non-stationary surface electromyograms (EMG) and spectral variables such as instantaneous mean frequency (IMNF) can provide valuable information on the long-term effects of FDS intervention in terms of changes in the motor unit (MU) recruitment during gait, secondary to improved dorsiflexion. OBJECTIVE: The aim of this study was to apply a wavelet-based TFA approach to assess the changes in neuromuscular activation of the tibialis anterior (TA), soleus (SOL), and gastrocnemius (GA) muscles after utilization of an FDS during gait post-stroke. METHODS: Surface EMG were collected bilaterally from the TA, SOL, and GA muscles from six participants (142.9 +/- 103.3 months post-stroke) while walking without the FDS at baseline and 6 months post-FDS utilization. Continuous wavelet transform was performed to get the averaged time-frequency distribution of band pass filtered (20-300 Hz) EMGs during multiple walking trials. IMNFs were computed during normalized gait and were averaged during the stance and swing phases. Percent changes in the energies associated with each frequency band of 25 Hz between 25 and 300 Hz were computed and compared between visits. RESULTS: Averaged time-frequency representations of the affected TA, SOL, and GA EMG show altered spectral attributes post-FDS utilization during normalized gait. The mean IMNF values for the affected TA were significantly lower than the unaffected TA at baseline (p = 0.026) and follow-up (p = 0.038) during normalized stance. The mean IMNF values significantly increased (p = 0.017) for the affected GA at follow-up during normalized swing. The frequency band of 250-275 Hz significantly increased in the energies post-FDS utilization for all muscles. CONCLUSION: The application of wavelet-based TFA of EMG and outcome measures (IMNF, energy) extracted from the time-frequency distributions suggest alterations in MU recruitment strategies after the use of FDS in individuals with chronic stroke. This further establishes the efficacy of FDS as a rehabilitation intervention that may promote motor recovery in addition to treating the secondary complications of foot drop due to post-stroke hemiplegia. PMID- 28900415 TI - Perinatal Western Diet Consumption Leads to Profound Plasticity and GABAergic Phenotype Changes within Hypothalamus and Reward Pathway from Birth to Sexual Maturity in Rat. AB - Perinatal maternal consumption of energy dense food increases the risk of obesity in children. This is associated with an overconsumption of palatable food that is consumed for its hedonic property. The underlying mechanism that links perinatal maternal diet and offspring preference for fat is still poorly understood. In this study, we aim at studying the influence of maternal high-fat/high-sugar diet feeding [western diet (WD)] during gestation and lactation on the reward pathways controlling feeding in the rat offspring from birth to sexual maturity. We performed a longitudinal follow-up of WD and Control offspring at three critical time periods (childhood, adolescence, and adulthood) and focus on investigating the influence of perinatal exposure to palatable diet on (i) fat preference, (ii) gene expression profile, and (iii) neuroanatomical/architectural changes of the mesolimbic dopaminergic networks. We showed that WD feeding restricted to the perinatal period has a clear long-lasting influence on the organization of homeostatic and hedonic brain circuits but not on fat preference. We demonstrated a period specific evolution of the preference for fat that we correlated with specific brain molecular signatures. In offspring from WD fed dams, we observed during childhood the existence of fat preference associated with a higher expression of key gene involved in the dopamine (DA) systems; at adolescence, a high-fat preference for both groups, progressively reduced during the 3 days test for the WD group and associated with a reduced expression of key gene involved in the DA systems for the WD group that could suggest a compensatory mechanism to protect them from further high-fat exposure; and finally at adulthood, a preference for fat that was identical to control rats but associated with profound modification in key genes involved in the gamma-aminobutyric acid network, serotonin receptors, and polysialic acid-NCAM-dependent remodeling of the hypothalamus. Altogether, these data reveal that maternal WD, restricted to the perinatal period, has no sustained impact on energy homeostasis and fat preference later in life even though a strong remodeling of the hypothalamic homeostatic and reward pathway involved in eating behavior occurred. Further functional experiments would be needed to understand the relevance of these circuits remodeling. PMID- 28900416 TI - Effect of Thermophilic Nitrate Reduction on Sulfide Production in High Temperature Oil Reservoir Samples. AB - Oil fields can experience souring, the reduction of sulfate to sulfide by sulfate reducing microorganisms. At the Terra Nova oil field near Canada's east coast, with a reservoir temperature of 95 degrees C, souring was indicated by increased hydrogen sulfide in produced waters (PW). Microbial community analysis by 16S rRNA gene sequencing showed the hyperthermophilic sulfate-reducing archaeon Archaeoglobus in Terra Nova PWs. Growth enrichments in sulfate-containing media at 55-70 degrees C with lactate or volatile fatty acids yielded the thermophilic sulfate-reducing bacterium (SRB) Desulfotomaculum. Enrichments at 30-45 degrees C in nitrate-containing media indicated the presence of mesophilic nitrate-reducing bacteria (NRB), which reduce nitrate without accumulation of nitrite, likely to N2. Thermophilic NRB (tNRB) of the genera Marinobacter and Geobacillus were detected and isolated at 30-50 degrees C and 40-65 degrees C, respectively, and only reduced nitrate to nitrite. Added nitrite strongly inhibited the isolated thermophilic SRB (tSRB) and tNRB and SRB could not be maintained in co-culture. Inhibition of tSRB by nitrate in batch and continuous cultures required inoculation with tNRB. The results suggest that nitrate injected into Terra Nova is reduced to N2 at temperatures up to 45 degrees C but to nitrite only in zones from 45 to 65 degrees C. Since the hotter zones of the reservoir (65-80 degrees C) are inhabited by thermophilic and hyperthermophilic sulfate reducers, souring at these temperatures might be prevented by nitrite production if nitrate reducing zones of the system could be maintained at 45-65 degrees C. PMID- 28900418 TI - LMOf2365_0442 Encoding for a Fructose Specific PTS Permease IIA May Be Required for Virulence in L. monocytogenes Strain F2365. AB - Listeria monocytogenes is a foodborne pathogen that causes listeriosis, which is a major public health concern due to the high fatality rate. LMOf2365_0442, 0443, and 0444 encode for fructose-specific EIIABC components of phosphotransferase transport system (PTS) permease that is responsible for sugar transport. In previous studies, in-frame deletion mutants of a putative fructose-specific PTS permease (LMOf2365_0442, 0443, and 0444) were constructed and analyzed. However, the virulence potential of these deletion mutants has not been studied. In this study, two in vitro methods were used to analyze the virulence potential of these L. monocytogenes deletion mutants. First, invasion assays were used to measure the invasion efficiencies to host cells using the human HT-29 cell line. Second, plaque forming assays were used to measure cell-to-cell spread in host cells. Our results showed that the deletion mutant DeltaLMOf2365_0442 had reduced invasion and cell-to-cell spread efficiencies in human cell line compared to the parental strain LMOf2365, indicating that LMOf2365_0442 encoding for a fructose specific PTS permease IIA may be required for virulence in L. monocytogenes strain F2365. In addition, the gene expression levels of 15 virulence and stress-related genes were analyzed in the stationary phase cells of the deletion mutants using RT-PCR assays. Virulence-related gene expression levels were elevated in the deletion mutants DeltaLMOf2365_0442-0444 compared to the wild type parental strain LMOf2365, indicating the down-regulation of virulence genes by this PTS permease in L. monocytogenes. Finally, stress-related gene clpC expression levels were also increased in all of the deletion mutants, suggesting the involvement of this PTS permease in stress response. Furthermore, these deletion mutants displayed the same pressure tolerance and the same capacity for biofilm formation compared to the wild-type parental strain LMOf2365. In summary, our findings suggest that the LMOf2365_0442 gene can be used as a potential target to develop inhibitors for new therapeutic and pathogen control strategies for public health. PMID- 28900417 TI - Integrated Translatome and Proteome: Approach for Accurate Portraying of Widespread Multifunctional Aspects of Trichoderma. AB - Genome-wide studies of transcripts expression help in systematic monitoring of genes and allow targeting of candidate genes for future research. In contrast to relatively stable genomic data, the expression of genes is dynamic and regulated both at time and space level at different level in. The variation in the rate of translation is specific for each protein. Both the inherent nature of an mRNA molecule to be translated and the external environmental stimuli can affect the efficiency of the translation process. In biocontrol agents (BCAs), the molecular response at translational level may represents noise-like response of absolute transcript level and an adaptive response to physiological and pathological situations representing subset of mRNAs population actively translated in a cell. The molecular responses of biocontrol are complex and involve multistage regulation of number of genes. The use of high-throughput techniques has led to rapid increase in volume of transcriptomics data of Trichoderma. In general, almost half of the variations of transcriptome and protein level are due to translational control. Thus, studies are required to integrate raw information from different "omics" approaches for accurate depiction of translational response of BCAs in interaction with plants and plant pathogens. The studies on translational status of only active mRNAs bridging with proteome data will help in accurate characterization of only a subset of mRNAs actively engaged in translation. This review highlights the associated bottlenecks and use of state of-the-art procedures in addressing the gap to accelerate future accomplishment of biocontrol mechanisms. PMID- 28900419 TI - Enhanced Killing and Antibiofilm Activity of Encapsulated Cinnamaldehyde against Candida albicans. AB - Candida sp. impelled opportunistic infection in immune-compromised patients ensuing from asymptomatic colonization to pathogenic forms. Moreover, slow spread of Candida species inducing refractory mucosal and invasive infections brings acute resistance to antifungal drugs. Hence, here we probed the effect of encapsulated preparation of cinnamaldehyde (CNMA) in multilamellar liposomes (ML) against Candida albicans. The efficacy of ML-CNMA against Candida biofilm was assessed by scanning electron microscopy, transmission electron microscopy, as well as light microscopy and its percent inhibition, was determined by XTT [2,3 bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] and crystal violet assay. ML-CNMA showed more fungicidal activity than free CNMA as well as multilamellar liposomal amphotericin B (ML-Amp B), which was further confirmed by spot test assay and Log-logistic dose-response analysis. Antifungal activity was driven by reactive oxygen species and cellular damage by sustained release of CNMA. Effect on hyphal formation during 48 h in presence/absence of ML-CNMA was observed under a microscope and further substantiated by RT-PCR by amplifying HWP1, the gene responsible for hyphal wall protein formation. Apoptotic programmed cell death was analyzed by FACS analysis which was further confirmed by cytochrome C release assay. This study elucidates the mechanistic insight of the enhanced antifungal activity of ML preparation of CNMA against Candida infections. PMID- 28900420 TI - Seed and Root Endophytic Fungi in a Range Expanding and a Related Plant Species. AB - Climate change is accelerating the spread of plants and their associated species to new ranges. The differences in range shift capacity of the various types of species may disrupt long-term co-evolved relationships especially those belowground, however, this may be less so for seed-borne endophytic microbes. We collected seeds and soil of the range-expanding Centaurea stoebe and the congeneric Centaurea jacea from three populations growing in Slovenia (native range of both Centaurea species) and the Netherlands (expanded range of C. stoebe, native range of C. jacea). We isolated and identified endophytic fungi directly from seeds, as well as from roots of the plants grown in Slovenian, Dutch or sterilized soil to compare fungal endophyte composition. Furthermore, we investigated whether C. stoebe hosts a reduced community composition of endophytes in the expanded range due to release from plant-species specific fungi while endophyte communities in C. jacea in both ranges are similar. We cultivated 46 unique and phylogenetically diverse endophytes. A majority of the seed endophytes resembled potential pathogens, while most root endophytes were not likely to be pathogenic. Only one endophyte was found in both roots and seeds, but was isolated from different plant species. Unexpectedly, seed endophyte diversity of southern C. stoebe populations was lower than of populations from the north, while the seed endophyte community composition of northern C. stoebe populations was significantly different southern C. stoebe as well as northern and southern C. jacea populations. Root endophyte diversity was considerably lower in C. stoebe than in C. jacea independent of plant and soil origin, but this difference disappeared when plants were grown in sterile soils. We conclude that the community composition of fungal endophytes not only differs between related plant species but also between populations of plants that expand their range compared to their native habitat. Our results suggest that fungal endophytes of two Centaurea species are not able to systemically infect plants. We highlight that endophytes remain poorly studied and further work should investigate the functional importance of endophytes. PMID- 28900421 TI - Efficacy Analysis of Combinatorial siRNAs against HIV Derived from One Double Hairpin RNA Precursor. AB - Combinatorial small interfering RNA duplexes (siRNAs) have the potential to be a gene therapy against HIV-1, and some studies have reported that transient combinatorial siRNA expression represses HIV replication, but the effects of long term siRNA expression on HIV replication have not been studied in detail. In this study, HIV-1 replication under the influence of stable combinatorial siRNA expression from a single RNA transcript was analyzed. First, a series of cassettes encoding short hairpin RNA (shRNA)/long hairpin RNA (lhRNA)/double long hairpins (dlhRNA) was constructed and subjected to an analysis of inhibitory efficacy. Next, an optimized dlhRNA encoding cassette was selected and inserted into lentiviral delivery vector FG12. Transient dlhRNA expression reduced replication of HIV-1 in TZM-bl cells and CD4+ T cells successfully. HIV-1 susceptible TZM-bl cells were transducted with the dlhRNA expressing lentiviral vector and sorted by fluorescence-activated cell sorting to obtain stable dlhRNA expressing cells. The generation of four anti-HIV siRNAs in these dlhRNA expressing cells was verified by stem-loop RT-PCR assay. dlhRNA expression did not activate a non-specific interferon response. The dlhRNA expressing cells were also challenged with HIV-1 NL4-3, which revealed that stable expression of combinatorial siRNAs repressed HIV-1 replication for 8 days, after which HIV-1 overcame the inhibitory effect of siRNA expression by expressing mutant versions of RNAi targets. The results of this evaluation of the long-term inhibitory effects of combinatorial siRNAs against HIV-1 provide a reference for researchers who utilize combinatorial RNA interference against HIV-1 or other error-prone viruses. PMID- 28900422 TI - Rab3a-Bound CD63 Is Degraded and Rab3a-Free CD63 Is Incorporated into HIV-1 Particles. AB - CD63, a member of the tetraspanin family, is involved in virion production by human immunodeficiency virus type 1 (HIV-1), but its mechanism is unknown. In this study, we showed that a small GTP-binding protein, Rab3a, interacts with CD63. When Rab3a was exogenously expressed, the amounts of CD63 decreased in cells. The Rab3a-mediated reduction of CD63 was suppressed by lysosomal and proteasomal inhibitors. The amount of CD63 was increased by reducing the endogenous Rab3a level using a specific shRNA. These results indicate that Rab3a binds to CD63 to induce the degradation of CD63. Rab3a is thought to be involved in exocytosis, but we found that another function of Rab3a affects the fate of CD63 in lysosomes. CD63 interacted with Rab3a and was incorporated into HIV-1 particles. However, Rab3a was not detected in HIV-1 virions, thereby indicating that Rab3a-free CD63, but not Rab3a-bound CD63, is incorporated into HIV-1 particles. Overexpression or silencing of Rab3a moderately reduced HIV-1 virion formation. Overexpression of Rab3a decreased CD63 levels, but did not affect the incorporation of CD63 into HIV-1 particles. This study showed that Rab3a binds to CD63 to induce the degradation of CD63, and only Rab3a-free CD63 is incorporated into HIV-1 particles. PMID- 28900423 TI - EsrE-A yigP Locus-Encoded Transcript-Is a 3' UTR sRNA Involved in the Respiratory Chain of E. coli. AB - The yigP locus is widely conserved among gamma-proteobacteria. Mutation of the yigP locus impacts aerobic growth of Gram-negative bacteria. However, the underlying mechanism of how the yigP locus influences aerobic growth remains largely unknown. Here, we demonstrated that the yigP locus in Escherichia coli encodes two transcripts; the mRNA of ubiquinone biosynthesis protein, UbiJ, and the 3' untranslated region small regulatory RNA (sRNA), EsrE. EsrE is an independent transcript that is transcribed using an internal promoter of the yigP locus. Surprisingly, we found that both the EsrE sRNA and UbiJ protein were required for Q8 biosynthesis, and were sufficient to rescue the growth defect ascribed to deletion of the yigP locus. Moreover, our data showed that EsrE targeted multiple mRNAs involved in several cellular processes including murein biosynthesis and the tricarboxylic acid cycle. Among these targets, sdhD mRNA that encodes one subunit of succinate dehydrogenase (SDH), was significantly activated. Our findings provided an insight into the important function of EsrE in bacterial adaptation to various environments, as well as coordinating different aspects of bacterial physiology. PMID- 28900424 TI - The Impact of the Staphylococcus aureus Virulome on Infection in a Developing Country: A Cohort Study. AB - We performed a cohort study to analyze the virulome of Staphylococcus aureus from the Democratic Republic of the Congo using whole genome sequencing and to assess its impact on the course of S. aureus infections. Community-associated S. aureus from nasal colonization (n = 100) and infection (n = 86) were prospectively collected. Phenotypic susceptibility testing and WGS was done for each isolate. WGS data were used to screen for 79 different virulence factors and for genotyping purposes (spa typing, multilocus sequence typing). The majority of the 79 virulence factors were equally distributed among isolates from colonization and infection. Panton-Valentine leukocidin (PVL) and the non-truncated hemolysin beta were associated with skin and soft tissue infection (SSTI) and recurrence of disease but did not influence the course of infection (i.e., mortality, surgical intervention). For the first time, we show that not only PVL but also hemolysin beta could contribute to the development of SSTI in PVL-endemic areas such as Africa. PMID- 28900425 TI - Corrigendum: Zika Virus: An Emerging Worldwide Threat. AB - [This corrects the article on p. 1417 in vol. 8, PMID: 28798738.]. PMID- 28900426 TI - Interleukin (IL)-18 Binding Protein Deficiency Disrupts Natural Killer Cell Maturation and Diminishes Circulating IL-18. AB - The cytokine interleukin (IL)-18 is a crucial amplifier of natural killer (NK) cell function. IL-18 signaling is regulated by the inhibitory effects of IL-18 binding protein (IL-18BP). Using mice deficient in IL-18BP (IL-18BPKO), we investigated the impact of mismanaged IL-18 signaling on NK cells. We found an overall reduced abundance of splenic NK cells in the absence of IL-18BP. Closer examination of NK cell subsets in spleen and bone marrow using CD27 and CD11b expression revealed that immature NK cells were increased in abundance, while the mature population of NK cells was reduced. Also, NK cells were polarized to greater production of TNF-alpha, while dedicated IFN-gamma producers were reduced. A novel subset of IL-18 receptor alpha- NK cells contributed to the expansion of immature NK cells in IL-18BPKO mice. Splenocytes cultured with IL-18 resulted in alterations similar to those observed in IL-18BP deficiency. NK cell changes were associated with significantly reduced levels of circulating plasma IL-18. However, IL-18BPKO mice exhibited normal weight gain and responded to LPS challenge with a >10-fold increase in IFN-gamma compared to wild type. Finally, we identified that the source of splenic IL-18BP was among dendritic cells/macrophage localized to the T cell-rich regions of the spleen. Our results demonstrate that IL-18BP is required for normal NK cell abundance and function and also contributes to maintaining steady-state levels of circulating IL-18. Thus, IL-18BP appears to have functions suggestive of a carrier protein, not just an inhibitor. PMID- 28900428 TI - C-Reactive Protein Binds to Cholesterol Crystals and Co-Localizes with the Terminal Complement Complex in Human Atherosclerotic Plaques. AB - Inflammation is a part of the initial process leading to atherosclerosis and cholesterol crystals (CC), found in atherosclerotic plaques, which are known to induce complement activation. The pentraxins C-reactive protein (CRP), long pentraxin 3 (PTX3), and serum amyloid P component (SAP) are serum proteins associated with increased risk of cardiovascular events and these proteins have been shown to interact with the complement system. Whether the pentraxins binds to CC and mediate downstream complement-dependent inflammatory processes remains unknown. Binding of CRP, PTX3, and SAP to CC was investigated in vitro by flow cytometry and fluorescence microscopy. CRP, PTX3, and SAP bound to CC in a concentration-dependent manner. CRP and PTX3 interacted with the complement pattern recognition molecule C1q on CC by increasing the binding of both purified C1q and C1q in plasma. However, CRP was the strongest mediator of C1q binding and also the pentraxin that most potently elevated C1q-mediated complement activation. In a phagocytic assay using whole blood, we confirmed that phagocytosis of CC is complement dependent and initiated by C1q-mediated activation. The pathophysiological relevance of the in vitro observations was examined in vivo in human atherosclerotic plaques. CRP, PTX3, and SAP were all found in atherosclerotic plaques and were located mainly in the cholesterol-rich necrotic core, but co-localization with the terminal C5b-9 complement complex was only found for CRP. In conclusion, this study identifies CRP as a strong C1q recruiter and complement facilitator on CC, which may be highly relevant for the development of atherosclerosis. PMID- 28900427 TI - Catalog of Differentially Expressed Long Non-Coding RNA following Activation of Human and Mouse Innate Immune Response. AB - Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs) are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes) and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells) following exposure to the pro inflammatory mediators, lipopolysaccharides (LPS), or interleukin-1beta. We show differential expression of 204 human and 210 mouse lncRNAs, with positional analysis demonstrating correlation with immune-related genes. These lncRNAs are predominantly cell-type specific, composed of large regions of repeat sequences, and show poor evolutionary conservation. Comparison within the human and mouse sequences showed less than 1% sequence conservation, although we identified multiple conserved motifs. Of the 204 human lncRNAs, 21 overlapped with syntenic mouse lncRNAs, of which five were differentially expressed in both species. Among these syntenic lncRNA was IL7-AS (antisense), which was induced in multiple cell types and shown to regulate the production of the pro-inflammatory mediator interleukin-6 in both human and mouse cells. In summary, we have identified and characterized those lncRNAs that are differentially expressed following activation of the human and mouse innate immune responses and believe that these catalogs will provide the foundation for the future analysis of the role of lncRNAs in immune and inflammatory responses. PMID- 28900429 TI - Plasma-Derived Polyreactive Secretory-Like IgA and IgM Opsonizing Salmonella enterica Typhimurium Reduces Invasion and Gut Tissue Inflammation through Agglutination. AB - Due to the increasing emergence of antibiotic-resistant strains of enteropathogenic bacteria, development of alternative treatments to fight against gut infections is a major health issue. While vaccination requires that a proper combination of antigen, adjuvant, and delivery route is defined to elicit protective immunity at mucosae, oral delivery of directly active antibody preparations, referred to as passive immunization, sounds like a valuable alternative. Along the gut, the strategy suffers, however, from the difficulty to obtain sufficient amounts of antibodies with the appropriate specificity and molecular structure for mucosal delivery. Physiologically, at the antibody level, the protection of gastrointestinal mucosal surfaces against enteropathogens is principally mediated by secretory IgA and secretory IgM. We previously demonstrated that purified human plasma-derived IgA and IgM can be associated with secretory component to generate biologically active secretory-like IgA and IgM (SCIgA/M) that can protect epithelial cells from infection by Shigella flexneri in vitro. In this study, we aimed at evaluating the protective potential of these antibody preparations in vivo. We now establish that such polyreactive preparations bind efficiently to Salmonella enterica Typhimurium and trigger bacterial agglutination, as observed by laser scanning confocal microscopy. Upon delivery into a mouse ligated intestinal loop, SCIgA/M-mediated aggregates persist in the intestinal environment and limit the entry of bacteria into intestinal Peyer's patches via immune exclusion. Moreover, oral administration to mice of immune complexes composed of S. Typhimurium and SCIgA/M reduces mucosal infection, systemic dissemination, and local inflammation. Altogether, our data provide valuable clues for the future appraisal of passive oral administration of polyreactive plasma-derived SCIgA/M to combat infection by a variety of enteropathogens. PMID- 28900430 TI - PRINS Non-Coding RNA Regulates Nucleic Acid-Induced Innate Immune Responses of Human Keratinocytes. AB - Cytosolic DNA fragments are recognized as pathogen- and danger-associated molecular patterns that induce a cascade of innate immune responses. Moreover, excessive cytosolic DNA can enhance chronic inflammation, predominantly by activating inflammasomes, and thereby contributing to the pathogenesis of chronic diseases, such as psoriasis. Psoriasis associated non-protein coding RNA induced by stress (PRINS) is a long non-coding RNA, which has been shown to be associated with psoriasis susceptibility and cellular stress responses; however, the precise mechanism of its action has not been determined. Here, we provide evidence that, in addition to inflammasome activation, cytosolic DNA induces intracellular inflammatory reactions while decreasing PRINS gene expression. Furthermore, PRINS overexpression can ameliorate the inflammatory-mediator production of keratinocytes induced by cytosolic DNA. Overexpression of PRINS resulted in decreased interleukin-6 (IL-6) and chemokine (C-C motif) ligand 5 (CCL-5) expression and secretion. In silico analysis predicted direct binding sites between PRINS and the mRNAs, which was confirmed by an in vitro binding assay and on cellular level. Our results indicated that PRINS binds directly to the mRNAs of IL-6 and CCL-5 at specific binding sites and eventually destabilizes these mRNAs, leading to a decrease in their expression and secretion of the corresponding proteins. These results may indicate a restrictive role for PRINS in inflammatory processes. PMID- 28900431 TI - Genome-Wide Identification and Evaluation of Reference Genes for Quantitative RT PCR Analysis during Tomato Fruit Development. AB - Gene expression analysis in tomato fruit has drawn increasing attention nowadays. Quantitative real-time PCR (qPCR) is a routine technique for gene expression analysis. In qPCR operation, reliability of results largely depends on the choice of appropriate reference genes (RGs). Although tomato is a model for fruit biology study, few RGs for qPCR analysis in tomato fruit had yet been developed. In this study, we initially identified 38 most stably expressed genes based on tomato transcriptome data set, and their expression stabilities were further determined in a set of tomato fruit samples of four different fruit developmental stages (Immature, mature green, breaker, mature red) using qPCR analysis. Two statistical algorithms, geNorm and Normfinder, concordantly determined the superiority of these identified putative RGs. Notably, SlFRG05 (Solyc01g104170), SlFRG12 (Solyc04g009770), SlFRG16 (Solyc10g081190), SlFRG27 (Solyc06g007510), and SlFRG37 (Solyc11g005330) were proved to be suitable RGs for tomato fruit development study. Further analysis using geNorm indicate that the combined use of SlFRG03 (Solyc02g063070) and SlFRG27 would provide more reliable normalization results in qPCR experiments. The identified RGs in this study will be beneficial for future qPCR analysis of tomato fruit developmental study, as well as for the potential identification of optimal normalization controls in other plant species. PMID- 28900433 TI - Changes in Species Diversity Patterns and Spatial Heterogeneity during the Secondary Succession of Grassland Vegetation on the Loess Plateau, China. AB - Analyzing the dynamic patterns of species diversity and spatial heterogeneity of vegetation in grasslands during secondary succession could help with the maintenance and management of these ecosystems. Here, we evaluated the influence of secondary succession on grassland plant diversity and spatial heterogeneity of abandoned croplands on the Loess Plateau (China) during four phases of recovery: 1-5, 5-10, 10-20, and 20-30 years. The species composition and dominance of the grassland vegetation changed markedly during secondary succession and formed a clear successional series, with the species assemblage dominated by Artemisia capillaris-> Heteropappus altaicus-> A. sacrorum. The diversity pattern was one of low-high-low, with diversity peaking in the 10-20 year phase, thus corresponding to a hump-backed model in which maximum diversity occurring at the intermediate stages. A spatially aggregated pattern prevailed throughout the entire period of grassland recovery; this was likely linked to the dispersal properties of herbaceous plants and to high habitat heterogeneity. We conclude that natural succession was conducive to the successful recovery of native vegetation. From a management perspective, native pioneer tree species should be introduced about 20 years after abandoning croplands to accelerate the natural succession of grassland vegetation. PMID- 28900434 TI - Contrasting Effects of Extreme Drought and Snowmelt Patterns on Mountain Plants along an Elevation Gradient. AB - Despite the evidence that increased frequency and magnitude of extreme climate events (ECE) considerably affect plant performance, there is still a lack of knowledge about how these events affect mountain plant biodiversity and mountain ecosystem functioning. Here, we assessed the short-term (one vegetation period) effects of simulated ECEs [extreme drought (DR), advanced and delayed snowmelt (AD and DE), respectively] on the performance of 42 plant species occurring in the Bavarian Alps (Germany) along an elevational gradient of 600-2000 m a.s.l. in terms of vegetative growth and reproduction performance. We demonstrate that plant vegetative and generative traits respond differently to the simulated ECEs, but the nature and magnitude treatment effects strongly depend on study site location along the elevational gradient, species' altitudinal origin and plant functional type (PFT) of the target species. For example, the negative effect of DR treatment on growth (e.g., lower growth rates and lower leaf nitrogen content) and reproduction (e.g., lower seed mass) was much stronger in upland sites, as compared to lowlands. Species' response to the treatments also differed according to their altitudinal origin. Specifically, upland species responded negatively to extreme DR (e.g., lower growth rates and lower leaf carbon concentrations, smaller seed set), whereas performance of lowland species remained unaffected (e.g., stable seed set and seed size) or even positively responded (e.g., higher growth rates) to that treatment. Furthermore, we were able to detect some consistent differences in responses to the ECEs among three PFTs (forbs, graminoids, and legumes). For instance, vegetative growth and sexual reproduction of highly adaptable opportunistic graminoids positively responded to nearly all ECEs, likely on the costs of other, more conservative, forbs and legumes. Our results suggest that ECEs can significantly modify the performance of specific plant groups and therefore lead to changes in plant community structure and composition under ongoing climate change. Our study therefore underlines the need for more experimental studies on the effects of extreme climate events to understand the potential consequences of climate change for the alpine ecosystem. PMID- 28900435 TI - An Integrated Method to Analyze Farm Vulnerability to Climatic and Economic Variability According to Farm Configurations and Farmers' Adaptations. AB - The need to adapt to decrease farm vulnerability to adverse contextual events has been extensively discussed on a theoretical basis. We developed an integrated and operational method to assess farm vulnerability to multiple and interacting contextual changes and explain how this vulnerability can best be reduced according to farm configurations and farmers' technical adaptations over time. Our method considers farm vulnerability as a function of the raw measurements of vulnerability variables (e.g., economic efficiency of production), the slope of the linear regression of these measurements over time, and the residuals of this linear regression. The last two are extracted from linear mixed models considering a random regression coefficient (an intercept common to all farms), a global trend (a slope common to all farms), a random deviation from the general mean for each farm, and a random deviation from the general trend for each farm. Among all possible combinations, the lowest farm vulnerability is obtained through a combination of high values of measurements, a stable or increasing trend and low variability for all vulnerability variables considered. Our method enables relating the measurements, trends and residuals of vulnerability variables to explanatory variables that illustrate farm exposure to climatic and economic variability, initial farm configurations and farmers' technical adaptations over time. We applied our method to 19 cattle (beef, dairy, and mixed) farms over the period 2008-2013. Selected vulnerability variables, i.e., farm productivity and economic efficiency, varied greatly among cattle farms and across years, with means ranging from 43.0 to 270.0 kg protein/ha and 29.4-66.0% efficiency, respectively. No farm had a high level, stable or increasing trend and low residuals for both farm productivity and economic efficiency of production. Thus, the least vulnerable farms represented a compromise among measurement value, trend, and variability of both performances. No specific combination of farmers' practices emerged for reducing cattle farm vulnerability to climatic and economic variability. In the least vulnerable farms, the practices implemented (stocking rate, input use...) were more consistent with the objective of developing the properties targeted (efficiency, robustness...). Our method can be used to support farmers with sector-specific and local insights about most promising farm adaptations. PMID- 28900436 TI - Molecular Resources from Transcriptomes in the Brassicaceae Family. AB - The rapidly falling costs and the increasing availability of large DNA sequence data sets facilitate the fast and affordable mining of large molecular markers data sets for comprehensive evolutionary studies. The Brassicaceae (mustards) are an important species-rich family in the plant kingdom with taxa distributed worldwide and a complex evolutionary history. We performed Simple Sequence Repeats (SSRs) mining using de novo assembled transcriptomes from 19 species across the Brassicaceae in order to study SSR evolution and provide comprehensive sets of molecular markers for genetic studies within the family. Moreover, we selected the genus Cochlearia to test the transferability and polymorphism of these markers among species. Additionally, we annotated Cochlearia pyrenaica transcriptome in order to identify the position of each of the mined SSRs. While we introduce a new set of tools that will further enable evolutionary studies across the Brassicaceae, we also discuss some broader aspects of SSR evolution. Overall, we developed 2012 ready-to-use SSR markers with their respective primers in 19 Brassicaceae species and a high quality annotated transcriptome for C. pyrenaica. As indicated by our transferability test with the genus Cochlearia these SSRs are transferable to species within the genus increasing exponentially the number of targeted species. Also, our polymorphism results showed substantial levels of variability for these markers. Finally, despite its complex evolutionary history, SSR evolution across the Brassicaceae family is highly conserved and we found no deviation from patterns reported in other Angiosperms. PMID- 28900437 TI - Genetics of Resistance and Pathogenicity in the Maize/Setosphaeria turcica Pathosystem and Implications for Breeding. AB - Northern corn leaf blight (NCLB), the most devastating leaf pathogen in maize (Zea mays L.), is caused by the heterothallic ascomycete Setosphaeria turcica. The pathogen population shows an extremely high genetic diversity in tropical and subtropical regions. Varietal resistance is the most efficient technique to control NCLB. Host resistance can be qualitative based on race-specific Ht genes or quantitative controlled by many genes with small effects. Quantitative resistance is moderately to highly effective and should be more durable combatting all races of the pathogen. Quantitative resistance must, however, be analyzed in many environments (= location * year combinations) to select stable resistances. In the tropical and subtropical environments, quantitative resistance is the preferred option to manage NCLB epidemics. Resistance level can be increased in practical breeding programs by several recurrent selection cycles based on disease severity rating and/or by genomic selection. This review aims to address two important aspects of the NCLB pathosystem: the genetics of the fungus S. turcica and the modes of inheritance of the host plant maize, including successful breeding strategies regarding NCLB resistance. Both drivers of this pathosystem, pathogen, and host, must be taken into account to result in more durable resistance. PMID- 28900432 TI - Assessing and Exploiting Functional Diversity in Germplasm Pools to Enhance Abiotic Stress Adaptation and Yield in Cereals and Food Legumes. AB - There is a need to accelerate crop improvement by introducing alleles conferring host plant resistance, abiotic stress adaptation, and high yield potential. Elite cultivars, landraces and wild relatives harbor useful genetic variation that needs to be more easily utilized in plant breeding. We review genome-wide approaches for assessing and identifying alleles associated with desirable agronomic traits in diverse germplasm pools of cereals and legumes. Major quantitative trait loci and single nucleotide polymorphisms (SNPs) associated with desirable agronomic traits have been deployed to enhance crop productivity and resilience. These include alleles associated with variation conferring enhanced photoperiod and flowering traits. Genetic variants in the florigen pathway can provide both environmental flexibility and improved yields. SNPs associated with length of growing season and tolerance to abiotic stresses (precipitation, high temperature) are valuable resources for accelerating breeding for drought-prone environments. Both genomic selection and genome editing can also harness allelic diversity and increase productivity by improving multiple traits, including phenology, plant architecture, yield potential and adaptation to abiotic stresses. Discovering rare alleles and useful haplotypes also provides opportunities to enhance abiotic stress adaptation, while epigenetic variation has potential to enhance abiotic stress adaptation and productivity in crops. By reviewing current knowledge on specific traits and their genetic basis, we highlight recent developments in the understanding of crop functional diversity and identify potential candidate genes for future use. The storage and integration of genetic, genomic and phenotypic information will play an important role in ensuring broad and rapid application of novel genetic discoveries by the plant breeding community. Exploiting alleles for yield-related traits would allow improvement of selection efficiency and overall genetic gain of multigenic traits. An integrated approach involving multiple stakeholders specializing in management and utilization of genetic resources, crop breeding, molecular biology and genomics, agronomy, stress tolerance, and reproductive/seed biology will help to address the global challenge of ensuring food security in the face of growing resource demands and climate change induced stresses. PMID- 28900438 TI - Chloroplasts Isolation from Chlamydomonas reinhardtii under Nitrogen Stress. AB - Triacylglycerols are produced in abundance through chloroplast and endoplasmic reticulum pathways in some microalgae exposed to stress, though the relative contribution of either pathway remains elusive. Characterization of these pathways requires isolation of the organelles. In this study, an efficient and reproducible approach, including homogenous batch cultures of nitrogen-deprived algal cells in photobioreactors, gentle cell disruption using a simple custom made disruptor with mechanical shear force, optimized differential centrifugation and Percoll density gradient centrifugation, was developed to isolate chloroplasts from Chlamydomonas reinhardtii subjected to nitrogen stress. Using this approach, the maximum limited stress duration was 4 h and the stressed cells exhibited 19 and 32% decreases in intracellular chlorophyll and nitrogen content, respectively. Chloroplasts with 48 - 300 MUg chlorophyll were successfully isolated from stressed cells containing 10 mg chlorophyll. These stressed chloroplasts appeared intact, as monitored by ultrastructure observation and a novel quality control method involving the fatty acid biomarkers. This approach can provide sufficient quantities of intact stressed chloroplasts for subcellular biochemical studies in microalgae. PMID- 28900439 TI - A Comparative Study of Sample Preparation for Staining and Immunodetection of Plant Cell Walls by Light Microscopy. AB - Staining and immunodetection by light microscopy are methods widely used to investigate plant cell walls. The two techniques have been crucial to study the cell wall architecture in planta, its deconstruction by chemicals or cell wall degrading enzymes. They have been instrumental in detecting the presence of cell types, in deciphering plant cell wall evolution and in characterizing plant mutants and transformants. The success of immunolabeling relies on how plant materials are embedded and sectioned. Agarose coating, wax and resin embedding are, respectively, associated with vibratome, microtome and ultramicrotome sectioning. Here, we have systematically carried out a comparative analysis of these three methods of sample preparation when they are applied for cell wall staining and cell wall immunomicroscopy. In order to help the plant community in understanding and selecting adequate methods of embedding and sectioning for cell wall immunodetection, we review in this article the advantages and limitations of these three methods. Moreover, we offer detailed protocols of embedding for studying plant materials through microscopy. PMID- 28900440 TI - Chlorophyll Fluorescence Imaging Uncovers Photosynthetic Fingerprint of Citrus Huanglongbing. AB - Huanglongbing (HLB) is one of the most destructive diseases of citrus, which has posed a serious threat to the global citrus production. This research was aimed to explore the use of chlorophyll fluorescence imaging combined with feature selection to characterize and detect the HLB disease. Chlorophyll fluorescence images of citrus leaf samples were measured by an in-house chlorophyll fluorescence imaging system. The commonly used chlorophyll fluorescence parameters provided the first screening of HLB disease. To further explore the photosynthetic fingerprint of HLB infected leaves, three feature selection methods combined with the supervised classifiers were employed to identify the unique fluorescence signature of HLB and perform the three-class classification (i.e., healthy, HLB infected, and nutrient deficient leaves). Unlike the commonly used fluorescence parameters, this novel data-driven approach by using the combination of the mean fluorescence parameters and image features gave the best classification performance with the accuracy of 97%, and presented a better interpretation for the spatial heterogeneity of photochemical and non photochemical components in HLB infected citrus leaves. These results imply the potential of the proposed approach for the citrus HLB disease diagnosis, and also provide a valuable insight for the photosynthetic response to the HLB disease. PMID- 28900441 TI - Bacillus amyloliquefaciens Confers Tolerance to Various Abiotic Stresses and Modulates Plant Response to Phytohormones through Osmoprotection and Gene Expression Regulation in Rice. AB - Being sessile in nature, plants have to withstand various adverse environmental stress conditions including both biotic and abiotic stresses. Comparatively, abiotic stresses such as drought, salinity, high temperature, and cold pose major threat to agriculture by negatively impacting plant growth and yield worldwide. Rice is one of the most widely consumed staple cereals across the globe, the production and productivity of which is also severely affected by different abiotic stresses. Therefore, several crop improvement programs are directed toward developing stress tolerant rice cultivars either through marker assisted breeding or transgenic technology. Alternatively, some known rhizospheric competent bacteria are also known to improve plant growth during abiotic stresses. A plant growth promoting rhizobacteria (PGPR), Bacillus amyloliquefaciens NBRI-SN13 (SN13) was previously reported by our lab to confer salt stress tolerance to rice seedlings. However, the present study investigates the role of SN13 in ameliorating various abiotic stresses such as salt, drought, desiccation, heat, cold, and freezing on a popular rice cv. Saryu-52 under hydroponic growth conditions. Apart from this, seedlings were also exogenously supplied with abscisic acid (ABA), salicylic acid (SA), jasmonic acid (JA) and ethephon (ET) to study the role of SN13 in phytohormone-induced stress tolerance as well as its role in abiotic and biotic stress cross-talk. All abiotic stresses and phytohormone treatments significantly affected various physiological and biochemical parameters like membrane integrity and osmolyte accumulation. SN13 also positively modulated stress-responsive gene expressions under various abiotic stresses and phytohormone treatments suggesting its multifaceted role in cross-talk among stresses and phytohormones in response to PGPR. To the best of our knowledge, this is the first report on detailed analysis of plant growth promotion and stress alleviation by a PGPR in rice seedlings subjected to various abiotic stresses and phytohormone treatments for 0, 1, 3, 10, and 24 h. PMID- 28900443 TI - HSV-1 Encephalitis: High Index of Clinical Suspicion, Prompt Diagnosis, and Early Therapeutic Intervention Are the Triptych of Success-Report of Two Cases and Comprehensive Review of the Literature. AB - Herpes Simplex Virus (HSV) encephalitis is an acute infectious disease of the Central Nervous System (CNS), usually affecting the limbic structures, the median temporal cortex, and the orbitofrontal regions. Its annual incidence has significantly increased over the last 20 years and the mortality rate is 7%, if early diagnosed and treated, and 70%, if left untreated, while it is associated with high rates of morbidity. It should be noted that even when Cerebrospinal fluid (CSF) analysis seems normal, imaging studies are not specific and HSV Polymerase Chain Reaction (PCR) test is negative; the clinician should be more aggressive, if clinical presentation is indicative for HSV encephalitis, by administrating acyclovir early after patient's admission. The latter may be a vital intervention for the patient, modifying the patient's clinical course. Through the presentation of two cases of HSV-1 encephalitis that we managed in our department over the last 1 year and after systematic and comprehensive research of the relevant literature, we aim at showing the crucial role of medical history and physical examination, along with the high index of clinical suspicion, in order to make promptly the diagnosis and administer timely intravenous acyclovir, limiting the possibility of complications during the disease's course. PMID- 28900442 TI - Impact of Preoperative Three-Dimensional Computed Tomography Cholangiography on Postoperative Resection Margin Status in Patients Operated due to Hilar Cholangiocarcinoma. AB - INTRODUCTION: The purpose of this study was to analyse the value of 3-dimensional computed tomography cholangiography (3D-ERC) compared to conventional retrograde cholangiography in the preoperative diagnosis of hilar cholangiocarcinoma (HC) with special regard to the resection margin status (R0/R1). PATIENTS AND METHODS: All hepatic resections performed between January 2011 and November 2013 in patients with HC at the Department of General, Visceral and Transplant Surgery of the RWTH Aachen University Hospital were analysed. All patients underwent an ERC and contrast-enhanced multiphase CT scan or a 3D-ERC. RESULTS: The patient collective was divided into two groups (group ERC: n = 17 and group 3D-ERC: n = 16). There were no statistically significant differences between the two groups with regard to patient characteristics or intraoperative data. Curative liver resection with R0 status was reached in 88% of patients in group ERC and 87% of patients in group 3D-ERC (p = 1.00). We could not observe any differences with regard to postoperative complications, hospital stay, and mortality rate between both groups. CONCLUSION: Based on our findings, preoperative imaging with 3D-ERC has no benefit for operative planning and R0 resection status. It cannot replace the exploration by an experienced surgeon in a centre for hepatobiliary surgery. PMID- 28900444 TI - More Than a Decade of Misdiagnosis of Alternating Hemiplegia of Childhood with Catastrophic Outcome. AB - Alternating hemiplegia of childhood (AHC) is a distinct clinical disorder characterized by recurrent episodes of hemiplegia, abnormal ocular movement, and progressive developmental delay. It is an extremely rare genetic disorder related to ATP1A3 gene mutations. In this paper, we present a case of AHC in which the diagnosis was missed for many years until severe hypoxic brain insult occurred from prolonged status epilepticus. Not only we are presenting an interesting clinical entity and radiological images, but also we are shedding the light on a rare genetic disease with catastrophic sequelae. The challenges in diagnosis and treatment lead to a poor outcome as seen in our case. Although early recognition and accurate diagnosis and treatment of the disease may not change the outcome, counseling of the family may change their expectation and reduce their frustration. Referral to a center with expertise in genetic disorders and access to genetic laboratories is of paramount importance in the diagnosis of this disease. Due to the rarity of this disease in Saudi Arabia, a genotype-phenotype correlation is not feasible. PMID- 28900445 TI - Anaphylactoid Purpura Associated with Streptococcal Cellulitis: A Case Report and Literature Review. AB - A 54-year-old Japanese man noticed painful swelling and redness of his left leg. He was admitted for treatment of cellulitis, which was accompanied with increased anti-streptolysin O and anti-streptokinase titers in his clinical course. After Piperacillin/Tazobactam administration, the skin lesion resolved. However, the patient then developed arthritis, palpable purpura, and intermittent abdominal pain, later found to be secondary to a severe duodenal ulcer. He was diagnosed with cellulitis-associated anaphylactoid purpura and was given prednisolone, which dramatically improved his symptoms. The anaphylactoid purpura was likely caused by Streptococcus-induced cellulitis, which was successfully treated with prednisolone. Association between these diseases is rare. PMID- 28900447 TI - Disinfection Byproducts in Drinking Water and Evaluation of Potential Health Risks of Long-Term Exposure in Nigeria. AB - Levels of trihalomethanes (THMs) in drinking water from water treatment plants (WTPs) in Nigeria were studied using a gas chromatograph (GC Agilent 7890A with autosampler Agilent 7683B) equipped with electron capture detector (ECD). The mean concentrations of the trihalomethanes ranged from zero in raw water samples to 950 MUg/L in treated water samples. Average concentration values of THMs in primary and secondary disinfection samples exceeded the standard maximum contaminant levels. Results for the average THMs concentrations followed the order TCM > BDCM > DBCM > TBM. EPA-developed models were adopted for the estimation of chronic daily intakes (CDI) and excess cancer incidence through ingestion pathway. Higher average intake was observed in adults (4.52 * 10-2 mg/kg-day), while the ingestion in children (3.99 * 10-2 mg/kg-day) showed comparable values. The total lifetime cancer incidence rate was relatively higher in adults than children with median values 244 and 199 times the negligible risk level. PMID- 28900448 TI - Scolicidal agents for protoscolices of Echinococcus granulosus hydatid cyst: Review of literature. AB - Hydatid cyst is the larval stage of dog tape worm Echinococcus granulosus. Protoscolices are parasite larvae that develop into adult worms in the final host intestine. During surgical treatment of human hydatidsosis spillage of live protoscolices is the major cause of hydatidosis recurrence. To prevent this problem scolicidal agent such as hypertonic salt are used to kill the protoscolices that may disseminate into the patient's tissues during surgery. However, they may have some unacceptable side effects. To find scolicidal agents with high efficacy, the effect of different compounds on protoscolices of hydatid cyst in vitro has been reviewed. Using PubMed, Scopus, Google Scholar, and SID databases articles about scolicidal effects of different agents on protoscolices of hydatid cyst in vitro were collected. Foeniculum vulgare after 5 min, metalonic extracts of Allium sativum and hypertonic saline after 10 min, and warm water after 2 min kill all alive protoscolices. The above agents that in minimum time and minimum concentration have 100% scolicidal activity, could be good candidates for further investigations. PMID- 28900449 TI - The aware, alert, avert strategy for immune reconstitution inflammatory syndrome in HIV/AIDS. PMID- 28900446 TI - Endothelial Progenitor Cells for Ischemic Stroke: Update on Basic Research and Application. AB - Ischemic stroke is one of the leading causes of human death and disability worldwide. So far, ultra-early thrombolytic therapy is the most effective treatment. However, most patients still live with varying degrees of neurological dysfunction due to its narrow therapeutic time window. It has been confirmed in many studies that endothelial progenitor cells (EPCs), as a kind of adult stem cells, can protect the neurovascular unit by repairing the vascular endothelium and its secretory function, which contribute to the recovery of neurological function after an ischemic stroke. This paper reviews the basic researches and clinical trials of EPCs especially in the field of ischemic stroke and addresses the combination of EPC application with new technologies, including neurovascular intervention, synthetic particles, cytokines, and EPC modification, with the aim of shedding some light on the application of EPCs in treating ischemic stroke in the future. PMID- 28900450 TI - The convergence of considerations in aluminum phosphide poisoning: The occurrence of injuries beyond the metabolic manifestations. PMID- 28900451 TI - Procalcitonin levels and other biochemical parameters in patients with or without diabetic foot complications. AB - BACKGROUND: Diagnosis of infection in diabetic foot ulcer (DFU) is not always simple. The analytic precision of procalcitonin (PCT) was evaluated to clarify the use of PCT for distinguish the presence of infection in DFU in comparison to other inflammatory markers. MATERIALS AND METHODS: This study comprised 88 subjects distributed into four groups: 16 nondiabetic healthy subjects (group control), 17 patients with type 2 diabetes mellitus without foot Complication (group DM), 25 patients with noninfected diabetic foot (group NIDF), and 30 patients with infected diabetic foot (group IDF). Fasting blood samples were taken for measurement of glucose, hemoglobin A1C, lipid profile, renal function, erythrocyte sedimentation rate (ESR), and white blood cell (WBC) and its derivatives. Plasma PCT was determined using an enzyme-linked immunosorbent assay. RESULTS: PCT, WBC, ESR, and neutrophils (NEU) were found significantly higher in IDF group than other groups. The receiver operating characteristic analysis showed that sensitivity, specificity, the best cutoff value, and the area under the curve were for ESR (100%, 93%, 31.5 mm/h, 1; P < 0.001), for PCT (87.5%, 86.7%, 66.55 pg/dl, 0.977; P < 0.001), for NEU (93.8%, 93.3%, 5.35, 0.957; P < 0.001) and for WBC (93.8%, 90%, 9.29 * 109/L, 0.942; P < 0.001), respectively. CONCLUSION: The outcomes of this study recommend that PCT can be an asymptomatic marker in the diagnosis of infection in DFU with higher Wagner grades in combination with different inflammatory markers. PMID- 28900453 TI - Periprocedural anticoagulation in transcatheter aortic valve replacement: Heparin vs bivalirudin. PMID- 28900452 TI - Postpartum home care and its effects on mothers' health: A clinical trial. AB - BACKGROUND: Postpartum home care plays an important role in prevention of postpartum complications. Regular visits of mothers during this period are imperative. This study aimed to provide postpartum home care for mothers to assess its effects on mothers' health in Iran. MATERIALS AND METHODS: This study was carried out in two phases. First, a comprehensive postpartum home care program was compiled by performing a comparative study, using the available guidelines in this regard in different countries and based on the opinions of the experts. Next, a clinical trial was carried out on 276 women who gave birth in the university hospitals affiliated to Shahid Beheshti University of Medical Sciences. There were 92 mothers in the intervention and 184 in the control group. The intervention group mothers were provided with postpartum home care service while the control group did not receive such a service. RESULTS: Outcome assessment at 60 days' postpartum revealed a significant difference between the two groups in terms of the use of supplements, birth control methods, postpartum depression, breastfeeding problems, constipation, and fatigue (P < 0.05). No significant differences were noted between the two groups with regard to hospitalization, hemorrhoids, backache and lumbar pain (P > 0.05). CONCLUSION: The postpartum home care program had a positive effect on some aspects of the mothers' health status and their satisfaction in our society. PMID- 28900454 TI - The effect of alpha-lipoic acid supplementation on anthropometric indices and food intake in patients who experienced stroke: A randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: Stroke as a devastating condition is a major cause of death worldwide. It is accountable for long-term disability with high personal and social cost in adults. Alpha-lipoic acid (ALA) is an eight-carbon, sulfur containing compound with antioxidant properties which reduces body weight, changes other anthropometric indices, and regulates food intake by suppressing appetite and increasing metabolism This study was designed to evaluate the possible effects of ALA supplementation on anthropometric indices and dietary intake in patients with stroke. MATERIALS AND METHODS: In this randomized, double blind, placebo-controlled clinical trial, 67 patients with stroke were randomly allocated to two groups (taking a 600 mg ALA supplement or placebo daily for 12 weeks). Weight, waist circumference, energy, carbohydrate, protein, and fat intake were measured, and body mass index (BMI) was calculated before and after intervention. Dietary intake and statistical analyses were carried out using Nutritionist IV and SPSS (version 16; SPSS Inc., Chicago, IL, USA) software, respectively. RESULTS: Primary features were similar in the intervention and placebo groups (P > 0.05). Waist circumference (P < 0.001), energy, carbohydrate, protein, and fat intake (P < 0.001) decreased significantly, after the intervention period, in ALA group compared with placebo. While no significant change was observed in weight (P = 0.26) and BMI (P = 0.56) in ALA supplementation group compared with placebo. CONCLUSION: Results of this trial indicated that 12-week supplementation with 600 mg ALA can decrease waist circumference and food intake (energy, carbohydrate, protein, and fat) in patients with stroke. PMID- 28900455 TI - Diverse pattern of gap junction beta-2 and gap junction beta-4 genes mutations and lack of contribution of DFNB21, DFNB24, DFNB29, and DFNB42 loci in autosomal recessive nonsyndromic hearing loss patients in Hormozgan, Iran. AB - BACKGROUND: We aimed to determine the contribution of four DFNB loci and mutation analysis of gap junction beta-2 (GJB2) and GJB4 genes in autosomal recessive nonsyndromic hearing loss (ARNSHL) in South of Iran. MATERIALS AND METHODS: A total of 36 large ARNSHL pedigrees with at least two affected subjects were enrolled in the current study. The GJB2 and GJB4 genes mutations were screened using direct sequencing method. The GJB2 and GJB4 negative families were analyzed for the linkage to DFNB21, DFNB24, DFNB29, and DFNB42 loci by genotyping the corresponding STR markers using polymerase chain reaction-PAGE method. RESULTS: We found a homozygous nonsense mutation W77X and a homozygous missense mutation C169W in 5.55% of studied families in GJB2 and GJB4 genes, respectively. Five heterozygous mutations including V63G, A78T, and R127H in GJB2 gene, and R103C and R227W in GJB4 gene were detected. We identified two novel variations V63G in GJB2 and R227W in GJB4. In silico analysis predicted that both novel variations are deleterious mutations. We did not unveil any linkage between DFNB21, DFNB24, DFNB29, and DFNB42 loci and ARNSHL among studied families. CONCLUSION: This is the first report of GJB2 and GJB4 mutations from Hormozgan population. According to the previous publications regarding GJB2 and GJB4 mutations, the distribution of the mutations is different from other parts of Iran that should be considered in primary health-care programs. Further investigations are needed to evaluate the contribution of other loci in ARNSHL subjects in South of Iran. PMID- 28900456 TI - Identification a novel mononucleotide deletion mutation in GAA in pompe disease patients. AB - BACKGROUND: Mutations in the acid alpha-glucosidase (GAA) gene usually lead to reduced GAA activity. In this study, we analyzed the mutations of GAA and GAA enzyme activity from one sibling suspected Pompe disease and their first-degree relatives. MATERIALS AND METHODS: In this cross-sectional study, GAA enzyme activity assay was assessed using tandem mass spectrometry. Polymerase chain reaction and Sanger sequencing were performed for GAA analysis. RESULTS: GAA enzyme activity was significantly decreased in patients compared to the normal range (P = 0.02). Two individuals showed ten alterations in the GAA sequence, in which one of them (c. 1650del G) has not been previously described in the literature. A single Guanine deletion (del-G) was detected at codon 551 in exon 12. CONCLUSION: According to the literature, the detected change is a novel mutation. We hypothesized that the discovered deletion in the GAA might lead to a reduced activity of the gene product. PMID- 28900457 TI - Comprehensibility of selected United States Pharmacopeia pictograms by illiterate and literate Farsi speakers: The first experience in Iran - Part II. AB - BACKGROUND: Conveying information to patients on how to use medications at the dispensing sessions and retention of this information by the patients is essential to the good pharmaceutical care. The aim of our study was to examine the comprehensibility of the selected three potentially usable pictograms by five groups of subjects who had different levels of literacy in both before and after mini educational sessions. MATERIALS AND METHODS: Nine experienced pharmacists selected three potentially usable pictograms in Isfahan pharmacies: Pictograms D through F representing respectively: "do not take medication during pregnancy," "keep medication in the refrigerator," and "take medication with plenty of water." Then, graduate students of two major universities (Groups 1 and 2), low literate and illiterate individuals (Groups 3 and 4), and walk - in patients in the pharmacies affiliated to the Isfahan School of Pharmacy (Group 5) were asked about the comprehensibility of these pictograms before and after mini-education sessions. The American National Standard Institute and International Organization for Standardization standards were used for comparisons. RESULTS: In the pre follow-up period, D and E pictograms were most understandable (87.4%, 87.2%). In the post-follow-up, E and D pictograms were understood most (98.0%, 95.3%), followed by F (92.9%). Among the improvements measured in post-follow-up, pictogram F showed the biggest improvement (P = 0.0). CONCLUSION: Pictograms depicting the use of medications during pregnancy (D) and storing medication in the refrigerator (E) was easier to understand by our study population. The groups with the high level of literacy interpreted the pictograms better than those with lower levels of literacy. PMID- 28900458 TI - Effects of Angelica dahurica and Rheum officinale Extracts on Excisional Wound Healing in Rats. AB - The main objective of wound treatments is to restore the functional skin properties and prevent infection. Traditional Chinese medicine provides alternative anti-inflammatory, antimicrobial, and wound healing therapies. Both Angelica dahurica extract (AE) and Rheum officinale extract (RE) possess antimicrobial activity. In this study, AE and RE were applied in wound treatment to investigate their healing effects. Thirty Sprague-Dawley rats with dorsal full thickness skin excision were divided into normal saline (NS), AE, RE, AE plus RE (ARE), and Biomycin (BM) groups. The treatment and area measurement of wounds were applied daily for 21 days. Wound biopsies and blood samples were obtained for histology examinations and cytokine analysis. Results showed that wound contraction in ARE group was significantly higher than that in NS and BM groups (P < 0.05). Histological analysis showed that more inflammatory cell infiltration, collagen fibers, and myofibroblasts were observed in ARE treated group than those in NS group on days 3-5. In ARE group, plasma IL-6 levels were elevated during days 3-5 (P > 0.05), and plasma TGF-beta1 levels were significantly lower than those in the NS group on days 3-4 (P < 0.05). In conclusion, ARE accelerates wound healing during inflammation and proliferation phases. PMID- 28900459 TI - Protective Effects of Bogijetong Decoction and Its Selected Formula on Neuropathic Insults in Streptozotocin-Induced Diabetic Animals. AB - Bogijetong decoction (BGJTD) is a mixture of herbal formulation which is used in the traditional Korean medicine for the treatment of neuropathic pain caused by diabetes. Here, we investigated the regulatory effects of BGJTD and its reconstituted decoction subgroups on the neuropathic responses in streptozotocin- (STZ-) induced diabetic animals. Be decoction (BeD) was formulated by selecting individual herbal components that induced neurite outgrowth most efficiently in each subgroup. BeD induced the neurite outgrowth in DRG neurons most efficiently among decoction subgroups and downregulated the production of TNF-alpha from the sciatic nerves in STZ-diabetic animals. While the levels of phospho-Erk1/2 were elevated in the sciatic nerves of STZ-diabetic animals by BGJTD and BeD treatments, p38 level was downregulated by BGJTD and BeD. A single herbal component of BeD induced neurite outgrowth comparable to BeD and was involved in the regulation of Erk1/2 activation and TNF-alpha production in DRG neurons. Oral administration of BGJTD and BeD in STZ-diabetic animals reduced the latency time responding to thermal stimulation. Our results suggest that the reconstituted formulation is as effective as conventional BGJTD in inducing biochemical and behavioral recoveries from the neuropathy in peripheral nerves and thus the experimental reductionism may be applied to develop the methodology for compositional analysis of herbal decoctions. PMID- 28900460 TI - Manual Acupuncture at PC6 Ameliorates Acute Restraint Stress-Induced Anxiety in Rats by Normalizing Amygdaloid Noradrenergic Response. AB - Acupuncture improves ethanol withdrawal-induced anxiety in rats in an acupoint dependent manner. Thus, the present study investigated the effects of acupuncture on acute restraint stress- (ARS-) induced anxiety. Male rats were exposed to ARS for 3 h followed by acupuncture at either PC6 (Neiguan), HT7 (Shenmen), or a nonacupoint (tail) once a day for three consecutive days. Five minutes after the third acupuncture treatment, anxiety-like behavior was evaluated in an elevated plus maze (EPM). Additionally, plasma corticosterone (CORT) levels were measured by radioimmunoassay and the concentrations of norepinephrine (NE) and 3-methoxy-4 hydroxy-phenylglycol (MHPG) in the central nucleus of the amygdala (CeA) were determined using high-performance liquid chromatography. Acupuncture at PC6, but not HT7 or a nonacupoint, attenuated anxiety-like behavior, but this attenuation was abolished by a postacupunctural intra-CeA infusion of NE. Acupuncture at PC6 also reduced the oversecretion of plasma CORT and inhibited increases in amygdaloid NE and MHPG induced by ARS. Further, Western blot analyses and real time polymerase chain reaction assays revealed that acupuncture at PC6 prevented ARS-induced enhancements in the protein and mRNA expressions of tyrosine hydroxylase in the CeA. These results suggest that acupuncture performed specifically at acupoint PC6 reduces ARS-induced anxiety-like behavior by dampening amygdaloid noradrenergic responses. PMID- 28900461 TI - Effects of Wannachawee Recipe with Antipsoriatic Activity on Suppressing Inflammatory Cytokine Production in HaCaT Human Keratinocytes. AB - Psoriasis is a chronic inflammatory and immune-mediated skin disease. The pathogenesis involves T cells activation via the IL-23/Th17 axis. Conventional treatments of psoriasis have adverse events influencing patients' adherence. Wannachawee Recipe (WCR) has been effectively used as Thai folk remedy for psoriasis patients; however, preclinical evidence defining how WCR works is still lacking. This study defined mechanisms for its antiproliferation and anti inflammatory effects in HaCaT cells. The cytotoxicity and antiproliferation results from SRB and CCK-8 assays showed that WCR inhibited the growth and viability of HaCaT cells in a concentration-dependent manner. The distribution of cell cycle phases determined by flow cytometry showed that WCR did not interrupt cell cycle progression. Interestingly, RT-qPCR revealed that WCR significantly decreased the mRNA expression of IL-1beta, IL-6, IL-8, IL-17A, IL-22, IL-23, and TNF-alpha but induced IL-10 expression in TNF-alpha- and IFN-gamma-induced HaCaT cells. At the protein level determined by ELISA, WCR significantly reduced the secretion of IL-17A, IL-22, and IL-23. The WCR at low concentrations was proved to possess anti-inflammatory effect without cytotoxicity and it did not interfere with cell cycle of keratinocytes. This is the first study to provide convincing evidence that WCR is a potential candidate for development of effective psoriasis therapies. PMID- 28900462 TI - Comparison of the Therapeutic Effects of Acupuncture at PC6 and ST36 for Chronic Myocardial Ischemia. AB - We aimed to compare the differences of the effects on chronic myocardial ischemia (MI) of acupuncture at PC6 and ST36. The chronic MI model of minipigs was created by implanting an Ameroid constrictor on the left anterior descending coronary artery (LAD) and then two weeks' acupuncture was stimulated at PC6 or ST36, respectively. The results showed that both acupoints' stimulation decreased the serous cardiac troponin T (cTnT) and ischemia modified albumin (IMA) significantly and improved the ischemic ECG changes. The amplitude of pathological Q wave in the PC6 group decreased more significantly than that of the ST36 group. The cardiovascular magnetic resonance imaging (cMRI) results showed that the decreased left ventricular ejection fraction (LVEF) was not improved obviously in both groups. The left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) enlarged progressively even after acupuncture. The left ventricular wall mass (LVWM) in the ST36 group increased more obviously than that of the PC6 group, which paralleled the decreasing angiotensin II (Ang II) concentration in the plasma. These results suggested that acupuncture at PC6 or ST36 was effective for protecting the myocardium from chronic ischemic injury, and the effect of PC6 seemed to be better. PMID- 28900463 TI - Researches on Transcriptome Sequencing in the Study of Traditional Chinese Medicine. AB - Due to its incomparable advantages, the application of transcriptome sequencing in the study of traditional Chinese medicine attracts more and more attention of researchers, which greatly promote the development of traditional Chinese medicine. In this paper, the applications of transcriptome sequencing in traditional Chinese medicine were summarized by reviewing recent related papers. PMID- 28900465 TI - Cytologic features of tubular adenoma of ampulla causing distal common bile duct stricture: A case report and review of the literature. AB - Adenomas of the ampulla of Vater are distinctly rare, representing <10% of periampullary neoplasms. Very few reports of the cytologic features of ampullary adenomas are present in literature, particularly in bile duct brushing samples. A case report and review of the literature is presented. The typical cytologic features of ampullary adenomas on cytologic preparations include tall, thin columnar cells with mildly hyperchromatic elongated nuclei and nuclear pseudostratification, in a relatively clean background. The key differential diagnostic entities include invasive adenocarcinoma, thermal artifact, and reactive atypia. PMID- 28900464 TI - Synergistic Antioxidant and Anti-Inflammatory Effects between Modified Citrus Pectin and Honokiol. AB - Inflammation is a normal physiological process; however, dysregulation of this process may contribute to inflammatory-based chronic disorders and diseases in animals and humans. Therefore, the antioxidant and anti-inflammatory properties of natural products, often recognized in traditional medicine systems, represent therapeutic modalities to reduce or prevent uncontrolled inflammatory processes which in turn potentially ameliorate or prevent sequelae of inflammatory-based symptoms of chronic diseases. We have investigated the antioxidant and anti inflammatory effects of honokiol (HNK) and modified citrus pectin (MCP) in vitro and examined whether the MCP : HNK combination has synergistic effects on antioxidant and anti-inflammatory properties. Although both HNK and MCP induced a dose-dependent increase in antioxidant activity, the latter has a consistently higher antioxidant effect. The MCP : HNK (9 : 1) combination induced a synergistic effect on antioxidant activity suggesting that the combination is significantly more efficacious than individual compounds. In mouse monocytes, the lipopolysaccharide- (LPS-) induced tumor necrosis-alpha (TNF-alpha) synthesis was significantly inhibited by HNK and the MCP : HNK combination in a dose-dependent manner and synergistic effects were clearly demonstrated with the combination on TNF-alpha inhibition. This combination effect was also evident on inhibition of nuclear factor-kappa B activity, cyclooxygenase-II activity, and lipid peroxidation in mouse monocytes. Further research into the combination is warranted. PMID- 28900466 TI - Can an inadequate cervical cytology sample in ThinPrep be converted to a satisfactory sample by processing it with a SurePath preparation? AB - BACKGROUND: The Norwegian Cervical Cancer Screening Program recommends screening every 3 years for women between 25 and 69 years of age. There is a large difference in the percentage of unsatisfactory samples between laboratories that use different brands of liquid-based cytology. We wished to examine if inadequate ThinPrep samples could be satisfactory by processing them with the SurePath protocol. MATERIALS AND METHODS: A total of 187 inadequate ThinPrep specimens from the Department of Clinical Pathology at University Hospital of North Norway were sent to Akershus University Hospital for conversion to SurePath medium. Ninety-one (48.7%) were processed through the automated "gynecologic" application for cervix cytology samples, and 96 (51.3%) were processed with the "nongynecological" automatic program. RESULTS: Out of 187 samples that had been unsatisfactory by ThinPrep, 93 (49.7%) were satisfactory after being converted to SurePath. The rate of satisfactory cytology was 36.6% and 62.5% for samples run through the "gynecology" program and "nongynecology" program, respectively. Of the 93 samples that became satisfactory after conversion from ThinPrep to SurePath, 80 (86.0%) were screened as normal while 13 samples (14.0%) were given an abnormal diagnosis, which included 5 atypical squamous cells of undetermined significance, 5 low-grade squamous intraepithelial lesion, 2 atypical glandular cells not otherwise specified, and 1 atypical squamous cells cannot exclude high grade squamous intraepithelial lesion. A total of 2.1% (4/187) of the women got a diagnosis of cervical intraepithelial neoplasia 2 or higher at a later follow-up. CONCLUSIONS: Converting cytology samples from ThinPrep to SurePath processing can reduce the number of unsatisfactory samples. The samples should be run through the "nongynecology" program to ensure an adequate number of cells. PMID- 28900467 TI - Products of Compartmental Models in Epidemiology. AB - We show that many structured epidemic models may be described using a straightforward product structure in this paper. Such products, derived from products of directed graphs, may represent useful refinements including geographic and demographic structure, age structure, gender, risk groups, or immunity status. Extension to multistrain dynamics, that is, pathogen heterogeneity, is also shown to be feasible in this framework. Systematic use of such products may aid in model development and exploration, can yield insight, and could form the basis of a systematic approach to numerical structural sensitivity analysis. PMID- 28900469 TI - Necrotic ulcerated and bleeding striae distensae following bevacizumab in a palliative setting for gliobastomatosis cerebri. AB - Glioblastoma cerebri is a rare paediatric malignancy with dismal prognosis [Chappe C, Riffaud L, and Treguier C et al (2013) Primary gliomatosis cerebri involving gray matter in pediatrics: a distinct entity? A multicenter study of 14 casesChilds Nerv Syst29 565-571 https://doi.org/10.1007/s00381-012-2016-1 PMID: 23306961] and no established standard of care. Here, we report a case of ulcerated and bleeding striae distensae in a teenage girl following palliative treatment with bevacizumab and steroids. PMID- 28900468 TI - Cancer of childhood in sub-Saharan Africa. AB - Measurement of incidence rates of childhood cancer in Africa is difficult. The study 'Cancer of Childhood in sub Saharan Africa' brings together results from 16 population-based registries which, as members of the African Cancer Registry Network (AFCRN), have been evaluated as achieving adequate coverage of their target population. The cancers are classified according to the third revision of the International Classification of Childhood Cancer (ICCC-3) and recorded rates in Africa are compared with those in childhood populations in the UK, France, and the USA. It is clear that, in many centres, lack of adequate diagnostic and treatment facilities leads to under-diagnosis (and enumeration) of leukaemias and brain cancers. However, for several childhood cancers, incidence rates in Africa are higher than those in high-income countries. This applies to infection-related cancers such as Kaposi sarcoma, Burkitt lymphoma, Hodgkin lymphoma and hepatocellular carcinoma, and also to two common embryonal cancers - retinoblastoma and nephroblastoma. These (and other) observations are unlikely to be artefact, and are of considerable interest when considering possible aetiological factors, including ethnic differences in risk (and hence genetic/familial antecedents). The data reported are the most extensive so far available on the incidence of cancer in sub Saharan Africa, and clearly indicate the need for more resources to be devoted to cancer registration, especially in the childhood age range, as part of an overall programme to improve the availability of diagnosis and treatment of this group of cancers, many of which have-potentially-an excellent prognosis. PMID- 28900470 TI - Mutational frequency of KRAS, NRAS, IDH2, PIK3CA, and EGFR in North Indian gallbladder cancer patients. AB - BACKGROUND: Gallbladder cancer (GBC) has a peculiar geographical distinction, with a high prevalence seen in North India and Chile. There are various aetiopathogenetic mechanisms of GBC causation; one of them is a series of pathogenic mutations, which is responsible for the malignant transformation of gallbladder epithelium. Therefore, the present study aimed to find out cancer specific hot spot mutations in five major cancer-related genes KRAS exon1 &2, NRAS exon1, IDH2 exon, PIK3CA exon 20, IDH2 exon 4 and EGFR exon 20 in North Indian GBC patients and their association with clinicopathological variables. MATERIAL AND METHODS: This study included 34 histopathologically confirmed GBC cases. The clinical material consisted of formalin-fixed paraffin-embedded (FFPE) blocks of the patients. DNA isolation was done from FFPE tissue. DNA sequencing was performed by the capillary electrophoresis method. The chi-square (chi2) test was used to test for a statistically significant relationship between two categorical study variables. RESULTS: The overall incidence of somatic mutations in KRAS exon 1&2, NRAS exon1, IDH2 exon4, PIK3CA exon20, and EGFR exon 20 in Indian GBC patients was found in 8/34 (23.5%), 3/34 (8.8%), 4/34 (11.7%), 7/34 (20.6%), 7/34 (20.6%), respectively. KRAS exon 1 and two mutations were found to be significantly associated with advanced stage GBC patients. CONCLUSION: KRAS, PIK3CA, and EGFR were found to be the most frequently mutated genes among the five tested in this study. PMID- 28900471 TI - Metastasizing pleomorphic adenoma of the parotid gland. AB - Salivary gland tumours are estimated to represent approximately 3% of all head and neck tumours. About 70-80% of these neoplasms occur in the major salivary glands, with the parotid gland being the most commonly affected site. The metastasizing pleomorphic adenoma (MPA) has histological characteristics of pleomorphic adenoma, but it has the capacity to generate local recurrences and distant metastases (mainly bones, lungs, and lymph nodes). Despite the fact that some authors consider it to be a benign neoplasia, the 2015 World Health Organisation (WHO) classification of head and neck tumours considers it to be malignant. We present a highly unusual case of metastasizing pleomorphic adenoma of the parotid gland and a bibliographic review. PMID- 28900472 TI - Predictive and prognostic impact of tumour-infiltrating lymphocytes in triple negative breast cancer treated with neoadjuvant chemotherapy. AB - INTRODUCTION: In locally and locally advanced triple-negative breast cancer (TNBC), neoadjuvant chemotherapy (NAC) only induces a pCR in 30-35% of patients. Clinical and pathological factors are not enough to distinguish the patients who have no chance of a pCR or not. The tumour microenvironment is critical for cancer and tumour-infiltrating lymphocytes (TIL). Moreover, the NAC scenario is the perfect setting to study possible changes in TIL levels. MATERIAL AND METHODS: Using our prospective maintained breast cancer (BC) database, we identified 164 TNBC patients treated with NAC between 1998 and 2015 with enough samples of diagnostic biopsy and after surgery. Evaluation of TILs before and after NAC followed a standardised methodology for visual assessment on haematoxylin-eosin sections and the amounts of TILs were quantitated in deciles. We categorised lymphocyte-predominant breast cancer cutoff according to a receiver operating characteristic (ROC) analysis. We categorised LPBC as involving > 40% lymphocytic infiltration tumour stroma. The primary end point was predictive value of TILs to NAC, and the secondary end point was disease-free survival (DFS). DFS was analysed using the Kaplan-Meier method and the groups were compared with a long-rank test. Univariate and multivariate Cox models were used to generate hazard ratios for determining associations between variables such as TIL after NAC and DFS. RESULTS: A total of 164 TNBC patients were treated with NAC and surgery. The main patients' characteristics are listed in Table 1. We identify different pathological complete response to anthracycline and taxane based NAC; LPBC subgroup 51 from 58 patients (88%) pCR versus non- lymphocyte predominant breast cancer (LPBC) subgroup 10 from 106 (9%) pCR, p = 0.001. At a median follow-up of 78 months, LPBC was associated with better DFS; the three year Kaplan-Meier estimates for DFS were 2% and 30 % for patients with LPBC and non-LPBC, respectively, p = 0.01. Univariate and multivariate analysis confirmed TIL to be an independent prognostic marker of DFS. CONCLUSIONS: Tumour infiltrating lymphocytes could be routinely used in locally advanced TNBC treated with anthracycline and taxane, such as biomarker, to be enabled the identification of different two subgroups: LPBC patients have a very high response to NAC pCR 88%, meanwhile non-LPBC patients only achieve 9%. Moreover, non-LPBC patients have a worse prognosis than LPBC patients. This data verified the predictive and prognostic value of TIL. PMID- 28900473 TI - Resection of rectal GIST using a novel technique: a report of two cases. AB - Rectal gastrointestinal stromal tumours (GISTs) are uncommon tumours and usually present with large sizes. We present two cases of rectal GIST. Imatinib was used in the setting of neoadjuvant and adjuvant therapy. Both tumours were resected transanally by the transanal endoscopic operation (TEO) platform. Oncosurgeons are recommended to implement sphincter-sparing surgeries for these cases. PMID- 28900474 TI - Malignant extra-adrenal pelvic paraganglioma in a paediatric patient. AB - The extra-adrenal paraganglioma is a neoplasm originating in regional structures, uncommon in paediatrics. We report on a case of a 13-year-old patient who began with severe arterial hypertension, tachycardia, dilated cardiomyopathy and elevated levels of catecholamines in the blood and urine. The presence of a retrovesical pelvic mass in contact with the right vaginal dome was determined by imaging studies. A diagnosis of malignant extra-adrenal pelvic paraganglioma with lymph node metastases was reached through biopsy and the surgical resection of subsequent local recurrences. Paragangliomas are usually located in the paravertebral zones from the base of the skull to the retroperitoneum and are benign in 90% of cases. This kind of neoplasia is uncommon in paediatrics, especially those located in the pelvis. In cases of masses of a gynaecological origin, a differential diagnosis should be considered, and a histological and immunohistochemical study is essential in certifying the diagnosis. PMID- 28900475 TI - Serum biomarkers to predict risk of testicular and penile cancer in AMORIS. AB - PURPOSE: To evaluate the association between commonly measured serum biomarkers of inflammation and penile and testicular cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. MATERIALS AND METHODS: A total of 205,717 subjects had baseline measurements of C-reactive protein, albumin, and haptoglobin. The association between quartiles and dichotomised values of inflammatory markers and penile and testicular cancer risk were analysed by using multivariate Cox proportional hazard models. RESULTS: A total of 125 men were diagnosed with testicular cancer and 50 with penile cancer during a mean follow-up of 20.3 years. No statistically significant trends were seen between serum inflammatory markers and risk of penile cancer, but higher albumin levels increased the risk of testicular cancer [HR for albumin (g/L): 1.10 (95% CI: 1.03-1.18)]. However, this trend was not observed when using medical cut-offs of albumin. CONCLUSIONS: In the present study, we did not find support for an association between commonly used markers of inflammation and risk of testicular or penile cancer. The role of inflammation may be more complicated and require assessment of more specialised measurements of inflammation in future studies. PMID- 28900477 TI - Breast density and impacts on health. AB - The World Health Organization states 'Early detection in order to improve breast cancer outcome and survival remains the cornerstone of breast cancer control' [WHO (World Health Organization) (2017) Breast cancer: prevention and control Available from: http://www.who.int/cancer/detection/breastcancer/en/]. Breast Density Matters UK is a non-profit breast cancer organization. The organization's mission is to educate about breast density and its screening and risk implications with the goal of achieving the earliest stage diagnosis possible for women with dense breasts. This educational mission is endorsed by breast imaging experts worldwide [Berg WA (2015-2017) Dense Breast-info Inc Available from: http://densebreast-info.org/about.aspx]. PMID- 28900476 TI - Breast cancer in Angola, molecular subtypes: a first glance. AB - PURPOSE: The aim of this study was to investigate the breast cancer (BC) molecular subtypes according to its surrogate immunohistochemistry (IHC) markers. We conducted a preliminary study, to correlate the clinical pathological profiles and molecular subtypes of breast cancer in Luanda, Angola. METHODS: From January 2011 to 30 December 2014, 140 consecutive cases of microscopically confirmed invasive breast carcinoma were classified regarding histology and IHC (ER, PR, HER2, and Ki-67). Surrogate molecular subtypes were classified according to ESMO recommendations. RESULTS: All patients were female; the median age was 47 years (24-84 years). Invasive carcinoma NST was the most common type (91.4%) and grade 2 was prevalent (70.7%). Most tumours were locally advanced (stage III - 65% and stage IV - 3.6%). In 140 studied cases, 74 (52.8%) malignancies were hormone receptor positive; 25.7% were luminal A like, 19.3% luminal B and HER2 negative like, 7.9% luminal B and HER2-positive like, 15.7% HER2 positive, and 31.4% were triple negative. CONCLUSION: Women's BC in Luanda-Angola is diagnosed at a young age and at an advanced stage. The two predominant molecular subtypes are HR positive and triple negative. The percentage of HER2-positive BC cases was high. Determining the molecular subtype using surrogate IHC markers has important treatment and prognostic implications for Angolan women with BC. There is an urgent need to study a prospective BC series in order to confirm the present results. PMID- 28900478 TI - Esophageal Cancer in Israel has Unique Clinico-Pathological Features: A Retrospective Study. AB - Introduction: Data regarding esophageal cancer (EC) in Israel are limited. The aim of this study was hence to characterize this entity in the Israeli population and to compare it to the literature. Patients/Methods: This is a retrospective study of all consecutive EC patients treated at our institution between 1997 2013. Data were retrieved from patients' medical files. Results: Two hundred patients were included. The median age at diagnosis was 70.5 years; 63.5% were males; 63% were Ashkenazi Jews, 29% were Sephardic Jews, and 0.5% were Arabs. Squamous cell carcinoma (SCC) was predominant: 52% versus 45.5% with adenocarcinoma (ADC). SCC was common even in the distal esophagus (45%). The overall 5-year survival rate was 25.5%. A temporal trend (2006-2013 vs 1997-2005) shows a decline in the proportion of SCC (47% vs 63%, p=0.061) and a rise in ADC (50% vs 33%, p=0.041), with a parallel decrease in patients' age (median: 68.5 vs 73 years, p=0.014). In the later period, patients received more treatment for localized and metastatic disease, with a trend for improved median survival (20.1 vs 14.9 months, p=0.658). Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041). Conclusion: EC in Israel represents an intermediate entity between the Western and the endemic subtypes, showing some unique features. These included delayed reversal of the SCC/ADC ratio, commonness of SCC in the distal esophagus, prevalence of other malignancies and predominance of Ashkenazi ethnicity. The reason for these findings is unclear and its further evaluation is warranted. PMID- 28900480 TI - HPV test results and histological follow-up results of patients with LSIL Cervical Cytology from the Largest CAP-certified laboratory in China. AB - BACKGROUND: Age-adjusted evaluations have explored the possible utility of (HPV test results in women with LSIL Pap. We investigated HPV test results and histopathologic follow-up results of LSIL patients from China's largest CAP certified laboratory. METHODS: Patients with LSIL between 2011 and 2015 from the Guangzhou Kingmed Diagnostics were retrospectively retrieved and their hrHPV test results and histological follow-up results were collected and analyzed. RESULTS: LSIL result was identified in 37,895 cases from 2,206,588 Pap tests (1.7%) including 1,513,265 liquid-based cytology and 693,323 conventional Pap tests. The average of these women was 38.4 years (15-88). The LSIL reporting rate in women <30 years was significantly higher than that in women > 30 years (2.1% vs 1.7%). The age specific reporting LSIL rates declined with increased age. 8,014 of 37,895 (21.2%) women with LSIL cytology also had HC2 HPV test results. 75.8% of women with LSIL Pap tests were hrHPV+ and the HPV+ rates declined with increased age except in patients older than 60 years. Overall histopathologic diagnoses within 6 months after LSIL were identified in 5,987 of 37,895 patients at Guangzhou Kingmed Diagnostics. CIN2/3 was identified in 15.2% patients, CIN1 in 66.9%, negative in 14.9% patients. No invasive carcinoma was found in all patients. Of 8014 patients with LSIL Pap test and HPV testing results, 1727 patients had histological follow-up within 6 months after Pap cytology test and HPV testing. The detection rate of CIN2/3 was significantly higher in patients with positive HPV testing result than that in patients with negative HPV testing result (17.8% vs. 8.1%). Among patients with LSIL/HPV negative tests, CIN2/3 was detected in 1 of 30 (3.3%) women aged 50 years and above, appearing lower than those in women less than 50 years (8.0%, 28/351, P=0.357). CONCLUSION: This is the largest histological follow-up study in women with LSIL Pap from China and the data are helpful in establishing a baseline for better understanding the status of cervical screening in China. The 85.1% positive predict value of LSIL Pap cytology for follow-up CIN lesion was within currently recognized benchmark ranges. PMID- 28900479 TI - Loss of Tff1 Promotes Pro-Inflammatory Phenotype with Increase in the Levels of RORgammat+ T Lymphocytes and Il-17 in Mouse Gastric Neoplasia. AB - Background: TFF1 deficiency induces a mucosal pro-inflammatory phenotype that contributes to gastric tumorigenesis in mouse and human. Methods: We utilized the Tff1-KO mouse model to assess the impact of TFF1 loss on immune cells infiltration in the stomach. We used single cell suspension, flow cytometry, immunohistochemistry, and quantitative PCR (qPCR) assays. Results: The Tff1-KO gastric mucosa demonstrated high chronic inflammatory scores (score: 3-4) at age 2 months, which exacerbated at age 8 months (score: 4-6). We next used single cell suspensions for flow cytometry analysis of total leukocytes (CD45+ cells), total T lymphocytes (CD45+CD3+cells), T cell subsets (CD4+, CD8+, and CD3+CD4-CD8 cells), and monocytes/macrophages (CD45+F4/80+cells). The results demonstrated an age-dependent (2 -> 8 month age) significant increase of leukocytes (p<0.05), T cells (p<0.05), and monocytes/macrophages (p<0.001) in the gastric mucosa of the Tff1-KO mice, as compared to Tff1-WT. A similar increase was observed in blood samples (p<0.05). Using ionomycin to activate CD4+ splenocytes, the results indicated that Tff1-KO CD4+ splenocytes secreted higher levels of IL-17A (p<0.05 at 2 and p<0.001 at 8 months) and IL-17F (p<0.05 at 2 and 8 months) than Tff1-WT splenocytes. Conversely, Tff1-KO CD8+-cells secreted less IL-17F, but comparable levels of IL-17A. In addition, we detected a significant upregulation of Il-17 mRNA expression in gastric tissues in the Tff1-KO, as compared to Tff1-WT (p<0.001). Conclusions: The results identify TFF1 loss as a major pro inflammatory step that modulates the tumor microenvironment and immune cell infiltration in the stomach. Furthermore, the data suggest that the increase of IL-17A and IL-17F in Th17 cells, derived from CD4+ T cells, reflects the chronic inflammation in gastric mucosa, whereas the absence of change of IL-17A and decrease of IL-17F in CD8+Tc17 cells suggest loss of cytotoxic function of CD8+Tc17 cells during gastric tumorigenesis of the Tff1-KO mice. PMID- 28900481 TI - Routine Pre-Treatment MRI for Breast Cancer in a Single-Payer Medical Center: Effects on Surgical Choices, Timing and Outcomes. AB - Introduction: Pre-operative MRI is being used with increasing frequency to evaluate breast cancer patients, but the debate surrounding risks and benefits of this use continues. At our institution, we instituted a standardized protocol for pre-operative MRI. Here, we compare patients seen prior to routine use of MRI to those seen after and examine effects on surgical choices, timing and outcomes. Methods: This is a retrospective review of a prospectively collected database of all new invasive breast cancers seen from January 2007 to December 2012. The control group (CG) did not receive MRI, while the MRI group (MRG) underwent MRI according to our pretreatment protocol. Groups were compared with regards to basic demographics, initial surgical choices, need for re-excision, and surgical timing. The electronic medical records of patients in the MRG who underwent mastectomy as their initial surgery were examined closely to determine the main factors leading to their choice of surgery. Finally, correlation between findings on MRI and final surgical pathology was analyzed. Results: Of 282 patients included, 38 were in the CG and 244 in the MRG; the groups were well matched. The MRG had a significantly higher percentage of patients choosing initial mastectomy (MRG: 47.1% vs CG 21.1%, p=0.003). Patients seen in the first 2 years of the study were less likely to choose mastectomy than those enrolled in the latter years (29.2%vs 48.6%, p=0.004). The MRG had a lower chance of return to the operating room for re-excision (15.2% vs 28.9%, p=0.035). The average time from initial imaging to initial surgery was approximately the same between groups (MRG: 39.7 days vs CG 42.1 days, p=0.45) and the MRG actually had shorter time to definitive (margin-negative) surgical management (MRG: 43.5 days vs CG: 50.3 days, p=0.079). One hundred-fifteen patients in the MRG underwent mastectomy as initial surgery. Of these, 64 (55.7%) had no additional findings on MRI and chose mastectomy based on patient preference; 30 patients (26.1%) (29 unilateral, 1 bilateral) had mastectomy because of MRI findings. Of the 31 breasts removed (29 unilateral and 1 bilateral mastectomies) because of MRI findings, 26 (83.9%) had histologic findings that correlated with the MRI findings, while 5 (16.1%) did not. Conclusion: Patients receiving routine pre-treatment MRI had an increased mastectomy rate, but had a lower re-excision rate. We found no delay to initial surgical therapy and, perhaps more importantly, a slight decrease in time to margin-negative surgical therapy in the MRI group. Women choosing mastectomy after MRI did so because of personal preference over half of the time, while MRI findings influenced this choice in 26% of these women. When MRI findings did lead to mastectomy, these findings were confirmed by pathology results in the vast majority of cases. PMID- 28900482 TI - Study on Inhibitory Effect of MaiMenDong Decoction and WeiJing Decoction Combination with Cisplatin on NCI-A549 Xenograft in Nude Mice and Its Mechanism. AB - MaiMenDong Decoction and WeiJing Decoction (Jin formula) is a traditional Chinese medication that consists of 8 medicinal plants, which recorded in the classical TCM literature Jin Kui Yao Lue and has been utilized in the treatment of lung diseases for hundreds of years in China. The present study aimed to determine the anti-tumor activity and the underlying mechanisms of Jin formula combined with cisplatin in the treatment of non-small cell lung cancer (NSCLC). Xenograft model of NCI-A549 was established in Balb/c nude mice. Five groups, including normal, MOCK, Jin, cisplatin (DDP), and Jin+DDP were included in the study. We found that Jin formula ameliorated the body weight loss caused by DDP 15 days after drug administration. Moreover, the combination of Jin with DDP enhanced the anti-tumor function of DDP. Microarray analysis showed that Jin suppressed gene expression of certain pathways which regulating cell cycle and apoptosis. Furthermore, DDP mainly decreased the gene expression level of angiogenesis associated factors, such as VEGFA, TGF-beta and MMP-1. Moreover, co-treatment with Jin and DDP not only down-regulated Bcl-2 and E2F1, but also decreased the expression of MYC, MET, and MCAM. In addition, co-formula decreased the levels of p-AKT (thr308) and p-PTEN, increased Bax/Bcl-2 value, and resulted in apoptosis of tumor cells. Taken together, Jin+DDP significantly inhibited the growth of A549 cell transplanted solid tumor with slight side effect compared to the treatment by DDP only, and had a better effect than the Jin group. The mechanisms may be mainly associated with inactivation of PI3K/AKT pathway and apoptosis induction. PMID- 28900483 TI - Sulforaphane Induced Apoptosis via Promotion of Mitochondrial Fusion and ERK1/2 Mediated 26S Proteasome Degradation of Novel Pro-survival Bim and Upregulation of Bax in Human Non-Small Cell Lung Cancer Cells. AB - Previous studies in our laboratory showed that sulforaphane (SFN) induced apoptosis by sustained activation of extracellular regulated protein kinases 1/2 (ERK1/2). However, the underlying mechanisms associated with SFN-induced apoptosis and downstream cascades which are modulated by ERK1/2 were not elucidated. Herein we demonstrated for the first time that alteration of mitochondrial dynamics contributed to SFN-induced apoptosis in human non-small cell lung cancer (NSCLC) cells. Reports showed that protein Bim not only induced apoptosis but also promoted proliferation under certain circumstances. We found that Bim was related to cell growth in NSCLC cells. Pro-survival Bim downregulation was shown to induce apoptosis in response to SFN. Further, Using the ERK1/2 inhibitor, PD98059, we found that SFN upregulated Bax and downregulated Bim through the ERK1/2-dependent signaling pathway. Furthermore, SFN activated ERK1/2 to increase 26S proteasome activity to degrade Bim, while the proteasome inhibitor MG132 reversed this effect. Therefore, SFN phosphorylated ERK1/2 and activated the proteasome system leading to the degradation of Bim, which contributed to apoptosis in NSCLC cells. These findings provided a novel insight into SFN-related therapeutics in cancer treatment. PMID- 28900484 TI - Chemokine Receptors CXCR4 and CXCR7 are Associated with Tumor Aggressiveness and Prognosis in Extramammary Paget Disease. AB - Chemokines are involved in many aspects of oncogenesis, including regulation of cancer cell growth, dissemination and host-tumor response. However, the potential of the chemokine receptors, CXCR4 and CXCR7, in serving as biomarkers in extramammary Paget's disease (EMPD) has been rarely examined. Expressions of CXCR4 and CXCR7 were evaluated in 92 EMPD specimens by immunohistochemistry. High expression of CXCR4 and CXCR7 were both correlated with regional lymph node metastasis and presence of lymphovascular invasion. High expression of CXCR7 also correlated with the depth of invasion. The prognostic value of these two chemokines were also investigated in progression-free survival (PFS) and cancer specific survival (CSS). Both high expression of CXCR4 and CXCR7 were indicative of shorter PFS and CSS. In the combined prognostic model, concomitant high expression of CXCR4 and CXCR7 were suggestive of poor prognosis compared with the other two groups. In the multivariate analysis, depth of invasion, combined prognostic model and regional lymph node metastasis at diagnosis were the independent prognostic factors for EMPD patients for PFS, and the former two factors independently impacted CSS. Our results demonstrated that CXCR4 and CXCR7 can be used as prognostic biomarkers and prediction of aggressiveness of EMPD. Therapy targeting CXCR4 and CXCR7 may helpful to prevent EMPD progression and improve the prognosis of EMPD. PMID- 28900485 TI - Uncarboxylated Osteocalcin Induces Antitumor Immunity against Mouse Melanoma Cell Growth. AB - Because of the poor response to chemotherapy and radiation therapy, new treatment approaches by immune-based therapy involving activated T cells are required for melanoma. We previously reported that the uncarboxylated form of osteocalcin (GluOC), derived from osteoblasts, potentially suppresses human prostate cancer cell proliferation by direct suppression of cell growth. However, the mechanisms in vivo have not been elucidated. In this study, we found that GluOC suppressed tumor growth of B16 mouse melanoma transplants in C57Bl/6N wild-type mice. Our data demonstrated that GluOC suppressed cell growth by downregulating phosphorylation levels of receptor tyrosine kinases and inducing apoptosis in vitro. Additionally, stimulation of primary mouse splenocytes with concanavalin A, a polyclonal T-cell mitogen, in the presence of GluOC increased T cell proliferation and their interferon-gamma production. Taken together, we demonstrate that GluOC exerts multiple antitumor effects not only in vitro, but also in vivo through cellular immunostimulatory effects against B16 mouse melanoma cells. PMID- 28900486 TI - Upregulation of Serum miR-10b Is Associated with Poor Prognosis in Patients with Melanoma. AB - Aberrant expression of microRNAs (miRNAs) are believed to play a central role in the initiation and development of cancer. The aim of our study was to determine the clinical significance of serum miR-10b in melanoma. A total of 85 and 30 serum samples were obtained from patients with melanoma and healthy volunteers respectively. qRT-PCR was performed to evaluate the expression level of miR-10b in the melanoma cell lines and the serum samples from the participants. Then the clinical significance of serum miR-10b was further determined. Our results showed that the expression level of miR-10b was significantly increased in metastasis melanoma cells and melanoma patients compared to their respective controls. In addition, serum miR-10b expression level was able to discriminate melanoma patients from healthy volunteers as well differentiate melanoma patients at different clinical stage with high accuracy. Moreover, upregulation of serum miR 10b was positively associated with enhanced lymph node metastasis, advanced clinical stage and a shortened survival rate. Finally serum miR-10b was an independent prognostic factor for melanoma. Collectively, our study suggests that serum miR-10b level is upregulated in melanoma and associated with poor prognosis. It may be used as a potential prognostic biomarker for melanoma. PMID- 28900487 TI - Chromosomal and Genomic Variations in Esophageal Squamous Cell Carcinoma: A Review of Technologies, Applications, and Prospections. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor prognosis worldwide. The poor prognosis is due to the advanced stage at the time of diagnosis and the limited clinical staging lacking significant molecular biomarkers to effectively stratify patients for treatment options. As cancer is a disease of genome instability and a resulting of accumulation of genetic alteration, mounting chromosomal and genomic technologies were developed and progressed rapidly which could be used for characterizing patients in genomics level. In this review, we summarized applications of multiple technologies and research progress at chromosomal and genomic level in ESCC. PMID- 28900488 TI - miR-618 Inhibits Prostate Cancer Migration and Invasion by Targeting FOXP2. AB - miRNAs play critical role in the development and progression of prostate cancer. Here we studied the role of miR-618 in prostate cancer migration and invasion. miR-618 was downregulated in metastatic androgen-independent prostate cancer (AIPC), patients with low miR-618 had poor outcome. Overexpression of miR-618 inhibited migration and invasion and induced mesenchymal to epithelial transition (MET). Conversely, knockdown of miR-618 promoted migration and invasion and induced epithelial to mesenchymal transition (EMT). FOXP2 was the direct target of miR-618, and promoted TGF-beta expression, inhibition of TGF-beta reversed the effect of miR-618 knockdown. We further analyzed the correlation between miR-618 expression and FOXP2 in human prostate cancer tissues, and found there was a negative correlation between miR-618 expression and FOXP2 levels. In conclusion, we found miR-618 inhibited prostate cancer migration and invasion by targeting FOXP2 and inhibiting TGF-beta. PMID- 28900489 TI - Rac3 Regulates Cell Invasion, Migration and EMT in Lung Adenocarcinoma through p38 MAPK Pathway. AB - Background: The role of Rac3 in cell proliferation in lung adenocarcinoma has been tackled in our previous study. However, the role of Rac3 in cell invasion and migration of lung adenocarcinoma is still not clear. Methods: The expression of Rac3 in lung adenocarcinoma specimens and paired noncancerous normal tissues were evaluated by immunohistochemistry. Lentivirus-mediated RNA interference (RNAi) was employed to silence Rac3 in lung adenocarcinoma cell lines A549 and H1299. A p38 MAPK inhibitor (LY2228820) was employed to inhibit activity of p38 MAPK pathway. Cell invasion and migration in vitro were examined by invasion and migration assays, respectively. PathScan(r) intracellular signaling array kit and western blot were employed in mechanism investigation. Results: Rac3 expression was frequently higher in lung adenocarcinoma than paired noncancerous normal tissues. Rac3 expression was an independent risk factor for lymphonode metastasis, and was associated with worse survival outcome. Silencing of Rac3 inhibited cell invasion and cell migration in lung adenocarcinoma cell lines. Knockdown of Rac3 decreased activity of p38 MAPK pathway. LY2228820, which was an important p38 MAPK inhibitor, inhibited Rac3-induced cell invasion and migration of lung adenocarcinoma. E-cadherin expression was increased and vimentin expression was decreased after silencing of Rac3 or following the treatment of LY2228820. Conclusions: Our findings suggest that Rac3 regulates cell invasion, migration and EMT via p38 MAPK pathway. Rac3 may be a potential biomarker of invasion and metastasis for lung adenocarcinoma, and knockdown of Rac3 may potentially serve as a promising therapeutic target for lung adenocarcinoma. PMID- 28900490 TI - Wnt3a Expression Is Associated with Epithelial-Mesenchymal Transition and Impacts Prognosis of Lung Adenocarcinoma Patients. AB - Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/beta-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients. Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/beta-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities. Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrell's C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities. Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients. PMID- 28900491 TI - The Clinical Effect of Metformin on the Survival of Lung Cancer Patients with Diabetes: A Comprehensive Systematic Review and Meta-analysis of Retrospective Studies. AB - Preclinical investigations have revealed an anti-cancer effect of metformin. Several studies of metformin treatment have demonstrated the improved clinical outcomes of lung cancer patients with diabetes; however, the results have been inconsistent among studies. Our systematic review and meta-analysis aimed to summarize the up-to-date effects of metformin on diabetic lung cancer patients. A systematic search was performed for studies published. Then, these studies were evaluated for inclusion, and relevant data was extracted. The summary risk estimates for the associations of metformin treatment with overall survival (OS) and progression-free survival (PFS) were analyzed using random/fixed-effects models. Analyses stratified by histological type were also conducted. Based on the 10 studies included in our analysis, metformin treatment was found to significantly improve survival, corresponding to reductions of 23% and 47% in OS [hazard ratio (HR)=0.77, 95% confidence interval (95%CI)=0.66-0.9, p=0.001] and PFS (HR=0.53, 95%CI=0.41-0.68, p<0.001), respectively. In addition, significant improvements in the OS for non-small cell lung cancer (NSCLC) (HR=0.77, 95%CI=0.71-0.84, p=0.002) and small cell lung cancer (SCLC) (HR=0.52, 95%CI=0.29 0.91, p=0.022) were observed in association with metformin treatment in analysis stratified by histological type. This stratified analysis also revealed a significant improvement in PFS for both NSCLC (HR=0.53, 95%CI=0.39-0.71, p<0.001) and SCLC (HR=0.54, 95%CI=0.34-0.84, p=0.007). We found that metformin treatment significantly improved the OS and PFS of diabetic lung cancer patients, and our findings suggest that metformin might be an effective treatment option for diabetic patients with lung cancer. PMID- 28900492 TI - Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2 based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo. Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo. Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors. PMID- 28900493 TI - A Multi-Center Prospective Study to Validate an Algorithm Using Urine and Plasma Biomarkers for Predicting Gleason >=3+4 Prostate Cancer on Biopsy. AB - Background: Unnecessary biopsies and overdiagnosis of prostate cancer (PCa) remain a serious healthcare problem. We have previously shown that urine- and plasma-based prostate-specific biomarkers when combined can predict high grade prostate cancer (PCa). To further validate this test, we performed a prospective multicenter study recruiting patients from community-based practices. Patients and Methods: Urine and plasma samples from 2528 men were tested prospectively. Results were correlated with biopsy findings, if a biopsy was performed as deemed necessary by the practicing urologist. Of the 2528 patients, biopsy was performed on only 524 (21%) patients. Results: Of the 524 patients, Gleason>=3+4 PCa was found in 161 (31%) and Gleason >=4+3 was found in 62 (12%) of the patients. The urine/plasma biomarkers algorithm showed sensitivity and specificity of 75% and 69% for predicting Gleason >=3+4. However, upon incorporating prostate size and prior history of biopsy in the algorithm, we achieved a sensitivity between 97% and 86% and a specificity between 36% and 57%, dependent on the used cut-off point. Sensitivity for predicting PCa Gleason >=4+3 was between 96% and 99% and specificity between 59% and 37%, dependent on the cut-off point. Diagnosis of Gleason >=3+4 was missed in 1% to 3% of tested patients and of Gleason >=4+3 in 0.2% to 1%. Conclusion: This test when integrated with prostate volume and the prior prostate biopsy enhance the sensitivity and specificity for predicting the presence of high grade prostate cancer with negative predictive value (NPV) of 90% to 97% for Gleason >=3+4 and between 98% to 99% for Gleason >=4+3. PMID- 28900494 TI - LHX6, An Independent Prognostic Factor, Inhibits Lung Adenocarcinoma Progression through Transcriptional Silencing of beta-catenin. AB - Introduction: Our previous study identified LIM homeobox domain 6 (LHX6) as a frequently epigenetically silenced tumor-suppressor gene in lung cancer. However, its clinical value has never been evaluated, and the in-depth anti-tumor mechanism remains unclear. Methods: Public database was used for lung cancer, lung adenocarcinoma and lung squamous carcinoma patients and tissue microarray data was used for lung adenocarcinoma patients to study prognostic outcome of LHX6 expression by Kaplan-Meier and Cox-regression analysis. In vitro proliferation, metastasis and in vivo nude mice model were used to evaluate the anti-tumor effect of LHX6 on lung adenocarcinoma cell lines. The mechanisms were explored using western blot, TOP/FOP flash assays and luciferase reporter assays. LHX6 expression and clinical stages data were collected from The Cancer Genome Atlas database (TCGA). Results: Expression of LHX6 was found to be a favorable independent prognostic factor for overall survival (OS) of total lung adenocarcinoma patients (P=0.014) and patients with negative lymph nodes status (P=0.014) but not related the prognostic outcome of lung squamous cell carcinoma patients. The expression status of LHX6 significantly correlated to histological grade (P<0.01), tumor size (P=0.026), lymph node status (P=0.039) and clinical stages (P<0.01) of lung adenocarcinoma patients. Functionally, LHX6 inhibited the proliferation and metastasis of lung adenocarcinoma cells in vitro and in vivo. Furthermore, LHX6 suppressed the Wnt/beta-catenin pathway through transcriptionally silencing the expression of beta-catenin, and the promoter region (-1161 bp to +27 bp) was crucial for its inhibitory activity. Conclusions: Our data indicate that the expression of LHX6 may serve as a favorable prognostic biomarker for lung adenocarcinoma patients and provide a novel mechanism of LHX6 involving in the tumorigenesis of lung adenocarcinoma. PMID- 28900495 TI - Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis. AB - Current studies indicate that long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers and implicated with prognosis in gastric cancer (GC). We intended to generate a multi-lncRNA signature to improve prognostic prediction of GC. By analyzing ten paired GC and adjacent normal mucosa tissues, 339 differentially expressed lncRNAs were identified as the candidate prognostic biomarkers in GC. Then we used LASSO Cox regression method to build a 12-lncRNA signature and validated it in another independent GEO dataset. An innovative 12 lncRNA signature was established, and it was significantly associated with the disease free survival (DFS) in the training dataset. By applying the 12-lncRNA signature, the training cohort patients could be categorized into high-risk or low-risk subgroup with significantly different DFS (HR = 4.52, 95%CI= 2.49-8.20, P < 0.0001). Similar results were obtained in another independent GEO dataset (HR=1.58, 95%CI=1.05 - 2.38, P=0.0270). Further analysis showed that the prognostic value of this 12-lncRNA signature was independent of AJCC stage and postoperative chemotherapy. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of combined model reached 0.869. Additionally, a well-performed nomogram was constructed for clinicians. Moreover, single-sample gene-set enrichment analysis (ssGSEA) showed that a group of pathways related to drug resistance and cancer metastasis significantly enriched in the high risk patients. A useful innovative 12-lncRNA signature was established for prognostic evaluation of GC. It might complement clinicopathological features and facilitate personalized management of GC. PMID- 28900496 TI - Decreased Overall and Cancer-Specific Mortality with Neoadjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma Treated by Intensity-modulated Radiotherapy: Multivariate Competing Risk Analysis. AB - Background: Value of neoadjuvant chemotherapy (NACT) is still controversial in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Based on competing risk analysis model, we aim at evaluating the efficacy of NACT in decreasing cancer-specific mortality for LA-NPC (except T3-4N0) treated by intensity modulated radiotherapy (IMRT). Methods: Data on 957 patients with LA-NPC were retrospectively reviewed. The cumulative incidence of cancer-specific and non cancer-specific (competing) mortality was determined by univariate and multivariate competing risk analysis. Results: 542 (56.6%) patients received NACT using docetaxel with cisplatin (TP) or fluorouracil with cisplatin (PF) regimens. The median follow-up duration was 57.23 months (range, 1.27-78.53 months). In total, 161/957 (16.8%) patients died, with 140 cancer-specific and 21 non-cancer specific deaths were observed, respectively. In univariate analysis, the 3- and 5 year cumulative cancer-specific mortality rates for NACT vs. non-NACT group were 8.58% vs. 7.32% and 14.74% vs. 14.52% (P = 0.95), respectively. With regard to competing mortality, the 3- and 5-year cumulative rates (0.93% vs. 1.22% and 1.31% vs. 3.06%; P = 0.196) were comparable between the two groups. Multivariate competing risk analysis established NACT as an independent prognostic factor in decreasing cancer-specific mortality (HR, 0.681; 95% CI, 0.488-0.951; P = 0.016) and overall mortality (HR, 0.654; 95% CI, 0.471-0.909; P = 0.011). Conclusions: NACT may be a powerful approach in decreasing cancer-specific mortality and overall mortality in LA-NPC treated by IMRT, and our findings would strengthen the role of NACT. PMID- 28900497 TI - Pretreatment Nomograms for Local and Regional Recurrence after Radical Radiation Therapy for Primary Nasopharyngeal Carcinoma. AB - Background: The aim of this study was to build nomograms to predict local recurrence (LR) and regional recurrence (RR) in patients with nasopharyngeal carcinoma (NPC) underwent intensity-modulated radiation therapy (IMRT). Patients and Methods : A total of 1811 patients with non-metastatic NPC treated with IMRT (with or without chemotherapy) between October 2009 and February 2012 at our center were involved for building the nomograms. Nomograms for LR-free rate and RR-free rate at 3- and 5- year were generated as visualizations of Cox proportional hazards regression models, and validated using bootstrap resampling, estimating discrimination and calibration. Results: With a median follow up of 49.50 months, the 3- and 5- year LR-free rate were 95.43% and 94.30% respectively; the 3- and 5- year RR-free rate were 95.94% and 95.41% respectively. The final predictive model for LR included age, the neutrophil/leukocyte ratio (NWR), pathological type, primary gross tumor volume, maxillary sinus invasion, ethmoidal sinus invasion and lacerated foramen invasion; the model for RR involved NWR, plasma Epstein-Barr virus (EBV) DNA copy number, cervical lymph node volume and N category. The models showed fairly good discriminatory ability with concordance indices (c-indices) of 0.76 and 0.74 for predicting LR and RR, respectively, as well as good calibration. The proposed stratification of risk groups based on the nomograms allowed significant distinction between Kaplan-Meier curves for LR and RR. Conclusions: The proposed nomograms resulted in more-accurate prognostic prediction for LR and RR with a high concordance, hence to inform patients with high risk of recurrence on more aggressive therapy. The prognostic nomograms could better stratify patients into different risk groups. PMID- 28900498 TI - Correlation between ERG Fusion Protein and Androgen Receptor Expression by Immunohistochemistry in Prostate, Possible Role in Diagnosis and Therapy. AB - Background: Recent discovery of gene rearrangements have brought a new look to the molecular pathogenesis of cancer. Gene fusions occur in nearly 60% of prostate adenocarcinoma, being the TMPRSS2-ERG one of the most common. Evidence supports the role of ERG fusion in tumorigenesis, progression and invasion via effecting pathways such as WNT, MYC, uPA, PI3K/AKT/PTEN, RAS/RAF/MAPF, NKX3.1, GST-pi and androgen receptor (AR) mediated signaling. Most of the ERG fusions involve 5'-partners androgen responsive. Therefore, we aimed to evaluate AR and ERG fusion protein expression on prostate tissue to find clinicopathological applications and possible role in therapy. Methods: One hundred three samples, including prostate core biopsies and radical prostatectomy specimens, were evaluated for ERG and AR expression by immunohistochemistry (IHC). ERG rearrangement was done by fluorescence in situ hybridization (FISH) on 11 randomly selected cases and correlated with IHC results. Results: From the total of 103 samples, eight (8/103) were benign, fourteen (14/103) had atypical glands, two (2/103) had prostatic intraepithelial neoplasia (PIN), and seventy nine (79/103) showed prostate adenocarcinoma. Forty four (44/79) tumor cases were Gleason score (GS) 6-7 (lower GS), and thirty five (35/79) were GS of 8-10 (higher GS). ERG immunoreaction was observed in 27.8% (22/79) of the tumor cases, showing higher expression in those with lower GS (68.2%, 15/22) compared to higher GS (31.8%, 7/22). Neither benign glands nor PIN stained with ERG. AR expression was observed in 75% of benign samples, 78.5% of atypical glands, 100% of PIN, and in 87.3% of tumor cases with no significant difference based on GS. Co-expression of ERG and AR was evaluated on all the tumor samples. ERG+/AR+ was seen in 77.3% (17/22) of the ERG+ tumor cases, with higher frequency in lower GS (64.7%, 11/17) compared to those with higher GS (35.3%, 6/17). All but five corresponding ERG+ tumor samples were negative for AR. Only 5 samples were ERG /AR- corresponding to adenocarcinoma GS of 6. Presence or absence of ERG rearrangement was confirmed by FISH and correlated with IHC results. Conclusions: Characterization of ERG status by IHC in prostate tissue has an excellent correlation with FISH. It may also assist in diagnosis since none of the benign glands stained with ERG. Co-expression of ERG+/AR+ in prostate tumor by IHC may suggest gene fusion between ERG and a 5'-partner driven by androgen signaling such as TMPRSS2, which it could represent an important ancillary test for clinical management and development of new therapeutic targets. PMID- 28900499 TI - Profiling chemotherapy-associated myelotoxicity among Chinese gastric cancer population receiving cytotoxic conventional regimens: epidemiological features, timing, predictors and clinical impacts. AB - Objectives: We aim to evaluate the epidemiological features, timing, predictors and clinical impacts of chemotherapy-associated myelotoxicity in Chinese gastric cancer population receiving six established cytotoxic conventional regimens (CF/XP, EC(O)F/EC(O)X, DC(O)F/DC(O)X, PC(O)F/PC(O)X, FOLFOX4, or mFOLFOX7/XELOX). Patients and methods: A 4-year multicenter, prospective, observational study was conducted in multiple hospitals/institutes spanning three major regions in China. A total of 1,285 patients with gastric cancer, treated with six selected regimens between 2010 and 2014 were included. Kaplan-meier analysis was applied to estimate the time to develop myelotoxicity events for each regimen. Multivariable logistic regression model was built to identify predictors associated with chemotherapy-induced myelotoxicity, evaluating detailed specific factors of patients, disease and treatment patterns. Results: Triplet regimens were associated with more moderate-to-severe myelotoxicity events than doublet regimens. DC(O)F/DC(O)X group presented with moderate-to-severe anaemia, thrombocytopenia, and leukopenia earlier than other regimen groups, with median time of 3.5, 4.8 and 3.3 cycles, respectively. PC(O)F/PC(O)X group had a shortest time to develop Moderate-to-Severe neutropenia (median time, 3.3 cycles). Multivariate analysis identified several independent predictors for moderate-to severe myelotoxicity, including: baseline Hb<12.0 g/dL, male gender, KPS<80, previously treated with surgery, tumor located at gastroesophageal junction(GEJ), DC(O)F/DC(O)X regimen, palliative intent, triplet combination therapy and No. of cycles received>=4. Dose reductions>=20% occurred in 16.7% of patients and treatment delays>=7 days presented in 21.1% of patients, resulting in patients receiving an actual average Relative Dose Intensity (RDI) of 0.733. Conclusions: Myelotoxicity events were frequently observed within the gastric cancer population undertaking multicycle polychemotherapy. Predictive models based on risk factors identified for moderate-to-severe myelotoxicity should enable the targeted use of appropriate supportive care in an effort to facilitate the delivery of full chemotherapy doses on schedule. PMID- 28900500 TI - CDC27 Induces Metastasis and Invasion in Colorectal Cancer via the Promotion of Epithelial-To-Mesenchymal Transition. AB - Distant metastasis is the primary cause of cancer-related death among patients with colorectal cancer (CRC), and the discovery of novel therapeutic targets by further exploring the molecular mechanisms of CRC metastasis is therefore urgently needed. We previously illustrated that CDC27 overexpression promoted proliferation in CRC, but no studies have emphasized the role of CDC27 in cancer metastasis thus far. Our previous data indicated that the expression of CDC27 was significantly associated with distant metastasis in patient tissues, and therefore, in this study, we focused on the investigation of the potential mechanisms of CDC27 in CRC metastasis. The results revealed that CDC27 promoted the metastasis, invasion and sphere-formation capacity of DLD1 cells, but that the inhibition of CDC27 in HCT116 cells suppressed metastasis both in vitro and in vivo. Mechanistic analyses revealed that CDC27 promoted epithelial-to mesenchymal transition (EMT), as demonstrated by the reduced expression of the epithelial markers ZO-1 and E-cadherin and the enhanced expression of the mesenchymal markers ZEB1 and Snail in HCT116 and DLD1 cells. Further mechanistic investigation indicated that CDC27 promoted metastasis and sphere-formation capacity in an ID1-dependent manner. In conclusion, we first demonstrated the role of CDC27 in cancer metastasis and showed that CDC27 may serve as a promising therapeutic target for CRC. PMID- 28900501 TI - Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP activated Protein Kinase. AB - Vincristine is extensively used chemotherapeutic medicine to treat leukemia. However, it remains a critical clinical problem with regard to its toxicity and drug-resistance. AMP-activated protein kinase (AMPK) is an energy sensor that is pivotal in maintaining cell metabolic homeostasis. It is reported that AMPK is involved in vincristine-induced apoptosis. However, whether AMPK is involved in chemotherapy-resistance is largely unclear. It is well-documented that metformin, a widely used medicine to treat type II diabetes, possesses anti-cancer activities, yet whether metformin affects leukemia cell viability via vincristine is unknown. In this study, we showed that both AMPKalpha1 mRNA and phosphorylated AMPK protein levels were significantly decreased in clinical leukemia samples. We further demonstrated that metformin sensitized leukemia cells to vincristine induced apoptosis in an AMPK-dependent manner. In addition, knockdown of AMPKalpha1 significantly reduced the effects of metformin on vincristine-induced apoptosis. Taken together, these results indicate that AMPK activation is critical in metformin effects on vincristine-induced apoptosis and suggest a putative strategy of a combination therapy using metformin and vincristine in treatment of leukemia. PMID- 28900502 TI - A BAP1 Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type BAP1. AB - Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent histologic subtype of kidney cancers in adults, which could be divided into two distinct subgroups according to the BRCA1 associated protein-1 (BAP1) mutation status. In the current study, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in ccRCC, with the aim to identify the differentially expressed miRNAs between BAP1 mutant and wild-type tumors, and generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild type BAP1. Methods: The BAP1 mutation status and miRNA profiles in BAP1 mutant and wild-type tumors were analyzed. Subsequently, the association of the differentially expressed miRNAs with patient survival was examined, and a BAP1 mutation-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate and multivariate Cox regression analyses. Finally, the bioinformatics methods were adopted for the target prediction of selected miRNAs and functional annotation analyses. Results: A total of 350 treatment-naive primary ccRCC patients were selected from The Cancer Genome Atlas project, among which 35 (10.0%) subjects carried mutant BAP1 and had a shorter overall survival (OS) time. Furthermore, 33 miRNAs were found to be differentially expressed between BAP1 mutant and wild-type tumors, among which 11 (miR-149, miR-29b-2, miR 182, miR-183, miR-21, miR-365-2, miR-671, miR-365-1, miR-10b, miR-139, and miR 181a-2) were significantly associated with OS in ccRCC patients with wild-type BAP1. Finally, a BAP1 mutation-specific miRNA signature consisting of 11 miRNAs was generated and validated as an independent prognostic parameter. Conclusions: In summary, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type BAP1. PMID- 28900503 TI - Label-free Rapid Viable Enrichment of Circulating Tumor Cell by Photosensitive Polymer-based Microfilter Device. AB - We present a clinical device for simple, rapid, and viable isolation of circulating tumor cells (CTCs) from cancer patient bloods. In spite of the clinical importance of CTCs, the lack of easy and non-biased isolation methods is a big hurdle for implementing CTC into clinical use. The present device made of photosensitive polymer was designed to attach to conventional syringe to isolate the CTCs at minimal resources. Its unique tapered-slits on the filter are capable not only to isolate the cell based on their size and deformability, but also to increase sample flow rate, thus achieving label-free rapid viable CTC isolation. We verified our device performance using 9 different types of cancer cells at the cell concentration from 5 to 100cells/ml, showing that the device capture 77.7% of the CTCs while maintaining their viability of 80.6%. We extended our study using the 18 blood samples from lung, colorectal, pancreatic and renal cancer patients and captured 1-172 CTCs or clustered CTCs by immunofluorescent or immunohistochemical staining. The captured CTCs were also molecularly assayed by RT-PCR with three cancer-associated genes (CK19, EpCAM, and MUC1). Those comprehensive studies proved to use our device for cancer study, thereby inaugurating further in-depth CTC-based clinical researches. PMID- 28900504 TI - Platelet-Targeted Delivery of Peripheral Blood Mononuclear Cells to the Ischemic Heart Restores Cardiac Function after Ischemia-Reperfusion Injury. AB - One of the major hurdles in intravenous regenerative cell therapy is the low homing efficiency to the area where these cells are needed. To increase cell homing toward areas of myocardial damage, we developed a bispecific tandem single chain antibody (Tand-scFvSca-1+GPIIb/IIIa) that binds with high affinity to activated platelets via the activated glycoprotein (GP)IIb/IIIa receptor, and to a subset of peripheral blood mononuclear cells (PBMC) which express the stem cell antigen-1 (Sca-1) receptor. Methods: The Tand-scFvSca-1+GPIIb/IIIa was engineered, characterized and tested in a mouse model of ischemia-reperfusion (IR) injury applying left coronary artery occlusion for 60 min. Fluorescence cell tracking, cell infiltration studies, echocardiographic and histological analyses were performed. Results: Treatment of mice undergoing myocardial infarction with targeted-PBMCs led to successful cell delivery to the ischemic-reperfused myocardium, followed by a significant decrease in infiltration of inflammatory cells. Homing of targeted-PBMCs as shown by fluorescence cell tracking ultimately decreased fibrosis, increased capillary density, and restored cardiac function 4 weeks after ischemia-reperfusion injury. Conclusion: Tand-scFvSca-1+GPIIb/IIIa is a promising candidate to enhance therapeutic cell delivery in order to promote myocardial regeneration and thereby preventing heart failure. PMID- 28900505 TI - Iron Oxide Nanozyme: A Multifunctional Enzyme Mimetic for Biomedical Applications. AB - Iron oxide nanoparticles have been widely used in many important fields due to their excellent nanoscale physical properties, such as magnetism/superparamagnetism. They are usually assumed to be biologically inert in biomedical applications. However, iron oxide nanoparticles were recently found to also possess intrinsic enzyme-like activities, and are now regarded as novel enzyme mimetics. A special term, "Nanozyme", has thus been coined to highlight the intrinsic enzymatic properties of such nanomaterials. Since then, iron oxide nanoparticles have been used as nanozymes to facilitate biomedical applications. In this review, we will introduce the enzymatic features of iron oxide nanozyme (IONzyme), and summarize its novel applications in biomedicine. PMID- 28900506 TI - Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer. AB - TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells. However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy. Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy. In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells. Specific inhibitors of miR-221 and/or miR-222, called sponge, TuD and miR-Zip were constructed, and their ability to overcome TRAIL resistance was compared. Among them, AAV-mediated gene therapy using co-expression of TRAIL with miR-221-Zip showed the most synergistic activity in the induction of apoptosis in vitro. In vivo treatment of nude mice bearing human TRAIL-resistant liver cancer xenografts with AAV-TRAIL-miR-221-Zip also led to growth inhibition. This sensitizing effect of miR-221-Zip was associated with increased expression of PTEN, the miR-221 target, as well as with decreasing levels of Survivin. Moreover, miR-221 expression was concomitant with promotion of Survivin expression and suppression of PTEN expression. TRAIL sensitivity of cancer cells isolated from liver cancer tissues or from patients was significantly correlated with miR-221 expression. And miR-221 blood expression levels in liver cancer patients were correlated with TRAIL sensitivity, thus it had the potential to be a predictor of TRAIL sensitivity in liver cancer. These data suggested the potential of combining AAV TRAIL with miR-221-Zip as a therapeutic intervention for liver cancer. PMID- 28900508 TI - Direct Macromolecular Drug Delivery to Cerebral Ischemia Area using Neutrophil Mediated Nanoparticles. AB - Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation. PMID- 28900509 TI - Biodegradable Hollow Mesoporous Silica Nanoparticles for Regulating Tumor Microenvironment and Enhancing Antitumor Efficiency. AB - There is accumulating evidence that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Herein, to remodel tumor immune microenvironment and elicit synergistic antitumor effects, lipid-coated biodegradable hollow mesoporous silica nanoparticle (dHMLB) was constructed with co-encapsulation of all-trans retinoic acid (ATRA), doxorubicin (DOX) and interleukin-2 (IL-2) for chemo-immunotherapy. The nanoparticle-mediated combinational therapy provided a benign regulation on tumor microenvironment through activation of tumor infiltrating T lymphocytes and natural killer cells, promotion of cytokines secretion of IFN-gamma and IL-12, and down-regulation of immunosuppressive myeloid-derived suppressor cells, cytokine IL-10 and TGF-beta. ATRA/DOX/IL-2 co-loaded dHMLB demonstrated significant tumor growth and metastasis inhibition, and also exhibited favorable biodegradability and safety. This nanoplatform has great potential in developing a feasible strategy to remodel tumor immune microenvironment and achieve enhanced antitumor effect. PMID- 28900510 TI - EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes. AB - Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF 1alpha. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer. PMID- 28900507 TI - Targeting MicroRNAs in Prostate Cancer Radiotherapy. AB - Radiotherapy is one of the most important treatment options for localized early stage or advanced-stage prostate cancer (CaP). Radioresistance (relapse after radiotherapy) is a major challenge for the current radiotherapy. There is great interest in investigating mechanisms of radioresistance and developing novel treatment strategies to overcome radioresistance. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level, participating in numerous physiological and pathological processes including cancer invasion, progression, metastasis and therapeutic resistance. Emerging evidence indicates that miRNAs play a critical role in the modulation of key cellular pathways that mediate response to radiation, influencing the radiosensitivity of the cancer cells through interplaying with other biological processes such as cell cycle checkpoints, apoptosis, autophagy, epithelial mesenchymal transition and cancer stem cells. Here, we summarize several important miRNAs in CaP radiation response and then discuss the regulation of the major signalling pathways and biological processes by miRNAs in CaP radiotherapy. Finally, we emphasize on microRNAs as potential predictive biomarkers and/or therapeutic targets to improve CaP radiosensitivity. PMID- 28900511 TI - A Nanosystem of Amphiphilic Oligopeptide-Drug Conjugate Actualizing Both alphavbeta3 Targeting and Reduction-Triggered Release for Maytansinoid. AB - To design a prodrug-based self-assembling nanosystem with both ligand targeting and stimuli-responsive features, and elucidate the superiority of each targeting strategy and the synergistic effect between them, we synthesized four small molecule amphiphilic peptide-drug conjugates (APDCs) using maytansinoid (DM1) as a cytotoxic agent, cRGDfK as a homing peptide, and disulfide (SS) or thioether (SMCC) as linker. Owing to their amphiphilicity, the APDCs could self-assemble into nanoparticles (APDC@NPs) which were evaluated in vitro in three different cell lines and in vivo in tumor-bearing C57BL/6 mice. The RSSD@NPs showed the strongest interaction with alphavbeta3 integrin, highest cell uptake and intracellular free drug level, and best antitumor efficacy in vitro and in vivo, while it shared the same goodness with other test nanosystems in terms of high drug loading, EPR effect and free of potentially toxic polymers. Especially, the in vivo efficacy of RSSD@NPs was 2 fold of free DM1 which is too cytotoxic to be a drug, while the active targeted APDC@NPs demonstrated acceptable system, tissue and blood compatibility. In alphavbeta3-positive cells or tumors, the RGD targeting contributed much more than disulfide in anticancer effect. The maximum synergism of the two strategies reached to 22 fold in vitro and 3 fold in vivo. Generally, the active targeting, prodrug and nanosystem could significantly decrease the toxicity of free DM1 and improve its therapy outcome via combining active targeting, prodrug and nanopreparation, especially the dual targeting strategies and their synergism. PMID- 28900512 TI - Aptavalve-gated Mesoporous Carbon Nanospheres image Cellular Mucin and provide On demand Targeted Drug Delivery. AB - In this report, we present a mesoporous carbon nanosphere that can target drugs to tumors and image tumor biomarkers. A single-strand DNA (P0 aptamer) aptavalve was capped on the surface of doxorubicin-loaded oxide mesoporous carbon nanospheres (Dox-OMCN-P0) through pi-pi stacking for real-time imaging-guided on demand targeting drug delivery. The Dox-OMCN-P0 could not only realize the detection of MUC1 tumor marker with a wide linear range (0.1 - 10.6 MUmol/L) and a low detection limit (17.5 nmol) based on different apparatuses, but also achieve in-situ targeting imaging of cellular MUC1 concentration in vitro and in vivo via "off-on" fluorescence biosensing. Much attractively, as a real-time feedback of the diagnostic/imaging outcomes, Dox-OMCN-P0 accomplished the on demand targeting drug delivery in quantitative response to MUC1. Controllable chemotherapy with sustained release and pH-sensitiveness, together with the potential photothermal therapy, were also clearly demonstrated. This is a simple but advanced platform, which could well achieve the real-time switchable imaging of cellular mucin for targeting cancer therapy. PMID- 28900513 TI - In Vivo Cancer Cells Elimination Guided by Aptamer-Functionalized Gold-Coated Magnetic Nanoparticles and Controlled with Low Frequency Alternating Magnetic Field. AB - Biomedical applications of magnetic nanoparticles under the influence of a magnetic field have been proved useful beyond expectations in cancer therapy. Magnetic nanoparticles are effective heat mediators, drug nanocarriers, and contrast agents; various strategies have been suggested to selectively target tumor cancer cells. Our study presents magnetodynamic nanotherapy using DNA aptamer-functionalized 50 nm gold-coated magnetic nanoparticles exposed to a low frequency alternating magnetic field for selective elimination of tumor cells in vivo. The cell specific DNA aptamer AS-14 binds to the fibronectin protein in Ehrlich carcinoma hence helps deliver the gold-coated magnetic nanoparticles to the mouse tumor. Applying an alternating magnetic field of 50 Hz at the tumor site causes the nanoparticles to oscillate and pull the fibronectin proteins and integrins to the surface of the cell membrane. This results in apoptosis followed by necrosis of tumor cells without heating the tumor, adjacent healthy cells and tissues. The aptamer-guided nanoparticles and the low frequency alternating magnetic field demonstrates a unique non-invasive nanoscalpel technology for precise cancer surgery at the single cell level. PMID- 28900514 TI - MicroRNA-647 Targets SRF-MYH9 Axis to Suppress Invasion and Metastasis of Gastric Cancer. AB - MicroRNAs (miRNAs) play important roles in regulating tumour development and progression. Here we show that miR-647 is repressed in gastric cancer (GC), and associated with GC metastasis. Moreover, we identify that miR-647 can suppress GC cell migration and invasion in vitro. Mechanistically, we confirm miR-647 directly binds to the 3' untranslated regions of SRF mRNA, and SRF binds to the CArG box located at the MYH9 promoter. CCG-1423, an inhibitor of RhoA/SRF mediated gene transcription, inhibits the expression of MYH9, especially in SRF downregulated cells. Overexpression of miR-647 inhibits MGC 80-3 cells' metastasis in orthotropic GC models, but increasing SRF expression in these cells reverses this change. Importantly, we found the synergistic inhibition effect of CCG-1423 and agomir-647, an engineered miRNA mimic, on cancer metastasis in orthotropic GC models. Our study demonstrates that miR-647 functions as a tumor metastasis suppressor in GC by targeting SRF/MYH9 axis. PMID- 28900515 TI - Fluorocarbons Enhance Intracellular Delivery of Short STAT3-sensors and Enable Specific Imaging. AB - Short oligonucleotide sequences are now being widely investigated for their potential therapeutic properties. The modification of oligonucleotide termini with short fluorinated residues is capable of drastically altering their behavior in complex in vitro and in vivo systems, and thus may serve to greatly enhance their therapeutic potential. The main goals of our work were to explore: 1) how modification of STAT3 transcription factor-binding oligodeoxynucleotide (ODN) duplexes (ODND) with one or two short fluorocarbon (FC)-based residues would change their properties in vitro and in vivo, and if so, how this would affect their intracellular uptake by cancer cells, and 2) the ability of such modified ODND to form non-covalent complexes with FC-modified carrier macromolecule. The latter has an inherent advantage of producing a 19F-specific magnetic resonance (MR) imaging signature. Thus, we also tested the ability of such copolymers to generate 19F-MR signals. Materials and Methods. Fluorinated nucleic acid residues were incorporated into ODN by using automated synthesis or via activated esters on ODN 5'-ends. To quantify ODND uptake by the cells and to track their stability, we covalently labeled ODN with fluorophores using internucleoside linker technology; the FC-modified carrier was synthesized by acylation of pegylated polylysine graft copolymer with perfluoroundecanoic acid (M5-gPLL PFUDA). Results. ODN with a single FC group exhibited a tendency to form duplexes with higher melting points and with increased stability against degradation when compared to control non-modified ODNs. ODND carrying fluorinated residues showed complex formation with M5-gPLL-PFUDA as predicted by molecular dynamics simulations. Moreover, FC groups modulated the specificity of ODND binding to the STAT3 target. Finally, FC modification resulted in greater cell uptake (2 to 4 fold higher) when compared to the uptake of non-modified ODND as determined by quantitative confocal fluorescence imaging of A431 and INS-1 cells. Conclusion. ODND modification with FC residues enables fine-tuning of protein binding specificity to double-strand binding motifs and results in an increased internalization by A431 and INS-1 cells in culture. Our results show that modification of ODN termini with FC residues is both a feasible and powerful strategy for developing more efficient nucleic acid-based therapies with the added benefit of allowing for non-invasive MR imaging of ODND therapeutic targeting and response. PMID- 28900516 TI - Sensitive in vivo Visualization of Breast Cancer Using Ratiometric Protease activatable Fluorescent Imaging Agent, AVB-620. AB - With the goal of improving intraoperative cancer visualization, we have developed AVB-620, a novel intravenously administered, in vivo fluorescent peptide dye conjugate that highlights malignant tissue and is optimized for human use. Matrix metalloproteinases (MMPs) hydrolyze AVB-620 triggering tissue retention and a ratiometric fluorescence color change which is visualized using camera systems capable of imaging fluorescence and white light simultaneously. AVB-620 imaging visualizes primary tumors and demonstrated high in vivo diagnostic sensitivity and specificity (both >95%) for identifying breast cancer metastases to lymph nodes in two immunocompetent syngeneic mouse models. It is well tolerated and single-dose toxicology studies in rats determined a no-observed-adverse-effect level (NOAEL) at >110-fold above the imaging and estimated human dose. Protease specificity and hydrolysis kinetics were characterized and compared using recombinant MMPs. To understand the human translation potential, an in vitro diagnostic study was conducted to evaluate the ability of AVB-620 to differentiate human breast cancer tumor from healthy adjacent tissue. Patient tumor tissue and healthy adjacent breast tissue were homogenized, incubated with AVB-620, and fluorogenic responses were compared. Tumor tissue had 2-3 fold faster hydrolysis than matched healthy breast tissue; generating an assay sensitivity of 96% and specificity of 88%. AVB-620 has excellent sensitivity and specificity for identifying breast cancer in mouse and human tissue. Significant changes were made in the design of AVB-620 relative to previous ratiometric protease-activated agents. AVB-620 has pharmaceutical properties, fluorescence ratio dynamic range, usable diagnostic time window, a scalable synthesis, and a safety profile that have enabled it to advance into clinical evaluation in breast cancer patients. PMID- 28900517 TI - Bone-Inspired Spatially Specific Piezoelectricity Induces Bone Regeneration. AB - The extracellular matrix of bone can be pictured as a material made of parallel interspersed domains of fibrous piezoelectric collagenous materials and non piezoelectric non-collagenous materials. To mimic this feature for enhanced bone regeneration, a material made of two parallel interspersed domains, with higher and lower piezoelectricity, respectively, is constructed to form microscale piezoelectric zones (MPZs). The MPZs are produced using a versatile and effective laser-irradiation technique in which K0.5Na0.5NbO3 (KNN) ceramics are selectively irradiated to achieve microzone phase transitions. The phase structure of the laser-irradiated microzones is changed from a mixture of orthorhombic and tetragonal phases (with higher piezoelectricity) to a tetragonal dominant phase (with lower piezoelectricity). The microzoned piezoelectricity distribution results in spatially specific surface charge distribution, enabling the MPZs to bear bone-like microscale electric cues. Hence, the MPZs induce osteogenic differentiation of stem cells in vitro and bone regeneration in vivo even without being seeded with stem cells. The concept of mimicking the spatially specific piezoelectricity in bone will facilitate future research on the rational design of tissue regenerative materials. PMID- 28900518 TI - Nail unit ultrasound: a complete guide of the nail diseases. AB - INTRODUCTION: The nails have a functional and esthetic importance for patients. Almost always, the nail disorders are diagnosed on the basis of clinical findings, but imaging methods may be required for a better assessment. These imaging methods, such as ultrasound and magnetic resonance, may help to establish an accurate diagnosis. Magnetic resonance imaging is not widely available and sometimes may be very expensive; that is why, ultrasound is an excellent imaging modality. Our objective is to expose the nail unit anatomy, the nail unit anatomy in ultrasound, and some of the frequent pathologies found in our daily practice. METHODS: A review of the literature was done to review the anatomy, technical aspects, and different findings in normal and abnormal nail unit ultrasound. RESULTS: Ultrasound offers an appropriate alternative for the evaluation of the nail unit, allows a real-time evaluation of each one of the components of the nail unit with an optimal visualization of these structures, and allows the evaluation of the thickness of the components, the vascularity, and blood flow by Doppler application. In addition, the nail unit disorder, such as infectious diseases, inflammatory and rheumatologic conditions, nail tumors, among others, may be assessed, not only in the diagnosis but also in the follow-up. Pre surgical evaluation, surgical follow-up, and some procedures, such as biopsies, may be done by this technique. CONCLUSIONS: Ultrasound is an excellent technique for evaluation of normal anatomy, diagnosis, and follow-up of patients with nail unit diseases. This is an alternative for other imaging methods and may be used for an accurate diagnosis approach. PMID- 28900519 TI - Point-of-care ultrasound in cardiopulmonary resuscitation: a concise review. AB - Point-of-care ultrasound (POCUS) is a widely used tool in critical care areas, allowing for the performance of accurate diagnoses and thus enhancing the decision-making process. Every major organ or system can be safely evaluated with POCUS. In that respect, the utility of POCUS in cardiac arrest is gaining interest. In this article, we will review the actual role of ultrasound in cardiac arrest and the main POCUS protocols focused to this scenario as well as discuss the potential role of POCUS in monitoring the efficacy of the chest compressions. PMID- 28900520 TI - First-year medical students use of ultrasound or physical examination to diagnose hepatomegaly and ascites: a randomized controlled trial. AB - PURPOSE: To compare point-of-care ultrasound and physical examination (PEx), each performed by first-year medical students after brief teaching, for assessing ascites and hepatomegaly. Ultrasound and PEx were compared on: (1) reliability, validity and performance, (2) diagnostic confidence, ease of use, utility, and applicability. METHODS: A single-center, randomized controlled trial was performed at a tertiary centre. First-year medical students were randomized to use ultrasound or PEx to assess for ascites and hepatomegaly. Cohen's kappa and interclass coefficient (ICC) were used to measure interrater reliability between trainee assessments and the reference standard (a same day ultrasound by a radiologist). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were compared. A ten-point Likert scale was used to assess trainee diagnostic confidence and perceptions of utility. RESULTS: There were no significant differences in interobserver reliability, sensitivity, specificity, accuracy, PPV, or NPV between the ultrasound and PEx groups. However, students in the ultrasound group provided higher scores for perceived utility (ascites 8.38 +/- 1.35 vs 7.08 +/- 1.86, p = 0.008; hepatomegaly 7.68 +/- 1.52 vs 5.36 +/- 2.48, p < 0.001) and likelihood of adoption (ascites 8.67 +/- 1.61 vs 7.46 +/- 1.79, p = 0.02; hepatomegaly 8.12 +/- 1.90 vs 5.92 +/- 2.32, p = 0.001). CONCLUSIONS: When performed by first-year medical students, the validity and reliability of ultrasound is comparable to PEx, but with greater perceived utility and likelihood of adoption. With similarly brief instruction, point-of-care ultrasonography can be as effectively learned and performed as PEx, with a high degree of interest from trainees. PMID- 28900521 TI - Effectiveness of ultrasonography and computed tomography in assessing thyroid cartilage invasion in laryngeal and hypopharyngeal cancers. AB - OBJECTIVE: To evaluate the adequacy of ultrasonography (US) and computed tomography (CT) in the assessment of thyroid cartilage invasion in patients with airway cancer. MATERIALS AND METHODS: Sixty-two consecutive patients referred to our institute underwent US and CT to stage laryngeal (n = 27) or hypopharyngeal (n = 35) cancer in this prospective study. Two radiologists, who were blinded to the patients' clinical histories and histopathology, evaluated thyroid cartilage invasion on US and CT separately and independently. Fifty-eight of the 64 patients (90%) underwent surgery. The histopathologic findings were used as the standard of reference for comparison and statistical analysis. RESULTS: For thyroid cartilage invasion, the detection rate on CT and US was 98%. CT achieved a sensitivity of 91% and a specificity of 75%, while US attained a sensitivity of 98% and a specificity of 75%. The difference between CT and US in terms of sensitivity was not statistically significant. CONCLUSION: US and CT have high diagnostic performance in evaluating thyroid cartilage invasion. US is more sensitive than CT in diagnosing invasion of the thyroid cartilage; however, the difference is not statistically significant. US can be used to solve the diagnostic dilemma of the presence or absence of cartilage invasion when CT is inconclusive, as CT is more widely used in staging laryngeal and hypopharyngeal cancers. PMID- 28900523 TI - Sonography in diagnosis of adhesive capsulitis of the shoulder: a case-control study. AB - PURPOSE: Adhesive capsulitis (AC) of the shoulder has been a diagnosis of exclusion on sonography due to lack of specific diagnostic criteria. This study prospectively assesses the efficacy of sonography using multiple static and dynamic parameters for diagnosis of AC. MATERIALS AND METHODS: Shoulder sonography was performed independently by two musculoskeletal radiologists on 90 subjects (60 symptomatic and 30 controls). All symptomatic subjects were subjected to an MRI. Based on clinical and MRI diagnosis, three groups were made: AC (n = 30), painful shoulders (PS) (n = 30), and control group (CL) (n = 30). The sonographic parameters studied were: coracohumeral ligament (CHL) thickness, increased soft tissue in rotator interval (static parameters) and restriction of abduction and external rotation on dynamic scanning. These were compared within the three groups and the accuracy of each parameter in isolation and in combination for diagnosis of AC was calculated. RESULTS: Sonographic visualisation of CHL (96.7%) and its mean thickness (1.2 mm) were highest in the AC group (p < 0.01). A cut-off value of 0.7 mm was found to be accurate (sensitivity 93.1%, specificity 94.4%) for diagnosing AC. Increased soft tissue in the rotator interval was seen in the AC group and had a high sensitivity of 86.2% and specificity of 92.8%. On dynamic scanning, restriction of external rotation was specific (sensitivity 86.2%, specificity 92.8%), whereas restriction in abduction was non-specific (specificity 6.7%). Inter-observer agreement was substantial for CHL visualisation (kappa 0.66). Overall, sonography, using multiple parameters, revealed a high sensitivity and specificity (100 and 87%, respectively) for diagnosis of AC of the shoulder. CONCLUSION: Sonography revealed a high accuracy for diagnosing AC of the shoulder and in differentiating it from other causes of painful shoulder. It, thus, has the potential to be adopted as a preferred imaging modality. PMID- 28900522 TI - Point shear wave ultrasound elastography with Esaote compared to real-time 2D shear wave elastography with supersonic imagine for the quantification of liver stiffness. AB - PURPOSE: Different shear wave elastography (SWE) machines able to quantify liver stiffness (LS) have been recently introduced by various companies. The aim of this study was to investigate the agreement between point SWE with Esaote MyLab Twice (pSWE.ESA) and 2D SWE with Aixplorer SuperSonic (2D SWE.SSI). Moreover, we assessed the correlation of these machines with Fibroscan in a subgroup of patients. METHODS: A total of 81 liver disease patients and 27 subjects without liver disease accessing the ultrasound lab were considered. Exclusion criteria were liver nodules, BMI >35, and severe comorbidities. LS was sampled from the same intercostal space with both pSWE.ESA and 2D SWE.SSI and values were tested with Lin's analysis and Bland-Altman analysis (B&A). Agreement between each SWE machine and Fibroscan was assessed in 26 liver disease patients with Spearman correlation. RESULTS: Precision and accuracy between pSWE.ESA and 2D SWE.SSI were, respectively, 0.839 and 0.999. B&A showed a mean of only -0.2 kPa, with no systematic deviation between the techniques and limits of agreement at -11.6 and 11.3 kPa. Spearman's rho correlation versus Fibroscan was 0.849 for pSWE.ESA and 0.878 for 2D SWE.SSI. The relationship became less strict in the higher range of LS (>=15.2 kPa), corresponding to cirrhosis. CONCLUSION: The overall degree of concordance of pSWE.ESA and 2D SWE.SSI in measuring LS resulted remarkable, also when compared with Fibroscan. The less strict correlation for patients with LS in the higher range would not affect the staging of disease as such patients are anyhow classified as cirrhotic. PMID- 28900524 TI - Distal intersection syndrome progressing to extensor pollicis longus tendon rupture: a case report with sonographic findings. AB - The purpose of this case report is to describe the value of musculoskeletal ultrasound (US) in diagnosing both distal intersection syndrome (DIS) and rupture of the extensor pollicis longus (EPL) tendon in the same patient. A 38-year-old female presented for evaluation of a painful bump of unknown etiology on the dorsolateral aspect of her non-dominant wrist. US demonstrated tenosynovitis distal to Lister's tubercle of the EPL and extensor carpi radialis tendon sheaths, consistent with DIS. Immobilization therapy was employed, during which time the patient suffered rupture of the EPL tendon. Follow-up US examination confirmed this additional diagnosis. Characteristic US findings of DIS and EPL tendon rupture were observed. Surgical intervention was required and the patient recovered without complication. Although EPL rupture is relatively common in the literature, DIS is rare. This is the first known case of imaging-proven DIS progressing to EPL tendon rupture. This case underscores the value of US as a widely available, cost effective, and dynamic imaging modality for evaluation of wrist complaints. PMID- 28900525 TI - A case of Legionella pneumophila evaluated with CT and ultrasound. AB - A 36-year-old man was admitted to the emergency department of "SS Annunziata" hospital in Chieti complaining of a sharp chest pain arisen some hours before admission. On examination, the patient looked sweaty; his vital signs showed tachycardia and augmented breath rate; sinus tachycardia and normal ventricular repolarization were observed on ECG, and no abnormalities were observed in the echoscan of the hearth. According to the clinical and electrocardiographic findings, and to previous episode of DVT in anamnesis, a thorax CT scan was performed in order to rule out pulmonary embolism. It showed an "area of parenchymal consolidation involving almost all the left lower lobe with patent bronchial structures"; given the patient's CURB 65 score, he was then admitted to the pneumology ward where empiric treatment with levofloxacin (750 mg PO once daily) was initiated. Thoracic ultrasound was performed using a multifrequency convex transducer, and the posterior left area was examined through intercostal approach, placing the patient in a sitting position. A subpleural patchy hypoechoic lesion with irregular boundaries was detected; the maximum diameter was 11 cm, and the multiple hyperechoic spots inside it (elsewhere defined as "air bronchogram") showed no Doppler signal. Given the positive result of the Legionella urinary antigen test, antibiotic treatment was switched to Levofloxacin 1000 mg PO once daily and Claritromicin 500 mg PO twice daily. After 3 days, his clinical conditions improved dramatically. Ultrasound performed after 5 days from the diagnosis showed decreased dimensions of the lesion previously identified (maximum diameter 8.25 cm) and a marked reduction of the hyperechoic spots in it. The patient was discharged in good clinical conditions, and both thorax CT scan obtained after 1 and 4 months from the diagnosis showed radiological resolution of the parenchymal consolidation. The key to ultrasound visualization of pneumonia is its contact with the pleural surface (86-98% in cases of CAP) and the relative loss of aeration of the portion involved by the infection and a concomitant increase in the fluid content. A paradigmatic US image for parenchymal inflammatory infiltrate has not been established yet; anyway, some typical findings, when combined with the clinical features, can confirm the diagnostic hypothesis. PMID- 28900526 TI - Lung US features of severe interstitial pneumonia: case report and review of the literature. AB - BACKGROUND: Chlamydia pneumonia is reported to account for a relatively large number of cases of CAP. In elderly patients in particular, the clinical presentation can be a severe form of diffuse interstitial pneumonia. The chest X ray presentation is aspecific. Lung US can show a typical pattern of diffuse interstitial lung syndrome; in some cases, like the present one, the association of multiple B lines with a coarse and thickened pleural line points to a more likely diagnosis of interstitial pneumonia. CASE REPORT: We present the case of an 87-year-old woman with severe interstitial chlamydial pneumonia, for whom lung US was very useful for directing diagnosis and for follow-up during therapy. CONCLUSIONS: The use of lung US in the diagnosis of interstitial syndrome is likely to improve the care of patients in whom the diagnosis is a consideration; it offers better characterization than a chest X-ray and is free from CT radiation. Furthermore, the concept of using lung US for monitoring a patient is one of the major innovations that has emerged from recent studies. PMID- 28900527 TI - Copeman nodule: a case report. AB - The Copeman nodule is a disease of the subcutaneous soft tissue consisting in subcutaneous adipose tissue herniation through the superficial muscular fascia. A 30-year-old female patient presented with chronic left pain just above the iliac crest. Ultrasound examination showed subcutaneous adipose tissue herniation through the superficial muscular fascia with a hernia gap of 15.9 mm in diameter. Then the patient underwent surgery under local anesthesia with suturing of the hernia gap and immediate regression of chronic pain. Ultrasound can accurately highlight or exclude the presence of Copeman nodule and, in our view, should be used as first examination in patients with superficial chronic pain to the right or left side. PMID- 28900528 TI - Neonatal adrenal hemorrhage presenting as "Acute Scrotum"-looking beyond the obvious: a sonographic insight. AB - Acute swelling and discoloration of scrotum in new born can have many localized causes like testicular torsion, inguinal hernia, scrotal or testicular edema, hydrocele, or even remote causes like adrenal hemorrhage. We report a neonate of adrenal hemorrhage presenting clinically as acute scrotum misguiding the clinician to rule out a local scrotal pathology. As the local clinical examination is not reliable in a newborn, it definitely requires an imaging evaluation to establish the diagnosis. This case report emphasizes being aware of the clinical association of acute adrenal hemorrhage and an acute scrotum and the role of ultrasonography in the evaluation of the various differential diagnoses leading to an acute scrotum. An optimum sonographic examination helps in suspecting an abdominal pathology as a cause of acute scrotum and in establishing the specific diagnosis of adrenal hemorrhage to avoid an unnecessary surgical exploration. PMID- 28900530 TI - Pseudoangiomatous stromal hyperplasia presenting as accessory axillary breast tissue. PMID- 28900529 TI - High-resolution ultrasonography and shear-wave sonoelastography of a cystic radial nerve Schwannoma. AB - Peripheral nerve tumors are often evaluated with magnetic resonance imaging (MRI), although there are many advantages offered with high-resolution ultrasonography (HRUS). This case report emphasizes the value of HRUS in the diagnosis and management of a patient with a cystic radial nerve Schwannoma. In addition, information on tumor stiffness, obtained with shear-wave sonoelastography (SWE), is presented. PMID- 28900531 TI - A Pedunculated Neoplasm of the Thigh. PMID- 28900533 TI - Seabuckthorn Paste Protects Lipopolysaccharide-Induced Acute Lung Injury in Mice through Attenuation of Oxidative Stress. AB - Oxidative stress is one of the major mechanisms implicated in endotoxin-induced acute lung injury. Seabuckthorn paste (SP), a traditional Tibetan medicine with high content of polyphenols and remarkable antioxidant activity, is commonly used in treating pulmonary diseases. In the present study, the protective effects and possible underlying mechanisms of SP on lipopolysaccharide- (LPS-) induced acute lung injury in mice were investigated. It was found that body weight loss, lung tissue microstructure lesions, transvascular leakage increase, malondialdehyde augmentation, and the reduction of superoxide dismutase and glutathione peroxidase levels caused by LPS challenge were all consistently relieved by SP treatment in a dose-dependent manner. Moreover, accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in lung nuclei caused by SP treatment was observed. Our study demonstrated that SP can provide significant protection against LPS-induced acute lung injury through maintaining redox homeostasis, and its mechanism involves Nrf2 nuclear translocation and activation. PMID- 28900532 TI - Mitochondrial Function and Mitophagy in the Elderly: Effects of Exercise. AB - Aging is a natural, multifactorial and multiorganic phenomenon wherein there are gradual physiological and pathological changes over time. Aging has been associated with a decrease of autophagy capacity and mitochondrial functions, such as biogenesis, dynamics, and mitophagy. These processes are essential for the maintenance of mitochondrial structural integrity and, therefore, for cell life, since mitochondrial dysfunction leads to an impairment of energy metabolism and increased production of reactive oxygen species, which consequently trigger mechanisms of cellular senescence and apoptotic cell death. Moreover, reduced mitochondrial function can contribute to age-associated disease phenotypes in model organisms and humans. Literature data show beneficial effects of exercise on the impairment of mitochondrial biogenesis and dynamics and on the decrease in the mitophagic capacity associated to aging. Thus, exercise could have effects on the major cell signaling pathways that are involved in the mitochondria quality and quantity control in the elderly. Although it is known that several exercise protocols are able to modify the activity and turnover of mitochondria, further studies are necessary in order to better identify the mechanisms of interaction between mitochondrial functions, aging, and physical activity, as well as to analyze possible factors influencing these processes. PMID- 28900534 TI - Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades. AB - The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF-kappaB-TNF-alpha/IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes. PMID- 28900535 TI - The Effects of Aerobic Exercises and 25(OH) D Supplementation on GLP1 and DPP4 Level in Type II Diabetic Patients. AB - BACKGROUND: The purpose of this study was to investigate the effects of an 8-week aerobic exercise and supplementation of 25(OH)D3 on GLP1 and DDP4 levels in men with type II diabetes. METHODS: In this semiexperimental research, among 40-60 year-old men with type II diabetes who were referred to the diabetic center of Isabn-E Maryam hospital in Isfahan; of whom, 48 patients were voluntarily accepted and then were randomly divided into 4 groups: aerobic exercise group, aerobic exercise with 25(OH) D supplement group, 25(OH) D supplement group, and the control group. An aerobic exercise program was conducted for 8 weeks (3 sessions/week, each session 60 to75 min with 60-80% HRmax). The supplement user group received 50,000 units of oral Vitamin D once weekly for 8 weeks. The GLP1, DPP4, and 25(OH) D levels were measured before and after the intervention. At last, the data were statistically analyzed using the ANCOVA and post hoc test of least significant difference. RESULTS: The results of ANCOVA showed a significant difference between the GLP1 and DPP4 levels in aerobic exercise with control group while these changes were not statistically significant between the 25(OH) D supplement group with control group (P < 0.05). CONCLUSIONS: Aerobic exercises have resulted an increase in GLP1 level and a decrease in DPP4 level. However, consumption of Vitamin D supplement alone did not cause any changes in GLP1and DPP4 levels but led to an increase in 25-hydroxy Vitamin D level. PMID- 28900536 TI - Construct and Criterion Validity of the PedsQLTM 4.0 Instrument (Pediatric Quality of Life Inventory) in Colombia. AB - BACKGROUND: This study aimed at determining the validity of the Pediatric Quality of Life Inventory 4.0 (PedsQLTM 4.0) for the measurement of health-related quality of life (HRQOL) in Colombian children. METHODS: Validation study of measurement instruments. The PedsQLTM 4.0 was applied by convenience sampling to 375 pairs of children and adolescents between the ages of 5 and 17 and to their parents-caregivers, as well as to 125 parents-caregivers of children between the ages of 2 and 4 in five cities of Colombia (Bogota, Medellin, Cali, Barranquilla and Bucaramanga). Construct validity was assessed through the use of exploratory and confirmatory factor analysis, and criterion validity was assessed by correlations between the PedsQLTM 4.0 and the KIDSCREEN-27. RESULTS: The instrument was applied to 375 children (ages 5-18) and 125 parents of children between the ages of 2 and 4. Factor analysis revealed four factors considered suitable for the sample in both the child and parent reports, whereas Bartlett's test of sphericity showed inter-correlation between variables. Scale and subscales showed proper indicators of internal consistency. It is recommended not to include or review some of the items in the Colombian version of the scale. CONCLUSIONS: The Spanish version for Colombia of the PedsQLTM 4.0 displays suitable indicators of criterion and construct validity, therefore becoming a valuable tool for measuring HRQOL in children in our country. Some modifications are recommended for the Colombian version of the scale. PMID- 28900537 TI - Protective Effect of Two Extracts of Cydonia oblonga Miller (Quince) Fruits on Gastric Ulcer Induced by Indomethacin in Rats. AB - BACKGROUND: In various studies, Cydonia oblonga Miller (quince) has been reported to have many properties such as antioxidant and anti-ulcerative effects. This study has aimed to investigate the protective effects of quince aqueous extract (QAE) and quince hydroalcoholic extract (QHE) on gastric ulcer caused by indomethacin and the relevant macroscopic, histopathology, and biochemical factors in rats. METHODS: Ten groups of male Wistar rats, six in each, were used in this study. These groups included: normal (distilled water), control (distilled water + indomethacin), reference (ranitidine or sucralfate + indomethacin), and test groups (QAE or QHE + indomethacin) treated with three increasing doses (200, 500, and 800 mg/kg). Extracts and drugs were given orally to rats 1 h before injecting the indomethacin (25 mg/kg, intraperitoneally). Six hours later, the abdomen of rats was exposed, its pylorus was legated, gastric acid content was extracted, and its pH and the amount of pepsin secreted were measured by Anson method. Then, histopathology indices, ulcer area, ulcer index, and myeloperoxidase (MPO) activity were measured in gastric mucus. RESULTS: Both extracts of quince were effective to reduce the acidity of stomach and pepsin activity. Compared to control group, the average of enzyme activity of MPO was significantly declined in all treated groups. Control group had the highest level of gastric ulcer indices including severity, area, and index while the evaluated parameters had decreased in all extract treated groups although it seems that QAE was somewhat more effective. CONCLUSIONS: Protective effect of QAE and QHE on gastric ulcer was done by undermining offensive factors including decreasing the secretion of gastric acid and pepsin activity and by strengthening the protective factors of gastric mucus including antioxidant capacity. PMID- 28900538 TI - Corrigendum: A 4-study replication of the moderating effects of greed on socioeconomic status and unethical behaviour. AB - [This corrects the article DOI: 10.1038/sdata.2016.120.]. PMID- 28900539 TI - Probing the internal micromechanical properties of Pseudomonas aeruginosa biofilms by Brillouin imaging. AB - Biofilms are organised aggregates of bacteria that adhere to each other or surfaces. The matrix of extracellular polymeric substances that holds the cells together provides the mechanical stability of the biofilm. In this study, we have applied Brillouin microscopy, a technique that is capable of measuring mechanical properties of specimens on a micrometre scale based on the shift in frequency of light incident upon a sample due to thermal fluctuations, to investigate the micromechanical properties of an active, live Pseudomonas aeruginosa biofilm. Using this non-contact and label-free technique, we have extracted information about the internal stiffness of biofilms under continuous flow. No correlation with colony size was found when comparing the averages of Brillouin shifts of two dimensional cross-sections of randomly selected colonies. However, when focusing on single colonies, we observed two distinct spatial patterns: in smaller colonies, stiffness increased towards their interior, indicating a more compact structure of the centre of the colony, whereas, larger (over 45 MUm) colonies were found to have less stiff interiors. PMID- 28900540 TI - Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. AB - A favorable effect of an inhibitor of the sodium-glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA 1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance. PMID- 28900541 TI - Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib. AB - Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin in vitro. Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both in vitro and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4highGADD45Blow was significantly poorer compared to patients with ACSL4lowGADD45Bhigh, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4highGADD45Blow. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4highGADD45Blow expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits. PMID- 28900543 TI - Switching to Aflibercept in Diabetic Macular Edema Not Responding to Ranibizumab and/or Intravitreal Dexamethasone Implant. AB - PURPOSE: To assess short-term functional and anatomical outcomes of refractory diabetic macular edema (DME) following a switch from ranibizumab or dexamethasone to aflibercept. METHODS: We included retrospectively eyes with persistent DME after at least 3 ranibizumab and/or one dexamethasone implant intravitreal injections (IVI). The primary endpoint was the mean change in visual acuity (VA) at month 6 (M6) after switching. RESULTS: Twenty-five eyes were included. Before switching to aflibercept, 23 eyes received a median of 9.5 ranibizumab, and among them, 6 eyes received one dexamethasone implant after ranibizumab and 2 eyes received only one dexamethasone implant. Baseline VA, before any IVI, was 52.9 +/ 16.5 letters, and preswitch VA was 57.1 +/- 19.6 letters. The mean VA gain was +8 letters (p = 0.01) between preswitch and M6. The mean central retinal thickness was 470.8 +/- 129.9 MUm before the switch and 303.3 +/- 59.1 MUm at M6 (p = 0.001). CONCLUSION: Switching to aflibercept in refractory DME results in significant functional and anatomical improvement. The study was approved by the France Macula Federation ethical committee (FMF 2017-138). PMID- 28900544 TI - Effect of Spherical Aberration on the Optical Quality after Implantation of Two Different Aspherical Intraocular Lenses. AB - PURPOSE: To compare the effect of spherical aberration on optical quality in eyes with two different aspherical intraocular lenses. METHODS: 120 eyes of 60 patients underwent phacoemulsification. In patients' eyes, an aberration-free IOL (Aspira-aA; Human Optics) or an aberration-correcting aspherical IOL (Tecnis ZCB00; Abott Medical Optics) was randomly implanted. After surgery, contrast sensitivity and wavefront measurements as well as tilt and decentration measurements were performed. RESULTS: Contrast sensitivity was significantly higher in eyes with Aspira lens under mesopic conditions with 12 cycles per degree (CPD) and under photopic conditions with 18 CPD (p = 0.02). Wavefront measurements showed a higher total spherical aberration with a minimal pupil size of 4 mm in the Aspira group (0.05 +/- 0.03) than in the Tecnis group (0.03 +/- 0.02) (p = 0.001). Strehl ratio was higher in eyes with Tecnis (0.28 +/- 0.17) with a minimal pupil size larger than 5 mm than that with Aspira (0.16 +/- 0.14) (p = 0.04). In pupils with a minimum diameter of 4 mm spherical aberration had a significant effect on Strehl ratio, but not in pupils with a diameter less than 4 mm. CONCLUSIONS: Optical quality was better in eyes with the aberration correcting Tecnis IOL when pupils were large. In contrast, this could not be shown in eyes with pupils under 4 mm or larger. This trial is registered with Clinicaltrials.gov NCT03224728. PMID- 28900542 TI - Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. AB - Mitochondrial DNA copy number is strictly regulated during development as naive cells differentiate into mature cells to ensure that specific cell types have sufficient copies of mitochondrial DNA to perform their specialised functions. Mitochondrial DNA haplotypes are defined as specific regions of mitochondrial DNA that cluster with other mitochondrial sequences to show the phylogenetic origins of maternal lineages. Mitochondrial DNA haplotypes are associated with a range of phenotypes and disease. To understand how mitochondrial DNA haplotypes induce these characteristics, we used four embryonic stem cell lines that have the same set of chromosomes but possess different mitochondrial DNA haplotypes. We show that mitochondrial DNA haplotypes influence changes in chromosomal gene expression and affinity for nuclear-encoded mitochondrial DNA replication factors to modulate mitochondrial DNA copy number, two events that act synchronously during differentiation. Global DNA methylation analysis showed that each haplotype induces distinct DNA methylation patterns, which, when modulated by DNA demethylation agents, resulted in skewed gene expression patterns that highlight the effectiveness of the new DNA methylation patterns established by each haplotype. The haplotypes differentially regulate alpha-ketoglutarate, a metabolite from the TCA cycle that modulates the TET family of proteins, which catalyse the transition from 5-methylcytosine, indicative of DNA methylation, to 5-hydroxymethylcytosine, indicative of DNA demethylation. Our outcomes show that mitochondrial DNA haplotypes differentially modulate chromosomal gene expression patterns of naive and differentiating cells by establishing mitochondrial DNA haplotype-specific DNA methylation patterns. PMID- 28900545 TI - Outcomes of Laparoscopic Gastric Greater Curvature Plication in Morbidly Obese Patients. AB - BACKGROUND: Laparoscopic gastric greater curvature plication (LGGCP) is a restrictive bariatric procedure without gastrectomy. However, limited literature on effectiveness of gastric plication exists. OBJECTIVES: We assessed LGGCP's efficacy, effects on associated comorbidities, safety and the rate of complications, and patient satisfaction with LGGCP's outcomes among morbidly obese patients. METHOD: Analysis of retrospectively data collected from medical records of 26 patients who had undergone LGGCP at Hamad General Hospital, Qatar, during 2011-2012. RESULTS: Most patients (92%) were Qatari nationals. The sample's mean age was 35.1 years. Mean duration of hospital stay was 3.9 +/- 1.2 days. Mean preoperative BMI was 40.7 kg/m2 that decreased at 2 years to 34.6 kg/m2. LGGCP's effects on comorbidities were such that 7.6% of patients experienced resolutions of their comorbidities. There were no mortality or postoperative complications that required reoperation. Six patients (23%) were satisfied with the LGGCP's outcomes while 10 patients (38.5%) underwent sleeve gastrectomy subsequently. CONCLUSION: LGGCP had acceptable short term weight loss results, exhibited almost no postoperative complications, and improved patients' comorbidities. Despite the durability of the gastric fold, some patients regained weight. Future research may assess the possibility of an increase in the gastric pouch size postplication associated with weight regain. PMID- 28900546 TI - Short-Term and Long-Term Effects of an Exercise-Based Patient Education Programme in People with Multiple Sclerosis: A Pilot Study. AB - Background. Although people with Multiple Sclerosis (pwMS) benefit from physical exercise, they still show reduced physical activity and exercise behaviour. This study aimed to investigate short- and long-term effects of an exercise-based patient education programme (ePEP) that focuses on empowering pwMS to a sustainable and self-regulated exercise training management. Methods. Fourteen pwMS were randomly assigned to immediate experimental group (EG-I: n = 8) and waitlist-control group (EG-W: n = 6) and attended biweekly in a six-week ePEP. All participants were measured for walking ability, quality of life, fatigue, and self-efficacy towards physical exercise before and after the ePEP, after 12 weeks, and one year after baseline. Short-term effects were analysed in a randomised control trial and long-term effects of all ePEP participants (EG-I + EG-W = EG-all) in a quasi-experimental design. Results. Only functional gait significantly improved in EG-I compared to EG-W (p = 0.008, r = -0.67). Moderate to large effects were found in EG-all for walking ability. Not significant, however, relevant changes were detected for quality of life and fatigue. Self efficacy showed no changes. Conclusion. The ePEP seems to be a feasible option to empower pwMS to a self-regulated and sustainable exercise training management shown in long-term walking improvements. PMID- 28900547 TI - Chagas Cardiomyopathy Presenting as Symptomatic Bradycardia: An Underappreciated Emerging Public Health Problem in the United States. AB - Chagas cardiomyopathy (CCM) is traditionally considered a disease restricted to areas of endemicity. However, an estimated 300,000 people living in the United States today have CCM, of which its majority is undiagnosed. We present a case of CCM acquired in an endemic area and detected in its early stage. A 42-year-old El Salvadoran woman presented with recurrent chest pain and syncopal episodes. Significant family history includes a sister in El Salvador who also began suffering similar episodes. Physical exam and ancillary studies were only remarkable for sinus bradycardia. The patient was diagnosed with symptomatic sinus bradycardia and a pacemaker was placed. During her hospital course, Chagas serology was ordered given the epidemiological context from which she came. With no other identifiable cause, CCM was the suspected etiology. This case highlights the underrecognized presence of Chagas in the United States and the economic and public health importance of its consideration in the etiological differential diagnosis of electrocardiographic changes among Latin American immigrants. While the United States is not considered an endemic area for Chagas disease, the influx of Latin American immigrants has created a new challenge to identify at risk populations, diagnose suspected cases, and provide adequate treatment for this disease. PMID- 28900548 TI - A Case of Female Acute Urinary Retention Presenting to the ED. AB - INTRODUCTION: Acute urinary retention is a rare occurrence in women necessitating further investigation. Potential underlying causes may be broadly classified into obstructive, neurological, pharmacological, and psychogenic categories. CASE: A 36-year-old nulliparous female presented to the Emergency Department with a two day history of acute urinary retention. Point-of-care ultrasonography and CT scan imaging confirmed the presence of a large uterine mass causing compression of the bladder. The acute retention was relieved with urethral catheterization. A Uterine leiomyoma was confirmed on histology after hysterectomy. DISCUSSION: Once the acute urinary retention has been relieved by insertion of a urethral catheter, the underlying cause of the obstruction must be determined. Although uterine leiomyoma is a fairly common finding in the general population, it is an extremely rare cause of acute urinary retention in women with just a handful of reported cases in the literature. PMID- 28900549 TI - Myoepithelioma of the Parotid Gland: A Case Report with Review of the Literature and Classic Histopathology. AB - Myoepithelioma is a rare salivary gland neoplasm. They most commonly affect the major and minor salivary glands with the parotid gland being the most common, approximately 40%. Only 1% of all salivary gland neoplasms are myoepitheliomas. Myoepithelioma is usually a benign tumor arising from neoplastic myoepithelial or basket cells which are found between the basement membrane and the basal plasma membrane of acinar cells. They also contain multiple cellular elements. We present a case of a 73-year-old female with myoepithelioma of the parotid gland, an extremely rare neoplasm. There have been approximately 42 cases reported through 1985 and fewer than 100 cases through 1993. We will discuss the clinical presentation, pathophysiology, diagnosis, and treatment of such neoplasms. PMID- 28900550 TI - Bilateral Mesenchymal Hamartoma of the Chest Wall in a 3-Month-Old Boy: A Case Report and Review of the Literature. AB - Mesenchymal hamartoma of the chest wall is a well-recognized but extremely rare entity. This entity is believed to be benign with no propensity for invasion or metastasis. Although the lesion manifests with alarming aggressive clinical, radiological, and histological features, it is considered benign and carries an excellent outcome. Therefore it is important to recognize this benign entity to avoid the possible misdiagnosis of malignancy and the unnecessary use of chemotherapy. We present a case of bilateral multifocal mesenchymal hamartomas of the chest wall in a male infant and a literature review of this entity. Our aim is to improve the awareness of this condition and highlight its benign behavior and satisfactory outcome following complete surgical resection. PMID- 28900551 TI - Appendicitis Caused by Primary Varicella Zoster Virus Infection in a Child with DiGeorge Syndrome. AB - INTRODUCTION: Chickenpox is caused by varicella zoster virus (VZV). Although predominantly a mild disease, it can cause considerable morbidity and in rare occasions even mortality in healthy children as well as increased morbidity and mortality in immunocompromised patients. The aetiology of appendicitis is largely unknown but is thought to be multifactorial. Appendicitis is a suspected, but not well documented, complication from varicella zoster virus infection. CASE PRESENTATION: A five-year-old girl diagnosed with DiGeorge syndrome and a prolonged primary VZV infection was admitted due to abdominal pain, increasing diarrhoea, vomiting, and poor general condition. She developed perforated appendicitis and an intraperitoneal abscess. VZV DNA was detected by PCR in two samples from the appendix and pus from the abdomen, respectively. The child was treated with acyclovir and antibiotics and the abscess was drained twice. She was discharged two weeks after referral with no sequela. CONCLUSION: Abdominal pain in children with viral infections can be a challenge, and appendicitis has to be considered as a complication to acute viral diseases, especially if the child is immunocompromised. PMID- 28900552 TI - Electronic Cigarette Use among Mississippi Adults, 2015. AB - Electronic cigarettes (e-cigarettes) are battery-powered devices that deliver nicotine in the form of aerosol. We identify differences and associations in e cigarette use by sociodemographic characteristics and describe the reported reasons for initiating use among Mississippi adults. We used the 2015 Mississippi Behavioral Risk Factor Surveillance System, which collected information on e cigarette use from 6,035 respondents. The prevalence of current e-cigarette use and having ever tried an e-cigarette was determined overall and by sociodemographic characteristics. Weighted prevalences and 95% confidence intervals were calculated, and prevalences for subgroups were compared using the X2 tests and associations were assessed using logistic regression. In 2015, 4.7% of Mississippi adults currently used e-cigarettes, while 20.5% had ever tried an e-cigarette. The prevalence of current e-cigarette use was significantly higher for young adults, whites, men, individuals unable to work, those with income $35,000-$49,999, and current smokers compared to their counterparts. Similar results were observed for having ever tried an e-cigarette. E-cigarette use was associated with age, race, income, and smoking status. Most (71.2%) of current e cigarette users and over half (52.1%) of those who have ever tried e-cigarettes reported that a main reason for trying or using e-cigarettes was "to cut down or quit smoking." PMID- 28900553 TI - Treatment of Partial Rotator Cuff Tear with Ultrasound-guided Platelet-rich Plasma. AB - BACKGROUND: The treatment of symptomatic partial rotator cuff tear has presented substantial challenge to orthopaedic surgeons as it can vary from conservative to surgical repair. Researches have established the influence of platelet rich plasma in healing damaged tissue. Currently very few data are available regarding the evidence of clinical and radiological outcome of partial rotator cuff tear treated with ultrasound guided platelet rich plasma injection in English literature. MATERIALS AND METHODS: 20 patients with symptomatic partial rotator cuff tears were treated with ultrasound guided platelet rich plasma injection. Before and after the injection of platelet rich plasma scoring was done with visual analogue score, Constant shoulder score, and UCLA shoulder score at 8 weeks and third month. A review ultrasound was performed 8 weeks after platelet rich plasma injection to assess the rotator cuff status. RESULTS: Our study showed statistically significant improvements in 17 patients in VAS pain score, constant shoulder score and UCLA shoulder score. No significant changes in ROM were noted when matched to the contra-lateral side (P < 0.001) at the 3 month follow-up. The study also showed good healing on radiological evaluation with ultrasonogram 8 weeks after platelet rich plasma injection. CONCLUSION: Ultrasound guided platelet rich plasma injection for partial rotator cuff tears is an effective procedure that leads to significant decrease in pain, improvement in shoulder functions, much cost-effective and less problematic compared to a surgical treatment. PMID- 28900554 TI - Primary Epithelioid Angiosarcoma of Lung: Radiologic and Clinicopathologic Correlation. AB - Primary pulmonary angiosarcoma is extremely rare. It is often characterized by a clinically indolent course and delayed diagnosis. To date, there have been <20 cases reported. By far, little article correlates the clinical presentation, the imaging findings with the pathology. The authors present a case of middle-aged gentleman with primary pulmonary epithelioid angiosacroma which we initially thought as tuberculosis (TB) infection. A 60-year-old gentleman, with a history of 6 months on and off blood stained sputum, was admitted for an episode of massive hemoptysis. Urgent computed tomography (CT) bronchial arteriogram excluded any dilated bronchial artery. Patchy consolidation with multiple small centrilobular ground-glass nodules was noted at left upper lobe. The bronchoscopy was negative for malignancy and infection. Autoimmune workup was negative. Despite negative bronchoscopy, fungal, acid-fast bacilli culture and cytology, and anti-TB treatment were empirically given. However, his hemoptysis was unresolved. He was followed up with high-resolution CT after a month showed an enlarging left upper lobe mass surrounding by a ground glass halo. Left thoracotomy and left upper lobe lobectomy were performed. Epithelioid angiosacroma was found in histology. Radiologic and clinical-pathological findings were correlated in this paper. PMID- 28900555 TI - The Utility of Dual Energy Computed Tomography in Musculoskeletal Imaging. AB - The objective of this article is to review the mechanisms, advantages and disadvantages of dual energy computed tomography (DECT) over conventional tomography (CT) in musculoskeletal imaging as DECT provides additional information about tissue composition and artifact reduction. This provides clinical utility in detection of urate crystals, bone marrow edema, reduction of beam hardening metallic artifact, and ligament and tendon analysis. PMID- 28900556 TI - THE DYNAMIC LEAP AND BALANCE TEST (DLBT): A TEST-RETEST RELIABILITY STUDY. AB - BACKGROUND: There is a need for new clinical assessment tools to test dynamic balance during typical functional movements. Common methods for assessing dynamic balance, such as the Star Excursion Balance Test, which requires controlled movement of body segments over an unchanged base of support, may not be an adequate measure for testing typical functional movements that involve controlled movement of body segments along with a change in base of support. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the reliability of the Dynamic Leap and Balance Test (DLBT) by assessing its test-retest reliability. It was hypothesized that there would be no statistically significant differences between testing days in time taken to complete the test. STUDY DESIGN: Reliability study. METHODS: Thirty healthy college aged individuals participated in this study. Participants performed a series of leaps in a prescribed sequence, unique to the DLBT test. Time required by the participants to complete the 20-leap task was the dependent variable. Subjects leaped back and forth from peripheral to central targets alternating weight bearing from one leg to the other. Participants landed on the central target with the tested limb and were required to stabilize for two seconds before leaping to the next target. Stability was based upon qualitative measures similar to Balance Error Scoring System. Each assessment was comprised of three trials and performed on two days with a separation of at least six days. RESULTS: Two-way mixed ANOVA was used to analyze the differences in time to complete the sequence between the three trial averages of the two testing sessions. Intraclass Correlation Coefficient (ICC3,1) was used to establish between session test-retest reliability of the test trial averages. Significance was set a priori at p <= 0.05. No significant differences (p > 0.05) were detected between the two testing sessions. The ICC was 0.93 with a 95% confidence interval from 0.84 to 0.96. CONCLUSION: This test is a cost effective, easy to administer and clinically relevant novel measure for assessing dynamic balance that has excellent test-retest reliability. CLINICAL RELEVANCE: As a new measure of dynamic balance, the DLBT has the potential to be a cost effective, challenging and functional tool for clinicians. LEVEL OF EVIDENCE: 2b. PMID- 28900557 TI - INTER- AND INTRA-RATER RELIABILITY OF PERFORMANCE MEASURES COLLECTED WITH A SINGLE-CAMERA MOTION ANALYSIS SYSTEM. AB - BACKGROUND: Previous reliability investigations of single-camera three dimensional (3D) motion analysis systems have reported mixed results. PURPOSE: The purpose of the current study was to determine the intra- and inter-rater reliability of a single-camera 3D motion analysis system for subject standing height, vertical jump height, and broad jump length. STUDY DESIGN: Experimental in vivo reliability study. PARTICIPANTS: Twelve subjects (age 20.6 +/- 4.9 years) from a cohort that included high school to adult athletes who participated in sports at a recreational or competitive level entered and completed the study. Performance measurements were collected by a single-camera 3D motion analysis system and two human testers for standard clinical techniques. Inter- and intra class correlation coefficients (ICC (2,k), ICC (2,1)) were determined. RESULT: Intra-tester and inter-tester reliability were excellent (ICC >= 0.935) for single-camera system measured variables. Single-camera system measurements were slightly more reliable than clinical measurements for intra-tester ratings (ICC difference 0.020) for the standing broad jump. Single-camera system measurements were slightly less reliable than clinical measures for both intra- and inter specimen standing height (mean ICC difference 0.003 and 0.043, respectively) and vertical jump height (mean ICC difference 0.017 and 0.036, respectively). CONCLUSIONS: The excellent reliability and previously demonstrated validity of the single-camera system along the anterior-posterior axis indicates that single camera motion analysis may be a valid surrogate for clinically accepted manual measurements of performance in the horizontal plane. However, this single-camera 3D motion analysis system is likewise reliable, but inaccurate, for vertically oriented performance measurements. LEVEL OF EVIDENCE: 2b. PMID- 28900558 TI - VALIDITY OF ATHLETIC TASK PERFORMANCE MEASURES COLLECTED WITH A SINGLE-CAMERA MOTION ANALYSIS SYSTEM AS COMPARED TO STANDARD CLINICAL MEASUREMENTS. AB - BACKGROUND: Previous investigations of single-camera 3D motion analysis camera systems validity have yielded mixed results for clinical applications. PURPOSE: The purpose of the current study was to determine the validity of a single-camera 3D motion analysis system for subject standing height, vertical jump height, and broad jump length. It was hypothesized that single-camera system values would demonstrate high correlation to the values obtained from accepted standard clinical measurements. STUDY DESIGN: Experimental in vivo validation study. METHODS: Twelve subjects (age 20.6 +/- 4.9 years) from a cohort that included high school to adult athletes who participate in sports at a recreational or competitive level entered and completed the study. Performance measurements for standing height, vertical jump height, and broad jump length were measured with standard clinical measurements and a single-camera 3D motion system. RESULT: Single-camera system measurements were significantly different than clinical measures for standing height (p < 0.01) and vertical jump height (p < 0.01). There was no statistically significant difference between single-camera system measures and clinical measures for broad jump distance (p > 0.07). The relative performance of subjects was highly correlated between single-camera and clinical measurements (r2 > 0.80). CONCLUSIONS: Single-camera measurements lacked precision along the vertical axis of motion, but correlated well with clinically accepted measurements for standing height, broad jump length, and vertical jump height. The single-camera system may be capable of making accurate performance assessments in the horizontal plane, but should be limited to relative assessments along the vertical axis of motion. Additional refinement to increase the data reporting accuracy of the motion system along the vertical axis should be considered before relying on this single-camera 3D motion analysis system over clinical techniques to measure vertical jump and standing broad jump performances. LEVEL OF EVIDENCE: 2b. PMID- 28900559 TI - PEAK HIP MUSCLE TORQUE MEASUREMENTS ARE INFLUENCED BY SAGITTAL PLANE HIP POSITION. AB - BACKGROUND: An optimal position for strength testing of the hip musculature has not been identified. However, sagittal plane hip position during testing has been shown to influence hip external rotation strength. HYPOTHESIS/PURPOSE: The purpose of this study was to compare hip extension, external rotation, and abduction isometric torque at positions with differing degrees of hip flexion using a handheld dynamometer. STUDY DESIGN: A cross-sectional laboratory study. METHODS: Twenty-nine healthy and physically active females participated in this study. Peak isometric contractions were measured with a handheld dynamometer secured with a non-elastic strap and then converted to torque using segment lengths. Hip external rotation and extension were tested at 0 degrees , 30 degrees , and 90 degrees of hip flexion. Hip abduction was tested at 0 degrees and 30 degrees of hip flexion and 5 degrees of extension. Testing was randomized and counterbalanced. Repeated measures ANOVAs with Sidak's test for multiple comparisons were used for statistical analysis. Significance was set at p<0.05. RESULTS: Significant main effects were found for hip extension (p<0.001) and external rotation (p<0.027), but not for abduction (p=0.085). Pairwise comparisons showed significant differences between all three testing positions for hip extension torque (0 degrees v30 degrees : p<0.001, 0 degrees v90 degrees : p<0.001, 30 degrees v90 degrees : p=0.002). Extension torque was highest in 90 degrees of flexion (1.43 +/- 0.50 Nm/kg*m) and lowest in 0 degrees of flexion (0.83 +/- 0.30 Nm/kg*m). Comparisons of hip external rotation torque tested at 0 degrees v90 degrees (p=0.096) and 30 degrees v90 degrees (p=0.080) were not significantly different but did have medium effect sizes. External rotation torque was highest in 90 degrees of flexion (0.29 +/- 0.13 Nm/kg*m). CONCLUSIONS: Direct comparisons of torque values of hip extension and external rotation tested at different sagittal plane positions should be cautioned due to differences. Hip extension and external rotation should be measured in consistent sagittal plane positions across examiners and testing sessions. Test position will be dependent upon the goals of strength testing. LEVEL OF EVIDENCE: 2b. PMID- 28900560 TI - BUILDING A BETTER GLUTEAL BRIDGE: ELECTROMYOGRAPHIC ANALYSIS OF HIP MUSCLE ACTIVITY DURING MODIFIED SINGLE-LEG BRIDGES. AB - BACKGROUND: Gluteal strength plays a role in injury prevention, normal gait patterns, eliminating pain, and enhancing athletic performance. Research shows high gluteal muscle activity during a single-leg bridge compared to other gluteal strengthening exercises; however, prior studies have primarily measured muscle activity with the active lower extremity starting in 90 degrees of knee flexion with an extended contralateral knee. This standard position has caused reports of hamstring cramping, which may impede optimal gluteal strengthening. HYPOTHESIS/PURPOSE: The purpose of this study was to determine which modified position for the single-leg bridge is best for preferentially activating the gluteus maximus and medius. STUDY DESIGN: Cross-Sectional. METHODS: Twenty-eight healthy males and females aged 18-30 years were tested in five different, randomized single-leg bridge positions. Electromyography (EMG) electrodes were placed on subjects' gluteus maximus, gluteus medius, rectus femoris, and biceps femoris of their bridge leg (i.e., dominant or kicking leg), as well as the rectus femoris of their contralateral leg. Subjects performed a maximal voluntary isometric contraction (MVIC) for each tested muscle prior to performing five different bridge positions in randomized order. All bridge EMG data were normalized to the corresponding muscle MVIC data. RESULTS: A modified bridge position with the knee of the bridge leg flexed to 135 degrees versus the traditional 90 degrees of knee flexion demonstrated preferential activation of the gluteus maximus and gluteus medius compared to the traditional single-leg bridge. Hamstring activation significantly decreased (p < 0.05) when the dominant knee was flexed to 135 degrees (23.49% MVIC) versus the traditional 90 degrees (75.34% MVIC), while gluteal activation remained similarly high (51.01% and 57.81% MVIC in the traditional position, versus 47.35% and 57.23% MVIC in the modified position for the gluteus maximus and medius, respectively). CONCLUSION: Modifying the traditional single-leg bridge by flexing the active knee to 135 degrees instead of 90 degrees minimizes hamstring activity while maintaining high levels of gluteal activation, effectively building a bridge better suited for preferential gluteal activation. LEVEL OF EVIDENCE: 3. PMID- 28900561 TI - EFFECTS OF A BAND LOOP ON LOWER EXTREMITY MUSCLE ACTIVITY AND KINEMATICS DURING THE BARBELL SQUAT. AB - BACKGROUND: Medial knee collapse can signal an underlying movement issue that, if uncorrected, can lead to a variety of knee injuries. Placing a band around the distal thigh may act as a proprioceptive aid to minimize medial collapse of the knee during squats; however, little is known about EMG and biomechanics in trained and untrained individuals during the squat with an elastic band added. HYPOTHESIS/PURPOSE: To investigate the effects of the TheraBand(r) Band Loop on kinematics and muscle activity of the lower extremity during a standard barbell back squat at different intensities in both trained and untrained individuals. STUDY DESIGN: Cross-sectional, repeated measures. METHODS: Sixteen healthy, male, university aged-participants were split into two groups of eight, consisting of a trained and untrained group. Participants performed both a 3-repetition maximum (3-RM) and a bodyweight load squat for repetitions to failure. Lower extremity kinematics and surface electromyography of four muscles were measured bilaterally over two sessions, an unaided squat and a band session (band loop placed around distal thighs). Medial knee collapse, measured as a knee width index, and maximum muscle activity were calculated. RESULTS: During the 3-RM, squat weight was unaffected by band loop intervention (p = 0.486) and the trained group lifted more weight than the untrained group (p<0.007). The trained group had a greater squat depth for both squat conditions, regardless of the band (p = 0.0043). Knee width index was not affected by the band during the eccentric phase of bodyweight squats in the trained (band: 0.76 +/- 0.08, no band: 0.73 +/- 0.08) or untrained group (band: 0.77 +/- 0.70, no band: 0.75 +/- 0.13) (p = 0.670). During the concentric phase, knee width index was significantly lower for 3-RM squats, regardless of group. CONCLUSION: Despite minimal changes in kinematics for the untrained group, increased muscle activity with the band loop may suggest that a training aid may, over time, lead to an increase in barbell squat strength by increasing activation of agonist muscles more than traditional, un-banded squats. Greater maximal muscle activity in most muscles during band loop sessions may provide enhanced knee stability via increased activation of stabilizing muscles. LEVEL OF EVIDENCE: 3. PMID- 28900562 TI - A Biomechanical Comparison Among Three Kinds of Rebound-Type Jumps in Female Collegiate Athletes. AB - BACKGROUND: Single-legged drop jumps (SDJ), single-legged repetitive jumps (SRJ), and single-legged side hops (SSH) are often used as plyometric training and functional performance tests. Differences in the kinetics and kinematic characteristics of lower extremity joints during these jumps are unclear. HYPOTHESIS/PURPOSE: The purpose of this study was to investigate the joint motion and mechanical work of the takeoff leg from foot contact to foot-off during SDJ, SRJ, and SSH in the sagittal and frontal planes in female athletes. It was hypothesized that the joint motion and mechanical work of the lower extremity joints during the SDJ and SRJ would be larger than the SSH in the sagittal plane, those during the SSH would be larger than the SDJ and SRJ in the frontal plane, and during SRJ would be larger than SDJ. STUDY DESIGN: Cross-sectional study. METHODS: Seventeen female collegiate athletes participated and performed the SDJ (0.15-m box height), and SRJ and SSH (by crossing two lines 0.3 m apart). Three dimensional coordinate data and ground reaction forces were collected. Contact time, jump height, jump index (i.e., the jump height divided by the contact time) of the SDJ and SRJ, and the total times of the SSH were calculated. Range of motion (ROM) from touchdown to the lowest center of mass, and the positive and negative (mechanical) work from touchdown to foot-off were analyzed. RESULTS: There were no significant differences in jump performance variables. Compared to the SSH, the SDJ and SRJ had significantly larger ankle and knee ROM and positive and negative work at the lower extremity joints, except for positive work at the hip joint, in the sagittal plane (p < 0.05). Compared to the SDJ and SRJ, the SSH had a significantly larger ankle ROM and positive work at the knee joint in the frontal plane (p < 0.05). Compared to the SDJ, the SRJ had a significantly larger ROM and negative work at each lower extremity joint in the frontal plane (p < 0.05). CONCLUSION: Although there were no significant differences in the jump performance variables, different characteristics of the takeoff leg ROM and mechanical work were found between three kinds of rebound-type jump tests. These findings may help clinicians choose jump methods to assess lower extremity function and to design plyometric training programs in sports and clinical fields. LEVEL OF EVIDENCE: 3b. PMID- 28900563 TI - CADAVERIC EVALUATION OF THE LATERAL-ANTERIOR DRAWER TEST FOR EXAMINING POSTERIOR CRUCIATE LIGAMENT INTEGRITY. AB - BACKGROUND: Common clinical tests often fail to identify posterior cruciate ligament (PCL) ruptures, leading to undetected tears and potential degenerative changes in the knee. The lateral-anterior drawer (LAD) test has been proposed but not yet evaluated regarding its effectiveness for diagnosing PCL-ruptures. HYPOTHESIS: The LAD will show greater tibial translation values in lateral anterior direction in a PCL-Cut condition compared to a PCL-Intact condition, thus serving as a useful test for clinical diagnosis of PCL integrity. STUDY DESIGN: Descriptive laboratory study. METHODS: Threaded markers were inserted into the distal femur and proximal tibia in eighteen cadaveric knees. Each femur was stabilized and the tibia translated in lateral-anterior direction for the LAD test versus in a straight posterior direction for the posterior sag sign (PSS). Each test was repeated three times with the PCL both intact and then cut, in that order. During each trial, digital images were captured at start and finish positions for the evaluation of tibial marker displacement. Tibial marker translation during each trial was digitally analyzed using photography. The PSS values served as a reference standard. RESULTS: The LAD tibial translation was significantly greater (U=-3.680; p<;0.002) during the PCL-Cut (10.6+/-5.6mm) versus PCL-Intact (7.7+/-5.1mm) conditions. The PSS tibial translation was significantly greater (U=-3.724; p<0.002) during the PCL-Cut (11.0+/-5.3mm) versus PCL-Intact (6.4+/-3.5mm) conditions. There was no significant difference (t=2.029; p=0.07) in mean tibial translation in respective directions after PCL dissection during the LAD test (2.9+/-2.1mm) versus the PSS (4.6+/-2.8mm). CONCLUSION: The LAD test detected changes in cadaveric tibial translation corresponding with changes in PCL integrity to a degree at least as effective for assessing PCL integrity as the PSS. Further clinical study will be required to assess the utility of the LAD as a physical examination tool for diagnosing PCL injuries. LEVEL OF EVIDENCE: 2 (laboratory study). PMID- 28900564 TI - RELATIONSHIPS AMONG COMMON VISION AND VESTIBULAR TESTS IN HEALTHY RECREATIONAL ATHLETES. AB - BACKGROUND: Disruption of the visual and vestibular systems is commonly observed following concussion. Researchers have explored the utility of screening tools to identify deficits in these systems in concussed patients, but it is unclear if these tests are measuring similar or distinct phenomena. PURPOSE: To determine the relationships between common vestibular tests including the King-Devick (K-D) test, Sensory Organization Test (SOT), Head Shake-Sensory Organization Test (HS SOT), and Dynamic Visual Acuity (DVA) test, when administered contiguously, to healthy recreational athletes aged 14 to 24 years. STUDY DESIGN: This study used a prospective design to evaluate relationships between the K-D, SOT, HS-SOT, and DVA tests in 60 healthy individuals. METHODS: Sixty participants (30 males, 30 females; mean age, 19.9 +/- 3.74 years) completed the four tests in a single testing session. RESULTS: Results did not support a relationship between any pair of the K-D, SOT, HS-SOT, and DVA tests. Pearson correlations between tests were poor, ranging from 0.14 to 0.20. As expected the relationship between condition 2 of the SOT and HS-SOT fixed was strong (ICC=0.81) as well as condition 5 of the SOT with HS-SOT sway (ICC=0.78). The test-retest reliability of all 4 tests was evaluated to ensure the relationships of the 4 tests were consistent between test trials and reliability was excellent with intraclass correlations ranging from 0.79 to 0.97. CONCLUSIONS: The lack of relationships in these tests is clinically important because it suggests that the tests evaluate different aspects of visual and vestibular function. Further, these results suggest that a comprehensive assessment of visual and vestibular deficits following concussion may require a multifaceted approach. LEVEL OF EVIDENCE: 2b: Individual Cohort Study. PMID- 28900565 TI - COMPARISON OF A HEAD MOUNTED IMPACT MEASUREMENT DEVICE TO THE HYBRID III ANTHROPOMORPHIC TESTING DEVICE IN A CONTROLLED LABORATORY SETTING. AB - BACKGROUND: Reports estimate that 1.6 to 3.8 million cases of concussion occur in sports and recreation each year in the United States. Despite continued efforts to reduce the occurrence of concussion, the rate of diagnosis continues to increase. The mechanisms of concussion are thought to involve linear and rotational head accelerations and velocities. One method of quantifying the kinematics experienced during sport participation is to place measurement devices into the athlete's helmet or directly on the athlete's head. PURPOSE: The purpose of this research to determine the accuracy of a head mounted device for measuring the head accelerations experienced by the wearer. This will be accomplished by identifying the error in Peak Linear Acceleration (PLA), Peak Rotational Acceleration (PRA) and Peak Rotational Velocity (PRV) of the device. STUDY DESIGN: Laboratory study. METHODS: A helmeted Hybrid III 50th percentile male headform was impacted via a pneumatic ram from the front, side, rear, front oblique and rear oblique at speeds from 1.5 to 5 m/s. The X2 Biosystems xPatch(r) (Seattle, WA) sensor was placed on the headform's right side at the approximate location of the mastoid process. Measures of PLA, PRA, PRV from the xPatch (r) and Hybrid III were analyzed for Root Mean Square Error (RMSE), and Absolute and Relative Error (AE, RE). RESULT: Seventy-six impacts were analyzed. All measures of correlation, fixed through the origin, were found to be strong: PLA R2=0.967 p<0.01, PRA R2=0.933 p<0.01, PRV R2=0.999 p<0.00. PLA RMSE was 34%, RE 31.0%+/ 14.0, and AE 31.1%+/-13.7. PRA RMSE was 23.4%, RE -6.7 +/- 22.4 and AE 18.9%+/ 13.8. PRV RMSE was 2.2%, RE 0.1 +/- 2.2, and AE 1.8 +/- 1.3. CONCLUSION: Without including corrections for effect of skin artifact, the xPatch(r) produces measurements highly correlated with the gold standard yet above the average error of testing devices in both PLA and PRA, but a low error in PRV. PLA measures from the xPatch(r) system demonstrated a high level of correlation with the PLA data from the Hybrid III mounted data collection system. LEVEL OF EVIDENCE: 3. PMID- 28900566 TI - TRANSVERSUS ABDOMINIS ELASTICITY DURING VARIOUS EXERCISES: A SHEAR WAVE ULTRASOUND ELASTOGRAPHY STUDY. AB - BACKGROUND: Although the transversus abdominis (TrA) is considered to play a significant role in maintaining trunk stability, there is little information regarding the type of exercise that best facilitates the development of tension in the TrA. Muscle elasticity shows a strong association with muscle tension. Shear wave ultrasound elastography provides a means by which the tension of TrA can be noninvasively estimated, by quantifying it's elasticity. PURPOSE: The purpose of this study was to examine the TrA elasticity during several exercises as measured by shear wave ultrasound elastography, and to determine which of the studied exercises demonstrated the greatest tension. METHODS: Ten healthy men performed abdominal hollowing, abdominal bracing, a hanging deadlift, elbow-toe plank with contralateral arm and leg lift, and back bridge with single leg lift. During these exercises, TrA elasticity was measured using ultrasound elastography. The same measurements were performed at rest before and after these exercises. RESULT: No significant difference was found for rest conditions measured before and after the exercises (p = 0.63). Abdominal bracing showed a significantly higher elasticity value than the other exercises (p < 0.05), except for hanging deadlift. CONCLUSION: Among the exercises, abdominal bracing was the exercise that elevated the TrA tension the most. The present results also suggested that hanging deadlift also produced comparably high TrA tension with abdominal bracing. LEVEL OF EVIDENCE: 2c. PMID- 28900567 TI - THE COMPARISON OF THE LUMBAR MULTIFIDUS MUSCLES FUNCTION BETWEEN GYMNASTIC ATHLETES WITH SWAY-BACK POSTURE AND NORMAL POSTURE. AB - BACKGROUND: The prevalence of sway back posture (SBP) is very high among elite gymnasts. This posture may be partly due to the improper function of lumbar multifidus muscles (LMM) as lumbar stabilizers muscles. PURPOSE: The aim of this study was to compare the thicknesses of LMM measured at rest and during the contraction elicited during an arm lift between elite gymnasts with SBP and normal posture. STUDY DESIGN: Observational, descriptive, comparative. METHODS: The participants consist of twenty gymnasts between the ages of 17 and 30 who had trained in gymnastics for more than ten years. They were assigned to two groups: SBP (n=10) and control (n=10). Posture analysis with grid paper and plumb line was performed for all subjects. The thickness of LMM on dominant side of spinal column was measured by a real-time ultrasound at five lumbar levels. The thickness of the LMM was measured both at rest and during the contraction elicited during an arm lift. The variation between the LMM thickness between the muscle at rest and muscle at the peak of contraction was regarded as LMM muscle function. RESULT: The thickness of LMM was less in SBP group than the control group at all lumbar segments. The variation in LMM thickness between the state of rest and muscle contraction was significantly less in athletes with SBP than controls when compared at all levels of the lumbar spine (p < 0.05). CONCLUSION: The function of LMM may be disturbed in athletes with SBP as demonstrated by decreased thicknesses of LMM found in gymnasts with SBP. Additionally, the thickness of the LMM as a strong antigravity and stabilizing muscle group was decreased during arm raising in gymnasts with SBP. LEVEL OF EVIDENCE: 3a. PMID- 28900568 TI - CAN RUNNERS PERCEIVE CHANGES IN HEEL CUSHIONING AS THE SHOE AGES WITH INCREASED MILEAGE? AB - BACKGROUND: For those runners who utilize footwear and have a rearfoot strike pattern, the durability of the midsole heel region has been shown to deteriorate as shoe mileage increases. PURPOSE: The purpose of this study was threefold: 1) to determine if the runner can self-report changes in heel cushioning properties of the midsole after an extended period of distance running, 2) to determine if force and plantar pressures measured in the heel region of the midsole using a capacitance sensor insole change after running 640 km, and 3) to determine if a durometer could be used clinically to objectively measure changes in the hardness of the material in the heel region of the midsole. STUDY DESIGN: Cross-sectional Study. METHODS: Fifteen recreational runners voluntarily consented to participate and were provided with a new pair of running shoes. Each participant's running style was observed and classified as having a rearfoot strike pattern. Inclusion criteria included running at least 24 km per week, experience running on a treadmill, no history of lower extremity congenital or traumatic deformity, or acute injury six months prior to the start of the study. The ability of each participant to self-perceive changes in shoe cushioning, comfort and fit was assessed using the Footwear Comfort Assessment Tool (FCAT). In-shoe plantar pressures and vertical forces were assessed using a capacitance sensor insole while runners ran over a 42-meter indoor runway. A Shore A durometer was used to measure the hardness of the midsole in the heel region. All measures were completed at baseline (zero km) and after running 160, 320, 480, and 640 km. In addition to descriptive statistics, a repeated measures analysis of variance was used to determine if the FCAT, pressures, forces, or midsole hardness changed because of increased running mileage. RESULT: While plantar pressures and vertical forces were significantly reduced in the midsole heel region, none of the runners self-reported a significant reduction in heel cushioning based on FCAT scores after running 640 km. The use of a durometer provided an objective measure of the changes in the heel region of the midsole that closely matched the reductions observed in pressure and force values. CONCLUSION: The results indicated that runners who have a rearfoot strike pattern will have a 16% to 33% reduction in the amount of cushioning in the heel region of the midsole after running 480 km. Although there were significant reductions in heel cushioning, the experienced recreational runners in this study were not able to self-perceive these changes after running 640 km. In addition, the use of a durometer provides a quick and accurate way to assess changes in the hardness of the heel region of the midsole as running mileage increases. LEVEL OF EVIDENCE: 3, Controlled laboratory study. PMID- 28900569 TI - THERE ARE NO BIOMECHANICAL DIFFERENCES BETWEEN RUNNERS CLASSIFIED BY THE FUNCTIONAL MOVEMENT SCREEN. AB - BACKGROUND: Running has been one of the main choices of physical activity in people seeking an active lifestyle. The Functional Movement Screen (FMSTM) is a screening tool that aims to discern movement competency. PURPOSE: The purposes of this study were to compare biomechanical characteristics between two groups rated using the composite FMSTM score, and to analyze the influence of specific individual tests. The hypothesis was that the group that scored above 14 would demonstrate better performance on biomechanical tests than the group that scored below 14. STUDY DESIGN: Cross-Sectional Study. METHODS: Runners were screened using the FMSTM and were dichotomized into groups based on final score: Functional, where the subjects scored a 14 or greater (G>=14, n = 16) and dysfunctional, when the subjects scored less than 14 (G < 14, n = 16). All runners were evaluated using measures for flexibility, postural balance, muscle strength, knee dynamic valgus during forward step down test and time for the electromyographic response of the transversus abdominis and fibularis longus muscles. All data were analyzed with SPSS (p <= 0.05) and the index of asymmetry (IS) was calculated with the mean score of nondominant limb divided by the mean score of the dominant limb, multiplied by 100. RESULTS: There were no statistically significant differences in flexibility, muscle strength, knee dynamic valgus, or myoelectric response time of the transversus abdominis and long fibular muscles. Index of asymmetry (IS) of global stability was 3.26 +/- 26.79% in G>=14 and 31.72 +/- 52.69% in G<14 (p = 0.02). In-line lunge and active straight-leg raise tests showed no significant difference between the groups (p > 0.05). CONCLUSIONS: Overall, there were no biomechanical differences between the groups of runners as classified by the FMSTM. In addition, in-line lunge and active strength-leg raise tests did not influence on the FMSTM final score. LEVEL OF EVIDENCE: 2b. PMID- 28900570 TI - RUNNING INJURY DEVELOPMENT: THE ATTITUDES OF MIDDLE- AND LONG-DISTANCE RUNNERS AND THEIR COACHES. AB - BACKGROUND: Behavioral science methods have rarely been used in running injury research. Therefore, the attitudes amongst runners and their coaches regarding factors leading to running injuries warrants formal investigation. PURPOSE: To investigate the attitudes of middle- and long-distance runners able to compete in national championships and their coaches about factors associated with running injury development. METHODS: A link to an online survey was distributed to middle and long-distance runners and their coaches across 25 Danish Athletics Clubs. The main research question was: "Which factors do you believe influence the risk of running injuries?". In response to this question, the athletes and coaches had to click "Yes" or "No" to 19 predefined factors. In addition, they had the possibility to submit a free-text response. RESULTS: A total of 68 athletes and 19 coaches were included in the study. A majority of the athletes (76% [95%CI: 66%; 86%]) and coaches (79% [95%CI: 61%; 97%]) reported "Ignoring pain" as a risk factor for running injury. A majority of the coaches reported "Reduced muscle strength" (79% [95%CI: 61%; 97%]) and "high running distance" (74% [95%CI: 54%; 94%]) to be associated with injury, while half of the runners found "insufficient recovery between running sessions" (53% [95%CI: 47%; 71%]) important. CONCLUSION: Runners and their coaches emphasize ignoring pain as a factor associated with injury development. The question remains how much running, if any at all, runners having slight symptoms or mild pain, are able to tolerate before these symptoms develop into a running-related injury. LEVEL OF EVIDENCE: 3b. PMID- 28900571 TI - CAVITATION SOUNDS DURING CERVICOTHORACIC SPINAL MANIPULATION. AB - BACKGROUND: No study has previously investigated the side, duration or number of audible cavitation sounds during high-velocity low-amplitude (HVLA) thrust manipulation to the cervicothoracic spine. PURPOSE: The primary purpose was to determine which side of the spine cavitates during cervicothoracic junction (CTJ) HVLA thrust manipulation. Secondary aims were to calculate the average number of cavitations, the duration of cervicothoracic thrust manipulation, and the duration of a single cavitation. STUDY DESIGN: Quasi-experimental study. METHODS: Thirty-two patients with upper trapezius myalgia received two cervicothoracic HVLA thrust manipulations targeting the right and left T1-2 articulation, respectively. Two high sampling rate accelerometers were secured bilaterally 25 mm lateral to midline of the T1-2 interspace. For each manipulation, two audio signals were extracted using Short-Time Fourier Transformation (STFT) and singularly processed via spectrogram calculation in order to evaluate the frequency content and number of instantaneous energy bursts of both signals over time for each side of the CTJ. RESULT: Unilateral cavitation sounds were detected in 53 (91.4%) of 58 cervicothoracic HVLA thrust manipulations and bilateral cavitation sounds were detected in just five (8.6%) of the 58 thrust manipulations; that is, cavitation was significantly (p<0.001) more likely to occur unilaterally than bilaterally. In addition, cavitation was significantly (p<0.0001) more likely to occur on the side contralateral to the clinician's short-lever applicator. The mean number of audible cavitations per manipulation was 4.35 (95% CI 2.88, 5.76). The mean duration of a single manipulation was 60.77 ms (95% CI 28.25, 97.42) and the mean duration of a single audible cavitation was 4.13 ms (95% CI 0.82, 7.46). In addition to single-peak and multi peak energy bursts, spectrogram analysis also demonstrated high frequency sounds, low frequency sounds, and sounds of multiple frequencies for all 58 manipulations. DISCUSSION: Cavitation was significantly more likely to occur unilaterally, and on the side contralateral to the short-lever applicator contact, during cervicothoracic HVLA thrust manipulation. Clinicians should expect multiple cavitation sounds when performing HVLA thrust manipulation to the CTJ. Due to the presence of multi-peak energy bursts and sounds of multiple frequencies, the cavitation hypothesis (i.e. intra-articular gas bubble collapse) alone appears unable to explain all of the audible sounds during HVLA thrust manipulation, and the possibility remains that several phenomena may be occurring simultaneously. LEVEL OF EVIDENCE: 2b. PMID- 28900572 TI - RETURN TO RUNNING FOLLOWING A KNEE DISARTICULATION AMPUTATION: A CASE REPORT. AB - BACKGROUND AND PURPOSE: The evolution of running-specific prostheses has empowered athletes with lower extremity amputations to run farther and faster than previously thought possible; but running with proper mechanics is still paramount to an injury-free, active lifestyle. The purpose of this case report was to describe the successful alteration of intact limb mechanics from a Rearfoot Striking (RFS) to a Non-Rearfoot Striking (NRFS) pattern in an individual with a knee disarticulation amputation, the associated reduction in Average Vertical Loading Rate (AVLR), and the improvement in functional performance following the intervention. CASE DESCRIPTION: A 30 year-old male with a traumatic right knee disarticulation amputation reported complaints of residual limb pain with running distances greater than 5 km, limiting his ability to train toward his goal of participating in triathlons. Qualitative assessment of his running mechanics revealed a RFS pattern with his intact limb and a NRFS pattern with his prosthetic limb. A full body kinematic and kinetic running analysis using 3D motion capture and force plates was performed. The average intact limb loading rate was four-times greater (112 body weights/s) than in his prosthetic limb which predisposed him to possible injury. He underwent a three week running intervention with a certified running specialist to learn a NRFS pattern with his intact limb. OUTCOMES: Immediately following the running intervention, he was able to run distances of over 10 km without pain. On a two-mile fitness test, he decreased his run time from 19:54 min to 15:14 min. Additionally, the intact limb loading rate was dramatically reduced to 27 body weights/s, nearly identical to the prosthetic limb (24 body weights/s). DISCUSSION: This case report outlines a detailed return to run program that targets proprioceptive and neuromuscular components, injury prevention, and specificity of training strategies. The outcomes of this case report are promising as they may spur additional research toward understanding how to eliminate potential injury risk factors associated with running after limb loss. LEVEL OF EVIDENCE: 4. PMID- 28900573 TI - THE EFFECTS OF A MULTIMODAL REHABILITATION PROGRAM ON PAIN, KINESIOPHOBIA AND FUNCTION IN A RUNNER WITH PATELLOFEMORAL PAIN. AB - BACKGROUND AND PURPOSE: Multimodal interventions possess the strongest evidence in the long-term management of patellofemoral pain, but despite receiving evidence-based treatments that are initially effective many patients report recurrent or persistent symptoms for years after the initial diagnosis. Untreated psychological factors could be a possible explanation for persistent symptoms and poor treatment outcome. The purpose of this case report was to describe and evaluate the effects of a multimodal rehabilitation program that included pain education, a graded program of lower limb strengthening, and running retraining on pain, kinesiophobia, and function in a runner with patellofemoral pain. CASE DESCRIPTION: The subject was a 37-year-old female runner reporting a 12-month history of anterior knee pain with previous failed physiotherapeutic treatment. She discontinued running when symptoms gradually worsened, approximately six months after initial onset. She was advised to avoid painful activities. Clinical examination revealed pain during the performance of a weight-bearing functional task, fear of movement, and functional limitations. Treatment focused on pain education, self-management strategies, and progressive loading of the involved tissues through a graduated program of exercises and running retraining. OUTCOMES: Clinically meaningful improvements were seen in pain, kinesiophobia, and function following a 21-week multimodal rehabilitation program. DISCUSSION: This case report illustrates several important aspects of clinical reasoning contributing to successful outcomes for a runner with patellofemoral pain. The multimodal rehabilitation program utilized was based upon the neurophysiology of pain (pain education) rather than the tissue pathology model. The findings from this case report may be used to benefit clinicians with similar subject presentations and drive future research into the use of these interventions based upon neurophysiology models of pain in the treatment of patellofemoral pain. LEVEL OF EVIDENCE: Level 4. PMID- 28900574 TI - A FOUR-PHASE PHYSICAL THERAPY REGIMEN FOR RETURNING ATHLETES TO SPORT FOLLOWING HIP ARTHROSCOPY FOR FEMOROACETABULAR IMPINGEMENT WITH ROUTINE CAPSULAR CLOSURE. AB - : Hip preservation surgery has become more common over the past decade and is now a preferred treatment modality for an increasingly diverse array of pathology in the young, active patient with hip pain. In particular, hip arthroscopy has become an increasingly popular treatment choice for active patients diagnosed with femoroacetabular impingement (FAI). Appropriate postoperative rehabilitation is critical for overall patient success and optimal long-term outcome. As surgical techniques continue to evolve, rehabilitation protocols must adapt to accommodate changes in the surgical procedure and ultimately provide the safest and fastest recovery of function for the patient. One such surgical modification has been the incorporation of routine capsular closure as part of the treatment of FAI in the young, active patient. The purpose of this clinical commentary is to present a four-phase rehabilitation protocol for returning to sport following arthroscopic correction of FAI with routine capsular closure. LEVEL OF EVIDENCE: 5. PMID- 28900575 TI - ENERGY SYSTEM DEVELOPMENT AND LOAD MANAGEMENT THROUGH THE REHABILITATION AND RETURN TO PLAY PROCESS. AB - : Return-to-play from injury is a complex process involving many factors including the balancing of tissue healing rates with the development of biomotor abilities. This process requires interprofessional cooperation to ensure success. An often-overlooked aspect of return-to-play is the development and maintenance of sports specific conditioning while monitoring training load to ensure that the athlete's training stimulus over the rehabilitation period is appropriate to facilitate a successful return to play. The purpose of this clinical commentary is to address the role of energy systems training as part of the return-to-play process. Additionally the aim is to provide practitioners with an overview of practical sports conditioning training methods and monitoring strategies to allow them to direct and quantify the return-to-play process. LEVEL OF EVIDENCE: 5. PMID- 28900576 TI - Comparison of Saccadic Vector Optokinetic Perimetry and Standard Automated Perimetry in Glaucoma. Part I: Threshold Values and Repeatability. AB - PURPOSE: We evaluated threshold saccadic vector optokinetic perimetry (SVOP) and compared results to standard automated perimetry (SAP). METHODS: A cross sectional study was done including 162 subjects (103 with glaucoma and 59 healthy subjects) recruited at a university hospital. All subjects underwent SAP and threshold SVOP. SVOP uses an eye tracker to monitor eye movement responses to stimuli and determines if stimuli have been perceived based on the vector of the gaze response. The test pattern used was equivalent to SAP 24-2 and stimuli were presented at Goldmann III. Average and pointwise sensitivity values obtained from both tests were compared using Pearson's correlation coefficient. Two versions of SVOP were evaluated. RESULTS: A total of 124 tests were performed with SAP and SVOP version 2. There was excellent agreement between mean threshold values obtained using SVOP and SAP (r = 0.95, P < 0.001). Excluding the blind spot, correlation between SVOP and SAP individual test point sensitivity ranged from 0.61 to 0.90, with 48 of 54 (89%) test points > 0.70. Overall SVOP showed good repeatability with a Pearson correlation of 0.88. The repeatability on a point-by point basis ranged from 0.66 to 0.98, with 45 of 54 points (83%) > 0.80. Repeatability of SAP was 0.87, ranging from 0.69 to 0.96, with 47 of 54 (87%) points > 0.80. CONCLUSION: Eye-tracking perimetry is repeatable and compares well with the current gold standard of SAP. The technique has advantages over conventional perimetry and could be useful for evaluating glaucomatous visual field loss, particularly in patients who may struggle with conventional perimetry. TRANSLATIONAL RELEVANCE: Suprathreshold SVOP already is in the field. To our knowledge, this is the first report of threshold SVOP and provides a benchmark for future iterations. PMID- 28900577 TI - Comparison of Threshold Saccadic Vector Optokinetic Perimetry (SVOP) and Standard Automated Perimetry (SAP) in Glaucoma. Part II: Patterns of Visual Field Loss and Acceptability. AB - PURPOSE: We compared patterns of visual field loss detected by standard automated perimetry (SAP) to saccadic vector optokinetic perimetry (SVOP) and examined patient perceptions of each test. METHODS: A cross-sectional study was done of 58 healthy subjects and 103 with glaucoma who were tested using SAP and two versions of SVOP (v1 and v2). Visual fields from both devices were categorized by masked graders as: 0, normal; 1, paracentral defect; 2, nasal step; 3, arcuate defect; 4, altitudinal; 5, biarcuate; and 6, end-stage field loss. SVOP and SAP classifications were cross-tabulated. Subjects completed a questionnaire on their opinions of each test. RESULTS: We analyzed 142 (v1) and 111 (v2) SVOP and SAP test pairs. SVOP v2 had a sensitivity of 97.7% and specificity of 77.9% for identifying normal versus abnormal visual fields. SAP and SVOP v2 classifications showed complete agreement in 54% of glaucoma patients, with a further 23% disagreeing by one category. On repeat testing, 86% of SVOP v2 classifications agreed with the previous test, compared to 91% of SAP classifications; 71% of subjects preferred SVOP compared to 20% who preferred SAP. CONCLUSIONS: Eye tracking perimetry can be used to obtain threshold visual field sensitivity values in patients with glaucoma and produce maps of visual field defects, with patterns exhibiting close agreement to SAP. Patients preferred eye-tracking perimetry compared to SAP. TRANSLATIONAL RELEVANCE: This first report of threshold eye tracking perimetry shows good agreement with conventional automated perimetry and provides a benchmark for future iterations. PMID- 28900578 TI - Restoration of Cone Photoreceptor Function in Retinitis Pigmentosa. PMID- 28900579 TI - Factors Inhibiting Physical Activity as Treatment for Diabetic Chuukese in Chuuk and Hawai'i. AB - Type 2 diabetes is epidemic in the US Pacific. Developing culturally sensitive physical activities and anti-sedentary interventions may reduce morbidity and mortality associated with type 2 diabetes. The purpose of the study was to identify sedentary and physical activity factors related to diabetes prevention and control among Chuukese living in Chuuk and Hawai'i. This study utilized grounded theory to identify socio-cultural influences that hinder or facilitate adherence to physical activity recommendations. Data was gathered through focus group discussions with individuals with diabetes and their caretakers. Findings include in-depth and detailed information on five different types of sedentary behaviors (purposeful sitting, lazy sitting, wasting time, resting and recreation sitting, and no-can move) and environmental factors that influenced participants' sedentary behaviors and physical activity. These findings underscore the need for physical activity and anti-sedentary interventions that are purposeful, collectivistic, age and gender appropriate and church based. PMID- 28900581 TI - Medical School Hotline: Connecting with Patients through Humanism and Humility. PMID- 28900580 TI - A Case Report of a Left Atrial Mass: The Importance of a Detailed Physical Exam. AB - Cardiac myxomas are rare clinical findings. They are frequently found in the left atrium and more commonly affect women. Clinical presentation can vary widely and symptoms can be vague and non-specific. We present a case of a 67-year-old woman presenting with 3 weeks of progressive heart failure symptoms that failed to respond to oral diuretic therapy. On physical exam, she was found to have a diastolic murmur, rumble and an early diastolic plop. Transthoracic echocardiogram revealed a 5.6 cm * 2.5 cm * 4.3 cm left atrial mass attached to the mitral valve causing left atrial outflow obstruction. The patient subsequently underwent surgical resection of the mass with resolution of symptoms immediately thereafter. Lack of recognition of this pathologic process as a cause of heart failure symptoms and lack of a quality physical exam can lead to a delay in diagnosis and treatment. PMID- 28900582 TI - Insights in Public Health: Improving Reproductive Life Planning in Hawai'i: One Key Question(r). PMID- 28900583 TI - The Daniel K. Inouye College of Pharmacy Scripts: Precision Medicine Through the Use of Pharmacogenomics: Current Status and Barriers to Implementation. AB - The precision medicine initiative brought forth by President Barack Obama in 2015 is an important step on the journey to truly personalized medicine. A broad knowledge and understanding of the implications of the pharmacogenomic literature will be critical to the achievement of this goal. While a great amount of data has been published in the areas of pharmacogenomics and pharmacogenetics, there are still relatively few instances in which the need for clinical intervention can be stated without doubt, and which are widely accepted and practiced by the medical community. As our knowledge base rapidly expands, issues such as insurance reimbursement for genetic testing and education of the health care workforce will be paramount to achieving the goal of precision medicine for all patients. PMID- 28900584 TI - Gold Humanism Honor Society Application Essay - On Humanist Medicine. PMID- 28900586 TI - Correction: Biochemistry in Endeavor Adventure Racers Study (BEARS). AB - [This corrects the article DOI: 10.7759/cureus.1024.]. PMID- 28900587 TI - Prevalence and Predictors of Depression Amongst Hypertensive Individuals in Karachi, Pakistan. AB - OBJECTIVE: While studies evaluating the prevalence of depression and hypertension have been extensively carried out in high income countries, there is a paucity of information assessing the prevalence of depression within hypertensive patients in low income nations. The primary objective of this study was to investigate the prevalence of undiagnosed depression in hypertensive patients within a tertiary care facility in Karachi, Pakistan. The secondary objective was to assess factors associated with undiagnosed depression in this group. METHODS: A cross-sectional study was conducted at the Civil Hospital Karachi Outpatient Department from January 2017 to April 2017. The sample population was composed of 411 hypertensive patients. Interviews were conducted after taking informed consent, with data concerning basic demographic details and lifestyle habits gathered. Blood pressure was recorded and its severity was classified as per the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines. Depression was evaluated and its severity classified as per the Patient Health Questionnaire-9 (PHQ-9) scale, with a score of 10 or above set as the cut-off point. Data were entered and analyzed using the IBM Statistical Package for the Social Sciences 23.0. (IBM, NY, USA). RESULTS: The prevalence of depression within 411 hypertensive patients was 40.1% (n = 165). The mean age of the sample was 45.7 +/- 11.2 years, and the majority were females (72%, n = 295), unemployed (72%, n = 296), had primary or no education (67%, n = 277), and were of low socioeconomic status (78%, n = 321). The average systolic and diastolic blood pressures were 143.8 +/- 21.7 and 93.3 +/- 15.5 mm Hg, respectively. Factors which had a significant association with depression were gender (p = 0.009), age class (p = 0.035), educational status (p = 0.000), employment status (p = 0.003), socioeconomic status (p = 0.008), physical activity (p = 0.025), smoking (p = 0.017), and family history of hypertension (p = 0.022). CONCLUSION: With such a high prevalence rate of undiagnosed depression within hypertensive patients, it is pertinent to establish screening programs for early detection and community programs to raise awareness regarding long-term complications of untreated depression. PMID- 28900588 TI - Correction: Hydration Status as a Predictor of High-altitude Mountaineering Performance. AB - [This corrects the article DOI: 10.7759/cureus.918.]. PMID- 28900589 TI - The use of a genetically encoded molecular crowding sensor in various biological phenomena. AB - We evaluated usability of a previously developed genetically encoded molecular crowding sensor in various biological phenomena. Molecular crowding refers to intracellular regions that are occupied more by proteins and nucleotides than by water molecules and is thought to have a strong effect on protein function. To evaluate intracellular molecular crowding, usually the diffusion coefficient of a probe is used because it is related to mobility of the surrounding molecular crowding agents. Recently, genetically encoded molecular crowding sensors based on Forster resonance energy transfer were reported. In the present study, to evaluate the usability of a genetically encoded molecular crowding sensor, molecular crowding was monitored during several biological events. Changes in molecular crowding during stem cell differentiation, cell division, and focal adhesion development and difference in molecular crowding in filopodia locations were examined. The results show usefulness of the genetically encoded molecular crowding sensor for understanding the biological phenomena relating to molecular crowding. PMID- 28900590 TI - High-speed atomic force microscopy imaging of live mammalian cells. AB - Direct imaging of morphological dynamics of live mammalian cells with nanometer resolution under physiological conditions is highly expected, but yet challenging. High-speed atomic force microscopy (HS-AFM) is a unique technique for capturing biomolecules at work under near physiological conditions. However, application of HS-AFM for imaging of live mammalian cells was hard to be accomplished because of collision between a huge mammalian cell and a cantilever during AFM scanning. Here, we review our recent improvements of HS-AFM for imaging of activities of live mammalian cells without significant damage to the cell. The improvement of an extremely long (~3 MUm) AFM tip attached to a cantilever enables us to reduce severe damage to soft mammalian cells. In addition, a combination of HS-AFM with simple fluorescence microscopy allows us to quickly locate the cell in the AFM scanning area. After these improvements, we demonstrate that developed HS-AFM for live mammalian cells is possible to image morphogenesis of filopodia, membrane ruffles, pits open-close formations, and endocytosis in COS-7, HeLa cells as well as hippocampal neurons. PMID- 28900591 TI - Comprehensive Raman study of epitaxial silicene-related phases on Ag(111). AB - The investigation of the vibrational properties of epitaxial silicene and two dimensional (2D) Si structures on the silver(111) surface aims for a better understanding of the structural differences and of the simplification of the seemingly complex phase diagrams reported over the last years. The spectral signatures of the main silicene phases epitaxially grown on Ag(111) were obtained using in situ Raman spectroscopy. Due to the obvious 2D nature of various epitaxial silicene structures, their fingerprints consist of similar sets of Raman modes. The reduced phase diagram also includes other Si phases, such as amorphous and crystalline silicon, which emerge on the Ag surface at low and high preparation temperatures, respectively. The Raman signatures obtained along with their interpretations provide the referential basis for further studies and for potential applications of epitaxial silicene. PMID- 28900592 TI - Micro- and nano-surface structures based on vapor-deposited polymers. AB - Vapor-deposition processes and the resulting thin polymer films provide consistent coatings that decouple the underlying substrate surface properties and can be applied for surface modification regardless of the substrate material and geometry. Here, various ways to structure these vapor-deposited polymer thin films are described. Well-established and available photolithography and soft lithography techniques are widely performed for the creation of surface patterns and microstructures on coated substrates. However, because of the requirements for applying a photomask or an elastomeric stamp, these techniques are mostly limited to flat substrates. Attempts are also conducted to produce patterned structures on non-flat surfaces with various maskless methods such as light directed patterning and direct-writing approaches. The limitations for patterning on non-flat surfaces are resolution and cost. With the requirement of chemical control and/or precise accessibility to the linkage with functional molecules, chemically and topographically defined interfaces have recently attracted considerable attention. The multifunctional, gradient, and/or synergistic activities of using such interfaces are also discussed. Finally, an emerging discovery of selective deposition of polymer coatings and the bottom-up patterning approach by using the selective deposition technology is demonstrated. PMID- 28900594 TI - Adsorption and electronic properties of pentacene on thin dielectric decoupling layers. AB - With the increasing use of thin dielectric decoupling layers to study the electronic properties of organic molecules on metal surfaces, comparative studies are needed in order to generalize findings and formulate practical rules. In this paper we study the adsorption and electronic properties of pentacene deposited onto h-BN/Rh(111) and compare them with those of pentacene deposited onto KCl on various metal surfaces. When deposited onto KCl, the HOMO and LUMO energies of the pentacene molecules scale with the work functions of the combined KCl/metal surface. The magnitude of the variation between the respective KCl/metal systems indicates the degree of interaction of the frontier orbitals with the underlying metal. The results confirm that the so-called IDIS model developed by Willenbockel et al. applies not only to molecular layers on bare metal surfaces, but also to individual molecules on thin electronically decoupling layers. Depositing pentacene onto h-BN/Rh(111) results in significantly different adsorption characteristics, due to the topographic corrugation of the surface as well as the lateral electric fields it presents. These properties are reflected in the divergence from the aforementioned trend for the orbital energies of pentacene deposited onto h-BN/Rh(111), as well as in the different adsorption geometry. Thus, the highly desirable capacity of h-BN to trap molecules comes at the price of enhanced metal-molecule interaction, which decreases the HOMO-LUMO gap of the molecules. In spite of the enhanced interaction, the molecular orbitals are evident in scanning tunnelling spectroscopy (STS) and their shapes can be resolved by spectroscopic mapping. PMID- 28900593 TI - Deposition of exchange-coupled dinickel complexes on gold substrates utilizing ambidentate mercapto-carboxylato ligands. AB - The chemisorption of magnetically bistable transition metal complexes on planar surfaces has recently attracted increased scientific interest due to its potential application in various fields, including molecular spintronics. In this work, the synthesis of mixed-ligand complexes of the type [NiII2L(L')](ClO4), where L represents a 24-membered macrocyclic hexaazadithiophenolate ligand and L' is a omega-mercapto-carboxylato ligand (L' = HS(CH2)5CO2- (6), HS(CH2)10CO2- (7), or HS(C6H4)2CO2- (8)), and their ability to adsorb on gold surfaces is reported. Besides elemental analysis, IR spectroscopy, electrospray ionization mass spectrometry (ESIMS), UV-vis spectroscopy, and X-ray crystallography (for 6 and 7), the compounds were also studied by temperature-dependent magnetic susceptibility measurements (for 7 and 8) and (broken symmetry) density functional theory (DFT) calculations. An S = 2 ground state is demonstrated by temperature-dependent susceptibility and magnetization measurements, achieved by ferromagnetic coupling between the spins of the Ni(II) ions in 7 (J = +22.3 cm-1) and 8 (J = +20.8 cm-1; H = -2JS1S2). The reactivity of complexes 6-8 is reminiscent of that of pure thiolato ligands, which readily chemisorb on Au surfaces as verified by contact angle, atomic force microscopy (AFM) and spectroscopic ellipsometry measurements. The large [Ni2L] tail groups, however, prevent the packing and self-assembly of the hydrocarbon chains. The smaller film thickness of 7 is attributed to the specific coordination mode of the coligand. Results of preliminary transport measurements utilizing rolled-up devices are also reported. PMID- 28900595 TI - Low uptake of silica nanoparticles in Caco-2 intestinal epithelial barriers. AB - Cellular barriers, such as the skin, the lung epithelium or the intestinal epithelium, constitute one of the first obstacles facing nanomedicines or other nanoparticles entering organisms. It is thus important to assess the capacity of nanoparticles to enter and transport across such barriers. In this work, Caco-2 intestinal epithelial cells were used as a well-established model for the intestinal barrier, and the uptake, trafficking and translocation of model silica nanoparticles of different sizes were investigated using a combination of imaging, flow cytometry and transport studies. Compared to typical observations in standard cell lines commonly used for in vitro studies, silica nanoparticle uptake into well-developed Caco-2 cellular barriers was found to be very low. Instead, nanoparticle association to the apical outer membrane was substantial and these particles could easily be misinterpreted as internalised in the absence of imaging. Passage of nanoparticles through the barrier was very limited, suggesting that the low amount of internalised nanoparticles was due to reduced uptake into cells, rather than a considerable transport through them. PMID- 28900596 TI - A review of demodulation techniques for amplitude-modulation atomic force microscopy. AB - In this review paper, traditional and novel demodulation methods applicable to amplitude-modulation atomic force microscopy are implemented on a widely used digital processing system. As a crucial bandwidth-limiting component in the z axis feedback loop of an atomic force microscope, the purpose of the demodulator is to obtain estimates of amplitude and phase of the cantilever deflection signal in the presence of sensor noise or additional distinct frequency components. Specifically for modern multifrequency techniques, where higher harmonic and/or higher eigenmode contributions are present in the oscillation signal, the fidelity of the estimates obtained from some demodulation techniques is not guaranteed. To enable a rigorous comparison, the performance metrics tracking bandwidth, implementation complexity and sensitivity to other frequency components are experimentally evaluated for each method. Finally, the significance of an adequate demodulator bandwidth is highlighted during high speed tapping-mode atomic force microscopy experiments in constant-height mode. PMID- 28900597 TI - Spin-chemistry concepts for spintronics scientists. AB - Spin chemistry and spintronics developed independently and with different terminology. Until now, the interaction between the two fields has been very limited. In this review, we compile the two "languages" in an effort to enhance communication. We expect that knowledge of spin chemistry will accelerate progress in spintronics. PMID- 28900598 TI - Cationic PEGylated polycaprolactone nanoparticles carrying post-operation docetaxel for glioma treatment. AB - Background: Brain tumors are the most common tumors among adolescents. Although some chemotherapeutics are known to be effective against brain tumors based on cell culture studies, the same effect is not observed in clinical trials. For this reason, the development of drug delivery systems is important to treat brain tumors and prevent tumor recurrence. The aim of this study was to develop core shell polymeric nanoparticles with positive charge by employing a chitosan coating. Additionally, an implantable formulation for the chemotherapeutic nanoparticles was developed as a bioadhesive film to be applied at the tumor site following surgical operation for brain glioma treatment. To obtain positively charged, implantable nanoparticles, the effects of preparation technique, chitosan coating concentration and presence of surfactants were evaluated to obtain optimal nanoparticles with a diameter of less than 100 nm and a net positive surface charge to facilitate cellular internalization of drug-loaded nanoparticles. Hydroxypropyl cellulose films were prepared to incorporate these nanoparticle dispersions to complete the implantable drug delivery system. Results: The diameter of core-shell nanoparticles were in the range of 70-270 nm, depending on the preparation technique, polymer type and coating. Moreover, the chitosan coating significantly altered the surface charge of the nanoparticles to net positive values of +30 to +50 mV. The model drug docetaxel was successfully loaded into all particles, and the drug release rate from the nanoparticles was slowed down to 48 h by dispersing the nanoparticles in a hydroxypropyl cellulose film. Cell culture studies revealed that docetaxel-loaded nanoparticles cause higher cytotoxicity compared to the free docetaxel solution in DMSO. Conclusion: Docetaxel-loaded nanoparticles dispersed in a bioadhesive film were shown to be suitable for application of chemotherapeutics directly to the action site during surgical operation. The system was found to release chemotherapeutics for several days at the tumor site and neighboring tissue. This can be suggested to result in a more effective brain tumor treatment when compared to chemotherapeutics administered as an intravenous bolus infusion. PMID- 28900599 TI - Development of polycationic amphiphilic cyclodextrin nanoparticles for anticancer drug delivery. AB - Background: Paclitaxel is a potent anticancer drug that is effective against a wide spectrum of cancers. To overcome its bioavailability problems arising from very poor aqueous solubility and tendency to recrystallize upon dilution, paclitaxel is commercially formulated with co-solvents such as Cremophor EL(r) that are known to cause serious side effects during chemotherapy. Amphiphilic cyclodextrins are favored oligosaccharides as drug delivery systems for anticancer drugs, having the ability to spontaneously form nanoparticles without surfactant or co-solvents. In the past few years, polycationic, amphiphilic cyclodextrins were introduced as effective agents for gene delivery in the form of nanoplexes. In this study, the potential of polycationic, amphiphilic cyclodextrin nanoparticles were evaluated in comparison to non-ionic amphiphilic cyclodextrins and core-shell type cyclodextrin nanoparticles for paclitaxel delivery to breast tumors. Pre-formulation studies were used as a basis for selecting the suitable organic solvent and surfactant concentration for the novel polycationic cyclodextrin nanoparticles. The nanoparticles were then extensively characterized with particle size distribution, polydispersity index, zeta potential, drug loading capacity, in vitro release profiles and cytotoxicity studies. Results: Paclitaxel-loaded cyclodextrin nanoparticles were obtained in the diameter range of 80-125 nm (depending on the nature of the cyclodextrin derivative) where the smallest diameter nanoparticles were obtained with polycationic (PC) betaCDC6. A strong positive charge also helped to increase the loading capacity of the nanoparticles with paclitaxel up to 60%. Interestingly, cyclodextrin nanoparticles were able to stabilize paclitaxel in aqueous solution for 30 days. All blank cyclodextrin nanoparticles were demonstrated to be non cytotoxic against L929 mouse fibroblast cell line. In addition, paclitaxel-loaded nanoparticles have a significant anticancer effect against MCF-7 human breast cancer cell line as compared with a paclitaxel solution in DMSO. Conclusion: According to the results of this study, both amphiphilic cyclodextrin derivatives provide suitable nanometer-sized drug delivery systems for safe and efficient intravenous paclitaxel delivery for chemotherapy. In the light of these studies, it can be said that amphiphilic cyclodextrin nanoparticles of different surface charge can be considered as a promising alternative for self-assembled nanometer sized drug carrier systems for safe and efficient chemotherapy. PMID- 28900600 TI - Formation of ferromagnetic molecular thin films from blends by annealing. AB - We report on a new approach for the fabrication of ferromagnetic molecular thin films. Co-evaporated films of manganese phthalocyanine (MnPc) and tetracyanoquinodimethane (TCNQ) have been produced by organic molecular beam deposition (OMBD) on rigid (glass, silicon) and flexible (Kapton) substrates kept at room temperature. The MnPc:TCNQ films are found to be entirely amorphous due to the size mismatch of the molecules. However, by annealing while covering the samples highly crystalline MnPc films in the beta-polymorph can be obtained at 60 degrees C lower than when starting with pure MnPc films. The resulting films exhibit substantial coercivity (13 mT) at 2 K and a Curie temperature of 11.5 K. PMID- 28900601 TI - Development of a nitrogen-doped 2D material for tribological applications in the boundary-lubrication regime. AB - The present paper describes a facile synthesis method for nitrogen-doped reduced graphene oxide (N-rGO) and the application of N-rGO as an effective additive for improving the tribological properties of base oil. N-rGO has been characterized by different characterization techniques such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy and Raman spectroscopy. N-rGO-based nanolubricants are prepared and their tribological properties are studied using a four-ball tester. The nanolubricants show excellent stability over a period of six months and a significant decrease in coefficient of friction (25%) for small amounts of N-rGO (3 mg/L). The improvement in tribological properties can be attributed to the sliding mechanism of N-rGO accompanied by the high mechanical strength of graphene. Further, the nanolubricant is prepared at large scale (700 liter) and field trials are carried out at one NTPC thermal plant in India. The implementation of the nanolubricant in an induced draft (ID) fan results in the remarkable decrease in the power consumption. PMID- 28900602 TI - Calcium fluoride based multifunctional nanoparticles for multimodal imaging. AB - New multifunctional nanoparticles (NPs) that can be used as contrast agents (CA) in different imaging techniques, such as photoluminescence (PL) microscopy and magnetic resonance imaging (MRI), open new possibilities for medical imaging, e.g., in the fields of diagnostics or tissue characterization in regenerative medicine. The focus of this study is on the synthesis and characterization of CaF2:(Tb3+,Gd3+) NPs. Fabricated in a wet-chemical procedure, the spherical NPs with a diameter of 5-10 nm show a crystalline structure. Simultaneous doping of the NPs with different lanthanide ions, leading to paramagnetism and fluorescence, makes them suitable for MR and PL imaging. Owing to the Gd3+ ions on the surface, the NPs reduce the MR T1 relaxation time constant as a function of their concentration. Thus, the NPs can be used as a MRI CA with a mean relaxivity of about r = 0.471 mL.mg-1.s-1. Repeated MRI examinations of four different batches prove the reproducibility of the NP synthesis and determine the long-term stability of the CAs. No cytotoxicity of NP concentrations between 0.5 and 1 mg.mL-1 was observed after exposure to human dermal fibroblasts over 24 h. Overall this study shows, that the CaF2:(Tb3+,Gd3+) NPs are suitable for medical imaging. PMID- 28900603 TI - A nanocomplex of C60 fullerene with cisplatin: design, characterization and toxicity. AB - The self-organization of C60 fullerene and cisplatin in aqueous solution was investigated using the computer simulation, dynamic light scattering and atomic force microscopy techniques. The results evidence the complexation between the two compounds. The genotoxicity of S60 fullerene, Cis and their complex was evaluated in vitro with the comet assay using human resting lymphocytes and lymphocytes after blast transformation. The cytotoxicity of the mentioned compounds was estimated by Annexin V/PI double staining followed by flow cytometry. The results clearly demonstrate that water-soluble C60 fullerene nanoparticles (0.1 mg/mL) do not induce DNA strand breaks in normal and transformed cells. C60 fullerene in the mixture with Cis does not influence genotoxic Cis activity in vitro, affects the cell-death mode in treated resting human lymphocytes and reduces the fraction of necrotic cells. PMID- 28900604 TI - Light-induced magnetoresistance in solution-processed planar hybrid devices measured under ambient conditions. AB - We report light-induced negative organic magnetoresistance (OMAR) measured in ambient atmosphere in solution-processed 6,13 bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene) planar hybrid devices with two different device architectures. Hybrid electronic devices with trench isolated electrodes (HED-TIE) having a channel length of ca. 100 nm fabricated in this work and, for comparison, commercially available pre-structured organic field-effect transistor (OFET) substrates with a channel length of 20 um were used. The magnitude of the photocurrent as well as the magnetoresistance was found to be higher for the HED-TIE devices because of the much smaller channel length of these devices compared to the OFETs. We attribute the observed light induced negative magnetoresistance in TIPS-pentacene to the presence of electron hole pairs under illumination as the magnetoresistive effect scales with the photocurrent. The magnetoresistance effect was found to diminish over time under ambient conditions compared to a freshly prepared sample. We propose that the much faster degradation of the magnetoresistance effect as compared to the photocurrent was due to the incorporation of water molecules in the TIPS pentacene film. PMID- 28900605 TI - Histopathological analysis of infiltrating T cell subsets in acute T cell mediated rejection in the kidney transplant. AB - AIM: To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes. METHODS: A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively. RESULTS: In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss. CONCLUSION: Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies. PMID- 28900606 TI - Lymphocyte recovery is an independent predictor of relapse in allogeneic hematopoietic cell transplantation recipients for acute leukemia. AB - AIM: To examine the optimal absolute lymphocyte count (ALC) cut-off utilizing receiver operator characteristics (ROC) in addition to graft characteristics associated with early ALC recovery. METHODS: Patients who received T-cell replete peripheral hematopoietic cell transplantation (HCT) for acute leukemia were identified. ALC cut-off was established using ROC analysis and subsequently the cohort was stratified. Time to endpoint analysis and cox regression modelling was computed to analyze outcomes. RESULTS: A total of 72 patients met the inclusion criteria and were analyzed. Optimal ALC cut-off was established to be on day 14 (D14) with ALC > 0.3 * 109/L. At 2 years, cumulative incidence of relapse was 16.9% vs 46.9% (P = 0.025) for early and delayed lymphocyte recovery cohorts, respectively. Chronic graft vs host disease was more prevalent in the early lymphocyte recovery (ELR) group at 70% vs 27%, respectively (P = 0.0006). On multivariable analysis for relapse, ELR retained its prognostic significance with HR = 0.27 (0.05-0.94, P = 0.038). CONCLUSION: ELR is an independent predictor for relapse in patients receiving allogeneic HCT for acute leukemia. ELR was influenced by graft characteristics particularly CD34 count. PMID- 28900607 TI - De novo intraocular amyloid deposition after hepatic transplantation in familial amyloidotic polyneuropathy. AB - The familiar amyloid polyneuropathy (FAP) is a rare autosomal-dominant systemic amyloidosis. Amyloid deposition occurs more frequently and extensively in the vitq. The increase in intraocular pressure (IOP) is a result of deposition of transthyretin (TTR) in trabecular meshwork. Rarely, the amyloid deposition in anterior segment can be more exuberant than in posterior segment. A 42 years old man, with FAP (Val30Met mutation), liver transplantation in 1997. He was asymptomatic, without any significant ocular abnormality until 2011. In 2011 he had an episode of pain in right eye (RE). Scalloped pupils, pupillary amyloid deposits and subtle vitreous opacities were detected. The IOP was 40 mmHg in RE and 28 mmHg in left eye (LE) with open angle. Optical coherence tomography detected a temporal superior retinal nerve fiber layer defect in LE and perimetry was normal. Topical timolol was initiated, and brimonidine was subsequently added to improve IOP control, which was achieved with topical medication until last evaluation. No progression occurred since 2011. Actually, with longer life expectancies, there is an increased risk of ocular involvement in FAP, even after liver transplantation. Although rare, a more exuberant amyloid deposition in anterior segment vs posterior segment can occur, and supports an important role of amyloid production in ciliary pigment epithelium in these patients. Medical control of IOP and a stable course are unusual in this secondary glaucoma. Ophthalmologists have an important task in the follow-up of patients and early diagnosis of risk factors for secondary glaucoma, such as scalloped pupils with amyloid deposits. PMID- 28900608 TI - Comparative Analysis of MicroRNA Expression among Benign and Malignant Tongue Tissue and Plasma of Patients with Tongue Cancer. AB - BACKGROUND: Identification of a microRNA (miRNA) pattern to be used as a biomarker for HNSCC is challenging given the heterogeneity of the disease and different methodologies used. To better define the field, we performed a prospective analysis of blood, tumor, and paired benign tissues in tongue squamous cell carcinoma (SCC) patients. METHODS: Plasma samples were collected prior to surgery, and paired tumor and benign tissue blocks were collected from tongue cancer resections. Circulating free and exosomal miRNA, and paired tumor and benign tissues miRNA were analyzed. TaqMan-based miRNA arrays were used to quantitate the expression of 747 human miRNAs. The comparative Ct method assessed the miRNA profile results, and Student's t-test determined statistical significance between tumor and benign samples. RESULTS: Sixteen of 359 miRNAs detected were differentially expressed between paired tumor and benign tissue. Nine were upregulated, and seven downregulated in tumor tissue. All nine upregulated and six of seven downregulated tumor miRNAs were expressed in circulating exosomes. In contrast, eight of nine upregulated and four of seven downregulated tumor miRNAs were circulating free in the plasma. CONCLUSION: An aberrantly expressed pattern of miRNA was identified in both tumor and plasma of patients with tongue SCC, suggesting this may be a biomarker for SCC of the oral tongue. Circulating exosomes appear to be a more reliable method for evaluation of circulating tumor-miRNA expression. Further studies with a larger cohort of patients and serial blood samples are needed to validate our findings. PMID- 28900610 TI - The Role of Intraoperative Thyroglobuline Level of Lymph Node in the Management of Papillary Thyroid Cancer (Determination of a Cutoff Point). AB - BACKGROUND: Some studies have shown that a preoperative high concentration of thyroglobulin (Tg) in wash out of fine-needle aspiration cytology of cervical lymph nodes mandate therapeutic lymph node dissection. However, there is disagreement about the minimum concentration of Tg which could have diagnostic value. Hence, according to our literature review, this study is the first one which designed to do intraoperatively. Therefore, this study was conducted and aimed to determine the clinical diagnostic value of Tg lymph nodes in the diagnosis of metastatic thyroid cancer. METHODS: In a cross-sectional study, 65 patients with papillary thyroid carcinoma (PTC) who were thyroidectomy candidates were chosen and during surgery, before the removal of lymph nodes in the neck, fine-needle sampling was performed and the level of Tg in the samples, nature of the sample sent for biopsy and Tg levels in affected and unaffected lymph nodes were determined. RESULTS: The mean levels of washout Tg in malignant and nonmalignant lymph nodes were 622.1 +/- 66.2 and 1.38 +/- 0.43 ng/ml, respectively, and the difference between the two groups was significant (P < 0.001). The Tg cut-off point for the detection of lymph node metastases was 0.7 ng/dl, and according to it, Tg washout sensitivity was 93.8%, specificity of 92.4%, false positives 7.76%, false negatives 6.3%, positive predictive value was 92.3%, and negative predictive value was 93.8% and accuracy was 93.1%. CONCLUSION: Based on the results, Tg level of cervical lymph nodes in patients with PTC is a suitable criterion for the diagnosis of lymph node which can be determined through fine-needle biopsy. Therefore, it is suggested that in patients with suspicion of lymph nodes involvement during surgery, fine-needle biopsy and determination of the Tg level performed. PMID- 28900611 TI - The Protective Effect of L-arginine in Cisplatin-induced Nephrotoxicity in Streptozotocin-induced Diabetic Rats. AB - BACKGROUND: Cisplatin (CP) is accompanied with a nephrotoxicity. L-arginine (LA) plays an important role in the regulation of renal function. The present study was designed to investigate the protective role of LA supplementation in CP induced nephrotoxicity in a diabetic rat's model. MATERIALS AND METHODS: Sixteen adult female and male Wistar rats were used and they received a single dose of streptozotocin (STZ) (60 mg/kg i.p.). Diabetic female and male rats were arranged as groups 1-5 and groups 6-10, respectively. Groups 1 and 6 (LA groups) received LA alone. Groups 2 and 7 (CP groups) received CP alone. Groups 3 and 8 (CP + LA [PT] groups) received LA as prophylaxis and then treated with LA and CP. Groups 4 and 9 (CP + LA [T] groups) were treated with LA and CP simultaneously. Groups 5 and 10 (CP + LA [P] groups) received LA as prophylaxis and then treated with CP. RESULTS: The serum creatinine (Cr) level of males in Groups 8 and 9 was significantly increased when compared with LA and CP (P < 0.05), whereas no differences were observed in Cr level in female groups. Blood urea nitrogen/Cr ratio and kidney weight were reduced in all CP-receiving male rats. Such observation was not seen in female rats. Different results related to weight loss were obtained between male and female animals. The kidney tissue damage score in CP + LA (PT) male group was significantly greater than CP group (P < 0.05). CONCLUSION: Our findings indicate that administration of LA in female and male rats has no protective effect on the severity of nephrotoxicity induced by CP in diabetic rats. PMID- 28900612 TI - Coexistence of Multiple Sclerosis and Brain Tumor: An Uncommon Diagnostic Challenge. AB - Nonneoplastic demyelinating processes of the brain with mass effect on magnetic resonance imaging can cause diagnostic difficulties. It requires differential diagnosis between the tumefactive demyelinating lesion and the coexistence of neoplasm. We document the case of 41-year-old woman with clinical and radiological findings suggestive of multiple sclerosis. Additional investigations confirmed the coexistence of astrocytoma. This report emphasizes the importance of considering brain tumors in the differential diagnosis of primary demyelinating disease presenting with a cerebral mass lesion. PMID- 28900609 TI - Genes Contributing to Porphyromonas gingivalis Fitness in Abscess and Epithelial Cell Colonization Environments. AB - Porphyromonas gingivalis is an important cause of serious periodontal diseases, and is emerging as a pathogen in several systemic conditions including some forms of cancer. Initial colonization by P. gingivalis involves interaction with gingival epithelial cells, and the organism can also access host tissues and spread haematogenously. To better understand the mechanisms underlying these properties, we utilized a highly saturated transposon insertion library of P. gingivalis, and assessed the fitness of mutants during epithelial cell colonization and survival in a murine abscess model by high-throughput sequencing (Tn-Seq). Transposon insertions in many genes previously suspected as contributing to virulence showed significant fitness defects in both screening assays. In addition, a number of genes not previously associated with P. gingivalis virulence were identified as important for fitness. We further examined fitness defects of four such genes by generating defined mutations. Genes encoding a carbamoyl phosphate synthetase, a replication-associated recombination protein, a nitrosative stress responsive HcpR transcription regulator, and RNase Z, a zinc phosphodiesterase, showed a fitness phenotype in epithelial cell colonization and in a competitive abscess infection. This study verifies the importance of several well-characterized putative virulence factors of P. gingivalis and identifies novel fitness determinants of the organism. PMID- 28900613 TI - Screening for Developmental Disorders in 3- and 4-Year-Old Italian Children: A Preliminary Study. AB - BACKGROUND: The "Osserviamo" project, coordinated by the Municipality of Rome and the Department of Pediatrics and Child Neuropsychiatry of Sapienza University, aimed to validate an Italian version of the Ages and Stages Questionnaire-3 and to collect, for the first time in Italy, data on developmental disorders in a sample of 4,000 children aged 3 and 4 years. The present paper presents the preliminary results of the "Osserviamo" project. METHODS: 600 parents of children between 39 and 50 months of age (divided in two age stages: 42 and 48 months) were contacted from 15 kindergarden schools. RESULTS: 23.35% of the whole sample scored in the risk range of at least one developmental area of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and 7.78% scored in the clinical range. Specifically, 23.97% of the children in the 42-month age stage scored in the risk range and 5.79% scored in the clinical range. Males scored lower than females in the fine motor skills and personal-social development domains. Moreover, 22.79% of the children in the 48-month age stage scored in the risk range, while 9.55% scored in the clinical range. Males scored lower than females in fine motor skills. CONCLUSION: Italian validation of the ASQ-3 and recruitment of all 4,000 participants will allow these data on the distribution of developmental disorders to be extended to the general Italian pediatric population. One main limitation of the study is the lack of clinical confirmation of the data yielded by the screening programme, which the authors aim to obtain in later stages of the study. PMID- 28900614 TI - Echocardiographic Evaluation of Pulmonary Pressures and Right Ventricular Function after Pediatric Cardiac Surgery: A Simple Approach for the Intensivist. AB - Pulmonary hypertension (PH) is diagnosed using cardiac catheterization and is defined as an elevation of mean pulmonary artery pressure (PAP) greater than 25 mmHg. Although invasive hemodynamics remains the gold standard and is mandatory for disease confirmation, transthoracic echocardiography (TTE) is an extremely useful non-invasive and widely available tool that allows for screening and follow-up, in particular, in the acute setting. TTE may be a valuable alternative, allowing for direct measurement and/or indirect assessment of PAP. Because of the complex geometric shape and pattern of contraction of the right ventricle (RV), as well as the inherent complexity of cardiac repair, no single view or measurement can provide definite information on RV function and PAP and/or pulmonary vascular resistance. In addition, specific training and expertise may be necessary to obtain the views and measurements required. Some simple measurements may be of help when rapid evaluation is mandatory and potentially life saving: the assessment of tricuspid and/or pulmonary valve regurgitant jet and the use of the Bernoulli equation allow for measurement of PAP. Measurements such as the analysis of the pulmonary Doppler wave flow, the septal curvature, or the eccentricity index, assessing ventricular interdependence, are useful for indirect assessment. A four-chamber view of the RV gives information on its size, hypertrophy, function (fractional area change), and tricuspid annular plane systolic excursion as an evaluation of the longitudinal function. Based on these simple measurements, TTE can provide detection of PH, measurement or estimation of PAP, and assessment of cardiac function. TTE is also of importance in follow up of PH as well as providing an assessment of therapeutic strategies in the postoperative setting of cardiac surgery. However, PAP may be misleading as it is dependent on cardiac output and requires accurate measurements. In the presence of residual lesions, analyses of some Doppler measurements may be misleading and not reflect real PAP. Should the TTE evaluation reveal non-conclusive, invasive hemodynamics remains the gold standard. PMID- 28900615 TI - Exploring Genetic Numeracy Skills in a Sample of U.S. University Students. AB - Misconceptions concerning numerical genetic risk exist even within educated populations. To more fully characterize and understand the extent of these risk misunderstandings, which have large potential impact on clinical care, we analyzed the responses from 2,576 students enrolled at 2 Southwestern universities using the PGRID tool, a 138-item web-based survey comprising measures of understanding of genetics, genetic disease, and genetic risk. The primary purpose of this study was to characterize the intersection of risk perception and knowledge, termed genetic numeracy (GN). Additionally, we identify sociodemographic factors that might shape varying levels of GN skills within the study sample and explore the impact of GN on genetic testing intentions using both the Marascuilo procedure and logistic regression analysis. Despite having some college coursework or at least one college degree, most respondents lacked high-level aptitude in understanding genetic inheritance risk, especially with respect to recessive disorders. Prior education about genetics and biology, as well as exposure to biomedical models of genetics, was associated with higher GN levels; exposure to popular media models of genetics was inversely associated with higher GN levels. Differing GN levels affects genetic testing intentions. GN will become more relevant as genetic testing is increasingly incorporated into general clinical care. PMID- 28900616 TI - Implementing Precision Antimicrobial Therapy for the Treatment of Bovine Respiratory Disease: Current Limitations and Perspectives. AB - The therapeutic efficacy of an early treatment protocol with an infection-stage adjusted fluoroquinolone regimen was evaluated in a field study on young bulls (YBs) presenting signs of bovine respiratory disease (BRD). A total of 195 YB (Charolais, Limousin, and Rouge-des-Pres breeds) from 6 farms implementing or not prophylactic antimicrobial treatments (PROPHY or absence) were randomly assigned to 1 of 2 experiment groups based on time of detection of BRD and first-line marbofloxacin regimen, early adjusted dose [Early 2 (E2)] or late standard dose [Late 10 (L10)]. Each YB was administered orally a reticulo-rumen bolus, allowing continuous monitoring of ruminal temperature. In the E2 group, YB presenting early signs of BRD, i.e., an increase in ruminal temperature over 40.2 degrees C and persisting more than 12 h, confirmed by a clinical examination showing no or mild signs of BRD, were given 2 mg/kg of marbofloxacin. In the L10 group, YBs presenting moderate or severe signs of BRD at visual inspection, confirmed at clinical examination, were given 10 mg/kg of marbofloxacin. If needed, YBs were given a relapse treatment. The YBs were followed for 30 days. The proportions of first and relapse treatments were calculated, as well as the therapeutic efficacy at day 10. In the E2 group, the first-line treatments' proportion was significantly higher (P < 0.05), while the relapse treatments' proportion tended to be higher (P = 0.08), than in the L10 group. Evolution of clinical scores (CSs) of diseased YB was followed for 10 days. In both groups, CS and rectal temperature decreased significantly 24 h after treatment (P < 0.05). Treatment incidences (TI) representing antimicrobial consumption assessed on used daily doses (UDD) were calculated. Antimicrobial consumption of marbofloxacin and relapse treatments were not significantly different between the groups. These values were strongly influenced by the recourse to a prophylactic antimicrobial treatment, accounting for more than 90% of the antimicrobial amount in the herds implementing prophylaxis. The higher number of treatments in the groups treated on the basis of ruminal temperature monitoring, the accuracy of the detection method, and the necessary conditions to implement precision antimicrobial therapy in the field are discussed in this article. PMID- 28900617 TI - Serum and Brain Metabolomic Variations Reveal Perturbation of Sleep Deprivation on Rats and Ameliorate Effect of Total Ginsenoside Treatment. AB - Sleep loss or sleep deprivation (SD) refers to shorter sleep than average baseline need, and SD has been a serious problem of modern societies which affects health and well-being. Panax ginseng is a well-known traditional Chinese medicine (TCM). Our previous study has demonstrated that total ginsenosides (GS), the extracts from Panax ginseng, could effectively improve cognition and behavior on SD rats. However, little is known about its metabolomic study. In this study, serum and brain metabolomic method based on gas chromatography coupled with mass spectrometry (GC/MS) was employed to evaluate the efficacy and study the mechanism of GS on a rat model of SD. With pattern recognition analysis of serum and brain tissue metabolite profile, a clear separation of the model group and control group was acquired for serum and brain tissue samples; the MGS (model + GS) group showed a tendency of recovering when compared to control group, which was consistent with behavioral and biochemical parameters. 39 and 40 potential biomarkers of brain tissues and serum samples, respectively, were identified and employed to explore the possible mechanism. Our work revealed that GS has significant protective effects on SD, and metabolomics is a useful tool for evaluating efficacy and elucidating mechanism in TCM. PMID- 28900618 TI - Comparative Genomic In Situ Hybridization and the Possible Role of Retroelements in the Karyotypic Evolution of Three Akodontini Species. AB - South American Akodontini rodents are characterized by a large number of chromosome rearrangements. Among them, the genus Akodon has been extensively analyzed with classical and molecular cytogenetics, which allowed the identification of a large number of intra- and interspecific chromosomal variation due to Robertsonian rearrangements, pericentric inversions, and heterochromatin additions/deletions. In order to shed some light on the cause of these rearrangements, we comparatively analyzed the karyotypes of three Akodontini species, Akodon cursor (2n = 14, FN = 19), A. montensis (2n = 24, FN = 42), and Necromys lasiurus (2n = 34, FN = 34), after GTG- and CBG-banding. The karyotypes differed by Robertsonian rearrangements, pericentric inversions, centromere repositioning, and heterochromatin variation. Genome comparisons were performed through interspecific fluorescent in situ hybridization (FISH) with total genomic DNAs of each species as probes (GISH). Our results revealed considerable conservation of the euchromatic portions among the three karyotypes suggesting that they mostly differ in their heterochromatic regions. FISH was also performed to assess the distribution of telomeric sequences, long and short interspersed repetitive elements (LINE-1 and B1 SINE) and of the endogenous retrovirus mysTR in the genomes of the three species. The results led us to infer that transposable elements have played an important role in the enormous chromosome variation found in Akodontini. PMID- 28900619 TI - Aquatic Plant Genomics: Advances, Applications, and Prospects. AB - Genomics is a discipline in genetics that studies the genome composition of organisms and the precise structure of genes and their expression and regulation. Genomics research has resolved many problems where other biological methods have failed. Here, we summarize advances in aquatic plant genomics with a focus on molecular markers, the genes related to photosynthesis and stress tolerance, comparative study of genomes and genome/transcriptome sequencing technology. PMID- 28900620 TI - Can Mixed Parasite Infections Thwart Targeted Malaria Elimination Program in India? AB - India is highly endemic to malaria with prevalence of all five species of human malaria parasites of Plasmodium genus. India is set for malaria elimination by 2030. Since cases of mixed Plasmodium species infections remain usually undetected but cause huge disease burden, in order to understand the distributional prevalence of both monospecies infections and mixed species infections in India, we collated published data on the differential infection incidences of the five different malaria parasites based on PCR diagnostic assay. About 11% of total cases were due to mixed species infection. Among several interesting observations on both single and mixed parasitic infections, incidences of Plasmodium falciparum monoinfection were found to be significantly higher than P. vivax monoinfection. Also, P. malariae seems to be emerging as a potential malaria threat in India. Putting all the facts together, it appears that the dream of achieving malaria elimination in India will not be completely successful without dealing with mixed species infection. PMID- 28900621 TI - Using a Cloud Computing System to Reduce Door-to-Balloon Time in Acute ST Elevation Myocardial Infarction Patients Transferred for Percutaneous Coronary Intervention. AB - BACKGROUND: This study evaluated the impact on clinical outcomes using a cloud computing system to reduce percutaneous coronary intervention hospital door-to balloon (DTB) time for ST segment elevation myocardial infarction (STEMI). METHODS: A total of 369 patients before and after implementation of the transfer protocol were enrolled. Of these patients, 262 were transferred through protocol while the other 107 patients were transferred through the traditional referral process. RESULTS: There were no significant differences in DTB time, pain to door of STEMI receiving center arrival time, and pain to balloon time between the two groups. Pain to electrocardiography time in patients with Killip I/II and catheterization laboratory to balloon time in patients with Killip III/IV were significantly reduced in transferred through protocol group compared to in traditional referral process group (both p < 0.05). There were also no remarkable differences in the complication rate and 30-day mortality between two groups. The multivariate analysis revealed that the independent predictors of 30-day mortality were elderly patients, advanced Killip score, and higher level of troponin-I. CONCLUSIONS: This study showed that patients transferred through our present protocol could reduce pain to electrocardiography and catheterization laboratory to balloon time in Killip I/II and III/IV patients separately. However, this study showed that using a cloud computing system in our present protocol did not reduce DTB time. PMID- 28900622 TI - Biomechanical Measurement Error Can Be Caused by Fujifilm Thickness: A Theoretical, Experimental, and Computational Analysis. AB - This is the first study to quantify the measurement error due to the physical thickness of Fujifilm for several material combinations relevant to orthopaedics. Theoretical and experimental analyses were conducted for cylinder-on-flat indentation over a series of forces (750 and 3000 N), cylinder diameters (0 to 80 mm), and material combinations (metal-on-metal, MOM; metal-on-polymer, MOP; metal on-bone, MOB). For the scenario without Fujifilm, classic Hertzian theory predicted the true line-type contact width as WO = {(8FDcyl)/(piLcyl)[(1 - nucyl2)/Ecyl + (1 - nuflat2)/Eflat]}1/2, where F is compressive force, Dcyl is cylinder diameter, Lcyl is cylinder length, nucyl and nuflat are cylinder and flat Poisson's ratios, and Ecyl and Eflat are cylinder and flat elastic moduli. For the scenario with Fujifilm, experimental measurements resulted in contact widths of WF = 0.1778 * F0.2273 * D0.2936 for MOM tests, WF = 0.0449 * F0.4664 * D0.4201 for MOP tests, and WF = 0.1647 * F0.2397 * D0.3394 for MOB tests, where F is compressive force and D is cylinder diameter. Fujifilm thickness error ratio WF /WO showed a nonlinear decrease versus cylinder diameter, whilst error graphs shifted down as force increased. Computational finite element analysis for several test cases agreed with theoretical and experimental data, respectively, to within 3.3% and 1.4%. Despite its wide use, Fujifilm's measurement errors must be kept in mind when employed in orthopaedic biomechanics research. PMID- 28900623 TI - Impact of Thyroid Hormone Levels on Functional Outcome in Neurological and Neurosurgical Early Rehabilitation Patients. AB - BACKGROUND: Neurological and neurosurgical early rehabilitation (NNER) is a specialized treatment option for patients with severe neurological disorders. The present study investigated whether thyroid hormone levels on admission have an impact on the outcome of NNER patients. METHOD: The study included 500 NNER patients who were admitted to the BDH-Clinic Hessisch Oldendorf between 2009 and 2010. Data such as age, sex, diagnoses, comorbidities, Glasgow Coma Scale score, length of stay, and thyroid hormone levels (obtained as part of clinical routine care) were analyzed retrospectively. Improvement in the Early Rehabilitation Barthel Index (ERBI) at the end of the NNER treatment was defined as outcome parameter. RESULTS: Most patients made functional progress during treatment, as reflected in significant enhancements of the ERBI. Approximately half of the patients were transferred to further rehabilitation treatment. Young age, early onset of NNER treatment, low functional impairment on admission, and, in particular, low total T3 levels were independently associated with a good outcome. CONCLUSION: Age, severity of disease, and time between injury and admission are known to predict outcome. The present study confirms the influence of these general factors. In addition, an association between thyroid hormones and functional outcome was demonstrated for NNER patients. PMID- 28900624 TI - Ultrasound Mediated Microbubbles Destruction Augmented Sonolysis: An In Vitro and In Vivo Study. AB - OBJECTIVE: This study was aimed at exploring ultrasound mediated microbubbles destruction (UMMD) assisted sonolysis in both the in vitro and in vivo clots. METHODS: Therapeutic ultrasound (TUS) and lipid microbubbles (MBs) were used in whole blood clots and divided into the control, TUS group, and TUS + MB group. Thrombolytic rates and microscopy were performed. Color Doppler flow imaging (CDFI) and angiography were performed to evaluate the recanalization rates and flow scores in femoral arterial thrombus (FAT) in rabbits. FAT were dyed with H&E. RESULTS: The average thrombolytic ratios of TUS + MB group were significantly higher than those of TUS group and the control group (both P < 0.05). Clots had different pathological changes. Recanalization rates and flow scores in TUS + MB group were significantly higher than the control and TUS group. Flow scores and recanalization ratios were grade 0 in 0% of the control group, grade I in 25% of TUS group, and grade II or higher in 87.5% of TUS + MB group after 30 min sonolysis. CONCLUSIONS: Both the in vitro and in vivo sonolysis can be significantly augmented by the introduction of MBs without thrombolytic agents, which might be induced by the enhanced cavitation via UMMD. PMID- 28900625 TI - Direct Assessment of Wall Shear Stress by Signal Intensity Gradient from Time-of Flight Magnetic Resonance Angiography. AB - The aim of the study was to calculate the arterial wall signal intensity gradient (SIG) from time-of-flight MR angiography (TOF-MRA) and represent arterial wall shear stress. We developed a new algorithm that uses signal intensity (SI) of a TOF-MRA to directly calculate the signal intensity gradient (SIG). The results from our phantom study showed that the TOF-MRA SIG could be used to distinguish the magnitude of blood flow rate as high (mean SIG +/- SD, 2.2 +/- 0.4 SI/mm for 12.5 +/- 2.3 L/min) and low (0.9 +/- 0.3 SI/mm for 8.5 +/- 2.6 L/min) in vessels (p < 0.001). Additionally, we found that the TOF-MRA SIG values were highly correlated with various flow rates (beta = 0.96, p < 0.001). Remarkably, the correlation coefficient between the WSS obtained from the computational fluid dynamics (CFD) analysis and the TOF-MRA SIG was greater than 0.8 in each section at the carotid artery (p < 0.001 for all beta values). This new technique using TOF-MRA could enable the rapid calculation of the TOF-MRA SIG and thereby the WSS. Thus, the TOF-MRA SIG can provide clinicians with an accurate and efficient screening method for making rapid decisions on the risk of vascular disease for a patient in clinical practice. PMID- 28900626 TI - Emotion Recognition from EEG Signals Using Multidimensional Information in EMD Domain. AB - This paper introduces a method for feature extraction and emotion recognition based on empirical mode decomposition (EMD). By using EMD, EEG signals are decomposed into Intrinsic Mode Functions (IMFs) automatically. Multidimensional information of IMF is utilized as features, the first difference of time series, the first difference of phase, and the normalized energy. The performance of the proposed method is verified on a publicly available emotional database. The results show that the three features are effective for emotion recognition. The role of each IMF is inquired and we find that high frequency component IMF1 has significant effect on different emotional states detection. The informative electrodes based on EMD strategy are analyzed. In addition, the classification accuracy of the proposed method is compared with several classical techniques, including fractal dimension (FD), sample entropy, differential entropy, and discrete wavelet transform (DWT). Experiment results on DEAP datasets demonstrate that our method can improve emotion recognition performance. PMID- 28900627 TI - Predictors of Hypertension among Nonpregnant Females Attending Health Promotion Clinic with Special Emphasis on Smokeless Tobacco: A Cross-Sectional Study. AB - AIM: To determine the predictors of hypertension among nonpregnant females attending a health promotion clinic. DESIGN AND SETTING: A cross-sectional study was conducted during March to June 2016, at the National Institute of Cancer Prevention and Research, India. METHODS: The study included 319 nonpregnant females of age 20-70 years. Demographics such as age, literacy, and income were noted. History regarding use, frequency, and quantity of smokeless tobacco was taken. Height, weight, and blood pressure were measured and body mass index was calculated. STATISTICAL ANALYSIS: Pearson's product-moment correlation coefficient was calculated between each of the variables of age, smokeless tobacco consumption, and body mass index versus systolic and diastolic blood pressure, respectively. The linear as well as multiple linear regression analysis was employed to identify the risk factors for hypertension. RESULTS: A univariate linear regression analysis showed that age, smokeless tobacco consumption, and body mass index were associated with systolic blood pressure (P value < 0.001 for each). For diastolic blood pressure, high body mass index was a predictor. Multiple linear regression analysis showed that both systolic and diastolic hypertension were associated with high body mass index and low level of education. Moreover, the systolic hypertension was associated with higher age and smokeless tobacco use. CONCLUSION: Health promotion requires control of body mass index and smokeless tobacco cessation for preventing hypertension and its complications. PMID- 28900628 TI - Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients. AB - Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the "neurotrophin-MAPK signaling pathway" was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment. PMID- 28900629 TI - SIAE Rare Variants in Juvenile Idiopathic Arthritis and Primary Antibody Deficiencies. AB - Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects. PMID- 28900630 TI - Determination of Vitamin D Status in a Population of Ecuadorian Subjects. AB - INTRODUCTION: Vitamin D is a preprohormone known to play a key role in phosphocalcic metabolism; its main source comes from the synthesis at the skin level by ultraviolet (UV) radiation. OBJECTIVE: The purpose of this study was to determine the levels of vitamin D in an Ecuadorian population. MATERIALS AND METHODS: Retrospective study of Ecuadorian subjects from the city of Guayaquil, who had an initial study of 25 (OH)-D serum, as the indicator of Vitamin D status, in the period of 2015-2016. RESULTS: A total of 269 Ecuadorian subjects were analyzed, with a mean age of 54.73 +/- 16.58; 85% (229) were females and 15% (41) males; mean vitamin D was 27.29 +/- 10.12 ng/dl [6.41-88.74]; 70% of the population showed levels below 30 ng/dL of vitamin D, whereas only 30% (81) had normal values. 69% (185) had levels between 29 and 10 ng/dl and 1% (3) levels below 10 ng/dl. High levels of vitamin D were evidenced in the summer months in relation to the winter months. CONCLUSION: It is evident that, despite the location of Ecuador and the intensity of UV rays it receives throughout the year, Ecuadorian subjects have insufficient levels of vitamin D. PMID- 28900631 TI - Single-Cell Phosphospecific Flow Cytometric Analysis of Canine and Murine Adipose Derived Stem Cells. AB - This study aimed to demonstrate single-cell phosphospecific flow cytometric analysis of canine and murine adipose-derived stem/stromal cells (ADSCs). ADSCs were obtained from clinically healthy laboratory beagles and C57BL/6 mice. Cell differentiation into adipocytes, osteocytes, and chondrocytes was observed for the cultured canine ADSCs (cADSCs) and murine ADSCs (mADSCs) to determine their multipotency. We also performed single-cell phosphospecific flow cytometric analysis related to cell differentiation and stemness. Cultured cADSCs and mADSCs exhibited the potential to differentiate into adipocytes, osteocytes, and chondrocytes. In addition, single-cell phosphospecific flow cytometric analysis revealed similar beta-catenin and Akt phosphorylation between mADSCs and cADSCs. On the other hand, it showed the phosphorylation of different Stat proteins. It was determined that cADSCs and mADSCs show the potential to differentiate into adipocytes, osteocytes, and chondrocytes. Furthermore, a difference in protein phosphorylation between undifferentiated cADSCs and mADSCs was identified. PMID- 28900632 TI - Clinical outcomes in ER+ HER2 -node-positive breast cancer patients who were treated according to the Recurrence Score results: evidence from a large prospectively designed registry. AB - The Recurrence Score(r) is increasingly used in node-positive ER+ HER2-negative breast cancer. This retrospective analysis of a prospectively designed registry evaluated treatments/outcomes in node-positive breast cancer patients who were Recurrence Score-tested through Clalit Health Services from 1/2006 through 12/2011 (N = 709). Medical records were reviewed to verify treatments/recurrences/survival. Median follow-up, 5.9 years; median age, 62 years; 53.9% grade 2; 69.8% tumors <= 2 cm; 84.5% invasive ductal carcinoma; 42.0% N1mi, and 37.2%/15.5%/5.2% with 1/2/3 positive nodes; 53.4% Recurrence Score < 18, 36.4% Recurrence Score 18-30, and 10.2% Recurrence Score >= 31. Overall, 26.9% received adjuvant chemotherapy: 7.1%, 39.5%, and 86.1% in the Recurrence Score < 18, 18-30, and >= 31 group, respectively. The 5-year Kaplan Meier estimates for distant recurrence were 3.2%, 6.3%, and 16.9% for these respective groups and the corresponding 5-year breast cancer death estimates were 0.5%, 3.4%, and 5.7%. In Recurrence Score < 18 patients, 5-year distant recurrence rates for N1mi/1 positive node/2-3 positive nodes were 1.2%/4.4%/5.4%. As patients were not randomized to treatment and treatment decision is heavily influenced by Recurrence Score, analysis of 5-year distant recurrence by chemotherapy use was exploratory and should be interpreted cautiously: In Recurrence Score < 18, recurrence rate was 7.7% in chemotherapy-treated (n = 27) and 2.9% in chemotherapy-untreated patients (n = 352); P = 0.245. In Recurrence Score 18-30, recurrence rate in chemotherapy-treated patients (n = 102) was significantly lower than in untreated patients (n = 156) (1.0% vs. 9.7% P = 0.019); in Recurrence Score <= 25 (the RxPONDER study cutoff), recurrence rate was 2.3% in chemotherapy-treated (n = 89) and 4.4% in chemotherapy-untreated patients (n = 488); P = 0.521. In conclusion, our findings support using endocrine therapy alone in ER+ HER2-negative breast cancer patients with micrometastases/1-3 positive nodes and Recurrence Score < 18. PMID- 28900635 TI - How many surface atoms in Co3O4 take part in oxygen evolution? Isotope labeling together with differential electrochemical mass spectrometry. AB - Understanding the mechanism underlying the oxygen evolution reaction (OER) on oxides is crucial for the development of many energy storage systems. Here, the mechanism of OER on a Co3O4 spinel catalyst is investigated in alkaline media using 18O-labeling combined with differential electrochemical mass spectrometry (DEMS). This work unravels the role of surface oxygen of the oxide in the OER. It is shown that in H218O-containing electrolyte the amount of 18O16O evolved increases from cycle to cycle together with a concomitant decrease of the amount of 16O2 with each cycle before reaching a steady-state value. 18O16O is also evolved from a H216O solution on a Co3O4 electrode pre-treated in H218O containing solution, indicating the formation of the 18O-labeled oxide in the previous step. Therefore, the oxide layer takes part in OER via an oxygen exchange mechanism. The total number of oxygen atoms of the oxide participating in OER is 0.1 to 0.2% of the total oxide loading, corresponding to about 10-30% of the surface atoms; these represent the catalytically active sites. Moreover, the real surface area of the catalyst is estimated using different methods (namely the ball model, double layer capacitance method, redox peak method, isotope exchange), and compared to the BET data. The surface areas calculated from the BET data, ball model and redox peak method are similar for small particles, which indicates their smooth surface; however they are smaller than that estimated from double-layer capacitance. For larger particles, the much larger surface area estimated from the redox peak in comparison to that expected from the ball model seems to be due to their roughness. Thus, this work highlights the importance of probing the mechanism when investigating the OER activity of a catalyst. PMID- 28900634 TI - Synergistic enhancement in the drug sequestration power and reduction in the cytotoxicity of surfactants. AB - Surfactants have often been employed for the sequestration of drugs from DNA. However, for an effective sequestration, the concentration of the surfactant needs to be higher than its critical micellar concentration (CMC). Use of such high concentrations of the surfactant may limit its practical usage as a sequestering agent due to its cytotoxicity. In the present study we have shown that sodium dodecyl sulfate (SDS) itself at a concentration less than its CMC failed to sequester a drug from DNA. However, the sequestration power of SDS at sub-CMC concentration could be enhanced to a significant extent when incorporated into Pluronic polymer micelles in the form of supramolecular assemblies. Such a sequestration process was monitored through detailed photophysical properties of a model drug using steady-state and time-resolved fluorescence techniques. It has also been demonstrated that unlike a conventional surfactant, the sequestration of drugs by SDS-polymer supramolecular assemblies can be controlled by their compositions. Two Pluronic polymers with different compositions have been used to understand the effect of polymer composition on the sequestration process. It has been shown that with the increase in the length of the hydrophilic blocks of the polymer, the extent of sequestration decreases due to the decrease in the sequestering force exerted on the intercalated drug. Most importantly, our in vitro cell viability studies show that the toxicity of the SDS surfactant is reduced to a remarkable extent due to its incorporation into the polymer micelles. PMID- 28900633 TI - Clinical outcomes in patients with node-negative breast cancer treated based on the recurrence score results: evidence from a large prospectively designed registry. AB - The 21-gene Recurrence Score(r) (RS) assay is a validated prognostic/predictive tool in ER + early-stage breast cancer. However, clinical outcome data from prospective studies in RS >= 11 patients are lacking, as are relevant real-life clinical practice data. In this retrospective analysis of a prospectively designed registry, we evaluated treatments/clinical outcomes in patients undergoing RS-testing through Clalit Health Services. The analysis included N0 ER + HER2-negative breast cancer patients who were RS-tested from 1/2006 through 12/2010. Medical records were reviewed to verify treatments/recurrences/survival. The cohort included 1801 patients (median follow-up, 6.2 years). Median age was 60 years, 50.4% were grade 2 and 81.1% had invasive ductal carcinoma; 48.9% had RS < 18, 40.7% RS 18-30, and 10.4% RS >= 31, with chemotherapy use of 1.4, 23.7, and 87.2%, respectively. The 5-year Kaplan-Meier estimates for distant recurrence were 0.8, 3.0, and 8.6%, for patients with RS < 18, RS 18-30 and RS >= 31, respectively; the corresponding 5-year Kaplan-Meier estimates for breast cancer death were 0.0, 0.9, and 6.2%. Chemotherapy-untreated patients with RS < 11 (n = 304) and 11-25 (n = 1037) (TAILORx categorization) had 5-year Kaplan-Meier estimates for distant recurrence risk/breast cancer death of 1.0%/0.0% and 1.3%/0.4%, respectively. Our results extend those of the prospective TAILORx trial: the 5-year Kaplan-Meier estimates for distant recurrence and breast cancer death rate for the RS < 18 patients were very low supporting the use of endocrine therapy alone. Furthermore, in chemotherapy-untreated patients with RS 11-25 (where TAILORx patients were randomized to chemoendocrine or endocrine therapy alone), 5-year distant recurrence rates were also very low, suggesting that chemotherapy would not have conferred clinically meaningful benefit. PMID- 28900636 TI - Examination of molecular packing in orthogonal smectic liquid crystal phases: a guide for molecular design of functional smectic phases. AB - The reported layer spacings (dsmectic) of six homologues of mesogens exhibiting orthogonal smectic phases (SmE, SmB, and SmA phases) are reexamined. The slopes of the linear dependences on chain length (n, the number of carbon atoms in the hydrocarbon chain) are clearly categorized into two groups: 1.9 A (CH2)-1 and 1.4 A (CH2)-1. It is clarified that in the former the molecules take a rod-like form (rod-form; category-I), whereas in the latter the molecules are bent around the connection between the core and chain moieties (bent-form; category-II). The average relative positions of adjacent molecules within the smectic structures are deduced from the intercept of the linear functions of dsmectic against n. The relation between and the features of molecules belonging to the two categories are discussed for molecular design of functional smectic liquid crystals. PMID- 28900637 TI - Beta transmutations in apatites with ferric iron as an electron acceptor - implication for nuclear waste form development. AB - Apatite-structured materials have been considered for the immobilization of a number of fission products from reprocessing nuclear fuel because of their chemical durability as well as compositional and structural flexibility. It is hypothesized that the effect of beta decay on the stability can be mitigated by introducing an appropriate electron acceptor at the neighboring sites in the structure. The decay series 137Cs -> 137Ba and 90Sr -> 90Y -> 90Zr were investigated using a spin-polarized DFT approach to test the hypothesis. Apatites with compositions of Ca10(PO4)6F2 and Ca4Y6(SiO4)6F2 were selected as model systems for the incorporation of radionuclides Cs and Sr, respectively. Ferric iron was introduced in the structure as an electron acceptor. Electron density of states, crystal and defect structures, and energies before and after beta decay were calculated. The calculated electron density of states suggests that the extra electron is localized at the ferric iron, which changes its oxidation state and becomes ferrous iron. The crystal and defect structures were analyzed based on the volume, lattice parameters, radial distribution functions, metal cation to coordinating oxygen distances, and the metaprism twist angle of the apatite crystal structure. The results show that there are minor changes in the crystal and defect structures of CsFeCa8(PO4)6F2 with Cs+ and Fe3+ substitutions undergoing the Cs -> Ba transmutation, and of Ca3SrY4Fe2(SiO4)6F2 with Sr2+ and Fe3+ substitutions undergoing the Sr -> Y -> Zr transmutations. The last decay change, from Y3+ -> Zr4+, causes relatively larger changes in the local defect structure around Zr involving the coordination environment but the change is not significant to the crystal structure. The results on calculated cohesive energy suggest that the transmutations Cs+ -> Ba2+ and Sr2+ -> Y3+ -> Zr4+ in both apatite compositions are energetically favorable, which is consistent with the minor structure distortions. Increased stability with favorable energetics and structural distortion by incorporating ferric ion is significant with respect without variable valence ions. The results confirm the structural and compositional adaptability of apatites upon beta transmutations. The study suggests that apatite-structured materials could be promising nuclear waste forms to mitigate the beta decay induced instability, by incorporating variable valence cations such as ferric iron in the structure. The study demonstrates a methodology which evaluates the structural stability of waste forms incorporating fission products undergoing beta decay. PMID- 28900638 TI - Acid- and hydrogen-bonding-induced switching between 22-pi and 18-pi electron conjugations in 2-aminothiazolo[4,5-c]porphycenes. AB - 2-Aminothiazolo[4,5-c]porphycenes are a novel class of 22-pi electron aromatic porphycene derivatives prepared by click reaction of porphycene isothiocyanates with primary and secondary amines with high potential as near-infrared theranostic labels. Herein, the optical and photophysical properties of 2 aminothiazolo[4,5-c]porphycenes have been studied, revealing a strong dependence on hydrogen bond donor solvents and acids. High hydrogen bond donor solvents and acids shift the absorption and fluorescence emission of 2-aminothiazolo[4,5 c]porphycenes to the blue due to a contraction of their aromatic system from 22 pi to 18-pi electrons. Finally, the aromatic shift has been successfully used to measure the pH using 2-aminothiazoloporphycene-labelled gold nanoclusters, paving the way for the use of these compounds as near infrared pH-sensitive probes. PMID- 28900639 TI - Geometric and electronic properties of ultrathin anatase TiO2(001) films. AB - Ultrathin anatase TiO2(001) films have recently been shown to exhibit many exotic properties, which are not observed in their thick counterpart. In this work, the dependence of the geometric and electronic properties of ultrathin anatase TiO2(001) films on the number of O-Ti-O trilayers is investigated on the basis of first-principles calculations. It is interesting to find that the lattice parameters, intertrilayer distances, electronic band gap and the position of the valence band edge for the films depend strongly on the number of trilayers, and they exhibit pronounced odd-even oscillations with the number of trilayers. Moreover, the convergence of geometric and electronic properties with the number of trilayers is rather slow, and not achieved even in films with 12 trilayers (~2.7 nm). In addition, the adsorption state of the H2O molecule on the surface depends strongly on the thickness of the film. On the other hand, because the TiO2(001) surface is well described by a (001) film containing more than four trilayers, films with different lattice parameters and more than four trilayers may also be regarded as (001) surfaces that have been strained to different extents. Then, the above results from them also apply to the strained TiO2(001) surfaces. These results not only present new physics of the TiO2(001) films and surfaces, but also are helpful for understanding and modulating their performance in photocatalytic water splitting. PMID- 28900640 TI - PPh4Cl in aqueous solution - the aggregation behavior of an antagonistic salt. AB - The initial definition of hydrotropy by Neuberg in 1916 describes a hydrotrope as a molecule which enhances the solubilization of hydrophobic substances in water. Sodium dodecyl sulfate (SDS) and sodium xylene sulfonate (SXS) are typical representatives fulfilling this old definition. They are either surfactants with a critical micellar concentration (CMC) or hydrotropes in the current sense of the term, showing a minimum hydrotrope concentration (MHC), respectively. In the present contribution, we consider the antagonistic salt PPh4Cl as a hydrotrope. Surface tension measurements and solubilization experiments on a hydrophobic dye confirm the solubilization behavior of PPh4Cl, which is in-between the one of SDS and SXS. With the help of scattering techniques (DLS, SLS, SAXS), NMR and conductivity measurements, we show that in contrast to SDS as a hydrotrope with an inherent CMC, PPh4Cl does not exhibit mesoscale aggregation. Therefore, PPh4Cl can be classified rather as a hydrotrope in the modern sense, with an inherent MHC just as SXS. PMID- 28900641 TI - Core-shell colloidal particles with dynamically tunable scattering properties. AB - We design polystyrene-poly(N'-isopropylacrylamide-co-acrylic acid) core-shell particles that exhibit dynamically tunable scattering. We show that under normal solvent conditions the shell is nearly index-matched to pure water, and the particle scattering is dominated by Rayleigh scattering from the core. As the temperature or salt concentration increases, both the scattering cross-section and the forward scattering increase, characteristic of Mie scatterers. The magnitude of the change in the scattering cross-section and scattering anisotropy can be controlled through the solvent conditions and the size of the core. Such particles may find use as optical switches or optical filters with tunable opacity. PMID- 28900643 TI - Unidirectional rotation of cholesteric droplets driven by UV-light irradiation. AB - We investigated the novel photo-induced dynamics of azobenzene-doped cholesteric (Ch) droplets coexisting with the isotropic (Iso) phase. When the hemispherical Ch droplets initially stuck to glass substrates were irradiated by UV-light, they were parted from the substrates due to the surface disordering caused by the photo-isomerization of azobenzene. Then, the spherical droplets floating in the Iso phase exhibited an unexpected motion - a continuous and unidirectional rotation along the light propagation direction. The rotational direction was reversed by the inversion of either the sample's chirality or the UV irradiation direction, and the rotational velocity increased with both the UV-light intensity and the concentration of the doped azobenzene, the dependences of which were described by linear and relaxation functions, respectively. We proposed a possible scenario based on Leslie's theory combining mass fluxes and torques, which well explained the photo-driven rotation of the Ch droplets. PMID- 28900644 TI - Properties of kinetic transition networks for atomic clusters and glassy solids. AB - A database of minima and transition states corresponds to a network where the minima represent nodes and the transition states correspond to edges between the pairs of minima they connect via steepest-descent paths. Here we construct networks for small clusters bound by the Morse potential for a selection of physically relevant parameters, in two and three dimensions. The properties of these unweighted and undirected networks are analysed to examine two features: whether they are small-world, where the shortest path between nodes involves only a small number or edges; and whether they are scale-free, having a degree distribution that follows a power law. Small-world character is present, but statistical tests show that a power law is not a good fit, so the networks are not scale-free. These results for clusters are compared with the corresponding properties for the molecular and atomic structural glass formers ortho-terphenyl and binary Lennard-Jones. These glassy systems do not show small-world properties, suggesting that such behaviour is linked to the structure-seeking landscapes of the Morse clusters. PMID- 28900642 TI - A mutation-resistant deoxyribozyme OR gate for highly selective detection of viral nucleic acids. AB - Highly selective probes hybridize only to fully complementary DNA or RNA sequences and, therefore, often fail to recognize mutated viral genomes. Here we designed a probe that possesses two seemingly incompatible properties: it tolerates some point mutations in genome, while it remains selective towards others. An OR deoxyribozyme logic gate was designed to fluorescently report the sequences of enterovirus 71 (EV71) covering ~90% of all known EV71 strains. Importantly, sequences of closely related coxsackieviruses that differed by single nucleotides were reliably differentiated in 7 out of 8 cases. PMID- 28900645 TI - Role of intermolecular charge delocalization and its dimensionality in efficient band-like electron transport in crystalline 2,5-difluoro-7,7,8,8 tetracyanoquinodimethane (F2-TCNQ). AB - Theoretical understanding of charge transport in organic semiconductors is exclusively important for organic electronics, but still remains a subject of debate. The recently discovered record-high band-like electron mobility in single crystals of 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ) is challenging from the theoretical viewpoint. First, the very small size of the F2 TCNQ molecule implies high reorganization energy that seems incompatible with efficient charge transport. Second, it is not clear why the crystals of a similar compound, 7,7,8,8-tetracyanoquinodimethane (TCNQ), show an inefficient hopping electron transport mechanism. To address these issues, we apply DFT and QM/MM calculations to the Fn-TCNQ (n = 0,2,4) crystal series. We show that multidimensional intermolecular charge delocalization is of key importance for efficient charge transport in materials consisting of small-sized molecules, and commonly used guidelines for the search for high-mobility organic semiconductors are to be corrected. PMID- 28900647 TI - A first-principles study on zigzag phosphorene nanoribbons passivated by iron group atoms. AB - We performed a first-principles study on Fe-, Co-, and Ni-terminated zigzag phosphorene nanoribbons (ZPNRs) with different widths. Magnetic edges were observed for Fe- and Co-terminated ZPNRs, whereas Ni-terminated ZPNRs were nonmagnetic. Interestingly, magnetism could be induced in Ni-ZPNRs by external electric fields, and the distribution of the magnetic moments could be tuned by the direction of the electric fields. Furthermore, Fe-ZPNRs and Co-ZPNRs exhibit semi-metallic and metallic characteristics, respectively, whereas Ni-ZPNRs are mainly semiconductors with band gaps generally increasing monotonously with the increase in nanoribbon width. These fascinating properties of iron-group atom terminated ZPNRs indicate their great potential applications in future spintronics, optoelectronics, and information technologies. PMID- 28900646 TI - Excited state dynamics of symmetric and asymmetric Cr3(dpa)4Cl2 measured using femtosecond transient absorption spectroscopy. AB - Herein, the excited-state dynamics of an extended metal atom chain complex, Cr3(dpa)4Cl2 (dpa = dipyridylamide), in tetrahydrofuran solution were investigated using femtosecond transient absorption spectroscopy. Upon excitation at a wavelength of 330 nm, two distinct excited-state absorption species with varied dynamics were identified and assigned to the symmetric (s-) and unsymmetric (u-) Cr3(dpa)4Cl2. The major species is s-Cr3(dpa)4Cl2 that undergoes rapid conversion at less than 100 fs from the ligand-centred pi-pi* state, which is the initially accessed state, to the metal-centred d-d state and then vibrational cooling accompanying the structural relaxation at a time constant ~2.2 ps. Most of the s-form is recovered to the ground state at ~200 ps. For u Cr3(dpa)4Cl2, a similar rapid conversion to d-d states is observed, and the geometric/vibrational relaxation is ~0.8 ps. The second recovery of the ground state with approximately equal amplitude is observed at a time constant of ~5 ns. This might be because many d-d states exist and about half of them inefficiently couple with the ground state surface. PMID- 28900648 TI - Structure and crystallization of SiO2 and B2O3 doped lithium disilicate glasses from theory and experiment. AB - Solid solutions of SiO2 and B2O3 in Li2O.2SiO2 are synthesized and characterized for the first time. Their structure and crystallization mechanisms are investigated employing a combination of simulations at the density functional theory level and experiments on the crystallization of SiO2 and B2O3 doped lithium disilicate glasses. The remarkable agreement of calculated and experimentally determined cell parameters reveals the preferential, kinetically controlled incorporation of [SiO4] and [BO4] at the Li+ lattice sites of the Li2O.2SiO2 crystal structure. While the addition of SiO2 increases the glass viscosity resulting in lower crystal growth velocities, glasses containing B2O3 show a reduction of both viscosities and crystal growth velocities. These observations could be rationalized by a change of the chemical composition of the glass matrix surrounding the precipitated crystal phase during the course of crystallization, which leads to a deceleration of the attachment of building units required for further crystal growth at the liquid-crystal interface. PMID- 28900649 TI - Ionic effects on the proton transfer mechanism in aqueous solutions. AB - Proton dissociation (PD) reactions of weak acids and proton transfer (PT) processes in aqueous solutions are strongly influenced by ions. However, a detailed molecular picture that describes how ions affect the rates of PD and PT processes is still missing. Here, we utilize time-resolved fluorescence spectroscopy combined with quantum chemical calculations to investigate the excited-state proton transfer (ESPT) reaction of a photoacid in aqueous metal chloride solutions. The activation energy (Ea) for the ESPT of the photoacid increases with increasing charge density of cations (rhocat). The local hydrogen bond (H-bond) structure of the photoacid in the ionic hydration shell is strongly related to both the Ea and the rhocat. Most importantly, the proton's positive charge in the transition state, which is delocalized through the H-bonded water channel, is more destabilized with an increase in the rhocat, leading to a higher Ea. Our experimental and computational results allow us to elucidate the underlying mechanism for the ionic effect on PD and the subsequent PT process at the molecular level. PMID- 28900650 TI - Sensitive detection of microRNAs by duplex specific nuclease-assisted target recycling and pyrene excimer switching. AB - Herein, we develop a simple fluorescence method for the sensitive detection of microRNAs based on duplex specific nuclease-assisted target recycling and pyrene excimer switching. This method is extremely sensitive with a detection limit of 0.58 fM, and it can be applied to absolutely detect endogenous microRNAs in cancer cells, holding great potential for clinical diagnosis and biomedical research studies. PMID- 28900651 TI - Erratum to: Silencing of a second dimethylallyltryptophan synthase of Penicillium roqueforti reveals a novel clavine alkaloid gene cluster. PMID- 28900652 TI - [Medical examination: Preparation for ENT specialisation : Part 32]. PMID- 28900653 TI - [Surgery and prognosis of malignent-functioning neuroendocrine tumors of the pancreas]. PMID- 28900654 TI - [Importance of portal vein embolization depending on the underlying hepatic malignancy]. PMID- 28900655 TI - [(Partial) arthrodesis of the hand and wrist]. PMID- 28900657 TI - ?. PMID- 28900656 TI - [Upgrade of the resident's job exchange platform]. PMID- 28900659 TI - Delayed presentation of uterine rupture in a didelphys uterus misdiagnosed as appendicitis: a case report and review of the literature. AB - INTRODUCTION: Uterine rupture during pregnancy caused by uterine dysplasia, such as the double uterus, is very rare and easily overlooked by the surgeon. CASE: A 25-year-old woman, at 17 weeks of gestation presented to our emergency center with acute right lower abdominal pain for more than 10 h. The initial diagnosis is acute appendicitis, but during the exploration, we found about 2500 mL of intraperitoneal hemorrhage, appendix was normal, pregnancy in one of the double uterine and ruptured at the right bottom. The pregnancy was removed and the uterine defect was repaired. CONCLUSION: Uterine rupture caused by double uterus is very rare and easily Ignored by the surgeon. The survival of patients suffered from uterine rupture depends on the time interval between rupture and intervention. PMID- 28900660 TI - [The drama of aging in film : Dramaturgic notes on a storybook about films about aging]. PMID- 28900662 TI - Erratum to: Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation. PMID- 28900663 TI - [Costs of allergic diseases and saving potential by allergen-specific immunotherapy : A personal assessment]. AB - BACKGROUND: The burden of allergic diseases is of particular relevance for the economy and the social welfare and health insurance framework. Allergic rhinitis (AR) has a life-time prevalence of approximately 30% and is one of the most common chronic diseases with considerable socioeconomic impact thus leading to substantial direct, indirect and intangible costs. This article explores the common hypothesis that allergen-specific immunotherapy (ASIT) saves national economic expenses in the long term in comparison to other standard symptomatic treatment or no therapy. METHODS: We conducted a selective search and analysis of the literature in PubMed and Medline including otherwise listed publications in German. Using a predefined model and data extrapolation over 9 years for data from different sources and short-term clinical studies we further discuss the problems and difficulties in analyzing heterogeneous datasets. RESULTS: Using a health-economic model with currently available and accepted variables ASIT proves to be cost-effective in comparison to symptomatic treatment in allergic rhinitis; however, numerous parameters from other models have to be controlled, such as adherence to therapy and therapy discontinuation, heterogeneous costs for different treatment modalities, effect sizes with respect to symptoms including cross-influences with symptomatic rescue medication, duration of efficacy after treatment discontinuation and asthma protection. DISCUSSION: The personal appraisal of the authors demonstrates not only the current knowledge but also the problems in health economical evaluation of ASIT in allergic diseases. PMID- 28900664 TI - [Prehospital care for stroke patients]. AB - The effectiveness of thrombolysis or mechanical recanalization for acute stroke is higher, the sooner these therapies are started. Therefore, acute stroke patients need to be evaluated by qualified staff for these therapies as soon as possible. Lay persons need to identify the typical symptoms of stroke as an emergency and act accordingly by calling the emergency medical system (EMS). The EMS team reassesses the symptoms and prompts cerebral imaging. Cerebral imaging is performed ideally in hospitals with a stroke unit where subsequent (stroke) treatments occur. On the way, the emergency team will measure and stabilize vital functions and obtain further important clinical information. Telemedicine allows communicating exact time of onset and severity of symptoms, as well as comorbidities and medication of the patient to the respective hospital. Thereby, the intrahospital workload will be disencumbered and accelerated. Some EMS vehicles now carry point-of-care laboratories and may measure lab values en route (glucose and INR [International Normalized Ratio] for example). Some ambulances are not only equipped with qualified staff, telemedicine technique, and point-of care labs but even computer tomography (CT) to perform imaging. Such mobile stroke emergency mobiles (STEMO) or mobile stroke units may perform thrombolysis prehospitally. Prehospital thrombolysis has been proven to be initiated faster and is safe. Preliminary results even suggest superiority to intrahospital thrombolysis with respect to clinical outcome. Moreover, STEMO may perform CT angiography and assess intracranial large-vessel status. If intracranial large vessel occlusion is present, patients will be brought directly to hospitals able to perform mechanical recanalization. Thus, secondary transports are no longer required. PMID- 28900665 TI - [Questionnaire for the utilization of the Emergency Department : Implications for the patient survey]. AB - BACKGROUND: For several years, Emergency Departments (ED) in Germany have observed increasing patient numbers, resulting in ED crowding. This leads to the question of whether patients with nonurgent conditions could also receive adequate treatment in primary care. Our objective was to develop a quantitative questionnaire to investigate in a larger patient group the reasons for this and to describe the implications for a patient survey in the ED. METHODS: The development of the questionnaire was based on a literature search and the results of the qualitative EPICS-2 study. Two pretest surveys were conducted in three EDs at the Charite - Universitatsmedizin Berlin. We included patients aged >= 18 years with outpatient treatment and the categories blue (nonurgent), green (standard), or yellow (urgent) according to the Manchester Triage System (MTS). RESULTS: In total, 189 patients were recruited in two surveys (pretest 1: n = 89, pretest 2 n = 100). The final questionnaire includes 24 items, which were evaluated and adapted during both pretests. The items evaluate basic clinical characteristics, reasons for choosing the ED, prior contacts in primary care, utilization of primary care after-hours services as well as sociodemographic characteristics. Data from the hospital information system were used to link the survey data with clinical characteristics. CONCLUSIONS: The questionnaire is based on reasons for ED utilization. We recommend the written, self-applied questionnaire for patient surveys with plausibility checks conducted by staff. It is necessary to consider the heterogenic study surroundings in the ED, which requires a lot of flexibility during data collection. PMID- 28900666 TI - [Psychotherapeutic approaches for treatment of the elderly]. AB - BACKGROUND: This article focusses on the possibilities, varieties, indications, and benefits of psychotherapy with elderly patients. OBJECTIVE: Which basic principles can be differentiated, what theoretical rationales are helpful for psychotherapy with the elderly and what kind and forms of psychotherapy are available? MATERIAL AND METHODS: Based on relevant references and research, clinically relevant and evidence-based psychotherapies are described, to understand the theoretical rationale, the goals, the procedure and main strategies. RESULTS: Cognitive behavior therapy, problem solving therapy, life review therapy, interpersonal psychotherapy, and psychodynamic psychotherapy are available to treat various psychological and somatic problems in elderly patients. In particular, cognitive behavior therapy, problem solving therapy, and life review therapy are evidence-based and empirically validated. Evidence for interpersonal psychotherapy is mixed and for psychodynamic psychotherapy is missing. CONCLUSION: Psychotherapy with old and very old patients is possible, well received, and successful. Age per se is no longer considered to be a relevant variable for indications of psychotherapy. PMID- 28900669 TI - [Back to life-a rocky road!] PMID- 28900668 TI - Validation of the Baragwanath mortality prediction score for cerebral gunshot wounds: the Pietermaritzburg experience. AB - INTRODUCTION: Cerebral gunshot wounds (GSW) are highly lethal injuries. To date, only one clinical scoring system to predict mortality in a developing world setting has been described. This is the Baragwanath mortality prediction score ("ABC": admission blood pressure, brain matter spillage and consciousness level). MATERIALS AND METHODS: We performed a retrospective review of prospectively entered data for a cohort of patients with isolated cerebral GSWs over a 5-year period (January 2010-December 2014) in our institution. We aimed to validate the Baragwanath ABC mortality prediction score in our population. RESULTS: During the 5-year study period, 102 patients with isolated cerebral GSWs were reviewed, 22% (22/102) of which died. Based on the total ABC score (1-5), the mortality was 0% for 1, 21% for 2, 67% for 3, 92% for 4, and 100% for 5. The ABC score has a sensitivity of 82% (95% CI 60-95%), specificity of 96% (95% CI 89-99%), PPV of 86% (95% CI 66-96%) and NPV of 95% (95% CI 86-99%). CONCLUSIONS: The Baragwanath mortality prediction score accurately predicts non survival of patients with a cerebral GSW in our patient cohort. Further validation studies in other populations are required before this system can be widely adopted. PMID- 28900667 TI - Ammonium trichloro [1,2-ethanediolato-O,O']-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked PI3K/Akt pathway. AB - In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O']-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (?93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking alpha4beta7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-kappaB for Th1 response. In silico docking and biochemical assays revealed AS101's affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis. PMID- 28900670 TI - Seasonality and microhabitat selection in a forest-dwelling salamander. AB - Many small terrestrial vertebrates exhibit limited spatial movement and are considerably exposed to changes in local environmental variables. Among such vertebrates, amphibians at present experience a dramatic decline due to their limited resilience to environmental change. Since the local survival and abundance of amphibians is intrinsically related to the availability of shelters, conservation plans need to take microhabitat requirements into account. In order to gain insight into the terrestrial ecology of the spectacled salamander Salamandrina perspicillata and to identify appropriate forest management strategies, we investigated the salamander's seasonal variability in habitat use of trees as shelters in relation to tree features (size, buttresses, basal holes) and environmental variables in a beech forest in Italy. We used the occupancy approach to assess tree suitability on a non-conventional spatial scale. Our approach provides fine-grained parameters of microhabitat suitability and elucidates many aspects of the salamander's terrestrial ecology. Occupancy changed with the annual life cycle and was higher in autumn than in spring, when females were found closer to the stream in the study area. Salamanders showed a seasonal pattern regarding the trees they occupied and a clear preference for trees with a larger diameter and more burrows. With respect to forest management, we suggest maintaining a suitable number of trees with a trunk diameter exceeding 30 cm. A practice of selective logging along the banks of streams could help maintain an adequate quantity of the appropriate microhabitat. Furthermore, in areas with a presence of salamanders, a good forest management plan requires leaving an adequate buffer zone around streams, which should be wider in autumn than in spring. PMID- 28900671 TI - [Wrist arthrodesis with a fixed-angle, "low-profile" fusion plate without carpometacarpal joint fixation]. AB - OBJECTIVE: Total wrist arthrodesis to improve functional use of the hand by reducing pain and increasing grip strength. INDICATIONS: Painful destruction of the radio- and midcarpal joints. CONTRAINDICATIONS: Analgesia and satisfactory hand function after motion-preserving surgical or conservative treatment. Chronic joint infection. SURGICAL TECHNIQUE: Posterior approach to the wrist. Removal of articular surfaces destroyed all the way down to cancellous bone. Filling of defects with cancellous bone graft taken from distal radius or iliac crest. Osteosynthesis with fixed-angle wrist fusion plate without carpometacarpal (CMC) III joint fixation. POSTOPERATIVE MANAGEMENT: Below-elbow cast for 2 weeks. Immediate active motion fingers exercises. X-ray control 6 weeks postoperatively. Gradual increase of normal hand use in daily life after bony consolidation. RESULTS: Total wrist arthrodesis was performed using a fixed-angle fusion plate without CMC III joint fixation in 28 patients (21 men, 7 women). A follow-up of 14/28 patients was performed at a mean of 21 (3-39) months postoperatively. Grip strength improved from 14 (0-38) kg preoperatively to 22 (12-40) kg postoperatively. The average postoperative DASH score was 40 (6-72) points. Pain measured with the VAS scale (0-10) improved from an average of 7 (3-10) points preoperatively to 2 (0-6) points postoperatively. Overall, 13/14 patients were satisfied with the treatment; 26/28 patients achieved primary bony consolidation. Postoperative complications found in 9 of 28 patients: 2 nonunion, pain in the CMC II (n = 3) or III (n = 1) joints, 2 screw breakage, 1 postoperative bleeding and 1 infection. Both cases of nonunion healed after plate removal, re osteosynthesis with a straight wrist arthrodesis plate, bridging the CMC III joint, and a bone graft from the iliac crest. All patients with CMC II joint pain were pain-free after removal of the protruding screw. One patient had chronic pain in the CMC III joint despite plate removal. In the 2 cases with screw breakage, no issues caused. In one patient, after primary bony consolidation, removal of the plate was performed for extensor tenolysis and not as a result of the broken screw. In the second patient, removal of the plate after primary bony consolidation was unnecessary as the patient was pain-free in the area of the broken screw, yet a protruding screw in the CMC II joint cavity was removed. PMID- 28900672 TI - Extracorporeal membrane oxygenation in adult patients with acute fulminant myocarditis : Clinical outcomes and risk factor analysis. AB - BACKGROUND: Our study aimed to summarize the clinical outcomes of extracorporeal membrane oxygenation (ECMO) in adult patients with acute fulminant myocarditis and to investigate the risk factors associated with its application. PATIENTS AND METHODS: We retrospectively examined patients with cardiogenic shock and acute fulminant myocarditis. The following data were collected: patients' preoperative general condition, related clinical factors during ECMO, complications, and outcomes of ECMO. The patients were divided into a survivor group and a nonsurvivor group. RESULTS: From a total of 33 patients, seven died in hospital. The survival rate was 78.7%. The following complications were observed during ECMO: 16 cases of acute renal failure (48.4%), seven cases of sepsis (21.2%), six cases of pulmonary infection (18.1%), six cases of multiple organ failure (MOF; 18.1%), three cases of cerebral hemorrhage (9%), and four cases of limb ischemia (12.1%). Pre-ECMO cardiopulmonary resuscitation, high levels of lactic acid, high amounts of blood transfusion during ECMO, renal failure, encephalorrhagia, gastrointestinal complications, lower-limb ischemia, high bilirubin levels, and MOF during ECMO were associated with unfavorable patient outcomes. CONCLUSION: ECMO is an effective auxiliary tool for treating acute fulminant myocarditis. Acute renal failure is the most common complication during ECMO. Improving tissue perfusion, reducing blood transfusions, and preventing acute kidney failure may improve patient outcomes. PMID- 28900673 TI - Eye-hand coordination during visuomotor adaptation: effects of hemispace and joint coordination. AB - We previously examined adaptive changes of eye-hand coordination during learning of a visuomotor rotation. Gazes during reaching movements were initially directed to a feedback cursor in early practice, but were gradually shifted toward the target with more practice, indicating an emerging gaze anchoring behavior. This adaptive pattern reflected a functional change of gaze control from exploring the cursor-hand relation to guiding the hand to the task goal. The present study further examined the effects of hemispace and joint coordination associated with target directions on this behavior. Young adults performed center-out reaching movements to four targets with their right hand on a horizontal digitizer, while looking at a rotated visual feedback cursor on a computer monitor. To examine the effect of hemispace related to visual stimuli, two out of the four targets were located in the ipsilateral workspace relative to the hand used, the other two in the contralateral workspace. To examine the effect of hemispace related to manual actions, two among the four targets were related to reaches made in the ipsilateral workspace, the other two to reaches made in the contralateral workspace. Furthermore, to examine the effect of the complexity of joint coordination, two among the four targets were reaches involving a direct path from the start to the target involving elbow movements (simple), whereas the other two targets were reaches involving both shoulder and elbow movements (complex). The results showed that the gaze anchoring behavior gradually emerged during practice for reaches made in all target directions. The speed of this change was affected mainly by the hemispace related to manual actions, whereas the other two effects were minimal. The gaze anchoring occurred faster for the ipsilateral reaches than for the contralateral reaches; gazes prior to the gaze anchoring were also directed less at the cursor vicinity but more at the mid-area between the starting point and the target. These results suggest that ipsilateral reaches result in a better predictability of the cursor-hand relation under the visuomotor rotation, thereby prompting an earlier functional change of gaze control through practice from a reactive to a predictive control. PMID- 28900674 TI - Who is willing to participate in low-risk pragmatic clinical trials without consent? AB - PURPOSE: General notification offers a possible alternative to written informed consent for pragmatic randomized controlled trials (pRCTs). It involves patients being informed through brochures, posters, and letters that research is being conducted simultaneously to providing clinical care and that patients will be enrolled in pRCTs without study-specific consent. A previous survey found that a substantial minority of respondents endorsed general notification. We aimed to know who is willing to enroll in this type of trials using general notification rather than written consent. METHODS: The previous study was a cross-sectional, probability-based survey, with a 2 * 2 factorial design. Two scenarios were assessed: two low-risk pRCTs in hypertension, one comparing two drugs with similar benefit/risk ratio and the other taking the same drug in the morning or at night. Each scenario had two routes: written consent vs verbal consent and written consent vs general notification. In this study, we were interested in the latter route in both scenarios. Respondents' preferences were measured based on their recommendation to the research ethics committee and the respondent's personal preference. We aimed to investigate the characteristics of those supporting general notification in either outcome or the variables explaining consistency and inconsistency between their personal preference and their recommendation. Based on the results of the original survey, we aimed to have at least 200 inconsistent respondents; to this end, the sample size was increased accordingly in a second wave of the survey. RESULTS: One thousand six hundre and ten respondents were included; 1003 from the original survey and 607 new ones belonging to the second wave. Thirty-nine percent of respondents chose general notification as personal preference and/or recommendation. Respondents with lower education levels were more prone to accept general notification than those holding a university degree [OR (95% CI)], primary school [2.959 (2.069-4.232)], secondary school [2.899 (2.09-4.021)], or high school [1.620 (1.184-2.217)]. Also unemployed [1.372 (1.064-1.770)] and retired [1.445 (1.049-1.990)], but not students, showed preference for general notification in comparison with those employed. Individuals more than 24 years old and having received high school or university (or postgraduate) education were statistically significantly more consistent in their decisions. CONCLUSIONS: Thirty-nine percent of respondents is open to not to be asked for their informed consent in low-risk pRCTs; of these, those being less educated and not having current job or being retired are significantly more open to general notification. The use of this alternative method to written consent for simultaneous conduct of pRCTs and care should be considered and educational programs settled up to, in the case of public acceptance, ensure its ethical appropriateness. PMID- 28900675 TI - Bone Disease in Connective Tissue Disease/Systemic Lupus Erythematosus. AB - This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2-4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies. PMID- 28900676 TI - Free Fatty Acid Receptor 4 Mediates the Beneficial Effects of n-3 Fatty Acids on Body Composition in Mice. AB - As populations continue to age worldwide, sarcopenic obesity has heightened interest due to its medical importance. Although much evidence now indicates that n-3 fatty acids (FAs) may have beneficial effects on body composition including fat and muscle, their exact mechanisms have not yet been elucidated. Because free FA receptor 4 (FFA4) has been reported to be a receptor for n-3 FAs, we hypothesized that the protective role of n-3 FAs on body composition could be mediated by FFA4. To test this possibility, we generated mice overexpressing n-3 FAs but lacking FFA4 by crossing fat-1 transgenic (fat-1 Tg+) and FFA4 knockout (Ffar4 -/-) mice. Because fat-1 Tg+ mice, in which n-6 is endogenously converted into n-3 FAs, contain high n-3 FA levels, they could be a good animal model for studying the effects of n-3 FAs in vivo. Male and female littermates were included in high-fat-diet- (HFD) and ovariectomy-induced models, respectively. In the HFD model, male fat-1 Tg+ mice had a lower percentage of fat mass and a higher percentage of lean mass than their wild-type littermates only when they had the Ffar4 +/+ not the Ffar4 -/- background. Female fat-1 Tg+ mice showed less increase of fat mass percentage and less decrease of lean mass percentage after ovariectomy than wild-type littermates. However, these effects on body composition were attenuated in the Ffar4 -/- background. Taken together, our results indicate that the beneficial effects of n-3 FAs on body composition were mediated by FFA4 and thus suggest that FFA4 may be a potential therapeutic target for modulating sarcopenic obesity. PMID- 28900678 TI - SOCS1: Regulator of T Cells in Autoimmunity and Cancer. AB - SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice have established a crucial role for SOCS1 in regulating CD8+ T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8+ T cells to synergistic cytokine stimulation and antigen non-specific activation. As cytokine stimulation of CD8+ T lymphocytes increases their sensitivity to low affinity TCR ligands, SOCS1 likely contributes to peripheral T cell tolerance by putting brakes on aberrant T cell activation driven by inflammatory cytokines. In addition, SOCS1 is critical to maintain the stability of T regulatory cells and control their plasticity to become pathogenic Th17 and Th1 cells under the harmful influence of inflammatory cytokines. SOCS1 also regulates T cell activation by dendritic cells via modulating their generation, maturation, antigen presentation, costimulatory signaling, and cytokine production. The above control mechanisms of SOCS1 on T cells, T regulatory cells and dendritic cells collectively contribute to immunological tolerance and prevent autoimmune manifestation. On other hand, silencing SOCS1 in dendritic cells or CD8+ T cells stimulates efficient antitumor immunity. Thus, even though SOCS1 is not a cell surface checkpoint inhibitor, its regulatory functions on T cell responses qualify SOCS1as a "non-classical" checkpoint blocker. SOCS1 also functions as a tumor suppressor in cancer cells by regulating oncogenic signal transduction pathways. The loss of SOCS1 expression observed in many tumors may have an impact on classical checkpoint pathways. The potential to exploit SOCS1 to treat inflammatory/autoimmune diseases and elicit antitumor immunity is discussed. PMID- 28900679 TI - CTLA-4, an Essential Immune-Checkpoint for T-Cell Activation. AB - The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition. Subsequent studies by many researchers revealed the more complex mode of T-cell inhibition by CTLA-4. After T-cell activation, CTLA-4 is stored in the intracellular vesicles, and recruited to the immunological synapse formed between T cells and APCs, and inhibits further activation of T cells by blocking signals initiated by T-cell receptors and CD28. CTLA-4-positive cells can also provide cell-extrinsic regulation on other autoreactive T cells, and are considered to provide an essential regulatory mechanism for FoxP3+ regulatory T cells. Genetic deficiency of CTLA-4 leads to CD28-mediated severe autoimmunity in mice and humans, suggesting its function as a fundamental brake that restrains the expansion and activation of self-reactive T cells. In cancer, therapeutic approaches targeting CTLA-4 by humanized blocking antibodies has been demonstrated to be an effective immunotherapy by reversing T-cell tolerance against tumors. This chapter introduces CTLA-4 biology, including its discovery and mechanism of action, and discusses questions related to CTLA-4. PMID- 28900677 TI - Tim-3, Lag-3, and TIGIT. AB - Co-inhibitory receptors play a key role in regulating T cell responses and maintaining immune homeostasis. Their inhibitory function prevents autoimmune responses but also restricts the ability of T cells to mount effective immune responses against tumors or persistent pathogens. T cells express a module of co inhibitory receptors, which display great diversity in expression, structure, and function. Here, we focus on the co-inhibitory receptors Tim-3, Lag-3, and TIGIT and how they regulate T cell function, maintenance of self-tolerance, their role in regulating ongoing T cell responses at peripheral tissues, and their synergistic effects in regulating autoimmunity and antitumor responses. PMID- 28900680 TI - Coordinating Organismal Metabolism During Protein Misfolding in the ER Through the Unfolded Protein Response. AB - The endoplasmic reticulum (ER) is a cellular organelle responsible for folding of secretory and membrane proteins. Perturbance in ER homeostasis caused by various intrinsic/extrinsic stimuli challenges the protein-folding capacity of the ER, leading to an ER dysfunction, called ER stress. Cells have developed a defensive response to adapt and/or survive in the face of ER stress that may be detrimental to cell function and survival. When exposed to ER stress, the cell activates a complex and elaborate signaling network that includes translational modulation and transcriptional induction of genes. In addition to these autonomous responses, recent studies suggest that the stressed tissue secretes peptides or unknown factors that transfer the signal to other cells in the same or different organs, leading the organism as a whole to cope with challenges in a non autonomous manner. In this review, we discuss the mechanisms by which cells adapt to ER stress challenges autonomously and transfer the stress signal to non stressed cells in different organs. PMID- 28900681 TI - Regulatory Dendritic Cells. AB - Dendritic cells (DCs) comprise heterogeneous subsets, functionally classified into conventional DCs (cDCs) and plasmacytoid DCs (pDCs). DCs are considered to be essential antigen (Ag)-presenting cells (APCs) that play crucial roles in activation and fine-tuning of innate and adaptive immunity under inflammatory conditions, as well as induction of immune tolerance to maintain immune homeostasis under steady-state conditions. Furthermore, DC functions can be modified and influenced by stimulation with various extrinsic factors, such as ligands for pattern-recognition receptors (PRRs) and cytokines. On the other hand, treatment of DCs with certain immunosuppressive drugs and molecules leads to the generation of tolerogenic DCs that show downregulation of both the major histocompatibility complex (MHC) and costimulatory molecules, and not only show defective T-cell activation, but also possess tolerogenic properties including the induction of anergic T-cells and regulatory T (Treg) cells. To develop an effective strategy for Ag-specific intervention of T-cell-mediated immune disorders, we have previously established the modified DCs with moderately high levels of MHC molecules that are defective in the expression of costimulatory molecules that had a greater immunoregulatory property than classical tolerogenic DCs, which we therefore designated as regulatory DCs (DCreg). Herein, we integrate the current understanding of the role of DCs in the control of immune responses, and further provide new information of the characteristics of tolerogenic DCs and DCreg, as well as their regulation of immune responses and disorders. PMID- 28900682 TI - Treatment of Staphylococcus aureus Infections. AB - Staphylococcus aureus, although generally identified as a commensal, is also a common cause of human bacterial infections, including of the skin and other soft tissues, bones, bloodstream, and respiratory tract. The history of S. aureus treatment is marked by the development of resistance to each new class of antistaphylococcal antimicrobial drugs, including the penicillins, sulfonamides, tetracyclines, glycopeptides, and others, complicating therapy. S. aureus isolates identified in the 1960s were sometimes resistant to methicillin, a beta lactam antimicrobial active initially against a majority S. aureus strains. These MRSA isolates, resistant to nearly all beta-lactam antimicrobials, were first largely confined to the health care environment and the patients who attended it. However, in the mid-1990s, new strains, known as community-associated (CA-) MRSA strains, emerged. CA-MRSA organisms, compared with health care-associated (HA-) MRSA strain types, are more often susceptible to multiple classes of non beta lactam antimicrobials. While infections caused by methicillin-susceptible S. aureus (MSSA) strains are usually treated with drugs in the beta-lactam class, such as cephalosporins, oxacillin or nafcillin, MRSA infections are treated with drugs in other antimicrobial classes. The glycopeptide drug vancomycin, and in some countries teicoplanin, is the most common drug used to treat severe MRSA infections. There are now other classes of antimicrobials available to treat staphylococcal infections, including several that have been approved after 2009. The antimicrobial management of invasive and noninvasive S. aureus infections in the ambulatory and in-patient settings is the topic of this review. Also discussed are common adverse effects of antistaphylococcal antimicrobial agents, advantages of one agent over another for specific clinical syndromes, and the use of adjunctive therapies such as surgery and intravenous immunoglobulin. We have detailed considerations in the therapy of noninvasive and invasive S. aureus infections. This is followed by sections on specific clinical infectious syndromes including skin and soft tissue infections, bacteremia, endocarditis and intravascular infections, pneumonia, osteomyelitis and vertebral discitis, epidural abscess, septic arthritis, pyomyositis, mastitis, necrotizing fasciitis, orbital infections, endophthalmitis, parotitis, staphylococcal toxinoses, urogenital infections, and central nervous system infections. PMID- 28900683 TI - MicroRNA in Immune Regulation. AB - The immune system protects us from enormously diverse microbial pathogens but needs to be tightly regulated to avoid deleterious immune-mediated inflammation and tissue damage. A wide range of molecular determinants and cellular components work in concert to control the magnitude and duration of a given immune response. In the past decade, microRNAs (miRNAs), a major class of small non-coding RNA species, have been extensively studied as key molecular players in immune regulation. In this chapter, we will discuss how miRNAs function as negative regulators to restrict innate and adaptive immune responses. Moreover, we will review the current reports regarding miRNAs in human immunological diseases. Finally, we will also address the emerging roles of other non-coding RNAs, long non-coding RNAs (lncRNAs) in particular, in the regulation of the immune system. PMID- 28900684 TI - Transcriptome changes in adaptive evolution of xylose-fermenting industrial Saccharomyces cerevisiae strains with delta-integration of different xylA genes. AB - It is of utmost importance to construct industrial xylose-fermenting Saccharomyces cerevisiae strains for lignocellulosic bioethanol production. In this study, two xylose isomerase-based industrial S. cerevisiae strains, O7 and P5, were constructed by delta-integration of the xylose isomerase (XI) gene xylA from the fungus Orpinomyces sp. and from the bacterium Prevotella ruminicola, respectively. The xylose consumption of the strains O7 and P5 at 48-h fermentation was 17.71 and 26.10 g/L, respectively, in synthetic medium with xylose as the sole sugar source. Adaptive evolution further improved the xylose fermentation capacity of the two strains to 51.0 and 28.9% in average, respectively. The transcriptomes of these two strains before and after evolution were analyzed using RNA-Seq. The expression levels of the genes involved in cell integrity, non-optimal sugar utilization, and stress response to environment were significantly up-regulated after evolution and did not depend on the origin of xylA; the expression levels of the genes involved in transmembrane transport, rRNA processing, cytoplasmic translation, and other processes were down regulated. The expression of genes involved in central carbon metabolism was fine tuned after the evolution. The analysis of transcription factors (TFs) indicated that most of the genes with significant differential expression were regulated by the TFs related to cell division, DNA damage response, or non-optimal carbon source utilization. The results of this study could provide valuable references for the construction of efficient xylose-fermenting XI strains. PMID- 28900685 TI - Double promoter expression systems for recombinant protein production by industrial microorganisms. AB - Using double promoter expression systems is a promising approach to increase heterologous protein production. In this review, current double promoter expression systems for the production of recombinant proteins (r-proteins) by industrially important bacteria, Bacillus subtilis and Escherichia coli; and yeasts, Saccharomyces cerevisiae and Pichia pastoris, are discussed by assessing their potentials and drawbacks. Double promoter expression systems need to be designed to maintain a higher specific product formation rate within the production domain. While bacterial double promoter systems have been constructed as chimeric tandem promoters, yeast dual promoter systems have been developed as separate expression cassettes. To increase production and productivity, the optimal transcriptional activity should be justified either by simultaneously satisfying the requirements of both promoters, or by consecutively stimulating the changeover from one to another in a biphasic process or via successive iterations. Thus, considering the dynamics of a fermentation process, double promoters can be classified according to their operational mechanisms, as: i) consecutively operating double promoter systems, and ii) simultaneously operating double promoter systems. Among these metabolic design strategies, extending the expression period with two promoters activated under different conditions, or enhancing the transcriptional activity with two promoters activated under similar conditions within the production domain, can be applied independently from the host. Novel studies with new insights, which aim a rational systematic design and construction of dual promoter expression vectors with tailored transcriptional activity, will empower r-protein production with enhanced production and productivity. Finally, the current state-of-the-art review emphasizes the advantages of double promoter systems along with the necessity for discovering new promoters for the development of more effective and adaptive processes to meet the increasing demand of r-protein industry. PMID- 28900687 TI - [Intensely pruritic eruptions of the skin in a male patient]. PMID- 28900686 TI - Changes in marijuana use symptoms and emotional functioning over 28-days of monitored abstinence in adolescent marijuana users. AB - RATIONALE: Advancing marijuana prevention and intervention efforts are important given the decreasing perception of harm among adolescents and increasing marijuana legalization. OBJECTIVES: This study evaluates how a monitored abstinence protocol may contribute to emotional functioning and changes in marijuana problems that can enhance successful outcomes for non-treatment-seeking adolescent marijuana users. METHODS: Adolescent marijuana users (n = 26) and demographically matched controls (n = 30) completed 28 days of monitored abstinence confirmed by biweekly urine toxicology. Participants were given measures of emotional functioning, marijuana use symptoms, and reward sensitivity during monitored abstinence. RESULTS: All participants (n = 56) completed the protocol, and 69% of marijuana users (n = 18 of 26) were confirmed abstinent for 28 days, with all users showing decreasing marijuana use. Reductions in subsyndromal depression, positive marijuana use expectancies, and poor sleep quality were observed by the end of the monitored abstinence period (n = 26, p values < .05). Marijuana users also reported more attentional impulsivity and less responsiveness to reward stimuli during the second week of abstinence compared to controls. Later age of onset of regular marijuana use and more cumulative lifetime use were associated with a greater degree of emotional change and increased recognition of the negative effects of marijuana use. CONCLUSIONS: Monitored abstinence programs may be beneficial in reducing marijuana use, subsyndromal emotional distress symptoms, and changing beliefs about marijuana use. Future prevention and intervention efforts may consider targeting reward sensitivity and impulsivity, in addition to marijuana use, expectancies, and emotional functioning. PMID- 28900688 TI - Intensive care medicine in 2050: multidisciplinary communication in-/outside ICU. PMID- 28900689 TI - Viewing geometry determines the contribution of binocular vision to the online control of grasping. AB - Binocular vision is often assumed to make a specific, critical contribution to online visual control of grasping by providing precise information about the separation between digits and object. This account overlooks the 'viewing geometry' typically encountered in grasping, however. Separation of hand and object is rarely aligned precisely with the line of sight (the visual depth dimension), and analysis of the raw signals suggests that, for most other viewing angles, binocular feedback is less precise than monocular feedback. Thus, online grasp control relying selectively on binocular feedback would not be robust to natural changes in viewing geometry. Alternatively, sensory integration theory suggests that different signals contribute according to their relative precision, in which case the role of binocular feedback should depend on viewing geometry, rather than being 'hard-wired'. We manipulated viewing geometry, and assessed the role of binocular feedback by measuring the effects on grasping of occluding one eye at movement onset. Loss of binocular feedback resulted in a significantly less extended final slow-movement phase when hand and object were separated primarily in the frontoparallel plane (where binocular information is relatively imprecise), compared to when they were separated primarily along the line of sight (where binocular information is relatively precise). Consistent with sensory integration theory, this suggests the role of binocular (and monocular) vision in online grasp control is not a fixed, 'architectural' property of the visuo-motor system, but arises instead from the interaction of viewer and situation, allowing robust online control across natural variations in viewing geometry. PMID- 28900690 TI - Community treatment orders and social outcomes for patients with psychosis: a 48 month follow-up study. AB - PURPOSE: Community treatment orders (CTOs) are widely used internationally despite a lack of evidence supporting their effectiveness. Most effectiveness studies are relatively short (12-months or less) and focus on clinical symptoms and service data, while a little attention is given to patients' social outcomes and broader welfare. We tested the association between the duration of CTO intervention and patients' long-term social outcomes. METHODS: A sub-sample (n = 114) of community-based patients from the Oxford Community Treatment Order Evaluation Trial (OCTET) were interviewed 48 months after randomisation. Multivariate regression models were used to examine the association between the duration of the CTO intervention and social outcomes as measured by the social network schedule, Objective Social Outcomes Index, Euro-Qol EQ-5D-3L (EQ-5D), and Oxford Capabilities Questionnaire for Mental Health. RESULTS: No significant association was found between the duration of CTO intervention and social network size (IRR = 0.996, p = .63), objective social outcomes (B = -0.003, p = .77), health-related quality of life (B = 0.001, p = .77), and capabilities (B = 0.046, p = .41). There were no between-group differences in social outcomes when outcomes were stratified by original arm of randomisation. Patients had a mean of 10.2 (SD = 5.9) contacts in their social networks, 42% of whom were relatives. CONCLUSIONS: CTO duration was not associated with improvements in patients' social outcomes even over the long term. This study adds to growing concerns about CTO effectiveness and the justification for their continued use. PMID- 28900691 TI - Quantification of N-phenyl-2-naphthylamine by gas chromatography and isotope dilution mass spectrometry and its percutaneous absorption ex vivo under workplace conditions. AB - N-Phenyl-2-naphthylamine (P2NA) is an antioxidant used to protect rubbers from flex-cracking. P2NA can be converted in vivo to 2NA, one of the most potent bladder carcinogens. Here, we report the specific and ultra-sensitive quantification of P2NA in the receptor fluid of Franz diffusion cells by gas chromatography and isotope-dilution tandem-mass spectroscopy (GC-MS/MS). The experimental conditions were optimized to minimize losses of P2NA due to surface absorption on glass, plastic, and rubber material, and subsequently validated. Static and dynamic diffusion cell conditions were used to study the percutaneous penetration of P2NA into freshly prepared porcine skin. The experimental settings closely resembled those of the printing industry in the 1960s/1970s in Germany where P2NA-containing solutions in dichloromethane have been used. P2NA penetrated the skin at very low levels (0.02 +/- 0.01 ug/cm2/h) with a cumulative penetrated amount of 0.80 +/- 0.26 ug/cm2, a lag time of 6.33 +/- 2.21 h and under dynamic conditions. Compared to the receptor fluid, 10-40-fold higher concentrations were found in the skin, predominantly in the dermis and the stratum corneum. Dichloromethane acted as a penetration enhancer by increasing the cumulative penetrated amounts and the recovery of P2NA in both the receptor fluid and the skin, while shortening its lag time. However, the flux remained unaffected. Due to its accumulation in subcutaneous layers, we finally proved that P2NA is continuously released into the receptor fluid despite exposure cessation up to 160 h. Overall, the results show that close attention has to be paid to dermal absorption of P2NA in exposed workers. PMID- 28900692 TI - TonB-Dependent Utilization of Dihydroxamate Xenosiderophores in Synechocystis sp. PCC 6803. AB - In Gram-negative bacteria, transport of ferric siderophores through outer membrane is a complex process that requires specific outer membrane transporters and energy-transducing TonB-ExbB-ExbD system in the cytoplasmic membrane. The genome of the non-siderophore-producing cyanobacterium Synechocystis sp. PCC 6803 encodes all putative components of the siderophore-mediated iron uptake system. So far, there has been no experimental evidence for the existence of such a pathway in this organism. On the contrary, its reductive iron uptake pathway has been studied in detail. We demonstrate that Synechocystis sp. PCC 6803 is capable of using dihydroxamate xenosiderophores, either ferric schizokinen (FeSK) or a siderophore of the filamentous cyanobacterium Anabaena variabilis ATCC 29413 (SAV), as the sole source of iron. Inactivation of the tonB gene or the exbB1 exbD1 gene cluster resulted in an inability to utilize these siderophores. At the same time, the inactivation of the feoB gene encoding FeoB plasma membrane ferrous iron transporter, or one of the futB or futC genes encoding permease and ATPase subunit of FutABC ferric iron transporter, did not impair the ability of cells to utilize FeSK or SAV as the sole source of iron for growth. Our data suggest that cyanobacterium Synechocystis sp. PCC 6803 is capable of acquiring iron-siderophore complexes in a TonB-dependent manner without iron reduction in the periplasm. PMID- 28900693 TI - Complete Genome Sequence of Geobacillus thermodenitrificans T12, A Potential Host for Biotechnological Applications. AB - In attempt to obtain a thermophilic host for the conversion of lignocellulose derived substrates into lactic acid, Geobacillus thermodenitrificans T12 was isolated from a compost heap. It was selected from over 500 isolates as a genetically tractable hemicellulolytic lactic acid producer, requiring little nutrients. The strain is able to ferment glucose and xylose simultaneously and can produce lactic acid from xylan, making it a potential host for biotechnological applications. The genome of strain T12 consists of a 3.64 Mb chromosome and two plasmids of 59 and 56 kb. It has a total of 3.676 genes with an average genomic GC content of 48.7%. The T12 genome encodes a denitrification pathway, allowing for anaerobic respiration. The identity and localization of the responsible genes are similar to those of the denitrification pathways found in strain NG80-2. The hemicellulose utilization (HUS) locus was identified based on sequence homology against G. stearothermophilus T-6. It appeared that T12 has all the genes that are present in strain T-6 except for the arabinan degradation cluster. Instead, the HUS locus of strain T12 contains genes for both an inositol and a pectate degradation pathway. Strain T12 has complete pathways for the synthesis of purine and pyrimidine, all 20 amino acids and several vitamins except D-biotin. The host-defense systems present comprise a Type II and a Type III restriction-modification system, as well as a CRISPR-Cas Type II system. It is concluded that G. thermodenitrificans T12 is a potentially interesting candidate for industrial applications. PMID- 28900694 TI - [Muscle injuries in athletes : The value of magnetic resonance imaging]. AB - Competitive sports yield high demands on the musculoskeletal system, accordingly muscle injuries are a common complication. Early imaging clarification of the muscles in cases of a trauma is essential in order to define the exact location of the lesion, the affected muscles, the extent and the degree of the injury as well as to define possible concomitant complications. In the case of a professional athlete, the assessment made by MRI is important for defining the individually required resting period for a riskless resumption of the sporting activities. PMID- 28900695 TI - [Electroconvulsive therapy to treat therapy-resistant vocalization in dementia]. PMID- 28900696 TI - A systematic approach to adnexal masses discovered on ultrasound: the ADNEx MR scoring system. AB - Adnexal lesions are a common occurrence in radiology practice and imaging plays a crucial role in triaging women appropriately. Current trends toward early detection and characterization have increased the need for accurate imaging assessment of adnexal lesions prior to treatment. Ultrasound is the first-line imaging modality for assessing adnexal lesions; however, approximately 20% of lesions are incompletely characterized after ultrasound evaluation. Secondary assessment with MR imaging using the ADNEx MR Scoring System has been demonstrated as highly accurate in the characterization of adnexal lesions and in excluding ovarian cancer. This review will address the role of MR imaging in further assessment of adnexal lesions discovered on US, and the utility of the ADNEx MR Scoring System. PMID- 28900697 TI - Principles of antimicrobial stewardship for bacterial and fungal infections in ICU. PMID- 28900699 TI - [A 50-year-old man with ankle pain]. PMID- 28900698 TI - Aestuarium zhoushanense gen. nov., sp. nov., Isolated from the Tidal Flat. AB - A gram-stain-negative, aerobic, ovoid or short rod-shaped, and non-motile strain, designed G7T was isolated from a tidal flat sample collected from the coast of East Sea in Zhoushan, China. Strain G7T grew at 4-40 degrees C and pH 6.0-9.0 (optimum, 28 degrees C and pH 7.5) and with 0-7% (w/v) NaCl (optimum, 1%). The predominant respiratory quinone was Q-10 and the major fatty acids (>10%) identified were C18:1 omega7c, C16:0 and summed feature 3 (C16:1 omega7c and/or C16:1 omega6c). The polar lipids of strain G7T consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, and four unidentified lipids. The genomic DNA G+C content was 56.7 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain G7T formed a distinct lineage belonging to the Roseobacter clade of the family Rhodobacteraceae. On the basis of morphological, physiological, and chemotaxonomic characteristics, together with the results of phylogenetic analysis, strain G7T is described as a novel species in a new genus, for which the name Aestuarium zhoushanense gen. nov., sp. nov. (type strain G7T = MCCC 1K03229T = KCTC 52584T) is proposed. PMID- 28900701 TI - The Phosphatome of Medicinal and Edible Fungus Wolfiporia cocos. AB - Wolfiporia cocos is an important medicinal and edible fungus that grows in association with pine trees, and its dried sclerotium has been used as a traditional medicine in China for centuries. However, the commercial production of W. cocos sclerotia is currently limited by shortages in pine wood resources. Since protein phosphatases (PPs) play significant roles in growth, signal transduction, development, metabolism, sexual reproduction, cell cycle, and environmental stress responses in fungi, the phosphatome of W. cocos was analyzed in this study by identifying PP genes, studying transcript profiles and assigning PPs to orthologous groups. Fifty-four putative PP genes were putatively identified in W. cocos genome based on homologous sequences searching using BLASTx program against the Saccharomyces cerevisiae, Fusarium graminearum, and Sclerotinia sclerotiorum databases. Based on known and presumed functions of orthologues of these PP genes found in other fungi, the putative roles of these W. cocos PPs in colonization, hyphal growth, sclerotial formation, secondary metabolism, and stress tolerance to environment were discussed in this study. And the level of transcripts from PP genes in the mycelium and sclerotium stages was also analyzed by qRT-PCR. Our study firstly identified and functional discussed the phosphatome in the medicinal and edible fungus W. cocos. The data from our study contribute to a better understanding of PPs potential roles in various cellar processes of W. cocos, and systematically provide comprehensive and novel insights into W. cocos economically important traits that could be extended to other fungi. PMID- 28900702 TI - [Religious beliefs and spirituality in medical residency : A survey among physicians in charge of training psychiatry and psychotherapy]. AB - Religion and spirituality (R/S) as empirically measurable and treatment-relevant variables are growing in significance in psychiatry and psychotherapy worldwide. In a survey conducted among physicians in charge of psychiatric residency training in Germany respondents were asked about the integration of R/S in their curricula. Data suggest that subjects (n = 285) attach considerable importance to R/S and especially to existential issues. The importance of R/S in psychiatric training is essentially linked to the trainers' personal views of the world and the corporate culture of the training centers. A possible selection bias and the need to integrate R/S in psychiatric training on the basis of scientific evidence and ethical considerations are discussed. PMID- 28900704 TI - Uterine wall resection strategy for abnormally invasive placenta: extirpative approach for control patients justifiable? PMID- 28900703 TI - Utility of (18) F-FDG PET/CT and CECT in conjunction with serum CA 19-9 for detecting recurrent pancreatic adenocarcinoma. AB - PURPOSE: The roles of different cross-sectional imaging in evaluating the recurrence of pancreatic adenocarcinoma are not well established. We evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced computed tomography (CECT) in the diagnosis of recurrent pancreatic adenocarcinoma in conjunction with the tumor marker CA 19-9. METHODS: We retrospectively reviewed the records of patients who underwent CECT and FDG PET/CT along with serum CA 19-9 measurement as a follow-up or on a clinical suspicion of recurrent disease after initial surgery for pancreatic adenocarcinoma. Two observers blinded to the other imaging modality results retrospectively reviewed and interpreted the images in consensus using a three-point scale (negative, equivocal, or positive). Pathologic analysis by biopsy or further clinical and radiologic follow-up determined the true status of the suspected recurrences. The imaging results were compared with CA 19-9 levels and true disease status. RESULTS: Thirty-nine patients were included in the study. Thirty-three patients (85%) had proven recurrent cancer and six patients (15%) had no evidence of disease. Twenty-four patients had elevated CA 19-9 and 15 patients had normal CA 19-9. Sensitivity, specificity, and accuracy for recurrence were 90.9%, 100.0%, and 92.3% for PET/CT and 72.2%, 66.6%, and 71.7% for CECT, respectively. Sensitivity for locoregional recurrence was 94.4% for PET/CT but only 61.1% for CECT. PET/CT detected recurrence in 12 patients who had normal levels of CA 19-9. PET/CT showed lesions not visible on CECT in five (15%) patients. Although the sensitivity and specificity of PET/CT were higher than those of CECT, they were not statistically significant (p = 0.489 and p = 0.1489, respectively). CONCLUSION: FDG PET/CT has a high sensitivity for pancreatic cancer recurrence. Normal CA 19-9 does not necessarily exclude these recurrences. FDG PET/CT is useful when CECT is equivocal and can detect recurrence in patients with normal CA 19-9. PMID- 28900700 TI - Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions. AB - Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation. PMID- 28900705 TI - Clinical relevance of neurological evaluation in patients suffering urinary retention in the absence of subvesical obstruction. AB - PURPOSE: Clinical relevance of neurological evaluation in patients suffered urinary retention in the absence of subvesical obstruction. Determining whether (1) women complaining residual bladder volume without prolapse and obstruction always suffer pudendal nerve damage; (2) neurogenic damage can be linked to patients history/clinical examination; (3) therapy alters regarding to neurological findings; and (4) electromyography (EMG) of musculus sphincter ani externus (MSAE) can be omitted with electronically stimulated pudendal nerve latency (ESPL) as the standard investigation. METHODS: Women with urinary retention without >=stage 2 prolapse or obstruction have neurological investigation including vaginally and anally pudendal terminal nerve latency (PTNL) (>2.4 ms considered abnormal) and EMG seen 7/2005-04/2010. RESULTS: (1) 148/180 (82.2%) suffered at least moderate neurogenic damage and (2) severe neurogenic damage occurs with urge odds ratio (OR) = 3.1 or age (OR = 3.2). Correlations: spasticity with therapy changes (OR = 11.1), latencies. (a) Anally: (i) right and peripheral neuropathy (PNP) (OR = 2.5), chemotherapy (OR = 5.0); (ii) left and PNP (OR = 3.9), chemotherapy (OR = 4.8); (iii) left or right with PNP (OR = 3.9), chemotherapy (OR = 6.8); and (iv) left and right with chemotherapy (OR = 5.0). (b) Vaginally: (i) right with age >60 (OR = 3.2), radical operation (OR = 10.6); (ii) left with diabetes mellitus (OR = 2.5); and (iii) left or right with age (OR = 3.3), radical operation (OR = 8.7). (3) 19.6% therapy changes (36 patients). (4) Neither EMG nor ESPL can be replaced one by another (p = 0.12 anal, p = 0.05 vaginal). CONCLUSION: Red flags are neurogenic damage, age >60, chemotherapy, PNP, radical operation or diabetes. In unclear situations, EMG and ESPL need to be performed to gain relevant information. PMID- 28900707 TI - Reply on letter to the editor "Uterine wall resection strategy for abnormally invasive placenta: extirpative approach for control patients justifiable?" PMID- 28900706 TI - Are Incidental Gallbladder Cancers Missed with a Selective Approach of Gallbladder Histology at Cholecystectomy? AB - BACKGROUND: Incidental gallbladder cancer (IGBC) is an unexpected finding when a cholecystectomy is performed upon a benign indication, and the use of routine or selective histological analysis of gallbladder specimen is still debated. The aim of this study was to investigate whether the proportion of submitted gallbladder specimens for pathological investigation influences the proportion of IGBC found, and what possible factors preoperatively or perioperatively could influence the selection process. METHODS: All cholecystectomies between January 2007 and September 2014 registered in the Swedish Registry of Gallstone Surgery and ERCP (GallRiks) were included. Proportion of histological analysis was divided into four subgroups (0-25%, >25-50%, >50-75%, >75-100%). RESULTS: A total of 81,349 cholecystectomies were registered, and 36,010 (44.3%) gallbladder specimens were sent for histological analysis. A total of 213 cases of IGBC were discovered, which constituted 0.26% of all cholecystectomies performed and 0.59% of the number of gallbladder specimens sent for histological analysis. Hospitals submitting >75-100% of the gallbladder specimens had significantly more IGBC/1000 cholecystectomies performed (p = 0.003). Hospitals with the most selective approach had a significantly higher proportion of IGBC/1000 gallbladders that were sent for histological analysis (p < 0.001). Factors such as higher age (p < 0.001), female gender (p = 0.048) and macroscopic cholecystitis (p < 0.001) were more common in gallbladder specimens from hospitals that had a selective approach to histological analysis. CONCLUSION: A routine approach to histological analysis in cholecystectomies with a benign indication for surgery can uncover a higher proportion of IGBC cases. When a selective approach is used, risk factors should be taken into account. PMID- 28900708 TI - Apparent activation energies of protein-protein complex dissociation in the gas phase determined by electrospray mass spectrometry. AB - We have developed a method to determine apparent activation energies of dissociation for ionized protein-protein complexes in the gas phase using electrospray ionization mass spectrometry following the Rice-Ramsperger-Kassel Marcus quasi-equilibrium theory. Protein-protein complexes were formed in solution, transferred into the gas phase, and separated from excess free protein by ion mobility filtering. Afterwards, complex disassembly was initiated by collision-induced dissociation with step-wise increasing energies. Relative intensities of ion signals were used to calculate apparent activation energies of dissociation in the gas phase by applying linear free energy relations. The method was developed using streptavidin tetramers. Experimentally determined apparent gas-phase activation energies for dissociation ([Formula: see text]) of complexes consisting of Fc parts from immunoglobulins (IgG-Fc) and three closely related protein G' variants (IgG-Fc*protein G'e, IgG-Fc*protein G'f, and IgG Fc*protein G'g) show the same order of stabilities as can be inferred from their in-solution binding constants. Differences in stabilities between the protein protein complexes correspond to single amino acid residue exchanges in the IgG binding regions of the protein G' variants. Graphical abstract Electrospray mass spectrometry and collision-induced dissociation delivers apparent activation energies and supramolecular bond force constants of protein-protein complexes in the gas phase. PMID- 28900709 TI - Pretransplant Intra-arterial Liver-Directed Therapy Does Not Increase the Risk of Hepatic Arterial Complications in Liver Transplantation: A Single-Center 10-Year Experience. AB - PURPOSE: To investigate the association between pretransplant intra-arterial liver-directed therapy (IAT) for hepatocellular carcinoma (HCC) and hepatic arterial complications (HAC) in orthotopic liver transplantation (OLT) [namely hepatic artery thrombosis (HAT) and/or the need for hepatic arterial conduit]. METHODS: A total of 175 HCC patients (mean age: 60 years) underwent IAT with either transarterial chemoembolization or yttrium-90 (90Y) transarterial radioembolization prior to OLT between 2003 and 2013. A matched control cohort of 159 HCC patients who underwent OLT without prior IAT was selected. Incidence of HAC in both cohorts was investigated. The categorical differences between both cohorts were calculated by chi-square test. RESULTS: Among the 175 patients (chemoembolization, n = 82; radioembolization, n = 93), 8 (5%) required conduits due to HA disease (chemoembolization, n = 6; radioembolization, n = 2), 3 (2%) developed HAT (chemoembolization, n = 2; radioembolization, n = 1). Eleven of 175 patients (6.7%) had HAC. Of the 159 control patients, 6 (4%) needed conduits for HA disease and 3 (2%) developed HAT. Nine of 159 patients (5.7%) had HAC. Chi square analysis between the IAT cohort and the control group yielded a p value of 0.810. When comparing chemoembolization to radioembolization, p = 0.076 (not significant at p < 0.05). CONCLUSION: Although aggressive pretransplant radioembolization and chemoembolization are both utilized in most liver transplant centers, neither appears to increase the risk of peri-transplant hepatic arterial complications in HCC patients. PMID- 28900710 TI - Coupling matrix-assisted ionization with high resolution mass spectrometry and electron transfer dissociation to characterize intact proteins and post translational modifications. AB - Matrix-assisted ionization (MAI) is a recently developed ionization technique that produces multiply charged ions on either electrospray ionization (ESI) or matrix-assisted laser desorption/ionization (MALDI) platform without the need of high voltage or laser ablation. In this study, MAI has been coupled to a high resolution accurate mass (HRAM) hybrid instrument, the Orbitrap Elite mass spectrometer, with electron transfer dissociation (ETD) module for fast peptide and intact protein characterization. The softness of MAI process preserves labile post-translational modifications (PTM) and allows fragmentation and localization by ETD. Moreover, MAI on ESI platform allows rapid sample preparation and analysis (~ 1 min/sample) due to the easiness of sample introduction. It significantly improves the throughput compared to ESI direct infusion and MAI on MALDI platform, which usually takes more than 10 min/sample. Intact protein standards, protein mixtures, and neural tissue extracts have been characterized using this instrument platform with both full MS and MS/MS (CID, HCD, and ETD) analyses. Furthermore, the performances of ESI, MALDI, and MAI on both platforms have been tested to provide a systematic comparison among these techniques. With improved ETD performance and PTM analysis capabilities, we anticipate that the HRAM MAI-MS with ETD module will offer greater utilities in large molecule characterization with enhanced speed and coverage. These advancements will enable promising applications in bottom-up and top-down protein analyses. Graphical abstract Matrix-assisted ionization (MAI) for characterizing intact proteins and post-translational modifications with representative mass spectra from intact proteins. PMID- 28900711 TI - Evidence of splinting in low back pain? A systematic review of perturbation studies. AB - PURPOSE: The purpose of this systematic review was to assess whether LBP patients demonstrate signs of splinting by evaluating the reactions to unexpected mechanical perturbations in terms of (1) trunk muscle activity, (2) kinetic and (3) kinematic trunk responses and (4) estimated mechanical properties of the trunk. METHODS: The literature was systematically reviewed to identify studies that compared responses to mechanical trunk perturbations between LBP patients and healthy controls in terms of muscle activation, kinematics, kinetics, and/or mechanical properties. If more than four studies reported an outcome, the results of these studies were pooled. RESULTS: Nineteen studies were included, of which sixteen reported muscle activation, five kinematic responses, two kinetic responses, and two estimated mechanical trunk properties. We found evidence of a longer response time of muscle activation, which would be in line with splinting behaviour in LBP. No signs of splinting behaviour were found in any of the other outcome measures. CONCLUSIONS: We conclude that there is currently no convincing evidence for the presence of splinting behaviour in LBP patients, because we found no indications for splinting in terms of kinetic and kinematic responses to perturbation and derived mechanical properties of the trunk. Consistent evidence on delayed onsets of muscle activation in response to perturbations was found, but this may have other causes than splinting behaviour. PMID- 28900712 TI - [STARflo-a suprachoroidal drainage implant in glaucoma surgery]. AB - BACKGROUND: The STARflo Glaucoma Device (iSTAR Medical, Wavre, Belgium) offers a new approach to bleb-free filtering surgery in which the intraocular pressure (IOP) is lowered by supporting outflow of the aqueous humor into the suprachoroidal space. MATERIALS AND METHODS: On the basis of a case series of 9 patients with open-angle glaucoma (OAG) unmanageable by drug-based treatment, intra- and postoperative experiences with the implant are presented. The implant, the implantation procedure, and the first results 6 months postoperatively are described. RESULTS: No intraoperative complications were observed. Postoperative complications such as increased astigmatism or ocular hypotony were rare and transient. After 6 months there was an IOP reduction from 29.1 mm Hg +/- 6.1 mm Hg with 2.7 +/- 1.1 local IOP-lowering medications to 16.1 +/- 4.1 mm Hg (IOP reduction of 44.7%) with additional 2.0 +/- 0.8 local IOP-lowering medications. DISCUSSION: The new STARflo Glaucoma Device shows promising results in reducing the IOP of medically uncontrolled OAG. Further investigations concerning the long time efficacy of the implant and additional IOP-lowering medication are still ongoing. PMID- 28900714 TI - Efficacy of peginterferon plus ribavirin in patients receiving opioid substitution therapy : Final results of the Austrian PegHope study. AB - BACKGROUND: Patients with a history of intravenous drug abuse included in an official opioid substitution program represent an important subgroup of patients with chronic hepatitis C. The objective of this study was to assess the efficacy of and adherence to treatment with peginterferon and ribavirin in Austrian patients on stable opioid substitution therapy (OST). METHODS: This prospective, multicenter, observational, non-interventional trial (clinicaltrials.gov identifier, NCT01416610) included treatment-naive patients with chronic hepatitis C on OST. Treatment consisted of peginterferon alpha-2a (PEGASYS(r), 180 ug/week) plus ribavirin (COPEGUS(r), 1000/1200 mg/day in genotypes (GT) 1/4 and 800 mg/day in GT 2/3) for 24-72 weeks, according to GT and viral response. RESULTS: The intention-to-treat (ITT) population comprised 88 patients. Mean duration of therapy was 6.0 +/- 2.8 months. Treatment was discontinued earlier than planned in 34 out of 88 patients (39%), mainly because of poor adherence or side effects of treatment. At the end of treatment 65/88 patients (74%) were PCR negative. During follow-up, 5 patients relapsed. Only 44/88 patients (50%) could be evaluated 24 weeks after the end of treatment. Sustained virologic response 24 weeks after end of therapy (SVR24) was documented in 39/88 patients (44%). If only patients were considered who finished treatment as planned and for whom results at follow-up week 24 were available, the SVR24 rate was 89% (32/36). CONCLUSION: Despite favorable prognostic factors, such as young age and a high proportion of GT3, SVR rates were low in this cohort of patients receiving OST, the main reason being poor adherence; however, in those patients completing treatment, the SVR rate was high. PMID- 28900715 TI - Radial versus femoral access site for percutaneous coronary intervention in patients suffering acute myocardial infarction : A randomized prospective multicenter trial. AB - BACKGROUND: Transradial access (TRA) in percutaneous coronary intervention (PCI) is a widely used standard technique with lower complication rates compared to transfemoral access (TFA). The aim of this study was to evaluate the impact of TRA versus TFA for PCI on clinically significant vascular access complications in the setting of acute myocardial infarction (AMI). METHODS: This multicenter study randomly assigned 250 patients in a 1:1 fashion (TRA vs. TFA) admitted with or without ST-segment elevation AMI undergoing immediate PCI. The primary endpoint was defined as the occurrence of hematoma, pseudo-aneurysm or local bleeding at the access site requiring any further intervention and/or prolonged hospital stay. Radiation exposure to the patient and operator was also investigated. RESULTS: In the study cohort (N = 250 patients, mean age 62 +/- 12.7 years, 76% males) 5 patients (2%) achieved the primary endpoint without a significant difference between groups, 4 out of 125 (3.2%) in the TFA group and 1 out of 125 (0.8%) in the TRA group (p = 0.17). Access site hematoma was significantly more frequent in the TFA group compared to the TRA group (24.8% vs. 8.8%, respectively; p < 0.0007). Local bleeding was only seen in the TFA group (3.2% vs. 0%, p = 0.04). Time intervals from admission to catheter laboratory to first balloon inflation were longer in the TRA compared to the TFA group (34 +/- 17 min vs 29.5 +/- 13 min, respectively; p = 0.018). Radiation exposure to the patient and operator was identical. CONCLUSION: The use of TRA was accompanied by lower rates of access site complications; however, the need for subsequent treatment or prolonged hospital stays was not observed using either of the two access approaches. PMID- 28900713 TI - Complement activation, a threat to pregnancy. AB - Pregnancy poses a challenge for the immune systems of placental mammals. As fetal tissues are semi-allogeneic and alloantibodies that commonly develop in the mother, the fetus and the placenta might be subject to complement-mediated immune attack with the potential risk of adverse pregnancy outcomes. Here, I describe how the use of animal models was pivotal in demonstrating that complement inhibition at the fetomaternal interface is essential for a successful pregnancy. Studies in animals also helped the identification of uncontrolled complement activation as a crucial effector in the pathogenesis of recurrent miscarriages, intrauterine growth restriction, preeclampsia, and preterm birth. Clinical studies employing complement biomarkers in plasma and urine showed an association between dysregulation of the complement system and adverse pregnancy outcomes. A better understanding of the role of the complement system in pregnancy complications will allow a rational approach to manipulate its activation as a potential therapeutic strategy with the goal of protecting pregnancies and improving long-term outcomes for mother and child. PMID- 28900716 TI - Brain MRI in a patient with classical galactosemia: acute event of unilateral hemispheric cerebral edema. PMID- 28900717 TI - Monitoring of oxidative status in three native Australian species during cold acclimation and cryopreservation. AB - KEY MESSAGE: Three wild species exhibited a significant reduction in antioxidants throughout the cryopreservation protocol, whilst the half-cell reduction potential became more oxidised. Antioxidant content recuperated in recovering shoot tips. Cryopreservation is the most efficient and cost-effective long-term storage solution for the conservation of a wide range of plant species and material. Changes in the levels of antioxidants during the process of cryopreservation are known to reduce post-cryogenic survival due to oxidative stress. Low-molecular-weight thiols (cysteine, gamma-glutamylcysteine, and glutathione) and ascorbic acid, which represent the two major water-soluble antioxidants in plants, were analysed at specific stages during cryopreservation of shoot tip material of three native Australian plant species [Anigozanthos viridis (Haemodoraceae), Lomandra sonderi (Asparagaceae), and Loxocarya cinerea (Restionaceae)] to quantify the oxidative stress experienced during cryopreservation. Post-cryogenic regeneration of shoot tips was greatest in A. viridis (78%) followed by L. sonderi (50%), whilst L. cinerea did not show any post-cryogenic regeneration. The application of a 3-week cold (5 degrees C) preconditioning regime, commonly used to increase post-cryogenic survival, resulted in significantly lower post-cryogenic regeneration for A. viridis (33%), but had little effect on the other two species. Total antioxidant concentration in shoot material decreased significantly with each step throughout the cryopreservation process, particularly in the cryoprotection and washing stages. Antioxidant levels in shoot tips then increased during the subsequent 7-day post cryopreservation recovery period, with the greatest increase measured in A. viridis. Concentrations of thiols and their corresponding disulphides were used to calculate the corresponding half-cell reduction potentials, whereby the ability of these plant species to maintain a strong reducing environment in shoot tissues throughout the cryopreservation protocol was found to correlate with post cryogenic survival. PMID- 28900718 TI - Prognosis of Cancer with Synchronous or Metachronous Malignant Pleural Effusion. AB - PURPOSE: Malignant pleural effusions (MPE) may either coincide with or follow the diagnosis of a primary tumor. Whether this circumstance influences prognosis has not been well substantiated. METHODS: Retrospective review of all consecutive patients who were cared for at a Spanish university hospital during an 11-year period and received a diagnosis of MPE. RESULTS: Of 401 patients, the MPE was the first evidence of cancer in 265 (66%), and it followed a previously diagnosed neoplasm in 136 (34%). Lung cancer predominated in the former group (131, 50%), and breast cancer in the latter (55, 40%). MPE that were the presenting manifestation of hematological and ovarian tumors had a statistically significant survival advantage as compared to those which developed in patients from a previously known cancer (respective absolute differences of 41 and 20 months; p < 0.005). CONCLUSIONS: In hematological and ovarian malignancies, the synchronous or metachronous diagnosis of MPE may have prognostic implications. PMID- 28900719 TI - The effects of exercise-induced muscle damage on critical torque. AB - OBJECTIVE: Exercise-induced muscle damage (EIMD) has been shown to reduce endurance exercise performance. This study examined the effects of EIMD on critical torque (CT) and the sum of the torque integral above CT during (? T total) during a 5-min all-out, intermittent isometric knee extension exercise. METHODS: CT was determined in eight participants prior to and 48-h following EIMD. EIMD was induced using electrically stimulated eccentric knee extensions until maximal voluntary strength (MVC) was reduced by 40%. EIMD was assessed by changes in MVC and ratings of muscle soreness using a VAS scale. EMG and near infrared spectroscopy (NIRS) were collected from the vastus lateralis and vastus medialis, respectively, during the CT test to assess neuromuscular electrical activity and microvascular circulation. RESULTS: MVC decreased 22% (p = 0.006) and soreness increased from 2.1 +/- 1.9 to 50.4 +/- 31.5 mm (p = 0.002) 48-h following eccentric exercise. CT declined from 61.6 +/- 17.8 to 52.0 +/- 14.1 Nm (-14%; p = 0.005) post-EIMD. ? T total declined 33% (p = 0.0006) post-EIMD. No changes were observed in neuromuscular electrical activity (p = 0.95 for EMG RMS and p = 0.57 for EMG median frequency) or any parameter of microvascular circulation (p = 0.60 for tissue saturation index, p = 0.27 for total hemoglobin and myoglobin, p = 0.51 for oxyhemoglobin, and p = 0.26 for deoxyhemoglobin) between conditions. CONCLUSIONS: Our finding that EIMD-reduced CT may explain the decrements in endurance performance following EIMD observed in the previous studies. The disproportionate reduction in ? T total compared to MVC and CT is suggestive of a more rapid depletion of anaerobic energy stores and/or accumulation of metabolic by-products leading to fatigue following EIMD. PMID- 28900720 TI - Respiration-related cerebral blood flow variability increases during control-mode non-invasive ventilation in normovolemia and hypovolemia. AB - PURPOSE: Increased variability in cerebral blood flow (CBF) predisposes to adverse cerebrovascular events. Oscillations in arterial blood pressure and PaCO2 induce CBF variability. Less is known about how heart rate (HR) variability affects CBF. We experimentally reduced respiration-induced HR variability in healthy subjects, hypothesizing that CBF variability would increase. METHODS: Internal carotid artery (ICA) blood velocity was recorded by Doppler ultrasound in ten healthy subjects during baseline, control-mode, non-invasive mechanical ventilation (NIV), i.e., with fixed respiratory rate, hypovolemia induced by lower body negative pressure, and combinations of these. ICA beat volume (ICABV) and ICA blood flow (ICABF) were calculated. HR, mean arterial blood pressure (MAP), respiratory frequency (RF), and end-tidal CO2 were recorded. Integrals of power spectra at each subject's RF +/- 0.03 Hz were used to measure variability. Phase angle/coherence measured coupling between cardiovascular variables. RESULTS: Control-mode NIV reduced HR variability (-56%, p = 0.002) and ICABV variability (-64%, p = 0.006) and increased ICABF variability (+140%, p = 0.002) around RF. NIV + hypovolemia reduced variability in HR and ICABV by 70-80% (p = 0.002) and doubled ICABF variability (p = 0.03). MAP variability was unchanged in either condition. Respiration-induced HR and ICABV oscillations were in inverse phase and highly coherent (coherence >0.9) during baseline, but this coherence decreased during NIV, in normovolemia and hypovolemia (p = 0.01). CONCLUSION: Controlling respiration in awake healthy humans reduced HR variability and increased CBF variability in hypovolemia and normovolemia. We suggest respiration induced HR variability to be a mechanism in CBF regulation. Maintaining spontaneous respiration in patients receiving ventilatory support may be beneficial also for cerebral circulatory purposes. PMID- 28900721 TI - Effects of PER3 clock gene polymorphisms on aging-related changes of the cerebral cortex. AB - Considerable evidence suggests that circadian rhythmicity is progressively disrupted in senescence. Among clock genes, Period3 (PER3) has been associated with circadian phenotypes, homeostatic regulation of sleep, and cognitive performance in young adults. However, the effects of PER3 genotype on aging related changes in both cognitive function and cortical integrity remain largely unknown. To shed light into this issue, we have investigated differences in cognitive performance, patterns of cortical thickness, and cortical glucose consumption in normal elderly subjects homozygous carriers of the short (PER34/4, n = 32) and long repeat alleles (PER35/5, n = 32). Relationships between cognitive performance and cortical thickness/metabolism were further explored for each PER3 genotype. We found that PER35/5 carriers had poorer cognitive performance (attention, executive function, semantic memory, and verbal fluency) and lower cortical integrity (structural and functional) than PER34/4. PER35/5 further showed thinning of temporo-parietal areas, and reductions of glucose consumption in fronto-temporo-parietal regions bilaterally. Moreover, PER35/5 subjects exhibited significant correlations between decreased glucose metabolism in fronto-parietal regions and poorer cognitive flexibility, though only correlations with lower glucose consumption of the supramarginal gyrus distinguished PER35/5 from PER34/4 groups. Overall, these findings enhance our understanding on the gene-brain interaction in aging, and may have further implications for the detection of subclinical cognitive decline associated with PER3 genotypes in late life. PMID- 28900722 TI - Molecular characterization of bovine Cryptosporidium isolated from diarrheic calves in the Sudan. AB - Cryptosporidiosis is a common protozoan infection causing morbidity and mortality in young cattle and may be zoonotically transmitted to humans. So far, there is no data available on the presence of Cryptosporidium spp. in the Sudan. The aim of this study was to isolate, identify, and genotype Cryptosporidium oocysts sampled from diarrheic calves housed at different farms in three different municipalities in Khartoum State (Khartoum, Khartoum North, Omdurman). A total of 149 fecal samples were evaluated microscopically for the presence of Cryptosporidium oocysts using the modified Ziehl-Neelsen staining method and 87 (58.3%) samples tested positive. Positive and negative samples were further analyzed by nested PCR targeting the SSU rRNA region. Positive samples were subjected to restriction enzyme analysis of PCR amplicons (PCR-RFLP). Nested PCR identified Cryptosporidium DNA in 53 samples (35.5%); restriction digestion of the PCR products revealed the presence of C. parvum (73.5%), C. ryanae (13.2%), C. andersoni (7.5%), and C. bovis (1.8%). Species distribution was clearly related to age with C. parvum being the predominant species in dysenteric pre weaned calves. Sequencing of three genes (SSU rRNA, COWP, and GP60) for three C. parvum isolates originating from the three different municipalities showed that all belong to C. parvum subtype family IId. Based on data obtained by GP60, sequencing the two C. parvum isolates from Khartoum and Omdurman represent subtype IIdA18G1, whereas oocysts isolated in Khartoum North belong to subtype IIdA19G1. The observed genotypes are zoonotic and thus C. parvum in calves is potentially a health risk to humans in Khartoum State, Sudan. To the best of our knowledge, this is the first reported attempt to characterize Cryptosporidium isolated from cattle in the Sudan. PMID- 28900723 TI - Diagnostic value of sentinel lymph node biopsy for cT1/T2N0 tongue squamous cell carcinoma: a meta-analysis. AB - The aim of this study was to systematically evaluate the diagnostic value of the sentinel lymph node biopsy (SLNB) for cT1/T2N0 tongue squamous cell carcinoma (TSCC) patients. A comprehensive and systematic literature review was performed by searching the Embase and PubMed databases for English language articles published up to December 2016. The pooled overall sentinel lymph node (SLN) detection rate, sensitivity and negative predictive value (NPV) were used to evaluate the diagnostic value of SLNB which used neck dissection or follow-up as a reference test. The Q test and I 2 statistic were used to assess the heterogeneity across the studies. Subgroup analyses were performed in consideration of higher contribution of different clinical characteristics on the SLNB diagnostic value. Begg's linear regression and Egger's regression tests were conducted to evaluate the publication bias. Thirty-five studies (with 1084 patients) were included. The pooled SLN detection rate was 98% (95% CI 97-100%). The pooled overall sensitivity and NPV of SLNB were 0.92 (95% CI 0.88-0.95) and 0.96 (95% CI 0.94-0.97), respectively. The subgroup analyses demonstrated that higher extracted number of patients (n >= 30) from the included studies achieved a more stable NPV than lower number of patients. SLNB can effectively predict the status of regional lymph nodes in cT1/T2N0 TSCC patients. With high sensitivity and NPV, SLNB can guide the treatment of SLNB-positive patients with neck dissections and those with negative SLNBs with follow-ups in order to avoid unnecessary surgical morbidity. PMID- 28900724 TI - Hypothalamic dysfunction is related to sleep impairment and CSF biomarkers in Alzheimer's disease. AB - Hypothalamus is a key brain region regulating several essential homeostatic functions, including the sleep-wake cycle. Alzheimer's disease (AD) pathology affects nuclei controlling sleep-wake rhythm sited in this brain area. Since only post-mortem studies documented the relationship between hypothalamic atrophy and sleep-wake cycle impairment, we investigated in AD patients the possible hypothalamic in vivo alteration using 2-deoxy-2-(18F) fluoro-D-glucose ([18F]FDG) positron emission tomography ([18F]FDG PET), and its correlations with sleep impairment and cerebrospinal-fluid (CSF) AD biomarkers (tau proteins and beta amyloid42). We measured sleep by polysomnography, CSF AD biomarkers and orexin levels, and hypothalamic [18F]FDG PET uptake in a population of AD patients compared to age- and sex-matched controls. We documented the significant reduction of hypothalamic [18F]FDG PET uptake in AD patients (n = 18) compared to controls (n = 18) (p < 0.01). Moreover, we found the increase of CSF orexin levels coupled with the marked alteration of nocturnal sleep in AD patients than controls. We observed the significant association linking the reduction of both sleep efficiency and REM sleep to the reduction of hypothalamic [18F]FDG PET uptake in the AD group, which in turn negatively correlated with the total tau/beta-amyloid42 ratio (index of more marked neurodegeneration). Moreover, controls but not AD patients showed [18F]FDG PET interconnections between hypothalamus and limbic system. We documented the in vivo dysfunction of hypothalamus in AD patients, which lost the physiological connections with limbic system and was correlated with both nocturnal sleep disruption and CSF AD biomarkers. PMID- 28900725 TI - Contrast-enhanced ultrasonography evaluation of hepatocellular carcinoma with peritumoral fat-spared area: a case report. AB - Peritumoral fat-spared area (PTFSA), a focal spared area surrounding hepatic tumors, is a specific finding of liver tumors in fatty livers. PTFSA mimics a liver tumor, making it difficult to recognize the tumor boundary. We report a case of a 56-year-old man with fatty liver who was diagnosed with a liver tumor. Ultrasonography (US) revealed a nearly homogeneous hyperechoic liver tumor measuring 40 mm in the left lobe. A thick hypoechoic area was observed around the tumor that spread more widely than an ordinary halo. Histological examination revealed that the hypoechoic area comprised a thin fibrous capsule and normal liver parenchyma without fat, which is PTFSA. Contrast-enhanced US (CEUS) indicated corona enhancement only at the inner part of the PTFSA. The inner part showed the same pattern as that of an ordinary halo and was a part of hepatocellular carcinoma, whereas the outer part showed the same pattern as that of the other liver parenchyma. CEUS was an effective modality for distinguishing the difference. Thus, CEUS was useful in defining the tumor boundary. Before initiating treatment, tumors should be evaluated using various modalities to detect their accurate boundary. CEUS may be a useful modality for detecting the boundary and making a diagnosis. PMID- 28900726 TI - [Acute and emergency care of geriatric patients : Old ways - new paths]. PMID- 28900727 TI - Uhrf2 deletion impairs the formation of hippocampus-dependent memory by changing the structure of the dentate gyrus. AB - Ubiquitin-like with PHD and ring finger domains 2 (Uhrf2) is distributed in many brain regions, including the cortex and hippocampus. Decreased Uhrf2 expression is involved in neurodegenerative disease. A recent study showed Uhrf2 deletion impaired spatial memory; however, the mechanism remains elusive. In our study, we determined that Uhrf2+/- and Uhrf2-/- mice had significant learning and memory deficiencies in contextual fear conditioning (CFC) and the novel place recognition test but not in the novel object recognition test. Interestingly, there were no changes in the Uhrf2 protein levels in the hippocampus of C57BL6 mice after CFC training, which suggests Uhrf2 in adult mice may not be related to the formation of CFC long-term memory. Based on Nissl staining, Uhrf2 deletion caused neuropathological changes specifically in the crest of the dentate gyrus (DG), such as cell swelling, a vague outline and confused boundary; however, no changes were identified in the medial prefrontal cortex (mPFC). Transmission electron microscope assay further indicated a series of abnormal ultrastructure changes in neurons and glia in the DG crest. These results suggested that Uhrf2 deletion selectively blocked the development of the DG crest and impaired hippocampus-dependent learning and memory. Our study will facilitate a better understanding of the role of Uhrf2 protein in the central nervous system. PMID- 28900728 TI - Calcium controls the formation of vacuoles from mitochondria to regulate microspore development in wheat. AB - Potassium antimonite was used to investigate the localisation of calcium in developing wheat anthers to examine the relationship between Ca2+ and pollen development. During anther development, calcium precipitate formation increased in anther wall cells prior to microspore mother cell meiosis and appeared in microspores, suggesting the presence of a calcium influx from anther wall cells into the locule. Initially, the precipitates in microspore cytoplasm primarily accumulated in the mitochondria and destroyed their inner membranes (cisterns) to become small vacuoles, which expanded and fused, ultimately becoming a large vacuole during microspore vacuolisation. After microspore division and large vacuole decomposition, many calcium precipitates again accumulated in the small vacuoles, indicating that calcium from the large vacuole moved back into the cytoplasm of bicellular pollen. PMID- 28900729 TI - Microbial healing of cracks in concrete: a review. AB - Concrete is the most widely used construction material of the world and maintaining concrete structures from premature deterioration is proving to be a great challenge. Early age formation of micro-cracking in concrete structure severely affects the serviceability leading to high cost of maintenance. Apart from conventional methods of repairing cracks with sealants or treating the concrete with adhesive chemicals to prevent the cracks from widening, a microbial crack-healing approach has shown promising results. The unique feature of the microbial system is that it enables self-healing of concrete. The effectiveness of microbially induced calcium carbonate precipitation (MICCP) in improving durability of cementitious building materials, restoration of stone monuments and soil bioclogging is discussed. Main emphasis has been laid on the potential of bacteria-based crack repair in concrete structure and the applications of different bacterial treatments to self-healing cracks. Furthermore, recommendations to employ the MICCP technology at commercial scale and reduction in the cost of application are provided in this review. PMID- 28900730 TI - Review of local injection of anti-TNF for perianal fistulising Crohn's disease. AB - BACKGROUND: Perianal fistulising Crohn's disease (PFCD) affects a third of Crohn's disease patients and represents a disabling phenotype with poor outcome. The anti-tumour necrosis factor alpha (TNF) therapies have been shown to maintain clinical remission in a third of patients after 1 year of treatment. Maintenance therapy with systematic administration schedules confers greatest benefit, but exposes patients to risks/side effects of continued systemic use and led to consideration of local drug delivery (first described in 2000). In this review, we analyse all published articles on local anti-TNF therapy in the treatment of PFCD. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines were used to systematically search Medline and Embase using the medical subject headings 'fistula', 'anus', 'Crohn disease', 'infliximab' and 'adalimumab'. This was combined with free text searches, e.g. 'local injection' and 'Crohn's perianal disease'. Studies/abstracts describing local injection treatment with anti-TNF were included in this review. RESULTS: Six pilot studies including a total of 92 patients were included in this review. Outcomes reported were mostly clinical and included 'complete/partial response' to therapy and short-term results varied between 40 and 100%. There were no significant adverse events and the local injections were well tolerated. CONCLUSIONS: There is paucity of data assessing this treatment modality. Local anti-TNF therapy appears safe, but outcome reporting is heterogeneous, subjective and long-term data are unavailable. Our review suggests a potential role may be in those in whom systemic treatment is contraindicated and calls for standardised reporting of outcomes in this field to enable better data interpretation. PMID- 28900731 TI - Selenium mitigates cadmium-induced oxidative stress in tomato (Solanum lycopersicum L.) plants by modulating chlorophyll fluorescence, osmolyte accumulation, and antioxidant system. AB - Pot experiments were conducted to investigate the role of selenium in alleviating cadmium stress in Solanum lycopersicum seedlings. Cadmium (150 mg L-1) treatment caused a significant reduction in growth in terms of height and biomass accumulation and affected chlorophyll pigments, gas exchange parameters, and chlorophyll fluorescence. Selenium (10 MUM) application mitigated the adverse effects of cadmium on growth, chlorophyll and carotenoid contents, leaf relative water content, and other physiological attributes. Lipid peroxidation and electrolyte leakage increased because of cadmium treatment and selenium-treated plants exhibited considerable reduction because of the decreased production of hydrogen peroxide in them. Cadmium-treated plants exhibited enhanced activity of antioxidant enzymes that protected cellular structures by neutralizing reactive free radicals. Supplementation of selenium to cadmium-treated plants (Cd + Se) further enhanced the activity of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR) by 19.69, 31.68, 33.14, and 54.47%, respectively. Osmolytes, including proline and glycine betaine, increased with selenium application, illustrating their role in improving the osmotic stability of S. lycopersicum under cadmium stress. More importantly, selenium application significantly reduced cadmium uptake. From these results, it is clear that application of selenium alleviates the negative effects of cadmium stress in S. lycopersicum through the modifications of osmolytes and antioxidant enzymes. PMID- 28900733 TI - Complexes of arzanol with a Cu2+ ion: a DFT study. AB - Arzanol (C22H26O7) is a naturally occurring acylphloroglucinol largely responsible for the anti-inflammatory, anti-oxidant, antibiotic and antiviral activities of Helichrysum italicum. Like all acylphloroglucinols, the molecule contains a carboxylic substituent (-COR group); for arzanol, this is a -COCH3 group. The molecule is further characterized by the presence of an alpha-pyrone ring bonded in meta to -COR through a methylene bridge, and of a prenyl chain bonded to the other meta position. The molecule can form up to three intramolecular hydrogen bonds (IHB) simultaneously, and their presence and patterns are the major stabilizing factors. This work considers complexes of representative conformers of arzanol with a Cu2+ ion, taking into account the different possibilities for the binding of the Cu2+ ion to the electron-density rich sites of the molecule and including simultaneous coordination to two geometrically suitable sites. Calculations were performed at the DFT/B3LYP level, using the 6-31+G(d,p) basis set for the C, O and H atoms and the LANL2DZ pseudopotential for the Cu2+ ion. Interaction energies show preference for simultaneous binding of Cu2+ to two sites. Simultaneous binding to the O of a phenol OH neighboring the prenyl chain and to the pi bond of the prenyl chain appears to be the most favorable option, followed by simultaneous binding to the sp2 O of the alpha-pyrone ring and the O of the phenol OH ortho to -COR on the side of the alpha-pyrone ring. The charge of the Cu2+ ion is reduced to +1 or slightly less in the complexes, which is consistent with the molecules' antioxidant (reducing) ability. Graphical abstract The copper ion prefers to attach to two sites of the arzanol molecule simultaneously. The arzanol molecule reduces the charge of the copper ion from +2 to +1 by transferring an electron to it; it becomes a radical molecular cation. The distribution of the unpaired electron in the molecule (as highlighted by the spin density maps) depends on the site/s to which the Cu2+ ion binds and on the molecule's conformer. PMID- 28900732 TI - Plant STAND P-loop NTPases: a current perspective of genome distribution, evolution, and function : Plant STAND P-loop NTPases: genomic organization, evolution, and molecular mechanism models contribute broadly to plant pathogen defense. AB - STAND P-loop NTPase is the common weapon used by plant and other organisms from all three kingdoms of life to defend themselves against pathogen invasion. The purpose of this study is to review comprehensively the latest finding of plant STAND P-loop NTPase related to their genomic distribution, evolution, and their mechanism of action. Earlier, the plant STAND P-loop NTPase known to be comprised of only NBS-LRRs/AP-ATPase/NB-ARC ATPase. However, recent finding suggests that genome of early green plants comprised of two types of STAND P-loop NTPases: (1) mammalian NACHT NTPases and (2) NBS-LRRs. Moreover, YchF (unconventional G protein and members of P-loop NTPase) subfamily has been reported to be exceptionally involved in biotic stress (in case of Oryza sativa), thereby a novel member of STAND P-loop NTPase in green plants. The lineage-specific expansion and genome duplication events are responsible for abundance of plant STAND P-loop NTPases; where "moderate tandem and low segmental duplication" trajectory followed in majority of plant species with few exception (equal contribution of tandem and segmental duplication). Since the past decades, systematic research is being investigated into NBS-LRR function supported the direct recognition of pathogen or pathogen effectors by the latest models proposed via 'integrated decoy' or 'sensor domains' model. Here, we integrate the recently published findings together with the previous literature on the genomic distribution, evolution, and distinct models proposed for functional molecular mechanism of plant STAND P-loop NTPases. PMID- 28900734 TI - The presence of minor salivary glands in the peritonsillar space. AB - Peritonsillar abscess (PTA) is traditionally considered only a purulent complication of acute tonsillitis (AT), but may be related to infection of minor salivary glands. We analysed the presence of peritonsillar minor salivary glands and inflammation patterns in 114 adult tonsils representing three patient groups: recurrent AT, chronic tonsillitis (CT), and PTA. Samples acquired from elective tonsillectomies were stored in formalin, and after preparation were microscopically examined for inflammation and fibrotic changes. Clinical features and histological characteristics were compared between the groups. Of all tonsils, the minor salivary glands were present in 77 (67.5%). Glands located near the tonsillar tissue showed signs of infection in 73 (94.8%), while only 3 (15.0%) of 20 glands located deeper in the peritonsillar space were infected. Compared to patients with recurrent AT and CT, those with PTA more often presented with periductal inflammation, p < 0.011 (PTA 82.1%, AT 42.9%, and CT 63.6%). The majority of our 114 tonsillectomy specimens, collected from patients with AT, CT, or PTA, presented with infected minor salivary glands, and inflammation of the peritonsillar space glands was evident. To further elucidate the association between these glands and PTA, tonsillar samples should be collected and analysed from patients during the acute phase of infection. PMID- 28900735 TI - 4-Chloro-3-nitro-N-butylbenzenesulfonamide acts on KV3.1 channels by an open channel blocker mechanism. AB - The effects of 4-chloro-3-nitro-N-butylbenzenesulfonamide (SMD2) on KV3.1 channels, heterologous expressed in L-929 cells, were studied with the whole cell patch-clamp technique. SMD2 blocks KV3.1 in a reversible and use-dependent manner, with IC50 around 10 uM, and a Hill coefficient around 2. Although the conductance vs. voltage relationship in control condition can be described by a single Boltzmann function, two terms are necessary to describe the data in the presence of SMD2. The activation and deactivation time constants are weakly voltage dependent both for control and in the presence of SMD2. SMD2 does not change the channel selectivity and tail currents show a typical crossover phenomenon. The time course of inactivation has a fast and a slow component, and SMD2 significantly decreased their values. Steady-state inactivation is best described by a Boltzmann equation with V 1/2 (the voltage where the probability to find the channels in the inactivated state is 50%) and K (slope factor) equals to -22.9 +/- 1.5 mV and 5.3 +/- 0.9 mV for control, and -30.3 +/- 1.3 mV and 6 +/ 0.8 mV for SMD2, respectively. The action of SMD2 is enhanced by high frequency stimulation, and by the time the channel stays open. Taken together, our results suggest that SMD2 blocks the open conformation of KV3.1. From a pharmacological and therapeutic point of view, N-alkylsulfonamides may constitute a new class of pharmacological modulators of KV3.1. PMID- 28900736 TI - Residential magnetic fields exposure and childhood leukemia: a population-based case-control study in California. AB - PURPOSE: Studies have reported an increased risk of childhood leukemia associated with exposure to magnetic fields. We conducted a large records-based case-control study of childhood leukemia risk and exposure to magnetic fields from power lines in California. METHODS: The study included 5,788 childhood leukemia cases (born in and diagnosed in California 1986-2008) matched to population-based controls on age and sex. We calculated magnetic fields at birth addresses using geographic information systems, aerial imagery, historical information on load and phasing, and site visits. RESULTS: Based on unconditional logistic regression controlling for age, sex, race/ethnicity, and socioeconomic status using subjects geocoded to a basic standard of accuracy, we report a slight risk deficit in two intermediate exposure groups and a small excess risk in the highest exposure group (odds ratio of 1.50 (95% confidence interval [0.70, 3.23])). Subgroup and sensitivity analyses as well as matched analyses gave similar results. All estimates had wide confidence intervals. CONCLUSION: Our large, statewide, record-based case-control study of childhood leukemia in California does not in itself provide clear evidence of risk associated with greater exposure to magnetic fields from power lines, but could be viewed as consistent with previous findings of increased risk. PMID- 28900738 TI - Novel temporary left ventricular assist system with hydrodynamically levitated bearing pump for bridge to decision: initial preclinical assessment in a goat model. AB - The management of heart failure patients presenting in a moribund state remains challenging, despite significant advances in the field of ventricular assist systems. Bridge to decision involves using temporary devices to stabilize the hemodynamic state of such patients while further assessment is performed and a decision can be made regarding patient management. We developed a new temporary left ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing. We used three adult goats (body weight, 58-68 kg) to investigate the 30-day performance and hemocompatibility of the newly developed left ventricular assist system, which included the pump, inflow and outflow cannulas, the extracorporeal circuit, and connectors. Hemodynamic, hematologic, and blood chemistry measurements were investigated as well as end organ effect on necropsy. All goats survived for 30 days in good general condition. The blood pump was operated at a rotational speed of 3000-4500 rpm and a mean pump flow of 3.2 +/- 0.6 L min. Excess hemolysis, observed in one goat, was due to the inadequate increase in pump rotational speed in response to drainage insufficiency caused by continuous contact of the inflow cannula tip with the left ventricular septal wall in the early days after surgery. At necropsy, no thrombus was noted in the pump, and no damage caused by mechanical contact was found on the bearing. The newly developed temporary left ventricular assist system using a disposable centrifugal pump with hydrodynamic bearing demonstrated consistent and satisfactory hemodynamic performance and hemocompatibility in the goat model. PMID- 28900737 TI - The benefit of the systematic revision of the acetabular implant in favor of a dual mobility articulation during the treatment of periprosthetic fractures of the femur: a 49 cases prospective comparative study. AB - INTRODUCTION: The SOFCOT symposium (2005) on periprosthetic fractures of the femur (PFFs) highlighted a high rate of dislocation (15.6% at 6 months) after change of prosthesis. So far, no study has ever proved the benefit of dual mobility articulation during PFFs revisions. We conducted a comparative study on two prospective cohorts in order to (1) assess the influence of systematic acetabular revision in favor of a double mobility on dislocation rate (2) and in order to evaluate the rate of morbidity associated with this extra surgical procedure. HYPOTHESIS: A systematic replacement of the cup in favor of a dual mobility articulation enables to reduce the dislocation rate in PFFs revisions without increasing morbidity. METHODOLOGY: We compared two prospective multicenter cohorts over a year (2005 and 2015) using the same methodology. Any fracture around hip prosthesis which occurred 3 months at least after surgery was included. Data collection was clinical and radiological on preoperative, intraoperative and 6 months after surgery. The 2015 "bipolar" group (n = 24) included patients who had a bipolar revision (both femoral and dual-mobility articulation). The 2005 "unipolar" group (n = 25) included patients who had only a femoral implant revision. Patients were comparable by age (p = 0.36), sex (p = 0.91), ASA score (p = 0.36), history of prosthetic revision (p = 1.00), Katz score (p = 0.50) and the type of fracture according to the Vancouver classification (p = 0.55). RESULTS: There was a 4% rate of dislocation in the "bipolar group" while there was 21% rate of dislocation in the "unipolar group" (8% of recurrent dislocation) (p = 0.19). The rate of all-cause complications 6 months after surgery was not significantly different (p = 0.07): 12.5% in the 2015 "bipolar" cohort (one dislocation, one non-symptomatic cup migration and one pseudarthrosis of the major trochanter) versus 35% in the "unipolar" cohort (5 dislocations, 1 major trochanter fracture and 1 femur pseudarthrosis, 1 secondary displacement associated with a superficial infection). The surgical revision after 6 months was not significantly different (1/23 or 4% vs. 4/25 or 16%, p = 0.35). CONCLUSION: We confirm the low rate of dislocations after fitting a dual mobility cup in case of revision of the femoral side in case of periprosthetic femoral fracture, as well as the need for additional cases to be carried out upon further studies to significantly confirm the interest of preventing instability after femoral revision. PMID- 28900739 TI - A frameshift mutation in BRCA1 leads to hereditary breast and ovarian cancer in one part of a family and to familial pancreatic cancer in another. PMID- 28900740 TI - CRISPR/Cas9-mediated multiple single guide RNAs potently abrogate pseudorabies virus replication. AB - Pseudorabies virus (PRV) is a swine herpesvirus that causes significant morbidity and mortality in swine populations and has caused huge economic losses in the worldwide swine industry. Currently, there is no effective antiviral drug in clinical use for PRV infection; it is also difficult to eliminate PRV from infected swine. In our study, we set out to combat these swine herpesvirus infections by exploiting the CRISPR/Cas9 system. We designed 75 single guide RNAs (sgRNA) by targeting both essential and non-essential genes across the genome of PRV. We applied a firefly luciferase-tagged reporter PRV virus for high throughput sgRNA screening and found that most of the sgRNAs significantly inhibited PRV replication. More importantly, using a transfection assay, we demonstrated that simultaneous targeting of PRV with multiple sgRNAs completely abolished the production of infectious viruses in cells. These data suggest that CRISPR/Cas9 could be a novel therapeutic agent against PRV in the future. PMID- 28900741 TI - Occurrence and distribution of antibiotic resistance genes in water supply reservoirs in Jingjinji area, China. AB - Jingjinji area occupies important position in developing of the Chinese economy, while there exists a sharp conflict between economic growth and limited water resources in this area. To ensure the safety of water consumption of cities in Jingjinji area, we investigated the abundance of three classes of antibiotic resistance genes (ARGs) in water and sediment of six water supply reservoirs in this area. The results showed that the detection frequency of sul1, tetM and ermB were 100%. However, the content ranges of these genes were different (10-5 to 10 2/16S gene copies for sul1, 10-5 to 10-3/16S gene copies for ermB, and 10-5 to 10 3/16S gene copies for tetM). The content of ribosome protection proteins (RPP) genes were the highest in all selected tet genes. The highest abundance of ARGs in water and sediment samples was sampled from Panjiakou reservoir and Guanting reservoir, respectively. Except COD, chla and tetM, there are no significant correlation between water quality parameters and ARGs. Overall, this study provides integrated profiles of the three types of ARGs in water supply reservoirs of Jingjinji area and thus helps to re-evaluate the effects of human activities to water supply reservoirs. PMID- 28900742 TI - Relationship between air mass type and emergency department visits for migraine headache across the Triangle region of North Carolina. AB - An estimated 240 million people worldwide suffer from migraines. Because migraines are often debilitating, understanding the mechanisms that trigger them is crucial for effective prevention and treatment. Synoptic air mass types and emergency department (ED) visits for migraine headaches were examined over a 7 year period within a major metropolitan area of North Carolina to identify potential relationships between large-scale meteorological conditions and the incidence of migraine headaches. Barometric pressure changes associated with transitional air masses, or changing weather patterns, were also analyzed for potential relationships. Bootstrapping analysis revealed that tropical air masses (moist and dry) resulted in the greatest number of migraine ED visits over the study period, whereas polar air masses led to fewer. Moist polar air masses in particular were found to correspond with the fewest number of migraine ED visits. On transitional air mass days, the number of migraine ED visits fell between those of tropical air mass days and polar air mass days. Transitional days characterized by pressure increases exhibited a greater number of migraine ED visits than days characterized by pressure decreases. However, no relationship was found between migraine ED visits and the magnitude of barometric pressure changes associated with transitional air masses. PMID- 28900743 TI - Catechin ameliorates doxorubicin-induced neuronal cytotoxicity in in vitro and episodic memory deficit in in vivo in Wistar rats. AB - Cognitive dysfunction by chemotherapy compromises the quality of life in cancer patients. Tea polyphenols are known chemopreventive agents. The present study was designed to evaluate the neuroprotective potential of (+) catechin hydrate (catechin), a tea polyphenol, in IMR-32 neuroblastoma cells in vitro and alleviation of episodic memory deficit in Wistar rats in vivo against a widely used chemotherapeutic agent, Doxorubicin (DOX). In vitro, neuroprotective studies were assessed in undifferentiated IMR-32 cells using percentage viability and in differentiated cells by neurite length. These studies showed catechin increased percentage viability of undifferentiated IMR-32 cells. Catechin pretreatment also showed an increase in neurite length of differentiated cells. In vivo neuroprotection of catechin was evaluated using novel object recognition task in time-induced memory deficit model at 50, 100 and 200 mg/kg dose and DOX-induced memory deficit models at 100 mg/kg dose. The latter model was developed by injection of DOX (2.5 mg/kg, i.p.) in 10 cycles over 50 days in Wistar rats. Catechin showed a significant reversal of time-induced memory deficit in a dose dependent manner and prevention of DOX-induced memory deficit at 100 mg/kg. In addition, catechin treatment showed a significant decrease in oxidative stress, acetylcholine esterase and neuroinflammation in the hippocampus and cerebral cortex in DOX-induced toxicity model. Hence, catechin may be a potential adjuvant therapy for the amelioration of DOX-induced cognitive impairment which may improve the quality of life of cancer survivors. This improvement might be due to the elevation of antioxidant defense, prevention of neuroinflammation and inhibition of acetylcholine esterase enzyme. PMID- 28900745 TI - Systematic review on maternal depression versus anxiety in relation to excessive infant crying: it is all about the timing. AB - Different types of studies suggest a link between maternal depression/anxiety and excessive infant crying (EC). However, comparability is hampered due to different designs, definitions and measurements. This systematic review investigates the specific role of maternal depression and anxiety considering them as preceding, concurrent and subsequent conditions of EC. A computerised literature search was conducted in January 2017 using Medline, PubMed, PsycINFO and Web of Science. After screening n = 399 records for inclusion/exclusion criteria, n = 33 records based on n = 30 projects were eligible for systematic qualitative data synthesis. All studies on maternal depression/anxiety and EC within the first 3 years of life were included. Included studies investigated predominantly maternal depression (25/30) and secondly maternal anxiety (17/30). Significant positive results were found in the majority of studies for maternal depression (21/25) as well as for maternal anxiety (12/17) in relation to EC. In-depth analyses further revealed that concurrent and subsequent maternal depression was robustly related with EC, whilst preceding maternal depression was not. In contrast, preceding and concurrent (but not subsequent) maternal anxiety was consistently related to subsequent EC. Maternal depression is more likely a correlate or even a consequence of EC, whereas anxiety is rather a temporally preceding condition and thus a potential risk factor or risk marker for both subsequent EC and associated maternal depression. Interventions for EC should address concurrent maternal depression, whilst preventive approaches might target preceding maternal anxiety as early as prior to or during pregnancy. PMID- 28900744 TI - Structural vertebral endplate nomenclature and etiology: a study by the ISSLS Spinal Phenotype Focus Group. AB - PURPOSE: Vertebral endplate abnormalities may be associated with disc degeneration and, perhaps, pain generation. However, consensus definitions for endplate findings on spine MRI do not exist, posing a challenge to compare findings between studies and ethnic groups. The following survey was created to characterize the variability among the global spine community regarding endplate structural findings with respect to nomenclature and etiology. METHODS: A working group within the International Society for the Study of the Lumbar Spine (ISSLS) Spinal Phenotype Focus Group was established to assess the endplate phenotype. A survey which consisted of 13 T2-weighted sagittal MRIs of the human lumbar spine illustrating the superior and inferior endplates was constructed based on discussion and agreement by the working group. A list of nomenclature and etiological terms with historical precedence was generated. Participants were asked to describe the endplates of each image and select from 14 possible nomenclatures and 10 etiological terms along with the option of free text response. The survey was entered into RedCap and was circulated throughout the ISSLS membership for data capture. Participants' demographics were also noted. RESULTS: The survey was completed by 55 participants (87% males; 85% above 45 years of age, 39 clinicians, and 16 researchers). Sixty-eight percent of researchers and seventy-four percent of clinicians reported more than 16 and 20 years of research and clinical experience. Considerable variation existed in selection of nomenclature, etiology, and degree of severity of the endplate structural findings (reliability coefficients for single measures in each case were 0.3, 0.08, and 0.2, respectively). Sixty-seven percent regarded Modic changes as being a structural endplate finding. Approximately 84 and 80% of clinicians and researchers, respectively, agreed that a standardized endplate nomenclature and understanding the etiology is clinically important and needed. CONCLUSIONS: This study found that variations exist with respect to endplate nomenclature and etiology between clinicians and basic scientists, and paves the way for a consensus process to formalize the definitions. PMID- 28900746 TI - Electrophysiological features and multimodal imaging in ritonavir-related maculopathy. AB - PURPOSE: The purpose of this study is to report a case of ritonavir-related retinal toxicity followed over a year. Electrophysiological features and multimodal imaging, including adaptive optics, are provided and discussed. METHODS: Electrophysiological recordings and multimodal imaging were performed and repeated over 1 year. RESULTS: Fundus examination revealed crystalline maculopathy in conjunction with pigment disruption. Spectral domain optical coherence tomography displayed thinning of the macula without cysts. Autofluorescence imaging revealed a mixed pattern of complete loss of the autofluorescence in the area of retinal pigment deposit and an increased transmission of the autofluorescence in the area of retinal thinning. Fluorescein angiography ruled out parafoveal telangiectasia. Indocyanine green angiography was not contributive. Increased spacing of the macular cone mosaic, crystal deposits and pigment migrations were seen with adaptive optics. Full-field electroretinogram was slightly reduced for both eyes, especially in the light adapted responses, and mfERG confirmed bilateral maculopathy. Functional and structural abnormalities did not change with follow-up besides constant pigmentary changes monitored with adaptive optics. CONCLUSION: Ritonavir-related retinal toxicity is a maculopathy with peculiar features including crystalline and pigment migration associated with central or temporofoveolar thinning and inconstant macular telangiectasia. Despite drug cessation, retinal remodelling continues to progress. PMID- 28900748 TI - Serum interleukin 6 levels are associated with depressive state of the patients with knee osteoarthritis irrespective of disease severity. AB - This cross-sectional study investigated the prevalence of depressive state and association between depressive state and serum interleukin (IL)-6 levels in knee osteoarthritis (OA) patients. A total of 115 painful knee OA patients were enrolled and divided into two groups according to the radiographic OA severity. Pain was evaluated using a visual analog scale (VAS). Depressive state was assessed by the self-rating depression scale (SDS). Serum IL-6 levels were also measured. Pearson's correlation coefficient was used to assess the correlation between the variants tested, and logistic regression analysis was used to identify factors associated with the depressive state. Fifty-two percent of the patients had an SDS score of >= 40, which is indicative of the depressive state. The pain VAS score (r = 0.22, p = 0.02) and serum IL-6 level (r = 0.31, p < 0.01) were independently associated with the SDS score of all early-stage knee OA patients (Kellgren-Lawrence [K/L] grade 2). However, only the serum IL-6 level was independently associated with the SDS scores of advanced-stage knee OA patients (K/L grades 3 and 4, r = 0.36, p < 0.01). A logistic regression analysis revealed that serum IL-6 level was the variable for the SDS score [odds ratio 1.41 (95% confidence interval 1.03-1.94, p < 0.03)]. Approximately half of the knee OA patients were found to be in the depressive state, and their serum IL-6 levels to be associated with the depressive state, irrespective of OA severity. PMID- 28900749 TI - Chromosomal polymorphisms are independently associated with multinucleated embryo formation. AB - PURPOSE: The purpose of this study is to explore the factors associated with embryo multinucleation, particularly focused on the influence of parental chromosomal polymorphisms in embryo multinucleation. METHODS: This is a retrospective case-control study involving 1260 infertile couples undergoing their first IVF/ICSI cycles. Couples were screened for abnormalities in their karyotype and were evaluated for blastomere persistence of multinucleation. Demographic characteristics, stimulation protocol, and pregnant outcomes were analyzed using logistic regression analysis. RESULTS: The level of basal FSH was lower in the multinucleated embryos group (5.37 vs 5.72 IU/L). The Multinucleated embryos group received less gonadotropins (1788.5 vs 1891.3 IU), and the level of LH on day of HCG triggering was lower (1.09 vs 1.30 IU/L). More oocytes were recovered in the multinucleated embryos group (11.51 vs 9.23). Chromosomal polymorphisms were seen in at least 1 out of 163 (12.9%) couples. Multivariate logistic regression analysis revealed that chromosomal polymorphisms were independently associated with an increase in the occurrence risk of multinucleated embryos (OR = 1.61, 95% CI, 1.06-2.44) in the first IVF/ICSI cycle. The miscarriage rate in the multinucleated embryos group was 10% higher than that of the control group. CONCLUSIONS: Chromosomal polymorphisms were independently associated with multinucleation embryo formation. A higher LH level on the day of HCG triggering was associated with a decreased chance of multinucleation. PMID- 28900750 TI - In response to Letter to the Editor entitled "Commentary on: Comparison of endoscopic and microscopic tympanoplasty". PMID- 28900747 TI - Transcriptome analysis and identification of significantly differentially expressed genes in Holstein calves subjected to severe thermal stress. AB - RNA-Seq analysis was used to characterize transcriptome response of Holstein calves to thermal stress. A total of eight animals aged between 2 and 3 months were randomly selected and subjected to thermal stress corresponding to a temperature humidity index of 95 in an environmentally controlled house for 12 h consecutively for 3 days. A set of 15,787 unigenes were found to be expressed and after a threshold of threefold change, and a Q value <0.05; 502, 394, and 376 genes were found to be differentially expressed on days 1, 2, and 3 out of which 343, 261 and 256 genes were upregulated and 159, 133, and 120 genes were downregulated. Only 356 genes out of these were expressed on all 3 days, and only they were considered as significantly differentially expressed. KEGG pathway analysis revealed that ten pathways were significantly enriched; the top two among them were protein processing in endoplasmic reticulum and MAPK signaling pathways. These results suggest that thermal stress triggered a complex response in Holstein calves and the animals adjusted their physiological and metabolic processes to survive. Many of the genes identified in this study have not been previously reported to be involved in thermal stress response. The results of this study extend our understanding of the animal's response to thermal stress and some of the identified genes may prove useful in the efforts to breed Holstein cattle with superior thermotolerance, which might help in minimizing production loss due to thermal stress. PMID- 28900751 TI - Effect of wavelength and beam width on penetration in light-tissue interaction using computational methods. AB - Penetration depth of ultraviolet, visible light and infrared radiation in biological tissue has not previously been adequately measured. Risk assessment of typical intense pulsed light and laser intensities, spectral characteristics and the subsequent chemical, physiological and psychological effects of such outputs on vital organs as consequence of inappropriate output use are examined. This technical note focuses on wavelength, illumination geometry and skin tone and their effect on the energy density (fluence) distribution within tissue. Monte Carlo modelling is one of the most widely used stochastic methods for the modelling of light transport in turbid biological media such as human skin. Using custom Monte Carlo simulation software of a multi-layered skin model, fluence distributions are produced for various non-ionising radiation combinations. Fluence distributions were analysed using Matlab mathematical software. Penetration depth increases with increasing wavelength with a maximum penetration depth of 5378 MUm calculated. The calculations show that a 10-mm beam width produces a fluence level at target depths of 1-3 mm equal to 73-88% (depending on depth) of the fluence level at the same depths produced by an infinitely wide beam of equal incident fluence. Meaning little additional penetration is achieved with larger spot sizes. Fluence distribution within tissue and thus the treatment efficacy depends upon the illumination geometry and wavelength. To optimise therapeutic techniques, light-tissue interactions must be thoroughly understood and can be greatly supported by the use of mathematical modelling techniques. PMID- 28900752 TI - Healthcare utilization, Medicare spending, and sources of patient distress identified during implementation of a lay navigation program for older patients with breast cancer. AB - PURPOSE: Despite benefits for patients, sustainability of breast cancer navigation programs is challenging due to the lack of reimbursement for navigators. This analysis describes distress reported by breast cancer patients to navigators and the impact of navigation on healthcare utilization for older adults with breast cancer. METHODS: We conducted a retrospective cohort study of Medicare administrative claims data and patient-reported distress assessments. The primary outcome was Medicare spending per beneficiary per quarter. Secondary outcomes included (1) the number of hospitalizations or ER visits in each quarter; (2) distress levels; and (3) causes of distress reported by patients to their navigators. A subset analysis was conducted for stage I/II/III versus stage IV patients. RESULTS: 776 navigated and 776 control patients were included in the analysis. The average age at diagnosis was 74 years; 13% of the subjects were African American; 95% of patients had stage I-III. Medicare spending declined faster for the navigated group than the matched comparison group by $528 per quarter per patient (95% CL -$667, -$388). Stage I/II/III navigated patients showed a statistically significant decline in Medicare spending, ER visits, and hospitalizations over time compared to the matched comparison group. No differences were observed for stage IV patients. Eighteen percent of patients reported moderate distress. Informational and physical distress were more common in late stage than in early-stage breast cancer. CONCLUSIONS: Lay navigation reduced healthcare utilization in older adults with breast cancer, with the greatest impact observed in early-stage breast cancer patients. PMID- 28900753 TI - Fertility treatment for the transgender community: a public opinion study. AB - PURPOSE: The purposes of this study were to evaluate public opinion regarding fertility treatment and gamete cryopreservation for transgender individuals and identify how support varies by demographic characteristics. METHODS: This is a cross-sectional web-based survey study completed by a representative sample of 1111 US residents aged 18-75 years. Logistic regression was used to calculate odd ratios (ORs) and 95% confidence intervals (CIs) of support for/opposition to fertility treatments for transgender people by demographic characteristics, adjusting a priori for age, gender, race, and having a biological child. RESULTS: Of 1336 people recruited, 1111 (83.2%) agreed to participate, and 986 (88.7%) completed the survey. Most respondents (76.2%) agreed that "Doctors should be able to help transgender people have biological children." Atheists/agnostics were more likely to be in support (88.5%) than Christian-Protestants (72.4%; OR = 3.10, CI = 1.37-7.02), as were younger respondents, sexual minorities, those divorced/widowed, Democrats, and non-parents. Respondents who did not know a gay person (10.0%; OR = 0.20, CI = 0.09-0.42) or only knew a gay person without children (41.4%; OR = 0.29, CI = 0.17-0.50) were more often opposed than those who knew a gay parent (48.7%). No differences in gender, geography, education, or income were observed. A smaller majority of respondents supported doctors helping transgender minors preserve gametes before transitioning (60.6%) or helping transgender men carry pregnancies (60.1%). CONCLUSIONS: Most respondents who support assisted and third-party reproduction also support such interventions to help transgender people have children. PMID- 28900754 TI - Surgery versus stereotactic radiosurgery for the treatment of multiple meningiomas in neurofibromatosis type 2: illustrative case and systematic review. AB - Neurofibromatosis type 2 (NF2) is a genetic neoplastic disorder that presents with hallmark bilateral vestibular schwannomas and multiple meningiomas. Though the current standard of care for meningiomas includes surgery, the multiplicity of meningiomas in NF2 patients renders complete resection of all developing lesions infeasible. Stereotactic radiosurgery (SRS) may be a viable non-invasive therapeutic alternative to surgery. We describe a particularly challenging case in a 39-year-old male with over 120 lesions who underwent more than 30 surgical procedures, and review the literature. We also searched three popular databases and compared outcomes of SRS versus surgery for the treatment of multiple meningiomas in patients with NF2. A total of 50 patients (27 radiosurgical and 23 surgical) were identified. For patients treated with SRS, local tumor control was achieved in 22 patients (81.5%) and distal control was achieved in 14 patients (51.8%). No malignant inductions were observed at an average follow-up duration of 90 months. Complications in the SRS-treated cohort were reported in 9 patients (33%). Eight patients (29.6%) died due to disease progression. Six patients experienced treatment failure and required further management. For NF2 patients treated with surgery, 11 patients (48%) showed tumor recurrence and 10 patients (43.5%) died due to neurological complications. SRS may be a safe and effective alternative for NF2-associated meningiomas. Further studies are required to identify the ideal radiosurgical candidate. PMID- 28900755 TI - Quantitative physiology and elemental composition of Kluyveromyces lactis CBS 2359 during growth on glucose at different specific growth rates. AB - The yeast Kluyveromyces lactis has received attention both from academia and industry due to some important features, such as its capacity to grow in lactose based media, its safe status, its suitability for large-scale cultivation and for heterologous protein synthesis. It has also been considered as a model organism for genomics and metabolic regulation. Despite this, very few studies were carried out hitherto under strictly controlled conditions, such as those found in a chemostat. Here we report a set of quantitative physiological data generated during chemostat cultivations with the K. lactis CBS 2359 strain, obtained under glucose-limiting and fully aerobic conditions. This dataset serves [corrected] as a basis for the comparison of K. lactis with the model yeast Saccharomyces cerevisiae in terms of their elemental compositions, as well as for future metabolic flux analysis and metabolic modelling studies with K. lactis. PMID- 28900756 TI - Systematic Review of Interventions for Depression for People Living with HIV in Africa. AB - Depression interventions for individuals with HIV/AIDS in Africa are being increasingly evaluated. MEDLINE was searched using key terms: depression, Africa, and HIV, to identify depression interventions for HIV-infected adults in Africa. Perinatal women were excluded. Results were extracted and relative change in depression scores for interventions and net effect calculated. The MEDLINE search yielded 18 articles. Six of seven studies evaluating feasibility were positive, and seven of seven studies evaluating acceptability were also positive. Three studies investigated the effect of psychotherapy (% relative decrease of depressive symptoms for intervention: %net decrease compared to controls) (73%:39% decrease). Four studies investigated task-shifting of psychotherapy (47%:34% decrease). Three studies evaluated antidepressants (79%:39% decrease). Three studies investigated task-shifting of antidepressant treatment (82%:65% decrease). An exercise intervention was evaluated (66%:49% decrease). One trial investigated minocycline with non-statistically significant results. Finally, three studies investigated other psychosocial interventions (44%:21% decrease). Overall, the results highlight the need for large, randomized trials to establish efficacy as well as implementation studies. PMID- 28900757 TI - Low incidence of postoperative urinary retention with the use of a nurse-led bladder scan protocol after hip and knee arthroplasty: a retrospective cohort study. AB - PURPOSE: Postoperative urinary retention (POUR), defined as the inability to empty the bladder voluntary after surgery, is a commonly reported complication. This study reports the incidence and possible risk factors for POUR after elective fast-track hip or knee arthroplasty when using a nurse-led bladder scan protocol. METHODS: This retrospective cohort study included data from 803 patients who underwent unilateral hip or knee arthroplasty. Patients' digital clinical records were reviewed for eligibility. Patients with incomplete data registration, preoperative bladder volume >250 ml, preexisting bladder catheterization, and/or patients following the outpatient pathway were excluded. Bladder volumes were assessed at different moments pre- and postoperatively. The outcome was the incidence of POUR, defined as the inability to void spontaneously with a bladder volume >600 ml, treated with indwelling catheterization. Further analysis between POUR and non-POUR patients was performed to detect possible risk factors for POUR. RESULTS: Six hundred and thirty-eight patients operated on primary unilateral hip or knee arthroplasty were analyzed. The incidence of POUR was 12.9% (n = 82, 95% CI 9.4-15.5). Gender, age, BMI, ASA classification, preoperative bladder volume, type of anesthesia, type of arthroplasty, and perioperative fluid administration were not significant different between POUR and non-POUR patients. Patients with a bladder volume of >200 ml at the recovery room were at higher risk (OR 5.049, 95% CI 2.815-9.054) for POUR. CONCLUSIONS: When using a nurse-led bladder scan protocol in fast-track hip and knee arthroplasty, the incidence of POUR was 12.9%, with a bladder volume of >200 ml at the recovery room as a risk factor for POUR. LEVEL OF EVIDENCE: A retrospective cohort study, Level III. PMID- 28900759 TI - Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease. AB - BACKGROUND: Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study. METHODS: This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2-4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4-1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded. RESULTS: Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference - 0.90 mg/dL, p = 0.001) and during the DTP (- 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP. CONCLUSIONS: Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified. PMID- 28900758 TI - In utero development of memory T cells. AB - Pathogen-specific immune memory develops subsequent to primary exposure to antigen, mainly in the context of infection or vaccination to provide protection. Although a safe fetal life requires a tolerogenic environment in order to circumvent unnecessary inflammatory responses, it needs to be prepared in utero to face the microbial environment outside the womb. The possibility of immune memory generation in the fetus would help such transition providing protection in early life. This requires fetal T cell exposure to foreign antigens presented by dendritic cells. There are evidences of fetal T cell priming in several cases of congenital infections or in uninfected children born of infected mothers. Fetal T cell memory seems to arise also without any reported infection during pregnancy. Such memory T cells display various effector functions, including Th1, Th2, or Th17 profiles, raising the issue of benefits and risks for postnatal life when considering maternal vaccination, susceptibility to infection, or environmental allergen sensitization. PMID- 28900760 TI - Corrigendum to: The Diversity and Prevalence of Sexual Orientation Self-Labels in a New Zealand National Sample (Greaves et al., 2017). PMID- 28900761 TI - A Novel Multi-objective Physiological Control System for Rotary Left Ventricular Assist Devices. AB - Various control and monitoring algorithms have been proposed to improve the left ventricular assist device (LVAD) therapy by reducing the still-occurring adverse events. We developed a novel multi-objective physiological control system that relies on the pump inlet pressure (PIP). Signal-processing algorithms have been implemented to extract the required features from the PIP. These features then serve for meeting various objectives: pump flow adaptation to the perfusion requirements, aortic valve opening for a predefined time, augmentation of the aortic pulse pressure, and monitoring of the LV pre- and afterload conditions as well as the cardiac rhythm. Controllers were also implemented to ensure a safe operation and prevent LV suction, overload, and pump backflow. The performance of the control system was evaluated in vitro, under preload, afterload and contractility variations. The pump flow adapted in a physiological manner, following the preload changes, while the aortic pulse pressure yielded a threefold increase compared to a constant-speed operation. The status of the aortic valve was detected with an overall accuracy of 86% and was controlled as desired. The proposed system showed its potential for a safe physiological response to varying perfusion requirements that reduces the risk of myocardial atrophy and offers important hemodynamic indices for patient monitoring during LVAD therapy. PMID- 28900762 TI - Novel reassortant clade 2.3.4.4 avian influenza A (H5N8) virus in a grey heron in South Korea in 2017. AB - We report the identification of a novel reassortant clade 2.3.4.4 H5N8 virus from a dead grey heron in Korea in 2017. Outbreaks of clade 2.3.4.4 H5 HPAIVs have been reported worldwide, and they have evolved into multiple genotypes among wild birds. Phylogenetic analysis indicated that this virus likely originated from Qinghai Lake and Western Siberia and further evolved through reassortment with Eurasian LPAI during the 2016 fall migration of wild birds. Enhanced surveillance and comparative genetic analysis will help to monitor the further evolution and dissemination of clade 2.3.4.4 HPAIVs. PMID- 28900763 TI - The association between fatty acid index and in vitro fertilization outcomes. AB - PURPOSE: Fatty acids have been shown to play an important role in oocyte competence and early implantation of the embryo. Our hypothesis-generating study sought to determine if individual fatty acids expressed as a percentage of total erythrocyte fatty acids are associated with embryo quality and other in vitro fertilization (IVF) outcomes. METHODS: This was a prospective cohort study at an academic fertility center. Sixty women undergoing their first IVF cycle were recruited. Serum measurements of 22 fatty acids were obtained. We calculated each fatty acid as a percentage of total fatty acids, defined as the index for that individual fatty acid. RESULTS: Omega-3 index had no correlation with IVF outcomes. A negative correlation was found between the trans fatty acid index, elaidic acid (EA), and IVF outcomes, including fertilization rate (r = - 0.261, p = 0.04), blastocyst conversion rate (r = - 0.41, p = 0.001), and number of usable blastocysts and embryos (r = - 0.411, p = 0.001). There was no correlation between EA index and number of oocytes retrieved, embryo grade, or clinical pregnancy. No consistent correlations were observed with the additional fatty acids analyzed. CONCLUSIONS: No correlation was observed between omega-3 index and IVF outcomes. Elevated erythrocyte EA index, the major trans fatty acid commonly consumed in hydrogenated oils, margarine, and fried foods, was negatively correlated with number of usable blastocysts and embryos, blastocyst conversion, and fertilization rate. Our findings suggest preliminary evidence that trans fat may be negatively associated with IVF outcomes. PMID- 28900764 TI - The Associations of Perceived Social Support with Key HIV Risk and Protective Factors Among Young Males Who Have Sex with Males in Bangkok and Chiang Mai, Thailand. AB - This study used respondent-driven sampling to explore the effects of social support on HIV risk and protective factors among young males who have sex with males (YMSM) in Bangkok (N = 273) and Chiang Mai (N = 243), Thailand. It compared different measures of social support, including living situation, the proportion of family and friends to whom the respondent had disclosed their same-sex attraction, and scores on the multi-dimensional scale of perceived social support as predictors of two outcomes of interest-coerced first sex and HIV knowledge. Social support from family played a mediating role in both outcomes among YMSM in Bangkok but not those from Chiang Mai. Though social support from friends was also studied, it was less strongly associated with the outcomes of interest. The findings support interventions designed to leverage social support networks to increase HIV knowledge and decrease coerced first sex among YMSM. At the same time, they demonstrate that there is not a single risk or demographic profile encompassing all YMSM. Successful programs and policies will need to consider the specific attributes and social environment of YMSM in particular locations in order to effectively address HIV risks. PMID- 28900765 TI - Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women. AB - PURPOSE: Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations. METHODS: In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations. RESULTS: Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61-1.84] for all lung cancer, 0.94 (95% CI 0.52 1.69) for NSCLC, and 0.91 (95% CI 0.49-1.68) for adenocarcinoma. Comparing serum 25(OH)D >= 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31 1.84) for all lung cancer, 0.71 (95% CI 0.27-1.86) for NSCLC, and 0.81 (95% CI 0.31-2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D3/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10). CONCLUSIONS: In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk. PMID- 28900766 TI - Diversity and distribution of CYP gene family in Bactrian camel. AB - Cytochrome P450 (CYP) enzymes belong to a superfamily of monooxygenases which are phase I enzymes responsible for the first pass metabolism of about 90% of drugs in animals. However, these enzymes are often polymorphic and metabolism of the same drug in different species or different individuals is influenced by genetic and non-genetic factors. Bactrian camels are capable of survival in harsh living environments, being able to consume diets that are often toxic to other mammals and can tolerate extreme water and food deprivation. The aim of this study was to investigate whether the Bactrian camel's special metabolic pathways and unique detoxification capabilities are attributable to particularities of the CYP gene family. The Bactrian camel's whole genome sequencing data were systemically analyzed and annotated, and then, CYP gene family was searched from the whole protein database and compared with CYP gene families of cattle, horse, chicken, and human. The total of 63 CYP gene copies were found in Bactrian camel's whole genome and were classified into 17 families and 38 subfamilies. Among them, 9 multi-gene families were found, and CYP2, CYP3, and CPY4 have 27, 6, and 7 subfamilies, accounting for 43, 10, and 11% in camel CYP gene, respectively. In comparison with cattle, chicken, horse, and human, the distribution of CYP gene subfamilies in camel is different, with more CYP2J and CYP3A copies in the Bactrian camel, which may contribute to the Bactrian camel's specific biological characteristics and metabolic pathways. Comparing to the cow, horse, chicken, and human CYP genes, the distribution of CYP gene subfamilies is distinct in the Bactrian camel. The higher copy number of CYP2J gene and CYP3A gene in Bactrian camel may be the important factors contributing to the distinct biological characteristics and metabolic pathways of Bactrian camels for adaptation to the harsh environments. PMID- 28900767 TI - Quantitative assessment of muscular stiffness in children with cerebral palsy using acoustic radiation force impulse (ARFI) ultrasound elastography. AB - PURPOSE: To evaluate the feasibility of quantitative analysis of muscle stiffness in the medial gastrocnemius muscle (GCM) by acoustic radiation force impulse (ARFI) ultrasound elastography in children with spastic cerebral palsy (CP). METHODS: Seventeen children with spastic CP and 25 healthy children participated in the study between the years 2016-2017. The medial GCM in the CP group was assessed using the Modified Ashworth Scale (MAS) by a physiatrist. ARFI was used to measure the shear-wave velocities (SWVs) of the medial GCM. The mean SWV value for each MAS score was calculated and used for statistics. RESULTS: The mean SWV values of the medial GCM in the CP and healthy groups were 3.17 +/- 0.81 m/s (mean +/- SD) and 1.45 +/- 0.25 m/s (mean +/- SD), respectively. The SWV of the medial GCM significantly increased in the CP patients when compared with controls (p < 0.001). In addition, the SWV values were correlated with the MAS scores (p < 0.001). The interobserver agreement expressed as the interclass correlation coefficient was 0.65 (95% CI 0.33-0.84, p < 0.001). CONCLUSIONS: ARFI imaging demonstrated a difference in muscle stiffness in the medial GCM between the CP and healthy groups. This method is a feasible imaging modality for the noninvasive assessment of contracting muscles in children with CP. PMID- 28900768 TI - Maternal and Paternal Infertility Disorders and Treatments and Autism Spectrum Disorder: Findings from the Study to Explore Early Development. AB - Previous studies of associations between ASD and conception using assisted reproductive technology (ART) are inconsistent and few studies have examined associations with other infertility treatments or infertility disorders. We examined associations between ASD and maternal/paternal infertility disorders and numerous maternal treatments among 1538 mother-child pairs in the Study to Explore Early Development, a population-based case-control study. ASD was associated with any female infertility diagnosis and several specific diagnoses: blocked tubes, endometriosis, uterine-factor infertility, and polycystic ovarian syndrome. Stratified analyses suggested associations were limited to/much stronger among second or later births. The findings were not explained by sociodemographic factors such as maternal age or education or multiple or preterm birth. ASD was not associated with ART or non-ART infertility treatments. PMID- 28900769 TI - Interface Scopulariopsis gracilis fungal keratitis following Descemet's stripping automated endothelial keratoplasty (DSAEK) with a contaminated graft. AB - PURPOSE: To report for the first time a case of interface Scopulariopsis gracilis fungal keratitis following Descemet's stripping automated endothelial keratoplasty (DSAEK) with a contaminated graft. METHODS: A 57-year-old man with bilateral keratoconus and previous bilateral penetrating keratoplasties (PK) developed graft failure in association with marked corneal ectasia. He underwent a successful DSAEK. Unfortunately, a contaminated graft was transplanted and the following morning we were contacted by the eye bank to inform us a slow-growing fungus had been detected in the culture plates inoculated with dextran solution used to store the issued corneoscleral button. Immediate patient review revealed four infiltrates in the interface between the donor and the recipient tissue. The patient returned to theatre for the removal of the infected graft and was successfully treated with topical amphotericin 0.15%, voriconazole 1% and oral voriconazole and later oral itraconazole. Two intracameral injections of 5 ug in 0.1 ml of amphotericin B were also performed. RESULTS: A reference laboratory cultured and identified the fungus as Scopulariopsis gracilis species. The patient responded to treatment and eventually achieved a spectacle-corrected logMAR visual acuity of 0.3 following a delayed PK. CONCLUSION: Scopulariopsis gracilis fungal keratitis is a rare infection, and the species can be difficult to eradicate. This is the first case report of an infection secondary to a contaminated graft with the species, and we report its successful treatment with an excellent visual outcome. PMID- 28900770 TI - How regularities of mortality statistics explain why we age despite having potentially ageless somatic stem cells. AB - Researchers working in the area of ageing have found numerous manifestations of this process at the molecular biological level, including DNA and protein damage, accumulation of metabolic by-products, lipids peroxidation, macromolecular cross linking, non-enzymatic glycosylation, anti-oxidant/pro-oxidant misbalance, rising of pro-inflammatory cytokines, etc. This results in an increase in the proportion of cells in growth arrest, reduction of the rate of information processing, metabolic rate decrease, and decrease in rates of other processes characterizing dynamic aspects of the organism's interaction with its environment. Such staggering multilevel diversity in manifestation of senescence precludes (without methodology of systems biology) development of a correct understanding of its primary causes and does not allow for developing approaches capable of postponing ageing or reducing organisms' ageing rate to attain health preservation. Moreover, it turns out that damage production and damage elimination processes, the misbalance of which results in the ageing process, can to a large extent be regulated by external signals. The purpose of this report is to provide evidence supporting this view and its compatibility with the regularities of mortality statistics, because the main idea is very simple. Even potentially a non senescent but certainly not immortal body must start to age under inadequate conditions (like a non-melting piece of ice taken out from the deepfreeze inevitably start to melt at the temperatures above zero Celsius). This conclusion is totally consistent with existing patterns of mortality and with agelessness potential of somatic stem cells. Therefore, there is no need to build up and explore too complicated, computational and sophisticated systems models of intrinsic ageing to understand the origin of this mainly extrinsic root cause of natural ageing, which is controlled by environmental signals. In our case, a simple phenomenological black-box approach with Input-Output analysis is ample. Here Input refers to the environmentally dependent initial force of mortality, whereas Output is a rate of age-related increase of mortality force. PMID- 28900771 TI - Health Concerns and Health Service Utilization in a Population Cohort of Young Adults with Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) have many health needs that place demands on the health service sector. This study used administrative data to compare health profiles in young adults 18-24 years of age with ASD to peers with and without other developmental disability. Young adults with ASD were more likely to have almost all the examined clinical health issues and health service use indicators compared to peers without developmental disability. They were more likely to have at least one psychiatric diagnosis, and visit the family physician, pediatrician, psychiatrist, and emergency department for psychiatric reasons, compared to peers with other developmental disability. Planning for the mental health care of transition age adults with ASD is an important priority for health policy. PMID- 28900773 TI - CT evaluation of musculoskeletal trauma: initial experience with cinematic rendering. AB - Multi-detector computed tomography (MDCT) scanners that can quickly acquire volumetric datasets composed of isotropic voxels laid the groundwork for the widespread clinical implementation of 3D MDCT reconstructions, with maximum intensity projection (MIP) and volumetric rendering (VR) becoming important parts of the imaging evaluation of patients with a wide variety of pathologic conditions. Recently, a new 3D reconstruction technique known as cinematic rendering (CR) has become available and is now U.S. FDA approved. CR bears fundamental similarities to VR, but utilizes a more complex lighting model to bring about photorealistic reconstructions. While a tremendous amount of work remains to be done in order to understand the advantages and disadvantages of CR in comparison to traditional 3D reconstruction methods, the images themselves are strikingly detailed and can be interactively manipulated to highlight a variety of different tissue types and anatomic structures. In the following pictorial essay, we provide a number of clinical examples of the use of CR in musculoskeletal imaging, including the evaluation of complex fractures, the delineation of the relationship of fractures to adjacent vasculature and overlying soft tissues, and the visualization of vascular and soft tissue injuries. PMID- 28900772 TI - Clathrin-dependent internalization, signaling, and metabolic processing of guanylyl cyclase/natriuretic peptide receptor-A. AB - Cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP), have pivotal roles in renal hemodynamics, neuroendocrine signaling, blood pressure regulation, and cardiovascular homeostasis. Binding of ANP and BNP to the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) induces rapid internalization and trafficking of the receptor via endolysosomal compartments, with concurrent generation of cGMP. However, the mechanisms of the endocytotic processes of NPRA are not well understood. The present study, using 125I-ANP binding assay and confocal microscopy, examined the function of dynamin in the internalization of NPRA in stably transfected human embryonic kidney-293 (HEK 293) cells. Treatment of recombinant HEK-293 cells with ANP time-dependently accelerated the internalization of receptor from the cell surface to the cell interior. However, the internalization of ligand-receptor complexes of NPRA was drastically decreased by the specific inhibitors of clathrin- and dynamin dependent receptor internalization, almost 85% by monodansylcadaverine, 80% by chlorpromazine, and 90% by mutant dynamin, which are specific blockers of endocytic vesicle formation. Visualizing the internalization of NPRA and enhanced GFP-tagged NPRA in HEK-293 cells by confocal microscopy demonstrated the formation of endocytic vesicles after 5 min of ANP treatment; this effect was blocked by the inhibitors of clathrin and by mutant dynamin construct. Our results suggest that NPRA undergoes internalization via clathrin-mediated endocytosis as part of its normal itinerary, including trafficking, signaling, and metabolic degradation. PMID- 28900774 TI - Readmission rate after ultrafiltration in acute decompensated heart failure: a systematic review and meta-analysis. AB - Significance of ultrafiltration in acute decompensated heart failure remains unclear. We performed meta-analysis to determine its role in reducing readmissions after acute decompensated heart failure. MEDLINE was searched using PUBMED from inception to March 22, 2017 for prospective randomized control trials comparing ultrafiltration to diuretics in acute decompensated heart failure. Five hundred ninety studies were found; nine studies with 820 patients were included. Studies with renal replacement therapy bar ultrafiltration, chronic decompensated heart failure, and non-English language were excluded. RevMan Version 5.3 was used for analysis. The primary outcomes analyzed were cumulative and 90 days readmissions secondary to heart failure and all-cause readmissions. Baseline characteristics were similar. One hundred eighty-eight patients were readmitted with heart failure, 77 vs 111 favoring ultrafiltration; risk ratio (RR) = 0.71 (95% confidence interval (CI), 0.49-1.02, p = 0.07, I 2 = 47%). Ninety days readmissions were 43 vs 67 favoring ultrafiltration; RR = 0.65 (95%CI, 0.47-0.90, p = 0.01, I 2 = 0%). Ultrafiltration showed significantly higher fluid removal and weight loss. Hypotension was common in ultrafiltration (24 vs 13, OR = 2.06, 95%CI = 0.98-4.32, p = 0.06, I 2 = 0%). Ultrafiltration showed reduced 90 days heart failure readmissions and trend towards reduced cumulative hospital readmissions. Renal and cardiovascular outcomes and hospital stay were similar. PMID- 28900775 TI - Specialization and production cost efficiency: evidence from ambulatory surgery centers. AB - In the U.S. health care sector, the economic logic of specialization as an organizing principle has come under active debate in recent years. An understudied case is that of ambulatory surgery centers (ASCs), which recently have become the dominant provider of specific surgical procedures. While the majority of ASCs focus on a single specialty, a growing number are diversifying to offer a wide range of surgical services. We take a multiple output cost function approach to an empirical investigation that compares production economies in single specialty ASCs with those in multispecialty ASCs. We applied generalized estimating equation techniques to a sample of Pennsylvania ASCs for the period 2004-2014, including 73 ASCs that specialized in gastrointestinal procedures and 60 ASCs that performed gastrointestinal as well as other specialty procedures. Results indicated that both types of ASC had small room for expansion. In simulation analysis, production of GI services in specialized ASCs had a cost advantage over joint production of GI with other specialty procedures. Our results provide support for the focused factory model of production in the ASC sector. PMID- 28900776 TI - Haloarchaea: worth exploring for their biotechnological potential. AB - Halophilic archaea are unique microorganisms adapted to survive under high salt conditions and biomolecules produced by them may possess unusual properties. Haloarchaeal metabolites are stable at high salt and temperature conditions that are useful for industrial applications. Proteins and enzymes of this group of archaea are functional under salt concentrations at which bacterial counterparts fail to be active. Such properties makes haloarchaeal enzymes suitable for salt based applications and their use under dehydrating conditions. For example, bacteriorhodopsin or the purple membrane protein present in halophilic archaea has the most recognizable applications in photoelectric devices, artificial retinas, holograms etc. Haloarchaea are also useful for bioremediation of polluted hypersaline areas. Polyhydroxyalkanoates and exopolysccharides produced by these microorganisms are biodegradable and have the potential to replace commercial non-degradable plastics and polymers. Moreover, halophilic archaea have excellent potential to be used as drug delivery systems and for nanobiotechnology by virtue of their gas vesicles and S-layer glycoproteins. Despite of possible applications of halophilic archaea, laboratory-to-industrial transition of these potential candidates is yet to be established. PMID- 28900777 TI - An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: a review. AB - Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome. Clinical features include hamartomatous polyps, mucocutaneous pigmentation and an increased predisposition towards developing malignancy. Variants in STK11, a tumour suppressor gene, located on Chromosome 19, predispose to PJS. Peutz-Jeghers Syndrome is associated with increased rates of malignancy, particularly gastrointestinal. However, PJS is also associated with increased gynaecological, testicular and thyroid papillary malignancy. Truncating variants in STK11 are thought to predispose to a more severe phenotype. Phenotype severity is based on earlier onset of gastrointestinal pathology arising from the polyps, such as intussusception or earlier onset malignancy. Missense variants are generally considered less severe than truncating variants. There remain a large number of variants of undetermined significance. Studies have attempted to correlate the location of variants with impact on protein structure and overall severity of the PJS phenotype. The results from these cohort studies have consistently found a non-random distribution of variants. Nevertheless, a consensus on phenotype severity based on variant location is yet to be established. A centralised database that collates all known variants would facilitate the interpretation of these variants, best under the governance of an international disease-specific organisation (InSiGHT). In particular, it could help explore the significance of variants based on their type or location. Understanding the genotype-phenotype link between STK11 variants and PJS could allow more personalised care for PJS patients and their families via appropriate risk stratification and personalised and targeted cancer screening. PMID- 28900778 TI - Early Gesture and Vocabulary Development in Infant Siblings of Children with Autism Spectrum Disorder. AB - This study examined longitudinal growth in gestures and words in infants at heightened (HR) versus low risk (LR) for ASD. The MacArthur-Bates Communicative Development Inventory was administered monthly from 8 to 14 months and at 18 and 24 months to caregivers of 14 HR infants diagnosed with ASD (HR-ASD), 27 HR infants with language delay (HR-LD), 51 HR infants with no diagnosis (HR-ND), and 28 LR infants. Few differences were obtained between LR and HR-ND infants, but HR LD and HR-ASD groups differed in initial skill levels and growth patterns. While HR-LD infants grew at rates comparable to LR and HR-ND infants, growth was attenuated in the HR-ASD group, with trajectories progressively diverging from all other groups. PMID- 28900779 TI - Mental Health Disparities, Treatment Engagement, and Attrition Among Racial/Ethnic Minorities with Severe Mental Illness: A Review. AB - Mounting evidence indicates that there are mental health disparities in the United States that disadvantage racial/ethnic minorities in medical and mental health settings. Less is known, however, about how these findings apply to a particularly vulnerable population, individuals with severe mental illness (SMI). The aim of this paper is to (1) provide a critical review of the literature on racial/ethnic disparities in mental health care among individuals with SMI; (2) identify factors which may contribute to the observed disparities; and (3) generate recommendations on how best to address these disparities. Specifically, this article provides an in-depth review of sociocultural factors that may contribute to differences in treatment engagement and rates of attrition from treatment among racial/ethnic minorities with SMI who present at medical and mental health facilities. This review is followed by a discussion of specific strategies that may promote engagement in mental health services and therefore reduce racial/ethnic disparities in SMI. PMID- 28900780 TI - Her2 positive subtype and breast cancer brain metastasis: any effect of anti-Her2 targeted therapy? PMID- 28900781 TI - Submillisievert imaging protocol using full reconstruction and advanced patient motion correction in 320-row area detector coronary CT angiography. AB - Radiation exposure remains a concern in the use of coronary CT angiography (CCTA). Full reconstruction (Full) and reconstruction using advanced patient motion correction (APMC) could obtain a lower radiation dose using low tube current scanning in a 320-row Area Detector CT (320-ADCT). The radiation dose for an imaging protocol using Full and APMC in daily practice was estimated. A total of 209 patients who underwent CCTA in 1 rotation scanning with 100 kv and adaptive iterative dose reduction 3D in 320-ADCT were enrolled. Imaging protocols were classified into 3 groups based on estimated slow filling time: (1) slow filling time >= 275 msec, Full with 30% of usual tube current (N = 43)(Full30%mA) (2) 206.3 msec <= slow filling time < 275 msec, APMC with 50% of usual tube current (N = 48)(APMC50%mA); and (3) 137.5 msec <= slow filling time < 206.3 msec, Half reconstruction with usual tube current (N = 118)(Half100%mA). Radiation dose was estimated by the effective dose. The diagnostic accuracy of CCTA was compared with that of invasive coronary angiography in 28 patients. The effective doses of Full30%mA, APMC50%mA, and Half100%mA were 0.77 +/- 0.31, 1.30 +/- 0.85, and 1.98 +/- 0.68, respectively. Of 28 patients, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value in vessel-based analyses were: Full30%mA, 66.7, 82.4, 80.0, 40.0, and 93.3%; APMC50%mA, 100.0, 80.0, 83.3, 50.05, and 100.0%; and Half100%mA, 90.9, 83.0, 86.3, 78.95, and 92.9%, respectively. An imaging protocol using Full30%mA and APMC50%mA was one of the methods how radiation dose could be reduced radiation dose maintained diagnostic accuracy compared to imaging using conventional Half100%mA. PMID- 28900783 TI - Effect of mass housing settlement type on the comfortable open areas in terms of noise. AB - The layout of the structures according to the noise source is an important parameter in terms of the level of noise reaching to both open usage areas and the structure surfaces. In this paper, it is aimed to reveal the effect of mass housing settlement type on the size of suitable open usage areas in terms of noise. Comfortable open usage areas in 25 mass housing alternatives are determined for the case of being affected by three different road noises. The reliability of the simulation results is validated by on-site noise level measurements. As a result, it is seen that better results are obtained in linear, L, C, and U type alternatives than point-type blocks. Especially in alternatives consisting of point-and linear-type blocks, if the noise level is above 75 Leq (dBA), the percentage of comfortable open usage areas is very low. It is determined that the percentage of comfortable open areas increases between 50 and 100% by means of appropriately designed noise barriers. PMID- 28900782 TI - Why are Antagonist Muscles Co-activated in My Simulation? A Musculoskeletal Model for Analysing Human Locomotor Tasks. AB - Existing "off-the-shelf" musculoskeletal models are problematic when simulating movements that involve substantial hip and knee flexion, such as the upstroke of pedalling, because they tend to generate excessive passive fibre force. The goal of this study was to develop a refined musculoskeletal model capable of simulating pedalling and fast running, in addition to walking, which predicts the activation patterns of muscles better than existing models. Specifically, we tested whether the anomalous co-activation of antagonist muscles, commonly observed in simulations, could be resolved if the passive forces generated by the underlying model were diminished. We refined the OpenSimTM model published by Rajagopal et al. (IEEE Trans Biomed Eng 63:1-1, 2016) by increasing the model's range of knee flexion, updating the paths of the knee muscles, and modifying the force-generating properties of eleven muscles. Simulations of pedalling, running and walking based on this model reproduced measured EMG activity better than simulations based on the existing model-even when both models tracked the same subject-specific kinematics. Improvements in the predicted activations were associated with decreases in the net passive moments; for example, the net passive knee moment during the upstroke of pedalling decreased from 36.9 N m (existing model) to 6.3 N m (refined model), resulting in a dramatic decrease in the co-activation of knee flexors. The refined model is available from SimTK.org and is suitable for analysing movements with up to 120 degrees of hip flexion and 140 degrees of knee flexion. PMID- 28900784 TI - Liver involvement in urea cycle disorders: a review of the literature. AB - Urea cycle disorders (UCDs) are inborn errors of metabolism of the nitrogen detoxification pathway and encompass six principal enzymatic deficiencies. The aging of UCD patients leads to a better knowledge of the long-term natural history of the condition and to the reporting of previously unnoticed manifestations. Despite historical evidence of liver involvement in UCDs, little attention has been paid to this organ until recently. Hence, we reviewed the available scientific evidence on acute and chronic liver dysfunction and liver carcinogenesis in UCDs and discuss their pathophysiology. Overall, liver involvement, such as acute liver failure or steatotic-like disease, which may evolve toward cirrhosis, has been reported in all six main UCDs. Excessive glycogen storage is also a prominent histologic feature, and hypoglycemia has been reported in citrin deficiency. Hepatocarcinomas seem frequent in some UCDs, such as in citrin deficiency, and can sometimes occur in non-cirrhotic patients. UCDs may differ in liver involvement according to the enzymatic deficiency. Ornithine transcarbamylase deficiency may be associated more with acute liver failure and argininosuccinic aciduria with chronic liver failure and cirrhosis. Direct toxicity of metabolites, downstream metabolic deficiencies, impaired tricarboxylic acid cycle, oxidative stress, mitochondrial dysfunction, energy deficit, and putative toxicity of therapies combine in various ways to cause the different liver diseases reported. PMID- 28900785 TI - Training to Provide Psychiatric Genetic Counseling: How Does It Impact Recent Graduates' and Current Students' Readiness to Provide Genetic Counseling for Individuals with Psychiatric Illness and Attitudes towards this Population? AB - Mental illness is extremely common and genetic counselors frequently see patients with mental illness. Genetic counselors report discomfort in providing psychiatric genetic counseling (GC), suggesting the need to look critically at training for psychiatric GC. This study aimed to investigate psychiatric GC training and its impact on perceived preparedness to provide psychiatric GC (preparedness). Current students and recent graduates were invited to complete an anonymous survey evaluating psychiatric GC training and outcomes. Bivariate correlations (p<.10) identified variables for inclusion in a logistic regression model to predict preparedness. Data were checked for assumptions underlying logistic regression. The logistic regression model for the 286 respondents [chi2(8)=84.87, p<.001] explained between 37.1% (Cox & Snell R2=.371) and 49.7% (Nagelkerke R2=.497) of the variance in preparedness scores. More frequent psychiatric GC instruction (OR=5.13), more active methods for practicing risk assessment (OR=4.43), and education on providing resources for mental illness (OR=4.99) made uniquely significant contributions to the model (p<.001). Responses to open-ended questions revealed interest in further psychiatric GC training, particularly enabling "hands on" experience. This exploratory study suggests that enriching GC training through more frequent psychiatric GC instruction and more active opportunities to practice psychiatric GC skills will support students in feeling more prepared to provide psychiatric GC after graduation. PMID- 28900786 TI - The pattern of secondary cancers in patients with Kaposi sarcoma in the United States. AB - PURPOSE: In the U.S., Kaposi sarcoma (KS) occurs mostly in HIV-infected patients, who are also at increased risk of developing secondary cancers. The trends in secondary cancer risk are unclear in the HAART era. METHODS: We extracted data from the SEER database on patients diagnosed with KS between 1981 and 2013, stratified into the pre-HAART (1981-1995) and HAART (1996-2013) eras. We compared the risk of secondary cancer in KS patients and the general population, and estimated the absolute risk. RESULTS: We followed 13,535 KS patients for 49,813 person-years, during which 1,041 secondary cancers were diagnosed: 774 in the pre HAART and 267 in the HAART era. In the pre-HAART era, non-Hodgkin's lymphoma (NHL) and anal carcinomas were the most common secondary cancers. The standard incidence ratio of secondary cancers decreased from 3.44 (pre-HAART era) to 1.94 (HAART era) in patients aged <70 years. The absolute excess risk decreased from 178 to 68 cases per 10,000 person-years. The risk of NHL decreased, while the risk of anal carcinoma did not change significantly. The risk of lung cancer was lower in KS patients than in the general population. The absolute risk of non AIDS-defining cancers increased fourfold in the HAART era. CONCLUSIONS: The absolute risk of non-AIDS-defining secondary cancers has increased in KS patients in the HAART era. However, the overall relative risk of secondary cancers has decreased, mainly due to a significant decrease in the risk of NHL. PMID- 28900787 TI - H+ translocation by weak acid uncouplers is independent of H+ electrochemical gradient. AB - According to the common view, weak acid uncouplers increase proton conductance of biological (and phospholipid bilayer) membranes, thus effecting H+ fluxes driven by their electrochemical gradients. Under certain conditions, however, uncouplers can induce unexpected effects opposite to the dissipation of H+ gradients. Results are presented here demonstrating CCCP-induced proton influx into Saccharomyces cerevisiae cytosol driven by the electrochemical potentials of CCCP and its CCCP- anions, independent of electrochemical H+-gradient. Another view of week acid uncouplers' action is proposed that is logically consistent with these observations. PMID- 28900788 TI - Take care of your neighborhood. AB - PURPOSE: Urban women in certain Washington, DC neighborhoods present with advanced breast cancer at high rates despite access to health insurance and health care. METHODS: Through a two-phase intervention, community health workers (CHWs) educated and surveyed individuals regarding healthcare utilization and breast health and cancer awareness. In phase I, CHWs educated and administered a survey to 1092 women, of whom 95.1% had health insurance, in an attempt to explain the high rate of advanced breast cancer despite having health insurance. In phase II, a targeted CHW-administered intervention was designed based on data collected from the phase I survey, and provided to 658 women. Preintervention and postintervention surveys were administered to assess its impact on knowledge and beliefs about breast health and cancer screening. RESULTS: During phase I, respondents most often identified personal factors (28.7%) and fear (27.7%) to explain the high rate of advanced breast cancer despite health insurance status. In phase II, the intervention improved perceptions of the safety and efficacy of mammograms with an absolute 15.4% increase in the respondents who believed that "A mammogram is the safest and most effective test available for finding early breast cancer." Perceived barriers discouraging mammograms were access (17.0%), pain (13.2%), and education (13.1%). CONCLUSIONS: Among an urban population of predominantly insured women with high rates of advanced breast cancer at diagnosis, personal factors and fear were cited as the greatest barriers to breast cancer screening. Educational intervention by CHWs showed a positive impact on respondents' perceptions regarding mammogram safety and efficacy. PMID- 28900789 TI - Gradient reconstitution of membrane proteins for solid-state NMR studies. AB - We here adapted the GRecon method used in electron microscopy studies for membrane protein reconstitution to the needs of solid-state NMR sample preparation. We followed in detail the reconstitution of the ABC transporter BmrA by dialysis as a reference, and established optimal reconstitution conditions using the combined sucrose/cyclodextrin/lipid gradient characterizing GRecon. We established conditions under which quantitative reconstitution of active protein at low lipid-to-protein ratios can be obtained, and also how to upscale these conditions in order to produce adequate amounts for NMR. NMR spectra recorded on a sample produced by GRecon showed a highly similar fingerprint as those recorded previously on samples reconstituted by dialysis. GRecon sample preparation presents a gain in time of nearly an order of magnitude for reconstitution, and shall represent a valuable alternative in solid-state NMR membrane protein sample preparation. PMID- 28900790 TI - Medical Images are Safe - an Enhanced Chaotic Scrambling Approach. AB - The patient data confidentiality is one of the vital security aspects in e-Health and m-Health services. In particular, providing confidentiality to the patient's medical image is essential and the protection approaches have to be explored in depth due to the rapid progress in the technologies of teleradiology and PACS. In this study, the pseudo random number generators (PRNGs), namely, the linear congruential generator (LCG) and XOR shift generator (XSG) are improved and combined with improved logistic 2D coupled chaotic map to provide enhanced chaos based encryption. The proposed scheme encrypts the Digital Imaging and Communication in Medicine (DICOM) images to protect the patient confidentiality during the storage and transfer in radiological information system (RIS). The cipher image was measured with various security analyses and tested with different test suites to prove its randomness. PMID- 28900792 TI - Relative binding affinity prediction of farnesoid X receptor in the D3R Grand Challenge 2 using FEP. AB - Physics-based free energy simulations have increasingly become an important tool for predicting binding affinity and the recent introduction of automated protocols has also paved the way towards a more widespread use in the pharmaceutical industry. The D3R 2016 Grand Challenge 2 provided an opportunity to blindly test the commercial free energy calculation protocol FEP+ and assess its performance relative to other affinity prediction methods. The present D3R free energy prediction challenge was built around two experimental data sets involving inhibitors of farnesoid X receptor (FXR) which is a promising anticancer drug target. The FXR binding site is predominantly hydrophobic with few conserved interaction motifs and strong induced fit effects making it a challenging target for molecular modeling and drug design. For both data sets, we achieved reasonable prediction accuracy (RMSD ~ 1.4 kcal/mol, rank 3-4 according to RMSD out of 20 submissions) comparable to that of state-of-the-art methods in the field. Our D3R results boosted our confidence in the method and strengthen our desire to expand its applications in future in-house drug design projects. PMID- 28900791 TI - Telomere length and antioxidant defense associate with parasite-induced retarded growth in wild brown trout. AB - Early growth conditions can have profound impacts on individuals' development, growth and physiology, with subsequent long-term consequences for individuals' fitness and life expectancy. Telomere length (TL) has been suggested to indicate both individual fitness and life expectancy in wide range of species, as the telomere attrition rate at early age can be accelerated due to exposure to various stressors, including parasites and inflammatory diseases, which increase production of reactive oxygen species (ROS) and influence antioxidant (AO) levels. We investigated impacts of Tetracapsuloides bryosalmonae infection, a causative agent of proliferative kidney disease (PKD), on AO status and TL in a natural population of juvenile brown trout (Salmo trutta). The fish with higher parasite load showed more severe kidney hyperplasia, anemia and smaller body size compared to less parasitized fish. Furthermore, fish with severe PKD symptoms had lower SOD-, CAT- and GST activity than fish with milder kidney hyperplasia. However, parasite load was not directly correlated either with AOs or with TL. Smaller fish showed shorter TLs, potentially reflecting lower individual quality. The fish, which were less sensitive to parasite-induced impaired growth, quantified as parasite load-adjusted fork length, showed also longer TLs, lower GR- and GST activity and less GSHtot compared to more sensitive fish. These results provide novel knowledge about the impacts of the PKD in brown trout at the molecular level and support the idea that TL may reflect individual quality and ability to cope with parasitic infections. PMID- 28900793 TI - Robotic Assisted Distal Gastrectomy for Gastric Cancer in a Patient with Situs Inversus Totalis: with Video. AB - Situs inversus totalis (SIT) is a relatively rare condition where the abdominal and/or thoracic organ is positioned as a "mirror image" of the normal position. We are presenting a video of robotic distal gastrectomy performed in a 52-year old female known to have SIT. Preoperative investigations revealed the patient has an early gastric cancer at the antrum. Ports were placed as mirror image to our usual port placement and upon exploration, the liver is visualized on the left side of the abdomen and the spleen is on the right. Lymph node dissection was performed in a similar approach to conventional robotic distal gastrectomy. After gastric resection, gastroduodenostomy was performed intracorporeally using a linear stapler. The operation took 195 min without intraoperative complications and minimal blood loss of 30 ml. The patient was discharged on postoperative day 5, uneventfully. The final pathology confirmed moderately differentiated adenocarcinoma confined to the mucosa without metastasis in 74 lymph nodes. Robotic distal gastrectomy can be safely performed in patients with situs inversus totalis and has similar surgical outcomes as usual robotic gastrectomy. Robotic technique can help surgeon's ambidexterity in performing such complex procedures. PMID- 28900794 TI - Diagnosis of parental balanced reciprocal translocations by trophectoderm biopsy and comprehensive chromosomal screening. AB - PURPOSE: This study investigates a case series of eight couples who underwent trophectoderm (TE) biopsy and comprehensive chromosomal screening (CCS) for routine aneuploidy screening and were found to have CCS results concerning for previously undetected parental balanced reciprocal translocations. METHODS: In each case, controlled ovarian hyperstimulation and in vitro fertilization (IVF) yielded multiple blastocysts that each underwent CCS with high-density oligonucleotide microarray comparative genomic hybridization (aCGH). RESULTS: Parental translocations were suspected based on the finding of identical break point mutations in multiple embryos from each couple. Confirmation of these suspected translocations within blastocysts was performed with next-generation sequencing (NGS). Subsequent parental karyotypic evaluation resulted in a diagnosis of parental balanced reciprocal translocation in each case. CONCLUSIONS: We demonstrated that high-resolution aCGH and NGS on TE biopsies can accurately detect parental reciprocal translocations when previously unrecognized. PMID- 28900795 TI - Haptoglobin levels, but not Hp1-Hp2 polymorphism, are associated with polycystic ovary syndrome. AB - PURPOSE: Proteomic studies suggest an association between haptoglobin (Hp) and polycystic ovary syndrome (PCOS). Hp is a classic inflammatory marker and binds to the intravascular hemoglobin, avoiding the oxidative damages that can be caused by free hemoglobin. Inflammation and oxidative stress are important in the pathogenesis of the PCOS, one of the most frequent metabolic diseases in women. METHODS: To validate these proteomic studies, we developed a controlled cross sectional study that aimed to evaluate the Hp levels and allelic and genotypic frequencies of Hp1-Hp2 polymorphism in Brazilian women with PCOS. We also investigated the correlation between Hp levels and several important parameters in PCOS as follows: body mass index (BMI), waist circumference (WC), fasting glucose, post-prandial glucose, homeostatic model assessment (HOMA), lipid accumulation product (LAP), C-reactive protein (CRP), and metabolization test of tetrazolium salts (MTTs-serum antioxidant capacity). RESULTS: Plasma Hp levels were higher in the PCOS group than in controls [8.20 (4.04) g/L; 7.98 (3.31) g/L; p = 0.018]. No significant difference was observed in the frequency of Hp1-Hp2 genotypes under additive, recessive, or dominant model of inheritance between the PCOS and the control groups. Plasma Hp levels did not differ according to the genotype. However, plasma Hp showed a negative correlation with MTT (r = - 0.383; p = 0.028), as well as a positive correlation with CRP (r = 0.361; p = 0.014) in the PCOS group. CONCLUSION: Hp1-Hp2 polymorphism is not associated with PCOS but plasma Hp could be a potential biomarker for PCOS and its complications. PMID- 28900796 TI - Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B. AB - At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecular dynamics results that accounts for the deleterious effect of replacing alanine 399 with valine. The proposed binding site, at the interface between domains I and III, is eminently hydrophobic and exists only in the GTP-bound conformation. Drug binding at this site is expected to disrupt neither loading of aa-tRNAs nor GTP hydrolysis but would give rise to stabilization of this particular conformational state, in consonance with reported experimental findings. The experimental solution of the three dimensional structure of mammalian eEF1A1 has proved elusive so far and the highly homologous eEF1A2 from rabbit muscle has been crystallized and solved only as a homodimer in a GDP-bound conformation. Interestingly, in this dimeric structure the large interdomain cavity where the drugs studied are proposed to bind is occupied by a mostly hydrophobic alpha-helix from domain I of the same monomer. Since binding of this alpha-helix and any of these drugs to domain III of eEF1A(1/2) is, therefore, mutually exclusive and involves two distinct protein conformations, one intriguing possibility that emerges from our study is that the potent antiproliferative effect of these natural products may arise not only from inhibition of protein synthesis, which is the current dogma, but also from interference with some other non-canonical functions. From this standpoint, this type of drugs could be considered antagonists of eEF1A1/2 oligomerization, a hypothesis that opens up novel areas of research. PMID- 28900797 TI - Improvement of Chia Seeds with Antioxidant Activity, GABA, Essential Amino Acids, and Dietary Fiber by Controlled Germination Bioprocess. AB - Chia (Salvia hispanica L.) plant is native from southern Mexico and northern Guatemala. Their seeds are a rich source of bioactive compounds which protect consumers against chronic diseases. Germination improves functionality of the seeds due to the increase in the bioactive compounds and associated antioxidant activity. The purpose of this study was to obtain functional flour from germinated chia seeds under optimized conditions with increased antioxidant activity, phenolic compounds, GABA, essential amino acids, and dietary fiber with respect to un-germinated chia seeds. The effect of germination temperature and time (GT = 20-35 degrees C, Gt = 10-300 h) on protein, lipid, and total phenolic contents (PC, LC, TPC, respectively), and antioxidant activity (AoxA) was analyzed by response surface methodology as optimization tool. Chia seeds were germinated inside plastic trays with absorbent paper moisturized with 50 mL of 100 ppm sodium hypochlorite dissolution. The sprouts were dried (50 degrees C/8 h) and ground to obtain germinated chia flours (GCF). The prediction models developed for PC, LC, TPC, and AoxA showed high coefficients of determination, demonstrating their adequacy to explain the variations in experimental data. The highest values of PC, LC, TPC, and AoxA were obtained at two different optimal conditions (GT = 21 degrees C/Gt = 157 h; GT = 33 degrees C/Gt = 126 h). Optimized germinated chia flours (OGCF) had higher PC, TPC, AoxA, GABA, essential amino acids, calculated protein efficiency ratio (C-PER), and total dietary fiber (TDF) than un-germinated chia seed flour. The OGCF could be utilized as a natural source of proteins, dietary fiber, GABA, and antioxidants in the development of new functional beverages and foods. PMID- 28900798 TI - Phenotypic plasticity in gene expression and physiological response in red drum Sciaenops ocellatus exposed to a long-term freshwater environment. AB - Red drum (Sciaenops ocellatus) is a euryhaline fish commonly found in the Gulf of Mexico and along the Atlantic coast of North America. Because of high commercial demand and its euryhaline characteristics, aquaculture of this species has diversified from marine to low-salinity aquaculture systems. In recent years, interest in the feasibility of producing red drum in inland freshwater systems has grown and this prompted us to investigate its osmoregulatory capacity after rearing for 8 months in a freshwater aquaculture system. We compared the activities of several genes and enzymes involved in the osmoregulatory process in freshwater-acclimatized (FW) and seawater (SW) red drum. The gene expression profiles were variable: the expression of genes encoding Na+/K+-ATPase (NKA) and the cystic fibrosis transmembrane regulator (CFTR) was slightly higher in SW than FW fish, while phosphoenolpyruvate carboxykinase (PEPCK) and the glucocorticoid receptor messenger RNA (mRNA) levels were higher in FW red drum. The total plasma K concentration was 60.3% lower, and gill NKA activity was 63.5% lower in FW than in SW fish. PEPCK activity was twofold higher in FW than in SW red drum. Similarly, liver glycogen was 60% higher in FW fish. In summary, both gene expression and the enzyme activity data support the phenotypic plasticity of red drum and suggest that the limited capacity for ion homeostasis observed, in particular the low plasma K concentration, was due to the composition of freshwater and does not necessarily reflect a physiological inability to osmoregulate. PMID- 28900799 TI - Peroxynitrite induces apoptosis of mouse cochlear hair cells via a Caspase independent pathway in vitro. AB - Peroxynitrite (ONOO-) is a potent and versatile oxidant implicated in a number of pathophysiological processes. The present study was designed to investigate the effect of ONOO- on the cultured cochlear hair cells (HCs) of C57BL/6 mice in vitro as well as the possible mechanism underlying the action of such an oxidative stress. The in vitro primary cultured cochlear HCs were subjected to different concentrations of ONOO-, then, the cell survival and morphological changes were examined by immunofluorescence and transmission electron microscopy (TEM), the apoptosis was determined by Terminal deoxynucleotidyl transferase dUNT nick end labeling (TUNEL) assay, the mRNA expressions of Caspase-3, Caspase-8, Caspase-9, Apaf1, Bcl-2, and Bax were analyzed by RT-PCR, and the protein expressions of Caspase-3 and AIF were assessed by immunofluorescence. This work demonstrated that direct exposure of primary cultured cochlear HCs to ONOO- could result in a base-to-apex gradient injury of HCs in a concentration-dependent manner. Furthermore, ONOO- led to much more losses of outer hair cells than inner hair cells mainly through the induction of apoptosis of HCs as evidenced by TEM and TUNEL assays. The mRNA expressions of Caspase-8, Caspase-9, Apaf1, and Bax were increased and, meanwhile, the mRNA expression of Bcl-2 was decreased in response to ONOO- treatment. Of interesting, the expression of Caspase-3 had no significant change, whereas, the expression alteration of AIF was observed. These results suggested that ONOO- can effectively damage the survival of cochlear HCs via triggering the apoptotic pathway. The findings from this work suggest that ONOO--induced apoptosis is mediated, at least in part, via a Caspase-independent pathway in cochlear HCs. PMID- 28900801 TI - Time for action: key considerations for implementing social accountability in the education of health professionals. AB - Within health professional education around the world, there exists a growing awareness of the professional duty to be socially responsible, being attentive to the needs of all members of communities, regions, and nations, especially those who disproportionately suffer from the adverse influence of social determinants. However, much work still remains to progress beyond such good intentions. Moving from contemplation to action means embracing social accountability as a key guiding principle for change. Social accountability means that health institutions attend to improving the performance of individual practitioners and health systems by directing educational and practice interventions to promote the health of all the public and assessing the systemic effects of these interventions. In this Reflection, the authors (1) review the reasons why health professional schools and their governing bodies should codify, in both curricular and accreditation standards, norms of excellence in social accountability, (2) present four considerations crucial to successfully implementing this codification, and (3) discuss the challenges such changes might entail. The authors conclude by noting that in adopting socially accountable criteria, schools will need to expand their philosophical scope to recognize social accountability as a vitally important part of their institutional professional identity. PMID- 28900800 TI - Resting-State Neurophysiological Activity Patterns in Young People with ASD, ADHD, and ASD + ADHD. AB - Altered power of resting-state neurophysiological activity has been associated with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which commonly co-occur. We compared resting-state neurophysiological power in children with ASD, ADHD, co-occurring ASD + ADHD, and typically developing controls. Children with ASD (ASD/ASD + ADHD) showed reduced theta and alpha power compared to children without ASD (controls/ADHD). Children with ADHD (ADHD/ASD + ADHD) displayed decreased delta power compared to children without ADHD (ASD/controls). Children with ASD + ADHD largely presented as an additive co occurrence with deficits of both disorders, although reduced theta compared to ADHD-only and reduced delta compared to controls suggested some unique markers. Identifying specific neurophysiological profiles in ASD and ADHD may assist in characterising more homogeneous subgroups to inform treatment approaches and aetiological investigations. PMID- 28900802 TI - Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta mediated pregnancy complications. AB - PURPOSE: The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. METHODS: Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). RESULTS: Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p < 0.001). Post hoc analyses demonstrated an association for IUGR and PB individually. A strong link between previous miscarriages and M2 carrier status was identified which may explain the predisposition to placental pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners. CONCLUSION: These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background. PMID- 28900803 TI - Making Decisions About Medication Use During Pregnancy: Implications for Communication Strategies. AB - Objective To explore women's perceptions of the risks and benefits associated with medication use during pregnancy and to better understand how women make decisions related to medication use in pregnancy. Methods We conducted online focus groups with 48 women who used medication during pregnancy or while planning a pregnancy, and 12 in-depth follow-up interviews with a subset of these women. Results We found that women were aware of general risks associated with medication use but were often unable to articulate specific negative outcomes. Women were concerned most about medications' impact on fetal development but were also concerned about how either continuing or discontinuing medication during pregnancy could affect their own health. Women indicated that if the risk of a given medication were unknown, they would not take that medication during pregnancy. Conclusion This formative research found that women face difficult decisions about medication use during pregnancy and need specific information to help them make decisions. Enhanced communication between patients and their providers regarding medication use would help address this need. We suggest that public health practitioners develop messages to (1) encourage, remind, and prompt women to proactively talk with their healthcare providers about the risks of taking, not taking, stopping, or altering the dosage of a medication while trying to become pregnant and/or while pregnant; and (2) encourage all women of childbearing age to ask their healthcare providers about medication use. PMID- 28900804 TI - A Nonparametric Multidimensional Latent Class IRT Model in a Bayesian Framework. AB - We propose a nonparametric item response theory model for dichotomously-scored items in a Bayesian framework. The model is based on a latent class (LC) formulation, and it is multidimensional, with dimensions corresponding to a partition of the items in homogenous groups that are specified on the basis of inequality constraints among the conditional success probabilities given the latent class. Moreover, an innovative system of prior distributions is proposed following the encompassing approach, in which the largest model is the unconstrained LC model. A reversible-jump type algorithm is described for sampling from the joint posterior distribution of the model parameters of the encompassing model. By suitably post-processing its output, we then make inference on the number of dimensions (i.e., number of groups of items measuring the same latent trait) and we cluster items according to the dimensions when unidimensionality is violated. The approach is illustrated by two examples on simulated data and two applications based on educational and quality-of-life data. PMID- 28900806 TI - Adenosine administration in supraventricular tachycardia. PMID- 28900805 TI - MGMT and MSH6 immunoexpression for functioning pituitary macroadenomas. AB - PURPOSE: Knowledge of biological behavior is crucial for clinical management of functioning pituitary macroadenomas. For recurrent cases unresponsive to standard treatment, temozolomide (TMZ) has been used as a therapeutic alternative. MGMT (O6-methyl-guanine-DNA methyltransferase) and MSH6 (mutS homolog 6) immunoexpression have been linked to the response to TMZ treatment and MGMT immunoexpression has been additionally linked to early recurrence of non functioning pituitary adenomas. The aim of this study was to assess the prognostic value of MGMT and MSH6 immunoexpression for aggressive functioning pituitary adenomas. METHODS: The study cohort comprised a single center series of 76 patients who underwent an operation for functioning pituitary macroadenoma. We retrospectively compared 38 patients with postoperative persistent or recurrent disease with another set of 38 patients who were in endocrine remission. RESULTS: Low-to-moderate MGMT immunoexpression (<50%) was significantly more frequent in the group with persistent/recurrent disease than in cases of endocrine remission (66 vs. 21%, p < 0.001). Furthermore, adenomas with low-to-moderate MGMT immunoexpression were significantly more often recurrent (76 vs. 30%, p < 0.001) and invasive (64 vs. 28%, p = 0.002). CONCLUSION: In our series, low-to-moderate MGMT immunoexpression was the only marker that significantly correlated with surgical invasiveness and recurrence in functioning pituitary macroadenomas. Therefore, in the future, MGMT status may be considered an additional marker for understanding the biological behavior of pituitary adenomas. PMID- 28900807 TI - Ecotoxicological impact assessment of the brine discharges from a desalination plant in the marine waters of the Algerian west coast, using a multibiomarker approach in a limpet, Patella rustica. AB - The aim of our study is to evaluate the impact of Bousfer desalination plant brine discharges on the Algerian west coast, on a natural population of the marine gastropod mollusc Patella rustica. The effects of a chronic exposure to such discharges are complex to understand due to the combined effects of environmental physico-chemical parameters (e.g., high salinity) and different pollutants that can modulate the physiological responses of this species to stress. In this context, we assessed the biological effects in a marine species P. rustica, by a multibiomarker approach that provided information on the health status of organisms in response to such an environmental stress. We measured biomarkers in the whole soft tissues of limpets as indicators of neurotoxicity (AChE activity), oxidative stress (CAT, SOD, GR, and GPx activities), biotransformation (GST), oxidative damage (LPO through TBARS levels), and genotoxicity (CSP 3-like activity). In parallel, hydrological parameters were measured in the Bay of Oran, at four selected sites: site H considered as a "hotspot," located at Bousfer desalination plant; two other sites E and W, at the east and the west of H respectively; finally, site R "reference" located in Madragh, which is considered as a remote clean site. Our analyses revealed that the activities of antioxidant defense enzymes reached the highest levels in P. rustica collected from site H. The activation of antioxidant defense system in these organisms translated the alteration of their status health, reflecting a level of environmental disruption generated by the desalination plant brine discharges and the high salinity in this area. We also observed that the tissues of limpets collected from site H as well as the two other sites, E and W, had undergone molecular damage, confirmed by the high levels of CSP 3-like activity. This damage resulted from chronic exposure to environmental conditions, potentially genotoxic, due to the desalination plant discharges. The present results indicate the adverse impact of brine effluents from desalination plants on marine fauna and suggest the need for a more consistent approach to environmental management of brine discharges. PMID- 28900808 TI - Aerial application of copper for dothistroma control in New Zealand's planted forests-effect on stream environments. AB - Limited information is available on the risk to aquatic environments from the aerial application of copper fungicides to treat dothistroma needle blight in managed forests. Cuprous oxide was aerially applied to three catchments of Pinus radiata of varying age classes in the central North Island of New Zealand. Copper was monitored in stream water and sediments prior to and for 1 month after application. Copper deposits collected from tracer plates deployed above the water surface along the stream channels within the treated areas at each site ranged from 13 to 406 ppm. Lowest concentrations occurred above small stream channels with dense overhead riparian vegetation. Peak copper concentrations in stream water across the three sites ranged from 28 to 60 MUg L-1 and were below the analytical detection limit within hours. Copper concentrations were higher and persisted for longer in stream sediment (range 1.7-6.1 mg kg-1, sampled at two sites only). Copper concentrations in sediments were below environmental guidelines. Copper concentrations in water and sediment indicated a low risk to aquatic organisms based on the exposure times to the concentrations measured in this study. PMID- 28900809 TI - Production, identification, and field evaluation of sex pheromone from calling females in Diaphania angustalis (Lepidoptera: Crambidae). AB - Insect sex pheromones play a crucial role in the mate finding and calling behavior of Lepidoptera pests. Currently, little is known about the chemical ecology of Diaphania angustalis Snellen (Lepidoptera: Crambidae), a severe and important defoliator attacking the medicinal plant, Alstonia scholaris. In the present study, the pheromone components of D. angustalis females were investigated using electrophysiological and behavioral methods. Distilled hexane extracts of female pheromone glands were analyzed through electroantennogram (EAG) and gas chromatography-electroantennogram detector (GC-EAD), and the active compounds were identified through gas chromatography-mass spectrometry (GC-MS). Production peak of female sex pheromone occurred on the third day of age at 5 h into the scotophase with the EAG test, and the hexane extracts were attractive to males in the wind tunnel test. GC-EAD analysis of virgin males to gland extracts that were subsequently evaluated showed two active compounds, (E,E)-10,12 hexadecadienal (E10E12-16:Ald) and (E,E)-10,12-hexadecadien-1-ol (E10E12-16:OH), based on comparison of retention time and mass spectrum, with suitable synthetic compounds. Under laboratory conditions, the blend of E10E12-16:Ald and E10E12 16:OH in a ratio of 9:1 elicited a stronger EAG response than other treatments or a single component. In the field, more male moths were captured by traps baited with the mixture of E10E2-16:Ald and E10E2-16:OH in a ratio of 9:1, whereas a mixture of 8:1 and 10:1 also caught males. Accordingly, E10E2-16:Ald and E10E2 16:OH were regarded as the major sex pheromone components in D. angustalis females. PMID- 28900811 TI - Capsule Commentary on Hwong et al., The Effects of Public Disclosure of Industry Payments to Physicians on Patient Trust: A Randomized Experiment. PMID- 28900810 TI - Efficacy and safety of extemporaneously prepared miconazole eye drops in Candida albicans-induced keratomycosis. AB - PURPOSE: Extemporaneously prepared miconazole eye drops (EPMD) are used by some eye care practitioners to manage keratomycosis in Ghana. This study therefore aimed to determine the efficacy and safety of EPMD using in vitro and in vivo experimental models. METHODS: The minimum inhibitory concentration (MIC) of EPMD was determined by the agar-well diffusion method. In vivo, the activity of EPMD on corneal ulcer, neovascularization, clouding, edema, carring and on keratomycotic conjunctivitis and corneal scarring (clinical features) associated with Candida albicans-induced keratomycosis in rabbits was determined by treating them with 0.034-1.08% (weight-in-volume) EPMD for a period of 30 days. The safety of EPMD on the healthy eye was determined by instilling various concentrations into the intact eye of the rabbits. RESULTS: The MIC of EPMD on Candida albicans was 1.08% (zone of inhibition of 13 mm +/- 0.578), which resulted in significantly better improvements (p <= 0.001) in clinical findings than eyes treated with sterile water (p > 0.05), and showed no significant difference (p > 0.05) compared to eyes treated with 0.3% fluconazole. There were no visible signs of ocular toxicity on instilling it into healthy eyes of rabbits. CONCLUSION: The extemporaneously prepared miconazole eye drops are effective and safe to use in keratomycosis. PMID- 28900812 TI - Radiomic features predict Ki-67 expression level and survival in lower grade gliomas. AB - To investigate the radiomic features associated with Ki-67 expression in lower grade gliomas and assess the prognostic values of these features. Patients with lower grade gliomas (n = 117) were randomly assigned into the training (n = 78) and validation (n = 39) sets. A total of 431 radiological features were extracted from each patient. Differential radiological features between the low and high Ki 67 expression groups were screened by significance analysis of microarrays. Then, generalized linear analysis was performed to select features that could predict the Ki-67 expression level. Predictive efficiencies were further evaluated in the validation set. Cox regression analysis was performed to investigate the prognostic values of Ki-67 expression level and Ki-67-related radiological features. A group of nine radiological features were screened for prediction of Ki-67 expression status; these achieved accuracies of 83.3% and 88.6% (areas under the curves, 0.91 and 0.93) in the training and validation sets, respectively. Of these features, only spherical disproportion (SD) was found to be a prognostic factor. Patients in the high SD group exhibited worse outcomes in the whole cohort (overall survival, p < 0.0001; progression-free survival, p < 0.0001). Ki-67 expression level and SD were independent prognostic factors in the multivariate Cox regression analysis. This study identified a radiomic signature for prediction of Ki-67 expression level as well as a prognostic radiological feature in patients with lower grade gliomas. PMID- 28900813 TI - Assessment of acute bowel function after radiotherapy for prostate cancer: Is it accurate enough? AB - BACKGROUND AND PURPOSE: Pelvic radiotherapy for prostate cancer can be associated with bowel toxicity, which may have a significant impact on quality of life. Our aim was to assess the adequacy of the tools currently used to assess bowel symptoms after radiotherapy, including physician and patient reported outcomes. This sub-study on acute toxicity was part of a prospective trial assessing long term bowel dysfunction. MATERIALS AND METHODS: Between February 2013 and July 2015, 75 patients with prostate cancer who received radiotherapy completed the LENT/SOMA and the EPIC questionnaires baseline and 2 weeks after the treatment. The Bristol stool scale and two additional questions on faecal urgency were added. Physicians assessed toxicity using Common Terminology Criteria for Adverse Events v.4.0. Agreement between patients and clinicians was assessed using the Cohen's kappa coefficient. RESULTS: Acute toxicity during radiotherapy was very low. The pattern of overall bowel bother was similar before and after treatment. Faecal urgency significantly increased after radiotherapy compared to baseline but was only detected by the additional questions and not by the physicians or the patient-reported outcomes (PRO) questionnaires. Correlation between physician and PRO was poor for most symptoms. CONCLUSION: Bowel symptoms such as urgency may remain undetected by usual tools to assess toxicity after radiotherapy. Assessment of bowel toxicity should be reappraised in order to identify those patients who may have symptoms with an impact on their quality of life. PMID- 28900814 TI - Sub-fertile sperm cells exemplify telomere dysfunction. AB - PURPOSE: The purpose of this study was to evaluate telomere homeostasis in sub fertile compared to fertile human sperm. METHODS: This observational, comparative study included 16 sub-fertile men who required intracytoplasmic sperm injection and 10 fertile men. At least 100 sperm cells from each participant were assessed. Main outcome measures were telomere length and telomere aggregates. Telomerase RNA component (TERC) copy number and telomere capture were assessed using fluorescence in situ hybridization technique and human telomerase reverse transcriptase (hTERT) using immunohistochemistry. RESULTS: Clinical backgrounds were similar. The percentage of sperm cells with shorter telomeres was higher among the sub-fertile compared to the fertile participants (3.3 +/- 3.1 vs. 0.6 +/- 1.2%, respectively; P < 0.005). The percentage of cells with telomere aggregates was significantly higher in the sub-fertile group (15.12 +/- 3.73 vs. 4.73 +/- 3.73%; P < 0.005). TERC gene copy number was similar between groups. The percentage of cells that were positive for hTERT was lower in the sub-fertile group (3.81 +/- 1.27 vs. 8.42 +/- 1.80%; P < 0.005). Telomere capture rates were higher among the sub-fertile sperm cells (P < 0.005). CONCLUSIONS: Sub-fertile sperm cells have short telomeres that are elongated by the alternative pathway of telomere capture. Dysfunctional telomeres may affect sperm fertilizability. PMID- 28900815 TI - Wavelet-based Encoding Scheme for Controlling Size of Compressed ECG Segments in Telecardiology Systems. AB - One of the major issues in time-critical medical applications using wireless technology is the size of the payload packet, which is generally designed to be very small to improve the transmission process. Using small packets to transmit continuous ECG data is still costly. Thus, data compression is commonly used to reduce the huge amount of ECG data transmitted through telecardiology devices. In this paper, a new ECG compression scheme is introduced to ensure that the compressed ECG segments fit into the available limited payload packets, while maintaining a fixed CR to preserve the diagnostic information. The scheme automatically divides the ECG block into segments, while maintaining other compression parameters fixed. This scheme adopts discrete wavelet transform (DWT) method to decompose the ECG data, bit-field preserving (BFP) method to preserve the quality of the DWT coefficients, and a modified running-length encoding (RLE) scheme to encode the coefficients. The proposed dynamic compression scheme showed promising results with a percentage packet reduction (PR) of about 85.39% at low percentage root-mean square difference (PRD) values, less than 1%. ECG records from MIT-BIH Arrhythmia Database were used to test the proposed method. The simulation results showed promising performance that satisfies the needs of portable telecardiology systems, like the limited payload size and low power consumption. PMID- 28900816 TI - Critical appraisal of genotype assessment in molybdenum cofactor deficiency. AB - INTRODUCTION: Molybdenum cofactor deficiency (MoCD) is an ultra-orphan, life threatening disease. Substrate substitution therapy has successfully been performed in single cases of MoCD type A and clinical trials are underway for drug registration. We present an innovative approach for classification of genotype severity to test the hypothesis that milder sequence variants in MoCD result in a less severe disease phenotype quantitated by patient survival. METHODS: All available worldwide published cases with clinical and genetic data were included (n = 40). We stratified the already published disease causing sequence variants as mild or severe with the use of in silico prediction programs, where possible and assessed the possible impact of the variants on the expression of the gene or function of the expressed protein. In a compound heterozygous situation the mildest sequence variant determined the genotype. Subsequently, clinical manifestations and outcomes of both groups were compared. RESULTS: Patients with a severe genotype showed a median survival of 15 months and had a lower probability of survival compared to patients with mild genotypes who were all alive at last reported follow-up (p = 0.0203, Log-rank test). DISCUSSION: The severity of the genotype assessed by in silico prediction and further classification explained survival in molybdenum cofactor deficiency and may therefore be considered a confounder for the outcome of therapeutic clinical trials requiring adjustment in the clinical trial design or analysis. These results should further be investigated by future in vitro or in vivo functional studies. Caution should be taken with this approach for the classification of variants in molecular genetic diagnostics or genetic counseling. PMID- 28900817 TI - Spleen dimensions are inversely associated with lysosomal acid lipase activity in patients with non-alcoholic fatty liver disease. AB - Fatty liver and splenomegaly are typical features of genetic lysosomal acid lipase (LAL) deficiency. No data in adult patients with non-genetic reduction of LAL activity are available. We investigate the association between spleen dimensions and LAL activity in non-alcoholic fatty liver disease (NAFLD) patients, in whom a reduced LAL activity has been reported. We include 425 consecutive patients who underwent abdominal ultrasound to evaluate hepatic steatosis and spleen dimensions. LAL activity was measured with dried blood spot method (Lalistat2). NAFLD was present in 74.1% of screened patients. Higher median spleen longitudinal diameter (10.6 vs. 9.9 cm; p < 0.001) and spleen area (SA) (32.7 vs. 27.7 cm2; p < 0.001), together with a higher and proportion of splenomegaly (17.8 vs. 5.5%, p = 0.001), are present in patients with NAFLD compared to those without. In NAFLD patients, median LAL activity is 0.9 nmol/spot/h. LAL activity is lower in 56 patients with splenomegaly, as compared to those without (p = 0.009). At multivariable logistic regression analysis, age (above median, OR 0.344; p = 0.003), LAL activity (below median, OR 2.206, p = 0.028), and platelets (OR 0.101, p = 0.002) are significantly associated with splenomegaly. NAFLD patients disclose a relatively high prevalence of spleen enlargement and splenomegaly, which are significantly associated with a reduced LAL activity, suggesting that LAL may contribute to spleen enlargement in this setting. PMID- 28900818 TI - The Effects of Chronic Aerobic Exercise on Cardiovascular Risk Factors in Persons with Diabetes Mellitus. AB - PURPOSE OF REVIEW: Aerobic exercise training is a component of diabetes mellitus (DM) care guidelines due to its favorable effects on glycemic control and cardiovascular disease (CVD) risk factors. The purpose of this review is to outline the recent evidence regarding the clinical effects of chronic aerobic exercise on CVD risk factors in persons with DM and to compare the effects of varying intensities and types of exercise. RECENT FINDINGS: Among individuals with DM, all types of aerobic exercise training can impact positively on some traditional and non-traditional risk factors for CVD. Training programs with a higher volume or intensity induce greater improvements in vascular function, cardiorespiratory fitness (CRF), and lipid profiles. The beneficial outcomes of aerobic training include improvements in glycemic control, endothelial function, oxidative stress, dyslipidemia, myocardial function, adiposity, and CRF. Findings regarding markers of inflammation are discrepant and further research should focus on the role of exercise to impact upon the chronic inflammation associated with DM. PMID- 28900819 TI - A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels. AB - We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations. PMID- 28900820 TI - Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells. AB - PURPOSE: Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach. METHODS/PATIENTS: Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure. RESULTS: Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4 year follow-up. CONCLUSIONS: Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors. PMID- 28900821 TI - Reliability of Physician-Level Measures of Patient Experience in Primary Care. AB - BACKGROUND: Patient experience measures are widely used to compare performance at the individual physician level. OBJECTIVE: To assess the impact of unmeasured patient characteristics on visit-level patient experience measures and the sample sizes required to reliably measure patient experience at the primary care physician (PCP) level. DESIGN: Repeated cross-sectional design. SETTING: Academic family medicine practice in California. PARTICIPANTS: One thousand one hundred forty-one adult patients attending 1319 visits with 56 PCPs (including 45 resident and 11 faculty physicians). MEASUREMENTS: Post-visit patient experience surveys including patient measures used for standard adjustment as recommend by the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Consortium and additional patient characteristics used for expanded adjustment (including attitudes toward healthcare, global life satisfaction, patient personality, current symptom bother, and marital status). RESULTS: The amount of variance in patient experience explained doubled with expanded adjustment for patient characteristics compared with standard adjustment (R2 = 20.0% vs. 9.6%, respectively). With expanded adjustment, the amount of variance attributable to the PCP dropped from 6.1% to 3.4% and the required sample size to achieve a reliability of 0.90 in the physician-level patient experience measure increased from 138 to 255 patients per physician. After ranking of the 56 PCPs by average patient experience, 8 were reclassified into or out of the top or bottom quartiles of average experience with expanded as compared to standard adjustment [14.3% (95% CI: 7.0-25.2%)]. CONCLUSIONS: Widely used methods for measuring PCP level patient experience may not account sufficiently for influential patient characteristics. If methods were adapted to account for these characteristics, patient sample sizes for reliable between-physician comparisons may be too large for most practices to obtain. PMID- 28900822 TI - An international review and meta-analysis of prehabilitation compared to usual care for cancer patients. AB - PURPOSE: The purpose of the study is to systematically review and synthesise randomised controlled trials investigating the effectiveness of prehabilitation compared to usual care for newly diagnosed, adult-onset cancer patients. METHODS: MEDLINE, EMBASE, PsycINFO, CINAHL and SSCI were searched up to April 2017. Studies were included if disease-related, treatment-related, patient-reported and health service utilisation outcomes were assessed. Two reviewers independently reviewed and appraised the risk of bias of each study. RESULTS: Eighteen studies were included. Interventions comprised one or more of the following components: psychological support, education and exercise. Meta-analyses found that pelvic floor muscle training (PFMT) significantly increased odds of continence at 3 months (OR = 3.29, 95% CI = 1.57-6.91), but did not significantly reduce daily pad use at 6 months post-surgery Mean Difference (MD)= ( = - 0.96, 95% CI = - 2.04-0.12) for prostate cancer patients. Although quality of life improved due to PFMT, functional ability or distress did not. Further meta-analyses indicated that pre-surgical exercise significantly reduced length of hospital stay (MD = - 4.18, 95% CI = - 5.43-- 2.93) and significantly lowered odds of post-surgery complications (OR = 0.25, 95% CI = 0.10-0.66) for lung cancer patients. Psychology-based prehabilitation significantly improved mood, physical well-being and immune function for prostate cancer patients and improved fatigue and psychological outcomes and a trend for better quality of life among breast cancer patients. Risk of bias was high for most studies. CONCLUSIONS: Prehabilitation appears to benefit cancer patients. Rigorous trials are needed to investigate the effectiveness of prehabilitation among other cancer sites and other related effects. The cost-effectiveness of prehabilitation remains unanswered. IMPLICATIONS FOR CANCER SURVIVORS: Providing interventions earlier in the care pathway may lead to better outcomes for patients during survivorship. PMID- 28900824 TI - External Nasal Neuralgia: an Update. AB - PURPOSE OF REVIEW: External nasal neuralgia is a rare syndrome of atypical facial pain for which there is limited reports in the scientific literature. We aim to review diagnosis and provide an update on treatments for this rare condition. RECENT FINDINGS: Etiology has been documented as post-traumatic due to direct trauma to the nose area and in few case reports, idiopathic. Sensory innervation of the nose arises from the ophthalmic and maxillary divisions of the trigeminal nerve. Direct injury to the nerve appears to be the etiology of post-traumatic external nasal neuralgia. Pathophysiology for idiopathic nasal neuralgia is poorly understood but it appears to be of a central etiology given lack of response to intranasal anesthetics. Pain can be episodic with episodes of tingling sensation lasting up to 30 min, two to three times per day, but for some patients it can be constant bruised sensation of mild to moderate pain. Diagnostic workup including magnetic resonance imaging of brain and computerized tomography of the sinuses are usually negative, but there have been few cases of a nasal contact point. Routine blood work including erythrocyte sedimentation rate is negative. Treatment for this rare condition is varied with very few patients responding to tricyclic antidepressants, specifically amitriptyline. Another medication used as prevention is pregabalin with good results as well. Most patients respond to nerve blockade with local anesthetic to the external nasal nerve and sphenopalatine ganglion block and radiofrequency ablation. More reports of this condition need to be published in the scientific literature to assist with proper diagnosis and treatment of this condition. PMID- 28900823 TI - Health-related quality of life, developmental milestones, and self-esteem in young adults with bleeding disorders. AB - BACKGROUND: The treatment of bleeding disorders improved in the last decades. However, the effect of growing up with bleeding disorders on developmental, emotional, and social aspects is understudied. Therefore, this study assesses HRQOL, developmental milestones, and self-esteem in Dutch young adults (YA) with bleeding disorders compared to peers. METHODS: Ninety-five YA (18-30 years) with bleeding disorders (78 men; mean 24.7 years, SD 3.5) and 17 women (mean 25.1 years, SD 3.8) participated and completed the Pediatric Quality of Life Inventory Young Adult version, the Course of Life Questionnaire, and the Rosenberg Self Esteem Scale. Differences between patients with bleeding disorders and their peers, and between hemophilia severity groups, were tested using Mann-Whitney U tests. RESULTS: YA men with bleeding disorders report a slightly lower HRQOL on the total scale, physical functioning, and school/work functioning in comparison to healthy peers (small effect sizes). YA men with severe hemophilia report more problems on the physical functioning scale than non-severe hemophilia. YA men with bleeding disorders achieved more psychosexual developmental milestones than peers, but show a delay in 'paid jobs, during middle and/or high school.' A somewhat lower self-esteem was found in YA men with bleeding disorders in comparison to peers (small effect size). For YA women with bleeding disorders, no differences were found on any of the outcomes in comparison to peers. CONCLUSION: This study demonstrates some impairments in HRQOL and self-esteem in YA men with bleeding disorders. By monitoring HRQOL, problems can be identified early, especially with regard to their physical and professional/school functioning. PMID- 28900825 TI - Frequency-associated transition from single-cell asynchronous motion to monotonic growth. AB - This paper presents a Fourier analysis of the Ortega equation that examines the growth dynamics of plants, specifically the pollen tubes or non-meristematic zones of elongating coleoptiles. A frequency-induced transition from highly nonlinear (periodical) growth-like the one observed in pollen tubes-to monotonically ascending and asymptotically saturated (sigmoid-like) growth, which is anticipated within the framework of a 'two-fluid model', is shown. A dynamic phase diagram is calculated and presented in the form of a live video clip. PMID- 28900826 TI - Comparative Examination of Temporal Glyoxalase 1 Variations Following Perforant Pathway Transection, Excitotoxicity, and Controlled Cortical Impact Injury. AB - Following acute neuronal lesions, metabolic imbalance occurs, the rate of glycolysis increases, and methylglyoxal (MGO) forms, finally leading to metabolic dysfunction and inflammation. The glyoxalase system is the main detoxification system for MGO and is impaired following excitotoxicity and stroke. However, it is not known yet whether alterations of the glyoxalase system are also characteristic for other neuronal damage models. Neuronal damage was induced in organotypic hippocampal slice cultures by transection of perforant pathway (PPT; 5 min to 72 h) and N-methyl-D-aspartate (NMDA; 50 MUM for 4 h) or in vivo after controlled cortical impact (CCI) injury (2 h to 14 days). Temporal and spatial changes of glyoxalase I (GLO1) were investigated by Western blot analyses and immunohistochemistry. In immunoblot, the GLO1 protein content was not significantly affected by PPT at all investigated time points. As described previously, NMDA treatment led to a GLO1 increase 24 and 48 h after the lesion, whereas PPT increased GLO1 immunoreactivity within neurons only at 48 h postinjury. Immunohistochemistry of brain tissue subjected to CCI unveiled positive GLO1 immunoreactivity in neurons and astrocytes at 1 and 3 days after injury. Two hours and 14 days after CCI, no GLO1 immunoreactivity was observed. GLO1 protein content changes are associated with excitotoxicity but seemingly not to fiber transection. Cell-specific changes in GLO1 immunoreactivity after different in vitro and in vivo lesion types might be a common phenomenon in the aftermath of neuronal lesions. PMID- 28900827 TI - Lifetime Radiation Exposure in Patients with Recurrent Nephrolithiasis. AB - Patients presenting with nephrolithiasis often undergo repeated imaging studies before, during, and after management. Considering the significant risk of stone recurrence in primary stone-formers, repeated imaging studies are not uncommon. Cumulative effects of ionizing radiation exposure from various imaging studies could potentially increase the risk for developing cataracts and solid malignancies in urolithiasis patients. Therefore, practitioners planning or performing imaging studies with ionizing radiation are compelled to keep radiation exposure to humans and the environment as low as possible, thus strictly adhering to the ALARA (As Low as Reasonably Achievable) principles. This chapter will review the latest literature on lifetime radiation exposure of nephrolithiasis patients and present the latest recommendations in minimizing radiation exposure to them pre-, intra-, and postoperatively. For patients presenting with acute renal colic, especially those with body mass index of < 30, low-dose noncontrast computed tomography is the current gold standard of imaging. Patients with opaque stones are followed with ultrasonography (US) and plain radiography (kidney, ureter, and bladder or KUB). Intraoperatively, pulsed fluoroscopy could be used to significantly reduce radiation during ureteroscopy and percutaneous nephrolithotomy. Immediately postoperatively and in the long term, US and KUB could be used to follow up patients with nephrolithiasis. Only symptomatic patients suspected of ureteral stricture should obtain tri-phasic CT urography. Following these latest imaging guidelines from the American Urological Association will dramatically reduce lifetime radiation exposure to patients with nephrolithiasis. PMID- 28900828 TI - Everyday life following hematopoietic stem cell transplantation: decline in physical symptoms within the first month and change-related predictors. AB - PURPOSE: Lower quality of life, especially in the physical domain (Physical-QOL), is common in patients after hematopoietic stem cell transplantation (HSCT). However, few studies explore changes in the Physical-QOL, i.e., physical symptoms, in everyday life of patients following HSCT. The present study addresses this gap by examining patient daily physical symptoms and their predictors in terms of demographic and clinical characteristics. METHODS: Physical symptoms were reported by 188 patients (56.9% men; aged 47.6 +/- 13.4 years) for 28 consecutive days after post-HSCT hospital discharge. Multilevel modeling was used to investigate fixed and random effects for physical symptom changes over time. RESULTS: The results indicated that the initial level of physical symptoms (immediately after hospital discharge) systematically decreased over 28 days. Treatment toxicity (WHO scale; beta = 0.09, p < .01) and baseline depressive symptoms (CES-D scale; beta = 0.06, p < .01) were associated with the initial level of physical symptoms. Patients with more depressive symptoms before HSCT and with more adverse treatment effects presented with more physical symptoms immediately after hospital discharge. The type of transplant, diagnosis, and conditioning regimen differentiated the course of physical symptoms. Patients with leukemias and other myeloid neoplasms (beta = 0.05, p < .01), after allogeneic HSCT (beta = -0.06, p < .01), and with non-myeloablative conditioning (beta = -0.09, p < .01) showed a significant lower decrease in symptoms over time. Patients with multiple myeloma presented with the most rapid improvement (beta = -.03, p < .05). CONCLUSIONS: The findings suggest a heterogeneous and rather positive response to HSCT. Treatment-related conditions occurred to be a significant predictor of the intensity of change in physical functioning after HSCT. PMID- 28900829 TI - Clinical, radiological, pathological and prognostic aspects of intraventricular oligodendroglioma: comparison with central neurocytoma. AB - Studies comparing intraventricular oligodendroglioma (IVO) and central neurocytoma (CN) in terms of their clinical, radiological and pathological features are scarce. We, therefore, investigated the similarities and differences between these types of tumors to get a better understanding of how they may be more properly diagnosed and treated. The clinical manifestations, CT/MRI findings, pathological characteristics and clinical outcomes of 8 cases of IVOs and 12 cases of CNs were analyzed retrospectively. Both IVO and CN occurred most commonly in young adults and manifested with symptoms of increased intracranial pressure secondary to obstructive hydrocephalus. However, they were radiologically different in location (p = 0.007), diffusion-weighted imaging (p = 0.001), "scalloping" appearance (p = 0.006), flow void sign (p = 0.006) and ventricular wall invasion (p = 0.000). Histologically, significant differences in mitotic count (p = 0.008) and parenchymal infiltration (p = 0.01) were noted. Immunohistochemically, significant differences in the expression of Olig2 (p = 0.000), Syn (p = 0.01) and NeuN (p = 0.000) were observed. In addition, MIB-1 labeling index (p = 0.035) and case fatality rate (p = 0.021) of IVO were much higher than those of CN, while survival rate of IVO was much lower than that of CN (p = 0.028). IVO and CN are similar in onset age and clinical manifestations, but have different imaging and pathological features. Patients with IVOs may have a relatively poorer prognosis compared to those with CNs. PMID- 28900830 TI - Transhiatal vs. Transthoracic Esophagectomy: A NSQIP Analysis of Postoperative Outcomes and Risk Factors for Morbidity. AB - BACKGROUND: Both transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE) are accepted procedures for esophageal resection. We aimed to compare postoperative outcomes between these procedures and identify risk factors for morbidity. METHODS: A retrospective analysis was performed using the American College of Surgeons National Surgical Quality Improvement Program database. Adult patients who underwent THE or TTE between 2005 and 2014 were included. Postoperative morbidity, length of stay, and 30-day mortality were compared. Multivariable logistic regression was used to determine risk factors for complications, and likelihood ratio tests were used to assess whether the effect of each risk factor was different across THE and TTE. RESULTS: A total of 4053 patients were included, 2362 (58.3%) underwent TTE and 1691 (41.7%) underwent THE. TTE was associated with higher incidences of postoperative pneumonia and bleeding requiring transfusion. THE had higher incidences of superficial wound infection, deep wound infection, urinary tract infection, and sepsis. There were no significant differences in occurrence of anastomotic leak (THE 7.6% vs. TTE 9.4%, p = 0.35) or 30-day mortality (THE 2.3% vs. TTE 2.5%, p = 0.63). Female gender, black race, hypertension, diabetes, chronic obstructive pulmonary disease, partially or fully dependent functional status, and an ASA score >= 3 were independently associated with postoperative complications. The impact of the risk factors on morbidity was similar across both procedures. CONCLUSIONS: THE and TTE have similar incidence of anastomotic leak and 30-day mortality. The impact of gender, race, and patients' comorbidities on postoperative complications is similar across both types of esophagectomy. PMID- 28900831 TI - [18F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice. AB - PURPOSE: The association of Zika virus (ZIKV) infection and development of neurological sequelae require a better understanding of the pathogenic mechanisms causing severe disease. The purpose of this study was to evaluate the ability and sensitivity of positron emission tomography (PET) imaging using [18F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, to detect and quantify neuroinflammation in ZIKV-infected mice. PROCEDURES: We assessed ZIKV-induced pathogenesis in wild-type C57BL/6 mice administered an antibody to inhibit type I interferon (IFN) signaling. [18F]DPA-714 PET imaging was performed on days 3, 6, and 10 post-infection (PI), and tissues were subsequently processed for histological evaluation, quantification of microgliosis, and detection of viral RNA by in situ hybridization (ISH). RESULTS: In susceptible ZIKV-infected mice, viral titers in the brain increased from days 3 to 10 PI. Over this span, these mice showed a two- to sixfold increase in global brain neuroinflammation using [18F]DPA-714 PET imaging despite limited, regional detection of viral RNA. No measurable increase in ionized calcium binding adaptor molecule 1 (Iba-1) expression was noted at day 3 PI; however, there was a modest increase at day 6 PI and an approximately significant fourfold increase in Iba-1 expression at day 10 PI in the susceptible ZIKV-infected group relative to controls. CONCLUSIONS: The results of the current study demonstrate that global neuroinflammation plays a significant role in the progression of ZIKV infection and that [18F]DPA-714 PET imaging is a sensitive tool relative to histology for the detection of neuroinflammation. [18F]DPA-714 PET imaging may be useful in dynamically characterizing the pathology associated with neurotropic viruses and the evaluation of therapeutics being developed for treatment of infectious diseases. PMID- 28900832 TI - Spatial discrimination of glioblastoma and treatment effect with histologically validated perfusion and diffusion magnetic resonance imaging metrics. AB - The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P < 0.05), whereas ADC, PSR, and PH could not (P > 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments. PMID- 28900833 TI - Cell Volume Regulation in the Proximal Tubule of Rat Kidney : Proximal Tubule Cell Volume Regulation. AB - We developed a dynamic model of a rat proximal convoluted tubule cell in order to investigate cell volume regulation mechanisms in this nephron segment. We examined whether regulatory volume decrease (RVD), which follows exposure to a hyposmotic peritubular solution, can be achieved solely via stimulation of basolateral K[Formula: see text] and [Formula: see text] channels and [Formula: see text]-[Formula: see text] cotransporters. We also determined whether regulatory volume increase (RVI), which follows exposure to a hyperosmotic peritubular solution under certain conditions, may be accomplished by activating basolateral [Formula: see text]/H[Formula: see text] exchangers. Model predictions were in good agreement with experimental observations in mouse proximal tubule cells assuming that a 10% increase in cell volume induces a fourfold increase in the expression of basolateral K[Formula: see text] and [Formula: see text] channels and [Formula: see text]-[Formula: see text] cotransporters. Our results also suggest that in response to a hyposmotic challenge and subsequent cell swelling, [Formula: see text]-[Formula: see text] cotransporters are more efficient than basolateral K[Formula: see text] and [Formula: see text] channels at lowering intracellular osmolality and reducing cell volume. Moreover, both RVD and RVI are predicted to stabilize net transcellular [Formula: see text] reabsorption, that is, to limit the net [Formula: see text] flux decrease during a hyposmotic challenge or the net [Formula: see text] flux increase during a hyperosmotic challenge. PMID- 28900835 TI - Osteitis fibrosa cystica-a forgotten radiological feature of primary hyperparathyroidism. AB - : Although bone disease and stone disease are the universally accepted classical manifestations of primary hyperparathyroidism, clinical parathyroid bone disease is rarely seen today in the United States (<5% of patients) and Western Europe. Nevertheless, in a given patient, classical skeletal involvement can be the first sign of primary hyperparathyroidism, but not recognized because it is not usually included, anymore, in the differential diagnosis of this manifestation of skeletal disease. We describe four cases of primary hyperparathyroidism in which the first clinical manifestation of the disease was a pathological fracture that masqueraded as a malignancy. The presence of large osteolytic lesions gave rise to the initial diagnosis of a primary or metastatic cancer. In none of the reported cases was primary hyperparathyroidism with osteitis fibrosa considered as the diagnosis. It would seem to us that this course is best explained by the fact that in many countries such manifestations of primary hyperparathyroidism have become a rarity. In fact, the incidence of osteitis fibrosa among patients with primary hyperparathyroidism in the US is estimated as so rare, that in majority of medical centers routine x-ray examinations of the bones in these patients is not recommended. The X-ray or computed tomography scan findings of osteitis fibrosa cystica include lytic or multilobular cystic changes. Multiple bony lesions representing brown tumors may be misdiagnosed on computed tomography scan as metastatic carcinoma, bone cysts, osteosarcoma, and especially giant-cell tumor. Distinguishing between primary hyperparathyroidism and malignancy is made readily by the concomitant measurement of parathyroid hormone which in primary hyperparathyroidism, again, will be markedly elevated. In the hypercalcemias of malignancy, such elevations of parathyroid hormone are virtually never seen. CONCLUSION: When radiographic evidence of a lytic lesion and hypercalcemia are present, primary hyperparathyroidism should always be considered in the differential diagnosis. PMID- 28900834 TI - CoQ10 increases mitochondrial mass and polarization, ATP and Oct4 potency levels, and bovine oocyte MII during IVM while decreasing AMPK activity and oocyte death. AB - PURPOSE: We tested whether mitochondrial electron transport chain electron carrier coenzyme Q10 (CoQ10) increases ATP during bovine IVM and increases %M2 oocytes, mitochondrial polarization/mass, and Oct4, and decreases pAMPK and oocyte death. METHODS: Bovine oocytes were aspirated from ovaries and cultured in IVM media for 24 h with 0, 20, 40, or 60 MUM CoQ10. Oocytes were assayed for ATP by luciferase-based luminescence. Oocyte micrographs were quantitated for Oct4, pAMPK (i.e., activity), polarization by JC1 staining, and mitochondrial mass by MitoTracker Green staining. RESULTS: CoQ10 at 40 MUM was optimal. Oocytes at 40 MUM enabled 1.9-fold more ATP than 0 MUM CoQ10. There was 4.3-fold less oocyte death, 1.7-fold more mitochondrial charge polarization, and 3.1-fold more mitochondrial mass at 40 MUM than at 0 MUM CoQ10. Increased ATP was associated with 2.2-fold lower AMPK thr172P activation and 2.1-fold higher nuclear Oct4 stemness/potency protein at 40 MUM than at 0 MUM CoQ10. CoQ10 is hydrophobic, and at all doses, 50% was lost from media into oil by ~ 12 h. Replenishing CoQ10 at 12 h did not significantly diminish dead oocytes. CONCLUSIONS: The data suggest that CoQ10 improves mitochondrial function in IVM where unwanted stress, higher AMPK activity, and Oct4 potency loss are induced. PMID- 28900836 TI - Using In Silico Fragmentation to Improve Routine Residue Screening in Complex Matrices. AB - Targeted residue screening requires the use of reference substances in order to identify potential residues. This becomes a difficult issue when using multi residue methods capable of analyzing several hundreds of analytes. Therefore, the capability of in silico fragmentation based on a structure database ("suspect screening") instead of physical reference substances for routine targeted residue screening was investigated. The detection of fragment ions that can be predicted or explained by in silico software was utilized to reduce the number of false positives. These "proof of principle" experiments were done with a tool that is integrated into a commercial MS vendor instrument operating software (UNIFI) as well as with a platform-independent MS tool (Mass Frontier). A total of 97 analytes belonging to different chemical families were separated by reversed phase liquid chromatography and detected in a data-independent acquisition (DIA) mode using ion mobility hyphenated with quadrupole time of flight mass spectrometry. The instrument was operated in the MSE mode with alternating low and high energy traces. The fragments observed from product ion spectra were investigated using a "chopping" bond disconnection algorithm and a rule-based algorithm. The bond disconnection algorithm clearly explained more analyte product ions and a greater percentage of the spectral abundance than the rule based software (92 out of the 97 compounds produced >=1 explainable fragment ions). On the other hand, tests with a complex blank matrix (bovine liver extract) indicated that the chopping algorithm reports significantly more false positive fragments than the rule based software. Graphical Abstract. PMID- 28900837 TI - Perseverative Cognition as an Explanatory Mechanism in the Relation Between Job Demands and Sleep Quality. AB - PURPOSE: The aim of this longitudinal three-wave study was to examine (i) reciprocal associations among job demands, work-related perseverative cognition (PC), and sleep quality; (ii) PC as a mediator in-between job demands and sleep quality; and (iii) continuous high job demands in relation to sleep quality and work-related PC over time. METHOD: A representative sample of the Swedish working population was approached in 2010, 2012, and 2014, and 2316 respondents were included in this longitudinal full-panel survey study. Structural equation modelling was performed to analyse the temporal relations between job demands, work-related PC, and sleep quality. Additionally, a subsample (N = 1149) consisting of individuals who reported the same level of exposure to job demands during all three waves (i.e. stable high, stable moderate, or stable low job demands) was examined in relation to PC and sleep quality over time. RESULTS: Analyses showed that job demands, PC, and poor sleep quality were positively and reciprocally related. Work-related PC mediated the normal and reversed, direct across-wave relations between job demands and sleep quality. Individuals with continuous high job demands reported significantly lower sleep quality and higher work-related PC, compared to individuals with continuous moderate/low job demands. CONCLUSION: This study substantiated reciprocal relations between job demands, work-related PC, and sleep quality and supported work-related PC as an underlying mechanism of the reciprocal job demands-sleep relationship. Moreover, this study showed that chronically high job demands are a risk factor for low sleep quality. PMID- 28900838 TI - Comparative nutritional value of Jatropha curcas protein isolate and soy protein isolate in common carp. AB - Jatropha seed cake (JSC) is an excellent source of protein but does contain some antinutritional factors (ANF) that can act as toxins and thus negatively affect the growth and health status of fish. While this can limit the use of JSC, detoxified Jatropha protein isolate (DJPI) may be a better option. An 8-week study was performed to evaluate dietary DJPI to common carp Cyprinus carpio. Five iso-nitrogenous diets (crude protein of 38%) were formulated that consisted of a C ontrol (fish meal (FM) based protein), J 50 or J 75 (50 and 75% of FM protein replaced by DJPI), and S 50 or S 75 (50 and 75% of FM protein replaced by soy protein isolate, SPI) and fed to triplicate groups of 75 carp fingerlings (75; av. wt. +/- SD; 11.4 +/- 0.25 g). The growth, feeding efficiencies, digestibility, plasma biochemistry, and intestinal enzymes were measured. Results showed that growth performance of fish fed the S 75- or DJPI-based diets were not significantly different from those fed the C ontrol diet, while carp fed the S 50 had significantly better growth than the J 75 diet. Fish fed the J 75 diet had significantly lower protein and lipid digestibility as well as significantly lower intestinal amylase and protease activities than all other groups. However, all plant protein-based diets led to significantly higher crude protein, crude lipid, and gross energy in the body of common carp compared to the control treatment. Plasma cholesterol and creatinine significantly decreased in the plant protein fed groups, although plasma triglyceride as well as the red blood cells count, hematocrit, albumin, globulin, total plasma protein, and lysozyme activity were higher in plant protein fed groups compared to FM fed group. White blood cells, hemoglobulin concentration, alkaline phosphatase and alanine transaminase activities, and glucose level in blood did not differ significantly among treatments. The results suggest that the DJPI is non-toxic to carp and can be used to replace FM in the diets of common carp up to 75%, but further research to potentially reduce some inherent ANF within this protein source, such as non starch polysaccharides, may improve nutrient utilization. PMID- 28900839 TI - Behavioral Health Integration into Primary Care: a Microsimulation of Financial Implications for Practices. AB - BACKGROUND: New payments from Medicare encourage behavioral health services to be integrated into primary care practice activities. OBJECTIVE: To evaluate the financial impact for primary care practices of integrating behavioral health services. DESIGN: Microsimulation model. PARTICIPANTS: We simulated patients and providers at federally qualified health centers (FQHCs), non-FQHCs in urban and rural high-poverty areas, and practices outside of high-poverty areas surveyed by the National Association of Community Health Centers, National Ambulatory Medical Care Survey, National Health and Nutrition Examination Survey, and National Health Interview Survey. INTERVENTIONS: A collaborative care model (CoCM), involving telephone-based follow-up from a behaviorist care manager, or a primary care behaviorist model (PCBM), involving an in-clinic behaviorist. MAIN MEASURES: Net revenue change per full-time physician. KEY RESULTS: When behavioral health integration services were offered only to Medicare patients, net revenue was higher under CoCM (averaging $25,026 per MD in year 1 and $28,548/year in subsequent years) than PCBM (-$7052 in year 1 and -$3706/year in subsequent years). When behavioral health integration services were offered to all patients and were reimbursed by Medicare and private payers, only practices adopting the CoCM approach consistently gained net revenues. The outcomes of the model were sensitive to rates of patient referral acceptance, presentation, and therapy completion, but the CoCM approach remained consistently financially viable whereas PCBM would not be in the long-run across practice types. CONCLUSIONS: New Medicare payments may offer financial viability for primary care practices to integrate behavioral health services, but this viability depends on the approach toward care integration. PMID- 28900840 TI - Risks and benefits of pelvic lymphadenectomy in octogenarians undergoing radical cystectomy due to urothelial carcinoma of the bladder. AB - OBJECTIVES: According to current guidelines, radical cystectomy (RC) should be combined with an extended pelvic lymphadenectomy (PLND) as therapeutic and staging instrument. Objective of this study was to analyze the influence of PLND on survival rates and complication rates in a selected group of elderly patients with a minimum age of 80 years. MATERIALS AND METHODS: In this single-center retrospective analysis, we evaluated 102 patients who underwent RC due to UCB from 2004 to 2015 at our institution. In 74 patients (73%), RC was combined with PLND; in 28 cases (27%), RC was performed without PLND. Impact of PLND on cancer specific survival (CSS), overall survival (OS) and progression-free survival (PFS) was analyzed using log-rank test and COX regression model. RESULTS: In univariate analysis of the data, we were not able to show a significant impact of PLND on CSS (p = 0.606), OS (p = 0.979) or PFS (p = 0.883). Also in multivariate analysis of the data, we were not able to identify PLND as an independent prognostic parameter on survival rates of patients undergoing RC, neither for CSS (p = 0.912) nor OS (p = 0.618) or PFS (p = 0.900). CONCLUSIONS: Our small and single-center study was not able to demonstrate a significant independent influence of PLND on CSS, OS and PFS in octogenarians undergoing RC due to UCB. There is no doubt that RC should usually be combined with PLND, but the results of this small data set with a selected patient cohort indicate that RC without PLND might be an option in selected cases of elderly patients. PMID- 28900841 TI - Right-Side Approach-Duet Totally Laparoscopic Distal Gastrectomy (R-Duet TLDG) Using a Three-Port to Treat Gastric Cancer. AB - BACKGROUND: Gastric cancer is commonly treated via minimally invasive surgery. The present study explored the feasibility of right-side approach-duet (R-duet) totally laparoscopic distal gastrectomy using a three-port compared with a four- or five-port. METHODS: A total of 251 patients who underwent curative totally laparoscopic distal gastrectomy for gastric cancer (72 R-duet, 74 four-port, and 105 five-port) at the Catholic Medical Center were enrolled. All operations were performed using conventional laparoscopic instruments. The clinicopathological characteristics, operative details, and postoperative short-term outcomes were analyzed retrospectively. RESULTS: The clinicopathological characteristics did not differ significantly among the groups, except that the N stage was higher in the five-port group. The operating time was significantly longer in the four-port than the R-duet group (R-duet, four-port, and five-port 148.2 +/- 30.7, 162.4 +/- 30.6, and 159.9 +/- 31.5 min, respectively; p = 0.024). The estimated blood loss did not differ significantly. Postoperatively, the times to flatus and to soft diet consumption and the hospital stay were significantly longer in the five-port group. The extent of postoperative complications did not differ among the groups. CONCLUSIONS: R-duet totally laparoscopic distal gastrectomy is a reliable form of reduced-port surgery when used to treat gastric cancer; no special instruments are required. PMID- 28900842 TI - Early postictal serum lactate concentrations are superior to serum creatine kinase concentrations in distinguishing generalized tonic-clonic seizures from syncopes. AB - Concentrations of serum creatine kinase (CK) and serum lactate are frequently measured to help differentiate between generalized tonic-clonic seizures (GTCS) and syncope. The aim of this prospective cohort study was to systematically compare these two markers. The primary outcome is the measurement of serum lactate and CK in blood samples drawn within 2 h of the event in patients admitted with either a GTCS (n = 49) or a syncope (n = 36). Furthermore, the specificity and sensitivity of serum lactate and CK are determined as diagnostic markers in distinguishing between GTCS and syncope. GTCS patients have significantly higher serum lactate levels compared to syncope patients (p < 0.001). In contrast, CK does not differ between groups at admission. Regarding the first hour after the seizure, we identify a cut-off for serum lactate of 2.45 mmol/l for diagnosing GTCS as the cause of an impairment of consciousness with a sensitivity of 0.94 and a specificity of 0.93 (AUC: 0.97; 95% CI 0.94-1.0). In the second hour after the event, the ROC analysis yields similar results (AUC: 0.94; 95% CI 0.85-1.0). Serum lactate is a sensitive and specific diagnostic marker to discriminate GTCS from syncope and is superior to CK early after admission to the emergency department. PMID- 28900843 TI - Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Procedure for Non resectable Peritoneal Carcinomatosis (with Video). AB - BACKGROUND: Peritoneal carcinomatosis (PC) is a common evolution of abdominal cancers and is associated with poor prognosis in the absence of aggressive multimodal therapy.1 Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a safe and innovative approach, which enhances the effect of chemotherapy 2 without reported renal/hepatic toxicity.3,4 It requires mastery of technical aspects to reduce postoperative morbidity, increase effectiveness, and prevent caregiver chemotherapy exposure. We, therefore, report herein the surgical protocol after 2 years of implementation in our university center specialized in PC management, accompanied by a short video, to share our experience. METHODS: The procedure was performed under general anesthesia and capnoperitoneum (12 mmHg, 37 degrees C) using two balloon trocars placed in the midline, in accordance with the open laparoscopic technique. Explorative laparoscopy allowed Sugarbaker peritoneal cancer index to be determined. Parietal biopsies were taken, and ascites was removed for peritoneal cytology. The nebulizer was inserted and connected to a high-pressure injector. A pressurized aerosol containing chemotherapy agents was then administered; cisplatin (7.5 mg/m2 in 150 ml 0.9%NaCl) immediately followed by doxorubicin (1.5 mg/m2 in 50 ml 0.9%NaCl), or oxaliplatin alone (92 mg/m2 in 150 ml 0.9%NaCl), based on PC origin and chemotherapy history. The aerosol was kept in a steady-state for 30 min then exhausted through a closed filter system, and trocars were retracted. Each step is illustrated in the video. CONCLUSION: This video protocol provides a better understanding of the PIPAC procedure and the safety measures essential for this method of chemotherapy administration. It should help all teams wishing to implement a PIPAC therapy program. PMID- 28900845 TI - Sanitary Worker's Death Unnerves Pakistan's Health Care Ethics to the Core. AB - Health care ethics is a sensitive domain, which if ignored, can lead to patient dissatisfaction, weakened doctor-patient interaction and episodes of violence. Little importance has been paid to medical ethics within undergraduate medical education in developing countries such as Pakistan. Three doctors in Pakistan are currently facing an official police complaint and arrest charges, following the death of a sanitary worker, who fell unconscious while cleaning a drain and was allegedly refused treatment as he was covered in sewage filth. The medical license of the doctors in question should be cancelled, if found guilty following a thorough investigation into the case. The 'right to life' has been universally assured by all moral, cultural and legal codes and no society can ever argue against the sacredness of a human life. It is quite clear that the aforesaid doctors' actions are not only against the core principles of the physicians' code, but also go against the doctrine of human rights. If serious efforts on an urgent basis are not made by the regulatory and governing bodies, one can definitely expect similar incidents for at least a few more decades before any noticeable change is seen. PMID- 28900844 TI - A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma. AB - Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet DigitalTM PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy. PMID- 28900846 TI - PET-based imaging to detect and characterize cardiovascular disorders: Unavoidable path for the foreseeable future. PMID- 28900847 TI - Effect of rituximab on primary central nervous system lymphoma: a meta-analysis. AB - The effect of rituximab on primary central nervous system lymphoma (PCNSL) is controversial. We performed this meta-analysis to assess the efficacy of treatment with or without rituximab for PCNSL. We first conducted a search for qualified studies using PubMed, the Cochrane Library, and the Web of Science. The meta-analysis was conducted to compare odds ratios (ORs) with the corresponding 95% confidence interval (95% CI) for complete remission (CR) rate, progression free survival (PFS), and overall survival (OS) using Review Manager 5.0. We included two randomized clinical trials and six retrospective studies in this meta-analysis. The results of our statistical analysis show that the use of rituximab was closely correlated with a higher CR (OR 1.70, 95% CI 1.17-2.46, P = 0.005), 2-year PFS (OR 2.11, 95% CI 1.08-4.11, P = 0.03), 5-year PFS (OR 2.54, 95% CI 1.64-3.93, P < 0.0001), 2-year OS (OR 2.40, 95% CI 1.73-3.34, P < 0.00001), and 5-year OS (OR 2.87, 95% CI 2.02-4.08, P < 0.00001). These results may help to inform therapeutic strategies including the use of rituximab and to improve therapeutic planning for PCNSL patients. PMID- 28900848 TI - Feasibility of Assessing Falls Risk and Promoting Falls Prevention in Beauty Salons. AB - Falls are a major public health risk and a leading cause of emergency room visits for people of all ages. Finding ways to increase access to information and evidence-based falls prevention strategies is critically important across the lifespan. We tested the feasibility of conducting a falls risk assessment and awareness program among customers who attend beauty salons. We enrolled 78 customers from 2 beauty salons who completed a written questionnaire as well as several biometric and functional balance tests designed to assess falls risk. On average, enrolled participants were 56 years of age (range: 19-90), female (n = 70, 91%), and Black (n = 47, 62%). Eleven percent of enrolled customers were classified as at high risk of falls because they had reported two or more falls in the last 6 months. We found that younger age, higher education, employment, moderate physical activity, and decreased frequency of salon visits were associated with fewer falls. Results demonstrated initial interest in, and the feasibility of recruiting and enrolling customers into a beauty salon-based falls risk assessment and awareness program. Beauty salons, which are in all communities, represent an innovative setting for reaching people of all ages with life-saving falls prevention information and services. PMID- 28900849 TI - Neuroprotective Effects of Kinetin Against Glutamate-Induced Oxidative Cytotoxicity in HT22 Cells: Involvement of Nrf2 and Heme Oxygenase-1. AB - Oxidative stress is considered as one of key factors related to Alzheimer's disease (AD), while kinetin (KT) has been reported to exert anti-oxidative activities as well as neuroprotective effects both in vivo and in vitro. Thus, in this study, the neuroprotective effects of KT against glutamate-induced oxidative toxicity in HT22 cells were investigated. To evaluate the anti-oxidative capabilities of KT itself, several anti-oxidative assays in vitro were conducted. To evaluate the neuroprotective effects of KT, the levels of intracellular reactive oxygen species (ROS) and calcium influx, mitochondrial membrane potential (MMP), and cell death were measured by flow cytometry. Nuclear translocation of apoptosis inducing factor (AIF) and content of intracellular ATP were also determined. In addition, the phosphorylation levels of apoptosis signal regulating kinase 1 (ASK-1), c-Jun N-terminal kinase (JNK), and p38 mitogen activated protein kinases (p38) were evaluated as well. Besides, nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) were also examined to reveal underlying mechanisms. Results showed that KT rescued cell death, and suppressed the accumulation of intracellular ROS and the increase of intracellular calcium influx. In addition, KT maintained normal function of mitochondria and inhibited the phosphorylation of ASK-1, JNK, and p38. KT also promoted nuclear translocation of Nrf2 and enhanced the expression of HO-1 both at protein and mRNA level. Importantly, blockage of Nrf2 almost completely abolished the neuroprotective effects of KT, while blockage of HO-1 expression partly neutralized its neuroprotective effects. Our results indicated that KT can protect HT22 cells from glutamate-induced cell death by activating Nrf2 pathway and inducing expression of HO-1, suggesting KT might be a drug candidate for treatment of AD and other neurodegenerative disorders related to oxidative stress. PMID- 28900850 TI - Assessment of Atrial Fibrillation and Ventricular Arrhythmia Risk after Bariatric Surgery by P Wave/QT Interval Dispersion. AB - BACKGROUND: The association of obesity with atrial fibrillation (AF) and with ventricular arrhythmias is well documented. OBJECTIVE: The aim of this study was to investigate whether weight reduction by a laparoscopic sleeve gastrectomy has any effect on P wave dispersion (PWD), a predictor of AF, and corrected QT interval dispersion (CQTD), a marker of ventricular arrhythmias, in obese individuals. METHODS: In a prospective study, a total of 114 patients (79 females, 35 males) who underwent laparoscopic sleeve gastrectomy were examined. The patients were followed 1 year. PWD and CQTD values before and 3rd, 6th, and 12th months after the surgery were calculated and compared. RESULTS: There was a statistically significant decline in body mass index (BMI), PWD, and CQTD values among baseline, 3rd, 6th, and 12th months (p < 0.001 for all comparisons). Correlation analysis showed a statistically significant correlation between DeltaPWD and DeltaBMI (r = 0.719, p < 0.001), DeltaPWD and Deltaleft ventricular end-diastolic diameter (LVEDD) (r = 0.291, p = 0.002), DeltaPWD and Deltaleft atrial diameter (LAD) (r = 0.65, p < 0.001), DeltaCQTD and DeltaBMI (r = 0.266, p = 0.004), DeltaCQTD and DeltaLVEDD (r = 0.35, p < 0.001), DeltaCQTD and DeltaLAD (r = 0.289, p = 0.002). In multiple linear regression analysis, there was a statistically significant relationship between DeltaPWD and DeltaBMI (beta = 0.713, p < 0.001), DeltaPWD and DeltaLVEDD (beta = 0.174, p = 0.016), DeltaPWD and DeltaLAD (beta = 0.619, p < 0.001), DeltaCQTD and DeltaBMI (beta = 0.247, p = 0.011), DeltaCQTD and DeltaLVEDD (beta = 0.304, p < 0.001), DeltaCQTD and DeltaLAD (beta = 0.235, p = 0.009). CONCLUSION: PWD and CQTD values of patients were shown to be attenuated after bariatric surgery. These results indirectly offer that there may be a reduction in risk of AF, ventricular arrhythmia, and sudden cardiac death after obesity surgery. PMID- 28900852 TI - The infiltration of classical Hodgkin lymphoma cells into pleural effusion. PMID- 28900853 TI - Coronary artery disease incidentally detected by routine oncology 18F fluorodeoxyglucose positron emission tomography. PMID- 28900851 TI - Tributyltin chloride disrupts aortic vascular reactivity and increases reactive oxygen species production in female rats. AB - Organotin compounds, such as tributyltin (TBT), are environment contaminants that induce bioaccumulation and have potential toxic effects on marine species and mammals. TBT have been banned by the International Maritime Organization in 2003. However, the assessment of butyltin and metal contents in marine sediments has demonstrated high residual levels of TBT in some cases exceeding 7000 ng Sn g-1. The acceptable daily intake (ADI) level for TBT established by the World Health Organization is 0.5 MUg/kg bw/day is based on genotoxicity, reproduction, teratogenicity, immunotoxicity, and mainly neurotoxicity. However, their effect on the cardiovascular system is not well understood. In this study, female rats were exposed to 0.5 MUg/kg/day of TBT for 15 days with the goal of understanding the effect of TBT on vascular function. Female Wistar rats were treated daily by gavage and divided into control (n = 10) and TBT (n = 10) groups. The aortic rings were incubated with phenylephrine in both the presence and absence of endothelium. The phenylephrine concentration-response curves were generated by exposing endothelium-intact samples to NG-nitro-L-arginine methyl ester (L-NAME), apocynin, superoxide dismutase (SOD), catalase, tiron, and allopurinol. Acetylcholine (ACh) and sodium nitroprusside (SNP) were used to evaluate the relaxation response. Exposure to TBT reduced serum 17beta-estradiol E2 levels and increased vascular reactivity. After incubation with L-NAME, the vascular reactivity to phenylephrine was significantly higher. Apocynin, SOD, catalase, and tiron decreased the vascular reactivity to phenylephrine to a significantly greater extent in TBT-treated rats than in the control rat. The relaxation induced by ACh and SNP was significantly reduced in TBT rats. Exposure to TBT induced aortic wall atrophy and increased superoxide anion production and collagen deposition. These results provide evidence that exposing rats to the current ADI for TBT (0.5 MUg/kg) for 15 days induced vascular dysfunction due to oxidative stress and morphological damage and should be considered an important cardiovascular risk factor. PMID- 28900854 TI - Relationships between serum PSA levels, Gleason scores and results of 68Ga PSMAPET/CT in patients with recurrent prostate cancer. AB - AIM: To investigate the relationship between serum PSA level, Gleason score of PCa and the outcomes of Ga68-PSMA PET/CT in patients with recurrent PCa. METHODS: A total of 109 consecutive patients (median age 71 years; range 48-89 years) who had PSA recurrence after RP and/or hormonotherapy and/or radiotherapy were included in this study. Local recurrences, lymph node metastasis (pelvic, abdominal and/or supradiaphragmatic), bone metastases (oligometastatic/multimetastatic) and other metastatic sites (lung, liver, brain, etc) were documented. RESULTS: In 91(83.4%) patients at least one lesion characteristic for PCa was detected by68Ga-PSMA PET/CT. The median serum total PSA (tPSA) was 6.5 (0.2-640) ng/ml.There was a significant difference between 68Ga-PSMA PET/CT positive and negative patients in terms of serum total PSA value. No statistical significance was found between positive and negative 68Ga PSMA PET/CT findings in terms of Gleason score. Local recurrence was detected in 56 patients. whereas lymph node metastases were demonstrated in 46 patients. Pelvic nodal disease was the most frequent presentation followed by abdominal and supradiaphragmaticnodal involvement. Bone metastases [oligometastasis, (n = 20); multimetastasis, (n = 35)? were also detected in 55 patients. In the ROC analysis for the study cohort, the optimal cut-off value of total serum PSA was determined as 0.67 ng/ml for distinguishing between positive and negative 68Ga-PSMA PET/CT images, with an area under curve of 0.952 (95% CI 0.911-0.993). CONCLUSIONS: 68Ga PSMA PET/CT was found to be an effective tool for the detection of recurrent PCa. Even though no relationship was detected between the GS and 68Ga-PSMA PET/CT findings, serum total PSA values may be used for estimating the likelihood of positive 68Ga-PSMA PET/CT results. PMID- 28900855 TI - Accuracy of Various Lymph Node Staging Criteria in Rectal Cancer with Magnetic Resonance Imaging. AB - INTRODUCTION: The accuracy of pretherapeutic staging of lymph nodes (LN) in rectal cancer by MR imaging (MRI) is still limited. The aim of the study was to determine the sensitivity and specificity of different morphological criteria in nodal staging. MATERIAL AND METHODS: LN were analyzed by MRI in 60 patients with rectal cancer and primary surgery. Signs of LN metastasis (cN+) were spiculated/indistinct border contour, inhomogeneous signal intensity, or LN size. The accuracy of these signs for clinical LN staging was analyzed with conclusive postoperative histological lymph node examination. RESULTS: 68.3% of patients with nodal metastasis (pN+) were correctly identified by size with a cutoff value of 7.2 mm. This, however, was not inferior to the 76.7% identified using the inhomogeneous morphological signal intensity and spiculated/indistinct border contour criteria (p = 0.096). 3.3 versus 5% were overstaged, and 28.3 versus 18.3% understaged by these criteria. Sensitivities/specificities for (a) size, (b) spiculated/indistinct border contour, and (c) inhomogeneous signal intensity and spiculated/indistinct border contour were (a) 32%/94%, (b) 56%/86%, and (c) 56%/91%, respectively. CONCLUSIONS: The accuracy of LN staging in rectal cancer was not improved by morphological criteria. These limitations suggest being reticent when recommending neoadjuvant chemoradiation merely based on preoperative positive LN staging. PMID- 28900858 TI - Methodological Aspects in Studies Based on Clinical Routine Data. AB - : Randomized controlled clinical trials are regarded as the gold standard for comparing different clinical interventions, but generally their conduct is operationally cumbersome, time-consuming, and expensive. Studies and investigations based on clinical routine data on the contrary utilize existing data acquired under real-life conditions and are increasingly popular among practitioners. In this paper, methodological aspects of studies based on clinical routine data are discussed. Important limitations and considerations as well as unique strengths of these types of studies are indicated and exemplarily demonstrated in a recent real-case study based on clinical routine data. In addition two simulation studies reveal the impact of bias in studies based on clinical routine data on the type I error rate and false decision rate in favor of the inferior intervention. It is concluded that correctly analyzing clinical routine data yields a valuable addition to clinical research; however, as a result of a lack of statistical foundation, internal validity, and comparability, generalizing results and inferring properties derived from clinical routine data to all patients of interest has to be considered with extreme caution. FUNDING: Grunenthal GmbH. PMID- 28900859 TI - Efficacy of Surah Al-Rehman in Managing Depression in Muslim Women. AB - The study empirically investigated the idea that Quranic verses (Surah Al-Rehman) can help manage depression. Abdullah Ibn Mas'ud (radiAllahu anhu) reported that the Prophet (salAllahu alayhi wasalam) said, "Everything has an adornment, and the adornment of the Qur'an is Surah Al-Rehman." Surah Al-Rehman is the most rhythmic surah of the Quran, so it was used for our experimental study. The idea of the study was drawn from the premise that music therapy helps reduce depression. The objective of the present study was to investigate the efficacy of Surah Al-Rehman for managing depression in Muslim women admitted for treatment of major depressive disorder in a psychiatry ward of a government hospital. It was hypothesized that women diagnosed with severe depression in the treatment group will have reduced level of depression as compared to control group at post assessment level. It was further hypothesized that the amount of decrease in depression in treatment group at the post-assessment level will be greater as compared to the control group. A purposive sample of 12 female patients diagnosed with depression was randomly assigned to the treatment group (n = 6) and control group (n = 6). Assessment was done at pre- and post-level by using Beck Depression Inventory-II. Both groups did not significantly differ on pre assessment depression scores. Twelve structured group sessions of 22 min, two times a day, were conducted for a period of 4 weeks with the groups. Treatment group was made to listen to Surah Al-Rehman recited by Qari Abdul Basit, and control group was exposed to music used for relaxation and treatment of depression. Wilcoxon signed ranks test was used to find the within-group differences between pre- and post-assessment scores. Both groups had decreased level of depression at post-assessment level, so it was important to assess if there was any difference in level of decrease. Mann-Whitney U test for comparison of groups on level of decrease at the post-assessment level endorsed that treatment group had significantly greater decrease than control group on depression. Our study highlights the efficacy of Surah Al-Rehman as a remedy to reduce depression. The Holy Quran intones, "This sacred book is 'shifa' for its followers." Hence, we recommend that researchers should focus on finding remedies for other psychological and physical diseases from Quranic verses. An exploration of possible mechanism (such as activated cognitions or associated emotions while listening to Quran) through which effects of recitation are reached, can also be subject of investigation for forthcoming studies. PMID- 28900856 TI - Incidence and Management of De Novo Lower Urinary Tract Symptoms After Pelvic Organ Prolapse Repair. AB - PURPOSE OF REVIEW: Pelvic organ prolapse (POP) is a significant problem with many options for surgical correction. Following prolapse surgery, de novo lower urinary tract symptoms (LUTS) are not uncommon. We review the current literature on de novo lower urinary tract symptoms following POP repair and discuss the role of urodynamics in the evaluation of the prolapse patient. RECENT FINDINGS: Patients with occult stress urinary incontinence (SUI) appear to be at higher risk of developing de novo SUI after POP repair. Prolapse reduction in patients undergoing urodynamic evaluation is important. Different types of POP repair influence rates of de novo SUI. Also, prophylactic anti-incontinence procedures at time of POP repair appear to lower the incidence of de novo SUI, but at the cost of increased risk of complications and morbidity. Pre-existing overactive bladder (OAB) symptoms may either improve or persist, and de novo OAB can develop. The specific role of urodynamic study testing for POP is still being determined. Increasingly, women are seeking surgical treatment for POP. Aside from complications related to surgery in general, proper patient counseling is important regarding the risk of development of de novo voiding problems following surgery. Despite a growing body of literature looking at de novo voiding symptoms after prolapse repair, more studies are still needed. PMID- 28900857 TI - Endovascular Biopsy: In Vivo Cerebral Aneurysm Endothelial Cell Sampling and Gene Expression Analysis. AB - There is limited data describing endothelial cell (EC) gene expression between aneurysms and arteries partly because of risks associated with surgical tissue collection. Endovascular biopsy (EB) is a lower risk alternative to conventional surgical methods, though no such efforts have been attempted for aneurysms. We sought (1) to establish the feasibility of EB to isolate viable ECs by fluorescence-activated cell sorting (FACS), (2) to characterize the differences in gene expression by anatomic location and rupture status using single-cell qPCR, and (3) to demonstrate the utility of unsupervised clustering algorithms to identify cell subpopulations. EB was performed in 10 patients (5 ruptured, 5 non ruptured). FACS was used to isolate the ECs and single-cell qPCR was used to quantify the expression of 48 genes. Linear mixed models and exploratory multilevel component analysis (MCA) and self-organizing maps (SOMs) were performed to identify possible subpopulations of cells. ECs were collected from all aneurysms and there were no adverse events. A total of 437 ECs was collected, 94 (22%) of which were aneurysmal cells and 319 (73%) demonstrated EC-specific gene expression. Ruptured aneurysm cells, relative controls, yielded a median p value of 0.40 with five genes (10%) with p values < 0.05. The five genes (TIE1, ENG, VEGFA, MMP2, and VWF) demonstrated uniformly reduced expression relative the remaining ECs. MCA and SOM analyses identified a population of outlying cells characterized by cell marker gene expression profiles different from endothelial cells. After removal of these cells, no cell clustering based on genetic co expressivity was found to differentiate aneurysm cells from control cells. Endovascular sampling is a reliable method for cell collection for brain aneurysm gene analysis and may serve as a technique to further vascular molecular research. There is utility in combining mixed and clustering methods, despite no specific subpopulation identified in this trial. PMID- 28900861 TI - Acute kidney injury caused by decompression illness successfully treated with hyperbaric oxygen therapy and temporary dialysis. AB - A 52-year-old Japanese male professional diver was referred to our hospital for decompression illness (DCI). After 1 h of diving operation at 20 m below sea level, he complained of dyspnea, chest pain, and abdominal pain. He dove again, intending to ease the symptoms, but the symptoms were never relieved. He dove for a total of 4 h. No neurological abnormalities were observed. Computed tomography images revealed portal venous gas and mesenteric venous gas, in addition to bubbles in the femoral veins, pelvis, lumbar canal, intracranial sinuses, and joints. Hyperbaric oxygen therapy (HBOT) was immediately administered. His symptoms improved after the first course of HBOT, however, the patient had anuria for almost 36 h after admission and exhibited acute kidney injury (AKI). Serum creatinine and creatine kinase (CK) levels were increased to maximal values of 6.16 mg/dL and 18,963 U/L, respectively. Blood flow signals were not detected on kidney Doppler ultrasound. We considered that AKI was caused by blood flow impairment and capillary leak syndrome due to DCI in addition to rhabdomyolysis secondary to arterial gas embolism in the skeletal muscles. Temporary dialysis was required to correct the acidemia and electrolyte disturbance. Diuretic phase was initiated, and the patient was put off dialysis on day 3. Serum creatinine and CK levels returned to normal on day 11. He was successfully treated without any complications. Although AKI is a rare manifestation, we should consider AKI risk in patients with severe DCI. PMID- 28900860 TI - Modified immunosuppressive therapy with porcine antilymphocyte globulin plus delayed cyclosporine A in children with severe aplastic anemia. AB - Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine (CsA) is the standard treatment for children with severe aplastic anemia (SAA) with no human leukocyte antigen-matched siblings. Due to the unavailability of horse ATG in China, porcine antilymphocyte globulin (p-ALG), which is less expensive and more effective than rabbit ATG, is widely used. We sought to evaluate the efficacy and safety profile of modified IST with p-ALG plus delayed CsA at day 21 in 50 SAA children. Eighteen SAA patients who progressed from nonsevere aplastic anemia (NSAA) were classified as SAA-II; the other 32 patients were classified as SAA-I. Overall response (OR) rates at 3, 6 and 12 months were 56, 64 and 62%, respectively. The 10-year overall survival (OS) rate and disease-free survival (DFS) rate were 80 and 56%. The OR, OS and DFS rates in the SAA-I group were clearly better than those in the SAA-II group. Death rate from infection within 30 days was 4%. Modified IST with p-ALG plus delayed CsA is a reliable and well-tolerated treatment for children with SAA, and reduces early death due to infection. Modified IST is more suitable for children with SAA-I. PMID- 28900865 TI - Genetic Counseling in Primary Immunodeficiency Disorders: An Emerging Experience in Egypt. AB - BACKGROUND: Primary immunodeficiency disorders (PIDs) are a heterogeneous group of diseases of the immune system leading to life-threatening infections, and, unless urgently treated with immune reconstitution, patients do not usually survive. With the continuing progress in molecular diagnosis, many mutations have been described in more than 300 genes. Genetic counseling has recently been considered an essential part of the management of PIDs. This study presents the experience of genetic counseling services in the largest PID center in Egypt, and reports on our management plan and the impact of prenatal diagnosis (PND) on families. METHODS: Based on the biochemical and molecular diagnosis of index cases, PND was offered for 10 families in 12 subsequent pregnancies. Five different genes were sequenced by Sanger sequencing in fetal samples. RESULTS: Seven fetuses were either normal or were carriers, while five fetuses were affected and human leukocyte antigen typing was performed, seeking a suitably related donor for stem cell transplantation. CONCLUSION: In spite of the genetic heterogeneity behind PIDs, genetic counseling should play a critical role in the management and future decisions of affected families. PMID- 28900863 TI - Metal-on-Metal Hip Joint Prostheses: a Retrospective Case Series Investigating the Association of Systemic Toxicity with Serum Cobalt and Chromium Concentrations. AB - INTRODUCTION: There have been concerns about prosthesis failure and the potential for systemic toxicity due to release of cobalt and chromium from metal-on-metal hip joint prostheses (MoM-HP). There is conflicting evidence on whether there is a correlation between higher cobalt and chromium concentrations and systemic toxicity. METHODS: We undertook a retrospective review of consecutive patients with MoM-HP referred for outpatient review in toxicology clinics in London, UK, and in the USA recorded in the Toxicology Investigators Consortium (ToxIC) Registry from June 2011 to June 2015. RESULTS: Thirty-one cases were identified; the median (IQR) serum cobalt concentration was 10.0 (3.8-32.8) mcg/L, and the median (IQR) serum chromium concentration was 6.9 (3.7-18.7) mcg/L. Twenty-three (74.2%) had symptoms, most commonly lethargy, hearing loss, and tinnitus. The odds ratios of symptomatic/asymptomatic patients for metal ion concentrations above/below 7 mcg/L were 1.87 (95% CI 0.37-9.57, p = 0.45) and 0.60 (95% CI 0.10 3.50, p = 0.57) for cobalt and chromium, respectively. Two (6.5%) patients with systemic cobalt toxicity had median (IQR) serum cobalt concentrations significantly higher than those without systemic features (630.4 [397.6-863.2] mcg/L versus 9.8 [2.9-16.4] mcg/L; p = 0.017). However, overall, there were no differences between cobalt (p = 0.38) or chromium (p = 0.92) concentrations between symptomatic and asymptomatic patients and no clinical features or investigation results correlated with cobalt or chromium concentration. CONCLUSION: Two (6.5%) of 31 individuals referred for assessment of MoM-HP were diagnosed with systemic cobalt toxicity. However, despite a high prevalence of reported symptoms, neither symptoms nor investigation results correlated with serum cobalt or chromium concentrations. PMID- 28900862 TI - The Influence of Growth and Maturation on Stretch-Shortening Cycle Function in Youth. AB - Hopping, skipping, jumping and sprinting are common tasks in both active play and competitive sports. These movements utilise the stretch-shortening cycle (SSC), which is considered a naturally occurring muscle action for most forms of human locomotion. This muscle action results in more efficient movements and helps optimise relative force generated per motor unit recruited. Innate SSC development throughout childhood and adolescence enables children to increase power (jump higher and sprint faster) as they mature. Despite these improvements in physical performance, the underpinning mechanisms of SSC development during maturational years remain unclear. To the best of our knowledge, a comprehensive review of the potential structural and neuromuscular adaptations that underpin the SSC muscle action does not exist in the literature. Considering the importance of the SSC in human movement, it is imperative to understand how neural and structural adaptations throughout growth and maturation can influence this key muscle action. By understanding the factors that underpin functional SSC development, practitioners and clinicians will possess a better understanding of normal development processes, which will help differentiate between training induced adaptations and those changes that occur naturally due to growth and maturation. Therefore, the focus of this article is to identify the potential underpinning mechanisms that drive development of SSC muscle action and to examine how SSC function is influenced by growth and maturation. PMID- 28900864 TI - Ventricular Tachycardia with ICD Shocks: When to Medicate and When to Ablate. AB - PURPOSE OF REVIEW: Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery and is associated with increased morbidity and mortality. In addition, shocks may have deleterious mechanical and psychological effects. Prevention of ventricular tachycardia (VT) recurrence with the use of antiarrhythmic drugs or catheter ablation may be warranted. Antiarrhythmic drugs are limited by incomplete efficacy and an unfavorable adverse effect profile. Catheter ablation can be effective but acute complications and long-term VT recurrence risk necessitating repeat ablation should be recognized. A shared clinical decision process accounting for patients' cardiac status, comorbidities, and goals of care is often required. RECENT FINDINGS: There are four published randomized trials of catheter ablation for sustained monomorphic VT (SMVT) in the setting of ischemic heart disease; there are no randomized studies for non-ischemic ventricular substrates. The most recent trial is the VANISH trial which randomly allocated patients with ICD, prior infarction, and SMVT despite first-line antiarrhythmic drug therapy to catheter ablation or more aggressive antiarrhythmic drug therapy. During 28 months of follow-up, catheter ablation resulted in a 28% relative risk reduction in the composite endpoint of death, VT storm, and appropriate ICD shock (p = 0.04). In a subgroup analysis, patients having VT despite amiodarone had better outcomes with ablation as compared to increasing amiodarone dose or adding mexiletine. There is evidence for the effectiveness of both catheter ablation and antiarrhythmic drug therapy for patients with myocardial infarction, an implantable defibrillator, and VT. If sotalol is ineffective in suppressing VT, either catheter ablation or initiation of amiodarone is a reasonable option. If VT occurs despite amiodarone therapy, there is evidence that catheter ablation is superior to administration of more aggressive antiarrhythmic drug therapy. Early catheter ablation may be appropriate in some clinical situations such as patients presenting with relatively slow VT below ICD detection, electrical storms, hemodynamically stable VT, or in very selected patients with left ventricular assist devices. The optimal first-line suppressive therapy for VT, after ICD implantation and appropriate programming, remains to be determined. Thus far, there has not been a randomized controlled trial to compare catheter ablation to antiarrhythmic drug therapy as a first-line treatment; the VANISH-2 study has been initiated as a pilot to examine this question. PMID- 28900866 TI - Progressive multifocal leukoencephalopathy 11 years after liver transplantation: a case report. AB - Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by JC virus. Only ten cases of PML have been reported so far in liver transplant recipients. We present a case of liver posttransplantation PML with characteristic clinical and brain MRI findings, but with an atypical late onset, developed 11 years after transplantation and after single-drug, long-term (8 years), and low-dose (750 mg twice a day) immunosuppression with mycophenolate mofetil (MMF). This is the latest onset of PML associated to liver transplant reported. The present case should help physicians to be aware of PML after transplantation, even in the long term and even under low doses of immunosuppressants, especially MMF. PMID- 28900868 TI - Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics. AB - Organoleptic agents constitute an important niche in the field of pharmaceutical excipients. These agents encompass a range of additives responsible for coloring, flavoring, sweetening, and texturing formulations. All these agents have come to play a significant role in pharmaceuticals and cosmetics due to their ability to increase patient compliance by elevating a formulation's elegance and esthetics. However, it is essential to review their physical and chemical attributes before use, as organoleptic agents, similar to active pharmaceutical ingredients (APIs), are susceptible to physical and chemical instability leading to degradation. These instabilities can be triggered by API-organoleptic agent interaction, exposure to light, air and oxygen, and changes in pH and temperature. These organoleptic agent instabilities are of serious concern as they affect API and formulation stability, leading to API degradation or the potential for manifestation of toxicity. Hence, it is extremely critical to evaluate and review the physicochemical properties of organoleptic agents before their use in pharmaceuticals and cosmetics. This literature review discusses commonly used organoleptic agents in pharmaceutical and cosmeceutical formulations, their associated instabilities, and probable approaches to overcoming them. PMID- 28900869 TI - Enabling Development of Paediatric Medicines in Europe: 10 Years of the EU Paediatric Regulation. AB - The year 2017 marks the tenth anniversary of entry into force of the Paediatric Regulation in the European Union (EU). This law aimed to stimulate the development of paediatric medicines and provide more information on their use, as a response to the lack of evidence and approval of medicines for children. The European Medicines Agency (EMA) has had a central role in the implementation of the Regulation. Pharmaceutical companies need to submit a paediatric investigation plan (PIP) to the EMA's Paediatric Committee (PDCO) for every new medicine, unless an exemption (waiver) is granted. The plans, which describe the development of drugs for children, must be agreed well in advance of the request for marketing authorization of the medicine. Deferrals of studies can be granted to allow approval in adults before the completion of paediatric studies. Between January 2007 and December 2016, a total of 273 new medicines and 43 additional pharmaceutical forms appropriate for use in children were authorized in the EU, and 950 PIPs were agreed by the EMA. In addition, 486 waivers of the development of a medicine in one or more medical conditions were agreed. The Paediatric Regulation has had a very positive impact on paediatric drug development, as exemplified by a comparison of two periods of 3 years before and after entry into force of the Regulation. We conclude that the Regulation has resulted in more medicines for children and more information on the pediatric use of medicines in the EU being available to clinicians. PMID- 28900867 TI - Recent Advances in the Etiopathogenesis of Inflammatory Bowel Disease: The Role of Omics. AB - Omics technology presents an exciting and timely opportunity to improve our understanding of the molecular etiology and pathogenesis of the group of chronic, heterogeneous, inflammatory disorders that comprise inflammatory bowel disease (IBD). Interest in the use of omics in the biomedical and clinical research communities is gaining pace due to its potential to make huge strides in our understanding of IBD causality, and pathology. Omics-related research also has applicability for biomarker discovery and the development of individualized treatments for patients, termed 'precision medicine'. This review will evaluate the omics analyses that have been performed in the context of IBD, with a focus on the significance of multi-omics IBD studies and the bioinformatic integration of omics data. Such an approach has the potential to provide a comprehensive analysis of the major determinants of IBD. The translation of omics data into individualized therapy will also be addressed. Major progress in understanding the changes that underlie inflammatory bowel diseases (IBDs) has been achieved; however, the key molecular changes in IBD that could be targeted for better treatments are undefined. This article reviews the latest IBD research on new high-throughput technologies called 'omics', which are measurements and analyses of large numbers of molecules from patients and healthy subjects. Omics data have the potential to dramatically improve therapy by providing new information to tailor highly specific treatments to individual patients with IBD. PMID- 28900870 TI - Death, near death, and an antibiotic. PMID- 28900871 TI - Incidence of Contrast-Induced Nephropathy in Patients with Multiple Myeloma Undergoing Contrast-Enhanced Procedures. AB - Multiple myeloma (MM) is a malignant disorder characterized by clonal proliferation of plasma cells. Renal impairment is a common complication. Contrast-induced nephropathy (CIN) is a form of acute renal failure that can occur in the setting of IV contrast administration. It is more commonly seen in patients with pre-existing renal impairment. Patients with MM commonly require contrast enhanced procedures. The literature regarding the safety of IV contrast in this cohort is lacking. A retrospective review was carried out in a university hospital to identify the incidence of CIN in patients with MM and to look for associated risk factors. 94 patients and 165 procedures were included in the analysis. 10% of procedures resulted in CIN. 59% (10/17) of creatinines had normalized within one month of the procedure. The only factor found to be significant for the development of CIN was the timing of the procedure (<18mths verses >18mths post diagnosis of MM; p = 0.045). CIN appears to occur at an increased rate in patients with MM. However this may be an over-estimation given the common occurrence of renal impairment in this cohort and the close temporal relationship which often exists between systemic illness and contrast-enhanced procedures. PMID- 28900872 TI - The use of bone mineral density measured by dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed microtomography in chronic kidney disease. AB - Chronic kidney disease (CKD) is a risk factor for fractures. The current evaluation of fracture risk is based upon the combination of various clinical factors and quantitative imaging of bone. X-ray-based tools were developed to evaluate bone status and predict fracture risk. Dual energy X-ray absorptiometry (DXA) is available worldwide. Longitudinal studies showed that low areal Bone Mineral Density (BMD) measured by DXA predicts fractures in the CKD population as it does in non uremic populations, with good specificity and moderate sensitivity. Peripheral quantitative computed tomography (pQCT) and high resolution pQCT are research tools which measure volumetric BMD at the tibia and radius. They are able to discriminate between the cortical and trabecular envelopes which are differentially affected by renal osteodystrophy. In CKD, a rapid thinning and increased porosity at the cortex is observed which is associated with increased the risk for fracture. PMID- 28900873 TI - Numerical analysis of intracochlear mechanical auditory stimulation using piezoelectric bending actuators. AB - Cochlear implantation can restore a certain degree of auditory impression of patients suffering from profound hearing loss or deafness. Furthermore, studies have shown that in case of residual hearing, patients benefit from the use of a hearing aid in addition to the cochlear implant. The presented studies aim at the improvement of this electromechanical stimulation (EMS) approach by substituting the external hearing aid by an internal stimulus provided by miniaturized piezoelectric actuators. Finite element analyses are performed in order to derive fundamental guidelines for the actuator layout aiming at maximal mechanical stimuli. Further analyses aim at investigating how the actuator position inside the cochlea influences the basilar membrane oscillation profile. While actuator layout guidelines leading to maximized acoustic stimuli could be derived, some of these guidelines are of complementary nature suggesting that further studies under realistic boundary conditions must be performed. Actuator positioning inside the cochlea is shown to have a significant influence on the resulting auditory impression of the patient. Based on the results, the main differences of external and internal stimulation of the cochlea mechanism are identified. It is shown that if the cochlea tonotopy is considered, the frequency selectivity resulting from the mechanical cochlea stimulus may be improved. PMID- 28900874 TI - Effect of renal transplantation on cognitive function in hemodialysis patients: a longitudinal study. AB - BACKGROUND: The literature notes high prevalence of cognitive function (CF) impairment among hemodialysis patients. Renal transplantation by reversing metabolic factors should improve cognitive function; however, results in post transplant patients are inconsistent. Lack of longitudinal studies, variable and small patient population, variable renal function and post-transplantation period and use of non-specific tests make results difficult to interpret. We looked at CF in stable hemodialysis patients just prior to live renal transplantation and approximately 3 months subsequently using well-validated electrophysiological study of P300 cognitive potential obtained by auditory oddball paradigm using multiple scalp electrodes. METHODS: Ten healthy age- and gender-matched controls (group 1) and 20 end-stage kidney disease (ESKD) male patients on maintenance hemodialysis with no other comorbidities that affect CF were studied before (group 2) and 3 months after successful transplantation (group 3). RESULTS: ESKD population had mean age of 29.7 +/- 7.5 years, with mean dialysis vintage and post-transplant period being 10.3 +/- 6.9 and 3.2 +/- 0.4 months, respectively. Mean P300 latencies in groups 1, 2 and 3 were 319 +/- 33.6, 348.6 +/- 27.8 and 316.4 +/- 33.4 ms, respectively (P < 0.001 group 1 vs 2 and group 2 vs 3; group 1 vs 3 NS). Mean P300 amplitude in groups 1, 2 and 3 was 27.9 +/- 12.8, 13.4 +/- 8.6 and 14.6 +/- 9.4 uV, respectively (P < 0.001 group 1 vs 2 and group 1 vs 3; group 2 vs 3 NS). P300 latencies correlated negatively with hemoglobin and serum albumin. CONCLUSIONS: ESKD patients have impaired CF as documented by prolonged P300 latencies. There was normalization of P300 latencies post-transplantation indicating role of uremic toxins in CF impairment. PMID- 28900875 TI - Single-Arm Study of Etanercept in Adult Patients with Moderate to Severe Rheumatoid Arthritis Who Failed Adalimumab Treatment. AB - INTRODUCTION: To evaluate the efficacy and safety of etanercept treatment in adult patients with moderate to severe rheumatoid arthritis (RA) who failed to respond (primary failure) or lost a satisfactory response (secondary failure) to adalimumab. METHODS: All patients discontinued prior adalimumab treatment and continued methotrexate with etanercept 50 mg once weekly for 24 weeks. The primary study endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at week 12. RESULTS: Eighty-five patients (mean age 56.6 years; female 80.0%) were evaluated for safety and 84 for efficacy. Thirty (35.7%) patients achieved ACR20 at week 12; the lower bound of the 95% confidence interval (CI; 25.6, 46.9) was greater than the prespecified goal of 24% based on previous research. Improvements from baseline in clinical outcomes and patient reported outcomes were observed at each study visit. In planned subgroup analyses, patients with anti-adalimumab antibodies and secondary adalimumab failure had the highest ACR20 response to etanercept at week 12 (11/17 patients; 64.7%). Among the patients with secondary adalimumab failure, those with anti adalimumab antibodies were fivefold more likely to have an ACR20 response to etanercept than those without anti-adalimumab antibodies (odds ratio 5.2; 95% CI 2.0, 13.5; P < 0.001). Adverse events were reported for 62 (72.9%) patients and were consistent with previous studies of etanercept. Most adverse events were mild or moderate in severity. CONCLUSION: Switching to etanercept is a therapeutic option in patients with RA who fail adalimumab treatment. The presence of anti-adalimumab antibodies may provide additional support for switching to etanercept, particularly in patients with secondary adalimumab failure. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01927757. PMID- 28900878 TI - Scientific, educational abstracts presented at the ASER 2017 annual scientific meeting and postgraduate course September 6-9, Toronto, Ontario, Canada. PMID- 28900876 TI - Improving Diagnostic and Therapeutic Outcomes in Pediatric Brain Tumors. AB - Pediatric brain tumors are the primary cause of cancer-related death during childhood. Unfortunately, the number of primary and metastatic brain tumors is steadily increasing while the mortality rates for many central nervous system (CNS) lesions have remained stagnant. Molecularly defined tumor classes have been added to the most recent 2016 World Health Organization (WHO) Classification System of Central Nervous System Brain Tumors, driving potential new treatments and identifying targets to improve survival for these patients. Focusing on the genetic mutations most commonly seen in the pediatric CNS tumor population provides the ability to better define tumors based on shared molecular characteristics. Consequently, there is the potential for greater efficacy in targeted therapy to treat these identified genetic aberrations. Understanding the growing importance of molecular diagnosis in pediatric CNS tumors is vital to successfully using novel targeted therapies and improving patient outcomes. PMID- 28900877 TI - Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case-Control Study. AB - BACKGROUND: Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH). METHODS: Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case-control study. The frequencies and distributions of genotypes and haplotypes were compared between the groups using three genetic models (dominant, recessive, and additive) to identify associations with susceptibility to ATDH. RESULTS: Patients with the rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A genotypes of SLCO1B1 had a significantly lower risk of ATDH, while those carrying the rs2417957 T/T and rs4149063 T/T genotypes had an increased risk. The rs4148323 A/A genotype of UGT1A1 was found to significantly reduce the risk of ATDH. Haplotype analysis showed the TGTG, TTTC, and GTTC haplotypes of SLCO1B1 were associated with an increased ATDH risk, whereas the GACC haplotype was related to a reduced risk. The ATG haplotype of UGT1A1 reduced the risk of ATDH. Moreover, treatment outcomes in tuberculosis patients were further affected by genetic variants of SLCO1B1. CONCLUSIONS: Genetic polymorphisms of SLCO1B1 and UGT1A1 were found to be associated with susceptibility to ATDH. Molecular identification of susceptibility genes provides a theoretical foundation for predicting the likelihood of ATDH and predicting treatment outcomes in tuberculosis patients. PMID- 28900879 TI - Darwinism in metaethics: What if the universal acid cannot be contained? AB - The aim of this article is to explore the impact of Darwinism in metaethics and dispel some of the confusion surrounding it. While the prospects for a Darwinian metaethics appear to be improving, some underlying epistemological issues remain unclear. We will focus on the so-called Evolutionary Debunking Arguments (EDAs) which, when applied in metaethics, are defined as arguments that appeal to the evolutionary origins of moral beliefs so as to undermine their epistemic justification. The point is that an epistemic disanalogy can be identified in the debate on EDAs between moral beliefs and other kinds of beliefs, insofar as only the former are regarded as vulnerable to EDAs. First, we will analyze some significant debunking positions in metaethics in order to show that they do not provide adequate justification for such an epistemic disanalogy. Then, we will assess whether they can avoid the accusation of being epistemically incoherent by adopting the same evolutionary account for all kinds of beliefs. In other words, once it is argued that Darwinism has a corrosive impact on metaethics, what if its universal acid cannot be contained? PMID- 28900880 TI - Characterizing Indeterminate Renal Masses with Molecular Imaging: the Role of 99mTc-MIBI SPECT/CT. AB - PURPOSE OF REVIEW: The majority of enhancing renal masses cannot be characterized through imaging as malignant or benign; however, such characterization could save patients from unnecessary surgery and/or biopsy and associated morbidity. Herein, we review the recent literature on the emerging use of 99mTc-MIBI SPECT/CT in preoperative differentiation of enhancing renal masses. RECENT FINDINGS: Recent reports have shown that 99mTc-MIBI SPECT/CT imaging can differentiate mitochondrial-rich, benign, or indolent renal masses from renal cell carcinoma. These studies demonstrate good correlation between a positive 99mTc-MIBI SPECT/CT scan and a pathologically proven diagnosis of renal oncocytoma and hybrid oncocytic/chromophobe tumor. In addition, there is excellent correlation between a negative scan and a diagnosis of clear cell subtype of renal cell carcinoma. Preoperative 99mTc-MIBI SPECT/CT offers a non-invasive method for differentiating renal lesions with low aggressiveness from other RCCs, in particular, clear cell renal cell carcinoma. PMID- 28900881 TI - Recognition-induced forgetting of faces in visual long-term memory. AB - Despite more than a century of evidence that long-term memory for pictures and words are different, much of what we know about memory comes from studies using words. Recent research examining visual long-term memory has demonstrated that recognizing an object induces the forgetting of objects from the same category. This recognition-induced forgetting has been shown with a variety of everyday objects. However, unlike everyday objects, faces are objects of expertise. As a result, faces may be immune to recognition-induced forgetting. However, despite excellent memory for such stimuli, we found that faces were susceptible to recognition-induced forgetting. Our findings have implications for how models of human memory account for recognition-induced forgetting as well as represent objects of expertise and consequences for eyewitness testimony and the justice system. PMID- 28900882 TI - Acute Paracoccidioidomycosis in a 40-Year-Old Man: A Case Report and Literature Review. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis that represents an important public health problem in Latin America due to its life-threatening character. It is considered occupational disease of agricultural workers. In this report, we present a rare and serious case of the acute form of the disease in a 40-year-old man with no history of contact with the rural environment. Diagnosis was made through cervical lymph node biopsy, and treatment was performed with antifungal drugs, which produced effective results. A literature review was conducted with discussion of clinical, pathophysiological and therapeutic aspects of PCM. PMID- 28900884 TI - The social dimension of biobanking: objectives and challenges. AB - The present article allows to explore, analyze and reflect on the consequences and problems posed by biobanks and attempts to prove the need of social and humanitarian support in establishing and functioning of biobanks as a new type of scientific institutions. The basis of the article is the latest publications devoted to social and humanitarian aspects of biobanking and Russian experience of the initial formation of this subject domain (before the first professional biobanks were established in Russia in the 2010-s, the only highly specialized collections of bio-samples had been registered). The article marks and classifies different aspects of biobanking that objectively demands the participation of specialists in ethics and social sciences. The cases of biobanking development and risks are estimated; the objective need of applied ethics and social sciences specialists' participation in biobanking is proved. PMID- 28900885 TI - Erratum to: One-level step section histological analysis is insufficient to confirm complete pathological response after neoadjuvant chemoradiation for rectal cancer. AB - Unfortunately, one of the author name was wrongly published in the original publication. The complete correct name should read as follows "Beatriz Camargo Azevedo". The original article was updated. PMID- 28900886 TI - The effect of obesity on laparoscopic and robotic-assisted colorectal surgery outcomes: an ACS-NSQIP database analysis. AB - Advantages of robotic-assisted colorectal surgery have been reported, but the effect on outcomes between obese and non-obese patients undergoing laparoscopic and robotic-assisted colorectal surgery remains unclear. Patients who underwent elective laparoscopic and robotic colon or rectal resections between 2012 and 2014 were identified in the ACS-NSQIP database. Propensity score matching was performed to determine the effect of obesity on laparoscopic and robotic-assisted 30-day surgical outcomes. 29,172 patients met inclusion criteria; 27,693 (94.9%) underwent laparoscopic colorectal surgery while 1479 (5.1%) underwent robotic assisted surgery. Mean BMI was 28.4 kg/m2 and 35% of patients had a BMI >=30 kg/m2. A 10-to-1 propensity matching of laparoscopic to robotic approaches was performed, resulting in 14,770 (90.9%) laparoscopic patients and 1477 (9.1%) robotic-assisted patients available for analysis. Robotic-assisted surgery was associated with lower conversion to laparotomy (2.4 vs 3.4%; p = 0.04) and decreased length-of-stay (4.5+/-3.2 vs 5.1+/-4.5 days; p < 0.0001). After adjusting for BMI and surgical approach, obese patients undergoing robotic assisted surgery had a reduced odds ratio for developing prolonged ileus (p = 0.03). Robotic-assisted colorectal surgery is associated with fewer conversions to laparotomy and shorter length-of-stays compared to laparoscopic surgery. Risk of prolonged ileus is significantly reduced in obese patients undergoing a robotic-assisted approach. PMID- 28900889 TI - 24th Annual Conference of the International Society for Quality of Life Research. PMID- 28900887 TI - Insomnia in tension-type headache: a population-based study. AB - BACKGROUND: Tension-type headache (TTH) represents the most common type of headache among the general population. Although such headaches are usually mild in severity, some individuals with TTH experience severe symptoms and psychiatric comorbidities. Such patients may also experience sleep disturbances, which have been associated with headache exacerbation. Nevertheless, information regarding the prevalence and impact of insomnia among individuals with TTH in a population based setting is limited. Therefore, the aim of the present study was to evaluate the prevalence and impact of insomnia among individuals with TTH using data from the Korean Headache-Sleep Study (KHSS). METHODS: We analysed data from the KHSS-a nation-wide, cross-sectional, population-based survey on headache and sleep involving Korean adults aged 19 to 69 years. Insomnia was defined as an Insomnia Severity Index score >= 10. RESULTS: Among 2695 participants, 570 (21.2%) and 290 (10.8%) were classified as having TTH and insomnia, respectively. Among individuals with TTH, 113 (19.8%) met the criteria for probable migraine (PM). The prevalence of insomnia among individuals with TTH was significantly higher than that among individuals without headache (13.2% vs. 5.8%, p < 0.001). However, among the TTH group, the prevalence of insomnia did not significantly differ between participants fulfilling PM criteria and those not fulfilling PM criteria (14.2% vs. 12.9%, p = 0.725). Among individuals with TTH, headache frequency [median and interquartile range (IQR): 1.0 (0.3-3.0) vs. 0.4 (0.2-1.0), p = 0.002], visual analogue scale scores for headache intensity [median and IQR: 5.0 (4.0-7.0) vs. 4.0 (3.0-6.0), p < 0.001], Headache Impact Test-6 scores [median and IQR: 46.0 (40.0-52.0) vs. 42.0 (38.0-46.0), p < 0.001], anxiety prevalence (28.0% vs. 6.7%, p < 0.001), and depression prevalence (21.3% vs. 1.6%, p < 0.001) were significantly higher in those with insomnia than in those without insomnia. CONCLUSIONS: Our findings indicate that insomnia is prevalent among individuals with TTH. Moreover, insomnia was associated with exacerbation of headache symptoms and psychiatric comorbidities. Therefore, identification of insomnia among individuals with TTH is required to improve the management of headache symptoms in such patients. PMID- 28900891 TI - Irish Endocrine Society 41st Annual Meeting, 13th and 14th October 2017, Grand Hotel, Malahide, Dublin. PMID- 28900890 TI - High level of venous thromboembolism in critically ill trauma patients despite early and well-driven thromboprophylaxis protocol. AB - BACKGROUND: Venous thromboembolism (VTE) is one of the most common preventable causes of in-hospital death in trauma patients surviving their injuries. We assessed the prevalence, incidence and risk factors for deep venous thrombosis (DVT) and pulmonary embolism (PE) in critically ill trauma patients, in the setting of a mature and early mechanical and pharmacological thromboprophylaxis protocol. METHODS: This was a prospective observational study on a cohort of patients from a surgical intensive care unit of a university level 1 trauma centre. We enrolled consecutive primary trauma patients expected to be in intensive care for >=48 h. Thromboprophylaxis was protocol driven. DVT screening was performed by duplex ultrasound of upper and lower extremities within the first 48 h, between 5 and 7 days and then weekly until discharge. We recorded VTE risk factors at baseline and on each examination day. Independent risk factors were analysed using a multivariate logistic regression. RESULTS: In 153 patients with a mean Injury Severity Score of 23 +/- 12, the prevalence of VTE was 30.7%, 95 CI [23.7-38.8] (29.4% DVT and 4.6% PE). The incidence was 18%, 95 CI [14-24] patients-week. The median time of apparition of DVT was 6 days [1; 4]. The global protocol compliance was 77.8% with a median time of introduction of the pharmacological prophylaxis of 1 day [1; 2]. We identified four independent risk factors for VTE: central venous catheter (OR 4.39, 95 CI [1.1-29]), medullar injury (OR 5.59, 95 CI [1.7-12.9]), initial systolic arterial pressure <80 mmHg (OR 3.64, 95 CI [1.3-10.8]), and pelvic fracture (OR 3.04, 95 CI [1.2-7.9]). CONCLUSION: Despite a rigorous, protocol-driven thromboprophylaxis, critically ill trauma patients showed a high incidence of VTE. Further research is needed to tailor pharmacological prophylaxis and balance the risks and benefits. PMID- 28900892 TI - Increased locus coeruleus tonic activity causes disengagement from a patch foraging task. AB - High levels of locus coeruleus (LC) tonic activity are associated with distraction and poor performance within a task. Adaptive gain theory (AGT; Aston Jones & Cohen, 2005) suggests that this may reflect an adaptive function of the LC, encouraging search for more remunerative opportunities in times of low utility. Here, we examine whether stimulating LC tonic activity using designer receptors (DREADDs) promotes searching for better opportunities in a patch foraging task as the value of a patch diminishes. The task required rats to decide repeatedly whether to exploit an immediate but depleting reward within a patch or to incur the cost of a time delay to travel to a new, fuller patch. Similar to behavior associated with high LC tonic activity in other tasks, we found that stimulating LC tonic activity impaired task performance, resulting in reduced task participation and increased response times and omission rates. However, this was accompanied by a more specific, predicted effect: a significant tendency to leave patches earlier, which was best explained by an increase in decision noise rather than a systematic bias to leave earlier (i.e., at higher values). This effect is consistent with the hypothesis that high LC tonic activity favors disengagement from current behavior, and the pursuit of alternatives, by augmenting processing noise. These results provide direct causal evidence for the relationship between LC tonic activity and flexible task switching proposed by AGT. PMID- 28900894 TI - Erratum to: Naturally occurring Vpr inhibitors from medicinal plants of Myanmar. PMID- 28900893 TI - Associations of Neighborhood Environmental Attributes with Walking in Japan: Moderating Effects of Area-Level Socioeconomic Status. AB - Several studies have examined how the associations of built environment attributes with walking behaviors may be moderated by socioeconomic status (SES). Such understanding is important to address socioeconomic inequalities in health through urban design initiatives. However, to date, there is no study examining the moderation effects of SES in the relationships of environmental attributes and walking in non-Western countries. The current study aims to examine associations of environmental attributes with walking behaviors among Japanese adults, and to test whether these associations were moderated by area-level SES. Data on walking were collected from Japanese adults using a nationwide Internet survey (N = 4605). Built environment measures including population density, street density, distance to the nearest public open space, and distance to the nearest commercial destination were calculated using geographic information systems software. An index of neighborhood deprivation was used as an area-level indicator of SES. Logistic regression models adjusted for clustering and sociodemographic variables were used. It was found that more residents in high SES areas walked for commuting, for errands, and for exercise compared with those who lived in low SES areas. When the whole sample was examined, all environmental attributes were associated with walking behaviors (except for street density not being associated with walking for exercise). Associations of environmental attributes with walking behaviors were moderated by area-level SES only in walking for exercise. Walking for exercise was associated with higher population density, higher street density (marginally significant), and shorter distance to the nearest commercial destination only in high SES areas. Our findings showed that the associations of these environmental attributes and walking behaviors were largely consistent across different SES levels. Therefore, urban design interventions focusing on low SES areas may help to reduce socioeconomic disparities in walking. PMID- 28900895 TI - Erratum to: Resin glycosides from Convolvulaceae plants. PMID- 28900896 TI - Fusion of gelonin and anti-insulin-like growth factor-1 receptor (IGF-1R) affibody for enhanced brain cancer therapy. AB - Owing to the extraordinary potency in inhibiting protein translation that could eventually lead to apoptosis of tumor cells, ribosome-inactivating proteins (RIPs) such as gelonin have been considered attractive drug candidates for cancer therapy. However, due to several critical obstacles (e.g., severe toxicity issues caused by a lack of selectivity in their mode of action and the low cytotoxicity via poor cellular uptake, etc.), clinical application of RIPs is yet far from being accomplished. To overcome these challenges, in the present study, we engineered gelonin fusion proteins with anti-insulin-like growth factor-1 receptor (IGF-1R) affibody ("IAFF") via the genetic recombinant method and the SpyCatcher/SpyTag-mediated conjugation method. To this end, recombinant gelonin anti-IGF-1R affibody (rGel-IAFF), gelonin-SpyCatcher (Gel-SpyCatcher) and SpyTag IAFF fusion proteins were produced from the E. coli expression system, and gelonin-IAFF conjugate was synthesized by mixing Gel-SpyCatcher and SpyTag-IAFF. After preparation of both rGel-IAFF and Gel-IAFF conjugate, their components' functionality was characterized in vitro. Our assay results confirmed that, while both Gel-IAFF and Gel-SpyCatcher retained equipotent N-glycosidase activity to that of gelonin, IAFF was able to selectively bind to IGF-1R overexpressed U87 MG brain cancer cells over low expression LNCaP cells. The results of cellular analyses showed that rGel-IAFF and Gel-IAFF conjugate both exhibited a greater cell uptake in the U87 MG cells than gelonin, but not in the LNCaP cells, yielding a significantly augmented cytotoxicity only in the U87 MG cells. Remarkably, rGel-IAFF and Gel-IAFF conjugate displayed 22- and 5.6-fold lower IC50 values (avg. IC50: 180 and 720 nM, respectively) than gelonin (avg. IC50: 4000 nM) in the U87 MG cells. Overall, the results of the present research demonstrated that fusion of gelonin with IAFF could provide an effective way to enhance the anti-tumor activity, while reducing the associated toxicity of gelonin. PMID- 28900897 TI - Ulipristal Acetate: A Review in Symptomatic Uterine Fibroids. AB - Oral ulipristal acetate (Esmya(r); Fibristal(r)), a synthetic selective progesterone receptor modulator, is the first selective progesterone modulator to be approved for the treatment of uterine fibroids. It was initially approved for the preoperative treatment of moderate to severe uterine fibroid symptoms in women of reproductive age. Recently, the indication was extended in the EU to include the intermittent treatment of moderate to severe uterine fibroid symptoms. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the preoperative and intermittent use of ulipristal acetate in patients with symptomatic uterine fibroids. Ulipristal acetate is an effective and generally well tolerated treatment for patients with symptomatic uterine fibroids, both as preoperative, single-course treatment and as intermittent, longer-term treatment. It is noninferior in efficacy to intramuscular leuprolide acetate, as a preoperative treatment, and is associated with a lower rate of hot flashes, a common adverse event with gonadotropin releasing hormone analogues. Thus, ulipristal acetate is an effective option for both preoperative and intermittent treatment of moderate to severe, symptomatic uterine fibroids in women of reproductive age. PMID- 28900899 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 28900898 TI - Methods for Practising Ethics in Research and Innovation: A Literature Review, Critical Analysis and Recommendations. AB - This paper provides a systematic literature review, analysis and discussion of methods that are proposed to practise ethics in research and innovation (R&I). Ethical considerations concerning the impacts of R&I are increasingly important, due to the quickening pace of technological innovation and the ubiquitous use of the outcomes of R&I processes in society. For this reason, several methods for practising ethics have been developed in different fields of R&I. The paper first of all presents a systematic search of academic sources that present and discuss such methods. Secondly, it provides a categorisation of these methods according to three main kinds: (1) ex ante methods, dealing with emerging technologies, (2) intra methods, dealing with technology design, and (3) ex post methods, dealing with ethical analysis of existing technologies. Thirdly, it discusses the methods by considering problems in the way they deal with the uncertainty of technological change, ethical technology design, the identification, analysis and resolving of ethical impacts of technologies and stakeholder participation. The results and discussion of our literature review are valuable for gaining an overview of the state of the art and serve as an outline of a future research agenda of methods for practising ethics in R&I. PMID- 28900900 TI - Mapping the Information Trace in Local Field Potentials by a Computational Method of Two-Dimensional Time-Shifting Synchronization Likelihood Based on Graphic Processing Unit Acceleration. AB - The local field potential (LFP) is a signal reflecting the electrical activity of neurons surrounding the electrode tip. Synchronization between LFP signals provides important details about how neural networks are organized. Synchronization between two distant brain regions is hard to detect using linear synchronization algorithms like correlation and coherence. Synchronization likelihood (SL) is a non-linear synchronization-detecting algorithm widely used in studies of neural signals from two distant brain areas. One drawback of non linear algorithms is the heavy computational burden. In the present study, we proposed a graphic processing unit (GPU)-accelerated implementation of an SL algorithm with optional 2-dimensional time-shifting. We tested the algorithm with both artificial data and raw LFP data. The results showed that this method revealed detailed information from original data with the synchronization values of two temporal axes, delay time and onset time, and thus can be used to reconstruct the temporal structure of a neural network. Our results suggest that this GPU-accelerated method can be extended to other algorithms for processing time-series signals (like EEG and fMRI) using similar recording techniques. PMID- 28900901 TI - Erratum to: Estimated Healthcare Costs of Melanoma in Australia Over 3 Years Post Diagnosis. AB - The last word in the first paragraph which previously read AU$25 million should read 25 million as this relates to population size. PMID- 28900902 TI - Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis. AB - BACKGROUND: Prognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP). METHODS: Patients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation. Using all 50 clinical and laboratory variables available on day 1 of critical care admission, Cox proportional hazards regression was fitted to select variables for inclusion in two prognostic models, using stepwise selection and nonparametric bootstrapping sampling techniques. Using Area under the receiver operating characteristic curve (AuROC) analysis, the performance of the models was compared to SOFA and APACHE II. RESULTS: Five variables (age, SOFA score, lowest temperature, highest heart rate, haematocrit) were entered into the prognostic models. The discriminatory performance of the 6 month prognostic model yielded an AuROC 0.81 (95% CI 0.76-0.86), 0.73 (95% CI 0.69-0.78) and 0.76 (95% CI 0.69-0.83) for the derivation, geographic and temporal external validation cohorts, respectively. The 28-day prognostic tool yielded an AuROC 0.82 (95% CI 0.77-0.88), 0.75 (95% CI 0.69-0.80) and 0.79 (95% CI 0.71-0.87) for the same cohorts. These AuROCs appeared consistently superior to those obtained with the SOFA and APACHE II scores alone. CONCLUSIONS: The two prognostic models developed for 6-month and 28-day mortality prediction in critically ill septic patients with FP, in the postoperative phase, enhanced the day one SOFA score's predictive utility by adding a few key variables: age, lowest recorded temperature, highest recorded heart rate and haematocrit. External validation of their predictive capability in larger cohorts is needed, before introduction of the proposed scores into clinical practice to inform decision making and the design of clinical trials. PMID- 28900903 TI - The cost of switching between taxonomic and thematic semantics. AB - Current models and theories of semantic knowledge primarily capture taxonomic relationships (DOG and WOLF) and largely do not address the role of thematic relationships in semantic knowledge (DOG and LEASH). Recent evidence suggests that processing or representation of thematic relationships may be distinct from taxonomic relationships. If taxonomic and thematic relations are distinct, then there should be a cost associated with switching between them even when the task remains constant. This hypothesis was tested using two different semantic relatedness judgment tasks: Experiment 1 used a triads task and Experiment 2 used an oddball task. In both experiments, participants were faster to respond when the same relationship appeared on consecutive trials than when the relationship types were different, even though the task remained the same and the specific relations were different on each trial. These results are consistent with the theory that taxonomic and thematic relations rely on distinct processes or representations. PMID- 28900904 TI - Lonoctocog Alfa: A Review in Haemophilia A. AB - Lonoctocog alfa (rVIII-SingleChain; Afstyla(r)) is a novel single-chain recombinant factor VIII (FVIII) molecule, with a truncated B-domain and the heavy and light chains covalently linked to form a stable and homogenous drug that binds with high affinity to von Willebrand factor (VWF). Intravenous lonoctocog alfa is approved for the prophylaxis and treatment of bleeding in patients with haemophilia A in several countries worldwide. In two pivotal, multicentre trials, lonoctocog alfa was effective in the treatment of bleeding episodes and as prophylaxis, including for perioperative management in adults, adolescents and children. In terms of haemostatic efficacy in controlling bleeding episodes, overall treatment and investigator-assessed success rates were high across all age groups, with the majority of these bleeds controlled with a single injection of lonoctocog alfa. Low median spontaneous, overall and traumatic annualized bleeding rates were evident with prophylactic lonoctocog alfa regimens in both trials. Lonoctocog alfa was generally well-tolerated, with very low rates of injection-site reactions. No previously treated patient experienced an anaphylactic reaction or developed an inhibitor. In conclusion, lonoctocog alfa is an effective and generally well-tolerated alternative to conventional FVIII products for the treatment and prophylaxis of bleeding, including in the surgical setting, in adults, adolescents and children with haemophilia A. PMID- 28900905 TI - Biodegradation of ramie stalk by Flammulina velutipes: mushroom production and substrate utilization. AB - In the textile industry, ramie stalk is byproducts with a low economic value. The potential use of this leftover as a substrate ingredient for Flammulina velutipes (F. velutipe) cultivation was evaluated. The degradation and utilization of ramie stalk by F. velutipes was evaluated through mushroom production, lignocelluloses degradation and lignocellulolytic enzymes activity. The best substrate mixture for F. velutipes cultivation comprised 50% ramie stalk, 20% cottonseed hulls, 25% wheat bran, 4% cornstarch and 2% CaCO3. The highest biological efficiency of fruiting bodies was reached 119.7%. F. velutipes appears to degrade 12.7-32.0% lignin, 14.4-30.2% cellulose and 9.3-25.7% hemicellulose during cultivation on the different substrates. The results of enzymes activities showed that laccase and peroxidase were higher before fruiting; while cellulase and hemicellulase showed higher activities after fruiting. The biological efficiency of fruiting bodies was positively correlated with the activities of cellulase, hemicellulase and ligninolytic enzyme. The results of this study demonstrate that ramie stalk can be used as an effective supplement for increasing mushroom yield in F. velutipes. PMID- 28900906 TI - Introduction. AB - This second edition volume will present an updated, state-of-the art description and analysis of the rapidly expanding field of store-operated Ca2+ entry (SOCE). And this first part will deal with the most fundamental mechanistic concepts underlying this process. In this brief introduction, I will try to summarize the historical development of the concept of store-operated Ca2+ entry and say a bit about some recent work that speaks to its general function in cell signaling. Much of the material below is taken from the Introduction to the first edition, updated for the second edition. PMID- 28900907 TI - The STIM-Orai Pathway: STIM-Orai Structures: Isolated and in Complex. AB - Considerable progress has been made elucidating the molecular mechanisms of calcium (Ca2+) sensing by stromal interaction molecules (STIMs) and the basis for Orai channel activity. This chapter focuses on the available high-resolution structural details of STIM and Orai proteins with respect to the regulation of store-operated Ca2+ entry (SOCE). Solution structures of the Ca2+-sensing domains of STIM1 and STIM2 are reviewed in detail, crystal structures of cytosolic coiled coil STIM fragments are discussed, and an overview of the closed Drosophila melanogaster Orai hexameric structure is provided. Additionally, we highlight structures of human Orai1 N-terminal and C-terminal domains in complex with calmodulin and human STIM1, respectively. Ultimately, the accessible structural data are discussed in terms of potential mechanisms of action and cohesiveness with functional observations. PMID- 28900909 TI - The STIM-Orai Pathway: The Interactions Between STIM and Orai. AB - A primary Ca2+ entry pathway in non-excitable cells is established by the Ca2+ release-activated Ca2+ channels. Their two limiting molecular components include the Ca2+-sensor protein STIM1 located in the endoplasmic reticulum and the Orai channel in the plasma membrane. STIM1 senses the luminal Ca2+ content, and store depletion induces its oligomerization into puncta-like structures, thereby triggering coupling to as well as activation of Orai channels. A C-terminal STIM1 domain is assumed to couple to both C- and N-terminal, cytosolic strands of Orai, accomplishing gating of the channel. Here we highlight the inter- and intramolecular steps of the STIM1-Orai signaling cascade together with critical sites of the pore structure that accomplishes Ca2+ permeation. PMID- 28900908 TI - The STIM-Orai Pathway: Orai, the Pore-Forming Subunit of the CRAC Channel. AB - This chapter focuses on the Orai proteins, Orai1-Orai3, with special emphasis on Orai1, in humans and other mammals, and on the definitive evidence that Orai is the pore subunit of the CRAC channel. It begins by reviewing briefly the defining characteristics of the CRAC channel, then discusses the studies that implicated Orai as part of the store-operated Ca2+ entry pathway and as the CRAC channel pore subunit, and finally examines ongoing work that is providing insights into CRAC channel structure and gating. PMID- 28900910 TI - The STIM-Orai Pathway: Conformational Coupling Between STIM and Orai in the Activation of Store-Operated Ca2+ Entry. AB - Store-operated Ca2+ entry fulfills a crucial role in controlling Ca2+ signals in almost all cells. The Ca2+-sensing stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER) undergo complex conformational changes in response to depleted ER luminal Ca2+, allowing them to unfold and become trapped in ER-plasma membrane (PM) junctions. Dimers of STIM proteins trap and gate the plasma membrane Orai Ca2+ channels within these junctions to generate discrete zones of high Ca2+ and regulate sensitive Ca2+-dependent intracellular signaling pathways. The STIM-Orai activating region (SOAR) of STIM1 becomes exposed upon store depletion and promotes trapping of Orai1 at the PM. Residue Phe-394 within SOAR forms an integral part of the high-affinity Orai1-interacting site. Our results demonstrate that only a single active site within the dimeric SOAR domain of STIM1 is required for the activation of Orai1 channel activity. This unimolecular model is strongly supported by evidence of variable STIM1:Orai1 stoichiometry reported in many studies. We hypothesize that unimolecular coupling promotes cross-linking of channels, localizing Ca2+ signals, and regulating channel activity. We have also identified a key "nexus" region in Orai1 near the C-terminal STIM1-binding site that can be mutated to constitutively activate Ca2+ entry, mimicking STIM1 activated channels. This suggests that STIM1 mediates gating of Orai1 in an allosteric manner via interaction with the Orai1 C-terminus alone. This model suggests the dual role of STIM1 in regulating both localization and gating of Orai1 channels and has important implications for the regulation of SOCE-mediated downstream signaling and the kinetics of channel activation. PMID- 28900911 TI - The STIM-Orai Pathway: Regulation of STIM and Orai by Thiol Modifications. AB - Cysteines are among the least abundant amino acids found in proteins. Due to their unique nucleophilic thiol group, they are able to undergo a broad range of chemical modifications besides their known role in disulfide formation, such as S sulfenylation (-SOH), S-sulfinylation (-SO(2)H), S-sufonylation (-SO(3)H), S glutathionylation (-SSG), and S-sulfhydration (-SSH), among others. These posttranslational modifications can be irreversible and act as transitional modifiers or as reversible on-off switches for the function of proteins. Disturbances of the redox homeostasis, for example, in situations of increased oxidative stress, can contribute to a range of diseases. Because Ca2+ signaling mediated by store-operated calcium entry (SOCE) is involved in a plethora of cellular responses, the cross-talk between reactive oxygen species (ROS) and Ca2+ is critical for homeostatic control. Identification of calcium regulatory protein targets of thiol redox modifications is needed to understand their role in biology and disease. PMID- 28900912 TI - The STIM-Orai Pathway: Light-Operated Ca2+ Entry Through Engineered CRAC Channels. AB - Ca2+ signals regulate a plethora of cellular functions that include muscle contraction, heart beating, hormone secretion, lymphocyte activation, gene expression, and metabolism. To study the impact of Ca2+ signals on biological processes, pharmacological tools and caged compounds have been commonly applied to induce fluctuations of intracellular Ca2+ concentrations. These conventional approaches, nonetheless, lack rapid reversibility and high spatiotemporal resolution. To overcome these disadvantages, we and others have devised a series of photoactivatable genetically encoded Ca2+ actuators (GECAs) by installing light sensitivities into a bona fide highly selective Ca2+ channel, the Ca2+ release-activated Ca2+ (CRAC) channel. Store-operated CRAC channel serves as a major route for Ca2+ entry in many cell types. These GECAs enable remote and precise manipulation of Ca2+ signaling in both excitable and non-excitable cells. When combined with nanotechnology, it becomes feasible to wirelessly photo modulate Ca2+-dependent activities in vivo. In this chapter, we briefly review most recent advances in engineering CRAC channels to achieve optical control over Ca2+ signaling, outline their design principles and kinetic features, and present exemplary applications of GECAs engineered from CRAC channels. PMID- 28900914 TI - STIM-TRP Pathways and Microdomain Organization: Contribution of TRPC1 in Store Operated Ca2+ Entry: Impact on Ca2+ Signaling and Cell Function. AB - Store-operated calcium entry (SOCE) is a ubiquitous Ca2+ entry pathway that is activated in response to depletion of ER-Ca2+ stores and critically controls the regulation of physiological functions in a wide variety of cell types. The transient receptor potential canonical (TRPC) channels (TRPCs 1-7), which are activated by stimuli leading to PIP2 hydrolysis, were first identified as molecular components of SOCE channels. While TRPC1 was associated with SOCE and regulation of function in several cell types, none of the TRPC members displayed I CRAC, the store-operated current identified in lymphocytes and mast cells. Intensive search finally led to the identification of Orai1 and STIM1 as the primary components of the CRAC channel. Orai1 was established as the pore-forming channel protein and STIM1 as the ER-Ca2+ sensor protein involved in activation of Orai1. STIM1 also activates TRPC1 via a distinct domain in its C-terminus. However, TRPC1 function depends on Orai1-mediated Ca2+ entry, which triggers recruitment of TRPC1 into the plasma membrane where it is activated by STIM1. TRPC1 and Orai1 form distinct store-operated Ca2+ channels that regulate specific cellular functions. It is now clearly established that regulation of TRPC1 trafficking can change plasma membrane levels of the channel, the phenotype of the store-operated Ca2+ current, as well as pattern of SOCE-mediated [Ca2+]i signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca2+]i signal generated by Orai1. This review will highlight current concepts of the activation and regulation of TRPC1 channels and its impact on cell function. PMID- 28900913 TI - STIM-TRP Pathways and Microdomain Organization: Ca2+ Influx Channels: The Orai STIM1-TRPC Complexes. AB - Ca2+ influx by plasma membrane Ca2+ channels is the crucial component of the receptor-evoked Ca2+ signal. The two main Ca2+ influx channels of non-excitable cells are the Orai and TRPC families of Ca2+ channels. These channels are activated in response to cell stimulation and Ca2+ release from the endoplasmic reticulum (ER). The protein that conveys the Ca2+ content of the ER to the plasma membrane is the ER Ca2+ sensor STIM1. STIM1 activates the Orai channels and is obligatory for channel opening. TRPC channels can function in two modes, as STIM1 dependent and STIM1-independent. When activated by STIM1, both channel types function at the ER/PM (plasma membrane) junctions. This chapter describes the properties and regulation of the channels by STIM1, with emphasis how and when TRPC channels function as STIM1-dependent and STIM1-independent modes and their unique Ca2+-dependent physiological functions that are not shared with the Orai channels. PMID- 28900915 TI - STIM-TRP Pathways and Microdomain Organization: Auxiliary Proteins of the STIM/Orai Complex. AB - The basic paradigm of a mechanism for calcium influx triggered after a reduction on calcium store content implies a sensor of calcium concentration on the endoplasmic reticulum (the stores) and a calcium channel immersed on the plasma membrane. These two basic components are STIM and Orai, the most fundamental and minimal molecular constituents of the store-operated calcium entry mechanism. However, even when minimal components can be reduced to these two proteins, the intricate process involved in approximating two cellular membranes (endoplasmic reticulum, ER and plasma membrane, PM) require the participation of several other components, many of which remain unidentified to this date. Here we review several of the proteins identified as constituents of the so-called store operated calcium influx complex (SOCIC) and discuss their role in modulating this complex phenomenon. PMID- 28900916 TI - Introduction. AB - In the title of this part of the book, the tail is wagging not just in a single dog but multiple dogs; in other words, a single process SOCE (tail) somehow involves a cross talk of (wagging) large and powerful organelle and cellular compartments (dogs). So how is this possible? Is this really necessary? Is the title actually appropriate?SOCE is a rather special process, it allows efficient signaling based on a ubiquitous second messenger (Ca2+) in multiple cell and tissue types, it has specific signaling modality (i.e., some downstream reactions depend specifically on SOCE and not just on global Ca2+ increase), it is vital for the normal functioning of multiple types of cells and tissues, and when misregulated it induces important pathological processes. The reader hopefully agree that such an important "tail" is more appropriate for a kangaroo than for a Chihuahua and that it has awesome wagging capacity. PMID- 28900917 TI - New Aspects of the Contribution of ER to SOCE Regulation: The Role of the ER and ER-Plasma Membrane Junctions in the Regulation of SOCE. AB - The junctions between the endoplasmic reticulum and the plasma membrane are essential platforms for the activation of store-operated Ca2+ influx. These junctions have specific dimensions and are nonuniformly distributed in polarized cells. The mechanisms involved in the formation of the junctions are currently undergoing vigorous investigation, and significant progress was attained in this research area during the last 10 years. Some cell types display stationary junctions, while in other cells, new junctions can form rapidly following cytosolic Ca2+ signals and/or the reduction of the Ca2+ concentration in the lumen of the endoplasmic reticulum; furthermore, in moving cells, junctions can undergo saltatory formation, long distance sliding, and dissolution. The proteins involved in the activation of the Ca2+ influx could be also involved in the formation of the junctions. The architecture, dynamics, and localization of the junctions are important for the regulation of Ca2+ signaling cascades and their downstream events. PMID- 28900918 TI - New Aspects of the Contribution of ER to SOCE Regulation: TRPC Proteins as a Link Between Plasma Membrane Ion Transport and Intracellular Ca2+ Stores. AB - Transient receptor potential canonical (TRPC) proteins were identified as molecular candidates of receptor- and/or store-operated channels because of their close homology to the Drosophila TRP and TRPL. Functional studies have revealed that TRPC channels play an integrated part of phospholipase C-transduced cell signaling, mediating the influx of both Ca2+ and Na+ into cells. As a consequence, the TRPC channels have diverse functional roles in different cell types, including metabotropic receptor-evoked membrane depolarization and intracellular Ca2+ concentration elevation. Depending on the cellular environment and the protein partners present in the channel complex, the TRPC channels display different biophysical properties and mechanisms of regulation, including but not limited to the Ca2+ filling state of the endoplasmic reticulum. Despite the overwhelming focus on STIM-regulated Orai channels for store-operated Ca2+ entry, evidence is growing for STIM-operated TRPC channel activities in various cell types, demonstrating both store-dependent and store-independent mechanisms of TRPC channel gating. The existence of physical and functional interactions between plasma membrane-localized TRPC channels and other proteins involved in sensing and regulating the intracellular Ca2+ store contents, such as inositol trisphosphate receptors, Junctate, and Homer, further argues for the role of TRPC proteins in linking plasma membrane ion transport with intracellular Ca2+ stores. The interplay among these proteins will likely define the functional significance of TRPC channel activation in different cellular contexts and under different modes of stimulations. PMID- 28900919 TI - The Role of Mitochondria in the Activation/Maintenance of SOCE: Store-Operated Ca2+ Entry and Mitochondria. AB - Mitochondria extensively modify virtually all cellular Ca2+ transport processes, and store-operated Ca2+ entry (SOCE) is no exception to this rule. The interaction between SOCE and mitochondria is complex and reciprocal, substantially altering and, ultimately, fine-tuning both capacitative Ca2+ influx and mitochondrial function. Mitochondria, owing to their considerable Ca2+ accumulation ability, extensively buffer the cytosolic Ca2+ in their vicinity. In turn, the accumulated ion is released back into the neighboring cytosol during net Ca2+ efflux. Since store depletion itself and the successive SOCE are both Ca2+-regulated phenomena, mitochondrial Ca2+ handling may have wide-ranging effects on capacitative Ca2+ influx at any given time. In addition, mitochondria may also produce or consume soluble factors known to affect store-operated channels. On the other hand, Ca2+ entering the cell during SOCE is sensed by mitochondria, and the ensuing mitochondrial Ca2+ uptake boosts mitochondrial energy metabolism and, if Ca2+ overload occurs, may even lead to apoptosis or cell death. In several cell types, mitochondria seem to be sterically excluded from the confined space that forms between the plasma membrane (PM) and endoplasmic reticulum (ER) during SOCE. This implies that high-Ca2+ microdomains comparable to those observed between the ER and mitochondria do not form here. In the following chapter, the above aspects of the many-sided SOCE-mitochondrion interplay will be discussed in greater detail. PMID- 28900920 TI - The Role of Mitochondria in the Activation/Maintenance of SOCE: Membrane Contact Sites as Signaling Hubs Sustaining Store-Operated Ca2+ Entry. AB - Store-operated Ca2+ entry (SOCE) is a cell signaling pathway essential for immune and muscle function controlled by dynamic interactions between Ca2+-sensing STIM proteins on the endoplasmic reticulum (ER) and Ca2+-permeable ORAI channels on the plasma membrane (PM). STIM-ORAI interactions occur at membrane contact sites (MCS), evolutionarily conserved cellular structures characterized by the close apposition (10-20 nm) between the ER and target membranes that facilitate the exchange of lipids by non-vesicular transport mechanisms. STIM-ORAI interactions were considered to be restricted to ER-PM MCS, but recent evidence indicates that productive interactions take place between ER-bound STIM1 and Ca2+ channels located in intracellular organelles. Interactions between the ER and endosomes or lysosomes regulate the lipid homeostasis of these organelles and the propagation of Ca2+ signals initiated by the release of Ca2+ from acidic stores. Intracellular MCS also regulate the efficiency of phagocytosis, a fundamental cellular process essential for immunity and tissue homeostasis, by ensuring the coordinated opening of Ca2+ channels on phagocytic vacuoles and of Ca2+ release channels on juxtaposed ER stores. In this chapter, we review the current knowledge on the molecular composition and architecture of membrane contact sites that sustain Ca2+ signals at the plasma membrane and in intracellular organelles. PMID- 28900921 TI - The Role of Mitochondria in the Activation/Maintenance of SOCE: The Contribution of Mitochondrial Ca2+ Uptake, Mitochondrial Motility, and Location to Store Operated Ca2+ Entry. AB - In most cell types, the depletion of internal Ca2+ stores triggers the activation of Ca2+ entry. This crucial phenomenon is known since the 1980s and referred to as store-operated Ca2+ entry (SOCE). With the discoveries of the stromal interacting molecules (STIMs) and the Ca2+-permeable Orai channels as the long awaited molecular constituents of SOCE, the role of mitochondria in controlling the activity of this particular Ca2+ entry pathway is kind of buried in oblivion. However, the capability of mitochondria to locally sequester Ca2+ at sites of Ca2+ release and entry was initially supposed to rule SOCE by facilitating the Ca2+ depletion of the endoplasmic reticulum and removing entering Ca2+ from the Ca2+-inhibitable channels, respectively. Moreover, the central role of these organelles in controlling the cellular energy metabolism has been linked to the activity of SOCE. Nevertheless, the exact molecular mechanisms by which mitochondria actually determine SOCE are still pretty obscure. In this essay we describe the complexity of the mitochondrial Ca2+ uptake machinery and its regulation, molecular components, and properties, which open new ways for scrutinizing the contribution of mitochondria to SOCE. Moreover, data concerning the variability of the morphology and cellular distribution of mitochondria as putative determinants of SOCE activation, maintenance, and termination are summarized. PMID- 28900922 TI - Tissue Specificity: The Role of Organellar Membrane Nanojunctions in Smooth Muscle Ca2+ Signaling. AB - In this chapter we examine the importance of cytoplasmic nanojunctions-nanometer scale appositions between organellar membranes including the molecular transporters therein-to the cell signaling machinery, with specific reference to Ca2+ transport and signaling in vascular smooth muscle and endothelial cells. More specifically, we will consider the extent to which quantitative modeling may aid in the development of our understanding of these processes. Testament to the requirement for such approaches lies in the fact that recent studies have provided evermore convincing evidence in support of the view that cytoplasmic nanospaces may be as significant to the process of Ca2+ signaling as the Ca2+ transporters, release channels, and Ca2+-storing organelles themselves. Moreover, the disruption and/or dysfunction of cytoplasmic nanospaces may be central to the origin of certain diseases. By way of introduction, we provide a historical perspective on the identification of smooth muscle cell plasma membrane (PM) sarcoplasmic reticulum (SR) nanospaces and the early evidence in support of their role in the generation of asynchronous Ca2+ waves. We then summarize how stochastic modeling approaches can aid and guide the development of our understanding of two basic functional steps leading to healthy smooth muscle cell contraction. We furthermore outline how more sophisticated and realistic quantitative stochastic modeling may be employed not only to test working hypotheses, but also to lead in their development in a manner that informs further experimental investigation. Finally, we consider more recently defined nanospaces such as the lysosome-SR junction, by way of demonstrating the importance of quantitative stochastic modeling to our understanding of signaling mechanisms. PMID- 28900923 TI - Tissue Specificity: SOCE: Implications for Ca2+ Handling in Endothelial Cells. AB - Many cellular functions of the vascular endothelium are regulated by fine-tuned global and local, microdomain-confined changes of cytosolic free Ca2+ ([Ca2+]i). Vasoactive agonist-induced stimulation of vascular endothelial cells (VECs) typically induces Ca2+ release through IP3 receptor Ca2+ release channels embedded in the membrane of the endoplasmic reticulum (ER) Ca2+ store, followed by Ca2+ entry from the extracellular space elicited by Ca2+ store depletion and referred to as capacitative or store-operated Ca2+ entry (SOCE). In vascular endothelial cells, SOCE is graded with the degree of store depletion and controlled locally in the subcellular microdomain where depletion occurs. SOCE provides distinct Ca2+ signals that selectively control specific endothelial functions: in calf pulmonary artery endothelial cells, the SOCE Ca2+ signal drives nitric oxide (an endothelium-derived relaxing factor of the vascular smooth muscle) production and controls activation and nuclear translocation of the transcription factor NFAT. Both cellular events are not affected by Ca2+ signals of comparable magnitude arising directly from Ca2+ release from intracellular stores, clearly indicating that SOCE regulates specific Ca2+ dependent cellular tasks by a unique and exclusive mechanism. This review discusses the mechanisms of intracellular Ca2+ regulation in vascular endothelial cells and the role of store-operated Ca2+ entry for endothelium-dependent smooth muscle relaxation and nitric oxide signaling, endothelial oxidative stress response, and excitation-transcription coupling in the vascular endothelium. PMID- 28900924 TI - Tissue Specificity: Store-Operated Ca2+ Entry in Cardiac Myocytes. AB - Calcium (Ca2+) is a key regulator of cardiomyocyte contraction. The Ca2+ channels, pumps, and exchangers responsible for the cyclical cytosolic Ca2+ signals that underlie contraction are well known. In addition to those Ca2+ signaling components responsible for contraction, it has been proposed that cardiomyocytes express channels that promote the influx of Ca2+ from the extracellular milieu to the cytosol in response to depletion of intracellular Ca2+ stores. With non-excitable cells, this store-operated Ca2+ entry (SOCE) is usually easily demonstrated and is essential for prolonging cellular Ca2+ signaling and for refilling depleted Ca2+ stores. The role of SOCE in cardiomyocytes, however, is rather more elusive. While there is published evidence for increased Ca2+ influx into cardiomyocytes following Ca2+ store depletion, it has not been universally observed. Moreover, SOCE appears to be prominent in embryonic cardiomyocytes but declines with postnatal development. In contrast, there is overwhelming evidence that the molecular components of SOCE (e.g., STIM, Orai, and TRPC proteins) are expressed in cardiomyocytes from embryo to adult. Moreover, these proteins have been shown to contribute to disease conditions such as pathological hypertrophy, and reducing their expression can attenuate hypertrophic growth. It is plausible that SOCE might underlie Ca2+ influx into cardiomyocytes and may have important signaling functions perhaps by activating local Ca2+-sensitive processes. However, the STIM, Orai, and TRPC proteins appear to cooperate with multiple protein partners in signaling complexes. It is therefore possible that some of their signaling activities are not mediated by Ca2+ influx signals, but by protein-protein interactions. PMID- 28900925 TI - Introduction: Overview of the Pathophysiological Implications of Store-Operated Calcium Entry in Mammalian Cells. AB - Since store-operated Ca2+ entry (SOCE) was proposed by Putney three decades ago (Putney. Cell Calcium 7:1-12, 1986), its functional role and involvement in the pathophysiology of a number of disorders has been investigated. The role of SOCE in cell physiology has been discussed in the previous chapters, and the following part is devoted to the current knowledge concerning the mechanisms underlying the development of certain diseases that involve SOCE abnormalities. PMID- 28900926 TI - Immunological Disorders: Regulation of Ca2+ Signaling in T Lymphocytes. AB - Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca2+-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway. Stimulation of TCRs triggers depletion of intracellular Ca2+ store and, in turn, activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration. SOCE in T cells is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels, which have been very well characterized in terms of their electrophysiological properties. Identification of STIM1 as a sensor to detect depletion of the endoplasmic reticulum (ER) Ca2+ store and Orai1 as the pore subunit of CRAC channels has dramatically advanced our understanding of the regulatory mechanism of Ca2+ signaling in T cells. In this review, we discuss our current understanding of Ca2+ signaling in T cells with specific focus on the mechanism of CRAC channel activation and regulation via protein interactions. In addition, we will discuss the role of CRAC channels in effector T cells, based on the analyses of genetically modified animal models. PMID- 28900927 TI - Cardiovascular and Hemostatic Disorders: Role of STIM and Orai Proteins in Vascular Disorders. AB - Store-operated Ca2+ entry (SOCE) mediated by STIM and Orai proteins is a highly regulated and ubiquitous signaling pathway that plays an important role in various cellular and physiological functions. Endoplasmic reticulum (ER) serves as the major site for intracellular Ca2+ storage. Stromal Interaction Molecule 1/2 (STIM1/2) sense decrease in ER Ca2+ levels and transmits the message to plasma membrane Ca2+ channels constituted by Orai family members (Orai1/2/3) resulting in Ca2+ influx into the cells. This increase in cytosolic Ca2+ in turn activates a variety of signaling cascades to regulate a plethora of cellular functions. Evidence from the literature suggests that SOCE dysregulation is associated with several pathophysiologies, including vascular disorders. Interestingly, recent studies have suggested that STIM proteins may also regulate vascular functions independent of their contribution to SOCE. In this updated book chapter, we will focus on the physiological role of STIM and Orai proteins in the vasculature (endothelial cells and vascular smooth muscle cells). We will further retrospect the literature implicating a critical role for these proteins in vascular disease. PMID- 28900928 TI - Cardiovascular and Hemostatic Disorders: SOCE and Ca2+ Handling in Platelet Dysfunction. AB - Among the Ca2+ entry mechanisms in platelets, store-operated Ca2+ entry (SOCE) plays a prominent role as it is necessary to achieve full activation of platelet functions and replenish intracellular Ca2+ stores. In platelets, as in other non excitable cells, SOCE has been reported to involve the activation of plasma membrane channels by the ER Ca2+ sensor STIM1. Despite electrophysiological studies are not possible in human platelets, indirect analyses have revealed that the Ca2+-permeable channels involve Orai1 and, most likely, TRPC1 subunits. A relevant role for the latter has not been found in mouse platelets. There is a body of evidence revealing a number of abnormalities in SOCE or in its molecular regulators that result in qualitative platelet disorders and, as a consequence, altered platelet responsiveness upon stimulation with multiple physiological agonists. Platelet SOCE abnormalities include STIM1 and Orai1 mutations. This chapter summarizes the current knowledge in this field, as well as the disorders associated to platelet SOCE dysfunction. PMID- 28900929 TI - Cardiovascular and Hemostatic Disorders: SOCE in Cardiovascular Cells: Emerging Targets for Therapeutic Intervention. AB - The discovery of the store-operated Ca2+ entry (SOCE) phenomenon is tightly associated with its recognition as a pathway of high (patho)physiological significance in the cardiovascular system. Early on, SOCE has been investigated primarily in non-excitable cell types, and the vascular endothelium received particular attention, while a role of SOCE in excitable cells, specifically cardiac myocytes and pacemakers, was initially ignored and remains largely enigmatic even to date. With the recent gain in knowledge on the molecular components of SOCE as well as their cellular organization within nanodomains, potential tissue/cell type-dependent heterogeneity of the SOCE machinery along with high specificity of linkage to downstream signaling pathways emerged for cardiovascular cells. The basis of precise decoding of cellular Ca2+ signals was recently uncovered to involve correct spatiotemporal organization of signaling components, and even minor disturbances in these assemblies trigger cardiovascular pathologies. With this chapter, we wish to provide an overview on current concepts of cellular organization of SOCE signaling complexes in cardiovascular cells with particular focus on the spatiotemporal aspects of coupling to downstream signaling and the potential disturbance of these mechanisms by pathogenic factors. The significance of these mechanistic concepts for the development of novel therapeutic strategies will be discussed. PMID- 28900930 TI - Cardiac Remodeling and Disease: SOCE and TRPC Signaling in Cardiac Pathology. AB - TRPC channels have been suggested as potential candidates mediating store operated Ca2+ entry (SOCE) in cardiomyocytes. There is increasing evidence that the TRPC isoforms TRPC1 and TRPC4 might fulfill the function as SOCs, in concert with or in parallel to the key players of SOCE, Orai1, and STIM1. Several other isoforms, e.g., TRPC3, TRPC6, and TRPC7, might rather associate to receptor activated diacylglycerol (DAG)-sensitive ion channels. However, the exact activation mode has not been elucidated yet, given the characteristic of TRPC channels to heteromerize to unpredictable ion channel assemblies. Despite the incomplete information about TRPC activation, there is common agreement that they are crucial Ca2+ components in cardiac signaling and disease. All TRPC isoforms, TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7, are differentially regulated in cardiac disease, and nearly all of them have been shown to impact cardiac signaling pathways that accelerate cardiac disease development. In particular, the calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway has repeatedly been linked to a TRPC-dependent Ca2+ influx in cardiomyocytes. Moreover, the protein kinases PKG and PKC have been found to modulate TRPC function and the hypertrophic response. Other signaling molecules, such as the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase II (CamKII) or the oxidative stress molecule, NADPH oxidase 2 (NOX2), have also been related to TRPC-dependent effects in the heart.The present chapter provides a comprehensive overview of TRPC channels as Ca2+ entities in cardiomyocytes, their interplay with Ca2+ signaling pathways, and role in cardiac pathology. PMID- 28900931 TI - Cardiac Remodeling and Disease: Current Understanding of STIM1/Orai1-Mediated Store-Operated Ca2+ Entry in Cardiac Function and Pathology. AB - For a long time, Ca2+ entry into cardiomyocytes was considered the sole domain of the L-type Ca2+ channel. Recently, STIM1/Orai1-mediated store-operated Ca2+ entry has been also reported to participate to Ca2+ influx in cardiac cells and has emerged as a key player to alter Ca2+ in the cardiomyocyte. In this review, we will highlight accumulated knowledge about the presence and the potential contribution of STIM1/Orai1-dependent SOCE to cardiac function and its role in the cardiac pathogenesis. Overall, even if STIM1/Orai1 proteins are present in the heart, contradictory results have been reported regarding their contribution to cardiac physiology and pathology, pointing out the necessity of further investigations, a major challenge over the coming years. PMID- 28900933 TI - Neurological and Motor Disorders: TRPC in the Skeletal Muscle. AB - Transient receptor potential canonical (TRPC) channels belong to the large family of TRPs that are mostly nonselective cation channels with a great variety of gating mechanisms. TRPC are composed of seven members that can all be activated downstream of agonist-induced phospholipase C stimulation, but some members are also stretch-activated and/or are part of the store-operated Ca2+ entry (SOCE) pathway. Skeletal muscles generate contraction via an explosive increase of cytosolic Ca2+ concentration resulting almost exclusively from sarcoplasmic reticulum Ca2+ channel opening. Even if neglected for a long time, it is now commonly accepted that Ca2+ entry via SOCE and other routes is essential to sustain contractions of the skeletal muscle. In addition, Ca2+ influx is required during muscle regeneration, and alteration of the influx is associated with myopathies. In this chapter, we review the implication of TRPC channels at different stages of muscle regeneration, in adult muscle fibers, and discuss their implication in myopathies. PMID- 28900934 TI - Fertility: Store-Operated Ca2+ Entry in Germ Cells: Role in Egg Activation. AB - At the time of fertilization, the sperm activates the egg and induces embryonic development by triggering an elevation in the egg's intracellular free Ca2+ concentration. In mammals the initial Ca2+ rise is followed by a series of repetitive Ca2+ transients (known as oscillations) that last for several hours. Although the source of Ca2+ during the signaling process is primarily the egg's smooth endoplasmic reticulum, the oscillations stop in the absence of extracellular Ca2+ indicating that a Ca2+ influx across the plasma membrane is essential to sustain them. Depletion of the intracellular stores using specific inhibitors generates a Ca2+ entry across the plasma membrane of eggs of various species, and a continuous influx of Ca2+ has been linked to the sperm-induced Ca2+ oscillations in the mouse; these data indicate that store-operated Ca2+ entry (SOCE) operates in eggs and may be the mechanism that maintains the long lasting Ca2+ signal at fertilization. Recent findings suggest that the signaling proteins STIM1 and Orai1 are present in eggs; they are responsible for mediating SOCE, and their functions are essential for proper Ca2+ signaling at fertilization to support normal embryo development. PMID- 28900935 TI - Metabolic Disorders and Cancer: Hepatocyte Store-Operated Ca2+ Channels in Nonalcoholic Fatty Liver Disease. AB - In steatotic hepatocytes, intracellular Ca2+ homeostasis is substantially altered compared to normal. Decreased Ca2+ in the endoplasmic reticulum (ER) can lead to ER stress, an important mediator of the progression of liver steatosis to nonalcoholic steatohepatitis, type 2 diabetes, and hepatocellular carcinoma. Store-operated Ca2+ channels (SOCs) in hepatocytes are composed principally of Orai1 and STIM1 proteins. Their main role is the maintenance of adequate Ca2+ in the lumen of the ER. In steatotic hepatocytes, store-operated Ca2+ entry (SOCE) is substantially inhibited. This inhibition is associated with a decrease in Ca2+ in the ER. Lipid-induced inhibition of SOCE is mediated by protein kinase C (PKC) and may involve the phosphorylation and subsequent inhibition of Orai1. Experimental inhibition of SOCE enhances lipid accumulation in normal hepatocytes incubated in the presence of exogenous fatty acids. The antidiabetic drug exendin 4 reverses the lipid-induced inhibition of SOCE and decreases liver lipid with rapid onset. It is proposed that lipid-induced inhibition of SOCE in the plasma membrane and of SERCA2b in the ER membrane leads to a persistent decrease in ER Ca2+, ER stress, and the ER stress response, which in turn enhances (amplifies) lipid accumulation. A low level of persistent SOCE due to chronic ER Ca2+ depletion in steatotic hepatocytes may contribute to an elevated cytoplasmic-free Ca2+ concentration leading to the activation of calcium-calmodulin kinase II (CaMKII), decreased lipid removal by autophagy, and insulin resistance. It is concluded that lipid-induced inhibition of SOCE plays an important role in the progression of liver steatosis to insulin insensitivity and hepatocellular carcinoma. PMID- 28900937 TI - Adenosine administration in supraventricular tachycardia. PMID- 28900936 TI - Metabolic Disorders and Cancer: Store-Operated Ca2+ Entry in Cancer: Focus on IP3R-Mediated Ca2+ Release from Intracellular Stores and Its Role in Migration and Invasion. AB - Store-operated calcium entry (SOCE) plays important roles in a multitude of cellular processes, from muscle contraction to cellular proliferation and migration. Dysregulation of SOCE is responsible for the advancement of multiple diseases, ranging from immune diseases, myopathies, to terminal ones like cancer. Naturally, SOCE has been a focus of many studies and review papers which, however, primarily concentrated on the principal players localized to the plasma membrane and responsible for Ca2+ entry into the cell. Much less has been said about other players participating in the entire SOCE event. This review aims to address this shortcoming by discussing the accumulated scientific knowledge focused on the inositol trisphosphate receptors (IP3Rs), principal player responsible for emptying intracellular Ca2+ stores in a majority of cells, and their involvement in regulation of cell migration and invasion in cancer. PMID- 28900932 TI - Neurological and Motor Disorders: Neuronal Store-Operated Ca2+ Signaling: An Overview and Its Function. AB - Calcium (Ca2+) is a ubiquitous second messenger that performs significant physiological task such as neurosecretion, exocytosis, neuronal growth/differentiation, and the development and/or maintenance of neural circuits. An important regulatory aspect of neuronal Ca2+ homeostasis is store operated Ca2+ entry (SOCE) which, in recent years, has gained much attention for influencing a variety of nerve cell responses. Essentially, activation of SOCE ensues following the activation of the plasma membrane (PM) store-operated Ca2+ channels (SOCC) triggered by the depletion of endoplasmic reticulum (ER) Ca2+ stores. In addition to the TRPC (transient receptor potential canonical) and the Orai family of ion channels, STIM (stromal interacting molecule) proteins have been baptized as key molecular regulators of SOCE. Functional significance of the TRPC channels in neurons has been elaborately studied; however, information on Orai and STIM components of SOCE, although seems imminent, is currently limited. Importantly, perturbations in SOCE have been implicated in a spectrum of neuropathological conditions. Hence, understanding the precise involvement of SOCC in neurodegeneration would presumably unveil avenues for plausible therapeutic interventions. We thus review the role of SOCE-regulated neuronal Ca2+ signaling in selecting neurodegenerative conditions. PMID- 28900938 TI - ? PMID- 28900939 TI - ? PMID- 28900940 TI - ? PMID- 28900941 TI - ? PMID- 28900942 TI - ? PMID- 28900943 TI - ? PMID- 28900944 TI - ? PMID- 28900945 TI - ? PMID- 28900946 TI - ? PMID- 28900948 TI - ? PMID- 28900947 TI - ? PMID- 28900949 TI - ? PMID- 28900950 TI - ? PMID- 28900951 TI - ? PMID- 28900952 TI - ? PMID- 28900954 TI - ? PMID- 28900953 TI - ? PMID- 28900955 TI - ? PMID- 28900956 TI - ? PMID- 28900957 TI - ? PMID- 28900958 TI - ? PMID- 28900959 TI - ? PMID- 28900960 TI - ? PMID- 28900961 TI - ? PMID- 28900963 TI - ? PMID- 28900964 TI - ? PMID- 28900966 TI - ? PMID- 28900965 TI - ? PMID- 28900967 TI - ? PMID- 28900968 TI - ? PMID- 28900969 TI - ? PMID- 28900970 TI - ? PMID- 28900971 TI - ? PMID- 28900973 TI - ? PMID- 28900972 TI - ? PMID- 28900974 TI - ? PMID- 28900975 TI - ? PMID- 28900976 TI - ? PMID- 28900977 TI - ? PMID- 28900978 TI - ? PMID- 28900979 TI - ? PMID- 28900980 TI - [Wild dreams and injured bed partners - The REM-sleep-behavior disorder as a precursor of neurodegenerative disorders]. PMID- 28900981 TI - [Burns in childhood]. PMID- 28900982 TI - ? PMID- 28900983 TI - [Updates on adjuvant therapy in gastrointestinal stromal tumor]. AB - Surgery remains the primary treatment for patients with localized gastrointestinal stromal tumor (GIST), however, even after complete resection of the tumor, there is still a part of patients with tumor recurrence and metastasis. Imatinib, as adjuvant therapy in GIST patients with intermediate and high risk of recurrence, can significantly improve the disease-free survival, but whether it can prolong the overall survival is still unknown. It has reached a consensus that the intermediate and high risk patients should receive adjuvant therapy, but the duration for adjuvant therapy is still under investigation, especially for high-risk patients. Adjuvant therapy is recommended for at least 3 years, while in the end of adjuvant therapy, some patients still develop recurrence and metastasis. In 2017, results from PERSIST-5 study reported by the ASCO conference indicated that 5-year adjuvant therapy may further prolong disease-free survival of intermediate and high risk patients. In addition, adjuvant therapy is still not individualized based on the combination with different genotypes, and present adjuvant therapy is recommended for GIST patients with positive CD117 and intermediate-high risk of recurrence. It remains controversial whether different genotypes are associated with alternative adjuvant treatment options. Results of more researches are expected to provide better guidance for clinical treatment in the future. PMID- 28900984 TI - [Targeted therapy combined with immunotherapy in gastrointestinal stromal tumor: a new era of hope and challenges]. AB - New immunotherapy represented by immune checkpoint inhibitor therapy and chimeric antigen receptor T-Cell immunotherapy (CAR-T) has already become hot trend in the treatment of malignant tumors. In gastrointestinal stromal tumor (GIST), with notable tumor-infiltrating immune cells existing in GIST tissues and immunological effects reported in imatinib mesylate (IM) treatment, the clinicians and researchers started to realize the possibilities of immunotherapy in GIST. Recent studies reported that PD-1/PD-L1 or CTLA-4 blockade may enhance the T-cell activity and anti-tumor effect of targeted therapy, which can be applied in advanced GIST, and anti-KIT CAR T-cells indicated a new immunotherapeutic targeted strategy for GIST patients with TKI resistance. All the immunotherapies in GIST mentioned above are frontline researches but their efficacies still need more evidence from clinical trials to verify. PMID- 28900985 TI - [Interpretation and evaluation of the American Joint committee on Cancer (AJCC) 8th Edition Staging System for patients with gastroenteropancreatic neuroendocrine tumors]. AB - American Joint Committeeon Cancer (AJCC) released the eighth edition staging system manual in October 2016. Based on the shortcomings in the seventh edition of AJCC staging system, staging classifications for gastroenteropancreatic neuroendocrine tumor (GEP-NET) were updated. The changes are as follow: small intestinal NET was divided into two groups, duodenal and jejunoileal NET and lymphatic metastasis was redefined into N1 and N2 in jejunoileal NET; stages were condensed except colorectal NET; the staging classification for pancreatic NET proposed by European Neuroendocrine Tumor Society(ENETS) was adopted. However, problems still exist in the eighth edition AJCC staging classifications for GEP NET. For instance, whether the definitions of N1 and N2 in jejunoileal NET are accurate in clinical management is still less understood. Thus, further clinical validations of the AJCC eighth edition staging system for GEP-NET are needed. Meanwhile, the eighth edition AJCC staging classifications for GEP-NET still did not step towards precision medicine and risks assessment models with high quality are still absent. PMID- 28900986 TI - [Consensus and controversy on subtype classification of gastric neuroendocrine neoplasms]. AB - Gastric neuroendocrine neoplasms (g-NENs) are a heterogeneous group of tumors. Often silent, g-NENs may however be aggressive and sometimes mimic the course of gastric adenocarcinoma. Well-differentiated gastric neuroendocrine tumors (NET) can be subclassified into 3 distinct groups (type1, type 2 and type 3) according to Neuroendocrine Neoplasm Society (ENETS) guideline version 2006 as well as North America Neuroendocrine Tumor Society (NANETS) and National Comprehensive Cancer Network (NCCN) guidelines. However, since the publication of ENETS guideline version 2012, the subtype classification of g-NENs has been confusing due to the revised definition of type 3 g-NEN in versions 2012 and 2016. ENETS version 2012 indicated that type 3 g-NEN was usually solitary and its pathology was mostly WHO grade 3 (neuroendocrine carcinoma, NEC G3) with higher Ki-67 index, greater tumor diameter and infiltrative growth. While ENETS version 2006 showed that type 3 g-NEN was well-differentiated or moderate-differentiated, neither type 1 nor type 2, and other g-NENs without basic diseases. Besides, in renewal consensus guidance of ENETS version 2016, description about clinical and histological features altered as "well-differentiated g-NEN can be classified as type 3", but its pathology is still NEC G3. According to such classification, those gastric NET patients with well-differentiated, neither type 1 nor type 2 tumors, seem to be unable to classify. In this article, description about the subtype classification of g-NENs in several guidelines, including ENETS versions 2006, 2012 and 2016, NANETS version 2010 and NCCN version 2016, is introduced and the controversy focuses on type 3 g-NEN definition by ENETS versions 2012 and 2016. Hence, the four-type classification of g-NENs is recommended, which has been written in Chinese Consensus for the Diagnosis and Management of GEP-NEN (version 2016). Well-differentiated gastric NET is classified as type 3, and poor differentiated gastric NEC as type 4. This four-type classification of g-NENs covers all the patients with g-NENs. Advances on clinical research of g-NENs in China are reviewed and the existing problems are analyzed. We also put forward the research direction in the future. PMID- 28900987 TI - [Consensus and controversy of endoscopic diagnosis and treatment of gastroenteropancreatic neuroendocrine tumors]. AB - Neuroendocrine neoplasms(NENs) are relatively rare tumors originating from the diffuse neuroendocrine system, and gastrointestinal tract is one of the most common location of the tumors. Currently, the European Neuroendocrine Neoplasm Society (ENETS) and the National Comprehensive Cancer Network (NCCN) have released the international guidelines for NENs management. And also, experts from Chinese Society of Clinical Oncology (CSCO) have proposed "The Consensus on Gastroenteropancreatic Neuroendocrine Neoplasm in China" in 2016, which is also one of the most important reference standard for the diagnosis and treatment of gastroenteropancreatic(GEP) NENs in China. Here we will interpret these three guidelines or consensus. There are few controversies about endoscopic management principle for GEP-NEN of different locations and sizes among these three guidelines or consensus, but for small NENs without involving intrinsic muscularis, endoscopic resection is recommended and considered. We hope that this interpretation may help clinicians for clinical decision making. PMID- 28900988 TI - [Analysis of primary site and pathology on 903 patients with neuroendocrine neoplasms]. AB - OBJECTIVE: To explore the primary site and pathological feature of neuroendocrine neoplasm (NEN), especially the NEN of digestive system. METHODS: Clinicopathological data of NEN patients at China-Japan Friendship Hospital from January 2012 to December 2016 were retrospectively analyzed. Tumor primary sites were summarized. Association between tumor site and pathological grading in gastroenteropancreatic neuroendocrine neoplasm(GEP-NEN) was examined. RESULTS: There were a total of 903 cases of NEN. Sites of primary tumor included the digestive system in 699 cases(77.4%), the thorax(including lung, thymus and mediastinum) in 87 cases(9.6%), other sites in 60 cases (6.6%), unknown in 57 cases(6.3%). Among 699 GEP-NEN cases, the primary sites included the stomachin in 207 cases (29.6%), pancreas in 201 (28.8%), rectumin in 185 (26.5%), duodenum in 43(6.2%), jejunum and ileum in 18(2.6%), appendix in 15 (2.1%), gallbladder in 11(1.6%), esophagus in 10(1.4%), and the colon in 9 cases (1.3%). Pathologically, the tumor grading was neuroendocrine tumor (NET) G1 in 336 cases(48.1%), NET G2 in 203 cases (29.0%), neuroendocrine carcinoma (NEC) G3 in 139 cases (19.9%). All the esophagus NEN(10/10), most gallbladder NEN(9/11) and colon NEN(6/9) were poorly-differentiated NEC (G3), while all appendix NEN(15/15), most stomach NEN(147/207, 71.0%), pancreas NEN (156/201, 77.6%), rectum NEN (169/185, 91.4%), duodenum NEN (31/43, 72.1%), jejunum and ileum NEN(16/18, 88.9%) were well differentiated NET G1 or G2. CONCLUSIONS: The most common primary site of NEN is the digestive system. The stomach, pancreas and rectum are most common primary sitesof GEP-NEN. Difference in pathological grading is quite greatin different primary sites of GEP-NEN. Most NENs fromesophagus, colon and gallbladder are poorly-differentiated NEC. PMID- 28900989 TI - [Clinicopathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms: an analysis of 119 cases]. AB - OBJECTIVE: To investigate the clinical characteristics, pathological classification and prognostic factors of gastrointestinal neuroendocrine neoplasms (GI-NENs). METHODS: Clinicopathological data of 119 GI-NENs patients at Shanghai Renji Hospital from November 2007 to December 2016 were analyzed retrospectively. According to the classification and grading criteria of the WHO Neuroendocrine Tumor 2010 edition, patients were classified pathologically to realize the malignant degree of tumors. The overall survival rate was calculated by Kaplan-Meier curve, the prognostic risk factors were analyzed by Cox regression model, and the factors including the platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) were included in the analysis in addition to the routine clinicopathological factors. RESULTS: Of 119 patients with GI NENs, there were 83 cases (69.7%) of male and 36 cases (30.3%) of female. The age of patients ranged from 24 to 86 (median 61) years. Tumor locations included the stomach(n=70, 58.8%), duodenum(n=10, 8.4%), small intestine(n=2, 1.7%), appendix(n=3, 2.5%), colon(n=12, 10.1%), and rectum(n=22, 18.5%). The tumor diameter was 0.6 to 20 cm, the mean diameter was 5.4 cm, and the median diameter was 4 cm. There were 25 cases of G1 neuroendocrine tumor (NET), 7 cases of G2 NET and 87 cases of G3 neuroendocrine carcinoma (NEC). Among the 119 patients, 113 cases (95%) had complete follow-up, and the median follow-up was 75 (1 to 112) months. The 5-years overall survival rate was 58.4%. The survival rate of G1 NET, G2 NET and G3 NEC were 100%, 71.4%, 44.4%, and the difference was statistically significant (P=0.000). Univariate analysis showed that age >=61 years (P=0.000), tumor located in the stomach, duodenum and colon (P=0.041), tumor size >=4 cm (P=0.002), pathology classification of G3 NEC (P=0.000), late TNM staging (P=0.000) and blood PLR >=133 (P=0.017) were associated with lower 5-year survival rate, but blood NLR level was not(P=0.263). Multivariate analysis showed that the patient age (HR=3.036, 95%CI: 1.548 to 5.956, P=0.001), the pathology classification(HR = 1.852, 95%CI:1.099 to 3.122, P=0.021), lymph node metastasis (HR=2.635, 95%CI:1.198 to 5.797, P=0.016) and distant metastasis (HR=2.685, 95%CI:1.383 to 5.214, P=0.004) were independent risk factors affecting the prognosis of patients, but the blood PLR level was not (HR=1.735, 95%CI: 0.947 to 3.176, P=0.074). CONCLUSIONS: The malignant degree of GI-NEN is quite high, and the prognosis of patients is relatively poor. The age, pathological type and TNM staging are closely related to the prognosis of patients. Preoperative blood PLR may play a role in the prediction of prognosis, but preoperative blood NLR is not related with the prognosis of patients. PMID- 28900990 TI - [Prognostic value of carcinoembryonic antigen, alpha fetoprotein, carbohydrate antigen 125 and carbohydrate antigen 19-9 in gastroenteropancreatic neuroendocrine neoplasms]. AB - OBJECTIVE: To study the rate of elevated common biomarkers of digestive tumors, including carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), carbohydrate antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19-9), in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) and their prognostic values in GEP-NEN. METHODS: Clinicopathological data of patients with GEP-NEN treated in The First Affiliated Hospital, Sun Yat-sen University from January 2011 to December 2016 were retrospectively studied. The inclusion criteria were as follows: patients with complete clinicopathological data including AFP, CEA, CA125 and CA19-9 level before treatment; patients without previous or other concomitant cancer; patients diagnosed as sporadic but not familial NEN. Serum AFP level >30 MUg/L, CEA level >7.5 MUg/L, CA125 level >52.5 MUg/L and CA19-9 level >52.5 kU/L were defined as elevation respectively. Kaplan-Meier analysis and Log-rank test were applied to investigate the prognostic role of these biomarkers. RESULTS: A total of 170 patients with GEP-NEN were enrolled, and 105 (61.8%) patients were male with median age of 52.5 years. Thirty-six (21.2%), 77 (45.3%) and 57 (33.5%) cases were gastric, intestinal and pancreatic NEN respectively. Elevated AFP, CEA, CA125 and CA19-9 were found in 3(1.8%), 19(11.2%), 22(12.9%) and 21(12.4%) patients. Elevated CEA was related with G3 disease (OR=4.78, 95%CI:1.28-17.85, P=0.020) and elevated CA125 was related with distant metastasis (OR=51.60, 95%CI:5.76-462.44, P=0.000) while elevated CA19-9 was related with both G3 disease (OR=3.81; 95%CI:1.21-11.99, P=0.022) and distant metastasis(OR=4.87; 95%CI:1.41-16.75, P=0.012). The median follow-up was 22.5 months. Forty-six patients (27.1%) died during the follow-up. Patients with elevated CEA, CA125 or CA19-9 had worse overall survival compared with their counterparts with the median survivals of 14 months (95%CI:5.4 to 22.6 months, chi2=15.582, P=0.000), 6 months (95%CI:3.2 to 8.8 months, chi2=37.627, P=0.001) and 10 months (95%CI:0 to 20.6 months, chi2=50.187, P=0.000) respectively. Furthermore, patients with more than two elevated biomarkers (median survival 6 months, 95%CI:4.37-7.63 months) had worse survival than patients with only one elevated biomarker (median survival 26 months, 95%CI:15.68-36.32 months, chi2=9.295, P=0.002). CONCLUSIONS: Elevation of AFP, CEA, CA125 or CA19-9 is not common in GEP-NEN. Patients with elevation of these biomarkers have poor survival. PMID- 28900991 TI - [Transanal endoscopic microsurgery for treatment of rectal neuroendocrine tumors]. AB - OBJECTIVE: To assess the efficacy of full-thickness excision using transanal endoscopic microsurgery (TEM) in the treatment of rectal neuroendocrine tumors (NET). METHODS: Clinicopathological and follow-up data of 90 rectal NET patients who underwent TEM between December 2006 and December 2016 at our department were retrospectively analyzed. TEM was performed as primary excision in 66 patients and as the second complete surgery because of suspected positive margin of samples after colonoscopic polypectomy in 24 patients. RESULTS: TEM was successfully performed in all the rectal NET patients, and in 10 patients(41.7%,10/24) among those undergoing the second excision, postoperative pathologic results showed remnant tumor. The mean diameter of all the tumors was (1.03+/-0.46) cm, and the mean tumor diameter of primary excision and secondary excision was (1.10+/-0.50) and (0.84+/-0.23) cm respectively (t=2.454, P=0.016). The mean distance from tumor low margin to anal verge was (7.7+/-1.8) cm for all the patients, and such distance for those undergoing primary excision and secondary excision was (7.4+/-1.7) cm and (8.4+/-1.8) cm respectively (t=2.233, P=0.028). Of all the patients, the mean intra-operative blood loss was (13.7+/ 5.1) ml, and the mean operation time was (56.6+/-12.1) min. The intra-operative blood loss and operative time were similar in primary excision and secondary excision (both P>0.05). Histopathologically, both fundus and lateral margins of all the samples were negative. Of the 76 samples, cancer tissue developed outside the mucosal layer in 37 samples, infiltrated into the submucosal layer (pT1 stage) in 33 samples, and infiltrated into the muscular layer (pT2 stage) in 6 samples; 57 samples were classified as grade G1 and 19 samples were classified as grade G2, respectively. The operative complication rate was 6.7%(6/90). The mean postoperative hospital stay was (3.0+/-1.5) d. No recurrence was noted during the follow-up (median 3.9, 0.4 to 10.0 years). CONCLUSIONS: TEM can be the preferred option for complete removal of middle-upper small (<2 cm) rectal NET(G1-2). For rectal NET with incomplete resection by colonoscopic polypectomy, the secondary TEM can still obtain ideal efficacy even though operative difficulty increases. PMID- 28900992 TI - [Clinicopathologic characteristics and prognosis of rectal neuroendocrine neoplasms]. AB - OBJECTIVE: To study the clinicopathologic characteristics and prognosis of rectal neuroendocrine neoplasms (NENs). METHODS: From January 2000 to May 2017, 84 patients were diagnosed as NENs by pathology and underwent surgical treatment in Peking University First Hospital. Their clinicopathological characteristics, surgial options and prognosis were analyzed retrospectively. RESULT: Among these 84 cases, 67 cases were NET G1, 6 cases were NET G2, 10 cases were NEC G3 and 1 case was MANEC G3. The median size was 0.8 (0.2 to 18.0) cm. There were 60 cases of stage I(, 2 cases of stage II(, 12 cases of stage III(, 10 cases of stage IIII(. Forty-nine patients accepted examinations because of non-specific symptoms, including altered bowel habits(22/49), bloody stool (19/49) and abdominal pain(10/49); the other 35 cases including 2 patients with liver metastasis were diagnosed by endoscopy or CT during routine physical examination. Forty-four patients received endoscopic ultrasonography(EUS) with 100% of sensitivity and 90.9% of accuracy. Among 20 cases (23.8%) with lymph node metastasis (all >=T2 stage), 12 cases were NET G1 and G2 (1 case of multiple NET G1) and 8 cases were NEC G3 and MANEC G3. The lymph node metastasis rate of stage T1 NET G1 and G2 was lower than that of stage T2 to T4 NET G1 and G2, also lower than that of NEC G3 and MANEC G3 (all P=0.000), however, stage T2 to T4 NET G1 and G2 showed the similar rate of lymph node metastasis with NEC G3 and MANCE G3(P>0.05). Synchronously distant metastasis was found in 10 (11.9%) patients at the first diagnosis, and ovarian metastasis was found in 1 case 9 years after curative resection of rectal NEN. Among 81 patients receiving operation, 57 patients underwent endoscopic mucosal resection (56 patients of stage T1 NET G1 and G2); 3 patients local excision without lymph node dissection; 13 patients curative resection; 1 patient curative resection with liver metastasis resection; 6 patients palliative surgery and 1 patient metastatic lesion resection only. Overall follw-up time was 1 month to 169 months, and the 3- and 5-year survival rates were 87.7% and 79.7% respectively. No recurrence or metastasis was observed in all the 62 patients with T1 G1 and G2, including 56 cases of ESD, 3 cases of local excision, 3 cases of curative resection, whose 3-year and 5-year survival rates were both 96%. The prognosis was closely associated with grade and stage of NENs (all P=0.000). CONCLUSIONS: The early symptoms of rectal NENs are insidious and atypical, therefore some patients are diagnosed as stage II( or higher at their first consultation. ESD is safe and effective for NET G1 and G2. The prognosis depends on grade and stage of NENs. PMID- 28900993 TI - [Comparison of modified NIH and AFIP risk-stratification criteria for gastrointestinal stromal tumors: A multicenter retrospective study]. AB - OBJECTIVE: To evaluate and compare the value of Modified NIH criteria and AFIP criteria for the risk classification of gastrointestinal stromal tumors (GIST). METHODS: Clinicopathological and follow-up data of 539 patients diagnosed as primary GIST with or without irregular tyrosine kinase inhibitors in the Nanfang Hospital(n=143), Sun Yat-sen University Cancer Center (n=138), Guangdong Provincial People's Hospital (n=102) and Wuhan Union Hospital (n=156) from January 2012 to December 2015 were retrospectively analyzed. Recurrence risks of these 539 patients were classified by the modified NIH criteria and AFIP criteria. Overall survival and tumor-free survival of patients with different risks were compared by Log-rank test and the accuracy of the two criteria in predicting postoperative recurrence was compared by receiver operating characteristic(ROC) curves. RESULTS: Of 539 GIST patients, 283 were male and 256 were female; the age was (56.5+/-12.5) years old; tumors of 390 cases (72.4%) located in the stomach; tumor diameter of 178 cases (33.0%) was more than 5 cm; nuclear division number of 164 cases(30.4%) was more than 5/50 high magnification. The mean follow-up time was (37.5+/-13.6) months. According to the modified NIH criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 52.0, 57.0, 56.9 and 53.6 months respectively (P=0.002), and the mean tumor-free survival time was 56.0, 58.1, 58.2 and 51.2 months respectively (P=0.000). According to the AFIP criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 54.1, 57.8, 55.5 and 52.0 months respectively(P=0.015), and the mean tumor-free survival time was 57.3, 56.6, 54.9 and 50.4 months respectively(P=0.000). While predicting the risk of postoperative recurrence, the ROC curve of AFIP criteria has a larger area under the curve compared to the curve of the modified NIH criteria(0.689 vs 0.641, P<0.05). CONCLUSION: Compared with the modified NIH criteria, AFIP criteria predicts the risk postoperative recurrence more accurately in GIST patients. PMID- 28900995 TI - [Association between genetic polymorphisms and variation of imatinib pharmacokinetics in gastrointestinal stromal tumors]. AB - OBJECTIVE: To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients. METHODS: Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS. CYP3A4 rs2242480, CYP1A2 rs762551, CYP2C19 rs28399505 and NR1I2 rs3814057 were genotyped by MassArray system. Association between drug concentration and polymorphism was examined by Whitney U test. P<=0.05 indicated close association and 0.050.10). CONCLUSIONS: CYP2C19 may play an important role in IM metabolism. Detection of CYP2C19 polymorphism may be beneficial to clinical monitoring of IM and decision making of individualized treatment. PMID- 28900994 TI - [Analysis of gastric gastrointestinal stromal tumors in Shandong Province: a midterm report of multicenter GISSG1201 study]. AB - OBJECTIVE: To summarize the treatment status of gastric gastrointestinal stromal tumor (GIST) in Shandong province,by analyzing the clinicopathological features and prognostic factors. METHODS: Clinicopathological and follow-up data of 1 165 patients with gastric GIST between January 2000 and December 2013 from 23 tertiary referral hospitals in Shandong Province were collected to establish a database. The risk stratification of all cases was performed according to the National Institutes of Health(NIH) criteria proposed in 2008. Kaplan-Meier method was used to calculate the survival rate. Log-rank test and Cox regression model were used for univariate and multivariate prognostic analyses. RESULTS: Among 1 165 cases of gastric GIST, 557 were male and 608 were female. The median age of onset was 60 (range 15-89) years. Primary tumors were located in the gastric fundus and cardia in 623 cases(53.5%), gastric body in 346 cases(29.7%), gastric antrum in 196 cases(16.8%). All the cases underwent resection of tumors, including endoscopic resection (n=106), local resection (n=589), subtotal gastrectomy(n=399), and total gastrectomy(n=72). Based on the NIH risk stratification, there were 256 cases (22.0%) at very low risk, 435 (37.3%) at low risk, 251 cases (21.5%) at intermediate risk, and 223 cases (19.1%) at high risk. A total of 1 116 cases(95.8%) were followed up and the median follow-up period was 40 (range, 1-60) months. During the period, 337 patients relapsed and the median time to recurrence was 34 (range 1-60) months. The 1-, 3-, and 5-year survival rates were 98.6%, 86.1% and 73.4%, respectively. The 5-year survival rates of patients at very low, low, intermediate, and high risk were 93.1%, 85.8%, 63.0% and 42.3% respectively, with a statistically significant difference (P=0.000). Multivariate analysis showed that primary tumor site (RR=0.580, 95%CI:0.402-0.835), tumor size (RR=0.450, 95%CI:0.266-0.760), intraoperative tumor rupture(RR=0.557, 95%CI:0.336-0.924), risk classification (RR=0.309, 95%CI:0.164-0.580) and the use of imatinib after surgery (RR=1.993, 95%CI:1.350 2.922) were independent prognostic factors. CONCLUSIONS: The choice of surgical procedure for gastric GIST patients should be based on tumor size. All the routine procedures including endoscopic resection, local excision, subtotal gastrectomy and total gastrectomy can obtain satisfactory curative outcomes. NIH classification has a high value for the prediction of prognosis. Primary tumor site, tumor size, intraoperative tumor rupture, risk stratification and postoperative use of imatinib are independent prognostic factors in gastric GIST patients. PMID- 28900996 TI - [Clinicopathologic characteristics and prognosis of gastric hepatoid adenocarcinoma]. AB - OBJECTIVE: To investigate the clinicopathological characteristics, diagnosis, treatment and prognosis of gastric hepatoid adenocarcinoma(HAS). METHODS: Retrospective analysis of clinicopathological data of 24 cases with gastric HAS diagnosed by surgery and pathology in Chinese PLA General Hospital from January 2013 to May 2016 were carried out. All the patients underwent preoperative serum alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), endoscopy and imaging examination (CT or B-mode ultrasonography), and those with elevated AFP were excluded from liver cancer, cirrhosis, endodermal sinus tumor and other diseases. The follow-up ended in June 2016 or the death of the patient. The survival was from the operation to the death of the patient or the end of follow-up. RESULTS: There were a total of 24 cases with gastic HAS, accounting for 1.03%(24/2 326) of the total number of patients with gastric cancer diagnosed at the same time in our center. There were 19 males and 5 females, the ratio of male to female was 3.8:1.0, the mean age of the patients was 55.9 (31 to 72) years, and 2 of them had liver metastasis. The first symptom in 50% (12/24) patients was epigastric pain, in 25%(6/24) was abdominal distension with vomiting, and the rest included dysphagia (12.5%, 3/24), hematemesis (8.3%, 2/24) and melena (4.2%, 1/24). Preoperative serum levels of AFP and CEA were elevated in 10 (41.7%) and 5 patients (20.8%) respectively. All the patients underwent surgical treatment, including 23 cases with D2 radical resection of gastric cancer and R0 resection, and the other of palliative gastrojejunostomy. Lesions of HAS located in gastric antrum in 11 cases (45.8%), in cardia in 7 cases (29.2%), and in gastric body in 6 cases (25%). Tumor maximum diameter of 10 cases was larger than 5 cm, and the average diameter was 5.7(1.0 to 12.0) cm. Postoperative pathological TNM staging: stage I(b was in 1 cases, stage II( in 7 cases, stage III( in 14 cases, stage IIII( in 2 cases; lymph node metastasis in stage N1-3 in 20 cases (83.3%). Poorly differentiated tumors were found in 21 cases (87.5%), and no well-differentiated tumors were found. There were 11 cases (45.8%) with formation of intravascular tumor thrombi. In immunohistochemistry, AFP positive expression was found in 11 cases(45.8%). Seventeen HAS cases (70.8%, 17/24) received postoperative SOX(oxaliplatin + S-1) or XELOX (oxaliplatin + capecitabine) as adjuvant chemotherapy, 5 cases postoperative immune therapy, and 2 cases postoperative traditional Chinese medicine. All the patients were followed up for 0.7 to 42.0 months (median 8 months). A total of 9 patients died, of whom, 1 case underwent gastrojejunostomy because of liver and peritoneal metastasis before operation, and died 20 days after surgery; 4 cases died of multiple liver metastases after 1.5 to 12.0 months with survival of 3 to 18 months; 3 cases presented local recurrence after 2 to 17 months with survival of 6 to 22 months; 1 cases had peritoneal metastasis after 12 month with survival of 26 months. CONCLUSIONS: HAS is a rare type of gastric cancer with poor prognosis. The diagnosis is mainly based on histopathology, and radical resection is the mainstay treatment. PMID- 28900997 TI - [Surgical treatment and prognostic analysis for 57 patients with gastrointestinal lymphoma]. AB - OBJECTIVE: To explore clinicopathologic characteristics, surgical features and prognostic factors in patients with primary gastrointestinal lymphoma(PGIL) in order to provide evidence for optimizing surgical treatment. METHODS: Clinicopathological data of 57 PGIL patients undergoing abdominal surgery in Sun Yat-sen University Cancer Center between October 1990 and January 2015 were retrospectively collected. The survival rates were compared among patients with different clinicopathologic characteristics by Kaplan-Meier method, while Cox regression model was employed to analyze the prognostic factors. RESULTS: Among 57 patients, 43 were male and 14 were female, with a median age of 48 (range 16 to 80) years. Seventeen (29.8%) cases were classified as Musshoff I( stage, 19 (33.3%) cases as II( stage, 9 (15.8%) cases as III( stage, and 12(21.1%) cases as IIII( stage. Forty-four (77.2%) cases underwent selective operation, 13(22.8%) cases underwent emergent operation due to acute abdomen. Thirty-two(56.1%) cases had radical resection, 18 (31.6%) cases had partial resection and the rest 7(12.3%) cases failed to perform resection. Four (7.0%) cases received simple surgical operation, and 53 (93.0%) cases received comprehensive treatment, including 5(8.8%) cases with preoperative chemotherapy and surgery, 40 (70.2%) cases with surgery and postoperative chemotherapy, and 8 (14.0%) cases with surgery and perioperative chemotherapy. Stage III( and IIII( accounted for 76.9%(10/13) in patients undergoing emergent operation and accounted for 25.0%(11/44) in patients undergoing selective operation, whose difference was statistically significant (chi2=9.503, P=0.002). Univariate prognostic analysis showed that T lymphocyte source pathological cell phenotype (P=0.000), clinical Musshoff stage III( and IIII((P=0.001), emergent operation (P=0.000) and incomplete tumor resection(P=0.007) had worse 5-year overall survival. Multivariate Cox regression analysis indicated that tumor pathological cell phenotype (HR=13.75, 95%CI:3.546-53.308, P=0.000) and surgical timing (HR=7.497, 95%CI:1.163-48.313, P=0.034) were independent prognostic risk factors of patients with stage I( and II(. CONCLUSIONS: Surgical operation is an important part of comprehensive treatment for PGIL. T lymphocyte source and ulcerative lymphoma indicates poorer prognosis. PMID- 28900998 TI - [Associated factors of postoperative relapse and metastasis in pT1bN0M0-pT4aN0M0 thoracic esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the associated high risk factors of postoperative relapse and metastasis for patients with confined tumors (grade pT1b-4a) without lymph-node metastases (pN0) in thoracic esophageal squamous cell carcinoma (ESCC). METHODS: Clinicopathological and follow up data of ESCC patients undergoing radical surgical resection as primary treatment in the Department of Thoracic Surgery, Shanghai Chest Hospital between January 2004 and December 2012 from Hospital Database were retrospectively collected. The inclusion criteria were as follows: (1) the first development of ESCC confirmed by histopathology without lymphatic and distant metastasis; (2) pathological stage of pT1bN0M0 to pT4aN0M0 according to the Union for International Cancer Control (UICC) in 2009; (3) curative trans-thoracic esophagectomy with R0 (tumor-free surgical margin) resection, using the Ivor-Lewis or McKeown procedure; two-field lymphadenectomy or three-field lymph node dissection based on the positive results of preoperative cervical ultrasonography examination or CT scan; (4) without adjuvant chemotherapy and/or radiotherapy before and after operation; (5) complete follow-up data. Logistic regression analysis was employed to identify the clinicopathological factors affecting the postoperative relapse and metastasis. RESULTS: A total of 112 patients were eligible, including 94 male cases and 18 female cases; age of (58.6+/-7.7) years; squamous carcinoma of upper thorax in 25 cases, of middle thorax in 67 cases and of lower thorax segment in 20 cases; 12 cases of high-differentiated ESCC, 49 cases of moderate differentiated ESCC, poorly-differentiated ESCC in 48 cases; 4 cases of I(a stage, 9 cases of I(b, 24 cases of II(a, 62 cases of II(b, 13 cases of III(a; the tumor length >4 cm in 43 cases, <=4 cm in 69 cases. Forty-three (38.4%) patients presented relapse or metastasis during the follow-up, including 24 (21.4%) of loco-regional relapse, 13 (11.6%) of distant metastasis, and 6(5.4%) of both above. Multivariate regression analysis revealed that poorly-differentiated tumor (OR=1.899, 95%CI:1.233-2.925, P=0.004), upper-middle location (OR=2.351, 95%CI:1.188-4.653, P=0.014), and tumor length >4 cm (OR=2.381, 95%CI:1.009-5.618, P=0.048) were independent risk factors of overall postoperative relapse and metastasis for thoracic ESCC with stage pT1b N0M0-T4aN0M0. Further stratified analysis identified that only poorly-differentiated tumor (OR=1.730, 95%CI:1.121 2.671, P=0.013) was an independent risk factor of loco-regional relapse, whereas pathological stage II(b-III(a (OR=3.372, 95%CI:1.206-9.428, P=0.021) was an independent risk factor of distant metastasis. CONCLUSIONS: Poorly-differentiated tumor, tumor length >4 cm, and upper-middle location may be regarded as high risk factors for predicting overall relapse and metastasis of pN0 thoracic ESCC patients after esophagectomy. Moreover, poorly-differentiated tumor is the only independent risk factor of postoperative loco-regional relapse, meanwhile it should be noted that pathological stage II(b-III(a is closely related to postoperative distant metastasis. PMID- 28900999 TI - [Study on the relationship between tumor regression grade and lymph node regression grade]. AB - OBJECTIVE: To investigate the relationship between tumor regression grade (TRG) and lymph node regression grade (LRG) after neoadjuvant chemoradiotherapy (CRT) for rectal cancer and its clinical implication. METHODS: Clinicopathological data of 176 rectal cancer patients undergoing radical excision after neoadjuvant CRT from January 2005 to December 2013 in our department were retrospectively analyzed. INCLUSION CRITERIA: (1) Radiology indicated locally advanced low rectal cancer and patients had strong desire to preserve the sphincter before neoadjuvant CRT; (2) there was no definite metastatic lesion before neoadjuvant CRT; (3) patients received whole course of neoadjuvant CRT (regular radiotherapy plus synchronous fluorouracil-like drugs chemotherapy); (4) patients underwent radical operation after neoadjuvant CRT. Patients with short-course CRT and emergency surgery were excluded. TRG and LRG of postoperative specimens (including tumor and lymph nodes) were carried out based on the percentage of the fibrosis and the cancer residue. No cancer residue was defined as TRG1 and LRG1; rare cancer cell residue as TRG2 and LRG2; fibrosis growth over residual cancer as TRG3 and LRG3; residual cancer growth over fibrosis as TRG4 and LRG4; absence of regressive changes as TRG5 and LRG5; and normal lymph nodes as LRG0. Spearman correlation test was used to assess the correlation between TRG and LRG. RESULTS: Of 176 patients, 111 were men and 65 were women. The mean age was (53.9+/-13.0) years. The number of patients with stage I(, II(, and III( before operation was 10, 49 and 62 while other 55 patients were unknown. Transabdominal low anterior resection (LAR) was performed in 118 cases and abdominal-perineal resection(APR) in 47 cases following the principle of total mesorectal excision (TME). Postoperative pathology of specimens revealed that the number of patients from TRG1 to TRG5 was 19 (10.8%), 25 (14.2%), 66 (37.5%), 47 (26.7%), 19 (10.8%), and from LRG0 to LRG5 was 35 (19.9%), 68 (38.6%), 10 (5.7%), 14 (8.0%), 15(8.5%), 34 (19.3%), respectively. TRG was correlated to LRG (P=0.005) while the Spearman correlation coefficient was only 0.24. The analysis of subgroup without LRG1 also showed that TRG was correlated to LRG(P=0.0005) and the Spearman correlation coefficient was 0.40. CONCLUSIONS: TRG can not represent LRG. Therefore, both TRG and LRG should be assessed when evaluating the response of rectal cancer to neoadjuvant CRT. PMID- 28901000 TI - [Diagnostic value of dynamic monitoring of C-reactive protein in drain drainage to predict early anastomotic leakage after colorectal cancer surgery]. AB - OBJECTIVE: To evaluate the diagnostic value of dynamic monitoring of C-reactive protein (CRP) in drainage fluid in predicting early anastomotic leakage after colorectal surgery. METHODS: This study enrolled 172 patients, who were diagnosed as colorectal cancer before operation and underwent radical surgery, without residual tumor tissues by postoperative pathology and perioperative infection, at the Tianjin Medical University Cancer Hospital between July 2015 and January 2016. The C-reactive(CRP) protein level in drainage fluid was continuously monitored from postoperative days (POD) 1 to 5. CRP level was compared between anastomotic leakage (AL) group and non-anastomotic leakage (NAL) group. Receiver operating characteristics (ROC) curve was used to estimate the value of monitoring CRP in drainage fluid to predict anastomotic leakage after colorectal surgery. RESULTS: Among 172 patients, 101 cases were male and 71 cases were female, with age of (59.9+/-10.3) years. Anastomotic leakage occurred after colorectal surgery in 24 cases(14.0%, AL group ) and other 148 cases were defined as NAL group. Other than body mass index (BMI), differences in baseline data were not statistically significant between two groups. The CRP lever in AL group and NAL group showed rising trend from POD1 to POD4 [Day 1: (6.7+/-8.4) g/L vs. (8.0+/-10.6) g/L; Day 2: (24.8+/-14.6) g/L vs. (28.3+/-21.1) g/L, Day 3: (54.8+/ 26.5) g/L vs. (53.8+/-27.6)g/L, Day 4: (62.0+/-32.2) g/L vs. (58.4+/-30.7) g/L], while the differences were not significant (all P>0.05). At POD 5, the CRP lever of AL group increased continuously, while that of NAL group decreased with significant difference [(65.3+/-38.9) g/L vs. (44.7+/-39.5) g/L, t=-2.85, P=0.005]. Further stratification analysis on AL group revealed CRP level in early AL (AL occurrence POD 10) showed rising trend from POD 1 to 4, then decreased slightly at POD 5, but whose differences were not significant (all P>0.05). ROC curve was drawn with AL condition as state variables and CRP level as test variables. The AUC of POD 1 to 4 was 0.425, 0.487, 0.510, 0.522 respectively and the AUC of POD 5 was the largest, 0.657 (95%CI:0.537-0.777). The largest Youden Index was 0.274. The critical value of CRP was 27.15 g/L. When this value was used as the point of tangency to predict the occurrence of AL, the sensitivity was 87.5%, the specificity was 39.9%, positive predictive value was 19.1%, and negative predictive value was 95.2%. CONCLUSION: Continuous increase of CRP level in abdominal drainage fluid from POD 1 to POD 5 indicates the occurrence of AL after colorectal cancer operation, especially the detection of CRP level at POD 5 is important. PMID- 28901001 TI - [Early versus traditional postoperative oral feeding in patients undergoing elective colorectal surgery: a meta-analysis of safety and efficacy]. AB - OBJECTIVE: To compare the outcomes of early oral feeding (EOF) and the traditional oral feeding (TOF) in postoperative patients with colorectal cancer using Meta-analysis. METHODS: The databases of PubMed, SCI, Ovid, The Cochrane Library, CNKI, CBM, VIP and Wanfang Data were searched to collect randomized controlled trial (RCT) about EOF versus TOF in patients undergoing elective colorectal surgery. The retrieval time span was from inception to June 1, 2016. The studies were screened according to the inclusion and exclusion criteria. The data were extracted and the quality was evaluated by 2 reviewers independently. The Meta-analysis was conducted using RevMan 5.2 software. RESULTS: A total of 14 studies with 1 807 patients (906 cases in EOF group and 901 cases in TOF group) were included. The time to first passage of flatus (MD=-16.11 h, 95%CI:-18.27 to 13.94 h, P=0.00), postoperative hospital stay (MD=-1.92 d, 95%CI:-2.83 to -1.01 d, P=0.00), hospitalization cost (ten thousand yuan) (MD=-0.58, 95%CI:-0.71 to 0.46, P=0.00) were less in EOF group compared to TOF group. EOF patients had lower total complication rate (OR=0.68, 95%CI:0.48 to 0.95, P=0.03), in which the pulmonary infection (OR=0.27, 95%CI:0.13 to 0.53, P=0.00), pharyngolaryngitis (OR=0.06, 95%CI:0.04 to 0.11, P=0.00) were lower than those in TOF group, while the tube reinsertion (OR=2.34, 95%CI:1.08 to 5.07, P=0.03) was higher. The incidence of anastomotic leakage, nausea, vomiting, abdominal distension, diarrhea, and wound infection between two groups was not significantly different(all P>0.05). There was no significant difference between two groups in IgM (P>0.05), while the IgA (MD=0.3, 95%CI:0.12 to 0.48, P=0.00), IgG (MD=2.13 ,95%CI:0.82 to 3.44, P=0.001), CD4+ (MD=3.80, 95%CI:2.55 to 5.04, P=0.00), CD4+/CD8+ (MD=0.22, 95%CI:0.04 to 0.41, P=0.02) in EOF group were higher than those in TOF group. Postoperative CRP decreased rapidly in EOF group (MD=-30.10, 95%CI:-48.07 to -12.13, P=0.00), and IL-6 was not significantly different (P>0.05). EOF patients had higher serum albumin level 5 days after operation (MD=3.27, 95%CI: 2.48 to 4.07, P=0.00). CONCLUSIONS: EOF can promote gas passage and defecation, reduce postoperative hospital stay and treatment costs. Also, it can decrease the incidence of complications and postoperative inflammation, and maintain immune function. PMID- 28901002 TI - [Current research status and progress of primary esophageal gastrointestinal stromal tumors in China]. AB - Primary esophageal gastrointestinal stromal tumors (GIST) is a rare independent disease with clinicopathological and molecular features different from other mesenchymal tumors. Authors searched and reviewed associated reports and summarized the morbidity trends, characteristics, diagnosis and treatment of esophageal GIST in China. Data show that the incidence and detection rate of esophageal GIST presents the rising trend. Imaging has some characteristics. Ultrasonography and CT are main methods and effective examinations to detect and prompt diagnosis of esophageal GIST. Pathology and immunohistochemistry are the evidence for a definite diagnosis. Risk classification is the important basis for selecting surgical methods and predicting prognosis. Surgery is the mainstay treatment. Very low and low risk patients with tumors less than 3 cm can choose endoscopic resection. For tumors of 3 to 5 cm, tumor resection must be considered. Thoracoscopy appears to be the first choice for surgery. Medium and high risk patients with tumors >5 cm should be treated with partial resection of esophagus. Surgery combined with targeted therapy and neoadjuvant therapy is the main treatment pattern and research direction. PMID- 28901003 TI - Expression of TIM-3 and LAG-3 in extranodal NK/T cell lymphoma, nasal type. AB - OBJECTIVE: To investigate the expression of TIM-3 and LAG-3 in extranodal NK/T cell lymphoma, nasal type (ENKTL), and evaluate the clinical and prognostic significance of TIM-3 and LAG-3 in ENKTL. METHODS: A total of 61 human paraffin embedded specimens including 41 ENKTL and 20 rhinitis were involved. We performed immunohistochemistry to detect the expression of TIM-3 and LAG-3. We analyzed correlation between expression of TIM-3 and LAG-3 and clinicopathological features of ENKTL. RESULTS: TIM-3 was positively expressed in 95 (39/41) ENKTL compared with 55% (11/20) in rhinitis, LAG-3 was positively expressed in 95 (39/41) ENKTL compared with 45% (9/20) in rhinitis. A positive correlation was found between TIM-3 and LAG-3. TIM-3 and LAG-3 had no significant correlation with ENKTL patients' age, gender, international prognostic index (IPI) score, B symptoms, LDH level, Ann Arbor stage and treatment regimens. High expression of TIM-3, high IPI score, elevated LDH level and late Ann Arbor stage were shown to be correlated with worse progression free survival (PFS). A multivariate COX regression model show that TIM-3 high expression rate was an independent prognostic factor for ENKTL patients' PFS. CONCLUSIONS: Our findings indicate that TIM-3 might be a promising predictive indicator for the ENKTL patients. PMID- 28901004 TI - Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis related gene expression in epidermal keratinocytes. AB - IL-22 induces STAT3 phosphorylation and mediates psoriasis-related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl-3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL-22 increased Bcl-3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human beta-defensin 2 mRNA expression caused by IL-22 were abolished by siRNA against Bcl-3. Although CCL20 expression was also augmented by IL-22, the knockdown of Bcl-3 increased its level. Moreover, the combination of IL-22 and IL-17A enhanced Bcl-3 production, IL-22-induced gene expression, and the expression of other psoriasis related genes, including those encoding IL-17C, IL-19, and IL-36gamma. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl-3. Bcl-3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl-3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl-3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL-22-STAT3-Bcl-3 pathway may be important in the pathogenesis of psoriasis. PMID- 28901006 TI - Reproductive aspects of the Atlantic angel shark Squatina dumeril in the southern Caribbean Sea. AB - The maturity and reproduction of the Atlantic angel shark Squatina dumeril were assessed using 77 females (29.2-110.4 cm total length; LT ) and 269 males (58.7 108.2 cm LT ) harvested by artisanal gillnetters off Venezuela. The biased sex ratio implied segregation or sex-specific gear selectivity. Based on the development of the reproductive tract, 50% LT at sexual maturity (LT50 , mean +/- s.e.) for females and males were estimated at 86.14 +/- 0.64 and 81.55 +/- 0.12 cm, respectively. Uterine fecundity ranged between one and six and with a maximum embryo size of 25.7 cm LT . Gravid females were observed from August to December, including those close to parturition and while the gestation period was not confirmed, the size of ovarian follicles among some specimens implied protraction. The low fecundity of the species supports close monitoring of catches. PMID- 28901007 TI - Pharmacological and mechanical interventions for labour induction in outpatient settings. AB - BACKGROUND: Induction of labour is carried out for a variety of indications and using a range of methods. For women at low risk of pregnancy complications, some methods of induction of labour or cervical ripening may be suitable for use in outpatient settings. OBJECTIVES: To examine pharmacological and mechanical interventions to induce labour or ripen the cervix in outpatient settings in terms of effectiveness, maternal satisfaction, healthcare costs and, where information is available, safety. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining outpatient cervical ripening or induction of labour with pharmacological agents or mechanical methods. Cluster trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed evidence using the GRADE approach. MAIN RESULTS: This updated review included 34 studies of 11 different methods for labour induction with 5003 randomised women, where women received treatment at home or were sent home after initial treatment and monitoring in hospital.Studies examined vaginal and intracervical prostaglandin E2 (PGE2), vaginal and oral misoprostol, isosorbide mononitrate, mifepristone, oestrogens, amniotomy and acupuncture, compared with placebo, no treatment, or routine care. Trials generally recruited healthy women with a term pregnancy. The risk of bias was mostly low or unclear, however, in 16 trials blinding was unclear or not attempted. In general, limited data were available on the review's main and additional outcomes. Evidence was graded low to moderate quality. 1. Vaginal PGE2 versus expectant management or placebo (5 studies)Fewer women in the vaginal PGE2 group needed additional induction agents to induce labour, however, confidence intervals were wide (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.27 to 0.99; 150 women; 2 trials). There were no clear differences between groups in uterine hyperstimulation (with or without fetal heart rate (FHR) changes) (RR 3.76, 95% CI 0.64 to 22.24; 244 women; 4 studies; low-quality evidence), caesarean section (RR 0.80, 95% CI 0.49 to 1.31; 288 women; 4 studies; low-quality evidence), or admission to a neonatal intensive care unit (NICU) (RR 0.32, 95% CI 0.10 to 1.03; 230 infants; 3 studies; low-quality evidence).There was no information on vaginal birth within 24, 48 or 72 hours, length of hospital stay, use of emergency services or maternal or caregiver satisfaction. Serious maternal and neonatal morbidity or deaths were not reported. 2. Intracervical PGE2 versus expectant management or placebo (7 studies) There was no clear difference between women receiving intracervical PGE2 and no treatment or placebo in terms of need for additional induction agents (RR 0.98, 95% CI 0.74 to 1.32; 445 women; 3 studies), vaginal birth not achieved within 48 to 72 hours (RR 0.83, 95% CI 0.68 to 1.02; 43 women; 1 study; low quality evidence), uterine hyperstimulation (with FHR changes) (RR 2.66, 95% CI 0.63 to 11.25; 488 women; 4 studies; low-quality evidence), caesarean section (RR 0.90, 95% CI 0.72 to 1.12; 674 women; 7 studies; moderate-quality evidence), or babies admitted to NICU (RR 1.61, 95% CI 0.43 to 6.05; 215 infants; 3 studies; low-quality evidence). There were no uterine ruptures in either the PGE2 group or placebo group.There was no information on vaginal birth not achieved within 24 hours, length of hospital stay, use of emergency services, mother or caregiver satisfaction, or serious morbidity or neonatal morbidity or perinatal death. 3. Vaginal misoprostol versus placebo (4 studies)One small study reported on the rate of perinatal death with no clear differences between groups; there were no deaths in the treatment group compared with one stillbirth (reason not reported) in the control group (RR 0.34, 95% CI 0.01 to 8.14; 77 infants; 1 study; low quality evidence).There was no clear difference between groups in rates of uterine hyperstimulation with FHR changes (RR 1.97, 95% CI 0.43 to 9.00; 265 women; 3 studies; low-quality evidence), caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 325 women; 4 studies; low-quality evidence), and babies admitted to NICU (RR 0.89, 95% CI 0.54 to 1.47; 325 infants; 4 studies; low-quality evidence).There was no information on vaginal birth not achieved within 24, 48 or 72 hours, additional induction agents required, length of hospital stay, use of emergency services, mother or caregiver satisfaction, serious maternal, and other neonatal, morbidity or death.No substantive differences were found for other comparisons. One small study found that women who received oral misoprostol were more likely to give birth within 24 hours (RR 0.65, 95% CI 0.48 to 0.86; 87 women; 1 study) and were less likely to require additional induction agents (RR 0.60, 95% CI 0.37 to 0.97; 127 women; 2 studies). Women who received mifepristone were also less likely to require additional induction agents (average RR 0.59, 95% CI 0.37 to 0.95; 311 women; 4 studies; I2 = 74%); however, this result should be interpreted with caution due to high heterogeneity. One trial each of acupuncture and outpatient amniotomy were included, but few review outcomes were reported. AUTHORS' CONCLUSIONS: Induction of labour in outpatient settings appears feasible and important adverse events seem rare, however, in general there is insufficient evidence to detect differences. There was no strong evidence that agents used to induce labour in outpatient settings had an impact (positive or negative) on maternal or neonatal health. There was some evidence that compared to placebo or no treatment, induction agents administered on an outpatient basis reduced the need for further interventions to induce labour, and shortened the interval from intervention to birth.We do not have sufficient evidence to know which induction methods are preferred by women, the interventions that are most effective and safe to use in outpatient settings, or their cost effectiveness. Further studies where various women-friendly outpatient protocols are compared head-to-head are required. As part of such work, women should be consulted on what sort of management they would prefer. PMID- 28901008 TI - Continuous-time capture-recapture in closed populations. AB - The standard approach to fitting capture-recapture data collected in continuous time involves arbitrarily forcing the data into a series of distinct discrete capture sessions. We show how continuous-time models can be fitted as easily as discrete-time alternatives. The likelihood is factored so that efficient Markov chain Monte Carlo algorithms can be implemented for Bayesian estimation, available online in the R package ctime. We consider goodness-of-fit tests for behavior and heterogeneity effects as well as implementing models that allow for such effects. PMID- 28901009 TI - Sample size determination for multilevel hierarchical designs using generalized linear mixed models. AB - A unified statistical methodology of sample size determination is developed for hierarchical designs that are frequently used in many areas, particularly in medical and health research studies. The solid foundation of the proposed methodology opens a new horizon for power analysis in presence of various conditions. Important features such as joint significance testing, unequal allocations of clusters across intervention groups, and differential attrition rates over follow up time points are integrated to address some useful questions that investigators often encounter while conducting such studies. Proposed methodology is shown to perform well in terms of maintaining type I error rates and achieving the target power under various conditions. Proposed method is also shown to be robust with respect to violation of distributional assumptions of random-effects. PMID- 28901005 TI - Delivery arrangements for health systems in low-income countries: an overview of systematic reviews. AB - BACKGROUND: Delivery arrangements include changes in who receives care and when, who provides care, the working conditions of those who provide care, coordination of care amongst different providers, where care is provided, the use of information and communication technology to deliver care, and quality and safety systems. How services are delivered can have impacts on the effectiveness, efficiency and equity of health systems. This broad overview of the findings of systematic reviews can help policymakers and other stakeholders identify strategies for addressing problems and improve the delivery of services. OBJECTIVES: To provide an overview of the available evidence from up-to-date systematic reviews about the effects of delivery arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on delivery arrangements and informing refinements of the framework for delivery arrangements outlined in the review. METHODS: We searched Health Systems Evidence in November 2010 and PDQ Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of delivery arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use, healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty or employment) and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the findings. Two overview authors independently screened reviews, extracted data, and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence), and assessments of the relevance of findings to low-income countries. MAIN RESULTS: We identified 7272 systematic reviews and included 51 of them in this overview. We judged 6 of the 51 reviews to have important methodological limitations and the other 45 to have only minor limitations. We grouped delivery arrangements into eight categories. Some reviews provided more than one comparison and were in more than one category. Across these categories, the following intervention were effective; that is, they have desirable effects on at least one outcome with moderate- or high-certainty evidence and no moderate- or high-certainty evidence of undesirable effects. Who receives care and when: queuing strategies and antenatal care to groups of mothers. Who provides care: lay health workers for caring for people with hypertension, lay health workers to deliver care for mothers and children or infectious diseases, lay health workers to deliver community-based neonatal care packages, midlevel health professionals for abortion care, social support to pregnant women at risk, midwife-led care for childbearing women, non-specialist providers in mental health and neurology, and physician-nurse substitution. Coordination of care: hospital clinical pathways, case management for people living with HIV and AIDS, interactive communication between primary care doctors and specialists, hospital discharge planning, adding a service to an existing service and integrating delivery models, referral from primary to secondary care, physician-led versus nurse-led triage in emergency departments, and team midwifery. Where care is provided: high-volume institutions, home-based care (with or without multidisciplinary team) for people living with HIV and AIDS, home-based management of malaria, home care for children with acute physical conditions, community-based interventions for childhood diarrhoea and pneumonia, out-of-facility HIV and reproductive health services for youth, and decentralised HIV care. Information and communication technology: mobile phone messaging for patients with long-term illnesses, mobile phone messaging reminders for attendance at healthcare appointments, mobile phone messaging to promote adherence to antiretroviral therapy, women carrying their own case notes in pregnancy, interventions to improve childhood vaccination. Quality and safety systems: decision support with clinical information systems for people living with HIV/AIDS. Complex interventions (cutting across delivery categories and other health system arrangements): emergency obstetric referral interventions. AUTHORS' CONCLUSIONS: A wide range of strategies have been evaluated for improving delivery arrangements in low-income countries, using sound systematic review methods in both Cochrane and non-Cochrane reviews. These reviews have assessed a range of outcomes. Most of the available evidence focuses on who provides care, where care is provided and coordination of care. For all the main categories of delivery arrangements, we identified gaps in primary research related to uncertainty about the applicability of the evidence to low-income countries, low- or very low-certainty evidence or a lack of studies. PMID- 28901010 TI - Habitat use of the European mudminnow Umbra krameri and association with other fish species in a disconnected Danube side arm. AB - Fish assemblages along the longitudinal course of an old, disconnected and modified side arm of the Danube floodplain downstream of Vienna, Austria, as well as habitat structure, hydro-morphological and hydro-chemical factors, were investigated in order to analyse the key environmental determinants of the European mudminnow Umbra krameri. Generally, U. krameri was the most abundant species in the system. It occurred in disconnected ditches, ponds and pools with dense reed belts and comparatively low nutrient content, indicating its natural association with marsh habitats. At infrequently disturbed sites it was associated with a small group of stagnophilious and highly specialized species with adaptations to strong oxygen fluctuations. At frequently flooded sites, the species was absent or occurred in low abundances, indicating its adaptation to water bodies in older successional stages and its low competitive power in permanently connected floodplain habitats. PMID- 28901012 TI - Pharmacology of cognition: a panacea for neuropsychiatric disease? AB - LINKED ARTICLES: This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. PMID- 28901011 TI - Persistent aberrant cortical phase-amplitude coupling following seizure treatment in absence epilepsy models. AB - KEY POINTS: In two monogenic models of absence epilepsy, interictal beta/gamma power is augmented in homozygous stargazer (stg/stg) but not homozygous tottering (tg/tg) mice. There are distinct gene-linked patterns of aberrant phase-amplitude coupling in the interictal EEG of both stg/stg and tg/tg mice, compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both genotypes, but the abnormal phase-amplitude coupling remains. Seizure-free stg/+ mice have normal power and phase-amplitude coupling, but beta/gamma power is significantly reduced with NMDA receptor blockade, revealing a latent cortical network phenotype that is separable from, and therefore not a result of, seizures. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers free from epileptiform activity, and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment. ABSTRACT: In childhood absence epilepsy, cortical seizures are brief and intermittent; however there are extended periods without behavioural or electrographic ictal events. This genetic disorder is associated with variable degrees of cognitive dysfunction, but no consistent functional biomarkers that might provide insight into interictal cortical function have been described. Previous work in monogenic mouse models of absence epilepsy have shown that the interictal EEG displays augmented beta/gamma power in homozygous stargazer (stg/stg) mice bearing a presynaptic AMPA receptor defect, but not homozygous tottering (tg/tg) mice with a P/Q type calcium channel mutation. To further evaluate the interictal EEG, we quantified phase-amplitude coupling (PAC) in stg/stg, stg/+, tg/tg and wild-type (+/+) mice. We found distinct gene-linked patterns of aberrant PAC in stg/stg and tg/tg mice compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both stg/stg and tg/tg, but the abnormal PAC remains. Stg/+ mice are seizure free with normal baseline beta/gamma power and normal theta-gamma PAC, but like stg/stg mice, beta/gamma power is significantly reduced by NMDA receptor blockade, a treatment that paradoxically enhances seizures in stg/stg mice. Stg/+ mice, therefore, have a latent cortical network phenotype that is veiled by NMDA-mediated neurotransmission. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers in the absence of epileptiform activity and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment. PMID- 28901013 TI - How active are young cardiac device patients? Objective assessment of activity in children with cardiac devices. AB - BACKGROUND: The daily activity of pediatric patients with implantable cardiac devices provides behavioral evidence of functional outcomes. Modern devices provide continuous accelerometer data that are sensitive to movement, but normative values have not been published for pediatric activity rates. This study provides the first normative accelerometer data on activity rates in a large sample of pediatric cardiac device patients. METHODS: Patients were between 3 and 18 years old (N = 1,905) and implanted with a cardiac device from a single device company, and enrolled in remote monitoring. RESULTS: The median age at implant was 14 years (interquartile range = 12-16); 61.3% were male. Data for 4 weeks were extracted from a company database at 53 weeks postimplant and an average of daily activity was calculated. Daily average activity for all patients was 5.4 hours (standard deviation = 2.0). In a multivariate analysis, increased level of activity was associated with: being male, having a pacemaker versus implantable cardioverter defibrillator (ICD), epicardial device location, rate response turned off, having experienced a shock, and younger age. CONCLUSIONS: These results provide the first baseline data of physical activity in children with implanted cardiac devices and provide a clinical guide to physical activity assessment in this population. Further, our data suggest physical activity in children with implantable cardiac devices may differ based on demographic variables, device type, device location, indication for implantation, and history of ICD shock. PMID- 28901017 TI - Efficiency of two sample tests via the restricted mean survival time for analyzing event time observations. AB - In comparing two treatments with the event time observations, the hazard ratio (HR) estimate is routinely used to quantify the treatment difference. However, this model dependent estimate may be difficult to interpret clinically especially when the proportional hazards (PH) assumption is violated. An alternative estimation procedure for treatment efficacy based on the restricted means survival time or t-year mean survival time (t-MST) has been discussed extensively in the statistical and clinical literature. On the other hand, a statistical test via the HR or its asymptotically equivalent counterpart, the logrank test, is asymptotically distribution-free. In this article, we assess the relative efficiency of the hazard ratio and t-MST tests with respect to the statistical power under various PH and non-PH models theoretically and empirically. When the PH assumption is valid, the t-MST test performs almost as well as the HR test. For non-PH models, the t-MST test can substantially outperform its HR counterpart. On the other hand, the HR test can be powerful when the true difference of two survival functions is quite large at end but not the beginning of the study. Unfortunately, for this case, the HR estimate may not have a simple clinical interpretation for the treatment effect due to the violation of the PH assumption. PMID- 28901018 TI - Reproductive morphology and its application in testing molecular systematic hypotheses in the family Gobiidae (Teleostei, Gobiiformes). AB - This study uses histological techniques to make a detailed comparison of the reproductive morphologies of four gobiid genera, Amblyeleotris, Ctenogobiops, Fusigobius and Kraemeria. Three distinct reproductive morphological patterns were observed. All species examined in the genus Fusigobius exhibit either an ovariform or testiform gonad and precursive accessory gonadal structures (pAGS) associated with each of the gonadal lobes, regardless of gonadal state. In contrast, among species of Amblyeleotris, Ctenogobiops and Kraemeria examined, pAGS were not found. Furthermore, Amblyeleotris and Ctenogobiops differ from both Kraemeria and Fusigobius in lacking AGS associated with the testiform gonad. These findings, based solely on reproductive morphology, suggest that Kraemeria and Fusigobius may be more closely related to each other than either is to Amblyeleotris and Ctenogobiops. Findings of this study support the view that reproductive morphological patterns could prove informative in elucidating evolutionary relationships within the family Gobiidae. PMID- 28901019 TI - Isolation and characterization of pathogenic Vibrio alginolyticus from sea cage cultured cobia (Rachycentron canadum (Linnaeus 1766)) in India. AB - : Mass mortalities of cobia, Rachycentron canadum, sub-adults occurred during August 2013 in cage culture in the Gulf of Mannar, Mandapam Tamil Nadu, India. The epizootic of disease was started with typical classical clinical signs followed by acute mortality. Grossly, severe haemorrhage and congestion were observed in the gastric mucosa. The abdomen was distended with peritoneal fluid. The heart revealed haemopericardium and fibrinous pericardium. Histologically, the gastric mucosa showed severe erosion and necrosis. Haemorrhagic pericarditis and an increased size of the melano macrophage centre (MMC) in the tail kidney were other histopathological changes. Vibrio sp. was isolated from the gastric lesions and heart blood swab of moribund fishes and it was found to be virulent to the cobia fingerlings. After the challenge, the same bacterium could be re isolated from moribund fingerlings. The 16S ribosomal RNA of the isolate was amplified and blast analysis of the sequence confirmed that the pathogen was Vibrio alginolyticus. The confirmation was also correlated with its cultural, biochemical and pathomorphological changes. This is the second report and the first incidence of epizootics with severe pathological lesions in cultured cobia in India. The study throws light on the pathology of vibriosis. By practising cage farm management measures, occurrences of infection may be prevented. SIGNIFICANCE AND IMPACT OF THE STUDY: The epizootics of vibriosis caused serious economic losses to farmers. Natural blooms of the pathogen can be prevented by sea cage management measures such as, changing the inner net of the cages, changing the location of the cages to relatively clean water (about 50 m apart) from the affected site and providing shade over the cages while the water temperature rises. Supplementation of the feed with immunostimulants and mineral mixture may be practised to improve the immune response against infection. Early diagnosis and sea cage management measures may prevent occurrences of the infection. PMID- 28901020 TI - The location of projection neurons to the biceps brachii muscle in the telencephalon of the pigeon. AB - Few studies regarding the anatomical distribution of motor neurons innervating muscles of the arm have been demonstrated in avian brains. The purpose of this study was to finely determine the localization of cerebral neurons innervating the biceps brachii muscle in the pigeon. The cholera toxin B subunit (CTB) was employed as a retrograde tracer to determine the location of neurons controlling the biceps brachii muscle in the telencephalon following intramuscular injection in male pigeons (n = 7), which were killed 14 days after intramuscular injection with CTB. We found that CTB-labelled neurons were located contralaterally in the hyperpallium apicale of the rostral telencephalon and that most of the CTB labelled neurons were pyramidal in shape. This study shows that CTB is easily taken up by nerve terminals which innervate the biceps brachii muscle of the pigeon and that cerebral motor neurons controlling the biceps brachii muscle are located in the hyperpallium apicale. PMID- 28901022 TI - In this issue October 2017. PMID- 28901021 TI - Optimisation of chemotherapy and radiotherapy for untreated Hodgkin lymphoma patients with respect to second malignant neoplasms, overall and progression-free survival: individual participant data analysis. AB - BACKGROUND: Efficacy and the risk of severe late effects have to be well-balanced in treatment of Hodgkin lymphoma (HL). Late adverse effects include secondary malignancies which often have a poor prognosis. To synthesise evidence on the risk of secondary malignancies after current treatment approaches comprising chemotherapy and/or radiotherapy, we performed a meta-analysis based on individual patient data (IPD) from patients treated for newly diagnosed HL. OBJECTIVES: We investigated several questions concerning possible changes in the risk of secondary malignancies when modifying chemotherapy or radiotherapy (omission of radiotherapy, reduction of the radiation field, reduction of the radiation dose, use of fewer chemotherapy cycles, intensification of chemotherapy). We also analysed whether these modifications affect progression free survival (PFS) and overall survival (OS). SEARCH METHODS: We searched MEDLINE and Cochrane CENTRAL trials databases comprehensively in June 2010 for all randomised trials in HL since 1984. Key international trials registries were also searched. The search was updated in March 2015 without collecting further IPD (one further eligible study found) and again in July 2017 (no further eligible studies). SELECTION CRITERIA: We included randomised controlled trials (RCTs) for untreated HL patients which enrolled at least 50 patients per arm, completed recruitment by 2007 and performed a treatment comparison relevant to our objectives. DATA COLLECTION AND ANALYSIS: Study groups submitted IPD, including age, sex, stage and the outcomes secondary malignant neoplasm (SMN), OS and PFS as time-to-event data. We meta-analysed these data using Petos method (SMN) and Cox regression with inverse-variance pooling (OS, PFS) for each of the five study questions, and performed subgroup and sensitivity analyses to assess the applicability and robustness of the results. MAIN RESULTS: We identified 21 eligible trials and obtained IPD for 16. For four studies no data were supplied despite repeated efforts, while one study was only identified in 2015 and IPD were not sought. For each study question, between three and six trials with between 1101 and 2996 participants in total and median follow-up between 6.7 and 10.8 years were analysed. All participants were adults and mainly under 60 years. Risk of bias was assessed as low for the majority of studies and outcomes. Chemotherapy alone versus same chemotherapy plus radiotherapy. Omitting additional radiotherapy probably reduces secondary malignancy incidence (Peto odds ratio (OR) 0.43, 95% confidence interval (CI) 0.23 to 0.82, low quality of evidence), corresponding to an estimated reduction of eight-year SMN risk from 8% to 4%. This decrease was particularly true for secondary acute leukemias. However, we had insufficient evidence to determine whether OS rates differ between patients treated with chemotherapy alone versus combined-modality (hazard ratio (HR) 0.71, 95% CI 0.46 to 1.11, moderate quality of evidence). There was a slightly higher rate of PFS with combined modality, but our confidence in the results was limited by high levels of statistical heterogeneity between studies (HR 1.31, 95% CI 0.99 to 1.73, moderate quality of evidence). Chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages) . There is insufficient evidence to determine whether smaller radiation field reduces SMN risk (Peto OR 0.86, 95% CI 0.64 to 1.16, low quality of evidence), OS (HR 0.89, 95% C: 0.70 to 1.12, high quality of evidence) or PFS (HR 0.99, 95% CI 0.81 to 1.21, high quality of evidence). Chemotherapy plus lower dose radiation versus same chemotherapy plus higher-dose radiation (early stages). There is insufficient evidence to determine the effect of lower radiation dose on SMN risk (Peto OR 1.03, 95% CI 0.71 to 1.50, low quality of evidence), OS (HR 0.91, 95% CI 0.65 to 1.28, high quality of evidence) or PFS (HR 1.20, 95% CI 0.97 to 1.48, high quality of evidence). Fewer versus more courses of chemotherapy (each with or without radiotherapy; early stages). Fewer chemotherapy courses probably has little or no effect on SMN risk (Peto OR 1.10, 95% CI 0.74 to 1.62), OS (HR 0.99, 95% CI 0.73 to1.34) or PFS (HR 1.15, 95% CI 0.91 to 1.45).Outcomes had a moderate (SMN) or high (OS, PFS) quality of evidence. Dose-intensified versus ABVD-like chemotherapy (with or without radiotherapy in each case). In the mainly advanced-stage patients who were treated with intensified chemotherapy, the rate of secondary malignancies was low. There was insufficient evidence to determine the effect of chemotherapy intensification (Peto OR 1.37, CI 0.89 to 2.10, low quality of evidence). The rate of secondary acute leukemias (and for younger patients, all secondary malignancies) was probably higher than among those who had treatment with standard-dose ABVD-like protocols. In contrast, the intensified chemotherapy protocols probably improved PFS (eight-year PFS 75% versus 69% for ABVD-like treatment, HR 0.82, 95% CI 0.7 to 0.95, moderate quality of evidence). Evidence suggesting improved survival with intensified chemotherapy was not conclusive (HR: 0.85, CI 0.70 to 1.04), although escalated-dose BEACOPP appeared to lengthen survival compared to ABVD-like chemotherapy (HR 0.58, 95% CI 0.43 to 0.79, moderate quality of evidence).Generally, we could draw valid conclusions only in terms of secondary haematological malignancies, which usually occur less than 10 years after initial treatment, while follow-up within the present analysis was too short to record all solid tumours. AUTHORS' CONCLUSIONS: The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results. PMID- 28901023 TI - Mosasaurs and snakes have a periodontal ligament: timing and extent of calcification, not tissue complexity, determines tooth attachment mode in reptiles. AB - Squamates present a unique challenge to our understanding of dental evolution in amniotes because they are the only extant tooth-bearing group for which a ligamentous tooth attachment is considered to be absent. This has led to the assumption that mammals and crocodilians have convergently evolved a ligamentous tooth attachment, composed of root cementum, periodontal ligament, and alveolar bone, whereas squamates are thought to possess a single bone of attachment tissue that fuses teeth to the jaws. The identity and homology of tooth attachment tissues between squamates, crocodilians, and mammals have thus been a focal point of debate for decades. We provide a novel interpretation of the mineralized attachment tissues in two focal taxa in this debate, mosasaurids and snakes, and compare dental tissue histology with that of the extant crocodilian Caiman sclerops. We identify a periodontal ligament in these squamates that usually exists temporarily as a soft connective tissue anchoring each tooth to the alveolar bone. We also identify two instances where complete calcification of the periodontal ligament does not occur: in a durophagous mosasaur, and in the hinged teeth of fossil and modern snakes. We propose that the periodontal ligament rapidly calcifies in the majority of mosasaurids and snakes, ankylosing the tooth to the jaw. This gives the appearance of a single, bone-like tissue fusing the tooth to the jaw in ankylosed teeth, but is simply the end stage of dental tissue ontogeny in most snakes and mosasaurids. PMID- 28901024 TI - Records of ocean sunfish Mola mola along the Norwegian coast spanning two centuries, 1801-2015. AB - Records of the ocean sunfish Mola mola along the Norwegian coast were compiled from all possible sources: literature, media, databases and museums. A total of 216 records were found between 1801 and 2015. They were distributed along the whole coast, except for the most north-eastern part. Nearly all years with more than five records were after 2000, with 1985 as the only exception and with a maximum of 23 records in 2014. Most, 92.4%, were from July to December. Records from before 1979 were more incidental and random and no sunfish were recorded in 54 separate years between 1879 and 2015. The northernmost record was from 70 degrees 44' N in December 1881. No relationship between year and latitude was found. Forty-four per cent of the records were of sunfish caught in fishing gear, 27% were found stranded and 30% were observed alive at sea. A trend of a decrease in numbers of observations of living individuals and an increase in numbers of strandings as dead individuals as autumn progressed was found. Geographical differences in the three categories of observation were also found. Among the specimens whose size was recorded, most were small, <30 kg and 70 cm in total length. Only 10 were heavier than 100 kg, all these were from before 1960. Annual numbers correlated weakly with sea temperatures. This was supported by a weak negative correlation with the North Atlantic Oscillation (NAO) index, because the majority of years since 2000 had a negative NAO. PMID- 28901026 TI - On authorship in the BJCP. PMID- 28901028 TI - A Reusable N-Doped-Carbon-Coated Mo2 C Composite Counter Electrode for High Efficiency Dye-Sensitized Solar Cells. AB - The design and development of efficient and stable nonprecious-metal-based catalysts for counter electrodes (CEs) in dye-sensitized solar cells (DSSCs) has received a great deal of attention. In this work, molybdenum carbide nanoparticles homogeneously distributed in a nitrogen-rich carbon matrix (Mo2 C@NC) have been synthesized from inexpensive raw materials (polyoxometalate and dicyandiamide) by a facile one-step solid-phase synthesis method. The novel Mo2 C@NC hybrid was not only used as a CE in a DSSC, but also showed superior catalytic activity towards I3- /I- as a redox electrolyte. The power conversion efficiency of a DSSC with Mo2 C@NC as the CE was as high as 6.49 %, comparable to that with Pt (6.38 %). The CE was prepared by a drop-coating method, without the addition of another conductive polymer. Most importantly, the method circumvents the problem of the sample falling off from the fluorine-doped tin oxide (FTO), and the CE could be repeatedly reused with unchanged efficiency. Therefore, it opens the way for the development of platinum-free catalysts with low cost, simple processing, good stability, and high efficiency. PMID- 28901029 TI - Successful venoarterial extracorporeal membrane oxygenation for postoperative septic shock in a child with liver transplantation: A case report. AB - Refractory septic shock after LT is a life-threatening complication. VA ECMO is used to treat refractory cardiorespiratory failure. We present herein the case of a 5-year-old girl with post-Kasai biliary atresia, who underwent a living donor LT and suffered refractory septic shock. VA ECMO was indicated due to progressive cardiac deterioration. After full recovery of her EF, she has been steadily improving and has shown good liver function and no neurological sequelae. This is the first report of successful VA ECMO in a post- LT patient with refractory septic shock. PMID- 28901030 TI - Treating OSA: Current and emerging therapies beyond CPAP. AB - Continuous positive airway pressure (CPAP) is the standard treatment for moderate to-severe obstructive sleep apnoea (OSA). However, adherence to CPAP is limited and non-CPAP therapies are frequently explored. Oral appliance (OA) therapy is currently widely used for the treatment of snoring, mild, moderate and severe OSA. The most commonly used and studied OA consists of a maxillary and mandibular splint which hold the lower jaw forward during sleep. The efficacy of OA is inferior to CPAP; however, the effectiveness as measured by sleepiness, quality of life, endothelial function and blood pressure is similar likely due to higher acceptance and subjective adherence. Upper airway stimulation augments neural drive by unilaterally stimulating the hypoglossal nerve. The Stimulation Therapy for Apnea Reduction (STAR) study enrolled 126 patients and demonstrated a 68% reduction in OSA severity. A high upfront cost and variable response are the main limitations. Oropharyngeal exercises consist of a set of isometric and isotonic exercises involving the tongue, soft palate and lateral pharyngeal wall. The collective reported trials (n = 120) showed that oropharyngeal exercises can ameliorate OSA and snoring (~30-40%). Nasal EPAP devices consist of disposable one-way resister valve. A systematic review (n = 345) showed that nasal EPAP reduced OSA severity by 53%. The Winx device consists of a mouthpiece placed inside the oral cavity that is connected by tubing to a console that generates negative pressure. Winx may provide successful therapy for ~30-40% of OSA patients. In conclusion, several non-CPAP therapies to treat OSA are currently available. PMID- 28901031 TI - Isomer separation and effect of the degree of polymerization on the gas-phase structure of chondroitin sulfate oligosaccharides analyzed by ion mobility and tandem mass spectrometry. AB - RATIONALE: Chondroitin sulfate (CS) glycosaminoglycans are bioactive sulfated polysaccharides comprising repeating units of uronic acid and N-acetyl galactose sulfated at various positions. The optimal length and sulfation pattern of the CS bioactive sequences remain elusive so that structure-activity relationships cannot be easily established. Development of efficient analytical methods allowing the differentiation of the various sulfation patterns of CS sequences is therefore of particular importance to correlate their biological functions to the sulfation pattern. METHODS: Discrimination of different oligomers (dp2 to dp6) of synthetic chondroitin sulfate isomers was evaluated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the negative-ion mode from deprotonated and alkali adduct species. In addition, ion mobility mass spectrometry (IMS-MS) was used to study the influence of both the degree of polymerization and sulfate group location on the gas-phase conformation of CS oligomers. RESULTS: ESI-MS/MS spectra of chondroitin sulfate isomers show characteristic product ions exclusively from alkali adduct species (Li, Na, K and Cs). Whatever the alkali adducts studied, MS/MS of chondroitin oligosaccharides sulfated at position 6 yields a specific product ion at m/z 139 while CS oligosaccharides sulfated at position 4 show a specific product ion at m/z 154. Being observed for the different CS oligomers di-, tetra- and hexasaccharides, these fragment ions are considered as diagnostic ions for chondroitin 6-O-sulfate and chondroitin 4-O sulfate, respectively. IMS-MS experiments reveal that collision cross-sections (CCS) of CS oligomers with low charge states evolved linearly with degrees of polymerization indicating a similar gas-phase conformation. CONCLUSIONS: This study allows the fast and unambiguous differentiation of CS isomers sulfated at position 6 or 4 for both saturated and unsaturated analogues from MS/MS experiments. In addition, the CCS linear evolution of CS oligomers in function of the degree of polymerization indicates that no folding occurs even for hexasaccharides. PMID- 28901032 TI - Role of routine post-operative laryngeal endoscopic assessment after lung cancer surgery. PMID- 28901033 TI - Effect of Silyl Ether-functinoalized Dimethoxydimethylsilane on Electrochemical Performance of a Ni-rich NCM Cathode. AB - Dimethoxydimethylsilane (DODSi) is used as an interface stabilizing additive through a selective HF scavenging reaction for layered Ni-rich oxide cathodes. Ex situ NMR analyses demonstrated that DODSi effectively removes HF from the electrolyte based on the matched chemical reactivity of Si with F- and O with H+ . The cells employing DODSi exhibit higher specific capacity with retention than those cycled with a DODSi-free electrolyte even under in situ HF generating conditions. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma-mass spectroscopy (ICP-MS) analyses indicate that DODSi effectively protects the Ni-rich oxide cathodes against HF corrosion, resulting in improved surface stability of Ni-rich cathodes. PMID- 28901034 TI - A 'dynamic' landscape of fear: prey responses to spatiotemporal variations in predation risk across the lunar cycle. AB - Ambiguous empirical support for 'landscapes of fear' in natural systems may stem from failure to consider dynamic temporal changes in predation risk. The lunar cycle dramatically alters night-time visibility, with low luminosity increasing hunting success of African lions. We used camera-trap data from Serengeti National Park to examine nocturnal anti-predator behaviours of four herbivore species. Interactions between predictable fluctuations in night-time luminosity and the underlying risk-resource landscape shaped herbivore distribution, herding propensity and the incidence of 'relaxed' behaviours. Buffalo responded least to temporal risk cues and minimised risk primarily through spatial redistribution. Gazelle and zebra made decisions based on current light levels and lunar phase, and wildebeest responded to lunar phase alone. These three species avoided areas where likelihood of encountering lions was high and changed their behaviours in risky areas to minimise predation threat. These patterns support the hypothesis that fear landscapes vary heterogeneously in both space and time. PMID- 28901035 TI - How much vitamin D is needed for healthy bones? PMID- 28901036 TI - Preterm birth rates in Japan from 1979 to 2014: Analysis of national vital statistics. AB - AIM: Secular trends of preterm birth in Japan between 1979 and 2014 were examined to determine whether changes could be explained by a shift in the distribution of maternal age at delivery and parity and/or by changes in age-specific preterm birth rates. METHODS: Live birth data for 1979 to 2014 were obtained from the Japanese Ministry of Health, Labour and Welfare. Analyses were limited to singleton children born in Japan (n = 43 632 786). Preterm birth was defined using two cut-offs at < 37 or < 34 weeks of gestation. Crude and standardized rates of preterm birth were calculated for firstborn and later-born singletons by maternal age at delivery for specific time periods. RESULTS: Throughout the study period, the rates of preterm birth (both at < 37 and < 34 weeks of gestation) were higher among mothers aged 20 and younger, and mid-30s and older, compared to mothers in their 20s or early 30s. The rates of preterm birth at < 37 (but not at < 34) weeks decreased for mothers aged in their late 30s and 40s, and increased for mothers in their 20s and early 30s. Standardized rates of preterm birth showed a secular increase for preterm births at < 37 but not < 34 weeks of gestation. CONCLUSION: The rates of preterm birth among mothers aged in their 20s and early 30s increased between 1979 and 2014, which contributed to the secular increase in rates of preterm birth at < 37 weeks. PMID- 28901037 TI - No consistent pollinator-mediated impacts of alien plants on natives. AB - The introduction of an alien plant is widely assumed to have negative consequences for the pollinator-mediated fitness of nearby natives. Indeed, a number of studies, including a highly cited meta-analysis, have concluded that the trend for such interactions is competitive. Here we provide evidence that publication bias and study design have obscured our ability to assess the pollinator-mediated impacts of alien plants. In a meta-analysis of 76 studies, we demonstrate that alien/native status does not predict the outcome of pollinator mediated interactions among plants. Moreover, we found no evidence that similarity in floral traits or phylogenetic distance between species pairs influences the outcome of pollinator-mediated interactions. Instead, we report that aspects of study design, such as distance between the control and nearest neighbour, and/or the arrangement of study plants better predict the impact of a neighbour than does alien/native status. Our study sheds new light on the role that publication bias and experimental design play in the evaluation of key patterns in ecology. We conclude that, due to the absence of clear, generalisable pollinator-mediated impacts of alien species, management schemes should base decisions on community-wide assessments of the impacts of individual alien plant species, and not solely on alien/native status itself. PMID- 28901038 TI - The developmental trajectory of children's auditory and visual statistical learning abilities: modality-based differences in the effect of age. AB - Infants, children and adults are capable of extracting recurring patterns from their environment through statistical learning (SL), an implicit learning mechanism that is considered to have an important role in language acquisition. Research over the past 20 years has shown that SL is present from very early infancy and found in a variety of tasks and across modalities (e.g., auditory, visual), raising questions on the domain generality of SL. However, while SL is well established for infants and adults, only little is known about its developmental trajectory during childhood, leaving two important questions unanswered: (1) Is SL an early-maturing capacity that is fully developed in infancy, or does it improve with age like other cognitive capacities (e.g., memory)? and (2) Will SL have similar developmental trajectories across modalities? Only few studies have looked at SL across development, with conflicting results: some find age-related improvements while others do not. Importantly, no study to date has examined auditory SL across childhood, nor compared it to visual SL to see if there are modality-based differences in the developmental trajectory of SL abilities. We addressed these issues by conducting a large-scale study of children's performance on matching auditory and visual SL tasks across a wide age range (5-12y). Results show modality-based differences in the development of SL abilities: while children's learning in the visual domain improved with age, learning in the auditory domain did not change in the tested age range. We examine these findings in light of previous studies and discuss their implications for modality-based differences in SL and for the role of auditory SL in language acquisition. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=3kg35hoF0pw. PMID- 28901039 TI - Mimicking of cyproconazole behavior in the presence of Cu and Zn. AB - RATIONALE: The frequently used pesticide cyproconazole (Cyp) interacts with the essential elements commonly present in soil which play important roles in various enzymatic processes. These interactions predetermine the Cyp degradation pathways. We suggest a simple experimental and theoretical approach for the prediction of pesticide behavior. METHODS: Cu/Cyp complexes are explored because of the typical Cu(II) reduction in complexes. Its level and the stability of the Cu-ligand bond depend on the type and the number of the surrounding ligands. Zn/Cyp complexes were compared as it is not expected that Zn(II) will reduce. The complexations were studied by means of electrospray ionization ion trap mass spectrometry and MS/MS collision-induced dissociations with comparative and explicative density functional theory calculations. RESULTS: The Cyp ligand allows both Cu(II) reduction as well as, in specific cases, it protects the higher Cu oxidation state. The reduction is observed in the complexes with solely neutral Cyp where the number of ligands is below 3; a higher number protects the Cu(II) state. The metal atom binds to Cyp via N2 of the triazole ring as well as via pi-electrons of the benzene ring; additional stabilization brings an interaction with the deprotonated OH group. CONCLUSIONS: The character of Cyp interactions with doubly charged metals (Cu(II), Zn(II)) clarified the creation of Cyp metabolites. The phenyl and triazole rings are bound to the metal cation and enable access for the isopropyl ring to be cleaved leaving the common metabolite (CAS Number: 58905-19-4). PMID- 28901040 TI - Selective C-O Bond Cleavage of Sugars with Hydrosilanes Catalyzed by Piers' Borane Generated In Situ. AB - Described herein is the selective reduction of sugars with hydrosilanes catalyzed by using Piers' borane [(C6 F5 )2 BH] generated in situ. The hydrosilylative C-O bond cleavage of silyl-protected mono- and disaccharides in the presence of a (C6 F5 )2 BH catalyst, generated in situ from (C6 F5 )2 BOH, takes place with excellent chemo- and regioselectivities to provide a range of polyols. A study of the substituent effects of sugars on the catalytic activity and selectivity revealed that the steric environment around the anomeric carbon (C1) is crucial. PMID- 28901041 TI - Safety and Effectiveness of Mirabegron in Patients with Overactive Bladder Aged >=75 Years: Analysis of a Japanese Post-Marketing Study. AB - OBJECTIVES: A 12-week post-marketing study was conducted to provide real-world data on Japanese patients with overactive bladder (OAB) initiating treatment with mirabegron. This post-hoc analysis focused on safety and effectiveness of mirabegron in patients aged >=75 versus <75 years. METHODS: Incidence of adverse drug reactions (ADR) was assessed following 12 weeks' mirabegron treatment. Overactive Bladder Symptom Score (OABSS) and International-Prostate Symptom Score Quality of Life (I-PSS QoL) were completed at baseline and at the end of treatment (EoT). A reduction of >=3 points in total OABSS was defined as a minimal clinically important change (MCIC). RESULTS: Of 9795 patients, a greater proportion aged >=75 versus <75 years had a lower body mass index (BMI; BMI < 18.5: 4.2% vs 3.2%), longer OAB duration (>=3 years: 24.6% vs 20.3%) and more severe OAB symptoms (severe: 17.0% vs 11.2%). A significantly greater percentage of patients aged >=75 versus <75 years had comorbidities (77.8% vs 66.0%) and used concomitant drugs (58.3% vs 48.7%; P < 0.001). Incidence of ADR was observed in 7.00% and 5.19% of patients aged >=75 versus <75 years, respectively. At EoT, mirabegron treatment was reported 'effective' in 79.3% versus 82.1% of patients aged >=75 versus <75 years, respectively. Mean total OABSS decreased significantly from baseline, and exceeded the MCIC in 61.0% and 65.9% of patients aged >=75 and <75 years, respectively. Similar changes were observed for I-PSS QoL in both groups. CONCLUSIONS: In a real-world clinical setting, mirabegron was well-tolerated and effective in patients aged >=75 and <75 years. PMID- 28901042 TI - Calcium Coordination Solids for pH-Triggered Release of Olsalazine. AB - Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H4 olz), an anti-inflammatory compound used for treatment of ulcerative colitis. The materials include one-dimensional Ca(H2 olz)?4 H2 O chains, two-dimensional Ca(H2 olz)?2 H2 O sheets, and a three-dimensional metal organic framework Ca(H2 olz)?2DMF (DMF=N,N-dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H2 olz) phase when exposed to aqueous HCl. The compounds Ca(H2 olz)?x H2 O (x=0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH-neutral intestines. All three calcium materials exhibited a delayed release of olsalazine relative to Na2 (H2 olz), the commercial formulation, illustrating how formulation of a drug within an extended coordination solid can serve to tune its solubility and performance. PMID- 28901043 TI - Survey design for precise fire management conservation targets. AB - Common goals of ecological fire management are to sustain biodiversity and minimize extinction risk. A novel approach to achieving these goals determines the relative proportions of vegetation growth stages (equivalent to successional stages, which are categorical representations of time since fire) that maximize a biodiversity index. The method combines data describing species abundances in each growth stage with numerical optimization to define an optimal growth-stage structure that provides a conservation-based operational target for managers. However, conservation targets derived from growth-stage optimization are likely to depend critically on choices regarding input data. There is growing interest in the use of growth-stage optimization as a basis for fire management, thus understanding of how input data influence the outputs is crucial. Simulated data sets provide a flexible platform for systematically varying aspects of survey design and species inclusions. We used artificial data with known properties, and a case-study data set from southeastern Australia, to examine the influence of (1) survey design (total number of sites and their distribution among growth stages) and (2) species inclusions (total number of species and their level of specialization) on the precision of conservation targets. Based on our findings, we recommend that survey designs for precise estimates would ideally involve at least 80 sites, and include at least 80 species. Greater numbers of sites and species will yield increasingly reliable results, but fewer might be sufficient in some circumstances. An even distribution of sites among growth stages was less important than the total number of sites, and omission of species is unlikely to have a major influence on results as long as several species specialize on each growth stage. We highlight the importance of examining the responses of individual species to growth stage before feeding survey data into the growth stage optimization black box, and advocate use of a resampling procedure to determine the precision of results. Collectively, our findings form a reproducible guide to designing ecological surveys that yield precise conservation targets through growth-stage optimization, and ultimately help sustain biodiversity in fire-prone systems. PMID- 28901044 TI - Native insect herbivory overwhelms context dependence to limit complex invasion dynamics of exotic weeds. AB - Understanding the role of consumers in density-dependent plant population dynamics is a long-standing goal in ecology. However, the generality of herbivory effects across heterogeneous landscapes is poorly understood due to the pervasive influence of context-dependence. We tested effects of native insect herbivory on the population dynamics of an exotic thistle, Cirsium vulgare, in a field experiment replicated across eight sites in eastern Nebraska. Using hierarchical Bayesian analysis and density-dependent population models, we found potential for explosive low-density population growth (lambda > 5) and complex density fluctuations under herbivore exclusion. However, herbivore access drove population decline (lambda < 1), suppressing complex fluctuations. While plant herbivore interaction outcomes are famously context-dependent, we demonstrated that herbivores suppress potentially invasive populations throughout our study region, and this qualitative outcome is insensitive to environmental context. Our novel use of Bayesian demographic modelling shows that native insect herbivores consistently prevent hard-to-predict fluctuations of weeds in environments otherwise susceptible to invasion. PMID- 28901045 TI - The lessons learned from the fentanyl overdose crises in British Columbia, Canada. PMID- 28901047 TI - Mild Decarboxylative C-H Alkylation: Computational Insights for Solvent-Robust Ruthenium(II) Domino Manifold. AB - Computational studies on decarboxylative C-H alkenylations provided key insights into the solvent-robust nature of C-H activation/decarboxylation domino reactions. These properties were exploited for ruthenium(II)-catalyzed C-H alkylations by a decarboxylative process with ample scope under copper-free and silver-free reaction conditions. PMID- 28901046 TI - Combined effects of agrochemicals and ecosystem services on crop yield across Europe. AB - Simultaneously enhancing ecosystem services provided by biodiversity below and above ground is recommended to reduce dependence on chemical pesticides and mineral fertilisers in agriculture. However, consequences for crop yield have been poorly evaluated. Above ground, increased landscape complexity is assumed to enhance biological pest control, whereas below ground, soil organic carbon is a proxy for several yield-supporting services. In a field experiment replicated in 114 fields across Europe, we found that fertilisation had the strongest positive effect on yield, but hindered simultaneous harnessing of below- and above-ground ecosystem services. We furthermore show that enhancing natural enemies and pest control through increasing landscape complexity can prove disappointing in fields with low soil services or in intensively cropped regions. Thus, understanding ecological interdependences between land use, ecosystem services and yield is necessary to promote more environmentally friendly farming by identifying situations where ecosystem services are maximised and agrochemical inputs can be reduced. PMID- 28901048 TI - Administration of erythropoiesis-stimulating agents in patients undergoing haemodialysis: A time and motion study. AB - BACKGROUND: International guidelines recommend treatment of anaemia due to chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs). OBJECTIVE: To document the time required and the cost in terms of nursing time to prepare and administer ESAs to patients on facility based haemodialysis (HD) with anaemia due to CKD before and after the introduction of long-acting ESAs. DESIGN: A time and motion study was implemented at four HD units in Australia to determine the time and costs associated with preparing and administering ESAs before and after the introduction of long-acting ESAs. PARTICIPANTS: This was a prospective, observational study of workplace practices at four HD units in Australia. MEASUREMENTS: Outcome data included the time taken to prepare, and administer ESAs. RESULTS: The time costs of preparation and administration per patient per year had a wide variability within each unit and ranged from Australian AUD$55.75 (38 euros) to AUD$90.49 (62 euros) before the introduction of long-acting ESAs. This dropped by 73-80% following the introduction of long acting ESAs, representing an annual cost savings of between AUD$2,591 and AUD$5,914 if all patients on HD were switched to a long acting ESA. CONCLUSION: Switching from a short-acting to a long-acting ESA in HD units leads to a significant reduction in time costs of health professionals in preparation and administration of ESAs by up to 80%. Practical application: This time and motion study has added further evidence on reduction of human effort by taking advantages of new research development, such as the long acting ESAs. PMID- 28901049 TI - Arousal responses to respiratory events during sleep: the role of pulse wave amplitude. AB - The study aims at assessing the changes in electroencephalography (as measured by the A-phases of cyclic alternating pattern) and autonomic activity (based on pulse wave amplitude) at the recovery of airway patency in patients with obstructive sleep apnea syndrome. Analysis of polysomnographic recordings from 20 male individuals with obstructive sleep apnea syndrome was carried out in total sleep time, non-rapid eye movement and rapid eye movement sleep. Scoring quantified the combined occurrence (time range of 4 s before and 4 s after respiratory recovery) or separate occurrence of A-phases (cortical activation), and pulse wave amplitude drops (below 30%) to apneas, hypopneas or flow limitation events. A dual response (A-phase associated with a pulse wave amplitude drop) was the most frequent response (71.8% in total sleep time) for all types of respiratory events, with a progressive reduction from apneas to hypopneas and flow limitation events. The highly significant correlation in total sleep time (r = 0.9351; P < 0.0001) between respiratory events combined with A phases and respiratory events combined with pulse wave amplitude drops was confirmed both in non-rapid eye movement (r = 0.9622; P < 0.0001) and rapid eye movement sleep (r = 0.7162; P < 0.0006). In conclusion, a dual cortical and autonomic activation is the most common manifestation at the recovery of airway patency. The significant correlation between A-phases and relevant pulse wave amplitude drops suggests a possible role of pulse wave amplitude as a marker of cerebral response to respiratory events. PMID- 28901050 TI - Do children understand fraction addition? AB - Many children fail to master fraction arithmetic even after years of instruction. A recent theory of fraction arithmetic (Braithwaite, Pyke, & Siegler, 2017) hypothesized that this poor learning of fraction arithmetic procedures reflects poor conceptual understanding of them. To test this hypothesis, we performed three experiments examining fourth to eighth graders' estimates of fraction sums. We found that roughly half of estimates of sums were smaller than the same child's estimate of one of the two addends in the problem. Moreover, children's estimates of fraction sums were no more accurate than if they had estimated each sum as the average of the smallest and largest possible response. This weak performance could not be attributed to poor mastery of arithmetic procedures, poor knowledge of individual fraction magnitudes, or general inability to estimate sums. These results suggest that a major source of difficulty in this domain is that many children's learning of fraction arithmetic procedures develops unconstrained by conceptual understanding of the procedures. Implications for education are discussed. PMID- 28901052 TI - Noninvasive, three-dimensional full-field body sensor for surface deformation monitoring of human body in vivo. AB - Noninvasive, three-dimensional (3-D), full-field surface deformation measurements of the human body are important for biomedical investigations. We proposed a 3-D noninvasive, full-field body sensor based on stereo digital image correlation (stereo-DIC) for surface deformation monitoring of the human body in vivo. First, by applying an improved water-transfer printing (WTP) technique to transfer optimized speckle patterns onto the skin, the body sensor was conveniently and harmlessly fabricated directly onto the human body. Then, stereo-DIC was used to achieve 3-D noncontact and noninvasive surface deformation measurements. The accuracy and efficiency of the proposed body sensor were verified and discussed by considering different complexions. Moreover, the fabrication of speckle patterns on human skin, which has always been considered a challenging problem, was shown to be feasible, effective, and harmless as a result of the improved WTP technique. An application of the proposed stereo-DIC-based body sensor was demonstrated by measuring the pulse wave velocity of human carotid artery. PMID- 28901051 TI - Noninvasive submental fat reduction using colder cryolipolysis. AB - BACKGROUND: Cryolipolysis has shown to significantly reduce localized subcutaneous fat, including submental fat. Temperatures below -11 degrees C have not been used to treat the submental region. OBJECTIVE: The purpose of this study was to evaluate safety and efficacy of Cryolipolysis for noninvasive reduction of submental fat using lower temperatures and reduced treatment time. METHODS: A small volume applicator was used to treat 15 subjects, using a noninvasive tissue cooling device (CoolSculpting System, ZELTIQ Aesthetics, Pleasanton, CA, USA) during 45 and 30 minutes at -12 and -15 degrees C, respectively, to induce reduction of submental fat. Two treatments with an interval of 10 weeks were performed. Adverse events were monitored to assess safety. Treated area was evaluated using digital photography, and caliper measurements prior treatment, 10 weeks after first treatment and 12 weeks after second treatment. All patients were also evaluated before and after 12-week postlast treatment by Magnetic Resonance Imaging (MRI). RESULTS: The mean (SD) reduction measured by skin fold caliper was 33% (3.2 mm [1.7 mm]), (95% CI, 0.2297-0.4236; P=.05), and by MRI, mean (SD) reduction was 1.78 mm (1.157 mm). Independent blinded panel was able to correctly identify 60% of before and after photographs; 12 of 15 subjects (80%) were satisfied or very satisfied with the treatment. Side effects were mild and resolved completely within 10 weeks, except for one hyperpigmentation, which resolved spontaneously within 6 months after last treatment. CONCLUSION: Cryolipolysis with colder temperature and reduced treatment time continues to be effective and is safe for noninvasive reduction of the submental fat. PMID- 28901053 TI - Tissue characterization with depth-resolved attenuation coefficient and backscatter term in intravascular optical coherence tomography images. AB - An important application of intravascular optical coherence tomography (IVOCT) for atherosclerotic tissue analysis is using it to estimate attenuation and backscatter coefficients. This work aims at exploring the potential of the attenuation coefficient, a proposed backscatter term, and image intensities in distinguishing different atherosclerotic tissue types with a robust implementation of depth-resolved (DR) approach. Therefore, the DR model is introduced to estimate the attenuation coefficient and further extended to estimate the backscatter-related term in IVOCT images, such that values can be estimated per pixel without predefining any delineation for the estimation. In order to exclude noisy regions with a weak signal, an automated algorithm is implemented to determine the cut-off border in IVOCT images. The attenuation coefficient, backscatter term, and the image intensity are further analyzed in regions of interest, which have been delineated referring to their pathology counterparts. Local statistical values were reported and their distributions were further compared with a two-sample t-test to evaluate the potential for distinguishing six types of tissues. Results show that the IVOCT intensity, DR attenuation coefficient, and backscatter term extracted with the reported implementation are complementary to each other on characterizing six tissue types: mixed, calcification, fibrous, lipid-rich, macrophages, and necrotic core. PMID- 28901054 TI - System calibration method for Fourier ptychographic microscopy. AB - Fourier ptychographic microscopy (FPM) is a recently proposed computational imaging technique with both high-resolution and wide field of view. In current FPM imaging platforms, systematic error sources come from aberrations, light emitting diode (LED) intensity fluctuation, parameter imperfections, and noise, all of which may severely corrupt the reconstruction results with similar artifacts. Therefore, it would be unlikely to distinguish the dominating error from these degraded reconstructions without any preknowledge. In addition, systematic error is generally a mixture of various error sources in the real situation, and it cannot be separated due to their mutual restriction and conversion. To this end, we report a system calibration procedure, termed SC-FPM, to calibrate the mixed systematic errors simultaneously from an overall perspective, based on the simulated annealing algorithm, the LED intensity correction method, the nonlinear regression process, and the adaptive step-size strategy, which involves the evaluation of an error metric at each iteration step, followed by the re-estimation of accurate parameters. The performance achieved both in simulations and experiments demonstrates that the proposed method outperforms other state-of-the-art algorithms. The reported system calibration scheme improves the robustness of FPM, relaxes the experiment conditions, and does not require any preknowledge, which makes the FPM more pragmatic. PMID- 28901055 TI - Phantom-based image quality test methods for photoacoustic imaging systems. AB - As photoacoustic imaging (PAI) technologies advance and applications arise, there is increasing need for standardized approaches to provide objective, quantitative performance assessment at various stages of the product development and clinical translation process. We have developed a set of performance test methods for PAI systems based on breast-mimicking tissue phantoms containing embedded inclusions. Performance standards for mature imaging modalities [magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound] were used to guide selection of critical PAI image quality characteristics and experimental methods. Specifically, the tests were designed to address axial, lateral, and elevational spatial resolution, signal uniformity, penetration depth, sensitivity, spatial measurement accuracy, and PAI-ultrasound coregistration. As an initial demonstration of the utility of these test methods, we characterized the performance of a modular, bimodal PAI-ultrasound system using four clinical ultrasound transducers with varying design specifications. Results helped to inform optimization of acquisition and data processing procedures while providing quantitative elucidation of transducer-dependent differences in image quality. Comparison of solid, tissue-mimicking polymer phantoms with those based on Intralipid indicated the superiority of the former approach in simulating real world conditions for PAI. This work provides a critical foundation for the establishment of well-validated test methods that will facilitate the maturation of PAI as a medical imaging technology. PMID- 28901056 TI - [Research progress of plant BAHD acyltransferase family]. AB - Acylation conducted by acyltransferase is a ubiquitous process in structure modification of secondary metabolites. It plays an important role in the structural diversity of natural products and contributes significantly to their improved stabilities, increased solubilities, and enhanced bioavailabilities. BAHD acyltransferase family is a typical kind of acyltransferase original from plants, which involved in the biosynthesis of various bioactive acylated natural products. In order to provide references for future investigations of BAHD acyltransferase family, research progresses on basic properties, three dimensional structures, catalytic mechanisms, enzymatic functional identifications and phylogenetic analyses of BAHD family from plants is summarized in this paper. PMID- 28901057 TI - [Research on photosynthetic and eco-physiological characteristics of Epimedium pseudowushannense in different growing age]. AB - Epimedium is a widely used medicinal plants. Due to excessive use of wild resources and resource constraints, artificial cultivation is the only way to achieve sustainable use of resources. E. pseudowushannense is intended to achieve the first cultivated species, but plant production technology is not yet fully mature.The diurnal variation of photosynthetic and eco-physiological characteristics of E. pseudowushannense in different growing age was studied by the CI-340 Portable Photosynthesis System under natural conditions. The net photosynthetic rate (Pn), stomatal conductance (C), intercellular CO2 concentration (Ci), photosynthetically active radiation (PAR), relative humidity (RH), air temperature (Ta), apparent mesophyll conductance (ALMC), transpiration rate (E), leaf temperature (Tl), water use efficiency (WUE) and other photosynthetic physiological factors and environmental factors were measured. The obtained data was analyzed by correlation analysis, path analysis and stepwise multiple-regression analysis to explore the relationship between net photosynthetic rate and physiological and ecological factors. The results show that: 1The daily variation of the Pn, E, ALMC, C of E. pseudowushannense in different growing age took on"two peak type", the Pn was with an obvious midday depression phenomenon at noon.2The Pn, ALMC and C of annuals' were significantly higher than biennial or three-year; but the Ci was basically a three-year > biennial> annual.3The correlation analysis, path analysis and stepwise regression analysis showed that ALMC, Ci, Ta might played important role in the Pn and ranked as ALMC>Ci>Ta. PMID- 28901058 TI - [Dissipation dynamics of spirodiclofen in wolfberry fruit]. AB - The dissipation of spirodiclofen in fresh fruit and dry fruit of wolfberry was detected in this study to provide a reference for its safe application.According to Pesticide Residue Test Criteria of China, the open-field experiment was conducted in Zhongning courty of Ningxia province, and the dissipation of spirodiclofen was studied by acetonitrile extraction and HPLC-MS/MS detection. The results showed that the half-lives of spirodiclofen in fresh wolfberry fruit and dry wolfberry fruit were 6.9-11.2 days and 8.5-10.4 days, respectively. Spirodiclofen belongs to the easily degradable pesticide type. According to the maximum residue limits (0.5 mg*kg-1) of spirodiclofen of EU for wolfberry, after recommended dosage being sprayed for once, fresh wolfberry fruit was safe to eat after 5 days, and dry wolfberry fruit was safe to eat after 21 days. PMID- 28901059 TI - [Effect of different water conditions on Panax notoginseng seeds after-ripening and germination physiology]. AB - Effect of different water conditions on the physiological indexes (e.g.seed water content, vigor, antioxidase activities)of Panax notoginseng seeds were studied under process of after-ripening and germination.The results showed show that compared with 2.5% treatment, under the treatment of 5%, P.notoginseng seeds possessed stable seed water content, the seed vigor was exceed by 51%,variation of antioxidant enzyme (SOD, POD, CAT) activity and malondialdehyde (MDA) content were small, crude fat and total sugar content decreased significantly.With the increase of PEG 6000 concentration, the germination characteristic indexes obviously decreased, antioxidase activities increased firstly and decreased afterwards, content of MDA, soluble protein and total sugar increased obviously.There were significant positive correlation between germination characteristic indexes and osmotic substance content(r>0.900, P<0.01), and significant negative correlation with MDA (r>0.900, P<0.01).In conclusion, because the characteristic of dehydration intolerance of P.notoginseng seeds, 5% water content of sand burying stratification treatment was the best for after ripening, 15% concentration of PEG 6000 treatment was the highest tolerance limit of germination process. PMID- 28901060 TI - [Karyotype and evolutionary trend analysis of Scutellaria species in Jinyun mountain, Chongqing]. AB - Traditional squash method was used to analyze chromosome number and karyotypes of four Scutellaria species in Chongqing Jinyun Mountain Natural Reserve: Scutellaria tsinyunensis, S.yunnanensis, S.franchetiana and S.indica.The result showed that the chromosome numbers were 26 except for S.franchetiana, which had 24 chromosomes.These species were all diploid with metacentric and submetacentric chromosomes.Their karyotypes were symmetrical and primitive.The karyotype formula of S.tsinyunensis is 2n=2x=26=24m+2sm, 1B type, As.k=55.28%; the karyotype formula of S.yunnanensis var.salicifolia is 2n=2x=26=26m, 1B type, As.k=56.11%; the karyotype formula of S.franchetiana is 2n=2x=24=20m+4sm, 2B type, As.k=58.50%; the karyotype formula of S.indica is 2n=2x=24=20m+4sm, 2B type, As.k=58.41%.The results were compared with the reported data of S.baicalensis and S.alaschanica.S.alaschanica is expected to be the most advanced one whereas S.tsinyunensis, and S.yunnanensis var. salicifolia primitive.These results are expected to provide some references to the origin and differentiation of genus Scutellaria. PMID- 28901061 TI - [Screening of meaningful endophytic fungi in Dendrobium officinale based on polysaccharides and flavonoids]. AB - To reveal the relationship between endophytic fungi and the functional components, saccharides and flavonoids in the mycelia or fermented liquor of 21 endophytic fungi in D.officinale were detected using HPLC and UV spectrophotometer.The results showed that the ethyl acetate extracts from 21 fungal strains all contain flavonoids.According to the chromatographic retention time of HPLC and UV spectra characteristics of flavonoids, strain DO49 was found produce naringenin, strains DO23, DO81 and DO83 were found produce rutin.The water-soluble extracts from 21 strains all had polysaccharides.However, there was difference in the composition of monosaccharides derived from polysaccharides among different strains.According to the composition of monosaccharides and the peak area ratio of mannose and glucose, the fungal strains including DO23, DO26, DO81, DO54, DO55, DO83 product polysaccharides associated with D.officinale were selected.In conclusion, based on the saccharides and flavonoids, the excellent endophytic fungal strains DO23, DO81 and DO83 were selected, which could produce the same flavonoids and similar polysaccharides in D.officinale. PMID- 28901062 TI - [Medicinal plant new records in Chongqing]. AB - By the fourth survey of Chinese medicinal resources, new medicinal plants records of 1 family, 2 genera and 6 species were reported in Chongqing.They are Annonaceae, Fissistigma, Monochasma, Sophora tonkinensis, Fissistigma retusum, Monochasma sheareri, Primula ranunculoids, Chirita pinnatifida and Hylotelephium sieboldii.All the voucher specimens are preserved in Herbarium of Chongqing Institute of Medicinal Plant Cultivation. PMID- 28901063 TI - [Impact of sulfur fumigation on quality of Scutellariae Radix]. AB - Sulfur fumigation usually causes transformation of chemical components of traditional Chinese medicine (TCM). As for the process and storage of TCM, the sulfur fumigation has been no longer recommended by the government. This study is to explore the impact of the sulfur fumigation on the quality of Scutellariae Radix. Distillation combined with ion-chromatography was used to evaluate the residue of sulfur dioxide in 180 batches of Scutellariae Radix decoction pieces and 26 batches of Scutellariae Radix herbs. In addition, LC-MS combined with principal component analysis (PCA) was used to compare the changes in chemical components and flavonoid content in radix scutellariae before and after sulfur fumigation. As a result, 74 batches of Scutellariae Radix decoction pieces were determined to be unqualified on the basis of the residue limit of sulfur dioxide in Chinese Pharmacopoeia 2015 Vol. IV (<=150 mg*kg-1), with a qualification rate of 35.9%. All of the unqualified samples were decoction pieces. The fingerprint and PCA indicates that flavonoid content of Scutellariae Radix had no change before and after sulfur fumigation, but flavonoid glycosides decreased after sulfur fumigation and baicalin decreased sharply. The flavonoid glycoside was hydrolyzed to flavone aglycone in the process of sulfur fumigation, which caused the decrease in content of falvonoid glycosides and had an impact on the quality of Scutellariae Radix. The decoction pieces of Scutellariae Radix were seriously fumigated with sulfur in the processing, suggesting the key regulatory point is the decoction pieces production process. PMID- 28901064 TI - [Physical fingerprint for quality control of traditional Chinese medicine extract powders]. AB - The physical properties of both raw materials and excipients are closely correlated with the quality of traditional Chinese medicine preparations in oral solid dosage forms. In this paper, based on the concept of the chemical fingerprint for quality control of traditional Chinese medicine products, the method of physical fingerprint for quality evaluation of traditional Chinese medicine extract powders was proposed. This novel physical fingerprint was built by the radar map, and consisted of five primary indexes (i.e. stackablity, homogeneity, flowability, compressibility and stability) and 12 secondary indexes (i.e. bulk density, tap density, particle size<50 MUm percentage, relative homogeneity index, hausner ratio, angle of repose, powder flow time, inter particle porosity, Carr index, cohesion index, loss on drying, hygroscopicity). Panax notoginseng saponins (PNS) extract was taken for an example. This paper introduced the application of physical fingerprint in the evaluation of source-to source and batch-to-batch quality consistence of PNS extract powders. Moreover, the physical fingerprint of PNS was built by calculating the index of parameters, the index of parametric profile and the index of good compressibility, in order to successfully predict the compressibility of the PNS extract powder and relevant formulations containing PNS extract powder and conventional pharmaceutical excipients. The results demonstrated that the proposed method could not only provide new insights into the development and process control of traditional Chinese medicine solid dosage forms. PMID- 28901065 TI - [1H-NMR-based metabonomics on chemical component groups with toxicity alleviation effect to Realgar in Niuhuang Jiedu tablet]. AB - To study the chemical component groups with toxicity alleviation effect to Realgar in Niuhuang Jiedu tablet based on 1H-NMR metabonomics. Twenty-four male Wistar rats were divided into four groups: control group, R group (treated with Realgar), RRSPG group (treated with Realgar, the root and rhizoma of Rheum palmatum, the root of Scutellaria baicalensis, the root of Platycodon grandiflorum and the root and rhizoma of Glycyrrhiza uralensis) and RC group (treated with total anthraquinones from the root and rhizoma of R. palmatum, total flavonoids from the root of S. baicalensis, total saponins from the root of P. grandiflorum, total flavonoids and saponins from the root and rhizoma of G. uralensis). Based on 1H-NMR spectra of urine and serum from rats, PLS-DA was performed to identify different metabolic profiles.The metabolic profiles of R group were different from that of control group, while the metabolic profiles of RC group were almost similar to control group.Total anthraquinones from the root and rhizoma of R. palmatum, total flavonoids from the root of S. baicalensis, total saponins from the root of P. grandiflorum, total flavonoids and saponins from the root and rhizoma of G. uralensis regulated energy, choline and amino acid metabolism and gut flora disorder affected by realgar's toxicity. PMID- 28901066 TI - [Rapid characterization of chemical constituents and rats metabolites of Kudiezi injection by UHPLC-LTQ-Orbitrap]. AB - A rapid and sensitive UHPLC-HR-MSn method was used for the identification of Kudiezi injection and its main metabolites in rat plasma. After the tail intravenous injection of Kudiezi, ACQUITY UHPLC BEH C18 (2.1 mm*100 mm, 1.7 MUm) was used, with 0.1% formic acid-acetonitrile solution as the mobile phase for gradient elution. Kudiezi injection and plasma were detected by ESI-LTQ-Orbitrap equipped with an ESI ion source in a negative mode. Based on the accurate mass measurements, the retention time and the mass fragmentation patterns, a total of 53 compounds were tentatively identified and characterized. Furthermore, metabolites in rat plasma after the intravenous administration of Kudiezi injection were also analyzed. A total of 38 compounds were identified, including 27 prototypes and 11 metabolites through metabolic pathways of methylation, glucuronide conjugation, sulfate conjugation and hydrolysis. As a result, UHPLC LTQ-Orbitrap technique was applied to comprehensively expound Kudiezi injection's chemical components and constituents migrating to rat plasma, and provide scientific basis for further studies on Kudiezi injection's in vivo metabolic process and effective material base. PMID- 28901067 TI - [Improvement of powder flowability and hygroscopicity of traditional Chinese medicine extract by surface coating modification technology]. AB - To study the improvement of powder flowability and hygroscopicity of traditional Chinese medicine extract by surface coating modification technology. The 1% hydrophobic silica nanoparticles were used as surface modifier, and andrographis extract powder was taken as a model drug. Three different techniques were used for coating model drugs, with angle of repose, compressibility, flat angle and cohesion as the comprehensive evaluation indexes for the powder flowability. The powder particle size and the size distribution were measured by Mastersizer 2000. FEI scanning electron microscope was used to observe the surface morphology and structure of the powder. The percentage of Si element on the powder surface was measured by energy dispersive spectrometer. The hygroscopicity of powder was determined by Chinese pharmacopoeia method. All of the three techniques can improve the flowability of powder extract. In particular, hygroscopicity of extract powder can also be improved by dispersion and then high-speed mixing, which can produce a higher percentage of Si element on the powder surface. The improvement principle may be correlated with a modifier adhered to the powder surface. PMID- 28901068 TI - [Solidification of magnolol phospholipid complex with polyvingypyrrolidone]. AB - In this study, magnolol phospholipid complex (MPC) was prepared and solidified with polyvingypyrrolidone (PVPP). The influence of PVPP on MPC's flowability, dissolution and oral bioavailability was investigated. The results of phase characterization using differential scanning calorimetry (DSC), infrared spectroscopy (IR), and scanning electron microscopy (SEM) showed that magnolol existed in solidified powder and MPC in an amorphous state. In flowability and dissolution experiments, solidified powder showed significant superiority. At the same time, it showed a higher oral bioavailability compared with MPC, with AUC0 infinity of 73.47 MUg*h*mL-1 vs. 63.48 MUg*h*mL-1. This process for solidifying powder with PVPP is simple and convenient. PMID- 28901069 TI - [Chemical constituents from ethyl acetate exaction of root of Paeonia lactiflora]. AB - Two new phenylpropanoids(1 and 2), together with thirteen known compounds(3-15), have been isolated from the root of Paeonia lactiflora by using various chromatographic techniques. Their structures were identified by spectroscopic data analysis(MS,IR,1D and 2D NMR)as(+)-(7R,8R)-1-guaiacyl-1,2 propanediolacetonide(1),(-)-(7R,8S)-1-guaiacyl-1,2-propanediolacetonide(2),O senecioyllomatin(3),O-angeloyllomatin(4),(+)-cis-3'-senecioyloxy-4'-angeloyloxy 3',4'-dihydroseselin(5),columbianadin(6), benzyl 2,5-dihydroxybenzoate(7),3,6 dimethyl-5-hydroxyBenzo-furan(8),(S)-evofolin-A(9),2,3-dihydroxy-4 methoxyacetophenone(10), 2,5-dihydroxy-4-methoxyacetophenone(11), 2,5-dihydroxy-4 methyl acetophenone(12),ethyl 4-hydroxybenzoate(13), vanillic acid(14),and 4 hydroxy-3-methoxybenzaldehyde(15).Compounds 1 and 2 were new compounds,and compounds 3-9 were obtained from the genus Paeonia for the first time. PMID- 28901070 TI - [Bioactive quinolizidine alkaloids from Sophora tonkinensis]. AB - Twelve quinolizidine alkaloids were isolated from Sophora tonkinensis by means of silica gel, preparative MPLC, and preparative HPLC. On analysis of NMR spectroscopic data, their structures were established as 3-(4-hydroxyphenyl)-4-(3 methoxy-4-hydroxyphenyl)-3,4-dehydroquinolizidine(1), lanatine A(2), cermizines C(3), senepodines G(4), senepodines H(5), jussiaeiines A(6), jussiaeiines B(7),(+)-5alpha-hydroxyoxysophocarpine(8),(-)-12beta-hydroxyoxysophocarpine(9),( )-clathrotropine(10),(-)-cytisine(11), and (-)-N-methylcytisine(12), respectively. Compounds 1-7 were first isolated from Sophora L. plant. In the in vitro assays,the isolated compounds 1, 3, 6-10 exhibited potent activity against CVB3 with IC50 of 6.40, 3.25, 4.66, 3.21, 0.12, 0.23 and 1.60, and with selective index values(SI=TC50/IC50)of 12.0, 5.6, 13.0, 15.1, 50.1, 26.2, and 23.6, respectively. Compounds 1, 3, and 7 exhibited activity against staphylococcus aureus(ATCC 29213)with MICvalues of 8.0, 3.5, 6.0 g*L-1, respectively. Compounds 1, 3, 7, and 12 exhibited activity against staphylococcus aureus(ATCC 33591)with MIC values of 18.0, 7.5, 8.0, 12.0 g*L-1, respectively. Compounds 2, 6, 7 exhibited activity against Escherichia coli(ATCC 25922) with MIC values of 1.0, 3.2, 0.8 g*L-1. PMID- 28901071 TI - [Triterpenoids from roots of Rosa laevigata]. AB - To study the triterpenoids from the roots of Rosa laevigata. The silica gel column chromatography was used to separate the chemical constituents from the roots of Rosa laevigata Michx. HPLC was used to analyze its purity, chemical and spectroscopy methods were used to determine their structures. 12 constituents were isolated and identified as(2R, 19R)methyl 2-acetyloxy-19- hydroxyl-3-oxo-urs 12-en-28-carboxylate(1), pomonic acid (2), 18, 19-seco, 2alpha, 3alpha-dihydroxy 19-oxo-urs-11, 13(18)-dien-28-oic acid(3), swinhoeic acid (4), myrianthic acid(5), 2alpha, 3beta, 19alpha-trihydroxy-24-oxo-urs-12-en-oic acid (6), tormentic acid(7), arjunic acid (8), 1beta-hydroxyeuscaphic acid(9), quadranoside VIII (10), alpinoside(11), rubuside B (12). Compounds 1-4, 6, 9, 11-12 were obtained from this plant for the first time. Compounds 2-4, 6, 11-12 were obtained from the genus Rosa for the first time. PMID- 28901072 TI - [Study on chemical constituents from Chloranthus multistachys]. AB - To investigate the chemical constituents from the shoots of Chloranthus multistachys.All compounds wereisolated by using a combination of various chromatographic techniques including silica gel, ODS, Sephadex LH-20, reversed phase HPLC, and other methods.Their structures were elucidated by the nuclear magnetic resonance (NMR), mass spectrometry, and other modernspectroscopies.As a result, 19 compounds were isolated from the shoots of C.multistachys and identified as zederoneepoxide(1), chlomultin C(2), curcolonol(3), sarcaglaboside A(4), zedoarofuran(5), (1E,4Z)-8-hydroxy-6-oxogermacra-1(10), 4,7(11)-trieno-12,8 lactone(6), chloranoside A(7), istanbulin A(8), (8alpha)-6,8-dihydroxycadina 7(11),10(15)-dien-12-oicacid-gamma-lactone(9), codonolactone(10), lasianthuslactone A(11), 12,15-epoxy-5alphaH,9betaH-labda-8(17),13-dien-19 oicacid(12), 12R,15-dihydroxylabda-8(17),13E-dien-19-oicacid(13), N transcinnamoyltyramine(14), trans-N-p-coumaroyltyramine(15), dibutyl phthalate (16), flavokawain A(17), bergenin(18), and enedione(19).Compounds 1, 2, 4, 7-10, 12-19 were isolated from C.multistachys for the first time and compounds 14-19 were obtained from the genus Chloranthus for the first time. PMID- 28901073 TI - [Isolation and identification of xanthones from Gentianella acuta]. AB - Twelve xanthones compounds were isolated from the ethanol extract of Gentianella acuta by means of reversed-phase preparative HPLC and various kinds of column chromatography including silica gel and ODS . Their structures were fully elucidated on the basis of MS, 1D and 2D-NMR data. The structures of xanthones were identified as 1, 7-dihydroxy-3-methoxyxanthone-7-O-beta-D-glucopyranoside (1), swertiapuniside (2), 1, 3, 8- trihydroxy -4, 5-dimethoxyxanthone-1-O-beta-D glucopyranosyl(6->1)-O-beta-D-glucopyranoside (3), 1, 2, 8-trihydroxy-5, 6 dimethoxyxanthone-2-O-beta-D-glucopyranoside (4), 1, 3, 7, 8-tetrahydroxyxanthone 1-O-beta-D-glucopyranoside (5), 1, 3, 5, 8-tetrahydroxy-5, 6, 7, 8 tetrahydroxanthone (6), 1, 3, 5-thihydroxyxanthone (7),1, 3, 5, 8 tetrahydroxyxanthone (8), 1, 2, 8-trihydroxy-5, 6-dimethoxyxanthone (9), bellidifolin (10), mangiferin (11), swertianolin (12). Compounds 1-9 were isolated from Gentianella genus for the first time. PMID- 28901074 TI - [HPLC specific chromatogram of Lamiophlomis Herba and its counterfeit and determination of four effective components]. AB - This study is to establish the HPLC specific chromatogram and determine four main effective components of Lamiophlomis Herba and its counterfeit.Chlorogenic acid, forsythoside B, acteoside and luteoloside were reference substance.HPLC analysis was performed on a Waters XSelect C18 column (4.6 mm*250 mm,5 MUm).The mobile phase was acetonitrile-0.5% phosphoric acid solution (18?82) with isocratic elution.The flow rate was 1.0 mL*min-1, the detection wavelength was 332 nm and the column temperature was 30 C.Chemometrics software Chempattern was employed to analyze the research data.HPLC specific chromatogram of Lamiophlomis Herba from different samples were of high similarity, but the similarity of the HPLC specific chromatogram of its counterfeit were less than 0.65.Both of cluster and principal component analysis can distinguish certified products and adulterants.The HPLC specific chromatogram and contents of four effective components can be used for the quality control of Lamiophlomis Herba and its preparations.It provided scientific basis to standardize the use of the crude drug. PMID- 28901075 TI - [Effects and mechanisms of UCG ameliorating renal interstitial fibrosis by regulating TGF-beta1/SnoN/Smads signaling pathway in renal failure rats]. AB - This study was aimed to demonstrate preliminarily the effects and mechanisms of uremic clearance granule (UCG) ameliorating renal interstitial fibrosis (RIF) by regulating transforming growth factor (TGF)-beta1/SnoN/Smads signaling pathway in vivo. Fifteen rats were randomly divided into 3 groups:the normal group,the model group and the UCG group. The rats with renal failure were induced by intragastric administration of adenine and unilateral ureteral obstruction (UUO). After modeling,the rats in the UCG group and in the other groups were intervened by intragastric administration of UCG and distilled water respectively during 3 weeks. The body weight and 24 h urinary protein excretion (Upro) in all rats were tested after drug administration. All rats were killed after drug administration for 3 weeks,blood and kidneys were collected and weighted,kidney appearance and renal morphological characteristics were observed. In addition,serum biochemical indices and the protein expressions of TGF-beta1,SnoN,phosphorylated Smad2/3 (p Smad2/3) and Smad7 in the kidney were evaluated respectively. The results indicated that,after the intervention of UCG,the general state of health,kidney appearance,serum creatinine (Scr),blood urea nitrogen (BUN),uric acid (UA),albumin (Alb),Upro and renal morphological change in model rats were improved in different degrees,respectively. Moreover,UCG down-regulated the protein expressions of TGF-beta1 and p-Smad2/3,and up-regulated the protein expressions of SnoN and Smad7 in the kidney. In conclusion,UCG reduces extracellular matrix (ECM) synthesis and delays the progression of renal failure via possibly multi-targeting at regulating TGF-beta1/SnoN/Smads signaling pathway in vivo. PMID- 28901076 TI - [Paeonol affects proliferation activity of rat vasular endothelial cells induced by lipopolysaccharide and co-cultured with smooth muscle cells via inhibiting pathway of PI3K/AKT-NF-kappaB signaling]. AB - This paper was aimed to observe the anti-atheroslerosis effect of paeonol (Pae) on the activation of PI3K/AKT-NF-kappaB and the proliferation activity of rat vasular endothelial cells induced by lipopolysaccharide (LPS) and co-cultured with smooth muscle cells. Primary rat vascular endothelial cells (VECs) and rat vascular smooth cells (VSMCs) were cultured by predigesting and adhering tissue blocks. The VEC-VSMC co-culture model was established by Transwell chamber. LPS (100 MUg*L -1, 7 h) was used to induce VEC injury. MTT assay were used to determine the VEC proliferation activity. Western blot was used to detect PI3K/AKT and NF-kappaB's signaling pathways related protein expressions. The concentration of LPS-induced VECs injury was 100 MUg*L -1, and the time was 7 h. After the intervention on the above cell model for 24 h, paeonol (15, 30, 60 MUmol*L -1) could effectively inhibit LPS-induced VECs injury, block PI3K/AKT-NF kappaB signal transduction pathway thereby significantly affecting the proliferation of LPS-induced VECs co-cultured with SMCs. The anti-atherosclerosis mechanism of paeonol may be related to the reducing the inhibitory effect of the signaling pathway associated proteins of VEC PI3K/AKT and NF-kappaB, thereby increasing the VEC livability under co-culture. PMID- 28901077 TI - [Research ontherapeutics effect of extract of Ornithogalum caudatum on liver fibrosis]. AB - Rat models of liver fibrosis were made by carbon tetrachloride, and the serum levels of AST, ALT, gamma-GT, MDA, GSH-px, SOD were detected, serum markers of PCIII, IV-C, LN, HA were detected by ELISA method. HE and Masson staining were conducted in hepatic tissues to observe pathological variations. Collagen III, TGF-beta, alpha-SMA, E-cadherin were detected by Western blot. The curative effect of the extract of Ornithogalum caudatum on rat liver fibrosis induced by CCl4was observed and the mechanism was discussed. The experiment results showed that the extract of O. caudatum (50, 150, 500 mg*kg-1) obviously decreased the serum levels of AST, ALT, gamma-GT, MDA, increased the serum levels of GSH-px, SOD, decreased the expression of serum markers of PCIII, IV-C, LN, HA, and improved the liver pathological variations of fibrotic rats. The experiment proved that the extract of O. caudatum could treat the liver fibrogenesis induced by CCl4 in rats. The positive medicine may inhibit accumulation of extracellular and activate hepatic stellate cell and epithelial-mesenchymal transition. PMID- 28901078 TI - [Puerarin attenuates PM2.5-induced vascular endothelial cells injury via ERK1/2 signaling pathway]. AB - To investigate the effect and the mechanism of puerarin in attenuating PM2.5 induced human umbilical vein endothelial cells (EA.hy926) injury, the samples of fine particulate matter (PM2.5) were collected and made into suspension. Different concentrations of PM2.5 (0,20, 200, 400 mg*L-1) were used to contaminate EA.hy926 cells for 24 h. The cells survival rate was detected by MTT assay; cells apoptosis of EA.hy926cells was detected by flow cytometry; the protein levels of p-ERK1/2, Bax and Bcl-2 were detected by Western blot; the contents of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), malonaldehyde (MDA), and the activities of superoxide dismutase (SOD) and lactic dehydrogenase (LDH) were measured by ELISA. Puerarin at different concentrations (10, 50, 100 MUmol*L-1) or a specific inhibitor of ERK1/2 pathway PD98059 (20 MUmol*L-1) was added into the EA.hy926 cells to observe the intervention effect and mechanism of puerarin. Compared with the control group, PM2.5 reduced the cells survival rate, up-regulatedp-ERK1/2 protein level and Bax/Bcl-2 ratio in a dose dependent manner to promote apoptosis; increased the contents of TNF-alpha, IL-6 and MDA, the activity of LDH, but decreased SOD activity in the EA.hy926 cells (P<0.05). Compared with PM2.5 group, puerarin increased the cells survival rate, down-regulated p-ERK1/2 protein level and Bax/Bcl-2 ratio in a dose dependent manner to inhibit the apoptosis; decreased the contents of TNF-alpha, IL-6 and MDA, the activity of LDH, but increased SOD activity in the EA.hy926 cells (P<0.05). The results indicated that puerarin could attenuate PM2.5-induced EA.hy926 cells injury via the inhibition of ERK1/2 pathway. PMID- 28901079 TI - [Protective effects of three phenylallyl compounds from Guizhi decoction ox-LDL induced oxidative stress injury of human brain microvascular endothelial cells]. AB - The main objective of this research is to observe protective effects of three phenylallyl compounds(cinnamyl alcohol,cinnamaldehyde and cinnamic acid)from Guizhi decoction against ox-LDL-induced oxidative stress injury on human brain microvascular endothelial cells(HBMEC).In this study,the toxicity and optimal protective concentration of three phenylallyl compounds from Guizhi decoction were determined by MTT assay.The HBMEC were divided into control group(DMSO),model group(ox-LDL),tert-butylhydroquinone (t-BHQ) group,cinnamyl alcohol group, cinnamaldehyde group and cinnamic acid group.The model group were treated with ox-LDL (50 mg*L-1)for 24 h,other groups were separately treated with t-BHQ, cinnamyl alcohol, cinnamaldehyde and cinnamic acid of 20 MUmol*L-1, and exposed to ox-LDL (50 mg*L-1) for 24 h at the same time.The survival rate of HBMEC was detected by MTT assay,reactive oxygen species(ROS) production of injured cells were detected using laser scanning confocal microscope (LSCM),the content of SOD, MDA, eNOS and NO in HBMEC was determined by ELISA, and the expressions of Nrf2 mRNA were detected by quantitative Real-time PCR(qRT-PCR).The results shows that oxidative stress injury of HBMEC could be induced by ox-LDL, the three phenylallyl compounds from Guizhi decoction did not affect morphology and viability of normal HBMEC.Compared with model group, the three phenylallyl compounds from Guizhi decoction could improve the above oxidative stress status and up-regulate Nrf2 mRNA expressions in injured HBMEC(P<0.05, P<0.01) .These findings suggested that the three phenylallyl compounds from Guizhi decoction have certain protective effects against ox-LDL-induced oxidative stress injury on HBMEC(cinnamaldehyde> t-BHQ> cinnamic acid>cinnamyl alcohol),the protective mechanism maybe related to regulation of antioxidant enzymes gene expression in HBMEC by Nrf2. PMID- 28901080 TI - [Effect of total saponins of Clematidis Radix et Rhizoma on serum metabolic profile in adjuvant arthritis rats based on GC-TOF-MS]. AB - To observe the effect of total saponins of Clematidis Radix et Rhizoma (TSCR) on serum metabolic profile changes in adjuvant arthritis(AA) rats, and explore its possible action mechanism for AA rats. The AA rat models were induced by Freund's complete adjuvant(FCA), and their histopathological changes were observed. Gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS), principal component analysis(PCA) and partial least squares-discriminant analysis (PLS-DA) were employed to analyze the metabolic profile among normal group, AA model group and TSCR group. Potential biomarkers in the serum were screened based on the variable importance projection(VIP) value>1, P<0.05. As compared with the normal group, 17 potential biomarkers such as aspartic acid, inositol and phenylacetaldehyde were found and identified in the serum of model group rats. As compared with the model group, the above biomarkers were regulated nearly to a normal state after TSCR administration for 16 days. Metabolomic analysis revealed that the total saponins of Clematidis Radix et Rhizoma has a certain therapeutic effect for AA rats, and the mechanism may be related to regulation of lipid metabolism, amino acid metabolism and energy metabolism. PMID- 28901082 TI - [Effect of Fuke Qianjin tablets on pharmacokinetics of Azithromycin in rats with chronic pelvic inflammatory disease]. AB - To investigate the effect of Fuke Qianjin tablets on the pharmacokinetics of Azithromycin(AZM) in rats with chronic pelvic inflammation, and evaluate the rationality of the drug combination. The animal models of chronic pelvic inflammatory disease were established by intrauterine injection of mixed bacterial suspension plus mechanic injury in female Sprague-Dawley(SD) rats. The model rats were randomly divided into control group and drug combination group. The rats in control group were given with Azithromycin 10 mg*kg-1*d-1 by intragastric administration, while the rats in drug combination group were given with Fuke Qianjin tablets 1.66 g*kg-1*d-1 by intragastric administration 2 hours after the equivalent dose of azithromycin, once a day, consecutively for 7 days. Plasma samples were collected at different time points and the concentration of AZM in plasma was determined by high performance liquid chromatography coupled with mass spectrometry(HPLC-MS). ADAPT 5.1 software was used to calculate the pharmacokinetic parameters of each group by Inverse Gaussian Function model. SPSS software was used for the statistical analysis of data in each group. The results showed that Fuke Qianjin tablets had no significant effects on the main pharmacokinetic parameters of AZM, including CLt, CLd, MIT and F. The study showed that Fuke Qianjin tablets can be combined with azithromycin for treatment of chronic pelvic inflammation disease. PMID- 28901081 TI - [Metabolism of six saponins by rat intestinal bacteria in vitro]. AB - To investigate the metabolism of six saponins by rat intestinal bacteria in vitro.Six saponins, including notoginsenoside R1, ginsenoside Rg1, ginsenoside Rg2, ginsenoside Re, ginsenoside Rd and ginsenoside Rb1, were incubated for 8 and 24 h with rat intestinal bacteria under anaerobic environment, respectively. After the samples were precipitated by acetonitrile and extracted with ethyl acetate, LC-Q-TOF-MS/MS was applied for the qualitative analysis of the metabolites. The potential metabolites in rat feces were analyzed by comparing the total ion current of the test samples and blank samples and analyzing the quasi-molecular ion and fragment ion of all chromatograms. The results showed that six saponins could be easily metabolized by rat intestinal bacteria. Notoginsenoside R1 was mainly metabolized into five metabolites, and it's metabolic pathway was notoginsenoside R1->ginsenoside Rg1->ginsenoside Rh1 and ginsenoside F1->protopanaxatriol->dehydrogenated protopanaxatriol. Ginsenoside Rg1 was mainly metabolized into four metabolites, and it's metabolic pathway was ginsenoside Rg1->ginsenoside Rh1 and ginsenoside F1->protopanaxatriol >dehydrogenated protopanaxatriol. Ginsenoside Rg2 was mainly metabolized into two metabolites, and it's metabolic pathway was ginsenoside Rg2-> protopanaxatriol >dehydrogenated protopanaxatriol. Ginsenoside Re was mainly metabolized into four metabolites, and it's metabolic pathway was ginsenoside Re->ginsenoside Rg2 >ginsenoside F1->protopanaxatriol->dehydrogenated protopanaxatriol. Ginsenoside Rd was mainly metabolized into four metabolites, and it's metabolic pathway was ginsenoside Rd->ginsenoside Rg3 and ginsenoside F2->ginsenoside Rh2 >protopanaxadiol. Ginsenoside Rb1 was mainly metabolized into five metabolites, and it's metabolic pathway was ginsenoside Rb1->ginsenoside Rd->ginsenoside Rg3 and ginsenoside F2->ginsenoside Rh2->protopanaxadiol. In summary, six saponins could be quickly metabolized by rat intestinal bacteria in vitro. Their major metabolic pathways were deglycosylation and dehydrogenation. PMID- 28901083 TI - [Analysis on regularity of prescriptions in "a guide to clinical practice with medical record" for diarrhoea based on traditional Chinese medicine inheritance support system]. AB - To analyze the regularities of prescriptions in "a guide to clinical practice with medical record" (Ye Tianshi) for diarrhoea based on traditional Chinese medicine inheritance support system(V2.5), and provide a reference for further research and development of new traditional Chinese medicines in treating diarrhoea. Traditional Chinese medicine inheritance support system was used to build a prescription database of Chinese medicines for diarrhoea. The software integration data mining method was used to analyze the prescriptions according to "four natures", "five flavors" and "meridians" in the database and achieve frequency statistics, syndrome distribution, prescription regularity and new prescription analysis. An analysis on 94 prescriptions for diarrhoea was used to determine the frequencies of medicines in prescriptions, commonly used medicine pairs and combinations, and achieve 13 new prescriptions. This study indicated that the prescriptions for diarrhoea in "a guide to clinical practice with medical record" are mostly of eliminating dampness and tonifying deficienccy, with neutral drug property, sweet, bitter or hot in flavor, and reflecting the treatment principle of "activating spleen-energy and resolving dampness". PMID- 28901084 TI - [Analysis and exploration on adverse reactions of four kinds of andrographolide injections]. AB - Concerned literature on four kinds of andrographolide injections in recent 15 years were searched in CNKI, Wanfang and VIP databases. The adverse drug reaction(ADR) cases of Chuanhuning, Yanhuning, Xiyanping and Lianbizhi injections were classified and analyzed statistically, including a total of 194 articles and 3 479 cases. The ADR clinical characteristics and occurrence regularity of these four andrographolide injections were analyzed and compared from the gender, age, primary disease, emergence time of ADR, clinical manifestation, allergy history, dosage, prognosis and combined medication of the patients. It is useful to provide valuable references for rational use of these andrographolide injections in clinical practice. PMID- 28901085 TI - [Standardized investigation on medicinal nature of ethnomedicine]. AB - This article recorded the analysis and comparison between the medicinal nature theory of traditional Chinese medicine(TCM) and ethnomedicine(EM). The vocabulary of "medicinal nature" was suggested to indicate the properties of ethnomedicine. Based on the influence of TCM medicinal nature theory on EM in China, the application of medicinal nature theory in EM was divided into 3 classes, and the standardizing principles for EM medicinal nature were proposed. It was suggested that medicinal quality, flavor, tendency, tropism, degree and efficiency can be used for the classification standard for EM medicinal nature. PMID- 28901086 TI - [Berberine action targets and its absorption behavior:how to use old drug for new mechanisms]. AB - A variety of pharmacological effects of berberine (BBR) are constantly being discovered with the deepening of BBR research. What followed is how to rationally use the drug according to these new pharmacological effects. Because of some cardiac toxicity and poor oral absorption, conflicts may arise between improving the bioavailability and controlling the toxicity of BBR. Meanwhile some new therapeutic uses of BBR, such as hypolipidemia, hypoglycemia as well as prevention and treatment of neurodegenerative diseases, need long-termoral administration, thereby may lead to alteration of intestinal flora and potentially affect body's other physiological functions. Based on the stated targets of BBR and related pharmaceutical properties, comprehensive analysis of these issues was conducted in this study. Some suggestions were presented below:the effect of long-term oral administration on body function, especially the intestinal flora, needs to be further investigated; risks shall be considered in changing the composition of the formulation to improve the absorption rate of oral administration; for the medication with higher concentration demand (such as anti-cancer), targeted drug-delivery is worthy to be considered. PMID- 28901087 TI - [Preliminary study of history of senna be used in China--On phenomenon about "reign medicine localized"]. AB - Senna is one of the commonly used traditional Chinese medicine at present. After the preliminary research that the drug medication history in China is not long, in our country ancient times, only "Hui prescription" in the records, other all kinds of traditional Chinese medicine literature rarely mentioned. Since modern times, the Chinese medicine in the medicine in the literature of the time and the modern western medicine books in the Chinese version of the time generally close, may be related to the introduction of Western medicine. At the end of Qing Dynasty and the early Republic of China, Chinese literature about the drug property theory of herbal medicine is seldom discussed, and had been seen as "western medicine" (foreign medicine), with the medication experience continue to accumulate, widespread popularity and other factors, the drug gradually Chinese scholars have constructed a relatively complete theory of the resistance, so as to realize the "localization". PMID- 28901088 TI - [Research progress of relationship between diabetes and intestinal epithelial tight junction barrier and intervetion of berberine]. AB - Intestinal tight junction is an important part of the small intestinal mucosa barrier. It plays a very significant role in maintaining the intestinal mucosal permeability and integrity, preventing the bacterial endotoxin and toxic macromolecular substances into the body so as to keep a stable internal environment. Numerous studies have shown that intestinal mucosal barrier dysfunction is closely related to the development of diabetes. Therefore, protecting intestinal tight junction and maintaining the mucosal barrier have great significance in the prevention and treatment of diabetes. The effect of berberine in diabetes treatment is obvious. However, the pharmacological study found that the bioavailability of berberine is extremely low. Some scholars put forward that the major site of pharmaceutical action of berberine might be in the gut. Studies have shown that berberine could regulate the intestinal flora and intestinal hormone secretion, protect the intestinal barrier, inhibit the absorption of glucose, eliminate the intestinal inflammation and so on. Recently studies have found that the hypoglycemic effect of berberine is likely to relate with the influence on intestinal tight junction and the protection of mucosal barrier. Here is the review about the association between intestinal tight junction barrier dysfunction and diabetes, and the related hypoglycemic mechanism of berberine. PMID- 28901089 TI - [Effects of Qizhi Jiangtang capsule on protein expressions of InsR, PI3K, GLUT2 and p-JNK in hepatic tissues of rats with type 2 diabetes]. AB - To observe the hypoglycemic effect of Qizhi Jiangtang capsule in rats with type 2 diabetes, and investigate the preliminary mechanism of its hypoglycemic effect, type 2 diabetes rat models were established by high glucose and high fat combined with small dose of streptozotocin (STZ). After continuous administration for 6 weeks, blood glucose, and glycosylated serum protein (GSP) levels were detected in all of the animals; immunohistochemistry assay was used to detect the number of islet beta cells; Western blot assay was used to detect the protein expression levels of insulin receptor (InsR), phosphoinositide-3 kinases (PI3K), glucose transporter-2 (GLUT2) and phosphorylated Jun N-terminal kinases (p-JNK)in hepatic tissues. The results showed that Qizhi Jiangtang capsule could reduce the blood sugar and GSP levels in serum in animals with type 2 diabetes mellitus, increase the level of insulin in serum and number of islet beta cells, increase the protein expression levels of InsR, PI3K and GLUT2, and reduce the level of p-JNK protein expression. In conclusion, Qizhi Jiangtang capsule has relatively stable hypoglycemic effect, and the mechanism may be associated with increasing the number of islet beta cells and level of insulin in serum, up-regulating the protein expression levels of InsR, PI3K and GLUT2, down-regulating the level of p JNK protein expression in hepatic tissues, and reducing the level of insulin in hepatic tissues. PMID- 28901090 TI - [Effects of berberine on mRNA expression levels of PPARgamma and adipocytokines in insulin-resistant adipocytes]. AB - Adipocytokines are closely associated with insulin resistance (IR) in adipose tissues, and they are more and more seriously taken in the study of the development of diabetes. This experiment was mainly to study the effect of berberine on mRNA expression levels of PPARgamma and adipocytokines in insulin resistant adipocytes, and investigate the molecular mechanism of berberine in enhancing insulin sensitization and application advantages of droplet digital PCR (ddPCR). ddPCR absolute quantification analysis was taken in this experiment to simply and intuitively determine the appropriate reference genes. ddPCR and quantitative Real-time PCR (qPCR) were used to compare the effect of different doses of berberine (10, 20, 50, 100 MUmol*L-1) on mRNA expression levels of PPARgamma, adiponectin, resistin and leptin in IR 3T3-L1adipocytes. Antagonist GW9662 was added to study the inherent correlation between PPARgamma and adiponectin mRNA expression levels. ddPCR results showed that the expression level of beta-actin in adipocytes was stable, and suitable as reference gene for normalization of quantitative PCR data. Both of ddPCR and qPCR results showed that, as compared with IR models, the mRNA expression levels of adiponectin were decreased in the treatment with berberine (10, 20, 50, 100 MUmol*L-1) in a dose dependent manner (P<0.01); the expression of PPARgamma was decreased by 20, 50, 100 MUmol*L-1 berberine in a dose-dependent manner in qPCR assay (P<0.01) and decreased only by 50 and 100 MUmol*L-1 berberine in ddPCR assay (P<0.05). PPARgamma specific antagonist GW9662 intervention experiment showed that adiponectin gene expression was directly relevant with PPARgamma (P<0.05). ddPCR probe assay showed that various doses of berberine could significantly reduce mRNA expression levels of resistin and leptin (P<0.01) in a dose-dependent manner. In conclusion, berberine enhanced insulin sensitization effect not by up regulating adiponect in expression of transcriptional level in PPARgamma dependent manner, but may by the elevated multimerization of adiponectin in the posttranslational regulation level. Berberine down-regulated the resistin and leptin expression levels, which could alleviate lipolysis and improve IR in adipocytes. ddPCR provided better sensitivity and linear range than qPCR, with obvious technical advantages for the detection of low abundance expression of target genes. PMID- 28901091 TI - [Protective effects and mechanism of glycosides/phenol component of Moutan Cortex on renal injury of diabetic nephropathy rats]. AB - To evaluate the protective effects of glycosides/phenol component of Moutan Cortex (MC) on renal injury of diabetic nephropathy (DN) rats based on renal function parameters and histopathological examinations(HE staining and transmission electron microscope),and explore its possible mechanism by establishing DN rat models induced by high-sugar high-fat diet combined with streptozotocin (STZ). The results showed that compared with the model group, the MC glycosides/phenol component high and low dose groups(0.808, 0.404 g*kg-1*d-1) could significantly improve serum creatinine, blood urea nitrogen, urine protein and other abnormal renal function parameters. HE staining and transmission electron microscope results showed thickening of glomerular basement membrane, proliferation of mesangial cells and damages of podocyte structure in major rats of model group. However, the intervention of glycosides/phenol component of MC could effectively protect the glomerular injury. To explore its possible mechanism, the expressions of TGF-beta1, fibronectin (FN) and collagen IV in renal tissues of rats in each group were detected by Western blot and immunohistochemical assay, and the phosphorylation levels of downstream effect factors (Smad2/3, p38MARK) of TGF-beta1 were detected. The results showed that glycosides/phenol component of MC could effectively antagonize the activity of TGF-beta1, lower the expressions of fibronectin (FN) and collagen IV inextracellular matrix (ECM), and resist against the thickening of glomerular basement membrane. More importantly, its protective effect on renal injury in DN rats may be associated with interfering the conduction of Smad, MARK pathways and resisting against the TGF-beta1-induced ECM accumulation. PMID- 28901092 TI - [Evaluate drug interaction of multi-components in Morus alba leaves based on alpha-glucosidase inhibitory activity]. AB - Column chromatography was used for enrichment and separation of flavonoids, alkaloids and polysaccharides from the extracts of Morus alba leaves; glucose oxidase method was used with sucrose as the substrate to evaluate the multi components of M. alba leaves in alpha-glucosidase inhibitory models; isobole method, Chou-Talalay combination index analysis and isobolographic analysis were used to evaluate the interaction effects and dose-effect characteristics of two components, providing scientific basis for revealing the hpyerglycemic mechanism of M. alba leaves. The components analysis showed that flavonoid content was 5.3%; organic phenolic acids content was 10.8%; DNJ content was 39.4%; and polysaccharide content was 18.9%. Activity evaluation results demonstrated that flavonoids, alkaloids and polysaccharides of M. alba leaves had significant inhibitory effects on alpha-glucosidase, and the inhibitory rate was increased with the increasing concentration. Alkaloids showed most significant inhibitory effects among these three components. Both compatibility of alkaloids and flavonoids, and the compatibility of alkaloids and polysaccharides demonstrated synergistic effects, but the compatibility of flavonoids and polysaccharides showed no obvious synergistic effects. The results have confirmed the interaction of multi-components from M. alba leaves to regulate blood sugar, and provided scientific basis for revealing hpyerglycemic effectiveness and mechanism of the multi-components from M. alba leaves. PMID- 28901093 TI - [HIS-based analysis of clinical characteristics and combined treatment of Chinese and western medicine in diabetes deaths]. AB - To understand the clinical characteristics and distribution of combined treatment of Chinese and western medicine in diabetes deaths, the hospitalization information of diabetes deaths from HIS system of 20 national 3A-grade general hospitals. Then the frequency statistics and association rules analysis were used to analyze the general information, complications, combined treatment, death time and other information of the patients died from diabetes. The results showed that most of the diabetes deaths were of middle aged and elderly people, more often in males than females. The complications with higher incidence included hypertension, pulmonary infection, coronary heart disease, cerebral infarction and renal inadequacy. In combined treatment rules, western medicines insulin, cefuroxime, furosemide, dopamine, nikethamide and sodium bicarbonate were used in combination at highest frequencies, followed by the combinations of traditional Chinese medicines panax notoginseng, radix bupleuri and western medicines, and the combinations between Chinese medicines had the lowest use frequency. Most of the diabetes deaths were of middle aged and elderly people, more often in males than females. They mainly died from 3 pm to 5 pm and from 5 pm to 7 pm. Therefore, the diabetes deaths often had complications of cardiovascular and cerebrovascular diseases, and early prevention shall be noted in clinics; the clinical treatment plan was basically in accordance with the guidelines for clinical treatment of diabetes; the drugs with promoting blood circulation to remove blood stasis and soothing liver-qi stagnation effects were the common Chinese medicines in treatment of diabetes. PMID- 28901094 TI - [Review on study of Dao-di herbs Artemisiae Annuae Herba]. AB - Artemisiae Annuae Herba has used as a medicine for more than 2 000 years. To infer based on the modern study results, Artemisiae Annuae Herba used for the treatment of malaria recorded in Zhou Hou Bei Ji Fang before 1 700 years should come from Artemisia annua. Based on the data of Chinese materia medica, from the field of treatment hotness and preventing attack of malaria etc., the Dao-di producing district of Artemisiae Annuae Herba should at Jingzhou (now Hubei) and surrounding areas in history. From the view of anti-malaria components artemisinin content, the Dao-di growing producing district of Artemisiae Annuae Herba should locate at Chongqing, Guangxi and its surrounding provinces. The study results showed that A. annua was harvested in flower bloom at autumn, and in this time it also had higher artemisinin content. If A. annua was stored exceed six months, artemisinin could be degraded about thirty percent. So it should be stored in a cool and dry place generally. Wild A. annua had a rich genetic diversity. Artemisinin content of A. annua breeding in experimental field could reache to two percent. PMID- 28901095 TI - [Effects of different endophytic fungi on seedling growth of Dendrobium devonianum]. AB - To obtain seedling growth-promoting fungi is a key step in restoration-friendly cultivation of medicinal Dendrobium species, since there are a large number of functionally-unknown endophytic fungi in the roots of Dendrobium plants.In this study, six functionally-unknown endophytic fungal strains were isolated from roots of D.devonianum using single peleton isolation technology, and used in inoculation experiments to test their effectiveness for seedling growth in D.devonianum.After 90 days of inoculation, comparing with the control treatment, FDdS-1, FDdS-2 and FDdS-4 showed strong pathogenic or fatal effects on seedlings; while, FDdS-12, FDdS-9 and FDdS-5 had different effects on seedling growth.FDdS-5 had significant promoting effects on height, fresh and dry weight, stem diameter and root numbers, while FDdS-9 only had significant promoting effect on seedling height, and FDdS-12 had a negative effect on seedling growth.According to the anatomical features of the inoculated roots, FDdS-5 fungi could infect the velamina of seedlings and the existence of symbiosis pelotons in the cortex cells, suggesting that FDdS-5 is a mycorrhiza fungi of D.devonianum.FDdS-5 and FDdS-9 were identified as Sebacina vermifera and Sebacina sp.by molecular technologies.By using FDdS-5 in the restoration-friendly cultivation of D.devonianum, it could effectively promote seedling growth and shorten the seedling growth periods.The results will aid in reintroduction and cultivation of D.devonianum. PMID- 28901096 TI - [Evaluation of efficiency of traps baited with frequency trembler grid lamps and trap plants for control Heortia vitessoides infectwed in Aquilaria sinensis]. AB - Heortia vitessoides has been a serious defoliating pest of Aquilaria sinensis forests in recent years.The adults displayed strong tropism to the frequency trembler grid lamps and the nectar source plants.The favorite nectar source plants of H.vitessoides adults as the trap plants and the frequency trembler grid lamps in the integrated management of H.vitessoides were studied in the adult eclosion period through both the laboratory and field.The results showed that Kuhnia rosmarnifolia and Santalum album plants showed strong attraction to the H.vitessoides adults, with significant differences among the different nectar source plants.K.rosmarnifolia and S.album as trap plants with board type of planting area to total planting area of 5%-10%, and the frequency trembler grid lamps trapped significantly more adults of H.vitessoides. These results suggested that the frequency trembler grid lamps and trap plants could play an important role in the integrated management of the pest H.vitessoides of A.sinensis. PMID- 28901097 TI - [Effects of stereoscopic cultivation on photosynthetic characteristics and growth of Tulipa edulis]. AB - The effect of stereoscopic cultivation on the growth, photosynthetic characteristics and yield of Tulipa edulis was studied to explore the feasibility of stereoscopic cultivation on efficient cultivation of T.edulis. Total leaf area and photosynthetic parameters of T.edulis under stereoscopic cultivation (the upper, middle and the lower layers ) and the control were measured using LI-3100 leaf area meter and LI-6400XT photosynthesis system in the growing peak period of T.edulis.Plant biomass and biomass allocation were also determined.In addition, the bulb regeneration and yield of T.edulis were measured in the harvesting time.The results indicated that in the middle layer of stereoscopic cultivation, leaf biomass proportion was the highest, but total bulb fresh and dry weight and output growth (fresh weight) were the lowest among the treatments.And total bulb fresh weight in the middle of stereoscopic cultivation reduced significantly, by 22.84%, compared with the control.Light intensity in the lower layer of stereoscopic cultivation was moderate, in which T.edulis net photosynthetic rate and water use efficiency were higher than those of the other layers of stereoscopic cultivation, and bulb biomass proportion was the highest in all the treatments.No significant difference was detected in the total bulb fresh weight, dry weight and output growth (fresh weight) between the middle layer of stereoscopic cultivation and the control.In general, there was no significant difference in the growth status of T.edulis between stereoscopic cultivation and the control.Stereoscopic cultivation increased the yield of T.edulis by 161.66% in fresh weight and 141.35% in dry weight compared with the control in the condition of the same land area, respectively.In conclusion, stereoscopic cultivation can improve space utilization, increase the production, and achieve the high density cultivation of T.edulis. PMID- 28901099 TI - [Testing methods for seed quality of Bletilla striata]. AB - In order to provide a basis for establishing seed testing rules and seed quality standard of Bletilla striata, the seed quality of B.striata from different producing area was measured referring to the Rules for Agricultural Seed Testing(GB/T 3543-1995).The results showed that the seeds of B.striata passed through 20-mesh sieve for purity analysis.The weight of seeds was measured by 1000-seed method and the water content was measured at the higher temperature (133+/-2) C for 3 hours.The seeds were cultured on the wet filter paper at 30 C for 4-20 days in light for germination testing.The method of testing seed viability was that seeds were dipped into 1% TTC solution for 7 hours at temperature of 40 C. PMID- 28901098 TI - [Cloning and expression analysis of a chitinase gene PnCHI1 from Panax notoginseng]. AB - Chitinases(EC3.2.1.14), which are present in various organisms, catalyze the hydrolytic cleavage of chitin and play a vital role in plant defense mechanisms against fungal pathogens.In addition, the chitinases are well known to regulate plant growth and development and are involved in programmed cell death(PCD).A chitinase expressed sequence tag(EST) was isolated from Panax notoginseng, and the full-length cDNA of this EST was cloned with the method of rapid amplification of cDNA ends and named as PnCHI1. PnCHI1 was 1 022 bp in length and contained an intact open reading frame(ORF) of 822 bp, a 26 bp 5'-untranslated region(UTR), and a 174 bp 3'-UTR.The predicted protein of PnCHI1 with 273 amino acid residues belongs to glycoside hydrolase family 19 and fell into the class IV of chitinases through phylogenetic analysis.QRT-PCR analysis showed that the expression of PnCHI1 was induced by methyl jasmonate, ethylene, H2O2, and salicylic acid.PnCHI1 was quickly induced after inoculation with Alternaria panax.Moreover, the expression level of PnCHI1 was increased after pretreatment with methyl jasmonate, and then the transcription level of PnCHI1was sharp increased after inoculation with Fusarium solani,and the highest transcription level was achieved at 4 h post inoculation.But the expression level of PnCHI1 in the sterile water pretreated P.notoginseng was increased gradually after inoculation with F.solani, and the highest expression level was achieved at 48 h post inoculation.All the results of present study indicated that PnCHI1 was involved in defense response of P.notoginseng against the F.solani and A.panax. PMID- 28901100 TI - [Influence of cutting seedling on growth, quality and yield of both aerial and underground part by cutting seedling in Scutellaria baicalensis]. AB - By measuring the growth data of Scutellaria baicalensis in different cutting seedling and determined active ingredient contents by HPLC and ultraviolet spectrophotometric determination. such as flavonoids. baicalin. wogonoside. baicalein. wogonin. oroxylin A. scutellarin. luteolin. and apigenin in the whole plant. Under circumstances of guaranteeing the quality and yield of medicinal materials. the yield of medicinal materials. and stems and leaves reached 193.60,63.21 kg/mu after twice cutting seedling. Not only yield but also active ingredient contents have been improved to some extent. the contents of flavonoids. baicalin. wogonoside. baicalein. wogonin. oroxylin A reached 18.52%. 15.13%. 4.03%. 1.04%. 1.04%. 0.12%. respectively in roots. Luteolin was not detected in young stems and leaves of S. baicalensis,the contents of other active ingredients such as scutellarin. luteolin and apigenin reached 7.00%. 0.96%. 0.04% respectively under twice cutting seedling. Therefore. regular cutting seedling could be regard as a new cultivation technique for wider range of promotion. And gaining high quality and yield of medicinal materials and tea with the purpose of rational utilization of natural resources and promoting the development of integration of herbal combination. PMID- 28901101 TI - [Analysis of codon usage bias based on Fritillaria cirrhosa transcriptome]. AB - Understanding of codon usage bias of Fritillaria cirrhosa can provide theoretical basis for heterologous biosynthesis of F. cirrhosa alkaloids by genetic engineering technology. A total of 9 843 full length coding sequences (CDS) from the F. cirrhosa transcriptome data were used for the analysis of codon usage bias. The GC and GC3s contents, effective number of codons(ENC) and relative synonymous codon usage (RSCU) were calculated using the CodonW software. The results show that the codon usage bias value is low in the CDS of F. cirrhosa. A total of 15 codons, including UUG, CUU, AUU, GUU, UCA, CCU, CCA, ACU, ACA, GCA, UAU, CAU, AAU, AGA and GGA, were identified as optimal codons in F. cirrhosa. The optimal codons generally end with A/T at the third codon position. By the transcriptome annotation, we found 26 CDSs possibly involved in the biosynthesis of alkaloids in the F. cirrhosa. The proportion of rare codons of Escherichia coli and Saccharomyces cerevisiae are low in these CDSs. We also proposed a method for the codonoptimization in these target genes. Our work lays the foundation for further study on the biosynthesis of alkaloids of the F. cirrhosa in heterologous species. PMID- 28901102 TI - [Metabolomic evaluation for anti-inflammatory effect of volatile oils from different preparations of Angelicae Sinensis Radix]. AB - To evaluate the anti-acute inflammation effects of volatile oils from different processed products of Angelicae Sinensis Radix(AS) in the rat model of acute inflammation established by the metabolomic method. Volatile oil of charred AS (C VOAS), wine-processed AS (J-VOAS), locally processed AS (T-VOAS) and oil-process AS (Y-VOAS) were applied to intervene the rat acute paw swelling inflammation model induced by Carrageenan. Changes in serum HIS, 5-HT, PGE2 and TNF-alpha content in rats were detected. Gas chromatography-mass spectrometry was used to detect the metabolites in plasma. Potential biomarkers were investigated according to principal component analysis method and partial least-squares discriminant analysis. According to the results, C-VOAS and J-VOAS could significantly inhibit inflammatory mediators Histamine, 5-hydroxytryptamine, prostaglandin-E2 and cytokine tumor necrosis factor-alpha (P<0.01), and T-VOAS and Y-VOAS also showed a significantly inhibitory effect (P<0.05). Compared with the normal group, 14 endogenous metabolite biomarkers showed metabolic disturbance in plasma (P<0.05 or P<0.01). Compared with acute inflammation model group, C-VOAS and J-VOAS could better recover the levels of the endogenous metabolites (P<0.05 or P<0.01) than T-VOAS and Y-VOAS (P<0.05 or P<0.01). This study suggests that C-VOAS and J-VOAS show a better anti-inflammatory effect than T-VOAS and Y-VOAS. Therefore, the metabolomic method could be used to expound the anti-inflammatory mechanism of volatile oils from different processed products of AS, and provide a theoretical basis for clinical application of VOAS. PMID- 28901103 TI - [Chemical variation in Aurantii Fructus before and after processing based on UHPLC-Q-TOF-MS]. AB - To explore the processing mechanism of Aurantii Fructus decoction pieces used in Guangdong province and Hong Kong by analysing the chemical variation between raw and processed Aurantii Fructus with different methods based on UHPLC-Q-TOF-MS. The total ion chromatograms detected in positive and negative ion modes, and ion peak area ratio before and after processing were taken as variation indexes in the comparison. The results indicated that fermented Aurantii Fructus could produce three new ingredients, namely eriodictyol-7-glucoside, hesperetin-7-O glucoside and 5-demethylnobiletin. At the same time, it could significantly increase the content of naringenin and hesperetin components, and could increase the content of such limonin derivatives as sudachinoid A, obacunoic acid and limoninand nomilinic acid. This suggests that the fermentation processing method of Aurantii Fructus decoction pieces used in Guangdong province and Hong Kong is of important significance for enhancing biological activity and bioavailability, and improving the clinical efficacy of Aurantii Fructus decoction pieces, and so is worth further protection and promotion. PMID- 28901104 TI - [Comparison between traditional processing and integration processing for Schizonepetae Herba based on chemical constituents and pharmacological effect]. AB - The GC-MS method was adopted to determine the contents of beta-myrcene, limonene, menthone, menthofuran, pulegone, beta-caryophyllene, 1-octen-3-one and 3-octanone in volatile in Schizonepetae Herba processed by traditional processing and integration processing methods. The efficacies of Schizonepetae Herba with different processing methods were detected based on the inhibition of ear swelling induced by dimethylbenzene in mice. The rationality of the integration processing was expounded based on the comparison of chemical constituents and their pharmacological effects. The results showed that the contents of the eight chemical components in the products processed with the integrated processing method were higher than those processed with the other method. And both of the processing methods could reduce the degree of swelling and the content of TNF alpha/IL-1beta/IL-6 in mice serum. However, the anti-inflammatory efficacy of the products processed with the integration processing method was superior to that processed with the other method. Compared with the traditional processing method, the integration processing method ensures the quality of decoction pieces, with lower time and labor costs and higher efficiency. PMID- 28901105 TI - [Effects of harvest and different processing methods on anti-thrombin activity of Poecilobdella manillensis]. AB - The effects of harvest and different processing methods on the anti-thrombin activity of Poecilobdella manillensis were respectively studied. The indicators included processing methods (vacuum freeze drying, fresh homogenate, drying under sunlight, freezing, scalding, baking under different temperatures), different parts (entire body, cephalon, pygidium, exudate) and body weights (<=10, 10-20, 20-30, 30-40, >=40 g). The anti-thrombin activities of P. manillensis with different processing methods were evaluated by direct anti-thrombin titration. The results indicated that the processing methods significantly affected the anti thrombin activities of P. manillensis. Among the 11 groups, the anti-thrombin activity of P. manillensis processed with vacuum freeze drying (1 303.56 U*g-1) was significantly highest than the other groups (P<0.05), and that processed with baking under 90 C (15.44 U*g-1) was the lowest. The anti-thrombin activity of the cephalon of P. manillensis (226.42 U*g-1) was the highest, and that of the pygidium (102.12 U*g-1) was lowest; the anti-thrombin activities for different body weights were significantly different (P<0.05); and among the five groups, the body weight of <=10 g (328.86 U*g-1) was the highest (P<0.05), and the body weight of >=40 g (87.71 U*g-1) was the lowest. In conclusion, harvest and different processing methods had a significant impact on the anti-thrombin activities of P. manillensis. In the study, for the optimal processing method for P. manillensis, the body weight between 20-30 g is recommended, and the vacuum freeze drying is preferred, which is followed by the drying under sunlight. PMID- 28901106 TI - [Evaluation for preparation and anticancer efficacy in vitro of drug-loaded nanoerythrosomes]. AB - The objective of this study is to develop a new-type biodegradable, biocompatible curcumin-loaded nanoerythrosomes (Cur-RBC-NPs) by means of the sonication method. The size of Cur-RBC-NPs was optimized by varying drug loading parameters. The morphology, size distribution, stability, in vitro release pattern, cellular uptake of nanoparticles and in vitro anti-tumor effects were evaluated, respectively. The results showed the prepared Cur-RBC-NPs were nearly uniform spheres, with an average diameter of (245.7 +/- 1.3) nm. Encapsulation efficiency (EE) and load efficiency (LE) of Cur-RBC-NPs were 50.65% +/- 1.36% and 6.27% +/- 0.29%. And the nanoparticles had a good sustained release property. According to the in vitro experiment, Cur-RBC-NPs were effectively taken in by tumor cells, and exhibited a significant anti-tumor effect. In conclusion, the method for preparing Cur-RBC-NPs is convenient, with a good sustained release behavior and anti-tumor efficacy, and so expected to be a new-type nano-drug delivery system in clinical practice. PMID- 28901107 TI - [Chemical constituents from leaves of Garcinia xanthochymus]. AB - The constituents were isolated and purified by the silica gel and semi preparative HPLC, and their structures were elucidated by NMR spectral and MS data. Fifteen compounds were isolated from the ethyl acetate fraction of 95% ethanol extract from the leaves of Garcinia xanthochymus, and identified as 5, 7, 4'-trihydroxy-6-(3-hydroxy-3-methylbutyl)-flavone(1), 1,5-dihydroxy-3 methoxyxanthone(2), 1, 3-dimethoxy-5-hydroxy xanthone(3), kaempferol(4),(2S,3S) trans-dihydrokaempferol(5), 3, 24, 25-trihydroxytirucall-7-ene(6), 4 hydroxycinnamic acid(7), isovanillic acid(8),(Z)-2-(2,4-dihydroxy-2, 6, 6 trimethylcyclohexylidene)acetic acid(9), volkensiflavone(10), morelloflavone(11), 3, 8"-biapigenin(12), bilobetin(13), fukugiside(14), GB2a glucoside(15). Compound 1 is a new compound, compounds 5, 6, 9 and 13 are isolated from the genus Garcinia for the first time, and compounds 4, 7-8, 10-12, 14 and 15 are firstly found from this plant. alpha-Amylase inhibitory activities of 10 compounds were determined using starch azure as the substrate, and the results show that compound 13 has the inhibitory activities against alpha-amylase, IC50 values of compound 13 and acarbose are 8.12, 4.32 MUmol*L-1 respectively. PMID- 28901108 TI - [Studies on sesquiterpene lactones from Carpesium faberi]. AB - By using various chromatographic techniques,18 sesquiterpene lactones were isolated from the acetone extract of Carpesium faberi. Their structures were identified on the basis of comprehensive spectroscopic data, involving 2 carabrane sesquiterpenoids [carabrone(1), 4R-carabrol(2)], 3 eudesmane sesquiterpenoids [granilin(3), 3-epi-isotelekin(4), 1alpha hydroxypinatifidin(5)], 8 guaiane sesquiterpenoids [4beta,10alpha-dihydroxy 5alpha(H)-1,11(13)-guaidien-8alpha,12-olide(6), 8-epi-helenium lactone(7), 4-epi isoinuviscolide(8), 9beta,10beta-epoxy-4alpha-hydroxy-1beta-H,11alpha-H-guaian 8alpha,12-olide(9), 4alpha,10alpha-dihydroxy-1beta(H),5beta(H)-guaian-11-(13)-en 8alpha,12-olide(10), 4alpha-hydroxy-9beta,10beta-epoxy-11beta-H,5alpha-H-guaian 11(13)-en-8alpha,12-olide(11), 4alpha-hydroxy-1beta,5alpha,11alpha-H-guaian-9(10) en-8alpha,12-olide(12), inuviscolide(13)], 1 pseudoguaiane sesquiterpenoid [(+) confertin(14)], 3 germacrane sesquiterpenoids [madolin B(15), carabrolactone A(16),11(13)-dehydroivaxillin(17)], 1 xanthane sesquiterpenoid [tomentosin(18)]. Furthermore, the absolute configuration of 1 was confirmed by Cu-Kalpha X-ray crystallographic analysis,and the R-configuration of the chiral center at C-4 in 2 was established by the modified Mosher's method.The compounds 2-5, 7 and 9-15 were isolated from this plant for the first time, and compounds 4-5, 7, and 12-15 were isolated from this genus for the first time.In addition, the neurotrophic activity of compounds 1-3, 6 and 17 were evaluated by morphological observation and statistical analysis of cells differentiation, using rat pheochromocytoma(PC12)cells as a model system. However, all compounds were inactive. PMID- 28901109 TI - [Study on cytotoxic secondary metabolites of endophytic fungus Diaporthe longicolla A616 from Pogostemon cablin]. AB - To study active secondary metabolites of endophytic fungus Diaporthe longicolla A616 isolated from Pogostemon cablin. Ten compounds were isolated from fermentation product of the strain 616 by silica gel, reverse phase silica gel, Sephadex-LH20, HPLC and so on. Their structures were identified as 1,3-diamino 1,3-dimethylurea(1),(7R,9R)-7-hydroxy-9-propyl-5-nonen-9-olide(2), Ergosta-5,7,22 trien-3beta-ol(3),(22E,24R)-ergosta-4,6,8(14)-22-tetraen-3-one(4),(22E,24R) 3beta,5alpha-dihydroxy-6beta-ergosta-7,22-diene(5), citreoisocoumarin(6), glycerol monolinoleate(7), 1-(2-hydroxyethoxy)ethyl(E)-octadec-9-enoate(8), cyclo (L-Pro-L-Ala)(9), cyclo(L)-Pro-(L)-Val(10), respectively, based on extensive spectroscopic analysis and literature comparisons. Compounds 6-10 were isolated from the genus Diaporthe for the first time. All isolated compounds were evaluated for in vitro cytotoxic activities against SF-268, MCF-7, NCI-H460 and HepG-2 tumor cell lines. Compounds 4 and 5 showed potent growth inhibitory activities against the four cell lines with IC50 values of 5.3, 6.5, 12.2, 6.1MUmol*L-1 and 8.2, 5.2, 6.1, 9.4MUmol*L-1, respectively. PMID- 28901110 TI - [Sesquiterpenoids of Acori Calami Rhizoma]. AB - To study the chemical constituents and antimicrobial activity of Acori Calami Rhizoma. Components were isolated through various chromatographic methods and identified by spectroscopic data. The agar dilution method was adopted to analyze antimicrobial activity of the compounds in vitro.Eleven sesquiterpenoids were isolated, and indentified as 4beta,6beta-dihydroxy-1alpha,5beta(H)-guai-9 ene(1),4beta,6beta-dihydroxy-1alpha,5beta(H)-guai-10(14)-ene(2), teuclatriol(3), isocalamendiol(4), calamendiol(5), calamusin H(6), oxyphyllenodiols A(7), oplodiol(8), ananosmin(9), epishyobunone(10), and bullatantriol(11). Compound 9 was isolated from genus Acorus for the first time. Compounds 3, 7-9, and 11 had significantly antimicrobial activity. There were good sterilizing effects that the MBC of compound 9 to the four tested strains were 20.00 mg*L-1, and compound 11 to Pseudomonas aeruginosa was 12.50 mg*L-1. PMID- 28901111 TI - [Identification of alkaloids and flavonoids in all parts of Fritillaria thunbergii using LC-LTQ-Orbitrap MSn]. AB - Alkaloids and flavonoids in flowers, flower buds, stems, leaves, and bulbs of Fritillaria thunbergii were identified by LC-LTQ-Orbitrap MSn.Alkaloids were identified by ACQUITY UPLC BEH C18(2.1 mm*50 mm, 1.7 MUm ) chromatographic column with a mobile phase of 10 mmol*L-1 ammonium formate-acetonitrile and gradient elution in positive MS scan mode.Meanwhile, flavonoids were analyzed by Agilent Zorbax SB C18 (4.6 mm*250 mm, 5 MUm) chromatographic column with a mobile phase of 0.2% acetic acid-acetonitrile and gradient elution in negative MS scan mode.Combined with literature reports, chemical constituents were identified and determined by accurate molecular weights and fragment ion peaks in the ESI-MS/MS spectra based on high resolution mass spectrometer.In all parts of F.thunbergii, 37 alkaloids including 7 alkaloids (zhebeininoside, peimisine, peimine, peiminine, ebeiedinone/puqiedinone, ebeiedine/ puqiedine, peimisine-N-oxide) were simultaneously analyzed.Moreover, 16 flavonoids including quercetin, kaempferol and their glycosides were identified.The results indicated that the aerial parts had the similar alkaloids as the bulbs on the whole.Meanwhile, it had a series of flavonoids undetected in the bulbs.Our results provided the scientific basis for the development and utilization of aerial parts of F.thunbergii. PMID- 28901112 TI - [Simultaneous determination of quercitrin, phloridzin and 3-hydroxyl phloridzin in leaves of Malus halliana by ultrasound-assisted ionic liquid-reversed phase liquid chromatography]. AB - To establish a method for the simultaneous determination of phloridzin, 3-hydroxy phloridzin and quercitrin in leaves of Malus halliana by ultrasonic-assisted ionic liquid coupled with RP-HPLC. An Agilent TC-C18 (4.6 mm*250 mm, 5 MUm) column was used, with the mobile phase of acetonitrile and 1% phosphoric acid water (20?80) by gradient elution at the detection wavelength of 270 nm. The flow rate was 0.8 mL*min-1, and chromatographic column temperature was controlled at the room temperature. Under the optimized conditions, the linear ranges for phloridzin, 3-hydroxy phloridzin and quercitrin were 0.9-112.5 MUg (r = 0.999 6), 0.093 2-11.65 MUg (r = 0.999 1) and 0.097 2-12.15 MUg (r = 0.999 8), respectively. The average recoveries of the three constituents were 99.35%, 98.80% and 98.19%, respectively. The method was environmental friendly, rapid, accurate and highly reproducible, and so suitable for the quantitative analysis of phloridzin, 3-hydroxy phloridzin and quercitrin in leaves of M. halliana. PMID- 28901113 TI - [Absorption characteristics of 5 components of Xinshao extract in Caco-2 cells]. AB - To study the absorption characteristics of Xinshao extracts in Caco-2 cells. In this paper, human colon adenocarcinoma cell line Caco-2 cell model was established, and UPLC-MS method was applied to determinate the contents of five components of Xinshao extracts(albiflorin, gallic acid, caffeic acid, scutellarin and apigenin-7-O-glucronide) in cell lysates. This model was also used to study the effect of different drug concentrations, pH, time and temperature on the absorption of five components, investigate the transport of the five components of Xinshao extracts under the conditions with or without P-glycoprotein inhibitors, and predict the absorption mechanism of these five components in Caco 2 cells. The experimental results showed that the absorption of five components of Xinshao extracts in Caco-2 cells was time-dependent at 37 C, and concentration dependent in the range of 0.5-12.5 g*L-1, with a passive diffusion mechanism. At the pH of 4-7.4, the absorption of caffeic acid, scutellarin and apigenin-7-O glucronide was significantly declined with the increase of pH(P<0.05). At the temperature of 4 to 37 C, the absorption of caffeic acid was declined with the increase of temperature, while the absorption of other four components was increased with the increase of temperature. Compared with the control group, caffeic acid and scutellarin cell absorption was significantly higher(P<0.05) after treatment with P-glycoprotein inhibitors(verapamil and cyclosporine A). The results indicated that, the absorption mechanism of five components in Xinshao extracts may be of passive diffusion, and the caffeic acid and scutellarin may be the substrates of P-glycoprotein. PMID- 28901115 TI - [Shenshuaining capsules as adjuvant treatment for chronic renal failure: systematic review and Meta-analysis of randomized controlled trials]. AB - Chronic renal failure(CRF) is one of the common diseases. Shenshuaining capsule (SSN) can be used to treat patients with CRF, and many randomized control trials(RCTs) have been conducted to investigate its efficacy. The current review aims to systematically evaluate the efficacy and safety of SSN as an adjuvant treatment for patients with CRF. Eleven English and Chinese electronic databases (up to October 2015), were searched to identify RCTs on SSN for CRF. Two reviewers independently extracted the data and assessed the quality of included studies by using Cochrane Handbook 5.1.Meta-analysis was carried out by using Revman 5.3 software. If the Meta-analysis was not suitable for some outcomes, only descriptive analysis would be conducted.429 related articles were identified and finally a total of 25 RCTs (1 937 patients including 1 059 patients of treatment group and 878 patients of control group) were included. The SSN treatment group was more effective than the control group in terms of clinical efficiency, blood urea nitrogen(BUN), serum creatinine(Scr) and creatinine clearance(Ccr). However, the efficacy of SSN on increasing hemoglobin (Hb) could not be determined. No serious adverse drug events or reactions were reported. SSN capsules have certain efficacy and safety in the adjuvant treatment for chronic renal failure. However, due to the generally low methodological quality of the included studies, this review can not provide high-quality evidence to prove the clinical efficacy of this drug. More well-designed and large-scale multi-center randomized controlled trials should be conducted in the future for verification. PMID- 28901114 TI - [Absorption characteristics of alkaloids in Fuzheng Xiaozheng Fang by rat everted intestinal sac models]. AB - Everted intestinal sac models were used to investigate the intestinal absorption of the 4 alkaloids(berberine, palmatine, coptisine, and epiberberine) in Fuzheng Xiaozheng Fang(FZ) at different intestine segments. The absorption parameters of each component were calculated; SPSS 20.0 software was used to analyze the data and evaluate the absorption characteristics at different intestinal segments. The results showed that all the four active ingredients conformed to zero-order absorption rate. There was significant difference in absorption rate constant (Ka) between the four ingredients at low dose and medium and high dose groups(P<0.05), but there was no significant difference in Ka between medium dose and high dose. The absorption mechanization of four ingredients presented two absorption manners: positive diffusion and passive absorption. The absorptive amount of 4 alkaloids in ileum was slightly greater than that of jejunum, but no significant differences were observed, which indicated that these four alkaloids had no specific absorption windows in intestinal segment. PMID- 28901117 TI - [Relationship between calcium overload and myocardial ischemia reperfusion injury and intervention strategy of Chinese herbal medicine]. AB - The recent report from National Cardiovascular Center shows that cardiovascular diseases account for more than 40% of disease deaths among residents, so it has become the first cause of death among the residents in our country, and the mortality of coronary heart disease is increasing year by year. Revascularization can quickly open the clogged blood vessels and restore coronary blood supply, so it is an important approach for the treatment of coronary heart disease. However, the revascularization can not terminate the pathological development of coronary heart disease because it is just a local treatment method. In addition, a series of reperfusion injuries after revascularization would seriously restrict its treatment effect for coronary heart disease. Myocardial ischemia reperfusion injury is a complex pathological process, which is closely related to oxygen free radicals, calcium overload and energy metabolism disorder. The calcium overload can be seen during reperfusion in the myocardial cells, and it can cause further damages to the myocardial cells through various mechanisms. Calcium overload is a common pathway of myocardial necrosis and apoptosis, so prevention and treatment of calcium overload is an important method to prevent ischemia reperfusion. The commonly used calcium channel blockers for preventing calcium overload has made great progress, all of which can act on L-type calcium channel of vascular smooth muscle to inhibit calcium overload. However, their clinical application was restrained to a certain extent due to the single target and great side effects. Traditional Chinese medicine (TCM) is a great treasure, and many drugs in TCM have similar effects with calcium antagonists, so the development and application of such drugs would be an important task for contemporary TCM doctors to make up for the deficiency of Western medicine. PMID- 28901116 TI - [Effect of tripterygium glycosides and Danshen injection on blood coagulation mechanism in children with allergic purpura nephritis]. AB - To observe the effect of tripterygium glycosides combined with Danshen injection on blood coagulation mechanism in children with allergic purpura nephritis, and investigate its treatment efficacy through a randomized controlled study. The results showed that before treatment, there were no significant differences in levels of D-D, APTT, PT, FIB and PLT between treatment group and control group; while after treatment, there were significant differences in levels of D-D, PT, FIB and PLT between two groups, but no difference in level of APTT. The effective rate was 90.38% in treatment group, significantly higher than 79.25% in the control group. There was no significant difference in incidence of adverse reactions between two groups. The results suggested that tripterygium glycosides combined with Danshen injection can enhance treatment efficacy and improve blood coagulation mechanism of children in the treatment of purpura nephritis, with high safety and no adverse effects. PMID- 28901118 TI - Randomized controlled trial of maximal strength training vs. standard rehabilitation following total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) alleviates pain, but muscle strength and function is reduced for a long period postoperatively. AIM: To investigate whether maximal strength training (MST) is more effective in improving muscle strength than standard rehabilitation (SR) after TKA. DESIGN: A randomized, controlled study. SETTING: Community physical therapy centers and University hospital research department. POPULATION: Forty-one adults <75 years with primary, unilateral osteoarthritis of the knee scheduled for TKA. METHODS: Participants were randomized to supervised MST of the lower extremities 3 times/week for 8 weeks and physiotherapy session1/week (N.=21) or to SR, including physiotherapy sessions/telephone contact 1/week and writing home exercise logs (N.=20). Maximal strength in leg press and knee extension, 6-minute walk test, patient-reported functional outcome score and pain were assessed preoperatively, 7 days, 10 weeks and 12 months postoperatively. RESULTS: The MST group exceeded preoperative levels of muscle strength in leg press and knee extension by 37% and 43%, respectively at 10 weeks' follow-up, and the increase was higher than in the SR group (P<=0.001). Strength differences persisted up to 12-months follow-up. At 12 months, both groups recovered to normative levels in the 6-Minute Walk Test, with no statistically significantly difference between the groups. CONCLUSIONS: Participants undergoing MST experienced superior increases in leg press and knee extension muscle strength compared with those managed with SR from 7-day to 10-week follow-up. The difference in muscle strength was maintained at 12-month follow-up. No differences in functional performance were found at any time-point. CLINICAL REHABILITATION IMPACT: Exercises after TKA should be performed with high intensity and target the operated leg specifically. PMID- 28901119 TI - Inter- and intra-rater reliability of the Modified Ashworth Scale: a systematic review and meta-analysis. AB - INTRODUCTION: The Modified Ashworth Scale is the most widely clinical scale used to measure the increase of muscle tone. Reliability is not an immutable property of a scale and can vary as a function of the variability and composition of the sample to which it is administered. The best method to examine how the reliability of a test scores varies is by conducting a systematic review and meta analysis of the reliability coefficients obtained in different applications of the test with the data at hand. The objectives of this systematic revision are: what is the mean inter- and intra-rater reliability of the Modified Ashworth Scale's scores in upper and lower extremities? Which study characteristics affect the reliability of the scores in this scale? EVIDENCE ACQUISITION: The PubMed, Embase and CINAHL databases were searched from 1987 to February 2015. Two reviewers independently selected empirical studies published in English or in Spanish that applied the Modified Ashworth Scale and reported any reliability coefficient with the data at hand in children, adolescents or adults with spasticity. EVIDENCE SYNTHESIS: Thirty-three studies reported any reliability estimate of Modified Ashworth Scale scores (N.=1065 participants). For lower extremities and inter-rater agreement, the mean intraclass correlation was ICC+=0.686 (95% CI: 0.563 and 0.780) and for kappa coefficients, kappa+=0.360 (95% CI: 0.241 and 0.468); for intra-rater agreement: ICC+=0.644 (95% CI: 0.543 and 0.726) and kappa+=0.488 (95% CI: 0.370 and 0.591). For upper extremities and inter-rater agreement: ICC+=0.781 (95% CI: 0.679 and 0.853) and kappa+=0.625 (95% CI: 0.350 and 0.801); for intra-rater agreement: ICC+=0.748 (95% CI: 0.671 and 0.809) and kappa+=0.593 (95% CI: 0.467 and 0.696). The type of design, the study focus, and the number of raters presented statistically significant relationships with ICC both for lower and upper extremities. CONCLUSIONS: Inter- and intra rater agreement for Modified Ashworth Scale scores was satisfactory. Modified Ashworth Scale' scores exhibited better reliability when measuring upper extremities than lower. Several characteristics of the studies were statistically associated to inter-rater reliability of the scores for lower and upper extremities. PMID- 28901120 TI - Perioperative stroke: incidence, etiologic factors, and prevention. AB - Stroke is a devastating complication that is difficult to diagnose in the perioperative setting because of the effects of anesthetic and analgesic agents. Lingering anesthesia effects hinder clinicians in identifying stroke symptoms, frequently resulting in a delay in diagnosis and treatment and in unfavorable outcomes. The authors performed a systematic search in PubMed and the Cochrane Central Register. The search aimed to identify studies published between January 1990 and December 2015 related to the common etiologic factors, incidence, risk factors, risk modifiers, and early management of perioperative stroke. Additional articles were identified after review of the references of selected articles. Although perioperative stroke is uncommon, the mortality rate is high. Patients have higher risk of perioperative stroke when undergoing cardiac and vascular operations than uncomplicated orthopedic and general procedures. Preoperative optimization for preexisting risk factors may reduce the rate of perioperative stroke. Prompt, early management can improve patient outcomes. Recognition of the incidence, risk factors, and causes of perioperative stroke may lead to prevention and proper management. PMID- 28901121 TI - SIAARTI-SARNePI Clinical-Organizational Standards for pediatric anesthesia. PMID- 28901122 TI - Correlative Microscopy Combining Secondary Ion Mass Spectrometry and Electron Microscopy: Comparison of Intensity-Hue-Saturation and Laplacian Pyramid Methods for Image Fusion. AB - Correlative microscopy combining various imaging modalities offers powerful insights into obtaining a comprehensive understanding of physical, chemical, and biological phenomena. In this article, we investigate two approaches for image fusion in the context of combining the inherently lower-resolution chemical images obtained using secondary ion mass spectrometry (SIMS) with the high resolution ultrastructural images obtained using electron microscopy (EM). We evaluate the image fusion methods with three different case studies selected to broadly represent the typical samples in life science research: (i) histology (unlabeled tissue), (ii) nanotoxicology, and (iii) metabolism (isotopically labeled tissue). We show that the intensity-hue-saturation fusion method often applied for EM-sharpening can result in serious image artifacts, especially in cases where different contrast mechanisms interplay. Here, we introduce and demonstrate Laplacian pyramid fusion as a powerful and more robust alternative method for image fusion. Both physical and technical aspects of correlative image overlay and image fusion specific to SIMS-based correlative microscopy are discussed in detail alongside the advantages, limitations, and the potential artifacts. Quantitative metrics to evaluate the results of image fusion are also discussed. PMID- 28901123 TI - Atomic-Layer-Deposition Growth of an Ultrathin HfO2 Film on Graphene. AB - Direct growth of an ultrathin gate dielectric layer with high uniformity and high quality on graphene remains a challenge for developing graphene-based transistors due to the chemically inert surface properties of graphene. Here, we develop a method to realize atomic-layer-deposition (ALD) growth of an ultrathin high-kappa dielectric layer on graphene through premodifying the graphene surface using electron beam irradiation. An amorphous carbon layer induced by electron beam scanning is formed on graphene and then acts as seeds for ALD growth of high kappa dielectrics. A uniform HfO2 layer with an equivalent oxide thickness of 1.3 nm was grown as a gate dielectric for top-gate graphene field-effect transistors (FETs). The achieved gate capacitance is up to 2.63 MUF/cm2, which is the highest gate capacitance on a graphene solid-state device to date. In addition, the fabricated top-gate graphene FETs present a high carrier mobility of up to 2500 cm2/(V.s) and a negligible gate leakage current of down to 0.1 mA/cm2, showing that the ALD-grown HfO2 dielectric layer is highly uniform and of very high quality. PMID- 28901124 TI - Understanding and Tailoring Grain Growth of Lead-Halide Perovskite for Solar Cell Application. AB - The fundamental mechanism of grain growth evolution in the fabrication process from the precursor phase to the perovskite phase is not fully understood despite its importance in achieving high-quality grains in organic-inorganic hybrid perovskites, which are strongly affected by processing parameters. In this work, we investigate the fundamental conversion mechanism from the precursor phase of perovskite to the complete perovskite phase and how the intermediate phase promotes growth of the perovskite grains during the fabrication process. By monitoring the morphological evolution of the perovskite during the film fabrication process, we observed a clear rod-shaped intermediate phase in the highly crystalline perovskite and investigated the role of the nanorod intermediate phase on the growth of the grains of the perovskite film. Furthermore, on the basis of these findings, we developed a simple and effective method to tailor grain properties including the crystallinity, size, and number of grain boundaries, and then utilized the film with the tailored grains to develop perovskite solar cells. PMID- 28901125 TI - Annealing Induced Morphology of Silver Nanoparticles on Pyramidal Silicon Surface and Their Application to Surface-Enhanced Raman Scattering. AB - This paper reports on a simple and cost-effective process of developing a stable surface-enhanced Raman scattering (SERS) substrate based on silver (Ag) nanoparticles deposited on silicon (Si) surface. Durability is an important issue for preparing SERS active substrate as silver nanostructures are prone to rapid surface oxidation when exposed to ambient conditions, which may result in the loss of the enhancement capabilities in a short period of time. Here, we employ the galvanic displacement method to produce Ag nanoparticles on Si(100) substrate prepatterned with arrays of micropyramids by chemical etching, and subsequently, separate pieces of such substrates were annealed in oxygen and nitrogen environments at 550 degrees C. Interestingly, while nitrogen-annealed Si substrates were featured by spherical-shaped Ag particles, the oxygen annealed Si substrates were dominated by the formation of triangular shape particles attached with the spherical one. Remarkably, the oxygen-annealed substrate thus produced shows very high SERS enhancement compared to the either unannealed or nitrogen annealed substrate. The hitherto unobserved coexistence of triangular morphology with the spherical one and the gap between the two (source of efficient hot spots) are the origin of enhanced SERS activity for the oxygen-annealed Ag particle-covered Si substrate as probed by the combined finite-difference time domain (FDTD) simulation and cathodoluminesensce (CL) experiment. As the substrate has already been annealed in an oxygen environment, further probability of oxidation is reduced in the present synthesis protocol that paves the way for making a novel long-lived thermally stable SERS substrate. PMID- 28901126 TI - MoS2-Based Mixed-Dimensional van der Waals Heterostructures: A New Platform for Excellent and Controllable Microwave-Absorption Performance. AB - It is widely recognized that constructing multiple interface structures for enhanced interface polarization is beneficial to microwave absorption. Here, we report our work of achieving excellent microwave-absorption performance and controlling better-defined interfaces in vertically stacked two-dimensional (2D) MoS2 with other dimensional building blocks. The optimal reflection loss and effective absorbing bandwidth (reflection loss <-10 dB) of several mixed dimensional van der Waals heterostructures are as follows: (i) for 2-0 type (2D MoS2/zero-dimensional Ni nanoparticles), -19.7 dB and 2.92 GHz; (ii) for 2-1 type (2D MoS2/one-dimensional carbon nanotubes), -47.9 dB and 5.60 GHz; and (iii) for 2-3 type (2D MoS2/three-dimensional carbon layers), -69.2 dB and 4.88 GHz. As a result, by selected synthesis of different types of microstructures, we can regulate and control microwave-absorption properties in MoS2 mixed-dimensional van der Waals heterostructures. In addition, attributing to the better-defined interfaces generated in mixed-dimensional van der Waals heterostructures, we found an alternative strategy to improve microwave attenuation properties of 2-0, 2-1, and 2-3 samples by controlling interfacial contacts. The results indicate that mixed-dimensional van der Waals heterostructures provide a new stage for the next generation of microwave-absorbing materials. PMID- 28901127 TI - Barrier-Layer Optimization for Enhanced GaN-on-Diamond Device Cooling. AB - GaN-on-diamond device cooling can be enhanced by reducing the effective thermal boundary resistance (TBReff) of the GaN/diamond interface. The thermal properties of this interface and of the polycrystalline diamond grown onto GaN using SiN and AlN barrier layers as well as without any barrier layer under different growth conditions are investigated and systematically compared for the first time. TBReff values are correlated with transmission electron microscopy analysis, showing that the lowest reported TBReff (~6.5 m2 K/GW) is obtained by using ultrathin SiN barrier layers with a smooth interface formed, whereas the direct growth of diamond onto GaN results in one to two orders of magnitude higher TBReff due to the formation of a rough interface. AlN barrier layers can produce a TBReff as low as SiN barrier layers in some cases; however, their TBReff are rather dependent on growth conditions. We also observe a decreasing diamond thermal resistance with increasing growth temperature. PMID- 28901128 TI - Can Toxicokinetic and Toxicodynamic Modeling Be Used to Understand and Predict Synergistic Interactions between Chemicals? AB - Some chemicals are known to enhance the effect of other chemicals beyond what can be predicted with standard mixture models, such as concentration addition and independent action. These chemicals are called synergists. Up until now, no models exist that can predict the joint effect of mixtures including synergists. The aim of the present study is to develop a mechanistic toxicokinetic (TK) and toxicodynamic (TD) model for the synergistic mixture of the azole fungicide, propiconazole (the synergist), and the insecticide, alpha-cypermethrin, on the mortality of the crustacean Daphnia magna. The study tests the hypothesis that the mechanism of synergy is the azole decreasing the biotransformation rate of alpha-cypermethrin and validates the predictive ability of the model on another azole with a different potency: prochloraz. The study showed that the synergistic potential of azoles could be explained by their effect on the biotransformation rate but that this effect could only partly be explained by the effect of the two azoles on cytochrome P450 activity, measured on D. magna in vivo. TKTD models of interacting mixtures seem to be a promising tool to test mechanisms of interactions between chemicals. Their predictive ability is, however, still uncertain. PMID- 28901130 TI - Sequential Feature-Density Doubling for Ultraviolet Plasmonics. AB - Patterning of nanostructures with sub-200 nm periodicities over cm2-scale areas is challenging using standard approaches. This paper demonstrates a scalable technique for feature-density doubling that can generate nanopatterned lines with periodicities down to 100 nm covering >3 cm2. We developed a process based on controlled wet overetching of atomic-layer deposited alumina to tune feature sizes of alumina masks down to several nm. These features transferred into silicon served as masters for template-stripping aluminum nanogratings with three different periodicities. The aluminum nanogratings supported surface plasmon polariton modes at ultraviolet wavelengths that, in agreement with calculations, depended on periodicity and incident excitation angle. PMID- 28901129 TI - Peptide-Level Interactions between Proteins and Small-Molecule Drug Candidates by Two Hydrogen-Deuterium Exchange MS-Based Methods: The Example of Apolipoprotein E3. AB - We describe a platform utilizing two methods based on hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (MS) to characterize interactions between a protein and a small-molecule ligand. The model system is apolipoprotein E3 (apoE3) and a small-molecule drug candidate. We extended PLIMSTEX (protein-ligand interactions by mass spectrometry, titration, and H/D exchange) to the regional level by incorporating enzymatic digestion to acquire binding information for peptides. In a single experiment, we not only identified putative binding sites, but also obtained affinities of 6.0, 6.8, and 10.6 MUM for the three different regions, giving an overall binding affinity of 7.4 MUM. These values agree well with literature values determined by accepted methods. Unlike those methods, PLIMSTEX provides site-specific binding information. The second approach, modified SUPREX (stability of unpurified proteins from rates of H/D exchange) coupled with electrospray ionization (ESI), allowed us to obtain detailed understanding about apoE unfolding and its changes upon ligand binding. Three binding regions, along with an additional site, which may be important for lipid binding, show increased stability (less unfolding) upon ligand binding. By employing a single parameter, DeltaC1/2%, we compared relative changes of denaturation between peptides. This integrated platform provides information orthogonal to commonly used HDX kinetics experiments, providing a general and novel approach for studying protein-ligand interactions. PMID- 28901132 TI - Regioselectivity of the OH Radical Addition to Uracil in Nucleic Acids. A Theoretical Approach Based on QM/MM Simulations. AB - Oxidation of nucleic acids is ubiquitous in living beings under metabolic impairments and/or exposed to external agents such as radiation, pollutants, or drugs, playing a central role in the development of many diseases mediated by DNA/RNA degeneration. Great efforts have been devoted to unveil the molecular mechanisms behind the OH radical additions to the double bonds of nucleobases; however, the specific role of the biological environment remains relatively unexplored. The present contribution tackles the study of the OH radical addition to uracil from the gas phase to a full RNA macromolecule by means of quantum chemistry methods combined with molecular dynamics simulations. It is shown that, in addition to the intrinsic reactivity of each position driven by the electronic effects, the presence of bridge water molecules intercalated into the RNA structure favors the addition to the C5 position of uracil in biological conditions. The results also suggest that diffusion of the OH radical does not play a relevant role in the regioselectivity of the reaction, which is mainly controlled at the chemical stage of the addition process. PMID- 28901133 TI - Synthesis and Structural and Optical Properties of Ga(As1-xPx)Ge3 and (GaP)yGe5 2y Semiconductors Using Interface-Engineered Group IV Platforms. AB - Epitaxial synthesis of Ga(As1-xPx)Ge3 alloys on Si(100) substrates is demonstrated using chemical vapor deposition reactions of [D2GaN(CH3)2]2 with P(GeH3)3 and As(GeH3)3 precursors. These compounds are chosen to promote the formation of GaAsGe3 and GaPGe3 building blocks which interlink to produce the desired crystalline product. Ge-rich (GaP)yGe5-2y analogues have also been grown with tunable Ge contents up to 90% by reactions of P(GeH3)3 with [D2GaN(CH3)2]2 under similar deposition protocols. In both cases, the crystal growth utilized Ge1-xSix buffer layers whose lattice constants were specifically tuned as a function of composition to allow perfect lattice matching with the target epilayers. This approach yielded single-phase materials with excellent crystallinity devoid of mismatch-induced dislocations. The lattice parameters of Ga(As1-xPx)Ge3 interpolated among the Ge, GaAs, and GaP end members, corroborating the Rutherford backscattering measurements of the P/As ratio. A small deviation from the Vegard's law that depends on the As/P ratio was observed and corroborated by ab initio calculations. Raman scattering shows evidence for the existence of Ga-As and Ga-P bonds in the Ge matrix. The As-rich samples exhibited photoluminescence with wavelengths similar to those observed for pure GaAsGe3, indicating that the emission profile does not change in any measurable manner by replacing As by P over a broad range up to x = 0.2. Furthermore, the photoluminescence (PL) data suggested a large negative bowing of the band gap as expected on account of a strong valence band localization on the As atoms. Spectroscopic ellipsometry measurements of the dielectric function revealed a distinct direct gap transition that closely matches the PL emission energy. These measurements also showed that the absorption coefficients can be systematically tuned as a function of composition, indicating possible applications of the new materials in optoelectronics, including photovoltaics. PMID- 28901134 TI - Diagnosis of Tuberculosis Using Colorimetric Gold Nanoparticles on a Paper-Based Analytical Device. AB - We have developed a colorimetric sensing strategy employing gold nanoparticles and a paper-based analytical platform for the diagnosis of tuberculosis (TB). By utilizing the surface plasmon resonance effect, we were able to monitor changes in the color of a gold nanoparticle colloid based on the effects of single stranded DNA probe molecules hybridizing with targeted double-stranded TB DNA. The hybridization event changes the surface charge density of the nanoparticles, causing them to aggregate to various degrees, which modifies the color of the solution in a manner that can be readily measured to determine the concentration of the targeted DNA analyte. In order to adapt this TB diagnosis method to resource-limited settings, we extended this label-free oligonucleotide and unmodified gold nanoparticle solution-based technique to a paper-based system that can be measured using a smartphone to obtain rapid parallel colorimetric results with low reagent consumption and without the need for sophisticated analytical equipment. In this study, we investigated various assay conditions, including the denaturing temperature and time, different oligonucleotide probe sequences, as well as the ratio of single stranded probe and double stranded target DNA. After optimizing these variables, we were able to achieve a detection limit of 1.95 * 10-2 ng/mL for TB DNA. Furthermore, multiple tests could be performed simultaneously with a 60 min turnaround time. PMID- 28901135 TI - Room-Temperature Large and Reversible Modulation of Photoluminescence by in Situ Electric Field in Ergodic Relaxor Ferroelectrics. AB - Ferroelectric oxides with luminescent ions hold great promise in future optoelectronic devices because of their unique photoluminescence and inherent ferroelectric properties. Intriguingly, the photoluminescence performance of ferroelectric ceramics could be modulated by an external electric field. However, researchers face a current challenge of the diminutive extent and degree of reversibility of the field-driven modification that hinder their use in room temperature practical applications. Within the scope of current contribution in rare-earth-doped bismuth sodium titanate relaxors, the most important information to be noted is the shifting of the depolarization temperature toward room temperature and the resulting considerable enhancement in ergodicity, as evidenced by the dielectric properties, polarization, and strain hysteresis, as well as the in situ Raman/X-ray diffraction studies. After the introduction of 1 mol % Eu, the induced composition and charge disorders disrupt the original long range ferroelectric macrodomains into randomly dynamic and weakly correlated polar nanoregions, which facilitates a reversible transformation between polar nanoregions and unstable ferroelectric state under an electric field, engendering a large strain. By virtue of this, both the extent and degree of reversibility of photoluminescence modulation are enhanced (~60%) considerably, and room temperature in situ tunable photoluminescence response is then achieved under electric field. These should be helpful for the realization of regulating the physical couplings (photoluminescent-ferroelectrics) in multifunctional inorganic ferroelectrics with a high ergodic state by reversibly tuning the structural symmetry. PMID- 28901136 TI - Tren-Capped Hexaphyrin Zinc Complexes: Interplaying Molecular Recognition, Mobius Aromaticity, and Chirality. AB - Over the past decade, the hexaphyrin skeleton has emerged as a multifaceted frame exhibiting strong interplay between topology, aromaticity, and metal coordination, opening new research areas beyond porphyrins. However, molecular recognition with hexaphyrins has been underexplored, mainly because of the lack of general synthetic strategies leading to sophisticated molecular hosts. Here we have developed a straightforward approach for capping the heteroannulene frame with tripodal units (e.g., tris(2-aminoethyl)amine [tren]) through postsynthetic modification of a readily accessible meso-(2-aminophenyl) tris-substituted platform. The resulting tren-capped hexaphyrins, obtained in three steps from a 5 (aryl)dipyrromethane precursor, display remarkable features: (i) Considering the 28pi-conjugated system, instantaneous and site-selective Zn(II) metalation at the level of a dipyrrin versus tren unit triggers a planar-to-singly twisted conformational change and hence a Huckel antiaromatic-to-Mobius aromatic transformation. In spite of the tripodal linkage, a smooth twist and efficient pi overlap are preserved. (ii) Selective and cooperative binding of both an acetato ligand and an amino ligand to zinc occurs in distinct confined environments, reminiscent of substrate discrimination at the buried metal centers of metalloenzymes. The ligand binding pockets are allosterically tuned by monoprotonation of the tren unit. (iii) Substantial chiral induction of the molecular twist is achieved using chiral amino ligands (diastereomeric excess up to 77%, the highest reported to date for a Mobius compound), to which is associated a strong chiroptical signature in circular dichroism. These results provide unprecedented insights into molecular recognition with hexaphyrins, paving the way to innovative Mobius-type molecular hosts for sensing and catalysis. PMID- 28901137 TI - Metamaterial Combining Electric- and Magnetic-Dipole-Based Configurations for Unique Dual-Band Signal Enhancement in Ultrahigh-Field Magnetic Resonance Imaging. AB - Magnetic resonance imaging and spectroscopy (MRI and MRS) are both widely used techniques in medical diagnostics and research. One of the major thrusts in recent years has been the introduction of ultrahigh-field magnets in order to boost the sensitivity. Several MRI studies have examined further potential improvements in sensitivity using metamaterials, focusing on single frequency applications. However, metamaterials have yet to reach a level that is practical for routine MRI use. In this work, we explore a new metamaterial implementation for MRI, a dual-nuclei resonant structure, which can be used for both proton and heteronuclear magnetic resonance. Our approach combines two configurations, one based on a set of electric dipoles for the low frequency band, and the second based on a set of magnetic dipoles for the high frequency band. We focus on the implementation of a dual-nuclei metamaterial for phosphorus and proton imaging and spectroscopy at an ultrahigh-field strength of 7 T. In vivo scans using this flexible and compact structure show that it locally enhances both the phosphorus and proton transmit and receive sensitivities. PMID- 28901138 TI - Solution-Processed CdS/Cu2S Superlattice Nanowire with Enhanced Thermoelectric Property. AB - Previously, the solution-based cation exchange reaction has been extensively studied for the synthesis of the complex heteroepitaxial nanocolloidals. Here, we demonstrated that the strain induced selective phase segregation technique can also be applied to large size nanowires in a well-studied CdS/Cu2S system, leading to the formation of superlattice nanowire structure with a simple solution-based cation exchange reaction. This structural evolution is driven by the distinct interface formation energy at different CdS facets as indicated by ab initio calculation. Because of the energy filtering effect, the superlattice nanowire shows an enhanced thermopower without significant decrease of the electrical conductivity. This study provides a promising low-cost solution process to produce superlattice nanostructures for practical thermoelectric applications. PMID- 28901139 TI - Injectable and Self-Healing Thermosensitive Magnetic Hydrogel for Asynchronous Control Release of Doxorubicin and Docetaxel to Treat Triple-Negative Breast Cancer. AB - Integration of two or more drugs into a multiagent delivery system has been considered to have profound impact on both in vitro and in vivo cancer treatment due to their efficient synergistic effect. This study presents a cheap and simple chitosan hydrogel cross-linked with telechelic difunctional poly(ethylene glycol) (DF-PEG-DF) for synthesis of an injectable and self-healing thermosensitive dual drug-loaded magnetic hydrogel (DDMH), which contains both doxorubicin (DOX) and docetaxel (DTX) for chemotherapy and iron oxide for magnetic hyperthermia induced stimuli responsive drug release. The as-prepared DDMH not only have good biocompatibility but also exhibit unique self-healing, injectable, asynchronous control release properties. Meanwhile, it shows an excellent magnetic field responsive heat-inducing property, which means that DDMH will produce a large amount of heat to control the surrounding temperature under the alternative magnetic field (AMF). A remarkably improved synergistic effect to triple negative breast cancer cell line is obtained by comparing the therapeutic effect of codelivery of DOX and DTX/PLGA nanoparticles (DTX/PLGA NPs) with DOX or DTX/PLGA NPs alone. In vivo results showed that DDMH exhibited significant higher antitumor efficacy of reducing tumor size compared to single drug-loaded hydrogel. Meanwhile, the AMF-trigger control release of drugs in codelivery system has a more efficient antitumor effect of cancer chemotherapy, indicating that DDMH was a promising multiagent codelivery system for synergistic chemotherapy in the cancer treatment field. PMID- 28901140 TI - Nickel-Catalyzed Synthesis of Stereochemically Defined Enamides via Bi- and Tricomponent Coupling Reaction. AB - The stereoselective synthesis of (E)-trisubstituted tertiary enamides is documented via site-selective Ni-catalyzed beta-arylation of allenamides with boronic acids in high yields (up to 89%). The nucleophilic character of the "organo-Ni" intermediates is further exploited to implement a one-pot tricomponent procedure involving the final allylation of aldehydes (yields up to 93%). Mechanistic insights and efficiency on a gram scale process were also documented. PMID- 28901141 TI - Cobalt(III)-Catalyzed Fast and Solvent-Free C-H Allylation of Indoles Using Mechanochemistry. AB - Mechanochemical conditions have been applied to a highly efficient cobalt(III) catalyzed C-H bond activation for the first time. In a subsequent step to the olefin insertion and beta-oxygen elimination, N-pyrimidinylindoles were allylated with vinylethylene carbonates in the absence of organic solvent under high-speed ball-milling condition. As the reaction afforded the desired products in up to 98% yields within a short time, this method constitutes an environmentally friendly and powerful alternative to the common solution-based approaches. PMID- 28901142 TI - Copper-Promoted Synthesis of 2-Fulleropyrrolines via Heteroannulation of [60]Fullerene with alpha-Amino Ketones. AB - A Cu(OAc)2-promoted heteroannulation of [60]fullerene with alpha-amino ketones has been exploited for the efficient synthesis of 2-fulleropyrrolines containing a trisubstituted or tetrasubstituted C?C bond via the formation of C-C and C-N bonds. Mechanistic study indicates that a radical process should be involved in this transformation. Furthermore, theoretical computations show that the process via the attack of the carbon radical generated from the employed alpha-amino ketone to [60]fullerene should be the preferred pathway. The electrochemical properties of the synthesized 2-fulleropyrrolines have also been investigated. PMID- 28901143 TI - Scanning Quadrupole Data-Independent Acquisition, Part A: Qualitative and Quantitative Characterization. AB - A novel data-independent acquisition (DIA) method incorporating a scanning quadrupole in front of a collision cell and orthogonal acceleration time-of flight mass analyzer is described. The method has been characterized for the qualitative and quantitative label-free proteomic analysis of complex biological samples. The principle of the scanning quadrupole DIA method is discussed, and analytical instrument characteristics, such as the quadrupole transmission width, scan/integration time, and chromatographic separation, have been optimized in relation to sample complexity for a number of different model proteomes of varying complexity and dynamic range including human plasma, cell lines, and bacteria. In addition, the technological merits over existing DIA approaches are described and contrasted. The qualitative and semiquantitative performance of the method is illustrated for the analysis of relatively simple protein digest mixtures and a well-characterized human cell line sample using untargeted and targeted search strategies. Finally, the results from a human cell line were compared against publicly available data that used similar chromatographic conditions but were acquired with DDA technology and alternative mass analyzer systems. Qualitative comparison showed excellent concordance of results with >90% overlap of the detected proteins. PMID- 28901144 TI - Visible-Light-Enabled Decarboxylative Mono- and Difluoromethylation of Cinnamic Acids under Metal-Free Conditions. AB - Several new mono- and difluoromethylation reactions of cinnamic acids using an Eosin Y catalytic system are reported. An efficient alkene fluoromethylation of alpha,beta-unsaturated carboxylic acids was accomplished under ambient temperature and metal-free conditions, with a wide range of functional group tolerance. A mechanism that involves a radical process is proposed for this reaction. PMID- 28901146 TI - Bay- and Ortho-Octasubstituted Perylenes. AB - A key intermediate compound, 2,5,8,11-tetrabromo-1,6,7,12-tetrabutoxyperylene (Per-4Br), was synthesized from 3,6-dibromo-2,7-dioxylnaphthalene via simple regioselective oxidative radical-radical coupling, followed by reduction and nucleophilic substitution. Various bay- and ortho-octasubstituted perylenes containing cyano, methoxy and aryl groups were then obtained by nucleophilic substitution or Pd-catalyzed coupling reactions. X-ray crystallographic analyses reveal that these new perylene molecules process a twisted structure due to steric congestion at the bay-regions and there is no obvious intermolecular pi-pi interaction. As a result, they exhibit moderate fluorescence quantum yields even in solid state. Therefore, Per-4Br can serve as a versatile building block for various functional perylene dyes with tunable optoelectronic property. PMID- 28901145 TI - Hollow Polycaprolactone Microspheres with/without a Single Surface Hole by Co Electrospraying. AB - We describe the co-electrospraying of hollow microspheres from a polycaprolactone (PCL) shell solution and various core solutions including water, cyclohexane, poly(ethylene oxide) (PEO), and polyethylene glycol (PEG), using different collectors. The morphologies of the resultant microspheres were characterized by scanning electron microscopy (SEM), confocal microscopy, and nano-X-ray computed tomography (nano-XCT). The core/shell solution miscibility played an important role in the co-electrospraying process and the formation of microsphere structures. Spherical particles were more likely to be produced from miscible combinations of core/shell solutions than from immiscible ones. Hollow PCL microspheres with a single hole in their surfaces were produced when an ethanol bath was used as the collector. The mechanism by which the core/shell structure is transformed into single-hole hollow microspheres is proposed to be primarily based on the evaporation through the shell and extraction by ethanol of the core solution and is described in detail. Additionally, we present a 3D macroscopic tubular structure composed of hollow PCL microspheres, directly assembled on a copper wire collector during co-electrospraying. SEM and nano-XCT confirm that microspheres in the 3D bulk structure remain hollow. PMID- 28901147 TI - Cobalt-Catalyzed Trifluoromethylation-Peroxidation of Unactivated Alkenes with Sodium Trifluoromethanesulfinate and Hydroperoxide. AB - Disclosed herein is an unprecedented cobalt-catalyzed trifluoromethylation peroxidation of unactivated alkenes. In this process the hydroperoxide acts as a radical initiator as well as a coupling partner. The cheap and readily available sodium trifluoromethanesulfinate serves as the CF3 source in the reaction. Various alkenes are transformed into vicinal trifluoromethyl-peroxide compounds in moderate to good yields. PMID- 28901148 TI - Total Synthesis of (-)-Bicubebin A, B, (+)-Bicubebin C and Structural Reassignment of (-)-cis-Cubebin. AB - The first total synthesis of (-)-bicubebin A, and two previously unreported dilignans, (-)-bicubebin B and (+)-bicubebin C has been achieved through the dimerization of (-)-cubebin, confirming the structure and absolute stereochemistry of (-)-bicubebin A. Analysis of the data for (-)-bicubebin B showed it matched that of reported compound (-)-cis-cubebin. The NMR data of the subsequently synthesized proposed structure of cis-cubebin confirmed that its original proposed structure was incorrect. PMID- 28901149 TI - Intramolecular Pd-Catalyzed Anomeric C(sp3)-H Activation of Glycosyl Carboxamides. AB - An expedient method for the synthesis of fused glycosylquinolin-2-ones and glycosylspirooxindoles through an unprecedented intramolecular Pd-catalyzed anomeric C-H activation of the sugar moiety of 2-bromophenyl glycosylcarboxamides is reported. The scope of the reaction is broad and tolerates a wide range of functional groups. PMID- 28901151 TI - Fine-Tuning Nanoparticle Packing at Water-Oil Interfaces Using Ionic Strength. AB - Nanoparticle-surfactants (NPSs) assembled at water-oil interfaces can significantly lower the interfacial tension and can be used to stabilize liquids. Knowing the formation and assembly and actively tuning the packing of these NPSs is of significant fundamental interest for the interfacial behavior of nanoparticles and of interest for water purification, drug encapsulation, enhanced oil recovery, and innovative energy transduction applications. Here, we demonstrate by means of interfacial tension measurements the high ionic strength helps the adsorption of NPSs to the water-oil interface leading to a denser packing of NPSs at the interface. With the reduction of interfacial area, the phase transitions from a "gas"-like to "liquid" to "solid" states of NPSs in two dimensions are observed. Finally, we provide the first in situ real-space imaging of NPSs at the water-oil interface by atomic force microcopy. PMID- 28901150 TI - Function-Oriented Studies Targeting Pectenotoxin 2: Synthesis of the GH-Ring System and a Structurally Simplified Macrolactone. AB - A chemical foundation for function-oriented studies of pectenotoxin 2 (PTX2) is described. A synthesis of the bicyclic GH-system, and the design and synthesis of a PTX2-analogue, is presented. While maintaining critical features for actin binding, and lacking the Achilles' heel for the natural product's anticancer activity (the AB-spiroketal), this first-generation analogue did not possess the anticancer properties of PTX2, an observation that indicates the molecular significance of features present in the natural product's CDEF-tetracycle. PMID- 28901152 TI - Acid-Mediated Migration of Bromide in an Antiaromatic Porphyrinoid: Preparation of Two Regioisomeric Ni(II) Bromonorcorroles. AB - The regioselective halogenation of porphyrinoids is critical for their selective functionalization, which enables the fine tuning of their electronic and optical properties. Here we report the synthesis of two regioisomeric Ni(II) bromonorcorroles on the basis of the acid-induced migration of the bromo substituent. Treatment of Ni(II) dimesitylnorcorrole with N-bromosuccinimide (NBS) selectively afforded Ni(II) 3-bromonorcorrole, which was further converted into Ni(II) 2-bromonorcorrole upon treatment with hydrogen bromide. In addition, the reaction of Ni(II) dimesitylnorcorrole with an excess amount of NBS afforded the octabrominated product. The reaction mechanism of the bromination reaction of Ni(II) dimesitylnorcorrole was investigated by theoretical calculations. PMID- 28901153 TI - A Direct Cycloaminative Approach to Imidazole Derivatives via Dual C-H Functionalization. AB - Organoiodine(III)-promoted C(sp3)-H azidation was a key step for the cycloaminative process. An unprecedented method for metal-free dehydrogenative N incorporation into C(sp3)-H and C(sp2)-H bonds for the synthesis of diverse imidazoles has been disclosed. The overall transformation involves the construction of four C-N bonds through hydroamination-azidation-cyclization sequence. The reaction can be easily handled and proceeds under mild conditions. Further, the potential of the present strategy is revealed by the practical synthesis of N-heterocyclic carbene (NHC) precursors. PMID- 28901154 TI - Palladium-Catalyzed Synthesis of 2-Cyanoindoles from 2-gem-Dihalovinylanilines. AB - An efficient Pd(0)-catalyzed synthesis of 2-cyanoindoles from 2-gem dihalovinylanilines is reported. Few methods have aimed to synthesize these scaffolds, which are found in many natural products and have high bioactivity. This protocol features a robust catalyst system utilizing Zn(TFA)2 to prolong the catalytic activity. Additionally, the amount of cyanide in the reaction phase is minimized by taking advantage of the solubility of Zn(CN)2 in a two-solvent mixture. PMID- 28901155 TI - Reactivity and Selectivity in the Intermolecular Alder-Ene Reactions of Arynes with Functionalized Alkenes. AB - The reactivity and selectivity of functionalized alkenes in intermolecular Alder ene reactions with arynes is described. The arynes generated from bis-1,3-diynes react with various trisubstituted and 1,1-disubstituted alkenes containing hydroxyl, amino, halo, carboxyl, boronate, and 1,3-dienyl functionalities, providing product distributions with varying degrees of selectivity between Alder ene and addition reactions. The geometry of alkenes is another important factor for the reactivity of di- and trisubstituted alkenes where the allylic hydrogen of cis-disposed alkenyl system is reactive, which is the opposite reactivity compared to the corresponding intramolecular reaction. PMID- 28901156 TI - Enantioselective Precipitate of Amines, Amino Alcohols, and Amino Acids via Schiff Base Reaction in the Presence of Chiral Ionic Liquid. AB - Two novel chiral ionic liquids are synthesized as the chiral selector. Racemates of amines, amino alcohols, and amino acids could generate enantioselective precipitate with multicomponent self-assemblies under mild conditions. The approach allows for enantioseparation with good yields (79-94%) and excellent ee's (>95%). PMID- 28901157 TI - Reaction of Amines with Aldehydes and Ketones Revisited: Access To a Class of Non Scorpionate Tris(pyrazolyl)methane and Related Ligands. AB - The reaction of amines with aldehydes and ketones has been exploited for over 150 years to produce Schiff bases, one of the most popular classes of compounds in both organic and coordination chemistry. In certain cases, however, compounds other than Schiff bases have been reported to result from such reactions. After conducting a representative reaction under various different conditions and identifying several reaction intermediates by NMR spectroscopy, mass spectrometry and X-ray crystallography, we now report a unified picture that explains the scattered and often inconsistent results obtained with 3(5)-aminopyrazole derivatives and other related molecules. Acid catalysis, which is often employed in Schiff base synthesis, radically changes the course of reaction and leads to bis(pyrazol-4-yl)methane derivatives instead of the expected Schiff base products. The stoichiometry of the reaction is also found to be crucial for obtaining quantitative conversions. A total of 31 new compounds have been isolated and characterized as a result of this study, including a reaction intermediate, 2 Schiff bases, and 28 bis- or tris(pyrazol-3(4)-yl)methane ligands. The latter defines a new class of "non-scorpionate" ligands, with three nonchelating pyrazole moieties, as opposed to the well-known "scorpionate" tris(pyrazol-1-yl)-borate and -methane ligands. PMID- 28901159 TI - Health Information Preferences of Parents in a Pediatric Emergency Department. AB - Parents of children seeking nonurgent care in the emergency department completed surveys concerning media use and preferences for health education material. Results were compiled using descriptive statistics, compared by health literacy level with logistic regression, adjusting for race/ethnicity and income. Semistructured qualitative interviews to elicit reasons for preferences, content preference, and impact of health information were conducted and analyzed using content analysis. Surveys (n = 71) showed that despite equal access to online health information, parents with low health literacy were more likely to use the internet less frequently than daily ( P < .01). Surveys and interviews (n = 30) revealed that health information will be most effective when distributed by a health care professional and must be made available in multiple modalities. Parents requested general information about childhood illness, including diagnosis, treatment, and signs and symptoms. Many parents believed that appropriate health information would change their decision-making regarding seeking care during their child's next illness. PMID- 28901158 TI - Hypertrophic obstructive cardiomyopathy: review of surgical treatment. AB - Hypertrophic cardiomyopathy ranks among the most common congenital cardiac diseases, affecting up to 1 in 200 of the general population. When it causes left ventricular outflow tract obstruction, treatment is guided to reduce symptoms and the risk of sudden cardiac death. Pharmacologic therapy is the first-line treatment, but when it fails, surgical myectomy or percutaneous ablation of the hypertrophic myocardium are the standard therapies to eliminate subaortic obstruction. Both surgical myectomy and percutaneous ablation are proven safe and effective treatments; however, myectomy is the gold standard with a significantly lower complication rate and more complete and lasting reduction of left ventricular outflow tract obstruction. PMID- 28901160 TI - Development of a plug and play ImmunoPCR technique for the analysis of biomolecules. AB - AIM: ImmunoPCR technology combines the advantages of specificity and robustness of a ligand binding assay with the amplification potential of PCR. We describe through three case studies a plug-and-play immuno polymerase chain reaction (iPCR) technique to measure biomolecules. RESULTS: Case Study 1 demonstrated feasibility of measurement of IgG1 in cerebrospinal fluid at the desired level of sensitivity with minimal cost and timelines of clinical assay implementation. Case Study 2 translated the iPCR protocol to measure multiple IgG1 analytes in cerebrospinal fluid. Case Study 3 demonstrated broad applicability of the technique to yet another analyte IL-6. CONCLUSION: The advantages of our iPCR approach were: lack of reliance on a single vendor for technology platform/software, minimal reliance on proprietary reagents and reduced method development times and cost. PMID- 28901161 TI - Polyphenolic compounds from Malus hupehensis and their free radical scavenging effects. AB - One new 4-chromanone glycoside, 5-O-beta-d-glucopyranoside-4-chromanone (1), together with 21 known polyphenols, was isolated from the leaves of Malus hupehensis. Their structures were elucidated on the basis of extensive spectroscopic methods including NMR (1D and 2D), mass (ESIMS and HRESIMS), IR, and by comparison with the data reported in the literature. Some of the isolated compounds were screened for antioxidant activity. Compounds 18 and 14 exhibited significant antioxidant activities with SC50 values 2.73 and 2.91 MUg/mL, respectively, while 17, 19, 11, 7, 20, 22, 12 and 13 exhibited moderate activities with SC50 values ranging from 5.24-11.86 MUg/mL. The HPLC fingerprint profiles of the leaves and fruits extracts were also analysed, which showed that the constituents were almost the same in both the extracts except for the content of phlorizin which was present in higher amount in the leaves. PMID- 28901162 TI - Imagining Autism: Feasibility of a drama-based intervention on the social, communicative and imaginative behaviour of children with autism. AB - We report the feasibility of a novel, school-based intervention, coined 'Imagining Autism', in which children with autism engage with drama practitioners though participatory play and improvisation in a themed multi-sensory 'pod' resembling a portable, tent-like structure. A total of 22 children, aged 7-12 years, from three UK schools engaged in the 10-week programme. Measures of social interaction, communication and emotion recognition, along with parent and teacher ratings, were collected before and up to 12 months after the intervention. Feasibility was evaluated through four domains: (1) process (recruitment, retention, blinding, inter-rater reliability, willingness of children to engage), (2) resources (space, logistics), (3) management (dealing with unexpected changes, ease of assessment) and (4) scientific (data outcomes, statistical analyses). Overall, the children, parents and teachers showed high satisfaction with the intervention, the amount of missing data was relatively low, key assessments were implemented as planned and evidence of potential effect was demonstrated on several key outcome measures. Some difficulties were encountered with recruitment, test administration, parental response and the logistics of setting up the pod. Following several protocol revisions and the inclusion of a control group, future investigation would be justified to more thoroughly examine treatment effects. PMID- 28901163 TI - Distribution of autistic traits and their association with sociodemographic characteristics in Japanese workers. AB - This study aimed to confirm whether autistic traits are normally distributed across a population and to describe their association with the sociodemographic characteristics of Japanese workers. The participants were 2075 workers aged 23 65 years from various parts of Japan. Autistic traits were measured using an abridged Japanese version of the Autism-Spectrum Quotient (AQ-Short). The AQ Short comprises five subcomponents assessing a fascination for numbers and patterns (numbers/patterns), difficulties with imagination, a preference for routine, difficulties with social skills, and difficulties with switching attention. The five subcomponents of the autistic phenotype as well as the overall autistic phenotype itself were continuously distributed across the sample population of Japanese workers. Men had significantly higher AQ-Short scores than women. AQ-Short scores were not associated with age. Except for the numbers/patterns scores, workers of a lower socioeconomic status had significantly higher AQ-Short scores than their respective counterparts. For the numbers/patterns trait, workers of a higher socioeconomic status scored higher. Workers with low general physical activity had or tended to have higher scores for total and all subcomponent traits, except for the numbers/patterns trait. Generally, the autistic phenotype was more prevalent in workers of a low socioeconomic status, while a particular trait was prevalent among workers of a high socioeconomic status. PMID- 28901164 TI - Falls in people with multiple sclerosis: experiences of 115 fall situations. AB - OBJECTIVES: The aim was to describe falls and the perceived causes, experienced by people with multiple sclerosis shortly after falling. DESIGN: A qualitative study using content analysis and quantitative data to illustrate where and why people report falls most commonly. Semi-structured telephone interviews were performed. Interviews were conducted shortly (0-10 days) after a fall. SUBJECTS: In all, 67 informants who had reported at least one fall during the previous three-month period and who used a walking aid participated. RESULTS: A total of 57 (85%) informants fell at least once during eight months resulting in 115 falls; 90 (78%) falls happened indoors, most commonly in the kitchen ( n = 20; 17%) or bathroom ( n = 16; 14%). Informants fell during everyday activities and walking aids had been used in more than a third of the reported falls. The falls were influenced of both intrinsic and extrinsic factors. Two categories emerged from the analysis: 'activities when falling' and 'influencing factors'. The category contained three (basic activities of daily living, instrumental activities of daily living and leisure and work) and six (multiple sclerosis related symptoms, fluctuating body symptoms, being distracted, losing body control, challenging surrounding and involvement of walking aid) subcategories, respectively. CONCLUSION: The majority of falls occurs indoors and in daily activities. Several factors interacted in fall situations and should be monitored and considered to reduce the gap between the person's capacity and the environmental demands that cause fall risk. Fluctuation of bodily symptoms between and within a day is a variable not earlier targeted in multiple sclerosis fall risk research. PMID- 28901165 TI - LC-MS/MS analysis of lipidized analogs of prolactin-releasing peptide utilizing a monolithic column and simple sample preparation. AB - AIM: Novel compounds for obesity treatment are currently being studied employing lipidized analogs of anorexigenic neuropeptides. Various analogs of prolactin releasing peptide have demonstrated their ability to decrease food intake. Adequate analytical tools are required to support corresponding research. Methodology & results: An analytical method was developed that includes simple dilution of plasma samples prior to liquid chromatography-mass spectrometry and employs a monolithic column for the determination of lipidized analogs of prolactin-releasing peptide in complex biological samples. A multiple reaction monitoring approach was applied that included matrix calibration and an internal standard and produced a linear calibration range 20-200 ng ml-1 in rat and macaque plasma samples. CONCLUSION: A straightforward, simple and reliable analytical method was developed satisfying major validation criteria. PMID- 28901166 TI - The in vitro and in vivo anti-inflammatory activities of alphitonin-4-O-beta-D glucopyranoside. AB - The anti-inflammatory compound, alphitonin-4-O-beta-D-glucopyranoside (1), has previously been isolated in the leaves of Artokapus tonkinensis and synthesised from taxifolin. This study aimed to investigate the inhibitory effect of this compound on inflammatory cytokines, including tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1, IL-6 and IL-10, in RAW264.7 macrophages and in an arthritis animal model. Compound 1 dose-dependently decreased the production of TNF-alpha, IL-1 and IL-6 in lipopolysaccharide-stimulated RAW264.7 cells. In contrast, the level of anti-inflammatory IL-10 increased. In a collagen antibody induced arthritis BALB/c mouse model, compound 1 at a dose of 125 and 250 mg/kg body weight significantly decreased arthritis incidence in comparison with dexamethasone. PMID- 28901167 TI - Effect of Ischemic Postconditioning on Myocardial Function and Infarct Size Following Reperfusion Injury in Diabetic Rats Pretreated With Vildagliptin. AB - BACKGROUND: Cardioprotective actions of ischemic postconditioning (IPostC) against ischemia/reperfusion (I/R) injury are abolished in diabetic hearts. This study has investigated the combined effects of IPostC and vildagliptin (Vilda) on myocardial function and infarct size (IS) against I/R injury in diabetic myocardium. METHODS: Diabetes was induced by a high-fat diet/low dose of streptozotocin (35 mg/kg; intraperitoneally) in Wistar rats (200-250 g) and lasted for 12 weeks. Vilda (6 mg/kg/d) was orally administered for 5 weeks in diabetic groups after seventh week of diabetes. At the end of the 12-week period, the hearts of rats were removed and subjected to 35-minute regional ischemia (through left anterior descending ligation) followed by 60-minute reperfusion, on Langendorff apparatus. Ischemic postconditioning was induced by 6 repetitive cycles of 10-second ischemia and 10-second reperfusion, immediately at the onset of the reperfusion. Myocardial hemodynamic was measured throughout the experiment. The IS was assessed by triphenyltetrazolium chloride staining method. The myocardial contents of troponin-I (cTnI), interleukin-6 (IL-6), and 8 isoprostane were measured in the homogenate from ischemic zone of left ventricles by enzyme-linked immunosorbent assay kit. RESULTS: Pretreatment of the diabetic rats with Vilda significantly recovered the diabetes-induced reduction in left ventricular developed pressures and contractility at the baseline ( P < .05 to P < .01). After I/R injury, IPostC could not significantly improve the myocardial function, cTnI content, and IS of the diabetic hearts. However, in Vilda-treated hearts, concomitant application of IPostC significantly recovered the heart functions, returned cTnI content as well as myocardial IL-6 and 8-isoprostane levels back to the control values ( P < .01 to P < .001), and reduced IS more effectively (by 45%) in comparison to the diabetic group ( P < .001). CONCLUSION: Besides its glycemic and lipid profile controlling effects, Vilda has a protective effect on heart function and tends to restore cardioprotective effects of IPostC on diabetic hearts. PMID- 28901168 TI - Comparative study on microsampling techniques in metabolic fingerprinting studies applying gas chromatography-MS analysis. AB - AIM: Sample collection and preparation are important steps in the metabolomics workflow. Any improvement should be aimed toward making them simpler, faster and more reproducible. This paper describes the evaluation of different types of whole blood microsampling techniques applied in a metabolic fingerprinting study of breast cancer patients. RESULTS: A total of 139, 124 and 128 metabolites were identified in protein precipitation, dried matrix on paper discs and Mitra(r) volumetric absorptive microsampling, respectively in 80% of the sample sets, where the quality control samples had a relative standard deviation of <30%. Ten metabolites in breast cancer samples were detected as being altered significantly (p < 0.05). CONCLUSION: Our results suggest that whole blood microsampling techniques do not obtain statistically different results in comparison with the metabolomics applied standard reference method of protein precipitation, in terms of the number of detected compounds, the reproducibility and modeling of differences between the groups. PMID- 28901169 TI - Predictors of response to occipital nerve stimulation in refractory chronic headache. AB - Background Occipital nerve stimulation is a promising treatment for refractory chronic headache disorders, but is invasive and costly. Identifying predictors of response would be useful in selecting patients. We present the results of an open label prospective cohort study of 100 patients (35 chronic migraine, 33 chronic cluster headache, 20 short-lasting unilateral neuralgiform headache attacks and 12 hemicrania continua) undergoing occipital nerve stimulation, using a multivariate binary regression analysis to identify predictors of response. Results Response rate of the cohort was 48%. Multivariate analysis showed short lasting unilateral neuralgiform headache attacks (OR 6.71; 95% CI 1.49-30.05; p = 0.013) and prior response to greater occipital nerve block (OR 4.22; 95% CI 1.35 13.21; p = 0.013) were associated with increased likelihood of response. Presence of occipital pain (OR 0.27; 95% CI 0.09-0.76; p = 0.014) and the presence of severe anxiety and/or depression (as measured on hospital anxiety and depression score) at time of implantation (OR 0.32; 95% CI 0.11-0.91; p = 0.032) were associated with reduced likelihood of response. Conclusion Possible clinical predictors of response to occipital nerve stimulation for refractory chronic headaches have been identified. Our data shows that those with short-lasting unilateral neuralgiform headache attacks respond better than those with chronic migraine, and that a prior response to greater occipital nerve block is associated with positive outcomes. This study suggests that the presence of occipital pain and severe mood disorder at time of implant are both associated with poor outcomes to occipital nerve stimulation. PMID- 28901170 TI - Hypogymnia tubulosa extracts: chemical profile and biological activities. AB - This study reports for the first time in the chemical composition of acetone, ether, ethyl acetate and dichloromethane extracts of Hypogymnia tubulosa determined by HPLC-UV, GC-FID and GC-MS as well as effect of H. tubulosa acetone extract on micronucleus distribution on human lymphocytes and on cholinesterase activity. Additionally, antioxidant (estimated via DPPH, ABTS, TRP, CUPRAC and TPC assays) and antibacterial activity against two Gram-positive and three Gram negative bacteria were also determined. The HPLC-UV analysis revealed the presence of depsidones, 3-hydroxyphysodic, 4-O-methyl physodic acid, physodic and physodalic acid together with two depsides, atranorin and chloroatranorin. GC-FID and GC-MS analyses enabled the identification of atranol, chloroatranol, atraric acid, olivetol, olivetonide and 3-hydroxyolivetonide as the main components. The results of present study show that H. tubulosa acetone extract is a promising candidate for in vivo experiments considering antioxidant activity. PMID- 28901171 TI - Recent China Food and Drug Administration reform: impact on the present and future of bioanalytical contract research organization laboratories in China. PMID- 28901172 TI - Traditional manual acupuncture combined with rehabilitation therapy for shoulder hand syndrome after stroke within the Chinese healthcare system: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the effectiveness of traditional manual acupuncture combined with rehabilitation therapy versus rehabilitation therapy alone for shoulder hand syndrome after stroke. DATA SOURCES: PubMed, EMBASE, the Cochrane Library, Chinese Biomedicine Database, China National Knowledge Infrastructure, VIP Information Database, Wan Fang Database and reference lists of the eligible studies were searched up to July 2017 for relevant studies. METHODS: Randomized controlled trials that compared the combined effects of traditional manual acupuncture and rehabilitation therapy to rehabilitation therapy alone for shoulder hand syndrome after stroke were included. Two reviewers independently screened the searched records, extracted the data and assessed risk of bias of the included studies. The treatment effect sizes were pooled in a meta-analysis using RevMan 5.3 software. RESULTS: A total of 20 studies involving 1918 participants were included in this study. Compared to rehabilitation therapy alone, the combined therapy significantly reduced pain on the visual analogue scale and improved limb movement on the Fugl-Meyer Assessment scale and the performance of activities of daily living (ADL) on the Barthel Index scale or Modified Barthel Index scale. Of these, the visual analogue scale score changes were significantly higher (mean difference = 1.49, 95% confidence interval = 1.15 1.82, P < 0.00001) favoring the combined therapy after treatment, with severe heterogeneity ( I2 = 71%, P = 0.0005). CONCLUSION: Current evidence suggests that traditional manual acupuncture integrated with rehabilitation therapy is more effective in alleviating pain, improving limb movement and ADL. However, considering the relatively low quality of available evidence, further rigorously designed and large-scale randomized controlled trials are needed to confirm the results. PMID- 28901174 TI - Do we have a mature LC-MS/MS methodology for therapeutic monoclonal antibody bioanalysis? PMID- 28901173 TI - Cyclin D2 is a critical mediator of exercise-induced cardiac hypertrophy. AB - A number of signaling pathways underlying pathological cardiac hypertrophy have been identified. However, few studies have probed the functional significance of these signaling pathways in the context of exercise or physiological pathways. Exercise studies were performed on females from six different genetic mouse models that have been shown to exhibit alterations in pathological cardiac adaptation and hypertrophy. These include mice expressing constitutively active glycogen synthase kinase-3beta (GSK-3betaS9A), an inhibitor of CaMK II (AC3-I), both GSK-3betaS9A and AC3-I (GSK-3betaS9A/AC3-I), constitutively active Akt (myrAkt), mice deficient in MAPK/ERK kinase kinase-1 (MEKK1-/-), and mice deficient in cyclin D2 (cyclin D2-/-). Voluntary wheel running performance was similar to NTG littermates for five of the mouse lines. Exercise induced significant cardiac growth in all mouse models except the cyclin D2-/- mice. Cardiac function was not impacted in the cyclin D2-/- mice and studies using a phospho-antibody array identified six proteins with increased phosphorylation (greater than 150%) and nine proteins with decreased phosphorylation (greater than 33% decrease) in the hearts of exercised cyclin D2-/- mice compared to exercised NTG littermate controls. Our results demonstrate that unlike the other hypertrophic signaling molecules tested here, cyclin D2 is an important regulator of both pathologic and physiological hypertrophy. Impact statement This research is relevant as the hypertrophic signaling pathways tested here have only been characterized for their role in pathological hypertrophy, and not in the context of exercise or physiological hypertrophy. By using the same transgenic mouse lines utilized in previous studies, our findings provide a novel and important understanding for the role of these signaling pathways in physiological hypertrophy. We found that alterations in the signaling pathways tested here had no impact on exercise performance. Exercise induced cardiac growth in all of the transgenic mice except for the mice deficient in cyclin D2. In the cyclin D2 null mice, cardiac function was not impacted even though the hypertrophic response was blunted and a number of signaling pathways are differentially regulated by exercise. These data provide the field with an understanding that cyclin D2 is a key mediator of physiological hypertrophy. PMID- 28901175 TI - Membrane-based distillation ion chromatography: a new method for bioanalysis. PMID- 28901176 TI - An Evaluation of the Effectiveness of the National Aeronautics and Space Administration Mission-X Child Health Promotion Program in the United States. AB - PURPOSE: To examine the effects of the National Aeronautics and Space Administration Mission-X: Train Like an Astronaut program (MX) on children's health-related knowledge and behaviors of a sample of US participants. DESIGN: A nonexperimental pilot intervention study in 5 cities with a pre-post comparison of children's health-related knowledge and behaviors in the United States in 2014 and 2015. SAMPLE: Children (n = 409) with a mean age (standard deviation) of 10.1 (1.7) years. MEASURES: Children answered pre- and postintervention questionnaires. We measured the differences in children's health knowledge on nutrition and physical fitness and behaviors on diet and physical activity as scores. INTERVENTION: A 6-week web- and school-based intervention for a healthier lifestyle by introducing physical fitness and science activities based on actual astronaut training under a teacher's supervision. ANALYSIS: Nonparametric analysis and logistic regression models. RESULTS: Participants significantly improved both of their health behaviors on physical activity ( P < .001) and diet ( P = .06) and their health knowledge regarding nutrition ( P < .001) and physical fitness ( P < .001) after the intervention. The improvement in children's behaviors ( P < .001), knowledge ( P < .001), and the total score ( P < .001) after intervention did not significantly vary by sex or age, after adjusting for year of participation and state of residency. DISCUSSION: The MX seems effective in improving health behaviors and health knowledge of participating children, which may serve as a model for sustainable global child health promotion program. Further research is needed to test its long-term effects on child health. PMID- 28901177 TI - Evaluation of an FcRn affinity chromatographic method for IgG1-type antibodies and evaluation of IgG variants. AB - AIM: The neonatal Fc-receptor (FcRn) mediates long serum half-life of therapeutic IgG-type antibodies. This interaction represents a critical quality attribute in terms of pharmacokinetics and should be covered by respective quality control strategies. Antibodies are taken up by cells unspecifically and can bind to FcRn in early endosomes preventing lysosomal degradation and allowing release back into circulation. Reflecting this complex cycle in an in vitro assay strategy represents a challenging task. METHODOLOGY: We report the qualification of an FcRn affinity chromatographic method and, for the first time, establish a noncriticality window. We analyzed different IgG-type antibodies, subtypes, glycoforms as well as mutants. CONCLUSION: The FcRn affinity chromatographic method allows the assessment of mAb samples with respect to their pH-dependent FcRn interaction. Furthermore, the method's capabilities and current limitations are discussed. PMID- 28901178 TI - Hitting two birds with one stone: An afterword on archeology and the history of science. AB - This afterword comments on the articles gathered together in this special section of History of Science ("Disassembling Archaeology, Reassembling the Modern World"). Criticizing the consistent lack of institutional infrastructure for histories of archaeology in the history of science, the piece argues that scholars should recognize the commonality of archaeology's practices with those of the nineteenth and twentieth century field sciences that have received more historical attention. The piece also suggests avenues to help take this approach further, such as combining expertise from historians of the biological sciences and of antiquarianism and archaeology to look at the history of the understanding of human variation and race. Finally, the afterword suggests that scholars should reconsider the idea of archaeology's reliance on institutionalised practices, thinking about the use and re-use of material culture in more diverse and pragmatic social contexts. PMID- 28901179 TI - Visualizing a monumental past: Archeology, Nasser's Egypt, and the early Cold War. AB - This article examines geographies of decolonization and the Cold War through a case study in the making of archeological knowledge. The article focuses on an archeological dig that took place in Egypt in the period between the July 1952 Free Officers' coup and the 1956 Suez crisis. Making use of the notion of the 'boundary object', this article demonstrates how the excavation of ancient Egyptian remains at the site of Mit Rahina helped to constitute Nasserist revolutionary modernity and its relationship to wider, post-Second World War political geographies. The dig took place as a result of an Egyptian-American collaboration designed to institute the possibility of archeology taking place along the lines of the Point Four modernization program promoted by the United States. The article discusses how this situation not only engendered contention surrounding the role of the international 'experts' appointed to run this excavation work, but also - and as a result - helped to constitute the monumental visual and material shape that archeological evidence relating to the Egyptian past could now take. Egypt's revolution sat within wider Cold War political struggles, yet the 'ground-up' realities of this relationship helped to constitute the sort of past (and future) monumentality proposed by Nasser's government. PMID- 28901180 TI - Connecting sites and images: Archeology as controversial knowledge in modern Izmir. AB - In Turkey, the period after the establishment of the Republic saw archeological representations play an active role in defining the ancient past and producing new disciplinary knowledge. Visual practices emerged as important sites for the formation of a new conception of the ancient past in the larger context of the political and cultural discourse over the modernization of the country. Based on museum guidebooks, official publications, and archival documents, this paper focuses on the Izmir region after the establishment of the Turkish Republic in 1923 and explores how the ancient past was perceived and displayed in relation to the historical and cultural transformations that occurred in Turkey after the Greco-Turkish War. PMID- 28901181 TI - Disassembling archeology, reassembling the modern world. AB - This article provides a substantive discussion of the relevance of the history of archeology to the history of science. At the same time, the article introduces the papers contained in this special issue as exemplars of this relevance. To make its case, the article moves through various themes in the history of archeology that overlap with key issues in the history of science. The article discusses the role and tension of regimes of science in antiquarian and archeological practices, and also considers issues of scale and place, particularly in relation to the field. Additionally, the piece attends to issues of professionalization and the constitution of an archeological public, at the same time as discussing issues of empire, colonialism, and the circulation of knowledge. Meanwhile, enriching discussions within and beyond the history of science, the article discusses the history of archeology and its relationship with museums, collecting, and material culture and materiality. Finally, the piece discusses the relationship of the history of archeology with wider discussions about scientific ethics. In conclusion, the article questions whether we should speak of 'the history of archeology' at all. PMID- 28901182 TI - Effects of Bone-Marrow-Derived MSC Transplantation on Functional Recovery in a Rat Model of Spinal Cord Injury: Comparisons of Transplant Locations and Cell Concentrations. AB - Spinal cord injury (SCI) is a widely disabling condition, constraining those affected by it to wheelchairs and requiring intense daily care and assistance. Cell replacement therapies, targeting regeneration of cells in the injured cord, are currently gaining momentum in the field of SCI research. Previous studies indicate that mesenchymal stem cells (MSCs) can reduce functional deficits through immunomodulation and production of trophic factors in a variety of neurological disorders. The present study assessed the efficacy of transplanted bone marrow-derived MSCs at different concentrations and locations for promoting functional recovery following SCI. Although effects were modest, MSCs facilitated an increase in the base of support, as measured by increased distance between the plantar surface of the hind paws, following incomplete contusive SCI, and reduced the density of astroglial scarring. Varying the concentrations or locations of transplanted cells did not provide additional benefits on these measures. These findings indicate that MSC transplants are safe at relatively high concentrations and confer therapeutic benefits that, when used as an adjunctive treatment, could significantly enhance functional recovery following SCI. PMID- 28901184 TI - Ex vivo Pretreatment of Islets with Mitomycin C: Reduction in Immunogenic Potential of Islets by Suppressing Secretion of Multiple Chemotactic Factors. AB - Strategies to reduce the immunogenicity of pancreatic islets and to prevent the activation of proinflammatory events are essential for successful islet engraftment. Pretransplant islet culture presents an opportunity for preconditioning to improve outcomes of islet transplantation. We previously demonstrated that ex vivo mitomycin C (MMC) pretreatment and subsequent culture significantly prolonged graft survival. Fully understanding the biological process of pretreatment could result in the development of a protocol to improve the survival of islet grafts. Microarrays were employed to conduct a comprehensive analysis of genes expressed in untreated or MMC-treated rat islets that were subsequently cultured for 3 d. A bioinformatics software was used to identify biological processes that were most affected by MMC pretreatment, and validation studies, including in vivo and in vitro assay, were performed. The gene expression analysis identified significant downregulation of annotated functions associated with cellular movement and revealed significant downregulation of multiple genes encoding proinflammatory mediators with chemotactic activity. Validation studies revealed significantly decreased levels of interleukin 6 (IL-6), monocyte chemoattractant protein 3 (MCP-3), and matrix metallopeptidase 2 (MMP2) in culture supernatants of MMC-treated islets compared with controls. Moreover, we showed the suppression of leukocyte chemotactic activity of MMC-treated islets in vitro. We also showed that MMC-treated islets secreted lower levels of chemoattractants that synergistically reduced the immunogenic potential of islets. Histological and immunohistochemical analyses of the implant site revealed that infiltration of monocytes, CD3-positive T cells, and B cells was decreased in MMC-treated islets. In conclusion, the ex vivo pretreatment of islets with MMC and subsequent culture can reduce the immunogenic potential and prolong the survival of islet grafts by inducing the suppression of multiple leukocyte chemotactic factors. PMID- 28901183 TI - PPAR-delta Agonist With Mesenchymal Stem Cells Induces Type II Collagen-Producing Chondrocytes in Human Arthritic Synovial Fluid. AB - Osteoarthritis (OA) is an inflammatory joint disease characterized by degeneration of articular cartilage within synovial joints. An estimated 27 million Americans suffer from OA, and the population is expected to reach 67 million in the United States by 2030. Thus, it is urgent to find an effective treatment for OA. Traditional OA treatments have no disease-modifying effect, while regenerative OA therapies such as autologous chondrocyte implantation show some promise. Nonetheless, current regenerative therapies do not overcome synovial inflammation that suppresses the differentiation of mesenchymal stem cells (MSCs) to chondrocytes and the expression of type II collagen, the major constituent of functional cartilage. We discovered a synergistic combination that overcame synovial inflammation to form type II collagen-producing chondrocytes. The combination consists of peroxisome proliferator-activated receptor (PPAR) delta agonist, human bone marrow (hBM)-derived MSCs, and hyaluronic acid (HA) gel. Interestingly, those individual components showed their own strong enhancing effects on chondrogenesis. GW0742, a PPAR-delta agonist, greatly enhanced MSC chondrogenesis and the expression of type II collagen and glycosaminoglycan (GAG) in hBM-MSC-derived chondrocytes. GW0742 also increased the expression of transforming growth factor beta that enhances chondrogenesis and suppresses cartilage fibrillation, ossification, and inflammation. HA gel also increased MSC chondrogenesis and GAG production. However, neither GW0742 nor HA gel could enhance the formation of type II collagen-producing chondrocytes from hBM-MSCs within human OA synovial fluid. Our data demonstrated that the combination of hBM MSCs, PPAR-delta agonist, and HA gel significantly enhanced the formation of type II collagen-producing chondrocytes within OA synovial fluid from 3 different donors. In other words, the novel combination of PPAR-delta agonist, hBM-MSCs, and HA gel can overcome synovial inflammation to form type II collagen cartilage within human OA synovial fluid. This novel articularly injectable formula could improve OA treatment in the future clinical application. PMID- 28901185 TI - Evaluation of Parametric Response Mapping to Assess Therapeutic Response to Human Mesenchymal Stem Cells after Experimental Stroke. AB - Stroke is the leading cause of disability in adults. After the very narrow time frame during which treatment by thrombolysis and mechanical thrombectomy is possible, cell therapy has huge potential for enhancing stroke recovery. Accurate analysis of the response to new therapy using imaging biomarkers is needed to assess therapeutic efficacy. The aim of this study was to compare 2 analysis techniques: the parametric response map (PRM), a voxel-based technique, and the standard whole-lesion approach. These 2 analyses were performed on data collected at 4 time points in a transient middle cerebral artery occlusion (MCAo) model, which was treated with human mesenchymal stem cells (hMSCs). The apparent diffusion coefficient (ADC), cerebral blood volume (CBV), and vessel size index (VSI) were mapped using magnetic resonance imaging (MRI). Two groups of rats received an intravenous injection of either 1 mL phosphate-buffered saline (PBS) glutamine (MCAo-PBS, n = 10) or 3 million hMSCs (MCAo-hMSC, n = 10). One sham group was given PBS-glutamine (sham, n = 12). Each MRI parameter was analyzed by both the PRM and the whole-lesion approach. At day 9, 1 d after grafting, PRM revealed that hMSCs had reduced the fraction of decreased ADC (PRMADC-: MCAo-PBS 6.7% +/- 1.7% vs. MCAo-hMSC 3.3% +/- 2.4%), abolished the fraction of increased CBV (PRMCBV+: MCAo-PBS 16.1% +/- 3.7% vs. MCAo-hMSC 6.4% +/- 2.6%), and delayed the fraction of increased VSI (PRMVSI+: MCAo-PBS 17.5% +/- 6.3% vs. MCAo-hMSC 5.4% +/- 2.6%). The whole-lesion approach was, however, insensitive to these early modifications. PRM thus appears to be a promising technique for the detection of early brain changes following treatments such as cell therapy. PMID- 28901186 TI - Recipient Adipose-Derived Stem Cells Enhance Recipient Cell Engraftment and Prolong Allotransplant Survival in a Miniature Swine Hind-Limb Model. AB - Donor mesenchymal stem cells (MSCs) could prolong vascularized composite allotransplantation (VCA) survival in our previous studies. However, recipient adipose tissue is easier to harvest than donor tissue for preconditioning modulation. Hence, this study investigated the efficacy of recipient autologous adipose-derived stem cells (rADSCs) for VCA survival. The heterotopic hind-limb transplantation from female donor to male recipient was performed in outbred miniature swine. Group I ( n = 6) was untreated controls. Group II ( n = 4) obtained rADSCs infusions (given on weeks 0, +1, +2, and +3). Group III ( n = 4) obtained tacrolimus (FK506, weeks 0 to +4). Group IV ( n = 8) received irradiation (IR; day -1), FK506 (weeks 0 to +4), and rADSC infusions (weeks 0, +1, +2, and +3). The results revealed treatment with multiple injections of rADSCs along with IR and FK506 resulted in a statistically significant increase in allograft survival. The percentage of CD4+/CD25+/Foxp3+ regulatory T cells were significantly increased in the rADSC-IR-FK506 group as compared to controls. Analysis of recipient peripheral blood revealed that transforming growth factor beta1 (TGFbeta1) was significantly increased in the rADSC-IR-FK506 group. The polymerase chain reaction (PCR) analysis and immunohistochemical staining showed recipient sex-determining region of Y (SRY) chromosome gene expression existed in donor allotissues in the rADSC-IR-FK506 group. These results indicate that rADSCs in addition to IR and transient immunosuppressant could prolong allotransplant survival, modulate T-cell regulation, and enhance recipient cell engraftment into the allotransplant tissues. PMID- 28901187 TI - Peptide-Modified Chitosan Hydrogels Accelerate Skin Wound Healing by Promoting Fibroblast Proliferation, Migration, and Secretion. AB - Skin wound healing is a complicated process that involves a variety of cells and cytokines. Fibroblasts play an important role in this process and participate in transformation into myofibroblasts, the synthesis of extracellular matrix (ECM) and fibers, and the secretion of a variety of growth factors. This study assessed the effects of peptide Ser-Ile-Lys-Val-Ala-Val (SIKVAV)--modified chitosan hydrogels on skin wound healing. We investigated the capability of peptide SIKVAV to promote cell proliferation and migration, the synthesis of collagen, and the secretion of a variety of growth factors using fibroblasts in vitro. We also treated skin wounds established in mice using peptide SIKVAV-modified chitosan hydrogels. Hematoxylin and eosin staining showed that peptide-modified chitosan hydrogels enhanced the reepithelialization of wounds compared with negative and positive controls. Masson's trichrome staining demonstrated that more collagen fibers were deposited in the wounds treated with peptide-modified chitosan hydrogels compared with the negative and positive controls. Immunohistochemistry revealed that the peptide-modified chitosan hydrogels promoted angiogenesis in the skin wound. Taken together, these results suggest that peptide SIKVAV modified chitosan hydrogels may be useful in wound dressing and the treatment of skin wounds. PMID- 28901188 TI - Engineered Microvasculature in PDMS Networks Using Endothelial Cells Derived from Human Induced Pluripotent Stem Cells. AB - In this study, we used a polydimethylsiloxane (PDMS)-based platform for the generation of intact, perfusion-competent microvascular networks in vitro. COMSOL Multiphysics, a finite-element analysis and simulation software package, was used to obtain simulated velocity, pressure, and shear stress profiles. Transgene-free human induced pluripotent stem cells (hiPSCs) were differentiated into partially arterialized endothelial cells (hiPSC-ECs) in 5 d under completely chemically defined conditions, using the small molecule glycogen synthase kinase 3beta inhibitor CHIR99021 and were thoroughly characterized for functionality and arterial-like marker expression. These cells, along with primary human umbilical vein endothelial cells (HUVECs), were seeded in the PDMS system to generate microvascular networks that were subjected to shear stress. Engineered microvessels had patent lumens and expressed VE-cadherin along their periphery. Shear stress caused by flowing medium increased the secretion of nitric oxide and caused endothelial cells s to align and to redistribute actin filaments parallel to the direction of the laminar flow. Shear stress also caused significant increases in gene expression for arterial markers Notch1 and EphrinB2 as well as antithrombotic markers Kruppel-like factor 2 (KLF-2)/4. These changes in response to shear stress in the microvascular platform were observed in hiPSC-EC microvessels but not in microvessels that were derived from HUVECs, which indicated that hiPSC-ECs may be more plastic in modulating their phenotype under flow than are HUVECs. Taken together, we demonstrate the feasibly of generating intact, engineered microvessels in vitro, which replicate some of the key biological features of native microvessels. PMID- 28901189 TI - Cryopreservation of Hepatocyte Microbeads for Clinical Transplantation. AB - Intraperitoneal transplantation of hepatocyte microbeads is an attractive option for the management of acute liver failure. Encapsulation of hepatocytes in alginate microbeads supports their function and prevents immune attack of the cells. Establishment of banked cryopreserved hepatocyte microbeads is important for emergency use. The aim of this study was to develop an optimized protocol for cryopreservation of hepatocyte microbeads for clinical transplantation using modified freezing solutions. Four freezing solutions with potential for clinical application were investigated. Human and rat hepatocytes cryopreserved with University of Wisconsin (UW)/10% dimethyl sulfoxide (DMSO)/5% (300 mM) glucose and CryoStor CS10 showed better postthawing cell viability, attachment, and hepatocyte functions than with histidine-tryptophan-ketoglutarate/10% DMSO/5% glucose and Bambanker. The 2 freezing solutions that gave better results were studied with human and rat hepatocytes microbeads. Similar effects on cryopreserved microbead morphology (external and ultrastructural), viability, and hepatocyte-functions post thawing were observed over 7 d in culture. UW/DMSO/glucose, as a basal freezing medium, was used to investigate the additional effects of cytoprotectants: a pan-caspase inhibitor (benzyloxycarbonyl Val-Ala-dl-Asp-fluoromethylketone [ZVAD]), an antioxidant (desferoxamine [DFO]), and a buffering and mechanical protectant (human serum albumin [HSA]) on RMBs. ZVAD (60 uM) had a beneficial effect on cell viability that was greater than with DFO (1 mM), HSA (2%), and basal freezing medium alone. Improvements in the ultrastructure of encapsulated hepatocytes and a lower degree of cell apoptosis were observed with all 3 cytoprotectants, with ZVAD tending to provide the greatest effect. Cytochrome P450 activity was significantly higher in the 3 cytoprotectant groups than with fresh microbeads. In conclusion, developing an optimized cryopreservation protocol by adding cytoprotectants such as ZVAD could improve the outcome of cryopreserved hepatocyte microbeads for future clinical use. PMID- 28901190 TI - Transcriptome Analysis of Induced Pluripotent Stem Cell (iPSC)-derived Pancreatic beta-like Cell Differentiation. AB - Diabetes affects millions of people worldwide, and beta-cell replacement is one of the promising new strategies for treatment. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type, including pancreatic beta cells, providing a potential treatment for diabetes. However, the molecular mechanisms underlying the differentiation of iPSC-derived beta cells have not yet been fully elucidated. Here, we generated pancreatic beta-like cells from mouse iPSCs using a 3-step protocol and performed deep RNA sequencing to get a transcriptional landscape of iPSC-derived pancreatic beta-like cells during the selective differentiation period. We then focused on the differentially expressed genes (DEGs) during the time course of the differentiation period, and these genes underwent Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, gene-act networks were constructed for these DEGs, and the expression of pivotal genes detected by quantitative real-time polymerase chain reaction was well correlated with RNA sequence (RNA-seq). Overall, our study provides valuable information regarding the transcriptome changes in beta cells derived from iPSCs during differentiation, elucidates the biological process and pathways underlying beta-cell differentiation, and promotes the identification and functional analysis of potential genes that could be used for improving functional beta-cell generation from iPSCs. PMID- 28901191 TI - Hypoxic Culture Promotes Dopaminergic-Neuronal Differentiation of Nasal Olfactory Mucosa Mesenchymal Stem Cells via Upregulation of Hypoxia-Inducible Factor 1alpha. AB - Olfactory mucosa mesenchymal stem cells (OM-MSCs) display significant clonogenic activity and may be easily propagated for Parkinson's disease therapies. Methods of inducing OM-MSCs to differentiate into dopaminergic (DAergic) neurons using olfactory ensheathing cells (OECs) are thus an attractive topic of research. We designed a hypoxic induction protocol to generate DAergic neurons from OM-MSCs using a physiological oxygen (O2) level of 3% and OEC-conditioned medium (OCM; HI group). The normal induction (NI) group was cultured in O2 at ambient air level (21%). The role of hypoxia-inducible factor-1alpha (HIF-1alpha) in the differentiation of OM-MSCs under hypoxia was investigated by treating cells with an HIF-1alpha inhibitor before induction (HIR group). The proportions of beta tubulin- and tyrosine hydroxylase (TH)-positive cells were significantly increased in the HI group compared with the NI and HIR groups, as shown by immunocytochemistry and Western blotting. Furthermore, the level of dopamine was significantly increased in the HI group. A slow outward potassium current was recorded in differentiated cells after 21 d of induction using whole-cell voltage clamp tests. A hypoxic environment thus promotes OM-MSCs to differentiate into DAergic neurons by increasing the expression of HIF-1alpha and by activating downstream target gene TH. This study indicated that OCM under hypoxic conditions could significantly upregulate key transcriptional factors involved in the development of DAergic neurons from OM-MSCs, mediated by HIF-1alpha. Hypoxia promotes DAergic neuronal differentiation of OM-MSCs, and HIF-1alpha may play an important role in hypoxia-inducible pathways during DAergic lineage specification and differentiation in vitro. PMID- 28901192 TI - Neuronal Cell Sheets of Cortical Motor Neuron Phenotype Derived from Human iPSCs. AB - Transplantation of stem cells that differentiate into more mature neural cells brings about functional improvement in preclinical studies of stroke. Previous transplant approaches in the diseased brain utilized injection of the cells in a cell suspension. In addition, neural stem cells were preferentially used for grafting. However, these cells had no specific relationship to the damaged tissue of stroke and brain injury patients. The injection of cells in a suspension destroyed the cell-cell interactions that are suggested to be important for promoting functional integrity of cortical motor neurons. In order to obtain suitable cell types for grafting in patients with stroke and brain damage, a protocol was modified for differentiating human induced pluripotent stem cells from cells phenotypically related to cortical motor neurons. Moreover, cell sheet technology was applied to neural cell transplantation, as maintaining the cell cell communications is regarded important for the repair of host brain architecture. Accordingly, neuronal cell sheets that were positive Forebrain Embryonic Zinc Finger (Fez) family zinc finger 2 (FEZF2), COUP-TF-interacting protein 2, insulin-like growth factor-binding protein 4 (IGFBP4), cysteine-rich motor neuron 1 protein precursor (CRIM1), and forkhead box p2 (FOXP2) were developed. These markers are associated with cortical motoneurons that are appropriate for the transplant location in the lesions. The sheets allowed preservation of cell-cell interactions shown by synapsin1 staining after transplantation to damaged mouse brains. The sheet transplantation brought about partial structural restoration and the improvement of motor functions in hemiplegic mice. Collectively, the novel neuronal cell sheets were transplanted into damaged motor cortices; the cell sheets maintained cell-cell interactions and improved the motor functions in the hemiplegic model mice. The motoneuron cell sheets are possibly applicable for stroke patients and patients with brain damage by using patient-specific induced pluripotent stem cells. PMID- 28901193 TI - ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia. AB - Hypoxia is a common cause of kidney injury and a major issue in kidney transplantation. Mitogen-activated protein kinases (MAPKs) are involved in the cellular response to hypoxia, but the precise roles of MAPKs in renal cell reactions to hypoxic stress are not well known yet. This work was conducted to investigate the regulation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and p38 and their signaling-relevant molecules in kidney epithelial cells exposed to prolonged hypoxia. Rat kidney epithelial cells Normal Rat Kidney (NRK)-52E were exposed to hypoxic conditions (1% O2) for 24 to 72 h. Cell morphology was examined by light microscopy, and cell viability was checked by 3 [4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxypheny]-2-[4-sulfophenyl]-2H tetrazolium (MTS). The expression of ERK1/2 and p38 MAPK, as well as their signaling-related molecules, was measured by Western blot and real-time polymerase chain (RT-PCR) reaction. At the 1% oxygen level, cell morphology had no appreciable changes compared to the control up to 72 h of exposure under light microscopy, whereas the results of MTS showed a slight but significant reduction in cell viability after 72 h of hypoxia. On the other hand, ERK1/2 and p38 phosphorylation remarkably increased in these cells after 24 to 72 h of hypoxia. In sharp contrast, the expression of transcription factor B-cell lymphoma 6 (Bcl 6) was significantly downregulated in response to hypoxic stress. Other intracellular molecules relevant to the ERK1/2 and p38 signaling pathway, such as protein kinase A, protein kinase C, Bcl-2, nuclear factor erythroid 2-related factor 2, tristetraprolin, and interleukin-10(IL-10), had no significant alterations after 24 to 72 h of hypoxic exposure. We conclude that hypoxic stress increases the phosphorylation of both ERK1/2 and p38 but decreases the level of Bcl-6 in rat kidney epithelial cells. PMID- 28901195 TI - Feedforward Coordinate Control of a Robotic Cell Injection Catheter. AB - Remote and robotically actuated catheters are the stepping-stones toward autonomous catheters, where complex intravascular procedures may be performed with minimal intervention from a physician. This article proposes a concept for the positional, feedforward control of a robotically actuated cell injection catheter used for the injection of myogenic or undifferentiated stem cells into the myocardial infarct boundary zones of the left ventricle. The prototype for the catheter system was built upon a needle-based catheter with a single degree of deflection, a 3-D printed handle combined with actuators, and the Arduino microcontroller platform. A bench setup was used to mimic a left ventricle catheter procedure starting from the femoral artery. Using Matlab and the open source video modeling tool Tracker, the planar coordinates ( y, z) of the catheter position were analyzed, and a feedforward control system was developed based on empirical models. Using the Student's t test with a sample size of 26, it was determined that for both the y- and z-axes, the mean discrepancy between the calibrated and theoretical coordinate values had no significant difference compared to the hypothetical value of u = 0. The root mean square error of the calibrated coordinates also showed an 88% improvement in the z-axis and 31% improvement in the y-axis compared to the unmodified trial run. This proof of concept investigation leads to the possibility of further developing a feedfoward control system in vivo using catheters with omnidirectional deflection. Feedforward positional control allows for more flexibility in the design of an automated catheter system where problems such as systemic time delay may be a hindrance in instances requiring an immediate reaction. PMID- 28901194 TI - Acute Renal Graft-Versus-Host Disease in a Murine Model of Allogeneic Bone Marrow Transplantation. AB - Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and is associated with a poor prognosis. Generally, the kidneys are assumed to not be no direct targets of graft-versus-host disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully major histocompatibility complex (MHC)-mismatched model of BALB/c mice conditioned and transplanted according to 2 different intensity protocols. Syngeneically transplanted and untreated animals served as controls. Four weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-d glucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (tumor necrosis factor alpha, interferon-gamma, interleukin 1 alpha [IL-1alpha], IL-2, IL-6, and IL-10), and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal impairment. PMID- 28901196 TI - In-Law and Mate Preferences in Chinese Society and the Role of Traditional Cultural Values. AB - Using 347 parent-child dyads as participants, this study directly examined in-law and mate preferences in a typical collectivist culture. The results showed (1) traits indicating social status and parental investment were more highly valued by the parents, while traits indicating genetic quality and traits related to romantic love were more highly valued by the children. (2) Parental preferences were moderated by gender of the in-laws. Good earning capacity was more preferred by parents in a son-in-law, traits connoting genetic quality and reproductive fitness were more preferred by parents in a daughter-in-law. (3) There was more convergence in in-law and mate preferences in Chinese culture than in Western cultures. (4) Traditional cultural values (i.e., filial piety) can be used as a predictor of traditional mate preferences and less parent-child divergences. Additionally, greater preference for kind and understanding by parents than by children as well as by daughters than by sons, and greater preference for social status by the daughters' than by the sons' parents have not been observed in the rating and the ranking instrument. These findings illustrated how culture handles the parent-child disagreement over mating by authorizing greater parental influence on children's mating decisions. PMID- 28901197 TI - Sexually Dimorphic Faciometrics in Humans From Early Adulthood to Late Middle Age: Dynamic, Declining, and Differentiated. AB - Faciometrics have widely been used in contemporary studies on gender-related behavioral traits, for example, perceived and actual aggression, co-operation and trustworthiness, prejudicial beliefs, unethical behavior, and achievement drive, as well as, but to a lesser degree, in nonhuman primates. For the large part, these studies have focused primarily on "student-aged" populations with little empirical scrutiny regarding the efficacy of applying these measures with older participants. This study therefore investigated sexual dimorphism across four age groups (20s, 30s, 40s, and 50s) in 444 participants (225 men). The expected sexual dimorphism was seen in the youngest age group in three of the four indices. The facial width to height ratio, however, although most commonly used empirically, was not found to be significantly different between men and women, consistent with more recent literature. Importantly, as age increased, sexual dimorphism decreased, but this was not consistent across all measures of it. Rather, it is evident that differing measures of sexual dimorphism follow distinct developmental trajectories. The only single marker which remained significantly different across all age-groups was cheekbone prominence. Sexual dimorphic faciometrics are therefore dynamic, declining, and differentiated through adulthood. Consequently, it is concluded that care should be taken in using faciometrics in studies involving older populations and that more research is needed to understand the impact of these distinct faciometric trajectories in gender- and masculinity-related studies. PMID- 28901198 TI - Regression standardization and attributable fraction estimation with between within frailty models for clustered survival data. AB - The between-within frailty model has been proposed as a viable analysis tool for clustered survival time outcomes. Previous research has shown that this model gives consistent estimates of the exposure-outcome hazard ratio in the presence of unmeasured cluster-constant confounding, which the ordinary frailty model does not, and that estimates obtained from the between-within frailty model are often more efficient than estimates obtained from the stratified Cox proportional hazards model. In this paper, we derive novel estimation techniques for regression standardization with between-within frailty models. We also show how between-within frailty models can be used to estimate the attributable fraction function, which is a generalization of the attributable fraction for survival time outcomes. We illustrate the proposed methods by analyzing a large cohort on preterm birth and attention deficit hyperactivity disorder. To facilitate use of the proposed methods, we provide R code for all analyses. PMID- 28901200 TI - What Physical Fitness Component Is Most Closely Associated With Adolescents' Blood Pressure? AB - This study aimed to determine which of four selected physical fitness variables, would be most associated with blood pressure changes (systolic and diastolic) in a large sample of adolescents. This was a descriptive and cross-sectional, epidemiological study of 1,117 adolescents aged 14-19 years from southern Brazil. Systolic and diastolic blood pressure were measured by a digital pressure device, and the selected physical fitness variables were body composition (body mass index), flexibility (sit-and-reach test), muscle strength/resistance (manual dynamometer), and aerobic fitness (Modified Canadian Aerobic Fitness Test). Simple and multiple linear regression analyses revealed that aerobic fitness and muscle strength/resistance best explained variations in systolic blood pressure for boys (17.3% and 7.4% of variance) and girls (7.4% of variance). Aerobic fitness, body composition, and muscle strength/resistance are all important indicators of blood pressure control, but aerobic fitness was a stronger predictor of systolic blood pressure in boys and of diastolic blood pressure in both sexes. PMID- 28901201 TI - Sex Differences in Balance Among Alpine Ski Racers: Cross-Sectional Age Comparisons. AB - Although balance is a key ability in the strength demands of alpine ski racing, affecting both performance and injury prevention, few studies have examined balance or related sex differences among still-maturing athletes. In this 10-year study, we investigated cross-sectional balance performances at different age periods of a representative sample of over 500 11-18-year-old elite skiers of both genders. Participants performed balance tests using the MFT S3-Check. Left right and forward-backward movements were used to calculate sensory and symmetry balance scores, which were both incorporated into a stability score. Mann-Whitney U tests assessed gender-specific differences by age-group with a significance level set at p < .05. Results showed gender differences only on forward-backward measurements for 14-16-year-olds, with females showing better stability and sensory (but not symmetry) scores than males. Thus, gender interacted with age and maturation to influence balance ability in these participants. Additionally, these rare 10-year data support coaches in their training and talent development of maturing athletes by providing important sport-, age-, and gender-specific normative comparison data for individual trainees. PMID- 28901202 TI - Intellectual disability, hate crime and other social constructions: A view from South Yorkshire. AB - The category of hate crime is a recent legislative response to the increasing levels of antisocial, criminal and discriminatory behaviours and practices that target a wide spectrum of individuals on the basis of their identification within certain minority sociological subcultures. People with intellectual disability are often targeted for this kind of behaviour. Here, we report on an evaluation of one English city's efforts to instigate a street-based scheme to offer some security and protection to its intellectually disabled citizens. The physical location of the premises and the engagement of the staff employed therein have some bearing on their potential to be effective in offering shelter and support to distressed individuals. But even where premises are well situated with positive staffing, the absence of local records to list the uptake of the scheme leaves room for doubt about its overall effectiveness. PMID- 28901199 TI - New tricks for the glycyl radical enzyme family. AB - Glycyl radical enzymes (GREs) are important biological catalysts in both strict and facultative anaerobes, playing key roles both in the human microbiota and in the environment. GREs contain a backbone glycyl radical that is post translationally installed, enabling radical-based mechanisms. GREs function in several metabolic pathways including mixed acid fermentation, ribonucleotide reduction and the anaerobic breakdown of the nutrient choline and the pollutant toluene. By generating a substrate-based radical species within the active site, GREs enable C-C, C-O and C-N bond breaking and formation steps that are otherwise challenging for nonradical enzymes. Identification of previously unknown family members from genomic data and the determination of structures of well characterized GREs have expanded the scope of GRE-catalyzed reactions as well as defined key features that enable radical catalysis. Here, we review the structures and mechanisms of characterized GREs, classifying members into five categories. We consider the open questions about each of the five GRE classes and evaluate the tools available to interrogate uncharacterized GREs. PMID- 28901204 TI - Experiences, behaviors, and perceptions of registered nurses regarding research ethics and misconduct. AB - BACKGROUND: Nurses engaging in research are held to research ethics standards. Research aim: Examine experiences, behaviors, and perceptions of nurses in Israel regarding research ethics and explore possible related factors. RESEARCH DESIGN: An original investigator-designed self-administered questionnaire measured five variables: (a) ethics in research, (b) encountered research misconduct during the course of one's studies, (c) the inclination to fabricate data, (d) the inclination to select or omit data, and (e) knowledge of research misconduct in the workplace. Additionally, demographic data were collected. Participants and research context: The questionnaire was completed by 151 Israeli registered nurses. 10.2% hold a PhD, 34 % hold an MA, 42.2% hold a BA, and 13.6% with no academic degree. Ethical considerations: The study was approved by the University's ethics committee; anonymity and consent of the respondents were respected. FINDINGS: Registered nurses' level of studies achieved was significantly associated with a lower inclination to fabricate data, with one exception-PhD nurses were more inclined to fabricate data than nurses with a Master's degree. A trend was found in which a higher level of studies is associated with higher knowledge of research misconduct in the workplace. DISCUSSION: Results indicate that nurses' perceptions of research ethics change throughout their academic studies, indicating a positive influence of level of studies, research experience, and work experience on ethics perceptions. Nevertheless, PhD nurses showed a greater inclination to actually select, omit, or even fabricate data than MA nurses. This may be related to pressure to publish. CONCLUSION: PhD nursing programs should include ethics training. Academic faculty members should serve as role models regarding research integrity. Research ethics deserves further emphasis on all levels of nurse education in Israel, as well as in the nurses' code of ethics and related documents. This may positively impact ethical research practices. PMID- 28901205 TI - Satisfaction, Burnout, and Turnover Among Nurse Practitioners and Physician Assistants: A Review of the Empirical Literature. AB - Examining the work-related psychological states of nurse practitioners and physician assistants is important, given their increased role expansion. The current PRISMA-guided review examined studies published between 2000 and 2016 for both these groups. The review also examined features of the research to draw conclusions about overall quality. Applying theories in job enrichment and job demands, 32 articles were identified that contained analyses of satisfaction, burnout, stress, and turnover. Key findings include the lack of robust research designs, overemphasis on job satisfaction, lower levels of satisfaction across both groups, and higher intrinsic versus extrinsic satisfaction levels generally. The literature can develop by using larger, more representative samples, including subgroup analyses that incorporate everyday work contexts, and more predictive modeling. The results suggest that both occupations experience role expansion in both positive and negative ways that may require additional policy or managerial interventions. PMID- 28901203 TI - The Role of Monocyte Percentage in Osteoporosis in Male Rheumatic Diseases. AB - Osteoporosis is easily overlooked in male patients, especially in the field of rheumatic diseases mostly prevalent with female patients, and its link to pathogenesis is still lacking. Attenuated monocyte apoptosis from a transcriptome wide expression study illustrates the role of monocytes in osteoporosis. This study tested the hypothesis that the monocyte percentage among leukocytes could be a biomarker of osteoporosis in rheumatic diseases. Eighty-seven males with rheumatic diseases were evaluated in rheumatology outpatient clinics for bone mineral density (BMD) and surrogate markers, such as routine peripheral blood parameters and autoantibodies. From the total number of 87 patients included in this study, only 15 met the criteria for diagnosis of osteoporosis. Both age and monocyte percentage remained independently associated with the presence of osteoporosis. Steroid dose (equivalent prednisolone dose) was negatively associated with BMD of the hip area and platelet counts were negatively associated with BMD and T score of the spine area. Besides age, monocyte percentage meets the major requirements for osteoporosis in male rheumatic diseases. A higher monocyte percentage in male rheumatic disease patients, aged over 50 years in this study, and BMD study should be considered in order to reduce the risk of osteoporosis-related fractures. PMID- 28901206 TI - Rural-urban differences in accessing mental health treatment in patients with psychosis. AB - BACKGROUND: Delay in accessing psychiatric treatment has considerable influence on the outcome of psychoses. Systematic studies examining the source of the delay are lacking in India. In this article, we examine rural-urban differences regarding delay in accessing psychiatric care in patients with psychosis, an issue which was hitherto not studied. AIMS: To evaluate the rural-urban differences in treatment seeking among patients with psychosis. METHODS: Patients with psychotic disorders who presented to the outpatient department of an academic psychiatric institute for the first time ( n = 551) were interviewed using a semi-structured interview tool to assess the date of onset of illness. RESULTS: Families in urban areas had significantly higher level of education and greater income than their rural counterparts. However, there was no difference in urban and rural patients in the duration of untreated illness (DUI). There was no correlation between average years of education of the family members and DUI (spearman's rho = -0.01; p = .77). CONCLUSIONS: Despite the proximity to psychiatric centers, better education and greater income, patients in urban areas do not access psychiatric care earlier than patients in rural areas. So, mere presence of services would not make patients access them early. PMID- 28901207 TI - Characterizing Citizens' Preferences for Engagement in Patient Care and Research in Adult and Pediatric Intensive Care Units. AB - RATIONALE: Engagement promotes and supports the active participation of patients and families in health care and research to strengthen their influence on decision-making. We sought to characterize how citizens wish to be engaged in care and research in the intensive care unit (ICU). METHODS: Interviewers administered questionnaires to visitors in 3 adult ICUs and 1 pediatric ICU. RESULTS: We surveyed 202 (adult [n = 130] and pediatric [n = 72]) visitors. Adults and pediatric visitors prioritized 3 patient care topics (family involvement in rounds, improving communication between family members and health care providers, and information transmission between health-care practitioners during patient transfers) and 2 research topics (evaluating prevention and recovery from critical illness). Preferred engagement activities included sharing personal experiences, identifying important topics and outcomes, and finding ways to make changes that respected their needs. Both respondent groups preferred to participate by completing electronic surveys or comment cards and answering questions on a website. Few respondents (<5%) wanted to participate in committees that met regularly. Although adult and pediatric respondents identified common facilitators and barriers to participation, they ranked them differently. Although both groups perceived engagement to be highly important, adult respondents were significantly less confident that their participation would impact care (7.6 +/- 2.2 vs 8.3 +/- 1.8; P = .01) and research (7.3 +/- 2.4 vs 8.2 +/- 2.0; P = .01) and were significantly less willing to participate in care (5.6 +/- 2.9 vs 6.7 +/- 3.0; P = .007) and research (4.7 +/- 3.0 vs +/- 5.8 +/- 3.0; P = .02). CONCLUSIONS: Adult and pediatric visitors expressed comparable engagement preferences, identified similar facilitators and barriers, and rated engagement highly. Adult visitors were significantly less confident that their participation would be impactful and were significantly less willing to engage in care and research. PMID- 28901208 TI - Outcomes of Critically Ill Patients Who Have Serotype 5 Invasive Pneumococcal Disease. AB - PURPOSE: To determine whether invasive pneumococcal disease (IPD) due to serotype 5, which occurred as a local outbreak in 2006 to 2007, is associated with intensive care unit (ICU) admission, hospital mortality, or organ supports in those who are critically ill. MATERIALS AND METHODS: Retrospective review of patients who presented with IPD to 2 tertiary hospitals in Vancouver, Canada, from July 2004 to June 2007. We compared patient characteristics, interventions, and outcomes between patients who had serotype 5 and other serotypes using bivariate and multivariate analyses. RESULTS: A total of 149 patients had serotype 5 and 106 had nonserotype 5. Patients with serotype 5 were younger, had lower prevalence of comorbid diseases, and had higher rates of substance use than patients with nonserotype 5. There were no differences in chest tube placement for complications of pneumonia or in ICU admission. Frequency of necrotizing pneumonia and hospital mortality were lower in the serotype 5 group. For the 71 patients with IPD who were admitted to ICU, there was no difference in severity of illness, ICU length of stay, or ICU mortality between the groups. There was also no difference in organ supports except that the serotype 5 group was more likely to receive vasopressors. CONCLUSION: Serotype 5 in patients who have IPD is associated with no difference in ICU admission but with increased use of vasopressors and lower hospital mortality. PMID- 28901209 TI - The distinct properties of natural and GM cry insecticidal proteins. AB - The Cry toxins are a family of crystal-forming proteins produced by the bacterium Bacillus thuringiensis. Their mode of action is thought to be to create pores that disrupt the gut epithelial membranes of juvenile insects. These pores allow pathogen entry into the hemocoel, thereby killing the insect. Genes encoding a spectrum of Cry toxins, including Cry mutants, Cry chimaeras and other Cry derivatives, are used commercially to enhance insect resistance in genetically modified (GM) crops. In most countries of the world, such GM crops are regulated and must be assessed for human and environmental safety. However, such risk assessments often do not test the GM crop or its tissues directly. Instead, assessments rely primarily on historical information from naturally occurring Cry proteins and on data collected on Cry proteins (called 'surrogates') purified from laboratory strains of bacteria engineered to express Cry protein. However, neither surrogates nor naturally occurring Cry proteins are identical to the proteins to which humans or other nontarget organisms are exposed by the production and consumption of GM plants. To-date there has been no systematic survey of these differences. This review fills this knowledge gap with respect to the most commonly grown GM Cry-containing crops approved for international use. Having described the specific differences between natural, surrogate and GM Cry proteins this review assesses these differences for their potential to undermine the reliability of risk assessments. Lastly, we make specific recommendations for improving risk assessments. PMID- 28901211 TI - Corrigendum. PMID- 28901210 TI - Does Working Memory Impact Functional Outcomes in Individuals With ADHD: A Qualitative and Comprehensive Literature Review. AB - OBJECTIVE: Working Memory (WM) is a domain of executive functioning often impaired in individuals with ADHD. Although assumed to cause difficulties across functioning, the scope of impairments from WM deficits in ADHD has not been investigated. The aim of this study was to examine outcomes associated with WM deficits in ADHD. METHOD: We conducted a search of the scientific literature on WM deficits, and Freedom From Distractibility (FFD), in ADHD using PubMed and PsycInfo databases. RESULTS: The final sample included 11 controlled studies of WM/FFD deficits in ADHD with operationalized assessment of outcomes in academic, social, and emotional areas. WM assessment was divided into auditory-verbal memory (AVM) and spatial-visual memory (SWM). Seven studies examined WM deficits in academic functioning, eight studies assessed WM deficits in social functioning, and three assessed WM deficits in psychopathology. CONCLUSION: The majority of the literature suggests that WM deficits affect primarily academic functioning. PMID- 28901213 TI - HIV prevalence and correlated factors of female sex workers and male clients in a border region of Yunnan Province, China. AB - Female sex workers (FSWs) and their male clients are vulnerable to HIV infection and serve as a bridge in HIV transmission from the high-risk population to the general, low-risk population. To examine the factors of FSWs and male clients that correlate with the prevalence of HIV infection in the Chinese-Vietnamese border region, a cross-sectional survey was conducted in 2014 in the Hekou county of the Yunnan province of China. We performed a questionnaire survey to collect data on demographics, sexual behavior, and drug use. Blood and urine samples were collected for testing of HIV/sexually transmitted infections and drug use. We found that the prevalence of HIV infection among FSWs was 2.74%, and 15 male clients (2.62%) were HIV-positive. Multivariate logistic regression analysis revealed that herpes simplex virus type 2 infection was a risk factor for HIV infection in FSWs and male clients, suggesting the increased role of sexual transmission in the HIV epidemic in the Chinese-Vietnamese border region. Positive urinalysis result for amphetamine-type stimulants was observed in FSWs with HIV infection. History of drug use was correlated with HIV infection, which increased the HIV infection risk of male clients, confirming that drug use is an important target in future interventions for HIV prevention. PMID- 28901214 TI - Total dose iron dextran infusion versus oral iron for treating iron deficiency anemia in pregnant women: a randomized controlled trial. AB - STUDY OBJECTIVE: To test safety, efficacy, and cost-effectiveness of total dose infusion (TDI) of low molecular weight (LMW) iron dextran for treatment of iron deficiency anemia (IDA) during pregnancy in comparison to oral ferrous fumarate. DESIGN: Prospective interventional randomized controlled trial (RCT). Design classification. Canadian Task Force II3. SETTING: Antenatal clinic and causality unit of a tertiary care referral facility and University Hospital. PATIENTS: A total 66 anemic pregnant women (hemoglobin level between 7-10 g/dl). INTERVENTION: Administration of a LMW iron dextran as a TDI (group A) or Oral iron ferrous fumarate 60 mg elemental iron three times daily (group B) followed by remeasurement of hemoglobin after 4 weeks. MEASURES AND MAIN RESULTS: The main outcome measure was clinical and laboratory improvement of anemia after 4 weeks of starting the therapy. Both groups showed a significant clinical improvement of anemia 4 weeks post-therapy. However, the first improvement of symptoms was significantly faster in group A. Complete blood count (CBC) as well as all iron indices were improved in both groups after 4 weeks of therapy, but were significantly better in group A than B. Side effects in group B were mainly gastrointestinal (GIT) while one case of mild hypersensitivity to TDI and another one case of local reaction at the site of injection were reported in group A. CONCLUSIONS: It is concluded that despite being equally effective in improving both clinical and laboratory evidence of IDA, TDI allows iron restoration with a single dose faster than oral iron therapy with a reasonable safety profile. It is a good example of office one-stop therapy. Nevertheless, noninvasive selfusage at home is a clear advantage of the cheaper oral iron therapy which makes it the first choice for treating IDA in the second and third trimesters of pregnancy in tolerable cases. PMID- 28901212 TI - A retrospective clinical audit of general practices in Australia to determine the motivation for switch to dolutegravir/abacavir/lamivudine and clinical outcomes. AB - The most common reasons for switching HIV-1 therapy in patients with virologic suppression are treatment regimen simplification and resolving tolerability issues. Single-pill regimens that include an integrase inhibitor are recommended options. A retrospective clinical audit was performed to determine the motivations for switching to dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) at high HIV-caseload general practice clinics in Australia. The most common reasons for switching from a prior suppressive therapy to DTG/ABC/3TC were simplification of regimen, resolving toxicity/intolerance and patient preference (73%, 13% and 12%, respectively). Kaplan-Meier analysis showed that the probability of patients remaining on DTG/ABC/3TC therapy at 12 months was 95.1%. Switching to DTG/ABC/3TC from a range of other regimens was associated with a discontinuation rate of 3.2%, with 2.5% of patients discontinuing due to adverse events and no patients discontinuing due to virologic failure. Switching to DTG/ABC/3TC was a viable treatment strategy in this cohort of Australian patients. PMID- 28901215 TI - Presentation, treatment, and outcomes in patients with spontaneous isolated celiac and superior mesenteric artery dissection. AB - Spontaneous isolated celiac or superior mesenteric artery (SMA) dissection (SICMAD) is a rare clinical entity. Not much is known about the natural history and appropriate treatment. We retrospectively queried a prospectively collected institutional radiology database for all patients diagnosed with SICMAD from 1990 to 2017. We identified 42 arteries in 40 patients (83.3% male), mean age 54.8 +/- 10.9 years, consisting of 24 celiac arteries and 18 SMA. SMA lesions were longer than celiac lesions (5.15 +/- 3.81 vs 2.38 +/- 1.40 cm, p = 0.008). Thirty-one patients had follow-up; mean follow-up was 4.9 +/- 4.8 years. Morphologic improvement was seen in 20 (48%) arteries. Sakamoto IV lesions were more likely to remodel (OR: 11.26, 95% CI: 1.13, 588.26, p = 0.039), and Sakamoto II lesions less likely to remodel (OR: 0, 95% CI: 0.00, 0.93, p = 0.05). Patients received an average of 2.35 scans during follow-up. Symptom resolution occurred in all symptomatic patients, and 16% of patients had recurrence of symptoms. Follow-up CT scans revealed a stable arterial diameter for the majority of patients. In conclusion, the majority of patients with SICMAD improve with medical therapy alone. Aneurysmal dilatation is uncommon. PMID- 28901216 TI - Creatine or vitamin D supplementation in individuals with a spinal cord injury undergoing resistance training: A double-blinded, randomized pilot trial. AB - PURPOSE: Determine whether creatine or vitamin D supplementation improves muscle strength in individuals with spinal cord injury undergoing resistance training. METHODS: Thirteen male and one female with spinal cord injury, from two Portuguese rehabilitation centers, were randomized to creatine (3g daily), vitamin D (25000 IU each two weeks) or placebo group in a double-blind design. All participants performed progressive resistance training during eight weeks. The outcome measures, obtained at baseline and after intervention, included: Sum of four skinfolds; Corrected arm muscle area; Seated medicine ball throw; Handgrip strength with dynamometer; Manual wheelchair slalom test and one repetition maximum for Chest press, Triceps, Pec deck and Lat pulldown. Vitamin D levels were obtained in all participants before and after intervention. RESULTS: 71.4% of participants had deficit values of vitamin D. The corrected arm muscle area improved significantly (p<0.05) in creatine group relatively to the control group. There was a significant correlation (p<0.05) between the one repetition maximum Pec deck and levels of vitamin D. CONCLUSIONS: Supplementation with creatine may improve muscle strength parameters in individuals with spinal cord injury. Vitamin D deficiency is highly prevalent in this population. It is recommended an initial screening of vitamin D levels at the beginning of the physical rehabilitation process. PMID- 28901217 TI - Ethical and methodological issues in qualitative studies involving people with severe and persistent mental illness such as schizophrenia and other psychotic conditions: a critical review. AB - Undertaking research studies in the field of mental health is essential in mental health nursing. Qualitative research methodologies enable human experiences to become visible and recognize the importance of lived experiences. This paper argues that involving people with schizophrenia in research is critical to promote their health and well-being. The quality of qualitative research needs scrutinizing according to methodological issues such as trustworthiness and ethical standards that are a fundamental part of qualitative research and nursing curricula. The aim of this study was to critically review recent qualitative studies involving people with severe and persistent mental illness such as schizophrenia and other psychotic conditions, regarding descriptions of ethical and methodological issues in data collection and analysis. A search for relevant papers was conducted in three electronic databases, in December 2016. Fifteen qualitative interview studies were included and reviewed regarding methodological issues related to ethics, and data collection and analysis. The results revealed insufficient descriptions of methodology regarding ethical considerations and issues related to recruitment and sampling in qualitative interview studies with individuals with severe mental illness, putting trustworthiness at risk despite detailed descriptions of data analysis. Knowledge from the perspective of individuals with their own experience of mental illness is essential. Issues regarding sampling and trustworthiness in qualitative studies involving people with severe mental illness are vital to counteract the stigmatization of mental illness. PMID- 28901218 TI - Four-week dietary supplementation with 10- and/or 15-fold basal choline caused decreased body weight in Sprague Dawley rats. AB - Choline is an essential nutrient utilized for phosphatidylcholine biosynthesis and lipoprotein packaging and secretion. Recently, choline supplementation has been used by athletes and the public for weight loss. However, the potential toxicological impact of choline dietary supplementation requires further investigation. This study examined the effects of choline dietary supplementation in Sprague Dawley rats for 4 weeks. Rats were fed diets containing basal choline levels (control) or 5-, 10-, or 15-fold (5*, 10*, or 15*) basal diet concentration. In groups fed choline-supplemented diets, there were no toxicologically relevant findings in clinical observations, food intake, clinical chemistry, liver weights, or liver histopathology. However, decreased mean body weights (8.5-10.2%) and body weight gains (24-31%) were noted for the 10* choline supplemented (females only) and 15* choline-supplemented (both sexes) groups relative to the control groups from day 3 onward. These body weight effects were not related to a persistent reduction in average food intake. Serum cholesterol was increased in the 15* choline-supplemented male rats relative to the controls, an expected effect of choline supplementation; however, there were no changes in the serum cholesterol of female rats. Serum choline concentrations were increased in female rats relative to the male rats across all treatment groups. The maximum tolerated dose for male and female rats were the 15* and 10* choline supplements, respectively, based on decreased mean body weight and body weight gains. This study supported the conclusions of a clinical trial that showed a high choline diet can decrease body weight in humans. PMID- 28901219 TI - Primary prevention of stroke and cardiovascular disease in the community (PREVENTS): Methodology of a health wellness coaching intervention to reduce stroke and cardiovascular disease risk, a randomized clinical trial. AB - Rationale Stroke is a major cause of death and disability worldwide, yet 80% of strokes can be prevented through modifications of risk factors and lifestyle and by medication. While management strategies for primary stroke prevention in high cardiovascular disease risk individuals are well established, they are underutilized and existing practice of primary stroke prevention are inadequate. Behavioral interventions are emerging as highly promising strategies to improve cardiovascular disease risk factor management. Health Wellness Coaching is an innovative, patient-focused and cost-effective, multidimensional psychological intervention designed to motivate participants to adhere to recommended medication and lifestyle changes and has been shown to improve health and enhance well-being. Aims and/or hypothesis To determine the effectiveness of Health Wellness Coaching for primary stroke prevention in an ethnically diverse sample including Maori, Pacific Island, New Zealand European and Asian participants. Design A parallel, prospective, randomized, open-treatment, single-blinded end point trial. Participants include 320 adults with absolute five-year cardiovascular disease risk >= 10%, calculated using the PREDICT web-based clinical tool. Randomization will be to Health Wellness Coaching or usual care groups. Participants randomized to Health Wellness Coaching will receive 15 coaching sessions over nine months. Study outcomes A substantial relative risk reduction of five-year cardiovascular disease risk at nine months post randomization, which is defined as 10% relative risk reduction among those at moderate five-year cardiovascular disease risk (10-15%) and 25% among those at high risk (>15%). Discussion This clinical trial will determine whether Health Wellness Coaching is an effective intervention for reducing modifiable risk factors, and hence decrease the risk of stroke and cardiovascular disease. PMID- 28901220 TI - Biomarkers of cardiometabolic health are associated with body composition characteristics but not physical activity in persons with spinal cord injury. AB - Objective To examine (i) the associations between physical activity dimensions, cardiorespiratory fitness and body composition and, (ii) the associations between physical activity dimensions, cardiorespiratory fitness, body composition and biomarkers of cardiometabolic health in persons with spinal cord injury (SCI). Methods A cross-sectional prospective cohort study with 7-day follow-up was conducted. Body composition, cardiorespiratory fitness and biomarkers of cardiometabolic health were measured in thirty-three participants with SCI (> 1 year post injury). Physical activity dimensions were objectively assessed over 7 days. Results Activity energy expenditure (r =.43), physical activity level (r =.39), and moderate-to-vigorous physical activity (MVPA) (r =.48) were significantly (P < 0.001) associated with absolute (L/min) peak oxygen uptake (VO2 peak). VO2 peak was significantly higher in persons performing >=150 MVPA minutes/week compared to <40 minutes/week (P = 0.003). Individual physical activity dimensions were not significantly associated with biomarkers of cardiometabolic health. However, body composition characteristics (BMI, waist and hip circumference) showed significant (P < 0.04), moderate (r >.30) associations with parameters of metabolic regulation, lipid profiles and inflammatory biomarkers. Relative VO2 peak (ml/kg/min) was moderately associated with only insulin sensitivity (r = 0.37, P = 0.03). Conclusions Physical activity dimensions are associated with cardiorespiratory fitness; however, stronger and more consistent associations suggest that poor cardiometabolic health is associated with higher body fat content. Given these findings, the regulation of energy balance should be an important consideration for researchers and clinicians looking to improve cardiometabolic health in persons with SCI. PMID- 28901221 TI - Direct oral anticoagulant reversal: how, when and issues faced. AB - INTRODUCTION: The number of atrial fibrillation (AF) patients requiring thrombo prophylaxis with oral anticoagulation is greatly increasing. The introduction of non-vitamin K oral anticoagulants (NOACs) in addition to standard therapy with dose-adjusted warfarin has increased the therapeutic options for AF patients. Despite a generally better safety profile of the NOACs, the risk of major bleedings still persists, and the management of serious bleeding is a clinical challenge. Areas covered: In the current review, risk of major bleeding in patients taking NOACs and general approaches to manage bleeding depending on severity, with a particular focus on specific reversal agents, are discussed. Expert commentary: Due to short half-life of NOACs compared to warfarin, discontinuation of drug, mechanical compression, and volume substitution are considered to be sufficient measures in most of bleeding cases. In case of life threatening bleeding or urgent surgery, hemostasis can be achieved with non specific reversal agents (prothrombin complex concentrates) in patients treated with factor Xa inhibitor until specific antidotes (andexanet alpha and ciraparantag) will receive approval. Thus far, idarucizumab has been the only reversal agent approved for dabigatran. PMID- 28901222 TI - Cell phone-based online biochemistry and molecular biology medical education curriculum. PMID- 28901223 TI - The Lymphatic System: The Achilles Heel of the Fontan-Kreutzer Circulation. AB - In spite of excellent long term survival the Fontan Kreutzer procedure commonly presents late failure due to end-organ damage. Several advances have been described to refine single ventricle management and surgical techniques. However, very little research has been dedicated to the lymphatic circulation in the precarious Fontan hemodynamic state. The lymphatic circulation is clearly affected since there is increased lymph production, which requires to be drained at a similar or higher pressure than it is produced, commonly resulting in chronic lymphedema. Chronic lymphedema induces fibrosis and end-organ failure even in normal circulation. Diverting lymph drainage to the low-pressured systemic atrium in Fontan may represent a valid alternative for the treatment of devastating complications as protein-losing enteropathy and plastic bronchitis and may prevent or decrease the development of end-organ fibrosis or failure. PMID- 28901224 TI - Coronary Revascularization in Children at a Mexican Cardiac Center: Thirteen-Year Outcomes. AB - BACKGROUND: The indications for pediatric coronary revascularization are diverse. There are a large proportion of patients with sequelae of severe inflammatory diseases such as Kawasaki disease, and other less common causes. METHODS: Retrospective review of ten pediatric patients undergoing coronary artery bypass surgery from January 2004 to December 2016. RESULTS: Ten children and adolescents ranging in age from 2 to 17 (median, 6) years at operation were followed up for as long as 13 years with a median follow-up of 2 years. The surgical indications include ischemia symptoms and/or coronary stenosis angiographically documented. Diagnoses include Kawasaki disease, anomalous origin of the left coronary artery from the pulmonary artery, and iatrogenic lesion of the right coronary artery. All the surgical procedures were performed with cardiopulmonary bypass with crystalloid cardioplegic arrest. The number of distal anastomoses was 1.6 per patient, and the left internal thoracic artery was used in one patient, the right internal thoracic artery in four patients, bilateral internal thoracic artery in four patients, and bilateral internal thoracic artery plus left radial artery in one patient, most frequently for right coronary artery revascularization. The patients underwent noninvasive diagnostic study during follow-up to evaluate their coronary status. The ten patients had no symptoms, and there was no mortality. CONCLUSIONS: Although survival was excellent after pediatric coronary bypass in our center, we need to continue the follow-up. Coronary revascularization by means of arterial grafting is a safe and reliable surgical modality for coronary disease in children. PMID- 28901225 TI - Promoting Pulmonary Arterial Growth via Right Ventricle-to-Pulmonary Artery Connection in Children With Pulmonary Atresia, Ventricular Septal Defect, and Hypoplastic Pulmonary Arteries. AB - BACKGROUND: Complete repair of pulmonary atresia (PA) ventricular septal defect (VSD) with hypoplastic or absent native pulmonary arteries, often with major aortopulmonary collateral arteries (MAPCAs), involves construction of an adequate sized pulmonary arterial tree. We report our results with a previously described staged strategy using initial right ventricle (RV)-to-reconstructed pulmonary arterial tree (RV-PA) connection to promote pulmonary arterial growth and facilitate later ventricular septation. METHODS: We retrospectively reviewed data for all patients (N = 10) with initial echocardiographic diagnosis of PA-VSD and hypoplastic pulmonary arteries operated in our center from October 2008 to August 2016. Pulmonary arterial vessel size measured on preoperative and postoperative angiography was used to calculate Nakata index. RESULTS: Seven patients had PA VSD, three had virtual PA-VSD, and seven had MAPCAs. All underwent creation of RV PA connection at a median age of 7.5 days and weight 3.6 kg. Eight patients had RV-PA conduits, two had a transannular patches, and seven had major pulmonary artery reconstruction simultaneously. There were no deaths or serious morbidity; one conduit required revision prior to complete repair. Complete repair with ventricular septation and RV pressure less than half systemic was achieved in all patients at a median age of 239 days. Nakata index in neonatal period was 54 mm2/m2 (range 15-144 mm2/m2) and at time of septation 184 mm2/m2 (range 56-510 mm2/m2; P = .004). Growth rates of right and left branch pulmonary arteries were similar. The 10 patients underwent 28 catheterizations with 13 interventions in 8 patients prior to full repair. CONCLUSION: Early palliative RV-PA connection promotes pulmonary arterial growth and facilitates eventual full repair with VSD closure with low RV pressure and operative risk. PMID- 28901226 TI - Isolated Right Juxtaposition of the Atrial Appendages in Adult With Bicuspid Aortic Valve Stenosis. AB - We report the case of a 30-year-old male who had symptomatic bicuspid aortic valve stenosis. Operative findings unexpectedly revealed right juxtaposition of the atrial appendages. This is a rare association, as juxtaposition of atrial appendages is generally associated with more complex forms of congenital heart disease. The patient underwent successful surgery with uneventful postoperative course. PMID- 28901227 TI - Mixed Total Anomalous Pulmonary Venous Return With Ascending and Descending Vertical Veins. PMID- 28901228 TI - The World Database for Pediatric and Congenital Heart Surgery: The Dawn of a New Era of Global Communication and Quality Improvement in Congenital Heart Disease. AB - The World Society for Pediatric and Congenital Heart Surgery was founded with the mission to "promote the highest quality comprehensive cardiac care to all patients with congenital heart disease, from the fetus to the adult, regardless of the patient's economic means, with an emphasis on excellence in teaching, research, and community service." Early on, the Society's members realized that a crucial step in meeting this goal was to establish a global database that would collect vital information, allowing cardiac surgical centers worldwide to benchmark their outcomes and improve the quality of congenital heart disease care. With tireless efforts from all corners of the globe and utilizing the vast experience and invaluable input of multiple international experts, such a platform of global information exchange was created: The World Database for Pediatric and Congenital Heart Disease went live on January 1, 2017. This database has been thoughtfully designed to produce meaningful performance and quality analyses of surgical outcomes extending beyond immediate hospital survival, allowing capture of important morbidities and mortalities for up to 1 year postoperatively. In order to advance the societal mission, this quality improvement program is available free of charge to WSPCHS members. In establishing the World Database, the Society has taken an essential step to further the process of global improvement in care for children with congenital heart disease. PMID- 28901229 TI - Intraoperative High-Frequency Jet Ventilation Is Equivalent to Conventional Ventilation During Patent Ductus Arteriosus Ligation. AB - BACKGROUND: Patent ductus arteriosus (PDA) treatment is typically pharmacologic, but if unsuccessful, surgical ligation is commonly performed. High-frequency jet ventilation (HFJV) is used at the University of Iowa Stead Family Children's Hospital for extremely low birth weight infants. Historically, neonates requiring PDA ligation were temporarily transferred to conventional ventilation (CV) prior to surgery. OBJECTIVE: The objective of this study was to determine whether conversion was necessary. METHODS: This retrospective cohort analysis examined outcomes following PDA ligation from 2014 to 2016 at the University of Iowa's Stead Family Children's Hospital. Infants who were transferred to CV prior to surgery and returned to HFJV postprocedure are referred to as the CV cohort. The HFJV cohort infants remained on HFJV throughout. RESULTS: We found no significant increases in morbidity or mortality with the use of intraoperative HFJV and potentially show some benefit through greater reduction in serum CO2. CONCLUSIONS: Mode of ventilation during PDA ligation does not affect surgical morbidity or mortality or short-term clinical outcomes. Conversion to CV from HFJV is not necessary. PMID- 28901230 TI - Clinical Progress in the Management of Tetralogy of Fallot in the Dominican Republic: A Case Series. AB - BACKGROUND: Definitive surgical interventions for Dominican children with congenital heart disease, like those of other low- and middle-income countries, have been historically limited. METHODS: We undertook review of a case series focusing on the surgical correction of complex forms of tetralogy of Fallot at a single center, CEDIMAT Centro Cardiovascular, in the Dominican Republic, over a 30-month period. RESULTS: According to our criteria, 43 cases were determined to be complex tetralogy of Fallot repairs from the two-year period. Besides tetralogy of Fallot, the cohort had an additional 55 anatomic anomalies that had to be addressed at the time of surgery. Median age at the time of surgery was notably 30 months, and an average of 42 months elapsed from the time of diagnosis to the time of surgery for this group. Only 33% of the cases reviewed had no hypercyanotic crises before repair. Median time to extubation for this group of patients was one day, with a three-day median length of stay in the intensive care setting. CONCLUSIONS: Our study importantly captures the present experience of a surgical congenital heart program that has recently transitioned from a traditional "mission model" to a now self-sustaining local practice. Both the number and the complexity of the lesions corrected in this caseload represent an advance from the level of care previously provided to children in the Dominican Republic. PMID- 28901231 TI - Single-Stage Repair of Coarctation of the Aorta and Ventricular Septal Defect: A Comparison of Surgical Strategies and Resource Utilization. AB - BACKGROUND: We sought to compare clinical outcomes and resource utilization for two surgical approaches for single-stage repair of coarctation of the aorta and ventricular septal defect (VSD). METHODS: This was a retrospective chart review of 21 consecutive neonates and infants undergoing single-stage repair of coarctation of the aorta and VSD. Group 1 included 13 patients with both arch repair and VSD repair completed via sternotomy. Group 2 included eight patients with off-pump arch repair via left thoracotomy followed by repositioning and VSD repair via sternotomy. Primary clinical outcome was arch reintervention. Secondary outcomes included various measures of resource utilization. RESULTS: Group 1 patients demonstrated younger age at repair (median of 10 days vs 57 days for group 2; P = .05) and lower proximal arch z scores (-4.2 vs -2.3 for group 2; P = .003). Arch reintervention occurred in 0 of 8 patients in group 2 and 1 (7.7%) of 13 patients in group 1 ( P = nonsignificant). Group 2 was associated with lower total charges (US$68,301 vs US$211,723 for group 1; P = .0007), shorter length of stay (8 days vs 23 days for group 1; P = .004), and shorter duration of postoperative mechanical ventilation (0.5 days vs 4.0 days for group 1; P = .0008). Group 2 was also associated with shorter total cardiopulmonary bypass time (86 minutes vs 201 minutes for group 1; P = .0009). CONCLUSION: Single-stage two-incision repair of coarctation and VSD in appropriately selected patients may be associated with higher value of care. Confirmation of this finding will require further study based on larger numbers of patients. PMID- 28901232 TI - Decellularized Allografts for Right Ventricular Outflow Tract Reconstruction in Children. AB - OBJECTIVE: Determine the midterm outcomes of decellularized allografts for right ventricular outflow tract (RVOT) reconstruction in children less than 12 years of age. METHODS: The study included all consecutive patients submitted to RVOT reconstruction with decellularized allografts between June 2006 and June 2016. Besides clinical and echocardiographic control, 20 patients with more than five years of follow-up were evaluated with computed tomography (CT) scans to determine allograft diameters and calcium scores. Structural valve deterioration was defined as any peak gradient above 40 mm Hg and/or insufficiency of moderate or severe degree. Conduit failure was defined as the need for allograft reintervention. RESULTS: There were 59 patients with a median age of six years (range = 0.01-12 years). The most common operation was the Ross procedure (34%). Mean clinical follow-up was 5.4 (2.8) years and was 94% complete. At eight years, only two patients needed a reintervention, with a 90.9% freedom from this event. Structural valve deterioration occurred in 13 patients, 5 due to stenosis and 8 due to insufficiency, with a freedom from structural valve deterioration due to any cause of 64.9% at eight years. Late CT scans demonstrated the absence or minimal calcification of the conduits. CONCLUSIONS: Decellularized allografts for RVOT reconstruction in children were associated with a low incidence of structural valve deterioration and conduit failure. Although these results still need to be confirmed in larger series and with longer follow-up, our data suggest favorable outcomes, at least in the first decade after the operation. PMID- 28901233 TI - A Quarter-Century After Primary Direct Arterial Switch Operation: Four-D-Flow MRI Video Imaging of Blood Flow Dynamics Outcomes. AB - Four-dimensional (4-D) flow magnetic resonance imaging (MRI) examination was performed 25 years after a neonatal direct arterial switch operation for simple transposition of the great arteries. The 4-D flow MRI video shows physiological spiral anatomical configuration and laminar streamlines in the great arteries. PMID- 28901234 TI - Risk Factors For Unfavorable Outcomes After Bidirectional Cavopulmonary Anastomosis. AB - BACKGROUND: Bidirectional cavopulmonary anastomosis (BCPA) is an important preliminary step toward the Fontan procedure; thus, understanding of risk factors for morbidity and mortality after BCPA may ultimately promote improved rates of success with Fontan completion and general survival. This study evaluated survival and predictors of unfavorable outcomes in patients after BCPA. METHODS: Clinical data of 157 patients who underwent BCPA from 2003 to 2015 at a single center were retrospectively analyzed. RESULTS: Three-year and nine-year survival after BCPA were 87.1% +/- 2.8% and 85.8% +/- 2.9%, respectively. Freedom from unfavorable outcomes (mortality, BCPA takedown, nonsuitability for Fontan procedure) was 83.8% +/- 3.1% at three years and 73.5% +/- 4.8% at nine years. Multivariate proportional hazards regression analysis revealed that total anomalous pulmonary venous connection (TAPVC; hazard ratio [HR]: 3.74, 95% confidence interval [CI]: 1.35-10.36; P = .01) and increased mean pressure in BCPA circuit (HR: 1.17, 95% CI: 1.02-1.34; P = .03) were independent risk factors for unfavorable outcomes. Postoperative mean pressure in BCPA circuit in patients with poor outcomes was median 16 mm Hg (interquartile range [IQR]: 14-18 mm Hg) versus median 14 mm Hg (IQR: 12-15.5 mm Hg) in patients with favorable outcomes ( P < .01). Preoperative (HR: 1.87, 95% CI: 1.20-2.91; P < .01) and postoperative atrioventricular valve regurgitation (AVVR; HR: 2.22, 95% CI: 1.24-3.94; P < .01) were also associated with unfavorable outcome in univariate Cox regression. CONCLUSIONS: Elevated mean pressure in the BCPA circuit is the main predictor of unfavorable outcome; therefore, thorough preoperative examination and careful patient selection are critical points for successful intermediate-stage and later Fontan completion. Total anomalous pulmonary venous connection and insufficient correction of AVVR worsen the prognosis in this patient group. PMID- 28901235 TI - Low-Dose Computed Tomographic Imaging of Partial Anomalous Pulmonary Venous Connection in Children. AB - BACKGROUND: In this study, we aimed to determine lobar distribution, drainage sites, and associated cardiovascular anomalies of partial anomalous pulmonary venous connection in pediatric patients using low-dose multidetector computed tomographic angiography. METHODS: Sixty-one cases (27 female, mean age: 4.7 years) with partial anomalous pulmonary venous connection diagnosed by multidetector computed tomographic angiography were included in this study. In all patients, multidetector computed tomographic angiography examinations were performed using dual-source 256-slice scanner without sedation. RESULTS: In 61 patients, 73 anomalous pulmonary veins were detected, 56 (77%) of them were right sided and 17 (23%) were left-sided. Of 56 right-sided anomalous pulmonary veins in 49 patients, 38 (68%) drained into superior vena cava, eight (14%) into atriocaval junction, six (11%) into inferior vena cava, three (5%) into right atrium, and one (2%) into levoatriocardinal vein. Of 17 left-sided anomalous pulmonary veins in 12 patients, 16 (94%) drained into left innominate vein, and one (6%) into coronary sinus. Only seven (12%) patients had isolated partial anomalous pulmonary venous connection, whereas 54 (88%) patients had additional cardiovascular anomalies. The most common (66%) associated anomaly is atrial septal defect. The overall mean effective radiation dose was 1.12 mSv (range: 0.15-7.41 mSv), and it was 0.58 mSv (range: 0.15-0.73) in the patients younger than one-year old. CONCLUSIONS: The presence and course of the anomalous pulmonary veins and associated cardiovascular anomalies can be reliably detected by dual-source 256-slice multidetector computed tomographic angiography with low radiation doses. PMID- 28901236 TI - Cardiac Tumors in Pediatric Patients: A Systematic Review. AB - This systematic review sought to investigate the current evidence regarding surgical management of primary cardiac tumors in children and adolescents. Twenty eight studies were deemed eligible, reporting on 745 pediatric patients. Rhabdomyoma was the most prevalent histologic type and echocardiography was the most common diagnostic tool. Cumulative 30-day mortality rate was 6.7%. Rhabdomyomas and teratomas had the highest 30-day mortality. The higher percentage of tumor relapse was noted for myxoma and teratoma. Although cardiac tumors are rare, their atypical clinical presentation, potential for recurrence, and the poor prognosis associated with recurrence elucidate the need for reliable diagnostic and therapeutic management. PMID- 28901240 TI - Celebrating exemplary ethical care: The Human Rights and Nursing Awards. PMID- 28901239 TI - Ethical issues in action-oriented research in Indonesia. AB - BACKGROUND: Action-oriented research is one of the most frequent research types implemented to transform community health in Indonesia. Three researchers and 11 graduate students from a developed country in East Asia conducted a fieldwork program in a remote area in South Sulawesi Province. Although the project was completed, whether or not the international standards for human subject research were applied into that study remains unclear. OBJECTIVES: This study aimed to examine ethical issues raised from that case, analyze constraints to the problems, and recommend alternatives to protect vulnerable populations from being exploited by local/international researchers. METHODS: A problem-solving approach was used in this study. It began with problem identification, evaluation of the action-oriented research goal, investigation of the constraints to the problem, and recommendation of some relevant alternatives to address the central issue. Ethical Consideration: The approval for conducting the action-oriented research that being investigated in this work was only obtained from the Head of local district. RESULTS: Some ethical issues were found in this case. No special protection for this population, no informed consent was obtained from the participants, exposure to social and economic risks, no future benefits for the subjects, and conflict of interests. Lack of control from the local research ethics committee and lack of competence of local researchers on human subject research were considered as the constraints to the problems. DISCUSSION: Creating an independent research ethics committee, providing research ethics training to the local researchers, obtaining written/video consents from underserved populations, and meeting local health needs were recommended alternatives to solve these problems. CONCLUSION: Indonesian government bodies should reform their international collaborative system on research involving human subjects. Exploitation may not occur if all participants as well as all local and national governing bodies understand the research ethics on human subjects and apply it into their practice. PMID- 28901241 TI - Citation for Martha Turner. PMID- 28901242 TI - Citations for the Human Rights and Nursing Awards 2017. PMID- 28901243 TI - An exploration into municipal waste charges for environmental management at local level: The case of Spain. AB - Municipal waste charges have been widely acknowledged as a crucial tool for waste management at the local level. This is because they contribute to financing the costly provision of waste collection and treatment services and they can be designed to provide an economic stimulus to encourage citizens and local businesses to improve separate collection and recycling. This work presents a methodology to evaluate a sample of 125 municipal waste charges in Spain for the year 2015, covering 33.91% of the Spanish population. The qualitative benchmarking of municipal waste charges shows that flat fees are frequent, whereas variable fees are set according to criteria that are weakly related to waste generation. The average fee per household is ?82.2 per year, which does not provide full cost recovery. The current configuration of municipal waste charges penalises taxpayers contributing to source separation of waste, while subsidising less environmentally friendly behaviours. In this sense, municipal waste charges in Spain are far from applying the polluter pays principle. Furthermore, it is argued that municipal waste charges are ineffective for promoting the proper application of the so-called 'waste hierarchy'. PMID- 28901244 TI - Inter-caste lovers' suicide pact - Case report from Nepal. AB - Discrimination on cultural and ethnic grounds is a crime in Nepal. [Caste Based Discrimination and Untouchability (Offence and Punishment) Act, 2068 (2011) * ?* There are two different dates which reflect the Bikram Sambat which is the official Hindu calendar in Nepal. This calendar is 57 years ahead of Gregorian calendar. For example, 19 August 2017 AD is 03 Bhadra 2074 Bikram Sambat. Thus, the date 2068 is in Bikram Sambat, 2011 is per Gregorian calendar which is unofficial so kept in parenthesis. This text is available online from: http://www.ilo.org/aids/legislation/WCMS_190732/lang-en/index.htm . ]. However, cases of caste-based discrimination continue and have been reported in the newspapers. They occur because most families refuse to accept inter-caste marriages in Nepal as they fear they will become social outcasts. We present a tragic case where a young couple in their 20s made a pact to end their lives by jumping from Nepal's highest suspension bridge. Preliminary police investigation suggested their inter-caste relationship was the reason. PMID- 28901245 TI - Investigation into perfluoroalkyl substances (PFASs) in a cranberry bog: method development and sampling results. AB - The contamination of groundwater and surface water from previous uses of perfluoroalkyl substances (PFASs), particularly products containing the contaminants perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), has become a concern for drinking water and as a potential exposure route to the food supply. In 2016, the Food and Drug Administration (FDA) was asked to investigate a bog in Massachusetts where the surface water was believed to be contaminated with PFASs. As a result, a method was developed for the analysis of PFASs in cranberries, and water and fruit from the affected bog were evaluated. A QuEChERS method was developed and validated for PFOA, PFOS, and six additional shorter chain PFASs. Method recoveries ranged from 60% to 115% for validation spikes performed at 10, 20 and 40 ng g-1 and method detection limits ranged from 0.2 to 5.6 ng g-1. Bog water samples were analysed using Environmental Protection Agency (EPA) method 537 for PFOA, PFOS and four additional short-chain PFASs. Surface water concentrations for PFOS ranged from 16 to 122 ng L-1 and input water concentrations were 132 ng L-1 and 206 ng L-1. Of the eight water samples, seven had water concentrations that exceeded the EPA health advisory level for PFOS of 70 ng L-1. Of the 42 cranberry samples analysed, none had detects of PFOA or PFOS above their method detection limits (0.4 and 0.5 ng g-1, respectively), nor any of the other short-chain PFASs. PMID- 28901246 TI - Editorial: Recent Advances in the Field of Kinases and Kinase Inhibitors. PMID- 28901247 TI - Effect on Morphology, Osmotic Fragility and Electro Kinetic Potential of Erythrocytes in Hypertension. AB - BACKGROUND: Hypertension is a common health problem concerning a large proportion of population and a leading global risk factor for the burden of cardiovascular disease (CVD). The purpose of this study was to assess the efficacy of the erythrocyte zeta potential as a potential additional indicator for cardiovascular disorder risk so that patients with this can be more rapidly identified and treated. METHODS: In the present study, blood samples were collected in 5% dextrose solution from patients suffering from hypertension and healthy volunteers (Not taken any medication). The mobility of individual RBCs was tracked by equipped Zeta meter-ZM4DAQ software using microscopicallyacquired video images, data were recorded 10 times for each sample and average zeta potential in mv was recorded. RESULTS: We found that mean erythrocytic ZP of control group was found to be 23.41 mv (+/- 1.87) whereas, erythrocytic ZP for Hypertensive patients was found to be 16.05 (+/-1.72) mV and Hypertensive patients with Diabetes is much lower from 6.96 mV to 22.76 (+3.88) mV along with structural deformities and increased osmotic fragility of erythrocytes. CONCLUSION: The data suggest that there are morphological changes in erythrocyte structure, increased osmotic fragility along with significantly lower ZP value as compared to that of healthy volunteers which may be the major cause for progression to the development of cardiovascular disease. PMID- 28901249 TI - Proteins Commonly Linked to Autism Spectrum Disorder and Alzheimer's Disease. AB - Several years after the first publication of Barker's Hypothesis the identification of common patterns and pathways between genetic and epigenetic risk factors in neurodegenerative disorders is still an open problem. For the cases of Alzheimer's disease and Autism and by taking into consideration the increasing number of diagnosed cases globally, scientists focused on commonly expressed and related proteins like Amyloid beta and the mechanisms of their underlying dysfunctionalities. In this review paper, an attempt to specify significant correlations between proteins linked to Autism Spectrum Disorders and Alzheimer's Disease is presented. Both diseases are highlighted with an emphasis on the macromolecules that play a fundamental role in their development. These proteins are described and analyzed concerning the underlying pathology of these diseases. PMID- 28901248 TI - Review on Synthetic Chemistry and Antibacterial Importance of Thiazole Derivatives. AB - BACKGROUND: Thiazole is one of the leading heterocyclic five-member ring compounds that contain nitrogen and sulphur atom. Many natural and/or synthetic compounds contain thiazole as an essential moiety and possess diverse therapeutic activities. The thiazole ring was modified at different positions to generate new molecules with potent antibacterial activities. Thus, the present review enumerates the antibacterial importance of thiazole and its derivatives. METHOD: The mining of literature has been performed using different database which includes only peer-reviewed journals. The quality of retrieved papers was appraised using standard tools. Moreover, the significant papers were described in detail to focus on thiazole derivatives showing considerable antibacterial activity. RESULT: The present review describes the chemistry, SAR (Structure Activity Relationship) studies and antibacterial importance of thiazole with different synthetic procedures. CONCLUSION: This particular study certainly benefits the researchers interested in exploiting the antibacterial activity of thiazoles in search of novel agents. PMID- 28901250 TI - XBP-1, a Cellular Target for the Development of Novel Anti-viral Strategies. AB - X-box binding protein 1 (XBP-1) is a key regulator of the unfolded protein response (UPR), which is activated in response to endoplasmic reticulum (ER) stress. Cells contain two protein isoforms of XBP-1, the active isoform (XBP-1S) and the inactive isoform (XBP-1U). Induction of UPR leads to the generation of XBP-1S while XBP-1U is dominant in ER stress-free cells. XBP-1S is a transcriptional activator and regulates the expression of a subset of UPR genes. Importantly, recent studies have demonstrated the essential role of XBP-1S in various human diseases, such as viral infections. Many viruses have evolved to manipulate UPR/XBP-1 of the infected cells to promote viral survival and replication. In this review, we will summarize the current findings on the involvement of XBP-1 in viral infection/ replication and discuss the potential anti-viral strategies by targeting XBP-1. PMID- 28901251 TI - Case Report: Severe Hematological, Muscle and Liver Toxicity Caused by Drugs and Artichoke Infusion Interaction in an Elderly Polymedicated Patient. AB - BACKGROUND: Case report, in a patient with a history of diabetes and hypertension, treated with metformin, gliclazide, enalapril + hydrochlorothiazide, amlodipine, aspirin and diazepam, recently medicated for a gouty crisis with colchicine and clonixin without improvement. Believing it could help in the treatment of gouty crisis symptoms he took about 1.5 L of artichoke infusion (Cynara cardunculus). He felt better and did agriculture work but developed a distal muscle pain, severe anemia, standard biochemical liver cholestasis, increase of alkaline phosphatase and marked increase of inflammatory parameters (hyperleucocytosis) and enters in the emergency department at the hospital. OBJECTIVE: Evaluation of the cause of complaints and laboratory abnormalities and the involvement of artichoke infusion. RESULTS: The prominence of the inflammatory parameters was ruled out because of exhaustive autoimmune, infectious or para-neoplastic syndrome (blood cultures, serology, diagnostic imaging, bone marrow and bone biopsy, muscle biopsy and nerve, abdominal angiography) were carried out showing normal results. The evaluation pointed out that the concomitant intake of artichoke infusion may have been involved in the framework developed, since the drugs which were being administered to/by the patient have a metabolism mainly mediated by CYP450 3A4 and 2C9 that could be compromised when these isoenzymes are inhibited by phenolic and flavonoid compounds from plants. Colchicine was one of the last drugs took that have as side effects most of the symptoms felt by patient including diarrhea and anemia. CONCLUSION: The spontaneous and complete recovery of the patient and the negativity of research looking for other causes, conduce to a strong possibility of the interaction between artichoke and the drugs in the clinical presentation of this case. PMID- 28901252 TI - The Origin and Identification of Mesenchymal Stem Cells in Teeth: from Odontogenic to Non-odontogenic. AB - BACKGROUND: Mesenchymal stem cells (MSCs) in teeth have been exploited as vital seed cells for stem cell-based dental medicine. To date, several mesenchymal stem cell populations originated from odontogenic tissue have been isolated and characterized by their expression of MSC surface markers and capacity of multi lineage differentiation, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP) and so on. However, their identity in vivo remains elusive, which hinders further understanding of their application in stem cell-based tooth regeneration. Label retaining and lineage tracing analyses, which serve as gold standards for identification of stem cells in vivo, provide feasibility for identifying MSCs in teeth. OBJECTIVES: In this review, we will discuss the issues of MSCs, including the origin and identification of both odontogenic and non-odontogenic MSCs, and address the role of nerve-derived Sonic hedgehog (Shh) in the regulation of MSCs in the neurovascular bundle (NVB). CONCLUSION: Based on label retaining and lineage tracing analyses, latest studies have found new populations of non odontogenic MSCs in teeth, periarterial-derived and glial-derived, regulated by the Shh derived from nerves in the NVB, which provides a new hope for tooth regeneration. PMID- 28901253 TI - Bacterial Toxins: A Hope Towards Angiogenic Ailments. AB - BACKGROUND: Angiogenesis is an essential physiological process for growth and maintenance of the body. Especially its role becomes indispendable during the embryonic development stage but lacks in adults with some exceptions like while wound repair and menstrual cycle. It is a tightly regulated process and relies on the cascade of several molecular signaling pathways with the involvement of many effectors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) etc. METHODS: Related literature/ information were retrieved, analyzed and compiled from the online published resources available in Medline, Pubmed, Pubmed Central, Science Direct and other scientific databases. RESULTS: Excessive angiogenesis leads to disorders like tumor, atherosclerosis, rheumatoid arthritis, diabetic retinopathy, endometriosis, psoriasis, and adiposity. While, reduced angiogenesis also results in several ailments like cardiac ischemia, low capillary density in brain of Alzheimer's patients and delayed wound healing. Therefore, both angio-proliferative and anti-angiogenic approaches may be of use in developing novel therapeutics. Bacterial toxins are known for modulating the process of angiogenesis by mimicking pro-angiogenic factors and/ or competing with them. Furthermore, they inactivate the receptors or keep them in ON status, hence can be used to treat angiogenic disorders. The ease in handling, cultivation and manipulating the toxins structure has enabled the use of bacteria as an ideal choice for novel therapeutic developments. CONCLUSION: This review intends to elucidate the molecular mechanisms through which certain bacteria may alter the level of angiogenesis and consequently can work as therapeutics against angiogenic disorders. PMID- 28901255 TI - Health Benefits of Manuka Honey as an Essential Constituent for Tissue Regeneration. AB - BACKGROUND: Honey is known for its therapeutic properties from ancient civilizations. Recently, the mechanism of action of Manuka honey in wound healing, epithelial regeneration, and ulcer treatments has been revealed. OBJECTIVE: In the current review, the health perspectives of honey, its chemical composition with special reference to flavonoids, polyphenol, and other bioactive trace compounds used in tissue regeneration have been discussed in detail. METHODS: We undertook a structured search using wide spectrum sources like Google Scholar, PubMed, and Scopus. RESULTS: The included papers showed that Manuka honey can inhibit the process of carcinogenesis by controlling different molecular processes, and progression of cancer cells. Manuka honey has been found to have various biological activities, including antioxidant, antimicrobial and anti-proliferative capacities. Scientists try to use Manuka honey in the area of tissue engineering to design a template for regeneration. Naturally derived antibacterial agents of Manuka honey are numerous mixtures of different compounds, which can influence antibacterial capacity. The non-peroxide bacteriostatic properties of Manuka honey are associated with the presence of methylglyoxal (MGO). CONCLUSION: In addition to bacterial growth inhibition, glyoxal (GO) and MGO from Manuka honey can enhance wound healing and tissue regeneration by their immunomodulatory property. Further studies are needed to provide detailed information about active components of Manuka honey and their potential efficacy in different diseases. PMID- 28901256 TI - Editorial: Frontier View on Drug Discoveries for Different Diseases - Part II. PMID- 28901257 TI - Molecular characterization of two polysaccharides from Phellinus vaninii Ljup and their anti-tumor activities. AB - Two water-soluble polysaccharides (PV-W, PV-B) were isolated and purified from fruiting bodies of P. vaninii Ljup (a traditional Chinese medicine) by hot water and sodium hydroxide, respectively. The chemical structure was analyzed by FT-IR, GC-MS analysis and 13C NMR spectra. The results illustrated that PV-W was a heteropolysaccharide, mainly composed of mannose, glucose, arabinose and galactose. PV-B was a beta-1, 3-D-glucan branched with beta-1, 6-D-glucose. The results of viscometry proved that PV-W and PV-B could be molecularly dispersed in water without aggregation. The results of SEC-MALLS-RI indicated that the two polysaccharides with the similar Mw but different chain conformation. PV-W was a stable chain with globular shape, while PV-B was a more expanded flexible random coils conformation. MTT assay indicated that PV-B showed higher inhibition effect on HepG2 and HeLa cells than PV-W in vitro. This work provided the important information of active components from traditional Chinese medicines and its potential applications in the food and medicine industry. PMID- 28901258 TI - From biology to therapy: Improvements of therapeutic options in Lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (non-small cell lung cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (epithelial growth factor receptor) mutations that predict sensitivity to the anti-EGFR tyrosine kinase inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intra-tumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (programmed death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor. PMID- 28901259 TI - Structure-Based Design: Synthesis, X-ray Crystallography, and Biological Evaluation of N-Substituted-4-Hydroxy-2-Quinolone-3-Carboxamides as Potential Cytotoxic Agents. AB - BACKGROUND: Oncogenic potential of phosphatidylinositol 3-kinase (PI3Kalpha) has been highlighted as a therapeutic target for anticancer drug design. OBJECTIVE: Target compounds were designed to address the effect of different substitution patterns at the N atom of the carboxamide moiety on the bioactivity of this series. METHODS: Synthesis of the targeted compounds, crystallography, biological evaluation tests against human colon carcinoma (HCT-116), and Glide docking studies. RESULTS: A new series of N-substituted- 4-hydroxy-2-quinolone-3 carboxamides was prepared and characterized by means of FT-IR, 1H and 13C NMR, and elemental analysis. In addition, the identity of the core nucleus 5 was successfully characterized with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human colon carcinoma (HCT-116) cell line. Results revealed that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Compounds 7, 14, and 17 which have H-bond acceptor moiety on p-position displayed promising PI3Kalpha inhibitory activity. On the other hand, derivatives tailored with bulky and hydrophobic motifs (16 and 18) on o- and m-positions exhibited moderate activity. Molecular docking studies against PI3Kalpha and caspase-3 showed an agreement between the predicted binding affinity (DeltaGobsd) and IC50 values of the derivatives for the caspase-3 model. Furthermore, Glide docking studies against PI3Kalpha demonstrated that the newly synthesized compounds accommodate PI3Kalpha kinase catalytic domain and form H bonding with key binding residues. CONCLUSION: The series exhibited a potential PI3Kalpha inhibitory activity in HCT-116 cell line. PMID- 28901260 TI - VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells. AB - AIMS: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. METHODS: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. RESULTS: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability. PMID- 28901254 TI - Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future. AB - BACKGROUND: Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials. METHODS: We performed a structured search of bibliographic databases for peer-reviewed research literature on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis. RESULTS: Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and antibodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiotics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparticles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other subunit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles). CONCLUSIONS: This review provides important insights into the various approaches to therapeutics and immunoprophylaxis against noroviruses and rotaviruses. PMID- 28901261 TI - Spices with Breast Cancer Chemopreventive and Therapeutic Potentials: A Functional Foods Based-Review. AB - BACKGROUND: Cancer is a multifaceted metabolic disease that affects sizeable dwellers of rural and urban areas. Among the various types of cancer, mammary cancer is one of the most frequently diagnosed cancers in women. Its menace can be curbed with locally consumed spices due to their multiple bioactive phytochemicals. AIMS: This review focuses on the breast cancer chemopreventive and therapeutic potentials of locally consumed spices. METHODS/RESULTS: The most commonly consumed spices with breast cancer chemopreventive and chemotherapeutic phytochemical include pepper, onions, ginger, garlic, curry and thyme containing many biologically active metabolites ranging from vitamins, fatty acids esters, polyphenols/phenolics, sulfurcontaining compounds and anthraquinones with proven antioxidant, anti-inflammatory, immuno-modulatory, antitumor and anticancer properties against breast cancer/carcinogenesis. Therefore, extracts and active principles of these spices could be explored in breast cancer chemoprevention and possibly therapeutically which may provide an avenue for reducing the risk and prevalence of breast cancer. PMID- 28901262 TI - Novel Findings of Anti-cancer Property of Propofol. AB - BACKGROUND: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. CONCLUSION: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms. PMID- 28901263 TI - alpha-Aroylketene Dithioacetal Mediated Synthesis of (E)-3-(benzo[d]thiazol-2 ylamino)-2-(1-methyl-1H-indole-3-carbonyl)-3-(methylthio)acrylonitrile Derivatives and their Biological Evaluation. AB - BACKGROUND: The blending of two pharmacophores would generate novel molecular templates that are likely to exhibit interesting biological properties. OBJECTIVE: A facile, efficient and high yielding synthesis of (E)-3 (benzo[d]thiazol-2-ylamino)-2-(1-methyl-1Hindole- 3-carbonyl)-3-(methylthio) acrylonitrile derivatives and evaluation of therapeutic potential. METHOD: The synthesis of target molecules has been achieved by reacting 2-aminobenzothiazole and substituted 2-(1-methyl-1H-indole-3-carbonyl)-3,3 bis(methylthio)acrylonitrile in the presence of a catalytic amount of sodium hydride in THF. Structural investigations were carried using 1H NMR, 13C NMR, FT IR, and HRMS data. RESULTS: In vitro anti-tumor evaluation of the synthesized compounds against MCF-7 (breast carcinoma) cell line revealed that they possess good anti-tumor activities. Compounds, 4j and 4i demonstrated significant activities against breast carcinoma (GI50 14.3 and 19.5 uM respectively). Most of the synthesized compounds were also found to be excellent NO, H2O2, DPPH, and superoxide radical scavengers. Anti-diabetic and antiinflammatory evaluation also displayed moderate activity. CONCLUSION: Among the compounds synthesized some of the compounds possess significant anticancer, antioxidant and anti-inflammatory properties. PMID- 28901264 TI - Inhibition of Proliferation and Induction of Apoptosis by Thymoquinone via Modulation of TGF Family, p53, p21 and Bcl-2alpha in Leukemic Cells. AB - INTRODUCTION: Adult T-cell leukemia (ATL) is an aggressive form of malignancy caused by human T- cell lymphotropic virus 1 (HTLV-1). Currently, there is no effective treatment for ATL. Thymoquinone has been reported to have anti-cancer properties. OBJECTIVE: The aim of this study is to investigatthe effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. MATERIALS AND METHODS: Cells were incubated with different thymoquinone concentrations for 24h. Cell cytotoxicity was assayed using the CytoTox 96(r) Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96(r) Non-Radioactive Cell Proliferation. Cell cycle analysis was performed by staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. RESULTS: At non-cytotoxic concentrations of TQ, it resulted in the inhibition of proliferation in a dose dependent manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increase DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFbeta1, p53 and p21 and a down-regulation of TGF-alpha and Bcl-2alpha. CONCLUSION: Thymoquinone presents antiproliferative and proapoptotic effects in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL. PMID- 28901265 TI - Stereocomplexation Assisted Assembly of Poly(gamma-glutamic Acid)-graft polylactide Nano-micelles and Their Efficacy as Anticancer Drug Carrier. AB - BACKGROUND: Micelles as drug carriers are characterized by their inherent instability due to the weak physical interactions that facilitate the self assembly of amphiphilic block copolymers. As one of the strong physical interactions, the stereocomplexation between the equal molar of enantiomeric polylactides, i.e., the poly(L-lactide) (PLLA) and poly(D-lactide) (PDLA), may be harnessed to obtain micelles with enhanced stability and drug loading capacity and consequent sustained release. AIMS/METHODS: In this paper, stereocomplexed micelles gama-PGA-g-PLA micelles) were fabricated from the stereocomplexation between poly(gama-glutamic acid)-graft-PLLA gama-PGA-g-PLA) and poly(gamaglutamic acid)-graft-PDLA gama-PGA-g-PLA). These stereocomplexed micelles exhibited a lower CMC than the corresponding enantiomeric micelles. RESULT: Furthermore, they showed higher drug loading content and drug loading efficiency in addition to more sustained drug release profile in vitro. In vivo imaging confirmed that the DiR-encapsulated stereocomplexed gama-PGA-g-PLA micelles can deliver anti-cancer drug to tumors with enhanced tissue penetration. Overall, gama-PGA-g-PLA micelles exhibited greater anti-cancer effects as compared with the free drug and the stereocomplexation may be a promising strategy for fabrication of anti-cancer drug carriers with significantly enhanced efficacy. PMID- 28901266 TI - Editorial: Challenges in the Treatment with New Oral Anticoagulants. PMID- 28901267 TI - Therapeutic Drug Monitoring in Pediatric IBD: Current Application and Future Perspectives. AB - BACKGROUND: as the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine and its role in the management of IBD patients is rapidly expanding. OBJECTIVE: to review the current knowledge that poses the rationale for the use of TDM, and the present and future role of TDM-based approaches in the management of pediatric IBD. METHOD: literature review. RESULTS: the concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti TNF therapies. TDM-based strategies proved to be costeffective in the management of patients with loss of response to biologics and, more recently, proactive TDM to optimize drug exposure has been shown to reduce treatment failure and drug adverse events. The role of TDM with new biologics and the usefulness of software systems support tools to guide drug dosing are now under investigation. CONCLUSION: Therapeutic drug monitoring has the potential to maximize the cost benefit profile of therapies and is becoming an essential part of IBD management. PMID- 28901268 TI - NRG1-ErbB Lost in Translation: A New Paradigm for Lung Cancer? AB - BACKGROUND: Molecular lesions of the NRG1 gene were recently described as a new molecular feature of Invasive Mucinous Adenocarcinoma of the lung. The NRG1 chimeric ligand leads to aberrant activation of the ErbB2/ErbB3 signaling via PI3K-AKT and MAPK cellular cascades. This review aims to highlight the current knowledge about the ErbB network and the effect of NRG1 deregulation in lung cancer and their merger into the ErbB/PI3K-AKT axis modulation by current pharmacologic strategies. METHODS: We performed a structured search of bibliographic databases for peer-reviewed literature to outline the state of the art with regard ErbB signaling deregulation and NRG1 function in lung cancer. The quality of retrieved papers was assessed using standard tools and one hundred thirty-five were included in the review. In many papers the molecular lesions affecting the ErbB receptors in lung cancer but also in other type of solid tumors were updated. Papers describing the physiological role of NRG1 in cells was also screened for the review preparation, as well as the paper reporting NRG1 fusions in lung cancer and their implication in aberrant ErbB pathway activation. RESULTS AND CONCLUSION: Overall, this review highpoints how the knowledge of new molecular mechanisms of ErbB pathway deregulation may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel molecular markers of patients' stratification. Moreover, this ultimately led the selection of new compounds designed to inhibit the bound between Nrg1-ErbB3 as a good alternative way to block the ErbB intracellular signaling. PMID- 28901269 TI - Recent Advances in Cancer Drug Development: Targeting Induced Myeloid Cell Leukemia-1 (Mcl-1) Differentiation Protein. AB - BACKGROUND: Anti-apoptotic members of the Bcl-2 family of proteins are upregulated in a majority of cancers and are potential therapeutic targets. Fragment-based design led to the development of clinical candidates that target Bcl-xL/Bcl-2. Although these BclxL/ Bcl-2 inhibitors showed promise in pre clinical studies, resistance to several Bcl-xL inhibitors was observed, when used alone. This is attributed to the over-expression of Mcl-1, another member of the Bcl-2 family of proteins. Indeed, Mcl-1 is highly amplified in numerous cancers, suggesting that it may contribute to malignant cell growth and evasion of apoptosis. Therefore, significant efforts have been made toward the development of direct Mcl-1 inhibitors for cancer therapy. METHODS: Following an extensive search of peer-reviewed articles on the development of Mcl-1-selective inhibitors, the literature retrieved is chronologically arranged and discussed in this review article. RESULTS: We have included 147 articles in this review; including articles that describe the development of stapled peptides with improved binding affinity as Mcl-1-selective BH3 mimetics, those describing fragment-based and structure-based design of small molecule Mcl-1 inhibitors by various research groups, and those detailing the use of natural products and their derivatives as potential Mcl-1 inhibitors. CONCLUSION: The therapeutic potential of targeting the Mcl-1 protein for cancer drug discovery is vast. Stapling BH3 peptides, as well as the development of small molecule inhibitors as BH3 mimetics, are viable strategies to develop selective Mcl-1 inhibitors. With no clinically approved candidate in hand, additional modes of perturbing the biological function of this protein will aid drug discovery efforts. PMID- 28901270 TI - Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs. AB - The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so called cGASSTING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus. PMID- 28901271 TI - The Role of Cannabinoid Receptors in Renal Diseases. AB - BACKGROUND: Chronic kidney disease (CKD) remains a major challenge for Public Health systems and corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for CKD except nephroprotective strategies. The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in CKD. METHODS: We performed PubMed searches using the terms "cannabinoid receptors" in combination with "kidney" or "renal disease" or "nephropathy" or "diabetes" or "renal fibrosis" or "cellular pathways" in various combinations. We analyzed full-text English-language papers. We also searched the reference lists of identified articles for further relevant papers. RESULTS: We gathered data regarding the current state of knowledge on the cannabinoid system in normal renal physiology and in various experimental nephropathies, especially diabetes. We also reviewed data obtained in models of diabetes and obesity as well as in non metabolic models of renal fibrosis when CB1 blockers and/or CB2 agonists were used. We also found that very few data are available so far regarding the cellular pathways involved downstream of the cannabinoid receptors in the development of renal fibrosis. CONCLUSION: Overall, we found that the cannabinoid receptors are a promising target in the development of renal disease and fibrosis, particularly in CKD and diabetes. PMID- 28901272 TI - Disorders of Mechanisms of Calcium Metabolism Control as Potential Risk Factors of Prostate Cancer. AB - Prostate cancer significantly affects the overall morbidity and mortality of malignant tumours in highly developed countries. Important risk factors include family predisposition and regional, racial and dietary determinants. The scientific literature contains a great deal of data on the role of calcium and dairy products in general in the process of neoplastic transformation of the prostate. This is most likely linked to the fact that changes in the concentration of calcium ions control such varied life processes as secretion of hormones and neurotransmitters, the level of cyclic nucleotides, and cell growth, division and differentiation. Research is conducted to demonstrate that disorders of cell cycle control due to differences in calcium ion concentrations may be crucial for the development and prevention of cancer. Disturbances of calcium homeostasis in the body can be caused by various mechanisms, such as excessive calcium intake in the diet, vitamin D deficiency, structural and functional changes in vitamin D receptor (VDR), Calcium-Sensing Receptor (CaSR), and parathyroid hormone receptor (PTH-1-R), changes in calcium ion channels, phosphate metabolism disorders (phosphatonin and the Klotho protein), changes in the level of parathyroid hormone-related protein (PTHrP), and others. The article presents data on the mechanisms maintaining calcium homeostasis at the molecular level and genetic aspects playing a role in the pathogenesis of prostate cancer. The data cited on the occurrence of abnormal mechanisms of calcium metabolism in prostate cancer suggest the need for individualized intake of this element in the diet, especially in the case of patients with a family history of PCa. PMID- 28901273 TI - Oleuropein: Molecular Dynamics and Computation. AB - BACKGROUND: Olive oil and table olive biophenols have been shown to significantly enrich the hedonic-sensory and nutritional quality of the Mediterranean diet. Oleuropein is one of the predominant biophenols in green olives and leaves, which not only has noteworthy freeradical quenching activity but also putatively reduces the incidence of various cancers. Clinical trials suggest that the consumption of extra virgin olive oil reduces the risk of several degenerative diseases. The oleuropein-based bioactives in olive oil could reduce tumor necrosis factor alpha, interleukin-1beta and nitric oxide. Therefore, the quality of olive biophenols should be preserved and even improved due to their disease fighting properties. OBJECTIVE: Understanding the molecular dynamics of oleuropein is crucial to increase olive oil and table olive quality. The objective of this review is to provide the molecular dynamics and computational mapping of oleuropein. METHOD: The oleuropein molecular bond sequential breaking mechanisms were analyzed through unimolecular reactions under electron spray ionization, collision activated dissociations, and fast atom bombardment mass spectrometry. RESULTS: Oleuropein is a biophenol-secoiridoid expressing different functionalities such as two pi-bonds, two esters, two acetals, one catechol, and four hexose hydroxyls within 540 mw. The oleuropein solvent-free reactivity is leading to glucose loss and bioactive aglycone-dialdehydes via secoiridoid ring opening. CONCLUSION: Oleuropein electron distribution revealed that the free radical non-polar processes occur from its highest occupied molecular orbital, while the lowest unoccupied molecular orbital is clearly devoted to nucleophilic and base site reactivity. This molecular dynamics and computational mapping of oleuropein could contribute to the engineering of olive-based biomedicine and/or functional food. PMID- 28901274 TI - Revalorizing lignocellulose for the production of natural pharmaceuticals and other high value bioproducts. AB - Lignocellulose is the most plentiful, renewable natural resource on earth and has been successfully used for the production of biofuels. A significant challenge is to develop cost-effective, environmentally friendly and efficient processes for the conversion of lignocellulose material into suitable substrates for biotransformation. A number of approaches have been explored to convert lignocellulose into sugars, e.g. combining chemical pretreatment and enzymatic hydrolysis. In nature, there are organisms that can biotransform the complex lignocellulose efficiently, such as wood-degrading fungi (brown rot and white rot fungi), bacteria (e.g. Clostridium thermocellum), arthropods (e.g. termite) and certain animals (e.g. ruminant). Here, we highlight recent case studies of the natural degraders and the mechanisms involved, providing new utilities in biotechnology. The sugars produced from such biotransformations can be used in metabolic engineering and synthetic biology for the complete biosynthesis of natural medicine. The unique opportunities in using lignocellulose directly to produce natural drug molecules with either using mushroom and/or 'industrial workhorse' organisms (Escherichia coli and Saccharomyces cerevisiae) will be discussed. PMID- 28901275 TI - Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists. AB - BACKGROUND: Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. OBJECTIVE: It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain. METHODS: Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis. RESULTS: Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome. CONCLUSIONS: Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations. PMID- 28901277 TI - Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. AB - BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life. METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block. RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases. PMID- 28901276 TI - Immunocontraception: Filamentous Bacteriophage as a Platform for Vaccine Development. AB - BACKGROUND: Population control of domestic, wild, invasive, and captive animal species is a global issue of importance to public health, animal welfare and the economy. There is pressing need for effective, safe, and inexpensive contraceptive technologies to address this problem. Contraceptive vaccines, designed to stimulate the immune system in order to block critical reproductive events and suppress fertility, may provide a solution. Filamentous bacteriophages can be used as platforms for development of such vaccines. OBJECTIVE: In this review authors highlight structural and immunogenic properties of filamentous phages, and discuss applications of phage-peptide vaccines for advancement of immunocontraception technology in animals. RESULTS: Phages can be engineered to display fusion (non-phage) peptides as coat proteins. Such modifications can be accomplished via genetic manipulation of phage DNA, or by chemical conjugation of synthetic peptides to phage surface proteins. Phage fusions with antigenic determinants induce humoral as well as cell-mediated immune responses in animals, making them attractive as vaccines. Additional advantages of the phage platform include environmental stability, low cost, and safety for immunized animals and those administering the vaccines. CONCLUSION: Filamentous phages are viable platforms for vaccine development that can be engineered with molecular and organismal specificity. Phage-based vaccines can be produced in abundance at low cost, are environmentally stable, and are immunogenic when administered via multiple routes. These features are essential for a contraceptive vaccine to be operationally practical in animal applications. Adaptability of the phage platform also makes it attractive for design of human immunocontraceptive agents. PMID- 28901278 TI - Neuroinflammation and the Immune-Kynurenine Pathway in Anxiety Disorders. AB - BACKGROUND: Recently, neuroinflammation and the immune-kynurenine pathway have received increased attention in the psychoimmunology field of major depressive disorder (MDD), while studies related to anxiety disorders have been very limited. OBJECTIVE: This study reviewed possible mechanisms by which stress or inflammation modulate anxiety through tryptophan metabolism and the kynurenine pathway. METHODS: Relevant literature was identified through a search of MEDLINE via PubMed. RESULTS: Accumulating evidence has indicated the modulatory effects of the immune-kynurenine pathway on anxiety. The tryptophan catabolites (TRYCATs) in the kynurenine pathway imbalanced by stress or inflammation induce serotonin and melatonin deficiency, making anxiety reactions more sensitive. In addition, TRYCATs cause or sustain anxiety by acting as endogenous anxiogens or anxiolytics, an NMDA agonist or antagonist, or a free radical generator. CONCLUSION: We hope that our understanding of the psychoimmunological mechanisms of anxiety will be expanded and anxiety-related studies will receive greater attention. PMID- 28901280 TI - Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. Numerous studies have shown that the expression and/or function of nAChRs is compromised in many neurological and psychiatric diseases. Furthermore, recent studies have shown that neuronal nAChRs are found in a large number of nonneuronal cell types including endothelial cells, glia, immune cells, lung epithelia and cancer cells where they regulate cell differentiation, proliferation and inflammatory responses. The aim of this review is to describe the most recent findings concerning the structure and function of native nAChRs inside and outside the nervous system. PMID- 28901282 TI - Antihistamines for treating rhinosinusitis: systematic review and meta-analysis of randomised controlled studies. AB - BACKGROUND: Without the release of histamines, patients with rhinosinusitis may not benefit from antihistamines. Additionally, anticholinergic effects may do more harm than good. This study aimed to investigate the effectiveness of antihistamines in treating rhinosinusitis. METHODS: An electronic search was performed. Randomised controlled trials comparing antihistamines with either placebo or other treatments for patients with rhinosinusitis were selected. RESULTS: Two studies (184 patients) met the inclusion criteria. Loratadine decreased nasal obstruction in allergic rhinitis patients with acute rhinosinusitis (mean difference = -0.58; confidence interval = -0.85 to -0.31, p < 0.01), but had no benefit on total symptom score (mean difference = -1.25; confidence interval = -2.77 to 0.27, p = 0.11), or rhinorrhoea symptoms (mean difference = -0.06; confidence interval = -0.37 to 0.25, p = 0.71). CONCLUSION: There is limited evidence to support the use of antihistamines in treating rhinosinusitis. The number of included studies in this systematic review is limited. Antihistamines may relieve nasal obstruction in allergic rhinitis patients with acute rhinosinusitis. PMID- 28901279 TI - The Role of Physical Exercise and Omega-3 Fatty Acids in Depressive Illness in the Elderly. AB - BACKGROUND: In adulthood, depression is the most common type of mental illness and will be the second leading cause of disease by 2020. Major depression dramatically affects the function of the central nervous system and degrades the quality of life, especially in old age. Several mechanisms underlie the pathophysiology of depressive illness, since it has a multifactorial etiology. Human and animal studies have demonstrated that depression is mainly associated with imbalances in neurotransmitters and neurotrophins, hypothalamic-pituitary adrenal axis alterations, brain volume changes, neurogenesis dysfunction, and dysregulation of inflammatory pathways. Also the gut microbiota may influence mental health outcomes. Although depression is not a consequence of normal aging, depressive disorders are common in later life, even if often undiagnosed or mis diagnosed in old age. When untreated, depression reduces life expectancy, worsens medical illnesses, enhances health care costs and is the primary cause of suicide among older people. To date, the underpinnings of depression in the elderly are still to be understood, and the pharmacological treatment is the most commonly used therapy. OBJECTIVE: Since a sedentary lifestyle and poor eating habits have recently emerged as crucial contributors to the genesis and course of depression, in the present review, we have focused on the effects of physical activity and omega-3 fatty acids on depressive illness in the elderly. RESULTS: A growing literature indicates that both exercise and dietary interventions can promote mental health throughout one's lifespan. CONCLUSION: There thus emerges the awareness that an active lifestyle and a balanced diet may constitute valid low cost prevention strategies to counteract depressive illness in the elderly. PMID- 28901284 TI - Correction: N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. PMID- 28901281 TI - Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. AB - BACKGROUND: The aim of this review was to identify the mechanisms by which serotonin receptors involved at the central level are able to modulate the nociceptive response. Pain is a defense mechanism of the body that entails physiological, anatomical, neurochemical, and psychological changes, and is defined as an unpleasant sensory and emotional experience with potential risk of tissue damage, comprising the leading cause of appointments with Physicians worldwide. Treatment for this symptom has generated several neuropharmacological lines of research, due to the different types of pain and the various drugs employed to treat this condition. Serotonin [5- HydroxyTryptamine (5-HT)] is a neurotransmitter with seven families (5-HT1-5-HT7) and approximately 15 receptor subtypes. Serotonin modulates neuronal activity; however, this neurotransmitter is related with a number of physiological processes, such as cardiovascular function, gastric motility, renal function, etc. On the other hand, several researches reported that serotonin modulates nociceptive response through 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the Central Nervous System (CNS). METHOD: In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation Index for studies evaluating the effects of 5-HT1, 5-HT2, 5-HT3, and 5 HT7 receptors in the CNS on the modulation of different types of pain. CONCLUSION: We concluded that 5-HT1, 5-HT2, 5-HT3, and 5-HT7 receptors in the CNS modulate the pain, but this depends on the distribution of the receptors, dose of agonists or antagonists, administration route, pain type and duration in order to inhibit, excite, or even maintain the nociceptive response. PMID- 28901283 TI - A systematic review of religious beliefs about major end-of-life issues in the five major world religions. AB - OBJECTIVE: The objective of this study was to examine the religious/spiritual beliefs of followers of the five major world religions about frequently encountered medical situations at the end of life (EoL). METHOD: This was a systematic review of observational studies on the religious aspects of commonly encountered EoL situations. The databases used for retrieving studies were: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycINFO, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Observational studies, including surveys from healthcare providers or the general population, and case studies were included for review. Articles written from a purely theoretical or philosophical perspective were excluded. RESULTS: Our search strategy generated 968 references, 40 of which were included for review, while 5 studies were added from reference lists. Whenever possible, we organized the results into five categories that would be clinically meaningful for palliative care practices at the EoL: advanced directives, euthanasia and physician-assisted suicide, physical requirements (artificial nutrition, hydration, and pain management), autopsy practices, and other EoL religious considerations. A wide degree of heterogeneity was observed within religions, depending on the country of origin, level of education, and degree of intrinsic religiosity. SIGNIFICANCE OF RESULTS: Our review describes the religious practices pertaining to major EoL issues and explains the variations in EoL decision making by clinicians and patients based on their religious teachings and beliefs. Prospective studies with validated tools for religiosity should be performed in the future to assess the impact of religion on EoL care. PMID- 28901285 TI - A case study for a psychographic-behavioral segmentation approach for targeted demand generation in voluntary medical male circumcision. AB - Public health programs are starting to recognize the need to move beyond a one size-fits-all approach in demand generation, and instead tailor interventions to the heterogeneity underlying human decision making. Currently, however, there is a lack of methods to enable such targeting. We describe a novel hybrid behavioral psychographic segmentation approach to segment stakeholders on potential barriers to a target behavior. We then apply the method in a case study of demand generation for voluntary medical male circumcision (VMMC) among 15-29 year-old males in Zambia and Zimbabwe. Canonical correlations and hierarchical clustering techniques were applied on representative samples of men in each country who were differentiated by their underlying reasons for their propensity to get circumcised. We characterized six distinct segments of men in Zimbabwe, and seven segments in Zambia, according to their needs, perceptions, attitudes and behaviors towards VMMC, thus highlighting distinct reasons for a failure to engage in the desired behavior. PMID- 28901287 TI - Causal evidence for lateral prefrontal cortex dynamics supporting cognitive control. AB - The lateral prefrontal cortex (LPFC) is essential for higher-level cognition, but the nature of its interactions in supporting cognitive control remains elusive. Previously (Nee and D'Esposito, 2016), dynamic causal modeling (DCM) indicated that mid LPFC integrates abstract, rostral and concrete, caudal influences to inform context-appropriate action. Here, we use continuous theta-burst transcranial magnetic stimulation (cTBS) to test this model causally. cTBS was applied to three LPFC sites and a control site in counterbalanced sessions. Behavioral modulations resulting from cTBS were largely predicted by information flow within the previously estimated DCM. However, cTBS to caudal LPFC unexpectedly impaired processes that are presumed to involve rostral LPFC. Adding a pathway from caudal to mid-rostral LPFC significantly improved the model fit and accounted for the observed behavioral findings. These data provide causal evidence for LPFC dynamics supporting cognitive control and demonstrate the utility of combining DCM with causal manipulations to test and refine models of cognition. PMID- 28901286 TI - Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. AB - Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Muller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss. PMID- 28901288 TI - Multiple conserved cell adhesion protein interactions mediate neural wiring of a sensory circuit in C. elegans. AB - Nervous system function relies on precise synaptic connections. A number of widely-conserved cell adhesion proteins are implicated in cell recognition between synaptic partners, but how these proteins act as a group to specify a complex neural network is poorly understood. Taking advantage of known connectivity in C. elegans, we identified and studied cell adhesion genes expressed in three interacting neurons in the mating circuits of the adult male. Two interacting pairs of cell surface proteins independently promote fasciculation between sensory neuron HOA and its postsynaptic target interneuron AVG: BAM-2/neurexin-related in HOA binds to CASY-1/calsyntenin in AVG; SAX 7/L1CAM in sensory neuron PHC binds to RIG-6/contactin in AVG. A third, basal pathway results in considerable HOA-AVG fasciculation and synapse formation in the absence of the other two. The features of this multiplexed mechanism help to explain how complex connectivity is encoded and robustly established during nervous system development. PMID- 28901292 TI - Control of gliding in a flying snake-inspired n-chain model. AB - Flying snakes of genus Chrysopelea possess a highly dynamic gliding behavior, which is dominated by an undulation in the form of lateral waves sent posteriorly down the body. The resulting high-amplitude periodic variations in the distribution of mass and aerodynamic forces have been hypothesized to contribute to the stability of the snake's gliding trajectory. However, a previous 2D analysis in the longitudinal plane failed to reveal a significant effect of undulation on the stability in the pitch direction. In this study, a theoretical model was used to examine the dynamics and stability characteristics of flying snakes in three dimensions. The snake was modeled as an articulated chain of airfoils connected with revolute joints. Along the lines of vibrational control methods, which employ high-amplitude periodic inputs to produce desirable stable motions in nonlinear systems, undulation was considered as a periodic input to the system. This was implemented either by directly prescribing the joint angles as periodic functions of time (kinematic undulation), or by assuming periodic torques acting at the joints (torque undulation). The aerodynamic forces were modeled using blade element theory and previously determined force coefficients. The results show that torque undulation, along with linearization-based closed loop control, could increase the size of the basin of stability. The effectiveness of the stabilization provided by torque undulation is a function of the amplitude and frequency of the input. In addition, kinematic undulation provides open-loop stability for sufficiently large frequencies. The results suggest that the snakes need some amount of closed-loop control despite the clear contribution of undulation to glide stability. However, as the closed-loop control system needs to work around a passively stable trajectory, undulation lowers the demand for a complex closed-loop control system. Overall, this study demonstrates the possibility of maintaining stability during gliding using a morphing body instead of symmetrically paired wings. PMID- 28901289 TI - Distinct stages of synapse elimination are induced by burst firing of CA1 neurons and differentially require MEF2A/D. AB - Experience and activity refine cortical circuits through synapse elimination, but little is known about the activity patterns and downstream molecular mechanisms that mediate this process. We used optogenetics to drive individual mouse CA1 hippocampal neurons to fire in theta frequency bursts to understand how cell autonomous, postsynaptic activity leads to synapse elimination. Brief (1 hr) periods of postsynaptic bursting selectively depressed AMPA receptor (R) synaptic transmission, or silenced excitatory synapses, whereas more prolonged (24 hr) firing depressed both AMPAR and NMDAR EPSCs and eliminated spines, indicative of a synapse elimination. Both synapse silencing and elimination required de novo transcription, but only silencing required the activity-dependent transcription factors MEF2A/D. Burst firing induced MEF2A/D-dependent induction of the target gene Arc which contributed to synapse silencing and elimination. This work reveals new and distinct forms of activity and transcription-dependent synapse depression and suggests that these processes can occur independently. PMID- 28901293 TI - Anomalous thermal conductance of graphyne under lower temperature. AB - The thermal transport properties of graphyne are investigated via equilibrium molecular dynamics (EMD) simulations and non-equilibrium Green's function (NEGF) method. It is found that the room-temperature thermal conductivity of graphyne is 93% lower than that of graphene with a similar size and decreases steeply with increasing the number of acetylenic linkages, which agrees with the results obtained by NEGF method qualitatively. Lattice dynamics calculations reveal that these phenomena can be attributed to the reduction of both phonon group velocities and phonon lifetimes in graphyne at low-frequency region. However, when the temperature is less than 30 K, the thermal conductance of graphyne exceeds that of graphene. Moreover, the anomalous thermal conductance behavior is not sensitive to the system lateral size. The underlying mechanisms for such phenomena are elaborated by the normal mode analysis. PMID- 28901294 TI - PEGylated anticancer-carbon nanotubes complex targeting mitochondria of lung cancer cells. AB - Although activating apoptosis in cancer cells by targeting the mitochondria is an effective strategy for cancer therapy, insufficient targeting of the mitochondria in cancer cells restricts the availability in clinical treatment. Here, we report on a polyethylene glycol-coated carbon nanotube-ABT737 nanodrug that improves the mitochondrial targeting of lung cancer cells. The polyethylene glycol-coated carbon nanotube-ABT737 nanodrug internalized into the early endosomes via macropinocytosis and clathrin-mediated endocytosis in advance of early endosomal escape and delivered into the mitochondria. Cytosol release of nanodrug led to apoptosis of lung cancer cells by abruption of the mitochondrial membrane potential, inducing Bcl-2-mediated apoptosis and generating intracellular reactive oxygen species. As such, this study provides an effective strategy for increasing the anti-lung cancer efficacy by increasing mitochondria accumulation rate of cytosol released anticancer nanodrugs. PMID- 28901295 TI - Fabrication of water-dispersible single-walled carbon nanotube powder using N methylmorpholine N-oxide. AB - Dispersion of nanocarbon materials in liquid media is one of prerequisites for practical applications via solution processing such as spraying, printing, spinning, etc. Here we report that water-dispersible single-walled carbon nanotubes (SWCNTs) were prepared through successive treatments with chlorosulfuric acid (CSA)/H2O2 and N-methylmorpholine N-oxide (NMO) monohydrate. The powder of the CSA/H2O2- and NMO-treated SWCNTs (N-SWCNTs) could be readily redispersed in water in concentrations as high as 1 g L-1 without requiring a dispersant. The mechanism responsible for the high dispersity of the N-SWCNT powder in polar solvents, including water, was elucidated based on the high polarity of the NMO molecule. In order to highlight the wide applicability of the N-SWCNTs, they were used successfully to prepare conducting thin films by spray coating plastic substrates with an aqueous hybrid solution containing the N SWCNTs and Ag nanowires (NWs). In addition, a flexible, large-area thin-film heater was prepared based on the N-SWCNT/AgNW hybrid film with a transmittance of 93% and sheet resistance of 30 Omega sq-1. PMID- 28901296 TI - Negative terahertz photoconductivity in 2D layered materials. AB - The remarkable qualities of 2D layered materials such as wide spectral coverage, high strength and great flexibility mean that ultrathin 2D layered materials have the potential to meet the criteria of next-generation optoelectronic devices. Photoconductivity is one of the critical parameters of materials applied to optoelectronics. In contrast to traditional semiconductors, specific ultrathin 2D layers present anomalous negative photoconductivity. This opens a new avenue for designing novel optoelectronic devices. It is important to have a deep understanding of the fundamentals of this anomalous response, in order to design and optimize such devices. In this review, we provide an overview of the observation of negative photoconductivity in 2D layered materials including graphene, topological insulators and transitional metal dichalcogenides. We also summarize recent reports on investigations into the fundamental mechanism using ultrafast terahertz (THz) spectroscopies. Finally, we conclude the review by discussing the existing challenges and proposing the possible prospects of this direction of research. PMID- 28901298 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 28901297 TI - Metabolic effects of inhaled salbutamol determined by exhaled breath analysis. AB - We explore whether real-time breath analysis by high resolution mass spectrometry is suitable to monitor changes at the metabolic level due to inhaling bronchodilator medication. We compared the breath levels of metabolites in a group of patients (n = 50) at baseline and 10 and 30 min after inhalation of 200 MUg salbutamol. The same procedure was performed with a group of controls (n = 48) inhaling a placebo spray. A total of 131 mass spectral features were significantly altered as a result of inhaling medication, but not after inhaling placebo. We found that homologous series of chemical classes correlated strongly with each other, strengthening the notion that certain biochemical processes can be monitored. For example, a series of fatty acids was found to be increased after salbutamol intake, suggesting lipolysis stimulation. Peaks corresponding to salbutamol, its main metabolite salbutamol-4-O-sulfate and formoterol were found to be generally increased in patients inhaling the drugs on an as-needed basis, as compared to non-medicated volunteers. Overall, these results suggest such real time breath analysis is a useful tool for non-invasive therapeutic drug monitoring. PMID- 28901299 TI - Focus on graphene and related materials. PMID- 28901300 TI - Expert consensus workshop report: Guideline for three-dimensional-printing template-assisted computed tomography-guided 125I seeds interstitial implantation brachytherapy. PMID- 28901301 TI - Expert consensus workshop report: Guideline for three-dimensional printing template-assisted computed tomography-guided 125I seeds interstitial implantation brachytherapy. AB - Radioactive 125I seeds (RIS) interstitial implantation brachytherapy has been a first-line treatment for early-stage cancer of the prostate gland. However, its poor accuracy and homogeneity has limited its indication and hampered its popularization for a long time. Intriguingly, scholars based in China introduced computed tomography (CT)-guided technology to improve the accuracy and homogeneity of RIS implantation and broadened the indications. Then, they creatively designed and introduced three-dimensional printing coplanar template (3D-PCT) and 3D printing noncoplanar template (3D-PNCT) into the practice of RIS implantation. Use of such templates makes RIS implantation more precise and efficacious and aids preoperative planning, real-time dose optimization, and postoperative planning. However, studies on the standard workflow for 3D-PT assisted CT-guided RIS implantation have not been published. Therefore, the China Northern Radioactive Seeds Brachytherapy Group organized multidisciplinary experts to formulate the guideline for this emerging treatment modality. This guideline aims at standardizing 3D-PT-assisted CT-guided RIS implantation procedures and criteria for selecting treatment candidates and assessing outcomes and for preventing and managing postoperative complications. PMID- 28901302 TI - The clinical application of HPV E6/E7 mRNA testing in triaging women with atypical squamous cells of undetermined significance or low-grade squamous intra epithelial lesion Pap smear: A meta-analysis. AB - OBJECTIVE: The aim is to evaluate the clinical application value and correlation with cervical lesions' progression of human papillomavirus (HPV) E6/E7 mRNA test in women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intraepithelial lesions (LSILs/mild dyskaryosis) cytological abnormalities. METHODS: A meta-analysis was conduct by searching China National Knowledge Infrastructure (1979-2016), Wanfang Date (1998 2016), VIP (1989-2016), PubMed (1950-2016), Web of Science (1950-2016) and Elsevier Science Direct (1998-2016), for studies on effect of HPV E6/E7 mRNA detection in women with ASCUS/LSIL/dyskaryosis. Study selection and appraisal were conducted independently by three authors, according to inclusive and exclusive criteria. Then, a meta-analysis was performed using the RevMan4.2 software. The subgroups analysis was conducted according to women's initial HPV DNA test results. RESULTS: Six articles with a total of 1024 subjects were included in the study. It was concluded that a positive HPV E6/E7 mRNA tested result have a higher risk of progressing to CIN2+ in future 2 years than a negative result. The pooled relative risk (RR) is 3.08, (95% confidence interval [CI] = 1.57-6.07, P < 0.05). The same situation was also observed in the subgroup of HPV DNA tested positive group and HPV DNA tested unlimited group. The pooled RR value of the two subgroups was, respectively, 1.98, (95% CI = 1.19-1.19, P < 0.05) and 7.58, (95% CI = 3.64-3.64, P < 0.05). CONCLUSION: A positive HPV E6/E7 mRNA testing result suggested the women with ASCUS, or LSIL Pap smear was in a truly dangerous position, which is an adverse prognostic factor. It suggested that cervical lesions stay in a progressing status and these women should be referred for colposcopy and strengthen follow-up promptly. Whereas, women with a negative HPV E6/E7 mRNA testing result can increase follow-up interval, by comprehensively considering their situation, thus, avoiding unnecessary colposcopy and reducing the rate of colposcopy and biopsy. PMID- 28901303 TI - Role of collagen triple helix repeat containing-1 in tumor and inflammatory diseases. AB - Initially, collagen triple helix repeat containing-1 (CTHRC1) is expressed mainly in adventitial fibroblasts and neointimal smooth muscle cells of balloon-injured vessels, and increases cell migration, promotes tissue repair in response to injury. A variety of studies demonstrated that over-expression of CTHRC1 in solid tumors results in enhancement of migration and invasion of tumor cells, and is associated with decreased overall survival and disease-free survival. CTHRC1 expression is elevated in hepatitis B virus-infected patients and highly correlated with hepatocellular carcinoma progression as well. Furthermore, CTHRC1 plays a pivotal role in a great many fields, including increases bone mass, prevents myelination, reverses collagen synthesis in keloid fibroblasts, and increases fibroblast-like synoviocytes migration speed and abundant production of arthritic pannus in rheumatoid arthritis. Therefore, it will provide new insight into the pathogenesis of tumor and autoimmune diseases, and will shed new light on the therapy of related clinical diseases. PMID- 28901304 TI - Efficacy comparison of radiofrequency ablation and hepatic resection for hepatocellular carcinoma: A meta-analysis. AB - OBJECTIVES: The objective of this study is to compare the therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A literature search was performed for comparative studies reporting outcomes of both RFA and HR for HCC. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: A total of 4812 patients with HCC were included, with 2419 in the RFA group and 2393 in the HR group. The 3- and 5-year overall survival rates in the HR group were significantly higher than those in the RFA group (OR: 0.68, 95% CI: 0.58-0.79, P < 0.00001; OR: 0.57, 95% CI: 0.50-0.65, P < 0.00001, respectively). 1-, 3-, 5-year disease-free survival and correspond recurrence-free survival rates were all better in HR group. CONCLUSION: RFA gets promising clinical outcomes for HCC treatments but is not yet comparable to surgery. HR is still the first-line treatment for HCC. PMID- 28901305 TI - Transarterial embolization with N-butyl 2-cyanoacrylate for the treatment of arterioportal shunts in patients with hepatocellular carcinoma. AB - AIMS: The aim of this study is to evaluate efficacy and safety of transarterial chemoembolization (TACE) with N-butyl 2-cyanoacrylate (NBCA) for the treatment of hepatocellular carcinoma (HCC) with arterioportal shunts (APS). SUBJECTS AND METHODS: From January 2008 to June 2014, 36 cases of HCC with APS were treated by TACE with NBCA. NBCA-lipiodol mixture was superselective delivered before routine TACE in HCC patients with APS. Recanalization of shunt, objective response, clinical adverse events, and survival rates was retrospectively studied. RESULTS: All interventional procedures were successful without any procedure relevant complications. The immediate APS improvement rate was 83.3% (30/36), and the APS improvement rate at first-time follow-up was 66.6% (20/30). Radiologically confirmed complete response (CR), partial response, stable disease, and progressive disease at 1 month after first chemoembolization were observed in 1 (2.7%), 19 (52.8%), 6 (16.7%), and 10 (27.8%) patients, respectively. Survival rates were 91.7% at 6 months, 47.2% at 1 year, and 13.9% at 2 years. The median survival time was 11 months. No severe adverse effects were noted. CONCLUSIONS: The preliminary experience indicates TACE with NBCA can be safely performed and may improve prognosis of HCC with arterioportal shunt. PMID- 28901306 TI - Bronchial artery chemoembolization combined with radioactive iodine-125 seed implantation in the treatment of advanced nonsmall cell lung cancer. AB - OBJECTIVE: The aim of this study was to investigate the short-term efficacy and safety of bronchial artery chemoembolization (BACE) combined with radioactive iodine-125 seed implantation in the treatment of nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty-two Stage III-IV NSCLC patients were divided into Groups A and B. Thirty cases were treated with BACE combined with radioactive iodine-125 seed implantation in the Group A and 32 cases were treated with BACE alone in the Group B until disease progression. Efficacy, incidence rate of adverse drug reactions, and survival rate were compared between the two groups. RESULTS: The local control rates and effective rates of Groups A and B were 90% and 59.3% and 74% and 40.6%, respectively, with P < 0.05 for each. The progression-free survival of the study group and the control group was 12.6 and 8.2 months, respectively; the median survival time of the Groups A and B was 644 and 544 days, and the difference was statistically significant (P = 0.034). CONCLUSION: BACE combined with radioactive iodine-125 seed implantation was safe and effective in the treatment of advanced NSCLC, with an efficacy superior to that of single BACE. PMID- 28901307 TI - A retrospective analysis of the efficacy of microparticle-mediated chemoembolization in liver metastases arising from gastrointestinal tumors. AB - PURPOSE: We evaluated the clinical efficacy of gelatin sponge microparticle (GSM) -mediated chemoembolization for the treatment of patients with liver metastases following surgery for gastrointestinal tumors. MATERIALS AND METHODS: In a retrospective analysis of 37 patients who were treated at our hospital with GSM mediated chemoembolization for liver metastases over 13 years, we evaluated outcomes using a modified response evaluation criteria in solid tumors system and also assessed liver function and adverse effects. All patients had previously undergone surgery for gastrointestinal tumors. RESULTS: Treatment produced various degrees of necrosis and shrinkage of lesions among our patients. Two patients achieved a complete response (CR), 27 showed a partial response (PR), five had stable disease, and three had progressive disease. The overall response rate (CR + PR) was 78%, and no severe adverse effects were observed. CONCLUSION: GSM-mediated chemoembolization showed good clinical efficacy in the treatment of liver metastases after gastrointestinal tumor surgery. However, larger cohort and clinical controlled studies are warranted. PMID- 28901308 TI - Utility of fluorescence in situ hybridization analysis for detecting upper urinary tract-urothelial carcinoma. AB - OBJECTIVES: The objective of this study was to evaluate the clinical utility of fluorescence in situ hybridization (FISH) in the detection of upper urinary tract urothelial carcinoma (UUT-UC). METHODS: Between November 2011 and November 2015, voided urine specimens from 52 consecutive patients with UUT-UC and 26 controls were collected for both FISH test and cytology. Sensitivity and specificity of FISH test and cytology were determined and compared. The frequency of chromosomal aberrations was also analyzed. RESULTS: For FISH analysis, the sensitivity was 79.5% and specificity was 96.3%. For cytology, the sensitivity was 27.3% and specificity was 100%. The overall sensitivity for FISH was significantly higher than that of in single value-based urine cytology (79.5% vs. 27.3%, respectively, P < 0.001). The sensitivities of FISH and cytology by grade were 64.3% vs. 28.6% for low-grade urothelial carcinomas (P = 0.128) and 86.7% vs. 26.7% for high grade urothelial carcinomas (P < 0.001), respectively. Twenty-seven (77.1%) cases were positive due to the gain of two or more chromosomes in five or more urinary cells, among which, 21 (60%) cases showed positivity in all the 4 chromosomes, 7 (20%) cases matched the criterion that 10 or more cells gained a single chromosome, whereas only 1 (2.9%) case was positive because of the homozygous deletion of 9p21 in 12 or more cells. CONCLUSIONS: FISH has superior sensitivity and similar specificity in the detection of UUT-UC, compared with cytology. The present findings indicated that FISH can be applied as a noninvasive diagnostic tool for suspected UUT-UC patients. PMID- 28901309 TI - Kinesin superfamily protein expression and its association with progression and prognosis in hepatocellular carcinoma. AB - OBJECTIVES: In this study, we characterized the expression of 32 other kinesin superfamily proteins (KIFs) and analyzed their association with the progression and prognosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The data from 295 HCC patients from The Cancer Genome Atlas were included in the study. An independent t-test was used to compare the KIF levels in HCC and adjacent tissues. Pearson's Chi-square test was used to assess the relationships of KIF expression with tumor biomarkers and clinicopathological parameters. Kaplan-Meier plots and log-rank tests were used to analyze survival, and univariate and multivariate analyses were used to identify independent prognostic factors. RESULTS: The expressions of 32 KIFs were compared between HCC and adjacent nontumor tissues. Among them, 12 KIFs showed no statistical significance, 17 KIFs were upregulated, and three KIFs were downregulated in tumor tissues. The levels of some KIFs were markedly correlated with that of biomarkers for the S phase and proliferation. KIF2A and KIFC3 expression was positively associated with biomarkers for cell invasion and migration. Some KIF overexpression was significantly associated with neoplastic pathological grade and tumor-node metastasis staging. Furthermore, KIF2C, KIF4A, and KIF11 overexpression were significantly associated with shorter relapse-free survival times. KIF2A, KIF2C, KIF3A, KIF4B, KIF11, KIF15, KIFC1, and KIFC3 overexpression was associated with shorter overall survival (OS) times, whereas higher expression of KIF19 was associated with a longer OS time. Further multivariate analyses suggested that only KIF4B was an independent prognostic factor for HCC. CONCLUSIONS: Most overexpressions of abnormal KIFs were significantly associated with HCC progression and prognosis, indicating that KIFs could be prognostic and therapeutic biomarkers for HCC. However, it is necessary to further study the function of KIFs and their mechanisms involved in HCC. PMID- 28901310 TI - Treatment outcomes of malignant fibrous histiocytoma of the maxillary sinus. AB - BACKGROUND: Malignant fibrous histiocytoma (MFH) is an uncommon neoplasm of maxillary sinus. This study was designed to investigate the clinical courses and summarize the experience of the treatment outcomes. MATERIALS AND METHODS: This is a retrospective analysis which included patients with MFH of the maxillary sinus from January 1980 to December 2008 treated in our institute. Survival data were analyzed by means of the Kaplan-Meier method using univariate analysis and Cox regression model using multivariate analysis. RESULTS: The study included 31 patients. Of which, one patient received radical radiotherapy, and thirty patients received surgical resection. Of these, thirty patients received preoperative radiotherapy, and 11 patients received postoperative radiotherapy. Radical resection with clear surgical margins was obtained in twelve patients (80%) after preoperative radiotherapy, and in eight patients (53.3%) with postoperative radiotherapy (P = 0.221). The 3-year overall survival rate (OS) and recurrence-free survival rate (RFS) were 59.0% and 43.5%, respectively. Patients treated with a radical resection had significantly better survival than patients with a nonradical resection. Three-year OS was 79.8% and 28.1%, 3-year RFS was 61.9% and 18.5%, respectively (P = 0.001 and 0.029, respectively). Local recurrence rate (LRR) was lower in patients resected with clear surgical margins than patients with unclear or uncertain margins, and the 3 years LRR was 33.3% and 72.2%, respectively (P = 0.052). CONCLUSIONS: Surgical resection is the mainstay of treatment for MFH of the maxillary sinus. A radical resection with clear margins is essential for excellent local control and long-term survival. PMID- 28901311 TI - Overexpression of KIAA1199: An independent prognostic marker in nonsmall cell lung cancer. AB - OBJECTIVE: KIAA1199 has been identified as an oncogene in many cancers. Here, we collected 153 cases of nonsmall cell lung cancer (NSCLC) tissues to investigate the relationships between KIAA1199 protein and clinical factors. MATERIALS AND METHODS: Immunohistochemistry (IHC) staining was used to detect the expression of KIAA1199. Follow-up included blood analysis, chest X-ray, ultrasound examination, and computed tomography was carried out every 3 months for the first 2 years and at 6-month intervals thereafter during the follow-up period (3 years). Kaplan Meier survival analysis and Cox analysis were applied to identify the relationship between KIAA1199 and NSCLC. RESULTS: IHC results showed that 76 (49.67%) specimens had strong expression of KIAA1199 protein, with poor differentiation (P = 0.003), higher positive lymph node metastasis (P = 0.037), and higher tumor node metastasis stage (P = 0.016). Using Kaplan-Meier survival analysis, it is found that patients with high KIAA1199 protein expression have poor overall survival (P = 0.004). Cox analysis suggested that the KIAA1199 protein was an independent prognostic marker for NSCLC patients (P = 0.040). CONCLUSION: Our findings revealed that KIAA1199 protein could be applied in predicting NSCLC patient's outcome. PMID- 28901312 TI - Magnetic resonance imaging evaluation after radiofrequency ablation for malignant lung tumors. AB - OBJECTIVE: The objective of this study was to investigate magnetic resonance imaging (MRI) assessment of the therapeutic response in small lung malignancies (<3 cm) immediately after radiofrequency ablation (RFA). MATERIALS AND METHODS: This is a retrospective analysis of MRI performance in 24 cases of small lung tumors (16 primary, 8 metastatic; 20 patients) immediately, post-RFA, and at follow-up. Variables measured included maximum diameters of tumors on pre-RFA MRI, central areas of low signal intensity (SI) on post-RFA T2-weighted images (T2WIs), and central areas of high SI on post-RFA T1WIs. Additional post-RFA measurements included the maximum diameters for areas of ground-glass opacities (GGOs) on computed tomography (CT), high SI on T2WIs, and isointense SI on T1WIs. Mean values were used for statistical analysis. RESULTS: Before RFA, 16 primary and seven metastatic lung tumors showed isointense signals on T1WIs and hyperintense signals on T2WIs. Immediately after RFA, the ablated lesions showed central low signals and peripheral high annular signals on T2WIs and central high signals and peripheral annular isointense signals on T1WIs, with reduced SI on diffusion-weighted images. Significant differences were found between the preoperative MRI maximum tumor diameter and post-RFA diameters of central low SI areas on T2WIs and central high SI areas on T1WIs. Furthermore, there were significant differences between the post-RFA maximum diameter of circumferential high signals on T2WIs and the post-RFA maximum diameters of both GGOs on CT and circumferential isointense signals on T1WIs. There were three cases of local recurrence (two pulmonary metastases and one primary) during follow-up. CONCLUSIONS: MRI evaluation of the therapeutic response of RFA for small malignant lung tumors (<3 cm) was precise and reliable. PMID- 28901313 TI - MicroRNA-30c inhibits metastasis of ovarian cancer by targeting metastasis associated gene 1. AB - BACKGROUND: It is important to find reliable molecular markers or biological targets that associate with ovarian cancer (OC) metastasis for diagnosis and treatment. In this study, researchers investigated the regulated chain of microRNA-30c (miR-30c) and metastasis-associated gene 1 (MTA1) in OC tissues and cells. MATERIALS AND METHODS: Expression of miR-30c and MTA1 was detected with quantitative real-time polymerase chain reaction and immunohistochemistry in 33 OC and matched adjacent tissues. MiR-30c mimics were synthetized and transfected into SKOV3 cells to target MTA1. The wound healing and transwell assays were detected to observe migration and invasion of transfected OC cells. RESULTS: Compared with matching normal ovarian tissues, the MTA1 expression was upregulated and localized in the cytoplasm, and the expression of miR-30c was significantly reduced. The expression intensity of MTA1 was correlated with the Federation of Gynecology and Obstetrics stage, tumor grade, and metastasis of OC. Transfecting miR-30c mimics could significantly reduce the expression of MTA1 in SKOV3 cells and obviously inhibit the migration and invasion of SKOV3 cells. CONCLUSION: MiR-30c and MTA1 abnormally expressed in OC, which may be related to metastasis of OC. In MiR-30c as a tumor suppressor gene, its expression in OC could lead to reduced expression of MTA1, which may be one of the mechanisms of metastasis of OC cells. PMID- 28901314 TI - Repeated percutaneous microwave ablation for local recurrence of inoperable Stage I nonsmall cell lung cancer. AB - BACKGROUND: The safety and effectiveness of repeated computed tomography-guided percutaneous microwave ablation (MWA) in the management of local recurrence (LR) in patients with medically inoperable Stage I nonsmall cell lung cancer (NSCLC) were retrospectively evaluated. MATERIALS AND METHODS: From February 2008 to August 2014, 104 patients with medically inoperable Stage I NSCLC received MWA. Patients with LR were given repeat MWA. The clinical outcomes and complications of repeat MWA for LR were evaluated. RESULTS: At a median follow-up of 47 months, LR occurred in 24/104 (23.1%) patients within 12 +/- 8 months after MWA. LR rates were higher in tumors> 3.5 cm than that of tumors <=3.5 cm (35.7% vs. 18.4%). Local control of the repeat MWA was achieved in 21 of 24 (87.5%) patients. Overall survival (OS) and progress-free survival (PFS) for patients without LR were similar to that of with LR and receiving repeat MWA (OS: 48 m vs. 41.5 m; PFS: 42 m vs. 32 m). The OS rates were 100%, 74.6%, 60.6%, and 27% for patients without LR at 1, 2, 3, and 5 years, and they were 96.4%, 69.5%, 60.6%, and 26.1% for patients with repeat MWA for LR. Repeat MWA for LR was not associated with more significant complications. CONCLUSION: The LR was higher in tumors> 3.5 cm than that of in tumors <=3.5 cm. For patients with LR, it was feasible and effective to use MWA repeatedly to achieve the similar OS and PFS as patients without LR. No additional complications were reported in the repeat MWA compared to the original MWA. PMID- 28901315 TI - Serum expression level of squamous cell carcinoma antigen, highly sensitive C reactive protein, and CA-125 as potential biomarkers for recurrence of cervical cancer. AB - OBJECTIVE: The aim of this study was to evaluate the serum expression levels of squamous cell carcinoma antigen (SCC-Ag), highly sensitive C-reactive protein (hs CRP), and CA-125 as potential serum biomarkers for recurrence of cervical cancer. METHODS: Eighty-six cervical cancer patients who received radical treatment were retrospectively included in this study from February 2011 to January 2014. Of the included 86 cases, 23 were recurred within the 36 months (recurrence group [RG]) and other 63 patients did not (non-RG [NRG]). The serum levels of SCC-Ag, hs-CRP, and CA-125 were examined and compared between the two groups. The prediction recurrence sensitivity, specificity area under the receiver operating characteristic curve were calculated by STATA11.0 software (http://www.stata.com). The correlation among SCC-Ag, hs-CRP, and CA-125 were analyzed by Pearson correlation test. RESULTS: The serum levels of SCC-Ag, hs CRP, and CA-125 were 1.29 (0.21-33.20) mg/mL, 4.78 (0.22-175.20) mg/mL, and 11.56 (2.028-123.66) IU/mL for NRG and 5.64 (0.50-136.80) mg/mL, 22.41 (0.56-588.90) mg/mL, and 25.41 (3.658-3687.00) IU/mL for RG, respectively. The serum levels of SCC-Ag, hs-CRP, and CA-125 in NG group were significant higher than those of NRG group (P < 0.05). The recurrence prediction sensitivity was 0.74, 0.65, and 0.74; specificity was 0.65, 0.63, and 0.58; area under the curve was 0.75, 0.66, and 0.67, respectively, for serum SCC-Ag, hs-CRP, and CA-125. Significant positive correlation between SCC-Ag and hs-CRP (rpearson = 0.20, P = 0.04), SCC-Ag and CA 125 (rpearson = 0.64, P < 0.001), hs-CRP and CA-125 (rpearson= -0.13, P = 0.56) was found in the RG patients. CONCLUSION: Serum SCC-Ag, hs-CRP, and CA-125 were higher in recurrence cervical patients which could be potential biomarkers for predicting cervical cancer recurrence risk. PMID- 28901316 TI - Comparison of different width detector on the gross tumor volume delineation of the solitary pulmonary lesion. AB - PURPOSE: To explore the impact of different width detector on the volume and geometric position of gross tumor volume (GTV) of the solitary pulmonary lesion (SPL), as well as the impact on scanning time and radiation dose during the simulation. MATERIALS AND METHODS: Twenty-three patients with SPL underwent three dimensional computed tomography (3DCT) simulation using different width detector, followed by four-dimensional computed tomography (4DCT) scans. GTV16 and GTV4 derived from different width detectors were compared with internal gross tumor volume (IGTV) generated from 4DCT on the volume and geometric position. Fourteen patients with lesions located in the upper lobe were defined as Group A and nine patients in the middle or lower lobe were defined as Group B. The scanning time and radiation dose during the simulation with the different width detector were compared as well. RESULTS: The volumes of IGTV, GTV16, and GTV4 in Group A were 13.86 +/- 14.42 cm3, 11.88 +/- 11.93 cm3, and 11.64 +/- 12.88 cm3, respectively, and the corresponding volumes in Group B were 12.84 +/- 11.48 cm3, 6.90 +/- 6.63 cm3, and 7.22 +/- 7.15 cm3, respectively. No difference was found between GTV16 and GTV4 in Groups A and B (PA = 0.11, PB = 0.86). Either GTV16 or GTV4 was smaller than IGTV (P16 = 0.001, P4 = 0.000). The comparison of the centroidal positions in x, y, and z directions for GTV16, GTV4, and IGTV showed no significant difference both in Groups A and B (Group A: Px = 0.19, Py = 0.14, Pz = 0.47. Group B: Px = 0.09, Py = 0.90, Pz = 0.90). The scanning time was shorter and radiation dose patient received was lower using 16 * 1.5 mm detector combination than 4 * 1.5 mm detector (P = 0.000). CONCLUSIONS: Different width detector had no impact on the volume and geometric position of GTV of SPL during 3DCT simulation. Using wide detector would save time and decrease radiation dose compared with the narrow one. 3DCT simulation using either 16 * 1.5 mm detector or 4 * 1.5 mm detector could not cover all tumor motion information that 4DCT offered under free breathing conditions. PMID- 28901317 TI - k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with nonsmall cell lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between k-RAS gene mutation and the resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with nonsmall-cell lung cancer (NSCLC). METHODS: Forty-five pathologies confirmed NSCLC patients who received EGFR-TKI (Gefitinib) treatment were retrospectively included in this study. The mutation of codon 12 and 13, located in exon1 and exon 2 of k-RAS gene were examined by polymerase chain reaction (PCR) and DAN sequencing in tumor samples of the included 45 NSCLC patients. The correlation between Gefitinib treatment response and k-RAS mutation status was analyzed in tumor samples of the 45 NSCLC patients. RESULTS: Eight tumor samples of the 45 NSCLC patients were found to be mutated in coden 12 or 13, with an mutation rate of 17.8% (8/45); the objective response rate (ORR) was 29.7%(11/37) with 1 cases of complete response (CR) and 10 cases of partial response in k-RAS mutation negative patients. Furthermore, the ORR was 0.0% in k-RAS mutation positive patients with none CR. The ORR between k-RAS mutation and nonmutation patients were significant different (P < 0.05). CONCLUSION: k-RAS gene mutation status was associated with the response of Gefitinib treatment in patients with NSCLC. PMID- 28901318 TI - Surgical treatment is an effective approach for patients with synchronous multiple primary lung cancers. AB - OBJECTIVE: The detection rate of synchronous multiple primary lung cancers (SMPLC) showed an increasing trend year by year. In an attempt to identify the optimal treatment strategy for SMPLC, we retrospectively analyzed our surgical treatment outcomes of a series of patients with SMPLC. MATERIALS AND METHODS: A total of 43 SMPLC patients who met the modified Martini-Melamed criteria and with clinical data retained between November 2012 and July 2016 underwent complete resection without any preoperative induction therapy at the Department of Thoracic Surgery, Shandong Provincial Hospital. The relationships between gender, age, family history of cancer, the number of tumors, the location of tumors, tumor size, tumor histology, regional lymph node metastasis, type of surgery, pathological stage, epidermal growth factor receptor (EGFR) mutation, mortality, and survival were further analyzed. RESULTS: Among the 43 patients, 29 (67.4%) patients had ipsilateral tumors, whereas 14 (32.6%) patients had contralateral tumors. Nine patients with contralateral tumors underwent one-stage surgical treatment, with mean postoperative hospitalization days of 9.8. EGFR mutations were detected in 5 patients with synchronous multiple primary lung adenocarcinomas (SMPLA) for each lesion independently. The results showed different tumors in the same patient could carry different EGFR mutations. The 1- and 3-year overall survival (OS) rates were 97.0% and 76.7%, respectively. Larger maximal tumor dimension (P = 0.015), advanced pN stage (P = 0.002), advanced pT stage (P = 0.046), advanced TNM stage (P = 0.013), and postoperative adjuvant chemotherapy (P = 0.025) were correlated with poor OS. CONCLUSIONS: SMPLC could be considered to be a local disease rather than the systemic disease. Surgical treatment is an effective approach for patients with SMPLC. Mutational status of EGFR could be used as a diagnostic criterion, especially in patients with SMPLA. PMID- 28901319 TI - Expression and significance of Twist, estrogen receptor, and E-cadherin in human breast cancer cells and tissues. AB - OBJECTIVES: Breast cancer is one of the most common malignancies in women, and the tumor cells' invasion and metastasis is the main cause of death. Recent reports showed that Twist, a transcription factor, plays multiple roles in breast cancer initiation, progress, and metastasis. However, the underlying mechanisms of Twist in tumor invasion and metastasis of breast cancer still remain unclear. Here, we examined the correlation between Twist, E-cadherin, and estrogen receptor (ER) in promoting invasion and metastasis in breast cancer cells and tissues. MATERIALS AND METHODS: The mRNA and protein expression of Twist, E cadherin, and ER in breast cancer cell lines (MCF-7, MDA-MB-435, MDA-MB-231, and ZR-75-30) and human invasive ductal carcinoma (IDC) tissues from 32 patients were detected by reverse transcription-polymerase chain reaction and immunohistochemistry (IHC), respectively. RESULTS: Expression of Twist in cells with high ability of invasion and metastasis was higher than that in MCF-7 cell line which has low ability of invasion and metastasis, while the expression of ER and E-cadherin was much more higher in MCF-7 cell line than in other cells. IHC showed that the expression rate of Twist in IDC tissues and adjacent tissues was 84.38% and 31.25% and the positive expression of E-cadherin and ER was 21.88% and 40.63% in IDC tissues and 81.25% and 84.38% in adjacent tissues, respectively. Interestingly, overexpression of Twist promoted cellular invasion and metastasis and decreased the expression of E-cadherin, ER, AKT, and p-AKT in HEK-293 cells. CONCLUSIONS: Taken together, these findings demonstrated that Twist was upregulated in high invasion and metastasis cell lines as well as IDC tissues companioned with downregulated expression of E-cadherin and ER, which provides important clues for the deeper study of breast cancer. PMID- 28901320 TI - Thyroid carcinoma in children and adolescents: Clinical characteristics and follow-up from two centers. AB - AIM OF STUDY: The aim of this study was to analyze the clinical features and outcomes of thyroid carcinoma (TC) in children and adolescent population treated in our institution. MATERIALS AND METHODS: We gathered 43 TC patients 18 years of age or under initial diagnosed between 2009 and 2010 from two hospitals. Patient's clinical characteristics, laboratory tests, and outcomes were collected and analyzed. RESULTS: (1) The incidence of TC is higher in women (2.4 vs. 1.6). Papillary carcinoma accounted for the major type (67.4%). There was significant difference in tumor number, extra thyroidal invasion, and distant metastasis when compared with the children group (P < 0.05). There were higher proportions of patients with lymph node metastasis (LNM) and radioiodine therapy in adolescent patients. (2) Thyroid peroxidase antibody, thyroglobulin, thyroglobulin antibody, and urine iodine had higher levels as compared to the normal reference range. Moreover, FT3 and urine iodine showed statistical significances in adolescent group (P < 0.05). (3) Papillary carcinoma and medullary TC are more likely to have LNM extrathyroidal invasion. (4) No significant differences were seen in recurrence rate or survival rate. Pulmonary metastasis was the most common way of cancer metastasis. CONCLUSION: The initial workup is crucial in determining benign from malignant lesions. Surgery is the most effective therapy even if it is associated with more complications in children. There is an extremely good prognosis for pediatric TC even distant metastasis happens. PMID- 28901321 TI - Supplemental conventional transarterial embolization/chemoembolization therapy via extrahepatic arteries for hepatocellular carcinoma. AB - PURPOSE: To assess the value of conventional transarterial embolization/chemoembolization (cTAE/TACE) therapy via extrahepatic arteries for patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC who underwent cTAE/TACE therapy via extrahepatic arteries between May 2008 and July 2016 across 4 medical centers were identified. The technical success, serum alpha-fetoprotein (AFP) levels changes, tumor response, disease control rate, survival rate, and major complication were analyzed. RESULTS: A total of 185 patients (167 male and 18 female) were included in this study. A total of 401 procedures were performed of the 185 patients, with 2.2 +/- 0.4 procedures for each patient. A total of 197 extrahepatic arteries were identified, including inferior phrenic artery (n = 80), omental artery (n = 39), gastric artery (n = 22), right renal capsular artery (n = 21), adrenal artery (n = 13), cystic artery (n = 11), and right internal mammary artery (n = 11). The technical success rate was 96.8% (179/185). The serum AFP levels were significantly reduced at 1 month after treatment in 71 patients whose AFP >=400 ng/mL preprocedure (P < 0.01). The disease control rate was 93% (172/185) at 3 months after cTAE/TACE, with partial response, stable disease, or progressive disease of 115, 57, and 13 patients, respectively. The cumulative survival rate from the time of cTAE/TACE via extrahepatic arteries was 100% at 6 months. There were no embolization-related major complications. CONCLUSION: cTAE/TACE therapy via the extrahepatic arteries can reduce the incidence of presence of residual HCC, and improve the therapeutic efficacy of cTAE/TACE. PMID- 28901322 TI - Effects of Macrothele raven venom on intrarenal invasion and metastasis of H22 liver cancer cells in mice. AB - BACKGROUND: Extrahepatic metastatic hepatocellular carcinoma (HCC) and its insensitivity to chemotherapy are the main causes of poor prognosis in patients with HCC. This study investigated the anti-cancer effect of Macrothele raveni venom on intrarenal metastatic HCC. MATERIALS AND METHODS: Subrenal capsule xenograft model of HCC was established by inoculation of H22 liver cancer cells. RESULTS: The general health, histology, and molecular changes were observed after administering 10 times of different dose of Macrothele raven venom injections. A volume of 0.8 MUg/ml and 1.0 MUg/ml of Macrothele raven venom significantly improved general health status in mice with subrenal capsule HCC tumors. Hematoxylin and eosin staining showed that Macrothele raven venom dose dependently reduced invasion and metastasis of liver cancer cells in the kidney. Immunohistochemistry and real-time polymerase chain reaction showed that Macrothele raven venom injection dose-dependently decreased PI3K mRNA and protein, Akt protein, and mTOR mRNA expression, but increased Bad mRNA and protein expression in the kidney with H22 tumor cell invasion. 0.8 MUg/ml is the most effective dose for the treatment of intrarenal metastatic HCC. CONCLUSIONS: Macrothele raven venom dose-dependently inhibits invasion and metastasis of intrarenal metastatic HCC through inhibition of PI3K-Akt-mTOR signaling and increase of Bad expression. PMID- 28901323 TI - Human epidermal growth factor receptor 2 amplification detection by droplet digital polymerase chain reaction in formalin-fixed paraffin-embedded breast and gastric cancer samples. AB - OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) is an important biomarker for the precise individualized treatment including trastuzumab of HER2 positive breast and gastric cancer. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the routine analyses for formalin-fixed paraffin embedded (FFPE) samples. However, IHC is variable and depends on the evaluator, and FISH is a labor intensive and expensive method. We evaluated the feasibility of droplet digital polymerase chain reaction (ddPCR) as a precise and quantitative method for HER2 amplification test. MATERIALS AND METHODS: We used ddPCR to confirm HER2 amplification status in 24 breast cancer and 29 gastric cancer samples to validate the HER2 cutoff value in ddPCR. After setting cutoff value, all the above-mentioned samples were tested by IHC. Afterward, another 51 equivocal IHC 2+ gastric cancer samples were further determined by FISH and ddPCR, respectively, and the concordance between ddPCR and FISH was calculated. RESULTS: We set the HER2 cutoff value at 1.8. The concordance rate of HER2 status between ddPCR and IHC was 94.4% (17 out of 18) in 24 breast cancer samples. In 29 gastric cancer specimens, the concordance rate of HER2 amplification between ddPCR and IHC was 100% (22 out of 22). At last, compared with FISH determined HER2 status, ddPCR HER2 scores correctly classified 44 of 51 cases with 86.3% concordance in 51 equivocal IHC 2+ gastric cancer samples. CONCLUSIONS: ddPCR was able to identify HER2 amplification status in breast and gastric cancers with precise correlation with IHC and FISH results. This method might become a standard method for testing FFPE samples. However, the technology requires further research. PMID- 28901324 TI - Linked color imaging technique assisted endoscopic diagnosis and interventions. PMID- 28901325 TI - Associations between socio-demographic characteristics and chemical concentrations contributing to cumulative exposures in the United States. AB - Association rule mining (ARM) has been widely used to identify associations between various entities in many fields. Although some studies have utilized it to analyze the relationship between chemicals and human health effects, fewer have used this technique to identify and quantify associations between environmental and social stressors. Socio-demographic variables were generated based on U.S. Census tract-level income, race/ethnicity population percentage, education level, and age information from the 2010-2014, 5-Year Summary files in the American Community Survey (ACS) database, and chemical variables were generated by utilizing the 2011 National-Scale Air Toxics Assessment (NATA) census tract-level air pollutant exposure concentration data. Six mobile- and industrial-source pollutants were chosen for analysis, including acetaldehyde, benzene, cyanide, particulate matter components of diesel engine emissions (namely, diesel PM), toluene, and 1,3-butadiene. ARM was then applied to quantify and visualize the associations between the chemical and socio-demographic variables. Census tracts with a high percentage of racial/ethnic minorities and populations with low income tended to have higher estimated chemical exposure concentrations (fourth quartile), especially for diesel PM, 1,3-butadiene, and toluene. In contrast, census tracts with an average population age of 40-50 years, a low percentage of racial/ethnic minorities, and moderate-income levels were more likely to have lower estimated chemical exposure concentrations (first quartile). Unsupervised data mining methods can be used to evaluate potential associations between environmental inequalities and social disparities, while providing support in public health decision-making contexts. PMID- 28901326 TI - Environmental and biological monitoring for the identification of main exposure determinants in vineyard mancozeb applicators. AB - Grapevine is a vulnerable crop to several fungal diseases often requiring the use of ethylenebisdithiocarbamate (EBDC) fungicides, such as mancozeb. This fungicide has been reported to have goitrogenic, endocrine disrupting, and possibly immunotoxic effects. The aim of this study was to assess workers' exposure in two scenarios of mancozeb application and analyse the main determinants of exposure in order to better understand their mechanism of influence. Environmental monitoring was performed using a modified Organisation for Economic Co-operation and Development (OECD) "patch" methodology and by hand-wash collection, while mancozeb's metabolite, ethylenethiourea (ETU), was measured in 24-h preexposure and postexposure urine samples. Liquid chromatography-mass spectrometry was used for determination of mancozeb and ETU in different kinds of samples. Closed tractor use resulted in 40 times lower potential exposure compared with open tractor. Coveralls reduced skin exposure 4 and 10 times in case of open and closed tractors, respectively. Gloves used during application resulted in 10 times lower hand exposure in open but increased exposure in closed tractors. This study has demonstrated that exposure to mancozeb is low if safe occupational hygiene procedures are adopted. ETU is confirmed as suitable biological marker of occupational exposure to mancozeb, but the absence of biological exposure limits significantly reduces the possibility to interpret biological monitoring results in occupationally exposed workers. PMID- 28901327 TI - Selective Lesioning of Nuclear Factor-kappaB Activated Cells in the Nucleus Accumbens Shell Attenuates Alcohol Place Preference. AB - Nuclear factor kappa-light chain enhancer of activated B cells (NF-kappaB) is a transcription factor commonly associated with innate immunity and is activated by infection and inflammation. NF-kappaB has recently gained attention as a mediator of complex psychiatric phenomena such as stress and addiction. In regards to alcohol, most research on NF-kappaB has focused on neurotoxicity and few studies have explored the role of NF-kappaB in alcohol reward, reinforcement, or consumption. In these studies, we used conditioned place preference to assess the activity of NF-kappaB in response to rewarding doses of alcohol. To measure NF kappaB activity we used a line of transgenic mice that express the LacZ gene under the control of an NF-kappaB-regulated promoter. In these animals, staining for beta-galactosidase (beta-gal) identifies cells in which NF-kappaB has been activated. We then used the Daun02 inactivation method to specifically silence NF kappaB-expressing cells during place preference conditioning. Daun02 is an inactive prodrug that is converted to the inhibitory molecule daunorubicin by beta-gal. After alcohol place conditioning, we observed increased beta-gal staining in the nucleus accumbens (NAC) shell and dorsal raphe nucleus, and found that disruption of NF-kappaB-expressing cells using Daun02 attenuated the development of alcohol place preference when infused into the NAC shell following conditioning sessions. We found this effect to be regionally and temporally specific. These results suggest that, in addition to its role in alcohol-induced neurotoxicity, NF-kappaB mediates the development of alcohol place preference via its actions in the NAC shell. PMID- 28901329 TI - Wakodecalines A and B, new decaline metabolites isolated from a fungus Pyrenochaetopsis sp. RK10-F058. AB - Two new decaline metabolites, wakodecalines A and B, were isolated from a fungus, Pyrenochaetopsis sp. RK10-F058, by screening for structurally unique metabolites using LC/MS analysis. Their structures were determined on the basis of NMR and mass spectrometric measurements. The absolute structures were confirmed by a combination of chemical methods including chemical degradation, a modified Mosher's method and Marfey's method, and comparison of the experimental electronic CD (ECD) spectrum with calculated one. Both compounds had a cyclopentanone-fused decaline skeleton and an N-methylated amino acid moiety derived from a serine. They showed moderate antimalarial activity against the Plasmodium falciparum 3D7 strain.The Journal of Antibiotics advance online publication, 13 September 2017; doi:10.1038/ja.2017.103. PMID- 28901328 TI - Autophagy-regulating protease Atg4: structure, function, regulation and inhibition. AB - Autophagy is an intracellular degradation system that contributes to cellular homeostasis through degradation of various targets such as proteins, organelles and microbes. Since autophagy is related to various diseases such as infection, neurodegenerative diseases and cancer, it is attracting attention as a new therapeutic target. Autophagy is mediated by dozens of autophagy-related (Atg) proteins, among which Atg4 is the sole protease that regulates autophagy through the processing and deconjugating of Atg8. As the Atg4 activity is essential and highly specific to autophagy, Atg4 is a prospective target for developing autophagy-specific inhibitors. In this review article, we summarize our current knowledge of the structure, function and regulation of Atg4 including efforts to develop Atg4-specific inhibitors.The Journal of Antibiotics advance online publication, 13 September 2017; doi:10.1038/ja.2017.104. PMID- 28901330 TI - A history of obesity leaves an inflammatory fingerprint in liver and adipose tissue. AB - BACKGROUND/OBJECTIVES: Dieting is a popular yet often ineffective way to lower body weight, as the majority of people regain most of their pre-dieting weights in a relatively short time. The underlying molecular mechanisms driving weight regain and the increased risk for metabolic disease are still incompletely understood. Here we investigate the molecular alterations inherited from a history of obesity. METHODS: In our model, male high-fat diet (HFD)-fed obese C57BL/6J mice were switched to a low caloric chow diet, resulting in a decline of body weight to that of lean mice. We measured body composition, as well as metrics of glucose, insulin and lipid homeostasis. This was accompanied by histological and gene expression analysis of adipose tissue and liver to assess adipose tissue inflammation and hepatosteatosis. Moreover, acute hypothalamic response to (re-) exposure to HFD was assessed by qPCR. RESULTS & CONCLUSIONS: Within 7 weeks after diet switch, most obesity-associated phenotypes, such as body mass, glucose intolerance and blood metabolite levels were reversed. However, hepatic inflammation, hepatic steatosis as well as hypertrophy and inflammation of perigonadal, but not subcutaneous, adipocytes persisted in formerly obese mice. Transcriptional profiling of liver and perigonadal fat revealed an upregulation of pathways associated with immune function and cellularity. Thus, we show that weight reduction leaves signs of inflammation in liver and perigonadal fat, indicating that persisting proinflammatory signals in liver and adipose tissue could contribute to an increased risk of formerly obese subjects to develop the metabolic syndrome upon recurring weight gain. PMID- 28901332 TI - Prolonged hypotension associated with Wernicke's encephalopathy. AB - A diagnosis of Wernicke's encephalopathy (WE) is difficult. Transient hypotension has been reported as a rare complication of WE. We herein report a case of prolonged hypotension and dysuautonomia associated with WE in a 69-year-old man with underlying alcohol abuse. Without apparent etiology of shock, this patient remained hypotensive for 9 days, requiring a vasopressor, despite daily administration of thiamine 600 mg. Fluctuation of blood pressure caused by postural change and bradycardia in the presence of shock indicated that this patient had dysautonomia. This case hereby proposes a possible association between hypotension, dysautonomia and Wernicke's encephalopathy. PMID- 28901331 TI - Raw BIA variables are predictors of muscle strength in patients with chronic obstructive pulmonary disease. AB - BACKGROUND/OBJECTIVES: Although loss of fat-free mass (FFM) and reduced muscle strength are highly prevalent in chronic obstructive pulmonary disease (COPD), only few data are available on the relationships of handgrip strength (HGS) and respiratory muscle strength with body composition in such disease. In particular, we aimed to assess whether raw bioelectrical impedance (BIA) variables were independent predictors of muscle strength in COPD patients, possibly more significant than anthropometric variables and BIA-based estimates of FFM. SUBJECTS/METHODS: Two hundred and thirty-seven COPD patients (161 males and 76 females) underwent respiratory, anthropometric, BIA, HGS and respiratory muscle strength (maximum inspiratory or expiratory pressure=MIP and MEP) measurements. Bioimpedance index (BI index=height square/whole-body impedance) and phase angle (PhA) were considered as raw BIA variables. FFM was estimated using three disease specific BIA equations. RESULTS: In COPD patients a stronger correlation was observed between HGS and PhA compared to the ones with anthropometric variables or FFM estimates. Multiple regression analysis showed that combining BI index and PhA (plus age in male patients) accounted for 50.2% and 42.6% of the variance in HGS in male and female patients, respectively. Similarly, BI index and PhA emerged as predictors of both MIP and MEP in males, while in females MIP was related only to PhA and MEP only to BI index. CONCLUSIONS: Raw BIA variables are independent and valuable predictors of HGS and respiratory muscle strength in COPD patients. BI index and PhA could provide useful information for evaluating body composition and better assessing muscle strength and physical fitness in COPD. PMID- 28901334 TI - Rainfall shocks are not necessarily a sensitive early indicator of changes in wasting prevalence. AB - Evidence on the impact of weather shocks on child nutrition focuses on linear growth retardation (stunting) and thus, associates the effect of a short-term measure (weather events) on a cumulative measure (attained height). Relatively little is known on how weather shocks predict increases in wasting in a population. This study explores whether deviation in rainfall in Ethiopia, a drought prone country, is a sensitive indicator of future increases in wasting. Around 12% of children 0-23 months were wasted, but we found no consistent association between the rainfall shock variables and child weight-for-height Z scores. The results indicate that monitoring rainfall does not provide a practical early warning to use for scaling up financing and management of preventative measures without additional information to increase precision. PMID- 28901333 TI - A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women. AB - BACKGROUND/OBJECTIVES: Different diets are used for weight loss. A Paleolithic type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. SUBJECTS/METHODS: A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. RESULTS: At baseline, median 24-UIC (71.0 MUg/l) and 24-UIE (134.0 MUg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 MUg/l (P=0.001) and 24 UIE to 77.0 MUg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. CONCLUSIONS: A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD. PMID- 28901335 TI - Enteral versus parenteral nutrition in critically ill patients with severe pancreatitis: a meta-analysis. AB - Whether enteral nutrition (EN) is superior to parenteral nutrition (PN) in critically ill patients with severe acute pancreatitis remains unknown. The objective of this meta-analysis was to assess the effects of EN versus PN on clinical outcomes in a subgroup of pancreatitis patients. Relevant randomized controlled trials (RCTs) were searched in Scopus, PubMed and Web of Science from inception to August 2016. Ultimately, five RCTs including 348 patients were enrolled in this analysis. Compared with PN, EN was associated with a significant reduction in overall mortality (risk ratio (RR)=0.36, 95% confidence interval (CI) 0.20-0.65, P=0.001) and the rate of multiple organ failure (RR=0.39, 95% CI 0.21-0.73, P=0.003). EN should be recommended as the preferred route of nutrition for critically ill patients with severe acute pancreatitis. PMID- 28901337 TI - Associations between dietary factors and markers of NAFLD in a general Dutch adult population. AB - BACKGROUND/OBJECTIVES: The objective of this sudy was to assess the relationship between dietary intake and fatty liver as scored by the validated Fatty Liver Index (FLI) in a large cross-sectional study among a general Dutch adult population. Diet is known to affect liver fat accumulation in humans. SUBJECTS/METHODS: 1128 men and women aged 20-70 years were included. Dietary intake was assessed using a validated semiquantitative food frequency questionnaire. FLI was derived from body mass index (BMI), waist circumference, triglycerides and gamma-glutamyltransferase. Associations were adjusted for energy intake, alcohol intake, age, sex, education, smoking and prevalence of hypertension and diabetes. RESULTS: In this population (mean age 53.0+/-11.4 years; BMI 25.9+/-4.0 kg/m2; FLI 35.0+/-27.7), the prevalence of fatty liver as indicated by an FLI>60 was 21.5%. Subjects in the highest FLI category were more likely to be male, older and less physically active. Total protein intake and animal protein intake were positively associated with the highest FLI score versus the lowest (odds ratio (OR) 1.25 per 1 en%, 95% confidence interval (CI) 1.15-1.37 and OR 1.27, 95% CI 1.17-1.38, respectively); for vegetable protein, an inverse association was observed (OR 0.81, 95% CI 0.69-0.94). A similar positive association with FLI was observed when carbohydrates and fat were iso-calorically exchanged for total and animal proteins. CONCLUSIONS: Subjects in the high FLI group consumed more protein, especially from animal origin, less carbohydrates and less dietary fibre. The presence of fatty liver was associated with a higher intake of animal protein and total fat, soft drinks and snacks. PMID- 28901340 TI - ? AB - Riassunto La pubblicazione di Unanticipated outcomes, la storia personale di Jerome P. Kassirer, ex direttore del New England Journal of Medicine, offre l'opportunita di considerare i principi etici dell'editoria biomedica e scientifica. Il conflitto di interessi, le dichiarazioni e la frode influenzano la credibilita della comunicazione medica, che poggia sulla robustezza e sulla trasparenza dei suoi processi. Non tutto e ancora perduto, ma dobbiamo essere guidati da forti principi morali e da un quadro coerente di valori. PMID- 28901336 TI - Vitamin D and probiotics supplement use in young children with genetic risk for type 1 diabetes. AB - BACKGROUND/OBJECTIVES: Vitamin D and probiotics are nutrients of interest in the context of type 1 diabetes (T1D). We assessed the prevalence of and factors associated with vitamin D and probiotic supplementations among young children with genetic risk of T1D. SUBJECTS/METHODS: Use of supplements during the first 2 years of life was collected prospectively from 8674 children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESULTS: Single and/or multivitamin/mineral (MVM) supplements were reported by 81% of the children. The majority of participants in Finland, Germany and Sweden (97-99%) and 50% in the United States received vitamin D supplements that were mostly MVMs. Probiotics use varied from 6% in the United States to 60% in Finland and was primarily from probiotics-only preparations. More than 80% of the vitamin D and probiotics supplementation was initiated during infancy, and more than half of the uses lasted longer than a year. Being the first child, longer duration of breastfeeding, born in a later year, older maternal age and higher maternal education level were associated with both vitamin D and probiotics use. Shorter gestational age and mother not smoking during pregnancy were associated with a higher likelihood of probiotics supplementation only. CONCLUSIONS: Vitamin D and probiotics supplementations are popular in children 0-2 years old and are associated with common factors. Data documented here will allow evaluation of the relationship between early childhood dietary intake and the development of islet autoimmunity and progression to T1D. PMID- 28901341 TI - [Healthcare services citizen's right and healthcare systems safeguard. Considerations rising from the Charlie Gard story.] AB - The story of Charlie Gard, an 11-month-old boy suffering from a rare inherited mitochondrial disease called 'infantile encephalomyopathic mitochondrial DNA depletion syndrome' and kept alive thanks to life supports, rises some issues regarding the provision of healthcare. Is there a right of an individual person to buy any healthcare benefits only because he has enough money to do so? If the answer is 'yes', in light of the distributive justice principle how do governments balance this right with the obligation to regulate health care systems ensuring that all treatments are useful and affordable for everybody? Many considerations of the best interest of patients can be found in this debate, but we cannot ignore neither the value of the scientific method as the cornerstone of the medical profession nor a commitment to support the moral integrity of clinical practice by refusing to provide treatments that do not meet a reasonable threshold of scientific justification evidence-based. PMID- 28901342 TI - [The recognition of peer reviewers activity: the potential promotion of a virtuous circle.] AB - Since several decades, peer review has become the standard to evaluate quality and priority of manuscripts submitted to scientific journals. During this process, manuscript is reviewed by scientists from the same field of the authors, with a competency on the topic of the manuscript (peer reviewers). Peer reviewers submit their comments to the journal editor, who then takes a decision on manuscript acceptance, need for revision of rejection. Several models for peer review exist, such as double-blind, single-blind, open, post publication. Hence the task of peer reviewer requires time, competency and carries a significant responsibility. Most peer reviewers perform these task as a service to the scientific community, but explicit recognition of this effort is still very limited. This has negative consequences on the publication process overall, since scientists often decline invitations to peer review and quality is not always ensured. In this article we overview the main options available for crediting peer reviewers for their efforts, focusing, in particular on the creation of a robust metrics able to attest the number and quality of peer reviews produced by this individual. This process implies the involvement of peer reviewers, journal editors and publishers and of a third, external, certification party. If implemented, this strategy could promote a virtuous circle, leading to an overall improvement of the process of peer review and ultimately of scientific publishing. PMID- 28901343 TI - [Italian guidelines in accordance with the new National Guidelines System: critical issues and perspectives.] AB - Law No. 24/2017 on professional responsibility has assigned a fundamental role to the guidelines, giving the Istituto Superiore di Sanita, through the new Centro Nazionale per l'Eccellenza Clinica, la Qualita e la Sicurezza delle Cure (CNEC), the role of methodological guarantor and of national governance of the guidelines production process. In a scenario marked by the increasing use of defensive medicine, the adherence to guidelines recognized as reliable by an institutional body can lead to the desired reduction of the malpractice claim, as well as to considerable clinical advantages, with the improvement of the quality of healthcare and of health outcomes and the reduction of unjustified variability of clinical practices in the national territory. If the opportunity that the new National Guidelines System (SNLG) offers is great and must be seized, at the same time the connection between guidelines and health responsibility presents some critical issues. In this context, it is of utmost importance to promote an efficient production mechanism of good quality national guidelines, informed by the best evidence available and responding to the population health needs, based on the criteria of relevance and clinical, economic and social impact, as well as to make the SNLG the pivotal instrument to achieve that alignment of clinical efficacy, professional and organizational appropriateness, fairness, security and humanization of care that can guarantee the sustainability of our National Health Service and its capacity to face the difficult challenges of the future. PMID- 28901344 TI - [WHO GLOSS: a global study to promote the reduction of preventable maternal and neonatal deaths related to sepsis.] AB - The study aims to promote the reduction of preventable maternal and neonatal deaths related to sepsis worldwide. To achieve this goal, the study will test new WHO criteria for early identification of maternal sepsis across both low and high resource settings, describe and analyze the frequency and outcomes of suspected or confirmed maternal sepsis for mothers and infants. Additionally, in the European participating countries, the study will describe the patterns of anti microbial usage amongst women with suspected maternal sepsis, explore migration status amongst women with possible severe maternal infection and describe any variations in their management. PMID- 28901345 TI - [Acute alcoholic hepatitis.] AB - Chronic alcohol related liver disease is characterized by a cascade of events defined as follows: steatosis, steatohepatitis/steatofibrosi, cirrhosis and hepatocellular carcinoma. On one of these histologic patterns may overlap acute alcoholic hepatitis (AAE) (mild, moderate, severe). Severe AAE can cause a severe clinical picture: jaundice with a duration of less than three months, jaundice in the first decompensation event, serum bilirubin higher than 5 mg/dL, ratio AST/ALT >2:1, AST less than 500 IU/L ALT <300 IU/L, neutrophil leukocytosis and increased GGT. In addition, it is possible the presence of encephalopathy, fever, fatigue, coagulopathy. The onset can also be characterized by portal hypertension related complications. An extremely severe clinical condition is the superposition of an acute insult to a chronic framework, not necessarily a cirrhotic one. This condition has been termed acute on chronic (acute on chronic liver failure - ACLF:), and it is possible to have a SIRS (systemic inflammation response syndrome) with a multi-organ system involvement. The diagnosis, in selected cases, can be confirmed by a transjugular biopsy that allows to reach a histologic prognostic stratification. Several indices are used for the assessment of prognosis and in particular the MDF and the MELD. In our clinical practice we use the MELD. In case of ACLF, the consortium organ failure score (CLIF-C OFS) is used. The therapy is characterized by alcohol abstention, and, in severe forms (MDF >32 and MELD >21) with absence of contraindications, it is possible to use steroids therapy. If a positive answers cannot be obtained, an early liver transplantation is proposed. This possibility, after a careful selection, now is promoted by several authors. PMID- 28901346 TI - [Procurement of medical devices based on cost-effectiveness data.] AB - The field of medical devices is characterized by a paucity of cost-effectiveness data that support their use. In this context, we have proposed a project based on the calculation of net monetary benefit (NMB) for each product subjected to procurement through tenders. This project consists of two steps: 1) calculation of NMB; 2) calculation of a value-based score to be used in the process of procurement and tendering. The NMB is defined as follows: NMB per patient= (monetary threshold of WTP) x (QALYs per patient) - (treatment cost per patient); WTP= willingness to pay]. Its main advantage is represented by the linear relation between NMB and unit price as opposed to the non-linear relationship that links the ICER to the unit price of the device. For all devices included in the same tender lot, our procedure firstly determines the valus of NMB and converts the NMB into a tender score determined on a 0-to-100 scale. The device with the worst pharmacoeconomic profile is assigned a tender score of 0 while the one with the best pharmacoeconomic profile is assigned a tender score of 100. PMID- 28901347 TI - HBV virological suppression: still not enough to save from hepatocellular carcinoma.A case report on a 15-year, real-life story AB - Among HIV-infected patients worldwide, 2-4 million are chronically infected with HBV. We report a 15-year, real-life story of a patient with HBV-HIV coinfection, who developed HCC despite high treatment adherence and complete viral suppression. The aim of our report is to alert the infectious diseases community to monitor the possible development of HCC regardless of high treatment adherence and complete viral suppression. PMID- 28901348 TI - ? PMID- 28901349 TI - ? PMID- 28901350 TI - Recent developments in the synthesis, properties, and biomedical applications of core/shell superparamagnetic iron oxide nanoparticles with gold. AB - In the last decade, magnetic nanoparticles (MNPs), especially superparamagnetic iron oxide nanoparticles (SPIONs), have immensely promoted the advancement of diagnostics and theranostics in the biomedical field. The unique properties of the SPIONs-core and the functional gold (Au)-shell together (SPIONS/Au core/shell or CS) have a wide range of biomedical applications including, but not limited to, magnetic resonance imaging (MRI), dual modality MRI/computed tomography (CT), photo-induced and magnetic fluid hyperthermia (MFH), drug delivery, biosensors, and bio-separation. Researchers have made much effort to develop synthesis strategies for size control and surface modifications to achieve the desired properties of these CSs for applications in in vitro and in vivo studies. This review highlights recent developments in the synthesis and biomedical applications of SPIONs/Au CSs, including gamma-Fe2O3/Au (maghemite), Fe3O4/Au (magnetite), and MFe2O4/Au (M = divalent metal ions) in the past seven years. More importantly, current trends of SPIONs/Au in relation to the biochemical industry are surveyed. Finally, we outline the developmental needs of SPIONs/Au from the perspective of material synthesis and their novel applications in disease diagnosis and treatment in the near future. PMID- 28901351 TI - All-solid-state ion-selective electrodes with redox-active lithium, sodium, and potassium insertion materials as the inner solid-contact layer. AB - All-solid-state ion-selective electrodes as potentiometric ion sensors for lithium, sodium, and potassium have been demonstrated by installing a composite layer containing a powder of alkali insertion materials, LixFePO4, Na0.33MnO2, and KxMnO2.nH2O, respectively, as an inner solid-contact layer between the electrode substrate and plasticized poly(vinyl chloride) (PVC)-based ion sensitive membrane containing the corresponding ionophores for Li+, Na+, and K+ ions. These double-layer ion-selective electrodes, consisting of the composite and PVC layers prepared by a simple drop cast method, exhibit a quick potential response (less than 5 s) to each alkali-metal ion with sufficient Nernstian slopes of calibration curves, ca. 59 mV per decade. The installation of the insertion materials as the inner solid-contact layers is highly efficient for the stabilization of membrane potential, resulting in a prompt response to the alkali ion activity in the analyte, compared to those of the electrodes without the alkali insertion materials. From alternating current impedance measurements for the electrodes, the inner layer of the installed alkali insertion materials drastically reduces the impedance of the membrane/electrode interface, leading to an improvement in their ion-sensing performance. PMID- 28901352 TI - Correction: An unsymmetrical non-fullerene acceptor: synthesis via direct heteroarylation, self-assembly, and utility as a low energy absorber in organic photovoltaic cells. AB - Correction for 'An unsymmetrical non-fullerene acceptor: synthesis via direct heteroarylation, self-assembly, and utility as a low energy absorber in organic photovoltaic cells' by Abby-Jo Payne et al., Chem. Commun., 2017, 53, 10168 10171. PMID- 28901353 TI - Separate mechanisms of ion oligomerization tune the physicochemical properties of n-butylammonium acetate: cation-base clusters vs. anion-acid dimers. AB - We investigated the ability of the ions comprising protic ionic liquids to strongly interact with their neutral acid and base forms through the characterization of n-butylammonium acetate ([C4NH3][OAc]) in the presence of excess n-butylamine (C4NH2) or excess acetic acid (HOAc). The conjugate and parent acid or base form new nonstoichiometric, noncovalently bound species (i.e., oligomeric ions) which change the physical and chemical properties of the resulting liquids, thus offering tunability. The effects of adding C4NH2 or HOAc to [C4NH3][OAc] on the resulting thermal and spectroscopic properties differ and suggest that C4NH2 interacts primarily with [C4NH3]+ to form 3-dimensional polymeric networks likely similar to those in H2O/[H3O]+, while HOAc interacts primarily with [OAc]- to form oligomeric ions (e.g., [H(OAc)2]-). The densities of the systems increased with the increase of acid content and reached a maximum when the acid molar fraction was 0.90, but decreased with increasing amine concentration. The viscosities decreased significantly with increasing acid or base concentration. The solvent properties of the mixtures were assessed by measuring the solubilities of benzene, ethyl acetate, diethyl ether, heptane, ibuprofen free acid, and lidocaine free base. The solubilities of the organic solutes and active pharmaceutical ingredients can be tuned with the concentration of acid or amine in the mixtures. In addition, crystallization of the active pharmaceutical ingredients can be induced with the modification of the composition of the mixtures. These observations support the usage of these mixtures for the synthesis and purification of acid or basic active pharmaceutical ingredients in the pharmaceutical industry. PMID- 28901355 TI - Two-dimensional metal NaCu6.3Sb3 and solid-state transformations of sodium copper antimonides. AB - A novel layered compound, NaCu6.3Sb3, has been successfully synthesized from elements. This unique structure crystallizes in the hexagonal space group P63/mmc and has lattice constants of a = 4.2166(2) A and c = 24.041(1) A. The structure consists of complex Cu/Sb 2D blocks separated by Na ions. These blocks contain graphene-like hexagonal layers of either Cu or CuSb. The solid-state transformations in the Na-Cu-Sb system between Cu2Sb-NaCu6.3Sb3-NaCu4Sb2 were explored using annealing at different partial vapor pressures of Na, differential scanning calorimetry, and in situ synchrotron powder X-ray diffraction. Full reversibility of the transformation was observed, indicating that the bulk 3D Cu2Sb phase is capable of reversible intercalation of Na ions, forming layered intercalated phases similar to intercalated graphite. The characterization of the transport properties shows that the metallic nature of the electrical conductivity is preserved, even for the Na-rich phase of NaCu4Sb2. Electronic structure calculations support metallic properties in the Cu-Sb layers and predict that no bands cross the Fermi level across the layers, supporting NaCu6.3Sb3 as a two-dimensional metal. PMID- 28901356 TI - Cyclometalated Pt(ii) complexes with a bidentate Schiff-base ligand displaying unexpected cis/trans isomerism: synthesis, structures and electronic properties. AB - Square planar platinum complexes are an important class of compounds used in (nano)technology, optoelectronics, medicinal chemistry and catalysis. The major research interests in cyclometalated Pt(ii) complexes focus on the selective modulation of their electronic properties and the control of the (cis/trans) geometry. For the first time, we unveil and demonstrate that cis-trans isomers of Pt(ii) complexes can be obtained in a derivative carrying the 1-phenyl-pirazolate (Hppz) and 2-hydroxy-1-naphtyl-(N-phenyl)imine ligands. The two isomers display significant differences in both optical and electronic properties. While luminescence is quenched in solution, they are brightly emissive in the PMMA matrix at room temperature and in the 2MeTHF rigid matrix at 77 K. The phosphorescent emission of the cis isomer, blue-shifted compared to that of the trans one, results from the significantly different trans influence of the ppz ligand. Theoretical investigation highlights the almost isoenergetic potential energy of the two isomers therefore explaining their formation and evidences a large geometry distortion of their triplet state, which should be responsible for the observed luminescence efficiency. PMID- 28901357 TI - An ortho C-methylation/O-glycosylation motif on a hydroxy-coumarin scaffold, selectively installed by biocatalysis. AB - Various bioactive natural products, like the aminocoumarin antibiotics novobiocin and coumermycin, exhibit an aromatic C-methyl group adjacent to a glycosylated phenolic hydroxyl group. Therefore, tailoring of basic phenolic scaffolds to contain the intricate C-methyl/O-glycosyl motif is of high interest for structural and functional diversification of natural products. We demonstrate site-selective 8-C-methylation and 7-O-beta-d-glucosylation of 4,5,7-trihydroxy-3 phenyl-coumarin (1) by S-adenosyl-l-methionine dependent C-methyltransferase (from Streptomyces niveus) and uridine 5'-diphosphate glucose dependent glycosyltransferase from apple (Malus * domestica). Both enzymes were characterized and shown to react readily with underivatized 1. However, glucosylation of the ortho-hydroxyl group prevented C-methylation, probably by precluding an essential substrate activation through deprotonation of 7-OH. Therefore, dual modification was only feasible when C-methylation occurred strictly before O-glucosylation. The target product was synthesized in near quantitative yield (98% conversion) from 500 MUM 1 and its structure was confirmed by NMR. Combination of C-methyltransferase and O-glycosyltransferase reactions for synthetic tailoring of a natural product through biocatalysis was demonstrated for the first time. PMID- 28901358 TI - Cadmium-1,4-cyclohexanedicarboxylato coordination polymers bearing different di alkyl-2,2'-bipyridines: syntheses, crystal structures and photoluminescence studies. AB - Four coordination polymers have been synthesized using self-assembly solution reactions under ambient conditions, reacting Cd(ii) ions with 1,4 cyclohexanedicarboxylic acid in the presence of different 2,2'-bipyridine co ligands: {[Cd(H2O)(e,a-cis-1,4-chdc)(2,2'-bpy)].H2O}n (1); [Cd2(H2O)2(e,a-cis-1,4 chdc)2(4,4'-dmb)2]n (2); {[Cd(e,a-cis-1,4-chdc)(5,5'-dmb)].H2O.CH3OH}n (3) and {[Cd(e,e-trans-1,4-chdc)(4,4'-dtbb)].CH3OH}n (4), where 1,4-chdc = 1,4 cyclohexanedicarboxylato, 2,2'-bpy = 2,2'-bipyridine, 4,4'-dmb = 4,4'-dimethyl 2,2'-bipyridine, 5,5'-dmb = 5,5'-dimethyl-2,2'-bipyridine and 4,4'-dtbb = 4,4'-di tert-butyl-2,2'-bipyridine. Crystallographic studies show that compound 1 has a 1D structure propagating along the crystallographic b-axis; the Cd ion in 1 is six-coordinated with a distorted-octahedral coordination sphere. Compound 2 has two crystallographic different Cd ions and both are six-coordinated with a distorted-octahedral coordination sphere. Compound 3 exhibits a seven-coordinated Cd ion having a distinctive distorted-monocapped trigonal prismatic geometry. In compound 4, the Cd ion is also seven-coordinated in a distorted monocapped octahedral geometry. Compounds 2, 3 and 4 possess rhombic-shaped dinuclear units (Cd2O2) as nodes to generate larger cycles made up of four dinuclear units, a Cd4 motif, bridged by four 1,4-chdc ligands, accomplishing, thus, 2D structures. Remarkably, in compound 4 the 1,4-chdc ligand conformation changes to the equatorial, equatorial trans, unlike the other compounds where the bridging ligand conformation is the more typical equatorial, axial cis. The solid state luminescence properties of 1-4 were investigated; polymers 3 and 4 exhibited a strong blue emission (lambdaem = 410-414 nm) compared to 1 and 2; structure related photoluminescence is attributed to the degree of hydration of the compounds. Furthermore, Cd-polymer 3 suspended in acetone allows the fluorescence selective sensing of acetonitrile over common organic solvents such as alcohols and DMF, based on turn-on fluorescence intensity with a limit of 53 MUmol L-1. PMID- 28901362 TI - What do we actually see in intracellular SERS? Investigating nanosensor-induced variation. AB - Plasmonic nanoparticles (NPs), predominantly gold (AuNPs), are easily internalised into cells and commonly employed as nanosensors for reporter-based and reporter-free intracellular SERS applications. While AuNPs are generally considered non-toxic to cells, many biological and toxicity studies report that exposure to NPs induces cell stress through the generation of reactive oxygen species (ROS) and the upregulated transcription of pro-inflammatory genes, which can result in severe genotoxicity and apoptosis. Despite this, the extent to which normal cellular metabolism is affected by AuNP internalisation remains a relative unknown along with the contribution of the uptake itself to the SERS spectra obtained from within so called 'healthy' cells, as indicated by traditional viability tests. This work aims to interrogate the perturbation created by treatment with AuNPs under different conditions and the corresponding effect on the SERS spectra obtained. We characterise the changes induced by varying AuNP concentrations and medium serum compositions using biochemical assays and correlate them to the corresponding intracellular reporter-free SERS spectra. The different serum conditions lead to different extents of nanoparticle internalisation. We observe that changes in SERS spectra are correlated to an increasing amount of internalisation, confirmed qualitatively and quantitatively by confocal imaging and ICP-MS analysis, respectively. We analyse spectra and characterise changes that can be attributed to nanoparticle induced changes. Thus, our study highlights a need for understanding condition-dependent NP-cell interactions and standardisation of nanoparticle treatments in order to establish the validity of intracellular SERS experiments for use in all arising applications. PMID- 28901363 TI - The mechanism for catalytic hydrosilylation by bis(imino)pyridine iron olefin complexes supported by broken symmetry density functional theory. AB - Density functional theory (DFT, B3LYP-D3 with implicit solvation in toluene) was used to investigate the mechanisms of olefin hydrosilylation catalyzed by PDI(Fe) (bis(imino)pyridine iron) complexes, where PDI = 2,6-(ArN[double bond, length as m-dash]CMe)2(C5H3N) with Ar = 2,6-R2-C6H3. We find that the rate-determining step for hydrosilylation is hydride migration from Et3SiH onto the Fe-bound olefin to form (PDI)Fe(alkyl)(SiEt3). This differs from the mechanism for the Pt Karstedt catalyst in that there is no prior Si-H oxidative addition onto the Fe center. (PDI)Fe(alkyl)(SiEt3) then undergoes C-Si reductive elimination to form (PDI)Fe, which coordinates an olefin ligand to regenerate the resting state (PDI)Fe(olefin). In agreement with experimental observations, we found that anti Markovnikov hydride migration has a 5.1 kcal mol-1 lower activation enthalpy than Markovnikov migration. This system has an unusual anti-ferromagnetic coupling between high spin electrons on the Fe center and the unpaired spin in the pi system of the non-innocent redox-active PDI ligand. To describe this with DFT, we used the "broken-symmetry" approach to establish the ground electronic and spin state of intermediates and transition states over the proposed catalytic cycles. PMID- 28901365 TI - 97 percent light absorption in an ultrabroadband frequency range utilizing an ultrathin metal layer: randomly oriented, densely packed dielectric nanowires as an excellent light trapping scaffold. AB - In this paper, we propose a facile and large scale compatible design to obtain perfect ultrabroadband light absorption using metal-dielectric core-shell nanowires. The design consists of atomic layer deposited (ALD) Pt metal uniformly wrapped around hydrothermally grown titanium dioxide (TiO2) nanowires. It is found that the randomly oriented dense TiO2 nanowires can impose excellent light trapping properties where the existence of an ultrathin Pt layer (with a thickness of 10 nm) can absorb the light in an ultrabroadband frequency range with an amount near unity. Throughout this study, we first investigate the formation of resonant modes in the metallic nanowires. Our findings prove that a nanowire structure can support multiple longitudinal localized surface plasmons (LSPs) along its axis together with transverse resonance modes. Our investigations showed that the spectral position of these resonance peaks can be tuned with the length, radius, and orientation of the nanowire. Therefore, TiO2 random nanowires can contain all of these features simultaneously in which the superposition of responses for these different geometries leads to a flat perfect light absorption. The obtained results demonstrate that taking unique advantages of the ALD method, together with excellent light trapping of chemically synthesized nanowires, a perfect, bifacial, wide angle, and large scale compatible absorber can be made where an excellent performance is achieved while using less materials. PMID- 28901366 TI - Graphene oxide inhibits malaria parasite invasion and delays parasitic growth in vitro. AB - The interactions between graphene oxide (GO) and various biological entities have been actively investigated in recent years, resulting in numerous potential bioapplications of these nanomaterials. Despite this, the biological interactions between GO and disease-causing protozoan parasites have not been well elucidated and remain relatively unexplored. Here, we investigate the in vitro interactions between GO nanosheets and a particular species of malaria parasites, Plasmodium falciparum (P. falciparum). We hypothesize that GO nanosheets may exhibit antimalarial characteristic via action mechanisms of physical obstruction of P. falciparum parasites as well as nutrient depletion. To ascertain this, we characterize the physical interactions between GO nanosheets, red blood cells (RBCs), and malarial parasites as well as the adsorption of several biomolecules necessary for parasitic survival and growth on GO nanosheets. Subsequent to establishing the origin of this antimalarial behavior of GO nanosheets, their efficiency in inhibiting parasite invasion is evaluated. We observe that GO nanosheets at various tested concentrations significantly inhibit the invasion of malaria parasites into RBCs. Furthermore, GO nanosheets delay parasite progression from the ring to the trophozoite stage. Overall, this study may further shed light on the graphene-parasite interactions and potentially facilitate the development of nanomaterial-based strategies for combating malaria. PMID- 28901367 TI - Effects of developmental arsenite exposure on hippocampal synapses in mouse offspring. AB - Arsenic exposure through drinking water can impair the learning and memory ability of children in China and other countries. Synaptic plasticity plays a key role in the process of learning and memory. Alterations in the expression of presynaptic and postsynaptic proteins can be used to evaluate synaptic plasticity, and further to evaluate impairment in learning and memory ability. Thereby, the aim of this study was to explore the mechanisms underlying arsenic neurotoxicity by focusing on alterations in the hippocampal synapses of mouse offspring induced by developmental arsenite exposure. Mother mice and their offspring were exposed to 0, 25, 50 or 100 mg L-1 arsenite via drinking water from the first day of gestation until postnatal day (PND) 35. The spatial learning and memory ability of PND 35 mice was evaluated using a Morris water maze. The levels of speciated arsenicals in the brain of PND 7, 14, 21 and 35 mice were analyzed by hydride generation coupled with atomic absorption spectrophotometry. Synaptic structure and protein expression of postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the hippocampus of PND 7, 14, 21 and 35 mice were examined. The findings from this study disclosed that the spatial learning ability of mice could be impaired by exposure to 25 mg L-1 arsenite; however spatial memory ability could not be impaired until exposure to 100 mg L-1 arsenite. The thickness of the postsynaptic density (PSD) decreased, whereas the width of the synaptic cleft widened significantly in arsenite exposure groups. Moreover, protein expression of both PSD-95 and SYP decreased significantly in arsenite exposure groups. In conclusion, the results of this study demonstrated that developmental arsenite exposure could depress the expression of synaptic proteins, subsequently cause alteration in synaptic structures, and finally contribute to arsenite-induced deficits in spatial learning and memory ability in mouse offspring. PMID- 28901368 TI - Deuteration and tautomeric reactivity of the 1-methyl functionality of free-base dipyrrins. AB - Regioselective reactivity of the 1-methyl group of free-base dipyrrins is explored, including discussion of tautomerism to provide exocyclic alkenyl reactivity. Deuterium is installed so as to generate dipyrrins substituted with deuterated methyl groups. Furthermore, the 1-methyl group reacts to become involved in C-C bonds involving only sp3-hybridised carbon atoms. The isolation of an elusive framework featuring a dipyrrin substituted with a pyrrole in a non vinylogous fashion is also reported. The use of asymmetric dipyrrins featuring an electron-withdrawing group on one of the pyrrolic units results in regioselective reaction of the alpha-methyl group distal to the electron-withdrawing group. PMID- 28901369 TI - Precisely tunable thickness of graphitic carbon nitride nanosheets for visible light-driven photocatalytic hydrogen evolution. AB - Graphitic carbon nitride (GCN) nanosheets with unique physicochemical properties have received increasing attention in the area of photocatalysis, yet tunable thickness for the straightforward production of this graphite-like two dimensional (2D) nanomaterial remains a challenge. In this work, GCN nanosheets with different thicknesses were firstly prepared by a direct calcination of melamine supramolecular aggregates (MSA) obtained from a hydrochloric acid (HCl) induced hydrothermal assembly approach. The resultant nanosheets over nanometer scale thickness could be precisely controlled via simply adjusting the HCl concentration. Compared to the bulk GCN (BGCN), the thinner nanosheets possessed a high specific surface area, a large electronic-band structure, and fast charge separation ability. The thinnest nanosheets with a thickness of approximately 4 nm exhibited excellent visible-light-driven photocatalytic water splitting performance in hydrogen evolution (524 MUmol h-1 g-1), which is over 9-fold higher than the BGCN powder. This work provides a thickness-dependent strategy for the preparation of metal-free GCN nanosheets and develops a promising 2D photocatalyst for application in solar energy conversion. PMID- 28901370 TI - A fluorescent pH probe for acidic organelles in living cells. AB - A water-soluble pH sensor, 2-(6-(4-aminostyryl)-1,3-dioxo-1H-benzo[de]isoquinolin 2(3H)-yl)-N, N-dimethylethanamine (ADA), was synthesized based on the molecular design of photoinduced electron transfer (PET) and intramolecular charge transfer (ICT). The fluorescence emission response against a pH value is in the range 3-6, which is suitable for labelling intracellular pH-dependent microenvironments. After biological evolution, ADA is more than a pH biosensor because it is also an endocytosis pathway tracking biosensor that labels endosomes, late endosomes, and lysosome pH gradients. From this, the emissive aggregates of ADA and protonated ADA in these organs were evaluated to explore how this probe stresses emission colour change to cause these unique cellular images. PMID- 28901371 TI - Synthesis of a multi-functional DNA nanosphere barcode system for direct cell detection. AB - Nucleic acid-based technologies have been applied to numerous biomedical applications. As a novel material for target detection, DNA has been used to construct a barcode system with a range of structures. This paper reports multi functionalized DNA nanospheres (DNANSs) by rolling circle amplification (RCA) with several functionalized nucleotides. DNANSs with a barcode system were designed to exhibit fluorescence for coding enhanced signals and contain biotin for more functionalities, including targeting through the biotin-streptavidin (biotin-STA) interaction. Functionalized deoxynucleotide triphosphates (dNTPs) were mixed in the RCA process and functional moieties can be expressed on the DNANSs. The anti-epidermal growth factor receptor antibodies (anti-EGFR Abs) can be conjugated on DNANSs for targeting cancer cells specifically. As a proof of concept, the potential of the multi-functional DNANS barcode was demonstrated by direct cell detection as a simple detection method. The DNANS barcode provides a new route for the simple and rapid selective recognition of cancer cells. PMID- 28901372 TI - Multivalent gold nanoparticle-peptide conjugates for targeting intracellular bacterial infections. AB - Although nanoparticle-tagged antimicrobal peptides have gained considerable importance in recent years, their structure-function correlation has not yet been explored. Here, we have studied the mechanism of action of a designed antimicrobial peptide, VG16KRKP (VARGWKRKCPLFGKGG), delivered via gold nanoparticle tagging against Salmonella infection by combining biological experiments with high- and low-resolution spectroscopic techniques. In comparison with the free VG16KRKP peptide or gold nanoparticle alone, the conjugated variant, Au-VG16KRKP, is non-cytotoxic to eukaryotic cells, but exhibits strong bacteriolytic activity in culture. Au-VG16KRKP can penetrate host epithelial and macrophage cells as well as interact with intracellular S. Typhi LPS under both in vitro and in vivo conditions. Treatment of mice with Au-VG16KRKP post infection with S. Typhi resulted in reduced intracellular bacterial recovery and highly enhanced protection against S. Typhi challenge. The three-dimensional high resolution structure of nanoparticle conjugated VG16KRKP depicted the generation of a well-separated amphipathic structure with slight aggregation, responsible for the increase of the local concentration of the peptide, thus leading to potent activity. This is the first report on the structural and functional characterization of a nanoparticle conjugated synthetic antimicrobial peptide that can kill intracellular pathogens and eventually protect against S. Typhi challenge in vivo. PMID- 28901373 TI - Kinesin and Dynein Mechanics: Measurement Methods and Research Applications. AB - Motor proteins play critical roles in the normal function of cells and proper development of organisms. Among motor proteins, failings in the normal function of two types of proteins, kinesin and dynein, have been shown to lead many pathologies, including neurodegenerative diseases and cancers. As such, it is critical to researchers to understand the underlying mechanics and behaviors of these proteins, not only to shed light on how failures may lead to disease, but also to guide research toward novel treatment and nano-engineering solutions. To this end, many experimental techniques have been developed to measure the force and motility capabilities of these proteins. This review will (a) discuss such techniques, specifically microscopy, atomic force microscopy (AFM), optical trapping, and magnetic tweezers, and (b) the resulting nanomechanical properties of motor protein functions such as stalling force, velocity, and dependence on adenosine triphosophate (ATP) concentrations will be comparatively discussed. Additionally, this review will highlight the clinical importance of these proteins. Furthermore, as the understanding of the structure and function of motor proteins improves, novel applications are emerging in the field. Specifically, researchers have begun to modify the structure of existing proteins, thereby engineering novel elements to alter and improve native motor protein function, or even allow the motor proteins to perform entirely new tasks as parts of nanomachines. Kinesin and dynein are vital elements for the proper function of cells. While many exciting experiments have shed light on their function, mechanics, and applications, additional research is needed to completely understand their behavior. PMID- 28901374 TI - Ferulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivo. AB - Ferulic acid (FA) is a derivative of cinnamic acid. It is used in the treatment of heart head blood-vessel disease and exerts protective effects against hypoxia/ischemia-induced cell injury in the brain. This study investigated the potential neuroprotective effects of FA against ischemia/reperfusion (I/R) induced brain injury in vivo and in vitro through hematoxylin and eosin (H&E) and Nissl staining assays, flow cytometry, Hoechst 33258 staining, quantitative PCR, western blot analysis and fluorescence microscopic analysis. In this study, models of cerebral I/R injury were established using rats and pheochromocytoma (PC-12) cells. The results revealed that treatment with FA significantly attenuated memory impairment, and reduced hippocampal neuronal apoptosis and oxidative stress in a dose-dependent manner. The results from in vitro experiments also indicated that FA protected the PC-12 cells against I/R-induced reactive oxygen species (ROS) generation and apoptosis by inhibiting apoptosis, Ca2+ influx, superoxide anion (O2-), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) production in a concentration-dependent manner. Moreover, FA inactivated the Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88) pathway. MyD88 overexpression abolished the neuroprotective effects of FA. On the whole, we found that FA attenuated memory dysfunction and exerted protective effects against oxidative stress and apoptosis induced by I/R injury by inhibiting the TLR4/MyD88 signaling pathway. This study supports the view that FA may be a promising neuroprotective agent for use in the treatment of cerebral ischemia. PMID- 28901375 TI - MicroRNA-7-5p regulates the proliferation and migration of intestinal epithelial cells by targeting trefoil factor 3 via inhibiting the phosphoinositide 3 kinase/Akt signalling pathway. AB - Trefoil factor 3 (TFF3) reconstructs the epithelial barrier by stimulating epithelial cell migration and proliferation, and significantly contributes to intestinal mucosal damage and healing. In a previous study, TFF3 was identified as a novel target of microRNA-7-5p (miR-7-5p). The aim of the present study was to investigate the roles and mechanisms of miR-7-5p in the proliferation and migration of intestinal epithelial cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression level of miR-7-5p in the experimental groups. In addition, western blot analysis was performed to examine the expression levels of TFF3, phosphoinositide 3-kinase (PI3K), Akt and phosphorylated (p)-AKT when miR-7-5p or TFF3 was overexpressed, and the effects of miR-7-5p and TFF3 on LS174T cell proliferation and migration were simultaneously investigated. miR-7-5p was demonstrated to decrease the expression level of TFF3, and inhibit LS174T cell proliferation and migration, which was accompanied by decreased expression levels of PI3K and p-Akt. miR-7-5p was decreased following combined treatment with the TFF3 plasmid and miR-7-5p mimics, compared with treatment with miR-7-5p mimics alone, which was accompanied by increased expression levels of TFF3, PI3K and p-Akt, and enhanced LS174T cell proliferation and migration effects. The expression levels of miR-7-5p in the miRNA negative control (NC) + LY294002 group, the miR-7-5p mimic + LY294002 group, and the miR-7-5p mimic + TFF3 plasmid + LY294002 group were higher than those in the NC group, the miR-7-5p mimic group and the miR-7-5p mimic + TFF3 plasmid group, respectively. Accordingly, the expression level of TFF3 was downregulated and the proliferation and migration ability of the cells was downregulated. The present study demonstrates that overexpressed miR-7-5p may inhibit the proliferation and migration of LS174T cells by targeting the expression of TFF3 via inhibiting the PI3K/Akt signalling pathway. The PI3K/Akt signalling pathway may exert a feedback regulation effect on miR-7-5p, inhibiting the activity of this signalling pathway, which increases the miR-7-5p expression levels and further enhances the effects of miR-7-5p on cell proliferation and migration. PMID- 28901376 TI - Mechanical loading modulates heterotopic ossification in calcific tendinopathy through the mTORC1 signaling pathway. AB - Excessive mechanical loading is a major factor affecting heterotopic ossification (HO), which is a major pathological alteration in calcific tendinopathy. However, physical therapies with mechanical loading as the functional element have exhibited promising results in the treatment of calcific tendinopathy. The dual effects that mechanical loading may have on the pathogenesis and rehabilitation of calcified tendinopathy remain unclear. The present study was designed to investigate the effects of mechanical loading on HO in calcific tendinopathy. In the present study, a tendon cell in vitro stretch model and an Achilles tenotomy rat model were used to simulate different elongation mechanical loading scenarios in order to investigate the effects of mechanical loading on HO of the tendon. In addition, rapamycin, a selective mammalian target of rapamycin complex-1 (mTORC1) signaling pathway inhibitor, was employed to determine whether mechanical loading modulates heterotopic ossification in calcific tendinopathy through the mTORC1 signaling pathway. The data indicate that mechanical loading modulated HO of the tendon through the mTORC1 signaling pathway, and that low elongation mechanical loading attenuated HO, while high elongation mechanical loading accelerated HO in vivo. This study may improve the understanding of the effect of physical therapies used to treat calcific tendinopathy, so as to guide clinical treatment more effectively. Furthermore, rapamycin may be a potential drug for the treatment of calcific tendinopathy. PMID- 28901377 TI - Anthocyanin-rich blackcurrant extract inhibits proliferation of the MCF10A healthy human breast epithelial cell line through induction of G0/G1 arrest and apoptosis. AB - Blackcurrants (Ribes nigrum L., Grossulariaceae) possess a high content of anthocyanin polyphenols, which have been demonstrated to exhibit beneficial effects on health due to their antioxidant and anticarcinogenic prope-rties. The present study investigated novel functions of anthocyanin-rich blackcurrant extracts (BCEs) in a healthy mammary epithelial cell line, MCF10A. The percentages of viable cells were 85, 75, 53 and 31% following exposure to 50, 100, 200 and 400 ug/ml BCE, respectively. The half-maximal response concentration of BCE was 237.7 ug/ml. Microarray and Ingenuity(r) Pathway Analysis demonstrated that BCE downregulated cell cycle signaling, including upstream genes with mitotic roles such as polo-like kinase signaling. BCE increased the number of cells in the G0/G1 phase and decreased the number of cells in the S and G2/M phases. Alkaline comet assays demonstrated that 50 and 100 ug/ml BCE induced DNA damage in a dose-dependent manner. Cultures treated with 0, 50, and 100 ug/ml BCE contained 4.6, 13.4 and 16.0% apoptotic cells, respectively. As compared with the untreated cultures (1.9%), the number of necrotic cells increased in the 100 ug/ml BCE-treated cultures (from 1.9 to 4.3%) but not in the 50 ug/ml BCE-treated cultures. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that BCE reduced mRNA expression of the genomic caretaker lysine specific demethylas 5B (KDM5B). The results suggested that blackcurrant anthocyanins may act as cell arrest and death inducers via KDM5B downregulation in healthy breast cells. PMID- 28901378 TI - Androgen-independent LNCaP cells are a subline of LNCaP cells with a more aggressive phenotype and androgen suppresses their growth by inducing cell cycle arrest at the G1 phase. AB - Androgen deprivation therapy (ADT, surgical or chemical castration) is the mainstay treatment for metastatic prostate cancer (PCa); however, patients ineluctably relapse despite extremely low androgen levels. This evolution of PCa indicates its lethal progression. In this study, to mimic the traits of clinical PCa progression in vitro, we investigated the alterations in the cell biological characteristics in androgen-independent LNCaP cells (LNCaP-AI cells) compared with LNCaP cells. We also examined the effects of androgen on LNCaP and LNCaP-AI cell proliferation, androgen receptor (AR) expression and prostate-specific antigen (PSA) secretion. Furthermore, AR was silenced in the LNCaP and LNCaP-AI cells to detect the roles taht AR plays in cell growth, apoptosis and PSA secretion. We found that prolonged androgen ablation increased the LNCaP-AI cell growth rate and cell invasiveness, and induced epithelial-mesenchymal transition in the LNCaP-AI cells. Moreover, despite the fact that the LNCaP and LNCaP-AI cells expressed equal amounts of AR protein, androgen induced a greater secretion of PSA in the LNCaP-AI cells than in the LNCaP cells. The proliferation of the LNCaP-AI cells was not dependent on, but was suppressed by androgen, which led to arrest at the G1 phase. Conversely, androgen significantly increased LNCaP cell proliferation by promoting the G1-S transition. Moreover, the silencing of AR suppressed LNCaP and LNCaP-AI cell growth by inducing cell cycle arrest at the G1 phase rather than promoting apoptosis, and reduced PSA secretion. On the whole, our data suggest that LNCaP-AI cells have a more more aggressive phenotype compared with the LNCaP cells; AR remains a critical factor in the LNCaP-AI cells, and androgen suppresses LNCaP-AI cell growth by blocking the cell cycle at the G1 phase. PMID- 28901379 TI - Eya2 overexpression promotes the invasion of human astrocytoma through the regulation of ERK/MMP9 signaling. AB - The overexpression of eyes absent (Eya) 2 has been found in several human cancers. However, its biological roles and clinical significance in human astrocytoma have not yet been explored. This study investigated the clinical significance and biological roles of Eya2 in human astrocytoma tissues and cell lines. Using immunohistochemistry, we found Eya2 overexpression in 33 out of 90 (36.7%) astrocytoma specimens. The rate of Eya2 overexpression was higher in grade III-IV (48.1%) than in grade I+II astrocytomas (21.1%). Transfection with an Eya2 expression plasmid was performed in A172 cells with a low endogenous expression of Eya2 and the knockdown of Eya2 was carried out in U251 cells with a high endogenous expression using siRNA. Eya2 overexpression induced A172 cell proliferation and invasion, while the knockdown of Eya2 using siRNA decreased the proliferation and invasion of U251 cells. In addition, we found that transfection with the Eya2 expression plasmid facilitated cell cycle progression, and that the knockdown of Eya2 inhibited cell cycle progression, accompanied by a change in the expression of cell cycle-related proteins, including cyclin D1 and cyclin E. Eya2 also positively regulated extracellular signal-regulated kinase (ERK) activity and matrix metalloproteinase (MMP)9 expression. The blockade of ERK signaling using an inhibitor abolished the effects of Eya2 on A172 cell invasion and MMP9 production. In addition, we found that there was a positive correlation between Eya2 and Six1 in the astrocytoma cell lines. Immunoprecipitation revealed that Eya2 interacted with Six1 protein in the U251 cell line, which exhibited a high expression of both proteins. Eya2 failed to upregulate MMP expression in the A172 cells in which Six1 was silenced. On the whole, our data indicate that Eya2 may serve as a potential oncoprotein in human astrocytoma. Eya2 regulates astrocytoma cell proliferation and invasion, possibly through the regulation of ERK signaling. PMID- 28901380 TI - Expression of CD19+CD24highCD38high B cells, IL-10 and IL-10R in peripheral blood from patients with systemic lupus erythematosus. AB - The present study aimed to examine the status and clinical significance of cluster of differentiation (CD) 19+CD24highCD38high regulatory B cells (Bregs), serum interleukin (IL)-10, serum transforming growth factor (TGF)-beta and IL-10 receptor (IL-10R) expression in peripheral blood from patients with systemic lupus erythematosus (SLE). A total of 56 patients with SLE and 35 healthy individuals were recruited to the present study. The SLE disease activity index (SLEDAI) was calculated, and other laboratory parameters were measured. Peripheral blood was collected from all participants. The frequency of CD19+CD24highCD38high Bregs and IL-10R+ expression on circulating lymphocytes was examined by flow cytometry. The serum levels of IL-10 and TGF-beta were measured using enzyme-linked immunosorbent assay. The associations between these measurements and SLEDAI or other laboratory parameters were analyzed by correlation analysis. The percentage of CD19+CD24highCD38high Bregs and the serum levels of IL-10 were significantly increased, whereas the expression of IL-10R on circulating lymphocytes was markedly reduced in patients with SLE compared with in healthy controls. The serum levels of TGF-beta1 were not markedly different between the groups. In addition, these factors were correlated with other SLE laboratory parameters, and inter-correlations were presented with different degrees of significance. The percentage of CD19+CD24highCD38high Bregs was positively correlated with the percentage of IL-10R+ lymphocytes, mean fluorescence intensity (MFI) of IL-10R+ lymphocytes and serum IL-10 levels. In addition, the percentage of IL-10R+ lymphocytes was positively correlated with its expression level (MFI), whereas serum TGF-beta1 levels were negatively correlated with serum IL-10 levels. The present results indicated that expansion of CD19+CD24highCD38high Bregs, upregulation of IL-10 and deficient lymphocyte associated IL-10R may serve as novel SLE biomarkers. It may be hypothesized that deficient IL-10R expression results in compensatory enhanced IL-10 expression, expansion of Bregs, and/or compromised Breg and IL-10 functions, thus contributing to SLE development. Therefore, targeting the 'Bregs/IL-10/IL-10R' system may provide a novel therapeutic approach for the treatment of SLE. PMID- 28901381 TI - Anti-allergic action of bacillus Calmette-Guerin extract in experimental mast cell-mediated anaphylactic models. AB - Allergy is an acquired hypersensitivity reaction of the immune system mediated by IgE-induced mast cell degranulation. In China, bacillus Calmette-Guerin extract (BCGE) has been shown to be clinically effective for regulating immunity, which enhances the resistance of the body to anaphylactic disease, infectious diseases and cancer. However, the mechanisms remain to be fully elucidated. The present study investigated the potential anti-allergic effects of BCGE in animal models of mast cell-dependent anaphylaxis and mechanisms of BCGE in mast cells. Anti allergic actions of BCGE were evaluated in passive cutaneous anaphylaxis, dextran T40-induced scratching behavior mouse models, and in ovalbumin (OVA)-induced contraction of intestinal tube isolated from OVA-sensitized guinea pigs. Direct mast cell-stabilizing effects of BCGE were examined in mast cells from the abdominal cavity of OVA-sensitized rats. Anti-allergic signaling mechanisms of BCGE in mast cells were investigated by detection of cyclic adenosine monophosphate levels and protein kinase A expression in mast cells. It was observed that BCGE prevented OVA-induced cutaneous vascular hyperpermeability, skin itching, elevation in plasma histamine levels and abdominal cavity fluid mast cell degranulation in animal models, in a dose-dependent manner. BCGE also suppressed OVA-mediated guinea pig intestinal tube contraction in vitro. In addition, BCGE was found to increase the levels of interferon-gamma, and reduce the levels of interleukin-4 and OVA-sIg E levels in OVA-sensitized rats. BCGE also increased levels of cyclic adenosine monophosphate and the expression of protein kinase A in mast cells separated from the abdominal cavity fluid of OVA sensitized rats. In conclusion, the results suggested that BCGE possesses anti allergic activity by inhibiting IgE-induced mast cell degranulation, providing a foundation for the development of BCGE for the treatment of mast cell-mediated allergic disorders. PMID- 28901382 TI - Construction of a chalcone reductase expression vector and transformation of soybean plants. AB - The present study aimed to clone the soybean chalcone reductase 3 (CHR3) and create a recombinant expression vector pCAMBIA3300-CHR3 containing Bar resistance gene as a selection marker, and then obtain transgenic soybean plants using Agrobacterium infection. The plant expression vector pCAMBIA3300-CHR3 was transferred into soybean receptor plants, Jinong 17 and Jilin 30. Polymerase chain reaction (PCR) and Southern blotting were used to confirm the positive transgenic plants. Additionally, reverse transcription-quantitative PCR (RT-qPCR) was used to detect CHR3 expression and isoliquiritigenin content was measured using high-performance liquid chromatography (HPLC) in the transgenic offspring. Soybean CHR3 (932 bp fragment) was successfully cloned into the plant expression vector pCAMBIA3300-CHR3, which was subsequently transferred into soybean receptor plants. In the T1 generation positive plants were validated by PCR analysis, including eight Jinong 17 and five Jilin 30 transgenic plants; Southern blotting demonstrated that the functional components of the pCAMBIA3300-CHR3 vector had been integrated into the soybean genome; RT-qPCR results demonstrated that the expression of CHR3 mRNA was increased by 2 to 20-fold in the transgenic plants compared with the non-transgenic soybean plants. Furthermore, the isoliquiritigenin content was increased by 8.56% in the transgenic Jinong 17, compared with control plants, as detected by HPLC. The CHR3 gene can produce isoliquiritigenin, a precursor of daidzein, which in turn can improve the ability of soybean to resist phytophthora root rot. PMID- 28901383 TI - Endothelial progenitor cell-derived extracellular vesicle-meditated cell-to-cell communication regulates the proliferation and osteoblastic differentiation of bone mesenchymal stromal cells. AB - Bone tissue engineering is a promising treatment strategy to increase bone regeneration. Endothelial progenitor cells (EPCs) and bone marrow stromal cells (BMSCs) are commonly used to promote vessel formation and osteoblastic differentiation in tissue engineering. Previous studies have demonstrated that EPCs regulate both proliferation and differentiation of BMSCs. However, the underlying mechanism remains unclear. Understanding this mechanism is critical to developing more effective treatments. The role of extracellular vesicles in cell to-cell communication has attracted substantial attention. These small vesicles deliver proteins, DNA, and RNA and consequently regulate the commitment, function, and differentiation of target cells. In the present study, EPC-derived extracellular vesicles (EPC-EVs were isolated using gradient ultracentrifugation and ultrafiltration and the influence of EPC-EVs on BMSC osteoblastic differentiation and proliferation was examined in vitro. The results indicated that EPC-EVs regulate the osteoblastic differentiation of BMSCs by inhibiting the expression of osteogenic genes and increasing proliferation in vitro. It is suggested that the results regarding the role of EPC-EVs will provide a novel way to explain the crosstalk between EPCs and BMSCs. PMID- 28901384 TI - Aminoguanidine exhibits an inhibitory effect on beta-amyloid-induced damage in F98 glioma cells. AB - The present study investigated the role of aminoguanidine in the prevention of harmful effects in astroglioma F98 cells induced by beta-amyloid treatment. MTT assay was used to analyze cell viability. Expression of inducible nitric oxide synthase (iNOS) was analyzed using western blot analysis. Treatment of the F98 cells with a 15 uM concentration of beta-amyloid for 12 h reduced cell viability to 18% compared with the control cells. However, pretreatment with a 30 uM concentration of aminoguanidine for 12 h completely prevented the beta-amyloid induced reduction in cell viability. The production of ROS and the expression of iNOS were significantly (P<0.005) higher in the beta-amyloid-treated F98 cells. Aminoguanidine pre-treatment inhibited the beta-amyloid-induced increase in the expression of ROS, with increased mRNA and proteins levels of iNOS12 h following treatment at a 30 uM concentration. The beta-amyloid treatment also resulted in a marked increase in the expression of cyclooxygenase-2 (COX-2) in F98 cells. By contrast, pre-treatment with aminoguanidine for 12 h led to reduction in the mRNA and protein expression levels of COX-2. Pre-treatment of the F98 cells with aminoguanidine at a 30 uM concentration for 12 h prior to incubation with beta amyloid significantly (P<0.002) reduced the expression of prostaglandin E2 (PGE2). Aminoguanidine pre-treatment also caused the inhibition of beta-amyloid induced translocation of nuclear factor (NF)-kappaB p65 into the cytosol. Thus, aminoguanidine prevented beta-amyloid-induced Alzheimer's disease through reductions in the expression levels of NO, iNOS, PGE2 and COX-2, and the inactivation of NF-kappaB. Therefore, aminoguanidine offers potential for use in the treatment of neurological disorders, including Alzheimer's disease. PMID- 28901385 TI - Protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulation of IL-6/STAT3 signaling. AB - The aim of the present study was to assess the effectiveness of Rhizoma Dioscoreae extract (RDE) on preventing rat alveolar bone loss induced by ovariectomy (OVX), and to determine the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in this effect. Female Wistar rats were subjected to OVX or sham surgery. The rats that had undergone OVX were treated with RDE (RDE group), vehicle (OVX group) or 17beta-estradiol subcutaneous injection (E2 group). Subsequently, bone metabolic activity was assessed by analyzing 3-D alveolar bone construction, bone mineral density, as well as the plasma biomarkers of bone turnover. The gene expression of alveolar bone in the OVX and RDE groups was evaluated by IL-6/STAT3 signaling pathway polymerase chain reaction (PCR) arrays, and differentially expressed genes were determined through reverse transcription-quantitative PCR. The inhibitory effect of RDE on alveolar bone loss in the OVX group was demonstrated in the study. In comparison with the OVX group, the RDE group exhibited 19 downregulated genes and 1 upregulated gene associated with the IL-6/STAT3 signaling pathway in alveolar bone. Thus, RDE was shown to relieve OVX-induced alveolar bone loss in rats, an effect which was likely associated with decreased abnormal bone remodeling via regulation of the IL-6/STAT3 signaling pathway. PMID- 28901386 TI - Aloin promotes A549 cell apoptosis via the reactive oxygen species-mitogen activated protein kinase signaling pathway and p53 phosphorylation. AB - Aloin has the potential to be a novel anticancer agent in cancer therapies. However, the detailed anticancer effect of Aloin remains to be fully elucidated. The present study analyzed the p53-dependent mechanisms in response to Aloin treatment. Using the p53-proficient A549 cells, an Aloin-induced apoptotic cell model was established, which was used to evaluate the potential underlying molecular mechanisms. The results demonstrated that 200, 300 and 400 uM Aloin induced intrinsic cell apoptosis, which was further confirmed by disruption of the mitochondrial membrane potential, elevation of cytosolic Ca2+ levels, and activation of B-cell lymphoma 2 (Bcl-2) homologous antagonist killer, Bcl-2 X associated protein, p53 upregulated modulator of apoptosis and phorbol-12 myristate-13-acetate-induced protein 1. Aloin-induced apoptosis was also accompanied by the induction of p53 phosphorylation on Serine (Ser)15, Threonine 18, Ser20 and Ser392; however, there were no significant differences in the expression of p53 and mouse double minute 2 homolog. Aloin-induced apoptosis was reactive oxygen species (ROS)- and c-Jun/p38-dependent, as specific inhibitors for ROS, phosphorylated (p)-c-Jun and p-p38 may attenuate Aloin-induced A549 cell proliferating inhibition. In conclusion, these results suggested that Aloin may induce apoptosis in A549 cells via the ROS-mitogen activated protein kinase signaling pathway, with p53 phosphorylation. These results implicate Aloin as a potential therapeutic agent for the treatment of lung cancer. PMID- 28901387 TI - Triptolide blocks the STAT3 signaling pathway through induction of protein tyrosine phosphatase SHP-1 in multiple myeloma cells. AB - Triptolide, an active component extracted from the medicinal plant Tripterygium wilfordii Hook F., has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. The present study investigated the effects of triptolide on multiple myeloma using western blotting and an electrophoretic mobility shift assay. Triptolide was found to suppress the inducible and constitutive activation of signal transducer and activator of transcription 3 (STAT3), which is closely associated with inflammation and tumorigenesis. Triptolide also inhibited the DNA binding of STAT3. This correlated with the downregulation of Src kinase and Janus kinase 1 and 2, and with the upregulation of protein tyrosine phosphatase non-receptor type 6 (also known as SHP-1). In addition, triptolide downregulated the expression of the STAT3-regulated antiapoptotic (Bcl-xL and myeloid cell leukemia-1), proliferative (cyclin D1), and angiogenic (vascular endothelial growth factor) genes, suggesting that triptolide can induce apoptosis of tumor cells. These results suggest that triptolide may be a potential therapeutic anticancer agent for the prevention and treatment of multiple myeloma; thus further in-depth investigations into its efficacy and toxicity are warranted. PMID- 28901388 TI - Inhibitory effects of 17beta-estradiol or a resveratrol dimer on hypoxia inducible factor-1alpha in genioglossus myoblasts: Involvement of ERalpha and its downstream p38 MAPK pathways. AB - Deficiency in the functioning of the genioglossus, which is one of the upper airway dilator muscles, is an important cause of obstructive sleep apnea/hypopnea syndrome (OSAHS). Estrogens have been reported to inhibit hypoxia-inducible factor-1alpha (HIF-1alpha) expression in hypoxia, regulating its target genes and exerting protective effects on the genioglossus in chronic intermittent hypoxia (CIH). This study aimed to investigate the role of 17beta-estradiol (E2) and a resveratrol dimer (RD) on HIF-1alpha and the underlying mechanism. Mouse genioglossus myoblasts were isolated and cultured, and the estrogen receptor alpha (ERalpha) shRNA lentivirus was used for gene knockdown. Then MTT assay was used to determine the effects of E2 and RD on the viability of the cells. Cells in different groups were treated with different agents (E2, or RD, or E2 and SB203580), incubated under normoxia or hypoxia for 24 h, and then expression levels of HIF-1alpha, ERalpha, ERbeta, total-p38 MAPK and phospho-p38 MAPK were detected. We observed that both E2 and RD inhibited the overexpression of HIF 1alpha induced by hypoxia at the mRNA and protein levels, and these effects were eliminated by genetic silencing of ERalpha by RNAi. In addition, we found that E2 activated p38 MAPK pathways to inhibit HIF-1alpha expression. On the whole, ERalpha may be responsible for downregulation of HIF-1alpha by E2 or RD via activation of downstream p38 MAPK pathways. PMID- 28901389 TI - Analysis of dermal fibroblasts isolated from neonatal and child cleft lip and adult skin: Developmental implications on reconstructive surgery. AB - The nonsyndromic cleft is one of the most frequent congenital defects in humans. Clinical data demonstrated improved and almost scarless neonatal healing of reparative surgery. Based on our previous results on crosstalk between neonatal fibroblasts and adult keratinocytes, the present study focused on characterization of fibroblasts prepared from cleft lip tissue samples of neonates and older children, and compared them with samples isolated from normal adult skin (face and breast) and scars. Although subtle variances in expression profiles of children and neonates were observed, the two groups differed significantly from adult cells. Compared with adult cells, differences were observed in nestin and smooth muscle actin (SMA) expression at the protein and transcript level. Furthermore, fibroblast to myofibroblast differentiation drives effective wound healing and is largely regulated by the cytokine, transforming growth factor-beta1 (TGF-beta1). Dysregulation of the TGF-beta signalling pathway, including low expression of the TGF-beta receptor II, may contribute to reducing scarring in neonates. Fibroblasts of facial origin also exhibited age independent differences from the cells prepared from the breast, reflecting the origin of the facial cells from neural crest-based ectomesenchyme. PMID- 28901390 TI - MicroRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma. AB - The prognosis of patients suffering from glioblastoma [also referred to as glioblastoma multiforme (GBM)] is dismal despite multimodal therapy. Chemotherapy with temozolomide may suppress tumor growth for a certain period of time (a few months); however, invariable tumor recurrence suggests that glioblastoma initiating cells (GICs) render these tumors persistant. Thus, the understanding of the molecular mechanisms of action of GICs as regards their role in the progression of GBM is important as such knowledge will be helpful in the discovery of novel drug targets, as well as in the design of novel therapeutic strategies for more effective treatment of the disease. In this study, we found that tumor suppressor candidate 3 (TUSC3) was downregulated in temozolomide resistant U87MG cells (U87MG-res cells) and its restoration sensitized U87MG-res cells to temozolomide. TUSC3 was able to inhibit the formation of GIC phenotypes in the U87MG-res cells. The overexpression of microRNA (miR)-132 inhibited TUSC3 protein expression in the U87MG cells. However, its overexpression did not degrade TUSC3 mRNA expression in the cells. miR-132 was upregulated in the U87MG res cells and its overexpression induced temozolomide resistance and the formation of cancer stem cell phenotypes in the U87MG cells. Thus, our data indicate that miR-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting TUSC3 in glioblastoma. PMID- 28901391 TI - Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced-size liver transplantation: Role of autophagy regulated by the ERK/mTOR signaling pathway. AB - Autophagy is a critical lysosomal pathway that degrades cytoplasmic components to maintain cell homeostasis and provide substrates for energy metabolism. A study revealed that heme oxygenase-1 (HO-1)-transduced bone marrow-derived mesenchymal stem cells (BM-MSCs) could protect 50% reduced-size liver transplantation (RSLT) in a rat model. However, the mechanisms remain mostly unknown. The aim of the present study was to explore the effects and related mechanism of autophagy on the protection conferred by HO-1-transduced BM-MSCs (HO-1/BM-MSCs) on 50% RSLT in a rat model. The authors established an acute rejection model following 50% RSLT in rats, with recipients divided into three groups receiving treatment with BM MSCs, HO-1/BM-MSCs or normal saline (NS) injected through the dorsal penile vein. Transplanted liver tissues at 0, 1, 3, 5, 7, 10 and 14 days following transplantation were acquired for further analysis. The results indicated that the expression of autophagy-related proteins LC3 and Beclin-1 increased, the levels of ERK and p-ERK increased, and the levels of mammalian target of rapamycin (mTOR) and p-mTOR decreased in the HO-1/BM-MSCs. These observations indicated that autophagy is involved in the protective effects of HO-1/BM-MSCs on liver grafts following RSLT, possibly via upregulation of autophagy-related proteins through the ERK/mTOR signaling pathway. PMID- 28901392 TI - Negative pressure wound therapy: Regulating blood flow perfusion and microvessel maturation through microvascular pericytes. AB - Negative pressure wound therapy (NPWT) has been demonstrated to accelerate wound healing by promoting angiogenesis. However, whether blood flow perfusion is regulated by microvessel maturation and pericytes following NPWT remains unclear, as well as the exact association between pericytes and collagen type IV. The aim of this study was to investigate the relevant association between blood flow perfusion and microvessel maturation and pericytes following NPWT, and to further explore the underlying molecular mechanisms. We also aimed to investigate the association between pericytes and collagen type IV. For this purpose, we created a rat model of diabetic wounds and microvascular blood flow perfusion was detected using a laser Doppler blood perfusion imager. The expression levels of angiogenin-1, tyrosine phosphorylation of tyrosine kinase receptor-2 (Tie-2), alpha-smooth muscle actin (alpha-SMA) and collagen type IV were detected and analyzed through immunohistochemistry, immunofluorescence, RT-qPCR and western blot analysis. The results revealed that NPWT promoted the overexpression of angiogenin-1, Tie-2, alpha-SMA and collagen type IV, and significantly increased blood flow perfusion coupled with microvessel maturation in the NPWT group at the later stages (7-10 days) of wound healing. Our results suggested that NPWT can preferentially enhance vessel maturation and increase the number of pericytes, thus regulating blood flow perfusion. On the other hand, pericytes and collagen type IV had a mutual interaction, promoting microvessel maturation. PMID- 28901393 TI - LPS-induced downregulation of microRNA-204/211 upregulates and stabilizes Angiopoietin-1 mRNA in EA.hy926 endothelial cells. AB - Angiopoietin-1 (ANG-1), a ligand of the endothelial cell-specific TIE2 surface receptor, acts in a complementary and coordinated manner with vascular endothelial growth factor during the process of angiogenesis. ANG-1 can be used as a clinically informative biomarker of disease severity and outcome in severe sepsis. The epithelium-specific Ets transcription factor 1 can activate ANG-1 transcription in the setting of inflammation; however, relatively little is known about the regulation of ANG-1 by microRNAs (miRs). It was observed that lipopolysaccharide (LPS) significantly increased ANG-1 mRNA and protein expression in EA.hy926 cells. ANG-1 was identified as a potential target gene of miR-204 and miR-211. Overexpression of miR-204/211 partially reversed the LPS induced ANG-1 expression in EA.hy926 cells. Furthermore, overexpression of miR 204/211 significantly reduced the activity of a luciferase reporter gene containing the wild-type ANG-1 3'-untranslated region (UTR), but did not influence the activity of a luciferase reporter gene containing the ANG-1 3'-UTR with a mutated miR-204/211 binding site, confirming that miR-204/211 can bind to the ANG-1 3'-UTR and post-transcriptionally regulate ANG-1. Additionally, LPS enhanced the stability of ANG-1 mRNA by reducing the abundance of miR-204/211. Overexpression of miR-204/211 reduced the migration of EA.hy926 cells in vitro. The present study demonstrated that ANG-1 is a novel direct target gene of miR 204 and miR-211; in addition, LPS was able to inhibit this effect by reducing the expression of miR-204 and miR-211. PMID- 28901394 TI - Overexpression of ATP5b promotes cell proliferation in asthma. AB - Asthma is a complicated systemic disease of the airways, which is characterized by variable symptoms, including bronchial hyper-responsive-ness, inflammation and airflow obstruction. The prevalence of asthma has increased 2-3-fold over recent decades in developed countries; however, the molecular mechanism of asthma remains unclear. In the current study, the expression of recombinant protein Dermatophagoides farinaeI (Derf I) was induced by isopropyl beta-D-1 thiogalactoside (IPTG) and purified using Ni-NTA. Derf I, an important antigen of asthma, was used to establish the animal model of asthma. Airway hyper responsiveness was mea-sured using unrestrained whole-body plethysmography with a four-chamber system. Immunoglobulin (Ig)E, IgG and IgG2a were analyzed using indirect enzyme-linked immunosorbent assay (ELISA). Proteomic technology was applied to detect the difference between the normal lung tissue and asthma lung tissue samples of the asthma model. Cytokines in bronchoalveolar lavage fluid and the splenocyte culture medium were measured by ELISA and reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect the mRNA expression of ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide (ATP5b). In addition, cell growth of arterial smooth muscle cells (ASMCs) was evaluated by MTT assay. In the current study, Derf I was successfully used to construct the animal model of asthma. Out of 23 proteins that exhibit 3 fold upregulation or downregulation, ATP5b was chosen for further investigation. The data indicated that ATP5b was overexpressed in the asthma lung tissue when compared with the normal lung tissue. However, when ATP5b was knocked down, cell growth decreased. Therefore, overexpressed ATP5b leads to airway smooth muscle cell (ASMC) proliferation and finally to ASM thickening. Thus, to the best of our knowledge, this is the first study to report that the expression level of ATP5b was markedly increased in lung tissue samples of an asthma model compared with the tissue samples from normal lungs, which promoted ASMC proliferation and contributed to airway remodeling. PMID- 28901395 TI - Role of matrix metalloproteinase-7 and apoptosis-associated gene expression levels in the pathogenesis of atrial fibrosis in a Beagle dog model. AB - The aim of the present study was to investigate the potential role of matrix metalloproteinase-7 (MMP-7) and apoptosis-associated genes [TIMP metallopeptidase inhibitor 2(TIMP-2), BCL2 associated X, apoptosis regulator (BAX) and BCL2, apoptosis regulator (BCL-2)] in the pathogenesis of atrial fibrillation (AF) in a Beagle dog model. A total of 20 adult male Beagle dogs were randomly assigned into the AF group (n=10; Beagle dogs were treated by Burst stimulation to induce AF) and the control group (n=10; healthy Beagle dogs). Echocardiography and Mallory staining were used to determine cardiac function and degree of atrial fibrosis, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine collagen type 1 (Col I), MMP-7, TIMP-2, BAX and BCL-2 mRNA and protein expression levels. Compared with the control group, the AF group presented increased degree of atrial fibrosis and level of Col I expression, elevated MMP-7 and BAX expression levels, but decreased TIMP-2 and BCL-2 expression levels. Correlation analysis demonstrated that MMP-7 and BAX protein expression levels were negatively correlated with left ventricular ejection fraction (LVEF), but positively correlated with the degree of atrial fibrosis. Negative correlation was observed between TIMP-2 and BCL-2 protein expression levels and degree of atrial fibrosis. In addition, a positive correlation between TIMP-2 and BCL-2 protein expression levels and LEVF was observed. These results demonstrate that MMP-7 and BAX were highly expressed, while TIMP-2 and BCL-2 were downregulated in a Beagle dog model of AF, indicating that MMP-7 and apoptosis-associated genes (TIMP-2, BAX and BCL 2) may be associated with the pathogenesis of AF. PMID- 28901396 TI - Effect of 1,25(OH)2D3 on high glucose-induced autophagy inhibition in peritoneum. AB - High glucose (HG) may damage the structure and function of the peritoneal membrane, and is considered to be one of the most important factors that leads to peritoneal fibrosis and ultrafiltration failure. Recently, 1,25(OH)2D3, the active form of vitamin D, was demonstrated to protect against epithelial mesenchymal transition and fibrosis in peritoneal mesothelium and other organs. Accumulating evidence has suggested that autophagy serves a protective role in certain diseases by regulating cell survival. The present study examined whether 1,25(OH)2D3 has an effect on autophagy in peritoneal mesothelial cells. The protein level of Beclin, anti-ubiquitin-binding protein p62 (p62), microtubule associated proteins 1A/1B light chain 3B (LC3-II), mechanistic target of rapamycin (mTOR) and phosphorylated mTOR were evaluated by western blot analysis. Autophagosomes were detected under transmission electron microscopy. It was revealed that exposure to HG inhibited autophagy in peritoneal mesothelial cells. However, 1,25(OH)2D3 alleviated autophagy inhibition induced by HG in human peritoneal mesothelial cells, which activated expression of autophagy-associated genes encoding Beclin-1 and LC3-II downregulated the expression of p62 via mTOR signaling pathway. In a mouse model of HG-treated peritoneal mesothelium, autophagy inhibition was observed in peritoneum, 1,25(OH)2D3 attenuated HG induced autophagy inhibition in peritoneal mesothelium via the mTOR signaling pathway. These findings suggested that 1,25(OH)2D3 may be a potential therapy for peritoneal injury. PMID- 28901397 TI - Beneficial effect of 20-hydroxyecdysone exerted by modulating antioxidants and inflammatory cytokine levels in collagen-induced arthritis: A model for rheumatoid arthritis. AB - Rheumatoid arthritis is a chronic autoimmune disease characterized by an elevated synovial inflammatory response, with destruction or erosion of articular cartilage in major joints. The aim of the present study was to examine whether 20 hydroxyecdysone (HES) is able to ameliorate oxidative stress and inflammatory responses in a collagen-induced rheumatoid arthritis (CIA) rat model. A total of 40 healthy male rats were selected arbitrarily and separated into four groups. Rats treated with saline served as a control (group I), rats subjected to CIA induction by intradermal injection of bovine collagen II type served as the induced group (group II), while rats induced with CIA and administered with 10 and 20 mg/kg bodyweight HES for 28 days served as treatment groups (groups III and IV). Biochemical parameters, including paw swelling (edema), arthritis score, indexes of thymus and spleen, antioxidant levels (superoxide dismutase, catalase and glutathione), articular elastase and anti-collagen II specific immunoglobulins (Ig)G, IgG1 and IgG2a, in addition to inflammatory markers [nitric oxide, C-reactive protein, interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and nuclear factor-kappaB p65 subunit] were significantly decreased (P<0.01) following supplementation with HES (10/20 mg/kg). Consistently, the protein expression pattern of inducible nitric oxide synthase and cyclooxygenease 2 were significantly downregulated (P<0.01) upon treatment with HES. In addition, histological analysis confirmed arthritis in CIA-induced rats by revealing the presence of greater polymorphonuclear cell infiltration, with eroded articular cartilage and prominent synovitis. However, administration of HES was demonstrated to alleviate the morphological changes and maintain the normal architecture of synovial joints. In conclusion, the results of the present study indicated that treatment with HES (particularly 20 mg/kg) may effectively eradicate the inflammatory cascade and oxidative stress process in CIA-induced rats and thereby exhibit anti-rheumatoid arthritis properties. PMID- 28901398 TI - Application of next-generation sequencing for molecular diagnosis in a large family with osteogenesis imperfecta type I. AB - Increased bone fragility and low bone mass are common features of osteogenesis imperfecta (OI), which is associated with connective tissue. Its type is distinguished by clinical phenotypes and molecular genetics. Although fifteen types (I-XV) of OI have been identified at present, the majority of patients are diagnosed as OI type I-IV. Type I collagen is responsible for OI type I-IV, consists of alpha1 (I) and alpha2 (I) chains and is encoded by COL1A1 and COL1A2. To identify the pathogenic gene of a large Chinese family with OI type I and explain genetic heterogeneity of the patients, next-generation sequencing (NGS) was conducted in a female with OI type I and her affected niece and daughter to search for the mutation. Subsequently, it was confirmed in other family members by Sanger sequencing. Analysis of COL1A1 gene identified a splicing mutation (c.471+1G>A, also termed IVS5+1G>A) that converted the 5' end of intron 5 from GT to AT. The current study aimed to investigate why there are different phenotypes with the same mutation observed within the same OI pedigree, and the results suggested that there may be environmental factors involved. The present study provided genetic counseling and prenatal diagnosis for the family members, however additionally provided insight into the phenotype-genotype association in OI. PMID- 28901399 TI - Downregulated SOCS1 expression activates the JAK1/STAT1 pathway and promotes polarization of macrophages into M1 type. AB - Macrophage polarization is flexible, and involves in different signaling pathways and various transcription factors. Suppressor of cytokine signaling (SOCS) is an important inhibitor of cytokine signaling pathways and also a key physiological regulator for natural and acquired immunity systems. Following transfection of SOCS1 short hairpin (sh)RNA into mouse macrophage cells, reverse transcription quantitative polymerase chain reaction demonstrated that the mRNA levels of Janus kinase (JAK)1 and signal transducer and activator of transcription (STAT)1 increased significantly. In addition, western blotting indicated that JAK1, STAT1 and p-STAT1 expression was significantly enhanced. Fludarabine can inhibit phosphorylation of STAT1 and SOCS1 expression. When fludarabine was added and SOCS1 shRNA was transfected, the inhibition of fludarabine was weakened, and p STAT1 expression was upregulated. Flow cytometry detection indicated that, following the downregulation of SOCS1 expression, M1-type cells significantly increased, but the proportion of M2-type cells did not change significantly. Fludarabine can reduce the effect of SOCS1 shRNA on promoting M1-type cell polarization, and macrophages can polarize into both M1 and M2 phenotypes. Further ELISA results presented that, when downregulating SOCS1 expression, interleukin (IL)-4 and IL-10 expression was both downregulated, and tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma expression was significantly upregulated. When adding fludarabine or injecting with the traditional Chinese medicine Xuebijing, IL-4 and IL-10 expression was both significantly upregulated, and TNF-alpha and IFN-gamma expression was significantly downregulated. When adding fludarabine and downregulating SOCS1, IL 4, IL-10, TNF-alpha and IFN-gamma expression presented no significant changes. The above results indicated that, when SOCS1 expression is downregulated, it will activate the JAK1/STAT1 pathway, and thereby promote the polarization of macrophages into M1 type. The findings are of great importance for understanding occurrence, development and treatment of various immune-related diseases. PMID- 28901401 TI - Urotensin II enhances transforming growth factor-beta1 expression and secretion in the kidney during aristolochic acid nephropathy. AB - Aristolochic acid is a component of many types of Chinese medicine, which are commonly used to treat almost all human diseases. However, aristolochic acid may cause nephropathy. Urotensin II (UII) and transforming growth factor (TGF)-beta1 are important signaling factors, which are expressed at elevated levels during the development of nephropathy. However, the association between UII and TGF beta1 expression remains unclear. In the current study, the regulatory association between UII and TGF-beta1 expression was investigated using a rat aristolochic acid nephropathy model and the NRK-52E cell line. The expression levels of UII and TGF-beta1 were identified to be constantly increased in the rat aristolochic acid nephropathy model, even 10 days after administration of Aristolochiae manshuriensis decoction was terminated. Notably, increases in the TGF-beta1 expression levels occurred later than those of UII. Furthermore, UII enhanced TGF-beta1 expression in, and secretion from, NRK-52E cells. These data indicate that UII and TGF-beta1 are important in the development of aristolochic acid nephropathy, and UII enhances TGF-beta1 expression levels and secretion during aristolochic acid nephropathy. However, the underlying mechanisms for the precise roles of UII and TGF-beta1 as well as the method by which UII regulates the expression TGF-beta1 in aristolochic acid nephropathy remain to be elucidated in future studies. PMID- 28901400 TI - Taurine alleviates lipopolysaccharide-induced liver injury by anti-inflammation and antioxidants in rats. AB - The aim of the present study was to investigate the protective effect of taurine on lipopolysaccharide (LPS)-induced liver injury and its mechanisms. Male rats were randomly divided into three groups: Normal saline, LPS model and taurine treatment. Experimental animals were treated with saline or taurine (dissolved in saline, 200 mg/kg/day) via intravenous injection. After 2 h, saline or LPS (0.5 mg/kg) was administrated via intraperitoneal injection. Markers of liver injury, pro-inflammatory cytokines and superoxide dismutase (SOD) activity were determined in plasma. Liver tissues were removed for morphological analysis and determination by western blot analysis. Taurine significantly reduced the elevation in the levels of LPS-induced aspartate transaminase and alanine transaminase and decreased the concentrations of LPS-induced inflammatory factors including tumor necrosis factor-alpha and interleukin-6. Taurine also increased the activity of SOD in serum and the expression of heme oxygenase-1 protein in liver tissue. Taurine pretreatment also reduced the elevated expression levels of LPS-induced cyclooxygenase-2, nuclear factor kappaB and extracellular regulated protein kinase. The results from the present study demonstrated that taurine alleviates LPS-induced liver injury. The beneficial role of taurine may be associated with its reduction of pro-inflammatory response and oxidative stress. PMID- 28901402 TI - Carbon monoxide-releasing molecule suppresses inflammatory and osteoclastogenic cytokines in nicotine- and lipopolysaccharide-stimulated human periodontal ligament cells via the heme oxygenase-1 pathway. AB - Smoking is identified as a risk factor for periodontitis. Carbon monoxide (CO) releasing molecule-3 (CORM-3) is a compound that has demonstrated anti inflammatory effects in vitro and in vivo studies. The present study aimed to investigate the effects of CORM-3 on the expression of inflammatory and osteoclastogenic cytokines in human periodontal ligament cells (PDLCs) stimulated by nicotine and lipopolysaccharide (LPS). The cells were pretreated with CORM-3 and then cultured in medium in the presence of nicotine and LPS. The mRNA and protein expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL) and heme oxygenase-1 (HO-1) were evaluated using reverse transcription quantitative polymerase chain reaction and western blot analysis. The mRNA and protein expression levels of these cytokines were also evaluated in PDLCs transiently transfected with HO-1 small interfering RNA (siRNA) in response to nicotine and LPS stimulation. CORM-3 attenuated the LPS- and nicotine-induced production of PGE2, COX-2 and RANKL in human PDLCs by releasing CO, and upregulated the expression of OPG. However, these effects of CORM-3 were abrogated when HO-1 siRNA was transiently transfected into the cells. These results demonstrate that CORM-3 exerts anti-inflammatory and anti osteoclastogenic effects on nicotine- and LPS-stimulated human PDLCs via the HO-1 pathway, which suggests its promising potential for use in the treatment of inflammatory periodontal disease. PMID- 28901403 TI - Whole Wiskott-Aldrich syndrome protein gene deletion identified by high throughput sequencing. AB - Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder, characterized by thrombocytopenia, small platelets, eczema and recurrent infections associated with increased risk of autoimmunity and malignancy disorders. Mutations in the WAS protein (WASP) gene are responsible for WAS. To date, WASP mutations, including missense/nonsense, splicing, small deletions, small insertions, gross deletions, and gross insertions have been identified in patients with WAS. In addition, WASP-interacting proteins are suspected in patients with clinical features of WAS, in whom the WASP gene sequence and mRNA levels are normal. The present study aimed to investigate the application of next generation sequencing in definitive diagnosis and clinical therapy for WAS. A 5 month-old child with WAS who displayed symptoms of thrombocytopenia was examined. Whole exome sequence analysis of genomic DNA showed that the coverage and depth of WASP were extremely low. Quantitative polymerase chain reaction indicated total WASP gene deletion in the proband. In conclusion, high throughput sequencing is useful for the verification of WAS on the genetic profile, and has implications for family planning guidance and establishment of clinical programs. PMID- 28901404 TI - Effects of anticholinergic agent on miRNA profiles and transcriptomes in a murine model of allergic rhinitis. AB - Anticholinergic agent, ipratropium bromide (IB) ameliorates symptoms of allergic rhinitis (AR) using neuroimmunologic mechanisms. However, the underlying molecular mechanism remains largely unclear. In the present study, 27 mice with AR induced by ovalbumin were randomly allocated to one of three groups: Model group, model group with IB treatment for 2 weeks, and model group with IB treatment for 4 weeks. Allergic symptoms were evaluated according to symptoms scores. Differentially expressed genes [microRNAs (miRNAs) and messenger RNAs (mRNAs)] of nasal mucosa were identified by microarray analysis. The expression levels of candidate genes were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The data indicates that the symptoms scores in allergic mice were significantly reduced by IB treatment. In the nasal mucosa of allergic mice with IB treatment, 207 mRNAs and 87 miRNAs were differentially expressed, when compared with the sham group. IB treatment significantly downregulated the expression levels of interleukin-4Ralpha and prostaglandin D2 synthase, whereas the leukemia inhibitory factor, A20 and nuclear receptor subfamily 4, group A, member 1 expression levels were upregulated. Similarly, the expression levels of mmu-miR-124-3p/5p, -133b-5p, -133a-3p/5p, -384-3p, -181a-5p, -378a-5p and -3071-5p were significantly increased. RT-qPCR data further validated these mRNA and miRNA expression levels. Thus, IB treatment regulated expression of allergic immune-associated mRNAs and miRNAs of the nasal mucosa in allergic mice, which may be associated with ameliorated nasal allergic symptoms. PMID- 28901405 TI - Genotype/phenotype analysis in a male patient with partial trisomy 4p and monosomy 20q due to maternal reciprocal translocation (4;20): A case report. AB - Translocations are the most frequent structural aberration in the human genome. Carriers of balanced chromosome rearrangement exhibit an increased risk of abortion and/or a chromosomally-unbalanced child. The present study reported a clinical and cytogenetic analysis of a child who exhibited typical trisomy 4p and monosomy 20q features, including intellectual disability, delayed speech, tall stature, seizures and facial dysmorphism. The karyotype of the proband exhibited 46, XY, add(20) (q13.3). The karyotype of the mother indicated a balanced translocation karyotype: 46, XX, t(4;20) (p15.2;q13.1). The array-based comparative genomic hybridization (aCGH) analysis identified partial trisomy of the short arm of chromosome 4 and partial monosomy of distal 20q in the proband due to maternal balanced reciprocal translocation 4;20. The analysis of genotype/phenotype correlation demonstrated that fibroblast growth factor receptor 3 and msh homeobox 1 may be the important genes for 4p duplication, and that potassium voltage-gated channel subfamily Q member 2, myelin transcription factor 1 and cholinergic receptor nicotinic alpha4 subunit may be the important genes for 20q deletion. To the best of our knowledge, the present study was the first to report an unbalanced translocation involving chromosomes 4p and 20q. The present study additionally demonstrated that aCGH analysis is able to reliably detect unbalanced submicroscopic chromosomal aberrations. PMID- 28901406 TI - FGFR2 mutations and associated clinical observations in two Chinese patients with Crouzon syndrome. AB - The aim of the present study was to identify mutations in the fibroblast growth factor receptor 2 (FGFR2) gene in patients with Crouzon syndrome and characterize the associated clinical features. A total of two Chinese patients diagnosed with Crouzon syndrome underwent complete examinations, including best-corrected visual acuity, slit-lamp, examination, fundus examination, optical coherence tomography and computed tomography of the skull. Genomic DNA was extracted from peripheral blood samples collected from the patients, as well as their family members and 200 unrelated control subjects from the same population. Exons 8 and 10 in the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Patient #1 had a heterozygous missense mutation (c.1025G>A, p.C342Y) in exon 10 of FGFR2. Patient #2 had a heterozygous mutation (c.1084+1 G>T; IVS10+1G>T) in intron 10. The mutations were not present in any of the unaffected family members or unrelated control subjects. These findings expand the mutation spectrum of FGFR2, and are valuable for genetic counseling in addition to prenatal diagnosis in patients with Crouzon syndrome. PMID- 28901407 TI - Colon cancer recurrence-associated genes revealed by WGCNA co-expression network analysis. AB - The present study aimed to identify the recurrence-associated genes in colon cancer, which may provide theoretical evidence for the development of novel methods to prevent tumor recurrence. Colon cancer and matched normal samples microarray data (E-GEOD-39582) were downloaded from ArrayExpress. Genes with significant variation were identified, followed by the screening of differentially expressed genes (DEGs). Subsequently, the co-expression network of DEGs was constructed using the weighted correlation network analysis (WGCNA) method, which was verified using the validation dataset. The significant modules associated with recurrence in the network were subsequently screened and verified in another independent dataset E-GEOD-33113. Function and pathway enrichment analyses were also conducted to determine the roles of selected genes. Survival analysis was performed to identify the association between these genes and survival. A total of 434 DEGs were identified in the colon samples, and stress associated endoplasmic reticulum protein family member 2 (SERP2) and long non coding RNA-0219 (LINC0219) were determined to be the vital DEGs between all the three sub-type groups with different clinical features. The brown module was identified to be the most significant module in the co-expression network associated with the recurrence of colon cancer, which was verified in the E-GEOD 33113 dataset. Top 10 genes in the brown module, including EGF containing fibulin like extracellular matrix protein 2 (EFEMP2), fibrillin 1 (FBN1) and secreted protein acidic and cysteine rich (SPARC) were also associated with survival time of colon cancer patients. Further analysis revealed that the function of cell adhesion, biological adhesion, extracellular matrix (ECM) organization, pathways of ECM-receptor interaction and focal adhesion were the significantly changed terms in colon cancer. In conclusion, SERP2, EFEMP2, FBN1, SPARC, and LINC0219 were revealed to be the recurrence-associated molecular and prognostic indicators in colon cancer by WGCNA co-expression network analysis. PMID- 28901408 TI - MicroRNA-382 inhibits cell proliferation and invasion of retinoblastoma by targeting BDNF-mediated PI3K/AKT signalling pathway. AB - It has previously been demonstrated that multiple microRNAs (miRNAs or miRs) are aberrantly expressed in retinoblastoma (RB) and contribute to RB initiation and progression. miR-382 has been revealed to be aberrantly expressed and therefore exhibits a key role in the progression of various types of cancer. However, the expression pattern, functional roles and underlying molecular mechanism of miR 382 in RB remain unknown. The present study investigated the expression levels of miR-382 and its effects on RB cells and the underlying regulatory mechanism of its action. It was demonstrated that miR-382 was downregulated in RB tissues and cell lines. Upregulation of miR-382 inhibited RB cell proliferation and invasion in vitro. Additionally, brain-derived neurotrophic factor (BDNF) was identified as a novel target of miR-382 in RB. BDNF was upregulated in RB tissues and negatively associated with miR-382 expression levels. Furthermore, BDNF overexpression rescued the tumour-suppressing effects on RB cells induced by miR 382. miR-382 inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway in RB. These findings suggested that miR-382 serves as a tumour suppressor in RB, in part, by targeting the BDNF-mediated PI3K/AKT signalling pathway. The results of the present study suggest a potential therapeutic strategy for treating RB patients in the future. PMID- 28901409 TI - Epigallocatechin-3-gallate protects from high glucose induced podocyte apoptosis via suppressing endoplasmic reticulum stress. AB - Podocytes serve a critical role in the development of many glomerular diseases, including diabetic nephropathy (DN). Epigallocatechin-3-gallate (EGCG), a predominant polyphenolic component of green tea, has indicated its therapeutic effects in diabetes. In the present study, mouse podocyte cells were cultured in vitro, cell injury was induced by high glucose, and the protective effect of EGCG on cell proliferation and apoptosis and the underlying mechanisms were investigated. The results demonstrated that high glucose significantly inhibited cell proliferation after 48 and 72 h compared with normal glucose and mannitol treatment. EGCG (20 umol/l) markedly promoted podocyte proliferation after 24, 48 and 72 h incubation with high glucose. Furthermore, high glucose significantly reduced WT-1 and nephrin expression in podocytes compared with the normal glucose and mannitol groups, while EGCG (20 umol/l) treatment largely restored their expression. High glucose also significantly increased the apoptotic cell population compared with normal glucose and mannitol groups. However, EGCG combined with high glucose greatly decreased the apoptotic cell number compared with high glucose treatment alone. Furthermore, high glucose treatment was demonstrated to significantly increase glucose-regulated protein 78 (GRP78), phosphorylated- PKR-like ER kinase (p-PERK) and caspase-12 protein expression levels, which is representative of endoplasmic reticulum (ER) stress, compared with the normal glucose and mannitol groups. However, EGCG treatment significantly attenuated GRP78, p-PERK and caspase-12 protein expression induced by high glucose. These findings suggested that EGCG serves a protective role in glucose-induced podocyte apoptosis via suppressing ER stress, and may provide a novel therapeutic strategy to ameliorate the process of DN. PMID- 28901410 TI - Depletion of ubiA prenyltransferase domain containing 1 expression promotes angiotensin II-induced hypertrophic response in AC16 human myocardial cells via modulating the expression levels of coenzyme Q10 and endothelial nitric oxide synthase. AB - UbiA prenyltransferase domain containing 1 (UBIAD1) is closely associated with cardiovascular diseases. However, at the cellular level, little is known about how UBIAD1 is expressed and functions in cardiomyocyte hypertrophy. The aim of the present study was to investigate the expression and role of UBIAD1 in angiotensin II (Ang II)-induced hypertrophy in AC16 cardiomyoblast cells. The loss-of-function approach was used to knock down UBIAD1 in vehicle- and Ang II stimulated AC16 cells. The levels of atrial natriuretic factor (ANF) and caspase 3 were measured and compared between vehicle- and Ang II-treated AC16 cells pretreated with control siRNA or siRNA against UBIAD1. In addition, the levels of coenzyme Q10 (CoQ10) and endothelial nitric oxide synthase (eNOS) were evaluated and compared between these groups. Ang II induced hypertrophy and apoptosis in AC16 cells, accompanied by increased expression of ANF and caspase-3, and decreased expression of UBIAD1. These effects were potentiated by UBIAD1 knockdown. In addition, Ang II treatment suppressed the expression of CoQ10 and eNOS, as well as the production of NO, and these inhibitory effects were also enhanced by UBIAD1 knockdown. Thus, silencing of UBIAD1 expression promotes a myocardial hypertrophic response to Ang II stimulation, in part, by suppressing the expression of CoQ10 and eNOS. PMID- 28901411 TI - Palmitate induces myocardial lipotoxic injury via the endoplasmic reticulum stress-mediated apoptosis pathway. AB - Increased free fatty acids in cardiomyocytes induce myocardial lipotoxic injury, but the underlying mechanisms are not well understood. Therefore, the aim of the present study was to explore the role of the endoplasmic reticulum (ER) stress mediated apoptosis pathway in palmitate (PA)-induced cardiomyocyte lipotoxicity. H9c2 cells were treated with various doses (100, 200 and 400 uM) of PA to mimic cardiomyocyte lipotoxicity in vitro. Oil Red O staining was used to determine the accumulation of intracellular lipids. An MTT assay was used to determine the cell viability. Lactate dehydrogenase (LDH) activity was used to measure the injury of H9c2 cells. Flow cytometry analysis was used to detect apoptosis. Western blotting was used to evaluate the expression change of ER stress-mediated apoptosis pathway proteins, including 78 kDa glucose-regulated protein (GRP78), eukaryotic initiation factor 2 alpha (eIF2alpha), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP) and cleaved caspase-12. The results demonstrated that various doses of PA promoted excessive lipid deposition in cardiomyocytes and resulted in decreased cell viability, and increased the LDH activity and apoptosis rate in a dose-dependent manner. Furthermore, the expression of GRP78, a marker of ER stress, and the phosphorylation of eIF2alpha and PERK were increased following treatment with PA. Notably, the levels of CHOP and cleaved caspase-12, critical regulators of ER stress-mediated apoptosis pathway, were also elevated, and this effect was reversed by a specific ER stress inhibitor (4-phenyl butyric acid). In conclusion, the results of the current study demonstrated that PA induces myocardial lipotoxic injury by triggering ER stress and the ER stress-mediated apoptosis pathway. PMID- 28901413 TI - microRNA-188 acts as a tumour suppressor in glioma by directly targeting the IGF2BP2 gene. AB - Glioma is the most common and aggressive human brain tumour and accounts for ~35 61% of intracranial tumours. Despite considerable advances in treatments for glioma, the prognosis for patients with this disease remains unsatisfactory. MicroRNAs (miRNAs of miRs) are small regulatory RNA molecules that have been identified as being involved in the initiation and progression of human cancers, and represent novel therapeutic targets for anticancer treatments. The dysregulation of miR-188 has been reported in various kinds of human cancer. However, its expression pattern, biological roles and potential mechanism in glioma remain unknown. Expression levels of miR-188 in glioma tissues and cell lines were detected through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 assays and migration and invasion assays were used to explore the effects of miR-188 on the proliferation, migration and invasion of glioma cells, respectively. Bioinformatics analysis and luciferase reporter assays were performed to examine insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) as a target gene of miR-188. RT-qPCR and Spearman's correlation analysis were then performed to measure IGF2BP2 mRNA expression in clinical glioma tissues and its correlation with miR-188 expression. The regulatory effect of miR-188 on IGF2BP2 expression was also investigated through RT-qPCR and western blotting analysis. Finally, the biological roles of IGF2BP2 in glioma cells were assessed. miR-188 levels were significantly reduced in glioma tissues and cell lines compared with adjacent normal tissues and normal human astrocytes, respectively. In addition, miR-188 overexpression suppressed cell proliferation, migration and invasion of glioma. The present study identified IGF2BP2 as a direct target of miR-188 in glioma, and IGF2BP2 under expression served tumour-suppressive roles in glioma growth and metastasis. Thus, miR-188 had a similar role in glioma by inhibiting the action of its downstream target, IGF2BP2. Therefore, miR-188 may be a potential therapeutic target for the prevention and treatment of patients with glioma. PMID- 28901412 TI - Differential miRNA expression profiles in human keratinocytes in response to protein kinase C inhibitor. AB - Aberrant expression of microRNAs (miRNAs) is widely accepted to be involved in keratinocyte differentiation and to be dependent on activation of the protein kinase C (PKC) pathway. However, the miRNA profiles and biological characteristics of keratinocytes induced by specific inhibitors of PKC have yet to be elucidated. The present study aimed to explore the differential miRNA expression profiles in keratinocytes treated with the PKC inhibitor GF109203X, by conducting a bioinformatics analysis. Parts of the GF109203X-induced keratinocytes formed distinct clones after 2 days of culture, and the expression of intergrin beta1, cytokeratin (CK)19 and CK14 were positive, whereas CK10 expression was negative. A total of 79 miRNAs were differentially expressed in keratinocytes treated with GF109203X, among which 45 miRNAs were upregulated and 34 were downregulated. The significantly upregulated microRNAs includedhsa-miR-1 3p and miR-181c-5p, whereas hsa-miR-31-5p and hsa-let-7c-3p were significantly downregulated. In addition, the results of reverse transcription-quantitative polymerase chain reaction exhibited consistency with the microarray results. An enrichment analysis demonstrated that certain target genes of the differentially expressed miRNAs serve an important role in cell proliferation and differentiation, cell cycle progression and apoptosis, etc. These results revealed that GF109203X induced the differential expression of certain miRNAs when keratinocytes began showing the characteristics of epidermal-like stem cells, which may provide a novel approach for wound healing and regeneration of skin tissues. PMID- 28901414 TI - Inhibitory effect of brassinin on TNF-alpha-induced vascular inflammation in human umbilical vein endothelial cells. AB - Brassinin, a phytoalexin firstly identified as a constituent of Chinese cabbage, has been demonstrated to exhibit antiproliferative effects on various cancer cell lines, by reducing reactive oxygen species (ROS) production via regulation of the antioxidant pathway. The present study aimed to explore the protective effects of brassinin in TNF-alpha-induced vascular inflammation in human umbilical vein endothelial cells (HUVECs). Pretreatment with brassinin significantly inhibited adhesion of U937 cells to TNF-alpha-induced HUVECs in a dose-dependent manner. Brassinin treatment decreased the expression levels of cell adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial-selectin (E-selectin) following stimulation with TNF-alpha in HUVECs. In addition, pretreatment with brassinin decreased the protein expression levels of nuclear factor (NF)-kappaB p65 in the nucleus, suggesting that brassinin inhibited NF-kappaB p65 nuclear translocation. Brassinin treatment also markedly decreased the mRNA expression levels of interleukin-8 in a dose-dependent manner. Finally, brassinin pretreatment significantly decreased TNF-alpha-induced intracellular reactive oxygen species (ROS) production in HUVECs compared with control. The present results therefore suggest that brassinin may serve as a potential therapeutic agent for atherosclerosis. PMID- 28901415 TI - Effect of continuous positive airway pressure therapy on inflammatory cytokines and atherosclerosis in patients with obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is known to be a risk factor for atherosclerosis (AS), derived from a series of chronic inflammatory reactions caused by hypoxia. However, the association between chronic inflammation and high blood pressure caused by hypoxia remains to be fully elucidated. The aim of the present study was to investigate the effect of continuous positive airway pressure (CPAP) therapy on inflammatory cytokines and AS. A total of 100 patients with OSAS and 50 healthy control subjects were enrolled. Fresh venous blood samples were collected prior to and following a 3-months period of CPAP treatment. The inflammatory factors, interleukin (IL)-18 and tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and P selectin, were detected using standard enzyme-linked immunosorbent assay kits. Intima-media thickness (IMT), brachial-ankle pulse wave velocity (Ba-PWV), apnea hypopnea index (AHI) and transcutaneous oxygen saturation (SpO2) were also detected to compare differences prior to and following treatment. The results showed that, compared with the pre-treatment data, the expression levels of IL-8, TNF-alpha, CRP, ICAM-1, VCAM-1, E-selectin and P-selectin were significantly decreased following treatment (P<0.05). The AHI, IMT, blood pressure and Ba-PWV values were significantly decreased (P<0.05), and the SpO2 was increased (P<0.05). Taken together, by comparing the pre- and post-intervention data, it was confirmed that inflammatory factors were involved in the process of AS in patients with OSAS. Following CPAP treatment, blood pressure and primary indicators in the patients improved. PMID- 28901416 TI - Protective role of berberine and Coptischinensis extract on T2MD rats and associated islet Rin-5f cells. AB - The aim of the present study was to compare the different effects of berberine (Ber) and Coptischinensis extract (CCE) on a rat model of type 2 diabetes mellitus (T2DM), and the islet Rin-5f cell line was used to examine the differences between Ber and CCE and the underlying mechanisms. CCE was extracted and purified prior to analysis. Male Sprague-Dawley rats were provided with a high-fat diet to induce insulin resistance prior to injecting with streptozotocinto establish the T2DM model, the T2DM rats were treated with Ber and CCE, and blood samples and pancreatic tissues were obtained and compared to examine T2DM metabolic syndromes among the groups of rats, which included healthy rats, model rats, and model rats treated with Ber and CCE at different doses between 0 and 8 weeks. The protective effects of Ber and CCE on the Rin-5f islet cell line were also evaluated. The effects on Rin-5f cell proliferation and cell cycle, glucose-stimulated insulin release test (GSIS), the anti-apoptotic effects caused by fat induction, and protein expression levels of poly ADP-ribose polymerase (PARP-1) were evaluated. The results showed that the content of the prepared CCE was 96.07% for five alkaloids. When it was used for treatment of the T2DM rats, compared with Ber, metformin and rosiglitazone, the fasting blood glucose, glucosylated serum protein (GSP) and glucose infusion rate indicesin the fasting rats were ameliorated, compared with those in the T2MD rats, with no significant differences between treatment with Ber or CCE and metformin or rosiglitazone. The indices of mean optical density and fasting beta-cell function index (FBCI) were different following treatment with Ber and CCE, compared with those in the model rats, which may have stimulated the pancreatic secretion of insulin. When Ber and CCE were used to examine the protective effects on Rin-5F cells, it was found that the Rin-5f cell GSIS, cell cycle, lipotoxic islet cell proliferation and protein expression of PARP-1 were altered and improved, which may have protected pancreatic islet beta-cells by improving islet beta-cell proliferation and the protein expression of PARP-1. CCE and Ber exerted similar effects when used for the treatment of T2MD rats, and may have stimulated the pancreatic secretion of insulin through the protective effect on islet beta-cells via improving islet beta-cell proliferation and the protein expression of PARP-1. PMID- 28901417 TI - Discrimination of the heterogeneity of bone marrow-derived dendritic cells. AB - The present study aimed to discriminate different subsets of cultured dendritic cells (DCs) to evaluate their immunological characteristics. DCs offer an important foundation for immunological studies, and mouse bone marrow (BM) cells cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used extensively to generate CD11c+/major histocompatibility complex II+ BM derived DCs (BMDCs). Immature DCs are considered to have strong migration and phagocytic antigen-capturing abilities, whereas mature DCs are thought to activate naive T cells and express high levels of costimulatory cytokines and adhesion molecules. In most culture systems, non-adherent cells are collected as mature and qualified DCs, and the remaining adherent cells are discarded. The output from GM-CSF cultures comprises mostly adherent cells, and only a small portion of them is non-adherent. This situation has resulted in ambiguities in the attempts to understand results from the use of cultured DCs. In the present study, DCs were divided into three subsets: i) Non-adherent cells; ii) adherent cells and iii) mixed cells. The heterogeneous features of cultured DCs were identified by evaluating the maturation status, cytokine secretion and the ability to activate allogeneic T cells according to different subsets. Results from the study demonstrated that BMDC culture systems were a heterogeneous group of cells comprising non-adherent cells, adherent cells, mixed cells and firmly adherent cells. Non-adherent cells may be used in future studies that require relatively mature DCs such as anticancer immunity. Adherent cells may be used to induce tolerance DCs, whereas mixed cells may potentiate either tolerogenicity or pro-tumorigenic responses. Firmly adherent cells were considered to have macrophage-like properties. The findings may aid in immunological studies that use cultured DCs and may lead to more precise DC research. PMID- 28901418 TI - Profilin-1 contributes to cardiac injury induced by advanced glycation end products in rats. AB - Cardiac injury, including hypertrophy and fibrosis, induced by advanced glycation end products (AGEs) has an important function in the onset and development of diabetic cardiomyopathy. Profilin-1, a ubiquitously expressed and multifunctional actin-binding protein, has been reported to be an important mediator in cardiac hypertrophy and fibrosis. However, whether profilin-1 is involved in AGE-induced cardiac hypertrophy and fibrosis remains to be determined. Therefore, the present study aimed to investigate the function of profilin-1 in cardiac injury induced by AGEs. The model of cardiac injury was established by chronic tail vein injection of AGEs (50 mg/kg/day for 8 weeks) in Sprague-Dawley rats. Rats were randomly assigned to control, AGEs, AGEs + profilin-1 shRNA adenovirus vectors (AGEs + S)or AGEs + control adenovirus vectors (AGEs + V) groups. Profilin-1 shRNA adenovirus vectors were injected via the tail vein to knockdown profilin-1 expression at a dose of 3x109 plaque forming units every 4 weeks. Echocardiography was performed to measure cardiac contractile function. Cardiac tissues were stained with Masson's trichrome stain to evaluate ventricular remodeling. The serum levels of procollagen type III N-terminal peptide were detected by ELISA. The expression of profilin-1, receptor for AGEs (RAGE), Rho, p65, atrial natriuretic peptide, beta-myosin heavy chain, matrix metalloproteinase (MMP)-2 and MMP-9 were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and/or western blot analysis and immunohistochemistry staining. The results demonstrated that chronic injection of exogenous AGEs led to cardiac dysfunction, hypertrophy and fibrosis, as determined by echocardiography, Masson trichrome staining and the expression of associated genes. The expression of profilin-1 was markedly increased in heart tissue at the mRNA and protein level following AGE administration, as determined by RT-qPCR and western blotting, which was further confirmed by immunohistochemistry staining. Furthermore, the expression of RAGE, Rho and p65 was also increased at the protein level. Notably, knockdown of profilin-1 expression ameliorated AGE-induced cardiac injury and reduced the expression of RAGE, Rho and p65. These results indicate an important role for profilin-1 in AGE induced cardiac injury, which may provide a novel therapeutic target for patients with diabetic heart failure. PMID- 28901419 TI - MicroRNA-21 increases cell viability and suppresses cellular apoptosis in non small cell lung cancer by regulating the PI3K/Akt signaling pathway. AB - MicroRNA (miRNA/miR), a type of non-coding RNA molecule, is able to inhibit the expression of target genes at multiple stagess. There are 800-1,000 known miRNAs in the human genome, which serve important roles in cell proliferation, differentiation, apoptosis and migration. Previous studies have demonstrated that the expression of miR-21 is upregulated in numerous types of malignant tumor, and that miR-21 participates in the occurrence and development of tumors via complex regulatory mechanisms. The present study aimed to investigate the association between miR-21 expression, cell viability and apoptosis in a lung cancer cell line, and to elucidate the potential mechanisms. miR-21 or small interfering RNA against miR-21 were transfected into A549 non-small cell lung cancer cells. The mRNA expression of miR-21 was confirmed. Cell viability and apoptosis were examined using MTT and flow cytometric assays, respectively. The expression of certain apoptosis-associated proteins was detected by western blotting. The results of the present study demonstrated that miR-21 was able to increase the proliferation of A549 cells by inhibiting cellular apoptosis. miR-21 inhibited apoptosis by modulating the activation of the phosphatidylinositol 3-kinase/Rac alpha serine/threonine protein kinase (Akt) pathway in A549 cells. Correspondingly, inhibition of Akt decreased the apoptosis of A549 cells in miR 21 siRNA-treated cells. Therefore, the results of the present study demonstrated that miR-21 increased cell viability by inhibiting apoptosis, through regulation of Akt activation. The present study demonstrated that miR-21 may be involved in the progression of lung cancer and may be a novel therapeutic target for the disease. PMID- 28901420 TI - Bioinformatics analysis of genetic variants of endoplasmic reticulum aminopeptidase 1 in ankylosing spondylitis. AB - According to the results of the first genome-wide association study of ankylosing spondylitis (AS), endoplasmic reticulum aminopeptidase 1 (ERAP1) may serve an important role. However, a number of case-control studies have not been able to replicate this result using the same genetic markers. In the present study, the role of common genetic variants of ERAP1 in AS was investigated using two-stage bioinformatics analysis. In the first stage, a classical meta-analysis was performed to assess AS susceptibility markers in ERAP1 using data from available published case-control association studies. The summary odds ratios for 10 single nucleotide polymorphisms (SNPs) were observed to be statistically significant in different studies. In the second stage, the functional effects of these genetic ERAP1 variants were investigated using prediction tools and structural analyses. The K528R (rs30187) substitution SNP in ERAP1 was termed as likely damaging by PolyPhen-2 software, was observed to be located close to the entrance of the substrate pocket, and was predicted to contribute to reduced ERAP1 aminopeptidase activity. In addition, the R725Q (rs17482078) SNP, which was an additional potentially damaging substitution, was suggested to decrease the enzymatic activity of ERAP1, as this substitution may lead to the loss of two hydrogen bonds between R725 and D766 and affect the stability of the C-terminus of ERAP1. In conclusion, the results of the two-stage bioinformatics analysis supported the hypothesis that ERAP1 may present an important susceptibility gene for AS. In addition, the results revealed that two functional SNPs (rs30187 and rs17482078) demonstrated the potential to decrease the enzymatic activity of ERAP1 by affecting its protein structure. Further protein structure-guided studies of the specificity and activity of these ERAP1 variants are therefore warranted. PMID- 28901421 TI - Uric acid induces the expression of TNF-alpha via the ROS-MAPK-NF-kappaB signaling pathway in rat vascular smooth muscle cells. AB - Hyperuricemia and artery atherosclerosis are closely associated and, as a classic inflammatory biomarker, tumor necrosis factor-alpha (TNF-alpha) has a direct role in atherogenesis. In the present study, it was demonstrated that uric acid was capable of inducing the generation of TNF-alpha in vascular smooth muscle cells (VSMCs). The expression levels of proteins were detected using enzyme-linked immunosorbent assays and western blot analysis. The expression levels of mRNAs were determined using reverse transcription-quantitative polymerase chain reaction analysis, and superoxide anion levels were detected using a fluorescence microscope. From the results, it was concluded that uric acid induced the expression of TNF-alpha in the VSMCs. The antioxidant, N-acetylcysteine, eliminated the uric acid-induced expression of TNF-alpha. In addition, uric acid increased the level of reactive oxygen species (ROS) and activated the phosphorylation of p38. Subsequent experiments confirmed that the p38 mitogen activated protein kinase (MAPK) inhibitor, SB203580, and nuclear factor (NF) kappaB inhibitor, pyrrolidine dithiocarbamate, eliminated the uric acid-induced expression of TNF-alpha. It was demonstrated that uric acid induced the expression of TNF-alpha via the ROS-MAPK-NF-kappaB signaling pathway in VSMCs, providing novel evidence supporting the pro-inflammatory and pro-atherosclerotic effects of uric acid. PMID- 28901422 TI - Association between endothelin-1 and fibromyalgia syndrome. AB - Fibromyalgia syndrome (FMS) is characterized by widespread chronic musculoskeletal pain, stiffness and pressure hyperalgesia at soft tissue tender points. Patients with FMS may exhibit a tendency towards cold extremities and cold-induced vasospasm. Endothelin-1 (EDN1) is a potent vasoconstrictor that is mainly produced by endothelial cells. The present study aimed to determine whether plasma expression levels avvnd single-nucleotide polymorphism (SNP; rs1800541) of the EDN1 gene were associated with FMS and/or any of its clinical variables. Plasma EDN1 levels were assessed by ELISA, and SNP genotypes were determined using polymerase chain reaction-high-resolution melting curve analysis. Patients with the TG genotype and the G allele may have an elevated risk of FMS. In addition, patients with FMS with the TG genotype and/or T allele exhibited higher plasma EDN1 levels compared with healthy controls. EDN1 levels increased significantly in patients with FMS compared with normal controls. In addition, EDN1 SNP was found to be associated with susceptibility to FMS. PMID- 28901423 TI - A multi-targeted tyrosine kinase inhibitor lenvatinib for the treatment of mice with advanced glioblastoma. AB - Glioblastoma is the most aggressive primary brain tumor that originates from the glial cells in adults. Aberrant angiogenesis is essential for malignant glioblastoma tumorigenesis, development and metastasis. Lenvatinib is a multi targeted anticancer agent that targets of receptor tyrosine kinases including vascular endothelial growth factor receptor 1 and 2, fibroblast growth factor receptor 1, platelet-derived growth factor receptor beta and v-kit Hardy Zuckerman 4 feline sarcoma viral oncogene homolog. In the present study, the therapeutic effects of lenvatinib as a treatment for glioblastoma were investigated in vivo and in vitro. The maximum dose toxicity (MDT) and treatment associated adverse events of lenvatinib were identified by cytotoxicity assay in experimental mice. Increasing levels of the pro-apoptosis genes caspase-3, -8, -9 and -10 following lenvatinib treatment were determined by reverse transcription quantitative polymerase chain reaction, and apoptosis of the malignant gliomas cells was analyzed by FACS. In vivo treatment with lenvatinib for BV-2 bearing male BALC/c nude mice was assessed via tumor growth suppression and long-term observation of survival. Subsequent cytotoxic T lymphocyte responses were further analyzed to determine the in vivo efficacy of lenvatinib treatment in mice with glioblastoma. The MDT of lenvatinib was identified as 0.24 mg, with relatively few side effects and improved efficacy in mice. Lenvatinib (0.24 mg) significantly increased apoptosis in BV-2, C6, BC3H1 and G422 glioma cell lines. Tumor growth was significantly inhibited and tumor-bearing mice demonstrated an improved survival rate following treatment with lenvatinib. In conclusion, lenvatinib provided an effective treatment outcome, and the results of the present study may help to achieve a comprehensive therapeutic schedule for clinical application. PMID- 28901424 TI - Tumor suppressor microRNA-613 inhibits glioma cell proliferation, invasion and angiogenesis by targeting vascular endothelial growth factor A. AB - MicroRNAs (miRNAs) are small non-coding RNAs which can serve as oncogenes or tumor suppressors in glioma. The present study aimed to investigate the expression of miR-613 in glioma. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect miR-613 in glioma cells and tissues and the relationship between miR-613 and vascular endothelial growth factor (VEGF) A was assessed using a luciferase reporter assay. In addition, glioma cells were transfected with miR-613 mimics and the mRNA and protein expression of VEGFA was detected using RT-qPCR and western blot analysis, respectively. The proliferative, invasive and tube formation capabilities of transfected cells were also assessed in vitro. Furthermore, a nude mouse tumor xenograft model was used to investigate the effects of miR-613 on tumor growth in vivo. The results of the present study demonstrated that the expression of miR-613 was decreased in glioma cell lines, and was associated with the grade of glioma. Ectopic expression of miR-613 markedly suppressed glioma cell proliferation and angiogenesis. Furthermore, the upregulation of miR-613 inhibited tumor angiogenesis and tumor growth in xenografted nude mice in vivo. VEGFA was demonstrated as a direct target of miR-613, as detected by western blot and luciferase reporter assays, and mediated miR-613 induced glioma cell proliferation and angiogenesis inhibition. PMID- 28901425 TI - Knockdown of Fstl1 attenuates hepatic stellate cell activation through the TGF beta1/Smad3 signaling pathway. AB - Follistatin-like 1 (Fstl1) is a secreted glycoprotein that belongs to the follistatin and SPARC (secreted protein, acidic and rich in cysteine) families and was identified to serve a critical role in lung fibrosis. However, the role of Fstl1 in liver fibrosis remains undefined. Therefore, the aim of the present study was to investigate the role of Fstl1 in liver fibrosis. The results indicated that Fstl1 was highly expressed in human hepatic fibrosis tissues and activated hepatic stellate cells (HSCs). Furthermore, knockdown of Fstl1effectively suppressed HSC proliferation and the protein expression levels of alpha-SMA and collagen I in transforming growth factor (TGF)-beta1-treated HSCs. Mechanistically, knockdown of Fstl1 remarkably decreased the phosphorylation level of Smad3 in TGF-beta1-induced HSCs. Taken together, the present study demonstrated that Fstl1serves an important role in liver fibrosis and target deletion of Fstl1 attenuated HSCs activation through suppressing TGF beta1/Smad3 signaling pathway. Therefore, Fstl1 may be a potential therapeutic target for the treatment of liver fibrosis. PMID- 28901426 TI - MicroRNA-373 promotes tumorigenesis of renal cell carcinoma in vitro and in vivo. AB - Renal cell carcinoma (RCC) is the most common type of malignancy in the kidney parenchyma. MicroRNAs (miRNAs) are small non-coding RNAs that serve a role in various biological processes associated with human cancer. The present study aimed to explore the potential role of miRNA (miR)-373 in the tumorigenesis of RCC. The effects of miR-373 on the proliferation and apoptosis of RCC cells were determined using MTT, colony formation and flow cytometry assays in vitro. The results demonstrated that miR-373 was significantly upregulated in RCC tissues and cell lines. Knockdown of miR-373 expression reduced cell proliferation and promoted cell apoptosis in 786-O and ACHN cell lines. Furthermore, an in vivo tumorigenicity assay revealed that knockdown of miR-373 expression reduced tumor growth in nude mice. Taken together, these data indicate that miR-373 may promote tumorigenesis in RCC, suggesting that miR-373 may act as a potential therapeutic target against RCC. PMID- 28901427 TI - MicroRNA-106b regulates skeletal muscle insulin sensitivity and glucose homeostasis by targeting mitofusion-2. AB - MicroRNA-106b (miR-106b) is reported to be closely associated with skeletal muscle insulin resistance. The present study further investigated the role of miR 106b in skeletal muscle insulin sensitivity and glucose homeostasis in vivo. Mice were randomly divided into 4 groups and infected with lentivirus expressing miR 106b (miR-106b mice), miR-106b sponge (miR-106b inhibition mice) or the corresponding empty vectors. Mitofusion-2 (Mfn2) protein expression levels and glucose transporter (Glut)-4 protein translocation were significantly reduced in the muscle of miR-106b mice, whereas they were unaffected in miR-106b inhibition mice. miR-106b mice had significantly increased blood glucose levels following 12 h of fasting and impaired glucose tolerance, whereas miR-106b inhibition mice had no significant alterations in fasting blood glucose levels and glucose tolerance. In vitro, the suppressive effect of miR-106b on glucose uptake and Glut4 translocation was completely inhibited in C2C12 myotubes infected with Mfn2 plasmids. Following treatment of C2C12 myotubes with Mfn2 small interfering RNA, miR-106b inhibition consistently increased Mfn2 protein levels and improved glucose uptake and Glut4 translocation. These results indicated that miR-106b targeted Mfn2 and regulated skeletal muscle insulin sensitivity and glucose tolerance. Therefore, increased miR-106b expression may be a potential mechanism underlying insulin resistance and type 2 diabetes. PMID- 28901428 TI - Emodin promotes the arrest of human lymphoma Raji cell proliferation through the UHRF1-DNMT3A-?Np73 pathways. AB - Emodin is an active constituent found in the roots and rhizomes of numerous Chinese medicinal herbs. It exerts antitumor activity against Dalton's lymphoma in vivo, although the detailed mechanisms by which emodin induces apoptosis remains to be elucidated. The present study aimed to analyze the mechanisms underlying the response to emodin treatment. Using lymphoma Raji cells, an emodin induced cell proliferating inhibition model was first established, then flow cytometry, western blotting, reverse transcription-quantitative polymerase chain reaction and luciferase reporter assay were performed. It was found that emodin decreased the percentage of Raji cell viability, induced apoptosis, and increased the activation of caspase 3, caspase 9 and poly (ADP-ribose) polymerase through the downregulation of ubiquitin-like protein containing PHD and RING domains 1 (UHRF1). The emodin-induced downregulation of UHRF1 led to an increase in the level of DNA methyltransferase 3A, which in turn inhibited the activity of p73 promoter 2 and decreased the levels of NH2-terminally truncated dominant-negative p73. The treatment of Raji cells with emodin combined with doxorubicin led increased cell death of Raji cells, indicating that emodin may sensitize Raji cells to doxorubicin-induced apoptosis. PMID- 28901429 TI - Monocytic cell junction proteins serve important roles in atherosclerosis via the endoglin pathway. AB - The formation of atherosclerosis is recognized to be caused by multiple factors including pathogenesis in monocytes during inflammation. The current study provided evidence that monocytic junctions were significantly altered in patients with atherosclerosis, which suggested an association between cell junctions and atherosclerosis. Claudin-1, occludin-1 and ZO-1 were significantly enhanced in atherosclerosis, indicating that the tight junction pathway was activated during the pathogenesis of atherosclerosis. In addition, the gene expression of 5 connexin members involved in the gap junction pathway were quantified, indicating that connexin 43 and 46 were significantly up-regulated in atherosclerosis. Furthermore, inflammatory factors including endoglin and SMAD were observed, suggesting that immune regulative factors were down-regulated in this pathway. Silicon-based analysis additionally identified that connexins and tight junctions were altered in association with monocytic inflammation regulations, endoglin pathway. The results imply that reduced expression of the immune regulation pathway in monocytes is correlated with the generation of gap junctions and tight junctions which serve important roles in atherosclerosis. PMID- 28901430 TI - Effect of early weaning on the expression of excitatory amino acid transporter 1 in the jejunum and ileum of piglets. AB - The present study aimed to compare the expression levels of excitatory amino acid transporters (EAATs) and growth status of piglets weaned at 10-20 days after birth with suckling piglets. A total of 40 hybrid piglets (Landrace x Large White x Duroc) born to 40 different sows, with similar body weight were selected for the present study. They were randomly divided into two groups (n=20 per group): Control group (suckling piglets) and experimental group (weaned piglets, reared in isolation). The experiment lasted for 10 days. At the end of the experiment, 12 piglets were randomly selected from each group and the jejunum and the ileum were collected in order to determine excitatory amino acid carrier 1 (EAAC1) expression levels and free amino acid content. The present study determined that early weaning significantly reduced EAAC1 gene and protein (57 and 73 kDa) expression levels and glutamate transporter associate protein 3-18 (GTRAP3-18; 50 kDa) in the jejunum and the ileum compared with the suckling group (P<0.05). Weaning led to an increased content of free glutamic acid (Glu) and total amino acids in the jejunum; however, content of free Glu and total amino acids in the ileum was significantly reduced (P<0.05). Early weaning reduced the expression of EAAC1 and GTRAP3-18, which was possibly due to the amino acid absorption and transport disorder in the small intestine due to the Glu deficiency. PMID- 28901431 TI - Isolated chromosome 8p23.2-pter deletion: Novel evidence for developmental delay, intellectual disability, microcephaly and neurobehavioral disorders. AB - The current study presents a patient carrying a de novo ~6 Mb deletion of the isolated chromosome 8p23.2-pter that was identified with a single-nucleotide polymorphism array. The patient was characterized by developmental delay (DD)/intellectual disability (ID), microcephaly, autism spectrum disorder, attention-deficit/hyperactivity disorders and mildly dysmorphic features. The location, size and gene content of the deletion observed in this patient were compared with those in 7 patients with isolated 8p23.2 to 8pter deletions reported in previous studies (4 patients) or recorded in the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) database (3 patients). The deletions reported in previous studies were assessed using a chromosomal microarray analysis. The 8p23.2-pter deletion was a distinct microdeletion syndrome, as similar phenotypes were observed in patients with this deletion. Furthermore, following a detailed review of the potential associations between the genes located from 8p23.2 to 8pter and their clinical significance, it was hypothesized that DLG associated protein 2, ceroid-lipofuscinosis neuronal 8, Rho guanine nucleotide exchange factor 10 and CUB and sushi multiple domains 1 may be candidate genes for DD/ID, microcephaly and neurobehavioral disorders. However, firm evidence should be accumulated from high-resolution studies of patients with small, isolated, overlapping and interstitial deletions involving the region from 8p23.2 to 8pter. These studies will allow determination of genotype-phenotype associations for the specific genes crucial to 8p23.2-pter. PMID- 28901432 TI - Effects of coadministration of low dose cannabinoid type 2 receptor agonist and morphine on vanilloid receptor 1 expression in a rat model of cancer pain. AB - Morphine is widely used as an analgesic to treat moderate to severe pain, but chronic morphine use is associated with development of tolerance and dependence, which limits its analgesic efficacy. Our previous research has showed that nonanalgetic dose of a cannabinoid type 2 (CB2) receptor agonist reduced morphine tolerance in cancer pain. A previous study showed the colocalization of CB2 and transient receptor potential vanilloid 1 (TRPV1) in human and rat dorsal root ganglia (DRG) sensory neurons. Whether coadministration of a CB2 receptor agonist and morphine could reduce TRPV1 expression in morphine-induced antinociception and tolerance in cancer pain is unclear. Therefore, we investigated the effects of coadministration of a CB2 receptor agonist AM1241 and morphine on TRPV1 expression and tolerance in cancer pain. Coadministration of AM1241 and morphine for 8 days significantly reduced morphine tolerance, as assessed by measuring paw withdrawal latency to a radiant heat stimulation, in Walker 256 tumor-bearing rats. Repeated morphine treatment for a period of 8 days induced upregulation of the TRPV1 protein expression levels in the DRG in the tumor-bearing rats, although no change in mRNA expression. Pretreatment with AM1241 reduced this morphine-induced upregulation of TRPV1 and the effect was reversed by the CB2 receptor antagonist AM630. Our findings suggest that coadministration of a CB2 receptor agonist AM1241 and morphine reduced morphine tolerance possibly through regulation of TRPV1 protein expression in the DRG in cancer pain. PMID- 28901434 TI - Sinulariolide suppresses LPS-induced phenotypic and functional maturation of dendritic cells. AB - The dendritic cell (DC) maturation process is essential for the development of T cell responses and immune tolerance. Accordingly, DCs are considered a major target in the development of immunomodulating agents. In the present study, the effect of sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, on lipopolysaccharide (LPS)-induced murine bone marrow derived DCs was evaluated. The different phenotypes, cytokine secretion and the mix-lymphocyte reaction of DCs were detected using flow cytometry and ELISA. The experimental results revealed that the phenotypic and functional maturation of DCs stimulated by LPS were markedly reduced by sinulariolide in a concentration dependent manner, including the expression of co-stimulatory molecules (CD40, CD80 and CD86). In addition, sinulariolide reduced the release of tumor necrosis factor-alpha, interleukin (IL)-6, IL-12 and nitric oxide from the LPS-activated DCs, decreased their abilities to stimulate allogeneic T cell proliferation, and inhibited LPS-induced nuclear factor-kappaB pathways. These findings offer novel insight into the immunopharmacological function of sinulariolide and its effects on DCs. PMID- 28901433 TI - Expression of long non-coding RNAs in human bone marrow mesenchymal stem cells co cultured with human amnion-derived mesenchymal stem cells. AB - Long non-coding RNAs (lncRNAs) serve a critical role in various biological processes including cell growth, transcriptional regulation and differentiation. Previous studies have demonstrated that human amnion-derived mesenchymal stem cells (HAMSCs) possess the potential to promote proliferation and osteogenic differentiation of human bone marrow mesenchymal stem cells (HBMSCs). However, little is known about the roles of lncRNAs in these mechanisms. The present study investigated the expression of lncRNAs in HBMSCs co-cultured with HAMSCs to study their involvement in the mechanism of osteogenic differentiation. RNA sequencing was used to compare the lncRNA expression profiles of HBMSCs co-cultured with or without HAMSCs during osteogenic differentiation. A total of 339 differentially expressed lncRNAs were identified [log2 (fold change)>2.0 or <-2.0; P<0.05], consisting of 131 downregulated and 208 upregulated lncRNAs. Among these lncRNAs, it was identified that the lncRNA-differentiation antagonizing non-protein coding RNA (DANCR) expression level in HBMSCs was significantly decreased by co culturing with HAMSCs, and DANCR overexpression inhibited the effect of HAMSCs on the promotion of runt-related transcription factor 2 expression. These data suggested that HAMSCs are likely to regulate differentiation processes in HBMSCs by influencing the DANCR, thus offering a novel insight into the complicated regulation mechanisms of HAMSC-derived osteogenic differentiation. PMID- 28901435 TI - Differential regulation by IFN-gamma on TNF-alpha-induced chemokine expression in synovial fibroblasts from temporomandibular joint. AB - Tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma, are inflammatory cytokines in the synovial fluid of patients with temporomandibular joint disorder (TMD). However, it remains unknown whether they participate in the regulation of various chemokine expression levels associated with TMD. The effects of TNF-alpha and IFN-gamma on the expression of several different inflammatory chemokines, including interleukin (IL)-8, C-X-C motif chemokine ligand (CXCL)1, C-C motif chemokine ligand (CCL)20, CXCL9, CXCL10, and CXCL11 in synovial fibroblasts obtained from the temporomandibular joint (TMJ) were examined. The results demonstrated that TNF-alpha increased the mRNA levels of all examined chemokines in synovial fibroblasts obtained from the TMJ. IFN-gamma treatment alone increased the mRNA expression levels of CXCR3 chemokines, including CXCL10, while they were significantly enhanced when administered in combination with TNF-alpha compared with either treatment alone. However, the combination of IFN-gamma and TNF-alpha resulted in lower mRNA expression levels of IL-8 and CXCL1 as compared with those induced by TNF-alpha alone. The nuclear factor-kappaB inhibitor, Bay 11-7082, decreased the TNF-alpha-mediated expression of IL-8 and CXCL10 in the absence, and presence of IFN-gamma. In addition, the JAK2 inhibitor, AG490, decreased CXCL10 expression when administered with TNF-alpha and IFN-gamma. Finally, the decrease in TNF-alpha-induced IL-8 caused by IFN-gamma was recovered by AG490. The results of the present study suggest that TNF-alpha and IFN-gamma function in a cooperative manner to regulate inflammatory chemokine expression in synovial fibroblasts, which may contribute to the pathological condition of the TMJ. PMID- 28901436 TI - Taurine-upregulated gene 1: A vital long non-coding RNA associated with cancer in humans (Review). AB - It is widely reported that long non-coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine-upregulated gene 1 (TUG1) has been shown to be expressed in a tissue-specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1. PMID- 28901437 TI - Implementing targeted region capture sequencing for the clinical detection of Alagille syndrome: An efficient and cost-effective method. AB - Alagille syndrome (AGS) is a highly variable, autosomal dominant disease that affects multiple structures including the liver, heart, eyes, bones and face. Targeted region capture sequencing focuses on a panel of known pathogenic genes and provides a rapid, cost-effective and accurate method for molecular diagnosis. In a Chinese family, this method was used on the proband and Sanger sequencing was applied to validate the candidate mutation. A de novo heterozygous mutation (c.3254_3255insT p.Leu1085PhefsX24) of the jagged 1 gene was identified as the potential disease-causing gene mutation. In conclusion, the present study suggested that target region capture sequencing is an efficient, reliable and accurate approach for the clinical diagnosis of AGS. Furthermore, these results expand on the understanding of the pathogenesis of AGS. PMID- 28901438 TI - Lysyl oxidase is involved in synovial hyperplasia and angiogenesis in rats with collagen-induced arthritis. AB - Lysyl oxidase (LOX) serves an important role in remodeling the extracellular matrix and angiogenesis in various types of cancer; however, whether LOX is involved in the pathogenesis of rheumatoid arthritis remains unknown. In order to investigate this in the present study, beta-aminopropionitrile, an inhibitor of LOX, was injected intraperitoneally into rats with type II collagen-induced arthritis (CIA). Subsequently, synovial hyperplasia was examined by hematoxyl in and eosin staining, and the microvascular density (MVD) and expression levels of LOX, matrix metalloproteinase (MMP)-2 and MMP-9 in the synovial membrane and fluid were determined by immunohistochemistry and ELISA, respectively. The enzyme activity of LOX was evaluated by the Amplex Red Hydrogen Peroxide method. The results demonstrated an increased amount of rough synovial membranes, higher MVD in these membranes and more synovial cell layers in CIA rats compared with in the control rats. In addition, higher enzymatic activity of LOX and higher expression levels of MMP-2 and MMP-9 were revealed in CIA rats compared with in the control rats. Notably, beta-aminopropionitrile inhibited paw swelling and the decreased the arthritis index, the MVD in the synovial membranes and the expression levels of MMP-2 and MMP-9. Furthermore, the expression level of LOX in the synovial membranes was positively associated with the MVD and the expression levels of MMP 2 and MMP-9, suggesting that LOX promotes synovial hyperplasia and angiogenesis and that LOX may be a potential therapeutic target for rheumatoid arthritis. PMID- 28901439 TI - Long noncoding RNA-p21 modulates cellular senescence via the Wnt/beta-catenin signaling pathway in mesenchymal stem cells. AB - Mesenchymal stem cell (MSC)-based therapies have demonstrated efficacy in animal models of cardiovascular diseases. However, MSCs decrease in quantity and quality with age, which reduces their capacity for damage repair. Long noncoding (lnc) RNAs regulate gene transcription and the fate of post-transcriptional mRNA, affecting a broad range of age-associated physiological and pathological conditions, including cardiovascular disease and cancer cell senescence. However, the functional role of lncRNAs in stem cell senescence remains largely unknown. The present study isolated bone marrow-derived MSCs from young (8-week-old) and aged (18-month-old) male C57BL/6 mice. Cell proliferation was measured using a Cell Counting kit-8 assay, and the secretion of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and insulin-like growth factor was measured by ELISA. Western blotting was performed to investigate beta-catenin protein expression. Oxidative stress was evaluated by detecting reactive oxygen species, and the activity of superoxide dismutase and malondialdehyde. MSCs isolated from aged mice demonstrated reduced proliferation and paracrine signaling, and increased oxidative stress and expression of lincRNA p21compared with MSCs from younger mice. Silencing lincRNA-p21 in aged MSCs using small interfering RNA (siRNA) enhanced cell growth and paracrine function, and decreased oxidative stress. These results were reversed when beta-catenin expression was silenced using siRNA. In conclusion, lincRNA-p21 may serve a role in MSC senescence, and silencing lincRNA-p21 may rejuvenate MSCs by interacting with the Wnt/beta-catenin signaling pathway. Targeting lincRNA-p21 may therefore have important therapeutic implications for restoring endogenous MSCs in aged individuals. PMID- 28901440 TI - Autophagy and ER stress in LPS/GalN-induced acute liver injury. AB - Numerous mechanisms and factors have been implicated in liver damage; however, the involvement of autophagy and endoplasmic reticulum (ER) stress during early stage liver injury remains to be fully elucidated. The present study was conducted to determine the expression of autophagy and ER-stress-associated proteins in hepatic tissues following injury. A murine model of liver injury was induced by intraperitoneally injecting lipopolysaccharide (LPS) and D galactosamine (GalN), and control mice were similarly injected with normal saline. The gross and histological appearance of the liver was examined, serum alanine aminotransferase (ALT) levels were detected, and protein expression evaluated via Western blot analysis. Co-administration of LPS and GalN effectively induced liver injury in mice, with severe liver damage manifesting at 6 h following induction. Furthermore, upregulation of autophagy-associated proteins, including microtubule-associated protein 1 light chain 3 (MAP1 LC3 or, briefly, LC3-II) and Beclin 1, were detected 3 h following liver injury. Consistently, the expression of the ER stress factor CCAAT/enhancer binding protein (C/EBP)-homologous protein decreased after 1 h, but increased 3 h after liver damage. Autophagy and ER stress occurred in early-stage liver injury induced by LPS-GalN administration in mice. Induction of autophagy may act as a compensatory mechanism during early liver injury. PMID- 28901441 TI - Profiling of differentially expressed genes in adipose tissues of multiple symmetric lipomatosis. AB - Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by aberrant multiple and symmetric subcutaneous adipose tissue accumulation in the face, neck, shoulders, back, chest and abdomen, severely affecting the quality of life of patients. At present, precise MSL etiology and pathogenesis remain to be elucidated. The present study first utilized a digital gene expression technique with a next-generation sequencing platform to profile differentially expressed genes in three cases of MSL vs. normal control tissue. cDNA libraries from these tissue specimens were constructed and DNA sequenced for identification of differentially expressed genes, which underwent bioinformatic analysis using the Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analyses. As a result, a total of 859 differentially expressed genes were identified, including 308 upregulated genes (C19orf80, Apelin, C21orf33, FAM166B and HSD11B2 were mostly upregulated 6.984-, 4.670-, 4.412-, 3.693- and 3.561-fold, respectively) and 551 downregulated genes [FosB proto-oncogene, AP-1 transcription factor subunit (FOSB), selectin (SEL) E, RAR related orphan receptor (ROR) B, salt inducible kinase (SIK)1 and epidermal growth factor-like protein (EGFL)6 were mostly downregulated -9.845, -8.243, 8.123, -7.702 and -7.664 fold, respectively). The GO functional enrichment analysis demonstrated these differentially expressed genes were predominantly involved in biological processes and cellular components, while the KEGG pathway enrichment analysis demonstrated that ribosome, non-alcoholic fatty liver disease, human T-lymphotropic virus type 1 (HTLV-I) infection and Alzheimer's disease pathways were altered in MSL. The PPI network data demonstrated ubiquitin C (UBC), translocator protein (TSPO), Jun Proto-Oncogene, AP-1 Transcription Factor (JUN) and FOS were among these differentially expressed genes that participated in regulation of adipocyte differentiation, although no previous study has linked them to MSL. In conclusion, the present study profiled differentially expressed genes in MSL and identified gene pathways that may be associated with MSL development and progression. PMID- 28901442 TI - The uptake exploration of 68Ga-labeled NGR in well-differentiated hepatocellular carcinoma xenografts: Indication for the new clinical translational of a tracer based on NGR. AB - 18F-FDG has low uptake and poor diagnostic efficiency in hepatocellular carcinoma (HCC), particularly in well-differentiated HCC. The NGR peptide selectively targets CD13, which is overexpressed in many types of tumor cells as well as neovasculature cells. In the present study, we aimed to evaluate the feasibility of utilizing 68Ga-NGR to image CD13-positive well-differentiated HCC xenografts. The in vitro cellular uptake, in vivo micro-PET/CT imaging and biodistribution studies of 68Ga-NGR and 18F-FDG were quantitatively compared in SMMC-7721-based well-differentiated HCC xenografts. The human fibrosarcoma (HT-1080) and human colorectal adenocarcinoma (HT-29) xenografts were respectively used as positive and negative reference groups for CD13. The expression of CD13 was qualitatively verified by immunofluorescence staining and immunohistostaining studies. The expression levels of CD13 and glucose-6-phosphatase (G6Pase) were semi quantitatively analyzed by western blotting. The in vitro SMMC-7721 cellular uptake of 68Ga-NGR was significantly higher than that of 18F-FDG (1.23+/-0.11 vs. 0.515+/-0.14%; P<0.01). The in vivo micro-PET/CT imaging results revealed that the uptake of 68Ga-NGR in SMMC-7721-derived tumors was 2.17+/-0.21% ID/g (percentage of injected dose per gram of tissue), which was higher compared to that of 18F-FDG (0.73+/-0.26% ID/g; P<0.01); however, the tumor/liver ratio of 68Ga-NGR was 2-fold higher than that of 18F-FDG. We concluded that the uptake of 68Ga-NGR was significantly higher both in vitro and in vivo than 18F-FDG in the well-differentiated HCC xenografts and therefore, it is promising for further clinical translation in well-differentiated HCC PET/CT diagnosis. PMID- 28901443 TI - Basic fibroblast growth factor increases IFT88 expression in chondrocytes. AB - Intraflagellar transport protein 88 (IFT88) is protein crucial for the assembly and maintenance of primary cilia in chondrocytes. Primary cilia regulate mechanical and chemical signals in chondrocytes; however, the effects of cytokines on IFT88 expression and cilia formation and maintenance remain to be elucidated. Therefore, the role of basic fibroblast growth factor (bFGF) on IFT88 expression were examined in theATDC5 murine chondrocytic line, in order to investigate the signaling pathways involved in this process. bFGF treatment upregulated IFT88 expression in a dose- and time-dependent manner in ATDC5 cells. The effects of bFGF on IFT88 protein expression were suppressed in the presence of the extracellular signal-regulated protein kinase (ERK) inhibitor PD0325901 and the FGF receptor inhibitor BGJ398. In addition, treatment with IFT88 trageting small interfering (si)RNA downregulated the protein expression of IFT88 and ERK, thus suggesting that the ERK signaling pathway may be involved in the regulation of IFT88 expression in ATDC5 cells. bFGF treatment increased the number of ciliated ATDC5 cells and primary cultured chondrocytes. Downregulation of IFT88 expression by PD0325901, BGJ398, or IFT88-targeting siRNA was revealed to reduce the number of ciliated cells. bFGF also upregulated the mRNA and protein expression of IFT88 in primary cultured chondrocytes. In conclusion, the findings of the present study suggested that bFGF may enhance the expression of IFT88, and promote primary cilia development, through the mitogen-activated protein kinase/ERK-mediated pathway in chondrocytes. PMID- 28901444 TI - Protein kinase Calpha stimulates hypoxia-induced pulmonary artery smooth muscle cell proliferation in rats through activating the extracellular signal-regulated kinase 1/2 pathway. AB - Hypoxic pulmonary hypertension (HPH) may contribute to vascular remodeling, and pulmonary artery smooth muscle cell (PASMC) proliferation has an important role in this process. However, no relevant information concerning the role and mechanism of protein kinase C (PKC)alpha in hypoxia-induced rat PASMC proliferation has been elucidated. The present study aimed to further investigate this by comparison of rat PASMC proliferation among normoxia for 72 h (21% O2), hypoxia for 72 h (3% O2), hypoxia + promoter 12-myristate 13-acetate control, hypoxia + safingol control, hypoxia + PD98059 control and hypoxia + U0126 control groups. The present study demonstrated that protein expression levels of PKCalpha in rat PASMCs were elevated. In conclusion, through activating the extracellular signal-regulated 1/2 signaling pathway, PKCalpha is involved in and initiates PASMC proliferation, thus bringing about pulmonary artery hypertension. These results add to the understanding of the mechanism PKCalpha in PH formation and lays a theoretical basis for prevention as well as treatment of HPH. PMID- 28901445 TI - Identification of genes associated with castration-resistant prostate cancer by gene expression profile analysis. AB - Prostate cancer (CaP) is a serious and common genital tumor. Generally, men with metastatic CaP can easily develop castration-resistant prostate cancer (CRPC). However, the pathogenesis and tumorigenic pathways of CRPC remain to be elucidated. The present study performed a comprehensive analysis on the gene expression profile of CRPC in order to determine the pathogenesis and tumorigenic of CRPC. The GSE33316 microarray, which consisted of 5 non-castrated samples and 5 castrated samples, was downloaded from the gene expression omnibus database. Subsequently, 201 upregulated and 161 downregulated differentially expressed genes (DEGs) were identified using the limma package in R and those genes were classified and annotated by plugin Mcode of Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using Database for Annotation, Visualization and Integrated Discovery and KEGG Orthology Based Annotation System 2.0 online tools to investigate the function of different gene modules. The BiNGO tool was used to visualize the level of enriched GO terms. Protein-protein interaction network was constructed using STRING and analyzed with Cytoscape. In conclusion, the present study determined that aldo-keto reductase 3, cyclin B2, regulator of G protein signaling 2, nuclear factor of activated T-cells and protein kinase C a may have important roles in the development of CRPC. PMID- 28901446 TI - A support vector machine classifier for the prediction of osteosarcoma metastasis with high accuracy. AB - In this study, gene expression profiles of osteosarcoma (OS) were analyzed to identify critical genes associated with metastasis. Five gene expression datasets were screened and downloaded from Gene Expression Omnibus (GEO). Following assessment by MetaQC, the dataset GSE9508 was excluded for poor quality. Subsequently, differentially expressed genes (DEGs) between metastatic and non metastatic OS were identified using meta-analysis. A protein-protein interaction (PPI) network was constructed with information from Human Protein Reference Database (HPRD) for the DEGs. Betweenness centrality (BC) was calculated for each node in the network and top featured genes ranked by BC were selected out to construct support vector machine (SVM) classifier using the training set GSE21257, which was then validated using the other three independent datasets. Pathway enrichment analysis was performed for the featured genes using Fisher's exact test. A total of 353 DEGs were identified and a PPI network including 164 nodes and 272 edges was then constructed. The top 64 featured genes ranked by BC were included in the SVM classifier. The SVM classifier exhibited high prediction accuracies in all of the 4 datasets, with accuracies of 100, 100, 92.6 and 100%, respectively. Further analysis of the featured genes revealed that 11 Gene Ontology (GO) biological pathways and 5 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly over-represented, including the regulation of cell proliferation, regulation of apoptosis, pathways in cancer, regulation of actin cytoskeleton and the TGF-beta signaling pathway. On the whole, an SVM classifier with high prediction accuracy was constructed and validated, in which key genes associated with metastasis in OS were also revealed. These findings may promote the development of genetic diagnostic methods and may enhance our understanding of the molecular mechanisms underlying the metastasis of OS. PMID- 28901447 TI - MicroRNA-146a promotes the proliferation of rat vascular smooth muscle cells by downregulating p53 signaling. AB - The present study aimed to detect and verify gene expression profile differences for microRNA (miR)-146a and its role in the proliferation of vascular smooth muscle cells (VSMCs). Artificially synthesized miR-146a mimics, miR-146 inhibitor, scramble-miRNA or PBS was transfected into cultured primary rat VSMCs in vitro. Reverse transcription-quantitative polymerase chain reaction confirmed that the miR-146a expression level was significantly decreased in VSMCs treated with miR-146a inhibitor (P<0.01). Cell Counting Kit-8 was used to determine the proliferation ability, which demonstrated that proliferation was significantly decreased in VSMCs treated with miR-146a inhibitor (P<0.01). Microarray expression profiling analysis revealed that the p53 signal pathway was upregulated in VSMCs treated with the miR-146a inhibitor. Compared with untransfected VSMCs, the mRNA and protein expression levels of caspase-3 and phosphatase and tensin homolog (PTEN) in p53 signal transduction pathway did not exhibit a significant difference (P>0.05); however, the mRNA and protein expression levels of p53 were significantly decreased in cells transfected with miR-146a mimics and increased in miR-146a inhibitor transfected cells (both P<0.01). The mRNA and protein expression levels of cyclin D1 significantly increased in miR-146a mimics transfected cells and decreased in cells transfected with the miR-146a inhibitor (both P<0.05). The present data indicated that miR 146a may promote the proliferation of rat VSMCs by downregulating p53 and upregulating cyclin D1 expression. PMID- 28901448 TI - Exposure of keratinocytes to non-thermal dielectric barrier discharge plasma increases the level of 8-oxoguanine via inhibition of its repair enzyme. AB - Oxidative stress enhances cellular DNA oxidation and may cause mutations in DNA bases, including 8-oxoguanine (8-oxoG). Our recent study reported that exposure of cells to non-thermal dielectric barrier discharge (DBD) plasma generates reactive oxygen species and damages DNA. The present study investigated the effect of non-thermal DBD plasma exposure on the formation of 8-oxoG in HaCaT human keratinocytes. Cells exposed to DBD plasma exhibited increased level of 8 oxoG. In addition, mRNA and protein expression levels of 8-oxoguanine glycosylase 1 (OGG1), an 8-oxoG repair enzyme, were reduced in plasma-exposed cells. Furthermore, the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates OGG1 gene expression, was reduced following exposure to DBD plasma. Pretreatment of cells with an antioxidant, N acetyl cysteine (NAC), prior to plasma exposure suppressed the formation of 8 oxoG and restored the expression levels of OGG1 and Nrf2. In addition, phosphorylation of protein kinase B (Akt), which regulates the activation of Nrf2, was reduced following plasma exposure. However, phosphorylation was restored by pretreatment with NAC. These findings suggested that non-thermal DBD plasma exposure generates 8-oxoG via inhibition of the Akt-Nrf2-OGG1 signaling pathway in HaCaT cells. PMID- 28901449 TI - FK506 suppresses hypoxia-induced inflammation and protects tight junction function via the CaN-NFATc1 signaling pathway in retinal microvascular epithelial cells. AB - The present study aimed to identify whether FK506 suppresses hypoxia-induced inflammation and protects tight junction function via the calcineurin-nuclear factor of activated T-cells 1 (CaN-NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans-epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions. The concentrations of inflammatory cytokines were measured using reverse transcription-quantitative polymerase chain reaction analysis and enzyme-linked immunosorbent assays. The protein expression levels of zonula occludens-1 (ZO-1) and nuclear factor of activated T-cell 1 (NFATc1) were identified using immunofluorescent microscopy and western blot analysis. The TEER value was decreased following hypoxia, but increased following treatment with FK506 (1 and 10 uM) for 24 and 48 h. The protein expression of ZO-1 was also increased following FK506 treatment for 24 h at 1 and 10 uM. By contrast, following treatment with FK506 (1 and 10 uM) for 24 and 48 h, the elevated cell permeability in the hypoxia group was significantly downregulated. Similarly, the concentrations of inflammatory cytokines, including cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemoattractant protein-1, interleukin-6, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, were downregulated following treatment with FK506 for 24 h at 1 and 10 uM. Following treatment with FK506, the level of total NFATc1 was downregulated and the level of phosphorylated NFATc1 was upregulated. Taken together, FK506 suppressed injury to the tight junctions and downregulated the expression of inflammatory cytokines in hypoxia-induced mRMECs via the CaN-NFATc1 signaling pathway. This suggests a potentially effective therapy for hypoxia-induced retinal microangiopathy. PMID- 28901450 TI - Role of hypoxia-mediated cellular prion protein functional change in stem cells and potential application in angiogenesis (Review). AB - Cellular prion protein (PrPC) can replace other pivotal molecules due to its interaction with several partners in performing a variety of important biological functions that may differ between embryonic and mature stem cells. Recent studies have revealed major advances in elucidating the putative role of PrPC in the regulation of stem cells and its application in stem cell therapy. What is special about PrPC is that its expression may be regulated by hypoxia-inducible factor (HIF)-1alpha, which is the transcriptional factor of cellular response to hypoxia. Hypoxic conditions have been known to drive cellular responses that can enhance cell survival, differentiation and angiogenesis through adaptive processes. Our group recently reported hypoxia-enhanced vascular repair of endothelial colony-forming cells on ischemic injury. Hypoxia-induced AKT/signal transducer and activator of transcription 3 phosphorylation eventually increases neovasculogenesis. In stem cell biology, hypoxia promotes the expression of growth factors. According to other studies, aspects of tissue regeneration and cell function are influenced by hypoxia, which serves an essential role in stem cell HIF-1alpha signaling. All these data suggest the possibility that hypoxia mediated PrPC serves an important role in angiogenesis. Therefore, the present review summarizes the characteristics of PrPC, which is produced by HIF-1alpha in hypoxia, as it relates to angiogenesis. PMID- 28901451 TI - Genomic profile of oral squamous cell carcinomas with an adjacent leukoplakia or with an erythroleukoplakia that evolved after the treatment of primary tumor: A report of two cases. AB - Oral leukoplakia and erythroleukoplakia are common oral potentially malignant disorders diagnosed in the oral cavity. The specific outcome of these lesions remains to be elucidated, as their malignant transformation rate exhibits great variation. The ability to predict which of those potentially malignant lesions are likely to progress to cancer would be vital to guide their future clinical management. The present study reported two patients with tongue squamous cell carcinoma: Case study 1 was diagnosed with a simultaneous leukoplakia and case study 2 developed an erythroleukoplakia following the primary tumor treatment. Whole genome copy number alterations were analyzed using array comparative genomic hybridization. The present study determined more genomic imbalances in the tissues from leukoplakia and erythroleukoplakia compared with their respective tumors. The present study also identified in tumor and potentially malignant lesions common alterations of chromosomal regions and genes, including FBXL5, UGT2B15, UGT2B28, KANSL1, GSTT1 and DUSP22, being some of these typical aberrations described in oral cancer and others are linked to chemoradioresistance. Several putative genes associated with hallmarks of malignancy that may have an important role in predicting the progression of leukoplakia and erythroleukoplakia to squamous cell carcinoma, namely gains in BNIPL, MCL1, STAG2, CSPP1 and ZNRF3 genes were also identified. PMID- 28901452 TI - Screening critical genes associated with malignant glioma using bioinformatics analysis. AB - Malignant gliomas are high-grade gliomas, which are derived from glial cells in the spine or brain. To examine the mechanisms underlying malignant gliomas in the present study, the expression profile of GSE54004, which included 12 grade II astrocytomas, 33 grade III astrocytomas and 98 grade IV astrocytomas, was downloaded from the Gene Expression Omnibus. Using the Limma package in R, the differentially expressed genes (DEGs) in grade III, vs. grade II astrocytoma, grade IV, vs. grade II astrocytoma, and grade IV, vs. grade III astrocytoma were analyzed. Venn diagram analysis and enrichment analyses were performed separately for the DEGs using VennPlex software and the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks were visualized using Cytoscape software, and subsequent module analysis of the PPI networks was performed using the ClusterONE tool. Finally, glioma associated genes and glioma marker genes among the DEGs were identified using the CTD database. A total of 27, 1,446 and 776 DEGs were screened for the grade III, vs. grade II, grade IV, vs. grade II, and grade IV, vs. grade III astrocytoma comparison groups, respectively. Functional enrichment analyses showed that matrix metalloproteinase 9 (MMP9) and chitinase 3-like 1 (CHI3L1) were enriched in the extracellular matrix and extracellular matrix structural constituent, respectively. In the PPI networks, annexin A1 (ANXA1) had a higher degree and MMP9 had interactions with vascular endothelial growth factor A (VEGFA). There were 10 common glioma marker genes between the grade IV, vs. grade II and the grade IV, vs. grade III comparison groups, including MMP9, CHI3L1, VEGFA and S100 calcium binding protein A4 (S100A4). This suggested that MMP9, CHI3L1, VEGFA, S100A4 and ANXA1 may be involved in the progression of malignant gliomas. PMID- 28901453 TI - The role of gene polymorphisms in endometriosis. AB - Endometriosis is a benign gynecologic disorder, affecting up to 10% of women, characterized by the presence of functional endometrial tissue at ectopic positions generally within the peritoneum. It is a heritable condition influenced by multiple genetic and environmental factors, with an overall heritability estimated at approximately 50%. In this study, we investigated whether single nucleotide polymorphisms (SNPs) rs7521902, rs10859871 and rs11031006, mapping to WNT4, VEZT and FSHB genetic loci, respectively, are associated with risk for endometriosis in a Greek population. This study included 166 women with histologically confirmed endometriosis diagnosed through surgery and 150 normal controls. Genotyping of the rs7521902, rs10859871 and rs11031006 SNPs was performed with Taqman primer/probe sets. A significant association was detected with the AC genotype of rs7521902 (WNT4) in patients with stage III and IV disease only. Evidence for association with endometriosis was also found for the AC genotype of the rs10859871 of VEZT. Notably, a significant difference in the distribution of the AG genotype and the minor allele A of FSHB rs11031006 SNP was found between the endometriosis patients and controls. We found a genetic association between rs11031006 (FSHB) SNP and endometriosis. WNT4 and VEZT genes constitute the most consistently associated genes with endometriosis. In the present study, an association of rs7521902 (WNT4) and rs10859871 (VEZT) was confirmed in women with endometriosis at the genotypic but not the allelic level. PMID- 28901454 TI - beta-thalassemia caused by compound heterozygous mutations and cured by bone marrow transplantation: A case report. AB - In the present study, a rare familial case of severe thalassemia with compound spontaneous mutations is reported. A 2.5-year-old boy, who suffered from severe anemia with yellowish skin, enlarged liver and spleen, was provided with a blood transfusion every 20 days to maintain hemoglobin levels between 90 and 100 g/l. Sanger sequencing combined with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Gap-PCR revealed that the proband was a carrier of 4 compound heterozygous mutations: Hemoglobin subunit beta (HBB):IVS-II 654(C>T)beta+; Southeast Asian-type-hereditary persistence of fetal hemoglobin (SEA-HPFH); HBB:c316-148G>T; hemoglobin subunit alpha2 (HBA2):c.46G>A. The father of the proband was identified as a carrier of the heterozygous SEA-HPFH mutation, the mother was a carrier of compound heterozygous mutations of HBB:IVS-II 654(C>T) and HBA2:c.46G>A, and the elder sister was heterozygous for HBB:IVS-II 654(C>T)beta+. Based on these genetic results, it was determined that the proband had both of heavy beta-thalassemia and alpha-thalassemia. Upon human leukocyte antigen matching, bone marrow transplantation (BMT) was successfully performed on the proband by selecting his HLA-compatible sister as a donor. Following treatment, the proband was revealed to only carry the IVS-II-654(C>T)beta+ heterozygous mutation, and further regular blood transfusions have been avoided; BMT results remained normal at six months follow-up. PMID- 28901455 TI - Identification of lncRNA EGOT as a tumor suppressor in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common type of kidney cancer and the prognosis of metastatic RCC remains poor, with a high rate of recurrence and mortality. Long non-coding RNA (lncRNA) is a class of RNA which serves important roles in multiple cellular processes and tumorigenesis. In the present study, the expression and function of lncRNA eosinophil granule ontogeny transcript (EGOT) were examined in RCC. In 24 paired tissues (RCC tissues and adjacent normal tissues) the results of reverse transcription-quantitative polymerase chain reaction analysis revealed that EGOT was downregulated in 22 RCC tissues compared with paired tissues. Upregulation of lncRNA EGOT by transfection of 786-O and ACHN RCC cells with pcDNA3.1-EGOT suppressed cell proliferation, migration and invasion, and induced RCC cell apoptosis. The results demonstrated that EGOT may serve as a tumor suppressor in RCC and may be a potential prognostic biomarker of RCC. PMID- 28901456 TI - The antitumor effects of arsenic trioxide in mantle cell lymphoma via targeting Wnt/beta-catenin pathway and DNA methyltransferase-1. AB - Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) with poor prognosis. The rapid progression and frequently relapse make it urgent to identify therapeutic agents with potent antitumor effect. Increasing evidence indicated that dysregulation of Wnt/beta-catenin pathway and abnormal methylation appeared to promote tumorigenesis. Arsenic trioxide (As2O3, ATO) has been reported effective in many hematologic malignancies in recent studies, however, the mechanism and effects of ATO in MCL still need further research. In this study, ATO was shown to promote apoptosis and to inhibit cell viability in MCL cell lines, whereas, the expression of DNA methyltransferase-1 (DNMT-1), beta catenin and the downstream molecules of Wnt/beta-catenin pathway such as c-myc, cyclin D1 and MMP7 were all decreased in a dose-dependent manner with ATO. ATO also attenuated upregulation of beta-catenin after LiCl stimulation and provided synergistic effect with 5-azacytidine (5-azaC) on the DNMT-1 inhibition. The results indicated that ATO may suppress MCL by targeting Wnt/beta-catenin pathway and DNMT-1. These findings may guide drug usage of ATO in clinical therapy for MCL. PMID- 28901457 TI - Screening and identification of key biomarkers in hepatocellular carcinoma: Evidence from bioinformatic analysis. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Intense efforts have been made to elucidate the pathogeny, but the molecular mechanisms of HCC are still not well understood. To identify the candidate genes in the carcinogenesis and progression of HCC, microarray datasets GSE19665, GSE33006 and GSE41804 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. A total of 273 DEGs were identified, consisting of 189 downregulated genes and 84 upregulated genes. The enriched functions and pathways of the DEGs include protein activation cascade, complement activation, carbohydrate binding, complement and coagulation cascades, mitotic cell cycle and oocyte meiosis. Sixteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell division, cell cycle and nuclear division. Survival analysis showed that BUB1, CDC20, KIF20A, RACGAP1 and CEP55 may be involved in the carcinogenesis, invasion or recurrence of HCC. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of HCC, and provide candidate targets for diagnosis and treatment of HCC. PMID- 28901458 TI - Neuroprotective effects of curcumin alleviate lumbar intervertebral disc degeneration through regulating the expression of iNOS, COX-2, TGF-beta1/2, MMP-9 and BDNF in a rat model. AB - Curcumin is a natural product with antimutagenic, antitumor, antioxidant and neuroprotective properties. However, to the best of our knowledge, curcumin has yet to be investigated for the treatment of lumbar intervertebral disc degeneration LIDD). The aim of the present study was to investigate whether curcumin can alleviate LIDD through regulating the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, transforming growth factor (TGF) beta1/2, matrix metalloproteinase (MMP)-9 and brain-derived neurotrophic factor (BDNF) in a rat model of LIDD. The results of the present study suggest that pretreatment with curcumin can prevent the development of LIDD in rats. It was revealed that treatment with curcumin significantly reduced interleukin (IL) 1beta and IL-6, iNOS, COX-2 and MMP-9 levels in rats with LIDD. In addition, treatment with curcumin reduced the mRNA expression levels of TGF-beta1 and TGF beta2, whereas it increased the mRNA expression levels of BDNF in rats with LIDD. In conclusion, the present findings indicate that curcumin may exert protective effects on LIDD development, exerting its action through the regulation of iNOS, COX-2, TGF-beta1/2, MMP-9 and BDNF. PMID- 28901459 TI - Effect of hyperoside on the apoptosis of A549 human non-small cell lung cancer cells and the underlying mechanism. AB - Hyperoside (HY) is a major pharmacologically active component from Prunella vulgaris L. and Hypericum perforatum. The present study aimed to determine the anticancer effect of HY and determine the underlying mechanisms involved. Human A549 cells were treated with HY (10, 50 and 100 uM), and cell viability was detected by an MTT assay. Cell apoptosis and mitochondrial membrane potential were determined by flow cytometry. Western blot analysis was used to identify the expression of apoptosis-associated proteins and phosphorylation of MAPK. The present study demonstrated that HY significantly inhibited the viability of A549 cells in a time- and dose-dependent manner, and enhanced the percentage of apoptotic cells. HY also significantly increased the protein phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), disrupted mitochondrial membrane penetrability, and triggered the release of mitochondrial cytochrome c and apoptosis-inducing factor into the cytosol. Treatment with HY also activated the expression of caspase-9 and caspase-3. These results suggested that HY-induced apoptosis was associated with activation of the p38 MAPK- and JNK-induced mitochondrial death pathway. HY may offer potential for clinical applications in treating human non-small cell lung cancer and improving cancer chemotherapy. PMID- 28901460 TI - Tumor necrosis factor-alpha and interleukin-6 suppress microRNA-1275 transcription in human adipocytes through nuclear factor-kappaB. AB - Obesity is a confirmed risk factor for hyperlipidemia, type-II diabetes, hypertension, and cardiovascular disease. MicroRNAs (miRs) have emerged as an important field of study within energy metabolism and obesity. A previous study demonstrated miR-1275 to be markedly down-regulated during maturation of human preadipocytes. It has been reported that miR-1275 dysregulates expression in several types of cancer and infections. Little is currently known about the regulation of miR-1275 transcription. The aim of the current study was to explore the mechanism underlying the expression of miR-1275 in mature human adipocytes. After differentiation, human adipocytes were incubated with tumor necrosis factor (TNF)-alpha and interleukin-6. The results of reverse transcription-quantitative polymerase chain reaction demonstrated that miR-1275 can be down-regulated by TNF alpha and IL-6, in human mature adipocytes. Bioinformatic analysis was used to predict nuclear factor (NF)-kappaB binding sites of miR-1275's promoter region. Luciferase assay and rescue experiments were performed in HEK293T cells. NF kappaB was involved in regulating miR-1275 transcription by binding to its promoter. In response to TNF-alpha, NF-kappaB was bound to the promoter of miR 1275 and inhibited its transcription. These results indicated that inflammatory factors could regulate miR-1275 transcription through NF-kappaB and influencing miR-1275 effects on obesity. PMID- 28901461 TI - miR106b regulates retinoblastoma Y79 cells through Runx3. AB - MicroRNAs are increasingly recognized as important regulators of cancer. The aim of the present study was to investigate the role of miR-106b in the regulation of Y79 retinoblastoma. Y79 cells were transfected with antisense oligonucleotides (ASO) against miR-106b (ASO-miR-106b) or ASO-control. After transfection, the levels of miR-106b were monitored with real-time PCR (RT-PCR). The effects of ASO miR-106b transfection on cell viability was evaluated by Cell Counting Kit-8 (CCK 8) analysis at 24, 48 and 72 h after transfection. Subsequently, the cells were stained with Annexin V-FITC and propidium iodide (PI) and subjected to flow cytometry to assess cell apoptosis. Transwell assay was used to analyze cell migration. Changes in Runt-related transcription factor 3 (Runx3) mRNA and proteins levels were also evaluated. miR-106b was downregulated by ASO-miR-106b at 48 and 72 h after transfection, accompanied by a decrease in cell viability and proliferation, as well as an increase in cell apoptosis. Transwell analysis indicated that cells treated with ASO-miR-106b exhibited significantly lower cell migratory abilities. The mRNA and protein level of Runx3 were upregulated after transfection. These results demonstrated that suppression of miR-106b inhibited Y79 cell proliferation and migration. The upregulation of Runx3 after miR-106b suppression ascertained that Runx3 is a tumor-suppressor in retinoblastoma and is a target of miR-106b. PMID- 28901462 TI - Role of ghrelin in small intestinal motility following pediatric intracerebral hemorrhage in mice. AB - Small intestinal motility (SIM) disorder is a common complication following pediatric intracerebral hemorrhage (ICH), leading to a poor prognosis in patients. Previous studies have shown that ghrelin is involved in SIM in various diseases; however, the role of ghrelin in pediatric ICH-induced SIM disorder remains to be elucidated. The present study was designed to investigate the association between ghrelin and SIM post-ICH, and to examine the effect of exogenous ghrelin administration on SIM in vivo. An ICH model was induced in mice by autologous blood infusion. Neurobehavioral deficits were evaluated using a Rotarod test, forelimb placing test, and corner turn test. Intestinal mucosal damage was examined using hematoxylin and eosin staining. SIM was measured using charcoal meal staining. An enzyme-linked immunosorbent assay was used to evaluate serum levels of ghrelin and nitric oxide (NO). Reverse transcription-quantitative polymerase chain reaction and western blot analyses were performed to determine the levels of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) at the mRNA and protein levels. Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), L arginine, atropine, phentolamine and propranolol were used to manipulate the putative pathways induced by ghrelin. Neurological dysfunction was observed post ICH. ICH caused damage to the intestinal mucosa and delayed SIM. Serum levels of ghrelin increased between 3 h and 3 days, peaking at 12 h, and showed a significant negative correlation with SIM post-ICH. Ghrelin administration dose dependently attenua-ted ICH-induced SIM disorder. Ghrelin also decreased NO levels by downregulating the mRNA and protein expression levels of iNOS, but not those of nNOS or eNOS, post-ICH. Consistently, the effect was enhanced by L-NAME and weakened by L-arginine, respectively. The protective effect of ghrelin was eradicated by atropine, but not phentolamine or propranolol. These findings suggested that ghrelin ameliorated SIM disorder by downregulating iNOS/NO via the cholinergic pathway. Therefore, ghrelin may serve as a potential biomarker and useful target in ICH-induced SIM disorder. PMID- 28901463 TI - MicroRNA expression profiles and networks in placentas complicated with selective intrauterine growth restriction. AB - The microRNA (miRNA) profiles of placentas complicated with selective intrauterine growth restriction (sIUGR) are unknown. In the present study, the sIUGR-associated placental miRNA expression was investigated using microarray and confirmatory reverse transcriptase-quantitative polymerase chain reaction studies. Placenta samples around the individual insertion region for each umbilical cord were collected from monochorionic twins complicated with (n=17) or without sIUGR (control, n=16). miRNA profile analysis was performed on two sIUGR cases and one control using an Affymetrix microRNA 4.0 Array system. A total of 14 miRNAs were identified to be specifically differentially expressed (7 upregulated and 7 downregulated) among larger twins of sIUGR cases compared with smaller twins of sIUGR cases. The target genes of the identified miRNAs participate in organ size, cell differentiation, cell proliferation and migration. In addition, according to the miRNA-pathway network analysis, key miRNAs and pathways (transforming growth factor-beta, mitogen-activated protein kinase and Wnt) were identified to be associated with the pathogenesis of sIUGR. To the best of our knowledge, the results of the current study have provided the most complete miRNA profiles and the most detailed miRNA regulatory networks of placental tissues complicated with sIUGR. PMID- 28901464 TI - MicroRNA-1288 promotes cell proliferation of human glioblastoma cells by repressing ubiquitin carboxyl-terminal hydrolase CYLD expression. AB - Previous studies have demonstrated that microRNAs (miRs) are important regulators involved in various cancers, including human glioblastoma (GBM). However, the underlying mechanism of miR-1288 remains poorly understood, and its role in GBM has not been reported. The present study confirmed that miR-1288 expression was markedly upregulated in GBM. Ectopic expression of miR-1288 promoted the prolife ration, colony formation and anchorage-independent growth of GBM cells. Bioinformatics analysis coupled with western blotting and luciferase report assays also indicated that miR-1288 promoted cell proliferation of GBM by targeting ubiquitin carboxyl-terminal hydrolase (CYLD). Knockdown of CYLD expression reversed the cell proliferation promotion by miR-1288-in in GBM. These results suggest that the miR-1288/CYLD axis may represent a potential therapeutic target for the treatment of GBM. PMID- 28901465 TI - 1H-NMR-based metabolic profiling of a colorectal cancer CT-26 lung metastasis model in mice. AB - Lung metastasis is an important cause for the low 5-year survival rate of colorectal cancer patients. Understanding the metabolic profile of lung metastasis of colorectal cancer is important for developing molecular diagnostic and therapeutic approaches. We carried out the metabonomic profiling of lung tissue samples on a mouse lung metastasis model of colorectal cancer using 1H nuclear magnetic resonance (1H-NMR). The lung tissues of mice were collected at different intervals after marine colon cancer cell line CT-26 was intravenously injected into BALB/c mice. The distinguishing metabolites of lung tissue were investigated using 1H-NMR-based metabonomic assay, which is a highly sensitive and non-destructive method for biomarker identification. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to analyze 1H-NMR profiling data to seek potential biomarkers. All of the 3 analyses achieved excellent separations between the normal and metastasis groups. A total of 42 metabolites were identified, ~12 of which were closely correlated with the process of metastasis from colon to lung. These altered metabolites indicated the disturbance of metabolism in metastatic tumors including glycolysis, TCA cycle, glutaminolysis, choline metabolism and serine biosynthesis. Our findings firstly identified the distinguishing metabolites in mouse colorectal cancer lung metastasis models, and indicated that the metabolite disturbance may be associated with the progression of lung metastasis from colon cancer. The altered metabolites may be potential biomarkers that provide a promising molecular approach for clinical diagnosis and mechanistic study of colorectal cancer with lung metastasis. PMID- 28901466 TI - miR-133b acts as a tumor suppressor and negatively regulates ATP citrate lyase via PPARgamma in gastric cancer. AB - MicroRNAs (miRNAs/miRs) are a class of small noncoding RNAs that negatively regulate protein expression by binding to protein-coding mRNAs and suppressing translation. Accumulating evidence suggests that miRNAs are involved in the development and progression of cancer by regulating cancer metabolism. Meanwhile, the cytosolic enzyme ATP citrate lyase (ACLY) is a promising target in the prevention and treatment of cancer. In the present study we revealed by western blot analysis and reverse transcription-quantitative PCR that miR-133b was downregulated in human gastric cancer (GC) tissues and cell lines, while ACLY was upregulated. The overexpression of miR-133b could decrease the proliferation and invasion of MKN-74 cells by inhibiting the expression and activation of ACLY. Furthermore, the nuclear distribution of peroxisome proliferator-activated receptor-gamma (PPARgamma) in GC tissues and cell lines was markedly decreased, and overexpression of miR-133b could increase the levels of nuclear PPARgamma in MKN-74 cells. Additionally, miR-133b decreased the transcriptional activity of ACLY in a PPARgamma-dependent manner, as determined by a dual-luciferase reporter assay. These results indicate that miR-133b targets ACLY and inhibits GC cell proliferation by regulating the expression of PPARgamma, suggesting that miR-133b may serve as a tumor-suppressive target in GC therapy. PMID- 28901467 TI - Aberrantly expressed transcription factors C/EBP and SOX4 have positive effects in the development of chronic myeloid leukemia. AB - The aim of the present study was to examine the expression and significance of CCAAT/enhancer binding protein alpha (C/EBPalpha) and SRY-related high mobility group box containing transcription factor 4 (SOX4) in chronic myeloid leukemia (CML). Bone marrow samples were collected from patients with CML, and peripheral blood mononuclear cells were collected from healthy controls. Protein and mRNA were extracted from the collected samples, and analyzed using western blotting and reverse transcription-quantitative polymerase chain reaction analyses, respectively. Spearman's method was used to evaluate the correlation between the expression levels of these two genes, with P<0.05 considered to indicate a statistically significant difference. A total of 79 patients, including 57 patients with newly diagnosed CML and 22 patients treated with imatinib therapy, and 30 controls were enrolled. The expression of SOX4 was upregulated in the patients with CML, whereas the expression of C/EBPalpha was downregulated (P<0.05). However, no differences were observed among the chronic, accelerated and blastic CML phases, respectively (P>0.05). In addition, no associations were found between the changes in expression and age, gender, white blood cells or the expression of breakpoint cluster region/abelson in patients (P>0.05). However, the expression of SOX4 was negatively correlated with the expression of C/EBPalpha (P<0.01). Following imatinib treatment, the expression of SOX4 was downregulated in the progression-free patients, but upregulated in the blastic phase patients, whereas the expression of C/EBPalpha showed the opposite trend. Therefore, C/EBPalpha and SOX4 were important and negatively associated with the process of CML, and the C/EBPalpha-SOX4 axis may be a novel potential therapeutic target for the treatment of CML. PMID- 28901468 TI - Apolipoprotein A5 regulates intracellular triglyceride metabolism in adipocytes. AB - It has previously been demonstrated that apolipoprotein A5 (apoA5) can be internalized by human adipocytes and significantly decreases intracellular triglyceride content. In the present study, endocytosis of apoA5 by adipocytes under different conditions, and the underlying mechanism by which apoA5 regulates cellular triglyceride storage, was investigated. The results revealed that the apoA5 protein was detected in human subcutaneous abdominal adipose tissues. In addition, the uptake of apoA5 was attenuated in human obese adipose tissues and in cultured adipocytes with hypertrophy or insulin resistance. Low-density lipoprotein receptor protein 1 (LRP1) knockdown in adipocytes resulted in a decrease in internalized apoA5 content, suggesting that LRP1 serves a role in apoA5 uptake. Treatment of adipocytes with apoA5 decreased the expression of the lipid droplet-associated proteins such as cidec and perilipin. ApoA5-treated adipocytes demonstrated an increase in lipolysis activity and expression of uncoupling protein 1, which is the molecular effector of thermogenesis in brown adipocytes. These results suggested that decreased triglyceride accumulation in adipocytes induced by apoA5 may be associated with enhanced lipolysis and energy expenditure, which may result from reduced expression of cidec and perilipin. In conclusion, the present study demonstrated a novel role of apoA5 in regulating the intracellular triglyceride metabolism of adipocytes. The results of the present study suggested that apoA5 may serve as a potential therapeutic target for the treatment of obesity and its related disorders. PMID- 28901469 TI - Glycogen synthase kinase-3beta inhibitor reduces LPS-induced acute lung injury in mice. AB - The aim of the present study was to examine the role of Wnt signaling in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). ARDS was induced by LPS and compared in mice treated with either glycogen synthase kinase-3beta inhibitor (GSKI) or PBS. The protein expression levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, IL-17, IL-18 and IL 1beta in the bronchoalveolar lavage fluid (BALF) were examined using murine cytokine-specific enzyme-linked immunosorbent assays. The accumulation of neutrophils and macrophages in the BALF were detected using flow cytometry. The extent of pathological lesions was evaluated using an immunohistochemical assay. The differentiation of mesenchymal stem cells (MSCs) into type II alveolar (ATII) epithelial cells was analyzed using immunofluorescence staining. Treatment with GSKI led to maintained body weights and survival in mice with LPS-induced ARDS. Treatment with GSKI effectively reduced the levels of total protein, albumin, IgM and keratinocyte growth factor in the BALF. Smith scores showed that GSKI significantly alleviated LPS-induced lung injury. GSKI also functioned to reduce inflammatory cell accumulation and pro-inflammatory cytokine secretion. Finally, it was found that GSKI promoted the differentiation of MSCs into ATII epithelial cells in vivo. Taken together, the GSKI-treated mice exhibited reduced acute lung injury through inhibited intra-fluid inflammatory cell infiltration and decreased expression of pro-inflammatory cytokines, and GSKI increased the differentiation of MSCs into ATII epithelial cells. PMID- 28901471 TI - CXC chemokine-7 inhibits growth and migration of oral tongue squamous cell carcinoma cells, mediated by the epithelial-mesenchymal transition signaling pathway. AB - Oral tongue squamous cell carcinoma (OTSCC) is the most common oral malignancy with different histopathological symptoms and etiology of tumorigenesis. Migration and invasion is the most important characteristics of OTSCC, and limits tumor therapy in clinics. The epithelial-to-mesenchymal transition (EMT) signaling pathway is an important process in the progress of tumor cell migration and invasion. Previous studies have indicated that C-X-C chemokine receptor-7 (CXCR-7) promotes the progression and metastasis of tumor cells, presenting a potential target molecule for cancer therapy. The present study investigated the inhibitory effects of C-X-C chemokine-7 (CXC-7) on human OTSCC cells both in vitro and in vivo. The results demonstrated that the Tca8113 human OTSCC cell line expressed higher levels of CXC-7 mRNA compared with the hNOE human normal oral epithelial cell line. MTT assays indicated that CXC-7 suppressed Tca8113 cell growth, and the cytotoxicity of CXC-7 was indicated as the cell survival of the negative control group was significantly decreased compared with the blank control and hNOE cells. Migration and invasion assays revealed that CXC-7 inhibited Tca8113 cell local expansion and distant metastasis. In addition, the results demonstrated that the extracellular signal-regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was inhibited after CXC-7 treatment in Tca8113 cells. N-cadherin, E-Cadherin, Snail and Slug expression levels in the ERK/AKT signaling pathway were inhibited in Tca8113 cells after treatment with CXC-7. It was demonstrated that important extracellular matrix proteins involved in cell migration, including Slug, collagen type I and Vimentin, were significantly downregulated by CXC-7 treatment. In conclusion, CXC-7 inhibited growth and migration in OTSCC cells, mediated by the EMT signaling pathway. This suggests that CXC-7 serves an inhibitory role in OTSCC migration, implicating CXCR-7 as a promising biomarker for chemokine receptor-based drug development. PMID- 28901470 TI - TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression. AB - Toll-like receptor (TLR)-mediated signaling induces cell migration or invasion in several tumors and various stages of cancer. Interactions of mesothelin, a 40-kDa cell surface glycoprotein, with cancer antigen 125 (CA125) is associated with drug resistance, metastasis, and poor clinical outcome of ovarian cancer patients. In this study, we examined the role of TLR5 and TLR7 in the metastasis of ovarian cancer through the induction of mesothelin/CA125 expression and investigated its underlying mechanism. TLR5 agonist (flagellin) and TLR7 agonist (imiquimod) upregulated mesenchymal phenotypes and produced epithelial mesenchymal transition (EMT)-related cytokines in the SKOV3 cells; however, TLR7 expressing CaOV3 cells had no response to the specific ligand, imiquimod, for enhancing its EMT processes. Stimulation of the SKOV3 cells with flagellin or imiquimod activated Wiskott-Aldrich syndrome protein verprolin-homologous 3 (WAVE3) and mesothelin/CA125, whereas it suppressed the expression of TAp63. Moreover, knockdown of TLR5 or TLR7 in SKOV3 cells profoundly impaired the TLR5- or TLR7-intiated downstream signaling pathway. Loss of WAVE3 in SKOV3 cells led to the inhibition of invasion, suppression of mesenchymal characteristics, prevention of OCT4/SOX2 secretion, and attenuation of mesothelin/CA125 expression after stimulation with flagellin or imiquimod. Although the disruption of mesothelin decreased the migratory activity of the TLR5/7-activated SKOV3 cells, knockdown of mesothelin failed to reduce the expression of mesenchymal markers, OCT4, and SOX2. In addition, targeting OCT4 or SOX2 with siRNA had no effect on the expression of mesothelin and the suppression of transcriptionally active p63 (TAp63) in the TLR5/7-stimulated SKOV3 cells. Our results suggest that TLR5/7 mediated WAVE3 activation not only controls the mesothelin-related EMT processes but also modulates OCT4/SOX2-mediated mesenchymal marker expression. Taken together, both TLR5 and TLR7 expression are critical for the TLR5/7-induced metastasis of ovarian cancer and the inhibition of WAVE3 might be a new therapeutic target to control ovarian cancer metastasis. PMID- 28901472 TI - Inositol hexaphosphate hydrolysate competitively binds to AKT to inhibit the proliferation of colon carcinoma. AB - Phytate, myto-inositol 1,2,3,4,5,6 hexaphosphate (IP6), is recognized as an anti nutrition phytochemical for decades. Recently, numerous studies have indicated that IP6 and its hydrolysates could suppress colon oncogenesis. However, very little is known concerning the mechanism of IP6 hydrolysates in regulating colon oncogenesis. The aim of the present study was to identify the underlying relationship between IP6 hydrolysates and colon cancer. Three types of human colorectal cancer cells were utilized in the present study. The proliferation inhibition and migration assays were employed to reveal that IP6 hydrolysates inhibited the proliferation of SW620 cells. Real-time PCR, cell-based ELISA and the AKT inhibitor assay were utilized to reveal that 20 and 30% degree of hydrolysis hydrolysates of IP6 inhibited SW620 cell growth by inhibiting the activation of AKT protein. The docking simulation study revealed that IP4 and IP5 could inhibit the activation of AKT by binding to PIP3 receptor. Collectively, our results indicated that the IP6 hydrolysates inhibit SW620 cell proliferation; IP4 and IP5, the probable primary constituents of the 20-30% degree of hydrolysis hydrolysates of IP6, inhibited the proliferation of SW620 cells by competitively inhibiting the AKT protein. PMID- 28901473 TI - PHD3 affects gastric cancer progression by negatively regulating HIF1A. AB - Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcription quantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent non-cancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of well differentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer. PMID- 28901474 TI - Inhibition of miR-23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3K/Akt pathway. AB - Epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKIs) have become first-line drugs used for non-small cell lung cancer (NSCLC) treatment. However, drug resistance to EGFR-TKIs will be developed inevitably due to the repeated use of these drugs. In the present study, we isolated cancer stem cells (CSCs) from the PC9 NSCLC cell line. We then observed that the PC9 CSCs showed significant resistance to erlotinib compared with the PC9 non-CSCs. Erlotinib failed to suppress the phosphorylation of PI3K and AKT in PC9 CSCs, although the EGFR was inhibited sufficiently. Mechanically, we observed aberrant upregulation of microRNA-23a (miR-23a) and downregulation of PTEN in PC9 CSCs compared to PC9 non-CSCs. Luciferase reporter assays proved that PTEN was the target of miR-23a in PC9 CSCs. Furthermore, knockdown of miR-23a enhanced the antitumor effect of erlotinib by increasing the expression of PTEN. In addition, transfection with miR-23a inhibitors promoted the erlotinib-dependent inhibition of PI3K/AKT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs. These results propose that upregulation of miR-23a is a potential mechanism associated with resistance to EGFR-TKIs in lung cancer stem cells. Inhibition of miR-23a serves as a novel therapeutic strategy to eliminate the EGFR-TKIs resistance of lung cancer stem cells. PMID- 28901475 TI - Valproic acid inhibits epithelial-mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression. AB - Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786 O and Caki-1 treated with VPA, the neural (N)-cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)-cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N-cadherin and simultaneously upregulated E cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA-mediated EMT-inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor-beta (TGF-beta) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1-gamma was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF-beta, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC. PMID- 28901476 TI - DADLE improves hepatic ischemia/reperfusion injury in mice via activation of the Nrf2/HO-1 pathway. AB - Hepatic ischemia/reperfusion (I/R) injury is a common pathophysiological process that occurs following liver surgery, which is associated with oxidative stress, and can cause acute liver injury and lead to liver failure. Recently, the development of drugs for the prevention of hepatic I/R injury has garnered interest in the field of liver protection research. Previous studies have demonstrated that [D-Ala2, D-Leu5]-Enkephalin (DADLE) exerts protective effects against hepatic I/R injury. To further clarify the specific mechanism underlying the effects of DADLE on hepatic I/R injury, the present study aimed to observe the effects of various doses of DADLE on hepatic I/R injury in mice. The results indicated that DADLE, at a concentration of 5 mg/kg, significantly reduced the levels of alanine aminotransferase and aspartate aminotransferase in the serum, and the levels of malondialdehyde in the liver homogenate. Conversely, the levels of glutathione, catalase and superoxide dismutase in the liver homogenate were increased. In addition, DADLE was able to promote nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation and upregulate the expression of heme oxygenase (HO)-1, which is a factor downstream of Nrf2, thus improving hepatic I/R injury in mice. In conclusion, the present study demonstrated that DADLE was able to significantly improve hepatic I/R injury in mice, and the specific mechanism may be associated with the Nrf2/HO-1 signaling pathway. PMID- 28901477 TI - Simultaneous multi-gene mutation screening using SNPscan in patients from ethnic minorities with nonsyndromic hearing-impairment in Northwest China. AB - The present study aimed to investigate the molecular etiology of nonsyndromic hearing impairment (HI) in hearing impaired populations of Hui, Tibetan, and Tu ethnicities in northwest China. A total of 283 unrelated subjects with HI who attended special education schools in northwest China were enrolled in the present study. Single-nucleotide polymorphisms (SNPs) in three common deafness related genes, gap junction protein beta2 (GJB2), solute carrier family 26 member 4 (SLC26A4) and mitochondrially encoded 12S RNA (mtDNA12SrRNA), were detected using a SNPscan technique. GJB2 mutations were detected in 14.89% of Hui patients, 9.37% of Tibetan patients and 11.83% of Tu patients. The most prevalent GJB2 mutation in the Hui and Tu patients was c.235delC. In the Tibetan patients, the c.109G>A SNP exhibited the highest allele frequency. SLC26A4 mutations were detected in 10.64% of Hui patients, 6.25% of Tibetan patients, and 8.6% of Tu patients. The most common SLC26A4 mutation was c.919-2A>Gin the Hui, Tibetan, and Tu patients, and the second most common SLC26A4 mutations in these patients were c.1517T>G, c.1226G>A andc.2168A>G, respectively. The mutation rates ofmtDNA12SrRNA in the Hui, Tibetan, and Tu patients were 1.06, 5.21, and 5.38%, respectively. These findings demonstrate that the mutation spectra of these deafness-related genes are unique amongst these three ethnic groups. This information will be helpful in designing a protocol for genetic testing for deafness and for achieving accurate molecular diagnoses in northwest China. PMID- 28901478 TI - MicroRNA-195 inhibits cell proliferation, migration and invasion in laryngeal squamous cell carcinoma by targeting ROCK1. AB - Laryngeal carcinoma is the second most common malignancy of the head and neck cancers. The most common type of laryngeal carcinoma comprises laryngeal squamous cell carcinoma (LSCC), which accounts for ~95% of laryngeal carcinoma cases. Despite great progress in diagnostic and therapeutic techniques over the last few decades, the prognosis for patients with LSCC remains poor. A number of studies reported that various miRNAs are dysregulated in LSCC and serve critical roles in LSCC tumorigenesis and tumor development. The present study aimed to evaluate the expression level of microRNA (miR)-195 and its possible roles in LSCC. Briefly, miR-195 was downregulated in LSCC tissues and cell lines. In addition, low miR 195 expression was significantly correlated with lymph node metastasis and TNM stage of LSCC patients. Further study has demonstrated that miR-195 overexpression suppressed cell proliferation, migration and invasion of LSCC. Moreover, rho-associated kinase 1 (ROCK1) was identified as a direct target gene of miR-195. Downregulation of ROCK1 exerted similar roles to that of miR-195 overexpression in LSCC, suggesting ROCK1 was a direct downstream target of miR 195. These findings elucidated a novel molecular mechanism for the pathogenic mechanism in LSCC carcinogenesis and progression, and may have a potential role in the treatment of patients with LSCC. PMID- 28901479 TI - Interaction with neutrophils promotes gastric cancer cell migration and invasion by inducing epithelial-mesenchymal transition. AB - Emerging evidence has revealed that neutrophils have phenotypic and functional plasticity. Neutrophils could be polarized towards a pro-tumor phenotype by tumor derived factors. In the present study, we investigated the role of the interaction with neutrophils on the functions of gastric cancer cells in vitro. Human promyelocytic leukemia HL-60 cells were induced to differentiate into neutrophil-like cells (HL-60N) using dimethyl sulfoxide (DMSO). Human gastric cancer cells were co-cultured with HL-60N cells or treated with the conditioned medium (CM) of cancer-activated HL-60N cells. The migration and invasion of gastric cancer cells were significantly enhanced while their proliferation was minimally altered. The expression of pro-inflammatory factors including IL-6, IL 8, IL-1beta, and TNFalpha was significantly increased in cancer-activated HL-60N cells, which induced the activation of the ERK pathway and epithelial-mesenchymal transition (EMT) in gastric cancer cells. Blocking the ERK pathway activation reversed the promoting effects of cancer-activated HL-60N cells on gastric cancer cell migration and invasion. In addition, mouse gastric cancer cell derived CM could also increase the expression of pro-inflammatory factors in mouse bone marrow neutrophils, which in turn enhanced the migration and invasion of mouse gastric cancer cells. Collectively, our findings revealed that the interaction with neutrophils promoted gastric cancer cell migration and invasion through the activation of the ERK pathway and the induction of EMT, indicating that neutrophils may play an important role in gastric cancer metastasis. Therefore, targeting neutrophil-cancer cell interaction may provide a new strategy for the treatment of gastric cancer. PMID- 28901480 TI - Radioiodine-labeled anti-epidermal growth factor receptor binding bovine serum albumin-polycaprolactone for targeting imaging of glioblastoma. AB - The aim of this study was to look for a new medicine in diagnosing and treating of glioblastoma. Radioiodine-labeled anti-epidermal growth factor receptor (EGFR) binding nanoparticles were constructed. In vitro cell-binding assays were confirmed by confocal microscopy and flow cytometry. Cell cytotoxicity assays were evaluated by MTT assay; radionuclide uptake assays were performed by gamma counter. Radioiodine-imaging studies were conducted using a xenograft nude mouse model in vivo. The results showed that EGFR significantly enhanced the uptake and accumulation of BSA-PCL in the experimental model of xenografts in nude mice, suggesting improved specific nanoparticle-based delivery. In conclusion, the data showed 131I-EGFR-BSA-PCL leading radioiodine therapy for U251 and U87 cells had a good effect in vitro and in vivo. Thus, 131I-EGFR-BSA-PCL may provide a new method for glioblastoma treatment. PMID- 28901481 TI - Silencing of histone methyltransferase NSD3 reduces cell viability in osteosarcoma with induction of apoptosis. AB - NSD3 is a histone lysine methyltransferase that methylates histone H3 at lysine 36. NSD3 is located at chromosome 8p11.23, the locus that exhibits strong cancer relevance. Thus, NSD3 is likely involved in multiple human cancers. Nevertheless, its roles in human carcinogenesis remain unknown. In the present study, we demonstrated that silencing of NSD3 in osteosarcoma, the most common primary bone cancer in children and adolescents, results in a marked decrease in the number of viable cancer cells, accompanied by increases in the cell population at the G2/M phase and the number of apoptotic cells. In addition, 549 NSD3-regulated genes were identified and a set of selected candidate genes were validated. Bioinformatic analysis revealed that NSD3 negatively regulates a number of genes that are involved in the process of negative regulation of signal transduction as well as negative regulation of signaling and cell communication. Our results indicate the oncogenic roles of NSD3 in the development and progression of human osteosarcoma, and implicate NSD3 as a potential molecular target for selective therapy for human osteosarcoma. PMID- 28901482 TI - Detection of RACK1 and CTNNBL1-induced activation of mouse splenocytes using an immunoprecipitation-based technique. AB - Tumor cell lysates (TCLs) have been reported to induce antitumor immunity; however, it remains unclear which elements serve a role in this process. The present study identified 768 proteins that were upregulated in TCL prepared from Lewis lung cancer cells compared with the lysate from type II alveolar epithelial cells. Among the proteins that were upregulated in TCL, receptor for activated C kinase 1 (RACK1) and catenin beta-like 1 (CTNNBL1) are closely associated with cell proliferation and the inhibition of apoptosis. To determine the role of these proteins in TCL, a protein extraction method was designed, which was based on immunoprecipitation. Using this method, RACK1 and CTNNBL1 were extracted, whereas the other proteins within the TCL were not affected. The modified TCL exhibited a stronger ability to induce splenocyte apoptosis, whereas the ability to promote cell activation was reduced. These findings suggested that the TCL depends on RACK1 and CTNNBL1 to activate mouse immunocytes, including monocytes and B lymphocytes, and inhibit apoptosis. Therefore, the present study may provide information regarding the composition of TCLs and their positive regulatory effect on immunocytes. PMID- 28901483 TI - Moderate hypothermia induces protein SUMOylation in bone marrow stromal cells and enhances their tolerance to hypoxia. AB - Acute cerebral infarction can progress rapidly, and there are limited specific and effective treatments. Small ubiquitin-like modifiers (SUMOs) provide an important post-translational modification of proteins. Following cerebral infarction, multiple proteins can combine with SUMOs to protect nerve cells. Furthermore, moderate hypothermia (core body temperature, 33-34C) can increase the level of SUMOylation on multiple proteins. In the present study, it was examined whether moderate hypothermia increases the survival rate of bone marrow stromal stem cells (BMSCs) implanted in the cerebral ischemic penumbra via SUMOylation of multiple proteins. Firstly, BMSCs were exposed to oxygen-glucose deprivation (OGD) under moderate hypothermic (33C) conditions. Subsequently, adult rats with middle cerebral artery occlusion were treated with a combination of BMSCs and moderate hypothermia (32-34C). The results demonstrated that hypothermia promoted the combination of multiple proteins with SUMOs in BMSCs, and induced transport of SUMOs from the cytoplasm to the nucleus. Moderate hypothermia additionally reduced damage to BMSCs following OGD and improved BMSC survival following transplantation into the penumbra. These data suggest that moderate hypothermia may protect against BMSC injury via rapid SUMOylation of intracellular proteins. Thus, BMSC transplantation combined with moderate hypothermia may be a potential therapeutic strategy to treat cerebral infarction. PMID- 28901484 TI - Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin. AB - One of the most dreaded clinical events for an oncology patient is resistance to treatment. Chemoresistance is a complex phenomenon based on alterations in apoptosis, the cell cycle and drug metabolism, and it correlates with the cancer stem cell phenotype and/or epithelial-mesenchymal transition. Molecular iodine (I2) exerts an antitumor effect on different types of iodine-capturing neoplasms by its oxidant/antioxidant properties and formation of iodolipids. In the present study, wild-type breast carcinoma cells (MCF-7/W) were treated chronically with 10 nM doxorubicin (DOX) to establish a low-dose DOX-resistant mammary cancer model (MCF-7/D). MCF-7/D cells were established after 30 days of treatment when the culture showed a proliferation rate similar to that of MCF-7/W. These DOX resistant cells also showed increases in p21, Bcl-2 and MDR-1 expression. Supplementation with 200 uM I2 exerted similar effects in both cell lines: it decreased the proliferation rate by ~40%, and I2 co-administration with DOX significantly increased the inhibitory effect (to ~60%) and also increased apoptosis (BAX/Bcl-2 index), principally by inhibiting Bcl-2 expression. The inhibition by I2 + DOX was also accompanied by impaired MDR-1 induction as well as by a significant increase in PPARgamma expression. All of these changes could be attributed to enhanced DOX retention and differential down-selection of CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations. I2 + DOX-selected cells showed a weak induction of xenografts in Foxn1nu/nu mice, indicating that the iodine supplements reversed the tumorogenic capacity of the MCF-7/D cells. In conclusion, I2 is able to reduce the drug resistance and invasive capacity of mammary cancer cells exposed to DOX and represents an anti-chemoresistance agent with clinical potential. PMID- 28901485 TI - A novel non-contact communication between human keratinocytes and T cells: Exosomes derived from keratinocytes support superantigen-induced proliferation of resting T cells. AB - It is widely accepted that keratinocytes act as non-professional antigen presenting cells and support superantigen-induced proliferation of resting T cells; however, it remains unknown whether keratinocytes function in situ with T cells via a non-contact mechanism. The current study used a transwell co-culture system and demonstrated, for the first time to the best of the authors' knowledge, that HaCaT cells (the human keratinocyte cell line) did induce T cell proliferation via indirect contact. The data further indicated that exosomes, small membrane vesicles that transfer antigens to recipient cells, are also involved in the superantigen-associated immunity of keratinocytes. The current study provided experimental evidence that HaCaT-exosomes contained MHC I and II, and could interact with T cells. In addition, following interferon gamma stimulation, Staphylococcal aureus enterotoxin B-loaded HaCaT cells secreted exosomes to induce the proliferation of CD4+ and CD8+ T cells in vitro. This novel biological function of exosomes reveals a new mechanism of how keratinocytes participate in bacterial superantigen-induced immune responses. PMID- 28901486 TI - miRNA-148a inhibits cell growth of papillary thyroid cancer through STAT3 and PI3K/AKT signaling pathways. AB - The function of miRNA-148a in lymphatic metastases of papillary thyroid cancer and its mechanism were tested. In this investigation, miRNA-148a expression of lymphatic metastases of papillary thyroid cancer patients was inhibited, compared with normal group. We found that miRNA-148a overexpression was effectively reduced cell cell proliferation and metastases, and induced apoptosis of papillary thyroid cancer in vitro. Overexpression of miRNA-148a significantly induced Bax protein expression and caspase-3/9 levels, and suppressed phosphorylation STAT3 (p-STAT3), PI3K and p-Akt protein expression of papillary thyroid cancer in vitro. Next, si-STAT3, could inhibit p-STAT3 protein expression, reducing cell-cell proliferation and metastases, and inducing apoptosis of papillary thyroid cancer following miRNA-148a overexpression. Then, the PI3K inhibitor was able to inhibit PI3K and p-Akt protein expression, reduced cell cell proliferation and metastases, and induced apoptosis of papillary thyroid cancer following miRNA-148a overexpression. Taken together, our results suggest that miRNA-148a inhibits lymphatic metastases of papillary thyroid cancer through STAT3 and PI3K/AKT signaling pathways. PMID- 28901487 TI - Association of SREBP2 gene polymorphisms with the risk of osteonecrosis of the femoral head relates to gene expression and lipid metabolism disorders. AB - Although lipid metabolism disorders have been recognized as a primary factor of osteonecrosis of the femoral head (ONFH), the molecular pathogenesis remains unclear. Sterol regulatory element-binding protein 2 (SREBP2) specifically regulates cholesterol and fatty acid metabolism to maintain lipid homeostasis. To explore the roles of the SREBP2 gene in the development of ONFH, the authors analyzed the gene polymorphism and gene expression of three tag single nucleotide polymorphisms of the SREBP2 gene, the serum lipids levels, and their associations with ONFH development in 182 ONFH patients and 179 healthy controls. The results demonstrated that the stage IV proportions of ONFH patients carrying the rs2267439CT or CC genotype were significantly higher and lower than the stage III proportions of ONFH patients (P=0.039), respectively. The serum triglyceride, low density lipoprotein (LDL)-c levels, and LDL-C/high-density lipoprotein (HDL)-C ratio in the ONFH group were significantly increased compared to those in the control group (P=0.01, P=0.005, P=0.0001) while the HDL-C level of ONFH group was remarkably lower than that of the control group (P=0.0001). Association analysis further revealed that the LDL-c levels of the rs226744 GG and AG genotype carriers were statistically higher than that of the AA genotype carriers (P=0.039, P=0.05). These results demonstrated that the gene polymorphism of SREBP2 not only significantly associated with the clinical phenotypes of ONFH but also closely related to lipid metabolism disorder. The results indicated that SREBP2 gene polymorphism and function may play key roles in the development of ONFH. PMID- 28901488 TI - The role of fructose-1,6-bisphosphatase 1 in abnormal development of ovarian follicles caused by high testosterone concentration. AB - The present study aimed to identify the molecular mechanisms underlying the effects of the fructose-1,6-bisphosphatase 1 (FBP1) signaling pathway within normal follicle development and in hyperandrogenism-induced abnormal follicle growth. To achieve this, murine primary follicles, granulosa cells (GCs) and theca-interstitial cells (TICs) were isolated, cultured in vitro and treated with a high concentration of androgens. A concentration of 1x10-5 mol/l testosterone was considerable to induce hyperandrogenism by MTT assay. All cells were divided into four groups, as follows: Control group, testosterone group, androgen receptor antagonist-flutamide group and flutamide + testosterone group. Flutamide was used in the present study as it blocks the effects of the androgen receptor. The mRNA expression levels of FBP1 were detected using reverse transcription quantitative polymerase chain reaction. The expression levels and localization of FBP1 were analyzed by western blot analysis and immunofluorescence staining. The experimental results demonstrated that androgen presence stimulated follicle development, whereas excessive testosterone inhibited development. FBP1 was identified as being mainly expressed in follicles; FBP1 protein was significantly expressed in GCs of the 14-day-cultured follicle, as well as in the cytoplasm and nuclei of GCs and TICs in vitro. Testosterone increased FBP1 expression during a specific range of testosterone concentrations. Testosterone increased the expression of FBP1 within GCs. Furthermore, FBP1 and phosphoenolpyruvate carboxykinase 1 (PCK1) mRNA expression was increased in GCs treated with testosterone, whereas forkhead box protein O1 (FOXO1) and peroxisome proliferator activated receptor gamma coactivator-1alpha mRNA expression was significantly decreased in the testosterone group. In TICs, testosterone and flutamide inhibited the mRNA expression levels of FOXO1 and glucose-6-phosphatase enzyme, and promoted the expression of PCK1. These results suggested that the FBP1 signaling pathway may serve an important role in normal follicle growth and hyperandrogenism-induced abnormal development, which may be associated with abnormal glucose metabolism induced by high concentrations of testosterone. PMID- 28901489 TI - UPLC-QTOFMS-based metabolomic analysis of the serum of hypoxic preconditioning mice. AB - Hypoxic preconditioning (HPC) is well-known to exert a protective effect against hypoxic injury; however, the underlying molecular mechanism remains unclear. The present study utilized a serum metabolomics approach to detect the alterations associated with HPC. In the present study, an animal model of HPC was established by exposing adult BALB/c mice to acute repetitive hypoxia four times. The serum samples were collected by orbital blood sampling. Metabolite profiling was performed using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS), in conjunction with univariate and multivariate statistical analyses. The results of the present study confirmed that the HPC mouse model was established and refined, suggesting significant differences between the control and HPC groups at the molecular levels. HPC caused significant metabolic alterations, as represented by the significant upregulation of valine, methionine, tyrosine, isoleucine, phenylalanine, lysophosphatidylcholine (LysoPC; 16:1), LysoPC (22:6), linoelaidylcarnitine, palmitoylcarnitine, octadecenoylcarnitine, taurine, arachidonic acid, linoleic acid, oleic acid and palmitic acid, and the downregulation of acetylcarnitine, malate, citrate and succinate. Using MetaboAnalyst 3.0, a number of key metabolic pathways were observed to be acutely perturbed, including valine, leucine and isoleucine biosynthesis, in addition to taurine, hypotaurine, phenylalanine, linoleic acid and arachidonic acid metabolism. The results of the present study provided novel insights into the mechanisms involved in the acclimatization of organisms to hypoxia, and demonstrated the protective mechanism of HPC. PMID- 28901492 TI - Interactions between hematopoietic progenitor kinase 1 and its adaptor proteins (Review). AB - Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 is a serine/threonine protein kinase. It is involved in various cellular events, including mitogen-activated protein kinase signaling, nuclear factor-kappaB signaling, cytokine signaling, cellular proliferation and apoptosis, T cell receptor/B cell receptor signaling and T/B/dendritic cell-mediated immune responses. Therefore, HPK1 has variety of roles in immunity, and is associated with the pathogenesis of autoimmune diseases, cancer, and the inflammatory response. In these cellular and immune events, HPK1 interacts with several adaptor proteins, including caspase recruitment domain family, member 11, hematopoietic cell-specific protein 1, HPK1 interacting protein of 55 kDa, the growth factor receptor-bound protein 2 family, linker for activated T-cells, the SH2 domain-containing leukocyte protein of 76 kDa family, the v-crk avian sarcoma virus CT10 oncogene homolog family, B-cell adaptor molecule of 32 kDa and non-catalytic region of tyrosine kinase adaptor protein. These adaptor proteins can couple HPK1 with various effector molecules, leading to the transmission of upstream signals to downstream targets. They are crucial in regulating the relocation, phosphorylation, activation and functions of HPK1. HPK1 can also phosphorylate certain proteins, consequently modulating their functions. This review aims to describe the adaptor proteins, which interact with HPK1, particularly focusing on their modes of interaction with HPK1, and the effects that these interactions cause. PMID- 28901491 TI - miR-21 attenuates contrast-induced renal cell apoptosis by targeting PDCD4. AB - Contrast medium (CM) is widely used in cardiac catheterization; however, it may induce acute kidney injury or renal failure, although the underlying mechanism remains to be elucidated. MicroRNA-21 (miR-21) is involved in renal disease and has been indicated to regulate cellular apoptosis and fibrosis, although its role in CM-induced renal cell injury is unknown. The present study examined the expression and potential targets of miR-21 in human renal proximal tubular epithelial (HK-2) cells following CM treatment. CM induced renal cell apoptosis and decreased miR-21 expression. The expression level of the apoptosis regulator protein, B-cell lymphoma 2 (Bcl-2) was upregulated, whereas that of the apoptosis regulator, Bcl-2-associated X protein (Bax) was downregulated upon transfection of miR-21 mimics; miR-21 overexpression additionally directly inhibited the expression of programmed cell death protein 4 (PDCD4), as determined by a dual luciferase reporter assay, and PDCD4 silencing reduced the rate of HK-2 cell apoptosis. The results of the present study indicated that miR-21 protected renal cells against CM-induced apoptosis by regulating PDCD4 expression. PMID- 28901490 TI - Targeting strategies of adenovirus-mediated gene therapy and virotherapy for prostate cancer (Review). AB - Prostate cancer (PCa) poses a high risk to older men and it is the second most common type of male malignant tumor in western developed countries. Additionally, there is a lack of effective therapies for PCa at advanced stages. Novel treatment strategies such as adenovirus-mediated gene therapy and virotherapy involve the expression of a specific therapeutic gene to induce death in cancer cells, however, wild-type adenoviruses are also able to infect normal human cells, which leads to undesirable toxicity. Various PCa-targeting strategies in adenovirus-mediated therapy have been developed to improve tumor-targeting effects and human safety. The present review summarizes the relevant knowledge regarding available adenoviruses and PCa-targeting strategies. In addition, future directions in this area are also discussed. In conclusion, although they remain in the early stages of basic research, adenovirus-mediated gene therapy and virotherapy are expected to become important therapies for tumors in the future due to their potential targeting strategies. PMID- 28901493 TI - High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase. AB - The chemoresistance of non-small cell lung cancer (NSCLC) that occurs in docetaxel (DOC) chemotherapy substantially decreases the survival of patients. To overcome DOC-induced chemoresistance, we established DOC-selected A549 lung cancer sublines (A549/D16 and A549/D32) and revealed that both sublines were cross-resistant to vincristine (VCR) and doxorubicin (DXR). Notably, both sublines were more sensitive to pemetrexed (PEM) than parental cells according to MTT and clonogenic assays. The expression levels of thymidylate synthase (TS) and gamma-glutamyl hydrolase (GGH) were downregulated in DOC-resistant sublines. When exogenous TS was overexpressed in A549/D16 cells, PEM sensitivity was significantly decreased, however it was not decreased by overexpression of exogenous GGH. PEM treatment induced more apoptotic sub-G1 cells in both DOC resistant sublines and in the in vivo PEM sensitivities of A549/D16 cells. These findings were further confirmed by a xenografted tumor model. To unmask the mediator of TS downregulation, we investigated human lung cancer cell lines that have various TP53 statuses using DOC treatment. The level of TS protein was significantly decreased in wild-type TP53-containing cells with DOC treatment; TS expression levels were not affected in mutant-TP53 and TP53-null cells under the same conditions. Furthermore, when the expression of TP53 was inhibited in A549 cells, the expression level of TS was increased. Our data indicated that DOC activated wild-type TP53 and suppressed TS expression under continuous DOC exposure. Therefore, the expression of TS remained at low levels in DOC-resistant A549 cancer cells. Our data revealed that for lung cancer with DOC resistance and wild-type TP53 status, the administration of PEM as a second-line agent to overcome DOC-resistance may benefit patients. PMID- 28901494 TI - Molecular mechanisms of pathogenesis in hepatocellular carcinoma revealed by RNA sequencing. AB - The present study aimed to explore the underlying molecular mechanisms of hepatocellular carcinoma (HCC). RNA-sequencing profiles GSM629264 and GSM629265, from the GSE25599 data set, were downloaded from the Gene Expression Omnibus database and processed by quality evaluation. GSM629264 and GSM629265 were from HCC and adjacent non-cancerous tissues, respectively. TopHat software was used for alignment analysis, followed by the detection of novel splicing sites. In addition, the Cufflinks software package was used to analyze gene expressions, and the Cuffdiff program was used to screen for differently expressed genes (DEGs) and differentially expressed splicing variants. Gene ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were also performed. Transcription factors (TFs) and microRNAs (miRNAs) that regulate DEGs were identified, and a protein-protein interaction (PPI) network was constructed. The hub node in the PPI network was obtained, and the TFs and miRNAs that regulated the hub node were further predicted. The quality of the sequencing data met the standards for analysis, and the clean reads were ~65%. Most sequencing reads mapped into coding sequence exons (CDS_exons), whereas other reads mapped into exon 3' untranslated regions (UTR_Exons), 5'UTR_Exons and Introns. Upregulated and downregulated DEGs between HCC and adjacent non-cancerous tissues were screened. Genes of differentially expressed splicing variants were identified, including vesicle-associated membrane protein 4, phosphatidylinositol glycan anchor biosynthesis class C, protein disulfide isomerase family A member 4 and growth arrest specific 5. Screened DEGs were enriched in the complement pathway. In the PPI network, ubiquitin C (UBC) was the hub node. UBC was predicted to be regulated by several TFs, including specificity protein 1 (SP1), FBJ murine osteosarcoma viral oncogene homolog (FOS), proto-oncogene c-JUN (JUN), FOS-like antigen 2 (FOSL2) and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), and several miRNAs, including miR-30 and miR 181. Results from the present study demonstrated that UBC, SP1, FOS, JUN, FOSL2, SMARCA4, miR-30 and miR-181 may participate in the development of HCC. PMID- 28901495 TI - Biochanin-A induces apoptosis and suppresses migration in FaDu human pharynx squamous carcinoma cells. AB - The aim of the present study was to investigate biochanin-A-induced anticancer effects and their cellular signaling pathway in FaDu pharyngeal squamous carcinoma cells. Biochanin-A induced cell death through increased cytotoxicity of FaDu cells in a dose- and time-dependent manner. The number of cells with nucleus condensation and the apoptotic population were increased in the FaDu cells stimulated with biochanin-A for 24 h. Furthermore, extrinsic apoptotic factors such as FasL and their downstream target caspase-8 were increased and activated in the FaDu cells treated with biochanin-A in a dose-dependent manner. Moreover, biochanin-A decreased the expression of intrinsic anti-apoptotic factors such as Bcl-2 and Bcl-xL, and increased the level and activation of intrinsic apoptotic factors such as Bad and caspase-9. Finally, biochanin-A induced the activation of caspase-3 and Poly(ADP ribose) polymerase (PARP) in FaDu cells. Our results suggest that biochanin-A-induced apoptosis was mediated by death receptor mediated-extrinsic and mitochondria-dependent intrinsic apoptotic signaling pathways. Biochanin-A also inhibited wound healing migration and proliferation of FaDu cells via the downregulation and inactivation of matrix metalloproteinase-2 and -9 that are mediated by the suppression of p38, mitogen activated protein kinase (MAPK), NF-kappaB and Akt cellular signaling pathways. Therefore, these data suggest that the biochanin-A may act as a potential chemotherapeutic compound to treat head and neck cancer. PMID- 28901496 TI - High CCL5 expression is associated with osteosarcoma metastasis and poor prognosis of patients with osteosarcoma. AB - Osteosarcoma is the most common primary malignant tumor of the skeletal system and is characterized by an aggressive clinical course and high metastatic potential. Regulated upon Activation Normal T cell Expressed and Secreted, also termed C-C motif chemokine ligand 5 (CCL5), is associated with metastasis and poor prognosis in various types of cancer. The aim of the current study was to investigate the association between CCL5 expression and clinicopathological features and prognosis in patients with osteosarcoma. Tissue microarrays and reverse transcription-quantitative polymerase chain reaction and immunohistochemistry were used to examine the expression of CCL5 in human osteosarcoma tissues. The prognostic value of CCL5 expression was evaluated by the Kaplan-Meier method and Cox proportional hazards regression model. The rate of high CCL5 expression was significantly higher in metastatic osteosarcomas than in osteosarcomas without metastases. The overall survival rates (P=0.001) and the metastasis-free survival rates (P<0.001) of the low CCL5 expression group were significantly higher than the CCL5 high expression group. Multivariate Cox regression analysis indicated that CCL5 expression had independent predictive value for the prognosis of patients with osteosarcoma. In conclusion, the data of the current study indicated that CCL5 may serve as a biomarker for prognosis of osteosarcoma, and may be a potential molecular target for osteosarcoma therapy. PMID- 28901497 TI - Regulation of UHRF1 by microRNA-378 modulates medulloblastoma cell proliferation and apoptosis. AB - A previous study revealed that ubiquitin-like with PHD and RING finger domains 1 (UHRF1) promoted cell proliferation and was a potential biomarker in medulloblastoma (MB). In the present study, we reported that miR-378 inhibited the expression of UHRF1 to affect the proliferation of MB through competitive binding to the same region of its 3'-UTR. We found that the expression of miR-378 was significantly downregulated in MB tissues and inversely correlated with the expression of UHRF1. Western blot analysis revealed that overexpression of miR 378 led to the suppression of UHRF1. Moreover, a dual-luciferase assay demonstrated that miR-378 negatively regulated the activity of target gene UHRF1 by binding to its 3'-UTR. An in vitro assay revealed that overexpression of miR 378 suppressed MB cell proliferation and promoted cell apoptosis. Ectopic expression of UHRF1 rescued miR-378-suppressed cell proliferation and miR-378 promoted cell apoptosis. Collectively, the present study demonstrated that miR 378 could inhibit the proliferation of MB by downregulation of UHRF1 and act as a potential therapeutic target against MB. PMID- 28901498 TI - GOLPH3 promotes cell proliferation and tumorigenicity in esophageal squamous cell carcinoma via mTOR and Wnt/beta-catenin signal activation. AB - The authors' previous study demonstrated that Golgi phosphoprotein 3 (GOLPH3) was significantly overexpressed in esophageal squamous cell carcinoma (ESCC), correlating with poor patient survival. In the present study, GOLPH3 stable overexpression and knockdown KYSE-140 cell lines were constructed. Cell proliferation, colony formation, cell cycle progression and tumorigenesis assays were performed. The results revealed that GOLPH3 promoted ESCC cell growth and proliferation. The effects of GOLPH3 on the mechanistic target of rapamycin (mTOR) and Wnt/beta-catenin signaling pathways were investigated using western blot analyis and dual-luciferase reporter assays, and were observed to be activated in cells with GOLPH3 overexpression. Furthermore, overexpression of GOLPH3 resulted in the downregulation of p21 protein, upregulation of cyclin D1 and increased retinoblastoma-associated protein phosphorylation, consequently leading to accelerated cell cycle progression. In addition, GOLPH3 knockdown resulted in reversed effects. The results of the current study suggest that GOLPH3 serves an important role in promoting tumorigenicity of ESCC via mTOR and Wnt/beta-catenin signaling pathway activation. PMID- 28901499 TI - Transfection with Livin and Survivin shRNA inhibits the growth and proliferation of non-small cell lung cancer cells. AB - Lung cancer is reported to be a major public health issue worldwide and the overall prognosis of patients remains poor. The expression levels of Livin and Survivin, of the inhibitors of apoptosis (IAP) family, are associated with prognostic significance in the majority of solid tumors. Therefore, in the presents study, short hairpin (sh)RNA expression vectors inhibiting the Livin and Survivin genes were constructed to examine the effects of the transfection of Livin shRNA and/or Survivin shRNA on the biological functions of tumor cells. The transfection efficiency was measured using fluorescence reverse transcription quantitative polymerase chain reaction and western blot analyses. The cell growth inhibition ratio was measured using a CCK assay. Cell apoptosis following transfection and in tumor tissues were measured using a TUNEL assay, and a cancer xenograft model was used to investigate the effect of Livin shRNA and/or Survivin shRNA on tumor growth. The results indicated that the mRNA and protein expression levels were suppressed following the transfection of Livin and Survivin shRNA into tumor cells (P<0.05, compared with control group). The growth of tumor cells in vivo and in vitro was significantly inhibited following transfection with Livin and Survivin shRNA, compared with that in the other groups (P<0.05). Taken together, the transfection of cells with Livin and Survivin inhibited tumor growth in vivo and in vitro, with the co-transfection of Livin and Survivin shRNA showing increased efficiency, compared with transfection of either the Livin vector or Survivin vector alone. The combined inhibition of Livin and Survivin may be a promising multitargeted gene therapeutic strategy in cancer treatment. PMID- 28901501 TI - mTOR inhibition reduces growth and adhesion of hepatocellular carcinoma cells in vitro. AB - Mechanistic target of rapamycin (mTOR) signaling is typically increased in hepatocellular carcinoma (HCC). A panel of HCC cell lines (HepG2, Hep3B and HuH6) was exposed to various concentrations of the mTOR inhibitors, everolimus and temsirolimus, in order to investigate their effects on cell growth, clonal formation, cell cycle progression, and adhesion and chemotactic migration using MTT and clonal cell growth assays, fluorometric detection of cell cycle phases and a Boyden chamber assay. In addition, integrin alpha and beta adhesion receptors were analyzed by flow cytometry and blocking studies using function blocking monoclonal antibodies were conducted to explore functional relevance. The results demonstrated that everolimus and temsirolimus significantly suppressed HCC cell growth and clonal formation, at 0.1 or 1 nM (depending on the cell line). In addition, the number of cells in G0/G1 phase was increased in response to drug treatment, whereas the number of G2/M phase cells was decreased. Drug treatment also considerably suppressed HCC cell adhesion to immobilized collagen. Integrin profiling revealed strong expression of integrin alpha1, alpha2, alpha6 and beta1 subtypes; and integrin alpha1 was upregulated in response to mTOR inhibition. Suppression of integrin alpha1 did not affect cell growth; however, it did significantly decrease adhesion and chemotaxis, with the influence on adhesion being greater than that on motility. Due to a positive association between integrin alpha1 expression and the extent of adhesion, whereby reduced receptor expression was correlated to decreased cell adhesion, it may be hypothesized that the adhesion-blocking effects of mTOR inhibitors are not associated with mechanical contact inhibition of the alpha1 receptor but with integrin alpha1-dependent suppression of oncogenic signaling, thus preventing tumor cell-matrix interaction. PMID- 28901502 TI - Harmine suppresses the proliferation and migration of human ovarian cancer cells through inhibiting ERK/CREB pathway. AB - Ovarian cancer is the most lethal gynaecological cancer and the sixth most common cause of cancer related death among Western women. Recent studies show that harmine, a small-molecular beta-carboline alkaloid present in medicinal plants, displayed obvious anticancer effects in several cancer cells. However, the effect of harmine on ovarian cancer is not well understood. In the present study, the effect of harmine on the cell proliferation and migration of ovarian cancer SKOV 3 cells and the underlying mechanism were investigated. Our results indicated that harmine significantly suppressed the proliferation of SKOV-3 cells in a dose dependent manner. Interestingly, it also inhibited the epidermal growth factor (EGF)-induced proliferation of SKOV-3 cells. Moreover, the migration of SKOV-3 cells was markedly inhibited by harmine treatment. Further study showed that harmine inhibited not only the basal phosphorylation level of extra-cellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) but also EGF-induced ERK1/2 and CREB phosphorylation. Finally, harmine significantly suppressed the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) family MMP-2, and MMP-9. In conclusion, our data revealed that harmine inhibited the proliferation and migration of SKOV-3 cells, which might be mediated by ERK/CREB pathway. These findings elucidate that harmine may act as a potential therapeutic drug for ovarian cancer treatment. PMID- 28901500 TI - Cell cycle and pluripotency: Convergence on octamer-binding transcription factor 4 (Review). AB - Embryonic stem cells (ESCs) have unlimited expansion potential and the ability to differentiate into all somatic cell types for regenerative medicine and disease model studies. Octamer-binding transcription factor 4 (OCT4), encoded by the POU domain, class 5, transcription factor 1 gene, is a transcription factor vital for maintaining ESC pluripotency and somatic reprogramming. Many studies have established that the cell cycle of ESCs is featured with an abbreviated G1 phase and a prolonged S phase. Changes in cell cycle dynamics are intimately associated with the state of ESC pluripotency, and manipulating cell-cycle regulators could enable a controlled differentiation of ESCs. The present review focused primarily on the emerging roles of OCT4 in coordinating the cell cycle progression, the maintenance of pluripotency and the glycolytic metabolism in ESCs. PMID- 28901503 TI - High glucose and high insulin conditions promote MCF-7 cell proliferation and invasion by upregulating IRS1 and activating the Ras/Raf/ERK pathway. AB - Diabetes mellitus is associated with an increased risk of breast cancer, but the molecular mechanism underlying this association remains unclear. The aim of the present study was to investigate the effect of high glucose and high insulin conditions on MCF-7 breast cancer cells and to elucidate the molecular mechanisms underlying these effects. High glucose and high insulin conditions resulted in increased viability, proliferation, and invasion in MCF-7 cells compared with normal glucose and low insulin conditions. Reverse transcription-quantitative polymerase chain reaction and western blot analyses revealed that insulin receptor substrate 1 (IRS1) was significantly upregulated following high glucose and high insulin treatment compared with normal glucose and low insulin conditions. Furthermore, high glucose and high insulin treatment increased the Ras family of proto-oncogenes (Ras) and RAF1 proto-oncogene (Raf-1) protein expression, and activated the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. These findings suggest that high glucose and high insulin conditions promoted the proliferation and invasion of MCF-7 cells by upregulating IRS1 and activating the Ras/Raf/ERK pathway. PMID- 28901504 TI - Soluble interleukin-2 receptor as a factor associated with angiogenesis in gastric cancer. AB - Angiogenesis serves a role in the growth, metastasis and prognosis of tumors. The aim of the present study was to evaluate the angiogenic ability and clinical significance of the immune biomarker soluble interleukin-2 receptor (sIL-2R) in gastric cancer (GC) patients. Serum levels of sIL-2R were measured in 35 GC patients with different stages of disease and 32 healthy individuals, and it was investigated whether the levels were associated with angiogenesis factors, including vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without recombinant human (rh)sIL-2R, VEGF and TGF-beta1 for 24 h, and then the HUVECSs were harvested to determine the degree of angiogenesis. The supernatants were also collected for VEGF and TGF-beta1 testing. Serum levels of sIL-2R were higher in GC patients than in healthy individuals, as were the levels of VEGF and TGF-beta1. In addition, serum levels of sIL-2R were positively associated with the levels of VEGF and TGF-beta1. Angiogenesis of HUVECs was also increased by rhsIL-2R pretreatment. VEGF and TGF beta1 secretion were also incre-ased in supernatants that were pretreated with rhsIL-2R. The results of the present study suggested that serum levels of sIL-2R contributes to the pathophysiology of GC progression and may be used as a prognostic biomarker for GC. PMID- 28901505 TI - SIRT1 confers protection against ischemia/reperfusion injury in cardiomyocytes via regulation of uncoupling protein 2 expression. AB - The development of a novel targeted therapy for acute myocardial infarction (AMI) remains a major hurdle in the treatment of cardiovascular disease. Previous studies indicate that mitochondrial uncoupling protein 2 (UCP-2) is involved in the progression of AMI. The present study uses lentivirus knockdown of Sirtuin 1 (SIRT1) in H9c2 cells under hypoxia conditions, and revealed that levels of SIRT1 are accompanied by the expression of UCP-2. Therefore, it was hypothesized that SIRT1 might be important in the development of myocardial infarction. The present study demonstrated that: i) exogenous expression of SIRT1 in vitro induced resistance to hypoxic injury in H9c2 cells, coinciding with a reduction in expression of UCP-2; ii) knockdown of UCP-2 conferred resistance to hypoxic injury in H9c2; iii) intraperitoneal injection of resveratrol and the resultant increase in SIRT1 levels may protect against ischemia/reperfusion injury in vivo, concomitant with decreased expression of UCP-2. These findings provide direct evidence that the SIRT1/UCP-2 axis might be important in myocardial infarction, and suggest that this axis may be a novel therapeutic target for the treatment of cardiovascular disease. PMID- 28901506 TI - Whole exome sequencing identifies FBN1 mutations in two patients with early-onset type B aortic dissection. AB - The etiology of thoracic aortic aneurysm and dissection (TAAD) is complex and heterogeneous. Emerging evidence has demonstrated that genetic causes may be a consideration in early-onset TAAD. Owing to overlapping clinical phenotypes and the genetic heterogeneity of TAAD, it is challenging for clinicians to make a molecular diagnosis of TAAD, particularly in those who present with non-specific syndromic features. In order to identify the causative mutation in two young patients with acute type B aortic dissection without syndromic features, whole exome sequencing (WES) was performed in the present study. A missense mutation (c.G6953A:p.C2318Y) and a nonsense mutation (c.C4786T:p.R1596X) were identified in the fibrillin 1 gene in patients T287 and T267, respectively. The present study emphasized the necessity of genetic testing for young patients with type B aortic dissection. WES is a timely, robust and inexpensive technique for molecular diagnosis, particularly for TAAD caused by numerous genes. Genetic diagnosis of Marfan syndrome could aid in periodic surveillance, prophylactic surgical measures, and genetic counseling. PMID- 28901507 TI - alpha7 nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway. AB - Considerable evidence has implied that alpha7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. The aim of the present study was to determine the role of endogenous alpha7nAChR signaling in tumor-associated macrophages (TAMs) in human colorectal cancer (CRC) metastasis and prognosis. alpha7nAChR expression in primary tumor cells and adjacent stroma cells especially in TAMs in 51 CRC patients was observed. Using a human monocyte THP-derived macrophages (TMs) with alpha7nAChR-siRNA knockdown (TMalpha7-/-) and a CRC cell Transwell co-culture model, the migration and invasion of two CRC cells, LoVo and SW620, were determined. Western blotting was carried out to investigate the expression of multiple molecules involved in the NF-kappaB, STAT3, PI3K signaling pathways in mimic TAMs, i.e., TMs exposed to in direct LoVo cell stimulation. A nicotinic alpha7 receptor antagonist [alpha bungarotoxin (alpha-Btx)] and three pharmaceutical inhibitors: AG490 (JAK2/STAT3 inhibitor), LY294002 (PI3K inhibitor) and Bay 11-7082 (NF-kappaB inhibitor) were applied to evaluate whether these signaling pathways were associated with the enhanced migration of CRC cells when co-cultured with alpha7nAChR knockdown TMs. The results revealed that the expression of alpha7nAChR in TAMs differed in patients. However, CRC patients who had a high incidence of hepatic metastasis showed no or low expression of alpha7nAChR in TAMs. TMs with alpha7nAChR-siRNA knockdown (TMalpha7-/-) significantly enhanced the migration and invasion of the two CRC cell lines LoVo and SW620. alpha7nAChR knockdown in TMs significantly downregulated phosphorylation of STAT3, PI3K p85 and NF-kappaB p65 after co culturing with LoVo cells. Inhibition of JAK2/STAT3 prevented the TMalpha7-/- enhanced migration of LoVo cells. alpha7nAChR expressed in TAMs in human CRC patients plays an important role in preventing metastasis and could be a prognostic marker in CRCs, which may be regulated by the JAK2/STAT3 signaling pathway. PMID- 28901508 TI - A novel method for obtaining highly enriched Schwann cell populations from mature monkey nerves based on in vitro pre-degeneration. AB - Schwann cells (SCs) are indispensable for cell therapy and tissue engineering of the peripheral nervous system. Easy access to activated, highly proliferative SCs is necessary for clinical applications. The present study developed a fast, efficient method for obtaining highly purified SCs from the peripheral nerve of a mature Rhesus monkey. The common peroneal nerves of 4-year-old Rhesus monkeys were harvested and subjected to in vitro pre-degeneration in a modified SC culture medium (SCCM). The nerve pieces were subsequently treated enzymatically to dissociate the cells and then cultured for 2 days in SCCM. Cultured cells were treated with purification medium containing Ara-C to assist in restricting the overgrowth of fibroblast-like cells, for 24 h. After another 24-h cultivation period, the cells were subsequently treated with a multiplex collagenase, which enabled SC detachment over fibroblast detachment, and thereby facilitated SC isolation. Finally, SCs were cultured in SCCM. The cell yield was determined by cell counting following enzyme digestion and SC purity was determined from the percentage of SCs with respect to the total number of cells. Following purification, 96.3+/-3.9% of cells were identified as SCs. In vitro pre degeneration in the presence of basic-fibroblast growth factor, heregulin beta1 and forskolin maximized the purity and yield of SCs that could be obtained from monkey peroneal nerves. The present study identified a novel technique that can efficiently isolate and purify SCs from mature monkey nerves based on in vitro pre-degeneration. PMID- 28901509 TI - CT45A1 siRNA silencing suppresses the proliferation, metastasis and invasion of lung cancer cells by downregulating the ERK/CREB signaling pathway. AB - The aim of the present study was to investigate the role of the cancer-testis antigen family 45 member A1 (CT45A1) in the proliferation, apoptosis, invasion and metastasis of lung cancer cells, and the associated molecular mechanisms. Western blotting determined that the expression of CT45A1 in normal lung cells was far lower than that observed in lung cancer cells. Following the transfection of CT45A1 small (or short) interfering (si)RNA and its negative control into A549 cells using Lipofectamine 2000, the CT45A1 protein and mRNA levels were determined further by western blotting and reverse transcription-polymerase chain reaction. Following CT45A1 siRNA transfection, the levels of CT45A1 in lung cancer cells were markedly reduced (P<0.01). Then, cell viability and apoptosis were investigated with a methyl thiazolyl tetrazolium assay and Annexin V FITC/propidium iodide staining, respectively. Transwell assays were employed to evaluate the migration and invasion of A549 cells. When compared with the negative control, the viability, migration and invasion of lung cancer cells treated with CT45A1 siRNA were suppressed and apoptosis was promoted (all P<0.01). In addition, the levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), survivin, matrix metalloproteinase 2 (MMP2), MMP9, extracellular signal regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (p-ERK1/2), cyclic AMP response element binding protein (CREB) and p-CREB were assessed by western blotting. Following CT45A1 silencing, the expressions of Bcl-2, survivin, MMP2, MMP9, p-ERK1/2 and p-CREB were downregulated and the expression of Bax was upregulated (all P<0.01). It was concluded that CT45A1 siRNA silencing suppressed the proliferation, metastasis and invasion of lung cancer cells by downregulating the ERK/CREB signalling pathway. PMID- 28901510 TI - Ferruginol exhibits anticancer effects in OVCAR-3 human ovary cancer cells by inducing apoptosis, inhibition of cancer cell migration and G2/M phase cell cycle arrest. AB - The primary aim of the current study was to investigate the antitumor effects of ferruginol in OVCAR-3 human ovary cancer cells. The effects of ferruginol on cell apoptosis, cell migration and cell cycle phase distribution were also evaluated. Cell cytotoxicity induced by ferruginol was determined by an MTT assay, while fluorescence microscopy and transmission electron microscopy (TEM) were performed to investigate apoptotic effects. Flow cytometry was employed to determine the effects of ferruginol on the cell cycle and an in vitro wound healing assay was performed to investigate effects on cancer cell migration. The results indicated that ferruginol inhibited the growth rate of OVACR-3 cells in a dose- and time dependent manner. When cells were treated with 20, 80 and 300 uM ferruginol, cells began to exhibit yellow fluorescence, which indicated the onset of apoptosis. TEM results demonstrated that untreated control cells exhibited intact nuclei and nucleolus. However, on treating cells with various doses of ferruginol, chromatin condensation occurred and disappearance of the nuclear envelope and formation of apoptotic bodies were also observed. The percentage of migrated cells, determined by the wound healing assay, decreased from 98.7% in control to 68.2% and 45.3 in 80 and 300 uM ferruginol-treated cells, respectively. Flow cytometry results demonstrated that ferruginol induced G2/M cell cycle arrest in OVCAR-3 cells. In conclusion, ferruginol may exhibit anticancer effects in OVCAR-3 human ovary cancer cells by inducing apoptosis, inhibiting cancer cell migration and inducing G2/M cell and may therefore prove beneficial in the treatment and management of ovarian cancer. PMID- 28901511 TI - N-acetylcysteine induces apoptosis via the mitochondria-dependent pathway but not via endoplasmic reticulum stress in H9c2 cells. AB - N-acetylcysteine (NAC), a precursor of glutathione, is a widely used thiol containing antioxidant and modulator of the intracellular redox state. Our previous study demonstrated that excess reduced glutathione (GSH) from NAC treatment paradoxically led to a reduction in glutathione redox potential, increased mitochondrial oxidation and caused cytotoxicity at lower reactive oxygen species levels in H9c2 cells. However, no detailed data are available on the molecular mechanisms of NAC-induced cytotoxicity on H9c2 cells. In the present study, it was demonstrated that NAC-induced cytotoxicity towards H9c2 cells was associated with apoptosis. The activation of caspase-9 and -3, and cleavage of procaspase-9 and -3, but not of caspase-8, were involved in NAC induced apoptosis. The dissipation of mitochondrial transmembrane potential, release of cytochrome c, translocation of B cell lymphoma-2 (Bcl-2)-associated X protein (Bax) to the mitochondria, and the increased ratio of Bax/Bcl-2 mRNA indicated that NAC treatment-induced apoptosis occurred mainly through the mitochondria-dependent pathway. Redox western blot analysis demonstrated that NAC did not disrupt the highly oxidized environment of the endoplasmic reticulum, which was indicated by maintenance of the oxidized form of protein disulfide isomerase, an essential chaperone in the formation of disulfide bond formation in the endoplasmic reticulum. In addition, no significant changes in the expression of binding immunoglobulin protein or C/EBP homologous protein were apparent in the process of NAC-induced apoptosis. Taken together, the present study demonstrated for the first time, to the best of our knowledge, that NAC induced apoptosis via the mitochondria-dependent pathway but not via endoplasmic reticulum stress in H9c2 cells, and the exogenous GSH from NAC did not alter the oxidized milieu of the endoplasmic reticulum. PMID- 28901512 TI - Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway. AB - Gamboge is the dried resin secreted by the Garcinia maingayi gambogic tree and is a substance that may be used to treat a variety of diseases, exhibits anti-tumor and detoxification effects and prevents bleeding. The primary active constituent is gambogic acid. The present study aimed to investigate the anti-inflammatory effects of gambogic acid in rheumatoid arthritis (RA) rats and to elucidate the mechanisms by which these effects occur. The swelling degree, the clinical arthritic scoring and pain threshold measurements were used to evaluate the effects of gambogic acid on RA. ELISA kits and western blot analysis were used to investigate inflammatory processes and the expression of RA-associated proteins, respectively. The present results demonstrated that gambogic acid significantly inhibited the degree of right foot swelling, increased pain thresholds and reduced clinical arthritic scores of RA rats. Treatment with gambogic acid suppressed the activities of interleukin (IL)-1beta and IL-6, promoted the protein expression of phosphorylated (p)-Akt serine/threonine kinase (Akt), p mammalian target protein of rapamycin (mTOR) and inhibited hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in RA rats. The results of the present study therefore suggest that the anti-inflammatory effects of gambogic acid in RA rats occur via regulation of the phosphoinositide 3 kinase/Akt/mTOR signaling pathway. PMID- 28901513 TI - Antitumor activity of 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2,5 cyclohexadiene-1,4-dione isolated from the aerial part of Atractylodes macrocephala in hepatocellular carcinoma. AB - 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methy l-2,5-cyclohexadiene-1,4-dione (DMD) is a compound isolated from Atractylodes macrocephala; however, its antitumor activity has not yet been investigated. Therefore, the present study aimed to investigate the antitumor activity of DMD in the H22 mouse hepatocellular carcinoma (HCC) cell line in vitro and in vivo. In the present study, the antiproliferative effects of DMD against H22 cells were evaluated using the MTT assay in vitro. Furthermore, xenograft nude mice were established to evaluate the antitumor effects of DMD on H22 cells in vivo. In addition, apoptosis of H22 cells was determined by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide staining, and western blotting was subsequently performed to examine the expression levels of proteins associated with apoptosis, and c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs). The results demonstrated that DMD exerts an antitumor effect against H22 cells in vitro and in vivo, and the underlying mechanism may be associated with mitochondria-mediated apoptosis through upregulation of cytochrome c, cleaved (c)-caspase-3, c-caspase-9, c caspase-7 and B-cell lymphoma 2 (Bcl-2)-associated X protein, and downregulation of Bcl-2. In addition, the antitumor effects of DMD against H22 cells may be also associated with the MAPK signaling pathway via increased p-JNK and reduced p ERK1/2 expression. In conclusion, the present study demonstrated the DMD exerts antitumor effects against HCC in mice and provides a scientific basis for the clinical use of DMD for the treatment of HCC. PMID- 28901514 TI - Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration resistant prostate cancer. AB - Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5-20 uM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7. PMID- 28901515 TI - Vulnerability study of myelinated and unmyelinated nerve fibers in acute ocular hypertension in rabbit. AB - In the current study, it was aimed to evaluate the changes in myelinated and unmyelinated nerve fibers in retinal ischemia-reperfusion injuries caused by acute ocular hypertension and to determine the sequence of these changes. Adult healthy New Zealand white rabbits were randomized to the hemodynamic group [n=12; used to determine the optimal intraocular pressure (IOP) for the subsequent experiments] and the hypertension group (n=6; 70-mmHg hypertension induced in one eye). IOP was adjusted using a cannula and saline. Doppler ultrasound was used to measure the velocity of the optic artery under different intraocular pressures. Immunohistochemistry for myelin basic protein (MBP) was performed. Apoptosis of retinal cells was detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay. Electron microscopy was used to investigate the changes in myelinated and unmyelinated nerve fibers. IOP of the hypertension eyes was maintained at 70.2+/-1.0 mmHg, while IOP of control eyes was 7-14 mmHg. Doppler ultrasound demonstrated an obvious decline of peak systolic velocity and an increase of resistance index of retinal bloodstream under a 70-mmHg IOP. MBP immunohistochemistry and electron microscopy demonstrated obvious injuries to the myelin fibers. TUNEL indicated a significantly higher apoptosis rate in the hypertension eyes compared with control eyes. The apoptosis rate of retinal ganglion cells and bipolar cells in unmyelinated regions was higher than in myelinated regions. In conclusion, an IOP of 70 mmHg led to incomplete retinal ischemia but was the threshold for retinal ischemia, leading to obvious injuries to the myelin fibers. PMID- 28901516 TI - Two novel peptides derived from Sinonovacula constricta inhibit the proliferation and induce apoptosis of human prostate cancer cells. AB - In China, the incidence of prostate cancer has been increasing. Toxicity, drug resistance and limited transient benefits in patients are the main problems associated with standard chemotherapeutic regimens, and new drugs are therefore required to treat prostate cancer. SCH-P9 and SCH-P10 proteins were obtained from Sinonovacula constricta hydrolysates. The amino acid sequences of SCH-P9 and SCH P10 were identified as Leu-Pro-Gly-Pro and Asp-Tyr-Val-Pro, with molecular weights of 382.46 Da and 492.53 Da, respectively. An MTT assay, annexin V fluorescein isothiocyanate (FITC) staining and cell cycle analysis were applied to identify the viability of cells, stages of apoptosis, and cell cycle distribution, respectively. SCH-P9 and SCH-P10 inhibited the growth of DU-145 and PC-3 cells in a dose- and time-dependent manner. Annexin V-FITC staining and flow cytometry analysis were employed to measure apoptosis and cell cycle arrest, respectively. SCH-P9 and SCH-P10 inhibited the growth of DU-145 cells by reducing the number of cells in G0/G1 phase, increasing the number in subG1 phase and inducing apoptosis. SCH-P9 reduced the number of PC-3 cells in subG1 and G0/G1 phases, increased the number of cells in G2/M phase and induced apoptosis. SCH P10 reduced the number of PC-3 cells in G2/M phase, increased the number of cells in G0/G1 phase and induced apoptosis. In conclusion, the results demonstrated that SCH-P9 and SCH-P10 induced apoptosis in DU-145 and PC-3 cells and may, therefore, exhibit potential for application in the treatment of prostate cancer. PMID- 28901517 TI - Cx32 inhibits TNFalpha-induced extrinsic apoptosis with and without EGFR suppression. AB - Tumor necrosis factor alpha (TNFalpha) and TNF-related apoptosis-inducing ligand (TRAIL) can trigger the extrinsic apoptosis pathway. Our previous study indicated that connexin32 (Cx32) inhibited streptonigrin-induced intrinsic apoptosis via the epidermal growth factor receptor (EGFR) pathway. However, whether Cx32 can exert effects on the extrinsic apoptosis pathway through EGFR signaling remains unclear. In the present study, we investigated the role of Cx32 in extrinsic apoptosis induced by treatment with TNFalpha + cycloheximide (CHX) or afatinib in human cervical cancer (CaCx) cells. In stable inducible Cx32-transfected HeLa cells (HeLa-Cx32), Cx32 expression was induced by treatment with doxycycline (Dox). Furthermore, C-33A cells, which natively express high levels of Cx32, were used as a cell model for knockdown of Cx32 with siRNA. To determine the non junctional function of Cx32 in apoptosis, 18alpha-glycyrrhetinic acid (18alpha GA), a gap junction intracellular communication (GJIC) inhibitor, was used. Our results showed that Cx32 could inhibit apoptosis induced by TNFalpha + afatinib with or without the GJIC inhibitor. In clinical cervical tissue samples, we found that the expression of survivin was markedly higher in CaCx than in normal cervix tissue, which was in accordance with the expression of Cx32 in our previous study. In HeLa-Cx32 cells, we also found that Cx32 upregulated the expression of Cox-2. In addition, Cx32 upregulated EGFR expression in low-density culture (lacking GJ formation). Cx32 could also promote the expression of EGFR, phospho STAT3 and phospho-ERK in HeLa-Cx32 cells following TNFalpha treatment. After knocking down Cx32 in C-33A cells, the expression levels of survivin and TNFalpha were downregulated. The present study verifies that Cx32 exerts an inhibitory effect on extrinsic apoptosis in CaCx cells, and suggests that Cx32 may regulate the progression and micro-environment of CaCx cells. PMID- 28901518 TI - Ailanthone induces G2/M cell cycle arrest and apoptosis of SGC-7901 human gastric cancer cells. AB - Ailanthone is a major quassinoid extracted from the Chinese medicinal herb Ailanthus altissima, which has been reported to exert antiproliferative effects on various cancer cells. The present study aimed to investigate the antitumor effects of ailanthone on SGC-7901 cells, and to analyze its underlying molecular mechanisms. Following treatment with ailanthone, Cell Counting kit-8 was used to detect the cytotoxic effects of ailanthone on SGC-7901 cells in vitro. The typical apoptotic morphology of SGC-7901 cells was observed by Hoechst 33258 staining. Cell cycle progression and apoptosis were measured by flow cytometry, and the protein and mRNA expression levels of Bcl-2 and Bax were analyzed by western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) respectively, in SGC-7901 cells. The results of the present study indicated that ailanthone inhibited the proliferation of SGC-7901 cells in a dose- and time-dependent manner in vitro, and also demonstrated that ailanthone induced G2/M phase cell cycle arrest and apoptosis of SGC-7901 cells. Furthermore, analysis of the underlying molecular mechanisms revealed that ailanthone downregulated the expression levels of Bcl-2, whereas the expression levels of Bax were upregulated at the protein and mRNA levels. In conclusion, ailanthone may inhibit the proliferation of SGC-7901 cells by inducing G2/M phase cell cycle arrest and apoptosis via altering the protein and mRNA expression levels of Bcl-2 and Bax in SGC-7901 cells. PMID- 28901519 TI - Salidroside, a scavenger of ROS, enhances the radioprotective effect of Ex-RAD(r) via a p53-dependent apoptotic pathway. AB - Salidroside (Sal), the predominant component of a Chinese medicinal herb, Rhodiola rosea L., has become an attractive bioagent due to its significant anti radiation, antioxidant and immune adjustment effects. We explored the radioprotective effect of Sal to ascertain whether it could enhance the anti radiation effect of ON 01210.Na (Ex-RAD(r)) in vivo and in vitro, and elucidate its underlying mechanism. Our data demonstrated that Sal inhibited radiation induced apoptosis, scavenged reactive oxygen species (ROS), and decreased the DNA damage of human umbilical vein endothelial cells (HUVECs). Sal downregulated the expression of Bax and p53 and increased the ratio of Bcl-2/Bax, which indicated that Sal inhibited the radiation-induced apoptosis through p53-dependent pathways. The radioprotection of the Sal pretreatment was also evidenced by an increasing survival rate of the mice, maintaining antioxidant enzyme levels in the liver, and accelerating hematopoietic recovery. The results suggest that Sal exhibits an excellent radioprotective effect with powerful antioxidant activity in vitro and in vivo. Sal enhanced the radioprotective effect of Ex-RAD by improving the antioxidant effect, the scavenging of ROS, by accelerating hematopoietic recovery and DNA repair as well as by regulating apoptotic and repair signaling pathways. Combined modality treatments were more effective than single-agent treatments, demonstrating the value of multiple-agent radioprotectants. PMID- 28901520 TI - Puerarin promotes the viability and differentiation of MC3T3-E1 cells by miR-204 regulated Runx2 upregulation. AB - Puerarin has attracted increasing attention because of its beneficial effects on anti-osteoporosis, but the molecular mechanisms underlying its actions on osteoblasts are not fully understood. The current study aimed to investigate the effect of puerarin on the cell viability and differentiation of mouse MC3T3-E1 osteoblast-like cells in vitro and its underlying mechanisms. The results indicated that 0.01, 0.1 and 1 mg/ml puerarin significantly promoted the viability of osteoblasts, enhanced alkaline phosphatase (ALP) activity and increased the expression of transforming growth factor-beta1, Smad2, Smad3 and Runt-related transcription factor (Runx)2. Micro (mi)RNA target prediction programs predicted that miR-204 may directly target Runx2. Following treatment with 0.1 mg/ml puerarin for 48 h, the expression level of miR-204 was downregulated. Besides, miR-204 dramatically repressed the luciferase activity of wildtype Runx2 3'-UTR transfected cells, but not that of the mutant ones. Overexpression of miR-204 in osteoblasts significantly decreased the protein expression of Runx2, while inhibition of miR-204 enhanced Runx2's expression. In addition, overexpression of miR-204 inhibited the cell viability and ALP activity of osteoblasts, while inhibition of miR-204 had the opposite effect. The results suggested that puerarin may promote MC3T3-E1 osteoblast-like cell viability and differentiation, which may be related to the downregulation of miR-204 and the following activation of Runx2. PMID- 28901521 TI - Adiponectin receptor agonist AdipoRon suppresses adipogenesis in C3H10T1/2 cells through the adenosine monophosphate-activated protein kinase signaling pathway. AB - The aim of the present study was to investigate the effects of AdipoRon, an adiponectin receptor agonist, on adipogenesis in C3H10T1/2 cells and to explore the underlying mechanisms. C3H10T1/2 cells were treated with increasing doses of AdipoRon for 8 days, and Oil Red O staining was used to assess lipid accumulation. The protein and mRNA expression levels of adipogenic transcription factors and adipocyte-specific genes were examined by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. AdipoRon treatment inhibited lipid accumulation in C3H10T1/2 cells in a dose dependent manner and significantly suppressed the expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma, CAAT/enhancer binding protein (C/EBP)-beta and C/EBPalpha. In addition, cells treated with AdipoRon exhibited a significant decrease in the expression of adipocyte-specific genes, including fatty acid binding protein 4, fatty acid synthase, leptin, adiponectin, and stearoyl-CoA desaturase-1. Notably, AdipoRon significantly increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC). The results indicated that AdipoRon exerted an inhibitory effect on adipogenesis in C3H10T1/2 cells by downregulating the expression of adipogenic transcription factors and adipocyte specific genes and by promoting the phosphorylation of AMPK and ACC, which suggested that AdipoRon may be a potential drug to prevent and treat diseases caused by abnormal adipogenesis, such as obesity. PMID- 28901522 TI - Glutathione system in Wolfram syndrome 1-deficient mice. AB - Wolfram syndrome 1 (WS) is a rare neurodegenerative disease that is caused by mutations in the Wolfram syndrome 1 (WFS1) gene, which encodes the endoplasmic reticulum (ER) glycoprotein wolframin. The pathophysiology of WS is ER stress, which is generally considered to induce oxidative stress. As WS has a well defined monogenetic origin and a model for chronic ER stress, the present study aimed to characterize how glutathione (GSH), a major intracellular antioxidant, was related to the disease and its progression. The concentration of GSH and the activities of reduction/oxidation system enzymes GSH peroxidase and GSH reductase were measured in Wfs1-deficient mice. The GSH content was lower in most of the studied tissues, and the activities of antioxidative enzymes varied between the heart, kidneys and liver tissues. The results indicated that GSH may be needed for ER stress control; however, chronic ER stress from the genetic syndrome eventually depletes the cellular GSH pool and leads to increased oxidative stress. PMID- 28901523 TI - MicroRNA-141 inhibits epithelial-mesenchymal transition, and ovarian cancer cell migration and invasion. AB - The effects of microRNA-141 (miR-141) on epithelial-mesenchymal transition (EMT), and ovarian cancer cell migration and invasion were investigated. SKOV3 cells were transfected with the miR-141 mimic (mimic group), inhibitor (inhibitor group) and nonspecific sequences (NC group), and left untransfected group (blank group). The reverse transcription-quantitative polymerase chain reaction (RT qPCR) was used to detect the expression of miR-141 in SKOV3 cell lines. Then, mRNA levels and protein expression of EMT markers were determined by RT-qPCR and western blotting, respectively. Cell proliferation was assessed using an MTT assay, followed by analysis of cell invasion and migration. SPSS software was used for statistical analysis. The results demonstrated that miR-141 expression in the mimic group was increased compared with the NC or blank group. Compared with the NC or blank group, upregulation of epithelial-cadherin (E-cadherin) and integrin-beta, and downregulation of zinc finger E-box-binding homeobox (ZEB) was observed in the mimic group. The rate of cell proliferation decreased in the mimic group and increased in the inhibitor group when compared with the NC group (P<0.05). The number of invasive cells significantly increased in the inhibitor group and decreased in the mimic group when compared with the NC group (P<0.01). Compared with the NC group, the migratory rate was decreased in the mimic group, and increased in the inhibitor group at 24 and 48 h (all P<0.01). In conclusion, overexpression of miR-141 caused upregulation of E-cadherin, inhibited cell proliferation and EMT, and decreased cell invasion and migration in the SKOV3 cell line. PMID- 28901524 TI - Synergistic protection of bone vasculature and bone mass by desferrioxamine in osteoporotic mice. AB - It has previously been demonstrated that impaired angiogenesis is associated with metabolic abnormalities in bone in addition to osteoporosis (including postmenopausal osteoporosis). Enhancing vessel formation in bone is therefore a potential clinical therapy for osteoporosis. The present study conducted an in depth investigation using desferrioxamine (DFO) in an ovariectomy (OVX)-induced osteoporotic mouse model in order to determine the time frame of alteration of bone characteristics and the therapeutic effect of DFO. It was demonstrated that OVX induced instant bone mass loss 1 week following surgery, as expected. In contrast, DFO treatment protected the mice against OVX-induced osteoporosis during the first week, however failed to achieve long-term protection at a later stage. A parallel alteration for cluster of differentiation 31/endomucin double positive vessels (type H vessels) was observed, which have previously been reported to be associated with osteogenesis. DFO administration not only partially prevented bone loss and maintained trabecular bone microarchitecture, however additionally enhanced the type H vessels during the first week post-OVX. The molecular mechanism of how DFO influences type H vessels to regulate bone metabolism needs to be further investigated. However, the findings of the present study provide preliminary evidence to support combined vascular and osseous therapies for osteoporotic patients. Pharmacotherapy may offer a novel target for improving osteoporosis by promoting type H vessel formation, which indicates potential clinical significance in the field of bone metabolism. PMID- 28901525 TI - Upregulation of MUC1 by its novel activator 14-3-3zeta promotes tumor invasion and indicates poor prognosis in lung adenocarcinoma. AB - Lung adenocarcinoma (LAC) is currently the predominant histological subtype of lung cancer. Despite recent advancement in targeted therapies, the average 5-year survival rate is only 15%, highlighting the need to identify previously unrecognized molecular events that propel cancer development. Herein, we showed knockdown of 14-3-3zeta suppresses cell proliferation, migration and invasion capability of A549 and H1299 cells. MUC1 was then identified as a novel target of 14-3-3zeta protein. Overexpression of MUC1 is found to induce epithelial mesenchymal transition and promote metastasis of lung cancer cells, while knockdown of 14-3-3zeta can completely abolish the oncogenic function of MUC1.Furthermore, we unraveled a novel mechanism that 14-3-3zeta activates NF kappaB signaling pathway, and therefore enhanced MUC1/NF-kappaB feedback loop to upregulate MUC1 expression. From a clinical point of view, we evaluated the expression of14-3-3zeta and MUC1 in GSE68465 datasets, in which high expression of14-3-3zeta and MUC1 emerged as poor prognostic factors in LAC patients. In conclusion, we provide novel evidence that 14-3-3zeta regulates MUC1 through MUC1/NF-kappaB feedback loop. 14-3-3zeta and MUC1 is a promising prognostic biomarker for lung cancer patients and therapeutic targeting of 14-3-3zeta and MUC1 may be a potential treatment option for patients with LAC. PMID- 28901526 TI - MicroRNA-214 targets Wnt3a to suppress liver cancer cell proliferation. AB - MicroRNAs (miRNAs/miRs) are crucial molecules that act as tumor suppressor genes or oncogenes in human cancer progression. The dysregulation of miRNA expression has been detected in liver cancer. The present study aimed to explore the molecular mechanisms by which miR-214 affects liver cancer cell proliferation. Reverse transcription-quantitative polymerase chain reaction was used to determine the expression of miR-214 in liver cancer cell lines and hepatocellular carcinoma (HCC) tissues. A luciferase reporter assay was performed to determine whether Wnt3a is a target gene of miR-214. Cell Counting kit-8 and cell cycle analysis were used to explore the effects of miR-214 on liver cancer cell proliferation. Immunohistochemistry was used to detect protein expression levels. Wnt3a knockdown was used to determine the function of Wnt3a in liver cancer cell proliferation. The results demonstrated that the expression levels of human miR 214 were reduced in HCC tissues and liver cancer cell lines compared with in control tissues and cells. Overexpression of miR-214 and Wnt3a silencing each inhibited liver cancer cell growth. Conversely, inhibition of miR-214 promoted liver cancer cell growth. The present study indicated that miR-214 acts as a tumor suppressor and may be considered a promising therapeutic target for the treatment of liver cancer. PMID- 28901527 TI - Hypoxia promotes migration/invasion and glycolysis in head and neck squamous cell carcinoma via an HIF-1alpha-MTDH loop. AB - Hypoxia is a hallmark of progressive cancer. Hypoxic cancer cells trigger glycolysis in response to a decreased O2 supply to meet metabolic and bioenergetic demands. Meanwhile, these responses to hypoxia and alterations of the microenvironment promote cancer cell metastasis by increasing transcription of hypoxia-inducible factor (HIF)-regulated genes. However, the detailed mechanism by which hypoxia regulates cancer cell metastasis and glycolysis remains to be investigated. In the present study, we identified that metadherin (MTDH), a multifaceted oncogene, is involved in the regulation of head and neck squamous cell carcinoma (HNSCC) metastasis and invasion under hypoxic conditions. Furthermore, the study indicated that there is a positive feedback loop between HIF-1alpha and MTDH in HNSCC cells, and that hypoxia promotes HNSCC cell metastasis and epithelial-mesenchymal transition by mediating the HIF-1alpha-MTDH loop. These findings implicate HIF-1alpha-MTDH as a promising target for anticancer drugs in solid tumors, and help to explain the pro-tumorigenic and unfavorable effect of MTDH on HNSCC observed in our previous studies. PMID- 28901528 TI - Beyond symptomatic effects: potential of donepezil as a neuroprotective agent and disease modifier in Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with neurodegenerative changes resulting clinically in progressive cognitive and functional deficits. The only therapies are the cholinesterase inhibitors donepezil, galantamine and rivastigmine and the N-methyl-D-aspartate-receptor antagonist memantine. Donepezil acts primarily on the cholinergic system as a symptomatic treatment, but it also has potential for disease modification and may reduce the rate of progression of AD. This review explores the potential for disease modifying effects of donepezil. Several neuroprotective mechanisms that are independent of cholinesterase inhibition, are suggested. Donepezil has demonstrated a range of effects, including protecting against amyloid beta, ischaemia and glutamate toxicity; slowing of progression of hippocampal atrophy; and up-regulation of nicotinic acetylcholine receptors. Clinically, early and continuous treatment with donepezil is considered to preserve cognitive function more effectively than delayed treatment. The possible neuroprotective effects of donepezil and the potential for disease pathway modification highlight the importance of early diagnosis and treatment initiation in AD. PMID- 28901529 TI - Dissecting the structure-function relationship in lysozyme domain of mycobacteriophage D29-encoded peptidoglycan hydrolase. AB - Most bacteriophages rapidly infect and kill bacteria and, therefore, qualify as the next generation therapeutics for rapidly emerging drug-resistant bacteria such as Mycobacterium tuberculosis. We have previously characterized the mycobacteriophage D29-generated endolysin, Lysin A, for its activity against mycobacteria. Here, we present a detailed characterization of the lysozyme domain (LD) of D29 Lysin A that hydrolyzes peptidoglycan of both gram-positive and gram negative bacteria with high potency. By characterizing an exhaustive LD protein variant library, we have identified critical residues important for LD activity and stability. We further complement our in vitro experiments with detailed in silico investigations. We present LD as a potent candidate for developing phage based broad-spectrum therapeutics. PMID- 28901530 TI - Metabolic orchestration of T lineage differentiation and function. AB - T cells are stimulated by the engagement of antigen, cytokine, pathogen, and hormone receptors. While research performed over many years has focused on deciphering the molecular components of these pathways, recent data underscore the importance of the metabolic environment in conditioning responses to receptor engagement. The ability of T cells to undergo a massive proliferation and cytokine secretion in response to receptor signals requires alterations to their bioenergetic homeostasis, allowing them to meet new energetic and biosynthetic demands. The metabolic reprogramming of activated T cells is regulated not only by changes in intracellular nutrient uptake and utilization but also by nutrient and oxygen concentrations in the extracellular environment. Notably, the extracellular environment can be profoundly altered by pathological conditions such as infections and tumors, thereby perturbing the metabolism and function of antigen-specific T lymphocytes. This review highlights the interplay between diverse metabolic networks and the transcriptional/epigenetic states that condition T-cell differentiation, comparing the metabolic features of T lymphocytes with other immune cells. We further address recent discoveries in the metabolic pathways that govern T-cell function in physiological and pathological conditions. PMID- 28901531 TI - Effects of mastery criterion on the emergence of derived equivalence relations. AB - In this study, we manipulated mastery criterion form (rolling or block) and stringency (across 6 or 12 trials) and measured the emergence of derived relations. College students learned neuroanatomy equivalence classes and experienced one of two rolling mastery criteria (6 or 12 consecutive correct responses) or a block mastery criterion (12 trials in a block) during training. The study found that block and rolling mastery criteria produced similar outcomes. Effectiveness was hampered when the criterion was less stringent. PMID- 28901532 TI - Cognitive functioning in children after haemorrhagic stroke. PMID- 28901533 TI - Characteristics of different mesh types for abdominal wall repair in an experimental model of peritonitis. AB - BACKGROUND: The use of synthetic mesh to repair a potentially contaminated incisional hernia may lead to higher failure rates. A biological mesh might be considered, but little is known about long-term results. Both biological and synthetic meshes were investigated in an experimental model of peritonitis to assess their characteristics in vivo. METHODS: Male Wistar rats were randomized into five groups and peritonitis was induced. A mesh was implanted after 24 h. Five meshes were investigated: PermacolTM (cross-linked collagen), StratticeTM (non-cross-linked collagen), XCM Biologic(r) (non-cross-linked collagen), Omyra(r) Mesh (condensed polytetrafluoroethylene) and ParieteneTM (polypropylene). The rats were killed after either 30, 90 or 180 days. Incorporation and shrinkage of the mesh, adhesion coverage, strength of adhesions and histology were analysed. RESULTS: Of 135 rats randomized, 18 died from peritonitis. Some 180 days after implantation, both XCM Biologic(r) and PermacolTM had significantly better incorporation than StratticeTM (P = 0.003 and P = 0.009 respectively). StratticeTM had significantly fewer adhesions than XCM Biologic(r) (P = 0.001) and PermacolTM (P = 0.020). Thirty days after implantation, PermacolTM had significantly stronger adhesions than StratticeTM (P < 0.001). Shrinkage was most prominent in XCM Biologic(r) , but no significant difference was found compared with the other meshes. Histological analysis revealed marked differences in foreign body response among all meshes. CONCLUSION: This experimental study suggested that XCM Biologic(r) was superior in terms of incorporation, macroscopic mesh infection, and histological parameters such as collagen deposition and neovascularization. There must be sufficient overlap of mesh during placement, as XCM Biologic(r) showed a high rate of shrinkage. Surgical relevance The use of synthetic mesh to repair a potentially contaminated incisional hernia is not supported unequivocally, and may lead to a higher failure rate. A biological mesh might be considered as an alternative. There are few long-term studies, as these meshes are expensive and rarely used. This study evaluated the use of biological mesh in a contaminated environment, and investigated whether there is an ideal mesh. A new non-cross linked biological mesh (XCM Biologic(r) ) was evaluated in this experiment. The new non-cross-linked biological mesh XCM Biologic(r) performed best and may be useful in patients with a potentially contaminated incisional hernia. PMID- 28901534 TI - Evaluation of the efficacy and safety of oral isotretinoin versus topical isotretinoin in the treatment of plane warts: a randomized open trial. AB - BACKGROUND: Plane warts are a common therapeutic problem. Our aim was to assess the efficacy and safety of oral versus topical isotretinoin in the treatment of plane warts. METHODS: Forty patients with multiple plane warts were randomized into two groups. Group A was treated with oral isotretinoin capsules in the dose of 0.5 mg/kg/d and Group B with topical isotretinoin 0.05% in gel formulation once daily at night. Treatment was given to the patients for 3 months or until the complete clearance of lesions, whichever was earlier. Patients with complete response were followed up monthly for 4 months to record the relapse rate. RESULTS: Results were analyzed in 16 patients of Group A and 13 patients of Group B. At the end of 3 months of therapy, 11 (69%) patients in Group A had complete remission whereas five (31%) had partial remission. In Group B, at the end of study, five (38%) patients had complete remission and six (46%) had partial remission, whereas two patients had no remission. The difference was statistically significant between two groups; P < 0.0001. The most common side effect in Group A was cheilitis. In Group B, five patients had to be dropped because they developed severe erythema and scaling. CONCLUSION: Oral isotretinoin showed better and earlier response than topical isotretinoin. Oral isotretinoin should definitely be given a trial particularly in cases of multiple facial warts before trying various destructive procedures. PMID- 28901535 TI - A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma. AB - Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework. PMID- 28901536 TI - Validation of the PedsQL Epilepsy Module: A pediatric epilepsy-specific health related quality of life measure. AB - OBJECTIVE: To validate a brief and reliable epilepsy-specific, health-related quality of life (HRQOL) measure in children with various seizure types, treatments, and demographic characteristics. METHODS: This national validation study was conducted across five epilepsy centers in the United States. Youth 5-18 years and caregivers of youth 2-18 years diagnosed with epilepsy completed the PedsQL Epilepsy Module and additional questionnaires to establish reliability and validity of the epilepsy-specific HRQOL instrument. Demographic and medical data were collected through chart reviews. Factor analysis was conducted, and internal consistency (Cronbach's alphas), test-retest reliability, and construct validity were assessed. RESULTS: Questionnaires were analyzed from 430 children with epilepsy (Mage = 9.9 years; range 2-18 years; 46% female; 62% white: non Hispanic; 76% monotherapy, 54% active seizures) and their caregivers. The final PedsQL Epilepsy Module is a 29-item measure with five subscales (i.e., Impact, Cognitive, Sleep, Executive Functioning, and Mood/Behavior) with parallel child and caregiver reports. Internal consistency coefficients ranged from 0.70-0.94. Construct validity and convergence was demonstrated in several ways, including strong relationships with seizure outcomes, antiepileptic drug (AED) side effects, and well-established measures of executive, cognitive, and emotional/behavioral functioning. SIGNIFICANCE: The PedsQL Epilepsy Module is a reliable measure of HRQOL with strong evidence of its validity across the epilepsy spectrum in both clinical and research settings. PMID- 28901538 TI - The impact of fatigue on the non-technical skills performance of critical care air ambulance clinicians. AB - BACKGROUND: The relationship between fatigue-related risk and impaired clinical performance is not entirely clear. Non-technical factors represent an important component of clinical performance and may be sensitive to the effects of fatigue. The hypothesis was that the sum score of overall non-technical performance is degraded by fatigue. METHODS: Nineteen physicians undertook two different simulated air ambulance missions, once when rested, and once when fatigued (randomised crossover design). Trained assessors blinded to participants' fatigue status performed detailed structured assessments based on expected behaviours in four non-technical skills domains: teamwork, situational awareness, task management, and decision making. Participants also provided self-ratings of their performance. The primary endpoint was the sum score of overall non-technical performance. RESULTS: The main finding, the overall non-technical skills performance rating of the clinicians, was better in rested than fatigued states (mean difference with 95% CI, 2.8 [2.2-3.4]). The findings remained consistent across individual non-technical skills domains; also when controlling for an order effect and examining the impact of a number of possible covariates. There was no difference in self-ratings of clinical performance between rested and fatigued states. CONCLUSION: Non-technical performance of critical care air transfer clinicians is degraded when they are fatigued. Fatigued clinicians may fail to recognise the degree to which their performance is compromised. These findings represent risk to clinical care quality and patient safety in the dynamic and isolated environment of air ambulance transfer. PMID- 28901537 TI - Tetrandrine antagonizes acute megakaryoblastic leukaemia growth by forcing autophagy-mediated differentiation. AB - BACKGROUND AND PURPOSE: The poor prognosis of acute megakaryoblastic leukaemia (AMKL) means there is a need to develop novel therapeutic methods to treat this condition. It was recently shown that inducing megakaryoblasts to undergo terminal differentiation is effective as a treatment for AMKL. This encouraged us to identify a compound that induces megakaryocyte differentiation, which could then act as a potent anti-leukaemia agent. EXPERIMENTAL APPROACH: The effects of tetrandrine on the expression of CD41 and cell morphology were investigated in AMKL cells. We used CRISPR/Cas9 knockout system to knock out ATG7 and verify the role of autophagy in tetrandrine-induced megakaryocyte differentiation. shNotch1 and CA-Akt were transfected into K562 cells to examine the downstream pathways of ROS signalling and the mechanistic basis of the tetrandrine-induced megakaryocyte differentiation. The anti-leukaemia effects of tetrandrine were analysed both in vitro and in vivo. KEY RESULTS: A low dose of tetrandrine induced cell cycle arrest and megakaryocyte differentiation in AMKL cells via activation of autophagy. Molecularly, we demonstrated that this effect is mediated by activation of Notch1 and Akt and subsequent accumulation of ROS. In contrast, in normal mouse fetal liver cells, although tetrandrine induced autophagy, it did not affect cell proliferation or promote megakaryocyte differentiation, suggesting a specific effect of tetrandrine in malignant megakaryoblasts. Finally, tetrandrine also showed in vivo efficacy in an AMKL xenograft mouse model. CONCLUSIONS AND IMPLICATIONS: Modulating autophagy-mediated differentiation may be a novel strategy for treating AMKL, and tetrandrine has the potential to be developed as a differentiation-inducing agent for AMKL chemotherapy. PMID- 28901539 TI - Evaluating increased effort for item disposal to improve recycling at a university. AB - An evaluation of increased response effort to dispose of items was conducted to improve recycling at a university. Signs prompting individuals to recycle and notifying them of the location of trash and recycling receptacles were posted in each phase. During the intervention, trashcans were removed from the classrooms, and one large trashcan was available in the hallway next to the recycling receptacles. Results showed that correct recycling increased, and trash left in classrooms increased initially during the second intervention phase before returning to baseline levels. PMID- 28901540 TI - Is it time to cease the single low-dose ketamine injection at induction of anesthesia? PMID- 28901541 TI - Helping parents identify their child's swallowing, feeding, and nutrition. PMID- 28901542 TI - Effects of response-contingent stimulus pairing on vocalizations of nonverbal children with autism. AB - Research on stimulus-stimulus pairing to induce novel vocalizations in nonverbal children has typically employed response-independent pairing (RIP) procedures to condition speech sounds as reinforcers. The purpose of the present study was to evaluate the effects of a response-contingent pairing (RCP) procedure on the vocalizations of three nonverbal boys diagnosed with autism spectrum disorder. During RCP, adult-delivered sounds that were either paired with a preferred item (target sounds) or not (nontarget sounds) were presented contingent on a button press response. In Experiment 1, RCP was compared with an RIP procedure, in which the timing of sound presentations was yoked to the preceding RCP session. RCP produced a greater effect on all participants' target vocalizations than RIP. Experiment 2 demonstrated the effects of differential reinforcement of the vocalizations induced in Experiment 1. The results suggest that RCP may develop vocalizations more reliably than RIP procedures. PMID- 28901544 TI - Effect of obesity on neonatal hypoglycaemia in mothers with gestational diabetes: A comparative study. AB - BACKGROUND: Rates of pre-gestational obesity and gestational diabetes mellitus (GDM) are increasing in Australia. While both are established risk factors for neonatal hypoglycaemia, the additive effect of both risks on neonatal hypoglycaemia is not well understood. AIMS: To determine the influence of obesity on neonatal hypoglycaemia among infants born to GDM mothers. The authors hypothesise the presence of a greater frequency and severity of neonatal hypoglycaemia in infants born to obese GDM women. MATERIALS AND METHODS: A cohort of 471 singleton GDM pregnancies was retrospectively studied. Women were divided into obese (body mass index (BMI) >= 30 kg/m2 ) and not-obese (BMI < 30 kg/m2 ) groups according to self-reported pre-pregnancy weight. Perinatal outcomes and details of hypoglycaemic episodes were obtained by reviewing medical records. RESULTS: Twenty-five percent (104/410) of the GDM mothers were obese, while 36% (146/410) exceeded pregnancy weight gain recommendations. GDM and obesity resulted in a greater frequency of neonatal hypoglycaemia as compared to women with GDM alone (obese 44%, not obese 34%, P = 0.046). Obesity increased the likelihood of having multiple hypoglycaemic episodes (P = 0.022). Excess weight gain increased the likelihood of the neonate requiring intravenous dextrose (P = 0.0012). No differences were found in the likelihood of nursery admissions or lowest plasma glucose levels. CONCLUSIONS: Pre-pregnancy obesity and weight gain during pregnancy above the recommended limits increased the likelihood of neonatal hypoglycaemia among infants of GDM mothers. Further studies with larger cohorts are warranted to confirm our findings. PMID- 28901545 TI - Teaching children with autism to respond to disguised mands. AB - Children with autism spectrum disorder (ASD) often have difficulty inferring the private events of others, including private verbal behavior (e.g., thoughts), private emotional responses, and private establishing operations, often referred to as "perspective taking" by the general psychology community. Children with ASD also have difficulty responding to disguised mands. Skinner's description of the "disguised mand" is verbal behavior wherein the speaker's mand directly describes neither its reinforcer nor the corresponding establishing operations. Appropriate responding to disguised mands is required for successful social interaction, making it a social skill worth teaching to children with ASD. We used a nonconcurrent multiple baseline across participants design to investigate the effects of a multiple exemplar training package consisting of rules, role play, and feedback for teaching three boys with ASD to respond to disguised mands. The intervention was effective and generalization to novel disguised mands and people was observed. PMID- 28901543 TI - Role of mHealth in overcoming the occurrence of post-stroke depression. AB - Depression associated with stroke affects roughly one-third of stroke survivors. Post-stroke depression (PSD) is thought to adversely influence functional outcome by limiting participation in rehabilitation, decreasing physical, social, and cognitive function, and affecting neuroplasticity thereby placing stroke survivors at high risk for future vascular events. PSD has also been associated with higher mortality rates after stroke. In Peru, a country where there is no national stroke program and mental health disorders are largely underdiagnosed and untreated, people with PSD are likely to be further challenged by dependency and impoverished conditions that will limit their use of ambulatory services, leading to inadequate clinical follow-up. In this scenario, mobile health (mHealth) technology offers a promising approach to extend access to high-quality and culturally tailored evidence-based psychological care to address PSD given that cell phone use, Internet connectivity, and digital health technology have met a rapid growth in the last years and thus contribute to the attainment of broader Sustainable Development Goals (SDGs). The limited evidence of the effectiveness of mHealth for PSD calls for researchers to fill a knowledge gap where Peru poses as an ideal setting because rapid expansion of digital technology and current mental healthcare reform could be leveraged to enhance post-stroke outcomes. This article proposes the rationale for a suitable evidence driven, mHealth-based, PSD self-management intervention called iMOODS Investigating the role of mHealth in overcoming occurrence of depression after stroke-that could be tested among recent stroke patients with PSD in resource constrained settings. PMID- 28901546 TI - Return of spontaneous circulation and long-term survival according to feedback provided by automated external defibrillators. AB - BACKGROUND: We aimed to investigate the effect of automated external defibrillator (AED) feedback mechanisms on survival in out-of-hospital cardiac arrest (OHCA) victims. In addition, we investigated converting rates in patients with shockable rhythms according to AED shock waveforms and energy levels. METHODS: We collected data on OHCA occurring between 2011 and 2014 in the Capital Region of Denmark where an AED was applied prior to ambulance arrival. Patient data were obtained from the Danish Cardiac Arrest Registry and medical records. AED data were retrieved from the Emergency Medical Dispatch Centre (EMDC) and information on feedback mechanisms, energy waveform and energy level was downloaded from the applied AEDs. RESULTS: A total of 196 OHCAs had an AED applied prior to ambulance arrival; 62 of these (32%) provided audio visual (AV) feedback while no feedback was provided in 134 (68%). We found no difference in return of spontaneous circulation (ROSC) at hospital arrival according to AV feedback; 34 (55%, 95% confidence interval (CI) [13-67]) vs. 72 (54%, 95% CI [45 62]), P = 1 (odds ratio (OR) 1.1, 95% CI [0.6-1.9]) or 30-day survival; 24 (39%, 95% CI [28-51]) vs. 53 (40%, 95% CI [32-49]), P = 0.88 (OR 1.1 (95% CI [0.6 2.0])). Moreover, we found no difference in converting rates among patients with initial shockable rhythm receiving one or more shocks according to AED energy waveform and energy level. CONCLUSIONS: No difference in survival after OHCA according to AED feedback mechanisms, nor any difference in converting rates according to AED waveform or energy levels was detected. PMID- 28901547 TI - Cognitive functioning following one-year natalizumab treatment: A non-randomized clinical trial. AB - OBJECTIVES: Cognitive impairment is common in multiple sclerosis (MS) and can have serious impact on social and occupational functioning. Natalizumab reduces relapse rates, magnetic resonance imaging (MRI) lesions, and progression of disability. Previous studies on cognitive functioning have not based inclusion on cognitive performance criteria. The aim of the present study was to determine any potential natalizumab-related cognitive effects on MS patients performing below normal limits on neuropsychological testing. MATERIALS AND METHODS: Patients starting natalizumab (n = 21) and a quasi-control group of stable MS patients (n = 13) on first line disease modifying treatment were included following neuropsychological assessment demonstrating subnormal cognitive performance. Assessment, using ten cognitive variables, was repeated after 12 months. Symptoms of fatigue, anxiety and depression were also examined. Raw scores on the cognitive tests were transformed into Z-scores based on published age-corrected normative data. RESULTS: Between-group analyses on difference Z-scores (baseline follow-up) yielded significant results on Paced Auditory Serial Addition Test-2 (PASAT-2) (P = .008), with the natalizumab group showing larger improvement than quasi control patients. On PASAT-2, 28,5% from the natalizumab group demonstrated >1 SD improvement, indicative of clinically meaningful change, compared with none in the quasi control group. Patients receiving natalizumab showed within-group improvements on six of the ten cognitive variables. There were no group differences in symptoms of fatigue, anxiety or depression. CONCLUSIONS: The results demonstrate improvement in information processing speed following 12 months of natalizumab treatment. The results are interpreted as reflection of anti-inflammatory properties of natalizumab rather than retest- or long-term restorative effects. PMID- 28901548 TI - Primary, congenital neuroaxonal dystrophy with peripheral nerve demyelination in Merino-Border Leicester * Polled Dorset lambs. AB - CASE REPORT: Clinicopathological features of neuroaxonal dystrophy (NAD) in newborn, Merino-Border Leicester * Polled Dorset lambs are described. The affected lambs were unable to walk at birth and microscopic examination of brainstem and spinal cord sections revealed bilaterally symmetrical accumulations of axonal swellings (spheroids), the histological hallmark of primary NAD. The neurological deficit was also exacerbated by myelin loss and secondary axonal degeneration, particularly in the spinal cord and sciatic nerves, but also, to a more limited extent, in brainstem and spinal nerves. CONCLUSIONS: Although lambs previously diagnosed with NAD have ranged in age from 2 days to 7 months, this is believed to be the first report of congenital NAD in this species. Moreover, the present cases are the only ones in which peripheral nerve demyelination has been found. PMID- 28901549 TI - Effects of red blood cell storage time on transfused patients in the ICU-protocol for a systematic review. AB - BACKGROUND: Patients in the intensive care unit (ICU) are often anaemic due to blood loss, impaired red blood cell (RBC) production and increased RBC destruction. In some studies, more than half of the patients were treated with RBC transfusion. During storage, the RBC and the storage medium undergo changes, which lead to impaired transportation and delivery of oxygen and may also promote an inflammatory response. Divergent results on the clinical consequences of storage have been reported in both observational studies and randomised trials. Therefore, we aim to gather and review the present evidence to assess the effects of shorter vs. longer storage time of transfused RBCs for ICU patients. METHODS: We will conduct a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials, and also include results of severe adverse events from large observational studies. Participants will be adult patients admitted to an ICU and treated with shorter vs. longer stored RBC units. We will systematically search the Cochrane Library, MEDLINE, Embase, BIOSIS, CINAHL and Science Citation Index for relevant literature, and we will follow the recommendation by the Cochrane Collaboration and the Preferred Reporting Items for Systemtic Review and Meta-Analysis (PRISMA)-statement. We will assess the risk of bias and random errors, and we will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the overall quality of evidence. CONCLUSION: We need a high-quality systematic review to summarise the clinical consequences of RBC storage time among ICU patients. PMID- 28901550 TI - Principles of plasticity in the developing brain. AB - : The developing brain is especially sensitive to a wide range of experiences, showing a remarkable capacity for plastic changes that influence behavioural outcomes throughout the lifetime. We review the principles that regulate this plasticity in development and consider the factors that modulate the developing brain. These include early sensory, motor, and language experience, early stress, caregiver interactions, peer interactions, psychoactive drugs, diet, microbiome, and the immune system. Emphasis is given to changes in behaviour, epigenetics, and neuronal morphology. WHAT THIS PAPER ADDS: A discussion of the surprising range of factors influencing brain development Life experiences interact resulting in a phenomenon called metaplasticity. PMID- 28901551 TI - "Train tracks" and "step ladders" on implantable cardioverter defibrillator interval plot in a patient with dual tachycardia: Putting the dots together. PMID- 28901552 TI - Improving the therapeutic relationship in inpatient psychiatric care: Assessment of the therapeutic alliance and empathy after implementing evidence-based practices resulting from participatory action research. AB - PURPOSE: To examine how evidence about the therapeutic alliance gleaned from participatory action project affected the level of this alliance and the degree of empathy of psychiatric nurses. DESIGN AND METHODS: Quasi-experimental study in two psychiatric units. In one group, evidence-based practices that affected the therapeutic alliance were implemented; in the comparison group, there was no such intervention. FINDINGS: The nurses from the intervention group improved their degree of empathy and factors such as agreement on objectives and tasks with the patient. PRACTICE IMPLICATIONS: The results confirm the possibility of measuring and improving the therapeutic relationship in psychiatric care. PMID- 28901553 TI - Total Leishmania antigens with Poly(I:C) induce Th1 protective response. AB - Our proposal was to develop a vaccine based on total Leishmania antigens (TLA) adjuvanted with polyinosinic-polycytidylic acid [Poly(I:C)] able to induce a Th1 response which can provide protection against Leishmania infection. Mice were vaccinated with two doses of TLA-Poly(I:C) administered by subcutaneous route at 3-week interval. Humoral and cellular immune responses induced by the immunization were measured. The protective efficacy of the vaccine was evaluated by challenging mice with infective promastigotes of Leishmania (Leishmania) amazonensis into the footpad. Mice vaccinated with TLA-Poly(I:C) showed a high anti-Leishmania IgG titre, as well as increased IgG1 and IgG2a subclass titres compared with mice vaccinated with the TLA alone. The high IgG2a indicated a Th1 bias response induced by the TLA-Poly(I:C) immunization. Accordingly, the cellular immune response elicited by the formulation was characterized by an increased production of IFN-gamma and no significant production of IL-4. The TLA Poly(I:C) immunization elicited good protection, which was associated with decreased footpad swelling, a lower parasite load and a reduced histopathological alteration in the footpad. Our findings demonstrate a promising vaccine against cutaneous leishmaniasis that is relatively economic and easy to develop and which should be taken into account for preventing leishmaniasis in developing countries. PMID- 28901554 TI - Perspectives of a tailored lifestyle program for people with severe mental illness receiving housing support. AB - PURPOSE: The purpose of the present study was to describe the acceptability of the lifestyle program PHYS/CAT and to get information about the tools used for assessment of functional exercise capacity, cognitive performance, and self health-related quality of life. DESIGN AND METHODS: The findings are based on focus groups and the researchers' experiences of conducting the program as well as using the assessment tools. FINDINGS: The acceptability of the program and the assessment tools was mainly satisfactory. PRACTICE IMPLICATIONS: The program with relational, educational, and supportive dimensions may be a promising tool to be integrated into daily nursing care. PMID- 28901555 TI - Dyspnea catastrophizing and neural activations during the anticipation and perception of dyspnea. AB - Dyspnea is an aversive symptom in various diseases. High levels of negative affectivity are typically associated with increased dyspnea and changes in its neural processing. Recently, more dyspnea-specific forms of negative affectivity such as dyspnea catastrophizing were suggested to contribute to increased perception of dyspnea beyond effects of rather unspecific negative affectivity such as general anxiety levels. The involved neural mechanisms have not yet been explored. Therefore, the present retrospective analysis examined the associations of dyspnea catastrophizing with neural activations during the anticipation and perception of dyspnea. Sixty-six healthy volunteers underwent 20 blocks of inspiratory resistive load breathing with parallel acquisition of fMRI data. Loads inducing either severe or mild dyspnea (dyspnea conditions) were presented in alternating order, with each condition being visually cued (anticipation conditions). Dyspnea catastrophizing and general trait anxiety were measured with the Breathlessness Catastrophizing Scale (BCS) and the State-Trait Anxiety Inventory, respectively. Correlating the BCS scores with neural activations during the perception of dyspnea yielded no significant results. However, during the anticipation of dyspnea, BCS scores correlated positively with activations of the anterior cingulate cortex (ACC), even after controlling for general anxiety levels. These activations in the ACC were not related to concurrent respiratory parameters. Results suggest that dyspnea catastrophizing in healthy volunteers is associated with stronger ACC recruitment during dyspnea anticipation. Given the established role of the ACC in processing affective states, affect regulation, and antinociception, this might reflect increased affective and/or top-down modulatory processing in individuals with higher dyspnea catastrophizing when anticipating dyspnea. PMID- 28901556 TI - Science is not just for research: More questions must be posed to the public .... PMID- 28901557 TI - Intrinsically Disordered Proteins and Desiccation Tolerance: Elucidating Functional and Mechanistic Underpinnings of Anhydrobiosis. AB - Over 300 years ago the father of microscopy, Antonie van Leeuwenhoek, observed dried rotifers (tiny animals) "coming back to life" upon rehydration. Since then, scientists have been fascinated by the enduring mystery of how certain organisms survive losing essentially drying out completely. Historically sugars, such as the disaccharide trehalose, have been viewed as major functional mediators of desiccation tolerance. However, some desiccation tolerant organisms do not produce this sugar, hinting that additional mediators, and potentially novel mechanisms exist. It has become apparent that a common theme among such organisms is the production and use of intrinsically disordered proteins (IDPs) to mediate survival in this dry state. However, the basic biology of these proteins - which unlike globular proteins lack persistent three-dimensional structure - is poorly understood, as are the functional mechanisms utilized by these enigmatic proteins that allow them to mediate desiccation tolerance. We purpose that probing the biochemical and biophysical nature of stress-related IDPs will provide mechanistic insights into these fascinating proteins. PMID- 28901558 TI - 'Things aren't so bad!': Preschoolers overpredict the emotional intensity of negative outcomes. AB - Adults often overpredict the emotional intensity of future events, but little is known about whether this 'intensity bias' is present in early childhood. We asked 48 3- to 5-year-olds to (1) predict and (2) report their emotions concerning two desirable (receiving four stickers, scoring up to two points in a ball toss) and two undesirable (receiving one sticker, scoring no points) outcomes. Children showed the intensity bias by overpredicting how negatively they would feel if they received one sticker, but not for scoring no points. We discuss how task factors (e.g., personal volition) and cognitive mechanisms (e.g., immune neglect) may influence children's tendency to show the intensity bias. Statement of contribution What is already known on this subject? Adults tend to overpredict the intensity of their emotional reactions to future events. Whether similar 'affective forecasting' errors characterize preschoolers' predictions is not known. What does this study add? We created two forecasting tasks ('sticker' and 'ball') with both desirable and undesirable outcomes. We obtained evidence for a 'negativity' but not a 'positivity' bias in children's predictions. On the sticker task, children overpredicted how badly they would feel after receiving one, versus, four stickers. PMID- 28901559 TI - Single nucleotide polymorphisms for DNA typing in the domestic horse. AB - Genetic markers are important resources for individual identification and parentage assessment. Although short tandem repeats (STRs) have been the traditional DNA marker, technological advances have led to single nucleotide polymorphisms (SNPs) becoming an attractive alternative. SNPs can be highly multiplexed and automatically scored, which allows for easier standardization and sharing among laboratories. Equine parentage is currently assessed using STRs. We obtained a publicly available SNP dataset of 729 horses representing 32 diverse breeds. A proposed set of 101 SNPs was analyzed for DNA typing suitability. The overall minor allele frequency of the panel was 0.376 (range 0.304-0.419), with per breed probability of identities ranging from 5.6 * 10-35 to 1.86 * 10-42 . When one parent was available, exclusion probabilities ranged from 0.9998 to 0.999996, although when both parents were available, all breeds had exclusion probabilities greater than 0.9999999. A set of 388 horses from 35 breeds was genotyped to evaluate marker performance on known families. The set included 107 parent-offspring pairs and 101 full trios. No horses shared identical genotypes across all markers, indicating that the selected set was sufficient for individual identification. All pairwise comparisons were classified using ISAG rules, with one or two excluding markers considered an accepted parent-offspring pair, two or three excluding markers considered doubtful and four or more excluding markers rejecting parentage. The panel had an overall accuracy of 99.9% for identifying true parent-offspring pairs. Our developed marker set is both present on current generation SNP chips and can be highly multiplexed in standalone panels and thus is a promising resource for SNP-based DNA typing. PMID- 28901560 TI - Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy-Report of 2 patients. AB - Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management. PMID- 28901561 TI - Eosinophils are rare in biopsy specimens of psoriasis vulgaris. AB - BACKGROUND: Histological features of lesional biopsies can be helpful in distinguishing psoriasis subtypes from disease mimickers. However, occasionally, classic histological features are not sufficient for distinction, and additional clues would be useful. There is a common belief that the presence of eosinophils in skin biopsies argues against psoriasis, but actual literature is scant. DESIGN: Skin biopsies with a diagnosis of psoriasis from 2013 to 2016 were reviewed. For inclusion, both histological and clinical features were required to be consistent with psoriasis. For biopsies meeting inclusion criteria, a detailed evaluation for typical histological parameters of psoriasis, as well as presence of dermal eosinophils, was performed. RESULTS: Of 85 cases meeting inclusion criteria, all had either individual or grouped intracorneal neutrophils and dilated papillary blood vessels. Diminished or complete loss of the granular cell layer was seen in 83 cases (98%), and parakeratosis was seen in 84 cases (99%). Alternatively, dermal eosinophils were seen in only 15 cases (18%). Of cases with eosinophils, none had more than 3 eosinophils upon examination of the entire dermis. Active treatment did not appear to impact presence/absence or numbers of eosinophils. CONCLUSION: Eosinophils are uncommon in psoriasis biopsies, and when present, they are found in small numbers. PMID- 28901562 TI - Involving institutionalised people with dementia in their care-planning meetings: lessons learnt by the staff. AB - BACKGROUND: Applying a person-centred care (PCC) approach is an aspiration for many services attending people with dementia (PwD). However, the implementation and assessment of PCC practices represent a challenge to health professionals. AIM: To evaluate the impact on staff of a programme aiming to involve people with dementia (PwD) in their individualised care-planning (ICP) meetings in long-term residential settings; specifically, to explore the lessons that staff perceived they had learned from the experience. METHODS: Twenty-one staff members working in residential facilities for older people were interviewed after the programme. Responses to two questions ('Do you think that your work has been affected in any way by the attendance of PwD at ICP meetings?' and 'Have you learnt something new as a result of these meetings?') were submitted to thematic analysis. RESULTS: Eighteen of the 21 participants identified at least one lesson they had learned from the experience. The lessons could be grouped under three main headings: (i) an increase in their understanding of PwD, (ii) questioning of their own care practices, and (iii) an improvement in teamwork. CONCLUSION: The involvement of PwD in ICP meetings had a positive impact on staff. They stated that the experience encouraged them to develop PCC-compatible attitudes and modify the way they treat PwD, thus improving the quality of care they deliver. The experience also seemed to empower staff (particularly the lesser trained members) and increase the cohesion of working teams. PMID- 28901563 TI - Analysis of serum levels and cutaneous expression of lipoprotein (a) in 38 patients with livedoid vasculopathy. AB - BACKGROUND: Coagulation disorders contribute to the development of livedoid vasculopathy (LV). Elevated plasma levels of lipoprotein(a) [Lp(a)] are an independent risk factor for the development of cardiovascular disease and associated with hypercoagulable states. Increased serum Lp(a) levels have been reported in patients with LV and may have an important role in the pathogenesis of LV. OBJECTIVES: To investigate Lp(a) expression in skin lesions and circulating serum Lp(a) levels in patients with LV. METHODS: Skin biopsy samples from 38 patients (27 women and 11 men) with active lesions diagnosed as LV and 9 samples of normal skin (5 women and 4 men) from control patients without LV were evaluated for skin expression of Lp(a) by immunohistochemistry. Plasma levels of Lp(a) were analyzed by immunoturbidimetry. RESULTS: We found that lesional skin in patients with LV expressed 10-fold higher Lp(a) immunostaining than controls. High plasma levels of Lp(a) were observed in LV patients. We did not find a correlation (P = .02) between expression of Lp(a) in the skin and plasma levels of Lp(a) in patients with LV. CONCLUSIONS: Increased Lp(a) expression in lesional skin of LV patients suggests the role of Lp(a) in the thrombo-occlusive vasculopathy observed in this disease. PMID- 28901564 TI - Synthesis and evaluation of 68 Ga-HBED-CC-EDBE-folate for positron-emission tomography imaging of overexpressed folate receptors on CT26 tumor cells. AB - The 68 Ga is a positron-emitting radionuclide that can be combined with bifunctional chelating agents and bioactive substances for use as positron emission tomography (PET) diagnostic agents. The HBED-CC is an acyclic chelating agent that is rapidly labeled with 68 Ga under mild conditions. To target cancer cells, bioactive substances can be conjugated to the carboxyl terminus of HBED CC. Because folic acid strongly binds to folate receptors that are overexpressed on the surfaces of many types of cancer cells, it was coupled with HBED-CC through a small polyethylene glycol-based linker (EDBE) to generate an active, receptor-selective targeting system. The HBED-CC-EDBE-folate (HCEF) precursor was readily labeled with 68 Ga in 5 minutes at room temperature (98% radiochemical yield; 99% radiochemical purity after isolation). In cellular uptake tests, higher uptakes of 68 Ga-HCEF were observed for the CT26 and KB cell lines (which express folate receptors) than for the A549 cell line (which does not). Finally, in vivo micro-PET measurements over 2 hours of binding in BALB/c mice into which CT26 tumors had been transplanted showed the selective accumulation of 68 Ga-HCEF in the folate receptor-expressing CT26 tumors. These results confirmed the potential of 68 Ga-HCEF as a PET diagnostic agent for tumors that express folate receptors. PMID- 28901565 TI - Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. AB - BACKGROUND: Advances in autoimmune hepatitis that transform current concepts of pathogenesis and management can be anticipated as products of ongoing investigations driven by unmet clinical needs and an evolving biotechnology. AIM: To describe the advances that are likely to become transformative in autoimmune hepatitis, based on the direction of current investigations. METHODS: Pertinent abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and a secondary bibliography was developed. The discovery process was repeated, and a tertiary bibliography was identified. The number of abstracts reviewed was 2830, and the number of full-length articles reviewed exceeded 150. RESULTS: Risk-laden allelic variants outside the major histocompatibility complex (rs3184504, r36000782) are being identified by genome wide association studies, and their gene products are potential therapeutic targets. Epigenetic changes associated with environmental cues can enhance the transcriptional activity of genes, and chromatin re-structuring and antagonists of noncoding molecules of ribonucleic acid are feasible interventions. The intestinal microbiome is a discovery field for microbial products and activated immune cells that may translocate to the periphery and respond to manipulation. Epidemiological studies and controlled interview-based surveys may implicate environmental and xenobiotic factors that warrant evidence-based changes in lifestyle, and site-directed molecular and cellular interventions promise to change the paradigm of treatment from one of blanket immunosuppression. CONCLUSIONS: Advances in genetics, epigenetics, pathophysiology, epidemiology, and site-directed molecular and cellular interventions constitute the next generation of transformative advances in autoimmune hepatitis. PMID- 28901566 TI - A new horizon in the prevention of the postembolization syndrome after transcatheter arterial chemoembolization for hepatocellular carcinoma. PMID- 28901567 TI - Do penile haemodynamics change in the presence of hydrogen sulphide (H2 S) donor in metabolic syndrome-induced erectile dysfunction? AB - Erectile dysfunction (ED) is defined in relation to the metabolic syndrome (metS). Hydrogen sulphide (H2 S), a gasotransmitter, has been revealed to get involved in hypertension, insulin secretion and regulation of vascular tone especially in erectile physiology. This study aimed to investigate the effect of H2 S on metS-induced ED. Animals were divided into two groups as control and metS, which were fed with standard diet or 60% high-fructose diet for 10 weeks respectively. The metS model was evaluated with biochemical analyses, waist circumference/tibia length ratio and HOMA index. Penile hemodynamic parameters were evaluated by the measurement of intracavernous pressure/mean arterial pressure ratio during cavernous nerve stimulation in the presence and absence of intracavernous injection of NaHS (100 MUg/50 MUl) and its control 0.9%NaCl (50 MUl) in both groups. H2 S levels were measured in penile tissues by methylene blue assay. H2 S levels were significantly decreased in the penile tissues of the metS group. Decreased intracavernous pressure/mean arterial pressure ratio improved after intracavernous administration of NaHS in the metS group. These results suggest the significant role of H2 S in the metS-induced erectile dysfunction that could be a new therapeutic target. PMID- 28901568 TI - Shared decision-making in the paediatric field: a literature review and concept analysis. AB - AIM: The concept of shared decision-making is poorly defined and often used interchangeably with related terms. The aim of this study was to delineate and clarify the concept of shared decision-making in the paediatric field. METHOD: Rodgers and Knafl's evolutionary concept analysis was used to delineate and clarify the concept. Following a search of the CINAHL, PubMed and MEDLINE databases and online journals between 1995 and 2016, we included a total of 42 articles that referred to shared decision-making in the paediatric field. RESULTS: The attributes included active participation of the three: parents, children and health professionals; collaborative partnership; reaching a compromise; and common goal for child's health. Antecedents were existing several options with different possible outcomes; substantial decisional conflict; recognising child's health situations that decision-making is needed; and willingness to participate in decision-making. Finally, the consequences included decreased decisional conflict; mutual empowerment; improved child health status; and improved quality of paediatric health care. CONCLUSION: This study provides a theoretical understanding of the concept of shared decision-making in the paediatric field; furthermore, by integrating this concept into paediatric practice, it may help to reduce the gap between theory and practice. The analysis could also provide nursing researchers with insight into paediatric decision making and establish a foundation to develop future interventions and situation specific theory for promoting high-quality decision-making in the paediatric field. PMID- 28901569 TI - Letter: lipid-lowering effect of tenofovir disoproxil fumarate in chronic hepatitis B-more evidence is needed. Authors' reply. PMID- 28901570 TI - Letter: Cuban immigrants to the US developing IBD have a progressive shortening of the lag between time of arrival and disease onset. Authors' reply. PMID- 28901571 TI - Letter: Cuban immigrants to the US developing IBD have a progressive shortening of the lag between time of arrival and disease onset. PMID- 28901572 TI - Letter: lipid-lowering effect of tenofovir disoproxil fumarate in chronic hepatitis B-more evidence is needed. PMID- 28901573 TI - Validation of a novel CARTOSEGTM segmentation module software for contrast enhanced computed tomography-guided radiofrequency ablation in patients with atrial fibrillation. AB - INTRODUCTION: Visualization of left atrial (LA) anatomy using image integration modules has been associated with decreased radiation exposure and improved procedural outcome when used for guidance of pulmonary vein isolation (PVI) in atrial fibrillation (AF) ablation. We evaluated the CARTOSEGTM CT Segmentation Module (Biosense Webster, Inc.) that offers a new CT-specific semiautomatic reconstruction of the atrial endocardium. METHODS: The CARTOSEGTM CT Segmentation Module software was assessed prospectively in 80 patients undergoing AF ablation. Using preprocedural contrast-enhanced computed tomography (CE-CT), cardiac chambers, coronary sinus (CS), and esophagus were semiautomatically segmented. Segmentation quality was assessed from 1 (poor) to 4 (excellent). The reconstructed structures were registered with the electroanatomic map (EAM). PVI was performed using the registered 3D images. RESULTS: Semiautomatic reconstruction of the heart chambers was successfully performed in all 80 patients with AF. CE-CT DICOM file import, semiautomatic segmentation of cardiac chambers, esophagus, and CS was performed in 185 +/- 105, 18 +/- 5, 119 +/- 47, and 69 +/- 19 seconds, respectively. Average segmentation quality was 3.9 +/- 0.2, 3.8 +/- 0.3, and 3.8 +/- 0.2 for LA, esophagus, and CS, respectively. Registration accuracy between the EAM and CE-CT-derived segmentation was 4.2 +/- 0.9 mm. Complications consisted of one perforation (1%) which required pericardiocentesis, one increased pericardial effusion treated conservatively (1%), and one early termination of ablation due to thrombus formation on the ablation sheath without TIA/stroke (1%). All targeted PVs (n = 309) were successfully isolated. CONCLUSIONS: The novel CT- CARTOSEGTM CT Segmentation Module enables a rapid and reliable semiautomatic 3D reconstruction of cardiac chambers and adjacent anatomy, which facilitates successful and safe PVI. PMID- 28901574 TI - Using a multi-feature paradigm to measure mismatch responses to minimal sound contrasts in children with cochlear implants and hearing aids. AB - Our aim was to explore whether a multi-feature paradigm (Optimum-1) for eliciting mismatch negativity (MMN) would objectively capture difficulties in perceiving small sound contrasts in children with hearing impairment (HI) listening through their hearing aids (HAs) and/or cochlear implants (CIs). Children aged 5-7 years with HAs, CIs and children with normal hearing (NH) were tested in a free-field setting using a multi-feature paradigm with deviations in pitch, intensity, gap, duration, and location. There were significant mismatch responses across all subjects that were positive (p-MMR) for the gap and pitch deviants (F(1,43) = 5.17, p = 0.028 and F(1,43) = 6.56, p = 0.014, respectively) and negative (MMN) for the duration deviant (F(1,43) = 4.74, p = 0.035). Only the intensity deviant showed a significant group interaction with MMN in the HA group and p-MMR in the CI group (F(2,43) = 3.40, p = 0.043). The p-MMR correlated negatively with age, with the strongest correlation in the NH subjects. In the CI group, the late discriminative negativity (LDN) was replaced by a late positivity with a significant group interaction for the location deviant. Children with severe HI can be assessed through their hearing device with a fast multi-feature paradigm. For further studies a multi-feature paradigm including more complex speech sounds may better capture variation in auditory processing in these children. PMID- 28901575 TI - Fuming with rage! Do members of low status groups signal anger more than members of high status groups? AB - Owuamalam, Weerabangsa, Karunagharan and Rubin found that Malaysians associate people in low status groups with anger more than their higher status counterparts: the hunchback heuristic. But is this belief accurate? Here, we propose the alternative possibility that members of low-status groups might deliberately suppress anger to counter this stigma, while members of high-status groups might disinhibit their anger to assert their superiority. To test these propositions, we manipulated undergraduate students' relative group status by leading them to believe that provocative comments about their undergraduate social identity came from a professor (low-status condition) or a junior foundation year student (high-status condition). Using eye-tracking, we then measured their gaze durations on the comments, which we used as a physiological signal of anger: dwelling (Experiment 1). Results revealed that dwelling was significantly greater in the high-status condition than in the low-status condition. Experiment 2 conceptually replicated this pattern using a self-report method and found that the suppression-disinhibition effect occurred only when reputational concerns were strong. PMID- 28901576 TI - Theory of mind in spina bifida: Relationship with intellectual and executive functioning. AB - This article investigates emotion recognition ability, a central aspect of Theory of Mind (ToM), in a group of individuals with spina bifida myelomeningocele (SBM) experiencing executive function deficits, and examine associations between emotion recognition, and intellectual and executive functioning. A total of 38 adult subjects with SBM were included in this study, participating in a randomized controlled trial evaluating the effects of a cognitive rehabilitation intervention for executive dysfunction. Reading the Mind in the Eyes Test (RMET) was used as a measure of emotion recognition, and neuropsychological tests and questionnaires were utilized as executive function measures. One third of the participants performed poorer on the emotion recognition task compared to normative data. Emotion recognition may represent an area being affected in adults with SBM, and it is related to verbal IQ. Findings also suggest that executive functions and emotion recognition ability in adults with SBM are independent. PMID- 28901577 TI - Suppression mediates the effect of 5-HTTLPR by stress interaction on depression. AB - A number of studies have shown that the presence of short (S), as opposed to long (L), allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with a higher risk for depression following exposure to stressful life events. However, many other studies failed to confirm this association. One reason for this inconsistency might be the fact that the interaction of the 5 HTTLPR polymorphism with stress may relate not to depression per se, but rather to adaptive or maladaptive emotion regulation strategies. Here we show that individuals homozygous for the long allele respond to stressful events by reappraising their emotional meaning, which may hamper the harmful effect of stress on mental health. In S genotype carriers, on the other hand, stress triggers the appearance of intrusive thoughts and vain attempts to suppress them, which in this group acts as a mediator between stress and depressive symptoms. These findings are in line with neuroimaging studies showing that 5-HTTLPR polymorphism has an effect on the connectivity among key areas involved in emotion regulation. PMID- 28901578 TI - Irritable bowel syndrome in Asia: Pathogenesis, natural history, epidemiology, and management. AB - Historically, the epidemiology of gastrointestinal diseases in Asia was different from that in Western countries. Early studies suggested a low prevalence of irritable bowel syndrome (IBS) in Asia. As the diagnosis of IBS is symptom-based and as symptom perception, expression, and interpretation are influenced by sociocultural perspectives including language, the presentation of IBS is expected to vary in different communities. Furthermore, the pathogenesis is multifactorial with psychosocial (stress, illness, behavior, and diet) and biological (infection, gut microbiota, and immune activation) variables interacting, and so, the present study can anticipate that the development of IBS will vary in different environments. In recognition of this aspect of functional gastrointestinal disorders, the recently published Rome IV documents have provided greater focus on cross-cultural factors. In this review, the present study seeks to highlight Asian perspectives by identifying historical trends and recent publications from the region and comparing these with the observations from Western societies. PMID- 28901579 TI - Formation and Photodynamic Behavior of Transition Metal Dichalcogenide Nanosheet Fullerene Inorganic/Organic Nanohybrids on Semiconducting Electrodes. AB - Composite films that consisted of C60 and well-exfoliated nanosheets of transition metal dichalcogenides (TMDs), such as MoS2 or WS2 , with a bulk heterojunction structure were easily fabricated onto a semiconducting SnO2 electrode via a two-step methodology: self-assembly into their composite aggregates by injection of a poor solvent into a good solvent with the dispersion, and subsequent electrophoretic deposition. Upon photoexcitation, the composites on SnO2 exhibited enhanced transient conductivity in comparison with single components of TMDs or C60 , which demonstrates that the bulk heterojunction nanostructure of TMD and C60 promoted the charge separation (CS). In addition, the decoration of the TMD nanosheets with C60 hindered the undesirable charge recombination (CR) between an electron in SnO2 and a hole in the TMD nanosheets. Owing to the accelerated CS and suppressed CR, photoelectrochemical devices based on the MoS2 -C60 and WS2 -C60 composites achieved remarkably improved incident photon-to-current efficiencies (IPCEs) as compared with the single-component films. Despite more suppressed CR in WS2 -C60 than MoS2 -C60 , the IPCE value of the device with WS2 -C60 was smaller than that with MoS2 -C60 owing to its inhomogeneous film structure. PMID- 28901580 TI - Feeding live invertebrate prey in zoos and aquaria: Are there welfare concerns? AB - Invertebrates constitute more than 90% of all species on earth, however, as a rule, humans do not regard invertebrates as creatures that can suffer and they are generally seen as creatures that should be eliminated. As a result, the importance of their welfare may be grossly unappreciated. For instance, the feeding of live food is often viewed as a good method of enrichment and invertebrates are commonly used as live prey in many zoological facilities. As a result, zoos may send mixed messages to their patrons in that welfare is considered only for the invertebrates that are part of their zoological collection and not necessarily for the invertebrates used as feed. Research indicates that many invertebrates possess nociceptors, opioid receptors, and demonstrate behavioral responses indicative of pain sensation. In addition, in some taxa, there may be evidence of higher cognitive functions such as emotions and learning, although studies in this area of research are preliminary and sparse. Therefore, the possibility for suffering exists in many invertebrate species and as such, zoological facilities have an ethical responsibility to take their welfare into consideration. This paper discusses the current research regarding invertebrates' capacity for suffering and discusses methods facilities can use to improve the welfare of their invertebrate live prey. PMID- 28901581 TI - Hybrid Copper-Nanowire-Reduced-Graphene-Oxide Coatings: A "Green Solution" Toward Highly Transparent, Highly Conductive, and Flexible Electrodes for (Opto)Electronics. AB - This study reports a novel green chemistry approach to assemble copper nanowires/reduced-graphene-oxide hybrid coatings onto inorganic and organic supports. Such films are robust and combine sheet resistances (<30 Omega sq-1 ) and transparencies in the visible region (transmittance > 70%) that are rivalling those of indium-tin oxide. These electrodes are suitable for flexible electronic applications as they show a sheet resistance change of <4% after 10 000 bending cycles at a bending radius of 1.0 cm, when supported on polyethylene terephthalate foils. Significantly, the wet-chemistry method involves the preparation of dispersions in environmentally friendly solvents and avoids the use of harmful reagents. Such inks are processed at room temperature on a wide variety of surfaces by spray coating. As a proof-of-concept, this study demonstrates the successful use of such coatings as electrodes in high performance electrochromic devices. The robustness of the electrodes is demonstrated by performing several tens of thousands of cycles of device operation. These unique conducting coatings hold potential for being exploited as transparent electrodes in numerous optoelectronic applications such as solar cells, light-emitting diodes, and displays. PMID- 28901582 TI - Prospective evaluation on the effect of interobserver variability of digital rectal examination on the performance of the Rotterdam Prostate Cancer Risk Calculator. AB - OBJECTIVES: To assess the level of agreement between digital rectal examination findings of two urologists and its effect on risk prediction using the digital rectal examination-based Rotterdam Prostate Cancer Risk Calculator. METHODS: The study sample consisted of a prospective cohort of asymptomatic unscreened men with prostate-specific antigen <=50.0 ng/mL and transrectal ultrasound volume <=110 mL who underwent transrectal ultrasound-guided prostate biopsy. Both urologists' digital rectal examination findings were graded normal or abnormal (nodularity and/or induration), and volume classified as 25, 40 or 60 mL, according to the risk calculator algorithm. Interrater agreement analysis using Cohen's kappa (kappa) statistic was carried out to determine consistency of digital rectal examination outcome and volume assessment. Receiver operating characteristic curve analysis and calibration plots were constructed to determine the effect of interrater differences. Decision curve analysis was applied to evaluate the clinical usefulness of the model. RESULTS: Of the 241 men included in the study, 41% (n = 98) had prostate cancer (81 were clinically significant, i.e. Gleason >=3 + 4). There was substantial agreement in the digital rectal examination (abnormal/normal; kappa = 0.78; P < 0.001) and volume estimation (kappa = 0.79; P < 0.001). Receiver operating characteristic analyses showed good discrimination (0.75-0.78) and were comparable for both urologists. In the high risk cohort, at a probability threshold of 25%, the risk calculator reduced the prostate biopsy rate by 9%, without missing cancers. CONCLUSIONS: Slight differences in digital rectal examination findings seem to have very limited impact on the performance of the Rotterdam Prostate Cancer Risk Calculator. Therefore, this can be considered a useful prostate biopsy outcome prediction tool. PMID- 28901583 TI - Improved protein contact predictions with the MetaPSICOV2 server in CASP12. AB - In this paper, we present the results for the MetaPSICOV2 contact prediction server in the CASP12 community experiment (http://predictioncenter.org). Over the 35 assessed Free Modelling target domains the MetaPSICOV2 server achieved a mean precision of 43.27%, a substantial increase relative to the server's performance in the CASP11 experiment. In the following paper, we discuss improvements to the MetaPSICOV2 server, covering both changes to the neural network and attempts to integrate contact predictions on a domain basis into the prediction pipeline. We also discuss some limitations in the CASP12 assessment which may have overestimated the performance of our method. PMID- 28901585 TI - Nutritional support in paediatric Crohn's disease: outcome at 12 months. AB - AIM: Paediatric Crohn's disease (CD) is associated with growth delay and poor nutritional status. Maintenance enteral nutrition (MEN) supplementation is a potential adjunct to improve growth/prolong remission. METHODS: Newly diagnosed CD patients were identified. Anthropometry, treatments and outcomes were collected for 12 months following diagnosis. Data are presented as medians. RESULTS: A total of 102 patients were identified (age = 13 years, 76% male), 58 (57%) completed exclusive enteral nutrition (EEN) as induction therapy, and 77 (75%) entered clinical remission. Following induction, 58 (57%) of all patients continued MEN and 44 (43%) consumed normal diet (ND). BMI Z-score increased (diagnosis-12 months) for EEN (-1.41 to -0.21 (p = <0.0001)) and steroid groups ( 0.97 to -0.11 (p = 0.001)). BMI Z-score increased (post induction - 12 months) for MEN (-0.62 to -0.44 (p = 0.04)) but not ND (-0.33 to -0.4 (p = 0.79)). Height Z-score did not increase for any treatment group over 12 months. MEN and ND group relapse rates were similar at six months, MEN = 21/58 (36%); ND = 21/44 (48%) (p = 0.24) and 12 months, MEN = 24/58 (41%); ND = 13/44 (30%) (p = 0.22). Fewer patients treated with EEN then MEN relapsed less than six months, 14 of 43 (33%), compared to patients treated with steroids then ND 16/29 (55%) (p = 0.09). CONCLUSION: BMI Z-score increased but height Z-score remained unchanged over 12 months for the MEN group. Use of MEN was not associated with prolonged time to relapse. Prospective studies are required to examine the utility of MEN. PMID- 28901586 TI - Long-term effects of cardiac resynchronization therapy on electrical remodeling in heart failure-A prospective study. AB - INTRODUCTION: Effects of cardiac resynchronization therapy (CRT) on arrhythmogenicity and sudden death have not been fully ascertained. CRT has been shown to increase transmural dispersion of repolarization (TDR) immediately on implantation, which may favorably remodel on long-term follow-up. However, such a hypothesis has not been prospectively evaluated. METHODS AND RESULTS: We included 35 consecutive patients who underwent CRT implantation between September 2013 and August 2014 (mean age 56.8 +/- 11.09 years; 71.43% males). QT and Tpeak-Tend (Tp e) intervals were measured during endocardial (RVendoP), epicardial (LVepiP), and biventricular pacing (BiVP) at CRT implantation and 1-year follow-up. Compared to RVendoP (130.41 +/- 16.75 ms), Tp-e was significantly prolonged during BiVP (142.06 +/- 21.98 ms; P < 0.001) and LVepiP (183.45 +/- 27.87 ms; P < 0.001) at baseline. There was a significant decrease in Tp-e during BiVP on follow-up (117.93 +/- 15.03 ms; P < 0.001). High responders had significantly lower Tp-e at 1 year compared to low responders (113.16 +/- 14.3 ms vs 129.59 +/- 9.75 ms, P = 0.004). Tp-e at 1 year had strong negative correlation with reduction in LV end systolic volumes (r = - 0.51; P = 0.003). Seven patients with sustained ventricular arrhythmias during follow-up had significantly longer baseline Tp-e compared to those without arrhythmias (158.19 +/- 17.59 ms vs 139.72 +/- 20.94 ms, P = 0.043). A baseline Tp-e value of >= 148 ms had a specificity of 75% and sensitivity of 71% to predict ventricular arrhythmias. CONCLUSIONS: Baseline TDR is greater during BiVP and LV epiP compared with RVendoP in patients with heart failure. However, BiVP causes a significant reduction in TDR reflective of reverse electrical remodeling on long-term follow-up. PMID- 28901584 TI - The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development. AB - The primary cilium is a solitary, antenna-like sensory organelle with many important roles in cartilage and bone development, maintenance, and function. The primary cilium's potential role as a signaling nexus in the growth plate makes it an attractive therapeutic target for diseases and disorders associated with bone development and maintenance. Many signaling pathways that are mediated by the cilium-such as Hh, Wnt, Ihh/PTHrP, TGFbeta, BMP, FGF, and Notch-are also known to influence endochondral ossification, primarily by directing growth plate formation and chondrocyte behavior. Although a few studies have demonstrated that these signaling pathways can be directly tied to the primary cilium, many pathways have yet to be evaluated in context of the cilium. This review serves to bridge this knowledge gap in the literature, as well as discuss the cilium's importance in the growth plate's ability to sense and respond to chemical and mechanical stimuli. Furthermore, we explore the importance of using the appropriate mechanism to study the cilium in vivo and suggest IFT88 deletion is the best available technique. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:533-545, 2018. PMID- 28901587 TI - Serum estradiol and progesterone profiles during estrus, pseudopregnancy, and active gestation in Steller sea lions. AB - While the proximate driver behind the decline of the Western stock of Steller sea lions (Eumetopias jubatus, >80% since 1970s) is likely multifactorial, the population reduction may have been powered by a decrease in fecundity. A harvest of Steller sea lions in the 1970s and 80s revealed a 30% reduction in the proportion of pregnant females from early (October-November) to late gestation (April-May). Identification and quantification of these reproductive failures are difficult when we lack species-specific data on endocrinology associated with discrete stages of the reproductive cycle (i.e., estrus, implantation, and gestation). We tracked changes in serum estradiol and progesterone in three adult female Steller sea lions from 2011 to 2015. In all years and most females, a discrete increase in estradiol was observed during the breeding season (June August), indicative of estrus. Estradiol concentrations from October to May in a pregnant female compared to her corresponding values when non-pregnant did not consistently differ through gestation. An elevation in progesterone was observed in all females and all years beginning approximately in June and lasting through November. This likely results from progesterone production by the corpus luteum in both pregnant and pseudopregnant females. Serum progesterone shows promise as a diagnostic tool to identify pregnancy during months 3-5 (December-February) of the 8-month active gestation following embryonic implantation. This study provides ranges of key hormones during estrus, embryonic diapause/pseudopregnancy, and gestation in pregnant and non-pregnant females for studying reproduction in Steller sea lions. PMID- 28901588 TI - Graphene in the Design and Engineering of Next-Generation Neural Interfaces. AB - Neural interfaces are becoming a powerful toolkit for clinical interventions requiring stimulation and/or recording of the electrical activity of the nervous system. Active implantable devices offer a promising approach for the treatment of various diseases affecting the central or peripheral nervous systems by electrically stimulating different neuronal structures. All currently used neural interface devices are designed to perform a single function: either record activity or electrically stimulate tissue. Because of their electrical and electrochemical performance and their suitability for integration into flexible devices, graphene-based materials constitute a versatile platform that could help address many of the current challenges in neural interface design. Here, how graphene and other 2D materials possess an array of properties that can enable enhanced functional capabilities for neural interfaces is illustrated. It is emphasized that the technological challenges are similar for all alternative types of materials used in the engineering of neural interface devices, each offering a unique set of advantages and limitations. Graphene and 2D materials can indeed play a commanding role in the efforts toward wider clinical adoption of bioelectronics and electroceuticals. PMID- 28901589 TI - The SubCons webserver: A user friendly web interface for state-of-the-art subcellular localization prediction. AB - SubCons is a recently developed method that predicts the subcellular localization of a protein. It combines predictions from four predictors using a Random Forest classifier. Here, we present the user-friendly web-interface implementation of SubCons. Starting from a protein sequence, the server rapidly predicts the subcellular localizations of an individual protein. In addition, the server accepts the submission of sets of proteins either by uploading the files or programmatically by using command line WSDL API scripts. This makes SubCons ideal for proteome wide analyses allowing the user to scan a whole proteome in few days. From the web page, it is also possible to download precalculated predictions for several eukaryotic organisms. To evaluate the performance of SubCons we present a benchmark of LocTree3 and SubCons using two recent mass spectrometry based datasets of mouse and drosophila proteins. The server is available at http://subcons.bioinfo.se/. PMID- 28901590 TI - The wear and tear on health: What is the role of occupation? AB - Health is well known to show a clear gradient by occupation. Although it may appear evident that occupation can affect health, there are multiple possible sources of selection that can generate a strong association, other than simply a causal effect of occupation on health. We link job characteristics to German panel data spanning 29 years to characterize occupations by their physical and psychosocial burden. Employing a dynamic model to control for factors that simultaneously affect health and selection into occupation, we find that selection into occupation accounts for at least 60% of the association. The effects of occupational characteristics such as physical strain and low job control are negative and increase with age: late-career exposure to 1 year of high physical strain and low job control is comparable to the average health decline from ageing 16 and 6 months, respectively. PMID- 28901591 TI - Evaluation of the correlation between Scoring Feline Allergic Dermatitis and Feline Extent and Severity Index and skin hydration in atopic cats. AB - BACKGROUND: Evaluation of the severity of clinical signs of cats with allergic skin diseases has used two scoring systems: Scoring Feline Allergic Dermatitis (SCORFAD) and the Feline Extent and Severity Index (FeDESI). The integrity of the cutaneous barrier can also be evaluated by measuring skin hydration. A correlation between the clinical score and skin hydration has been observed in humans and dogs with atopic dermatitis (AD). HYPOTHESIS: To demonstrate a correlation between the clinical score and skin hydration of cats affected with presumed AD. ANIMALS: European short hair cats (n = 18): 11 females and seven males with a confirmed diagnosis of AD. METHODS: SCORFAD and FeDESI scores were calculated and the measurements of skin hydration were assessed from seven body sites using corneometry. The correlation between the SCORFAD and FeDESI systems and skin hydration of each site, and the average skin hydration was calculated. RESULTS: There was a positive correlation between the SCORFAD score and skin hydration for the axilla, thorax and forelimb; for FeDESI and axilla and lumbar sites. There was a negative correlation between the FeDESI and skin hydration for the pinna (r = -0.47). CONCLUSIONS AND CLINICAL IMPORTANCE: Measurements of skin hydration could be a useful tool for the evaluation of allergic cats. There is limited evidence of any useful correlation between clinical scoring systems and measurements of hydration. The pinna may be a suitable region for the assessment of skin barrier function in normal and allergic cats. PMID- 28901592 TI - Child stunting is associated with weaker human capital among native Amazonians. AB - OBJECTIVES: We assessed associations between child stunting, recovery, and faltering with schooling and human capital skills in a native Amazonian society of horticulturalists-foragers (Tsimane'). METHODS: We used cross-sectional data (2008) from 1262 children aged 6 to 16 years in 53 villages to assess contemporaneous associations between three height categories: stunted (height-for age Z score, HAZ<-2), moderately stunted (-2 <= HAZ<=-1), and nonstunted (HAZ> 1), and three categories of human capital: completed grades of schooling, test based academic skills (math, reading, writing), and local plant knowledge. We used annual longitudinal data (2002-2010) from all children (n = 853) in 13 villages to estimate the association between changes in height categories between the first and last years of measure and schooling and academic skills. RESULTS: Stunting was associated with 0.4 fewer completed grades of schooling (~24% less) and with 13-15% lower probability of showing any writing or math skills. Moderate stunting was associated with ~20% lower scores in local plant knowledge and 9% lower probability of showing writing skills, but was not associated with schooling or math and writing skills. Compared with nonstunted children, children who became stunted had 18-21% and 15-21% lower probabilities of showing math and writing skills, and stunted children had 0.4 fewer completed grades of schooling. Stunted children who recovered showed human capital outcomes that were indistinguishable from nonstunted children. CONCLUSIONS: The results confirm adverse associations between child stunting and human capital skills. Predictors of growth recovery and faltering can affect human capital outcomes, even in a remote, economically self-sufficient society. PMID- 28901594 TI - Quantitative evaluation of breast cancer response to neoadjuvant chemotherapy by diffusion tensor imaging: Initial results. AB - BACKGROUND: Diffusion tensor imaging (DTI) yields several parameters that have not been tested in response evaluation to neoadjuvant chemotherapy (NAC). PURPOSE: To evaluate and compare in reference to histopathology findings the ability of DTI and dynamic contrast-enhanced (DCE) MRI to monitor response to NAC. STUDY TYPE: Retrospective. POPULATION: Twenty patients treated with neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 1.5T MRI axial, bilateral T2 weighted, DTI, and DCE-MRI. ASSESSMENT: A standardized blinded image analysis at pixel resolution generated color-coded maps of DTI and DCE parameters STATISTICAL TESTS: Pearson's correlation analysis and Bland-Altman plots of the DTI and DCE size changes and of the pathological final residual tumor diameter and DCE or DTI final diameter, from pre- to post-NAC. Spearman coefficient of rank correlation between the DTI and DCE size changes from pre- to post-NAC and Miller and Payne (M&P) pathological response grading. Receiver operating characteristic curve analyses to differentiate between responders to nonresponders on the basis of the DTI and DCE percent size changes and the changes in DTI parameters. RESULTS: DTI and DCE changes in the cancers' diameter and volume from pre- to post-NAC exhibited high and significant Pearson correlation (r = 0.82 P = 1.2 * 10-5 ). The DTI volume changes exhibited a significant Spearman coefficient rank correlation (0.68, P = 0.001) with the pathological M&P grading and differentiated between responders and nonresponders with area-under-the-curve (AUC) of 0.83 +/- 0.10. A similar AUC for differentiating responders from nonresponders was exhibited by the changes in the highest diffusion coefficient (0.84 +/- 0.11) and the mean diffusivity (0.83 +/- 0.11). The DTI residual-tumor diameter showed a high and significant Pearson correlation (r = 0.87 P = 1.2 * 10 6 ) to pathology tumor diameter. DATA CONCLUSION: DTI monitors changes in cancer size and diffusion tensor parameters in response to NAC with an accuracy equivalent to that of DCE, enabling differentiation of responders from nonresponders and assessment of residual tumor size in high congruence with pathology. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1080-1090. PMID- 28901593 TI - Interactive comparison and remediation of collections of macromolecular structures. AB - Often similar structures need to be compared to reveal local differences throughout the entire model or between related copies within the model. Therefore, a program to compare multiple structures and enable correction any differences not supported by the density map was written within the Phenix framework (Adams et al., Acta Cryst 2010; D66:213-221). This program, called Structure Comparison, can also be used for structures with multiple copies of the same protein chain in the asymmetric unit, that is, as a result of non crystallographic symmetry (NCS). Structure Comparison was designed to interface with Coot(Emsley et al., Acta Cryst 2010; D66:486-501) and PyMOL(DeLano, PyMOL 0.99; 2002) to facilitate comparison of large numbers of related structures. Structure Comparison analyzes collections of protein structures using several metrics, such as the rotamer conformation of equivalent residues, displays the results in tabular form and allows superimposed protein chains and density maps to be quickly inspected and edited (via the tools in Coot) for consistency, completeness and correctness. PMID- 28901595 TI - Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum. AB - BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult onset isolated dystonia. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28901596 TI - Merging arts and bioethics: An interdisciplinary experiment in cultural and scientific mediation. AB - How to engage the public in a reflection on the most pressing ethical issues of our time? What if part of the solution lies in adopting an interdisciplinary and collaborative strategy to shed light on critical issues in bioethics? An example is Art + Bioethique, an innovative project that brought together bioethicists, art historians and artists with the aim of expressing bioethics through arts in order to convey the "sensitive" aspect of many health ethics issues. The aim of this project was threefold: 1) to identify and characterize mechanisms for the meeting of arts and bioethics; 2) to experiment with and co-construct a dialogue between arts and bioethics; and 3) to initiate a public discussion on bioethical issues through the blending of arts and bioethics. In connection with an exhibition held in March 2016 at the Espace Projet, a non-profit art space in Montreal (Canada), the project developed a platform that combined artworks, essays and cultural & scientific mediation activities related to the work of six duos of young bioethics researchers and emerging artists. Each duo worked on a variety of issues, such as the social inclusion of disabled people, the challenges of practical applications of nanomedicine and regenerative medicine, and a holistic approach to contemporary diseases. This project, which succeeded in stimulating an interdisciplinary dialogue and collaboration between bioethics and arts, is an example of an innovative approach to knowledge transfer that can move bioethics reflection into the public space. PMID- 28901597 TI - The limits of the treatment-enhancement distinction as a guide to public policy. AB - Many believe that the treatment-enhancement distinction (TED) marks an important ethical boundary that we should use to shape public policy on biomedical interventions. A common justification for this purported normative force appeals to the idea that, whereas treatments respond to genuine medical needs, (most) enhancements can only satisfy mere preferences or "expensive tastes". This article offers a critique of that justification, while still accepting the TED as a conceptual tool, as well as some of the key ethical axioms endorsed by its proponents. I begin by laying out the TED, the practical implications that tend to be drawn from it, and the justification just sketched for these implications. Using examples drawn from preventive medicine, biomedical technology, and other categories of biomedical interventions, I then go on to challenge both the presupposition of a fundamental dichotomy between treatments and enhancements, and the assumption that enhancements - barring rare exceptions - cannot serve legitimate medical needs. Finally, I consider some ways in which supporters of the TED might try re-formulating the distinction to blunt the force of my critique. I conclude that such a move cannot fully succeed, and that while the TED does have some degree of normative force, it nevertheless cannot play the role that its advocates expect from it. Seeking to justify a general presumption against enhancements based on the rationale I critique here would mean ignoring their various potential benefits, including medical or therapeutic, and would reflect a prejudice - which I refer to as "treatment fetishism". PMID- 28901598 TI - Public health agencies' obligations and the case of Zika. AB - This article focuses on the initial reactions to the Zika epidemic by national and international public health agencies. It presents and analyzes some responses public officials made about sexual and reproductive health at the inception of the epidemic. It also describes the different challenges and obligations faced by local and international public health agencies, as these have not been clearly outlined. The article argues that these agencies have different obligations and should fulfill them despite existing obstacles. While international agencies should honor their leadership role and make recommendations at a meta-level, local agencies should provide, in the case of Zika, a framework for empowerment and grant women the freedom to achieve sexual and reproductive health so that they can avoid the consequences of this epidemic. PMID- 28901599 TI - Balancing bioethics by sensing the aesthetic. AB - This article is critical of "bioethics" as it is widely understood and taught, noting in particular an emphasis given to philosophical justification, reason and rationality. It is proposed that "balancing" bioethics be achieved by giving greater weight to practice and the aesthetic: Defined in terms of sensory perception, emotion and feeling. Each of those three elements is elaborated as a non-cognitive capacity and, when taken together, comprise aesthetic sensitivity and responsiveness. This is to recognise the aesthetic as a productive element in bioethics as practice. Contributions from the philosophy of art and aesthetics are drawn into the discussion to bring depth to an understanding of "the aesthetic". This approach is buttressed by philosophers - including Foucault and 18th century German philosophers (in particular Kant) - who recognized a link between ethics and aesthetics. The article aims to give substance to a claim that bioethics necessarily comprises a cognitive component, relating to reason, and a non-cognitive component that draws on aesthetic sensibility and relates to practice. A number of advantages of bioethics, understood to explicitly acknowledge the aesthetic, are proffered. Having defined bioethics in conventional terms, there is discussion of the extent to which other approaches to bioethics (including casuistry, virtue ethics, and narrative ethics) recognize aesthetic sensitivity in their practice. It is apparent that they do so to varying extents although not always explicitly. By examining this aspect of applied ethics, the paper aims to draw attention to aesthetic sensitivity and responsiveness as integral to ethical and effective health care. PMID- 28901600 TI - Ethical issues raised by thyroid cancer overdiagnosis: A matter for public health? AB - Current practices of identifying and treating small indolent thyroid cancers constitute an important but in some ways unusual form of overdiagnosis. Overdiagnosis refers to diagnoses that generally harm rather than benefit patients, primarily because the diagnosed condition is not a harmful form of disease. Patients who are overdiagnosed with thyroid cancer are harmed by the psycho-social impact of a cancer diagnosis, as well as treatment interventions such partial or total thyroidectomy, lifelong thyroid replacement hormone, monitoring, surgical complications and other side effects. These harms seem to outweigh any putative benefit of knowing about a cancer that would not have caused problems if left undiscovered. In addition to harms to patients, thyroid cancer overdiagnosis leads to significant opportunity costs at a societal level, due to costs of diagnosis and treatment. Unlike many other overdiagnosed cancers, accurate risk stratification is possible with thyroid cancer. At the individual patient level, use of this risk information might support informed choice and/or shared decision-making, as mandated by clinical ethics frameworks. And this approach might, to some extent, help to reduce rates of diagnosis and intervention. In practice, however, it is unlikely to stem the rising incidence and associated harms and costs of overdiagnosed thyroid cancer, especially in situations where health professionals have conflicts of interest. We argue in this article that thyroid cancer overdiagnosis may be usefully understood as a public health problem, and that some public health approaches will be readily justifiable and are more likely to be effective in minimising its harms. PMID- 28901601 TI - Family interests and medical decisions for children. AB - Medical decisions for children are usually justified by the claim that they are in a child's best interests. More recently, following criticisms of the best interests standard, some advocate that the family's interests should influence medical decisions for children, although what is meant by family interests is often not made clear. I argue that at least two senses of family interests may be discerned. There is a 'weak' sense (as the amalgamated interests of family members) of family interests and a 'strong' sense (that the family itself has interests over and above the interests of individuals). I contend that there are problems with both approaches in making medical decisions for children but that the weak sense is more plausible. Despite this, I argue that claims for family interests are not helpful in making medical decisions for children. PMID- 28901602 TI - IAB Presidential address: "Searching for Justice". PMID- 28901603 TI - Fertility, immigration, and the fight against climate change. AB - Several philosophers have recently argued that policies aimed at reducing human fertility are a practical and morally justifiable way to mitigate the risk of dangerous climate change. There is a powerful objection to such "population engineering" proposals: even if drastic fertility reductions are needed to prevent dangerous climate change, implementing those reductions would wreak havoc on the global economy, which would seriously undermine international antipoverty efforts. In this article, we articulate this economic objection to population engineering and show how it fails. We argue, first, that the economic objection paints an inaccurate picture of the complicated relationship between demographic change and economic growth, and second, that any untoward economic effects of fertility reduction can be mitigated with additional policies. Specifically, we argue that supplementing fertility reduction with policies that facilitate the emigration of younger people from developing nations to developed nations could allow for both global reductions in GHG emissions and continued economic stability. Further, we show that moral arguments against such unprecedented increases in immigration are unsuccessful. We conclude that population engineering is a practical and morally justifiable tool for addressing the twin evils of climate change and global poverty. PMID- 28901604 TI - Are children rational decision makers when they are asked to value their own health? A contingent valuation study conducted with children and their parents. AB - Despite the importance of including children's preferences in the valuation of their own health benefits, no study has investigated the ability of children to understand willingness-to-pay (WTP) questions. Using a contingent valuation method, we elicit children's and parents' WTP to reduce children's risk of an asthma attack. Our results suggest that children are able to understand and value their own health risk reductions, and their ability to do so improves with age. Child age was found to be inversely related to parents' and children's WTP. The results also suggest that non-paternalistic altruism is predictive of children's WTP. For parents, care for their own health was found to be inversely related with their WTP for children's risk reductions. Comparison of parents' and children's WTP suggests that parents are willing to sacrifice for their child's health risk reduction an amount that is approximately twice that of their children. The analysis of matched pairs of parents and children suggest that there are within-household similarities as the child's WTP is positively related to parents' WTP. PMID- 28901605 TI - Enzalutamide-warfarin interaction necessitating warfarin dosage adjustment: A case report of successful clinical management. AB - WHAT IS KNOWN AND OBJECTIVES: Enzalutamide package labeling recommends avoiding concurrent warfarin use due to potential reductions in warfarin concentrations via enzalutamide-associated hepatic enzyme induction. A case of successful management of this interaction via warfarin adjustments is reported. CASE DESCRIPTION: A 77-year-old Caucasian male, previously relatively stable on warfarin 42-45 mg weekly, reported to clinic after the recent start of enzalutamide and subsequent hospitalization with a subtherapeutic International Normalized Ratio (INR). A 50% increase in weekly warfarin dose resulted in a therapeutic INR. Enzalutamide was temporarily discontinued, and a 33% weekly warfarin dose decrease resulted in two therapeutic INRs. WHAT IS NEW AND CONCLUSION: This is the first case to highlight the clinical significance of this interaction, noting that patients taking enzalutamide may require approximately 30%-50% adjustment in their warfarin dosage to maintain a therapeutic INR. PMID- 28901606 TI - James G. Kereiakes, Ph.D. PMID- 28901607 TI - Bias-variance tradeoff in anticorrelated noise reduction for spectral CT. AB - PURPOSE: In spectral CT, basis material decomposition is commonly used to generate a set of basis images showing the material composition at each point in the field of view. The noise in these images typically contains anticorrelations between the different basis images, which leads to increased noise in each basis image. These anticorrelations can be removed by changing the basis functions used in the material decomposition, but the resulting basis images can then no longer be used for quantitative measurements. Recent studies have demonstrated that reconstruction methods which take the anticorrelations into account give reduced noise in the reconstructed image. The purpose of this work is to analyze an analytically solvable denoising model problem and investigate its effect on the noise level and bias in the image as a function of spatial frequency. METHOD: A denoising problem with a quadratic regularization term is studied as a mathematically tractable model for such a reconstruction method. An analytic formula for the resulting image in the spatial frequency domain is presented, and this formula is applied to a simple mathematical phantom consisting of an iodinated contrast agent insert embedded in soft tissue. We study the effect of the denoising on the image in terms of its transfer function and the visual appearance, the noise power spectrum and the Fourier component correlation coefficient of the resulting image, and compare the result to a denoising problem which does not model the anticorrelations in the image. RESULTS: Including the anticorrelations in the noise model of the denoising method gives 3-40% lower noise standard deviation in the soft-tissue image while leaving the iodine standard deviation nearly unchanged (0-1% difference). It also gives a sharper edge-spread function. The studied denoising method preserves the noise level and the anticorrelated structure at low spatial frequencies but suppresses the noise and removes the anticorrelations at higher spatial frequencies. Cross-talk between images gives rise to artifacts at high spatial frequencies. CONCLUSIONS: Modeling anticorrelations in a denoising problem can decrease the noise level in the basis images by removing anticorrelations at high spatial frequencies while leaving low spatial frequencies unchanged. In this way, basis image cross-talk does not lead to low spatial frequency bias but it may cause artifacts at edges in the image. This theoretical insight will be useful for researchers analyzing and designing reconstruction algorithms for spectral CT. PMID- 28901608 TI - Optimization of the geometry and speed of a moving blocker system for cone-beam computed tomography scatter correction. AB - PURPOSE: X-ray scatter is a significant barrier to image quality improvements in cone-beam computed tomography (CBCT). A moving blocker-based strategy was previously proposed to simultaneously estimate scatter and reconstruct the complete volume within the field of view (FOV) from a single CBCT scan. A blocker consisting of lead stripes is inserted between the X-ray source and the imaging object, and moves back and forth along the rotation axis during gantry rotation. While promising results were obtained in our previous studies, the geometric design and moving speed of the blocker were set empirically. The goal of this work is to optimize the geometry and speed of the moving block system. METHODS: Performance of the blocker was examined through Monte Carlo (MC) simulation and experimental studies with various geometry designs and moving speeds. All hypothetical designs employed an anthropomorphic pelvic phantom. The scatter estimation accuracy was quantified by using lead stripes ranging from 5 to 100 pixels on the detector plane. An iterative reconstruction based on total variation minimization was used to reconstruct CBCT images from unblocked projection data after scatter correction. The reconstructed image was evaluated under various combinations of lead strip width and interspace (ranging from 10 to 60 pixels) and different moving speed (ranging from 1 to 30 pixels per projection). RESULTS: MC simulation showed that the scatter estimation error varied from 0.8% to 5.8%. Phantom experiment showed that CT number error in the reconstructed CBCT images varied from 13 to 35. Highest reconstruction accuracy was achieved when the strip width was 20 pixels and interspace was 60 pixels and the moving speed was 15 pixels per projection. CONCLUSIONS: Scatter estimation can be achieved in a large range of lead strip width and interspace combinations. The moving speed does not have a very strong effect on reconstruction result if it is above 5 pixels per projection. Geometry design of the blocker affected image reconstruction accuracy more. The optimal geometry of the blocker has a strip width of 20 pixels and an interspace three times the strip width, which means 25% detector is covered by the blocker, while the optimal moving speed is 15 pixels per projection. PMID- 28901609 TI - Adaptive non-local means on local principle neighborhood for noise/artifacts reduction in low-dose CT images. AB - PURPOSE: Low-dose CT (LDCT) technique can reduce the x-ray radiation exposure to patients at the cost of degraded images with severe noise and artifacts. Non local means (NLM) filtering has shown its potential in improving LDCT image quality. However, currently most NLM-based approaches employ a weighted average operation directly on all neighbor pixels with a fixed filtering parameter throughout the NLM filtering process, ignoring the non-stationary noise nature of LDCT images. In this paper, an adaptive NLM filtering scheme on local principle neighborhoods (PC-NLM) is proposed for structure-preserving noise/artifacts reduction in LDCT images. METHODS: Instead of using neighboring patches directly, in the PC-NLM scheme, the principle component analysis (PCA) is first applied on local neighboring patches of the target patch to decompose the local patches into uncorrelated principle components (PCs), then a NLM filtering is used to regularize each PC of the target patch and finally the regularized components is transformed to get the target patch in image domain. Especially, in the NLM scheme, the filtering parameter is estimated adaptively from local noise level of the neighborhood as well as the signal-to-noise ratio (SNR) of the corresponding PC, which guarantees a "weaker" NLM filtering on PCs with higher SNR and a "stronger" filtering on PCs with lower SNR. The PC-NLM procedure is iteratively performed several times for better removal of the noise and artifacts, and an adaptive iteration strategy is developed to reduce the computational load by determining whether a patch should be processed or not in next round of the PC NLM filtering. RESULTS: The effectiveness of the presented PC-NLM algorithm is validated by experimental phantom studies and clinical studies. The results show that it can achieve promising gain over some state-of-the-art methods in terms of artifact suppression and structure preservation. CONCLUSIONS: With the use of PCA on local neighborhoods to extract principal structural components, as well as adaptive NLM filtering on PCs of the target patch using filtering parameter estimated based on the local noise level and corresponding SNR, the proposed PC NLM method shows its efficacy in preserving fine anatomical structures and suppressing noise/artifacts in LDCT images. PMID- 28901610 TI - Low-dose dynamic myocardial perfusion CT imaging using a motion adaptive sparsity prior. AB - PURPOSE: Dynamic myocardial perfusion computed tomography (DM-PCT) imaging offers benefits over quantitative assessment of myocardial blood flow (MBF) for diagnosis and risk stratification of coronary artery disease. However, one major drawback of DM-PCT imaging is that a high radiation level is imparted by repeated scanning. To address this issue, in this work, we developed a statistical iterative reconstruction algorithm based on the penalized weighted least-squares (PWLS) scheme by incorporating a motion adaptive sparsity prior (MASP) model to achieve high-quality DM-PCT imaging with low tube current dynamic data acquisition. For simplicity, we refer to the proposed algorithm as "PWLS-MASP''. METHODS: The MASP models both the spatial and temporal structured sparsity of DM PCT sequence images with the assumption that the differences between adjacent frames after motion correction are sparse in the gradient image domain. To validate and evaluate the effectiveness of the present PWLS-MASP algorithm thoroughly, a modified XCAT phantom and preclinical porcine DM-PCT dataset were used in the study. RESULTS: The present PWLS-MASP algorithm can obtain high quality DM-PCT images in both phantom and porcine cases, and outperforms the existing filtered back-projection algorithm and PWLS-based algorithms with total variation regularization (PWLS-TV) and robust principal component analysis regularization (PWLS-RPCA) in terms of noise reduction, streak artifacts mitigation, and time density curve estimation. Moreover, the PWLS-MASP algorithm can yield more accurate diagnostic hemodynamic parametric maps than the PWLS-TV and PWLS-RPCA algorithms. CONCLUSIONS: The study indicates that there is a substantial advantage in using the present PWLS-MASP algorithm for low-dose DM PCT, and potentially in other dynamic tomography areas. PMID- 28901611 TI - Consistency-based respiratory motion estimation in rotational angiography. AB - PURPOSE: Rotational coronary angiography enables 3D reconstruction but suffers from intra-scan cardiac and respiratory motion. While gating handles cardiac motion, respiratory motion requires compensation. State-of-the-art algorithms rely on 3D-2D registration that depends on initial reconstructions of sufficient quality. We propose a compensation method that is applied directly in projection domain. It overcomes the need for reconstruction and thus complements the state of-the-art. METHODS: Virtual single-frame background subtraction based on vessel segmentation and spectral deconvolution yields non-truncated images of the contrasted lumen. This allows motion compensation based on data consistency conditions. We compensate craniocaudal shifts by optimizing epipolar consistency to (a) devise an image-based surrogate for cardiac motion and (b) compensate for respiratory motion. We validate our approach in two numerical phantom studies and three clinical cases. RESULTS: Correlation of the image-based surrogate for cardiac motion with the ECG-based ground truth was excellent yielding a Pearson correlation of 0.93 +/- 0.04. Considering motion compensation, the target error measure decreased by 98% and 69%, respectively, for the phantom experiments while for the clinical cases the same figure of merit improved by 46 +/- 21%. CONCLUSIONS: The proposed method is entirely image-based and accurately estimates craniocaudal shifts due to respiration and cardiac contraction. Future work will investigate experimental trajectories and possibilities for simplification of the single-frame subtraction pipeline. PMID- 28901613 TI - Advances and Trends in image formation in x-ray CT. PMID- 28901612 TI - Compression of CT sinogram data by decimation in the view direction. AB - PUPOSE: In clinical computed tomography (CT), the image data is acquired during continuous rotation. If the time during which the signal is integrated (the frame time) is too long, the data is blurred in the view direction (i.e., azimuthal blur). This can be overcome by having a high angular sampling rate, but for systems with limited bandwidth, the increased amount of data can be a problem. In this paper, we evaluate the benefit of maintaining a high angular sampling rate on the CT gantry and performing a decimation (digital low-pass filtration followed by a downsampling) in the view direction before the bottleneck of the data transfer chain. METHODS: A theoretical evaluation of the effects of the decimation is presented and the implementation of the digital filter is discussed. The compression scheme is evaluated on image data of a CATPHAN(r) 504 phantom and a human skull phantom. RESULTS: It is shown that digital decimation can be used to compress data before read-out with more remaining data fidelity compared to having longer frame times. Specifically, the method is shown to preserve the detail in the reconstruction of the CATPHAN resolution patterns and the human skull phantom. It is also demonstrated that the method can be used to prevent aliasing artifacts. CONCLUSIONS: Decimation in the view direction is presented as an alternative to increasing the frame time for CT systems with limited bandwidth of the data read-out. The method can be used to either remove aliasing artifacts or preserve spatial resolution. The proposed compression scheme can be implemented on the CT gantry and thus reduce the bandwidth requirements on the data transfer. PMID- 28901614 TI - Investigating simulation-based metrics for characterizing linear iterative reconstruction in digital breast tomosynthesis. AB - PURPOSE: Simulation-based image quality metrics are adapted and investigated for characterizing the parameter dependences of linear iterative image reconstruction for DBT. METHODS: Three metrics based on a 2D DBT simulation are investigated: (1) a root-mean-square-error (RMSE) between the test phantom and reconstructed image, (2) a gradient RMSE where the comparison is made after taking a spatial gradient of both image and phantom, and (3) a region-of-interest (ROI) Hotelling observer (HO) for signal-known-exactly/background-known-exactly (SKE/BKE) and signal-known-exactly/background-known-statistically (SKE/BKS) detection tasks. Two simulation studies are performed using the aforementioned metrics, varying voxel aspect ratio, and regularization strength for two types of Tikhonov regularized least-squares optimization. The RMSE metrics are applied to a 2D test phantom with resolution bar patterns at varying angles, and the ROI-HO metric is applied to two tasks relevant to DBT: lesion detection, modeled by use of a large, low-contrast signal, and microcalcification detection, modeled by use of a small, high-contrast signal. The RMSE metric trends are compared with visual assessment of the reconstructed bar-pattern phantom. The ROI-HO metric trends are compared with 3D reconstructed images from ACR phantom data acquired with a Hologic Selenia Dimensions DBT system. RESULTS: Sensitivity of the image RMSE to mean pixel value is found to limit its applicability to the assessment of DBT image reconstruction. The image gradient RMSE is insensitive to mean pixel value and appears to track better with subjective visualization of the reconstructed bar-pattern phantom. The ROI-HO metric shows an increasing trend with regularization strength for both forms of Tikhonov-regularized least-squares; however, this metric saturates at intermediate regularization strength indicating a point of diminishing returns for signal detection. Visualization with the reconstructed ACR phantom images appear to show a similar dependence with regularization strength. CONCLUSIONS: From the limited studies presented it appears that image gradient RMSE trends correspond with visual assessment better than image RMSE for DBT image reconstruction. The ROI-HO metric for both detection tasks also appears to reflect visual trends in the ACR phantom reconstructions as a function of regularization strength. We point out, however, that the true utility of these metrics can only be assessed after amassing more data. PMID- 28901615 TI - Model-based dose reconstruction for CT dose estimation. AB - PURPOSE: Our goal is to develop a model-based approach for CT dose estimation. We previously presented a CT dose estimation method that offered good accuracy in soft tissue regions but lower accuracy in bone regions. In this work, we propose an improved physic-based approach to achieve high accuracy for any materials and realistic clinical anatomies. METHODS: Like Monte Carlo techniques, we start from a model or image of the patient and we model all relevant x-ray interaction processes. Unlike Monte Carlo techniques, we do not track each individual photon, but we compute the average behavior of the x-ray interactions, combining pencil beam calculations for the first-order interactions and kernels for the higher order interactions. The new algorithm more accurately models the variation of materials in the human body, especially for higher attenuation materials such as bone, as well as the various x-ray attenuation processes. We performed validation experiments with analytic phantoms and a polychromatic x-ray spectrum, comparing to Monte Carlo simulation (GEANT4) as the ground truth. RESULTS: The results show that the proposed method has improved accuracy in both soft tissue region and bone region: less than 6% voxel-wise errors and less than 3.2% ROI-based errors in an anthropomorphic phantom. The computational cost is on the order of a low resolution filtered backprojection reconstruction. CONCLUSIONS: We introduced improved physics-based models in a fast CT dose reconstruction approach. The improved approach demonstrated quantitatively good correspondence to a Monte Carlo gold standard in both soft tissue and bone regions in a chest phantom with a realistic polychromatic spectrum and could potentially be used for real-time applications such as patient- and organ-specific scan planning and organ dose reporting. PMID- 28901616 TI - Regularization of nonlinear decomposition of spectral x-ray projection images. AB - PURPOSE: Exploiting the x-ray measurements obtained in different energy bins, spectral computed tomography (CT) has the ability to recover the 3-D description of a patient in a material basis. This may be achieved solving two subproblems, namely the material decomposition and the tomographic reconstruction problems. In this work, we address the material decomposition of spectral x-ray projection images, which is a nonlinear ill-posed problem. METHODS: Our main contribution is to introduce a material-dependent spatial regularization in the projection domain. The decomposition problem is solved iteratively using a Gauss-Newton algorithm that can benefit from fast linear solvers. A Matlab implementation is available online. The proposed regularized weighted least squares Gauss-Newton algorithm (RWLS-GN) is validated on numerical simulations of a thorax phantom made of up to five materials (soft tissue, bone, lung, adipose tissue, and gadolinium), which is scanned with a 120 kV source and imaged by a 4-bin photon counting detector. To evaluate the method performance of our algorithm, different scenarios are created by varying the number of incident photons, the concentration of the marker and the configuration of the phantom. The RWLS-GN method is compared to the reference maximum likelihood Nelder-Mead algorithm (ML NM). The convergence of the proposed method and its dependence on the regularization parameter are also studied. RESULTS: We show that material decomposition is feasible with the proposed method and that it converges in few iterations. Material decomposition with ML-NM was very sensitive to noise, leading to decomposed images highly affected by noise, and artifacts even for the best case scenario. The proposed method was less sensitive to noise and improved contrast-to-noise ratio of the gadolinium image. Results were superior to those provided by ML-NM in terms of image quality and decomposition was 70 times faster. For the assessed experiments, material decomposition was possible with the proposed method when the number of incident photons was equal or larger than 105 and when the marker concentration was equal or larger than 0.03 g.cm-3 . CONCLUSIONS: The proposed method efficiently solves the nonlinear decomposition problem for spectral CT, which opens up new possibilities such as material specific regularization in the projection domain and a parallelization framework, in which projections are solved in parallel. PMID- 28901617 TI - Dual-rotation C-arm cone-beam computed tomography to increase low-contrast detection. AB - PURPOSE: This paper investigates the capabilities of a dual-rotation C-arm cone beam computed tomography (CBCT) framework to improve non-contrast-enhanced low contrast detection for full volume or volume-of-interest (VOI) brain imaging. METHOD: The idea is to associate two C-arm short-scan rotational acquisitions (spins): one over the full detector field of view (FOV) at low dose, and one collimated to deliver a higher dose to the central densest parts of the head. The angular sampling performed by each spin is allowed to vary in terms of number of views and angular positions. Collimated data is truncated and does not contain measurement of the incoming X-ray intensities in air (air calibration). When targeting full volume reconstruction, the method is intended to act as a virtual bow-tie. When targeting VOI imaging, the method is intended to provide the minimum full detector FOV data that sufficiently corrects for truncation artifacts. A single dedicated iterative algorithm is described that handles all proposed sampling configurations despite truncation and absence of air calibration. RESULTS: Full volume reconstruction of dual-rotation simulations and phantom acquisitions are shown to have increased low-contrast detection for less dose, with respect to a single-rotation acquisition. High CNR values were obtained on 1% inserts of the Catphan(r) 515 module in 0.94 mm thick slices. Image quality for VOI imaging was preserved from truncation artifacts even with less than 10 non-truncated views, without using the sparsity a priori common to such context. CONCLUSION: A flexible dual-rotation acquisition and reconstruction framework is proposed that has the potential to improve low-contrast detection in clinical C-arm brain soft-tissue imaging. PMID- 28901618 TI - Technical Note: A model-based sinogram correction for beam hardening artifact reduction in CT. AB - PURPOSE: This study aims to propose a physics-based method of reducing beam hardening artifacts induced by high-attenuation materials such as metal stents or other metallic implants. METHODS: The proposed approach consists of deriving a sinogram inconsistency formula representing the energy dependence of the attenuation coefficient of high-attenuation materials. This inconsistency formula more accurately represents the inconsistencies of the sinogram than that of a previously reported formula (called the MAC-BC method). This is achieved by considering the properties of the high-attenuation materials, which include the materials' shapes and locations and their effects on the incident X-ray spectrum, including their attenuation coefficients. RESULTS: Numerical simulation and phantom experiment demonstrate that the modeling error of MAC-BC method are nearly completely removed by means of the proposed method. CONCLUSION: The proposed method reduces beam-hardening artifacts arising from high-attenuation materials by relaxing the assumptions of the MAC-BC method. In doing so, it outperforms the original MAC-BC method. Further research is required to address other potential sources of metal artifacts, such as photon starvation, scattering, and noise. PMID- 28901619 TI - Nonuniqueness in dual-energy CT. AB - PURPOSE: The goal is to determine whether dual-energy computed tomography (CT) leads to a unique reconstruction using two basis materials. METHODS: The beam hardening equation is simplified to the single-voxel case. The simplified equation is rewritten to show that the solution can be considered to be linear operations in a vector space followed by a measurement model which is the sum of the exponential of the coordinates. The case of finding the concentrations of two materials from measurements of two spectra with three photon energies is the simplest non-trivial case and is considered in detail. RESULTS: Using a material basis of water and bone, with photon energies of 30 keV, 60 keV, and 100 keV, a case with two solutions is demonstrated. CONCLUSIONS: Dual-energy reconstruction using two materials is not unique as shown by an example. Algorithms for dual energy, dual-material reconstructions need to be aware of this potential ambiguity in the solution. PMID- 28901620 TI - Assessment of the spectral performance of hybrid photon counting x-ray detectors. AB - PURPOSE: Hybrid Photon Counting (HPC) detectors profoundly improved x-ray diffraction experiments at third generation synchrotron facilities. Enabling the simultaneous measurement of x-ray intensities in multiple energy bins, they also have many potential applications in the field of medical imaging. A prerequisite for this is a clean spectral response. To quantify how efficiently HPC detectors are able to assign photons to the correct energy bin, a quantity called Spectral Efficiency (SE) is introduced. This figure of merit measures the number of x-rays with correctly assigned energy normalized to the number of incoming photons. METHODS: A prototype HPC detector has been used to perform precision measurements of x-ray spectra at the BESSY synchrotron. The detector consists of a novel ASIC with pixels of 75 * 75 MUm2 size and a 750 MUm thick CdTe sensor. The experimental data are complemented by the results of a Monte-Carlo (MC) simulation, which not only includes the physical detection process but also pulse pile-up at high photon fluxes. The spectra and the measured photon flux are used to infer the Spectral Efficiency. RESULTS: In the energy range from 10 to 60 keV, both the Quantum Efficiency and the Spectral Efficiency were precisely measured and simulated. Good agreement between simulation and experiment has been achieved. For the small pixels of the prototype detector, a SE between 15% and 77% has been determined. The MC simulation is used to predict the SE for various pixel sizes at different photon fluxes. For a typical flux of 5?107 photons/mm2 /s used in human Computed Tomography (CT), the highest SE is achieved for pixel sizes in the range between 150 * 150 MUm2 and 300 * 300 MUm2 . CONCLUSIONS: The Spectral Efficiency turns out to be a useful figure of merit to quantify the spectral performance of HPC detectors. It allows a quantitative comparison of detectors with different sensor and ASIC configurations over a broad range of x ray energies and fluxes. The maximization of the SE is a prerequisite for a successful usage of HPC detectors in the field of medical imaging. PMID- 28901621 TI - Objective comparison of high-contrast spatial resolution and low-contrast detectability for various clinical protocols on multiple CT scanners. AB - PURPOSE: We sought to compare objectively computed tomography (CT) scanner performance for three clinically relevant protocols using a task-based image quality assessment method in order to assess the potential for radiation dose reduction. METHODS: Four CT scanners released between 2003 and 2007 by different manufacturers were compared with four CT scanners released between 2012 and 2014 by the same manufacturers using ideal linear model observers (MO): prewhitening (PW) MO and channelized Hotelling (CHO) MO with Laguerre-Gauss channels for high contrast spatial resolution and low-contrast detectability (LCD) performance, respectively. High-contrast spatial resolution was assessed using a custom-made phantom that enabled the computation of the target transfer function (TTF) and noise power spectrum (NPS). Low-contrast detectability was assessed using a commercially available anthropomorphic abdominal phantom providing equivalent diameters of 24, 29.6, and 34.6 cm. Three protocols were reviewed: a head (trauma) and an abdominal (urinary stones) protocol were applied to assess high contrast spatial resolution performance; and another abdominal (focal liver lesions) protocol was applied for LCD. The liver protocol was tested using fixed and modulated tube currents. The PW MO was proposed for assessing high-contrast detectability performance of the various CT scanners. RESULTS: Compared with older generation CT scanners, three newer systems displayed significant improvements in high-contrast detectability over that of their predecessors. A fourth, newer system had lower performance. The CHO MO was appropriate for assessing LCD performance and revealed that an excellent level of image quality could be obtained with newer scanners at significantly lower dose levels. CONCLUSIONS: This study shows that MO can objectively benchmark CT scanners using a task-based image quality method, thus helping to estimate the potential for further dose reductions offered by the latest systems. Such an approach may be useful for adequately and quantitatively comparing clinically relevant image quality among various scanners. PMID- 28901623 TI - New link between Parkinson's and Alzheimer's: Research uncovers the role of mutant leucine rich repeat kinase 2 and amyloid precursor protein. PMID- 28901622 TI - Assessment of prior image induced nonlocal means regularization for low-dose CT reconstruction: Change in anatomy. AB - PURPOSE: Repeated computed tomography (CT) scans are prescribed for some clinical applications such as lung nodule surveillance. Several studies have demonstrated that incorporating a high-quality prior image into the reconstruction of subsequent low-dose CT (LDCT) acquisitions can either improve image quality or reduce data fidelity requirements. Our proposed previous normal-dose image induced nonlocal means (ndiNLM) regularization method for LDCT is an example of such a method. However, one major concern with prior image based methods is that they might produce false information when the prior image and the current LDCT image show different structures (for example, if a lung nodule emerges, grows, shrinks, or disappears over time). This study aims to assess the performance of the ndiNLM regularization method in situations with change in anatomy. METHOD: We incorporated the ndiNLM regularization into the statistical image reconstruction (SIR) framework for reconstruction of subsequent LDCT images. Because of its patch-based search mechanism, a rough registration between the prior image and the current LDCT image is adequate for the SIR-ndiNLM method. We assessed the performance of the SIR-ndiNLM method in lung nodule surveillance for two different scenarios: (a) the nodule was not found in a baseline exam but appears in a follow-up LDCT scan; (b) the nodule was present in a baseline exam but disappears in a follow-up LDCT scan. We further investigated the effect of nodule size on the performance of the SIR-ndiNLM method. RESULTS: We found that a relatively large search-window (e.g., 33 * 33) should be used for the SIR-ndiNLM method to account for misalignment between the prior image and the current LDCT image, and to ensure that enough similar patches can be found in the prior image. With proper selection of other parameters, experimental results with two patient datasets demonstrated that the SIR-ndiNLM method did not miss true nodules nor introduce false nodules in the lung nodule surveillance scenarios described above. We also found that the SIR-ndiNLM reconstruction shows improved image quality when the prior image is similar to the current LDCT image in anatomy. These gains in image quality might appear small upon visual inspection, but they can be detected using quantitative measures. Finally, the SIR-ndiNLM method also performed well in ultra-low-dose conditions and with different nodule sizes. CONCLUSIONS: This study assessed the performance of the SIR-ndiNLM method in situations in which the prior image and the current LDCT image show substantial anatomical differences, specifically, changes in lung nodules. The experimental results demonstrate that the SIR-ndiNLM method does not introduce false lung nodules nor miss true nodules, which relieves the concern that this method might produce false information. However, there is insufficient evidence that these findings will hold true for all kinds of anatomical changes. PMID- 28901624 TI - The 12th International Conference on Brain Energy Metabolism (ICBEM): "Energy Metabolism and Neuron-Glia Interactions in Brain: From Molecular Mechanisms to Novel Therapeutic Approaches". PMID- 28901626 TI - Acute poisonings during pregnancy and in other non-pregnant women in emergency departments of four government hospitals, Addis Ababa, Ethiopia: 2010-2015. AB - OBJECTIVE: To characterise acute poisonings in pregnant and non-pregnant women treated at emergency departments of government hospitals in Addis Ababa, Ethiopia, between 2010 and 2015. METHODS: All data for acutely poisoned women were retrospectively collected from patient medical charts at the emergency departments of Saint Paul's Hospital Millennium Medical College, Ras Desta Memorial Hospital, Yekatit 12 Hospital Medical College and Zewditu Memorial Hospital. Data were collected by extraction questionnaire and analysed using SPSSv. 20 statistical software. RESULTS: During the study period, 998 cases of acutely poisoned women were listed in the hospital registries. Of these, complete data for inclusion in the study were available for 592. 36.3% of the study participants were in the age group of 20-24, with a mean (+/-SD) age of 23.03 (+/ 6.3) years. 80.9% were from Addis Ababa; 4.6% were pregnant. The mean arrival time of all cases was 4.14 h. 85.5% of all study cases were due to intentional self-poisoning, of whom 42.1% were discharged without complications. The most common poisons were bleach and organophosphates; 25.9% of pregnant cases and 32.6% of non-pregnant cases were poisoned by bleach; and 18.5% of pregnant cases and 18.9% of non-pregnant cases had organophosphate poisoning. 0.7% had a history of poisoning; all were non-pregnant women. The common route of poison exposure was oral, and the case fatality rate of organophosphate poisoning in pregnant and non-pregnant women was 20 and 1.87%, respectively. The pre-hospital intervention for the majority of the women was milk, in 12.0% of cases. CONCLUSION: Acute poisoning remains a public health problem in our community. Bleach is the most common poisons. Our present findings indicate the necessity of educational programmes on preventable reasons of acute poisonings and their outcomes on pregnant and non-pregnant women. PMID- 28901625 TI - Systemic challenges in bipolar disorder management: A patient-centered approach. AB - OBJECTIVES: As part of a series of Patient-Centered Outcomes Research Institute funded large-scale retrospective observational studies on bipolar disorder (BD) treatments and outcomes, we sought the input of patients with BD and their family members to develop research questions. We aimed to identify systemic root causes of patient-reported challenges with BD management in order to guide subsequent studies and initiatives. METHODS: Three focus groups were conducted where patients and their family members (total n = 34) formulated questions around the central theme, "What do you wish you had known in advance or over the course of treatment for BD?" In an affinity mapping exercise, participants clustered their questions and ranked the resulting categories by importance. The research team and members of our patient partner advisory council further rated the questions by expected impact on patients. Using a Theory of Constraints systems thinking approach, several causal models of BD management challenges and their potential solution were developed with patients using the focus group data. RESULTS: A total of 369 research questions were mapped to 33 categories revealing 10 broad themes. The top priorities for patient stakeholders involved pharmacotherapy and treatment alternatives. Analysis of causal relationships underlying 47 patient concerns revealed two core conflicts: for patients, whether or not to take pharmacotherapy, and for mental health services, the dilemma of care quality vs quantity. CONCLUSIONS: To alleviate the core conflicts identified, BD management requires a coordinated multidisciplinary approach including: improved access to mental health services, objective diagnostics, sufficient provider visit time, evidence-based individualized treatment, and psychosocial support. PMID- 28901627 TI - Microstructural white matter alterations in patients with drug induced parkinsonism. AB - Drug-induced parkinsonism (DIP) is the second most common etiology of parkinsonism. And yet, there is little information on structural imaging in DIP to elucidate the accurate underlying pathomechanisms. To investigate microstructural white matter (WM) in patients with DIP using diffusion tensor image and to determine its relationship to severity of parkinsonian motor symptoms and cognitive function. A total of 42 patients with DIP, 65 with Parkinson's disease, and 33 control subjects were recruited from a movement disorders outpatient clinic. We performed comparative analysis of fractional anisotropy (FA) and mean diffusivity (MD) values among groups using tract-based spatial statistics. Correlation analysis between WM integrity and parkinsonian motor symptoms and cognitive performance was also performed in DIP patients using voxel-wise statistical analysis. DIP patients had significantly lower FA and higher MD values over widespread WM areas than control subjects. The patients with DIP had poor cognitive performance relative to control subjects, which correlated well with WM properties. Additionally, the parkinsonian motor symptoms were negatively correlated with FA values. In contrast, exposure time to the offending drugs prior to the development of parkinsonism or duration of parkinsonism showed no significant association with FA or MD values. The present study demonstrates that disruption of the WM microstructure is extensive in patients with DIP, and it is correlated with clinical parameters of parkinsonism and cognitive performance. This suggests that DIP may be reflective of underlying abnormality of microstructural WM. Hum Brain Mapp 38:6043-6052, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28901629 TI - Complex radial sclerosing lesion of the breast-A great cancer mimicker. PMID- 28901628 TI - Total cosine R-to-T for predicting ventricular arrhythmic and mortality outcomes: A systematic review and meta-analysis. AB - BACKGROUND: The total cosine R-to-T (TCRT), a vectorcardiographic marker reflecting the spatial difference between the depolarization and repolarization wavefronts, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. However, its prognostic value has been controversial. OBJECTIVE: This systematic review and meta-analysis evaluated the significance of TRCT in predicting arrhythmic and/or mortality endpoints. METHODS: PubMed and Embase databases were searched through December 31, 2016. RESULTS: Of the 890 studies identified initially, 13 observational studies were included in our meta-analysis. A total of 11,528 patients, mean age 47 years old, 72% male, were followed for 43 +/- 6 months. Data from five studies demonstrated lower TCRT values in myocardial infarction patients with adverse events (syncope, ventricular arrhythmias, or sudden cardiac death) compared to those without these events (mean difference = -0.36 +/- 0.05, p < .001; I2 = 48%). By contrast, only two studies analyzed outcomes in heart failure, and pooled meta-analysis did not demonstrate significant difference in TCRT between event-positive and event-negative patients (mean difference = -0.01 +/- 0.10, p > .05; I2 = 80%). CONCLUSION: TCRT is lower in MI patients at high risk of adverse events when compared to those free from such events. It can provide additional risk stratification beyond the use of clinical parameters and traditional electrocardiogram markers. Its value in other diseases such as heart failure requires further studies. PMID- 28901630 TI - Role of robot-assisted radical prostatectomy in locally advanced prostate cancer. AB - Locally advanced prostate cancer is regarded as a very high-risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot-assisted radical prostatectomy is currently carried out even in high-risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot-assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot-assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer. PMID- 28901631 TI - Equine behavioral enrichment toys as tools for non-invasive recovery of viral and host DNA. AB - Direct collection of samples from wildlife can be difficult and sometimes impossible. Non-invasive remote sampling for the purpose of DNA extraction is a potential tool for monitoring the presence of wildlife at the individual level, and for identifying the pathogens shed by wildlife. Equine herpesviruses (EHV) are common pathogens of equids that can be fatal if transmitted to other mammals. Transmission usually occurs by nasal aerosol discharge from virus-shedding individuals. The aim of this study was to validate a simple, non-invasive method to track EHV shedding in zebras and to establish an efficient protocol for genotyping individual zebras from environmental DNA (eDNA). A commercially available horse enrichment toy was deployed in captive Grevy's, mountain, and plains zebra enclosures and swabbed after 4-24 hr. Using eDNA extracted from these swabs four EHV strains (EHV-1, EHV-7, wild ass herpesvirus and zebra herpesvirus) were detected by PCR and confirmed by sequencing, and 12 of 16 zebras present in the enclosures were identified as having interacted with the enrichment toy by mitochondrial DNA amplification and sequencing. We conclude that, when direct sampling is difficult or prohibited, non-invasive sampling of eDNA can be a useful tool to determine the genetics of individuals or populations and for detecting pathogen shedding in captive wildlife. PMID- 28901632 TI - Forty years of collaborative computational crystallography. AB - A brief overview is provided of the history of collaborative computational crystallography, with an emphasis on the Collaborative Computational Project No. 4. The key steps in its development are outlined, with consideration also given to the underlying reasons which contributed, and ultimately led to, the unprecedented success of this venture. PMID- 28901633 TI - Response to Mortazavi's comment. PMID- 28901634 TI - Optimal target vessel selection for composite and sequential radial artery grafting with an in situ internal thoracic artery. AB - OBJECTIVES: We retrospectively evaluated graft patency in patients who underwent no-touch aortic arterial off-pump coronary artery bypass grafting to determine the optimal selection of target vessels for improved graft patency of composite and sequential radial artery I-grafts. METHODS: The radial artery was anastomosed to the end of an in situ internal thoracic artery and was sequentially anastomosed to non-left anterior descending arteries. This composite graft was defined as an "I-graft." We evaluated 145 I-grafts with 2, 3, or 4 sequential anastomoses (437 graft segments). A graft segment with the final distal anastomosis of every I-graft was defined as the last graft segment (LGS). When a sequential anastomosis was initiated from the left coronary branch, the I-graft assumed a clockwise course (69.0%). When a sequential anastomosis was initiated from the right coronary branch, the I-graft assumed a counterclockwise course (31.0%). RESULTS: On multivariable analysis, right coronary branch (P < 0.001), moderately stenotic (50-75%) target vessel (P = 0.004), and LGS with moderately stenotic target vessel (P = 0.005) were predictors of mid-term graft occlusion. In situations where the LGS was anastomosed to a severely stenotic target vessel (>75%) with a clockwise course, when the number of moderately stenotic target vessels among sequential graft segments was 0, 1, or >=2, the mid-term graft patency rates of I-grafts were 94.0%, 86.0%, and 81.4%, respectively. CONCLUSIONS: The selection of target vessels for severely stenotic lesions among sequential graft segments and the clockwise course enhance the mid-term graft patency of sequential radial I-grafts. PMID- 28901635 TI - Investigation and management of gastro-oesophageal reflux in United Kingdom neonatal intensive care units. AB - AIM: In 2004, wide variation in the investigation and management of gastro oesophageal reflux (GOR) of infants on UK major neonatal units was demonstrated. Our aim was to resurvey neonatal practitioners to determine current practice and whether it was now evidence based. METHODS: A questionnaire was sent to all 207 UK neonatal units. RESULTS: Responses were obtained from 84% of units. The most frequent 'investigation' was a trial of therapy (83% of units); pH studies were used in 38%, upper GI contrast studies in 19% and multichannel intraluminal impedance (MII)/pH studies in 5%. Only six units suggested a threshold for an abnormal pH study and two units for an abnormal MII study. Infants were commenced on antireflux medication without investigation always in 32% of units, often in 29%, occasionally in 19% and only never in 1%. Gaviscon was used as first line treatment in 60% of units, and other medications included ranitidine in 53%, thickening agents in 27%, proton pump inhibitors in 23%, domperidone in 22% and erythromycin in 6%. CONCLUSION: There remains a wide variation in diagnostic and treatment strategies for infants with suspected GOR on neonatal intensive care units, emphasising the need for randomised trials to determine appropriate GOR management. PMID- 28901636 TI - Risk analysis and technology assessment in support of technology development: Putting responsible innovation in practice in a case study for nanotechnology. AB - Governments invest in "key enabling technologies," such as nanotechnology, to solve societal challenges and boost the economy. At the same time, governmental agencies demand risk reduction to prohibit any often unknown adverse effects, and industrial parties demand smart approaches to reduce uncertainties. Responsible research and innovation (RRI) is therefore a central theme in policy making. Risk analysis and technology assessment, together referred to as "RATA," can provide a basis to assess human, environmental, and societal risks of new technological developments during the various stages of technological development. This assessment can help both governmental authorities and innovative industry to move forward in a sustainable manner. Here we describe the developed procedures and products and our experiences to bring RATA in practice within a large Dutch nanotechnology consortium. This is an example of how to put responsible innovation in practice as an integrated part of a research program, how to increase awareness of RATA, and how to help technology developers perform and use RATA. Integr Environ Assess Manag 2018;14:9-16. (c) 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 28901637 TI - PET/CT versus bone marrow biopsy in the initial evaluation of bone marrow infiltration in various pediatric malignancies. AB - : Accurate staging is essential in the prognosis and management of pediatric malignancies. Current protocols require screening for marrow infiltration with bone marrow biopsy (BMB) as the gold standard. Positron emission tomography computed tomography (PET-CT) is commonly used to complete the staging process and can also be used to evaluate marrow infiltration. OBJECTIVE: To compare PET-CT and BMB in the initial evaluation of bone marrow infiltration in pediatric cancers. DESIGN/METHOD: We retrospectively reviewed new cases of EWS, rhabdomyosarcoma, neuroblastoma, and lymphoma diagnosed between January 2009 and October 2014. Each case had undergone both PET-CT and BMB within 4 weeks without treatment in the interval between screening modalities. RESULTS: We reviewed 69 cases. Bone marrow infiltration was demonstrated in 34 cases by PET-CT and in 18 cases by BMB. The sensitivity and negative predictive value of PET-CT were both 100%. Interestingly, the cases in which infiltration was not detected on BMB had an abnormal marrow signal on PET-CT focal or distant to iliac crest. CONCLUSION: PET-CT has a high sensitivity when assessing marrow infiltration in pediatric malignancies. Advances in radiologic modalities may obviate the use of invasive, painful, and costly procedures like BMB. Furthermore, biopsy results are limited by insufficient tissue or the degree of marrow infiltration (diffuse vs. focal disease). PET-CT can improve the precision of biopsy when used as a guiding tool. This study proposes the use of PET-CT as first-line screening for bone marrow infiltration to improve the accuracy of staging in new diagnoses. PMID- 28901638 TI - ADC-derived spatial features can accurately classify adnexal lesions. AB - BACKGROUND: The role of quantitative apparent diffusion coefficient (ADC) maps in differentiating adnexal masses is unresolved. PURPOSE/HYPOTHESIS: To propose an objective diagnostic method devised based on spatial features for predicting benignity/malignancy of adnexal masses in ADC maps. STUDY TYPE: Prospective. POPULATION: In all, 70 women with sonographically indeterminate and histopathologically confirmed adnexal masses (38 benign, 3 borderline, and 29 malignant) were considered for this study. FIELD STRENGTH/SEQUENCE: Conventional and diffusion-weighted magnetic resonance (MR) images (b-values = 50, 400, 1000 s/mm2 ) were acquired on a 3T scanner. ASSESSMENT: For each patient, two radiologists in consensus manually delineated lesion borders in whole ADC map volumes, which were consequently analyzed using spatial models (first-order histogram [FOH], gray-level co-occurrence matrix [GLCM], run-length matrix [RLM], and Gabor filters). Two independent radiologists were asked to identify the attributed (benign/malignant) classes of adnexal masses based on morphological features on conventional MRI. STATISTICAL TESTS: Leave-one-out cross-validated feature selection followed by cross-validated classification were applied to the feature space to choose the spatial models that best discriminate benign from malignant adnexal lesions. Two schemes of feature selection/classification were evaluated: 1) including all benign and malignant masses, and 2) scheme 1 after excluding endometrioma, hemorrhagic cysts, and teratoma (14 benign, 29 malignant masses). The constructed feature subspaces for benign/malignant lesion differentiation were tested for classification of benign/borderline/malignant and also borderline/malignant adnexal lesions. RESULTS: The selected feature subspace consisting of RLM features differentiated benign from malignant adnexal masses with a classification accuracy of ~92%. The same model discriminated benign, borderline, and malignant lesions with 87% and borderline from malignant with 100% accuracy. Qualitative assessment of the radiologists based on conventional MRI features reached an accuracy of 80%. DATA CONCLUSION: The spatial quantification methodology proposed in this study, which works based on cellular distributions within ADC maps of adnexal masses, may provide a helpful computer aided strategy for objective characterization of adnexal masses. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1061 1071. PMID- 28901639 TI - Predicting changes in flow category in patients with severe aortic stenosis and preserved left ventricular ejection fraction on medical therapy. AB - BACKGROUND/OBJECTIVES: Controversy surrounds the prognosis and management of patients with paradoxical low-flow severe aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF). It was not certain if patients in a particular flow category remained in the same category as disease progressed. We investigated whether there were switches in categories and if so, their predictors. METHODS: Consecutive subjects (n = 203) with isolated severe AS and paired echocardiography (>180 days apart) were studied. They were divided into 4 groups, based on their flow categories and if they progressed on subsequent echocardiography to switch or remain in the same flow category. Univariate analyses of clinical and echocardiographic parameters identified predictors of these changes in flow category. RESULTS: One hundred eighteen were normal flow (SVI >= 35 mL/m2 ), while 85 were low flow on index echocardiography. In the patients with normal flow, 33% switched to low flow. This was associated with higher valvuloarterial impedance (Zva, P < .001) and lower systemic arterial compliance (SAC, P < .001) compared to index echocardiography, and predicted by higher initial Zva (optimized cutoff >4.77 mm Hg/mL/m2 , AUC = 0.81 [95% CI:0.75 0.87, P < .001]). In patients with low flow, 25% switched to normal flow, which was associated with lower Zva and higher SAC and the switch was predicted by a higher initial mean transaortic pressure gradient. CONCLUSIONS: A significant number of patients switched flow categories in severe AS with preserved LVEF on subsequent echocardiography. Changes in flow were reflected by respective changes in Zva and SAC. Identifying echocardiographic predictors of a switch in category may guide prognostication and management of such patients. PMID- 28901640 TI - Minimally invasive insertion of off-pump central extracorporeal membrane oxygenation. PMID- 28901641 TI - A Temporary vs. Permanent Anchored Percutaneous Lead Trial of Spinal Cord Stimulation: A Comparison of Patient Outcomes and Adverse Events. AB - OBJECTIVES: A trial of spinal cord stimulation (SCS) is a prerequisite to determine efficacy of the therapy prior to placement of a permanent implanted system. A trial may be conducted employing a percutaneously placed temporary cylindrical lead or via a permanently anchored cylindrical lead placed and subsequently secured via open surgical method. There has been little investigation comparing the two methods of trial. This study is a comparative analysis of the two methods both for prediction of success as well as associated morbidity. STUDY DESIGN: Retrospective chart review. MATERIALS AND METHODS: SCS outcomes of percutaneous temporary lead trial or the temporary lead (TL) group and permanent anchored lead trial or permanent lead (PL) group were analyzed for lack of relief, poor paresthesia coverage, false positive trial phase, fading relief, and biological complications. RESULTS: Outcome data was analyzed for 148 patients in the TL group and 138 patients in the PL group. In comparing the two trial methods, false positive rate of trial was higher (p < 0.05) in the PL group as compared to the TL group (6.35 vs. 1.35%). Cumulative wound infections (6.52 vs. 1.35%), and poor wound healing (4.35 vs. 0%) were also significantly higher in the PL group. Rate of success in the trial phase was equal in both groups. CONCLUSION: The percutaneous temporary lead trial group was associated with fewer false positives and wound related complications as compared to permanent anchored lead trial group. There was very little technical advantage of routinely anchoring the trial lead. PMID- 28901642 TI - Impact of mimicking natural dispersion on breeding success of captive North American Cheetahs (Acinonyx jubatus). AB - This paper examines the effects of transfer away from natal facility and littermate presence on cheetah breeding success in the AZA Species Survival Plan (SSP) population. Transfer and breeding history data for captive males and females were gathered from seven and four AZA SSP breeding facilities, respectively, to identify factors influencing breeding success. The results indicate that transfer history (p = 0.032), age at transfer (p = 0.013), and female littermate presence/absence (p = 0.04) was associated with breeding success, with females transferred away from their natal facility before sexual maturity and without littermates present accounting for the highest breeding success. Keeping males at their natal facility and/or removing them from their coalitions did not negatively affect their breeding success. Males appeared to demonstrate the same fecundity regardless of transfer history or coalition status, indicating that dispersal away from natal environment was not as critical for the breeding success of males compared with female cheetahs. These results highlight the significance of moving females away from their natal environment, as would occur in the wild, and separating them from their female littermates for optimization of breeding success in the ex situ population. PMID- 28901644 TI - The truncated NLR protein TIR-NBS13 is a MOS6/IMPORTIN-alpha3 interaction partner required for plant immunity. AB - Importin-alpha proteins mediate the translocation of nuclear localization signal (NLS)-containing proteins from the cytoplasm into the nucleus through nuclear pore complexes (NPCs). Genetically, Arabidopsis IMPORTIN-alpha3/MOS6 (MODIFIER OF SNC1, 6) is required for basal plant immunity and constitutive disease resistance activated in autoimmune mutant snc1 (suppressor of npr1-1, constitutive 1), suggesting that MOS6 plays a role in the nuclear import of proteins involved in plant defense signaling. Here, we sought to identify and characterize defense regulatory cargo proteins and interaction partners of MOS6. We conducted both in silico database analyses and affinity purification of functional epitope-tagged MOS6 from pathogen-challenged stable transgenic plants coupled with mass spectrometry. We show that among the 13 candidate MOS6 interactors we selected for further functional characterization, the TIR-NBS-type protein TN13 is required for resistance against Pseudomonas syringae pv. tomato (Pst) DC3000 lacking the type-III effector proteins AvrPto and AvrPtoB. When expressed transiently in N. benthamiana leaves, TN13 co-immunoprecipitates with MOS6, but not with its closest homolog IMPORTIN-alpha6, and localizes to the endoplasmic reticulum (ER), consistent with a predicted N-terminal transmembrane domain in TN13. Our work uncovered the truncated NLR protein TN13 as a component of plant innate immunity that selectively binds to MOS6/IMPORTIN-alpha3 in planta. We speculate that the release of TN13 from the ER membrane in response to pathogen stimulus, and its subsequent nuclear translocation, is important for plant defense signal transduction. PMID- 28901643 TI - Renal function monitoring in heart failure - what is the optimal frequency? A narrative review. AB - The second most common cause of hospitalization due to adverse drug reactions in the UK is renal dysfunction due to diuretics, particularly in patients with heart failure, where diuretic therapy is a mainstay of treatment regimens. Therefore, the optimal frequency for monitoring renal function in these patients is an important consideration for preventing renal failure and hospitalization. This review looks at the current evidence for optimal monitoring practices of renal function in patients with heart failure according to national and international guidelines on the management of heart failure (AHA/NICE/ESC/SIGN). Current guidance of renal function monitoring is in large part based on expert opinion, with a lack of clinical studies that have specifically evaluated the optimal frequency of renal function monitoring in patients with heart failure. Furthermore, there is variability between guidelines, and recommendations are typically nonspecific. Safer prescribing of diuretics in combination with other antiheart failure treatments requires better evidence for frequency of renal function monitoring. We suggest developing more personalized monitoring rather than from the current medication-based guidance. Such flexible clinical guidelines could be implemented using intelligent clinical decision support systems. Personalized renal function monitoring would be more effective in preventing renal decline, rather than reacting to it. PMID- 28901645 TI - Measuring achievement goal motivation, mindsets and cognitive load: validation of three instruments' scores. AB - OBJECTIVE: Measurement of motivation and cognitive load has potential value in health professions education. Our objective was to evaluate the validity of scores from Dweck's Implicit Theories of Intelligence Scale (ITIS), Elliot's Achievement Goal Questionnaire-Revised (AGQ-R) and Leppink's cognitive load index (CLI). METHODS: This was a validity study evaluating internal structure using reliability and factor analysis, and relationships with other variables using the multitrait-multimethod matrix. Two hundred and thirty-two secondary school students participated in a medical simulation-based training activity at an academic medical center. Pre-activity ITIS (implicit theory [mindset] domains: incremental, entity) and AGQ-R (achievement goal domains: mastery-approach, mastery-avoidance, performance-approach, performance-avoidance), post-activity CLI (cognitive load domains: intrinsic, extrinsic, germane) and task persistence (self-directed repetitions on a laparoscopic surgery task) were measured. RESULTS: Internal consistency reliability (Cronbach's alpha) was > 0.70 for all domain scores except AGQ-R performance-avoidance (alpha 0.68) and CLI extrinsic load (alpha 0.64). Confirmatory factor analysis of ITIS and CLI scores demonstrated acceptable model fit. Confirmatory factor analysis of AGQ-R scores demonstrated borderline fit, and exploratory factor analysis suggested a three domain model for achievement goals (mastery-approach, performance and avoidance). Correlations among scores from conceptually-related domains generally aligned with expectations, as follows: ITIS incremental and entity, r = -0.52; AGQ-R mastery-avoidance and performance-avoidance, r = 0.71; mastery-approach and performance-approach, r = 0.55; performance-approach and performance-avoidance, r = 0.43; mastery-approach and mastery-avoidance, r = 0.36; CLI germane and extrinsic, r = -0.35; ITIS incremental and AGQ-R mastery-approach, r = 0.34; ITIS incremental and CLI germane, r = 0.44; AGQ-R mastery-approach and CLI germane, r = 0.48 (all p < 0.001). We found no correlation between the number of task repetitions (i.e. persistence) and mastery-approach scores, r = -0.01. CONCLUSIONS: ITIS and CLI scores had appropriate internal structures and relationships with other variables. AGQ-R scores fit a three-factor (not four factor) model that collapsed avoidance into one domain, although relationships of other variables with the original four domain scores generally aligned with expectations. Mastery goals are positively correlated with germane cognitive load. PMID- 28901647 TI - Attribution biases in assigning blame for medical error. PMID- 28901648 TI - Early clinical exposure requires facilitated access to support learning. PMID- 28901649 TI - In defence of teaching point-of-care ultrasound in undergraduate medical education. PMID- 28901650 TI - 'When I say... dual-processing theory': evidence, not assertion. PMID- 28901651 TI - Getting real: preparing medical students and physicians for error disclosure. PMID- 28901652 TI - Empowering junior doctors to maximise medical student learning in the clinical setting. PMID- 28901653 TI - Medical appraisal: an amber zone of opportunity? PMID- 28901654 TI - Clinical learning environments: place, artefacts and rhythm. AB - CONTEXT: Health care practitioners learn through experience in clinical environments in which supervision is a key component, but how that learning occurs outside the supervision relationship remains largely unknown. This study explores the environmental factors that inform and support workplace learning within a clinical environment. METHODS: An observational study drawing on ethnographic methods was undertaken in a general medicine ward. Observers paid attention to interactions among staff members that involved potential teaching and learning moments that occurred and were visible in the course of routine work. General purpose thematic analysis of field notes was undertaken. RESULTS: A total of 376 observations were undertaken and documented. The findings suggest that place (location of interaction), rhythm (regularity of activities occurring in the ward) and artefacts (objects and equipment) were strong influences on the interactions and exchanges that occurred. Each of these themes had inherent tensions that could promote or inhibit engagement and therefore learning opportunities. Although many learning opportunities were available, not all were taken up or recognised by the participants. CONCLUSIONS: We describe and make explicit how the natural environment of a medical ward and flow of work through patient care contribute to the learning architecture, and how this creates or inhibits opportunities for learning. Awareness of learning opportunities was often tacit and not explicit for either supervisor or learner. We identify strategies through which tensions inherent within space, artefacts and the rhythms of work can be resolved and learning opportunities maximised. PMID- 28901655 TI - Clinically insignificant prostate cancer suitable for active surveillance according to Prostate Cancer Research International: Active surveillance criteria: Utility of PI-RADS v2. AB - BACKGROUND: Active surveillance (AS) is an important treatment strategy for prostate cancer (PCa). Prostate Imaging-Reporting and Data System (PI-RADS) v2 has been addressed, but few studies have reported the value of PI-RADS v2 for assessing risk stratification in patients with PCa, especially on selecting potential candidates for AS. PURPOSE: To investigate the utility of PI-RADS v2 and apparent diffusion coefficient (ADC) in evaluating patients with insignificant PCa, who are suitable for AS. STUDY TYPE: Retrospective. SUBJECTS: In all, 238 patients with PCa who met the Prostate Cancer Research International: Active Surveillance criteria underwent radical prostatectomy. FIELD STRENGTH/SEQUENCE: 3.0T, including T2 -weighted, diffusion-weighted, and dynamic contrast-enhanced imaging. ASSESSMENT: Insignificant cancer was defined histopathologically as an organ-confined disease with a tumor volume <0.5 cm3 without Gleason score 4-5. Patients were divided into two groups based on the PI RADS v2 and tumor ADC: A, PI-RADS score <=3 and ADC >=1.095 * 10-3 mm2 /s; and B, PI-RADS score 4-5 or ADC <1.095 * 10-3 mm2 /s. Preoperative clinical and imaging variables were evaluated regarding the associations with insignificant cancer. RESULTS: Of the 238 patients, 101 (42.8%) were diagnosed with insignificant cancer on pathological findings. The number of positive cores, prostate-specific antigen density (PSAD), PI-RADS v2 and tumor ADC were significantly associated with insignificant cancer on univariate analysis (P < 0.05). However, multivariate analysis indicated tumor ADC (odds ratio [OR] = 4.57, P < 0.001) and PI-RADS v2 (OR = 3.60, P < 0.001) were independent predictors of insignificant cancer. Area under the receiver operating characteristics curve (AUC) reached 0.803 when PI-RADS v2 (AUC = 0.747) was combined with tumor ADC (AUC = 0.786). DATA CONCLUSION: The PI-RADS v2 together with tumor ADC may be a useful marker for predicting patients with insignificant PCa when considering AS. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1072 1079. PMID- 28901656 TI - The effects of seasonal affective disorder and alcohol abuse on sleep and snoring functions in a population-based study in Finland. AB - Seasonal affective disorder (SAD) is a recurrent depressive disorder with a seasonal pattern. In addition to some specific symptoms such as sad mood, low energy or carbohydrate craving, this mood disorder is also characterized by the presence of sleeping problems and alcohol disorders. Interestingly, there is a strong link between alcohol use and sleeping deficits. Although previous studies have focused extensively on the sleep patterns in SAD patients and patients with alcohol use disorder (AUD), no research has yet been conducted on subjects with comorbid SAD and AUD. The aim of this study was to examine the differences in sleep functioning between subjects with SAD, AUD and SAD+AUD. A total of 4554 Finnish subjects from the population-based Health 2011 survey were interviewed, and of these 2430 individuals completed all the questionnaires. We selected those participants who fulfilled the criteria for SAD (n = 298), AUD (n = 359), SAD+AUD (n = 69), controls 1 (no current alcohol use, n = 226) and controls 2 (current alcohol use but not AUD, n = 1445). Controls with a history of alcohol abuse were excluded (n = 33). All the participants completed the EuroQoL five-dimensions questionnaire (EQ-5), the Seasonal Pattern Assessment Questionnaire (SPAQ), the Alcohol Use Disorders Identification Test (AUDIT) and several questions about sleeping, based on the Basic Nordic Sleep Questionnaire (BNSQ). Our results showed that those subjects with SAD+AUD reported the highest levels of subjective sleeping problems compared to controls, SAD and AUD. These findings suggest the relevance of examining the comorbidity of SAD and AUD when studying sleep functioning in these groups of patients. PMID- 28901657 TI - Longitudinal patterns in BMI and percent total body fat from peak height velocity through emerging adulthood into young adulthood. AB - OBJECTIVES: Emerging adulthood, a potential critical period, is an understudied period of fat mass accrual. The aim of this study was to describe patterns of fat mass accrual, and weight status, from adolescence, through emerging adulthood, into young adulthood. METHODS: One-hundred-eighteen participants (59 male) were measured repeatedly for 20 years. Annual measures of height, weight, and body composition (DXA) were taken. Calculated measures included: peak height velocity (PHV), biological age (BA; years from PHV), body mass index (BMI), and percent total body fat (%TBF). Weight status groupings (normal NW, and overweight/obese OWO) were created using age and sex specific BMI and %TBF cut-offs. Analysis included t-tests and logistic regression. RESULTS: BMI and %TBF increased significantly until 8 years post PHV (P < .05), plateaued for 7 years (P > .05), and then began increasing again (P < .05). At PHV, 9% of males and 14% of females were OWO rising to 65% and 32% respectively 15 years post PHV. OWO status at PHV did not predict OWO status in early adulthood (P > .05). CONCLUSIONS: During emerging adulthood, the prevalence of OWO increased. Being NW at PHV was not protective against being overweight in young adulthood. Emerging adulthood appears to be a potential critical period for fat accrual and warrants further attention. PMID- 28901658 TI - Monoclonal Antibodies Production Platforms: An Opportunity Study of a Non-Protein A Chromatographic Platform Based on Process Economics. AB - Monoclonal antibodies currently dominate the biopharmaceutical market with growing sales having reached 80 billion USD in 2016. As most top-selling mAbs are approaching the end of their patent life, biopharmaceutical companies compete fiercely in the biosimilars market. These two factors present a strong motivation for alternative process strategies and process optimization. In this work a novel purification strategy for monoclonal antibodies comprising phenylboronic acid multimodal chromatography for capture followed by polishing by ion-exchange monolithic chromatography and packed bed hydrophobic interaction chromatography is presented and compared to the traditional protein-A-based process. Although the capital investment is similar for both processes, the operation cost is 20% lower for the novel strategy. This study shows that the new process is worthwhile investing in and could present a viable alternative to the platform process used by most industrial players. PMID- 28901659 TI - Using gamma index to flag changes in anatomy during image-guided radiation therapy of head and neck cancer. AB - During radiation therapy of head and neck cancer, the decision to consider replanning a treatment because of anatomical changes has significant resource implications. We developed an algorithm that compares cone-beam computed tomography (CBCT) image pairs and provides an automatic alert as to when remedial action may be required. Retrospective CBCT data from ten head and neck cancer patients that were replanned during their treatment was used to train the algorithm on when to recommend a repeat CT simulation (re-CT). An additional 20 patients (replanned and not replanned) were used to validate the predictive power of the algorithm. CBCT images were compared in 3D using the gamma index, combining Hounsfield Unit (HU) difference with distance-to-agreement (DTA), where the CBCT study acquired on the first fraction is used as the reference. We defined the match quality parameter (MQPx ) as a difference between the xth percentiles of the failed-pixel histograms calculated from the reference gamma comparison and subsequent comparisons, where the reference gamma comparison is taken from the first two CBCT images acquired during treatment. The decision to consider re-CT was based on three consecutive MQP values being less than or equal to a threshold value, such that re-CT recommendations were within +/-3 fractions of the actual re-CT order date for the training cases. Receiver-operator characteristic analysis showed that the best trade-off in sensitivity and specificity was achieved using gamma criteria of 3 mm DTA and 30 HU difference, and the 80th percentile of the failed-pixel histogram. A sensitivity of 82% and 100% was achieved in the training and validation cases, respectively, with a false positive rate of ~30%. We have demonstrated that gamma analysis of CBCT acquired anatomy can be used to flag patients for possible replanning in a manner consistent with local clinical practice guidelines. PMID- 28901660 TI - Local steroid injection versus wrist splinting for carpal tunnel syndrome: A randomized clinical trial. AB - AIM: We conducted a prospective randomized parallel clinical trial comparing the efficacy of local steroid injection and nocturnal wrist splinting in patients with carpal tunnel syndrome (CTS). METHODS: The well-validated and disease specific Boston Carpal Tunnel Questionnaire (BCTQ) was employed and its score at 4 weeks after treatment was used as the primary outcome measure. Important secondary outcomes included patient satisfaction, the change of an objective finger dexterity test and the side effects. RESULTS: Twenty-five patients in the local steroid group and 25 patients in the wrist splinting group completed the study procedures. At 4 weeks after treatment, there was significant improvement of the BTCQ scores in both the steroid group and splinting group. There was improvement of the finger dexterity test only in the steroid group but not in the splinting group. However, there was no statistically significant difference in the changes of BTCQ scores between the two groups after treatment. Patient satisfaction score was higher in the steroid group. Patients in the steroid group took fewer painkillers after treatment. Four patients developed side effects after splinting and three after local steroid injection, which was not statistically significant. CONCLUSION: Although local steroid injection and nocturnal wrist splinting were equally effective in the treatment of patients with CTS, only the former improved objective hand function. Local steroid injection also resulted in better patient satisfaction and less painkiller use without causing more side effects. PMID- 28901661 TI - D40/KNL1/CASC5 and autosomal recessive primary microcephaly. AB - Autosomal recessive primary microcephaly (MCPH) is a very rare neuro developmental disease with brain size reduction. More than a dozen loci encoding proteins of diverse function have been shown to be responsible for MCPH1-13. Mutations in the D40/KNL1/CASC5 gene, which was initially characterized as a gene involved in chromosomal translocation in leukemia and as a member of the cancer/testis gene family, was later found to encode a kinetochore protein essential for mitotic cell division and to cause MCPH4. Although our previous studies showed that this gene is required for cell growth and division in vitro and in animal experiments, the revelation that mutations in this gene caused microcephaly provides in vivo evidence of a critical role in brain growth. In this review, we describe mutated gene targets responsible for MCPH1-13 and summarize clinical studies of, and molecular and biological aspects of the gene and encoded protein responsible for MCPH4. PMID- 28901662 TI - Acute hypoxaemia and vascular function in healthy humans. AB - NEW FINDINGS: What is the central question of this study? Endothelium-dependent flow-mediated dilatation (FMD) is impaired during acute (60 min) exposure to moderate hypoxia. We examined whether FMD is impaired to the same degree during exposure to milder hypoxia. Additionally, we assessed whether smooth muscle vasodilatory capacity [glyceryl trinitrate (GTN)-induced dilatation] is impaired during acute hypoxic exposure. What is the main finding and its importance? A graded impairment in FMD and GTN-induced dilatation was evident during acute (<=60 min) exposure to mild and moderate hypoxia. This study is the first to document these graded impairments, and provides rationale to examine the relationship between graded increases in sympathetic nerve activity with hypoxia on FMD and GTN-induced dilatation. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent dilatation [induced with glyceryl trinitrate (GTN)] are impaired at high altitude (5050 m), and FMD is impaired after acute exposure (<60 min) to normobaric hypoxia equivalent to ~5050 m (inspired oxygen fraction ~0.11). Whether GTN-induced dilatation is impaired acutely and whether FMD is impaired during milder hypoxia are unknown. Therefore, we assessed brachial FMD at baseline and after 30 min of mild (end-tidal PO2 74 +/- 2 mmHg) and moderate (end-tidal PO2 50 +/- 3 mmHg) normobaric hypoxia (n = 12) or normoxia (time-control trial; n = 10). We also assessed GTN-induced dilatation after the hypoxic FMD tests and in normoxia on a separate control day (n = 8). Compared with the normoxic baseline, reductions during mild and moderate hypoxic exposure were evident in FMD (mild versus moderate, -1.2 +/- 1.1 versus -3.1 +/- 1.7%; P = 0.01) and GTN-induced dilatation (-2.1 +/- 1.0 versus -4.2 +/- 2.0%; P = 0.01); the declines in FMD and GTN-induced dilatation were greater during moderate hypoxia (P < 0.01). When allometrically corrected for baseline diameter and FMD shear rate under the curve, FMD was attenuated in both conditions (mild versus moderate, 0.6 +/- 0.9 versus 0.8 +/- 0.7%; P <= 0.01). After 30 min of normoxic time control, FMD was reduced (-0.6 +/- 0.3%; P = 0.02). In summary, there was a graded impairment in FMD during mild and moderate hypoxic exposure, which appears to be influenced by shear patterns and incremental decline in smooth muscle vasodilator capacity (impaired GTN-induced dilatation). Our findings from the normoxic control study suggest the decline in FMD in acute hypoxia also appears to be influenced by 30 min of supine rest/inactivity. PMID- 28901663 TI - Antifungal and Mechanical Properties of Tissue Conditioner Containing Plant Derived Component: An In Vitro Study. AB - PURPOSE: To evaluate the antifungal activity and mechanical properties of a novel antifungal tissue conditioner containing Juncus powder. MATERIALS AND METHODS: Juncus powder was mixed with GC tissue conditioner at concentrations of 2.5%, 5.0%, and 10.0% by mass. The cylindrical specimens of Juncus-mixed tissue conditioner (dimensions: 10 mm in diameter and 2 and 6 mm in height for antimicrobial and mechanical tests, respectively) were prepared. The specimens placed on the bottom of the 24-well tissue culture plate were cultured with Candida albicans CAD1 for 2 and 4 days. The proliferation of the C. albicans in the wells was determined by measuring the optical density of fungal culture, and the surface of the specimens were also observed by scanning electron microscopy (SEM). To assess the mechanical properties of the specimens, the fluidity and hardness of Juncus-mixed tissue conditioner were measured using the methods certified according to ISO 10139-1. RESULTS: Juncus-mixed tissue conditioner significantly exhibited growth inhibitory effect in a Juncus concentration dependent manner after both 2- and 4- day cultures. SEM observation showed that the amount of C. albicans on Juncus-mixed specimens drastically decreased, and biofilm formation was markedly inhibited. Moreover, both mechanical properties were found to be within the ranges regulated and specified by ISO. CONCLUSION: These findings demonstrated that the tissue conditioner including Juncus powder has a significant growth inhibitory effect against C. albicans, and it is suggested that the application of Juncus-mixed tissue conditioner may prevent denture stomatitis and oral candidiasis in denture wearers. PMID- 28901664 TI - Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors. AB - Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 MUm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5. PMID- 28901665 TI - Kansas nurse leader residency programme: advancing leader knowledge and skills. AB - AIMS: To evaluate the effectiveness of the Kansas Nurse Leader Residency (KNLR) programme in improving nurses' leadership knowledge and skills and its acceptability, feasibility and fidelity. BACKGROUND: The Future of Nursing Report (Institute of Medicine, 2011) calls for nurses to lead change and advance health. The 6-month KNLR programme was developed by the Kansas Action Coalition to support nurses' leadership development. METHODS: Nurses (n = 36) from four nursing specialties (acute care, long-term care, public health and school health) participated in the programme. The adapted Leader Knowledge and Skill Inventory was used to assess leadership knowledge and skills. Programme acceptability, feasibility and implementation fidelity also were evaluated. RESULTS: The programme completion rate was 67.7% (n = 24). Programme completers had significantly improved self-assessed and mentor-assessed leadership knowledge and skills (p < .05). These post-programme gains were maintained 3 months after programme completion. CONCLUSIONS: The KNLR programme effectively improved leadership knowledge and skills and was positively evaluated by participants. The implementation of the KNLR programme using a hybrid format of in-person sessions and online modules was feasible across four specialty areas in both rural and urban regions. IMPLICATIONS FOR NURSING MANAGEMENT: The next steps include the development of an advanced programme. Residency programmes for new nurse leaders are critical for successful transition into management positions. PMID- 28901666 TI - Clinicopathological and molecular characteristics of pediatric meningiomas. AB - Molecular and clinical characteristics of pediatric meningiomas are poorly defined. Therefore, we analyzed clinical, morphological and molecular profiles of pediatric meningiomas. Forty pediatric meningiomas from January 2002 to June 2015 were studied. 1p36, 14q32 and 22q-deletion were assessed by fluorescent in situ hybridization and mutations of most relevant exons of AKT, SMO, KLF4, TRAF and pTERT using sequencing. Expression of GAB1, stathmin, progesterone receptor (PR), p53 along with MIB-1 LI was examined using immunohistochemistry. There were 36 sporadic and four NF2 associated meningiomas. Among sporadic meningiomas, the majority (72.2%) of cases harbored 22q-deletion. Difference in frequency of combined 1p/14q deletion in Grade-I versus Grade-II/III tumors was not significant (13.7% vs 28.5%, P = 0.57). PR immunoreactivity was seen in 65.5% of Grade-I and 14.2% of Grade-II/III tumors (P = 0.03). The majority (97.2%) of meningiomas were immunonegative for p53. Stathmin and GAB co-expression was observed in 58.3% of cases. Notably, AKT, SMO, KLF4, TRAF7 (exon 17) and pTERT mutations were seen in none of the cases analyzed. 1p/14q codeletion was frequent in skull base as compared to non-skull base meningiomas (23% vs 11.1%, P = 0.37). All NF2 meningiomas harbored 22q-deletion and showed GAB and stathmin co expression while none showed 1p/14q loss. Pediatric meningiomas share certain phenotypic and cytogenetic characteristics with adult counterparts, but GAB and stathmin co-expression in the majority of cases and non-significant difference in frequency of 1p/14q co-deletion between low- and high-grade meningiomas indicate an inherently aggressive nature. Characteristic AKT/SMO, KLF4/TRAF7 and pTERT genetic alterations seen in adults are distinctly absent in pediatric meningiomas. PMID- 28901667 TI - Variables affecting the manifestation of and intensity of pacing behavior: A preliminary case study in zoo-housed polar bears. AB - High-speed video analysis was used to quantify two aspects of gait in 10 zoo housed polar bears. These two variables were then examined as to how they differed in the conditions of pacing versus locomoting for each bear. Percent difference calculations measured the difference between pacing and locomoting data for each bear. We inferred that the higher the percent difference between pacing and locomoting in a given subject, the more intense the pacing may be. The percent difference values were analyzed alongside caregiver survey data defining the locations, frequency, and anticipatory nature of pacing in each bear, as well as each bear's age and sex, to determine whether any variables were correlated. The frequency and intensity of pacing behavior were not correlated. However, location of pacing was significantly correlated both with the subjects' age and whether or not the subject was classified as an anticipatory pacer. Bears appeared to select specific spots within their exhibits to pace, and the location therefore seemed tied to underlying motivation for the behavior. Additionally, bears that were classified in the survey as pacing anticipatorily displayed significantly more intense pacing behavior as quantified by gait analysis. PMID- 28901668 TI - Dilatation of the ductus arteriosus by diazoxide in fetal and neonatal rats. AB - BACKGROUND: Diazoxide, an ATP-sensitive potassium channel opener, is the main therapeutic agent for treating hyperinsulinemic hypoglycemia. The aim of this study was to determine the in vivo ductus arteriosus (DA)-dilating effects of diazoxide in fetal and neonatal rats. METHODS: Near-term rat pups delivered via cesarean section were housed at 33 degrees C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were injected i.p. with diazoxide (10 and 100 mg/kg) 4 h before delivery, and the neonatal DA diameter was measured at 0, 30, or 60 min after birth. The newborn rats were also injected i.p. with diazoxide (10 and 100 mg/kg) at birth or 60 min after birth. DA was measured at 0, 30, or 60 min after injection. In the fetal investigation, the effect of diazoxide was studied via simultaneous application of indomethacin (10 mg/kg) and L-nitroarginine methyl ester (L-NAME) on gestational days 21 and 19. RESULTS: The control rats had rapid postnatal DA constriction (diameter, 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Diazoxide had a dose dependent inhibitory effect on postnatal DA constriction. Prenatal diazoxide (10 mg/kg) inhibited postnatal DA closure (0.20 mm at 60 min after birth). The diazoxide injection (10 mg) at birth inhibited postnatal DA closure (0.14 mm at 60 min after birth). Diazoxide injection in 60-min-old rats dilated the constricted DA at 60 min (0.10 mm vs. 0.02 mm in the controls). In the fetal investigation, diazoxide inhibited the fetal DA constrictive effect of indomethacin and L-NAME. CONCLUSION: Diazoxide attenuates postnatal DA constriction and dilates a closing DA in fetal and neonatal rats. PMID- 28901669 TI - Automating tasks in protein structure determination with the clipper python module. AB - Scripting programming languages provide the fastest means of prototyping complex functionality. Those with a syntax and grammar resembling human language also greatly enhance the maintainability of the produced source code. Furthermore, the combination of a powerful, machine-independent scripting language with binary libraries tailored for each computer architecture allows programs to break free from the tight boundaries of efficiency traditionally associated with scripts. In the present work, we describe how an efficient C++ crystallographic library such as Clipper can be wrapped, adapted and generalized for use in both crystallographic and electron cryo-microscopy applications, scripted with the Python language. We shall also place an emphasis on best practices in automation, illustrating how this can be achieved with this new Python module. PMID- 28901670 TI - Specificity of wide QRS complex tachycardia criteria and algorithms in patients with ventricular preexcitation. AB - BACKGROUND: Despite substantial progress in the field of differentiation between ventricular tachycardia (VT) and supraventricular tachycardia (SVT) with wide QRS complexes, differentiation between VT and preexcited SVT remains largely unresolved due to significant overlap in QRS morphology. Our aim was to assess the specificities of various single ECG criteria and sets of criteria (Brugada algorithm, aVR algorithm, Steurer algorithm, and the VT score) for diagnosis of VT in a sizable cohort of patients with preexcitation. METHODS: We performed a retrospective study of consecutive accessory pathway ablation procedures to identify preexcited tachycardias. Among 670 accessory pathway ablation procedures, 329 cases with good quality ECG with either bona fide preexcited SVT (n = 30) or a surrogate preexcited SVT (fast paced atrial rhythm with full preexcitation, n = 299) were identified. ECGs were analyzed with the use of wide QRS complex algorithms/criteria to determine specificities of these methods. RESULTS: The Steurer algorithm and VT score (>=3 points), with specificities of 97.6% and 96.1%, respectively, were significantly (p < .01) more specific for the diagnosis of VT than Brugada algorithm, aVR algorithm, and Pava criterion with specificities of 31%, 11.6%, and 57.1%, respectively. The first step of the Brugada algorithm and the first step of the aVR algorithm had also high specificities of 93.3% and 96.0%, respectively. CONCLUSION: There are sufficient electrocardiographical differences between VT and preexcited SVT to allow electrocardiographic differentiation. VT score, Steurer algorithm, and some single criteria do not overdiagnose VT in patients with preexcitation. PMID- 28901672 TI - Reading Comprehension Difficulties in Chinese-English Bilingual Children. AB - The co-occurrence of reading comprehension difficulties for first language (L1) Chinese and second language (L2) English and associated longitudinal cognitive linguistic correlates in each language were investigated. Sixteen poor comprehenders in English and 16 poor comprehenders in Chinese, 18 poor readers in both, and 18 children with normal performance in both were identified at age 10. The prevalence rate for being poor in both was 52.94%, suggesting that approximately half of children who are at risk for Chinese reading comprehension difficulty are also at risk for English reading comprehension difficulty. Chinese word reading, phonological, and morphological awareness were longitudinal correlates of poor comprehension in Chinese. English word reading and vocabulary were longitudinal correlates of poor comprehension in English. Chinese phonological awareness was an additional correlate of poor comprehension in English. Moreover, poor comprehenders in both Chinese and English showed slower rapid automatized naming scores than the other groups. Findings highlight some factors that might be critical for reading comprehension in L1 Chinese and L2 English; fluency is likely to be a critical part of reading comprehension across languages. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28901671 TI - Aspartate tightens the anchoring of staphylococcal lipoproteins to the cytoplasmic membrane. AB - In gram-negative bacteria, the ABC transporter LolCDE complex translocates outer membrane-specific lipoproteins (Lpp) from the inner membrane to the outer membrane. Lpp possessing aspartate (Asp) at position +2 are not translocated because it functions as a LolCDE avoidance signal. In gram-positive bacteria, lacking an outer membrane and the Lol system, Lpp are only anchored at the outer leaflet of the cytoplasmic membrane. However, the release of Lpp particularly in pathogenic or commensal species is crucial for immune modulation. Here, we provide evidence that in Staphylococcus aureus Asp at position +2 plays a role in withholding Lpp to the cytoplasmic membrane. Screening of published exoproteomic data of S. aureus revealed that Lpp mainly with Gly or Ser at position +2 were found in exoproteome, but there was no Lpp with Asp+2. The occurrence of Lpp with Asp+2 is infrequent in gram-positive bacteria. In S. aureus USA300 only seven of the 67 Lpp possess Asp+2; among them five Lpp represented Lpl lipoproteins involved in host cell invasion. Our study demonstrated that replacing the Asp+2 present in Lpl8 with a Ser enhances its release into the supernatant. However, there is no different release of Asp+2 and Ser+2 in mprF mutant that lacks the positive charge of lysyl-phosphatidylglycerol (Lys-PG). Moreover, substitution of Ser+2 by Asp in SitC (MntC) did not lead to a decreased release indicating that in staphylococci positions +3 and +4 might also be important for a tighter anchoring of Lpp. Here, we show that Asp in position +2 and adjacent amino acids contribute in tightening the anchoring of Lpp by interaction of the negative charged Asp with the positive charged Lys-PG. PMID- 28901673 TI - Catanionic Coacervate Droplets as a Surfactant-Based Membrane-Free Protocell Model. AB - We report on the formation of surfactant-based complex catanionic coacervate droplets in mixtures of decanoic acid and cetylpyridinium chloride or cetyltrimethylammonium bromide. We show that coacervation occurs over a broad range of composition, pH, and ionic strength. The catanionic coacervates consist of elongated micelles, sequester a wide range of solutes including water-soluble organic dyes, polysaccharides, proteins, enzymes, and DNA, and can be structurally stabilized by sodium alginate or gelatin-based hydrogelation. These results suggest that catanionic coacervates could be exploited as a novel surfactant-based membrane-free protocell model. PMID- 28901674 TI - Atrial fibrillation is associated with cognitive decline in stroke-free subjects: the Tromso Study. AB - BACKGROUND AND PURPOSE: Previous studies have shown associations between atrial fibrillation (AF) and cognitive decline. We investigated this association in a prospective population study, focusing on whether stroke risk factors modulated this association in stroke-free women and men. METHODS: We included 4983 participants (57% women) from the fifth survey of the Tromso Study (Tromso 5, 2001), of whom 2491 also participated in the sixth survey (Tromso 6, 2007-2008). Information about age, education, blood pressure, body mass index, lipids, smoking, coffee consumption, physical activity, depression, coronary and valvular heart disease, heart failure and diabetes was obtained at baseline. AF status was based on hospital records. The outcome was change in cognitive score from Tromso 5 to Tromso 6, measured by the verbal memory test, the digit-symbol coding test and the tapping test. RESULTS: Mean age at baseline was 65.4 years. The mean reduction in the tapping test scores was significantly larger in participants with AF (5.3 taps/10 s; 95% CI: 3.9, 6.7) compared with those without AF (3.8 taps/10 s; 95% CI: 3.5, 4.1). These estimates were unchanged when adjusted for other risk factors and were similar for both sexes. AF was not associated with change in the digit-symbol coding or the verbal memory tests. CONCLUSION: Atrial fibrillation in stroke-free participants was independently associated with cognitive decline as measured with the tapping test. PMID- 28901675 TI - Sudden cardiac death in isolated right ventricular hypertrabeculation/noncompaction cardiomyopathy. AB - Hypertrabeculation/noncompaction of the myocardium is a rare disorder that involves most commonly the left ventricle of the heart and it has been recognized as a distinct cardiomyopathy by the World Health Organization. However, it is extremely rare for this condition to involve exclusively the right ventricle. We report the cases of three patients who presented with ventricular tachyarrhythmia and sudden cardiac death. They were found to have isolated right ventricular hypertrabeculation/noncompaction on echocardiography. This supports the hypothesis that this condition is highly arrhythmogenic and is associated with high mortality similarly to the left ventricular hypertrabeculation/noncompaction cardiomyopathy. PMID- 28901676 TI - Neural mechanisms of motion perceptual learning in noise. AB - Practice improves our perceptual ability. However, the neural mechanisms underlying this experience-dependent plasticity in adult brain remain unclear. Here, we studied the long-term neural correlates of motion perceptual learning. Subjects' behavioral performance and BOLD signals were tracked before, immediately after, and 2 weeks after practicing a motion direction discrimination task in noise over six daily sessions. Parallel to the specificity and persistency of the behavioral learning effect, we found that training sharpened the cortical tuning in MT, and enhanced the connectivity strength from MT to the intraparietal sulcus (IPS, a motion decision-making area). In addition, the decoding accuracy for the trained motion direction was improved in IPS 2 weeks after training. The dual changes in the sensory and the high-level cortical areas suggest that learning refines the neural representation of the trained stimulus and facilitates the information transmission in the decision process. Our findings are consistent with the functional specialization in the visual cortex, and provide empirical evidence to the reweighting theory of perceptual learning at a large spatial scale. Hum Brain Mapp 38:6029-6042, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28901677 TI - Natriuretic peptides in the control of lipid metabolism and insulin sensitivity. AB - Natriuretic peptides have long been known for their cardiovascular function. However, a growing body of evidence emphasizes the role of natriuretic peptides in human substrate and energy metabolism, thereby connecting the heart with several insulin-sensitive organs like adipose tissue, skeletal muscle and liver. Obesity may be associated with an impaired regulation of the natriuretic peptide system, also indicated as a natriuretic handicap. Evidence points towards a contribution of this natriuretic handicap to the development of obesity, type 2 diabetes mellitus and cardiometabolic complications, although the causal relationship is not fully understood. Nevertheless, targeting the natriuretic peptide pathway may improve metabolic health in obesity and type 2 diabetes mellitus. This review will focus on current literature regarding the metabolic roles of natriuretic peptides with emphasis on lipid metabolism and insulin sensitivity. Furthermore, it will be discussed how exercise and lifestyle intervention may modulate the natriuretic peptide-related metabolic effects. PMID- 28901678 TI - Improving Inhibitory Control Abilities (ImpulsE)-A Promising Approach to Treat Impulsive Eating? AB - Although there is preliminary evidence that inhibitory control training improves impulsive eating, less is known about the effects on eating behaviour and weight loss in clinical samples. Sixty-nine treatment-seeking adults with obesity (binge eating disorder 33.3%; other specific feeding and eating disorders 40.6%) were randomly blockwise allocated to ImpulsE, an intervention to improve inhibitory control and emotion regulation abilities or a guideline-appropriate cognitive behavioural therapy (CBT)-based treatment as usual. Self-reported and performance based impulsivity, eating disorder pathology and BMI were compared at baseline (T1), post-treatment (T2) and 1- or 3-month follow-up. ImpulsE led to better food specific inhibition performance (p = .004), but groups did not differ regarding improvements in global Eating Disorder Examination Questionnaire (EDE-Q) score at T2. At 3-month follow-up, binge eaters benefited most from ImpulsE (p = .028) and completers of ImpulsE demonstrated a significantly greater weight reduction (p = .030). The current findings propose ImpulsE as a promising approach to treat obesity, illustrating acceptability and additional benefits for course of weight. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28901679 TI - Laser-Initiated Radical Trifluoromethylation of Peptides and Proteins: Application to Mass-Spectrometry-Based Protein Footprinting. AB - Described is a novel, laser-initiated radical trifluoromethylation for protein footprinting and its broad residue coverage. . CF3 reacts with 18 of the 20 common amino acids, including Gly, Ala, Ser, Thr, Asp, and Glu, which are relatively silent with regard to . OH. This new approach to footprinting is a bridge between trifluoromethylation in materials and medicinal chemistry and structural biology and biotechnology. Its application to a membrane protein and to myoglobin show that the approach is sensitive to protein conformational change and solvent accessibility. PMID- 28901680 TI - Evaluation of polyacrylonitrile electrospun nano-fibrous mats as leukocyte removal filter media. AB - Removal of leukocytes from blood products is the most effective means for elimination of undesirable side effects and prevention of possible reactions in recipients. Micro-fibrous mats are currently used for removal of leukocytes from blood. In this study, samples of electrospun nano-fibrous mats were produced. The performance of the produced electrospun nano-fibrous mats as means of leukocytes removal from fresh whole blood was both evaluated and compared with that of commercially available micro-fibrous mats. In order to produce the samples, polyacrylonitrile (PAN) nano-fibrous mats were made under different electrospinning conditions. Mean fiber diameter, pore characterization and surface roughness of the PAN nano-fibrous mats were determined using image processing technique. In order to evaluate the surface tension of the fabricated mats, water contact angle was measured. The leukocyte removal performance, erythrocytes recovery percent and hemolysis rate of the nano-fibrous mats were compared. The effectiveness of nano-fibrous mats in removing leukocyte was established using both scanning electron microscope and optical microscope. Results showed that for given weight, the fabricated nano-fibrous mats were not only more efficient but also more cost-effective than their commercial counterparts. Results confirmed that changes in mean fiber diameter, the number of layer and weight of each layer in the absence of any chemical reaction or physical surface modification, the fabricated nano-fibrous mats were able to remove 5-log of leukocytes. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1759-1769, 2018. PMID- 28901682 TI - Referral population studies underestimate differences between human papillomavirus assays in primary cervical screening. AB - OBJECTIVE: We studied how representative cytologically abnormal women ("referral populations") are with respect to uncovering differences between human papillomavirus (HPV) assays in the primary screening where most women are cytologically normal. METHODS: A total of 4997 women were tested with SurePath(r) cytology, and Hybrid Capture 2 (HC2), cobas, CLART and APTIMA HPV assays. Women with positive test results were offered a follow-up. For all detected HPV infections and HPV-positive high-grade cervical intraepithelial neoplasia (>=CIN2), we studied the distributions of assay-specific signal strengths in the baseline samples as documented by the assays' automatically generated reports. We calculated the likelihood of test result discordance as the proportion of HPV positive samples that were not confirmed by all four assays. RESULTS: Median signal strengths for HPV infections were weaker in normal than abnormal cytology (P<.001, adjusted for women's age, multiple infections and the reason for taking the sample). For HC2, they were RLU/CO 11.0 (interquartile range, IQR: 3.3-52.8) vs 124.2 (IQR: 22.8-506.9), respectively; for cobas, Ct 33.5 (IQR: 29.6-37.5) vs 26.9 (IQR: 23.7-31.3), respectively; for APTIMA, S/CO 10.2 (IQR: 5.8-11.3) vs 11.1 (IQR: 9.4-15.5), respectively. Similar patterns were observed for HPV positive >=CIN2. The four HPV assays more frequently returned discordant test results in normal than in abnormal cytology. Relative frequency of discordance in detecting HPV infections was 0.39 (95% confidence interval: 0.33-0.48) for abnormal vs normal cytology. CONCLUSIONS: These data suggest that referral population studies, by not including sufficient numbers of cytology normal women, underestimate the differences between HPV assays that would become apparent in primary screening. PMID- 28901681 TI - A VIGS screen identifies immunity in the Arabidopsis Pla-1 accession to viruses in two different genera of the Geminiviridae. AB - Geminiviruses are DNA viruses that cause severe crop losses in different parts of the world, and there is a need for genetic sources of resistance to help combat them. Arabidopsis has been used as a source for virus-resistant genes that derive from alterations in essential host factors. We used a virus-induced gene silencing (VIGS) vector derived from the geminivirus Cabbage leaf curl virus (CaLCuV) to assess natural variation in virus-host interactions in 190 Arabidopsis accessions. Silencing of CH-42, encoding a protein needed to make chlorophyll, was used as a visible marker to discriminate asymptomatic accessions from those showing resistance. There was a wide range in symptom severity and extent of silencing in different accessions, but two correlations could be made. Lines with severe symptoms uniformly lacked extensive VIGS, and lines that showed attenuated symptoms over time (recovery) showed a concomitant increase in the extent of VIGS. One accession, Pla-1, lacked both symptoms and silencing, and was immune to wild-type infectious clones corresponding to CaLCuV or Beet curly top virus (BCTV), which are classified in different genera in the Geminiviridae. It also showed resistance to the agronomically important Tomato yellow leaf curl virus (TYLCV). Quantitative trait locus mapping of a Pla-1 X Col-0 F2 population was used to detect a major peak on chromosome 1, which is designated gip-1 (geminivirus immunity Pla-1-1). The recessive nature of resistance to CaLCuV and the lack of obvious candidate genes near the gip-1 locus suggest that a novel resistance gene(s) confers immunity. PMID- 28901684 TI - Comparison of initial patient setup accuracy between surface imaging and three point localization: A retrospective analysis. AB - PURPOSE: Historically, the process of positioning a patient prior to imaging verification used a set of permanent patient marks, or tattoos, placed subcutaneously. After aligning to these tattoos, plan specific shifts are applied and the position is verified with imaging, such as cone-beam computed tomography (CBCT). Due to a variety of factors, these marks may deviate from the desired position or it may be hard to align the patient to these marks. Surface-based imaging systems are an alternative method of verifying initial positioning with the entire skin surface instead of tattoos. The aim of this study was to retrospectively compare the CBCT-based 3D corrections of patients initially positioned with tattoos against those positioned with the C-RAD CatalystHD surface imager system. METHODS: A total of 6000 individual fractions (600-900 per site per method) were randomly selected and the post-CBCT 3D corrections were calculated and recorded. For both positioning methods, four common treatment site combinations were evaluated: pelvis/lower extremities, abdomen, chest/upper extremities, and breast. Statistical differences were evaluated using a paired sample Wilcoxon signed-rank test with significance level of <0.01. RESULTS: The average magnitudes of the 3D shift vectors for tattoos were 0.9 +/- 0.4 cm, 1.0 +/- 0.5 cm, 0.9 +/- 0.6 cm and 1.4 +/- 0.7 cm for the pelvis/lower extremities, abdomen, chest/upper extremities and breast, respectively. For the CatalystHD, the average magnitude of the 3D shifts for the pelvis/lower extremities, abdomen, chest/upper extremities and breast were 0.6 +/- 0.3 cm, 0.5 +/- 0.3 cm, 0.5 +/- 0.3 cm and 0.6 +/- 0.2 cm, respectively. Statistically significant differences (P < 0.01) in the 3D shift vectors were found for all four sites. CONCLUSION: This study shows that the overall 3D shift corrections for patients initially aligned with the C-RAD CatalystHD were significantly smaller than those aligned with subcutaneous tattoos. Surface imaging systems can be considered a viable option for initial patient setup and may be preferable to permanent marks for specific clinics and patients. PMID- 28901685 TI - Diagnostic performance of CT, gadoxetate disodium-enhanced MRI, and PET/CT for the diagnosis of colorectal liver metastasis: Systematic review and meta analysis. AB - BACKGROUND: Imaging studies, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), have an essential role in the detection and localization of colorectal liver metastasis (CRLM). PURPOSE: To systematically determine the diagnostic accuracy of multidetector row CT (MDCT), gadoxetate disodium-enhanced MRI, and PET/CT for diagnosing CRLM and the sources of heterogeneity between the reported results. STUDY TYPE: Systematic review and meta-analysis. SUBJECTS: In all, 2151 lesions in CT studies, 2301 lesions in MRI studies, 1846 lesions in PET/CT studies, FIELD STRENGTH: 1.5T and 3.0T. ASSESSMENT: We identified research studies that investigated MDCT, gadoxetate disodium-enhanced MRI, and PET/CT to diagnose CRLM by performing a systematic search of PubMed MEDLINE and EMBASE. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). STATISTICAL TESTS: According to the types of imaging tests, study heterogeneity and the threshold effect were analyzed and the meta-analytic summary of sensitivity and specificity were estimated. Meta-regression analysis was performed to further investigate study heterogeneity. RESULTS: Of the 860 articles screened, we found 36 studies from 24 articles reporting a diagnosis of CRLM (11 CT studies, 12 MRI studies, and 13 PET/CT studies). The meta-analytic summary sensitivity for CT, MRI, and PET/CT were 82.1% (95% confidence interval [CI], 74.0-88.1%), 93.1% (95% CI, 88.4-96.0%), and 74.1% (95% CI, 62.1-83.3%), respectively. The meta-analytic summary specificity for CT, MRI, and PET/CT were 73.5% (95% CI, 53.7-86.9%), 87.3% (95% CI, 77.5-93.2%), and 93.9% (95% CI, 83.9 97.8%), respectively. There was no threshold effect in any of the imaging tests. Neoadjuvant chemotherapy significantly decreased the sensitivity of CT and MRI (P < 0.01), although it did not significantly affect the sensitivity of PET/CT. The study design, type of reference standard, and study quality also affected the diagnostic performances of imaging studies. DATA CONCLUSION: Despite the heterogeneous accuracy between studies, gadoxetate disodium-enhanced MRI showed the highest sensitivity, and gadoxetate disodium-enhanced MRI and PET/CT had similar specificities for diagnosing CRLM. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1237-1250. PMID- 28901686 TI - Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype. AB - Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. PMID- 28901687 TI - Treatment of multiple maxillary adjacent class I and II gingival recessions with modified coronally advanced tunnel and a new xenogeneic acellular dermal matrix. AB - OBJECTIVE: To evaluate the treatment of maxillary Miller Class I and II multiple adjacent gingival recessions using the modified coronally advanced tunnel technique (MCAT) combined with a new porcine acellular dermal matrix (PADM). MATERIALS AND METHODS: Twelve patients exhibiting at least six adjacent maxillary Miller Class I and II gingival recessions were consecutively treated by means of MCAT and a PADM. Recession depth (RD), recession width (RW), probing pocket depth (PD), keratinized tissue height (KT), clinical attachment level (CAL), mean root coverage (RC), and complete root coverage (CRC) were recorded. RESULTS: At 12 months, CRC was obtained in 43% of the 100 gingival recessions, while the mean RC measured 84.35%. Mean RD reduction was 3.16 +/- 0.75 mm (P < 0.001), mean RW reduction was 1.73 +/- 0.65 mm (P < 0.001), while the gain of CAL was 3.26 +/- 1.33 mm (P < 0.001). All patients were satisfied with the esthetic appearance and would undergo the same surgery again. CONCLUSION: Within their limits, the present results indicate that treatment of Miller Class I and II multiple gingival recessions using PADM in conjunction with the MCAT could be successfully used as an alternative to connective tissue grafts, with the advantage of avoiding the discomfort and morbidity of connective tissue harvesting. CLINICAL SIGNIFICANCE: The modified coronally advanced tunnel technique using the new porcine acellular dermal matrix represents a clinically and esthetically satisfactory treatment of multiple Miller Class 1 and 2 recession defects. PMID- 28901688 TI - Poly(glycerol sebacate) combined with chondroitinase ABC promotes spinal cord repair in rats. AB - This study was to investigate the feasibility of PGS combined with ChABC for repairing the transection of spinal cords (TSC) in rats. A thoracic 10 (T10) TSC model of rats was employed. The effects of PGS with ChABC on the morphology and histological structure of the spinal cords, Basso, Beattie, Bresnahan (BBB) scores, and the expression of GAP-43 and NF-200 were comparatively studied. The BBB scores indicated that all rats with TSC were paralyzed immediately after surgery and then recovered hind limb movement gradually, but did not fully recover until the end of week 12. The rats treated with PGS alone, ChABC alone, and PGS/ChABC recovered significantly (p < 0.05) better than the control rats with TSC only. The PGS/ChABC treated rats recovered significantly (p < 0.05) more movement function than the rats treated with PGS or ChABC treated alone. The spinal cords in the control rats showed lusterless surfaces, big holes, and big scars; in both PGS rats and ChABC rats showed lucent surfaces, small holes, and small scars; in PGS/ChABC rats showed the best. The expression of GAP-43 and NF 200 in the TSC region was hardly detected in the control rats, moderately detected in PGS or ChABC rats, and highly detected in PGS/ChABC rats. In conclusion, both PGS and ChABC alone could promote nerve regeneration and partially recover the movement function in TSC rats. A combination of PGS and ChABC resulted in augmented nerve regeneration and functional recovery. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1770 1777, 2018. PMID- 28901689 TI - Prevascularization of 3D printed bone scaffolds by bioactive hydrogels and cell co-culture. AB - Vascularization is a fundamental prerequisite for large bone construct development and remains one of the main challenges of bone tissue engineering. Our current study presents the combination of 3D printing technique with a hydrogel-based prevascularization strategy to generate prevascularized bone constructs. Human adipose derived mesenchymal stem cells (ADMSC) and human umbilical vein endothelial cells (HUVEC) were encapsulated within our bioactive hydrogels, and the effects of culture conditions on in vitro vascularization were determined. We further generated composite constructs by forming 3D printed polycaprolactone/hydroxyapatite scaffolds coated with cell-laden hydrogels and determined how the co-culture affected vascularization and osteogenesis. It was demonstrated that 3D co-cultured ADMSC-HUVEC generated capillary-like networks within the porous 3D printed scaffold. The co-culture systems promoted in vitro vascularization, but had no significant effects on osteogenesis. The prevascularized constructs were subcutaneously implanted into nude mice to evaluate the in vivo vascularization capacity and the functionality of engineered vessels. The hydrogel systems facilitated microvessel and lumen formation and promoted anastomosis of vascular networks of human origin with host murine vasculature. These findings demonstrate the potential of prevascularized 3D printed scaffolds with anatomical shape for the healing of larger bone defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1788-1798, 2018. PMID- 28901690 TI - Hypothenar hammer syndrome in an office worker. AB - Hypothenar hammer syndrome (HHS) is an uncommon cause of unilateral Raynaud's phenomenon, splinter haemorrhages and hypothenar weakness. The typical patient is a male blue-collar worker who uses their hypothenar eminence to hammer objects as part of their work. The distal ulnar artery beyond Guyon's canal is superficial and vulnerable to blunt trauma. CTA and MRA are common initial investigations and can suggest the diagnosis. DSA is the gold standard imaging modality and offers therapeutic opportunities. Management is controversial, but unless there is critical digital ischaemia, conservative treatment is first line. PMID- 28901691 TI - Psychodynamic day treatment programme for patients with schizophrenia spectrum disorders: Dynamics and predictors of therapeutic change. AB - OBJECTIVES: The purpose of this study was to test whether a psychodynamically based group psychotherapeutic programme might improve symptoms, social functions, or quality of life in patients with schizophrenia spectrum disorders and to investigate factors that might predict clinical improvement or dropouts from the programme. DESIGN: A quantitative prospective cohort study. METHODS: We have investigated 81 patients with schizophrenia spectrum disorders who participated in a 9-month psychodynamically based psychotherapeutic day programme. The patients were assessed at the beginning and end of the programme, and then at 1 year follow-up. The assessment included psychotic manifestations (HoNOS), quality of life (WHOQOL-BREF), demographic data, and daily doses of medication. 21 patients dropped out from the programme, and 46 patients succeeded in undergoing follow-up assessment. RESULTS: The psychotic manifestations (self-rating version of HoNOS) and quality of life measured with WHOQOL-BREF (domains of social relationships and environment) were significantly improved at the end of the programme and at follow-up. However, the manifestations on the version for external evaluators of HoNOS were improved only at follow-up. Years of psychiatric treatment, number of hospitalizations or suicide attempts, and experience of relationships with a partner were negatively related to clinical improvement, whereas symptom severity, current working, or study activities were related positively. CONCLUSIONS: The results show that a group psychodynamic programme may improve the clinical status and quality of life of patients with schizophrenia spectrum disorders. This type of programme is more beneficial for patients with higher pre-treatment symptom severity and the presence of working or study activities. PRACTITIONER POINTS: A psychodynamically based group programme improves the clinical status and quality of life in patients with schizophrenia spectrum disorders. Data indicate that changes on the subjective level are detectable by the end of the programme, while changes on the objective level are detectable at follow-up assessment. Symptom severity and working or study activities are positively related to the clinical improvement in this type of programme, while a high number of years in psychiatric treatment or psychiatric hospitalizations are negatively related. The doses of medication (antipsychotics or antidepressants) show no significant relationship to clinical improvement. PMID- 28901693 TI - Prevention of Early-onset Neonatal Group B Streptococcal Disease: Green-top Guideline No. 36. PMID- 28901694 TI - The role of cognitive biases in short-term psychodynamic psychotherapy. AB - : The concept of biased thinking - or cognitive biases - is relevant to psychotherapy research and clinical conceptualization, beyond cognitive theories. The present naturalistic study aimed to examine the changes in biased thinking over the course of a short-term dynamic psychotherapy (STDP) and to discover potential links between these changes and symptomatic improvement. This study focuses on 32 self-referred patients consulting for Adjustment Disorder according to DSM-IV-TR. The therapists were experienced psychodynamically oriented psychiatrists and psychotherapists. Coding of cognitive biases (using the Cognitive Errors Rating Scale; CERS) was made by external raters based on transcripts of interviews of psychotherapy; the reliability of these ratings on a randomly chosen 24% of all sessions was established. Based on the Symptom Check List SCL-90-R given before and after, the Reliable Change Index (RCI) was used. The assessment of cognitive errors was done at three time points: early (session 4-7), mid-treatment (session 12-17), and close to the end (after session 20) of the treatment. The results showed that the total frequency of cognitive biases was stable over time (p = .20), which was true both for positive and for negative cognitive biases. In exploring the three main subscales of the CERS, we found a decrease in selective abstraction (p = .02) and an increase in personalization (p = .05). A significant link between RCI scores (outcome) and frequency of positive cognitive biases was found, suggesting that biases towards the positive might have a protective function in psychotherapy. PRACTITIONER POINTS: Therapists may be attentive to changes in biased thinking across short-term dynamic psychotherapy for adjustment disorder. Therapists may foster the emergence of positive cognitive biases at mid-treatment for adjustment disorder. PMID- 28901692 TI - Synthesis and Multiple Incorporations of 2'-O-Methyl-5-hydroxymethylcytidine, 5 Hydroxymethylcytidine and 5-Formylcytidine Monomers into RNA Oligonucleotides. AB - The synthesis of 2'-O-methyl-5-hydroxymethylcytidine (hm5 Cm), 5 hydroxymethylcytidine (hm5 C) and 5-formylcytidine (f5 C) phosphoramidite monomers has been developed. Optimisation of mild post-synthetic deprotection conditions enabled the synthesis of RNA containing all four naturally occurring cytosine modifications (hm5 Cm, hm5 C, f5 C plus 5-methylcytosine). Given the considerable interest in RNA modifications and epitranscriptomics, the availability of synthetic monomers and RNAs containing these modifications will be valuable for elucidating their biological function(s). PMID- 28901695 TI - Vitamin D: Australian dietitian's knowledge and practices. AB - AIM: To survey dietitians on their knowledge and practices regarding vitamin D (VitD) intake, sources, supplementation and effect on disease state. METHODS: An online survey was disseminated to members of the Dietitian Association Australia via the weekly online state newsletter during April 2015. Response rate was 3%, with 134 respondents completing the survey. The survey included questions about knowledge and current practices. Descriptive statistics were used to analyse the results. RESULTS: Dietitians have good knowledge regarding dietary sources of VitD and roles in the body, but there is confusion around supplement doses for treatment and prevention of deficiency and sun exposure guidelines. CONCLUSIONS: Dietitians are well positioned to provide patients with advice on VitD supplementation and sun exposure practices, but not all are confident to provide this care. There is a need for clear and well-disseminated guidelines for VitD management by dietitians. PMID- 28901696 TI - Creating the dietitians of the future. PMID- 28901697 TI - Qualitative study of patients and health-care professionals' views on the efficacy of the nutrition as medication oral nutrition supplement program. AB - AIM: The use of concentrated oral nutrition supplements dispensed in small volumes throughout the day at medication rounds is a common nutrition support strategy. Often termed 'Nutrition as Medication' or NAM, it is associated with excellent rates of patient consumption. However, administration of NAM has been described as suboptimal. The aim of the present study was to identify and explore factors influencing the efficacy of the NAM program from a qualitative perspective. This included exploring issues relating to knowledge, administration and patient consumption from a patient and health professional perspective. METHODS: Semistructured interviews with patients (n = 7) and eight focus groups with nursing, medical, pharmacy and dietetic staff (n = 63) were conducted. Interviews were conducted in the workplace and were recorded and transcribed verbatim. Data were analysed from a realist theoretical position using the thematic framework approach. RESULTS: Five themes were identified that impact on the efficacy of the NAM program. These include the need for clear role delineation among health professionals regarding responsibility for each aspect of NAM. Other themes that emerged included misconceptions about the importance and relevance of the treatment; perceptions of poor palatability and issues associated with the logistics of providing the supplements within the hospital setting. CONCLUSIONS: Dietitians should be aware that there are a range of factors that influence the efficacy of the NAM strategy, including the knowledge and values of individual health professional staff. In addition, increased awareness is required by dietitians regarding the structural barriers to administration and receiving of NAM at the ward level. PMID- 28901698 TI - Online training introduces a novel approach to the Dietetic Care Process documentation. AB - AIM: Nutrition professionals in Israel are developing a system to document the Dietetic Care Process (DCP) tailored for specific patient sectors and compliant with national health guidelines. The ultimate goal is to achieve uniform documentation and improve nutrition care. Israeli dietetic practitioners work in specific patient sectors; therefore, a patient population-specific reporting system is proposed instead of the typical singular format applied across all patient populations. The purpose of this project was to evaluate learning outcomes and attitudes among registered dietitians (RDs) after online training of a novel DCP documentation system. METHODS: A total of 80 Israeli RDs working in geriatric practice completed an eight-week online educational program learning documentation that is compatible for use with electronic health records and compliant with Israeli standards of practice. A paired sample t-test and McNemar test were used to analyse pre- to post-test performance, while Pearson's r, point biserial, Spearman's and ANOVA were used to assess relationships among variables. RESULTS: Post-test knowledge scores increased significantly, t (67) = -9.007, P = 0.000; 95% CI (-26.713, -17.019). Age, education, geographic location and previous experience with online courses were not correlated with academic performance, suggesting that demographic characteristics did not impact training. Overall, RDs (>80%) responded positively to the training model and were highly interested in future proficiency online learning opportunities (98%). CONCLUSIONS: A sectoral DCP online training program significantly improved knowledge and was rated favourably by Israeli RDs. DCP training for clinical practitioners may be optimised when standardised nutrition care and reporting systems are adapted to specific patient populations. PMID- 28901699 TI - Attitudes towards and experiences with research: Differences between dietetics students and professionals in Australia and the United States. AB - AIM: Research conducted by dietitians is encouraged by national and international organisations, yet research output remains low. The attitudes towards and experiences with research and research methods course work of students and practitioners in Australia and the United States were examined. METHODS: A cross sectional online survey was conducted. Participants were contacted by email; 173 Australian (N = 50 students; 123 practitioners) and 499 US (N = 231 students; 268 practitioners) respondents completed the survey. RESULTS: A smaller proportion of American students (74%) indicated that they would consider conducting research in the future compared to Australian students (84%) (P < 0.001). More Australian than American practitioners indicated interest in conducting research in their current position (87% vs 66%; P < 0.001). Research training did not increase future research plans, but respondents who had conducted research either as a student or at work responded more favourably to conducting research in the future (P < 0.001). In general, Australian respondents were more supportive of and more experienced with research. CONCLUSIONS: Unlike classroom training, past research experiences supported plans for future research. Further work needs to investigate how the culture of the profession can be changed to support more dietitian-conducted research. PMID- 28901700 TI - Successful long-term maintenance following Nutrition Care Process Terminology implementation across a state-wide health-care system. AB - AIM: Three years following a state-wide Nutrition Care Process Terminology (NCPT) implementation project, the present study aimed to (i) assess changes in NCPT knowledge and attitudes, (ii) identify implementation barriers and enablers and (iii) seek managers' opinions post-implementation. METHODS: Pre-implementation and three years post-implementation, all Queensland Government hospitals state wide were invited to repeat a validated NCPT survey. Additionally, a separate survey sought dietetic managers' opinions regarding NCPT's use and acceptance, usefulness for patient care, role in service planning and continued use. RESULTS: A total of 238 dietitians completed the survey in 2011 and 82 dietitians in 2014. Use of diagnostic statement in the previous six months improved (P < 0.001). Perceptions of NCPT's importance (P < 0.020) and benefits of incorporating NCPT into practice (P = 0.029) increased. Time to complete NCPT documentation (P < 0.013) and access to mentors decreased (P < 0.001). Other areas including enhanced attitudes, familiarity, confidence, views, knowledge and incorporation into practice were sustained (P > 0.05). Key elements in sustaining NCPT implementation over three years included ongoing management support, workshops/tutorials, discussion and mentor and peer support. The most valued resources were pocket guides, ongoing workshops/tutorials and mentor support. Dietetic managers held many positive NCPT views, however, opinions differed around the usefulness of service planning, safer practice, improving patient care and facilitating communication. Some managers would not support NCPT unless it was recommended for practice. CONCLUSIONS: Immediate improvements following the NCPT implementation project were sustained over three years. Moving forward, a professional focus on continuing to incorporate NCPT into standard practice will provide structure for process and outcomes assessment. PMID- 28901701 TI - Exploring extended scope of practice in dietetics: A systems approach. AB - AIM: The aim of this study was to explore health professionals' perceptions of an extended scope of a practice clinic, and develop a framework using a systems approach to facilitate extended scope models across various health settings. METHODS: A qualitative investigation using semi-structured interviews with four health professionals involved in an extended scope dietitian-led gastroenterology clinic in a hospital in regional Queensland was conducted. A case study design was utilised to investigate interviewees' perceptions of the clinic. Participants were conveniently, purposively sampled. Transcript analysis involved a descriptive analytical approach. Interviewee responses were coded and categorised into themes, and investigator triangulation was used to ensure consistency between individual analyses. A secondary interpretative analysis was conducted where relationships between key themes were mapped to the Systems Engineering Initiative for Patient Safety work system model. RESULTS: Interviewees identified various factors as vital inputs to the work system. These were categorised into the four key elements: stakeholder support, resources, planning and the dietitian. Clinic outcomes were categorised into the impact on four key groups: patients, the dietitian, the multidisciplinary team and the health system. Mapping of the relationships between inputs and outcomes resulted in an implementation framework for extended scope of practice. CONCLUSIONS: Extended scope of practice in dietetics may provide positive outcomes for various stakeholders. However, further development of extended scope roles for dietitians requires increased advocacy and support from governments, professional bodies, training institutions and dietitians. We have developed an implementation framework which can be utilised by health professionals interested in embracing an extended scope model of care. PMID- 28901702 TI - Eating attitudes and behaviours of students enrolled in undergraduate nutrition and dietetics degrees. AB - AIM: The prevalence of disordered eating has been frequently reported in university students; however, the prevalence amongst Australian undergraduate students studying degrees with a focus on nutrition is uncertain. The aims of this study were to: (i) assess eating attitudes and behaviours of students enrolled in nutrition and dietetics, (ii) compare those to students enrolled in another health degree of occupational therapy (OT) and (iii) explore possible relationships between eating attitudes and behaviours and other characteristics of both cohorts. METHODS: This cross-sectional observational study investigated self-reported anthropometric characteristics, eating attitudes and behaviours and self-esteem using a series of questionnaires. RESULTS: Participants included 137 students (119 females, 18 males) with a mean age of 27.1 +/- 8.7 years. Fourteen percent of nutrition and dietetics and 11% of OT students had disordered eating attitudes scores that were symptomatic of an eating disorder. Mean eating attitude scores did not differ between the degrees of study. Students in nutrition and dietetics showed significantly higher levels of cognitive restraint and less emotional eating than OT students. Enrolment in the first year of study was the strongest predictor of symptomatic eating attitudes. CONCLUSIONS: These findings support previously expressed concern about presence of disordered eating in nutrition and dietetics undergraduates. Collaboratively developed support mechanisms for preventing and managing disordered relationships with food would be of benefit to students enrolled in nutrition degrees to ensure ongoing professional integrity. PMID- 28901703 TI - Development of a structured diabetes self-management education program specific to the cultural and ethnic population of New Zealand. AB - AIM: To develop and pilot a diabetes self-management education (DSME) program specific to the needs of New Zealanders with type 2 diabetes mellitus (T2DM). METHODS: There were two parts in the present study. The first was the development of the program. This involved a literature review, consultation with end-user groups and drafting the content of the program. In the second part, the program was tested and modified according to feedback provided by both participants and facilitators. RESULTS: The present study achieved its primary goal of developing, piloting and modifying a DSME program specific to the New Zealand population. The DSME program was developed using concepts and content of international DSME programs. The content and concept was extensively tested via discussion groups with 71 individuals with T2DM and practice nurses to ensure the program met the unique cultural needs of New Zealanders with T2DM. Twenty-seven participants with T2DM were recruited into the pilot, of which 13 attended four of six sessions. Feedback from participants, observing nurses and facilitators was incorporated into the final program. CONCLUSIONS: DSME programs are an effective vehicle for providing individuals with T2DM the initial information and support to start self managing their diabetes. However, to ensure DSME programs help individuals with the highest rates of diabetes and diabetes-related complications, it is important end-users participate in the development of the program. This DSME program now requires longitudinal trial to determine if in the New Zealand context it is able generate the same improvements in both clinical and qualitative outcomes as seen in similar international programs. PMID- 28901704 TI - Audit of the dietetic care of patients with type 1 diabetes at a large Australian paediatric tertiary hospital and comparison with the International Society for Paediatric and Adolescent Diabetes nutrition guidelines. AB - AIM: Optimal glycaemic control is important in children and adolescents with type 1 diabetes (T1D) to reduce the risk of developing microvascular complications. Modest reductions in HbA1c translate to significant risk reductions of these complications. Research indicates that targeted dietetic care using evidence based guidelines improves HbA1c levels. The aim of this study was to audit the dietetic care provided to patients with T1D at the Women's and Children's Hospital (WCH) and compare the service provided to the International Society for Paediatric and Adolescent Diabetes (ISPAD) nutrition guidelines. METHODS: A retrospective medical records audit of the dietetic service was conducted on 410 (99% of eligible) patients who attended the WCH Diabetes Outpatient Clinic between 1 January 2010 and 30 June 2013. These data were then compared to the ISPAD nutrition guidelines, with a focus on the key service delivery targets. RESULTS: Of the newly diagnosed patients (n = 128), 100% received initial dietary advice by a paediatric diabetes dietitian; 61% of these patients then received a follow-up appointment within one month of diagnosis. Of those who were >1 year post-diagnosis (n = 389), only 6% were seen annually; 79% of patients were identified with a condition requiring more frequent review, of whom 23% were seen more frequently. CONCLUSIONS: This large and comprehensive audit, conducted for a 3.5-year period, has shown that the dietetic care of newly diagnosed children and adolescents is mostly in line with ISPAD guidelines, but there is suboptimal follow-up after diagnosis. PMID- 28901705 TI - Peer-assisted learning and small-group teaching to improve practice placement quality and capacity in dietetics. AB - AIM: Peer-assisted learning (PAL) has been positively evaluated during practice placements for medical, nursing and some allied health professional students. The aim of this study was to evaluate a PAL and small-group teaching model of dietetic practice placement education implemented in the UK setting as part of a quality improvement process. METHODS: A PAL placement model was adapted from a previously published Australian model, implemented and evaluated among dietetic students at King's College London and with their practice educators. Process evaluation with students and practice educators from PAL practice placements at two sites and traditional 1:1 practice placements at six sites consisted of weekly questionnaires and end-of-placement focus groups with 16 students and 35 practice educators. Perceptions of the barriers, concerns and strengths of the novel model were identified. RESULTS: Implementing the PAL placement model at just two sites increased placement capacity by 12 students, a 1.3-fold increase across London. Students on PAL placements reported a good learning experience (89.3 vs 67.7%; P < 0.001) and a satisfactory workload (83.1 vs 61.3%, P = 0.005) more frequently than those on a traditional 1:1 placement. Practice educators reported significantly less time undertaking direct student supervision on PAL practice placements compared to 1:1 placements (153 minutes/week 95% confidence interval (CI) 124-183 vs 264 minutes/week 95% CI 204-324; P = 0.001). CONCLUSIONS: PAL practice placements offer potential benefits to placement capacity and possibly quality. The detailed evaluation will enable others to implement similar novel models of dietetics placements. PMID- 28901706 TI - Development of advanced practice competency standards for dietetics in Australia. AB - AIM: This study aimed to explore the work roles, major tasks and core activities of advanced practice dietitians in Australia to define the Competency Standards for advanced practice. METHODS: A qualitative approach was used to review advanced dietetic practice in Australia involving experienced professionals, mostly dietitians. Four focus groups were conducted with a total of 17 participants and an average of 20 years experience: 15 dietitian practitioners plus 2 employers (1 dietitian and 1 non-dietitian). The focus groups explored the key purpose, roles and outcomes of these practitioners. Data from the focus groups were confirmed with in-depth interviews about their core activities with a purposive sample of 10 individuals recently recognised as Advanced Accredited Practising Dietitians. Data from both focus groups and interviews were analysed adductively to identify key themes. RESULTS: The key theme that emerged to define advanced dietetics practice was leadership, with four subthemes that described in more detail the major work roles and outcomes of advanced practice. These subthemes identified that advanced practitioners were (i) outcome-focused, having impact; (ii) influence others and advocate; (iii) innovate and embrace change; and (iv) inspire others and are recognised for their practice. These outcomes were conceptualised within a broad generalist framework to generate revised Competency Standards. CONCLUSIONS: This study confirmed that leadership rather than specialist practice skills is the key determinant of advanced practice. PMID- 28901707 TI - Taking a systems-thinking approach to competency-based assessment for dietetics. PMID- 28901708 TI - Dietitians Association of Australia 33rd National Conference: Lecture in honour of Dr Fiona Cumming-Life, Leadership and Landing. PMID- 28901709 TI - Exploring subjectivity in competency-based assessment judgements of assessors. AB - AIM: The aim of this research was to measure variations in assessors' judgements of a student dietitian's performance and to explore the influence of group discussion on their judgements. METHODS: The assessments of a student's performance, as observed from a video recording of an authentic nutrition consultation, were measured pre- and post-group discussion by 26 experienced assessors using a mixed-methods questionnaire. The instrument included a validated 7-point visual analogue scale (VAS) rating (1 = novice; 7 = competent), a qualitative global description of performance and an assessor's confidence rating (1 = not at all confident; 10 = extremely confident). Scales were analysed descriptively and qualitative responses coded for key themes. RESULTS: No agreement was found in assessors' rating in either the pretest (median = 4, range = 5) or post-test (median = 4, range = 4); however, the discussion led 78% of participants (20/26) to change their VAS ratings (9/26) and/or confidence levels (16/26). Three themes emerged from the thematic analysis of the participants' global descriptions of performance: (i) discourse supports assessors to justify their judgements, identify assumptions and learn from the observations of others; (ii) discourse leads assessors to more holistic judgements; and (iii) multiple sources of evidence and student reflections are necessary for credible judgement. CONCLUSIONS: This research questions the notion that 'actual' performance can be objectively measured and, rather, considers assessments as 'interpretations'. This research calls for an integrated interpretivist student-centred approach to competency-based assessment. PMID- 28901710 TI - Reduced urothelial regeneration in rat bladders augmented with permeable porcine small intestinal submucosa assessed by magnetic resonance imaging. AB - Augmentation enterocystoplasty remains the gold standard surgical bladder reconstruction procedure to increase the capacity and compliance of dysfunctional bladders. Since the use of the patient's intestine has severe risks of complications, alternative biodegradable matrices have been explored. Porcine small intestinal submucosa (SIS) has gained immense interests in bladder reconstruction due to its favorable properties. However, trials have shown inconsistent regeneration with SIS, attributed to the heterogeneity in microstructures and mechanical properties. We hypothesize that uneven SIS permeability to urine is a factor responsible for the inconsistency. We measured permeability to urine in situ using a contrast enhanced-magnetic resonance imaging (MRI), and evaluated urothelium regeneration using immunohistochemical staining of urothelial cell markers in SIS-augmented rat bladders. Results showed significant differences in permeability among SIS-augmented rat bladders. Commercial SIS scaffolds were then categorized into nonleaky and leaky groups based on MRI results. Hematoxylin and eosin staining showed higher numbers of inflammatory cells in leaky SIS on day 14 relative to nonleaky SIS. In addition, trichrome staining showed major changes in the distribution of collagen on day 28 between SIS-augmented bladder groups. Furthermore, expressions of urothelium associated markers (cytokeratins AE1/AE3, claudin 4, and uroplakin III) were completed in bladders augmented with nonleaky SIS, whereas limited urothelial differentiation was noticed in leaky SIS-augmented bladders at post-augmentative day 14. These results show that scaffold permeability to urine may be responsible for variations in regenerative capacity of porcine SIS. Applications of MRI technique will be helpful to understand a relationship between biomaterial property and regenerative capacity. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1778-1787, 2018. PMID- 28901711 TI - Learning to name smells increases activity in heteromodal semantic areas. AB - Semantic description of odors is a cognitively demanding task. Learning to name smells is, however, possible with training. This study set out to examine how improvement in olfactory semantic knowledge following training reorganizes the neural representation of smells. First, 19 nonexpert volunteers were trained for 3 days; they were exposed (i) to odorants presented without verbal labels (perceptual learning) and (ii) to other odorants paired with lexicosemantic labels (associative learning). Second, the same participants were tested in a brain imaging study (fMRI) measuring hemodynamic responses to learned odors presented in both the perceptual and associative learning conditions. The lexicosemantic training enhanced the ability to describe smells semantically. Neurally, this change was associated with enhanced activity in a set of heteromodal areas-including superior frontal gyrus-and parietal areas. These findings demonstrate that odor-name associative learning induces recruitment of brain areas involved in the integration and representation of semantic attributes of sensory events. They also offer new insights into the brain plasticity underlying the acquisition of olfactory expertise in lay people. Hum Brain Mapp 38:5958-5969, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28901712 TI - Engineering Concepts in Stem Cell Research. AB - The field of regenerative medicine integrates advancements made in stem cells, molecular biology, engineering, and clinical methodologies. Stem cells serve as a fundamental ingredient for therapeutic application in regenerative medicine. Apart from stem cells, engineering concepts have equally contributed to the success of stem cell based applications in improving human health. The purpose of various engineering methodologies is to develop regenerative and preventive medicine to combat various diseases and deformities. Explosion of stem cell discoveries and their implementation in clinical setting warrants new engineering concepts and new biomaterials. Biomaterials, microfluidics, and nanotechnology are the major engineering concepts used for the implementation of stem cells in regenerative medicine. Many of these engineering technologies target the specific niche of the cell for better functional capability. Controlling the niche is the key for various developmental activities leading to organogenesis and tissue homeostasis. Biomimetic understanding not only helped to improve the design of the matrices or scaffolds by incorporating suitable biological and physical components, but also ultimately aided adoption of designs that helped these materials/devices have better function. Adoption of engineering concepts in stem cell research improved overall achievement, however, several important issues such as long-term effects with respect to systems biology needs to be addressed. Here, in this review the authors will highlight some interesting breakthroughs in stem cell biology that use engineering methodologies. PMID- 28901714 TI - Modular Organization of the Thermobifida fusca Exoglucanase Cel6B Impacts Cellulose Hydrolysis and Designer Cellulosome Efficiency. AB - : Cellulose deconstruction can be achieved by three distinct enzymatic paradigms: free enzymes, multifunctional enzymes, and self-assembled, multi-enzyme complexes (cellulosomes). To study their comparative efficiency, the simple and efficient cellulolytic system of the aerobic bacterium, Thermobifida fusca, is developed as an enzymatic model. In previous studies, most of its cellulases are successfully converted to the cellulosomal mode and exhibited high cellulolytic activities, except for Cel6B, a key exoglucanase of the T. fusca enzymatic system. Here, the impact of the modular organization of Cel6B on enzymatic activity is investigated. The position of the cellulose-binding module (CBM), its family and linker segment are shown to affect activity. Surprisingly, exchange of the native family-2 CBM to family-3 generates an increase in Cel6B activity on cellulosic substrates. Conversion of Cel6B to the cellulosomal mode by fusing a cohesin to the catalytic module enables formation of divalent enzyme complexes with dockerin bearing enzymes. The resultant pseudo-cellulosomes, containing Cel6B combined with endoglucanase Cel5A, exhibits enhanced enzymatic activity, compared to mixtures of wild-type enzymes or bifunctional enzymes, unlike similar pseudo cellulosomes containing endoglucanase Cel6A or proccessive endoglucanase Cel9A. Insight into the different enzymatic paradigms benefits ongoing development of efficient cellulolytic systems for conversion of plant-derived biomass into valuable sugars. NOVELTY STATEMENT: The protein engineering of the modular arrangement of a key exoglucanase from a highly cellulolytic bacterium, Thermobifida fusca, served to explore and compare three major enzymatic paradigms for cellulose degradation. This approach revealed highly active chimaeric forms of the exoglucanase that act in synergy together with a potent endoglucanase in bifunctional enzymes or divalent pseudo-cellulosome-like complexes. Such engineered enzymes could be further integrated into larger enzymatic complexes, thereby providing a significant step forward towards conversion of the entire T. fusca free cellulolytic system into the cellulosomal modex and the enhanced conversion of cellulosic biomass into soluble sugars. PMID- 28901715 TI - Engineering Microbial Metabolite Dynamics and Heterogeneity. AB - As yields for biological chemical production in microorganisms approach their theoretical maximum, metabolic engineering requires new tools, and approaches for improvements beyond what traditional strategies can achieve. Engineering metabolite dynamics and metabolite heterogeneity is necessary to achieve further improvements in product titers, productivities, and yields. Metabolite dynamics, the ensemble change in metabolite concentration over time, arise from the need for microbes to adapt their metabolism in response to the extracellular environment and are important for controlling growth and productivity in industrial fermentations. Metabolite heterogeneity, the cell-to-cell variation in a metabolite concentration in an isoclonal population, has a significant impact on ensemble productivity. Recent advances in single cell analysis enable a more complete understanding of the processes driving metabolite heterogeneity and reveal metabolic engineering targets. The authors present an overview of the mechanistic origins of metabolite dynamics and heterogeneity, why they are important, their potential effects in chemical production processes, and tools and strategies for engineering metabolite dynamics and heterogeneity. The authors emphasize that the ability to control metabolite dynamics and heterogeneity will bring new avenues of engineering to increase productivity of microbial strains. PMID- 28901713 TI - Neural correlates of interoception: Effects of interoceptive focus and relationship to dimensional measures of body awareness. AB - Interoception has been defined as the sensing of the physiological condition of the body, with interoceptive sensibility (IS) characterizing an individual's self reported awareness of internal sensation. IS is a multidimensional construct including not only the tendency to be aware of sensation but also how sensations are interpreted, regulated, and used to inform behavior, with different dimensions relating to different aspects of health and disease. Here we investigated neural mechanisms of interoception when healthy individuals attended to their heartbeat and skin temperature, and examined the relationship between neural activity during interoception and individual differences in self-reported IS using the Multidimensional Scale of Interoceptive Awareness (MAIA). Consistent with prior work, interoception activated a network involving insula and sensorimotor regions but also including occipital, temporal, and prefrontal cortex. Differences based on interoceptive focus (heartbeat vs skin temperature) were found in insula, sensorimotor regions, occipital cortex, and limbic areas. Factor analysis of MAIA dimensions revealed 3 dissociable components of IS in our dataset, only one of which was related to neural activity during interoception. Reduced scores on the third factor, which reflected reduced ability to control attention to body sensation and increased tendency to distract from and worry about aversive sensations, was associated with greater activation in many of the same regions as those involved in interoception, including insula, sensorimotor, anterior cingulate, and temporal cortex. These data suggest that self-rated interoceptive sensibility is related to altered activation in regions involved in monitoring body state, which has implications for disorders associated with abnormality of interoception. Hum Brain Mapp 38:6068-6082, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28901716 TI - NIR-Absorbing Donor-Acceptor Based 1,1,4,4-Tetracyanobuta-1,3-Diene (TCBD)- and Cyclohexa-2,5-Diene-1,4-Ylidene-Expanded TCBD-Substituted Ferrocenyl Phenothiazines. AB - A series of unsymmetrical (D-A-D1 , D1 -pi-D-A-D1 , and D1 -A1 -D-A2 -D1 ; A=acceptor, D=donor) and symmetrical (D1 -A-D-A-D1 ) phenothiazines (4 b, 4 c, 4 c', 5 b, 5 c, 5 d, 5 d', 5 e, 5 e', 5 f, and 5 f') were designed and synthesized by a [2+2] cycloaddition-electrocyclic ring-opening reaction of ferrocenyl substituted phenothiazines with tetracyanoethylene (TCNE) and 7,7,8,8 tetracyanoquinodimethane (TCNQ). The photophysical, electrochemical, and computational studies show a strong charge-transfer (CT) interaction in the phenothiazine derivatives that can be tuned by varying the number of TCNE/TCNQ acceptors. Phenothiazines 4 b, 4 c, 4 c', 5 b, 5 c, 5 d, 5 d', 5 e, 5 e', 5 f and 5 f' show redshifted absorption in the lambda=400 to 900 nm region, as a result of a low HOMO-LUMO gap, which is supported by TD-DFT calculations. The electrochemical study exhibits reduction waves at low potential due to strong 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) and cyclohexa-2,5-diene-1,4-ylidene expanded TCBD acceptors. The incorporation of cyclohexa-2,5-diene-1,4-ylidene expanded TCBD stabilized the LUMO energy level to a greater extent than TCBD. PMID- 28901717 TI - Preliminary result with incisional negative pressure wound therapy and pectoralis major muscle flap for median sternotomy wound infection in a high-risk patient population. AB - Deep sternal wound infection (DSWI) represents a dangerous complication that can follow open-heart surgery with median sternotomy access. Muscle flaps, such as monolateral pectoralis major muscle flap (MPMF), represent the main choices for sternal wound coverage and infection control. Negative pressure incision management system has proven to be able to reduce the incidence of these wounds' complications. PrevenaTM represents one of these incision management systems and we aimed to evaluate its benefits. A total of 78 patients with major risk factors that presented post-sternotomy DSWI following cardiac surgery was selected. Thrity patients were treated with MPMF and PrevenaTM (study group). Control group consisted of 48 patients treated with MPMF and conventional wound dressings. During the follow-up period, 4 (13%) adverse events occurred in the study group, whereas 18 complications occurred (37.5%) in the control group. Surgical revision necessity and mean postoperative time spent in the intensive care unit were both higher in the control group. Our results evidenced PrevenaTM system's ability in improving the outcome of DSWI surgical treatment with MPMF in a high-risk patient population. PMID- 28901719 TI - Appropriate fabrication method for pressure-formed mouthguards using ethylene vinyl acetate sheets. AB - BACKGROUND/AIMS: Fabrication of mouthguards should be performed properly. However, the appropriate heating temperature for fabricating a pressure-formed mouthguard has not been determined. The aim of this study was to examine the influence of the heating temperature on the fabrication of a pressure-formed mouthguard. MATERIALS AND METHODS: Mouthguard sheets of 3.8 mm ethylene vinyl acetate were pressure-formed on a working model at three heating temperatures: 80, 100, and 120 degrees C. The thickness of the mouthguard was measured at the labial surface of the central incisor, and the buccal and occlusal surfaces of the first molar. The fit of the mouthguard was examined at the central incisor and first molar by measuring the distance between the mouthguard and the cervical margin of the working model. Differences in the thickness of the mouthguards according to the heating temperatures were analyzed by two-way analysis of variance, and differences in the fit were analyzed by one-way analysis of variance. RESULTS: Mouthguard thickness varied among the measured regions of the central incisors and first molars (P < .01). The greatest thickness was found at the labial surface of the central incisor and the buccal surface of the first molar in mouthguards fabricated at the heating temperature of 120 degrees C (P < .01). Mouthguard fit varied among the heating temperatures of the central incisors, and the greatest fit was obtained in mouthguards fabricated at the heating temperatures of 100 and 120 degrees C (P < .01). CONCLUSIONS: Heating the ethylene vinyl acetate sheet until the temperature reached 120 degrees C was the best fabrication method to maintain the pressure-formed mouthguard thickness with proper fit. PMID- 28901718 TI - Chondroitin sulfate proteoglycans negatively regulate the positioning of mitochondria and endoplasmic reticulum to distal axons. AB - Chondroitin sulfate proteoglycans (CSPGs) are components of the extracellular matrix that inhibit the extension and regeneration of axons. However, the underlying mechanism of action remains poorly understood. Mitochondria and endoplasmic reticulum (ER) are functionally inter-linked organelles important to axon development and maintenance. We report that CSPGs impair the targeting of mitochondria and ER to the growth cones of chicken embryonic sensory axons. The effect of CSPGs on the targeting of mitochondria is blocked by inhibition of the LAR receptor for CSPGs. The regulation of the targeting of mitochondria and ER to the growth cone by CSPGs is due to attenuation of PI3K signaling, which is known to be downstream of LAR receptor activation. Dynactin is a required component of the dynein motor complex that drives the normally occurring retrograde evacuation of mitochondria from growth cones. CSPGs elevate the levels of p150Glu dynactin found in distal axons, and inhibition of the interaction of dynactin with dynein increased axon lengths on CSPGs. CSPGs decreased the membrane potential of mitochondria, and pharmacological inhibition of mitochondria respiration at the growth cone independent of manipulation of mitochondria positioning impaired axon extension. Combined inhibition of dynactin and potentiation of mitochondria respiration further increased axon lengths on CSPGs relative to inhibition of dynactin alone. These data reveal that the regulation of the localization of mitochondria and ER to growth cones is a previously unappreciated aspect of the effects of CSPGs on embryonic axons. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1351-1370, 2017. PMID- 28901720 TI - Vitellogenin expression in the oilseed rape pest Meligethes aeneus. AB - When investigating insecticide resistance of pest insects, for example, the pollen beetle Meligethes aeneus, it is relevant to differentiate toxicological and molecular genetic data between male and female specimens. A molecular sex determination method would allow resistance testing to be run without prior sorting of the samples. A one-step quantitative RT-PCR method for quantification of the yolk protein vitellogenin expression in the pollen beetle was established. The expression level of vitellogenin relative to tubulin was determined. Pollen beetles were tested at different time points during their development to determine if vitellogenin is a reliable molecular marker for detection of sexually mature females. The differentiation between females and males by relative expression of vitellogenin to tubulin is conditional regarding the life cycle. Sexually mature females and males could easily be distinguished, whereas immature specimens could not be seperated. Vitellogenin expression is a successful marker for identification of sexually mature pollen beetles. Females from the spring populations showed vitellogenin expression when the temperature was above 10.2 degrees C. Further, detailed observations of vitellogenin throughout the spring indicated a strong relationship between daily temperatures and vitellogenin expression, which is an indicator of oviposition ability. PMID- 28901721 TI - Bioluminescence Resonance Energy Transfer (BRET)-coupled Annexin V-functionalized Quantum Dots for Near-Infrared Optical Detection of Apoptotic Cells. AB - Deregulation in apoptosis induces numerous diseases such as cancer, cardiovascular, and neurodegenerative diseases. Detection of apoptotic cells is crucial for understanding the mechanism of these diseases and for therapy development. Although optical imaging using visible-emitting fluorescent probes, such as FITC-labeled annexin V, is widely used for the detection of apoptotic cells, there are very limited probes that can be used in the near-infrared region (NIR) over 700 nm. Compared with visible light, NIR light is highly permeable in turbid biological samples and tissues. In addition, optical imaging in the NIR region shows low autofluorescence from biological samples, leading to clearer images with high signal to background ratios. Here, we report the synthesis of bioluminescence resonance energy transfer (BRET)-coupled annexin V-functionalized quantum dots (QDs) and their application to NIR optical detection of apoptotic cells. PMID- 28901723 TI - The arms race between heliconiine butterflies and Passiflora plants - new insights on an ancient subject. AB - Heliconiines are called passion vine butterflies because they feed exclusively on Passiflora plants during the larval stage. Many features of Passiflora and heliconiines indicate that they have radiated and speciated in association with each other, and therefore this model system was one of the first examples used to exemplify coevolution theory. Three major adaptations of Passiflora plants supported arguments in favour of their coevolution with heliconiines: unusual variation of leaf shape within the genus; the occurrence of yellow structures mimicking heliconiine eggs; and their extensive diversity of defence compounds called cyanogenic glucosides. However, the protection systems of Passiflora plants go beyond these three features. Trichomes, mimicry of pathogen infection through variegation, and production of extrafloral nectar to attract ants and other predators of their herbivores, are morphological defences reported in this plant genus. Moreover, Passiflora plants are well protected chemically, not only by cyanogenic glucosides, but also by other compounds such as alkaloids, flavonoids, saponins, tannins and phenolics. Heliconiines can synthesize cyanogenic glucosides themselves, and their ability to handle these compounds was probably one of the most crucial adaptations that allowed the ancestor of these butterflies to feed on Passiflora plants. Indeed, it has been shown that Heliconius larvae can sequester cyanogenic glucosides and alkaloids from their host plants and utilize them for their own benefit. Recently, it was discovered that Heliconius adults have highly accurate visual and chemosensory systems, and the expansion of brain structures that can process such information allows them to memorize shapes and display elaborate pre-oviposition behaviour in order to defeat visual barriers evolved by Passiflora species. Even though the heliconiine Passiflora model system has been intensively studied, the forces driving host plant preference in these butterflies remain unclear. New studies have shown that host-plant preference seems to be genetically controlled, but in many species there is some plasticity in this choice and preferences can even be induced. Although much knowledge regarding the coevolution of Passiflora plants and heliconiine butterflies has accumulated in recent decades, there remain many exciting unanswered questions concerning this model system. PMID- 28901722 TI - alpha6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward. AB - Dopamine (DA) neuron excitability is regulated by inhibitory GABAergic synaptic transmission and modulated by nicotinic acetylcholine receptors (nAChRs). The aim of this study was to evaluate the role of alpha6 subunit-containing nAChRs (alpha6*-nAChRs) in acute ethanol effects on ventral tegmental area (VTA) GABA and DA neurons. alpha6*-nAChRs were visualized on GABA terminals on VTA GABA neurons, and alpha6*-nAChR transcripts were expressed in most DA neurons, but only a minority of VTA GABA neurons from GAD67 GFP mice. Low concentrations of ethanol (1-10 mM) enhanced GABAA receptor (GABAA R)-mediated spontaneous and evoked inhibition with blockade by selective alpha6*-nAChR antagonist alpha conotoxins (alpha-Ctxs) and lowered sensitivity in alpha6 knock-out (KO) mice. Ethanol suppression of VTA GABA neuron firing rate in wild-type mice in vivo was significantly reduced in alpha6 KO mice. Ethanol (5-100 mM) had no effect on optically evoked GABAA R-mediated inhibition of DA neurons, and ethanol enhancement of VTA DA neuron firing rate at high concentrations was not affected by alpha-Ctxs. Ethanol conditioned place preference was reduced in alpha6 KO mice compared with wild-type controls. Taken together, these studies indicate that relatively low concentrations of ethanol act through alpha6*-nAChRs on GABA terminals to enhance GABA release onto VTA GABA neurons, in turn to reduce GABA neuron firing, which may lead to VTA DA neuron disinhibition, suggesting a possible mechanism of action of alcohol and nicotine co-abuse. PMID- 28901724 TI - Codeine influences the serum and urinary profile of endogenous androgens but does not interact with the excretion rate of administered testosterone. AB - Today's doping tests involve longitudinal monitoring of urinary steroids including the testosterone glucuronide and epitestosterone glucuronide ratio (T/E) in an Athlete Biological Passport (ABP). The aim of this study was to investigate the possible influence of short-term use of codeine on the urinary excretion of androgen metabolites included in the steroidal module of the passport prior to and after the co-administration with testosterone. The study was designed as an open study with the subjects being their own control. Fifteen healthy male volunteers received therapeutic doses of codeine (Kodein Meda) for 6 days. On Day 3, 500 mg or 125 mg of testosterone enanthate (Testoviron(r)-Depot) was administered. Spot urine samples were collected for 17 days, and blood samples were collected at baseline, 3, 6, and 14 days after codeine intake. The circulatory concentration of total testosterone decreased significantly by 20% after 3 days' use of codeine (p = 0.0002) and an atypical ABP result was noted in one of the subjects. On the other hand, the concomitant use of codeine and testosterone did not affect the elevated urinary T/E ratio. In 75% of the individuals, the concentration of urinary morphine (a metabolite of codeine) was above the decision limit for morphine. One of the participants displayed a morphine/codeine ratio of 1.7 after codeine treatment, indicative of morphine abuse. In conclusion, our study shows that codeine interferes with the endogenous testosterone concentration. As a result, the urinary steroid profile may lead to atypical findings in the doping test. PMID- 28901725 TI - Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA dependent mechanisms. AB - INTRODUCTION: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. AIM: We tested the hypothesis that alamandine, a vasoactive peptide of the renin angiotensin system (RAS), could reverse HHcy-induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (PKA) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations. METHOD: The abdominal aorta was excised from New Zealand white rabbits (n = 15) and incubated with 3 mmol/L Hcy (to mimic HHcy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine. RESULT: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 +/- 5.0%; Hcy, 30.3 +/- 9.8%; alamandine + Hcy, 59.7 +/- 4.8%, P < .0001). KT5720 (PKA inhibitor) significantly inhibited the ability of alamandine to attenuate the impaired vasodilation caused by HHcy (KT5720 + Hcy + alamandine, 27.1 +/- 24.1, P < .01). Following immunohistochemistry analysis, the MrgD receptor was highly expressed within the media and endothelial layer of aortic rings in HHcy compared to control (media: 0.23 +/- 0.003 vs control 0.16 +/- 0.01, P < .05 and endothelium: 0.68 +/- 0.07 vs control 0.13 +/- 0.02, P < .01, in PA/I (A.U) units). Computational studies also propose certain interactions of alamandine within the MrgD transmembrane domain. CONCLUSION: This study shows that alamandine is effective in reversing HHcy-induced vascular dysfunction, possibly through the PKA signaling pathway via MrgD. Our results indicate a therapeutic potential of alamandine in reversing the detrimental effects of HHcy. PMID- 28901726 TI - Antimicrobial stewardship in paediatric oncology: Impact on optimising gentamicin use in febrile neutropenia. AB - OBJECTIVES: To evaluate the impact of an antimicrobial stewardship (AMS) intervention, involving introduction of new guidelines on the treatment of febrile neutropenia (FN), on improving the use of gentamicin in paediatric oncology patients. DESIGN AND INTERVENTION: Updated guidelines for gentamicin usage in paediatrics with FN were implemented at a tertiary children's teaching hospital, in Brisbane, Australia. Data on gentamicin usage before and after the guideline change were collected retrospectively from children with cancer admitted to hospital with FN between January 2012 and December 2013. Gentamicin use, duration of gentamicin therapy and therapeutic monitoring practice were compared against bacterial culture status for admissions before and after the guideline change to assess the impact on practice. RESULTS: Data were collected from 227 children corresponding to 453 separate admissions, 195 preguideline and 257 post-guideline change. Following guideline change, the proportion of admissions in which gentamicin was administered reduced from 79.0 to 20.9% (P value < 0.001) and administrations not associated with a cultured Gram-negative organism dropped from 87.2 to 58.2% (P-value < 0.001), indicating a change in practice according to the new guideline. Following guideline change, admissions in which gentamicin was used for >48 hr despite the absence of a confirmed Gram negative infection decreased from 85.6 to 46.9% (P-value < 0.001). CONCLUSIONS: Guideline changes driven through an AMS initiative involving paediatric oncology patients significantly improved targeted- and nontargeted-antimicrobial use potentially reducing the risk of emergence of resistance against gentamicin in this cohort. PMID- 28901727 TI - Retention rates of adalimumab, etanercept and infliximab as first-line biotherapy agent for rheumatoid arthritis patients in daily practice - Auvergne experience. AB - OBJECTIVE: To compare, in real-life conditions, the retention rates of anti-tumor necrosis factor (anti-TNF) treatment (etanercept [ETN], adalimumab [ADA] and infliximab [IFX]) initiated as first-line biotherapy for rheumatoid arthritis (RA) and to evaluate, in case of failure, the switch to another anti-TNF or a non anti-TNF biological. METHODS: Monocentric retrospective cohort including all patients with RA starting a first anti-TNF between 2001 and 2015. RESULTS: Among the 346 patients analyzed, 201 received ETN, 82 ADA and 63 IFX. The first anti TNF was interrupted in 151 cases. The retention rates were 82.8%, 67.6%, 46.5%, 28.1% and 22.5% at 1, 2, 5, 10 and 15 years, respectively, with a median retention duration of 52.8 (18.9-136.2) months (ETN: 59.3 [19.1-NA), ADA: 79.9 [19.3-136.2] and IFX: 37.2 [17.5-134.5], P = 0.49). The predictive factors of discontinuation were active RA (Disease Activity Score of 28 joints - C-reactive protein [DAS28-CRP] hazards ratio [HR]: 1.22 [1.03-1.45]), inflammatory syndrome (erythrocyte sedimentation rate HR: 1.01 [1.0-1.02]; CRP HR: 1.00 [1.00-1.01]), absence of methotrexate treatment (HR: 0.60 [0.43-0.83]), and corticosteroid use (HR: 1.91 [1.31-2.78]). The patients who switched to another anti-TNF treatment had an inferior retention than those who switched to a non-anti-TNF treatment (HR: 0.39 [0.17-0.87], P = 0.02). CONCLUSION: In real life, there was no difference in retention among the three anti-TNF agents, and 25% of patients continued them at 15 years. After failure of an anti-TNF, the switch to a non anti-TNF biotherapy showed better retention. PMID- 28901728 TI - GABA type a receptor trafficking and the architecture of synaptic inhibition. AB - Ubiquitous expression of GABA type A receptors (GABAA R) in the central nervous system establishes their central role in coordinating most aspects of neural function and development. Dysregulation of GABAergic neurotransmission manifests in a number of human health disorders and conditions that in certain cases can be alleviated by drugs targeting these receptors. Precise changes in the quantity or activity of GABAA Rs localized at the cell surface and at GABAergic postsynaptic sites directly impact the strength of inhibition. The molecular mechanisms constituting receptor trafficking to and from these compartments therefore dictate the efficacy of GABAA R function. Here we review the current understanding of how GABAA Rs traffic through biogenesis, plasma membrane transport, and degradation. Emphasis is placed on discussing novel GABAergic synaptic proteins, receptor and scaffolding post-translational modifications, activity-dependent changes in GABAA R confinement, and neuropeptide and neurosteroid mediated changes. We further highlight modern techniques currently advancing the knowledge of GABAA R trafficking and clinically relevant neurodevelopmental diseases connected to GABAergic dysfunction. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 238-270, 2018. PMID- 28901729 TI - Magnetic field dose effects on different radiation beam geometries for hypofractionated partial breast irradiation. AB - PURPOSE: Hypofractionated partial breast irradiation (HPBI) involves treatment to the breast tumor using high doses per fraction. Recent advances in MRI-Linac solutions have potential in being applied to HPBI due to gains in the soft tissue contrast of MRI; however, there are potentially deleterious effects of the magnetic field on the dose distribution. The purpose of this work is to determine the effects of the magnetic field on the dose distribution for HPBI tumors using a tangential beam arrangement (TAN), 5-beam intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). METHODS: Five patients who have received HPBI were selected with two patients having bilateral disease resulting in a total of two tumors in this study. Six planning configurations were created using a treatment planning system capable of modeling magnetic field dose effects: TAN, IMRT and VMAT beam geometries, each of these optimized with and without a transverse magnetic field of 1.5 T. RESULTS: The heart and lung doses were not statistically significant when comparing plan configurations. The magnetic field had a demonstrated effect on skin dose: for VMAT plans, the skin (defined to a depth of 3 mm) D1cc was elevated by +11% and the V30 by +146%; for IMRT plans, the skin D1cc was increased by +18% and the V30 by +149%. Increasing the number of beam angles (e.g., going from IMRT to VMAT) with the magnetic field on reduced the skin dose. CONCLUSION: The impact of a magnetic field on HPBI dose distributions was analyzed. The heart and lung doses had clinically negligible effects caused by the magnetic field. The magnetic field increases the skin dose; however, this can be mitigated by increasing the number of beam angles. PMID- 28901730 TI - Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders. AB - We describe here the outcomes of reduced-toxicity alternate-donor stem cell transplant (SCT) with posttransplant cyclophosphamide (PTCy) for primary immunodeficiency disorders (PIDs) in eight children (haploidentical-seven and matched unrelated donor-one). The conditioning was with serotherapy (alemtuzumab 3/rabbit-anti-thymoglobulin-5); fludarabine, cyclophosphamide, and total body irradiation-5 (additional thiotepa-3); fludarabine and treosulfan-2; and fludarabine and busulfan-1. All received PTCy 50 mg/kg on days 3 and 4 as graft versus host disease prophylaxis along with tacrolimus and mycophenolate. Mean CD34 dose was 13.8 * 106 /kg. Two children died because of PIDs. Acute graft versus host disease up to grades I and II was seen in three children. All six survivors are fully donor and disease free at median follow-up of 753 days. Alternate donor SCT with PTCy is feasible in PID and has good outcomes. PMID- 28901731 TI - Response to combination of mycophenolate mofetil, cyclosporin A and corticosteroid treatment in lupus nephritis patients with persistent proteinuria. AB - OBJECTIVE: To study the response of lupus nephritis (LN) patients with persistent proteinuria (>= 1 g/day after >= 6 months corticosteroid and single immunosuppressant treatment, or >= 3 g/day after >= 3 months of corticosteroid and single immunosuppressant treatment) to corticosteroid combined with two immunosuppressants, and to evaluate associated factors of response within 1 year. METHOD: A retrospective study of proteinuria and renal function observed in LN patients with persistent proteinuria after adding a second immunosuppressant at 3, 6, 9 and 12 months. RESULT: Twenty-one LN patients (100.0% female) with persistent proteinuria were treated with corticosteroid and two immunosuppressants (mycophenolate mofetil [MMF] plus cyclosporine A [CSA]). Their mean age and duration from first immunosuppressant to initiating a combination therapy were 33.2 +/- 10.2 years and 17.5 +/- 15.7 months, respectively. Twelve (57.1%) patients had proteinuria levels >= 3 g/day. The renal pathology from 18 patients were Classes III or IV in 11 (61.1%). Fifteen patients (71.4%) responded to treatment (complete remission [CR], proteinuria <= 0.5 g/day, in seven patients and partial remission [PR], proteinuria reduced > 50%, in eight patients). Changing from a single immunosuppressant to combined immunosuppressants was associated with CR within 1 year (hazards ratio = 0.88; 95% CI = 0.78-0.99). Adverse events consisted of one patient with severe infection, two herpes zoster and one with transient increased serum creatinine level. CONCLUSION: Approximately 70% of LN patients with persistent proteinuria responded to MMF plus CSA. However, infection should be a concern with these patients. PMID- 28901732 TI - Black Silicon/Elastomer Composite Surface with Switchable Wettability and Adhesion between Lotus and Rose Petal Effects by Mechanical Strain. AB - Although many recent studies demonstrate surfaces with switchable wettability under various external stimuli, a deliberate effort to self-propel liquid droplets utilizing a surface wetting mode switch between slippery lotus and adhesive rose petal states via a mechanical strain has not been made yet, which would otherwise further benefit microfluidic applications. In this work, we present a black silicon/elastomer (bSi/elastomer) composite surface which shows switchable wettability and adhesion across the two wetting modes by mechanical stretching. The composite surface is composed of a scale-like nanostructured silicon platelet array that covers an elastomer surface. The gap between the neighboring silicon platelets is reversibly changeable as a function of a mechanical strain, leading to the transition between the two wetting modes. Moreover, the composite surface is highly flexible although its wetting properties primarily originate from superhydrophobic bSi platelets. Different wetting characteristics of the composite surface in various mechanical strains are studied, and droplet manipulation such as droplet self-propulsion and pick and-place using the composite surface is demonstrated, which highlights its potentials for microfluidic applications. PMID- 28901733 TI - Preparation of Graphene Sheets by Electrochemical Exfoliation of Graphite in Confined Space and Their Application in Transparent Conductive Films. AB - A novel electrochemical exfoliation mode was established to prepare graphene sheets efficiently with potential applications in transparent conductive films. The graphite electrode was coated with paraffin to keep the electrochemical exfoliation in confined space in the presence of concentrated sodium hydroxide as the electrolyte, yielding ~100% low-defect (the D band to G band intensity ratio, ID/IG = 0.26) graphene sheets. Furthermore, ozone was first detected with ozone test strips, and the effect of ozone on the exfoliation of graphite foil and the microstructure of the as-prepared graphene sheets was investigated. Findings indicate that upon applying a low voltage (3 V) on the graphite foil partially coated with paraffin wax that the coating can prevent the insufficiently intercalated graphite sheets from prematurely peeling off from the graphite electrode thereby affording few-layer (<5 layers) holey graphene sheets in a yield of as much as 60%. Besides, the ozone generated during the electrochemical exfoliation process plays a crucial role in the exfoliation of graphite, and the amount of defect in the as-prepared graphene sheets is dependent on electrolytic potential and electrode distance. Moreover, the graphene-based transparent conductive films prepared by simple modified vacuum filtration exhibit an excellent transparency and a low sheet resistance after being treated with NH4NO3 and annealing (~1.21 kOmega/? at ~72.4% transmittance). PMID- 28901734 TI - Environmentally Friendly Plasma-Treated PEDOT:PSS as Electrodes for ITO-Free Perovskite Solar Cells. AB - Solution processed poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) transparent electrodes (TEs) offer great potential as a low cost alternative to expensive indium tin oxide (ITO). However, strong acids are typically used for enhancing the conductivity of PEDOT:PSS TEs, which produce processing complexity and environmental issues. This work presents an environmentally friendly acid free approach to enhance the conductivity of PEDOT:PSS using a light oxygen plasma treatment, in addition to solvent blend additives and post treatments. The plasma treatment was found to significantly reduce the sheet resistance of PEDOT:PSS TEs from 85 to as low as 15 Omega sq-1, which translates to the highest reported conductivity of 5012 S/cm for PEDOT:PSS TEs. The plasma treated PEDOT:PSS TE resulted in an ITO-free perovskite solar cell efficiency of 10.5%, which is the highest reported efficiency for ITO-free perovskite solar cells with a PEDOT:PSS electrode that excludes the use of acid treatments. This research presents the first demonstration of this technology. Moreover, the PEDOT:PSS TEs enabled better charge extraction from the perovskite solar cells and reduced hysteresis in the current density-voltage (J-V) curves. PMID- 28901735 TI - LiMn2O4 Surface Chemistry Evolution during Cycling Revealed by in Situ Auger Electron Spectroscopy and X-ray Photoelectron Spectroscopy. AB - This work utilizes in situ electrochemical and analytical characterization during cycling of LiMn2O4 (LMO) equilibrated at different potentials in an ultrahigh vacuum (UHV) environment. The LMO reacts with organic molecules in the vacuum to form a high surface concentration of Li2CO3 (~50% C) during initial charging to 4.05 V. Charging to higher potentials reduces the overall Li2CO3 concentration (~15% C). Discharging to 3.0 V increases the Li2CO3 concentration (~30% C) and over discharging to 0.1 V again reduces its concentration (~15% C). This behavior is reproducible over 5 cycles. The model geometry utilized suggests that oxygen from LMO can participate in redox of carbon, where LMO contributes oxygen to form the carbonate in the solid electrolyte interphase (SEI). Similar results were obtained from samples cycled ex situ, suggesting that the model in situ geometry provides reasonably representative information about surface chemistry evolution. Carbon redox at LMO and the inherent voltage instability of the Li2CO3 likely contributes significantly to its capacity fade. PMID- 28901736 TI - Facile Fabrication of a Flexible LiNbO3 Piezoelectric Sensor through Hot Pressing for Biomechanical Monitoring. AB - Wearable pressure sensors have attracted increasing attention for biomechanical monitoring due to their portability and flexibility. Although great advances have been made, there are no facile methods to produce sensors with good performance. Here, we present a simple method for manufacturing flexible and self-powered piezoelectric sensors based on LiNbO3 (LN) particles. The LN particles are dispersed in polypropylene (PP) doped with multiwalled carbon nanotubes (MWCNTs) by hot pressing (200 degrees C) to form a flexible LN/MWCNT/PP piezoelectric composite film (PCF) sensor. This cost-effective sensor has high sensitivity (8 Pa), fast response time (ca. 40 ms), and long-term stability (>3000 cycles). Measurements of pressure changes from peripheral arteries demonstrate the applicability of the LN/MWCNT/PP PCF sensor to biomechanical monitoring as well as its potential for biomechanics-related clinical diagnosis and forecasting. PMID- 28901737 TI - Melatonin Improves Cognitive Deficits via Restoration of Cholinergic Dysfunction in a Mouse Model of Scopolamine-Induced Amnesia. AB - Melatonin is known to improve cognitive deficits, and its functions have been studied in various disease models, including Alzheimer's disease. In this study, we investigated effects of melatonin on cognition and the cholinergic system of the septum and hippocampus in a mouse model of scopolamine-induced amnesia. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were administered intraperitoneally to mice for 2 and 4 weeks. The Morris water maze and passive avoidance tests revealed that both treatments of scopolamine significantly impaired spatial learning and memory; however, 2- and 4-week melatonin treatments significantly improved spatial learning and memory. In addition, scopolamine treatments significantly decreased protein levels and immunoreactivities of choline acetyltransferase (ChAT), high-affinity choline transporter (CHT), vesicular acetylcholine transporter (VAChT), and muscarinic acetylcholine receptor M1 (M1R) in the septum and hippocampus. However, the treatments with melatonin resulted in increased ChAT-, CHT-, VAChT-, and M1R-immunoreactivities and their protein levels in the septum and hippocampus. Our results demonstrate that melatonin treatment is effective in improving the cognitive deficits via restoration of the cholinergic system in the septum and hippocampus of a mouse model of scopolamine-induced amnesia. PMID- 28901738 TI - Determination of the 13C/12C Carbon Isotope Ratio in Carbonates and Bicarbonates by 13C NMR Spectroscopy. AB - This paper is the first study focused on the innovative application of 13C NMR (nuclear magnetic resonance) spectroscopy to determine the bulk 13C/12C carbon isotope ratio, at natural abundance, in inorganic carbonates and bicarbonates. In the past, 13C NMR spectroscopy (irm-13C NMR) was mainly used to measure isotope ratio monitoring with the potential of conducting 13C position-specific isotope analysis of organic molecules with high precision. The reliability of the newly developed methodology for the determination of stable carbon isotope ratio was evaluated in comparison with the method chosen in the past for these measurements, i.e., isotope ratio mass spectrometry (IRMS), with very encouraging results. We determined the 13C/12C ratio of carbonates and bicarbonates (~50-100 mg) with a precision on the order of 10/00 in the presence of a relaxation agent, such as Cr(acac)3, and CH313COONa as an internal standard. The method was first applied to soluble inorganic carbonates and bicarbonates and then extended to insoluble carbonates by converting them to Na2CO3, following a simple procedure and without observing isotopic fractionation. Here, we demonstrate that 13C NMR spectroscopy can also be successfully adopted to characterize the 13C/12C isotope ratio in inorganic carbonates and bicarbonates with applications in different fields, such as cultural heritage and geological studies. PMID- 28901739 TI - Back Electron Transfer at TiO2 Nanotube Photoanodes in the Presence of a H2O2 Hole Scavenger. AB - Adding charge scavengers, which usually are more unstable than water, is an effective method to quantify the quantum efficiency loss of photoelectrode during the charge separation, transfer, and injection processes of the water splitting reaction. Here, we detected, on TiO2 nanotube photoanodes after using hydrogen peroxide (H2O2) as a hole scavenger, a nearly 40% saturated photocurrent decrease in alkaline electrolyte and a negligible saturated photocurrent difference in acid electrolyte. We found that the photoelectrons were trapped in the surface states of TiO2 with nearly the same storage capacity of electrons in a wide range of pH values from 1.0 to 13.6. However, kinetics of a back reaction, H2O2 reduction by the photoelectrons trapped in surface states, is about 10 times higher for that in alkaline electrolyte than in acid electrolyte. As a result, the pH-dependent kinetic difference in H2O2 reduction induced the negative effects on the saturated photocurrent. Our results offer a new insight into understanding the effects of back electron transfer on electrochemical behaviors of surface states and charge scavengers. PMID- 28901740 TI - Inhibiting Metastasis and Preventing Tumor Relapse by Triggering Host Immunity with Tumor-Targeted Photodynamic Therapy Using Photosensitizer-Loaded Functional Nanographenes. AB - Effective cancer therapy depends not only on destroying the primary tumor but also on conditioning the host immune system to recognize and eliminate residual tumor cells and prevent metastasis. In this study, a tumor integrin alphavbeta6 targeting peptide (the HK peptide)-functionalized graphene oxide (GO) was coated with a photosensitizer (HPPH). The resulting GO conjugate, GO(HPPH)-PEG-HK, was investigated whether it could destroy primary tumors and boost host antitumor immunity. We found that GO(HPPH)-PEG-HK exhibited significantly higher tumor uptake than GO(HPPH)-PEG and HPPH. Photodynamic therapy (PDT) using GO(HPPH)-PEG suppressed tumor growth in both subcutaneous and lung metastatic mouse models. Necrotic tumor cells caused by GO(HPPH)-PEG-HK PDT activated dendritic cells and significantly prevented tumor growth and lung metastasis by increasing the infiltration of cytotoxic CD8+ T lymphocytes within tumors as evidenced by in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging. These results demonstrate that tumor-targeted PDT using GO(HPPH)-PEG-HK could effectively ablate primary tumors and destroy residual tumor cells, thereby preventing distant metastasis by activating host antitumor immunity and suppressing tumor relapse by stimulation of immunological memory. PMID- 28901741 TI - Glycoforest 1.0. AB - Tandem mass spectrometry, when combined with liquid chromatography and applied to complex mixtures, produces large amounts of raw data, which needs to be analyzed to identify molecular structures. This technique is widely used, particularly in glycomics. Due to a lack of high throughput glycan sequencing software, glycan spectra are predominantly sequenced manually. A challenge for writing glycan sequencing software is that there is no direct template that can be used to infer structures detectable in an organism. To help alleviate this bottleneck, we present Glycoforest 1.0, a partial de novo algorithm for sequencing glycan structures based on MS/MS spectra. Glycoforest was tested on two data sets (human gastric and salmon mucosa O-linked glycomes) for which MS/MS spectra were annotated manually. Glycoforest generated the human validated structure for 92% of test cases. The correct structure was found as the best scoring match for 70% and among the top 3 matches for 83% of test cases. In addition, the Glycoforest algorithm detected glycan structures from MS/MS spectra missing a manual annotation. In total 1532 MS/MS previously unannotated spectra were annotated by Glycoforest. A portion containing 521 spectra was manually checked confirming that Glycoforest annotated an additional 50 MS/MS spectra overlooked during manual annotation. PMID- 28901742 TI - Surface Modification of Poly(dimethylsiloxane) with Polydopamine and Hyaluronic Acid To Enhance Hemocompatibility for Potential Applications in Medical Implants or Devices. AB - Poly(dimethylsiloxane) (PDMS) has been widely utilized in micro-electromechanical systems (MEMS) and implantable devices. To improve the hemocompatibility of a PDMS-based implant, a facile technique was developed by modifying PDMS with a hyaluronic acid (HA) and polydopamine (PDA) composite (HA/PDA). Under appropriate ratio of HA to PDA, platelet adhesion and activation were considerably reduced on modified PDMS substrates, indicating an enhanced hemocompatibility compared to native PDMS or those coated with HA or PDA solely. HA/PDA coating also posed minimal cytotoxicity on the adhesion and proliferation of endothelial cells (HUVECs). The anti-inflammation effect of the modified PDMS surface was characterized based on the expression of critical cytokines in adherent macrophages. This study revealed that the hemocompatibility, cytotoxicity, and anti-inflammation properties could be tailored conveniently by adjusting the ratio of HA and PDA composite on the modified PDMS surface, which has an exceptional potential as the core or packaging material for constructing implantable devices in biomedical applications. PMID- 28901743 TI - Guiding the Growth of a Conductive Filament by Nanoindentation To Improve Resistive Switching. AB - Redox-based memristor devices, which are considered to have promising nonvolatile memory, mainly operate through the formation/rupture of nanoscale conductive filaments. However, the random growth of conductive filaments is an obstacle for the stability of memory devices and the cell-to-cell uniformity. Here, we investigate the guiding effect of nanoindentation on the growth of conductive filaments in resistive memory devices. The nanoindented top electrodes generate an electric field concentration and the resultant precise control of a conductive filament in two typical memory devices, Ag/SiO2/Pt and W/Ta2O5/Pt. The nanoindented cells possess a much larger ON/OFF ratio, a sharper RESET process, a higher response speed, and better cell-to-cell uniformity compared with the conventional cells. Our finding reflects that the use of large-scale nanotransfer printing might be a unique way to improve the performance of resistive random access memory. PMID- 28901744 TI - Time-Resolved Fluorescence Immunochromatographic Assay Developed Using Two Idiotypic Nanobodies for Rapid, Quantitative, and Simultaneous Detection of Aflatoxin and Zearalenone in Maize and Its Products. AB - Aflatoxins and zearalenone (ZEN) are highly common mycotoxins in maize and maize based products. This study aimed to report a time-resolved fluorescence immunochromatographic assay (TRFICA) developed using two idiotypic nanobodies for rapid, quantitative, and simultaneous detection of aflatoxin B1 (AFB1) and ZEN in maize and its products. A novel Eu/Tb(III) nanosphere with enhanced fluorescence was prepared as a label and conjugated to anti-idiotypic nanobody (AIdnb) and monoclonal antibody (mAb). On the basis of nanosphere-antibody conjugation, two patterns of competitive time-resolved strip methods (AIdnb-TRFICA and mAb-TRFICA) were established and compared. The half inhibition concentration of AIdnb-TRFICA was 0.46 and 0.86 ng.mL-1 for AFB1 and ZEN, which was 18.3- and 20.3-fold more sensitive than that of mAb-TRFICA for AFB1 and ZEN, respectively. Under optimal conditions, AIdnb-TRFICA for dual mycotoxin was established and provided a quantitative relationship ranging from 0.13 to 4.54 ng.mL-1 for AFB1 and 0.20 to 2.77 ng.mL-1 for ZEN, with a detection limit of 0.05 and 0.07 ng.mL-1 in the buffer solution, respectively. AIdnb-TRFICA showed good recoveries (72.6%-106.6%) in samples and was applied to detect dual mycotoxin in maize samples with satisfying results. To the best of our knowledge, it is the first report about a time-resolved strip method based on AIdnbs for dual mycotoxin. PMID- 28901745 TI - Terminating DNA Tile Assembly with Nanostructured Caps. AB - Precise control over the nucleation, growth, and termination of self-assembly processes is a fundamental tool for controlling product yield and assembly dynamics. Mechanisms for altering these processes programmatically could allow the use of simple components to self-assemble complex final products or to design processes allowing for dynamic assembly or reconfiguration. Here we use DNA tile self-assembly to develop general design principles for building complexes that can bind to a growing biomolecular assembly and terminate its growth by systematically characterizing how different DNA origami nanostructures interact with the growing ends of DNA tile nanotubes. We find that nanostructures that present binding interfaces for all of the binding sites on a growing facet can bind selectively to growing ends and stop growth when these interfaces are presented on either a rigid or floppy scaffold. In contrast, nucleation of nanotubes requires the presentation of binding sites in an arrangement that matches the shape of the structure's facet. As a result, it is possible to build nanostructures that can terminate the growth of existing nanotubes but cannot nucleate a new structure. The resulting design principles for constructing structures that direct nucleation and termination of the growth of one dimensional nanostructures can also serve as a starting point for programmatically directing two- and three-dimensional crystallization processes using nanostructure design. PMID- 28901746 TI - Lab-on-Skin: A Review of Flexible and Stretchable Electronics for Wearable Health Monitoring. AB - Skin is the largest organ of the human body, and it offers a diagnostic interface rich with vital biological signals from the inner organs, blood vessels, muscles, and dermis/epidermis. Soft, flexible, and stretchable electronic devices provide a novel platform to interface with soft tissues for robotic feedback and control, regenerative medicine, and continuous health monitoring. Here, we introduce the term "lab-on-skin" to describe a set of electronic devices that have physical properties, such as thickness, thermal mass, elastic modulus, and water-vapor permeability, which resemble those of the skin. These devices can conformally laminate on the epidermis to mitigate motion artifacts and mismatches in mechanical properties created by conventional, rigid electronics while simultaneously providing accurate, non-invasive, long-term, and continuous health monitoring. Recent progress in the design and fabrication of soft sensors with more advanced capabilities and enhanced reliability suggest an impending translation of these devices from the research lab to clinical environments. Regarding these advances, the first part of this manuscript reviews materials, design strategies, and powering systems used in soft electronics. Next, the paper provides an overview of applications of these devices in cardiology, dermatology, electrophysiology, and sweat diagnostics, with an emphasis on how these systems may replace conventional clinical tools. The review concludes with an outlook on current challenges and opportunities for future research directions in wearable health monitoring. PMID- 28901747 TI - Deep Eutectic Solvent Functionalized Graphene Composite as an Extremely High Potency Flame Retardant. AB - We report a simple and green approach to develop the deep eutectic solvent functionalized graphene derivative as an effective flame retardant. The deep eutectic solvent functionalized graphene oxide (DESGO) was synthesized by introducing nitrogen-supported phosphorus functional groups on the surface of graphene derivative via a deep eutectic solvent, which is prepared by the treatment of monosodium dihydrogen orthophosphate and choline chloride. Subsequently, the resultant DESGO material is characterized by X-ray photoelectron spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The as prepared DESGO solution coated cloth piece was sustaining its initial shape and size by releasing a little amount of smoke at the early stage without catching fire for more than 540 s (9 min), whereas the pristine cloth is totally burned out within 10 s, leaving small amounts of black mass. This simple method of directly functionalized deep eutectic solvent on a graphene oxide surface can be a common process for the cost-effective bulk production of a nano carbon template for extremely high potency, nontoxic flame retardant applications. PMID- 28901748 TI - Strong In-Plane Anisotropies of Optical and Electrical Response in Layered Dimetal Chalcogenide. AB - An interesting in-plane anisotropic layered dimetal chalcogenide Ta2NiS5 is introduced, and the optical and electrical properties with respect to its in plane anisotropy are systematically studied. The Raman vibration modes have been identified by Raman spectra measurements combined with calculations of phonon related properties. Importantly, the Ta2NiS5 flakes exhibit strong anisotropic Raman response under the angle-resolved polarized Raman spectroscopy measurements. We found that Raman intensities of the Ag mode not only depend on rotation angle but are also related to the sample thickness. In contrast, the infrared absorption with light polarized along the a axis direction is always larger than that in the c axis direction regardless of thickness under the polarization-resolved infrared spectroscopy measurements. Remarkably, the first principles calculations combined with angle-resolved conductance measurements indicate strong anisotropic conductivity of Ta2NiS5. Our results not only prove Ta2NiS5 is a promising in-plane anisotropic 2D material but also provide an interesting platform for future functionalized electronic devices. PMID- 28901749 TI - A Highly Stretchable and Washable All-Yarn-Based Self-Charging Knitting Power Textile Composed of Fiber Triboelectric Nanogenerators and Supercapacitors. AB - Rapid advancements in stretchable and multifunctional wearable electronics impose a challenge on corresponding power devices that they should have comparable portability and stretchability. Here, we report a highly stretchable and washable all-yarn-based self-charging knitting power textile that enables both biomechanical energy harvesting and simultaneously energy storing by hybridizing triboelectrical nanogenerator (TENG) and supercapacitor (SC) into one fabric. With the weft-knitting technique, the power textile is qualified with high elasticity, flexibility, and stretchability, which can adapt to complex mechanical deformations. The knitting TENG fabric is able to generate electric energy with a maximum instantaneous peak power density of ~85 mW.m-2 and light up at least 124 light-emitting diodes. The all-solid-state symmetrical yarn SC exhibits lightweight, good capacitance, high flexibility, and excellent mechanical and long-term stability, which is suitable for wearable energy storage devices. The assembled knitting power textile is capable of sustainably driving wearable electronics (for example, a calculator or temperature-humidity meter) with energy converted from human motions. Our work provides more opportunities for stretchable multifunctional power sources and potential applications in wearable electronics. PMID- 28901750 TI - Synthesis, Assembly, and Applications of Hybrid Nanostructures for Biosensing. AB - The robust, sensitive, and selective detection of targeted biomolecules in their native environment by prospective nanostructures holds much promise for real time, accurate, and high throughput biosensing. However, in order to be competitive, current biosensor nanotechnologies need significant improvements, especially in specificity, integration, throughput rate, and long-term stability in complex bioenvironments. Advancing biosensing nanotechnologies in chemically "noisy" bioenvironments require careful engineering of nanoscale components that are highly sensitive, biorecognition ligands that are capable of exquisite selective binding, and seamless integration at a level current devices have yet to achieve. This review summarizes recent advances in the synthesis, assembly, and applications of nanoengineered reporting and transducing components critical for efficient biosensing. First, major classes of nanostructured components, both inorganic reporters and organic transducers, are discussed in the context of the synthetic control of their individual compositions, shapes, and properties. Second, the design of surface functionalities and transducing path, the characterization of interfacial architectures, and the integration of multiple nanoscale components into multifunctional ordered nanostructures are extensively examined. Third, examples of current biosensing structures created from hybrid nanomaterials are reviewed, with a distinct emphasis on the need to tailor nanosensor designs to specific operating environments. Finally, we offer a perspective on the future developments of nanohybrid materials and future nanosensors, outline possible directions to be pursued that may yield breakthrough results, and envision the exciting potential of high-performance nanomaterials that will cause disruptive improvements in the field of biosensing. PMID- 28901751 TI - Sulfate Aerosols Promote Lung Cancer Metastasis by Epigenetically Regulating the Epithelial-to-Mesenchymal Transition (EMT). AB - Secondary inorganic aerosols (SIA), particularly sulfate aerosols, are central particulate matter (PM) constituents of severe haze formation in China and exert profound impacts on human health; however, our understanding of the mechanisms by which sulfate aerosols cause malignancy in lung carcinogenesis remains incomplete. Here, we show that exposure to secondary inorganic aerosols induced the invasion and migration of lung epithelial cells, and that (NH4)2SO4 exerted the most serious effects in vitro and promoted lung tumor metastasis in vivo. This action was associated with alterations of phenotype markers in the epithelial-to-mesenchymal transition (EMT), such as the up-regulation of fibronectin (Fn1) and the down-regulation of E-cadherin (E-cad). Hypoxia inducible factor 1alpha (HIF-1alpha)-Snail signaling, regulated by the generation of reactive oxygen species (ROS), was involved in the (NH4)2SO4-induced EMT, and the potent antioxidant N-acetylcysteine (NAC) inhibited the activation of HIF 1alpha-Snail and blocked the EMT, cell invasion, and migration in response to (NH4)2SO4. Additionally, CpG hypermethylation in the E-cad promoter regions partly contributed to the (NH4)2SO4-regulated E-cad repression, and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) restored the (NH4)2SO4 induced down-regulation of E-cad. Our findings reveal a potential mechanistic basis for exploring the association between sulfate aerosol exposure and increased malignancy during lung carcinogenesis, and suggest new approaches for the treatment, improvement, and prevention of lung cancer resulting from sulfate aerosol exposure in severe haze-fog. PMID- 28901752 TI - Large Coercive Field of 45 kOe in a Magnetic Film Based on Metal-Substituted epsilon-Iron Oxide. AB - Magnetic ferrites are stable, sustainable, and economical. Consequently, they have been used in various fields. The development of large coercive field (large Hc) magnetic ferrites is a very important but challenging issue to accelerate the spread of use and to expand practical applications. In this study, we prepared a rhodium-substituted epsilon-iron oxide film and observed a remarkably large Hc value of 35 kOe at room temperature. This is the largest value among magnetic ferrites to date. Such a large-Hc ferrite is expected to greatly expand the application of magnetic ferrites. Furthermore, when the temperature dependence of the magnetic properties was measured, an even larger Hc value of 45 kOe was recorded at 200 K. Such large Hc values are much larger than those of conventional hard magnetic ferrites. PMID- 28901753 TI - Synthesis of a Cu-Filled Rh17S15 Framework: Microwave Polyol Process Versus High Temperature Route. AB - Metal-rich, mixed copper-rhodium sulfide Cu3-deltaRh34S30 that represents a new Cu-filled variant of the Rh17S15 structure has been synthesized and structurally characterized. Copper content in the [CuRh8] cubic cluster was found to vary notably dependent on the chosen synthetic route. Full site occupancy was achieved only in nanoscaled Cu3Rh34S30 obtained by a rapid, microwave-assisted reaction of CuCl, Rh2(CH3CO2)4 and thiosemicarbazide at 300 degrees C in just 30 min; whereas merely Cu-deficient Cu3-deltaRh34S30 (2.0 >= delta >= 0.9) compositions were realized via conventional high-temperature ceramic synthesis from the elements at 950 degrees C. Although Cu3-deltaRh34S30 is metallic just like Rh17S15, the slightly enhanced metal content has a dramatic effect on the electronic properties. Whereas the Rh17S15 host undergoes a superconducting transition at 5.4 K, no signs of the latter were found for the Cu-derivatives at least down to 1.8 K. This finding is corroborated by the strongly reduced density of states at the Fermi level of the ternary sulfide and the disruption of long range Rh-Rh interactions in favor of Cu-Rh interactions as revealed by quantum chemical calculations. PMID- 28901754 TI - Dysprosium Heteroleptic Corrole-Phthalocyanine Triple-Decker Complexes: Synthesis, Crystal Structure, and Electrochemical and Magnetic Properties. AB - Two triple-decker dinuclear sandwich dysprosium complexes, which are represented as Dy2[Pc(OC5H11)8]2[Cor(FPh)3] (1) and Dy2[Pc(OC5H11)8]2[Cor(ClPh)3] (2), were synthesized and characterized by spectroscopic and electrochemical methods in nonaqueous media. Their electronic structures were also investigated on the basis of TD-DFT calculations. The sandwich triple-decker nature with the molecular conformation of [Pc(OC5H11)8]Dy[Cor(FPh)3]Dy[Pc(OC5H11)8] for compound 1 was unambiguously revealed by single-crystal X-ray diffraction analysis and showed each dyprosium ion to be octacoordinated by the isoindole and pyrrole nitrogen atoms of an outer phthalocyanine ring and the central corrole ring, respectively. In addition, the magnetic properties of both compounds have also been characterized for exploring the functionalities of these types of triple-decker complexes. PMID- 28901756 TI - Using Fundamental Spectroscopy to Elucidate Kinetic and Energetic Mechanisms within Environmentally Relevant Inductively Coupled Plasma Systems. AB - Understanding energy distributions and kinetic processes in NxOy plasma systems is vital to realizing their potential in a range of applications, including pollution abatement. Energy partitioning between degrees of freedom and multiple molecules formed within NxOy plasma systems (N2, N2O, N2/O2) was investigated using both optical emission and broadband absorption spectroscopies. Specifically, we determined electron temperatures (Te) as well as rotational (TR) and vibrational (TV) temperatures for various N2 (B3Pig and C3Piu) and NO (X2Pi and A2Sigma+) states. TR and TV for both molecules (regardless of state) show a strong positive correlation with applied plasma power, as well as a negative correlation with system pressure. In all cases, TV values are significantly higher than TR for both species, suggesting vibrational modes are preferentially excited over rotational degrees of freedom. Time-resolved optical emission spectroscopy was utilized to determine rate constants, providing mechanistic insight and establishing the relationships between system parameters and plasma chemistry. Ultimately, the combination of these data allows us to glean information regarding both the kinetics and energetics of N2 and NO molecules formed within nitrogen- and oxygen-containing plasma systems for potential applications in gas remediation of pollutants. PMID- 28901755 TI - Probing Frontier Orbital Energies of {Co9(P2W15)3} Polyoxometalate Clusters at Molecule-Metal and Molecule-Water Interfaces. AB - Functionalization of polyoxotungstates with organoarsonate coligands enabling surface decoration was explored for the triangular cluster architectures of the composition [CoII9(H2O)6(OH)3(p-RC6H4AsVO3)2(alpha-PV2WVI15O56)3]25- ({Co9(P2W15)3}, R = H or NH2), isolated as Na25[Co9(OH)3(H2O)6(C6H5AsO3)2(P2W15O56)3].86H2O (Na-1; triclinic, P1, a = 25.8088(3) A, b = 25.8336(3) A, c = 27.1598(3) A, alpha = 78.1282(11) degrees , beta = 61.7276(14) degrees , gamma = 60.6220(14) degrees , V = 13888.9(3) A3, Z = 2) and Na25[Co9(OH)3(H2O)6(H2NC6H4AsO3)2(P2W15O56)3].86H2O (Na-2; triclinic, P1, a = 14.2262(2) A, b = 24.8597(4) A, c = 37.9388(4) A, alpha = 81.9672(10) degrees , beta = 87.8161(10) degrees , gamma = 76.5409(12) degrees , V = 12920.6(3) A3, Z = 2). The axially oriented para-aminophenyl groups in 2 facilitate the formation of self-assembled monolayers on gold surfaces and thus provide a viable molecular platform for charge transport studies of magnetically functionalized polyoxometalates. The title systems were isolated and characterized in the solid state, in aqueous solutions, and on metal surfaces. Using conducting tip atomic force microscopy, the energies of {Co9(P2W15)3} frontier molecular orbitals in the surface-bound state were found to directly correlate with cyclic voltammetry data in aqueous solution. PMID- 28901757 TI - Metal-Free Borylation of Heteroarenes Using Ambiphilic Aminoboranes: On the Importance of Sterics in Frustrated Lewis Pair C-H Bond Activation. AB - Two novel frustrated Lewis pair (FLP) aminoboranes, (1-Pip-2-BH2-C6H4)2 (2; Pip = piperidyl) and (1-NEt2-2-BH2-C6H4)2 (3; NEt2 = diethylamino), were synthesized, and their structural features were elucidated both in solution and in the solid state. The reactivity of these species for the borylation of heteroarenes was investigated and compared to previously reported (1-TMP-2-BH2-C6H4)2 (1; TMP = tetramethylpiperidyl) and (1-NMe2-2-BH2-C6H4)2 (4; NMe2 = dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1. Kinetic studies and density functional theory calculations were performed with 1 and 2 to ascertain the influence of the amino group of this FLP-catalyzed transformation. The C-H activation step was found to be more facile with smaller amines at the expense of a more difficult dissociation of the dimeric species. The bench-stable fluoroborate salts of all catalysts (1F-4F) have been synthesized and tested for the borylation reaction. The new precatalysts 2F and 3F are showing higher reaction rates and yields for multigram-scale syntheses. PMID- 28901758 TI - Single Atomic Iron Catalysts for Oxygen Reduction in Acidic Media: Particle Size Control and Thermal Activation. AB - It remains a grand challenge to replace platinum group metal (PGM) catalysts with earth-abundant materials for the oxygen reduction reaction (ORR) in acidic media, which is crucial for large-scale deployment of proton exchange membrane fuel cells (PEMFCs). Here, we report a high-performance atomic Fe catalyst derived from chemically Fe-doped zeolitic imidazolate frameworks (ZIFs) by directly bonding Fe ions to imidazolate ligands within 3D frameworks. Although the ZIF was identified as a promising precursor, the new synthetic chemistry enables the creation of well-dispersed atomic Fe sites embedded into porous carbon without the formation of aggregates. The size of catalyst particles is tunable through synthesizing Fe-doped ZIF nanocrystal precursors in a wide range from 20 to 1000 nm followed by one-step thermal activation. Similar to Pt nanoparticles, the unique size control without altering chemical properties afforded by this approach is able to increase the number of PGM-free active sites. The best ORR activity is measured with the catalyst at a size of 50 nm. Further size reduction to 20 nm leads to significant particle agglomeration, thus decreasing the activity. Using the homogeneous atomic Fe model catalysts, we elucidated the active site formation process through correlating measured ORR activity with the change of chemical bonds in precursors during thermal activation up to 1100 degrees C. The critical temperature to form active sites is 800 degrees C, which is associated with a new Fe species with a reduced oxidation number (from Fe3+ to Fe2+) likely bonded with pyridinic N (FeN4) embedded into the carbon planes. Further increasing the temperature leads to continuously enhanced activity, linked to the rise of graphitic N and Fe-N species. The new atomic Fe catalyst has achieved respectable ORR activity in challenging acidic media (0.5 M H2SO4), showing a half-wave potential of 0.85 V vs RHE and leaving only a 30 mV gap with Pt/C (60 MUgPt/cm2). Enhanced stability is attained with the same catalyst, which loses only 20 mV after 10 000 potential cycles (0.6-1.0 V) in O2 saturated acid. The high-performance atomic Fe PGM-free catalyst holds great promise as a replacement for Pt in future PEMFCs. PMID- 28901759 TI - An Effective Route to Dinuclear Niobium and Tantalum Imido Complexes. AB - Thermal treatment of the trichloro complexes [MCl3(NR)py2] (R = tBu, Xyl; M = Nb, Ta) (Xyl = 2,6-Me2C6H3) under vacuum affords the dinuclear imido species [MCl2(MU Cl)(NR)py]2 (R = tBu, Xyl; M = Nb 1, 3; Ta 2, 4) with loss of pyridine. Complexes 1-4 can be easily transformed to the mononuclear starting materials [MCl3(NR)py2] (R = tBu, Xyl; M = Nb, Ta) upon reaction with pyridine. While reactions of compounds 1 and 2 with a series of alkylating reagents render the mononuclear peralkylated imido complexes [MR3(NtBu)] (R = Me, CH2Ph, CH2CMe3, CH2CMePh, CH2SiMe3), the analogous treatment with allylmagnesium chloride results in the formation of the dinuclear niobium(IV) derivative [(NtBu)(eta3-C3H5)M(MU-C3H5)(MU Cl)2M(NtBu)py2] (5). Additionally, the treatment of the starting materials 1 and 2 with the organosilicon reductant 1,4-bis(trimethylsilyl)-1,4-diaza-2,5 cyclohexadiene yields the pyridyl-bridged dinuclear derivatives [M2Cl2(MU Cl)2(NtBu)2py2]2(MU-NC4H4N)2 (M = Nb 6, Ta 7). Controlled hydrolysis reaction of 1 and 2 affords the oxo chlorido-bridged products [MCl(MU-Cl)(NtBu)py]2(MU-O) (M = Nb 8, Ta 9) in a quantitative way, while the treatment of these latter with one more equivalent of pyridine led to complexes [MCl2(NtBu)py2]2(MU-O) (M = Nb 10, Ta 11). Structural study of these dinuclear imido derivatives has been also performed by X-ray crystallography. PMID- 28901761 TI - A Mild Rhodium Catalyzed Direct Synthesis of Quinolones from Pyridones: Application in the Detection of Nitroaromatics. AB - A rhodium catalyzed direct regioselective oxidative annulation by double C-H activation is described to synthesize highly substituted quinolones from pyridones. The reaction proceeds at mild conditions with broad scope and wide functional group tolerance. These novel quinolones were explored to recognize nitroaromatic compounds. PMID- 28901760 TI - Whole Ribosome NMR: Dipolar Couplings and Contributions to Whole Cells. AB - Solid-state NMR is a powerful tool for quantifying chemical composition and structure in complex assemblies and even whole cells. We employed N{P} REDOR NMR to obtain atomic-level distance propensities in intact 15N-labeled E. coli ribosomes. The experimental REDOR dephasing of shift-resolved lysyl amine nitrogens by phosphorus was comparable to that expected from a calculation of N-P distances involving the lysines included in the crystal structure coordinates. Among the nitrogen contributions to the REDOR spectra, the strongest dephasing emerged from the dipolar couplings to phosphorus involving nitrogen peaks ascribed primarily to rRNA, and the weakest dephasing arose from protein amide nitrogens. This approach is applicable to any macromolecular system and provides quantitative comparisons of distance proximities between shift-resolved nuclei of one type and heteronuclear dephasing spins. Enhanced molecular specificity could be achieved through the use of spectroscopic filters or specific labeling. Furthermore, ribosome 13C and 15N CPMAS spectra were compared with those of whole cells from which the ribosomes were isolated. Whole-cell signatures of ribosomes were identified and should be of value in comparing overall cellular ribosome content in whole-cell samples. PMID- 28901762 TI - Synthesis, Structure, and Reactivity of a Terminal Magnesium Hydride Compound with a Carbatrane Motif, [TismPriBenz]MgH: A Multifunctional Catalyst for Hydrosilylation and Hydroboration. AB - The tris[(1-isopropylbenzimidazol-2-yl)dimethylsilyl)]methyl ligand, [TismPriBenz], has been employed to form the magnesium carbatrane compound, [TismPriBenz]MgH, which possesses a terminal hydride ligand. Specifically, [TismPriBenz]MgH is obtained via the reaction of [TismPriBenz]MgMe with PhSiH3. The reactivity of [TismPriBenz]MgMe and [TismPriBenz]MgH allows access to a variety of other structurally characterized carbatrane derivatives, including [TismPriBenz]MgX [X = F, Cl, Br, I, SH, N(H)Ph, CH(Me)Ph, O2CMe, S2CMe]. In addition, [TismPriBenz]MgH is a catalyst for (i) hydrosilylation and hydroboration of styrene to afford the Markovnikov products, Ph(Me)C(H)SiH2Ph and Ph(Me)C(H)Bpin, and (ii) hydroboration of carbodiimides and pyridine to form N boryl formamidines and N-boryl 1,4- and 1,2-dihydropyridines, respectively. PMID- 28901763 TI - Bioassay-Guided Isolation of Antibacterial Metabolites from Emericella sp. TJ29. AB - Bioassay-guided isolation of metabolites from cultures of the plant-derived fungus Emericella sp. TJ29 yielded three new terpene-polyketide hybrid meroterpenoids, emervaridones A-C (1-3), two new polyketides, varioxiranediols A and B (5 and 6), and three known analogues (4, 7, and 8). The structures and absolute configurations of these new compounds were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, Mo2(OAc)4-induced electronic circular dichroism (ECD) data, and ECD calculations. To date, only one compound (4) bearing the emervaridone-type carbocyclic skeleton has been reported. The structures of emervaridones A-C (1-3) are new members of this type of natural product, and 1 features the first example of an alpha-directional H-7' in this structural category. Compounds 1 and 5 were active against five drug-resistant microbial pathogens [methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), Pseudomonas aeruginosa, and Klebsiella pneumoniae] with minimum inhibitory concentration (MIC) values in the micrograms per milliliter range. Notably, the inhibitory effect of emervaridone A (1) against ESBL-producing E. coli was comparable to that of the clinically used antibiotic amikacin, with an MIC value of 2 MUg/mL. Compounds 1 and 5, both with low toxicities to mammalian cells, were bacteriostatic and bactericidal, respectively. Importantly, these two compounds may provide novel chemical scaffolds for the discovery of antibacterial agents for drug-resistant microbial pathogens. PMID- 28901764 TI - Equilibrium Passive Sampling of POP in Lipid-Rich and Lean Fish Tissue: Quality Control Using Performance Reference Compounds. AB - Passive sampling is widely used to measure levels of contaminants in various environmental matrices, including fish tissue. Equilibrium passive sampling (EPS) of persistent organic pollutants (POP) in fish tissue has been hitherto limited to application in lipid-rich tissue. We tested several exposure methods to extend EPS applicability to lean tissue. Thin-film polydimethylsiloxane (PDMS) passive samplers were exposed statically to intact fillet and fish homogenate and dynamically by rolling with cut fillet cubes. The release of performance reference compounds (PRC) dosed to passive samplers prior to exposure was used to monitor the exchange process. The sampler-tissue exchange was isotropic, and PRC were shown to be good indicators of sampler-tissue equilibration status. The dynamic exposures demonstrated equilibrium attainment in less than 2 days for all three tested fish species, including lean fish containing 1% lipid. Lipid-based concentrations derived from EPS were in good agreement with lipid-normalized concentrations obtained using conventional solvent extraction. The developed in tissue EPS method is robust and has potential for application in chemical monitoring of biota and bioaccumulation studies. PMID- 28901765 TI - A Simple and Versatile Strategy for Rapid Color Fading and Intense Coloration of Photochromic Naphthopyran Families. AB - Benzo-annulated chromenes, i.e., naphthopyrans, are well-known photochromic molecules that undergo photochemical ring-opening reactions to form two colored open-ring isomers, the transoid-cis and transoid-trans forms, upon light irradiation. Though the transoid-cis form returns thermally to the uncolored closed form, the fading rate of the transoid-trans form is extremely slow because of its higher thermal stability. This slow fading behavior of the transoid-trans form is responsible for the persistence of residual color for several minutes to hours, and prevents the application of such molecules to fast photoswitching materials. We have found a new simple and versatile strategy to substantially reduce the amount of the undesirable long-lived colored transoid-trans form by introducing an alkoxy group at the 1-position of azino-fused chromenes, i.e., 8H pyranoquinazolines. The alkoxy group effectively reduces the formation of the transoid-trans form due to C-H...O intramolecular hydrogen bonding in the transoid-cis form. Moreover, the introduction of a condensed aromatic ring at the 3-position was found to be effective to increase the photosensitivity of the ring opening reaction. This strategy can also be applied for naphthopyran derivatives and is useful for the development of fast photoresponsive photochromic lenses and fast photoswitching applications such as dynamic holographic materials and molecular actuators. PMID- 28901766 TI - Steric Scale of Common Substituents from Rotational Barriers of N-(o-Substituted aryl)thiazoline-2-thione Atropisomers. AB - A steric scale of 20 recurrent groups was established from comparison of rotational barriers on N-(o-substituted aryl)thiazoline-2-thione atropisomers. The resulting energy of activation DeltaG?rot reflects the spatial requirement of the ortho substituent borne by the aryl moiety, electronic aspects and external parameters (temperature and solvent) generating negligible contributions. Concerning divergent rankings reported in the literature, the great sensitivity of this model allowed us to show unambiguously that a methyl appears bigger than a chlorine and gave the following order in size: CN > OMe > OH. For the very bulky CF3 and iPr groups, constraints in the ground state decreased the expected DeltaG?rot values resulting in a minimization of their apparent sizes. PMID- 28901767 TI - 6,7-Seco-ent-Kauranoids Derived from Oridonin as Potential Anticancer Agents. AB - Structurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of their antitumor activities. Previously, a convenient conversion of commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro lactone-type ent-kaurene derivatives bearing various substituents at the C-1 and C-14 positions were further designed and synthesized from the natural product oridonin. Moreover, a number of seven-membered C-ring-expanded 6,7-seco-ent kaurenes were also identified for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation of cancer cells, with an IC50 value as low as 0.55 MUM. An investigation on its mechanism of action showed that the representative compound 7b affected the cell cycle and induced apoptosis at a low micromolar level in MCF-7 human breast cancer cells. Furthermore, compound 7b inhibited liver tumor growth in an in vivo mouse model and exhibited no observable toxic effects. Collectively, the results warrant further preclinical investigations of these spiro-lactone-type ent kaurenes as potential novel anticancer agents. PMID- 28901768 TI - Importance and Difficulties in the Use of Chiroptical Methods to Assign the Absolute Configuration of Natural Products: The Case of Phytotoxic Pyrones and Furanones Produced by Diplodia corticola. AB - alpha-Pyrones and furanones are metabolites produced by Diplodia corticola, a pathogen of cork oak. Previously, the absolute configuration (AC) of diplopyrone was defined by chiroptical methods and Mosher's method. Using X-ray and chiroptical methods, the AC of sapinofuranone C was assigned, while that of the (4S,5S)-enantiomer of sapinofuranone B was established by enantioselective total synthesis. Diplofuranone A and diplobifuranylones A-C ACs are still unassigned. Here electronic and vibrational circular dichroism (ECD and VCD) and optical rotatory dispersion (ORD) spectra are reported and compared with density functional theory computations. The AC of the (4S,5S)-enantiomer of sapinofuranone B and sapinofuranone C is checked for completeness. The AC of diplobifuranylones A-C is assigned as (2S,2'S,5'S,6'S), (2S,2'R,5'S,6'R), and (2S,2'S,5'R,6'R), respectively, with the Mosher's method applied to define the absolute configuration of the carbinol stereogenic carbon. The AC assignment of sapinofuranones is problematic: while diplofuranone A is (4S,9R), sapinofuranones B and C are (4S,5S) according to ORD and VCD, but not to ECD. To eliminate these ambiguities, ECD and VCD spectra of a di-p-bromobenzoate derivative of sapinofuranone C are measured and calculated. For phytotoxicity studies, it is relevant that all six compounds share the S configuration for the stereogenic carbon atom of the lactone moiety. PMID- 28901769 TI - Enantioselective Pd-Catalyzed Decarboxylative Allylic Alkylation of Thiopyranones. Access to Acyclic, Stereogenic alpha-Quaternary Ketones. AB - A catalytic, enantioselective decarboxylative allylic alkylation of 4 thiopyranones is reported. The alpha-quaternary 4-thiopyranones produced are challenging to access by standard enolate alkylation owing to facile ring-opening beta-sulfur elimination. In addition, reduction of the carbon-sulfur bonds provides access to elusive acyclic alpha-quaternary ketones. The alkylated products are obtained in up to 92% yield and 94% enantiomeric excess. PMID- 28901770 TI - Stereodivergent Synthesis of Pseudotabersonine Alkaloids. AB - An eight-step stereodivergent synthesis of enantiomerically pure (-)-14-epi pseudotabersonine and (+)-pseudotabersonine has been developed from a common N tert-butanesulfinyl ketimine key intermediate. PMID- 28901771 TI - Ex Situ Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates. AB - A convenient transformation of phenols into the corresponding aryl fluorosulfates is presented: the first protocol to completely circumvent direct handling of gaseous sulfuryl fluoride (SO2F2). The proposed method employs 1,1' sulfonyldiimidazole as a precursor to generate near-stoichiometric amounts of SO2F2 gas using a two-chamber reactor. With NMR studies, it was shown that this ex situ gas evolution is extremely rapid, and a variety of phenols and hydroxylated heteroarenes were fluorosulfated in good to excellent yields. PMID- 28901772 TI - Electron-Poor Bowl-Shaped Polycyclic Aromatic Dicarboximides: Synthesis, Crystal Structures, and Optical and Redox Properties. AB - Two new bowl-shaped polycyclic aromatic hydrocarbons, based on corannulene and naphthalene dicarboximide, are synthesized by an improved Suzuki-Miyaura cross coupling and C-H arylation cascade reaction. Crystallographic analyses confirm structural assignments and provide insight into molecular interactions in the solid state. The new bowl-shaped molecules show reversible oxidation and reduction, intense visible range absorption, and high fluorescence quantum yields. These molecules can be considered bowl-shaped congeners of planar perylene dicarboximides. PMID- 28901773 TI - Transformation of the B Ring to the C Ring of Bryostatins by Csp3-H Amination and Z to E Isomerization. AB - An interesting approach to transform the B ring of bryostatins to the C ring has been developed. The key tactics of the approach feature an intramolecular Csp3-H bond amination to form spirocyclic hemiaminal, which undergoes ring opening to afford the C ring found in bryostatin 17. The subsequent epoxidation/oxidation sequence results in Z to E isomerization of the exo-cyclic enoate, delivering the common precursor, which could be transformed into the C ring found in bryostatins 1, 2, 4-9, 12, 14, and 15. PMID- 28901774 TI - Sulfoxonium Ylides as a Carbene Precursor in Rh(III)-Catalyzed C-H Acylmethylation of Arenes. AB - Sulfoxonium ylides act as an efficient carbene precursor in rhodium(III) catalyzed C-H acylmethlyation of a variety of arenes assisted by different chelating groups, and both aryl- and alkyl-substituted beta-carbonyl sulfoxonium ylides are applicable. The system proceeded under redox-neutral conditions with a broad scope, high efficiency, and functional group tolerance. PMID- 28901775 TI - Synthesis and Properties of Quinoidal Fluorenofluorenes. AB - The synthesis and optoelectronic properties of 24 pi-electron, formally antiaromatic fluoreno[3,2-b]fluorene and fluoreno[4,3-c]fluorene (FF), are presented. The solid-state structure of [4,3-c]FF along with computationally analogous molecules shows that the outer rings are aromatic while the central four rings possess a bond-localized 2,6-naphthoquinodimethane motif. The antiaromaticity and biradical character of the FFs is assessed computationally, the results of which indicate the dominance of the closed-shell ground state for these molecules. PMID- 28901776 TI - Liposomal Delivery of Diacylglycerol Lipase-Beta Inhibitors to Macrophages Dramatically Enhances Selectivity and Efficacy in Vivo. AB - Diacylglycerol lipase-beta (DAGLbeta) hydrolyzes arachidonic acid (AA)-containing diacylglycerols to produce bioactive lipids including endocannabinoids and AA derived eicosanoids involved in regulation of inflammatory signaling. Previously, we demonstrated that DAGLbeta inactivation using the triazole urea inhibitor KT109 blocked macrophage inflammatory signaling and reversed allodynic responses of mice in inflammatory and neuropathic pain models. Here, we tested whether we could exploit the phagocytic capacity of macrophages to localize delivery of DAGLbeta inhibitors to these cells in vivo using liposome encapsulated KT109. We used DAGLbeta-tailored activity-based probes and chemical proteomic methods to measure potency and selectivity of liposomal KT109 in macrophages and tissues from treated mice. Surprisingly, delivery of ~5 MUg of liposomal KT109 was sufficient to achieve ~80% inactivation of DAGLbeta in macrophages with no apparent activity in other tissues in vivo. Our macrophage-targeted delivery resulted in a >100-fold enhancement in antinociceptive potency compared with free compound in a mouse inflammatory pain model. Our studies describe a novel anti inflammatory strategy that is achieved by targeted in vivo delivery of DAGLbeta inhibitors to macrophages. PMID- 28901777 TI - Concise Synthesis of Tetrazole Macrocycle. AB - A concise two step synthesis of tetrazole containing macrocycles from readily accessible starting materials is presented. The first step comprises a chemoselective amidation of amino acid derived isocyanocarboxylicacid esters with unprotected symmetrical diamines to afford diverse alpha-isocyano-omega-amines. In the second step, the alpha-isocyano-omega-amines undergo an Ugi tetrazole reaction to close the macrocycle. Advantageously, this strategy allows short access to 11-19-membered macrocycles in which substituents can be independently varied at three different positions. PMID- 28901778 TI - Regio- and Enantioselective Synthesis of Chiral Pyrimidine Acyclic Nucleosides via Rhodium-Catalyzed Asymmetric Allylation of Pyrimidines. AB - A direct route to branched N-allylpyrimidine analogues is herein reported via the highly regio- and enantioselective asymmetric allylation of pyrimidines with racemic allylic carbonates. With [Rh(COD)Cl]2/chiral diphosphine as the catalyst, a range of chiral pyrimidine acyclic nucleosides could be obtained under neutral conditions in good yields (up to 95% yield) with high levels of regio- and enantioselectivities (15:1 to >40:1 B/L and up to 99% ee). Furthermore, chiral pyrimidine acyclic nucleoside bearing two adjacent chiral centers has been successfully synthesized by asymmetric dihydroxylation. PMID- 28901779 TI - Initial consonant deletion in bilingual Spanish-English-speaking children with speech sound disorders. AB - The purpose of this study was to utilize a theoretical model of bilingual speech sound production as a framework for analyzing the speech of bilingual children with speech sound disorders. In order to distinguish speech difference from speech disorder, we examined between-language interaction on initial consonant deletion, an error pattern found cross-linguistically in the speech of children with speech sound disorders. Thirteen monolingual English-speaking and bilingual Spanish-and English-speaking preschoolers with speech sound disorders were audio recorded during a single word picture-naming task and their recordings were phonetically transcribed. Initial consonant deletion errors were examined both quantitatively and qualitatively. An analysis of cross-linguistic effects and an analysis of phonemic complexity were performed. Monolingual English-speaking children exhibited initial consonant deletion at a significantly lower rate than bilingual children in their Spanish productions; however, no other quantitative differences were found across groups or languages. Qualitative differences yielded between-language interaction in the error patterns of bilingual children. Phonemic complexity appeared to play a role in initial consonant deletion. Evidence from the speech of bilingual children with speech sound disorders supports analysing bilingual speech using a cross-linguistic framework. Both theoretical and clinical implications are discussed. PMID- 28901780 TI - Cognitive correlates of pragmatic language comprehension in adult traumatic brain injury: A systematic review and meta-analyses. AB - Effective pragmatic comprehension of language is critical for successful communication and interaction, but this ability is routinely impaired following Traumatic Brain Injury (TBI) (1,2). Individual studies have investigated the cognitive domains associated with impaired pragmatic comprehension, but there remains little understanding of the relative importance of these domains in contributing to pragmatic comprehension impairment following TBI. This paper presents a systematic meta-analytic review of the observed correlations between pragmatic comprehension and cognitive processes following TBI. Five meta-analyses were computed, which quantified the relationship between pragmatic comprehension and five key cognitive constructs (declarative memory; working memory; attention; executive functions; social cognition). Significant moderate-to-strong correlations were found between all cognitive measures and pragmatic comprehension, where declarative memory was the strongest correlate. Thus, our findings indicate that pragmatic comprehension in TBI is associated with an array of domain general cognitive processes, and as such deficits in these cognitive domains may underlie pragmatic comprehension difficulties following TBI. The clinical implications of these findings are discussed. PMID- 28901781 TI - Genetic analyses of partial egg production in Japanese quail using multi-trait random regression models. AB - 1. The aim of the present study was to estimate genetic parameters for average egg weight (EW) and egg number (EN) at different ages in Japanese quail using multi-trait random regression (MTRR) models. 2. A total of 8534 records from 900 quail, hatched between 2014 and 2015, were used in the study. Average weekly egg weights and egg numbers were measured from second until sixth week of egg production. 3. Nine random regression models were compared to identify the best order of the Legendre polynomials (LP). The most optimal model was identified by the Bayesian Information Criterion. A model with second order of LP for fixed effects, second order of LP for additive genetic effects and third order of LP for permanent environmental effects (MTRR23) was found to be the best. 4. According to the MTRR23 model, direct heritability for EW increased from 0.26 in the second week to 0.53 in the sixth week of egg production, whereas the ratio of permanent environment to phenotypic variance decreased from 0.48 to 0.1. Direct heritability for EN was low, whereas the ratio of permanent environment to phenotypic variance decreased from 0.57 to 0.15 during the production period. 5. For each trait, estimated genetic correlations among weeks of egg production were high (from 0.85 to 0.98). Genetic correlations between EW and EN were low and negative for the first two weeks, but they were low and positive for the rest of the egg production period. 6. In conclusion, random regression models can be used effectively for analysing egg production traits in Japanese quail. Response to selection for increased egg weight would be higher at older ages because of its higher heritability and such a breeding program would have no negative genetic impact on egg production. PMID- 28901782 TI - A Radiographic Dye Method for Intraoperative Evaluation of Syndesmotic Injuries. AB - BACKGROUND: The Chertsey test has been recently defined as an intraoperative test for the detection of the syndesmotic injuries by the application of intra articular contrast. However, no study has investigated the reliability and comparative analysis of the Chertsey test. The purpose of this study was to explore the diagnostic accuracy of the Chertsey test in predicting syndesmosis instability of the injured ankle, with correlation to preoperative computed tomography (CT) findings. METHODS: A total of 39 patients who were operated on due to the unilateral ankle fracture and had no complaint on the contralateral ankle joint were included in the study. An intraoperative Chertsey test was performed on all ankle fractures and bilateral ankle CT was obtained preoperatively. Ankles were classified as Chertsey +, Chertsey -, and contralateral control group. The morphology categorization, width, and volume of the syndesmotic region were measured on axial images of the CT. Mann-Whitney U test was used to compare the data. Intraobserver and interobserver agreements were accessed by calculating the intraclass correlation coefficient (ICC) for radiologic parameters and the Chertsey test. RESULTS: The Chertsey test was positive in 13 (33.3%) of 39 ankle fractures. Patients with a positive Chertsey test showed a significant increase in syndesmotic width and volume compared with Chertsey - and control group. However, there was no significant difference between Chertsey - and the control group. All the ICC values were excellent for both radiologic measurements and test. CONCLUSION: The Chertsey test is a reliable and useful test that can be used intraoperatively in the diagnosis of syndesmotic injuries. LEVEL OF EVIDENCE: III, comparative series. PMID- 28901784 TI - Impact of Maillard reaction products on nutrition and health: Current knowledge and need to understand their fate in the human digestive system. AB - The Maillard Reaction (MR) is a non-enzymatic chemical reaction which results in the linkage between the amino group of amino acids and the carbonyl group of reduced sugars. MR products (MRPs) are common components of processed foods, mainly as a result of heating, especially in the Western diet. MRPs are classified as into three stages: initial, intermediate, and final stages, indicative of increased complexity and size, incurring different flavor, aroma, and texture. MRPs presence is known to reduce the nutritional quality of foods, particularly by reducing protein digestibility. Early reports have linked MRPs, especially advanced glycation end-products (AGEs) present in high concentration in the typical Western diet, to health conditions and diseases. However conflicting data has since been reported, and only a few (acrylamide, heterocyclic amines and 5-Hydroxymethylfurfural) MRPs have documented potential toxic or carcinogenic effects. High molecular weight MRPs are not available for direct absorption in the higher gastrointestinal tract, and are thus mostly metabolized by resident colonic microbes. MRPs have been the subject of sparse research interest in comparison with other non-digestible dietary elements. In this review, we outline the state of knowledge on MRPs in nutrition and health, and highlight the need to develop the limited knowledge on their impact on the gut microbiota and which metabolites derive from MRPs fermentation. PMID- 28901783 TI - Quantification of manganese and mercury in toenail in vivo using portable X-ray fluorescence (XRF). AB - BACKGROUND AND OBJECTIVE: Toenail is an advantageous biomarker to assess exposure to metals such as manganese and mercury. Toenail Mn and Hg are in general analyzed by chemical methods such as inductively coupled plasma mass spectrometry and atomic absorption spectrophotometry. In this project, a practical and convenient technology-portable X-ray florescence (XRF)-is studied for the noninvasive in vivo quantification of manganese and mercury in toenail. MATERIAL AND METHODS: The portable XRF method has advantages in that it does not require toenail clipping and it can be done in 3 min, which will greatly benefit human studies involving the assessment of manganese and mercury exposures. This study mainly focused on the methodology development and validation which includes spectral analysis, system calibration, the effect of toenail thickness, and the detection limit of the system. Manganese- and mercury-doped toenail phantoms were made. Calibration lines were established for these measurements. RESULTS: The results show that the detection limit for manganese is 3.65 MUg/g (ppm) and for mercury is 0.55 MUg/g (ppm) using 1 mm thick nail phantoms with 10 mm soft tissue underneath. DISCUSSION AND CONCLUSION: We conclude that portable XRF is a valuable and sensitive technology to quantify toenail manganese and mercury in vivo. PMID- 28901785 TI - A new anti-inflammatory meroterpenoid from the fungus Aspergillus terreus H010. AB - An unusual austinoid, 1,2-dehydro-terredehydroaustin (1), together with two known meroterpenoids (2 and 3), were isolated from the mangrove endophytic fungus Aspergillus terreus. The structures were elucidated on the basis of spectroscopic data, X-ray diffraction and ECD calculations. The anti-inflammatory activity was assayed and compound 1 exhibited weak inhibition effect against the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 246.7 mouse macrophages with an IC50 value of 42.3 MUM. PMID- 28901786 TI - Effect of gestational age on the epidemiology of late-onset sepsis in neonatal intensive care units - a review. AB - INTRODUCTION: Neonatal sepsis is a major cause of morbidity and mortality. Late onset sepsis affects a significant percentage of infants admitted to the neonatal intensive care unit (NICU). Most affected newborns are preterm or low birth weight, but late-onset sepsis also affects late preterm and term infants. Understanding how gestational age affects the epidemiology of late-onset sepsis can be of use when defining strategies for its prevention and clinical management in NICU. Areas covered: Available evidence suggests the incidence and mortality of late-onset sepsis is higher in preterm and VLBW infants, but pathogen distribution and risk exposure is similar across all infants admitted to NICU. More research is required for late-onset sepsis in late preterm and term infants admitted to NICU. There is some research insight on the impact of gut bacteria in the epidemiology of Gram-negative sepsis, which could benefit from further dedicated studies. Expert commentary: Understanding the manner in which some infants develop severe sepsis and others don't and what the long-term outcomes are is fundamental to guide management strategies. Further research should focus both on infants' characteristics and on pathogenic processes. The ultimate goal is to be able to design guidelines for prevention and management of sepsis that are adapted to a varied neonatal population. PMID- 28901787 TI - Medication management strategies used by older adults with heart failure: A systems-based analysis. AB - BACKGROUND: Older adults with heart failure use strategies to cope with the constraining barriers impeding medication management. Strategies are behavioral adaptations that allow goal achievement despite these constraining conditions. When strategies do not exist, are ineffective or maladaptive, medication performance and health outcomes are at risk. While constraints to medication adherence are described in literature, strategies used by patients to manage medications are less well-described or understood. AIM: Guided by cognitive engineering concepts, the aim of this study was to describe and analyze the strategies used by older adults with heart failure to achieve their medication management goals. METHODS: This mixed methods study employed an empirical strategies analysis method to elicit medication management strategies used by older adults with heart failure. Observation and interview data collected from 61 older adults with heart failure and 31 caregivers were analyzed using qualitative content analysis to derive categories, patterns and themes within and across cases. RESULTS: Data derived thematic sub-categories described planned and ad hoc methods of strategic adaptations. Stable strategies proactively adjusted the medication management process, environment, or the patients themselves. Patients applied situational strategies (planned or ad hoc) to irregular or unexpected situations. Medication non-adherence was a strategy employed when life goals conflicted with medication adherence. The health system was a source of constraints without providing commensurate strategies. CONCLUSIONS: Patients strived to control their medication system and achieve goals using adaptive strategies. Future patient self-mangement research can benefit from methods and theories used to study professional work, such as strategies analysis. PMID- 28901788 TI - Catastrophic uterine rupture associated with placenta accreta after previous B Lynch sutures. PMID- 28901789 TI - Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. AB - The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects. This review describes the current knowledge regarding BTKi and potential pathophysiologic mechanisms of AF and discusses the management of BTKi-associated AF. Finally, a review of the second generation BTKi is provided and gaps in knowledge in this evolving field are highlighted. PMID- 28901790 TI - Anti-CD123 chimeric antigen receptor T-cells (CART): an evolving treatment strategy for hematological malignancies, and a potential ace-in-the-hole against antigen-negative relapse. AB - Chimeric antigen receptor-modified T-cells (CART) are a potent and targeted immunotherapy which have induced remissions in some patients with chemotherapy refractory or relapsed (RR) hematologic malignancies. Hundreds of patients have now been treated worldwide with anti-CD19 CART cells, with complete response rates of up to 90%. CART therapy has a unique toxicity profile, and unfortunately not all responses are durable. Treatment failure occurs via two main routes - by loss of the CART cell population, or relapse with antigen loss. Emerging data indicate that targeting an alternative antigen instead of, or as well as CD19, could improve CART cell efficacy and reduce antigen-negative relapse. Other strategies include the addition of other immune-based therapies. This review explores the rationale, pre-clinical data and currently investigative strategies underway for CART therapy targeting the myeloid and lymphoid stem/progenitor antigen CD123. PMID- 28901791 TI - Determinants of 1-year survival in critically ill acute leukemia patients: a GRRR OH study. AB - Acute leukemia (AL) is the most common hematological malignancy requiring intensive care unit (ICU) management. Data on long-term survival are limited. This is a post hoc analysis of the prospective multicenter data from France and Belgium: A Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique [A Research Group on Acute Respiratory Failure in Onco-Hematological Patients (French)] Study, to identify determinants of 1-year survival in critically ill AL patients. A total of 278 patients were admitted in the 17 participating ICUs. Median age was 58 years and 70% had newly diagnosed leukemia. ICU mortality rate was 28.6 and 39.6% of the patients alive at 1 year. Admission for intensive monitoring was independently associated with better 1-year survival by multivariate analysis. Conversely, relapsed/refractory disease, secondary leukemia, mechanical ventilation and renal replacement therapy were independently associated with 1-year mortality. This study confirms the impact of organ dysfunction on long-term survival in ICU patients with AL. Follow-up studies to assess respiratory and renal recovery are warranted. PMID- 28901792 TI - Methicillin-sensitive Staphylococcus aureus chorioamnionitis and foetal death after mechanical induction of labour: a case report. PMID- 28901794 TI - Silybin Against Liver Ischemia-Reperfusion Injury: Something Old, Something New.... AB - Ischemia reperfusion injury (IRI) is a life threatening condition that may develop after elective liver surgery or liver transplantation. Numerous surgical and pharmacological approaches have shown varying degrees of protection against liver IRI. A group of protective compounds are the flavonoids but their intestinal absorbtion and bioavailability are low and impredictible. In this issue Tsaroucha et al. reports significantly decreased hepatocellular injury, Fas/FasL expression and inhibited HMGB1 release in rats receiving a hydrosoluble, lyophilized complex of SLB and hydroxypropyl-beta-cyclodextrin (SLB-HP-beta-CD) intravenously. PMID- 28901793 TI - Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. AB - INTRODUCTION: With the worldwide increase in the rates of antimicrobial resistance, antimicrobials with novel mechanisms of action are needed to fill a void in the antimicrobial armamentarium. Areas covered: Intravenous fosfomycin has been studied extensively in a wide variety of infections including cUTI, lower respiratory tract infection, bone and joint infections, endocarditis, meningitis, and bacteremia outside of the United States. This paper reviews the in vitro activity, pharmacokinetic properties, and clinical experience of intravenous fosfomycin in hospitalized patients with serious infections. Expert commentary: Drug resistant infections in hospitalized and critically ill patients are associated with high morbidity and mortality. Fosfomycin is an epoxide antimicrobial that acts by inhibiting cell wall synthesis earlier in the process compared to other classes of antimicrobial agents. Fosfomycin exerts bactericidal activity against a broad range of gram-negative and gram-positive pathogens, including extended-spectrum beta-lactamase- and carbapenemase-producing bacteria. Although an oral formulation of fosfomycin is approved by the United States (US) Food and Drug Administration for uncomplicated urinary tract infections, intravenous fosfomycin at a dose of 18 g/day is currently under clinical development for the treatment of complicated urinary tract infection (cUTI), including pyelonephritis in the US. PMID- 28901795 TI - Clinical and Radiographic Outcomes of Unipolar and Bipolar Radial Head Prosthesis in Patients with Radial Head Fracture: A Systemic Review and Meta-Analysis. AB - PURPOSE: To compare clinical outcomes of unipolar and bipolar radial head prosthesis in the treatment of patients with radial head fracture. MATERIALS AND METHODS: Medline, Cochrane, EMBASE, Google Scholar databases were searched until April 18, 2016 using the following search terms: radial head fracture, elbow fracture, radial head arthroplasty, implants, prosthesis, unipolar, bipolar, cemented, and press-fit. Randomized controlled trials, retrospective, and cohort studies were included. RESULTS: The Mayo elbow performance score (MEPS), disabilities of the arm, shoulder, and hand (DASH) score, radiologic assessment, ROM, and grip strength following elbow replacement were similar between prosthetic devices. The pooled mean excellent/good ranking of MEPS was 0.78 for unipolar and 0.73 for bipolar radial head arthroplasty, and the pooled mean MEPS was 86.9 and 79.9, respectively. DASH scores for unipolar and bipolar prosthesis were 19.0 and 16.3, respectively. Range of motion outcomes were similar between groups, with both groups have comparable risk of flexion arc, flexion, extension deficit, rotation arc, pronation, and supination (p values <0.001 for both unipolar and bipolar prosthesis). However, bipolar radial head prosthesis was associated with an increased chance of heterotopic ossification and lucency (p values <=0.049) while unipolar prosthesis was not (p values >=0.088). Both groups had risk for development of capitellar osteopenia or erosion/wear (p values <=0.039). CONCLUSION: Unipolar and bipolar radial head prostheses were similar with respect to clinical outcomes. Additional comparative studies are necessary to further compare different radial head prostheses used to treat radial head fracture. PMID- 28901797 TI - Predictive performance of early warning scores in acute leukemia patients receiving induction chemotherapy. PMID- 28901796 TI - Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension. AB - BACKGROUND: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint. RESULTS: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups. CONCLUSIONS: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes. PMID- 28901798 TI - Multifunctional micelle delivery system for overcoming multidrug resistance of doxorubicin. AB - Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and results in the failure of chemotherapy. Multifunctional micelles emerge as a valid strategy to load DOX by physical encapsulation or chemical binding to be delivered to cancer cells against MDR. In this review, mechanism of MDR of DOX is simply described. Multifunctional co-delivery micelles of DOX and main MDR modulators have been summarised in detail. DOX-loaded multifunctional polymeric micelles are also introduced to alleviate MDR of DOX, in which polymers act as MDR modulators. PMID- 28901799 TI - Protective effect of thymoquinone against lead-induced antioxidant defense system alteration in rat liver. AB - Alteration of the antioxidant system may be related to lead (Pb) hepatotoxicity. This study was carried out to investigate the possible beneficial effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver antioxidant defense system impairment. Adult male rats were randomized into four groups: control group received no treatment, Pb group was exposed to 2000 ppm of Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per os) and TQ group receiving only TQ. All treatments were applied for five weeks. TQ alone did not induce any significant changes in the enzymatic and non-enzymatic antioxidant status. By contrast, Pb exposure significantly decreased not only reduced glutathione level, but also superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase activities in the liver tissue. Interestingly, when coadministrated with Pb, TQ significantly improved the affected antioxidant parameters. In conclusion, our results indicate a protective effect of TQ against Pb-induced liver antioxidant capacity impairment and suggest that this component might be a clinically promising alternative in Pb hepatotoxicity. PMID- 28901800 TI - Changes in expression of neuropeptides and their receptors in the hypothalamus and gastrointestinal tract of calorie restricted hens. AB - The list of orexigenic and anorexigenic peptides, those are known to alter feed intake, is continuously growing. However, most of them are studied in mammalian species. We aimed to investigate plasma level and mRNA expression of the pituitary adenylate cyclase-activating polypeptide (PACAP), gene expression of its receptor (PAC1), furthermore the gene expression of galanin (GAL), neuromedin U (NMU), and its two receptors (NMUR1 and NMUR2) in the hypothalamus, proventriculus, and jejunum of hens exposed to 40% calorie restriction. Feed restriction resulted in a 88% increase in mRNA and a 27% increase in peptide level of PACAP in proventriculus measured with qPCR and RIA, respectively. Increases were found in the gene expression of PAC1 (49%) and NMUR1 (63%) in the hypothalamus. Higher expressions of peptide encoding genes (76% for PACAP, 41% for NMU, 301% for NMUR1 and 308% for GAL, P < 0.05) were recorded in the jejunum of hens exposed to restricted nutrition. The results indicate that PACAP level responds to calorie restriction in the proventriculus and jejunum, but not in the hypothalamus and plasma. PMID- 28901801 TI - Screening of some biological activities of Alyssum fulvescens var. fulvescens known as ege madwort. AB - In this research, the phenolic composition, antioxidant, antibacterial and cytotoxic activities of the methanolic extracts obtained from Alyssum fulvescens var. fulvescens aerial parts known as Ege kuduzotu in western Turkey, were firstly investigated. The antioxidant activity of the extract was determined by DPPH, metal chelating, phosphomolybdenum, beta-carotene/linoleic acid and ferric reducing power assays. Moreover, total phenolic and flavonoid contents in the extract were investigated. The brine shrimp (Artemia salina L.) lethality test was used to investigate for the possible cytotoxic activity of the extract. Microdilution broth method was used to study antibacterial potency of extract against Gram-positive and Gram-negative bacteria. The extract exhibited good biological activities. Total phenolic and flavonoid contents in the extract were significantly correlated with antioxidant potentials. HPLC analysis showed that chlorogenic acid was the major phenolic in extract tested. The results indicated that the extract of A. fulvescens var. fulvescens may be considered as a potential source of biological agents and in vivo investigations are needed to test the biological effects of A. fulvescens var. fulvescens. PMID- 28901802 TI - Isolation and quantitative analysis of physalin D in the fruit and calyx of Physalis alkekengi L. AB - Physalin D was isolated from the methanol extract of Physalis alkekengi L. fruits by combination of different chromatographic methods (CPC, TLC, HPLC). The structure was elucidated based on 1H and 13C NMR spectral analysis with the aid of 2D-correlation spectroscopy (1H, 1H-COSY, HSQC and HMBC) and comparison with literature data. The quantity of physalin D in mature and immature fruits and calyces was determined by RP-HPLC-UV method. Among the studied samples, immature calyx showed the highest content of physalin D (0.7880 +/- 0.0612%), while mature calyx contained 4 times less amount (0.2028 +/- 0.016%). The physalin D content of the fruit was much lower; immature fruits contained 0.0992 +/- 0.0083% physalin D and mature fruits 0.0259 +/- 0.0021%. The antiproliferative activity of the CHCl3 extract and its fractions was tested on three cancer cell lines (HeLa, MCF-7 and A431). The antiproliferative activity of physalin D is discussed with regard the published data. PMID- 28901803 TI - In vitro activity of calcium channel blockers in combination with conventional antifungal agents against clinically important filamentous fungi. AB - Despite the current therapeutic options, filamentous fungal infections are associated with high mortality rate especially in immunocompromised patients. In order to find a new potential therapeutic approach, the in vitro inhibitory effect of two antiarrhythmic agents, diltiazem and verapamil hydrochloride were tested against different clinical isolates of ascomycetous and mucoralean filamentous fungi. The in vitro combinations of these non-antifungal drugs with azole and polyene antifungal agents were also examined. Susceptibility tests were carried out using the broth microdilution method according to the instructions of the Clinical and Laboratory Standards Institute document M38-A2. Checkerboard microdilution assay was used to assess the interactions between antifungal and non-antifungal drugs. Compared to antifungal agents, diltiazem and verapamil hydrochloride exerted a relatively low antifungal activity with high minimal inhibitory concentration values (853-2731 MUg/ml). Although in combination they could increase the antifungal activity of amphotericin B, itraconazole and voriconazole. Indifferent and synergistic interactions were registered in 33 and 17 cases, respectively. Antagonistic interactions were not revealed between the investigated compounds. However, the observed high MICs suggest that these agents could not be considered as alternative systemic antifungal agents. PMID- 28901804 TI - Histological and antimicrobial study of Ononis arvensis L. AB - In this study field restharrow (Ononis arvensis) was investigated for histological and antimicrobial features. The aerial part and the root were embedded in synthetic resin and investigated following sectioning by a rotation microtome. The antimicrobial activity and minimum inhibitory concentration of the solvent fractions of the aerial part were studied against four bacterial strains and one fungus. According to histology, the root covered by rhizodermis contains contiguous vascular elements, which are surrounded by sclerenchyma cells. The epidermis cells are anisodiametric in the stem, sepal, and petal. The bundles of the stem form a Ricinus type thickening. The adaxial side of the heterogeneous leaf is covered by unbranching non-glandular and capitate glandular trichomes. The stipule, petiole, sepals and petals are isolateral having mesomorphic stomata. Pollen grains are tricolpate. The different extracts of the herb showed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Salmonella Typhimurium, Staphylococcus aureus, and Candida albicans. Data show that the extracts of the leaf contain compounds which may be responsible for the antifungal effect, while extracts obtained from display against the tested bacteria, except Escherichia coli. Further studies are required to complete the phytochemical analysis and identify the antimicrobial compounds of extracts. PMID- 28901805 TI - Fusiform vateritic inclusions observed in European eel (Anguilla anguilla L.) sagittae. AB - Microscopic inclusions have been observed in 7 out of 106 European eel (Anguilla anguilla L.) sagittae using polarizing microscope and scanning electron microscope meanwhile the annual increments were studied to characterize the age structure of the population living in Lake Balaton. The presence of vaterite, a rare calcium carbonate polymorph was observed in these inclusions using Raman spectroscopy. Vateritic sagittae in wild fish are usually considered as symptom of physiological stress. The observed fusiform inclusions represent a new morphological type of vaterite inclusions in eel otolith. Two alternatives are hypothesized to explain their formation: 1) metabolic disorder, such as erroneous protein synthesis; 2) introduction of an alien protein into the eel's inner ear. The origin and physiological significance of this new morphological type of vateritic inclusions is still an open question. Same as whether it can be found in other species or specific only to eel otoliths. PMID- 28901806 TI - Optimised selenium enrichment of Artemia sp. feed to improve red drum (Sciaenops ocellatus) larvae rearing. AB - Selenium is an essential microelement for the normal functioning of life processes. Moreover, it is a component of enzymes with antioxidant effects. However, it has the smallest window of any micronutrient between requirement and toxicity. Selenium is a regularly used element in fish feeds; moreover, enriching zooplankton with selenium to rear larvae is also a well-known technology. It is accepted that the most common starter foods of fish larvae, natural rotifers contain the smallest dosage of selenium, but providing selenium enriched Artemia sp. instead could increase survival and growth rate of fish. However, no such references are available for the red drum (Sciaenops ocellatus) larvae. Therefore, in this study, Artemia sp. was enriched with nano-selenium of verified low toxicity and easy availability in 5 treatments (1, 5, 10, 50, 100 mg/l Se), and then, fish larvae were fed with four of these enriched Artemia stocks (1, 5, 10, 50 mg/l Se) and a control group. At the end of the 9-day-long experiment, survival rate (S) and growth parameters (SL, W, K-factor, SGR) of fish larvae were calculated as well as their selenium retention and glutathione peroxidase enzyme activity were analysed. It was revealed that a moderate level of selenium enrichment (~4 mg/kg dry matter) of Artemia sp. positively influences the rearing efficiency (i.e. survival and growth) of fish larvae, but higher dosages of selenium could cause adverse effects. PMID- 28901807 TI - Exogenous ascorbic acid improves defence responses of sunflower (Helianthus annuus) exposed to multiple stresses. AB - Ascorbic acid is an important antioxidant that plays role both on growth and development and also stress response of the plant. The purpose of this study was to determine the effect of ascorbate on physiological and biochemical changes of sunflower that was exposed to multiple stresses. Chlorophyll and carotenoid contents decreased and glutathione, ascorbate and malondialdehyde contents as well as antioxidant enzyme activities increased for sunflower plant that was exposed to 50 mM NaCl and pendimethalin at different concentrations. These changes were found to be more significant in groups simultaneously exposed to both stress factors. While malondialdehyde content decreased, chlorophyll, carotenoid, ascorbate, glutathione contents and antioxidant enzyme activities increased in plants treated exogenously with ascorbate, compared to the untreated samples. According to the findings of our study; compared to individual stress, the effect of stress is more pronounced in sunflower exposed to multiple stresses, and treatment with exogenous ascorbate reduces the negative effects of stress. PMID- 28901808 TI - Morphometric characteristics and COI haplotype diversity of Arctodiaptomus spinosus (Copedoda) populations in soda pans in Hungary. AB - Arctodiaptomus spinosus (Daday, 1891) is a characteristic species of the soda pan zooplankton in the Great Hungarian Plain. The biogeographical distribution of the species is interesting, since its range expands from the Pannonian Biogeographic region to the other side of the Carpathians, occurring in saline lakes in Eastern Anatolia, Armenia, Iran and in temporary waters in Ukraine. Our investigations focused on the morphometric characteristics and the COI haplotype diversity of four Hungarian populations in the Kiskunsag area. We detected substantial morphological differences between the Boddi-szek population and the rest of the sampling sites, however considerable differences were not observable in the COI haplotypes in the populations. The 20 animals investigated for COI haplotypes belonged to the same haplotype network. Tajima's D indicated departures from the neutral Wright - Fisher population model and suggested population expansion. The genetic composition of Arctodiaptomus spinosus populations in the Kiskunsag area is rather uniform. PMID- 28901809 TI - Glycaemic studies: Food for thought and fuel for debate. PMID- 28901810 TI - The Incidence of Ocular Tuberculosis in Australia Over the Past 10 Years (2006 2015). AB - PURPOSE: To determine the incidence and clinical phenotype of ocular tuberculosis in Australia based on the mandatory jurisdictional health notification records for TB. METHODS: A whole population retrospective case series (Australia). Patients diagnosed with ocular tuberculosis were identified over the past 10 years (1 January 2006 to 31 December 2015) as recorded by individual Health Department jurisdictions per mandatory health notifications. The incidence rates were calculated based on the available Australian census data. Incidence rates were age and sex standardized. RESULTS: A total of 162 cases of ocular tuberculosis were identified across Australia over a 10-year time period. Of these, 156 participants were overseas born. The 10-year Australian incidence of ocular tuberculosis was 0.77 per 100,000 people. While there has been a downward trend in overall TB annual incidence rates from 2010 to 2015, over the same period the annual incidence of ocular TB has increased compared to the 4 previous years. Descriptive clinical data regarding the ocular manifestations of TB was available in 73/157 patients. In these 73 patients the commonest manifestations of ocular TB were unspecified uveitis (50.1%), focal, multifocal or serpiginous choroiditis or chorioretinitis (12.3%) and retinal vasculitis (11.0%). Of patients with ocular TB, 4/162 (2.47%) had associated pulmonary TB and 8/162 (4.94%) had associated systemic (non-pulmonary) TB. Systemic anti-TB therapy was administered to 161 patients. CONCLUSIONS: The annual Australian incidence of ocular tuberculosis was 0.077 per 100,000 people. Increasing notifications in the past 6 years may demonstrate increased awareness and changing diagnostic criteria of the disease in the Australian population. PMID- 28901811 TI - The efficacy of stretching exercises to reduce posterior shoulder tightness acutely in the postoperative population: a single blinded randomized controlled trial. AB - BACKGROUND: Posterior shoulder tightness (PST) is a postoperative complication leading to pain, impaired mobility, and reduced function. Despite the potential morbidity associated with PST, no studies have investigated the efficacy of shoulder-stretching methods in the postsurgical population. The purpose of this study was to determine the short-term efficacy of two stretches designed to reduce PST. METHODS: The study enrolled 63 patients [mean age 51 (12) years, height 173.7 (3.6) cm, body mass 88.2 (17.9) kg]. The study was a single-blinded randomized control trial in which patients who had arthroscopic shoulder surgery were assigned to one of three groups: [(horizontal adduction stretch (n = 21), supine sleeper (n = 21), or control (n = 21)]. Dependent variables included measurements of internal rotation mobility, sidelying PST, pain, and the QuickDASH. Following the physical therapy (PT) initial evaluation, subjects were instructed to perform the allocated intervention twice daily until their first follow-up appointment 48-72 h following the initial PT visit. RESULTS: Between group analyses of dependent variables revealed significant differences within PST measurements (p = 0.005) (eta squared = 0.14) taken at baseline and follow-up (48 72 h) favoring horizontal adduction stretching. Post-hoc testing demonstrated superiority of horizontal adduction stretching over both the supine sleeper group (p = 0.01) and control (p = 0.002). DISCUSSION AND CONCLUSION: The horizontal adduction stretch is more effective at reducing acute PST in the postoperative shoulder population when compared to the supine sleeper stretch and no stretch at all. Knowledge of efficacious stretching methods may serve to reduce the potential morbidity associated with postoperative stiffness. PMID- 28901812 TI - Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. AB - Objectives The safety and efficacy of the 3C-like protease inhibitor GC376 was tested on a cohort of client-owned cats with various forms of feline infectious peritonitis (FIP). Methods Twenty cats from 3.3-82 months of age (mean 10.4 months) with various forms of FIP were accepted into a field trial. Fourteen cats presented with wet or dry-to-wet FIP and six cats presented with dry FIP. GC376 was administered subcutaneously every 12 h at a dose of 15 mg/kg. Cats with neurologic signs were excluded from the study. Results Nineteen of 20 cats treated with GC376 regained outward health within 2 weeks of initial treatment. However, disease signs recurred 1-7 weeks after primary treatment and relapses and new cases were ultimately treated for a minimum of 12 weeks. Relapses no longer responsive to treatment occurred in 13 of these 19 cats within 1-7 weeks of initial or repeat treatment(s). Severe neurologic disease occurred in 8/13 cats that failed treatment and five cats had recurrences of abdominal lesions. At the time of writing, seven cats were in disease remission. Five kittens aged 3.3 4.4 months with wet FIP were treated for 12 weeks and have been in disease remission after stopping treatment and at the time of writing for 5-14 months (mean 11.2 months). A sixth kitten was in remission for 10 weeks after 12 weeks of treatment, relapsed and is responding to a second round of GC376. The seventh was a 6.8-year-old cat with only mesenteric lymph node involvement that went into remission after three relapses that required progressively longer repeat treatments over a 10 month period. Side effects of treatment included transient stinging upon injection and occasional foci of subcutaneous fibrosis and hair loss. There was retarded development and abnormal eruption of permanent teeth in cats treated before 16-18 weeks of age. Conclusions and relevance GC376 showed promise in treating cats with certain presentations of FIP and has opened the door to targeted antiviral drug therapy. PMID- 28901813 TI - HPV-related cancer prevention through coalition building. PMID- 28901814 TI - Exploring How Live Theaters Promote Participation for Children with Special Needs. AB - AIM: Increasing usage of cultural arts venues by children with special needs has created a need to optimize participation planning. A team of three occupational therapy graduate students and one faculty researcher was invited to provide a local children's theater staff with training for supporting children with special needs. The team aimed to determine how their collaboration with the theater could contribute to understandings of best practices in community participation planning. METHOD: The team participated in theater events, conducted a facility assessment, interviewed staff members with varying role responsibilities, and surveyed staff before and after conducting a participation-planning workshop. RESULTS: The collaborative approach to participation planning utilized strategies that provided practical applications for theater staff, including planning for sensory processing and regulation challenges, and providing staff with behavior management and communication tips for interacting with children. CONCLUSION: Through training, staff participation planning evolved from reacting to present day problems to proactively planning for future initiatives. Staff expressed desires to have some of their own members become in-house experts for participation planning, allowing others to pursue the theater's mission: providing live children's theater performances and programs. PMID- 28901815 TI - High-grade B-cell lymphoma of the peritoneum as a result of transformation of a CD5-negative monoclonal B lymphocytosis population in a patient with myelodysplastic syndrome treated with 5-azacytidine. PMID- 28901817 TI - Treatment and prognosis of stage I follicular lymphoma in the modern era - does PET matter? AB - Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of "genuine" stage I disease. PMID- 28901818 TI - Brachialis muscle transfer for reconstructing digital flexion after brachial plexus injury or forearm injury. AB - : Restoration of digital flexion after brachial plexus injury or forearm injury has been a great challenge for hand surgeons. Nerve transfer and forearm donor muscle transfer surgeries are not always feasible. The present study aimed at evaluating the effectiveness of restoring digital flexion by brachialis muscle transfer. Ten lower brachial plexus- or forearm-injured patients were enrolled. After at least 12 months following surgery, the middle-finger-to-palm distance was less than 2.5 cm in six patients. In the other four patients with less satisfactory results, secondary tenolysis surgery was performed and the middle finger-to-palm distances were reduced to 2.0-4.0 cm. The average grasp strength was 20 +/- 4 kg. Elbow flexion was not adversely affected. In conclusion, brachialis muscle transfer is an effective method for reconstructing digital flexion, not only in lower brachial plexus injury, but also in forearm injury patients. LEVEL OF EVIDENCE: IV. PMID- 28901820 TI - Response to: "Students to Surgeons: Increasing Matriculation in Surgical Specialties". PMID- 28901819 TI - DNA methylation changes in human lung epithelia cells exposed to multi-walled carbon nanotubes. AB - Humans are increasingly exposed to nanoparticles and, although many of their physiological effects have been described, the molecular mechanisms underlying them are still largely unknown. The present study aimed to determine the possible role of certain epigenetic mechanisms in the cellular response of human lung epithelial cells that are triggered by long-term exposure to titanium dioxide nanoparticles (TiO2NPs) and multi-walled carbon nanotubes (MWCNTs). The results showed that exposure to TiO2NPs had only minor effects on genome-wide DNA methylation. However, we identified 755 CpG sites showing consistent DNA hypomethylation in cells exposed to MWCNTs. These sites were mainly located at low density CpG regions and enhancers, and very frequently on the X chromosome. Our results thus suggest that long-term MWCNT exposure may have important effects on the epigenome. PMID- 28901821 TI - British Surgeon Frederick Salmon (1796-1868) and His "Trans-Fixing Pins and Excision" Surgical Procedure for the "Rectum Prolapsus". AB - Frederick Salmon was born in Bath. From his early career, he was fond of surgery, mostly interested in proctology. He had been specialized in London at St Bartholomew's Hospital. He was the founder of "The Infirmary for the Relief of the Poor Afflicted with Fistula and Other Disease of the Rectum," and the writer of one of the most important surgical treatises, the " Practical Observations on Prolapsus of the Rectum." In this book, Salmon described an innovative operation for procidentia, based on the principle "trans-fixing pins and excision." Although his work was too significant for the era, he was almost completely neglected by historians, most probably due to his clash with his fellow surgeons, who had been considered by him as scientifically inadequate in anorectal diseases. PMID- 28901822 TI - Semi-quantitative cerebral blood flow parameters derived from non-invasive [15O]H2O PET studies. AB - Quantification of regional cerebral blood flow (CBF) using [15O]H2O positron emission tomography (PET) requires the use of an arterial input function. Arterial sampling, however, is not always possible, for example in ill conditioned or paediatric patients. Therefore, it is of interest to explore the use of non-invasive methods for the quantification of CBF. For validation of non invasive methods, test-retest normal and hypercapnia data from 15 healthy volunteers were used. For each subject, the data consisted of up to five dynamic [15O]H2O brain PET studies of 10 min and including arterial sampling. A measure of CBF was estimated using several non-invasive methods earlier reported in literature. In addition, various parameters were derived from the time-activity curve (TAC). Performance of these methods was assessed by comparison with full kinetic analysis using correlation and agreement analysis. The analysis was repeated with normalization to the whole brain grey matter value, providing relative CBF distributions. A reliable, absolute quantitative estimate of CBF could not be obtained with the reported non-invasive methods. Relative (normalized) CBF was best estimated using the double integration method. PMID- 28901823 TI - Comics as a Medium for Providing Information on Adult Immunizations. AB - This study compared the following effects of two vaccine information flyers-one developed by the Centers for Disease Control and Prevention (CDC) versus one adapted from this information to a comic medium (comic)-on adults: (a) attitude toward the flyer; (b) perceived informativeness of the flyer; (c) intention to seek more information about adult immunizations after viewing the flyer; and (d) intention to get immunized after viewing the flyer. A between-group, randomized trial was used to randomly assign adults (age 18 years or older) at an ambulatory care center to review the CDC or comic flyer. Participants were asked to complete a survey to measure several outcome variables. Items were measured using a 7 point semantic differential scale. Independent-samples t-test was used for comparisons. A total of 265 surveys (CDC n = 132 vs comic n = 133) were analyzed. The comic flyer had a statistically significant effect on participants' attitudes and their perception of the flyer's informativeness compared to the CDC flyer. Flyer type did not have a statistically significant effect on intention-related variables. The study findings showed that the comic flyer was positively evaluated compared to the CDC flyer. These findings could provide a new direction for developing adult educational materials. PMID- 28901824 TI - Repeated split-belt treadmill walking improved gait ability in individuals with chronic stroke: A pilot study. AB - This study investigated the effects of repeated split-belt treadmill (SBT) walking on gait ability in individuals poststroke. Twelve individuals with a first unilateral cerebral stroke (10 males; mean age 53 (SD 8.74); mean time poststroke 25 months (SD 23.5); 9 left-sided stroke) and initial step length (SL) asymmetry (ratio = 1.10-2.05) volunteered for the study. They were trained by physiotherapists from an outpatient rehabilitation center six times over 2-3 weeks using a SBT protocol. After only six sessions of training, all participants reduced their SL asymmetry from an average ratio of 1.39 to 1.17 (p = 0.002) and increased walking speed (p = 0.043). Improvements in symmetry and speed were retained over 1 month (p <= 0.008). No effect was observed in participants' endurance, assessed with the 6-min walk test. These findings suggest that the present SBT protocol has potential to be an efficient intervention to improve not only SL symmetry but also gait speed, in individuals poststroke. PMID- 28901825 TI - Beyond Homonegativity: Understanding Hong Kong People's Attitudes About Social Acceptance of Gay/Lesbian People, Sexual Orientation Discrimination Protection, and Same-Sex Marriage. AB - This study examined attitudes about social acceptance, discrimination protection, and marriage equality for gay/lesbian people with a representative sample of 1,008 Hong Kong Chinese adults via a telephone survey. Despite majority endorsement of homosexuality (52.29% positive vs. 34.12% negative) and discrimination protection (50.72% favorable vs. 14.64% opposed), attitudes toward same-sex marriage diverged (32.79% favorable vs. 39.41% opposed). There was a sharp distinction in accepting gay/lesbian people as co-workers (83.57%) and friends (76.92%) versus relatives (40.19%). Having more homosexual/bisexual friends or co-workers contributed to greater endorsement of social acceptance and discrimination protection but not same-sex marriage. Age, religion, political orientation, and homonegativity consistently predicted attitudes toward social acceptance, discrimination protection, and same-sex marriage, whereas gender-role beliefs, conformity to norms, and cultural orientations had varying impacts. This article informs theory and advocacy by disentangling homonegativity from attitudes about gay/lesbian issues and highlighting the centrality of family kinship and relative-outsider delineation in Chinese societies. PMID- 28901826 TI - Nuclear networking. AB - Nuclear lamins are intermediate filament proteins that represent important structural components of metazoan nuclear envelopes (NEs). By combining proteomics and superresolution microscopy, we recently reported that both A- and B-type nuclear lamins form spatially distinct filament networks at the nuclear periphery of mouse fibroblasts. In particular, A-type lamins exhibit differential association with nuclear pore complexes (NPCs). Our studies reveal that the nuclear lamina network in mammalian somatic cells is less ordered and more complex than that of amphibian oocytes, the only other system in which the lamina has been visualized at high resolution. In addition, the NPC component Tpr likely links NPCs to the A-type lamin network, an association that appears to be regulated by C-terminal modification of various A-type lamin isoforms. Many questions remain, however, concerning the structure and assembly of lamin filaments, as well as with their mode of association with other nuclear components such as peripheral chromatin. PMID- 28901827 TI - Retrograde nuclear transport from the cytoplasm is required for tRNATyr maturation in T. brucei. AB - Retrograde transport of tRNAs from the cytoplasm to the nucleus was first described in Saccharomyces cerevisiae and most recently in mammalian systems. Although the function of retrograde transport is not completely clear, it plays a role in the cellular response to changes in nutrient availability. Under low nutrient conditions tRNAs are sent from the cytoplasm to nucleus and presumably remain in storage there until nutrient levels improve. However, in S. cerevisiae tRNA retrograde transport is constitutive and occurs even when nutrient levels are adequate. Constitutive transport is important, at least, for the proper maturation of tRNAPhe, which undergoes cytoplasmic splicing, but requires the action of a nuclear modification enzyme that only acts on a spliced tRNA. A lingering question in retrograde tRNA transport is whether it is relegated to S. cerevisiae and multicellular eukaryotes or alternatively, is a pathway with deeper evolutionary roots. In the early branching eukaryote Trypanosoma brucei, tRNA splicing, like in yeast, occurs in the cytoplasm. In the present report, we have used a combination of cell fractionation and molecular approaches that show the presence of significant amounts of spliced tRNATyr in the nucleus of T. brucei. Notably, the modification enzyme tRNA-guanine transglycosylase (TGT) localizes to the nucleus and, as shown here, is not able to add queuosine (Q) to an intron-containing tRNA. We suggest that retrograde transport is partly the result of the differential intracellular localization of the splicing machinery (cytoplasmic) and a modification enzyme, TGT (nuclear). These findings expand the evolutionary distribution of retrograde transport mechanisms to include early diverging eukaryotes, while highlighting its importance for queuosine biosynthesis. PMID- 28901829 TI - Resilience to Discrimination and Rejection Among Young Sexual Minority Males and Transgender Females: A Qualitative Study on Coping With Minority Stress. AB - Sexual minority and transgender status is associated with mental health disparities, which have been empirically and theoretically linked to stressors related to social stigma. Despite exposure to these unique stressors, many sexual minority and transgender individuals will not experience mental health disorders in their lifetime. Little is known about the specific processes that sexual minority and transgender youth use to maintain their wellbeing in the presence of discrimination and rejection. Semistructured interviews were conducted with 10 sexual minority males and transgender females aged 18-22 years, who currently met criteria for an operationalized definition of resilience to depression and anxiety. Data were analyzed qualitatively, yielding information related to a wide variety of problem-solving, support-seeking, and accommodative coping strategies employed by youth in the face of social stigma. Results are discussed in light of their clinical implications. PMID- 28901828 TI - Protein kinase C enhances plasma membrane expression of cardiac L-type calcium channel, CaV1.2. AB - L-type-voltage-dependent Ca2+ channels (L-VDCCs; CaV1.2, alpha1C), crucial in cardiovascular physiology and pathology, are modulated via activation of G protein-coupled receptors and subsequently protein kinase C (PKC). Despite extensive study, key aspects of the mechanisms leading to PKC-induced Ca2+ current increase are unresolved. A notable residue, Ser1928, located in the distal C-terminus (dCT) of alpha1C was shown to be phosphorylated by PKC. CaV1.2 undergoes posttranslational modifications yielding full-length and proteolytically cleaved CT-truncated forms. We have previously shown that, in Xenopus oocytes, activation of PKC enhances alpha1C macroscopic currents. This increase depended on the isoform of alpha1C expressed. Only isoforms containing the cardiac, long N-terminus (L-NT), were upregulated by PKC. Ser1928 was also crucial for the full effect of PKC. Here we report that, in Xenopus oocytes, following PKC activation the amount of alpha1C protein expressed in the plasma membrane (PM) increases within minutes. The increase in PM content is greater with full-length alpha1C than in dCT-truncated alpha1C, and requires Ser1928. The same was observed in HL-1 cells, a mouse atrium cell line natively expressing cardiac alpha1C, which undergoes the proteolytic cleavage of the dCT, thus providing a native setting for exploring the effects of PKC in cardiomyocytes. Interestingly, activation of PKC preferentially increased the PM levels of full length, L-NT alpha1C. Our findings suggest that part of PKC regulation of CaV1.2 in the heart involves changes in channel's cellular fate. The mechanism of this PKC regulation appears to involve the C-terminus of alpha1C, possibly corroborating the previously proposed role of NT-CT interactions within alpha1C. PMID- 28901830 TI - "Why Am I the Way I Am?" Narrative Work in the Context of Stigmatized Identities. AB - There are particular complexities faced by people attempting to tell their stories in the context of social stigma, such as the hostility which often surrounds injecting drug use. In this article, we identify some of the distinct advantages of taking a narrative approach to understanding these complexities by exploring a single case study, across two life-history interviews, with "Jimmy," a young man with a history of social disadvantage, incarceration, and heroin dependence. Drawing on Miranda Fricker's notion of "hermeneutical injustice," we consider the effects of stigmatization on the sociocultural practice of storytelling. We note the way Jimmy appears both constrained and released by his story-how he conforms to but also resists the master narrative of the "drug user." Narrative analysis, we conclude, honors the complex challenges of the accounting work evident in interviews such as Jimmy's, providing a valuable counterpoint to other forms of qualitative inquiry in the addictions field. PMID- 28901831 TI - Collaboration Between Biomedical and Complementary and Alternative Care Providers: Barriers and Pathways. AB - We examined the scope of collaborative care for persons with mental illness as implemented by traditional healers, faith healers, and biomedical care providers. We conducted semistructured focus group discussions in Ghana, Kenya, and Nigeria with traditional healers, faith healers, biomedical care providers, patients, and their caregivers. Transcribed data were thematically analyzed. A barrier to collaboration was distrust, influenced by factionalism, charlatanism, perceptions of superiority, limited roles, and responsibilities. Pathways to better collaboration were education, formal policy recognition and regulation, and acceptance of mutual responsibility. This study provides a novel cross-national insight into the perspectives of collaboration from four stakeholder groups. Collaboration was viewed as a means to reach their own goals, rooted in a deep sense of distrust and superiority. In the absence of openness, understanding, and respect for each other, efficient collaboration remains remote. The strongest foundation for mutual collaboration is a shared sense of responsibility for patient well-being. PMID- 28901833 TI - Corrigendum. PMID- 28901834 TI - Association Between Gait and Dual Task With Cognitive Domains in Older People With Cognitive Impairment. AB - The authors investigated whether impaired gait and dual-task performances are associated with specific cognitive domains among older people with preserved cognition (PC), mild cognitive impairment (MCI), and mild Alzheimer's disease (AD). The sample comprised 40 older adults with PC, 40 with MCI, and 38 with mild AD. The assessment consisted of gait (measured by 10-m walk test and Timed Up and Go Test [TUGT]), dual task (measured by TUGT associated with a cognitive-motor task of calling a phone number), and cognition (domains of the Addenbrooke Cognitive Examination-Revised and Frontal Assessment Battery [FAB]). For data analysis, the Pearson product-moment correlation and the backward stepwise linear regression were conducted. Language, fluency, and visuospatial domains predicted the 10-m walk test measure specifically in PC, MCI, and AD groups. Only the visuospatial domain was independently associated with the TUGT measure in the MCI and AD groups. FAB score, language domain, and FAB score and fluency domain were the strongest predictors for the isolated cognitive-motor task measure in the PC, MCI, and AD groups, respectively. The visuospatial domain was independently associated with the dual-task test measure in all 3 groups. The study findings demonstrate the influence of specific cognitive domains in daily mobility tasks in people with different cognitive profiles. PMID- 28901836 TI - The overlap of sleep disturbance and depression in primary care patients treated with buprenorphine. AB - BACKGROUND: Sleep disturbance is common among patients receiving long-term opioid therapies, such as methadone maintenance. However, little is known about sleep disturbances in patients receiving medication treatment with buprenorphine. We sought to determine the frequency of subjective sleep disturbance in a sample of patients receiving medication treatment and to examine clinical factors related to sleep disturbance. METHODS: Participants were 328 persons receiving buprenorphine at 3 primary care sites. Sleep difficulty was assessed 2 questions adapted from the Patient Health Questionnaire-9 (PHQ-9) item assessing sleep. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CESD)-10 and PHQ-2. In addition, information was gathered on participant demographics and treatment characteristics. Demographics, buprenorphine treatment history, and depressive symptoms were compared for those with and without self-reported sleep difficulty. Logistic regression was used to estimate the adjusted association of sleep disturbance with these correlates. RESULTS: Seventy-one percent of persons receiving medication treatment with buprenorphine in the present study reported sleep difficulty. Persons reporting sleep disturbance reported shorter time in buprenorphine treatment and more depressed mood compared with those without sleep difficulty (p < .01). Men were significantly less likely to report disturbed sleep than women (odds ratio [OR] = 0.57, 95% confidence interval [CI]: 0.33, 0.98). Sleep disturbance was not associated significantly with age, ethnicity, educational attainment, or buprenorphine dose. CONCLUSIONS: Sleep disturbance is common in patients receiving medication treatment with buprenorphine and is associated with more depressive symptoms as well as a shorter duration of medication treatment. Future research, using subjective and objective sleep measures, is warranted to understand whether sleep disturbance is mitigated by longer buprenorphine treatment and whether difficulty sleeping predicts buprenorphine discontinuation among patients seeking treatment for opioid dependence. PMID- 28901838 TI - Investigation of associations between exposures to pesticides and testosterone levels in Thai farmers. AB - We conducted a cross-sectional study to assess the relationship between pesticide exposures and testosterone levels in 133 male Thai farmers. Urine and serum samples were collected concurrently from participants. Urine was analyzed for levels of specific and nonspecific metabolites of organophosphates (OPs), pyrethroids, select herbicides, and fungicides. Serum was analyzed for total and free testosterone. Linear regression analyses revealed significant negative relationships between total testosterone and the herbicide 2,4 dichlorophenoxyacetic acid (2,4-D) after controlling for covariates (eg, age, BMI, smoking status). Positive significant associations were found between some OP pesticides and total testosterone. Due to the small sample size and the observational nature of the study, future investigation is needed to confirm our results and to elucidate the biological mechanisms. PMID- 28901832 TI - Chemical biology approaches for studying posttranslational modifications. AB - Posttranslational modification (PTM) is a key mechanism for regulating diverse protein functions, and thus critically affects many essential biological processes. Critical for systematic study of the effects of PTMs is the ability to obtain recombinant proteins with defined and homogenous modifications. To this end, various synthetic and chemical biology approaches, including genetic code expansion and protein chemical modification methods, have been developed. These methods have proven effective for generating site-specific authentic modifications or structural mimics, and have demonstrated their value for in vitro and in vivo functional studies of diverse PTMs. This review will discuss recent advances in chemical biology strategies and their application to various PTM studies. PMID- 28901837 TI - Minimal requirements for reverse polymerization and tRNA repair by tRNAHis guanylyltransferase. AB - tRNAHis guanylyltransferase (Thg1) has unique reverse (3'-5') polymerase activity occurring in all three domains of life. Most eukaryotic Thg1 homologs are essential genes involved in tRNAHis maturation. These enzymes normally catalyze a single 5' guanylation of tRNAHis lacking the essential G-1 identity element required for aminoacylation. Recent studies suggest that archaeal type Thg1, which includes most archaeal and bacterial Thg1 enzymes is phylogenetically distant from eukaryotic Thg1. Thg1 is evolutionarily related to canonical 5'-3' forward polymerases but catalyzes reverse 3'-5'polymerization. Similar to its forward polymerase counterparts, Thg1 encodes the conserved catalytic palm domain and fingers domain. Here we investigate the minimal requirements for reverse polymerization. We show that the naturally occurring minimal Thg1 enzyme from Ignicoccus hospitalis (IhThg1), which lacks parts of the conserved fingers domain, is catalytically active. And adds all four natural nucleotides to RNA substrates, we further show that the entire fingers domain of Methanosarcina acetivorans Thg1 and Pyrobaculum aerophilum Thg1 (PaThg1) is dispensable for enzymatic activity. In addition, we identified residues in yeast Thg1 that play a part in preventing extended polymerization. Mutation of these residues with alanine resulted in extended reverse polymerization. PaThg1 was found to catalyze extended, template dependent tRNA repair, adding up to 13 nucleotides to a truncated tRNAHis substrate. Sequencing results suggest that PaThg1 fully restored the near correct sequence of the D- and acceptor stem, but also produced incompletely and incorrectly repaired tRNA products. This research forms the basis for future engineering efforts towards a high fidelity, template dependent reverse polymerase. PMID- 28901839 TI - The effectiveness of a group-based educational program on the self-efficacy and self-acceptance of menopausal women: A randomized controlled trial. AB - This study aimed to assess the effectiveness of a group-based educational training on the self-efficacy and self-acceptance of Iranian menopausal women using the PRECEDE-PROCEED model. This Randomized Controlled Trial (RCT) was conducted on 80 menopausal women in the age range of 47-55 years residing in the northeast of Iran. The participants were divided randomly into a test group (n = 40) and a control group (n = 40). We found that designing and implementation of a group-based educational training according to the PRECEDE-PROCEED model can significantly enhance the knowledge and performance of the test group with regard to self-efficacy and self-acceptance. PMID- 28901840 TI - Reentry Program and Social Work Education: Training the Next Generation of Criminal Justice Social Workers. AB - PURPOSE: Social work plays a marginal role in opposing the trend of mass incarceration and high rates of recidivism, and social work education offers limited opportunities for students to specialize in working with people who are currently or were previously incarcerated. How to train students of social work to work against mass-incarceration is still challenging. METHODS: The authors devised and implemented an in-school social service agency devoted to working with people pre and post release from a prison system. The agency is a field practicum setting where interested students study and practice reentry work. In this article, the authors describe and assess the educational merit of this in school agency. RESULTS: Findings from surveys of students and alumni suggest that the program attained its educational goals of connecting classroom education to practice experience and training students for careers in the criminal justice system. The authors also discuss pending challenges. DISCUSSION: The experience of the Goldring Reentry Initiative suggests that by developing their own social work agencies, the authors may be able to heighten their students educational experience and expand their contribution to social work practice broadly. PMID- 28901841 TI - Re-Reading Homonationalism: An Israeli Spatial Perspective. AB - In this article we stress the need for specifically located understandings of the concept of homonationalism, by introducing an analysis of spatial and political power relations dissecting disparate constructions of LGBT arenas. The article explores three spaces: Tel-Aviv-an urban space of LGBT belonging; Jerusalem-the Israeli capital where being an LGBT individual is problematic both in public and in private spaces; and Kiryat-Shmona-a conservative and peripheral underprivileged town in the north of Israel. By showing how local understandings of queer space shape power relations and translate into subjective spaces within wide-ranging power dynamics, we claim that homonationalism cannot be seen as one unitary, consolidated category or logic. Instead, we argue, homonationalism should be considered a multidirectional and multiscale political stance, manifesting cultural practices and political relationship with the state and society in distinct settings. By expanding considerations of the nuanced interplay of state power and LGBT spaces we aim to elucidate some paradoxes of homonationalism. PMID- 28901842 TI - Rheumatoid granulomatous disease and pachymeningitis successfully treated with rituximab. AB - Granulomatous disease and pachymeningitis rarely occur in rheumatoid arthritis patients and confer a challenging differential diagnosis. Our patient, treated with a tumor necrosis factor alpha inhibitor, presented with meningitis and diffuse granulomatous adenopathies. Opportunistic infections and malignancy were excluded after confirmation of negative broath serologic, molecular analysis, and negative cytology. Because of the time frame and the clinical presentation, this case was considered as a rare systemic manifestation of RA. He was treated with rituximab with beneficial clinical evolution. This case offers an excellent opportunity to focus on the diagnostic and therapeutic approach in pachymeningitis and granulomatous disease in rheumatoid arthritis patients. PMID- 28901844 TI - Acute hepatitis C in HIV-uninfected men who have sex with men who do not report injecting drug use. PMID- 28901843 TI - Coevolution of the translational machinery optimizes initiation with unusual initiator tRNAs and initiation codons in mycoplasmas. AB - Initiator tRNAs (i-tRNAs) are characterized by the presence of three consecutive GC base pairs (GC/GC/GC) in their anticodon stems in all domains of life. However, many mycoplasmas possess unconventional i-tRNAs wherein the highly conserved sequence of GC/GC/GC is represented by AU/GC/GC, GC/GC/GU or AU/GC/GU. These mycoplasmas also tend to preferentially utilize non-AUG initiation codons. To investigate if initiation with the unconventional i-tRNAs and non-AUG codons in mycoplasmas correlated with the changes in the other components of the translation machinery, we carried out multiple sequence alignments of genes encoding initiation factors (IF), 16S rRNAs, and the ribosomal proteins such as uS9, uS12 and uS13. In addition, the occurrence of Shine-Dalgarno sequences in mRNAs was analyzed. We observed that in the mycoplasmas harboring AU/GC/GU i tRNAs, a highly conserved position of R131 in IF3, is represented by P, F or Y and, the conserved C-terminal tail (SKR) of uS9 is represented by the TKR sequence. Using the Escherichia coli model, we show that the change of R131 in IF3 optimizes initiation with the AU/GC/GU i-tRNAs. Also, the SKR to TKR change in uS9 was compatible with the R131P variation in IF3 for initiation with the AU/GC/GU i-tRNA variant. Interestingly, the mycoplasmas harboring AU/GC/GU i tRNAs are also human pathogens. We propose that these mycoplasmas might have evolved a relaxed translational apparatus to adapt to the environment they encounter in the host. PMID- 28901845 TI - A Review of Patents on Therapeutic Potential and Delivery of Hydroge n Sulfide. AB - BACKGROUND: Hydrogen sulfide (H2S) is a colorless gas with a characteristic smell of rotten eggs. Once only thought of as a toxic gas, evidence now shows that H2S plays major roles in pathological and physiological activities. These roles are being utilized to treat diseases and disorders ranging from hypertension, inflammation, edema, cardiovascular issues, chronic pain, cancer, and many more. Challenges facing the use of H2S currently involve achieving the optimum therapeutic concentrations, synthesizing chemically and physiologically stable donors, and developing clinically appropriate delivery systems. METHODS: We did an extensive literature search on therapeutic potentials and related issues of H2S which were presented in a systematic flow pattern in introduction. Patents accepted/filed on various aspects of hydrogen sulfide were searched using the United States Patent and Trademark Office database at http://patft.uspto.gov/ and google patents at https://patents.google.com/. The important search terms combined with H2S were therapeutic effect, pharmacological action, biochemistry, measurement, and delivery. We also incorporated our own experiences and publications while discussing the delivery approaches and associated challenges. RESULTS: In the process, researchers have discovered novel techniques in preparing the noxious gas by discovering and synthesizing H2S donors and developing controlled and predictable delivery systems. Donors utilized thus far include derivatives of anti-inflammatory drugs like H2S -aspirin, Allium sativum extracts, inorganic salts, phosphorodithioate derivatives, and thioaminoacid derivatives. Use of controlled delivery systems for H2S is critical to maintain its physiological stability, optimum therapeutic window, increase patient compliance, and make it easier to manufacture and administer. Numerous patents overcoming the challenges of using H2S therapeutically with various donors and delivery mechanisms have been reviewed. CONCLUSION: The scientific knowledge gained from the last decade researches has moved H2S from a foul smelling pungent gas to the status of a gasotransmitter with many potential therapeutic applications. However, developing a suitable donor and a delivery system using that donor for providing precise and sustained release of H2S for an extended period, is critically needed for any further development towards its translation into clinical practices. PMID- 28901846 TI - Applications of Nanoflowers in Biomedicine. AB - BACKGROUND: Nanotechnology has opened new windows for biomedical researches and treatment of diseases. Nanostructures with flower-like shapes (nanoflowers) which have exclusive morphology and properties have been interesting for many researchers. METHODS: In this review, various applications of nanoflowers in biomedical researches and patents from various aspects have been investigated and reviewed. RESULTS: Nanoflowers attracted serious attentions in whole biomedical fields such as cardiovascular diseases, microbiology, sensors and biosensors, biochemical and cellular studies, cancer therapy, healthcare, etc. The competitive power of nanoflowers against other in use technologies provides successful achievements in the progress of mentioned biomedical studies. CONCLUSION: The use of nanoflowers in biomedicine leads to improving accuracy, reducing time to achieve the results, reducing costs, creating optimal treatment conditions as well as avoiding side effects of the treatment of specific diseases, and increasing functional strength. PMID- 28901847 TI - microRNAs to Monitor Pain-migraine and Drug Treatment. AB - BACKGROUND: Migraine is a prevalent neurovascular disorders with a complex pathophysiology and therapeutic options characterized by important side effects or problems related to drug abuse. No specific biomarkers are recognized to be univocal for this subclinical condition, yet. In this concern microRNAs (miRNAs) have been suggested as potentially useful screening/diagnostic tool, and research is underway to recognize the most effective candidate(s). In this concern in the present review we Herein we highlighted miRs involvement in pain and migraine, as well as drug response and efficacy focusing also on miRs panel results from mice model with multiple induced pain conditions, and human patients with migraine in order to understand if there are similar miRs expression pattern may useful into human translational studies. RESULTS: During human migraine attack specific miRs were found dysregulated, as well as in mouse models with different pain conditions. Amongst all the miRs screened in mice/human suffering of pain the miR 590-5p was found alterated. This latter miR, in mice is modulated by celecoxib, while in human is dysregulated in the complex regional pain syndrome, condition where migraine assume a risk factor for its development. Recently has been reported that pharmacological treatments, indirectly can pertubate miRNA expression results. Therefore, miR-590-5p could assume an interesting double meaning for a clinical point of view. It can be considered biomarker of general pain, including migraine and also biomarker to evaluate the efficacy of the drug treatment. This could be of great importance in infant-juvenile segment, where the diagnosis of migraine is very challenging. In this view, since therapy is often started with NSAIDs herein we discuss also how the discovery of the new role of miRNAs in determining drug efficacy open a new scenario in the pain migraine tailored therapy and pharmacogenomics concept. CONCLUSION: miRNAs could have a pleiotropic meaning in the clinical management of migraine and could represent biomarkers of pathology, of drug efficacy as well as drug adherence to the treatment. PMID- 28901848 TI - Pulmonary Hypertension secondary to Left Heart Disease. AB - Pulmonary Hypertension (PH) related to Left Heart Disease (LHD) is the most common form of PH, accounting for more than two third of all PH cases. The hemodynamic abnormalities seen in PHLHD are complex, and there are currently minimal evidence-based recommendations for the management of PH-LHD. While it is accepted that PH in the context of left heart disease is a marker of worse prognosis, it remains unclear whether its primary treatment is beneficial or harmful. In this article, we discuss the prevalence and significance of PH in patients with Heart Failure (HF) with Reduced Ejection Fraction (HFrEF) as well as HF with Preserved Ejection Fraction (HFpEF), and those with valvular heart disease and provide insights into the complex pathophysiology of cardiopulmonary interrelationship in individuals with PH due to left heart disease. Furthermore, we provide a framework for diagnostic testing and an approach to optimal management of these complex patients based on current European Society of Cardiology (ESC) guidelines. PMID- 28901849 TI - COMMENTARY: Transcranial Magnetic Stimulation in Multiple Sclerosis: A Method to Improve Movement. PMID- 28901850 TI - Point-of-Care Lung Ultrasound in Critically ill Patients. AB - BACKGROUND: Lung ultrasound is increasingly being used by the bedside physicians to complement the findings of physical examination. Lung ultrasound is non invasive, devoid of radiation exposure and can be performed rapidly and repeatedly as needed at bedside. This review aims to elucidate the evidence base and the future directions for bedside point-of-care lung ultrasound in critically ill patients. METHODS: Research articles, review papers and online contents related to point-of-care ultrasound in critically ill patients were reviewed. RESULTS: The diagnostic accuracy of lung ultrasound for common conditions like pleural effusion, pneumothorax, pulmonary edema and pneumonia is superior to chest radiograph and is comparable to chest CT scan. Lung ultrasound is helpful to evaluate the progress of lung pathology and response to treatment, over time. Ultrasound guidance for thoracocentesis decreases the complication rates. CONCLUSION: Bedside lung ultrasound in critically ill patients can serve as a tool to diagnose common lung pathologies, monitor its course and guide clinical management. PMID- 28901851 TI - Gestational Diabetes Mellitus: Post-partum Risk and Follow Up. AB - BACKGROUND: Women with gestational diabetes mellitus (GDM) are at an increased risk for developing metabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovascular disease. In this review, we will discuss postpartum cardiovascular and diabetes risk in women with a history of GDM and different ways to improve postpartum screening. METHODS: This review involves a comprehensive literature review on gestational diabetes and postpartum risk for cardiovascular disease and diabetes mellitus as well as post-partum screening methods. RESULTS: Cardiovascular risk post-partum is potentiated by increased inflammatory markers leading to worsening atherosclerosis and cardiovascular events downstream. Decreased insulin sensitivity and beta cell compensation, recurrent GDM, maternal factors such as pre and post-partum weight gain and lactation may contribute to T2DM risk. Postpartum glucose testing is essential in screening women as hyperglycemia in pregnancy has long term effects on both cardiovascular disease and diabetes risk on the mother. CONCLUSION: Long and short term improvement to post-partum glucose testing is essential to decreasing cardiometabolic and diabetes risk in women with gestational diabetes mellitus. PMID- 28901852 TI - Recent Advancement of Direct-acting Antiviral Agents (DAAs) in Hepatitis C Therapy. AB - Hepatitis C virus (HCV) infection is a major health problem worldwide. Approximately, 170-200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. In 2011, the first-generation protease inhibitors boceprevir (BOC) telaprevir (TVR) were approved by FDA as the direct-acting antiviral agents. A number of promising new direct-acting antiviral agents (DAAs) have been developed in the past few years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs are in use for patients with chronic HCV and cirrhosis patients. In this review, we will discuss the results of clinical trials of several DAAs and the approved combinations, including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. A number of drugs, including Sovaldi(r), Harvoni(r) Viekira Pak(r), Epclusa(r), Zepatier(r) have been approved by FDA in the past two-three years. The latest advancement of DAA therapy and related side effects due to the therapy are also discussed. PMID- 28901853 TI - Synthesis of New Bis-Spiropyrazoles as Antitumor Agents under Ultrasound Irradiation. AB - OBJECTIVE AND BACKGROUND: Hydrazonoyl halides were used as precursors for the synthesis of a new series of bis-spiropyrazoles via reaction with 3,5-diarylidene piperidone derivatives under ultrasound irradiation. The products were secluded in good yield after short reaction periods. CONCLUSION: The anticancer activity of bis-spiropyrazoles against HepG2 (hepatic cancer), A549 (lung cancer) and CaCo2 (colon cancer) cell lines was screened. Three tested compounds 4b, 4c and 4f showed promising activity. PMID- 28901857 TI - Editorial: Modern and Alternative Matters in Oral Health Maintenance). PMID- 28901854 TI - Pharmacophore Comparison and Development of Recently Discovered Long Chain Arylpiperazine and Sulfonamide Based 5-HT7 Ligands. AB - The serotonin system exerts its effects on the CNS and many peripheral systems. Of the 14 serotonin receptors, the 5-HT7 receptor is the most recently discovered. The 5-HT7 receptor has been shown to be involved in stress reduction, depression, and nociceptive control. Despite the 20 years since the discovery of 5-HT7R, there are still few truly selective ligands. Two of the common scaffolds for 5-HT7R ligands are long chain arylpiperazines (LCAPs) and sulfonamide containing compounds. This review focuses on recently developed (2014-2016) 5 HT7R ligands, their selectivity for the receptor, and suggests the possible new pharmacophore models for these ligands. PMID- 28901856 TI - Recent Patents and Emerging Therapeutics on Ocular Inflammation and Allergy. AB - BACKGROUND: Ocular inflammation and allergic eye diseases range from mild to severe may disturb visual function and affect' quality of life. Since these diseases require intensive therapies, the pathophysiology and treatments of these conditions are highlighted. OBJECTIVE: The ocular diseases caused by inflammation and allergy are extensively studied in this review to provide an overview of the newer compounds, novel delivery approaches, preclinical and clinical trials for the treatment of allergic conjunctivitis, dry eye syndrome, and uveitis. METHOD: The eye is divided into two segments; anterior and posterior. Both segments provide barriers to the drug delivery to the eye. Despite many efforts by scientists, several potential drug candidates are often dropped from the initial screening portfolio due to failure in overcoming these barriers. Thus to overcome unmet challenges, remarkable progresses have been made towards the design of novel ocular therapeutics with enhanced activity and minimal toxicity to the ocular tissue. A comprehensible understanding of the diseased conditions, physiological barriers and pharmacokinetics of the eye would significantly accelerate the development of new therapeutics. Moreover, identification of new targets drives the discovery of novel drug molecules for the ocular disease treatment. RESULTS: The advancement in the drug discovery and dosage from design showcases the increasing number of patent applications being filed and issued for allergic conjunctivitis, dry eye syndrome, and uveitis. In addition, preclinical and clinical trials are now becoming available showing the newer generation of ocular drugs. CONCLUSION: This review presented a brief background on the disease condition, types, treatment, advancement in the delivery approaches, focus on emerging therapeutics, related patents and clinical trials for the treatment of allergic conjunctivitis, dry eye syndrome, and uveitis. PMID- 28901858 TI - Expression of a Nitric Oxide Synthesizing Protein in Arterial Endothelial Cells in Response to Different Anti-Anginal Agents Used in Acute Coronary Syndromes. AB - BACKGROUND: Organic "nitro" compounds such as nitroglycerine, isosorbide dinitrate are useful in the control of chest pain in acute coronary syndrome. But the mechanism of it in pain regulation remains speculative. Here, increase of NO production was investigated by the possible regulation of constitutive nitric oxide synthase (cNOS) function from goat arterial endothelial cells. This protein was purified and sequence wise characterized as protein disulfide isomerase (PDI) in response to different nitro compounds. METHOD: The NO generating protein was isolated from arterial endothelial cells and prepared to homogeneity. NO was determined by methemoglobin method. Protein sequence was analyzed by (uLC/MS/MS). RESULTS: A protein of Mr. ~57 kDa was isolated and found to be activated by not only "nitro" compounds but also by acetyl salicylic acid, insulin and glucose. The global BLAST of the protein sequence showed a significant alignment of the protein sequence with PDI. This protein trivially called pluri activator stimulated endothelial NOS (PLASENOS). The enzyme was stimulated by the above mentioned activators in the presence of Ca2+. Lineweaver-Burk plot of this NOS like activities were demonstrated with its specific substrate l-arginine as Vmax = 5(nmol NO/mg of protein/hr) and Km~ 0.5uM by the above activators. The enzyme activity was inhibited by the l-NAME, the specific inhibitor of NOS. CONCLUSION: The organic nitro compounds, acetyl salicylic acid, insulin and glucose were found to activate PLASENOS in the arterial endothelial cells for a continuous supply of NO to control the chest pain in acute coronary syndrome. PMID- 28901859 TI - COMMENTARY: Magnetic Resonance Techniques Applied to Parkinson's Disease. PMID- 28901860 TI - Editorial: Brain Imaging and Automatic Analysis in Neurological and Psychiatric Diseases - Part II. PMID- 28901861 TI - Research Highlights BAY 1436032: A Novel Pan-mutant IDH1 Inhibitor Extends Survival of Mice with Experimental Brain Tumors. PMID- 28901863 TI - Tissue Fatty Acid Profile is Differently Modulated from Olive Oil and Omega-3 Polyunsaturated Fatty Acids in ApcMin/+ Mice. AB - BACKGROUND: Fatty acid profile can be considered an appropriate biomarker for investigating the relations between the patterns of fatty acid metabolism and specific diseases, as cancer, cardiovascular and degenerative diseases. OBJECTIVE: Aim of this study was to test the effects of diets enriched with olive oil and omega-3 Polyunsaturated Fatty Acids (PUFAs) on fatty acid profile in intestinal tissue of ApcMin/+ mice. METHOD: Three groups of animals were considered: control group, receiving a standard diet; olive oilgroup, receiving a standard diet enriched with olive oil; omega-3 group, receiving a standard diet enriched with salmon fish. Tissue fatty acid profile was evaluated by gas chromatography method. RESULTS: Olive oil and omega-3 PUFAs in the diet differently affect the tissue fatty acid profile. Compared to control group, the levels of Saturated Fatty Acids (SFAs) were lower in olive oil group, while an increase of SFAs was found in omega-3 group. Monounsaturated Fatty Acids (MUFAs) levels were enhanced after olive oil treatment, and in particular, a significant increase of oleic acid levels was detected; MUFAs levels were instead reduced in omega-3 group in line with the decrease of oleic acid levels. The total PUFAs levels were lower in olive oil respect to control group. Moreover, a significant induction of Saturation Index (SI) levels was observed after omega-3 PUFAs treatment, while its levels were reduced in mice fed with olive oil. CONCLUSION: Our data demonstrated a different effect of olive oil and omega-3 PUFAs on tissue lipid profile in APCMin/+ mice. PMID- 28901864 TI - Prenatal Stress Enhances Susceptibility to Allergic Diseases of Offspring. AB - BACKGROUND AND OBJECTIVES: Maternal prenatal stress (MPS) may result in a range of longterm consequences in the offspring among which there is susceptibility to allergic diseases. This review presents the current knowledge on the pathways through which MPS may affect the fetus, and the existing evidence regarding the association between MPS and development of allergy in the offspring. RESULT AND DISCUSSION: A pivotal mediator triggered in response to stress is the release of glucocorticoids (GC). GC may affect gene expression through binding to GC receptors, thus affecting fetal development in general, and allergic vulnerability in particular. A series of recent findings also indicate that MPS may affect the fetus programming of immune functions and lead to vulnerability of the immune system. MPS may hinder the gradual process in the offspring's cytokine production towards a Th1 type immune response. Prenatal factors may also influence the intrauterine microbiome and thereby the maternal bacteria transferred into the fetal gastrointestinal tract. The imbalances of intestinal microbiota in infancy could result in deviations in the development of systemic immune function, predisposing to allergic sensitization. Epidemiological studies in humans also suggest that there is an association of MPS and allergic vulnerability of the offspring. CONCLUSION: Although the existing evidence support a relationship of MPS with allergic predisposition of the offspring, further studies are needed to elucidate whether the association is dependent on the type of stress and whether it involves any type of allergic predisposition or not. PMID- 28901865 TI - Penile and Testicular Measurements in Male Neonates and Infants: Single Center Egyptian Study. AB - BACKGROUND: Universal reference values of penile length, circumferences and testicular volume in newborns and infants are inappropriate to be used in variable ethnic backgrounds. OBJECTIVE: The aim of this prospective study was to establish normal reference values for stretched penile length, penile circumference and testicular volume for Egyptian newborn and infants. SUBJECTS AND METHODS: This observational cross-sectional study included 1850 healthy male full term newborn and infants applied for routine check-up, aged 0 -24 months, the newborn and infants were recruited from Tanta University Hospital in the period from July 2015 to January 2017. Penile length, penile circumference, testicular volume, weight, length and occipito-frontal circumference were measured. RESULTS: The studied infants were divided into five groups. Group I: 1 4 weeks, the mean penile length was 3.51 +/- 0.49 cm, penile circumference was 3.95 +/- 0.48 cm, and testicular size was (right 1.81 +/- 0.44 cm and left 1.67 +/- 0.47 cm). Group II: > 1-6 months age, the mean penile length was 3.99 +/- 0.46 cm, penile circumference was 4.10 +/- 0.38 cm, and testicular size was (right 2.10 +/- 0.33 cm and left 2.04 +/- 0.27 cm). Group III: >6-12 months age, the mean penile length was 4.45 +/- 0.48 cm, penile circumference was 4.21 +/- 0.33 cm, and testicular size was (right 2.13 +/- 0.33 cm and left 2.06 +/- 0.28 cm). Group IV: >12-18 months age, the mean penile length was 4.55 +/- 0.54 cm, penile circumference was 4.28 +/- 0.32 cm, and testicular size was (right 2.12 +/ 0.33 cm and left 2.09 +/- 0.32 cm). Group V: >18-24 months age, the mean penile length was 4.89 +/- 0.63 cm, penile circumference was 4.45 +/- 0.33 cm, and testicular size was (right 2.28 +/- 0.45 cm and left 2.25 +/- 0.45 cm). There were significant positive correlations between penile length, penile circumference, left and right testicular volumes with each other and also with all other anthropometric measures including: weight, height and head circumference. CONCLUSION AND RECOMMENDATION: The age-related values of penile and testicular measurements must be known to be able to determine the abnormal sizes and to monitor treatment of underlying diseases. Our study is a step to achieve accurate reference values of penile and testicular measurements for Egyptian male newborns and infants. Therefore multicenter studies are recommended to establish Egyptian norms. PMID- 28901867 TI - MDH volume 61 Issue 4 Cover and Back matter. PMID- 28901866 TI - A Novel Potential Reproductive Effects of Pterocarpus marsupium Methanolic Extract on Testosterone Propionate Induced Polycystic Ovary Syndrome in Female Albino Rats. AB - OBJECTIVE: To investigate potential reproductive effects of Pterocarpus marsupium methanolic extract on testosterone propionate induced Polycystic Ovarian Syndrome (PCOS) in female albino rats. METHODOLOGY: PCOS was induced in female albino rats by daily injecting testosterone propionate for 15 days intraperitoneally. Animals are divided into five groups with six rats per group. Group 1: Control group received olive oil, Group 2: Testosterone propionate+natural recovery, Group 3: Testosterone propionate + a dose of clomiphene citrate (standard), Group 4 and 5: Testosterone propionate + low dose (200mg/kg) and high dose (400mg/kg) b.w respectively for 15 days. Various biochemical and histopathological investigations were assessed. RESULTS: Methanol extract of Pterocarpus marsupium was able to exert its protective effect successfully by restoring all the parameters to normal and diminishing the cysts found in ovaries. CONCLUSION: Pterocarpus marsupium showed potential reproductive effects on testosterone propionate induced PCOS female albino rats and could be used as an alternative therapy in the treatment of PCOS. PMID- 28901868 TI - Calculable People? Standardising Assessment Guidelines for Alzheimer's Disease in 1980s Britain. AB - This article shows how funding research on Alzheimer's disease became a priority for the British Medical Research Council (MRC) in the late 1970s and 1980s, thanks to work that isolated new pathological and biochemical markers and showed that the disease affected a significant proportion of the elderly population. In contrast to histories that focus on the emergence of new and competing theories of disease causation in this period, I argue that concerns over the use of different assessment methods ensured the MRC's immediate priority was standardising the ways in which researchers identified and recorded symptoms of Alzheimer's disease in potential research subjects. I detail how the rationale behind the development of standard assessment guidelines was less about arriving at a firm diagnosis and more about facilitating research by generating data that could be easily compared across the disciplines and sites that constitute modern biomedicine. Drawing on criticism of specific tests in the MRC's guidelines, which some psychiatrists argued were 'middle class biased', I also show that debates over standardisation did not simply reflect concerns specific to the fields or areas of research that the MRC sought to govern. Questions about the validity of standard assessment guidelines for Alzheimer's disease embodied broader concerns about education and social class, which ensured that distinguishing normal from pathological in old age remained a contested and historically contingent process. PMID- 28901869 TI - The Expulsion of South Africa and Rhodesia from the Commonwealth Medical Association, 1947-70. AB - In 1970 the medical associations of South Africa and Rhodesia (now, Zimbabwe) were expelled from the Commonwealth Medical Association. The latter had been set up, as the British Medical Commonwealth Medical Conference, in the late 1940s by the British Medical Association (BMA). These expulsions, and the events leading up to them, are the central focus of this article. The BMA's original intention was to establish an organisation bringing together the medical associations of the constituent parts of the expanding Commonwealth. Among the new body's preoccupations was the relationship between the medical profession and the state in the associations' respective countries. It thus has to be seen as primarily a medico-political organisation rather than one concerned with medicine per se. Although, there were also tensions from the outset regarding the membership of the Southern African medical associations. Such stresses notwithstanding, these two organisations remained in the BMA-sponsored body even after South Africa and Rhodesia had left the Commonwealth. This was not, however, a situation which could outlast the growing number of African associations which joined in the wake of decolonisation; and hardening attitudes towards apartheid. The article therefore considers: why the BMA set up this Commonwealth body in the first place and what it hoped to achieve; the history of the problems associated with South African and Rhodesian membership; and how their associations came to be expelled. PMID- 28901871 TI - Citizenship and Learning Disabled People: The Mental Health Charity MIND's 1970s Campaign in Historical Context. AB - Current policy and practice directed towards people with learning disabilities originates in the deinstitutionalisation processes, civil rights concerns and integrationist philosophies of the 1970s and 1980s. However, historians know little about the specific contexts within which these were mobilised. Although it is rarely acknowledged in the secondary literature, MIND was prominent in campaigning for rights-based services for learning disabled people during this time. This article sets MIND's campaign within the wider historical context of the organisation's origins as a main institution of the inter-war mental hygiene movement. The article begins by outlining the mental hygiene movement's original conceptualisation of 'mental deficiency' as the antithesis of the self-sustaining and responsible individuals that it considered the basis of citizenship and mental health. It then traces how this equation became unravelled, in part by the altered conditions under the post-war Welfare State, in part by the mental hygiene movement's own theorising. The final section describes the reconceptualisation of citizenship that eventually emerged with the collapse of the mental hygiene movement and the emergence of MIND. It shows that representations of MIND's rights-based campaigning (which have, in any case, focused on mental illness) as individualist, and fundamentally opposed to medicine and psychiatry, are inaccurate. In fact, MIND sought a comprehensive community-based service, integrated with the general health and welfare services and oriented around a reconstruction of learning disabled people's citizenship rights. PMID- 28901872 TI - 'Speaking Kleinian': Susan Isaacs as Ursula Wise and the Inter-War Popularisation of Psychoanalysis. AB - How did the complex concepts of psychoanalysis become popular in early twentieth century Britain? This article examines the contribution of educator and psychoanalyst Susan Isaacs (1885-1948) to this process, as well as her role as a female expert in the intellectual and medical history of this period. Isaacs was one of the most influential British psychologists of the inter-war era, yet historical research on her work is still limited. The article focuses on her writing as 'Ursula Wise', answering the questions of parents and nursery nurses in the popular journal Nursery World, from 1929 to 1936. Researched in depth for the first time, Isaacs' important magazine columns reveal that her writing was instrumental in disseminating the work of psychoanalyst Melanie Klein in Britain. Moreover, Isaacs' powerful rebuttals to behaviourist, disciplinarian parenting methods helped shift the focus of caregivers to the child's perspective, encouraging them to acknowledge children as independent subjects and future democratic citizens. Like other early psychoanalysts, Isaacs was not an elitist; she was in fact committed to disseminating her ideas as broadly as possible. Isaacs taught British parents and child caregivers to 'speak Kleinian', translating Klein's intellectual ideas into ordinary language and thus enabling their swift integration into popular discourse. PMID- 28901873 TI - Homeopathy 'for Mexicans': Medical Popularisation, Commercial Endeavours, and Patients' Choice in the Mexican Medical Marketplace, 1853-1872. AB - This paper focuses on homeopaths' strategies to popularise homeopathy from 1850 to 1870. I argue that homeopaths created a space for homeopathy in Mexico City in the mid-nineteenth century by facilitating patients' access to medical knowledge, consultation and practice. In this period, when national and international armed conflicts limited the diffusion and regulation of academic medicine, homeopaths popularised homeopathy by framing it as a life-enhancing therapy with tools that responded to patients' needs. Patients' preference for homeopathy evolved into commercial endeavours that promoted the practice of homeopathy through the use of domestic manuals. Using rare publications and archival records, I analyse the popularisation of homeopathy in Ramon Comellas's homeopathic manual, the commercialisation of Julian Gonzalez's family guides, and patients' and doctors' reception of homeopathy. I show that narratives of conversion to homeopathy relied on the different experiences of patients and trained doctors, and that patients' positive experience with homeopathy weighed more than the doctors' efforts to explain to the public how academic medicine worked. The fact that homeopaths and patients used a shared language to describe disease experiences framed the possibility of a horizontal transmission of medical knowledge, opening up the possibility for patients to become practitioners. By relying on the long tradition of domestic medicine in Mexico, the popularisation of homeopathy disrupted the professional boundaries that academic physicians had begun to build, making homeopaths the largest group that challenged the emergent medical academic culture and its diffusion in Mexico in the nineteenth century. PMID- 28901883 TI - Digitizing Doctors: Methodologies for Creating a Database from Historical Directories of Physicians. PMID- 28901885 TI - Teaching and Researching the History of Medicine in the Era of (Big) Data: Reflections. PMID- 28901886 TI - Consumption of whole grains, fruit and vegetables is not associated with indices of renal function in the population-based longitudinal Doetinchem study. AB - Emerging evidence suggests that diet and renal function are related. Little is known, however, about the association of consumption of whole grains, fruit and vegetables with urinary albumin:creatinine ratio (ACR) and changes in estimated glomerular filtration rate (eGFR). We investigated this in a population-based cohort aged 26-65 years. Data were from 3787 participants from the Doetinchem cohort study, who were examined >=3 times, 5 years apart. Consumption of food groups was assessed at each round with a validated FFQ. GFR was estimated at each round from routinely measured cystatin C and creatinine using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation. ACR was measured at the last round. Generalised estimated equation models were performed to examine associations with changes in eGFR. Linear regression was used to examine associations with ACR. Adjustments were made for covariates related to lifestyle, biological factors and diet. Mean baseline eGFR was 104.5 (sd 13.7) and mean annual decline was -0.95 (sd 0.67) ml/min per 1.73 m2 over a 15-year follow-up. A trend was observed towards slightly less annual decline in eGFR among those with higher consumption of whole grains (P=0.06). This association, however, was attenuated and no longer significant in multivariate models (P=0.29). Consumption of fruit and vegetables was not associated with changes in eGFR and urinary ACR. In conclusion, consumption of whole grains, fruit and vegetables is not associated with changes in eGFR and mean ACR. As this was the first longitudinal study into this association in the general population, and as results are only partially in line with related studies, further research is recommended. PMID- 28901887 TI - Microcytosis is associated with low cognitive outcomes in healthy 2-year-olds in a high-resource setting. AB - Fe deficiency in early childhood is associated with long-term consequences for cognitive, motor and behavioural development; however explorations in healthy children from low risk, high-resource settings have been limited. We aimed to explore associations between Fe status and neurodevelopmental outcomes in low risk, healthy 2-year-olds. This study was a secondary analysis of a nested case control subgroup from the prospective, maternal-infant Cork Babies after Screening for Pregnancy Endpoints: Evaluating the Longitudinal Impact using Neurological and Nutritional Endpoints (BASELINE) Birth Cohort Study. At 2 years, serum ferritin, Hb and mean corpuscular volume (MCV) were measured and neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development (n 87). Five children had Fe deficiency (ferritin <12 ug/l) and no child had Fe deficiency anaemia (Hb<110 g/l+ferritin<12 ug/l). Children with microcytosis (MCV<74 fl, n 13) had significantly lower mean cognitive composite scores (88.5 (sd 13.3) v. 97.0 (sd 7.8), P=0.04, Cohen's d effect size=0.8) than those without microcytosis. The ferritin concentration which best predicted microcytosis was calculated as 18.4 ug/l (AUC=0.87 (95% CI 0.75, 0.98), P<0.0001, sensitivity 92 %, specificity 75 %). Using 18.5 ug/l as a threshold, children with concentrations <18.5 ug/l had significantly lower mean cognitive composite scores (92.3 (sd 10.5) v. 97.8 (sd 8.1), P=0.012, Cohen's d effect size=0.6) compared with those with ferritin >=18.5 ug/l. All associations were robust after adjustment for potential confounding factors. Despite a low prevalence of Fe deficiency using current diagnostic criteria in this healthy cohort, microcytosis was associated with lower cognitive outcomes at 2 years. This exploratory study emphasises the need for re-evaluation of the diagnostic criteria for Fe deficiency in young children, with further research in adequately powered studies warranted. PMID- 28901888 TI - Effects of oral Lactobacillus administration on antioxidant activities and CD4+CD25+forkhead box P3 (FoxP3)+ T cells in NZB/W F1 mice. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by a dysregulation of the immune system, which causes inflammation responses, excessive oxidative stress and a reduction in the number of cluster of differentiation (CD)4+CD25+forkhead box P3 (FoxP3)+ T cells. Supplementation with certain Lactobacillus strains has been suggested to be beneficial in the comprehensive treatment of SLE. However, little is known about the effect and mechanism of certain Lactobacillus strains on SLE. To investigate the effects of Lactobacillus on SLE, NZB/W F1 mice were orally gavaged with Lactobacillus paracasei GMNL-32 (GMNL-32), Lactobacillus reuteri GMNL-89 (GMNL-89) and L. reuteri GMNL-263 (GMNL-263). Supplementation with GMNL-32, GMNL-89 and GMNL-263 significantly increased antioxidant activity, reduced IL-6 and TNF-alpha levels and significantly decreased the toll-like receptors/myeloid differentiation primary response gene 88 signalling in NZB/W F1 mice. Notably, supplementation with GMNL-263, but not GMNL-32 and GMNL-89, in NZB/W F1 mice significantly increased the differentiation of CD4+CD25+FoxP3+ T cells. These findings reveal beneficial effects of GMNL-32, GMNL-89 and GMNL-263 on NZB/W F1 mice and suggest that these specific Lactobacillus strains can be used as part of a comprehensive treatment of SLE patients. PMID- 28901889 TI - Effect of breakfast omission and consumption on energy intake and physical activity in adolescent girls: a randomised controlled trial. AB - It is not known if breakfast consumption is an effective intervention for altering daily energy balance in adolescents when compared with breakfast omission. This study examined the acute effect of breakfast consumption and omission on free-living energy intake (EI) and physical activity (PA) in adolescent girls. Using an acute randomised cross-over design, forty girls (age 13.3 (sd 0.8) years, BMI 21.5 (sd 5.0) kg/m2) completed two, 3-d conditions in a randomised, counter-balanced order: no breakfast (NB) and standardised (approximately 1962 kJ) breakfast (SB). Dietary intakes were assessed using food diaries combined with digital photographic records and PA was measured via accelerometry throughout each condition. Statistical analyses were completed using repeated-measures ANOVA. Post-breakfast EI was 483 (sd 1309) kJ/d higher in NB v. SB (P=0.025), but total daily EI was 1479 (sd 11311) kJ/d higher in SB v. NB (P<0.0005). Daily carbohydrate, fibre and protein intakes were higher in SB v. NB (P<0.0005), whereas daily fat intake was not different (P=0.405). Effect sizes met the minimum important difference of >=0.20 for all significant effects. Breakfast manipulation did not affect post-breakfast macronutrient intakes (P>=0.451) or time spent sedentary or in PA (P>=0.657). In this sample of adolescent girls, breakfast omission increased post-breakfast free-living EI, but total daily EI was greater when a SB was consumed. We found no evidence that breakfast consumption induces compensatory changes in PA. Further experimental research is required to determine the effects of extended periods of breakfast manipulation in young people. PMID- 28901890 TI - Dietary l-arginine inhibits intestinal Clostridium perfringens colonisation and attenuates intestinal mucosal injury in broiler chickens. AB - We investigated the effects of dietary l-arginine level and feeding duration on the intestinal damage of broilers induced by Clostridium perfringens (CP) in vivo, and the antimicrobial effect of its metabolite nitric oxide (NO) in vitro. The in vivo experiment was designed as a factorial arrangement of three dietary treatments*two challenge statuses. Broilers were fed a basal diet (CON) or a high arginine diet (ARG) containing 1.87 % l-arginine, or CON for the first 8 d and ARG from days 9 to 28 (CON/ARG). Birds were co-infected with or without Eimeria and CP (EM/CP). EM/CP challenge led to intestinal injury, as evidenced by lower plasma d-xylose concentration (P<0.01), higher paracellular permeability in the ileum (P<0.05) and higher numbers of Escherichia coli (P<0.05) and CP (P<0.001) in caecal digesta; however, this situation could be alleviated by l-arginine supplementation (P<0.05). The intestinal claudin-1 and occludin mRNA expression levels were decreased (P<0.05) following EM/CP challenge; this was reversed by l arginine supplementation (P<0.05). Moreover, EM/CP challenge up-regulated (P<0.05) claudin-2, interferon-gamma (IFN-gamma), toll-like receptor 2 and nucleotide-binding oligomerisation domain 1 (NOD1) mRNA expression, and l arginine supplementation elevated (P<0.05) IFN-gamma, IL-10 and NOD1 mRNA expression. In vitro study showed that NO had bacteriostatic activity against CP (P<0.001). In conclusion, l-arginine supplementation could inhibit CP overgrowth and alleviate intestinal mucosal injury by modulating innate immune responses, enhancing barrier function and producing NO. PMID- 28901891 TI - Dietary intake of fat and fibre according to reference values relates to higher gut microbiota richness in overweight pregnant women. AB - The diet-microbiota-metabolism relationships during pregnancy are mostly unknown. We explored the effect of the habitual diet and adherence to the dietary reference values on gut microbiota composition and diversity. Further, the association of gut microbiota with serum lipidomics and low-grade inflammation was evaluated. Overweight and obese women (BMI 30.7 (sd 4.4) kg/m2, n 100) were studied at early pregnancy (<=17 weeks). Intakes of nutrients were calculated from 3-d food diaries. Faecal microbiota composition was analysed using 16S rRNA gene sequencing. Fasting serum lipidomic profiles were determined by NMR. High sensitivity C-reactive protein, glycoprotein acetylation (GlycA) and lipopolysaccharide activity were used as markers for low-grade inflammation. The recommended dietary intake of fibre and fat was related to higher gut microbiota richness and lower abundance of Bacteroidaceae. Correlations were observed between gut microbiota richness and GlycA and between a few microbiota genera and serum lipoprotein particles. As a conclusion, adherence to the dietary reference intake of fat and fibre was associated with beneficial gut microbiota composition, which again contributed to lipidomic profile. Higher gut microbiota richness and nutrient intakes were linked to a lower level of low-grade inflammation marker GlycA. This finding offers novel insights and opportunities for dietary modification during pregnancy with potential of improving the health of the mother and the child. PMID- 28901892 TI - The effect of anthocyanin supplementation in modulating platelet function in sedentary population: a randomised, double-blind, placebo-controlled, cross-over trial. AB - The anti-thrombotic properties of anthocyanin (ACN) supplementation was evaluated in this randomised, double-blind, placebo (PBO) controlled, cross-over design, dietary intervention trial in sedentary population. In all, sixteen participants (three males and thirteen females) consumed ACN (320 mg/d) or PBO capsules for 28 d followed by a 2-week wash-out period. Biomarkers of thrombogenesis and platelet activation induced by ADP; platelet aggregation induced by ADP, collagen and arachidonic acid; biochemical, lipid, inflammatory and coagulation profile were evaluated before and after supplementation. ACN supplementation reduced monocyte platelet aggregate formation by 39 %; inhibited platelet endothelial cell adhesion molecule-1 expression by 14 %; reduced platelet activation-dependant conformational change and degranulation by reducing procaspase activating compound-1 (PAC-1) (?10 %) and P-selectin expression (?14 %), respectively; and reduced ADP-induced whole blood platelet aggregation by 29 %. Arachidonic acid and collagen-induced platelet aggregation; biochemical, lipid, inflammatory and coagulation parameters did not change post-ACN supplementation. PBO treatment did not have an effect on the parameters tested. The findings suggest that dietary ACN supplementation has the potential to alleviate biomarkers of thrombogenesis, platelet hyperactivation and hyper-aggregation in sedentary population. PMID- 28901893 TI - Using item response theory to address vulnerabilities in FFQ. AB - The limitations for self-reporting of dietary patterns are widely recognised as a major vulnerability of FFQ and the dietary screeners/scales derived from FFQ. Such instruments can yield inconsistent results to produce questionable interpretations. The present article discusses the value of psychometric approaches and standards in addressing these drawbacks for instruments used to estimate dietary habits and nutrient intake. We argue that a FFQ or screener that treats diet as a 'latent construct' can be optimised for both internal consistency and the value of the research results. Latent constructs, a foundation for item response theory (IRT)-based scales (e.g. Patient Reported Outcomes Measurement Information System) are typically introduced in the design stage of an instrument to elicit critical factors that cannot be observed or measured directly. We propose an iterative approach that uses such modelling to refine FFQ and similar instruments. To that end, we illustrate the benefits of psychometric modelling by using items and data from a sample of 12 370 Soldiers who completed the 2012 US Army Global Assessment Tool (GAT). We used factor analysis to build the scale incorporating five out of eleven survey items. An IRT driven assessment of response category properties indicates likely problems in the ordering or wording of several response categories. Group comparisons, examined with differential item functioning (DIF), provided evidence of scale validity across each Army sub-population (sex, service component and officer status). Such an approach holds promise for future FFQ. PMID- 28901894 TI - Dietary starch types affect liver nutrient metabolism of finishing pigs. AB - This study aimed to evaluate the effect of different starch types on liver nutrient metabolism of finishing pigs. In all ninety barrows were randomly allocated to three diets with five replicates of six pigs, containing purified waxy maize starch (WMS), non-waxy maize starch (NMS) and pea starch (PS) (the amylose to amylopectin ratios were 0.07, 0.19 and 0.28, respectively). After 28 d of treatments, two per pen (close to the average body weight of the pen) were weighed individually, slaughtered and liver samples were collected. Compared with the WMS diet, the PS diet decreased the activities of glycogen phosphorylase, phosphoenolpyruvate carboxykinase and the expression of phosphoenolpyruvate carboxykinase 1 in liver (P0.05). Compared with the WMS diet, the PS diet reduced the expressions of glutamate dehydrogenase and carbamoyl phosphate synthetase 1 in liver (P<0.05). PS diet decreased the expression of the insulin receptor, and increased the expressions of mammalian target of rapamycin complex 1 and ribosomal protein S6 kinase beta-1 in liver compared with the WMS diet (P<0.05). These findings indicated that the diet with higher amylose content could down regulate gluconeogenesis, and cause less fat deposition and more protein deposition by affecting the insulin/PI3K/protein kinase B signalling pathway in liver of finishing pigs. PMID- 28901895 TI - Agaribacterium haliotis gen. nov., sp. nov., isolated from abalone faeces. AB - A marine bacterium, named strain feces2T, was isolated from the excreted faeces of an abalone, Haliotis discus hannai. The bacterium was Gram-stain-negative, rod shaped and had a polar flagellum. It formed a white, small and crater-like colony on an agar plate, and had the capability of degrading agar. Activity of oxidase was positive and that of catalase was negative. Strain feces2T grew at 16 to 40 degrees C with an optimum of 28-30 degrees C. The nearly full-length 16S rRNA gene of strain feces2T had the greatest sequence similarity of 92.9 % with Marinibactrumhalimedae Q-192T, followed by of 92.8 % with Teredinibacterturnerae T7902T. Phylogenetic analysis indicated that strain feces2T belonged to the family Cellvibrionaceae, representing an independent clade with an uncultured bacterium clone NEP3-15 (98 % sequence similarity of 16S rRNA gene) derived from the phycosphere of Enteromorphaprolifera. The respiratory quinone was ubiquinone Q-8. The predominant fatty acids consisted of summed feature 8 (C18 : 1 omega7c/C18 : 1 omega6c), C16 : 0 and summed feature 3 (C16 : 1 omega6c/C16 : 1omega7c). The polar lipids were identified as phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified amino phospholipid and four unknown lipids. The genomic DNA G+C content was 50.5 mol%. On the basis of polyphasic characterizations, strain feces2T represented a novel species and a novel genus in the family Cellvibrionaceae of the order Cellvibrionales within the Gammaproteobacteria, for which the name Agaribacteriumhaliotis gen. nov., sp. nov. is proposed, with the type strain being feces2T (=MCCC 1A11450T=KCTC 52708T). PMID- 28901896 TI - Paludicola psychrotolerans gen. nov., sp. nov., a novel psychrotolerant chitinolytic anaerobe of the family Ruminococcaceae. AB - A psychrotolerant chitinolytic bacterium, designated NC1253T, was isolated from Zoige wetland on the Qinghai-Tibetan Plateau. This strain was a Gram-stain positive, spore-forming and rod-shaped anaerobe. NC1253T grew at 4-35 degrees C, at pH 6.0-8.5 and could grow on chitin as the only carbon resource. Phylogenetic analysis, based on the 16S rRNA gene sequence, showed that strain NC1253T represented a novel bacterial genus within the family Ruminococcaceae. Strain NC1253T has less than 91.0 % similarity with other type strains, such as Harryflintia acetispora V20-281aT (90.9 %), Clostridium methylpentosum DSM 5476T (90.8 %), Anaerotruncus colihominis DSM 17241T (89.8 %), Eubacterium siraeum DSM 15702T (89.6 %), and Acetanaerobacterium elongatum Z7T (89.6 %). The major components of the cellular fatty acids were iso-C14 : 0, anteiso-C15 : 0, C16 : 0 and anteiso-C17 : 0. The genomic DNA G+C content was 35.4 mol%. Phenotypic, chemotaxonomic and phylogenetic characteristics allowed strain NC1253T to be clearly distinguished from genera in the family Ruminococcaceae. On the basis of polyphasic taxonomic data, the isolate is considered to represent a novel genus and novel species in the family Ruminococcaceae, for which the name Paludicola psychrotolerans gen. nov., sp. nov., is proposed. The type species is NC1253T (DSM 104738T=KCTC 15582T). PMID- 28901897 TI - Hymenobacter frigidus sp. nov., isolated from a glacier ice core. AB - A psychrophilic, Gram-stain-negative, rod-shaped, red-pigmented bacterium, designated strain B1789T, was isolated from an ice core of Muztagh Glacier on the Tibetan Plateau in China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain B1789T was related to members of the genus Hymenobacter and had highest sequence similarity with Hymenobacter antarcticus JCM 17217T (97.9 %). The major menaquinone was MK-7 and the major polar lipid was phosphatidylethanolamine. The predominant fatty acids were iso-C15 : 0, anteiso C15 : 0 and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The DNA G+C content was 59.4 mol%. In DNA-DNA hybridization tests, strain B1789T shared 42 % relatedness with H. antarcticus JCM 17217T. Based on the results of phenotypic and chemotaxonomic tests, strain B1789T was considered as representing a novel species of the genus Hymenobacter, for which the name Hymenobacter frigidus sp. nov. is proposed. The type strain is B1789T (=JCM 30595T=CGMCC 1.14966T). PMID- 28901898 TI - Propioniciclava sinopodophylli sp. nov., isolated from leaves of Sinopodophyllum hexandrum (Royle) Ying. AB - A Gram-reaction-positive, facultatively anaerobic, rod-shaped and non-motile bacterial strain, designated TEYR-7T, was isolated from the leaves of Sinopodophyllum hexandrum collected from the Qinling Mountains in Shaanxi Province, northwest China. Growth of strain TEYR-7T occurred at 15-37 degrees C (optimum, 28-30 degrees C), at pH 6.0-9.0 (optimum, pH 7.0) and in the presence of 0-3 % (w/v) NaCl (optimum, 0-1 %). Propionate and acetate were produced from glucose fermentation. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TEYR-7T was a member of the phylum Actinobacteria, exhibiting the highest sequence similarity to Propioniciclava tarda DSM 22130T (94.3 %). The only respiratory quinone detected in strain TEYR-7T was menaquinone MK-9(H4) and the major cellular fatty acids (>10 %) were anteiso-C15 : 0 and C16 : 0. The polar lipid profile consisted of phosphatidylglycerol, diphosphatidylglycerol, two unidentified glycolipids, an unidentified phospholipid and three unidentified lipids. The genomic DNA G+C content was 71.2 mol%. meso-Diaminopimelic acid was detected in the peptidoglycan. On the basis of data from the present polyphasic taxonomic study, strain TEYR-7T is considered to represent a novel species of the genus Propioniciclava, for which the name Propioniciclava sinopodophylli sp. nov. is proposed. The type strain is TEYR-7T (=CCTCC AB 2015257T=KCTC 33808T). PMID- 28901899 TI - Massilia glaciei sp. nov., isolated from the Muztagh Glacier. AB - A Gram-stain-negative, rod-shaped, bacterial strain, B448-2T, was isolated from an ice core from the Muztagh Glacier, on the Tibetan Plateau. B448-2T grew optimally at pH 7.0 and 20 degrees C in the presence of 0-1.0 % (w/v) NaCl. The results of 16S rRNA gene sequence similarity analysis indicated that B448-2T was closely related to Massilia eurypsychrophila CGMCC 1.12828T, Rugamonas rubra CCM3730T and Duganella zoogloeoides JCM20729T at levels of 97.8, 97.7 and 97.3 %, respectively. The predominant fatty acids of B448-2T were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The predominant isoprenoid quinone was Q-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The genomic DNA G+C content of the strain was 66.1 mol%. In DNA-DNA hybridization tests, B448-2T shared 37.6 % DNA-DNA relatedness with Massilia eurypsychrophila CGMCC 1.12828T. On the basis of the results for phenotypic and chemotaxonomic characteristics, B448-2T was considered to represent a novel species of the genus Massilia, for which the name Massiliaglaciei sp. nov. is proposed. The type strain is B448-2T (=JCM 30271T=CGMCC 1.12920T). PMID- 28901900 TI - Persistence of RSV promotes proliferation and epithelial-mesenchymal transition of bronchial epithelial cells through Nodal signaling. AB - PURPOSE: Nodal may play an important role in the development of cancers. The present study was designed to determine the effects of Nodal induced by respiratory syncytial virus (RSV) infection on the occurrence and development of lung cancer and the underlying mechanisms. METHODOLOGY: After verification of RSV infection by observation of cytopathic effect and indirect immunofluorescence, real-time PCR, Western blot and methylation assays were used to verify the influence of RSV on Nodal expression. Then, a Nodal overexpressed vector was constructed and the effects of Nodal on the proliferation and apoptosis of bronchial epithelial cells (BECs) and epithelial-mesenchymal transition (EMT) were assayed by flow cytometry and Western blot, respectively. Moreover, Lefty and pSmad2/3 were assayed by Western blot and Cyclin D1, CDK4, c-myc and Bcl-2 induced by Nodal overepression or RSV infection were also assayed by real-time PCR. RESULTS: The results showed that Nodal over expression and demethylation of the promoter were observed in BECs after RSV infection. Activation of Nodal promoted proliferation, colony formation and EMT and inhibited apoptosis of BECs. Nodal also promoted malignant change by promoting expression of cyclin D1 and related-dependent kinase and inhibiting apoptosis. Besides, RSV infection inhibited Lefty expression and promoted the activation of pSmad2/3. RSV also promoted Cyclin D1, CDK4, c-myc and Bcl-2 expression through the activation of pSmad2/3. CONCLUSIONS: Our data showed that persistence of RSV promoted the proliferation, epithelial-mesenchymal transition and expression of oncogenes through Nodal signaling, which may be associated with the occurrence and development of lung cancers. PMID- 28901901 TI - Salinimicrobium flavum sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, non-gliding, facultatively anaerobic and rod-shaped bacterium, designated X7T, was isolated from marine sediment taken from the coast of Weihai, China. Strain X7T grew optimally at 28-30 degrees C, at pH 7.0 and in the presence of 2-3 % (w/v) NaCl. Based on the 16S rRNA gene sequence analysis, strain X7T was a member of the genus Salinimicrobium and was most closely related to the species Salinimicrobium gaetbulicola with a 96.3 % 16S rRNA gene sequence similarity value. The major cellular fatty acids of strain X7T were anteiso-C15 : 0, iso-C15 : 0, anteiso-C17 : 1omega9c, iso-C17 : 1omega9c, C17 : 0 2-OH and iso C17 : 0 3-OH. The major polar lipids of strain X7T were phosphatidylethanolamine, one unidentified phospholipid, two unidentified aminolipids and five unidentified lipids. The predominant respiratory quinone was MK-6, and the genomic DNA G+C content was 46.7 mol%. Phylogenetic, phenotypic, chemotaxonomic and genotypic results indicated that strain X7T represents a novel species of the genus Salinimicrobium, for which the name Salinimicrobium flavum sp. nov. is proposed. The type strain is X7T (=KCTC 42585T=MCCC 1H00115T). PMID- 28901902 TI - Simian varicella virus inhibits the interferon gamma signalling pathway. AB - The alphaherpesvirus simian varicella virus (SVV) causes varicella and zoster in nonhuman primates. Herpesviruses evolved elaborate mechanisms to escape host immunity, but the immune evasion strategies employed by SVV remain ill-defined. We analysed whether SVV impairs the cellular response to key antiviral cytokine interferon-gamma (IFNgamma). SVV infection inhibited the expression of IFNgamma induced genes like C-X-C motif chemokine 10 and interferon regulatory factor 1. Phosphorylation and nuclear translocation of the signal transducer and activator of transcription 1 (STAT1) was blocked in SVV-infected cells, which did not involve cellular and viral phosphatases. SVV infection did not downregulate IFNgamma receptor alpha and beta chain expression on the cell surface. Instead, STAT1, Janus tyrosine kinases 1 (JAK1) and JAK2 protein levels were significantly decreased in SVV-infected cells. Collectively, these results demonstrate that SVV targets three proteins in the IFNgamma signal transduction pathway to escape the antiviral effects of IFNgamma. PMID- 28901903 TI - Halobacterium litoreum sp. nov., isolated from a marine solar saltern. AB - Halophilic archaeal strain ZS-54-S2T was isolated from Zhoushan marine solar saltern, China. Cells were rod-shaped, Gram-stain-negative and formed red pigmented colonies on an agar plate. Strain ZS-54-S2T was able to grow at 20-50 degrees C (optimum 35 degrees C), at 1.7-4.8 M NaCl (optimum 3.9 M), at 0.005 1.0 M MgCl2 (optimum 0.05 M) and at pH 5.0-9.5 (optimum pH 7.0). The cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was found to be 5 % (w/v). The major polar lipids of the strain were phosphatidic acid, phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, two glycolipids, which were chromatographically identical to sulfated galactosyl mannosyl galactofuranosyl glucosyl diether and galactosyl mannosyl glucosyl diether, and an unidentified glycolipid, which was chromatographically identical to one detected in Halobacterium salinarum ATCC 33171T. The 16S rRNA gene and rpoB' gene of strain ZS-54-S2T were phylogenetically related to the corresponding genes of Halobacterium noricense JCM 15102T (97.5 % and 90.6 % relatedness, respectively), Halobacterium jilantaiense CGMCC 1.5337T (96.9 and 91.2 %), Halobacterium rubrum CGMCC 1.12575T (96.8 and 90.3 %) and Halobacterium salinarum CGMCC 1.1958T (96.5 and 88.4 %). The DNA G+C content of strain ZS-54-S2T was 66.7 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain ZS-54-S2T (=CGMCC 1.12562T=JCM 30038T) represents a new species of Halobacterium, for which the name Halobacteriumlitoreum sp. nov. is proposed. PMID- 28901904 TI - Chryseomicrobium deserti sp. nov., isolated from desert soil in South Korea. AB - A Gram-stain positive, aerobic, non-motile, rod-shaped bacterium (THG-T1.18T) was isolated from desert soil. Growth occurred at 20-35 degrees C (optimum 28-30 degrees C), at pH 5-7 (optimum 7) and at 0-4 % NaCl (optimum 0-1 %). Based on 16S rRNA sequence analysis, the nearest phylogenetic neighbours of strain THG-T1.18T were identified as Chryseomicrobium amylolyticum DSM 23442T (96.6 %), Chryseomicrobium imtechense JCM 16573T (96.3 %) and Chryseomicrobium aureum KACC 17219T (96.1 %). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids and one unidentified glycolipid. The quinone system was composed of MK-7, MK-8 and MK 6. The major fatty acids were iso C15 : 0 and anteiso C15 : 0. The type of peptidoglycan was A4beta, containing of l-Orn-D-Glu. The DNA G+C content of strain THG-T1.18T was 50.4 mol%. DNA-DNA hybridization values between strain THG T1.18T and C. amylolyticum DSM 23442T, C. imtechense JCM 16573T, C. aureum KACC 17219T were 24.7 % (20.1 % reciprocal analysis), 19.5 % (16.1 %) and 10.4 % (6.7 %) respectively. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-T1.18T represents a novel species of the genus Chryseomicrobium, for which the name Chryseomicrobium deserti sp. nov. is proposed. The type strain is THG-T1.18T (=KACC 18929T=CCTCC AB 2016179T). PMID- 28901905 TI - Hydrogenophaga aquatica sp. nov., isolated from a hot spring. AB - A polyphasic approach was used to characterize an aerobic, Gram-negative, rod shaped bacterium (designated strain CC-KL-3T) isolated from a hot spring. Phylogenetic analyses based on 16S rRNA genes indicated that strain CC-KL-3T showed highest sequence similarity to Hydrogenophaga bisanensis (97.7 %) and Hydrogenophaga atypica (97.6 %) and lower sequence similarity to other species (less than 97.6 %). The levels of DNA-DNA relatedness between strain CC-KL-3T, H. bisanensis and H. atypica were estimated to be 13.0 and 8.7 % (the reciprocal value was 14.7 and 6.3 %). Strain CC-KL-3T was non-motile, without apparent flagella and able to grow between 15-42 degrees C (optimal 30 degrees S), pH 6.0-8.0 (optimal 7.0) and 0-2 % (w/v) NaCl (optimal 0 %). The DNA G+C content was 61.4 mol% and the major quinone system was ubiquinone (Q-8). The polyamine profile revealed the predominance of 2-hydroxyputrescine and putrescine and the dominant cellular fatty acids were C16 : 0 (28.9 %), C16 : 1omega7c/C16 : 1omega6c (41.4 %) and C18 : 1omega7c/C18 : 1omega6c (11.9 %). These data corroborated the affiliation of strain CC-KL-3T to the genus Hydrogenophaga. Based on the distinct phylogenetic, phenotypic and chemotaxonomic traits, and the results of comparative 16S rRNA gene sequence analysis, strain CC-KL-3T is considered to represent a novel species of the genus Hydrogenophaga, affiliated to the family Comamonadaceae, for which the name Hydrogenophaga aquatica sp. nov. is proposed. The type strain is CC-KL-3T (=BCRC 80937T=JCM 31216T). PMID- 28901906 TI - Hydrogenophaga crassostreae sp. nov., isolated from a Pacific oyster. AB - A Gram-negative, motile, rod-shaped, and aerobic bacterial strain, designated LPB0072T, was isolated from a Pacific oyster (Crassostrea gigas). Autotrophic growth with hydrogen gas was not observed. Cells oxidized thiosulfate to sulfate and reduced nitrate to nitrite. The complete genome sequence of strain LPB0072T (CP017476) is 4.94 Mb in length and contains 4459 protein-coding genes, with a G+C content of 61.3 mol%. Analysis of the 16S rRNA gene sequence indicated that strain LPB0072T belongs to the genus Hydrogenophaga, with greatest sequence similarity to the type strain of Hydrogenophaga taeniospiralis (97.5 %). The isoprenoid quinone (Q-8) and the major cellular fatty acids (C16 : 1omega7c and/or C16 : 1omega6c, C16 : 0 and C17 : 1omega6c) identified were concordant with the chemotaxonomic properties of the genus Hydrogenophaga. The average nucleotide identities with closely related species were below the suggested boundary for species delineation, indicating that the isolate is a novel species. Numerous physiological and biochemical features also distinguished the isolate from other known Hydrogenophaga species. Based on the polyphasic data presented in this study, strain LPB0072T should be classified as a novel species in the genus Hydrogenophaga, and the name Hydrogenophaga crassostreae sp. nov. is proposed. The type strain is LPB0072T (=KACC 18705T=JCM 31188T). PMID- 28901907 TI - Isolates of Lactobacillus plantarum and L. reuteri display greater antiproliferative and antipathogenic activity than other Lactobacillus isolates. AB - PURPOSE: Lactic acid bacteria (LAB) have been associated with many beneficial effects in human digestive physiology. The aim of this study was to evaluate such effect, including attachment, antiproliferation and anti pathogenic/antibacterial/antimicrobial properties of LAB isolated from healthy humans. METHODOLOGY: Thirteen isolates, obtained from fecal samples of healthy individuals, were identified by phenotypic and molecular methods. Human colon adenocarcinoma cell line HT-29 and the cell proliferation kit II (XTT) assay were used for examination of the Lactobacillus adherence and antiproliferative activity, respectively. In addition, the inhibitory effect of Lactobacillus isolates against pathogenic bacteria was examined. RESULTS: Out of 13 Lactobacillus isolates, 5 (38 %) isolates were non-adhesive, 4 (31 %) were adhesive and 4 (31 %) were strongly adhesive. Amongst the isolated lactobacilli, L. reuteri showed the highest degree of inhibitory effect against the attachment of the enteropathogens. The XTT assay showed that 3 different isolates had the strongest antiproliferative activity with the maximum effect observed by L. plantarum isolates. CONCLUSION: Our results described that different Lactobacillus species isolated from normal fecal samples had different degrees of antiproliferative and anti-pathogenic/antibacterial/antimicrobial activities. However, no isolates showed all of the examined properties concurrently, suggestive that a combination of Lactobacillus species is needed for an active biological defense system. PMID- 28901908 TI - Performance of point-of-care Xpert HIV-1 plasma viral load assay at a tertiary HIV care centre in Southern India. AB - BACKGROUND: Sustainable suppression of HIV replication forms the basis of anti retroviral therapy (ART) medication. Thus, reliable quantification of HIV viral load has become an essential factor to monitor the effectiveness of the ART. Longer turnaround-time (TAT), batch testing and technical skills are major drawbacks of standard real-time PCR assays. METHODS: The performance of the point of-care Xpert HIV-1 viral load assay was evaluated against the Abbott RealTime PCR m2000rt system. A total of 96 plasma specimens ranging from 2.5 log10 copies ml-1 to 4.99 log10 copies ml-1 and proficiency testing panel specimens were used. Precision and accuracy were checked using the Pearson correlation co-efficient test and Bland-Altman analysis. RESULTS: Compared to the Abbott RealTime PCR, the Xpert HIV-1 viral load assay showed a good correlation (Pearson r=0.81; P<0.0001) with a mean difference of 0.27 log10 copies ml-1 (95 % CI, -0.41 to 0.96 log10 copies ml-1; sd, 0.35 log10 copies ml-1). CONCLUSION: Reliable and ease of testing individual specimens could make the Xpert HIV-1 viral load assay an efficient alternative method for ART monitoring in clinical management of HIV disease in resource-limited settings. The rapid test results (less than 2 h) could help in making an immediate clinical decision, which further strengthens patient care. PMID- 28901909 TI - Usefulness of a la carte antigens for bird fancier's lung serodiagnosis: total dropping extract and/or dropping's microflora antigens. AB - Bird fancier's lung (BFL) is a pulmonary disease caused by inhalation of avian proteins. The involvement of the microorganisms of droppings has been assumed in the past and this idea still persists today. Our study aimed to compare by immunoprecipitation assay the detection of antibodies against both droppings and microorganisms in the sera of patients (n=15) and asymptomatic exposed controls (n=18). We found that 14/15 BFL patients had negative serological results for isolated microorganisms of the droppings, only one positive against Enterobacter sakasakii. Serological arguments were in accordance with diagnosis in 87 % of cases by testing a la carte antigens from each bird dropping versus 20 % using the standard antigenic panel. Otherwise, the microorganisms antigens issued from dropping flora were negative in 93 % of cases. Consequently, it's preferable to use the total extract from the patient's bird droppings to establish the serodiagnosis of the disease. PMID- 28901910 TI - Alternative oxidase impacts ganoderic acid biosynthesis by regulating intracellular ROS levels in Ganoderma lucidum. AB - The alternative oxidase (AOX), which forms a branch of the mitochondrial respiratory electron transport pathway, functions to sustain electron flux and alleviate reactive oxygen species (ROS) production. In this article, a homologous AOX gene was identified in Ganoderma lucidum. The coding sequence of the AOX gene in G. lucidum contains 1038 nucleotides and encodes a protein of 39.48 kDa. RNA interference (RNAi) was used to study the function of AOX in G. lucidum, and two silenced strains (AOXi6 and AOXi21) were obtained, showing significant decreases of approximately 60 and 50 %, respectively, in alternative pathway respiratory efficiency compared to WT. The content of ganoderic acid (GA) in the mutant strains AOXi6 and AOXi21 showed significant increases of approximately 42 and 44 %, respectively, compared to WT. Elevated contents of intermediate metabolites in GA biosynthesis and elevated transcription levels of corresponding genes were also observed in the mutant strains AOXi6 and AOXi21. In addition, the intracellular ROS content in strains AOXi6 and AOXi21 was significantly increased, by approximately 1.75- and 1.93-fold, respectively, compared with WT. Furthermore, adding N-acetyl-l-cysteine (NAC), a ROS scavenger, significantly depressed the intracellular ROS content and GA accumulation in AOX-silenced strains. These results indicate that AOX affects GA biosynthesis by regulating intracellular ROS levels. Our research revealed the important role of AOX in the secondary metabolism of G. lucidum. PMID- 28901912 TI - Enabling Evolving Practice for Healthcare Professionals: A Regulator's Journey. AB - The inherent risk involved in the provision of healthcare services leads to the inevitable requirement of health human resource oversight to protect the public from harm (Bayne 2012). As healthcare systems evolve, so do theoretical models for, and practical applications of, health human resource oversight policy and processes. The College of Medical Laboratory Technologists of Ontario (CMLTO), as one of 26 health regulatory bodies in Ontario, implements programs or processes to enact and support changes in the knowledge, skill and judgment of their members. Determining what healthcare trends are affecting different healthcare professions and professionals, and how a regulatory institution, with a very specific mandate prescribed by government legislation, can enable necessary changes is explored in this paper through a case study of the CMLTO's journey to redefine "professionalism" and enable evolving practices of medical laboratory technologists (MLTs). A brief overview of health professional regulation, explored through a functional taxonomy, provides a contextual foundation to the CMLTO's journey to redefine professionalism. This approach also enables a discussion of the "sharpening" of certain regulatory approaches, that is, that opportunities to improve regulatory approaches are revealed via public feedback and modifications are made to rectify the historic experiences of the public. As the role of regulatory institutions continues to evolve to include a more prominent focus on proactive approaches to regulation, the ability to enable and support healthcare practitioners to respond to changes in the healthcare system becomes increasingly important. The case of the CMLTO's journey to redefine professionalism highlights an opportunity for a profession, and indeed its professionals, to evolve their culture to contribute their unique value to the healthcare system in response to system-level trends. PMID- 28901911 TI - Defining Health Profession Regulators' Roles in the Canadian Healthcare System. AB - Health professions regulation today faces a myriad of challenges, due to both the perceived performance of regulatory colleges, how health systems have evolved, and even larger political and economic shifts such as the renegotiation of NAFTA. In this issue of Healthcare Papers, Wilkie and Tzountzouris (2017) describe the work of the College of Medical Laboratory Technologists of Ontario (CMLTO) to redefine professionalism in the context of these challenges. Their paper, and the comments of the responding authors in this issue highlight that there, is an overarching perception that health regulatory structures - across a range of professions - are not working as effectively as they should. Across this issue of Healthcare Papers, attention is drawn to the fact that more can be done to improve both the function and perception of professional regulatory bodies. However, each paper presents a different approach to how improvements in function and perception are possible. PMID- 28901913 TI - Professional Healthcare Regulation and Practice: The Case of Medicine in Britain. AB - This contribution comments selectively on the themes of the lead paper by Wilkie and Tzountzouris (2017) on aspects of Canadian healthcare regulation that impact on the crucial agenda of public protection. In a more skeptical sociopolitical climate in the modern world, these authors particularly highlight the need to ensure professional attitudes and behaviours enhance and sustain safe patient care - using the recent stance on professionalism of the College of Medical Laboratory Technologists of Ontario as an illustration of good practice. It is argued, though, that this important analysis could be sharpened further both academically and practically with greater awareness of the theoretical complexity surrounding this area and by drawing more fully on comparative international exemplars - particularly in relation to medicine in Britain, on which this paper focuses. The commentary concludes by noting that - notwithstanding its many merits - the lead paper could usefully show greater recognition of cognate research on health regulation in the Canadian context and, as British research has clearly indicated, professional impediments to the translation of formally designated regulatory frameworks into practice on the ground. In addition, there needs to be more awareness of the impact of the wider environment in which physicians and other healthcare professionals operate. PMID- 28901914 TI - Evolving Professional Regulation: Keeping up with Health System Evolution. AB - In this article, we reflected on the notion that an evolving healthcare system requires evolving professional regulation to keep pace with system growth and change. The importance of interprofessional and patient-centred care for Ontario's healthcare system is clear. However, the profession specificity of the system is strongly embedded through Ontario's institutional and legislative structures. The result is an evolving system of care with the system of health professional regulation being somewhat left behind. Health professional regulators now have a challenge to "un-silo" regulation in a healthcare system that is evolving toward "un-siloed" care. Regulatory structures that govern single professions in a system that requires collective and additive competence is thus potentially problematic and may lead to attribution of blame to individuals where improvement is required at the level of the team. The shift in culture needed for interprofessional regulation challenges both how providers see themselves in the healthcare system, and the very foundations of professional autonomy. PMID- 28901915 TI - Medical Laboratory Technologists as Quality Improvement Team Members. AB - While Medical Laboratory Technologists (MLTs) do not generally work directly with clinical healthcare teams they have proven to be invaluable contributors to team based systematic quality improvement in healthcare. They were early adopters of standardized systemic performance measures coupled with explicit strategies for improving suboptimal performance. Their attentiveness to systemic analysis of systemic factors influencing performance has proven to be valuable in our quest to make care optimally safe and high quality. PMID- 28901916 TI - Using Trends to Inform Regulatory Practices. AB - Health professions regulators charged with the role of public protection are challenged to balance their mandate with appropriate policy interventions, particularly within a self-regulatory model. Applied strategically, emerging methods and trends in health systems and health professions regulation can inform regulatory practices in keeping with the regulator's role of reducing harm to the public. This requires a shift in thinking from a focus on how (i.e., resources and tools), to a focus on what, including clear problem identification, intended risks to be mitigated and consideration of outcomes and measurability of impact at the outset. Regulators should be enablers, not barriers to system change, but it is not their place to take on all of the challenges associated with monitoring and implementing interventions in response to health system evolution. Instead regulators must know their role, be willing to collaborate with other system players and work to implement regulatory interventions that complement rather than duplicate those better carried out by others. PMID- 28901917 TI - Ensuring Proactive Regulatory Initiatives Align with the Public Interest. AB - Regulation of health professions in Ontario has been under scrutiny in recent years with critical media attention and multiple legislative reform measures. The College of Medical Laboratory Technologists of Ontario's proactive regulatory initiative on steering professional culture, described by Wilkie and Tzountzouris (2017) in their discussion paper, is an example of a regulator evolving its role in the face of changing healthcare demands. In this response, we emphasize how regulators considering these types of initiatives need to ensure the focus remains on transparently carrying out their legislative duty of serving and protecting the public interest. We suggest future proactive regulatory initiatives could benefit from public engagement and regulatory collaboration. PMID- 28901918 TI - Enhancing the Relationship Between Regulators and Their Profession. AB - Regulators face unique pressures to balance competing priorities related to patient safety, public accountability, and practitioners' expectations. Historically, the collegial model of self-regulation has been used as a tool for risk management, to recognize the importance of profession- and context-specific judgment in complex, ambiguous clinical situations. Increasingly, as public accountability concerns have grown dominant within regulatory bodies, this collegial model has shifted toward a more antagonistic relationship between the regulators and the regulated. Wilkie and Tzountzouris (2017) highlight one profession's journey toward embedding professionalism within regulatory practices and policies through application of a right-touch regulatory philosophy. Given the complexity of regulatory work, this shift required significant strategic and deliberative thinking. The challenges of facilitating this sort of cultural shift in the role of a regulator are significant, but so too are the potential gains associated with a more engaged relationship between regulators and their practitioners. PMID- 28901919 TI - Acting in the Public Interest: The Heart of Professional Regulation. AB - In their article, Wilke and Tzountzouris (2017) describe the traditional and emerging approaches to professional regulation as restrictive (e.g., setting entry to practice requirements for registration), reactive (responding to complaints and where necessary restricting, suspending or revoking registration) or proactive (ensuring continuing competency and supporting registrants to adapt to changes in practice environments). They note the tension that exists with proactive approaches to regulation that can be seen as professional advocacy. We argue that by ensuring best practices in organizational governance and day-to-day regulatory operations that clearly situate the regulator to be acting solely in the public interest, regulatory colleges can manage the proactive regulatory approach and eliminate any perception of professional advocacy. This is critical for sustaining the professionally led model for health regulation that exists in Canada as it does today. PMID- 28901920 TI - Regulatory Models and Model Behaviours. AB - We appreciate the thoughtful and thought-provoking commentaries to our lead paper (Wilkie and Tzountzouris 2017) in this issue. Clearly, the question of how to best enable the behaviours of healthcare professionals to optimize their impact on our healthcare system is a complex one. We approach the question from the position of a health regulatory authority with a recognition that we cannot act alone. In our response to the valuable contributions to this issue of Healthcare Papers, we seek to educe the common themes that are presented. Many questions remain unresolved and are best explored in a collaborative and iterative manner. It is of utmost importance that health professional regulatory models and professional behaviours are all coordinated in focus to meet the needs of patients and the public. PMID- 28901921 TI - Extreme rain, flooding, and health. PMID- 28901922 TI - CAR T-cells: an exciting frontier in cancer therapy. PMID- 28901923 TI - Pushing the boundaries in paediatric surgery. PMID- 28901924 TI - Surgical trials for chronic pancreatitis. PMID- 28901925 TI - Long-term implications and global impact of paediatric surgery. PMID- 28901926 TI - Offline: North Korea-the case for health diplomacy. PMID- 28901927 TI - High stakes for research in US 2018 budget negotiations. PMID- 28901928 TI - The history of anaesthesia and the patient-reduced to a body? PMID- 28901930 TI - The physician as dictator. PMID- 28901931 TI - The Global Gag Rule: placing the health and lives of women and girls at risk. PMID- 28901932 TI - Life-sustaining technologies in resource-limited settings. PMID- 28901933 TI - Life-sustaining technologies in resource-limited settings - Authors' reply. PMID- 28901934 TI - Conscious sedation or general anaesthesia for lumbar puncture in children in Poland. PMID- 28901936 TI - Advances in paediatric urology. AB - Paediatric urological surgery is often required for managing congenital and acquired disorders of the genitourinary system. In this Series paper, we highlight advances in the surgical management of six paediatric urological disorders. The management of vesicoureteral reflux is evolving, with advocacy ranging from a less interventional assessment and antimicrobial prophylaxis to surgery including endoscopic injection of a bulking agent and minimally invasive ureteric reimplantation. Evidence supports early orchidopexy to improve fertility and reduce malignancy in boys with undescended testes. A variety of surgical techniques have been developed for hypospadias, with excellent outcomes for distal but not proximal hypospadias. Pelvi-ureteric junction obstruction is mostly detected prenatally; indications for surgery have been refined with evidence, and minimally invasive pyeloplasty is now standard. The outlook for patients with neurogenic bladder has been transformed by a combination of clean intermittent catheterisation, algorithms of diagnostic investigations, and innovative medical and surgical therapies. Posterior urethral valves are associated with considerable mortality; fetal diagnosis allows stratification of candidates for intervention, but ongoing bladder dysfunction in patients after valve ablation remains a cause of long-term morbidity. PMID- 28901937 TI - Advances in paediatric gastroenterology. AB - Recent developments in paediatric gastrointestinal surgery have focused on minimally invasive surgery, the accumulation of high-quality clinical evidence, and scientific research. The benefits of minimally invasive surgery for common disorders like appendicitis and hypertrophic pyloric stenosis are all supported by good clinical evidence. Although minimally invasive surgery has been extended to neonatal surgery, it is difficult to establish its role for neonatal disorders such as oesophageal atresia and biliary atresia through clinical trials because of the rarity of these disorders. Advances in treatments for biliary atresia and necrotising enterocolitis have been achieved through specialisation, multidisciplinary management, and multicentre collaboration in research; similarly robust clinical evidence for other rare gastrointestinal disorders is needed. As more neonates with gastrointestinal diseases survive into adulthood, their long-term sequelae will also need evidence-based multidisciplinary care. Identifying cures for long-term problems of a complex developmental anomaly such as Hirschsprung's disease will rely on unravelling its pathogenesis through genetics and the development of stem-cell therapy. PMID- 28901938 TI - Islam and depression. PMID- 28901939 TI - One of the more unusual talents: Dreams That Money Can Buy. PMID- 28901935 TI - Partial pancreatoduodenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicentre, randomised, controlled, double-blind ChroPac trial. AB - BACKGROUND: There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. METHODS: This randomised, controlled, double blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. FINDINGS: Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75.3 [SD 16.4] for partial pancreatoduodenectomy vs 73.0 [16.4] for DPPHR; mean difference -2.3, 95% CI -6.6 to 2.0; p=0.284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. INTERPRETATION: No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. FUNDING: German Research Foundation (DFG). PMID- 28901940 TI - Light and shade. PMID- 28901941 TI - Panorama's prescription. PMID- 28901942 TI - White. PMID- 28901943 TI - A Meta-Analysis and an Evaluation of Trends in Obesity Prevalence among Children and Adolescents in Turkey: 1990 through 2015. AB - OBJECTIVE: Obesity in childhood and adolescence is one of the most serious public health problems due to a remarkable increase in prevalence in recent years and its close relationship with non-communicable diseases, such as diabetes and hypertension, resulting in increased adult morbidity and mortality. This study aims to quantify the secular trend in different regions of Turkey from 1990 to 2015 by performing a meta-analysis of childhood and adolescent obesity prevalence studies conducted. METHODS: Uludag University Library Database was searched for relevant articles published prior to March 2017. The heterogeneity of the studies in the meta-analysis was tested by the I2 statistic and Cochran's Q test. The obesity trend analyses were examined by chi-square trend analysis with respect to five year periods. The statistical significance level was taken as alpha=0.05. RESULTS: A total of 76 papers were initially identified addressing childhood and adolescent obesity in Turkey. Fifty-eight papers were selected for analysis. The prevalence of obesity increased from 0.6% to 7.3% with an 11.6-fold increase between the periods 1990-1995 to 2011-2015. The prevalence of obesity increased in both genders. However, boys were more likely to be obese than girls. CONCLUSION: Studies on obesity prevalence in the 5-19 age group in Turkey have gained importance, especially in the 2000s. While a remarkable number of prevalence studies, mostly regional, have been conducted between 2005-2011, a gradual decline was observed thereafter. Further national and population-based surveys on prevalence of obesity in children and adolescents are definitely needed in Turkey. PMID- 28901945 TI - Correction: Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open label, Phase IIIb study. PMID- 28901944 TI - Vitamin D Deficiency in Pregnant Women and Their Infants. AB - OBJECTIVE: Vitamin D deficiency is a serious health problem despite a general improvement in socio-economic status in Turkey. The aim of this study was to evaluate maternal vitamin D status and its effect on neonatal vitamin D concentrations after a support programme for pregnant women was introduced. A second aim was to identify risk factors for vitamin D deficiency in a district of Istanbul. METHODS: A total of 97 pregnant women and 90 infants were included in this study, conducted between January and October 2016. The demographic data, risk factors and daily vitamin intake were recorded. Serum levels of vitamin D, calcium, phosphorus and alkaline phosphatase in all subjects were measured. The mothers and newborns were divided into groups based on their vitamin D levels. The relationship between vitamin D levels and risk factors was analyzed. RESULTS: Mean +/- standard deviation vitamin D levels for the women and their infants were found to be 14.82+/-11.45 and 13.16+/-7.16 ng/mL, respectively. The number of mothers and infants was significantly higher in the deficient group, and their mean vitamin D levels significantly lower (9.02+/-1.34 and 8.80+/-1.06 ng/mL, respectively) (p<0.001, p<0.001). Only 14.4% of pregnant women took 1000-1200 IU/day of vitamin D. When the mother groups were evaluated in terms of risk factors, there were significant differences in daily vitamin intake and clothing style (p<0.001 and p<0.001 respectively). CONCLUSION: Vitamin D deficiency in pregnant women and their infants is still a serious health problem in Turkey, although a vitamin D support programme during pregnancy has been launched by the department of health. PMID- 28901946 TI - Design of sEMG assembly to detect external anal sphincter activity: a proof of concept. AB - OBJECTIVE: Conditional trans-rectal stimulation of the pudendal nerve could provide a viable solution to treat hyperreflexive bladder in spinal cord injury. A set threshold of the amplitude estimate of the external anal sphincter surface electromyography (sEMG) may be used as the trigger signal. The efficacy of such a device should be tested in a large scale clinical trial. As such, a probe should remain in situ for several hours while patients attend to their daily routine; the recording electrodes should be designed to be large enough to maintain good contact while observing design constraints. The objective of this study was to arrive at a design for intra-anal sEMG recording electrodes for the subsequent clinical trials while deriving the possible recording and processing parameters. APPROACH: Having in mind existing solutions and based on theoretical and anatomical considerations, a set of four multi-electrode probes were designed and developed. These were tested in a healthy subject and the measured sEMG traces were recorded and appropriately processed. MAIN RESULTS: It was shown that while comparatively large electrodes record sEMG traces that are not sufficiently correlated with the external anal sphincter contractions, smaller electrodes may not maintain a stable electrode tissue contact. It was shown that 3 mm wide and 1 cm long electrodes with 5 mm inter-electrode spacing, in agreement with Nyquist sampling, placed 1 cm from the orifice may intra-anally record a sEMG trace sufficiently correlated with external anal sphincter activity. SIGNIFICANCE: The outcome of this study can be used in any biofeedback, treatment or diagnostic application where the activity of the external anal sphincter sEMG should be detected for an extended period of time. PMID- 28901947 TI - A robust optimisation approach accounting for the effect of fractionation on setup uncertainties. AB - Proton plans are subject to a number of uncertainties which must be accounted for to ensure that they are delivered safely. Misalignment resulting from residual errors in daily patient positioning can result in both a displacement and distortion of dose distributions. This can be particularly important for intensity modulated proton therapy treatments where the accurate alignment of highly modulated fields may be required to deliver the intended treatment. A number of methods to generate plans that are robust to these uncertainties exist. These include robust optimisation approaches which account for the effect of uncertainties on the dose distribution within the optimisation process. However, robustness to uncertainty comes at the cost of plan quality. For this reason, it is important that the uncertainties considered are realistic. Existing approaches to robust optimisation have neglected the role of fractionated treatment deliveries in reducing the uncertainties that result from random setup errors. Here, a method of robust optimisation which accounts for this effect is presented and is evaluated using a 2D planning environment. The optimisation algorithm considers the dose in the estimated upper and lower bounds of the dose distribution under the effect of setup and range errors. A comparison with plans robustly optimised without consideration of the effect of fractionation and conventionally optimised plans is presented. Fractionation incorporated robust optimisation demonstrates a reduced sensitivity to uncertainty compared to conventionally optimised plans and a reduced integral dose compared to robustly optimised plans. PMID- 28901948 TI - Ultrathin MoSe2@N-doped carbon composite nanospheres for stable Na-ion storage. AB - Two-dimensional transition metal dichalcogenides are widely studied as anode materials for metal ion batteries. This application requires high electric conductivity which can be achieved by forming composites with conductive carbon. In this work, we demonstrate the creation of nanospheres composed of Mo-based thin nanosheets (MoS2, MoSe2 and Mo2C) uniform embedded within a N-doped carbon matrix. Using MoSe2/N-doped carbon nanospheres as an example, we investigate in detail the electrochemical property in Na ion storage and reveal the advantage over previously reported MoSe2 electrodes (higher capacity and improved capacity retention up to 500 cycles). Furthermore, we provide evidence by ex situ x-ray diffraction to the nominal irreversible conversion reaction during the first discharge. PMID- 28901949 TI - Silver nanoflowers for single-particle SERS with 10 pM sensitivity. AB - Surface-enhanced Raman scattering (SERS) has received considerable attention as a noninvasive optical sensing technique with ultrahigh sensitivity. While numerous types of metallic particles have been actively investigated as SERS substrates, the development of new SERS agents with high sensitivity and their reliable characterization are still required. Here we report the preparation and characterization of flower-shaped silver (Ag) nanoparticles that exhibit high sensitivity single-particle SERS performance. Ag nanoflowers (NFs) with bud sizes in the range 220-620 nm were synthesized by the wet synthesis method. The densely packed nanoscale petals with thicknesses in the range 9-22 nm exhibit a large number of hot spots that significantly enhance their plasmonic activity. A single Ag NF particle (530-620 nm) can detect as little as 10-11 M 4-mercaptobenzoic acid, and thus provides a sensitivity three orders of SERS magnitude greater than that of a spherical Ag nanoparticle. The analytical enhancement factors for single Ag NF particles were found to be as high as 8.0 * 109, providing unprecedented high SERS detectivity at the single particle level. Here we present an unambiguous and systematic assessment of the SERS performances of the Ag NFs and demonstrate that they provide highly sensitive sensing platforms by single SERS particle. PMID- 28901950 TI - Detecting drug-target binding in cells using fluorescence-activated cell sorting coupled with mass spectrometry analysis. AB - The assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity-the toxicity-affinity-permeability-selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets. PMID- 28901951 TI - Real-time non-rigid target tracking for ultrasound-guided clinical interventions. AB - Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of ~1.5 mm and submillimeter precision. This, together with a computational performance of 20 images per second make the proposed method an attractive solution for real-time target tracking during US-guided clinical interventions. PMID- 28901952 TI - Photoluminescence study in Ho3+/Tm3+/Yb3+/Li+:Gd2(MoO4)3 nanophosphors for near white light emitting diode and security ink applications. AB - Ho3+/Yb3+/Tm3+/Li+:Gd2(MoO4)3 nanophosphors successfully synthesised via solid state reaction method have been structurally and optically characterised. Under 980 nm diode laser excitation the nanophosphors emit intense blue, green, red and NIR emissions peaking at ~476 nm, ~543 nm, ~646 nm and ~798 nm corresponding to the 1G4 -> 3H6 (Tm3+), 5F4, 5S2 -> 5I8 (Ho3+), 5F 5 -> 5I8 (Ho3+) and 3H4 -> 3H6 (Tm3+) transitions respectively. The upconversion emission intensity enhancement in the Ho3+-Yb3+-Tm3+-Li+:Gd2(MoO4)3 nanophosphors for the green band is found to be ~367, ~50 and ~9 times compared to the singly Ho3+ doped, Ho3+-Yb3+ co-doped and Ho3+-Yb3+-Tm3+ tri-doped Gd2(MoO4)3 nanophosphors. The enhancement observed has been explained on the basis of energy transfer process and local field modifications around the rare earth ions. The energy transfer efficiency ~5% is determined in the tridoped nanophosphors. The interaction involved between rare earth ions for energy transfer process is found to be dipole-dipole type. On changing the Tm3+ ions concentration the colour emitted from the tridoped nanophosphors is tuned from near white to blue region. In the tridoped nanophosphors, on varying the pump power the colour tunability has been observed. PMID- 28901953 TI - Enhanced magnetostriction derived from magnetic single domain structures in cluster-assembled SmCo films. AB - Cluster-assembled SmCo alloy films were prepared by low energy cluster beam deposition. The structure, magnetic domain, magnetization, and magnetostriction of the films were characterized. It is shown that the as-prepared films are assembled in compact and uniformly distributed spherical cluster nanoparticles, most of which, after vacuum in situ annealing at 700 K, aggregated to form cluster islands. These cluster islands result in transformations from superparamagnetic states to magnetic single domain (MSD) states in the films. Such MSD structures contribute to the enhanced magnetostrictive behaviors with a saturation magnetostrictive coefficient of 160 * 10-6 in comparison to 105 * 10-6 for the as-prepared films. This work demonstrates candidate materials that could be applied in nano-electro-mechanical systems, low power information storage, and weak magnetic detecting devices. PMID- 28901955 TI - HepG2 and human healthy hepatocyte in vitro culture and co-culture in PCL electrospun platforms. AB - The discovery of new drugs to treat pathological cells in the case of aggressive liver primary cancer is imposing the identification of high-throughput screening systems to predict the in vivo response of new therapeutic molecules, in order to reduce current use of animals and drug testing costs. Recently, micro/nanostructured scaffolds have been adopted to reproduce the hepatic microenvironment due to their higher similarity to the biological niche with respect to the traditional two-dimensional culture plate, so providing novel in vitro models for reliably understanding molecular mechanisms related to cancer cells activity. Herein, we propose the study of electrospun scaffolds made of polycaprolactone as in vitro model that can mimic the morphological organization of native extracellular matrix and the co-culture of hepatic cell lines-i.e., HepG2, human healthy hepatocytes (HHH). The micro- and nano-scale morphological features of fibers with diameter equal to (3.22 +/- 0.42) MUm and surface roughness of (17.84 +/- 4.43) nm-allow the reproduction of the in vivo scenario influencing the adhesion and proliferation rate of the cultured cells. A much lower proliferation rate is observed for the HepG2 cells compared to the HHH cells, when cultured on the fibrous scaffolds over a time course of 4 weeks. Moreover, results on oxidative stress mechanisms indicate an antioxidant effect of fibers mainly in the case of co-colture, thus suggesting a promising use as new in vitro models to explore alternative therapeutic strategies in hepatocarcinoma treatment. PMID- 28901954 TI - Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study. AB - Electroporation based treatments consist in applying one or multiple high voltage pulses to the tissues to be treated. As an undesired side effect, these pulses cause electrical stimulation of excitable tissues such as nerves and muscles. This increases the complexity of the treatments and may pose a risk to the patient. To minimize electrical stimulation during electroporation based treatments, it has been proposed to replace the commonly used monopolar pulses by bursts of short bipolar pulses. In the present study, we have numerically analyzed the rationale for such approach. We have compared different pulsing protocols in terms of their electroporation efficacy and their capability of triggering action potentials in nerves. For that, we have developed a modeling framework that combines numerical models of nerve fibers and experimental data on irreversible electroporation. Our results indicate that, by replacing the conventional relatively long monopolar pulses by bursts of short bipolar pulses, it is possible to ablate a large tissue region without triggering action potentials in a nearby nerve. Our models indicate that this is possible because, as the pulse length of these bipolar pulses is reduced, the stimulation thresholds raise faster than the irreversible electroporation thresholds. We propose that this different dependence on the pulse length is due to the fact that transmembrane charging for nerve fibers is much slower than that of cells treated by electroporation because of their geometrical differences. PMID- 28901956 TI - Single particle tracking of internalized metallic nanoparticles reveals heterogeneous directed motion after clathrin dependent endocytosis in mouse chromaffin cells. AB - Most accepted single particle tracking methods are able to obtain high-resolution trajectories for relatively short periods of time. In this work we apply a straightforward combination of single-particle tracking microscopy and metallic nanoparticles internalization on mouse chromaffin cells to unveil the intracellular trafficking mechanism of metallic-nanoparticle-loaded vesicles (MNP V) complexes after clathrin dependent endocytosis. We found that directed transport is the major route of MNP-Vs intracellular trafficking after stimulation (92.6% of the trajectories measured). We then studied the MNP-V speed at each point along the trajectory, and found that the application of a second depolarization stimulus during the tracking provokes an increase in the percentage of low-speed trajectory points in parallel with a decrease in the number of high-speed trajectory points. This result suggests that stimulation may facilitate the compartmentalization of internalized MNPs in a more restricted location such as was already demonstrated in neuronal and neuroendocrine cells (Bronfman et al 2003 J. Neurosci. 23 3209-20). Although further experiments will be required to address the mechanisms underlying this transport dynamics, our studies provide quantitative evidence of the heterogeneous behavior of vesicles mobility after endocytosis in chromaffin cells highlighting the potential of MNPs as alternative labels in optical microscopy to provide new insights into the vesicles dynamics in a wide variety of cellular environments. PMID- 28901957 TI - Chiral quantum spin liquid on the repulsive Haldane-Hubbard model in square lattices. AB - In this paper, we present a study on the repulsive Haldane-Hubbard model with spin-rotation symmetry in square lattices by deriving non-linear sigma model for magnetic states. It is found that a chiral spin liquid state as the ground state of the correlated system exists in the [Formula: see text] topological spin density wave proposed by Wu et al (2016 J. Phys.: Condens. Matter 28 115602), of which the low energy physics can be determined by the Chern-Simons-Hopf gauge field theory. PMID- 28901959 TI - Oxymetazoline-Induced Asthma. PMID- 28901960 TI - Sudden Death in an Adult Due to Nontraumatic Diaphragmatic Hernia. AB - Sudden death due to diaphragmatic hernia in an adult is exceptionally rare. A 43 year-old man was found dead by his cohabiting mother, lying supine on the floor in his house. He had complained of epigastric discomfort for 1 month, and respiratory symptoms occurred 1 day before his death. He had no history of trauma. Postmortem computed tomography scan revealed the enlarged fluid-filled stomach herniated into the left pleural cavity, compressing the left lung with a mediastinal shift to the right. At autopsy, the left pleural cavity was occupied by herniated abdominal contents with mediastinal shift. The herniation of the stomach, the whole spleen, a portion of the colon, and omentum into the left pleural cavity had occurred through a smooth oval 9 * 5-cm defect in the posterolateral part of the light diaphragm. The stomach was markedly distended and contained 1600 mL of yellowish brown liquid with food residue. Ischemic changes of the herniated organs were not observed. Death was attributed to respiratory failure from abdominal viscera herniation into the left pleural cavity. PMID- 28901958 TI - Pilot Study of the Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms. AB - BACKGROUND: Insomnia is common in the elderly and is associated with chronic disease, but use of hypnotics increases the incidence of falls. Montmorency tart cherry juice has improved insomnia by self-report questionnaire. STUDY QUESTION: Is insomnia confirmed by polysomnography and is tryptophan availability a potential mechanism for treating insomnia? STUDY DESIGN: A placebo-controlled balanced crossover study with subjects older than 50 years and insomnia were randomized to placebo (2 weeks) or cherry juice (2 weeks) (240 mL 2 times/d) separated by a 2-week washout. MEASURES AND OUTCOMES: Sleep was evaluated by polysomnography and 5 validated questionnaires. Serum indoleamine 2,3-dioxygenase (IDO), the kynurenine-to-tryptophan ratio, and prostaglandin E2 were measured. In vitro, Caco-2 cells were stimulated with interferon-gamma, and the ability of cherry juice procyanidin to inhibit IDO which degrades tryptophan and stimulates inflammation was measured. The content of procyanidin B-2 and other major anthocyanins in cherry juice were determined. RESULTS: Eleven subjects were randomized; 3 with sleep apnea were excluded and referred. The 8 completers with insomnia increased sleep time by 84 minutes on polysomnography (P = 0.0182) and sleep efficiency increased on the Pittsburgh Sleep Quality Index (P = 0.03). Other questionnaires showed no significant differences. The serum kynurenine-to tryptophan ratio decreased, as did the level of prostaglandin E2 (both P < 0.05). In vitro, cherry juice procyanidin B-2 dose-dependently inhibited IDO. CONCLUSIONS: Cherry juice increased sleep time and sleep efficiency. Cherry juice procyanidin B-2 inhibited IDO, increased tryptophan availability, reduced inflammation, and may be partially responsible for improvement in insomnia. PMID- 28901961 TI - Effect of Stretching on Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model. AB - OBJECTIVE: Stretching of fascia is an important component of manual and movement therapies. We previously showed that in pigs, a unilateral thoracolumbar fascia injury combined with movement restriction (hobble) produced contralateral loss of fascia mobility (shear strain during passive trunk flexion measured with ultrasound) similar to findings in human subjects with chronic low back pain. We now tested whether such abnormalities could be reversed by removing the hobble with or without daily stretching for 1 mo. DESIGN: Thirty pigs were randomized to control, injury, or injury + hobble for 8 wks. The hobble restricted hip extension ipsilateral to the injury. At week 8, the injury + hobble group was subdivided into continued hobble, removed hobble, and removed hobble + stretching (passively extending the hip for 10 min daily). RESULTS: Removing hobbles restored normal gait speed but did not restore fascia mobility. Daily passive stretching was not superior to removing hobbles, as there was no significant improvement in fascia mobility with either treatment group (removed hobble or stretching). CONCLUSIONS: Reduced fascia mobility in response to injury and movement restriction worsens over time and persists even when movement is restored. Reversing fascia abnormalities may require either longer than 1 mo or a different treatment "dose" or modality. PMID- 28901962 TI - Ability of polymer-bound P-glycoprotein inhibitor ritonavir to overcome multidrug resistance in various resistant neuroblastoma cell lines. AB - Polymer prodrugs can considerably improve the treatment of tumors with multidrug resistance, often caused by overexpression of P-glycoprotein (P-gp). Here, we present the effect of the N-(2-hydroxypropyl) methacrylamide-based polymer conjugate with P-gp inhibitor ritonavir (RIT) on the increase of free doxorubicin (DOX) and polymer-bound DOX cytotoxicity in the human neuroblastoma 4 cell line and its resistant clones to different cytostatics. The increase in cytotoxicity after polymer-RIT conjugate pretreatment was higher for the lines overexpressing P-gp and less pronounced for those with decreased P-gp levels. Moreover, the effect of polymer conjugate containing inhibitor and DOX on the same polymer chain was lower than that of two individual polymer conjugates used sequentially. In conclusion, the polymer-RIT conjugate can significantly increase the cytotoxicity of free DOX and polymer-DOX conjugates in cells with various multidrug resistance origins and can thus be considered a suitable therapeutic enhancer of polymer prodrugs. PMID- 28901963 TI - Underlying Chronic Disease, Medication Use, History of Running Injuries and Being a More Experienced Runner Are Independent Factors Associated With Exercise Associated Muscle Cramping: A Cross-Sectional Study in 15778 Distance Runners. AB - BACKGROUND: Exercise-associated muscle cramping (EAMC) is a significant medical complication in distance runners, yet factors associated with EAMC are poorly documented. OBJECTIVE: To document risk factors associated with EAMC in runners. DESIGN: Cross-sectional study. SETTING: Two ocean races (21.1 km, and 56 km). PARTICIPANTS: Fifteen thousand seven hundred seventy-eight race entrants. METHODS: Participants completed a prerace medical history screening tool including: training, cardiovascular disease (CVD), risk factors for, and symptoms of CVD, history of diseases affecting major organ systems, cancer, allergies, medication use, and running injury. Runners were grouped as having a history of EAMC (hEAMC group = 2997) and a control group (Control = 12 781). RESULTS: Independent factors associated with a higher prevalence ratio (PR) of hEAMC were any risk factor for CVD (PR = 1.16; P = 0.0002), symptoms of CVD (PR = 2.38; P < 0.0001), respiratory disease (PR = 1.33; P < 0.0001), gastrointestinal disease (PR = 1.86; P < 0.0001), nervous system or psychiatric disease (PR = 1.51; P < 0.0001), kidney or bladder disease, (PR = 1.60; P < 0.0001), haematological or immune disease (PR = 1.54; P = 0.0048), cancer (PR = 1.34; P = 0.0031), allergies (PR = 1.37; P < 0.0001), regular medication use (PR = 1.80; P < 0.0001), statin use (PR = 1.26; P = 0.0127), medication use during racing (PR = 1.88; P < 0.0001), running injury (PR = 1.66; P < 0.0001), muscle injury (PR = 1.82; P < 0.0001), tendon injury (PR = 1.62; P < 0.0001), and runners in the experienced category (PR = 1.22; P < 0.0001). CONCLUSION: Novel risk factors associated with EAMC in distance runners were underlying chronic disease, medication use, a history of running injuries, and experienced runners. These factors must be identified as possible associations, and therefore be considered in the diagnosis and treatment of EAMC. PMID- 28901964 TI - The Role of the Surgical Pathologist in the Diagnosis of Gastrointestinal Polyposis Syndromes. AB - Polyps of the gastrointestinal tract are very common lesions and most frequently sporadic in nature. Some polyp subtypes are associated with rare hereditary polyposis syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. However, many sporadic benign lesions of the gastrointestinal tract can mimic some of these syndromic hamartomatous polyps. The role of the surgical pathologist is to raise the possibility of a hereditary condition in case of suggestive polyp histology and to look for clinical information to support the suspected diagnosis. In this review, the clinical presentation and the pathology associated with these rare hamartomatous polyposis syndromes are discussed in an attempt to provide pathologists clues in suggesting one such syndrome on the basis of histologic findings and clinical context. Identification of affected individuals is important because of the increased gastrointestinal and other malignancies. Recently, new adenomatous polyposis syndromes have been discovered, expanding the genetic causes of patient diagnosed with multiple colonic adenomas. By being aware of the clinical phenotype and the tumor spectrum associated with gastrointestinal polyposis syndromes, surgical pathologists can play a critical role in recommending genetic counseling when suspicious of such a diagnosis. This may lead to the identification of a genetic cause and appropriate surveillance of affected family members to screen for associated malignancies. PMID- 28901965 TI - Anaplastic gliomas in adults: an update. AB - PURPOSE OF REVIEW: The current review summarizes recent advances on the oncogenesis, classification and treatment of adult anaplastic gliomas. RECENT FINDINGS: According to the 2016 WHO classification, three main molecular subgroups of adult diffuse anaplastic gliomas can be distinguished based on the 1p/19q codeletion and isocitrate dehydrogenase (IDH) mutation status. In the future, this classification may be further refined based on the telomerase reverse transcriptase promoter and alpha thalassemia/mental retardation syndrome X-linked mutation status, gene expression, DNA methylation and genomic profiling. Both newly diagnosed 1p/19q codeleted and 1p/19q-intact anaplastic gliomas benefit from the addition of chemotherapy to radiotherapy. However, in 1p/19q codeleted anaplastic gliomas, Procarbazine, CCNU and Vincristine chemotherapy seems more effective than temozolomide. At recurrence, 1p/19q-intact anaplastic gliomas do not benefit from the addition of bevacizumab to temozolomide. The use of poly(adenosine 5'-diphosphate-ribose) inhibitors may be another way of specifically targeting IDH-mutant gliomas in addition to specific inhibitors, demethylating agents and anti-IDH vaccines. v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant anaplastic xanthoastrocytomas and gangliogliomas may benefit from BRAF and mitogen-activated protein kinase inhibitors. SUMMARY: Molecular characterization is mandatory for integrated diagnosis and appropriate management of adult anaplastic gliomas. Both 1p/19q codeleted and 1p/19q-intact anaplastic diffuse gliomas benefit from early chemotherapy. At recurrence, preliminary data suggest a potential role for targeted therapies in specific molecular subgroups. PMID- 28901966 TI - Mouse models of inflammatory bowel disease for investigating mucosal immunity in the intestine. AB - PURPOSE OF REVIEW: Currently several mouse models are considered representative of inflammatory bowel disease (IBD). This review presents recent developments regarding the role of animal models of intestinal inflammation as research tools in IBD. RECENT FINDINGS: Preclinical studies in animal models of intestinal inflammation have generated novel findings in several areas of IBD research. The combination of chemical and genetically engineered models have revealed protective or harmful roles for various components of the innate immune system in response to acute injury and repair mechanisms for the intestinal mucosa. Advances in the use of endoscopic and radiologic techniques have allowed identification of inflammatory biomarkers and in-vivo monitoring of cell trafficking towards inflammatory sites. Translational research has shed light on pathogenic mechanisms through which recent biological treatments may exert their beneficial effects in patients with IBD. Finally, novel therapies are continuously tested in animal models of IBD as part of preclinical drug development programs. SUMMARY: Animal models of intestinal inflammation continue to be important research tools with high significance for understanding the pathogenesis of IBD and exploring novel therapeutic options. Development of additional experimental models that address existing limitations, and more closely resemble the characteristics of Crohn's disease and ulcerative colitis are greatly needed. PMID- 28901967 TI - Intervention Mapping Approach in the Design of an Interactive Mobile Health Application to Improve Self-care in Heart Failure. AB - Heart failure is a complex syndrome among older adults who may experience and interpret symptoms differently. These differences in symptom interpretation may influence decision-making in symptom management. A well-informed and motivated person may develop the knowledge and skills needed to successfully manage symptoms. Therefore, the patient-centered mobile health application HeartMapp was designed to engage patients with heart failure in self-care management by offering tailored alerts and feedback using mobile phones. The main objective of this article is to describe the six-step intervention mapping approach including (1) the initial needs assessment, (2) proximal program objective, (3) selection of theory-based methods, (4) the translation of objectives into an actual program plan for mobile health intervention, (5) adaptation and implementation plan, and (6) evaluation plan that assisted the team in the development of a conceptual framework and intervention program matrix during the development of HeartMapp. The HeartMapp intervention takes the information, motivation, and behavioral skills model as the theoretical underpinning, with "patient engagement" as the key mediator in achieving targeted and persistent self-care behavioral changes in patients with heart failure. The HeartMapp intervention is proposed to improve self-care management and long-term outcomes. PMID- 28901968 TI - Medical comorbidity in polycystic ovary syndrome with special focus on cardiometabolic, autoimmune, hepatic and cancer diseases: an updated review. AB - PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is defined by hyperandrogenism, irregular menses and polycystic ovaries when other causes are excluded. The possible implication of increased morbidity in PCOS for screening and follow-up is uncertain and is reviewed in this article. RECENT FINDINGS: The increased risk of type 2 diabetes and cardiovascular disease in PCOS is closely associated with BMI. Women with PCOS should be screened for the elements of the metabolic syndrome upon diagnosis. Measurement of HbA1c and the lipid accumulation product could be important tools to differentiate women with high metabolic risk. The immune function in PCOS is impaired with increased secretion of autoantibodies and increased risk of type 1 diabetes, asthma and thyroid disease. The occurrence of thyroid disease could be modified by BMI and D-vitamin status. Screening for diabetes and thyroid disease is part of routine evaluation for endocrine diseases at baseline in PCOS, whereas the necessity of prospective screening for thyroid disease awaits future studies. Especially obese women with PCOS are at an increased risk of nonalcoholic fatty liver disease, gall bladder disease and endometrial cancer. SUMMARY: Recent data support that screening and follow-up in patients with PCOS should be stratified according to BMI. PMID- 28901969 TI - Disorders of consciousness after severe brain injury: therapeutic options. AB - PURPOSE OF REVIEW: Very few options exist for patients who survive severe traumatic brain injury but fail to fully recover and develop a disorder of consciousness (e.g. vegetative state, minimally conscious state). RECENT FINDINGS: Among pharmacological approaches, Amantadine has shown the ability to accelerate functional recovery. Although with very low frequency, Zolpidem has shown the ability to improve the level of consciousness transiently and, possibly, also in a sustained fashion. Among neuromodulatory approaches, transcranial direct current stimulation has been shown to transiently improve behavioral responsiveness, but mostly in minimally conscious patients. New evidence for thalamic deep brain stimulation calls into question its cost/benefit trade-off. SUMMARY: The growing understanding of the biology of disorders of consciousness has led to a renaissance in the development of therapeutic interventions for patients with disorders of consciousness. High-quality evidence is emerging for pharmacological (i.e. Amantadine) and neurostimulatory (i.e. transcranial direct current stimulation) interventions, although further studies are needed to delineate preconditions, optimal dosages, and timing of administration. Other exciting new approaches (e.g. low intensity focused ultrasound) still await systematic assessment. A crucial future direction should be the use of neuroimaging measures of functional and structural impairment as a means of tailoring patient-specific interventions. PMID- 28901970 TI - The 2016 WHO classification of central nervous system tumors: what neurologists need to know. AB - PURPOSE OF REVIEW: The 2016 WHO classification of tumors of the central nervous system (2016 CNS WHO) features many changes that are relevant to neurologists treating patients with brain tumors as well as neurologists involved in basic, clinical, and epidemiological research. This review summarizes what neurologists need to know and will need to know in the next years. RECENT FINDINGS: The 2016 CNS WHO introduces diagnostic terms that 'integrate' histological and molecular information and suggests presenting diagnoses in a four-layered reporting format. In addition, it utilizes a 'not otherwise specified' designation to identify diagnostic categories that are not precisely defined. A better understanding of the biology of entities further led to changes in the tumor nosology, for example, diffuse gliomas based on IDH gene status. Meaningful molecular subgroups could also be identified in embryonal tumors and other entities. Given the pace of change in the field of brain tumor classification, there will likely be additional practical advances that emerge over the next few years. A new initiative entitled Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy intends to formulate recommendations between WHO updates. SUMMARY: The 2016 CNS WHO includes major changes in the way brain tumors are classified, with molecular parameters being incorporated into diagnostic criteria for a substantial number of such entities. PMID- 28901972 TI - Normothermic machine perfusion of the kidney. AB - PURPOSE OF REVIEW: Normothermic machine perfusion (NMP) is a preservation method that is generating increasing interest. The aim of this review is to summarise the current status of NMP in regards of kidney viability assessment, reducing organ damage and improving transplant logistics. RECENT FINDINGS: The results of recent large animal experiments and clinical trials show that continuous prolonged normothermic ex-vivo kidney perfusion appears better than a brief period of NMP after static cold storage in terms of renal injury and function. A recently developed clinical scoring system appears to correlate with renal and tubular function. A prospective clinical phase II trial to investigate the initial graft function after 1 h of NMP or static cold storage in kidneys from donors after circulatory death has been initiated in the United Kingdom. SUMMARY: Progress has been made in normothermic kidney perfusion, mainly in experimental settings. These results need to be translated into clinical trials to evaluate long-term NMP and its impact in human organs. Future investigations of optimal perfusion parameters are needed. PMID- 28901973 TI - Identifying palliative care needs in people with dementia. AB - PURPOSE OF REVIEW: Dementia is now recognized as a progressive life-limiting illness where many patients can benefit from access to palliative care. RECENT FINDINGS: The present review has focused on three areas namely, advanced care planning in supporting palliative care for dementia, hospice provision for people with dementia and provision of care within family home. In advanced care planning, there is little research on systematically developed and implemented advance care planning interventions or whether they achieve desired outcomes for end-of-life care. There is limited research on hospice-based care for patients with dementia and most studies are U.S. based. Equally studies exploring how family carers can be supported and facilitated to care at home for the person with dementia to the end of life are exploratory rather than determining what factors may be important. SUMMARY: There are relatively few studies, especially quantitative studies or intervention studies being carried out to determine most effective means of providing palliative care for people with dementia, particularly with respect to advanced care planning, the provision of hospice based care and support at home. Despite increased public awareness of dementia as a terminal illness, more research is required to support patients with dementia and their families at the end of life. PMID- 28901971 TI - Xenotransplantation: past, present, and future. AB - PURPOSE OF REVIEW: To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. RECENT FINDINGS: Starting from early 2000, with the introduction of galactose-alpha1,3-galactose (Gal)-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to non-Gal antigens continue to be the hurdle to overcome. The production of genetically engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently clustered regularly interspaced short palindromic repeats (CRISPR) technology made the production of genetically engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached more than 900, more than 400, and more than 600 days, respectively. The availability of multiple-gene pigs (five or six genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. SUMMARY: Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation. PMID- 28901974 TI - R Function for Additive Interaction Measures. PMID- 28901975 TI - Dietary Fiber Intake and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men. AB - BACKGROUND: The limited literature suggests that dietary fiber intake from whole grains, fruits, and vegetables is negatively associated with chronic obstructive pulmonary disease (COPD) via fiber's anti-inflammatory properties. Therefore, we investigated the association between total fiber and fiber sources and risk of COPD in the population-based prospective Cohort of Swedish Men (45,058 men, ages 45-79 years) with no history of COPD at baseline. METHODS: Dietary fiber intake was assessed with a self-administered questionnaire in 1997 and was energy adjusted using the residual method. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) adjusted for potential confounders. RESULTS: During a mean follow-up of 13.1 years (1998-2012), 1,982 incident cases of COPD were ascertained via linkage to the Swedish health registers. A strong inverse association between total fiber intake (>=36.8 vs. <23.7 g/day) and COPD was observed in current smokers (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.43, 0.67) and ex-smokers (HR = 0.62; 95% CI = 0.50, 0.78) but not in never smokers (HR = 0.93; 95% CI = 0.60, 1.45; P interaction = 0.04). For cereal fiber, HRs for highest versus lowest quintile were 0.62 (95% CI = 0.51, 0.77; P trend < 0.001) in current smokers and 0.66 (95% CI = 0.52, 0.82; P trend < 0.001) in ex-smokers; for fruit fiber, the HR was 0.65 (95% CI = 0.52, 0.81; P trend < 0.001) in current smokers and 0.77 (95% CI = 0.61, 0.98; P trend = 0.17) in ex-smokers; and for vegetable fiber, it was 0.71 (95% CI = 0.57, 0.88; P trend = 0.003) in current smokers and 0.92 (95% CI = 0.71, 1.19; P trend = 0.48) in ex-smokers. CONCLUSIONS: Our findings indicate that high fiber intake was inversely associated with COPD incidence in men who are current or ex-smokers. PMID- 28901977 TI - Enhanced Recovery After Surgery: History, Evolution, Guidelines, and Future Directions. PMID- 28901976 TI - Determinants of Short-term Movement in a Developing Region and Implications for Disease Transmission. AB - BACKGROUND: Human mobility is important for infectious disease spread. However, little is known about how travel varies by demographic groups and how this heterogeneity influences infectious disease risk. METHODS: We analyzed 10 years of survey data from 15 communities in a remote but rapidly changing region in rural Ecuador where road development in the past 15-20 years has dramatically changed travel. We identify determinants of travel and incorporate them into an infection transmission model. RESULTS: Individuals living in communities more remote at baseline had lower travel rates compared with less remote villages (adjusted odds ratio [OR] = 0.51; 95% confidence interval [CI] = 0.38, 0.67). Our model predicts that less remote villages are, therefore, at increased disease risk. Though road building and travel increased for all communities, this risk differential remained over 10 years of observation. Our transmission model also suggests that travelers and nontravelers have different roles in disease transmission. Adults travel more than children (adjusted OR = 1.73; 95% CI = 1.30, 2.31) and therefore disseminate infection from population centers to rural communities. Children are more likely than adults to be infected locally (attributable fraction = 0.24 and 0.09, respectively) and were indirectly affected by adult travel patterns. CONCLUSIONS: These results reinforce the importance of large population centers for regional transmission and show that children and adults may play different roles in disease spread. Changing transportation infrastructure and subsequent economic and social transitions are occurring worldwide, potentially causing increased regional risk of disease. PMID- 28901979 TI - Analysis of Goal-directed Fluid Therapy and Patient Monitoring in Enhanced Recovery After Surgery. PMID- 28901980 TI - Concepts in Physiology and Pathophysiology of Enhanced Recovery after Surgery. PMID- 28901981 TI - Multimodal Approaches to Analgesia in Enhanced Recovery After Surgery Pathways. PMID- 28901982 TI - Creating and Communicating Clinical Protocols. PMID- 28901983 TI - Enhanced Recovery After Surgery: Evidence for Delivering Value-based Care. PMID- 28901984 TI - Institution-wide Implementation Strategies, Finance, and Administration for Enhanced Recovery After Surgery Programs. PMID- 28901985 TI - A Guide to Implementing Enhanced Recovery After Surgery Protocols: Creating, Scaling, and Managing a Perioperative Consult Service. PMID- 28901986 TI - Enhanced Recovery for Orthopedic Surgery. PMID- 28901987 TI - Enhanced Recovery After Surgery in the Setting of the Perioperative Surgical Home. PMID- 28901988 TI - Enhanced Recovery after Cardiac Surgery: An Update on Clinical Implications. PMID- 28901989 TI - Decreasing the Surgical Stress Response and an Initial Experience from the Enhanced Recovery After Surgery Colorectal Surgery Program at an Academic Institution. PMID- 28901990 TI - The impact of frailty on outcomes in dialysis. AB - PURPOSE OF REVIEW: Frailty is highly prevalent in the dialysis population and is associated with mortality. Recent studies have suggested that other dialysis outcomes are compromised in frail individuals. While we do not yet have a consensus as to the best measure of frailty, identification of these poor outcomes and their magnitude of association with frailty will help improve prognostication, allow for earlier interventions, and improve provider-to-patient communication. RECENT FINDINGS: The most widely used assessment of frailty is Fried's physical performance criteria. However, regardless of assessment method, frailty remains highly associated with mortality. More recently, frailty has been associated with falls, fractures, cognitive impairment, vascular access failure, and poor quality of life. Recent large cohort studies provide strong evidence that frailty assessment can provide important prognostic information for providers and patients both before and after initiation of dialysis. Trials aimed at improving frailty are limited and show the promise of augmenting quality of life, although more studies are needed to firmly establish mortality benefits. SUMMARY: We underscore the importance of frailty as a prognostic indicator and identify other recently established consequences of frailty. Widespread adoption of frailty assessment remains limited and researchers continue to find ways of simplifying the data collection process. Timely and regular assessment of frailty may allow for interventions that can mitigate the onset of poor outcomes and identify actionable targets for dialysis providers. PMID- 28901991 TI - Dose-Dependent Achilles Tendinopathy in a Patient on Aripiprazole. PMID- 28901992 TI - European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the elderly. AB - : The risk for postoperative venous thromboembolism (VTE) is increased in patients aged more than 70 years and in elderly patients presenting with co morbidities, for example cardiovascular disorders, malignancy or renal insufficiency. Therefore, risk stratification, correction of modifiable risks and sustained perioperative thromboprophylaxis are essential in this patient population. Timing and dosing of pharmacoprophylaxis may be adopted from the non aged population. Direct oral anti-coagulants are effective and well tolerated in the elderly; statins may not replace pharmacological thromboprophylaxis. Early mobilisation and use of non-pharmacological means of thromboprophylaxis should be exploited. In elderly patients, we suggest identification of co-morbidities increasing the risk for VTE (e.g. congestive heart failure, pulmonary circulation disorder, renal failure, lymphoma, metastatic cancer, obesity, arthritis, post menopausal oestrogen therapy) and correction if present (e.g. anaemia, coagulopathy) (Grade 2C). We suggest against bilateral knee replacement in elderly and frail patients (Grade 2C). We suggest timing and dosing of pharmacological VTE prophylaxis as in the non-aged population (Grade 2C). In elderly patients with renal failure, low-dose unfractionated heparin (UFH) may be used or weight-adjusted dosing of low molecular weight heparin (Grade 2C). In the elderly, we recommend careful prescription of postoperative VTE prophylaxis and early postoperative mobilisation (Grade 1C). We recommend multi-faceted interventions for VTE prophylaxis in elderly and frail patients, including pneumatic compression devices, low molecular weight heparin (and/or direct oral anti-coagulants after knee or hip replacement) (Grade 1C). : This article is part of the European guidelines on perioperative venous thromboembolism prophylaxis. For details concerning background, methods, and members of the ESA VTE Guidelines Task Force, please, refer to:Samama CM, Afshari A, for the ESA VTE Guidelines Task Force. European guidelines on perioperative venous thromboembolism prophylaxis. Eur J Anaesthesiol 2018; 35:73-76.A synopsis of all recommendations can be found in the following accompanying article: Afshari A, Ageno W, Ahmed A, et al., for the ESA VTE Guidelines Task Force. European Guidelines on perioperative venous thromboembolism prophylaxis. Executive summary. Eur J Anaesthesiol 2018; 35:77-83. PMID- 28901993 TI - Vascular Complications and Use of a Distal Perfusion Cannula in Femorally Cannulated Patients on Extracorporeal Membrane Oxygenation. AB - Femoral arterial cannulation in adult venoarterial (VA) extracorporeal membrane oxygenation (ECMO) predisposes patients to ipsilateral limb ischemia. Placement of a distal perfusion catheter (DPC) is one of few techniques available to prevent or manage this complication. Although frequently used, the indications for and timing of DPC placement are poorly characterized, and no guidelines are available to guide its use. The purpose of this study was to compare the incidences of vascular complications and limb ischemia between patients who did and did not receive a DPC at the time of primary ECMO cannulation. Between June 2009 and April 2015, 132 adults underwent VA ECMO cannulation at our institution. Of the 80 femoral cannulations comprising this retrospective single-center study cohort, 14 (17.5%) received a DPC at the time of primary cannulation. Demographics, indications for ECMO, and cardiovascular history and risk factors were not significantly different between comparison groups. Median arterial cannula size was 17 French in both groups. Vascular complications occurred in 2 of the 14 patients with initial DPC (14.3%) compared with 21 of 66 without initial DPC (31.8%; p = 0.188). Limb ischemia occurred in 2 of 14 patients in the DPC group (14.3%) and 15 of 66 in the non-DPC group (22.7%; p = 0.483). In hospital mortality was comparable between groups. DPC placement at the time of primary cannulation may lower the incidence of limb ischemia. The benefit of DPC placement once evidence of limb ischemia is apparent remains unclear. PMID- 28901994 TI - Biomineralized Conductive PEDOT: PSS-Coated PLA/PHBV/HA Nanofibrous Membranes. AB - Conductive materials are potential candidates for developing bone tissue engineering scaffolds as they are nontoxic and can enhance bone tissue regeneration. Their bioactivity can be enhanced by depositing biomineralization in simulated body fluid (SBF). In the current study, a composite electrospun membrane made up of poly(lactic) acid, poly(3-hydroxybutyrate-co-3 hydroxyvalerate), and hydroxyapatite was fabricated using an electrospinning method. The fabricated membranes were dip-coated with a conductive polymer solution, poly(3,4-ethylenedioxythiophene) poly(4-styrenesulfonate), to induce conductivity. Characterization of the membranes based on characteristics such as morphology, chemical bonding, and wettability was conducted using scanning electron microscopy, field emission scanning electron microscopy, energy dispersive X-ray spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy, and contact angle measurement. From the results, biomineralization of both coated and noncoated composite membranes was observed on the surface of nanofibers after 21 days in SBF. The membranes provide a superhydrophilic surface as shown by the contact angle. In conclusion, this biomimetic electrospun composite membrane could be used to further support cell growth for bone tissue engineering application. PMID- 28901995 TI - Therapeutic food claims: a global perspective. AB - PURPOSE OF REVIEW: Medical foods in the United States, and foods for special medical purposes in other countries, are food formulations used to manage specific chronic diseases or conditions under medical or physician supervision. The process of reviewing and approving food claims for health benefits varies widely from country to country. RECENT FINDINGS: CODEX Alimentarius, a 187 country and one-member (European Union) organization, has standardized not only nutrition labeling and food safety worldwide but has also recently taken on a prominent role in analyzing therapeutic and health claims for food in member countries by providing a framework to study these issues. Two recent activities at CODEX - analyzing foods for special dietary uses and foods for special medical purposes therapeutic food claims - have focused on both how these food categories are formulated for patients with specific conditions and diseases. SUMMARY: Food and specially formulated foods can play a role in preventing or mitigating disease and other health-related conditions. This article will examine the means by which regulatory authorities across the globe address health claims for foods and food-derived products to alter human physiology and disease outcome. PMID- 28901996 TI - Intracranial hemorrhage in congenital bleeding disorders. AB - : Intracranial hemorrhage (ICH), as a life-threatening bleeding among all kinds of congenital bleeding disorders (CBDs), is a rare manifestation except in factor XIII (FXIII) deficiency, which is accompanied by ICH, early in life, in about one third of patients. Most inherited platelet function disorders (IPFDs) are mild to moderate bleeding disorders that can never experience a severe bleeding as in ICH; however, Glanzmann's thrombasthenia, a common and severe inherited platelet function disorder, can lead to ICH and occasional death. This bleeding feature can also be observed in grey platelet syndrome, though less frequently than in Glanzmann's thrombasthenia. In hemophilia, intracerebral hemorrhage is affected by various risk factors one of which is the severity of the disease. The precise prevalence of ICH in these patients is not clear but an estimated incidence of 3.5-4% among newborns with hemophilia is largely ascertained. Although ICH is a rare phenomenon in CBDs, it can be experienced by every patient with severe hemophilia A and B, FXIII deficiency (FXIIID), FVIID, FXD, FVD, FIID, and afibrinogenemia. Upon observing the general signs and symptoms of ICH such as vomiting, seizure, unconsciousness, and headache, appropriate replacement therapies and cranial ultrasound scans must be done to decrease ICH-related morbidity and mortality. PMID- 28901997 TI - Risk factors associated with intraventricular hemorrhage in extremely premature neonates. AB - : Intraventricular hemorrhage (IVH) is a significant cause of morbidity in extremely premature infants despite many advances in neonatal intensive care. We conducted an institutional retrospective review aimed to correlate risk factors associated with IVH. Clinical variables reported to the Vermont-Oxford Network on less than 30 weeks gestational age infants over a 5-year period were evaluated with Pearson's chi-square and multivariate logistic regression. Of 618 infants born less than 30-week gestational age, 178 (28.8%) experienced IVH. Of those less than 1000 g, 105 (36.5%) of 288 infants experienced IVH. Multivariate analysis revealed that thrombocytopenia [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.30-3.19, P = 0.0020] and cardiopulmonary resuscitation (CPR) +/- intubation at delivery (OR 1.84, 95% CI 1.12-3.02, P = 0.0162) were independently associated with IVH. Among infants less than 1000 g, thrombocytopenia (OR 2.09, 95% CI 1.22-3.60, P = 0.0077) and CPR +/- intubation at delivery (OR 2.01, 95% CI 1.10-3.68, P = 0.0229) were also significantly associated with IVH. IVH is a complex phenomenon with many contributing risk factors. In our study, infants less than 30-week gestational age and less than 1000 g revealed thrombocytopenia and CPR +/- intubation in delivery room were independently associated with IVH. These data should alert clinicians to those neonates most likely to suffer IVH. PMID- 28901998 TI - Relationships Between Components of Emotional Intelligence and Suicidal Behavior in Alcohol-dependent Patients. AB - OBJECTIVES: The importance of investigating various emotional skills in assessment of suicide risk in alcohol-dependent (AD) individuals has recently become the focus of increasing interest. The objective of this study was to explore the relationships between self-reported components of emotional intelligence and lifetime prevalence of suicide attempts in a clinical sample of AD subjects. METHODS: A group of 80 inpatients entering an alcohol treatment program in Warsaw, Poland, was recruited. Baseline information about demographics, psychopathological symptoms, personality, and severity of alcohol problems was obtained. The Schutte Self-Report Emotional Intelligence Test was utilized for assessment of emotional processing. Lifetime history of suicide attempts was obtained from the MINI International Neuropsychiatric Interview. RESULTS: After accounting for affect-related suicide risk factors (severity of depression, anxiety, neuroticism), and also other significant predictors (eg, age, sex, history of childhood abuse), mood regulation/optimism deficits remained a significant correlate of lifetime suicide attempts in AD patients. In the mediation models, mood regulation appeared to fully mediate the relationship between history of suicide attempts and depression, and also neuroticism. CONCLUSIONS: The results of this study support the evidence that poor mood regulation might be related to the risk for suicidal behavior in AD individuals. These findings point towards the significance of addressing the issue of emotion related skills in the therapy of those AD subjects who are at risk for suicide. PMID- 28902000 TI - Evaluation of Fracture and Osteotomy Union in the Setting of Osteogenesis Imperfecta: Reliability of the Modified Radiographic Union Score for Tibial Fractures (RUST). AB - BACKGROUND: Evaluation of the union of osteotomies and fractures in patients with osteogenesis imperfecta (OI) is a critical component of patient care. Studies of the OI patient population have so far used varied criteria to evaluate bony union. The radiographic union score for tibial fractures (RUST), which was subsequently revised to the modified RUST, is an objective standardized method of evaluating fracture healing. We sought to evaluate the reliability of the modified RUST in the setting of the tibias of patients with OI. METHODS: Tibial radiographs of 30 patients with OI fractures, or osteotomies were scored by 3 observers on 2 separate occasions. Each of the 4 cortices was given a score (1=no callus, 2=callus present, 3=bridging callus, and 4=remodeled, fracture not visible) and the modified RUST is the sum of these scores (range, 4 to 16). The interobserver and intraobserver reliabilities were evaluated using intraclass coefficients (ICC) with 95% confidence intervals. RESULTS: The ICC representing the interobserver reliability for the first iteration of scores was 0.926 (0.864 to 0.962) and for the second series was 0.915 (0.845 to 0.957). The ICCs representing the intraobserver reliability for each of the 3 reviewers for the measurements in series 1 and 2 were 0.860 (0.707 to 0.934), 0.994 (0.986 to 0.997), and 0.974 (0.946 to 0.988). CONCLUSIONS: The modified RUST has excellent interobserver and intraobserver reliability in the setting of OI despite challenges related to the poor quality of the bone and its dysplastic nature. The application and routine use of the modified RUST in the OI population will help standardize our evaluation of osteotomy and fracture healing. LEVEL OF EVIDENCE: Level III-retrospective study of nonconsecutive patients. PMID- 28901999 TI - Recruitment of prefrontal-striatal circuit in response to skilled motor challenge. AB - A variety of physical fitness regimens have been shown to improve cognition, including executive function, yet our understanding of which parameters of motor training are important in optimizing outcomes remains limited. We used functional brain mapping to compare the ability of two motor challenges to acutely recruit the prefrontal-striatal circuit. The two motor tasks - walking in a complex running wheel with irregularly spaced rungs or walking in a running wheel with a smooth internal surface - differed only in the extent of skill required for their execution. Cerebral perfusion was mapped in rats by intravenous injection of [C] iodoantipyrine during walking in either a motorized complex wheel or in a simple wheel. Regional cerebral blood flow (rCBF) was quantified by whole-brain autoradiography and analyzed in three-dimensional reconstructed brains by statistical parametric mapping and seed-based functional connectivity. Skilled or simple walking compared with rest, increased rCBF in regions of the motor circuit, somatosensory and visual cortex, as well as the hippocampus. Significantly greater rCBF increases were noted during skilled walking than for simple walking. Skilled walking, unlike simple walking or the resting condition, was associated with a significant positive functional connectivity in the prefrontal-striatal circuit (prelimbic cortex-dorsomedial striatum) and greater negative functional connectivity in the prefrontal-hippocampal circuit. Our findings suggest that the level of skill of a motor training task determines the extent of functional recruitment of the prefrontal-corticostriatal circuit, with implications for a new approach in neurorehabilitation that uses circuit-specific neuroplasticity to improve motor and cognitive functions. PMID- 28902001 TI - Guided Growth of the Proximal Femur for the Management of Hip Dysplasia in Children With Cerebral Palsy. AB - BACKGROUND: Progressive hip displacement is one of the most common and debilitating deformities seen in children with cerebral palsy (CP). The aim of this study was to evaluate the results of temporary medial hemiepiphysiodesis of the proximal femur (TMH-PF) using a transphyseal screw to control hip migration during growth in children with CP. METHODS: This was a retrospective study of children with CP and hip dysplasia, age 4 to 11 years and GMFCS levels III-V. There were 28 patients with 56 hips that underwent TMH-PF surgery between 2007 and 2010. Clinical and radiologic evaluation was performed preoperatively, at 6, 12, and 60 months following the index surgery. Acetabular index (AI), neck-shaft angle (NSA) and migration percentage (MP) were measured. All complications were recorded. RESULTS: All radiographic measurements were significantly improved at the final follow-up. Positive correlations were found between NSA, MP, and AI. Multiple regression analysis revealed that MP, time from surgery, and age were influenced by the decrease of the NSA. The femoral physis grew off the screw in 9 hips within 36 months. The screw head broke during attempted screw exchange in 1 hip. The remain cases (4 hips) were treated by placing a second screw parallel to the existing one. Finally, progressive subluxation occurred in 3 hips when the physis grew off the screw and were treated by skeletal reconstruction. CONCLUSIONS: TMH-PF was effective in controlling progressive subluxation of the hip in the majority of cases, obviating the need for major reconstructive surgery in these children with CP. LEVEL OF EVIDENCE: Level IV. PMID- 28902003 TI - American Surgical Association Presidential Forum: A Lifetime of Surgical Education: Can We Do better? PMID- 28902004 TI - Antiretroviral Therapy in HIV-Infected Children With Tuberculosis: A Systematic Review. AB - BACKGROUND: Tuberculosis (TB) is the major cause of mortality in HIV-infected children globally. Current guidelines about the management of antiretroviral therapy in children with TB are based on a limited number of nonrandomized studies involving small numbers of participants. The aim of the study was to systematically retrieve and critically appraise available evidence on the efficacy and safety of different antiretroviral regimens in children with HIV infection who are receiving treatment for active TB. METHODS: We conducted a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Records were retrieved through March 2016 from Medline, Embase and manual screening of key conference proceedings. Four specific research questions assessing available treatment options were defined. RESULTS: Although 4 independent searches were conducted (1 for each Population, Intervention, Comparator, Outcomes question), results were elaborated and interpreted together because of significant overlap among the retrieved records. Six observational studies were selected for qualitative synthesis while meta-analysis could not be performed. CONCLUSION: Evidence for optimal treatment options for HIV/TB coinfected children is limited. As the global community strives to reach the fast-track HIV treatment targets and eliminate childhood TB deaths, it must ensure that coinfected children are included in key treatment studies and expand this neglected but crucial area of research. PMID- 28902005 TI - Propionibacterium Acnes: Cause of Cerebrospinal Fluid Shunt Infection. AB - Infection after implantation of ventriculo-peritoneal shunts is associated with significant morbidity and mortality. We describe a 9-year-old girl with Propionibacterium acnes shunt infection with negative cerebrospinal fluid cultures, diagnosed by broad-range 16S-rRNA gene polymerase chain reaction. This case supports the use of this molecular diagnostic technique in shunt infections, where the offending pathogens are difficult to culture using traditional methods. PMID- 28902006 TI - Development of Survey Scales for Measuring Exposure and Behavioral Responses to Disruptive Intraoperative Behavior. AB - OBJECTIVES: Disruptive intraoperative behavior has detrimental effects to clinicians, institutions, and patients. How clinicians respond to this behavior can either exacerbate or attenuate its effects. Previous investigations of disruptive behavior have used survey scales with significant limitations. The study objective was to develop appropriate scales to measure exposure and responses to disruptive behavior. METHODS: We obtained ethics approval. The scales were developed in a sequence of steps. They were pretested using expert reviews, computational linguistic analysis, and cognitive interviews. The scales were then piloted on Canadian operating room clinicians. Factor analysis was applied to half of the data set for question reduction and grouping. Item response analysis and theoretical reviews ensured that important questions were not eliminated. Internal consistency was evaluated using Cronbach alpha. Model fit was examined on the second half of the data set using confirmatory factor analysis. Content validity of the final scales was re-evaluated. Consistency between observed relationships and theoretical predictions was assessed. Temporal stability was evaluated on a subsample of 38 respondents. RESULTS: A total of 1433 and 746 clinicians completed the exposure and response scales, respectively. Content validity indices were excellent (exposure = 0.96, responses = 1.0). Internal consistency was good (exposure = 0.93, responses = 0.87). Correlations between the exposure scale and secondary measures were consistent with expectations based on theory. Temporal stability was acceptable (exposure = 0.77, responses = 0.73). CONCLUSIONS: We have developed scales measuring exposure and responses to disruptive behavior. They generate valid and reliable scores when surveying operating room clinicians, and they overcome the limitations of previous tools. These survey scales are freely available. PMID- 28902007 TI - A Comparison of Error Rates Between Intravenous Push Methods: A Prospective, Multisite, Observational Study. AB - OBJECTIVES: Current literature estimates the error rate associated with the preparation and administration of all intravenous (IV) medications to be 9.4% to 97.7% worldwide. This study aims to compare the number of observed medication preparation and administration errors between the only commercially available ready-to-administer product (Simplist) and IV push traditional practice, including a cartridge-based syringe system (Carpuject) and vials and syringes. METHODS: A prospective, multisite, observational study was conducted in 3 health systems in various states within the United States between December 2015 and March 2016 to observe IV push medication preparation and administration. Researchers observed a ready-to-administer product and IV push traditional practice using a validated observational method and a modified data collection sheet. All observations were reconciled to the original medication order to determine if any errors occurred. RESULTS: Researchers collected 329 observations (ready to administer = 102; traditional practice = 227) and observed 260 errors (ready to administer = 25; traditional practice = 235). The overall observed error rate for ready-to-administer products was 2.5%, and the observed error rate for IV push traditional practice was 10.4%. CONCLUSIONS: The ready-to-administer group demonstrated a statistically significant lower observed error rate, suggesting that use of this product is associated with fewer observed preparation and administration errors in the clinical setting. Future studies should be completed to determine the potential for patient harm associated with these errors and improve clinical practice because it relates to the safe administration of IV push medications. PMID- 28902009 TI - Risk Vessels of Retropharyngeal Hematoma During Stellate Ganglion Block. AB - BACKGROUND AND OBJECTIVE: Bleeding into the retropharyngeal space is a potential complication in stellate ganglion block (SGB). Retropharyngeal hematoma formation is considered to be due to damage of small arteries in the region, although only scanty details of the region are available. The aim of this study was to map the risk blood vessels in the retropharyngeal space to avoid accidental damage during SGB. METHODS: Contrast-enhanced 3-dimensional computed tomography images performed on 80 patients were reanalyzed retrospectively to construct detailed map of cervical blood vessels that are prone to damage and bleeding during SGB. RESULTS: Of the 160 bilateral necks, 6 (3.8%) and 82 (51.3%) small arteries were identified in the medial portions of the ventral surface of the transverse processes of the sixth and seventh cervical vertebrae, respectively. In particular, 5 of the 6 small arteries detected in the medial portion of the ventral surface of the transverse process of the sixth cervical vertebra were the inferior thyroid artery (ITA). Of the 160 vertebral arteries, 2 arteries were missing, 4 (2.5%) entered the transverse foramen of the fifth cervical vertebra, whereas 1 artery (0.6%) entered the transverse foramen of the fourth cervical vertebra. CONCLUSIONS: Three-dimensional computed tomography identified the ITA in the medial portion of the ventral surface of the transverse process of the sixth cervical vertebra. The risk vessels of retropharyngeal hematoma during SGB could include the ITA. PMID- 28902008 TI - Fibrous Catalyst-Enhanced Acanthamoeba Disinfection by Hydrogen Peroxide. AB - SIGNIFICANCE: Hydrogen peroxide (H2O2) disinfection systems are contact-lens patient problem solvers. The current one-step, criterion-standard version has been widely used since the mid-1980s, without any significant improvement. This work identifies a potential next-generation, one-step H2O2, not based on the solution formulation but rather on a case-based peroxide catalyst. PURPOSE: One step H2O2 systems are widely used for contact lens disinfection. However, antimicrobial efficacy can be limited because of the rapid neutralization of the peroxide from the catalytic component of the systems. We studied whether the addition of an iron-containing catalyst bound to a nonfunctional propylene:polyacryonitrile fabric matrix could enhance the antimicrobial efficacy of these one-step H2O2 systems. METHODS: Bausch + Lomb PeroxiClear and AOSept Plus (both based on 3% H2O2 with a platinum-neutralizing disc) were the test systems. These were tested with and without the presence of the catalyst fabric using Acanthamoeba cysts as the challenge organism. After 6 hours' disinfection, the number of viable cysts was determined. In other studies, the experiments were also conducted with biofilm formed by Stenotrophomonas maltophilia and Elizabethkingia meningoseptica bacteria. RESULTS: Both control systems gave approximately 1-log10 kill of Acanthamoeba cysts compared with 3.0-log10 kill in the presence of the catalyst (P < .001). In the biofilm studies, no viable bacteria were recovered following disinfection in the presence of the catalyst compared with >=3.0-log10 kill when it was omitted. In 30 rounds' recurrent usage, the experiments, in which the AOSept Plus system was subjected to 30 rounds of H2O2 neutralization with or without the presence of catalytic fabric, showed no loss in enhanced biocidal efficacy of the material. The catalytic fabric was also shown to not retard or increase the rate of H2O2 neutralization. CONCLUSIONS: We have demonstrated the catalyst significantly increases the efficacy of one-step H2O2 disinfection systems using highly resistant Acanthamoeba cysts and bacterial biofilm. Incorporating the catalyst into the design of these one-step H2O2 disinfection systems could improve the antimicrobial efficacy and provide a greater margin of safety for contact lens users. PMID- 28902010 TI - Posterior Amorphous Corneal Dystrophy Associated With Keratoglobus: A Case Report. AB - PURPOSE: Posterior amorphous corneal dystrophy (PACD) is a rare disorder characterized by sheet-like opacification of the posterior corneal stroma, corneal thinning, and decreased corneal curvature. It is not known to be associated with progressive corneal ectasia. In this report, we examine the course of a patient with PACD who developed bilateral keratoglobus-type corneal ectasia. METHODS: The clinical history of a single patient is reviewed from birth through age 15. Visual acuity, refraction, ultrasound pachymetry, anterior segment optical coherence tomography, corneal topography, and corneal tomography are presented. RESULTS: The patient was noted to have bilateral cloudy corneas at birth. Congenital infection, metabolic disease, and glaucoma were ruled out. Anterior segment optical coherence tomography demonstrated posterior stromal opacification typical of PACD. Over time, the patient progressed from best uncorrected visual acuity of 20/20-2 OD and 20/25-3 OS to PROSE lens-corrected visual acuity of 20/30-3 OD and 20/30-3 OS. Central corneal thinness progressed from 491 to 408 MUm in the right eye and from 505 to 389 MUm in the left eye. Steepening in corneal axial/sagittal curvature developed in both eyes beginning inferiorly then involving the corneas diffusely. CONCLUSIONS: In this case report, we illustrate progressive corneal ectasia in a patient with PACD. Although both conditions may represent changes in the structure and integrity of corneal collagen, whether an association exists between the 2 conditions is unknown. PMID- 28902011 TI - Meibomian Gland Dysfunction Associated With Periocular Radiotherapy. AB - PURPOSE: To investigate the influence of periocular radiotherapy on meibomian glands. METHODS: We evaluated 28 patients (40 eyes) who received radiotherapy (RT group) for conjunctival or orbital lymphoma and 30 age-matched control subjects (60 eyes). Subjects underwent slit-lamp examination of the eyelids, Schirmer test, meibography, and evaluation of tear film breakup time (TBUT), Ocular Surface Disease Index (OSDI) scores, meibomian glands evaluation (meiboscore, meibum expressibility, and lid margin abnormality scores), and tear film lipid layer thickness using an ocular surface interferometer. These parameters were compared between subjects in the RT and control groups. RESULTS: Meiboscores as well as meibum expressibility and OSDI scores in the RT group were significantly higher compared with those in the control group (1.6 +/- 0.9 vs. 0.4 +/- 0.6, 1.6 +/- 1.0 vs. 0.2 +/- 0.4, and 48.1 +/- 21.4 vs. 6.2 +/- 4.4, respectively, P < 0.001, all), whereas the Schirmer value (9.2 +/- 5.1 vs. 12.3 +/- 5.2, P = 0.004), TBUT (4.2 +/- 2.5 vs. 6.4 +/- 2.6, P = 0.001), and lipid layer thickness (61.0 +/- 29.3 vs. 85.2 +/- 20.0, P < 0.001) in the RT group were lower compared with those in the control group. The percentage of meibomian gland dropout was significantly correlated with age (P = 0.025) and total radiation dose (P = 0.012), regardless of the target location of irradiation. Even low-dose irradiated eyes (<30 Gy) exhibited significantly higher meiboscores (P < 0.001) and shorter TBUT (P = 0.005) compared with control eyes. CONCLUSIONS: Eyes that received periocular radiotherapy exhibited relatively high tear film instability induced by meibomian gland dysfunction, contributing to the high severity of dry eye symptoms. PMID- 28902012 TI - Comparison of Oral Voriconazole Versus Oral Ketoconazole as an Adjunct to Topical Natamycin in Severe Fungal Keratitis: A Randomized Controlled Trial. AB - PURPOSE: To compare the efficacy of oral voriconazole (VCZ) with oral ketoconazole (KCZ) as an adjunct to topical natamycin in severe fungal keratitis. METHODS: Fifty eyes of 50 patients with proven severe fungal keratitis, (>5 mm size, involving >4 mm central cornea and >50% stromal depth), smear, and/or culture positive were randomized to receive either oral VCZ (n = 25) or oral KCZ (n = 25) 200 mg twice a day. Both groups received topical natamycin along with oral medication. The primary outcome measure was best spectacle-corrected visual acuity (BSCVA) at 3 months of follow-up. Secondary outcomes were the percentage of healed cases and scar size. RESULTS: The mean BSCVA after treatment was 1.3 +/ 0.35 logarithm of minimum angle of resolution units in the VCZ group and 1.6 +/- 0.39 logarithm of minimum angle of resolution units in the KCZ group [P = 0.004, 95% confidence interval (CI), -0.10 to 0.54]. The final mean scar size was smaller for oral VCZ than for oral KCZ (P = 0.04, 95% CI, -0.01 to 0.93 mm). The percentage of cases healed were 80% and 72% in VCZ and KCZ groups, respectively (P = 0.51, 95% CI, -0.15 to 0.31). The ratio of tear film to serum concentration of oral VCZ was better than oral KCZ at days 14 (P = 0.002) and 21 (P = 0.006). CONCLUSIONS: Although the duration and percentage of healing was similar in both groups, oral VCZ attained a significantly better tear film concentration with a smaller scar size and better BSCVA compared with oral KCZ. Thus, oral VCZ may be preferred over oral KCZ in severe fungal keratitis. PMID- 28902013 TI - "Bubble-in-the-Roll" Technique Using the Endoject DMEK Injector: Influence of the Air Bubble on Endothelial Cell Loss. AB - PURPOSE: To evaluate the impact of the air bubble on endothelial cell loss using the "bubble-in-the-roll" technique during Descemet membrane endothelial keratoplasty (DMEK). METHODS: Twenty DMEK grafts not suitable for transplantation were manually prepared from organ-cultured corneoscleral discs and injected into culture media using the Endoject DMEK injector (Medicel AG, Wolfhalden, Switzerland). Based on the injection method, the grafts were divided into 2 groups: In group A (n = 10), a small air bubble was placed inside the graft roll while it was in the injector. In group B (n = 10), the grafts were injected without an air bubble inside the graft roll. Main outcome measures included endothelial cell density (ECD) after graft stripping and graft injection. RESULTS: There were no statistically significant differences between groups A and B in donor age, storage duration, and donor ECD. ECD decreased from 1929 +/- 145 cells/mm to 1796 +/- 303 cells/mm after graft stripping in group A and from 1801 +/- 226 cells/mm to 1709 +/- 290 cells/mm in group B. ECD after graft injection further decreased to 1683 +/- 291 cells/mm in group A and to 1651 +/- 292 cells/mm in group B. Endothelial cell loss after graft stripping and graft injection was not statistically significant between groups A and B (P = 0.29 and P = 1, respectively). CONCLUSIONS: The bubble-in-the-roll technique for injection and unfolding of the graft is a safe method for graft delivery into the anterior chamber guaranteeing orientation of the graft without harming the endothelium. PMID- 28902014 TI - Reply. PMID- 28902015 TI - "Progress in Corneal Research and Practice in Japan and Abroad," 22nd Annual Meeting of the Kyoto Cornea Club, November 25 and 26, 2016. PMID- 28902016 TI - Raman Microscopy: A Noninvasive Method to Visualize the Localizations of Biomolecules in the Cornea. AB - PURPOSE: In vivo and in situ visualization of biomolecules without pretreatment will be important for diagnosis and treatment of ocular disorders in the future. Recently, multiphoton microscopy, based on the nonlinear interactions between molecules and photons, has been applied to reveal the localizations of various molecules in tissues. We aimed to use multimodal multiphoton microscopy to visualize the localizations of specific biomolecules in rat corneas. METHODS: Multiphoton images of the corneas were obtained from nonlinear signals of coherent anti-Stokes Raman scattering, third-order sum frequency generation, and second-harmonic generation. RESULTS: The localizations of the adhesion complex containing basement membrane and Bowman layer were clearly visible in the third order sum frequency generation images. The fine structure of type I collagen was observed in the corneal stroma in the second-harmonic generation images. The localizations of lipids, proteins, and nucleic acids (DNA/RNA) was obtained in the coherent anti-Stokes Raman scattering images. CONCLUSIONS: Imaging technologies have progressed significantly and been applied in medical fields. Optical coherence tomography and confocal microscopy are widely used but do not provide information on the molecular structure of the cornea. By contrast, multiphoton microscopy provides information on the molecular structure of living tissues. Using this technique, we successfully visualized the localizations of various biomolecules including lipids, proteins, and nucleic acids in the cornea. We speculate that multiphoton microscopy will provide essential information on the physiological and pathological conditions of the cornea, as well as molecular localizations in tissues without pretreatment. PMID- 28902018 TI - Mechanism of Proliferation of Cultured Human Corneal Endothelial Cells. AB - Because human corneal endothelial cells (HCECs) do not proliferate once the endothelial monolayer has formed, corneal wound healing is believed to be mediated by cell enlargement or migration, rather than by proliferation. However, the cellular mechanisms involved in wound healing by HCECs have not been fully determined. In this review, we focus on the effects of promyelocytic leukemia zinc finger (PLZF), a DNA-binding transcription factor, and transforming growth factor (TGF)-beta2 on the proliferation and migration of cultured HCECs. Involvement of the mitogen-activated protein kinase (MAPK) signaling pathway in the migration of HCECs was also investigated. Expression of PLZF mRNA decreased as cell-cell contact was disrupted and returned to the original level as cell cell contact was re-formed. Assessment with a real-time cell electronic sensing system revealed that proliferation of cultured HCECs was inhibited after infection with Ad-PLZF and exposure to TGF-beta2. Migration of cultured HCECs was increased by TGF-beta2 through p38 MAPK activation. We conclude that PLZF expression in cultured HCECs is closely related to the formation of cell-cell contact and that TGF-beta2 suppresses proliferation of cultured HCECs, while promoting their migration through p38 MAPK activation. PMID- 28902017 TI - Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation. AB - Among different species of mites, Demodex folliculorum and Demodex brevis are the only 2 that affect the human eye. Because demodicosis is highly age-dependent and can be found in asymptomatic adults, the pathogenicity of these mites has long been debated. In this study, we summarize our research experience including our most recent study regarding Demodex infestation as a potential cause of ocular inflammatory diseases. Specifically, we describe the pathogenesis of demodicosis and then discuss the results of work investigating the associations and relationships between ocular demodicosis and blepharitis, meibomian gland diseases, and keratitis, in turn. This is followed by some discussion of the diagnosis of demodicosis and concludes with a brief discussion of evidence for different treatments for ocular demodicosis. Collectively, our studies suggest a strong correlation between ocular demodicosis and ocular surface inflammatory conditions, such as blepharitis, chalazia, meibomian gland dysfunction, and keratitis. Further investigation of the underlying pathogenic mechanism is warranted. PMID- 28902019 TI - A Randomized Evaluator-Blinded Trial Comparing Subsurface Monopolar Radiofrequency With Microfocused Ultrasound for Lifting and Tightening of the Neck. AB - BACKGROUND: Both subsurface monopolar radiofrequency (SMRF) and microfocused ultrasound with visualization (MFU-V) have demonstrated the ability to lift and tighten the neck. No head-to-head comparison study exists of these 2 technologies. OBJECTIVE: To compare the efficacy and safety of SMRF and MFU-V for the lifting and tightening of neck. MATERIALS AND METHODS: Twenty subjects aged from 18 to 65 with moderate neck skin laxity were randomized to receive either one treatment of SMRF or MFU-V. RESULTS: At Days 0, 30, 90, and 180, the mean (SD) investigator-assessed Neck Laxity Grade was 2.7 (0.67), 2.1 (1.1), 1.6 (1.2), and 0.86 (0.7), respectively, for patients treated with SMRF, and 2.8 (0.63), 2.4 (1.07), 1.5 (0.53), and 1.4 (0.7), respectively, for those treated with MFU-V. Both SMRF and MFU-V led to a significant decrease in the mean investigator-assessed Neck Laxity Grade by Day 90 and persistent to Day 180. Subject assessment of firmness, texture, and laxity also significantly improved by Day 90 and persistent to Day 180. Adverse events were mild and transient. CONCLUSION: There were no were statistically significant differences between SMRF and MFU-V in investigator-assessed and patient-assessed measures of neck laxity, patient satisfaction, and adverse events. Microfocused ultrasound with visualization was associated with more procedural pain. PMID- 28902020 TI - Ensuring Consistent Results When Microneedling Perioral Rhytides. PMID- 28902021 TI - ATX-101 (Deoxycholic Acid Injection) Treatment in Men: Insights From Our Clinical Experience. AB - BACKGROUND: Excess submental fat (SMF), also called a double chin, is an area of concern for men that can be addressed clinically. ATX-101 (deoxycholic acid injection; Kybella in the United States and Belkyra in Canada, Australia, and various European countries) is the first injectable approved for reduction of SMF. OBJECTIVE: To share the authors' clinical experience using ATX-101 in men with submental fullness and offer insights regarding how this treatment may be presented to men as an option to improve their submental profile. METHODS: Retrospective review of the authors' medical records for male patients treated with ATX-101. RESULTS: To allow for fewer ATX-101 treatments, it is recommended that a large surface area be treated at the first session. The positive changes and outcomes achieved with ATX-101 build confidence between the physician and patient, which often leads to male patients seeking other aesthetic treatments to improve their overall appearance. CONCLUSION: ATX-101 treatment is often an effective introduction to aesthetic medicine for men. PMID- 28902022 TI - Repair of a Full-Thickness Defect of the Right Upper Lip Extending Into Multiple Cosmetic Subunits. PMID- 28902023 TI - Novel Modality for Neck Rejuvenation: A Prospective Multicenter Trial of Percutaneous Radiofrequency Ablation of the Cervical Branch of the Facial Nerve. AB - BACKGROUND: Neck rejuvenation offers few modalities of treatments limited to either invasive plastic surgery or temporary neuromodulation using botulinum toxin. OBJECTIVE: To access the efficacy, longevity, and safety of percutaneous monopolar radiofrequency (RF) ablation of the cervical branch of the facial nerve innervating the platysma for neck rejuvenation. MATERIALS AND METHODS: This prospective, multicenter trial enrolled 19 adult patients with noticeable platysmal banding at 2 different centers. All patients underwent RF ablation on the cervical branch of the facial nerve. Response was assessed immediately after treatment and then at 1, 4, 12, and 24 weeks after the procedure using photography. Masked investigators compared baseline photography and follow-up intervals to evaluate the results. RESULTS: Seventeen of the 18 patients had improvement in the platysmal banding. One patient was disqualified after ablation. Long-term sequalae such as scarring, burns, ulceration, hypopigmentation, or hyperpigmentation were not reported. CONCLUSION: The results of this multicenter study support that RF ablation of the cervical branch of the facial nerve is a novel technique that results in improvement of platysmal banding. This technique is an emerging alternative, nonsurgical option for neck rejuvenation that is relatively safe, with little downtime for the patient. PMID- 28902024 TI - Association of Socioeconomic and Geographic Factors With Google Trends for Tanning and Sunscreen. AB - BACKGROUND: Internet search trends are used to track both infectious diseases and noncommunicable conditions. OBJECTIVE: The authors sought to characterize Google Trends search volume index (SVI) for the terms "sunscreen" and tanning ("tanning salon" and "tanning bed") in the United States from 2010 to 2015 and analyze association with educational attainment, average income, and percent white data by state. METHODS: SVI is search frequency data relative to total search volume. Analysis of variance, univariate, and multivariate analyses were performed to assess seasonal variations in SVI and the association of state-level SVI with state latitudes and census data. RESULTS: Hawaii had the highest SVI for sunscreen searches, whereas Alaska had the lowest. West Virginia had the highest SVI for tanning searches, whereas Hawaii had the lowest. There were significant differences between seasonal SVI for sunscreen and tanning searches (p < .001). Sunscreen SVI by state was correlated with an increase in educational attainment and average income, and a decrease in latitude (p < .05) in a multivariate model. Tanning SVI was correlated with a decrease in educational attainment and average income, and an increase in latitude (p < .05). CONCLUSION: Internet search trends for sunscreen and tanning are influenced by socioeconomic factors, and could be a tool for skin-related public health. PMID- 28902025 TI - Comparison of Pain Levels in Anterior Versus Cephalic Approach for Supraorbital/Supratrochlear Nerve Blocks. PMID- 28902026 TI - Chemical Peels: Indications and Special Considerations for the Male Patient. AB - BACKGROUND: Chemical peels are a mainstay of aesthetic medicine and an increasingly popular cosmetic procedure performed in men. OBJECTIVE: To review the indications for chemical peels with an emphasis on performing this procedure in male patients. MATERIALS AND METHODS: Review of the English PubMed/MEDLINE literature and specialty texts in cosmetic dermatology, oculoplastic, and facial aesthetic surgery regarding sex-specific use of chemical peels in men. RESULTS: Conditions treated successfully with chemical peels in men include acne vulgaris, acne scarring, rosacea, keratosis pilaris, melasma, actinic keratosis, photodamage, resurfacing of surgical reconstruction scars, and periorbital rejuvenation. Chemical peels are commonly combined with other nonsurgical cosmetic procedures to optimize results. Male patients may require a greater number of treatments or higher concentration of peeling agent due to increased sebaceous quality of skin and hair follicle density. CONCLUSION: Chemical peels are a cost-effective and reliable treatment for a variety of aesthetic and medical skin conditions. Given the increasing demand for noninvasive cosmetic procedures among men, dermatologists should have an understanding of chemical peel applications and techniques to address the concerns of male patients. PMID- 28902027 TI - Clinical Outcomes of Radiofrequency Ablation for Unilateral and Bilateral Varicose Veins. AB - BACKGROUND: Approximately 20% of varicose vein are bilateral. Patients prefer a simultaneous bilateral procedure instead of 2 separate unilateral procedures. There is currently little evidence comparing bilateral and unilateral varicose vein surgeries. OBJECTIVE: To report the clinical outcomes of unilateral and bilateral radiofrequency ablation (RFA) for varicose veins. MATERIALS AND METHODS: The authors retrospectively collected data on clinical outcomes of patients who underwent RFA. They investigated clinical, etiologic, anatomic, and pathophysiologic (CEAP) score, venous clinical severity score (VCSS), and quality of life (QoL) score. RESULTS: Radiofrequency ablation was performed in 546 limbs in 385 patients. Women comprised 60.4% of the patients. The mean age was 52.3 +/- 11.6 years (range, 19-84). The occlusion rate after 2 years was 94.5%. Clinical outcomes of CEAP score, VCSS, and QoL scores improved significantly from 2.15 +/- 0.45, 2.70 +/- 2.04, and 6.91 +/- 6.69 at baseline to 2.10 +/- 0.32, 0.63 +/- 0.04, and 3.38 +/- 4.74 at the study end, respectively. The preoperative and postoperative differences in CEAP score for unilateral and bilateral RFA were 0.02 +/- 0.21 and 0.13 +/- 0.49, respectively (p = .073). Those of VCSS for unilateral and bilateral RFA were 1.87 +/- 1.50 and 4.01 +/- 2.93, respectively (p < .001). CONCLUSION: Good clinical outcomes were shown after RFA with respect to CEAP, VCSS, and QoL scores. The simultaneous bilateral RFA can be performed with effectiveness. PMID- 28902028 TI - A-101, a Proprietary Topical Formulation of High-Concentration Hydrogen Peroxide Solution: A Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Study of the Dose-Response Profile in Subjects With Seborrheic Keratosis of the Face. AB - BACKGROUND: Seborrheic keratosis (SK) is a common benign skin tumor, yet no topical treatments are approved in the United States. OBJECTIVE: To evaluate the proprietary, stabilized, high-concentration hydrogen peroxide-based topical solution A-101 (32.5% and 40% concentrations) for treatment of facial SK lesions. MATERIALS AND METHODS: In this multicenter, double-blind, vehicle-controlled study, eligible subjects were randomly assigned to receive up to 2 treatments of A-101 40%, A-101 32.5%, or vehicle solution applied to a single facial SK lesion. The primary efficacy assessment was the Physician's Lesion Assessment (PLA), a validated 4-ordinal scale. RESULTS: The primary end point, the mean reduction in PLA grade from baseline to Day 106 was 1.7 for A-101 40%, 1.4 for A-101 32.5%, and 0.1 for vehicle (p < .001, both concentrations vs vehicle). Lesions for 68%, 62%, and 5% of subjects, respectively, were judged to be clear or near clear (p < .001, both concentrations vs vehicle). Local skin reactions were predominantly mild and transient. No subjects discontinued because of treatment-related adverse events. CONCLUSION: A-101 solution demonstrated efficacy in treating SKs on the face. Greater magnitude of effect was seen with the 40% concentration than the 32.5% concentration. A-101 solution had a favorable safety and tolerability profile at both concentrations. PMID- 28902029 TI - Shave Versus Elliptical Biopsy for Melanoma Substantially Increases Re-excision Area and Length. PMID- 28902030 TI - Multimodal Approach for Treating Horizontal Neck Wrinkles Using Intensity Focused Ultrasound, Cohesive Polydensified Matrix Hyaluronic Acid, and IncobotulinumtoxinA. AB - BACKGROUND: For the restoration of horizontal neck wrinkles, multimodal approaches using neuromodulators, intensity focused ultrasound (IFU), and fine line fillers are recommended. OBJECTIVE: To evaluate the efficacy and safety of a 1-day, multimodal approach for horizontal neck wrinkles. METHODS: Twelve female patients with horizontal neck wrinkles were treated with a combined treatment of IFU, cohesive polydensified matrix hyaluronic acid (CPMHA), and incobotulinumtoxinA. Therapeutic outcomes were assessed on Day 0 and 1, 2, 3, and 6 months thereafter. RESULTS: Horizontal neck wrinkles decreased significantly in length from a median at baseline of 269.75 mm (interquatile range [IQR], 235.35 302.94 mm) to 91.5 mm (IQR, 51.4-108.61 mm) at 1 month, 92.3 mm (IQR, 69.66 132.07 mm) at 2 months, 101.88 mm (IQR, 86-146.77 mm) at 3 months, and 109.48 mm (IQR, 85.06-148.17 mm) at 6 months after the combined treatment. The median global aesthetic improvement scale scores were 3.5 (IQR, 2-4) at 1 month, 3 (IQR, 3-3.5) at 2 months, 3 (IQR, 2-4) at 3 months, and 3 (IQR, 3-3) at 6 months. Post treatment petechiae resolved completely within 7 days, and CPMHA-induced lumps disappeared within 1 month. CONCLUSION: The present data demonstrated that the multimodal, combined treatment used in the present study provides satisfactory and long-lasting therapeutic outcomes by targeting different pathogenetic factors of horizontal neck wrinkles. PMID- 28902031 TI - Commentary on The Nasal Tip Rotation Flap for Reconstruction of the Lateral Nasal Tip, Anterior Ala, and Soft Triangle. PMID- 28902032 TI - Repair of Defects of the Central Forehead With a Modified Banner Transposition Flap. PMID- 28902033 TI - Reactive Eccrine Syringofibroadenoma Associated With Basal Cell Carcinoma: A Histologic Mimicker of Fibroepithelioma of Pinkus. PMID- 28902034 TI - Safety and Efficacy of a Noninvasive 1,060-nm Diode Laser for Fat Reduction of the Flanks. AB - BACKGROUND: Preliminary reports indicate a hyperthermic diode laser treatment could be a safe and effective method for noninvasive fat reduction using the 1,060-nm wavelength. This wavelength penetrates the skin to heat subcutaneous adipocytes causing cellular disruption, leaving extracellular lipids, and cellular debris to be evacuated naturally by the body. OBJECTIVE: To evaluate the safety and effectiveness of this modality for noninvasive fat reduction of the flanks. MATERIALS AND METHODS: Forty-nine subjects received single laser treatment to 1 flank. Ultrasound images were taken at baseline, follow-up at 6 and 12 weeks after treatment. High-resolution photographs were taken at baseline and 12 weeks after treatment and then evaluated by independent reviewers. Adverse events recorded at all visits. Subjects completed a satisfaction questionnaire at the conclusion of the trial. RESULTS: Ultrasound images showed statistically significant (p < .001) average fat reduction of 2.6 +/- 1.1 mm. Reviewers correctly ordered photographs 90.3% of the time. Ninety-six percentage of subjects rated that they were satisfied. Noted side effects were transient mild to moderate tenderness which subsided within 1 to 3 weeks; no serious adverse events were reported. CONCLUSION: The hyperthermic 1,060-nm diode laser treatment used in this study was safe and effective for noninvasive fat reduction of the flank. PMID- 28902035 TI - Small-Particle Hyaluronic Acid Gel Treatment of Photoaged Hands. AB - BACKGROUND: Aging hands tend to lose subcutaneous volume resulting in prominence of the underlying vessels, tendons, and bone contributing to an aged appearance. Dermal fillers have been successfully used to improve the appearance of the aging dorsal hand. OBJECTIVE: The objective is to evaluate the safety and efficacy of a small-particle hyaluronic acid (SPHA) injectable gel for the treatment of photoaged volume loss of the hands. MATERIALS AND METHODS: This is an open-label, prospective, randomized, interventional, study. Twenty-five healthy female volunteer subjects aged 40 to 70 years with photoaged thinning of the hands received an injection of an SPHA gel to the dorsal aspect of 1 hand. Subjects were followed up for 6 months. The hands were evaluated at regular intervals according to a 5-point validated hand grading scale. RESULTS: The average hand grading scores demonstrated statistically significant improvement at all time points compared with baseline. Eighty-eight percent to 100% of subjects achieved improvement at 1 month after treatment, and 50% to 83% maintained at least 1 point improvement at 6 months. There were no adverse events reported. CONCLUSION: The investigated SPHA is a safe and effective method for improving the thinned and photoaged appearance of the hands. PMID- 28902036 TI - Clinical and Histological Evaluations of Enlarged Facial Skin Pores After Low Energy Level Treatments With Fractional Carbon Dioxide Laser in Korean Patients. AB - BACKGROUND: Enlarged facial pores can be an early manifestation of skin aging and they are a common aesthetic concern for Asians. However, studies of improving the appearance of enlarged pores have been limited. OBJECTIVE: The authors aimed to study the application of CO2 fractional laser treatment in patients with enlarged facial pores. METHODS: A total of 32 patients with dilated facial pores completed 3 consecutive sessions of low energy level treatments with a fractional CO2 laser at 4-week intervals. Image analysis was performed to calculate the number of enlarged pores before each treatment session and 12 weeks after the final treatment. RESULTS: After application of laser treatments, there was a significant decrease in the number of enlarged pores. The mean number of enlarged pores was decreased by 28.8% after the second session and by 54.5% at post treatment evaluation. Post-treatment side effects were mild and transitory. Histological and immunohistochemical analyses demonstrated clear increases in the number of collagen fibers and the expression of transforming growth factor-beta1. CONCLUSION: The short-term results showed that treatment with low energy level CO2 fractional laser therapy could be a safe and effective option for patients with Fitzpatrick skin Types III and IV who are concerned with enlarged pores. PMID- 28902037 TI - Esophagojejunostomy With Linear Staplers in Laparoscopic Total Gastrectomy: Experience With 168 Cases in 5 Consecutive Years. AB - PURPOSE: We evaluate surgical outcomes of intracorporeal esophagojejunostomy in laparoscopic total gastrectomy using 2 linear stapler methods. MATERIALS AND METHODS: The functional end-to-end anastomosis (FEEA) method was chosen as a first choice. The overlap method was chosen in cases with esophageal invasion. We retrospectively analyzed the early and late surgical outcomes of consecutive 168 laparoscopic total gastrectomy cases from April 2011 to December 2016. RESULTS AND CONCLUSIONS: The FEEA method was selected in 120 cases, and the overlap method was selected in 48 cases. The mean time of esophagojejunostomy for the FEEA and overlap method was 13.2 and 36.5 minutes, respectively. Two cases with FEEA method and 3 cases with overlap method experienced complications due to esophagojejunostomy leakage. These cases were treated without performing a reoperation. One case with FEEA method was complicated due to esophagojejunostomy stenosis. This case was endoscopically treated. Our procedures are safe and feasible. PMID- 28902038 TI - Removal of Hazardous Surgical Smoke Using a Built-in-Filter Trocar: A Study in Laparoscopic Rectal Resection. AB - BACKGROUND: Surgical smoke containing potentially carcinogenic and harmful materials is an inevitable consequence of surgical energy devices, and constitutes a substantial occupational hazard in the operating room. This study aimed to evaluate the efficacy of a built-in-filter trocar in eliminating hazardous surgical smoke during laparoscopic and robotic rectal surgery. METHODS: Ten patients who underwent rectal cancer resection were enrolled. Five patients underwent surgery utilizing a nonfiltered trocar, and the remaining 5 utilized a built-in-filter trocar. Gas samples were aspirated from the peritoneal cavity over 30 minutes of electrocauterization and collected in a Tedlar bag. Concentrations of surgical smoke were measured using ultraperformance liquid chromatography and gas chromatography. RESULTS: Eleven hazardous chemical compounds (benzene, toluene, ethylbenzene, xylene, styrene, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isovaleraldehyde, and valeraldehyde) were identified in the surgical smoke. With the built-in-filter trocar, removal rates of 69% for benzene (P=0.028), 72% for toluene (P=0.009), 67% for butyraldehyde (P=0.047), 46% for ethylbenzene (P=0.092), 44% for xylene (P=0.086), 35% for styrene (P=0.106), 39% for formaldehyde (P=0.346), and 33% for propionaldehyde (P=0.316) were achieved. CONCLUSIONS: This study confirmed the presence of harmful materials in surgical smoke. Evacuation of surgical smoke through a disposable built-in-filter trocar is a simple and effective way in reducing volatile organic compounds concentrations. PMID- 28902039 TI - Topical Mitomycin C Application Is Effective Even in Esophageal Strictures Resistant to Dilatation Therapy in Children. AB - PURPOSE: Several treatment techniques may be used in the treatment of esophageal strictures. The purpose of this study was to present the effects of topical mitomycin C (TMC) as an useful adjunct to dilatation therapy in esophageal strictures. MATERIALS AND METHODS: A retrospective analysis of patients who underwent TMC between February 2015 and July 2016 was performed. Dysphagia score, periodic dilatation index, and number of dilatations were compared before and after intervention to investigate the efficacy of TMC. RESULTS: TMC was performed on 20 patients with a median age of 3.5 years (2 to 17 y). The diagnosis was corrosive esophageal strictures in 14 patients, anastomotic strictures in 5 patients, and congenital esophageal stricture in 1 patient. The length of the stricture was long in 10 patients (50%). The median dysphagia score decreased from 2 (1 to 3) to 0 (0 to 2) after application (P<0.001). The median number of dilatation sessions decreased from 5 (1 to 41) to 1 (0 to 11) after intervention (P<0.001). The median periodic dilatation index decreased from 1 (0.66 to 1.34) to 0 (0 to 1.33) after TMC (P<0.001). Regular esophageal dilatation was not necessary in 16 patients after application (80%). The length of the stricture did not affect the efficacy of TMC. The success of treatment was lower in patients with a long treatment period before TMC (>3 y) (50%). No complications were seen in a median follow-up period of 16 months (7 to 22 mo). CONCLUSIONS: TMC application has a significant positive effect as an adjunct to dilatation therapy in most of the patients with different types of esophageal strictures. It should be performed as a safe and efficient treatment option even in patients who were resistant to dilatation therapy. PMID- 28902040 TI - Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome. AB - BACKGROUND: Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis, with poor survival. Rifaximin is a gut-selective broad-spectrum antibiotic. AIM: The aim of this study was to evaluate the role of rifaximin as a primary prevention of HRS. PATIENTS AND METHODS: Eighty patients with liver cirrhosis and ascites were enrolled. They were randomized into two groups: control (n=40) and rifaximin group (n=40). Baseline liver function tests, renal function tests, complete blood count, international normalized ratio, urine analysis, and abdominal ultrasonography were carried out. Rifaximin 550 mg was administered twice daily for 12 weeks. Renal functions were measured every 4 weeks with monitoring of HRS occurrence and possible precipitating factor. RESULTS: Both groups were matched for age, sex, virology, serum bilirubin, serum albumin, aspartate aminotransferase, alanine aminotransferase, hemoglobin, white blood cells, platelets, international normalized ratio, potassium, and Child-Pugh score. In contrast to the rifaximin group, the control group showed statistically significant serial blood urea nitrogen (18.84+/-7.17, 19.85+/-6.10, 21.54+/-4.79, and 22.96+/-5.82 mg/dl; P=0.001) and serum creatinine (0.94+/-0.25, 1.02+/-0.24, 1.12+/-0.16, and 1.21+/-0.17 mg/dl; P=0.001) levels. The overall blood urea nitrogen and serum creatinine change was statistically higher in the control group than the rifaximin group (20.8 vs. 18.24 mg/dl and 1.07 vs. 0.99 mg/dl, respectively). HRS developed more in the control group than the rifaximin group [9 (22.5%) vs. 2 (5%); P=0.048]. In both groups, HRS was precipitated by spontaneous bacterial peritonitis mainly and large volume paracentesis. The Child Pugh score, control group, baseline serum sodium, and creatinine were predictors of HRS. CONCLUSION: Rifaximin may be useful as a primary prevention of HRS. PMID- 28902041 TI - Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results. AB - BACKGROUND: Biological agents, such as infliximab, have transformed the outcomes of patients with immune-mediated inflammatory diseases. The advent of biosimilar treatment options such as CT-P13 promises to improve the availability of biological therapy, yet real-world switching data are currently limited. Here, we assess the effectiveness and safety of switching to CT-P13 from infliximab reference product (RP) in patients with inflammatory bowel disease. MATERIALS AND METHODS: This was a prospective single-center observational study in patients with moderate to severe Crohn's disease (CD) and ulcerative colitis (UC). All patients were switched from infliximab RP (Remicade) to CT-P13 treatment and followed up for up to 12 months. The efficacy endpoint was the change in clinical response assessed at 3-monthly intervals, according to the Harvey-Bradshaw score and partial Mayo score for patients with CD and UC, respectively. C-reactive protein (CRP) was also measured. Adverse events were monitored and recorded throughout the study. RESULTS: A total of 98 patients with inflammatory bowel disease (67 CD/31 UC) were included. A total of 83.6% (56/67) of patients with CD were in remission at the time of the switch and 62.7% were in remission at 12 months. The Harvey-Bradshaw score showed a significant change at 12 months (P=0.007) but no significant change was observed in median CRP at this timepoint (P=0.364). A total of 80.6% (25/31) of patients with UC were in remission at the time of the switch and 65.3% (18/28) were in remission at 12 months. No significant changes in the median partial Mayo score (P=0.058) or CRP (P=0.329) were observed at 12 months. Serious adverse events related to medication were reported in 11 (11.2%) patients. CONCLUSION: Switching from infliximab RP to CT P13 is efficacious and well tolerated in patients with CD or UC for up to 12 months. PMID- 28902043 TI - Need a Quick Ethics Refresher? PMID- 28902042 TI - Performance of a quick pregnancy test on whole blood in early pregnancy units: a prospective cohort study. AB - OBJECTIVE: To assess the diagnostic performance of the NG-Test human chorionic gonadotropin (hCG) WB, which is a new point-of-care (POC) hCG whole-blood test. MATERIALS AND METHODS: This prospective study included women consulted in early pregnancy units for vaginal bleeding and/or pelvic pain with unknown pregnancy status after medical consultation including a pelvic ultrasound scan. A new POC test (the NG-Test hCG WB) and the usual laboratory serum test (considered the gold standard) were performed in patients. The results were interpreted in a blinded manner. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the NG-Test hCG WB. RESULTS: During the study period, 200 patients were included. The pregnancy rate was 17%. For the laboratory test, with a 5 UI/l hCG positivity threshold, the sensitivity, specificity, PPV, NPV, and Youden index of the NG-Test hCG WB were 89.7, 100, 100, 97.9, and 0.90%, respectively. Considering a 10 UI/l hCG positivity threshold, test sensitivity, specificity, PPV, NPV, and Youden index were 96.3, 100, 100, 99.3, and 0.96%, respectively. False-negative cases were either extremely brief pregnancies or residual hCG after miscarriage. The result was obtained within 5 min with the NG-Test hCG WB versus 90+/-31 min with the laboratory test. It was easy to use. CONCLUSION: The NG-Test hCG WB showed a high sensitivity, specificity, PPV, and NPV. Its use as triage in the case of a negative pelvic ultrasound exam is a potential strategy to improve patient flow, with an average time saving of 85 min. PMID- 28902044 TI - NCF @ Work. PMID- 28902045 TI - Etc. PMID- 28902046 TI - Human Personhood & Dignity. PMID- 28902047 TI - Nursing in the Church. PMID- 28902048 TI - Student TXT. PMID- 28902049 TI - Spiritual Alarm Fatigue. PMID- 28902050 TI - Faith and Ethics, Covenant and Code: The 2015 Revision of the ANA Code of Ethics for Nurses with Interpretive Statements. AB - How does and should the American Nurses Association Code of Ethics for Nurses with Interpretive Statements, with foundations from the late 1800s, impact today's nursing practice? How can the Code help you? The earlier 2001 Code was revised and became effective January 2015. The nine provisions received modest revision, as did the corresponding interpretive statements. However, Provisions 8 and 9 and their interpretive statements received more substantial revision. This article explains the Code and summarizes the 2015 revisions, considering points of particular interest for nurses of faith. PMID- 28902051 TI - Hypertension in the Faith Community: A Four-Week, Nurse Led, Diet/Exercise Intervention. AB - Inadequate blood pressure (BP) control in hypertension carries a major financial and public health burden. This study examined the efficacy of behavioral and lifestyle changes on BP control among African American adults, aged 55 years and older in a faith-based setting. The study was supported by clergy who helped to engage participants in interventions. Nurse-led diet and exercise teaching with BP monitoring led to lower BP readings over a 4-week intervention. PMID- 28902052 TI - Overcoming Education Failures and Retakes: A Spiritual Process. AB - The retention of students is a major challenge for nursing education programs. Although students who fail can often retake courses, negative internalities may occur. After a failure, students regularly present with emotional distress. A mental health practitioner, who is a nursing faculty member, is ideal to assist these students and offer support. The integration of spirituality as a coping mechanism for these students can serve as a protective factor. PMID- 28902053 TI - Welcome Day: A Community Interprofessional Model for Meeting the Needs of Migrant Workers. AB - Welcome Day, one specific day in the life of Hartville Migrant Ministry (HMM), a faith-based ministry in Ohio, illustrates the organization's vision, mission, and community collaboration. Migrant and seasonal farm workers, the Migrant Head Start program, HMM and Welcome Day, interprofessional collaboration, and Malone University School of Nursing faculty and students support are discussed. Programs and activities presented here could be reproduced in other communities. PMID- 28902054 TI - Ethical Issues with Genetic Testing for Tay-Sachs. AB - Several genetic disorders are specific to Jewish heritage; one of the most devastating is Tay-Sachs disease.Tay-Sachs is a fatal hereditary disease, causing progressive neurological problems for which there is no cure. Ethical issues surrounding genetic testing for Tay-Sachs within the Jewish community continue to be complex and multifaceted. A perspective of Tay-Sachs, using rights-based ethics and virtue ethics as a theoretical framework, is explored. PMID- 28902055 TI - Poetry, Art, and the Bible. PMID- 28902056 TI - What Are the Spiritual Needs Associated with Grief? PMID- 28902057 TI - Bullying Students Impacts Future Nurses. PMID- 28902059 TI - Resources. PMID- 28902058 TI - Right Time, Right Place. PMID- 28902060 TI - PulseBeats. PMID- 28902061 TI - Student Perspective Improves Spiritual Care Curriculum. AB - Spiritual nursing care is a fundamental aspect of care often unobserved during students' clinical experiences. A nursing student shares her disillusionment about the lack of spiritual care she observed during a clinical rotation. Her instructor used the negative experience to identify areas for curriculum improvement to develop and address the lack of spiritual nursing care education. PMID- 28902062 TI - African American Hemodialysis Patients' Perceptions of Faith and Nursing. AB - Numerous quantitative studies have been conducted with African Americans (AAs) receiving hemodialysis. This article shares a portion of a larger qualitative study that explored the role spirituality plays in the lives of AAs undergoing hemodialysis for management of end-stage renal disease (ESRD). Interview questions centered on the roles of spirituality, health beliefs, and different social support systems used in coping. By understanding the perceptions of AAs with ESRD, nurses and other providers can offer better support. PMID- 28902063 TI - Faith and Ethics, Covenant and Code: The 2015 Revision of the ANA Code of Ethics for Nurses with Interpretive Statements. PMID- 28902064 TI - Hypertension in the Faith Community: A Four-Week, Nurse Led, Diet/Exercise Intervention. PMID- 28902065 TI - Relationship Between Unsupervised Time and Participation in an Emotion Regulation Intervention and Risk Outcomes. AB - OBJECTIVE: This study is a secondary analysis of outcomes examining risk behavior in the context of the naturalistic occurrence of parental monitoring and participation in an emotion regulation intervention over a 12-month period. METHOD: Early adolescents with mental health symptoms (N=420), ages 12-14 years, were recruited and randomized into either an Emotional Regulation (ER) or Health Promotion (HP) condition. Assessments included adolescent self-report of unsupervised time, substance use and sexual behavior at baseline, 6-months, and one year post-intervention. Analytic groups were formed by intervention condition (ER or HP) and baseline reports of unsupervised time (<=1* per week or >1* per week of unsupervised time with opposite sex peers) resulting in a total of four groups. Logistic regression and time-to-event analyses were used to test differences in substance use and delay of sexual initiation between the groups. RESULTS: Participation in the ER intervention in the presence of low unsupervised time was superior in reducing both substance use and sexual initiation than either factor alone; and either factor alone was more effective than the absence of both. CONCLUSION: Findings suggest that interventions targeting health risk behaviors, including substance use and sexual risk behavior, among early adolescents with mental health symptoms may be more effective when targeting both internal (e.g., emotional regulation) and external (e.g., unsupervised time spent with peers) protective factors. Limiting unsupervised time spent with peers through parental monitoring may serve to scaffold and reinforce early adolescent acquisition of effective emotion regulation which can be employed during emotionally arousing risk situations. PMID- 28902066 TI - Latent Class Analysis of ADHD Neurodevelopmental and Mental Health Comorbidities. AB - OBJECTIVE: Many children diagnosed with attention-deficit/hyperactivity disorder (ADHD) experience co-occurring neurodevelopmental and psychiatric disorders, and those who do often exhibit higher levels of impairment than children with ADHD alone. This study provides a latent class analysis (LCA) approach to categorizing children with ADHD into comorbidity groups, evaluating condition expression and treatment patterns in each group. METHODS: Parent-reported data from a large probability-based national sample of children diagnosed with ADHD (2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome) were used for an LCA to identify groups of children with similar groupings of neurodevelopmental and psychiatric comorbidities among children with current ADHD (n = 2495). Differences between classes were compared using multivariate logistic regressions. RESULTS: LCA placed children who were indicated to have ADHD into 4 classes: (low comorbidity [LCM] [64.5%], predominantly developmental disorders [PDD] [13.7%], predominantly internalizing disorders [PID] [18.5%], and high comorbidity [HCM] [3.3%]). Children belonging to the HCM class were most likely to have a combined ADHD subtype and the highest number of impaired domains. Children belonging to the PDD class were most likely to be receiving school services, whereas children in the PID class were more likely to be taking medication than those belonging to the LCM class who were least likely to receive psychosocial treatments. CONCLUSION: Latent classes based on co-occurring psychiatric conditions predicted use of varied treatments. These findings contribute to the characterization of the ADHD phenotype and may help clinicians identify how services could be best organized and coordinated in treating ADHD. PMID- 28902067 TI - Preventing Preschool Mental Health Problems: Population-Based Cluster Randomized Controlled Trial. AB - OBJECTIVE: Prevention of child behavior problems may reduce later mental health problems. We compared the effectiveness, at the population level, of an efficacious targeted prevention program alone or following a universal parenting program. METHODS: Three-arm, cluster randomized controlled trial. One thousand three hundred fifty-three primary caregivers and healthy 8-month-old babies recruited from July 2010 to January 2011 from well-child centers (randomization unit). PRIMARY OUTCOME: Child Behavior Checklist (CBCL) externalizing and internalizing scales* at child ages 3 and 4.5 years. SECONDARY OUTCOMES: Parenting Behavior Checklist* and over-involved/protective parenting (primary caregiver report). Secondary caregivers completed starred measures at age 3. RESULTS: Retention was 76% and 77% at ages 3 and 4.5 years, respectively. At 3 years, intention-to-treat analyses found no statistically significant differences (adjusted mean difference [95% confidence interval (CI); p-value]) for externalizing (targeted vs usual care -0.2 [-1.7 to 1.2; p = .76]; combined vs usual care 0.4 [-1.1 to 1.9; p = .60]) or internalizing behavior problems (targeted vs usual care 0.2 [-1.2 to 1.6; p = .76]; combined vs usual care 0.4 [ 1.1 to 2.0; p = .58]). Primary outcomes were similar at 4.5 years. At 3 years, primary and secondary caregivers reported less over-involved/protective parenting in both the combined and targeted versus usual care arm; secondary caregivers also reported less harsh discipline in the combined and targeted versus usual care arm. Mean program costs per family were A$218 (targeted arm) and A$682 (combined arm). CONCLUSION: When translated to the population level by existing staff, pre-existing programs seemed ineffective in improving child behavior, alone or in combination, but improved parenting. PMID- 28902068 TI - Factors Affecting Suicide Method Lethality Among Suicide Attempters in the Korea National Suicide Survey. AB - This is the first national survey study in South Korea investigating the relationship between suicide lethality and the clinical information of suicide attempters. An interview questionnaire was used to assess their sociodemographic factors, medical and psychiatric information, and two suicide scales, the Columbia-Suicide Severity Rating Scale and the Suicide Intent Scale. Suicide methods were categorized as low and high lethality; low lethality covered drug overdose or self-cutting behavior, and high lethality covered all other methods. High and low lethality suicide method groups were significantly different in demographic, medical, and psychiatric factors. The two scale score distributions differed significantly across two groups, and the difference was also valid for the subcategory analyses of the Suicide Intent Scale. Multiple factors such as older age, male sex, no previous psychiatric history, and previous suicide attempt, as well as high suicide intent by means of suicide scale, affect selection of suicide method of high lethality. PMID- 28902069 TI - Anti-Inflammatory Strategies in Intrahepatic Islet Transplantation: A Comparative Study in Preclinical Models. AB - BACKGROUND: The identification of pathway(s) playing a pivotal role in peritransplant detrimental inflammatory events represents the crucial step toward a better management and outcome of pancreatic islet transplanted patients. Recently, we selected the CXCR1/2 inhibition as a relevant strategy in enhancing pancreatic islet survival after transplantation. METHODS: Here, the most clinically used anti-inflammatory compounds (IL1-receptor antagonist, steroids, and TNF-alpha inhibitor) alone or in combination with a CXCR1/2 inhibitor were evaluated in their ability to improve engraftment or delay graft rejection. To rule out bias related to transplantation site, we used well-established preclinical syngeneic (250 C57BL/6 equivalent islets in C57BL/6) and allogeneic (400 Balb/c equivalent islets in C57BL6) intrahepatic islet transplantation platforms. RESULTS: In mice, we confirmed that targeting the CXCR1/2 pathway is crucial in preserving islet function and improving engraftment. In the allogeneic setting, CXCR1/2 inhibitor alone could reduce the overall recruitment of transplant-induced leukocytes and significantly prolong the time to graft rejection both as a single agent and in combination with immunosuppression. No other anti-inflammatory compounds tested (IL1-receptor antagonist, steroids, and TNF-alpha inhibitor) alone or in combination with CXCR1/2 inhibitor improve islet engraftment and significantly delay graft rejection in the presence of MMF + FK 506 immunosuppressive treatment. CONCLUSIONS: These findings indicate that only the CXCR1/2-mediated axis plays a crucial role in controlling the islet damage and should be a target for intervention to improve the efficiency of islet transplantation. PMID- 28902070 TI - Contending With Preplanned Death: Questions for Clinicians. AB - BACKGROUND AND OBJECTIVES: The goal of this column is to assist readers in reflecting on their attitudes and responses toward clinical and nonclinical situations involving preplanned deaths by decisionally capable individuals. Such circumstances range from encountering individuals in one's personal and professional lives who desire and intend to end their lives under their own terms, to having such individuals request assistance with predeath and postdeath arrangements. METHODS: Attending to pertinent literature, this essay uses Socratic inquiry to question conventional assumptions and attitudes, push readers' thoughts beyond typical comfort zones, and consider alternative modes of responding to challenges posed by preplanned death. RESULTS: Studies indicate that, for their own end-of-life circumstances, physicians would prefer a briefer, higher quality life to prolonged low-quality life, dignity in infirmity and death, and avoidance of terminal suffering. Lay people generally endorse similar preferences. Although contemporary society generally shuns contemplating preplanned death, cultural attitudes regarding preplanned death are rapidly evolving, and variations of "Death with Dignity" legislation have gained traction in increasing numbers of US states as well as internationally. As yet, no broad consensus exists as to how clinicians should manage circumstances involving preplanned death. CONCLUSIONS: Considerations regarding preplanned deaths merit greater professional and public discussion. Many options exist for improving how professionals address the quality of human experiences surrounding death. PMID- 28902071 TI - Importance of Risk Perception: Predictors of PrEP Acceptance Among Thai MSM and TG Women at a Community-Based Health Service. AB - BACKGROUND: HIV prevalence among Thai men who have sex with men (MSM) and transgender women (TG) are 9.15% and 11.8%, respectively, compared with 1.1% in the general population. To better understand early adopters of pre-exposure prophylaxis (PrEP) in Thailand, we analyzed biobehavioral and sociodemographic characteristics of PrEP-eligible MSM and TG. SETTING: Four Thai urban community clinics between October 2015 and February 2016. METHODS: Sociodemographics, HIV risk characteristics, and PrEP knowledge and attitudes were analyzed in association with PrEP initiation among eligible Thai MSM and TG. Adjusted analysis explored factors associated with PrEP acceptance. We then analyzed HIV risk perception, which was strongly associated with PrEP initiation. RESULTS: Of 297 participants, 55% accepted PrEP (48% of MSM, 54% of TG). Perceived HIV risk levels were associated with PrEP acceptance [odds ratio (OR): 4.3; 95% confidence interval (95% CI): 1.5 to 12.2. OR: 6.3; 95% CI: 2.1 to 19.0. OR: 14.7; 95% CI: 3.9 to 55.1; for minimal, moderate, and high perceived risks, respectively]. HIV risk perception was associated with previous HIV testing (OR: 2.2; 95% CI: 1.4 to 3.5); inconsistent condom use (OR: 1.8; 95% CI: 1.1 to 2.9); amphetamine use in the past 6 months (OR: 3.1; 95% CI: 1.1 to 8.6); and uncertainty in the sexually transmitted infection history (OR: 2.3; 95% CI: 1.4 to 3.7). Approximately half of those who reported either inconsistent condom use (46%), multiple partners (50%), group sex (48%), or had baseline bacterial sexually transmitted infection (48%) perceived themselves as having no or mild HIV risk. CONCLUSIONS: HIV risk perception plays an important role in PrEP acceptance. Perception does not consistently reflect actual risk. It is therefore critical to assess a client's risk perception and provide education about HIV risk factors that will improve the accuracy of perceived HIV risk. PMID- 28902072 TI - HIV Transmission Dynamics Among Foreign-Born Persons in the United States. AB - BACKGROUND: In the United States (US), foreign-born persons are disproportionately affected by HIV and differ epidemiologically from US-born persons with diagnosed HIV infection. Understanding HIV transmission dynamics among foreign-born persons is important to guide HIV prevention efforts for these populations. We conducted molecular transmission network analysis to describe HIV transmission dynamics among foreign-born persons with diagnosed HIV. METHODS: Using HIV-1 polymerase nucleotide sequences reported to the US National HIV Surveillance System for persons with diagnosed HIV infection during 2001-2013, we constructed a genetic distance-based transmission network using HIV-TRACE and examined the birth region of potential transmission partners in this network. RESULTS: Of 77,686 people, 12,064 (16%) were foreign born. Overall, 28% of foreign-born persons linked to at least one other person in the transmission network. Of potential transmission partners, 62% were born in the United States, 31% were born in the same region as the foreign-born person, and 7% were born in another region of the world. Most transmission partners of male foreign-born persons (63%) were born in the United States, whereas most transmission partners of female foreign-borns (57%) were born in their same world region. DISCUSSION: These finding suggests that a majority of HIV infections among foreign-born persons in our network occurred after immigrating to the United States. Efforts to prevent HIV infection among foreign-born persons in the United States should include information of the transmission networks in which these individuals acquire or transmit HIV to develop more targeted HIV prevention interventions. PMID- 28902073 TI - Cryotherapy Reduces Progression of Cervical Intraepithelial Neoplasia Grade 1 in South African HIV-Infected Women: A Randomized, Controlled Trial. AB - BACKGROUND: HIV-infected women are at an increased risk of cervical cancer, especially in resource-limited countries. Cervical cancer prevention strategies focus treating cervical high-grade squamous intraepithelial lesions (HSIL). The management of low-grade squamous intraepithelial lesions (LSIL) in HIV-infected women is unknown. SETTING: HIV treatment clinic in Johannesburg, South Africa. METHODS: We randomized HIV-infected women with histologic cervical LSIL to cervical cryotherapy vs. no treatment (standard of care). Cervical high-risk human papillomavirus testing (hrHPV) was performed at baseline. All women underwent cervical cytology and colposcopic biopsies 12 months after enrollment. The primary end point was HSIL on histology at month 12. Chi-square was used to compare arms. RESULTS: Overall, 220 HIV-infected women were randomized to cryotherapy (n = 112) or no treatment (n = 108). Median age was 38 years, 94% were receiving antiretroviral therapy; median CD4 was 499 cells per cubic millimeter, and 59% were hrHPV positive. Cryotherapy reduced progression to HSIL: 2/99 (2%) in the cryotherapy arm and 15/103 (15%) in the no treatment arm developed HSIL, 86% reduction (95% confidence interval: 41% to 97%; P = 0.002). Among 17 HSIL end points, 16 were hrHPV+ at baseline. When restricting the analysis to hrHPV+ women, HSIL occurred in 2/61 (3%) in the cryotherapy arm vs. 14/54 (26%) in the no treatment arm, 87% reduction (95% confidence interval: 47% to 97%; P = 0.0004). Participants in the cryotherapy arm experienced greater regression to normal histology and improved cytologic outcomes. CONCLUSIONS: Treatment of cervical LSIL with cryotherapy decreased progression to HSIL among HIV-infected women especially if hrHPV positive. These results support treatment of LSIL in human papillomavirus test-and-treat approaches for cervical cancer prevention in resource-constrained settings. PMID- 28902075 TI - Hypocalcemic Tetany After Transfusion of a Small Amount of Blood Product. PMID- 28902074 TI - Plasma Tenofovir Levels to Support Adherence to TDF/FTC Preexposure Prophylaxis for HIV Prevention in MSM in Los Angeles, California. AB - BACKGROUND: Tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) is effective against HIV acquisition when taken as prescribed. Strategies that identify and intervene with those challenged by adherence to daily medication are needed. SETTING: PATH-PrEP was an open-label single-arm interventional cohort study conducted at 2 community-based clinical sites in Los Angeles, CA. METHODS: We enrolled self-identified men who have sex with men and transgender women >=18 years of age at an elevated risk of HIV acquisition. Participants received a postexposure prophylaxis (PEP)-based or PrEP-based HIV prevention package for at least 48 weeks. Plasma tenofovir levels from each PrEP visit assessed as below the limit of quantitation (<10 ng/mL) triggered increased adherence support. RESULTS: Three hundred one participants enrolled. Forty-eight week retention in the PrEP cohort was 75.1%. Biomarker evidence of PrEP adherence consistent with >=4 doses per week at weeks 4, 12, 24, 36, and 48 was found in 83.1%, 83.4%, 75.7%, 71.6%, and 65.5% of participants, respectively; younger and African American participants were less likely to have protective drug levels. Most of those with suboptimal adherence had adherence improvement after brief intervention. One seroconversion occurred in a participant who discontinued PrEP. Nearly half (46.4%) of participants were diagnosed with at least 1 incident sexually transmitted infection during 48 weeks of study follow-up. CONCLUSIONS AND RELEVANCE: PrEP was acceptable and well tolerated in a diverse population of men who have sex with men in Los Angeles. A brief intervention triggered from biomarkers of poor adherence was associated with improved adherence. Drug level monitoring has the potential to allow targeting of additional adherence support to those struggling with daily tablet adherence. PMID- 28902076 TI - Therapy-related Acute Leukemia With Mixed Phenotype and Novel t(1: 6)(q25;p23) After Treatment for High-risk Neuroblastoma. AB - Neuroblastoma is the most common extracranial malignancy of childhood. Patients with high-risk disease receive multimodal treatment including chemotherapy combinations containing alkylating agents and topoisomerase inhibitors with potential for inducing therapy-related malignancy later in life. Most commonly, cytogenetic changes of pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia involve chromosome 5 or 7. Here we report a novel case of therapy-related myelodysplastic syndrome/acute myeloid leukemia 30 months after treatment for high-risk neuroblastoma with biphenotypic cell surface markers and a not yet described translocation t(1;6)(q25;p23). PMID- 28902077 TI - Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome in a Child With Klinefelter Syndrome. PMID- 28902078 TI - Squamous Cell Carcinoma With Hyper-IgE Syndrome: A Case Report. AB - BACKGROUND: Hyper-immunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disease characterized by recurrent infections and elevated levels of serum immunoglobulin E, usually over 2000 IU/mL. Recurrent and chronic infection of the epidermis and squamous epithelium may also be a cause of squamous cell carcinoma (SCC). SCC is rare with HIES. CASE REPORT: A 17-year-old male patient who was diagnosed as HIES was admitted with purulent right ear discharge. The patient had a history of eczema starting from the age of 7 months and a history of recurrent middle ear infection starting from the age of 5. Biopsy specimens were taken from the lesion in the external auditory canal, and the lesion was reported as SCC. CONSLUSION: Patients with autosomal recessive HIES are at an increased risk for infections and malignancies. SCC should be considered in the differential diagnosis of the patients presenting with recurrent middle ear infections and immunodeficiency. PMID- 28902079 TI - Concomitant Administration of High-dose Methotrexate and Low-dose Aspirin Without Any Delay in Methotrexate Clearance in a Patient With Osteosarcoma: A Case Report and Review of the Literature. AB - BACKGROUND: Methotrexate (MTX) is a commonly used agent in the treatment of oncology patients whose clearance depends on renal health maintaining glomerular filtration and tubular secretion. Thus concomitant use of other drugs that utilize the same mechanism of clearance are generally avoided as this may contribute to increased MTX-associated toxicity. OBSERVATION: Herein, we describe the use of low-dose aspirin with high-dose MTX in a patient with osteosarcoma. CONCLUSION: Concomitant aspirin use did not affect the clearance of high-dose MTX and the patient did not experience any MTX-related toxicity including mucositis or renal impairment. PMID- 28902080 TI - Cutaneous Melanoma in Association With Ichthyosis Vulgaris. PMID- 28902081 TI - Activated Partial Thromboplastin Time versus Anti-Factor Xa Levels for Monitoring Unfractionated Heparin Therapy in Children: An Institutional Experience. PMID- 28902082 TI - Contrast-enhanced 3-dimensional Fluid-attenuated Inversion Recovery Sequences Have Greater Sensitivity for Detection of Leptomeningeal Metastases in Pediatric Brain Tumors Compared With Conventional Spoiled Gradient Echo Sequences. AB - Postcontrast 3-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequences have reduced vascular and flow-related artifacts and high sensitivity to low gadolinium concentrations. We compared the performance of postcontrast spoiled gradient echo images to 3D-FLAIR in the detection of leptomeningeal metastases in 47 pediatric patients with brain tumors. We found 10 cases with more leptomeningeal signal abnormalities on 3D-FLAIR. Overall there were significantly more lesions on 3D-FLAIR than spoiled gradient echo sequences. We believe the increased detection of leptomeningeal signal abnormality is due to increased sensitivity for low concentrations of gadolinium in regions of early blood brain barrier breakdown. Our study was limited by the lack of leptomeningeal metastases in cerebrospinal fluid sampling. We plan to conduct future studies which will determine whether the time-based concentration of gadolinium affects the performance and results. Future studies will also require more cases of pathology-proven leptomeningeal disease. PMID- 28902083 TI - Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li Fraumeni Syndrome Having a Germline TP53 D49H Mutation. AB - Germline mutations in TP53 are the primary cause of Li-Fraumeni syndrome (LFS). Most mutations are reported within the DNA-binding domain. We report a case of a 15-year-old boy with LFS who developed early-stage nodular lymphocyte-predominant Hodgkin lymphoma, a rare subtype of Hodgkin lymphomas. His sister was diagnosed with embryonal rhabdomyosarcoma at the age of 1.5 years. Sequence analysis revealed a germline mutation in the transactivation domain of TP53, c.145G>C (p.D49H), in the patient, his sister, and father. One family with LFS with a germline TP53 D49H mutation has previously been reported. This report supports the pathogenicity of this mutation. PMID- 28902084 TI - Children and Adolescent Hodgkin Lymphoma in Argentina: Long-term Results After Combined ABVD and Restricted Radiotherapy. AB - OBJECTIVE: Prospective analysis of clinical characteristics and long-term treatment results of a pediatric cohort with Hodgkin lymphoma (HL) treated in a single institution with ABVD and restricted radiotherapy (RT). PATIENTS AND METHODS: Between September 2000 and December 2015, 165 new consecutive assessable patients with HL were registered at our institution. Lymphocyte predominant nodular HL was excluded. Low risk (LR) patients were stage I and IIA (no bulky disease, <4 involved ganglionar areas and no lung hilar nodes), high risk (HR) was assigned to stage IV and any other stage with bulky mediastinum. The rest of the cohort was treated as intermediate risk (IR). Chemotherapy for LR and IR patients was 4 and 6 courses of ABVD regimen, respectively. These subsets received Low-dose involved field radiotherapy only in case of partial remission at the end of chemotherapy (21 Gy in initially involved areas, plus 14 Gy boost on residual disease). The HR group was treated with 6 courses of ABVD followed always with 21 Gy involved field radiotherapy if complete remission (CR) was achieved. A boost of 14 Gy was added to residual disease in case of partial remission. RESULTS: Median age was 10.6 years (range, 2.7 to 17 y). Males: 117 (71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76 (46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine (30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%) to HR. Forty-three patients (26%) had "bulky" mediastinum involvement. One hundred thirty (79%) patients achieved CR after chemotherapy and 161 (98%) after RT. Four patients (all HR), did not respond to initial therapy and died of disease. One patient died in first CR due to adenovirus infection on previously therapy-related damaged lungs. Seventeen (10%) patients relapsed and 13 of them remained in second CR after further therapy. Seventy-six (46%) patients could be spared from RT and cured of disease (88% of LR patients and 67% of IR patients). With a median follow-up of 5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95 (SE: 0.02), respectively. Overall survival according to risk group was 1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late effects due to therapy were not significant. CONCLUSIONS: The strategy of avoiding RT for LR and IR patients that responded completely to ABVD chemotherapy achieved very good results. For the HR group, the combination of 6 cycles of ABVD and Low-dose involved field radiotherapy was efficacious with similar good results. Nearly half of the patients could be cured without RT. PMID- 28902085 TI - Proximal Screw Configuration Alters Peak Plate Strain Without Changing Construct Stiffness in Comminuted Supracondylar Femur Fractures. AB - OBJECTIVES: Assess the effect of proximal screw configuration on the strain in lateral plating of a simulated comminuted supracondylar femur fracture. METHODS: Fractures were simulated in 12 synthetic femurs by removing a 200-mm section of bone, located 60 mm from the intercondylar fossa and repaired using a 16-hole locked lateral plate instrumented with 8 uniaxial strain gauges. Three proximal screw type configurations were evaluated: (1) 4 nonlocking screws, (2) 4 locking screws, and (3) a hybrid configuration of 2 nonlocking screws flanked by a locking screw at each end of the proximal fragment. Each screw type was compared for 2 working lengths (~90 and 160 mm). The longer working length was created by removing the proximal screw closest to the fracture gap. Testing consisted of a vertical load (500 N) applied to the head of femur. Configurations were compared using plate strain, construct stiffness, and fracture gap displacement as outcome measures. RESULTS: Plate strain immediately above the fracture gap was reduced with nonlocking screws compared with the other screw types. Plate strains were reduced around the fracture gap with the longer working length but increased for the nonlocking construct at the location of the removed screw. Construct stiffness was not altered by screw type or working length. An increase in fracture gap displacement was only evident in shear translation with the longer working length. CONCLUSIONS: Plate strain in lateral plating of supracondylar femur fractures is decreased using nonlocking screws proximal to the fracture. Increasing the working length reduces plate strains over the working length yet should be cautioned because of increased interfragmentary shear motion. PMID- 28902086 TI - Operative Stabilization of Flail Chest Injuries Reduces Mortality to That of Stable Chest Wall Injuries. AB - OBJECTIVE: To determine the prevalence, management and outcomes of patients with flail chest injuries, compared to patients without flail chest injuries (single rib fractures and multiple rib fractures without a flail segment). DESIGN: Retrospective cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Ontario residents over the age of 16 years who had been admitted to hospital with a chest wall injury from 2004 to 2015 were identified using administrative health care databases. MAIN OUTCOME MEASUREMENTS: Outcomes included treatment modalities such as rate of surgical repair, days on mechanical ventilation, days in the intensive care unit, days in hospital, rate of chest tube placement; and rates of complication, including pneumonia, tracheostomy, readmission, and death. RESULTS: In total 117,204 patients with fractures of the chest wall were identified. Of the entire cohort, 1.5% of them had a flail chest injury, 41% had multiple rib fractures, and 58% had single rib fractures. Patients with flail chest injuries had significantly worse outcomes compared to patients with multiple rib fractures in all categories (P < 0.0001). Similarly, patients with multiple rib fractures had significantly worst outcomes compared with patients with single rib fractures (P < 0.0001). Only 4.5% of patients with flail chest injuries were treated surgically, however, the number increased from 1% before 2010 to 10% after 2010 (P < 0.0001). After adjustment for potential confounders, patients with flail chest injuries treated surgically had a reduced risk of early mortality compared to those treated nonoperatively (OR 0.16, P = 0.019). CONCLUSIONS: Surgical stabilization of flail chest injuries has increased significantly in recent years. The results of this study provide preliminary evidence that the increasing rate of surgical intervention may be warranted by reducing mortality. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28902087 TI - Invited Commentary related to: Any Cortical Bridging Predicts Healing of Supracondylar Femur Fractures After Treatment With Locked Plating. PMID- 28902088 TI - Obesity Increases Risk of Loss of Reduction After Casting for Diaphyseal Fractures of the Radius and Ulna in Children: An Observational Cohort Study. AB - OBJECTIVES: To determine if high body mass index (BMI) increases the risk of loss of reduction (LOR) following closed reduction and casting for displaced concomitant fractures of the radial and ulnar shafts in pediatric patients. DESIGN: Retrospective cohort study. SETTING: A single, tertiary care, urban children's hospital. PATIENTS/PARTICIPANTS: Pediatric patients 2-18 years of age with closed, displaced, concomitant diaphyseal fractures of the radius and ulna (OTA/AO 22-A3) who underwent closed reduction and casting at the study site. MAIN OUTCOME MEASURES: BMI percentile of >=95 was defined as obese. For nonobese patients, BMI percentile of >=85 was defined as overweight. BMI percentile category, fracture angulation, sex, age, fracture location, and number of follow up visits were recorded. Radiographs and health records were reviewed to note clinical and radiographic cases of LOR. The primary outcome was LOR (clinical or radiographic). RESULTS: Overall, 124 subjects (74 male and 50 female subjects) underwent acceptable closed reduction and casting. Median patient age was 7.6 years (range, 2.2-17.8 years). There were 14 cases of LOR. LOR rates were 7.2%, 16.7%, and 44.4% for the nonoverweight, overweight, and obese cohorts, respectively (P = 0.005). Regression analysis revealed that LOR was positively associated with higher BMI category (odds ratio for overweight 4.49; P = 0.082; odds ratio for obese 7.52; P = 0.020) and patient age in years (odds ratio, 1.38; P = 0.001). CONCLUSIONS: Given the high risk of LOR in overweight and obese children with displaced concomitant fractures of the radial and ulnar shafts, our findings suggest that attentive and frequent follow-up is warranted. In these patients, the initial reduction should be closely scrutinized, and a lower threshold for surgical fixation may be considered. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28902089 TI - New Insights in Vanishing White Matter Disease: Isolated Bilateral Optic Neuropathy in Adult Onset Disease. AB - BACKGROUND: Vanishing white matter disease (VWMD) is a rare disease affecting cerebral white matter. The adult form is even rarer and manifests with motor symptoms, behavioral problems, and dementia. There is no treatment and progression is inevitable. We describe a case with atypical manifestations and an unusual course. METHODS: Description of a 42-year-old man with VWMD complaining of progressive visual loss in the right eye. RESULTS: The patient's visual acuity was 20/60, right eye, and 20/25, left eye, with pale optic nerves bilaterally. MRI showed atrophy of the corpus callosum, diffuse rarefaction of cerebral white matter including the anterior and posterior visual pathways. CONCLUSION: Our patient had no further symptoms besides loss of visual acuity, which is rare in patients with VWMD of the same age and genetic mutation. PMID- 28902091 TI - Neuropathic Pain as Potential Source of Feed-induced Dystonia in Children With Severe Central Nervous System Disorders. PMID- 28902090 TI - Endocrine Mucin-Producing Sweat Gland Carcinoma of the Eyelid Associated With Mucinous Adenocarcinoma. AB - Endocrine mucin-producing sweat gland carcinoma, a rare, low-grade neoplasm with predilection for the eyelids, has been posited as a precursor to invasive mucinous adenocarcinoma. Endocrine mucin-producing sweat gland carcinoma and its concurrence with mucinous adenocarcinoma have received little attention in the ophthalmic literature. The combination of the 2 histologic patterns parallels endocrine ductal carcinoma in situ of the breast and its transition to Type B invasive mucinous carcinoma. The authors describe a 59-year-old man who developed a tumor of the right upper eyelid showing endocrine mucin-producing sweat gland carcinoma in the outer dermis and extensive mucinous carcinoma in the deeper tissue. Immunohistochemical analysis showed positivity for endocrine markers chromogranin, synaptophysin, CD56, estrogen, and progesterone in each histologic component of the tumor. This research was conducted in conformity with the Helsinki Declaration and HIPPA regulations. PMID- 28902092 TI - Drugs for Neuropathic Pain Are Promising in Treating Feed-induced Dystonia in Central Nervous System Disabled Children. PMID- 28902093 TI - Bile Acid Synthesis Disorders in Arabs: A 10-year Screening Study. AB - OBJECTIVES: Early diagnosis of bile acid synthesis disorders (BASDs) is important because, untreated, these conditions can be fatal. Our objectives were to screen children with cholestasis or unexplained liver disease for BASD and in those with confirmed BASD to evaluate the effectiveness of cholic acid therapy. METHODS: A routine serum total bile acid measurement was performed on children with cholestasis, liver cirrhosis, and liver failure. Patients were screened for BASD by fast atom bombardment ionization-mass spectrometry (FAB-MS) analysis of urine, and molecular analysis confirmed diagnosis. Treatment response to oral cholic acid (10-15 mg/kg bw/day) was assessed from liver function tests and fat-soluble vitamin levels. FAB-MS analysis of urine was used to monitor compliance and biochemical response. RESULTS: Between 2007 and 2016, 626 patients were evaluated; 450 with infantile cholestasis. Fifteen cases of BASD were diagnosed: 12 presented with infantile cholestasis (2.7%, 7 boys), an 8-year-old boy presented with cirrhosis, and two 18-month-old boys presented with hepatomegaly and rickets. Eleven were caused by 3beta-hydroxy-Delta-C27-steroid oxidoreductase dehydrogenase deficiency, 3 from Delta-3-oxosteroid 5beta-reductase deficiency, and 1 had Zellweger spectrum disorder. In all but 1, serum total bile acids were normal or low. With cholic acid therapy, 10 are alive and healthy with their native liver. Liver failure developed in 3 infants despite therapy; 2 died and 1 underwent liver transplantation. CONCLUSIONS: BASDs are rare but treatable causes of metabolic liver disease in Saudi Arabia. BASD should be considered in infants with cholestasis and low or normal serum total bile acid concentrations. PMID- 28902095 TI - DETECTION OF TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION BY SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To compare the detection rate of choroidal neovascularization (CNV) in treatment-naive neovascular age-related macular degeneration by swept source optical coherence tomography angiography (SS-OCTA, Topcon's DRI Triton) working at 1,050 nm wavelength versus fluorescence angiography. METHODS: Cross-sectional analysis of 156 eyes (107 neovascular age-related macular degeneration and 49 dry AMD) in 98 patients, previously diagnosed by multimodal imaging using fluorescein (FA) and indocyanine green angiography (Heidelberg's Spectralis) in a tertiary retina center, evaluated by SS-OCTA 4.5 mm * 4.5 mm and 6 mm * 6 mm macular cubes. Main outcome measures were sensitivity and specificity of SS-OCTA in AMD. Potential factors influencing CNV detection rate were analyzed. RESULTS: Swept source optical coherence tomography angiography detected CNV in 81 of 107 eyes, resulting in a sensitivity of 75.7%. In 49 eyes with dry AMD, no CNV could be identified (specificity 100%). A statistical significance was calculated for nondetection of treatment-naive CNV by SS-OCTA in pigment epithelial detachment over 400 MUm (P = 0.0238). CONCLUSION: Topcon's SS-OCTA was not able to detect all CNV lesions. Large pigment epithelial detachments were associated with signal loss. Fluorescence angiography still remains the gold standard, but the tested SS OCTA device can be considered as a feasible additional diagnostic tool in AMD. PMID- 28902094 TI - Reference values for fluorine-18-fluorodeoxyglucose and fluorine-18-sodium fluoride uptake in human arteries: a prospective evaluation of 89 healthy adults. AB - OBJECTIVE: Reference values of fluorine-18-fluorodeoxyglucose (F-FDG) and fluorine-18-sodium fluoride (F-NaF) uptake in human arteries are unknown. The aim of this study was to determine age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake. PARTICIPANTS AND METHODS: Uptake of F-FDG and F NaF was determined in the ascending aorta, aortic arch, and descending thoracic aorta. In addition, F-FDG uptake was determined in the carotid arteries and F-NaF uptake was determined in the coronary arteries. Arterial F-FDG and F-NaF uptake were quantified as the blood pool subtracted maximum activity concentration in kBq/ml (BS F-FDGmax and BS F-NaFmax, respectively). In addition to determining reference values, we evaluated the influence of age and sex on BS F-FDGmax and BS F-NaFmax. RESULTS: Arterial F-FDG and F-NaF uptake was assessed in 89 healthy adults aged 21-75 years (mean age: 44+/-14 years, 53% men). Both BS F-FDGmax and BS F-NaFmax increased with age. BS F-FDGmax increased with age in the descending aorta (beta=0.28; P=0.003), whereas BS F-NaFmax increased with age in the ascending aorta (beta=0.18; P<0.001), aortic arch (beta=0.19; P=0.006), descending aorta (beta=0.33; P<0.001), and coronary arteries (beta=0.20; P=0.009), respectively. BS F-FDGmax and BS F-NaFmax were not influenced by sex, except for BS F-FDGmax in the ascending aorta. CONCLUSION: Prospective evaluation of 89 healthy adults generated age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake. Our findings indicate that arterial F-FDG and F NaF uptake tend to increase with age. PMID- 28902096 TI - ASSOCIATIONS BETWEEN INDIVIDUAL RETINAL LAYER THICKNESSES AND DIABETIC PERIPHERAL NEUROPATHY USING RETINAL LAYER SEGMENTATION ANALYSIS. AB - PURPOSE: To evaluate clinical correlations between the thicknesses of individual retinal layers in the foveal area of diabetic patients and the presence of diabetic peripheral neuropathy (DPN). METHODS: This retrospective, observational, cross-sectional study enrolled a total of 120 eyes from 120 patients. The eyes were divided into 3 groups: normal controls (n = 42 eyes), patients with diabetes mellitus (n = 42 eyes) but no DPN, and patients with diabetes mellitus and DPN (n = 36 eyes). The primary outcome measures were the thickness of all retinal layers in the central 1-mm zone measured using the segmentation analysis of spectral domain optical coherence tomography. Correlations between the thicknesses of the individual retinal layers and the presence of DPN were also analyzed. Logistic regression analyses were used to determine which change in layer thickness had the most significant association with the presence of DPN. RESULTS: The mean thicknesses and the ratios of retinal nerve fiber layers to total retina thicknesses in the DPN group were 10.77 +/- 1.79 MUm and 4.10 +/- 0.55%, which was significantly lower than those in normal controls and the diabetes mellitus with no DPN group (P = 0.014 and P = 0.001, respectively). Logistic regression analyses also showed that the decrease in thicknesses of the retinal nerve fiber layers and the inner nuclear layer are significant factors for predicting a higher risk for DPN development (odds ratio = 7.407 and 1.757; P < 0.001 and P = 0.001, respectively). CONCLUSION: A decrease in the retinal nerve fiber layer and the inner nuclear layer thickness was significantly associated with the presence of DPN. PMID- 28902097 TI - RETINAL MICROVASCULATURE AND VISUAL ACUITY AFTER INTRAVITREAL AFLIBERCEPT IN EYES WITH CENTRAL RETINAL VEIN OCCLUSION: An Optical Coherence Tomography Angiography Study. AB - PURPOSE: To investigate vascular perfusion and foveal avascular zone area in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) after intravitreal aflibercept therapy in central retinal vein occlusion eyes and their association with best-corrected visual acuity. METHODS: Thirty-five subjects with central retinal vein occlusion and macular edema were evaluated. After macular edema resolution following intravitreal aflibercept, subjects underwent optical coherence tomography angiography to measure SCP and DCP perfusion and the foveal avascular zone within a 3 * 3-mm area. Correlations between best-corrected visual acuity and optical coherence tomography angiography measurements were examined. RESULTS: After intravitreal aflibercept therapy, mean retinal vascular area was 3.41 +/- 0.74 mm in the SCP and 3.25 +/- 0.91 mm in the DCP. Foveal avascular zone area was 1.03 +/- 1.04 mm in the SCP and 1.78 +/- 1.73 mm in the DCP. Improved best-corrected visual acuity was significantly associated with better SCP and DCP perfusion (both P < 0.001) and with smaller SCP and DCP foveal avascular zone areas (both P < 0.001). Additionally, SCP and DCP perfusion were negatively correlated with macular edema before treatment (P < 0.05) and ischemia (determined via pretreatment fluorescein angiography, P < 0.05), and positively correlated with photoreceptor integrity (P < 0.001). CONCLUSION: Patients with better retinal perfusion and less retinal ischemia are associated with better visual outcomes after aflibercept in eyes with central retinal vein occlusion. PMID- 28902100 TI - Point of View. PMID- 28902098 TI - Repair of the Thumb Ulnar Collateral Ligament With Suture Tape Augmentation. AB - One of the most commonly injured structures of the thumb metacarpophalangeal (MCP) joint is the ulnar collateral ligament (UCL). An acute injury of this ligament is often amenable to primary repair. Despite the favorable outcomes of primary repair, the thumb is often restricted during initial healing of the ligament with immobilization and delayed rehabilitation. We present a novel technique to augment the repair of the UCL with suture tape to provide immediate biomechanical support and strength during the critical time of ligament healing. We describe the surgical technique of suture tape augmentation for thumb UCL repair. At the ulnar aspect of the thumb MCP joint, a longitudinal midaxial incision is made. Subsequently, the adductor pollicis aponeurosis and extensor mechanism are identified, incised, and retracted. The UCL is exposed and usually torn off the volar-ulnar base of the proximal phalanx. A 2.5-mm PushLock anchor loaded with 1.3-mm SutureTape and 3-0 FiberWire suture, is placed into a hole at the volar-ulnar base of the proximal phalanx after preparation with a 1.8-mm drill bit. The 3-0 FiberWire is used for direct repair of the ligament. Both tails of the 1.3-mm SutureTape is then brought proximally over the ligament and loaded into a 3.5-mm SwiveLock anchor. A 3.2-mm drill bit is then used to make a hole at the ulnar aspect of the metacarpal head, just proximal to the attachment of the proximal UCL. With the thumb MCP joint held in at least 30 degrees of flexion, the tape-loaded 3.5-mm SwiveLock anchor is inserted into metacarpal head. Reinforcement of the repair is then carried out with fine absorbable suture to surrounding capsular tissue. We present a representative case of a professional basketball player treated with this novel procedure. After the surgical repair, the patient was placed in a plaster splint for 3 days to immobilize the thumb and wrist. At 3 days postsurgery, the splint was removed and therapy initiated. Practice drills were initiated at 1 week postsurgery with the use of a removable hand-based thumb spica custom splint. During the entire postoperative period, the left thumb MCP joint had excellent stability to radial stress at full extension and 30 degrees of flexion. In addition, at 3 weeks postsurgery, the patient was able to oppose the thumb tip to the palmar-digital crease of the small finger and MCP joint motion was 0 to 50 degrees. The patient began strengthening exercises at this time, along with the ability to participate in all position-specific drills. At 5 weeks postsurgery, the patient was cleared to return to full play, without use of a splint. At 37 days postsurgery, the patient returned to competitive play. During competitive play, the player completed the entire remaining season of 25 games as well as extended competition into the playoffs of 7 games without further incident or time missed. At the latest follow-up, the patient is 6 months postprocedure and continues to remain asymptomatic with full participation in playing sports. During the critical time of ligament healing, the UCL repair can be enhanced with synthetic material to obviate the need for prolonged postoperative immobilization. We offer a novel surgical technique that enhances primary repair of the thumb UCL through appended biomechanical support. Under these circumstances, with structural support augmentation, the recovery and rehabilitation process can be expedited for patients to allow an earlier return to activities. PMID- 28902101 TI - Early Ambulation Decreases Length of Hospital Stay, Perioperative Complications and Improves Functional Outcomes in Elderly Patients Undergoing Surgery for Correction of Adult Degenerative Scoliosis. AB - STUDY DESIGN: Ambispective cohort review. OBJECTIVE: To examine the effects of early mobilization on patient outcomes, complications profile, and 30-day readmission rates. SUMMARY OF BACKGROUND DATA: Prolonged immobilization after surgery can result in functional decline and an increased risk of hospital associated complications. METHODS: We conducted an ambispective study of 125 elderly patients (>65 years) undergoing elective spinal surgery for correction of adult degenerative scoliosis. We identified all unplanned readmissions within 30 days of discharge. Unplanned readmissions were defined to have occurred as a result of either a surgical or a nonsurgical complication. "Days of immobility" was defined as the number of days until a patient moved out of bed beyond a chair. Patients in the top and bottom quartiles were dichotomized into "early ambulators" and "late ambulators", respectively. Early ambulators were ambulatory within 24 hours of surgery, whereas late ambulators were ambulatory at a minimum of 48 hours after surgery. Complication rates, duration of hospital stay, and 30 day readmission rates were compared between early ambulators and late ambulators. RESULTS: Baseline characteristics were similar between both cohorts. Compared with patients with a longer duration of immobility (i.e., late ambulators), the prevalence of at least one perioperative complication was significantly lower in the early ambulators cohort (30% vs. 54%, P = 0.06). The length of inhospital stay was 34% shorter in the early ambulators cohort (5.33 days vs. 8.11 days, P = 0.01). Functional independence was superior in the early ambulators cohort, with the majority of patients discharged directly home after surgery compared with late ambulators (71.2% vs. 22.0%, P = 0.01). CONCLUSION: Early ambulation after surgery significantly reduces the incidence of perioperative complications, shortens duration of inhospital stay, and contributes to improved perioperative functional status in elderly patients. Even a delay of 24 hours to ambulation is associated with higher complication rates and inferior functional outcomes. LEVEL OF EVIDENCE: 3. PMID- 28902102 TI - Post-traumatic Spinal Hygroma Causing Cord Compression in Type III Odontoid Fracture With Vertical Atlantoaxial Instability. AB - STUDY DESIGN: Case report. OBJECTIVE: To report the first case in the literature of a traumatic cervical spine subdural cerebrospinal fluid (CSF) collection (hygroma) under tension causing cord compression. We suggest etiopathogenesis and modality of treatment. SUMMARY OF BACKGROUND DATA: Hygromas are subdural cranial CSF collection. A literature review showed no previous published case of post traumatic spinal hygroma. This was a potential life-threatening sequelae of a high cervical injury that warranted early diagnosis and emergency treatment. METHODS: We present a case of a young adult who sustained a traumatic vertical atlantoaxial dislocation associated with a type III odontoid fracture. He was initially scored C6 ASIA D. Magnetic resonance imaging (MRI) demonstrated cord contusion at the craniocervical junction and a small fluid collection anterior to the cervical cord. On day 5 after his injury he developed complete paraplegia and priapism. An urgent MRI of his spine revealed expansion of the intraspinal fluid collection with distortion of the cord. He was treated with an emergency surgical decompression. The cervical fluid collection was found to be subdural extra arachnoidal CSF. A subdural-pleural shunt was inserted. The atlantoaxial injury was reduced and fixed with posterior instrumentation. RESULTS: At 1 year from the injury the patient was independent and fully ambulant. MRI and computed tomography images of his spine demonstrated complete resolution of the cervical hygroma, appropriate placement of the cervical-pleural shunt, and stability of the atlantoaxial injury. CONCLUSION: We describe a unique case of post-traumatic spinal hygroma causing cord compression in a patient with an unstable craniocervical injury. The early recognition and correction of this dangerous complication is of paramount importance to savage cord function. LEVEL OF EVIDENCE: 5. PMID- 28902103 TI - TO THE EDITOR. PMID- 28902105 TI - Clinical Effectiveness of Intra-articular Pulsed Radiofrequency Compared to Intra articular Corticosteroid Injection for Management of Atlanto-occipital Joint Pain: A Prospective Randomized Controlled Pilot Study. AB - STUDY DESIGN: A prospective randomized controlled pilot study. OBJECTIVE: We aimed to assess the effectiveness of pulsed radiofrequency (PRF) stimulation on the atlanto-occipital (AO) joint in patients with chronic joint pain. In addition, we compared the effects of AO intra-articular (IA) PRF and AO IA corticosteroid. SUMMARY OF BACKGROUND DATA: IA injection of corticosteroids into the AO joint is widely used for the management of head and upper cervical pain, and its effectiveness has been shown in previous studies. However, little is known about the effect of PRF stimulation on the AO joint for controlling chronic head or upper cervical pain. METHODS: Twenty-three consecutive patients with chronic upper cervical pain were enrolled according to the inclusion criteria and divided into one of two groups. Twelve patients received PRF stimulation with a PRF needle electrode in the IA space of the AO joint (PRF group) and 11 patients received AO IA corticosteroid injection (ICI group. Pain intensity was assessed using a numeric rating scale (NRS) before treatment and 1, 3, and 6 months afterward. Successful pain relief was defined as >=50% reduction in NRS score 6 months post-treatment compared to pretreatment. RESULTS: Mean NRS scores were significantly reduced compared to those pretreatment (P < 0.001) in both groups. Temporal changes in NRS score were not significantly different between groups (P = 0.227). Successful pain relief was achieved in 66.7% and 63.6% of patients in the PRF and ICI groups, respectively. CONCLUSION: IA PRF stimulation significantly relieved AO joint pain and its effect persisted for at least 6 months after treatment. In addition, the degree of pain relief after IA PRF was not significantly different from that after ICI. We think that PRF stimulation of the AO joint could be a useful clinical treatment for patients with AO joint pain. LEVEL OF EVIDENCE: 2. PMID- 28902104 TI - A Replication Study for the Association of rs11190870 With Curve Severity in Adolescent Idiopathic Scoliosis in Japanese. AB - STUDY DESIGN: Case-only study. OBJECTIVE: The aim of this study was to confirm the association of rs11190870 with adolescent idiopathic scoliosis (AIS) severity in Japanese patients with AIS. SUMMARY OF BACKGROUND DATA: Although the association of rs11190870 with AIS susceptibility is replicated in multiple ethnics, the association of rs11190870 with curve severity is controversial. Since the previous studies are of small, we performed a replication study using far larger number of patients than previous studies. METHODS: A total of 1860 Japanese patients with AIS who had reached skeletal maturity or undergone surgical fusion were included in the study. We evaluated the association between rs11190870 and AIS progression for the entire group, and then for patients grouped according to a severe curve (a Cobb angle of >=40 degrees ) or mild curve (a Cobb angle <30 degrees ). Because braces could affect the results of the present study, patients in the mild-curve group were divided according to whether or not they had worn a brace. We then evaluated associations between rs11190870 genotype and curve severity in these groups. RESULTS: The mean Cobb angles were 54.8 degrees +/- 12.1 degrees in the severe-curve group and 24.4 degrees +/- 4.0 degrees in the mild-curve group. The difference in rs11190870 risk-allele frequency between the severe- and mild-curve groups was evaluated. No significant differences were observed. We then examined the association of rs11190870 risk allele frequency between patients in the mild- and severe-curve groups using the chi test for three models, and found a marginal association between rs11190870 and curve severity in the dominant model (P = 0.035, odds ratio = 1.51). CONCLUSION: We found no association between rs11190870 and curve severity using the criteria of previous study. However, we found a marginal association between rs11190870 and curve severity. Large-scale replication studies that consider skeletal maturity and brace history, including replication studies in other ethnic groups, would be helpful for clarifying the association. LEVEL OF EVIDENCE: 4. PMID- 28902106 TI - Fine-tuning the Predictive Model for Proximal Junctional Failure in Surgically Treated Patients With Adult Spinal Deformity. AB - STUDY DESIGN: Multicenter retrospective study. OBJECTIVE: To validate and improve the predictive model for proximal junctional failure (PJF) with or without the bone mineral density (BMD) score. SUMMARY OF BACKGROUND DATA: PJF is a serious complication of surgery for adult spinal deformity (ASD). A predictive model for PJF was recently reported that has good accuracy, but does not include BMD, a known PJF risk factor, as a variable. METHODS: We included 145 surgically treated ASD patients who were older than 50 at the time of surgery and had been followed up for at least 2 years. Variables included age, sex, body mass index (BMI), fusion level, upper and lower instrumented vertebral (UIV and LIV) level, primary or revision surgery, pedicle subtraction osteotomy (PSO), Schwab-SRS type, and BMD. PJF was defined as a >= 20 degrees increase from baseline (immediately postoperative) of the proximal junctional angle with concomitant deterioration of at least 1 SRS-Schwab sagittal modifier grade, or any proximal junctional kyphosis requiring revision. Decision-making trees were constructed using the C5.0 algorithm with 10 different bootstrapped models, and validated by a 7:3 data split for training and testing; 112 patients were categorized as training and 33 as testing samples. RESULTS: PJF incidence was 20% in the training samples. Univariate analyses showed that BMD, BMI, pelvic tilt (PT), UIV level, and LIV level were PJF risk factors. Our predictive model was 100% accurate in the testing samples with an AUC of 1.0, indicating excellent fit. The best predictors were (strongest to weakest): PT, BMD, LIV level (pelvis), UIV level (lower thoracic), PSO, global alignment, BMI, pelvic incidence minus lumbar lordosis, and age. CONCLUSION: A successful model was developed for predicting PJF that included BMD. Our model could inform physicians about patients with a high risk of developing PJF in the perioperative period. LEVEL OF EVIDENCE: 4. PMID- 28902107 TI - Reliability of the maximal resisted sprint load test and relationships with performance measures and anthropometric profile in female field sport athletes. AB - Resisted sled sprint (RSS) training is an effective modality for the improvement of linear sprint speed. Previous methods of RSS load prescription e.g. an absolute load or as a percentage of body mass (%BM), do not account for inter individual differences in strength, power or speed characteristics, although the 'maximum resisted sled load' (MRSL) method of RSS load prescription may provide a solution. MRSL is defined as the final RSS load before an athlete can no longer accelerate between two phases (10-15 m and 15-20 m) of a 20 m linear sprint. However, the MRSL test has not been analysed for reliability. Additionally, MRSL performance has not been compared to the outcome of other performance tests. The primary aim of this study was to investigate the reliability of the MRSL testing protocol in female field sport athletes. Participants (age, 20.8 +/- 1.9 y; body mass, 64.3 +/- 8.4 kg; height, 1.66 +/- 0.65 m) tested for anthropometric measurements, strength and power performance testing and twice for MRSL. MRSL values ranged from 20.7 to 58.9%BM. MRSL test-retest reliability intraclass correlation coefficient, confidence intervals and coefficient of variations were 0.95, 0.85-0.98 and 7.6%, respectively. MRSL was 'moderately' and 'strongly' correlated with a number of anthropometric and performance tests (p < 0.05) including % fat free mass, countermovement jump, loaded countermovement jump, rate of force development, horizontal jump and horizontal bound performance. MRSL is a reliable measure for determining the RSS load at which an individual can no longer accelerate during a single RSS effort over 0-20 m. MRSL also accounts for inter-individual variation in body composition, power and speed characteristics of female field sport players. PMID- 28902108 TI - Effects of Two Different Self-Adapted Occlusal Splints on Electromyographic and Force Parameters During Elbow Flexors Isometric Contraction. AB - Limonta, E, Arienti, C, Rampichini, S, Venturelli, M, Ce, E, Veicsteinas, A, and Esposito, F. Effects of two different self-adapted occlusal splints on electromyographic and force parameters during elbow flexors isometric contraction. J Strength Cond Res 32(1): 230-236, 2018-The study was aimed at determining the acute effects of 2 types of occlusal splints on maximum isometric strength and fatigue of the elbow flexors muscles. The hypothesis was that splint induced masticatory muscle repositioning might improve primary muscles recruitment by stretching masticatory muscles especially with the thicker splint. On 9 physically active volunteers with no temporomandibular joint and masticatory muscles disorders, we assessed maximum voluntary contraction (MVC) of the elbow flexors with diurnal (OSD, 1-mm thick) and sport (OSSP, 3-mm thick) splints, and without splint (control, Ctrl). On different days, participants performed 60 seconds of isometric contraction at 100% MVC (100%60s) and 80% MVC contraction until exhaustion (80%exh) under OSD, OSSP, and Ctrl in random order. Time of force output within target (t-target), force distance from target (DeltaF), and force coefficient of variation were calculated. Percentage of force decay (DeltaFi-Fe) was determined during 100%60s. From the electromyographic (EMG) signal, root mean square (EMG RMS) and mean frequency (EMG MF) were determined. Neuromuscular efficiency (NE) was calculated as the ratio between force and EMG RMS. MVC contraction and NE were significantly higher in OSSP and OSD than in Ctrl. During MVC, EMG MF was significantly lower in both splint conditions, and EMG RMS showed a nonstatistical tendency to lower values under both splint conditions. During 80%exh, t-target was longer in OSD and OSSP (+7.8% and +5.2%, respectively) than in Ctrl. DeltaFi-Fe was lower in OSSP than in Ctrl and OSD. These results support the hypothesis of a NE improvement of the elbow flexors possibly induced by acute, splint-induced masticatory muscles repositioning. PMID- 28902109 TI - Validity And Reliability Of The Stages Cycling Power Meter. AB - PURPOSE: This study aimed to determine the validity and the reliability of the Stages power meter crank system (Boulder, United States) during several laboratory cycling tasks. METHODS: Eleven trained participants completed laboratory cycling trials on an indoor cycle fitted with SRM Professional and Stages systems. The trials consisted of an incremental test at 100W, 200W, 300W, 400W and four 7s sprints. The level of pedaling asymmetry was determined for each cycling intensity during a similar protocol completed on a Lode Excalibur Sport ergometer. The reliability of Stages and SRM power meters was compared by repeating the incremental test during a test-retest protocol on a Cyclus 2 ergometer. RESULTS: Over power ranges of 100-1250W the Stages system produced trivial to small differences compared to the SRM (standardized typical error values of 0.06, 0.24 and 0.08 for the incremental, sprint and combined trials, respectively). A large correlation was reported between the difference in power output (PO) between the two systems and the level of pedaling asymmetry (r=0.58, p < 0.001). Recalculating PO of the Stages system according to the level of pedaling asymmetry provided only marginal improvements in PO measures. The reliability of the Stages power meter at the sub-maximal intensities was similar to the SRM Professional model (coefficient of variation: 2.1 and 1.3% for Stages and SRM, respectively). CONCLUSIONS: The Stages system is a suitable device for PO measurements, except when a typical error of measurement <3.0% over power ranges of 100-1250W is expected. PMID- 28902110 TI - Asymmetries of Maximum Trunk, Hand, and Leg Strength in Comparison to Volleyball and Fitness Athletes. AB - Mattes, K, Wollesen, B, and Manzer, S. Asymmetries of maximum trunk, hand, and leg strength in comparison to volleyball and fitness athletes. J Strength Cond Res 32(1): 57-65, 2018-Playing volleyball and corresponding training loads lead to specific strains and might result in asymmetric muscle pattern. The study aimed to identify volleyball-specific maximum bilateral strength asymmetries in comparison to fitness athletes. The cross-sectional study design compared an age matched male volleyball group (n = 23; 27.9 +/- 5 years) with a fitness group (n = 30; 26.3 +/- 3 years). The participants performed an isometric maximum handgrip strength test followed by 2 isokinetic concentric maximum strength tests to determine the performance capacity of the axial trunk rotators (left-right) and bilateral leg extensors. Differences between groups and left-right side (within group) were proven by variance analysis with repeated measurements. There was a left-right difference with higher maximum forces for the rotation in the right direction in the volleyball group (p = 0.0058) but the group interaction effect was not significant after alpha error accumulation. The results of the leg press indicated a stronger left leg in the fitness group (nonsignificant) in comparison to the volleyball group. Overall, the volleyball group displayed symmetry in maximum handgrip and leg strength and asymmetry in trunk rotation with higher strength in right rotation. This asymmetry for the right trunk rotation showed a small effect size. The resulting asymmetry might be an adaptation to the volleyball techniques, but it remains unclear if this is a cause for or of injury. As a practical implication, the asymmetries should be examined to develop individualized strength training programs for both groups. PMID- 28902111 TI - The influence of foam rolling on recovery from exercise-induced muscle damage. AB - The purpose of this study was to examine the impact of foam rolling (FR) on recovery from exercise-induced muscle damage (EIMD). Thirty-seven males performed 40 x 15 m sprints, inducing muscle damage. Immediately following sprinting and in the four days following, perceived muscle soreness, hip abduction range of motion (ROM), hamstring muscle length, vertical jump, and agility measures were recorded. Eighteen subjects (mean +/- sd; age 22.4 +/- 2.0 yrs; BMI 26.9 +/- 4.2 kgm) foam rolled prior to testing each day (FR), while 19 (mean +/- sd; age 23.2 +/- 3.2 yrs; BMI 26.3 +/- 4.0 kgm) served as a non-foam rolling control (CON). Measurements recorded during the five days of recovery from the repeated sprint protocol were compared to week one baseline measurements. The area under the curve (AUC) was calculated by summing all five scores as they changed from baseline measurement, and these data were compared by condition using a two tailed Mann-Whitney U test (alpha level = 0.05). Perceived soreness, hip abduction ROM, hamstring muscle length, and vertical jump were not significantly different between groups (p >= 0.25). Agility was less impaired in the FR condition (p = 0.0049) as AUC was higher in CON (2.88 s +/- 2.45) than FR (0.33 s +/- 2.16). Based upon these data, FR appears to expedite recovery of agility following EIMD instigated by a repeated sprint protocol. FR may be useful for athletes requiring adequate agility who need to recover quickly from demanding bouts of exercise. PMID- 28902112 TI - The Efficacy of Repeated Cold Water Immersion on Recovery Following a Simulated Rugby Union Protocol. AB - Training and athletic competition frequently results in exercise induced muscle damage (EIMD). The purpose of this study was to investigate the efficacy of repeated cold water immersion (CWI) on recovery following a simulated rugby union match. Sixteen male, club level rugby players were matched for body mass and randomly assigned to either a CWI group or control (CON) group. Following the simulated rugby match the CWI group underwent 2 x 5 min immersions at a temperature of 10 degrees C separated by 2.5 min seated at room temperature, whilst the CON group remained seated for 15 min. Creatine kinase (CK), perceived muscle soreness, counter movement jump (CMJ) and maximal voluntary isometric contraction (MVIC) of the knee extensors were measured pre-exercise, post exercise, 24 h and 48 h following exercise. Large effect sizes were observed for muscle soreness at 24 and 48 h post exercise with lower soreness values observed in the CWI group. Large effect sizes were observed for CMJ at all time points and at 24 and 48 h post for MVIC with improved recovery of muscle function observed in the CWI group compared to the CON group. Lastly a moderate effect size was observed for CK immediately post exercise followed by large effect sizes at 24 and 48h post exercise, with CK concentration blunted in the CWI group. Overall these findings provide some support for the use of CWI to enhance recovery from EIMD following a simulated rugby union match. PMID- 28902113 TI - Comparative effects of two interval shuttle-run training modes on physiological and performance adaptations in female professional futsal players. AB - The purpose of the present study was to analyze the effects of two shuttle-run interval training (SRIT) models with one and three directional changes per running bout on the aerobic and anaerobic performances of elite female futsal players. Sixteen players competing in the Brazilian National Division League took part in the study. The training protocols consisted of shuttle-run intervals organized in four sets of 4-min bouts with 3- min of rest intervals between the sets. The SRIT models were composed of one (7.5 s running and 7.5 s pause [SRIT7.5x7.5]; n=7) or three (15 s running and 15 s pause [SRIT15x15]; n=9) directional changes. The athletes performed the following tests before and after a 5-week training period: incremental treadmill test (ITT), Futsal Intermittent Endurance Test (FIET) [with respective peak speeds (PS)] and a repeated sprint ability (RSA) test. After the training period, PSFIET and speed at the second lactate turnpoint were very likely and almost certainly increased in both training regimens, respectively. SRIT15x15 induced possibly greater improvements in PSITT (+3.28%, 90%CL -0.16 to 6.82) and RSAmean (+1.17%, 90% CL -0.68 to 3.05) than SRIT7.5x7.5. In addition, SRIT15x15 resulted in a likely greater improvement in running economy (+4.33%, 90% CL -0.35 to 9.23) compared with SRIT7.5x7.5. In elite female futsal players, SRIT15x15 is a promising strategy to enhance performance-related physical fitness attributes in a shortterm period (5 weeks) during the preseason, due to its superior effects on these important aerobic and anaerobic qualities than a protocol with fewer directional changes. PMID- 28902114 TI - Effects of repeated-sprints with changes of direction on youth soccer player's performance: Impact of initial fitness level. AB - The aim of this study was to assess the effect of an 8-week repeated sprint with change of direction training program on repeated sprint, intermittent endurance and change of direction performance in youth soccer players with different aerobic fitness levels. Athletes were randomly assigned into a soccer-only (n=9; age, 14.9+/-0.4 yr) and soccer plus repeated sprint with change of direction (RS COD) training programs for players with high (n=10; age, 14.4+/-0.5 yr) and low (n=10; age, 14.4+/-0.5 yr) aerobic fitness. RS-COD was completed two days per week, involving three sets of ten 18-m sprints with two changes of direction of 90 degrees . The soccer-only group achieved greater improvements in intermittent endurance (ES = 0.61) and sprint decrement during RS ability test (ES = 0.77) compared to the RS-COD groups (ES = 0.19 to 0.24; ES = -0.27 to 0.02; respectively). RS-COD training improved repeated sprint (ES = 0.16 to 0.38) and change of direction (ES = 0.48) performance in high, but not in low fitness players (ES = 0.03 to 0.13; ES = 0.16; respectively). Moreover, improvements in repeated sprint and change of direction were (possibly) greater in high compared to low fitness and soccer-only trained players (possibly to very likely). In conclusion, although RS-COD training may positively affect repeated sprint and change of direction performance, its effects may vary according to the initial aerobic fitness of youth soccer players, with trivial effect on intermittent endurance in high-aerobic fitness players and possible beneficial effect on low aerobic fitness players. PMID- 28902115 TI - Repeated High-Intensity Cycling Performance Is Unaffected by Timing of Carbohydrate Ingestion. AB - Shei, R-J, Paris, HL, Beck, CP, Chapman, RF, and Mickleborough, TD. Repeated high intensity cycling performance is unaffected by timing of carbohydrate ingestion. J Strength Cond Res 32(8): 2243-2249, 2018-To determine whether carbohydrate (CHO) feeding taken immediately before, early, or late in a series of high intensity cycling exercises affected cycling performance. A total of 16 trained, male cyclists (>6 hours postprandial) performed 3-, 4-km cycling time trials (TT1, TT2, and TT3) separated by 15 minutes of active recovery on 4 separate occasions. Carbohydrate feeding (80 g) was given either before TT1 (PRE1), before TT2 (PRE2), before TT3 (PRE3), or not at all (control, CTL). Treatment order was randomized. Sweet placebo was given before the other TTs. Blood glucose (BG) concentration was measured before each trial. Mean power output (Pmean) and time to completion (TTC) were recorded. Pmean was higher in TT1 compared with TT2 (p = 0.001) and TT3 (p = 0.004) in all conditions, but no differences were observed between treatments. Time to completion was lower in TT1 compared with TT2 (p = 0.01), but no other differences in TTC (within or between treatments) were observed. Within CTL and PRE1, BG did not differ between TT1, TT2, and TT3. In PRE2, BG was significantly higher in TT2 compared with TT1 (p = 0.006), in TT3 compared with TT1 (p = 0.001), and in TT3 compared with TT2 (p = 0.01). In PRE3, BG was significantly higher in TT3 compared with TT1 and TT2 (p = 0.001 for both). Given that performance was not influenced by the timing of CHO ingestion, athletes engaging in repeated, high-intensity cycling exercise do not need to ingest CHO before- or between-exercise bouts; furthermore, athletes should refrain from ingesting CHO between bouts if they wish to avoid a rise in BG. PMID- 28902116 TI - Adding whole body vibration to preconditioning squat exercise increases cycling sprint performance. AB - This study investigated the effect of performing a preconditioning exercise with or without whole-body vibration (WBV) on a subsequent cycling sprint performance. Fourteen trained subjects performed two separate test sessions in randomized order. After a warm-up, the preconditioning exercise (body-loaded half squats) was applied: 30-seconds of half-squats with WBV (40 Hz, 2 mm) or 30-seconds of half-squats without WBV with a 10-second all-out sprint performed after one minute. Surface electromyography (EMG) was measured from the vastus medialis, vastus lateralis and gastrocnemius medialis during the sprints. Blood lactate level (BL), heart rate (HR) and rating of perceived exertion (RPE) were determined immediately after the 10-second sprint. Performing preconditioning exercise with WBV resulted in superior peak (1693 +/- 356 W vs. 1637 +/- 349 W, p <= 0.05) and mean power output (1121 +/- 174 W vs. 1085 +/- 175 W, p <= 0.05) compared to preconditioning exercise without WBV. Effect sizes showed a moderate and large practical effect of WBV vs. no WBV on peak and mean power output, respectively. No differences were observed between the conditions for BL, HR and RPE after the sprints and in EMG activity during the sprints. In conclusion, it is plausible to suggest that body-loaded half-squats with WBV acutely induces higher power output levels. The practical application of the current study is that body-loaded squats with WBV can be incorporated into preparations for specific sprint training to improve the quality of the sprint training and also in order to improve sprint performance in relevant competitions. PMID- 28902117 TI - Factors Influencing Spike Jump Height in Female College Volleyball Players. AB - Ikeda, Y, Sasaki, Y, and Hamano, R. Factors influencing spike jump height in female college volleyball players. J Strength Cond Res 32(1): 267-273, 2018-The purpose of this study was to examine factors influencing spike jump (SPJ) performance by female competitive volleyball players through comparisons of the kinematic data of SPJ with those of the standing long jump (SLJ) and vertical jump (VJ). Seventeen female competitive volleyball players were asked to perform SPJ, SLJ, and VJ. Motion data of SPJ including the approach phase were recorded. Regarding SLJ and VJ, jumping motion and ground reaction force were recorded during each performance. The results obtained showed that SPJ height correlated with vertical velocity at take-off, horizontal velocity at third step contact, and the deceleration of horizontal velocity from third step contact to take-off. Regarding the relationship among SPJ, SLJ, and VJ, the relationship between SPJ and SLJ was stronger than that with VJ. The contributions of the hip, knee, and ankle muscles to the propulsive phase of SLJ were 39.7%, 21.1%, and 39.2%, respectively, whereas their contributions to VJ were 36.2%, 30.2%, and 33.6%, respectively. The vertical velocity of SPJ at take-off correlated with hip work and ankle peak power in SLJ and knee peak power in VJ. These results suggest the importance of enhancing horizontal and vertical jumping abilities separately to improve the height of SPJ because the primary generator for power production seems to depend on jump direction. PMID- 28902118 TI - Concurrent Training Followed by Detraining: Does the Resistance Training Intensity Matter? AB - Sousa, AC, Marinho, DA, Gil, MH, Izquierdo, M, Rodriguez-Rosell, D, Neiva, HP, and Marques, MC. Concurrent training followed by detraining: does the resistance training intensity matter? J Strength Cond Res 32(3): 632-642, 2018-The aim of this study was to analyze the training and detraining (DT) effects of concurrent aerobic training and resistance training against 3 different external loads on strength and aerobic variables. Thirty-two men were randomly assigned to 4 groups: low-load (LLG, n = 9), moderate-load (MLG, n = 9), high-load (HLG, n = 8), and control group (CG, n = 6). Resistance training consisted of full squat (FS) with a low load (40-55% 1 repetition maximum [1RM]), a moderate load (55-70% 1RM), or a high load (70-85% 1RM) combined with jump and sprint exercises. Aerobic training was performed at 75% of the maximal aerobic speed for 15-20 minutes. The training period lasted for 8-week, followed by 4-week DT. Pretraining, post-training, and post-DT evaluations included 20-m running sprints (0-10 m: T10; 0-20 m: T20), shuttle run test, countermovement vertical jump (CMJ) test, and loading test (1RM) in FS. All the experimental groups showed improvements (p <= 0.05) in all the parameters assessed, except the LLG for T10 and the HLG for T20. The LLG, MLG, and HLG showed great changes in 1RM and V[Combining Dot Above]O2max compared with the CG (p <= 0.05), whereas the HLG and MLG showed a greater percentage change than the CG in T10 (p < 0.001) and CMJ (p <= 0.05). The 4-week DT period resulted in detrimental effects in all variables analyzed for all 3 experimental groups. In conclusion, our results suggest that strength training programs with low, moderate, or high external loads combined with low-intensity aerobic training could be effective for producing significant gains in strength and aerobic capacities. Moreover, the higher loads used increased gains in explosive efforts. PMID- 28902119 TI - Determination of Vertical Jump as a Measure of Neuromuscular Readiness and Fatigue. AB - Watkins, CM, Barillas, SR, Wong, MA, Archer, DC, Dobbs, IJ, Lockie, RG, Coburn, JW, Tran, TT, and Brown, LE. Determination of vertical jump as a measure of neuromuscular readiness and fatigue. J Strength Cond Res 31(12): 3305-3310, 2017 Coaches closely monitor training loads and periodize sessions throughout the season to create optimal adaptations at the proper time. However, only monitoring training loads ignores the innate physiological stress each athlete feels individually. Vertical jump (VJ) is widely used as a measure of lower-body power, and has been used in postmatch studies to demonstrate fatigue levels. However, no pretraining monitoring by VJ performance has been previously studied. Therefore, the purpose of this study was to determine the sensitivity of VJ as a measure of readiness and fatigue on a daily sessional basis. Ten healthy resistance-trained males (mass = 91.60 +/- 13.24 kg; height = 179.70 +/- 9.23 cm; age = 25.40 +/- 1.51 years) and 7 females (mass = 65.36 +/- 12.29 kg; height = 162.36 +/- 5.75 cm; age = 25.00 +/- 2.71 years) volunteered to participate. Vertical jump and BRUNEL Mood Assessment (BAM) were measured 4 times: pre-workout 1, post-workout 1, pre-workout 2, and post-workout 2. Workout intensity was identical for both workouts, consisting of 4 sets of 5 repetitions for hang cleans, and 4 sets of 6 repetitions for push presses at 85% 1 repetition maximum (1RM), followed by 4 sets to failure of back squats (BSs), Romanian deadlift, and leg press at 80% 1RM. The major finding was that VJ height decrement (-8.05 +/- 9.65 cm) at pre workout 2 was correlated (r = 0.648) with BS volume decrement (-27.56 +/- 24.56%) between workouts. This is important for coaches to proactively understand the current fatigue levels of their athletes and their readiness to resistance training. PMID- 28902120 TI - Competition Intensity and Fatigue in Elite Fencing. AB - Turner, AN, Kilduff, LP, Marshall, GJG, Phillips, J, Noto, A, Buttigieg, C, Gondek, M, Hills, FA, and Dimitriou, L. Competition intensity and fatigue in elite fencing. J Strength Cond Res 31(11): 3128-3136, 2017-As yet, no studies have characterized fencing competitions. Therefore, in elite male foilists and across 2 competitions, we investigated their countermovement jump height, testosterone (T), cortisol (C), alpha-amylase (AA), immunoglobulin A (IgA), heart rate (HR), blood lactate (BL), and rating of perceived exertion (RPE). Average (+/-SD) scores for RPE, BL, and HR (average, max, and percentage of time >=80% HRmax) were highest in the knockout bouts compared with poules (8.5 +/- 1.3 vs. 5.7 +/- 1.3, 3.6 +/- 1.0 vs. 3.1 +/- 1.4 mmol.L, 171 +/- 5 vs. 168 +/- 8 b.min, 195 +/- 7 vs. 192 +/- 7 b.min, 74 vs. 68%); however, only significant (p <= 0.05) for RPE. Countermovement jump height, albeit nonsignificantly (p > 0.05), increased throughout competition and dropped thereafter. Although responses of C, AA, and IgA showed a tendency to increase during competition and drop thereafter (T and T:C doing the opposite), no significant differences were noted for any analyte. Results suggest that fencing is a high-intensity anaerobic sport, relying on alactic energy sources. However, some bouts evoke BL values of >=4 mmol.L and thus derive energy from anaerobic glycolysis. High HRs appear possible on account of ample within- and between-bout rest. The small competition load associated with fencing competitions may explain the nonsignificant findings noticed. PMID- 28902122 TI - On P values and effect modification. AB - AIM: A crucial element of evidence-based healthcare is the sound understanding and use of statistics. As part of instilling sound statistical knowledge and practice, it seems useful to highlight instances of unsound statistical reasoning or practice, not merely in captious or vitriolic spirit, but rather, to use such error as a springboard for edification by giving tangibility to the concepts at hand and highlighting the importance of avoiding such error. This article aims to provide an instructive overview of two key statistical concepts: effect modification and P values. METHODS AND RESULTS: A recent article published in the Journal of the American College of Cardiology on side effects related to statin therapy offers a notable example of errors in understanding effect modification and P values, and although not so critical as to entirely invalidate the article, the errors still demand considerable scrutiny and correction. In doing so, this article serves as an instructive overview of the statistical concepts of effect modification and P values. CONCLUSION: Judicious handling of statistics is imperative to avoid muddying their utility. This article contributes to the body of literature aiming to improve the use of statistics, which in turn will help facilitate evidence appraisal, synthesis, translation, and application. PMID- 28902121 TI - Critical Care Resources in Guangdong Province of China: Three Surveys from 2005 to 2015. AB - OBJECTIVES: Data about the critical care resources in China remain scarce. The purpose of this study was to investigate the variation and distribution of critical care resources in Guangdong province from 2005 to 2015. DESIGN: Data in regard to critical care resources were collected through questionnaires and visits every 5 years from 2005. SETTING: All hospitals in Guangdong province were screened and hospitals that provide critical care services were enrolled. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: One hundred eleven, 158, and 284 hospitals that provide critical care services were enrolled in the three consecutive surveys respectively. The number of ICUs, ICU beds, intensivists, and nurses increased to 324, 3,956, 2,470, and 7,695, respectively, by 2015. Adjusted by population, the number of ICU beds per 100,000 (100,000) population increased by 147.7% from 2005 to 2015, and the number of intensivists and nurses per 100,000 population increased by 35.3% and 55.1% from 2011 to 2015. However, the numbers in the Pearl River Delta, a richer area, were higher than those in the non-Pearl River Delta area (ICU beds: 4.64 vs 2.58; intensivists: 2.90 vs 1.61; nurses: 9.30 vs 4.71 in 2015). In terms of staff training, only 17.85% of intensivists and 14.29% of nurses have completed a formal accredited critical care training program by 2015. CONCLUSIONS: Our study was the first one to investigate the trend and distribution of critical care resources in China. The quantity of ICU beds and staff has been increasing rapidly, but professional training for staff was inadequate. The distribution of critical care resources was unbalanced. Our study can be beneficial for healthcare policymaking and the allocation of critical care resources in Guangdong province and other provinces in China. PMID- 28902123 TI - Bidirectional Regulation of Circadian Disturbance and Inflammation in Inflammatory Bowel Disease. AB - BACKGROUND: Tight crosstalk between the circadian and immune systems has been reported in several inflammatory diseases. We hypothesized that circadian timekeeping was perturbed in inflammatory bowel disease (IBD), and that the bidirectional regulation of circadian disturbance and inflammation may be involved in the pathogenesis of IBD. METHODS: Patients with ulcerative colitis (51) and Crohn's disease (39) and 42 healthy controls were recruited and their circadian gene expression levels evaluated. Dextran sodium sulfate/2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse models, and lipopolysaccharide-stimulated macrophages, were examined to detect the influence of inflammation on circadian gene expression, both in vivo and in vitro. Light/dark shift and time-restricted feeding models were also used to evaluate the influence of circadian disturbance on a mouse colitis model. RESULTS: We found that (1) almost all circadian genes were reduced in both intestinal biopsies and the peripheral blood mononuclear cells of patients with IBD, especially in patients with ulcerative colitis. Nearly all circadian genes of biopsy tissues showed negative correlations with a Mayo score or a simplified endoscopic activity score for Crohn's disease. Circadian genes of peripheral blood mononuclear cells correlated well with erythrocyte sedimentation rate and C reactive protein levels in IBD. (2) Exposure to dextran sodium sulfate/2,4,6 trinitrobenzene sulfonic acid and lipopolysaccharide-induced marked changes in circadian gene expression profiles. (3) A phase shift exacerbated colitis in mice, with the increased secretion of proinflammatory cytokines and activation of inflammatory-related signaling pathways. CONCLUSIONS: Our results suggested that inflammation and circadian genes showed complex bidirectional regulations that were relevant to IBD. Consequently, the circadian clock seems to be a potential target for IBD therapy. PMID- 28902124 TI - Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohn's Disease. AB - BACKGROUND: With 25% prevalence of Crohn's disease, Familial GUCY2C diarrhea syndrome (FGDS) is a monogenic disorder potentially suited to study initiating factors in inflammatory bowel disease (IBD). We aimed to characterize the impact of an activating GUCY2C mutation on the gut microbiota in patients with FGDS controlling for Crohn's disease status and to determine whether changes share features with those observed in unrelated patients with IBD. METHODS: Bacterial DNA from fecal samples collected from patients with FGDS (N = 20), healthy relatives (N = 11), unrelated healthy individuals (N = 263), and IBD controls (N = 46) was subjected to sequencing of the V3-V4 region of the 16S rRNA gene to determine gut microbiota composition. Food frequency questionnaires were obtained from patients with FGDS and their relatives. RESULTS: Compared with healthy controls, FGDS displayed prominent changes in many microbial lineages including increase in Enterobacteriaceae, loss of Bifidobacterium and Faecalibacterium prausnitzii but an unchanged intraindividual (alpha) diversity. The depletion of F. prausnitzii is in line with what is typically observed in Crohn's disease. There was no significant difference in the dietary profile between the patients and related controls. The gut microbiota in related and unrelated healthy controls was also similar, suggesting that diet and familial factors do not explain the gut microbiota alterations in FGDS. CONCLUSIONS: The findings support that the activating mutation in GUCY2C creates an intestinal environment with a major influence on the microbiota, which could contribute to the increased susceptibility to IBD in patients with FGDS. PMID- 28902125 TI - Epidemiology of Youth Boys' and Girls' Lacrosse Injuries in the 2015 to 2016 Seasons. AB - PURPOSE: Examinations of injury among younger populations of lacrosse players that are beginning their development is limited. This study describes the epidemiology of youth boys' and girls' lacrosse injuries during the 2015 to 2016 seasons. METHODS: Surveillance data originated from a convenience sample of 10 leagues in five states with 1090 boy lacrosse players and 408 girl lacrosse players from the U9-U15 divisions. Athletic trainers reported injury and exposure data at games and practices. Time loss (TL) injuries were defined as resulting in >=24 h of participation restriction time. Injury counts and rates per 1000 athlete games/practices were calculated. Injury rate ratios (IRR) with 95% confidence intervals (CI) compared rates by sex and age division. RESULTS: Overall, 241 and 59 injuries were reported in boys' and girls' youth lacrosse, respectively, of which 17.0% and 18.6% were TL. Compared with girls, boys had a higher overall injury rate (12.7 vs 8.7/1000 athlete games/practices; IRR, 1.5; 95% CI, 1.1-1.9). U13/U15 boys had a higher TL injury rate than U9/U11 boys (2.6 vs 1.0/1000 athlete game/practices; IRR, 2.6; 95% CI, 1.1-6.1). Most injuries were diagnosed as contusions (boys, 53.7%; girls, 47.2%) and resulted from stick contact (boys, 34.1%; girls, 30.6%) and ball contact (boys, 17.1%; girls, 25.0%). Among girls, ball contact contributed to 75.0% (n = 9) of all head/face injuries. Among the 14 concussions reported in boys, player contact was the most common injury mechanism (50.0%, n = 7), followed by stick contact (35.7%, n = 5). CONCLUSIONS: Boys' lacrosse has a higher injury incidence than girls' lacrosse, reflecting the contact nature of the boys' game. The high incidence of stick- and ball-related injuries suggests the need for youth-specific rules to better protect youth players. PMID- 28902126 TI - Work Rate during Self-paced Exercise is not Mediated by the Rate of Heat Storage. AB - PURPOSE: To date, there have been mixed findings on whether greater anticipatory reductions in self-paced exercise intensity in the heat are mediated by early differences in rate of body heat storage. The disparity may be due to an inability to accurately measure minute-to-minute changes in whole-body heat loss. Thus, we evaluated whether early differences in rate of heat storage can mediate exercise intensity during self-paced cycling at a fixed rate of perceived exertion (RPE of 16; hard-to-very-hard work effort) in COOL (15 degrees C), NORMAL (25 degrees C), and HOT (35 degrees C) ambient conditions. METHODS: On separate days, nine endurance-trained cyclists exercised in COOL, NORMAL, and HOT conditions at a fixed RPE until work rate (measured after first 5 min of exercise) decreased to 70% of starting values. Whole-body heat loss and metabolic heat production were measured by direct and indirect calorimetry, respectively. RESULTS: Total exercise time was shorter in HOT (57 +/- 20 min) relative to both NORMAL (72 +/- 23 min, P = 0.004) and COOL (70 +/- 26 min, P = 0.045). Starting work rate was lower in HOT (153 +/- 31 W) compared with NORMAL (166 +/- 27 W, P = 0.024) and COOL (170 +/- 33 W, P = 0.037). Rate of heat storage was similar between conditions during the first 4 min of exercise (all P > 0.05). Thereafter, rate of heat storage was lower in HOT relative to NORMAL and COOL until 30 min of exercise (last common time-point between conditions; all P < 0.05). Further, rate of heat storage was significantly higher in COOL compared with NORMAL at 15 min (P = 0.026) and 20 min (P = 0.020) of exercise. No differences were measured at end exercise. CONCLUSIONS: We show that rate of heat storage does not mediate exercise intensity during self-paced exercise at a fixed RPE in cool to hot ambient conditions. PMID- 28902127 TI - Altered Gene Expression of RNF34 and PACAP Possibly Involved in Mechanism of Exercise-Induced Analgesia for Neuropathic Pain in Rats. AB - Despite the availability of several modalities of treatment, including surgery, pharmacological agents, and nerve blocks, neuropathic pain is often unresponsive and sometimes progresses to intractable chronic pain. Although exercise therapy is a candidate for treatment of neuropathic pain, the mechanism underlying its efficacy has not been elucidated. To clarify the molecular mechanism for pain relief induced by exercise, we measured Rnf34 and Pacap mRNA levels in the spinal cord dorsal horn of SNL rats, a model of neuropathic pain. SNL model rats exhibited stable mechanical hyperalgesia for at least 6 weeks. When the rats were forced to exercise on a treadmill, mechanical and thermal hyperalgesia were significantly ameliorated compared with the non-exercise group. Accordingly, gene expression level of Rnf34 and Pacap were also significantly altered in the time course analysis after surgery. These results suggest that exercise therapy possibly involves pain relief in SNL rats by suppressing Rnf34 and Pacap expression in the spinal cord. PMID- 28902128 TI - Induced Pluripotent Stem Cells: Advances in the Quest for Genetic Stability during Reprogramming Process. AB - Evaluation of the extent and nature of induced pluripotent stem cell (iPSC) genetic instability is important for both basic research and future clinical use. As previously demonstrated regarding embryonic stem cells, such DNA aberrations might affect the differentiation capacity of the cells and increase their tumorigenicity. Here, we first focus on the contribution of multiple DNA damage response pathways during cellular reprogramming. We then discuss the origin and mechanisms responsible for the modification of genetic material in iPSCs (pre existing variations in somatic cells, mutations induced by reprogramming factors, and mutations induced by culture expansion) and deepen the possible functional consequences of genetic variations in these cells. Lastly, we present some recent improvements of iPSC generation methods aimed at obtaining cells with fewer genetic variations. PMID- 28902129 TI - Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. AB - CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL. PMID- 28902130 TI - The Chloroplast Genome Sequence of Scutellaria baicalensis Provides Insight into Intraspecific and Interspecific Chloroplast Genome Diversity in Scutellaria. AB - Scutellaria baicalensis Georgi (Lamiaceae) is the source of the well-known traditional Chinese medicine "HuangQin" (Radix Scutellariae). Natural sources of S. baicalensis are rapidly declining due to high market demand and overexploitation. Moreover, the commercial products of Radix Scutellariae have often been found to contain adulterants in recent years, which may give rise to issues regarding drug efficacy and safety. In this study, we developed valuable chloroplast molecular resources by comparing intraspecific and interspecific chloroplast genome. The S. baicalensis chloroplast genome is a circular molecule consisting of two single-copy regions separated by a pair of inverted repeats. Comparative analyses of three Scutellaria chloroplast genomes revealed six variable regions (trnH-psbA, trnK-rps16, petN-psbM, trnT-trnL, petA-psbJ, and ycf1) that could be used as DNA barcodes. There were 25 single nucleotide polymorphisms(SNPs) and 29 indels between the two S. baicalensis genotypes. All of the indels occurred within non-coding regions. Phylogenetic analysis suggested that Scutellarioideae is a sister taxon to Lamioideae. These resources could be used to explore the variation present in Scutellaria populations and for further evolutionary, phylogenetic, barcoding and genetic engineering studies, in addition to effective exploration and conservation of S. baicalensis. PMID- 28902131 TI - Identification of the Ovine Keratin-Associated Protein 26-1 Gene and Its Association with Variation in Wool Traits. AB - Keratin-associated proteins (KAPs) are structural components of wool and hair fibres, and are believed to play a role in defining the physico-mechanical properties of the wool fibre. In this study, the putative ovine homologue of the human KAP26-1 gene (KRTAP26-1) was sequenced and four variants (named A-D) were identified. The sequences shared some identity with each other and with other KRTAPs, but they had the greatest similarity with the human KRTAP26-1 sequence. This suggests they represent different variants of ovine KRTAP26-1. The association of these KRTAP26-1 variants with wool traits was investigated in the 383 Merino-Southdown cross sheep. The presence of B was associated (p < 0.05) with an increase in mean fibre diameter (MFD), mean fibre curvature, and prickle factor (PF). The presence of C was found to be associated (p < 0.05) with an increase in wool yield (Yield) and mean staple length (MSL), and a decrease in MFD, fibre diameter standard deviation (FDSD), and PF. The results suggest that sheep with C have, on average, higher wool quality. These results may be useful in the future development of breeding programs based on decreasing wool MFD and FDSD, or on increasing wool MSL. PMID- 28902132 TI - Penile Injuries in Immunocastrated and Entire Male Pigs of One Fattening Farm. AB - Penile injuries in boars have been discussed as a relevant welfare problem in pork production with entire males (EM). The incidence of penile injuries with immunocastrated boars has not been described so far. Thus, it was the aim of this study to systematically compare frequency and severity of penile injuries in EM and IC. Incidence and size of penile injuries (wounds, scars, hematomas) were evaluated in 192 IC and 215 EM from one farm after slaughter (120 kg live weight; four batches (BA) in at least weekly intervals over five weeks). 75.8% EM and 48.4% IC showed injuries at the pars libra of the penis. Scars were observed in 71.2% EM and 44.8% IC. Scars/animal were significantly influenced by treatment (IC vs. EM), B and treatment x B and increased with age in EM (BA1: 2.61 +/- 3.05; BA4: 3.59 +/- 3.47), but not in IC (BA1: 2.00 +/- 3.02; BA4: 1.22 +/- 1.91). Wounds were obvious in 17.2% EM and 8.3% IC. Wounds/animal were only influenced significantly by treatment and were lower in IC than in EM. Thus, it is concluded that immunocastration reduces the frequency and severity of penile injuries in IC when compared to EM of same age and weight. PMID- 28902133 TI - Effects of Wildflower Strips and an Adjacent Forest on Aphids and Their Natural Enemies in a Pea Field. AB - Landscape diversification is a key element for the development of sustainable agriculture. This study explores whether the implementation of habitats for pest natural enemies enhances conservation biological control in an adjacent field. In the present study conducted in Gembloux (Belgium) in 2016, the effect of two different habitats (wildflower strips and a forest) and aphid abundance on the density of aphid natural enemies, mummified aphids and parasitism on pea plants was assessed through visual observations. The effect of the habitats on aphids was also evaluated. The habitats but not aphid density significantly affected hoverfly larvae, which were more abundant adjacent to wildflower strips than to the forest. The contrary was observed for ladybeetle adults, which were positively related with aphids but not affected by the adjacent habitats. The abundance of mummies and the parasitism rate were significantly affected by both the habitats and aphid density. They were both significantly enhanced adjacent to wildflower strips compared to the forest, but the total parasitism rate was low (<1%), questioning whether parasitoids could significantly control aphids on the pea crop. As for the aphids, their abundance was not significantly affected by the adjacent habitats. These results are discussed with respect to the potential of these habitats to provide overwintering sites and food resources for natural enemies, and thereby enhance conservation biological control. PMID- 28902134 TI - Retention of Antibacterial Activity in Geranium Plasma Polymer Thin Films. AB - Bacterial colonisation of biomedical devices demands novel antibacterial coatings. Plasma-enabled treatment is an established technique for selective modification of physicochemical characteristics of the surface and deposition of polymer thin films. We investigated the retention of inherent antibacterial activity in geranium based plasma polymer thin films. Attachment and biofilm formation by Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was significantly reduced on the surfaces of samples fabricated at 10 W radio frequency (RF) power, compared to that of control or films fabricated at higher input power. This was attributed to lower contact angle and retention of original chemical functionality in the polymer films fabricated under low input power conditions. The topography of all surfaces was uniform and smooth, with surface roughness of 0.18 and 0.69 nm for films fabricated at 10 W and 100 W, respectively. Hardness and elastic modules of films increased with input power. Independent of input power, films were optically transparent within the visible wavelength range, with the main absorption at ~290 nm and optical band gap of ~3.6 eV. These results suggest that geranium extract-derived polymers may potentially be used as antibacterial coatings for contact lenses. PMID- 28902135 TI - Point Prevalence Surveys of Antimicrobial Use among Hospitalized Children in Six Hospitals in India in 2016. AB - The prevalence of antimicrobial resistance in India is among the highest in the world. Antimicrobial use in inpatient settings is an important driver of resistance, but is poorly characterized, particularly in hospitalized children. In this study, conducted as part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) project, we examined the prevalence of and indications of antimicrobial use, as well as antimicrobial agents used among hospitalized children by conducting four point prevalence surveys in six hospitals between February 2016 and February 2017. A total of 681 children were hospitalized in six hospitals across all survey days, and 419 (61.5%) were prescribed one or more antimicrobials (antibacterials, antivirals, antifungals). Antibacterial agents accounted for 90.8% (547/602) of the total antimicrobial prescriptions, of which third-generation cephalosporins (3GCs) accounted for 38.9% (213/547) and penicillin plus enzyme inhibitor combinations accounted for 14.4% (79/547). Lower respiratory tract infection (LRTI) was the most common indication for prescribing antimicrobials (149 prescriptions; 24.8%). Although national guidelines recommend the use of penicillin and combinations as first-line agents for LRTI, 3GCs were the most commonly prescribed antibacterial agents (55/149 LRTI prescriptions; 36.9%). In conclusion, 61.5% of hospitalized children were on at least one antimicrobial agent, with excessive use of 3GCs. Hence there is an opportunity to limit their inappropriate use. PMID- 28902137 TI - Sensitivity Enhancement in Low Cutoff Wavelength Long-Period Fiber Gratings by Cladding Diameter Reduction. AB - The diameter of long-period fiber gratings (LPFGs) fabricated in optical fibers with a low cutoff wavelength was be reduced by hydrofluoric acid etching, enhancing the sensitivity to refractive index by more than a factor of 3, to 2611 nm/refractive index unit in the range from 1.333 to 1.4278. The grating period selected for the LPFGs allowed access to the dispersion turning point at wavelengths close to the visible range of the optical spectrum, where optical equipment is less expensive. As an example of an application, a pH sensor based on the deposition of a polymeric coating was analyzed in two situations: with an LPFG without diameter reduction and with an LPFG with diameter reduction. Again, a sensitivity increase of a factor of near 3 was obtained, demonstrating the ability of this method to enhance the sensitivity of thin-film-coated LPFG chemical sensors. PMID- 28902136 TI - Dual Strands of Pre-miR-149 Inhibit Cancer Cell Migration and Invasion through Targeting FOXM1 in Renal Cell Carcinoma. AB - Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre miR-144, pre-miR-145, and pre-miR-150, act as antitumor microRNAs (miRNAs) in several cancers. The involvement of passenger strands of miRNAs in cancer pathogenesis is a novel concept in miRNA research. The analysis of a miRNA expression signature in clear cell renal cell carcinoma (ccRCC) has revealed that the guide strand of pre-miR-149 is significantly downregulated in cancer tissues. The aims of this study were to investigate the functional significance of miR 149's guide strand (miR-149-5p) and passenger strand (miR-149-3p), and to identify the oncogenic genes regulated by these miRNAs in ccRCC cells. The ectopic expression of these miRNAs significantly inhibited cancer cell migration and invasion in ccRCC cells. Forkhead box protein M1 (FOXM1) was directly regulated by miR-149-5p and miR-149-3p in ccRCC cells. Knockdown studies using si FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness. Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 * 10-6). Taken together, dual strands of pre-miR-149 (miR-149 5p and miR-149-3p) acted as antitumor miRNAs through the targeting of FOXM1 in ccRCC cells. PMID- 28902139 TI - Autonomous Sensors Powered by Energy Harvesting from von Karman Vortices in Airflow. AB - In this paper an energy harvesting system based on a piezoelectric converter to extract energy from airflow and use it to power battery-less sensors is presented. The converter is embedded as a part of a flexure beam that is put into vibrations by von Karman vortices detached from a bluff body placed upstream. The vortex street has been investigated by Computational Fluid Dynamics (CFD) simulations, aiming at assessing the vortex shedding frequency as a function of the flow velocity. From the simulation results the preferred positioning of the beam behind the bluff body has been derived. In the experimental characterization the electrical output from the converter has been measured for different flow velocities and beam orientations. Highest conversion effectiveness is obtained by an optimal orientation of the beam, to exploit the maximum forcing, and for flow velocities where the repetition frequency of the vortices allows to excite the beam resonant frequency at its first flexural mode. The possibility to power battery-less sensors and make them autonomous has been shown by developing an energy management and signal conditioning electronic circuit plus two sensors for measuring temperature and flow velocity and transmitting their values over a RF signal. A harvested power of about 650 MUW with retransmission intervals below 2 min have been obtained for the optimal flow velocity of 4 m/s. PMID- 28902138 TI - Evolution of RAD- and DIV-Like Genes in Plants. AB - Developmental genetic studies of Antirrhinum majus demonstrated that two transcription factors from the MYB gene family, RADIALIS (RAD) and DIVIRICATA (DIV), interact through antagonism to regulate floral dorsoventral asymmetry. Interestingly, similar antagonistic interaction found among proteins of FSM1 (RAD like) and MYBI (DIV-like) in Solanum lycopersicum is involved in fruit development. Here, we report the reconstruction of the phylogeny of I-box-like and R-R-type clades, where RAD- and DIV-like genes belong, respectively. We also examined the homology of these antagonistic MYB proteins using these phylogenies. The results show that there are likely three paralogs of RAD-/I-box-like genes, RAD1, RAD2, and RAD3, which originated in the common ancestor of the core eudicots. In contrast, R-R-type sequences fall into two major clades, RR1 and RR2, the result of gene duplication in the common ancestor of both monocots and dicots. RR1 was divided into clades RR1A, RR1B, and RR1C, while RR2 was divided into clades RR2A/DIV1, RR2B/DIV2, and RR2C/DIV3. We demonstrate that among similar antagonistic interactions in An. Majus and So. lycopersicum, RAD-like genes originate from the RAD2 clade, while DIV-like genes originate from distantly related paralogs of the R-R-type lineage. The phylogenetic analyses of these two MYB clades lay the foundation for future comparative studies including testing the evolution of the antagonistic relationship of proteins. PMID- 28902140 TI - Iron Absorption from Three Commercially Available Supplements in Gastrointestinal Cell Lines. AB - This study compares the absorption characteristics of two iron-based dietary supplements and their biocompatibility to bisglycinate iron, a common chelated iron form. The Caco-2 cell line-a model of human intestinal absorption-and GTL-16 cell line-a model of gastric epithelial cells-were used to perform the experiments; in the first experiments, the kinetics of absorption have been evaluated analyzing the divalent metal transporter 1 (DMT1) expression. Three different iron combinations containing 50 uM iron (named Fisioeme(r), Sideral(r) and bisglycinate) were used for different stimulation times (1-24 h). After this, the effects of the three iron formulations were assessed in both a short and a long time, in order to understand the extrusion mechanisms. The effects of the three different formulations were also analyzed at the end of stimulation period immediately after iron removal, and after some time in order to clarify whether the mechanisms were irreversibly activated. Findings obtained in this study demonstrate that Fisioeme(r) was able to maintain a significant beneficial effect on cell viability compared to control, to Sideral(r), and to iron bisglycinate. This observation indicates that Fisioeme(r) formulation is the most suitable for gastric and intestinal epithelial cells. PMID- 28902141 TI - The Impacts of Heating Strategy on Soil Moisture Estimation Using Actively Heated Fiber Optics. AB - Several recent studies have highlighted the potential of Actively Heated Fiber Optics (AHFO) for high resolution soil moisture mapping. In AHFO, the soil moisture can be calculated from the cumulative temperature ( T cum ), the maximum temperature ( T max ), or the soil thermal conductivity determined from the cooling phase after heating ( lambda ). This study investigates the performance of the T cum , T max and lambda methods for different heating strategies, i.e., differences in the duration and input power of the applied heat pulse. The aim is to compare the three approaches and to determine which is best suited to field applications where the power supply is limited. Results show that increasing the input power of the heat pulses makes it easier to differentiate between dry and wet soil conditions, which leads to an improved accuracy. Results suggest that if the power supply is limited, the heating strength is insufficient for the lambda method to yield accurate estimates. Generally, the T cum and T max methods have similar accuracy. If the input power is limited, increasing the heat pulse duration can improve the accuracy of the AHFO method for both of these techniques. In particular, extending the heating duration can significantly increase the sensitivity of T cum to soil moisture. Hence, the T cum method is recommended when the input power is limited. Finally, results also show that up to 50% of the cable temperature change during the heat pulse can be attributed to soil background temperature, i.e., soil temperature changed by the net solar radiation. A method is proposed to correct this background temperature change. Without correction, soil moisture information can be completely masked by the background temperature error. PMID- 28902143 TI - Joint Resource Optimization for Cognitive Sensor Networks with SWIPT-Enabled Relay. AB - Energy-constrained wireless networks, such as wireless sensor networks (WSNs), are usually powered by fixed energy supplies (e.g., batteries), which limits the operation time of networks. Simultaneous wireless information and power transfer (SWIPT) is a promising technique to prolong the lifetime of energy-constrained wireless networks. This paper investigates the performance of an underlay cognitive sensor network (CSN) with SWIPT-enabled relay node. In the CSN, the amplify-and-forward (AF) relay sensor node harvests energy from the ambient radio frequency (RF) signals using power splitting-based relaying (PSR) protocol. Then, it helps forward the signal of source sensor node (SSN) to the destination sensor node (DSN) by using the harvested energy. We study the joint resource optimization including the transmit power and power splitting ratio to maximize CSN's achievable rate with the constraint that the interference caused by the CSN to the primary users (PUs) is within the permissible threshold. Simulation results show that the performance of our proposed joint resource optimization can be significantly improved. PMID- 28902144 TI - Implementing Low-Cost, Community-Based Exercise Programs for Middle-Aged and Older Patients with Type 2 Diabetes: What Are the Benefits for Glycemic Control and Cardiovascular Risk? AB - BACKGROUND: The purpose of this study was to analyze the effects of a long-term, community-based, combined exercise program developed with low-cost exercise strategies on glycemic control and cardiovascular risk factors in middle-aged and older patients with type 2 diabetes. METHODS: Participants (n = 124; 63.25 +/- 7.20 years old) engaged in either a 9-month supervised exercise program (n = 39; consisting of combined aerobic, resistance, agility/balance, and flexibility exercise; three sessions per week; 70 min per session) or a control group (n = 85) who maintained their usual care. Glycemic control, lipid profile, blood pressure, anthropometric profile, and the 10-year risk of coronary artery disease were assessed before and after the 9-month intervention. RESULTS: A significant time * group interaction effect (p < 0.001) was identified in the values of the glycated hemoglobin, fasting plasma glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, and the 10-year risk of coronary artery disease. CONCLUSIONS: A long-term, community-based, combined exercise program developed with low-cost exercise strategies was effective in inducing significant benefits on glycemic control, lipid profile, blood pressure, anthropometric profile, and the 10-year risk of coronary artery disease in middle aged and older patients with type 2 diabetes. Clinical Trial Identification Number: ISRCTN09240628. PMID- 28902142 TI - Blood-Brain Barrier Dysfunction and the Pathogenesis of Alzheimer's Disease. AB - Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). While amyloid-beta (Abeta) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist. Although further clinical studies should clarify whether BBB disruption is a specific feature of AD pathogenesis, increasing evidence indicates that each component of the neurovascular unit is significantly affected in the presence of AD-related pathologies in animal models and human patients. Conversely, since some portions of Abeta are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in exacerbated Abeta accumulation in the brain. Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Abeta accumulation and neurovascular unit impairments during disease progression. PMID- 28902145 TI - Replacing American Breakfast Foods with Ready-To-Eat (RTE) Cereals Increases Consumption of Key Food Groups and Nutrients among US Children and Adults: Results of an NHANES Modeling Study. AB - Replacing the typical American breakfast with ready-to-eat cereals (RTECs) may improve diet quality. Our goal was to assess the impact of RTECs on diet quality measures for different age groups, using substitution modeling. Dietary intakes came from the 2007-2010 National Health and Examination Surveys (NHANES; n = 18,112). All breakfast foods, excluding beverages, were replaced on a per calorie basis, with frequency-weighted and age/race specific RTECs. Model 1 replaced foods with RTECs alone; Model 2 replaced foods with RTECs and milk. Diet quality measures were based on desirable food groups and nutrients, Healthy Eating Index (HEI)-2010 scores, and estimated diet costs. Model 1 diets were significantly higher in whole grains (+84.6%), fiber (+14.3%), vitamin D (+14.0%), iron (+54.5%) and folic acid (+104.6%), as compared to observed diets. Model 2 diets were additionally higher in dairy (+15.8%), calcium (+11.3%) and potassium (+3.95%). In Model 1, added sugar increased (+5.0%), but solid fats declined ( 10.9%). Energy from solid fats and added sugars declined (-3.2%) in both models. Model 2 offered higher diet quality (57.1 vs. 54.6, p-value < 0.01) at a lower cost ($6.70 vs. $6.92; p < 0.01), compared to observed diets. Substitution modeling of NHANES data can assess the nutritional and economic impact of dietary guidance. PMID- 28902146 TI - Community Capacity Building for Physical Activity Promotion among Older Adults-A Literature Review. AB - Community-based interventions to promote physical activity (PA) among older adults are of high interest in health promotion since they promise to be effective strategies to reach this population group. Community capacity building, that is, the local promotion of knowledge, skills, commitment, structures, and leadership, is among the recommended core strategies. However, little guidance is provided on how to achieve a high degree of community capacity. This study aims to identify practical strategies to enhance community capacities for PA promotion among older adults (50 years or older) and to evaluate their success. A literature review was conducted using scientific databases (PsycInfo and Web of Sciences) and grey literature (national and international project databases), and 14 studies (16 articles) were identified. Five groups of capacity building strategies emerged from the literature: (1) building community coalitions and networks, (2) training of professionals, (3) training of laypersons, (4) strengthening competence and awareness in the target population, and (5) allocation of financial resources. All studies used more than one strategy. Coalition building and strengthening competence and awareness were most frequently used. Feasibility and acceptability of the capacity building strategies were demonstrated. However, intervention effects on PA behavior and other relevant outcomes were inconsistent. The one study that systematically compared different capacity building approaches did not find any evidence for beneficial effects of intensified capacity building. More rigorous research evaluating the efficacy of specific strategies to enhance community capacities for PA promotion is needed. PMID- 28902147 TI - Chlordetect: Commercial Calcium Aluminate Based Conductimetric Sensor for Chloride Presence Detection. AB - Chloride presence affects different environments (soil, water, concrete) decreasing their qualities. In order to assess chloride concentration this paper proposes a novel sensor for detecting and measuring it. This sensor is based on electric changes of commercial monocalcium aluminate (CA) when it interacts with chloride aqueous solutions. CA is used as a dielectric material between two coplanar capacitors. The geometry proposed for this sensor allows to assess the chloride content profile, or to make four times the same measurement. Besides, the experimental design gives us the possibility of study not just the chloride effect, but also the time and some geometric effects due to the sensor design. As a result, this sensor shows a limit of detection, sensitivity, and response time: 0.01 wt % Cl- and 0.06 wt % Cl-, and 2 min, respectively, comparable with other non invasive techniques as optical fibre sensors. PMID- 28902148 TI - A Fatigue Crack Size Evaluation Method Based on Lamb Wave Simulation and Limited Experimental Data. AB - This paper presents a systematic and general method for Lamb wave-based crack size quantification using finite element simulations and Bayesian updating. The method consists of construction of a baseline quantification model using finite element simulation data and Bayesian updating with limited Lamb wave data from target structure. The baseline model correlates two proposed damage sensitive features, namely the normalized amplitude and phase change, with the crack length through a response surface model. The two damage sensitive features are extracted from the first received S0 mode wave package. The model parameters of the baseline model are estimated using finite element simulation data. To account for uncertainties from numerical modeling, geometry, material and manufacturing between the baseline model and the target model, Bayesian method is employed to update the baseline model with a few measurements acquired from the actual target structure. A rigorous validation is made using in-situ fatigue testing and Lamb wave data from coupon specimens and realistic lap-joint components. The effectiveness and accuracy of the proposed method is demonstrated under different loading and damage conditions. PMID- 28902149 TI - Highly Portable, Sensor-Based System for Human Fall Monitoring. AB - Falls are a very dangerous situation especially among elderly people, because they may lead to fractures, concussion, and other injuries. Without timely rescue, falls may even endanger their lives. The existing optical sensor-based fall monitoring systems have some disadvantages, such as limited monitoring range and inconvenience to carry for users. Furthermore, the fall detection system based only on an accelerometer often mistakenly determines some activities of daily living (ADL) as falls, leading to low accuracy in fall detection. We propose a human fall monitoring system consisting of a highly portable sensor unit including a triaxis accelerometer, a triaxis gyroscope, and a triaxis magnetometer, and a mobile phone. With the data from these sensors, we obtain the acceleration and Euler angle (yaw, pitch, and roll), which represents the orientation of the user's body. Then, a proposed fall detection algorithm was used to detect falls based on the acceleration and Euler angle. With this monitoring system, we design a series of simulated falls and ADL and conduct the experiment by placing the sensors on the shoulder, waist, and foot of the subjects. Through the experiment, we re-identify the threshold of acceleration for accurate fall detection and verify the best body location to place the sensors by comparing the detection performance on different body segments. We also compared this monitoring system with other similar works and found that better fall detection accuracy and portability can be achieved by our system. PMID- 28902150 TI - An Electrochemical, Low-Frequency Seismic Micro-Sensor Based on MEMS with a Force Balanced Feedback System. AB - Electrochemical seismic sensors are key components in monitoring ground vibration, which are featured with high performances in the low-frequency domain. However, conventional electrochemical seismic sensors suffer from low repeatability due to limitations in fabrication and limited bandwidth. This paper presents a micro-fabricated electrochemical seismic sensor with a force-balanced negative feedback system, mainly composed of a sensing unit including porous sensing micro electrodes immersed in an electrolyte solution and a feedback unit including a feedback circuit and a feedback magnet. In this study, devices were designed, fabricated, and characterized, producing comparable performances among individual devices. In addition, bandwidths and total harmonic distortions of the proposed devices with and without a negative feedback system were quantified and compared as 0.005-20 (feedback) Hz vs. 0.3-7 Hz (without feedback), 4.34 +/- 0.38% (without feedback) vs. 1.81 +/- 0.31% (feedback)@1 Hz@1 mm/s and 3.21 +/- 0.25% (without feedback) vs. 1.13 +/- 0.19% (feedback)@5 Hz@1 mm/s (ndevice = 6, n represents the number of the tested devices), respectively. In addition, the performances of the proposed MEMS electrochemical seismometers with feedback were compared to a commercial electrochemical seismic sensor (CME 6011), producing higher bandwidth (0.005-20 Hz vs. 0.016-30 Hz) and lower self-noise levels ( 165.1 +/- 6.1 dB vs. -137.7 dB at 0.1 Hz, -151.9 +/- 7.5 dB vs. -117.8 dB at 0.02 Hz (ndevice = 6)) in the low-frequency domain. Thus, the proposed device may function as an enabling electrochemical seismometer in the fields requesting seismic monitoring at the ultra-low frequency domain. PMID- 28902151 TI - APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel KV10.1. AB - The human ether-a-go-go channel (hEag1 or KV10.1) is a cancer-relevant voltage gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel KV10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on KV10.1 by measuring whole-cell currents as expressed in Xenopus laevis oocytes using the two-microelectrode voltage clamp technique. Fractions that showed activity on Kv10.1 were further purified by RP-HPLC. The amino acid sequence of the peptide was determined by a combination of MALDI- LIFT-TOF/TOF MS/MS and CID-ESI-FT-ICR MS/MS and showed a high similarity with APETx1 and APETx3 and was therefore named APETx4. Subsequently, the peptide was electrophysiologically characterized on KV10.1. The selectivity of the toxin was investigated on an array of voltage-gated ion channels, including the cardiac human ether-a-go-go-related gene potassium channel (hERG or Kv11.1). The toxin inhibits KV10.1 with an IC50 value of 1.1 MUM. In the presence of a similar toxin concentration, a shift of the activation curve towards more positive potentials was observed. Similar to the effect of the gating modifier toxin APETx1 on hERG, the inhibition of Kv10.1 by the isolated toxin is reduced at more positive voltages and the peptide seems to keep the channel in a closed state. Although the peptide also induces inhibitory effects on other KV and NaV channels, it exhibits no significant effect on hERG. Moreover, APETx4 induces a concentration-dependent cytotoxic and proapoptotic effect in various cancerous and noncancerous cell lines. This newly identified KV10.1 inhibitor can be used as a tool to further characterize the oncogenic channel KV10.1 or as a scaffold for the design and synthesis of more potent and safer anticancer drugs. PMID- 28902152 TI - MicroRNAs as Biomarkers in Colorectal Cancer. AB - MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various malignancies, including colorectal cancer (CRC), which is one of the leading causes of cancer-related death worldwide. miRs have also been shown to have applications as diagnostic, prognostic, and predictive biomarkers because of their high tissue specificity, stability, and altered expression in tumor development. In this report, we examined the role of miRs as biomarkers in CRC through a review of meta-analyses and large-scale analyses having strong statistical confidence in the study outcomes. We also discuss current issues in the clinical application of these miRs. PMID- 28902154 TI - Leak Detection and Location of Water Pipes Using Vibration Sensors and Modified ML Prefilter. AB - This paper proposes a new leak detection and location method based on vibration sensors and generalised cross-correlation techniques. Considering the estimation errors of the power spectral densities (PSDs) and the cross-spectral density (CSD), the proposed method employs a modified maximum-likelihood (ML) prefilter with a regularisation factor. We derive a theoretical variance of the time difference estimation error through summation in the discrete-frequency domain, and find the optimal regularisation factor that minimises the theoretical variance in practical water pipe channels. The proposed method is compared with conventional correlation-based techniques via numerical simulations using a water pipe channel model, and it is shown through field measurement that the proposed modified ML prefilter outperforms conventional prefilters for the generalised cross-correlation. In addition, we provide a formula to calculate the leak location using the time difference estimate when different types of pipes are connected. PMID- 28902155 TI - One-Step Facile Synthesis of Aptamer-Modified Graphene Oxide for Highly Specific Enrichment of Human A-Thrombin in Plasma. AB - The enrichment of low-abundance proteins in complex biological samples plays an important role in clinical diagnostics and biomedical research. This work reports a novel one-step method for the synthesis of aptamer-modified graphene oxide (GO/Apt) nanocomposites, without introducing the use of gold, for the rapid and specific separation and enrichment of human alpha-thrombin from buffer solutions with highly concentrated interferences. The obtained GO/Apt nanocomposites had remarkable aptamer immobilization, up to 44.8 nmol/mg. Furthermore, GO/Apt nanocomposites exhibited significant specific enrichment efficiency for human alpha-thrombin (>90%), even under the presence of 3000-fold interference proteins, which was better than the performance of other nanomaterials. Finally, the GO/Apt nanocomposites were applied in the specific capturing of human alpha thrombin in highly concentrated human plasma solutions with negligible nonspecific binding of other proteins, which demonstrated their prospects in rare protein analysis and biosensing applications. PMID- 28902156 TI - Pitting Initiation and Propagation of X70 Pipeline Steel Exposed to Chloride Containing Environments. AB - Inclusion-induced pitting initiation mechanisms in X70 steel were investigated by scanning electron microscopy, scanning Kelvin probe force microscopy (SKPFM), immersion and electrochemical polarization tests in chloride-containing ion solutions. There are three inclusion types in the X70 steel. Corrosion test results indicated that pitting corrosion resistance of type A inclusion < type C inclusion < type B inclusion, i.e., (Mn, Ca)S < matrix < (Al, Ca)O. SKPFM test results show that the type A inclusion exhibited both lower and higher potentials than the matrix, while the type B inclusion exhibited higher potential than the matrix. The corrosion test and the SKPFM potential test results are consistent. Potentiodynamic polarization results indicate that the type A and C are active inclusions, while the type B is an inactive inclusion. Three kinds of possible mechanisms of inclusion-induced pitting corrosion are established for the X70 steel. PMID- 28902153 TI - Bacterial Biofilm Control by Perturbation of Bacterial Signaling Processes. AB - The development of effective strategies to combat biofilm infections by means of either mechanical or chemical approaches could dramatically change today's treatment procedures for the benefit of thousands of patients. Remarkably, considering the increased focus on biofilms in general, there has still not been invented and/or developed any simple, efficient and reliable methods with which to "chemically" eradicate biofilm infections. This underlines the resilience of infective agents present as biofilms and it further emphasizes the insufficiency of today's approaches used to combat chronic infections. A potential method for biofilm dismantling is chemical interception of regulatory processes that are specifically involved in the biofilm mode of life. In particular, bacterial cell to cell signaling called "Quorum Sensing" together with intracellular signaling by bis-(3'-5')-cyclic-dimeric guanosine monophosphate (cyclic-di-GMP) have gained a lot of attention over the last two decades. More recently, regulatory processes governed by two component regulatory systems and small non-coding RNAs have been increasingly investigated. Here, we review novel findings and potentials of using small molecules to target and modulate these regulatory processes in the bacterium Pseudomonas aeruginosa to decrease its pathogenic potential. PMID- 28902158 TI - Controlled Shrinkage of Expanded Glass Particles in Metal Syntactic Foams. AB - Metal matrix syntactic foams have been fabricated via counter-gravity infiltration of a packed bed of recycled expanded glass particles (EG) with A356 aluminum alloy. Particle shrinkage was studied and has been utilized to increase the particles' strength and tailor the mechanical properties of the expanded glass/metal syntactic foam (EG-MSF). The crushing strength of particles could be doubled by shrinking them for 20 min at 700 degrees C. Owing to the low density of EG (0.20-0.26 g/cm3), the resulting foam exhibits a low density (1.03-1.19 g/cm3) that increases slightly due to particle shrinkage. Chemical and physical analyses of EG particles and the resulting foams were conducted. Furthermore, metal syntactic foam samples were tested in uni-axial compression tests. The stress-strain curves obtained exhibit three distinct regions: elastic deformation followed by a stress plateau and densification commencing at 70-80% macroscopic strain. Particle shrinkage increased the mechanical strength of the foam samples and their average plateau stress increased from 15.5 MPa to 26.7 MPa. PMID- 28902157 TI - Triarylborane-Based Materials for OLED Applications. AB - Multidisciplinary research on organic fluorescent molecules has been attracting great interest owing to their potential applications in biomedical and material sciences. In recent years, electron deficient systems have been increasingly incorporated into fluorescent materials. Triarylboranes with the empty p orbital of their boron centres are electron deficient and can be used as strong electron acceptors in conjugated organic fluorescent materials. Moreover, their applications in optoelectronic devices, energy harvesting materials and anion sensing, due to their natural Lewis acidity and remarkable solid-state fluorescence properties, have also been investigated. Furthermore, fluorescent triarylborane-based materials have been commonly utilized as emitters and electron transporters in organic light emitting diode (OLED) applications. In this review, triarylborane-based small molecules and polymers will be surveyed, covering their structure-property relationships, intramolecular charge transfer properties and solid-state fluorescence quantum yields as functional emissive materials in OLEDs. Also, the importance of the boron atom in triarylborane compounds is emphasized to address the key issues of both fluorescent emitters and their host materials for the construction of high-performance OLEDs. PMID- 28902159 TI - Exogenous Melatonin Alleviates Alkaline Stress in Malus hupehensis Rehd. by Regulating the Biosynthesis of Polyamines. AB - Since melatonin was identified in plants decades ago, much attention has been devoted to discovering its role in plant science. There is still a great deal to learn about the functional importance of melatonin, as well as its functional mode. In this paper, we examine the role of melatonin treatment in the response of Malus hupehensis Rehd. to alkaline conditions. Stressed seedlings showed chlorosis and suppressed growth. However, this phenotype was ameliorated when 5 uM melatonin was added to the irrigation solution. This supplementation was also associated with a reduction in cell membrane damage and maintenance of a normal root system architecture. Fewer reactive oxygen species (ROS) were accumulated due to the enhanced scavenging activity of antioxidant enzymes superoxide dismutase, peroxidase, and catalase. In addition, alkaline-stressed seedlings that received the melatonin supplement accumulated more polyamines compared with untreated seedlings. Transcript levels of six genes involved in polyamine synthesis, including SAMDC1, -3, and -4, and SPDS1, -3, and -5, -6, were upregulated in response to melatonin application. All of these results demonstrate that melatonin has a positive function in plant tolerance to alkaline stress because it regulates enzyme activity and the biosynthesis of polyamines. PMID- 28902160 TI - Chitosan Gel Sheet Containing Polymeric Micelles: Synthesis and Gelation Properties of PEG-Grafted Chitosan. AB - Wound-dressing sheet biomaterials can cover wound sites and enhance wound healing. In this study, a detailed evaluation of the factors affecting both the PEG modification percentage (PMP) in poly(ethylene glycol) (PEG)-grafted chitosan synthesis and the gelation properties of PEG-grafted chitosan was presented for constructing our novel hybrid hydrogel sheet consisting of PEG-grafted chitosan (a gel-forming polymer) and a reactive polymeric micelle (a crosslinker). It was confirmed that various factors (i.e., the weight ratio of PEG/chitosan, the pH of the buffer solution, reaction times, and reaction temperatures) in the preparation stage of PEG-grafted chitosans affected the PMP of PEG-grafted chitosans. Furthermore, the PMP of PEG-grafted chitosans affected their gelation properties. Finally, a 'flexible' hydrogel sheet that can be reversibly dried and moistened was successfully obtained. The dried rigid, thin sheet is expected to be suitable for stable preservation. The results obtained in this paper show that the incorporation of drug carriers into biomaterials is a novel approach to improve functionality. PMID- 28902161 TI - Biological Evaluation of Flexible Polyurethane/Poly l-Lactic Acid Composite Scaffold as a Potential Filler for Bone Regeneration. AB - Degradable bone graft substitute for large-volume bone defects is a continuously developing field in orthopedics. With the advance in biomaterial in past decades, a wide range of new materials has been investigated for their potential in this application. When compared to common biopolymers within the field such as PLA or PCL, elastomers such as polyurethane offer some unique advantages in terms of flexibility. In cases of bone defect treatments, a flexible soft filler can help to establish an intimate contact with surrounding bones to provide a stable bone material interface for cell proliferation and ingrowth of tissue. In this study, a porous filler based on segmented polyurethane incorporated with poly l-lactic acid was synthesized by a phase inverse salt leaching method. The filler was put through in vitro and in vivo tests to evaluate its potential in acting as a bone graft substitute for critical-sized bone defects. In vitro results indicated there was a major improvement in biological response, including cell attachment, proliferation and alkaline phosphatase expression for osteoblast-like cells when seeded on the composite material compared to unmodified polyurethane. In vivo evaluation on a critical-sized defect model of New Zealand White (NZW) rabbit indicated there was bone ingrowth along the defect area with the introduction of the new filler. A tight interface formed between bone and filler, with osteogenic cells proliferating on the surface. The result suggested polyurethane/poly l lactic acid composite is a material with the potential to act as a bone graft substitute for orthopedics application. PMID- 28902162 TI - Percentage of Body Fat and Fat Mass Index as a Screening Tool for Metabolic Syndrome Prediction in Colombian University Students. AB - High body fat is related to metabolic syndrome (MetS) in all ethnic groups. Based on the International Diabetes Federation (IDF) definition of MetS, the aim of this study was to explore thresholds of body fat percentage (BF%) and fat mass index (FMI) for the prediction of MetS among Colombian University students. A cross-sectional study was conducted on 1687 volunteers (63.4% women, mean age = 20.6 years). Weight, waist circumference, serum lipids indices, blood pressure, and fasting plasma glucose were measured. Body composition was measured by bioelectrical impedance analysis (BIA) and FMI was calculated. MetS was defined as including more than or equal to three of the metabolic abnormalities according to the IDF definition. Receiver operating curve (ROC) analysis was used to determine optimal cut-off points for BF% and FMI in relation to the area under the curve (AUC), sensitivity, and specificity in both sexes. The overall prevalence of MetS was found to be 7.7%, higher in men than women (11.1% vs. 5.3%; p < 0.001). BF% and FMI were positively correlated to MetS components (p < 0.05). ROC analysis indicated that BF% and FMI can be used with moderate accuracy to identify MetS in university-aged students. BF% and FMI thresholds of 25.55% and 6.97 kg/m2 in men, and 38.95% and 11.86 kg/m2 in women, were found to be indicative of high MetS risk. Based on the IDF criteria, both indexes' thresholds seem to be good tools to identify university students with unfavorable metabolic profiles. PMID- 28902163 TI - Infants' and Children's Salt Taste Perception and Liking: A Review. AB - Sodium is an essential nutrient for the human body. It is widely used as sodium chloride (table salt) in (processed) foods and overconsumed by both children and adults, placing them at risk for adverse health effects such as high blood pressure and cardiovascular diseases. The current review focusses on the development of salt taste sensitivity and preferences, and its association with food intake. Three -to- four month old infants are able to detect and prefer sodium chloride solutions over plain water, which is thought to be a biological unlearned response. Liking for water with sodium chloride mostly decreases when infants enter early childhood, but liking for sodium chloride in appropriate food contexts such as soup and snack foods remains high. The increased acceptance and preference of sodium chloride rich foods coincides with infants' exposure to salty foods, and is therefore thought to be mostly a learned response. Children prefer higher salt concentrations than adults, but seem to be equally sensitive to salt taste. The addition of salt to foods increases children's consumption of those foods. However, children's liking for salt taste as such does not seem to correlate with children's consumption of salty foods. Decreasing the exposure to salty tasting foods during early infancy is recommended. Salt plays an important role in children's liking for a variety of foods. It is, however, questionable if children's liking for salt per se influences the intake of salty foods. PMID- 28902164 TI - SlBIR3 Negatively Regulates PAMP Responses and Cell Death in Tomato. AB - Bri1-associated kinase 1 (BAK1)-interacting receptor-like kinase (BIR) proteins have been shown to play important roles in regulating growth and development, pathogen associated molecular pattern (PAMP)-triggered immunity (PTI) responses, and cell death in the model plant, Arabidopsis thaliana. We identified four BIR family members in tomato (Solanum lycopersicum), including SlBIR3, an ortholog of AtBIR3 from A. thaliana. SlBIR3 is predicted to encode a membrane localized non arginine-aspartate (non-RD) kinase that, based on protein sequence, does not have autophosphorylation activity but that can be phosphorylated in vivo. We established that SlBIR3 interacts with SlBAK1 and AtBAK1 using yeast two-hybrid assays and co-immunoprecipitation and maltose-binding protein pull down assays. We observed that SlBIR3 overexpression in tomato (cv. micro-tom) and A. thaliana has weak effect on growth and development through brassinosteroid (BR) signaling. SlBIR3 overexpression in A. thaliana suppressed flg22-induced defense responses, but did not affect infection with the bacterial pathogen Pseudomonas syringae (PstDC3000). This result was confirmed using virus-induced gene silencing (VIGS) in tomato in conjunction with PstDC3000 infection. Overexpression of SlBIR3 in tomato (cv. micro-tom) and A. thaliana resulted in enhanced susceptibility to the necrotrophic fungus Botrytis cinerea. In addition, co-silencing SlBIR3 with SlSERK3A or SlSERK3B using VIGS and the tobacco rattle virus (TRV)-RNA2 vector containing fragments of both the SlSERK3 and SlBIR3 genes induced spontaneous cell death, indicating a cooperation between the two proteins in this process. In conclusion, our study revealed that SlBIR3 is the ortholog of AtBIR3 and that it participates in BR, PTI, and cell death signaling pathways. PMID- 28902165 TI - Development of Novel Nrf2/ARE Inducers Bearing Pyrazino[2,1-a]isoquinolin Scaffold with Potent In Vitro Efficacy and Enhanced Physicochemical Properties. AB - Pyrazino[2,1-a]isoquinolin analogues were reported as potent activators of Nrf2/ARE signaling both in vitro and in vivo by our group. In this study, we simplified the ring system to investigate the functions of various parts of the pyrazino[2,1-a]isoquinolin scaffold. We proved that the tetrahydroisoquinoline was not essential for activity and the pyrido[1,2-a]pyrazin analogues 3b and 3g retained the cellular Nrf2/ARE activation activity. Besides, this simplification significantly enhanced water solubility and membrane permeability, indicating that these compounds are more favourable for the further development of therapeutic agents around Nrf2 activation. PMID- 28902167 TI - Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl Substituted Benzene-Sulfonamide Conjugates with Amino Acids. AB - Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (>=95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures. PMID- 28902168 TI - Measuring the Pull-Off Force of an Individual Fiber Using a Novel Picoindenter/Scanning Electron Microscope Technique. AB - We employed a novel picoindenter (PI)/scanning electron microscopy (SEM) technique to measure the pull-off force of an individual electrospun poly(vinylidene fluoride) (PVDF) fibers. Individual fibers were deposited over a channel in a custom-designed silicon substrate, which was then attached to a picoindenter. The picoindenter was then positioned firmly on the sample stage of the SEM. The picoindenter tip laterally pushed individual fibers to measure the force required to detach it from the surface of substrate. SEM was used to visualize and document the process. The measured pull-off force ranged between 5.8 +/- 0.2 MUN to ~17.8 +/- 0.2 MUN for individual fibers with average diameter ranging from 0.8 to 2.3 MUm. Thus, this study, a first of its kind, demonstrates the use of a picoindenter to measure the pull-off force of a single micro/nanofiber. PMID- 28902166 TI - Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases. AB - Protein homeostasis or proteostasis is a fundamental cellular property that encompasses the dynamic balancing of processes in the proteostasis network (PN). Such processes include protein synthesis, folding, and degradation in both non stressed and stressful conditions. The role of the PN in neurodegenerative disease is well-documented, where it is known to respond to changes in protein folding states or toxic gain-of-function protein aggregation. Dual-specificity phosphatases have recently emerged as important participants in maintaining balance within the PN, acting through modulation of cellular signaling pathways that are involved in neurodegeneration. In this review, we will summarize recent findings describing the roles of dual-specificity phosphatases in neurodegeneration and offer perspectives on future therapeutic directions. PMID- 28902169 TI - Whispering-Gallery Mode Resonators for Detecting Cancer. AB - Optical resonators are sensors well known for their high sensitivity and fast response time. These sensors have a wide range of applications, including in the biomedical fields, and cancer detection is one such promising application. Sensor diagnosis currently has many limitations, such as being expensive, highly invasive, and time-consuming. New developments are welcomed to overcome these limitations. Optical resonators have high sensitivity, which enable medical testing to detect disease in the early stage. Herein, we describe the principle of whispering-gallery mode and ring optical resonators. We also add to the knowledge of cancer biomarker diagnosis, where we discuss the application of optical resonators for specific biomarkers. Lastly, we discuss advancements in optical resonators for detecting cancer in terms of their ability to detect small amounts of cancer biomarkers. PMID- 28902170 TI - Lipase Activity in the Larval Midgut of Rhynchophorus palmarum: Biochemical Characterization and the Effects of Reducing Agents. AB - Lipases have key roles in insect lipid acquisition, storage, and mobilization and are also fundamental to many physiological processes in insects. Lipids are an important component of insect diets, where they are hydrolyzed in the midgut lumen, absorbed, and used for the synthesis of complex lipids. The South American palm weevil Rhynchophorus palmarum is one of the most important pests on commercial palm plantations. However, there are few studies about lipid digestion for this insect. In this work, we have described the biochemical characterization of the lipase activity in the posterior midgut of the R. palmarum palm weevil. Lipase activity was highest between the temperatures of 37 degrees C and 45 degrees C and at pH 6.5. Lipase activity was also sensitive to variations in salt and calcium concentrations. Lipases have been described structurally as enzymes with the Ser-His-Asp Catalytic Triad, containing an active serine. The serine protease inhibitor PMSF (phenylmethane sulfonyl fluoride) inhibited the lipases from R. palmarum, demonstrating the importance of a serine residue for this activity. The ability of the lipases to hydrolyze p-Nitrophenyl esters with different chain lengths has revealed the activities of a broad range of substrates. The lipase activities of R. palmarum increased in the presence of reduced glutathione (GSH) and dithiothreitol (DTT), while in the presence of oxidized glutathione (GSSG), activities were drastically reduced. To our knowledge, this study has provided the first information about lipase activity in the R. palmarum palm weevil. PMID- 28902171 TI - A Possible Indicator of Oxidative Damage in Smokers: (13Z)-Lycopene? AB - In vitro, the gaseous phase of cigarette smoke is known to induce both isomerization and degradation of dietary carotenoids, such as beta-carotene and lycopene. However, the effects of cigarette smoke on the composition of circulating lycopene in vivo are not well understood. In this study, we examined the lycopene profiles of plasma from non-smokers and smokers. No oxidative intermediates of lycopene that have been observed previously in vitro were detected in the plasma, but evidence of isomerization of the carotenoid was seen. Four geometric forms of lycopene were detected in the plasma of both smokers and non-smokers, namely the (5Z), (9Z), (13Z) and (all-E) forms. The relative amounts of these isomers differed between the two cohorts and there was a significant difference (p < 0.05) between smokers and non-smokers for the ratio of total Z:all-E lycopene, and in the relative amounts of (13Z) and (all-E)-lycopene. The ratio of (all-E):(13Z)-lycopene was 0.84:1.00 in smokers compared to 1.04:1.00 in non-smokers. In smokers, the (13Z)-isomer was generated in preference to the more thermodynamically stable (5Z) and (9Z)-isomers. This mirrors the scenario seen in vitro, in which the formation of (13Z)-lycopene was the main isomer that accompanied the depletion of (all-E) lycopene, when exposed to cigarette smoke. The results suggest that the relative amount of (13Z)-lycopene could be used as an indicator of oxidative damage to lycopene in vivo. PMID- 28902172 TI - Behavioral and Neurochemical Consequences of Pentylenetetrazol-Induced Kindling in Young and Middle-Aged Rats. AB - (1) Objectives: Epilepsy disorder is likely to increase with aging, leading to an increased incidence of comorbidities and mortality. In spite of that, there is a lack of information regarding this issue and little knowledge of cognitive and emotional responses in aging subjects following epileptogenesis. We investigated whether and how aging distress epilepsy-related behavioral and biochemical outcomes are associated with cognition and emotion. (2) Methods: Young and middle aged Wistar rats (3 or 12 months old) were treated with pentylenetetrazol (PTZ, 35 mg/kg) and injected on alternated days for 20 (young rats) and 32 days (middle aged rats). Kindling was reached after two consecutive stages 4 plus one stage 5 or 6 in Racine scale. Control and kindled rats were evaluated in the elevated plus-maze (EPM) and object-recognition tests and their hippocampus was collected 24 h later for mitogen-activated protein kinases (MAPK) dosage. (3) Results: Middle-aged rats presented a higher resistance to develop kindling, with a decrease in the seizure severity index observed following the 4th and 9th PTZ injections. Middle-aged rats displayed an increased duration of the first myoclonic seizure and an increased latency to the first generalized seizure when compared to younger rats. The induction of kindling did not impair the animals' performance (regardless of age) in the object-recognition task and the EPM test as well as it did not alter the hippocampal levels of MAPKs. (4) Significance: Our findings reveal that, despite age-related differences during epileptogenesis, middle-aged rats evaluated after kindling performed similarly during discriminative learning and emotional tasks in comparison to young animals, with no alteration of hippocampal MAPKs. Additional investigation must be carried out to explore the electrophysiological mechanisms underlying these responses, as well as the long-term effects displayed after kindling. PMID- 28902173 TI - Concept for Recycling Waste Biomass from the Sugar Industry for Chemical and Biotechnological Purposes. AB - The objective of this study was to develop a method for the thermally-assisted acidic hydrolysis of waste biomass from the sugar industry (sugar beet pulp and leaves) for chemical and biotechnological purposes. The distillates, containing furfural, can be catalytically reduced directly into furfurayl alcohol or tetrahydrofurfuryl alcohol. The sugars present in the hydrolysates can be converted by lactic bacteria into lactic acid, which, by catalytic reduction, leads to propylene glycol. The sugars may also be utilized by microorganisms in the process of cell proliferation, and the biomass obtained used as a protein supplement in animal feed. Our study also considered the effects of the mode and length of preservation (fresh, ensilage, and drying) on the yields of furfural and monosaccharides. The yield of furfural in the distillates was measured using gas chromatography with flame ionization detector (GC-FID). The content of monosaccharides in the hydrolysates was measured spectrophotometrically using enzymatic kits. Biomass preserved under all tested conditions produced high yields of furfural, comparable to those for fresh material. Long-term storage of ensiled waste biomass did not result in loss of furfural productivity. However, there were significant reductions in the amounts of monosaccharides in the hydrolysates. PMID- 28902174 TI - Distribution of Non-Persistent Endocrine Disruptors in Two Different Regions of the Human Brain. AB - Non-persistent endocrine disrupting chemicals (npEDCs) can affect multiple organs and systems in the body. Whether npEDCs can accumulate in the human brain is largely unknown. The major aim of this pilot study was to examine the presence of environmental phenols and parabens in two distinct brain regions: the hypothalamus and white-matter tissue. In addition, a potential association between these npEDCs concentrations and obesity was investigated. Post-mortem brain material was obtained from 24 individuals, made up of 12 obese and 12 normal-weight subjects (defined as body mass index (BMI) > 30 and BMI < 25 kg/m2, respectively). Nine phenols and seven parabens were measured by isotope dilution TurboFlow-LC-MS/MS. In the hypothalamus, seven suspect npEDCs (bisphenol A, triclosan, triclocarban and methyl-, ethyl-, n-propyl-, and benzyl paraben) were detected, while five npEDCs (bisphenol A, benzophenone-3, triclocarban, methyl-, and n-propyl paraben) were found in the white-matter brain tissue. We observed higher levels of methylparaben (MeP) in the hypothalamic tissue of obese subjects as compared to controls (p = 0.008). Our findings indicate that some suspected npEDCs are able to cross the blood-brain barrier. Whether the presence of npEDCs can adversely affect brain function and to which extent the detected concentrations are physiologically relevant needs to be further investigated. PMID- 28902175 TI - Prediction Equations Overestimate the Energy Requirements More for Obesity Susceptible Individuals. AB - Predictive equations to estimate resting metabolic rate (RMR) are often used in dietary counseling and by online apps to set energy intake goals for weight loss. It is critical to know whether such equations are appropriate for those susceptible to obesity. We measured RMR by indirect calorimetry after an overnight fast in 26 obesity susceptible (OSI) and 30 obesity resistant (ORI) individuals, identified using a simple 6-item screening tool. Predicted RMR was calculated using the FAO/WHO/UNU (Food and Agricultural Organisation/World Health Organisation/United Nations University), Oxford and Miflin-St Jeor equations. Absolute measured RMR did not differ significantly between OSI versus ORI (6339 vs. 5893 kJ.d-1, p = 0.313). All three prediction equations over-estimated RMR for both OSI and ORI when measured RMR was <=5000 kJ.d-1. For measured RMR <=7000 kJ.d-1 there was statistically significant evidence that the equations overestimate RMR to a greater extent for those classified as obesity susceptible with biases ranging between around 10% to nearly 30% depending on the equation. The use of prediction equations may overestimate RMR and energy requirements particularly in those who self-identify as being susceptible to obesity, which has implications for effective weight management. PMID- 28902176 TI - Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative. AB - Doxorubicin (Dox) is an effective anti-cancer medication with poor oral bioavailability and systemic toxicities. DoxQ was developed by conjugating Dox to the lymphatically absorbed antioxidant quercetin to improve Dox's bioavailability and tolerability. The purpose of this study was to characterize the pharmacokinetics and safety of Dox after intravenous (IV) and oral (PO) administration of DoxQ or Dox (10 mg/kg) and investigate the intestinal lymphatic delivery of Dox after PO DoxQ administration in male Sprague-Dawley rats. Drug concentrations in serum, urine, and lymph were quantified by HPLC with fluorescence detection. DoxQ intact IV showed a 5-fold increase in the area under the curve (AUC)-18.6 +/- 1.98 compared to 3.97 +/- 0.71 MUg * h/mL after Dox-and a significant reduction in the volume of distribution (Vss): 0.138 +/- 0.015 versus 6.35 +/- 1.06 L/kg. The fraction excreted unchanged in urine (fe) of IV DoxQ and Dox was ~5% and ~11%, respectively. Cumulative amounts of Dox in the mesenteric lymph fluid after oral DoxQ were twice as high as Dox in a mesenteric lymph duct cannulation rat model. Oral DoxQ increased AUC of Dox by ~1.5-fold compared to after oral Dox. Concentrations of beta-N-Acetylglucosaminidase (NAG) but not cardiac troponin (cTnI) were lower after IV DoxQ than Dox. DoxQ altered the pharmacokinetic disposition of Dox, improved its renal safety and oral bioavailability, and is in part transported through intestinal lymphatics. PMID- 28902177 TI - The Use of Terrestrial Laser Scanning for Determining the Driver's Field of Vision. AB - Terrestrial laser scanning (TLS) is currently one of the most progressively developed methods in obtaining information about objects and phenomena. This paper assesses the TLS possibilities in determining the driver's field of vision in operating agricultural and forest machines with movable and immovable components in comparison to the method of using two light point sources for the creation of shade images according to ISO (International Organization for Standardization) 5721-1. Using the TLS method represents a minimum time saving of 55% or more, according to the project complexity. The values of shading ascertained by using the shadow cast method by the point light sources are generally overestimated and more distorted for small cabin structural components. The disadvantage of the TLS method is the scanner's sensitivity to a soiled or scratched cabin windscreen and to the glass transparency impaired by heavy tinting. PMID- 28902179 TI - Water Diffusion through a Titanium Dioxide/Poly(Carbonate Urethane) Nanocomposite for Protecting Cultural Heritage: Interactions and Viscoelastic Behavior. AB - Water diffusion through a TiO2/poly (carbonate urethane) nanocomposite designed for the eco-sustainable protection of outdoor cultural heritage stonework was investigated. Water is recognized as a threat to heritage, hence the aim was to gather information on the amount of water uptake, as well as of species of water molecules absorbed within the polymer matrix. Gravimetric and vibrational spectroscopy measurements demonstrated that diffusion behavior of the nanocomposite/water system is Fickian, i.e., diffusivity is independent of concentration. The addition of only 1% of TiO2 nanoparticles strongly betters PU barrier properties and water-repellency requirement is imparted. Defensive action against penetration of water free from, and bonded through, H-bonding association arises from balance among TiO2 hydrophilicity, tortuosity effects and quality of nanoparticle dispersion and interfacial interactions. Further beneficial to antisoiling/antigraffiti action is that water-free fraction was found to be desorbed at a constant rate. In environmental conditions, under which weathering processes are most likely to occur, nanocomposite Tg values remain suitable for heritage treatments. PMID- 28902180 TI - Vision-Based Real-Time Traversable Region Detection for Mobile Robot in the Outdoors. AB - Environment perception is essential for autonomous mobile robots in human-robot coexisting outdoor environments. One of the important tasks for such intelligent robots is to autonomously detect the traversable region in an unstructured 3D real world. The main drawback of most existing methods is that of high computational complexity. Hence, this paper proposes a binocular vision-based, real-time solution for detecting traversable region in the outdoors. In the proposed method, an appearance model based on multivariate Gaussian is quickly constructed from a sample region in the left image adaptively determined by the vanishing point and dominant borders. Then, a fast, self-supervised segmentation scheme is proposed to classify the traversable and non-traversable regions. The proposed method is evaluated on public datasets as well as a real mobile robot. Implementation on the mobile robot has shown its ability in the real-time navigation applications. PMID- 28902178 TI - Tumor Inhibitory Effect of IRCR201, a Novel Cross-Reactive c-Met Antibody Targeting the PSI Domain. AB - Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth. PMID- 28902181 TI - Platelet-derived growth factor receptor alpha-positive cells: a new cell type in the human ureteropelvic junction. AB - BACKGROUND: Ureteropelvic junction (UPJ) obstruction is the most common cause of congenital hydronephrosis. Normal ureteral motility requires coordinated interaction between neurons, smooth muscle cells (SMCs), and interstitial Cajal like cells (IC-LCs). Recently, a new type of interstitial cell, platelet-derived growth factor receptor alpha-positive (PDGFRalpha+) cells, was discovered in the gastrointestinal tract and bladder.MethodsWe used immunohistochemistry to study PDGFRalpha protein distribution in normal human UPJ and congenital UPJ obstruction. Western blot and real-time PCR (RT-PCR) were used to study PDGFRalpha protein and gene expression levels. In addition, closely associated cells and small conductance Ca2+-activated K+ (SK) channels were investigated.ResultsPDGFRalpha+ cells were distinct from IC-LCs and SMCs and were in close proximity to nerve fibers. PDGFRalpha+ cells expressed SK3 channels, which are thought to mediate purinergic inhibitory neurotransmission in SMCs. The distribution of PDGFRalpha+ cells was similar in UPJ obstruction vs. CONTROLS: However, the expression of SK3 channels in PDGFRalpha+ cells was decreased in UPJ obstruction vs. CONTROLS: ConclusionThis study shows, for the first time, the PDGFRalpha+ cell expression in the human UPJ. Altered SK3 channel expression observed in PDGFRalpha+ cells in UPJ obstruction suggests that the impairment of SK3 activity across the UPJ may perturb upper urinary tract peristalsis in this urological condition. PMID- 28902182 TI - Gestational age-dependent relationship between cerebral oxygen extraction and blood pressure. AB - BackgroundPremature infants may lack mature cerebrovascular autoregulatory function and fail to adapt oxygen extraction to decreasing systemic perfusion.MethodsInfants <=28 weeks of gestational age (GA) were recruited. Systemic oxygen saturation (SpO2), mean arterial blood pressure (MABP), and cerebral saturation (near-infrared spectroscopy, SctO2) were measured continuously over the first 72 h. Resulting data underwent error-processing. For each remaining 10 m window, the mean MABP and fractional tissue oxygen extraction (FTOE) were calculated. The infants were divided into two groups (23-25 and 26-28 weeks). The median FTOE at low, medium, and high MABP values (empirically defined within each group based on the 25th and 75th centile) were compared between estimated gestational age (EGA) groups.ResultsSample n=68, mean+/-SD GA=25.5+/ 1.3 weeks, and birthweight (BW)=823+/-195 g. The median FTOE in the more preterm group vs. more mature group was statistically different at lower value of MABP (P<0.01) and higher values of MABP (P=0.01), but not at medium values (P=0.55).ConclusionThe more mature group (GA 26-28 weeks) displayed an appropriate increase in oxygen extraction during hypotension, steadily decreasing as MABP increased, suggesting mature autoregulation. An opposite response was noted in the more preterm group, suggesting an inability to mount a compensatory response when BP is outside of the physiologic range. PMID- 28902183 TI - Patient characteristics affect the response to ketamine and opioids during the treatment of vaso-occlusive episode-related pain in sickle cell disease. AB - BackgroundN-methyl-D-aspartate receptor activation has been implicated in the pathobiology of inflammatory, nociceptive and neuropathic pain, opioid tolerance, opioid-induced hyperalgesia, and central sensitization. Some of those mechanisms underlie sickle cell disease(SCD)-associated pain.MethodsWe conducted an exploratory cohort study of SCD patients who during vaso-occlusive episodes (VOEs) received subanesthetic doses of the N-methyl-D-aspartate receptor antagonist, ketamine, as an adjunct to opioids. We sought to identify predictors of changes in pain scores and of the percentage of ketamine infusions associated with meaningful changes (>=20% reduction) in pain and opioid consumption.ResultsEight-five patients received 181 ketamine infusions for VOE associated pain. Combined with opioids, ketamine yielded significant decrease in pain scores and opioid consumption. Ketamine administered to males and to younger patients yielded greater pain score decrease compared with females (P=0.013) and older patients (P=0.018). Fifty-four percent of infusions yielded meaningful reductions in pain scores, and in multivariate analysis, sex, age group, pain location, and infusion duration independently predicted pain score changes.ConclusionThis study suggests that in SCD patients admitted with VOE associated pain, ketamine has age- and sex-dependent effects. These data can inform sample and effect size calculations for controlled trials to determine which SCD patients would benefit most from ketamine. PMID- 28902185 TI - Influences of medications on the developing fetus: toward deciphering the unknowns. PMID- 28902186 TI - Early career investigator highlight-November. PMID- 28902184 TI - The relationship between infancy growth rate and the onset of puberty in both genders. AB - BackgroundIn this study, we examined the hypothesis that weight gain and linear growth during the first years of life influence the onset of puberty both in girls and in boys.MethodsA cohort of 157 healthy children, aged 6-9 years, was evaluated and their growth patterns were analyzed retrospectively. Repeated measures mixed model was used to examine the longitudinal anthropometric data.ResultsGirls with pubertal signs were heavier than their peers starting at 9 months of age (P=0.02), and the difference became more evident over time (P<0.001). Accelerated weight gain between 6 and 15 months of age was found to increase the odds of having a pubertal sign at the study visit (odds ratio (OR)=34.5) after adjusting for birth weight, gestational age and current age, height, weight, and BMI (P=0.004). Anthropometric indices of boys with or without pubertal signs were not significantly different at the study visit, but boys with accelerated height gain between 9 and 15 months of age were more likely to have pubertal signs (OR=15.8) after adjusting for birth weight, gestational age and current age, height, weight, and BMI (P=0.016).ConclusionEarly growth acceleration might be important for the timing of puberty in both genders. PMID- 28902187 TI - "Pressure" to feed the preterm newborn: associated with "positive" outcomes? PMID- 28902188 TI - Reproductive interference and fecundity affect competitive interactions of sibling species with low mating barriers: experimental and theoretical evidence. AB - When allopatric species with incomplete prezygotic isolation come into secondary contact, the outcome of their interaction is not easily predicted. The parasitoid wasp Encarsia suzannae (iES), infected by Cardinium inducing cytoplasmic incompatibility (CI), and its sibling species E. gennaroi (EG), not infected by bacterial endosymbionts, may have diverged because of the complementary action of CI and asymmetric hybrid incompatibilities. Whereas postzygotic isolation is now complete because of sterility of F1 hybrid progeny, prezygotic isolation is still incipient. We set up laboratory population cage experiments to evaluate the outcome of the interaction between ES and EG in two pairwise combinations: iES vs EG and cured ES (cES, where Cardinium was removed with antibiotics) vs EG. We also built a theoretical model aimed at exploring the role of life-history differences and asymmetric mating on competitive outcomes. In three of four cages in each treatment, ES dominated the interaction. We found evidence for reproductive interference, driven by asymmetric mating preferences, that gave a competitive edge to ES, the species that better discriminated against heterospecifics. However, we did not find the fecundity cost previously shown to be associated with Cardinium infection in iES. The model largely supported the experimental results. The finding of only a slight competitive edge of ES over EG in population cages suggests that in a more heterogeneous environment the species could coexist. This is supported by evidence that the two species coexist in sympatry, where preliminary data suggest reproductive character displacement may have reinforced postzygotic isolation. PMID- 28902191 TI - Polyoxometalates as sialidase mimics: selective and non-destructive removal of sialic acid from a glycoprotein promoted by phosphotungstic acid. AB - The selective hydrolysis of the glycosidic bond between the terminal sialic acid and the penultimate sugar has been achieved in the alpha-2-HS-glycoprotein (Fetuin-A) in the presence of H3PW12O40, a Keggin type polyoxometalate. A controlled liberation of sialic acid from the glycoprotein could be achieved at pH 3.0 and 37 degrees C without the destruction of the protein backbone. PMID- 28902189 TI - Admixture on the northern front: population genomics of range expansion in the white-footed mouse (Peromyscus leucopus) and secondary contact with the deer mouse (Peromyscus maniculatus). AB - Range expansion has genetic consequences expected to result in differentiated wave-front populations with low genetic variation and potentially introgression from a local species. The northern expansion of Peromyscus leucopus in southern Quebec provides an opportunity to test these predictions using population genomic tools. Our results show evidence of recent and post-glacial expansion. Genome wide variation in P. leucopus indicates two post-glacial lineages are separated by the St. Lawrence River, with a more recent divergence of populations isolated by the Richelieu River. In two of three transects we documented northern populations with low diversity in at least one genetic measure, although most relationships were not significant. Consistent with bottlenecks and allele surfing during northward expansion, we document a northern-most population with low nucleotide diversity, divergent allele frequencies and the most private alleles, and observed heterozygosity indicates outcrossing. Ancestry proportions revealed putative hybrids of P. leucopus and P. maniculatus. A formal test for gene flow confirmed secondary contact, showing that a reticulate population phylogeny between P. maniculatus and P. leucopus was a better fit to the data than a bifurcating model without gene flow. Thus, we provide the first genomic evidence of gene flow between this pair of species in natural populations. Understanding the evolutionary consequences of secondary contact is an important conservation concern as climate-induced range expansions are expected to result in new hybrid zones between closely related species. PMID- 28902190 TI - The effects of outbreeding on a parasitoid wasp fixed for infection with a parthenogenesis-inducing Wolbachia symbiont. AB - Trichogramma wasps can be rendered asexual by infection with the maternally inherited symbiont Wolbachia. Previous studies indicate the Wolbachia strains infecting Trichogramma wasps are host-specific, inferred by failed horizontal transfer of Wolbachia to novel Trichogramma hosts. Additionally, Trichogramma can become dependent upon their Wolbachia infection for the production of female offspring, leaving them irreversibly asexual, further linking host and symbiont. We hypothesized Wolbachia strains infecting irreversibly asexual, resistant to horizontal transfer Trichogramma would show adaptation to a particular host genetic background. To test this, we mated Wolbachia-dependent females with males from a Wolbachia-naive population to create heterozygous wasps. We measured sex ratios and fecundity, a proxy for Wolbachia fitness, produced by heterozygous wasps, and by their recombinant offspring. We find a heterozygote advantage, resulting in higher fitness for Wolbachia, as wasps will produce more offspring without any reduction in the proportion of females. While recombinant wasps did not differ in total fecundity after 10 days, recombinants produced fewer offspring early on, leading to an increased female-biased sex ratio for the whole brood. Despite the previously identified barriers to horizontal transfer of Wolbachia to and from Trichogramma pretiosum, there were no apparent barriers for Wolbachia to induce parthenogenesis in these non-native backgrounds. This is likely due to the route of infection being introgression rather than horizontal transfer, and possibly the co-evolution of Wolbachia with the mitochondria rather than the nuclear genome. These results help to elucidate the mechanisms by which Wolbachia adapt to hosts and the evolution of host-symbiont phenotypes. PMID- 28902192 TI - Growth and assembly of cobalt oxide nanoparticle rings at liquid nanodroplets with solid junction. AB - Using liquid cell TEM, we imaged the formation of CoO nanoparticle rings. Nanoparticles nucleated and grew tracing the perimeter of droplets sitting on the SiNx solid substrate, and finally formed necklace-like rings. By tracking single nanoparticle trajectories during the ring formation and an estimation of the forces between droplets and nanoparticles using a simplified model, we found the junction of liquid nanodroplets with a solid substrate is the attractive site for CoO nanoparticles. Coalescing droplets were capable of pushing nanoparticles to the perimeter of the new droplet and nanoparticles on top of the droplets rolled off toward the perimeter. We propose that the curved surface morphology of the droplets created a force gradient that contributed to the assembly of nanoparticles at the droplet perimeter. Revealing the dynamics of nanoparticle movements and the interactions of nanoparticles with the liquid nanodroplet provides insights on developing novel self-assembly strategies for building precisely defined nanostructures on solid substrates. PMID- 28902193 TI - Solid state vibrational circular dichroism towards molecular recognition: chiral metal complexes intercalated in a clay mineral. AB - Vibrational circular dichroism (VCD) spectroscopy was applied to study chirality recognition in the interlayer space of a clay mineral. Clay intercalation compounds including two kinds of chiral molecules were prepared. Firstly a cationic metal complex, Delta- or Lambda-[Ru(phen)3]2+ (phen = 1,10 phenanthroline), was ion-exchanged into sodium montmorillonite. Thereafter a neutral organic molecule, R- or S-1,1'-bi-2-naphthol (denoted as R- or S-BINOL), was co-adsorbed. The solid state VCD spectra were recorded on the hybrid compounds thus prepared. The intensity of VCD peaks in the region of 1300-1400 cm 1, which were assigned to the bending vibrations of OH groups in BINOL, was remarkably dependent on the chirality relation between the two intercalated species. This implied that BINOL took a different conformation in response to the chirality of co-existing [Ru(phen)3]2+. PMID- 28902194 TI - Elucidating the role of surface passivating ligand structural parameters in hole wave function delocalization in semiconductor cluster molecules. AB - This article describes the mechanisms underlying electronic interactions between surface passivating ligands and (CdSe)34 semiconductor cluster molecules (SCMs) that facilitate band-gap engineering through the delocalization of hole wave functions without altering their inorganic core. We show here both experimentally and through density functional theory calculations that the expansion of the hole wave function beyond the SCM boundary into the ligand monolayer depends not only on the pre-binding energetic alignment of interfacial orbitals between the SCM and surface passivating ligands but is also strongly influenced by definable ligand structural parameters such as the extent of their pi-conjugation [pi delocalization energy; pyrene (Py), anthracene (Anth), naphthalene (Naph), and phenyl (Ph)], binding mode [dithiocarbamate (DTC, -NH-CS2-), carboxylate (-COO-), and amine (-NH2)], and binding head group [-SH, -SeH, and -TeH]. We observe an unprecedentedly large ~650 meV red-shift in the lowest energy optical absorption band of (CdSe)34 SCMs upon passivating their surface with Py-DTC ligands and the trend is found to be Ph- < Naph- < Anth- < Py-DTC. This shift is reversible upon removal of Py-DTC by triethylphosphine gold(i) chloride treatment at room temperature. Furthermore, we performed temperature-dependent (80-300 K) photoluminescence lifetime measurements, which show longer lifetime at lower temperature, suggesting a strong influence of hole wave function delocalization rather than carrier trapping and/or phonon-mediated relaxation. Taken together, knowledge of how ligands electronically interact with the SCM surface is crucial to semiconductor nanomaterial research in general because it allows the tuning of electronic properties of nanomaterials for better charge separation and enhanced charge transfer, which in turn will increase optoelectronic device and photocatalytic efficiencies. PMID- 28902195 TI - Driving and photo-regulation of myosin-actin motors at molecular and macroscopic levels by photo-responsive high energy molecules. AB - We employed an azobenzene based non-nucleoside triphosphate, AzoTP, in a myosin actin motile system and demonstrated its efficiency as an energy molecule to drive and photo-regulate the myosin-actin motile function at the macroscopic level along with an in vitro motility assay. The AzoTP in its trans state induced shortening of a glycerinated muscle fibre whilst a cis isomer had no significant effect. Direct photoirradiation of a cis-AzoTP infused muscle fibre induced shortening triggered by a locally photo-generated trans-AzoTP in the muscle fibre. Furthermore, we designed and synthesized three new derivatives of AzoTPs that served as substrates for myosin by driving and photo-regulating the myosin actin motile function at the molecular as well as the macroscopic level with varied efficiencies. PMID- 28902196 TI - A facile route to segmented copolymers by fusing ambient temperature step-growth and RAFT polymerization. AB - We introduce the facile synthesis of segmented copolymers by a catalyst-free Diels-Alder (DA) reaction at ambient temperature via step-growth and subsequent reversible addition fragmentation chain transfer (RAFT) polymerization. High molecular weight step-growth polymers are readily obtained (Mw = 40 000 g mol-1), featuring trithiocarbonate moieties in their chain, which allow monomer insertion via RAFT polymerization yielding high molecular weight species. PMID- 28902197 TI - Fast and reproducible iSERS microscopy of single HER2-positive breast cancer cells using gold nanostars as SERS nanotags. AB - Speed is often a bottleneck in conventional Raman microscopy on biological specimens. In immuno-Raman microspectroscopy, or for short iSERS microscopy, the acquisition times per pixel have been reduced by more than one order of magnitude over the past decade since its proof of concept. Typically rather high laser power densities are employed with the intention of compensating for the shorter acquisition times, without checking the reproducibility of the results in repeated experiments on the same sample. Here, we systematically analyze this aspect at the single-cell level since it forms the basis of quantification and is very important for reinspection of the same specimen. Specifically, we investigate experimentally the role of the laser power density in conjunction with the acquisition times per pixel in a series of repeated iSERS experiments on the same single cell overexpressing the breast cancer tumor marker human epidermal growth factor receptor 2 (HER2). Confocal iSERS mapping experiments were guided by wide-field fluorescence microscopy for selecting the regions of interest. We demonstrate that the combination of ca. a 1-2 mW laser power (40* objective, NA 0.6), 50 ms acquisition time per pixel and a high EM-CCD signal gain yields highly reproducible iSERS images in a series of four repeated experiments on the same single cell. In contrast, longer acquisition times (0.8 s, no EM gain) and in particular higher laser power (4 mW up to 18 mW) densities lead to non-reproducible iSERS results due to signal degradation. PMID- 28902198 TI - Total synthesis and functional analysis of microbial signalling molecules. AB - Communication is essential for all domains of life. Bacteria use a plethora of small molecules to sense and orchestrate intra- and interspecies communication. Within this review, we will discuss different groups of signalling molecules, including autoinducers, virulence factors and morphogenic substances. On selected examples, we will shortly discuss their ecological roles and biosynthetic proposals. The major part of this review will focus on a systematic overview of the different synthetic methods applied towards the synthesis of signalling molecules and derivatives thereof. The described examples highlight the importance of organic synthetic method development and diversity-oriented total syntheses for structure verification, structure-function analysis and target identification. PMID- 28902199 TI - Tuning the electronic structure in stanene/graphene bilayers using strain and gas adsorption. AB - Epitaxial growth of stanene monolayers on graphene substrates is an attractive synthesis route for atomically-thin electronic components, however, it remains unclear how such composites will tolerate lattice strain and exposure to ambient atmosphere. Using density functional theory, we identified several epitaxial configurations for the stanene-graphene bilayer system and determined the effect of strain and water adsorption. In addition to previously reported co-aligned bilayers, we identify a second family of low energy structures involving rotation of one layer by thirty degrees. The band structures of the rotated configurations exhibit a fully metallic interface, whereas the co-aligned structures are poised at the transition between semimetallic and semiconductor characteristics. In general, the electronic states are directly correlated with differences in the buckling parameter of the tin layer assigned to the competition between sp2 and sp3 hybridization schemes. This can be controlled by strain to yield a metal insulator transition in special circumstances. For the equilibrium structure, H2O preferentially adsorbs on the stanene layer, and the system remains metallic with a mixture of Dirac and parabolic bands at the Fermi surface. PMID- 28902200 TI - Molecular simulations of palladium catalysed hydrodeoxygenation of 2 hydroxybenzaldehyde using density functional theory. AB - The catalytic conversion of 2-hydroxybenzaldehyde (2-HB) is carried out numerically over a Pd(111) surface using density functional theory. The palladium catalyst surface is designed using a 12 atom monolayer and verified with the adsorption of phenol, benzene, anisole, guaiacol, and vanillin; it is found that the adsorption energies along with the adsorption configurations of phenol and benzene are in excellent agreement with the literature. The conversion of 2-HB over the Pd(111) catalyst surface is performed using four reaction schemes: (i) dehydrogenation of the formyl group followed by elimination of CO and association of hydrogen with 2-hydroxyphenyl to produce phenol, (ii) direct elimination of CHO from 2-HB followed by elimination of hydrogen from adsorbed CHO and association of hydrogen with 2-hydroxyphenyl to produce phenol, (iii) direct dehydroxylation of 2-HB followed by association of a hydrogen atom with 2 formylphenyl to produce benzaldehyde, and (iv) dehydrogenation of the hydroxyl group of 2-HB followed by elimination of an oxygen atom and association of a hydrogen atom with 2-formylphenyl to produce benzaldehyde. Along with the reaction mechanisms and their barrier heights, all reaction steps are considered for kinetic modelling in the temperature range 498-698 K with 50 K intervals. The rate constants, pre-exponential factors, and equilibrium constants of all elementary reaction steps are evaluated for each temperature. Kinetic analyses of the catalytic conversion of 2-HB over the Pd(111) surface suggests the production of phenol as an intermediate, instead of benzaldehyde, via dehydrogenation of the formyl group of 2-HB as a first elementary reaction step because of its low activation barrier and the high rate constant of the rate controlling step. Furthermore, the equilibrium constants of the rate controlling step in the production of phenol from 2-HB over the Pd(111) surface report a major fraction of the product in the product mixture even at a low temperature of 498 K. PMID- 28902201 TI - Correction: Lactobacillus casei CCFM419 attenuates type 2 diabetes via a gut microbiota dependent mechanism. AB - Correction for 'Lactobacillus casei CCFM419 attenuates type 2 diabetes via a gut microbiota dependent mechanism' by Gang Wang et al., Food Funct., 2017, DOI: 10.1039/c7fo00593 h. PMID- 28902202 TI - Responsive photonic barcodes for sensitive multiplex bioassay. AB - Barcodes have a demonstrated value for multiplex high-throughput bioassays. The tendency of this technology is to pursue high sensitivity target screening. Herein, we presented a new type of inverse opal-structured poly(N isopropylacrylamide) (pNIPAM) hydrogel photonic crystal (PhC) barcodes with the function of fluorescent signal self-amplification for the detection. During the bio-reaction process at body temperature, the pNIPAM hydrogel barcodes kept swelling, and their inverse opal structure with interconnected pores provided unblocked channels for the targets to diffuse into the voids of the barcodes and react. During the detection process, the barcodes were kept at a volume phase transition temperature (VPTT) to shrink their volume; this resulted in an obvious increase in the density of fluorescent molecules and signal amplification. It was demonstrated that the responsive barcodes could achieve the limits of detection (LOD) of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) at 0.623 ng mL-1 and 0.492 ng mL-1, respectively. In addition, the proposed barcodes showed good multiplex detection capacity with acceptable cross-reactivity, accuracy, and reproducibility, and the results were consistent with those of common clinical laboratory methods for the detection of clinical samples. These features of the inverse opal-structured responsive hydrogel barcodes indicate that they are ideal technology for high-sensitive multiplex bioassays. PMID- 28902203 TI - Molecular engineering solutions for therapeutic peptide delivery. AB - Proteins and their interactions in and out of cells must be well-orchestrated for the healthy functioning and regulation of the body. Even the slightest disharmony can cause diseases. Therapeutic peptides are short amino acid sequences (generally considered <50 amino acids) that can naturally mimic the binding interfaces between proteins and thus, influence protein-protein interactions. Because of their fidelity of binding, peptides are a promising next generation of personalized medicines to reinstate biological harmony. Peptides as a group are highly selective, relatively safe, and biocompatible. However, they are also vulnerable to many in vivo pharmacologic barriers limiting their clinical translation. Current advances in molecular, chemical, and nanoparticle engineering are helping to overcome these previously insurmountable obstacles and improve the future of peptides as active and highly selective therapeutics. In this review, we focus on self-assembled vehicles as nanoparticles to carry and protect therapeutic peptides through this journey, and deliver them to the desired tissue. PMID- 28902205 TI - Electron-phonon scattering effect on the lattice thermal conductivity of silicon nanostructures. AB - Nanostructuring technology has been widely employed to reduce the thermal conductivity of thermoelectric materials because of the strong phonon-boundary scattering. Optimizing the carrier concentration can not only improve the electrical properties, but also affect the lattice thermal conductivity significantly due to the electron-phonon scattering. The lattice thermal conductivity of silicon nanostructures considering electron-phonon scattering is investigated for comparing the lattice thermal conductivity reductions resulting from nanostructuring technology and the carrier concentration optimization. We performed frequency-dependent simulations of thermal transport systematically in nanowires, solid thin films and nanoporous thin films by solving the phonon Boltzmann transport equation using the discrete ordinate method. All the phonon properties are based on the first-principles calculations. The results show that the lattice thermal conductivity reduction due to the electron-phonon scattering decreases as the feature size of nanostructures goes down and could be ignored at low feature sizes (50 nm for n-type nanowires and 20 nm for p-type nanowires and n-type solid thin films) or a high porosity (0.6 for n-type 500 nm-thick nanoporous thin films) even when the carrier concentration is as high as 1021 cm 3. Similarly, the size effect due to the phonon-boundary scattering also becomes less significant with the increase of carrier concentration. The findings provide a fundamental understanding of electron and phonon transports in nanostructures, which is important for the optimization of nanostructured thermoelectric materials. PMID- 28902204 TI - Rational design and structure-activity relationship studies of quercetin-amino acid hybrids targeting the anti-apoptotic protein Bcl-xL. AB - Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein. IFD calculations determined their binding cavity while Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations provided an insight into the binding enthalpies of the analogues. The quercetin analogues were synthesized and their binding to Bcl xL was verified with fluorescence spectroscopy. The binding affinity and the thermodynamic parameters between Bcl-xL and quercetin-glutamic acid were estimated through Isothermal Titration Calorimetry. 2D 1H-15N HSQC NMR chemical shift perturbation mapping was used to chart the binding site of the quercetin analogues in the Bcl-xL that overlapped with the predicted poses generated by both IFD and MD calculations. Furthermore, evaluation of the four conjugates against the prostate DU-145 and PC-3 cancer cell lines, revealed quercetin glutamic acid and quercetin-alanine as the most potent conjugates bearing the higher cytostatic activity. This pinpoints that the chemical space of natural products can be tailored to exploit new hits for difficult tractable targets such as protein-protein interactions. PMID- 28902206 TI - Surface modification induced enhanced CO2 sorption in cucurbit[6]uril, an organic porous material. AB - The CO2 adsorption properties of an organic macrocycle, cucurbit[6]uril (CB[6]), have been evaluated through experimental and theoretical studies. Quantum mechanical calculations show that CB[6] is capable of adsorbing the CO2 molecule selectively within its cavity relative to nitrogen. Adsorption experiments at 298 K and at 1 bar pressure gave a CO2 adsorption value of 1.23 mmol g-1 for the unmodified material. Significant enhancements in the CO2 adsorption capacity of the material were experimentally demonstrated through surface modification using physical and chemical methods. Ethanolamine (EA) modified CB[6] provided an excellent sorption selectivity value of 121.4 for CO2/N2 at 323 K and is unique with respect to its discrimination potential between CO2 and N2. The chemical nature of the interaction between CO2 and amine is shown to be the primary mechanism for the enhanced CO2 absorption performance. PMID- 28902207 TI - Preparation and characterization of CrFeWTiO2 photoanodes and their photoelectrochemical activities for water splitting. AB - The chemical bath deposition (CBD) method was successfully applied to prepare WTiO2 nanotube arrays co-deposited with chromium, iron and chromium-iron nanoparticles. Various methods have been used in the characterization of synthetic co-deposited nanostructures. WTiO2 nanotubes can keep the nanotubular structures at low iron concentration in the CBD solution, as indicated by our FESEM results. Iron and chromium can be applied to improve the absorption capability of the WTiO2 nanotubes for the visible-light, according to the UV-Vis results. Based on the photoelectrochemical performance and photocatalytic hydrogen evolution characteristics of the CrFeWTiO2 catalysts, the co-deposited nanoparticles contribute to the improvement in the photocatalytic efficiency. The best photocatalytic activity was shown by the CrFeWTiO2-1 sample formed by immersion in a CBD solution containing 0.08 M ClCl3.6H2O + 0.02 M FeCl3.6H2O. The hydrogen evolution reaction of the new photocatalysts showed that their photocatalytic activity was very stable. A facile method has been developed in this study for the synthesis of high performance co-deposited photocatalysts with excellent stability and reliability in photoelectrochemical water splitting. A stable and high photocatalytic activity for hydrogen evolution in the absence of a Pt co-catalyst was exhibited by the novel CrFeWTiO2 compounds prepared. PMID- 28902209 TI - Application of the Eckart frame to soft matter: rotation of star polymers under shear flow. AB - The Eckart co-rotating frame is used to analyze the dynamics of star polymers under shear flow, either in melt or solution and with different types of bonds. This formalism is compared with the standard approach used in many previous studies on polymer dynamics, where an apparent angular velocity omega is obtained from the relation between the tensor of inertia and angular momentum. A common mistake is to interpret omega as the molecular rotation frequency, which is only valid for rigid-body rotation. The Eckart frame, originally formulated to analyze the infrared spectra of small molecules, dissects different kinds of displacements: vibrations without angular momentum, pure rotation, and vibrational angular momentum (leading to a Coriolis cross-term). The Eckart frame co-rotates with the molecule with an angular frequency Omega obtained from the Eckart condition for minimal coupling between rotation and vibration. The standard and Eckart approaches are compared with a straight description of the star's dynamics taken from the time autocorrelation of the monomer positions moving around the molecule's center of mass. This is an underdamped oscillatory signal, which can be described by a rotation frequency omegaR and a decorrelation rate Gamma. We consistently find that Omega coincides with omegaR, which determines the characteristic tank-treading rotation of the star. By contrast, the apparent angular velocity omega < Omega does not discern between pure rotation and molecular vibrations. We believe that the Eckart frame will be useful to unveil the dynamics of semiflexible molecules where rotation and deformations are entangled, including tumbling, tank-treading motions and breathing modes. PMID- 28902211 TI - Controlling the magnetic and optical responses of a MoS2 monolayer by lanthanide substitutional doping: a first-principles study. AB - The electronic, magnetic and optical properties of lanthanide substitutional doping (~2% concentration) on the MoS2 monolayer have been investigated within the density functional theory formalism together with the Hubbard correction (DFT+U). The dopants investigated include Ce, Eu, Gd, Lu and Tm. The calculated dopant substitutional energies under both Mo-rich and S-rich conditions suggest that it is possible to experimentally realize the lanthanide doped MoS2 monolayer systems. The Eu, Gd and Tm dopants induce strong magnetization in the host lattice. The electronic structure calculations reveal that the dopants have a p type character and they exhibit a half-metallic behavior in the Gd and Eu doped systems. A dilute magnetic semiconducting behavior can also be realized in Gd, Eu and Tm doped systems by slightly tuning the Fermi level. All the dopants refine the optical responses of the host system with the onset of the optical absorption edge shifting to lower energies within the visible range (red shift phenomenon). We observe an optical anisotropy for two different directions of the electric field (E) polarizations, i.e. parallel, E?, and perpendicular, E?, to the xy plane. Lanthanide substitutional doping significantly influences the electron energy loss spectra (EELS), absorption spectra, and dielectric properties of the host MoS2 monolayer. Furthermore, we notice that lanthanide substitutional doping could enhance the photocatalytic properties of the MoS2 monolayer. PMID- 28902212 TI - Switchable aerobic/anaerobic multi-substrate biofuel cell operating on anodic and cathodic enzymatic cascade assemblies. AB - Enzymatic fuel cells may become more accessible for applications powering portable electronic devices by broadening the range of potentially usable fuels and oxidizers. In this work we demonstrate the operation of an integrated, yet versatile multi-substrate biofuel cell utilizing either glucose, fructose, sucrose or combinations of thereof as biofuels, and molecular oxygen originating from solution phase and/or an internal chemical source, as the oxidizer. In order to achieve this goal we designed an enzymatic cascade-functionalized anode consisting of invertase (INV), mutarotase (MUT), glucose oxidase (GOX), and fructose dehydrogenase (FDH), deposited on top of a mesoporous carbon nanoparticle matrix, in which electron relay molecules had been entrapped. The anode was then conjugated to a compatible enzymatic cathode that employs a cascade of catalase (CAT) and bilirubin oxidase (BOD), allowing the cell to operate in an aerobic environment and/or to utilize, under anaerobic conditions for instance, hydrogen peroxide as a source for the oxygen oxidizer. While operated in the presence of the sugar mixture and hydrogen peroxide, the power output of the dually cascaded biofuel cell reaches a peak power density of 0.25 mW cm-2 and demonstrates an open circuit potential of 0.65 V. To our knowledge this is the first reported biofuel cell that discharges with both anodic and cathodic enzymatic cascade architectures and the first biofuel cell that is repeatedly switched between aerobic and anaerobic conditions without any significant decrease in the discharge performance. PMID- 28902215 TI - One-pot synthesis of 2,3-difunctionalized indoles via Rh(iii)-catalyzed carbenoid insertion C-H activation/cyclization. AB - Reported herein is the first Rh(iii)-catalyzed carbenoid insertion C-H activation/cyclization of N-arylureas and alpha-diazo beta-keto esters. The redox neutral reaction has the following features: good to excellent yields, broad substrate/functional group tolerance, exclusive regioselectivity, and no need for additional oxidants or additives, which render this methodology as a more efficient and versatile alternative to the existing methods for the synthesis of 2,3-difunctionalized indoles. PMID- 28902216 TI - Primitive chain network simulations of probe rheology. AB - Probe rheology experiments, in which the dynamics of a small amount of probe chains dissolved in immobile matrix chains is discussed, have been performed for the development of molecular theories for entangled polymer dynamics. Although probe chain dynamics in probe rheology is considered hypothetically as single chain dynamics in fixed tube-shaped confinement, it has not been fully elucidated. For instance, the end-to-end relaxation of probe chains is slower than that for monodisperse melts, unlike the conventional molecular theories. In this study, the viscoelastic and dielectric relaxations of probe chains were calculated by primitive chain network simulations. The simulations semi quantitatively reproduced the dielectric relaxation, which reflects the effect of constraint release on the end-to-end relaxation. Fair agreement was also obtained for the viscoelastic relaxation time. However, the viscoelastic relaxation intensity was underestimated, possibly due to some flaws in the model for the inter-chain cross-correlations between probe and matrix chains. PMID- 28902217 TI - A bifunctional old yellow enzyme from Penicillium roqueforti is involved in ergot alkaloid biosynthesis. AB - The blue cheese-making fungus Penicillium roqueforti produces isofumigaclavine A as the main ergot alkaloid. Recently, genome mining revealed the presence of two DNA loci bearing the genetic potential for its biosynthesis. In this study, a short-chain dehydrogenase/reductase (SDR) from one of the loci was proved to be responsible for the conversion of chanoclavine-I to its aldehyde. Furthermore, a putative gene coding for an enzyme with high homology to Old Yellow Enzymes (OYEs) involved in the ergot alkaloid biosynthesis was found outside the two clusters. Biochemical characterisation of this enzyme, named FgaOx3Pr3, showed that it can indeed catalyse the formation of festuclavine in the presence of a festuclavine synthase FgaFS, as had been observed for other OYEs in ergot alkaloid biosynthesis. Differing from other homologues, FgaOx3Pr3 does not convert chanoclavine-I aldehyde to its shunt products in the absence of FgaFS. Instead, it increases significantly the product yields of several SDRs for the conversion of chanoclavine-I to its aldehyde. Kinetic studies proved that overcoming the product inhibition is responsible for the observed enhancement. To the best of our knowledge, this is the first report on the bifunctionality of an OYE and its synergistic effect with SDRs. PMID- 28902220 TI - Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7 methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives. AB - Two facile and efficient one-step procedures for the regioselective synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines have been developed, via reactions of 3,5-diamino-1,2,4-triazole with variously substituted 1-aryl-1,3-butanediones and 1-aryl-2-buten-1-ones, respectively. The excellent yield and/or regioselectivity shown by the reactions decreased when ethyl 5-amino-1,2,4-triazole-3-carboxylate was used. [1,2,4]Triazolo[1,5 a]pyrimidine being a privileged scaffold, the procedures herein reported may be useful for the preparation of biologically active compounds. In this study, the preparation of a set of compounds based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold led to the identification of compound 20 endowed with a very promising ability to inhibit influenza virus RNA polymerase PA-PB1 subunit heterodimerization. PMID- 28902221 TI - Two-field surface pattern control via marginally stable magnetorheological elastomers. AB - The stability and post-bifurcation of a non-linear magnetoelastic film/substrate block is experimentally exploited to obtain active control of surface roughness. The non-intuitive interplay between magnetic field and elastic deformation owes to material and geometry selection, namely a ferromagnetic particle composite film bonded on a compliant passive foundation. Cooperation of the two otherwise independent loading mechanisms-mechanical pre-compression and magnetic field allows one to bring the structure near a marginally stable state and then destabilize it with either magnetic or mechanical fields. We demonstrate for the first time that the critical magnetic field is a decreasing function of pre compression and vice versa. The experimental results are then probed successfully with full-field finite element simulations at large strains and magnetic fields. The magnetoelastic coupling allows for reversible on/off control of surface wrinkling under adjustable critical magnetic and mechanical fields, thus this study constitutes a first step towards realistic active haptic and morphing devices. PMID- 28902225 TI - Optical tracking of relaxation dynamics in semi-dilute hydroxypropylcellulose solutions as a precise phase transition probe. AB - Phase separation of thermo-responsive polymers in solution is a complex process, whose understanding is essential to screen and design materials with diverse technological applications. Here we report on a method based on dynamic light scattering (DLS) experiments to investigate the phase separation of thermo responsive polymer solutions and precisely define the transition temperature (TPS). Our results are applied on hydroxypropylcellulose (HPC) solutions as an important biosourced green water-soluble polymer. As determined by DLS, the amplitudes of the fast and slow modes of relaxation dynamics evolve as temperature gets closer to the phase transition point eventually leading to phase separation. The evolution of relaxation modes with temperature is markedly different for concentrations below the overlap concentration (c*) (dilute regime), above c* (semi-dilute regime) and above the entanglement concentration (ce). In the three cases though, the fast and slow mode amplitudes undergo a sharp transition in a narrow temperature range, defining accurately the phase separation locus. The results agree with turbidimetric analysis for the phase transition determination but with a better precision. Our results also show that the one-phase dynamics and phase separation dynamics in the two-phase region are only in continuity for c > ce, revealing mechanistic details about the HPC phase separation process. Above TPS we identify a temperature range where the intensity autocorrelation function has a single-exponential shape. In the latter regime, we monitor the growth kinetics of polymer domains and provide clues to rationalize the stabilizing effects of the interfaces leading to the arrested-like phase separation behavior observed for HPC. PMID- 28902226 TI - Thermo-, photo-, and mechano-responsive liquid crystal networks enable tunable photonic crystals. AB - Tunable photonic crystals exhibiting optical properties that respond reversibly to external stimuli have been developed using liquid crystal networks (LCNs) and liquid crystal elastomers (LCEs). These tunable photonic crystals possess an inverse opal structure and are photo-responsive, but circumvent the usual requirement to contain dye molecules in the structure that often limit their applicability and cause optical degradation. Herein, we report tunable photonic crystal films that reversibly tune the reflection peak wavelength under thermo-, photo- and mechano-stimuli, through bilayering a stimuli-responsive LCN including azobenzene units with a colourless inverse opal film composed of non-responsive, flexible durable polymers. By mechanically deforming the azobenzene containing LCN via various stimuli, the reflection peak wavelength from the bilayered film assembly could be shifted on demand. We confirm that the reflection peak shift occurs due to the deformation of the stimuli-responsive layer propagating towards and into the inverse opal layer to change its shape in response, and this shift behaviour is repeatable without optical degradation. PMID- 28902228 TI - Comparative analysis of initial vocalizations of preterm and full-term infants with and without risk for development. AB - Purpose: To compare the evolution of vocalization in preterm and full-term infants, with and without risk for development, analyzing the possible association of sociodemographic, obstetric and psychosocial variables with vocalization. Methods: The study sample consisted of 30 infants, aged 3 months and 1 day to 4 months and 29 days (Phase 1) and 6 months and 1 day to 7 months and 29 days (Phase 2), of both genders, with gestational age <37 weeks (preterm group) and >37 weeks (full-term group). The following instruments were used for data collection: Child Development Risk Indicators (IRDl), the Denver II Test, an interview on the experience of motherhood with sociodemographic, obstetric and psychosocial data, as well as filming of the mother-infant dyad at the two phases of the research. Footage was analyzed using the EUDICO Linguistic Annotator (ELAN) software and the results were statistically analyzed on the STATISTICA 9.0 software. Results: The larger the total number of Phase II infants' and mothers' vocalizations using motherese, the greater the number of IRDls present. Significant increase in vocalizations without motherese was also observed in Phase 2. Sociodemographic variables, gestational age, weight at birth, maternal schooling, and the Brazil Criterion did not directly affect the infants' vocalization level. Conclusion: Analysis of the infants' vocalizations was sensitive to risk development and Child Development Risk Indicators in Phase 1; the Denver-language test was more effective in Phase 2. No influence of the sociodemographic variables was observed in the phases studied. PMID- 28902227 TI - A genetically encoded cyclobutene probe for labelling of live cells. AB - We have identified an aminoacyl-tRNA synthetase/tRNA pair for the efficient and site-specific incorporation of a cyclobutene-containing amino acid into proteins in response to an amber nonsense codon. Fast and fluorescent labeling of purified proteins and intact proteins in live cells was demonstrated using the inverse electron demand Diels-Alder reaction with a tetrazine. PMID- 28902229 TI - Correlation between vocal tract symptoms and modern singing handicap index in church gospel singers. AB - Objective: To verify the correlation between vocal tract discomfort symptoms and perceived voice handicaps in gospel singers, analyzing possible differences according to gender. Methods: 100 gospel singers volunteered, 50 male and 50 female. All participants answered two questionnaires: Vocal Tract Discomfort (VTD) scale and the Modern Singing Handicap Index (MSHI) that investigates the vocal handicap perceived by singers, linking the results of both instruments (p<0.05). Results: Women presented more perceived handicaps and also more frequent and higher intensity vocal tract discomfort. Furthermore, the more frequent and intense the vocal tract symptoms, the higher the vocal handicap for singing. Conclusion: Female gospel singers present higher frequency and intensity of vocal tract discomfort symptoms, as well as higher voice handicap for singing than male gospel singers. The higher the frequency and intensity of the laryngeal symptoms, the higher the vocal handicap will be. PMID- 28902230 TI - Chronic kidney disease and metabolic syndrome as risk factors for cardiovascular disease in a primary care program. AB - INTRODUCTION: Cardiovascular disease (CVD) is especially prevalent in patients with chronic kidney disease (CKD). OBJECTIVE: To evaluate the role of CKD and metabolic syndrome (MS), which is a cluster of risk factors for CVD, as predictors of CVD. METHODS: Observational, cross-sectional study with a random sample aged 45 or more years extracted from the population assisted by the primary care program in Niteroi city in the state of Rio de Janeiro, Brazil. CKD was diagnosed by the K/DOQI guidelines and MS, by the harmonized criteria. CVD was said to be present if the participant had one or more of the following findings: echocardiographic abnormalities, and history of myocardial infarction, stroke or heart failure. A logistic regression model was developed to analyze risk factors for CVD using CKD as the variable of primary interest. RESULTS: Fifty hundred and eighty-one participants (38.2% male) with a mean age of 59.4 +/ 10.2 years were analyzed. The prevalence rate of CKD was 27.9%. In participants without CKD, MS was associated with a slight but statistically significant increase in the risk for CVD (OR = 1.52, p = 0.037); in those with CKD but without MS the risk for CVD was also statistically significant and at a greater magnitude (OR = 2.42, p = 0.003); when both were present the risk for CVD was substantially higher (OR = 5.13, p < 0.001). CONCLUSION: In this study involving a population assisted by a primary care program, CKD was confirmed as an independent risk factor for CVD. The presence of MS concurrent with CKD substantially amplified the risk for CVD. PMID- 28902231 TI - Risk factors for the progression of chronic kidney disease after acute kidney injury. AB - INTRODUCTION: The incidence of chronic kidney disease (CKD) is increasing with the increasing age of the population and the increasing number of elderly survivors of acute kidney injury (AKI). The risk factors for the progression of CKD after AKI are unclear. OBJECTIVE: To investigate the association between AKI and its progression to CKD and the risk factors involved. METHODS: An observational, retrospective study of AKI patients followed from 2009 to 2012 was carried out. We evaluated the etiology of AKI, the use of vasoactive drugs and mechanical ventilation, the need for dialysis, the presence of comorbidities, the glomerular filtration rate (GFR), the length of stay and the progression of CKD. Statistical analyses, including the Chi-square test and Pearson's correlation, were performed using SPSS. RESULTS: The 207 patients analyzed had a mean age of 70.1 +/- 13.1, and 84.6% of the male patients exhibited decreased renal function and CKD (vs. 60.4% of the female patients). The progression of AKI to CKD was more frequent in patients admitted to wards (63.8%), cancer patients (74.19%), patients with sepsis (67.18%) and patients with obstruction (91.66%). Dialyses were performed in 16.4% of the patients, but this was not correlated with the progression of CKD. CONCLUSIONS: Being an elderly male patient with AKI due to sepsis and obstruction was correlated with progression to CKD following discharge. PMID- 28902232 TI - Advanced glycation end-products (AGEs) accumulation in skin: relations with chronic kidney disease-mineral and bone disorder. AB - INTRODUCTION: Chronic kidney disease (CKD) is associated with high morbidity and mortality rates, main causes related with cardiovascular disease (CVD) and bone mineral disorder (CKD-BMD). Uremic toxins, as advanced glycation end products (AGEs), are non-traditional cardiovascular risk factor and play a role on development of CKD-BMD in CKD. The measurement of skin autofluorescence (sAF) is a noninvasive method to assess the level of AGEs in tissue, validated in CKD patients. OBJECTIVE: The aim of this study is analyze AGEs measured by sAF levels (AGEs-sAF) and its relations with CVD and BMD parameters in HD patients. METHODS: Twenty prevalent HD patients (HD group) and healthy subjects (Control group, n = 24), performed biochemical tests and measurements of anthropometric parameters and AGEs-sAF. In addition, HD group performed measurement of intact parathormone (iPTH), transthoracic echocardiogram and radiographies of pelvis and hands for vascular calcification score. RESULTS: AGEs-sAF levels are elevated both in HD and control subjects ranged according to the age, although higher at HD than control group. Single high-flux HD session does not affect AGEs-sAF levels. AGEs sAF levels were not related to ventricular mass, interventricular septum or vascular calcification in HD group. AGEs-sAF levels were negatively associated with serum iPTH levels. CONCLUSION: Our study detected a negative correlation of AGEs-sAF with serum iPTH, suggesting a role of AGEs on the pathophysiology of bone disease in HD prevalent patients. The nature of this relation and the clinical application of this non-invasive methodology for evaluation AGEs deposition must be confirmed and clarified in future studies. PMID- 28902233 TI - Clinical outcomes of 11,436 kidney transplants performed in a single center - Hospital do Rim. AB - INTRODUCTION: Kidney transplantation is considered a cost-effective treatment compared to dialysis but accounts for a significant percentage of the public health care resources. Therefore, efficient systems capable of performing high number of procedures are attractive and sustainable. OBJECTIVE: The aim of this study was to evaluate clinical outcomes of 11,436 kidney transplants regularly performed in a single transplant dedicated center over the last 18 years. METHODS: This was a retrospective study performed in a single specialized transplant center. All consecutive patients who underwent transplantation between 08/18/1998 and 12/31/2015 were included in the analysis. RESULTS: The annual number of transplants increased from 394 in 1999 to 886 in 2015, with a progressive reduction in the proportion of living donor kidney transplants (70% vs. 23%) and yielding over 8869 patients in regular follow up. Of 11,707 kidney transplants performed, 5348 (45.7%) were from living, 3614 (30.9%) standard and 1618 (13.8%) expanded criteria deceased donors, 856 (7.3%) pediatric and 271 (2.3%) simultaneous kidney-pancreas transplants. Comparing 1998-2002 and 2011 2014, five-years graft survival increased for kidney transplants performed with living donors (83.3% vs. 93.1%, p < 0.001), standard deceased donors (60.7% vs. 79.7%, p < 0.001), expanded criteria donors (46.5% vs. 71.5%, p < 0.001) and for the pediatric population (79.8% vs. 80.9%, p = 0.684). CONCLUSION: The implementation of a dynamic and efficacious health care system was associated with a progressive increase in the number of kidney transplants, in the cumulative number of patients in follow up and a shift from living related to deceased donor kidney transplants, with associated progressive increase in patient and graft survivals. PMID- 28902234 TI - Monitoring of post-vaccination anti-HBs titles vaccine in children and adolescents in the pre-dialysis of chronic kidney disease. AB - INTRODUCTION: Bacterial or viral diseases are one of the major causes of death in patients with chronic kidney disease (CKD). These patients show a quantitative reduction of levels of antibodies over time. Among the infectious diseases that affect CKD patients, stands out hepatitis B (HB). Immunization and control of antibodies levels against the hepatitis B surface antigen (anti-HBs) are ways to prevent the HB infection in this population. Patients with anti-HBs levels >=10 IU/ml are considered adequate responders, whereas those with anti-HBs levels >= 100 IU/ml are considered excellent responders. OBJECTIVE: To analyze the variation of the anti-HBs levels obtained after vaccination against HB in children and adolescents in the pre-dialysis stage of CKD. METHODS: A retrospective cohort study on anti-HBs levels of children and adolescents in the pre-dialysis stage of CKD. Correlation between levels of anti-HBs titers and time since the vaccination were estimated. RESULTS: From the total of 116 studied patients most of the studied patients were considered excellent responders, obtaining in the three anti-HBs titers percentages of 70.7%, 62.1% and 54.9% respectively. The anti-HBs titer levels showed a negative correlation with the time since vaccination (Kendall Tau-b = -0.16; p = 0.02). CONCLUSION: The majority of the studied population was vaccinated by PNI and showed excellent anti-HBs titer levels, even experiencing a progressive reduced response over the time. PMID- 28902235 TI - Trends in restorative composites research: what is in the future? AB - Clinical trials have identified secondary caries and bulk fracture as the main causes for composite restoration failure. As a measure to avoid frequent reinterventions for restoration replacement, composites with some sort of defense mechanism against biofilm formation and demineralization, as well as materials with lower susceptibility to crack propagation are necessary. Also, the restorative procedure with composites are very time-consuming and technically demanding, particularly concerning the application of the adhesive system. Therefore, together with bulk-fill composites, self-adhesive restorative composites could reduce operator error and chairside time. This literature review describes the current stage of development of remineralizing, antibacterial and self-healing composites. Also, an overview of the research on fiber-reinforced composites and self-adhesive composites, both introduced for clinical use in recent years, is presented. PMID- 28902236 TI - Should my composite restorations last forever? Why are they failing? AB - Composites resins have become the first choice for direct anterior and posterior restorations. The great popularity is related to their esthetic appearance and reduced need of sound tissue removal as compared with former treatments. Several studies have demonstrated that composite restorations may last long in clinical service. In this review we discuss the factors playing a role on the long-term longevity. Composite restorations have demonstrated a good clinical performance with annual failure rates varying from 1% to 3% in posterior teeth and 1% to 5% in anterior teeth. Factors related to the patients such as caries risk and occlusal stress risk, in addition to socioeconomic factors, may affect the survival significantly. Characteristics of the clinical operators, particularly their decision making when it comes to observing or approaching an existing restoration, are decisive for longevity. Cavity features such as the number of restored walls, composite volume, and presence of endodontic treatment are of major importance and may dictate the service time of the restorative approach. The choice of restorative composite seems to have a minor effect on longevity provided that appropriate technical procedures are used. The main reasons for failure in posterior teeth are secondary caries and fracture (restoration or tooth/restoration), while in anterior teeth esthetic concerns are the main reasons leading to restoration failures. Composite resin restorations can be considered a reliable treatment as long as both the professional and the patient are aware of the factors involved in restoration failures. PMID- 28902237 TI - Bonding efficiency and durability: current possibilities. AB - Bonding plays a major role in dentistry nowadays. Dental adhesives are used in association with composites to solve many restorative issues. However, the wide variety of bonding agents currently available makes it difficult for clinicians to choose the best alternative in terms of material and technique, especially when different clinical situations are considered. Moreover, although bonding agents allow for a more conservative restorative approach, achieving a durable adhesive interface remains a matter of concern, and this mainly due to degradation of the bonding complex in the challenging oral environment. This review aims to present strategies that are being used or those still in development which may help to prevent degradation. It is fundamental that professionals are aware of these strategies to counteract degradation as much as possible. None of them are efficient to completely solve this problem, but they certainly represent reasonable alternatives to increase the lifetime of adhesive restorations. PMID- 28902238 TI - Dental ceramics: a review of new materials and processing methods. AB - The evolution of computerized systems for the production of dental restorations associated to the development of novel microstructures for ceramic materials has caused an important change in the clinical workflow for dentists and technicians, as well as in the treatment options offered to patients. New microstructures have also been developed by the industry in order to offer ceramic and composite materials with optimized properties, i.e., good mechanical properties, appropriate wear behavior and acceptable aesthetic characteristics. The objective of this literature review is to discuss the main advantages and disadvantages of the new ceramic systems and processing methods. The manuscript is divided in five parts: I) monolithic zirconia restorations; II) multilayered dental prostheses; III) new glass-ceramics; IV) polymer infiltrated ceramics; and V) novel processing technologies. Dental ceramics and processing technologies have evolved significantly in the past ten years, with most of the evolution being related to new microstructures and CAD-CAM methods. In addition, a trend towards the use of monolithic restorations has changed the way clinicians produce all-ceramic dental prostheses, since the more aesthetic multilayered restorations unfortunately are more prone to chipping or delamination. Composite materials processed via CAD-CAM have become an interesting option, as they have intermediate properties between ceramics and polymers and are more easily milled and polished. PMID- 28902239 TI - Efficiency of polymerization of bulk-fill composite resins: a systematic review. AB - This systematic review assessed the literature to evaluate the efficiency of polymerization of bulk-fill composite resins at 4 mm restoration depth. PubMed, Cochrane, Scopus and Web of Science databases were searched with no restrictions on year, publication status, or article's language. Selection criteria included studies that evaluated bulk-fill composite resin when inserted in a minimum thickness of 4 mm, followed by curing according to the manufacturers' instructions; presented sound statistical data; and comparison with a control group and/or a reference measurement of quality of polymerization. The evidence level was evaluated by qualitative scoring system and classified as high-, moderate- and low- evidence level. A total of 534 articles were retrieved in the initial search. After the review process, only 10 full-text articles met the inclusion criteria. Most articles included (80%) were classified as high evidence level. Among several techniques, microhardness was the most frequently method performed by the studies included in this systematic review. Irrespective to the "in vitro" method performed, bulk fill RBCs were partially likely to fulfill the important requirement regarding properly curing in 4 mm of cavity depth measured by depth of cure and / or degree of conversion. In general, low viscosities BFCs performed better regarding polymerization efficiency compared to the high viscosities BFCs. PMID- 28902240 TI - Randomized clinical trials of dental bleaching - Compliance with the CONSORT Statement: a systematic review. AB - We reviewed the literature to evaluate: a) The compliance of randomized clinical trials (RCTs) on bleaching with the CONSORT; and b) the risk of bias of these studies using the Cochrane Collaboration risk of bias tool (CCRT). We searched the Cochrane Library, PubMed and other electronic databases, to find RCTs focused on bleaching (or whitening). The articles were evaluated in compliance with CONSORT in a scale: 0 = no description, 1 = poor description and 2 = adequate description. Descriptive analyses of the number of studies by journal, follow-up period, country and quality assessments were performed with CCRT for assessing risk of bias in RCTs. 185 RCTs were included for assessment. More than 30% of the studies received score 0 or 1. Protocol, flow chart, allocation concealment and sample size were more critical items, as 80% of the studies scored 0. The overall CONSORT score for the included studies was 16.7 +/- 5.4 points, which represents 52.2% of the maximum CONSORT score. A significant difference among journal, country and period of time was observed (p < 0.02). Only 7.6% of the studies were judged at "low" risk; 62.1% were classified as "unclear"; and 30.3% as "high" risk of bias. The adherence of RCTs evaluating bleaching materials and techniques to the CONSORT is still low with unclear/high risk of bias. PMID- 28902241 TI - Light curing in dentistry and clinical implications: a literature review. AB - Contemporary dentistry literally cannot be performed without use of resin-based restorative materials. With the success of bonding resin materials to tooth structures, an even wider scope of clinical applications has arisen for these lines of products. Understanding of the basic events occurring in any dental polymerization mechanism, regardless of the mode of activating the process, will allow clinicians to both better appreciate the tremendous improvements that have been made over the years, and will also provide valuable information on differences among strategies manufacturers use to optimize product performance, as well as factors under the control of the clinician, whereby they can influence the long-term outcome of their restorative procedures. PMID- 28902242 TI - Polymerization shrinkage stress of composite resins and resin cements - What do we need to know? AB - Polymerization shrinkage stress of resin-based materials have been related to several unwanted clinical consequences, such as enamel crack propagation, cusp deflection, marginal and internal gaps, and decreased bond strength. Despite the absence of strong evidence relating polymerization shrinkage to secondary caries or fracture of posterior teeth, shrinkage stress has been associated with post operative sensitivity and marginal stain. The latter is often erroneously used as a criterion for replacement of composite restorations. Therefore, an indirect correlation can emerge between shrinkage stress and the longevity of composite restorations or resin-bonded ceramic restorations. The relationship between shrinkage and stress can be best studied in laboratory experiments and a combination of various methodologies. The objective of this review article is to discuss the concept and consequences of polymerization shrinkage and shrinkage stress of composite resins and resin cements. Literature relating to polymerization shrinkage and shrinkage stress generation, research methodologies, and contributing factors are selected and reviewed. Clinical techniques that could reduce shrinkage stress and new developments on low-shrink dental materials are also discussed. PMID- 28902243 TI - Editorial. PMID- 28902244 TI - Dental Press Journal of Orthodontics: One year later, and more growth. PMID- 28902245 TI - Tooth resorptions are not hereditary. AB - Root resorptions caused by orthodontic movement are not supported by consistent scientific evidence that correlate them with heredity, individual predisposition and genetic or familial susceptibility. Current studies are undermined by methodological and interpretative errors, especially regarding the diagnosis and measurements of root resorption from orthopantomographs and cephalograms. Samples are heterogeneous insofar as they comprise different clinical operators, varied types of planning, and in insufficient number, in view of the prevalence of tooth resorptions in the population. Nearly all biological events are coded and managed through genes, but this does not mean tooth resorptions are inherited, which can be demonstrated in heredograms and other methods of family studies. In orthodontic root resorption, one cannot possibly determine percentages of how much would be due to heredity or genetics, environmental factors and unknown factors. There is no need to lay the blame of tooth resorptions on events taking place outside the orthodontic realm since in the vast majority of cases, resorptions are not iatrogenic. In orthodontic practice, when all teeth are analyzed and planned using periapical radiography or computerized tomography, and when considering all predictive factors, tooth resorptions are not iatrogenic in nature and should be considered as one of the clinical events inherent in the treatment applied. PMID- 28902246 TI - An interview with Kee-Joon Lee. PMID- 28902247 TI - Debonding forces of different pads in a lingual bracket system. AB - Objective:: To evaluate the shear bond strength of lingual orthodontic brackets with resin or metal pads, the location of bond failure and the adhesive remnant index (ARI). Methods: : A total of 40 extracted upper premolars were randomly divided into two groups of 20 each: bonding with brackets having (1) pads with extended resin directly on the lingual surface of teeth, and (2) pads with metal custom base on the lingual surface of teeth. The debonding force was measured with an Instron universal testing machine. A Student's t-test was used to assess the difference between groups (alpha = 0.05). Results: : The results showed a significant difference between the groups (p < 0.001). The shear bond strength of metal pads was significantly higher than resin pads. Conclusions: : Within the limitations of this in vitro study, it was concluded that the bond strength of lingual brackets with metal pads was higher than that of brackets with composite resin pads, due to the metal part being a single unit and welded. The failure location in the region between the bracket and the resin pad affected a higher percentage of the resin pads than the metal pads. PMID- 28902248 TI - Facial profile esthetics in operated children with bilateral cleft lip and palate. AB - Objective:: The aim of this study was to evaluate the facial profile esthetics of rehabilitated children with complete bilateral cleft lip and palate (BCLP), comparing the judgment of professionals related and not related to cleft rehabilitation and laypersons. Methods:: Thirty children in the mixed dentition (24 male; 6 female) with a mean age of 7.8 years were evaluated using facial profile photographs by 25 examiners: 5 orthodontists and 5 plastic surgeons with experience in cleft care, 5 orthodontists and 5 plastic surgeons without experience in oral cleft rehabilitation and 5 graduated laymen. Their facial profiles were classified into esthetically unpleasant (grade 1 to 3), esthetically acceptable (grade 4 to 6), and esthetically pleasant (grade 7 to 9). Intraexaminer and interexaminer errors were evaluated using Spearman correlation coefficient and Kendall's test, respectively. Inter-rater differences were analyzed using Friedman test and Student-Newman-Keuls test for multiple comparisons. Results: : Orthodontists dealing with oral clefts rehabilitation considered the majority of the sample as esthetically pleasant. Plastic surgeons of the cleft team and laypersons classified most of the sample as esthetically acceptable. Most of the orthodontists and plastic surgeons not related to cleft care evaluated the facial profile as esthetically unpleasant. The structures associated to unpleasant profiles were the nose, the midface and the upper lip. Conclusions: : The facial profile of children with BCLP was classified as esthetically acceptable by laypersons. Professionals related to cleft rehabilitation were more lenient and those not related to cleft care were stricter to facial esthetics than laypersons. PMID- 28902249 TI - Effect of surface treatment of prefabricated teeth on shear bond strength of orthodontic brackets. AB - Objective:: The aim of this in vitro study was to evaluate and compare the effects of grinding, drilling, sandblasting, and ageing prefabricated teeth (PfT) on the shear bond strength (SBS) of orthodontic brackets, as well as the effects of surface treatments on the adhesive remnant index (ARI). Methods:: One-hundred ninety-two PfT were divided into four groups (n = 48): Group 1, no surface treatment was done; Group 2, grinding was performed with a cylindrical diamond bur; Group 3, two drillings were done with a spherical diamond bur; Group 4, sandblasting was performed with 50-um aluminum oxide. Before the experiment, half of the samples stayed immersed in distilled water at 37oC for 90 days. Brackets were bonded with Transbond XT and shear strength tests were carried out using a universal testing machine. SBS were compared by surface treatment and by ageing with two-way ANOVA, followed by Tukey's test. ARI scores were compared between surface treatments with Kruskal-Wallis test followed by Dunn's test. Results: : Surface treatments on PfT enhanced SBS of brackets (p< 0.01), result not observed with ageing (p= 0.45). Groups II, III, and IV showed higher SBS and greater ARI than the Group 1 (p< 0.05). SBS was greater in the groups 3 and 4 (drilling, sandblasting) than in the Group 2 (grinding) (p< 0.05). SBS and ARI showed a positive correlation (Spearman's R2= 0.57; p< 0.05). Conclusion: : Surface treatment on PfT enhanced SBS of brackets, however ageing did not show any relevance. Sandblasting and drilling showed greater SBS than grinding. There was a positive correlation between SBS and ARI. PMID- 28902250 TI - Effect of CPP-ACP paste with and without CO2 laser irradiation on demineralized enamel microhardness and bracket shear bond strength. AB - Introduction:: Many patients seeking orthodontic treatment already have incipient enamel lesions and should be placed under preventive treatments. The aim of this in vitro study was to evaluate the effect of CPP-ACP paste and CO2 laser irradiation on demineralized enamel microhardness and shear bond strength of orthodontic brackets. Methods: : Eighty caries-free human premolars were subjected to a demineralization challenge using Streptococcus mutans. After demineralization, the samples were randomly divided into five equal experimental groups: Group 1 (control), the brackets were bonded without any surface treatment; Group 2, the enamel surfaces were treated with CPP-ACP paste for 4 minutes before bonding; Group 3, the teeth were irradiated with CO2 laser beams at a wavelength of 10.6 um for 20 seconds. The samples in Groups 4 and 5 were treated with CO2 laser either before or through CPP-ACP application. SEM photomicrographs of a tooth from each group were taken to observe the enamel surface. The brackets were bonded to the buccal enamel using a conventional method. Shear bond strength of brackets and ARI scores were measured. Vickers microhardness was measured on the non-bonded enamel surface. Data were analyzed with ANOVA and Tukey test at the p< 0.05 level. Results:: The mean shear bond strength and microhardness of the laser group were higher than those in the control group and this difference was statistically significant (p< 0.05). All groups showed a higher percentage of ARI score 4. Conclusion: : CO2 laser at a wavelength of 10.6 um significantly increased demineralized enamel microhardness and enhanced bonding to demineralized enamel. PMID- 28902251 TI - Skeletal effects of RME in the transverse and vertical dimensions of the nasal cavity in mouth-breathing growing children. AB - Introduction:: Maxillary constriction is a dentoskeletal deformity characterized by discrepancy in maxilla/mandible relationship in the transverse plane, which may be associated with respiratory dysfunction. Objective: : The objective of this study was to evaluate the skeletal effects of RME on maxillary and nasal transverse dimensions and compare the differences between males and females. Methods: : Sixty-one mouth-breathers patients with skeletal maxillary constriction (35 males and 26 females, mean age 9.6 years) were included in the study. Posteroanterior (PA) radiographs were taken before expansion (T1) and 3 months after expansion (T2). Data obtained from the evaluation of T1 and T2 cephalograms were tested for normality with the Kolmogorov-Smirnov method. The Student's t-test was performed for each measurement to determine sex differences. Results: : RME produced a significant increase in all linear measurements of maxillary and nasal transverse dimensions. Conclusions: : No significant differences were associated regarding sex. The RME produced significant width increases in the maxilla and nasal cavity, which are important for treatment stability, improving respiratory function and craniofacial development. PMID- 28902252 TI - Assessing bone thickness in the infrazygomatic crest area aiming the orthodontic miniplates positioning: a tomographic study. AB - Introduction:: Due to the increasing use of miniplates for anchorage purposes in orthodontics, it is very important to know more about infrazigomatic crest anatomy (thickness), in adult patients. Objectives: : Evaluate the infrazygomatic crest region thickness, in adult (male and female) patients. Methods: : Cone-beam computerized tomography (CBCT) images from 40 patients were used to assess cross sectional measurements of the infrazygomatic crest region. Measurement 1 considered thickness 2 mm above the distobuccal root of the permanent maxillary first molar, while measurement 2 was taken 2 mm above the first measurement. Results: : The mean thickness of the infrazygomatic crest in males was 3.55 mm for measurement 1 and 2.84 mm for measurement 2, while in females these were 2.37 mm and 2.24 mm, respectively. Conclusion: : The authors concluded that the overall mean thickness of the infrazygomatic crest was 2.49 mm with respect to measurement 1, and 2.29 mm for measurement 2, with no statistically significant differences between gender. PMID- 28902253 TI - Bacterial adhesion on conventional and self-ligating metallic brackets after surface treatment with plasma-polymerized hexamethyldisiloxane. AB - Introduction:: Plasma-polymerized film deposition was created to modify metallic orthodontic brackets surface properties in order to inhibit bacterial adhesion. Methods:: Hexamethyldisiloxane (HMDSO) polymer films were deposited on conventional (n = 10) and self-ligating (n = 10) stainless steel orthodontic brackets using the Plasma-Enhanced Chemical Vapor Deposition (PECVD) radio frequency technique. The samples were divided into two groups according to the kind of bracket and two subgroups after surface treatment. Scanning Electron Microscopy (SEM) analysis was performed to assess the presence of bacterial adhesion over samples surfaces (slot and wings region) and film layer integrity. Surface roughness was assessed by Confocal Interferometry (CI) and surface wettability, by goniometry. For bacterial adhesion analysis, samples were exposed for 72 hours to a Streptococcus mutans solution for biofilm formation. The values obtained for surface roughness were analyzed using the Mann-Whitney test while biofilm adhesion were assessed by Kruskal-Wallis and SNK test. Results:: Significant statistical differences (p< 0.05) for surface roughness and bacterial adhesion reduction were observed on conventional brackets after surface treatment and between conventional and self-ligating brackets; no significant statistical differences were observed between self-ligating groups (p> 0.05). Conclusion: : Plasma-polymerized film deposition was only effective on reducing surface roughness and bacterial adhesion in conventional brackets. It was also noted that conventional brackets showed lower biofilm adhesion than self-ligating brackets despite the absence of film. PMID- 28902254 TI - Condylectomy and "surgery first" approach: An expedited treatment for condylar hyperplasia in a patient with facial asymmetry. AB - Condylar Hyperplasia (CH) is a self-limiting pathology condition that produces severe facial deformity at the expense of mandibular asymmetry. In this case report a 15-year-old female patient was diagnosed with Unilateral Condylar Hiperplasia (UCH) by mean of single-photon emission computed tomography (SPECT) and histological study. A high condylectomy in the right condyle was performed to stop the active status of the hyperplasia. A month after condylectomy, orthognathic jaw impaction and asymmetric mandibular setback surgery was performed with the Surgery First Approach (SFA). After 10 days, orthodontic appointments were made every two weeks during 4 months. The active phase of treatment lasted 14 months. Excellent facial and occlusal outcomes were obtained and after 24 months in retention the results remained stable. PMID- 28902255 TI - Taking advantage of an unerupted third molar: a case report. AB - Introduction:: Treatments with dental surgery seek to displace tooth to the correct position within the dental arch. Objective:: To report a clinical case that took advantage of an unerupted third molar. Case history: : A male patient, 18 years of age, was referred by his dentist to evaluate the third molars. The clinical exam revealed no visible lower third molars. The computed tomography (CT) exam showed the presence of a supernumerary tooth in the region of the mandibular ramus, on the left side, and impaction of the third molar, which was causing root resorption on the second molar, thus making it impossible to remain in the buccal cavity. The preferred option, therefore, was to remove both second molar and the supernumerary tooth, in addition to attaching a device to the third molar during surgery for further traction. Results: : After 12 months, the third molar reached the proper position. Conclusion: : When a mandibular second permanent molar shows an atypical root resorption, an impacted third molar can effectively substitute the tooth by using an appropriate orthodontic-surgical approach. PMID- 28902256 TI - Class II Division 2 subdivision left malocclusion associated with anterior deep overbite in an adult patient with temporomandibular disorder. AB - The orthodontic treatment of patients with chief complaint of temporomandibular disorders (TMD) presents doubtful prognosis, due to the poor correlation between malocclusions and TMDs. The present case report describes the treatment of an adult patient with Angle Class II Division 2 subdivision left malocclusion associated with anterior deep overbite and TMD. This case was presented to the Brazilian Board of Orthodontics and Dentofacial Orthopedics (BBO), as part of the requirements to obtain the title of BBO Diplomate. PMID- 28902257 TI - Sustainability in Orthodontics: what can we do to save our planet? AB - The sustainability of the natural resources of our planet is a topic for worldwide debate. Mankind, during its evolution as a species, has not been greatly concerned about conserving the environment in which we live. Nowadays we are reaping the fruits of this neglect. Climatic changes and storms are good examples of this. We, humans, must re-think our attitudes in order to leave the planet in a healthy state to be used by our descendants. But thinking of orthodontics, what can we do as orthodontists? From this perspective, the authors of the present study aimed, in a clear and objective manner, to present simple and sustainable ways to proceed during our activity as orthodontists, in order to minimize the effects on nature, caused by man. PMID- 28902258 TI - Phlebotomines in an area endemic for American cutaneous leishmaniasis in northeastern coast of Brazil. AB - Phlebotomines have worldwide distribution with many species present in Brazil, including the northeastern region, where the fauna is very diverse. The aim of this study was to identify the sandfly fauna in an area endemic for American cutaneous leishmaniasis (ACL) in the state of Pernambuco. Sandflies were caught on three consecutive nights every month from October 2015 to September 2016, from 5 pm to 5 am, using seven light traps of Centers for Disease Control (CDC) type. Females were identified and used for molecular Leishmania detection. A total of 2,174 specimens belonging to ten species were collected: Lutzomyia choti (88.2%; 1,917/2,174) was the most abundant species, followed by Lutzomyia whitmani (8.1%; 176/2,174) and Lutzomyia sordellii (1.5%; 33/2,174). The majority of the specimens were collected in peridomestic areas (64.1%; 1,394/2,174) and during the rainy period. All the samples examined were negative for Leishmania spp. The presence of Lutzomyia whitmani indoors and in peridomestic areas indicates that the inhabitants of this area are exposed to the risk of infection by the parasites responsible for ACL. PMID- 28902259 TI - Clinical and hematological evaluation of Rangelia vitalii-naturally infected dogs in southeastern Brazil. AB - Rangelia vitalii, a tick-borne piroplasm that infects dogs, has been recently molecularly characterized in Brazil, Uruguay and Argentina. Studies on molecular characterization of these piroplasms in different Brazilian regions are scarce. The aim of this study was to evaluate clinical and hematological changes in dogs caused by R. vitalii in the mountainous region of the state of Rio de Janeiro. Blood samples from 36 dogs were evaluated for piroplasms and hematological disorders using light microscopy and molecular analysis. Blood samples from all the animals included in this study were confirmed to be positive for R. vitalii through genetic sequencing. Clinical signspresented by 24 of the 36 dogs of the study were evaluated during appointments or hospitalization within private practice. The most frequent clinical disorders in these dogs that were naturally infected with R. vitalii were fever, spontaneous cutaneous bleeding and diarrhea. Normochromic non-regenerative anemia and thrombocytopenia were the most common hematological disorders in these R. vitalii-positive dogs and therefore should be considered in hematological evaluations on suspected cases. PMID- 28902260 TI - Hepatozoon caimani in Caiman crocodilus yacare (Crocodylia, Alligatoridae) from North Pantanal, Brazil. AB - Hepatozoon species are the most common intracellular hemoparasite found in reptiles. Hepatozoon caimani, whose vectors are Culex mosquitoes, has been detected in a high prevalence among caimans in Brazil by blood smears examinations. The present work aimed to detect and characterize the Hepatozoon spp. found in 33 caimans (24 free-ranging and 9 captive; 28 males and 5 females) (Caiman crocodilus yacare) sampled at Pocone, North Pantanal, state of Mato Grosso, Brazil, using blood smears examinations and molecular techniques. Hepatozoon spp.-gametocytes were found in 70.8% (17/24) and 88.8% (8/9) of blood smears from free-ranging and captive caimans, respectively. Hepatozoon spp. 18S rRNA DNA was found in 79.2% (19/24) and 88.8% (8/9) of free-ranging and captive caimans, respectively. Comparative analysis of parasitized and non-parasitized erythrocytes showed that all analyzed features were significantly different (P<0.05) for both linear and area dimensions. Phylogenetic analysis based on 18S rRNA sequences grouped the Hepatozoon spp. sequences detected in the present study together with H. caimani, recently detected in caimans in southern Pantanal. PMID- 28902261 TI - Detection of Anaplasma sp. phylogenetically related to A. phagocytophilum in a free-living bird in Brazil. AB - Wild animals play an important role in carrying vectors that may potentially transmit pathogens. Several reports highlighted the participation of wild animals on the Anaplasma phagocytophilum cycle, including as hosts of the agent. The aim of this study was to report the molecular detection of an agent phylogenetically related to A. phagocytophilum isolated from a wild bird in the Midwest of the state of Parana, Brazil. Fifteen blood samples were collected from eleven different bird species in the Guarapuava region. One sample collected from a Penelope obscura bird was positive in nested PCR targeting the 16S rRNA gene of Anaplasma spp. The phylogenetic tree based on the Maximum Likelihood analysis showed that the sequence obtained was placed in the same clade with A. phagocytophilum isolated from domestic cats in Brazil. The present study reports the first molecular detection of a phylogenetically related A. phagocytophilum bacterium in a bird from Parana State. PMID- 28902262 TI - Morphological and morphometric features of nematode-cysts in Gymnotus inaequilabiatus liver in the Brazilian Pantanal. AB - The aim of this study was to determine the morphometric measures and morphological aspects of nematode-cysts in Gymnotus inaequilabiatus, and the presence of melanomacrophage centers (MMCs) associated with the periphery of cysts and in the liver parenchyma. Adult specimens, 34 female (123.1 +/- 43.9g) and 45 male (135.5 +/- 43.4g), from Paraguay River, Corumba, Brazil, were used. The number of nematode-cysts was determined in 79 livers and 25 of them randomly selected for histopathological analysis and morphometric measures of nematode cysts (mean diameter, thickness of collagen layer, and cyst-wall layer). The percentage of cysts with MMCs on the periphery and density in the liver parenchyma was estimated. The average number of macroscopic cysts was of 48.7 +/- 2.78. Granulomatous reaction was observed surrounding the cysts. Diameter, collagen layer and cyst-wall measurements were 293.0 +/- 75.18 (um), 17.72 +/- 6.01 (um) and 12.21 +/- 9.51 (um), respectively. The number of nematode-cysts was correlated with hepatosomatic index, (r=0.26, P<0.05). Collagen layer was correlated with cyst diameter (r=0.62, P<0.01). Pericystic and parenchymatous MMCs were moderately (r=0.48) and highly (r=0.90) correlated with nematode-cysts number. Morphological characteristics of hepatic tissue and cysts-nematodes measures suggest that G. inaequilabiatus acts as a paratenic host to nematodes in the larval stage. PMID- 28902263 TI - Factors associated with timely treatment of malaria in the Brazilian Amazon: a 10 year population-based study. AB - Objective: To identify factors associated with timely treatment of malaria in the Brazilian Amazon. Malaria, despite being treatable, has proven difficult to control and continues to be an important public health problem globally. Brazil accounted for almost half of the 427 000 new malaria cases notified in the Americas in 2013. Methods: This was a cross-sectional study using secondary data on all notified malaria cases for the period from 2004 - 2013. Timely treatment was considered to be all treatment started within 24 hours of symptoms onset. Multivariate logistic regression was used to identify independent factors associated with timely treatment. Results: The proportion of cases starting treatment on a timely basis was 41.1%, tending to increase in more recent years (OR = 1.40; 95%CI: 1.37 - 1.42 in 2013). Furthermore, people starting within < 24 hours were more likely to: reside in the states of Rondonia (OR = 1.50; 95%CI: 1.49 - 1.51) or Acre (OR = 1.53; 95%CI: 1.55 - 1.57); be 0 - 5 years of age (OR = 1.39; 95%CI: 1.34 - 1.44) or 6 - 14 years of age (OR = 1.34; 95%CI: 1.32 - 1.36); be indigenous (OR = 1.41; 95%CI: 1.37 - 1.45); have a low level of schooling (OR = 1.20; 95%CI: 1.19 - 1.22); and be diagnosed by active detection (OR = 1.39; 95%CI: 1.38 - 1.39). Conclusion: In the Brazilian Amazon area, individuals were more likely to have timely treatment of malaria if they were young, residing in Acre or Rondonia states, have little schooling, and be identified through active detection. Identifying groups vulnerable to late treatment is important for preventing severe cases and malaria deaths. PMID- 28902264 TI - Intimate partner violence as a predictor of antenatal care service utilization in Honduras. AB - Objective: To describe the relationship between exposure to physical and/or sexual intimate partner violence (IPV) and indicators of antenatal care (ANC) service utilization among Honduran women of reproductive age. Methods: Data from the 2011-2012 Honduras Demographic and Health Survey were analyzed to describe the relationship between self-reported exposure to IPV and two ANC outcomes: (1) sufficient ANC visits (defined by the Honduran Ministry of Health as five or more visits) and (2) early ANC initiation (within the first trimester). Multiple logistic regression was used to estimate effects of physical and sexual IPV on the outcomes, controlling for women's age, education, literacy, residence, household size, religion, parity, wealth, husband's age, and husband's education. Results: Of women who were married, had at least one living child 5 years or younger, and completed the IPV module (N = 6 629), 13.5% of them reported any physical IPV, and 4.1% reported both physical and sexual IPV. There was no significant association between IPV and early ANC; however, a significant relationship between IPV and sufficient ANC was found. Women who experienced any physical IPV (adjusted odds ratios (aOR) = 1.25; 95% confidence interval (CI): 1.00-1.56) or sexual IPV (aOR = 1.53; 95% CI: 1.08-2.16) were, respectively, 25% and 53% more likely to receive insufficient ANC. Conclusions: Honduras has one of highest rates of interpersonal violence of any nation in the world. In Honduras, IPV is a contributor to this broader category of interpersonal violence as well as a risk factor for insufficient ANC. Our findings suggest that universal IPV screening during ANC as well as future initiatives aimed at reducing IPV might improve ANC utilization in the country. PMID- 28902265 TI - [Model for a risk-focused approach to health inspection, surveillance, and control in Colombia]. AB - Colombian Ministry of Health Resolution 1229 of 2013 established that health inspection, surveillance, and control (IVC, Spanish acronym) should be based on a risk-focused approach. In 2014 Colombia's National Food and Drugs Surveillance Institute (INVIMA) designed and implemented a risk-based health surveillance model called IVC-SOA. This model measures the risks of drugs, medical devices, food, and cosmetics by taking into account three factors: severity of the product (S), occurrence of product failure (O), and the potentially affected population (A) - hence its name, SOA. The model incorporates 40 variables and statistical methods that make it possible to create a risk profile for each entity surveyed, and thus to generate a ranking to determine which should be inspected. The objective of this report is to describe the methodology and results obtained following the design and implementation of the IVC-SOA model created by the regulatory agency in Colombia, and its impact on health surveillance effectiveness. PMID- 28902266 TI - Infant morbidity and mortality attributable to prenatal smoking in Chile. AB - Objective: To estimate annual infant morbidity and mortality attributable to prenatal smoking in Chile during 2008-2012. Methods: Population-attributable fractions (PAFs) for several infant outcomes were calculated based on previous study estimates of prenatal smoking prevalence and odds ratios associated with exposure (prenatal smoking relative to non-prenatal smoking). Prenatal smoking attributable infant morbidity and mortality cases were calculated by multiplying the average annual number of morbidity and mortality cases registered in Chile during 2008-2012 by the corresponding PAF. Results: PAFs for 1) births <= 27 weeks; 2) births at 28-33 weeks; 3) births at 34-36 weeks; and 4) full-term low birth-weight infants were 12.3%, 10.6%, 5.5%, and 27.4% respectively. PAFs for deaths caused by preterm-related causes and deaths caused by sudden infant death syndrome were 11.9% and 40.0% respectively. Annually, 2 054 cases of preterm birth and full-term low-birth-weight (1 in 9 cases), 68 deaths caused by preterm related causes (1 in 8 cases), and 26 deaths caused by sudden infant death syndrome (1 in 3 cases) were attributable to prenatal smoking. Conclusions: In Chile, infant morbidity and mortality attributable to prenatal smoking are unacceptably high. Comprehensive individual and population-based interventions for tobacco control should be a public health priority in the country, particularly among female adolescents and young women who will be the mothers of future generations. PMID- 28902267 TI - [Public production as a key factor for access to antivenoms in the Region of the Americas]. AB - Injuries caused by venomous animals affect vast areas of Latin America, Southern Asia, Southeast Asia, sub-Saharan Africa, and Oceania, and pose a serious problem for global public health. Based on an analysis of the current panorama of global production of ophidian and arachnid antivenoms, it is concluded that they are semi-orphaned products. This is a favorable scenario in which to strengthen public laboratory production. Governments should make a political decision in this regard in the interest of equity in population health. In the Region of the Americas, these actions could be part of a program led by the Pan American Health Organization to ensure the availability of these biologicals in strategically located health centers. Twelve public facilities producing antivenoms have been identified in the Region, including Brazil and Mexico, which are the biggest public producers. These laboratories should be managed like industrial operations that produce tangible goods without ignoring strategic planning. National regulatory authorities should help the public laboratories that produce them by providing necessary technical assistance and consultancy without any loss of impartiality or rigor in the evaluation of their quality management systems. New superior production technologies using hyperimmune mammalian plasma are in the experimental phase; no information on its production has been found in the literature. PMID- 28902268 TI - Cystic echinococcosis in South America: a call for action. AB - Cystic echinococcosis (CE) or hydatidosis, a parasitic zoonosis caused by a cestode of the family Taeniidae, species Echinococcus granulosus, is endemic in Argentina, Chile, Peru, Uruguay, and southern Brazil. This report presents CE figures for these five countries in 2009 - 2014 and proposes indicators to measure national control programs. Nearly 5 000 new CE cases were diagnosed annually in the five countries during the study period. The average case fatality rate was 2.9%, which suggests that CE led to approximately 880 deaths in these countries during the 6-year period. CE cases that required secondary or tertiary health care had average hospital stays of 10.6 days, causing a significant burden to health systems. The proportion of new cases (15%) in children less than 15 years of age suggests ongoing transmission. Despite figures showing that CE is not under control in South America, the long-standing implementation of national and local control programs in three of the five countries has achieved reductions in some of the indicators. The Regional Initiative for the Control of CE, which includes the five countries and provides a framework for networking and collaboration, must intensify its efforts. PMID- 28902269 TI - Development of in-house serological methods for diagnosis and surveillance of chikungunya. AB - Objective: To develop and evaluate serological methods for chikungunya diagnosis and research in Nicaragua. Methods: Two IgM ELISA capture systems (MAC-ELISA) for diagnosis of acute chikungunya virus (CHIKV) infections, and two Inhibition ELISA Methods (IEM) to measure total antibodies against CHIKV were developed using monoclonal antibodies (mAbs) and hyperimmune serum at the National Virology Laboratory of Nicaragua in 2014-2015. The sensitivity, specificity, predictive values, and agreement of the MAC-ELISAs were obtained by comparing the results of 198 samples (116 positive; 82 negative) with the Centers for Disease Control and Prevention's IgM ELISA (Atlanta, Georgia, United States; CDC-MAC-ELISA). For clinical evaluation of the four serological techniques, 260 paired acute and convalescent phase serum samples of suspected chikungunya cases were used. Results: All four assays were standardized by determining the optimal concentrations of the different reagents. Processing times were substantially reduced compared to the CDC-MAC-ELISA. For the MAC-ELISA systems, a sensitivity of 96.6% and 97.4%, and a specificity of 98.8% and 91.5% were obtained using mAb and hyperimmune serum, respectively, compared with the CDC method. Clinical evaluation of the four serological techniques versus the CDC real-time RT-PCR assay resulted in a sensitivity of 95.7% and a specificity of 88.8%-95.9%. Conclusion: Two MAC-ELISA and two IEM systems were standardized, demonstrating very good quality for chikungunya diagnosis and research demands. This will achieve more efficient epidemiological surveillance in Nicaragua, the first country in Central America to produce its own reagents for serological diagnosis of CHIKV. The methods evaluated here can be applied in other countries and will contribute to sustainable diagnostic systems to combat the disease. PMID- 28902270 TI - Public health response and lessons learned from the 2014 chikungunya epidemic in Grenada. AB - In June 2014, the first cases of chikungunya virus (CHIKV) were diagnosed on the island of Carriacou, part of the tri-island state of Grenada. In the three months that followed, CHIKV spread rapidly, with conservative estimates of the population infected of at least 60%. Multiple challenges were encountered in the battle to manage the spread and impact of this high-attack rate virus, including 1) limited indigenous laboratory diagnostic capabilities; 2) an under-resourced health care system; 3) a skeptical general public, hesitant to accept facts about the origin and mode of transmission of the new virus; and 4) resistance to the vector control strategies used. Lessons learned from the outbreak included the need for 1) a robust and reliable epidemiological surveillance system; 2) effective strategies for communicating with the general population; 3) exploration of other methods of mosquito vector control; and 4) a careful review of all health care policies and protocols to ensure that effective, organized responses are triggered when an infectious outbreak occurs. PMID- 28902271 TI - [Clinical and epidemiological characterization of chikungunya fever in Mexico]. AB - On 6 December 2013, the Pan American Health Organization (PAHO) and the World Health Organization (WHO) reported confirmation of the first two cases of indigenous transmission of chikungunya fever (CHIK) in the Region of the Americas on the island of Sint Maarten (Netherlands Antilles). For the period 2013-2014, a total of 25 627 confirmed autochthonous cases were distributed in 43 countries, with Mexico reporting 155 cases in five states. Information on cases of CHIK in Mexico was obtained from the database of the General Directorate of Epidemiology (Ministry of Health of Mexico). The distribution of confirmed autochthonous cases of CHIK for 2015, by sex, was 64% female (5 583) and 36% male (3 085). The most frequent symptoms were fever in 98% of cases (8 564), followed by headache in 91.6% (7 941), myalgia in 89.9% (7 792), mild arthralgias in 73.5% (6 367), severe polyarthralgia in 72.6% (6 295), and exanthema in 58% (5 032). The clinical presentation of autochthonous cases of CHIK in Mexico has shown several clinical manifestations different from those seen in outbreaks in African and Asian countries and other regions in the Americas; for example, a greater percentage of cases with headache and myalgia and a smaller percentage of cases with arthralgia. PMID- 28902272 TI - [Chikungunya seroprevalence and clinical case rate in Nicaragua, 2014-2015]. AB - Objective: Estimate seroprevalence, clinical case rate, and proportion of subclinical infections from chikungunya. Methods: A cross-sectional study was conducted in October 2015 at 39 sites distributed across Nicaragua. Demographic and clinical information was compiled through a personal survey. Blood samples were collected to detect chikungunya antibodies using the ELISA inhibition method developed by Nicaragua's National Diagnostic and Reference Center. Results were analyzed using generalized linear models and multilevel Poisson models. Results: A total of 11 722 participants aged >2 years were enrolled and 11 280 samples were processed. National seroprevalence was 32.8% (95% CI [95% confidence interval]: 31.9-33.6), with a clinical case rate of 26.5% (95% CI: 25.7-27.3) and a proportion of subclinical infections of 19.1% (95% CI: 17.8-20.4). Seroprevalence varied among the 39 sites and was greater at sites with higher vector infestation indices. Individually, seroprevalence was higher in participants aged >11 years. Conclusion: Since its introduction, this is the first study on chikungunya seroprevalence in continental Latin America to determine national prevalence, clinical case rate, and proportion of subclinical infections. The study model, employing broad community participation and leadership by the Ministry of Health of Nicaragua, can be an example for conducting similar studies in the region. PMID- 28902273 TI - Chikungunya: important lessons from the Jamaican experience. AB - Objectives: To describe the clinical presentation of chikungunya virus (CHIKV) illness in adults during the 2014 outbreak in Jamaica and to determine the predictive value of the case definition. Methods: A cross-sectional study was conducted using clinical data from suspected cases of CHIKV that were reported to the Ministry of Health in April - December 2014. In addition, charts were reviewed of all individuals over 15 years of age with suspected CHIKV based on a diagnosis of CHIKV or "acute viral illness" that presented to four major health centers in Jamaica during the week prior to and the peak week of the epidemic. Data abstracted from these charts using a modified CHIKV Case Investigation Form included demographics, clinical findings, and laboratory tests. Results: In 2014, the Ministry of Health of Jamaica received 4 447 notifications of CHIKV infection. PCR testing was conducted on 137 suspected CHIKV cases (56 men and 81 women; median age 28 years) and was positive for 89 (65%) persons. In all, 205 health charts were identified that met the selection criteria (51 men and 154 women, median age 43 years). The most commonly reported symptoms were arthralgia (86%) and fever (76%). Of those who met the epidemiologic case definition for CHIKV as defined by the Pan American Health Organization, only 34% had this diagnosis recorded. Acute viral illness was the most frequently recorded diagnosis (n = 79; 58%). Conclusions: Broader case definitions for acute CHIKV illness may be needed to identify suspected cases during an outbreak. Standardized data collection forms and validation of case definitions may be useful for future outbreaks. PMID- 28902274 TI - Chikungunya virus outbreak in Sint Maarten, 2013-2014. AB - This report describes the outbreak of chikungunya virus (CHIKV) in Sint Maarten, a constituent country of Kingdom of the Netherlands comprising the southern part of the Caribbean island of Saint Martin, from 22 December 2013 (first reported case) through 5 December 2014. The outbreak was first reported by the French overseas collectivity of Saint-Martin in the northern part of the island-the first site in the Americas to report autochthonous transmission of CHIKV. By 5 December 2014, Sint Maarten had reported a total of 658 cases-an overall attack rate of 1.76%. Actual prevalence may have been higher, as some cases may have been misdiagnosed as dengue. Fever and arthralgia affected 71% and 69% of reported cases respectively. Of the 390 laboratory-confirmed cases, 61% were female and the majority were 20-59 years old (mean: 42; range: 4-92). The spread of CHIKV to Sint Maarten was inevitable given the ease of movement of people, and the vector, island-wide. Continuing their history of collaboration, the French and Dutch parts of the island coordinated efforts for prevention and control of the disease. These included a formal agreement to exchange epidemiological information on a regular basis and provide alerts in a timely manner; collaboration among personnel through joint island-wide planning of mosquito control activities, especially along borders; notification of all island visitors, upon their arrival at airports and seaports, of preventative measures to avoid being bitten by mosquitoes; dissemination of educational materials to the public; and island-wide public awareness campaigns, particularly in densely populated areas, for both residents and visitors. The information provided in this report could help increase understanding of the epidemiological characteristics of CHIKV and guide other countries dealing with vector-borne epidemics. PMID- 28902275 TI - Evaluation of three commercially-available chikungunya virus immunoglobulin G immunoassays. AB - The emergence of chikungunya virus in the Americas means the affected population is at risk of developing severe, chronic, rheumatologic disease, even months after acute infection. Accurate diagnostic methods for past infections are essential for differential diagnosis and consequence management. This study evaluated three commercially-available chikungunya Immunoglobulin G immunoassays by comparing them to an in-house Enzyme-Linked ImmunoSorbent Assay conducted by the Centers for Disease Control and Prevention (Atlanta, Georgia, United States). Results showed sensitivity and specificity values ranging from 92.8% - 100% and 81.8% - 90.9%, respectively, with a significant number of false-positives ranging from 12.5% - 22%. These findings demonstrate the importance of evaluating commercial kits, especially regarding emerging infectious diseases whose medium and long-term impact on the population is unclear. PMID- 28902276 TI - First detection of dengue and chikungunya viruses in natural populations of Aedes aegypti in Martinique during the 2013 - 2015 concomitant outbreak. AB - Dengue and chikungunya viruses are transmitted by Aedes mosquitoes. In Martinique, an island of the French West Indies, Aedes aegypti is the suspected vector of both arboviruses; there is no Aedes albopictus on the island. During the concomitant outbreak of 2013 - 2015, the authors collected wild A. aegypti populations, and for the first time, detected dengue and chikungunya viruses in field-collected females. This paper demonstrates the mosquito's role in transmission of both dengue and chikungunya on the island, and also highlights a tool that public health authorities can use for preventing outbreaks. PMID- 28902277 TI - Clinical manifestations of chikungunya among university professors and staff in Santo Domingo, the Dominican Republic. AB - Objective: To further characterize chikungunya virus infection and its associated clinical manifestations, using a sample of university professors and staff in Santo Domingo, the Dominican Republic. Methods: A cross-sectional study with quota sampling by department was performed to obtain a convenience sample of professors (n = 736) and staff (n = 499) at the Universidad Autonoma de Santo Domingo. Surveys were used to collect demographic and infection data during the fall term of 2014. Univariate and bivariate analyses were carried out to quantify infection and clinical manifestation prevalence and to assess relationships of these outcomes with age, sex, and acute phase duration. Results: Of 1 236 participants, 49% reported infection (professors = 41%; staff = 61%). Of these, 53% also reported the presence of chronic effects, largely arthralgia (48%). Significant relationships were observed between reported infection and sex (P = 0.023), age (P < 0.001), and occupation (P < 0.001). More headache (P = 0.008) and edema (P < 0.001) in females, more headache (P = 0.005) in younger subjects, and more myalgia (P = 0.006) in those with longer acute symptoms were found. Additionally, more chronic arthralgia (P < 0.001; P = 0.003) and chronic edema (P < 0.001; P = 0.001) in females and older subjects, and more chronic myalgia (P = 0.041) and chronic edema (P = 0.037) in those with longer acute symptoms were observed. Conclusions: To the authors knowledge, this is the first population based chikungunya prevalence study in the Dominican Republic, and the first to explore clinical manifestations in a university setting. The findings reflect results from studies following the 2005 - 2006 Reunion Island outbreak: prevalence of infection and chronic arthralgia, as well as associations with sex, age, and acute intensity. Longitudinal research can provide further insight into these effects. PMID- 28902278 TI - Minimum infectious dose for chikungunya virus in Aedes aegypti and Ae. albopictus mosquitoes. AB - Understanding the ability of the chikungunya virus (CHIKV) to be transmitted by Aedes vectors in the Americas is critical for assessing epidemiological risk. One element that must be considered is the minimum infectious dose of virus that can lead to transmission following the extrinsic incubation period. This study aimed to determine the minimum infection rate for the two Aedes species studied. The results revealed that doses as low as 3.9 log10 plaque-forming units per mL (pfu/mL) of an Asian genotype CHIKV strain can lead to transmission by Ae. albopictus, and doses of at least 5.3 log10 pfu/mL from the same strain are needed for transmission from Ae. aegypti. These low infecting doses suggest that infected individuals may be infectious for almost the entire period of their viremia, and therefore, to prevent further cases, measures should be taken to prevent them from getting bitten by mosquitoes during this period. PMID- 28902279 TI - [Aging and long-term care in Chile: challenges in the OECD context]. AB - Chile is fully in the process of demographic transition, with a rapidly aging population. This situation poses multiple public policy challenges, including those in the public health sector. Specifically, the association between aging and the loss of autonomy calls for the rapid design of a long-term care policy in the country. The purpose of this article is to describe Chile's current situation with respect to long-term care in aging, using the experience of the countries of the Organisation for Economic Co-operation and Development to draw attention to the need to move forward with the design and financing of a coordinated policy in the country that will permit early action to meet the challenges of aging in the coming decades. PMID- 28902280 TI - [Impact of physical inactivity on mortality and the economic costs of cardiovascular deaths: evidence from Argentina]. AB - Objective: Estimate mortality and economic costs from cardiovascular diseases attributable to physical inactivity in Argentina. Methods: Attributable mortality (AM) from physical inactivity was estimated as the product of the population attributable fraction and the number of deaths caused by associated cardiovascular diseases. Value of statistical life (VSL) was calculated using the human capital approach, in which VSL was estimated through lost productivity from premature death. Economic costs were calculated using AM and VSL, stratifying by sex, age group, and physical activity level. A sensitivity analysis was used to evaluate how costs vary in three possible scenarios. Results: AM from low and moderate physical activity ranged from 33 (18 to 24 years) to 7 857 (>84 years) deaths annually in both sexes. VSL ranged from I$441 005 (international dollars) (18 to 24 years) to I$4,121 (>84 years). Assessment of total costs by sex indicates that economic losses amounted to I$752.5 million for men and I$444.5 million for women. Conclusion: Economic losses ranged from 0.61% of GDP for the minimum scenario, 0.85% for the average scenario, and 1.48% for the maximum scenario. Stronger public policy-making aimed at reduction of sedentary lifestyles in Argentina is recommended. PMID- 28902281 TI - The United States-Mexico border environmental public health: the challenges of working with two systems. AB - This report shares the challenges and opportunities encountered by a binational project that examined the availability of environmental and public health information for the United States-Mexico border area. The researchers interviewed numerous national and binational agencies on both sides of the border, endeavoring to develop a framework to advance the knowledge of academic and public health professionals in the area of environmental border health. However, the lack of standardized indicators and metrics in both countries validates the emergent need to establish a viable framework for the collection, analysis, and dissemination of environmental information. Recommendations for next steps are included. PMID- 28902282 TI - [Women's health prevention indicator: a proposal for combining mammography and Papanicolaou smear]. AB - This article proposes a women's health prevention indicator (WHPI) reflecting the combined status of mammography and Papanicolaou (Pap) smear according to the recommendations for age and considering the time elapsed since the last exam/test. The WHPI classifies prevention status into desirable, alert, or risk categories. The risk category includes women of all ages who never had a Pap smear, those aged >60 years who had a Pap smear more than 3 years ago but never had a mammography, and those aged >=71 years who are up to date with the Pap smear but never had a mammography. The desirable category includes women with a Pap smear in the past 3 years, except women aged >=41 who never had a mammography and those aged >=51 years who had a mammography more than 2 years earlier. The alert category includes women whose Pap smear is more than three years old with the exception of those >=61 years who never had a mammography and those aged >=71 years whose mammography is more than 2 years old. For women who had experienced a Pap smear in the past 3 years, the alert category includes those aged 41-50 years who never had mammography, those aged 51-70 years with mammography older than 2 years or no mammography, and those aged >=71 years with mammography older than 2 years. Applying the WHPI to data from the National Household Sample Survey of 2008 revealed that 24.8% of Brazilian women were at risk and 24.2% were in the alert category. The Northeast and the North had the highest risk rates (31.5% and 29.6% respectively). Of those >70 years old, 49.5% were in the risk category. The WHPI can be used to assess public initiatives and compare preventive status within and across regions. PMID- 28902283 TI - New perspectives on the nutritional factors influencing growth rate of Candida albicans in diabetics. An in vitro study. AB - BACKGROUND: The link between Candida albicans and diabetes mellitus is well acknowledged, but incompletely elucidated. OBJECTIVES: The purpose of this study is to assess the growth rate of C. albicans (CA) in the presence of different concentrations of glucose and fructose, two of the main pathophysiologic and nutritionally relevant sugars in diabetic patients, in order to obtain a better understanding of the nutrient acquisition strategy and its possible relation to the hyperglycemic status of diabetic patients. METHODS: The effects of different concentrations of glucose and fructose (1000 mg%, 500 mg%, 250 mg% and 100 mg% w/v) on the growth rate of CA have been studied by flow-cytometry. FINDINGS: We found that glucose concentration is directly related to CA growth, which may be linked to the frequent yeast infections that occur in non-controlled diabetic patients; we also show that fructose inhibits CA growth rate. MAIN CONCLUSIONS: As a consequence of our hypothesis, the study demonstrates that fructose containing food may prevent the development of candidiasis, at least in oral sites. PMID- 28902284 TI - Retrieving ascarid and taeniid eggs from the biological remains of a Neolithic dog from the late 9th millennium BC in Western Iran. AB - BACKGROUND: Paleoparasitology reveals the status of parasitic infections in humans and animals in ancient times based on parasitic particles found in biological remains from archaeological excavations. This line of research emerged in Iran in 2013. OBJECTIVE: The identification of parasites from Neolithic times is an attractive subject that shows the oldest origins of parasitic infections in a given geographical region. From an archaeological point of view, this archaeological site is well-known for animal domestication and agriculture in ancient Iran. METHODS: In this study, soil deposited on the surface and in the pores of a dog pelvic bone was carefully collected and rehydrated using trisodium phosphate solution. FINDINGS: The results showed ascarid and taeniid eggs retrieved from the biological remains of a dog excavated at the East Chia Sabz archaeological site, which dates back to the Neolithic period (8100 BC). MAIN CONCLUSION: The current findings clearly illustrate the natural circulation of nematode and cestode parasites among dogs at that time. These ancient helminth eggs can also be used to track the oldest parasitic infections in the Iranian plateau and contribute to the paleoparasitological documentation of the Fertile Crescent. PMID- 28902285 TI - Dipyridamole potentiated the trypanocidal effect of nifurtimox and improved the cardiac function in NMRI mice with acute chagasic myocarditis. AB - BACKGROUND: As chronic Chagas disease does not have a definitive treatment, the development of alternative therapeutic protocols is a priority. Dipyridamole (DPY) is an alternative to counteract the pathophysiological phenomena involved in Chagas cardiomyopathy. OBJECTIVE: To evaluate the therapeutic efficacy of DPY associated with nifurtimox (Nfx) in epimastigote axenic cultures and in mice with acute Chagas disease. METHODS: NMRI adult male mice were divided into nine groups: three healthy and six Trypanosoma cruzi-infected groups. Mice received vehicle, Nfx or DPY, alone or combined. The doses assayed were Nfx 10 and 40 mg/kg and DPY 30 mg/kg. The treatment efficacy was evaluated by clinical, electrocardiographic, parasitological, biochemical and histopathological methods. FINDINGS: In vitro, DPY and Nfx had a trypanocidal effect with IC50 values of 372 +/- 52 and 21.53 +/- 2.13 uM, respectively; DPY potentiated the Nfx effect. In vivo, Nfx (40 mg/kg) with or without DPY had a therapeutic effect, which was reflected in the 84-92% survival rate and elimination of parasitaemia and heart tissue amastigotes. Nfx (10 mg/kg) had a subtherapeutic effect with no survival and persistence of amastigotes, inflammation and fibrosis in heart tissue; adding DPY increased the survival rate to 85%, and all tested parameters were significantly improved. MAIN CONCLUSION: DPY has a trypanocidal effect in vitro and enhances the Nfx therapeutic effect in an in vivo murine model. PMID- 28902286 TI - Specific antigen serologic tests in leprosy: implications for epidemiological surveillance of leprosy cases and household contacts. AB - BACKGROUND: There is a lack of straightforward tests for field application and known biomarkers for predicting leprosy progression in infected individuals. OBJECTIVE: The aim was to analyse the response to infection by Mycobacterium leprae based on the reactivity of specific antigens: natural disaccharide linked to human serum albumin via an octyl (NDOHSA), a semisynthetic phenolic glycolipid I (PGL-I); Leprosy Infectious Disease Research Institute Diagnostic-1 (LID-1) and natural disaccharide octyl - Leprosy Infectious Disease Research Institute Diagnostic-1 (NDOLID). METHODS: The study population consisted of 130 leprosy cases diagnosed between 2010 and 2015 and 277 household contacts. An enzyme linked immunosorbent assay (ELISA) was used to analyse the reactivity of antibodies against NDOHSA, LID-1 and NDOLID. The samples and controls were tested in duplicate, and the antibody titer was expressed as an ELISA index. Data collection was made by home visits with application of questionnaire and dermatological evaluation of all household contacts to identify signs and symptoms of leprosy. FINDINGS: Significant differences in the median ELISA results were observed among leprosy cases in treatment, leprosy cases that had completed treatment and household contacts. Higher proportions of seropositivity were observed in leprosy cases in treatment. Seropositivity was also higher in multibacillary in relation to paucibacillary, with the difference reaching statistical significance. Lower titers were observed among cases with a longer treatment time or discharge. For household contacts, the differences according to the clinical characteristics of the leprosy index case were less pronounced than expected. Other factors, such as the endemicity of leprosy, exposure outside the residence and genetic characteristics, appeared to have a greater influence on the seropositivity. MAIN CONCLUSIONS: Serologic tests could be used as auxiliary tools for determining the operational classification, in addition to identifying infected individuals and as a strategy for surveillance of household contacts. PMID- 28902287 TI - Structural insights into leishmanolysins encoded on chromosome 10 of Leishmania (Viannia) braziliensis. AB - BACKGROUND: Leishmanolysins have been described as important parasite virulence factors because of their roles in the infection of promastigotes and resistance to host's defenses. Leishmania (Viannia) braziliensis contains several leishmanolysin genes in its genome, especially in chromosome 10. However, the functional impact of such diversity is not understood, but may be attributed partially to the lack of structural data for proteins from this parasite. OBJECTIVES: This works aims to compare leishmanolysin sequences from L. (V.) braziliensis and to understand how the diversity impacts in their structural and dynamic features. METHODS: Leishmanolysin sequences were retrieved from GeneDB. Subsequently, 3D models were built using comparative modeling methods and their dynamical behavior was studied using molecular dynamic simulations. FINDINGS: We identified three subgroups of leishmanolysins according to sequence variations. These differences directly affect the electrostatic properties of leishmanolysins and the geometry of their active sites. We identified two levels of structural heterogeneity that might be related to the ability of promastigotes to interact with a broad range of substrates. MAIN CONCLUSION: Altogether, the structural plasticity of leishmanolysins may constitute an important evolutionary adaptation rarely explored when considering the virulence of L. (V.) braziliensis parasites. PMID- 28902288 TI - Basal core promoter and precore mutations among hepatitis B virus circulating in Brazil and its association with severe forms of hepatic diseases. AB - BACKGROUND: In Brazil, few studies have investigated the prevalence of infection with the precore (PC) and basal core promoter (BCP) mutants of the hepatitis B virus (HBV). OBJECTIVES: This study aimed to analyse the frequency of PC and BCP mutations among patients infected with HBV and to evaluate the association between the variants and advanced hepatic disease. METHODS: A total of 161 patients infected with HBV were studied. To identify PC and BCP mutations, a 501 bp fragment of HBV DNA was amplified and sequenced. FINDINGS: PC and BCP regions from HBV strains were successfully amplified and sequenced in 129 and 118 cases, respectively. PC and BCP mutations were detected in 61.0% and 80.6% of the cases, respectively. The A1762T/G1764A variant was identified in 36.7% of the patients with grade 1 and 2 liver fibrosis (29/79) and in 81.8% of the patients with grade 3 and 4 liver fibrosis (9/11) (p < 0.01); in 76.9% of the patients with cirrhosis (10/13) and in 38.1% of the patients without cirrhosis (40/105) (p = 0.01); and in 77.8% of the patients with hepatocellular carcinoma (HCC) (7/9) and in 39.4% of the patients without HCC (43/109) (p = 0.03). MAIN CONCLUSIONS: A high prevalence of HBV PC and BCP mutants was found. The A1762T/G1764A variant was independently associated with advanced forms of liver fibrosis, hepatic cirrhosis, and HCC. PMID- 28902289 TI - Exposure source prevalence is associated with gender in hepatitis C virus patients from Rio de Janeiro, Brazil. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a worldwide public health problem. A characterisation of the differences in exposure sources among genders will enable improvements in surveillance actions. METHODS: Exposure data were obtained for 1180 confirmed HCV cases Brazil's mandatory reporting to epidemiological surveillance, which was directed by a reference laboratory in Rio de Janeiro, Brazil. The Chi-square test (chi2) was used to assess the associations between exposure sources and gender. The prevalence ratio (PR) was calculated for exposures that showed an association. RESULTS: The results showed 57.7% cases were female, and associations with snorting drugs, sexual activity, surgery, aesthetic procedures, blood transfusions, and educational level were observed (p < 0.001). Men showed 2.53 (1.33-3.57), 4.83 (3.54-6.59), and 2.18 (1.33-3.57) times more exposure to sniffing drugs, risky sex and higher levels of education, respectively, than women. Women demonstrated 4.46 (3.21-6.21), 1.94 (1.43-2.63), and 3.10 (2.09-4.61) times more exposure to surgery, aesthetic procedures, and blood transfusions, respectively, than men. CONCLUSION: Our results showed differences in risk behaviours associated with gender among HCV carriers. These data are likely to significantly influence clinical practice regarding the adoption of specific approaches for counselling and control policies to prevent the emergence of new cases and break the chain of transmission of the virus. PMID- 28902290 TI - Effect of secondary infection on epithelialisation and total healing of cutaneous leishmaniasis lesions. AB - BACKGROUND: Cutaneous leishmaniasis (CL) generally presents with a single or several localised cutaneous ulcers without involvement of mucous membranes. Ulcerated lesions are susceptible to secondary contamination that may slow the healing process. OBJECTIVE: This study verified the influence of non-parasitic wound infection on wound closure (epithelialisation) and total healing. METHODS: Twenty-five patients with a confirmed diagnosis of CL and ulcerated lesions underwent biopsy of ulcer borders. One direct microbial parameter (germ identification in cultures) and four indirect clinical parameters (secretion, pain, burning sensation, pruritus) were analysed. FINDINGS Biopsies of ten lesions showed secondary infection by one or two microorganisms (Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Streptococcus pyogenes and Candida parapsilosis). "Secretion" and "burning sensation" influenced epithelialisation time but not total healing time. Positive detection of germs in the ulcer border and "pain" and "pruritus" revealed no influence on wound closure. CONCLUSIONS: Our borderline proof of clinical CL ulcer infection inhibiting CL wound healing supports the need to follow antimicrobial stewardship in CL ulcer management, which was recently proposed for all chronic wounds. PMID- 28902291 TI - Emergence of methicillin-resistant Staphylococcus aureus from clonal complex 398 with no livestock association in Brazil. AB - CC398 is a livestock-associated Staphylococcus aureus. However, it has also been isolated from humans with no previous contact with livestock. A surveillance of methicillin-resistant S. aureus colonisation among children attending public day care centres and hospitals in Niteroi and Rio de Janeiro, Brazil, between 2011 and 2013, resulted in the isolation of six cases of CC398 from individuals with no previous exposure to livestock. These isolates showed a high frequency of the erm(C) gene (4/6, 66.7%) with induced resistance to clindamycin, and a relatively high frequency of SEs and lukS/lukF genes. These results suggest the emergence of a non-LA-CC398 in Brazil. PMID- 28902292 TI - Increased number of deaths during a chikungunya epidemic in Pernambuco, Brazil. AB - In early 2016, it was suspected that there were more deaths in Pernambuco than in previous years during an epidemic of chikungunya. This study tested whether there was an increased number of deaths and, if so, whether this increase could be related to a chikungunya epidemic. Indeed, there was an increase of 4235 deaths in 2016 compared to the average of the four previous years, and the highest differences were found during the peak period of the epidemic. It was evident that not all of these deaths could be attributed to complications of chikungunya. However, considering the temporal overlap, some of these deaths may have been caused by the aggravation of pre-existing comorbidities or complications caused directly by chikungunya virus infection. PMID- 28902293 TI - Characterization of Leishmania (L.) infantum chagasi in visceral leishmaniasis associated with hiv co-infection in Northeastern Brazil. AB - Visceral leishmaniasis, associated with HIV/AIDS coinfection, is becoming a more aggressive disease, complicating an accurate prognosis. A 21-year-old HIV positive female presenting with clinical features of visceral leishmaniasis was enrolled in this study. Bone marrow cytology, Novy-MacNeal-Nicolle culture and kDNA PCR of peripheral blood were all positive. Typing methods, multilocus enzyme electrophoresis and ITS1-RFLP PCR of peripheral blood confirmed infection by Leishmania (L.) infantum chagasi . PCR has proved to be safer and more affordable than other characterization methods; ITS1-RFLP PCR can diagnose and type Leishmania spp. in both endemic and non-endemic areas, favoring the prognosis and allowing the appropriate treatment of patients. PMID- 28902294 TI - Oral health conditions in leprosy cases in hyperendemic area of the Brazilian Amazon. AB - Leprosy is a hyperendemic chronic condition in the Rondonia State . Despite the significant impact of oral health on the quality of life and clinical evolution of leprosy patients, systematic evaluation of oral health status has been neglected. To analyze the dental-clinical profile, self-perceived oral health and dental health service access of leprosy cases in the municipality of Cacoal in Rondonia State , North Brazil, from 2001 to 2012. A descriptive, cross-sectional study design was performed based on dental evaluation and standardized structured instruments. We investigated clinically assessed and self-perceived oral health status, as well as dental health service access. A total of 303 leprosy cases were included; 41.6% rated their oral health as good, and 42.6% reported being satisfied with their oral health. Self-reported loss of upper teeth was 45.5%. The clinical evaluation revealed that 54.5% had active caries. Most (97.7%) cases reported having been to the dentist at least once in their life and 23.1% used public health services. The poor standard of oral health in this population may increase the risk for leprosy reactions, consequently reducing quality of life. Low access to public health dental services and poor self-perceived oral health reinforce the need to achieve comprehensive health care in this population. PMID- 28902295 TI - Sandfly fauna (Diptera: Psychodidae) in an urban area, Central-West of Brazil. AB - Biological and ecological relations among vectors and their pathogens are important to understand the epidemiology of vector-borne diseases. Camapua is an endemic area for visceral and tegumentary leishmaniasis. The aim of this study was to characterize the sandfly fauna present in Camapua , MS, Brazil. Sand flies were collected every fortnight from May 2014 to April 2015 using automatic light traps in the domicile and peridomicile of twelve neighborhoods and forest. The collected specimens were identified based on morphology according to the valid identification keys. In total, 2005 sandflies of five genera and nine species were collected. Nyssomyia whitmani and Lutzomyia cruzi were the most abundant species. Males were more abundant, with a male-to-female ratio of 2.14. The highest diversity was observed in peripheral neighborhood, with abundant plant cover. The peridomicile presented greater abundance of sandflies, with the predominance of Ny. whitmani . No significant correlation between the absolute frequencies of the most abundant species and the precipitation variable was observed; however, there was a predominance of Lu. cruzi in the rainy season. We observed a high frequency of sandflies in urban area, especially vector species. The presence of Nyssomyia whitmani and Lutzomyia cruzi indicate the necessity for health surveillance in the municipality. Additional method of collection such as sticky trap is also recommended for appropriate faunestic study. PMID- 28902297 TI - The influence of serial fecal sampling on the diagnosis of giardiasis in humans, dogs, and cats. AB - Giardia infection is a common clinical problem in humans and pets. The diagnosis of giardiasis is challenging as hosts intermittently excrete protozoan cysts in their feces. In the present study, we comparatively evaluated two methods of serial fecal sampling in humans, dogs, and cats from Rio de Janeiro, Brazil. The Faust et al. technique was used to examine fecal specimens collected in triplicate from 133 patients (52 humans, 60 dogs, and 21 cats). Specimens from 74 patients were received from the group assigned to carry out sampling on consecutive days - 34 humans, 35 dogs, and 5 cats, and specimens from 59 patients were received from the group assigned to carry out sampling on non-consecutive, separate days - 18 human beings, 25 dogs, and 16 cats. G. duodenalis cysts were found in stools of 30 individuals. Multiple stool sampling resulted in an increase in the number of samples that were positive for Giardia in both groups. The authors therefore conclude that multiple stool sampling increases the sensitivity of the Faust et al . technique to detect G. duodenalis cysts in samples from humans, cats and dogs. PMID- 28902298 TI - Nursing infant with acquired toxoplasmosis in the first months of life - a case report. AB - Toxoplasmosis is caused by Toxoplasma gondii and the probability of this infection occurring in the first months of life is usually low because its transmission is related to eating habits. A 6-month-old nursing infant was diagnosed with acute toxoplasmosis, which was identified through anti- T. gondii IgA, IgM and low-avidity IgG serologic assays, polymerase chain reaction (PCR) and mouse bioassay test although its mother was seronegative. This serological divergence between mother and child led us to interview the mother regarding epidemiological factors. During this interview, she reported that she had given her 2-month-old baby a piece of undercooked beef to suck on. After some time, the baby presented fever and cervical lymphadenitis. This report emphasizes the importance of serological surveys of toxoplasmosis in nursing infants presenting with fever and lymphadenitis, in view of the possible acquisition of toxoplasmosis in the first months of life. PMID- 28902296 TI - An unusual case of bacillary angiomatosis in the oral cavity of an AIDS patient who had no concomitant tegumentary lesions - case report and review. AB - Bacillary angiomatosis (BA) is an angioproliferative disease of immunocompromised patients that usually presents as vascular tumors in the skin and subcutaneous tissues. It is caused by chronic infections with either Bartonella henselae or B. quintana. Oral cavity BA is exceedingly rare and even rarer without simultaneous cutaneous disease. We report herein the case of a 51-year-old HIV-infected man who presented severe odynophagia and an eroded lesion on the hard palate that progressed to an oronasal fistula. No cutaneous lesions were recorded. Doxycycline led to complete resolution. To the best of our knowledge, only six previous cases of oral BA without tegumentary disease have been previously reported and none of them progressed to fistula. PMID- 28902299 TI - [Serological evidence of Trypanosoma cruzi infection in dogs treated at veterinary clinics in the conurbation of Cuernavaca, Morelos]. PMID- 28902300 TI - [Intimidation at school, suicidal ideation and attempts in Colombian adolescents]. PMID- 28902301 TI - [Overweight and obesity in medical students. A new challenge for the Peruvian health system?] PMID- 28902302 TI - [Family dysfunction in patients with attempted suicide in pediatric emergency areas]. PMID- 28902303 TI - [Chronic diseases and insured spending in Colombia]. PMID- 28902304 TI - [Births of children small for gestational age]. PMID- 28902305 TI - [Participation of kitchen staff in the dissemination of microorganisms in full time schools' cafeterias]. PMID- 28902306 TI - [Multidrug-resistant tuberculosis: a barrier to achieving the Sustainable Development Goals]. PMID- 28902307 TI - [Can the promotion of resilience in schools contribute to public health policy?] PMID- 28902308 TI - [Food guides: an option to face nutritional problems in Peru]. PMID- 28902309 TI - [Lead poisoning and marginalization in newborns of Morelos, Mexico]. AB - Objective:: To determine the prevalence of lead (Pb) poisoning at birth in Morelos, analyze its distribution by social marginalization level, and estimate the association with the use of lead glazed ceramics (LGC). Materials and methods:: Blood lead level (BLL) in umbilical cord was measured in a representative sample of 300 randomly selected births at the Morelos Health Services and state IMSS. Results:: The prevalence of Pb poisoning at birth (BLL> 5MUg/dL) was 14.7% (95%CI: 11.1, 19.3) and 22.2% (95%CI: 14.4, 32.5) in the most socially marginalized municipalities. 57.1% (95%CI: 51.3, 62.7) of the mothers used LGC during pregnancy, and the frequency of use was significantly associated with BLL. Conclusion:: This is the first study to document the proportion of newborns with Pb poisoning who are at risk of experiencing the related adverse effects. It is recommended to monitor BLL at birth and take action to reduce this exposure, especially in socially marginalized populations. PMID- 28902310 TI - [Implementation of quality of care indicators for third-level public hospitals in Mexico]. AB - Objective:: To select, pilot test and implement a set of indicators for tertiary public hospitals. Materials and methods:: Quali-quantitative study in four stages: identification of indicators used internationally; selection and prioritization by utility, feasibility and reliability; exploration of the quality of sources of information in six hospitals; pilot feasibility and reliability, and follow-up measurement. Results:: From 143 indicators, 64 were selected and eight were prioritized. The scan revealed sources of information deficient. In the pilot, three indicators were feasible with reliability limited. Has conducted workshops to improve records and sources of information; nine hospitals reported measurements of a quarter. Conclusions:: Eight priority indicators could not be measured immediately due to limitations in the data sources for its construction. It is necessary to improve mechanisms of registration and processing of data in this group of hospital. PMID- 28902311 TI - [Teenagers' access to contraception in Mexico City]. AB - Objective:: To study and understand the phenomenon of access to contraceptive methods in Mexican teenages, through the use of the Levesque model, which allows for the observation of both the system and the system and the user's participation in the access process. Materials and methods:: A qualitative study was conducted with focus groups technique in a middle and high school of Mexico City. Results:: The perception of ability to access to health care is limited, teenagers do not know the mechanisms of care or supply of contraceptive methods. Prejudices of service providers provoke a negative reaction. The family is a source of information for adolescents to make decisions. Conclusions:: The model allowed the assessment of access to contraceptive methods in teenagers. It were identified different aspects that act as barriers to access and may inform health care providers about this population in their sexual and reproductive health. PMID- 28902312 TI - Feasibility of a multifaceted educational strategy for strengthening rural primary health care. AB - Objective:: To evaluate the feasibility and acceptability of a comprehensive educational strategy designed to improve care quality in rural areas of Mexico. Materials and methods:: A demonstration study was performed in 18 public rural health centers in Mexico, including an educational intervention that consists of the following steps: Development of the strategy; Selection and training of instructors (specialist physicians from the referral hospital and multidisciplinary field teams); Implementation of the strategy among health care teams for six priority causes of visit, through workshops, individual tutorials, and round-table case-review sessions. Feasibility and acceptability were evaluated using checklists, direct observation, questionnaires and in-depth interviews with key players. Results:: Despite some organizational barriers, the strategy was perceived as worthy by the participants because of the personalized tutorials and the improved integration of health teams within their usual professional practice. Conclusion:: The educational strategy proved to be acceptable; its feasibility for usual care conditions will depend on the improvement of organizational processes at rural facilities. PMID- 28902313 TI - Variables associated with disordered eating behaviors among freshman students from Mexico City. AB - Objective:: To estimate the prevalence of disordered eating behaviors (DEB) and identify their associations with demographic and psychological variables among freshman students at a public university in Mexico City. Materials and methods:: A sample of 892 subjects participated in the study. Bivariate and multinomial models were performed to determine associations between DEB and covariates. Results:: Of those surveyed, 6.8% of the women and 4.1% of the men exhibited DEB (p<0.05). The variables increasing the risk of eating disorders (ED) for women were internalization of the aesthetic thin ideal (IATI), body mass index (BMI), self-esteem and physical activity, while for men they were IATI, drive for muscularity, and self-esteem. Conclusions:: The frequency of DEB among women and men and the internalization of the thin ideal in both sexes suggest the possibility of a change in the precursor conditions for eating disorders, particularly for men, who exhibit increased risk of such behaviors. PMID- 28902314 TI - Validity of self-reported anthropometry in adult Mexican women. AB - Objective:: To compare direct and self-reported anthropometry in Mexican women. Materials and methods:: Women aged 30-72 years, participating in the Mexican Teachers' Cohort, completed a questionnaire with their anthropometric data in 2006-2008. After eleven months (median time), technicians performed anthropometry in 3756 participants. We calculated correlations and multivariable-adjusted mean differences between direct and self-reported anthropometric measures. Results:: Correlations between direct and self-reported anthropometric measures ranged from 0.78 (waist circumference) to 0.93 (weight). On average, women over-reported their height by 2.2 cm and underreported their weight, body mass index (BMI) and waist and hip circumferences by 1.3 kg, 1.3 kg/m2, 1.8 cm and 1.9 cm, respectively. Errors in self-reported anthropometry increased with rising measured BMI and were also independently associated with age, education and socioeconomic status. Conclusion:: Self-reported anthropometry is sufficiently valid for epidemiological purposes in adult Mexican women. Errors in self reported anthropometry might result in underestimation of the prevalence of overweight and obesity. PMID- 28902315 TI - [Health education trough the development of scientific skills in Chilean schools]. AB - Objective:: To describe the interests, preferred topics and learning in public health issues emerging from Chilean students with their participation in a science education experience. Materials and methods:: A qualitative exploratory study was conducted in 29 school research groups through the project Salud Con Ciencia en tu Barrio, based on a content analysis of texts and narratives of students. Results:: Students prioritize the situation of abandoned animals, waste management, security and urban infrastructure, mainly. They view the role of social actors, the positive/negative impacts on the community, valuing the knowledge gained through observation neighborhoods and interaction with neighbors. Conclusions:: Scientific inquiry school in the neighborhood context provides teaching strategies for the promotion of local health, develops basic notions of community health and motivation in students linked to the socio environmental reality of their neighborhoods. PMID- 28902316 TI - Dietary intake and adequacy of energy and nutrients in Mexican older adults: results from two National Health and Nutrition Surveys. AB - Objective:: To describe energy and nutrient intakes and their adequacies in older Mexican adults participating in the National Health and Nutrition Survey (Ensanut) 2006 and 2012. Materials and methods:: Dietary information was obtained through a semiquantitative food frequency questionnaire (SFFQ) from 526 adults 60 y and older participating in Ensanut 2012 and 3 326 in Ensanut 2006 in Mexico. Quantile and logistic regression models were used to obtain medians and marginal effects of each nutrient, adjusting by confounders and survey design. Results:: Dietary intake of energy and nutrients was similar in both surveys. Most common micronutrients at risk of dietary deficiency were, for vitamins: A, B-12, C, D and folate, and for minerals: calcium, iron and zinc, in both surveys. Excessive intake of sugar and saturated fat and low fiber intake were common. Conclusions:: Diet in older Mexican adults is low in micronutrient essentials, and excessive in fat and sugar. Attention to the diet in this age group through targeted interventions is necessary to promote a healthy diet. PMID- 28902317 TI - [Methodological design of the National Health and Nutrition Survey 2016]. AB - Objective:: Describe the design methodology of the halfway health and nutrition national survey (Ensanut-MC) 2016. Materials and methods: The Ensanut-MC is a national probabilistic survey whose objective population are the inhabitants of private households in Mexico. The sample size was determined to make inferences on the urban and rural areas in four regions. Describes main design elements: target population, topics of study, sampling procedure, measurement procedure and logistics organization. Results: A final sample of 9 479 completed household interviews, and a sample of 16 591 individual interviews. The response rate for households was 77.9%, and the response rate for individuals was 91.9%. Conclusions: The Ensanut-MC probabilistic design allows valid statistical inferences about interest parameters for Mexico's public health and nutrition, specifically on overweight, obesity and diabetes mellitus. Updated information also supports the monitoring, updating and formulation of new policies and priority programs. PMID- 28902318 TI - Prevalence of dental fluorosis in Mexico 2005-2015: a literature review. AB - Objective:: To perform a literature review regarding current dental fluorosis prevalence in Mexico reported from 2005 to 2015. Materials and methods:: A comprehensive scientific literature review, in both English and Spanish, was performed in four databases up to June 2015. Search terms: fluorosis or dental fluorosis (mesh), prevalence (mesh), distribution (mesh), cases (mesh), epidemiology (mesh), Mexico. Results:: 17 publications were included. Reported prevalence of dental fluorosis in Mexico ranged from 15.5 to 100%. Most of the studies were conducted in areas where water fluoride levels are low or optimal (<=1.5ppmF) and in which a prevalence of 15.5 to 81.7% was observed. In areas with higher levels of naturally fluoridated water (>1.5ppmF), prevalence ranged from 92 to 100%. Fluorosis severity ranged from questionable to severe. Conclusion:: High prevalence of dental fluorosis was observed even in areas where fluoride concentration in water was low or optimal. In addition to fluoride in groundwater, there are multiple risk factors that should be controlled. PMID- 28902319 TI - [Performance based regulation: a strategy to increase breastfeeding rates]. AB - : The decreasing breastfeeding rate in Mexico is of public health concern. In this paper we discus an innovative regulatory approach -Performance Based Regulation- and its application to improve breastfeeding rates. This approach, forces industry to take responsibility for the lack of breastfeeding and its consequences. Failure to comply with this targets results in financial penalties. Applying performance based regulation as a strategy to improve breastfeeding is feasible because: the breastmilk substitutes market is an oligopoly, hence it is easy to identify the contribution of each market participant; the regulation's target population is clearly defined; it has a clear regulatory standard which can be easily evaluated, and sanctions to infringement can be defined under objective parameters. RECOMMENDATIONS: modify public policy, celebrate concertation agreements with the industry, create persuasive sanctions, strengthen enforcement activities and coordinate every action with the International Code of Marketing of Breast-milk Substitutes. PMID- 28902321 TI - [30th anniversary of Mexico's National Institute of Public Health]. PMID- 28902320 TI - [Investing in health: the economic case. Report of the WISH Investing in Health Forum 2016]. AB - Developing country governments and aid agencies face difficult decisions on how best to allocate their finite resources. Investments in many different sectors including education, water and sanitation, transportation, and health- can all reap social and economic benefits. This report focuses specifically on the health sector. It presents compelling evidence of the value of scaling-up health investments. The economic case for increasing these investments in health has never been stronger. Having made progress in reducing maternal and child mortality, and deaths from infectious diseases, it is essential that policymakers do not become complacent. These gains will be quickly reversed without sustained health investments. Scaled-up investments will be needed to tackle the emerging non-communicable disease (NCD) burden and to achieve universal health coverage (UHC). The value of investment in health far beyond its performance is reflected in economic prosperity through gross domestic product (GDP). People put a high monetary value on the additional years of life that health investments can bring an inherent value to being alive for longer, unrelated to productivity. Policymakers need to do more to ensure that spending on health reflects people's priorities. To make sure services are accessible to all, governments have a clear role to play in financing health. Without public financing, there will be some who cannot afford the care they need, and they will be forced to choose sickness perhaps even death- and financial ruin; a devastating choice that already pushes 150 million people into poverty every year. In low-income countries (LICs) and middle-income countries (MICs), public financing should be used to achieve universal coverage with a package of highly cost-effective interventions ('best buys'). Governments failing to protect the health and wealth of their people in this way will be unable to reap the benefits of long-term economic prosperity and growth. Public financing has the benefit of being more efficient and better at controlling costs than private financing and is the only sustainable way to reach UHC. In addition, people put a high economic value on the protection against financial risk that public financing provides. This report addresses three key questions: 1) What is the economic rationale for investing in health?; 2) what is the best way to finance health?, and 3) which interventions should be prioritized? PMID- 28902322 TI - Evaluation of body posture in nursing students. AB - OBJECTIVE: To investigate the body posture of nursing students before and after clinical practice. METHOD: The study was developed in two stages. Initially the body posture of students of the 2nd, 4th, 6th, and 8th periods were assessed through photogrammetry. All images were analyzed in a random and masked manner with CorporisPro(r) 3.1.3 software. Three evaluations were performed for each angle and then the mean value was calculated. Two years later, when the 4th period students had developed their clinical internships, their body posture was again evaluated. RESULTS: The total sample consisted of 112 students. Comparison of their posture with the normality pattern showed that all the angles presented significant differences (p< 0.00), except for the angle of the Thales triangle. Reassessment of these students evidenced significant differences in the angles of the acromioclavicular joint (p=0.03), knee flexion (p< 0.00) and in the tibiotarsal angle (p< 0.00). CONCLUSION: All the students presented alterations when compared to the normality values. The segments that presented significant differences between before and after practice were the acromioclavicular angle, knee flexion, and tibiotarsal angle; the latter two were in the rolling position. OBJETIVO: Investigar a postura dos estudantes de enfermagem antes e apos a pratica clinica. METODO: O estudo foi desenvolvido em duas etapas, inicialmente com estudantes (2o, 4 degrees , 6 degrees e 8o periodos) tiveram sua postural corporal avaliada por meio da fotogrametria. Todas as imagens foram analisadas, de maneira aleatoria e mascarada, por meio do software CorporisPro(r) 3.1.3. Foram realizadas tres avaliacoes para cada angulo e calculada a media. Dois anos depois, quando os estudantes do 4o periodo desenvolveram os estagios clinicos, foram novamente avaliados quanto a postura corporal. RESULTADOS: A amostra total foi composta por 112 estudantes. Comparando-se os estudantes com o padrao de normalidade, todos os angulos apresentaram diferenca significativa (p< 0,00), com excecao do angulo triangulo de Tales. Reavaliando os mesmos estudantes, houve diferenca significativa nos angulos da articulacao acromioclavicular (p=0,03), da flexao de joelhos (p< 0,00) e no angulo tibiotarsico (p< 0,00). CONCLUSAO: Todos os estudantes apresentaram alteracoes, comparadas aos valores de normalidade. Os segmentos com diferenca significativa, comparando-se antes e apos a pratica, foram o angulo acromioclavicular, flexo de joelho e angulo tibiotarsico, sendo os dois ultimos na posicao de rolamento. PMID- 28902323 TI - Hand hygiene compliance of healthcare professionals in an emergency department. AB - OBJECTIVE: To analyze compliance with hand hygiene by healthcare professionals in an emergency department unit. METHOD: This is a longitudinal quantitative study developed in 2015 with healthcare professionals from a university hospital in the state of Rio Grande do Sul. Each professional was monitored three times by direct non-participant observation at WHO's five recommended moments in hand hygiene, taking the concepts of opportunity, indication and action into account. Descriptive and analytical statistics were used. RESULTS: Fifty-nine healthcare professionals participated in the study. The compliance rate was 54.2%. Nurses and physiotherapists showed a compliance rate of 66.6% and resident physicians, 41.3%. When compliance was compared among professional categories, nurses showed greater compliance than resident physicians (OR = 2.83, CI = 95%: 1.09-7.34). CONCLUSION: Hand hygiene compliance was low. Multidisciplinary approaches could be important strategies for forming partnerships to develop learning and implementation of hand hygiene practices. OBJETIVO: Analisar a adesao a higienizacao das maos dos profissionais de saude em unidade de Pronto-Socorro. METODO: Estudo quantitativo longitudinal desenvolvido com profissionais de saude de um Hospital Universitario do Rio Grande do Sul, em 2015. Para cada profissional, realizaram-se tres acompanhamentos com observacao direta nao participante nos cinco momentos preconizados para higienizacao das maos, levando se em conta os conceitos de Oportunidade, Indicacao e Acao. Utilizou-se da estatistica descritiva e analitica. RESULTADOS: Participaram do estudo 59 profissionais de saude. A taxa de adesao foi de 54,2%. Os enfermeiros e fisioterapeutas obtiveram a taxa de adesao de 66,6% e os medicos residentes, de 41,3%. Ao ser comparada a adesao entre as categorias profissionais, os enfermeiros tiveram maior aderencia do que os medicos residentes (RC=2,83; IC=95%:1,09-7,34). CONCLUSAO: A adesao a higienizacao das maos foi baixa. Abordagens multidisciplinares podem ser estrategias importantes para formar parcerias que desenvolvam a aprendizagem e a efetivacao de praticas de HM. PMID- 28902324 TI - Influence of sociodemographic and clinical characteristics on the quality of life of patients with schizophrenia. AB - OBJECTIVE: Evaluating the quality of life of Portuguese patients with schizophrenia and linking it to sociodemographic and clinical aspects. METHOD: A quantitative cross-sectional study carried out with individuals affected by schizophrenia, living in the entire continental territory of Portugal, through application of a sociodemographic and clinical questionnaire and the Quality of Life Scale short version (QLS7PT). Parametric and non-parametric tests were performed to evaluate the correlation between variables. RESULTS: The sample consisted of 282 participants. The results point to a better quality of life for individuals living in autonomous residences or with their parents, who are employed/students, who have had the disorder for less time and are younger, who have completed the 12th grade of schooling and who are not medicated with first generation neuroleptics. CONCLUSION: The results indicate that some sociodemographic and clinical characteristics influence the quality of life of patients with schizophrenia and should be considered in the patient evaluation and in planning appropriate and effective strategies for their psychosocial rehabilitation. OBJETIVO: Avaliar a qualidade de vida dos individuos portugueses com esquizofrenia e relaciona-la com aspetos sociodemograficos e clinicos. METODO: Estudo quantitativo de natureza transversal realizado com portadores de esquizofrenia, residentes em todo o territorio continental de Portugal, tendo sido aplicado um questionario sociodemografico e clinico e a Quality of Life Scale versao reduzida (QLS7PT). Foram realizados testes parametricos e nao parametricos para avaliar a correlacao entre as variaveis. RESULTADOS: A amostra foi constituida por 282 participantes. Apontam para uma melhor qualidade de vida os individuos que vivem em residencias autonomas ou com os pais, empregados/estudantes, com transtorno ha menos tempo e menor idade, com o 12o ano de escolaridade e nao medicados com neurolepticos de primeira geracao. CONCLUSAO: Os resultados indicam que algumas caracteristicas sociodemograficas e clinicas influenciam a qualidade de vida dos individuos com esquizofrenia, pelo que devem ser consideradas na avaliacao psiquiatrica e no planejamento das estrategias adaptadas e eficazes a sua reabilitacao psicossocial. OBJETIVO: Evaluar la calidad de vida de los individuos portugueses con esquizofrenia y relacionarla con aspectos sociodemograficos y clinicos. METODO: Estudio cuantitativo de naturaleza transversal realizado con portadores de esquizofrenia, residentes en todo el territorio continental de Portugal, habiendo sido aplicado un cuestionario sociodemografico y clinico y la Quality of Life Scale version reducida (QLS7PT). Se realizaron pruebas parametricas y no parametricas para evaluar la correlacion entre las variables. RESULTADOS: La muestra fue constituida por 282 participantes. Los resultados apuntan a una mejor calidad de vida de quienes residen en residencias autonomas o con los padres, los empleados / estudiantes, con trastorno por menos tiempo y menor edad, con 12 anos de escolaridad y no medicados con neurolepticos de primera generacion. CONCLUSION: Los resultados indican que algunas caracteristicas sociodemograficas y clinicas influyen en la calidad de vida de los individuos con esquizofrenia, por lo que deben ser consideradas en la evaluacion psiquiatrica y en la planificacion de las estrategias adaptadas y eficaces a su rehabilitacion psicosocial. PMID- 28902325 TI - Interface between social support, quality of life and depression in users eligible for palliative care. AB - OBJECTIVE: Analyzing the relationship between social support, quality of life and depression in patients eligible for palliative care at Primary Health Care of a municipality in the interior of Minas Gerais, Brazil. METHOD: A correlational cross-sectional study carried out with patients treated in six primary health care units. Data were submitted to descriptive statistical analysis, tests for differences between averages and medians, and correlation tests. The significance level was 0.05. RESULTS: The sample consisted of 115 participants, and it was identified that the higher the social support, the better the global quality of life (p<0.001) and functional quality of life (p=0.035); the greater the presence of physical symptoms, the lower the level of social support (p=0.012) and the higher the level of depression (p<0.001); the higher the symptoms of depression, the worse the global quality of life (p<0.001), functional quality of life (p<0.001) and the lower the levels of social support (p<0.001). CONCLUSION: Levels of quality of life, social support and depression of patients eligible for palliative care are influenced by socioeconomic factors such as marital status, gender, age, income, education and presence of a caregiver. OBJETIVO: Analisar a relacao entre apoio social, qualidade de vida e depressao em pacientes elegiveis para cuidados paliativos atendidos na Atencao Primaria a Saude de um municipio no interior de Minas Gerais, Brasil. METODO: Estudo transversal correlacional, realizado com pacientes atendidos em seis unidades da atencao primaria a saude. Os dados foram submetidos a analise estatistica descritiva, testes de diferencas entre medias e medianas e testes de correlacao. O nivel de significancia adotado foi 0,05. RESULTADOS: A amostra foi composta por 115 participantes, e identificou se que quanto maior o apoio social, melhor e a qualidade de vida global (p<0,001) e funcional (p=0,035); quanto maior a presenca de sintomas fisicos, menor o nivel de apoio social (p=0,012) e maior o nivel de depressao (p<0,001); quanto maiores os sintomas de depressao, pior e a qualidade de vida global (p<0,001), funcional (p<0,001) e menores os niveis de apoio social (p<0,001). CONCLUSAO: Os niveis de qualidade de vida, apoio social e depressao de pacientes elegiveis para cuidados paliativos sao influenciados por fatores socioeconomicos, tais como estado conjugal, sexo, idade, renda, escolaridade e presenca de cuidador. OBJETIVO: Analizar la relacion entre apoyo social, calidad de vida y depresion en pacientes elegibles para cuidados paliativos atendidos en la Atencion Primaria a la Salud de un municipio en el interior de Minas Gerais, Brasil. METODO: Estudio transversal correlacional, realizado con pacientes atendidos en seis unidades de atencion primaria a la salud. Los datos fueron sometidos al analisis estadistico descriptivo, pruebas de diferencias entre medias y medianas y pruebas de correlacion. El nivel de significancia adoptado fue 0,05. RESULTADOS: La muestra fue compuesta por 115 participantes, y se identifico que cuanto mayor el apoyo social, mejor es la calidad de vida global (p <0,001) y funcional (p = 0,035); cuanto mayor sea la presencia de sintomas fisicos, menor el nivel de apoyo social (p = 0,012) y mayor el nivel de depresion (p <0,001); cuanto mayores los sintomas de depresion, peor es la calidad de vida global (p <0,001), funcional (p <0,001) y menores los niveles de apoyo social (p <0,001). CONCLUSION: Los niveles de calidad de vida, apoyo social y depresion de pacientes elegibles para cuidados paliativos son influenciados por factores socioeconomicos, tales como estado conyugal, sexo, edad, renta, escolaridad y presencia de cuidador. PMID- 28902326 TI - Microstructural evaluation by confocal and electron microscopy in thrombi developed in central venous catheters. AB - OBJECTIVE: Evaluating thrombi microstructure developed in central venous catheters using confocal and electron microscopy. METHOD: An experimental, descriptive study carrying out a microstructural evaluation of venous thrombi developed in central venous catheters using Scanning Electron Microscopy and Confocal Laser Scanning Microscopy. RESULTS: A total of 78 venous catheters were collected over a period of three months. Different fibrin structures were distinguished: fibrin plates, fibrin network, and fibrin fibers. It was observed that the thrombus had thick fibrin plates adhered to the catheter wall openings in both a catheter with three days of permanence as well as in a catheter with 20 days of insertion in the patient. However, a greater amount of erythrocytes and fibrin fibers were found in the central region of the thrombus. CONCLUSION: This study contributes to improving health care and can have a positive impact on clinical practice, as easy adherence of platelets and fibrins to the catheter wall demonstrated in this study makes it possible to adopt thrombus prevention strategies such as therapy discontinuation for an extended period, blood reflux by a catheter, slow infusion rate and hypercoagulo pathyclinical conditions. OBJETIVO: Avaliar a microestrutura por microscopia confocal e eletronica em trombos desenvolvidos em cateteres venosos centrais. METODO: Pesquisa experimental, descritiva, em que foi feita uma avaliacao microestrutural de trombos venosos desenvolvidos em cateteres venosos centrais por Microscopia Eletronica de Varredura e Microscopia Confocal de Varredura a Laser. RESULTADOS: Foram coletados 78 cateteres venosos centrais num periodo de tres meses. Distinguiram-se diferentes estruturas de fibrina: a placa de fibrina, a rede de fibrina e as fibras de fibrina. Observou-se que tanto em um cateter com tres dias de permanencia quanto em um cateter com 20 dias inserido no paciente o trombo apresentou placas de fibrina espessas aderidas as paredes dos orificios dos cateteres. Na regiao central do trombo, no entanto, observou-se maior quantidade de eritrocitos e fibras de fibrina. CONCLUSAO: O trabalho contribui para uma melhoria da assistencia a saude e pode gerar um impacto positivo na pratica clinica, uma vez que a facilidade de aderencia de plaquetas e fibrinas a parede do cateter demonstrada neste estudo possibilita a adocao de estrategias de prevencao do trombo, tais como a interrupcao de terapia por tempo prolongado, o refluxo de sangue pelo cateter, a velocidade lenta de infusao e os estados clinicos de hipercoagulopatia. PMID- 28902327 TI - Anxiety in pregnancy: prevalence and associated factors. AB - OBJECTIVE: Evaluating the occurrence of anxiety in pregnant women and the factors associated with its occurrence; comparing the presence of anxiety in each gestational trimester. METHOD: A descriptive, correlational cross-sectional study. Data were collected from January to May 2013 using the Hospital Anxiety Subscale and a form composed of socioeconomic characterization; gestational anamnesis; life-changing habits and events; preexisting conditions and interpersonal relationships. RESULTS: A total of 209 pregnant women from a municipality in the south of Minas Gerais, Brazil, participated in the study. Anxiety was present in 26.8% of the pregnant women, being more frequent in the third trimester (42.9%). Occupation (p=0.04), complications in previous pregnancies (p=0.00), history of miscarriage risk of preterm birth (p=0.05), maternal desire regarding the pregnancy (p=0.01), number of abortions (p=0.02), number of cigarettes smoked daily (p=0.00) and drug use (p=0.01) were statistically associated with the occurrence of anxiety during pregnancy. CONCLUSION: Anxiety occurred frequently during pregnancy. Understanding the factors associated with its occurrence allows for elaborating preventive measures in prenatal care. OBJETIVO: Avaliar a ocorrencia da ansiedade em gestantes e os fatores associados a sua ocorrencia; comparar a presenca de ansiedade em cada trimestre gestacional. METODO: Estudo descritivo, correlacional, de corte transversal. A coleta de dados ocorreu de janeiro a maio de 2013, utilizou-se da Subescala Hospitalar de Ansiedade e de um formulario composto por caracterizacao socioeconomica; anamnese gestacional; habitos e eventos marcantes de vida; patologias preexistentes e relacionamentos interpessoais. RESULTADOS: Participaram do estudo 209 gestantes de um municipio do sul de Minas Gerais. A ansiedade esteve presente em 26,8% das gestantes, sendo mais frequente no terceiro trimestre (42,9%). Ocupacao (p=0,04), complicacoes em gestacoes anteriores (p=0,00), historico de abortamento/ameaca de parto prematuro (p=0,05), desejo materno em relacao a gravidez (p=0,01), numero de abortamentos (p=0,02), quantidade de cigarros consumidos diariamente (p=0,00) e uso de drogas (p=0,01) apresentaram associacao estatisticamente significativa com a ocorrencia da ansiedade na gravidez. CONCLUSAO: A ansiedade se mostrou frequente na gestacao. O conhecimento dos fatores associados a sua ocorrencia oportuniza a elaboracao de medidas preventivas na assistencia pre-natal. PMID- 28902328 TI - Whither (or Wither) Adherence to Retina Trial Protocols in Clinical Practice? PMID- 28902329 TI - Cataract Surgery in Patients With Wet Macular Degeneration. PMID- 28902331 TI - Quantitative and Qualitative Features of Spectral-Domain Optical Coherence Tomography Provide Prognostic Indicators for Visual Acuity in Patients With Choroideremia. AB - BACKGROUND AND OBJECTIVE: To identify qualitative and quantitative features of spectral-domain optical coherence tomography (SD-OCT) as prognostic indicators of visual acuity (VA) loss in patients with choroideremia (CHM). PATIENTS AND METHODS: Retrospective study of 57 male patients with CHM. Central foveal thickness (CFT), subfoveal choroidal thickness (SCT), fundus autofluorescence area, and evidence of outer retinal and choroidal degeneration were analyzed by SD-OCT. RESULTS: Best-corrected VA logMAR at baseline was associated with CFT at baseline (r = -0.47; P < .01), CFT at most recent follow-up (r = -0.27; P < .01), and SCT at baseline (r = -0.31; P < .01). Ellipsoid zone (EZ) rupture was associated with a higher CFT loss (r = 0.33; P < .01) and macular cystic spaces (MCS) with a reduction in VA over time (hazard risk = 0.48; P = .05). CONCLUSION: Reduced CFT at baseline, EZ rupture, and MCS are poor prognostic indicators for VA outcome. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:711-716.]. PMID- 28902330 TI - Centrifugal Extension of Retinal Atrophy in Retinal Pigment Epithelium Tears Secondary to Age-Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: To investigate the progression of retinal atrophy in patients with retinal pigment epithelium (RPE) tears secondary to neovascular age related macular degeneration. PATIENTS AND METHODS: In this retrospective case series, patients were analyzed at two high-volume referral centers. The extension of the areas without RPE was analyzed yearly from baseline to last examination through fundus autofluorescence (FAF) imaging using Region Finder (Heidelberg Engineering, Heidelberg, Germany). RESULTS: Sixteen eyes of 14 patients were included in the study. Mean follow-up was 70.11 months +/- 15.5 months. The average area of atrophy was 6.89 mm2 +/- 5.4 mm2 at baseline and 9.21 mm2 +/- 7.7 mm2 at the last visit (P < .0001). This accounts for a progression of 0.36 mm2 +/ 0.46 mm2/year. In all cases, FAF revealed centrifugal extension of retinal atrophy. CONCLUSIONS: In this series, the area of retinal atrophy enlarged over time. Atrophy enlargement is characterized by centrifugal extension from the base of the tear. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:705-710.]. PMID- 28902332 TI - High-Dose Decanted Triamcinolone for Treatment-Resistant Persistent Macular Edema. AB - BACKGROUND AND OBJECTIVE: To report the outcomes of decanted high-dose intravitreal triamcinolone acetonide (HD-IVTA) injection for treatment-resistant persistent macular edema (ME). PATIENTS AND METHODS: Seventy-seven eyes of 70 consecutive patients who failed prior treatments for persistent ME received as needed HD-IVTA injections. Best-corrected visual acuity and central macular thickness (CMT) were assessed at all follow-up visits. RESULTS: Thirty-three eyes (42.8%) had ME following pars plana vitrectomy. The mean ETDRS letter score from baseline improved by 6.3 letters +/- 11.5 letters at 3 months (P < .001) and 4.8 letters +/- 11.4 letters at 12 months (P = .016). The mean change in CMT from baseline was significant at all follow-up visits (P < .001). During 1-year follow up, 49 eyes (63.6%) required only one HD-IVTA injection. The mean time for reinjection was 6 months +/- 2.4 months (range: 1.6 months to 10.5 months) after the first injection of HD-IVTA. The incidence of elevated intraocular pressure was 40.2% (31 of 77 eyes). Of these, one eye required glaucoma surgery. Among 14 phakic eyes, 21.4% (three eyes) developed cataract formation requiring surgery. CONCLUSION: A single HD-IVTA injection can provide a long duration of effect on ME of up to 6 months. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:717-726.]. PMID- 28902333 TI - Multi-Modal Imaging Including Optical Coherence Tomography Angiography in Patients With Posterior Multifocal Placoid Pigment Epitheliopathy. AB - BACKGROUND AND OBJECTIVE: New imaging methods provide novel insights into the pathogenesis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). PATIENTS AND METHODS: Four patients (eight eyes) in acute, subacute, and late phases of the disease were analyzed with multi-modal imaging methods including optical coherence tomography angiography (OCTA), structural OCT, fundus photography, and fundus autofluorescence. One patient was observed during the entire disease course. RESULTS: In acute and subacute phases of the disease, an early blockage in fluorescein angiography was found. OCTA showed perfusion defects in choriocapillaris and choroid slabs. During the course of disease, perfusion deficits observed in OCTA imaging resolved first in the choroid and then in the choriocapillaris slab. CONCLUSION: Multi-modal imaging including OCTA supports the thesis that the underlying pathology of APMPPE is an inflammatory impairment of the choroidal circulation with secondary damage to the outer retina. OCTA might be able to replace fluorescein and indocyanine angiography in the diagnostic work-up of APMPPE. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:727-733.]. PMID- 28902334 TI - Multicenter, Randomized Clinical Trial to Assess the Effectiveness of Intravitreal Injections of Bevacizumab, Triamcinolone, or Their Combination in the Treatment of Diabetic Macular Edema. AB - BACKGROUND AND OBJECTIVE: To evaluate the efficacy of combined bevacizumab triamcinolone intravitreal injection in the treatment of diabetic macular edema (DME) compared to monotherapy. PATIENTS AND METHODS: At eight clinical sites, 111 patients with DME were randomly assigned to receive an intravitreal injection of bevacizumab (Avastin; Genentech, South San Francisco, CA), triamcinolone (Ophthalmos Pharmaceutical Industry, Sao Paulo-SP, Brazil), or their combination. The primary outcome was visual acuity (VA) at 6 months' follow-up. RESULTS: The average number of injections was 3.2 in the bevacizumab group, 2.4 in the combined group, and 2.1 in the triamcinolone group. All groups presented with improvements in VA (P < .001); however, no differences between groups were observed (P = .436). Mean reduction in central retinal thickness was statistically different only between the triamcinolone and bevacizumab groups (P < .015). CONCLUSION: Mono- or combination therapy was effective for DME treatment. No synergistic effects were observed; however, triamcinolone alone or a drug combination may reduce the number of injections required when compared to bevacizumab alone. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:734-740.]. PMID- 28902335 TI - En Face Optical Coherence Tomography Angiography Imaging Versus Fundus Photography in the Measurement of Choroidal Nevi. AB - BACKGROUND AND OBJECTIVES: Choroidal nevi are common benign intraocular tumors with a small risk of malignant transformation. This retrospective study investigates the use of en face spectral-domain optical coherence tomography angiography (SD-OCTA) in determining the clinical features and measurement of choroidal nevi. PATIENTS AND METHODS: Patients with choroidal nevi were imaged with both OCTA and a fundus photography device. Greatest longitudinal dimension (GLD), perpendicular dimension (PD), and the GLD/PD ratio were assessed on each device. Inter-device variation and intra- and inter-rater reliability analyses were performed. RESULTS: Fourteen patients with choroidal nevi were included. No significant difference between the GLD/PD ratio as measured by all three devices was found (Chi-square = 2.8, 2 df, P = .247). Intraclass correlation coefficients were greater than 0.7 for repeated measures on all devices, suggesting good repeatability and reproducibility. CONCLUSION: This study demonstrated inter device consistency and high intra- and inter-rater reliability when measuring choroidal nevi. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:741-747.]. PMID- 28902336 TI - Switching Anti-VEGF Drugs in the Treatment of Diabetic Macular Edema. AB - Since their introduction in the late 2000s, anti-vascular endothelial growth factor (VEGF) agents have become the first-line choice for center-involved diabetic macular edema (DME). Even with its proven effectiveness, there are still cases that do not respond satisfactorily. In those cases, a treatment option is to change to another anti-VEGF drug. In this paper, the authors review studies on switching between different anti-VEGF drugs in the treatment of persistent DME. An extensive bibliographic review was done using PubMed, Embase, and Scopus. Fourteen studies published from March 2010 to April 2017 reporting switching from anti-VEGF drugs in DME treatment were included. All reported good anatomical results after conversion; however, visual acuity outcomes showed great variability between publications. Therefore, switching to other anti-VEGFs in patients with DME not responding to previous anti-VEGF therapy may be an option, but the results are still not well-known due to a lack of randomized clinical trials. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:748-754.]. PMID- 28902337 TI - Multimodal Imaging of Astrocytic Hamartomas Associated With Tuberous Sclerosis. AB - An 11-year-old patient was diagnosed with tuberous sclerosis complex based on retinal and cutaneous findings and confirmed by genetic testing. Spectral-domain optical coherence tomography (OCT) demonstrated subtle solid intraretinal tumors that focally replaced the inner retina and displaced the outer retinal layers. OCT angiography demonstrated prominent intrinsic vascularity but no feeder vessels. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:756-758.]. PMID- 28902338 TI - Confluent Endpoint Subthreshold Argon Laser for Serous Macular Detachment in Tilted Disc Syndrome Refractory to Anti-VEGF. AB - A 70-year-old woman presented with 20/200 visual acuity in the right eye. Multimodal imaging revealed tilted disc syndrome (TDS) with macular serous detachment (MSD) and pigmentary changes at the temporal margin of the optic disc. Subretinal fluid persisted after three monthly intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) injections and threshold focal laser photocoagulation. Subsequently, confluent subthreshold argon laser was applied over the entire area of retinal pigment epithelium (RPE) abnormalities, resulting in the resolution of subretinal fluid without recurrence through 3 years of follow-up. Subthreshold argon laser treatment may serve as a therapeutic option for MSD in TDS. Targeting leakage sites and stimulating RPE cells might help absorb subretinal fluid. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:760 763.]. PMID- 28902339 TI - Terson Syndrome Associated With Acute Macular Neuropathy Type 2. AB - Terson syndrome is defined as the incidence of intraocular hemorrhage in patients following a subarachnoid or intracranial bleed. A 38-year-old female with both intraretinal and subretinal hemorrhages secondary to Terson syndrome underwent repair of a ruptured cerebral aneurysm. One month following resolution of the macular hemorrhages, a paracentral scotoma persisted. Multimodal imaging (morphological and functional) confirmed the presence of acute macular neuroretinopathy Type 2 associated with deep retinal capillary ischemia. Optical coherence tomography angiography illustrated the selective involvement of the deep retinal capillary plexus. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:764-767.]. PMID- 28902340 TI - Venous Loop Reveals an Occult Retinoblastoma Tumor. AB - A 14-day-old girl presented with bilateral hereditary retinoblastoma. At 3 months, a slight bend in the superotemporal arcade was observed to have developed into a venous loop. With concern for an occult lesion along the arcade, handheld optical coherence tomography (hhOCT) confirmed a small tumor and helped to guide prompt laser treatment while sparing the venous arcade. A venous loop is a previously unrecognized clinical finding that preceded the clinical detection and hhOCT confirmation of the tumor. The authors hypothesize that the venous loop was induced by pro-angiogenic factors secreted by the tumor. Portable hhOCT is a valuable adjunct imaging modality in the diagnosis and management of small retinoblastoma tumors. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:768-770.]. PMID- 28902341 TI - Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived 'Stem Cells' in a Patient With Exudative Macular Degeneration. AB - A 77-year-old woman with exudative macular degeneration underwent bilateral intravitreal injections of "stem cells" at a clinic in Georgia. One month and 3 months after injection, she developed retinal detachments in the left and right eyes, respectively. Increased awareness within the medical community of such poor outcomes is critical so that clinics offering untested practices that have been shown to be potentially harmful to patients can be identified and brought under U.S. Food and Drug Administration oversight. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:772-775.]. PMID- 28902342 TI - Osthole induces apoptosis and suppresses proliferation via the PI3K/Akt pathway in intrahepatic cholangiocarcinoma. AB - Osthole is a natural coumarin isolated from Umbelliferae plant monomers. Previous research has indicated that osthole exerts a wide variety of biological effects, acting as anti-seizure, anti-osteoporosis and anti-inflammation. However, the regulatory effect and related molecular mechanism of osthole in intrahepatic cholangiocarcinoma (ICC) remain unknown. In the present study, the authors found that osthole inhibited ICC cell lines in a dose- and time-dependent manner. Osthole also significantly induced mitochondrial-dependent apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9, and cleaved poly ADP ribose polymerase expression, and by downregulating Bcl-2 expression. Moreover, the levels of p-Akt and PI3K were significantly decreased, while total Akt protein levels were unchanged. Following transfection with wild-type-Akt and constitutively active (CA)-Akt plasmids, the effects of osthole were decreased. Osthole was also able to suppress tumor growth in vivo. Together, these data demonstrated that osthole induces mitochondrial-dependent apoptosis via the PI3K/Akt pathway, suggesting that osthole may represent a novel and effective agent for the treatment of ICC. PMID- 28902344 TI - Insulin-like growth factor-1 promotes the proliferation and odontoblastic differentiation of human dental pulp cells under high glucose conditions. AB - Insulin-like growth factor-1 (IGF-1) promotes human dental pulp stem cell proliferation and osteogenic differentiation. However, the effects of IGF-1 on the proliferation, apoptosis and odontoblastic differentiation (mineralization) of dental pulp cells (DPCs) under high glucose (GLU) conditions remain unclear. In this study, isolated primary human DPCs were treated with various concentrations of high GLU. Cell proliferation and apoptosis were determined by Cell Counting Kit-8 and Annexin V-FITC/PI assays, respectively. The cells were cultured in odontoblastic induction medium containing various concentrations of high GLU. Odontoblastic differentiation was determined by alkaline phosphatase (ALP) activity assay. Mineralization formation was evaluated by von Kossa staining. The expression levels of IGF family members were measured by western blot analysis and RT-qPCR during proliferation and differentiation. The cells were then exposed to 25 mM GLU and various concentrations of IGF-1. Cell proliferation, apoptosis, ALP activity, mineralization formation and the levels of mineralization-related proteins were then evaluated. Our results revealed that high GLU significantly inhibited cell proliferation and promoted cell apoptosis. GLU (25 and 50 mM) markedly reduced ALP activity and mineralization on days 7 and 14 after differentiation. The levels of IGF family members were markedly decreased by high GLU during proliferation and differentiation. However, IGF-1 significantly reversed the effects of high GLU on cell proliferation and apoptosis. Additionally, IGF-1 markedly restored the reduction of ALP activity and mineralization induced by high GLU. Our findings thus indicate that IGF-1 attenuates the high GLU-induced inhibition of DPC proliferation, differentiation and mineralization. PMID- 28902343 TI - Connexin 43 in the development and progression of breast cancer: What's the connection? (Review). AB - Connexin 43 is a prominent gap junction protein within normal human breast tissue. Thus far, there have been a number of research studies performed to determine the function of connexin 43 in breast tumor formation and progression. Within primary tumors, research suggests that the level of connexin 43 expression in breast tumors is altered when compared to normal human breast tissue. While some reports indicate that connexin 43 levels decrease, other evidence suggests that connexin 43 levels are increased and protein localization shifts from the plasma membrane to the cytoplasm. In either case, the prevailing theory is that breast tumor cells have reduced gap junction intercellular communication within primary tumors. The current consensus appears to be that the loss of connexin 43 gap junction intercellular communication is an early event in malignancy, with the possibility of gap junction restoration in the event of metastasis. However, additional evidence is needed to support the latter claim. The purpose of this report is to review the connexin 43 literature that describes studies using human tissue samples, in order to evaluate the function of connexin 43 protein in normal human breast tissue as well as the role of connexin 43 in human breast tumor formation and metastatic progression. PMID- 28902345 TI - Cx32 suppresses extrinsic apoptosis in human cervical cancer cells via the NF kappaB signalling pathway. AB - Tumour necrosis factor alpha (TNFalpha) and TNF-related apoptosis inducing ligand (TRAIL) usually trigger either survival or apoptosis signals in various cell types, and nuclear factor kappaB (NF-kappaB) is a key factor that regulates their biological effects. Connexin 32 (Cx32) is a gap junction (GJ) protein that plays vital roles in tumourigenesis and tumour progression. Our previous study explored abnormal Cx32 expression in para-nuclear areas, exacerbated prognostic parameters and suppressed streptonigrin/cisplatin-induced apoptosis in human cervical cancer (CaCx) cells. In this study, we investigated the role of Cx32 in the extrinsic apoptosis pathway of CaCx cells. In transgenic HeLa cells and C-33A cells, Cx32 expression was manipulated using doxycycline or Cx32 siRNA. GJ inhibitors or low density culturing was used to change the status of gap junction intracellular communication (GJIC). We found that apoptosis induced by TNFalpha and TRAIL was suppressed by Cx32 expression despite the presence or absense of GJIC. We also found that Cx32 upregulated the expression of nuclear NF-kappaB and its downstream targets c-IAP1, MMP-2, and MMP-9 in HeLa-Cx32 and C-33A cells. Following our previous study design, our clinical data showed that NF-kappaB and MMP-2 levels increased in human CaCx specimens with high Cx32 expression compared to levels in para-carcinoma of cervical specimens. SC75741 and JSH-23, NF-kB signalling pathway inhibitors, inhibited the anti-apoptotic effects of Cx32. In conclusion, Cx32 suppressed TNFalpha /TRAIL-induced extrinsic apoptosis by upregulating the NF-kappaB signalling pathway. This study demonstrates a novel mechanism for Cx32's anti-apoptotic effect and provides a reasonable explanation for the pro-tumour effect of Cx32 in human CaCx cells. PMID- 28902346 TI - Prediction of radiosensitive patients with gastric cancer by developing gene signature. AB - Adjuvant radiotherapy is an important clinical treatment for the majority of gastric cancer, a common cancer. However, radiotherapy is a double-edged sword. It is necessary to develop a method to predict radiosensitive patients who are most likely to benefit from radiotherapy. Using the publicly available data of gastric cancer from The Cancer Genome Atlas (TCGA), we developed a gene signature that predicts radiosensitive patients through estimating a new index, nominal HR (nHR) (HR product of sensitive genes), for each patient. In this study, we provided several results to validate our prediction. Cross-validation results showed that the predicted radiosensitive patients who received radiotherapy had significantly better survival than predicted radiosensitive patients who did not receive radiotherapy. After adjusting for other clinical factors, including age, sex, target therapy, histologic diagnosis, tumor stage, the benefit of radiotherapy on predicted radiosensitive patient remained significant. In addition, predicted radiosensitive patients who received radiotherapy had a significantly reduced rate of disease progression. Taken together, we have obtained a set of genes, to identify radiosensitive patients with gastric cancer. These genes may be potential biomarkers for diagnosis and treatment of gastric cancer, which could give new insight for revealing the underlying mechanism of radiosensitivity of gastric cancer. PMID- 28902347 TI - Measuring the response of human head and neck squamous cell carcinoma to irradiation in a microfluidic model allowing customized therapy. AB - Radiotherapy is the standard treatment for head and neck squamous cell carcinoma (HNSCC), however, radioresistance remains a major clinical problem despite significant improvements in treatment protocols. Therapeutic outcome could potentially be improved if a patient's tumour response to irradiation could be predicted ex vivo before clinical application. The present study employed a bespoke microfluidic device to maintain HNSCC tissue whilst subjecting it to external beam irradiation and measured the responses using a panel of cell death and proliferation markers. HNSCC biopsies from five newly-presenting patients [2 lymph node (LN); 3 primary tumour (PT)] were divided into parallel microfluidic devices and replicates of each tumour were subjected to single-dose irradiation (0, 5, 10, 15 and 20 Gy). Lactate dehydrogenase (LDH) release was measured and tissue sections were stained for cytokeratin (CK), cleaved-CK18 (cCK18), phosphorylated-H2AX (gammaH2AX) and Ki-67 by immunohistochemistry. In addition, fragmented DNA was detected using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Compared with non-irradiated controls, higher irradiation doses resulted in elevated CK18-labelling index in two lymph nodes [15 Gy; 34.8% on LN1 and 31.7% on LN2 (p=0.006)] and a single laryngeal primary tumour (20 Gy; 31.5%; p=0.014). Significantly higher levels of DNA fragmentation were also detected in both lymph node samples and one primary tumour but at varying doses of irradiation, i.e., LN1 (20 Gy; 27.6%; p=0.047), LN2 (15 Gy; 15.3%; p=0.038) and PT3 (10 Gy; 35.2%; p=0.01). The gammaH2AX expression was raised but not significantly in the majority of samples. The percentage of Ki-67 positive nuclei reduced dose-dependently following irradiation. In contrast no significant difference in LDH release was observed between irradiated groups and controls. There is clear inter- and intra-patient variability in response to irradiation when measuring a variety of parameters, which offers the potential for the approach to provide clinically valuable information. PMID- 28902348 TI - Suppression of CUL4A attenuates TGF-beta1-induced epithelial-to-mesenchymal transition in breast cancer cells. AB - Transforming growth factor-beta1 (TGF-beta1) plays a vital role in the process of epithelial-to-mesenchymal transition (EMT) in breast cancer and the cullin 4A (CUL4A) gene is overexpressed in primary breast cancer. However, whether TGF beta1 signaling can induce CUL4A expression has not been investigated to date, at least to the best of our knowledge. In this study, using breast cancer cell lines, we found that the CUL4A expression level was increased following EMT induced by TGF-beta1. Silencing CUL4A expression or CUL4A inhibition by thalidomide suppressed the EMT process induced by TGF-beta1. We also found that CUL4A was associated with the expression of zinc finger E-box-binding homeobox 1 (ZEB1) which was induced by TGF-beta1. These results suggest that CUL4A is upregulated in TGF-beta1-induced EMT, and has a regulatory function in this process. The identification of CUL4A as a downstream target of TGF-beta1 represents a critical pro-survival mechanism in breast cancer progression and provides another point for therapeutic intervention in breast cancer. PMID- 28902349 TI - TUG1 promotes osteosarcoma tumorigenesis by upregulating EZH2 expression via miR 144-3p. AB - lncRNA-TUG1 (Taurine upregulated 1) is up-regulated and highly correlated with poor prognosis and disease status in osteosarcoma. TUG1 knockdown inhibits osteosarcoma cell proliferation, migration and invasion, and promotes apoptosis. However, its mechanism of action has not been well addressed. Growing evidence documented that lncRNA works as competing endogenous (ce)RNAs to modulate the expression and biological functions of miRNA. As a putative combining target of TUG1, miR-144-3p has been associated with the progress of osteosarcoma. To verify whether TUG1 functions through regulating miR-144-3p, the expression levels of TUG1 and miR-144-3p in osteosarcoma tissues and cell lines were determined. TUG1 was upregulated in osteosarcoma tissues and cell lines, and negatively correlated with miR-144-3p. TUG1 knockdown induced miR-144-3p expression in MG63 and U2OS cell lines. Results from dual luciferase reporter assay, RNA-binding protein immuno-precipitation (RIP) and applied biotin-avidin pull-down system confirmed TUG1 regulated miR-144-3p expression through direct binding. EZH2, a verified target of miR-144-3p was upregulated in osteosarcoma tissues and negatively correlated with miR-144-3p. EZH2 was negatively regulated by miR-144-3p and positively regulated by TUG1. Gain-and loss-of-function experiments were performed to analyze the role of TUG1, miR-144-3p and EZH2 in the migration and EMT of osteosarcoma cells. EZH2 over-expression partly abolished TUG1 knockdown or miR-144-3p overexpression induced inhibition of migration and EMT in osteosarcoma cells. In addition, TUG1 knockdown represses the activation of Wnt/beta-catenin pathway, which was reversed by EZH2 over-expression. The activator of Wnt/beta-catenin pathway LiCl could partially block the TUG1 knockdown induced osteosarcoma cell migration and EMT inhibition. In conclusion, our results showed that TUG1 plays an important role in osteosarcoma development through miRNA-144-3p/EZH2/Wnt/beta-catenin pathway. PMID- 28902350 TI - Trophic and neurotrophic factors in human pituitary adenomas (Review). AB - The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in functional or non-functional, depending on their hormonal activity. Some trophic and neurotrophic factors seem to play a key role in the development and maintenance of the pituitary function and in the regulation of hypothalamo pituitary-adrenocortical axis activity. Several lines of evidence suggest that trophic and neurotrophic factors may be involved in pituitary function, thus suggesting a possible role of the trophic and neurotrophic factors in the normal development of pituitary gland and in the progression of pituitary adenomas. Additional studies might be necessary to better explain the biological role of these molecules in the development and progression of this type of tumor. In this review, in light of the available literature, data on the following neurotrophic factors are discussed: ciliary neurotrophic factor (CNTF), transforming growth factors beta (TGF-beta), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), vascular endothelial growth inhibitor (VEGI), fibroblast growth factors (FGFs) and epidermal growth factor (EGF) which influence the proliferation and growth of pituitary adenomas. PMID- 28902351 TI - Anoctamin5 regulates cell migration and invasion in thyroid cancer. AB - Anoctamin/TMEM16 family members have recently been identified as novel calcium activated chloride channels, and dysregulation of many family members participates in tumorigenesis and progression. However, the exact role of anoctamin5 (ANO5), one member of this family, in thyroid cancer is still not clarified. In this study, we firstly found that the expression levels of ANO5 was significantly downregulated in thyroid cancer compared to adjacent normal tissue by mining the public GEO database. Subsequently, we further demonstrated that the expression levels of ANO5 was significantly downregulated in 69.5% (57/82) clinical thyroid cancer tissues using real-time PCR assay. Moreover, western blot assay also showed that ANO5 was downregulated in papillary thyroid cancer and follicular thyroid cancer compared to adjacent noncancerous tissues. Furthermore, some biological and functional in vitro experiments proved that ANO5 knockdown promotes thyroid cancer cell migration and invasion but overexpression of ANO5 inhibits these phenotypes. By analyzing gene set enrichment, we found that lower ANO5 expression was positively associated with JAK/STAT3 signaling pathway. Collectively downregulation of ANO5 promotes thyroid cancer cell migration and invasion by affecting JAK/STAT3 pathway. PMID- 28902352 TI - GPER promotes tamoxifen-resistance in ER+ breast cancer cells by reduced Bim proteins through MAPK/Erk-TRIM2 signaling axis. AB - Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Our previous studies find that GPER and its down-stream signaling play a pivotal role in the development of tamoxifen (TAM) resistance. cDNA array analysis indicated a set of genes associated with cell apoptosis are aberrant in GPER activated and TAM-resistant MCF-7R cells compared with TAM-sensitive MCF-7 cells. Among these genes, Bim (also named BCL2-L11), a member of the BH3-only pro apoptotic protein family is significantly decreased, and TRIM RING finger protein TRIM2 (a ubiquitin ligase) is highly expressed in MCF-7R. To understand the mechanism of TAM-resistance in GPER activated ER+ breast cancer, the function of TRIM2 and Bim inducing cell apoptosis was studied. By using immunohistochemical and western blot analysis, there is an adverse correlation between TRIM2 and Bim in TAM-resistant breast tumor tissues and MCF-7R cells. Knockdown Bim in TAM sensitive MCF-7 cells or overexpression of Bim in TAM-resistant MCF-7 cells significantly changed its sensibility to TAM through altering the levels of cleaved PARP and caspase-3. Activation of GPER and its downstream signaling MAPK/ERK, not PI3K/AKT, led to enhanced TRIM2 protein levels and affected the binding between TRIM2 and Bim which resulted in a reduced Bim in TAM-resistant breast cancer cells. Thus, the present study provides a novel insight to TAM resistance in ER-positive breast cancer cells. PMID- 28902353 TI - Identification of WISP1 as a novel oncogene in glioblastoma. AB - Glioblastoma is the most common and aggressive primary brain tumor and has a high mortality in humans. However, mechanisms and factors involved in the progression of glioblastoma remain elusive. WISP1 (WNT1 inducible signaling pathway protein 1), has been suggested to be a critical regulator of cancer development. The aim of this study was to investigate the role of WISP1 in regulating the progression of glioblastoma. Clinicopathological characteristics of glioblastoma were assessed, and higher levels of WISP1 were positively associated with advanced clinical stage and a poor prognosis. Consistently, WISP1 expression was significantly upregulated in glioblastoma tissue and cell lines compared with normal tissue and cells. Additionally, inhibition of WISP1 greatly suppressed cell proliferation, migration, and invasion and promoted apoptosis and cell cycle arrest of glioblastoma cells. Further study indicated that downregulation of WISP1 suppressed cell proliferation associated with the gene expression of c-myc and cyclin D1 and cellular signaling such as through the ERK pathway, while inhibiting epithelial-mesenchymal transition and MMP9. Finally, knockdown of WISP1 markedly suppressed in vivo tumor growth and sensitized glioblastoma cells to temozolomide. This study identified WISP1 as an oncogene in glioblastoma and suggests that WISP1 may serve as a potential molecular marker and treatment target for glioblastoma. PMID- 28902355 TI - Establishment of two ovarian cancer orthotopic xenograft mouse models for in vivo imaging: A comparative study. AB - Orthotopic tumor animal models are optimal for preclinical research of novel therapeutic interventions. The aim of the present study was to compare two types of ovarian cancer orthotopic xenograft (OCOX) mouse models, i.e. cellular orthotopic injection (COI) and surgical orthotopic implantation (SOI), regarding xenograft formation rate, in vivo imaging, tumor growth and metastasis, and tumor microenvironment. The tumor formation and progression were monitored by bioluminescent in vivo imaging. Cell proliferation and migration abilities were detected by EdU and scratch assays, respectively. Expression of alpha-SMA, CD34, MMP2, MMP9, vimentin, E-cadherin and Ki67 in tumor samples were detected by immunohistochemistry. As a result, we successfully established COI- and SOI-OCOX mouse models using ovarian cancer cell lines ES2 and SKOV3. The tumor formation rate in the COI and SOI models were 87.5 and 100%, respectively. Suspected tumor cell leakage occurred in 37.5% of the COI models. The SOI xenografts grew faster, held larger primary tumors, and were more metastatic than the COI xenografts. The migration and proliferation properties of the cells that generated SOI xenografts were significantly starker than those deriving COI xenografts in vitro. The tumor cells in SOI xenografts exhibited a mesenchymal phenotype and proliferated more actively than those in the COI xenografts. Additionally, compared with the COI tumors, the SOI tumors contained more cancer associated fibroblasts, matrix metallopeptidase 2 and 9. In conclusion, SOI is a feasible and reliable technique to establish OCOX mouse models mimicking the clinical process of ovarian cancer growth and metastasis, although SOI is more technically difficult and time consuming than COI. PMID- 28902354 TI - EWS-FLI1 positively regulates autophagy by increasing ATG4B expression in Ewing sarcoma cells. AB - Ewing sarcoma (ES) is the most common malignant bone tumor in children and young adults. It is characterized by chromosomal translocations fusing the EWS gene with an ETS oncogene, most frequently FLI1. In the present study, the authors aimed to investigate the function of EWS-FLI1 in autophagy in ES cells, and identified that EWS-FLI1 positively regulates autophagy in ES cells. ATG4B expression was observed markedly upregulated by EWS-FLI1 overexpression, and silencing of ATG4B dramatically inhibits autophagy in ES cells. Furthermore, apoptosis was inhibited in ATG4B overexpressed ES cells, and ATG4B-potentiated autophagy is required for ES cells survival. Taken together, the authors demonstrated the role of EWS-FLI1 and ATG4B in autophagy in ES cells, and suggested EWS-FLI1 and ATG4B as potential therapeutic targets for ES. PMID- 28902356 TI - miR-378 functions as an onco-miRNA by targeting the ST7L/Wnt/beta-catenin pathway in cervical cancer. AB - Upregulation or downregulation of microRNAs (miRNAs) has been identified in human cervical cancer (CC). However, the character and function of miR-378 in CC remains unknown. In the present study, the authors demonstrated that miR-378 was upregulated in CC used the reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) assay, and promoted cell proliferation by accelerating the progress of cell cycle and repressing cell apoptosis in CC cells. The predicted target genes of miR-378 were determined by enhanced green fluorescent protein (EGFP) reporter assays, RT-qPCR assay and western blot analysis. miR-378 suppressed the expression of suppression of tumorigenicity 7-like (ST7L) by targeting the 3'-untranslated region (3'-UTR) of ST7L mRNA in HeLa and SiHa cells. ST7L was downregulated in CC using the RT-qPCR assay, and the malignant phenotype of HeLa and SiHa cells were inhibited by ST7L overexpression. In addition, miR-378 activated the Wnt/beta-catenin pathway by targeting ST7L in CC cells. In short, miR-378 functions as an onco-miRNA by directly downregulating ST7L mRNA and protein level in HeLa and SiHa cells, and serves important roles in the malignancy of CC. PMID- 28902357 TI - Expression of Wnt3a in hepatocellular carcinoma and its effects on cell cycle and metastasis. AB - Invasion and metastasis are the primary causes of mortality from hepatocellular carcinoma (HCC). Effective inhibition against participants in the tumourigenesis and metastasis process is critical for treatment of HCC. Wnt3a is involved in the development and metastasis of many malignant tumours. However, the specific mechanisms of Wnt3a-mediated cell proliferation, invasion and metastasis in HCC remain unclear. In this study, we found that Wnt3a and its target gene c-Myc showed higher expression in tumour tissues than normal liver tissues in HCC patients; 71.8% of the cases studied had high Wnt3a and c-Myc expression levels (n=32); Wnt3a expression positively correlated with its target genes MMP-7 and c Myc. Intriguingly, the expression of Wnt3a, MMP-7 and c-Myc is significantly correlated with Notch3 and Hes1 expression. In vitro experiments showed that Wnt3a was highly expressed in MHcc97H and SK-Hep-1 cells. Therefore, Wnt3a expression was silenced with siRNA, and then, MTT, flow cytometry, wound healing and Transwell assays were performed to analyse cell proliferation, cycle, migration and invasion. The results demonstrated that downregulation of Wnt3a expression inhibited cell viability and induced G0/G1 cell cycle arrest via decreased expression of cyclin D1 and c-Myc and increased expression of p21 and p27. In addition, deletion of Wnt3a significantly inhibited migration and invasion by downregulating MMP-2/-7/-9 expression via the MAPK (p38, ERK1/2 and JNK) pathway. In conclusion, our data show that Wnt3a is involved in HCC development. Wnt3a may be an effective target for treatment of HCC. PMID- 28902358 TI - SERP1 is a novel marker of poor prognosis in pancreatic ductal adenocarcinoma patients via anti-apoptosis and regulating SRPRB/NF-kappaB axis. AB - Stress associated endoplasmic reticulum protein 1 (SERP1), can cause accumulation of unfolded proteins in ER stress. However, studies on the role of SERP1 in pancreatic ductal adenocarcinoma (PDAC) are still incomplete. The present study aimed at identifying whether SERP1 acts as a potential novel prognostic marker of PDAC, and analyzed its possible mechanism. GEO database analysis showed SERP1 was significantly upregulated in PDAC tissues, and strongly associated with advanced clinical stage of PDAC patients from TCGA database. Univariate and multivariate Cox regression analysis further revealed SERP1 high expression was an independent factor for the prognosis of PDAC. Gene set enrichment analysis (GSEA) revealed that SERP1 was mainly involved in regulating cell apoptosis and nuclear factor kappaB (NF-kappaB) signaling pathway, and downregulated SERP1 significantly promoted PANC-1 cell apoptosis. To further explore its possible mechanism, protein-protein interaction (PPI) and gene ontology (GO) analysis showed the functions of proteins interacting with SERP1 were mainly enriched in regulating cell apoptosis, and SRP receptor beta subunit (SRPRB) was the core of the whole PPI network. The expression of SERP1 was negatively correlated with SRPRB expression. In vitro, downregulated SERP1 significantly increased SRPRB expression. Furthermore, upregulated SRPRB could increase cell apoptosis rate and decreased the expression level of NF-kappaB and the phosphorylation NF-kappaB. The above results indicated that SERP1 as a potential novel prognostic marker of PDAC probably via regulating cell apoptosis and NF-kappaB activation, which may be associated with SRPRB. PMID- 28902359 TI - Isoastragaloside I inhibits NF-kappaB activation and inflammatory responses in BV 2 microglial cells stimulated with lipopolysaccharide. AB - The excessive activation of microglia in many neurodegenerative diseases is detrimental to neuronal survival. Isoastragaloside I (ISO I) is a natural saponin molecule found within the roots of Astragalus membranaceus, a famous traditional Chinese medicine. In the present study, the anti-inflammatory effects and the mechanisms of action of ISO I on activated BV-2 cells stimulated with lipopolysaccharide (LPS) were investigated. ISO I dose-dependently inhibited the excessive release of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha in the LPS-stimulated BV-2 cells. Moreover, it decreased the production of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and mitigated the gene expression of interleukin (IL)-1beta, TNF-alpha and iNOS induced by LPS. Further experiments revealed that ISO I decreased the phosphorylation levels of nuclear factor-kappaB (NF-kappaB), and suppressed its nuclear translocation and transactivation activity. In addition, it inhibited the activation of signaling pathway molecules, such as PI3K, Akt and mitogen-activated protein kinases (MAPKs). Taken together, our findings suggest that ISO I prevents LPS-induced microglial activation probably by inhibiting the activation of the NF-kappaB via PI3K/Akt and MAPK signaling pathways, indicating its therapeutic potential for neurological diseases relevant to neuroinflammation. PMID- 28902360 TI - Expression of periostin in breast cancer cells. AB - Periostin (POSTN) is a protein involved in multiple processes important for cancer development, both at the stage of cancer initiation and progression, as well as metastasis. The aim of this study was to determine the expression of POSTN in the cells of non-invasive ductal breast carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) and to correlate it with clinicopathological data. Immunohistochemical studies (IHC) were conducted on 21 cases of fibrocystic breast change (FC), 44 cases of DCIS and 92 cases of IDC. POSTN expression at mRNA (real-time PCR) and protein level (western blot analysis) was also confirmed in selected breast cancer cell lines (MCF-7, SK-BR-3, MDA-MB-231 and BO2). Statistically significant higher level of POSTN expression in IDC and DCIS cancer cells compared to FC was noted. Also, the level of POSTN expression in the cytoplasm of IDC cells was shown to increase with the increasing degree of tumour malignancy (G) and significantly higher expression of POSTN was observed in each degree of tumour malignancy (G) relative to FC. Statistically significant higher POSTN expression was observed in tumours with estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) phenotypes in comparison to estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) cases, as well as significant negative correlation between POSTN expression in cancer cells and expression of ER and PR (p<0.05). Additionally, statistically significant differences in POSTN expression were shown between particular breast cancer cell lines, both at mRNA and protein level. Observed POSTN expression was the lowest in the case of MCF-7, and the highest in MDA-MB-231 and BO2 of the most aggressive potential clinically corresponding to G3 tumours. POSTN expression in the cytoplasm of IDC cancer cells may play an important role in cancer transformation mechanism. PMID- 28902362 TI - Histone lysine methylation and congenital heart disease: From bench to bedside (Review). AB - Histone post-translational modifications (PTM) as one of the key epigenetic regulatory mechanisms that plays critical role in various biological processes, including regulating chromatin structure dynamics and gene expression. Histone lysine methyltransferase contributes to the establishment and maintenance of differential histone methylation status, which can recognize histone methylated sites and build an association between these modifications and their downstream processes. Recently, it was found that abnormalities in the histone lysine methylation level or pattern may lead to the occurrence of many types of cardiovascular diseases, such as congenital heart disease (CHD). In order to provide new theoretical basis and targets for the treatment of CHD from the view of developmental biology and genetics, this review discusses and elaborates on the association between histone lysine methylation modifications and CHD. PMID- 28902361 TI - Cooperative oncogenic effect and cell signaling crosstalk of co-occurring HER2 and mutant PIK3CA in mammary epithelial cells. AB - Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20 30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2. To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment. PMID- 28902363 TI - Ginkgetin induces G2-phase arrest in HCT116 colon cancer cells through the modulation of b-Myb and miRNA34a expression. AB - Ginkgetin has been reported to display antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in CRC cells remains to be identified. In this study, ginkgetin treated HCT116 CRC cells exhibited significant dose-dependent growth inhibition with a GI50 value of 4.0 uM for 48-h treatment, together with apoptosis, via G2 phase cell cycle arrest. When HCT116 cells were treated with 10 uM ginkgetin for 48 h, the percentage of cells in G2/M phase increased by 2.2-fold (43.25%) versus the untreated control (19.69%). Ginkgetin regulated the expression of genes that are critically involved in G2 phase arrest cells, such as b-Myb, CDC2 and cyclin B1. Furthermore, we found that the suppression of b-Myb expression by ginkgetin was rescued ~5.1-fold by treatment with a miR-34a inhibitor (500 nM) and b-Myb was downregulated by >80% by 100 nM miR-34a mimic. These data suggest that the miRNA34a/b-Myb/cyclin B1 cascade plays a critical role in ginkgetin-induced G2 cell cycle arrest, as well as in the inhibition of HCT116 cell proliferation. Moreover, the administration of ginkgetin (10 mg/kg) reduced tumor volumes by 36.5% and tumor weight by 37.6% in the mice xenografted with HCT116 cells relative to their vehicle-treated counterparts. Therefore, ginkgetin is the first compound shown to regulate b-Myb by modulating miR-34a, and we suggest the use of ginkgetin as an inducer of G2 arrest for the treatment of CRC. PMID- 28902365 TI - APPL1 promotes the migration of gastric cancer cells by regulating Akt2 phosphorylation. AB - As a multifunctional adaptor protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif 1) is overexpressed in many cancers, and has been implicated in tumorigenesis and tumor progression. The present study investigated the expression of APPL1 in gastric carcinoma and the function in regulating cell migration. We investigated the expression of APPL1 in gastric carcinoma based upon The Cancer Genome Atlas (TCGA) database. The expression of APPL1 in collected gastric carcinoma tissues and cultured cells was measured by qRT-PCR and western blot analysis. Transwell assay and wound healing assay were used to analyze the effects of APPL1 on tumor cell migration. The statistical results based upon TCGA database showed significantly higher expression of APPL1 in gastric carcinoma compared to adjacent normal tissues, and we confirmed these findings by measuring APPL1 expression in collected gastric carcinoma tissues and cultured cells. The results of transwell assay and wound healing assay showed that when APPL1 was silenced by siRNA, cell migration was inhibited and overexpression of APPL1 promoted migration. Western blot results demonstrated that changes in several mesenchymal markers were consistent with the observed reduction or enhancement of cell migration. Importantly, the expression of APPL1 significantly affected the phosphorylation of Akt2. In addition, MMP2 and MMP9, downstream effectors of Akt2 changed accordingly, which is a critical requirement for Akt2-mediated cell migration. The results demonstrate an important new function of APPL1 in regulating cell migration through a mechanism that depends on Akt2 phosphorylation. PMID- 28902364 TI - Functional roles of C/EBPalpha and SUMO-modification in lung development. AB - CCAAT enhancer binding protein alpha (C/EBPalpha) is a transcription factor regulating the core aspects of cell growth and differentiation. The present study investigated the level and functional role of C/EBPalpha during the development of the rat lung. C/EBPalpha protein exhibits a dynamic expression pattern. The correlation between the expression of C/EBPalpha protein and the content of glycogen during lung maturation was analyzed to understand the function of C/EBPalpha in lung differentiation. The high expression of C/EBPalpha coincides with the reduction of glycogen in the fetal lung. In addition, the authors identified that changes in the level of C/EBPalpha are associated with the secretion of pulmonary surfactant. C/EBPalpha is modified by small ubiquitin related modifier (SUMO) post-translationally. The results of double immunofluorescence staining and immunoprecipitation demonstrated that SUMO modified C/EBPalpha was present in the lung. The sumoylated C/EBPalpha gradually decreased during lung differentiation and was negatively correlated with pulmonary surfactant secretion, thereby suggesting that the SUMO modification may participate in C/EBPalpha-mediated lung growth and differentiation. These results indicated that C/EBPalpha played a role in lung development and provided the insight into the mechanism underlying SUMO-modification. PMID- 28902366 TI - Heat shock protein 27 (HSPB1) suppresses the PDGF-BB-induced migration of osteoblasts. AB - Heat shock protein 27 (HSP27/HSPB1), one of the small heat shock proteins, is constitutively expressed in various tissues. HSP27 and its phosphorylation state participate in the regulation of multiple physiological and pathophysiological cell functions. However, the exact roles of HSP27 in osteoblasts remain unclear. In the present study, we investigated the role of HSP27 in the platelet-derived growth factor-BB (PDGF-BB)-stimulated migration of osteoblast-like MC3T3-E1 cells. PDGF-BB by itself barely upregulated the expression of HSP27 protein, but stimulated the phosphorylation of HSP27 in these cells. The PDGF-BB-induced cell migration was significantly downregulated by HSP27 overexpression. The PDGF-BB induced migrated cell numbers of the wild-type HSP27-overexpressing cells and the phospho-mimic HSP27-overexpressing (3D) cells were less than those of the unphosphorylatable HSP27-overexpressing (3A) cells. PD98059, an inhibitor of MEK1/2, SB203580, an inhibitor of p38 mitogen-activated protein kinase, and SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) reduced the PDGF-BB-induced migration of these cells, whereas Akt inhibitor or rapamycin, an inhibitor of upstream kinase of p70 S6 kinase (mTOR), barely affected the migration. However, the PDGF-BB-induced phosphorylation of p44/p42 MAPKappa, p38 MAPK and SAPK/JNK was not affected by HSP27 overexpression. There were no significant differences in the phosphorylation of p44/p42 MAPKappa, p38 MAP kinase or SAPK/JNK between the 3D cells and the 3A cells. These results strongly suggest that HSP27 functions as a negative regulator in the PDGF-BB stimulated migration of osteoblasts, and the suppressive effect is amplified by the phosphorylation state of HSP27. PMID- 28902367 TI - Identification of hub genes, key miRNAs and potential molecular mechanisms of colorectal cancer. AB - Colorectal cancer (CRC) is the most common cancer of the digestive system. The aim of the present study was to identify the potential biomarkers and uncover the underlying mechanisms. The gene and miRNA expression profiles were obtained from GEO database. The differentially expressed genes (DEGs) and miRNAs (DE miRNAs) were identified by GEO2R. The gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by KOBAS 3.0. The protein-protein interaction (PPI) network and miRNA-gene network were constructed by Cytoscape software. Then, the identified genes were verified by quantitative real-time PCR in both CRC tissue samples and cell lines. A total of 600 upregulated DEGs, 283 downregulated DEGs, 13 upregulated DE miRNAs and 7 downregulated DE miRNAs were identified. GO analysis results showed that upregulated DEGs were significantly enriched in binding, organelle and cellular process. Downregulated DEGs were enriched in binding, extracellular region and chemical homeostasis. KEGG analysis showed that the DEGs were mostly enriched in cell cycle and pathways in cancer. A total of eight genes were identified as biomarkers, including CAD, ITGA2, E2F3, BCL2, PRKACB, IGF1, SGK1 and NR3C1. Experimental validation showed that seven of the eight identified genes had the same expression trend as predicted, except for ITGA2. Besides, hsa-miR-552 and hsa-miR-30a were identified as key miRNAs. the present study provides a series of biomarkers and mechanisms for the diagnosis and therapy of CRC. We also prove that although bioinformatics analysis is a wonderful approach, experiment validation is necessary. PMID- 28902368 TI - Smad4 re-expression increases the sensitivity to parthenolide in colorectal cancer. AB - Parthenolide (PT), a sesquiterpene lactone extracted from the plant feverfew, has been demonstrated to have anti-inflammatory and anticancer properties. Although PT has been revealed to markedly inhibit colorectal cancer cell proliferation, the inhibitory effects decrease with administration time. These findings revealed that colorectal cancer cells develop resistance to PT. However, the underlying mechanism is unclear. In the present study we observed significantly low expression of Smad4 in 3 PT-resistant cell lines (HCT-116/PT, HT-29/PT and Caco 2/PT), which were obtained using in vitro concentration gradient-increased induction, but not in their parental cells. In the present study we used the lentiviral-mediated transfection method to upregulate Smad4 in resistant colorectal cancer cell lines. Flow cytometry assay was used to assess cell apoptosis. Cell migration was detected using a QCMTM 24-well Fluorimetric Cell Migration Assay kit. Our study showed that Smad4 overexpression notably decreased the half maximal inhibitory concentration (IC50) values for PT in the 3 PT resistant cell lines, and improved the inhibitory effects of PT on cell migration and enhanced apoptosis in vitro as well as suppressed xenografted tumors in a PT resistant colorectal cancer mouse model. Further study by western blotting into the underlying mechanism demonstrated that Smad4 overexpression suppressed the expression of MDR1 in the resistant cells, and resulted in the accumulation of PT, which in turn promoted the expession of caspase-3 and Bax and inhibited the expression of Bcl-2 and the phosphorylation of NF-kappaB p65. In short, Smad4 re expression may be crucial for enhancing the sensitivity and reversing the resistance to PT in PT-resistant colorectal cancer cells. PMID- 28902369 TI - Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo. AB - The present study was designed to investigate the synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 (Aspp2-ad) and oxaliplatin via p53-independent pathway in vitro and in vivo. After being treated with Aspp2-ad and/or oxaliplatin for 24-48 h, HepG2P53-/- and Hep3B cells showed a significant growth inhibition compared with vehicle control. Combination group showed a synergetic effect, the inhibitory rates were all above 80% at 48 h point in HepG2P53-/- and Hep3B cells. The apoptotic cell numbers of Aspp2-ad and/or oxaliplatin treatment groups were increased remarkably, especially for the combined therapy group in the liver cancer cells. The Hep3B xenograft experiment also showed similar inhibition of Aspp2-ad and/or oxaliplatin to the in vitro experiment. H&E results showed that combination group had the least mitotic indexes and the most necrosis. The immunohistochemistry results showed that PCNA, CD31 expression decreased greatly in treatment groups. These results suggested that Aspp2-ad might inhibit proliferation and vascular growth of hepatocarcinoma. Aspp2 induced apoptosis protein expression in Aspp2-ad and combination groups, the Aspp2, Bax and activation of caspase-3 expression increased greatly both in vitro and in vivo. But interestingly, the autophagy proteins showed different responses not only in HepG2P53-/- and Hep3B cells but also in vitro and in vivo. We found that Aspp2-ad downregulated the p-ERK, p-STAT3 expression, the synergistic effects were observed in combination group, while there was not response of mTOR to Aspp2-ad. In conclusion, Aspp2-ad, in P53-independent manner, regulated ERK and STAT3 signal moleculars to inhibit hepatocarcinoma in coordination with oxaliplatin by influencing the protein expression of proliferation, apoptosis, autophagy and vascular growth. Aspp2-ad has the potential to be developed in gene therapy for HCC, especially for P53 deletion or mutation in HCC. PMID- 28902370 TI - Nano Let-7b sensitization of eliminating esophageal cancer stem-like cells is dependent on blockade of Wnt activation of symmetric division. AB - The poor therapy response and poor prognosis of esophageal cancer has made it one of the most malignant carcinoma, and the complicated multidisciplinary treatment failed to achieve a long-term disease-free survival. To diagnose esophageal cancer at an earlier stage, and to improve the effect of anticancer therapy would improve the therapeutic efficacy. After retrospective analysis of the cancer samples of patients who received esophagectomy, we found the relevance between ratio of either ALDH1 or CD133-positive cancer stem cells and 2-year recurrence. Higher ratios of cancer stem cells indicated later clinical stages, and Wnt signaling activation was more frequent in later esophageal carcinoma. Further in bench studies, we explored the suppressive roles and the mechanisms involved in Let-7 on self-renewal in ECA-109 and ECA-9706 esophageal cancer stem cells. Isolated cancer stem cells naturally divide symmetrically and are therapy resistant. Therapy of fluorouracil and docetaxel both enriched the stem cells, proving the resistant characteristics of cancer stem cells. Wnt activation stimulated more symmetric division of stem cells, resulting in self-renewal promotion, which could be blocked by Let-7 overexpression. Furthermore, enforced Let-7 sensitized the stem cells to chemotherapies in a Wnt pathway inhibition dependent manner, contributing to Let-7 sensitization of chemotherapeutic response. Wnt activation weakened the suppressive Let-7b through the sponge functions of CCAT-1, forming the negative feedback loop of Let-7b/Wnt/CCAT1. These results identified the crucial participation of stem cells in esophageal cancer occurrence and progression as the potent indicator, and also indicate the potential powerful agent of Let-7 nano-particles in treatment of cancer. PMID- 28902371 TI - No Difference in Functional Outcomes after Total Knee Arthroplasty with or without Pinless Navigation. AB - This study aims to investigate the functional outcomes of pinless navigation (BrainLAB VectorVision Knee 2.5 navigation system; Munich, Germany) as an intraoperative alignment guide in total knee arthroplasty (TKA). A prospective, 24-month follow-up study of 100 patients who were scheduled and randomized into two groups, the pinless navigation and conventional surgery, was conducted. All TKAs were performed with the surgical aim of achieving neutral coronal alignment with the 180-degree mechanical axis. The outcomes measured in this study were Oxford Knee Score (OKS), Knee Society Score (KSS), Short Form-36 (SF-36), and range of motion (ROM). At 24-month postoperatively, four and two patients were lost to follow-up from the pinless navigation group and conventional group, respectively. There were no significant differences in absolute scores of the OKS, KSS, and ROM, as well as changes from preoperative baseline, between pinless navigation and conventional groups at both 6 and 24 months postoperatively. Pinless navigation results in comparable functional outcomes as conventional TKA at 6 and 24 months postoperatively. PMID- 28902372 TI - [Cost assessment for endoscopic procedures in the German diagnosis-related-group (DRG) system - 5 year cost data analysis of the German Society of Gastroenterology project]. AB - Background In the German hospital reimbursement system (G-DRG) endoscopic procedures are listed in cost center 8. For reimbursement between hospital departments and external providers outdated or incomplete catalogues (e. g. DKG NT, GOA) have remained in use. We have assessed the cost for endoscopic procedures in the G-DRG-system. Methods To assess the cost of endoscopic procedures 74 hospitals, annual providers of cost-data to the Institute for the Hospital Remuneration System (InEK) made their data (2011 - 2015; S 21 KHEntgG) available to the German-Society-of-Gastroenterology (DGVS) in anonymized form (4873 809 case-data-sets). Using cases with exactly one endoscopic procedure (n = 274 186) average costs over 5 years were calculated for 46 endoscopic procedure tiers. Results Robust mean endoscopy costs ranged from 230.56 ? for gastroscopy (144 666 cases), 276.23 ? (n = 32 294) for a simple colonoscopy, to 844.07 ? (n = 10 150) for ERCP with papillotomy and plastic stent insertion and 1602.37 ? (n = 967) for ERCP with a self-expanding metal stent. Higher costs, specifically for complex procedures, were identified for University Hospitals. Discussion For the first time this catalogue for endoscopic procedure-tiers, based on S 21 KHEntgG data-sets from 74 InEK-calculating hospitals, permits a realistic assessment of endoscopy costs in German hospitals. The higher costs in university hospitals are likely due to referral bias for complex cases and emergency interventions. For 46 endoscopic procedure-tiers an objective cost-allocation within the G-DRG system is now possible. By international comparison the costs of endoscopic procedures in Germany are low, due to either greater efficiency, lower personnel allocation or incomplete documentation of the real expenses. PMID- 28902373 TI - Berzelius Symposium 93: International Conference on Thrombosis and Embolism. PMID- 28902375 TI - Provider and Patient Knowledge and Views of Office Practices on Weight Gain and Exercise during Pregnancy. AB - OBJECTIVE: This study sought to assess provider and patient knowledge and beliefs on gestational weight gain (GWG) and exercise during pregnancy, outline current clinical practices and the perceived value of educational tools. STUDY DESIGN: Providers and patients at the George Washington Medical Faculty Associates Obstetricians and Gynecologists clinic were recruited for a voluntary survey. Descriptive statistics of responses were compared and chi-square analysis tested for significant associations. RESULTS: A total of 461 patient and 36 provider questionnaires were analyzed. Providers recommended GWG consistent with the Institute of Medicine guidelines for a "normal" body mass index (82.9%); however, a majority (52.8%) recommended GWG below guidelines for obese women. All providers reported counseling patients on GWG, but only 53.4% of patients reported discussing personal recommendations. About half of providers reported distributing educational materials for GWG (60.0%); however, only 30.6% of patients reported receiving them. African American patients self-reported receiving the highest rates of counseling and educational materials, though a lower rate of recommendations to exercise. Patients perceived educational tools to be more useful than did providers. CONCLUSION: Our findings suggest a gap between provider-patient perceptions regarding counseling and provision of informational materials. Future research should study whether implementing various educational tools might increase the efficacy of current practices. PMID- 28902374 TI - Bupleurum chinense Roots: a Bioactivity-Guided Approach toward Saponin-Type NF kappaB Inhibitors. AB - The roots of Bupleurum chinense have a long history in traditional medicine to treat infectious diseases and inflammatory disorders. Two major compounds, saikosaponins A and D, were reported to exert potent anti-inflammatory activity by inhibiting NF-kappaB. In the present study, we isolated new saikosaponin analogues from the roots of B. chinese interfering with NF-kappaB activity in vitro. The methanol-soluble fraction of the dichloromethane extract of Radix Bupleuri was subjected to activity-guided isolation yielding 18 compounds, including triterpenoids and polyacetylenes. Their structures were determined by spectroscopic methods as saikogenin D (1), prosaikogenin D (2), saikosaponins B2 (3), W (4), B1 (5), Y (6), D (7), A (8), E (9), B4 (10), B3 (11), and T (12), saikodiyne A (13), D (14), E (15) and F (16), falcarindiol (17), and 1-linoleoyl sn-glycero-3-phosphorylcholine (18). Among them, 4, 15, and 16 are new compounds, whereas 6, previously described as a semi-synthetic compound, is isolated from a natural source for the first time, and 13-17 are the first reports of polyacetylenes from this plant. Nine saponins/triterpenoids were tested for inhibition of NF-kappaB signaling in a cell-based NF-kappaB-dependent luciferase reporter gene model in vitro. Five of them (1, 2, 4, 6, and 8) showed strong (> 50%, at 30 uM) NF-kappaB inhibition, but also varying degrees of cytotoxicity, with compounds 1 and 4 (showing no significant cytotoxicity) presenting IC50 values of 14.0 uM and 14.1 uM in the cell-based assay, respectively. PMID- 28902376 TI - [Priorities of German Oncologists. Results of the "choosing wisely" survey of the German Society of Hematology and Medical Oncology (DGHO)]. AB - Background During the preparation of "choosing wisely" recommendations, the German Society of Hematology and Medical Oncology (DGHO) had performed a member survey. The large body of replies was systematically and quantitatively analyzed for this report. Methods Replies to the draft recommendations are quantified. Free text replies were iteratively categorized in three levels according to medical categories and additionally, according to their general target of necessary action. Results 492 members completed the survey within the given limit of 2 weeks. Draft recommendations against oversupply were widely supported (77 % 88 %). 1598 free text replies were analyzed. Unnecessary use of resources was requested in several fields in accordance with our recommendations. Strong demand was put forward regarding soft factors: "talking medicine", individually tailored therapy, supportive medicine and palliative care (51 % together) and social resources (11 %). Possible under-supply was less frequently described in fields of expensive measures (17 % of replies). Conclusion In the replies to our survey, we found a strong statement for a plus in talking medicine in oncology. Every physician caring for these patients can contribute to this demand. Structural improvements in continuing education and reimbursement in this field are desirable. PMID- 28902378 TI - [Organ Interactions in Intensive Care]. PMID- 28902377 TI - [Implementation of the National Guidelines for the treatment of Diabetes mellitus type 2 in secondary diabetes centers]. AB - Background The German National Disease Management Guideline (NVL) on treatment of Type 2 Diabetes recommends lowering of blood glucose in four therapy steps. There is little evidence, how NVL is implemented for the individual patients. Methods 810 patients in secondary diabetes centers were examined within the DiabCheckOCTplus trial. Data about the patient's health status (electronic medical record) were classified according to the NVL treatment steps. The degree of implementation was assessed for every person with diabetes type 2 (NCT02 311 504). Results Related to the levels of treatment, 81 % of patients received metformin in level 2, 48 % the dual combination of metformin with DPP4-Inhibitors (level 3) and 41 % an intensified insulin therapy in combination with metformin (level 4). The overall percentage for metformin was 67 %, for DPP4-Inhibitors 20 % and 10 % for sulfonylureas.The duration of diabetes significantly increased with higher NVL level. After 3 years of diabetes 55 % received more than one antihyperglycemic drug. Half of the patients were treated with complex insulin strategies after 9 years, however almost all after 25 years. Conclusion The therapy in secondary care centers met national guidelines to a large extent. Similar proof of implementation would be important for primary care by general practitioners. As the factual information of the therapy level strongly correlated with the duration of disease, it might be used for structured communication (risk profile). PMID- 28902379 TI - [86-Year-Old Man with Dyspnea]. PMID- 28902380 TI - [Organ Interactions: Heart and kidney]. AB - The interactions between heart and kidney are various and of clinical relevance. Worsening of one organ often influences the function of the other. With NYHA and KDIGO we have classification systems for heart and kidney failure and those should be used for cardiorenal systems as well. Furthermore there is a useful classification system for cardiorenal syndromes itself. Cardiorenal syndrome is a complex illness which should be treated by interdisciplinary medical teams. A key roll in pathophysiology is the renin-angiotensin-aldosteron-system (RAAS). It's activation is followed by an increased salt and water retention as well as increased systemic an renal vasoconstriction leading to hypervolaemia an left ventricular hyperthrophy. General recommendations for the prevention of cardiovascular disease are good for the prevention of cardiorenal syndromes as well. RAAS-blockers should be used to stop cardial remodelling. A good regulation of hypertension and diabetes is important. Most important is a balanced intravasal volume. With volume overload negative balances can improve renal perfusion and therefor renal function. The furosemide stress test is a good cinical tool to check wether there is appropriate urine excretion and if volume overload can be treated by loop diuretics. Preload reduction can reduce cardiac output ahd renal function can be worsened especially in the beginning of overload reduction. This may be acceptable. PMID- 28902381 TI - [Organ Interactions: Heart and Lung - Management of the Acute Right Heart Failure]. AB - The pathophysiology and the management of patients with acute right heart failure are very complex. The bed-side focused echocardiography is the basis of differential diagnosis and acute diagnosis. Individual therapy monitoring is complex due to the strong preload dependence of the right ventricle and the limitation of non-invasive estimation of pulmonary-vascular hemodynamics, so that the indication for a pulmonary artery catheter should be liberal in acute right heart failure. The treatment goals of acute right heart failure are the treatment of the underlying disease or triggering factors in combination with individualized optimization of hemodynamic tailored to current right-ventricular function. PMID- 28902382 TI - [Organinteraction between liver and kidney]. AB - Alterations of the kidney function can be observed often in patients with liver diseases. Different mechanisms are leading to alterations in kidney funciton in these patients. New onset of kidney function alterations in patients with acute- or chronic liver disease often leads to acute kidney injury. This Review will inform you about the most importatant clinical interactions of the kidneys and the liver. PMID- 28902383 TI - [BCGitis with Involvement of Lung, Liver and Bone Marrow after Immunotherapy of Urothelial Cancer]. AB - Medical history A 77-year-old patient with transurethral resection of a bladder tumor was transferred due to persistent fever and progressive dyspnea despite antibiotic therapy for suspected urinary tract infection. Repeating the medical history revealed that a BCG immunotherapy of his non-muscle-invasive bladder carcinoma was performed the day before fever developed. Therefore, BCGitis was suspected. Examinations Laboratory parameters showed pancytopenia, elevated liver enzymes, eleveated C-reactive protein and hypoxemia. The CT scan showed multiple miliary lesions of the lung, the bone marrow biopsy revealed granuloma. Diagnosis M. bovis BCG was cultured from urine and bronchoalveolar lavage fluid. Therapy and course Therapy with isoniazide, rifampine, ethambutol and initially prednisolone caused rapid improvement. Conclusion BCGitis is a rare complication of BCG immunotherapy of non-muscle-invasive bladder carcinoma. PMID- 28902384 TI - [Multiple endocrine neoplasia]. AB - Multiple endocrine neoplasia type 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types, in MEN1 parathyroid tumors, pituitary tumors, and pancreas tumors, in MEN2 medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. The autosomal dominant inherited tumor syndromes are caused by mutations in the MEN1 gene, a tumor suppressor gene, and mutations in the RET gene, an activated oncogene, in MEN2. The clinical expression of the different tumors can vary within and between families, with a good genotype-phenotype correlation in MEN2. Early diagnosis and therapy is possible by using biochemical and imaging screening in the families. Early thyroidectomy in young patients with MEN2 results in a high cure rate of MTC. PMID- 28902385 TI - [Standard Operating Procedures in Clinical Medicine]. AB - Standard operating procedures (SOP) in hospital care have the potential to improve treatment quality and transparency. However, after arriving at the decision to generate a SOP for the own hospital or ward, the upcoming question is often, how to start?The present article tries to give some interdisciplinary guidance about reasonable structures and contents of SOPs that could be understood as a basic matrix for individual work. PMID- 28902386 TI - Consequences of Individual Differences in Children's Formal Understanding of Mathematical Equivalence. AB - Experts claim that individual differences in children's formal understanding of mathematical equivalence have consequences for mathematics achievement; however, evidence is lacking. A prospective, longitudinal study was conducted with a diverse sample of 112 children from a midsized city in the Midwestern United States (Mage [second grade] = 8:1). As hypothesized, understanding of mathematical equivalence in second grade predicted mathematics achievement in third grade, even after controlling for second-grade mathematics achievement, IQ, gender, and socioeconomic status. Most children exhibited poor understanding of mathematical equivalence, but results provide clues about which children are on the path to constructing an understanding and which may need extra support to overcome their misconceptions. Findings suggest that mathematical equivalence may deserve more attention from educators. PMID- 28902387 TI - Physical calculations of resistance to water loss improve species range models: reply. PMID- 28902388 TI - Transcriptional repression in macrophages-basic mechanisms and alterations in metabolic inflammatory diseases. AB - Macrophage differentiation and signal responses are coordinated by closely linked transcriptional and epigenomic mechanisms that trigger gene expression. In contrast to well-characterized transcriptional activation pathways in response to diverse metabolic and inflammatory signals, we just begin appreciating that transcriptional repression is equally important. Here, we will highlight macrophage pathways that are controlled by multifaceted repression events, along with a discussion of underlying regulatory mechanisms and components. We will particularly discuss pro- versus anti-inflammatory action of a fundamental corepressor complex, transcription factor cross-talk, repression at enhancers and during elongation, and diverse corepressor knockout mouse models. We will finally emphasize how alterations of macrophage repression pathways in humans contribute to, or even cause, metabolic inflammatory diseases such as obesity and type 2 diabetes. PMID- 28902389 TI - Women's experiences of continuous fetal monitoring - a mixed-methods systematic review. AB - INTRODUCTION: Antepartum stillbirth is often preceded by detectable signs of fetal compromise, including changes in fetal heart rate and movement. It is hypothesized that continuous fetal monitoring could detect these signs more accurately and objectively than current forms of fetal monitoring and allow for timely intervention. This systematic review aimed to explore available evidence on women's experiences of continuous fetal monitoring to investigate its acceptability before clinical implementation and to inform clinical studies. MATERIAL AND METHODS: Systematic searching of four electronic databases (Embase, PsycINFO, MEDLINE and CINAHL), using key terms defined by initial scoping searches, identified a total of 35 studies. Following title and abstract screening by two independent researchers, five studies met the inclusion criteria. Studies were not excluded based on language, methodology or quality assessment. An integrative methodology was used to synthesize qualitative and quantitative data together. RESULTS: Forms of continuous fetal monitoring used included Monica AN24 monitors (n = 4) and phonocardiography (n = 1). Four main themes were identified: practical limitations of the device, negative emotions, positive perceptions, and device implementation. Continuous fetal monitoring was reported to have high levels of participant satisfaction and was preferred by women to intermittent cardiotocography. CONCLUSION: This review suggests that continuous fetal monitoring is accepted by women. However, it has also highlighted both the paucity and heterogeneity of current studies and suggests that further research should be conducted into women's experiences of continuous fetal monitoring before such devices can be used clinically. PMID- 28902391 TI - Parental distress 6 months after a pediatric cancer diagnosis in relation to family psychosocial risk at diagnosis. AB - BACKGROUND: This study was aimed at assessing fathers' and mothers' distress 6 months after a pediatric cancer diagnosis and at determining whether this is related to the level of family psychosocial risk 1 month after the diagnosis. METHODS: A sample of 192 families completed the electronic Psychosocial Assessment Tool (ePAT) 1 month after the diagnosis. At 6 months after the diagnosis, 119 mothers and 98 fathers completed the Distress Thermometer for Parents (DT-P; of which n=132 had also completed the ePAT at baseline). The DT-P consists of a thermometer score ranging from 0 to 10 (with a score >= 4 indicating clinical distress), problem domains (total, practical, social, emotional, physical, cognitive, and parenting for children < 2 years old and for children >= 2 years old), and a desire for a referral. The DT-P scores of mothers and fathers were compared with the scores of a reference group of 671 mothers and 463 fathers with healthy children. Within the pediatric cancer group, the DT-P scores of families with elevated total ePAT-scores were compared with the DT-P scores of parents with universal ePAT scores. RESULTS: Parents of children with cancer more often reported clinical distress on the DT-P than parents of healthy children (fathers, 59.2% vs 32.3%; P < .001; mothers, 63% vs 42.3%; P < .001) and reported more problems on all DT-P domains (P < .001 to P = .042) except for the parenting domain for children < 2 years old. Furthermore, the ePAT predicted parental distress 6 months after the diagnosis because parents with elevated ePAT scores reported more problems than parents with universal scores on the DT-P thermometer and most of the DT-P domains (P < .001 to P = 1.00). CONCLUSIONS: Initial ePAT risk scores at diagnosis are predictive of future mean levels of parental distress. Cancer 2018;124:381-90. (c) 2017 American Cancer Society. PMID- 28902392 TI - Expanding the clinical and molecular spectrum of PRMT7 mutations: 3 additional patients and review. AB - Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 7 patients have been described harboring compound heterozygous or homozygous variants in the PRMT7 gene, causing a novel intellectual disability syndrome, known as SBIDDS syndrome (Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures). We report on 3 additional patients from 2 consanguineous families with severe/moderate intellectual disability, short stature, brachydactyly and dysmorphisms. Exome sequencing revealed 2 novel homozygous mutations in PRMT7. Our findings expand the clinical and molecular spectrum of homozygous PRMT7 mutations, associated to the SBIDDS syndrome, showing a possible correlation between the type of mutation and the severity of the phenotype. PMID- 28902393 TI - Fine Motor Control Underlies the Association Between Response Inhibition and Drawing Skill in Early Development. AB - Previous research shows that the development of response inhibition and drawing skill are linked. The current research investigated whether this association reflects a more fundamental link between response inhibition and motor control. In Experiment 1, 3- and 4-year-olds (n = 100) were tested on measures of inhibition, fine motor control, and drawing skill. Data revealed an association between inhibition and fine motor control, which was responsible for most of the association observed with drawing skill. Experiment 2 (n = 100) provided evidence that, unlike fine motor control, gross motor control and inhibition were not associated (after controlling for IQ). Alternative explanations for the link between inhibition and fine motor control are outlined, including a consideration of how these cognitive processes may interact during development. PMID- 28902390 TI - Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis. AB - BACKGROUND: There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL). METHODS: Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study. RESULTS: Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study. CONCLUSIONS: Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. (c) 2017 American Cancer Society. PMID- 28902394 TI - Quantity and quality limit detritivore growth: mechanisms revealed by ecological stoichiometry and co-limitation theory. AB - Resource quantity and quality are fundamental bottom-up constraints on consumers. Best understood in autotroph-based systems, co-occurrence of these constraints may be common but remains poorly studied in detrital-based systems. Here, we used a laboratory growth experiment to test limitation of the detritivorous caddisfly larvae Pycnopsyche lepida across a concurrent gradient of oak litter quantity (food supply) and quality (phosphorus : carbon [P:C ratios]). Growth increased simultaneously with quantity and quality, indicating co-limitation across the resource gradients. We merged approaches of ecological stoichiometry and co limitation theory, showing how co-limitation reflected shifts in C and P acquisition throughout homeostatic regulation. Increased growth was best explained by elevated consumption rates and improved P assimilation, which both increased with elevated quantity and quality. Notably, C assimilation efficiencies remained unchanged and achieved maximum 18% at low quantity despite pronounced C limitation. Detrital C recalcitrance and substantive post assimilatory C losses probably set a minimum quantity threshold to achieve positive C balance. Above this threshold, greater quality enhanced larval growth probably by improving P assimilation toward P-intensive growth. We suggest this interplay of C and P acquisition contributes to detritivore co-limitation, highlighting quantity and quality as potential simultaneous bottom-up controls in detrital-based ecosystems, including under anthropogenic change like nutrient enrichment. PMID- 28902395 TI - Finding Homologs in Amino Acid Sequences Using Network BLAST Searches. AB - BLAST, the Basic Local Alignment Search Tool, is used more frequently than any other biosequence database search program. We show how to run searches on the Web, and demonstrate how to increase performance by fine-tuning arguments for a specific research project. We offer guidance for interpreting results, statistical significance and biological relevance issues, and suggest complementary analyses. This unit covers both protein-to-protein (blastp) searches and translated searches (blastx, tblastn, tfastx). blastx conceptually translates the query sequence and tblastn translates all nucleotide sequences in a database, while tblastx translates both the query and the database sequences into amino acid sequences. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902396 TI - Data Analysis Pipeline for RNA-seq Experiments: From Differential Expression to Cryptic Splicing. AB - RNA sequencing (RNA-seq) is a high-throughput technology that provides unique insights into the transcriptome. It has a wide variety of applications in quantifying genes/isoforms and in detecting non-coding RNA, alternative splicing, and splice junctions. It is extremely important to comprehend the entire transcriptome for a thorough understanding of the cellular system. Several RNA seq analysis pipelines have been proposed to date. However, no single analysis pipeline can capture dynamics of the entire transcriptome. Here, we compile and present a robust and commonly used analytical pipeline covering the entire spectrum of transcriptome analysis, including quality checks, alignment of reads, differential gene/transcript expression analysis, discovery of cryptic splicing events, and visualization. Challenges, critical parameters, and possible downstream functional analysis pipelines associated with each step are highlighted and discussed. This unit provides a comprehensive understanding of state-of-the-art RNA-seq analysis pipeline and a greater understanding of the transcriptome. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902397 TI - Using SQL Databases for Sequence Similarity Searching and Analysis. AB - Relational databases can integrate diverse types of information and manage large sets of similarity search results, greatly simplifying genome-scale analyses. By focusing on taxonomic subsets of sequences, relational databases can reduce the size and redundancy of sequence libraries and improve the statistical significance of homologs. In addition, by loading similarity search results into a relational database, it becomes possible to explore and summarize the relationships between all of the proteins in an organism and those in other biological kingdoms. This unit describes how to use relational databases to improve the efficiency of sequence similarity searching and demonstrates various large-scale genomic analyses of homology-related data. It also describes the installation and use of a simple protein sequence database, seqdb_demo, which is used as a basis for the other protocols. The unit also introduces search_demo, a database that stores sequence similarity search results. The search_demo database is then used to explore the evolutionary relationships between E. coli proteins and proteins in other organisms in a large-scale comparative genomic analysis. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902398 TI - Using ProteomeScout: A Resource of Post-Translational Modifications, Their Experiments, and the Proteins That They Annotate. AB - Post-translational modifications (PTMs) of protein amino acids are ubiquitous and important to protein function, localization, degradation, and more. In recent years, there has been an explosion in the discovery of PTMs as a result of improvements in PTM measurement techniques, including quantitative measurements of PTMs across multiple conditions. ProteomeScout is a repository for such discovery and quantitative experiments and provides tools for visualizing PTMs within proteins, including where they are relative to other PTMS, domains, mutations, and structure. ProteomeScout additionally provides analysis tools for identifying statistically significant relationships in experimental datasets. This unit describes four basic protocols for working with the ProteomeScout Web interface or programmatically with the database download. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902399 TI - Using the Contextual Hub Analysis Tool (CHAT) in Cytoscape to Identify Contextually Relevant Network Hubs. AB - Highly connected nodes in biological networks are called network hubs. Hubs are topologically important to the structure of the network and have been shown to be preferentially associated with a range of phenotypes of interest. The relative importance of a hub node, however, can change depending on the biological context. Here, we provide a step-by-step protocol for using the Contextual Hub Analysis Tool (CHAT), an application within Cytoscape 3, which enables users to easily construct and visualize a network of interactions from a gene or protein list of interest, integrate contextual information, such as gene or protein expression data, and identify hub nodes that are more highly connected to contextual nodes than expected by chance. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902400 TI - Using the PRIDE Database and ProteomeXchange for Submitting and Accessing Public Proteomics Datasets. AB - The ProteomeXchange (PX) Consortium is the unifying framework for world-leading mass spectrometry (MS)-based proteomics repositories. Current members include the PRIDE database (U.K.), PeptideAtlas/PASSEL, and MassIVE (U.S.A.), and jPOST (Japan). The Consortium standardizes submission and dissemination of public proteomics data worldwide. This is achieved through implementing common data submission guidelines and enforcing metadata requirements by each of the members. Furthermore, the members use a common identifier space. Each dataset receives a unique (PXD) accession number and is publicly accessible as soon as the associated scientific publications are released. The two basic protocols provide a step-by-step guide on how to submit data to the PRIDE database, and describe how to access the PX portal (called ProteomeCentral), which can be used to search datasets available in any of the PX members. (c) 2017 by John Wiley & Sons, Inc. PMID- 28902402 TI - Safety-net versus private hospital setting for brain metastasis patients treated with radiosurgery alone: Disparities in follow-up care and outcomes. AB - BACKGROUND: Stereotactic radiosurgery (SRS) alone is an increasingly accepted treatment for brain metastases, but it requires adherence to frequently scheduled follow-up neuroimaging because of the risk of distant brain metastasis. The effect of disparities in access to follow-up care on outcomes after SRS alone is unknown. METHODS: This retrospective study included 153 brain metastasis patients treated consecutively with SRS alone from 2010 through 2016 at an academic medical center and a safety-net hospital (SNH) located in Los Angeles, California. Outcomes included neurologic symptoms, hospitalization, steroid use and dependency, salvage SRS, salvage whole-brain radiotherapy, salvage neurosurgery, and overall survival. RESULTS: Ninety-three of the 153 patients were private hospital (PH) patients, and 60 were SNH patients. The median follow up time was 7.7 months. SNH patients received fewer follow-up neuroimaging studies (1.5 vs 3; P = .008). In a multivariate analysis, the SNH setting was a significant risk factor for salvage neurosurgery (hazard ratio [HR], 13.65; P < .001), neurologic symptoms (HR, 3.74; P = .002), and hospitalization due to brain metastases (HR, 6.25; P < .001). More clinical visits were protective against hospitalizations due to brain metastases (HR, 0.75; P = .002), whereas more neuroimaging studies were protective against death (HR, 0.65; P < .001). CONCLUSIONS: SNH patients with brain metastases treated with SRS alone had fewer follow-up neuroimaging studies and were at higher risk for neurologic symptoms, hospitalization for brain metastases, and salvage neurosurgery in comparison with PH patients. Clinicians should consider the practice setting and patient access to follow-up care when they are deciding on the optimal strategy for the treatment of brain metastases. Cancer 2018;124:167-75. (c) 2017 American Cancer Society. PMID- 28902401 TI - Variation in the use of active surveillance for low-risk prostate cancer. AB - BACKGROUND: This study assessed the use of active surveillance in men with low risk prostate cancer and evaluated institutional factors associated with the receipt of active surveillance. METHODS: A retrospective, hospital-based cohort of 115,208 men with low-risk prostate cancer diagnosed between 2010 and 2014 was used. Multivariate and mixed effects models were used to examine variation and factors associated with active surveillance. RESULTS: During the study period, the use of active surveillance increased from 6.8% in 2010 to 19.9% in 2014 (estimated annual percentage change, +28.8%; 95% confidence interval [CI], + 19.6% to + 38.7%; P = .002). The adjusted probability of active-surveillance receipt by institution was highly variable. Compared with patients treated at comprehensive community cancer centers, patients treated at community cancer programs (odds ratio [OR], 2.00; 95% CI, 1.50-2.67; P < .001) and academic institutions (OR, 2.47; 95%, CI, 1.81-3.37; P < .001) had higher odds of receiving active surveillance. Compared with patients treated at very low-volume facilities, patients treated at very high-volume facilities had higher odds of receiving active surveillance (OR, 3.57; 95% CI, 1.94-6.55; P < .001). Patient and hospital characteristics accounted for 60.2% of the overall variation, whereas the treating institution accounted for 91.5% of the unexplained variability. CONCLUSIONS: Within this hospital-based cohort, the use of active surveillance for low-risk prostate cancer increased significantly over time. Significant variation was found in the use of active surveillance. Most of the variation was attributable to facility-related factors such as the facility type, facility volume, and institution. Policies to achieve consistent and higher rates of active surveillance, when appropriate, should be a priority of professional societies and patient advocacy groups. Cancer 2018;124:55-64. (c) 2017 American Cancer Society. PMID- 28902403 TI - S-nitrosylation/denitrosylation as a regulatory mechanism of salt stress sensing in sunflower seedlings. AB - Nitric oxide (NO) and various reactive nitrogen species produced in cells in normal growth conditions, and their enhanced production under stress conditions are responsible for a variety of biochemical aberrations. The present findings demonstrate that sunflower seedling roots exhibit high sensitivity to salt stress in terms of nitrite accumulation. A significant reduction in S-nitrosoglutathione reductase (GSNOR) activity is evident in response to salt stress. Restoration of GSNOR activity with dithioerythritol shows that the enzyme is reversibly inhibited under conditions of 120 mM NaCl. Salt stress-mediated S-nitrosylation of cytosolic proteins was analyzed in roots and cotyledons using biotin-switch assay. LC-MS/MS analysis revealed opposite patterns of S-nitrosylation in seedling cotyledons and roots. Salt stress enhances S-nitrosylation of proteins in cotyledons, whereas roots exhibit denitrosylation of proteins. Highest number of proteins having undergone S-nitrosylation belonged to the category of carbohydrate metabolism followed by other metabolic proteins. Of the total 61 proteins observed to be regulated by S-nitrosylation, 17 are unique to cotyledons, 4 are unique to roots whereas 40 are common to both. Eighteen S nitrosylated proteins are being reported for the first time in plant systems, including pectinesterase, phospholipase d-alpha and calmodulin. Further physiological analysis of glyceraldehyde-3-phosphate dehydrogenase and monodehydroascorbate reductase showed that salt stress leads to a reversible inhibition of both these enzymes in cotyledons. However, seedling roots exhibit enhanced enzyme activity under salinity stress. These observations implicate the role of S-nitrosylation and denitrosylation in NO signaling thereby regulating various enzyme activities under salinity stress in sunflower seedlings. PMID- 28902404 TI - Quality of life after surgery for intracranial meningioma. AB - BACKGROUND: To the authors' knowledge, limited data exist regarding long-term quality of life (QOL) for patients diagnosed with intracranial meningioma. METHODS: The data in the current study concerned 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013, and 1622 controls who were frequency matched to the cases by age, sex, and geography. These individuals were participants in a large, population-based, case-control study. Telephone interviews were used to collect data regarding QOL at the time of initial diagnosis or contact, using the Medical Outcomes Study Short-Form 36 Health Survey. QOL outcomes were compared by case/control status. RESULTS: Patients diagnosed with meningioma reported levels of physical, emotional, and mental health functioning below those reported in a general healthy population. Case participants and controls differed most significantly with regard to the domains of Physical and Social Functioning, Role-Physical, Role-Emotional, and Vitality. CONCLUSIONS: In the current study, patients with meningioma experienced statistically significant decreases in QOL compared with healthy controls of a similar demographic breakdown, although these differences were found to vary in clinical significance. Cancer 2018;124:161-6. (c) 2017 American Cancer Society. PMID- 28902405 TI - Preparation and characterization of Dendrobium officinale powders through superfine grinding. AB - BACKGROUND: Dendrobium officinale has been used in China for several thousand years as a health food and has become one of the most expensive tea materials worldwide as a result of extremely scarce resources in the wild and an increasing demand. Hence, it is very important to improve the depth and width of its application. In the present study, the physico-chemical, surface chemistry and thermal properties of micron range particles and coarse particles prepared by superfine grinding and shear pulverization were investigated. RESULTS: As the particle size decreased, the specific surface area of D. officinale powders increased significantly. Microscopy observations confirmed that superfine grinding effectively changed the original structure of D. officinale. The Fourier transform infrared spectroscopy spectra depicted the characteristic bands shifted in terms of absorbance and/or wave number as the powder particle size decreased. The crystallinity and intensity of the crystal peaks of D. officinale powders increased as the particle size decreased. Moisture sorption isotherms suggested that superfine powders were more unstable as a result of the increase in surface area, as well as the exposure of polar groups. CONCLUSION: The results of the present study suggest that superfine grinding may provide new methods of processing for D. officinale with respect to further enhancement of its application value. (c) 2017 Society of Chemical Industry. PMID- 28902406 TI - Genetic and epigenetic insights into uveal melanoma. AB - Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to exam the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifications and signaling pathways as well as possible biomarkers in UM. In addition, different research models for UM are discussed. New insights and major challenges are outlined in order to evaluate the current status for this potentially devastating disease. PMID- 28902407 TI - TRPC6 expression in neurons is differentially regulated by NR2A- and NR2B containing NMDA receptors. AB - The expression of transient receptor potential canonical 6 (TRPC6) in central nervous system (CNS) is important for neuronal functions and certain neural disorders. However, the regulatory mechanism of TRPC6 expression in neurons is still obscure. In this study, we show that TRPC6 expression in the primary cultured cortical neurons is bidirectionally regulated by glutamate. Activation of NR2A-containing NMDARs induces TRPC6 transcription through a calcineurin dependent pathway. In contrast, activation of NR2B-containing NMDARs causes TRPC6 degradation through calpain. Thus, TRPC6 expression in neurons is regulated by glutamate in a bidirectional manner that is dependent on NR2A and NR2B. PMID- 28902408 TI - Inhibition of influenza virus replication by adlay tea. AB - BACKGROUND: The present study was conducted aiming to examine the antiviral activity of adlay tea and its components against influenza viruses. We further aimed to clarify the mechanism by which these components regulate virus replication. RESULTS: Adlay tea at a concentration suitable for drinking inhibited the multiplication of influenza viruses. Moreover, our results suggest that individual components of the tea had antiviral activities against the influenza A/PR/8/34 virus. Adlay tea inhibited multiplication of the H1N1, H3N2 and B types of influenza virus, including oseltamivir-resistant viruses. In addition, adlay tea inhibited influenza infection during the periods of virus adsorption to the cell and virus replication. Adlay tea did not suppress hemagglutination inhibition or cell fusion, although it slightly inhibited virus binding to Malin Darby canine kidney cells. Furthermore, our findings suggest that the antiviral compounds included in adlay tea were ingredients other than polyphenols and that there were several types of effective compounds in adlay tea inhibiting several steps of viral replication. CONCLUSION: The results of the present study demonstrate that adlay tea had antiviral effects against influenza viruses. Our findings with respect to adlay tea suggest that the polyphenols might have a small influence on its antiviral activity and that other ingredients might have more influence. (c) 2017 Society of Chemical Industry. PMID- 28902409 TI - Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia. AB - Vascular cognitive impairment and dementia (VCID) is a major public health concern because of the increased incidence of vascular disease in the aging population and the impact of vascular disease on Alzheimer's disease. VCID is a heterogeneous group of diseases for which there are no proven treatments. Biomarkers can be used to select more homogeneous populations. Small vessel disease is the most prevalent form of VCID and is the optimal form for treatment trials because there is a progressive course with characteristic pathological changes. Subcortical ischemic vascular disease of the Binswanger type (SIVD-BD) has a characteristic set of features that can be used both to identify patients and to follow treatment. SIVD-BD patients have clinical, neuropsychological, cerebrospinal fluid (CSF) and imaging features that can be used as biomarkers. No one feature is diagnostic, but a multimodal approach defines the SIVD-BD spectrum disorder. The most important features are large white matter lesions with axonal damage, blood-brain barrier disruption as shown by magnetic resonance imaging and CSF, and neuropsychological evidence of executive dysfunction. We have used these features to create a Binswanger Disease Scale and a probability of SIVD-BD, using a machine-learning algorithm. The patients discussed in this review are derived from published studies. Biomarkers not only aid in early diagnosis before the disease process has progressed too far for treatment, but also can indicate response to treatment. Refining the use of biomarkers will allow dementia treatment to enter the era of precision medicine. This article is part of the Special Issue "Vascular Dementia". PMID- 28902410 TI - Monascus-fermented red mold dioscorea protects mice against alcohol-induced liver injury, whereas its metabolites ankaflavin and monascin regulate ethanol-induced peroxisome proliferator-activated receptor-gamma and sterol regulatory element binding transcription factor-1 expression in HepG2 cells. AB - BACKGROUND: Alcoholic hepatitis is a necroinflammatory process that is associated with fibrosis and leads to cirrhosis in 40% of cases. The hepatoprotective effects of red mold dioscorea (RMD) from Monascus purpureus NTU 568 were evaluated in vivo using a mouse model of chronic alcohol-induced liver disease (ALD). RESULTS: ALD mice were orally administered vehicle (ALD group) or vehicle plus 307.5, 615.0 or 1537.5 mg kg-1 (1 *, 2 * and 5 *) RMD for 5 weeks. RMD lowered serum leptin, hepatic total cholesterol, free fatty acid and hepatic triglyceride levels and increased serum adiponectin, hepatic alcohol dehydrogenase and antioxidant enzyme levels. Furthermore, ankaflavin (AK) and monascin (MS), metabolites of RMD fermented with M. purpureus 568, induced peroxisome proliferator-activated receptor-gamma expression and the concomitant suppression of ethanol-induced elevation of sterol regulatory element-binding transcription factor-1 and TG in HepG2 cells. CONCLUSION: These results indicate the hepatoprotective effect of Monascus-fermented RMD. Moreover, AK and MS were identified as the active constituents of RMD for the first time and were shown to protect against ethanol-induced liver damage. (c) 2017 Society of Chemical Industry. PMID- 28902411 TI - Functional changes in the neural retina occur in the absence of mitochondrial dysfunction in a rodent model of diabetic retinopathy. AB - Diabetic retinopathy is a neurovascular diabetes complication resulting in vision loss. A wealth of literature reports retinal molecular changes indicative of neural deficits, inflammation, and vascular leakage with chronic diabetes, but the mechanistic causes of disease initiation and progression are unknown. Microvascular mitochondrial DNA (mtDNA) damage leading to mitochondrial dysfunction has been proposed to drive vascular dysfunction in retinopathy. However, growing evidence suggests that neural retina dysfunction precedes and may cause vascular damage. Therefore, we tested the hypothesis that neural mtDNA damage and mitochondrial dysfunction are an early initiating factor of neural diabetic retinopathy development in a rat streptozotocin-induced, Type I diabetes model. Mitochondrial function (oxygen consumption rates) was quantified in retinal synaptic terminals from diabetic and non-diabetic rats with paired retinal structural and function assessment (optical coherence tomography and electroretinography, respectively). Mitochondrial genome damage was assessed by identifying mutations and deletions across the mtDNA genome by high depth sequencing and absolute mtDNA copy number counting through digital PCR. Mitochondrial protein expression was assessed by targeted mass spectrometry. Retinal functional deficits and neural anatomical changes were present after 3 months of diabetes and prevented/normalized by insulin treatment. No marked dysfunction of mitochondrial activity, maladaptive changes in mitochondrial protein expression, alterations in mtDNA copy number, or increase in mtDNA damage was observed in conjunction with retinal functional and anatomical changes. These results demonstrate that neural retinal dysfunction with diabetes begins prior to mtDNA damage and dysfunction, and therefore retinal neurodegeneration initiation with diabetes occurs through other, non-mitochondrial DNA damage, mechanisms. PMID- 28902413 TI - Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. AB - Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. PMID- 28902414 TI - Genome-wide identification, classification and expression analysis of the serine carboxypeptidase-like protein family in poplar. AB - Previous studies have shown that the serine carboxypeptidase-like (SCPL) proteins in several plants play a key part in plant growth, development and stress responses. However, little is known about the functions of the SCPL genes in poplar. We identified 57 SCPL genes and divided into 3 subfamilies, which were unevenly distributed on 19 poplar chromosomes. Gene structure indicated that SCPL genes contain more introns, and motifs of each subfamily were relatively conserved. There were a total of 14 pairs of paralogs, with 6 pairs of these paralogs generated by segmental duplication and 1 generated by tandem duplication. In microsynteny analysis, large-scale duplication events played a key part in the expansion of Carboxypeptidase III genes. Expression of these genes was higher in mature leaf. Quantitative real-time PCR showed that majority of the SCPL genes were induced by methyl jasmonate (MeJA) treatment. PtSCPL27 and PtSCPL40 were located on the cytomembrane by conducting subcellular localization analysis. Our paper provides a theoretical basis for further functional research of PtSCPL genes and will benefit the molecular breeding for resistance to disease in poplar. PMID- 28902415 TI - Surgical treatment of peri-implantitis: Prognostic indicators of short-term results. AB - AIM: To evaluate the clinical and radiographic short-term (6 months) effect of surgical treatment of peri-implantitis, and to identify prognostic indicators affecting the outcome using a multilevel statistical model. MATERIALS & METHODS: A total of 143 implants (45 patients) with a diagnosis of progressive peri implantitis (progressive bone loss (PBL) >=2.0 mm and bleeding on probing (BoP)/suppuration) received surgical treatment. Clinical and radiographic parameters were assessed 6 months postoperatively. Potential prognostic indicators on subject, implant and site level prior to surgery were analysed to evaluate the effect on individual and composite outcomes using multilevel logistic regression analysis. RESULTS: At the 6-month evaluation, none of the implants demonstrated PBL and 14% of the implants were registered with the absence of bleeding and no pocket probing depth >=6 mm. Multilevel regression analysis identified, among others, suppuration, pocket probing depth >8 mm, bone loss >7 mm and the presence of plaque as criteria associated with the outcome. CONCLUSION: Resective peri-implantitis surgery seemed to reduce the amount of peri-implant inflammation. However, most of the sites continued to have BoP/suppuration. Thus, long-term maintenance and evaluation is warranted. The effect of treatment was reduced by some prognostic indicators such as the presence of suppuration prior to interception and peri-implant bone loss exceeding 7 mm. PMID- 28902412 TI - Interventions for treating tuberculous pericarditis. AB - BACKGROUND: Tuberculous pericarditis can impair the heart's function and cause death; long term, it can cause the membrane to fibrose and constrict causing heart failure. In addition to antituberculous chemotherapy, treatments include corticosteroids, drainage, and surgery. OBJECTIVES: To assess the effects of treatments for tuberculous pericarditis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (27 March 2017); the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2017, Issue 2); MEDLINE (1966 to 27 March 2017); Embase (1974 to 27 March 2017); and LILACS (1982 to 27 March 2017). In addition we searched the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal using 'tuberculosis' and 'pericard*' as search terms on 27 March 2017. We searched ClinicalTrials.gov and contacted researchers in the field of tuberculous pericarditis. This is a new version of the original 2002 review. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search outputs, evaluated study eligibility, assessed risk of bias, and extracted data; and we resolved any discrepancies by discussion and consensus. One trial assessed the effects of both corticosteroid and Mycobacterium indicus pranii treatment in a two-by-two factorial design; we excluded data from the group that received both interventions. We conducted fixed-effect meta-analysis and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Seven trials met the inclusion criteria; all were from sub-Saharan Africa and included 1959 participants, with 1051/1959 (54%) HIV-positive. All trials evaluated corticosteroids and one each evaluated colchicine, M. indicus pranii immunotherapy, and open surgical drainage. Four trials (1841 participants) were at low risk of bias, and three trials (118 participants) were at high risk of bias.In people who are not infected with HIV, corticosteroids may reduce deaths from all causes (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.09; 660 participants, 4 trials, low certainty evidence) and the need for repeat pericardiocentesis (RR 0.85, 95% CI 0.70 to 1.04; 492 participants, 2 trials, low certainty evidence). Corticosteroids probably reduce deaths from pericarditis (RR 0.39, 95% CI 0.19 to 0.80; 660 participants, 4 trials, moderate certainty evidence). However, we do not know whether or not corticosteroids have an effect on constriction or cancer among HIV-negative people (very low certainty evidence).In people living with HIV, only 19.9% (203/1959) were on antiretroviral drugs. Corticosteroids may reduce constriction (RR 0.55, 0.26 to 1.16; 575 participants, 3 trials, low certainty evidence). It is uncertain whether corticosteroids have an effect on all-cause death or cancer (very low certainty evidence); and may have little or no effect on repeat pericardiocentesis (RR 1.02, 0.89 to 1.18; 517 participants, 2 trials, low certainty evidence).For colchicine among people living with HIV, we found one small trial (33 participants) which had insufficient data to make any conclusions about any effects on death or constrictive pericarditis.Irrespective of HIV status, due to very low certainty evidence from one trial, it is uncertain whether adding M. indicus pranii immunotherapy to antituberculous drugs has an effect on any outcome.Open surgical drainage for effusion may reduce repeat pericardiocentesis In HIV-negative people (RR 0.23, 95% CI 0.07 to 0.76; 122 participants, 1 trial, low certainty evidence) but may make little or no difference to other outcomes. We did not find an eligible trial that assessed the effects of open surgical drainage in people living with HIV.The review authors found no eligible trials that examined the length of antituberculous treatment needed nor the effects of other adjunctive treatments for tuberculous pericarditis. AUTHORS' CONCLUSIONS: For HIV-negative patients, corticosteroids may reduce death. For HIV-positive patients not on antiretroviral drugs, corticosteroids may reduce constriction. For HIV-positive patients with good antiretroviral drug viral suppression, clinicians may consider the results from HIV-negative patients more relevant.Further research may help evaluate percutaneous drainage of the pericardium under local anaesthesia, the timing of pericardiectomy in tuberculous constrictive pericarditis, and new antibiotic regimens. PMID- 28902416 TI - Ross D. Crosby: Scholar, teacher, mentor, and friend. Introducing a virtual issue honoring the contributions of Ross D. Crosby to the field of eating disorders. PMID- 28902417 TI - Genetic variants related to disease susceptibility and immunotolerance in the Duffy antigen receptor for chemokines (DARC, Fy) gene in the black lion tamarin (Leontopithecus chrysopygus, primates). AB - The DARC (Duffy antigen receptor for chemokines) gene encodes the DARC protein, which serves multiple roles in the immune system, as a binding site for the malarial parasites Plasmodium vivax and Plasmodium knowlesi, a promiscuous chemokine receptor and a blood group antigen. Variation in DARC may play particularly significant roles in innate immunity, immunotolerance and pathogen entry in callitrichines, such as the black lion tamarin (Leontopithecus chrysopygus). We compared amino acid sequences of DARC in the black lion tamarin (BLT) to non-human Haplorhine primates and Homo sapiens. Consistent with prior studies in other Haplorhines, we observed that the chemokine receptor experiences two opposing selection forces: (1) positive selection on the Plasmodium binding site and (2) purifying selection. We observed also that D21N, F22L, and V25L differentiated BLT from humans at a critical site for P. vivax and P. knowlesi binding. One amino acid residue, F22L, was subject to both positive selection and fixation in New World monkeys, suggesting a beneficial role as an adaptive barrier to Plasmodium entry. Unlike in humans, we observed no variation in DARC among BLTs, suggesting that the protein does not play a role in immunotolerance. In addition, lion tamarins differed from humans at the blood compatibility Fya /Fyb antigen-binding site 44, as well as at the putative destabilizing residues A61, T68, A187, and L215, further supporting a difference in the functional role of DARC in these primates compared with humans. Further research is needed to determine whether changes in the Plasmodium and Fya /Fyb antigen-binding sites disrupt DARC function in callitrichines. PMID- 28902418 TI - Cloninger's Temperament and Character Dimensions of Personality and Binge Drinking Among College Students. AB - BACKGROUND: Temperament and character dimensions of personality remain largely unexplored in young adults exhibiting binge drinking (BD) patterns. Moreover, the available studies do not consider gender differences and dismiss possible personality heterogeneity among binge drinkers. In this study, we aimed to compare temperament and character dimensions between young binge drinkers and age and sex-matched social drinkers. We further applied cluster analysis to investigate the potential heterogeneity of personality patterns among BD college students. METHODS: This study included 200 university students of 18 to 24 years of age, who were recruited via an invitation to take an alcohol use survey. These participants included 100 individuals (50 females and 50 males) with a BD pattern, and 100 participants (50 females and 50 males) with a social drinking (SD) pattern. These subjects were evaluated with regard to their use of alcohol and other substances, impulsiveness, sensation seeking, mood, and Cloninger's Temperament and Character Inventory. RESULTS: Between-group comparisons revealed that both male and female binge drinkers were characterized by high levels of novelty seeking, and low levels of persistence and self-directedness. However, cluster analyses within the binge drinker group revealed 2 distinct groups that differed between males and females. These groups shared similarities with Cloninger's type I (high harm-avoidance) and II (high novelty-seeking) alcoholism typology. CONCLUSIONS: The present findings support the subdivision of binge drinkers according to gender and personality dimensions. Male and female binge drinkers should not be considered a unitary group, but rather a population of individuals that encompasses at least 2 distinct personality patterns. These findings have major implications for prevention and treatment approaches. PMID- 28902419 TI - Reassessing the safety concerns of utilizing blood donations from patients with hemochromatosis. AB - Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism that may lead to iron overload. Clinical penetrance is low, however those afflicted may develop cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy. Treatment of HH involves regular phlebotomy to reduce the systemic iron burden. In many countries-including the United States-numerous blood centers do not accept donated blood obtained from HH patients during therapeutic phlebotomy and there are inconsistent positions regarding this globally. This refusal of blood is borne out of a few concerns. First, there is a theoretical increase in the infectious risk of these blood products, particularly by siderophilic organisms such as Yersinia enterocolitica. Second, given the increased incidence of hepatitis C infection from nonvoluntary donors in the 1970s, there is a concern that blood units from HH donors may harbor additional risk given the nonvoluntary nature of their presentation. In this review, we examine the existing biological and clinical data concerning infectious risk and summarize clinical experience from centers allowing HH donors, and demonstrate that blood from HH patients is safe and should be allowed into the donor pool. We conclude that there is no convincing evidence to exclude this population from serving as blood donors. (Hepatology 2018;67:1150-1157). PMID- 28902420 TI - One-piece zirconia oral implants for single-tooth replacement: Three-year results from a long-term prospective cohort study. AB - AIM: This 3-year report of a prospective long-term cohort investigation aimed to evaluate the clinical and radiographic outcomes of a one-piece zirconia oral implant for single-tooth replacement. MATERIALS AND METHODS: Sixty-five patients received a 1-stage implant surgery with immediate temporization. Standardized radiographs were taken at implant insertion, after 1 year, and after 3 years to monitor peri-implant bone levels. A univariate analysis of the association of different baseline parameters on marginal bone loss from implant insertion to 36 months was performed. Soft-tissue parameters were evaluated at prosthesis insertion, after 6 months, after 1 year, and at the 3-year follow-up. RESULTS: After 3 years, six posterior site implants were lost, giving a cumulative survival rate of 90.8%. The mean marginal bone loss was 1.45 mm; 35% of the implants lost at least 2 mm bone, and 22% more than 3 mm. The univariate analysis did not identify any parameter associated with marginal bone loss. Probing depth, clinical attachment level, and bleeding index increased over 3 years, and plaque index decreased. CONCLUSIONS: The low survival rate of the presented ceramic implant and especially the high frequency of advanced bone loss are noticeable but remain unexplained. PMID- 28902421 TI - The impact of white matter fiber orientation in single-acquisition quantitative susceptibility mapping. AB - The aim of this work was to assess the impact of tissue structural orientation on quantitative susceptibility mapping (QSM) reliability, and to provide a criterion to identify voxels in which measures of magnetic susceptibility (chi) are most affected by spatial orientation effects. Four healthy volunteers underwent 7-T magnetic resonance imaging (MRI). Multi-echo, gradient-echo sequences were used to obtain quantitative maps of frequency shift (FS) and chi. Information from diffusion tensor imaging (DTI) was used to investigate the relationship between tissue orientation and FS measures and QSM. After sorting voxels on the basis of their fractional anisotropy (FA), the variations in FS and chi values over tissue orientation were measured. Using a K-means clustering algorithm, voxels were separated into two groups depending on the variability of measures within each FA interval. The consistency of FS and QSM values, observed at low FA, was disrupted for FA > 0.6. The standard deviation of chi measured at high FA (0.0103 ppm) was nearly five times that at low FA (0.0022 ppm). This result was consistent through data across different head positions and for different brain regions considered separately, which confirmed that such behavior does not depend on structures with different bulk susceptibility oriented along particular angles. The reliability of single-orientation QSM anticorrelates with local FA. QSM provides replicable values with little variability in brain regions with FA < 0.6, but QSM should be interpreted cautiously in major and coherent fiber bundles, which are strongly affected by structural anisotropy and magnetic susceptibility anisotropy. PMID- 28902422 TI - Transplantation of Noncultured Stromal Vascular Fraction Cells of Adipose Tissue Ameliorates Osteonecrosis of the Jaw-Like Lesions in Mice. AB - The precise pathoetiology and effective treatment strategies for bisphosphonate related osteonecrosis of the jaw (BRONJ) remain unknown. Transplantation of noncultured stromal vascular fraction (SVF) cells has been shown to be a useful method for regenerative medicine in place of stem cell therapy. This study investigated the effects of noncultured SVF transplantation on tooth extraction socket healing in mice. Both chemotherapeutic/bisphosphonate combination therapy for 7 weeks and tooth extraction of maxillary first molars at 3 weeks after drug administration were performed using female C57BL/6J mice. Osseous and soft tissue wound healing were validated at 4 weeks postextraction using gross wound healing and histomorphometry. Here, we created a new animal model of high-prevalence ONJ like lesions that mimic human progression, because human ONJ mainly occurs in female patients taking both chemotherapeutic and bisphosphonate following tooth extraction. Moreover, mice with chemotherapeutic and bisphosphonate combination therapy for 5 weeks received SVF transplantation just after tooth extraction at 3 weeks post-drug administration. Euthanasia was performed at 2 weeks postextraction to assess the transplantation effects on wound healing using gross wound healing, histomorphometry, immunohistomorphometry, quantitative real-time polymerase chain reaction, and microcomputed tomography. We showed that systemic transplantation of noncultured SVF cells ameliorates ONJ-like lesions by improving both osseous and soft tissue healing of tooth extraction sockets. SVF therapy significantly increased blood vessels and the ratio of M2/M1 macrophages. In addition, SVF transplantation reduced the increases in tartrate-resistant acid phosphatase-positive (TRAP+ ) mononuclear cells (MNCs) and nonattached osteoclasts from the bone surface, which were significantly detected in the connective tissue of tooth extraction sockets and bone marrow by chemotherapeutic/bisphosphonate combination therapy. Our findings suggest that transplantation of noncultured SVF cells is a suitable treatment for BRONJ. Abnormal TRAP+ MNCs and nonattached osteoclasts in systemic and local environments may contribute to the development of BRONJ. (c) 2017 American Society for Bone and Mineral Research. PMID- 28902423 TI - Partitioning k-space for cylindrical three-dimensional rapid acquisition with relaxation enhancement imaging in the mouse brain. AB - Three-dimensional rapid acquisition with relaxation enhancement (RARE) scans require the assignment of each phase encode step in two dimensions to an echo in the echo train. Although this assignment is frequently made across the entire Cartesian grid, collection of only the central cylinder of k-space by eliminating the corners in each phase encode dimension reduces the scan time by ~22% with negligible impact on image quality. The recipe for the assignment of echoes to grid points for such an acquisition is less straightforward than for the simple full Cartesian acquisition case, and has important implications for image quality. We explored several methods of partitioning k-space-exploiting angular symmetry in one extreme or emulating a cropped Cartesian acquisition in the other and acquired three-dimensional RARE magnetic resonance imaging (MRI) scans of the ex vivo mouse brain. We evaluated each partitioning method for sensitivity to artifacts and then further considered strategies to minimize these through averaging or interleaving of echoes and by empirical phase correction. All scans were collected 16 at a time with multiple-mouse MRI. Although all schemes considered could be used to generate images, the results indicate that the emulation of a standard Cartesian echo assignment, by partitioning preferentially along one dimension within the cylinder, is more robust to artifacts. Samples at the periphery of the bore showed larger phase deviations and higher sensitivity to artifacts, but images of good quality could still be obtained with an optimized acquisition protocol. A protocol for high-resolution (40 MUm) ex vivo images using this approach is presented, and has been used routinely with a success rate of 99% in over 1000 images. PMID- 28902424 TI - Anatomy and evolution of database search engines-a central component of mass spectrometry based proteomic workflows. AB - Sequence database search engines are bioinformatics algorithms that identify peptides from tandem mass spectra using a reference protein sequence database. Two decades of development, notably driven by advances in mass spectrometry, have provided scientists with more than 30 published search engines, each with its own properties. In this review, we present the common paradigm behind the different implementations, and its limitations for modern mass spectrometry datasets. We also detail how the search engines attempt to alleviate these limitations, and provide an overview of the different software frameworks available to the researcher. Finally, we highlight alternative approaches for the identification of proteomic mass spectrometry datasets, either as a replacement for, or as a complement to, sequence database search engines. PMID- 28902425 TI - Efficient Catalytic Microreactors with Atomic-Layer-Deposited Platinum Nanoparticles on Oxide Support. AB - Microreactors attract a significant interest for chemical synthesis due to the benefits of small scales such as high surface to volume ratio, rapid thermal ramping, and well-understood laminar flows. The suitability of atomic layer deposition for application of both the nanoparticle catalyst and the support material on the surfaces of channels of microfabricated silicon microreactors is demonstrated in this research. Continuous-flow hydrogenation of propene into propane at low temperatures with TiO2 -supported catalytic Pt nanoparticles was used as a model reaction. Reaction yield and mass transport were monitored by high-sensitivity microcoil NMR spectroscopy as well as time-of-flight remote detection NMR imaging. The microreactors were shown to be very efficient in propene conversion into propane. The yield of 100 % was achieved at 50 degrees C with a reactor decorated with Pt nanoparticles of average size of roughly 1 nm and surface coverage of 3.2 % in 20 mm long reaction channels with a residence time of 1100 ms. The activity of the Pt catalyst surfaces was on the order of several to tens of mmol s-1 m-2 . PMID- 28902426 TI - Surgical treatment of peri-implantitis: 3-year results from a randomized controlled clinical trial. AB - OBJECTIVES: This study reports on the 3-year follow-up of patients enrolled in a randomized controlled clinical trial on surgical treatment of advanced peri implantitis. MATERIAL AND METHODS: A total of 100 patients with advanced peri implantitis were randomly assigned to one of four treatment groups. Surgical therapy aiming at pocket elimination was performed and, in three test groups, supplemented by either systemic antibiotics, use of an antiseptic agent for implant surface decontamination or both. Outcomes were evaluated after 1 and 3 years by means of clinical and radiological examinations. Differences between groups were explored by regression analysis. RESULTS: Clinical examinations at 3 years after treatment revealed (i) improved peri-implant soft tissue health with a mean reduction in probing depth of 2.7 mm and a reduction in bleeding/suppuration on probing of 40% and (ii) stable peri-implant marginal bone levels (mean bone loss during follow-up: 0.04 mm). Implant surface characteristics had a significant impact on 3-year outcomes, in favour of implants with non-modified surfaces. Benefits of systemic antibiotics were limited to implants with modified surfaces and to the first year of follow-up. CONCLUSION: It is suggested that surgical treatment of peri-implantitis is effective and that outcomes of therapy are affected by implant surface characteristics. Potential benefits of systemic antibiotics are not sustained over 3 years. PMID- 28902427 TI - NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL-17 and TNF in mice. AB - : The NLRP3 inflammasome, a caspase-1 activation platform, plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL-17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis, gain-of-function Nlrp3A350V knock-in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL-17 or TNF. Livers of Nlrp3A350V knock-in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of chemokine (C-X-C motif) ligand (CXCL) 1 and CXCL2 chemokines, activated inflammatory macrophages, and elevated levels of IL-17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3A350V mutants, but still significant inflammatory changes when compared to the nonmutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL-1beta levels. Intact Nlrp3A350V mutants showed changes in liver fibrosis, as evidenced by morphometric quantitation of Sirius Red staining and increased mRNA levels of profibrotic genes, including connective tissue growth factor and tissue inhibitor of matrix metalloproteinase 1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, whereas Tnf-deficient mutants showed no signs of fibrosis when compared to littermate controls. CONCLUSION: Our study uncovers key roles for TNF and, to a lesser extent, IL-17 as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid derived cells. These findings may lead to therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogeneses driven by NLRP3 activation. (Hepatology 2017). PMID- 28902428 TI - Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease. AB - : Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1. CONCLUSION: Several variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710-1725). PMID- 28902429 TI - Chirality sensing with stereodynamic copper(I) complexes. AB - Three Cu(I) complexes derived from stereodynamic diphosphine ligands were synthesized and used for chirality sensing. The coordination of diamines and amino acids to these complexes generates distinct circular dichroism signals. The chiroptical sensor response allows determination of the absolute configuration and the enantiomeric excess of the analyte at low concentrations. This method is operationally simple, fast, and attractive for high-throughput sensing applications. PMID- 28902431 TI - Cardiovascular predictors of death in patients with cirrhosis. AB - : Cirrhotic cardiomyopathy is associated with poor outcomes in patients with cirrhosis. We investigated if subclinical cardiac morphologic and functional modifications can influence survival in patients with cirrhosis during follow-up. A series of patients with cirrhosis without cardiovascular or pulmonary disease underwent standard and tissue Doppler echocardiography to assess left ventricular geometry, systolic/diastolic function, and the main haemodynamic parameters. After baseline evaluation 115 patients with cirrhosis were followed up for at least 6 years. During follow-up 54 patients died (47%). On univariate analysis, age, body surface area (BSA), Model for End-Stage Liver Disease (MELD), mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, and the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e) were associated with increased risk of death. In a Cox hazard regression analysis including these factors and other hypothesized important factors (but not MELD), increased age (P = 0.04) and left atrial dimension (P = 0.005) and lower BSA (P = 0.03) were the strongest predictors of death. When MELD was included in the analysis, the main predictors were MELD, age, and BSA. When multivariate analysis was performed incorporating only cardiovascular parameters, increased E/e (P = 0.003) and heart rate (P = 0.03) and reduced mean blood pressure (P = 0.01) were significantly associated with poor prognosis. CONCLUSION: In a large cohort of patients with cirrhosis and after a long follow-up, MELD, age, and BSA were the main predictors of death; among cardiovascular parameters, left atrium enlargement, increased heart rate and E/e, and reduced mean blood pressure were independent predictors of death. (Hepatology 2018). PMID- 28902430 TI - Reduced Serum IGF-1 Associated With Hepatic Osteodystrophy Is a Main Determinant of Low Cortical but Not Trabecular Bone Mass. AB - Hepatic osteodystrophy is multifactorial in its pathogenesis. Numerous studies have shown that impairments of the hepatic growth hormone/insulin-like growth factor-1 axis (GH/IGF-1) are common in patients with non-alcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and chronic cholestatic liver disease. Moreover, these conditions are also associated with low bone mineral density (BMD) and greater fracture risk, particularly in cortical bone sites. Hence, we addressed whether disruptions in the GH/IGF-1 axis were causally related to the low bone mass in states of chronic liver disease using a mouse model of liver-specific GH-receptor (GHR) gene deletion (Li-GHRKO). These mice exhibit chronic hepatic steatosis, local inflammation, and reduced BMD. We then employed a crossing strategy to restore liver production of IGF-1 via hepatic IGF 1 transgene (HIT). The resultant Li-GHRKO-HIT mouse model allowed us to dissect the roles of liver-derived IGF-1 in the pathogenesis of osteodystrophy during liver disease. We found that hepatic IGF-1 restored cortical bone acquisition, microarchitecture, and mechanical properties during growth in Li-GHRKO-HIT mice, which was maintained during aging. However, trabecular bone volume was not restored in the Li-GHRKO-HIT mice. We found increased bone resorption indices in vivo as well as increased basal reactive oxygen species and increased mitochondrial stress in osteoblast cultures from Li-GHRKO and the Li-GHRKO-HIT compared with control mice. Changes in systemic markers such as inflammatory cytokines, osteoprotegerin, osteopontin, parathyroid hormone, osteocalcin, or carboxy-terminal collagen cross-links could not fully account for the diminished trabecular bone in the Li-GHRKO-HIT mice. Thus, the reduced serum IGF-1 associated with hepatic osteodystrophy is a main determinant of low cortical but not trabecular bone mass. (c) 2017 American Society for Bone and Mineral Research. PMID- 28902432 TI - C1q/TNF-related protein 9 improves the anti-contractile effects of perivascular adipose tissue via the AMPK-eNOS pathway in diet-induced obese mice. AB - The anti-contractile property of perivascular adipose tissue (PVAT) is abolished through an endothelium-dependent pathway in obesity. C1q/tumor necrosis factor related protein (CTRP)9 improved endothelial function by promoting endothelium dependent vasodilatation. The aims of this study were to investigate whether CTRP9 improves the anti-contractile effect of PVAT and protects against PVAT dysfunction in obese mice. The mice were treated with a high-fat diet with or without CTRP9 treatment. Thoracic aortas with or without PVAT (PVAT+ or PVAT-) were prepared, and concentration-dependent responses to phenylephrine were measured. Obese mice showed a significantly increased contractile response, which was suppressed by CTRP9 treatment both with and without PVAT. PVAT significantly reduced the anti-contractile effect in obese mice, which was partially restored by CTRP9 treatment. Treatment of the aortic rings (PVAT+) with inhibitors of AMP protein kinase (AMPK), Akt and endothelial nitric oxide synthase (eNOS) attenuated the beneficial effect of CTRP9 on PVAT. Similar results were observed when we pretreated the aortic rings with CTRP9 ex vivo. CTRP9 significantly enhanced the phosphorylation levels of AMPK, Akt and eNOS, and reduced superoxide production and TNF-alpha levels in PVAT from obese mice. Our study suggests that CTRP9 enhanced the anti-contractile effect of PVAT and improved PVAT function by activating the AMPK-eNOS pathway in obese mice. PMID- 28902433 TI - Curcumin alleviates IL-17A-mediated p53-PAI-1 expression in bleomycin-induced alveolar basal epithelial cells. AB - Bleomycin-mediated inflammatory pathway is known to play an important role in the up regulation of oxidative stress. IL-17A is a pro-inflammatory cytokine involved in the modulation of fibrosis. The complex underlying mechanism for the said phenomenon remains unclear. This newly defined investigation was designed to understand the changes associated with 1L-17A mediated up-regulation of p53 and PAI-1 expression and the role of curcumin in attenuating this process. A549 cells were treated with bleomycin (BLM) and IL-17A to induce the inflammatory response in vitro. Curcumin, a known anti-inflammatory bioactive compound was administered as an intervention. Cytotoxicity in the treatment groups was assessed using Methyl thiazolyl tetrazolium (MTT) assay. Cell migration was evaluated using scratch assay. Protein expressions were studied using Western blot analysis for the downstream effector molecules of IL-17A mediated inflammatory pathways. In MTT assay, BLM treatment showed cytotoxicty upto 88% at a concentration of 1000 MUM after 48 h of treatment. Cell migration assay results revealed that curcumin blocked the migration of cells to the area of the scratch. BLM treatment to the cells significantly induced the expression of pro-inflammatory cytokine IL-17A, which in turn modulated p53-PAI-1 expression. Bioactive compound curcumin showed anti-inflammatory and anti-apoptotic activity. Curcumin also regulated the BLM and IL-17A mediated changes in p53-PAI-1 expression. Curcumin has the ability to regulate inflammatory cytokines during BLM-induced injury and their effect on p53 PAI-1 expression. It can be used as a potential anti-inflammatory and anti fibrinolytic component for intervening the epithelial cell damage.Very little information is provided till date on the inflammatory mechanism controlling the fibrinolytic system in acute lung injury (ALI). Damage to alveolar epithelial cells during ALI is important in the development of pulmonary fibrosis (PF). Most forms of ALI are characterized by defective alveolar fibrinolysis, inflammation, and fibrotic lesions. Recent reports show that alveolar epithelial cells express uPA, uPAR, and p53-mediated changes inhibit epithelial cell viability contributing to ALI. Thus, the roles of pulmonary epithelial cells in the inflammatory cascades activated after noninfectious injury, and the key signaling mediators of this process were actively investigated in this study. This investigation revealed that curcumin is an effective inhibitor of BLM-induced inflammation, apoptosis, and migration of basal alveolar epithelial cells. These results throw an insight into the possibility of developing curcumin as a novel therapeutic for ALI. PMID- 28902434 TI - Biologically active quinoline and quinazoline alkaloids part I. AB - Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. PMID- 28902435 TI - Longitudinal Effects of Single Hindlimb Radiation Therapy on Bone Strength and Morphology at Local and Contralateral Sites. AB - Radiation therapy (RTx) is associated with increased risk for late-onset fragility fractures in bone tissue underlying the radiation field. Bone tissue outside the RTx field is often selected as a "normal" comparator tissue in clinical assessment of fragility fracture risk, but the robustness of this comparison is limited by an incomplete understanding of the systemic effects of local radiotherapy. In this study, a mouse model of limited field irradiation was used to quantify longitudinal changes in local (irradiated) and systemic (non irradiated) femurs with respect to bone density, morphology, and strength. BALB/cJ mice aged 12 weeks underwent unilateral hindlimb irradiation (4 * 5 Gy) or a sham procedure. Femurs were collected at endpoints of 4 days before treatment and at 0, 1, 2, 4, 8, 12, and 26 weeks post-treatment. Irradiated (RTx), Contralateral (non-RTx), and Sham (non-RTx) femurs were imaged by micro computed tomography and mechanically tested in three-point bending. In both the RTx and Contralateral non-RTx groups, the longer-term (12- to 26-week) outcomes included trabecular resorption, loss of diaphyseal cortical bone, and decreased bending strength. Contralateral femurs generally followed an intermediate response compared with RTx femurs. Change also varied by anatomic compartment; post-RTx loss of trabecular bone was more profound in the metaphyseal than the epiphyseal compartment, and cortical bone thickness decreased at the mid diaphysis but increased at the metaphysis. These data demonstrate that changes in bone quantity, density, and architecture occur both locally and systemically after limited field irradiation and vary by anatomic compartment. Furthermore, the severity and persistence of systemic bone damage after limited field irradiation suggest selection of control tissues for assessment of fracture risk or changes in bone density after radiotherapy may be challenging. (c) 2017 American Society for Bone and Mineral Research. PMID- 28902436 TI - Neuroprotective effect of amantadine on corticosterone-induced abnormal glutamatergic synaptic transmission of CA3-CA1 pathway in rat's hippocampal slices. AB - Depression is a psychiatric disorder and chronic stress, leading to altered glucocorticoid secretion patterns, is one of the factors that induce depression. Our previous study showed that amantadine significantly attenuated the impairments of synaptic plasticity and cognitive function a rat model of CUS. However, little is known regarding the underlying mechanism. In the present study, the whole-cell patch-clamp technique was applied to examine the protection effect of amantadine on the hippocampus CA3-CA1 pathway. Evoked excitatory postsynaptic currents (eEPSCs), miniature excitatory postsynaptic currents (mEPSCs), paired-pulse ratio (PPR) and the action potentials of CA3 neurons were recorded. Our data showed that corticosterone increased the amplitude of eEPSCs and decreased the value of paired-pulse ratio (PPR), but both of them were significantly reversed by amantadine. In addition, the frequency of mEPSC was considerably increased by corticosterone, but it was reduced by amantadine. Moreover, we used the Fluo-3/AM image to detect the Ca2+ influx in primary cultured hippocampal neurons. The results showed that the intracellular calcium levels were significantly decreased by amantadine in the corticosterone treated neurons. Additionally, the superoxide dismutase (SOD) and catalase (CAT) activities were reduced by corticosterone, while they were enhanced by either amantadine or low-calcium artificial cerebral spinal fluid (ACSF). These results suggest that amantadine significantly improves corticosterone-induced abnormal glutamatergic synaptic transmission of CA3-CA1 synapses presynaptically and alleviates the activities of antioxidant enzymes via regulating the calcium influx. PMID- 28902438 TI - Colony-level behavioural variation correlates with differences in expression of the foraging gene in red imported fire ants. AB - Among social insects, colony-level variation is likely to be widespread and has significant ecological consequences. Very few studies, however, have documented how genetic factors relate to behaviour at the colony level. Differences in expression of the foraging gene have been associated with differences in foraging and activity of a wide variety of organisms. We quantified expression of the red imported fire ant foraging gene (sifor) in workers from 21 colonies collected across the natural range of Texas fire ant populations, but maintained under standardized, environmentally controlled conditions. Colonies varied significantly in their behaviour. The most active colonies had up to 10 times more active foragers than the least active colony and more than 16 times as many workers outside the nest. Expression differences among colonies correlated with this colony-level behavioural variation. Colonies with higher sifor expression in foragers had, on average, significantly higher foraging activity, exploratory activity and recruitment to nectar than colonies with lower expression. Expression of sifor was also strongly correlated with worker task (foraging vs. working in the interior of the nest). These results provide insight into the genetic and physiological processes underlying collective differences in social behaviour. Quantifying variation in expression of the foraging gene may provide an important tool for understanding and predicting the ecological consequences of colony-level behavioural variation. PMID- 28902437 TI - Pyriculins A and B, two monosubstituted hex-4-ene-2,3-diols and other phytotoxic metabolites produced by Pyricularia grisea isolated from buffelgrass (Cenchrus ciliaris). AB - Pyricularia grisea has been identified as a foliar pathogen on buffelgrass (Cenchrus ciliaris) in North America and was studied as a potential source of phytotoxins for buffelgrass control. Two monosubstituted hex-4-ene-2,3-diols, named pyriculins A and B, were isolated from its culture filtrate organic extract together with (10S,11S)-(-)-epipyriculol, trans-3,4-dihydro-3,4,8-trihydroxy 1(2H)-napthalenone, and (4S)-(+)-isosclerone. Pyriculins A and B were characterized by spectroscopic (essentially nuclear magnetic resonance [NMR], High-resolution electrospray ionization mass spectrometry [HRESIMS]) and chemical methods such as (4E)-1-(4-hydroxy-1,3-dihydroisobenzofuran-1-yl)hex-4-ene-2,3 diols. The relative and absolute configuration of these compounds was determined by a combination of spectroscopic (NMR, electronic circular dichroism [ECD]) and computational tools. When bioassayed in a buffelgrass coleoptile and radicle elongation test, (10S,11S)-(-)-epipyriculol proved to be the most toxic compound. Seed germination was much reduced and slowed with respect to the control and radicles failed to elongate. All five compounds delayed germination, but only (10S,11S)-(-)-epipyriculol was able to prevent radicle development of buffelgrass seedlings. It had no effect on coleoptile elongation, while the other four compounds caused significantly increased coleoptile development relative to the control. PMID- 28902439 TI - Promoting mastery of complex biological mechanisms. AB - This article describes efforts aimed at improving comprehension and retention of complex molecular mechanisms commonly studied in undergraduate biology and biochemistry courses. The focus is on the design of appropriate assessments, an active classroom emphasizing formative practice, and more effective out-of-class study habits. Assessments that require students to articulate their understanding through writing are the most effective. Frequent formative practice improves performance on problems that require intellectual transfer, the ability to apply conceptual principles in novel settings. We show that success with such problems is a function of mastery of the intrinsic logic of the biology in play, not variations in the way they are written. Survey data demonstrate that many students would prefer a learning style not dominated by memorization of factual details, but how to develop a more effective strategy is rarely intuitive. Matching individual students with specific learning styles has not proven useful. Instead, teachers can strongly promote individual metacognitive appraisal during both classroom activities and other study environments. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):7-21, 2018. PMID- 28902440 TI - Real-Time Control of the Enantioselectivity of a Supramolecular Catalyst Allows Selecting the Configuration of Consecutively Formed Stereogenic Centers. AB - The enantiomeric state of a supramolecular copper catalyst can be switched in situ in ca. five seconds. The dynamic property of the catalyst is provided by the non-covalent nature of the helical assemblies supporting the copper centers. These assemblies are formed by mixing an achiral benzene-1,3,5-tricarboxamide (BTA) phosphine ligand (for copper coordination) and both enantiomers of a chiral phosphine-free BTA co-monomer (for chirality amplification). The enantioselectivity of the hydrosilylation reaction is fixed by the BTA enantiomer in excess, which can be altered by simple BTA addition. As a result of the complete and fast stereochemical switch, any combination of the enantiomers was obtained during the conversion of a mixture of two substrates. PMID- 28902441 TI - Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States. AB - The study of the oxidative amination of tetrahydroisoquinolines under chiral anion phase-transfer (CAPT) catalysis by multidimensional correlation analysis (MCA) is revisited. The parameterization of the transition states (TSs) for the uncatalyzed reaction, the introduction of conformational descriptors, and the use of computed interaction energies and distances as parameters allowed access to a considerably simplified mathematical correlation of substrate and catalyst structure to enantioselectivity. The equation obtained is suggestive of key interactions occurring at the TS. Specifically, the CAPT catalyst is proposed to coordinate the intermediate iminium cation by P=O???H-O hydrogen-bonding and N???H-C electrostatic interactions. The conformational freedom of the benzyl substituent of the substrate was also found to be important in providing an efficient mode of molecular recognition. PMID- 28902442 TI - Spectroscopic investigations on the conformational changes of lysozyme effected by different sizes of N-acetyl-l-cysteine-capped CdTe quantum dots. AB - The effect of N-acetyl-l-cysteine-capped CdTe quantum dots (NAC-CdTe QDs) with different sizes on lysozyme was investigated by isothermal titration calorimetry (ITC), enzyme activity assays, and multi-spectroscopic methods. ITC results proved that NAC-CdTe QDs can spontaneously bind with lysozyme and hydrophobic force plays a major role in stabilizing QDs-lysozyme complex. Multi-spectroscopic measurements revealed that NAC-CdTe QDs caused strong quenching of the lysozyme's fluorescence in a size-dependent quenching manner. Moreover, the changes of secondary structure and microenvironment in lysozyme caused by the NAC-CdTe QDs were higher with a bigger size. The results of enzyme activity assays showed that the interaction between lysozyme and NAC-CdTe QDs inhibited the activity of lysozyme and the inhibiting effect was in a size-dependent manner. Based on these results, we conclude that NAC-CdTe QDs with larger particle size had a larger impact on the structure and function of lysozyme. PMID- 28902443 TI - Comment on: Redo coloanal anastomosis for anastomotic leakage after low anterior resection for rectal cancer; an analysis of 59 cases. PMID- 28902445 TI - Nutrients and temperature additively increase stream microbial respiration. AB - Rising temperatures and nutrient enrichment are co-occurring global-change drivers that stimulate microbial respiration of detrital carbon, but nutrient effects on the temperature dependence of respiration in aquatic ecosystems remain uncertain. We measured respiration rates associated with leaf litter, wood, and fine benthic organic matter (FBOM) across seasonal temperature gradients before (PRE) and after (ENR1, ENR2) experimental nutrient (nitrogen [N] and phosphorus [P]) additions to five forest streams. Nitrogen and phosphorus were added at different N:P ratios using increasing concentrations of N (~80-650 MUg/L) and corresponding decreasing concentrations of P (~90-11 MUg/L). We assessed the temperature dependence, and microbial (i.e., fungal) drivers of detrital mass specific respiration rates using the metabolic theory of ecology, before vs. after nutrient enrichment, and across N and P concentrations. Detrital mass specific respiration rates increased with temperature, exhibiting comparable activation energies (E, electronvolts [eV]) for all substrates (FBOM E = 0.43 [95% CI = 0.18-0.69] eV, leaf litter E = 0.30 [95% CI = 0.072-0.54] eV, wood E = 0.41 [95% CI = 0.18-0.64] eV) close to predicted MTE values. There was evidence that temperature-driven increased respiration occurred via increased fungal biomass (wood) or increased fungal biomass-specific respiration (leaf litter). Respiration rates increased under nutrient-enriched conditions on leaves (1.32*) and wood (1.38*), but not FBOM. Respiration rates responded weakly to gradients in N or P concentrations, except for positive effects of P on wood respiration. The temperature dependence of respiration was comparable among years and across N or P concentration for all substrates. Responses of leaf litter and wood respiration to temperature and the combined effects of N and P were similar in magnitude. Our data suggest that the temperature dependence of stream microbial respiration is unchanged by nutrient enrichment, and that increased temperature and N + P availability have additive and comparable effects on microbial respiration rates. PMID- 28902444 TI - Genomewide association studies of suicide attempts in US soldiers. AB - Suicide is a global public health problem with particular resonance for the US military. Genetic risk factors for suicidality are of interest as indicators of susceptibility and potential targets for intervention. We utilized population based nonclinical cohorts of US military personnel (discovery: N = 473 cases and N = 9778 control subjects; replication: N = 135 cases and N = 6879 control subjects) and a clinical case-control sample of recent suicide attempters (N = 51 cases and N = 112 control subjects) to conduct GWAS of suicide attempts (SA). Genomewide association was evaluated within each ancestral group (European-, African-, Latino-American) and study using logistic regression models. Meta analysis of the European ancestry discovery samples revealed a genomewide significant locus in association with SA near MRAP2 (melanocortin 2 receptor accessory protein 2) and CEP162 (centrosomal protein 162); 12 genomewide significant SNPs in the region; peak SNP rs12524136-T, OR = 2.88, p = 5.24E-10. These findings were not replicated in the European ancestry subsamples of the replication or suicide attempters samples. However, the association of the peak SNP remained significant in a meta-analysis of all studies and ancestral subgroups (OR = 2.18, 95%CI 1.70, 2.80). Polygenic risk score (PRS) analyses showed some association of SA with bipolar disorder. The association with SNPs encompassing MRAP2, a gene expressed in brain and adrenal cortex and involved in neural control of energy homeostasis, points to this locus as a plausible susceptibility gene for suicidality that should be further studied. Larger sample sizes will be needed to confirm and extend these findings. PMID- 28902446 TI - Proteomics Insights into Autophagy. AB - Autophagy, a conserved cellular process by which cells recycle their contents either to maintain basal homeostasis or in response to external stimuli, has for the past two decades become one of the most studied physiological processes in cell biology. The 2016 Nobel Prize in Medicine and Biology awarded to Dr. Ohsumi Yoshinori, one of the first scientists to characterize this cellular mechanism, attests to its importance. The induction and consequent completion of the process of autophagy results in wide ranging changes to the cellular proteome as well as the secretome. MS-based proteomics affords the ability to measure, in an unbiased manner, the ubiquitous changes that occur when autophagy is initiated and progresses in the cell. The continuous improvements and advances in mass spectrometers, especially relating to ionization sources and detectors, coupled with advances in proteomics experimental design, has made it possible to study autophagy, among other process, in great detail. Innovative labeling strategies and protein separation techniques as well as complementary methods including immuno-capture/blotting/staining have been used in proteomics studies to provide more specific protein identification. In this review, we will discuss recent advances in proteomics studies focused on autophagy. PMID- 28902447 TI - Synthesis of monodisperse silica microspheres and modification with diazoresin for mixed-mode ultra high performance liquid chromatography separations. AB - Monodisperse silica particles with average diameters of 1.9-2.9 MUm were synthesized by a modified Stober method, in which tetraethyl orthosilicate was continuously supplied to the reaction mixture containing KCl electrolyte, water, ethanol, and ammonia. The obtained silica particles were modified by self assembly with positively charged photosensitive diazoresin on the surface. After treatment with ultraviolet light, the ionic bonding between silica and diazoresin was converted into covalent bonding through a unique photochemistry reaction of diazoresin. Depending on the chemical structure of diazoresin and mobile phase composition, the diazoresin-modified silica stationary phase showed different separation mechanisms, including reversed phase and hydrophilic interactions. Therefore, a variety of baseline separation of benzene analogues and organic acids was achieved by using the diazoresin-modified silica particles as packing materials in ultra high performance liquid chromatography. According to the pi-pi interactional difference between carbon rings of fullerenes and benzene rings of diazoresin, C60 and C70 were also well separated by ultra-high performance liquid chromatography. Because it has a small size, the ~2.5 MUm monodisperse diazoresin modified silica stationary phase shows ultra-high efficiency compared with the commercial C18 -silica high-performance liquid chromatography stationary phase with average diameters of ~5 MUm. PMID- 28902448 TI - Synthesis and Biological Evaluation of New Natural Phenolic (2E,4E,6E)-Octa-2,4,6 trienoic Esters. AB - In the present study the esterification of the OH groups of resveratrol, caffeic acid, ferulic acid, and beta-sitosterol with an antioxidant polyconjugated fatty acid, (2E,4E,6E)-octa-2,4,6-trienoic acid, was achieved. As the selective esterification of OH groups of natural compounds can affect their biological activity, a selective esterification of resveratrol and caffeic acid was performed by an enzymatic approach. The new resulting compounds were characterized spectroscopically (FT-IR, NMR mono, and bidimensional techniques); when necessary the experimental data were integrated by quantum chemical calculations. The antioxidant, anti-inflammatory and proliferative activity was evaluated. The good results encourage the use of these molecules as antioxidant and/or anti-inflammatory agents in dermocosmetic application. PMID- 28902449 TI - Enzyme Encapsulation by a Ferritin Cage. AB - Ferritins, conserved across all kingdoms of life, are protein nanocages that evolved to mineralize iron. The last several decades have shown that these cages have considerable technological and medical potential owing to their stability and tolerance to modification, as well as their ability to template nanoparticle synthesis and incorporate small molecules. Here we show that it is possible to encapsulate proteins in a ferritin cage by exploiting electrostatic interactions with its negatively charged interior. Positively supercharged green fluorescent protein is efficiently taken up by Archaeoglobus fulgidus ferritin in a tunable fashion. Moreover, several enzymes were readily incorporated when genetically tethered to this fluorescent protein. These fusion proteins retained high catalytic activity and showed increased tolerance to proteolysis and heat. Equipping ferritins with enzymatic activity paves the way for many new nanotechnological and pharmacological applications. PMID- 28902450 TI - Current status of portal vein thrombosis in Japan: Results of a questionnaire survey by the Japan Society for Portal Hypertension. AB - AIM: To investigate the current status of portal vein thrombosis (PVT) in Japan, the Clinical Research Committee of the Japan Society of Portal Hypertension undertook a questionnaire survey. METHODS: A questionnaire survey of 539 cases of PVT over the previous 10 years was carried out at institutions affiliated with the Board of Trustees of the Japan Society of Portal Hypertension. RESULTS: The most frequent underlying etiology of PVT was liver cirrhosis in 75.3% of patients. Other causes included inflammatory diseases of the hepatobiliary system and the pancreas, malignant tumors, and hematologic diseases. The most frequent site was the main trunk of the portal vein (MPV) in 70.5%, and complete obstruction of the MPV was present in 11.5%. Among the medications for PVT, danaparoid was given to 45.8%, warfarin to 26.2%, heparin to 17.3%, and anti thrombin III to 16.9%. Observation of the course was practiced in 22.4%. Factors contributing to therapeutic efficacy were implementation of various medications, thrombi localized to either the right or left portal vein only, non-complete obstruction of the MPV and Child-Pugh class A liver function. A survival analysis showed that the prognosis was favorable with PVT disappearance regardless of treatment. CONCLUSION: The questionnaire survey showed the current status of PVT in Japan. Any appropriate medication should be given to a patient with PVT when PVT is recognized. It is necessary to compile a large amount of information and reach a consensus on safe and highly effective management of PVT. PMID- 28902451 TI - Ectopic expression of glycosyltransferase UGT76E11 increases flavonoid accumulation and enhances abiotic stress tolerance in Arabidopsis. AB - Although plant glycosyltransferases are thought to play important roles in growth and interaction with the environment, little is known about their physiological roles for most members of the plant glycosyltransferase family. We cloned and characterised an Arabidopsis glycosyltransferase gene, UGT76E11. Its in vivo physiological effects on flavonoid accumulation and plant tolerance to abiotic stresses were investigated. The UGT76E11 gene was up-regulated in transcription expression under stress conditions of salinity, drought and H2 O2 treatment. Transgenic plants ectopically overexpressing UGT76E11 showed substantially enhanced tolerance to salinity and drought at germination and during post germination growth. Enzyme activity of UGT76E11 to glucosylate quercetin and other flavonoids was confirmed. Ectopic expression of UGT76E11 resulted in significantly increased flavonoid content in transgenic plants compared to wild type, suggesting a contribution of UGT76E11 to modulation of flavonoid metabolism. Consistent with this result, several biosynthesis genes in the flavonoid pathway were clearly up-regulated in transgenic plants. Furthermore, overexpression of UGT76E11 also enhanced the scavenging capacity for ROS and increased expression levels of a number of stress-related genes. Based on these results, we suggest that the glycosyltransferase UGT76E11 plays an important role in modulating flavonoid metabolism and enhancing plant adaptation to environmental stresses. Our findings might allow use of glycosyltransferase UGT76E11 in crop improvement, towards both enhanced stress tolerance and increased flavonoid accumulation. PMID- 28902452 TI - MGRN1-mediated ubiquitination of alpha-tubulin regulates microtubule dynamics and intracellular transport. AB - MGRN1-mediated ubiquitination of alpha-tubulin regulates microtubule stability and mitotic spindle positioning in mitotic cells. This study elucidates the effect of MGRN1-mediated ubiquitination of alpha-tubulin in interphase cells. Here, we show that MGRN1-mediated ubiquitination regulates dynamics of EB1 labeled plus ends of microtubules. Intracellular transport of mitochondria and endosomes are affected in cultured cells where functional MGRN1 is depleted. Defects in microtubule-dependent organellar transport are evident in cells where noncanonical K6-mediated ubiquitination of alpha-tubulin by MGRN1 is compromised. Loss of MGRN1 has been previously correlated with late-onset spongiform neurodegeneration. Mislocalised cytosolically exposed PrP (Ctm PrP) interacts with MGRN1 leading to its loss of function. Expression of Ctm PrP generating mutants of PrP[PrP(A117V) and PrP(KHII)] lead to decrease in MGRN1-mediated ubiquitination of alpha-tubulin and intracellular transport defects. Brain lysates from PrP(A117V) transgenic mice also indicate loss of tubulin polymerization as compared to non-transgenic controls. Depletion of MGRN1 activity may hamper physiologically important processes like mitochondrial movement in neuronal processes and intracellular transport of ligands through the endosomal pathway thereby contributing to the pathogenesis of neurodegeneration in certain types of prion diseases. PMID- 28902453 TI - Implementing a web-based introductory bioinformatics course for non bioinformaticians that incorporates practical exercises. AB - A recent scientific discipline, bioinformatics, defined as using informatics for the study of biological problems, is now a requirement for the study of biological sciences. Bioinformatics has become such a powerful and popular discipline that several academic institutions have created programs in this field, allowing students to become specialized. However, biology students who are not involved in a bioinformatics program also need a solid toolbox of bioinformatics software and skills. Therefore, we have developed a completely online bioinformatics course for non-bioinformaticians, entitled "BIF-1901 Introduction a la bio-informatique et a ses outils (Introduction to bioinformatics and bioinformatics tools)," given by the Department of Biochemistry, Microbiology, and Bioinformatics of Universite Laval (Quebec City, Canada). This course requires neither a bioinformatics background nor specific skills in informatics. The underlying main goal was to produce a completely online up-to-date bioinformatics course, including practical exercises, with an intuitive pedagogical framework. The course, BIF-1901, was conceived to cover the three fundamental aspects of bioinformatics: (1) informatics, (2) biological sequence analysis, and (3) structural bioinformatics. This article discusses the content of the modules, the evaluations, the pedagogical framework, and the challenges inherent to a multidisciplinary, fully online course. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):31-38, 2018. PMID- 28902454 TI - Early flowering and rapid grain filling determine early maturity and escape from harvesting in weedy rice. AB - BACKGROUND: Early maturity is an important trait that is essential to the survival of weedy rice. To explore the mechanism of early maturity in weedy rice, the reproductive development of a large sample of weedy rice accessions and cultivars was compared in a common garden study. A selected sample of both weedy and cultivated rice was sown at different dates in two years to study in more detail their flowering and grain-filling patterns. RESULTS: The weedy rice from three major cropping regions matured 7-8 days earlier than their associated cultivars. Representative weedy rice accessions planted on conventional sowing dates flowered 3-26 days earlier than cultivars; delayed sowing caused divergence in the flowering regimes in weedy rice. However, regardless of the sowing date, weedy rice filled its grain 7-21 days faster than cultivars in both study years. Vegetative and reproductive traits of weedy and cultivated rice have different patterns of variation with delayed planting. CONCLUSION: Early maturity is an essential factor determining the persistence of weedy rice by contributing to the escape of its seed from being harvested with the rice crop. Both early flowering and shorter grain-filling stages determine early maturity, and flowering is more plastic than grain filling. (c) 2017 Society of Chemical Industry. PMID- 28902455 TI - Synthesis of 2-amino-3-cyanopyridine derivatives and investigation of their carbonic anhydrase inhibition effects. AB - The conversion of carbon dioxide (CO2 ) and bicarbonate (HCO3- ) to each other is very important for living metabolism. Carbonic anhydrase (CA, E.C.4.2.1.1), a metalloenzyme familly, catalyzes the interconversion of these ions (CO2 and HCO3- ) and are very common in living organisms. In this study, a series of novel 2 amino-3-cyanopyridines supported with some functional groups was synthesized and tested as potential inhibition effects against both cytosolic human CA I and II isoenzymes (hCA I and II) using by Sepharose-4B-l-tyrosine-sulfanilamide affinity chromatography. The structural elucidations of novel 2-amino-3-cyanopyridines were achieved by NMR, IR, and elemental analyses. Ki values of the novel synthesized compounds were found in range of 2.84-112.44 MUM against hCA I and 2.56-31.17 MUM against hCA II isoenzyme. While compound 7d showed the best inhibition activity against hCA I (Ki : 2.84 MUM), the compound 7b demonstrated the best inhibition profile against hCA II isoenzyme (Ki : 2.56 MUM). PMID- 28902456 TI - Safety and efficacy of hydroxyapatite scaffold in the prevention of jaw osteonecrosis in vivo. AB - Two scaffolds of chitosan/sodium alginate/hydroxyapatite (Ch/NaAlg/Hap) 1:1:0.2 and 1:1:0.6 were evaluated in the prevention of bisphosphonate-induced jaw osteonecrosis. Two groups of rats (n = 24, according to the euthanasia time: 15 or 30 days after the last Zoledronic acid (ZA) administration) were subdivided in four subgroups (n = 6): I - Control (saline + teeth extraction); II - ZA 0.6 mg/kg + teeth extraction; III - ZA + teeth extraction + scaffold 1:1:0.2; IV - ZA + teeth extraction + scaffold 1:1:0.6. Jaws were evaluated histologically and blood was evaluated for hematological and biochemical parameters. Histopathology showed significant osteonecrosis in AZ group. The scaffold's implantation, despite the inflammatory process, were able to prevent the osteonecrosis. In the 15-day euthanasia group, an increase in red blood cells and platelets was observed in the subgroup II. Hemoglobin and hematocrit decreased in subgroup IV compared to II. Hepatic transaminases and creatinine concentration increased significantly in subgroup II. Calcium concentration increased in subgroup IV compared to II. In the 30-day euthanasia group, no differences among the groups were observed for any parameter. Scaffolds proved to be efficient and safe to liver and kidney function. Some hematological parameters were altered by the scaffold, but returned to normal concentrations over time. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1799-1808, 2018. PMID- 28902457 TI - The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research. AB - The circadian clock system drives daily rhythms in physiology, metabolism, and behavior in mammals. Molecular mechanisms of this system consist of multiple clock genes, with Circadian Locomotor Output Cycles Kaput (CLOCK) as a core member that plays an important role in a wide range of behaviors. Alterations in the CLOCK gene are associated with common psychiatric disorders as well as with circadian disturbances comorbidities. This review addresses animal, molecular, and genetic studies evaluating the role of the CLOCK gene on many psychiatric conditions, namely autism spectrum disorder, schizophrenia, attention deficit/hyperactivity disorder, major depressive disorder, bipolar disorder, anxiety disorder, and substance use disorder. Many animal experiments focusing on the effects of the Clock gene in behavior related to psychiatric conditions have shown consistent biological plausibility and promising findings. In humans, genetic and gene expression studies regarding disorder susceptibility, sleep disturbances related comorbidities, and response to pharmacological treatment, in general, are in agreement with animal studies. However, the number of controversial results is high. Literature suggests that the CLOCK gene exerts important influence on these conditions, and influences the susceptibility to phenotypes of psychiatric disorders. PMID- 28902458 TI - The impact of some natural phenolic compounds on carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and alpha-glycosidase enzymes: An antidiabetic, anticholinergic, and antiepileptic study. AB - Natural products from food and plant sources have been used for medicinal usage for ages. Also, natural products with therapeutic significance are compounds derived from animals, plants, or any microorganism. In this study, chrysin, carvacrol, hesperidin, zingerone, and naringin as natural phenols showed excellent inhibitory effects against human (h) carbonic anhydrase (CA) isoforms I and II (hCA I and II), alpha-glucosidase (alpha-Gly), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). These phenolic compounds were tested for the inhibition of alpha-glycosidase, hCA I, hCA II, AChE, and BChE enzymes and demonstrated efficient inhibition profiles with Ki values in the range of 3.70 +/- 0.92-79.66 +/- 20.81 nM against hCA I, 2.98 +/- 0.33-84.88 +/- 40.32 nM against hCA II, 4.93 +/- 2.01-593.60 +/- 134.74 nM against alpha-Gly, 0.52 +/- 0.18-46.80 +/- 17.15 nM against AChE, and 1.25 +/- 0.22-32.08 +/- 2.68 against BChE. PMID- 28902460 TI - Arabic validation of the tinnitus handicap inventory and the mini-tinnitus questionnaire on 100 adult patients. PMID- 28902459 TI - Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance. AB - Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based test results, protein-protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR < 0.1, association was detected for rs10941112 (p = 2.1 * 10-5 ; q-value = 0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (p = 5.5 * 10-4 ), including brain tissue data from the Genotype-Tissue Expression project (minimum p = 6.0 * 10-5 ). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (p = 2.8 * 10-5 ; q-value = 0.073). PPIs among our top gene-based association results (p < 0.05; n = 359 genes) reveal significant enrichment of genes involved in NCAM mediated neurite outgrowth (p = 3.0 * 10-5 ), while exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase-mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance. PMID- 28902462 TI - Are CNM-Attended Births in Texas Hospitals Underreported? AB - INTRODUCTION: Accurate data on the number of births attended by certified nurse midwives and certified midwives (CNMs/CMs) are required to establish the public health benefits attributed to the midwifery model of care and the role of CNMs/CMs in the US health care system. However, the number of CNM/CM-attended births may be underreported in birth certificate data. The purpose of this project was to estimate the number of births CNM practices attended in Texas hospitals in 2014 and to describe Texas CNMs' knowledge about their hospitals' policies on naming CNMs as birth attendants. METHODS: CNMs from Texas practices employing CNMs completed a survey. Descriptive statistics were used to summarize respondent data. These results were used to impute data for practices that did not respond to the survey so that total estimates for the state could be calculated. RESULTS: CNM-attended hospital births in Texas in 2014 may be underreported by 65%. Most CNMs (90%) keep records of births attended, but only 19% of practices receive facility reports with the births CNMs in the practice attended. DISCUSSION: CNMs/CMs need to regularly verify that they are being named as the provider on birth certificates for births they attend and work with advocacy groups, hospital administrators, physicians, legislators, and policy makers to improve the accuracy of birth certificate data. PMID- 28902461 TI - Behavioral responses of pest mole crickets, Neoscapteriscus spp. (Orthoptera: Gryllotalpidae), to selected insecticides. AB - BACKGROUND: Mole crickets (Neoscapteriscus spp.) consume turfgrasses and pasture grasses and uproot plants by their tunneling, which is detrimental to turf aesthetics and decreases forage quantity and quality. Insecticides are frequently used to prevent damage. In typical field trials, damage symptoms, not percent mortality or achieved level of control, are used to assess treatment efficacy. Here, however, laboratory tests assessed the direct effect of key insecticides on Neoscapteriscus mole cricket behavior. RESULTS: Mole crickets, Neoscapteriscus spp., were able to detect and avoid areas treated with fipronil [formulated product (FP)] and imidacloprid (FP). They tunneled less in sand treated with fipronil and avoided sand treated with fipronil and imidacloprid if given a choice. Mole crickets escaped areas treated with acephate, bifenthrin and fipronil. Bifenthrin and acephate caused increased tunneling during the first 90 min of observation. Fipronil and imidacloprid significantly reduced overall tunneling on treated areas. CONCLUSION: Tested insecticides elicited two types of behavioral changes in Neoscapteriscus mole crickets: increased locomotory activity and tunneling [acephate (organophosphate) and bifenthrin (pyrethroid)] and reduced spatial movement [fipronil (phenylpyrazole) and imidacloprid (neonicotinoid)]. These behavioral responses resulted mainly from contact chemoreception and inherent neurotoxicity of the chemicals on Neoscapteriscus mole crickets. (c) 2017 Society of Chemical Industry. PMID- 28902464 TI - Updates From the Literature, September/October 2017. PMID- 28902463 TI - Renoprotective effects of montelukast in an experimental model of cisplatin nephrotoxicity in rats. AB - Renal toxicity is one of the most severe complications that can occur with cisplatin (CIS) administration in cancer patients. Montelukast (ML) renoprotective outcome contrary to CIS-drawn nephrotoxicity remains obscure. Therefore, adult male Sprague-Dawley rats were orally given ML (10 and 20 mg/kg/day) 5 days before and after single CIS (5 mg/kg; i.p.) treatment. ML returned blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase that were elevated by CIS to normal level. The improved kidney function tests corroborated the attenuation of CIS renal injury at the microscopical level. It also reduced serum/renal nitric oxide and renal hemeoxygenase-1. Meanwhile, ML hindered the raised levels of serum endothelin-1, serum and renal tumor necrosis factor-alpha, and monocyte chemoattractant protein 1. These effects were associated by deceased caspase-3 expression in kidney after ML treatment. In conclusion, ML guards against CIS-induced nephrotoxicity via anti-inflammatory and antiapoptotic properties. PMID- 28902465 TI - A modified reporting approach for thyroid FNA in the NIFTP era: A 1-year institutional experience. AB - BACKGROUND: The reclassification of noninvasive follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has created diagnostic and management issues for thyroid fine-needle aspiration (FNA). In response to these challenges, the authors' laboratory adopted a NIFTP policy including 1) stringent criteria (requiring pseudo-inclusions, papillae, and/or psammoma bodies) for a malignant diagnosis of papillary carcinoma to limit false-positive results due to NIFTP and 2) the use of explanatory notes in cases with cytomorphologic features suggestive of possible NIFTP to encourage lobectomy over thyroidectomy. This study examined the effects of this policy on FNA classification and subsequent surgical management. METHODS: All thyroid FNAs performed at Brigham and Women's Hospital (n = 1300) during a 1-year period were evaluated for changes in the use of diagnostic categories, explanatory NIFTP notes, and surgical follow-up in comparison with historical controls. RESULTS: The use of specific Bethesda categories did not significantly change. Only a single case of NIFTP was mistakenly classified as malignant. NIFTP was seldom suspected prospectively (17 of 1300; 1.3%); when NIFTP was suspected, cases were reported as suspicious for a follicular neoplasm/follicular neoplasm (n = 10) or suspicious for malignancy (SUS; n = 7). Five of the 7 SUS cases (71%) underwent partial thyroidectomy, compared to 19% of those classified as SUS without an explanatory NIFTP note (P < .02). CONCLUSIONS: Thyroid FNA reporting modifications due to NIFTP affect only a small subset of specimens. When NIFTP is suspected, an explanatory note promotes limited surgical excision. More stringent criteria for malignancy affect few cases while potentially limiting false-positive diagnosis due to NIFTP. Cancer Cytopathol 2017;125:854-64. (c) 2017 American Cancer Society. PMID- 28902466 TI - Learning-based deformable registration for infant MRI by integrating random forest with auto-context model. AB - PURPOSE: Accurately analyzing the rapid structural evolution of human brain in the first year of life is a key step in early brain development studies, which requires accurate deformable image registration. However, due to (a) dynamic appearance and (b) large anatomical changes, very few methods in the literature can work well for the registration of two infant brain MR images acquired at two arbitrary development phases, such as birth and one-year-old. METHODS: To address these challenging issues, we propose a learning-based registration method, which can handle the anatomical structures and the appearance changes between the two infant brain MR images with possible time gap. Specifically, in the training stage, we employ a multioutput random forest regression and auto-context model to learn the evolution of anatomical shape and appearance from a training set of longitudinal infant images. To make the learning procedure more robust, we further harness the multimodal MR imaging information. Then, in the testing stage, for registering the two new infant images scanned at two different development phases, the learned model will be used to predict both the deformation field and appearance changes between the images under registration. After that, it becomes much easier to deploy any conventional image registration method to complete the remaining registration since the above-mentioned challenges for state-of-the-art registration methods have been well addressed. RESULTS: We have applied our proposed registration method to intersubject registration of infant brain MR images acquired at 2-week-old, 3-month-old, 6 month-old, and 9-month-old with the images acquired at 12-month-old. Promising registration results have been achieved in terms of registration accuracy, compared with the counterpart nonlearning based registration methods. CONCLUSIONS: The proposed new learning-based registration method have tackled the challenging issues in registering infant brain images acquired from the first year of life, by leveraging the multioutput random forest regression with auto context model, which can learn the evolution of shape and appearance from a training set of longitudinal infant images. Thus, for the new infant image, its deformation field to the template and also its template-like appearances can be predicted by the learned models. We have extensively compared our method with state-of-the-art deformable registration methods, as well as multiple variants of our method, which show that our method can achieve higher accuracy even for the difficult cases with large appearance and shape changes between subject and template images. PMID- 28902467 TI - EAACI guidelines on allergen immunotherapy: Prevention of allergy. AB - Allergic diseases are common and frequently coexist. Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated allergic disease with effects beyond cessation of AIT that may include important preventive effects. The European Academy of Allergy and Clinical Immunology (EAACI) has developed a clinical practice guideline to provide evidence-based recommendations for AIT for the prevention of (i) development of allergic comorbidities in those with established allergic diseases, (ii) development of first allergic condition, and (iii) allergic sensitization. This guideline has been developed using the Appraisal of Guidelines for Research & Evaluation (AGREE II) framework, which involved a multidisciplinary expert working group, a systematic review of the underpinning evidence, and external peer-review of draft recommendations. Our key recommendation is that a 3-year course of subcutaneous or sublingual AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-AIT in addition to its sustained effect on AR symptoms and medication. Some trial data even suggest a preventive effect on asthma symptoms and medication more than 2 years post-AIT. We need more evidence concerning AIT for prevention in individuals with AR triggered by house dust mites or other allergens and for the prevention of allergic sensitization, the first allergic disease, or for the prevention of allergic comorbidities in those with other allergic conditions. Evidence for the preventive potential of AIT as disease modifying treatment exists but there is an urgent need for more high-quality clinical trials. PMID- 28902469 TI - Time-Dependent Changes in the Structure of Calcified Fibrocartilage in the Rat Achilles Tendon-Bone Interface With Sciatic Denervation. AB - The enthesis transmits a physiological load from soft to hard tissue via fibrocartilage. The histological alterations induced by this physiological loading remain unclear. This study was performed to examine the histomorphological alterations in the collagen fiber bundle alignment and depth of collagen interdigitation between the calcified fibrocartilage and the bone. We examined the Achilles enthesis of rats with sciatic denervation to explore the mechanical effects of structural changes in the enthesis. The parallelism of the collagen fiber bundles was significantly reduced 8 weeks after denervation. However, the depth of collagen interdigitation significantly increased at 2 and 4 weeks after denervation and then significantly decreased 8 weeks after denervation. In conclusion, a lack of muscle loading induced structural alterations in the distal calcified fibrocartilage. These findings suggest that while structural changes in the enthesis are necessary for the development of physiological loading, structural deformities are required in the long term. Anat Rec, 300:2166-2174, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28902468 TI - Fine-needle aspiration of lipoblastoma: Cytological, molecular, and clinical features. AB - BACKGROUND: Lipoblastomas are rare, benign adipocytic tumors that present mostly during infancy. In about 70% of cases, these tumors carry abnormalities in chromosome 8, mainly leading to rearrangements of the PLAG1 gene. METHODS: We report a series of histologically proven lipoblastomas with previous fine-needle aspiration (FNA) cytology from 9 patients (n = 10 samples) and describe their clinical, cytological, and molecular features. RESULTS: Our cohort included 5 boys and 4 girls (median age, 2.5 years [range, 10 months to 13 years]) who presented with soft tissue masses in the thorax (n = 3), abdomen (n = 2), axilla (n = 2), and thigh (n = 2). In 1 patient, the FNA diagnosis was inconclusive due to hypocellularity, and in another patient a diagnosis of benign lipomatous tumor was made. In the remaining 8 samples (one of which confirmed relapse), a correct preoperative FNA diagnosis was rendered. Smears were hypo- to moderately cellular and contained fragments of mature adipose tissue with thin branching vessels admixed with some lipoblasts in a myxoid matrix. Spindle cells and naked oval nuclei with no atypia were observed in the background. Of the 4 patients tested for PLAG1 rearrangement using FISH probes, 3 harbored this alteration (1 was made on a FNA smear and 1 was made in a tumor imprint). All the patients are alive and well, except for 1 patient with a retroperitoneal tumor who, after an initial incomplete excision, died of local disease progression. CONCLUSION: FNA, especially if used together with molecular biology techniques (eg, PLAG1 FISH analysis), is a reliable and accurate diagnostic tool. Cancer Cytopathol 2017;125:934-9. (c) 2017 American Cancer Society. PMID- 28902470 TI - Female fecundity and offspring survival are not increased through sexual cannibalism in the spider Larinioides sclopetarius. AB - Many hypotheses explaining the evolution and maintenance of sexual cannibalism incorporate the nutritional aspect of the consumption of males. Most studies have focused on a fecundity advantage through consumption of a male; however, recent studies have raised the intriguing possibility that consumption of a male may also affect offspring quality. In particular, recent studies suggest prolonged survival for offspring from sexually cannibalistic females. Here, we measured the protein and lipid content of males compared to insect prey (crickets), quantified female nutrient intake of both prey types and finally assessed how sexual cannibalism affects female fecundity and spiderling quality in the orb-web spider Larinioides sclopetarius. We found no evidence that sexual cannibalism increased fecundity when compared to a female control group fed a cricket. Contrary to previous studies, spiderlings from females fed a male showed reduced survival under food deprivation compared to spiderlings from the control group. Offspring from females fed a male also tended to begin web construction sooner. The low lipid content of males compared to crickets may have reduced offspring survival duration. Whether additional proteins obtained through consumption of a male translate to enhanced silk production in offspring requires further investigation. PMID- 28902471 TI - Narrow hybrid zones in spite of very low population differentiation in neutral markers in an island bird species complex. AB - Patterns of phenotypic and genic frequencies across hybrid zones provide insight into the origin and evolution of reproductive isolation. The Reunion grey white eye, Zosterops borbonicus, exhibits parapatrically distributed plumage colour forms across the lowlands of the small volcanic island of Reunion (Mascarene archipelago). These forms meet and hybridize in regions that are natural barriers to dispersal (rivers, lava fields). Here, we investigated the relationship among patterns of differentiation at neutral genetic (microsatellite) markers, phenotypic traits (morphology and plumage colour) and niche characteristics across three independent hybrid zones. Patterns of phenotypic divergence revealed that these hybrid zones are among the narrowest ever documented in birds. However, the levels of phenotypic divergence stand in stark contrast to the lack of clear population neutral genetic structure between forms. The position of the hybrid zones coincides with different natural physical barriers, yet is not associated with steep changes in vegetation and related climatic variables, and major habitat transitions are shifted from these locations by at least 18 km. This suggests that the hybrid zones are stabilized over natural dispersal barriers, independently of environmental boundaries, and are not associated with niche divergence. A striking feature of these hybrid zones is the very low levels of genetic differentiation in neutral markers between forms, suggesting that phenotypic divergence has a narrow genetic basis and may reflect recent divergence at a few linked genes under strong selection, with a possible role for assortative mating in keeping these forms apart. PMID- 28902473 TI - Preoperative biliary drainage for malignant biliary obstruction: results from a national database. AB - BACKGROUND: The impact of preoperative biliary drainage (PBD) on postoperative morbidity and mortality in patients with malignant biliary obstruction is still unclear. We examined short-term surgical outcomes among drained and non-drained patients. METHODS: Patients who underwent surgical resection for their malignancies with biliary obstruction were identified using the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files from 2014 to 2015. Mortality and morbidity were compared among patients who had PBD to those who did not undergo biliary drainage prior to surgery. RESULTS: A total of 2,306 patients were included; of these 1,803 (77.8%) had PBD. The postoperative mortality was 3.0% and 2.2% among direct surgery (DS) group and PBD group, respectively (P = 0.3). Postoperative complications were higher in the PBD group compared to the DS group (27.1% vs. 19.5%; P = 0.0005). Patients in the PBD group had higher risk of sepsis (13.5% vs. 7.2%; P = 0.0001), wound infections (16.5% vs. 10.9%; P = 0.002) and pancreatic fistula (17.5% vs. 12.4%; P = 0.006) compared to the DS group. CONCLUSION: Preoperative biliary drainage is associated with increased risk of sepsis and wound infections, but does not impact the postoperative mortality of patients undergoing PBD. PMID- 28902472 TI - The mushroom body D1 dopamine receptor controls innate courtship drive. AB - Mating is critical for species survival and is profoundly regulated by neuromodulators and neurohormones to accommodate internal states and external factors. To identify the underlying neuromodulatory mechanisms, we investigated the roles of dopamine receptors in various aspects of courtship behavior in Drosophila. Here, we report that the D1 dopamine receptor dDA1 regulates courtship drive in naive males. The wild-type naive males actively courted females regardless their appearance or mating status. On the contrary, the dDA1 mutant (dumb) males exhibited substantially reduced courtship toward less appealing females including decapitated, leg-less and mated females. The dumb male's reduced courtship activity was due to delay in courtship initiation and prolonged intervals between courtship bouts. The dampened courtship drive of dumb males was rescued by reinstated dDA1 expression in the mushroom body alpha/beta and gamma neurons but not alpha/beta or gamma neurons alone, which is distinct from the previously characterized dDA1 functions in experience-dependent courtship or other learning and memory processes. We also found that the dopamine receptors dDA1, DAMB and dD2R are dispensable for associative memory formation and short-term memory of conditioned courtship, thus courtship motivation and associative courtship learning and memory are regulated by distinct neuromodulatory mechanisms. Taken together, our study narrows the gap in the knowledge of the mechanism that dopamine regulates male courtship behavior. PMID- 28902474 TI - Electrospun Nanofibrous Meshes Cultured With Wharton's Jelly Stem Cell: An Alternative for Cartilage Regeneration, Without the Need of Growth Factors. AB - Many efforts are being directed worldwide to the treatment of OA-focal lesions. The majority of those efforts comprise either the refinement of surgical techniques or combinations of biomaterials with various autologous cells. Herein, we tested electrospun polycaprolactone (PCL) nanofibrous meshes for cartilage tissue engineering. For that, articular chondrocytes (hACs) isolated from human osteoarthritic joints and Wharton's Jelly Stem Cells (hWJSCs) are cultured on electrospun nanofiber meshes, without adding external growth factors. We observed higher glycosaminoglycans production and higher over-expression of cartilage related genes from hWJSCs cultured with basal medium, when compared to hACs isolated from osteoarthritic joints. Moreover, the presence of sulfated proteoglycans and collagen type II is observed on both types of cell cultures. We believe that this effect is due to either the electrospun nanofibers topography or the intrinsic chondrogenic differentiation potential of hWJSCs. Therefore, we propose the electrospun nanofibrous scaffolds in combination with hWJSCs as a viable alternative to the commercial membranes used in autologous chondrogenic regeneration approaches. PMID- 28902475 TI - Commentary - Food for thought on food environments in Canada. PMID- 28902476 TI - The healthfulness and prominence of sugar in child-targeted breakfast cereals in Canada. AB - INTRODUCTION: The objective of this study was to compare the nutritional content and healthfulness of child-targeted and "not child-targeted" breakfast cereals and to assess the predominance of added sugar in these products. METHODS: We collected data on the nutritional content of 262 unique breakfast cereals found in the five largest grocery store chains in Ottawa (Ontario) and Gatineau (Quebec). We noted the first five ingredients and the number of added sugars present in each cereal from the ingredients list. The various cereal brands were then classified as either "healthier" or "less healthy" using the UK Nutrient Profile Model. We assessed each cereal to determine if it was child-targeted or not, based on set criteria. Statistical comparisons were made between child and not child-targeted cereals. RESULTS: 19.8% of all breakfast cereals were child targeted, and these were significantly lower in total and saturated fat. Child targeted cereals were significantly higher in sodium and sugar and lower in fibre and protein, and were three times more likely to be classified as "less healthy" compared to not child-targeted cereals. No child-targeted cereals were sugar free, and sugar was the second most common ingredient in 75% of cereals. Six breakfast cereal companies had child-targeted product lines that consisted entirely of "less healthy" cereals. CONCLUSION: There is a need for regulations that restrict food marketing to children and youth under the age of 17 on packaging to reduce their appeal to this age group. Children's breakfast cereals also need to be reformulated through government-set targets, or through regulation should compliance be deemed unacceptable. PMID- 28902477 TI - Food marketing to children in Canada: a settings-based scoping review on exposure, power and impact. AB - INTRODUCTION: Food marketing impacts children's food knowledge, behaviours and health. Current regulations in Canada focus on restricting promotional aspects of food marketing with little-to-no consideration of the places where children experience food. Understanding food marketing in children's everyday settings is necessary to protect children. This scoping review describes the current literature on food marketing to children in Canada by setting. METHODS: The author searched databases for Canadian research on children's exposure to food marketing, and the power and impact of food marketing to children (2-17 years) across settings, and on how current regulations may mediate the effect of food marketing on children. Peer-reviewed studies in English, published between 2000 and 2016, were included. RESULTS: Twenty-five studies documented children's exposure to food marketing and its power and/or impact on them in homes (via television, or online) (n = 12), public schools (n = 1), grocery stores (n = 8), fast food restaurants (n = 2), and in general (n = 2). Research trends suggest that unhealthy foods are targeted at children using multiple promotional techniques that overlap across settings. Several research gaps exist in this area, leading to an incomplete, and potentially underestimated, picture of food marketing to children in Canada. Available evidence suggests that current Canadian approaches have not reduced children's exposure to or the power of food marketing in these settings, with the exception of some positive influences from Quebec's statutory regulations. CONCLUSION: The settings where children eat, buy or learn about food expose them to powerful, often unhealthy food marketing. The current evidence suggests that "place" may be an important marketing component to be included in public policy in order to broadly protect children from unhealthy food marketing. Organizations and communities can engage in settings-based health promotion interventions by developing their own marketing policies that address the promotion and place of unhealthy food and beverages. PMID- 28902478 TI - Development, reliability and use of a food environment assessment tool in supermarkets of four neighbourhoods in Montreal, Canada. AB - INTRODUCTION: The food environment is a promising arena in which to influence people's dietary habits. This study aimed to develop a comprehensive food environment assessment tool for businesses and characterize the food environment of a low-tomedium income area of Montreal, Canada. METHODS: We developed a tool, Mesure de l'environnement alimentaire du consommateur dans les supermarches (MEAC S), and tested it for reliability. We used the MEAC-S to assess the consumer food environment of 17 supermarkets in four neighbourhoods of Montreal. We measured the shelf length, variety, price, display counts and in-store positions of fruits and vegetables (FV) and ultra-processed food products (UPFPs). We also assessed fresh FV for quality. Store size was estimated using the total measured shelf length for all food categories. We conducted Spearman correlations between these indicators of the food environment. RESULTS: Reliability analyses revealed satisfactory results for most indicators. Characterization of the food environment revealed high variability in shelf length, variety and price of FV between supermarkets and suggested a disproportionate promotion of UPFPs. Display counts of UPFPs outside their normal display location ranged from 7 to 26, and they occupied 8 to 33 strategic in-store positions, whereas the number of display counts of fresh FV outside their normal display location exceeded 1 in only 2 of the 17 stores surveyed, and they occupied a maximum of 2 strategic in-store positions per supermarket. Price of UPFPs was inversely associated with their prominence (p < .005) and promotion (p < .003). Store size was associated with display counts and strategic in-store positioning of UPFPs (p < .001), but not FV, and was inversely associated with the price of soft drinks (p < .003). CONCLUSION: This study illustrates the variability of the food environment between supermarkets and underscores the importance of measuring in-store characteristics to adequately picture the consumer food environment. PMID- 28902479 TI - Support for healthy eating at schools according to the comprehensive school health framework: evaluation during the early years of the Ontario School Food and Beverage Policy implementation. AB - INTRODUCTION: Provincial, national and international public health agencies recognize the importance of school nutrition policies that help create healthful environments aligned with healthy eating recommendations for youth. School-wide support for healthy living within the pillars of the comprehensive school health (CSH) framework (social and physical environments; teaching and learning; healthy school policy; and partnerships and services) has been positively associated with fostering improvements to student health behaviours. This study used the CSH framework to classify, compare and describe school support for healthy eating during the implementation of the Ontario School Food and Beverage Policy (P/PM 150). METHODS: We collected data from consenting elementary and secondary schools in a populous region of Ontario in Time I (2012/13) and Time II (2014). Representatives from the schools completed the Healthy School Planner survey and a food environmental scan (FES), which underwent scoring and content analyses. Each school's support for healthy eating was classified as either "initiation," "action" or "maintenance" along the Healthy School Continuum in both time periods, and as "high/increased," "moderate" or "low/decreased" within individual CSH pillars from Time I to Time II. RESULTS: Twenty-five school representatives (8 elementary, 17 secondary) participated. Most schools remained in the "action" category (n = 20) across both time periods, with varying levels of support in the CSH pillars. The physical environment was best supported (100% high/increased support) and the social environment was the least (68% low/decreased support). Only two schools achieved the highest rating (maintenance) in Time II. Supports aligned with P/PM 150 were reportedly influenced by administration buy-in, stakeholder support and relevancy to local context. CONCLUSION: Further assistance is required to sustain comprehensive support for healthy eating in Ontario school food environments. PMID- 28902480 TI - The Ontario Food and Nutrition Strategy: identifying indicators of food access and food literacy for early monitoring of the food environment. AB - INTRODUCTION: To address challenges Canadians face within their food environments, a comprehensive, multistakeholder, intergovernmental approach to policy development is essential. Food environment indicators are needed to assess population status and change. The Ontario Food and Nutrition Strategy (OFNS) integrates the food, agriculture and nutrition sectors, and aims to improve the health of Ontarians through actions that promote healthy food systems and environments. This report describes the process of identifying indicators for 11 OFNS action areas in two strategic directions (SDs): Healthy Food Access, and Food Literacy and Skills. METHODS: The OFNS Indicators Advisory Group used a five step process to select indicators: (1) potential indicators from national and provincial data sources were identified; (2) indicators were organized by SD, action area and data type; (3) selection criteria were identified, pilot tested and finalized; (4) final criteria were applied to refine the indicator list; and (5) indicators were prioritized after reapplication of selection criteria. RESULTS: Sixty-nine potential indicators were initially identified; however, many were individual-level rather than system-level measures. After final application of the selection criteria, one individual-level indicator and six system-level indicators were prioritized in five action areas; for six of the action areas, no indicators were available. CONCLUSION: Data limitations suggest that available data may not measure important aspects of the food environment, highlighting the need for action and resources to improve system-level indicators and support monitoring of the food environment and health in Ontario and across Canada. PMID- 28902487 TI - Angiostrongylus cantonensis: Agent of a Sometimes Fatal Globally Emerging Infectious Disease (Rat Lungworm Disease). AB - Angiostrongylus cantonensis, the rat lungworm, is a dangerous invasive species that is the agent of a potentially fatal globally emerging infectious disease. Humans are infected most commonly by ingestion, deliberately or inadvertently, of the parasite larvae in their intermediate snail hosts. The larvae make their way to the brain where they can cause severe neurological damage before eventually dying. Symptoms of the disease are diverse, making it difficult to diagnose. Treatment is primarily with corticosteroids to reduce inflammation, while treatment with anthelmintics to kill the worms remains controversial. There have been almost 3000 cases globally, the majority in southern China, but the parasite is spreading and now occurs much more widely. In the USA, almost all cases have been in Hawaii, but the parasite is also present in southeastern states. As the climate warms, this tropical/subtropical parasite is likely to spread further. PMID- 28902488 TI - Strain Release Induced Novel Fluorescence Variation in CVD-Grown Monolayer WS2 Crystals. AB - Tensile strain is intrinsic to monolayer crystals of transition metal disulfides such as Mo(W)S2 grown on oxidized silicon substrates by chemical vapor deposition (CVD) owing to the much larger thermal expansion coefficient of Mo(W)S2 than that of silica. Here we report fascinating fluorescent variation in intensity with aging time in CVD-grown triangular monolayer WS2 crystals on SiO2 (300 nm)/Si substrates and formation of interesting concentric triangular fluorescence patterns in monolayer crystals of large size. The novel fluorescence aging behavior is recognized to be induced by the partial release of intrinsic tensile strain after CVD growth and the induced localized variations or gradients of strain in the monolayer crystals. The results demonstrate that strain has a dramatic impact on the fluorescence and photoluminescence of monolayer WS2 crystals and thus could potentially be utilized to tune electronic and optoelectronic properties of monolayer transition metal disulfides. PMID- 28902489 TI - Oral siRNA Delivery to Treat Colorectal Liver Metastases. AB - Convenient multiple dosing makes oral administration an ideal route for delivery of therapeutic siRNA. However, hostile GI environments and nonspecific biological trafficking prevent achieving appropriate bioavailability of siRNA. Here, an orally administered AuNP-siRNA-glycol chitosan-taurocholic acid nanoparticle (AR GT NPs) was developed to selectively deliver Akt2 siRNA and treat colorectal liver metastases (CLM). AR-GT NPs are dual padlocked nonviral vectors in which the initially formed AuNP-siRNA (AR) conjugates are further encompassed by bifunctional glycol chitosan-taurocholic acid (GT) conjugates. Covering the surface of AR with GT protected the Akt2 siRNA from GI degradation, facilitated active transport through enterocytes, and enhanced selective accumulation in CLM. Our studies in CLM animal models resulted in the reduction in Akt2 production, followed by initiation of apoptosis in cancer cells after oral administration of Akt2 siRNA-loaded AR-GT. This therapeutic siRNA delivery system may be a promising approach in treating liver-associated diseases. PMID- 28902490 TI - Direct Intranuclear Anticancer Drug Delivery via Polydimethylsiloxane Nanoparticles: in Vitro and in Vivo Xenograft Studies. AB - Direct delivery of anticancer drugs to nuclei of tumor cells is required to enhance the therapeutic activity, which can be achieved by a nuclear localization signal (NLS) or peptide-decorated nanovehicles. However, NLS/peptide-based approaches may create certain undesirable immunological responses and the utilized synthesis processes are generally labor intensive. To this end, we report ligand-free, enhanced intranuclear delivery of Doxorubicin (Dox) to different cancer cells via porous polydimethylsiloxane (PDMS) nanoparticles (NPs). PDMS NPs were prepared by sacrificial silica template-based approach and Dox was loaded into the pores of PDMS NPs. These Dox-loaded PDMS NPs show enhanced cytotoxicity and reduce the IC50 values by 84 and 54% for HeLa and PC-3, respectively, compared to free Dox. Further, DNA damage in HeLa cells was estimated using comet assay suggesting enhanced DNA damage (72%) with Dox-loaded PDMS NPs as compared to free Dox (12%). The therapeutic efficiency of PDMS-Dox drug delivery system was tested in prostate cancer (PC-3) xenografts in NOD/SCID mice which showed enhanced tumor reduction (~66%) as compared to free Dox. Taken together, our PDMS-Dox delivery system shows efficient and enhanced transportation of Dox to tumor cells which can be harnessed to develop advanced chemotherapy-based approaches to treat prostate and other cancers. PMID- 28902492 TI - Rheotaxis of Bimetallic Micromotors Driven by Chemical-Acoustic Hybrid Power. AB - Rheotaxis is a common phenomenon in nature that refers to the directed movement of micro-organisms as a result of shear flow. The ability to mimic natural rheotaxis using synthetic micro/nanomotors adds functionality to enable their applications in biomedicine and chemistry. Here, we present a hybrid strategy that can achieve both positive and negative rheotaxis of synthetic bimetallic micromotors by employing a combination of chemical fuel and acoustic force. An acoustofluidic device is developed for the integration of the two propulsion mechanisms. Using acoustic force alone, bimetallic microrods are propelled along the bottom surface in the center of a fluid channel. The leading end of the microrod is always the less dense end, as established in earlier experiments. With chemical fuel (H2O2) alone, the microrods orient themselves with their anode end against the flow when shear flow is present. Numerical simulations confirm that this orientation results from tilting of the microrods relative to the bottom surface of the channel, which is caused by catalytically driven electro osmotic flow. By combining this catalytic orientation effect with more powerful, density-dependent acoustic propulsion, both positive and negative rheotaxis can be achieved. The ability to respond to flow stimuli and collectively propel synthetic microswimmers in a directed manner indicates an important step toward practical applications. PMID- 28902491 TI - Biodegradable Viral Nanoparticle/Polymer Implants Prepared via Melt-Processing. AB - Viral nanoparticles have been utilized as a platform for vaccine development and are a versatile system for the display of antigenic epitopes for a variety of disease states. However, the induction of a clinically relevant immune response often requires multiple injections over an extended period of time, limiting patient compliance. Polymeric systems to deliver proteinaceous materials have been extensively researched to provide sustained release, which would limit administration to a single dose. Melt-processing is an emerging manufacturing method that has been utilized to create polymeric materials laden with proteins as an alternative to typical solvent-based production methods. Melt-processing is advantageous because it is continuous, solvent-free, and 100% of the therapeutic protein is encapsulated. In this study, we utilized melt-encapsulation to fabricate viral nanoparticle laden polymeric materials that effectively deliver intact particles and generate carrier specific antibodies in vivo. The effects of initial processing and postprocessing on particle integrity and aggregation were studied to develop processing windows for scale-up and the creation of more complex materials. The dispersion of particles within the PLGA matrix was studied, and the effect of additives and loading level on the release profile was determined. Overall, melt-encapsulation was found to be an effective method to produce composite materials that can deliver viral nanoparticles over an extended period and elicit an immune response comparable to typical administration schedules. PMID- 28902493 TI - Direct Synthesis of Alloyed Si1-xGex Nanowires for Performance-Tunable Lithium Ion Battery Anodes. AB - Here we report the formation of high capacity Li-ion battery anodes from Si1-xGex alloy nanowire arrays that are grown directly on stainless steel current collectors, in a single-step synthesis. The direct formation of these Si1-xGex nanowires (ranging from Si0.20Ge0.80 to Si0.67Ge0.33) represents a simple and efficient processing route for the production of Li-ion battery anodes possessing the benefits of both Si (high capacity) and Ge (improved rate performance and capacity retention). The nanowires were characterized through SEM, TEM, XRD and ex situ HRSEM/HRTEM. Electrochemical analysis was conducted on these nanowires, in half-cell configurations, with capacities of up to 1360 mAh/g (Si0.67Ge0.33) sustained after 250 cycles and in full cells, against a commercial cathode, where capacities up to 1364 mAh/g (Si0.67Ge0.33) were retained after 100 cycles. PMID- 28902494 TI - Fully Atomistic Understanding of the Electronic and Optical Properties of a Prototypical Doped Charge-Transfer Interface. AB - The current study generates profound atomistic insights into doping-induced changes of the optical and electronic properties of the prototypical PTCDA/Ag(111) interface. For doping K atoms are used, as KxPTCDA/Ag(111) has the distinct advantage of forming well-defined stoichiometric phases. To arrive at a conclusive, unambiguous, and fully atomistic understanding of the interface properties, we combine state-of-the-art density-functional theory calculations with optical differential reflectance data, photoelectron spectra, and X-ray standing wave measurements. In combination with the full structural characterization of the KxPTCDA/Ag(111) interface by low-energy electron diffraction and scanning tunneling microscopy experiments (ACS Nano 2016, 10, 2365-2374), the present comprehensive study provides access to a fully characterized reference system for a well-defined metal-organic interface in the presence of dopant atoms, which can serve as an ideal benchmark for future research and applications. The combination of the employed complementary techniques allows us to understand the peculiarities of the optical spectra of K2PTCDA/Ag(111) and their counterintuitive similarity to those of neutral PTCDA layers. They also clearly describe the transition from a metallic character of the (pristine) adsorbed PTCDA layer on Ag(111) to a semiconducting state upon doping, which is the opposite of the effect (degenerate) doping usually has on semiconducting materials. All experimental and theoretical efforts also unanimously reveal a reduced electronic coupling between the adsorbate and the substrate, which goes hand in hand with an increasing adsorption distance of the PTCDA molecules caused by a bending of their carboxylic oxygens away from the substrate and toward the potassium atoms. PMID- 28902495 TI - Selective Synthesis of Primary Anilines from Cyclohexanone Oximes by the Concerted Catalysis of a Mg-Al Layered Double Hydroxide Supported Pd Catalyst. AB - Although the selective conversion of cyclohexanone oximes to primary anilines would be a good complement to the classical synthetic methods for primary anilines, which utilize arenes as the starting materials, there have been no general and efficient methods for the conversion of cyclohexanone oximes to primary anilines until now. In this study, we have successfully realized the efficient conversion of cyclohexanone oximes to primary anilines by utilizing a Mg-Al layered double hydroxide supported Pd catalyst (Pd(OH)x/LDH) under ligand-, additive-, and hydrogen-acceptor-free conditions. The substrate scope was very broad with respect to both cyclohexanone oximes and cyclohexenone oximes, which gave the corresponding primary anilines in high yields with high selectivities (17 examples, 75% to >99% yields). The reaction could be scaled up (gram-scale) with a reduced amount of the catalyst (0.2 mol %). Furthermore, the one-pot synthesis of primary anilines directly from cyclohexanones and hydroxylamine was also successful (five examples, 66-99% yields). The catalysis was intrinsically heterogeneous, and the catalyst could be reused for the conversion of cyclohexanone oxime to aniline at least five times with keeping its high catalytic performance. Kinetic studies and several control experiments showed that the high activity and selectivity of the present catalyst system were attributed to the concerted catalysis of the basic LDH support and the active Pd species on LDH. The present transformation of cyclohexanone oximes to primary anilines proceeds through a dehydration/dehydrogenation sequence, and herein the plausible reaction mechanism is proposed on the basis of several pieces of experimental evidence. PMID- 28902496 TI - Photosensitization Behavior of Ir(III) Complexes in Selective Reduction of CO2 by Re(I)-Complex-Anchored TiO2 Hybrid Catalyst. AB - A series of cationic Ir(III) complexes ([Ir(btp)2(bpy-X2)]+ (Ir-X+: btp = (2 pyridyl)benzo[b]thiophen-3-yl; bpy-X2 = 4,4'-X2-2,2'-bipyridine (X = OMe, tBu, Me, H, and CN)) were applied as visible-light photosensitizer to the CO2 reduction to CO using a hybrid catalyst (TiO2/ReP) prepared by anchoring of Re(4,4'-Y2-bpy)(CO)3Cl (ReP; Y = CH2PO(OH)2) on TiO2 particles. Irradiation of a solution containing Ir-X+, TiO2/ReP particles, and an electron donor (1,3 dimethyl-2-phenyl-1,3-dihydrobenzimidazole) in N,N-dimethylformamide at greater than 400 nm resulted in the reduction of CO2 to CO with efficiencies in the order X = OMe > tBu ~ Me > H; Ir-CN+ has no photosensitization effect. A notable observation is that Ir-tBu+ and Ir-Me+ are less efficient than Ir-OMe+ at an early stage of the reaction but reveal persistent photosensitization behavior for a much longer period of time unlike the latter. Comparable experiments showed that (1) the Ir-X+ sensitizers are commonly superior compared to Ru(bpy)32+, a widely used transition-metal photosensitizer, and (2) the system comprising Ir OMe+ and TiO2/ReP is much more efficient than a homogeneous-solution system using Ir-OMe+ and Re(4,4'-Y'2-bpy)(CO)3Cl (Y' = CH2PO(OEt)2). Implications of the present observations involving reaction mechanisms associated with the different behavior of the photosensitizers are discussed in detail. PMID- 28902497 TI - What Is the Contribution of City-Scale Actions to the Overall Food System's Environmental Impacts?: Assessing Water, Greenhouse Gas, and Land Impacts of Future Urban Food Scenarios. AB - This paper develops a methodology for individual cities to use to analyze the in- and trans-boundary water, greenhouse gas (GHG), and land impacts of city-scale food system actions. Applied to Delhi, India, the analysis demonstrates that city scale action can rival typical food policy interventions that occur at larger scales, although no single city-scale action can rival in all three environmental impacts. In particular, improved food-waste management within the city (7% system wide GHG reduction) matches the GHG impact of preconsumer trans-boundary food waste reduction. The systems approach is particularly useful in illustrating key trade-offs and co-benefits. For instance, multiple diet shifts that can reduce GHG emissions have trade-offs that increase water and land impacts. Vertical farming technology (VFT) with current applications for fruits and vegetables can provide modest system-wide water (4%) and land reductions (3%), although implementation within the city itself may raise questions of constraints in water stressed cities, with such a shift in Delhi increasing community-wide direct water use by 16%. Improving the nutrition status for the bottom 50% of the population to the median diet is accompanied by proportionally smaller increases of water, GHG, and land impacts (4%, 9%, and 8%, systemwide): increases that can be offset through simultaneous city-scale actions, e.g., improved food-waste management and VFT. PMID- 28902498 TI - Cobinding of Pharmaceutical Compounds at Mineral Surfaces: Mechanistic Modeling of Binding and Cobinding of Nalidixic Acid and Niflumic Acid at Goethite Surfaces. AB - Although emerging contaminants rarely exist individually in environmental contaminated systems, only limited information on their adsorption mechanisms in multicomponent solutions is currently available. To address this shortcoming, this work examines for the first time the accuracy of a surface complexation model in predicting the cooperative adsorption of nalidixic acid (NA) and niflumic acid (NFA) at goethite (alpha-FeOOH) surfaces. Our model adequately predicts cobinding of an outer-sphere (OS) complex of NFA onto NA bound to goethite through metal-bonded (MB), hydrogen-bonded (HB), or OS complexes. More positive charge is introduced in the system via sodium interactions in order to describe the NFA adsorption at high NaCl concentrations in both single and binary systems. Our model confidently predicts multilayers of NA on goethite as well as NFA binding on goethite-bound NA over a large range of pH and salinity values as well as NA and NFA loadings. These findings have strong implications in the assessment and prediction of contaminant fate in multicomponent contaminated systems by invoking a nontraditional form of ligand-ligand interaction in this field of study. PMID- 28902499 TI - The Lowest Triplet of Tetracyanoquinodimethane via UV-vis Absorption Spectroscopy with Br-Containing Solvents. AB - This study was undertaken to find the previously unknown lowest triplet of the isolated molecule of tetracyanoquinodimethane (TCNQ), which is a widely used organic semiconductor. The problem is topical because the triplet excitation of this compound is involved in some processes which occur in electronic devices incorporating TCNQ and its derivatives, and information on the TCNQ triplet is needed for better understanding of these processes. The lowest triplet of TCNQ was obtained at 1.96 eV using UV-vis absorption spectroscopy with Br-containing solvents. Production of the triplet band with sufficient intensity in the spectra was provided by the capacity of the Br atom to augment the triplet excitation and through using a 100 mm cuvette. The assignment of the corresponding spectral band to the triplet transition was made by observation that this band appeared only in the spectra recorded in Br-containing solvents but not in spectra recorded in other solvents. Additional support for the triplet assignment came from the overall UV-vis absorption spectra of TCNQ recorded in various solvents, using a 10 mm cuvette, in the 1.38-6.5 eV energy range. Singlet transitions of the neutral TCNQo molecule and doublet transitions of the TCNQ- negative ion were identified in these overall spectra and were assigned with TD B3LYP/6-31G calculations. Determination of the lowest triplet of TCNQ attained in this work may be useful for theoretical studies and practical applications of this important compound. PMID- 28902501 TI - Catalyst Architecture for Stable Single Atom Dispersion Enables Site-Specific Spectroscopic and Reactivity Measurements of CO Adsorbed to Pt Atoms, Oxidized Pt Clusters, and Metallic Pt Clusters on TiO2. AB - Oxide-supported precious metal nanoparticles are widely used industrial catalysts. Due to expense and rarity, developing synthetic protocols that reduce precious metal nanoparticle size and stabilize dispersed species is essential. Supported atomically dispersed, single precious metal atoms represent the most efficient metal utilization geometry, although debate regarding the catalytic activity of supported single precious atom species has arisen from difficulty in synthesizing homogeneous and stable single atom dispersions, and a lack of site specific characterization approaches. We propose a catalyst architecture and characterization approach to overcome these limitations, by depositing ~1 precious metal atom per support particle and characterizing structures by correlating scanning transmission electron microscopy imaging and CO probe molecule infrared spectroscopy. This is demonstrated for Pt supported on anatase TiO2. In these structures, isolated Pt atoms, Ptiso, remain stable through various conditions, and spectroscopic evidence suggests Ptiso species exist in homogeneous local environments. Comparing Ptiso to ~1 nm preoxidized (Ptox) and prereduced (Ptmetal) Pt clusters on TiO2, we identify unique spectroscopic signatures of CO bound to each site and find CO adsorption energy is ordered: Ptiso ? Ptmetal < Ptox. Ptiso species exhibited a 2-fold greater turnover frequency for CO oxidation than 1 nm Ptmetal clusters but share an identical reaction mechanism. We propose the active catalytic sites are cationic interfacial Pt atoms bonded to TiO2 and that Ptiso exhibits optimal reactivity because every atom is exposed for catalysis and forms an interfacial site with TiO2. This approach should be generally useful for studying the behavior of supported precious metal atoms. PMID- 28902502 TI - Insight into the Electrochemical Sodium Insertion of Vanadium Superstoichiometric NASICON Phosphate. AB - A slight deviation of the stoichiometry has been introduced in Na3-3xV2+x(PO4)3 (0 <= x <= 0.1) samples to determine the effect on the structural and electrochemical behavior as a positive electrode in sodium-ion batteries. X-ray diffraction and XPS results provide evidence for the flexibility of the NASICON framework to allow a limited vanadium superstoichiometry. In particular, the Na2.94V2.02(PO4)3 formula reveals the best electrochemical performance at the highest rate (40C) and capacity retention upon long cycling. It is attributed to the excellent kinetic response and interphase chemical stability upon cycling. The electrochemical performance of this vanadium superstoichiometric sample in a full sodium-ion cell is also described. PMID- 28902500 TI - Stratified UWHAM and Its Stochastic Approximation for Multicanonical Simulations Which Are Far from Equilibrium. AB - We describe a new analysis tool called Stratified unbinned Weighted Histogram Analysis Method (Stratified-UWHAM), which can be used to compute free energies and expectations from a multicanonical ensemble when a subset of the parallel simulations is far from being equilibrated because of barriers between free energy basins which are only rarely (or never) crossed at some states. The Stratified-UWHAM equations can be obtained in the form of UWHAM equations but with an expanded set of states. We also provide a stochastic solver, Stratified RE-SWHAM, for Stratified-UWHAM to remove its computational bottleneck. Stratified UWHAM and Stratified RE-SWHAM are applied to study three test topics: the free energy landscape of alanine dipeptide, the binding affinity of a host-guest binding complex, and path sampling for a two-dimensional double well potential. The examples show that when some of the parallel simulations are only locally equilibrated, the estimates of free energies and equilibrium distributions provided by the conventional UWHAM (or MBAR) solutions exhibit considerable biases, but the estimates provided by Stratified-UWHAM and Stratified RE-SWHAM agree with the benchmark very well. Lastly, we discuss features of the Stratified UWHAM approach which is based on coarse-graining in relation to two other maximum likelihood-based methods which were proposed recently, that also coarse-grain the multicanonical data. PMID- 28902503 TI - Correction to "Design Principles of Electronic Couplings for Intramolecular Singlet Fission in Covalently-Linked Systems". PMID- 28902504 TI - Synthesis of Altrose Poly-amido-saccharides with beta-N-(1->2)-d-amide Linkages: A Right-Handed Helical Conformation Engineered in at the Monomer Level. AB - The design and synthesis of amide-linked saccharide oligomers and polymers, which are predisposed to fold into specific ordered secondary structures, is of significant interest. Herein, right-handed helical poly amido-saccharides (PASs) with beta-N-(1->2)-d-amide linkages are synthesized by the anionic ring-opening polymerization of an altrose beta-lactam monomer (alt-lactam). The right-handed helical conformation is engineered into the polymers by preinstalling the beta configuration of the lactam ring in the monomer via the stereospecific [2+2] cycloaddition of trichloroacetyl isocyanate with a d-glycal possessing a 3 benzyloxy group oriented to the alpha-face of the pyranose. The tert-butylacetyl chloride initiated polymerization of the alt-lactam proceeds smoothly to afford stereoregular polymers with narrow dispersities. Birch reduction of the benzylated polymers gives water-soluble altrose PASs (alt-PASs) in high yields without degradation of the polymer backbone. Circular dichroism analysis shows the alt-PASs adopt a right-handed helical conformation in aqueous solutions. This secondary conformation is stable over a wide range of different conditions, such as pH (2.0 to 12.0), temperature (5 to 75 degrees C), ionic salts (2.0 M LiCl, NaCl, and KCl), as well as in the presence of protein denaturants (4.0 M urea and guanidinium chloride). Cytotoxicity studies reveal that the alt-PASs are nontoxic to HEK, HeLa, and NIH3T3 cells. The results showcase the ability to direct solution conformation of polymers through monomer design. This approach is especially well-suited and straightforward for PASs as the helical conformations formed result from constraints imposed by the relatively rigid and sterically bulky repeating units. PMID- 28902506 TI - Noninvasive Synchrotron-Based X-ray Raman Scattering Discriminates Carbonaceous Compounds in Ancient and Historical Materials. AB - Carbon compounds are ubiquitous and occur in a diversity of chemical forms in many systems including ancient and historic materials ranging from cultural heritage to paleontology. Determining their speciation cannot only provide unique information on their origin but may also elucidate degradation processes. Synchrotron-based X-ray absorption near-edge structure (XANES) spectroscopy at the carbon K-edge (280-350 eV) is a very powerful method to probe carbon speciation. However, the short penetration depth of soft X-rays imposes stringent constraints on sample type, preparation, and analytical environment. A hard X-ray probe such as X-ray Raman scattering (XRS) can overcome many of these difficulties. Here we report the use of XRS at ~6 keV incident energy to collect carbon K-edge XANES data and probe the speciation of organic carbon in several specimens relevant to cultural heritage and natural history. This methodology enables the measurement to be done in a nondestructive way, in air, and provides information that is not compromised by surface contamination by ensuring that the dominant signal contribution is from the bulk of the probed material. Using the backscattering geometry at large photon momentum transfer maximizes the XRS signal at the given X-ray energy and enhances nondipole contributions compared to conventional XANES, thereby augmenting the speciation sensitivity. The capabilities and limitations of the technique are discussed. We show that despite its small cross section, for a range of systems the XRS method can provide satisfactory signals at realistic experimental conditions. XRS constitutes a powerful complement to FT-IR, Raman, and conventional XANES spectroscopy, overcoming some of the limitations of these techniques. PMID- 28902505 TI - Activation Mechanism of the Streptomyces Tyrosinase Assisted by the Caddie Protein. AB - Tyrosinase (EC 1.14.18.1), which possesses two copper ions at the active center, catalyzes a rate-limiting reaction of melanogenesis, that is, the conversion of a phenol to the corresponding ortho-quinone. The enzyme from the genus Streptomyces is generated as a complex with a "caddie" protein that assists the transport of two copper ions into the active center. In this complex, the Tyr98 residue in the caddie protein was found to be accommodated in the pocket of the active center of tyrosinase, probably in a manner similar to that of l-tyrosine as a genuine substrate of tyrosinase. Under physiological conditions, the addition of the copper ion to the complex releases tyrosinase from the complex, in accordance with the aggregation of the caddie protein. The release of the copper-bound tyrosinase was found to be accelerated by adding reducing agents under aerobic conditions. Mass spectroscopic analysis indicated that the Tyr98 residue was converted to a reactive quinone, and resonance Raman spectroscopic analysis indicated that the conversion occurred through the formations of MU-eta2:eta2 peroxo-dicopper(II) and Cu(II)-semiquinone. Electron paramagnetic resonance analysis under anaerobic conditions and Fourier transform infrared spectroscopic analysis using CO as a structural probe under anaerobic conditions indicated that the copper transportation process to the active center is a reversible event in the tyrosinase/caddie complex. Aggregation of the caddie protein, which is triggered by the conversion of the Tyr98 residue to dopaquinone, may ensure the generation of fully activated tyrosinase. PMID- 28902507 TI - [a]-Phenanthrene-Fused BF2 Azadipyrromethene (AzaBODIPY) Dyes as Bright Near Infrared Fluorophores. AB - A new substitution pattern of BF2 azadipyrromethene (azaBODIPY) dyes was obtained by phenanthrene fusion through a key palladium-catalyzed intramolecular C-H activation reaction. These [a]-phenanthrene-fused azaBODIPYs have a near planar structure of the phenanthrene-fused azadipyrromethene core in the crystalline state. The chromophore absorbs (log epsilon > 5) and fluoresces (phi = 0.32-0.38) strongly above 700 nm with excellent photostability and may be used as an attractive bright NIR bioimaging agent. PMID- 28902508 TI - Single-Molecule Fluorescence Microscopy Reveals Local Diffusion Coefficients in the Pore Network of an Individual Catalyst Particle. AB - We used single-molecule fluorescence microscopy to study self-diffusion of a feedstock-like probe molecule with nanometer accuracy in the macropores of a micrometer-sized, real-life fluid catalytic cracking (FCC) particle. Movies of single fluorescent molecules allowed their movement through the pore network to be reconstructed. The observed tracks were classified into three different states by machine learning and all found to be distributed homogeneously over the particle. Most probe molecules (88%) were immobile, with the molecule most likely being physisorbed or trapped; the remainder was either mobile (8%), with the molecule moving inside the macropores, or showed hybrid behavior (4%). Mobile tracks had an average diffusion coefficient of D = 8 * 10-14 +/- 1 * 10-13 m2 s 1, with the standard deviation thought to be related to the large range of pore sizes found in FCC particles. The developed methodology can be used to evaluate, quantify and map heterogeneities in diffusional properties within complex hierarchically porous materials. PMID- 28902509 TI - Exploring a New Approach for Discovery of Conformational Heterogeneity in Homeodomain-DNA Complexes. PMID- 28902511 TI - Exploring the Stability of Ligand Binding Modes to Proteins by Molecular Dynamics Simulations: A Cross-docking Study. AB - Docking has become an indispensable approach in drug discovery research to predict the binding mode of a ligand. One great challenge in docking is to efficiently refine the correct pose from various putative docking poses through scoring functions. We recently examined the stability of self-docking poses under molecular dynamics (MD) simulations and showed that equilibrium MD simulations have some capability to discriminate between correct and decoy poses. Here, we have extended our previous work to cross-docking studies for practical applications. Three target proteins (thrombin, heat shock protein 90-alpha, and cyclin-dependent kinase 2) of pharmaceutical interest were selected. Three comparable poses (one correct pose and two decoys) for each ligand were then selected from the docking poses. To obtain the docking poses for the three target proteins, we used three different protocols, namely: normal docking, induced fit docking (IFD), and IFD against the homology model. Finally, five parallel MD equilibrium runs were performed on each pose for the statistical analysis. The results showed that the correct poses were generally more stable than the decoy poses under MD. The discrimination capability of MD depends on the strategy. The safest way was to judge a pose as being stable if any one run among five parallel runs was stable under MD. In this case, 95% of the correct poses were retained under MD, and about 25-44% of the decoys could be excluded by the simulations for all cases. On the other hand, if we judge a pose as being stable when any two or three runs were stable, with the risk of incorrectly excluding some correct poses, approximately 31-53% or 39-56% of the two decoys could be excluded by MD, respectively. Our results suggest that simple equilibrium simulations can serve as an effective filter to exclude decoy poses that cannot be distinguished by docking scores from the computationally expensive free-energy calculations. PMID- 28902510 TI - Stereospecific Formation of E- and Z-Disubstituted Double Bonds by Dehydratase Domains from Modules 1 and 2 of the Fostriecin Polyketide Synthase. AB - The dehydratase domain FosDH1 from module 1 of the fostriecin polyketide synthase (PKS) catalyzed the stereospecific interconversion of (3R)-3-hydroxybutyryl FosACP1 (5) and (E)-2-butenoyl-FosACP1 (11), as established by a combination of direct LC-MS/MS and chiral GC-MS. FosDH1 did not act on either (3S)-3 hydroxybutyryl-FosACP1 (6) or (Z)-2-butenoyl-FosACP1 (12). FosKR2, the ketoreductase from module 2 of the fostriecin PKS that normally provides the natural substrate for FosDH2, was shown to catalyze the NADPH-dependent stereospecific reduction of 3-ketobutyryl-FosACP2 (23) to (3S)-3-hydroxybutyryl FosACP2 (8). Consistent with this finding, FosDH2 catalyzed the interconversion of the corresponding triketide substrates (3R,4E)-3-hydroxy-4-hexenoyl-FosACP2 (18) and (2Z,4E)-2,4-hexadienoyl-FosACP2 (21). FosDH2 also catalyzed the stereospecific hydration of (Z)-2-butenoyl-FosACP2 (14) to (3S)-3-hydroxybutyryl FosACP2 (8). Although incubation of FosDH2 with (3S)-3-hydroxybutyryl-FosACP2 (8) did not result in detectable accumulation of (Z)-2-butenoyl-FosACP2 (14), FosDH2 catalyzed the slow exchange of the 3-hydroxy group of 8 with [18O]-water. FosDH2 unexpectedly could also support the stereospecific interconversion of (3R)-3 hydroxybutyryl-FosACP2 (7) and (E)-2-butenoyl-FosACP2 (13). PMID- 28902513 TI - Coexistence of Physisorbed and Solvated HCl at Warm Ice Surfaces. AB - The interfacial ionization of strong acids is an essential factor of multiphase and heterogeneous chemistry in environmental science, cryospheric science, catalysis research and material science. Using near ambient pressure core level X ray photoelectron spectroscopy, we directly detected a low surface coverage of adsorbed HCl at 253 K in both molecular and dissociated states. Depth profiles derived from XPS data indicate the results as physisorbed molecular HCl at the outermost ice surface and dissociation occurring upon solvation deeper in the interfacial region. Complementary X-ray absorption measurements confirm that the presence of Cl- ions induces significant changes to the hydrogen bonding network in the interfacial region. This study gives clear evidence for nonuniformity across the air-ice interface and questions the use of acid-base concepts in interfacial processes. PMID- 28902512 TI - Cloud Processing of Secondary Organic Aerosol from Isoprene and Methacrolein Photooxidation. AB - Aerosol-cloud interaction contributes to the largest uncertainties in the estimation and interpretation of the Earth's changing energy budget. The present study explores experimentally the impacts of water condensation-evaporation events, mimicking processes occurring in atmospheric clouds, on the molecular composition of secondary organic aerosol (SOA) from the photooxidation of methacrolein. A range of on- and off-line mass spectrometry techniques were used to obtain a detailed chemical characterization of SOA formed in control experiments in dry conditions, in triphasic experiments simulating gas-particle cloud droplet interactions (starting from dry conditions and from 60% relative humidity (RH)), and in bulk aqueous-phase experiments. We observed that cloud events trigger fast SOA formation accompanied by evaporative losses. These evaporative losses decreased SOA concentration in the simulation chamber by 25 32% upon RH increase, while aqueous SOA was found to be metastable and slowly evaporated after cloud dissipation. In the simulation chamber, SOA composition measured with a high-resolution time-of-flight aerosol mass spectrometer, did not change during cloud events compared with high RH conditions (RH > 80%). In all experiments, off-line mass spectrometry techniques emphasize the critical role of 2-methylglyceric acid as a major product of isoprene chemistry, as an important contributor to the total SOA mass (15-20%) and as a key building block of oligomers found in the particulate phase. Interestingly, the comparison between the series of oligomers obtained from experiments performed under different conditions show a markedly different reactivity. In particular, long reaction times at high RH seem to create the conditions for aqueous-phase processing to occur in a more efficient manner than during two relatively short cloud events. PMID- 28902514 TI - Chemoselective Double Annulation of Two Different Isocyanides: Rapid Access to Trifluoromethylated Indole-Fused Heterocycles. AB - An unprecedented chemoselective double annulation of alpha-trifluoromethylated isocyanides with o-acylaryl isocyanides has been developed. This new reaction provides a rapid, efficient, and complete atom-economic strategy for the synthesis of trifluoromethylated oxadiazino[3,2-a]indoles in a single operation from readily available starting materials. Isocyanide insertion into C?O double bonds is disclosed for the first time as indicated by the results of 18O-labeling experiment. A mechanism for this domino reaction is proposed involving chemoselective heterodimerization of two different isocyanides, followed by indole-2,3-epoxide formation and rearrangement. PMID- 28902515 TI - Theoretical and Experimental Investigation of Acidity of the Glutamate Receptor Antagonist 6,7-Dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding. AB - The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pKa of 6.99 +/- 0.02 and 10.57 +/- 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, omegaB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1' binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2. PMID- 28902516 TI - Electronic Band Structure of Helical Polyisocyanides. AB - Restricted Hartree-Fock computations are reported for a methyl isocyanide polymer (repeating unit -C?N-CH3), whose most stable conformation is expected to be a helical chain. The computations used a standard contracted Gaussian orbital set at the computational levels STO-3G, 3-21G, 6-31G, and 6-31G**, and studies were made for two line-group configurations motivated by earlier work and by studies of space-filling molecular models: (1) A structure of line-group symmetry L95, containing a 9-fold screw axis with atoms displaced in the axial direction by 5/9 times the lattice constant, and (2) a structure of symmetry L41 that had been proposed, containing a 4-fold screw axis with translation by 1/4 of the lattice constant. Full use of the line-group symmetry was employed to cause most of the computational complexity to depend only on the size of the asymmetric repeating unit. Data reported include computed bond properties, atomic charge distribution, longitudinal polarizability, band structure, and the convoluted density of states. Most features of the description were found to be insensitive to the level of computational approximation. The work also illustrates the importance of exploiting line-group symmetry to extend the range of polymer structural problems that can be treated computationally. PMID- 28902517 TI - Te Monolayer-Driven Spontaneous van der Waals Epitaxy of Two-dimensional Pnictogen Chalcogenide Film on Sapphire. AB - Demands on high-quality layer structured two-dimensional (2D) thin films such as pnictogen chalcogenides and transition metal dichalcogenides are growing due to the findings of exotic physical properties and potentials for device applications. However, the difficulties in controlling epitaxial growth and the unclear understanding of van der Waals epitaxy (vdWE) for a 2D chalcogenide film on a three-dimensional (3D) substrate have been major obstacles for the further advances of 2D materials. Here, we exploit the spontaneous vdWE of a high-quality 2D chalcogenide (Bi0.5Sb1.5Te3) film by the chalcogen-driven surface reconstruction of a conventional 3D sapphire substrate. It is verified that the in situ formation of a pseudomorphic Te atomic monolayer on the surface of sapphire, which results in a dangling bond-free surface, allows the spontaneous vdWE of 2D chalcogenide film. Since this route uses the natural surface reconstruction of sapphire with chalcogen under vacuum condition, it can be scalable and easily utilized for the developments of various 2D chalcogenide vdWE films through conventional thin-film fabrication technologies. PMID- 28902518 TI - The Reaction between Sodium Hydroxide and Atomic Hydrogen in Atmospheric and Flame Chemistry. AB - We report the first direct kinetic study of the gas-phase reaction NaOH + H -> Na + H2O, which is central to the chemistry of sodium in the upper atmosphere and in flames. The reaction was studied in a fast flow tube, where NaOH was observed by multiphoton ionization and time-of-flight mass spectrometry, yielding k(NaOH + H, 230-298 K) = (3.8 +/- 0.8) * 10-11 cm3 molecule -1 s-1 (at 2sigma confidence level), showing no significant temperature dependence over the indicated temperature range and essentially in agreement with previous estimates of the rate constant in hydrogen-rich flames. We show, using theoretical trajectory calculations, that the unexpectedly slow, yet T-independent, rate coefficient for NaOH + H is explained by severe constraints in the angle of attack that H can make on NaOH to produce H2O. This reaction is also central to explaining Na catalyzed flame inhibition, which has been proposed to occur via the sequence Na + OH (+ M) -> NaOH followed by NaOH + H -> Na + H2O, thereby effectively recombinating H and OH to H2O. RRKM calculations for the recombination of Na and OH yield k(Na + OH + N2, 300-2400 K) = 2.7 * 10-29 (300/T)1.2 cm6 molecule-2 s-1, in agreement with a previous flash photolysis measurement at 653 K and Na-seeded flame studies in the 1800-2200 K range. These results therefore provide strong evidence to support the mechanism of flame inhibition by Na. PMID- 28902519 TI - Effects of Chromophoric Dissolved Organic Matter on Anthracene Photolysis Kinetics in Aqueous Solution and Ice. AB - We measured photolysis kinetics of the PAH anthracene in aqueous solution, in bulk ice, and at ice surfaces in the presence and absence of chromophoric dissolved organic matter (CDOM). Self-association, which occurs readily at ice surfaces, may be responsible for the faster anthracene photolysis observed there. Photolysis rate constants in liquid water increased under conditions where anthracene self-association was observed. Concomitantly, kinetics changed from first-order to second-order, indicating that the photolysis mechanism at ice surfaces might be different than that in aqueous solution. Other factors that could lead to faster photolysis at ice surfaces were also investigated. Increased photon fluxes due to scattering in the ice samples can account for at most 20% of the observed rate increase, and other factors including singlet oxygen (1O2*) production and changes in pH and polarity were determined not to be responsible for the faster photolysis. CDOM (in the form of fulvic acid (FA)) did not affect anthracene photolysis kinetics in aqueous solution but suppressed photolysis in ice cubes and ice granules (by 30% and 56%, respectively). This was primarily due to competitive photon absorption (the inner filter effect). Freeze-concentration (or "salting out") appears to slightly increase the suppressing effects of FA on anthracene photolysis. This may be due to increased competitive photon absorption or to physical interactions between anthracene and FA. PMID- 28902520 TI - Cascade Radical Cyclization of N-Propargylindoles: Substituents Dictate Stereoselective Formation of N-Fused Indolines versus Indoles. AB - An efficient protocol for the synthesis of pyrrolo[1,2-a]indole derivatives having sulfide functionality using cascade radical cyclization on propargylindole is described. The nature of the substituents at the propargylic carbon bearing nitrogen of the indole has a profound effect on the rate, yield, and nature of the product obtained by the cascade radical cyclization. An expeditious one-pot route for cascade radical cyclization-desulfurization is also presented. Products obtained were elaborated to the core of the putative structure of the yuremamine and indoline derivative with five contiguous stereocenters. PMID- 28902521 TI - Identification of Novel Protein Expression Changes Following Cisplatin Treatment and Application to Combination Therapy. AB - Determining the effect of chemotherapeutic treatment on changes in protein expression can provide important targets for overcoming resistance. Due to challenges in simultaneously measuring large numbers of proteins, a paucity of data exists on global changes. To overcome these challenges, we utilized microwestern arrays that allowed us to measure the abundance and modification state of hundreds of cell signaling and transcription factor proteins in cells following drug exposure. HapMap lymphoblastoid cell lines (LCLs) were exposed to cisplatin, a chemotherapeutic agent commonly used to treat testicular, head and neck, non-small cell lung, and gynecological cancers. We evaluated the expression of 259 proteins following 2, 6, and 12 h of cisplatin treatment in two LCLs with discordant sensitivity to cisplatin. Of these 259 proteins, 66 displayed significantly different protein expression changes (p < 0.05). Fifteen of these proteins were evaluated in a second pair of LCLs with discordant sensitivities to cisplatin; six demonstrated significant differences in expression. We then evaluated a subset of 63 proteins in a second set of LCLs with discordant sensitivity, and 40% of those that were significant in the first pair were also significant in the second part with concordant directionality (p < 0.05). We functionally validated one of the top proteins identified, PDK1, and demonstrated a synergistic relationship between cisplatin and a PDK1 inhibitor in multiple lung cancer lines. This study highlights the potential for identifying novel targets through an understanding of cellular changes in protein expression and modification following drug treatments. PMID- 28902522 TI - Delinquency and sexual experiences across adolescence: does depression play a role? AB - PURPOSE: To elucidate a possible connection between delinquency and adolescent sexual behaviours in different age groups from 14 to 20 and the role of depression therein. MATERIALS AND METHODS: Data were gathered from the cross sectional Finnish School Health Promotion Study 2010 and 2011 with 186,632 respondents. We first examined the bivariate relationship between delinquency and sexual behaviour, and then proceeded to multivariate models accounting for self reported depression. Analyses were conducted separately for girls and boys, in seven age groups. The main outcomes were analysed by chi2 test and logistic regression. RESULTS: Delinquency was connected to having experienced sexual intercourse across all age groups, and was related to reporting multiple sexual partners among sexually active adolescents, in both boys and girls, before and after controlling for depression. Delinquency and depression were independently associated with the sexual behaviours studied. CONCLUSIONS: Being sexually active and engaging in risky sexual behaviours are related to delinquency in the adolescent population throughout the developmental phase, even in late adolescence when being sexually active is developmentally normative. Being sexually active is further connected to depression until middle adolescence, and risky sexual behaviours across adolescence. Clinicians working with adolescents presenting with delinquent behaviour with or without depression need to address their sexual health needs. PMID- 28902523 TI - Functional assessment of lesion severity without using the pressure wire: coronary imaging and blood flow simulation. AB - INTRODUCTION: Hemodynamic indices derived from measurements with the pressure wire (primarily fractional flow reserve [FFR]) have been established as a reliable tool for assessing coronary stenoses and improving clinical decision making. However, the use of the pressure wire constitutes a hurdle for the universal adoption of physiology-guided patient management. Technological advancements have enabled the large-scale application of blood flow simulation (computational fluid dynamics [CFD]) to medical imaging, thereby enabling the virtual assessment of coronary physiology. Areas covered: This review summarizes the stand-alone non-invasive (coronary computed tomographic imaging) and invasive (coronary angiography) imaging approaches which were initially used for predicting FFR, and focuses on the use of blood flow modeling for functional assessment of coronary lesions in clinical practice. Expert commentary: Validation studies of CFD-derived methodologies for functional assessment have shown that virtual indices correlate well and have good diagnostic accuracy compared to pressure wire-FFR despite inherent limitations of spatial resolution and assumptions regarding boundary conditions in flow modeling. Beyond point-to point agreement with FFR, further studies are needed to demonstrate the clinical safety/efficacy of these computational tools regarding patient outcomes. Such evidence base could support the incorporation of these methodologies into routine patient management for decision making and reliable risk stratification. PMID- 28902524 TI - Molecular Cytogenetic Characterization Identified the Murine B-Cell Lymphoma Cell Line A-20 as a Model for Sporadic Burkitt's Lymphoma. AB - Here, we report the first molecular cytogenetic characterization of the BALB/cAnN mouse derived B-cell non-Hodgkin lymphoma (B-cell NHL) cell lines A-20. Even though previously used as a model for testing of, for example, dexametason, up to present, no data in the genetic properties of A-20 were available. The present study closed this gap and provides evidence that A-20 is a model for B-cell NHL subgroup sporadic Burkitt's lymphoma. C-myc oncogene is involved in a translocation and copy number alterations as gain of murine 14q material could be observed. Interestingly, the cell line showed the karyotype 39,X,-X or Y,t(2;15)(qE5;qD2),del(6)(qB3qC3),del(9)(qA3qA4),dup(14)(qE1qE4) in ~95% of the cells, being exceptionally stable for cell lines being established 38 years ago. Still, ~5% of the cells showed polyploidization followed by chromothripsis. It remains to be determined if this can be observed also in other cell lines, just has not been reported yet, and/or if it is a unique feature of A-20. Overall, finally here, the necessary genetic data to identify A-20 as a model for human sporadic Burkitt's lymphoma are provided. PMID- 28902525 TI - Lurasidone: efficacy and safety in the treatment of psychotic and mood disorders. AB - INTRODUCTION: Lurasidone ([3aR,4S,7R,7aS]-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3 yl)piperazin-1yl-methyl] cyclohexylmethyl]-hexahydro-4,7-methano-2H-isoindole-1,3 dione hydrochloride; Latuda(r)) is a novel benzisothiazole, second-generation antipsychotic drug developed by Dainippon Sumitomo Pharma Corporation in Japan. Similar to other atypical antipsychotics it has a distinctive pharmacodynamic profile, Areas covered: This review updates reported research findings on the efficacy, safety and tolerability of LRSD for treatment of psychotic and major affective disorders, with meta-analyses. Short-term efficacy of LRSD in schizophrenia is supported by several randomized, controlled trials with daily doses of 40-160 mg, yielding relatively modest symptomatic improvements. Lurasidone has regulatory approval for treatment of undefined duration in schizophrenia. Long-term benefits and effects in schizophrenia, and both short- and long-term use for other psychotic disorders and mania have not been tested. LRSD shows unusual efficacy in acute bipolar depression even without psychotic features. However, trials of adding LRSD to lithium or valproate for bipolar disorder have yielded inconsistent findings. Expert opinion: Available research findings indicate that LRSD is effective and well-tolerated for short-term treatment of schizophrenia, and for acute bipolar depression. It has low risk of inducing weight-gain, metabolic, or cardiac abnormalities, but its risk of akathisia may exceed that of other modern antipsychotics. Needed is adequate long term testing in schizophrenia and bipolar disorder and testing for other indications, including against alternative treatments. PMID- 28902526 TI - Driving Performance After Self-Regulated Control Transitions in Highly Automated Vehicles. AB - OBJECTIVE: This study aims to explore whether driver-paced, noncritical transitions of control may counteract some of the aftereffects observed in the contemporary literature, resulting in higher levels of vehicle control. BACKGROUND: Research into control transitions in highly automated driving has focused on urgent scenarios where drivers are given a relatively short time span to respond to a request to resume manual control, resulting in seemingly scrambled control when manual control is resumed. METHOD: Twenty-six drivers drove two scenarios with an automated driving feature activated. Drivers were asked to read a newspaper or monitor the system and relinquish or resume control from the automation when prompted by vehicle systems. Driving performance in terms of lane positioning and steering behavior was assessed for 20 seconds post resuming control to capture the resulting level of control. RESULTS: It was found that lane positioning was virtually unaffected for the duration of the 20-second time span in both automated conditions compared to the manual baseline when drivers resumed manual control; however, significant increases in the standard deviation of steering input were found for both automated conditions compared to baseline. No significant differences were found between the two automated conditions. CONCLUSION: The results indicate that when drivers self-paced the transfer back to manual control they exhibit less of the detrimental effects observed in system-paced conditions. APPLICATION: It was shown that self-paced transitions could reduce the risk of accidents near the edge of the operational design domain. Vehicle manufacturers must consider these benefits when designing contemporary systems. PMID- 28902527 TI - Smoking in the family is most predictive of the development of childhood asthma in preterm babies <30 weeks gestation: Results of the Respiratory Outcomes Study 2 (RESPOS2). AB - OBJECTIVES: The Respiratory Outcomes Study 2 (RESPOS2) investigated the relationship between neonatal outcomes (specifically, chronic lung disease [CLD]) and environmental factors on the development of asthma and atopic outcomes at primary school age for preterm babies (PBs) <30 weeks gestational age (GA). METHODS: The study included all surviving PBs <30 weeks GA admitted to the Neonatal Intensive Care Unit at Canberra Hospital, Australian Capital Territory between 2007 and 2009. Parents were sent a questionnaire regarding asthma and atopy symptoms when the PBs were aged 5-7 years old. Data were compared based on CLD status. RESULTS: There were 103 PBs included in the study with a 68.9% response rate to the respiratory questionnaire (71/103). Of these PBs, 15/71 (21.1%) received a diagnosis of CLD. There were no significant differences with regards to asthma, hay fever or eczema in PBs either with or without CLD. The most significant predictor for the development of asthma was smoking in the family (Odds Ratio [OR]: 11.66, 95% Confidence Interval [CI]: 2.01-67.56) with a trend toward significance for family history of asthma (OR: 3.83, 95% CI: 0.85 17.25). CONCLUSION: The RESPOS2 has confirmed previous reports that CLD in PBs <30 weeks GA is not associated with the development of childhood asthma, hay fever or eczema. In our group of PBs, the strongest predictor of the development of asthma was smoking in the family. PMID- 28902528 TI - Serbian medical students' fertility awareness and attitudes towards future parenthood. AB - OBJECTIVES: Medical students represent a group particularly at risk of involuntary childlessness due to their highly demanding careers and university curriculum. The aim of this study was to investigate Serbian medical students' attitudes towards future parenthood and their awareness of fertility issues. METHODS: A cross-sectional study was conducted among fourth year students at the Faculty of Medicine, University of Belgrade, Serbia, between 12 and 16 December 2016. Data were collected through an anonymous 56-item validated questionnaire, translated into the Serbian language. The participation rate was 87.1%. RESULTS: More than 95% of students, regardless of gender, wanted to have children in the future; most indicated three as the desired number of children. Both genders equally rated the importance of having children. Women rated significantly higher the likelihood of IVF treatment or child adoption if faced with infertility (both p = .001). All students wanted to have their first child before the age of 35 years. Knowledge about the age-related decline in female fertility was not satisfactory. Women found it more important to have children when they felt sufficiently mature, were in a stable relationship, were financially secure, had completed their studies, were not too old to have children, and had access to childcare, although these prerequisites were rated highly by both genders. CONCLUSION: Serbian medical students greatly value and have a positive perception of future parenthood. Appropriate education is needed, however, because of their inadequate knowledge of the age-related decline in female fertility. PMID- 28902529 TI - Evaluation of the 2016 Infectious Diseases Society of America/American Thoracic Society Guideline Criteria for Risk of Multidrug-Resistant Pathogens in Patients with Hospital-acquired and Ventilator-associated Pneumonia in the ICU. PMID- 28902530 TI - Corrigendum. PMID- 28902531 TI - Estradiol in hormonal contraception: real evolution or just same old wine in a new bottle? PMID- 28902532 TI - Comparison of Spectrophotometry, Chromate Inhibition, and Cytofluorometry Versus Gene Sequencing for Detection of Heterozygously Glucose-6-Phosphate Dehydrogenase Deficient Females. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency worldwide. Detection of heterozygously deficient females can be difficult as residual activity in G6PD-sufficient red blood cells (RBCs) can mask deficiency. In this study, we compared accuracy of 4 methods for detection of G6PD deficiency in females. Blood samples from females more than 3 months of age were used for spectrophotometric measurement of G6PD activity and for determination of the percentage G6PD-negative RBCs by cytofluorometry. An additional sample from females suspected to have G6PD deficiency based on the spectrophotometric G6PD activity was used for measuring chromate inhibition and sequencing of the G6PD gene. Of 165 included females, 114 were suspected to have heterozygous deficiency. From 75 females, an extra sample was obtained. In this group, mutation analysis detected 27 heterozygously deficient females. The sensitivity of spectrophotometry, cytofluorometry, and chromate inhibition was calculated to be 0.52 (confidence interval [CI]: 0.32-0.71), 0.85 (CI: 0.66 0.96), and 0.96 (CI: 0.71-1.00, respectively, and the specificity was 1.00 (CI: 0.93-1.00), 0.88 (CI: 0.75-0.95), and 0.98 (CI: 0.89-1.00), respectively. Heterozygously G6PD-deficient females with a larger percentage of G6PD-sufficient RBCs are missed by routine methods measuring total G6PD activity. However, the majority of these females can be detected with both chromate inhibition and cytofluorometry. PMID- 28902535 TI - Toward a Public Health Politics of Consequence: An Autobiographical Reflection. PMID- 28902536 TI - Income and Wealth Gaps, Inequitable Public Policies, and the Tentacles of Racism. PMID- 28902533 TI - Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. AB - Purpose This phase III trial evaluated the efficacy and safety of pazopanib versus placebo in patients with locally advanced renal cell carcinoma (RCC) at high risk for relapse after nephrectomy. Patients and Methods A total of 1,538 patients with resected pT2 (high grade) or >= pT3, including N1, clear cell RCC were randomly assigned to pazopanib or placebo for 1 year; 403 patients received a starting dose of 800 mg or placebo. To address toxicity attrition, the 800-mg starting dose was lowered to 600 mg, and the primary end point analysis was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135). Primary analysis was performed after 350 DFS events in the intent-to treat (ITT) pazopanib 600 mg group (ITT600mg), and DFS follow-up analysis was performed 12 months later. Secondary end point analyses included DFS with ITT pazopanib 800 mg (ITT800mg) and safety. Results The primary analysis results of DFS ITT600mg favored pazopanib but did not show a significant improvement over placebo (hazard ratio [HR], 0.86; 95% CI, 0.70 to 1.06; P = .165). The secondary analysis of DFS in ITT800mg (n = 403) yielded an HR of 0.69 (95% CI, 0.51 to 0.94). Follow-up analysis in ITT600mg yielded an HR of 0.94 (95% CI, 0.77 to 1.14). Increased ALT and AST were common adverse events leading to treatment discontinuation in the pazopanib 600 mg (ALT, 16%; AST, 5%) and 800 mg (ALT, 18%; AST, 7%) groups. Conclusion The results of the primary DFS analysis of pazopanib 600 mg showed no benefit over placebo in the adjuvant setting. PMID- 28902537 TI - Leveraging Interest to Decrease Rural Health Disparities in the United States. PMID- 28902538 TI - Growing Economic Inequality Sustains Health Disparities. PMID- 28902534 TI - Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG 706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer. AB - Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m2 IV and carboplatin area under the concentration-time curve 6 mg/mL ? min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade >= 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. PMID- 28902540 TI - AJPH Global News. PMID- 28902539 TI - Can Population Health Science Counter In-Kind Dangerous Oversimplifications? A Public Health of Consequence, October 2017. PMID- 28902541 TI - Years of Life Lost, Age Discrimination, and the Myth of Productivity. PMID- 28902542 TI - Despair in the American Heartland? A Focus on Rural Health. PMID- 28902543 TI - Clarivate Analytics (Formerly Produced by Thomson Reuters) Journal Metrics and AJPH. PMID- 28902544 TI - Using All Means to Protect Public Health in Israel From Emerging Tobacco Products. PMID- 28902545 TI - The Complex Road Ahead for Preexposure Prophylaxis: A Primary Care Physician Perspective. PMID- 28902546 TI - Consumer-Directed Health Care for Medicaid Patients: Past and Future Reforms. PMID- 28902547 TI - Effect of Police Training and Accountability on the Mental Health of African American Adults. PMID- 28902548 TI - Antiretroviral Drugs as the Linchpin for Prevention of HIV Infections in the United States. PMID- 28902549 TI - Brexit: Severe Risks to Britain's National Health Service. PMID- 28902550 TI - The World Health Organization, Public Health Ethics, and Surveillance: Essential Architecture for Social Well-Being. PMID- 28902551 TI - Global Health and the "Inequality Machine". PMID- 28902552 TI - Despair as a Cause of Death: More Complex Than It First Appears. PMID- 28902553 TI - ERRATUM. PMID- 28902554 TI - Deaths of Despair: Why? What to Do? PMID- 28902555 TI - Obesity Prevention in the Supermarket-Choice Architecture and the Supplemental Nutrition Assistance Program. PMID- 28902556 TI - Musculoskeletal Disorders: A Neglected Group at Public Health and Epidemiology Meetings? PMID- 28902557 TI - Will Automated Driving Technologies Make Today's Effective Restraint Systems Obsolete? PMID- 28902560 TI - On Being Transnational and Transgender: Human Rights and Public Health Considerations. PMID- 28902562 TI - Preexposure Prophylaxis: Adapting HIV Prevention Models to Achieve Worldwide Access. PMID- 28902563 TI - Low-Income Housing Tax Credit: Optimizing Its Impact on Health. PMID- 28902564 TI - Relations of Shared and Unique Components of Personality and Psychosocial Functioning to Depressive Symptoms. AB - Consistent with theories of depression, several personality (e.g., high neuroticism, low extraversion) and psychosocial (e.g., interpersonal problems, cognitive content) variables predict depressive symptoms substantively. In this extended replication, we clarified whether 13 theoretically relevant personality and psychosocial variables were unique versus overlapping predictors of symptoms among 351 adult outpatients with recurrent major depressive disorder who received acute-phase cognitive therapy (CT). Using factor analysis and regression methods, we partitioned the measures' variance into general components common across the two types of measures (psychosocial and personality), within-type components shared only with other measures of the same type, and scale-specific components. From early to late in CT, and from late in CT through 8 months after response, the general components were the strongest (median r = .23)-and scale-specific components the weakest (median r = .01)-forward predictors of symptoms. We discuss implications for measurement and treatment of depression. PMID- 28902565 TI - Molecular Cloning and Characterization of Ribosomal Protein RPS9 in Echinococcus granulosus. AB - Ribosomal protein S9 (RPS9) is an essential functional gene that participates in DNA repair and developmental regulations. A sequence homolog of RPS9 has been found to be upregulated in the protoscoleces (PSCs) of Echinococcus granulosus treated with artemisinin. However, E. granulosus RPS9 (EgRPS9) has not been identified before. In the present study, the 657-base pair (bp) cDNA encoding EgRPS9 was cloned. Amino acid sequence analysis showed that EgRPS9 was similar to the RSP9 proteins from Schistosoma japonicum (SjRPS9, 86%) and Schistosoma mansoni (SmRPS9, 79%). Phylogenetic tree analysis showed that EgRPS9, SmRPS9, and SjRPS9 were clustered together. We detected the EgRPS9 gene and protein expression in PSCs exposed to artesunate (AS) which displayed a dose-dependent reduction in PSC viability for 24 hr. The results showed that the EgRPS9 ratio of the 10-MUM AS-treated ( P < 0.01) and 40-MUM AS-treated ( P < 0.05) groups were increased from that of the control group. In addition, the level of reactive oxygen species (ROS) in the AS-treated groups increased in a dose-dependent manner compared to the level in the control group. In conclusion, the expression of EgRPS9 could be induced by ROS and might participate in the oxidative damage based anti-parasite mechanism of AS treatment. PMID- 28902566 TI - Jane Eva Huffman-Roscoe B.A., M.A., Ph.D., M.P.H., C.W.F.S. PMID- 28902567 TI - Phase II cancer clinical trials for biomarker-guided treatments. AB - The design and analysis of cancer clinical trials with biomarker depend on various factors, such as the phase of trials, the type of biomarker, whether the used biomarker is validated or not, and the study objectives. In this article, we demonstrate the design and analysis of two Phase II cancer clinical trials, one with a predictive biomarker and the other with an imaging prognostic biomarker. Statistical testing methods and their sample size calculation methods are presented for each trial. We assume that the primary endpoint of these trials is a time to event variable, but this concept can be used for any type of endpoint. PMID- 28902569 TI - A New Classification of Glaridacris Cooper, 1920 (Cestoda: Caryophyllidea), Parasites of Suckers (Catostomidae) in North America, Including Erection of Pseudoglaridacris N. Gen. AB - A taxonomic study of monozoic cestodes of the genus Glaridacris Cooper, 1920 (Cestoda: Caryophyllidea), parasites of catostomid fishes in North America, confirmed artificial character of the genus which is split to 2 different, morphologically distinct, and not closely related genera. Glaridacris is newly circumscribed to include only 3 species, Glaridacris catostomi Cooper, 1920 (type species), Glaridacris terebrans ( Linton, 1893 ), and Glaridacris vogei Mackiewicz, 1976 , which are characterized by an elongate body, a cuneiloculate or wedge-shaped scolex with 6 shallow loculi, male and female gonopores at a distance from each other, follicular ovary, and circum-medullary vitelline follicles (lateral and median). A new genus, Pseudoglaridacris n. gen., is proposed to accommodate 3 species characterized by a shorter body, a bothrioloculodiscate scolex with a pair of deeper median bothria and 2 shallower loculi, male and female gonopores close together, non-follicular ovary, and with only lateral vitelline follicles. The species are: Pseudoglaridacris laruei ( Lamont, 1921 ) n. comb. (type species), Pseudoglaridacris confusa (Hunter, 1929) n. comb., and Pseudoglaridacris oligorchis ( Haderlie, 1953 ) n. comb. An annotated list of all species of both genera, with data on their hosts and distribution and keys to their identification, is provided. PMID- 28902568 TI - Interlinked bistable mechanisms generate robust mitotic transitions. AB - The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit, 1 and the mitotic checkpoint. 2 Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states. PMID- 28902570 TI - Tragedy, Perseverance, and Chance - The Story of CAR-T Therapy. PMID- 28902571 TI - Pain Perception and Body Awareness Among Individuals With Borderline Personality Disorder. AB - Studies indicate that individuals with borderline personality disorder (BPD) often demonstrate attenuated pain perception, termed hypoalgesia. This study examines the hypothesis that body awareness moderates the association between BPD and pain perception. Participants consisted of 46 women diagnosed with BPD and 47 healthy controls. Sensory testing included the measurement of heat-pain thresholds, ratings of suprathreshold stimuli, measurement of temperature evoking moderate pain, and temporal summation of noxious mechanical stimuli. Body awareness was assessed by a self-report questionnaire. As hypothesized, among subjects with low levels of body awareness, those with BPD demonstrated hypoalgesia as manifested in their lower suprathreshold pain ratings and moderate pain evoked by higher temperature, in comparison with the controls. Among those with high levels of body awareness, BPD subjects demonstrated increased reactivity to pain as manifested in their higher pain ratings and moderate pain evoked by lower temperature, in comparison with the controls. PMID- 28902572 TI - Unique and Interactive Associations Between Maltreatment and Complex Emotion Recognition Deficits and Psychopathic Traits in an Undergraduate Sample. AB - Psychopathy is defined by affective and interpersonal deficits, deviant lifestyle, and antisocial behaviors. Poor recognition of emotions and childhood maltreatment are two risk factors implicated in psychopathy. The current study examined whether childhood maltreatment and complex emotion recognition deficits showed unique and interactive associations with psychopathic traits among 261 undergraduate students. Results indicate that maltreatment was related to higher general psychopathy scores within a bifactor model comprising a general psychopathy factor and four specific factors tapping underlying dimensions of psychopathy (i.e., affective, interpersonal, lifestyle, and antisocial). A significant interaction emerged whereby maltreatment was related to higher antisocial factor scores among individuals showing poor recognition of positive emotions. In an intriguing interaction, more maltreatment was related to lower interpersonal factor scores among individuals with low/mean levels of neutral emotion recognition. The interaction of positive emotion recognition deficits and maltreatment highlights a potential intervention target among antisocial individuals who have experienced maltreatment. PMID- 28902574 TI - Dreams Deferred - The Public Health Consequences of Rescinding DACA. PMID- 28902573 TI - Preparation of umami octopeptide with recombined Escherichia coli: Feasibility and challenges. AB - The taste of umami peptide H-Lys-Gly-Asp-Glu-Glu-Ser-Leu-Ala-OH (LGAGGSLA) is controversial. One possible reason for this controversy is the use of chemically synthesized LGAGGSLA to confirm its taste. To explore other ways to further confirm the flavor of LGAGGSLA, we developed a new strategy to prepare a bio source peptide by adopting a gene engineering method to express LGAGGSLA in recombinant Escherichia coli. In our previous work, we structured the LGAGGSLA recombinant expression system and optimized the culturing conditions for preparing a fusion protein. However, the fusion protein was not cleaved by enterokinase to obtain LGAGGSLA. Because the cleavage conditions of commercial enterokinase were not specific and recombinant engineered bacteria had the potential to be used in industrial processes, in this addendum, we calculated the mass and volume yields of key processing steps in the preparation of LGAGGSLA, and established a model of cleavage conditions with the cleavage ratio of LGAGGSLA. When the LGAGGSLA was confirmed to show umami taste, it is considered as a new umami or umami enhancer. The gene information of LGAGGSLA should have a great potential in the development of new flavor product and food product containing high umami flavor. PMID- 28902575 TI - Sample-Size Planning for More Accurate Statistical Power: A Method Adjusting Sample Effect Sizes for Publication Bias and Uncertainty. AB - The sample size necessary to obtain a desired level of statistical power depends in part on the population value of the effect size, which is, by definition, unknown. A common approach to sample-size planning uses the sample effect size from a prior study as an estimate of the population value of the effect to be detected in the future study. Although this strategy is intuitively appealing, effect-size estimates, taken at face value, are typically not accurate estimates of the population effect size because of publication bias and uncertainty. We show that the use of this approach often results in underpowered studies, sometimes to an alarming degree. We present an alternative approach that adjusts sample effect sizes for bias and uncertainty, and we demonstrate its effectiveness for several experimental designs. Furthermore, we discuss an open source R package, BUCSS, and user-friendly Web applications that we have made available to researchers so that they can easily implement our suggested methods. PMID- 28902576 TI - Caring for patients with brain tumors compared to patients with non-brain tumors: Experiences and needs of informal caregivers in home care settings. AB - BACKGROUND/OBJECTIVE: Informal caregivers of patients with advanced cancer experience a challenging time, especially while caring for the patient at home. The aim of this study is to compare experiences, perceived burdens, and needs during home care of informal caregivers of brain tumor patients and informal caregivers of non-brain tumor patients. METHODS: 28 informal caregivers (17 brain tumor group, 11 non-brain tumor group) participated in this study. Semi structured interviews were conducted to gather information retrospectively. Data was analyzed using principles of thematic analysis method. RESULTS: The results support existing evidence that the themes assessment of the situation, dealing with the situation, effects of the situation, and support by others are of importance to all informal caregivers. Caregivers in the brain tumor group put more emphasis on information and perception of the situation by others than caregivers in the non-brain tumor group. CONCLUSION: The emerging need for information of caregivers and the effects for caregivers of changes in the perception of the situation by others should be addressed to better support informal caregivers of brain tumor patients. PMID- 28902577 TI - Post-irradiation promotes susceptibility to reprogramming to pluripotent state in human fibroblasts. AB - Ionizing radiation causes not only targeted effects in cells that have been directly irradiated but also non-targeted effects in several cell generations after initial exposure. Recent studies suggest that radiation can enrich for a population of stem cells, derived from differentiated cells, through cellular reprogramming. Here, we elucidate the effect of irradiation on reprogramming, subjected to two different responses, using an induced pluripotent stem cell (iPSC) model. iPSCs were generated from non-irradiated cells, directly-irradiated cells, or cells subsequently generated after initial radiation exposure. We found that direct irradiation negatively affected iPSC induction in a dose-dependent manner. However, in the post-irradiated group, after five subsequent generations, cells became increasingly sensitive to the induction of reprogramming compared to that in non-irradiated cells as observed by an increased number of Tra1-81 stained colonies as well as enhanced alkaline phosphatase and Oct4 promoter activity. Comparative analysis, based on reducing the number of defined factors utilized for reprogramming, also revealed enhanced efficiency of iPSC generation in post-irradiated cells. Furthermore, the phenotypic acquisition of characteristics of pluripotent stem cells was observed in all resulting iPSC lines, as shown by morphology, the expression of pluripotent markers, DNA methylation patterns of pluripotency genes, a normal diploid karyotype, and teratoma formation. Overall, these results suggested that reprogramming capability might be differentially modulated by altered radiation-induced responses. Our findings provide that susceptibility to reprogramming in somatic cells might be improved by the delayed effects of non-targeted response, and contribute to a better understanding of the biological effects of radiation exposure. PMID- 28902578 TI - Associations between the HLA-A/B/DRB1 polymorphisms and aplastic anemia: evidence from 17 case-control studies. AB - OBJECTIVE: To estimate the associations between HLA-A/B/DRB1 polymorphisms and aplastic anemia (AA), we carried out the meta-analysis. METHODS: In this meta analysis, all publications in English and Chinese were considered up to 30 September 2015. The electronic databases we searched were Pubmed, Science Direct, Embase, Web of Science, CNKI, Wanfang Data and VIP. We conducted all statistical data analyses in the Stata11.0 software. RESULTS: A total of 17 studies including 9164 subjects (containing 1372 cases and 7792 controls) were retrieved, which studied the relationship between HLA-A/B/DRB1 and AA. Odds ratios (ORs) with 95% confidence intervals (CIs) for the comparisons between cases and controls were calculated. The result revealed that HLA-A*02 and HLA-DRB1 (*0407, *15 and *1501) polymorphisms might increase the risk of AA. Otherwise, HLA-DRB1 (*0301, *04, *0406, *0802, *1301, *1302 and *14) were protective against AA. But, other sites of HLA-A/B/DRB1 in our study had no correlations with AA (all Pc > 0.05). CONCLUSION: In conclusion, HLA-A/B/DRB1 polymorphisms may play an important role in AA, but higher quality and larger sample studies are needed to confirm. PMID- 28902579 TI - Effect of liver histopathology on islet cell engraftment in the model mimicking autologous islet cell transplantation. AB - BACKGROUND: The inflammatory milieu in the liver as determined by histopathology is different in individual patients undergoing autologous islet cell transplantation. We hypothesized that inflammation related to fatty-liver adversely impacts islet survival. To test this hypothesis, we used a mouse model of fatty-liver to determine the outcome of syngeneic islet transplantation after chemical pancreatectomy. METHODS: Mice (C57BL/6) were fed a high-fat-diet from 6 weeks of age until attaining a weight of >=28 grams (6-8 weeks) to produce a fatty liver (histologically > 30% fat);steatosis was confirmed with lipidomic profile of liver tissue. Islets were infused via the intra-portal route in fatty liver and control mice after streptozotocin induction of diabetes. Outcomes were assessed by the rate of euglycemia, liver histopathology, evaluation of liver inflammation by measuring tissue cytokines IL-1beta and TNF-alpha by RT-PCR and CD31 expression by immunohistochemistry. RESULTS: The difference in the euglycemic fraction between the normal liver group (90%, 9/10) and the fatty liver group (37.5%, 3/8) was statistically significant at the 18th day post- transplant and was maintained to the end of the study (day 28) (p = 0.019, X2 = 5.51). Levels of TNF-alpha and IL-1beta were elevated in fatty-liver mice (p = 0.042, p = 0.037). Compared to controls cytokine levels were elevated after islet cell transplantation and in transplanted fatty-liver mice as compared to either fatty- or islet transplant group alone (p = NS). A difference in the histochemical pattern of CD31 could not be determined. CONCLUSION: Fatty-liver creates an inflammatory state which adversely affects the outcome of autologous islet cell transplantation. PMID- 28902581 TI - Case 28-2017. A 13-Month-Old Girl with Pneumonia and a 33-Year-Old Woman with Hip Pain. PMID- 28902582 TI - Marfan's Syndrome with Ectopia Lentis. PMID- 28902583 TI - Transplanting HCV-Infected Kidneys into Uninfected Recipients. PMID- 28902584 TI - Transplanting HCV-Infected Kidneys into Uninfected Recipients. PMID- 28902585 TI - Transplanting HCV-Infected Kidneys into Uninfected Recipients. PMID- 28902586 TI - Vaccination Rates among Younger Siblings of Children with Autism. PMID- 28902587 TI - Hospital-Readmission Risk - Isolating Hospital Effects from Patient Effects. AB - BACKGROUND: To isolate hospital effects on risk-standardized hospital-readmission rates, we examined readmission outcomes among patients who had multiple admissions for a similar diagnosis at more than one hospital within a given year. METHODS: We divided the Centers for Medicare and Medicaid Services hospital-wide readmission measure cohort from July 2014 through June 2015 into two random samples. All the patients in the cohort were Medicare recipients who were at least 65 years of age. We used the first sample to calculate the risk standardized readmission rate within 30 days for each hospital, and we classified hospitals into performance quartiles, with a lower readmission rate indicating better performance (performance-classification sample). The study sample (identified from the second sample) included patients who had two admissions for similar diagnoses at different hospitals that occurred more than 1 month and less than 1 year apart, and we compared the observed readmission rates among patients who had been admitted to hospitals in different performance quartiles. RESULTS: In the performance-classification sample, the median risk-standardized readmission rate was 15.5% (interquartile range, 15.3 to 15.8). The study sample included 37,508 patients who had two admissions for similar diagnoses at a total of 4272 different hospitals. The observed readmission rate was consistently higher among patients admitted to hospitals in a worse-performing quartile than among those admitted to hospitals in a better-performing quartile, but the only significant difference was observed when the patients were admitted to hospitals in which one was in the best-performing quartile and the other was in the worst performing quartile (absolute difference in readmission rate, 2.0 percentage points; 95% confidence interval, 0.4 to 3.5; P=0.001). CONCLUSIONS: When the same patients were admitted with similar diagnoses to hospitals in the best-performing quartile as compared with the worst-performing quartile of hospital readmission performance, there was a significant difference in rates of readmission within 30 days. The findings suggest that hospital quality contributes in part to readmission rates independent of factors involving patients. (Funded by Yale-New Haven Hospital Center for Outcomes Research and Evaluation and others.). PMID- 28902588 TI - Head Positioning in Acute Stroke. PMID- 28902589 TI - Head Positioning in Acute Stroke. PMID- 28902591 TI - Recent Developments in Radiotherapy. PMID- 28902592 TI - Tipping Point for Patent Foramen Ovale Closure. PMID- 28902594 TI - Waving Hello to Noninvasive Deep-Brain Stimulation. PMID- 28902595 TI - Patent Foramen Ovale after Cryptogenic Stroke - Assessing the Evidence for Closure. PMID- 28902580 TI - Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. AB - BACKGROUND: The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions. METHODS: In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging. RESULTS: We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval [CI], 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients [5.7%] vs. 20 patients [11.3%]; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P=0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure. CONCLUSIONS: Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894 .). PMID- 28902597 TI - Iridodonesis. PMID- 28902596 TI - Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis. AB - BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid. METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions. RESULTS: Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 MUg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 MUg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 MUg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater. CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327 .). PMID- 28902598 TI - Correction to: Viral Immunol 2017;30:298-301. DOI: 10.1089/vim.2016.0152. PMID- 28902599 TI - The Potential Role of Inhibitory Receptors in the Treatment of Psoriasis. AB - Psoriasis is a common autoimmune disorder that affects the skin. Approximately 30% of individuals with psoriasis will develop inflammatory arthritis, often in the setting of human leukocyte antigen B27. Both forms of disease are thought to be the result of prolonged inflammation mediated by T lymphocytes, dendritic cells, and keratinocytes. While there are treatments aimed at immunomodulation, targeting T cell co-inhibitory receptors signaling pathways may provide therapeutic benefit. This review will discuss in detail four T cell co-inhibitory receptors and their potential application for the treatment of psoriasis and psoriatic arthritis. PMID- 28902600 TI - Contact Analysis of Horizontal Cleavage Tear Treatment. AB - Horizontal cleavage tears (HCT) commonly occur in the posterior horn of the medial meniscus due to aging and degeneration. The purpose of this study was to investigate the surgical treatment of HCTs and their effect on dynamic tibiofemoral contact mechanics. The tibiofemoral contact mechanics of 10 cadaver knees were investigated using a custom dynamic loading apparatus, pressure sensor, and motion sensing camera. Three loading conditions were analyzed: 500 N compressive load, 500 N compressive load with 100 N posterior shear, and 500 N compressive load with 2.5 Nm of internal torque. Real-time peak contact pressures and contact areas were recorded throughout the full range of motion. After testing the intact meniscal state, a horizontal cleavage tear was created and included 50% of the width of the meniscus. The following procedures were performed, and the loading conditions described above were analyzed: HCT superior flap removal (5 specimens), HCT inferior flap removal (remaining 5 specimens), and both flaps removed (all 10 specimens). Statistical analysis was performed using a mixed linear effects model using the R-statistical package. The mixed linear effects statistical model identified statistically significant differences between independent variables, including the procedure performed, meniscal flap removed, meniscal region, loading condition, and knee flexion angle with respect to contact area and peak contact pressure. Peak contact pressure and contact area were not affected by selective flap removal (superior vs. inferior) or removal of both flaps of the HCT. We recommend that in the treatment of horizontal cleavage tears of the posterior horn of the medial meniscus, the outer 50% of the posterior horn of the medial meniscus should be maintained for load transmission. PMID- 28902601 TI - Impact of Diabetes on Perioperative Complications in Patients Undergoing Elective Total Shoulder Arthroplasty. AB - INTRODUCTION: Diabetes has been associated with negative outcomes following orthopaedic surgery. While previous studies have reported on diabetes-associated complications in shoulder arthroplasty, those cohorts were heterogeneous in terms of patient population, nature of elective surgery, and arthroplasty type. Given that the number of elective total shoulder arthroplasties (TSAs) performed has grown substantially in volume and is predicted to rise even further, it is important to recognize the role that diabetes may play in developing in-hospital complications within a more homogenous sample of patients undergoing elective TSA. METHODS: The Nationwide Inpatient Sample (NIS) was searched for the year 2012 to identify all patients undergoing elective TSA. Patients with diabetes were identified, and differences regarding demographics and in-hospital outcomes were compared to non-diabetics using multivariate logistic regression. RESULTS: A total of 44,050 patients underwent elective total shoulder arthroplasty (TSA) in 2012. Diabetic patients tended to be older, of minority racial status, and had a greater medical comorbidity burden. When controlling for preoperative factors and comorbidities, diabetes was an independent risk factor for non-home bound discharge (OR 1.285; 95% CI 1.093-1.509, p = 0.002), length of stay in 75th percentile (OR 1.390; 95% CI 1.233-1.567, p < 0.001), total charges in the 75th percentile (OR 1.136; 95% CI 1.006-1.283, p = 0.040), and postoperative acute renal failure (OR 1.460; 1.002-2.128, p = 0.048). CONCLUSION: Diabetes was associated with marginal increases in non-home bound discharge, length of stay, and total charges, following elective TSA. Subgroup analysis revealed that diabetic patients undergoing reverse total shoulder arthroplasty (rTSA) have higher comorbidity burden and worse outcomes than diabetic patients undergoing anatomic total shoulder arthroplasty (aTSA). PMID- 28902602 TI - Reestablishment of the Posterior Stability After the Posterior Cruciate Ligament Released Cruciate Retaining Total Knee Arthroplasty. AB - PURPOSE: The cruciate retaining (CR) design was developed to obtain knee stability with the natural posterior cruciate ligament (PCL) in total knee arthroplasty (TKA). However, the preservation of the PCL can limit knee exposure and increase the technical challenge during the procedure. Knee exposure is easily achieved under the released PCL, and we hypothesized that the PCL naturally repairs after release, thus re-establishing the posterior stability. Accordingly, the objective of this study was to evaluate the varying of the posterior stability after the PCL-released CR TKA over time. METHODS: Eight consecutive patients received the CR TKA in which the entire PCL was subperiostealy released at its femoral insertion. Thereafter, the patients were examined with the Knee Society Score, the posterior drawer examination, and the knee ligament arthrometer postoperatively. RESULTS: Once the PCL was released, the tibia was easily subluxated, and the knee was clearly exposed intraoperatively. However, the posterior stability significantly improved with time postoperatively. We also had confirmed the reestablishment of the PCL directly at revision TKAs, one case of which is shown. CONCLUSION: The reestablishment of the posterior stability after the PCL-released CR TKA was demonstrated. This procedure to release the entire PCL subperiostealy is recommended as a means of facilitating CR TKA. PMID- 28902603 TI - The Utility of Conservative Treatment Modalities in the Management of Osteonecrosis. AB - INTRODUCTION: Osteonecrosis is an ischemic pathologic process associated with a number of conditions affecting a range of age groups. The problem faced in the management of osteonecrosis is whether conservative treatment is a viable and effective option for patients. In this systematic review, we investigated the efficacy of various nonoperative treatment modalities for hip and knee osteonecrosis, including pharmacological management and biophysical modalities. METHODS: We identified 16 studies based on electronic searches through the PubMed, Embase, CINAHL Plus, and Cochrane databases from January 2001 to November 2015. The therapies we assessed for the conservative osteonecrosis management included bisphosphonates, prostaglandin agents, enoxaparin, statins, hyperbaric oxygen, extracorporeal shockwave therapy, and pulsed electromagnetic field therapy. RESULTS: Several studies have reported that early intervention (Fiscat stage I/II) osteonecrosis can be effectively managed conservatively. Pain levels and rate of bone necrosis was decreased with bisphosphonate use. Iloprost was seen to have improvement in pain, functional, and radiological outcomes. Progression of osteonecrosis was curbed with enoxaparin use. Statin use was seen to have protective effects on bone in patients taking high dose corticosteroids. The biophysical modalities (hyperbaric oxygen, extracorporeal shockwave therapy, and pulsed electromagnetic field therapy) all saw delay and partial reversal of disease progression. CONCLUSION: Generally, stage I and II, prior to subchondral collapse, can be approached with both pharmacological and biophysical treatment modalities before more invasive measures, such as core decompression, are considered. At stage III and beyond, these conservative treatments are no longer viable treatment options. Further research must be performed to determine which modality carries the best cost to risk to benefit ratio in order to establish a standard of care for the treatment of osteonecrosis. PMID- 28902593 TI - Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. AB - BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (+/-SD) of 5.3+/ 2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .). PMID- 28902604 TI - Age of Recurrence in Idiopathic Clubfoot Treated with the Ponseti Method. AB - OBJECTIVES: While studies of patients undergoing the Ponseti method for idiopathic clubfoot demonstrate excellent correction after initial treatment, recurrence can occur in more than half of the cases. Few studies have demonstrated the age at which recurrence typically occurs or if age at discontinuation of the foot ankle orthosis (FAO) is associated with risk for surgical intervention. METHODS: Patients with idiopathic clubfoot treated with the Ponseti method with greater than 3 years of follow-up were evaluated. Age at presentation, need for percutaneous Achilles tenotomy, age of initiation of foot abduction orthosis, adherence with FAO, and need for additional treatment were recorded. Severity scores were recorded at initial presentation and yearly throughout follow-up. RESULTS: 110 patients were followed for an average of 5.9 years, and 32 patients required surgical intervention. Patients who eventually required surgery had significantly higher severity scores at presentation. Though they maintained higher scores throughout the follow-up period, they did not demonstrate significantly higher scores until 3 years of age. FAO was used until an average age of 2.6 years (range: 0.4 to 5.1 years). There was a significant difference in the age at which the FAO was stopped in those patients who eventually required surgery versus those who did not (2.2 years versus 2.8 years). CONCLUSIONS: Patients with recurrence after initially successful Ponseti treatment generally do not become distinguishable by our current classification systems until 3 years of age. Patients who used the FAO for more than 2 years were 2.77 times less likely to require surgery than those who used it less than 2 years. FAO use should be continued until at least 3 years of age in patients undergoing Ponseti treatment for idiopathic clubfoot. PMID- 28902605 TI - Trigger Finger Location and Association of Comorbidities. AB - Trigger finger is a common cause of hand pain in the adult population. Studies in the past have suggested that ring finger and thumb are the most prevalent trigger fingers. Risk factors, such as diabetes and hypothyroidism, have been reportedly linked to trigger fingers. This observational prospective study was carried out to identify the most commonly affected trigger finger and observe associated comorbidities. At a single clinical site, a total of 46 patients with 54 trigger fingers on 49 hands were identified over a 7-week period. Ring finger, thumb, and long finger were observed to be the most frequent trigger fingers. No strong association between trigger finger and comorbidities, such as diabetes or hypothyroidism was observed. PMID- 28902606 TI - An Evaluation of Patient Risk Factors to Determine Eligibility to Undergo Orthopaedic Surgery in a Freestanding Ambulatory Center A Survey of 4,242 Consecutive Patients. AB - INTRODUCTION: The value proposition of surgery at freestanding ambulatory surgery centers (FSASCs) in terms of efficiency, safety, and patient satisfaction is well established and has led to increased FSASC utilization. However, there are comorbid conditions that disqualify certain patients from surgery at FSASCs. Understanding the percentage of patients whose comorbid conditions exclude them from FSASCs is important for the proper planning and utilization of operating room assets. We aim to understand the percentage of excluded patients, and we predict that certain procedures have higher rates of disqualification due to the types of patients who undergo them. METHODS: We reviewed the records of 4,242 consecutive patients undergoing outpatient orthopaedic surgeries in our hospital system from July 2015 to February 2016. Patient characteristics, comorbidities, and procedures performed were included in our database. We analyzed each case and determined eligibility for surgery at our FSASC based on established comorbidity exclusionary guidelines. Chi-square and t-tests were used to establish statistical significance. RESULTS: Of 4,242 patients, 878 (20.7%) were ineligible for surgery at our FSASC based on accepted exclusionary guidelines. The average body mass index (BMI) of FSASC-eligible patients was 27.37, compared to 31.68 for FSASC-ineligible patients (p < 0.001). The majority, 85.6% (543/634), of American Society of Anesthesiologists (ASA) class 3 patients were FSASC-ineligible. The most common reasons for excluding patients from surgery at our FSASC were morbid obesity (25.4% of ineligible cases), untreated obstructive sleep apnea (22.1%), age less than 13 (19.6%), and coronary artery disease with prior intervention (13.3%). When stratifying by procedure, the operations most likely to be FSASC ineligible were contracture releases (39.13% ineligible, p = 0.03), trigger finger releases (36.14%, p < 0.001), carpal tunnel releases (30.63%, p = 0.009), tumor resections (38.89%, p = 0.056), rotator cuff repairs (25.47%, p = 0.078), and subacromial decompressions (30.23%, p = 0.12), primarily because these patients have more comorbidity (ASA 2.20 vs. 1.88, p < 0.001). CONCLUSIONS: Roughly 1 in 5 patients is ineligible for surgery at a freestanding ASC due to disqualifying comorbidities. Although FSASCs offer cost effective care that satisfies patients, we must understand that certain patients cannot have their surgeries at these venues. In addition, we must use additional caution when scheduling certain procedures at a FSASC. Therefore, as the number and complexity of the surgeries performed at FSASCs increase, we must better understand the factors that make patients better candidates for surgery in a hospital setting, thus minimizing transfers and readmissions and maximizing the value proposition of FSASCs. PMID- 28902607 TI - The Relationship Between Hospital-Specific Hip Arthroplasty Surgical Site Infection Rate and the Overall Hospital Infection Rate. AB - Surgical site infections (SSIs) following hip arthroplasty are a rare but devastating complication. The New York State Health Data website was analyzed for all health care acquired infections from 2008 to 2013 in all New York hospitals. Data points were SSI rates and standardized infection ratio (SIR) for each hospital-year. Pearson correlation coefficient was calculated for each SSI rate comparison. As coronary artery bypass graft and hysterectomy SSI data was not available for many hospital-years, primary comparisons to hip SSI rate were between colon SSI rate and SIR. No correlation was found between hip and other SSI rate trends and SIR, which shows that hospital environment may not be as important to SSI prevention as department- and surgeon-specific measures. PMID- 28902608 TI - Technique Tricks for the Gleich-Koutsogiannis Surgical Procedure for Correction of the Adult Acquired Flatfoot. AB - Gleich-Koutsogiannis is a widely known extra-articular closing calcaneal osteotomic technique for correction of the adult flatfoot. Absolute care must be observed during each procedural step to avoid undesirable drawbacks, such as nerves and tendons lesions, incorrect fixation, and hardware painful prominence. It is the purpose of this report to introduce tricks to critical steps in order to improve the technique and minimize potential surgical complications. PMID- 28902609 TI - Knee Extension Loss Secondary to a "Cyclops-Like" Gouty Tophus A Case Report and Literature Review. AB - While gouty arthritis of the knee is not uncommon, associated mechanical block to extension is a rarely seen complication. This report presents a unique case of extension loss due to a single, isolated intra-articular gouty tophus. Only a few similar reports have been described in the literature involving cases that are often initially suspected to be related to inherent structural knee pathology as opposed to a systemic condition or illness. PMID- 28902610 TI - Transient Vasospastic Response Following the Injection of Corticosteroid into the Hand. AB - A sixty-year-old right hand dominant woman with longstanding left basal joint arthritis and right small trigger finger presented for corticosteroid injections to both areas. She had previously received injections with no adverse effects and good relief of symptoms. Following this most recent injection of corticosteroid, she experienced transient ischemia of the left hand and the right long and ring fingers. Corticosteroid injections can rarely cause local vasospasm, even when not inadvertently injected into the vascular system. This condition is self limited following supportive treatment. PMID- 28902611 TI - Accelerated Degenerative Joint Disease After Staged Hip Arthroscopy and Periacetabular Osteotomy in a Patient with Hip Dysplasia. AB - Hip dysplasia, when significant, is effectively treated with periacetabular osteotomy. There have been good results reported with hip arthroscopy when dysplasia is mild. However, when dysplasia is significant, hip arthroscopy with labral repair alone has led to poor results and even rapid decline to end stage arthritis. Staged hip arthroscopy and periacetabular osteotomy would potentially treat the labral lesion and correct the underlying bony abnormality that resulted in the labral pathology. Such a staged treatment plan should help prevent progression to degenerative joint disease. We report a case of a 33-year-old woman who presented with left hip pain and was diagnosed with mild hip dysplasia and a labral tear. She underwent staged hip arthroscopy and labral repair followed by periacetabular osteotomy 2 weeks later. Three and a half months after surgery she developed constant pain and began limping at 5 months. Radiographs showed progression to severe degenerative joint disease. The patient was indicated for total hip arthroplasty. PMID- 28902612 TI - Monkeys overharvest shellfish. AB - The use of stone tools by macaques in Thailand has reduced the size and population density of coastal shellfish: previously it was thought that overharvesting effects resulted from human activity alone. PMID- 28902613 TI - Identification of Genes Differentially Expressed Between Midgestational and Postnatal Mouse Skin Through Suppression Subtractive Hybridization. AB - OBJECTIVE: The aim of this study was to identify differentially expressed genes between the skin of midgestational (embryonic day [ED] 14) and postnatal mice that might be involved in the wound healing process. MATERIALS AND METHODS: BALB/c mice with dated pregnancy underwent laparotomy and hysterotomy on ED14, and skin from 20 fetuses were harvested. Full-thickness dorsal skin was also harvested from 30 three-month-old postnatal mice. Total ribonucleic acid (RNA) and mRNA were purified side-by-side from the harvested skins. Differentially expressed cDNA fragments were isolated by suppression subtractive hybridization (SSH). The cDNA fragments were subsequently cloned, sequenced, and identified through a Nucelotide Basic Local Alignment Search Tool (BLASTN) search. RESULTS: Twenty differentially expressed transcripts were identified, including 18 uniquely expressed in fetal mice skin and 2 from postnatal mice skin. The known genes identified include RPS29, Nedd5, EndoA, TIEG, and eEF-1alpha, which may play an important role in scarless wound healing of embryonic mice. Two novel genes uniquely expressed in fetal mouse skin were also identified. CONCLUSION: Through SSH, 20 differentially expressed genes in the skin of midgestational and postnatal mice were identified. Two novel genes were identified that were uniquely expressed in the midgestational mouse skin. The authors suggest these genes might be involved in the scarless wound healing process. PMID- 28902614 TI - Can a combination of average of normals and "real time" External Quality Assurance replace Internal Quality Control? AB - Internal Quality Control and External Quality Assurance are separate but related processes that have developed independently in laboratory medicine over many years. They have different sample frequencies, statistical interpretations and immediacy. Both processes have evolved absorbing new understandings of the concept of laboratory error, sample material matrix and assay capability. However, we do not believe at the coalface that either process has led to much improvement in patient outcomes recently. It is the increasing reliability and automation of analytical platforms along with improved stability of reagents that has reduced systematic and random error, which in turn has minimised the risk of running less frequent IQC. We suggest that it is time to rethink the role of both these processes and unite them into a single approach using an Average of Normals model supported by more frequent External Quality Assurance samples. This new paradigm may lead to less confusion for laboratory staff and quicker responses to and identification of out of control situations. PMID- 28902615 TI - Irregular analytical errors in diagnostic testing - a novel concept. AB - BACKGROUND: In laboratory medicine, routine periodic analyses for internal and external quality control measurements interpreted by statistical methods are mandatory for batch clearance. Data analysis of these process-oriented measurements allows for insight into random analytical variation and systematic calibration bias over time. However, in such a setting, any individual sample is not under individual quality control. The quality control measurements act only at the batch level. Quantitative or qualitative data derived for many effects and interferences associated with an individual diagnostic sample can compromise any analyte. It is obvious that a process for a quality-control-sample-based approach of quality assurance is not sensitive to such errors. CONTENT: To address the potential causes and nature of such analytical interference in individual samples more systematically, we suggest the introduction of a new term called the irregular (individual) analytical error. Practically, this term can be applied in any analytical assay that is traceable to a reference measurement system. For an individual sample an irregular analytical error is defined as an inaccuracy (which is the deviation from a reference measurement procedure result) of a test result that is so high it cannot be explained by measurement uncertainty of the utilized routine assay operating within the accepted limitations of the associated process quality control measurements. SUMMARY: The deviation can be defined as the linear combination of the process measurement uncertainty and the method bias for the reference measurement system. Such errors should be coined irregular analytical errors of the individual sample. The measurement result is compromised either by an irregular effect associated with the individual composition (matrix) of the sample or an individual single sample associated processing error in the analytical process. OUTLOOK: Currently, the availability of reference measurement procedures is still highly limited, but LC-isotope dilution mass spectrometry methods are increasingly used for pre-market validation of routine diagnostic assays (these tests also involve substantial sets of clinical validation samples). Based on this definition/terminology, we list recognized causes of irregular analytical error as a risk catalog for clinical chemistry in this article. These issues include reproducible individual analytical errors (e.g. caused by anti-reagent antibodies) and non-reproducible, sporadic errors (e.g. errors due to incorrect pipetting volume due to air bubbles in a sample), which can both lead to inaccurate results and risks for patients. PMID- 28902617 TI - Analytical quality: an unfinished journey. PMID- 28902616 TI - MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy. AB - BACKGROUND: The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. METHODS: The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. CONCLUSIONS: This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease. PMID- 28902618 TI - High-sensitivity assays for cardiac troponins - continued. PMID- 28902619 TI - A case-control association study of 12 candidate genes and attempted suicide in French adolescents. AB - Background Suicide is the second leading cause of death for 10-19-year-olds. Evidence has shown that attempted suicide is a complex interplay of genes and environmental factors. In the adult population, possible associations between genetic polymorphisms and suicidal behaviors have been investigated for several genes, most often with inconsistent findings and poor replicability of significant associations. This study aimed to identify gene variants conferring risk for adolescent suicide attempt. Methods We selected the genes and variants after an analysis of the literature and a selection of the most significant associations identified. We performed analysis on 22 single nucleotide polymorphisms (SNPs) in 12 genes (COMT, CRHR1, FKBP5, SLC6A4, HTR1B, HTR2A, TPH1, TPH2, BDNF, NTRK2, NOS1 and IL28RA) for association with suicide attempt, hopelessness and impulsivity in an independent sample, composed of 98 adolescent suicide attempters who required hospitalization based on emergency assessments, and 150 healthy volunteers. Quality controls, deviations from the Hardy-Weinberg disequilibrium and statistical tests of association (case/control) were calculated using PLINK. Asymptotic p-values were corrected with the Benjamini Hochberg method. The level of significance was set to 0.05. Results We identified four polymorphisms of interest, rs10868235 (NTRK2), rs1659400 (NTRK2), rs2682826 (NOS1) and rs7305115 (TPH2), with significant associations for suicide attempts or for the quantitative hopelessness or impulsivity phenotypes. However, none of the associations withstand statistical correction tests. Conclusion Our results do not support the role of the 22 SNPs selected in suicide attempt or hopelessness and impulsivity in adolescent population. However, the relatively small sample size and the probable effect of gene-gene interaction or gene environment interaction on suicidal behavior could not be ruled out. PMID- 28902620 TI - Associations between body weight status, psychological well-being and disordered eating with intuitive eating among Malaysian undergraduate university students. AB - Intuitive eating, which can be defined as reliance on physiological hunger and satiety cues to guide eating, has been proposed as a healthy weight management strategy. To date, there has not been a published study on intuitive eating in the context of Malaysia. Therefore, this cross-sectional study aims to determine associations between body weight status, psychological well-being and disordered eating behaviors with intuitive eating among undergraduate university students. A total of 333 undergraduate respondents (21.3% males and 78.7% females) from three randomly selected faculties in a public university in Malaysia participated in this study. Respondents completed a self-administered questionnaire which featured socio-demographic characteristics, intuitive eating, self-esteem, body appreciation, general unconditional acceptance, body acceptance by others, body function and disordered eating. Body weight, height, body fat percentage and waist circumference were measured. The results from this study revealed that there was no difference (t = 0.067, p = 0.947) in intuitive eating scores between males (75.69 +/- 7.16) and females (75.62 +/- 7.90). Multiple linear regression results have shown that body appreciation (beta = 0.385, p < 0.001) and disordered eating (beta = -0.168, p = 0.001) were significant predictors of intuitive eating, which accounted for 19.6% of the variance in intuitive eating. Health promotion programs should highlight the importance of enhancing body appreciation and preventing disordered eating behaviors among university students in order to promote intuitive eating as one of the healthy weight management approaches. PMID- 28902590 TI - Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. AB - BACKGROUND: Whether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown. METHODS: In a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory. RESULTS: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. CONCLUSIONS: Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270 .). PMID- 28902621 TI - Online Teaching Efficacy: A Product of Professional Development and Ongoing Support. AB - The purpose of the pilot study was to investigate the perceptions of online teaching efficacy of nursing faculty who teach courses in which 51% or more of the content is offered online. Bandura's psychological construct of self-efficacy served as the conceptual framework. The research survey was administered to nursing faculty in a state university system located in the southeastern United States of America, plus two private universities. The Michigan Nurse Educator's Sense of Efficacy for Online Teaching Scale, which contains 32 items that measure how nurse educators judge their current capabilities for teaching online nursing courses, was used to gather data. Overall, the scores reflected that faculty perceived themselves as quite a bit efficacious on a scale that ranged from 1 to 9. As nursing educators received more support in designing and implementing online courses, their efficacy increased. It is critical that faculty are supported on an ongoing basis to increase and develop online teaching skills in order to teach high-quality courses in online programs. Faculty members must also be recognized for their work, time, and commitment required to be effective online educators. The findings of this study revealed those participants who had a number of professional development supports and release time to develop online courses have a greater sense of efficacy. PMID- 28902622 TI - Functional interaction between N-methyl-D-aspartate receptor and ascorbic acid during neuropathic pain induced by chronic constriction injury of the sciatic nerve. AB - BACKGROUND: Neuropathic pain is a chronic pain condition, which is resistant to therapy. Ascorbate was released because of the activation of glutaminergic neurons. Due to the important role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of neuropathic pain, this study investigated the analgesic efficacy of ascorbic acid (AA) in neuropathic pain condition and the role of NMDA receptors in this effect. METHODS: For this purpose, adult male rats were randomly allocated to experimental groups (n=8 in each group). Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. During the second week after CCI, animals received a single injection of 1, 3, 5, or 10 mg/kg of AA intraperitoneally and pain threshold was determined 15 and 60 min later. The antinociceptive effect of chronic administration was also evaluated by intraperitoneal injection (IP) of 3 mg/kg AA for 3 weeks. To determine the role of NMDA receptors, separate groups of animals 30 min after single injection of AA (1 mg/kg) animals received i.p. injection of ketamine (5 mg/kg), MK-801 (0.01 mg/kg), or glutamate (1000 nmol) and were tested 20 min afterwards. Data analyzed by ANOVA and Newman-Keuls tests and p<0.05 were considered as significant. RESULTS: IP of 3, 5 and 10 mg/kg increased the pain threshold during the second week after CCI (p<0.05, F=3 in tactile allodynia and p<0.01, F=3.2 in thermal and mechanical hyperalgeisa). Chronic administration of AA also produced antinociceptive effect. Ascorbic acid (1 mg/kg, i.p.) inhibited MK-801 and ketamine-induced antinociception response significantly (p<0.001, F=2). It also prevented the analgesic effect of glutamate administration (p<0.001, F=2). CONCLUSIONS: The results indicated that AA produced a dose-dependent antinociceptive effect that seems to mediate through its interaction with NMDA receptors. PMID- 28902623 TI - Chronic endurance exercise antagonizes the cardiac UCP2 and UCP3 protein up regulation induced by nandrolone decanoate. AB - BACKGROUND: Several lines of evidence revealed that chronic treatment of anabolic androgenic steroids (AASs) is accompanied with some cardiovascular side effects and in addition they also negatively mask the beneficial effects of exercise training on cardiac performance. METHODS: The present study examined whether the nandrolone decanoate (ND)-induced cardiac effects were mediated by changing the cardiac uncoupling protein 2 (UCP2) and 3 (UCP3) expression. Five groups of male wistar-albino rats including sedentary control (SC), sedentary vehicle (SV), sedentary nandrolone decanoate (SND), exercise control (EC), and exercise nandrolone decanoate (END) were used. ND was injected (10 mg/kg/week, intramuscular) to the animals in the SND and END groups and endurance exercise training was performed on a treadmill five times per week. RESULTS: The protein expressions of cardiac UCP2 and UCP3 have significantly increased in both the SND and EC groups compared to the SC ones. In contrast to UCP3, no significant differences were found between UCP2 protein expressions of the END and SC groups. Compared with the SND group, the exercise training significantly decreased the UCP2 and UCP3 protein expressions in the END group. CONCLUSIONS: The study has indicated that endurance exercise in combination with ND can result in that the exercise effectively antagonizes the effects of ND treatment on UCP2 and UCP3 up regulation. PMID- 28902625 TI - Biological Big Bytes: Integrative Analysis of Large Biological Datasets. PMID- 28902624 TI - RNA-Seq Mouse Brain Regions Expression Data Analysis: Focus on ApoE Functional Network AB - ApoE expression status was proved to be a highly specific marker of energy metabolism rate in the brain. Along with its neighbor, Translocase of Outer Mitochondrial Membrane 40 kDa (TOMM40) which is involved in mitochondrial metabolism, the corresponding genomic region constitutes the neuroenergetic hotspot. Using RNA-Seq data from a murine model of chronic stress a significant positive expression coordination of seven neighboring genes in ApoE locus in five brain regions was observed. ApoE maintains one of the highest absolute expression values genome-wide, implying that ApoE can be the driver of the neighboring gene expression alteration observed under stressful loads. Notably, we revealed the highly statistically significant increase of ApoE expression in the hypothalamus of chronically aggressive (FDR < 0.007) and defeated (FDR < 0.001) mice compared to the control. Correlation analysis revealed a close association of ApoE and proopiomelanocortin (Pomc) gene expression profiles implying the putative neuroendocrine stress response background of ApoE expression elevation therein. PMID- 28902626 TI - Pediatric differentiated thyroid carcinoma: trends in practice and outcomes over 40 years at a single tertiary care institution. AB - BACKGROUND: This study aims to analyze changes in characteristics, practice and outcomes of pediatric differentiated thyroid cancer (DTC) at our tertiary care institution. METHODS: Patients <21 years of age diagnosed between 1973 and 2013 were identified. Clinicopathological data, treatment and outcomes were obtained by a retrospective review. RESULTS: Thirteen males and 68 females were divided into Group A (n=35, diagnosed before July 1993) and Group B (n=46, diagnosed after July 1993). Group B was more likely to undergo neck ultrasound (US) (70% vs. 23%, p<0.0001) and fine-needle aspiration (FNA) biopsy (80% vs. 26%, p<0.0001). Patients in Group B more often underwent total thyroidectomy as a definitive surgical treatment (87% vs. 69%, p=0.04). There was no difference in radioactive iodine use. Recurrence-free survival was similar. CONCLUSIONS: Increased use of US and FNA has affected initial surgical management in the latter part of the study, possibly due to extension of adult DTC guidelines. The effects of the new pediatric DTC guidelines need further study. PMID- 28902628 TI - Physical activity and bone mineral density at the femoral neck subregions in adolescents with Down syndrome. AB - BACKGROUND: Low bone mineral density (BMD) has been frequently described in subjects with Down syndrome (DS). Reduced physical activity (PA) levels may contribute to low BMD in this population. The objective of the study was to investigate whether PA levels were related to the femoral neck bone mass distribution in a sample of 14 males and 12 females with DS aged 12-18 years. METHODS: BMD was evaluated by dual energy X-ray absorptiometry (DXA) at the integral, superolateral and inferomedial femoral neck regions and PA levels were assessed by accelerometry. The BMDs between the sexes and PA groups (below and above the 50th percentile of the total PA) were compared using independent t tests and analyses of covariance (ANCOVAs) controlling for age, height and body weight. RESULTS: No differences were found between the BMDs of males and females in any femoral neck region (p>0.05). Females with higher PA levels demonstrated increased integral (0.774 g/cm2 vs. 0.678 g/cm2) and superolateral femoral neck BMDs (0.696 g/cm2 vs. 0.595 g/cm2) compared to those with lower PA levels (p<0.05). In males, no differences (p<0.05) were found in the BMDs between the PA groups. CONCLUSIONS: This investigation shows that females accumulating more total PA presented increased BMDs at the integral and superolateral femoral neck regions (14.1% and 17.0%, respectively) when compared to their less active peers. These data highlight the importance of PA in females with DS to counteract their low bone mass and to improve their bone health. PMID- 28902627 TI - Serum alpha-klotho levels are not informative for the evaluation of growth hormone secretion in short children. AB - BACKGROUND: alpha-Klotho is a transmembrane protein that can be cleaved and act as a circulating hormone (s-klotho). s-Klotho serum levels seem to reflect growth hormone (GH) secretory status. We investigated the role of s-klotho as a reliable marker of GH secretion in short children and the factors influencing its secretion. METHODS: We enrolled 40 short Egyptian children (20 GH deficiency [GHD] and 20 idiopathic short stature [ISS]). They underwent a pegvisomant-primed insulin tolerance test (ITT) and were accordingly reclassified as 16 GHD and 24 ISS. The samples obtained before and 3 days after pegvisomant administration, prior to the ITT, were used for assaying insulin-like growth factor (IGF)-I and s klotho. RESULTS: IGF-I and s-klotho serum levels were not significantly different (p=0.059 and p=0.212, respectively) between GHD and ISS. After pegvisomant, a significant reduction in IGF-I and s-klotho levels was found in both groups. s Klotho significantly correlated only with IGF-I levels in both groups. CONCLUSIONS: s-Klotho mainly reflects the IGF-I status and cannot be considered a reliable biomarker for GH secretion in children. PMID- 28902629 TI - Individualised growth response optimisation (iGRO) tool: an accessible and easy to-use growth prediction system to enable treatment optimisation for children treated with growth hormone. AB - BACKGROUND: Growth prediction models (GPMs) exist to support clinical management of children treated with growth hormone (GH) for growth hormone deficiency (GHD), Turner syndrome (TS) and for short children born small for gestational age (SGA). Currently, no prediction system has been widely adopted. CONTENT: The objective was to develop a stand-alone web-based system to enable the widespread use of an 'individualised growth response optimisation' (iGRO) tool across European endocrinology clinics. A modern platform was developed to ensure compatibility with IT systems and web browsers. Seventeen GPMs derived from the KIGS database were included and tested for accuracy. SUMMARY: The iGRO system demonstrated prediction accuracy and IT compatibility. The observed discrepancies between actual and predicted height may support clinicians in investigating the reasons for deviations around the expected growth and optimise treatment. CONCLUSIONS: This system has the potential for wide access in endocrinology clinics to support the clinical management of children treated with GH for these three indications. PMID- 28902631 TI - Rare cases of galactose metabolic disorders: identification of more than two mutations per patient. PMID- 28902630 TI - Pseudohypoparathyroidism type 1B associated with assisted reproductive technology. AB - Evidence suggests an increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART). Maternal loss-of methylation at GNAS exon A/B, observed in pseudohypoparathyroidism type 1b (PHP1B), leads to decreased expression of the stimulatory Gsalpha. We present a patient conceived by ART, who presented at age 4 years with delayed neurocognitive development and persistently increased creatine kinase (CK). At 6 years an elevated PTH was detected with normal calcium and a low 25(OH) vitamin D level (25OHD). Physical exam showed a narrow forehead, nasal bridge hypoplasia and micropenis. After normalizing vitamin D, PTH remained elevated and PHP1B was therefore considered as the underlying diagnosis. An almost complete loss-of methylation was observed at GNAS exons A/B and AS, but not at exon XL, which was associated with a gain-of-methylation at exon NESP. There was no evidence of a microdeletion within the GNAS/STX16 region and analysis of several microsatellite markers for the GNAS region on Chr.20q revealed no evidence for paternal uniparental disomy (patUPD20q). Established facts Increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART) Pseudohypoparathyroidism is caused by imprinting abnormalities. Novel Insights First report of a possible association between a methylation defects that causes PHP1B and assisted conception Increased creatine kinase level was associated with an increase in PTH concentration. PMID- 28902632 TI - E-cigarettes: risk mitigation for smokers or a public health disaster? PMID- 28902634 TI - Antiproliferative activity of synthesized some new benzimidazole carboxamidines against MCF-7 breast carcinoma cells. AB - Breast cancer is the most endemic cause of cancer among women in both developed and developing countries. Benzimidazole derivatives exemplify one of the chemical classes that show strong cytotoxic activity especially against breast cancer cells (MCF-7). Aromatic amidine derivatives are known as a group of DNA interactive compounds that bind minor groove of the genome, especially A-T base pairs, and show significant in vitro and in vivo toxicity toward cancer cells. In light of these studies, some new mono/dicationic amidino benzimidazole derivatives were synthesized and evaluated for cytotoxic activity on cultured MCF 7 breast cancer cells. Some of these compounds have strongly inhibited MCF-7 cell viability in a dose-dependent manner compared with clinically used reference compounds, imatinib mesylate and docetaxel. Among them, 4-[(5(6)-bromo-1H benzimidazole-2-yl)amino]benzene-1-carboxamidine (30) showed the best inhibitory activity with IC50 value of 4.6 nM. PMID- 28902635 TI - GC-MS characterization of n-hexane soluble fraction from dandelion (Taraxacum officinale Weber ex F.H. Wigg.) aerial parts and its antioxidant and antimicrobial properties. AB - A comparative investigation of n-hexane soluble compounds from aerial parts of dandelion (Taraxacum officinale Weber ex F.H. Wigg.) collected during different vegetative stages was carried out. The GC-MS analysis of the n-hexane (unpolar) fraction showed the presence of 30 biologically active compounds. Phytol [14.7% of total ion current (TIC)], lupeol (14.5% of TIC), taraxasteryl acetate (11.4% of TIC), beta-sitosterol (10.3% of TIC), alpha-amyrin (9.0% of TIC), beta-amyrin (8.3% of TIC), and cycloartenol acetate (5.8% of TIC) were identified as the major components in n-hexane fraction. The unpolar fraction exhibited promising antioxidant activity - 46.7 mmol Trolox equivalents/g extract (determined by 1,1 diphenyl-2-picrylhydrazyl method). This fraction demonstrated insignificant antimicrobial activity and can be used in cosmetic and pharmaceutical industries. PMID- 28902633 TI - Ginkgetin inhibits proliferation of human leukemia cells via the TNF-alpha signaling pathway. AB - Ginkgetin is known to be an anticancer agent in many studies. However, its effectiveness in treating chronic myeloid leukemia [corrected] remains unknown. The present study aimed to evaluate the effects of ginkgetin on the growth of the K562 cell line. The MTT assay was employed to examine the proliferation of K562, and a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining was conducted to detect the apoptotic rates. Furthermore, changes of tumor necrosis factor-alpha (TNF-alpha) were detected by Western blot analysis. Ginkgetin inhibited the proliferation of K562 cells in a dose- and time-dependent manner. Concentrations of ginkgetin required to induce 50% death of K562 at 24, 48 and 72 h were 38.9, 31.3 and 19.2 MUM, respectively. Moreover, treatment of ginkgetin increased K562 apoptosis in vitro along with increased levels of TNF-alpha. Interestingly, anti-TNF-alpha antibody prevented ginkgetin-induced K562 cell apoptosis and growth inhibition via deactivation of caspase-8, caspase-9 and caspase-3. Concomitantly, downregulation of TNF-alpha by etanercept in vivo attenuated ginkgetin-induced inhibitory effects on the tumor growth in an xenograft mouse model. Our results indicate that ginkgetin effectively inhibits K562 cell proliferation, and TNF-alpha plays a key role in ginkgetin-induced cell apoptosis. PMID- 28902636 TI - Providing successful faculty development to graduate medical education program directors. PMID- 28902637 TI - Development of fish collagen/bioactive glass/chitosan composite nanofibers as a GTR/GBR membrane for inducing periodontal tissue regeneration. AB - The development of a guided tissue or bone regeneration (GTR/GBR) membrane with excellent performance has been a major challenge in the biomedical field. The present study was designed to prepare a biomimetic electrospun fish collagen/bioactive glass/chitosan (Col/BG/CS) composite nanofiber membrane and determine its structure, mechanical property, antibacterial activity, and biological effects on human periodontal ligament cells (HPDLCs). The effects of this composite membrane on inducing periodontal tissue regeneration were evaluated using a dog class II furcation defect model. It was found that the composite membrane had a biomimetic structure with good hydrophilicity (the contact angle was 12.83 +/- 3 degrees ) and a tensile strength of 13.1 +/- 0.43 Mpa. Compared to the pure fish collagen membrane, the composite membrane showed some degree of antibacterial activity on Streptococcus mutans. The composite membrane not only enhanced the cell viability and osteogenic gene expression of the HPDLCs, but also promoted the expression of RUNX-2 and OPN protein. Further animal experiments confirmed that the composite membrane was able to promote bone regeneration in the furcation defect of dogs. In conclusion, a biomimetic fish Col/BG/CS composite membrane has been developed in the present study, which can induce tissue regeneration with a certain degree antibacterial activity, providing a basis for potential application as a GTR/GBR membrane. PMID- 28902638 TI - [How to design studies on premature myocardial infarction?] PMID- 28902639 TI - The role of specialized prevention clinics for the short term follow-up of acute coronary syndromes. AB - OBJECTIVE: This study aimed to investigate the effect of specialized prevention clinics and standard clinics follow-ups on secondary protection after acute coronary syndrome (ACS) on cardiovascular risk factors. METHODS: A total of 118 patients who received thrombolytic therapy after being diagnosed with ST-segment elevation myocardial infarction were followed up for 6 months. After ACS, patients in a specialized prevention clinic (Group 1) (n=67) and those in a standard clinic (Group 2) (n=51) were compared in terms of the change in their lifestyle, management of risk factors, and drug compliance. RESULTS: No significant difference was found between groups in terms of baseline clinical and laboratory findings except for triglyceride level (Group 1: median 174 mg/dL; Group 2: median 136 mg/dL; p=0.039). Six months after indexing, smoking cessation (72.4% vs. 50%, p=0.037), diet compliance (43% vs.19.6%, p=0.012), and exercise rates (31% vs. 13.7%, p=0.044) were significantly higher in Group 1. Although the weight control rate was higher in Group 1, no significant difference was noted between the groups (27% vs. 15.6%, p=0.219). The rate of systolic and diastolic blood pressures >140/90 mmHg was significantly higher in Group 2 (23.5% vs. 9%, p=0.029) at 6 months. The median low-density lipoprotein cholesterol (LDL-C) value was significantly lower in Group 1 patients (Group 1: 91 mg/dL; Group 2: 102 mg/dL; p=0.042). Moreover, the rate of LDL-C <=70 mg/dL or >=50% reduction compared with baseline was significantly higher in Group 1 (32.8% vs. 13.7%, p=0.016). Although the recommended treatments were similar in both groups, the statin use rate was significantly higher in Group 1 (95.5% vs. 80.3%, p=0.021) at 6 months. CONCLUSION: The results of the study showed that specialized prevention clinics were more effective during the management of cardiovascular risk factors after ACS. PMID- 28902640 TI - Is neutrophyl to lymphocyte ratio really a useful marker for all grades of degenerative aortic stenosis? AB - OBJECTIVE: Inflammatory processes play an important role in cardiac valve calcification and ossification. The aim of this study was to investigate the relationship between the neutrophil-lymphocyte ratio (NLR) and degenerative aortic stenosis (AS). METHODS: A total of 220 patients with AS and 158 healthy individuals who were a control group were included in the study. The NLR was calculated by dividing the number of neutrophils by number of lymphocytes in peripheral blood samples. RESULTS: The study group consisted of 220 AS patients (mild/ moderate group: n=110; severe group: n=110) and 157 healthy controls. Both the mild/moderate AS group (p<0.001) and the severe AS group (p<0.001) had a significantly higher NLR compared with the control group. The NLR in the severe AS group was significantly higher than that of the mild/moderate AS group (p<0.001). The groups were similar with respect to other baseline characteristics. A receiver operating characteristic curve analysis yielded a strong predictive ability of NLR for the presence of AS (Area under the curve=0.930; 95% CI [confidence interval], 0.898-0.963; p<0.001). A cut-off value of 2.310 for NLR had a sensitivity and specificity of 80.4% and 92.4%, respectively, for the presence of AS. In multivariate logistic regression analysis, NLR (Odds ratio: 43.8; 95% CI, 14.7-130.7) was the only independent predictor of AS. CONCLUSION: The discriminative performance of NLR for AS is high. NLR is strongly and independently associated with AS. PMID- 28902641 TI - Assessment of the association between the personality traits of young patients with acute coronary syndrome and the severity of coronary artery disease. AB - OBJECTIVE: The role of psychosocial risk factors is becoming increasingly important in the etiology of acute coronary syndrome (ACS). The purpose of this study was to assess an association between the personality types of young patients with ACS and the prevalence and severity of coronary artery disease (CAD). METHODS: Patients younger than 45 years of age who presented with ACS and who underwent coronary angiography in the period from 2012 to 2016 were included in the study. The coronary angiography records of the patients were examined and their Gensini score (GS) was calculated; GS >=20 was considered to be severe CAD. The Eysenck Personality Questionnaire-Revised Short Form scales were used to measure psychoticism, extraversion, lying, and neuroticism. RESULTS: A total of 139 patients were included in the study. The median psychoticism score of patients with GS <20 was found to be significantly higher than that of patients with GS >=20 [1.0 (25th and 75th percentile: 0.0-2.0) vs. 1.0 (25th and 75th percentile: 0.0-1.0); p=0.015]. The median psychoticism score was 1.0 (25th and 75th percentile: 1.0-2.0) in the unstable angina pectoris group, 0.5 (25th and 75th percentile: 0.0-1.0) in the ST segment elevation myocardial infarction group, and 1.0 (25th and 75th percentile: 0.0-1.0) in the non-ST segment elevation myocardial infarction group (p=0.004). CONCLUSION: The presence of psychoticism characteristics in patients who present with ACS is associated with less severe CAD. PMID- 28902642 TI - The association between apelin gene polymorphism and coronary artery disease in young patients with acute obstructive coronary syndrome. AB - OBJECTIVE: The purpose of this study was to evaluate the association between V103V, 6140AG, TGA-Stop-TAA Stop, and 6016CA polymorphisms of the apelin (APLN) gene detected for the first time among young patients with acute coronary syndrome (ACS) and coronary artery disease (CAD). METHODS: This was a prospective cross-sectional study. The study population was divided into 2 groups. The first group included 132 patients who were found to have critical lesions in their coronary arteries, while the control group consisted of 41 patients who were found to have normal coronary arteries or non-critical atherosclerotic lesions. RESULTS: Among the gene polymorphisms, V103V was found to be more common in the critical CAD patients with the GG genotype compared with the control group (67.4% vs. 46.3%). On the other hand, the GT genotype was more common in the control group (53.7% vs. 32.6%). Univariate and multivariate logistic regression analysis revealed that the GG genotype of V103V was an independent predictor for the presence of critical CAD (odds ratio: 2.397; 95% confidence interval, 1.174 4.892; p=0.016). CONCLUSION: In cases of V103V polymorphism of the APLN gene, patients with the GG genotype were at a greater risk for the presence of atherosclerotic critical lesions compared with the control group. PMID- 28902643 TI - Prevalence and characteristics of coronary artery anomalies in children with congenital heart disease diagnosed with coronary angiography. AB - OBJECTIVE: Aim of the present study was to determine the prevalence of coronary artery anomalies in children with congenital heart disease. METHODS: Data of 1138 consecutive patients who were referred for cardiac catheterization and angiography for assessment of coronary anomaly between January 2005 and December 2009 were retrospectively analyzed. Total of 515 patients whose coronary arteries could be examined through left ventricle and aortic root injection were included in the study. RESULTS: Of 515 angiograms with visible coronaries, 42 patients (20 males, 22 females; mean age: 5.3+/-2.0 years) were found to have final diagnosis of coronary anomaly. Prevalence of coronary artery anomalies was 8.16% in this study. It was determined that 38 (90.4%) were anomalies of origination, 2 (4.8%) were anomalies of intrinsic coronary arterial anatomy, and 2 (4.8%) were anomalies of coronary termination. Most common coronary artery abnormality was anomalous origin of the right coronary artery from the left aortic sinus (16 patients; 38.1%), and the most common congenital heart disease was tetralogy of Fallot (18 patients; 42.9%). CONCLUSION: Recognizing variability of coronary artery anomalies is critical when considering surgical or interventional therapies in children with congenital heart disease. PMID- 28902644 TI - Serum oxidized low-density lipoprotein level as a marker of oxidative stress in patients undergoing hyperbaric oxygen therapy. AB - OBJECTIVE: Oxidative stress (OS) is involved in the pathogenesis of atherosclerosis. Hyperbaric oxygen therapy (HBOT), in which 100% oxygen is inhaled under hyperbaric pressure, may create OS. Therefore, the aim of this research was to measure the serum oxidized low-density lipoprotein (oxLDL) level in patients undergoing HBOT. METHODS: Twenty-nine patients who underwent HBOT to treat various diseases were enrolled in this study. The serum oxLDL level was measured at the beginning of the first and after the 10th therapy session. RESULTS: There was no significant difference between the oxLDL level of patients before and after HBOT (4.96+/-0.1 vs. 4.94+/-0.1 U/mL; p=0.36). CONCLUSION: HBOT seems to be safe in terms of oxLDL production up to 10 sessions. However, further large-scale studies investigating longer duration of HBOT treatment are required to understand the role of OS. PMID- 28902645 TI - [A rare cause of cyanosis in childhood: Pulmonary arteriovenous malformation]. AB - Pulmonary arteriovenous malformation, which is defined as the presence of an ab normal connection between the pulmonary artery and pulmonary vein, is rarely seen. Although it generally presents as a congenital condition, it may be accompanied by hereditary hemorrhagic telangiectasia. Clinical signs vary according to the amount of shunt in proportion to the number and size of the fistulae. Patients may present with cyanosis and respiratory trouble. If the disease remains untreated, it may result in cardiac failure and ineffective endocarditis, thereby leading to the rupture of the an-eurysmal fistula. Transcatheter embolization of abnormal vascular connection is the current treatment method in this disease. This article describes the case of an 81/2-year old child. He was presented with the symptom of getting tired quickly. Transcutaneous oxygen saturation of 75%, and pulmonary arteriovenous malfor mation was detected in his examination. Successful transcatheter fistula embolization was performed. PMID- 28902646 TI - A massive left-to-right shunt due to delayed spontaneous perforation of polyvinyl alcohol membrane of atrial septal occluder. AB - Percutaneous closure of an atrial septal defect (ASD) has emerged as an alternative to surgery. A 54-yearold woman with a history of percutaneous ASD closure with a 30-mm Cardia Ultrasept septal occluder (Cardia Inc., Eagan, MN, USA) comprising 2 discs made of Nitinol wire mesh covered with polyvinyl alcohol (PVA) membrane, was admitted to the hospital with unstable angina pectoris. In a routine examination, transthoracic echocardiography revealed a left-to-right shunt through the device. Transesophageal echocardiography (TEE) also demonstrated significant left-to-right shunt through the central portion of the prosthesis. Coronary angiography was performed, which disclosed severe stenosis in the right and left anterior descending coronary arteries. Threedimensional TEE showed multiple perforations of the PVA membrane with intact nitinol frame. Surgical removal of failing device and closure of the ASD with a pericardial patch was performed together with coronary artery bypass graft surgery. On perioperative view, the device appeared to have been correctly implanted, and the device frame was completely intact; however, the PVA membrane of both the right and left discs had almost completely disappeared and there was incomplete endothelialization around the frame. Surgeons must be aware of this rarely seen complication and they should re-examine all patients implanted with Cardia devices in regular follow-up examinations for a long period of time. PMID- 28902647 TI - Isolated left-sided partial anomalous pulmonary venous connection in a child. AB - Isolated left-sided partial anomalous pulmonary venous connection with intact interatrial septum is a rare diagnosis in childhood. In these cases, a vertical vein drains the left upper pulmonary lobe into the brachiocephalic vein and finally to the right atrium. Surgical treatment is performed to prevent right ventricular failure and pulmonary artery disease in advanced age. In this report, the rare entity of isolated left-sided anomalous pulmonary venous connection in a 14-year-old girl and successful minimally invasive surgery without cardiopulmonary bypass are described. PMID- 28902648 TI - [Fabry disease: An overlooked diagnosis in adult cardiac patients]. AB - Fabry disease is a rare, X-linked, lysosomal glycosphingolipid storage disorder. A deficiency of the enzyme alpha-galactosidase results in intracellular accumulation of globotriaosylceramide in multiple cell types, such as those of the nerves, kidneys, cardiac, and cutaneous tissues, leading to a multisystem disease. Male patients are more severely affected; however, heterozygous female patients may also be afflicted, though often the symptoms develop later. Cardiac involvement can include left ventricular hypertrophy, conduction abnormalities, arrhythmias, valvular abnormalities, and heart failure. A variant of the disease affects only cardiac tissue and mostly manifests as unexplained ventricular hypertrophy. Presently described are 2 cases of Fabry disease and the signs and symptoms of cardiac involvement, as well as the importance of early diagnosis to start enzyme replacement therapy before the development of irreversible tissue damage. PMID- 28902649 TI - Percutaneous treatment of a superior mesenteric artery pseudoaneurysm and arteriovenous fistula with coil embolization: a case report. AB - Visceral artery pseudoaneurysm and arteriovenous fistula following penetrating abdominal injuries is a rarely observed complication. Presently described is the case of a 44-year-old male admitted to the hospital after having previously experienced penetrating abdominal trauma. The patient had developed a pseudoaneurysm in the superior mesenteric artery and an arteriovenous fistula between the superior mesenteric artery and vein following surgery. The patient underwent successful coil embolization procedure and he was discharged 1 day after intervention. PMID- 28902650 TI - A rare cause of cyanosis and hypoxia that should not be forgotten after implantable cardioverter defibrillator implantation. AB - Transvenous pacemaker or implantable cardioverter defibrillator (ICD) implantation procedures are usually performed under local anesthetic, and prilocaine is the most common agent to be used. The data regarding methemoglobinemia after cardiac device implantation are scarce. Thus, presently described is the case of a 47-year-old female patient with arrhythmogenic right ventricular cardiomyopathy/dysplasia who underwent ICD implantation for secondary prophylaxis and developed cyanosis as a result of prilocaine-associated methemoglobinemia. Prilocaine was administered during the procedure. To our knowledge, this is the second case in the literature presenting methemoglobinemia due to local anesthetic after transvenous cardiac device implantation. PMID- 28902651 TI - Anticoagulant therapy for acute venous thromboembolism. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) are currently defined as venous thromboembolism (VTE) since they share pathophysiological features and the treatment is similar in many respects. It has been determined that more than 90% of PE cases originate from DVT in the legs. PE, which is difficult to diagnose, has a mortality rate of 12% when untreated. The worldwide increase in obesity, cancer diseases, and average survival time also contribute to the increase in the incidence of VTE. Traditional treatment of VTE includes heparin, low-molecular weight heparin, and warfarin. Despite availability for oral use, warfarin has a narrow therapeutic range and a wide range of food interactions. After many years of research, new oral anticoagulant agents (NOACs) are expected to overcome these handicaps in treatment. In this review, the use of NOACs in the treatment of VTE is investigated in the light of current guidelines. PMID- 28902652 TI - Case Image: Occurrence of atrial fibrillation while isolating the left atrial appendage due to vasospasm at the sinoatrial node artery. PMID- 28902653 TI - Case Image: Inferior and anterior ST-segment elevation and successful percutaneous coronary intervention in a patient with anomalous right coronary artery originating from the mid-left anterior descending artery. PMID- 28902654 TI - Case Image: Acquired pseudoaneurysm of the sinus of Valsalva. PMID- 28902655 TI - Case Image: Conservative treatment of localized periatrial hematoma associated with functional mitral stenosis, a complication of percutaneous coronary intervention. PMID- 28902656 TI - Association of neutrophil/lymphocyte ratio and CHA2DS2-VASc score with left atrial thrombus in patients who are candidates for percutaneous mitral balloon valvuloplasty. PMID- 28902657 TI - Authors' reply. PMID- 28902658 TI - Occupation, Sitting, and Weight Change in a Cohort of Women Employees. AB - OBJECTIVE: Few studies have looked at occupation and weight gain over time. We examined the influence of occupation on sitting and weight change in employed women. METHODS: A total of 228 women working as appointment coordinators or clinical assistants were surveyed regarding sitting and physical activity. Medical records were reviewed to determine changes in weight while employed in that position. Follow-up averaged 6.9 years. RESULTS: Eight hours or more of sitting daily was seen in 74% of appointment coordinators and 38% of clinical assistants (P < 0.001). Appointment coordinators were not as physically active (P = 0.026) and gained more weight (P = 0.045) over time than clinical assistants. Controlling for physical activity modestly attenuated the effect of occupation on weight gain over time (P = 0.061). CONCLUSIONS: Occupation has a profound influence on sitting and may influence physical activity and weight gain over time. PMID- 28902660 TI - Lisfranc Injury in the Athlete. PMID- 28902659 TI - Tranexamic Acid in Shoulder Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The role of tranexamic acid (TXA) in reducing blood loss following primary shoulder arthroplasty has been demonstrated in small retrospective and controlled clinical trials. This study comprehensively evaluates current literature on the efficacy of TXA to reduce perioperative blood loss and transfusion requirements following shoulder arthroplasty. METHODS: PubMed, MEDLINE, CENTRAL, and Embase were searched from the database inception date through October 27, 2016, for all articles evaluating TXA in shoulder arthroplasty. Two reviewers independently screened articles for eligibility and extracted data for analysis. A methodological quality assessment was completed for all included studies, including assessment of the risk of bias and strength of evidence. The primary outcome was change in hemoglobin and the secondary outcomes were drain output, transfusion requirements, and complications. Pooled outcomes assessing changes in hemoglobin, drain output, and transfusion requirements were determined. RESULTS: Five articles (n = 629 patients), including 3 Level-I and 2 Level-III studies, were included. Pooled analysis demonstrated a significant reduction in hemoglobin change (mean difference [MD], 0.64 g/dL; 95% confidence interval [CI], -0.84 to -0.44 g/dL; p < 0.00001) and drain output (MD, -116.80 mL; 95% CI, -139.20 to -94.40 mL; p < 0.00001) with TXA compared with controls. TXA was associated with a point estimate of the treatment effect suggesting lower transfusion requirements (55% lower risk); however, the wide CI rendered this effect statistically nonsignificant (risk ratio, 0.45; 95% CI, 0.18 to 1.09; p = 0.08). Findings were robust with sensitivity analysis of pooled outcomes from only Level-I studies. CONCLUSIONS: Moderate-strength evidence supports use of TXA for decreasing blood loss in primary shoulder arthroplasty. Further research is necessary to evaluate the efficacy of TXA in revision shoulder arthroplasty and to identify the optimal dosing and route of administration of TXA in shoulder arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28902661 TI - Giant thoracoabdominal aortic aneurysm. PMID- 28902662 TI - Circadian hemodynamics in men and women with high blood pressure: dipper vs. nondipper and racial differences. AB - OBJECTIVE: The 'nondipping' pattern of circadian blood pressure (BP) variation is an established independent predictor of adverse cardiovascular outcomes. Although this phenomenon has been widely studied, its underlying circadian hemodynamics of cardiac output and systemic vascular resistance (SVR) have not been well characterized. We evaluated the hypothesis that BP nondipping would be associated with a blunted night-time reduction in SVR in a biracial sample of 140 (63 African-American and 77 white) men and women with elevated clinic BP (130-159/85 99 mmHg). METHODS AND RESULTS: Twenty-four-hour ambulatory hemodynamics were assessed using standard ambulatory BP monitoring coupled with synchronized ambulatory impedance cardiography. Using the criterion of less than 10% dip in SBP, there were 51 nondippers (SBP dip = 7.3 +/- 2.6%) and 89 dippers (SBP dip = 15.5 +/- 3.4%). There was minimal change in cardiac output from daytime to night time in both dippers and nondippers. However, SVR decreased from daytime to night time, but nondippers compared with dippers exhibited a significantly attenuated decrease in SVR from daytime to night-time (7.8 vs. 16.1%, P < 0.001). Relative to their white counterparts, African-Americans also exhibited blunted SBP dipping (10.9 vs. 14.6%, P < 0.001) as well as an attenuated decrease in SVR (10.8 vs. 15.6%, P < 0.001). CONCLUSION: Overall, these findings indicate that blunted night-time BP dipping is associated with impairment of the systemic vasodilation that is characteristic of the night-time sleep period and is especially prominent among African-Americans. In the context of high BP, these findings suggest that nondipping may be a manifestation, or marker, of more advanced vascular disease. PMID- 28902663 TI - Aldosterone induces left ventricular subclinical systolic dysfunction: a strain imaging study. AB - BACKGROUND: Primary aldosteronism is associated with a higher incidence of left ventricular (LV) hypertrophy and diastolic dysfunction than essential hypertension. However, systolic function via endocardial measurements is similar between patients with primary aldosteronism and essential hypertension. Speckle tracking echocardiography is a sensitive tool which can detect subclinical impairments in systolic function. The aim of this study was to investigate aldosterone-induced subclinical impairments in systolic function. METHODS: We prospectively enrolled patients with primary aldosteronism and essential hypertension and analyzed their clinical data, biochemical data, and echocardiographic parameters, including myocardial strain [global longitudinal strain (GLS)]. RESULTS: Thirty-six patients with primary aldosteronism and 31 patients with essential hypertension were enrolled for analysis. The patients with primary aldosteronism had significantly lower serum potassium levels, lower plasma renin activity, higher aldosterone-to-renin ratio (ARR), and higher 24-h urinary aldosterone levels than patients with essential hypertension. With regards to echocardiographic parameters, the patients with primary aldosteronism had a thicker ventricular wall and higher LV mass index than those with essential hypertension. Most importantly, we found significant degradation of GLS in the patients with primary aldosteronism compared with those with essential hypertension (-17.84 +/- 2.36 vs. -20.13 +/- 2.32, P < 0.001). In correlation analysis, GLS was significantly correlated with serum potassium level, LV mass index, log-transformed plasma renin activity, log-transformed ARR, and log transformed 24-h urinary aldosterone levels (all P < 0.05). Multivariate linear regression analysis further identified log-transformed ARR (beta = 0.771, 95% confidence interval: 0.011-1.530, P = 0.047), and log-transformed 24-h urinary aldosterone level (beta = 1.765, 95% confidence interval: 0.01-3.529, P = 0.050) as independent factors correlated with GLS. CONCLUSION: Patients with primary aldosteronism have a lower magnitude of GLS than patients with essential hypertension, suggesting that aldosterone induces a subclinical decline in LV systolic function. PMID- 28902664 TI - Comparison of the Inhibitory Mechanisms of Diethyl Citrate, Sodium Citrate, and Phosphonoformic Acid on Calcification Induced by High Inorganic Phosphate Contents in Mouse Aortic Smooth Muscle Cells. AB - OBJECTIVE: This study aimed to investigate the differences and inhibitory effects of diethyl citrate (Et2Cit), sodium citrate (Na3Cit), and phosphonoformic acid (PFA) on calcification induced by high inorganic phosphate (Pi) contents in mouse aortic smooth muscle cells (MOVAS) and to develop drugs that can induce anticoagulation and inhibit vascular calcification (VC). METHODS: Alive and fixed MOVAS were assessed for 14 days in the presence of high Pi with increasing Et2Cit, Na3Cit, and PFA concentrations. Calcification on MOVAS was measured through Alizarin red staining and the deposited calcium amount; apoptosis was detected by annexin V staining; and cell transdifferentiation was examined by measuring smooth muscle lineage gene (alpha-SMA) expression and alkaline phosphatase activity. RESULTS: Coincubation of MOVAS with Et2Cit, Na3Cit, and PFA significantly decreased Pi-induced VC in live MOVAS, and the apoptotic rate was reduced by low inhibitor concentrations. The 3 inhibitors could prevent the alkaline phosphatase activity induced by high Pi contents and increased the expression of alpha-smooth muscle actin genes. Thus, the transdifferentiation of MOVAS into osteoblast-like cells was blocked. Their inhibitory effects exhibited concentration dependence. The inhibitory effect of each inhibitor at the same concentration showed the following trend: PFA > Na3Cit > Et2Cit. CONCLUSIONS: Et2Cit, Na3Cit, and PFA prevented the calcification of MOVAS and inhibited the osteochondrocytic conversion of vascular smooth muscle cells. Thus, Et2Cit and Na3Cit as anticoagulants may alleviate VC in clinical applications. PMID- 28902665 TI - Dissecting Surgeon Behavior: Leveraging the Theoretical Domains Framework to Facilitate Evidence-based Surgical Practice. PMID- 28902666 TI - What is in a Pronoun?: Why Gender-fair Language Matters. AB - MINI: Mounting evidence demonstrates that gender inequity is perpetuated by language. As such, understanding the ways in which linguistic bias reinforces gender and other stereotypes is paramount to creating a culture of inclusivity. This perspective reviews the science detailing the ways language reinforces gender inequality and offers strategies to reduce linguistic bias. PMID- 28902667 TI - The Liver Tunnel: Intention-to-treat Validation of a New Type of Hepatectomy. AB - OBJECTIVE: This prospective intention-to-treat validation study evaluated the liver tunnel (LT) technique for patients having >=1 deep centrally located liver tumor, with or without middle hepatic vein (MHV) invasion. BACKGROUND: Conservative surgery has been proposed for patients with deep liver tumors having complex relationships. LT is one such novel technique. METHODS: Eligible patients were prospectively enrolled for LT. LT relies on tumor-vessel detachment, and the presence of communicating veins if MHV resection is necessary. RESULTS: Twenty consecutive patients met the inclusion criteria: 17 had colorectal liver metastases, 1 had hepatocellular carcinoma, 1 had mass-forming cholangiocarcinoma, and 1 had mixed hepatocellular carcinoma-mass-forming cholangiocarcinoma. Nineteen patients underwent LT. The MHV was resected in 6 patients, always sparing segments 4i and 5. Overall, 180 lesions were removed (median 7; range 1-37): 79 lesions were included in the LT specimen (median 3; range 1-13). There was no in-hospital 90-day mortality. Overall morbidity occurred in 10 (50%) patients: major in 2 (10%). All complications were managed conservatively. After a median 15-month follow-up (range 6-48), 2 instances of cut-edge local recurrences were observed. CONCLUSIONS: This study shows that LT is technically feasible and safe. Further studies are needed for standardizing its use. PMID- 28902668 TI - Functional Results and Quality of Life Following Magnetic Anal Sphincter Augmentation in Severely Incontinent Patients. AB - OBJECTIVE: Magnetic anal sphincter augmentation is a novel surgical option in the treatment of severe fecal incontinence. This study aimed to analyze functional results, quality of life, and satisfaction after implantation in the mid-term, and to identify factors associated with success of this new treatment. METHODS: All patients, who underwent magnetic anal sphincter augmentation procedure at a single center between December 2008 and January 2016, were consecutively included. Symptom severity [Cleveland Clinic Incontinence Score (CCIS)], quality of life [Fecal-Incontinence Quality of Life Questionnaire (FIQL)], bowel diary data, and patients' satisfaction were assessed before and after implantation. RESULTS: Forty-five patients (43 female), mean (s.d.) age 66.82 (+/-10.07), were followed for a median of 36 months (range 6-84). Two patients were explanted and 1 lost to follow-up. On a 3-week diary, major leakage rate significantly improved as did CCIS and FIQL. No significant difference was seen for flatus and minor leaks. Postoperative decrease of CCIS by >=5.5 points correlated best with satisfaction, expressed by 22 patients (48% in intention-to-treat analysis). An independent predictive factor for success after implantation was no previous fecal incontinence surgical treatment. CONCLUSIONS: Satisfaction, functional, and quality of life outcomes improve significantly following magnetic anal sphincter augmentation. PMID- 28902669 TI - ALPPS Improves Resectability Compared With Conventional Two-stage Hepatectomy in Patients With Advanced Colorectal Liver Metastasis: Results From a Scandinavian Multicenter Randomized Controlled Trial (LIGRO Trial). AB - OBJECTIVE: The aim of the study was to evaluate if associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) could increase resection rates (RRs) compared with two-stage hepatectomy (TSH) in a randomized controlled trial (RCT). BACKGROUND: Radical liver metastasis resection offers the only chance of a cure for patients with metastatic colorectal cancer. Patients with colorectal liver metastasis (CRLM) and an insufficient future liver remnant (FLR) volume are traditionally treated with chemotherapy with portal vein embolization or ligation followed by hepatectomy (TSH). This treatment sometimes fails due to insufficient liver growth or tumor progression. METHODS: A prospective, multicenter RCT was conducted between June 2014 and August 2016. It included 97 patients with CRLM and a standardized FLR (sFLR) of less than 30%. Primary outcome-RRs were measured as the percentages of patients completing both stages of the treatment. Secondary outcomes were complications, radicality, and 90-day mortality measured from the final intervention. RESULTS: Baseline characteristics, besides body mass index, did not differ between the groups. The RR was 92% [95% confidence interval (CI) 84%-100%] (44/48) in the ALPPS arm compared with 57% (95% CI 43%-72%) (28/49) in the TSH arm [rate ratio 8.25 (95% CI 2.6-26.6); P < 0.0001]. No differences in complications (Clavien-Dindo >=3a) [43% (19/44) vs 43% (12/28)] [1.01 (95% CI 0.4-2.6); P = 0.99], 90-day mortality [8.3% (4/48) vs 6.1% (3/49)] [1.39 [95% CI 0.3-6.6]; P = 0.68] or R0 RRs [77% (34/44) vs 57% (16/28)] [2.55 [95% CI 0.9-7.1]; P = 0.11)] were observed. Of the patients in the TSH arm that failed to reach an sFLR of 30%, 12 were successfully treated with ALPPS. CONCLUSION: ALPPS is superior to TSH in terms of RR, with comparable surgical margins, complications, and short-term mortality. PMID- 28902670 TI - Neuroprotective effects of coenzyme Q10 on paraquat-induced Parkinson's disease in experimental animals. AB - Parkinson's disease (PD) affects ~1-2% of the elderly population. Development of a neuroprotective therapy that may be initiated early in the course of the disease to retard/prevent disease progression is highly desirable. This study aimed to investigate prophylactic treatment with coenzyme Q10 (CoQ10) before paraquat (PQ) exposure, a herbicide known to increase the risk for PD, to attain neuroprotection. In addition, therapeutic intervention with CoQ10 in mice already exposed to PQ (24 h) might halt ongoing neurodegeneration and behavioural deterioration. PD was induced experimentally in mice by an injection of PQ (10 mg/kg, intraperitoneal), twice a week for 3 consecutive weeks, either before or after the initiation of treatment with CoQ10 (200 mg/kg). The results of the sustained supplementation with CoQ10, prophylactically and therapeutically, were compared with L-DOPA (100 mg/kg). A battery of behavioural tests was performed, in addition to estimation of protein carbonyl in the brain. CoQ10 elicited a remarkable improvement in most of the behavioural tests and decreased protein carbonyl content in the brain, particularly when it was initiated before rather than after PQ induction of PD. Therefore, CoQ10, which protects against mitochondrial damage, may be beneficial in slowing the progression of PD, particularly when initiated as prophylactic treatment. PMID- 28902671 TI - Telemedicine: From Microsurgery and Free Flaps to Total Body Skin Examination. PMID- 28902672 TI - Teledermatology: Is it Beneficial to Patients? PMID- 28902673 TI - Malignant Hyperthermia Susceptibility and Related Diseases. PMID- 28902674 TI - Disruption of Hippocampal Multisynaptic Networks by General Anesthetics. AB - BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function. METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal). RESULTS: Monosynaptic population excitatory postsynaptic potentials at the basal and apical dendrites of CA1 were significantly decreased at greater than or equal to 0.25% (n = 4) and greater than or equal to 1.0% (n = 6) isoflurane, respectively. The perforant path evoked multisynaptic response at CA1 was decreased by ~50% at greater than or equal to 0.25% isoflurane (n = 5). A decreased population excitatory postsynaptic potential was accompanied by increased paired-pulse facilitation. Population spike amplitude in relation to apical dendritic population excitatory postsynaptic potential was not significantly altered by isoflurane. Spontaneous hippocampal local field potential at 0.8 to 300 Hz was dose-dependently suppressed by isoflurane (n = 6), with local field potential power in the 50- to 150-Hz band showing the highest decrease with isoflurane dose, commensurate with the decrease in trisynaptic CA1 response. Low-dose pentobarbital (n = 7) administration decreased the perforant path evoked trisynaptic CA1 response and hippocampal local field potentials at 78 to 125 Hz. CONCLUSIONS: Hippocampal networks are sensitive to low doses of isoflurane and pentobarbital, possibly through both glutamatergic and gamma aminobutyric acid-mediated transmission. Network disruption could help explain the impairment of hippocampal-dependent cognitive functions with low-dose anesthetic. PMID- 28902676 TI - Validation of the Pangao PG-800B26 upper arm blood pressure monitor in the general population according to the European Society of Hypertension and the British Hypertension Society protocols. AB - OBJECTIVE: This study aimed to evaluate the accuracy of the automated oscillometric upper arm blood pressure monitor Pangao PG-800B26 for home blood pressure monitoring according to the European Society of Hypertension International Protocol (ESH-IP) revision 2010 and the British Hypertension Society (BHS) protocols. PARTICIPANTS AND METHODS: Systolic and diastolic blood pressures were measured sequentially in 33 and 85 adults, respectively, on the basis of the ESH-IP and BHS protocols using a mercury sphygmomanometer (two observers) and the device (one supervisor). The procedures and analysis methods of the protocols were followed precisely. RESULTS: The device fulfilled the criteria of the ESH-IP, with device-observer differences of 1.01+/-5.16 and 0.58+/-4.17 mmHg for systolic and diastolic blood pressure, respectively. Furthermore, the A/A grade of the BHS protocol was also achieved for overall grading and for the three pressure levels, with average differences of 0.85+/ 6.35 and -0.15+/-5.65 mmHg for systolic and diastolic blood pressure, respectively, which also fulfilled the requirements of the Association for the Advancement of Medical Instrumentation. CONCLUSION: The Pangao PG-800B26 fulfilled the criteria of the ESH-IP 2010 and achieved the A/A grade of the BHS protocol, and hence can be recommended for home use in adults. PMID- 28902677 TI - Disparities in Awareness of HIV Postexposure and Preexposure Prophylaxis Among Notified Partners of HIV-Positive Individuals, New York City 2015-2017. AB - BACKGROUND: Named sex- or needle-sharing partners of HIV-positive individuals are a priority prevention population due to their known HIV exposure. Understanding postexposure and preexposure prophylaxis (PEP and PrEP) awareness and use among them is important for successful interventions. METHODS: Data from notified partners of HIV-positive individuals (New York City, May 2015-April 2017) were analyzed to describe PEP/PrEP awareness, provider discussion, and use by sociodemographic and risk characteristics. Multivariate logistic regression was used to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of partners' PEP and PrEP awareness. RESULTS: Among notified partners (n = 621), PEP and PrEP awareness were 34% and 44%, respectively; provider discussion of PEP was reported by 32% and of PrEP by 42%; PEP use was reported by 2% and PrEP use by 14%. PEP awareness was higher among men who have sex with men sex partners than among heterosexual sex partners (aOR: 4.21; 95% CI: 2.10 to 8.44). Odds of PrEP awareness were lower among black (aOR: 0.34; 95% CI: 0.15 to 0.75) and Hispanic partners (aOR: 0.37; 95% CI: 0.17 to 0.84) than among white partners, and higher among men who have sex with men than heterosexual sex partners (aOR: 4.60; 95% CI: 2.38 to 8.87). Black partners were less likely than whites to report a provider discussion of PrEP. Postnotification HIV-positive test results were significantly lower among partners reporting PEP awareness than among those who had not heard of PEP. CONCLUSIONS: Low levels of PEP/PrEP awareness and of provider PEP/PrEP discussion among notified partners, particularly blacks, Hispanics, and heterosexual sex partners, indicate the timeliness of tailored prevention messaging, provider training, and sensitization, to avoid disparities in PEP/PrEP use. PMID- 28902675 TI - Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept. AB - This article reviews advancements in the genetics of malignant hyperthermia, new technologies and approaches for its diagnosis, and the existing limitations of genetic testing for malignant hyperthermia. It also reviews the various RYR1 related disorders and phenotypes, such as myopathies, exertional rhabdomyolysis, and bleeding disorders, and examines the connection between these disorders and malignant hyperthermia. PMID- 28902678 TI - Brief Report: High Need to Switch cART or Comedication With the Initiation of DAAs in Elderly HIV/HCV-Coinfected Patients. AB - BACKGROUND: To describe the use of nonantiretroviral comedication and combination antiretroviral therapy (cART) in patients coinfected with HIV/hepatitis C virus (HCV) and to predict the potential for drug-drug interactions (DDIs) with direct acting antivirals (DAAs) against HCV. METHODS: This is a retrospective, cross sectional study, using the Dutch, nationwide ATHENA observational HIV cohort database. All patients with a known HIV/HCV coinfection on January 1, 2015, were included. Comedication and cART registered in the database were listed. The potential for DDIs between DAAs and comedication/cART were predicted using http://hep-druginteractions.org. DDIs were categorized as: (1) no clinically relevant DDI; (2) possible DDI; (3) contraindication; or (4) no information available. RESULTS: We included 777 patients of whom 488 (63%) used nonantiretroviral comedication. At risk for a category 2/3 DDI with nonantiretroviral comedications were 299 patients (38%). Most DDIs were predicted with paritaprevir/ritonavir, ombitasvir +/- dasabuvir (47% of the drugs) and least with grazoprevir/elbasvir (11% of the drugs). Concerning cART, daclatasvir/sofosbuvir is the most favorable combination as no cART is contraindicated with this combination. In genotype 1/4 patients, grazoprevir/elbasvir is least favorable as 75% of the patients must alter their cART. CONCLUSIONS: This study showed that comedication use in the aging HIV/HCV population is frequent and diverse. There is a high potential for DDIs between DAAs and comedication/cART. PMID- 28902679 TI - Brief Report: Peripheral Monocyte/Macrophage Phenotypes Associated With the Evolution of Cognitive Performance in HIV-Infected Patients. AB - BACKGROUND: The contribution of monocyte activation in the development of HIV associated neurocognitive disorders is not completely understood. This study aimed to explore the predictive value of peripheral monocyte/macrophage (M/M) phenotypes on the evolution of cognitive performance in a population of virologically suppressed HIV-infected patients. SETTING: Prospective, observational, longitudinal study. METHODS: HIV-1-infected patients with HIV-RNA <50copies/mL for >12 months underwent neuropsychological examination at baseline and after 1 year. Cognitive performance was evaluated using Z-transformed scores, and neurocognitive impairment (NCI) was defined according to Frascati criteria. Peripheral M/M phenotypes (classic CD14CD16, intermediate CD14CD16, and nonclassic CD14CD16) and specific surface activation markers (eg, CD163, CD11b, and CD38) were evaluated using flow cytometry at baseline. Predictive value of peripheral M/M phenotypes on the evolution of cognitive performance over 1-year follow-up was also evaluated. RESULTS: Overall, 54 patients [85.2% men, median age 50 years (range 27-60 years), 27.8% hepatitis C virus coinfected, 48.1% with past AIDS-defining events, median nadir CD4 83 cells/MUL (range 1-334), median baseline CD4 547 cells/MUL (range 136-1652)] were enrolled. Proportion of patients with NCI was low, accounting for 13% at baseline and 16.5% after 1 year (P = 0.687). Memory was the only single domain in which decreased performance after 1 year was observed (-0.25 Z-score, P = 0.025). In patients with significant decrease (>=0.5 SD) in memory performance (n = 20), significantly lower CD14CD16CD163 (% CD14CD16) (P = 0.038) and higher CD14CD38 (% CD14) (P = 0.030) levels were observed. CONCLUSIONS: In virologically suppressed HIV infected patients, the evolution of memory performance could be linked to the expression of certain peripheral activated M/M phenotypes. Such associations should be verified in larger populations over the long term. PMID- 28902680 TI - Multicountry Validation of SAMBA - A Novel Molecular Point-of-Care Test for HIV-1 Detection in Resource-Limited Setting. AB - INTRODUCTION: Early diagnosis of HIV-1 infection and the prompt initiation of antiretroviral therapy are critical to achieving a reduction in the morbidity and mortality of infected infants. The Simple AMplification-Based Assay (SAMBA) HIV-1 Qual Whole Blood Test was developed specifically for early infant diagnosis and prevention of mother-to-child transmission programs implemented at the point-of care in resource-limited settings. METHODS: We have evaluated the performance of this test run on the SAMBA I semiautomated platform with fresh whole blood specimens collected from 202 adults and 745 infants in Kenya, Uganda, and Zimbabwe. Results were compared with those obtained with the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 assay as performed with fresh whole blood or dried blood spots of the same subjects, and discrepancies were resolved with alternative assays. RESULTS: The performance of the SAMBA and CAP/CTM assays evaluated at 5 laboratories in the 3 countries was similar for both adult and infant samples. The clinical sensitivity, specificity, positive predictive value, and negative predictive value for the SAMBA test were 100%, 99.2%, 98.7%, and 100%, respectively, with adult samples, and 98.5%, 99.8%, 99.7%, and 98.8%, respectively, with infant samples. DISCUSSION: Our data suggest that the SAMBA HIV-1 Qual Whole Blood Test would be effective for early diagnosis of HIV-1 infection in infants at point-of-care settings in sub-Saharan Africa. PMID- 28902681 TI - Early Warning Scores to Predict Noncritical Events Overnight in Hospitalized Medical Patients: A Prospective Case Cohort Study. AB - BACKGROUND: Physicians are often called to evaluate patients overnight with varying levels of clinical deterioration. Early warning scores predict critical clinical deterioration in patients; however, it is unknown whether they are able to reliably predict which patients will need to be seen overnight and whether these patients will require further resource use. METHODS: A prospective case cohort study of 522 patient nights in a single tertiary care hospital in Vancouver, British Columbia, Canada, was conducted to assess the ability of Modified Early Warning Score (MEWS) and National Early Warning Score (NEWS) to predict patients who will need to be seen overnight by physicians and will require other healthcare resources. Prediction ability was assessed using area under the receiver operating characteristic curve and logistic regression models. RESULTS: The MEWS and NEWS both significantly predicted which patients needed to be seen overnight, and area under the receiver operating characteristic curves (95% confidence interval) for MEWS and NEWS were 0.72 (0.66-0.78) and 0.69 (0.63 0.76), respectively. Odds ratios (95% confidence interval) for MEWS and NEWS predicting need to be seen overnight were 1.52 (1.34-1.73) and 1.22 (1.14-1.31), respectively. CONCLUSIONS: Both MEWS and NEWS have fair ability to predict patients who will need to be seen overnight. This may be useful for improving handover and resource allocation for overnight care. PMID- 28902682 TI - The Influence of Foot-Strike Technique on the Neuromechanical Function of the Foot. AB - PURPOSE: The aim of this study was to investigate the influence of foot-strike technique on longitudinal arch mechanics and intrinsic foot muscle function during running. METHODS: Thirteen healthy participants ran barefoot on a force instrumented treadmill at 2.8 ms with a forefoot (FFS) and rearfoot (RFS; habitual) running technique, whereas kinetic, kinematic, and electromyographic data from the intrinsic foot muscles were collected simultaneously. The longitudinal arch was modeled as a single "midfoot" joint representing motion of the rearfoot (calcaneus) relative to the forefoot (metatarsals). An inverse dynamic analysis was performed to estimate joint moments generated about the midfoot, as well as mechanical work and power. RESULTS: The midfoot was more plantar flexed (higher arch) at foot contact when running with a forefoot running technique (RFS 0.2 +/- 1.8 vs FFS 6.9 +/- 3.0 degrees , effect size (ES) = 2.7); however, there was no difference in peak midfoot dorsiflexion in stance (RFS 11.6 +/- 3.0 vs FFS -11.4 +/- 3.4 degrees , ES = 0.63). When running with a forefoot technique, participants generated greater moments about the midfoot (27% increase, ES = 1.1) and performed more negative work (240% increase, ES = 2.2) and positive work (42% increase, ES = 1.1) about the midfoot. Average stance phase muscle activation was greater for flexor digitorum brevis (20% increase, ES = 0.56) and abductor hallucis (17% increase, ES = 0.63) when running with a forefoot technique. CONCLUSIONS: Forefoot running increases loading about the longitudinal arch and also increases the mechanical work performed by the intrinsic foot muscles. These findings have substantial implications in terms of injury prevention and management for runners who transition from a rearfoot to a forefoot running technique. PMID- 28902683 TI - Exercise Oscillatory Ventilation: Interreviewer Agreement and a Novel Determination. AB - INTRODUCTION: Determination of exercise oscillatory ventilation (EOV) is subjective, and the interreviewer agreement has not been reported. The purposes of this study were, among patients with heart failure (HF), as follows: 1) to determine the interreviewer agreement for EOV and 2) to describe a novel, objective, and quantifiable measure of EOV. METHODS: This was a secondary analysis of the HEART Camp: Promoting Adherence to Exercise in Patients with Heart Failure study. EOV was determined through a blinded review by six individuals on the basis of their interpretation of the EOV literature. Interreviewer agreement was assessed using Fleiss kappa (kappa). Final determination of EOV was based on agreement by four of the six reviewers. A new measure (ventilation dispersion index; VDI) was calculated for each test, and its ability to predict EOV was assessed with the receiver operator characteristics curve. RESULTS: Among 243 patients with HF (age, 60 +/- 12 yr; 45% women), the interreviewer agreement for EOV was fair (kappa = 0.303) with 10-s discrete data averages and significantly better, but only moderate (kappa = 0.429) with 30-s rolling data averages. Prevalence rates of positive and indeterminate EOVs were 18% and 30% with the 10-s discrete averages and 14% and 13% with the 30-s rolling averages, respectively. VDI was strongly associated with EOV, with areas under the receiver operator characteristics curve of 0.852 to 0.890. CONCLUSIONS: Interreviewer agreement for EOV in patients with HF is fair to moderate, which can negatively affect risk stratification. VDI has strong predictive validity with EOV; as such, it might be a useful measure of prognosis in patients with HF. PMID- 28902685 TI - Navigating a new narrative for developing countries: rising strong. PMID- 28902687 TI - Evidence implementation in lower- and middle-income countries: where the recipe is incomplete. PMID- 28902686 TI - "Worlds apart": the case of evidence utilization in Ghanaian health facilities. PMID- 28902688 TI - Facilitators and barriers to modern contraception use among reproductive-aged women living in sub-Saharan Africa: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The main objective of this qualitative review is to synthesize the best available evidence on facilitators and barriers of modern contraception use among reproductive-aged (15-49 years) women living in sub Saharan Africa [SSA].The specific review questions are. PMID- 28902684 TI - Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle. AB - The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka estrogen synthase), metabotropic glutamate receptor 1 (mGluR1), and MOR. During diestrus, spinal mERs, activated by locally synthesized estrogens, act with mGluR1 to suppress spinal EM2/MOR antinociception. The emergence of robust spinal EM2 antinociception during proestrus results from the loss of mER-mGluR1 suppression, a consequence of altered interactions within the oligomer. The chemical pairing of aromatase with mERs within the oligomer containing MOR and mGluR1 allows estrogens to function as intracellular messengers whose synthesis and actions are confined to the same signaling oligomer. This form of estrogenic signaling, which we term "oligocrine," enables discrete, highly compartmentalized estrogen/mER mGluR1 signaling to regulate MOR-mediated antinociception induced by EM2. Finally, spinal neurons were observed not only to coexpress MOR, mERalpha, aromatase, and mGluR1 but also be apposed by EM2 varicosities. This suggests that modulation of spinal analgesic responsiveness to exogenous EM2 likely reflects changes in its endogenous analgesic activity. Analogous suppression of spinal EM2 antinociception in women (eg, around menses, comparable with diestrus in rats) as well as the (pathological) inability to transition out of that suppressed state at other menstrual cycle stages could underlie, at least in part, the much greater prevalence and severity of chronic pain in women than men. PMID- 28902689 TI - Experiences of adults with intellectual disability who identify as lesbian, gay, bisexual, transgender, queer or questioning, intersex or asexual: a systematic review protocol. AB - REVIEW OBJECTIVE/QUESTION: The purpose of this systematic review is to identify, appraise and synthesize the best available qualitative evidence on the lived experiences of adults with intellectual disability who identify as lesbian, gay, bisexual, transgender, queer or questioning, intersex or asexual in mainstream society. PMID- 28902690 TI - Effectiveness of population based risk reduction programs for risky sexual behavior among young people in low- and middle-income countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to synthesize the best available evidence on the effectiveness of population based (public health) risk reduction interventions (programs and services) on sexual risk taking among young people (aged 10 to 24 years old) in low- and middle-income countries (LMICs).The specific review questions are. PMID- 28902691 TI - Foot self-management for adults with diabetes in western countries: a scoping review protocol. AB - SCOPING REVIEW OBJECTIVE/QUESTION: The objective of this scoping review is to examine and map the range of issues related to self-management of feet in adults with diabetes with similar lifestyles, risks and health care in western countries. PMID- 28902693 TI - Nutritional interventions to reduce symptoms in children and adults with attention deficit hyperactivity disorder: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this scoping review is to examine and map reported nutritional interventions and their outcomes in relieving symptoms of attention deficit hyperactivity disorder (ADHD) in the daily lives of children and adults. A further objective is to determine if experiences of people diagnosed with ADHD, their relatives or staff in being on a diet or having to eat or avoid eating specific food items have been reported in the existing literature.Specifically the scoping review questions are. PMID- 28902692 TI - The association between maternal exposure to pollutant particulate matter 2.5 and neonatal congenital heart defects: a systematic review protocol. AB - REVIEW QUESTION: The objective of this review is to identify if there is an association between maternal exposure to pollutant particulate matter 2.5 during the first trimester of pregnancy and neonatal congenital heart defects within the first year of life. PMID- 28902694 TI - Safety and effectiveness of pharmacotherapy for depression in adults who have sustained a traumatic brain injury: a systematic review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this systematic review is to synthesize the current evidence on the effectiveness and harms of pharmacotherapy in the management of depression in adults who have sustained a traumatic brain injury. PMID- 28902695 TI - Effectiveness of droxidopa compared to midodrine in standing blood pressure and orthostatic tolerance in adults with neurogenic orthostatic hypotension: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what is the effectiveness of droxidopa compared to midodrine on standing blood pressure and orthostatic intolerance symptoms in adults with neurogenic orthostatic hypotension? PMID- 28902696 TI - Impact of conditional cash transfers on child nutritional outcomes among sub Saharan African countries: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to assess the impact of conditional cash transfers on child nutritional outcomes among sub-Saharan African countries. More specifically, the objectives are to assess the impact of conditional cash transfers on child anthropometry, micro-nutrient, and improvement in dietary diversity of households. PMID- 28902697 TI - Effect of Aloe vera on glycemic outcomes in patients with diabetes mellitus: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective is to identify the effectiveness of Aloe vera on glycemic outcomes (fasting blood glucose level and glycosylated hemoglobin) in patients with diabetes mellitus. Specifically, the review question is: what is the effectiveness of oral A. vera (Aloe barbadensis) on glycemic outcomes in adult patients with pre-diabetes and type 2 diabetes mellitus as compared to a placebo group? PMID- 28902698 TI - Effect of educational and support interventions on long-term breastfeeding rates in primiparous women: a systematic review and meta-analysis. AB - BACKGROUND: Long-term breastfeeding, including exclusive breastfeeding for six months and continuation of breastfeeding with complementary food until two years of age, has been recommended by the World Health Organization. However, despite the clear benefits of long-term breastfeeding (six months and beyond), the rates of breastfeeding still continue to remain low. Although there are some individual interventional studies that aimed to increase prolonged breastfeeding rates among both multiparous and primiparous women, there is no systematic review or meta analysis to examine the effectiveness of those interventions among primiparous women who had no previous breastfeeding experience. OBJECTIVES: The aim of this review was to identify the effects of professional educational and support interventions on breastfeeding rates at six months and up to two years postpartum compared to the standard care among primiparous women. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Studies that included primiparous women aged 18 and over who intended to breastfeed. TYPES OF INTERVENTION(S): Studies that investigated the effect of educational and support interventions provided by health professionals during the antenatal, postnatal period or both. TYPES OF STUDIES: Randomized controlled trials. OUTCOMES: Studies with reported breastfeeding rates at six months or up to two years postpartum. SEARCH STRATEGY: A three-step search strategy was utilized in this review. The search was conducted in Cochrane, MEDLINE and CINAHL databases. Only trials that met the inclusion criteria and published in English were considered for this review. Databases were searched from their commencement year to May 2016. METHODOLOGICAL QUALITY: Two independent reviewers selected the papers using the standardized critical appraisal tool from the Joanna Briggs Institute. DATA EXTRACTION AND DATA SYNTHESIS: Data was extracted using the standardized Joanna Briggs Institute data extraction instrument. Quantitative data were, where possible, pooled in statistical meta analysis using RevMan v5.3 (Copenhagen: The Nordic Cochrane Centre, Cochrane). In the absence of trials comparing the same outcomes, meta-analysis could not be performed; the findings have therefore been presented in a narrative form, including tables and figures to aid in data presentation where appropriate. RESULTS: Ten randomized controlled trials were included in this review. Interventions with only one antenatal or postnatal component were not effective in increasing breastfeeding rates at six months. However, based on one trial, an intervention that included antenatal education and support in combination with postnatal education and support doubled the rate of breastfeeding at six months among primiparous women randomized to the intervention group compared to the control group (p = 0.28). CONCLUSION: Despite the good methodological quality of the trials, due to the heterogeneity of the interventions and outcome measures (types of breastfeeding) it was not possible to identify any specific effective intervention. However, based on a single trial, it appears that a combination of antenatal and postnatal education interventions may be useful in increasing breastfeeding rates at six months. PMID- 28902699 TI - Experiences of and support for nurses as second victims of adverse nursing errors: a qualitative systematic review. AB - BACKGROUND: Second victims are clinicians who have made adverse errors and feel traumatized by the experience. The current published literature on second victims is mainly representative of doctors, hence nurses' experiences are not fully depicted. This systematic review was necessary to understand the second victim experience for nurses, explore the support provided, and recommend appropriate support systems for nurses. OBJECTIVES: To synthesize the best available evidence on nurses' experiences as second victims, and explore their experiences of the support they receive and the support they need. INCLUSION CRITERIA PARTICIPANTS: Participants were registered nurses who made adverse errors. PHENOMENA OF INTEREST: The review included studies that described nurses' experiences as second victims and/or the support they received after making adverse errors. CONTEXT: All studies conducted in any health care settings worldwide. TYPES OF STUDIES: The qualitative studies included were grounded theory, discourse analysis and phenomenology. SEARCH STRATEGY: A structured search strategy was used to locate all unpublished and published qualitative studies, but was limited to the English language, and published between 1980 and February 2017. The references of studies selected for eligibility screening were hand-searched for additional literature. METHODOLOGICAL QUALITY: Eligible studies were assessed by two independent reviewers for methodological quality using a standardized critical appraisal instrument from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI QARI). DATA EXTRACTION: Themes and narrative statements were extracted from papers included in the review using the standardized data extraction tool from JBI QARI. DATA SYNTHESIS: Data synthesis was conducted using the Joanna Briggs Institute meta-aggregation approach. RESULTS: There were nine qualitative studies included in the review. The narratives of 284 nurses generated a total of 43 findings, which formed 15 categories based on similarity of meaning. Four synthesized findings were generated from the categories: (i) The error brings a considerable emotional burden to the nurse that can last for a long time. In some cases, the error can alter nurses' perspectives and disrupt workplace relations; (ii) The type of support received influences how the nurse will feel about the error. Often nurses choose to speak with colleagues who have had similar experiences. Strategies need to focus on helping them to overcome the negative emotions associated with being a second victim; (iii) After the error, nurses are confronted with the dilemma of disclosure. Disclosure is determined by the following factors: how nurses feel about the error, harm to the patient, the support available to the nurse, and how errors are dealt with in the past; and (iv) Reconciliation is every nurse's endeavor. Predominantly, this is achieved by accepting fallibility, followed by acts of restitution, such as making positive changes in practice and disclosure to attain closure (see "Summary of findings"). CONCLUSION: Adverse errors were distressing for nurses, but they did not always receive the support they needed from colleagues. The lack of support had a significant impact on nurses' decisions on whether to disclose the error and his/her recovery process. Therefore, a good support system is imperative in alleviating the emotional burden, promoting the disclosure process, and assisting nurses with reconciliation. This review also highlighted research gaps that encompass the characteristics of the support system preferred by nurses, and the scarcity of studies worldwide. PMID- 28902700 TI - Effectiveness of collaboration between emergency department and intensive care unit teams on mortality rates of patients presenting with critical illness: a systematic review. AB - BACKGROUND: The increasing volume of adult patients with critical illness entering emergency departments (EDs) burdens the resources of EDs worldwide. This subpopulation faces a high risk of mortality because they require specialized care which many EDs are not yet poised to deliver. An element crucial to delivering care and decreasing the mortality of critically ill patients in the ED is expert collaborative practice across disciplines. Several ED and intensive care unit (ICU) collaborative models exist including: emergency department intensive care units (EDICU) and medical emergency teams (MET). OBJECTIVES: To evaluate the effectiveness of collaboration between the ED and ICUs on the mortality rates of critically ill adult ED patients. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Adult ED patients, 18 years and over, with non-surgical critical illness meeting the criteria for ICU admission. TYPES OF INTERVENTION(S): Collaboration between the ED and ICU in the management of critically ill patients in the ED. TYPES OF STUDIES: Observational and descriptive studies. TYPE OF OUTCOME: All-cause mortality, including 30-day mortality and in-hospital mortality rates at any time period. SEARCH STRATEGY: The comprehensive literature search included published and unpublished studies in English from the beginning of each database through November 30, 2016. Databases searched included: PubMed, CINAHL, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). A search for gray literature and electronic hand searching of relevant journals was also performed. METHODOLOGICAL QUALITY: Studies were assessed for methodological quality by four independent reviewers using standardized appraisal tools from the Joanna Briggs Institute (JBI). DATA EXTRACTION: Data related to the methods, participants, interventions and findings were extracted using a standardized data extraction tool from JBI. DATA SYNTHESIS: Statistical pooling into a meta analysis was not possible due to the clinical and methodological heterogeneity in the interventions and outcome measures of the included studies. Results are presented in a narrative form. RESULTS: Three collaborative models (EDICU, Direct Provider-Provider Collaboration and MET) were identified across five studies. Findings from these studies showed conflicting results. The reviewers were unable to synthesize the evidence to state conclusively the effectiveness of collaborative models on mortality rates of critically ill patients. CONCLUSIONS: There is limited and conflicting evidence related to the effectiveness of EDICU collaborative models on the mortality rates of critically ill patients preventing the development of practice recommendations. This review underscores the need for more research into the benefits of collaborative models between the ED and ICU. PMID- 28902701 TI - Diabetes self-management education training for community health center nurses in Indonesia: a best practice implementation project. AB - BACKGROUND: Diabetes complications can increase progressively, leading to morbidity and mortality among diabetes sufferers. To address this, diabetes self management education is a strategy to increase patients' knowledge and awareness in self-care. However some issues related to diabetes self-management education have emerged for health care providers and patients. OBJECTIVES: The objective of this project was to improve nurses' skills and confidence in delivering diabetes self-management education among type 2 diabetes patients by promoting evidence based practice in community health centers, thereby enhancing patients' knowledge and skills in performing self-care. METHODS: The Joanna Briggs Institute three phase Practical Application of Clinical Evidence System and Getting Research into Practice audit and feedback tool were utilized in this project for promoting evidence utilization and changes in the community health setting. In phase 1 of the project, stakeholders were engaged and 12 evidence-based audit criteria were developed. A baseline audit was conducted by the project team in 41 community health centers. In phase 2, barriers underpinning areas of noncompliance found in the baseline audit were identified and strategies developed to target three key areas - staff, administration and patients. In phase 3, a follow-up audit was conducted. RESULTS: The baseline audit results showed that eight of the 12 criteria recorded zero percent compliance, with the remaining four recording below 50%, representing poor compliance with the current evidence. Strategies implemented during phase 2 of the project included a diabetes educator training program, development of diabetes education curriculum and media, and a patient's logbook. After implementation of the strategies, the follow-up audit showed that all 12 criteria achieved 100% compliance. CONCLUSIONS: The diabetes training program for community health center nurses increased their skills and confidence in delivering diabetes self-management education to patients. PMID- 28902702 TI - Assessment and management of burn pain at the Komfo Anokye Teaching Hospital: a best practice implementation project. AB - BACKGROUND: Pain management is a significant issue in health facilities in Ghana. For burn patients, this is even more challenging as burn pain has varied facets. Despite the existence of pharmacological agents for pain management, complaints of pain still persist. OBJECTIVES: The aim of this project was to identify pain management practices in the burns units of Komfo Anokye Teaching Hospital, compare these approaches to best practice, and implement strategies to enhance compliance to standards. METHODS: Ten evidence-based audit criteria were developed from evidence summaries. Using the Joanna Briggs Institute Practical Application of Clinical Evidence Software (PACES), a baseline audit was undertaken on a convenience sample of ten patients from the day of admission to the seventh day. Thereafter, the Getting Research into Practice (GRiP) component of PACES was used to identify barriers, strategies, resources and outcomes. After implementation of the strategies, a follow-up audit was undertaken using the same sample size and audit criteria. RESULTS: The baseline results showed poor adherence to best practice. However, following implementation of strategies, including ongoing professional education and provision of assessment tools and protocols, compliance rates improved significantly. Atlhough the success of this project was almost disrupted by an industrial action, collaboration with external bodies enabled the successful completion of the project. CONCLUSION: Pain management practices in the burns unit improved at the end of the project which reflects the importance of an audit process, education, providing feedback, group efforts and effective collaboration. PMID- 28902703 TI - Effect of Schooling on Age-Disparate Relationships and Number of Sexual Partners Among Young Women in Rural South Africa Enrolled in HPTN 068. AB - BACKGROUND: Attending school may have a strong preventative association with sexually transmitted infections among young women, but the mechanism for this relationship is unknown. One hypothesis is that students who attend school practice safer sex with fewer partners, establishing safer sexual networks that make them less exposed to infection. SETTING: We used longitudinal data from a randomized controlled trial of young women aged 13-20 years in the Bushbuckridge district, South Africa, to determine whether the percentage of school days attended, school dropout, and grade repetition are associated with having a partner 5 or more years older (age-disparate) and with the number of sexual partners in the previous 12 months. METHODS: Risks of having an age-disparate relationship and number of sexual partners were compared using inverse probability of exposure weighted Poisson regression models. Generalized estimating equations were used to account for repeated measures. RESULTS: Young women who attended fewer school days (<80%) and who dropped out of school were more likely to have an age-disparate relationship (risk difference 9.9%, 95% confidence interval [CI]: 3.9% to 16.0%; risk difference (%) dropout 17.2%, 95% CI: 5.4% to 29.0%) and those who dropped out reported having fewer partners (count difference dropout 0.343, 95% CI: 0.192 to 0.495). Grade repetition was not associated with either behavior. CONCLUSION: Young women who less frequently attend school or who drop out are more likely to have an age-disparate relationship. Young women who drop out have overall more partners. These behaviors may increase the risk of exposure to HIV infection in young women out of school. PMID- 28902705 TI - Effects of Vitamin D Supplementation on Bone Mineral Density and Bone Markers in HIV-Infected Youth. AB - BACKGROUND: Low bone mineral density (BMD) is a significant comorbidity in HIV. However, studies evaluating vitamin D supplementation on bone health in this population are limited. This study investigates changes in bone health parameters after 12 months of supplementation in HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating changes in bone parameters with 3 different vitamin D3 doses [18,000 (standard/control dose), 60,000 (moderate dose), and 120,000 IU/monthly (high dose)] in HIV-infected youth 8-25 years old with baseline serum 25 hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL. BMD and bone turnover markers were measured at baseline and 12 months. RESULTS: One hundred two subjects enrolled. Over 12 months, serum 25(OH)D concentrations increased with all doses, but the high dose (ie, 120,000 IU/monthly) maintained serum 25(OH)D concentrations in an optimal range (>=30 or >=20 ng/mL) throughout the study period for more subjects (85% and 93%, respectively) compared with either the moderate (54% and 88%, respectively) or standard dose (63% and 80%, respectively). All dosing groups showed some improvement in BMD; however, only the high-dose arm showed significant decreases in bone turnover markers for both procollagen type 1 aminoterminal propeptide (-3.7 ng/mL; P = 0.001) and Beta CrossLaps (-0.13 ng/mL; P = 0.0005). CONCLUSIONS: High-dose vitamin D supplementation (120,000 IU/mo) given over 12 months decreases bone turnover markers in HIV-infected youth with vitamin D insufficiency, which may represent an early, beneficial effect on bone health. High vitamin D doses are needed to maintain optimal serum 25(OH)D concentrations. PMID- 28902706 TI - Cognitive Impairment in a Clinical Setting. PMID- 28902704 TI - HIV Preexposure Prophylaxis Implementation at Local Health Departments: A Statewide Assessment of Activities and Barriers. AB - BACKGROUND: Expanding access to HIV preexposure prophylaxis (PrEP) could help reduce rates of HIV infection in the United States. This study characterizes activities and barriers to PrEP implementation at local health departments (LHDs) in North Carolina (NC), which contains a large rural population. METHODS: In May 2016, a web-based survey was distributed to health directors of all county and district health departments in NC to assess PrEP-related activities, perceived barriers to PrEP implementation, and desired PrEP-related resources. RESULTS: Of 85 LHDs in NC, 56 (66%) responded to the survey. Of these, 2 (4%) reported PrEP prescribing and 7 (13%) externally referred for PrEP services. Among the 54 departments not prescribing PrEP, the most frequently cited reasons were cost concerns (n = 25, 46%), lack of formal prescribing protocols (n = 21, 39%), and belief that PrEP would be better managed at primary care or specialty clinics (n = 19, 35%). Among the 47 departments not prescribing or referring clients for PrEP, the most frequently cited reasons for the lack of PrEP referral were the absence of local PrEP providers (n = 29, 62%), lack of PrEP knowledge among staff (n = 13, 28%), and perceived lack of PrEP candidates (n = 12, 26%). The most frequently requested PrEP-related resources included training to help identify PrEP candidates (n = 39, 70%) and training on PrEP prescribing and management (n = 38, 68%). CONCLUSIONS: PrEP prescribing and referral among LHDs in NC remains extremely limited. Increased PrEP-related training and support for LHD-based providers could enhance PrEP access, especially in rural and underserved areas. PMID- 28902707 TI - Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice. AB - Recently, we showed that murine dorsal root ganglion (DRG) Car8 expression is a cis-regulated eQTL that determines analgesic responses. In this report, we show that transduction through sciatic nerve injection of DRG with human wild-type carbonic anhydrase-8 using adeno-associated virus viral particles (AAV8-V5-CA8WT) produces analgesia in naive male C57BL/6J mice and antihyperalgesia after carrageenan treatment. A peak mean increase of about 4 s in thermal hindpaw withdrawal latency equaled increases in thermal withdrawal latency produced by 10 mg/kg intraperitoneal morphine in these mice. Allometric conversion of this intraperitoneal morphine dose in mice equals an oral morphine dose of about 146 mg in a 60-kg adult. Our work quantifies for the first time analgesia and antihyperalgesia in an inflammatory pain model after DRG transduction by CA8 gene therapy. PMID- 28902708 TI - The effects of MLC901 on tau phosphorylation. AB - Tauopathies are neurodegenerative diseases that are characterized by the presence of hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain and include Alzheimer's disease and frontotemporal dementia, which lack effective disease-modifying treatments. The presence of NFTs is known to correlate with cognition impairment, suggesting that targeting tau hyperphosphorylation may be therapeutically effective. MLC901 is a herbal formulation that is currently used in poststroke recovery and consists of nine herbal components. Previously, several components of MLC901 have been shown to have an effect on tau phosphorylation, but it remains unknown whether MLC901 itself has the same effect. The objective of this study was to assess the effects of MLC901 on ameliorating tau phosphorylation at epitopes associated with NFT formation. A stably transfected cell culture model expressing tau harboring the P301S mutation was generated and treated with various concentrations of MLC901 across different time points. Tau phosphorylation profiles and protein levels of enzymes associated with tau phosphorylation were assessed using western blotting. One-way analysis of variance with Bonferroni post-hoc analysis showed that MLC901 significantly reduced tau phosphorylation at epitopes recognized by the AT8, AT270, and PHF-13 antibodies. MLC901 also induced a significant increase in the s9 phosphorylation of glycogen synthase kinase 3beta and a concurrent decrease in the activation of cyclin-dependent kinase 5, as measured by a significant decrease in the levels of p35/cyclin-dependent kinase 5. Our results provide supporting evidence to further study the effects of MLC901 on tau pathology and cognition using mouse models of tauopathy. PMID- 28902709 TI - Effect of food deprivation on the hypothalamic gene expression of the secretogranin II-derived peptide EM66 in rat. AB - EM66 is a peptide derived from the chromogranin, secretogranin II (SG-II). Recent findings in mice indicate that EM66 is a novel anorexigenic neuropeptide that regulates hypothalamic feeding behavior, at least in part, by activating the POMC neurons of the arcuate nucleus. The present study aimed to investigate the mechanism of action of EM66 in the control of feeding behavior and, more specifically, its potential interactions with the NPY and POMC systems in rat. We analyzed by Q-PCR the gene expression of the EM66 precursor, SG-II, in hypothalamic extracts following 2, 3, or 4 days of food deprivation and compared it with the expression levels of the two major neuropeptidergic systems, that is, POMC and NPY, modulating feeding behavior. Our results show that fasting for 2 and 3 days has no effect on SG-II mRNA levels. However, 4 days of food deprivation induced a significant alteration in the expression levels of the three genes studied, with a significant increase in SG-II and NPY mRNAs, and conversely, a significant decrease in POMC mRNA. These data indicate that the EM66 gene expression is modulated by a negative energy status and suggest interactions between EM66 and NPY to regulate food intake through the POMC system. PMID- 28902710 TI - A novel method of organotypic spinal cord slice culture in rats. AB - This study was undertaken to establish a method for the culture of organotypic spinal cord slices. A long-term organotypic spinal cord slice culture was conducted from postnatal rats. Lumbar spinal cord was isolated, and meninges were removed from the spinal cord. The spinal cord was embedded in 4% agarose, and was sectioned by vibratome into slices. Then the slices were cultured on the surface of the membrane inserts, which were placed in six-well plates containing 1 ml of growth medium at 37 degrees C in an incubator with 5% humidified carbon dioxide. The cultured organotypic spinal cord slices were examined by light microscopy and immunocytochemistry. The organotypic spinal cord slices were fully attached to the membrane inserts after 10 days in vitro. The general change in color and transparency from whitish to transparent gray appeared at the seventh and eighth day. Under the light microscope, the outgrowth of cells from the edge of the living slices arose from the second day of the culture, and arose to peak at the sixth and seventh day. The organotypic spinal cord slices were characterized as clear, semitransparent structures with bright and good refraction until the 14th day of culture. The viability of the slices was excellent as assessed by the trypan blue exclusion method at the 28th day, and they were positive for NeuN and GFAP. This culture technique, which does not require complex operation skills, might be a simple and efficient method for obtaining organotypic spinal cord slices in sufficient number, high viability, and contamination-free from postnatal rats. PMID- 28902711 TI - Triggering of inflammasome by impaired autophagy in response to acute experimental Parkinson's disease: involvement of the PI3K/Akt/mTOR pathway. AB - Several lines of evidence suggest that the inflammasome activation is involved in the progression of neurodegenerative diseases. However, the relation between Parkinson's disease (PD) and the inflammasome is still unclear. This study was designed to assess the involvement of inflammasome in acute experimental PD. Specifically, acute PD was induced in C57BL/6 mice by an injection of 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). At seven days from MPTP induction, mice were euthanized and the midbrains were sampled to carry out immunohistochemical evaluations and western blot analysis. Our results show the activation of Nod like receptor-3 inflammasome in acute MPTP mice, as suggested by the increase of nuclear factor-kappaB expression, which represents the first signal for inflammasome induction. The Nod-like receptor-3 assembly induces the activation of caspase-1, which in turn activates interleukin-1beta and interleukin-18 production, as confirmed by our evaluations. A dysregulation of autophagy system was also found in acute MPTP mice by looking at the expression of Beclin-1, LC-3, and Bcl-2, chosen as markers of autophagy. Thus, in an effort to identify the molecular mechanism underlying the well-known crosstalk between autophagy and the inflammasome, we evaluated the involvement of the phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, which plays a key role in autophagy. Our results showed a clear upregulation of this signaling after MPTP induction. Taken together, our findings suggest that the triggering of inflammasome could be linked to impaired autophagy because of aberrant upstream activation of the PI3K/Akt/mTOR pathway. Finally, our results propose the inflammasome as a new potential therapeutic target in the management of PD. PMID- 28902712 TI - Attenuation of pentylenetrazole-induced acute status epilepticus in rats by adenosine involves inhibition of the mammalian target of rapamycin pathway. AB - Adenosine (ADO) has been characterized as an endogenous anticonvulsant and alternative therapeutic drug, but its mechanism is not entirely clear. This study aimed to examine the relationship of ADO with the mammalian target of rapamycin (mTOR) in a Wistar rat model of pentylenetetrazole (PTZ)-induced acute status epilepticus. ADO (200 mg/kg) was administered intraperitoneally 30 min before PTZ (55-65 mg/kg) treatment, and Western blot assays and immunohistochemistry were performed 3 h after the onset of acute status epilepticus to detect phospho-TOR and the downstream target of mTOR, phospho-S6. The expression of these phosphoproteins in the hippocampus was significantly increased in PTZ-treated rats, but this increase was attenuated by the addition of ADO. To further verify a role for ADO in attenuating mTOR activity, we also evaluated its ability to suppress mTOR activity in normal rats that were not treated with PTZ. Our results suggest that ADO suppresses mTOR and S6 phosphorylation in normal rats and that this suppression can be reversed by the application of Compound C, an inhibitor of AMP-activated protein kinase, which functions as an upstream suppressor of the mTOR pathway. Thus, our results provide a novel antiepileptic mechanism for ADO in suppressing mTOR pathway activation upon PTZ-induced acute status epilepticus. PMID- 28902713 TI - Long-lasting repetitive transcranial magnetic stimulation modulates electroencephalography oscillation in patients with disorders of consciousness. AB - Repetitive transcranial magnetic stimulation (rTMS) has been applied for the treatment of patients with disorders of consciousness (DOC). Timely and accurate assessments of its modulation effects are very useful. This study evaluated rTMS modulation effects on electroencephalography (EEG) oscillation in patients with chronic DOC. Eighteen patients with a diagnosis of DOC lasting more than 3 months were recruited. All patients received one session of 10-Hz rTMS at the left dorsolateral prefrontal cortex and then 12 of them received consecutive rTMS treatment everyday for 20 consecutive days. Resting-state EEGs were recorded before the experiment (T0) after one session of rTMS (T1) and after the entire treatment (T2). The JFK Coma Recovery Scale-Revised scale scores were also recorded at the time points. Our data showed that application of 10-Hz rTMS to the left dorsolateral prefrontal cortex decreased low-frequency band power and increased high-frequency band power in DOC patients, especially in minimal conscious state patients. Considering the correlation of the EEG spectrum with the consciousness level of patients with DOC, quantitative EEG might be useful for assessment of the effect of rTMS in DOC patients. PMID- 28902714 TI - Altered subcellular localization of fragile X mental retardation signaling partners and targets in superior frontal cortex of individuals with schizophrenia. AB - Schizophrenia is a severe, debilitating, neurodevelopmental disorder that affects 1% of the world's population. Recent findings from our laboratory have identified reduced levels of fragile X mental retardation protein (FMRP) and several downstream FMRP targets in superior frontal cortex of individuals with schizophrenia. We hypothesized that altered subcellular expression of FMRP and its signaling partners may explain these changes. In the current study we employed subcellular fractionation and western blotting to determine levels of FMRP, phosphorylated-FMRP as well as selected signaling partners [protein phosphatase 2A catalytic subunit (PP2AC), p70 S6 kinase (p70 S6K), and amyloid beta A4 precursor protein (APP)] in the total homogenate, nuclear, and rough endoplasmic reticulum fractions in superior frontal cortex of individuals with schizophrenia versus controls (N=12/group). In total homogenate of individuals with schizophrenia, we identified significantly lower levels of FMRP, phosphorylated-FMRP, and PP2AC. In the nuclear fraction of individuals with schizophrenia we found significantly higher levels of PP2AC, p70 S6K, APP 120 kDa, and APP 88 kDa proteins. Finally, in rough endoplasmic reticulum of individuals with schizophrenia, we identified significantly lower protein levels of p70 S6K and APP 120 kDa. These results provide evidence for a potential mechanism to explain altered FMRP expression in schizophrenia. PMID- 28902715 TI - Protecting the heart from ischemia/reperfusion injury: an update on remote ischemic preconditioning and postconditioning. AB - PURPOSE OF REVIEW: The most effective strategy for reducing acute myocardial ischemic injury is timely and effective reperfusion. However, myocardial reperfusion can induce further cardiomyocyte death (reperfusion injury). Interventions that protect the heart from ischemia/reperfusion injury, reducing infarct size, can involve remote ischemic preconditioning and postconditioning. These interventions have a promising potential clinical application, and have been the focus of recent research. In this review, we provide an update of remote ischemic preconditioning and postconditioning mechanisms. RECENT FINDINGS: Remote ischemic preconditioning cardioprotection can occur via a humoral pathway and/or a neural pathway. These two pathways have been described as mechanistically different, but it has been suggested that they could be interdependent. However, remote ischemic postconditioning mainly involves the humoral pathway. In this review, we will discuss the different pathways and mechanisms involved in remote ischemic preconditioning and postconditioning. SUMMARY: Remote ischemic preconditioning and postconditioning is possible to perform in a clinical setting by intermittent ischemia of an upper or lower limb. Furthermore, clinical trials using this procedure in the context of predictable ischemia-reperfusion have produced promising results, and other studies to define the potential clinical use of these strategies are ongoing. PMID- 28902716 TI - Volumetric high-resolution computed tomography in evaluating pulmonary metastases from differentiated thyroid carcinoma: considerations for evolving the optimal diagnostic pathway. PMID- 28902717 TI - New approaches to address dyslipidemia. AB - PURPOSE OF REVIEW: Although lipid-lowering treatment with statins, ezetimibe, and PCSK9 inhibitors is a very successful strategy to prevent cardiovascular events, there is a need for further drug developments. Not all patients respond sufficiently to the available therapy (very high baseline values, intolerance). Furthermore, patients may be characterized by dyslipidemias not accessible to available drugs such as patients with homozygous familial hypercholesterolemia, chylomicronemia syndrome, or elevated lipoprotein(a). A number of drugs are being developed to close these gaps. RECENT FINDINGS: The focus is on new antibodies, antisense oligonucleotides, and small molecules that address different aspects of lipid metabolism. Many of these developments are promising as they decrease LDL cholesterol and/or non-HDL-cholesterol and/or triglycerides and/or lipoprotein(a) in patients who so far cannot be treated sufficiently. These drugs are currently in different stages of development and being tested in clinical trials. SUMMARY: Some of the new lipid-lowering drugs have a very promising profile. However, eventually phase 3 and outcome trials will be required to prove the usefulness of these compounds in clinical practice. Furthermore, it is unlikely that they will change the primary lipidological approach (statin and ezetimibe) even if they prove successful. PMID- 28902718 TI - Effect of drug-coated balloon on stent restenosis, neointimal proliferation, and coronary dissection: an optical coherence tomography analysis. AB - AIM: The aim of this study was to assess the acute and mid-term effects of drug coated balloon (DCB) in terms of the healing process of non-flow-limiting dissections and changes in the neointimal area after DCB treatment using frequency domain optical coherence tomography (FD-OCT). PATIENTS AND METHODS: Thirty-six consecutive patients with in-stent restenosis pretreated with a scoring balloon were evaluated (19 and 17 patients with and without a DCB, respectively). FD-OCT was performed before and after each procedure during percutaneous coronary intervention and at 6 months of follow-up. RESULTS: Clinical characteristics and baseline FD-OCT findings were comparable between the two groups. No patient required stent implantation because of low-pressure DCB related dissections. In the acute phase, the DCB distributed paclitaxel to the vessel wall without increasing dissections. The DCB did not reduce the neointimal area by itself. At 6 months, more dissections healed in the DCB group (-4.5+/-2.3 vs. -2.7+/-1.3, P=0.02). The DCB group showed less change in the neointimal area (-0.04+/-0.92 vs. 1.06+/-1.57 mm, P=0.03). CONCLUSION: The low-pressure DCB was not intended to expand the lumen, but instead to attach paclitaxel to the vessel wall by using FD-OCT examination. The DCB reduced the number of dissections and prevented neointimal proliferation during the mid-term follow-up. PMID- 28902719 TI - Wound closure and tissue adhesives in clear corneal incision cataract surgery. AB - PURPOSE OF REVIEW: Achieving secure wound closure in clear corneal incision cataract surgery remains highly desired for its role in reducing infection risk and leak-related complications, including hypotony, corneal edema, and lens dislocation. Although classic techniques of stromal hydration or wound suturing represent traditional approaches, the introduction of newer and more effective ocular surface adhesives has increased the options that are available. This review aims to provide an update on the peer-reviewed literature regarding wound closure and the currently available and investigational tissue adhesives used to seal clear corneal incisions in cataract surgery. RECENT FINDINGS: Stromal hydration and sutured closure of clear corneal incisions remain viable options for wound closure. Wound sealants, particularly polyethylene glycol (PEG)-based hydrogels, have been found to provide watertight wound seal with less foreign body sensation and surgically induced astigmatism compared with sutures, and less adverse effects and greater ease of use compared with cyanoacrylate and fibrin glues. SUMMARY: Stromal hydration, sutured closure, and use of a corneal adhesive are all wound closure options for clear corneal incisions. Of the currently available tissue adhesives, PEG hydrogel sealants have become the most widely accepted, with an improved side-effect and biocompatibility profile. PMID- 28902720 TI - Evaluation of the macula prior to cataract surgery. AB - PURPOSE OF REVIEW: To describe recent evidence regarding methods of evaluation of retinal structure and function prior to cataract surgery. RECENT FINDINGS: Studies in patients with cataract but no clinically detectable retinal disease have shown that routine use of optical coherence tomography (OCT) prior to cataract surgery can detect subtle macular disease, which may alter the course of treatment or lead to modification of consent. The routine use of OCT has been especially useful in patients being considered for advanced-technology intraocular lenses (IOLs) as subtle macular disease can be a contraindication to the use of these lenses. The cost-effectiveness of routine use of OCT prior to cataract surgery has not been studied. Other technologies that assess retinal function rather than structure, such as microperimetry and electroretinogram (ERG) need further study to determine whether they can predict retinal potential in cataract patients. SUMMARY: There is growing evidence for the importance of more detailed retinal evaluation of cataract patients even with clinically normal exam. OCT has been the most established and studied method for retinal evaluation in cataract patients, but other technologies such as microperimetry and ERG are beginning to be studied. PMID- 28902721 TI - HIV-associated pulmonary hypertension. AB - PURPOSE OF REVIEW: HIV-associated pulmonary arterial hypertension (HIV-PAH) is a well-recognized severe cardiovascular complication of HIV infection that confers an adverse prognosis irrespective of the stage of disease. This review will summarize the available data on HIV-PAH epidemiology and provide insights into the pathophysiology and therapeutic strategies currently available. RECENT FINDINGS: Patients with HIV are several thousand times more likely to develop HIV PAH compared to the incidence of idiopathic PAH. Several HIV viral proteins are implicated in the pathogenesis although the exact mechanism remains unknown. In the past two decades, there have been several new treatment strategies that appear effective in treating HIV-PAH. Novel pathophysiologic mechanisms implicating the transforming growth factor beta receptor family may offer novel therapeutic targets in the future. SUMMARY: As antiretroviral therapy continues to improve health outcomes for patients with HIV, there needs to be a shift in focus of care toward chronic noncommunicable diseases. Among cardiovascular disease-complicating chronic HIV infection, HIV-PAH is a severe progressive disease that leads to right heart failure and death. Currently available treatment strategies are effective, however, furthering our understanding of HIV PAH will be critical as it is likely to become the commonest cause of PAH worldwide. PMID- 28902722 TI - Diagnostic Approach to Ocular Infections Using Various Techniques From Conventional Culture to Next-Generation Sequencing Analysis. AB - Ocular infection is caused by both endogenous (resident) and exogenous (environmental) microbes. As the ocular surface interacts with both outer environment and its own resident microbiota, clinical ocular samples are predicted to contain a diverse set of microorganisms. Microscopy of sample smears is an important step in the diagnostic process of infectious diseases to interpret the culture results. Traditional culture techniques have several limitations in the detection and/or identification of uncharacterized bacteria of environmental origin. Molecular biological techniques, such as polymerase chain reaction of pathogen-specific virulence genes, 16S rRNA gene clone library analysis, and next-generation sequencing of 16S rDNA amplicons, compensate for diagnostic culture techniques in diagnosing infectious diseases. These techniques are expected to provide novel insights into the ocular microbiota and pathology of ocular infections. In this article, we describe various ocular infections, including contact lens-related keratitis, silicone buckle infection, and dacryocystitis, which were analyzed using molecular biological techniques. The advantages and disadvantages of these highly sensitive and inclusive microbiological detection systems for ocular infections are discussed. PMID- 28902723 TI - Evaluation of Transient Motion During Gadoxetic Acid-Enhanced Multiphasic Liver Magnetic Resonance Imaging Using Free-Breathing Golden-Angle Radial Sparse Parallel Magnetic Resonance Imaging. AB - OBJECTIVES: The aims of this study were to observe the pattern of transient motion after gadoxetic acid administration including incidence, onset, and duration, and to evaluate the clinical feasibility of free-breathing gadoxetic acid-enhanced liver magnetic resonance imaging using golden-angle radial sparse parallel (GRASP) imaging with respiratory gating. MATERIALS AND METHODS: In this institutional review board-approved prospective study, 59 patients who provided informed consents were analyzed. Free-breathing dynamic T1-weighted images (T1WIs) were obtained using GRASP at 3 T after a standard dose of gadoxetic acid (0.025 mmol/kg) administration at a rate of 1 mL/s, and development of transient motion was monitored, which is defined as a distinctive respiratory frequency alteration of the self-gating MR signals. Early arterial, late arterial, and portal venous phases retrospectively reconstructed with and without respiratory gating and with different temporal resolutions (nongated 13.3-second, gated 13.3 second, gated 6-second T1WI) were evaluated for image quality and motion artifacts. Diagnostic performance in detecting focal liver lesions was compared among the 3 data sets. RESULTS: Transient motion (mean duration, 21.5 +/- 13.0 seconds) was observed in 40.0% (23/59) of patients, 73.9% (17/23) of which developed within 15 seconds after gadoxetic acid administration. On late arterial phase, motion artifacts were significantly reduced on gated 13.3-second and 6 second T1WI (3.64 +/- 0.34, 3.61 +/- 0.36, respectively), compared with nongated 13.3-second T1WI (3.12 +/- 0.51, P < 0.0001). Overall, image quality was the highest on gated 13.3-second T1WI (3.76 +/- 0.39) followed by gated 6-second and nongated 13.3-second T1WI (3.39 +/- 0.55, 2.57 +/- 0.57, P < 0.0001). Only gated 6-second T1WI showed significantly higher detection performance than nongated 13.3-second T1WI (figure of merit, 0.69 [0.63-0.76]) vs 0.60 [0.56-0.65], P = 0.004). CONCLUSIONS: Transient motion developed in 40% (23/59) of patients shortly after gadoxetic acid administration, and gated free-breathing T1WI using GRASP was able to consistently provide acceptable arterial phase imaging in patients who exhibited transient motion. PMID- 28902724 TI - Validation of the Integrated Model of Health Literacy in Patients With Breast Cancer. AB - BACKGROUND: Health literacy (HL) enables patients with breast cancer to actively participate in health decisions and promote positive health outcomes. The Integrated Model of Health Literacy (IMHL), defined as the personal, situational, and societal/environmental factors that predict the level of HL that can influence health outcomes, incorporates the concepts, determinants, and consequences of HL. OBJECTIVE: The aim of this study was to examine the mechanisms and completeness of the IMHL in patients with breast cancer. METHODS: Five hundred eleven Taiwanese patients were prospectively recruited. We conducted structural equation modeling to confirm and modify the predictive pathways linking the HL-related factors in the IMHL. RESULTS: Results on a total of 511 breast cancer patients showed good model-data fit. An alternative model revealed better fit with 2 pathways added from cancer stage to self-rated health and from cancer duration to shared decision making. Both the original model and alternative model modification revealed that only personal determinants (age, education, cancer stage, and duration) and not situational determinants (marital status) or social/environmental determinants (residence and occupation) could significantly predict the 3 domains of HL. Theorized consequences of HL were significantly influenced by HL in both models. CONCLUSIONS: Our results partially support the relationships proposed in the IMHL for patients with breast cancer as only personal determinants significantly predicted HL. IMPLICATIONS FOR PRACTICE: Understanding the predictive pathways of the integrated HL model could help clinicians to tailor HL interventions using a patient's personal determinants to facilitate participation in decision making and promote health for breast cancer patients. PMID- 28902725 TI - Exercise and Pharmacology as Medicine for Cardiovascular Diseases: From Bench to Bedside and Back. PMID- 28902726 TI - Incremental dialysis: review of recent literature. AB - PURPOSE OF REVIEW: There are clinical, physiological, financial, and practical reasons to perform incremental hemodialysis in selected patients, incident to end stage renal disease. Recent papers inform us further, especially in the large database studies. RECENT FINDINGS: Small studies suggested, then a larger study corroborated, that incremental hemodialysis was associated with preservation of residual kidney function whenever compared with conventional hemodialysis. The well tolerated nutritional status of incremental hemodialysis was questioned in a small study but a larger study was more reassuring. The mortality rate of patients undergoing incremental hemodialysis is similar to that in conventional hemodialysis, but only if the comorbidity burden is low. SUMMARY: Incremental hemodialysis in incident patients can be performed safely, and probably is associated with preserved residual kidney function and a similar mortality rate to convention initiation of hemodialysis. Patients must be prudently selected and managed for this approach to the initiation of dialysis. PMID- 28902727 TI - Solitary Osteogenic Sternum Plasmacytoma on Bone Scintigraphy and FDG PET/CT. AB - We reported a rare solitary osteogenic sternum plasmacytoma case. A 49-year-old woman experienced progressing pain in the sternum for 2 years. Abnormal Tc-MDP accumulation and increase in F-FDG uptake (SUVmax, 4.4) were co-localized with the osteogenic lesion in the sternum body detected by diagnostic CT. The lesion was histologically confirmed as plasma cell neoplasm suggestive of plasmacytoma. The patient had good response to radiotherapy. PMID- 28902728 TI - Crohn Disease: FDG PET/CT Before and After Initial Dose of Anti-Tumor Necrosis Factor Therapy to Predict Long-term Response. AB - PURPOSE: Clinical assessments of Crohn disease activity are limited in their capacity to assess treatment response to biologic therapy. The purpose of this study was to determine if changes in FDG activity between baseline PET and repeat PET performed prior to the second dose of induction anti-tumor necrosis factor (TNF) therapy correlate with clinical response. METHODS: In this prospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant pilot study of 8 adult patients with active Crohn disease, FDG activity before and 2 weeks after initiation of anti-TNF therapy was assessed using low-dose PET/CT. FDG activity was measured in the most inflamed bowel loop using an SUVratio (SUVmax/liver SUVmean). Changes in SUVratio were compared with a blinded gastroenterologist assessment of clinical response and steroid-free remission, as well as C-reactive protein (CRP), during a 12-month follow-up period. RESULTS: Of 8 patients, 7 showed FDG activity decline at 2 weeks, 5 of whom achieved a clinical response and steroid-free remission at 8, 26, and 52 weeks. The remaining 2 patients with FDG activity decline did not achieve a clinical response or steroid-free remission at these time points, but there were reductions in CRP. The 1 patient without FDG activity decline was a clinical nonresponder, had no reduction in CRP, and did not achieve steroid-free remission. CONCLUSIONS: A change in FDG activity at FDG PET/CT performed prior to the second induction dose of anti-TNF therapy has the potential to predict clinical response and steroid-free remission in patients with Crohn disease. PMID- 28902729 TI - Comparative Effectiveness of Ultrasonography, 99mTc-Sestamibi, and 18F Fluorocholine PET/CT in Detecting Parathyroid Adenomas in Patients With Primary Hyperparathyroidism. AB - PURPOSE: Accurate preoperative localization of parathyroid lesion(s) is crucial for successful surgical management of primary hyperparathyroidism (PHPT). This study was conducted to compare the effectiveness of ultrasonography (USG) of the neck, Tc-sestamibi (MIBI) imaging with or without SPECT/CT, and F-fluorocholine (FCH) PET/CT imaging in the preoperative localization of parathyroid lesions in patients with PHPT. METHODS: Fifty-four consecutive patients with PHPT were included in this prospective study who underwent preoperative localization of the parathyroid lesion(s) using 3 diagnostic modalities followed by surgery. The sensitivity, positive predictive value, and accuracy of the 3 imaging procedures to accurately detect abnormal parathyroid glands were determined using histopathology as criterion standard with postoperative biochemical response confirmation. RESULTS: F-fluorocholine PET/CT detected 52 of 54 patients and 52 of 56 lesions with histopathologically proven parathyroid adenomas on patient based and lesion-based analysis, respectively. Preoperative USG, MIBI, and FCH PET/CT localized abnormal parathyroid gland(s) in 39 (72.2%), 43 (79.6%), and 54 (100%) patients, respectively. The sensitivity and positive predictive value were 69.3% and 87.1% for USG, 80.7% and 97.6% for MIBI, and 100% and 96.3% for FCH PET/CT. The accuracy was 62.9%, 79.6%, and 96.3% for USG, MIBI, and FCH PET/CT, respectively, in patient-wise analysis. In 6 patients with ectopic lesions, FCH PET/CT demonstrated higher sensitivity and accuracy than MIBI and USG (100% vs 66.6% and 16.7%, respectively). CONCLUSIONS: Among the 3 imaging techniques tested simultaneously, FCH PET/CT was superior for accurate preoperative localization of parathyroid adenomas, especially for ectopic or small parathyroid lesions. PMID- 28902730 TI - Dural MALT Lymphoma Detected by 11C-Methionine PET/CT. AB - A 53-year-old man had a diagnosis of mucosa-associated lymphoid tissue lymphomas of the dura in the left tentorium. The patient underwent whole-body F-FDG PET/CT and C-methionine PET/CT in order to complete the staging of dural mucosa associated lymphoid tissue lymphoma. C-methionine uptake was detected in multiple meningeal sites, including left tentorium, with no significant FDG uptake in the same regions. PMID- 28902731 TI - Re: 18F-Fluorocholine PET/CT of Incidental Male Breast Cancer. PMID- 28902732 TI - Multimodality Radionuclide Imaging in a Patient With Hereditary Paraganglioma Pheochromocytoma Syndrome. AB - Hereditary paraganglioma (PGL)-pheochromocytoma (PCC) syndrome is a genetic disorder caused by a mutation of the tumor suppressor gene SDHD that results in a predisposition for head and neck PGLs and PCCs. We present a case of a 33-year old woman where F-FDG PET/CT showed areas of increased uptake in both the adrenal and cervical regions, consistent with PCCs and PGLs, respectively. Further imaging revealed that PCCs were I-MIBG avid, whereas the PGLs were In-octreotide avid. This demonstrates the varying sensitivities of different imaging modalities in regard to neuroendocrine tumors and the potential for treatment using multiple targeted therapies. PMID- 28902733 TI - 131I Whole-Body Scan Incidental Uptake Due to Spermatocele. AB - A 46-year-old man with papillary thyroid cancer post total thyroidectomy was referred for post radioiodine (I) whole-body scan. Whole-body images revealed intense I uptake in the bed thyroid and a focal abnormal uptake in the testicular area. Subsequent SPECT/CT demonstrated that the focal uptake corresponded to the left epididymis, and the pathology report revealed a spermatocele with no immunohistochemical features for thyroid tissue. Many cases of unexpected radioiodine uptake have been reported, and spermatocele could be counted for another possibility of incidental I uptake despite an unclear mechanism. PMID- 28902734 TI - Incidental Detection of Hepatocellular Carcinoma on 68Ga-Labeled Prostate Specific Membrane Antigen PET/CT. AB - A 66-year-old man with history of prostate carcinoma underwent Ga-labeled prostate-specific membrane antigen PET/CT for surveillance of rising prostate specific antigen. Intense tracer uptake was noted in segments 2, 7, and 8 of the liver. The lesions were not FDG avid on F-FDG PET/CT. Further characterization with magnetic resonance cholangiopancreatography with Gd-EOB (Primovist) contrast revealed ill-defined arterially enhancing lesions with central washout in the venous phase. CT-guided core biopsy was performed, and histopathology confirmed well-differentiated hepatocellular carcinoma. PMID- 28902735 TI - Positive Captopril Renography Without Renal Artery Stenosis but a Renal Cell Carcinoma. AB - A positive captopril renography indicates that patient's hypertension is renin dependent, most commonly caused by renal artery stenosis. The authors reported a case of positive captopril renography; however, CT demonstrated that renal arteries were intact, but there was a huge chromophobe renal cell carcinoma. Renin-dependent hypertension was relieved soon after nephrectomy. It is an uncommon cause of positive captopril renography. PMID- 28902736 TI - Incidental 131I Activity in the Deltoid Region on Posttherapy Radioiodine Scan. AB - A 71-year-old woman underwent a posttherapy radioiodine scan after I administration for papillary thyroid carcinoma. On day 1 of the posttreatment hospital isolation, the patient received a Pneumovax injection in the left deltoid muscle. A localized hypersensitivity reaction ensued with development of soft tissue edema and erythema at the Pneumovax injection site. This localized reaction persisted up to the subsequent posttherapy radioiodine scan 5 days after injection. Increased activity at the left deltoid region suggests a false positive finding related to radiotracer sequestration due to inflammation from a localized postvaccination hypersensitivity reaction. PMID- 28902737 TI - Propranolol 18F-FDG PET/CT: A Noninvasive Approach for Differential Diagnosis of Hibernoma and Liposarcoma. AB - A 76-year-old woman was referred for F-FDG PET/CT assessment of a colorectal cancer. A 9-cm F-FDG-avid fatty mass was depicted in the right thigh, suggesting either hibernoma or liposarcoma. Because MRI could not rule out well differentiated liposarcoma, and biopsy was difficult, surveillance was decided. Follow-up PET/CT showed an increase of F-FDG uptake in the fatty mass. We repeated PET/CT after oral administration of 60 mg of propranolol 1 hour before F FDG injection. A dramatic decrease in F-FDG uptake was observed, strongly supporting the diagnosis of hibernoma. PMID- 28902740 TI - Comparative Effectiveness of Treatments for Chronic Low Back Pain. PMID- 28902738 TI - False-Positive Pancreatic Uptake Detected on 68Ga-PSMA PET/CT: A Priority Changing Incidental Finding While Assessing the Need for a Prostate Biopsy. AB - A 72-year-old man underwent Ga-PSMA PET/CT because of an elevated prostate specific antigen level despite prior prostatectomy. Besides low-intensity prostatic PSMA reactivities, a faintly PSMA-positive lesion in the pancreatic corpus drew attention, which seemed suggestive of a primary pancreatic cancer on the subsequent MRI and therefore had to be excised. The final diagnosis was pT3 low-grade neuroendocrine tumor. PSMA-positive incidentalomas, detected on Ga-PSMA PET/CT, can reveal more clinically significant extraprostatic disorders. PMID- 28902739 TI - High-definition i-Scan colonoscopy is superior in the detection of diminutive polyps compared with high-definition white light colonoscopy: a prospective randomized-controlled trial. AB - INTRODUCTION: Recognition of flat and small neoplastic lesions by colonoscopy is still challenging. High-definition (HD) i-Scan colonoscopy is a promising technique to maximize the sensitivity of colonoscopy; however, whether i-Scan can increase the detection rate of polyps is still unclear. The aim of this study was to prospectively compare HD i-Scan colonoscopy with HD colonoscopy for the detection rate of polyps in routine practice. MATERIALS AND METHODS: A total of 449 patients who underwent total colonoscopy for the first time were randomized in a 1 : 1 ratio to undergo HD+i-Scan colonoscopy or HD colonoscopy. Detected colorectal polyps were judged according to type, location, and size. The primary endpoint was the detection rate and the total number of polyps. RESULTS: The number of polyps identified in the HD+i-Scan group was significantly higher than that in the HD group (P=0.041), and this difference was more obvious for diminutive polyps (P=0.035). The number of patients with at least one polyp was not significantly different between the two groups irrespective of the size or the location. Overall, 268 polyps were removed, 130 in the HD+i-Scan group and 138 in the HD group. Among these, three high-grade intraepithelial neoplasia were found in diminutive polyps. CONCLUSION: HD+i-Scan colonoscopy is superior to HD colonoscopy in detecting diminutive polyps on the basis of this prospective randomized-controlled trial. PMID- 28902741 TI - The Influence of Geography, Time, and Payer Type on the Utilization of Bone Morphogenetic Protein (BMP) Between 2005 and 2015. AB - Bone morphogenetic protein (BMP) is a critical compound for endochondral bone formation and is used as a bone graft substitute to promote spinal fusion and fracture healing. We sought to identify rate, type, and applications of use of BMP in spinal fusion surgery during 2005 to 2015. The Medicare 5% national sample (SAF5) database and the Humana Orthopaedics database (HORTHO) were searched for patients who underwent spinal fusion with BMP. Rate of use over time and influence of geographic region and payer type on utilization of BMP during 2005 to 2015 were analyzed. A total of 9879 and 12,598 patients were treated with BMP within the SAF5 database and HORTHO databases, respectively. There was a statistically significant variation in use of BMP among geographic regions. Rate of BMP usage for patients above 65 years old was 11.02 and 58.91 patients per 100,000 members for SAF5 and HORTHO databases, respectively (P<0.001). Rate of use of BMP did not vary significantly during 2005 to 2012 within the SAF5 database (P=0.153). There was a trend toward lower use of BMP in the HORTHO database between 2007 and 2015 (P=0.081). BMP use was higher for private pay than Medicare. PMID- 28902742 TI - Effectiveness of Surgical Treatment for Tarlov Cysts: A Systematic Review of Published Literature. AB - OF BACKGROUND DATA: In the general population, it has been estimated that 1.5% of people have >=1 Tarlov cysts, with about 13% of those being symptomatic. Despite a range of options for treatment, there is debate about when, and how to optimally treat individuals with Tarlov cysts among clinicians, and among policy decision makers. OBJECTIVE: To summarize the current evidence on surgical treatment of Tarlov cysts. STUDY DESIGN: A systematic review was completed. METHODS: Nine databases were searched. Abstracts and full-texts were assessed by 2 reviewers. To be included, studies had to assess safety, efficacy, or effectiveness of treating Tarlov cysts, had to be written in English or French, and had to be a randomized, quasi-randomized, observational cohort, case control, or case series design including >=2 participants. Logistic regression analysis was undertaken on the patient-level data collected to assess the association of patient and cyst characteristics on treatment success. RESULTS: In total, 31 studies were included in this systematic review; all were case series. Among the 646 participants included in these 31 studies, 210 experienced complete resolution of symptoms (32%), 327 had partial resolution (50%), 106 did not have any improvement or worsening of symptoms (16%), and 3 had their symptoms worsen after surgery (0.4%). A number of adverse events were reported after surgery; however, all were temporary. The analysis of 49 patients with data on cyst size resulted in the odds of complete resolution of symptoms being lower for patients with larger cysts (odds ratio=0.53, P-value=0.107) although this finding is not statistically significant. For those with a cyst >1.5 cm the odds of complete resolution were (odds ratio=0.36, P-value=0.190) compared with those with a cyst <1.5 cm. CONCLUSIONS: The evidence suggests that surgery for symptomatic Tarlov cysts may be an effective option for partially or completely relieving symptoms. Contrary to previous findings larger cysts were not associated with completely relieving symptoms. PMID- 28902743 TI - Use of an Alternative Surgical Corridor in Oblique Lateral Interbody Fusion at the L5-S1 Segment: A Technical Report. AB - STUDY DESIGN: Technical report. OBJECTIVE: To demonstrate the use of an alternative surgical corridor in oblique lateral interbody fusion (OLIF) at the L5-S1 segment. SUMMARY OF BACKGROUND DATA: OLIF L5-S1 is essentially performed through the central disk space between the bifurcations of the iliac vessels, which is sometimes difficult due to the vascular structures that obstruct the surgical field. Another concern is retrograde ejaculation following superior hypogastric plexus injury in male patients. MATERIALS AND METHODS: The alternative surgical corridor involves the lateral disk space external to the left iliac vessels. The patient position and the retroperitoneal approach are similar to those used in the conventional OLIF L5-S1. The left iliac vessels are identified and mobilized medially to the midline of the L5-S1 disk space. The vascular structures are then protected using the conventional OLIF 51 retractor system. RESULTS: Six patients underwent OLIF L5-S1 through the alternative lateral surgical corridor. The L5-S1 disk spaces were always exposed sufficiently for disk preparation and cage insertion. The postoperative radiographs showed a satisfactory L5-S1 reconstruction with good cage position. There were no perioperative complications during the surgical access and reconstruction procedures. CONCLUSIONS: When the central approach to the L5-S1 disk space poses a risk of vascular or superior hypogastric plexus injury, use of a lateral approach external to the left iliac vessels can be an alternative method to perform OLIF L5-S1. PMID- 28902744 TI - ACSM Clinician Profile. PMID- 28902745 TI - Is Heat Stress Nephropathy a Concern for Endurance Athletes? PMID- 28902747 TI - Exertional Heat Stroke. PMID- 28902748 TI - Pad Placement Pearl for Metatarsalgia. PMID- 28902749 TI - Replacement of Doped Olympic Medalists. PMID- 28902750 TI - How Do Athletes with Chronic Ankle Instability Suffer from Impaired Balance? An Update on Neurophysiological Mechanisms. PMID- 28902751 TI - Lunate Dislocation in a Division 1 Football Player. PMID- 28902752 TI - High-Stepping Cross-Country Athlete: A Unique Case of Foot Drop and a Novel Treatment Approach. PMID- 28902753 TI - Nonoperative Management and Novel Imaging for Posterior Circumflex Humeral Artery Injury in Volleyball. AB - We report on a 34-yr-old male elite volleyball player with symptomatic emboli in the spiking hand from a partially thrombosed aneurysm of the posterior circumflex humeral artery (PCHA) in his dominant shoulder. At initial diagnosis and follow up, a combination of time-resolved and high-resolution steady state contrast enhanced magnetic resonance angiography (CE-MRA) enabled detailed visualization of: (1) emboli that were not detectable by vascular ultrasound; and (2) the PCHA aneurysm, including compression during abduction and external rotation (ABER provocation). At 15-month follow-up, including forced cessation of volleyball activities over the preceding 9 months, the PCHA aneurysm remained unchanged. Central filling defects in the palmar arch and digital arteries resolved over time and affected arterial vessel segments showed postthrombotic changes. Digital blood pressure values improved substantially and almost normalized during follow up. In conclusion, this case report is the first to show promising results of nonoperative management for a vascular shoulder overuse injury in a professional volleyball player as an alternative to invasive therapeutic options. PMID- 28902754 TI - Wrist Pain in Gymnasts: A Review of Common Overuse Wrist Pathology in the Gymnastics Athlete. AB - Injury rates among gymnasts are among the highest of any sport at the high school and collegiate level per athletic exposure. The wrist has increased injury risk due to repetitive physical stresses predisposing it to acute injury, overuse, and degenerative damage. This article will review the most common overuse wrist injuries seen in gymnasts. Prompt evaluation and management is necessary to avoid the negative sequelae that can often accompany these injuries. Little is known about effective sport-specific injury prevention strategies, but general guidelines for overuse injury prevention including limiting excessive loading of the wrist, maintaining wrist joint flexibility, an emphasis on proper technique, and incorporating wrist and general core strengthening seem beneficial. General return to play principles are similar for all gymnast-related wrist injuries, including resolution of pain, restoration of normal wrist joint function, completion of a progressive rehabilitation program, and use of proper technique. PMID- 28902755 TI - Treatment of Acute Carpal Bone Fractures. AB - Carpal bone fractures are common hand fractures that can be complicated by concomitant damage to surrounding structures, chronic comorbidities, or delays in diagnosis. This article provides an overview of wrist anatomy, an expedited review of the athlete's presenting condition, and a systematic approach to the evaluation of the wrist. Recommended treatment plans are based on a review of the literature and an evidence-based approach to imaging studies. It is imperative that sports medicine providers be aware of current literature for carpal bone fractures and collaborate with other medical subspecialties and the athlete to provide recommendations for a safe return to play. PMID- 28902756 TI - Sacroiliac Joint Dysfunction in the Athlete: Diagnosis and Management. AB - Sacroiliac joint (SIJ) dysfunction is a common cause of low back pain in the athlete, especially in sports with repetitive, asymmetric loading. Complex anatomy and broad pain referral pattern make diagnosis difficult. Identifying three or more positive physical examination maneuvers for the SIJ improves examination sensitivity and specificity. Imaging is rarely helpful in establishing the diagnosis but is often used to rule out other pathology. Conservative management with activity modification, medication, physical therapy, manipulation and bracing is first line treatment. After at least 6 weeks of conservative efforts or if pain limits the athlete's tolerance of these measures, diagnostic and therapeutic intra-articular or periarticular injections or nerve blocks can be used. Radiofrequency ablation is recommended as the next approach for treatment. When all other options have been exhausted, surgical management can be considered. For athletes, once the underlying dysfunction is adequately addressed, gradual progression to full participation is encouraged. PMID- 28902757 TI - Severe Exercise-Associated Hyponatremia in a Collegiate American Football Player. PMID- 28902758 TI - A Case Series of Pectoralis Major Injuries on One Collegiate Football Team. PMID- 28902759 TI - Competitive Diving Principles and Injuries. AB - Competitive diving is a sport that has evolved over time to become an admired present-day aquatic sport, especially in the Olympic setting. Despite its popularity, sparse research has been written as it applies to our understanding of competitive diving injuries. This article attempts to discuss common principles of competitive diving as they relate to the sport, especially as it relates to the extreme physical forces encountered by the diver and also the repetitive nature of diving. Next, these principles will be applied in the context of musculoskeletal and medical diving specific injuries. PMID- 28902760 TI - Common Ice Hockey Injuries and Treatment: A Current Concepts Review. AB - Injuries are common in ice hockey, a contact sport where players skate at high speeds on a sheet of ice and shoot a vulcanized rubber puck in excess of one hundred miles per hour. This article reviews the diagnoses and treatment of concussions, injuries to the cervical spine, and lower and upper extremities as they pertain to hockey players. Soft tissue injury of the shoulder, acromioclavicular joint separation, glenohumeral joint dislocation, clavicle fractures, metacarpal fractures, and olecranon bursitis are discussed in the upper-extremity section of the article. Lower-extremity injuries reviewed in this article include adductor strain, athletic pubalgia, femoroacetabular impingement, sports hernia, medial collateral and anterior cruciate ligament tears, skate bite, and ankle sprains. This review is intended to aid the sports medicine physician in providing optimal sports-specific care to allow their athlete to return to their preinjury level of performance. PMID- 28902761 TI - Care of Water Polo Players. AB - Water polo is a team sport that combines swimming with overhead throwing and wrestling. This places water polo players at risk for a unique group of illnesses and injuries. In addition to the medical problems and injuries seen in competitive swimmers, water polo players are at risk for a variety of traumatic injuries, including concussions, eye injuries, tympanic membrane perforation, fractures, dislocations, and lacerations. Repetitive overhead throwing also places these athletes at risk for related injuries, such as shoulder problems, including rotator cuff strain and impingement, and elbow problems, such as ulnar collateral ligament injuries, posteromedial impingement, and osteochondritis dissecans of the radial capitellum. This article serves as an overview of these illnesses and injuries, as well as how the aquatic environment affects pathogenesis, treatment, and return to play. PMID- 28902762 TI - The Use and Abuse of the Therapeutic Use Exemptions Process. PMID- 28902763 TI - Response to the Letter to the Editor. PMID- 28902764 TI - Development of a Prognostic Model That Predicts Survival After Pancreaticoduodenectomy for Ampullary Cancer. AB - OBJECTIVES: The aims of this study were to (i) identify independent predictors of survival after pancreaticoduodenectomy for ampullary cancer and (ii) develop a prognostic model of survival. METHODS: Data were analyzed retrospectively on 110 consecutive patients who underwent pancreaticoduodenectomy between 2002 and 2013. Subjects were categorized into 3 nodal subgroups as per the recently proposed nodal subclassification: N0 (node negative), N1 (1-2 metastatic nodes), or N2 (>=3 metastatic nodes). Clinicopathological features and overall survival were compared by Kaplan-Meier and Cox regression analyses. RESULTS: The overall 1-, 3 , and 5-year survival rates were 79.8%, 42.2%, and 34.9%, respectively. The overall 1-, 3-, and 5-year survival rates for the N0 group were 85.2%, 71.9%, and 67.4%, respectively. The 1-, 3-, 5-year survival rates for the N1 and N2 subgroups were 81.5%, 49.4%, and 49.4% and 75%, 19.2%, and 6.4%, respectively (log rank, P < 0.0001). After performing a multivariate Cox regression analysis, vascular invasion and lymph node ratio were the only independent predictors of survival. Hence, a prediction model of survival was constructed based on those 2 variables. CONCLUSIONS: Using data from a carefully selected cohort of patients, we created a pilot prognostic model of postresectional survival. The proposed model may help clinicians to guide treatments in the adjuvant setting. PMID- 28902765 TI - Low-dose 90Y PET/CT imaging optimized for lesion detectability and quantitative accuracy: a phantom study to assess the feasibility of pretherapy imaging to plan the therapeutic dose. AB - OBJECTIVE: The overall aim of this work is to optimize the reconstruction parameters for low-dose yttrium-90 (Y) PET/CT imaging, and to determine Y minimum detectable activity, in an endeavor to investigate the feasibility of performing low-dose Y imaging in-vivo to plan the therapeutic dose in radioembolization. MATERIALS AND METHODS: This study was carried out using a Siemens Biograph 6 True Point PET/CT scanner. A Jaszczak phantom containing five hot syringes was imaged serially over 15 days. For 128 reconstruction parameters/algorithms, detectability performance and quantitative accuracy were evaluated using the contrast-to-noise ratio and the recovery coefficient, respectively. RESULTS: For activity concentrations greater than 2.5 MBq/ml, the linearity of the scanner was confirmed while the corresponding relative error was below 10%. Reconstructions with smaller numbers of iterations and smoother filters led to higher detectability performance, irrespective of the activity concentration and lesion size. In this study, the minimum detectable activity was found to be 3.28+/-10% MBq/ml using the optimized reconstruction parameters. Although the recovered activities were generally underestimated, for lesions with activity concentration greater than 4 MBq/ml, the amount of underestimation is limited to -15% for optimized reconstructions. CONCLUSION: Y PET/CT imaging, even with a low activity concentration, is feasible for depicting the distribution of Y implanted microspheres using optimized reconstruction parameters. As such, in-vivo PET/CT imaging of low-dose Y in the pretherapeutic stage may be feasible and fruitful to optimally plan the therapeutic activity delivered to patients undergoing radioembolization. PMID- 28902766 TI - Future cardiac events in patients with ischemic ECG changes during adenosine infusion as a myocardial stress agent and normal cardiac scan. AB - BACKGROUND: We sought to determine the prognostic importance of adenosine-induced ischemic ECG changes in patients with normal single-photon emission computed tomography myocardial perfusion images (MPI). PATIENTS AND METHODS: We carried out a retrospective analysis of 765 patients undergoing adenosine MPI between January 2013 and January 2015. Patients with baseline ECG abnormalities and/or abnormal scan were excluded. RESULTS: Overall, 67 (8.7%) patients had ischemic ECG changes during adenosine infusion in the form of ST depression of 1 mm or more. Of these, 29 [43% (3.8% of all patients)] had normal MPI (positive ECG group). An age-matched and sex-matched group of 108 patients with normal MPI without ECG changes served as control participants (negative ECG group). During a mean follow-up duration of 33.3+/-6.1 months, patients in the positive ECG group did not have significantly more adverse cardiac events than those in the negative ECG group. One (0.9%) patient in the negative ECG group had a nonfatal myocardial infarction (0.7% annual event rate after a negative MPI). Also in this group, two (1.8%) patients admitted with a diagnosis of CAD where they have been ruled out by angiography. A fourth case in this, in the negative ECG group, was admitted because of heart failure that proved to be secondary to a pulmonary cause and not CAD. A case only in the positive ECG group was admitted as a CAD that was ruled out by coronary angiography. CONCLUSION: Patients with normal myocardial perfusion scintigraphy in whom ST-segment depression develops during adenosine stress test appear to have no increased risk for future cardiac events compared with similar patients without ECG evidence of ischemia. PMID- 28902768 TI - Economic and Clinical Outcomes Resulting From the Stage 4 Chronic Kidney Disease Case Management Quality Improvement Initiative. AB - PURPOSE OF STUDY: Chronic kidney disease (CKD) is a costly and burdensome public health concern. The goal of this study was to evaluate the impact on outcomes and utilization of a pilot program to identify and engage beneficiaries with CKD at risk for progression from Stage 4 to Stage 5. PRIMARY PRACTICE SETTINGS: A quality improvement initiative was conducted to assess the impact of case management on costs and outcomes among 7,720 Cigna commercial medical beneficiaries with Stage 4 CKD enrolled in the United States between January 2012 and October 2012. METHODOLOGY AND SAMPLE: Claims data were analyzed to compare 3,861 beneficiaries randomized to receive condition-focused case management with 3,859 controls, with follow-up through July 2013. After using an algorithm to identify beneficiaries at highest risk of progression, a case management team implemented, among those assigned to the intervention, an evidence-based assessment tool, provided education and follow-up, engaged nephrologists and other providers, and conducted weekly rounds. Primary outcome measures were hospital admissions, emergency department visits, nephrologist visits, dialysis, arteriovenous (AV) fistula creation, and total medical costs. Analysis of variance techniques were used to test group differences. RESULTS: As compared with controls, intervention beneficiaries were 12% more likely to have fistula creation (p = .004). Intervention beneficiaries were observed to have savings of $199 per member per month (PMPM), F = 23.05, p = .04. This difference equated to 6% lower total medical costs in the intervention group. Savings observed were derived half from improved in-network utilization and half from reduced hospital costs. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: . PMID- 28902769 TI - Factors Associated With Financial Relationships Between Spine Surgeons and Industry: An Analysis of the Open Payments Database. AB - STUDY DESIGN: A retrospective review of Centers for Medicare and Medicaid Services Database. OBJECTIVE: Utilizing Open Payments data, we aimed to determine the prevalence of industry payments to orthopedic and neurospine surgeons, report the magnitude of those relationships, and help outline the surgeon demographic factors associated with industry relationships. SUMMARY OF BACKGROUND DATA: Previous Open Payments data revealed that orthopedic surgeons receive the highest value of industry payments. No study has investigated the financial relationship between spine surgeons and industry using the most recent release of Open Payments data. METHODS: A database of 5898 spine surgeons in the United States was derived from the Open Payments website. Demographic data were collected, including the type of residency training, years of experience, practice setting, type of medical degree, place of training, gender, and region of practice. Multivariate generalized linear mixed models were utilized to determine the relationship between demographics and industry payments. RESULTS: A total of 5898 spine surgeons met inclusion criteria. About 91.6% of surgeons reported at least one financial relationship with industry. The median total value of payments was $994.07. Surgeons receiving over $1,000,000 from industry during the reporting period represented 6.6% of the database and accounted for 83.5% of the total value exchanged. Orthopedic training (P < 0.001), academic practice setting (P < 0.0001), male gender (P < 0.0001), and West or South region of practice (P < 0.0001) were associated with industry payments. Linear regression analysis revealed a strong inverse relationship between years of experience and number of payments from industry (r = -0.967, P < 0.0001). CONCLUSION: Financial relationships between spine surgeons and industry are highly prevalent. Surgeon demographics have a significant association with industry-surgeon financial relationships. Our reported value of payments did not include ownership or research payments and thus likely underestimates the magnitude of these financial relationships. LEVEL OF EVIDENCE: 3. PMID- 28902770 TI - Decompression Versus Decompression and Fusion for Degenerative Lumbar Stenosis in a Workers' Compensation Setting: Erratum. PMID- 28902771 TI - Attention and Visual Motor Integration in Young Children with Uncorrected Hyperopia. AB - SIGNIFICANCE: Among 4- and 5-year-old children, deficits in measures of attention, visual-motor integration (VMI) and visual perception (VP) are associated with moderate, uncorrected hyperopia (3 to 6 diopters [D]) accompanied by reduced near visual function (near visual acuity worse than 20/40 or stereoacuity worse than 240 seconds of arc). PURPOSE: To compare attention, visual motor, and visual perceptual skills in uncorrected hyperopes and emmetropes attending preschool or kindergarten and evaluate their associations with visual function. METHODS: Participants were 4 and 5 years of age with either hyperopia (>=3 to <=6 D, astigmatism <=1.5 D, anisometropia <=1 D) or emmetropia (hyperopia <=1 D; astigmatism, anisometropia, and myopia each <1 D), without amblyopia or strabismus. Examiners masked to refractive status administered tests of attention (sustained, receptive, and expressive), VMI, and VP. Binocular visual acuity, stereoacuity, and accommodative accuracy were also assessed at near. Analyses were adjusted for age, sex, race/ethnicity, and parent's/caregiver's education. RESULTS: Two hundred forty-four hyperopes (mean, +3.8 +/- [SD] 0.8 D) and 248 emmetropes (+0.5 +/- 0.5 D) completed testing. Mean sustained attention score was worse in hyperopes compared with emmetropes (mean difference, -4.1; P < .001 for 3 to 6 D). Mean Receptive Attention score was worse in 4 to 6 D hyperopes compared with emmetropes (by -2.6, P = .01). Hyperopes with reduced near visual acuity (20/40 or worse) had worse scores than emmetropes (-6.4, P < .001 for sustained attention; -3.0, P = .004 for Receptive Attention; -0.7, P = .006 for VMI; -1.3, P = .008 for VP). Hyperopes with stereoacuity of 240 seconds of arc or worse scored significantly worse than emmetropes (-6.7, P < .001 for sustained attention; -3.4, P = .03 for Expressive Attention; -2.2, P = .03 for Receptive Attention; -0.7, P = .01 for VMI; -1.7, P < .001 for VP). Overall, hyperopes with better near visual function generally performed similarly to emmetropes. CONCLUSIONS: Moderately hyperopic children were found to have deficits in measures of attention. Hyperopic children with reduced near visual function also had lower scores on VMI and VP than emmetropic children. PMID- 28902772 TI - Urinary CXCL10 Chemokine Is Associated With Alloimmune and Virus Compartment Specific Renal Allograft Inflammation. AB - BACKGROUND: Urinary CXC chemokine ligand 10 (CXCL10) is a promising biomarker for subclinical tubulointerstitial inflammation, but limited data exist regarding its correlation with (micro)vascular inflammation. Furthermore, no study has evaluated whether concomitant serum CXCL10 improves the discrimination for (micro)vascular inflammation. METHODS: We investigated whether serum/urinary CXCL10 reflect subclinical inflammation within different renal compartments. Patients (n = 107) with 107 surveillance biopsies were classified as: normal histology (n = 47), normal histology with polyomavirus BK (BKV) or cytomegalovirus (CMV) viremia (n = 17), moderate-severe tubulointerstitial inflammation (tubulitis >=2, n = 18), pure microvascular inflammation (n = 15), and isolated v lesions (n = 10). Serum and urinary CXCL10 Enzyme-linked Immunosorbent Assay was performed. An independent validation set was evaluated for urine CXCL10: normal histology (n = 14), normal histology with BKV or CMV viremia (n = 19), tubulitis >=2 (n = 15), pure microvascular inflammation (n = 41), and isolated v lesions (n = 14). RESULTS: Elevated urinary CXCL10 reflected inflammation within the tubulointerstitial (urinary CXCL10/creatinine, 1.23 ng/mmol vs 0.46 ng/mmol; P = 0.02; area under the curve, 0.69; P = 0.001) and microvascular compartments (urinary CXCL10/creatinine, 1.72 ng/mmol vs 0.46 ng/mmol; P = 0.03; area under the curve, 0.69; P = 0.02) compared to normal histology. Intriguingly, urinary CXCL10 was predominantly elevated with peritubular capillaritis, but not glomerulitis (P = 0.04). Furthermore, urinary CXCL10 corresponded with BKV, but not CMV viremia (P = 0.02). These urine CXCL10 findings were confirmed in the independent validation set. Finally, serum CXCL10 was elevated with BKV and CMV viremia but was not associated with microvascular or vascular inflammation (P >= 0.19). CONCLUSIONS: Urinary CXCL10 reflects subclinical inflammation within the tubulointerstitial and peritubular capillary spaces, but not the vascular/systemic compartments; this was consistent with BKV (tubulointerstitial) and CMV viremia (systemic). Serum CXCL10 was not a useful marker for (micro)vascular inflammation. PMID- 28902774 TI - Subcutaneous Islet Allotransplantation Without Immunosuppression Therapy: The Dream of the Diabetologists and of Their Patients. PMID- 28902775 TI - mTOR Inhibition for Transplantation: More May Not Be Better. PMID- 28902773 TI - Reduced TCR Signaling Contributes to Impaired Th17 Responses in Tolerant Kidney Transplant Recipients. AB - BACKGROUND: The development of spontaneous kidney transplant tolerance has been associated with numerous B cell-related immune alterations. We have previously shown that tolerant recipients exhibit reduced B-cell receptor signalling and higher IL-10 production than healthy volunteers. However, it is unclear whether cluster of differentiation (CD)4 T cells from tolerant recipients also display an anti-inflammatory profile that could contribute to graft maintenance. METHODS: CD4 T cells were isolated from kidney transplant recipients who were identified as being tolerant recipients, patients with chronic rejection or healthy volunteers. CD4 T cells from the 3 groups were compared in terms of their gene expression profile, phenotype, and functionally upon activation. RESULTS: Gene expression analysis of transcription factors and signalling proteins, in addition to surface proteins expression and cytokine production, revealed that tolerant recipients possessed fewer Th17 cells and exhibited reduced Th17 responses, relative to patients with chronic rejection or healthy volunteers. Furthermore, impaired T-cell receptor signalling and altered cytokine cooperation by monocytes contributed to the development of Th17 cells in tolerant recipients. CONCLUSIONS: These data suggest that defective proinflammatory Th17 responses may contribute to the prolonged graft survival and stable graft function, which is observed in tolerant recipients in the absence of immunosuppressive agents. PMID- 28902776 TI - Pancreatic Cancer Arising From the Remnant Pancreas: Is It a Local Recurrence or New Primary Lesion? AB - Local recurrence of pancreatic cancer (PC) can occur in the pancreatic remnant. In addition, new primary PC can develop in the remnant. There are limited data available regarding this so-called remnant PC. The aim of this review was to describe the characteristics and therapeutic strategy regarding remnant PC. A literature search was performed using Medline published in English according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The incidence of remnant PC has been reported to be 3% to 5%. It is difficult to distinguish local recurrence from new primary PC. Genetic diagnosis such as Kirsten rat sarcoma viral oncogene homolog mutation may resolve this problem. For patients with remnant PC, repeated pancreatectomy can be performed. Residual total pancreatectomy is the most common procedure. Recent studies have described the safety of the operation because of recent surgical progress and perioperative care. The patients with remnant PC without distant metastasis have shown good long-term outcomes, especially those who underwent repeated pancreatectomy. Adjuvant chemotherapy may contribute to longer survival. In conclusion, this review found that both local recurrence and new primary PC can develop in the pancreatic remnant. Repeated pancreatectomy for the remnant PC is a feasible procedure and can prolong patient survival. PMID- 28902777 TI - Operative Versus Nonoperative Management of Blunt Pancreatic Trauma in Children: A Systematic Review. AB - The aim of this study was to compare operative versus nonoperative management of blunt pancreatic trauma in children. A systematic literature search was performed. Studies including children with blunt pancreatic injuries classified according to the American Association for the Surgery of Trauma classification were included. The primary outcome was pseudocyst formation. After screening 526 studies, 23 studies with 928 patients were included. Sufficient data were available for 674 patients (73%). Of 309 patients with grade I or II injuries, 258 (83%) were initially managed nonoperatively with a 96% success rate. Of 365 patients with grade III, IV, or V injuries, nonoperative management was initially chosen for 167 patients (46%) with an 89% success rate. Pseudocysts occurred in 18% of patients managed nonoperatively versus 4% of patients managed operatively (P < 0.01), of whom 65% were treated nonoperatively. Hospitalization was 20.5 days after nonoperative versus 15.1 days after operative management (nonparametric t test, P = 0.41). Blunt pancreatic trauma in children can be managed nonoperatively in the majority of patients with grade I or II injuries and in about half of the patients with grade III to V injuries. Although pseudocysts are more common after nonoperative management, two thirds can be managed nonoperatively. PMID- 28902778 TI - Incidences of Pancreatic Malignancy and Mortality in Patients With Untreated Branch-Duct Intraductal Papillary Mucinous Neoplasms Undergoing Surveillance: A Systematic Review. AB - OBJECTIVE: The aim of this study was to pool incidences of increased cyst size, malignant branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs), pancreatic malignancy, and pancreatic malignancy-related death during follow-up (FU) of BD-IPMN patients. METHODS: Searches were performed from January 2010 to April 2016. All hits were checked on inclusion criteria, and outcomes were extracted. Incidences were pooled. Three subgroups were defined: (1) including only BD-IPMN patients, (2) short-interval FU (maximum 6 months), and (3) long interval FU (>6 months). RESULTS: Thirty-one articles were enrolled, including 8455 patients (mean age, 66.4 years). Twenty-two studies included subgroup 1; 10 and 6 studies included, respectively, subgroups 2 and 3. Incidence of increased cyst size was 17.4%. In subgroups 1, 2, and 3, incidences were, respectively, 20.0%, 17.2%, and 31.7%. Incidence of malignant BD-IPMN was 2.5. In subgroups 1, 2, and 3, incidences were, respectively, 3.0%, 2.4%, and 3.3%. Incidence of pancreatic malignancy was 2.6%. In subgroups 1, 2, and 3, incidences were, respectively, 2.3%, 1.2%, and 4.0%. Incidence of death was 0.5%. In subgroups 1, 2, and 3, incidences were, respectively, 0.4%, 0.04%, and 0.12%. CONCLUSIONS: Although not significant, all incidences on long-interval FU were higher; therefore, short-interval FU seems necessary to find resectable lesions. PMID- 28902779 TI - Increased Burden of Pediatric Acute Pancreatitis on the Health Care System. AB - OBJECTIVES: The incidence of pediatric acute pancreatitis (AP) increased over the past 2 decades and is estimated to be 3 to 13 per 100,000. The impact of rising AP incidence on health care costs is unknown. Our aim was to examine pediatric AP admissions and associated hospital costs in the United States between years 2004 and 2014. METHODS: Acute pancreatitis admission and cost data were extracted from the Pediatric Health Information System. We determined AP admission and cost percentages each year, as well as the ratio of AP cost to admission percentages to estimate AP "burden." Length of stay, costs of hospitalization, and the effect of intensive care unit care on these estimates were examined. RESULTS: Between 2004 and 2014, AP admission percentages increased (P = 0.002). Length of stay decreased over time (P < 0.0001) and was longer for those requiring intensive care unit care (P < 0.0001). Acute pancreatitis admissions cost per day significantly increased over time (P < 0.0001). Median AP cost percentage remained 1.2 to 1.7 times higher than AP admission percentage. CONCLUSIONS: Acute pancreatitis admissions constitute an expensive burden on the health care system relative to the percentage of all admissions. If AP admissions continue to increase, the cost of AP admissions may pose a substantial financial health care burden. PMID- 28902780 TI - Is Multifocality an Indicator of Aggressive Behavior in Small Bowel Neuroendocrine Tumors? AB - OBJECTIVES: Many patients with small bowel neuroendocrine tumors (SBNETs) have multifocal tumors (MFTs), but the frequency of MFTs has varied widely across SBNET studies. It is also unclear whether patients with MFTs have more advanced disease or worse clinical course than do those with unifocal SBNETs. We set out to determine the frequency of multifocal and unifocal SBNETs and compare clinicopathologic factors, somatostatin receptor 2 expression, and survival. METHODS: Clinicopathologic variables from 179 patients with surgically managed SBNETs were collected. Statistical comparisons were made using Welch t-test, Wilcoxon test, and Fisher's exact test. Survival was assessed using the Kaplan Meier method. Somatostatin receptor 2 expression was analyzed by quantitative polymerase chain reaction, and Ki-67 expression by immunohistochemistry. RESULTS: Multifocal tumors were found in 45% of patients with SBNETs. Clinicopathologic factors such as grade, TNM stage, presence of distant metastases, mean somatostatin receptor 2 expression, success of imaging modalities, and preoperative and postoperative hormone levels were not significantly different between multifocal and unifocal groups. Progression-free survival and overall survival were also not significantly affected by multifocality. CONCLUSIONS: Clinicopathologic features and survival of patients with MFTs and unifocal tumors are remarkably similar. Although the etiology of MFTs is unclear, patients with MFTs do not have a more aggressive clinical course than patients with unifocal SBNETs. PMID- 28902781 TI - Efficacy of Peptide Receptor Radionuclide Therapy in a United States-Based Cohort of Metastatic Neuroendocrine Tumor Patients: Single-Institution Retrospective Analysis. AB - OBJECTIVES: The aim of this study was to analyze in a retrospective cohort study the outcomes of a United States-based group of metastatic neuroendocrine tumor (NET) patients who underwent peptide receptor radionuclide therapy (PRRT). METHODS: Twenty-eight patients from a single US NET Center were treated with PRRT. Toxicities were assessed using Common Terminology Criteria for Adverse Events version 4.03. Progression was determined by the Response Evaluation Criteria in Solid Tumors version 1.1. Univariate and multivariate Cox regression was performed to identify potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: The median age at NET diagnosis was 56 years, 50% of the patients were male, 46% of NET primaries were located in the pancreas, 71% of tumors were nonfunctional, 25% were World Health Organization (WHO) grade III, and 20% had at least a 25% hepatic tumor burden. Anemia (36%) was the most common post-PRRT toxicity, followed by leukopenia (31%), nephrotoxicity (27%), and thrombocytopenia (24%). Median PFS was 18 months, and median OS was 38 months. Having a WHO grade III NET and receiving systemic chemotherapy prior to PRRT were found to be to independent predictors of shorter PFS and OS. CONCLUSIONS: Peptide receptor radionuclide therapy is an effective therapy in a US population. Progression-free survival and OS were better in WHO grade I/II NETs and when PRRT was sequenced prior to systemic chemotherapy. PMID- 28902782 TI - Impact of MUC1 Expression on the Progression of Intraductal Papillary Mucinous Neoplasm With Worrisome Features During Follow-up. AB - OBJECTIVES: The aim of this study was to investigate whether MUC1 expression is associated with progression of intraductal papillary mucinous neoplasms with worrisome features during follow-up. METHODS: Fifteen patients positive for MUC1 and negative for MUC2 (MUC1 group) and 16 patients negative for MUC1 and MUC2 (control group) were followed up and examined for changes in diameters of the main and ectatic branches of pancreatic ducts, enlargement of mural nodules, and appearance of a solid mass, by imaging studies. All of them presented worrisome features, and none had "high-risk stigmata." RESULTS: The sizes of the main and ectatic branches of pancreatic ducts increased in 8 (53.3%) and 8 (53.3%) patients, respectively, of the MUC1 group and in 1 (6.3%) and 1 (6.3%) patients, respectively, of the control group (P = 0.0059 and 0.0059, respectively). A solid mass developed in 6 patients (33.3%) of the MUC1 group but in none of the control group patients (P = 0.0373). CONCLUSIONS: Positive MUC1 expression in cell block cytology specimens may be associated with progressive dilation of the main and ectatic branches of pancreatic ducts and appearance of a solid mass in patients with intraductal papillary mucinous neoplasm with worrisome features during follow-up. PMID- 28902783 TI - A Normal Preoperative Lipase Serum Level Is an Easy and Objective Risk Factor of Pancreatic Fistula After Pancreaticoduodenectomy. AB - OBJECTIVES: The evaluation of the risk of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy is crucial to optimize perioperative strategies. Many risk factors of POPF have been identified and were included in scores. Performances of these scores have to be improved because of the use of subjective and/or intraoperative factors. We tried to identify new risk factors of POPF that could improve the performance of validated scores. METHODS: We analyzed data from a prospective database of 191 consecutive patients who underwent a pancreaticoduodenectomy. Recorded data included a comprehensive inventory of pre , intra- and postoperative clinical, biological and radiological data. RESULTS: The rate of POPF was significantly increased in patients with a normal preoperative lipase serum level (LSL) (29.8% vs 6.8%; P = 0.001). After multivariate analysis, a normal preoperative LSL was a strong independent risk factor of both POPF (odds ratio, 7.06; P = 0.001) and clinically relevant POPF (odds ratio, 3.11; P = 0.036). The addition of the normality of the preoperative LSL to the Fistula Risk Score significantly improved its performance (P < 0.001). CONCLUSIONS: A normal preoperative LSL was a strong, easy, and objective preoperative risk factor of POPF. Its addition to the Fistula Risk Score improved its performance and allows a more accurate evaluation of the risk of POPF. PMID- 28902784 TI - Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-Producing Cells in the Pancreas. AB - OBJECTIVES: The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. METHODS: We used transgenic mice expressing green fluorescent protein via the collagen type I alpha1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. RESULTS: Collagen producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. CONCLUSIONS: Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells. PMID- 28902786 TI - Diagnosing Chronic Pancreatitis: Comparison and Evaluation of Different Diagnostic Tools. AB - OBJECTIVES: This study aims to compare the M-ANNHEIM, Buchler, and Luneburg diagnostic tools for chronic pancreatitis (CP). METHODS: A cross-sectional analysis of the development of CP was performed in a prospectively collected multicenter cohort including 669 patients after a first episode of acute pancreatitis. We compared the individual components of the M-ANNHEIM, Buchler, and Luneburg tools, the agreement between tools, and estimated diagnostic accuracy using Bayesian latent-class analysis. RESULTS: A total of 669 patients with acute pancreatitis followed-up for a median period of 57 (interquartile range, 42-70) months were included. Chronic pancreatitis was diagnosed in 50 patients (7%), 59 patients (9%), and 61 patients (9%) by the M-ANNHEIM, Luneburg, and Buchler tools, respectively. The overall agreement between these tools was substantial (kappa = 0.75). Differences between the tools regarding the following criteria led to significant changes in the total number of diagnoses of CP: abdominal pain, recurrent pancreatitis, moderate to marked ductal lesions, endocrine and exocrine insufficiency, pancreatic calcifications, and pancreatic pseudocysts. The Buchler tool had the highest sensitivity (94%), followed by the M-ANNHEIM (87%), and finally the Luneburg tool (81%). CONCLUSIONS: Differences between diagnostic tools for CP are mainly attributed to presence of clinical symptoms, endocrine insufficiency, and certain morphological complications. PMID- 28902785 TI - Predictors of Pancreatic Cancer-Associated Weight Loss and Nutritional Interventions. AB - OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. METHODS: Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. RESULTS: Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76 2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09-2.87). CONCLUSIONS: Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC. PMID- 28902787 TI - Venous Thromboembolism Is Associated With Adverse Outcomes in Hospitalized Patients With Acute Pancreatitis: A Population-Based Cohort Study. AB - OBJECTIVES: The systemic inflammatory cascade and vascular stasis in hospitalized patients with acute pancreatitis (AP) serve as a milieu for development of venous thromboembolism (VTE). Our aim was to estimate the prevalence and risk factors of VTE in AP and to evaluate its impact on clinical outcomes of AP. METHODS: The Nationwide Inpatient Sample (2002-2011) was reviewed to identify all patients hospitalized with AP. Patients with a concomitant diagnosis of VTE were compared with those without. The primary clinical outcome (inpatient mortality) and secondary resources outcomes (length of stay and total hospital charges) were analyzed using univariate and multivariate comparisons. RESULTS: Among 2,382,426 patients with AP, 22,205 (0.93%) had VTE. Multivariate analysis showed patients with greater comorbidity (odds ratio [OR], 1.47), white race (OR, 1.11), acute kidney injury (OR, 1.08), acute respiratory failure (OR, 1.40), pseudocyst (OR, 1.41), total parenteral nutrition (OR, 1.28), and central venous catheter placement (OR, 3.01) were associated with a diagnosis of VTE. Venous thromboembolism was also independently associated with increased mortality (OR, 1.31) and prolonged duration of hospitalization by 6.5 days (P < 0.001) and contributed to an excess $44,882 (P < 0.001) in hospitalization costs. CONCLUSIONS: Venous thromboembolism is adversely associated with mortality and health care resource utilization in AP. PMID- 28902788 TI - Effects of Rab27A and Rab27B on Invasion, Proliferation, Apoptosis, and Chemoresistance in Human Pancreatic Cancer Cells. AB - OBJECTIVES: Rab family members are key regulatory factors that function as molecular switches in multiple phases of vesicular trafficking. Our previous study demonstrated that Rab27A and Rab27B overexpression may predict a poor outcome of pancreatic ductal adenocarcinoma. The purpose of this study was to investigate the role of Rab27A and Rab27B in the progression of pancreatic cancer. METHODS: We down-regulated Rab27A and Rab27B expression in pancreatic cancer cell lines. The regulatory effects of knockdown Rab27A and Rab27B on pancreatic cancer cell were measured by cisplatin assay, invasion assay, proliferation assay, and Western blot assay. RESULTS: Rab27A and Rab27B down regulation enhances sensitivity to cisplatin and induces apoptosis in ASPC-1 and PANC-1 cells. In addition, down-regulation of Rab27A reduced the invasive and proliferative ability of ASPC-1 cells, and Rab27B knockdown significantly prevented cancer invasion and proliferation in PANC-1 cells. CONCLUSIONS: Our findings provide evidence that Rab27A and Rab27B play significant roles in cell invasion, proliferation, and apoptosis, as well as in chemotherapy resistance. PMID- 28902790 TI - Impact of Treatments on Diabetic Control and Gastrointestinal Symptoms After Total Pancreatectomy. AB - OBJECTIVES: The aims of this study were to compare the safety, efficacy, and patients' quality of life with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDIs) in type 3c diabetes mellitus (T3cDM) following total pancreatectomy (TP) and pancreatic enzyme usage. METHODS: Thirty nine patients with T3cDM (18 CSII patients vs 21 MDI patients) who underwent TP between 2000 and 2016 at 3 Harvard-affiliated hospitals and the University of Minnesota returned prospectively obtained questionnaires examining quality of life and both endocrine and exocrine pancreatic functions. RESULTS: Main indications for TP were as follows: chronic pancreatitis (n = 19), intraductal papillary mucinous neoplasm (n = 12), and adenocarcinoma (n = 4). Median hemoglobin A1c using MDIs was 8.1% versus 7.3% in CSII. Severe hypoglycemic events using MDIs were increased compared with CSII (P = 0.02). There were no significant differences in quality-of-life measures with CSII versus MDIs. Pancreatic enzyme dose per meal (P < 0.05) differed between the hospitals. Gastrointestinal symptoms and unintended weight loss (P < 0.01) were more common with low doses of pancreatic enzymes. CONCLUSIONS: After TP, CSII therapy is safe compared with MDIs in T3cDM and not associated with an increase in severe hypoglycemic events. Pancreatic enzyme replacement therapy is highly variable with low doses associated with unintentional weight loss and gastrointestinal symptoms. PMID- 28902789 TI - Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Chemotherapy. AB - OBJECTIVES: The aim of this study was to examine tumor-infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. METHODS: Intratumoral CD4, CD8, and FOXP3 lymphocytes were examined by immunohistochemistry using a computer assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathological parameters and survival. RESULTS: High CD4 TILs in treated PDAC were associated with high CD8 TILs (P = 0.003), differentiation (P = 0.04), and a lower frequency of recurrence (P = 0.02). Patients with high CD4 TILs had longer disease-free survival and overall survival (OS) than did patients with low CD4 TILs (P < 0.01). The median OS of patients with a high CD8/FOXP3 lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8/FOXP3 lymphocyte ratio (28.3 [standard deviation, 2.3] months; P = 0.01). In multivariate analysis, high CD4 TILs were an independent prognostic factor for disease-free survival (hazard ratio, 0.49; 95% confidence interval, 0.30-0.81; P = 0.005) and OS (hazard ratio, 0.54; 95% confidence interval, 0.33 0.89; P = 0.02). CONCLUSIONS: High level of CD4 lymphocytes is associated with tumor differentiation and lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy. PMID- 28902791 TI - Initial Features of Hepatic Metastases From Pancreatic Cancer: Histological and Radiolographical Appraisal of Hepatic Micrometastases Detected by Real-Time Fluorescent Imaging. AB - OBJECTIVE: The pathophysiology of primary-stage hepatic metastases from gastrointestinal cancers may provide clues to their formation. We investigated initial features of hepatic metastases from pancreatic cancer by examining the histologies of radiographically occult hepatic micrometastases. METHODS: We examined 133 consecutive pancreatic cancer patients with no evident hepatic metastases on preoperative imaging. An indocyanine green near-infrared camera system was used to detect hepatic metastases during surgery; preoperatively acquired images of patients were then retrospectively reviewed. RESULTS: Hepatic micrometastases were histologically confirmed in 20 patients (15%). Immunohistochemically, the metastatic cells were with higher positivity of carcinoembryonic antigen (100%), p53 overexpression (40%), and Ki-67 labeling index (38%, median). All the micrometastases were portal thromboemboli in the intrahepatic portal triad that invaded extravenous structures, causing desmoplasis, local biliary obstruction, and indocyanine green-contained bile stasis A review of preoperative dynamic computed tomography or magnetic resonance images revealed focal circular alterations presenting as arterioportal shunts in 50% of the patient with micrometastases and 11% of those without (P < 0.01). CONCLUSIONS: Hepatic metastasis from pancreatic cancer involves portal vein thrombosis that alters local circulation and bile stasis at the portal triad; this is detectable by presurgical radiological examination or intraoperative fluorescent imaging. PMID- 28902792 TI - Paracrine Secretion of Transforming Growth Factor beta by Ductal Cells Promotes Acinar-to-Ductal Metaplasia in Cultured Human Exocrine Pancreas Tissues. AB - OBJECTIVE: We aimed to evaluate the contribution of acinar-to-ductal metaplasia (ADM) to the accumulation of cells with a ductal phenotype in cultured human exocrine pancreatic tissues and reveal the underlying mechanism. METHODS: We sorted and cultured viable cell populations in human exocrine pancreatic tissues with a flow cytometry-based lineage tracing method to evaluate possible mechanisms of ADM. Cell surface markers, gene expression pattern, and sphere formation assay were used to examine ADM. RESULTS: A large proportion of acinar cells gained CD133 expression during the 2-dimensional culture and showed down regulation of acinar markers and up-regulation of ductal markers, assuming an ADM phenotype. In a serum-free culture condition, ADM induction was mainly dependent on transforming growth factor beta (TGF-beta) secreted from cultured ductal cells. Human acinar cells when cultured alone for a week in a serum-free condition do not undergo ADM. However, serum may contain other factors besides TGF-beta to induce ADM in human acinar cells. In addition, we found that TGF-beta cannot induce ADM of murine acinar cells. CONCLUSIONS: Ductal cells are the major source of TGF-beta that induces ADM in cultured human exocrine pancreatic tissues. This culture system might be a useful model to investigate the mechanism of ADM in human cells. PMID- 28902793 TI - The Risk Factors for Moderately Severe and Severe Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis According to the Revised Atlanta Classification. AB - OBJECTIVES: The aim of this study was to confirm the value of the revised Atlanta classification for predicting the severity of post-endoscopic retrograde choloangiopancreatography pancreatitis (PEP) and to validate the risk factors for moderately severe and severe PEP. METHODS: Among 2672 patients, 86 with PEP and 172 randomly selected control patients were included in this study. Post endoscopic retrograde choloangiopancreatography pancreatitis was evaluated according to Cotton criteria and the revised Atlanta classification. The agreements between the 2 sets of criteria were compared, and the risk factors for moderately severe and severe PEP were identified. RESULTS: According to the revised Atlanta classification, 72 patients (83.7%) had mild, 11 (12.8%) had moderately severe, and 3 (3.5%) had severe disease. The agreement between the revised Atlanta classification and Cotton criteria was fair (kappa = 0.285). Statistically significant risk factors for PEP were difficult cannulation and dye injection in the pancreatic duct, including acinarization. For moderately severe or severe PEP, obesity (hazard ratio, 3.384 [95% confidence interval, 1.023 11.191]) was the only statistically significant risk factor. CONCLUSIONS: The revised Atlanta classification of acute pancreatitis is an effective and feasible classification system for predicting PEP severity. Obesity was identified as an important risk factor predicting moderately severe and severe PEP. PMID- 28902794 TI - Lymph Node Metastasis in the Prognosis of Gastroenteropancreatic Neuroendocrine Tumors. AB - OBJECTIVES: This study aimed to determine the prognostic use of the extent of lymph node (LN) involvement in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) by analyzing population-based data. METHODS: Patients in the Surveillance, Epidemiology, and End Results registry were identified with histologically confirmed, surgically resected GEP-NETs. We divided patients into 3 lymph node ratio (LNR) groups based on the ratio of positive LNs to total LNs examined: 0.2 or less, greater than 0.2 to 0.5, and greater than 0.5. Disease-specific survival was compared according to LNR group. RESULTS: We identified 3133 patients with surgically resected GEP-NETs. Primary sites included the stomach (11% of the total), pancreas (30%), colon (32%), appendix (20%), and rectum (7%). Survival was worse in patients with LNRs of 0.2 or less (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.2-2.0), greater than 0.2 to 0.5 (HR, 2.0; 95% CI, 1.6-2.5), and greater than 0.5 (HR, 3.1; 95% CI, 2.5-3.9) compared with N0 patients. Ten-year disease-specific survival decreased as LNR increased from N0 (81%) to 0.2 or less (69%), greater than 0.2 to 0.5 (55%), and greater than 0.5 (50%). Results were consistent for patients with both low- and high-grade tumors from most primary sites. CONCLUSIONS: Degree of LN involvement is a prognostic factor at the most common GEP-NET sites. Higher LNR is associated with decreased survival. PMID- 28902795 TI - Magnetic Resonance Imaging of Neuroendocrine Tumor Hepatic Metastases: Does Hepatobiliary Phase Imaging Improve Lesion Conspicuity and Interobserver Agreement of Lesion Measurements? AB - OBJECTIVE: The aim of this study was to determine if magnetic resonance imaging (MRI) performed with hepatobiliary phase imaging results in higher lesion conspicuity and produces lesion measurements with higher interobserver agreement than other MRI sequences when imaging neuroendocrine hepatic metastases. METHODS: Patients who had MRIs with both gadoxetate disodium and gadopentetate dimeglumine contrast within a 6-month span were identified, and 23 hepatic lesions were selected. Three radiologists and 1 oncologist measured the greatest diameter of each lesion on the following sequences: T2 weighted, T1 weighted, postcontrast (dynamic, delayed, and hepatobiliary phase), and diffusion weighted. Signal intensity ratio (SIlesion/SIliver) and contrast-to-noise ratio ([SIlesion - SIliver]/noise) were calculated for all lesions on each sequence. The interobserver agreement of measurements on each sequence was calculated using concordance correlation coefficient. RESULTS: Diffusion-weighted sequences had the highest signal intensity ratio ranging from 147% to 187% (vs other sequences range of 19.6%-130%). One hepatobiliary sequence had the highest contrast-to noise ratio with a value of 41 (vs other sequences range of 3.2-28.1). Lesion measurements on all sequences showed high-interobserver agreement, with hepatobiliary sequences showing some of the highest levels of agreement. CONCLUSIONS: Our results support the use of contrast agents with hepatobiliary excretion when imaging neuroendocrine tumors metastatic to liver. PMID- 28902796 TI - Carcinosarcoma of the Pancreas: Case Report With Comprehensive Literature Review. AB - Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed mullerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible. PMID- 28902797 TI - Polymorphism in DPPIV Gene in Acute Pancreatitis. PMID- 28902798 TI - Cumulative Radiation Exposure in Pancreatic Drainage: Could it be Improved? PMID- 28902799 TI - Current Strategies for Detection and Treatment of Recurrence of Pancreatic Ductal Adenocarcinoma After Resection: A Nationwide Survey. PMID- 28902800 TI - Pancreatic Steatosis Is Not Associated With Exocrine Pancreatic Function in Overweight Type 2 Diabetes Patients. PMID- 28902801 TI - The Characteristics of Aborted Procedures in Total Pancreatectomy With Islet Autotransplantation for Chronic Pancreatitis. PMID- 28902802 TI - Audiological Outcomes and Map Characteristics in Children With Perimodiolar and Slim Straight Array Cochlear Implants in Opposite Ears. AB - OBJECTIVE: To identify differences in outcomes and map characteristics in pediatric bilateral cochlear implants with modiolar conforming and lateral wall arrays in opposite ears. STUDY DESIGN: Retrospective case series. SETTING: Tertiary care pediatric referral center. PATIENTS: Fourteen children who received a perimodiolar array in one ear and a slim straight array in the opposite ear in sequential surgeries. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Consonant nucleus-consonant test (CNC) word recognition score, battery life, power levels, electrical compound action potential (ECAP) thresholds, and electrical threshold and comfort charge levels. RESULTS: Speech perception outcomes were poorer in the lateral wall ears than the perimodiolar ears, and scores in the bilateral condition were better than with the lateral wall device alone. Sequential placement was a factor with differences in preoperative candidacy time correlating with greater difference in speech perception. There was no difference in charge levels between ears, in spite of higher ECAP threshold values for the lateral wall devices. CONCLUSION: While bilateral speech perception was good, speech perception with the lateral wall device alone was poorer. This cannot be explained solely by the device, as differences in preoperative candidacy time were a significant factor. ECAP thresholds are significantly higher for lateral wall electrodes, but that did not translate in to higher psychophysical measurements. PMID- 28902803 TI - Cochlear Implantation in Otosclerosis: Surgical and Auditory Outcomes With a Brief on Facial Nerve Stimulation. AB - OBJECTIVES: 1) To review the surgical and auditory outcomes in patients of cochlear implantation in otosclerosis. 2) To review complications and postimplantation facial nerve stimulation (FNS). 3) To compare the auditory outcomes between patients displaying cochlear ossification to the nonossified ones. STUDY DESIGN: Retrospective study. SETTING: Quaternary Otology and Skull base surgery center. SUBJECTS AND METHODS: Charts of 36 patients (38 ears) with otosclerosis undergoing cochlear implantation were reviewed from the cochlear implant database. Demographic features, operative findings, auditory outcomes, and postimplantation FNS were analyzed. Operative findings included extent of cochlear ossification, approach (posterior tympantomy/subtotal petrosectomy), electrode insertion (partial/complete, scala tympani/vestibuli), and complications. All the patients underwent implantation using straight electrodes. Auditory outcomes were assessed over a 4-year follow-up period using vowel, word, sentence, and comprehension scores. Patients were divided into two groups (with and without cochlear ossification) for comparison of auditory outcomes. RESULTS: The mean age and duration of deafness of patients was 59.72 and 28.9 years respectively. Twenty-three of 38 ears had cochlear ossification, with exclusive round window involvement in 60% of the patients, with the rest having partial or complete basal turn ossification. 36.8% ears underwent subtotal petrosectomy for cochlear ossification. One patient underwent scala vestibuli insertion and two had incomplete electrode insertion. Patients with no ossification had no intra or postoperative complications. One patient had bilateral FNS managed by alterations in programming strategy. Auditory outcomes in patients without any ossification were better than in patients with ossification, though statistically insignificant in most parameters. CONCLUSION: Cochlear implantation in otosclerosis provides good auditory outcomes, despite high incidence of cochlear ossification. Patients of FNS can be managed by alterations in programming strategy, without affecting auditory outcomes. PMID- 28902804 TI - Long-Term Patient-Reported Outcomes After Surgery for Superior Canal Dehiscence Syndrome. AB - OBJECTIVE: Evaluate the long-term patient-reported outcomes of surgery for superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Cross-sectional survey. SETTING: Tertiary referral center. PATIENTS: Adults who have undergone surgery for SCDS with at least 1 year since surgery. MAIN OUTCOME MEASURE(S): Primary outcome: change in symptoms that led to surgery. SECONDARY OUTCOMES: change in 11 SCDS-associated symptoms, change in psychosocial metrics, and willingness to recommend surgery to friends with SCDS. RESULTS: Ninety-three (43%) respondents completed the survey with mean (SD) time since surgery of 5.3 (3.6) years. Ninety five percent of respondents reported the symptoms that led them to have surgery were "somewhat better," "much better," or "completely cured." Those with unilateral symptoms were more likely to report improvement than those with bilateral symptoms. There was no difference between those with short (1-5 yr) versus long (5-20 yr) follow-up. Each of the SCDS-associated symptoms showed significant improvement. The largest improvements were for autophony, pulsatile tinnitus, audible bodily sounds, and sensitivity to loud sound. Headaches, imbalance, dizziness, and brain fog showed the least improvements. Most patients reported improvements in quality of life, mood, and ability to function at work and socially. Ninety-five percent of patients would recommend SCDS surgery. CONCLUSIONS: Respondents demonstrated durable improvements in the symptoms that led them to have surgery. Auditory symptoms had the greatest improvements. Headaches, imbalance, dizziness, and brain fog showed the least improvements. Nearly, all patients would recommend SCDS surgery to others. These results can be used to counsel patients regarding the lasting benefits of surgery for SCDS. PMID- 28902805 TI - The Effect of Hearing Aids and Cochlear Implants on Balance During Gait. AB - HYPOTHESIS: Auditory input in people with hearing impairment will improve balance while walking. BACKGROUND: Auditory input is increasingly recognized as an additional input for balance. Several studies have found auditory cues to improve static balance measured on a sway platform. The effect of audition on gait, a dynamic task also linked to fall risk, has not been fully examined. If a positive effect were shown between audition and balance, it would further indicate that improving hearing could also improve balance. METHODS: Inertial sensors quantified gait parameters of 13 bilateral hearing aid users and 12 bilateral cochlear implant (CI) users with their hearing devices on and off. Outcome measures included gait velocity, stride length variability, swing time variability, and double support phase. RESULTS: Group analysis of each of the gait outcomes showed no significant differences between the aided and unaided conditions in both the hearing aid and CI groups. Gait velocity, an outcome most strongly linked to fall risk had 95% confidence interval differences of -2.16 to 1.52 and -1.45 to 4.17 cm/s in hearing aid and CI users, respectively (aided versus unaided condition). There was considerable variation among participants with some individuals improving in all four parameters. CONCLUSION: The overall findings were not statistically significant, however, a small subset of our population improved clinically across several outcomes. This demonstrates that audition may have a clinically beneficial effect on balance in some patients. PMID- 28902806 TI - Response to "Letter to Editor" Skin Necrosis After Implantation with the Baha Attract: A Case Report and Review of the Literature. PMID- 28902808 TI - [Anticoagulant therapy of venous thromboembolic complications: balancing between risks]. AB - This article is a review of the literature, related to the problem of recurrence of venous thromboembolic complications and the possibilities of their secondary prevention. The problems of determining the rational duration of anticoagulant therapy on the basis of an individual assessment of its benefit and risk are considered. The information on modern prognostic models allowing quantitative assessment of the probability of hemorrhagic and thrombotic events occurrence is presented (Vienna prediction model, DASH, HAS-BLED, stratification according to ACCP 2016). Particular attention is paid to the effectiveness and safety of new oral anticoagulants and acetylsalicylic acid in the context of secondary prevention of deep vein thrombosis and pulmonary embolism. A review and a critical analysis of the EINSTEIN CHOICE study were carried out. The results demonstrated the high efficacy and safety of rivaroxaban 10 and 20 mg in the frame of prolonged therapy of venous thromboembolic complications in patients, who completed the standard 6-12-month course of treatment and who do not need further use therapeutic doses of anticoagulants. The study demonstrated that the use of rivaroxaban in both doses for 12 months is characterized by greater efficacy and a similar frequency of occurrence of large and clinically significant bleeding compared with the intake of 100 mg of acetylsalicylic acid. The authors attempted to determine rational indications for the application of 10 mg of rivaroxaban in the frame of prolonged anticoagulant therapy, which will be possible after making appropriate changes to the official instruction for the drug. PMID- 28902807 TI - External Validation of Pooled Cohort Risk Equations to Predict 1-Year Clinical Outcome in Ischemic Stroke Patients. AB - BACKGROUND The present study aimed to validate the pooled cohort risk (PCR) equations in a Chinese ischemic stroke population and to explore its prognostic value in predicting stroke recurrence, coronary heart disease, and vascular death. MATERIAL AND METHODS Patients were selected from the China National Stroke Registry. The C statistic was used to examine the clinical prediction of the scores. To analyze the relevant risk factors, univariate and multivariate logistic regressions were performed. RESULTS Out of a total of 22 216 patients, 8287 patients (including 7652 acute ischemic stroke [AIS] and 635 transient ischemic attack [TIA] patients) were selected and enrolled in the study. At 1 year follow-up, for stroke recurrence rate, the C statistic value was 0.584 in AIS patients and 0.573 in all patients. For non-fatal myocardial infarction, the C statistic value was 0.533 in AIS patients and 0.493 in all patients. For vascular death, the C statistic value was 0.592 in AIS patients and 0.592 in all patients. For all events, the C statistic value was 0.582 in AIS patients and 0.575 in all patients. For AIS patients, the 12-month cumulative rates for recurrent stroke, vascular death, and combined vascular events were higher in the high-PCR group (PCR >=20%). CONCLUSIONS Pooled cohort risk equations may serve as potential tools to predict and stratify the 1-year risk of recurrent stroke and combined vascular events in AIS/TIA patients in China. PMID- 28902809 TI - [Peculiarities of secretion of cytokines and chemokines by human blood monocytes in atherosclerosis]. AB - The study included apparently healthy people, conventionally healthy people predisposed to atherosclerosis, and as well as people with preclinical atherosclerosis (50 subjects in each group). Monocytes were isolated from whole blood and transferred to culture followed by studying pro- and anti-inflammatory activation of monocytes in response to stimulation by interferon-gamma and interleukin-4, respectively. As a marker of pro-inflammatory activation was the level of secretion of tumour necrosis factor-alpha (TNF-alpha) in the culture medium measured by means of immunoenzymatic assay. Chemokine CCL18 served as a marker of anti-inflammatory activation. We also examined secretion of a series of other chemokines and cytokines: MCO-1, IL-6, IL-1beta, IL-8, GM-CFS, and others. Pronounced individual differences of cytokines and chemokines secretion were revealed in all groups. We carried out assessment the degree of altering secretion of cytokines and chemokines by stimulated monocytes compared with unstimulated culture. This approach may serve as an effective tool for assessment an individual reaction of congenital immunity. PMID- 28902810 TI - Biochemical markers in blood serum of patients undergoing various methods of carotid endarterectomy. AB - The authors studied the concentration of CRP, sE-selectin, sP-selectin, sICAM-1, sICAM-3, sVCAM-1, sPECAM and endothelin-1 in blood serum of patients presenting with stenotic lesions of carotid arteries and undergoing various methods of carotid endarterectomy (CEAE): eversion CEAE (Group I) and CEAE using a xenopericardium patch (Group II). Within the time frame of the study, patients in both groups were found to have an elevated CRP level in the early postoperative period, having returned to the baseline values at 6 postoperative months, as well as an increase in the concentration of endothelin-1 at six months after surgery and a decrease of the sE-selectin concentration in the early postoperative period. The level of sP-selectin in Group II patients was noted to increase considerably six months after correction of stenosis. The content of sICAM-1 and sVCAM-1 did not differ in the early postoperative and baseline periods, and was noted to decrease 6 months after the operation. Group II patients demonstrated a decrease in the sPECAM concentration during postoperative day one, followed by returning to the initial values six months after CEAE. The above-mentioned biochemical markers may be used during the postoperative follow-up period for early detection and appropriate correction of endothelial dysfunction and hyperplasia of the intima of the zone of reconstruction. PMID- 28902811 TI - [Oxidative carbonylation of proteins in experimental hind-limb ischaemia reperfusion injury]. AB - Formation of carbonylated protein derivatives is one of the key signalling pathways in cellular damage and may be regarded as a reliable marker in cellular injury. It allows evaluating both direct effects of reactive oxygen species and indirect interrelations with the secondary by-products of oxidation. The present study was undertaken to investigate the activity of lysosomal cysteine proteinases (cathepsins B and L) in blood serum and the arterial wall in an experimental model of ischaemia and ischaemia-reperfusion injury. To this was added comprehensive assessment of oxidative modification of proteins derived from blood serum and the arterial wall, namely, calculating the area under the curve of the absorption spectrum of the products of protein carbonylation, the proportion of the primary and secondary markers of oxidative stress, as well as the reserve and adaptation potential. The obtained findings were indicative of the development of oxidative stress in the model of ischaemia-reperfusion injury from day 1 to day 7, and in the ischaemia model on day 3 and day 5 in both the vascular wall and blood serum, which was accompanied by activation of cathepsins B and L. Reversible oxidation of proteins was observed on days 3 and 5 in the experimental ischaemia model and on days 1 and 7 in the ischaemia-reperfusion injury model, which was confirmed by the predominance of the primary markers of oxidative stress. Irreversible oxidation of proteins, i. e., the predominance of the secondary markers, was suggestive of the enhancement of oxidative stress, its transition to the late stage, leading to the loss of biological properties of proteins and eventually followed by their aggregation and degradation as seen in the ischaemia-reperfusion injury model on days 3 and 5. Analysing the obtained findings revealed direct correlation between the total area under the curve of oxidative modification of proteins and overall activity of cathepsin L in the ischaemia model: in blood serum on days 3 and 5, in the vascular wall for cathepsins B and L on day 5; in the ischaemia-reperfusion injury model: the activity of cathepsin L in blood serum on day 3, in the vascular wall on day 5 for cathepsins B and L. PMID- 28902812 TI - [The use nicergoline in the treatment of diabetes mellitus]. AB - Presented herein is a literature review aimed at investigating the appropriateness and possibility of using nicergoline (sermion) for treatment of patients suffering from diabetes mellitus. The analysis includes the most clinically significant results of scientific studies. The material to be reviewed was retrieved using the following key words: 'nicergoline', 'sermion', and 'diabetes mellitus' (with their respective Russian equivalents) in such databases as Medline, PubMed, ScienceDirect, PMC, Cochrane, as well as archives of both Russian and foreign journals, guidelines (clinical guidelines on rendering medical care for patients with diabetes mellitus, selected lectures on endocrinology). A broad spectrum of action and no significant side effects have made it possible to use this drug in various pathological conditions. At the same time, because of limited experience of using nicergoline for vascular diseases and an insufficient number of the carried out studies the precise role of this therapeutic agent in clinical practice has not yet been conclusively defined. Special attention is given to the analysis of efficacy of nicergoline in atherosclerosis and diabetes mellitus. PMID- 28902813 TI - [Surgical decision-making during treatment of a patient with multifocal atherosclerosis based on intraoperative epiaortic scanning]. AB - The article deals with a clinical case report regarding surgical management of a patient presenting with multifocal atherosclerosis. Taking into consideration critical stenoses of the anterior interventricular artery (80%) and circumflex artery (80%), as well as subocclusion of the left internal carotid artery and stenosis of the right internal carotid artery (60%), there were high risks for intraoperative cerebral circulation impairment. It was decided to perform a two stage operation on the coronary and carotid beds. The envisaged scope of the intervention comprised: carotid endarterectomy on the left and coronary bypass grafting of the anterior interventricular and circumflex arteries in conditions of assisted circulation. The intraoperative epiaortic scanning revealed atheromatosis of the ascending portion of the aorta, thus making it impossible to cross-clamp the aorta for establishing distal anastomoses on the non-beating heart and proximal anastomoses on the aorta. A decision was made to change the treatment policy. The patient was subjected to endarterectomy from the left internal carotid artery and mammarocoronary bypass grafting of the anterior interventricular artery on the beating heart with the help of the Octopus myocardial stabiliser. The second stage consisted in stenting of the circumflex artery. This clinical case report demonstrates the necessity of precision diagnosis of an atherosclerotic lesion of the aorta by means of epiaortic scanning in order to prevent perioperative acute impairments of cerebral circulation. PMID- 28902814 TI - ['Life-saving' interventions in subacute thrombosis of crural and plantar arteries]. AB - The authors report a clinical case concerning successful endovascular treatment for subacute thrombosis of crural and plantar arteries in a patient with the only leg, substantiating therapeutic decision making with due regard for the duration of thrombosis and localization of the lesion of the arterial bed. Taking into consideration the statistical data on survival in case of performing major amputation in this cohort of patients, an 'aggressive' endovascular approach including three vascularizations made it possible not only to preserve the leg but also to save the patient's life. PMID- 28902815 TI - [Endovascular treatment of a patient with post-thrombotic disease and obstruction of a cava filter]. AB - Balloon angioplasty and stenting have increasingly been gaining widespread application for treatment of post-thrombotic alterations in the system of the vena cava. Endovascular ultrasonographic examination makes it possible with the utmost degree of reliability to determine both the extension and degree of the narrowing of venous segments, thus proving a possibility of choosing a venous stent of an appropriate diameter. Restoration of an adequate venous lumen leads to normalization of blood flow and elimination of venous hypertension. However, unsolved as yet remains the problem concerning proper management of post thrombotic obstructions of the inferior vena cava at the level of a cava filter. Owing to a wide variety of configurations of cava filters to deploy, there are no common approaches to elimination of such obstruction. Presented herein is a clinical case report regarding successful endovascular treatment of a patient diagnosed with post-thrombotic disease secondary to endured thrombosis. The findings of both phlebography and endovascular ultrasonographic examination made it possible to diagnose obstruction of the left common iliac vein, external iliac vein, and inferior vena cava to the level of the cava filter previously deployed. In the segment of the inferior vena cava at the level of the cava filter also revealed was a pronounced luminal narrowing exceeding 90% of its diameter. We carried out stenting of the common and external iliac veins, inferior vena cava, and the cava filter. Swelling of the left leg subsided spontaneously within 2 weeks and the first postoperative month was accompanied by gradual disappearance of the previously existing feeling of heaviness in the lower limbs and a dramatic decrease in fatigue by the end of the working day. PMID- 28902816 TI - [Diagnosis and treatment of deep vein thrombosis in neonates and nurselings]. AB - The authors share herein their experience in diagnosis and treatment of deep vein thrombosis in neonates and nurselings. We examined a total of 132 infants undergoing treatment in an intensive care unit. Of these, 15 infants were diagnosed with various-localization thromboses. Ultrasonographic study was the main method of diagnosis. Management consisted in anticoagulant therapy. Timely administration of anticoagulant therapy made it possible to achieve complete recanalization of venous lumens in 80% of cases. Only 20% of infants were found to have vein occlusion preserved, thus requiring further follow up and treatment. Neither complications nor relapsing thromboses were observed. A conclusion was drawn that characteristic of neonates and infants under 12 months of life is a specific profile of etiopathogenesis of deep vein thrombosis. In the majority of cases thrombosis appears to be catheter-related, and only in sporadic cases it forms spontaneously. Treatment of thromboses is typically associated with high successfulness of medicamentous therapy. PMID- 28902817 TI - [Clinical efficacy of electric stimulation of crural muscles in comprehensive treatment of post-thrombotic disease]. AB - The purpose of the study was to evaluate clinical efficacy of electromyostimulation (EMS) of the crural muscles as part of comprehensive therapy for post-thrombotic disease in patients with residual venous obstruction in the femoropopliteal segment. We carried out a prospective comparative clinical study enrolling patients having endured a fist episode of clinically unprovoked venous thrombosis of the femoropopliteal segment and completed the standard 6 month course of anticoagulant therapy and presenting with ultrasonographic signs of complete recanalization of the proximal venous segments (stenosis of 20% and more from the vessel's initial diameter), as well as scoring 5 points and more by the Villalta scale. The study included a total of 60 patients (38 men and 22 women, mean age 58.5+/-11.4 years) subdivided into two groups consisting of 30 patients each. Patients of both the Study and Control Groups underwent comprehensive therapy including wearing a compression knee sock (23-32 mmHg), a course phlebotrophic drugs, and dosed walking (not less than 5,000 steps a day). The Study Group patients were additionally subjected to daily electrical stimulation of the crural muscles with the "Veinoplus VI" unit (three 30-minute sessions a day). The duration of the follow up amounted to 12 months. The criteria for assessing therapeutic efficacy were as follows: severity of the disease by the VCSS and Villalta scales, quality of life as assessed by the CIVIQ 20 questionnaire, and lack of relapses of the venous thrombus. Clinical and instrumental assessment of the patients' condition was carried out monthly, with the disease's severity and quality of life assesses each 6 months. Relapses of venous thrombosis were registered in 7 (23.3%) patients from the Control Group and were not observed in patients undergoing EMS (p=0.011). In 5 cases, thrombosis was asymptomatic and in 4 cases it was presented by reocclusion of the involved venous segments. Patients of the Study Group were found to have a decrease in the disease's severity, reflected in points: VCSS (9.9+/-1.6 - 7.8 +/ 1.6 - 6.1+/-1.5 (p <0.0001)); Villalta scale (18.9+/-3.9 - 12.8+/-4.0 - 8.3+/ 2.7 (p<0.0001)); CIVIQ-20 score (67.8+/-8.4 - 51.3+/-8.4 - 40.0+/-10.5 (p<0.001)). The Control Group patients showed a similar tendency for the disease's severity: 8.1+/-2.8 - 7.3+/-2.1 - 7.2+/-2.1 points by the VCSS (p=0.014); 12.7+/-6.7 - 10.9+/-5.6 - 10.2+/-5.4 points by the Villalta scale (p=0.002), but not for quality of life: 48.2+/-19.3 - 46.7+/-17.3 - 47.4+/-16.2 points by the CIVIQ-20 (p>0.05). On the background of using EMS, the alterations in the studied parameters were characterized by higher velocity and intensity (p<0.05). The use of electromyostimulation as part of comprehensive treatment for post-thrombotic disease makes it possible to efficiently eliminate both subjective and objective signs of venous insufficiency, improve patients' quality of life and decrease the risk for the development of relapsing venous thrombosis. PMID- 28902818 TI - [Efficacy of sulodexide in treatment of chronic venous insufficiency. Results of the ACCORD trial]. AB - OBJECTIVE: The purpose of our study was to evaluate both clinical and laboratory efficacy of sulodexide given at a daily dose of 500 lipasemic units (LSU) in patients presenting with class C3-C4 chronic venous insufficiency (CVI) according to the CEAP classification. PATIENTS AND METHODS: The study included a total of 25 patients diagnosed with C3-C4 CVI and prescribed to receive sulodexide at a daily dose of 500 LSU for 90 days. Efficacy was comprehensively controlled by the following tools: the disease-specific Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ), visual-analogue methods of assessment separate symptoms; the Venous Clinical Severity Score (VCSS), as well as ultrasonographic determination of the thickness of subcutaneous fat and crural fascia. Amongst the key laboratory indices determined by means of the ELISA test were the levels of interleukin-1 alpha (IL-1alpha), interleukin-1 beta (IL-1beta), matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), vascular endothelial growth factor A (VEGF-A), vasopressin and endothelin. RESULTS AND DISCUSSION: Of the initially enrolled 25 subjects, twenty-two patients completed the study and were taken as 100%. The 90-day treatment yielded favourable results manifesting themselves in complete disappearance of convulsions in the calf muscles detected at the first visit in 22.7% of patients (p=0.0485), a significant reduction in the frequency of complaints of decreased tolerance to static loads from 27.3 to 9.1% (p=0.2404). The volume of the crus of the control lower extremity decreased from 134.18+/-14. 92 to 128.42+/-12.46 cm3 (p=0.0006), subcutaneous fat thickness at the fixed point decreased from 1.50+/-0.53 to 1.32+/-0.46 cm (p=0.0007), and fascial thickness decreased from 0.14+/-0.7 to 0.11+/-0.04 (p=0.0359). Pain syndrome according to the visual analogue scale (VAS) decreased from 36.45+/ 25.60 to 17.50+/-19.27 mm (p=0.0002). The global index of quality of life (GIQoL) according to the CIVIQ-20 increased by 27.7% compared with the baseline level (p = 0.0001), the VCSS index decreased from 6.00+/-1.83 to 4.86+/-2.05 points (p=0.0002). as for the laboratory markers of endothelial dysfunction, there was a significant decrease in the levels of MMP-2 - from 178.53+/-36.30 to 176.35+/ 36.67 ng/ml (p=0.0152), MMP-9 - from 90.84+/-20.41 to 89.78+/-20.32 ng/ml (p=0.0394), and that of endothelin - from 0.42+/-0.10 to 0.39+/-0.10 fmol/ml. CONCLUSION: Sulodexide exerting a statistically significant clinical and endothelium-protecting effect turned out to be an effective drug for treatment of initial forms of chronic venous insufficiency of lower limbs. PMID- 28902819 TI - [Chronic venous diseases: valvular function and leukocyte-endothelial interaction, possibilities of pharmacotherapy]. AB - This article provides a review of the literature focusing on the data elucidating the pathogenesis of chronic venous diseases from the positions of macrohaemodynamic (venous valvular function) and microcirculatory impairments. Presented herein are confirmations of the interaction between two important mechanisms, as well as the literature data concerning the role of the venous microvalvular structures and possible haemodynamic impairments in functional venous insufficiency. Also presented are substantiations in confirmation of the theory of leukocyte-endothelial interaction, forming the basis for contemporary understanding of the pathogenesis of chronic venous diseases. This is followed by elucidating the role of venoactive drugs in conservative treatment of patients with chronic venous diseases, and, finally, touching upon current problems and promising approaches to solve them. PMID- 28902820 TI - The operative technique of shunting to the third (V3) segment of the vertebral artery. AB - The authors provide a detailed description of the step-by-step technique of performing the operation of shunting to the V3 segment of the vertebral artery in patients with clinical manifestations of vertebrobasilar insufficiency (VBI). Reported are surgical outcomes in a total of 57 patients with VBI. Of these, 5 patients underwent arterial bypass grafting and 52 patients endured autovenous shunting. One patient developed shunt thrombosis in the early postoperative period and, unfortunately, died, with the remaining 51 shunts being patent. At 3 years of follow up, shunt thrombosis occurred in four (80%) patients with the arterial bypass and only in one (1.7%) of the 52 autovein-treated patients. The total duration of postoperative follow up amounted to 10 years. Long-term freedom from VBI clinical manifestations was achieved in 88.7 % of patients after 3 years and in 78.3% after 7 years, with the 3- and 7-year patency rate of the autovenous shunts amounting to 98.1 and 96.2%, respectively. PMID- 28902821 TI - [Outcomes of open endovascular operations on the internal carotid artery in acute stage of ischaemic stroke]. AB - INTRODUCTION: The authors share their experience in diagnosis and treatment of patients with acute ischaemic stroke. PATIENTS AND METHODS: The study included a total of 33 patients. Of these, 20 patients (Study Group) were operated on at terms ranging from 2 to 7 days after onset of acute cerebral circulatory impairment. The Control Group was composed of 13 patients with ischaemic stroke, having refused surgical prevention of recurrent stroke. Both groups were matched by age, gender, level of neurological deficiency and size of cerebral ischaemic foci. Surgical management in the Study Group consisted in either carotid endarterectomy (n=15) or stenting of the internal carotid artery (n=5). Depending on the severity of coronary artery lesion and the presence of accompanying therapeutic pathology, options of operative treatment with various anaesthesiological support were offered. RESULTS: At discharge, neurological deficit in the Study Group patients was lower - 1.2 points by the NIH Stroke Scale versus 2.7 points in the Control Group, however, this difference was not statistically significant (p=0.45). In the Study Group there were two complications: haematoma of the postoperative injury requiring its revision and a transient ischaemic attack during stenting of the internal carotid artery, having disappeared on the operation table after the distal cerebral protection device was removed. Significantly better results were obtained by the following parameters: in the Study Group the number of patients discharged with no neurological deficit (scoring 0 by the NIHSS scale) was significantly higher compared with the Control Group; 50% vs 7.7% (p<0.001). There were no lethal outcomes in either group. One patient (7.7%) from the Study Group developed recurrent ischaemic stroke, whereas neither intra- nor postoperative stroke was registered in the Control Group patients (p<0.001). CONCLUSIONS: In carefully selected patients with ischaemic stroke (neurological deficit not exceeding 3 points by the Rankin scale and not more than 11 points by the NIHSS, with the size of the ischaemic focus not exceeding 4 cm), surgical prevention of recurrent stroke within 7 days after the onset of an ischaemic event may be performed effectively and safely. Early operation effectively prevents relapsing ischaemic events at the in-hospital stage. Besides, reconstruction of brachiocephalic arteries during an acute stage of stroke in operated patients improves the neurological status in the postoperative period, decreases the degree of motor and sensory disorders and makes it possible in half of patients to completely eliminate neurological deficit present at admission. PMID- 28902822 TI - Assessing the effect of endoprosthetic repair of the thoracic portion on aortic remodelling after surgical correction for DeBakey type I dissection. AB - OBJECTIVE: The purpose of the study was to evaluate the influence of endoprosthetic repair of the aortic thoracic portion on remodelling of the descending aorta in patients after the surgical stage of correction for DeBakey type I aortic dissection. PATIENTS AND METHODS: The authors retrospectively analysed a group of 12 patients (9 men and 3 women) subjected to endoprosthetic repair of the aortic thoracic portion after previously performed surgical correction of the ascending aorta and its braches. The average age of the patients amounted to 48 (43-56.7) years. All patients underwent multispiral computed tomography (MSCT) first performed at admission, then immediately after implantation of the stent graft and at 6, 12 and 24 months after discharge. The Control Group consisted of nine patients with a previous history of DeBakey type I aortic dissection, who had endured only surgical correction of the ascending aorta and arch. RESULTS: The success rate of the intervention amounted to 100%. There were no signs of ischaemia of the spinal cord, visceral organs or lower limbs. The diameter of the implanted stent grafts varied from 28 to 40 mm and the length ranged from 140 to 204 mm. Seven (58%) patients of the Study Group as early as during a year were found to have no blood flow along the false channel. The false channel remained patent in 100% of the Control Group patients. Over a two-year period of follow up, in patients after endoprosthetic repair, the diameter of the false channel did not increase. In the Control Group patients during the same period of follow up, there was a tendency towards an increase in the aortic diameter at the expense of dilatation of the false channel, with an enlargement of the false channel of the descending aorta at the level of the diaphragm from 1.8 (1.57-2.1) to 2.05 (1.7-2.31) cm (p=0.4) and at the level of the renal arteries from 1.5 (1.32-1.8) to 1.8 (1.58-1.97) cm (p=0.4). There were no lethal outcomes during follow up. CONCLUSION: Endoprosthetic repair of the thoracic portion after surgical correction was in the remote period accompanied and followed by stabilization of the diameter of the descending aorta, as well as contributed to closure of the false channel. PMID- 28902823 TI - [Comparing the risks for the development of perioperative complications in carotid endarterectomy and carotid angioplasty]. AB - The article is a literature review presenting a comparative analysis of 30-day risks of mortality and complications after carotid endarterectomy and carotid angioplasty with stenting. The risks studied were as follows: myocardial infarction, stroke, transitory ischaemic attacks, bradycardia, hypotension, postoperative haematomas, and damages to the craniocerebral nerves. The authors analysed a series of recently published foreign studies and meta-analyses dedicated to the problem concerned. The obtained findings revealed that carotid endarterectomy turned out to be associated with a higher perioperative risk for the development of myocardial infarction, postoperative haematomas and damages to the craniocerebral nerves, whereas carotid angioplasty with stenting appeared to be associated with an increased risk for the development of stroke, bradycardia and hypotension within the first 30 postoperative days. As far as mortality is concerned, it proved to be relatively similar for both methods of revascularization. The use of systems of protection of the brain from embolism during stenting of carotid arteries decreases the perioperative risks, however, it seems difficult to unequivocally affirm which of the methods of cerebral protection demonstrates better results. PMID- 28902824 TI - [Aneurysm of the extracranial portion of the internal carotid artery combined with kinking of its distal segment]. AB - Presented herein is a clinical case report regarding successful operation for an aneurysm of the left internal carotid artery (measuring 4.5*8.3 cm) combined with pathological tortuosity in its distal portion. The patient was subjected to aneurysmectomy of the left internal carotid artery with prosthetic repair. Kinking in the distal portion of the aneurysm made it possible with minimal technical difficulties to establish a distal anastomosis during prosthetic repair. The diagnosis of an atherosclerotic-aetiology aneurysm was morphologically confirmed. PMID- 28902825 TI - [Treatment of patients with critical lower limb ischaemia: endovascular methods or reconstructive operations]. AB - Presented herein is a review of the literature related to endovascular methods of treatment of patients with critical lower limb ischaemia. This is followed by comparative assessment of the outcomes of endovascular and open surgical interventions. Also covered are problems concerning appropriate therapeutic decision making, taking into consideration peculiarities of lower limb ischaemia and the state at the expense of insufficiency of inflow/outflow. PMID- 28902826 TI - [Treatment of type IB endoleak after endoprosthetic repair of infrarenal aneurysm]. AB - The article deals with a case report regarding successful surgical management of late type IB endoleak caused by dislocation of the leg of the stent graft, occurring three years after endoprosthetic repair of an aneurysm of the aortic infrarenal portion with the COOK stent graft, aneurysmectomy with prosthetic repair of the right common femoral artery using the linear vascular graft Intergard 8CH20. The patient underwent surgical treatment: endoprosthetic repair of the iliac branch ZSLE-24-90-90 ZT of the Zenith Spiral AAA stent graft. The findings of the check-up angiography and ultrasonographic examination revealed no evidence of endoleak, with the stent graft's patency preserved. The early postoperative period was marked with moderate manifestations of asthenic syndrome. The patient was discharged in a satisfactory condition. Cases concerning removal of similar complication in the remote period following endoprosthetic repair of the aorta are mentioned sporadically in the available literature. PMID- 28902827 TI - [Repeat prosthetic repair of the internal carotid artery]. AB - Described herein is a clinical case report regarding reoperation on carotid arteries for thrombosis of a synthetic graft of the internal carotid artery in a patient presenting with a multifocal atherosclerotic lesion. Despite medicamentous treatment carried out after the primary operation, the presence of major risk factors had unfavourably contributed to progression of the disseminated atherosclerotic process. During eight years, the patient had endured reconstructive interventions on the brachiocephalic and coronary arteries, as well as on the vessels of the iliac-femoral-popliteal segment. Taking into consideration the peculiarities of the vascular anatomy, the degree of stenosis of the internal carotid artery with the presence of thrombotic masses in the lumen, and thrombosis inside the graft, a decision was made to perform repeat "open" reconstruction consisting in successful common carotid-internal carotid prosthetic repair using a synthetic graft with resection of the external carotid artery. PMID- 28902828 TI - [Open surgical treatment of a giant renal cyst on the background of an arteriovenous fistula of the right renal artery]. AB - Presented herein is a clinical case report concerning open surgical treatment of an arteriovenous fistula of the renal artery with a large venous aneurysm in the hilum of the right kidney and a giant cyst of the upper pole in a 28-year-old woman. The intraoperative findings revealed disunion of the arteriovenous fistula, followed by edge-to-edge suturing of the arterial defect. The venous aneurysm in the hilum of the right kidney was dissected and sutured by the edge to-edge technique, with the additional varicose renal vein ligated. The postoperative period turned out to be uneventful with favourable convalescence and no complications. The check MSCT angiography performed 3 months later showed that the venous aneurysm was thrombosed, with no evidence of arterial blood ingress revealed. The excretory function of the kidney was preserved. Also discussed in the article are variants of diagnosis and treatment of an arteriovenous fistula of this localization and complications thereof. PMID- 28902829 TI - [Compression knitwear VENOTEKS TREND in treatment of patients with chronic venous diseases of the lower limbs]. AB - The authors assessed efficacy and safety of class 2 compression knitwear VENOTEKS TREND used in conservative and injection phlebosclerosing therapy of patients presenting with clinical class C1-C3 chronic venous diseases of the lower limbs. The study included a total of 30 patients. The compliance rate amounted to 92%. It was demonstrated that class 2 compression knitwear Venoteks Trend statistically significantly decreases the degree of subjective symptomatology, is efficient and safe in therapy for oedematous syndrome in the programmes of conservative treatment and after sclerotherapy. PMID- 28902830 TI - [Use of Tachocomb agent in cardiovascular surgery]. AB - The article contains a review of the literature concerning the use of the Tachocomb haemostatic sponge in cardiovascular surgery. This is followed by enumerating the pharmacological properties of the agent, mechanism of its action, and methods of application. Also shown herein is a high haemostatic effect of the sponge, exceeding that of other means of topical haemostasis. Both safety and a hypoallergenic nature make it possible to widely use Tachocomb in surgical practice. PMID- 28902831 TI - [Endovenous thermal interventions in treatment of patients with lower limb varicose veins]. AB - The problem regarding treatment of patients suffering from lower limb varicose veins remains a matter of current concern and is important today because of high prevalence of the pathology concerned and a steadily growing number of newly diagnosed cases. Mention should be made that both Russian and foreign phlebologists along with an open surgical operation on veins have more and more often been using minimally invasive endovenous techniques in comprehensive management of patients presenting with varicose veins. The present article is a literature review dedicated to a detailed discussion of two most commonly performed and efficient procedures, namely, radiofrequency ablation of lower limb veins and endovasal laser coagulation. This is accompanied and followed by demonstrating advantages of these techniques, describing the immediate and remote results obtained, as well as possible complications, both typical and rarely occurring. The majority of specialists employing radiofrequency ablation of lower limb veins and endovasal endovenous laser coagulation report high effectiveness of their use for treatment of patients with lower limb varicose veins, including those diagnosed with pronounced trophic impairments. The findings obtained by many authors while comparing efficacy of various endovenous procedures make it possible to assess them objectively and to correctly determine the indications for a particular intervention. PMID- 28902832 TI - [Thrombosis of lower-limb deep veins: a present-day view on conservative treatment]. AB - The article contains a review of the literature data concerning different variants of conservative treatment of patients suffering from lower limb deep vein thrombosis. This is accompanied and followed by demonstrating the manner of alterations in the views on using various anticoagulants, as well as analysing the attitude towards the place of compression therapy in treatment of patients with lower limb deep vein thrombosis. PMID- 28902833 TI - Rabies screen reveals GPe control of cocaine-triggered plasticity. AB - Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations. PMID- 28902834 TI - Alternative evolutionary histories in the sequence space of an ancient protein. AB - To understand why molecular evolution turned out as it did, we must characterize not only the path that evolution followed across the space of possible molecular sequences but also the many alternative trajectories that could have been taken but were not. A large-scale comparison of real and possible histories would establish whether the outcome of evolution represents an optimal state driven by natural selection or the contingent product of historical chance events; it would also reveal how the underlying distribution of functions across sequence space shaped historical evolution. Here we combine ancestral protein reconstruction with deep mutational scanning to characterize alternative histories in the sequence space around an ancient transcription factor, which evolved a novel biological function through well-characterized mechanisms. We find hundreds of alternative protein sequences that use diverse biochemical mechanisms to perform the derived function at least as well as the historical outcome. These alternatives all require prior permissive substitutions that do not enhance the derived function, but not all require the same permissive changes that occurred during history. We find that if evolution had begun from a different starting point within the network of sequences encoding the ancestral function, outcomes with different genetic and biochemical forms would probably have resulted; this contingency arises from the distribution of functional variants in sequence space and epistasis between residues. Our results illuminate the topology of the vast space of possibilities from which history sampled one path, highlighting how the outcome of evolution depends on a serial chain of compounding chance events. PMID- 28902835 TI - Reversing behavioural abnormalities in mice exposed to maternal inflammation. AB - Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation. PMID- 28902837 TI - Neuroscience: Mum's bacteria linked to baby's behaviour. PMID- 28902836 TI - Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors. AB - Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory. Early LTP (less than 1 h) had initially been explained either by presynaptic increases in glutamate release or by direct modification of postsynaptic AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid) receptor function. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional postsynaptic AMPA receptors (AMPARs), sourced either from an intracellular reserve pool by exocytosis or from nearby extra-synaptic receptors pre-existing on the neuronal surface. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during early LTP remains unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Here, using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion markedly impairs synaptic potentiation of Schaffer collaterals and commissural inputs to the CA1 area of the mouse hippocampus in cultured slices, acute slices and in vivo. Our data also identify distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus inhibited fear conditioning, indicating that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning. PMID- 28902838 TI - The cryo-electron microscopy structure of human transcription factor IIH. AB - Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 A resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Additionally, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity. PMID- 28902839 TI - SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis. AB - Pericyclic reactions-which proceed in a concerted fashion through a cyclic transition state-are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon-carbon bonds. They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels-Alder reaction, and the Cope and the Claisen rearrangements) have been characterized. Here we report a versatile S adenosyl-l-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels-Alder and hetero-Diels-Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin. Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme 'toolboxes'. The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis. PMID- 28902840 TI - Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. AB - Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote TH17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal TH17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1beta, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce TH17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes. PMID- 28902841 TI - cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. AB - Cytosolic DNA arising from intracellular pathogens triggers a powerful innate immune response. It is sensed by cyclic GMP-AMP synthase (cGAS), which elicits the production of type I interferons by generating the second messenger 2'3' cyclic-GMP-AMP (cGAMP). Endogenous nuclear or mitochondrial DNA can also be sensed by cGAS under certain conditions, resulting in sterile inflammation. The cGAS dimer binds two DNA ligands shorter than 20 base pairs side-by-side, but 20 base-pair DNA fails to activate cGAS in vivo and is a poor activator in vitro. Here we show that cGAS is activated in a strongly DNA length-dependent manner both in vitro and in human cells. We also show that cGAS dimers form ladder-like networks with DNA, leading to cooperative sensing of DNA length: assembly of the pioneering cGAS dimer between two DNA molecules is ineffective; but, once formed, it prearranges the flanking DNA to promote binding of subsequent cGAS dimers. Remarkably, bacterial and mitochondrial nucleoid proteins HU and mitochondrial transcription factor A (TFAM), as well as high-mobility group box 1 protein (HMGB1), can strongly stimulate long DNA sensing by cGAS. U-turns and bends in DNA induced by these proteins pre-structure DNA to nucleate cGAS dimers. Our results suggest a nucleation-cooperativity-based mechanism for sensitive detection of mitochondrial DNA and pathogen genomes, and identify HMGB/TFAM proteins as DNA-structuring host factors. They provide an explanation for the peculiar cGAS dimer structure and suggest that cGAS preferentially binds incomplete nucleoid-like structures or bent DNA. PMID- 28902842 TI - The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. AB - Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces. PMID- 28902844 TI - Melioidosis in lower provincial Cambodia: A case series from a prospective study of sepsis in Takeo Province. AB - Melioidosis is a severe infectious disease caused by the gram-negative soil bacterium Burkholderia pseudomallei. Melioidosis is well known to be a major cause of morbidity and mortality in Southeast Asia, particularly in Thailand. However, melioidosis remains underreported in surrounding areas such as Cambodia. We report a case series of melioidosis in seven patients from Takeo Province, Cambodia. The patients, aged 24-65 years, were enrolled from May 2014 to May 2015 during a one year prospective study of sepsis at Takeo Provincial Hospital. They presented with fever, rigors, dyspnea, fatigue, diaphoresis, productive cough, and skin abscesses. Six of the seven patients were also hyponatremic. B. pseudomallei was cultured from the blood of six patients and the sputum of one patient. In this manuscript, we provide a detailed description of the clinical presentation, case management and laboratory confirmation of B. pseudomallei, as well as discuss the difficulties of identifying and treating melioidosis in low resource settings. PMID- 28902843 TI - The Apostasia genome and the evolution of orchids. AB - Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms. PMID- 28902845 TI - Clinical and epidemiologic characteristics of dengue and other etiologic agents among patients with acute febrile illness, Puerto Rico, 2012-2015. AB - Identifying etiologies of acute febrile illnesses (AFI) is challenging due to non specific presentation and limited availability of diagnostics. Prospective AFI studies provide a methodology to describe the syndrome by age and etiology, findings that can be used to develop case definitions and multiplexed diagnostics to optimize management. We conducted a 3-year prospective AFI study in Puerto Rico. Patients with fever <=7 days were offered enrollment, and clinical data and specimens were collected at enrollment and upon discharge or follow-up. Blood and oro-nasopharyngeal specimens were tested by RT-PCR and immunodiagnostic methods for infection with dengue viruses (DENV) 1-4, chikungunya virus (CHIKV), influenza A and B viruses (FLU A/B), 12 other respiratory viruses (ORV), enterovirus, Leptospira spp., and Burkholderia pseudomallei. Clinical presentation and laboratory findings of participants infected with DENV were compared to those infected with CHIKV, FLU A/B, and ORV. Clinical predictors of laboratory-positive dengue compared to all other AFI etiologies were determined by age and day post-illness onset (DPO) at presentation. Of 8,996 participants enrolled from May 7, 2012 through May 6, 2015, more than half (54.8%, 4,930) had a pathogen detected. Pathogens most frequently detected were CHIKV (1,635, 18.2%), FLU A/B (1,074, 11.9%), DENV 1-4 (970, 10.8%), and ORV (904, 10.3%). Participants with DENV infection presented later and a higher proportion were hospitalized than those with other diagnoses (46.7% versus 27.3% with ORV, 18.8% with FLU A/B, and 11.2% with CHIKV). Predictors of dengue in participants presenting <3 DPO included leukopenia, thrombocytopenia, headache, eye pain, nausea, and dizziness, while negative predictors were irritability and rhinorrhea. Predictors of dengue in participants presenting 3-5 DPO were leukopenia, thrombocytopenia, facial/neck erythema, nausea, eye pain, signs of poor circulation, and diarrhea; presence of rhinorrhea, cough, and red conjunctiva predicted non-dengue AFI. By enrolling febrile patients at clinical presentation, we identified unbiased predictors of laboratory-positive dengue as compared to other common causes of AFI. These findings can be used to assist in early identification of dengue patients, as well as direct anticipatory guidance and timely initiation of correct clinical management. PMID- 28902846 TI - Downregulation of microRNA-145 may contribute to liver fibrosis in biliary atresia by targeting ADD3. AB - BACKGROUND AND OBJECTIVES: Biliary atresia (BA) is a pediatric liver disease characterized by fibro-obliteration and obstruction of the extrahepatic biliary system, that invariably leads to cirrhosis and even death, if left untreated for extended time. However, its pathology and etiology still remained unknown. In this study, we tested the expression of adducin 3 (ADD3), the gene identified as a susceptibility gene in BA by GWAS, and uncovered its upstream regulatory microRNA in the pathogenesis of BA. METHODS: In this study, 14 infants with BA and 14 infants with choledochal cyst (CC) were enrolled as experimental group and control group, respectively. ADD3 and microRNA-145 (miR-145) expression profiles in liver tissues of BA and CC were determined using qPCR. Luciferase reporter assay was performed to verify the direct interaction between miR-145-5p and ADD3 3' Untranslated Regions (3'UTR). The Lentiviral vectors containing miR-145, miR 145-3p inhibitor, miR-145-5p inhibitor, empty vector were transfected into human hepatic stellate cell line (LX-2) to determine the functional effect of miR-145 on ADD3 expression at both mRNA and protein level. RESULTS: MiR-145 was shown to be down-regulated in liver tissues of infants with BA compared to CC (p = 0.0267). ADD3, verified as a target of miR-145-5p, was shown to be overexpressed in infants with BA at the mRNA level (p = 0.0118). Transfection of lentiviruses containing miR-145 into LX-2 cells decreased the expression of ADD3 at both mRNA and protein level compared to negative control group, and suppressed the expression of p-Akt at protein level. CONCLUSIONS: Our study has shown that overexpressed ADD3 and downregulated miR-145 were detected in BA liver tissues. MiR-145-5p was confirmed to target ADD3 by luciferase reporter assay. The downregulation of miR-145 may contribute to liver fibrosis in BA by upregulating the expression of ADD3. PMID- 28902847 TI - First insights in the variability of Borrelia recurrentis genomes. AB - BACKGROUND: Borrelia recurrentis is the causative agent of louse-borne relapsing fever, endemic to the Horn of Africa. New attention was raised in Europe, with the highest number of cases (n = 45) reported among migrants in 2015 in Germany and sporadically from other European countries. So far only one genome was sequenced, hindering the development of specific molecular diagnostic and typing tools. Here we report on modified culture conditions for B. recurrentis and the intraspecies genome variability of six isolates isolated and cultured in different years in order to explore the possibility to identify new targets for typing and examine the molecular epidemiology of the pathogen. METHODOLOGY/PRINCIPAL FINDINGS: Two historical isolates from Ethiopia and four isolates from migrants from Somalia (n = 3) and Ethiopia (n = 1) obtained in 2015 were cultured in MPK-medium supplemented with 50% foetal calf serum. Whole DNA was sequenced using Illumina MiSeq technology and analysed using the CLC Genomics Workbench and SPAdes de novo assembler. Compared to the reference B. recurrentis A1 29-38 SNPs were identified in the genome distributed on the chromosome and plasmids. In addition to that, plasmids of differing length, compared to the available reference genome were identified. CONCLUSIONS/SIGNIFICANCE: The observed low genetic variability of B. recurrentis isolates is possibly due to the adaptation to a very conserved vector-host (louse-human) cycle, or influenced by the fastidious nature of the pathogen and their resistance to in vitro growth. Nevertheless, isolates obtained in 2015 were bearing the same chromosomal SNPs and could be distinguished from the historical isolates by means of whole genome sequencing, but not hitherto used typing methods. This is the first study examining the molecular epidemiology of B. recurrentis and provides the necessary background for the development of better diagnostic tools. PMID- 28902849 TI - To what degree does the missing-data technique influence the estimated growth in learning strategies over time? A tutorial example of sensitivity analysis for longitudinal data. AB - Longitudinal data is almost always burdened with missing data. However, in educational and psychological research, there is a large discrepancy between methodological suggestions and research practice. The former suggests applying sensitivity analysis in order to the robustness of the results in terms of varying assumptions regarding the mechanism generating the missing data. However, in research practice, participants with missing data are usually discarded by relying on listwise deletion. To help bridge the gap between methodological recommendations and applied research in the educational and psychological domain, this study provides a tutorial example of sensitivity analysis for latent growth analysis. The example data concern students' changes in learning strategies during higher education. One cohort of students in a Belgian university college was asked to complete the Inventory of Learning Styles-Short Version, in three measurement waves. A substantial number of students did not participate on each occasion. Change over time in student learning strategies was assessed using eight missing data techniques, which assume different mechanisms for missingness. The results indicated that, for some learning strategy subscales, growth estimates differed between the models. Guidelines in terms of reporting the results from sensitivity analysis are synthesised and applied to the results from the tutorial example. PMID- 28902848 TI - The effect of HIV infection and HCV viremia on inflammatory mediators and hepatic injury-The Women's Interagency HIV Study. AB - Hepatitis C virus infection induces inflammation and while it is believed that HIV co-infection enhances this response, HIV control may reduce inflammation and liver fibrosis in resolved or viremic HCV infection. Measurement of systemic biomarkers in co-infection could help define the mechanism of inflammation on fibrosis and determine if HIV control reduces liver pathology. A nested case control study was performed to explore the relationship of systemic biomarkers of inflammation with liver fibrosis in HCV viremic and/or seropositive women with and without HIV infection. Serum cytokines, chemokines, growth factors and cell adhesion molecules were measured in HIV uninfected (HIV-, n = 18), ART-treated HIV-controlled (ARTc, n = 20), uncontrolled on anti-retroviral therapy (ARTuc, n = 21) and elite HIV controllers (Elite, n = 20). All were HCV seroreactive and had either resolved (HCV RNA-; <50IU/mL) or had chronic HCV infection (HCV RNA+). In HCV and HIV groups, aspartate aminotransferase to platelet ratio (APRI) was measured and compared to serum cytokines, chemokines, growth factors and cell adhesion molecules. APRI correlated with sVCAM, sICAM, IL-10, and IP-10 levels and inversely correlated with EGF, IL-17, TGF-alpha and MMP-9 levels. Collectively, all HCV RNA+ subjects had higher sVCAM, sICAM and IP-10 compared to HCV RNA-. In the ART-treated HCV RNA+ groups, TNF-alpha, GRO, IP-10, MCP-1 and MDC were higher than HIV-, Elite or both. In ARTuc, FGF-2, MPO, soluble E selectin, MMP-9, IL-17, GM-CSF and TGF-alpha are lower than HIV-, Elite or both. Differential expression of soluble markers may reveal mechanisms of pathogenesis or possibly reduction of fibrosis in HCV/HIV co-infection. PMID- 28902850 TI - Copy number variation analysis in cytochromes and glutathione S-transferases may predict efficacy of tyrosine kinase inhibitors in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations. CNV detection was performed using SALSA MLPA P128-C1 Cytochrome P450 probe mix. Patients with optimal response and with failure of TKI therapy showed different frequencies of wild type and mutated CYPs and GST (p<0.0013). Validation in the group of 15 patients proved high prognostic value (p = 0.02): positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Wild type genotypes of CYP and GST associate with a worse response to TKI treatment in CML patients. This test can be recommended for further clinical trials. PMID- 28902851 TI - Redox-mediated quorum sensing in plants. AB - The rhizosphere, the narrow zone of soil around plant roots, is a complex network of interactions between plants, bacteria, and a variety of other organisms. The absolute dependence on host-derived signals, or xenognosins, to regulate critical developmental checkpoints for host commitment in the obligate parasitic plants provides a window into the rhizosphere's chemical dynamics. These sessile intruders use H2O2 in a process known as semagenesis to chemically modify the mature root surfaces of proximal host plants and generate p-benzoquinones (BQs). The resulting redox-active signaling network regulates the spatial and temporal commitments necessary for host attachment. Recent evidence from non-parasites, including Arabidopsis thaliana, establishes that reactive oxygen species (ROS) production regulates similar redox circuits related to root recognition, broadening xenognosins' role beyond the parasites. Here we compare responses to the xenognosin dimethoxybenzoquinone (DMBQ) between the parasitic plant Striga asiatica and the non-parasitic A. thaliana. Exposure to DMBQ simulates the proximity of a mature root surface, stimulating an increase in cytoplasmic Ca2+ concentration in both plants, but leads to remarkably different phenotypic responses in the parasite and non-parasite. In S. asiatica, DMBQ induces development of the host attachment organ, the haustorium, and decreases ROS production at the root tip, while in A. thaliana, ROS production increases and further growth of the root tip is arrested. Obstruction of Ca2+ channels and the addition of antioxidants both lead to a decrease in the DMBQ response in both parasitic and non-parasitic plants. These results are consistent with Ca2+ regulating the activity of NADPH oxidases, which in turn sustain the autocatalytic production of ROS via an external quinone/hydroquinone redox cycle. Mechanistically, this chemistry is similar to black and white photography with the emerging dynamic reaction-diffusion network laying the foundation for the precise temporal and spatial control underlying rhizosphere architecture. PMID- 28902852 TI - Genome-wide chromatin mapping with size resolution reveals a dynamic sub nucleosomal landscape in Arabidopsis. AB - All eukaryotic genomes are packaged as chromatin, with DNA interlaced with both regularly patterned nucleosomes and sub-nucleosomal-sized protein structures such as mobile and labile transcription factors (TF) and initiation complexes, together forming a dynamic chromatin landscape. Whilst details of nucleosome position in Arabidopsis have been previously analysed, there is less understanding of their relationship to more dynamic sub-nucleosomal particles (subNSPs) defined as protected regions shorter than the ~150bp typical of nucleosomes. The genome-wide profile of these subNSPs has not been previously analysed in plants and this study investigates the relationship of dynamic bound particles with transcriptional control. Here we combine differential micrococcal nuclease (MNase) digestion and a modified paired-end sequencing protocol to reveal the chromatin structure landscape of Arabidopsis cells across a wide particle size range. Linking this data to RNAseq expression analysis provides detailed insight into the relationship of identified DNA-bound particles with transcriptional activity. The use of differential digestion reveals sensitive positions, including a labile -1 nucleosome positioned upstream of the transcription start site (TSS) of active genes. We investigated the response of the chromatin landscape to changes in environmental conditions using light and dark growth, given the large transcriptional changes resulting from this simple alteration. The resulting shifts in the suites of expressed and repressed genes show little correspondence to changes in nucleosome positioning, but led to significant alterations in the profile of subNSPs upstream of TSS both globally and locally. We examined previously mapped positions for the TFs PIF3, PIF4 and CCA1, which regulate light responses, and found that changes in subNSPs co localized with these binding sites. This small particle structure is detected only under low levels of MNase digestion and is lost on more complete digestion of chromatin to nucleosomes. We conclude that wide-spectrum analysis of the Arabidopsis genome by differential MNase digestion allows detection of sensitive features hereto obscured, and the comparisons between genome-wide subNSP profiles reveals dynamic changes in their distribution, particularly at distinct genomic locations (i.e. 5'UTRs). The method here employed allows insight into the complex influence of genetic and extrinsic factors in modifying the sub-nucleosomal landscape in association with transcriptional changes. PMID- 28902853 TI - The human bitter taste receptor T2R38 is broadly tuned for bacterial compounds. AB - T2R38 has been shown to be a specific bacterial detector implicated in innate immune defense mechanism of human upper airway. Several clinical studies have demonstrated that this receptor is associated with the development of chronic rhinosinusitis (CRS). T2R38 was previously reported to bind to homoserine lactones (HSL), quorum sensing molecules specific of Pseudomonas Aeruginosa and other gram negative species. Nevertheless, these bacteria are not the major pathogens found in CRS. Here we report on the identification of bacterial metabolites acting as new agonists of T2R38 based on a single cell calcium imaging study. Two quorum sensing molecules (Agr D1 thiolactone from Staphylococcus Aureus and CSP-1 from Streptococcus Pneumoniae) and a list of 32 bacterial metabolites from pathogens frequently implicated in CRS were tested. First, we observed that HSL failed to activate T2R38 in our experimental system, but that the dimethylsulfoxide (DMSO), used as a solvent for these lactones may, by itself, account for the agonistic effect previously described. Secondly, we showed that both Agr D1 thiolactone and CSP-1 are inactive but that at least 7 bacterial metabolites (acetone, 2-butanone, 2-pentanone, 2-methylpropanal, dimethyl disulfide, methylmercaptan, gamma-butyrolactone) are able to specifically trigger this receptor. T2R38 is thus much more broadly tuned for bacterial compounds than previously thought. PMID- 28902854 TI - An experimental study of the Online Information Paradox: Does en-route information improve road network performance? AB - This study investigates the empirical presence of a theoretical transportation paradox, defined as the "Online Information Paradox" (OIP). The paradox suggests that, for certain road networks, the provision of online information deteriorate travel conditions for all users of that network relative to the situation where no online information is provided to users. The analytical presence of the paradox was derived for a specific network structure by using two equilibrium models, the first being the Expected User Equilibrium (EUE) solution (no information scenario) and the other being the User Equilibrium with Recourse (UER) solution (with information scenario). An incentivised computerised route choice game was designed using the concepts of experimental economics and administered in a controlled laboratory environment to investigate the physical presence of the paradox. Aggregate statistics of path flows and Total System Travel Costs (TSTC) were used to compare the experimental results with the theoretical findings. A total of 12 groups of 12 participants completed the experiment and the OIP and the occurrence of the OIP being significant was observed in 11 of the 12 cases. Though information increased travel costs for users on average, it reduced the volatility of travel costs experienced in the no information scenario indicating that information can achieve a more reliable system. Further replications of similar experiments and more importantly field based identification of the phenomena will force transport professionals to be aware of the emergence of the paradox. In addition, studies such as this emphasise the need for the adoption of adaptive traffic assignment techniques to appropriately model the acquisition of information on a road network. PMID- 28902855 TI - Improving heterologous membrane protein production in Escherichia coli by combining transcriptional tuning and codon usage algorithms. AB - High-level, recombinant production of membrane-integrated proteins in Escherichia coli is extremely relevant for many purposes, but has also been proven challenging. Here we study a combination of transcriptional fine-tuning in E. coli LEMO21(DE3) with different codon usage algorithms for heterologous production of membrane proteins. The overexpression of 6 different membrane proteins is compared for the wild-type gene codon usage variant, a commercially codon-optimized variant, and a codon-harmonized variant. We show that transcriptional fine-tuning plays a major role in improving the production of all tested proteins. Moreover, different codon usage variants significantly improved production of some of the tested proteins. However, not a single algorithm performed consistently best for the membrane-integrated production of the 6 tested proteins. In conclusion, for improving heterologous membrane protein production in E. coli, the major effect is accomplished by transcriptional tuning. In addition, further improvements may be realized by attempting different codon usage variants, such as codon harmonized variants, which can now be easily generated through our online Codon Harmonizer tool. PMID- 28902856 TI - Effect of vital dyes on human corneal endothelium and elasticity of Descemet's membrane. AB - The purpose of this study was to evaluate the effects of vital dyes on human Descemet's membranes (DMs) and endothelia. DMs of 25 human cadaveric corneas with research consent were treated with dyes routinely used in Descemet membrane endothelial keratoplasty (DMEK), 0.05% Trypan blue (TB) or a combination of 0.15% Trypan blue, 0.025% Brilliant blue and 4% Polyethylene glycol (commercial name Membrane Blue Dual; MB). The effects of these two dyes on (i) endothelial cell viability, (ii) DM mechanical properties as assessed by atomic force microscopy, and iii) qualitative DM dye retention were tested for two varying exposure times (one or four minutes). No significant differences in cell toxicity were observed between treatments with TB and MB at the two different exposure times (P = 0.21). Further, both dyes led to a significant increase in DM stiffness: exposure to TB and MB for one minute increased the apparent elastic modulus of the DM by 11.2% (P = 8*10-3) and 17.7%, respectively (P = 4*10-6). A four-minute exposure led to an increase of 8.6% for TB (P = 0.004) and 13.6% for MB (P = 0.03). Finally, at 25 minutes, the dye retention of the DM was considerably better for MB compared to TB. Taken together, a one-minute exposure to MB was found to improve DM visibility compared to TB, with a significant increase in DM stiffness and without detrimental effects on endothelial cell viability. The use of MB could therefore improve (i) visibility of the DM scroll, and (ii) intraoperative unfolding, enhancing the probability of successful DMEK surgery. PMID- 28902858 TI - Modeling the spatial distribution of African buffalo (Syncerus caffer) in the Kruger National Park, South Africa. AB - The population density of wildlife reservoirs contributes to disease transmission risk for domestic animals. The objective of this study was to model the African buffalo distribution of the Kruger National Park. A secondary objective was to collect field data to evaluate models and determine environmental predictors of buffalo detection. Spatial distribution models were created using buffalo census information and archived data from previous research. Field data were collected during the dry (August 2012) and wet (January 2013) seasons using a random walk design. The fit of the prediction models were assessed descriptively and formally by calculating the root mean square error (rMSE) of deviations from field observations. Logistic regression was used to estimate the effects of environmental variables on the detection of buffalo herds and linear regression was used to identify predictors of larger herd sizes. A zero-inflated Poisson model produced distributions that were most consistent with expected buffalo behavior. Field data confirmed that environmental factors including season (P = 0.008), vegetation type (P = 0.002), and vegetation density (P = 0.010) were significant predictors of buffalo detection. Bachelor herds were more likely to be detected in dense vegetation (P = 0.005) and during the wet season (P = 0.022) compared to the larger mixed-sex herds. Static distribution models for African buffalo can produce biologically reasonable results but environmental factors have significant effects and therefore could be used to improve model performance. Accurate distribution models are critical for the evaluation of disease risk and to model disease transmission. PMID- 28902857 TI - Willingness to use pre-exposure prophylaxis for HIV prevention among men who have sex with men in Malaysia: Findings from an online survey. AB - OBJECTIVE: We examined willingness to use pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men (MSM) in Malaysia. METHODS: An online survey of 990 MSM was conducted between March and April 2016. Eligibility criteria included being biological male, Malaysian citizen, 18 years of age or above, identifying as MSM, and being HIV negative or unknown status. Participants' demographics, sexual and drug use behaviors, attitudes towards PrEP, and preferences regarding future access to PrEP were collected. Bivariate analysis and logistic regression were performed to determine factors associated with willingness to use PrEP. RESULTS: Fewer than half of participants (44%) knew about PrEP before completing the survey. Overall, 39% of the sample were willing to take PrEP. Multivariate logistic regression indicated that Malay men (AOR: 1.73, 95% CI:1.12, 2.70), having 2 or more male anal sex partners in the past 6 months (AOR: 1.98, 95% CI: 1.29, 3.05), previous knowledge of PrEP (AOR: 1.40, 95%CI: 1.06, 1.86), lack of confidence in practising safer sex (AOR: 1.36, 95% CI: 1.02, 1.81), and having ever paid for sex with a male partner (AOR: 1.39, 95% CI: 1.01, 1.91) were independently associated with greater willingness to use PrEP, while men who identified as heterosexual were less willing to use PrEP (AOR, 0.36, 95% CI: 0.13, 0.97). Majority of participants preferred to access PrEP at affordable cost below 100 Malaysian Ringgit (USD25) per month from community based organisations followed by private or government hospitals. CONCLUSIONS: Overall, MSM in Malaysia reported a relatively low level of willingness to use PrEP, although willingness was higher among those previously aware of PrEP. There is a need to provide PrEP at affordable cost, increase demand and awareness of PrEP, and to provide access to this preventative medication via diverse, integrated and tailored sexual health services. PMID- 28902859 TI - Effects of roasting on kernel peroxide value, free fatty acid, fatty acid composition and crude protein content. AB - Roasting nuts may alter their chemical composition leading to changes in their health benefits. However, the presence of testa may alleviate the negative effects of thermal treatments. Hence, this study aimed to explore the effects of roasting on kernel chemical quality and colour development of Canarium indicum and examine to what extent testa would protect kernels against damage from roasting. Roasting decreased peroxide value but increased free fatty acid, probably due to increased cell destruction and lack of enzyme inactivation, respectively. Protein content of kernels significantly decreased after roasting compared to raw kernels. However, testa-on kernels contained significantly higher protein content compared to testa-off kernels. Whilst colour development and mottling were observed in temperatures beyond 120 degrees C, roasting did not alter fatty acid compositions of kernels. The mild roasting and presence of testa in kernels can be used to enhance health benefits of kernels. PMID- 28902860 TI - Alien species pathways to the Galapagos Islands, Ecuador. AB - Alien species, one of the biggest threats to natural ecosystems worldwide, are of particular concern for oceanic archipelagos such as Galapagos. To enable more effective management of alien species, we reviewed, collated and analysed all available records of alien species for Galapagos. We also assembled a comprehensive dataset on pathways to and among the Galapagos Islands, including tourist and resident numbers, tourist vessels, their itineraries and visitation sites, aircraft capacity and occupancy, air and sea cargo and biosecurity interceptions. So far, 1,579 alien terrestrial and marine species have been introduced to Galapagos by humans. Of these, 1,476 have become established. Almost half of these were intentional introductions, mostly of plants. Most unintentional introductions arrived on plants and plant associated material, followed by transport vehicles, and commodities (in particular fruit and vegetables). The number, frequency and geographic origin of pathways for the arrival and dispersal of alien species to and within Galapagos have increased over time, tracking closely the increase in human population (residents and tourists) on the islands. Intentional introductions of alien species should decline as biosecurity is strengthened but there is a danger that unintentional introductions will increase further as tourism on Galapagos expands. This unique world heritage site will only retain its biodiversity values if the pathways for invasion are managed effectively. PMID- 28902861 TI - Epigenetic regulation of metalloproteinases and their inhibitors in rotator cuff tears. AB - Rotator cuff tear is a common orthopedic condition. Metalloproteinases (MMP) and their inhibitors (TIMP) seem to play a role in the development of joint injuries and in the failure of tissue healing. However, the mechanisms of regulation of gene expression in tendons are still unknown. Epigenetic mechanisms, such as DNA methylation and microRNAs regulation, are involved in the dynamic control of gene expression. Here, the mRNA expression and DNA methylation status of MMPs (MMP1, MMP2, MMP3, MMP9, MMP13, and MMP14) and TIMPs (TIMP1-3) and the expression of miR 29 family members in ruptured supraspinatus tendons were compared with non injured tendons of individuals without this lesion. Additionally, the gene expression and methylation status at the edge of the ruptured tendon were compared with macroscopically non-injured rotator cuff tendon samples from the anterior and posterior regions of patients with tendon tears. Moreover, the possible associations between the molecular alterations and the clinical and histologic characteristics were investigated. Dysregulated expression and DNA methylation of MMP and TIMP genes were found across the rotator cuff tendon samples of patients with supraspinatus tears. These alterations were influenced at least in part by age at surgery, sex, smoking habit, tear size, and duration of symptoms. Alterations in the studied MMP and TIMP genes may contribute to the presence of microcysts, fissures, necrosis, and neovascularization in tendons and may thus be involved in the tendon healing process. In conclusion, MMPs and their inhibitors are regulated by epigenetic modifications and may play a role in rotator cuff tears. PMID- 28902862 TI - Distinct genetic clades of enterovirus D68 detected in 2010, 2013, and 2015 in Osaka City, Japan. AB - The first upsurge of enterovirus D68 (EV-D68), a causative agent of acute respiratory infections (ARIs), in Japan was reported in Osaka City in 2010. In this study, which began in 2010, we surveyed EV-D68 in children with ARIs and analyzed sequences of EV-D68 strains detected. Real-time PCR of 19 respiratory viruses or subtypes of viruses, including enterovirus, was performed on 2,215 specimens from ARI patients (<10 years of age) collected between November 2010 and December 2015 in Osaka City, Japan. EV-D68 was identified in 18 enterovirus positive specimens (n = 4 in 2013, n = 1 in 2014, and n = 13 in 2015) by analysis of viral protein 1 (VP1) or VP4 sequences, followed by a BLAST search for similar sequences. All EV-D68 strains were detected between June and October (summer to autumn), except for one strain detected in 2014. A phylogenetic analysis of available VP1 sequences revealed that the Osaka strains detected in 2010, 2013, and 2015 belonged to distinct clusters (Clades C, A, and B [Subclade B3], respectively). Comparison of the 5' untranslated regions of these viruses showed that Osaka strains in Clades A, B (Subclade B3), and C commonly had deletions at nucleotide positions 681-703 corresponding to the prototype Fermon strain. Clades B and C had deletions from nucleotide positions 713-724. Since the EV-D68 epidemic in 2010, EV-D68 re-emerged in Osaka City, Japan, in 2013 and 2015. Results of this study indicate that distinct clades of EV-D68 contributed to re emergences of this virus in 2010, 2013, and 2015 in this limited region. PMID- 28902863 TI - Identification of vaccine-derived rotavirus strains in children with acute gastroenteritis in Japan, 2012-2015. AB - Two live attenuated oral rotavirus vaccines, Rotarix and RotaTeq, have been introduced as voluntary vaccination in Japan since 2011 and 2012, respectively. Effectiveness of the vaccines has been confirmed, whereas concerns such as shedding of the vaccine strains and gastroenteritis cases caused by vaccine strains are not well assessed. We aimed to identify the vaccine strains in children with acute gastroenteritis (AGE) to investigate the prevalence of AGE caused by vaccination or horizontal transmission of vaccine strains. A total of 1,824 stool samples were collected from children with AGE at six outpatient clinics in 2012-2015. Among all, 372 group A rotavirus (RVA) positive samples were screened for vaccine components by real-time RT-PCR which were designed to differentiate vaccine strains from rotavirus wild-type strains with high specificity. For samples possessing both vaccine and wild-type strains, analyses by next-generation sequencing (NGS) were conducted to characterize viruses existed in the intestine. As a result, Rotarix-derived strains were identified in 6 of 372 (1.6%) RVA positive samples whereas no RotaTeq strain was detected. Among six samples, four possessed Rotarix-derived strains while two possessed both Rotarix-derived strains and wild-type strains. In addition, other pathogens such as norovirus, enterovirus and E.coli were detected in four samples. The contribution of these vaccine strains to each patient's symptoms was unclear as all of the cases were vaccinated 2-14 days before sample collection. Proportion of average coverage for each segmented gene by NGS strongly suggested the concurrent infection of the vaccine-derived strain and the wild-type strain rather than reassortment of these two strains in one sample. This is the first study to report the prevalence of vaccine-derived strains in patients with RVA AGE in Japan as 1.6% without evidence of horizontal transmission. The results emphasized the importance of continuous monitoring on vaccine strains and their clinical impacts on children. PMID- 28902864 TI - Comparative skull anatomy of terrestrial and crevice-dwelling Trachylepis skinks (Squamata: Scincidae) with a survey of resources in scincid cranial osteology. AB - Skinks account for more than 25% of all lizard species; however, representatives of fewer than a quarter of all species have been characterized osteologically. All but a few of the available cranial descriptions concentrate solely on characters that can be seen externally on the intact skull. Mabuyid skinks of the genus Trachylepis are the dominant, fully limbed skinks in Sub-Saharan Africa, and nearly all species have the same generalized body plan. Although a few rock crevice-dwelling species possess slight body depression, extreme dorsoventral depression is observed only in Trachylepis laevis. We investigated the detailed skull anatomy of three Trachylepis skinks (T. laevis, T. sulcata, and T. gonwouoi, a recently described species allied to T. affinis) using high resolution X-ray micro-computed tomography. Our goals were to review the scincid cranial osteology literature in a phylogenetic context, provide a detailed anatomical atlas for the mabuyid lineage, and investigate the morphological adaptations of the highly modified T. laevis. Our results demonstrate that there is significant morphological variation between these three taxa, including the loss and fusion of structures, as well as changes in the shape, scale, and relationship between individual elements. Trachylepis laevis possesses several osteological modifications that have produced a reducton in head depth that are likely functional consequences of extreme rupicolous habits, including a flat skull roof, many strongly recumbent elements, and a depressed neurocranium.We hypothesize these modifications may correspond to descreased bite force and increased capabilities of cranial kinesis. Our study is the first element-by element description of a skink using computed tomography technology. PMID- 28902865 TI - Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol. AB - Human PrimPol is a DNA primase/polymerase involved in DNA damage tolerance and prevents nuclear genome instability. PrimPol is also localized to the mitochondria, but its precise function in mitochondrial DNA maintenance has remained elusive. PrimPol works both as a translesion (TLS) polymerase and as the primase that restarts DNA replication after a lesion. However, the observed biochemical activities of PrimPol vary considerably between studies as a result of different reaction conditions used. To reveal the effects of reaction composition on PrimPol DNA polymerase activity, we tested the polymerase activity in the presence of various buffer agents, salt concentrations, pH values and metal cofactors. Additionally, the enzyme stability was analyzed under various conditions. We demonstrate that the reaction buffer with pH 6-6.5, low salt concentrations and 3 mM Mg2+ or 0.3-3 mM Mn2+ cofactor ions supports the highest DNA polymerase activity of human PrimPol in vitro. The DNA polymerase activity of PrimPol was found to be stable after multiple freeze-thaw cycles and prolonged protein incubation on ice. However, rapid heat-inactivation of the enzyme was observed at 37oC. We also for the first time describe the purification of human PrimPol from a human cell line and compare the benefits of this approach to the expression in Escherichia coli and in Saccharomyces cerevisiae cells. Our results show that active PrimPol can be purified from E. coli and human suspension cell line in high quantities and that the activity of the purified enzyme is similar in both expression systems. Conversely, the yield of full-length protein expressed in S. cerevisiae was considerably lower and this system is therefore not recommended for expression of full-length recombinant human PrimPol. PMID- 28902866 TI - 5-year long-term efficacy of 120-W GreenLight photoselective vaporization of the prostate for benign prostate hyperplasia. AB - PURPOSE: To investigate 5-year long-term postoperative efficacy in benign prostate hyperplasia (BPH) following 120-W GreenLight high-performance system photoselective vaporization of the prostate (HPS-PVP). METHODS: This was a retrospective study of surgical outcomes in 159 men who underwent HPS-PVP and were followed over 60 months postoperatively. Definitions of treatment success were established based on the following three variables: international prostate symptom scores (IPSS), maximum flow rates (Qmax), and quality of life scores QoL). Logistic regression analyses were performed to determine predictors of the postoperative success. RESULTS: Postoperative IPSS/QoL, Qmax and post-voided residual urine volume were significantly improved after HPS-PVP. Postoperative Prostate specific antigen and prostate volume were also well reduced and sustained for 5 years. The postoperative success rate was assessed as 82.1%, 80.8% and 76.1% for each 1-, 3-, and 5-year. Thirty-eight (23.9%) patients had immediate postoperative complications, which were managed successfully with nonsurgical methods. None required transfusions, two (1.2%) patients required endoscopic reoperation for postoperative voiding difficulty due to bladder neck contracture or urethral stricture, and five (3.1%) required HPS-PVP reoperation. Presence of diabetes, voiding symptom subscore, QoL, maximal cystometric capacity, and bladder outlet obstructive index were valuable preoperative parameters for predicting postoperative success. CONCLUSIONS: HPS-PVP is an effective, long-term treatment option for BPH, with sustained efficacy of 76.1% at 5-year follow up. Several preoperative parameters could help to predict the durable surgical improvements. PMID- 28902867 TI - Analysis of the relationship between coexpression domains and chromatin 3D organization. AB - Gene order is not random in eukaryotic chromosomes, and co-regulated genes tend to be clustered. The mechanisms that determine co-regulation of large regions of the genome and its connection with chromatin three-dimensional (3D) organization are still unclear however. Here we have adapted a recently described method for identifying chromatin topologically associating domains (TADs) to identify coexpression domains (which we term "CODs"). Using human normal breast and breast cancer RNA-seq data, we have identified approximately 500 CODs. CODs in the normal and breast cancer genomes share similar characteristics but differ in their gene composition. COD genes have a greater tendency to be coexpressed with genes that reside in other CODs than with non-COD genes. Such inter-COD coexpression is maintained over large chromosomal distances in the normal genome but is partially lost in the cancer genome. Analyzing the relationship between CODs and chromatin 3D organization using Hi-C contact data, we find that CODs do not correspond to TADs. In fact, intra-TAD gene coexpression is the same as random for most chromosomes. However, the contact profile is similar between gene pairs that reside either in the same COD or in coexpressed CODs. These data indicate that co-regulated genes in the genome present similar patterns of contacts irrespective of the frequency of physical chromatin contacts between them. PMID- 28902868 TI - Discovery of numerous novel small genes in the intergenic regions of the Escherichia coli O157:H7 Sakai genome. AB - In the past, short protein-coding genes were often disregarded by genome annotation pipelines. Transcriptome sequencing (RNAseq) signals outside of annotated genes have usually been interpreted to indicate either ncRNA or pervasive transcription. Therefore, in addition to the transcriptome, the translatome (RIBOseq) of the enteric pathogen Escherichia coli O157:H7 strain Sakai was determined at two optimal growth conditions and a severe stress condition combining low temperature and high osmotic pressure. All intergenic open reading frames potentially encoding a protein of >= 30 amino acids were investigated with regard to coverage by transcription and translation signals and their translatability expressed by the ribosomal coverage value. This led to discovery of 465 unique, putative novel genes not yet annotated in this E. coli strain, which are evenly distributed over both DNA strands of the genome. For 255 of the novel genes, annotated homologs in other bacteria were found, and a machine-learning algorithm, trained on small protein-coding E. coli genes, predicted that 89% of these translated open reading frames represent bona fide genes. The remaining 210 putative novel genes without annotated homologs were compared to the 255 novel genes with homologs and to 250 short annotated genes of this E. coli strain. All three groups turned out to be similar with respect to their translatability distribution, fractions of differentially regulated genes, secondary structure composition, and the distribution of evolutionary constraint, suggesting that both novel groups represent legitimate genes. However, the machine-learning algorithm only recognized a small fraction of the 210 genes without annotated homologs. It is possible that these genes represent a novel group of genes, which have unusual features dissimilar to the genes of the machine-learning algorithm training set. PMID- 28902869 TI - High mortality rates in men initiated on anti-retroviral treatment in KwaZulu Natal, South Africa. AB - In attaining UNAIDS targets of 90-90-90 to achieve epidemic control, understanding who the current utilizers of HIV treatment services are will inform efforts aimed at reaching those not being reached. A retrospective chart review of CAPRISA AIDS Treatment Program (CAT) patients between 2004 and 2013 was undertaken. Of the 4043 HIV-infected patients initiated on ART, 2586 (64.0%) were women. At ART initiation, men, compared to women, had significantly lower median CD4+ cell counts (113 vs 131 cells/mm3, p <0.001), lower median body mass index (BMI) (21.0 vs 24.2 kg/m2, p<0.001), higher mean log viral load (5.0 vs 4.9 copies/ml, p<0.001) and were significantly older (median age: 35 vs. 32 years, p<0.001). Men had higher mortality rates compared to women, 6.7 per 100 person years (p-y), (95% CI: 5.8-7.8) vs. 4.4 per 100 p-y, (95% CI: 3.8-5.0); mortality rate ratio: 1.54, (95% CI: 1.27-1.87), p <0.001. Age-standardised mortality rate was 7.9 per 100 p-y (95% CI: 4.1-11.7) for men and 5.7 per 100 p-y (95% CI: 2.7 to 8.6) for women (standardised mortality ratio: 1.38 (1.15 to 1.70)). Mean CD4+ cell count increases post-ART initiation were lower in men at all follow-up time points. Men presented later in the course of their HIV disease for ART initiation with more advanced disease and experienced a higher mortality rate compared to women. PMID- 28902870 TI - Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies. AB - Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the "insulin paradox"). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders. PMID- 28902872 TI - Anodal transcranial direct current stimulation of the right anterior temporal lobe did not significantly affect verbal insight. AB - Humans often utilize past experience to solve difficult problems. However, if past experience is insufficient to solve a problem, solvers may reach an impasse. Insight can be valuable for breaking an impasse, enabling the reinterpretation or re-representation of a problem. Previous studies using between-subjects designs have revealed a causal relationship between the anterior temporal lobes (ATLs) and non-verbal insight, by enhancing the right ATL while inhibiting the left ATL using transcranial direct current stimulation (tDCS). In addition, neuroimaging studies have reported a correlation between right ATL activity and verbal insight. Based on these findings, we hypothesized that the right ATL is causally related to both non-verbal and verbal insight. To test this hypothesis, we conducted an experiment with 66 subjects using a within-subjects design, which typically has greater statistical power than a between-subjects design. Subjects participated in tDCS experiments across 2 days, in which they solved both non verbal and verbal insight problems under active or sham stimulation conditions. To dissociate the effects of right ATL stimulation from those of left ATL stimulation, we used two montage types; anodal tDCS of the right ATL together with cathodal tDCS of the left ATL (stimulating both ATLs) and anodal tDCS of the right ATL with cathodal tDCS of the left cheek (stimulating only the right ATL). The montage used was counterbalanced across subjects. Statistical analyses revealed that, regardless of the montage type, there were no significant differences between the active and sham conditions for either verbal or non verbal insight, although the finding for non-verbal insight was inconclusive because of a lack of statistical power. These results failed to support previous findings suggesting that the right ATL is the central locus of insight. PMID- 28902871 TI - PreImplantation Factor in endometriosis: A potential role in inducing immune privilege for ectopic endometrium. AB - Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial epithelial and stromal cells outside the uterine cavity. In addition to Sampson's theory of retrograde menstruation, endometriosis pathogenesis is facilitated by a privileged inflammatory microenvironment, with T regulatory FoxP3+ expressing T cells (Tregs) being a significant factor. PreImplantation Factor (PIF) is a peptide essential for pregnancy recognition and development. An immune modulatory function of the synthetic PIF analog (sPIF) has been successfully confirmed in multiple animal models. We report that PIF is expressed in the epithelial ectopic cells in close proximity to FoxP3+ stromal cells. We provide evidence that PIF interacts with FoxP3+ cells and modulates cell viability, dependent on cell source and presence of inflammatory mediators. Our finding represent a novel PIF-based mechanism in endometriosis that has potential for novel therapeutics. PMID- 28902873 TI - Sarcopenia in patients with hip fracture: A multicenter cross-sectional study. AB - BACKGROUND: Sarcopenia is prevalent in older persons and is a risk factor for falls, fractures, and mortality. The aim of this study was to determine a) the feasibility of determining sarcopenia in patients with acute hip fracture, b) the prevalence of sarcopenia and c) associations of sarcopenia with nutritional status and comorbidities. METHODS: A multicenter cross-sectional study on sarcopenia in male and female patients with acute hip fracture. Participants were previously ambulatory and living in the community. Sarcopenia was assessed postoperatively with muscle mass estimated by anthropometry using triceps skinfold, arm circumference, height, weight and sex. Grip strength was measured by Jamar dynamometer and pre-fracture mobility was by self-report using the New Mobility Score. RESULTS: Out of 282 patients, 202 were assessed for sarcopenia of whom 74 (37%) were diagnosed as sarcopenic. Sarcopenia was associated with age, odds ratio (OR) 1.4 per 5 years, 95% confidence interval (CI) [1.1, 1.8], ASA Physical Status Classification System score, OR 2.3 per point, 95% CI [1.3, 4.3] and number of medications at discharge, OR 1.2 per medication, 95% CI [1.0, 1.3] and inversely associated with BMI, OR 0.8, 95% CI [0.7, 0.9] and serum albumin, OR 0.9, 95% CI [0.8,1.0]. CONCLUSIONS: Thirty-seven percent of assessed subjects were diagnosed with sarcopenia. Our data demonstrates that the prevalence of sarcopenia is associated with older age, malnutrition and comorbidities. Determining sarcopenia at the bedside was feasible in postoperative hip fracture patients by using grip strength, estimation of muscle mass by anthropometry and self-reported mobility. PMID- 28902874 TI - Psychometric properties of the Brisbane Burn Scar Impact Profile in adults with burn scars. AB - OBJECTIVE: The aim of the study was to determine the longitudinal validity, reproducibility, responsiveness and interpretability of the adult version of the Brisbane Burn Scar Impact Profile, a patient-report measure of health-related quality of life. METHODS: A prospective longitudinal cohort study of patients with or at risk of burn scarring was conducted at three assessment points (at baseline around the time of wound healing, one to two weeks post-baseline and 1 month post-baseline). Participants attending a major metropolitan adult burn centre at baseline were recruited. Participants completed the Brisbane Burn Scar Impact Profile and the 36-item Short Form Health Survey and Patient Observer Scar Assessment Scale. Intraclass Correlation Coefficients (ICCs), smallest detectable change, percentage of those who improved, stayed the same or worsened and Area under the Receiver Operating Characteristic Curve (AUC) were used to test the aim. RESULTS: Data were included for 118 participants at baseline, 68 participants at one to two weeks and 57 participants at 1-month post-baseline. All groups of items had acceptable reproducibility, except for the overall impact of burn scars (ICC = 0.69), the impact of sensations which was not expected to be stable (ICC = 0.63), mobility and daily activities (ICC = 0.63, 0.67 respectively). The responsiveness of six out of seven groups of items able to be tested against external criterion was supported (AUC = 0.72-0.75). Hypothesised correlations of changes in the Brisbane Burn Scar Impact Profile items with changes in criterion measures generally supported longitudinal validity (e.g., nine out of thirteen hypotheses using the SF-36 as an external criterion were supported). Internal consistency estimates, item-total and inter-item correlations indicated there was likely redundancy of some groups of items, particularly in the relationships and social interaction, appearance and emotional reactions items (Chronbach's alpha range = 0.94-0.95). CONCLUSION: Support was found for the reproducibility, longitudinal validity, responsiveness and interpretability of most groups of Brisbane Burn Scar Impact Profile items and some individual items in the test population. Potential redundancy of items should be investigated further. PMID- 28902875 TI - Interferon-gamma treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjogren's Syndrome. AB - Inflammation and impaired secretion by lacrimal and salivary glands are hallmarks of the autoimmune disease, Sjogren's Syndrome. These changes in the lacrimal gland promote dryness and inflammation of the ocular surface, causing pain, irritation and corneal damage. The changes that initiate and sustain autoimmune inflammation in the lacrimal gland are not well-established. Here we demonstrate that interferon-gamma (IFN-gamma) is significantly elevated in lacrimal gland and tears of the male NOD mouse, a model of autoimmune dacryoadenitis which exhibits many ocular characteristics of Sjogren's Syndrome, by 12 weeks of age early in lacrimal gland inflammation. Working either with primary cultured lacrimal gland acinar cells from BALB/c mice and/or rabbits, in vitro IFN-gamma treatment for 48 hr decreased expression of Rab3D concurrent with increased expression of cathepsin S. Although total cellular cathepsin S activity was not commensurately increased, IFN-gamma treated lacrimal gland acinar cells showed a significant increase in carbachol-stimulated secretion of cathepsin S similar to the lacrimal gland in disease. In vitro IFN-gamma treatment did not increase the expression of most components of major histocompatibility complex (MHC) class II-mediated antigen presentation although antigen presentation was slightly but significantly stimulated in primary cultured lacrimal gland acinar cells. However, exposure of cultured human corneal epithelial cells to IFN-gamma more robustly increased expression and activity of cathepsin S in parallel with increased expression and function of MHC class II-mediated antigen presentation. We propose that early elevations in IFN-gamma contribute to specific features of ocular disease pathology in Sjogren's Syndrome. PMID- 28902876 TI - Postoperative lead migration in deep brain stimulation surgery: Incidence, risk factors, and clinical impact. AB - INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for multiple movement disorders and shows substantial promise for the treatment of some neuropsychiatric and other disorders of brain neurocircuitry. Optimal neuroanatomical lead position is a critical determinant of clinical outcomes in DBS surgery. Lead migration, defined as an unintended post-operative displacement of the DBS lead, has been previously reported. Despite several reports, however, there have been no systematic investigations of this issue. This study aimed to: 1) quantify the incidence of lead migration in a large series of DBS patients, 2) identify potential risk factors contributing to DBS lead migration, and 3) investigate the practical importance of this complication by correlating its occurrence with clinical outcomes. METHODS: A database of all DBS procedures performed at UF was queried for patients who had undergone multiple post operative DBS lead localization imaging studies separated by at least two months. Bilateral DBS implantation has commonly been performed as a staged procedure at UF, with an interval of six or more months between sides. To localize the position of each DBS lead, a head CT is acquired ~4 weeks after lead implantation and fused to the pre-operative targeting MRI. The fused targeting images (MR + stereotactic CT) acquired in preparation for the delayed second side lead implantation provide an opportunity to repeat the localization of the first implanted lead. This paradigm offers an ideal patient population for the study of delayed DBS lead migration because it provides a large cohort of patients with localization of the same implanted DBS lead at two time points. The position of the tip of each implanted DBS lead was measured on both the initial post operative lead localization CT and the delayed CT. Lead tip displacement, intracranial lead length, and ventricular indices were collected and analyzed. Clinical outcomes were characterized with validated rating scales for all cases, and a comparison was made between outcomes of cases with lead migration versus those where migration of the lead did not occur. RESULTS: Data from 138 leads in 132 patients with initial and delayed lead localization CT scans were analyzed. The mean distance between initial and delayed DBS lead tip position was 2.2 mm and the mean change in intracranial lead length was 0.45 mm. Significant delayed migration (>3 mm) was observed in 17 leads in 16 patients (12.3% of leads, 12.1% of patients). Factors associated with lead migration were: technical error, repetitive dystonic head movement, and twiddler's syndrome. Outcomes were worse in dystonia patients with lead migration (p = 0.035). In the PD group, worse clinical outcomes trended in cases with lead migration. CONCLUSIONS: Over 10% of DBS leads in this large single center cohort were displaced by greater than 3 mm on delayed measurement, adversely affecting outcomes. Multiple risk factors emerged, including technical error during implantation of the DBS pulse generator and failure of lead fixation at the burr hole site. We hypothesize that a change in surgical technique and a more effective lead fixation device might mitigate this problem. PMID- 28902877 TI - Purification and characterization of a highly specific polyclonal antibody against human extracellular signal-regulated kinase 8 and its detection in lung cancer. AB - Extracellular signal-regulated kinase 8 (ERK8), proposed as a novel potential therapeutic target for cancer, has been implicated in cell transformation, apoptosis, the protection of genomic integrity, and autophagy. To facilitate ERK8 research, a highly specific anti-ERK8 antibody is needed. In this article, we use the Immune Epitope Database and Analysis Resource online tool to predict B-cell epitopes of human ERK8 protein, and choose a 28 aa-peptide sequence to generate the GST-ERK8(28aa) fusion protein as the antigen for developing polyclonal antibody against ERK8. The specificity and sensitivity of anti-ERK8 antibody were robustly validated by immunoblotting, immunocytochemical and immunohistochemical analyses; and we found that both the endogenous and ectopically-expressed human ERK8 proteins can be recognized by our anti-ERK8 antibody. This suggested that our characterized anti-ERK8 antibody will be a valuable tool for the elucidation of the distribution of ERK8 at cellular and histological levels. Finally, our tissue array analysis also demonstrated that the ERK8 protein was localized in both the nucleus and cytoplasm of human lung cancers. PMID- 28902878 TI - Continuous selection pressure to improve temperature acclimation of Tisochrysis lutea. AB - Temperature plays a key role in outdoor industrial cultivation of microalgae. Improving the thermal tolerance of microalgae to both daily and seasonal temperature fluctuations can thus contribute to increase their annual productivity. A long term selection experiment was carried out to increase the thermal niche (temperature range for which the growth is possible) of a neutral lipid overproducing strain of Tisochrysis lutea. The experimental protocol consisted to submit cells to daily variations of temperature for 7 months. The stress intensity, defined as the amplitude of daily temperature variations, was progressively increased along successive selection cycles. Only the amplitude of the temperature variations were increased, the daily average temperature was kept constant along the experiment. This protocol resulted in a thermal niche increase by 3 degrees C (+16.5%), with an enhancement by 9% of the maximal growth rate. The selection process also affected T. lutea physiology, with a feature generally observed for 'cold-temperature' type of adaptation. The amount of total and neutral lipids was significantly increased, and eventually productivity was increased by 34%. This seven month selection experiment, carried out in a highly dynamic environment, challenges some of the hypotheses classically advanced to explain the temperature response of microalgae. PMID- 28902879 TI - Chronic Plasmodium brasilianum infections in wild Peruvian tamarins. AB - There is an increased interest in potential zoonotic malarias. To date, Plasmodium malariae that infects humans remains indistinguishable from Plasmodium brasilianum, which is widespread among New World primates. Distributed throughout tropical Central and South America, the Callitrichidae are small arboreal primates in which detection of natural Plasmodium infection has been extremely rare. Most prior screening efforts have been limited to small samples, the use of low-probability detection methods, or both. Rarely have screening efforts implemented a longitudinal sampling design. Through an annual mark-recapture program of two sympatric callitrichids, the emperor (Saguinus imperator) and saddleback (Saguinus fuscicollis) tamarins, whole blood samples were screened for Plasmodium by microscopy and nested PCR of the cytochrome b gene across four consecutive years (2012-2015). Following the first field season, approximately 50% of the samples collected each subsequent year were from recaptured individuals. In particular, out of 245 samples from 129 individuals, 11 samples from 6 individuals were positive for Plasmodium, and all but one of these infections was found in S. imperator. Importantly, the cytochrome b sequences were 100% identical to former isolates of P. malariae from humans and P. brasilianum from Saimiri sp. Chronic infections were detected as evidenced by repeated infections (7) from two individuals across the 4-year study period. Furthermore, 4 of the 5 infected emperor tamarins were part of a single group spanning the entire study period. Overall, the low prevalence reported here is consistent with previous findings. This study identifies two new natural hosts for P. brasilianum and provides evidence in support of chronic infections in wildlife populations. Given that callitrichids are often found in mixed-species associations with other primates and can be resilient to human-disturbed environments, they could contribute to the maintenance of P. malariae populations if future work provides entomological and epidemiological evidence indicating human zoonotic infections. PMID- 28902880 TI - Cost and cost-effectiveness of a school-based education program to reduce salt intake in children and their families in China. AB - OBJECTIVE: The School-based Education Program to Reduce Salt Intake in Children and Their Families study was a cluster randomized control trial among grade five students in 28 primary schools and their families in Changzhi, China. It achieved a significant effect in lowering systolic blood pressure (SBP) in all family adults by 2.3 mmHg and in elderlies (aged > = 60 years) by 9.5 mmHg. The aim of this study was to assess the cost-effectiveness of this salt reduction program. METHODS: Costs of the intervention were assessed using an ingredients approach to identify resource use. A trial-based incremental cost-effectiveness ratio (ICER) was estimated based on the observed effectiveness in lowering SBP. A Markov model was used to estimate the long-term cost-effectiveness of the intervention, and then based on population data, extrapolated to a scenario where the program is scaled up nationwide. Findings were presented in terms of an incremental cost per quality-adjusted life year (QALY). The perspective was that of the health sector. RESULTS: The intervention cost Int$19.04 per family and yielded an ICER of Int$2.74 (90% CI: 1.17-12.30) per mmHg reduction of SBP in all participants (combining children and adult participants together) compared with control group. If scaled up nationwide for 10 years and assumed deterioration in treatment effect of 50% over this period, it would reach 165 million families and estimated to avert 42,720 acute myocardial infarction deaths and 107,512 stroke deaths in China. This would represent a gain of 635,816 QALYs over 10-year time frame, translating into Int$1,358 per QALY gained. CONCLUSION: Based on WHO-CHOICE criteria, our analysis demonstrated that the proposed salt reduction strategy is highly cost-effective, and if scaled up nationwide, the benefits could be substantial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01821144. PMID- 28902881 TI - Perioperative factors that are significantly correlated with final visual acuity in eyes after successful rhegmatogenous retinal detachment surgery. AB - PURPOSE: To determine the perioperative factors that are significantly correlated with the final visual acuity following reattachment of a macula-off rhegmatogenous retinal detachment (RRD) by vitrectomy. METHODS: Twenty-nine eyes of 29 patients with a successfully reattached RRD by vitrectomy were retrospectively analyzed. Spectral-domain optical coherence tomographic images of the macular regions were used to measure the thicknesses of the retinal layers and the integrity of the microstructures of the photoreceptors at 2 weeks, 1, 2, 3, 6, 9, and 12 months following the vitrectomy. The best-corrected visual acuities (BCVA) were evaluated at the same times. RESULTS: The improvement of the BCVA from the preoperative BCVA to that at postoperative Week 2 (-0.67 +/- 0.69 logMAR units) was the largest change between adjacent observation periods for the entire study duration. It was significantly greater than the improvement between Week 2 and Month 12 (-0.32 +/- 0.22 logMAR units; P<0.001). The thickness of the ellipsoid zone (EZ)-retinal pigment epithelium (RPE) increased significantly with time (P<0.001). The final BCVA was significantly correlated with the BCVA at Week 2 (r = 0.61, P<0.001), the EZ-RPE thickness at Week 2 (r = -0.40, P = 0.035), the integrity of the external limiting membrane (ELM) (r = -0.61, P = 0.003), and an intact EZ (r = -0.66, P = 0.001) at Week 2. Multiple stepwise regression analyses of the final BCVA showed that the BCVA at Week 2 (P = 0.017) and the integrity of the EZ at Week 2 (P = 0.006) were independent predictors of the final BCVA. CONCLUSIONS: The significantly better BCVA and presence of an intact EZ at 2 weeks following vitrectomy and their significant correlations with the BCVA at Month 12 indicate that these perioperative values can be used to predict the BCVA at Month 12 after a reattachment of macula-off RRD following vitrectomy. PMID- 28902882 TI - Risk of myeloid neoplasms after radiotherapy among older women with localized breast cancer: A population-based study. AB - BACKGROUND: There are inconsistent and limited data regarding the risk of myeloid neoplasms (MN) among breast cancer survivors who received radiotherapy (RT) in the absence of chemotherapy. Concern about subsequent MN might influence the decision to use adjuvant RT for women with localized disease. As patients with therapy-related MN have generally poor outcomes, the presumption of subsequent MN being therapy-related could affect treatment recommendations. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to study older women with in-situ or stage 1-3 breast cancer diagnosed 2001-2009 who received surgery. Chemotherapy and RT were ascertained using Medicare claims, and new MN diagnoses were captured using both SEER registry and Medicare claims. We excluded women who received chemotherapy for initial treatment, and censored at receipt of subsequent chemotherapy. Competing-risk survival analysis was used to assess the association between RT and risk of subsequent MN adjusting for relevant characteristics. RESULTS: Median follow-up for 60,426 eligible patients was 68 months (interquartile range, 46 to 92 months), with 47.6% receiving RT. In total, 316 patients (0.52%) were diagnosed with MN; the cumulative incidence per 10,000 person-years was 10.6 vs 9.0 among RT-treated vs non-RT-treated women, respectively (p = .004); the increased risk of subsequent MN persisted in the adjusted analysis (hazard ratio = 1.36, 95% confidence interval: 1.03-1.80). The results were consistent in multiple sensitivity analyses. CONCLUSIONS: Our data suggest that RT is associated with a significant risk of subsequent MN among older breast cancer survivors, though the absolute risk increase is very small. These findings suggest the benefits of RT outweigh the risks of development of subsequent MN. PMID- 28902883 TI - Association between E/e' ratio and fluid overload in patients with predialysis chronic kidney disease. AB - BACKGROUND: Chronic fluid overload is common in patients with chronic kidney disease (CKD) and can with time lead to diastolic dysfunction and heart failure. We investigated whether markers of fluid status, such as NT-proBNP and bioimpedance spectroscopy (BIS), can predict echocardiographic findings of diastolic dysfunction in non-dialysis CKD5 patients. METHODS: BIS, echocardiography, and measurement of serum NT-proBNP were performed in patients with non-dialysis CKD stage 5 at a single study visit. E/e' ratio reflect mean LV diastolic pressure and a ratio greater than 15 was used as a definition of diastolic dysfunction. RESULTS: Eighty-four patients were analyzed. Forty-six patients (54.76%) had E/e' ratio <=15 and 38 patients (45.24%) had E/e' > 15 (diastolic dysfunction). Patients with E/e'>15 had significantly higher serum NT proBNP (14,650 pg/mL) than patients with to E/e'<=15 (4,271 pg/mL) and had more overhydration (OH), 5.1 liters compared to 2.4 liters. The cut-off values predicting diastolic dysfunction were found to be 2,797 pg/mL for NT-proBNP and 2.45 liters for OH. CONCLUSIONS: Regular monitoring of fluid status by BIS and NT proBNP can be used to find patient with risk of developing diastolic dysfunction. Treatments to correct fluid overload may reduce the risk of developing diastolic dysfunction and improve cardiovascular outcome in patients with CKD. PMID- 28902884 TI - Development of EST-SSR markers in flowering Chinese cabbage (Brassica campestris L. ssp. chinensis var. utilis Tsen et Lee) based on de novo transcriptomic assemblies. AB - Flowering Chinese cabbage is one of the most important vegetable crops in southern China. Genetic improvement of various agronomic traits in this crop is underway to meet high market demand in the region, but the progress is hampered by limited number of molecular markers available in this crop. This study aimed to develop EST-SSR markers from transcriptome sequences generated by next generation sequencing. RNA-seq of eight cabbage samples identified 48,975 unigenes. Of these unigenes, 23,267 were annotated in 56 gene ontology (GO) categories, 6,033 were mapped to 131 KEGG pathways, and 7,825 were assigned to clusters of orthologous groups (COGs). From the unigenes, 8,165 EST-SSR loci were identified and 98.57% of them were 1-3 nucleotide repeats with 14.32%, 41.08% and 43.17% of mono-, di- and tri-nucleotide repeats, respectively. Fifty-eight types of motifs were identified with A/T, AG/CT, AT/AT, AC/GT, AAG/CTT and AGG/CCT the most abundant. The lengths of repeated nucleotide sequences in all SSR loci ranged from 12 to 60 bp, with most (88.51%) under 20 bp. Among 170 primer pairs were randomly selected from a total of 4,912 SSR primers we designed, 48 yielded unambiguously polymorphic bands with high reproducibility. Cluster analysis using 48 SSRs classified 34 flowering Chinese cabbage cultivars into three groups. A large number of EST-SSR markers identified in this study will facilitate marker assisted selection in the breeding programs of flowering Chinese cabbage. PMID- 28902885 TI - Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: A meta-epidemiological investigation. AB - OBJECTIVE: Abstracts of scientific reports are sometimes criticized for exaggerating significant results when compared to the corresponding full texts. Such abstracts can mislead the readers. We aimed to conduct a systematic review of overstatements in abstract conclusions in psychiatry trials. METHODS: We searched for randomized controlled trials published in 2014 that explicitly claimed effectiveness of any intervention for mental disorders in their abstract conclusion, using the Cochrane Register of Controlled Trials. Claims of effectiveness in abstract conclusion were categorized into three types: superiority (stating superiority of intervention to control), limited superiority (intervention has limited superiority), and equal efficactiveness (claiming equal effectiveness of intervention with standard treatment control), and full text results into three types: significant (all primary outcomes were statistically significant in favor of the intervention), mixed (primary outcomes included both significant and non-significant results), or all results non-significant. By comparing these classifications, we assessed whether each abstract was overstated. Our primary outcome was the proportion of overstated abstract conclusions. RESULTS: We identified and included 60 relevant trials. 20 out of 60 studies (33.3%) showed overstatements. Nine reports reported only significant results although none of their primary outcomes were significant. Large sample size (>300) and publication in high impact factor (IF>10) journals were associated with low occurrence of overstatements. CONCLUSIONS: We found that one in three psychiatry studies claiming effectiveness in their abstract conclusion, either superior to control or equal to standard treatment, for any mental disorders were overstated in comparison with the full text results. Readers of the psychiatry literature are advised to scrutinize the full text results regardless of the claims in the abstract. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000018668). PMID- 28902886 TI - Metabolic engineering to simultaneously activate anthocyanin and proanthocyanidin biosynthetic pathways in Nicotiana spp. AB - Proanthocyanidins (PAs), or condensed tannins, are powerful antioxidants that remove harmful free oxygen radicals from cells. To engineer the anthocyanin and proanthocyanidin biosynthetic pathways to de novo produce PAs in two Nicotiana species, we incorporated four transgenes to the plant chassis. We opted to perform a simultaneous transformation of the genes linked in a multigenic construct rather than classical breeding or retransformation approaches. We generated a GoldenBraid 2.0 multigenic construct containing two Antirrhinum majus transcription factors (AmRosea1 and AmDelila) to upregulate the anthocyanin pathway in combination with two Medicago truncatula genes (MtLAR and MtANR) to produce the enzymes that will derivate the biosynthetic pathway to PAs production. Transient and stable transformation of Nicotiana benthamiana and Nicotiana tabacum with the multigenic construct were respectively performed. Transient expression experiments in N. benthamiana showed the activation of the anthocyanin pathway producing a purple color in the agroinfiltrated leaves and also the effective production of 208.5 nmol (-) catechin/g FW and 228.5 nmol (-) epicatechin/g FW measured by the p-dimethylaminocinnamaldehyde (DMACA) method. The integration capacity of the four transgenes, their respective expression levels and their heritability in the second generation were analyzed in stably transformed N. tabacum plants. DMACA and phoroglucinolysis/HPLC-MS analyses corroborated the activation of both pathways and the effective production of PAs in T0 and T1 transgenic tobacco plants up to a maximum of 3.48 mg/g DW. The possible biotechnological applications of the GB2.0 multigenic approach in forage legumes to produce "bloat-safe" plants and to improve the efficiency of conversion of plant protein into animal protein (ruminal protein bypass) are discussed. PMID- 28902887 TI - A checklist is associated with increased quality of reporting preclinical biomedical research: A systematic review. AB - Irreproducibility of preclinical biomedical research has gained recent attention. It is suggested that requiring authors to complete a checklist at the time of manuscript submission would improve the quality and transparency of scientific reporting, and ultimately enhance reproducibility. Whether a checklist enhances quality and transparency in reporting preclinical animal studies, however, has not been empirically studied. Here we searched two highly cited life science journals, one that requires a checklist at submission (Nature) and one that does not (Cell), to identify in vivo animal studies. After screening 943 articles, a total of 80 articles were identified in 2013 (pre-checklist) and 2015 (post checklist), and included for the detailed evaluation of reporting methodological and analytical information. We compared the quality of reporting preclinical animal studies between the two journals, accounting for differences between journals and changes over time in reporting. We find that reporting of randomization, blinding, and sample-size estimation significantly improved when comparing Nature to Cell from 2013 to 2015, likely due to implementation of a checklist. Specifically, improvement in reporting of the three methodological information was at least three times greater when a mandatory checklist was implemented than when it was not. Reporting the sex of animals and the number of independent experiments performed also improved from 2013 to 2015, likely from factors not related to a checklist. Our study demonstrates that completing a checklist at manuscript submission is associated with improved reporting of key methodological information in preclinical animal studies. PMID- 28902888 TI - Dendrimer-based selective autophagy-induction rescues DeltaF508-CFTR and inhibits Pseudomonas aeruginosa infection in cystic fibrosis. AB - BACKGROUND: Cystic Fibrosis (CF) is a genetic disorder caused by mutation(s) in the CF-transmembrane conductance regulator (Cftr) gene. The most common mutation, DeltaF508, leads to accumulation of defective-CFTR protein in aggresome-bodies. Additionally, Pseudomonas aeruginosa (Pa), a common CF pathogen, exacerbates obstructive CF lung pathology. In the present study, we aimed to develop and test a novel strategy to improve the bioavailability and potentially achieve targeted drug delivery of cysteamine, a potent autophagy-inducing drug with anti-bacterial properties, by developing a dendrimer (PAMAM-DEN)-based cysteamine analogue. RESULTS: We first evaluated the effect of dendrimer-based cysteamine analogue (PAMAM-DENCYS) on the intrinsic autophagy response in IB3-1 cells and observed a significant reduction in Ub-RFP and LC3-GFP co-localization (aggresome-bodies) by PAMAM-DENCYS treatment as compared to plain dendrimer (PAMAM-DEN) control. Next, we observed that PAMAM-DENCYS treatment shows a modest rescue of DeltaF508-CFTR as the C-form. Moreover, immunofluorescence microscopy of HEK-293 cells transfected with DeltaF508-CFTR-GFP showed that PAMAM-DENCYS is able to rescue the misfolded-DeltaF508-CFTR from aggresome-bodies by inducing its trafficking to the plasma membrane. We further verified these results by flow cytometry and observed significant (p<0.05; PAMAM-DEN vs. PAMAM-DENCYS) rescue of membrane DeltaF508-CFTR with PAMAM-DENCYS treatment using non-permeabilized IB3-1 cells immunostained for CFTR. Finally, we assessed the autophagy-mediated bacterial clearance potential of PAMAM-DENCYS by treating IB3-1 cells infected with PA01 GFP, and observed a significant (p<0.01; PAMAM-DEN vs. PAMAM-DENCYS) decrease in intracellular bacterial counts by immunofluorescence microscopy and flow cytometry. Also, PAMAM-DENCYS treatment significantly inhibits the growth of PA01 GFP bacteria and demonstrates potent mucolytic properties. CONCLUSIONS: We demonstrate here the efficacy of dendrimer-based autophagy-induction in preventing sequestration of DeltaF508-CFTR to aggresome-bodies while promoting its trafficking to the plasma membrane. Moreover, PAMAM-DENCYS decreases Pa infection and growth, while showing mucolytic properties, suggesting its potential in rescuing Pa-induced DeltaF508-CF lung disease that warrants further investigation in CF murine model. PMID- 28902889 TI - On specimen killing in the era of conservation crisis - A quantitative case for modernizing taxonomy and biodiversity inventories. AB - BACKGROUND TO THE WORK: For centuries taxonomy has relied on dead animal specimens, a practice that persists today despite the emergence of innovative biodiversity assessment methods. Taxonomists and conservationists are engaged in vigorous discussions over the necessity of killing animals for specimen sampling, but quantitative data on taxonomic trends and specimen sampling over time, which could inform these debates, are lacking. METHODS: We interrogated a long-term research database documenting 2,723 land vertebrate and 419 invertebrate taxa from Madagascar, and their associated specimens conserved in the major natural history museums. We further compared specimen collection and species description rates for the birds, mammals and scorpions over the last two centuries, to identify trends and links to taxon descriptions. RESULTS: We located 15,364 specimens documenting endemic mammals and 11,666 specimens documenting endemic birds collected between 1820 and 2010. Most specimens were collected at the time of the Mission Zoologique Franco-Anglo-Americaine (MZFAA) in the 1930s and during the last two decades, with major differences according to the groups considered. The small mammal and bat collections date primarily from recent years, and are paralleled by the description of new species. Lemur specimens were collected during the MZFAA but the descriptions of new taxa are recent, with the type series limited to non-killed specimens. Bird specimens, particularly of non passerines, are mainly from the time of the MZFAA. The passerines have also been intensely collected during the last two decades; the new material has been used to solve the phylogeny of the groups and only two new endemic taxa of passerine birds have been described over the last two decades. CONCLUSIONS: Our data show that specimen collection has been critical for advancing our understanding of the taxonomy of Madagascar's biodiversity at the onset of zoological work in Madagascar, but less so in recent decades. It is crucial to look for alternatives to avoid killing animals in the name of documenting life, and encourage all efforts to share the information attached to historical and recent collections held in natural history museums. In times of conservation crisis and the advancement in digital technologies and open source sharing, it seems obsolete to kill animals in well-known taxonomic groups for the sake of enriching natural history collections around the world. PMID- 28902890 TI - Simultaneous trimodal PET-MR-EEG imaging: Do EEG caps generate artefacts in PET images? AB - Trimodal simultaneous acquisition of positron emission tomography (PET), magnetic resonance imaging (MRI), and electroencephalography (EEG) has become feasible due to the development of hybrid PET-MR scanners. To capture the temporal dynamics of neuronal activation on a millisecond-by-millisecond basis, an EEG system is appended to the quantitative high resolution PET-MR imaging modality already established in our institute. One of the major difficulties associated with the development of simultaneous trimodal acquisition is that the components traditionally used in each modality can cause interferences in its counterpart. The mutual interferences of MRI components and PET components on PET and MR images, and the influence of EEG electrodes on functional MRI images have been studied and reported on. Building on this, this study aims to investigate the influence of the EEG cap on the quality and quantification of PET images acquired during simultaneous PET-MR measurements. A preliminary transmission scan study on the ECAT HR+ scanner, using an Iida phantom, showed visible attenuation effect due to the EEG cap. The BrainPET-MR emission images of the Iida phantom with [18F]Fluordeoxyglucose, as well as of human subjects with the EEG cap, did not show significant effects of the EEG cap, even though the applied attenuation correction did not take into account the attenuation of the EEG cap itself. PMID- 28902891 TI - TEMs but not DKK1 could serve as complementary biomarkers for AFP in diagnosing AFP-negative hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is prevalent worldwide. Despite its limitations, serum alpha-fetoprotein (AFP) remains the most widely-used biomarker for the diagnosis of HCC. This study aimed to assess whether measurement of peripheral plasma Dickkopf-1 (DKK1) and Tie2 expressing monocytes (TEMs) could overcome the limitations of AFP and improve the diagnostic accuracy of HCC. METHODS: Plasma DKK1 level and the percentage of TEMs in peripheral CD14+CD16+ monocytes from HCC patients (n = 82), HBV-related liver cirrhosis (LC) patients (n = 29), chronic hepatitis B (CHB) infected patients (n = 28) and healthy volunteers (n = 31) were analyzed by ELISA and flow cytometry. Receiver operating characteristic (ROC) curves were used to analyze a single biomarker, or a combination of two or three biomarkers. Univariate and multivariate analyses were performed to assess the significance of each marker in prediction of HCC and AFP-negative HCC from LC patients. RESULTS: The percentage of TEMs in peripheral CD14+CD16+ monocytes and plasma level of DKK1 in HCC group were significantly higher than those in LC, CHB and healthy control groups (all P values <0.05). The percentage of TEMs alone was also significantly higher in AFP negative HCC group than that in LC, CHB and healthy control groups (all P-values <0.05). Plasma DKK1 level alone could not distinguish between AFP-negative HCC and LC patients. ROC curves showed that the optimal diagnostic cutoff value was 550.93 ng/L for DKK1 and 4.95% for TEMs. There was no significant difference in AUC of DKK1, TEMs and AFP in HCC diagnosis between the four groups (all P>0.05). A combination of DKK1, TEMs and AFP measurements increased the AUC for HCC diagnosis as compared with either marker alone (0.833; 95%CI 0.768-0.886). The AUC for TEMs was 0.692 (95% CI 0.564-0.819) in differentiating AFP-negative HCC from LC, with a sensitivity of 80.0% and a specificity of 65.52%. Only TEMs prevailed as a significant predictor for AFP-negative HCC differentiating from LC patients in univariate and multivariate analyses (P = 0.016, P = 0.023). CONCLUSIONS: TEMs and DKK1 may prove to be potential complementary biomarkers for AFP in the diagnosis of HCC. TEMs rather than DKK1 could serve as a complementary biomarker for AFP in the differential diagnosis of AFP-negative HCC versus LC patients. PMID- 28902892 TI - Neanderthal and Denisova tooth protein variants in present-day humans. AB - Environment parameters, diet and genetic factors interact to shape tooth morphostructure. In the human lineage, archaic and modern hominins show differences in dental traits, including enamel thickness, but variability also exists among living populations. Several polymorphisms, in particular in the non collagenous extracellular matrix proteins of the tooth hard tissues, like enamelin, are involved in dental structure variation and defects and may be associated with dental disorders or susceptibility to caries. To gain insights into the relationships between tooth protein polymorphisms and dental structural morphology and defects, we searched for non-synonymous polymorphisms in tooth proteins from Neanderthal and Denisova hominins. The objective was to identify archaic-specific missense variants that may explain the dental morphostructural variability between extinct and modern humans, and to explore their putative impact on present-day dental phenotypes. Thirteen non-collagenous extracellular matrix proteins specific to hard dental tissues have been selected, searched in the publicly available sequence databases of Neanderthal and Denisova individuals and compared with modern human genome data. A total of 16 non-synonymous polymorphisms were identified in 6 proteins (ameloblastin, amelotin, cementum protein 1, dentin matrix acidic phosphoprotein 1, enamelin and matrix Gla protein). Most of them are encoded by dentin and enamel genes located on chromosome 4, previously reported to show signs of archaic introgression within Africa. Among the variants shared with modern humans, two are ancestral (common with apes) and one is the derived enamelin major variant, T648I (rs7671281), associated with a thinner enamel and specific to the Homo lineage. All the others are specific to Neanderthals and Denisova, and are found at a very low frequency in modern Africans or East and South Asians, suggesting that they may be related to particular dental traits or disease susceptibility in these populations. This modern regional distribution of archaic dental polymorphisms may reflect persistence of archaic variants in some populations and may contribute in part to the geographic dental variations described in modern humans. PMID- 28902893 TI - Correlation of optic nerve sheath diameter with directly measured intracranial pressure in Korean adults using bedside ultrasonography. AB - OBJECTIVES: The correlation of optic nerve sheath diameter (ONSD) as seen on ultrasonography (US) and directly measured intracranial pressure (ICP) has been well described. Nevertheless, differences in ethnicity and type of ICP monitor used are obstacles to the interpretation. Therefore, we investigated the direct correlation between ONSD and ventricular ICP and defined an optimal cut-off point for identifying increased ICP (IICP) in Korean adults with brain lesions. METHODS: This prospective study included patients who required an external ventricular drainage (EVD) catheter for ICP control. IICP was defined as an opening pressure over 20 mmHg. ONSD was measured using a 13 MHz US probe before the procedure. Linear regression analysis and receiver operator characteristic (ROC) curve were used to assess the association between ONSD and ICP. Optimal cut off value for identifying IICP was defined. RESULTS: A total of 62 patients who underwent ONSD measurement with simultaneous EVD catheter placement were enrolled in this study. Thirty-two patients (51.6%) were found to have IICP. ONSD in patients with IICP (5.80 +/- 0.45 mm) was significantly higher than in those without IICP (5.30 +/- 0.61 mm) (P < 0.01). The IICP group showed more significant linear correlation with ONSD (r = 0.57, P < 0.01) compared to the non IICP group (r = 0.42, P = 0.02). ONSD > 5.6 mm disclosed a sensitivity of 93.75% and a specificity of 86.67% for identifying IICP. CONCLUSION: ONSD as seen on bedside US correlated well with directly measured ICP in Korean adults with brain lesions. The optimal cut-off point of ONSD for detecting IICP was 5.6 mm. PMID- 28902895 TI - Optimal pseudorandom sequence selection for online c-VEP based BCI control applications. AB - BACKGROUND: In a c-VEP BCI setting, test subjects can have highly varying performances when different pseudorandom sequences are applied as stimulus, and ideally, multiple codes should be supported. On the other hand, repeating the experiment with many different pseudorandom sequences is a laborious process. AIMS: This study aimed to suggest an efficient method for choosing the optimal stimulus sequence based on a fast test and simple measures to increase the performance and minimize the time consumption for research trials. METHODS: A total of 21 healthy subjects were included in an online wheelchair control task and completed the same task using stimuli based on the m-code, the gold-code, and the Barker-code. Correct/incorrect identification and time consumption were obtained for each identification. Subject-specific templates were characterized and used in a forward-step first-order model to predict the chance of completion and accuracy score. RESULTS: No specific pseudorandom sequence showed superior accuracy on the group basis. When isolating the individual performances with the highest accuracy, time consumption per identification was not significantly increased. The Accuracy Score aids in predicting what pseudorandom sequence will lead to the best performance using only the templates. The Accuracy Score was higher when the template resembled a delta function the most and when repeated templates were consistent. For completion prediction, only the shape of the template was a significant predictor. CONCLUSIONS: The simple and fast method presented in this study as the Accuracy Score, allows c-VEP based BCI systems to support multiple pseudorandom sequences without increase in trial length. This allows for more personalized BCI systems with better performance to be tested without increased costs. PMID- 28902894 TI - What determines sclerobiont colonization on marine mollusk shells? AB - Empty mollusk shells may act as colonization surfaces for sclerobionts depending on the physical, chemical, and biological attributes of the shells. However, the main factors that can affect the establishment of an organism on hard substrates and the colonization patterns on modern and time-averaged shells remain unclear. Using experimental and field approaches, we compared sclerobiont (i.e., bacteria and invertebrate) colonization patterns on the exposed shells (internal and external sides) of three bivalve species (Anadara brasiliana, Mactra isabelleana, and Amarilladesma mactroides) with different external shell textures. In addition, we evaluated the influence of the host characteristics (mode of life, body size, color alteration, external and internal ornamentation and mineralogy) of sclerobionts on dead mollusk shells (bivalve and gastropod) collected from the Southern Brazilian coast. Finally, we compared field observations with experiments to evaluate how the biological signs of the present-day invertebrate settlements are preserved in molluscan death assemblages (incipient fossil record) in a subtropical shallow coastal setting. The results enhance our understanding of sclerobiont colonization over modern and paleoecology perspectives. The data suggest that sclerobiont settlement is enhanced by (i) high(er) biofilm bacteria density, which is more attracted to surfaces with high ornamentation; (ii) heterogeneous internal and external shell surface; (iii) shallow infaunal or attached epifaunal life modes; (iv) colorful or post-mortem oxidized shell surfaces; (v) shell size (<50 mm2 or >1,351 mm2); and (vi) calcitic mineralogy. Although the biofilm bacteria density, shell size, and texture are considered the most important factors, the effects of other covarying attributes should also be considered. We observed a similar pattern of sclerobiont colonization frequency over modern and paleoecology perspectives, with an increase of invertebrates occurring on textured bivalve shells. This study demonstrates how bacterial biofilms may influence sclerobiont colonization on biological hosts (mollusks), and shows how ecological relationships in marine organisms may be relevant for interpreting the fossil record of sclerobionts. PMID- 28902896 TI - Pathological grooming: Evidence for a single factor behind trichotillomania, skin picking and nail biting. AB - Although trichotillomania (TTM), skin picking (SP), and nail biting (NB) have been receiving growing scientific attention, the question as to whether these disorders can be regarded as separate entities or they are different manifestations of the same underlying tendency is unclear. Data were collected online in a community survey, yielding a sample of 2705 participants (66% women, mean age: 29.1, SD: 8.6). Hierarchical factor analysis was used to identify a common latent factor and the multiple indicators and multiple causes (MIMIC) modelling was applied to test the predictive effect of borderline personality disorder symptoms, impulsivity, distress and self-esteem on pathological grooming. Pearson correlation coefficients between TTM, SP and NB were between 0.13 and 0.29 (p < 0.01). The model yielded an excellent fit to the data (CFI = 0.992, TLI = 0.991, chi2 = 696.65, p < 0.001, df = 222, RMSEA = 0.030, Cfit of RMSEA = 1.000), supporting the existence of a latent factor. The MIMIC model indicated an adequate fit (CFI = 0.993, TLI = 0.992, chi2 = 655.8, p < 0.001, df = 307, RMSEA = 0.25, CI: 0.022-0.028, pclose = 1.000). TTM, SP and NB each were loaded significantly on the latent factor, indicating the presence of a general grooming factor. Impulsivity, psychiatric distress and contingent self-esteem had significant predictive effects, whereas borderline personality disorder had a nonsignificant predictive effect on the latent factor. We found evidence that the category of pathological grooming is meaningful and encompasses three symptom manifestations: trichotillomania, skin picking and nail biting. This latent underlying factor is not better explained by indicators of psychopathology, which supports the notion that the urge to self-groom, rather than general psychiatric distress, impulsivity, self-esteem or borderline symptomatology, is what drives individual grooming behaviours. PMID- 28902897 TI - Testing the effects of sensory stimulation as a collateral-based therapeutic for ischemic stroke in C57BL/6J and CD1 mouse strains. AB - Utilizing a rat model of ischemic stroke, we have previously shown that sensory stimulation can completely protect rats from impending ischemic damage of cortex if this treatment is delivered within the first two hours post-permanent middle cerebral artery occlusion (pMCAo). The current study sought to extend our findings in rats to mice, which would allow new avenues of research not available in rats. Thus, young adult C57BL/6J and CD1 mice were tested for protection from ischemic stroke with the same protective sensory stimulation-based treatment. Cortical activity and blood flow were assessed with intrinsic signal optical imaging (ISOI) and laser speckle imaging (LSI), respectively, and histological analysis (TTC) was performed at the completion of the experiments. Standing in stark contrast to the positive results observed in rats, in both strains we found that there were no differences between treated and untreated mice at 24 hours post-pMCAo in terms of infarct volume, negative functional imaging results, and major reduction in retrograde collateral blood flow as compared to pre-pMCAo baseline and surgical controls. Also, no differences were found between the strains in terms of theses variables. Potential reasons for the differences between rats and mice are discussed. PMID- 28902898 TI - Identification and characterization of preferred DNA-binding sites for the Thermus thermophilus transcriptional regulator FadR. AB - One of the primary transcriptional regulators of fatty acid homeostasis in many prokaryotes is the protein FadR. To better understand its biological function in the extreme thermophile Thermus thermophilus HB8, we sought to first determine its preferred DNA-binding sequences in vitro using the combinatorial selection method Restriction Endonuclease Protection, Selection, and Amplification (REPSA) and then use this information to bioinformatically identify potential regulated genes. REPSA determined a consensus FadR-binding sequence 5'-TTRNACYNRGTNYAA-3', which was further characterized using quantitative electrophoretic mobility shift assays. With this information, a search of the T. thermophilus HB8 genome found multiple operons potentially regulated by FadR. Several of these were identified as encoding proteins involved in fatty acid biosynthesis and degradation; however, others were novel and not previously identified as targets of FadR. The role of FadR in regulating these genes was validated by physical and functional methods, as well as comparative genomic approaches to further characterize regulons in related organisms. Taken together, our study demonstrates that a systematic approach involving REPSA, biophysical characterization of protein-DNA binding, and bioinformatics can be used to postulate biological roles for potential transcriptional regulators. PMID- 28902899 TI - Selective autonomic stimulation of the AV node fat pad to control rapid post operative atrial arrhythmias. AB - Junctional ectopic tachycardia (JET) and atrial fibrillation (AF) occur in patients recovering from open-heart surgery (OHS). Pharmacologic treatment is used for the control of post-operative atrial arrhythmias (POAA), but is associated with side effects. There is a need for a reversible, modulated solution to rate control. We propose a non-pharmacologic technique that can modulate AV nodal conduction in a selective fashion. Ten mongrel dogs underwent OHS. Stimulation of the anterior right (AR) and inferior right (IR) fat pad (FP) was done using a 7-pole electrode. The IR was more effective in slowing the ventricular rate (VR) to AF (52 +/- 20 vs. 15 +/- 10%, p = 0.003) and JET (12 +/- 7 vs. 0 +/- 0%, p = 0.02). Selective site stimulation within a FP region could augment the effect of stimulation during AF (57 +/- 20% (maximum effect) vs. 0 +/ 0% (minimum effect), p<0.001). FP stimulation at increasing stimulation voltage (SV) demonstrated a voltage-dependent effect (8 +/- 14% (low V) vs. 63 +/- 17 (high V) %, p<0.001). In summary, AV node fat pad stimulation had a selective effect on the AV node by decreasing AV nodal conduction, with little effect on atrial activity. PMID- 28902901 TI - Correction: Long-Term Regional Shifts in Plant Community Composition Are Largely Explained by Local Deer Impact Experiments. AB - [This corrects the article DOI: 10.1371/journal.pone.0115843.]. PMID- 28902900 TI - Possible clinical effects of molecular hydrogen (H2) delivery during hemodialysis in chronic dialysis patients: Interim analysis in a 12 month observation. AB - BACKGROUND AND AIM: It is supposed that enhanced oxidative stress and inflammation are involved with the poor clinical outcomes in patients on chronic dialysis treatment. Recent studies have shown that molecular hydrogen (H2) is biologically active as an anti-inflammatory agent. Thus, we developed a novel hemodialysis (E-HD) system which delivers H2 (30 to 80 ppb)-enriched dialysis solution, to conduct a prospective observational study (UMIN000004857) in order to compare the long-term outcomes between E-HD and conventional-HD (C-HD) in Japan. The present interim analysis aimed to look at potential clinical effects of E-HD during the first 12 months observation. SUBJECTS AND METHOD: 262 patients (140, E-HD; 122, C-HD) were subjected for analysis for comprehensive clinical profiles. They were all participating in the above mentioned study, and they had been under the respective HD treatment for 12 consecutive months without hospitalization. Collected data, such as, physical and laboratory examinations, medications, and self-assessment questionnaires on subjective symptoms (i.e., fatigue and pruritus) were compared between the two groups. RESULTS: In a 12 month period, no clinical relevant differences were found in dialysis-related parameters between the two groups. However, there were differences in the defined daily dose of anti-hypertensive agents, and subjective symptoms, such as severe fatigue, and pruritus, which were all less in the E-HD group. Multivariate analysis revealed E-HD was an independent significant factor for the reduced use of anti-hypertensive agents as well as the absence of severe fatigue and pruritus at 12 months after adjusting for confounding factors. CONCLUSION: The data indicates E-HD could have substantial clinical benefits beyond conventional HD therapy, and support the rationale to conduct clinical trials of H2 application to HD treatment. PMID- 28902902 TI - Multiscale biphasic modelling of peritumoural collagen microstructure: The effect of tumour growth on permeability and fluid flow. AB - We present an in-silico model of avascular poroelastic tumour growth coupled with a multiscale biphasic description of the tumour-host environment. The model is specified to in-vitro data, facilitating biophysically realistic simulations of tumour spheroid growth into a dense collagen hydrogel. We use the model to first confirm that passive mechanical remodelling of collagen fibres at the tumour boundary is driven by solid stress, and not fluid pressure. The model is then used to demonstrate the influence of collagen microstructure on peritumoural permeability and interstitial fluid flow. Our model suggests that at the tumour periphery, remodelling causes the peritumoural stroma to become more permeable in the circumferential than radial direction, and the interstitial fluid velocity is found to be dependent on initial collagen alignment. Finally we show that solid stresses are negatively correlated with peritumoural permeability, and positively correlated with interstitial fluid velocity. These results point to a heterogeneous, microstructure-dependent force environment at the tumour peritumoural stroma interface. PMID- 28902903 TI - Visuo-perceptual capabilities predict sensitivity for coinciding auditory and visual transients in multi-element displays. AB - In order to obtain a coherent representation of the outside world, auditory and visual information are integrated during human information processing. There is remarkable variance among observers in the capability to integrate auditory and visual information. Here, we propose that visuo-perceptual capabilities predict detection performance for audiovisually coinciding transients in multi-element displays due to severe capacity limitations in audiovisual integration. In the reported experiment, we employed an individual differences approach in order to investigate this hypothesis. Therefore, we measured performance in a useful-field of-view task that captures detection performance for briefly presented stimuli across a large perceptual field. Furthermore, we measured sensitivity for visual direction changes that coincide with tones within the same participants. Our results show that individual differences in visuo-perceptual capabilities predicted sensitivity for the presence of audiovisually synchronous events among competing visual stimuli. To ensure that this correlation does not stem from superordinate factors, we also tested performance in an unrelated working memory task. Performance in this task was independent of sensitivity for the presence of audiovisually synchronous events. Our findings strengthen the proposed link between visuo-perceptual capabilities and audiovisual integration. The results also suggest that basic visuo-perceptual capabilities provide the basis for the subsequent integration of auditory and visual information. PMID- 28902905 TI - Bio-physical characterisation of polynyas as a key foraging habitat for juvenile male southern elephant seals (Mirounga leonina) in Prydz Bay, East Antarctica. AB - Antarctic coastal polynyas are persistent open water areas in the sea ice zone, and regions of high biological productivity thought to be important foraging habitat for marine predators. This study quantified southern elephant seal (Mirounga leonina) habitat use within and around the polynyas of the Prydz Bay region (63 degrees E- 88 degrees E) in East Antarctica, and examined the bio physical characteristics structuring polynyas as foraging habitat. Output from a climatological regional ocean model was used to provide context for in situ temperature-salinity vertical profiles collected by tagged elephant seals and to characterise the physical properties structuring polynyas. Biological properties were explored using remotely-sensed surface chlorophyll (Chl-a) and, qualitatively, historical fish assemblage data. Spatially gridded residence time of seals was examined in relation to habitat characteristics using generalized additive mixed models. The results showed clear polynya usage during early autumn and increasingly concentrated usage during early winter. Bathymetry, Chl-a, surface net heat flux (representing polynya location), and bottom temperature were identified as significant bio-physical predictors of the spatio-temporal habitat usage. The findings from this study confirm that the most important marine habitats for juvenile male southern elephant seals within Prydz Bay region are polynyas. A hypothesis exists regarding the seasonal evolution of primary productivity, coupling from surface to subsurface productivity and supporting elevated rates of secondary production in the upper water column during summer autumn. An advancement to this hypothesis is proposed here, whereby this bio physical coupling is likely to extend throughout the water column as it becomes fully convected during autumn-winter, to also promote pelagic-benthic linkages important for benthic foraging within polynyas. PMID- 28902904 TI - Assessing coastal wetland vulnerability to sea-level rise along the northern Gulf of Mexico coast: Gaps and opportunities for developing a coordinated regional sampling network. AB - Coastal wetland responses to sea-level rise are greatly influenced by biogeomorphic processes that affect wetland surface elevation. Small changes in elevation relative to sea level can lead to comparatively large changes in ecosystem structure, function, and stability. The surface elevation table-marker horizon (SET-MH) approach is being used globally to quantify the relative contributions of processes affecting wetland elevation change. Historically, SET MH measurements have been obtained at local scales to address site-specific research questions. However, in the face of accelerated sea-level rise, there is an increasing need for elevation change network data that can be incorporated into regional ecological models and vulnerability assessments. In particular, there is a need for long-term, high-temporal resolution data that are strategically distributed across ecologically-relevant abiotic gradients. Here, we quantify the distribution of SET-MH stations along the northern Gulf of Mexico coast (USA) across political boundaries (states), wetland habitats, and ecologically-relevant abiotic gradients (i.e., gradients in temperature, precipitation, elevation, and relative sea-level rise). Our analyses identify areas with high SET-MH station densities as well as areas with notable gaps. Salt marshes, intermediate elevations, and colder areas with high rainfall have a high number of stations, while salt flat ecosystems, certain elevation zones, the mangrove-marsh ecotone, and hypersaline coastal areas with low rainfall have fewer stations. Due to rapid rates of wetland loss and relative sea-level rise, the state of Louisiana has the most extensive SET-MH station network in the region, and we provide several recent examples where data from Louisiana's network have been used to assess and compare wetland vulnerability to sea-level rise. Our findings represent the first attempt to examine spatial gaps in SET-MH coverage across abiotic gradients. Our analyses can be used to transform a broadly disseminated and unplanned collection of SET-MH stations into a coordinated and strategic regional network. This regional network would provide data for predicting and preparing for the responses of coastal wetlands to accelerated sea-level rise and other aspects of global change. PMID- 28902906 TI - Users' participation and social influence during information spreading on Twitter. AB - Online Social Networks generate a prodigious wealth of real-time information at an incessant rate. In this paper we study the empirical data that crawled from Twitter to describe the topology and information spreading dynamics of Online Social Networks. We propose a measurement with three measures to state the efforts of users on Twitter to get their information spreading, based on the unique mechanisms for information retransmission on Twitter. It is noticed that small fraction of users with special performance on participation can gain great influence, while most other users play a role as middleware during the information propagation. Thus a community analysis is performed and four categories of users are found with different kinds of participation that cause the information dissemination dynamics. These suggest that exiting topological measures alone may reflect little about the influence of individuals and provide new insights for information spreading. PMID- 28902907 TI - PCR detection of human herpesviruses in colonic mucosa of individuals with inflammatory bowel disease: Comparison with individuals with immunocompetency and HIV infection. AB - BACKGROUND: Detection of human herpesviruses (HHVs) other than cytomegalovirus (CMV) in colonic mucosa of individuals with inflammatory bowel disease (IBD) remains unknown. This study identified eight HHVs in the colonic mucosa of individuals with IBD and compared the results with immunocompetent and human immunodeficiency virus (HIV)-infected individuals. METHODS: A total of 89 individuals who had colorectal ulcer on colonoscopy were enrolled: 26 with immunocompetency (n = 26), 41 with IBD, and 22 with HIV infection. We examined the colonic ulcers for the presence of eight HHVs-herpes simplex virus (HSV)-1/2, varicella zoster virus (VZV), CMV, Epstein-Barr virus (EBV), HHV-6, HHV-7, and HHV-8-using mucosal PCR. RESULTS: The IBD group had positivity rates of 0%, 0%, 0%, 53.7%, 24.4%, 39%, 39%, and 0% for HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-7, and HHV-8, respectively. The positivity rates of EBV and CMV in colonic mucosa increased significantly in the order of the immunocompetent, IBD, and HIV groups (EBV: 23.1%, 53.7%, 72.7%, P for trend = 0.0005; CMV, 7.7%, 24.4%, 54.5%, P for trend = 0.0003, respectively), but no increase was found in the other HHVs. Median mucosal EBV DNA values in the immunocompetent, IBD, and HIV groups were 0, 76, and 287 copies/MUg DNA, respectively (P for trend = 0.002). Corresponding median mucosal CMV DNA values were 0, 0, and 17 copies/MUg DNA (P for trend = 0.0001). There was no significant difference in the positivity rates of the eight HHVs between ulcerative colitis and Crohn's disease. CONCLUSION: The HHVs of EBV, CMV, HHV-6, and HHV-7, but not of HSV-1, HSV-2, VZV, or HHV-8, were identified in the colonic mucosa of IBD individuals. EBV and CMV in colonic mucosa was correlated with host immune status in increasing order of immunocompetent, IBD, and HIV-infected individuals. PMID- 28902908 TI - Histological assessment of granulomas in natural and experimental Schistosoma mansoni infections using whole slide imaging. AB - The pathology of schistosomiasis mansoni, a neglected tropical disease of great clinical and socioeconomic importance, results from the parasite eggs that become trapped in host tissues, particularly in the liver and intestines. Continuous antigenic stimulation from these eggs leads to recruitment of inflammatory cells to the sites of infection with formation of periovular granulomas. These complex structures have variable size and composition and are the most striking histopathological feature of schistosomiasis mansoni. However, evaluation of granulomas by conventional microscopy methods is time-consuming and limited, especially in large-scale studies. Here, we used high resolution Whole Slide Imaging (WSI), which allows fast scanning of entire histological slides, and multiple morphometric evaluations, to assess the granulomatous response elicited in target organs (liver, small and large intestines) of two models of schistosomiasis mansoni. One of the advantages of WSI, also termed virtual microscopy, is that it generates images that simultaneously offer high resolution and a wide field of observation. By using a model of natural (Nectomys squamipes, a wild reservoir captured from endemic areas in Brazil) and experimental (Swiss mouse) infection with Schistosoma mansoni, we provided the first detailed WSI characterization of granulomas and other pathological aspects. WSI and quantitative analyses enabled a fast and reliable assessment of the number, evolutional types, frequency and areas of granulomas and inflammatory infiltrates and revealed that target organs are differentially impacted by inflammatory responses in the natural and experimental infections. Remarkably, high-resolution analysis of individual eosinophils, key cells elicited by this helminthic infection, showed a great difference in eosinophil numbers between the two infections. Moreover, features such as the intestinal egg path and confluent granulomas were uncovered. Thus, WSI may be a suitable tool for detailed and precise histological analysis of granulomas and other pathological aspects for clinical and research studies of schistosomiasis. PMID- 28902910 TI - Pituitary genomic expression profiles of steers are altered by grazing of high vs. low endophyte-infected tall fescue forages. AB - Consumption of ergot alkaloid-containing tall fescue grass impairs several metabolic, vascular, growth, and reproductive processes in cattle, collectively producing a clinical condition known as "fescue toxicosis." Despite the apparent association between pituitary function and these physiological parameters, including depressed serum prolactin; no reports describe the effect of fescue toxicosis on pituitary genomic expression profiles. To identify candidate regulatory mechanisms, we compared the global and selected targeted mRNA expression patterns of pituitaries collected from beef steers that had been randomly assigned to undergo summer-long grazing (89 to 105 d) of a high-toxic endophyte-infected tall fescue pasture (HE; 0.746 MUg/g ergot alkaloids; 5.7 ha; n = 10; BW = 267 +/- 14.5 kg) or a low-toxic endophyte tall fescue-mixed pasture (LE; 0.023 MUg/g ergot alkaloids; 5.7 ha; n = 9; BW = 266 +/- 10.9 kg). As previously reported, in the HE steers, serum prolactin and body weights decreased and a potential for hepatic gluconeogenesis from amino acid-derived carbons increased. In this manuscript, we report that the pituitaries of HE steers had 542 differentially expressed genes (P < 0.001, false discovery rate <= 4.8%), and the pattern of altered gene expression was dependent (P < 0.001) on treatment. Integrated Pathway Analysis revealed that canonical pathways central to prolactin production, secretion, or signaling were affected, in addition to those related to corticotropin-releasing hormone signaling, melanocyte development, and pigmentation signaling. Targeted RT-PCR analysis corroborated these findings, including decreased (P < 0.05) expression of DRD2, PRL, POU1F1, GAL, and VIP and that of POMC and PCSK1, respectively. Canonical pathway analysis identified HE dependent alteration in signaling of additional pituitary-derived hormones, including growth hormone and GnRH. We conclude that consumption of endophyte infected tall fescue alters the pituitary transcriptome profiles of steers in a manner consistent with their negatively affected physiological parameters. PMID- 28902909 TI - The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival. AB - The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase beta-subunit knockout (H/K-beta KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-beta KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival. PMID- 28902911 TI - Serum calcium, alkaline phosphotase and hemoglobin as risk factors for bone metastases in bladder cancer. AB - Early detection of bone metastases is helpful for the treatment of bladder cancer (BC). In this study, we investigated the potential risk factors for bone metastasis in newly diagnosed patients with BC. A total of 902 patients diagnosed with BC between January 2000 and August 2016 were retrospectively reviewed. Of these patient, 50 (5.5%) were identified with bone metastasis. The serum levels of alkaline phosphatase (ALP) and calcium were significantly higher in patients with bone metastases than those without bone metastases (P = 0.015 and P<0.001). And the concentration of hemoglobin (HB) was significant lower in bone metastatic patients compared with non bone metastatic patients (P = 0.009). Multivariate logistic regression analysis indicated that ALP, HB and calcium were independent risk factors for bone metastases in patients with BC. The cut off values of ALP, HB and calcium were 116 U/L, 37.5g/L and 2.54 mmol/L according to the receiver operating characteristic (ROC) curves analysis. And combined ALP, HB with calcium had the highest diagnostic accuracy for predicting bone metastases in BC patients (AUC = 0.760, P<0.001). Therefore, for newly diagnosed patients with BC, the concentrations of ALP >116 U/L, HB <37.5 g/Land calcium >2.54 mmol/L were the risk factors for developing bone metastases. Combined ALP, HB with calcium was more useful to diagnose the bone metastases. PMID- 28902912 TI - Differential response to mosquito host sex and parasite dosage suggest mixed dispersal strategies in the parasite Ascogregarina taiwanensis. AB - Mixed dispersal strategies are a form of bet hedging in which a species or population utilizes different dispersal strategies dependent upon biotic or abiotic conditions. Here we provide an example of a mixed dispersal strategy in the Aedes albopictus / Ascogregarina taiwanensis host/parasite system, wherein upon host emergence, the gregarine parasite is either carried with an adult mosquito leaving the larval habitat, or released back into the larval habitat. We show that the parasite invests a larger proportion of its dispersing (oocyst) life stage into adult female mosquitoes as opposed to adult male mosquitoes at low parasite exposure levels. However, as the exposure level of parasite increases, so does the parasite investment in adult males, whereas there is no change in the proportion of oocysts in the adult female, regardless of dose. Thus, A. taiwanensis is utilizing several dispersal strategies, depending upon host sex and intraspecific density. Furthermore, we demonstrate that this parasite reduces body size, increases time to emergence in females, and leads to a reduction in estimates of per capita growth rate of the host. PMID- 28902913 TI - Identification of diverse viruses in upper respiratory samples in dromedary camels from United Arab Emirates. AB - Camels are known carriers for many viral pathogens, including Middle East respiratory syndrome coronavirus (MERS-CoV). It is likely that there are additional, as yet unidentified viruses in camels with the potential to cause disease in humans. In this study, we performed metagenomic sequencing analysis on nasopharyngeal swab samples from 108 MERS-CoV-positive dromedary camels from a live animal market in Abu Dhabi, United Arab Emirates. We obtained a total of 846.72 million high-quality reads from these nasopharyngeal swab samples, of which 2.88 million (0.34%) were related to viral sequences while 512.63 million (60.5%) and 50.87 million (6%) matched bacterial and eukaryotic sequences, respectively. Among the viral reads, sequences related to mammalian viruses from 13 genera in 10 viral families were identified, including Coronaviridae, Nairoviridae, Paramyxoviridae, Parvoviridae, Polyomaviridae, Papillomaviridae, Astroviridae, Picornaviridae, Poxviridae, and Genomoviridae. Some viral sequences belong to known camel or human viruses and others are from potentially novel camel viruses with only limited sequence similarity to virus sequences in GenBank. A total of five potentially novel virus species or strains were identified. Co-infection of at least two recently identified camel coronaviruses was detected in 92.6% of the camels in the study. This study provides a comprehensive survey of viruses in the virome of upper respiratory samples in camels that have extensive contact with the human population. PMID- 28902914 TI - Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients. AB - Oxidative stress is one of the key factors that contributes to the pathogenesis of keratoconus (KC). Macroautophagy is a vital cellular mechanism that is activated in response to oxidative stress. The aim of this study was to understand the role of the autophagic lysosomal pathway in the oxidative damage of KC corneal epithelium and the human corneal epithelial cell line (HCE).The corneal epithelium was collected from 78 KC patients undergoing corneal cross linking or topography guided photorefractive keratectomy. We performed microarray, qPCR and western blot analysis for the expression of autophagy markers on this epithelium from patients with different clinical grades of KC. A differential expression pattern of autophagy related markers was observed in the diseased corneal cone-specific epithelium compared to matched peripheral epithelium from KC patients with increasing clinical severity. Human corneal epithelial cells exposed to oxidative stress were analyzed for the expression of key proteins associated with KC pathogenesis and the autophagic pathway. Oxidative stress led to an increase in reactive oxygen species and an imbalanced expression of autophagy markers in the HCE cells. Further, reduced levels of Akt/p70S6 Kinase, which is a known target of the mTOR pathway was observed in HCE cells under oxidative stress as well as in KC epithelium. Our results suggest that an altered expression of proteins suggestive of defective autophagy and is a consequence of oxidative damage. This could play a possible role in the pathogenesis of KC. PMID- 28902915 TI - Social interactions between live and artificial weakly electric fish: Electrocommunication and locomotor behavior of Mormyrus rume proboscirostris towards a mobile dummy fish. AB - Mormyrid weakly electric fish produce short, pulse-type electric organ discharges for actively probing their environment and to communicate with conspecifics. Animals emit sequences of pulse-trains that vary in overall frequency and temporal patterning and can lead to time-locked interactions with the discharge activity of other individuals. Both active electrolocation and electrocommunication are additionally accompanied by stereotypical locomotor patterns. However, the concrete roles of electrical and locomotor patterns during social interactions in mormyrids are not well understood. Here we used a mobile fish dummy that was emitting different types of electrical playback sequences to study following behavior and interaction patterns (electrical and locomotor) between individuals of weakly electric fish. We confronted single individuals of Mormyrus rume proboscirostris with a mobile dummy fish designed to attract fish from a shelter and recruit them into an open area by emitting electrical playbacks of natural discharge sequences. We found that fish were reliably recruited by the mobile dummy if it emitted electrical signals and followed it largely independently of the presented playback patterns. While following the dummy, fish interacted with it spatially by displaying stereotypical motor patterns, as well as electrically, e.g. through discharge regularizations and by synchronizing their own discharge activity to the playback. However, the overall emission frequencies of the dummy were not adopted by the following fish. Instead, social signals based on different temporal patterns were emitted depending on the type of playback. In particular, double pulses were displayed in response to electrical signaling of the dummy and their expression was positively correlated with an animals' rank in the dominance hierarchy. Based on additional analysis of swimming trajectories and stereotypical locomotor behavior patterns, we conclude that the reception and emission of electrical communication signals play a crucial role in mediating social interactions in mormyrid weakly electric fish. PMID- 28902918 TI - Phylogeography and larval spine length of the dragonfly Leucorhinia dubia in Europe. AB - Presence or absence of predators selects for different kind of morphologies. Hence, we expect variation in traits that protect against predators to vary over geographical areas where predators vary in past and present abundance. Abdominal larval spines in dragonfly larvae provide protection against fish predators. We studied geographical variation in larval spine length of the dragonfly Leucorrhinia dubia across Western Europe using a phylogenetic approach. Larvae were raised in a common garden laboratory experiment in the absence of fish predators. Results show that larvae from northern Europe (Sweden and Finland) had significantly longer larval spines compared to larvae from western and central Europe. A phylogeny based on SNP data suggests that short larval spines is the ancestral stage in the localities sampled in this study, and that long spines have evolved in the Fenno-Scandian clade. The role of predators in shaping the morphological differences among the sampled localities is discussed. PMID- 28902916 TI - Targeted N-glycan deletion at the receptor-binding site retains HIV Env NFL trimer integrity and accelerates the elicited antibody response. AB - Extensive shielding by N-glycans on the surface of the HIV envelope glycoproteins (Env) restricts B cell recognition of conserved neutralizing determinants. Elicitation of broadly neutralizing antibodies (bNAbs) in selected HIV-infected individuals reveals that Abs capable of penetrating the glycan shield can be generated by the B cell repertoire. Accordingly, we sought to determine if targeted N-glycan deletion might alter antibody responses to Env. We focused on the conserved CD4 binding site (CD4bs) since this is a known neutralizing determinant that is devoid of glycosylation to allow CD4 receptor engagement, but is ringed by surrounding N-glycans. We selectively deleted potential N-glycan sites (PNGS) proximal to the CD4bs on well-ordered clade C 16055 native flexibly linked (NFL) trimers to potentially increase recognition by naive B cells in vivo. We generated glycan-deleted trimer variants that maintained native-like conformation and stability. Using a panel of CD4bs-directed bNAbs, we demonstrated improved accessibility of the CD4bs on the N-glycan-deleted trimer variants. We showed that pseudoviruses lacking these Env PNGSs were more sensitive to neutralization by CD4bs-specific bNAbs but remained resistant to non neutralizing mAbs. We performed rabbit immunogenicity experiments using two approaches comparing glycan-deleted to fully glycosylated NFL trimers. The first was to delete 4 PNGS sites and then boost with fully glycosylated Env; the second was to delete 4 sites and gradually re-introduce these N-glycans in subsequent boosts. We demonstrated that the 16055 PNGS-deleted trimers more rapidly elicited serum antibodies that more potently neutralized the CD4bs-proximal-PNGS-deleted viruses in a statistically significant manner and strongly trended towards increased neutralization of fully glycosylated autologous virus. This approach elicited serum IgG capable of cross-neutralizing selected tier 2 viruses lacking N-glycans at residue N276 (natural or engineered), indicating that PNGS deletion of well-ordered trimers is a promising strategy to prime B cell responses to this conserved neutralizing determinant. PMID- 28902917 TI - Hsp70/J-protein machinery from Glossina morsitans morsitans, vector of African trypanosomiasis. AB - Tsetse flies (Glossina spp.) are the sole vectors of the protozoan parasites of the genus Trypanosoma, the causative agents of African Trypanosomiasis. Species of Glossina differ in vector competence and Glossina morsitans morsitans is associated with transmission of Trypanosoma brucei rhodesiense, which causes an acute and often fatal form of African Trypanosomiasis. Heat shock proteins are evolutionarily conserved proteins that play critical roles in proteostasis. The activity of heat shock protein 70 (Hsp70) is regulated by interactions with its J protein (Hsp40) co-chaperones. Inhibition of these interactions are emerging as potential therapeutic targets. The assembly and annotation of the G. m. morsitans genome provided a platform to identify and characterize the Hsp70s and J proteins, and carry out an evolutionary comparison to its well-studied eukaryotic counterparts, Drosophila melanogaster and Homo sapiens, as well as Stomoxys calcitrans, a comparator species. In our study, we identified 9 putative Hsp70 proteins and 37 putative J-proteins in G. m. morsitans. Phylogenetic analyses revealed three evolutionarily distinct groups of Hsp70s, with a closer relationship to orthologues from its blood-feeding dipteran relative Stomoxys calcitrans. G. m. morsitans also lacked the high number of heat inducible Hsp70s found in D. melanogaster. The potential localisations, functions, domain organisations and Hsp70/J-protein partnerships were also identified. A greater understanding of the heat shock 70 (Hsp70) and J-protein (Hsp40) families in G. m. morsitans could enhance our understanding of the cell biology of the tsetse fly. PMID- 28902919 TI - Factors associated with pulmonary impairment in HIV-infected South African adults. AB - BACKGROUND: HIV-infected individuals have increased risk of developing obstructive lung disease (OLD). Studies from developed countries report high viral load, low CD4 counts, and anti-retroviral therapy (ART) to be associated with OLD; but these findings may not be generalizable to populations in resource limited settings. METHODS: We conducted a prospective cohort study of lung function in 730 HIV-infected black South African adults. Pre-bronchodilator spirometry was performed at enrollment and repeated annually for three years. Logistic regression models were used to identify factors associated with OLD, defined as FEV1/FVC<0.70, at enrollment. Excess annual declines in FEV1 and FVC were modelled as the product-term of follow-up time and exposures using random effects regression. RESULTS: Median (IQR) age at enrollment was 36 (32-41) years, 85% were female and 30% ever-smoked with a median (IQR) exposure of 3 (1-6) pack years. Median (IQR) CD4 count and viral load at enrollment were 372 (261-518) cells/mm3 and 2655 (91-13,548) copies/mL respectively. Overall, 25% were receiving ART at enrollment, 16% of whom reported at least 6 months of ART receipt. OLD was found in 35 (5%) at enrollment. Increasing age (aOR = 2.08 per 10-years [95%CI 1.22-3.57], p = 0.007), current smoking (aOR = 3.55 [95%CI 1.20 10.53], p = 0.02), and CRP (aOR = 1.01 per unit-increase [95%CI 1.00-1.03], p = 0.04) were significantly associated with OLD at enrollment; while increasing CD4 count (aOR = 1.02 per-100 cells/mm3 [95%CI 0.85-1.22], p = 0.82), viral load (aOR = 0.67 per log-increase [95%CI 0.43-1.10], p = 0.12) and receipt of ART (aOR = 0.57 [95%CI 0.18-1.75], p = 0.32) were not. The median (IQR) follow-up time was 18 (12-24) months. Participants with a history of tuberculosis (TB) had a 35 mL (95%CI 2-68, p = 0.03) and 57 mL (95%CI 19-96, p = 0.003) per year excess loss of FEV1 and FVC respectively. CONCLUSION: Prevalent OLD was associated with older age, current smoking and higher CRP levels, but not CD4 counts and ART, in HIV infected South African adults. Better understanding of the long-term effects of TB, smoking and inflammation on lung function in HIV-infected populations is urgently needed. PMID- 28902920 TI - Use of airborne lidar data to improve plant species richness and diversity monitoring in lowland and mountain forests. AB - We explored the potential of airborne laser scanner (ALS) data to improve Bayesian models linking biodiversity indicators of the understory vegetation to environmental factors. Biodiversity was studied at plot level and models were built to investigate species abundance for the most abundant plants found on each study site, and for ecological group richness based on light preference. The usual abiotic explanatory factors related to climate, topography and soil properties were used in the models. ALS data, available for two contrasting study sites, were used to provide biotic factors related to forest structure, which was assumed to be a key driver of understory biodiversity. Several ALS variables were found to have significant effects on biodiversity indicators. However, the responses of biodiversity indicators to forest structure variables, as revealed by the Bayesian model outputs, were shown to be dependent on the abiotic environmental conditions characterizing the study areas. Lower responses were observed on the lowland site than on the mountainous site. In the latter, shade tolerant and heliophilous species richness was impacted by vegetation structure indicators linked to light penetration through the canopy. However, to reveal the full effects of forest structure on biodiversity indicators, forest structure would need to be measured over much wider areas than the plot we assessed. It seems obvious that the forest structure surrounding the field plots can impact biodiversity indicators measured at plot level. Various scales were found to be relevant depending on: the biodiversity indicators that were modelled, and the ALS variable. Finally, our results underline the utility of lidar data in abundance and richness models to characterize forest structure with variables that are difficult to measure in the field, either due to their nature or to the size of the area they relate to. PMID- 28902921 TI - Correction: CD4 is expressed on a heterogeneous subset of hematopoietic progenitors, which persistently harbor CXCR4 and CCR5-tropic HIV proviral genomes in vivo. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006509.]. PMID- 28902923 TI - Molecular, microbiological and clinical characterization of Clostridium difficile isolates from tertiary care hospitals in Colombia. AB - In Colombia, the epidemiology and circulating genotypes of Clostridium difficile have not yet been described. Therefore, we molecularly characterized clinical isolates of C.difficile from patients with suspicion of C.difficile infection (CDI) in three tertiary care hospitals. C.difficile was isolated from stool samples by culture, the presence of A/B toxins were detected by enzyme immunoassay, cytotoxicity was tested by cell culture and the antimicrobial susceptibility determined. After DNA extraction, tcdA, tcdB and binary toxin (CDTa/CDTb) genes were detected by PCR, and PCR-ribotyping performed. From a total of 913 stool samples collected during 2013-2014, 775 were included in the study. The frequency of A/B toxins-positive samples was 9.7% (75/775). A total of 143 isolates of C.difficile were recovered from culture, 110 (76.9%) produced cytotoxic effect in cell culture, 100 (69.9%) were tcdA+/tcdB+, 11 (7.7%) tcdA /tcdB+, 32 (22.4%) tcdA-/tcdB- and 25 (17.5%) CDTa+/CDTb+. From 37 ribotypes identified, ribotypes 591 (20%), 106 (9%) and 002 (7.9%) were the most prevalent; only one isolate corresponded to ribotype 027, four to ribotype 078 and four were new ribotypes (794,795, 804,805). All isolates were susceptible to vancomycin and metronidazole, while 85% and 7.7% were resistant to clindamycin and moxifloxacin, respectively. By multivariate analysis, significant risk factors associated to CDI were, staying in orthopedic service, exposure to third-generation cephalosporins and staying in an ICU before CDI symptoms; moreover, steroids showed to be a protector factor. These results revealed new C. difficile ribotypes and a high diversity profile circulating in Colombia different from those reported in America and European countries. PMID- 28902922 TI - Molecular clustering of patients with diabetes and pulmonary tuberculosis: A systematic review and meta-analysis. AB - INTRODUCTION: Many studies have explored the relationship between diabetes mellitus (DM) and tuberculosis (TB) demonstrating increased risk of TB among patients with DM and poor prognosis of patients suffering from the association of DM/TB. Owing to a paucity of studies addressing this question, it remains unclear whether patients with DM and TB are more likely than TB patients without DM to be grouped into molecular clusters defined according to the genotype of the infecting Mycobacterium tuberculosis bacillus. That is, whether there is convincing molecular epidemiological evidence for TB transmission among DM patients. Objective: We performed a systematic review and meta-analysis to quantitatively evaluate the propensity for patients with DM and pulmonary TB (PTB) to cluster according to the genotype of the infecting M. tuberculosis bacillus. MATERIALS AND METHODS: We conducted a systematic search in MEDLINE and LILACS from 1990 to June, 2016 with the following combinations of key words "tuberculosis AND transmission" OR "tuberculosis diabetes mellitus" OR "Mycobacterium tuberculosis molecular epidemiology" OR "RFLP-IS6110" OR "Spoligotyping" OR "MIRU-VNTR". Studies were included if they met the following criteria: (i) studies based on populations from defined geographical areas; (ii) use of genotyping by IS6110- restriction fragment length polymorphism (RFLP) analysis and spoligotyping or mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) or other amplification methods to identify molecular clustering; (iii) genotyping and analysis of 50 or more cases of PTB; (iv) study duration of 11 months or more; (v) identification of quantitative risk factors for molecular clustering including DM; (vi) > 60% coverage of the study population; and (vii) patients with PTB confirmed bacteriologically. The exclusion criteria were: (i) Extrapulmonary TB; (ii) TB caused by nontuberculous mycobacteria; (iii) patients with PTB and HIV; (iv) pediatric PTB patients; (v) TB in closed environments (e.g. prisons, elderly homes, etc.); (vi) diabetes insipidus and (vii) outbreak reports. Hartung-Knapp-Sidik-Jonkman method was used to estimate the odds ratio (OR) of the association between DM with molecular clustering of cases with TB. In order to evaluate the degree of heterogeneity a statistical Q test was done. The publication bias was examined with Begg and Egger tests. Review Manager 5.3.5 CMA v.3 and Biostat and Software package R were used. RESULTS: Selection criteria were met by six articles which included 4076 patients with PTB of which 13% had DM. Twenty seven percent of the cases were clustered. The majority of cases (48%) were reported in a study in China with 31% clustering. The highest incidence of TB occurred in two studies from China. The global OR for molecular clustering was 0.84 (IC 95% 0.40-1.72). The heterogeneity between studies was moderate (I2 = 55%, p = 0.05), although there was no publication bias (Beggs test p = 0.353 and Eggers p = 0.429). CONCLUSION: There were very few studies meeting our selection criteria. The wide confidence interval indicates that there is not enough evidence to draw conclusions about the association. Clustering of patients with DM in TB transmission chains should be investigated in areas where both diseases are prevalent and focus on specific contexts. PMID- 28902924 TI - Molecular analysis of CIB4 gene and protein in Kermani sheep. AB - The human calcium- and integrin-binding protein (CIB) family is composed of CIB1, CIB2, CIB3, and CIB4 proteins and the CIB4 gene affects fertility. Kermani sheep is one of the most important breeds of Iranian sheep breeds. The aim of this study was to analyze for the first time molecular characteristics of the CIB4 gene and protein in Kermani sheep. Different tissues were collected from the Kermani sheep and real time PCR was performed. The PCR products were sequenced, comparative analyses of the nucleotide sequences were performed, a phylogenetic tree was constructed, and different characteristics of CIB4 proteins were predicted. Real time PCR results showed that the CIB4 gene is expressed only in testis of Kermani sheep. The cDNA nucleotide sequence was identical with small tail Han sheep, cattle, goat, camel, horse, dog, mouse and human, respectively 100, 99, 99, 98, 98, 96, 96, and 96%. Hence, it can be suggested that the CIB4 gene plays a role in male fertility. Based on the phylogenetic analysis, sheep CIB4 gene has a close relationship with goat and cattle first, and then with camel and whale. Although we demonstrated that CIB4 is a testis-specific gene, expressed only in the testis and it interacts with other proteins, the mechanisms by which CIB4 expression is regulated need to be elucidated. PMID- 28902925 TI - Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension. AB - Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR related CH-PAH. PMID- 28902926 TI - Down-regulation of single-stranded DNA-binding protein 1 expression induced by HCMV infection promotes lipid accumulation in cells. AB - The objective of this study was to observe the infection of human cytomegalovirus (HCMV) to human umbilical vein endothelial cells, and its effect on the expression of single-stranded DNA-binding protein (SSBP1) and on lipid metabolism in endothelial cells. We screened the differential expression of mRNAs after HCMV infection by suppression subtractive hybridization and the expression levels of SSBP1 mRNA and protein after HCMV infection by real-time PCR and western blot. After verification of successful infection by indirect immunofluorescent staining and RT-PCR, we found a differential expression of lipid metabolism-related genes including LDLR, SCARB, CETP, HMGCR, ApoB and LPL induced by HCMV infection. The expression levels of SSBP1 mRNA and protein after HCMV infection were significantly down-regulated. Furthermore, we found that upregulation of SSBP1 inhibited the expression of atherosclerosis-associated LDLR, SCARB, HMGCR, CETP as well as the accumulation of lipids in the cells. The results showed that the inhibition of SSBP1 by HCMV infection promotes lipid accumulation in the cells. PMID- 28902927 TI - Bradykinin, insulin, and glycemia responses to exercise performed above and below lactate threshold in individuals with type 2 diabetes. AB - The aim of this study was to analyze the acute responses of bradykinin, insulin, and glycemia to exercise performed above and below lactate threshold (LT) in individuals with type 2 diabetes mellitus (T2D). Eleven participants with a diagnosis of T2D randomly underwent three experimental sessions 72 h apart: 1) 20 min of exercise performed at 120% of LT (120%LT), 2) 20 min of exercise performed at 80% of LT (80%LT), and 3) 20 min of control session. Blood glucose was analyzed before, during, and at 45 min post-exercise. Bradykinin and insulin were analyzed before and at 45 min post-exercise. Both exercise sessions elicited a parallel decrease in glucose level during exercise (P<=0.002), with a greater decrease being observed for 120%LT (P=0.005). Glucose decreased 22.7 mg/dL (95%CI=10.3 to 35, P=0.001) at the 45 min post-exercise recovery period for 80%LT and decreased 31.2 mg/dL (95%CI=18.1 to 44.4, P<0.001) for 120%LT (P=0.004). Insulin decreased at post-exercise for 80%LT (P=0.001) and control (P<=0.035). Bradykinin increased at 45 min post-exercise only for 80%LT (P=0.013), but was unrelated to the decrease in glucose (r=-0.16, P=0.642). In conclusion, exercise performed above and below LT reduced glycemia independently of insulin, but exercise above LT was more effective in individuals with T2D. However, these changes were unrelated to the increase in circulating bradykinin. PMID- 28902928 TI - Synthesis and evaluation of coumarin derivatives against human lung cancer cell lines. AB - Series of novel coumarin derivatives [I (a-d) and II (a-d)] were successfully synthesized and their structures were determined based on infrared 1H-nuclear magnetic resonance (NMR), HRMS, and single crystal X-ray crystallography. Additionally, the new synthesized compounds were evaluated to identify the molecular characteristics that contribute to their cytotoxicity, which was tested against SK-LU-1, SPC-A-1 and 95D human lung cancer cell lines, using the MTT assay. The results of this study showed that compounds Ic, Id, IIc, and IId exhibited an efficient percentage of inhibition of cell proliferation. PMID- 28902929 TI - Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface. AB - Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor beta (TGF-beta), VDR and 1 alpha-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-beta were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA. PMID- 28902930 TI - Association between polymorphisms in the APOB gene and hyperlipidemia in the Chinese Yugur population. AB - We investigated the influence of apolipoprotein B gene (APOB) variants on the risk of hyperlipidemia (HL) in 631 middle-aged and elderly members of the Chinese Yugur population (HL, n=336; normolipidemia, n=295). APOB polymorphisms were identified using mass spectrometry, and five single nucleotide polymorphisms (rs1042034, rs2163204, rs512535, rs676210, and rs679899) and serum lipids were further analyzed. rs1042034 and rs676210 were significantly associated with HL (P<0.05). Compared with the GG or AA genotype, individuals with AG and AG+AA in rs1042034 and with AG and AG+GG in rs676210 had a 1.67-fold (95%CI=1.20 2.33),1.63-fold (95%CI=1.19-2.24), 1.72-fold (95%CI=1.24-2.40), and 1.67-fold (95%CI=1.21-2.291) increased risk of high HL, respectively. rs2163204 was in strong linkage disequilibrium with rs1042034, rs676210, and rs679899, and strong disequilibrium was observed between rs1042034 and rs676210 (D'>0.9). Compared with the GTGAA haplotype, haplotypes ATGGA and ATAGG were more strongly associated with HL [odds ratio (OR)=1.46, 95%CI=0.02-2.11; OR=1.63, 95%CI=1.03 2.60, respectively]. The risk factors age (P=0.008), body mass index (P<0.0001), GA+GG genotype in rs676210 (P=0.009), and alcohol consumption (P=0.056) contributed strongly to HL development. The A allele of rs1042034 and the G allele of rs676210 may thus predispose middle-aged and elderly members of the Chinese Yugur population to HL in combination with other genetic or nutritional factors, and could be used as new genetic markers for HL screening. PMID- 28902931 TI - Binge drinking: a pattern associated with a risk of problems of alcohol use among university students. AB - Objective:: to evaluate problems associated with alcohol use among university students who reported binge drinking in comparison to students who consumed alcohol without binging. Method:: a cross-sectional study among university students (N=2,408) who accessed the website about alcohol use. Logistic and linear regression models were included in the statistical analyzes. Results:: alcohol use in the last three months was reported by 89.2% of university students; 51.6% reported binge drinking. Compared to students who did not binge drink, university students who presented this pattern were more likely to report all evaluated problems, among them: black out (aOR: 5.4); having academic problems (aOR: 3.4); acting impulsively and having regrets (aOR: 2.9); getting involved in fights (aOR: 2.6); drinking and driving (aOR: 2.6) and accepting a ride with someone who had drunk alcohol (aOR: 1.8). Students who binged also had higher scores on the Alcohol Use Disorders Identification Test (b=4.6; p<0.001), more negative consequences (b=1.0; p<0.001) and a reduced perception of the negativity of the consequences (b=-0.5; p<0.01). Conclusion:: binge drinking was associated with an increase in the chances of manifesting problems related to alcohol use. The conclusions of this study cannot be generalized for all of the Brazilian population. Objetivo:: avaliar problemas associados ao uso de alcool entre universitarios que relataram binge drinking em comparacao a estudantes que consumiram alcool sem binge drinking. Metodo:: estudo transversal entre universitarios (N=2.408) que acessaram website sobre o uso de alcool. Nas analises estatisticas incluiram-se modelos de regressao logistica e linear. Resultados:: o uso de alcool, nos ultimos tres meses, foi relatado por 89,2% dos universitarios e 51,6% referiram uso binge. Comparados a estudantes que nao praticaram binge, universitarios que apresentaram esse padrao tiveram maior chance de relatar todos os problemas avaliados, entre eles: incapacidade de lembrar o que aconteceu (aOR:5,4); problemas academicos (aOR:3,4); agir impulsivamente e se arrepender (aOR:2,9); envolver-se em brigas (aOR:2,6); dirigir apos beber (aOR:2,6) e pegar carona com alguem que bebeu (aOR:1,8). Estudantes que consumiram alcool no padrao binge tambem apresentaram maior pontuacao no Alcohol Use Disorders Identification Test (b=4,6; p<0,001), mais consequencias negativas (b=1,0; p<0,001) e menos percepcao da negatividade das consequencias (b=-0,5; p<0,01). Conclusao:: a pratica de binge drinking esteve associada ao aumento das chances de manifestacao de problemas relacionados ao uso de alcool. As conclusoes deste estudo nao podem ser reproduzidas para toda realidade brasileira. Objetivo:: evaluar problemas asociados al uso de alcohol entre estudiantes universitarios que relataron binge drinking en comparacion a estudiantes que consumieron alcohol sin binge drinking. Metodo:: estudio transversal entre estudiantes universitarios (N=2.408) que visitaron una pagina web sobre el uso de alcohol. En los analisis estadisticos, fueron incluidos modelos de regresion logistica y linear. Resultados:: el uso de alcohol, en los ultimos tres meses, fue relatado por 89,2% de los estudiantes universitarios, y entre ellos 51,6% relataron uso binge. En comparacion a estudiantes universitarios que no practicaron binge, los estudiantes que presentaron ese estandar tuvieron una mayor oportunidad de relatar todos los problemas evaluados, entre ellos: incapacidad de recordar lo que sucedio (aOR:5,4); problemas academicos (aOR:3,4); actuar por impulso y arrepentirse (aOR:2,9); involucrarse en peleas (aOR:2,6); manejar despues de beber (aOR:2,6) y compartieron viaje con alguien que bebio (aOR:1,8). Estudiantes que consumieron alcohol dentro del estandar binge tambien presentaron una mayor puntuacion en el Alcohol Use Disorders Identification Test (b=4,6; p<0,001), mas consecuencias negativas (b=1,0; p<0,001) y menor percepcion de la negatividad de las consecuencias (b= 0,5; p<0,01). Conclusion:: la practica de binge drinking estuvo asociada al aumento de las oportunidades de manifestacion de problemas relacionados al alcohol. Las conclusiones de este estudio no pueden ser adaptadas a toda la realidad brasilena. PMID- 28902932 TI - Non-pharmacological interventions to promote the sleep of patients after cardiac surgery: a systematic review. AB - Objective:: to analyze evidence available in the literature concerning non pharmacological interventions that are effective to treat altered sleep patterns among patients who underwent cardiac surgery. Method:: systematic review conducted in the National Library of Medicine-National Institutes of Health, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences Literature, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO databases, and also grey literature. Results:: ten controlled, randomized clinical trials were included in this review. Non-pharmacological interventions were grouped into three main categories, namely: relaxation techniques, devices or equipment to minimize sleep interruptions and/or induce sleep, and educational strategies. Significant improvement was found in the scores assessing sleep quality among studies testing interventions such as earplugs, sleeping masks, muscle relaxation, posture and relaxation training, white noise, and educational strategies. In regard to the studies' methodological quality, high quality studies as established by Jadad scoring were not found. Conclusion:: significant improvement was found among the scores assessing sleep in the studies testing interventions such as earplugs, sleeping masks, muscle relaxation, posture and relaxation training, white noise and music, and educational strategies. Objetivo:: analisar as evidencias disponiveis, na literatura, sobre as intervencoes nao farmacologicas, efetivas para o tratamento da alteracao do padrao do sono em pacientes submetidos a cirurgia cardiaca. Metodo:: revisao sistematica realizada por meio de busca nas bases de dados National Library of Medicine National Institutes of Health, Cochrane Central Register of Controlled Trials, Literatura Latino-Americana e do Caribe em Ciencias da Saude, Scopus, Embase, Cumulative Index to Nursing and Allied Health Literature e PsycINFO, e na literatura cinzenta. Resultados:: dez ensaios clinicos controlados e randomizados foram incluidos na revisao. Constatou se que as intervencoes nao farmacologicas agruparam-se em tres categorias principais, a saber: tecnicas de relaxamento, dispositivos ou equipamentos para minimizar a interrupcao do sono e/ou induzir o sono e estrategias educacionais. Houve melhoria significativa nos escores de avaliacao do sono entre os estudos que testaram intervencoes como tampoes de ouvidos, mascara de olhos, relaxamento muscular, treinamento de postura e relaxamento, producao sonora e estrategia educacional. Em relacao a qualidade metodologica dos estudos, nao foram encontrados estudos considerados de alta qualidade pelo escore de Jadad. Conclusao:: houve melhora significativa nos escores de avaliacao do sono em estudos que avaliaram intervencoes como tampoes de ouvidos, mascara de olhos, relaxamento muscular, treinamento de postura e relaxamento, producao sonora e estrategia educacional. Objetivo:: analizar las evidencias disponibles en la literatura sobre las intervenciones no farmacologicas, eficientes para el tratamiento de la alteracion del patron del sueno en pacientes sometidos a una cirugia cardiaca. Metodo:: revision sistematica realizada mediante busqueda en las bases de datos de la Libreria Nacional de Medicina (National Library of Medicine), de los Institutos Nacionales de la Salud (National Institutes of Health), del Registro Central Cochrane de Ensayos Controlados (Cochrane Central Register of Controlled Trials), de la literatura latinoamericana y del Caribe, en Ciencias de la Salud, Scopus, Embase, Indice Acumulado de Enfermeria y Literatura en Ciencias de la Salud, CINAHL (Cumulative Index to Nursing and Allied Health Literature) y PsycINFO, y en la literatura gris. Resultados:: se incluyeron en la revision diez ensayos clinicos controlados y aleatorizados. Se constato que las intervenciones no farmacologicas se agruparon en tres categorias principales: tecnicas de relajacion, dispositivos o equipos para minimizar la interrupcion del sueno y/o inducirlo, y estrategias educativas. Hubo una mejora significativa en las puntuaciones de la evaluacion del sueno entre los estudios que probaron las intervenciones como tapon de oidos, mascara de ojos, relajacion muscular, entrenamiento de postura y relajacion, produccion sonora y estrategia educacional. Con respecto a la calidad metodologica de los estudios, no se hallaron los considerados de alta calidad mediante la puntuacion de Jadad. Conclusion:: hubo una mejora significativa en las puntuaciones de la evaluacion del sueno en los estudios que evaluaron intervenciones como tapones de oidos, mascara de ojos, relajacion muscular, entrenamiento de postura y relajacion, produccion sonora y estrategia educacional. PMID- 28902933 TI - Prototype of a computerized scale for the active search for potential organ donors. AB - Objective:: to develop a prototype of a computerized scale for the active search for potential organ and tissue donors. Method:: methodological study, with the analysis of 377 electronic medical records of patients who died due to encephalic death or cardiorespiratory arrest in the intensive care units of a tertiary hospital. Among the deaths due to cardiorespiratory arrest, the study aimed to identify factors indicating underreported encephalic death cases. The Acute Physiology and Chronic Health Evaluation II and Sepsis Related Organ Failure Assessment severity indexes were applied in the protocols. Based on this, a scale was built and sent to five experts for assessment of the scale content, and subsequently, it was computerized by using a prototyping model. Results:: 34 underreported encephalic death cases were identified in the medical records of patients with cardiorespiratory arrest. Statistically significant differences were found in the Wilcoxon test between the scores of hospital admissions in the intensive care unit and the opening of the encephalic death protocol for both severity indexes. Conclusion:: the prototype was effective for identifying potential organ donors, as well as for the identification of the degree of organ dysfunction in patients with encephalic death. Objetivo:: desenvolver prototipo de escala informatizada para busca ativa de potenciais doadores de orgaos e tecidos. Metodo:: pesquisa metodologica, com analise de 377 prontuarios eletronicos de pacientes que evoluiram a obito, por morte encefalica, ou parada cardiorrespiratoria, nas unidades de terapia intensiva de hospital terciario. Nos obitos por parada cardiorrespiratoria, buscou-se identificar fatores que indicassem subnotificacao de morte encefalica. Nos protocolos, foram aplicados os indices de gravidade Acute Physiology and Chronic Health Evaluation II e Sepsis Related Organ Failure Assessment. A partir disso, construiu-se a escala que foi encaminhada a cinco especialistas, para avaliacao de conteudo, e, posteriormente, foi informatizada por modelo de prototipacao. Resultados:: foram identificadas 34 subnotificacoes de morte encefalica nos prontuarios dos casos de parada cardiorrespiratoria. O teste de Wilcoxon demonstrou diferenca estatisticamente significativa entre os escores de admissao em unidade de terapia intensiva e abertura do protocolo de morte encefalica, para ambos os indices de gravidade. Conclusao:: o prototipo foi efetivo para identificacao de potenciais doadores, bem como o grau de disfuncao organica de pacientes em morte encefalica. Objetivo:: desarrollar un prototipo de escala informatizada para la busqueda activa de potenciales donantes de organos y tejidos. Metodo:: investigacion metodologica, con el analisis de 377 registros medicos electronicos de pacientes, que fallecieron por muerte encefalica o paro cardiorrespiratorio, en las unidades de cuidados intensivos de un hospital terciario. Entre las muertes por paro cardiorrespiratorio, se busco identificar los factores que indicasen subnotificacion de muerte encefalica. Las puntuaciones de los indices de gravedad Acute Physiology and Chronic Health Evaluation II y Sepsis Related Organ Failure Assessment se aplicaron en los protocolos. A partir de eso, la escala fue construida y enviada a cinco expertos para la evaluacion del contenido, y posteriormente, fue informatizada mediante un modelo de prototipacion. Resultados:: se identificaron 34 casos de subnotificacion de muerte encefalica en los registros medicos de los casos de paro cardiorrespiratorio. Se encontraron diferencias estadisticamente significativas en la prueba de Wilcoxon, entre las puntuaciones de los ingresos hospitalarios en unidad de cuidados intensivos y apertura del protocolo de muerte encefalica para ambos indices de gravedad. Conclusion:: el prototipo fue eficaz para la identificacion de potenciales donantes, asi como para la identificacion del grado de disfuncion organica en pacientes con muerte encefalica. PMID- 28902934 TI - Assessment and management of pain in newborns hospitalized in a Neonatal Intensive Care Unit: a cross-sectional study. AB - Objective:: to determine the frequency of pain, to verify the measures adopted for pain relief during the first seven days of hospitalization in the Neonatal Intensive Care Unit and to identify the type and frequency of invasive procedures to which newborns are submitted. Method:: cross-sectional retrospective study. Out of the 188 hospitalizations occurred during the 12-month period, 171 were included in the study. The data were collected from the charts and the presence of pain was analyzed based on the Neonatal Infant Pain Scale and on nursing notes suggestions of pain. For statistical analysis, the Statistical Package for the Social Sciences was used, and the significance level was set at 5%. Results:: there was at least one record of pain in 50.3% of the hospitalizations, according to the pain scale adopted or nursing note. The newborns underwent a mean of 6.6 invasive procedures per day. Only 32.5% of the pain records resulted in the adoption of pharmacological or non-pharmacological intervention for pain relief. Conclusion:: newborns are frequently exposed to pain and the low frequency of pharmacological or non-pharmacological interventions reinforces the undertreatment of this condition. Objetivo:: determinar a frequencia de dor e verificar as medidas realizadas para seu alivio durante os sete primeiros dias de internacao na Unidade de Terapia Intensiva Neonatal, bem como identificar o tipo e frequencia de procedimentos invasivos aos quais os recem-nascidos foram submetidos. Metodo:: estudo retrospectivo transversal. Das 188 internacoes ocorridas no periodo estipulado de 12 meses, 171 foram incluidas na pesquisa. Os dados foram coletados a partir dos prontuarios e a presenca de dor foi analisada tanto com base na escala de dor Neonatal Infant Pain Scale quanto mediante anotacao de enfermagem sugestiva de dor. Para analise estatistica, utilizou-se o programa Statistical Package for the Social Sciences, adotando-se nivel de significancia de 5%. Resultados:: em 50,3% das internacoes houve ao menos um registro de dor, conforme escala de dor adotada ou anotacao de enfermagem. Os recem-nascidos foram submetidos a media de 6,6 procedimentos invasivos por dia. Apenas 32,5% dos registros de dor resultaram na adocao de condutas farmacologicas ou nao farmacologicas para seu alivio. Conclusao:: observa-se que os recem nascidos sao frequentemente expostos a dor e a baixa frequencia de intervencoes farmacologicas ou nao farmacologicas reforca o subtratamento dessa condicao. Objetivo:: determinar la frecuencia del dolor, comprobar las medidas tomadas para su alivio durante los siete primeros dias de internacion en una Unidad de Terapia Intensiva Neonatal e identificar el tipo de procedimientos invasivos y la frecuencia a que se sometieron los recien nacidos. Metodo:: estudio retrospectivo transversal. De las 188 internaciones realizadas en el periodo estipulado de 12 meses, se incluyeron 171 en la investigacion. Los datos se recolectaron a partir de los prontuarios; la presencia de dolor se analizo segun la Escala de Valorizacion del Dolor en el Neonato (Neonatal Infant Pain Scale) y las notas de enfermeria sobre el dolor. Para el analisis estadistico, se utilizo el programa 'Paquete estadistico para las ciencias sociales' (Statistical Package for the Social Sciences), adoptandose el nivel de significacion del 5%. Resultados:: en el 50,3% de las internaciones hubo al menos un registro de dolor, segun la escala de dolor adoptada o las notas de la enfermeria. Se sometio a los recien nacidos a un promedio de 6,6 procedimientos invasivos por dia. Solo el 32,5% de los registros de dolor resultaron en la adopcion de conductas farmacologicas o no farmacologicas para su alivio. Conclusion:: se observa que los recien nacidos a menudo estan expuestos al dolor, y la frecuencia baja de intervenciones farmacologicas o de las no farmacologicas refuerza el subtratamiento de dicha condicion. PMID- 28902935 TI - Perconditioning combined with postconditioning on kidney ischemia and reperfusion. AB - Purpose:: To evaluate if combination of perconditioning and postconditioning provides improved renal protection compared to perconditioning alone in a model of renal reperfusion injury. Methods: : Thirty rats were assigned into 6 groups: normality; sham; ischemia and reperfusion; postconditioning; perconditioning; perconditioning + postconditioning. Animals were subjected to right nephrectomy and left renal ischemia for 30 minutes. Postconditioning consisted of 3 cycles of 5 min renal perfusion followed by 5 min of renal ischemia after major ischemic period. Perconditioning consisted of 3 cycles of 5 min hindlimb ischemia followed by 5 min of hindlimb perfusion contemporaneously to renal major ischemic period. After 24 hours, kidney was harvested and blood collected to measure urea and creatinine. Results: : Perconditioning obtained better values for creatinine and urea level than only postconditioning (p<0.01); performing both techniques contemporaneously had no increased results (p>0.05). Regarding tissue structure, perconditioning was the only technique to protect the glomerulus and tubules (p<0.05), while postconditioning protected only the glomerulus (p<0.05). Combination of both techniques shows no effect on glomerulus or tubules (p>0.05). Conclusions:: Perconditioning had promising results on ischemia and reperfusion induced kidney injury, enhanced kidney function and protected glomerulus and tubules. There was no additive protection when postconditioning and perconditioning were combined. PMID- 28902936 TI - Corneal angiogenesis based on different protocols of alkaline cauterization in murine models. AB - Purpose: : To establish and compare protocols of alkaline cauterization for inducing corneal angiogenesis in murine models. Methods: : Twenty-four adult Wistar rats were distributed into four groups (G1, G2, G3, and G4). The right eye cornea from each rat was cauterized using filter paper (3 mm), soaked in a solution of silver and potassium nitrates (3:1). Cauterization times were 10 (G1 and G4), or 20 seconds (G2 and G3). Cauterized corneas were washed with Ringer's lactate solution. The filter paper was either removed before washing (G1 and G2), or kept on the corneas (G3 and G4). Corneas were photographed at multiple time points (2, 4, 6, 8, 11, 13, and 15 days after the procedure), and neovascularization parameters were assayed. Results: : Neovascularization was observed in 66% of G1 corneas, and 100% of G2, G3, and G4 corneas. On day 15, G1 corneas showed smaller vascularized areas (12.63 +/- 12.59%) compared to those in the G3 (41.95 +/- 17.32%) and G4 (33 +/- 11.74%) (P < 0.05) groups. Conclusions:: The silver and potassium nitrate solution effectively induced corneal angiogenesis. The G2, G3, and G4 protocols showed excellent reproducibility, and induced vascularization in 100% of corneas. PMID- 28902937 TI - Inside-out and standard vein grafts associated with platelet-rich plasma (PRP) in sciatic nerve repair. A histomorphometric study. AB - Purpose:: To evaluated the tubulization technique with standard and inside-out vein, filled or not with platelet-rich plasma (PRP), in sciatic nerve repair. Methods:: Seventy male Wistar rats were randomly divided into five groups: IOVNF (Inside-Out Vein with No Filling); IOVPRP (Inside-Out Vein filled with PRP); SVNF (Standard Vein with No Filling); SVPRP (Standard Vein filled with PRP); Sham (Control). The left external jugular vein was used as graft in a 10 mm nervous gap. Results:: In the morphological analysis of all groups, myelinated nerve fibers with evident myelin sheath, neoformation of the epineurium and perineurium, organization of intraneural fascicles and blood vessels were observed. In the morphometry of the distal stump fibers, SVPRP group had the highest means regarding fiber diameter (3.63+/-0.42 MUm), axon diameter (2.37+/ 0.31 MUm) and myelin sheath area (11.70+/-0.84 MUm2). IOVPRP group had the highest means regarding axon area (4.39+/-1.16 MUm2) and myelin sheath thickness (0.80+/-0.19 MUm). As for values of the fiber area, IOVNF group shows highest means (15.54+/-0.67 MUm2), but are still lower than the values of the Sham group. Conclusion: : The graft filled with platelet-rich plasma, with use standard (SVPRP) or inside-out vein (IOVPRP), promoted the improvement in axonal regeneration on sciatic nerve injury. PMID- 28902938 TI - Evaluation of the effectiveness of sodium hyaluronate, sesame oil, honey, and silver nanoparticles in preventing postoperative surgical adhesion formation. An experimental study. AB - Purpose:: To evaluate the effectiveness of sodium hyaluronate, sesame oil, honey, and silver nanoparticles in preventing of postoperative surgical adhesion formation. Methods:: Forty male Wistar rats were randomly assigned into five groups with eight rats in each group including control, hyaluronate, sesame, honey and silver groups. After two weeks the animals underwent laparotomy and were evaluated by two different blinded surgeons for severity of adhesions based on the two different classification scoring systems including Nair classification and cumulative adhesion scoring scale. Results:: The scores of severity of adhesions in the hyaluronate and sesame groups were significantly lower than the control group based on the Nair classification (both P-values = 0.02), however based on the cumulative adhesion scoring scale just the score of severity of adhesions in the hyaluronate group was significantly lower than the control group (P-value = 0.02). In the hyaluronate group the severity of adhesions was decreased by 48% based on the cumulative adhesion scoring scale. Conclusions:: Sodium hyaluronate and sesame oil may have a significant effect in preventing postoperative surgical adhesion formation. PMID- 28902939 TI - Hyperin protects against cisplatin-induced liver injury in mice. AB - Purpose:: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. Methods: : Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. Results:: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. Conclusion:: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice. PMID- 28902940 TI - Bacterial translocation and mortality on rat model of intestinal ischemia and obstruction. AB - Purpose:: To develop an experimental model of intestinal ischemia and obstruction followed by surgical resection of the damaged segment and reestablishment of intestinal transit, looking at bacterial translocation and survival. Methods:: After anesthesia, Wistar rats was subject to laparotomy, intestinal ischemia and obstruction through an ileal ligature 1.5cm of ileum cecal valve; and the mesenteric vessels that irrigate upstream of the obstruction site to approximately 7 to 10 cm were ligated. Abdominal wall was closed. Three, six or twenty-four hours after, rats were subject to enterectomy followed by an end to end anastomosis. After 24h, mesenteric lymph nodes, liver, spleen and lung tissues were surgically removed. It was studied survival rate and bacterial translocation. GraphPadPrism statistical program was used. Results:: Animals with intestinal ischemia and obstruction for 3 hours survived 24 hours after enterectomy; 6hx24h: survival was 70% at 24 hours; 24hx24h: survival was 70% and 40%, before and after enterectomy, respectively. Culture of tissues showed positivity on the 6hx24h and negativity on the 3hx24h. Conclusion: : The model that best approached the clinic was the one of 6x24h of ischemia and intestinal obstruction, in which it was observed bacterial translocation and low mortality rate. PMID- 28902941 TI - Intestinal inflammatory and redox responses to the perioperative administration of teduglutide in rats. AB - Purpose: : To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis. Methods:: Wistar rats (n=62) were allocated into four groups: "Ileal Resection and Anastomosis" vs. "Laparotomy", each one split into "Postoperative Teduglutide Administration" vs. "No Treatment"; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1alpha, MCP-1, TNF-alpha, IFN-gamma and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining). Results:: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day. Conclusion: : Those findings suggest an intestinal pro-oxidative and anti inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing. PMID- 28902942 TI - A study on reducing the absorption of lidocaine from the airway in cats. AB - Purpose: : To determine if the combination of lidocaine with epinephrine or gamma globulin would decrease the rate or reduce the amount of local absorption of lidocaine through the airway. Methods:: Twenty adult male cats were randomly and evenly distributed into four groups: 1) Group LG: lidocaine administered with gamma globulin; 2) Group LS: lidocaine administered with physiological saline); 3) Group LE: lidocaine administered with epinephrine; 4) Group C: control group. Invasive blood pressure, heart rate, and concentration of lidocaine were recorded before and after administration. Results: : The peak of plasma concentrations appeared difference (Group LG: 1.39 +/- 0.23 mg/L; Group LS: 1.47 +/- 0.29 mg/L and Group LE: 0.99 +/- 0.08 mg/L). Compared to Group C, there were significant differences in the average heart rate of Groups LG, LS, and LE (P < 0.05). The average systolic blood pressures were significantly different when each group was compared to Group C (P < 0.05). The biological half-life, AUC0-120, peak time, and half-life of absorption among the three groups have not presented statistically significant differences (P > 0.05). Conclusion:: Administering lidocaine in combination with gamma globulin through airway causes significant decrease the rate and reduce the amount of local absorption of lidocaine in cats. PMID- 28902943 TI - Use of fibrinogen and thrombin sponge in pediatric split liver transplantation. AB - Purpose:: To analyze the use of this sponge in pediatric patients undergoing split-liver transplantation. Methods:: Retrospective study, including 35 pediatric patients undergoing split-liver transplantation, divided into two groups according to the use of the sponge: 18 patients in Group A (no sponge) and 17 in Group B (with sponge). Results: : The characteristics of recipients and donors were similar. We observed greater number of reoperation due to bleeding in the wound area in Group A (10 patients - 55.5%) than in Group B (3 patients - 17.6%); p = 0.035. The median volume of red blood cells transfused in Group A was significantly higher (73.4 +/- 102.38 mL/kg) than that in Group B (35.1 +/- 41.67 mL/kg); p = 0.048. Regarding bile leak there was no statistical difference. Conclusion:: The use of the human fibrinogen and thrombin sponge, required lower volume of red blood cell transfusion and presented lower reoperation rates due to bleeding in the wound area. PMID- 28902944 TI - Fixation of the short-term central venous catheter. A comparison of two techniques. AB - Purpose:: To compare the fixation of the central venous catheter (CVC) using two suture techniques. Methods:: A clinical, analytical, interventional, longitudinal, prospective, controlled, single-blind and randomized study in adult, intensive care unit (ICU) patients. After admission and indication of CVC use, the patients were allocated to the Wing group (n = 35, catheter fixation with clamping wings and retainers) or Shoelace group (n = 35, catheter fixation using shoelace cross-tied sutures around the device). Displacement, kinking, fixation failure, hyperemia at the insertion site, purulent secretion, loss of the device, psychomotor agitation, mental confusion, and bacterial growth at the insertion site were evaluated. Results: : Compared with the Wing group, the Shoelace group had a lower occurrence of catheter displacement (n=0 versus n =4; p = 0.04), kinking (n=0 versus n=8; p=0.001), and fixation failure (n=2 versus n=8; p=0.018). No significant difference was found in bacterial growth (n=20 versus n=14; p=0.267) between groups. Conclusion: : The Shoelace fixation technique presented fewer adverse events than the Wing fixation technique. PMID- 28902945 TI - Distinct Patterns and Aetiology of Chromonychia. AB - Abnormal colouring of the nails may be a sign of underlying systemic or local disorders. This study investigated the prevalence and causes of chromonychia as a whole, as well as of each subtype. Among 163 patients with chromonychia, trauma was the pathogenesis in up to 20.9% (34/163) of cases. The most common subtype was melanonychia (54.0%; 88/163), followed by leukonychia (23.9%), red (8.6%), green (6.7%), yellow (4.9%) and blue (1.8%) nails. Nail matrix naevus (33.3%; 29/88) was the most common cause of melanonychia, while skin diseases (41.0%; 16/39), such as psoriasis (75%, 12/16) and alopecia areata (18.8%; 3/16), in addition to systemic diseases (33.3%; 13/39) including anaemia (38.5%, 5/13) and chronic renal failure (15.4%; 2/13) were the dominant causes of leukonychia. As chromonychia may be the first or only sign of an underlying disorder, it should alert physicians and patients to the need for a prompt and thorough evaluation. PMID- 28902946 TI - The Association Between Low Grade Systemic Inflammation and Skin Diseases: A Cross-sectional Survey in the Northern Finland Birth Cohort 1966. AB - Low grade inflammation is associated with many noncommunicable diseases. The association between skin diseases in general and systemic inflammation has not previously been studied at the population level. A whole-body investigation on 1,930 adults belonging to Northern Finland Birth Cohort 1966 was performed and high sensitive C-reactive protein (CRP) level was measured as a marker of low grade inflammation in order to determine the association between low grade inflammation and skin diseases in an unselected adult population. After adjustment for confounding factors the following skin disorders were associated with low grade inflammation in multinomial logistic regression analysis: atopic eczema (OR 2.2, 95% CI 1.2-3.9), onychomycosis (OR 2.0, 1.2-3.2) and rosacea (OR 1.7, 1.1-2.5). After additionally adjusting for body mass index and systemic diseases, the risks for atopic eczema (OR 2.4, 1.3-4.6) and onychomycosis (OR 1.9, 1.1-3.1) remained statistically significant. In conclusion, low grade inflammation is present in several skin diseases. PMID- 28902947 TI - Clinical Characteristics of the Halo Phenomenon in Infants with Neurofibromatosis 1: A Case Series. PMID- 28902948 TI - Psychological Health Status and Health-related Quality of Life in Adults with Atopic Dermatitis: A Nationwide Cross-sectional Study in South Korea. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Patients with AD often experience psychological distress and poor health-related quality of life (HRQoL). The aim of this study was to investigate the association of several psychological health statuses and poor HRQoL in an adult population with AD in South Korea. A total of 37,578 adults who participated in the Korean National Health and Nutrition Examination Survey, a nationwide, population-based, cross sectional health survey between 2008 and 2013 were included. HRQoL was assessed by EuroQoL (EQ) 5-dimension questionnaire and EQ-visual analogue scale scores. Multiple logistic regression analysis was performed to identify the association of stress, sleep duration, depressive mood, depression, suicidal ideation, and HRQoL with AD relative to matched controls. After adjusting in patients with AD confounding factors, stress, depressive mood, depression, suicidal ideation and poor HRQoL were significantly associated with AD. Dermatologists should be concerned with improving HRQoL and managing the psychological health status of adult patients with AD. PMID- 28902949 TI - Long-standing Verrucous Plaques on the Buttocks: A Quiz. Tuberculosis verrucosa cutis. PMID- 28902950 TI - Pre-emptive Evaluation of Venom Allergy in a Patient with Systemic Mastocytosis. PMID- 28902951 TI - Brachioradial Pruritus and Notalgia Paraesthetica: A Comparative Observational Study of Clinical Presentation and Morphological Pathologies. AB - Brachioradial pruritus (BRP) and notalgia paraesthetica (NP) represent 2 of the most common neuropathic itch syndromes. A total of 58 consecutive patients presenting at the Center for Chronic Pruritus, University Hospital Munster, were analysed with regard to clinical presentation, anatomical and morphological pathologies, impairment in quality of life, and response to treatment with topical capsaicin. Patients with BRP reported stinging and burning more often than those with NP. In the BRP group structural magnetic resonance imaging abnormalities more frequently correlated with localization of the symptoms compared with in patients with NP. In addition, intraepidermal nerve fibre density was decreased in lesional skin in patients with BRP, but not in those with NP, confirming the neuropathic origin in BRP. Topical capsaicin resulted in a significantly higher alleviation of itch and pain intensity and improvement in quality of life in patients with BRP compared with those with NP, which may reflect clinical and aetiological differences between the conditions. PMID- 28902952 TI - Successful Treatment of Severe Recalcitrant Hidradenitis Suppurativa with the Interleukin-17A Antibody Secukinumab. PMID- 28902953 TI - Dystrophic Calcification in a Patient with Primary Localized Cutaneous Nodular Amyloidosis: An Uncommon Ultrasound Finding. PMID- 28902954 TI - Predominant Contribution of CD4 T Cells to Human Herpesvirus 6 (HHV-6) Load in the Peripheral Blood of Patients with Drug-induced Hypersensitivity Syndrome and Persistent HHV-6 Infection. PMID- 28902955 TI - Regulation of citrus responses to the combined action of drought and high temperatures depends on the severity of water deprivation. AB - Plants grown in natural environment are regularly subjected to different combinations of abiotic stresses. Recent studies revealed that citrus plants subjected to a combination of severe drought and high temperatures displayed specific physiological, hormonal, molecular and metabolic responses. In the present study, we have performed a long-term experiment combining moderate drought and heat in Cleopatra mandarin to evaluate the impact of the stress sequence, intensity and duration. Our results support previous observation of high sensitivity of Cleopatra mandarin to abiotic stresses that include high temperatures. In this sense, a combination of drought and heat stress negatively impacts Cleopatra seedlings independently of the drought intensity. However, some responses to combined drought and heat depend on drought intensity, especially those involved in stomatal regulation. The intricate natural environment, abiotic stress combinations and global climatic changes increase the complexity of studying plant responses to stress factors in the laboratory. Consequently, new experimental approaches taking in consideration different stress combinations should be implemented to study the viability of Cleopatra mandarin as a rootstock in a rapidly changing environment. PMID- 28902957 TI - Research in Nursing & Health Author Guidelines. PMID- 28902956 TI - The First Gold(III) Formate: Evidence for beta-Hydride Elimination. AB - The first stable gold(III) formate and experimental evidence for its beta-hydride elimination are described. A catalytic dehydrogenation of formic acid together with mechanistic studies shed light on potential pathways operating in fundamental gold-catalyzed transformations. PMID- 28902958 TI - Nonregenerative immune-mediated anemia associated with a diffuse large B-cell lymphoma in a captive jaguar (Panthera onca). AB - An 18-year-old male castrated jaguar (Panthera onca) was presented with anorexia and continuous bleeding from the oral cavity after a history of fighting with the partner animal. Clinical evaluation revealed ulcerating lesions on the gingiva and hard palate and a hematoma on the tongue. Computed tomography of the head and endoscopic examination of the esophagus and stomach were unremarkable. Hematology and clinical chemistry revealed severe nonregenerative anemia, mild thrombocytopenia, and moderate azotemia. Several PCRs for feline hemotropic mycoplasmas (Mycoplasma haemofelis, M heamominutium, M turicensis), Babesia felis, and Bartonella spp., as well as an FeLV antigen test were negative. The cytologic examination of a bone marrow aspirate was consistent with ineffective erythropoiesis, most likely due to immune-mediated destruction of the erythroid precursor cells. Prednisolone therapy was initiated (1.25 mg/kg/day), and the CBC returned to normal 16 days after the initiation of the therapy. Anemia relapsed after 4 months and severe splenomegaly was noted. A repeat bone marrow aspirate revealed active erythropoiesis in the presence of erythroid precursor phagocytosis suggesting an immune-mediated process. Splenic fine-needle aspiration and tissue biopsies were taken, and all findings including histology and immunohistochemistry were consistent with a diffuse large B-cell lymphoma (DLBCL). Five days later, the clinical condition deteriorated and the jaguar died. Histopathology following necropsy showed infiltration with neoplastic lymphoblasts in the spleen, liver, and abdominal lymph nodes. This case report describes a nonregenerative immune-mediated anemia associated with a DLBCL in a jaguar. PMID- 28902959 TI - Insight into the Activation of In Situ Generated Chiral RhI Catalysts and Their Application in Cyclotrimerizations. AB - We report a detailed study concerning the efficient generation of highly active chiral rhodium complexes of the general structure [Rh(diphosphine)(solvent)2 ]+ as well as their exemplary successful utilization as catalysts for cyclotrimerizations. Such solvent complexes could likewise be prepared from novel ammonia complexes of the type [Rh(diphosphine)(NH3 )2 ]+ . A valuable, feasible approach to generate novel chiral RhI complexes was found by in situ generation from Wilkinson's catalyst [RhCl(PPh3 )3 ] with chiral P,N ligands. The generated catalysts led to moderate to good enantioselectivities and excellent yields in the cyclotrimerizations of triynes, showcasing their usefulness in the synthesis of axially chiral benzene derivatives. PMID- 28902960 TI - The prognostic significance of lung function in stable heart failure outpatients. AB - BACKGROUND: This study investigated the impact on all-cause mortality of airflow limitation indicative of chronic obstructive pulmonary disease or restrictive spirometry pattern (RSP) in a stable systolic heart failure population. HYPOTHESIS: Decreased lung function indicates poor survival in heart failure. METHODS: Inclusion criteria: NYHA class II-IV and left ventricular ejection fraction (LVEF) < 45%. Prognosis was assessed with multivariate Cox proportional hazards models. Two criteria of obstructive airflow limitation were applied: FEV1 /FVC < 0.7 (GOLD), and FEV1 /FVC < lower limit of normality (LLN). RSP was defined as FEV1 /FVC > 0.7 and FVC<80% or FEV1 /FVC > LLN and FVC VO2+ > V4 > HVO42-. Ring-electrode collection efficiency indicated that the reduction product of V10 was stable, while those of VO2+, HVO42-, and V4 had short half-lives that ranged from milliseconds to seconds. With molar ratios of phosphate to vanadium(V) varying from 0 to 1, phosphate accelerated the reduction kinetics of V10 and V4 and enhanced the stability of the reduction products of VO2+, V4, and HVO42-. This study suggests that phosphate complexation could enhance the reductive removal of vanadium(V) and inhibit the reoxidation of its reduction product in water treatment. PMID- 28902988 TI - Improvement of LOD in Fluorescence Detection with Spectrally Nonuniform Background by Optimization of Emission Filtering. AB - The limit-of-detection (LOD) in analytical instruments with fluorescence detection can be improved by reducing noise of optical background. Efficiently reducing optical background noise in systems with spectrally nonuniform background requires complex optimization of an emission filter-the main element of spectral filtration. Here, we introduce a filter-optimization method, which utilizes an expression for the signal-to-noise ratio (SNR) as a function of (i) all noise components (dark, shot, and flicker), (ii) emission spectrum of the analyte, (iii) emission spectrum of the optical background, and (iv) transmittance spectrum of the emission filter. In essence, the noise components and the emission spectra are determined experimentally and substituted into the expression. This leaves a single variable-the transmittance spectrum of the filter-which is optimized numerically by maximizing SNR. Maximizing SNR provides an accurate way of filter optimization, while a previously used approach based on maximizing a signal-to-background ratio (SBR) is the approximation that can lead to much poorer LOD specifically in detection of fluorescently labeled biomolecules. The proposed filter-optimization method will be an indispensable tool for developing new and improving existing fluorescence-detection systems aiming at ultimately low LOD. PMID- 28902989 TI - Characterizing the Impacts of Deposition Techniques on the Performance of MnO2 Cathodes for Sodium Electrosorption in Hybrid Capacitive Deionization. AB - Capacitive deionization (CDI) is currently limited by poor ion-selectivity and low salt adsorption capacity of porous carbon electrodes. To enhance selectivity and capacity via sodium insertion reactions, carbon aerogel electrodes were modified by depositing amorphous manganese dioxide layers via cyclic voltammetry (CV) and electroless deposition (ED). MnO2-coated electrodes were evaluated in a hybrid capacitive deionization system to understand the relationship between oxide coating morphology, electrode capacitance, and sodium removal efficacy. Both deposition techniques increased electrode capacitance, but only ED electrodes improved desalination performance over bare aerogels. SEM imaging revealed ED deposition distributed MnO2 throughout the aerogel, while CV deposition created a discrete crust, indicating that CV electrodes were limited by diffusion. Sodium adsorption capacity of ED electrodes increased with MnO2 mass deposition, reaching a maximum of 0.77 mmol-Na+ per gram of cathode (2.29 mmol-Na+ g-MnO2-1), and peak charge efficiency of 0.95. The presence of MnO2 also positively shifted the electrode potential window of sodium removal, reducing parasitic oxygen reduction and inverting the desalination cycle so that energy discharge coincides with salt removal (1.96 kg-NaCl kWh-1). These results highlight the importance of deposition technique in improving desalination with MnO2-coated electrodes. PMID- 28902990 TI - High-Purity Semiconducting Single-Walled Carbon Nanotubes: A Key Enabling Material in Emerging Electronics. AB - Semiconducting single-walled carbon nanotubes (sc-SWCNTs) are emerging as a promising material for high-performance, high-density devices as well as low cost, large-area macroelectronics produced via additive manufacturing methods such as roll-to-roll printing. Proof-of-concept demonstrations have indicated the potential of sc-SWCNTs for digital electronics, radiofrequency circuits, radiation hard memory, improved sensors, and flexible, stretchable, conformable electronics. Advances toward commercial applications bring numerous opportunities in SWCNT materials development and characterization as well as fabrication processes and printing technologies. Commercialization in electronics will require large quantities of sc-SWCNTs, and the challenge for materials science is the development of scalable synthesis, purification, and enrichment methods. While a few synthesis routes have shown promising results in making near monochiral SWCNTs, gram quantities are available only for small-diameter sc SWCNTs, which underperform in transistors. Most synthesis routes yield mixtures of SWCNTs, typically 30% metallic and 70% semiconducting, necessitating the extraction of sc-SWCNTs from their metallic counterparts in high purity using scalable postsynthetic methods. Numerous routes to obtain high-purity sc-SWCNTs from raw soot have been developed, including density-gradient ultracentrifugation, chromatography, aqueous two-phase extraction, and selective DNA or polymer wrapping. By these methods (termed sorting or enrichment), >99% sc SWCNT content can be achieved. Currently, all of these approaches have drawbacks and limitations with respect to electronics applications, such as excessive dilution, expensive consumables, and high ionic impurity content. Excess amount of dispersant is a common challenge that hinders direct inclusion of sc-SWCNTs into electronic devices. At present, conjugated polymer extraction may represent the most practical route to sc-SWCNTs. By the use of polymers with a pi conjugated backbone, sc-SWCNTs with >99.9% purity can be dispersed in organic solvents via a simple sonication and centrifugation process. With 1000 times less excipient and the flexibility to accommodate a broad range of solvents via diverse polymer constructs, inks are readily deployable in solution-based fabrication processes such as aerosol spray, inkjet, and gravure. Further gains in sc-SWCNT purity, among other attributes, are possible with a better understanding of the structure-property relationships that govern conjugated polymer extraction. This Account covers three interlinked topics in SWCNT electronics: metrology, enrichment, and SWCNT transistors fabricated via solution processes. First, we describe how spectroscopic techniques such as optical absorption, fluorescence, and Raman spectroscopy are applied for sc-SWCNT purity assessment. Stringent requirements for sc-SWCNTs in electronics are pushing the techniques to new levels while serving as an important driver toward the development of quantitative metrology. Next, we highlight recent progress in understanding the sc-SWCNT enrichment process using conjugated polymers, with special consideration given to the effect of doping on the mechanism. Finally, developments in sc-SWCNT-based electronics are described, with emphasis on the performance of transistors utilizing random networks of sc-SWCNTs as the semiconducting channel material. Challenges and advances associated with using polymer-based dielectrics in the unique context of sc-SWCNT transistors are presented. Such transistor packages have enabled the realization of fully printed transistors as well as transparent and even stretchable transistors as a result of the unique and excellent electrical and mechanical properties of sc-SWCNTs. PMID- 28902991 TI - Coupled-Cluster in Real Space. 2. CC2 Excited States Using Multiresolution Analysis. AB - We report a first quantized approach to calculate approximate coupled-cluster singles and doubles CC2 excitation energies in real space. The cluster functions are directly represented on an adaptive grid using multiresolution analysis. Virtual orbitals are neither calculated nor needed in this approach. The nuclear and electronic cusps are taken into account explicitly regularizing the corresponding equations exactly. First calculations on small molecules are in excellent agreement with the best available LCAO results. PMID- 28902992 TI - Removal of Antibiotic Florfenicol by Sulfide-Modified Nanoscale Zero-Valent Iron. AB - Florfenicol (FF, C12H14Cl2FNO4S), an emerging halogenated organic contaminant of concern was effectively degraded in water by sulfidized nanoscale zerovalent iron (S-nZVI). Sulfidized nZVI (62.5 m2 g-1) that was prepared using a one-step method resulted in small Fe0/Fe-sulfide particles that were more stable against aggregation than unsulfidized nZVI (10.2 m2 g-1). No obvious removal of FF was observed by unsulfidized nZVI. S-nZVI degraded FF, having a surface area normalized reaction rate constant of 3.1 * 10-4 L m-2 min-1. The effects of the S/Fe molar ratio, initial FF concentration, initial pH, temperature, and water composition on the removal of FF by S-nZVI, and on the formation of reaction products, were systematically investigated. Both dechlorination and defluorination were observed, resulting in four degradation products (C12H15ClFNO4S, C12H16FNO4S, C12H17NO4S, and C12H17NO5S). High removal efficiencies of FF by S-nZVI were achieved in groundwater, river water, seawater, and wastewater. The reactivity of S-nZVI was relatively unaffected by the presence of both dissolved ions and organic matter in the waters tested. PMID- 28902993 TI - Correction to "Silver Nanoassemblies Constructed from Boranephosphonate DNA". PMID- 28902994 TI - Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. AB - The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development. PMID- 28902995 TI - Anion-pi Catalysis on Fullerenes. AB - Anion-pi interactions on fullerenes are about as poorly explored as the use of fullerenes in catalysis. However, strong exchange-correlation contributions and the localized pi holes on their surface promise unique selectivities. To elaborate on this promise, tertiary amines are attached nearby. Dependent on their positioning, the resulting stabilization of anionic transition states on fullerenes is shown to accelerate disfavored enolate addition and exo Diels-Alder reactions enantioselectively. The found selectivities are consistent with computational simulations, particularly concerning the discrimination of differently planarized and charge-delocalized enolate tautomers by anion-pi interactions. Enolate-pi interactions on fullerenes are much shorter than standard pi-pi interactions and anion-pi interactions on planar surfaces, and alternative cation-pi interactions are not observed. These findings open new perspectives with regard to anion-pi interactions in general and the use of carbon allotropes in catalysis. PMID- 28902996 TI - Modular, Scalable Synthesis of Group A Streptogramin Antibiotics. AB - Streptogramin antibiotics are used clinically to treat multidrug-resistant bacterial infections, but their poor physicochemical properties and narrow spectra of activity have limited their utility. New methods to chemically modify streptogramins would enable structural optimization to overcome these limitations as well as to combat growing resistance to the class. Here we report a modular, scalable synthesis of group A streptogramin antibiotics that proceeds in 6-8 linear steps from simple chemical building blocks. We have applied our route to the synthesis of four natural products in this class including two that have never before been accessed by fully synthetic routes. We anticipate that this work will lead to the discovery of new streptogramin antibiotics that overcome previous limitations of the class. PMID- 28902997 TI - Coupled-Cluster in Real Space. 1. CC2 Ground State Energies Using Multiresolution Analysis. AB - A framework to calculate CC2 approximated coupled-cluster ground state correlation energies in a multiresolution basis is derived and implemented into the MADNESS library. The CC2 working equations are formulated in first quantization which makes them suitable for real-space methods. The first quantized equations can be interpreted diagrammatically using the usual diagrams from second quantization with adjusted interpretation rules. Singularities arising from the nuclear and electronic potentials are regularized by explicitly taking the nuclear and electronic cusps into account. The regularized three- and six-dimensional cluster functions are represented directly on an adaptive grid. The resulting equations are free of singularities and virtual orbitals, which results in a low intrinsic scaling. Correlation energies close to the basis set limit are computed for small molecules. This work is the first step toward CC2 excitation energies in a multiresolution basis. PMID- 28902998 TI - Activation of C-H Bonds of Alkyl- and Arylnitriles by the TaCl5-PPh3 Lewis Pair. AB - A new pathway of activation of C-H bonds of alkyl- and arylnitriles by a cooperative action of TaCl5 and PPh3 under mild conditions is reported. Coordination of nitriles to the highly Lewis acidic Ta(V) center resulted in an activation of their aliphatic and aromatic C-H bonds, allowing nucleophilic attack and deprotonation by the relatively weak base PPh3. The propensity of Ta(V) to form multiple bonds to nitrogen-containing ligands is an important driving force of the reaction as it led to a sequence of bond rearrangements and the emergence of, in the case of benzonitrile, a zwitterionic enediimido complex of Ta(V) through C?C double bond formation between two activated nitrile fragments. These transformations highlight the special role of the high-valent transition metal halide in substrate activation and distinguish the reactivity of the TaCl5-PPh3 system from both non-metal- and late transition metal-based frustrated Lewis pairs. PMID- 28903001 TI - Open-Source Assisted Laboratory Automation through Graphical User Interfaces and 3D Printers: Application to Equipment Hyphenation for Higher-Order Data Generation. AB - Higher-order data generation implies some automation challenges, which are mainly related to the hidden programming languages and electronic details of the equipment. When techniques and/or equipment hyphenation are the key to obtaining higher-order data, the required simultaneous control of them demands funds for new hardware, software, and licenses, in addition to very skilled operators. In this work, we present Design of Inputs-Outputs with Sikuli (DIOS), a free and open-source code program that provides a general framework for the design of automated experimental procedures without prior knowledge of programming or electronics. Basically, instruments and devices are considered as nodes in a network, and every node is associated both with physical and virtual inputs and outputs. Virtual components, such as graphical user interfaces (GUIs) of equipment, are handled by means of image recognition tools provided by Sikuli scripting language, while handling of their physical counterparts is achieved using an adapted open-source three-dimensional (3D) printer. Two previously reported experiments of our research group, related to fluorescence matrices derived from kinetics and high-performance liquid chromatography, were adapted to be carried out in a more automated fashion. Satisfactory results, in terms of analytical performance, were obtained. Similarly, advantages derived from open source tools assistance could be appreciated, mainly in terms of lesser intervention of operators and cost savings. PMID- 28902999 TI - Self-Assembled 2D Free-Standing Janus Nanosheets with Single-Layer Thickness. AB - We report the thermodynamically controlled growth of solution-processable and free-standing nanosheets via peptide assembly in two dimensions. By taking advantage of self-sorting between peptide beta-strands and hydrocarbon chains, we have demonstrated the formation of Janus 2D structures with single-layer thickness, which enable a predetermined surface heterofunctionalization. A controlled 2D-to-1D morphological transition was achieved by subtly adjusting the intermolecular forces. These nanosheets provide an ideal substrate for the engineering of guest components (e.g., proteins and nanoparticles), where enhanced enzyme activity was observed. We anticipate that sequence-specific programmed peptides will offer promise as design elements for 2D assemblies with face-selective functionalization. PMID- 28903000 TI - Structural Revision of Baulamycin A and Structure-Activity Relationships of Baulamycin A Derivatives. AB - Total synthesis of the proposed structure of baulamycin A was performed. The spectral properties of the synthetic compound differ from those reported for the natural product. On the basis of comprehensive NMR study, we proposed two other possible structures for natural baulamycin A. Total syntheses of these two substances were performed, which enabled assignment of the correct structure of baulamycin A. Key features of the convergent and fully stereocontrolled route include Evans Aldol and Brown allylation reactions to construct the left fragment, a prolinol amide-derived alkylation/desymmetrization to install the methyl-substituted centers in the right fragment, and finally, a Carreira alkynylation to join both fragments. In addition, we have determined the inhibitory activities of novel baulamycin A derivatives against the enzyme SbnE. This SAR study provides useful insight into the design of novel SbnE inhibitors that overcome the drug resistance of pathogens, which cause life-threatening infections. PMID- 28903002 TI - Quaternized alpha,alpha'-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones. AB - An efficient synthesis protocol is presented for accessing quaternized alpha amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an alpha-monosubstituted malonate imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic alpha-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an alpha-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-transC-N conformation. PMID- 28903004 TI - Infrared Spectroscopic Study of the Acidic CH Bonds in Hydrated Clusters of Cationic Pentane. AB - Infrared spectroscopy of the hydrated clusters of cationic pentane, which are generated through the vacuum ultraviolet photoionization in the gas phase, is carried out to probe the acidic properties of their CH bonds. The monohydrated pentane cation forms the proton-shared structure, in which the proton of CH in cationic pentane is shared between the pentyl radical and water molecule. In the di- and trihydrated clusters, the proton of CH is completely transferred to the water moiety so that the clusters are composed of the pentyl radical and protonated water cluster. These results indicate that two water molecules are enough to cause the proton transfer from CH of cationic pentane, and thus its acidity is highly enhanced with the ionization. PMID- 28903003 TI - Tumor Cell-Specific Nuclear Targeting of Functionalized Graphene Quantum Dots In Vivo. AB - Specific targeting of tumor tissues is essential for tumor imaging and therapeutics but remains challenging. Here, we report an unprecedented method using synthetic sulfonic-graphene quantum dots (sulfonic-GQDs) to exactly target the cancer cell nuclei in vivo without any bio- ligand modification, with no intervention in cells of normal tissues. The key factor for such selectivity is the high interstitial fluid pressure (IFP) in tumor tissues, which allows the penetration of sulfonic-GQDs into the plasma membrane of tumor cells. In vitro, the sulfonic-GQDs are repelled out of the cell membrane because of the repulsive force between negatively charged sulfonic-GQDs and the cell membranes which contributes to the low distribution in normal tissues in vivo. However, the plasma membrane-crossing process can be activated by incubating cells in ultrathin film culture medium because of the attachment of sulfonic-GQDs on cell memebranes. Molecular dynamics simulations demonstrated that, once transported across the plasma membrane, the negatively charged functional groups of these GQDs will leave the membrane with a self-cleaning function retaining a small enough size to achieve penetration through the nuclear membrane into the nucleus. Our study showed that IFP is a previously unrecognized mechanism for specific targeting of tumor cell nuclei and suggested that sulfonic-GQDs may be developed into novel tools for tumor-specific imaging and therapeutics. PMID- 28903005 TI - Afterglow Luminescence in Wet-Chemically Synthesized Inorganic Materials: Ultra Long Room Temperature Phosphorescence Instead of Persistent Luminescence. AB - Wet-chemically synthesized amorphous yttrium-aluminum-borates (a-YAB) exhibit intense visible photoluminescence (PL). Preliminary investigations revealed a correlation of PL with the presence of carbon-related impurities; however, their exact nature is still under investigation. These powders also exhibit afterglow luminescence that lasts for several seconds at room-temperature (RT). A comparison with persistent phosphors and phosphorescent dye revealed that the afterglow in a-YAB is a phosphorescence phenomenon and not the persistence luminescence, which is more common in inorganic solids. The unusual RT phosphorescence in a-YAB could be achieved due to triplet-state stabilization of trapped luminescent organic moieties in glassy matrix. This is indeed an important step forward in understanding the complex luminescence mechanism in such promising wet-chemically synthesized functional materials. Moreover, phosphorescence is detectable for over 10 s at RT, suggesting rigid glassy inorganic matrix is more efficient in preserving phosphorescence at elevated temperatures, opening the path for several attractive applications including time resolved bioimaging and thermometry. PMID- 28903006 TI - Constructing a Multiplexed DNA Pattern by Combining Precise Magnetic Manipulation and DNA-Driven Assembly. AB - There is an urgent demand to construct multiplexed biomolecular patterns to obtain more biological information from a single experiment. However, with only limited reports focusing on defective top-down approaches, challenges remain to develop a bottom-up strategy for multiplexed patterning. To this end, a novel strategy has been proposed to fabricate multiplexed DNA patterns via macroscopic assembly through combined precise magnetic manipulation and DNA hybridization driven self-assembly. Therefore, a multiplexed DNA pattern composed of glass fibers loaded with multiple specific strands of DNA was constructed, and its potential application in simultaneous detection of multiplex target DNA was demonstrated. Moreover, the fabricated multiplexed DNA pattern shows an erasable behavior because the hybridized DNA can be disassembled by strand displacement. PMID- 28903007 TI - Characterization of Repulsive Forces and Surface Deformation in Thin Micellar Films via AFM. AB - Here we examine how the force on an atomic force microscope (AFM) tip varies as it approaches micellar surfactant films, and use this information to discern the film's surface structure and Young's modulus. Rows of wormlike hemimicelles were created at a graphite interface using 10 mM sodium dodecyl sulfate (SDS). We found that the repulsive force on a silicon nitride tip as it approached the surface was exponential, with a decay length of 2.0 +/- 0.1 nm. The addition of Na2SO4 was found to cause a change in this behavior, with a clear split into two exponential regions at concentrations above 1 mM. We also observed that the range of these forces increased with added salt from ~15 nm in pure SDS to ~20 nm at a Na2SO4 concentration of 1.34 mM. These forces were inconsistent with electrostatic repulsion, and were determined to be steric in nature. We show that the behavior at higher salt concentrations is consistent with the theory of polyelectrolyte brushes in the osmotic regime. From this, we hypothesize the presence of micellar brushes at the surface that behave similarly to adsorbed polymer chains. In addition, the Young's modulus of the film was taken from data near the interface using Sneddon's model, and found to be 80 +/- 40 MPa. Similar experiments were performed with 10 mM dodecylamine hydrochloride (DAH) solutions in the presence of added magnesium chloride. The decay length for the pure DAH solution was found to be 2.6 +/- 0.3 nm, and the addition of 1.34 mM of MgCl2 caused this to increase to 3.7 +/- 0.3 nm. No decay length splitting was observed for DAH. We conclude that the behavior at the surface resembles that of an uncharged polymer brush, as the ionic and surface charge densities are much lower for DAH than for SDS. PMID- 28903009 TI - The Role of Licensure in Breastfeeding Support in Indonesia. PMID- 28903008 TI - Criticized, Fired, Sued, or Prosecuted: Hindsight and Public Health Accountability. PMID- 28903010 TI - Effect of Loading on In Vivo Tibiofemoral and Patellofemoral Kinematics of Healthy and ACL-Reconstructed Knees. AB - BACKGROUND: Although knees that have undergone anterior cruciate ligament reconstruction (ACLR) often exhibit normal laxity on clinical examination, abnormal kinematic patterns have been observed when the joint is dynamically loaded during whole body activity. This study investigated whether abnormal knee kinematics arise with loading under isolated dynamic movements. HYPOTHESIS: Tibiofemoral and patellofemoral kinematics of ACLR knees will be similar to those of the contralateral uninjured control knee during passive flexion-extension, with bilateral differences emerging when an inertial load is applied. STUDY DESIGN: Controlled laboratory study. METHODS: The bilateral knees of 18 subjects who had undergone unilateral ACLR within the past 4 years were imaged by use of magnetic resonance imaging (MRI). Their knees were cyclically (0.5 Hz) flexed passively. Subjects then actively flexed and extended their knees against an inertial load that induced stretch-shortening quadriceps contractions, as seen during the load acceptance phase of gait. A dynamic, volumetric, MRI sequence was used to track tibiofemoral and patellofemoral kinematics through 6 degrees of freedom. A repeated-measures analysis of variance was used to compare secondary tibiofemoral and patellofemoral kinematics between ACLR and healthy contralateral knees during the passive and active extension phases of the cyclic motion. RESULTS: Relative to the passive motion, inertial loading induced significant shifts in anterior and superior tibial translation, internal tibial rotation, and all patellofemoral degrees of freedom. As hypothesized, tibiofemoral and patellofemoral kinematics were bilaterally symmetric during the passive condition. However, inertial loading induced bilateral differences, with the ACLR knees exhibiting a significant shift toward external tibial rotation. A trend toward greater medial and anterior tibial translation was seen in the ACLR knees. CONCLUSION: This study demonstrates that abnormal knee kinematic patterns in ACLR knees emerge during a simple, active knee flexion-extension task that can be performed in an MRI scanner. CLINICAL RELEVANCE: It is hypothesized that abnormal knee kinematics may alter cartilage loading patterns and thereby contribute to increased risk for osteoarthritis. Recent advances in quantitative MRI can be used to detect early cartilage degeneration in ACLR knees. This study demonstrates the feasibility of identifying abnormal ACLR kinematics by use of dynamic MRI, supporting the combined use of dynamic and quantitative MRI to investigate the proposed link between knee motion, cartilage contact, and early biomarkers of cartilage degeneration. PMID- 28903011 TI - Inter-individual responses to sprint interval training, a pilot study investigating interactions with the sirtuin system. AB - Sprint interval training (SIT) is reported to improve blood glucose control and may be a useful public health tool. The sirtuins and associated genes are emerging as key players in blood glucose control. This study investigated the interplay between the sirtuin/NAD system and individual variation in insulin sensitivity responses after SIT in young healthy individuals. Before and after 4 weeks of SIT, body mass and fat percentage were measured and oral glucose tolerance tests performed in 20 young healthy participants (7 females). Blood gene expression profiles (all 7 mammalian sirtuin genes and 15 enzymes involved in conversion of tryptophan, bioavailable vitamin B3, and metabolic precursors to NAD). NAD/NADP was measured in whole blood. Significant reductions in body weight and body fat post-SIT were associated with altered lipid profiles, NAD/NADP, and regulation of components of the sirtuin/NAD system (NAMPT, NMNAT1, CD38, and ABCA1). Variable improvements in measured metabolic health parameters were evident and attributed to different responses in males and females, together with marked inter-individual variation in responses of the sirtuin/NAD system to SIT. PMID- 28903012 TI - In Vitro Chondrotoxicity of Nonsteroidal Anti-inflammatory Drugs and Opioid Medications. AB - BACKGROUND: A variety of medications are administered to the intra-articular space for the relief of joint pain. While amide-type local anesthetics have been extensively studied, there is minimal information regarding the potential chondrotoxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid medications. PURPOSE: To investigate the in vitro chondrotoxicity of single-dose equivalent concentrations of ketorolac, morphine, meperidine, and fentanyl on human chondrocytes. STUDY DESIGN: Controlled laboratory study. METHODS: Human cartilage was arthroscopically harvested from the intercondylar notch and expanded in vitro. Gene expression of cultured chondrocytes before treatment was performed with quantitative polymerase chain reaction for type I collagen, type II collagen, aggrecan, and SOX9. Chondrocytes were then exposed to 0.01%, 0.02%, and 0.04% morphine sulfate; 0.3% and 0.6% ketorolac tromethamine; 0.5%, 1.0%, and 1.5% meperidine hydrochloride; 0.0005% and 0.001% fentanyl citrate; and saline. A custom bioreactor was used to constantly deliver medications, with the dosage of each medication and the duration of exposure based on standard dose equivalents, medication half-lives, and differences in the surface area between the 6-well plates and the native joint surface. After treatment, a live/dead assay was used to assess chondrocyte viability and if minimal cell death was detected. A subset of samples after treatment was maintained to analyze for possible delayed cell death. RESULTS: All tested concentrations of ketorolac and meperidine caused significantly increased cell death versus the saline control, demonstrating a dose-response relationship. The morphine and fentanyl groups did not show increased chondrotoxicity compared with the saline group, even after 2 weeks of additional culture. CONCLUSION: In vitro exposure of chondrocytes to single-dose equivalent concentrations of either ketorolac or meperidine demonstrated significant chondrotoxicity, while exposure to morphine or fentanyl did not lead to increased cell death. PMID- 28903014 TI - Impact of Preterm Birth on Glucocorticoid Variability in Human Milk. AB - BACKGROUND: Preterm birth is a stressful event for both the mother and infant. Whereas the initiation of breastfeeding is important for preterm infant health, little is known of the glucocorticoid hormones (cortisol and cortisone) in human milk following preterm birth. Research aim: The aim of this study was to investigate the relationship between human milk glucocorticoid concentrations and preterm birth. METHODS: Human milk was sampled weekly for up to 6 weeks from 22 women who delivered a preterm infant at 28 to 32 weeks' gestation. Human milk was analyzed for total and free cortisol and cortisone concentrations using liquid chromatography-tandem mass spectrometry. RESULTS: Milk sampled from mothers of preterm infants had more cortisone than cortisol ( p < .001), with a strong correlation between both hormones ( p = .001, r = .85). The cortisone was significantly higher in the milk of mothers who delivered infants after 30 weeks compared with those who delivered before 30 weeks of gestation ( p = .02). Glucocorticoid concentrations did not change over the sampling time (weeks 1 to 6 postpartum) and did not differ by infant gender. CONCLUSION: Glucocorticoids were present in all milk samples following preterm birth. Cortisone concentration tended to be higher in those who delivered after 30 weeks' gestation but did not increase further over the weeks following birth. PMID- 28903015 TI - Kept clinical visits, as scheduled in the first 6 months of antiretroviral treatment, determine long-term treatment outcomes in people living with HIV: a large retrospective cohort study in China. AB - : Background Routine HIV clinical monitoring is vital for people living with HIV (PLHIV) after treatment initiation. The relationship between clinical visits during the first 6 months after initial antiretroviral therapy (ART) and long term, HIV-related mortality and service retention was investigated. METHODS: A retrospective ART observational research database was established based on de identified data extracted from 6959 records of adult HIV-positive registrants held by Hunan CDC (Center for Disease Control and Prevention) between 2003 and 2013. RESULTS: During the first 6 months of initiation into ART, 2364 (34.0%) of PLHIV had completed four scheduled visits, meeting the Chinese ART clinical monitoring standards. From 6 months onwards (up to 36 months), this group had the lowest HIV-related mortality (4.4%) compared with those who had more or less than four kept visits in the first 6 months [one visit only: adjusted hazards ratio (AHR)=3.15, 95% CI 2.24-3.88; two visits: AHR=2.24, 95% CI 1.80-3.01; three visits: AHR=1.86, 95% CI 1.69-2.05; and >4 visits: AHR=1.37, 95% CI 1.11-1.72]. Those with less than three kept visits were also at increased risk of cohort loss to follow up (ART discontinuation, prolonged service disengagement or death). A myriad of personal, clinical and social factors are identified to be associated with increased HIV-related mortality and clinical retention. CONCLUSIONS: Enabling PLHIV to complete four scheduled clinical visits during the first 6 months of ART initiation, as recommended by the Chinese CDC, is critical. PMID- 28903016 TI - Arthroscopic meniscectomy for degenerative meniscal tears reduces knee pain but is not cost-effective in a routine health care setting: a multi-center longitudinal observational study using data from the osteoarthritis initiative. AB - OBJECTIVES: It is disputed whether arthroscopic meniscectomy is an (cost-) effective treatment for degenerative meniscus tears in day-to-day clinical practice. The objective of this study was to assess the cost-effectiveness of arthroscopic meniscectomy in subjects with knee osteoarthritis, in routine clinical practice, while taking into account the increased risk for future knee replacement surgery. We compared cost-effectiveness of arthroscopic meniscectomy compared to no surgery. DESIGN: We used a state transition (Markov) simulation model to evaluate the cost-effectiveness of arthroscopic meniscectomy compared to no surgery in subjects with knee osteoarthritis (age range 45-79 years). Data used in the preparation of the current study were obtained from the Osteoarthritis Initiative (AOI) database. We applied a 9 years' time horizon (which is equal to the current OAI study follow up period), and evaluated cost effectiveness from a societal perspective. The main outcome measure was the incremental cost-effectiveness ratio (Euros per quality adjusted life-year (QALY) gained). RESULTS: Arthroscopic meniscectomy was associated with 8.09 (SD +/- 0.07) QALYs at a cost of ? 21,345 (SD +/- 841), whereas the no surgery was associated with 8.05 (SD +/- 0.07) QALYs at a cost of ? 16,284 (SD +/- 855). For arthroscopic meniscectomy, the incremental cost per QALY gained was ? 150,754. CONCLUSIONS: In day-to-day clinical practice, arthroscopic meniscectomy in subjects with knee osteoarthritis is associated with ? 150,754 per QALY gained, which exceeds the generally accepted willingness to pay (WTP) (range ? 20,000-? 80,000). PMID- 28903013 TI - Spatiotemporally Non-Uniform Ca2+ Dynamics of Cardiac Purkinje Fibers in Mouse Myocardial Infarct. AB - Surviving Purkinje fibers in myocardial infarct are regarded as an important substrate in arrhythmogenesis. However, poorly understood are functional properties of Purkinje fibers in the infarcted heart. We sought to visualize intracellular Ca2+ ([Ca2+]i) dynamics of Purkinje fiber networks in the mouse myocardial infarct. Using 3- to 4-day-old or 7- to 9-day-old infarcted hearts after the left coronary-artery ligation corresponding, respectively, to acute or healing phase, we conducted rapid fluo4-fluorescence imaging on the endocardial surface of the left ventricular septum by macro-zoom fluorescence microscopy and rapid-scanning confocal microscopy. In contrast with the intact heart, where uniform Ca2+ transients propagated rapidly, the infarcted heart exhibited slow, non-uniform impulse propagations. On confocal microscopy, Purkinje fibers in the peri-infarct zone exhibited non-uniform [Ca2+]i dynamics: beat-to-beat alternans of the Ca2+ transient amplitude in and among the individual fibers, whereas the intact fibers exhibited uniform Ca2+ transients. Such non-uniform [Ca2+]i dynamics were more conspicuous in the acute infarcted hearts than in the healing ones. In accordance with [Ca2+]i dynamics, fixed fluo4-loaded heart preparations exhibited definitive connexin-40 plaques in the peri-infarct Purkinje fibers, whereas the subjacent myocardium presented coagulative necrosis and granulation tissues, respectively. The surviving Purkinje fibers in the peri-infarct zone exhibited non-uniform [Ca2+]i dynamics, which may lead to arrhythmogenesis. PMID- 28903017 TI - Is a high tibial osteotomy (HTO) superior to non-surgical treatment in patients with varus malaligned medial knee osteoarthritis (OA)? A propensity matched study using 2 randomized controlled trial (RCT) datasets. AB - OBJECTIVE: No randomized controlled trial (RCT) has compared the high tibial osteotomy (HTO) with non-surgical treatment in patients with medial knee osteoarthritis (OA) and varus malalignment. The aim was to compare the effectiveness of an unloader brace treatment or a usual care program to the HTO regarding pain severity and knee function. DESIGN: Surgical treatment (HTO) to two non-surgical options was compared by combining the data of two RCTs. One RCT (n = 117) compared an unloader brace to usual care treatment; the other RCT (n = 92) compared closing to opening wedge HTO. One-to-many propensity score matching was used to equalize patient characteristics. We compared clinical outcome at 1 year follow-up (VAS pain (0-10) and knee function (HSS, 0-100)) with mixed model analysis. RESULTS: Propensity score matching resulted in a comparison of 30 brace patient with 83 HTO patients, and of 28 usual care patients with 71 HTO patients. Pain at 1 year after HTO (VAS 3.8) was lower than after valgus bracing (VAS 5.0) with a mean difference of -1.1 (95% CI -2.2; -0.1). Function showed a nonsignificant mean difference of 2.1 [95% CI -3.1; 7.3]. Comparing HTO to usual care a difference was seen in pain (-1.7 [95% CI -2.8; -0.6]) and function (6.6 [95% CI 0.2; 13.1]), in favor of the HTO. CONCLUSIONS: Our data suggest that HTO was more effective in pain reduction compared to both non-surgical treatments. Function improved only when HTO was compared to usual care treatment. These small differences question the benefits of surgical treatment over the brace treatment. PMID- 28903018 TI - Structural Plasticity of Eph-Receptor A4 Facilitates Cross-Class Ephrin Signaling. PMID- 28903019 TI - Preparation of Multimilligram Quantities of Large, Linear DNA Molecules for Structural Studies. PMID- 28903020 TI - MicroRNA-Containing T-Regulatory-Cell-Derived Exosomes Suppress Pathogenic T Helper 1 Cells. PMID- 28903021 TI - MBD3/NuRD Facilitates Induction of Pluripotency in a Context-Dependent Manner. PMID- 28903022 TI - Phosphorus and mortality risk in end-stage renal disease: A meta-analysis. AB - BACKGROUND: Studies on the association of abnormal serum phosphorus level with all-cause mortality in patients with end-stage renal disease (ESRD) have yielded inconsistent results. OBJECTIVE: To evaluate the association of abnormal serum phosphorus level with all-cause mortality in patients with ESRD requiring dialysis by conducting a meta-analysis. METHODS: Pubmed and Embase databases were searched through March 2017 to identify all observational studies that assessed the association between abnormal serum phosphorus level and all-cause mortality risk in patients with ESRD requiring dialysis. Pooled hazard risk (HR) with 95% confidence interval (CI) was calculated for the highest versus referent phosphorus category and lower versus referent phosphorus category, separately. RESULTS: Nine cohort studies were eligible for analysis. During 12 to 97.6months follow-up duration, 24,463 death events occurred among 1,992,869 ESRD patients. Meta-analysis showed that the pooled HR of all-cause mortality was 1.16 (95% CI 1.06-1.28) for the lower versus referent serum phosphorus category. Similarly, patients with highest serum phosphorus levels were associated with an increased risk of all-cause mortality (HR 1.39; 95% CI 1.31-1.47) compared with those in the referent phosphorus category. Subgroup analyses revealed that the effect of phosphorus on the all-cause mortality risk appeared to be stronger within 2years follow-up. CONCLUSIONS: Both very high and very low values of phosphorus are independently associated with an increased risk for all-cause mortality in ESRD patients requiring dialysis. This meta-analysis highlighted a non-linear association of serum phosphorus with all-cause mortality among dialysis-dependent ESRD patients. PMID- 28903023 TI - Platelet to lymphocyte ratio in biliary tract cancer: Review and meta-analysis. AB - BACKGROUND: The platelet to lymphocyte ratio (PLR) has been found to predict clinical outcomes in multiple malignancies. The aim of this study was to assess the prognostic value of pretreatment PLR in biliary tract cancer (BTC). METHODS: We searched the MEDLINE, EMBASE, and Cochrane databases to identify studies evaluating the prognostic significance of pretreatment PLR in BTC. The end points were overall survival (OS), recurrence-free survival (RFS). Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed-effects/random-effects models. RESULTS: A total of eleven studies comprising 2392 patients were included in the study. Pooled results showed that elevated PLR was significantly associated with decreased overall survival (HR: 1.59, 95% confidence interval [CI]: 1.42-1.78, p<0.001) and recurrence-free survival (HR: 1.53, 95% CI: 1.16-2.00, p=0.002). Subgroup analyses suggested that a high PLR predicted decreased OS in patient with BTC, regardless of sample size (<200 or >=200), treatment methods (surgery, mixed, or chemotherapy), tumor stage (mixed or metastatic), analysis methods (univariate or multivariate), cut-off values (<150 or >=150), and NOS score (<7 or >=7). CONCLUSIONS: Elevated pretreatment PLR may be an unfavorable prognostic factor for clinical outcomes in patients with biliary tract cancer. PMID- 28903025 TI - Experimental Neospora caninum infection in chickens (Gallus gallus domesticus) with oocysts and tachyzoites of two recent isolates reveals resistance to infection. AB - The importance of birds in the biological cycle of Neospora caninum is not clear. We report unsuccessful Neospora infection in chickens (Gallus gallus domesticus) using two isolates of N. caninum. In experiment #1, 30 White Leghorn chickens were orally inoculated with viable N. caninum oocysts (NC-SP1 isolate, 200 oocysts per bird) via the crop at 21days of age. Groups of three birds were euthanised at intervals of 7days (a total of 9weeks) and one group was challenged with the same oocyst dose at 37daysp.i. and observed for 11weeks. Blood samples were collected weekly, and sera were tested using IFAT. Chicken tissues were collected for PCR, quantitative PCR and immunohistochemistry. Two dogs approximately 45days of age were fed with tissues from chickens euthanised at 138 and 159daysp.i. The results indicated that the chickens were resistant to neosporosis as revealed by failure to seroconvert, to detect parasite DNA or N. caninum antigen by immunohistochemistry in inoculated bird tissues, and by no oocyst excretion by the dogs fed avian tissues. Similar results were obtained in experiment #2, in which 34 1-week-old chickens were each s.c. inoculated with 100,000 tachyzoites of the NcWTDMn1 isolate of N. caninum. The chickens were euthanised on days 7, 15, 22, 28, 36 and 60p.i. At necropsy, all tissues and serum from each bird were collected. All chickens remained asymptomatic, and N. caninum antigen was not detected by immunohistochemistry. Seven chickens euthanised at day 60p.i. demonstrated low (1:25 dilution) levels of antibodies by using the Neospora agglutination test. Two 12-week-old dogs fed tissues pooled from 10 inoculated chickens euthanised at day 60p.i. did not excrete N. caninum oocysts. This investigation indicates that chickens are resistant to experimental infection by N. caninum. PMID- 28903024 TI - Neospora caninum in non-pregnant and pregnant mouse models: cross-talk between infection and immunity. AB - Neospora caninum is a cyst-forming coccidian which causes abortion in cattle, with a high economic impact globally. Vaccination is considered to be the most cost-effective strategy to control and prevent bovine neosporosis. However, there is no commercial vaccine available to date. To investigate this disease under laboratory conditions, mouse models were developed, and they have been efficiently used as an initial proof-of-concept platform to investigate different immunogenic formulations. We here provide a detailed review on the current knowledge on immunity against neosporosis in non-pregnant as well as pregnant mice, and present a general overview of the most relevant parameters that may be responsible for protective immunity, which in turn could be relevant for vaccine development. Despite the considerable differences in immunity between cattle and mice, it is essential to understand how mice respond immunologically to Neospora caninum infection and how this response influences congenital infection and offspring survival. In this context, pregnant mouse models play a key role, and allow correlation of the outcome of congenital neosporosis with specific immune mechanisms which could also be relevant in cattle. PMID- 28903027 TI - Sexually Dimorphic Tridimensionally Preserved Pterosaurs and Their Eggs from China. PMID- 28903026 TI - Differential expression of genes in fetal brain as a consequence of maternal protein deficiency and nematode infection. AB - Maternal dietary protein deficiency and gastrointestinal nematode infection during early pregnancy have negative impacts on both maternal placental gene expression and fetal growth in the mouse. Here we used next-generation RNA sequencing to test our hypothesis that maternal protein deficiency and/or nematode infection also alter the expression of genes in the developing fetal brain. Outbred pregnant CD1 mice were used in a 2*2 design with two levels of dietary protein (24% versus 6%) and two levels of infection (repeated sham versus Heligmosomoides bakeri beginning at gestation day 5). Pregnant dams were euthanized on gestation day 18 to harvest the whole fetal brain. Four fetal brains from each treatment group were analyzed using RNA Hi-Seq sequencing and the differential expression of genes was determined by the edgeR package using NetworkAnalyst. In response to maternal H. bakeri infection, 96 genes (88 up regulated and eight down-regulated) were differentially expressed in the fetal brain. Differentially expressed genes were involved in metabolic processes, developmental processes and the immune system according to the PANTHER classification system. Among the important biological functions identified, several up-regulated genes have known neurological functions including neuro development (Gdf15, Ing4), neural differentiation (miRNA let-7), synaptic plasticity (via suppression of NF-kappabeta), neuro-inflammation (S100A8, S100A9) and glucose metabolism (Tnnt1, Atf3). However, in response to maternal protein deficiency, brain-specific serine protease (Prss22) was the only up-regulated gene and only one gene (Dynlt1a) responded to the interaction of maternal nematode infection and protein deficiency. In conclusion, maternal exposure to GI nematode infection from day 5 to 18 of pregnancy may influence developmental programming of the fetal brain. PMID- 28903028 TI - Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation. PMID- 28903029 TI - Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency. PMID- 28903030 TI - Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency. PMID- 28903031 TI - Chronic Palmitate Exposure Inhibits Insulin Secretion by Dissociation of Ca2+ Channels from Secretory Granules. PMID- 28903032 TI - Drosha Regulates Gene Expression Independently of RNA Cleavage Function. PMID- 28903033 TI - Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824. PMID- 28903034 TI - Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells. AB - Sophisticated mechanisms that preserve genome integrity are critical to ensure the maintenance of regenerative capacity while preventing transformation of somatic stem cells (SCs), yet little is known about mechanisms regulating genome maintenance in these cells. Here, we show that intestinal stem cells (ISCs) induce the Argonaute family protein Piwi in response to JAK/STAT signaling during acute proliferative episodes. Piwi function is critical to ensure heterochromatin maintenance, suppress retrotransposon activation, and prevent DNA damage in homeostasis and under regenerative pressure. Accordingly, loss of Piwi results in the loss of actively dividing ISCs and their progenies by apoptosis. We further show that Piwi expression is sufficient to allay age-related retrotransposon expression, DNA damage, apoptosis, and mis-differentiation phenotypes in the ISC lineage, improving epithelial homeostasis. Our data identify a role for Piwi in the regulation of somatic SC function, and they highlight the importance of retrotransposon control in somatic SC maintenance. PMID- 28903035 TI - Functional Insights into ANP32A-Dependent Influenza A Virus Polymerase Host Restriction. AB - Host restriction of influenza A virus limits pandemic emergence. The viral RNA polymerase (vPol) is an essential enzyme that must adapt for avian viruses to replicate in humans. Species differences in host ANP32A dictate adaptation: human ANP32A lacks an uncharacterized 33 amino-acid insertion that is present in avian ANP32A. Here, we uncover important contributions of host SUMOylation to vPol activity, including avANP32A function. We also identify a hydrophobic SUMO interaction motif (SIM)-like sequence unique to avANP32A that critically supports avian-signature vPol. Unrelated SIM sequences partially recapitulate this function when introduced into huANP32A. By investigating ANP32A-vPol interactions, we find that huANP32A interacts weakly with both human- and avian signature vPols, while the hydrophobic motif of avANP32A promotes stronger interactions. Furthermore, we identify a highly acidic stretch in avANP32A that constitutes a major site of vPol interaction. Our data suggest compensatory mechanisms underlying vPol adaptation to host ANP32A independent of species specific interactions. PMID- 28903036 TI - Culturing CTLs under Hypoxic Conditions Enhances Their Cytolysis and Improves Their Anti-tumor Function. AB - Cytotoxic T lymphocytes (CTLs) used in immunotherapy are typically cultured under atmospheric O2 pressure but encounter hypoxic conditions inside tumors. Activating CTLs under hypoxic conditions has been shown to improve their cytotoxicity in vitro, but the mechanism employed and the implications for immunotherapy remain unknown. We activated and cultured OT-I CD8 T cells at either 1% or 20% O2. Hypoxic CTLs survived, as well as normoxic ones, in vitro but killed OVA-expressing B16 melanoma cells more efficiently. Hypoxic CTLs contained similar numbers of cytolytic granules and released them as efficiently but packaged more granzyme-B in each granule without producing more perforin. We imaged CTL distribution and motility inside B16-OVA tumors using confocal and intravital 2-photon microscopy and observed no obvious differences. However, mice treated with hypoxic CTLs exhibited better tumor regression and survived longer. Thus, hypoxic CTLs may perform better in tumor immunotherapy because of higher intrinsic cytotoxicity rather than improved migration inside tumors. PMID- 28903037 TI - Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. AB - Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15. PMID- 28903038 TI - Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency. AB - Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism. PMID- 28903039 TI - Polyploidy and the Cellular and Areal Diversity of Rat Cortical Layer 5 Pyramidal Neurons. AB - In many species, polyploidy, in which an increase in nuclear DNA content is accompanied by an increase in cell size, contributes to cellular diversity. In the rat visual cortex, most neurons are small and homogeneous in size, while layer 5 cells are heterogeneous, containing some very large neurons. To measure DNA content, we quantified nuclear chromocenters and integrated DNA/DAPI fluorescence. The results suggest that most cortical neurons, non-neuronal cells, parvalbumin-positive interneurons, and large entorhinal layer 2 stellate projection neurons are diploid. In contrast, chromocenter counts and integrated fluorescence are ~2-fold higher for some excitatory neurons in layer 5, suggesting that large Ctip2-negative and Ctip2-positive layer 5 neurons might be tetraploid. The distribution of putatively tetraploid neurons differed between areas and showed sharp borders aligned with functional subdivisions of the somatosensory cortex. Telomere counting and flow cytometry supported layer 5 polyploidy. We conclude that polyploidy contributes to cellular and areal diversity of rat cortex. PMID- 28903041 TI - miR-150-Mediated Foxo1 Regulation Programs CD8+ T Cell Differentiation. AB - MicroRNA (miR)-150 is a developmental regulator of several immune-cell types, but its role in CD8+ T cells is largely unexplored. Here, we show that miR-150 regulates the generation of memory CD8+ T cells. After acute virus infection, miR 150 knockout (KO) mice exhibited an accelerated differentiation of CD8+ T cells into memory cells and improved production of effector cytokines. Additionally, miR-150 KO CD8+ T cells displayed an enhanced recall response and improved protection against infections with another virus and bacteria. We found that forkhead box O1 (Foxo1) and T cell-specific transcription factor 1 (TCF1) are upregulated during the early activation phase in miR-150 KO CD8+ T cells and that miR-150 directly targets and suppresses Foxo1. These results suggest that miR-150 mediated suppression of Foxo1 regulates the balance between effector and memory cell differentiation, which might aid in the development of improved vaccines and T cell therapeutics. PMID- 28903040 TI - miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb. AB - MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified. Without miR-150, c-Myb was upregulated and anti-apoptotic targets of c-Myb, such as Bcl-2 and Bcl-xL, were also increased, suggesting a miR-150-c-Myb survival circuit during memory CD8 T cell development. Indeed, overexpression of non-repressible c-Myb rescued the memory CD8 T cell defects caused by overexpression of miR-150. Overall, these results identify a key role for miR-150 in memory CD8 T cells through a c-Myb-controlled enhanced survival circuit. PMID- 28903042 TI - Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy. AB - Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S alpha-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder. PMID- 28903043 TI - Mechanism of Catalytic Microtubule Depolymerization via KIF2-Tubulin Transitional Conformation. AB - Microtubules (MTs) are dynamic structures that are fundamental for cell morphogenesis and motility. MT-associated motors work efficiently to perform their functions. Unlike other motile kinesins, KIF2 catalytically depolymerizes MTs from the peeled protofilament end during ATP hydrolysis. However, the detailed mechanism by which KIF2 drives processive MT depolymerization remains unknown. To elucidate the catalytic mechanism, the transitional KIF2-tubulin complex during MT depolymerization was analyzed through multiple methods, including atomic force microscopy, size-exclusion chromatography, multi-angle light scattering, small-angle X-ray scattering, analytical ultracentrifugation, and mass spectrometry. The analyses outlined the conformation in which one KIF2core domain binds tightly to two tubulin dimers in the middle pre-hydrolysis state during ATP hydrolysis, a process critical for catalytic MT depolymerization. The X-ray crystallographic structure of the KIF2core domain displays the activated conformation that sustains the large KIF2-tubulin 1:2 complex. PMID- 28903044 TI - Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors. AB - Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering. PMID- 28903045 TI - Receptor Quaternary Organization Explains G Protein-Coupled Receptor Family Structure. AB - The organization of Rhodopsin-family G protein-coupled receptors (GPCRs) at the cell surface is controversial. Support both for and against the existence of dimers has been obtained in studies of mostly individual receptors. Here, we use a large-scale comparative study to examine the stoichiometric signatures of 60 receptors expressed by a single human cell line. Using bioluminescence resonance energy transfer- and single-molecule microscopy-based assays, we found that a relatively small fraction of Rhodopsin-family GPCRs behaved as dimers and that these receptors otherwise appear to be monomeric. Overall, the analysis predicted that fewer than 20% of ~700 Rhodopsin-family receptors form dimers. The clustered distribution of the dimers in our sample and a striking correlation between receptor organization and GPCR family size that we also uncover each suggest that receptor stoichiometry might have profoundly influenced GPCR expansion and diversification. PMID- 28903046 TI - Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity. AB - Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. Generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis. PMID- 28903047 TI - Caloric Restriction Promotes Structural and Metabolic Changes in the Skin. AB - Caloric restriction (CR) is the most effective intervention known to enhance lifespan, but its effect on the skin is poorly understood. Here, we show that CR mice display fur coat remodeling associated with an expansion of the hair follicle stem cell (HFSC) pool. We also find that the dermal adipocyte depot (dWAT) is underdeveloped in CR animals. The dermal/vennule annulus vasculature is enlarged, and a vascular endothelial growth factor (VEGF) switch and metabolic reprogramming in both the dermis and the epidermis are observed. When the fur coat is removed, CR mice display increased energy expenditure associated with lean weight loss and locomotion impairment. Our findings indicate that CR promotes extensive skin and fur remodeling. These changes are necessary for thermal homeostasis and metabolic fitness under conditions of limited energy intake, suggesting a potential adaptive mechanism. PMID- 28903048 TI - Set2 Methyltransferase Facilitates DNA Replication and Promotes Genotoxic Stress Responses through MBF-Dependent Transcription. AB - Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex dependent transcription in fission yeast. Set2 loss leads to reduced MBF dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast. PMID- 28903049 TI - A Mass Spectrometry-Based Approach for Mapping Protein Subcellular Localization Reveals the Spatial Proteome of Mouse Primary Neurons. AB - We previously developed a mass spectrometry-based method, dynamic organellar maps, for the determination of protein subcellular localization and identification of translocation events in comparative experiments. The use of metabolic labeling for quantification (stable isotope labeling by amino acids in cell culture [SILAC]) renders the method best suited to cells grown in culture. Here, we have adapted the workflow to both label-free quantification (LFQ) and chemical labeling/multiplexing strategies (tandem mass tagging [TMT]). Both methods are highly effective for the generation of organellar maps and capture of protein translocations. Furthermore, application of label-free organellar mapping to acutely isolated mouse primary neurons provided subcellular localization and copy-number information for over 8,000 proteins, allowing a detailed analysis of organellar organization. Our study extends the scope of dynamic organellar maps to any cell type or tissue and also to high-throughput screening. PMID- 28903050 TI - Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury. AB - Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor C-JUN regulates the expression of certain micro RNAs in repair Schwann cells, in particular miR-21 and miR-34. Surprisingly, unlike during development, changes in CpG methylation are limited in injury, restricted to specific locations, such as enhancer regions of Schwann cell-specific genes (e.g., Nedd4l), and close to local enrichment of AP-1 motifs. These genetic and epigenomic changes broaden our mechanistic understanding of the formation of repair Schwann cell during peripheral nervous system tissue repair. PMID- 28903052 TI - Resolution Mediator Chemerin15 Reprograms the Wound Microenvironment to Promote Repair and Reduce Scarring. PMID- 28903051 TI - Features of the Chaperone Cellular Network Revealed through Systematic Interaction Mapping. AB - A comprehensive view of molecular chaperone function in the cell was obtained through a systematic global integrative network approach based on physical (protein-protein) and genetic (gene-gene or epistatic) interaction mapping. This allowed us to decipher interactions involving all core chaperones (67) and cochaperones (15) of Saccharomyces cerevisiae. Our analysis revealed the presence of a large chaperone functional supercomplex, which we named the naturally joined (NAJ) chaperone complex, encompassing Hsp40, Hsp70, Hsp90, AAA+, CCT, and small Hsps. We further found that many chaperones interact with proteins that form foci or condensates under stress conditions. Using an in vitro reconstitution approach, we demonstrate condensate formation for the highly conserved AAA+ ATPases Rvb1 and Rvb2, which are part of the R2TP complex that interacts with Hsp90. This expanded view of the chaperone network in the cell clearly demonstrates the distinction between chaperones having broad versus narrow substrate specificities in protein homeostasis. PMID- 28903053 TI - Human Hippocampus Arbitrates Approach-Avoidance Conflict. PMID- 28903054 TI - Mechanical Forces of Fission Yeast Growth. PMID- 28903055 TI - Interneuronal Mechanism for Tinbergen's Hierarchical Model of Behavioral Choice. PMID- 28903056 TI - Quality of bystander cardiopulmonary resuscitation during real-life out-of hospital cardiac arrest. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) can increase survival in out-of hospital cardiac arrest (OHCA). However, little is known about bystander CPR quality in real-life OHCA. AIM: To describe bystander CPR quality based on automated external defibrillator (AED) CPR process data during OHCA and compare it with the European Resuscitation Council 2010 and 2015 Guidelines. METHODS: We included OHCA cases from the Capital Region, Denmark, (2012-2016) where a Zoll AED was used before ambulance arrival. For cases with at least one minute of continuous data, the initial 10min of CPR data were analysed for compression rate, depth, fraction and compressions delivered for each minute of CPR. Data are presented as median [25th;75th percentile]. RESULTS: We included 136 cases. Bystander median compression rate was 101min-1 [94;113], compression depth was 4.8cm [3.9;5.8] and compressions per minute were 62 [48;73]. Of all cases, the median compression rate was 100-120min-1 in 42%, compression depth was 5-6cm in 26%, compression fraction>=60% in 51% and compressions delivered per minute exceeded 60 in 54%. In a minute-to-minute analysis, we found no evidence of deterioration in CPR quality over time. The median peri-shock pause was 27s [23;31] and the pre-shock pause was 19s [17;22]. CONCLUSIONS: The median CPR performed by bystanders using AEDs with audio-feedback in OHCA was within guideline recommendations without deterioration over time. Compression depth had poorer quality compared with other parameters. To improve bystander CPR quality, focus should be on proper compression depth and minimizing pauses. PMID- 28903057 TI - Failure of non-vacuum steam sterilization processes for dental handpieces. AB - BACKGROUND: Dental handpieces are used in critical and semi-critical operative interventions. Although some dental professional bodies recommend that dental handpieces are sterilized between patient use there is a lack of clarity and understanding of the effectiveness of different steam sterilization processes. The internal mechanisms of dental handpieces contain narrow lumens (0.8-2.3 mm) which can impede the removal of air and ingress of saturated steam required to achieve sterilization conditions. AIM: To identify the extent of sterilization failure in dental handpieces using a non-vacuum process. METHODS: In-vitro and in vivo investigations were conducted on widely used UK bench-top steam sterilizers and three different types of dental handpieces. The sterilization process was monitored inside the lumens of dental handpieces using thermometric (TM; dataloggers), chemical indicator (CI), and biological indicator (BI) methods. FINDINGS: All three methods of assessing achievement of sterility within dental handpieces that had been exposed to non-vacuum sterilization conditions demonstrated a significant number of failures [CI: 8/3024 (fails/no. of tests); BI: 15/3024; TM: 56/56] compared to vacuum sterilization conditions (CI: 2/1944; BI: 0/1944; TM: 0/36). The dental handpiece most likely to fail sterilization in the non-vacuum process was the surgical handpiece. Non-vacuum sterilizers located in general dental practice had a higher rate of sterilization failure (CI: 25/1620; BI: 32/1620; TM: 56/56) with no failures in vacuum process. CONCLUSION: Non-vacuum downward/gravity displacement, type N steam sterilizers are an unreliable method for sterilization of dental handpieces in general dental practice. The handpiece most likely to fail sterilization is the type most frequently used for surgical interventions. PMID- 28903058 TI - Insuperable problems of the genetic code initially emerging in an RNA world. AB - Differential equations for error-prone information transfer (template replication, transcription or translation) are developed in order to consider, within the theory of autocatalysis, the advent of coded protein synthesis. Variations of these equations furnish a basis for comparing the plausibility of contrasting scenarios for the emergence of specific tRNA aminoacylation, ultimately by enzymes, and the relationship of this process with the origin of the universal system of molecular biological information processing embodied in the Central Dogma. The hypothetical RNA World does not furnish an adequate basis for explaining how this system came into being, but principles of self organisation that transcend Darwinian natural selection furnish an unexpectedly robust basis for a rapid, concerted transition to genetic coding from a peptide.RNA world. PMID- 28903059 TI - Cognitive flexibility in neurological disorders: Cognitive components and event related potentials. AB - Performance deficits on the Wisconsin Card Sorting Test (WCST) in patients with prefrontal cortex (PFC) lesions are traditionally interpreted as evidence for a role of the PFC in cognitive flexibility. However, WCST deficits do not occur exclusively after PFC lesions, but also in various neurological and psychiatric disorders. We propose a multi-component approach that can accommodate this pattern of omnipresent WCST deficits: the WCST is not a pure test of cognitive flexibility, but relies on the effective functioning of multiple dissociable cognitive components. Our review of recent efforts to decompose WCST performance deficits supports this view by revealing that WCST deficits in different neurological disorders can be attributed to alterations in different components. Frontoparietal changes underlying impaired set shifting seem to give rise to WCST deficits in patients with amyotrophic lateral sclerosis, whereas the WCST deficits associated with primary dystonia and Parkinson's disease are rather related to frontostriatal changes underlying deficient rule inference. Clinical implications of these findings and of a multi-component view of WCST performance are discussed. PMID- 28903060 TI - Effects of curcumin and curcumin analogues on TRP channels. AB - A series of 33 curcumin analogues was synthesized and tested on TRPA1, TRPM8, and TRPV1 channels. Twenty of them acted as good modulators of TRPA1 channels. None was able to significantly activate TRPM8 channels, while curcumin itself and six curcuminoids belonging to the 1,3-dicarbonyl and acyclic series behaved as 'true' antagonists with IC50 values<5MUM. Only few curcuminoids were able to modulate TRPV1 channels with EC50 and IC50 values ranging from 3.4 and 6.0MUM. PMID- 28903061 TI - Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases. AB - The belief that the vertebrate brain functions normally without classical lymphatic drainage vessels has been held for many decades. On the contrary, new findings show that functional lymphatic drainage does exist in the brain. The brain lymphatic drainage system is composed of basement membrane-based perivascular pathway, a brain-wide glymphatic pathway, and cerebrospinal fluid (CSF) drainage routes including sinus-associated meningeal lymphatic vessels and olfactory/cervical lymphatic routes. The brain lymphatic systems function physiological as a route of drainage for interstitial fluid (ISF) from brain parenchyma to nearby lymph nodes. Brain lymphatic drainage helps maintain water and ion balance of the ISF, waste clearance, and reabsorption of macromolecular solutes. A second physiological function includes communication with the immune system modulating immune surveillance and responses of the brain. These physiological functions are influenced by aging, genetic phenotypes, sleep-wake cycle, and body posture. The impairment and dysfunction of the brain lymphatic system has crucial roles in age-related changes of brain function and the pathogenesis of neurovascular, neurodegenerative, and neuroinflammatory diseases, as well as brain injury and tumors. In this review, we summarize the key component elements (regions, cells, and water transporters) of the brain lymphatic system and their regulators as potential therapeutic targets in the treatment of neurologic diseases and their resulting complications. Finally, we highlight the clinical importance of ependymal route-based targeted gene therapy and intranasal drug administration in the brain by taking advantage of the unique role played by brain lymphatic pathways in the regulation of CSF flow and ISF/CSF exchange. PMID- 28903063 TI - Cooperative regulation of Gja1 expression by members of the AP-1 family cJun and cFos in TM3 Leydig and TM4 Sertoli cells. AB - Within the testis, connexin43 encoded by Gja1 plays an important role in cell-to cell communication between Leydig cells as well as between Sertoli cells and spermatogonia. In the adult male, Leydig cells are the principal producers of testosterone sustaining spermatogenesis, while Sertoli cells nourish, protect and support the differentiating germ cells. It has been shown previously that members of the AP-1 family regulate Gja1 expression in myometrial cells, suggesting that such regulatory mechanism may also be relevant within the testis. Thus, we performed cotransfections of AP-1 expression plasmids with different mouse Gja1 promoter/luciferase reporter constructs within TM3 Leydig and TM4 Sertoli cells. We showed that a functional cooperation between cJun and cFos activates Gja1 expression and requires an AP-1 DNA regulatory element located between -132 and 26 bp. In addition, such synergy relies on the recruitment of cFos to this region of the mouse Gja1 promoter. Hence, our data indicate that AP-1 members are important for optimal expression of Gja1 within Sertoli and Leydig cells from the testis. PMID- 28903062 TI - Inflammatory dietary patterns and depressive symptoms in Italian older adults. AB - BACKGROUND: Older adults are more susceptible to higher inflammatory levels and depression. Moreover, diet may influence inflammation as well as depression but no previous study examined whether inflammatory dietary patterns are related to depression in an older population. To investigate the longitudinal association between inflammatory dietary patterns (using reduced rank regression (RRR)) and depressive symptoms in a population sample of Italian older adults. METHODS: We included 827 participants (aged>=65years) at baseline in 1998. Follow-up measurements were collected after 3, 6 and 9years. We used RRR to identify inflammatory dietary patterns at baseline. The Centre for Epidemiologic Studies Depression (CES-D) scale was used to assess depressive symptoms by using continuous scores and depression by using a cut-off point (CES-D>=20). RESULTS: We identified two inflammatory dietary patterns using different sets of response variables. Dietary pattern I was related to inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor alpha and was characterized by high intakes of refined grains, sweet snacks, pasta and rice. After full adjustment for confounders, no longitudinal association was found when comparing extreme quartiles of this dietary pattern and depressive symptoms (Q1vs Q4, model 4: B=0.04, 95% CI: -0.06, 0.13) or depression (Q1vs Q4, model 4: OR=0.90, 95% CI: 0.55, 1.45). Dietary pattern II was related to inflammatory markers CRP, IL-18, IL-1beta, IL-1 receptor antagonist and was characterized by high intakes of pasta, sugar-sweetened beverages, processed meat and chocolate and sweets. When comparing extreme quartiles, this dietary pattern was not longitudinally associated with depressive symptoms (Q1vs Q4, model 4: B=-0.04, 95% CI: -0.13, 0.05) but an inverse association was found for depression (Q1vs Q4, model 4: OR=0.56, 95% CI: 0.40, 0.94). CONCLUSION: Our study does not support the hypothesis that dietary patterns linked to inflammatory markers are associated with higher depressive symptoms and higher depression incidence. However, dietary intake in our population of older adults was quite homogeneous which makes it difficult to show clear associations. PMID- 28903064 TI - Isolation and characterization of peroxiredoxin 1 gene of Dunaliella salina. AB - Peroxiredoxin 1 (Prdx1) is a ubiquitously expressed protein in eukaryotic cells, and plays an important role in cell proliferation, differentiation, apoptosis, and redox signaling. Although Prdx1 has been better studied in yeasts and humans, only few Prdx1 genes have been cloned in green algae. The microalga Dunaliella salina (D. salina) is a model for the study of a variety of human cilia-related diseases. In this study, a suppression subtractive hybridization cDNA library of D. salina was constructed, and 6 flagellum-associated genes including D. salina Prdx1 (DsPrdx1) were isolated and identified. A 956bp full-length cDNA of DsPrdx1 was cloned using rapid amplification of cDNA end (RACE). The open reading frame (ORF) of this DNA sequence encodes a polypeptide of 201 amino acids with a predicted molecular weight of 22kDa and a theoretical isoelectric point (pI) of 5.27. Sequence comparison showed that Prdx1 is highly evolutionarily conserved from the unicellular green alga D. salina to human. To our knowledge, this is the first reported full-length sequence of Prdx1 in D. salina. Interestingly, the protein expression of DsPrdx1 was obviously increased during flagellar disassembly in D. salina. Additionally, a yeast two-hybrid assay showed interaction between Prdx1 and RNA, and suggested that DsPrdx1 can protect RNA from degradation by RNase. Taken together, DsPrdx1 not only participates in flagellar disassembly, but also protects RNA from degradation. PMID- 28903066 TI - Development of fine solid-crystal suspension with enhanced solubility, stability, and aerosolization performance for dry powder inhalation. AB - Dry powder for inhalation (DPI) is an attractive approach for the treatment of local lung diseases. However, the application of drugs with poor water solubility is often limited due to the dissolution obstacles in the fluid layer of the lung lining. In this study, fine solid-crystal suspension (FSCS) was proposed as a solvent-free method to improve the solubility of a drug with poor solubility (itraconazole) and achieve high deposition efficiency simultaneously. The FSCS, in which the crystalline drug particle was highly dispersed in the crystalline excipient, was initially prepared as drug-excipient extrudate by hot melt extrusion, followed by jet milling into fine particles. Unlike the amorphous solid dispersion in the high-energy state, which is liable to recrystallize and aggregate, the FSCS was expected not only to improve the solubility of itraconazole, but also to maintain excellent physical stability. As evidenced in the solubility and stability studies, the solubility of itraconazole in the FSCS was approximately 145-fold greater than that of the raw material, and the crystalline form of itraconazole in the FSCS was also unchanged after storage in the accelerated condition for 6 months (40 degrees C and 75% relative humidity [RH]). The improved solubility might be ascribed to the reduced crystal size and increased wettability, as confirmed by the particle size and contact angle test. The FSCS also showed an encouragingly high fine-particle fraction of 50.59+/ 0.67%, which might have benefited from the appropriate particle size. Therefore, the FSCS was suggested as a promising DPI for delivery of drugs with poor water solubility. PMID- 28903065 TI - Inflammation polymorphisms and prostate cancer risk in Jamaican men: Role of obesity/body size. AB - African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR>=0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score>=7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent. PMID- 28903067 TI - Carboxymethyl chitosan/phospholipid bilayer-capped mesoporous carbon nanoparticles with pH-responsive and prolonged release properties for oral delivery of the antitumor drug, Docetaxel. AB - In this article, a new type of carboxymethyl chitosan/phospholipid bilayer-capped mesoporous carbon nanomatrix (CCS/PL/MC) was fabricated as a potential nano-drug delivery system. In this drug delivery system, a mesoporous carbon nanomatrix (MC) acts as the support for loading drug molecules, a positively charged phospholipid (PL) layer works as the inner shell for prolonged drug release and a negatively charged carboxymethyl chitosan (CCS) layer serves as the outer shell for pH-responsive drug release. Docetaxel (DTX) was selected as a model drug. The drug-loaded CCS/PL/MC was synthesized via a combination approach of double emulsion/solvent evaporation followed by lyophilization. The drug-loaded nanoparticles were characterized for their particle size, structure, morphology, zeta (zeta)-potential, specific surface area, porosity, drug loading and solid state. In vitro drug release tests showed that the drug-loaded CCS/PL/MC nanoparticles possess a good pH-sensitivity and prolonged releasing ability with negligible release in gastric media and controlled release in intestinal media. Compared with MC and PL-capped MC, CCS/PL/MC had a greater mucoadhesiveness. Moreover, cellular uptake study indicated that CCS/PL/MC might improve intracellular drug delivery. These results suggest that this hybrid nanocarrier, combining the beneficial features of CCS, PL and MC, is a promising drug delivery system able to improve the oral absorption of antitumor drugs. PMID- 28903068 TI - The influence of hydroalcoholic media on the performance of Grewia polysaccharide in sustained release tablets. AB - Co-administration of drugs with alcohol can affect the plasma concentration of drugs in patients. It is also known that the excipients used in the formulation of drugs may not always be resistant to alcohol. This study evaluates effect of varying alcohol concentrations on theophylline release from two grades of Grewia mollis polysaccharides. X-ray microtomography showed that native polysaccharide formulation compacts were not homogenous after the mixing process resulting in its failure in swelling studies. Removal of starch from the native polysaccharide resulted in homogenous formulation compacts resistant to damage in high alcoholic media in pH 6.8 (40%v/v absolute ethanol). Destarched polymer compacts had a significantly higher hardness (375N) than that of the native polysaccharide (82N) and HPMC K4M (146N). Dissolution studies showed similarity at all levels of alcohol tested (f2=57-91) in simulated gastric media (pH 1.2). The dissolution profiles in the simulated intestinal fluids were also similar (f2=60-94), with the exception of the native polysaccharide in pH 6.8 (40%v/v absolute ethanol) (f2=43). This work highlights the properties of Grewia polysaccharide as a matrix former that can resist high alcoholic effects therefore; it may be suitable as an alternative to some of the commercially available matrix formers with wider applications for drug delivery as a cheaper alternative in the developing world. PMID- 28903069 TI - Cell reprogramming: Therapeutic potential and the promise of rejuvenation for the aging brain. AB - Aging is associated with a progressive increase in the incidence of neurodegenerative diseases, with Alzheimer's (AD) and Parkinson's (PD) disease being the most conspicuous examples. Within this context, the absence of efficacious therapies for most age-related brain pathologies has increased the interest in regenerative medicine. In particular, cell reprogramming technologies have ushered in the era of personalized therapies that not only show a significant potential for the treatment of neurodegenerative diseases but also promise to make biological rejuvenation feasible. We will first review recent evidence supporting the emerging view that aging is a reversible epigenetic phenomenon. Next, we will describe novel reprogramming approaches that overcome some of the intrinsic limitations of conventional induced-pluripotent-stem-cell technology. One of the alternative approaches, lineage reprogramming, consists of the direct conversion of one adult cell type into another by transgenic expression of multiple lineage-specific transcription factors (TF). Another strategy, termed pluripotency factor-mediated direct reprogramming, uses universal TF to generate epigenetically unstable intermediates able to differentiate into somatic cell types in response to specific differentiation factors. In the third part we will review studies showing the potential relevance of the above approaches for the treatment of AD and PD. PMID- 28903070 TI - Role of the AMPK pathway in promoting autophagic flux via modulating mitochondrial dynamics in neurodegenerative diseases: Insight into prion diseases. AB - Neurons are highly energy demanding cells dependent on the mitochondrial oxidative phosphorylation system. Mitochondria generate energy via respiratory complexes that constitute the electron transport chain. Adenosine triphosphate depletion or glucose starvation act as a trigger for the activation of adenosine monophosphate-activated protein kinase (AMPK). AMPK is an evolutionarily conserved protein that plays an important role in cell survival and organismal longevity through modulation of energy homeostasis and autophagy. Several studies suggest that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. Mild mitochondrial dysfunction leads to activated AMPK signaling, but severe endoplasmic reticulum stress and mitochondrial dysfunction may lead to a shift from autophagy towards apoptosis and perturbed AMPK signaling. Hence, controlling mitochondrial dynamics and autophagic flux via AMPK activation might be a useful therapeutic strategy in neurodegenerative diseases to reinstate energy homeostasis and degrade misfolded proteins. In this review article, we discuss briefly the role of AMPK signaling in energy homeostasis, the structure of AMPK, activation mechanisms of AMPK, regulation of AMPK, the role of AMPK in autophagy, the role of AMPK in neurodegenerative diseases, and finally the role of autophagic flux in prion diseases. PMID- 28903071 TI - Highly conserved M2e and hemagglutinin epitope-based recombinant proteins induce protection against influenza virus infection. AB - Highly pathogenic influenza viruses continue to cause serious threat to public health due to their pandemic potential, calling for an urgent need to develop effective, safe, convenient, and universal vaccines against influenza virus infection. In this study, we constructed two recombinant protein vaccines, 2H5M2e 2H7M2e-H5FP-H7FP (hereinafter M2e-FP-1) and 2H5M2e-H5FP-2H7M2e-H7FP (hereinafter M2e-FP-2), by respectively linking highly conserved sequences of two molecules of ectodomain of M2 (M2e) and one molecule of fusion peptide (FP) epitope of hemagglutinin (HA) of H5N1 and H7N9 influenza viruses in different orders. The Escherichia coli-expressed M2e-FP-1 and M2e-FP-2 proteins induced similarly high titer M2e-FP-specific antibodies in the immunized mice. Importantly, both proteins were able to prevent lethal challenge of heterologous H1N1 influenza virus, with significantly reduced viral titers and alleviated pathological changes in the lungs, as well as increased body weight and complete survivals, in the challenge mice. Taken together, our study demonstrates that highly conserved M2e and FP epitope of HA of H5N1 and H7N9 influenza viruses can be used as important targets for development of safe and economical universal influenza vaccines, and that the position of H7N9 M2e and H5N1 HA epitope sequences in the vaccine components has no significant effects on the immunogenicity and efficacy of M2e-FP-based subunit vaccines. PMID- 28903072 TI - The role of nuclear NS1 protein in highly pathogenic H5N1 influenza viruses. AB - The non-structural protein (NS1) of influenza A viruses (IAV) performs multiple functions during viral infection. NS1 contains two nuclear localization signals (NLS): NLS1 and NLS2. The NS1 protein is located predominantly in the nucleus during the early stages of infection and subsequently exported to the cytoplasm. A nonsense mutation that results in a large deletion in the carboxy-terminal region of the NS1 protein that contains the NLS2 domain was found in some IAV subtypes, including highly pathogenic avian influenza (HPAI) H7N9 and H5N1 viruses. We introduced different mutations into the NLS domains of NS1 proteins in various strains of IAV, and demonstrated that mutation of the NLS2 region in the NS1 protein of HPAI H5N1 viruses severely affects its nuclear localization pattern. H5N1 viruses expressing NS1 protein that is unable to localize to the nucleus are less potent in antagonizing cellular antiviral responses than viruses expressing wild-type NS1. However, no significant difference was observed with respect to viral replication and pathogenesis. In contrast, the replication and antiviral defenses of H1N1 viruses are greatly attenuated when nuclear localization of the NS1 protein is blocked. Our data reveals a novel functional plasticity for NS1 proteins among different IAV subtypes. PMID- 28903073 TI - Reconciling disparate information in continuity of care documents: Piloting a system to consolidate structured clinical documents. AB - BACKGROUND: Due to the nature of information generation in health care, clinical documents contain duplicate and sometimes conflicting information. Recent implementation of Health Information Exchange (HIE) mechanisms in which clinical summary documents are exchanged among disparate health care organizations can proliferate duplicate and conflicting information. MATERIALS AND METHODS: To reduce information overload, a system to automatically consolidate information across multiple clinical summary documents was developed for an HIE network. The system receives any number of Continuity of Care Documents (CCDs) and outputs a single, consolidated record. To test the system, a randomly sampled corpus of 522 CCDs representing 50 unique patients was extracted from a large HIE network. The automated methods were compared to manual consolidation of information for three key sections of the CCD: problems, allergies, and medications. RESULTS: Manual consolidation of 11,631 entries was completed in approximately 150h. The same data were automatically consolidated in 3.3min. The system successfully consolidated 99.1% of problems, 87.0% of allergies, and 91.7% of medications. Almost all of the inaccuracies were caused by issues involving the use of standardized terminologies within the documents to represent individual information entries. CONCLUSION: This study represents a novel, tested tool for de-duplication and consolidation of CDA documents, which is a major step toward improving information access and the interoperability among information systems. While more work is necessary, automated systems like the one evaluated in this study will be necessary to meet the informatics needs of providers and health systems in the future. PMID- 28903074 TI - SIZ1-mediated SUMOylation during phosphate homeostasis in plants: Looking beyond the tip of the iceberg. AB - Availability of phosphate (Pi) is often limited in rhizospheres in different agroclimatic zones and adversely affects growth and development of plants. To circumvent this impasse, there is an urgent need and global consensus to develop Pi use efficient crops. To achieve this goal, it is essential to identify the molecular entities that exert regulatory influences on the sensing and signaling cascade governing Pi homeostasis. SIZ1 encodes a small ubiquitin-like modifier (SUMO E3) ligase, and plays a pivotal role in the post-translational SUMOylation of proteins. In this review, we discuss the reverse genetics approach conventionally used for providing circumstantial evidence towards the regulatory influences of SIZ1 on several morphophysiological and molecular traits that govern Pi homeostasis in taxonomically diverse Arabidopsis thaliana (Arabidopsis) and Oryza sativa (rice) model species. However, the efforts have been rather modest in identifying SUMO protein targets that play key roles in the maintenance of Pi homeostasis in these model plants contrary to the plethora of them now known in lower organisms and animals. Therefore, to predict the SIZ1-mediated SUMOylome involved in Pi homeostasis, the state-of-the-art high-throughput technologies often used for animals thus provide an attractive paradigm towards achieving the long-term goal of developing Pi use efficient crops. PMID- 28903075 TI - Hidden Bias in Cost-Analysis Research: What Is the Prevalence of Under-Reporting Cost Perspective in the General Surgical Literature? PMID- 28903076 TI - Role of human DNA2 (hDNA2) as a potential target for cancer and other diseases: A systematic review. AB - DNA nuclease/helicase 2 (DNA2), a multi-functional protein protecting the high fidelity of genomic transmission, plays critical roles in DNA replication and repair processes. In the maturation of Okazaki fragments, DNA2 acts synergistically with other enzymes to cleave the DNA-RNA primer flaps via different pathways. DNA2 is also involved in the stability of mitochondrial DNA and the maintenance of telomeres. Moreover, DNA2 potentially participates in controlling the cell cycle by repairing the DNA replication faults at main checkpoints. In addition, previous evidences demonstrated that DNA2 also functions in the repair process of DNA damages, such as base excision repair (BER). Currently, large studies revealed the structures and functions of DNA2 in prokaryotes and unicellular eukaryotes, such as bacteria and yeast. However, the studies that highlighted the functions of human DNA2 (hDNA2) and the relationships with other multifunctional proteins are still elusive, and more precise investigations are immensely needed. Therefore, this review mainly encompasses the key functions of DNA2 in human cells with various aspects, especially focusing on the genome integrity, and also generalizes the recent insights to the mechanisms related to the occurrence of cancer and other diseases potentially linked to the mutations in DNA2. PMID- 28903077 TI - Assessing toxicity of metal contaminated soil from glassworks sites with a battery of biotests. AB - The present study addresses toxicological properties of metal contaminated soils, using glassworks sites in south-eastern Sweden as study objects. Soil from five selected glassworks sites as well as from nearby reference areas were analysed for total and water-soluble metal concentrations and general geochemical parameters. A battery of biotests was then applied to assess the toxicity of the glassworks soil environments: a test of phytotoxicity with garden cress (Lepidium sativum); the BioToxTM test for toxicity to bacteria using Vibrio fischeri; and analyses of abundancies and biomass of nematodes and enchytraeids. The glassworks and reference areas were comparable with respect to pH and the content of organic matter and nutrients (C, N, P), but total metal concentrations (Pb, As, Ba, Cd and Zn) were significantly higher at the former sites. Higher metal concentrations in the water-soluble fraction were also observed, even though these concentrations were low compared to the total ones. Nevertheless, toxicity of the glassworks soils was not detected by the two ex situ tests; inhibition of light emission by V. fischeri could not be seen, nor was an effect seen on the growth of L. sativum. A decrease in enchytraeid and nematode abundance and biomass was, however, observed for the landfill soils as compared to reference soils, implying in situ toxicity to soil-inhabiting organisms. The confirmation of in situ bioavailability and negative effects motivates additional studies of the risk posed to humans of the glassworks villages. PMID- 28903078 TI - Derivation of reliable empirical models describing lead transfer from metal polluted soils to radish (Raphanus sativa L.): Determining factors and soil criteria. AB - Reliable models describing Pb transfer from soils to food crops are useful in the improvement of soil protection guidelines. This study provides mechanistic insights from in-situ soil solution measurement on the Pb uptake in the root tissues (RF) of radish, grown in 25 representative Pb-contaminated agricultural soils. Lead speciation and regression analysis indicate that >88.6% of the variation in RF Pb is attributable to free Pb2+ activity (aPb2+) in the soil solution, which is predominantly controlled by pH and DOC. Higher DOC would increase the total dissolved Pb (CSol-Pb) in the soil solution but reduce the bioavailability of Pb to radish. CSol-Pb performs poorly in predicting RF Pb unless pH and DOC are included. However, 0.01M CaCl2 extractable Pb (CCC-Pb) alone can satisfactorily predict RF Pb, attributable to the fact that CCC-Pb is consistent with aPb2+. CCC-Pb can be predicted using CSol-Pb and pH. Total soil Pb (CT-Pb), or 0.43M HNO3 extractable Pb (CNA-Pb) has a strong, non-linear correlation with CSol-Pb or CCC-Pb and it is therefore not surprising that CT-Pb or CNA-Pb, together with pH and CEC, can also satisfactorily predict RF Pb. Derived models are effective in identification of soils where RF Pb exceeds the food quality standard (FQS). Soil Pb criteria based on CT-Pb, CNA-Pb and CCC-Pb are derived by inverse use of empirical models. The derived Pb criterion (target value) based on CCC-Pb is 0.02mgkg-1 and the stricter criterion (safe value) is 0.01mgkg-1, which allows a 5% probability for RF Pb to exceed FQS. Safe values based on CT-Pb and CNA-Pb ranged from 26 to 1036mgkg-1 and 9 to 745mgkg-1, respectively. PMID- 28903079 TI - Escalating patterns of emergency health care prior to first admission with amphetamine psychosis: A window of opportunity? AB - AIM: To describe health service contact in the two years prior to a first hospital admission with amphetamine-related psychosis, and to identify possible opportunities for early intervention. METHOD: Routine health data collections were used to identify 6130 persons aged 16-65 who had a first hospital admission with amphetamine-related psychosis in New South Wales (NSW), Australia, between 2005 and 2016. Health service contacts in the two years prior to first admission were identified, using public hospital, emergency department and community mental health data. Prior care was compared to 41,444 people with first psychosis admissions without amphetamine diagnoses. RESULTS: Two thirds of people with amphetamine-related psychosis had health service contact in the two years prior to their first psychosis admission. Of these, 45% had ED contacts and 30% had prior general hospital admissions. The likelihood of contact escalated throughout the two years prior to admission. Prior substance-related conditions, infectious diseases, injuries and accidents were common. Compared to other first psychosis admissions, people with amphetamine-related psychoses were less likely to have prior specialised mental health care (OR 0.84, 95% CI 0.78, 0.89) and more likely to have prior general health care (OR 1.40, 95% CI 1.29, 1.51). CONCLUSION: Emergency departments and units treating people with infectious diseases or injuries should consider strategies to detect amphetamine and other substance use. Early detection and referral to specialist mental health or drug and alcohol care may prevent some amphetamine-related psychoses. PMID- 28903080 TI - Transplacental transfer of maternal respiratory syncytial virus (RSV) antibody and protection against RSV disease in infants in rural Nepal. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia in children. RSV-specific antibody (ab) protects infants from disease, and may be increased by a potential strategy of maternal RSV vaccination. OBJECTIVES: To describe the effect of RSV antibody on RSV infection risk in infants in a resource-limited setting. STUDY DESIGN: In a prospective study in Nepal, women were enrolled during pregnancy and maternal and infant cord blood were collected at birth. Weekly surveillance for respiratory illness was performed from birth to 180days. Nasal swabs were tested for RSV by PCR and serum was tested using an RSV antibody microneutralization assay. Antibody concentrations at time of RSV infection were estimated based on a decay rate of 0.026 log2/day. RESULTS: Cord:maternal RSV antibody transfer ratio was 1.03 (0.88 1.19), with RSV antibody concentration of log2 11.3 and log2 11.7 in 310 paired maternal and infant samples, respectively. Cord blood RSV antibody was log2 12.1 versus 11.6 in those with or without RSV infection (P=0.86). Among infants with RSV infection, estimated RSV antibody concentration at time of infection did not differ in infants with upper (n=8; log2 10.7) versus lower respiratory tract infection (n=21; log2 9.8; P=0.37). Cord blood RSV antibody concentrations did not correlate with age at primary RSV infection (R=0.11; P=0.57). CONCLUSIONS: Transplacental transfer of RSV antibody from mother to the fetus was highly efficient in mother-infant pairs in rural Nepal, though higher antibody concentrations were not protective against earlier or more severe RSV infection in infants. PMID- 28903081 TI - Ethical practices in community-based research in non-suicidal self-injury: A systematic review. AB - BACKGROUND: The growing interest in community-based research on non-suicidal self injury (NSSI) reflects the high prevalence rates found among vulnerable adolescents and young adults. A significant concern in research with vulnerable populations, and on sensitive topics, is the development of an ethical framework that protects the needs and rights of the participants while responding to researchers' goals and limitations and the broader clinical and public health concerns. AIM: The aim of the present study was to review the ethical practices followed in community-based research on NSSI. METHOD: A systematic review of literature was conducted, based on PRISMA guidelines, on community-based surveys in NSSI, published between 1995 and 2016. A total of 93 studies were included in the review. RESULTS: The results examine a range of ethical issues; the procedures for consent and assent for study participation, protection of confidentiality and the limits of confidentiality, assessment of imminent risk of suicide and subsequent processes, and debriefing measures. The interaction between the study characteristics and the reported ethical procedures has been examined, with a focus on participant age, study design (cross-sectional or longitudinal), survey modality (paper-based survey or online survey) and primary variable/s of interest (only NSSI or NSSI and suicidal ideation/behavior) under study. The review describes the typical ethical practices in community-based research on NSSI, identifies the gaps in the existing literature, and has implications for the formulation of best-practice guidelines. PMID- 28903082 TI - Hesperidin, a citrus bioflavonoid, alleviates trichloroethylene-induced oxidative stress in Drosophila melanogaster. AB - Trichloroethylene (TCE) is a chlorinated organic pollutant of groundwater with diverse toxic effects in animals and humans. Here, we investigated the ameliorative role of hesperidin, a citrus bioflavonoid on TCE-induced toxicity in Drosophila melanogaster. Four groups of D. melanogaster (50 flies/vial, with 5 vials/group) were exposed to ethanol (2.5%, control), HSP (400mg/10g diet), TCE (10MUM/10g diet) and TCE (10MUM/10g diet)+HSP (400mg/10g diet) respectively in the diet for 5days. Then, selected oxidative stress and antioxidant markers were evaluated. The results showed that TCE significantly increased the level of reactive oxygen species (ROS) and inhibited catalase, glutathione S-transferase and acetylcholinesterase (AChE) activities with concurrent depletion of total thiol level. However, co-administration of TCE and hesperidin mitigated TCE induced depletion of antioxidants, and restored ROS level and AChE activity in the flies (p<0.05). Overall, hesperidin offered protective potency on TCE-induced oxidative stress in the flies via anti-oxidative mechanism. PMID- 28903083 TI - Delirium characteristics and outcomes in medical and surgical lnpatients: A subgroup analysis. AB - PURPOSE: Persistent delirium can negatively affect patients, increase healthcare costs, and extend the length of hospital stays. This investigation was undertaken to explore associations between patient characteristics and delirium outcomes. MATERIALS AND METHODS: Intensive care unit (ICU) and medical and surgical ward inpatients for whom psychiatric consultation was requested for delirium were included in this study. Delirium screening and ongoing assessments were conducted using the Confusion Assessment Method for ICU patients. RESULTS: Postoperative delirium developing as a secondary complication following surgery was found to be of significantly longer duration and associated with greater length of hospitalization compared with postoperative delirium attributable to surgery and delirium in medical patients. Medical patients with delirium had lower delirium recovery rates at discharge compared with surgical patients. CONCLUSIONS: The findings that patient type and timing of postoperative delirium are associated with differential delirium outcomes suggest that targeted screening and intervention approaches may be needed. Medical patients were more likely to be discharged before recovery from delirium compared with surgical patients. Differences in underlying chronic medical conditions may account for the observed differences in discharge condition between medical and surgical patients with delirium. PMID- 28903084 TI - Sepsis mortality score for the prediction of mortality in septic patients. AB - PURPOSE: To derive a prediction equation for 30-day mortality in sepsis using a multi-marker approach and compare its performance to the Sequential Organ Failure Assessment (SOFA) score. METHODS: This study included 159 septic patients admitted to an intensive care unit. Leukocytes count, procalcitonin (PCT), interleukin-6 (IL-6), and paraoxonase (PON) and arylesterase (ARE) activities of PON-1 were assayed from blood obtained on ICU presentation. Logistic regression was used to derive sepsis mortality score (SMS), a prediction equation describing the relationship between biomarkers and 30-day mortality. RESULTS: The 30-day mortality rate was 28.9%. The SMS was [elogit(p)/(1+elogit(p))]*100; logit(p)=0.74+(0.004*PCT)+(0.001*IL-6)-(0.025*ARE)-(0.059*leukocytes count). The SMC had higher area under the receiver operating characteristic curve (95% Cl) than SOFA score [0.814 (0.736-0.892) vs. 0.767 (0.677-0.857)], but is not statistically significant. When the SMS was added to the SOFA score, prediction of 30-day mortality improved compared to SOFA score used alone [0.845 (0.777 0.899), p=0.022]. CONCLUSIONS: A sepsis mortality score using baseline leukocytes count, PCT, IL-6 and ARE was derived, which predicted 30-day mortality with very good performance and added significant prognostic information to SOFA score. PMID- 28903085 TI - Multiscale molecular dynamics simulations of lipid interactions with P glycoprotein in a complex membrane. AB - P-glycoprotein (P-gp) can transport a wide range of very different hydrophobic organic molecules across the membrane. Its ability to extrude molecules from the cell creates delivery problems for drugs that target proteins in the central nervous system (CNS) and also causes drug-resistance in many forms of cancer. Whether a drug will be susceptible to export by P-gp is difficult to predict and currently this is usually assessed with empirical and/or animal models. Thus, there is a need to better understand how P-gp works at the molecular level in order to fulfil the 3Rs: Refinement, reduction and replacement of animals in research. As structural information increasingly becomes available, our understanding at the molecular level improves. Proteins like P-gp are however very dynamic entities and thus one of the most appropriate ways to study them is with molecular dynamics simulations, especially as this can capture the influence of the surrounding environment. Recent parameterization developments have meant that it is now possible to simulate lipid bilayers that more closely resemble in vivo membranes in terms of their composition. In this report we construct a complex lipid bilayer that mimics the composition of brain epithelial cells and examine the interactions of it with P-gp. We find that the negatively charged phosphatidylserine lipids in the inner leaflet of the membrane tend to form an annulus around P-gp. We also observed the interaction of cholesterol with three distinct areas of the P-gp. Potential of mean force (PMF) calculations suggest that a crevice between transmembrane helices 10 and 12 has particularly favourable interaction energy for cholesterol. PMID- 28903086 TI - An efficient size-dependent shear deformable shell model and molecular dynamics simulation for axial instability analysis of silicon nanoshells. AB - Understanding the size-dependent behavior of structures at nanoscale is essential in order to have an effective design of nanosystems. In the current investigation, the surface elasticity theory is extended to study the nonlinear buckling and postbuckling response of axially loaded silicon cylindrical naoshells. Thereby, an efficient size-dependent shear deformable shell model is developed including the size effect of surface free energy. A boundary layer theory of shell buckling in conjunction with a perturbation-based solution methodology is employed to predict the size dependency in the buckling loads and postbuckling behavior of silicon nanoshells having various thicknesses. After that, on the basis of the Tersoff empirical potential, a molecular dynamics (MD) simulation is performed for a silicon cylindrical nanoshell with thickness of four times of silicon lattice constant, the critical buckling load and critical shortening of which are extracted and compared with those of the developed non classical shell model. It is demonstrated that by taking the effects of surface free energy into account, a very good agreement is achieved between the results of the developed size-dependent continuum shell model and those of MD simulation. PMID- 28903087 TI - Control strategies for nitrous oxide emissions reduction on wastewater treatment plants operation. AB - The present paper focused on reducing greenhouse gases emissions in wastewater treatment plants operation by application of suitable control strategies. Specifically, the objective is to reduce nitrous oxide emissions during the nitrification process. Incomplete nitrification in the aerobic tanks can lead to an accumulation of nitrite that triggers the nitrous oxide emissions. In order to avoid the peaks of nitrous oxide emissions, this paper proposes a cascade control configuration by manipulating the dissolved oxygen set-points in the aerobic tanks. This control strategy is combined with ammonia cascade control already applied in the literature. This is performed with the objective to take also into account effluent pollutants and operational costs. In addition, other greenhouse gases emissions sources are also evaluated. Results have been obtained by simulation, using a modified version of Benchmark Simulation Model no. 2, which takes into account greenhouse gases emissions. This is called Benchmark Simulation Model no. 2 Gas. The results show that the proposed control strategies are able to reduce by 29.86% of nitrous oxide emissions compared to the default control strategy, while maintaining a satisfactory trade-off between water quality and costs. PMID- 28903088 TI - On-Line two dimensional liquid chromatography based on skeleton type molecularly imprinted column for selective determination of sulfonylurea additive in Chinese patent medicines or functional foods. AB - Substandard and counterfeit anti-diabetic medicines directly influence the health and impose a great danger to individual patients and to public health. Counterfeiting has become a serious and underreported problem in the pharmaceutical industry. There are a large number of counterfeit medicines flooded in anti-diabetic markets which effect human health directly and indirectly. Therefore, some novel analytical techniques are necessary to be established for detecting these counterfeit drugs. In this study, a novel skeleton type molecularly imprinted column was successfully prepared. Based on the column, a simple, fast and reliable two-dimensional chromatography analytical system was established for selective determination of the illegal sulfonylurea additive in traditional Chinese patent medicines and functional foods. The developed method was validated. The linearitiesof the method were tested with calibration curves using ten calibration points in the concentration range of 0.25-12.5MUg/g. The LODs were 0.0125MUg/g and 0.01MUg/g for tolbutamide and glibenclamide respectively. The five batches of Chinese patent medicines and dietary supplements obtained from different markets and online websites were tested by the validated method. With good retention time and spectral confirmation, chemical anti-diabetic substances were identified and quantified in traditional Chinese medicine and in dietary supplements. PMID- 28903089 TI - Simultaneous determination of pentoxifylline, metabolites M1 (lisofylline), M4 and M5, and caffeine in plasma and dried blood spots for pharmacokinetic studies in preterm infants and neonates. AB - Advances in bioanalytical methods are facilitating micro-volume and dried blood spot (DBS) analysis of drugs in biological matrices for pharmacokinetic studies in children and neonates. We sought to develop a UPLC-MS/MS assay for simultaneous measurement of caffeine, pentoxifylline (PTX) and three metabolites of PTX in both plasma and DBS. Caffeine, PTX, the metabolites M1 (lisofylline), M4 and M5, and the internal standards (caffeine-d9 and PTX-d6) were separated using a Waters Aquity T3 UPLC C18 column and gradient mobile phase (water methanol-formic acid). Retention times for caffeine, M5, M4, PTX and M1 were 1.6, 1.7, 1.9, 2.0 and 2.1min, respectively, with a run time of 5min. The precision (<=10%) and accuracy (<=15%) across the concentration range 0.1-50mg/L for caffeine, PTX and the three metabolites in plasma and DBS were within accepted limits, as were the limits of quantification (100MUg/L for caffeine and 10MUg/L for PTX, M1, M4 and M5). Caffeine, PTX and the metabolites were stable in DBS for >34days at room and refrigerated temperatures. Plasma and DBS samples were obtained from 24 preterm infants recruited into a clinical pharmacokinetic study of PTX. Paired analysis indicated that DBS concentrations were 9% lower than concurrent plasma concentrations for caffeine, 7% lower for PTX (consistent with the blood:plasma ratio) and 13% lower for M1 (lisofylline). The validated UPLC MS/MS method is suitable for micro-volume plasma and DBS analysis of caffeine, PTX and its metabolites for pharmacokinetic studies in paediatric patients. PMID- 28903090 TI - A descriptive analysis of alcohol behaviors across gender subgroups within a sample of transgender adults. AB - OBJECTIVE: Transgender (trans) adults are identified as an at-risk group for problem alcohol use. Descriptive empirical data examining alcohol behaviors among trans adults is limited. The present study investigates alcohol behaviors - quantity, frequency, alcohol-related problems, and drinking to cope motives - across sex assigned at birth, gender expression, and gender identity subgroups within a sample of trans adults. METHOD: A total of 317 trans participants were recruited to complete a cross-sectional battery of online measures assessing alcohol use behaviors, alcohol-related problems, and drinking to cope. Gender identity was assessed through two methods: (1) an open-ended question in which participants wrote-in their primary gender identity; and (2) participants rated the extent to which they identified with 14 gender identity categories. RESULTS: This sample had high rates of alcohol use, alcohol-related problems, and drinking to cope motives relative to the general population. Significant and meaningful differences in drinking frequency, alcohol-related problems and drinking motives were found according to gender expression, but not sex assigned at birth or gender identity. CONCLUSIONS: Future work should examine alcohol behaviors among trans individuals, including investigation of predictors and causal pathways, to inform prevention and intervention work aimed at reducing trans people's risk for alcohol-related problems. PMID- 28903091 TI - Environmental relevant concentrations of a chlorpyrifos commercial formulation affect two neotropical fish species, Cheirodon interruptus and Cnesterodon decemmaculatus. AB - The increase of cultivated areas together with the intensive use of pesticides have greatly contributed to impair the quality of aquatic systems along different areas of South America. The main goal of the present study was to assess the effects of a commercial formulation of chlorpyrifos at environmentally relevant concentrations on two native fish species, Cheirodon interruptus and Cnesterodon decemmaculatus. Adult individuals were exposed during 48 h to the following concentrations: 0.084 nl/l (Ci-Cf 1) and 0.84 nl/l (Ci-CF 2) in C. interruptus (Ci) of Clorfox (CF), and 0.84 nl/l (Cd-CF 1) and 8.4 nl/l (Cd-CF 2) in C. decemmaculatus (Cd). Fish behavior was evaluated through locomotor activity and space usage variables. The activity of acetylcholinesterase (AChE) in brain and muscle, catalase (CAT) and glutathione-S-transferase (GST) in brain, liver, muscle and gills, and aspartate amino-transferase (AST), alanine amino transferase (ALT), AST/ALT ratio and alkaline phosphatase (ALP) in liver, were measured. Both locomotor activity and space usage varied between the two species studied and between CF treatments. The enzyme activities showed significant variations in CAT for C. interruptus and in CAT, GST, AChE, AST, and AST/ALT for C. decemmaculatus under the exposure conditions. Given that both species responded to CF and the concentrations we tested are environmentally relevant, the presence of this pesticide in freshwater systems could impose a risk for populations of both native fish studied at field. PMID- 28903092 TI - Lethal and sublethal effects of the pirimicarb-based formulation Aficida(r) on Boana pulchella (Dumeril and Bibron, 1841) tadpoles (Anura, Hylidae). AB - Acute lethal and sublethal toxicity of the pirimicarb-based commercial formulation Aficida(r) were evaluated on Boana pulchella tadpoles. Whereas mortality was used as end point for lethality, frequency of micronuclei and other nuclear abnormalities as well as alterations in the frequency of erythroblasts in circulating blood as biomarkers for genotoxicity and cytotoxicity, respectively. Swimming, growth, developmental and morphological abnormalities were also employed as sublethal end points. Results show that the species is within the 13th percentile of the distribution of acute sensitivity of species to pirimicarb for aquatic vertebrates. Results revealed values of 23.78 and 101.45mg/L pirimicarb as LC5096h for GS25 and GS36 tadpoles, respectively. The most evident effects were related with the swimming activity with NOEC and LOEC values within the 0.005-0.39mg/L pirimicarb concentration range. Aficida(r) induced DNA damage at the chromosomal level by increasing micronuclei frequency and other nuclear abnormalities, i.e., lobbed and notched nuclei and binucleated cells. Cellular cytotoxicity was found after Aficida(r) treatment. The presence of abdominal oedemas in exposed organisms and thus flotation response of organisms could be proposed as a new sensitive exposure parameter. The multiple end point assessment approach used allowed a complete understanding the multi level of effects occurring by exposure to pirimicarb, at least in B. pulchella. PMID- 28903093 TI - Chlorination, chloramination and ozonation of carbamazepine enhance cytotoxicity and genotoxicity: Multi-endpoint evaluation and identification of its genotoxic transformation products. AB - Investigations have focused on the removal and transformation of pharmaceuticals during drinking water and wastewater treatment. In the present study, we investigated for the first time the changes of the cytotoxicity and genotoxicity based on different modes of action (MoAs) during chlorination, chloramination and ozonation processes of the anti-epileptic drug carbamazepine (CBZ). The results illustrated that ozonation enhanced the cytotoxicity and the chromosome damage effects on CHO-K1 cells detected by cytokinesis-block micronucleus (CBMN) assay based on high-content screening technique, though ozonation showed the highest removal efficiency for CBZ. Non-target chemical analysis followed by quantitative structure-activity relationship (QSAR) analysis for the transformation products (TPs) suggested that the chromosomal damage effects could probably be attributed to 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM) and 1-(2 benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD). In contrast to CBZ itself and the ozonated sample, the chlorinated and chloraminated samples caused DNA damage effects in SOS/umu test. Acridine, 9 (10) H-acridone, chlorinated 9 (10) H acridone and TP-237, which were first identified in the chlorination or chloramination processes, were predicted to be the DNA damaging agents. These genotoxic TPs were primarily generated from the oxidation of seven-membered N heterocyclic in CBZ. This study highlighted the potential adverse effects generated in ozonation process and the oxidation of N-heterocyclic containing pollutants. PMID- 28903094 TI - Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting. AB - BACKGROUND: Most Crohn's disease (CD) patients develop endoscopic recurrence within one year of intestinal resection. The best treatment method to prevent post-operative CD recurrence remains uncertain. METHODS: A total of 155 CD patients from 2 referral centres, who were undergoing intestinal resection with ileo-colonic anastomosis (January 2004-January 2015), were included. All subjects received preventive therapy with tumour necrosis factor antagonists (anti-TNFs), thiopurinesor mesalazine. The primary outcome was the rate of endoscopic recurrence (Rutgeerts score >=i2) in the 3 treatment groups. RESULTS: Patients treated with anti-TNFs were at significantly lower risk of endoscopic recurrence during the follow-up than those receiving thiopurines or mesalazine (incidence rates of 2.2, 3.0 and 4.8 per 100 person-months, respectively, log-rank, p = 0.011). The median time to recurrence was significantly longer in patients treated with anti-TNFs than in those who received thiopurines or mesalazine (37.0, 13.7, and 16.8 months, respectively, log-rank, p = 0.011). Anti-TNFs were more effective than mesalazine (univariable analysis, hazard ratio [HR] 0.45, 95% CI 0.26-0.77, p = 0.004; multivariable analysis, HR 0.45, 95% CI 0.26-0.77, p = 0.004), and non-significantly superior over thiopurines. CONCLUSION: Anti-TNF therapy was the most effective strategy for the prevention of endoscopic CD recurrence. PMID- 28903095 TI - Injury Resistance in the Setting of Liver Fibrosis Is Accompanied by the Inhibition of High-Mobility Group Box-1 Translocation and Release. AB - BACKGROUND: Injury resistance occurring in the setting of liver fibrosis is an interesting phenomenon not yet well characterized. In the present study, we investigated dynamically the injury resistance against acute challenge using animal models of hepatic fibrosis and spontaneous resolution, and focused on high mobility group box-1 (HMGB1), an important proinflammatory mediator. METHODS: The hepatic damage of control, fibrosis (CCl4, 6 weeks), and regressive mice with or without CCl4 challenge was dynamically observed and compared. The translocation and release of HMGB1 were assessed by immunohistochemical staining and enzyme linked immunosorbent assay, respectively. The gene expression of proinflammatory mediators was detected by real-time PCR. RESULTS: Our data showed that the fibrotic mice were invulnerable to acute CCl4 insult. The injury resistance diminished along with the resolution of liver fibrosis. Acute insult triggered the translocation and release of HMGB1 in control mice, which were remarkably inhibited in fibrotic mice, even under acute challenge. Nevertheless, regressive mice exhibited obvious translocation upon insult, especially for R12d mice. HMGB1 related proinflammatory immune responses were suppressed in fibrotic mice; however, they were restored in regressive mice upon insult. CONCLUSION: The injury resistance in the setting of liver fibrosis is accompanied by the inhibition of HMGB1 translocation and release as well as the suppression of HMGB1 related proinflammatory immune responses. PMID- 28903096 TI - Early Screening Parameters for Dysphagia in Acute Ischemic Stroke. AB - BACKGROUND: Dysphagia is a frequent symptom in patients with acute stroke. It is associated with malnutrition, aspiration and mortality. The identification of early screening parameters for dysphagia promptly leading to a professional swallowing examination is therefore of utmost importance. This study aimed to detect early and easily assessable predictors of dysphagia in a large cohort of patients with acute ischemic stroke. METHODS: Our analysis was based on data from a prospective in-hospital registry. Patients with ischemic stroke were included over the course of 3 years. Patients were scheduled to undergo a clinical swallowing investigation within the first 24 h after hospital admission. Step wise multivariate logistic regression was used to identify independent predictors of dysphagia in general and of pneumonia in particular. RESULTS: 1,646 patients with ischemic stroke were included. Stroke severity in terms of higher National Institute of Health Stroke Scale (NIHSS) values (p < 0.001), male gender (p = 0.006) and higher age (p < 0.001) independently predicted dysphagia. A receiver operating characteristics analysis revealed an NIHSS cut-off value of 4.5 for optimal differentiation between patients with and without dysphagia (sensitivity 0.77; specificity 0.77). Dysphagia (p < 0.001), male gender (p = 0.002), higher NIHSS scores (p < 0.001) and higher age (p = 0.002) were factors that were independently associated with pneumonia. The NIHSS cut-off value for differentiating between patients with and without pneumonia was 5.5 (sensitivity 0.91; specificity 0.67). CONCLUSIONS: Stroke severity in terms of NIHSS is a simple and reliable predictor of dysphagia. Patients with NIHSS values >=5 should be quickly directed towards a professional swallowing examination. Dysphagia was confirmed to be a strong predictor of pneumonia. PMID- 28903097 TI - 21st Surgical Research Days. Section of Surgical Research of the German Society of Surgery. September 21-23, 2017, Cologne, Germany: Abstracts. PMID- 28903098 TI - Cognitive Behavioral Analysis System of Psychotherapy versus Escitalopram in Patients with Chronic Depression: Results from a Naturalistic Long-Term Follow Up. PMID- 28903099 TI - Resilience Mediates the Influence of a Polymorphism in the Serotonin Transporter Gene on the Relationship between the Burden of Chronic Illness and Depression. PMID- 28903100 TI - From the Lesson of George Engel to Current Knowledge: The Biopsychosocial Model 40 Years Later. PMID- 28903101 TI - Citation Classics in Stroke: The Top-100 Cited Articles on Hemorrhagic Stroke. AB - BACKGROUND: Stroke is a disastrous disease and a major health burden worldwide, especially in Korea. Hemorrhagic stroke (HS) accounts for approximately 20% of all the types of strokes. It is important to be able to evaluate stroke diagnoses and evolving treatments. OBJECTIVE: We aimed to identify the top-100 cited articles and assess a paradigm shift that occurred in the field of HS. METHODS: We searched all articles that had been cited more than 100 times using the Web of Science citation search tool during January 2016. Among a total of 2,651 articles, we identified the top-100 cited articles on HS. RESULTS: The number of citations for the articles analyzed in this study ranged from 1,746 to 211, and the number of annual citations ranged from 125.6 to 5.5. Most of the articles that were published in Stroke (35%) and Journal of Neurosurgery (22%), originated in the United States (n = 56), were original articles (64%), and dealt with the natural history or etiology (n = 37) and vasospasm in subarachnoid hemorrhage (n = 8). CONCLUSIONS: We analyzed the top-100 cited articles in the field of HS based on citation rates. The results provide a unique perspective on historical and academic developments in this field. PMID- 28903102 TI - "Abandonment Psychotherapy" for Suicidal Patients with Borderline Personality Disorder: Long-Term Outcome. PMID- 28903103 TI - Change of Unresolved Attachment in Borderline Personality Disorder: RCT Study of Transference-Focused Psychotherapy. PMID- 28903104 TI - Basilar Artery Diameter Is Inversely Associated with Fetal Type Circle of Willis. AB - BACKGROUND: The relationship between basilar artery (BA) diameter and Circle of Willis (CoW) configuration has been scarcely investigated. We aimed to assess this association in community-dwelling older adults. METHODS: MRAs of 346 individuals were reviewed. Using generalized linear models adjusted for demographics and cardiovascular risk factors, we assessed the relationship between BA diameter and fetal and non-fetal types CoW, as well as the impact of this relationship on BA ectasia prevalence. RESULTS: In the total population, the mean BA diameter was 3.13 +/- 0.68 mm and 7 subjects (2%) had ectasia (BA diameter >4.5 mm). In 248 subjects with non-fetal types CoW, the mean BA diameter was 3.32 +/- 0.62 mm, and 2.8% had ectasia. In 98 subjects with fetal type CoW, the mean BA diameter was 2.66 +/- 0.58 mm, and no individual had ectasia. The BA diameter was smaller in subjects with fetal type CoW than in those with non-fetal types (beta 0.65; 95% CI 0.51-0.79; p < 0.001). Individuals with fetal type CoW have an 18% reduction in BA diameter compared to those with non-fetal types, independently of demographics and cardiovascular risk factors. CONCLUSION: This study shows an inverse relationship between the BA diameter and the presence of fetal type CoW. PMID- 28903105 TI - Salvage Hepatectomy for Recurrent Hepatocellular Carcinoma after Radiofrequency Ablation and/or Transcatheter Arterial Chemoembolization: A Propensity Score Matched Analysis. AB - AIM: We aimed to evaluate the short- and long-term surgical outcomes of salvage hepatectomy for recurrent hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) and/or transcatheter arterial chemoembolization (TACE). METHODS: We reviewed the surgical outcomes of 90 recurrent HCC patients after RFA and/or TACE (salvage group) and 490 HCC patients without preoperative treatment (primary group). We performed 1:1 propensity score matching (PSM) between the 2 groups and matched 87 patients in each group. RESULTS: Before PSM, the salvage group was pathologically more advanced than the primary group. After PSM, there were no significant differences in the clinicopathological features between the groups. The outcomes of propensity score-matched groups were compared and there was no statistically significant difference between the 2 groups regarding perioperative outcomes and survival. Univariate and multivariate analyses of propensity score matched HCC patients revealed that stage, tumor size, differentiation, and portal vein invasion were independent prognostic factors for survival. Preoperative RFA and/or TACE was not a prognostic factor in a propensity score-matched cohort. CONCLUSIONS: The short- and long-term surgical outcomes of the primary and salvage groups were similar under the matched clinicopathological background. Salvage hepatectomy might be an acceptable treatment for recurrent HCC patients after RFA and/or TACE. PMID- 28903106 TI - Constantin Tsiminakis (1875-1942): Neurologist, Neuropathologist, Statesman. AB - The article is a 75-year memorial tribute to the Greek neurologist, Constantin Tsiminakis (1875-1942). Coming from a family of physicians, Tsiminakis graduated from the University of Athens in 1897, and trained in Vienna under Nothnagel, Frankl-Hochwart, and Obersteiner. In 1905, he was appointed Reader in Neurology and Psychiatry at his alma mater. He published over 40 articles on topics of neurology and neuropathology, including megalencephaly, hydrocephalus, progressive paralysis, epidemic encephalitis, dengue fever, and narcolepsy. However, his main focus of interest was epilepsy, including post-encephalitic forms. To differentially diagnose true from feigned epilepsy, he devised a method of compressing the carotids, which became known as the "Tsiminakis maneuver". A cultivated man and a talented poet, he rebutted the Freudian interpretation of artistic creativity. Finally, in the national legislative election in 1923, Tsiminakis was elected a Plenipotentiary Member of the Hellenic Parliament under the Liberal Party and served until 1925. PMID- 28903108 TI - Editorial. PMID- 28903107 TI - Dose Escalation of Antidepressants in Unipolar Depression: A Meta-Analysis of Double-Blind, Randomized Controlled Trials. AB - BACKGROUND: As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure. METHODS: We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes. RESULTS: Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (N [number of studies] = 2, n [number of patients] = 448), sertraline (N = 2, n = 272), paroxetine (N = 2, n = 146), duloxetine (N = 1, n = 255), and maprotiline (N = 1, n = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (N = 7, n = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; p = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes. CONCLUSIONS: According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression. PMID- 28903109 TI - Does Breastfeeding Shape Food Preferences? Links to Obesity. AB - The first 2 years of life have been recognized as a critical window for obesity prevention efforts. This period is characterized by rapid growth and development and, in a relatively short period of time, a child transitions from a purely milk based diet to a more varied solid-food diet. Much learning about food and eating occurs during this critical window, and it is well-documented that early feeding and dietary exposures predict later food preferences, eating behaviors, and dietary patterns. The focus of this review will be on the earliest feeding experiences - breast- and formula-feeding - and the unique role of breastfeeding in shaping children's food preferences. Epidemiological data illustrate that children who were breastfed have healthier dietary patterns compared to children who were formula-fed, even after controlling for relevant sociodemographic characteristics associated with healthier dietary and lifestyle patterns. These dietary differences are underlined, in part, by early differences in the opportunities for flavor learning and preference development afforded by breast- versus formula-feeding. In particular, the flavors of the mothers' diet are transmitted from mother to child through the amniotic fluid and breastmilk. The flavors experienced in these mediums shape later food preferences and acceptance of the solid foods of the family and culture onto which the infant is weaned. All infants learn from flavor experiences in utero, but only breastfed infants receive the additional reinforcement and flavor learning provided by continued repeated exposure to a wide variety of flavors that occurs during breastfeeding. Given the numerous benefits of breastfeeding, promotion of breastfeeding during early infancy is an important focus for primary prevention efforts and should be combined with efforts to ensure that mothers consume healthy, varied diets during pregnancy and lactation, and expose their infants to a wide array of foods during weaning and solid-food feeding. PMID- 28903110 TI - Flavor Perception and Preference Development in Human Infants. AB - As most parents and caregivers are aware, feeding children a nutritionally balanced diet can be challenging. Children are born with a biological predisposition to prefer sweet and to avoid bitter foods such as green leafy vegetables. It has been hypothesized that this predisposition evolved to attract children to energy-dense foods while discouraging the consumption of toxins. Although this may have enhanced survival in environments historically characterized by food scarcity, it is clearly maladaptive in many of today's food environments where children are surrounded by an abundance of sweet-tasting, unhealthful foods and beverages that place them at risk for excessive weight gain. Because overweight or obese children tend to become overweight or obese adults who are at risk for a range of cardiovascular diseases, it is of primary importance to develop effective evidence-based strategies to promote the development of healthy eating styles. Fortunately, accumulating evidence suggests that, starting before birth and continuing throughout development, there are repeated and varied opportunities for children to learn to enjoy the flavors of healthful foods. Because flavors are transmitted from the maternal diet to amniotic fluid and breast milk, mothers who consume a variety of healthful foods throughout pregnancy and lactation provide their infants with an opportunity to learn to like these flavors. This in turn eases the transition to healthful foods at weaning. In contrast, infants fed formula learn to prefer its invariant flavor profile, which differs from breast milk, and may initially be less accepting of flavors not found in formula. This process can continue throughout weaning and into childhood if infants are repeatedly exposed to a variety of healthful foods, even if they initially dislike them. These early-life sensory experiences establish food preferences and dietary patterns that set the stage for lifelong dietary habits. PMID- 28903111 TI - Type 1 Taste Receptors in Taste and Metabolism. AB - Our sense of taste allows us to evaluate the nutritive value of foods prior to ingesting them. Sweet taste signals the presence of sugars, and savory taste signals the presence of amino acids. The ability to identify these macronutrients in foods was likely crucial for the survival of our species when nourishing food sources were sparse. In modern, industrialized settings, taste perception continues to play an important role in human health as we attempt to prevent and treat conditions stemming from overnutrition. Recent research has revealed that type 1 taste receptors (T1Rs), which are largely responsible for sweet and umami taste, may also influence the absorption and metabolism of the foods we eat. Preliminary research shows that T1Rs contribute to intestinal glucose absorption, blood sugar and insulin regulation, and the body's responses to excessive energy intake. In light of these findings, T1Rs have come to be understood as nutrient sensors, among other roles, that facilitate the selection, digestion, and metabolism of foods. PMID- 28903112 TI - Savoring Sweet: Sugars in Infant and Toddler Feeding. AB - During the first years of life, the sweetness of sugars has a capacity to hinder or to help in laying a strong nutritional foundation for food preferences that often extend over a lifetime. Aside from supplying 4 g/kcal of energy, sugars are non-nutritive. However, sugars have a powerful attribute, sweetness, which strongly influences human food preference. A child's first relationship with sweet taste begins even before birth and continues to evolve throughout complementary feeding. The sweetness of breastmilk encourages consumption and soothes the neonate. Conversely, inappropriate introduction of non-milk solids and beverages that are sweet at 0-4 months of age raises the newborn's risk for later obesity and may discourage the acceptance of other bitter or sour foods. Although cereals, fruits, 100% fruit juices, and some grains have naturally occurring sugars that impart sweet flavor notes, there is no clear role for added sugars between 6 and 12 months of age. Yet, 60% of infants are introduced to foods and beverages containing added sugars, threatening diet quality. Pairing foods with naturally occurring sugars, such as fruits, with foods that tend to be resisted initially, such as vegetables, can mask bitterness and promote acceptance. Utilizing the infants' extraordinary capacity for sensory-motor exploration is another strategy to expose them repeatedly to challenging tastes and flavors. The transitional year, as breast milk and infant formula are withdrawn, is a time when nutritional needs are high and diet quality often precarious. Rapid growth, along with brain and cognitive development, demand high quality nutrition. Snacks are necessary both for energy and valuable nutrients. However, the selection of snack foods often exposes toddlers to items that offer concentrated energy with low nutrient value. Recent trends suggest a rapid fall in added sugars among infants and toddlers. Parenting practices that use small amounts of sugars to promote nutrient-rich foods from all 5 food groups can enhance rather than hinder their child's emerging dietary pattern. PMID- 28903114 TI - A Reply to Stiefel et al. "Losing the 'Person' in Personalized Medicine". PMID- 28903115 TI - ERAP1 and PDE8A Are Downregulated in Cattle Protected against Bovine Tuberculosis. AB - Bovine tuberculosis (bTB) is a zoonotic disease caused by Mycobacterium bovis that is responsible for significant economic losses worldwide. In spite of its relevance, the limited knowledge about the host immune responses that provide effective protection against the disease has long hampered the development of an effective vaccine. The identification of host proteins with an expression that correlates with protection against bTB would contribute to the understanding of the cattle defence mechanisms against M. bovis infection. In this study, we found that ERAP1 and PDE8A were downregulated in vaccinated cattle that were protected from experimental M. bovis challenge. Remarkably, both genes encode proteins that have been negatively associated with immune protection against bTB. PMID- 28903116 TI - Poorer Long-Term Outcomes among Persons with Major Depressive Disorder Treated with Medication. PMID- 28903117 TI - The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis. AB - BACKGROUND: Antidepressants (ADs) are commonly prescribed medications, but their long-term health effects are debated. ADs disrupt multiple adaptive processes regulated by evolutionarily ancient biochemicals, potentially increasing mortality. However, many ADs also have anticlotting properties that can be efficacious in treating cardiovascular disease. We conducted a meta-analysis assessing the effects of ADs on all-cause mortality and cardiovascular events in general-population and cardiovascular-patient samples. METHODS: Two reviewers independently assessed articles from PubMed, EMBASE, and Google Scholar for AD related mortality controlling for depression and other comorbidities. From these articles, we extracted information about cardiovascular events, cardiovascular risk status, and AD class. We conducted mixed-effect meta-analyses testing sample type and AD class as moderators of all-cause mortality and new cardiovascular events. RESULTS: Seventeen studies met our search criteria. Sample type consistently moderated health risks. In general-population samples, AD use increased the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular patients, AD use did not significantly affect risks. AD class also moderated mortality, but the serotonin reuptake inhibitors were not significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI: 0.93-1.31, p = 0.27). Only "other ADs" were differentiable from TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased when we analyzed the subset of studies controlling for premedication depression, suggesting the absence of confounding by indication. CONCLUSIONS: The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients. PMID- 28903118 TI - No Association between Vitiligo and Obesity: A Case-Control Study. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between vitiligo and body mass index (BMI) to assess the possible association between vitiligo and obesity. SUBJECTS AND METHODS: This was a case-control study on a total of 400 participants, i.e., 200 patients with vitiligo and 200 healthy volunteers. Medical assessments were performed by dermatologists using the modified Vitiligo European Task Force form. The height and weight of all of the participants were measured and used to calculate the BMI. Data were analyzed using multivariate logistic regression models. Adjustment for age and gender was carried out preliminarily in the case-control analysis, whereas a forward stepwise selection algorithm was used to assess which independent factors were associated with a BMI >=30 or a BMI <=18.5. RESULTS: Comparison of the vitiligo and control groups revealed the absence of a significant association. The multivariate analysis of factors associated with a high BMI (>=30) in vitiligo patients showed a significant association between a high BMI and a sudden onset of vitiligo (p = 0.021; OR = 3.83; 95% CI 1.22-11.99) and the presence of inflammation and pruritus (p = 0.031; OR = 3.26; 95% CI 1.11-9.57). No significant association was observed in the analysis of factors associated with a low BMI (<=18.5) in vitiligo patients. CONCLUSION: In this study, vitiligo did not appear to be associated with a high BMI; obesity might not be a risk factor for vitiligo, in contrast to most autoimmune diseases which are significantly associated with obesity. PMID- 28903119 TI - Multimodal Brain Analysis of Functional Neurological Disorders: A Functional Stroke Mimic Case Series. PMID- 28903120 TI - Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis. AB - BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation. PMID- 28903121 TI - Losing the "Person" in Personalized Medicine. PMID- 28903122 TI - Impact of Ixekizumab Treatment on Depressive Symptoms and Systemic Inflammation in Patients with Moderate-to-Severe Psoriasis: An Integrated Analysis of Three Phase 3 Clinical Studies. AB - BACKGROUND: Depression is a common comorbidity in psoriasis, and both conditions are associated with systemic inflammation. The efficacy of ixekizumab, a high affinity monoclonal antibody that selectively targets interleukin (IL)-17A, was evaluated in patients with moderate-to-severe plaque psoriasis (psoriasis) and depressive symptoms that were at least moderately severe. METHODS: Data were integrated from 3 randomized, double-blind, controlled phase 3 trials. At baseline and week 12, depressive symptoms and inflammation were assessed by the 16-item Quick Inventory of Depressive Symptomology - Self-Report (QIDS-SR16) and by a high-sensitivity assay of serum C-reactive protein (hsCRP), respectively. A subgroup of patients with at least moderately severe depressive symptoms at baseline (QIDS-SR16 total score >=11) was analyzed. Improvement in psoriasis was assessed by the Psoriasis Area and Severity Index (PASI). RESULTS: Approximately 10% of the overall psoriasis population had at least moderately severe depressive symptoms at baseline. At week 12, comorbid patients treated with ixekizumab had significantly greater improvements in their QIDS-SR16 total score (ixekizumab 80 mg every 2 weeks [Q2W], -7.1; ixekizumab 80 mg every 4 weeks [Q4W], -6.1) vs. placebo (-3.4) (p < 0.001, both comparisons) and higher rates of remission of depressive symptoms (ixekizumab Q2W, 45.2%; ixekizumab Q4W, 33.6%) vs. placebo (17.8%) (p <= 0.01, both comparisons). Patients treated with ixekizumab also had significant reductions in hsCRP and PASI compared to placebo. Etanercept treatment was not associated with significant improvements in depressive symptoms compared to placebo. CONCLUSIONS: In this comorbid population, 12 weeks of ixekizumab therapy resulted in remission of depression for approximately 40% of patients and improved systemic inflammation as indicated by hsCRP. PMID- 28903123 TI - Potential Effects of Hormone Therapy in Type 2 Idiopathic Macular Telangiectasia. AB - PURPOSE: To investigate the influence of hormone therapy with tamoxifen or estrogens on morphological changes in macular telangiectasia (MacTel) type 2 patients as revealed clinically in multiple imaging modalities. METHODS: Patients with a history of tamoxifen or estrogen use were selected from the cohort of the MacTel Study. A race-, age- and best-corrected visual acuity-matched group of MacTel participants not under hormone therapy served as the comparison group. The frequencies of typical features of the MacTel phenotype apparent in color fundus, red-free, fluorescein angiographic and optical coherence tomographic images were graded and analyzed statistically. RESULTS: Thirty-nine MacTel patients were included in the analyses, of whom 13 were receiving tamoxifen, 13 estrogens and 13 patients no hormone treatment. Patients treated with estrogens showed significantly fewer breaks in the ellipsoid zone on optical coherence tomography (7 eyes, 29.1%, vs. tamoxifen: 14 eyes, 53.8%, and vs. controls: 14 eyes, 53.8%, p = 0.04 in both analyses, Fisher exact test). Retinal crystalline deposits were significantly more frequent in patients receiving estrogens (12 eyes, 16.2%, vs. 2 eyes, 2.7%, p = 0.003, Fisher exact test). No significant between-group differences were apparent with regard to other features of the phenotype (extent of retinal low reflective spaces, late hyperfluorescence on fluorescein angiography or retinal thickness). CONCLUSIONS: Tamoxifen treatment does not seem to accentuate structural changes in patients with MacTel type 2. Treatment with estrogens may exhibit a neuroprotective effect as suggested by the decreased frequency of ellipsoid zone breaks in corresponding patients, although corroborative studies are warranted to confirm these exploratory data. PMID- 28903124 TI - Early monitoring of osteoporosis treatment response by technetium-99m-methylene diphosphonate bone scan. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of a technetium-99m-methylene diphosphonate (Tc-MDP) bone scan and the bone mineral density (BMD) test in monitoring the efficacy of osteoporosis (OP) treatment. PATIENTS AND METHODS: A total of 50 women with OP were prospectively enrolled in this study from January 2011 to October 2016 in our hospital. All the patients underwent a Tc-MDP whole-body bone scan and the BMD test before and after alendronate sodium treatment at 3, 6, 12 and 18 months, respectively. Bone metabolism rate on the Tc-MDP bone scan was analysed and expressed as the region of-interest (ROI) ratio of target bones (L1-L4 vertebrae and femoral neck) to the control right tibia shaft, which was subsequently compared with the bone mass on BMD test at each time point of the treatment. RESULTS: The mean ROI ratio of the L1 vertebra on the Tc-MDP bone scans decreased significantly starting at 3 months and continued to decrease at 6, 12 and 18 months, respectively (P<0.001). The mean ROI ratio decreased significantly starting at 6 months at the L2 (P<0.001) and L3 (P<0.001) and starting at 12 months at the L4 (P<0.001) and the right femoral head (P<0.001), respectively. In contrast, the BMD levels of the L1, L2, L3 and L4 vertebrae and the femoral neck increased significantly after 12, 12, 18, 18 and 18 months alendronate treatment respectively. CONCLUSION: Tc-MDP bone scan can detect the alendronate therapeutic efficacy for OP much earlier than the BMD test. PMID- 28903127 TI - Considerations for Using the HIRI-MSM Screening Tool to Identify MSM Who Would Benefit Most From PrEP. PMID- 28903128 TI - Performance of Virological Testing for Early Infant Diagnosis: A Systematic Review: Erratum. PMID- 28903129 TI - Improving Detection of HIV-Associated Cognitive Impairment: Comparison of the International HIV Dementia Scale and a Brief Screening Battery: Erratum. PMID- 28903126 TI - Substance Use and HIV Risk Among Men Who Have Sex With Men in Africa: A Systematic Review. AB - BACKGROUND: Substance use and its relation to HIV risk among men who have sex in Africa, a population at high risk for HIV, has received little attention. METHODS: This systematic review summarizes and discusses findings from 68 empirical studies, published between 1980 and 2016 that included data about substance use in men who have sex with men (MSM) in Africa. RESULTS: Substance use has rarely been the primary focus of studies in African MSM. In general, measurement of substance use was suboptimal. Whereas prevalence of alcohol use varied across studies, partly resulting from variety in assessment strategies, it seemed higher than in the general male population across countries. Alcohol use was associated with sexual risk practices, but not with HIV infection. The most frequently reported drug used by African MSM was cannabis. The use of other drugs, such as cocaine and heroin seemed relatively rare, although injection drug use was exceptionally high in a few studies. As alcohol, drugs were regularly used in conjunction with sex. Both alcohol and drug use were often associated with other risk factors for HIV infection, including violence and transactional sex. No interventions were found addressing substance use among African MSM. CONCLUSIONS: Given high HIV risk and prevalence in this population, substance use should be studied more in-depth, taking into account the specific social and cultural context. Assessment of substance use practices in this population has to be improved. The available information suggests, though, that there is an urgent need for interventions addressing substance use tailored to the needs of this critical population. PMID- 28903130 TI - Addressing Minority Representation in Dermatology: Answering a Call to Action Through Structured Mentorship and Instruction. PMID- 28903132 TI - Generalized Net-like Erythema and Stroke in a Young Female. PMID- 28903133 TI - Factors to Consider for Reducing US Opioid-Related Deaths: Looking Beyond Access Reply: Factors to Consider for Reducing US Opioid-Related Deaths-Reply. PMID- 28903131 TI - Association of O6-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer. AB - Importance: Loss of O6-methylguanine-DNA methyltransferase (MGMT) protein expression has been reported in several malignant tumors and predicts dismal survival outcomes. In gastric cancer, existing studies on this topic are limited and the association between MGMT and fluorouracil-based adjuvant chemotherapy remains obscure. Objective: To investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy. Design, Setting, and Participants: This study recruited 445 consecutive patients with resectable gastric cancer who underwent radical gastrectomy between August 1, 2007, and December 30, 2008, at Zhongshan Hospital at Fudan University in Shanghai, China. Patients were randomly divided into a discovery data set (n = 200) and a validation data set (n = 245), and the range of follow-up time was from 2 to 76 months for the discovery group and 2 to 79 months for the validation group. The immunoreactivity for MGMT in cancer cells was reviewed under a light microscope by 2 pathologists who were blinded to the clinicopathological data. The association of MGMT expression with clinicopathological characteristics and measures and prognosis was inspected. Data and specimens were collected from patients from the date of surgery to April 25, 2014. Data analysis took place from May 9, 2016, to July 15, 2016. Main Outcomes and Measures: Estimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk. Results: Of the 445 patients included in the study, 315 (70.8%) were men, and the mean (SD) age of all patients was 60 (12) years. Positive expression of MGMT indicated better overall survival for patients with stage II or III gastric cancer in both the discovery data set (HR, 0.52; 95% CI, 0.32-0.84; P = .003) and the validation data set (HR, 0.63; 95% CI, 0.43 0.93; P = .01). Multivariate analysis identified MGMT expression and TNM stage as 2 independent prognostic factors for overall survival. In stage II disease, the benefit from fluorouracil-based adjuvant chemotherapy was superior among MGMT positive patients (HR, 0.35; 95% CI, 0.13-0.95; P = .007 for interaction) compared with MGMT-negative patients. Conclusions and Relevance: Positive expression of MGMT in gastric cancer was identified as an independent, favorable prognostic factor. Incorporating MGMT expression into the current TNM staging system could lead to better prognostic accuracy. These findings should be confirmed within the framework of randomized clinical trials associated with genomic DNA sequencing studies. PMID- 28903134 TI - Task Shifting in Dermatology: A Call to Action. AB - Clinical Question: Can task shifting be used to improve the delivery of dermatologic care in resource-poor settings worldwide? Bottom Line: Task shifting is a means of redistributing available resources, whereby highly trained individuals train an available workforce to provide necessary care in low resource settings. Limited evidence exists for task shifting in dermatology; however, studies from psychiatry demonstrate its efficacy. In the field of dermatology there is a need for high-quality evidence including randomized clinical trials to validate the implementation of task shifting in low-resource settings globally. PMID- 28903135 TI - What Is the Optimal Revascularization Strategy for Left Main Coronary Stenosis? PMID- 28903136 TI - When Is a Little Breast Tissue Too Much?: Nipple-Sparing Risk-Reducing Mastectomy in BRCA Carriers. PMID- 28903137 TI - Nationwide Coverage and Cost-Sharing for PCSK9 Inhibitors Among Medicare Part D Plans. PMID- 28903138 TI - Improvement of Genetic Testing for Cutaneous Melanoma in Countries With Low to Moderate Incidence: The Rule of 2 vs the Rule of 3. AB - Importance: Genetic testing for melanoma-prone mutation in France, a country with low to moderate incidence of melanoma, is proposed in cases with 2 invasive cutaneous melanomas and/or related cancers in the same patient, or in first- or second-degree relatives (rule of 2). In preclinical studies, these rules led to disclosure of mutation(s) in more than 10% of these families, the threshold widely accepted to justify genetic testing for cancers. Objective: To reconsider these criteria in a general population testing of patients. Design, Setting, and Participants: This was a retrospective study, performed from 2004 to 2015 at Angers and Lyons University Hospitals, of a cohort of 1032 patients who underwent genetic testing. Main Outcomes and Measures: Frequency of mutation in high (CDKN2A, CDK4, and BAP1) and intermediate (MITF) susceptibility genes; statistical effect of histologic subtype, age, dysplastic nevi syndrome, and associated cancers on mutation rate; and evaluation of cases with anamnestic uncertainty. Results: The mutation rate was 67 of 1032 patients (6.5%). Their mean (SD) age was 54.5 (14.2) years [range, 18-89 years], and 543 (52.6%) were men. It increased to 38 of 408 patients (9.3%) when applying a rule of 3 (those with >=3 primary melanomas or genetically related cancers) (P = .68) and to 27 of 150 patients (18.0%) with a rule of 4 (4 primary melanomas or related cancer) (P < .001). The impact of age at first melanoma was observed only in those younger than 40 years, with a rate of 32 of 263 (12.1%) (P = .12) for the rule of 2 and 22 of 121 (18.2%) (P = .001) for the rule of 3. Use of the rule of 2 in patients younger than 40 years reduced the number of missed CDKN2A-mutated-families when applying the rule of 3 from 14 of 43 to 7 of 43. Anamnestic uncertainty, found in 88 families (8.5%), if excluded, would have led us to withdraw of only 21 cases (23.8%), and only 1 mutation would have been missed. Conclusions and Relevance: We propose using the rule of 3 to recommend genetic testing in France and countries with low to moderate incidence of melanoma, except in families and patients with a first melanoma occurrence before age 40 years in whom the rule of 2 could be maintained. PMID- 28903140 TI - Humanitarian Surgical Care in the US Military Treatment Facilities in Afghanistan From 2002 to 2013. PMID- 28903139 TI - Percutaneous Coronary Intervention vs Coronary Artery Bypass Grafting in Patients With Left Main Coronary Artery Stenosis: A Systematic Review and Meta-analysis. AB - Importance: In patients with left main coronary artery (LMCA) stenosis, coronary artery bypass grafting (CABG) has been the standard therapy for several decades. However, some studies suggest that percutaneous coronary intervention (PCI) with drug-eluting stents may be an acceptable alternative. Objective: To compare the long-term safety of PCI with drug-eluting stent vs CABG in patients with LMCA stenosis. Data Sources: PubMed, Scopus, EMBASE, Web of Knowledge, and ScienceDirect databases were searched from December 18, 2001, to February 1, 2017. Inclusion criteria were randomized clinical trial, patients with LMCA stenosis, PCI vs CABG, exclusive use of drug-eluting stents, and clinical follow up of 3 or more years. Data Extraction and Synthesis: Trial-level hazard ratios (HRs) and 95% CIs were pooled by fixed-effect and random-effects models with inverse variance weighting. Time-to-event individual patient data for the primary end point were reconstructed. Sensitivity analyses according to drug-eluting stent generation and coronary artery disease complexity were performed. Main Outcomes and Measures: The primary end point was a composite of all-cause death, myocardial infarction, or stroke at long-term follow-up. Secondary end points included repeat revascularization and a composite of all-cause death, myocardial infarction, stroke, or repeat revascularization at long-term follow-up. Results: A total of 4 randomized clinical trials were pooled; 4394 patients were included in the analysis. Of these, 3371 (76.7%) were men; pooled mean age was 65.4 years. According to Grading of Recommendations, Assessment, Development and Evaluation, evidence quality with respect to the primary composite end point was high. Percutaneous coronary intervention and CABG were associated with a comparable risk of all-cause death, myocardial infarction, or stroke both by fixed-effect (HR, 1.06; 95% CI, 0.90-1.24; P = .48) and random-effects (HR, 1.06; 95% CI, 0.85 1.32; P = .60) analysis. Sensitivity analyses according to low to intermediate Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score (random effects: HR, 1.02; 95% CI, 0.74-1.41; P = .89) and drug-eluting stent generation (first generation: HR, 0.90; 95% CI, 0.68-1.20; P = .49; second generation: HR, 1.19; 95% CI, 0.82-1.73; P = .36) were consistent. Kaplan-Meier curve reconstruction did not show significant variations over time between the techniques, with a 5-year incidence of all-cause death, myocardial infarction, or stroke of 18.3% (319 events) in patients treated with PCI and 16.9% (292 events) in patients treated with CABG. However, repeat revascularization after PCI was increased (HR, 1.70; 95% CI, 1.42-2.05; P < .001). Other individual secondary end points did not differ significantly between groups. Finally, pooled estimates of trials with LMCA stenosis tended overall to differ significantly from those of trials with multivessel coronary artery disease without left main LMCA stenosis. Conclusions and Relevance: Percutaneous coronary intervention and CABG show comparable safety in patients with LMCA stenosis and low to intermediate complexity coronary artery disease. However, repeat revascularization is more common after PCI. PMID- 28903142 TI - History of the Hemostat. PMID- 28903144 TI - Dermatologic Radiotherapy and Radioactive Quackery-Discovery and Tragedy at the Turn of the 20th Century. PMID- 28903143 TI - Arsenic in Dermatology-From Dermatologic Therapy to Carcinogen. PMID- 28903145 TI - Orangeness-Peeling Back the Myths Behind Carotenemia. PMID- 28903146 TI - An Average Face. PMID- 28903147 TI - Herpes-A Not So Simple(x) History. PMID- 28903148 TI - Psoriasis. PMID- 28903150 TI - Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice. AB - Purpose: The cone-rod homeobox (CRX) transcription factor is essential for photoreceptor gene expression, differentiation, and survival. Human CRX mutations can cause dominant retinopathies of varying onset and phenotype severity. In animal models, dominant frameshift Crx mutations introduce a premature termination codon (PTC), producing inactive truncated proteins that interfere with normal CRX function. Previously, a mutant mouse, TVRM65, was reported to carry a recessive late PTC mutation, Crx-L253X. More detailed phenotype analysis of the pathogenicity of Crx-L253X sheds new light on the variability of CRX linked diseases. Methods: Homozygous (L253X/X); heterozygous (L253X/+); Crx-/- and control C57BL/6J (WT) mice were analyzed at various ages for changes in retinal function (ERG), morphology (histology) and photoreceptor gene expression (qRT-PCR). Results: At 1 month, L253X/X mice lack visual function, show greater reductions in retinal thickness, and distinct gene expression changes relative to Crx-/-, suggesting that the phenotype of L253X/X is more severe than Crx-/-. L253X/+ mice have reduced rod/cone function, but normal retinal morphology at all ages tested. qRT-PCR assays described a complex phenotype in which both developing and mature photoreceptors are unable to maintain proper gene expression. L253X mRNA/protein is overexpressed relative to normal Crx, suggesting a pathogenic mechanism similar to early PTC mutations. However, the overexpression is less pronounced, correlating with a relatively mild dominant phenotype. Conclusions: The L253X mouse provides a valuable model for CRX associated retinopathy. The pathogenicity of CRX frameshift mutations depends on the position of the PTC, which in turn determines the degree of mutant mRNA/protein overproduction. PMID- 28903151 TI - Anterior Chamber Invasion in Retinoblastoma: Not an Indication for Adjuvant Chemotherapy. AB - Purpose: In retinoblastoma, adjuvant chemotherapy after enucleation is given in eyes with histopathological high-risk features (HRFs) to reduced mortality. Anterior chamber seeds (AC seeds) on histopathological evaluation are a contentious finding. This study attempts to determine the effect of AC seeds on the survival rate. Methods: This is a retrospective case record review. Eyes were divided into four groups: those with neither AC seeds nor HRFs, those with only HRFs, those with only AC seeds, and those with both HRFs and AC seeds. The groups were compared for demographic and clinical features and survival curves were plotted for each. Results: For the 212 eyes included in the study, mean age was 30.5 +/- 36.8 months. Children with only AC seeds were significantly older (75.3 +/- 94.6 months) (P = 0.004). Chemotherapy was administered in 81 (38.2%) of 212 eyes; 16 (13.7%) of 117 eyes without HRF and in 65 (68.4%) of 95 eyes with HRFs (P < 0.001). The survival rate at 1, 3, and 5 years was the highest for the group with only AC seeds, although the difference was not statistically significant. Conclusions: We conclude that AC seeds do not, by themselves, constitute an independent risk factor for metastasis. These children need not be treated with immediate adjuvant chemotherapy, but, instead, can be followed with regular screening for metastasis. However, AC seeds are seen in only a small proportion of enucleated eyes. A larger study would better validate our study results. PMID- 28903152 TI - Nuclear Respiratory Factor-1 (NRF-1) Regulates Transcription of the CXC Receptor 4 (CXCR4) in the Rat Retina. AB - Purpose: The CXC receptor 4 (CXCR4) is required for various physiologic and pathologic processes in the eye, including stem cell trafficking, neuronal development, immune responses, and ocular neovascularization. Here, we used the rat retina models to determine the mechanisms driving CXCR4 transcription. Methods: The expression pattern of CXCR4 and nuclear respiratory factor-1 (NRF-1) were profiled in the rat retina during the course of development. Chromatin immunoprecipitation (CHiP) assay determined the transcriptional mechanism of CXCR4 in rat retina. A rat model of oxygen-induced retinopathy (OIR) that mimics retinal ischemia-reperfusion injury was established. Under either normoxic or hypoxic conditions, CXCR4 and NRF-1 expression in rat retinas was tracked by RT PCR and Western analysis. Immunofluorescence staining localized CXCR4 and NRF-1. Results: Both CXCR4 and NRF-1 were highly expressed in the neonatal rat retina, down-regulated in parallel, and silenced in fully developed retinas (1 month of age). ChIP assays revealed that NRF-1 was required for CXCR4 promoter activity in rat retinas. In the OIR rat model, retinal hypoxia induced up-regulation of CXCR4 and NRF-1 concurrently. Conclusions: Our findings suggest that NRF-1 regulates the expression of CXCR4 in normal retinal development and in pathologic processes of retinal hypoxia and neovascularization. PMID- 28903155 TI - Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons. PMID- 28903153 TI - Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection. AB - Purpose: Herpes simplex virus type-1 (HSV-1) is a leading cause of neurotrophic keratitis, characterized by decreased or absent corneal sensation due to damage to the sensory corneal innervation. We previously reported the elicited immune response to infection contributes to the mechanism of corneal nerve regression/damage during acute HSV-1 infection. Our aim is to further establish the involvement of infiltrated macrophages in the mechanism of nerve loss upon infection. Methods: Macrophage Fas-Induced Apoptosis (MAFIA) transgenic C57BL/6 mice were systemically treated with AP20187 dimerizer or vehicle (VEH), and their corneas, lymph nodes, and blood were assessed for CD45+CD11b+GFP+ cell depletion by flow cytometry (FC). Mice were ocularly infected with HSV-1 or left uninfected. At 2, 4, and/or 6 days post infection (PI), corneas were assessed for sensitivity and harvested for FC, nerve structure by immunohistochemistry, viral content by plaque assay, soluble factor content by suspension array, and activation of signaling pathways by Western blot analysis. C57BL6 mice were used to compare to the MAFIA mouse model. Results: MAFIA mice treated with AP20187 had efficient depletion of CD45+CD11b+GFP+ cells in the tissues analyzed. The reduction of CD45+CD11b+GFP+ cells recruited to the infected corneas of AP20187 treated mice correlated with preservation of corneal nerve structure and function, decreased protein concentration of inflammatory cytokines, and decreased STAT3 activation despite no changes in viral content in the cornea compared to VEH-treated animals. Conclusions: Our results suggest infiltrated macrophages are early effectors in the nerve regression following HSV-1 infection. We propose the neurodegeneration mechanism involves macrophages, local up-regulation of IL-6, and activation of STAT3. PMID- 28903156 TI - Left Main Revascularization in 2017: Coronary Artery Bypass Grafting or Percutaneous Coronary Intervention? PMID- 28903154 TI - Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. AB - Importance: Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack clinical fidelity and can be affected by changing diagnosis and coding practices over time. Objective: To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. Design, Setting, and Population: Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. Exposures: Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance. Main Outcomes and Measures: Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews. Results: A total of 173 690 sepsis cases (mean age, 66.5 [SD, 15.5] y; 77 660 [42.4%] women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009 2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y [95% CI, -2.3% to 3.5%], P = .67) whereas incidence per claims increased (+10.3%/y [95% CI, 7.2% to 13.3%], P < .001). In-hospital mortality using clinical criteria declined (-3.3%/y [95% CI, -5.6% to -1.0%], P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (-1.3%/y [95% CI, -3.2% to 0.6%], P = .19). In contrast, mortality using claims declined significantly (-7.0%/y [95% CI, -8.8% to -5.2%], P < .001), as did death or discharge to hospice (-4.5%/y [95% CI, -6.1% to -2.8%], P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% [95% CI, 52.9% to 92.0%] vs 32.3% [95% CI, 24.4% to 43.0%], P < .001), with comparable positive predictive value (70.4% [95% CI, 64.0% to 76.8%] vs 75.2% [95% CI, 69.8% to 80.6%], P = .23). Conclusions and Relevance: In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance. PMID- 28903157 TI - Transgender Surgery-Not the Benchmark for Gender Marker Determination. PMID- 28903159 TI - Communication as the Key to Breast Conservation. PMID- 28903158 TI - Surgeon Influence on Variation in Receipt of Contralateral Prophylactic Mastectomy for Women With Breast Cancer. AB - Importance: Rates of contralateral prophylactic mastectomy (CPM) have markedly increased but we know little about the influence of surgeons on variability of the procedure in the community. Objective: To quantify the influence of the attending surgeon on rates of CPM and clinician attitudes that explained it. Design, Setting, and Participants: In this population-based survey study, we identified 7810 women with stages 0 to II breast cancer treated in 2013 to 2015 through the Surveillance, Epidemiology, and End Results registries of Georgia and Los Angeles County. Surveys were sent approximately 2 months after surgery. Surveys were also sent to 488 attending surgeons identified by the patients. Main Outcomes and Measures: We conducted multilevel analyses to examine the impact of surgeon influence on variations in patient receipt of CPM using information from patient and surgeon surveys merged to Surveillance, Epidemiology, and End Results data. Results: A total of 5080 women responded to the survey (70% response rate), and 377 surgeons responded (77% response rate). The mean (SD) age of responding women was 61.9 (11) years; 28% had an increased risk of second primary cancer, and 16% received CPM. Half of surgeons (52%) practiced for more than 20 years and 30% treated more than 50 new patients with breast cancer annually. Attending surgeon explained a large amount (20%) of the variation in CPM, controlling for patient factors. The odds of a patient receiving CPM increased almost 3-fold (odds ratio, 2.8; 95% CI, 2.1-3.4) if she saw a surgeon with a practice approach 1 SD above a surgeon with the mean CPM rate (independent of age, diagnosis date, BRCA status, and risk of second primary). One-quarter (25%) of the surgeon influence was explained by attending attitudes about initial recommendations for surgery and responses to patient requests for CPM. The estimated rate of CPM was 34% for surgeons who least favored initial breast conservation and were least reluctant to perform CPM vs 4% for surgeons who most favored initial breast conservation and were most reluctant to perform CPM. Conclusions and Relevance: In this study, attending surgeons exerted influence on the likelihood of receipt of CPM after a breast cancer diagnosis. Variations in surgeon attitudes about recommendations for surgery and response to patient requests for CPM explain a substantial amount of this influence. PMID- 28903162 TI - Suicide and Attempted Suicide in the United States During the 21st Century. PMID- 28903160 TI - Safety of Systemic Agents for the Treatment of Pediatric Psoriasis. AB - Importance: Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. Objective: To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. Design, Setting, and Participants: A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. Main Outcomes and Measures: The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. Results: For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P < .001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P = .003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Conclusions and Relevance: Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis. PMID- 28903163 TI - Myocardial Infarction and Postacute Care: Does One Size Fit All? PMID- 28903161 TI - National Trends in Suicide Attempts Among Adults in the United States. AB - Importance: A recent increase in suicide in the United States has raised public and clinical interest in determining whether a coincident national increase in suicide attempts has occurred and in characterizing trends in suicide attempts among sociodemographic and clinical groups. Objective: To describe trends in recent suicide attempts in the United States. Design, Setting, and Participants: Data came from the 2004-2005 wave 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the 2012-2013 NESARC-III. These nationally representative surveys asked identical questions to 69 341 adults, 21 years and older, concerning the occurrence and timing of suicide attempts. Risk differences adjusted for age, sex, and race/ethnicity (ARDs) assessed trends from the 2004 2005 to 2012-2013 surveys in suicide attempts across sociodemographic and psychiatric disorder strata. Additive interactions tests compared the magnitude of trends in prevalence of suicide attempts across levels of sociodemographic and psychiatric disorder groups. The analyses were performed from February 8, 2017, through May 31, 2017. Main Outcomes and Measures: Self-reported attempted suicide in the 3 years before the interview. Results: With use of data from the 69 341 participants (42.8% men and 57.2% women; mean [SD] age, 48.1 [17.2] years), the weighted percentage of US adults making a recent suicide attempt increased from 0.62% in 2004-2005 (221 of 34 629) to 0.79% in 2012-2013 (305 of 34 712; ARD, 0.17%; 95% CI, 0.01%-0.33%; P = .04). In both surveys, most adults with recent suicide attempts were female (2004-2005, 60.17%; 2012-2013, 60.94%) and younger than 50 years (2004-2005, 84.75%; 2012-2013, 80.38%). The ARD for suicide attempts was significantly larger among adults aged 21 to 34 years (0.48%; 95% CI, 0.09% to 0.87%) than among adults 65 years and older (0.06%; 95% CI, -0.02% to 0.14%; interaction P = .04). The ARD for suicide attempts was also significantly larger among adults with no more than a high school education (0.49%; 95% CI, 0.18% to 0.80%) than among college graduates (0.03%; 95% CI, 0.17% to 0.23%; interaction P = .003); the ARD was also significantly larger among adults with antisocial personality disorder (2.16% [95% CI, 0.61% to 3.71%] vs 0.07% [95% CI, -0.09% to 0.23%]; interaction P = .01), a history of violent behavior (1.04% [95% CI, 0.35% to 1.73%] vs 0.00% [95% CI, -0.12% to 0.12%]; interaction P = .003), or a history of anxiety (1.43% [95% CI, 0.47% to 2.39%] vs 0.18% [95% CI, 0.04% to 0.32%]; interaction P = .01) or depressive (0.99% [95% CI, -0.09% to 2.07%] vs -0.08% [95% CI, -0.20% to 0.04%]; interaction P = .05) disorders than among adults without these conditions. Conclusions and Relevance: A recent overall increase in suicide attempts among adults in the United States has disproportionately affected younger adults with less formal education and those with antisocial personality disorder, anxiety disorders, depressive disorders, and a history of violence. PMID- 28903164 TI - Counting Sepsis, an Imprecise but Improving Science. PMID- 28903166 TI - Factors to Consider for Reducing US Opioid-Related Deaths: Looking Beyond Access. PMID- 28903165 TI - Association of Panic Disorder, Generalized Anxiety Disorder, and Benzodiazepine Treatment During Pregnancy With Risk of Adverse Birth Outcomes. AB - Importance: Registry data show that maternal panic disorder, or anxiety disorders in general, increase the risk for adverse pregnancy outcomes. However, diagnoses from registries may be imprecise and may not consider potential confounding factors, such as treatment with medication and maternal substance use. Objective: To determine whether panic disorder or generalized anxiety disorder (GAD) in pregnancy, or medications used to treat these conditions, are associated with adverse maternal or neonatal pregnancy outcomes. Design, Setting, and Participants: This cohort study conducted between July 1, 2005, and July 14, 2009, recruited women at 137 obstetric practices in Connecticut and Massachusetts before 17 weeks of pregnancy and reassessed them at 28 (+/-4) weeks of pregnancy and 8 (+/-4) weeks postpartum. Psychiatric diagnoses were determined by answers to the World Mental Health Composite International Diagnostic Interview. Assessments also gathered information on treatment with medications and confounding factors, such as substance use, previous adverse birth outcomes, and demographic factors. Exposure: Panic disorder, GAD, or use of benzodiazepines or serotonin reuptake inhibitors. Main Outcomes and Measures: Among mothers: preterm birth, cesarean delivery, and hypertensive diseases of pregnancy. Among neonates: low birth weight, use of minor respiratory interventions, and use of ventilatory support. Results: Of the 2654 women in the final analysis (mean [SD] age, 31.0 [5.7] years), most were non-Hispanic white (1957 [73.7%]), 98 had panic disorder, 252 had GAD, 67 were treated with a benzodiazepine, and 293 were treated with a serotonin reuptake inhibitor during pregnancy. In adjusted models, neither panic disorder nor GAD was associated with maternal or neonatal complications of interest. Most medication exposures occurred early in pregnancy. Maternal benzodiazepine use was associated with cesarean delivery (odds ratio [OR], 2.45; 95% CI, 1.36-4.40), low birth weight (OR, 3.41; 95% CI, 1.61-7.26), and use of ventilatory support for the newborn (OR, 2.85; 95% CI, 1.2-6.9). Maternal serotonin reuptake inhibitor use was associated with hypertensive diseases of pregnancy (OR, 2.82; 95% CI, 1.58-5.04), preterm birth (OR, 1.56; 95% CI, 1.02 2.38), and use of minor respiratory interventions (OR, 1.81; 95% CI, 1.39-2.37). With maternal benzodiazepine treatment, rates of ventilatory support increased by 61 of 1000 neonates and duration of gestation was shortened by 3.6 days; with maternal serotonin reuptake inhibitor use, gestation was shortened by 1.8 days, 152 of 1000 additional newborns required minor respiratory interventions, and 53 of 1000 additional women experienced hypertensive diseases of pregnancy. Conclusions and Relevance: Panic disorder and GAD do not contribute to adverse pregnancy complications. Women may require treatment with medications during pregnancy, which can shorten the duration of gestation slightly. Maternal treatment with a serotonin reuptake inhibitor is also associated with hypertensive disease of pregnancy and cesarean delivery. PMID- 28903167 TI - Oncologic Safety of Prophylactic Nipple-Sparing Mastectomy in a Population With BRCA Mutations: A Multi-institutional Study. AB - Importance: Nipple-sparing mastectomy (NSM) offers superior cosmetic outcomes and has been gaining wide acceptance; however, its role among patients with BRCA mutations remains controversial. Objective: To report on the oncologic safety of NSM and provide evidence-based data to patients and health care professionals regarding preservation of the nipple-areolar complex during a risk-reducing mastectomy in a population with BRCA mutations. Design, Setting, and Participants: We retrospectively reviewed the outcomes of 9 institutions' experience with prophylactic NSM from 1968 to 2013 in a cohort of patients with BRCA mutations. Patients with breast cancer were included if they underwent contralateral risk-reducing mastectomy; however, only the prophylactic side was considered in the analysis. Patients found to have an occult primary breast cancer at the time of risk-reducing mastectomy, those having variant(s) of unknown significance, and those undergoing free nipple grafts were excluded. Main Outcomes and Measures: The primary outcome measure was development of a new breast cancer after risk-reducing NSM. Three reference data sources were used to model the expected number of events, and this was compared with our observed number of events. Results: A total of 548 risk-reducing NSMs in 346 patients were performed at 9 institutions. The median age at NSM was 41 years (interquartile range, 34.5-47.5 years). Bilateral prophylactic NSMs were performed in 202 patients (58.4%), and 144 patients (41.6%) underwent a unilateral risk-reducing NSM secondary to cancer in the contralateral breast. Overall, 201 patients with BRCA1 mutations and 145 with BRCA2 mutations were included. With median and mean follow-up of 34 and 56 months, respectively, no ipsilateral breast cancers occurred after prophylactic NSM. Breast cancer did not develop in any patients undergoing bilateral risk-reducing NSMs. Using risk models for BRCA1/2 mutation carriers, approximately 22 new primary breast cancers were expected without prophylactic NSM. Prophylactic NSM resulted in a significant reduction in breast cancer events (test of observed vs expected events, P < .001). Conclusions and Relevance: Nipple-sparing mastectomies are highly preventive against breast cancer in a BRCA population. Although the follow-up remains relatively short, NSM should be offered as a breast cancer risk-reducing strategy to appropriate patients with BRCA mutations. PMID- 28903168 TI - [Sharing bacterial microbiota between owners and their pets (dogs, cats)]. AB - INTRODUCTION: The microbiological aspect of a relationship between pets (dogs/cats) and their owners is mainly concerned with the incidence of shared bacterial species, in particular potential pathogens. Given the great popularity of sharing homes with pets (dogs/cats) in the Czech Republic, there is an increased possibility of communication between microbiota of the two macroorganisms (pet and owner). The aim of the study was to determine the biodiversity of shared bacteria and possibility of exchange of genes of resistance to antimicrobial agents between potential pathogens based on the close relationship between pets and humans. METHODS: A total of 103 samples were collected from 20 pairs (20 owners, 16 dogs and 4 cats). All owners completed a questionnaire with their pets' veterinarians. In owners, swabs were collected from the nasal mucosa, armpit and interdigital spaces of the foot. In pets, swabs were obtained from the external auditory meatus and nasal mucosa. In individuals with skin lesions, samples were also collected from the affected areas. Bacterial species were identified by culture and matrix-assisted laser desorption/ionization - time of flight (MALDI-TOF) mass spectrometry. In shared species, susceptibility to antibiotics was tested by the disk diffusion method. Statistical methods were used to correlate the closeness of relationship with the number of shared bacterial species and to correlate previous antimicrobial therapy with shared resistance of the common bacteria. RESULTS: Analysis of the questionnaires showed that 65 % of owners who participated in the study kept more pets at home than only the tested one. In the previous year, 5 % of pets and 5 % of owners received antimicrobial therapy. As many as 45 % of dogs or cats slept in their owners' beds and 80 % rested on a sofa together with their owners. Also, 45 % owners had their faces licked by pets. Eighty percent of pets were fed with several types of food (dry food and cooked food). Further, 70 % of pets lived permanently with their owners in the same household. A total of 76 bacterial species of 33 genera were identified. The most frequently isolated species (29 samples) was S. intermedius. Seventeen bacterial species occurring in both humans and animals were found and identified. At least one bacterial species was shared by 11 pairs and two shared species were found in two pairs. The shared species were S. intermedius, E. coli, E. faecalis, A. lwoffii, P. putida and S. aureus. Antimicrobial susceptibility was tested in the shared species. Common antimicrobial resistance was found in four pairs. In one pair, shared E. faecalis showed identical resistance to co-trimoxazole; in another pair, S. intermedius was resistant to gentamycin, erythromycin, clindamycin and co-trimoxazole. The third resistant bacterial species was E. coli; in one pair, it showed borderline resistance to colistin; in the second case, it was fully resistant to this antimicrobial agent. The other pairs with shared bacteria did not show any common resistance. CONCLUSION: The study results showed that there was an association between closeness of the human-pet relationship and the prevalence of shared bacterial species. Pairs with a close relationship were 37.5 % more likely to share bacteria than pairs with a less close relationship. The study suggests that antimicrobial therapy in at least one pair member may increase the risk of shared bacterial resistance. PMID- 28903169 TI - [A rare mechanism of resistance to colistin in Escherichia coli isolated from raw poultry meat]. AB - Plasmid-mediated resistance to colistin is a recently described phenomenon. The study reports this new type of colistin resistance in food isolates of Escherichia coli in the Czech Republic. Strains with phenotypically determined colistin resistance were studied for presence of the mcr-1 and mcr-2 genes. A positive finding of E. coli harboring the mcr-1 gene was confirmed in a sample of raw minced turkey meat imported from Poland. Two different strains of E. coli carrying the mcr-1 gene were detected in the same sample. This is the first reported case of this type of resistance in E. coli strains isolated from foods at retail in the Czech Republic. PMID- 28903170 TI - [Salmonellosis in an infant as a result of indirect contact with reptiles]. AB - Reported is a case of enteritis caused by Salmonella Oranienburg in an approximately one-month-old infant due to indirect contact with reptiles. An epidemiological investigation included tests of faeces of bearded dragons (Pogona vitticeps) kept in the patient's household that revealed Salmonella Oranienburg. The comparison of Salmonella isolates obtained from the infant's stools and the reptiles' faeces using macrorestriction analysis showed 100% similarity, confirming that the reptiles were the source of the infection. The transfer of Salmonella was probably indirect through the other family members. The detection of rare Salmonella serotypes should -lead to inclusion of less common sources of infection such as reptiles into epidemiological investigations. PMID- 28903171 TI - [Intraabdominal infections]. AB - Intraabdominal infections are the second most common cause of sepsis in intensive care units. Intraabdominal infections represent a wide variety of pathological conditions that involve lesions of all the intraabdominal organs. They also include intraperitoneal, retroperitoneal and parenchymal abscesses. The etiology of these infections usually includes organisms derived from the gut microbiota. The increasing rate of bacterial resistance is alarming. The treatment of intraabdominal infections is complex and involves source control and antibiotics. The choice of an antibiotic plays a key role and reflects the source of infection and its etiology. PMID- 28903172 TI - [Guideline for the diagnosis and treatment of acute bacterial meningitis]. AB - Acute bacterial meningitis is a severe infectious disease of the central nervous system. Its incidence decreases but lethality and sequelae remain high. The early initiation of appropriate treatment is a factor strongly determining the patient's prognosis. The authors submit the Czech national guideline for diagnosis and treatment of community-acquired acute bacterial meningitis which has to provide clear and simple recommendations for clinicans involved in the care of meningitis in adults and children. The national guideline was based on the European guideline published in 2016 and adapted for the situation in the Czech Republic. It was acknowledged (approved? ratified?) by the Society for Epidemiology and Microbiology and the Society for Medical Microbiology of the Czech Medical Association. PMID- 28903173 TI - Climatic and watershed controls of dissolved organic matter variation in streams across a gradient of agricultural land use. AB - Human land use has led to significant changes in the character of dissolved organic matter (DOM) in lotic ecosystems. These changes are expected to have important environmental and ecological consequences. However, high spatiotemporal variability has been reported in previous studies, and the underlying mechanisms remain inadequately understood. This study assessed variation in the properties of stream water DOM within watersheds across a gradient of agricultural land use with grazing pasture lands as the dominant agricultural type in the southeastern United States. We collected water samples under baseflow conditions five times over eight months from a regional group of first- to fourth-order streams. Samples were analyzed for dissolved organic carbon (DOC) concentration, DOM quality based on absorbance and fluorescence properties, as well as DOM biodegradability. We found that air temperature and antecedent hydrological conditions (indicated by antecedent precipitation index and stream water sodium concentrations) positively influenced stream water DOC concentration, DOM fluorescence index, and the proportion of soil-derived, microbial humic fluorescence. This observation suggests that elevated production and release of microbial DOM in soils facilitated by high temperature, in conjunction with strong soil-stream hydrological connectivity, were important drivers for changes in the concentration and composition of stream water DOM. By comparison, watersheds with a high percentage of agricultural land use showed higher DOC concentration, larger proportion of soil-derived, humic-like DOM compounds, and higher DOC biodegradability. These observations reflect preferential mobilization of humic DOM compounds from shallow organic matter-rich soils in agricultural watersheds, likely due to enhanced soil erosion, organic matter oxidation and relatively shallow soil-to-stream flow paths. PMID- 28903174 TI - Greenhouse gases emission from the sewage draining rivers. AB - Carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) concentration, saturation and fluxes in rivers (Beitang drainage river, Dagu drainage rive, Duliujianhe river, Yongdingxinhe river and Nanyunhe river) of Tianjin city (Haihe watershed) were investigated during July and October in 2014, and January and April in 2015 by static headspace gas chromatography method and the two-layer model of diffusive gas exchange. The influence of environmental variables on greenhouse gases (GHGs) concentration under the disturbance of anthropogenic activities was discussed by Spearman correlative analysis and multiple stepwise regression analysis. The results showed that the concentration and fluxes of CO2, CH4 and N2O were seasonally variable with >winter>fall>summer, spring>summer>winter>fall and summer>spring>winter>fall for concentrations and spring>summer>fall>winter, spring>summer>winter>fall and summer>spring>fall>winter for fluxes respectively. The GHGs concentration and saturation were higher in comprehensively polluted river sites and lower in lightly polluted river sites. The three GHGs emission fluxes in two sewage draining rivers of Tianjin were clearly higher than those of other rivers (natural rivers) and the spatial variation of CH4 was more obvious than the others. CO2 and N2O air-water interface emission fluxes of the sewage draining rivers in four seasons were about 1.20-2.41 times and 1.13-3.12 times of those in the natural rivers. The CH4 emission fluxes of the sewage draining rivers were 3.09 times in fall to 10.87 times in spring of those in the natural rivers in different season. The wind speed, water temperature and air temperature were related to GHGs concentrations. Nitrate and nitrite (NO3-+NO2--N) and ammonia (NH4+-N) were positively correlated with CO2 concentration and CH4 concentration; and dissolved oxygen (DO) concentration was negatively correlated with CH4 concentration and N2O concentration. The effect of human activities on carbon and nitrogen cycling in river is great. PMID- 28903175 TI - Chelant-enhanced washing of CCA-contaminated soil: Coupled with selective dissolution or soil stabilization. AB - Remediation of CCA-contaminated soil (Cr, Cu, and As) by biodegradable chelant enhanced washing (EDDS, S,S-ethylene-diamine-disuccinic-acid) needs further enhancement. This study investigated the effectiveness of coupling with pre treatment by selective dissolution and post-treatment by soil amendments, respectively. Three groups of reagents (reductants, alkaline solvents, and organic ligands) were adopted in the pre-treatment to dissolve the oxide minerals before EDDS extraction. In the post-treatment, soil amendments (coal fly ash (CFA), acid mine drainage sludge (AMDS), green waste compost (GWC)), and their mixtures) were used for a 2-month stabilization after 2-h EDDS washing. Multi endpoint evaluation was performed by assessing the chemical state, leachability, mobility, bioaccessibility, and plant-availability of residual metal(loid)s as well as the cytotoxicity, enzyme activities, and available nutrients of the treated soils. Pre-treatment by dithionite-citrate-bicarbonate significantly enhanced extraction efficiency, but also increased the leachability of As and Cr and bioaccessibility of Cr in the treated soils. While sodium hydroxide removed the majority of As without increasing its leachability and bioaccessibility, it increased the cytotoxicity and inhibited the acid phosphatase activity. Post treatment with AMDS and CFA effectively controlled the mobility and leachability of residual As and Cr after EDDS washing. However, destabilized Cu was only marginally immobilized by GWC due to strong Cu-EDDS complexation. The bioaccessibility and phytoavailability of Cu was primarily reduced by EDDS washing, while those of As and Cr could be attenuated by AMDS and CFA. This study indicates that coupling chemical extraction with subsequent soil amendment plays complementary roles in mitigating effects of residual metal(loid)s and improving environmental quality. PMID- 28903176 TI - Assessment of PCBs and exposure risk to infants in breast milk of primiparae and multiparae mothers in an electronic waste hot spot and non-hot spot areas in Ghana. AB - The aim of the study was to assess the levels of PCBs in the breast milk of some Ghanaian women at suspected hotspot and relatively non-hotspot areas and to find out if the levels of these PCBs pose any risk to the breastfed infants. A total of 128 individual human breast milk were sampled from both primiparae and multiparae mothers. The levels of PCBs in the milk samples were compared. Some of these mothers (105 individuals) work or reside in and around Agbogbloshie (hot spot), the largest electric and electronic waste dump and recycling site in Accra, Ghana. Others (23 donor mothers) also reside in and around Kwabenya (non hotspot) which is a mainly residential area without any industrial activities. Samples were analyzed using GC-MS/MS. The total mean levels and range of Sigma7PCBs were 3.64ng/glipidwt and ?LOD-29.20ng/glipidwt, respectively. Mean concentrations from Agbogbloshie (hot-spot area) and Kwabenya (non-hotspot areas) were 4.43ng/glipidwt and 0.03ng/glipidwt, respectively. PCB-28 contributed the highest of 29.5% of the total PCBs in the milk samples, and PCB-101 contributed the lowest of 1.74%. The estimated daily intake of PCBs and total PCBs concentrations in this work were found to be lower as compared to similar studies across the world. The estimated hazard quotient using Health Canada's guidelines threshold limit of 1MUg/kgbw/day showed no potential health risk to babies. However, considering minimum tolerable value of 0.03MUg/kgbw/day defined by the Agency for Toxic Substances and Disease Registry (ATSDR), the values of some mothers were found to be at the threshold limit. This may indicate a potential health risk to their babies. Mothers with values at the threshold levels of the minimum tolerable limits are those who work or reside in and around the Agbogbloshie e-waste site. PMID- 28903177 TI - Changes in bacteria composition and efficiency of constructed wetlands under sustained overloads: A modeling experiment. AB - The average organic and hydraulic loads that Constructed Wetlands (CWs) receive are key parameters for their adequate long-term functioning. However, over their lifespan they will inevitably be subject to either episodic or sustained overloadings. Despite that the consequences of sustained overloading are well known (e.g., clogging), the threshold of overloads that these systems can tolerate is difficult to determine. Moreover, the mechanisms that might sustain the buffering capacity (i.e., the reduction of peaks in nutrient load) during overloads are not well understood. The aim of this work is to evaluate the effect of sudden but sustained organic and hydraulic overloads on the general functioning of CWs. To that end, the mathematical model BIO_PORE was used to simulate five different scenarios, based on the features and operation conditions of a pilot CW system: a control simulation representing the average loads; 2 simulations representing +10% and +30% sustained organic overloads; one simulation representing a sustained +30% hydraulic overload; and one simulation with sustained organic and hydraulic overloads of +15% each. Different model outputs (e.g., total bacterial biomass and its spatial distribution, effluent concentrations) were compared among different simulations to evaluate the effects of such operation changes. Results reveal that overloads determine a temporary decrease in removal efficiency before microbial biomass adapts to the new conditions and COD removal efficiency is recovered. Increasing organic overloads cause stronger temporary decreases in COD removal efficiency compared to increasing hydraulic loads. The pace at which clogging develops increases by 10% for each 10% increase on the organic load. PMID- 28903178 TI - The effects of beta-caryophyllene oxide and trans-nerolidol on the efficacy of doxorubicin in breast cancer cells and breast tumor-bearing mice. AB - BACKGROUND: One approach to improve effect of chemotherapy is combination of classical cytostatic drugs with natural compounds, e. g. sesquiterpenes. In our previous study, sesquiterpenes beta-caryophyllene oxide (CAO) and trans-nerolidol (NER) improved the anti-proliferative effect of doxorubicin (DOX) in intestinal cancer cell lines. PURPOSE: The present study was designed to evaluate the effect of CAO and NER on DOX efficacy, focusing on cell proliferation, migration, apoptosis and DOX accumulation in breast cancer cells MDA-MB-231 and MCF7 in vitro and in mice bearing solid Ehrlich tumors (EST) in vivo. METHODS: The impact of cytotoxic effect was assessed by the neutral red uptake test. The ability to migrate was tested using real-time measurement in x-CELLigence system. Expressions of molecules were examined using western blot analysis. The accumulation of DOX inside the cells using time lapse microscopy was observed. The mice with inoculated EST cells were treated repeatedly with DOX and DOX+CAO or DOX+NER and the growth of tumors were monitored. DOX concentrations in plasma and tumor were assayed using HPLC. RESULTS: In MDA-MB-231, combination of DOX with CAO enhanced anti-proliferative effect and acted strongly synergistic. NER increased accumulation of DOX inside the cells; moreover combination DOX with NER suppressed migration ability in vitro. In vivo, apoptosis was activated especially in group treated with DOX and CAO. However, none of tested sesquiterpenes was able to improve DOX accumulation in tumors and DOX-mediated inhibition of tumor growth. CONCLUSION: In conclusion, sesquiterpenes CAO and NER increased the efficacy of DOX in breast cancer cells in vitro, but did not improve its effect in vivo, in Ehrlich solid tumor bearing mice. PMID- 28903179 TI - Antinociceptive, anti-inflammatory and anxiolytic-like effects of the ethanolic extract, fractions and Hibalactone isolated from Hydrocotyle umbellata L. (Acaricoba) - Araliaceae. AB - Hydrocotyle umbellata Linn. (Araliaceae) is specie used in the treatment of inflammatory diseases. Crude extract (E-HU) was prepared from H. umbellata subterraneous parts and fractionated by liquid-liquid partition, resulting hexane fraction (HF-HU), dichloromethane fraction (DF-HU), ethyl acetate fraction (EAF HU) and aqueous fraction (AF-HU). The hibalactone (HU-1) was isolated from the DF HU and its structure was elucidated by 1H NMR and 13C NMR Spectroscopy, mass spectrometry and crystallographic x-ray analysis. The formalin-induced nociception was used to evaluate antinociceptive activity; carrageenan-induced edema and pleurisy tests to evaluate anti-inflammatory activity and light-dark box to evaluate anxiolytic-like activity in mice. The acute oral treatments with E-HU (1000mg/kg), DF-HU (150mg/kg), EAF-HU (400mg/kg) and HU-1 (33mg/kg) decreased the licking time in both phases of the formalin test. In the carrageenan-induced inflammation models, the treatment with the same doses of E HU, DF-HU, EAF-HU and HU-1 reduced the paw edema formation and leukocytes account into pleural cavity. In silico findings suggest that hibalactone present anti inflammatory activity by interacting with the enzymes 5-lipoxygenase and cyclooxygenase-2. In the light dark box, the treatments with DF-HU, EAF-HU and HU 1 revealed an anxiolytic like effect. Thus, the E-HU and fractions of H. umbellata showed antinociceptive, anti-inflammatory and anxiolytic like activities, as also hibalactone, a possible phytoconstituent responsible for the biological effects of this specie. PMID- 28903180 TI - Diamine derivative anti-Trichomonas vaginalis and anti-Tritrichomonas foetus activities by effect on polyamine metabolism. AB - Human and bovine trichomoniasis are sexually transmitted diseases (STD) caused by Trichomonas vaginalis and Tritrichomonas foetus, respectively. Human trichomoniasis is the most common non-viral STD in the world and bovine trichomoniasis causes significant economic losses to breeders. Considering the significant impact of the infections caused by these protozoa and the treatment failures, the search for new therapeutic alternatives becomes crucial. In this study the effect of diamines and amino alcohols in the in vitro viability of trichomonads was evaluated. Screening demonstrated the high activity of diamine 4 against these protozoa. Although cytotoxicity against HMVII cell line and slight hemolysis were observed in vitro, the compound showed no toxic effect on the Galleria mellonella in vivo model. Importantly, diamine 4 was active against both trichomonads species at 6h and 24h of incubation, and these effects was reverted by putrescine, a polyamine, suggesting competition for the same metabolic pathway. These findings indicate that the mechanism of action of diamine 4 is through the polyamine metabolism, a pathway distinct from that presented by metronidazole, the drug usually used to treat trichomoniasis and to which resistance is widely reported. These data demonstrate the importance of diamines as potential novel candidates as anti-T. vaginalis and anti-T. foetus agents. PMID- 28903181 TI - Development and characterization of hyaluronic acid modified PLGA based nanoparticles for improved efficacy of cisplatin in solid tumor. AB - Cisplatin is a potent and widely used chemotherapeutic agent to treat a variety of tumors. However, its clinical use is associated with undesirable side effects and acquired resistance to cisplatin. In this study, cisplatin loaded hyaluronic acid (HA) functionalized poly (lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles (CP-HA-PLGA-PEG-NPs) were fabricated using double emulsion solvent evaporation method to target CD44 receptor expressed on cancerous cells. The developed nanoconstructs were characterized for various in vitro parameters, including size distribution, zeta potential, morphology, drug loading and in vitro release. The HA content on the HA-PLGA-PEG-NPs was quantified by a turbidimetric method. The in vitro anticancer study in human ovarian cancer (SKOV 3) cells showed significantly (p<0.05) higher cytotoxicity of CP-HA-PLGA-PEG NPs as compared to free cisplatin and non-targeted nanoparticles (CP-PLGA-PEG NPs). Further, laser scanning confocal microscopy revealed that there was enhanced cellular uptake of HA-PLGA-PEG NPs in CD44-over expressing ovarian cancer cell line (SKOV-3). The in vivo antitumor activity of CP-HA-PLGA-PEG-NPs was significantly (p<0.05) higher than free cisplatin and CP-PLGA-PEG-NPs in Ehrlich tumor (solid) bearing mice. The results demonstrated the potential of target specific nanoconstruct of cisplatin in the improved cancer chemotherapy. PMID- 28903182 TI - Molecular estimation of alteration in intestinal microbial composition in Hashimoto's thyroiditis patients. AB - The gut microbiota has a crucial effect on human health and physiology. Hypothyroid Hashimoto's thyroiditis (HT) is an autoimmune disorder manifested with environmental and genetic factors. However, it is hypothesized that intestinal microbes might play a vital role in the pathogenesis of HT. The aim of current was to investigate and characterize the gut microbial composition of HT patients both quantitatively and qualitatively. The fecal samples from 29 HT patients and 12 healthy individuals were collected. The PCR-DGGE targeted V3 site of 16S rRNA gene and real time PCR for Bifidobacterium Lactobacillus, Bacteroides vulgatus and Clostridium leptum were performed. Pyrosequencing of 16S rRNA gene with V4 location was performed on 20 randomly selected samples. The comparative analysis of diversity and richness indices revealed diversification of gut microbiota in HT as compared to control. The statistical data elucidate the alterations in phyla of HT patients which was also affirmed at the family level. We observed the declined abundance of Prevotella_9 and Dialister, while elevated genera of the diseased group included Escherichia-Shigella and Parasutterella. The alteration in gut microbial configuration was also monitored at the species level, which showed an increased abundance of E. coli in HT. Therefore, the current study is in agreement with the hypothesis that HT patients have intestinal microbial dysbiosis. The taxa statistics at species-level along with each gut microbial community were modified in HT. Thus, the current study may offer the new insights into the treatment of HT patients, disease pathway, and mechanism. PMID- 28903183 TI - Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin. AB - Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug HemangeolTM has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas. PMID- 28903184 TI - Dexmedetomidine exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury. AB - OBJECTIVE: This study aims to explore the neuroprotective effects of dexmedetomidine (Dex) in rats suffering from traumatic brain injury (TBI) via the PI3K/Akt/mTOR signaling pathway. METHODS: A weight drop model was performed for TBI model establishment. A total of 150 Sprague Dawley rats were selected and assigned into control, sham, TBI, TBI+Dex, TBI+LY294002 (LY) and TBI+Dex+LY groups. Modified Neurological Severity Score (mNSS) was conducted in order to evaluate the neurological injury. The water content in brain tissues was measured. The expressions of PI3K/Akt/mTOR signaling pathway-related proteins, tight junction proteins (ZO-1 and Claudin-5) and autophagy proteins (LC3 I/II and Beclin-1) were detected using Western blot assay. A TUNEL assay was applied for cell apoptosis, immunofluorescence was employed for the detection of the positive expression of LC3, and ELISA was applied for detection of levels of inflammatory factors [tumor necrosis factor-alph (TNF-a), interleukin-1beta (IL-1beta), interferon-gamma (INF-gamma) as well as IL-6], respectively. RESULTS: Compared with the control group, the other four groups exhibited increased mNSS, brain water content, expression of LC3, TNF-a, IL-1beta, INF-gamma and IL-6, and positive expression of LC3, expression of LC3 I/II and Beclin-1, but decreased expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t-mTOR, ZO-1 and Claudin-5. Compared with the TBI group, the TBI+Dex group exhibited reduced mNSS, brain water content, expression of LC3, TNF-a, IL-1beta, INF-gamma and IL-6, positive expression of LC3, as well as expression of LC3 I/II and Beclin-1 but demonstrated an elevated expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t mTOR, ZO-1 and Claudin-5, while opposite trends were observed in the TBI+LY group. The TBI+Dex group exhibited reduced mNSS, brain water content, expression of LC3, TNF-a, IL-1beta, INF-gamma and IL-6, positive expression of LC3, as well as expression of LC3 I/II and Beclin-1 but demonstrated an elevated expression of pp-PI3K/t-PI3K, p-Akt/t-Akt, p-mTOR/t-mTOR, ZO-1 and Claudin-5, while opposite trends were observed in the TBI+LY group, as compared with the TBI+Dex+LY group. CONCLUSION: The data shows that Dex exerts a neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with TBI. PMID- 28903185 TI - Mixed micelles for encapsulation of doxorubicin with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines versus Doxil(r). AB - Doxorubicin (DOX) is used as a "first-line" antineoplastic drug in ovarian and metastatic breast cancer. However, serious side effects, such as cardiotoxicity have been reported after DOX intravenous administration. Hence, we investigated different micelle-former biomaterials, as Soluplus(r), Pluronic F127, Tetronic T1107 and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) to develop a potential mixed micellar nanocarrier for DOX delivery. Since DOX hydrochloride is a poor candidate to be encapsulated inside the hydrophobic core of the mixed micelles, we assayed a hydrophobic complex between DOX and sodium deoxycholate (NaDC) as an excellent candidate to be encapsulated within polymeric micelles. The combination of T1107:TPGS (1:3, weight ratio) demonstrated the best physicochemical properties together with a high DL capacity (6.43% w/v). Particularly, DOX in vitro release was higher at acidic tumour microenvironment pH value (5.5) than at physiological counterpart (7.4). The hydrodynamic diameter of the DOX/NaDC-loaded mixed micellar system was 10.7nm (PDI=0.239). The in vitro cytotoxicity of the mixed micellar formulation resulted significantly (p<0.05) higher than Doxil(r) against ovarian (SKOV-3) and triple-negative breast cancer cells (MDA-MB- 231). Further, the in vitro cellular uptake assays demonstrated a significant increment (p<0.05) of the DOX intracellular content for the mixed micelles versus Doxil(r) for both, SKOV-3 (at 2, 4 and 6h of incubation) and MDA MB-231 (at 4h of incubation) cells. These findings suggest that T1107:TPGS (1:3) mixed micelles could be employed as a potential nanotechnological platform for drug delivery of DOX. PMID- 28903186 TI - Maslinic acid inhibits impairment of endothelial functions induced by high glucose in HAEC cells through improving insulin signaling and oxidative stress. AB - Impaired endothelial functions are closely associated with many chronic vascular related diseases. Maslinic acid (MA), a natural pentacyclic triterpene compound, has received more and more attentions in recent years due to a variety of bioactivities. In the present study, we investigated the effect of MA on impaired endothelial functions in human aortic endothelial cells (HAEC) induced by high glucose treatment and discussed its possible mechanism. We showed that MA decreased the ROS level, inhibited the inflammatory cytokines expression, facilitated insulin-mediated IRS-1/PI3K/Akt/eNOS signaling and suppressed the cellular apoptosis ratio induced by high glucose. The molecular docking results showed that MA may regulate multiple targets to improve the endothelial dysfunction in HAECs exposed to high glucose. These results revealed potential application of MA in improving endothelia dysfunction. PMID- 28903187 TI - COMPARATIVE PHYSIOCHEMICAL ANALYSIS OF HYDROPHOBINS PRODUCED IN ESCHERICHIA COLI AND PICHIA PASTORIS. AB - Hydrophobins (HFBs) are small surface-active proteins secreted by filamentous fungi. Being amphiphilic, they spontaneously form layers that convert surfaces from hydrophilic to hydrophobic and vice versa. We have compared properties of the class II HFB4 and HFB7 from Trichoderma virens as produced in Escherichia coli and Pichia pastoris. Since the production in E. coli required denaturation/renaturation steps because of inclusion bodies, this treatment was also applied to HFBs produced and secreted in yeast. The protein yields for both systems were similar. Both HFBs produced by E. coli proved less active on PET compared to HFBs produced in P. pastoris. HFBs produced in E. coli decreased the hydrophilicity of glass the most, which correlated with the adsorption of a more dense protein layer on glass compared to HFBs produced in P. pastoris. The hydrophobins produced in P. pastoris formed highly structured monolayers. Layers of hydrophobins produced in E. coli were less prone to self-organization. Our data suggests that irrespective of the production host, the HFBs could be used in various applications that are based on their surface activity. However, the production host and the subsequent purification procedure will influence the stability of HFB layers. In the area of high-value biomedical devices and nanomaterials, where the formation of highly ordered protein monolayers is essential, our results point to P. pastoris as the preferred production host. Furthermore, the choice of an appropriate hydrophobin for a given application appears to be equally important. PMID- 28903188 TI - Hair-on-hair static friction coefficient can be determined by tying a knot. AB - Characterizing the tribological properties of the hair-hair interface is important to quantify the manageability of hair and to assess the performance of hair care products. Audoly et al. (Phys. Rev. Lett. 99, 164301, 2007) derived an equation relating the self-friction coefficient of an elastic fiber to the dimensions of a simple, relaxed overhand knot made from this fiber. I experimentally tested and validated their equation using nylon thread and an independent measurement of its self-friction coefficient. I show that this methodology can be applied to provide high-throughput data on the static self friction coefficient of single hair fibers in various conditions and to quantitatively assess how hair care treatments (conditioner, relaxant) alter frictional properties. I find that treatment of hair with 1M sodium hydroxide leads to a quick, irreversible self-friction coefficient increase; the resulting fine frictional fibers can be used to form very small knots for microsurgical vessel and organ ligature in medicine or embryology. The relaxed overhand knot method can more generally be used to measure the self-friction coefficients of a wide range of elastic fibers from the nano- (e.g. proteins, nanotubes) to the macro-scale (e.g. textile fiber, fiberglass). PMID- 28903190 TI - The Relative Performance of NDIR-based Sensors in the Near Real-time Analysis of CO2 in Air. AB - In this study, the reliability of NDIR-based sensors was explored by evaluatingthe comparability between measurement systems in the near real-time analysis of CO2. Forthis purpose, replicate analyses were performed using sensors of two different model types(H-550 and B-530, ELT Company, Korea). Three replicate data of each sensor typecollected continuously by side-by-side analysis in three second intervals (a duration of 304hour) were evaluated for the relative performance of NDIR sensors. The reproducibility ofsensors, when assessed by relative standard error (RSE %) values of all sensor units,showed moderate changes with time with the overall mean of 2.33%. When CO2measurements from all NDIR sensor units were evaluated by correlation analysis, theresults showed strong comparability, regardless of the model type. The overall results ofthis study suggest that NDIR sensors are reliable enough to produce highly comparabledata at least in a relative sense. PMID- 28903191 TI - High Resolution Marine Magnetic Survey of Shallow Water Littoral Area. AB - The purpose of this paper is to present a system developed for detection andaccurate mapping of ferro-metallic objects buried below the seabed in shallow waters. Thesystem comprises a precise magnetic gradiometer and navigation subsystem, both installedon a non-magnetic catamaran towed by a low-magnetic interfering boat. In addition wepresent the results of a marine survey of a near shore area in the vicinity of Atlit, a townsituated on the Mediterranean coast of Israel, about 15 km south of Haifa. The primarypurpose of the survey was to search for a Harvard airplane that crashed into the sea in 1960.A magnetic map of the survey area (3.5 km2 on a 0.5 m grid) was created revealing theanomalies at sub-meter accuracy. For each investigated target location a correspondingferro metallic item was dug out, one of which turned to be very similar to a part of thecrashed airplane. The accuracy of location was confirmed by matching the position of theactual dug artifacts with the magnetic map within a range of +/- 1 m, in a water depth of 9 m. PMID- 28903189 TI - Mechanosensor Channels in Mammalian Somatosensory Neurons. AB - Mechanoreceptive sensory neurons innervating the skin, skeletal muscles andviscera signal both innocuous and noxious information necessary for proprioception, touchand pain. These neurons are responsible for the transduction of mechanical stimuli intoaction potentials that propagate to the central nervous system. The ability of these cells todetect mechanical stimuli impinging on them relies on the presence of mechanosensitivechannels that transduce the external mechanical forces into electrical and chemical signals.Although a great deal of information regarding the molecular and biophysical properties ofmechanosensitive channels in prokaryotes has been accumulated over the past two decades,less is known about the mechanosensitive channels necessary for proprioception and thesenses of touch and pain. This review summarizes the most pertinent data onmechanosensitive channels of mammalian somatosensory neurons, focusing on theirproperties, pharmacology and putative identity. PMID- 28903192 TI - Modeling of Photoinduced Deformation in Silicon Microcantilever. AB - A model for prediction the photostriction effect in silicon microcantilevers is built up based on the fundamentals of mechanics and semiconductor physics. By considering the spatial distribution and surface recombination of photoinduced carriers in silicon, the model interprets the cause of the photoinduced bending. The results from our model much more closely approximate the experimental values than the former model built up by Datskos, Rajic and Datskou [1](APL, Vol.73 (1998) No.16, pp 3219-2321), represented by the reduction of the error between calculation and measurement from 25 times to 0.85 times. PMID- 28903193 TI - Reliability of a MEMS Actuator Improved by Spring Corner Designs and Reshaped Driving Waveforms. AB - In this paper, we report spring corner designs and driving waveforms to improve the reliability for a MEMS (Micro-Electro-Mechanical System) actuator. In order to prevent the stiction problems, no stopper or damping absorber is adopted. Therefore, an actuator could travel long distance by electromagnetic force without any object in moving path to absorb excess momentum. Due to long displacement and large mass, springs of MEMS actuators tend to crack from weak points with high stress concentration and this situation degrades reliability performance. Stress distribution over different spring designs were simulated and a serpentine spring with circular and wide corner design was chosen due to its low stress concentration. This design has smaller stress concentration versus displacement. Furthermore, the resonant frequencies are removed from the driving waveform based on the analysis of discrete Fourier transfer function. The reshaped waveform not only shortens actuator switching time, but also ensures that the spring is in a small displacement region without overshooting so that the maximum stress is kept below 200 MPa. The experimental results show that the MEMS device designed by theses principles can survive 500 g (gravity acceleration) shock test and pass 150 million switching cycles without failure. PMID- 28903194 TI - Cross-Reactive Sensor Array for Metal Ion Sensing Based on Fluorescent SAMs. AB - Fluorescent self assembled monolayers (SAMs) on glass were previouslydeveloped in our group as new sensing materials for metal ions. These fluorescent SAMs arecomprised by fluorophores and small molecules sequentially deposited on a monolayer onglass. The preorganization provided by the surface avoids the need for complex receptordesign, allowing for a combinatorial approach to sensing systems based on small molecules.Now we show the fabrication of an effective microarray for the screening of metal ions andthe properties of the sensing SAMs. A collection of fluorescent sensing SAMs wasgenerated by combinatorial methods and immobilized on the glass surfaces of a custom-made 140 well microtiter-plate. The resulting libraries are easily measured and show variedresponses to a series cations such as Cu2+ , Co2+ , Pb2+ , Ca2+ and Zn2+ . These surfaces are notdesigned to complex selectively a unique analyte but rather they are intended to producefingerprint type responses to a range of analytes by less specific interactions. The unselectiveresponses of the library to the presence of different cations generate a characteristic patternfor each analyte, a "finger print" response. PMID- 28903195 TI - A Wireless, Passive Sensor for Quantifying Packaged Food Quality. AB - This paper describes the fabrication of a wireless, passive sensor based on aninductive-capacitive resonant circuit, and its application for in situ monitoring of thequality of dry, packaged food such as cereals, and fried and baked snacks. The sensor ismade of a planar inductor and capacitor printed on a paper substrate. To monitor foodquality, the sensor is embedded inside the food package by adhering it to the package'sinner wall; its response is remotely detected through a coil connected to a sensor reader. Asfood quality degrades due to increasing humidity inside the package, the paper substrateabsorbs water vapor, changing the capacitor's capacitance and the sensor's resonantfrequency. Therefore, the taste quality of the packaged food can be indirectly determined bymeasuring the change in the sensor's resonant frequency. The novelty of this sensortechnology is its wireless and passive nature, which allows in situ determination of foodquality. In addition, the simple fabrication process and inexpensive sensor material ensure alow sensor cost, thus making this technology economically viable. PMID- 28903196 TI - Study of the origin of bending induced by bimetallic effect on microcantilever. AB - An analytical model for predicting the deflection and force of a bimaterialcantilever is presented. We introduce the clamping effect characterised by an axial loadupon temperature changes. This new approach predicts a non linear thermal dependence ofcantilever strain. A profilometry technique was used to measure the thermal strain.Comparison with experimental results is used to verify the model. The concordance of theanalytical model presented with experimental measurements is better than 10. PMID- 28903197 TI - Time Series Forecasting Energy-efficient Organization of Wireless Sensor Networks. AB - Due to their wide potential applications, wireless sensor networks have recentlyreceived tremendous attention. The strict energy constraints of sensor nodes result in thegreat challenges for energy efficiency. This paper investigates the energy efficiency problemand proposes an energy-efficient organization method with time series forecasting. Theorganization of wireless sensor networks is formulated for target tracking. Target model,multi-sensor model and energy model are defined accordingly. For the target trackingapplication, target localization is achieved by collaborative sensing with multi-sensor fusion.The historical localization results are utilized for adaptive target trajectory forecasting.Empirical mode decomposition is implemented to extract the inherent variation modes in thetime series of a target trajectory. Future target position is derived from autoregressivemoving average (ARMA) models, which forecast the decomposition components,respectively. Moreover, the energy-efficient organization method is presented to enhance theenergy efficiency of wireless sensor networks. The sensor nodes implement sensing tasksaccording to the probability awakening in a distributed manner. When the sensor nodestransfer their observations to achieve data fusion, the routing scheme is obtained by antcolony optimization. Thus, both the operation and communication energy consumption canbe minimized. Experimental results verify that the combination of the ARMA model andempirical mode decomposition can estimate the target position efficiently and energy savingis achieved by the proposed organization method in wireless sensor networks. PMID- 28903198 TI - Energy-efficient Optimization of Reorganization-Enabled Wireless Sensor Networks. AB - This paper studies the target tracking problem in wireless sensor networkswhere sensor nodes are deployed randomly. To achieve tracking accuracy constrained byenergy consumption, an energy-efficient optimization approach that enablesreorganization of wireless sensor networks is proposed. The approach includes threephases which are related to prediction, localization and recovery, respectively. A particlefilter algorithm is implemented on the sink node to forecast the future movement of thetarget in the first prediction phase. Upon the completion of this phase, the most energyefficient sensor nodes are awakened to collaboratively locate the target. Energy efficiencyis evaluated by the ratio of mutual information to energy consumption. The recoveryphase is needed to improve the robustness of the approach. It is performed when thetarget is missed because of the incorrect predicted target location. In order to recapture thetarget by awakening additional sensor nodes as few as possible, a genetic-algorithm basedmechanism is introduced to cover the recovery area. We show that the proposed approachhas excellent tracking performance. Moreover, it can efficiently reduce energyconsumption, prolong network lifetime and reduce network overheads. PMID- 28903199 TI - Multi-scale Analysis of MEMS Sensors Subject to Drop Impacts. AB - The effect of accidental drops on MEMS sensors are examined within the frame-work of a multi-scale finite element approach. With specific reference to a polysilicon MEMSaccelerometer supported by a naked die, the analysis is decoupled into macro-scale (at dielength-scale) and meso-scale (at MEMS length-scale) simulations, accounting for the verysmall inertial contribution of the sensor to the overall dynamics of the device. Macro-scaleanalyses are adopted to get insights into the link between shock waves caused by the impactagainst a target surface and propagating inside the die, and the displacement/acceleration his tories at the MEMS anchor points. Meso-scale analyses are adopted to detect the most stresseddetails of the sensor and to assess whether the impact can lead to possible localized failures.Numerical results show that the acceleration at sensor anchors cannot be considered an ob-jective indicator for drop severity. Instead, accurate analyses at sensor level are necessary toestablish how MEMS can fail because of drops. PMID- 28903200 TI - Measurement of the Mass and Rigidity of Adsorbates on a Microcantilever Sensor. AB - When microcantilevers are used in the dynamic mode, the resonance shift uponmaterial adsorption depends on the position of the adsorbate along the microcantilever. Wehave previously described that the adsorbate stiffness needs to be considered in addition toits mass in order to correctly interpret the resonance shift. Here we describe a method thatallows obtaining the Young's modulus of the adsorbed bacteria derived from themeasurement of the frequency shift when adsorbates are placed close to the clampingregion. As a model system we have used E. Coli bacteria deposited on the cantileversurface by the ink-jet technique. We demonstrate that the correct information aboutadsorbed mass can be extracted by recording the cantilever profile and its resonanceresponse. Also, the position and extent of adsorbates is determined by recording themicrocantilever profile. We use a theoretical model based on the Euler - Bernouilliequation for a beam with both mass and flexural rigidity local increase due to the depositedmaterial. PMID- 28903201 TI - A Compact Laboratory Spectro-Goniometer (CLabSpeG) to Assess the BRDF of Materials. Presentation, Calibration and Implementation on Fagus sylvatica L. Leaves. AB - The design and calibration of a new hyperspectral Compact Laboratory Spectro Goniometer (CLabSpeG) is presented. CLabSpeG effectively measures the bidirectionalreflectance Factor (BRF) of a sample, using a halogen light source and an AnalyticalSpectral Devices (ASD) spectroradiometer. The apparatus collects 4356 reflectance datareadings covering the spectrum from 350 nm to 2500 nm by independent positioning of thesensor, sample holder, and light source. It has an azimuth and zenith resolution of 30 and15 degrees, respectively. CLabSpeG is used to collect BRF data and extract BidirectionalReflectance Distribution Function (BRDF) data of non-isotropic vegetation elements suchas bark, soil, and leaves. Accurate calibration has ensured robust geometric accuracy of theapparatus, correction for the conicality of the light source, while sufficient radiometricstability and repeatability between measurements are obtained. The bidirectionalreflectance data collection is automated and remotely controlled and takes approximatelytwo and half hours for a BRF measurement cycle over a full hemisphere with 125 cmradius and 2.4 minutes for a single BRF acquisition. A specific protocol for vegetative leafcollection and measurement was established in order to investigate the possibility to extractBRDF values from Fagus sylvatica L. leaves under laboratory conditions. Drying leafeffects induce a reflectance change during the BRF measurements due to the laboratorySensors 2007, 7 1847 illumination source. Therefore, the full hemisphere could not be covered with one leaf. Instead 12 BRF measurements per leaf were acquired covering all azimuth positions for a single light source zenith position. Data are collected in radiance format and reflectance is calculated by dividing the leaf cycle measurement with a radiance cycle of a Spectralon reference panel, multiplied by a Spectralon reflectance correction factor and a factor to correct for the conical effect of the light source. BRF results of measured leaves are presented. PMID- 28903203 TI - The Investigation of a Shape Memory Alloy Micro-Damper for MEMS Applications. AB - Some shape memory alloys like NiTi show noticeable high damping property inpseudoelastic range. Due to its unique characteristics, a NiTi alloy is commonly used forpassive damping applications, in which the energy may be dissipated by the conversion frommechanical to thermal energy. This study presents a shape memory alloy based micro-damper, which exploits the pseudoelasticity of NiTi wires for energy dissipation. Themechanical model and functional principle of the micro-damper are explained in detail.Moreover, the mechanical behavior of NiTi wires subjected to various temperatures, strainrates and strain amplitudes is observed. Resulting from those experimental results, thedamping properties of the micro-damper involving secant stiffness, energy dissipation andloss factor are analyzed. The result indicates the proposed NiTi based micro-damper exhibitsgood energy dissipation ability, compared with conventional materials damper. PMID- 28903202 TI - Electrodeposited and Sol-gel Precipitated p-type SrTi1-xFexO3-delta Semiconductors for Gas Sensing. AB - In the present contribution, three methods for the preparation of nanoscaledSrTi1 xFexO3-delta sensor films for hydrocarbon sensing were investigated. Besides screen-printed thick films based on sol-precipitated nanopowders, two novel synthesis methods,electrospinning and electrospraying, were tested successfully. All of these sensor devicesshowed improved sensor functionality in comparison to conventional microscaled thickfilms. In order to explain the impact of the enhanced surface-to-volume ratio on sensorproperties in a quantitative way, a mechanistic model was applied to micro- and nanoscaleddevices. In contrast to the conventional diffusion-reaction model that has been proposed forn-type semiconducting sensors, it contained novel approaches with respect to themicroscopic mechanism. With very few fit variables, the present model was found torepresent well sensor functionality of p-type conducting SrTi0.8Fe0.2O3 delta films. In additionto the temperature dependency of the sensor response, the effect of the specific surface areaon the sensor response was predicted. PMID- 28903204 TI - Hybrid Integrated Silicon Microfluidic Platform for Fluorescence Based Biodetection. AB - The desideratum to develop a fully integrated Lab-on-a-chip device capable ofrapid specimen detection for high throughput in-situ biomedical diagnoses and Point-of-Care testing applications has called for the integration of some of the novel technologiessuch as the microfluidics, microphotonics, immunoproteomics and Micro ElectroMechanical Systems (MEMS). In the present work, a silicon based microfluidic device hasbeen developed for carrying out fluorescence based immunoassay. By hybrid attachment ofthe microfluidic device with a Spectrometer on-chip, the feasibility of synthesizing anintegrated Lab-on-a-chip type device for fluorescence based biosensing has beendemonstrated. Biodetection using the microfluidic device has been carried out usingantigen sheep IgG and Alexafluor 647 tagged antibody particles and the experimentalresults prove that silicon is a compatible material for the present application given thevarious advantages it offers such as cost-effectiveness, ease of bulk microfabrication,superior surface affinity to biomolecules, ease of disposability of the device etc., and is thussuitable for fabricating Lab-on-a-chip type devices. PMID- 28903205 TI - Wetland Restoration Response Analysis using MODIS and Groundwater Data. AB - Vegetation cover and groundwater level changes over the period of restorationare the two most important indicators of the level of success in wetland ecohydrologicalrestoration. As a result of the regular presence of water and dense vegetation, the highestevapotranspiration (latent heat) rates usually occur within wetlands. Vegetation cover andevapotranspiration of large areas of restoration like that of Kissimmee River basin, SouthFlorida will be best estimated using remote sensing technique than point measurements.Kissimmee River basin has been the area of ecological restoration for some years. Thecurrent ecohydrological restoration activities were evaluated through fractional vegetationcover (FVC) changes and latent heat flux using Moderate Resolution ImagingSpectroradiometer (MODIS) data. Groundwater level data were also analyzed for selectedeight groundwater monitoring wells in the basin. Results have shown that the averagefractional vegetation cover and latent heat along 10 km buffer of Kissimmee River betweenLake Kissimmee and Lake Okeechobee was higher in 2004 than in 2000. It is evident thatover the 5-year period of time, vegetated and areas covered with wetlands have increasedsignificantly especially along the restoration corridor. Analysis of groundwater level data(2000-2004) from eight monitoring wells showed that, the average monthly level ofgroundwater was increased by 20 cm and 34 cm between 2000 and 2004, and 2000 and2003, respectively. This change was more evident for wells along the river. PMID- 28903206 TI - The Airborne Visible / Infrared Imaging Spectrometer AVIS: Design, Characterization and Calibration. AB - The Airborne Visible / Infrared imaging Spectrometer AVIS is a hyperspectralimager designed for environmental monitoring purposes. The sensor, which wasconstructed entirely from commercially available components, has been successfullydeployed during several experiments between 1999 and 2007. We describe the instrumentdesign and present the results of laboratory characterization and calibration of the system'ssecond generation, AVIS-2, which is currently being operated. The processing of the datais described and examples of remote sensing reflectance data are presented. PMID- 28903207 TI - Development of a Surface Plasmon Resonance n-dodecane Vapor Sensor. AB - Using a high density polyethylene thin film over gold layer, a Surface PlasmonResonance sensor for detecting n-dodecane vapor is developed. Preliminary results will bepresented, showing that samples in the range of a few hundred ppm(V) of n-dodecanevapor in butane gas can be sensed. Also, studying the response as a function of time, it isdemonstrated that the sensing process is quickly reversible. PMID- 28903208 TI - Global Distribution and Density of Constructed Impervious Surfaces. AB - We present the first global inventory of the spatial distribution and density ofconstructed impervious surface area (ISA). Examples of ISA include roads, parking lots,buildings, driveways, sidewalks and other manmade surfaces. While high spatialresolution is required to observe these features, the new product reports the estimateddensity of ISA on a one-km2 grid based on two coarse resolution indicators of ISA - thebrightness of satellite observed nighttime lights and population count. The model wascalibrated using 30-meter resolution ISA of the USA from the U.S. Geological Survey.Nominally the product is for the years 2000-01 since both the nighttime lights andreference data are from those two years. We found that 1.05% of the United States landarea is impervious surface (83,337 km2) and 0.43 % of the world's land surface (579,703km2) is constructed impervious surface. China has more ISA than any other country(87,182 km2), but has only 67 m2 of ISA per person, compared to 297 m2 per person in theUSA. The distribution of ISA in the world's primary drainage basins indicates that watersheds damaged by ISA are primarily concentrated in the USA, Europe, Japan, China and India. The authors believe the next step for improving the product is to include reference ISA data from many more areas around the world. PMID- 28903209 TI - Models of Hydrogel Swelling with Applications to Hydration Sensing. AB - Hydrogels, polymers and various other composite materials may be used insensing applications in which the swelling or de-swelling of the material in response tosome analyte is converted via a transducer to a measurable signal. In this paper, we analyzemodels used to predict the swelling behavior of hydrogels that may be used in applicationsrelated to hydration monitoring in humans. Preliminary experimental data related toosmolality changes in fluids is presented to compare to the theoretical models. Overall,good experimental agreement with the models is achieved. PMID- 28903210 TI - Integrated Love Wave Device Dedicated to Biomolecular Interactions Measurements in Aqueous Media. AB - Mass-sensitive electro-acoustic devices such as surface acoustic wave (SAW)micro balances, capable to operate with aqueous media are particularly favorable for thedevelopment of biosensors. Their dimensions and physical properties offer a large potentialin biological fluid investigations, especially for measuring physical phenomenon (massdeposition, adsorption, pressure...). In this work, we propose a specific gratingconfiguration to lower the influence of viscosity of fluids which reduces the signal dynamicsof the surface wave transducers. A dedicated liquid cell also has been developed to isolatethe electro-active part of the device. The fabrication of the cell is achieved using theSU-8TMphoto resist, allowing for manufacturing thick structures preventing any contact between thetested liquids and the transducers. Furthermore, the sensing area has been optimized tooptimize the sensor gravimetric sensitivity. The operation of the sensor is illustrated bydetecting bovine serum albumin (BSA) adsorption in the sensing area. PMID- 28903211 TI - Development of Standardization and Management System for the Severity of Unpaved Test Courses. AB - The vibration environment essentially accompanied by vehicle operation on theground is determined by the shape of road surface, which is called as profile. This paperfocuses on the development of profile measurement and severity analysis system forunpaved test courses. In general, the profile and severity of unpaved road is an importantissue in the reliability of endurance test. In order to measure and maintain unpaved roadprofile and severity, it is necessary to develop a profilometer system. The developedprofilometer system is composed of data processing computer, power unit, air compressorand sensors(encoder, vertical gyro and laser displacement). This study presents themeasuring system configuration, measurement principle of road profile and analysismethod of road characteristics used at CPG (Chang-won Proving Ground) for this purpose.In order to standardize and manage the severity of unpaved test courses, neural network isapplied. PMID- 28903212 TI - A Wetness Index Using Terrain-Corrected Surface Temperature and Normalized Difference Vegetation Index Derived from Standard MODIS Products: An Evaluation of Its Use in a Humid Forest-Dominated Region of Eastern Canada. AB - In this paper we develop a method to estimate land-surface water content in amostly forest-dominated (humid) and topographically-varied region of eastern Canada. Theapproach is centered on a temperature-vegetation wetness index (TVWI) that uses standard 8-day MODIS-based image composites of land surface temperature (TS) and surface reflectanceas primary input. In an attempt to improve estimates of TVWI in high elevation areas, terrain-induced variations in TS are removed by applying grid, digital elevation model-basedcalculations of vertical atmospheric pressure to calculations of surface potential temperature(thetaS). Here, thetaS corrects TS to the temperature value to what it would be at mean sea level (i.e.,~101.3 kPa) in a neutral atmosphere. The vegetation component of the TVWI uses 8-daycomposites of surface reflectance in the calculation of normalized difference vegetation index(NDVI) values. TVWI and corresponding wet and dry edges are based on an interpretation ofscatterplots generated by plotting thetaS as a function of NDVI. A comparison of spatially-averaged field measurements of volumetric soil water content (VSWC) and TVWI for the 2003-2005 period revealed that variation with time to both was similar in magnitudes. Growing season, point mean measurements of VSWC and TVWI were 31.0% and 28.8% for 2003, 28.6% and 29.4% for 2004, and 40.0% and 38.4% for 2005, respectively. An evaluation of the long term spatial distribution of land-surface wetness generated with the new thetaS NDVI function and a process-based model of soil water content showed a strong relationship (i.e., r2 = 95.7%). PMID- 28903213 TI - Investigation on Clarified Fruit Juice Composition by Using Visible Light Micro Raman Spectroscopy. AB - Liquid samples of clarified apple and apricot juices at different productionstages were investigated using visible light micro-Raman spectroscopy in order to assessits potential in monitoring fruit juice production. As is well known, pectin plays a strategicrole in the production of clarified juice and the possibility of using Raman for its detectionduring production was therefore evaluated. The data analysis has enabled the clearidentification of pectin. In particular, Raman spectra of apple juice samples from washedand crushed fruits revealed a peak at 845 cm-1 (typical of pectin) which disappears in theRaman spectra of depectinised samples. The fructose content was also revealed by thepresence of four peaks at 823 cm-1, 872 cm-1, 918 cm-1 and 975 cm-1. In the case of apricotjuice, several Raman fingerprints of beta-carotene at 1008, 1159 and 1520 cm-1 were alsohighlighted. Present results resulted interesting for the exclusive use of optical methods forthe quantitative determination of the above mentioned substances in place of thebiochemical assays generally used for this purpose, which are time consuming and requiredifferent chemical reagents for each of them. PMID- 28903214 TI - Quantitative Boundary Support Characterization for Cantilever MEMS. AB - Microfabrication limitations are of concern especially for suspended Micro Electro-Mechanical-Systems (MEMS) microstructures such as cantilevers. The static anddynamic qualities of such microscale devices are directly related to the invariant and variantproperties of the microsystem. Among the invariant properties, microfabrication limitationscan be quantified only after the fabrication of the device through testing. However, MEMSare batch fabricated in large numbers where individual testing is neither possible nor costeffective. Hence, a suitable test algorithm needs to be developed where the test resultsobtained for a few devices can be applied to the whole fabrication batch, and also to thefoundry process in general. In this regard, this paper proposes a method to test MEMScantilevers under variant electro-thermal influences in order to quantify the effectiveboundary support condition obtained for a foundry process. A non-contact optical sensingapproach is employed for the dynamic testing. The Rayleigh-Ritz energy method usingboundary characteristic orthogonal polynomials is employed for the modeling andtheoretical analysis. PMID- 28903215 TI - Determination of DPPH Radical Oxidation Caused by Methanolic Extracts of Some Microalgal Species by Linear Regression Analysis of Spectrophotometric Measurements. AB - The demonstrated modified spectrophotometric method makes use of the 2,2-diphenyl 1-picrylhydrazyl (DPPH) radical and its specific absorbance properties. Theabsorbance decreases when the radical is reduced by antioxidants. In contrast to otherinvestigations, the absorbance was measured at a wavelength of 550 nm. This wavelengthenabled the measurements of the stable free DPPH radical without interference frommicroalgal pigments. This approach was applied to methanolic microalgae extracts for twodifferent DPPH concentrations. The changes in absorbance measured vs. the concentrationof the methanolic extract resulted in curves with a linear decrease ending in a saturationregion. Linear regression analysis of the linear part of DPPH reduction versus extractconcentration enabled the determination of the microalgae's methanolic extractsantioxidative potentials which was independent to the employed DPPH concentrations. Theresulting slopes showed significant differences (6 - 34 MUmol DPPH g-1 extractconcentration) between the single different species of microalgae (Anabaena sp.,Isochrysis galbana, Phaeodactylum tricornutum, Porphyridium purpureum, Synechocystissp. PCC6803) in their ability to reduce the DPPH radical. The independency of the signal on the DPPH concentration is a valuable advantage over the determination of the EC50 value. PMID- 28903216 TI - Synthesis, Characterization and Metal Ion Detection of Novel Fluoroionophores Based on Heterocyclic Substituted Alanines. AB - The synthesis of new fluorescent probes containing the thiophene andbenzoxazole moieties combined with an alanine residue is described. The resulting highlyfluorescent heterocyclic alanine derivatives respond via a quenching effect, withparamagnetic Cu(II) and Ni(II) metal ions and with diamagnetic Hg(II), as shown by theabsorption and steady-state fluorescence spectroscopy studies. The formation ofmononuclear or dinuclear metal complexes was postulated based on the presence of thefree carboxylic acid as binding site and also with the interaction with the donor atoms inthe chromophore. Interaction with other important biological metal ions such as Zn(II),Ca(II) and Na(I) was also explored. PMID- 28903217 TI - Modeling Forest Productivity Using Envisat MERIS Data. AB - The aim of this study was to derive land cover products with a 300-m pixelresolution of Envisat MERIS (Medium Resolution Imaging Spectrometer) to quantify netprimary productivity (NPP) of conifer forests of Taurus Mountain range along the EasternMediterranean coast of Turkey. The Carnegie-Ames-Stanford approach (CASA) was usedto predict annual and monthly regional NPP as modified by temperature, precipitation,solar radiation, soil texture, fractional tree cover, land cover type, and normalizeddifference vegetation index (NDVI). Fractional tree cover was estimated using continuoustraining data and multi-temporal metrics of 47 Envisat MERIS images of March 2003 toSeptember 2005 and was derived by aggregating tree cover estimates made from high-resolution IKONOS imagery to coarser Landsat ETM imagery. A regression tree algorithmwas used to estimate response variables of fractional tree cover based on the multi-temporal metrics. This study showed that Envisat MERIS data yield a greater spatial detailin the quantification of NPP over a topographically complex terrain at the regional scalethan those used at the global scale such as AVHRR. PMID- 28903218 TI - Improving Estimation Performance in Networked Control Systems Applying the Send on-delta Transmission Method. AB - This paper is concerned with improving performance of a state estimationproblem over a network in which a send-on-delta (SOD) transmission method is used. TheSOD method requires that a sensor node transmit data to the estimator node only if itsmeasurement value changes more than a given specified delta value. This method has beenexplored and applied by researchers because of its efficiency in the network bandwidthimprovement. However, when this method is used, it is not ensured that the estimator nodereceives data from the sensor nodes regularly at every estimation period. Therefore, wepropose a method to reduce estimation error in case of no sensor data reception. When theestimator node does not receive data from the sensor node, the sensor value is known to bein a (-deltai , deltai ) interval from the last transmitted sensor value. This implicit information hasbeen used to improve estimation performance in previous studies. The main contribution ofthis paper is to propose an algorithm, where the sensor value interval is reduced to(-deltai / 2, deltai / 2) in certain situations. Thus, the proposed algorithm improves the overallestimation performance without any changes in the send-on-delta algorithms of the sensornodes. Through numerical simulations, we demonstrate the feasibility and the usefulness ofthe proposed method. PMID- 28903219 TI - Physical-Mechanical Properties of Nitrodopes Affected by Ultra-Violet Radiation. AB - The FTIR spectroscopy has been employed in this research work to monitor theprocess of nitrodope photodegradation, by measuring surfaces of bands typical of a nitrogroup. Nitric esters are subject to degradation, which is reflected on a quantitative ratio ofthe surfaces of the IR bands that originate from the nitric ester. The obtained results showthat the length of the UV rays' activity on the samples over the time periods of 240, 480and 960 minutes directly affects the spectrum appearance of the same sample before andafter the irradiation. The longer the action time of the UV rays and the higher a masspercentage of nitrocellulose in the nitrodope is, the smaller the bands' surfaces become, i.e.the level of degradation is higher. In order to confirm the degradation of nitrodope, thedegree of crosslinking has also been examined by determining the Konig hardness and alsothe mean viscosity molar mass has been defined repeatedly applying the capillaryviscosimetry method. PMID- 28903220 TI - Wireless Sensor/Actuator Network Design for Mobile Control Applications. AB - Wireless sensor/actuator networks (WSANs) are emerging as a new generationof sensor networks. Serving as the backbone of control applications, WSANs will enablean unprecedented degree of distributed and mobile control. However, the unreliability ofwireless communications and the real-time requirements of control applications raise greatchallenges for WSAN design. With emphasis on the reliability issue, this paper presents anapplication-level design methodology for WSANs in mobile control applications. Thesolution is generic in that it is independent of the underlying platforms, environment,control system models, and controller design. To capture the link quality characteristics interms of packet loss rate, experiments are conducted on a real WSAN system. From theexperimental observations, a simple yet efficient method is proposed to deal withunpredictable packet loss on actuator nodes. Trace-based simulations give promisingresults, which demonstrate the effectiveness of the proposed approach. PMID- 28903221 TI - Magnetostrictive Micro Mirrors for an Optical Switch Matrix. AB - We have developed a wireless-controlled compact optical switch by siliconmicromachining techniques with DC magnetron sputtering. For the optical switchingoperation, micro mirror is designed as cantilever shape size of 5mm*800MUm*50MUm.TbDyFe film is sputter-deposited on the upper side of the mirror with the condition as: Argas pressure below 1.2*10-9 torr, DC input power of 180W and heating temperature of up to250 degrees C for the wireless control of each component. Mirrors are actuated by externallyapplied magnetic fields for the micro application. Applied beam path can be changedaccording to the direction and the magnitude of applied magnetic field. Reflectivity changes,M-H curves and X ray diffractions of sputtered mirrors are measured to determine magneto-optical, magneto-elastic properties with variation in sputtered film thickness. The deflectedangle-magnetic field characteristics of the fabricated mirror are measured. PMID- 28903222 TI - High-rise Buildings versus Outdoor Thermal Environment in Chongqing. AB - This paper gives a brief description of the over quick urbanization sinceChongqing, one of the biggest cities in China, has been a municipality directly under theCentral Government in 1997, excessive development and exceeding increase of high-risebuildings because of its special geographical position which finally leads to the worseningof the urban outdoor thermal environment. Then, this paper makes a bright balance to thefield measurement and simulated results of the wind speed field, temperature field of onemultifunctional high-rise building in Chongqing university located in the city center, andthe contrasted results validate the correctness of CFD in the outdoor thermal environmentalsimulation, expose the disadvantages of high-rise buildings on the aspects of blocking thewind field, decreasing wind speed which results in accumulation of the air-conditioningheat revolving around and periscian region where sunshine can not rip into. Finally, inorder to improve the urban outdoor thermal environment near the high-rise buildingsespecially for the angle of natural ventilation, this paper simulates the wind environment indifferent architectural compositions and architectural layouts by CFD, and the simulatedresults show that freestyle and tower buildings which can guarantee the wind speed andtake the air-conditioning heat away are much suitable and reasonable for the specialChongqing geography. These conclusions can also be used as a reference in othermountain cities, especially for the one with a great number of populations. PMID- 28903223 TI - Multi-agent Negotiation Mechanisms for Statistical Target Classification in Wireless Multimedia Sensor Networks. AB - The recent availability of low cost and miniaturized hardware has allowedwireless sensor networks (WSNs) to retrieve audio and video data in real worldapplications, which has fostered the development of wireless multimedia sensor networks(WMSNs). Resource constraints and challenging multimedia data volume makedevelopment of efficient algorithms to perform in-network processing of multimediacontents imperative. This paper proposes solving problems in the domain of WMSNs fromthe perspective of multi-agent systems. The multi-agent framework enables flexible networkconfiguration and efficient collaborative in network processing. The focus is placed ontarget classification in WMSNs where audio information is retrieved by microphones. Todeal with the uncertainties related to audio information retrieval, the statistical approachesof power spectral density estimates, principal component analysis and Gaussian processclassification are employed. A multi-agent negotiation mechanism is specially developed toefficiently utilize limited resources and simultaneously enhance classification accuracy andreliability. The negotiation is composed of two phases, where an auction based approach isfirst exploited to allocate the classification task among the agents and then individual agentdecisions are combined by the committee decision mechanism. Simulation experiments withreal world data are conducted and the results show that the proposed statistical approachesand negotiation mechanism not only reduce memory and computation requi. PMID- 28903224 TI - An Optical Biosensor based on Immobilization of Laccase and MBTH in Stacked Films for the Detection of Catechol. AB - The fabrication of an optical biosensor by using stacked films where 3-methyl-2 benzothiazolinone hydrazone (MBTH) was immobilized in a hybrid nafion/sol gelsilicate film and laccase in a chitosan film for the detection of phenolic compounds wasdescribed. Quinone and/or phenoxy radical product from the enzymatic oxidation ofphenolic compounds was allowed to couple with MBTH to form a colored azo-dye productfor spectrophometric detection. The biosensor demonstrated a linear response to catecholconcentration range of 0.5-8.0 mM with detection limit of 0.33 mM and response time of10 min. The reproducibility of the fabricated biosensor was good with RSD value of 5.3 %(n = 8) and stable for at least 2 months. The use of the hybrid materials of nafion/sol-gelsilicate to immobilize laccase has altered the selectivity of the enzyme to various phenoliccompounds such as catechol, guaicol, o-cresol and m-cresol when compared to the non immobilized enzyme. When immobilized in this hybrid film, the biosensor response onlyto catechol and not other phenolic compounds investigated. Immobilization in this hybridmaterial has enable the biosensor to be more selective to catechol compared with the non-immobilized enzyme. This shows that by a careful selection of different immobilizationmatrices, the selectivity of an enzyme can be modified to yield a biosensor with goodselectivity towards certain targeted analytes. PMID- 28903225 TI - A Urea Biosensor from Stacked Sol-Gel Films with Immobilized Nile Blue Chromoionophore and Urease Enzyme. AB - An optical urea biosensor was fabricated by stacking several layers of sol gelfilms. The stacking of the sol-gel films allowed the immobilization of a Nile Bluechromoionophore (ETH 5294) and urease enzyme separately without the need of anychemical attachment procedure. The absorbance response of the biosensor was monitoredat 550 nm, i.e. the deprotonation of the chromoionophore. This multi layer sol-gel filmformat enabled higher enzyme loading in the biosensor to be achieved. The urea opticalbiosensor constructed from three layers of sol-gel films that contained urease demonstrateda much wider linear response range of up to 100 mM urea when compared with biosensorsthat constructed from 1-2 layers of films. Analysis of urea in urine samples with thisoptical urea biosensor yielded results similar to that determined by a spectrophotometricmethod using the reagent p-dimethylaminobenzaldehyde (R2 = 0.982, n = 6). The averagerecovery of urea from urine samples using this urea biosensor is approximately 103%. PMID- 28903226 TI - Enhancement of BSA Binding on Au Surfaces by calix[4]bisazacrown Monolayer. AB - Effective investigation of biomolecular structure and function with chip basedmodern instruments often requires reliable and steady attachment of designatedbiomolecules on substrate. Here, we investigated the formation of self assembled monolayer(SAM) with a new calix[4]arene derivative containing bisazacrown ether at the lower rim(calix[4]bisazacrown) where ammonium moieties of proteins can mainly be interacted with.Immobilization process of protein using bovine serum albumin (BSA) on the Au surfacemodified with calix[4]bisazacrown monolyer as an artificial linker system was monitored bysurface plasmon resonance (SPR) technique. The surface concentration of BSA calculatedby the simulation of SPR experimental data was higher than that of a well-known similarcommercial protein linker. These results can help in modeling and understanding of proteinimmobilization on solid surface as well as further development lab-on-a chip (LOC) devicesfor biomedical diagnosis kit of certain protein related diseases as biomarkers. PMID- 28903227 TI - Modeling Potential Distribution and Carbon Dynamics of Natural Terrestrial Ecosystems: A Case Study of Turkey. AB - We derived a simple model that relates the classification of biogeoclimatezones, (co)existence and fractional coverage of plant functional types (PFTs), and patternsof ecosystem carbon (C) stocks to long-term average values of biogeoclimatic indices in atime- and space-varying fashion from climate vegetation equilibrium models. ProposedDynamic Ecosystem Classification and Productivity (DECP) model is based on the spatialinterpolation of annual biogeoclimatic variables through multiple linear regression (MLR)models and inverse distance weighting (IDW) and was applied to the entire Turkey of780,595 km2 on a 500 m x 500 m grid resolution. Estimated total net primary production(TNPP) values of mutually exclusive PFTs ranged from 108 26 to 891 207 Tg C yr-1under the optimal conditions and from 16 7 to 58 23 Tg C yr-1 under the growth-limiting conditions for all the natural ecosystems in Turkey. Total NPP values ofcoexisting PFTs ranged from 178 36 to 1231 253 Tg C yr-1 under the optimalconditions and from 23 8 to 92 31 Tg C yr-1 under the growth-limiting conditions. Thenational steady state soil organic carbon (SOC) storage in the surface one meter of soil wasestimated to range from 7.5 1.8 to 36.7 7.8 Pg C yr 1 under the optimal conditions andfrom 1.3 0.7 to 5.8 2.6 Pg C yr-1 under the limiting conditions, with the national range of 1.3 to 36.7 Pg C elucidating 0.1% and 2.8% of the global SOC value (1272.4 Pg C), respectively. Our comparisons with literature compilations indicate that estimated patterns of biogeoclimate zones, PFTs, TNPP and SOC storage by the DECP model agree reasonably well with measurements from field and remotely sensed data. PMID- 28903228 TI - Impact of Climate Change on Irrigation Demand and Crop Growth in a Mediterranean Environment of Turkey. AB - A simulation study was carried out to describe effects of climate change on cropgrowth and irrigation water demand for a wheat-maize cropping sequence in aMediterranean environment of Turkey. Climate change scenarios were projected using dataof the three general circulation models-GCMs (CGCM2, ECHAM4 and MRI) for theperiod of 1990 to 2100 and one regional climate model-RCM-for the period of 2070 to2079. Potential impacts of climate change based on GCMs data were estimated for the A2scenario in the Special Report on Emission Scenarios (SRES). The forcing data for theboundary condition of the RCM were given by the MRI model. Daily CGCM2 and RCMdata were used for computations of water balance and crop development. Predictionsderived from the models about changes in irrigation and crop growth in this study coveredthe period of 2070 to 2079 relative to the baseline period of 1994 to 2003. The effects ofclimate change on water demand and on wheat and maize yields were predicted using thedetailed crop growth subroutine of the SWAP (Soil-Water-Atmosphere-Plant) model. Precipitation was projected to decrease by about 163, 163 and 105 mm during the periodof 1990 to 2100 under the A2 scenario of the CGCM2, ECHAM4 and MRI models,respectively. The CGCM2, ECHAM4 and MRI models projected a temperature rise of 4.3,5.3 and 3.1 oC, respectively by 2100. An increase in temperature may result in a higherevaporative demand of the atmosphere. However, actual evapotranspiration (ETa) fromwheat cropland under a doubling CO2 concentration for the period of 2070 to 2079 wasSensors 2007, 7 2298 predicted to decrease by about 28 and 8% relative to the baseline period based on the CGCM2 and RCM data, respectively. According to these models, irrigation demand by wheat would be higher for the same period due to a decrease in precipitation. Both ETa and irrigation water for maize cropland were projected to decrease by 24 and 15% according to the CGCM2, and 28 and 22% according to the RCM, respectively. The temperature rise accelerated crop development but shortened the growing period by 24 days for wheat and 9 days for maize according to the CGCM2 data. The shortened growth duration with a higher temperature reduced the biomass accumulation of both crops regardless of CO2-fertilization effect. With the combined effect of CO2-fertilization and increased temperature, the CGCM2 and RCM projections resulted in an increase by 16 and 36% in grain yield of wheat and a decrease by about 25% and an increase by 3% in maize yield, respectively. PMID- 28903229 TI - Non-invasive Optical Biosensor for Probing Cell Signaling. AB - Cell signaling mediated through a cellular target is encoded by spatial andtemporal dynamics of downstream signaling networks. The coupling of temporal dynamicswith spatial gradients of signaling activities guides cellular responses upon stimulation.Monitoring the integration of cell signaling in real time, if realized, would provide a newdimension for understanding cell biology and physiology. Optical biosensors includingresonant waveguide grating (RWG) biosensor manifest a physiologically relevant andintegrated cellular response related to dynamic redistribution of cellular matters, thusproviding a non invasive means for cell signaling study. This paper reviews recentprogresses in biosensor instrumentation, and theoretical considerations and potentialapplications of optical biosensors for whole cell sensing. PMID- 28903230 TI - Effect of Estimated Daily Global Solar Radiation Data on the Results of Crop Growth Models. AB - The results of previous studies have suggested that estimated daily globalradiation (RG) values contain an error that could compromise the precision of subsequentcrop model applications. The following study presents a detailed site and spatial analysis ofthe RG error propagation in CERES and WOFOST crop growth models in Central Europeanclimate conditions. The research was conducted i) at the eight individual sites in Austria andthe Czech Republic where measured daily RG values were available as a reference, withseven methods for RG estimation being tested, and ii) for the agricultural areas of the CzechRepublic using daily data from 52 weather stations, with five RG estimation methods. In thelatter case the RG values estimated from the hours of sunshine using the angstrom-Prescottformula were used as the standard method because of the lack of measured RG data. At thesite level we found that even the use of methods based on hours of sunshine, which showedthe lowest bias in RG estimates, led to a significant distortion of the key crop model outputs.When the angstrom-Prescott method was used to estimate RG, for example, deviationsgreater than +/-10 per cent in winter wheat and spring barley yields were noted in 5 to 6 percent of cases. The precision of the yield estimates and other crop model outputs was lowerwhen RG estimates based on the diurnal temperature range and cloud cover were used (mean bias error 2.0 to 4.1 per cent). The methods for estimating RG from the diurnal temperature range produced a wheat yield bias of more than 25 per cent in 12 to 16 per cent of the seasons. Such uncertainty in the crop model outputs makes the reliability of any seasonal yield forecasts or climate change impact assessments questionable if they are based on this type of data. The spatial assessment of the RG data uncertainty propagation over the winter wheat yields also revealed significant differences within the study area. We found that RG estimates based on diurnal temperature range or its combination with daily total precipitation produced a bias of to 30 per cent in the mean winter wheat grain yields in some regions compared with simulations in which RG values had been estimated using the angstrom-Prescott formula. In contrast to the results at the individual sites, the methods based on the diurnal temperature range in combination with daily precipitation totals showed significantly poorer performance than the methods based on the diurnal temperature range only. This was due to the marked increase in the bias in RG estimates with altitude, longitude or latitude of given region. These findings in our view should act as an incentive for further research to develop more precise and generally applicable methods for estimating daily RG based more on the underlying physical principles and/or the remote sensing approach. PMID- 28903231 TI - An Electronic Measurement Instrumentation of the Impedance of a Loaded Fuel Cell or Battery. AB - In this paper we present an inexpensive electronic measurement instrumentationdeveloped in our laboratory, to measure and plot the impedance of a loaded fuel cell orbattery. Impedance measurements were taken by using the load modulation method. Thisinstrumentation has been developed around a VXI system stand which controls electroniccards. Software under Hpvee(r) was developed for automatic measurements and the layout ofthe impedance of the fuel cell on load. The measurement environment, like the ambienttemperature, the fuel cell temperature, the level of the hydrogen, etc..., were taken withseveral sensors that enable us to control the measurement. To filter the noise and theinfluence of the 50Hz, we have implemented a synchronous detection which filters in a verynarrow way around the useful signal. The theoretical result obtained by a simulation underPspice(r) of the method used consolidates the choice of this method and the possibility ofobtaining correct and exploitable results. The experimental results are preliminary results ona 12V vehicle battery, having an inrush current of 330A and a capacity of 40Ah (impedancemeasurements on a fuel cell are in progress, and will be the subject of a forthcoming paper).The results were plotted at various nominal voltages of the battery (12.7V, 10V, 8V and 5V)and with two imposed currents (0.6A and 4A). The Nyquist diagram resulting from theexperimental data enable us to show an influence of the load of the battery on its internalimpedance. The similitude in the graph form and in order of magnitude of the valuesobtained (both theoretical and practical) enables us to validate our electronic measurementinstrumentation. One of the future uses for this instrumentation is to integrate it with several control sensors, on a vehicle as an embedded system to monitor the degradation of fuel cell membranes. PMID- 28903232 TI - Development of QCM Trimethylamine Sensor Based on Water Soluble Polyaniline. AB - A rapid, sensitive, low-cost device to detect trimethylamine was presented in thispaper. The preparation of water soluble polyaniline was firstly studied. Then the polyanilinewas characterized via Fourier transform infrared spectroscopy (FTIR), UV-visiblespectroscopy and scanning electron microscopy (SEM). Based on the water solublepolyaniline film, a quartz crystal microbalance (QCM) sensor for trimethylamine detectionwas fabricated and its characteristics were examined. The sensor consisted of one quartzcrystal oscillator coated with the polyaniline film for sensing and the other one forreference. Pretreated with trimethylamine, the QCM sensor had an excellent linearsensitivity to trimethylamine. Easily recovered by N2 purgation, the response of the sensorexhibited a good repeatability. Responses of the sensor to trimethylamine, ethanol and ethylacetate were compared, and the results showed that the response was related to the polarityof the analyte vapor. Experimental result also showed that the sensitivity of the sensor wasrelatively stable within one month. The simple and feasible method to prepare and coat thepolyaniline sensing film makes it promising for mass production. PMID- 28903233 TI - A MEMS-based Air Flow Sensor with a Free-standing Micro-cantilever Structure. AB - This paper presents a micro-scale air flow sensor based on a free standingcantilever structure. In the fabrication process, MEMS techniques are used to deposit asilicon nitride layer on a silicon wafer. A platinum layer is deposited on the silicon nitridelayer to form a piezoresistor, and the resulting structure is then etched to create afreestanding micro-cantilever. When an air flow passes over the surface of the cantileverbeam, the beam deflects in the downward direction, resulting in a small variation in theresistance of the piezoelectric layer. The air flow velocity is determined by measuring thechange in resistance using an external LCR meter. The experimental results indicate that theflow sensor has a high sensitivity (0.0284 omega/ms-1), a high velocity measurement limit (45ms-1) and a rapid response time (0.53 s). PMID- 28903234 TI - Utilizing of Square Wave Voltammetry to Detect Flavonoids in the Presence of Human Urine. AB - About biological affecting of flavonoids on animal organisms is known less,thus we selected flavonoids, flavanones and flavones, and their glycosides, which wereexamined as potential inducers of cytochrome(s) P450 when administrated by gavages intoexperimental male rats. The study was focused on induction of CYP1A1, the majorcytochrome P450 involved in carcinogen activation. The data obtained demonstrate thenecessity of taking into account not only ability of flavonoids to bind to Ah receptor(induction factor) but also to concentrate on their distribution and metabolism (includingcolon microflora) in the body. After that we examined certain flavonoids as potential inducers of cytochrome P450, we wanted to suggest and optimize suitable electrochemical technique for determination of selected flavonoids (quercetin, quercitrin, rutin, chrysin and diosmin) in body liquids. For these purposes, we selected square wave voltannetry using carbon paste electrode. Primarily we aimed on investigation of their basic electrochemical behaviour. After that we have optimized frequency, step potential and supporting electrolyte. Based on the results obtained, we selected the most suitable conditions for determination of the flavonoids as follows: frequency 180 Hz, step potential 1.95 mV/s and phosphate buffer of pH 7 as supporting electrolyte. Detection limits (3 S/N) of the flavonoids were from units to tens of nM except diosmin, where the limit were higher than MUM. In addition, we attempted to suggest a sensor for analysis of flavonoids in urine. It clearly follows from the results obtained that flavonoids can be analysed in the presence of animal urine, because urine did not influence much the signals of flavonoids (recoveries of the signals were about 90 %). PMID- 28903235 TI - Shapes of Differential Pulse Voltammograms and Level of Metallothionein at Different Animal Species. AB - Metallothioneins play a key role in maintaining homeostasis of essential metalsand in protecting of cells against metal toxicity as well as oxidative damaging. Exceptinghumans, blood levels of metallothionein have not yet been reported from any animalspecies. Blood plasma samples of 9 animal species were analysed by the adsorptive transferstripping technique to obtain species specific voltammograms. Quite distinct records wereobtained from the Takin (Budorcas taxicolor), while other interesting records were observedin samples from the European Bison (Bison bonasus bonasus) and the Red-eared Slider(Trachemys scripta elegans). To quantify metallothionein the catalytic peak Cat2 was used,well developed in the Domestic Fowl (Gallus gallus f. domestica) and showing a very lowsignal in the Red Deer (Cervus elaphus). The highest levels of metallothionein reachingover 20 MUM were found in the Domestic Fowl. High levels of MT were also found in theBearded Dragon (Pogona vitticeps) and the Grey Wolf (Canis lupus lupus). The lowestvalues of about 1-3 MUM were determined in the Red-eared Slider, Takin and Red Deer. Employing a simple electrochemical detection it was possible to examine variation in blood metallothionein in different species of vertebrates. PMID- 28903236 TI - Planar Array Sensor for High-speed Component Distribution Imaging in Fluid Flow Applications. AB - A novel planar array sensor based on electrical conductivity measurements ispresented which may be applied to visualize surface fluid distributions. The sensor ismanufactured using printed-circuit board fabrication technology and comprises of 64 x 64interdigital sensing structures. An associated electronics measures the electricalconductivity of the fluid over each individual sensing structure in a multiplexed manner byapplying a bipolar excitation voltage and by measuring the electrical current flowing from adriver electrode to a sensing electrode. After interrogating all sensing structures, a two-dimensional image of the conductivity distribution over a surface is obtained which in turnrepresents fluid distributions over sensor's surface. The employed electronics can acquire upto 2500 frames per second thus being able to monitor fast transient phenomena. The systemhas been evaluated regarding measurement accuracy and depth sensitivity. Furthermore, theapplication of the sensor in the investigation of two different flow applications is presented. PMID- 28903237 TI - Electrochemical Sensor for Tryptophan Determination Based on Copper-cobalt Hexacyanoferrate Film Modified Graphite Electrode. AB - In this work, the development of a tryptophan sensor and its application to milkare described. The mixed metal (copper and cobalt) hexacynoferrates are electrodepositedon the graphite electrode, and this film exhibits an electrocatalytic activity towards for theoxidation of tryptophan. The experimental conditions, including the scan cycles, the ratio ofcopper(II) and cobalt(II), pH value, applied potential, are investigated in detail. At theoptimal conditions, the eletctrocatalytic response is a linear relationship with theconcentration of tryptophan in the range of 10 MUM and 900 MUM, with a detection limit ofabout 6 MUM. This modified electrode was also successfully used to detect the tryptophanconcentration in milk. PMID- 28903238 TI - Operational Mapping of Soil Moisture Using Synthetic Aperture Radar Data: Application to the Touch Basin (France). AB - Soil moisture is a key parameter in different environmental applications, suchas hydrology and natural risk assessment. In this paper, surface soil moisture mappingwas carried out over a basin in France using satellite synthetic aperture radar (SAR)images acquired in 2006 and 2007 by C-band (5.3 GHz) sensors. The comparisonbetween soil moisture estimated from SAR data and in situ measurements shows goodagreement, with a mapping accuracy better than 3%. This result shows that themonitoring of soil moisture from SAR images is possible in operational phase. Moreover,moistures simulated by the operational Meteo-France ISBA soil vegetation-atmospheretransfer model in the SIM-Safran-ISBA-Modcou chain were compared to radar moistureestimates to validate its pertinence. The difference between ISBA simulations and radarestimates fluctuates between 0.4 and 10% (RMSE). The comparison between ISBA andgravimetric measurements of the 12 March 2007 shows a RMSE of about 6%. Generally,these results are very encouraging. Results show also that the soil moisture estimatedfrom SAR images is not correlated with the textural units defined in the European Soil Geographical Database (SGDBE) at 1:1000000 scale. However, dependence was observed between texture maps and ISBA moisture. This dependence is induced by the use of the texture map as an input parameter in the ISBA model. Even if this parameter is very important for soil moisture estimations, radar results shown that the textural map scale at 1:1000000 is not appropriate to differentiate moistures zones. PMID- 28903239 TI - D-galactose/D-glucose-binding Protein from Escherichia coli as Probe for a Non consuming Glucose Implantable Fluorescence Biosensor. AB - D-Galactose/D-glucose-binding protein from E. coli (GGBP) is a monomer thatbinds glucose with high affinity. The protein structure of GGBP is organized in twoprincipal domains linked by a hinge region that form the sugar-binding site. In this workwe show that the mutant form of GGBP at the amino acid position 182 can be utilized as aprobe for the development of a non-consuming analyte fluorescence biosensor to monitorthe glucose level in diabetes health care. PMID- 28903240 TI - Refractive Index Measurement within a Photonic Crystal Fibre Based on Short Wavelength Diffraction. AB - A new class of refractive index sensors using solid core photonic crystal fibres isdemonstrated. Coherent scattering at the cladding lattice is used to optically characterizematerials inserted into the fibre holes. The liquid to solid phase transition of water uponfreezing to ice 1h is characterized by determining the refractive index. PMID- 28903241 TI - Formation and Fluorimetric Characterization of Micelles in a Micro-flow Through System with Static Micro Mixer. AB - The formation and behaviour of micelles of sodium dodecylsulfate in water byuse of a static micro mixer were studied. Trisbipyridylruthenium(II) was applied asindicator dye, 9-methylanthracene was used for fluorescence quenching. All experimentswere carried out by a micro fluid arrangement with three syringe pumps, a 2 1 two-stepstatic micro mixer (IPHT Jena) and a on-line micro fluorimetry including a luminescencediode for excitation, a blue glass filter (BG 7, Linos), two edge filters (RG 630, Linos) anda photo counting module (MP 900, Perkin Elmer). It was possible to measure thefluorescence inside the PTFE tube (inner diameter 0.5 mm) directly. A linear dependenceof fluorescence intensity from dye concentration was observed in absence of quencher andsurfactant as expected. An aggregation number of about 62 was found in the flow raterange between 300 and 800 MUL/min. The fluorescence intensity increases slightly, butsignificant with increasing flow rate, if no quencher is present. In the presence of quencher,the fluorescence intensity decreases with decreasing surfactant concentration and withenhanced flow rate. The strength of the flow rate effect on the fluorescence increases withdecreasing surfactant concentration. The size of micelles was determined in micro channelsby the micro fluorimetric method in analogy to the conventional system. The micellesextract the quencher from the solution and lower, this way, the quenching effect. The sizeof micelles was estimated and it could be shown, that the flow rate has only low effect onthe aggregation number at the investigated flow rates. The effect of flow rate andsurfactant concentration on the fluorescence in the presence of quencher was interpreted asa shift in the micelle concentration due to the shear forces. It is expected, that thefluorescence intensity is lowered, if more quencher molecules are molecular disperse distributed inside the solution. Obviously, the lowered fluorescence intensity at higher flow rates suggests a reduction of the micelle density causing an increase of quencher concentration outside the micelles. PMID- 28903242 TI - Electrochemical Detection of a Dengue-related Oligonucleotide Sequence Using Ferrocenium as a Hybridization Indicator. AB - A simple method for electrochemical detection of a synthetic 20-bpoligonucleotide sequence related with dengue virus genome was developed. Acomplimentary DNA probe sequence was electrostatically immobilized onto a glassycarbon electrode modified with chitosan. Electrochemical detection of hybridizationbetween probe and target was performed by cyclic voltammetry, using ferrocene (Fc ) as ahybridization label. After hybridization, the peak current response of Fc oxidationincreased around 26%. A higher voltammetric decay rate constant (kd) and a lower half lifeperiod (t1/2) for the interaction of Fc with dsDNA compared to those with ssDNAquantitatively characterize the different strengths of interaction with both types of DNA.By combining the simplicity of DNA immobilization onto a chitosan film and suitablevoltammetric detection of hybridization concomitant with ferrocene attachment, a gooddiscrimination between ssDNA and dsDNA was obtained. PMID- 28903243 TI - Sub-pixel Area Calculation Methods for Estimating Irrigated Areas. AB - The goal of this paper was to develop and demonstrate practical methods forcomputing sub-pixel areas (SPAs) from coarse-resolution satellite sensor data. Themethods were tested and verified using: (a) global irrigated area map (GIAM) at 10-kmresolution based, primarily, on AVHRR data, and (b) irrigated area map for India at 500-mbased, primarily, on MODIS data. The sub-pixel irrigated areas (SPIAs) from coarse-resolution satellite sensor data were estimated by multiplying the full pixel irrigated areas(FPIAs) with irrigated area fractions (IAFs). Three methods were presented for IAFcomputation: (a) Google Earth Estimate (IAF-GEE); (b) High resolution imagery (IAF-HRI); and (c) Sub-pixel de composition technique (IAF-SPDT). The IAF-GEE involvedthe use of "zoom-in-views" of sub-meter to 4-meter very high resolution imagery (VHRI)from Google Earth and helped determine total area available for irrigation (TAAI) or netirrigated areas that does not consider intensity or seasonality of irrigation. The IAF-HRI isa well known method that uses finer-resolution data to determine SPAs of the coarser-resolution imagery. The IAF-SPDT is a unique and innovative method wherein SPAs aredetermined based on the precise location of every pixel of a class in 2-dimensionalbrightness-greenness-wetness (BGW) feature-space plot of red band versus near-infraredband spectral reflectivity. The SPIAs computed using IAF-SPDT for the GIAM was within2 % of the SPIA computed using well known IAF HRI. Further the fractions from the 2 methods were significantly correlated. The IAF-HRI and IAF-SPDT help to determine annualized or gross irrigated areas (AIA) that does consider intensity or seasonality (e.g., sum of areas from season 1, season 2, and continuous year-round crops). The national census based irrigated areas for the top 40 irrigated nations (which covers about 90% of global irrigation) was significantly better related (and had lesser uncertainties and errors) when compared to SPIAs than FPIAs derived using 10-km and 500-m data. The SPIAs were closer to actual areas whereas FPIAs grossly over-estimate areas. The research clearly demonstrated the value and the importance of sub-pixel areas as opposed to full pixel areas and presented 3 innovative methods for computing the same. PMID- 28903244 TI - SU-8 Guiding Layer for Love Wave Devices. AB - SU-8 is a technologically important photoresist used extensively for thefabrication of microfluidics and MEMS, allowing high aspect ratio structures to beproduced. In this work we report the use of SU-8 as a Love wave sensor guiding layerwhich allows the possibility of integrating a guiding layer with flow cell during fabrication.Devices were fabricated on ST-cut quartz substrates with a single-single finger design suchthat a surface skimming bulk wave (SSBW) at 97.4 MHz was excited. SU-8 polymer layerswere successively built up by spin coating and spectra recorded at each stage; showing afrequency decrease with increasing guiding layer thickness. The insertion loss andfrequency dependence as a function of guiding layer thickness was investigated over thefirst Love wave mode. Mass loading sensitivity of the resultant Love wave devices wasinvestigated by deposition of multiple gold layers. Liquid sensing using these devices wasalso demonstrated; water-glycerol mixtures were used to demonstrate sensing of density viscosity and the physical adsorption and removal of protein was also assessed usingalbumin and fibrinogen as model proteins. PMID- 28903245 TI - Flexible Time-Triggered Sampling in Smart Sensor-Based Wireless Control Systems. AB - Wireless control systems (WCSs) often have to operate in dynamic environmentswhere the network traffic load may vary unpredictably over time. The sampling in sensors isconventionally time triggered with fixed periods. In this context, only worse-than-possiblequality of control (QoC) can be achieved when the network is underloaded, whileoverloaded conditions may significantly degrade the QoC, even causing system instability.This is particularly true when the bandwidth of the wireless network is limited and sharedby multiple control loops. To address these problems, a flexible time-triggered samplingscheme is presented in this work. Smart sensors are used to facilitate dynamic adjustment ofsampling periods, which enhances the flexibility and resource efficiency of the system basedon time-triggered sampling. Feedback control technology is exploited for adapting samplingperiods in a periodic manner. The deadline miss ratio in each control loop is maintainedat/around a desired level, regardless of workload variations. Simulation results show that theproposed sampling scheme is able to deal with dynamic and unpredictable variations innetwork traffic load. Compared to conventional time-triggered sampling, it leads to muchbetter QoC in WCSs operating in dynamic environments. PMID- 28903246 TI - Mapping and Assessment of Degraded Land in the Heihe River Basin, Arid Northwestern China. AB - Land degradation is a great threat in the Heihe River Basin, located in the aridinland of northwestern China and land desertification is one of the main aspects ofenvironmental changes in this basin. Previous studies have focused on water resourceutilization and soil erosion, but the status of degraded land in the Heihe River Basin, suchas its distribution, extent and precise characteristics is often inadequately known. Based onfield observations and TM images from the year 2003, this study provides classificationand evaluation information concerning the degraded land in the basin of the Heihe River.There are five types of degraded land types in the Heihe River Basin: water eroded in thesouthern mountains, sandified and vegetation degraded near the oases, aridized in the lowreaches, and salinized in the lowlands. The total degraded area covers 29,355.5 km2,22.58% of the land in the study area. Finally, degraded land in the Heihe River Basin wasevaluated according to changes in the physical structure and chemical components of soils,land productivity, secondary soil salt, and water conditions. PMID- 28903247 TI - Determining Position Inside Non-industrial Buildings Using Ultrasound Transducers. AB - The position determination inside a building where no GPS signal is beingreceived can be ascertained using laser transmitters in industrial situations where there areno people or using triangulation of the signal strength, normally electro magnetic signals,if the required accuracy is more than a metre. Our solution is aimed at situations wherepeople are present and where the required accuracy is less than 30 cm, such as in shoppingprecincts or supermarkets. To achieve this, a network of ultrasonic transmitters is fittedinto the ceiling which receives a synchronised time signal. Each transmitter has a uniqueidentifier code and emits its code with a delay with respect to the common time signalwhich is proportional to its code number with an ASK modulation over the ultrasonic bandcentred on 40 KHz. The receivers circulating beneath the transmitters receive the codes ofthose within their detection range, translate the time delays into distances and then obtaintheir position by triangulation since the receivers know the position of every transmitter.Since the receivers are not synchronised with the common time signal or the actual speedof the sound, whose value varies appreciably with temperature, relative humidity andatmospheric pressure, a consecutive approximation algorithm has been introduced. This isbased on the fact that the Z coordinator of the receiver is known and constant and thus it is possible, with only three different identifiers received, to deduce the phase of the common time signal and estimate the speed of the sound with a fourth identifier. PMID- 28903248 TI - Biochemical Markers for Assessing Aquatic Contamination. AB - Biochemical markers, specifically enzymes of the first phase of xenobiotic transformation - cytochrome P450 and ethoxyresorufin-O-deethylase (EROD) - were used to determine the quantities of persistent organic pollutants (POPs) in fish muscle (PCB, HCB, HCH, OCS, DDT). Eight rivers were monitored (Orlice, Chrudimka, Cidlina, Jizera, Vltava, Ohre and Bilina; and the River Blanice was used as a control). The indicator species selected was the chub (Leuciscus cephalus L.). There were no significant differences in cytochrome P450 content between the locations monitored. The highest concentration of cytochrome P450 in fish liver was in the Vltava (0.241 nmol mg-1 protein), and the lowest was in the Orlice (0.120 nmol mg-1 protein). Analysis of EROD activity showed a significant difference between the Blanice and the Vltava (P< 0.05), and also between the Orlice and the Vltava (P< 0.01), the Orlice and the Bilina (P< 0.01), and the Orlice and the Ohre (P< 0.05). The highest EROD activity in fish liver was in the Vltava (576.4 pmol min-1 mg-1 protein), and the lowest was in the Orlice (63.05 pmol min-1 mg-1 protein). In individual locations, results of chemical monitoring and values of biochemical markers were compared. A significant correlation (P< 0.05) was found between biochemical markers and OCS, and PCB. Among the tributaries studied those that contaminated the Elbe most were the Vltava and the Bilina. These tributaries should not be considered the main sources of industrial contamination of the River Elbe, because the most important contamination sources were along the river Elbe itself. PMID- 28903249 TI - Glucose Determination by Means of Steady-state and Time-course UV Fluorescence in Free or Immobilized Glucose Oxidase. AB - Changes in steady-state UV fluorescence emission from free or immobilizedglucose oxidase have been investigated as a function of glucose concentration.Immobilized GOD has been obtained by entrapment into a gelatine membrane. Changes insteady state UV fluorescence have been quantitatively characterized by means ofoptokinetic parameters and their values have been compared with those previouslyobtained for FAD fluorescence in the visible range. The results confirmed that greatercalibration ranges are obtained from UV signals both for free and immobilized GOD inrespect to those obtained under visible fluorescence excitation. An alternative method tothe use UV fluorescence for glucose determination has been investigated by using timecourse measurements for monitoring the differential fluorescence of the redox forms of theFAD in GOD. Also in this case quantitative analysis have been carried out and acomparison with different experimental configurations has been performed. Time coarsemeasurements could be particularly useful for glucose monitoring in complex biologicalfluids in which the intrinsic UV fluorescence of GOD could be not specific by consideringthe presence of numerous proteins. PMID- 28903250 TI - Carbon-based Composite Electrodes: Preparation, Characterization and Application in Electroanalysis. AB - Electrodes based on carbon, i.e., expanded graphite (20%, wt.)-epoxy composite(20EG-Epoxy) and expanded graphite (20%, wt.)-polystyrene composite (20EG-PS) havebeen prepared, characterized using scanning electron microscopy (SEM) and cyclicvoltammetry (CV), and tested as anodic sensors. The electrodes exhibited good mechanicalresistance and low electrical resistances. Scan rate dependent cyclic voltammetry responsesat 20EG-Epoxy and 20EG-PS composite electrodes, which were exemplified for thiourea(TU), a toxic sulphur organic compound selected as testing target analyte in 0.1 M Na2SO4 supporting electrolyte, were investigated. The obtained voltammetric data were inaccordance with those for a random array of microelectrodes. The voltammetric andchronoamperometric detection results of TU in tap water samples, without a supplementaryaddition of supporting electrolyte, at 20EG-Epoxy electrode proved its use for directanalysis of environmental samples. PMID- 28903251 TI - Sensitivity of the Enhanced Vegetation Index (EVI) and Normalized Difference Vegetation Index (NDVI) to Topographic Effects: A Case Study in High-density Cypress Forest. AB - Vegetation indices play an important role in monitoring variations in vegetation.The Enhanced Vegetation Index (EVI) proposed by the MODIS Land Discipline Groupand the Normalized Difference Vegetation Index (NDVI) are both global-based vegetationindices aimed at providing consistent spatial and temporal information regarding globalvegetation. However, many environmental factors such as atmospheric conditions and soilbackground may produce errors in these indices. The topographic effect is another veryimportant factor, especially when the indices are used in areas of rough terrain. In thispaper, we theoretically analyzed differences in the topographic effect on the EVI and theNDVI based on a non-Lambertian model and two airborne-based images acquired from amountainous area covered by high-density Japanese cypress plantation were used as a casestudy. The results indicate that the soil adjustment factor "L" in the EVI makes it moresensitive to topographic conditions than is the NDVI. Based on these results, we stronglyrecommend that the topographic effect should be removed in the reflectance data beforethe EVI was calculated-as well as from other vegetation indices that similarly include a term without a band ratio format (e.g., the PVI and SAVI)-when these indices are used in the area of rough terrain, where the topographic effect on the vegetation indices having only a band ratio format (e.g., the NDVI) can usually be ignored. PMID- 28903252 TI - Application to Temperature Sensor Based on Green Up-conversion of Er3+ Doped Silicate Glass. AB - The green up-conversion emissions centered at the wavelengths of about 534nmand 549nm of the Er3+ doped silicate glass were recorded, using a 978 nm semiconductorlaser diode (LD) as an excitation source. The fluorescence intensity ratio (FIR) of the greenup-conversion emissions at about 534nm and 549nm in the Er3+ doped silicate glass wasstudied as a function of temperature over the temperature range of 296K-673K. Themaximum sensitivity and the temperature resolution derived from the FIR of the green up-conversion emissions are approximately 0.0023K-1 and 0.8K, respectively. It isdemonstrated that the prototype optical temperature sensor based on the FIR technique fromthe green up conversion emissions in the Er3+ doped silicate glass could play a major role intemperature measurement. PMID- 28903253 TI - Modeling and Manufacturing of Micromechanical RF Switch with Inductors. AB - This study presents the simulation, fabrication and characterization ofmicromechanical radio frequency (RF) switch with micro inductors. The inductors areemployed to enhance the characteristic of the RF switch. An equivalent circuit model isdeveloped to simulate the performance of the RF switch. The behaviors of themicromechanical RF switch are simulated by the finite element method software,CoventorWare. The micromechanical RF switch is fabricated using the complementarymetal oxide semiconductor (CMOS) and a post-process. The post process employs a wetetching to etch the sacrificial layer, and to release the suspended structures of the RF switch.The structure of the RF switch contains a coplanar waveguide (CPW), a suspendedmembrane, eight springs and two inductors in series. Experimental results reveal that theinsertion loss and isolation of the switch are 1.7 dB at 21 GHz and 19 dB at 21 GHz,respectively. The driving voltage of the switch is about 13 V. PMID- 28903254 TI - Electrochemical Interrogation of Interactions between Surface-Confined DNA and Methylene Blue. AB - In this work, we reported a systematic investigation on the interactions betweenmethylene blue (MB) and surface-confined DNA by using electrochemical methods. Wedemonstrated that the redox potential of MB and binding and dissociation kinetics of MB toDNA differed significantly for single-stranded DNA (ss-DNA) and double-stranded DNA(ds-DNA) immobilized on gold electrodes. This was possibly due to the different bindingmechanism between MB and ss- or ds-DNA. This work might provide useful informationfor developing MB-based sequence-specific electrochemical DNA sensors. PMID- 28903255 TI - Four-Wire Impedance Spectroscopy on Planar Zeolite/Chromium Oxide Based Hydrocarbon Gas Sensors. AB - Impedometric zeolite hydrocarbon sensors with a chromium oxide intermediatelayer show a very promising behavior with respect to sensitivity and selectivity. Theunderlying physico-chemical mechanism is under investigation at the moment. In order toverify that the effect occurs at the electrode and that zeolite bulk properties remain almostunaffected by hydrocarbons, a special planar setup was designed, which is very close to realsensor devices. It allows for conducting four-wire impedance spectroscopy as well as two-wire impedance spectroscopy. Using this setup, it could be clearly demonstrated that thesensing effect can be ascribed to an electrode impedance. Furthermore, by combining two-and four-wire impedance measurements at only one single frequency, the interference of thevolume impedance can be suppressed and an easy signal evaluation is possible, withouttaking impedance data at different frequencies. PMID- 28903256 TI - Hierarchical Wireless Multimedia Sensor Networks for Collaborative Hybrid Semi Supervised Classifier Learning. AB - Wireless multimedia sensor networks (WMSN) have recently emerged as one ofthe most important technologies, driven by the powerful multimedia signal acquisition andprocessing abilities. Target classification is an important research issue addressed in WMSN,which has strict requirement in robustness, quickness and accuracy. This paper proposes acollaborative semi-supervised classifier learning algorithm to achieve durative onlinelearning for support vector machine (SVM) based robust target classification. The proposedalgorithm incrementally carries out the semi-supervised classifier learning process inhierarchical WMSN, with the collaboration of multiple sensor nodes in a hybrid computingparadigm. For decreasing the energy consumption and improving the performance, somemetrics are introduced to evaluate the effectiveness of the samples in specific sensor nodes,and a sensor node selection strategy is also proposed to reduce the impact of inevitablemissing detection and false detection. With the ant optimization routing, the learningprocess is implemented with the selected sensor nodes, which can decrease the energyconsumption. Experimental results demonstrate that the collaborative hybrid semi-supervised classifier learning algorithm can effectively implement target classification inhierarchical WMSN. It has outstanding performance in terms of energy efficiency and timecost, which verifies the effectiveness of the sensor nodes selection and ant optimizationrouting. PMID- 28903257 TI - Modelling a Peroxidase-based Optical Biosensor. AB - The response of a peroxidase-based optical biosensor was modelled digitally.A mathematical model of the optical biosensor is based on a system of non-linear reaction-diffusion equations. The modelling biosensor comprises two compartments, an enzyme layerand an outer diffusion layer. The digital simulation was carried out using finite differencetechnique. The influence of the substrate concentration as well as of the thickness of both theenzyme and diffusion layers on the biosensor response was investigated. Calculations showedcomplex kinetics of the biosensor response, especially at low concentrations of the peroxidaseand of the hydrogen peroxide. PMID- 28903258 TI - Ammonia Optical Sensing by Microring Resonators. AB - A very compact (device area around 40 MUm2) optical ammonia sensor based on amicroring resonator is presented in this work. Silicon-on-insulator technology is used insensor design and a dye doped polymer is adopted as sensing material. The sensor exhibitsa very good linearity and a minimum detectable refractive index shift of sensing materialas low as 8x10-5, with a detection limit around 4 0/00. PMID- 28903259 TI - Metalloporphyrin - based Electronic Tongue: an Application for the Analysis of Italian White wines. AB - An Electronic Tongue system (ET) composed of "all-solid-state" potentiometricsensors was developed and applied for the identification of white wines. The sensingproperties were due to the PVC based membranes doped with several metallo-porphyrinsdeposited on the surface of glassy carbon working electrodes; potentiometric responsetowards several ions in a concentration range from 10-5 M to 10-1 M were studied and cross-sensitivity of sensors was estimated. The sensor array was applied both for the classificationand quantitative analysis of "Verdicchio D.O.C." Italian dry white wines produced by ninecantinas. Peculiar parameters of white wines (namely alcoholic degree, volatile acidity, SO2,L-Malic Acid, L-Lactic Acid and Total Polyphenols) individuated by standard analyticalmethods were compared with the values evaluated by metalloporphyrin-based ET. Thesystem satisfactory discriminates between an artificial wine control and analyzed winescoming from different cantinas and produced in different years. A satisfactory correlationbetween results of wine analysis performed by certified methods and ET response has beenobtained for SO2, L-Malic Acid, and Total Phenols content. The developed procedureallows the monitoring of the acetic acid amount in wines and hence to control wine volatileacidity, so indicating the initial steps of wine spoilage process. PMID- 28903260 TI - Statistical Modeling of Spatio-Temporal Variability in Monthly Average Daily Solar Radiation over Turkey. AB - Though one of the most significant driving forces behind ecological processessuch as biogeochemical cycles and energy flows, solar radiation data are limited or non-existent by conventional ground-based measurements, and thus, often estimated from othermeteorological data through (geo)statistical models. In this study, spatial and temporalpatterns of monthly average daily solar radiation on a horizontal surface at the ground levelwere quantified using 130 climate stations for the entire Turkey and its conventionally-accepted seven geographical regions through multiple linear regression (MLR) models as afunction of latitude, longitude, altitude, aspect, distance to sea; minimum, maximum andmean air temperature and relative humidity, soil temperature, cloudiness, precipitation, panevapotranspiration, day length, maximum possible sunshine duration, monthly average dailyextraterrestrial solar radiation, and time (month), and universal kriging method. Theresulting 20 regional best-fit MLR models (three MLR models for each region) based onparameterization datasets had R2adj values of 91.5% for the Central Anatolia region to 98.0%for the Southeast Anatolia region. Validation of the best-fit MLR models for each region led to R2 values of 87.7% for the Mediterranean region to 98.5% for the Southeast Anatoliaregion. The best-fit anisotropic semi-variogram models for universal kriging as a result ofone-leave out cross-validation gave rise to R2 values of 10.9% in July to 52.4% inNovember. Surface maps of monthly average daily solar radiation were generated overTurkey, with a grid resolution of 500 m x 500 m. PMID- 28903261 TI - Robust Forecasting for Energy Efficiency of Wireless Multimedia Sensor Networks. AB - An important criterion of wireless sensor network is the energy efficiency inspecified applications. In this wireless multimedia sensor network, the observations arederived from acoustic sensors. Focused on the energy problem of target tracking, this paperproposes a robust forecasting method to enhance the energy efficiency of wirelessmultimedia sensor networks. Target motion information is acquired by acoustic sensornodes while a distributed network with honeycomb configuration is constructed. Thereby,target localization is performed by multiple sensor nodes collaboratively through acousticsignal processing. A novel method, combining autoregressive moving average (ARMA)model and radial basis function networks (RBFNs), is exploited to perform robust targetposition forecasting during target tracking. Then sensor nodes around the target areawakened according to the forecasted target position. With committee decision of sensornodes, target localization is performed in a distributed manner and the uncertainty ofdetection is reduced. Moreover, a sensor-to-observer routing approach of the honeycombmesh network is investigated to solve the data reporting considering the residual energy ofsensor nodes. Target localization and forecasting are implemented in experiments.Meanwhile, sensor node awakening and dynamic routing are evaluated. Experimentalresults verify that energy efficiency of wireless multimedia sensor network is enhanced bythe proposed target tracking method. PMID- 28903263 TI - Piezoelectric Biosensor for a Simple Serological Diagnosis of Tularemia in Infected European Brown Hares (Lepus europaeus). AB - Piezoelectric biosensor was used for diagnosis of infection by Francisellatularensis subsp. holarctica in European brown hares. Two kinds of experiments wereperformed in this study. First, sera from experimentally infected European brown hares(Lepus europaeus) were assayed by piezoelectric biosensor and the seventh day postinfection was found as the first one when statistically significant diagnosis of tularemia waspossible; all other sera collected from hares later than on day 7 following the infection werefound tularemia positive. Typing to classify the field strain of F. tularensis used for theexperimental infection was confirmed by proteome study. Second, sera from 35 Europeanbrown hare specimens sampled at hunting grounds and tested as tularemia positive by slowagglutination allowed diagnosis of tularemia by the piezoelectric biosensor. All these sera ofnaturally infected hares were found as tularemia positive, too. Efficacy of the piezoelectricbiosensor for the serological diagnosis of tularemia is discussed. PMID- 28903262 TI - Antimicrobial Peptides: New Recognition Molecules for Detecting Botulinum Toxins. AB - Many organisms secrete antimicrobial peptides (AMPs) for protection againstharmful microbes. The present study describes detection of botulinum neurotoxoids A, Band E using AMPs as recognition elements in an array biosensor. While AMP affinitieswere similar to those for anti-botulinum antibodies, differences in binding patterns wereobserved and can potentially be used for identification of toxoid serotype. Furthermore,some AMPs also demonstrated superior detection sensitivity compared to antibodies: toxoidA could be detected at 3.5 LD50 of the active toxin in a 75-min assay, whereas toxoids B andE were detected at 14 and 80 LD50 for their respective toxins. PMID- 28903264 TI - Study on a Concentric Tube Bulb Manometer and its Performance Compared to U shaped Manometer. AB - This paper presents comparative study of a new type of manometer calledconcentric tube bulb (C.T.B) manometer. Its performance of measuring differential heightis studied against conventional U-shaped manometer. Pressure drops and mass flow ratesare calculated by taking various systems comprising of different flow measuring devicessuch as orifice and venturimeters using both U- shaped and C.T.B manometers.Comparison between the physically measured values of differential pressure drops andmass flow rates with the calculated values based on theoretical equations is also made.Experiments are carried out using mercury and CCl4 in these manometers as sensing fluids.Water is used as flowing fluid for mass flow rate and pressure drop measurements, whereasin gauge pressure measurements air is used. PMID- 28903265 TI - Quantitative Accelerated Life Testing of MEMS Accelerometers. AB - Quantitative Accelerated Life Testing (QALT) is a solution for assessing thereliability of Micro Electro Mechanical Systems (MEMS). A procedure for QALT is shownin this paper and an attempt to assess the reliability level for a batch of MEMSaccelerometers is reported. The testing plan is application-driven and contains combinedtests: thermal (high temperature) and mechanical stress. Two variants of mechanical stressare used: vibration (at a fixed frequency) and tilting. Original equipment for testing at tiltingand high temperature is used. Tilting is appropriate as application-driven stress, because thetilt movement is a natural environment for devices used for automotive and aerospaceapplications. Also, tilting is used by MEMS accelerometers for anti-theft systems. The testresults demonstrated the excellent reliability of the studied devices, the failure rate in the"worst case" being smaller than 10-7h-1. PMID- 28903266 TI - Object-Based Classification of Ikonos Imagery for Mapping Large-Scale Vegetation Communities in Urban Areas. AB - Effective assessment of biodiversity in cities requires detailed vegetation maps.To date, most remote sensing of urban vegetation has focused on thematically coarse landcover products. Detailed habitat maps are created by manual interpretation of aerialphotographs, but this is time consuming and costly at large scale. To address this issue, wetested the effectiveness of object-based classifications that use automated imagesegmentation to extract meaningful ground features from imagery. We applied thesetechniques to very high resolution multispectral Ikonos images to produce vegetationcommunity maps in Dunedin City, New Zealand. An Ikonos image was orthorectified and amulti-scale segmentation algorithm used to produce a hierarchical network of image objects.The upper level included four coarse strata: industrial/commercial (commercial buildings),residential (houses and backyard private gardens), vegetation (vegetation patches larger than0.8/1ha), and water. We focused on the vegetation stratum that was segmented at moredetailed level to extract and classify fifteen classes of vegetation communities. The firstclassification yielded a moderate overall classification accuracy (64%, kappa = 0.52), which ledus to consider a simplified classification with ten vegetation classes. The overallclassification accuracy from the simplified classification was 77% with a kappa value close tothe excellent range (kappa = 0.74). These results compared favourably with similar studies inother environments. We conclude that this approach does not provide maps as detailed as those produced by manually interpreting aerial photographs, but it can still extract ecologically significant classes. It is an efficient way to generate accurate and detailed maps in significantly shorter time. The final map accuracy could be improved by integrating segmentation, automated and manual classification in the mapping process, especially when considering important vegetation classes with limited spectral contrast. PMID- 28903267 TI - Tempo-Spatial Patterns of Land Use Changes and Urban Development in Globalizing China: A Study of Beijing. AB - This study examines the temporal and spatial changes in land use as aconsequence of rapid urban development in the city of Beijing. Using a combination oftechniques of remote sensing and GIS, the study identifies a substantial loss of plaindryland and a phenomenal expansion of urban construction land over the recent decade.Geographically, there is a clear shifting of urban construction land from the inner city tothe outskirts as a consequence of suburbanization. The outward expansion of the ring-roadsystem is found to be one of the most important driving forces explaining the temporal andspatial pattern of land use change. The uneven distribution of population stands as anotherfactor with significant correlation with land use change. The application of the techniquesof remote sensing and GIS can enhance the precision and comparability of research onland use change and urban transformation in China. PMID- 28903268 TI - Novel Deployment Schemes for Mobile Sensor Networks. AB - Virtual Force Algorithm (VFA) is becoming a main solution to area coverage forhomogeneous wireless sensor networks with random distribution of mobile sensor nodes.Consider the factors of the convergence, the boundary in Region Of Interest (ROI), effec-tive distance of acting force and useless moving, etc, VFA is improved to overcome the aboveproblems. Furthermore, an expression of exponential function for the relationship of vir-tual force is proposed to converge rapidly. Extensive simulation results indicate that theseimproved VFA get better performance in coverage rate, moving energy consumption, conver-gence etc. than original VFA. PMID- 28903269 TI - Enhanced Sensory Properties of a Multichannel Quartz Crystal Microbalance Coated with Polymeric Nanobeads. AB - In this study the sensorial performances of a four-channel quartz crystalmicrobalance implemented on a single quartz plate are reported and compared with those offour independent quartz crystal microbalances. Particular attention has been devoted to bothcross talk in responses and sensor sensitivity. A recently synthesized nanostructuredpolymer, poly[phenylacetylene-(co-2 hydroxyethyl methacrylate)], has been used aschemical interactive material. The interactions of our sensor system with relative humidityare also reported. The multichannel device shows a better homogeneity of the masssensitivity with a spread of the values less then 4% compared to a 50% spread observed inthe set of four microbalances. PMID- 28903270 TI - Magnetostrictive Microcantilever as an Advanced Transducer for Biosensors. AB - The magnetostrictive microcantilever (MSMC) as a high-performance transducer was introduced for the development of biosensors. The principle and characterization of MSMC are presented. The MSMC is wireless and can be easily actuated and sensed using magnetic field/signal. More importantly, the MSMC exhibits a high Q value and works well in liquid. The resonance behavior of MSMC is characterized in air at different pressures and in different liquids, respectively. It is found that the Q value of the MSMC in water reaches about 40. Although the density and viscosity of the surrounding media affect the resonance frequency and the Q value of MSMC, the density has a stronger influence on the resonance frequency and the viscosity has a stronger influence on the Q value, which result in that, for MSMC in air at pressure of less than 100 Pa, the resonance frequency of MSMC is almost independent of the pressure, while the Q value increases with decreasing pressure. MSMC array was developed and characterized. It is experimentally demonstrated that the characterization of an MSMC array is as simple as the characterization of a single MSMC. A filamentous phage against Salmonella typhimurium was utilized as bio-recognition unit to develop an MSMC based biosensor. The detection of S. typhimurium in water demonstrated that the MSMC works well in liquid. PMID- 28903271 TI - Monitoring Transport Across Modified Nanoporous Alumina Membranes. AB - This paper describes the use of several characterization methods to examinealumina nanotubule membranes that have been modified with specific silanes. The functionof these silanes is to alter the transport properties through the membrane by changing thelocal environment inside the alumina nanotube. The presence of alkyl groups, either long(C18) or short and branched (isopropyl) hydrocarbon chains, on these silanes significantlydecreases the rate of transport of permeant molecules through membranes containingalumina nanotubes as monitored via absorbance spectroscopy. The presence of an ionicsurfactant can alter the polarity of these modified nanotubes, which correlates to anincreased transport of ions. Fluorescent spectroscopy is also utilized to enhance thesensitivity of detecting these permeant molecules. Confirmation of the alkylsilaneattachment to the alumina membrane is achieved with traditional infrared spectroscopy,which can also examine the lifetime of the modified membrane. The physical parameters ofthese silane-modified porous alumina membranes are studied via scanning electronmicroscopy. The alumina nanotubes are not physically closed off or capped by the silanesthat are attached to the alumina surfaces. PMID- 28903272 TI - Tactile Fabric Panel in an Eight Zones Structure. AB - By introducing a percentage of conductive material during the manufacture ofsewing thread, it is possible to obtain a fabric which is able to detect variations in pressurein certain areas. In previous experiments the existence of resistance variations has beendemonstrated, although some constrains of cause and effect were found in the fabric. Theresearch has been concentrated in obtaining a fabric that allows electronic detection of itsshape changes. Additionally, and because a causal behavior is needed, it is necessary thatthe fabric recovers its original shape when the external forces cease. The structure of thefabric varies with the type of deformation applied. Two kinds of deformation aredescribed: those caused by stretching and those caused by pressure. This last type ofdeformation gives different responses depending on the conductivity of the object used tocause the pressure. This effect is related to the type of thread used to manufacture thefabric. So, if the pressure is caused by a finger the response is different compared to theresponse caused by a conductive object. Another fact that has to be mentioned is that apressure in a specific point of the fabric can affect other detection points depending on theforce applied. This effect is related to the fabric structure. The goals of this article arevalidating the structure of the fabric used, as well as the study of the two types ofdeformation mentioned before. PMID- 28903273 TI - Recent Advances in High-Birefringence Fiber Loop Mirror Sensors. AB - Recent advances in devices and applications of high-birefringence fiber loopmirror sensors are addressed. In optical sensing, these devices may be used as strain andtemperature sensors, in a separate or in a simultaneous measurement. Other describedapplications include: refractive index measurement, optical filters for interrogate gratingsstructures and chemical etching control. The paper analyses and compares different types ofhigh-birefringence fiber loop mirror sensors using conventional and microstructured opticalfibers. Some configurations are presented for simultaneous measurement of physicalparameters when combined with others optical devices, for example with a long periodgrating. PMID- 28903274 TI - A Novel Gas Sensor Transducer Based on Phthalocyanine Heterojunction Devices. AB - Experimental data concerning the changes in the current-voltage (I-V) perfor mances of a molecular material-based heterojunction consisting of hexadecafluorinatednickel phthalocyanine (Ni(F16Pc)) and nickel phthalocyanine (NiPc),(Au|Ni(F16Pc)|NiPc|Al) are introduced as an unprecedented principle of transduction for gassensing performances. The respective n- and p-type doped insulator behaviors of therespective materials are supported, owing to the observed changes in surface potential(using the Kelvin probe method) after submission to electron donor (ammonia) and electronacceptor gases (ozone). On the other hand, the bilayer device exhibits strong variations inthe built-in potential of the junction and in its rectification ratio. Moreover, large increasesoccur in forward and reverse currents in presence of ammonia vapors. These make possiblea multimodal principle of detection controlled by a combined effect between theheterojunction and the NiPc|Al contact. Indeed, this metal/organic junction plays a criticalrole regarding the steady asymmetry of the I-V profiles during the device's doping evenusing high ammonia concentrations. This approach offers a more sophisticated alternative tothe classically studied, but at times rather operation-limited, resistive gas sensors. PMID- 28903275 TI - Effect of Electrical Contact on the Contact Residual Stress of a Microrelay Switch. AB - This paper investigates the effect of electrical contact on the thermal contactstress of a microrelay switch. A three-dimensional elastic-plastic finite element model withcontact elements is used to simulate the contact behavior between the microcantilever beamand the electrode. A model with thermal electrical coupling and thermal-stress coupling isused in the finite element analysis. The effects of contact gap, plating film thickness andnumber of switching cycles on the contact residual stress, contact force, plastic deformation,and temperature rise of the microrelay switch are explored. The numerical results indicatethat the residual stress increases with increasing contact gap or decreasing plating filmthickness. The results also show that the residual stress increases as the number of switchingcycles increases. A large residual stress inside the microcantilever beam can decrease thelifecycle of the microrelay. PMID- 28903276 TI - Influence of Damping on the Dynamical Behavior of the Electrostatic Parallel plate and Torsional Actuators with Intermolecular Forces. AB - The influence of damping on the dynamical behavior of the electrostaticparallel plate and torsional actuators with the van der Waals (vdW) or Casimir force(torque) is presented. The values of the pull-in parameters and the number of theequilibrium points do not change whether there is damping or not. The ability ofequilibrium points is varied with the appearance of damping. One equilibrium point is anunstable saddle with a different damping coefficient, the other equilibrium point is astable node when the damping coefficient is greater than some critical value, andotherwise it is a stable focus. Then there are two heteroclinic orbits passing from theunstable saddle point to the stable node or focus. PMID- 28903277 TI - State Key Laboratory of Nonlinear Mechanics (LNM), Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, China. AB - This paper reviews current state-of-the-art methods of measuring pH levels that are based on polymer materials. These include polymer-coated fibre optic sensors, devices with electrodes modified with pH-sensitive polymers, fluorescent pH indicators, potentiometric pH sensors as well as sensors that use combinatory approach for ion concentration monitoring. PMID- 28903278 TI - Reducing the Discrepancy Between ASTER and MODIS Land Surface Temperature Products. AB - Human-induced global warming has significantly increased the importance ofsatellite monitoring of land surface temperature (LST) on a global scale. The MODerate-resolution Imaging Spectroradiometer (MODIS) provides a 1-km resolution LST productwith almost daily coverage of the Earth, invaluable to both local and global change studies.The Advanced Spaceborne Thermal Emission Reflection Radiometer (ASTER) provides aLST product with a high spatial resolution of 90-m and a 16-day recurrent cycle,simultaneously acquired at the same height and nadir view as MODIS. ASTER andMODIS are complementary in resolution, offering a unique opportunity for scale-relatedstudies. ASTER and MODIS LST have been widely used but the errors in LST were mostlydisregarded. Correction of ASTER-to-MODIS LST discrepancies is essential for studiesreliant upon the joint use of these sensors. In this study, we compared three correctionapproaches: the Wan et al.'s approach, the refined Wan et al.'s approach, and thegeneralized split window (GSW) algorithm based approach. The Wan et al.'s approachcorrects the MODIS 1-km LST using MODIS 5-km LST. The refined approach modifiesthe Wan et al.'s approach through incorporating ASTER emissivity and MODIS 5-km data.The GSW algorithm approach does not use MODIS 5-km but only ASTER emissivity data. We examined the case over a semi-arid terrain area for the part of the Loess Plateau of China. All the approaches reduced the ASTER-to-MODIS LST discrepancy effectively. With terrain correction, the original ASTER-to-MODIS LST difference reduced from 2.7+/ 1.28 K to -0.1+/-1.87 K for the Wan et al.'s approach, 0.2+/-1.57 K for the refined approach, and 0.1+/-1.33 K for the GSW algorithm based approach. Among all the approaches, the GSW algorithm based approach performed best in terms of mean, standard deviation, root mean square root, and correlation coefficient. PMID- 28903279 TI - Development of a Space-charge-sensing System. AB - A system for remotely measuring the distribution of air space charge in real time is developed. The system consists of a loudspeaker and an electric field antenna. By propagating a burst of directional sound wave from the speaker, a modulation in the space charge and, therefore, an electric field change at ground is produced. The distribution of the space charge density is derived from the E field change which can be measured by the E- field antenna. The developed system has been confirmed by both laboratory and field experiments. PMID- 28903280 TI - Three Cavity Tunable MEMS Fabry Perot Interferometer. AB - In this paper a four-mirror tunable micro electro-mechanical systems (MEMS)Fabry Perot Interferometer (FPI) concept is proposed with the mathematical model. Thespectral range of the proposed FPI lies in the infrared spectrum ranging from 2400 to 4018(nm). FPI can be finely tuned by deflecting the two middle mirrors (or by changing the threecavity lengths). Two different cases were separately considered for the tuning. In case one,tuning was achieved by deflecting mirror 2 only and in case two, both mirrors 2 and 3 weredeflected for the tuning of the FPI. PMID- 28903281 TI - Animals as Mobile Biological Sensors for Forest Fire Detection. AB - This paper proposes a mobile biological sensor system that can assist in earlydetection of forest fires one of the most dreaded natural disasters on the earth. The main ideapresented in this paper is to utilize animals with sensors as Mobile Biological Sensors(MBS). The devices used in this system are animals which are native animals living inforests, sensors (thermo and radiation sensors with GPS features) that measure thetemperature and transmit the location of the MBS, access points for wireless communicationand a central computer system which classifies of animal actions. The system offers twodifferent methods, firstly: access points continuously receive data about animals' locationusing GPS at certain time intervals and the gathered data is then classified and checked tosee if there is a sudden movement (panic) of the animal groups: this method is called animalbehavior classification (ABC). The second method can be defined as thermal detection(TD): the access points get the temperature values from the MBS devices and send the datato a central computer to check for instant changes in the temperatures. This system may beused for many purposes other than fire detection, namely animal tracking, poachingprevention and detecting instantaneous animal death. PMID- 28903282 TI - Fiber Optic Sensors For Detection of Toxic and Biological Threats. AB - Protection of public and military personnel from chemical and biological warfareagents is an urgent and growing national security need. Along with this idea, we havedeveloped a novel class of fiber optic chemical sensors, for detection of toxic and biologicalmaterials. The design of these fiber optic sensors is based on a cladding modificationapproach. The original passive cladding of the fiber, in a small section, was removed and thefiber core was coated with a chemical sensitive material. Any change in the opticalproperties of the modified cladding material, due to the presence of a specific chemicalvapor, changes the transmission properties of the fiber and result in modal powerredistribution in multimode fibers. Both total intensity and modal power distribution (MPD)measurements were used to detect the output power change through the sensing fibers. TheMPD technique measures the power changes in the far field pattern, i.e. spatial intensitymodulation in two dimensions. Conducting polymers, such as polyaniline and polypyrrole,have been reported to undergo a reversible change in conductivity upon exposure tochemical vapors. It is found that the conductivity change is accompanied by optical propertychange in the material. Therefore, polyaniline and polypyrrole were selected as the modifiedcladding material for the detection of hydrochloride (HCl), ammonia (NH3), hydrazine(H4N2), and dimethyl-methl-phosphonate (DMMP) {a nerve agent, sarin stimulant},respectively. Several sensors were prepared and successfully tested. The results showeddramatic improvement in the sensor sensitivity, when the MPD method was applied. In thispaper, an overview on the developed class of fiber optic sensors is presented and supportedwith successful achieved results. PMID- 28903283 TI - Lanthanide Recognition: an Asymetric Erbium Microsensor Based on a Hydrazone Derivative. AB - N'-(2-hydroxy-1,2-diphenylethylidene)benzohydrazide (HDB) was found tohave a very selective and sensitive behavior towards erbium(III) ions, in comparison tothirteen lanthanide ions, inner transition and representative metal ions and was hence usedas a neutral ion carrier in construction of an Er(III) microelectrode. Theoretical calculationsand conductance studies of HDB to erbium and some other metal ions were carried out andconfirmed selectivity toward Er(III) ions.The best performance was obtained with a membrane contain 3% potassium tetrakis(p-chlorophenyl)borate (KTpClPB) as an anionic additive, 72% dibutyl phthalate (DBP) assolvent mediator, 5% HDB, and 20% poly(vinyl chloride) (PVC). The proposed Er(III)microelectrode exhibits a near Nernstian response of 17.5+/-0.5 mV per decade of erbiumactivity, and a very wide linear range 1.0*10-3 3.0*10-10 M. It can work well in the pHrange of 3.0-9.0. The lower detection limit (LDL) of the microelectrode was calculated tobe 2.0*10-10 M. PMID- 28903284 TI - Non-Destructive Evaluation of Historical Paper Based on pH Estimation from VOC Emissions. AB - Volatile organic compounds (VOCs) emitted from materials during degradationcan be a valuable source of information. In this work, the emissions of furfural and aceticacid from cellulose were studied using solid-phase micro-extraction (SPME) incombination with gas chromatography-mass spectrometry. Two sampling techniques wereemployed: static headspace sampling using SPME for 1 h at 40 oC after 18-h samplepreparation at 80 oC in a closed glass vial, and contact SPME in a stack of paper (or abook). While a number of VOCs are emitted from paper under conditions of natural oraccelerated degradation, two compounds were confirmed to be of particular diagnosticvalue: acetic acid and furfural. The emissions of furfural are shown to correlate with pH ofthe cellulosic environment. Since pH is one of the most important parameters regardingdurability of this material, the developed method could be used for non-destructiveevaluation of historical paper. PMID- 28903285 TI - About Optimal Fractional Hold Circuits for Inter- sample Output Reconstruction in Sampled-data Systems. AB - The design of fractional order-holds (FROH) of correcting gains beta ? [ - 1 , 1 ](potentially and possibly including zero-order-holds, ZOH with beta=0, and first order-holds,FROH with beta=1) is discussed related to achieving output deviations being close withrespect to its sampled values. A squared error time- integral between the current output andits sampled values is minimized to yield the appropriate correcting gain of the FROH in ananalytic way. PMID- 28903286 TI - Near-Field Thermometry Sensor Based on the Thermal Resonance of a Microcantilever in Aqueous Medium. AB - A new concept using a near-field thermometry sensor is presented, employing atipless microcantilever experimentally validated for an aqueous medium within approximatelyone cantilever width from the solid interface. By correlating the thermal Brownian vibratingmotion of the microcantilever with the surrounding liquid temperature, the near-fieldmicroscale temperature distributions at the probing site are determined at separation distancesof z = 5, 10, 20, and 40 MUm while the microheater temperature is maintained at 50 degrees C, 70 degrees C, or90 degrees C. In addition, the near-field correction of the correlation is discussed to account for thequenched cantilever vibration frequencies, which are quenched due to the no-slip solid-wallinterference. Higher thermal sensitivity and spatial resolution is expected when the vibrationfrequencies increase with a relatively short and thick cantilever and the dimensions of themicrocantilever are reduced. Use of the microcantilever thermometry sensor can also reduce thecomplexity and mitigate the high cost associated with existing microfabricated thermocouplesor thermoresistive sensors. PMID- 28903287 TI - Thermally Stable Merocyanine Form of Photochromic Spiropyran with Aluminum Ion as a Reversible Photo-driven Sensor in Aqueous Solution. AB - A reversible photo-driven sensor for aluminum ions based on photochromicspiropyran was reported with rapid response time. The detection of aluminum wasperformed via the chelation of aluminum ions with the merocyanine form (MC) ofphotochromic spiropyran. 1H NMR studies confirmed the conversation from the MC forminto the Al3+ -MC form. Addition of aluminum ions to the spiropyran (SP) in a MeCN/H2Omixture results in obvious color changes with a loss in absorbance at 539 nm and anenhancement in absorbance at about 420 nm after irradiation at 365 nm. The metal chelationcomplex (Al3+ -MC) can also be converted into the original SP form by irradiation withvisible light. Aluminum ions can be detected down to 0.5 MUM levels in a fast response ofless than 5 seconds with no interference from other ionic species. PMID- 28903288 TI - Fuzzy Logic Control Based QoS Management in Wireless Sensor/Actuator Networks. AB - Wireless sensor/actuator networks (WSANs) are emerging rapidly as a newgeneration of sensor networks. Despite intensive research in wireless sensor networks(WSNs), limited work has been found in the open literature in the field of WSANs. Inparticular, quality-of-service (QoS) management in WSANs remains an important issue yetto be investigated. As an attempt in this direction, this paper develops a fuzzy logic controlbased QoS management (FLC-QM) scheme for WSANs with constrained resources and indynamic and unpredictable environments. Taking advantage of the feedback controltechnology, this scheme deals with the impact of unpredictable changes in traffic load on theQoS of WSANs. It utilizes a fuzzy logic controller inside each source sensor node to adaptsampling period to the deadline miss ratio associated with data transmission from the sensorto the actuator. The deadline miss ratio is maintained at a pre-determined desired level sothat the required QoS can be achieved. The FLC-QM has the advantages of generality,scalability, and simplicity. Simulation results show that the FLC-QM can provide WSANswith QoS support. PMID- 28903289 TI - Design Considerations for Aural Vital Signs Using PZT Piezoelectric Ceramics Sensor Based on the Computerization Method. AB - The purpose was to illustrate how system developed for measurement of the aural vital signs such as patient's heart and lung sounds in the hospital. For heart sounds measurement must operate the frequency response between 20 - 800 Hz, and lung sounds measurement must operate the frequency response between 160 - 4,000 Hz. The method was designed PZT piezoelectric ceramics for both frequency response in the same PZT sensor. It converts a signal from aural vital sign form to voltage signal. The signal is suitably amplified and re-filtered in band pass frequency band. It is converted to digital signal by an analog to digital conversion circuitry developed for the purpose. The results were that all signals can fed to personal computer through the sound card port. With the supporting software for drawing of graphic on the screen, the signal for a specific duration is accessed and stored in the computer's memory in term of each patient's data. In conclusion, the data of each patient call dot pcg (.pcg) for drawing graph and dot wave (.wave) for sound listening or automatic sending via electronic mail to the physician for later analysis of interpreting the sounds on the basis of their time domain and frequency domain representation to diagnose heart disorders. PMID- 28903290 TI - Remote Sensing Sensors and Applications in Environmental Resources Mapping and Modelling. AB - The history of remote sensing and development of different sensors for environmental and natural resources mapping and data acquisition is reviewed and reported. Application examples in urban studies, hydrological modeling such as land-cover and floodplain mapping, fractional vegetation cover and impervious surface area mapping, surface energy flux and micro-topography correlation studies is discussed. The review also discusses the use of remotely sensed-based rainfall and potential evapotranspiration for estimating crop water requirement satisfaction index and hence provides early warning information for growers. The review is not an exhaustive application of the remote sensing techniques rather a summary of some important applications in environmental studies and modeling. PMID- 28903291 TI - Integrating Map Algebra and Statistical Modeling for Spatio- Temporal Analysis of Monthly Mean Daily Incident Photosynthetically Active Radiation (PAR) over a Complex Terrain. AB - This study aims at quantifying spatio-temporal dynamics of monthly mean dailyincident photosynthetically active radiation (PAR) over a vast and complex terrain such asTurkey. The spatial interpolation method of universal kriging, and the combination ofmultiple linear regression (MLR) models and map algebra techniques were implemented togenerate surface maps of PAR with a grid resolution of 500 x 500 m as a function of fivegeographical and 14 climatic variables. Performance of the geostatistical and MLR modelswas compared using mean prediction error (MPE), root-mean-square prediction error(RMSPE), average standard prediction error (ASE), mean standardized prediction error(MSPE), root mean-square standardized prediction error (RMSSPE), and adjustedcoefficient of determination (R2adj.). The best-fit MLR- and universal kriging-generatedmodels of monthly mean daily PAR were validated against an independent 37-year observeddataset of 35 climate stations derived from 160 stations across Turkey by the Jackknifingmethod. The spatial variability patterns of monthly mean daily incident PAR were moreaccurately reflected in the surface maps created by the MLR based models than in thosecreated by the universal kriging method, in particular, for spring (May) and autumn(November). The MLR-based spatial interpolation algorithms of PAR described in thisstudy indicated the significance of the multifactor approach to understanding and mappingspatio-temporal dynamics of PAR for a complex terrain over meso-scales. PMID- 28903292 TI - Detection of Brominated By-Products Using a Sensor Array Based on Nanostructured Thin Films of Conducting Polymers. AB - The detection of the carcinogenic trihalomethanes (THM) in public water supplysystems using low-cost equipment has become an essential feature, since these compoundsmay be generated as by-products of water-treatment processes. Here we report on a sensorarray that extends the concept of an "electronic tongue" to detect small amounts ofbromoform, bromodichloromethane and dibromochloromethane, with detection limits aslow as 0.02 mg L-1. The sensor array was made up of 10 sensing units, in whichnanostructured films of conducting and natural polymers were deposited onto goldinterdigitated electrodes. The principle of detection was impedance spectroscopy, withmeasurements carried out in the range between 1 Hz to 1 MHz. Using data at 1 kHz, atwhich the electrical response varied considerably by changing the analyte, we demonstratedwith principal component analysis (PCA) that samples with the 3 brominatedtrihalomethanes can be distinguished from each other and for various concentrations. PMID- 28903293 TI - PVC Membrane Sensors for Potentiometric Determination of Acebutolol. AB - The construction and general performance characteristics of two novelpotentiometric membrane sensors responsive to the acebutolol are described. Thesensors are based on the use of ion-association complexes of acebutolol (AC) withtetraphenylborate(TPB) (I) and phosphomolybdate(PM) (II) as exchange sites in a PVCmatrix. The sensors show a fast, stable and near- Nernstian for the mono charge cationof AC over the concentration range 1*10-3 - ~10-6 M at 25 degrees C over the pH range 2.0 -6.0 with cationic slope of 51.5 +/- 0.5 and 53.0 +/- 0.5 per concentration decade for AC-Iand AC-II sensors respectively. The lower detection limit is 6*10-6 M and 4*0-6 M withthe response time 20-30 s in the same order of both sensors. Selectivity coefficients ofAC related to a number of interfering cation and some organic compounds wereinvestigated. There are negligible interferences are caused by most of the investigatedspecies. The direct determination of 3 - 370 MUg/ml of AC shows an average recovery of 99.4 and 99.5% and a mean relative standard deviation of 1 . 5 % at 100.0 MUg/ml forsensor I and II respectively. The results obtained by determination of AC in tablets usingthe proposed sensors which comparable favorably with those obtained by the Britishpharmacopoeia method. In the present investigation the electrodes have been utilized asend point indicator for some precipitation titration reactions. PMID- 28903294 TI - From Hearing to Listening: Design and Properties of an Actively Tunable Electronic Hearing Sensor. AB - An important step towards understanding the working principles of the mammalian hearing sensor is the concept of an active cochlear amplifier. Theoretical arguments and physiological measurements suggest that the active cochlear amplifiers originate from systems close to a Hopf bifurcation. Efforts to model the mammalian hearing sensor on these grounds have, however, either had problems in reproducing sufficiently close essential aspects of the biological example (Magnasco, M.O. Phys. Rev. Lett. 90, 058101 (2003); Duke, T. & Julicher, F. Phys. Rev. Lett. 90, 158101 (2003)), or required complicated spatially coupled differential equation systems that are unfeasible for transient signals (Kern, A. & Stoop, R. Phys. Rev. Lett. 91, 128101 (2003)). Here, we demonstrate a simple system of electronically coupled Hopf amplifiers that not only leads to the desired biological response behavior, but also has real-time capacity. The obtained electronic Hopf cochlea shares all salient signal processing features exhibited by the mammalian cochlea and thus provides a simple and efficient design of an artificial mammalian hearing sensor. PMID- 28903295 TI - Gold Nanoparticles With Special Shapes: Controlled Synthesis, Surface-enhanced Raman Scattering, and The Application in Biodetection. AB - Specially shaped gold nanoparticles have intrigued considerable attention becausethey usually possess high-sensitivity surface-enhanced Raman scattering (SERS) and thusresult in large advantages in trace biodetermination. In this article, starch-capped goldnanoparticles with hexagon and boot shapes were prepared through using a nontoxic andbiologically benign aqueous-phase synthetic route. Shape effects of gold nanoparticles onSERS properties were mainly investigated, and found that different-shaped goldnanoparticles possess different SERS properties. Especially, the boot-shaped nanoparticlescould induce more 100 fold SERS enhancements in sensitivity as compared with those fromgold nanospheres. The extremely strong SERS properties of gold nanoboots have beensuccessfully applied to the detection of avidin. The unique nanoboots with high-sensitivitySERS properties are also expected to find use in many other fields such as biolabel,bioassay, biodiagnosis, and even clinical diagnosis and therapy. PMID- 28903296 TI - Evaluation of Grassland Dynamics in the Northern-Tibet Plateau of China Using Remote Sensing and Climate Data. AB - The grassland ecosystem in the Northern-Tibet Plateau (NTP) of China is verysensitive to weather and climate conditions of the region. In this study, we investigate thespatial and temporal variations of the grassland ecosystem in the NTP using theNOAA/AVHRR ten-day maximum NDVI composite data of 1981-2001. The relationshipsamong Vegetation Peak-Normalized Difference Vegetation Index (VP NDVI) and climatevariables were quantified for six counties within the NTP. The notable and unevenalterations of the grassland in response to variation of climate and human impact in theNTP were revealed. Over the last two decades of the 20th century, the maximum greennessof the grassland has exhibited high increase, slight increase, no-change, slight decrease andhigh decrease, each occupies 0.27%, 8.71%, 77.27%, 13.06% and 0.69% of the total area ofthe NTP, respectively. A remarkable increase (decrease) in VP-NDVI occurred in thecentral eastern (eastern) NTP whereas little change was observed in the western andnorthwestern NTP. A strong negative relationship between VP-NDVI and ET0 was foundin sub-frigid, semi-arid and frigid- arid regions of the NTP (i.e., Nakchu, Shantsa, Palgonand Amdo counties), suggesting that the ET0 is one limiting factor affecting grasslanddegradation. In the temperate-humid, sub-frigid and sub-humid regions of the NTP (Chaliand Sokshan counties), a significant inverse correlation between VP-NDVI and populationindicates that human activities have adversely affected the grassland condition as waspreviously reported in the literature. Results from this research suggest that the alterationand degradation of the grassland in the lower altitude of the NTP over the last two decades of the 20th century are likely caused by variations of climate and anthropogenic activities. PMID- 28903297 TI - pH Sensitivity of Novel PANI/PVB/PS3 Composite Films. AB - This paper reports on the results from the investigation into the pH sensitivity ofnovel PANI/PVB/PS3 composite films. The conductimetric sensing mode was chosen as itis one of the most promising alternatives to the mainstream pH-sensing methods and it is theleast investigated due to the popularity of other approaches. The films were deposited usingboth screen-printing and a drop-coating method. It was found that the best response to pHwas obtained from the screen printed thick films, which demonstrated a change inconductance by as much as three orders of magnitude over the pH range pH2-pH11. Thedevices exhibited a stable response over 96 hours of operation. Several films were immersedin buffer solutions of different pH values for 96 hours and these were then investigated usingXPS. The resulting N 1s spectra for the various films confirmed that the change inconductance was due to deprotonation of the PANI polymer backbone. SEM andProfilometry were also undertaken and showed that no considerable changes in themorphology of the films took place and that the films did not swell or contract due toexposure to test solutions. PMID- 28903298 TI - Lidar-based Studies of Aerosol Optical Properties Over Coastal Areas. AB - Aerosol size distribution and concentration strongly depend on wind speed,direction, and measuring point location in the marine boundary layer over coastal areas.The marine aerosol particles which are found over the sea waves in high wind conditionsaffect visible and near infrared propagation for paths that pass very close to the surface aswell as the remote sensing measurements of the sea surface. These particles are producedby various air sea interactions. This paper presents the results of measurements taken atnumerous coastal stations between 1992 and 2006 using an FLS-12 lidar system togetherwith other supporting instrumentation. The investigations demonstrated that near-waterlayers in coastal areas differ significantly from those over open seas both in terms ofstructure and physical properties. Taking into consideration the above mentioned factors,aerosol concentrations and optical properties were determined in the marine boundary layeras a function of offshore distance and altitude at various coastal sites in two seasons. Thelidar results show that the remote sensing algorithms used currently in coastal areas needverification and are not fully reliable. PMID- 28903299 TI - A Novel Pulse Measurement System by Using Laser Triangulation and a CMOS Image Sensor. AB - This paper presents a novel, non-invasive, non-contact system to measure pulsewaveforms of artery via applying laser triangulation method to detect skin surfacevibration. The proposed arterial pulsation measurement (APM) system chiefly consists of alaser diode and a low cost complementary metal-oxide semiconductor (CMOS) imagesensor. Laser triangulation and centroid method are combined with the Fast FourierTransform (FFT) in this study. The shape and frequency of the arterial pulsation can bedetected rapidly by using our APM system. The relative variation of the pulse at differentmeasurement points near wrist joint is used as a prognostic guide in traditional Chinesemedicine (TCM). An extensive series of experiments was conducted to evaluate theperformance of the designed APM system. From experimental results, the pulse amplitudeand frequency at the Chun point (related to the small intestine) of left hand showed anobvious increase after having food. In these cases, the peak to peak amplitudes and thefrequencies of arterial pulsations range from 38 to 48 MUm and from 1.27 to 1.35 Hz,respectively. The height of arterial pulsations on the area near wrist joint can be estimatedwith a resolution of better than 4 MUm. This research demonstrates that applying a CMOSimage sensor in designing a non-contact, portable, easy-to-use, low cost pulse measurementsystem is feasible. Also, the designed APM system is well suited for evaluating and pre-diagnosing the health of a human being in TCM clinical practice. PMID- 28903300 TI - Modeling and Fabrication of Micro FET Pressure Sensor with Circuits. AB - This paper presents the simulation, fabrication and characterization of a microFET (field effect transistor) pressure sensor with readout circuits. The pressure sensorincludes 16 sensing cells in parallel. Each sensing cell that is circular shape is composed ofan MOS (metal oxide semiconductor) and a suspended membrane, which the suspendedmembrane is the movable gate of the MOS. The CoventorWare is used to simulate thebehaviors of the pressure sensor, and the HSPICE is employed to evaluate the characteristicsof the circuits. The pressure sensor integrated with circuits is manufactured using thecommercial 0.35 MUm CMOS (complementary metal oxide semiconductor) process and apost-process. In order to obtain the suspended membranes, the pressure sensor requires apost-CMOS process. The post-process adopts etchants to etch the sacrificial layers in thepressure sensors to release the suspended membranes, and then the etch holes in the pressuresensor are sealed by LPCVD (low pressure chemical vapor deposition) parylene. Thepressure sensor produces a change in current when applying a pressure to the sensing cells.The circuits are utilized to convert the current variation of the pressure sensor into thevoltage output. Experimental results show that the pressure sensor has a sensitivity of 0.032mV/kPa in the pressure range of 0-500 kPa. PMID- 28903301 TI - Six-Degree-of-Freedom Sensor Fish Design and Instrumentation. AB - Fish passing through dams may be injured or killed despite advances in turbinedesign, project operations and other fish bypass systems. The six-degree of-freedom (6DOF)Sensor Fish device is an autonomous sensor package that characterizes the physical conditionsand physical stresses to which fish are exposed when they pass through complex hydraulicenvironments. It has been used to identify the locations and operations where conditions aresevere enough to injure or kill fish. During the design process, a set of governing equationsof motion for the Sensor Fish was derived and simulated to understand the design implica tions of instrument selection and placement within the body of the device. The Sensor Fishpackage includes three rotation sensors, three acceleration sensors, a pressure sensor, and atemperature sensor with a sampling frequency of 2,000 Hz. Its housing is constructed of clearpolycarbonate plastic. It is 24.5 mm in diameter and 90 mm in length and weighs about 43 g,similar to the size and density of a yearling salmon smolt. The accuracy of the pressure sensorwas determined to be within 0.2 psi. In laboratory acceptance tests, the relative errors of boththe linear acceleration and angular velocity measurements were determined to be less than5%. An exposure is defined as a significant event when the acceleration reaches predefinedthresholds. Based on the different characteristic of acceleration and rotation velocities, theexposure event is categorized as either a collision between the Sensor Fish and a solid struc-ture or shear caused by turbulence. Since its development in 2005, the 6DOF Sensor Fish hasbeen deployed successfully at many major dams in the United States. PMID- 28903302 TI - Satellite-based Flood Modeling Using TRMM-based Rainfall Products. AB - Increasingly available and a virtually uninterrupted supply of satellite estimatedrainfall data is gradually becoming a cost-effective source of input for flood predictionunder a variety of circumstances. However, most real-time and quasi-global satelliterainfall products are currently available at spatial scales ranging from 0.25o to 0.50o andhence, are considered somewhat coarse for dynamic hydrologic modeling of basin-scaleflood events. This study assesses the question: what are the hydrologic implications ofuncertainty of satellite rainfall data at the coarse scale? We investigated this question onthe 970 km2 Upper Cumberland river basin of Kentucky. The satellite rainfall productassessed was NASA's Tropical Rainfall Measuring Mission (TRMM) Multi-satellitePrecipitation Analysis (TMPA) product called 3B41RT that is available in pseudo real timewith a latency of 6-10 hours. We observed that bias adjustment of satellite rainfall data canimprove application in flood prediction to some extent with the trade-off of more falsealarms in peak flow. However, a more rational and regime-based adjustment procedureneeds to be identified before the use of satellite data can be institutionalized among floodmodelers. PMID- 28903303 TI - Determination of Primary Spectral Bands for Remote Sensing of Aquatic Environments. AB - About 30 years ago, NASA launched the first ocean-color observing satellite:the Coastal Zone Color Scanner. CZCS had 5 bands in the visible-infrared domain with anobjective to detect changes of phytoplankton (measured by concentration of chlorophyll) inthe oceans. Twenty years later, for the same objective but with advanced technology, theSea-viewing Wide Field-of-view Sensor (SeaWiFS, 7 bands), the Moderate-ResolutionImaging Spectrometer (MODIS, 8 bands), and the Medium Resolution ImagingSpectrometer (MERIS, 12 bands) were launched. The selection of the number of bands andtheir positions was based on experimental and theoretical results achieved before thedesign of these satellite sensors. Recently, Lee and Carder (2002) demonstrated that foradequate derivation of major properties (phytoplankton biomass, colored dissolved organicmatter, suspended sediments, and bottom properties) in both oceanic and coastalenvironments from observation of water color, it is better for a sensor to have ~15 bands inthe 400 - 800 nm range. In that study, however, it did not provide detailed analysesregarding the spectral locations of the 15 bands. Here, from nearly 400 hyperspectral (~ 3-nm resolution) measurements of remote-sensing reflectance (a measure of water color)taken in both coastal and oceanic waters covering both optically deep and optically shallowwaters, first- and second-order derivatives were calculated after interpolating themeasurements to 1-nm resolution. From these derivatives, the frequency of zero values foreach wavelength was accounted for, and the distribution spectrum of such frequencies wasobtained. Furthermore, the wavelengths that have the highest appearance of zeros wereidentified. Because these spectral locations indicate extrema (a local maximum orminimum) of the reflectance spectrum or inflections of the spectral curvature, placing the bands of a sensor at these wavelengths maximizes the potential of capturing (and then restoring) the spectral curve, and thus maximizes the potential of accurately deriving properties of the water column and/or bottom of various aquatic environments with a multi-band sensor. PMID- 28903305 TI - Use of a Dynamic Enclosure Approach to Test the Accuracy of the NDIR Sensor: Evaluation Based on the CO2 Equilibration Pattern. AB - As part of a quality assurance (QA) study for sensor systems, an enclosureapproach is applied to assess the accuracy of non-dispersive infrared (NDIR)-based CO2sensors. To examine the performance of the sensor system, an enclosure chambercontaining six sensor units of the two model types (B-530 and H 500) was equilibratedwith calibrated CO2 standards at varying concentration levels. Initially, the equilibrationpattern was analyzed by CO2-free gas (0 ppm) at varying flow rates (i.e., 100, 200, 500, and1000 mL min-1). Results of the test yielded a highly predictable and quantifiable empiricalrelationship as a function of such parameters as CO2 concentration, flow rate, andequilibration time for the enclosure system. Hence, when the performance of the NDIR-method was evaluated at other concentrations (i.e., 500 and 1000 ppm), all the sensor unitsshowed an excellent compatibility, at least in terms of the correlation coefficients (r >0.999, p = 0.01). According to our analysis, the NDIR sensor system seems to attain anoverall accuracy near the 5% level. The relative performance of the NDIR sensor for CO2analysis is hence comparable with (or superior to) other methods previously investigated.The overall results of this study indicate that NDIR sensors can be used to provide highlyaccurate and precise analyses of CO2 both in absolute and relative terms. PMID- 28903304 TI - An Overview of Label-free Electrochemical Protein Sensors. AB - Electrochemical-based protein sensors offer sensitivity, selectivity and reliabilityat a low cost, making them very attractive tools for protein detection. Although the sensorsuse a broad range of different chemistries, they all depend on the solid electrode surface,interactions with the target protein and the molecular recognition layer. Traditionally, redoxenzymes have provided the molecular recognition elements from which target proteins haveinteracted with. This necessitates that the redox-active enzymes couple with electrodesurfaces and usually requires the participation of added diffusional components, or assemblyof the enzymes in functional chemical matrices. These complications, among many others,have seen a trend towards non-enzymatic-based electrochemical protein sensors. Severalelectrochemical detection approaches have been exploited. Basically, these have fallen intotwo categories: labeled and label-free detection systems. The former rely on a redox-activesignal from a reporter molecule or a label, which changes upon the interaction of the targetprotein. In this review, we discuss the label-free electrochemical detection of proteins,paying particular emphasis to those that exploit intrinsic redox-active amino acids. PMID- 28903306 TI - Combination of On-line pH and Oxygen Transfer Rate Measurement in Shake Flasks by Fiber Optical Technique and Respiration Activity MOnitoring System (RAMOS). AB - Shake flasks are commonly used for process development in biotechnologyindustry. For this purpose a lot of information is required from the growth conditions duringthe fermentation experiments. Therefore, Anderlei et al. developed the RAMOS technology[1, 2], which proviedes on-line oxygen and carbondioxide transfer rates in shake flasks.Besides oxygen consumption, the pH in the medium also plays an important role for thesuccessful cultivation of micro-organisms and for process development. For online pHmeasurement fiber optical methods based on fluorophores are available. Here a combinationof the on-line Oxygen Transfer Rate (OTR) measurements in the RAMOS device with anon-line, fiber optical pH measurement is presented. To demonstrate the application of thecombined measurement techniques, Escherichia coli cultivations were performed and on-line pH measurements were compared with off-line samples. The combination of on lineOTR and pH measurements gives a lot of information about the cultivation and, therefore, itis a powerful technique for monitoring shake flask experiments as well as for processdevelopment. PMID- 28903307 TI - Naked-eye and Selective Detection of Mercury (II) Ions in Mixed Aqueous Media Using a Cellulose-based Support. AB - A test paper for high-selectivity detecting Hg2+ ions in mixed acetonitrile watersolutions has been achieved using a bis(ferrocenyl) azine, as chromogenic chemosensormolecule, and a solid cellulose fibre, as a substrate. Depending on the amount of mercuryions in contact with the detecting molecule a spectacular color change in the celluloseindicator is produced, being possible to determine the concentration of Hg2+ ions either bynaked eye or spectroscopically. PMID- 28903309 TI - Analysis of Mean Access Delay in Variable-Window CSM. AB - The paper addresses the problem of the mean access delay characteristics in termof the channel load for networked sensor/control systems in LonWorks/EIA-709 technology.The system modelling is focused on the Media Access Control protocol that provides theload prediction and determines the key network characteristics. The network model assumesthe consistency of load prediction between the nodes, and that the Transaction ControlSublayer does not introduce limitations on the data transmission. The latter means that thenumbers of concurrent outgoing transactions being in progress are unlimited. Furthermore, itis assumed that the destination addresses of transmitted messages are distributed rather thanconcentrated on particular nodes. The analytical approach based on Markov chains isapplied. The calculation of transition probabilities of the Markov chain is exemplified by theload scenario where all the transactions are acknowledged, unicast, and the optionalcollision detection is enabled. On the basis of the stochastic analysis, the probabilities of asuccessful transmission and collision, respectively, are computed. Furthermore, thenumerical results of the mean access delay are reported. The simulative validation ofanalytical results is provided. PMID- 28903308 TI - Optical Fiber Sensing Using Quantum Dots. AB - Recent advances in the application of semiconductor nanocrystals, or quantumdots, as biochemical sensors are reviewed. Quantum dots have unique optical properties thatmake them promising alternatives to traditional dyes in many luminescence basedbioanalytical techniques. An overview of the more relevant progresses in the application ofquantum dots as biochemical probes is addressed. Special focus will be given toconfigurations where the sensing dots are incorporated in solid membranes and immobilizedin optical fibers or planar waveguide platforms. PMID- 28903310 TI - Characterization of physiochemical properties of caveolin-1 from normal and prion infected human brains. AB - Caveolin-1 is a major component protein of the caveolae-a type of flask shaped, 50-100 nm, nonclathrin-coated, microdomain present in the plasma membrane of most mammalian cells. Caveolin-1 functions as a scaffolding protein to organize and concentrate signaling molecules within the caveolae, which may be associated with its unique physicochemical properties including oligomerization, acquisition of detergent insolubility, and association with cholesterol. Here we demonstrate that caveolin-1 is detected in all brain areas examined and recovered in both detergent-soluble and -insoluble fractions. Surprisingly, the recovered molecules from the two different fractions share a similar molecular size ranging from 200 to 2,000 kDa, indicated by gel filtration. Furthermore, both soluble and insoluble caveolin-1 molecules generate a proteinase K (PK)-resistant C-terminal core fragment upon the PK-treatment, by removing ~36 amino acids from the N terminus of the protein. Although it recognizes caveolin-1 from A431 cell lysate, an antibody against the C-terminus of caveolin-1 fails to detect the brain protein by Western blotting, suggesting that the epitope in the brain caveolin-1 is concealed. No significant differences in the physicochemical properties of caveolin-1 between uninfected and prion-infected brains are observed. PMID- 28903311 TI - Development of hepatoma-derived, bidirectional oval-like cells as a model to study host interactions with hepatitis C virus during differentiation. AB - Directed differentiation of human stem cells including induced pluripotent stem cells into hepatic cells potentially leads to acquired susceptibility to hepatitis C virus (HCV) infection. However, cellular determinants that change their expression during cell reprogramming or hepatic differentiation and are pivotal for supporting the HCV life cycle remain unclear. In this study, by introducing a set of reprogramming factors, we established HuH-7-derived oval like cell lines, Hdo-17 and -23, which possess features of bipotential liver precursors. Upon induction of hepatocyte differentiation, expression of mature hepatocyte markers and hepatoblast markers in cells increased and decreased, respectively. In contrast, in response to cholangiocytic differentiation induction, gene expression of epithelium markers increased and cells formed round cysts with a central luminal space. Hdo cells lost their susceptibility to HCV infection and viral RNA replication. Hepatic differentiation of Hdo cells potentially led to recovery of permissiveness to HCV RNA replication. Gene expression profiling showed that most host-cell factors known to be involved in the HCV life cycle, except CD81, are expressed in Hdo cells comparable to HuH-7 cells. HCV pseudoparticle infectivity was significantly but partially recovered by ectopic expression of CD81, suggesting possible involvement of additional unidentified factors in HCV entry. In addition, we identified miR200a-3p, which is highly expressed in Hdo cells and stem cells but poorly expressed in differentiated cells and mature hepatocytes, as a novel negative regulator of HCV replication. In conclusion, our results showed that epigenetic reprogramming of human hepatoma cells potentially changes their permissivity to HCV. PMID- 28903312 TI - GNP-GAPDH1-22 nanovaccines prevent neonatal listeriosis by blocking microglial apoptosis and bacterial dissemination. AB - Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013-2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti GAPDH1-22 titres and tumor necrosis factor (TNF)/interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyco-nanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH1-22 nanovaccinesformulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-alpha-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1beta and interferon-alpha/beta. In contrast, neonates born to GNP-GAPDH1-22-vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti GAPDH1-22 antibodies, suggesting good induction of LM-specific memory. PMID- 28903313 TI - SNX10 promotes phagosome maturation in macrophages and protects mice against Listeria monocytogenes infection. AB - Listeria monocytogenes (L. monocytogenes), which is a facultative intracellular bacterial pathogen that causes listeriosis, is widely used to study the mammalian immune response to infection. After phagocytosis by professional phagocytes, L. monocytogenes is initially contained within phagosomes, which mature into phagolysosomes, where the bacteria are degraded. Although phagocytosis and subsequent phagosome maturation is essential for the clearance of infectious microbial pathogens, the underlying regulatory mechanisms are still unclear. SNX10 (Sorting nexin 10) has the simplest structure of the SNX family and has been reported to regulate endosomal morphology, which might be crucial for macrophage function, including phagocytosis and digestion of pathogens, inflammatory response, and antigen presentation. Our results showed that SNX10 expression was upregulated following L. monocytogenes infection in macrophages. It was also revealed that SNX10 promoted phagosome maturation by recruiting the Mon1-Ccz1 complex to endosomes and phagosomes. As a result, SNX10 deficiency decreased the bacterial killing ability of macrophages, and SNX10-deficient mice showed increased susceptibility to L. monocytogenes infection in vivo. Thus, this study revealed an essential role of SNX10 in controlling bacterial infection. PMID- 28903314 TI - PAQR3 suppresses the proliferation, migration and tumorigenicity of human prostate cancer cells. AB - As a newly discovered tumor suppressor, the potential function of PAQR3 in human prostate cancer has not been demonstrated. In this study, we report that PAQR3 is able to inhibit the growth and migration of human prostate cancer cells both in vitro and in vivo. Overexpression of PAQR3 inhibits the proliferation of PC3 and DU145 cells by both MTT and colony formation assays. Consistently, knockdown of PAQR3 enhances the proliferation of these cells. In wound-healing and transwell assays, overexpression of PAQR3 reduces the migration of PC3 and DU145 cells, while PAQR3 knockdown increases it. In a tumor xenograft model, overexpression of PAQR3 suppresses tumor growth of PC3 cells in vivo, while PAQR3 knockdown promotes the tumor growth. PAQR3 is also able to inhibit serum-induced phosphorylation of AKT and ERK in both PC3 and DU145 cells. In addition, PAQR3 suppresses the expression of epithelial-mesenchymal transition (EMT) markers in PC3 cells. Collectively, these data indicate that PAQR3 has a tumor suppressive activity in human prostate cancer cells and may stand out as a potential therapeutic target for prostate cancers. PMID- 28903315 TI - Risk assessment models for genetic risk predictors of lung cancer using two-stage replication for Asian and European populations. AB - In the past ten years, great successes have been accumulated by taking advantage of both candidate-gene studies and genome-wide association studies. However, limited studies were available to systematically evaluate the genetic effects for lung cancer risk with large-scale and different ethnic populations. We systematically reviewed relevant literatures and filtered out 241 important genetic variants identified in 124 articles. A two-stage case-control study within specific subgroups was performed to assess the effects [Training set: 2,331 cases vs. 3,077 controls (Chinese population); testing set: 1,937 cases vs. 1,984 controls (European population)]. Variable selection and model development were used LASSO penalized regression and genetic risk score (GRS) system. Further change in area under the receiver operator characteristic curves (AUC) made by the epidemiologic model with and without GRS was used to compare predictions. It kept 38 genetic variants in our study and the ratios of lung cancer risk for subjects in the upper quartile GRS was three times higher compared to that in the low quartile (odds ratio: 4.64, 95% CI: 3.87-5.56). In addition, we found that adding genetic predictors to smoking risk factor-only model improved lung cancer predictive value greatly: AUC, 0.610 versus 0.697 (P < 0.001). Similar performance was derived in European population and the combined two data sets. Our findings suggested that genetic predictors could improve the predictive ability of risk model for lung cancer and highlighted the application among different populations, indicating that the lung cancer risk assessment model will be a promising tool for high risk population screening and prediction. PMID- 28903316 TI - MDM2 antagonists synergize with PI3K/mTOR inhibition in well differentiated/dedifferentiated liposarcomas. AB - BACKGROUND: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. METHODS: WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. Western blotting, histopathology, and tumor volume evolution were used for the assessment of treatment efficacy. RESULTS: The PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed. Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone, BEZ235 alone and a combination of both agents. Consistent with these observations, we found a significant increase in apoptosis with the combination versus the single agent treatment alone. We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS. The combination regimen significantly reduced tumor growth rate in comparison with single agent alone. CONCLUSIONS: Our results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS. PMID- 28903317 TI - PD-L1 and c-MET expression and survival in patients with small cell lung cancer. AB - BACKGROUND: Blocking the binding between the PD-1 and PD-L1 has been reported to produce antitumor responses. The MET/HGF axis appears to be another signaling pathway frequently altered in small cell lung cancer (SCLC). Our study was aimed to investigate the expression and prognostic roles of PD-L1 and c-MET in SCLC. METHODS: The expression levels of PD-L1 and c-MET were evaluated by immunohistochemical analysis in 83 SCLC specimens. Survival analysis was performed using the Kaplan-Meier method. RESULTS: Of the SCLC specimens, 51.8% and 25.3% exhibited positivity for PD-L1 and c-MET, respectively. Higher PD-L1 expression in tumor specimens was significantly correlated with a limited disease (LD) stage, normal levels of serum lactate dehydrogenase (LDH) and neuron specific enolase (NSE). No association was found between the levels of c-MET and PD-L1 expression or between c-MET expression and other clinical characteristics. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than patients with PD-L1-negative tumors (17.0 vs 9.0, p=0.018). Conversely, those with positive c-MET expression exhibited a shorter OS trend (12.0 vs 15.0, p=0.186). However, sub-analysis of LD-stage patients revealed longer OS among the c-MET-negative group (25.0 vs 14.0; p=0.011). The OS of patients with positivity for both PD-L1 and c-MET showed no significant difference compared with other patients (p=0.17). According to multivariate analyses, neither PD-L1 nor c-MET immunoreactivity was a prognostic factor. CONCLUSION: Expression of PD-L1 was correlated with LD stage and might serve as a prognostic for better OS in SCLC patients. In LD-stage patients, high c-MET expression might be predictive of a poor outcome. PMID- 28903318 TI - MYC-dependent recruitment of RUNX1 and GATA2 on the SET oncogene promoter enhances PP2A inactivation in acute myeloid leukemia. AB - The SET (I2PP2A) oncoprotein is a potent inhibitor of protein phosphatase 2A (PP2A) that regulates many cell processes and important signaling pathways. Despite the importance of SET overexpression and its prognostic impact in both hematologic and solid tumors, little is known about the mechanisms involved in its transcriptional regulation. In this report, we define the minimal promoter region of the SET gene, and identify a novel multi-protein transcription complex, composed of MYC, SP1, RUNX1 and GATA2, which activates SET expression in AML. The role of MYC is crucial, since it increases the expression of the other three transcription factors of the complex, and supports their recruitment to the promoter of SET. These data shed light on a new regulatory mechanism in cancer, in addition to the already known PP2A-MYC and SET-PP2A. Besides, we show that there is a significant positive correlation between the expression of SET and MYC, RUNX1, and GATA2 in AML patients, which further endorses our results. Altogether, this study opens new directions for understanding the mechanisms that lead to SET overexpression, and demonstrates that MYC, SP1, RUNX1 and GATA2 are key transcriptional regulators of SET expression in AML. PMID- 28903319 TI - Loss of giant obscurins alters breast epithelial cell mechanosensing of matrix stiffness. AB - Obscurins are a family of RhoGEF-containing proteins with tumor and metastasis suppressing roles in breast epithelium. Downregulation of giant obscurins in normal breast epithelial cells leads to reduced levels of active RhoA and of its downstream effectors. Herein, we elucidate how depletion of giant obscurins affects the response of breast epithelial cells to changes in the mechanical properties of the microenvironment. We find that knockdown of obscurins increases cell morphodynamics, migration speed, and diffusivity on polyacrylamide gels of >= 1 kPa, presumably by decreasing focal adhesion area and density as well as cell traction forces. Depletion of obscurins also increases cell mechanosensitivity on soft (0.4-4 kPa) surfaces. Similar to downregulation of obscurins, pharmacological inhibition of Rho kinase in breast epithelial cells increases migration and morphodynamics, suggesting that suppression of Rho kinase activity following obscurin knockdown can account for alterations in morphodynamics and migration. In contrast, inhibition of myosin light chain kinase reduces morphodynamics and migration, suggesting that temporal changes in cell shape are required for efficient migration. Collectively, downregulation of giant obscurins facilitates cell migration through heterogeneous microenvironments of varying stiffness by altering cell mechanobiology. PMID- 28903320 TI - E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2alpha in clear cell renal cell carcinoma. AB - The E2F3 transcriptional regulatory pathway plays a major part in multiple-cancer progression, but the specific contributions of this pathway to tumor formation and the progression of clear cell renal cell carcinoma (ccRCC) are not fully understood. Clinically, we demonstrated that E2F3 was overexpressed in advanced tumor features. Moreover, cytoplasmic restoration predicted the poor overall survival of ccRCC patients. As a remarkable oncogene for ccRCC, high HIF-2alpha levels closely correlated with E2F3 upregulation. We observed in vitro that E2F3 overexpression and knockdown regulated HIF-2alpha expression. Furthermore, we found that HIF-2alpha harbored multiple E2F3 binding sites in the promoters. Mechanistically, E2F3 acted to transactivate HIF-2alpha transcription, which in turn exerted a serial effect on the pivotal epithelial-mesenchymal transition related genes. The RNA interference-mediated silencing of HIF-2alpha attenuated E2F3-enhanced cell migration and invasion in vitro and in vivo. Overall, our results identified HIF-2alpha as a direct target gene for E2F3 upregulation, which was critical for carcinogenesis and progression of ccRCC. Thus, targeting the E2F3-HIF-2alpha interaction may be a promising approach to ccRCC treatment. PMID- 28903321 TI - Alu-based cell-free DNA: a novel biomarker for screening of gastric cancer. AB - Gastric cancer (GC) is the fourth most common cancer and the second major cause of cancer-related deaths worldwide. In our previous study, a novel and sensitive method for quantifying cell-free DNA (CFD) in human blood was established and tested for its ability to predict patients with tumor. We want to investigate CFD expression in the sera of GC patients in an attempt to explore the clinical significance of CFD in improving the early screening of GC and monitoring GC progression by the branched DNA (bDNA)-based Alu assay. The concentration of CFD was quantitated by bDNA-based Alu assay. CEA, CA19-9, C72-4 and CA50 concentrations were determined by ABBOTT ARCHITECT I2000 SR. We found the CFD concentrations have significant differences between GC patients, benign gastric disease (BGD) patients and healthy controls (P < 0.05). CFD were weakly correlated with CEA (r = -0.197, P < 0.05) or CA50 (r = 0.206, P < 0.05), and no correlation with CA19-9 (r = -0.061, P > 0.05) or CA72-4 (r = 0.011, P > 0.05). In addition, CFD concentrations were significantly higher in stage I GC patients than BGD patients and healthy controls (P < 0.05), but there was no significant difference in CEA, CA19-9 and CA50 among the three traditional tumor markers (P > 0.05). Our analysis showed that CFD was more sensitive than CEA, CA19-9, CA72-4 or CA50 in early screening of GC. Compared with CEA, CA19-9, CA72-4 and CA50, CFD may prove to be a better biomarker for the screening of GC, thus providing a sensitive biomarker for screening and monitoring progression of GC. PMID- 28903322 TI - Evaluation of a community-based integrated heroin addiction treatment model in Chinese patients. AB - In this study, we analyzed the efficacy and feasibility of a community-based integrated heroin addiction treatment model in Chinese patients. The 210 heroin addicts belonging to six Chinese communities received an integrated biopsychosocial intervention that included pharmacological treatment, counseling and social assistance. High proportions of study participants were retained at the 12-month (91.9%; 193/210) and 24-month (88.1%; 185/210) follow-up visits. The number of morphine-positive subjects declined from 61.4% at baseline to 36.2% and 30.5% (Q=52.01; P<0.001) after 12 and 24 months, respectively. The crime rate decreased from 32.4% at baseline to 2.2% and 1.6% (Q=7.84; P<0.001) after 12 and 24 months, respectively. The number of patients that were employed increased from 24.3% at baseline to 37.8% and 50.8% after 12 and 24 months, respectively (Q=41.68; P<0.001). Addiction-related issues and mental health status improved according to Addiction Severity Index (ASI) and Symptom Checklist-90 (SCL-90). We therefore conclude that this community-based, integrated heroin addiction treatment model is highly feasible with high treatment retention, reduced drug use, a lower crime rate, improved health and increased employment. PMID- 28903323 TI - The pancreatic tumor microenvironment drives changes in miRNA expression that promote cytokine production and inhibit migration by the tumor associated stroma. AB - The pancreatic adenocarcinoma (PDAC) microenvironment is largely comprised of fibrotic tumor associated stroma (TAS) that contributes to the lethal biology of PDAC. microRNA (miRNA) are small non-coding RNAs that regulate gene expression. We hypothesized that interactions between PDAC cells and TAS cells within the microenvironment modulate miRNA expression and thus, tumor biology. We observed that miR-205 and members of the miR-200 family (miR-200a, -200b, -200c, -141 and miR-429) were exclusively expressed in PDAC cells, consistent with an epithelial miRNA signature, while miR-145 and miR-199 family members (miR-199a and -199b) were solely expressed in TAS cells, consistent with a stromal miRNA signature. This finding was confirmed by qRT-PCR of RNA obtained by laser-capture microdissection of surgical specimens. Using an in vitro co-culture model, we further demonstrated regulation of miRNA expression by cell-cell contact. Forced expression in TAS cells of miR-200b/-200c and miR-205 to mimic these observed changes in miRNA concentrations induced secretion of GM-CSF and IP10, and notably inhibited migration. These data suggest interactions within the tumor microenvironment alter miRNA expression, which in turn have a functional impact on TAS. PMID- 28903324 TI - The PWWP domain of the human oncogene WHSC1L1/NSD3 induces a metabolic shift toward fermentation. AB - WHSC1L1/NSD3, one of the most aggressive human oncogenes, has two isoforms derived from alternative splicing. Overexpression of long or short NSD3 is capable of transforming a healthy into a cancer cell. NSD3s, the short isoform, contains only a PWWP domain, a histone methyl-lysine reader involved in epigenetic regulation of gene expression. With the aim of understanding the NSD3s PWWP domain role in tumorigenesis, we used Saccharomyces cerevisiae as an experimental model. We identified the yeast protein Pdp3 that contains a PWWP domain that closely resembles NSD3s PWWP. Our results indicate that the yeast protein Pdp3 and human NSD3s seem to play similar roles in energy metabolism, leading to a metabolic shift toward fermentation. The swapping domain experiments suggested that the PWWP domain of NSD3s functionally substitutes that of yeast Pdp3, whose W21 is essential for its metabolic function. PMID- 28903325 TI - CXCL12/CXCR4 pathway is activated by oncogenic JAK2 in a PI3K-dependent manner. AB - JAK2 activation is the driver mechanism in BCR-ABL-negative myeloproliferative neoplasms (MPN). These diseases are characterized by an abnormal retention of hematopoietic stem cells within the bone marrow microenvironment and their increased trafficking to extramedullary sites. The CXCL12/CXCR4 axis plays a central role in hematopoietic stem cell/ progenitor trafficking and retention in hematopoietic sites. The present study explores the crosstalk between JAK2 and CXCL12/CXCR4 signaling pathways in MPN. We show that JAK2, activated by either MPL-W515L expression or cytokine stimulation, cooperates with CXCL12/CXCR4 signaling to increase the chemotactic response of human cell lines and primary CD34+ cells through an increased phosphatidylinositol-3-kinase (PI3K) signaling. Accordingly, primary myelofibrosis (MF) patient cells demonstrate an increased CXCL12-induced chemotaxis when compared to controls. JAK2 inhibition by knock down or chemical inhibitors decreases this effect in MPL-W515L expressing cell lines and reduces the CXCL12/CXCR4 signaling in some patient primary cells. Taken together, these data indicate that CXCL12/CXCR4 pathway is overactivated in MF patients by oncogenic JAK2 that maintains high PI3K signaling over the threshold required for CXCR4 activation. These results suggest that inhibition of this crosstalk may contribute to the therapeutic effects of JAK2 inhibitors. PMID- 28903326 TI - Distinct clinicopathological features in metanephric adenoma harboring BRAF mutation. AB - BRAF mutation recently has been reported in metanephric adenoma. We sought to determine the clinical and morphologic features of BRAF-mutated metanephric adenoma and to correlate BRAF mutation with BRAF V600E immunohistochemical staining results. A series of 48 metanephric adenomas and 15 epithelial predominant nephroblastomas were analyzed for the occurrence of BRAF mutation (BRAF V600E/V600E complex, BRAF V600D, BRAF V600K and BRAF V600R) using the BRAF RGQ PCR kit (Qiagen). Immunohistochemistry was performed using monoclonal mouse antibodies against p16INK4 and VE1 (Spring Bioscience), recognizing the BRAF V600E mutant protein. Forty-one of 48 cases (85%) showed BRAF V600E mutation; none of the other BRAF variants was detected. Of 41 BRAF-mutated metanephric adenomas, 33 showed positive VE1 immunostaining (sensitivity 80%, specificity 100%); in all cases we detected p16INK4 expression regardless of BRAF mutation status. All epithelial-predominant nephroblastomas were BRAF-wild-type and none expressed VE1. The following features were associated with BRAF V600E mutation: older patients (p=0.01), female predominance (p=0.005) and the presence of a predominantly acinar architecture (p=0.003). In summary, BRAF-mutated metanephric adenomas were associated with older age, female predominance, and the presence of a predominant acinar component. A subset (20%) of BRAF-mutated metanephric adenomas was not detected by VE1 immunostaining. PMID- 28903327 TI - Pericardial effusion is correlated with clinical outcome after pulmonary artery denervation for pulmonary arterial hypertension. AB - OBJECTIVES: Pericardial effusion (PE) is correlated with outcomes in patients with pulmonary arterial hypertension (PAH). Pulmonary artery denervation (PADN) was used for treatment of PAH. The present study aimed to analyze the prognostic value of PE for outcomes after PADN in patients with WHO Group I, Group II and Group IV PAH. RESULTS: PE, frequently seen in patients with connective tissue disease, was featured by fast heart rate, decreased exercise capacity, more syncope, worsening pulmonary arterial hemodynamic and right atrium size. PADN procedure resulted in dramatic reduction of PE. After a median of 376 days follow up, the rate of PAH-related event, all-cause death and rehospitalization increased over the PE amount and occurred in 29.8%, 19.7% and 25.2% of patients with PE, different to 3.4%, 3.4% and 6.8% of patients without PE (p = 0.034, p = 0.041 and p = 0.039, respectively). The reduction of PE during follow-up was similar among three groups. MATERIALS AND METHODS: Between March 2012 and July 2014, a total of 66 consecutive patients (52 +/- 16 years) who underwent PADN were stratified by no PE (n = 20), PE < 10 mm (n = 29) and PE >= 10 mm (n = 17) according to baseline echocardiograph. Dynamic change of PE and its correlation with PAH-related event after PADN were measured. CONCLUSIONS: PE is associated with increased PAH-related event after PADN. PADN results in significant similar reduction of PE among patients with Group I, Group II and Group IV PAH. PMID- 28903328 TI - CD164 promotes lung tumor-initiating cells with stem cell activity and determines tumor growth and drug resistance via Akt/mTOR signaling. AB - CD164 is a cell adhesion molecule that increases hematopoietic stem cell proliferation, adhesion, and migration via C-X-C chemokine receptor type 4 (CXCR4) signaling. Emerging evidence indicates that elevated CD164 expression is associated with aggressive metastasis, advanced stages, and shorter overall survival in lung cancer. However, no data are available regarding the clinical significance of CD164 expression in lung cancer. This study explores whether CD164 promotes tumor-initiation and drug resistance through the stem cell property. Using tissue microarrays, we determine that CD164 expression is correlated with clinicopathological characteristics in human lung cancer. The CD164 overexpression in normal lung epithelial cells (BEAS2B cells) leads to malignant transformation in vitro, tumorigenicity in xenografted mice, stem cell like property, and drug resistance through ATP-binding cassette transporters. The CD164 overexpression increases CXCR4 expression and activates Akt/mTOR signaling. Rapamycin, an mTOR inhibitor, hinders cell proliferation along with sphere formation in vitro and impedes tumor growth in vivo. In conclusion, we have provided evidence that CD164 promotes the growth of lung tumor-initiating cells with stem cell properties and induces tumor growth and drug resistance through Akt/mTOR signaling. Therefore, identification of CD164 as a cancer stem cell therapeutic marker may develop an effective therapy in patients with chemoresistant lung cancer. PMID- 28903329 TI - Fractalkine/CX3CL1 induced intercellular adhesion molecule-1-dependent tumor metastasis through the CX3CR1/PI3K/Akt/NF-kappaB pathway in human osteosarcoma. AB - Osteosarcoma is the most common primary bone tumor in children and teens. The exact molecular mechanism underlying osteosarcoma progression still remains unclear. The CX3CL1/fractalkine has been implicated in various tumors but not in osteosarcoma. This study is the first to show that fractalkine promotes osteosarcoma metastasis by promoting cell migration. Fractalkine expression was higher in osteosarcoma cell lines than in normal osteoblasts. Fractalkine induced cell migration by upregulating intercellular adhesion molecule-1 (ICAM-1) expression via CX3CR1/PI3K/Akt/NF-kappaB pathway in human osteosarcoma cells. Knockdown of fractalkine expression markedly inhibited cell migration and lung metastasis in osteosarcoma. Finally, we showed a clinical correlation between CX3CL1 expression and ICAM-1 expression as well as tumor stage in human osteosarcoma tissues. In conclusion, our results indicate that fractalkine promotes cell migration and metastasis of osteosarcoma by upregulating ICAM-1 expression. Thus, fractalkine could serve a novel therapeutic target for preventing osteosarcoma metastasis. PMID- 28903330 TI - Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice. AB - Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. In the present study, we assessed the function(s) of HSF1 in hepatocarcinogenesis via in vitro and in vivo approaches. In particular, we determined the importance of HSF1 on v-Akt murine thymoma viral oncogene homolog (AKT)-induced liver cancer development in mice. We found that knockdown of HSF1 activity via specific siRNA triggered growth restraint by suppressing cell proliferation and inducing massive cell apoptosis in human HCC cell lines. At the molecular level, HSF1 inhibition was accompanied by downregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade and related metabolic pathways. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery led to the inhibition of mouse hepatocarcinogenesis driven by overexpression of AKT. In human liver cancer specimens, we detected that HSF1 is progressively induced from human non tumorous surrounding livers to HCC, reaching the highest expression in the tumors characterized by the poorest outcome (as defined by the length of patients' survival). In conclusion, HSF1 is an independent prognostic factor in liver cancer and might represent an innovative therapeutic target in HCC subsets characterized by activation of the AKT/mTOR pathway. PMID- 28903331 TI - The antigenic identity of human class I MHC phosphopeptides is critically dependent upon phosphorylation status. AB - Dysregulated post-translational modification provides a source of altered self antigens that can stimulate immune responses in autoimmunity, inflammation, and cancer. In recent years, phosphorylated peptides have emerged as a group of tumour-associated antigens presented by MHC molecules and recognised by T cells, and represent promising candidates for cancer immunotherapy. However, the impact of phosphorylation on the antigenic identity of phosphopeptide epitopes is unclear. Here we examined this by determining structures of MHC-bound phosphopeptides bearing canonical position 4-phosphorylations in the presence and absence of their phosphate moiety, and examining phosphopeptide recognition by the T cell receptor (TCR). Strikingly, two peptides exhibited major conformational changes upon phosphorylation, involving a similar molecular mechanism, which focussed changes on the central peptide region most critical for T cell recognition. In contrast, a third epitope displayed little conformational alteration upon phosphorylation. In addition, binding studies demonstrated TCR interaction with an MHC-bound phosphopeptide was both epitope-specific and absolutely dependent upon phosphorylation status. These results highlight the critical influence of phosphorylation on the antigenic identity of naturally processed class I MHC epitopes. In doing so they provide a molecular framework for understanding phosphopeptide-specific immune responses, and have implications for the development of phosphopeptide antigen-specific cancer immunotherapy approaches. PMID- 28903332 TI - Myeloid-derived suppressor cell and macrophage exert distinct angiogenic and immunosuppressive effects in breast cancer. AB - The immunosuppressive tumor microenvironment is a key obstacle to hinder a cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) have been considered as a major player in immunosuppression. In this study, we find that tumor-infiltrating MDSCs (tiMDSCs) are less immunosuppressive than tumor-associated macrophages (TAMs) in multiple murine orthotopic breast tumor models. Compared to TAMs, tiMDSCs produce higher levels of pro-inflammatory factors and lower levels of anti-inflammatory factors. Furthermore, tiMDSCs are preferentially located in hypoxic areas and are more pro-angiogenic than TAMs. Consistent with these functional disparities, a shift from tiMDSCs to TAMs is observed during the progression of breast cancer. Moreover, infiltration of tiMDSCs is also noted in distal colonization of breast cancer cells in the lung. Taken together, our findings indicate that tiMDSCs are more pro-angiogenic and promote tumor initiation, while TAMs are more immunosuppressive and facilitate tumor immune evasion. This study suggests that selectively targeting on TAMs could alleviate the immunosuppressive tumor microenvironment and potentiate cancer immunotherapy. PMID- 28903333 TI - Effect of PKC inhibitor on experimental autoimmune myocarditis in Lewis rats. AB - Myocarditis is a major cause of sudden, unexpected death in young people. However, it is still one of the most challenging diseases to treat in cardiology. In the present study, we showed that both expression level and activity of PKC alpha were up-regulated in the rat heart of experimental autoimmune myocarditis (EAM). Intraperitoneal administration of PKC inhibitor (Ro-32-0432) at the end of the most severe inflammation period of EAM still significantly reduced the EAM induced expression of failure biomarkers. Furthermore, Ro-32-0432 reduced the ratio of Bax/Bcl-2 and suppressed the expression of cleaved caspase-3, both of which were increased in the heart of the EAM rats, suggesting an anti-apoptotic role of Ro-32-0432. Besides, Ro-32-0432 suppressed EAM-induced cardiac fibrosis and release of pro-inflammatory cytokines IL-1beta and IL-17. These results suggest that inhibition of PKC may serve as a potential therapeutic strategy for the treatment of myocarditis. PMID- 28903334 TI - Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy. AB - Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients' clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC. PMID- 28903335 TI - Sodium selenite prevents suppression of mucosal humoral response by AFB1 in broiler's cecal tonsil. AB - Aflatoxin B1 (AFB1), the most common mycotoxin in human food and animal feed, produces hepatotoxic, genotoxic and immunosuppressive effects in multiple species. Selenium (Se) has emerged as an important element in the dietary prevention of various toxic agents. The present study was designed to scrutinize the protective effects of sodium selenite on the histological lesions and suppression of mucosal humoral response in the cecal tonsil generated by AFB1. A total of 156 one-day-old broilers were divided into four groups and fed on basal diet (control group), 0.6 mg/kg AFB1 (AFB1 group), 0.4 mg/kg Se supplement (+Se group), and 0.6 mg/kg AFB1 + 0.4 mg/kg Se supplement (AFB1+Se group) respectively for 21 days. Our results showed that 0.4 mg/kg Se supplement in broiler's diets could improve the AFB1-induced histological lesions in the cecal tonsils including the depletion of lymphocytes in the lymphatic nodules as well as the shedding of microvilli in the absorptive cells. Moreover, Se could restore the decreased number of IgA+ cells and expression levels of pIgR, IgA, IgG, and IgM mRNA induced by AFB1 to be close to those in the control group. These results demonstrated that 0.4 mg/kg supplemented dietary Se in the form of sodium selenite could protect the cecal tonsils from the histological lesions and suppression of the mucosal humoral response provoked by 0.6 mg/kg AFB1. Our study may provide new experimental evidences for better understanding of AFB1-induced damage of mucosal immunity and protective effect of Se against this toxin. PMID- 28903336 TI - G protein-coupled receptor kinase 6 is overexpressed in glioma and promotes glioma cell proliferation. AB - The expression and potential biological functions of G protein-coupled receptor kinase 6 (GRK6) in human glioma are tested in this study. We show that protein and mRNA expression of GRK6 in human glioma tissues was significantly higher than that in the normal brain tissues. Further immunohistochemistry assay analyzing total 118 human glioma tissues showed that GRK6 over-expression was correlated with glioma pathologic grade and patients' Karnofsky performance status (KPS) score. At the molecular level, in the GRK6-low H4 glioma cells, forced over expression of GRK6 promoted cell proliferation. Reversely, siRNA-mediated knockdown of GRK6 in the U251MG (GRK6-high) cells led to proliferation inhibition and cell cycle arrest. Intriguingly, GRK6 could also be an important temozolomide resistance factor. Temozolomide-induced cytotoxicity was prominent only in GRK6 low H4 glioma cells. On the other hand, knockdown of GRK6 by targeted siRNA sensitized U251MG cells (GRK6-high) to temozolomide. Thus, GRK6 over-expression in glioma is important for cell proliferation and temozolomide resistance. PMID- 28903337 TI - Targeting the apoptotic Mcl-1-PUMA interface with a dual-acting compound. AB - Despite intensive efforts in the search for small molecules with anti-cancer activity, it remains challenging to achieve both high effectiveness and safety, since many agents lack the selectivity to only act on cancer cells. The interface of two apoptotic proteins, myeloid cell leukemia-1 (Mcl-1) and p53 upregulated modulator of apoptosis (PUMA), has been recently affirmed as a target for treating cancers, as the disruption of Mcl-1-PUMA binding can reduce cancer cell survival and protect normal cells from apoptosis. However, therapeutic agents that target this interface are yet to be found. In this work, we combined pharmacophore modelling and biological tests to seek small molecules which target the Mcl-1-PUMA interface. For the first time, a small-molecule compound was identified. Its dual activity has been validated to reduce PUMA-dependent apoptosis while deactivating Mcl-1-mediated anti-apoptosis in cancer cells. Our results would provide a new avenue for the development of effective and safe anti cancer agents. PMID- 28903338 TI - TLR2 activation induces antioxidant defence in human monocyte-macrophage cell line models. AB - When monocytes are recruited to inflammation/infection sites, extravasate and differentiate into macrophages, they encounter increasing levels of oxidative stress, both from exogenous and endogenous sources. In this study, we aimed to determine whether there are specific biochemical mechanisms responsible for an increase in oxidative stress resistance in differentiating macrophages. We performed experiments on in vitro cell line models of the monocyte-macrophage differentiation axis (less differentiated THP-1 cells and more differentiated Mono Mac 6 cells). At the same time, we verified the hypothesis that activating monocyte/macrophage innate immune response by pathogens (exemplified by stimulating the TLR2 pattern recognition receptor) would further strengthen cellular antioxidant defences. We found that resistance to exogenous oxidative stress increased substantially both during differentiation and upon activation of TLR2. This increase in antioxidant resistance was accompanied by decrease in free radical damage to cellular proteins. On the molecular level, this resistance was mediated especially by increased levels and activity of glutathione, glutathione related antioxidant enzymes and Mn superoxide dismutase, as shown by gene expression assays, Western blotting and enzyme activity assays. Moreover, upon TLR2 activation additional molecular mechanisms came into play, conferring additional resistance levels even upon differentiated macrophage-like cells, mainly related to thioredoxin-linked antioxidant enzymes. PMID- 28903339 TI - ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways. AB - ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family, whose functions have been involved in the regulation of chromatin remodeling, cell cycle progression, proliferation and apoptosis. Our previous study has shown that ING5 overexpression inhibits lung cancer aggressiveness via suppressing epithelial to mesenchymal transition (EMT). However, the mechanisms remain largely unknown. In the current study, by Phospho-Kinase array and western blot, we have defined significantly upregulated EGFR/PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways in ING5 knockdown A549 cells, which could be downregulated by ING5 overexpression. PI3K inhibitor ZSTK474 or STAT3 inhibitor Niclosamide not only abolished ING5 knockdown-promoted proliferation, colony formation, migration and invasion of lung cancer A549 cells, but also impaired ING5 knockdown stimulated metastasis of cancer cells in mouse xenograft models with tail vein injection of A549 cells. Furthermore, treatment with ZSTK474 or Niclosamide decreased protein level of EGFR, p-Akt, IL-6 and p-STAT3, and reversed ING5 knockdown-promoted EMT, as indicated by downregulated expression of EMT marker E cadherin, an epithelial marker, increased expression of N-cadherin, a mesenchymal marker, and EMT-related transcription factors including Snail, Slug, Smad3 and Twist. Taken together, these results demonstrate that loss of ING5 enhances aggressiveness of lung cancer cells by promoting EMT via activation of EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways. PMID- 28903340 TI - Multi-modality imaging-monitored creation of rat orthotopic pancreatic head cancer with obstructive jaundice. AB - PURPOSE: To investigate the feasibility of using multi-modality imaging to monitor the creation of rat models with orthotopic pancreatic head cancer with obstructive jaundice. RESULTS: 27 of 52 rats (51.92%) developed pancreatic head cancer. The tumor formation rate was significantly higher in the animal group receiving bioluminescent tumor, compared to the group receiving non bioluminescent donor tumors [78.1% (25/32 rats) vs 10.0% (2/20 rats), P = 0.0001]. Both ultrasound imaging and MRI clearly characterized the orthotopic tumors. Laboratory biochemistry test for those rats with obstructive jaundice showed elevated levels of bilirubin, aspartate transaminase (AST), alkaline phosphatase (ALT) and gamma-glutamyl transpeptidase (lambda-GGT), compared with those rats without jaundice (P < 0.05). Correlative pathology confirmed that all tumors were ductal adenocarcinomas, and located in pancreatic head regions. MATERIALS AND METHODS: Rat pancreatic adenocarcinoma cells (DSL-6A/C1) were first transfected with lentivirus/mCherry-luciferase genes, and then subcutaneously implanted into flanks of donor immunocompetent Lewis rats, to create pancreatic tumor tissues. The tumor tissues from donor rats with either bioluminescence signal or without the signal were then transplanted into the pancreatic heads of 52 recipient Lewis rats. Bioluminescence optical and ultrasound imaging, as well as magnetic resonance imaging (MRI), were performed to follow up the tumor formation and growth in these tumor-transplanted rats. Physical examination and biochemistry test were used to discern the rats with obstructive jaundice. The rats were euthanized for subsequent histologic correlation and confirmation. CONCLUSIONS: We successfully created a new rat model with orthotopic pancreatic head cancer, which can be accurately monitored and visualized by different imaging modalities. PMID- 28903341 TI - APOBEC3G acts as a therapeutic target in mesenchymal gliomas by sensitizing cells to radiation-induced cell death. AB - Genomic, transcriptional, and proteomic analyses of brain tumors reveal that subtypes differ in their pathway activity, progression, and response to therapy. We performed an expression profiling of Glioma Initiating Cells (GICs) and comparative analysis between different groups of GICs indicates major variations in gene expression. Hierarchical clustering analysis revealed groups of GICs reflecting their heterogeneity, and among some of the genes as major regulators of mesenchymal phenotype, we identified ABOBEC3G as one of the most discriminating genes in mesenchymal group. ABOBEC3G revealed a strong correlation with overall survival in TCGA GBM patient cohorts. APOBEC3G regulates cell invasion and silencing of this gene in GICs inhibits cell invasion and also glioma sphere initiation. APOBEC3G controls invasion through TGFbeta/Smad2 pathway by regulating Smad2 target genes Thrombospondin 1, matrix metallopeptidase 2 and TIMP metallopeptidase inhibitor 1. We also show that targeting APOBEC3G can sensitize cancer cells to radiation induced cell death by attenuating activation of the DNA repair pathway. This response is mainly shown by decreased pChk2 expression in knockdown APOBEC3G cells. Taken together, we show that APOBEC3G gene is a mesenchymal enriched gene that controls invasion and knockdown of APOBEC3G sensitizes cells to radiation induced cell death, suggesting that APOBEC3G can be considered for use in stratifying patients with GBM for prognostic considerations. PMID- 28903343 TI - A study on the anti-tumor mechanism of total flavonoids from Radix Tetrastigmae against additional cell line based on COX-2-mediated Wnt/beta-catenin signaling pathway. AB - This study is to explore the effect of total flavonoids from Radix Tetrastigmae (TF) against hepatic cancer and discuss the acting mechanism. Proliferation of HepG2 cells was promoted by PGE2 and Butaprost. Using AH6809 as the positive control, the inhibitory effect of TF on additional cell line was detected through a CCK-8 assay, the apoptosis rate was detected by flow cytometry, and the nuclear morphology of cells were observed by Hochest33258 staining. Then PCR was applied to determine the mRNA expression. The corresponding Protein expression were determined by Western Blot. The effects of TF on the body weight, tumor growth volume and tumor inhibition rate were observed in nude mice model of human hepatocellular carcinoma by vivo experiments. The results showed TF had an obvious inhibitory effect on HepG2 cells with a significant dose-dependent manner (P<0.01). Pyknosis was found under the fluorescence microscope after TF treatment for 24h by Hochest33258 staining. Typical features of apoptosis were observed in HepG2 cells treated with TF and the apoptosis rate increased with increase of concentration of the TF. mRNA expression levels of GSK-3beta, Akt, VEGF, COX-2 and beta-catenin were down regulated greatly by the TF in HepG2 cells. Moderate and high concentrations of TF led to an obvious down regulation of GSK-3beta, p GSK-3beta, Akt, p-Akt, VEGF, COX-2 and beta-catenin in HepG2 cells, while p-beta catenin was up regulated. The tumor inhibition rates with high, medium and low dose of TF were 64.07%, 53.64%, 46.69%, respectively. The inhibitory effect of total flavonoids on tumor growth in mice was better than that of CTX, and the inhibitory effect of TF on tumor growth was less than CTX. TF exhibited a significant inhibitory effect on HepG2 cells, promoting the apoptosis of HepG2 cells in a dose-dependent manner. TF was also regulatory of the COX-2-Wnt/beta catenin signaling pathway, which was presumed to be the working mechanism of Tetrastigmae. PMID- 28903342 TI - Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions. AB - Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup. PMID- 28903344 TI - Establishing a patient-derived xenograft model of human myxoid and round-cell liposarcoma. AB - Myxoid and round cell liposarcoma (MRCL) is a common type of soft tissue sarcoma. The lack of patient-derived tumor xenograft models that are highly consistent with human tumors has limited the drug experiments for this disease. Hence, we aimed to develop and validate a patient-derived tumor xenograft model of MRCL. A tumor sample from a patient with MRCL was implanted subcutaneously in an immunodeficient mouse shortly after resection to establish a patient-derived tumor xenograft model. After the tumor grew, it was resected and divided into several pieces for re-implantation and tumor passage. After passage 1, 3, and 5 (i.e. P1, P3, and P5, respectively), tumor morphology and the presence of the FUS DDIT3 gene fusion were consistent with those of the original patient tumor. Short tandem repeat analysis demonstrated consistency from P1 to P5. Whole exome sequencing also showed that P5 tumors harbored many of the same gene mutations present in the original patient tumor, one of which was a PIK3CA mutation. PF 04691502 significantly inhibited tumor growth in P5 models (tumor volumes of 492.62 +/- 652.80 vs 3303.81 +/- 1480.79 mm3, P < 0.001, in treated vs control tumors, respectively) after 29 days of treatment. In conclusion, we have successfully established the first patient-derived xenograft model of MRCL. In addition to surgery, PI3K/mTOR inhibitors could potentially be used for the treatment of PIK3CA-positive MRCLs. PMID- 28903345 TI - Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic miRNAs detectable in plasma. AB - BACKGROUND: Current diagnostic and prognostic blood-based biomarkers for neuroendocrine tumors are limited. MiRNAs have tumor-specific expression patterns, are relatively stable, and can be measured in patient blood specimens. We performed a multi-stage study to identify and validate characteristic circulating miRNAs in patients with metastatic small intestine neuroendocrine tumors, and to assess associations between miRNA levels and survival. METHODS: Using a 742-miRNA panel, we identified candidate miRNAs similarly expressed in 19 small intestine neuroendocrine tumors and matched plasma samples. We refined our panel in an independent cohort of plasma samples from 40 patients with metastatic small intestine NET and 40 controls, and then validated this panel in a second, large cohort of 120 patients with metastatic small intestine NET and 120 independent controls. RESULTS: miRNA profiling of 19 matched small intestine neuroendocrine tumors and matched plasma samples revealed 31 candidate miRNAs similarly expressed in both tissue and plasma. We evaluated expression of these 31 candidate miRNAs in 40 independent cases and 40 normal controls, and identified 4 miRNAs (miR-21-5p, miR-22-3p, miR-29b-3p, and miR-150-5p) that were differently expressed in cases and controls (p<0.05). We validated these 4 miRNAs in a separate, larger panel of 120 cases and 120 controls. We confirmed that high circulating levels of miR-22-3p (p<0.0001), high levels of miR 21-5p, and low levels of miR-150-5p (p=0.027) were associated with the presence of metastatic small intestine NET. While levels of 29b-3p were lower in cases than in controls in both the initial cohort and the validation cohort, the difference in the validation cohort did not reach statistical significance. We further found that high levels of circulating miR-21-5p, high levels of circulating miR-22-3p and low levels of circulating miR-150-5p were each independently associated with shorter overall survival. A combined analysis using all three markers was highly prognostic for survival (HR 0.47, 95% CI 0.27-0.82). CONCLUSIONS: Our study suggests that elevated circulating levels of miR-21-5p and miR-22-3p and low levels of miR-150-5p are characteristic in patients with metastatic small intestine neuroendocrine tumors, and further suggests that levels of these miRNAs are associated with overall survival. These observations provide the basis for further validation studies, as well as studies to assess the biological function of these miRNAs in small intestine neuroendocrine tumors. PMID- 28903346 TI - Glutathione peroxidase 7 suppresses cancer cell growth and is hypermethylated in gastric cancer. AB - Gastric cancer (GC) is one of the most common cancers in the world, and remains the third leading cause of cancer-related deaths worldwide. Glutathione peroxidase 7 (GPX7) is a member of GPX family which is downregulated in some cancer types. In this study, we investigated the expression, regulation, and molecular function of GPX7 in gastric cancer using 2D and 3D in vitro models and de-identified human tissue samples. Quantitative real-time RT-PCR, immunofluorescence, Western blot, 3D organotypic cultures, and pyrosequencing assays were used. We detected downregulation of GPX7 in all 7 gastric cancer cell lines that we tested and in approximately half (22/45) of human gastric cancer samples, as compared to histologically normal gastric tissues. Quantitative bisulfite pyrosequencing methylation analysis demonstrated DNA hypermethylation (> 10% methylation level) of GPX7 promoter in all 7 gastric cancer cell lines and in 56% (25/45) of gastric cancer samples, as compared to only 13% (6/45) in normal samples (p < 0.0001). Treatment of AGS and SNU1 cells with 5-Aza-2' deoxycytidine led to a significant demethylation of GPX7 promoter and restored the expression of GPX7. In vitro assays showed that reconstitution of GPX7 significantly suppressed gastric cancer cell growth in both 2D and 3D organotypic cell culture models. This growth suppression was associated with inhibition of cell proliferation and induction of cell death. We detected significant upregulation of p27 and cleaved PARP and downregulation of Cyclin D1 upon reconstitution of GPX7. Taken together, we conclude that epigenetic silencing of GPX7 could play an important role in gastric tumorigenesis and progression. PMID- 28903347 TI - Retrospective analysis of risk factors associated with Kawasaki disease in China. AB - In order to provide early intervention for coronary artery lesion (CAL) caused by Kawasaki Disease (KD), we analyzed clinical characteristics of typical and incomplete KD cases from 1998 to 2008 in Northwest and Central China. A total of 383 patients included 298 cases of typical KD and 85 cases of incomplete KD. The morbidity of incomplete KD was 28.5%, a percentage significantly lower than that of typical KD. The occurrence of bulbar conjunctiva congestion, erythra, crissum red, film-like decrustation, lip red, rhagades, raspberry tongue, bilateral toe end decrustation, limb sclerosis, cervical lymph nodes enlargement, agitation and irritability in incomplete KD group was lower than that in the group of typical KD (p < 0.05); however, the occurrence of unilateral toe-end decrustation, scar reappearance erythema, malaise, fatigue, liver incidence was significant higher in incomplete KD group (p < 0.05). Based on lab assays and inspection index comparisons, the incomplete KD cases whose C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly increased, had significantly higher reduction in blood platelet (PLT). Interestingly, the KD patients with CPR higher than 30 mg/L, ESR higher than 40 mm/h, hepatomegaly and IVIG ineffectiveness, had higher incidence of CAL development. Altogether, our data have indicated differential clinical characteristics between incomplete KD and typical KD, and have identified several high risk factors of KD for CAL, such as hepatomegaly. PMID- 28903348 TI - Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. AB - The nuclear receptor (NR) superfamily contains hormone-inducible transcription factors that regulate many physiological and pathological processes through regulating gene expression. NR4A1 is an NR family member that still does not have an identified endogenous ligand, and its role in cancer is also currently unclear and controversial. In this study, we aimed to define the expression profiles and specific role of NR4A1 in the highly malignant triple-negative breast cancer (TNBC), which still lacks available targeted therapies. Bioinformatic analysis revealed a decrease of NR4A1 mRNA expression in human TNBC samples. Semi quantitative analysis of NR4A1 protein expression by immunohistochemistry also identified a progressive NR4A1 reduction during the development of mouse basal like mammary tumors and a significant NR4A1 downregulation in human TNBC samples. Furthermore, the expression levels of NR4A1 in human TNBC were negatively associated with tumor stage, lymph node metastasis and disease recurrence. Moreover, ectopic expression of NR4A1 in MDA-MB-231, a TNBC cell line with little endogenous NR4A1, inhibited the proliferation, viability, migration and invasion of these cells, and these inhibitions were associated with an attenuated JNK1-AP 1-cyclin D1 pathway. NR4A1 expression also largely suppressed the growth and metastasis of these cell-derived tumors in mice. These results demonstrate that NR4A1 is downregulated in TNBC and restoration of NR4A1 expression inhibits TNBC growth and metastasis, suggesting that NR4A1 is a tumor suppressor in TNBC. PMID- 28903349 TI - The G-protein-coupled bile acid receptor Gpbar1 (TGR5) protects against renal inflammation and renal cancer cell proliferation and migration through antagonizing NF-kappaB and STAT3 signaling pathways. AB - Gpbar1 (TGR5), a G-protein-coupled bile acid membrane receptor, is well known for its roles in regulation of glucose metabolism and energy homeostasis. In the current work, we found that TGR5 activation by its ligand suppressed lipopolysaccharide (LPS)-induced proinflammatory gene expression in wild-type (WT) but not TGR5-/- mouse kidney. Furthermore, we found that TGR5 is a suppressor of kidney cancer cell proliferation and migration. We show that TGR5 activation antagonized NF-kappaB and STAT3 signaling pathways through suppressing the phosphorylation of IkappaBalpha, the translocation of p65 and the phosphorylation of STAT3. TGR5 overexpression with ligand treatment inhibited gene expression mediated by NF-kappaB and STAT3. These results suggest that TGR5 antagonizes kidney inflammation and kidney cancer cell proliferation and migration at least in part by inhibiting NF-kappaB and STAT3 signaling. These findings identify TGR5 may serve as an attractive therapeutic tool for human renal inflammation related diseases and cancer. PMID- 28903350 TI - ZEB1 confers stem cell-like properties in breast cancer by targeting neurogenin 3. AB - Cancer stem cells (CSCs) are a subpopulation of cancer cells believed to be implicated in cancer initiation, progression, and recurrence. Here, we report that ectopic expression of zinc finger E-box binding homeobox 1 protein (ZEB1) results in the acquisition of CSC properties by breast cancer cells, leading to tumor initiation and progression in vitro and in vivo. The neurogenin 3 gene (Ngn3) is a bona fide target of ZEB1, and its repression is a key factor contributing to ZEB1-induced cancer cell stemness. ZEB1 suppressed Ngn3 transcription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase 1 (HDAC1) complex on the Ngn3 promoter, leading to promoter hypermethylation and gene silencing. The rescue of Ngn3 expression attenuated ZEB1-induced cancer stemness and symmetric CSC division. Immunohistological analysis of human breast cancer specimens revealed a strong inverse relationship between ZEB1 and NGN3 protein expression. Thus, our findings suggest ZEB1 mediated silencing of Ngn3 is required for breast tumor initiation and maintenance. Targeted therapies against the ZEB1/Ngn3 axis may be highly valuable for the prevention and treatment of breast cancer. PMID- 28903351 TI - Preoperative transcatheter arterial chemotherapy may suppress oxidative stress in hepatocellular carcinoma cells and reduce the risk of short-term relapse. AB - In this study, we aim to investigate oxidative stress in hepatocellular carcinoma (HCC) tissues in patients receiving preoperative transcatheter arterial chemotherapy (TAC) and its association with prognosis. A total of 89 HCC patients enrolled in this study, 39 received preoperative TAC 1 week before surgery (pTAC group) and 50 did not (non-pTAC group). All patients underwent hepatectomy and postoperative TAC and were followed up to 400 weeks. Samples of liver tissue without HCC and hepatitis (n = 15) served as normal controls. Cellular levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), TP53, and p21waf1/cip1 were measured in both cancer and surrounding tissues using an immunohistochemistry assay. Taken together, our data suggested that preoperative TAC might postpone postoperative HCC relapse within 1 year via suppression of tumor cells by induction of high levels of oxidative stress. PMID- 28903352 TI - Analysis of Bos taurus and Sus scrofa X and Y chromosome transcriptome highlights reproductive driver genes. AB - The biology of sperm, its capability of fertilizing an egg and its role in sex ratio are the major biological questions in reproductive biology. To answer these question we integrated X and Y chromosome transcriptome across different species: Bos taurus and Sus scrofa and identified reproductive driver genes based on Weighted Gene Co-Expression Network Analysis (WGCNA) algorithm. Our strategy resulted in 11007 and 10445 unique genes consisting of 9 and 11 reproductive modules in Bos taurus and Sus scrofa, respectively. The consensus module calculation yields an overall 167 overlapped genes which were mapped to 846 DEGs in Bos taurus to finally get a list of 67 dual feature genes. We develop gene co expression network of selected 67 genes that consists of 58 nodes (27 down regulated and 31 up-regulated genes) enriched to 66 GO biological process (BP) including 6 GO annotations related to reproduction and two KEGG pathways. Moreover, we searched significantly related TF (ISRE, AP1FJ, RP58, CREL) and miRNAs (bta-miR-181a, bta-miR-17-5p, bta-miR-146b, bta-miR-146a) which targeted the genes in co-expression network. In addition we performed genetic analysis including phylogenetic, functional domain identification, epigenetic modifications, mutation analysis of the most important reproductive driver genes PRM1, PPP2R2B and PAFAH1B1 and finally performed a protein docking analysis to visualize their therapeutic and gene expression regulation ability. PMID- 28903353 TI - Direct inhibition of STAT signaling by platinum drugs contributes to their anti cancer activity. AB - Platinum-based chemotherapeutics are amongst the most powerful anti-cancer drugs. Although their exact mechanism of action is not well understood, it is thought to be mediated through covalent DNA binding. We investigated the effect of platinum based chemotherapeutics on signaling through signal transducer and activator of transcription (STAT) proteins, which are involved in many oncogenic signaling pathways. We performed in vitro experiments in various cancer cell lines, investigating the effects of platinum chemotherapeutics on STAT phosphorylation and nuclear translocation, the expression of STAT-modulating proteins and downstream signaling pathways. Direct binding of platinum to STAT proteins was assessed using an AlphaScreen assay. Nuclear STAT3 expression was determined by immunohistochemistry and correlated with disease-free survival in retrospective cohorts of head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-based chemoradiotherapy (n= 65) or with radiotherapy alone (n = 32). At clinically relevant concentrations, platinum compounds inhibited STAT phosphorylation, resulting in loss of constitutively activated STAT proteins in multiple distinct cancer cell lines. Platinum drugs specifically inhibited phospho-tyrosine binding to SH2 domains, thereby blocking STAT activation, and subsequently downregulating pro-survival- and anti-apoptotic- target genes. Importantly, we found that active STAT3 in tumors directly correlated with response to cisplatin-based chemoradiotherapy in HNSCC patients (p = 0.006). These findings provide insight into a novel, non-DNA-targeted mechanism of action of platinum drugs, and could be leveraged into the use of STAT expression as predictive biomarker for cisplatin chemotherapy and to potentiate other therapeutic strategies such as immunotherapy. PMID- 28903354 TI - HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response. AB - Full-length HER2 oncoprotein and splice variant Delta16 are co-expressed in human breast cancer. We studied their interaction in hybrid transgenic mice bearing human full-length HER2 and Delta16 (F1 HER2/Delta16) in comparison to parental HER2 and Delta16 transgenic mice. Mammary carcinomas onset was faster in F1 HER2/Delta16 and Delta16 than in HER2 mice, however tumor growth was slower, and metastatic spread was comparable in all transgenic mice. Full-length HER2 tumors contained few large vessels or vascular lacunae, whereas Delta16 tumors presented a more regular vascularization with numerous endothelium-lined small vessels. Delta16-expressing tumors showed a higher accumulation of i.v. injected doxorubicin than tumors expressing full-length HER2. F1 HER2/Delta16 tumors with high full-length HER2 expression made few large vessels, whereas tumors with low full-length HER2 and high Delta16 contained numerous small vessels and expressed higher levels of VEGF and VEGFR2. Trastuzumab strongly inhibited tumor onset in F1 HER2/Delta16 and Delta16 mice, but not in full-length HER2 mice. Addiction of F1 tumors to Delta16 was also shown by long-term stability of Delta16 levels during serial transplants, in contrast full-length HER2 levels underwent wide fluctuations. In conclusion, full-length HER2 leads to a faster tumor growth and to an irregular vascularization, whereas Delta16 leads to a faster tumor onset, with more regular vessels, which in turn could better transport cytotoxic drugs within the tumor, and to a higher sensitivity to targeted therapeutic agents. F1 HER2/Delta16 mice are a new immunocompetent mouse model, complementary to patient derived xenografts, for studies of mammary carcinoma onset, prevention and therapy. PMID- 28903355 TI - Anti-proliferative, pro-apoptotic and anti-invasive effect of EC/EV system in human osteosarcoma. AB - Osteosarcoma is the most common and aggressive bone tumor in children. The Endocannabinoid/Endovanilloid system has been proposed as anticancer target in tumor of different origins. This system is composed of two receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel and their ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells. We investigated the effects of JWH 133 (CB2 agonist) and RTX (TRPV1 agonist) in six human Osteosarcoma cell lines: MG-63, U-2OS, MNNG/HOS, Saos-2, KHOS/NP, Hs888Lu, by Apoptosis and Migration Assay. We also compared the effects of these compounds on Caspase-3, AKT, MMP-2 and Notch-1 regulation by Q-PCR and Western Blotting. We observed an anti proliferative, pro-apoptotic, anti-invasive effect. Our results show that both CB2 stimulation and TRPV1 activation, in different Osteosarcoma cell lines, can act on the same pathways to obtain the same effect, indicating the Endocannabinoid/Endovanilloid system as a new therapeutic target in Osteosarcoma. PMID- 28903356 TI - Sexual life satisfaction and its associated socio-demographic and workplace factors among Chinese female nurses of tertiary general hospitals. AB - Adverse workplace factors such as job stress are reported to be associated with poor physical and mental health of nurses. However, associations between occupational factors and sexual life satisfaction (SLS) of nurses remain understudied. This study investigated SLS of Chinese female nurses of tertiary general hospitals and socio-demographic and occupational factors associated with reduced SLS of nurses. In this cross-sectional survey, 393 Chinese female nurses of four tertiary general hospitals completed a standardized socio-demographic and occupational characteristics questionnaire, Zung's Self-rating Scale for Depression, Job Content Questionnaire, and a self-report SLS question. Multiple ordinal logistic regression was used to identify factors related to reduced SLS. Fourteen point five percent female nurses were dissatisfied with their current sex lives. In multiple regression, related factors for decreased SLS included being unmarried (OR = 1.49), shift work (OR = 1.92), contract employment (OR = 1.63), high job demands (OR = 2.21), low job control (OR = 1.88), inadequate social support (OR = 2.32), and depression (OR = 3.14). Chinese female nurses of tertiary general hospitals have poor SLS. Reducing job stress and providing psycho-social support may help improve SLS of nurses. PMID- 28903357 TI - Intratumoral acidosis fosters cancer-induced bone pain through the activation of the mesenchymal tumor-associated stroma in bone metastasis from breast carcinoma. AB - Cancer-induced bone pain (CIBP) is common in patients with bone metastases (BM), significantly impairing quality of life. The current treatments for CIBP are limited since they are often ineffective. Local acidosis derived from glycolytic carcinoma and tumor-induced osteolysis is only barely explored cause of pain. We found that breast carcinoma cells that prefer bone as a metastatic site have very high extracellular proton efflux and expression of pumps/ion transporters associated with acid-base balance (MCT4, CA9, and V-ATPase). Further, the impairment of intratumoral acidification via V-ATPase targeting in xenografts with BM significantly reduced CIBP, as measured by incapacitance test. We hypothesize that in addition to the direct acid-induced stimulation of nociceptors in the bone, a novel mechanism mediated by the acid-induced and tumor associated mesenchymal stroma might ultimately lead to nociceptor sensitization and hyperalgesia. Consistent with this, short-term exposure of cancer-associated fibroblasts, mesenchymal stem cells, and osteoblasts to pH 6.8 promotes the expression of inflammatory and nociceptive mediators (NGF, BDNF, IL6, IL8, IL1b and CCL5). This is also consistent with a significant correlation between breakthrough pain, measured by pain questionnaire, and combined high serum levels of BDNF and IL6 in patients with BM, and also by immunofluorescence staining showing IL8 expression that was more in mesenchymal stromal cells rather than in tumors cells, and close to LAMP-2 positive acidifying carcinoma cells in BM tissue sections. In summary, intratumoral acidification in BM might promote CIBP also by activating the tumor-associated stroma, offering a new target for palliative treatments in advanced cancer. PMID- 28903358 TI - MRI-based radiotherapy planning method using rigid image registration technique combined with outer body correction scheme: a feasibility study. AB - An alternative pseudo CT generation method for magnetic resonance image (MRI) based radiotherapy planning was investigated in the work. A pseudo CT was initially generated using the rigid image registration between the planning MRI and previously acquired diagnostic CT scan. The pseudo CT generated was then refined to have the same morphology with that of the referenced planning image scan by applying the outer body correction scheme. This method was applied to some sample of brain image data and the feasibility of the method was assessed by comparing dosimetry results with those from the current gold standard CT-based calculations. Validation showed that nearly the entire pixel doses calculated from pseudo CT were agreed well with those from actual planning CT within 2% in dosimetric and 1mm in geometric uncertainty ranges. The results demonstrated that the method suggested in the study was sufficiently accurate, and thus could be applicable to MRI-based brain radiotherapy planning. PMID- 28903359 TI - Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Guerin (BCG) and to oxidative damage. AB - The sialyl-Tn (sTn) antigen is an O-linked carbohydrate chain aberrantly expressed in bladder cancer (BC), whose biosynthesis is mainly controlled by the sialyltransferase ST6GALNAC1. Treatment with Bacillus Calmette-Guerin (BCG) is the most effective adjuvant immunotherapy for superficial BC but one third of the patients fail to respond. A poorly understood correlation between the expression of sTn and BC patient's response to BCG was previously observed. By analyzing tumor tissues, we showed that patients with high ST6GALNAC1 and IL-6 mRNA expression were BCG responders. To investigate the role of sTn in BC cell biology and BCG response, we established the cell lines MCRsTn and MCRNc by retroviral transduction of the BC cell line MCR with the ST6GALNAC1 cDNA or with an empty vector, respectively. Compared with MCRNc, BCG-stimulated MCRsTn secreted higher levels of IL-6 and IL-8 and their secretome induced a stronger IL-6, IL-1beta, and TNFalpha secretion by macrophages, suggesting the induction of a stronger inflammatory response. Transcriptomic analysis of MCRNc and MCRsTn revealed that ST6GALNAC1/sTn expression modulates hundreds of genes towards a putative more malignant phenotype and down-regulates several genes maintaining genomic stability. Consistently, MCRsTn cells displayed higher H2O2 sensitivity. In MCRsTn,, BCG challenge induced an increased expression of several regulatory non coding RNA genes. These results indicate that the expression of ST6GALNAC1/sTn improves the response to BCG therapy by inducing a stronger macrophage response and alters gene expression towards malignancy and genomic instability, increasing the sensitivity of BC cells to the oxidizing agents released by BCG. PMID- 28903360 TI - Variants in the CXCL12 gene was associated with coronary artery disease susceptibility in Chinese Han population. AB - BACKGROUND: Coronary artery disease (CAD) is one of the most serious diseases all around the world. Previous studies have shown the function of CXCL12 in the process of atherosclerosis. The aim of this research is to examine whether variants of CXCL12 contribute to CAD. MATERIALS AND METHODS: To examine whether variants of CXCL12 contribute to CAD, we selected 6 single nucleotide polymorphisms (SNPs) of CXCL12, and genotyped by Sequenom MassARRAY technology in 597 CAD patients and 685 healthy control. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age and gender. We also analysis the differences in continuous variables among the subjects with three genotypes of related genes were assessed using the ANOVA. RESULTS: We found significant differences in apoB concentrations with rs1065297 and rs10793538 different genotype. In the allele model, rs1065297, rs266089 and rs10793538 in CXCL12 gene associated with the risk of CAD. Stratified according to gender, rs266089 and rs2839693 in CXCL12 gene were associated with the risk of CAD in men, while rs1065297 and rs10793538 in CXCL12 gene were associated with the risk of CAD in women. Stratified according to age, rs197452 decreased the risk of CAD in less than 50 years old group. While in more than 50 years old group, not find significant results. Haplotype analysis shown that haplotype "TGCC" in the block increased CAD risk (OR=1.26, 95%CI: 1.00-1.58, p=0.046). CONCLUSION: This study provides an evidence for polymorphism of CXCL12 gene associated with CAD development in Chinese Han population. PMID- 28903361 TI - Fulvestrant 500 milligrams as endocrine therapy for endocrine sensitive advanced breast cancer patients in the real world: the Ful500 prospective observational trial. AB - The observational prospective trial herein presented aimed at evaluating the efficacy of fulvestrant 500 mg in the treatment of endocrine sensitive advanced breast cancer patients from the real world setting. The primary end point was clinical benefit rate (CBR). Secondary end points were overall survival (OS), progression free survival (PFS) and tolerability. One hundred sixty three patients were enrolled. At a median follow up of 20 months, the 61% of patients reached CBR, whose median duration was 10.8 months. Median PFS and OS were 7 and 35 months, respectively. Endocrine sensitive patients showed better PFS and OS. No relevant toxicity appeared when analyzing safety data. In multivariate analysis, visceral involvement, endocrine sensitivity and previous endocrine therapy were prognostic factor for PFS, whereas endocrine sensitivity and metastasis at diagnosis had prognostic relevance for OS. Estrogen receptor expression >50%, single metastatic site, and no prior endocrine therapy for advanced disease were predictive of CBR. In this prospective trial, fulvestrant 500 mg appeared to be a safe and active treatment and confirmed its efficacy in the daily clinical practice. A high percent expression of estrogen receptors (above 50%) was associated with higher CBR. Treatment was very well tolerated. Endocrine sensitivity had a major impact on treatment outcome. As expected, patients who had received first-line endocrine therapy for advanced disease exhibited worse outcome and a lower CBR. PMID- 28903362 TI - Cell-free circulating DNA integrity is an independent predictor of impending breast cancer recurrence. AB - Non-invasive blood-based molecule markers are evaluated as promising biomarkers these days. Here we investigated the potential of cell-free circulating DNA Integrity (cfDI) as blood-based marker for the prediction of recurrence during the follow-up of breast cancer patients within a prospective study cohort. cfDI was determined in plasma of 212 individuals, by measuring ALU and LINE1 repetitive DNA elements using quantitative PCR. A significant decrease of cfDI in recurrent breast cancer patients was observed. The group of patients who had impending recurrence during the follow-up had significant lower cfDI compared to the group of non-recurrent patients (P < 0.001 for ALU and LINE1 cfDI). cfDI could differentiate recurrent breast cancer patients from non-recurrent breast cancer subjects (area under the curve, AUC = 0.710 for ALU and 0.704 for LINE1). Univariate and multivariate analysis confirmed a significant association of recurrence and cfDI. Breast cancer patients with a lower cfDI had a much higher risk to develop recurrence than the patients with a higher cfDI (P = 0.020 for ALU cfDI and P = 0.019 for LINE1 cfDI, respectively). Further we show that cfDI is an independent predictor of breast cancer recurrence. In combination with other molecular markers, cfDI might be a useful biomarker for the prediction for breast cancer recurrence in clinic utility. We propose that cfDI might also be useful for the prediction of recurrence during the follow-up of other cancers. PMID- 28903363 TI - P53 prevent tumor invasion and metastasis by down-regulating IDO in lung cancer. AB - In present study, we are to clear demonstrate the genetic evidence of IDO signaling's impact on invasion and metastasis in lung cancer. Here we examined IDO1 expression levels in non-small cell lung cancer (NSCLC) patients (64) tumor/normal pairs underwent RT-PCR and comprehensive histological, immunohistochemica and clinical analysis. The NSCLC cells stably expressing IDO1 was analyzed for migration and invasion assays and the regulatory mechanism in vitro and metastasis assays in vivo. As results, we reported that IDO1 expression increased by more than 3.2-fold in lung cancer compared with their corresponding non-tumor tissues, and the up-regulation of IDO1 is significantly correlated to TNM stage and lymph node-metastasis. The over-expression of IDO1 significantly encouraged the metastasis and invasion of lung cancer cells, and IDO1 could promote metastasis formation in vivo. Furthermore, we further found that p53 could attenuate IDO signaling in lung cancer cell migration partly. In conclusion, these results demonstrate that the IDO signaling's impact on invasion and metastasis and the suppressive effect of p53 on IDO1 in lung cancer, present one novel therapeutic strategy for early metastatic lung cancer in clinical. PMID- 28903364 TI - KIF7 attenuates prostate tumor growth through LKB1-mediated AKT inhibition. AB - This study investigated kinesin family member 7 (KIF7) expression and function in prostate cancer (PCa). Our results showed that KIF7 was significantly downregulated in PCa, compared with normal, benign prostatic hyperplasia and prostate intraepithelial neoplasia tissues, partially through promoter hypermethylation. We further investigated the effects of KIF7 coiled coil (CC) domain and motor domain (MD) on PCa development in vitro and in vivo. Our results showed that KIF7-CC but not KIF7-MD significantly attenuated proliferation and colony formation, impeded migration and invasion, induced apoptosis and sensitized PCa cells to paclitaxel. Further analysis revealed that KIF7-CC enhanced LKB1 expression and phosphorylation at Ser428, which induced PTEN phosphorylation at Ser380/Thr382/383 and consequently blocked AKT phosphorylation at Ser473. Downregulation of LKB1 significantly attenuated the suppressive effects of KIF7-CC on cell proliferation, colony formation and AKT phosphorylation. Furthermore, our in vivo studies showed that KIF7-CC reduced prostate tumorigenesis in cell-derived xenografts. Downregulation of LKB1 abrogated the anti-tumor effects of KIF7-CC in these xenografts. Taken together, these findings provide the first evidence to support the role of KIF7 as a negative regulator that inhibits PCa development partially through LKB1-mediated AKT inhibition. PMID- 28903365 TI - Protective effects of circulating microvesicles derived from myocardial ischemic rats on apoptosis of cardiomyocytes in myocardial ischemia/reperfusion injury. AB - OBJECTIVE: To investigate the effects of circulating microvesicles derived from myocardial ischemia (I-MVs) on apoptosis in myocardial ischemia/reperfusion (I/R) injury in rats. METHODS: I-MVs from rats undergoing myocardial left anterior descending (LAD) coronary artery ligation were isolated by ultracentrifugation from circulating blood and characterized by flow cytometry. I-MVs were administered intravenously (4.8 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min of ischemia and 120-min of reperfusion of LAD in rats. RESULTS: Treatment with I-MVssignificantly reduced the size of myocardial infarction, the activities of serum CK-MB and LDH, and the number of apoptotic cardiomyocytes. The activities of caspase 3, caspase 9 and caspase 12 in myocardium were also decreased significantly with I-MVs treatment. Moreover, the expression of Bax was decreased but Bcl-2 was increased. The expression of glucose regulated protein 78 (GRP78), sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and phosphorylated phospholamban (p-PLB) were increased after being treated with I-MVs. CONCLUSION: I-MVs could protect hearts from I/R injury in rats through SERCA2 and p-PLB of calcium regulatory proteins to alleviate intrinsic myocardial apoptosis including mitochondrial and endoplasmic reticulum pathways. PMID- 28903366 TI - Systematic analysis of coronary artery disease datasets revealed the potential biomarker and treatment target. AB - Coronary artery disease caused about 1 of every 7 deaths in the United States and early prevention was potential to decrease the incidence and mortality. We aimed to figure the genes involving in the coronary artery disease using meta-anlaysis. Five datasets of coronary heart disease from GEO series were retrieved and data preprocessing and quality control were carried out. Moderated t-test was used to decide the differentially expressed genes for a single dataset. And the combined p-value using systematic-analysis methods were conducted using MetaDE. The pathway enrichment was carried out using Reactome database. Protein-protein interactions of the identified differentially expressed genes were also analyzed using STRING v10.0 online tool. After removing unidentified or intermediate samples and a total of 238 cases and 189 matched or partially matched control from five microarray datasets were retrieved from GEO. Six different quality control measures were calculated and PCA biplots were plotted in order to visualize the quantitative measure. The first two PCs captured 91% of the variance and we decided to include all of the datasets for systematic analysis. Using the FDR cut-off as 0.1, nine genes, including LFNG, ID3, PLA2G7, FOLR3, PADI4, ARG1, IL1R2, NFIL3 and MGAM, were differentially expressed according to maxP. Their protein-protein interactions showed that they were closely connected and 24 Reactome pathways were related to coronary artery disease. We concluded that pathways related to immune responses, especially neutrophil degranulation, were associated with coronary heart disease. PMID- 28903367 TI - Exploratory investigation of PSCA-protein expression in primary breast cancer patients reveals a link to HER2/neu overexpression. AB - BACKGROUND: Prostate stem cell antigen (PSCA) has been suggested as biomarker and therapeutic target for prostate cancer. Recent advances showed that PSCA is up regulated in other cancer entities, such as bladder or pancreatic cancer. However, the clinical relevance of PSCA-expression in breast cancer patients has not yet been established and is therefore addressed by the current study. METHODS: PSCA-protein expression was assessed in 405 breast cancer patients, using immunohistochemistry (PSCA antibody MB1) and tissue microarrays. RESULTS: PSCA-expression was detected in 94/405 patients (23%) and correlated with unfavorable histopathological grade (p=0.011) and increased Ki67 proliferation index (p=0.006). We observed a strong positive correlation between PSCA-protein expression and HER2/neu receptor status (p<0.001). PSCA did not provide prognostic information in the analyzed cohort. Interestingly, the distribution of PSCA-expression among triple negative patients was comparable to the total population. CONCLUSION: We identified a subgroup of PSCA-positive breast cancer patients, which could be amenable for a PSCA-targeted therapy. Moreover, given that we found a strong positive correlation between PSCA- and HER/neu expression, targeting PSCA may provide an alternative therapeutic option in case of trastuzumab resistance. PMID- 28903368 TI - Expression analysis of LC3B and p62 indicates intact activated autophagy is associated with an unfavorable prognosis in colon cancer. AB - Autophagy is a lysosomal degradation and recycling process implicated in cancer progression and therapy resistance. We assessed the impact of basal autophagy in colon cancer (CC) in vitro and ex vivo. Functional autophagy was demonstrated in CC cell lines (LoVo; HT-29) showing a dose-dependent increase of the autophagy markers LC3B, p62 and autophagic vesciles upon increasing concentrations of the autophagy inhibitor chloroquine, which was demonstrated by immunoblotting, immunofluorescence and electron microscopy. Next, tissue microarrays with 292 primary resected CC, with cores from different tumor regions, and normal mucosa were analyzed by immunohistochemistry for LC3B and p62. CC tissue showed LC3B dot like, p62 dot-like, cytoplasmic and nuclear staining in various levels without significant intratumoral heterogeneity. Tumoral LC3B and p62 expression was significantly higher than in normal tissue (p<0.001). No associations between staining patterns and pathological features (e.g. TNM categories; grading) were observed. Both low LC3B dot-like and low p62 dot-like-cytoplasmic staining were associated with worse overall survival (p=0.005 and p=0.002). The best prognostic discrimination, however, was seen for a combination of LC3B dot-like/p62 dot-like cytoplasmic staining: high expression of both markers, indicative of impaired activated autophagy, was associated with the best overall survival. In contrast, high LC3B dot-like/low p62 dot-like-cytoplasmic expression, indicative of intact activated autophagy, was associated with the worst outcome (p<0.001 in univariate and HR=0.751; CI=0.607-0.928; p=0.008 in multivariate analysis). These specific expression patterns of LC3B and p62 pointing to different states of autophagy associated with diverging clinical outcomes highlighte the potential significance of basal autophagy in CC biology. PMID- 28903369 TI - Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice. AB - Salmonella typhimurium A1-R (S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 * 105 and 5 * 105 were tolerated. A single dose of 1 * 106 resulted in mouse death. S. typhimurium A1-R (5 * 105 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of S. typhimurium A1-R. PMID- 28903370 TI - Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling. AB - The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein that is regarded as one of the markers for tumor initiating cells (TIC) in human hepatocellular carcinoma (HCC). Much work has been directed towards targeting these TICs as a mean of placing these master regulators of cell proliferation and drug resistance under control. Human bone marrow-derived mesenchymal stem cells are known to exhibit an innate property of tumor tropism. However, the possible relationship between MSC and TIC is not well understood. In this study, we show that MSC migration to HCC can be effectively inhibited by TACE and gamma-secretase inhibitors that stop the activation of EpCAM signaling event. Silencing of EpCAM expression through siRNA and antibody approaches also resulted in impaired MSC migration. By contrast, increase levels of EpICD proteins in HCC cells and HCC mouse xenografts resulted in enhanced MSC migration. Taken together, these findings show that MSC is drawn to the more oncogenic population of HCC, and could potentially serve as a cell-based carrier of therapeutic genes to target EpICD-enriched hepatic tumor cells. PMID- 28903371 TI - Sociodemographic and economic factors are associated with weight gain between before and after cancer diagnosis: results from the prospective population-based NutriNet-Sante cohort. AB - PURPOSE: While many cancer patients are affected by weight loss, others tend to gain weight, which may impact prognosis and risk of recurrence and of second cancer. The aim of this prospective study was to investigate weight variation between before and after cancer diagnosis and socio-demographic, economic, lifestyle and clinical factors associated with moderate-to-severe weight gain. METHODS: 1051 incident cases of first primary cancer were diagnosed in the NutriNet-Sante cohort between 2009 and 2015. Weight was prospectively collected every 6 months since subjects' inclusion (i.e. an average of 2y before diagnosis). Mean weights before and after cancer diagnosis were compared with paired Student's t-test. Factors associated with moderate-to-severe weight gain (>=5% of initial weight) were investigated by age and sex-adjusted logistic regression. RESULTS: Weight loss was observed in men (-3.54+/-4.39kg in those who lost weight, p=0.0002) and in colorectal cancer patients (-3.94+/-4.40kg, p=0.001). Weight gain was observed in breast and skin cancers (2.83+/-3.21kg, p=0.04, and 2.96+/-2.75kg, p=0.04 respectively). Women (OR=1.75[1.06 2.87],p=0.03), younger patients (2.44[1.51-3.70],p<0.0001), those with lower income (OR=1.30[1.01-1.72],p-trend=0.007), lower education (OR=1.32[1.03-2.70],p trend=0.03), excess weight before diagnosis (OR=1.64[1.12-2.42],p=0.01), lower physical activity (OR=1.28[1.01-1.64],p=0.04) and those who stopped smoking (OR=4.31[1.99-9.35],p=0.005]) were more likely to gain weight. In breast cancer patients, induced menopause was associated with weight gain (OR=4.12[1.76-9.67]), but no association was detected for tumor characteristics or treatments. CONCLUSION: This large prospective cohort provided original results on weight variation between before and after cancer diagnosis, highlighting different weight trajectories. Socio-demographic and economic factors appeared to influence the risk of weight gain, illustrating social inequalities in health. PMID- 28903372 TI - Myosin Va plays essential roles in maintaining normal mitosis, enhancing tumor cell motility and viability. AB - Myosin Va, a member of Class V myosin, functions in organelle motility, spindle formation, nuclear morphogenesis and cell motility. The purpose of this study is to explore the expression and localization of myosin Va in testicular cancer and prostate cancer, and its specific roles in tumor progression including cell division, migration and proliferation. We detected myosin Va in testicular and prostate tumor tissues using sqRT-PCR, western blot, and immunofluorescence. Tumor samples showed an increased expression of myosin Va, abnormal actin and myosin Va distribution. Immunofluorescence images during the cell cycle showed that myosin Va tended to gather at cytoplasm during anaphase but co-localized with nucleus during other phases, suggesting the roles of myosin Va in disassembly of spindle microtubule, movement of chromosomes and normal cytokinesis. In addition, multi-nucleation and aberrant nuclear morphology were observed in myosin Va-knockdown cells. Wounding assay and CCK-8-based cell counting were conducted to explore myosin Va roles in cell migration, viability and proliferation. Our results suggest that myosin Va plays essential roles in maintaining normal mitosis, enhancing tumor cell motility and viability, and these properties are the hallmark of tumor progression and metastasis development. Therefore, an increased understanding of myosin Va expression and function will assist in the development of future oncodiagnosis and -therapy. PMID- 28903373 TI - Pre-operative to post-operative serum carcinoembryonic antigen ratio is a prognostic indicator in colorectal cancer. AB - We explored the prognostic significance of the pre-operative-to-post-operative serum carcinoembryonic antigen (pre-post-CEA) ratio in colorectal cancer (CRC). We detected pre- and post-operative CEA levels in 2035 CRC patients surgically treated at First Affiliated Hospital of Zhengzhou University between June 2001 and June 2011. Univariate analysis revealed the pre-post-CEA ratio is associated with distant metastasis and degree of tumor differentiation (both P < 0.05). Multivariate analysis showed that the pre-post-CEA ratio is associated with lymphatic and distant metastasis, tumor-node-metastasis (TNM) stage and degree of tumor differentiation (all P < 0.01). The pre-CEA levels, pre-post-CEA ratios, distant metastasis, TNM stage and degree of tumor differentiation were all associated with 5-yr overall survival (all P < 0.05) based on multivariate analysis. Consequently, pre-CEA levels, pre-post-CEA ratios, distant metastasis and TNM stage are independent risk factors for CRC. We have thus demonstrated that the pre-post-CEA ratio is a prognostic indicator for CRC patients. PMID- 28903374 TI - Resveratrol enhances polyubiquitination-mediated ARV7 degradation in prostate cancer cells. AB - Although androgen deprivation therapy (ADT) serves as the primary treatment option for localized or metastatic prostate cancer, most cases eventually develop into castration-resistant prostate cancer (CRPC). However, androgen receptor (AR) continues to be functional in CRPC through various mechanisms, including the development of AR splicing variants, especially ARV7. Since it lacks the ligand binding domain but retains the intact DNA binding domain, ARV7 is constitutively active, which makes ARV7-positive prostate cancer responsive to neither abiraterone nor enzalutamide. In this study, we explored the effect of resveratrol on ARV7 transcriptional activity and the potential for development of resveratrol as a treatment for ARV7-positive prostate cancer. First, we ectopically expressed ARV7 in PC3 cells, an AR-negative prostate cancer cell line, and demonstrated that resveratrol is capable of inhibiting ARV7 transcriptional activity by downregulating ARV7 protein levels. Of note, resveratrol does not affect the mRNA levels of ARV7 nor its nuclear translocation. Next, we demonstrated that resveratrol is capable of downregulating the levels of the endogenously expressed ARV7 as well as AR target gene mRNAs in 22RV1 prostate cancer cells. Mechanistically, resveratrol downregulates ARV7 by enhancing ARV7 polyubiquitination and subsequent proteasome mediated degradation. These findings suggest that resveratrol could be a potential treatment for ARV7-positive CPRC. PMID- 28903375 TI - Transcription factor Yin Yang 2 is a novel regulator of the p53/p21 axis. AB - Yin Yang 2 (YY2) is a multifunctional zinc-finger transcription factor that belongs to YY family. Unlike the well-characterized YY1, our understanding regarding the biological functions of YY2 is still very limited. Here we found for the first time that in contrast to YY1, which had been reported to be oncogenic, the expression level of YY2 in tumor cells and/or tissues was downregulated compared with its expression level in the normal ones. We also demonstrated that YY2 exerts biological function contrary to YY1 in cell proliferation. We elucidated that YY2 positively enhances p21 expression, and concomitantly, its silencing promotes cells to enter G2/M phase and enhances cell proliferation. Furthermore, we found that YY2 regulation on p21 occurs p53 dependently. Finally, we identified a novel YY2 binding site in the promoter region of tumor suppressor p53. We found that YY2 binds to the p53 promoter and activates its transcriptional activity, and subsequently, regulates cell cycle progression via p53/p21 axis. Taken together, our study not only identifies YY2 as a novel tumor suppressor gene that plays a pivotal role in cell cycle regulation, but also provides new insights regarding the regulatory mechanism of the conventional p53/p21 axis. PMID- 28903376 TI - Improving circulating tumor cells enumeration and characterization to predict outcome in first line chemotherapy mCRPC patients. AB - INTRODUCTION: There is a critical need of new surrogate markers for improving the therapeutic selection and monitoring of metastatic prostate cancer patients. Nowadays clinical management of these patients is been driven by biochemical and clinical parameters without enough accuracy to allow a real personalized medicine. The present study was conducted to go insight the molecular profile of circulating tumor cells (CTCs) isolated from advanced metastatic castration resistant prostate cancer (mCRPC) with the aim of identifying prognostic marker with potential utility for therapy selection and monitoring. MATERIALS AND METHODS: CTCs isolation was carried out in peripheral blood samples from 29 mCRPC patients that undergo systemic chemotherapy based on taxanes (docetaxel/cabazitaxel) and 19 healthy controls using in parallel CellSearch and an alternative EpCAM-based immunoisolation followed by RT-qPCR analysis to characterize the CTC population. A panel of 17 genes related with prostate biology, hormone regulation, stem properties, tumor aggressiveness and taxanes responsiveness was analysed to identify an expression signature characterizing the CTCs. RESULTS: Patients with >= 5 CTCs/7.5ml of peripheral blood at baseline and during the treatment showed lower progression free survival (PFS) and overall survival (OS). Changes of CTCs levels during the treatment were also associated with the patient's outcome. These results confirmed previous data obtained using CellSearch in mCRPC. In addition, we found a CTC profile mainly characterized by the expression of relevant genes for the hormone dependent regulation of PCa such as AR and CYP19 together with genes strongly implicated in PCa progression and resistance development such as BIRC5, TUB1A, GDF15, RAB7 and SPINK1. Our gene expression profiling also permitted the identification of valuable prognostic biomarkers. Thus, high levels of AR, CYP19 and GDF15 were associated with poor PFS rates while AR, GDF15 and BIRC5 were also found as reliable predictors of OS. Besides, a logistic model using KLK3 and BIRC5 showed a high specificity and sensitivity compared to CellSearch to discriminate patients with a more aggressive evolution. CONCLUSIONS: The molecular characterization of CTCs from advanced mCRPC patients provided with a panel of specific biomarkers, including genes related to taxanes resistance, with a promising applicability as "liquid biopsy" for the management of these patients. PMID- 28903378 TI - AGO2 involves the malignant phenotypes and FAK/PI3K/AKT signaling pathway in hypopharyngeal-derived FaDu cells. AB - Argonaute 2 (AGO2) protein is usually overexpressed in various head and neck squamous cell carcinoma. However, the precise molecular mechanisms of AGO2 in hypopharyngeal cancer have not yet been clearly understood. Here we found the AGO2 expression in hypopharyngeal cancer tissues were generally higher comparing with that of the corresponding adjacent noncancerous epithelium tissues, and these were associated with the more aggressive clinicopathologic features and the poor clinical outcomes. Stable knockdown of AGO2 protein retarded cell proliferation, migration, invasion, arrested cell cycle and induced apoptosis. Meanwhile the knockdown also inhibited the FAK/PI3K/AKT signaling pathway in hypopharyngeal-derived FaDu cells. These findings suggested that AGO2 gene might act as an oncogene which contributed to the tumorigenesis and progression, and has potential values for molecular diagnosis, clinical therapies and prognosis evaluation in hypopharyngeal cancer. PMID- 28903377 TI - PD-L1/PD-1 expression and tumor-infiltrating lymphocytes in conjunctival melanoma. AB - Conjunctival melanoma (CM) is an infrequent but potentially lethal malignancy, with limited therapeutic options for metastases. Recent inhibitors of the interaction of programmed cell death protein 1 (PD-1) and its ligand PD-L1 are associated with good clinical responses in many malignancies. To investigate the therapeutic potential of targeting the PD-1/PD-L1 axis in CM, we analyzed the expression of PD-1 and PD-L1 and the density of various types of tumor infiltrating lymphocytes (TILs) in primary CM (n = 27), using immunofluorescence staining. Results were compared with clinical parameters and outcome. Flow cytometry was exploited to determine the PD-L1 and PD-1 protein expression in conjunctival and cutaneous melanoma cell lines. PD-L1 expression was identified on tumor cells in five (19%) primary CM and on stromal cells (mainly CD68+CD163+ M2 macrophages) in 16 (59%) cases. PD-L1 expression on tumor cells was associated with the presence of distant metastases and a worse melanoma-related survival. PD 1 expression was seen in 17 (63%) cases, all of which were T2 stage tumors. Small tumors had a higher density of TILs than large tumors. The density of TILs was not correlated with survival, tumoral/stromal PD-L1 or PD-1 expression. In vitro results showed that most CM and cutaneous melanoma cell lines do not constitutively express PD-L1. However, expression could be upregulated after interferon gamma stimulation. Our findings suggest that blocking the PD-1/PD-L1 axis should be evaluated as a treatment for CM. PMID- 28903379 TI - Extracorporeal shock wave treatment attenuated left ventricular dysfunction and remodeling in mini-pig with cardiorenal syndrome. AB - This study tested the hypothesis that extracorporeal shock wave (ECSW) treatment can improve ischemia-induced left ventricular (LV) dysfunction in mini-pig with co-existing chronic kidney disease (CKD). LV ischemia in mini-pigs was induced by applying an ameroid constrictor over mid-left anterior descending artery (LAD), while model of CKD was established by right nephrectomy with partial ligation of left renal arterioles 2 weeks before LAD constriction. Thirty mini-pigs were randomly divided into group 1 (sham-control), group 2 (LV-ischemia), group 3 (LV ischemia + CKD), Group 4 [LV-ischemia + ECSW (applied 1200 shots at 0.1 mJ/m2/equally to 4-ischemic regions by day-90 after LAD constriction], and group 5 (LV-ischemia-CKD + ECSW). By day-180 after CKD induction, echocardiography showed that LV ejection fraction (LVEF) was highest in group 1, lowest in group 3, significantly lower in group 2 than that in groups 4 and 5, and significantly lower in group 5 than that in group 4, whereas LV-end systolic and diastolic dimensions displayed an opposite pattern (all p<0.001). Protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (cleaved-caspase 3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-beta/Smad3), pressure/volume overload (BNP/beta-MHC), endothelial (CD31/vWF) and mitochondrial-integrity (PGC 1/mitochondrial-cytochrome-C) biomarkers exhibited a pattern identical to that of LVEF, whereas angiogenesis factors (VEGF/CXCR4/SDF-1alpha) showed significant progressive increase among all groups (all p<0.0001). Microscopic findings of CD31+cells/vWF+cells/small-vessel density/sarcomere-length showed an identical pattern, whereas collagen-deposition area/fibrotic area/apoptotic nuclei expressed an opposite pattern compared to that of LVEF among all groups (all p<0.0001). In conclusion, CKD aggravated ischemia-induced LV dysfunction and remodeling and molecular-cellular perturbations that were reversed by ECSW treatment. PMID- 28903380 TI - Mex3a expression and survival analysis of bladder urothelial carcinoma. AB - OBJECTIVE: Bladder urothelial carcinoma is a common tumor in humans and a multifactorial disease. The gene mex3a is associated with tumor formation and may promote cell proliferation and migration. Therefore, this study aimed to determine the relationship between mex3a and bladder urothelial carcinoma. METHODS: The clinical and RNA sequencing expression data in patients with bladder urothelial carcinoma were downloaded from the The Cancer Genome Atlas data portal. A total of 412 bladder urothelial carcinoma samples were available in the database, for which the clinical information was acquired, of which 412 are RNA sequencing samples with a total of 19 paired samples. Univariate and multivariate Cox analyses and univariate logistic regression analysis were conducted using the software SPSS version 22.0 and P<0.05 was considered statistically significant. RESULTS: The results of the independent t-test of 19 paired samples indicated that the expression level of mex3a was significantly higher in tumor tissues compared with adjacent normal tissues. Mex3a expression as a categorical dependent variable was not associated with overall survival, and the overall survival of bladder urothelial carcinoma was associated with the group of age, cancer status, lymphatic vascular invasion, pathological stage, pathological size, and pathological lymph metastasis. The multivariable Cox model adjusted for the group of mex3a expression level, age, gender, tumor status, and pathological stage showed that only the age and cancer status groups were associated with the overall survival. CONCLUSION: Mex3a expression was not a poor prognostic factor of bladder urothelial carcinoma. Moreover, the expression levels of mex3a in the papillary type of bladder urothelial carcinoma were higher than those of the non papillary type. PMID- 28903381 TI - Tumor location impacts immune response in mouse models of colon cancer. AB - Existing preclinical models of human colorectal cancer (CRC) that rely on syngeneic subcutaneous grafts are problematic, because of increasing evidence that the immune microenvironment in subcutaneous tissue is significantly different from the gastrointestinal tract. Similarly, existing orthotopic models that use a laparotomy for establishing grafts are also problematic, because the surgical procedure results in extensive inflammation, thereby creating a nonphysiologic tumor microenvironment. To facilitate the bench-to-bedside translation of CRC immunotherapy strategies, we developed a novel orthotopic model in mice that uses endoscopy-guided microinjection of syngeneic cancer cells. When we compared immune system infiltration, we found that tumors in the subcutaneous model had fewer T cells, B cells, and natural killer (NK) cells, but more immunosuppressive myeloid cells; in contrast, tumors in our orthotopic model had a higher number of tumor-infiltrating T cells, B cells, and NK cells, with fewer immunosuppressive myeloid cells. The number of immune-stimulating cytokines, such as interleukin (IL)-2, IL-6, interferon (IFN)-gamma, and granzyme B, was also higher in tumors in our model, as compared with the subcutaneous model. Those differences resulted in heightened sensitivity to immune checkpoint blockade therapy in our endoscopy-guided orthotopic CRC model. Our study indicates that tumor location affects immune response in CRC mouse models; choosing the appropriate preclinical model is important when testing immunotherapy in CRC. PMID- 28903382 TI - MicroRNA16 regulates glioma cell proliferation, apoptosis and invasion by targeting Wip1-ATM-p53 feedback loop. AB - The present study aimed to investigate the role and underlying mechanisms of microRNA16 (miR-16) on proliferation, apoptosis and invasion of glioma cells. The cell models of miR-16 upregulation and Negative control group (NC group) were built. The cell functions of different groups were detected by colony formation assay, transwell chamber assay, proliferation, apoptosis and cycle experiments. The intracranial orthotopic transplantation animal models were built to different groups: miR-16 agomir group, miR-16 antagomir group and their NC group. The expressions of miR-16, Wip1, ATM and p53 were measured by qRT-PCR, western blot and immunohistochemistry. As a result, miR-16 overexpressed groups had lower cloning formation rate and proliferation rate, less invasive cells, higher early apoptosis rate than the control groups. G1 phase was significantly smaller compared miR-16 overexpressed groups with the control groups, and S phase significantly lesser. Cell growth was retardated. Differences were statistically significant (P <0.05). Compared with miR-16 overexpressed groups and NC groups, the Wip1 gene and protein expression were downregulated, while ATM and p53 genes, p-ATM and p-p53 proteins were upregulated. The differences were statistically significant (P <0.05). Taken together, our findings demonstrated that miR-16 suppressed glioma cell proliferation and invasion, promoted apoptosis and inhibited cell cycle by targeting Wip1-ATM-p53 signaling pathway. PMID- 28903383 TI - Association between ABO blood types and sporadic pancreatic neuroendocrine tumors in the Chinese Han population. AB - BACKGROUND: Although the relationship between non-O blood types and the risk of exocrine pancreatic cancer has been demonstrated, the association between ABO blood types and sporadic pancreatic neuroendocrine tumor (PNET) has not been reported thus far. METHODS: This hospital-based, case-control study included 387 patients with PNET and 542 age- and sex-matched controls. Unconditional multivariable logistic regression analysis was performed to estimate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs). The relationship between ABO blood types and clinicopathologic features was also analyzed. RESULTS: After adjusting for age, sex, smoking status, alcohol drinking, and first-degree family history of any cancer, the AORs (95% CI) of functional PNET were 0.87 (0.59-1.28) for blood type A, 0.86 (0.58-1.28) for blood type B, and 0.71 (0.39-1.26) for blood type AB compared with subjects with blood type O. A similar ABO blood-type distribution was observed among cases with non-functional PNETs compared with controls. On comparing blood type B with non-B blood type, cases with non functional PNETs had marginally higher rates of lymph node invasion (P = 0.047), distant metastasis (P = 0.044), and advanced European Neuroendocrine Tumor Society Stage (P = 0.040). CONCLUSIONS: There is no association between the ABO blood group and the development of functional and non-functional PNETs. The ABO blood types are not associated with the clinicopathologic features in patients with functional and non-functional PNETs. PMID- 28903384 TI - A novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasion. AB - SHARPIN (Shank-associated RH domain interacting protein) is the main component of the linear ubiquitin chain activation complex (LUBAC). SHARPIN is involved in regulating inflammation and cancer progression. However, whether SHARPIN plays an important role in lung cancer metastasis and the potential underlying mechanism are still unknown. Here, for the first time, we reported that SHARPIN expression is closely related to lung cancer progression. Moreover, SHARPIN plays a central role in controlling lung cancer cell metastasis. Mechanistic studies further revealed that PRMT5 (Protein arginine methyltransferase 5), responsible for catalyzing arginine methylation on histones, is a novel cofactor of SHARPIN. This finding provides the basis for further study of the crosstalk between protein ubiquitination and histone methylation. We further found that SHARPIN-PRMT5 is essential for the monomethylation of histones of chromatins at key metastasis related genes, defining a new mechanism regulating cancer invasion. A novel MLL complex (ASH2 and WDR5) was implied in the link between histone arginine2 monomethylation (H3R2me1) and histone lysine4 trimethylation (H3K4me3) for the activation of metastasis-related genes. These novel findings establish a new epigenetic paradigm in which SHARPIN-PRMT5 has distinct roles in orchestrating chromatin environments for cancer-related genes via integrating signaling between H3R2me1 and H3K4me3. PMID- 28903385 TI - DPP-4 enzyme deficiency protects kidney from acute ischemia-reperfusion injury: role for remote intermittent bowel ischemia-reperfusion preconditioning. AB - We analyzed the effects of acute ischemia-reperfusion (KIR) injury on the status of kidney function and architecture in dipeptidyl peptidase4-difficient (DPP4D) rats and the effect of remote small bowel ischemia-reperfusion (BIR) preconditioning. DPP4-deficient (DPP4D) and normal Fischer344 (F344) rats were divided into 6 groups: (1) sham-F344, (2) sham-DPP4D, (3) KIR-F344 (4) KIR-DPP4D, (5) DPP4D-KIR-extendin-9-39 and (6) BIR-KIR-F344. Blood creatinine and urea nitrogen levels and the urinary protein-to-creatinine ratio was higher in KIR F344 rats than BIR-KIR-F344 or KIR-DPP4D rats 72 h after acute KIR. Conversely, the circulating glucagon-like peptide 1 (GLP-1) levels were higher in BIR-KIR F344 and KIR-DPP4D than KIR-F344 rats after acute KIR. KIR-F344 rats showed greater inflammation, oxidative stress, apoptosis, DNA damage and kidney injury than other rat groups. Damage to the kidney architecture in KIR-F344 rats was greater than in BIR-KIR-F344 or KIR-DPP4D rats. Expression of antioxidant proteins and GLP-1 receptor was higher in kidneys from KIR-DPP4D and BIR-KIR-F344 than KIR-F344 rats, which suggests better intrinsic responses. We therefore suggest that elevated circulating GLP-1 levels due to DPP4 deficiency and BIR preconditioning protect kidney function and architecture during acute IR injury. PMID- 28903386 TI - Synergistic inhibition of colon cancer growth by the combination of methylglyoxal and silencing of glyoxalase I mediated by the STAT1 pathway. AB - Methylglyoxal (MG), an extremely reactive glucose metabolite, exhibits antitumor activity. Glyoxalase I (GLOI), which catalyzes MG metabolism, is associated with the progression of human malignancies. While the roles of MG or GLOI have been demonstrated in some types of cancer, their effects in colon cancer and the mechanisms underlying these effects remain largely unknown. For this study, MG and GLOI levels were manipulated in colon cancer cells and the effects on their viability, proliferation, apoptosis, migration, and invasion in vitro were quantified by Cell Counting Kit-8, colony formation assay, flow cytometry, and transwell assays. The expression levels of STAT1 pathway-associated proteins and mRNAs in these cells were quantified by western blot and qRT-PCR, respectively. The antitumor effects of MG and silencing of GLOI were investigated in vivo in a SW620 colon cancer xenograft model in BALB/c nude mice. Our findings demonstrate that MG in combination with silencing of GLOI synergistically inhibited the cancer cells' proliferation, colony formation, migration, and invasion and induced apoptosis in vitro compared with the controls. Furthermore, these treatments up-regulated STAT1 and Bax while down-regulating Bcl-2 in vitro. MG treatment alone or in combination with silencing of GLOI also reduced the growth of the SW620 tumors in mice by up-regulation of STAT1 and Bax and down-regulation of Bcl-2. Taken together, our findings suggest that MG in combination with silencing of GLOI merits further evaluation as a targeted therapeutic strategy for colon cancer. PMID- 28903387 TI - Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRalpha/AKT cascade restrains tuberous sclerosis complex-associated tumor development. AB - Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor alpha (PDGFRalpha) expression was mediated by mTORC1. Moreover, mTORC1 inhibited PDGFRalpha expression via suppression of forkhead box O3a (FOXO3a) mediated PDGFRalpha gene transcription. In addition, ectopic expression of PDGFRalpha promoted AKT activation and enhanced proliferation and tumorigenic capacity of Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), and vice versa. Most importantly, rapamycin in combination with AG1295, a PDGFR inhibitor, significantly inhibited growth of TSC1/TSC2 complex-deficient cells in vitro and in vivo. Therefore, downregulated FOXO3a/PDGFRalpha/AKT pathway exerts a protective effect against hyperactivated mTORC1-induced tumorigenesis caused by loss of TSC1/TSC2 complex, and the combination of rapamycin and AG1295 may be a new effective strategy for TSC-associated tumors treatment. PMID- 28903388 TI - Cancer-associated mutations in the canonical cleavage site do not influence CD99 shedding by the metalloprotease meprin beta but alter cell migration in vitro. AB - Transendothelial cell migration (TEM) is crucial for inflammation and metastasis. The adhesion molecule CD99 was shown to be important for correct immune cell extravasation and is highly expressed on certain cancer cells. Recently, we demonstrated that ectodomain shedding of CD99 by the metalloprotease meprin beta promotes TEM in vitro. In this study, we employed an acute inflammation model (air pouch/carrageenan) and found significantly less infiltrated cells in meprin beta knock-out animals validating the previously observed pro-inflammatory activity. To further analyze the impact of meprin beta on CD99 shedding with regard to cell adhesion and proliferation we characterized two lung cancer associated CD99 variants (D92H, D92Y), carrying point mutations at the main cleavage site. Interestingly, ectodomain shedding of these variants by meprin beta was still detectable. However the cleavage site shifted to adjacent positions. Nevertheless, expression of CD99 variants D92H and D92Y revealed partial misfolding and proteasomal degradation. A previously observed influence of CD99 on Src activation and increased proliferation could not be confirmed in this study, independent of wild-type CD99 or the variants D92H and D92Y. However, we identified meprin beta as a potent inducer of Src phosphorylation. Importantly, we found significantly increased cell migration when expressing the cancer-associated CD99 variant D92H compared to the wild-type protein. PMID- 28903389 TI - Epithelial HO-1/STAT3 affords the protection of subanesthetic isoflurane against zymosan-induced lung injury in mice. AB - Epithelial dysfunction is a key characteristic of acute lung injury (ALI). Isoflurane (ISO) confers lung protection via anti-inflammatory and anti-apoptotic properties. However, the specific role and potential mechanisms of subanesthetic ISO in lung epithelium protection during zymosan-induced ALI remain unclear. In this study, zymosan increased the expression and activity of beneficial heme oxygenase-1 (HO-1) and signal transducers and activators of transcription 3 (STAT3) in the lung and isolated type II alveolar epithelial cells (AECs-II) from wild-type (WT) mice, which was further enhanced by ISO treatment. ISO reduced the mortality, lung edema, histological changes and pulmonary cell apoptosis, and simultaneously decreased total cells, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in bronchoalveolar lavage fluid in the zymosan-stimulated WT mice but not in HO-1-deficient mice. Moreover, ISO abated zymosan-augmented lactate dehydrogenase activity, TNF-alpha and IL-1beta production, and apoptosis in WT AECs-II but not in HO-1- or STAT3-silenced cells. Mechanisticly, the epithelial protective effects of ISO on zymosan insult in vivo and in vitro were mediated by a positive feedback loop comprising STAT3 and HO-1. Pro-survival and anti-apoptosis by ISO was highly reliant on activated STAT3, involving in downstream Akt activation and reduced ratio of pro-apoptotic/anti apoptotic molecules. Overall, HO-1/STAT3 signaling is in favor of lung epithelial protection of ISO in zymosan-challenged mice, suggesting ISO as a valuable therapeutic agent for ALI. PMID- 28903390 TI - Association between the functional polymorphism Ile31Phe in the AURKA gene and susceptibility of hepatocellular carcinoma in chronic hepatitis B virus carriers. AB - Aurora kinase A (AURKA) is a serine threonine kinase which affects chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. Two functional nonsynonymous polymorphisms of the AURKA gene (Ile31Phe and Val57Ile) have been reported recently. We analyzed the association between the two polymorphisms and risk of the occurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Guangxi population consisting of 348 patients with HCC and 359 control subjects, and then validated the significant association in the Guangdong population consisting of 440 cases and 456 controls. All of the participants were of Chinese origin and HBV carriers. The two polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay or Sequenom MassARRAY iPLEX platform. In the Guangxi population, carriers of the AURKA 31Phe allele (Ile/Phe + Phe/Phe) were significantly associated with decreased susceptibility to HBV-related HCC when compared with noncarriers (Ile/Ile) (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.46-0.86, P = 3.4 * 10-3). On the contrary, no significant association was found between Val57Ile and HBV-related HCC occurrence. The association of Ile31Phe with HBV-related HCC occurrence was confirmed in the Guangdong population (OR = 0.64, 95% CI = 0.49-0.83, P = 8.0 * 10-4). The pooled analysis gave a joint P value of 5.5 * 10-6 (joint OR = 0.63, 95% CI = 0.52 0.77). Our findings suggest that AURKA Ile31Phe may play a role in mediating the susceptibility to HBV-related HCC among Chinese. PMID- 28903391 TI - Cancer/testis antigen PIWIL2 suppresses circadian rhythms by regulating the stability and activity of BMAL1 and CLOCK. AB - Circadian rhythms are regulated by transcriptional and post-translational feedback loops generated by appropriate functions of clock proteins. Rhythmic degradation of the circadian clock proteins is critical for maintenance of the circadian oscillations. Notably, circadian clock does not work during spermatogenesis and can be disrupted in tumors. However, the underlying mechanism that suppresses circadian rhythms in germ cells and cancer cells remains largely unknown. Here we report that the cancer/testis antigen PIWIL2 can repress circadian rhythms both in the testis and cancer cells. By facilitating SRC binding with PI3K, PIWIL2 activates the PI3K-AKT pathway to phosphorylate and deactivate GSK3beta, suppressing GSK3beta-induced phosphorylation and degradation of circadian protein BMAL1 and CLOCK. Meanwhile, PIWIL2 can bind with E-Box sequences associated with the BMAL1/CLOCK complex to negatively regulate the transcriptional activation activity of promoters of clock-controlled genes. Taken together, our results first described a function for the germline-specific protein PIWIL2 in regulation of the circadian clock, providing a molecular link between spermatogenesis as well as tumorigenesis to the dysfunction of circadian rhythms. PMID- 28903392 TI - A role for BRG1 in the regulation of genes required for development of the lymphatic system. AB - Lymphatic vasculature is an important part of the cardiovascular system with multiple functions, including regulation of the return of interstitial fluid (lymph) to the bloodstream, immune responses, and fat absorption. Consequently, lymphatic vasculature defects are involved in many pathological processes, including tumor metastasis and lymphedema. BRG1 is an important player in the developmental window when the lymphatic system is initiated. In the current study, we used tamoxifen inducible Rosa26CreERT2-BRG1floxed/floxed mice that allowed temporal analysis of the impact of BRG1 inactivation in the embryo. The BRG1floxed/floxed/Cre-TM embryos exhibited edema and hemorrhage at embryonic day 13 and began to die. BRG1 deficient embryos had abnormal lymphatic sac linings with fewer LYVE1 positive lymphatic endothelial cells. Indeed, loss of BRG1 attenuated expression of a subset of lymphatic genes in-vivo. Furthermore, BRG1 binds at the promoters of COUP-TFII and LYVE1, suggesting that BRG1 modulates expression of these genes in the developing embryos. Conversely, re-expression of BRG1 in cells lacking endogenous BRG1 resulted in induction of lymphatic gene expression in-vitro, suggesting that BRG1 was both required and sufficient for lymphatic gene expression. These studies provide important insights into intrinsic regulation of BRG1-mediated lymphatic-gene expression, and further an understanding of lymphatic gene dysregulation in lymphedema and other disease conditions. PMID- 28903393 TI - EB1 protein alteration characterizes sporadic but not ulcerative colitis associated colorectal cancer. AB - BACKGROUND: While carcinogenesis in Sporadic Colorectal Cancer (SCC) has been thoroughly studied, less is known about Ulcerative Colitis associated Colorectal Cancer (UCC). This study aimed to identify and validate differentially expressed proteins between clinical samples of SCC and UCC to elucidate new insights of UCC/SCC carcinogenesis and progression. RESULTS: Multiplex-fluorescence two dimensional gel electrophoresis (2-D DIGE) and mass spectrometry identified 67 proteoforms representing 43 distinct proteins. After analysis by Ingenuity Pathway Analysis(r) (IPA), subsequent Western blot validation proofed the differential expression of Heat shock 27 kDA protein 1 (HSPB1) and Microtubule associated protein R/EB family, member 1 (EB1) while the latter one showed also expression differences by immunohistochemistry. MATERIALS AND METHODS: Fresh frozen tissue of UCC (n = 10) matched with SCC (n = 10) was investigated. Proteins of cancerous intestinal mucosal cells were obtained by Laser Capture Microdissection (LCM) and compared by 2-D DIGE. Significant spots were identified by mass spectrometry. After IPA, three proteins [EB1, HSPB1, and Annexin 5 (ANXA5)] were chosen for further validation by Western blotting and tissue microarray-based immunohistochemistry. CONCLUSIONS: This study identified significant differences in protein expression of colorectal carcinoma cells from UCC patients compared to patients with SCC. Particularly, EB1 was validated in an independent clinical cohort. PMID- 28903394 TI - Melittin suppresses tumor progression by regulating tumor-associated macrophages in a Lewis lung carcinoma mouse model. AB - Tumor-associated macrophages (TAM) are a major component of tumor stroma. It has been reported that TAMs have M2-like phenotype and facilitate tumor progression by promoting angiogenesis and immunosuppression. Melittin, a major polypeptide of bee venom, has been widely studied as an anti-cancer drug due to its cytotoxicity to malignant cells. However, very little is known regarding the effect of melittin on immune cells in the tumor microenvironment. This study focuses on the effect of melittin on TAMs in a Lewis lung carcinoma mouse model. Melittin inhibited the rapid tumor growth compared to the control in vivo. Melittin increased the M1/M2 ratio of TAMs by selectively reducing the number of CD206+ M2 like TAMs while not altering the population of CD86+ M1-like TAMs. Melittin also preferentially binds to M2 macrophages, and this binding was not associated with phagocytosis. Gene and protein expression of vascular endothelial growth factor (Vegf) and mannose receptor C type 1 (Mrc1/CD206) was reduced in M2-like bone marrow-derived macrophages by melittin treatment, but there was no significant change in the gene level of Vegf and FMS-like tyrosine kinase 1 (Flt1/VEGFR1) in tumor cells in vitro. Additionally, the levels of VEGF and CD31, markers of angiogenesis, were significantly decreased by melittin treatment in tumor tissues. This study revealed a novel role for melittin in tumor treatment and suggested that melittin could be a promising therapeutic agent for targeting M2 like TAMs. PMID- 28903395 TI - TGF-beta2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone. AB - Although emerging studies have implicated that Aiopoietin-like 4 Protein (ANGPTL4) is related to the aggressiveness and metastasis of many tumors, the role of ANGPLT4 in giant cell tumor (GCT) of bone was rarely investigated. The mechanism of ANGPLT4 in tumor-induced osteoclastogenesis still remains unclear. In this study, we first demonstrated that ANGPTL4 was highly expressed in GCT compared to normal tissues, while we showed that TGF-beta2 released by osteoclasts induced bone resorption could increase the expression of ANGPTL4 in GCTSCs. By using the luciferase reporter assay, we found that two downstreams of TGF-beta2, Smad3 and Smad4, could directly activate the promoter of ANGPTL4, which might explain the mechanism of TGF-beta2-induced ANGPLT4 expression. Moreover, knockout of ANGPTL4 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. By using the chick chorio allantoic membrane (CAM) models, we further showed that inhibition of ANGPTL4 suppressed tumor growth and giant cell formation in vivo. In addition, some new pathways involved in ANGPTL4 application were identified through microarray assay, which may partly explain the mechanism of ANGPTL4 in GCT. Taken together, our study for the first time identified the role of ANGPLT4 in GCT of bone, which may provide a new target for the diagnosis and treatment of GCT. PMID- 28903396 TI - IGFBP2 plays an important role in heat shock protein 27-mediated cancer progression and metastasis. AB - Heat shock protein 27 (Hsp27) is a key chaperone that interacts with over 200 client proteins. The expression of Hsp27 might be correlated with poor outcome in many types of cancer. Previous study indicated that Hsp27 might be an important biomarker in hepatocellular carcinoma (HCC). However, the detailed mechanism is less well understood. The shRNA-mediated silencing of Hsp27 decreased the proliferation, migration and invasion of HCC cells. In a xenograft model, the silencing of Hsp27 reduced tumor progression. We revealed that the silencing of Hsp27 led to a reduction in insulin-like growth factor binding protein 2 (IGFBP2), which might mediate proliferation and metastasis through vimentin, snail and beta-catenin. The overexpression of IGFBP2 reversed the reductions in cell growth, migration and invasion. The tissue array results showed that HCC patients with high Hsp27 expression exhibited poor prognosis and increased metastasis. The Hsp27 expression was highly correlated with IGFPB2 in CRC specimen. ChIP and luciferase assays showed that Hsp27 does not directly bind the IGFBP2 promoter region to regulate the transcription of IGFBP2. In conclusion, our study demonstrated that Hsp27 is a key mediator of HCC progression and metastasis and that Hsp27 might regulate proliferation and metastasis through IGFBP2. This pathway might provide a new direction for the development of a novel therapeutic strategy for HCC. PMID- 28903397 TI - DlgR2 knockdown boosts dendritic cell activity and inhibits hepatocellular carcinoma tumor in-situ growth. AB - Tumor-specific hepatic stellate cells (tHSCs) positively participate in human hepatocellular carcinoma (HCC) tumorigenesis and progression. Our previous studies have shown that tHSCs co-culture with dendritic cells (DCs) induced DIgR2 (dendritic cell-derived immunoglobulin receptor 2) expression. The latter is a member of IgSF inhibitory receptor suppressing DCs-initiated antigen-specific T cell responses. In the current study, we show that hepatic artery injection of DlgR2 siRNA significantly inhibited in-situ HCC xenograft growth in rat livers. Further, 5-FU-medied inhibition of in-situ HCC growth was dramatically sensitized with DlgR2 silence. DlgR2 siRNA injection indeed downregulated DlgR2 in ex-vivo cultured tumor-derived DCs (tDCs). More importantly, tDCs activity was boosted following DlgR2 siRNA. These cells presented with upregulated CD80, CD86 and MHC II. Production of interleukin-12 and tumor necrosis factor-alpha was also increased in the DlgR2-silenced tDCs. We propose that DlgR2 knockdown likely boosts the activity of tumor-associated DCs, and inhibits growth of in-situ HCC xenografts. PMID- 28903398 TI - New perspectives of cobalt tris(bipyridine) system: anti-cancer effect and its collateral sensitivity towards multidrug-resistant (MDR) cancers. AB - Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1-6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo. The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies. PMID- 28903399 TI - Phosphatidylcholine-specific phospholipase C inhibition reduces HER2 overexpression, cell proliferation and in vivo tumor growth in a highly tumorigenic ovarian cancer model. AB - Antagonizing the oncogenic effects of human epidermal growth factor receptor 2 (HER2) with current anti-HER2 agents has not yet yielded major progress in the treatment of advanced HER2-positive epithelial ovarian cancer (EOC). Using preclinical models to explore alternative molecular mechanisms affecting HER2 overexpression and oncogenicity may lead to new strategies for EOC patient treatment. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) exerts a pivotal role in regulating HER2 overexpression in breast cancer cells. The present study, conducted on two human HER2-overexpressing EOC cell lines - SKOV3 and its in vivo-passaged SKOV3.ip cell variant characterized by enhanced in vivo tumorigenicity - and on SKOV3.ip xenografts implanted in SCID mice, showed: a) about 2-fold higher PC-PLC and HER2 protein expression levels in SKOV3.ip compared to SKOV3 cells; b) physical association of PC-PLC with HER2 in non-raft domains; c) HER2 internalization and ca. 50% reduction of HER2 mRNA and protein expression levels in SKOV3.ip cells exposed to the PC-PLC inhibitor tricyclodecan-9-yl-potassium xanthate (D609); d) differential effects of D609 and trastuzumab on HER2 protein expression and cell proliferation; e) decreased in vivo tumor growth in SKOV3.ip xenografts during in vivo treatment with D609; f) potential use of in vivo magnetic resonance spectroscopy (MRS) and imaging (MRI) parameters as biomarkers of EOC response to PC-PLC inhibition. Overall, these findings support the view that PC-PLC inhibition may represent an effective means to target the tumorigenic effects of HER2 overexpression in EOC and that in vivo MR approaches can efficiently monitor its effects. PMID- 28903400 TI - Hyperglycemia and advanced glycation end products (AGEs) suppress the differentiation of 3T3-L1 preadipocytes. AB - Aging is characterized by mild hyperglycemia and accumulation of advanced glycation end products (AGEs). Effects of chronic exposure to hyperglycemia or AGEs on the adipogenic differentiation of 3T3-L1 preadipocytes remain unclear. We examined the chronic effect of AGEs and high glucose on the differentiation of 3T3-L1 cells by culturing 3T3-L1 cells in the presence of AGEs or 25 mM glucose for 1 month. Chronic incubation of 3T3-L1 cells with AGEs or high glucose blocked their differentiation into mature adipocytes as evidenced by reduced levels of adipocyte markers such as accumulated oil droplets, GPDH, aP2, adiponectin and of adipogenesis regulators PPARgamma and C/EBPalpha. Levels or activities of Src, PDK1, Akt, and NF-kappaB were higher in AGEs- and high glucose-treated cells than those in 3T3-L1 cells. Levels of Bcl-2 were elevated in AGEs- and high glucose treated cells, and were attenuated by inhibitors of PI3-kinase, Akt and NF kappaB. Moreover, adipogenesis was attenuated in 3T3-L1 cells stably expressing Bcl-2 or YAP. These results suggest that chronic AGEs and high glucose treatments up-regulate Bcl-2 and YAP via the Akt-NF-kappaB pathway and impair adipogenesis. PMID- 28903401 TI - 7-deacetylgedunin suppresses inflammatory responses through activation of Keap1/Nrf2/HO-1 signaling. AB - Macrophages play a critical role in a variety of inflammatory diseases. Activation of Keap1/Nrf2/HO-1 signaling results in inactivation of macrophages and amelioration of inflammatory and autoimmune conditions. Hence, discovery for the activators of Keap1/Nrf2/HO-1 signaling has become a promising strategy for treatment inflammatory diseases. In the current study, the anti-inflammatory potential of 7-deacetylgedunin (7-DGD), a limonin chemical isolated from the fruits of Toona sinensis (A. Juss.) Roem, was intensively examined in vivo and in vitro for the first time. Results showed that 7-DGD alleviated mice mortality induced by LPS. Mechanistic study showed that 7-DGD suppressed macrophage proliferation via induction of cell arrest at the G0/G1 phase. Furthermore, 7-DGD inhibited iNOS expression, which is correlated with the increases of NQO1, HO-1 and UGT1A1 mRNA expression as well as HO-1 protein expression level in the cells. More importantly, 7-DGD markedly decreased Keap1 expression, promoted p62 expression, and facilitated Nrf2 translocation and localization in the nucleus of macrophages, and in turn up-regulates these anti-oxidant enzymes expression, eventually mediated anti-inflammatory effect. Collectively, 7-DGD suppresses inflammation in vivo and in vitro, indicating that the compound is valuable for further investigation as an anti-inflammatory agent in future. PMID- 28903402 TI - Impact of chronic methamphetamine treatment on the atherosclerosis formation in ApoE-/- mice fed a high cholesterol diet. AB - BACKGROUND: We previously reported that methamphetamine could promote atherosclerosis (AS) in ApoE-/- mice fed normal chow. We herein observed the impact of methamphetamine on AS in ApoE-/- mice fed a high cholesterol diet and explored the potential mechanisms. RESULTS AND MATERIALS AND METHODS: Male ApoE-/ mice fed a high cholesterol diet were treated with saline (NS, n = 5) or methamphetamine [8 mg/kg/day (M8, n = 6) through intraperitoneal injection] for 24 weeks. Afterwards, the percentage area of atheromatous plaque in aortic root (44.31 +/- 3.21% vs. 32.91 +/- 3.58%, P < 0.01) and atherosclerotic lesion area on Oil red O stained en face aorta (32.74 +/- 6.97% vs. 18.72 +/- 3.65%, P < 0.01) were significantly higher in M8 group than in NS group. The percentages of Th1 cells and Th17 cells in spleen were significantly higher while the percentages of Th2 cells and CD4+CD25+Foxp3+ Tregs were significantly lower in M8 group than in NS group. mRNA expressions of TNF-alpha, IFN-gamma, and IL-17 were significantly up-regulated, IL-4, IL-10, Foxp3, and TGF-beta were significantly down-regulated in carotid artery and in spleen in M8 group compared to NS group. CONCLUSIONS: Chronic methamphetamine treatment can enhance atherosclerotic plaque formation possibly through promoting proinflammatory cytokine secretions in ApoE /- mice fed a high cholesterol diet. PMID- 28903403 TI - Cofilin-1 and phosphoglycerate kinase 1 as promising indicators for glioma radiosensibility and prognosis. AB - Glioma is a primary malignancy in central nervous system. Radiotherapy has been used as one of the standard treatments for glioma for decades. Since radioresistance can reduce the curative efficacy of radiotherapy in glioma, investigating the cause of radioresistance and predicting the tumour radiosensibility appeared particularly important. We previously reported that CFL1 and PGK1 are over-expressed in radioresistant U251 glioma cells. In this study, the level of CFL1 and PGK1 of 113 glioma tissues were measured by ELISA method. The relevance of the expression of these two proteins to radiosensibility was analyzed by mean test and multivariate logistic regression. The survival analysis was carried out in 85 irradiated patients and 105 followed-up patients respectively. The relationship between protein expression and clinical parameters was explored in overall 113 patients, and the correlation between CFL1 and PGK1 were determined as well. Our results showed that the expression of CFL1 and PGK1 were significantly higher (P < 0.001) in radioresistant patients than others. The multivariate Logistic regression demonstrated that the expression of CFL1 (p < 0.001) and PGK1 (p < 0.001) were associated with radioresistance in glioma. The multivariate Cox regression in overall survival suggested that CFL1 level or PGK1 level could be the independent prognosis factor for poor prognosis in 113 glioma patients. In addition, CFL1 expression was positively correlated with PGK1 expression in glioma. The results suggested that as promising indicators, CFL1 and PGK1 could be used to evaluate glioma radiosensibility and prognosis. These two proteins could also be the potential therapeutic targets of glioma. PMID- 28903404 TI - Tumor-specific hepatic stellate cells (tHSCs) induces DIgR2 expression in dendritic cells to inhibit T cells. AB - Tumor-specific hepatic stellate cells (tHSCs) contributes to tumorigenesis and progression of hepatocellular carcinoma (HCC). The potential function of tHSCs on dendritic cells (DCs) was studied here. We discovered that tHSCs co-culture induced upregulation of DIgR2 (dendritic cell-derived immunoglobulin receptor 2) in bone marrow-derived DCs (mDCs). Activation of MEK-ERK is required for DIgR2 expression in mDCs. MEK-ERK inhibitors or shRNA-mediated silence of MEK1/2 in mDCs inhibited tHSCs-induced DIgR2 expression. Meanwhile, tHSCs stimulation decreased production of multiple cytokines (CD80, CD86 and IL-12) in mDCs. Such an effect was almost reversed by DIgR2 shRNA in mDCs. Further, tHSCs-stimulated mDCs induced T-cell hypo-responsiveness, leading to decreased cytotoxic T lymphocyte (CTL) activity and reduced IFN-gamma production in splenic T cells. T cell proliferation inhibition and apoptosis were also noticed. These actions on T cells were again largely inhibited by DIgR2 shRNA in mDCs. Together, our results indicate that tHSCs directly induces DIgR2 expression in DCs to inhibit T cells. PMID- 28903405 TI - Uptake of PSMA-ligands in normal tissues is dependent on tumor load in patients with prostate cancer. AB - : Radioligand therapy (RLT) with Lu-177-labeled PSMA-ligands is a new therapy option for prostate cancer. Biodistribution in normal tissues is of interest for therapy planning. We evaluated if the biodistribution of Ga-68-PSMA-11 is influenced by tumor load. RESULTS: In patients with high tumor load, SUVmean was reduced to 61.5% in the lacrimal glands, to 56.6% in the parotid glands, to 63.7% in the submandibular glands, to 61.3% in the sublingual glands and to 55.4% in the kidneys (p < 0.001). Further significant differences were observed for brain, mediastinum, liver, spleen and muscle. Total tracer retention was higher in patients with high tumor load (p < 0.05). SUV in lacrimal, salivary glands and kidneys correlated negatively with PSA. MATERIALS AND METHODS: 135 patients were retrospectively evaluated. SUV was measured in the lacrimal and salivary glands, brain, heart, liver, spleen, kidneys, muscle and bone. SUV was correlated with visual tumor load, total tracer retention and PSA. CONCLUSIONS: Patients with high tumor load show a significant reduction of tracer uptake in dose-limiting organs. As similar effects might occur when performing RLT using Lu-177-labeled PSMA-ligands, individual adaptations of therapy protocols based on diagnostic PSMA PET imaging before therapy might help to further increase efficacy and safety of RLT. PMID- 28903406 TI - Presence of Salmonella AvrA in colorectal tumor and its precursor lesions in mouse intestine and human specimens. AB - Evidence directly supporting an association between Salmonella infection and colorectal cancer in human subjects is sparse. It has been well recognized that Salmonella infection increases the risk of gallbladder cancer. AvrA, a bacterial protein from Salmonella enterica, plays a crucial role in establishing chronic infection. To our knowledge, the presence of the bacterial AvrA has never been studied in human samples. Here, we demonstrated the presence and cellular localization of AvrA in inflamed, colorectal tumor and its precursor lesions, using both animal experimental infection models and human clinical specimens. We performed a newly developed AvrA serological assay and to determine the presence of anti-Salmonella AvrA antibody in chronic infected mouse serum samples. Further, we tested the presence of AvrA gene in healthy human fecal samples, in order to advance etiological studies of Salmonella AvrA in human population. Our study suggests a potential role of this bacterial protein in human colorectal cancer. Moreover, our new serological assay may serve a useful tool to identify individuals at increased risk for colorectal cancer. PMID- 28903408 TI - Derlin-1 is a target to improve radiotherapy effect of esophageal squamous cell carcinoma. AB - Radiotherapy is widely used for treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the role of Derlin-1 on the sensitivity of ESCC to radiotherapy and its underlying mechanism. We examined the clinical significance of Derlin-1 in 125 ESCC tissues. We found that Derlin-1 protein was higher in ESCC tissues than that in normal esophageal epithelial tissues. Derlin 1 overexpression was correlated with chemoradiotherapy resistance in ESCC patients and served an independent predictor for short overall survival. siRNA knockdown and plasmid transfection were carried out in ESCC cell lines. Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth. Derlin-1 overexpression in Eca-109 cells dramatically enhanced its resistance to radiotherapy with decreased apoptosis rate. On the contrary, Derlin-1 depletion in TE-1 cell line showed the opposite effects. In addition, radioresistance conferred by Derlin-1 was attributed to its role of activating AKT/Bcl-2 signaling pathway and reducing caspase3 cleavage. Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance. Furthermore, Derlin-1 could interact with PI3K p110alpha in ESCC cell lines. Taken together, Our data demonstrate that Derlin-1 overexpression predicts poor prognosis and protects ESCC from irradiation induced apoptosis through PI3K/AKT/Bcl-2 signaling pathway. Derlin-1 may serve as a novel predictor for radiosentivity and a molecular target for ESCC. PMID- 28903407 TI - miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression. AB - RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3'-untranslated regions of PLCgamma1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa. PMID- 28903409 TI - Acetyl-lupeolic acid inhibits Akt signaling and induces apoptosis in chemoresistant prostate cancer cells in vitro and in vivo. AB - The triterpenoid acetyl-lupeolic acid (ac-LA) isolated from the oleogum resin of Boswellia carterii reduced the viability of a panel of cancer cell lines more efficiently than lupeol. There was no detectable intracellular conversion of ac LA to lupeol and vice versa. In contrast to docetaxel, ac-LA did not induce selection of treatment-resistant cancer cells. By various parameters including DNA fragmentation, ac-LA was shown to induce apoptosis in androgen-independent PC 3 cells, whereas in MDA-MB-231 breast cancer cells, ac-LA led to cell accumulation in the G2/M phase of the cell cycle, but not to apoptosis. In silico docking combined with in vitro kinase assays implied that ac LA potently inhibits Akt mainly by direct binding to the pleckstrin homology domain. Consistently, an Akt1 mutant deficient of the PH domain afforded partial resistance to ac-LA and complete resistance to lupeol and the Akt inhibitor III. Ac-LA inhibited phosphorylation of downstream targets of the Akt signaling pathway, which was followed by inhibition of the mTOR target p70 ribosomal six protein kinase and the nuclear accumulation of p65/NF-kappaB, beta-catenin, and c-myc, as well as loss of the mitochondrial membrane potential. Ac-LA exhibited antiproliferative, proapoptotic, and antitumorigenic effects on PC-3-tumors xenografted either on chick chorioallantoic membranes or in nude mice. Ac-LA exhibited a clearly better safety profile than docetaxel or lupeol during chronic administration in vivo. In contrast to lupeol, ac-LA also inhibited release of vascular endothelial growth factor in vitro and accordingly angiogenesis in vivo. Thus, ac-LA deserves further exploration as a potential new antitumor compound. PMID- 28903410 TI - RASSF6 downregulation promotes the epithelial-mesenchymal transition and predicts poor prognosis in colorectal cancer. AB - Distant metastasis is the primary barrier for the successful treatment of patients with colorectal cancer, and thus, searching for new therapeutic targets by further exploring the molecular mechanisms of colorectal cancer metastasis is important. In this study, we investigated the biological and clinical significance of RASSF6 in colorectal cancer as well as the underlying molecular mechanisms. We found that low RASSF6 expression corresponds to a poor prognosis in colorectal cancer patients, and low RASSF6 expression is distinctly associated with tumour progression. Our in vitro analysis revealed that RASSF6 suppresses the proliferation and metastasis of DLD1 cells, and RASSF6 knockdown in HCT116 cells confirmed these observations. Our mechanistic investigation revealed that RASSF6 inhibits the expression of the classical target genes of Wnt signalling, as demonstrated by the reduced expression of TCF1, c-Jun, and c-Myc in RASSF6 overexpressing DLD1 stable cell lines. Furthermore, we show that RASSF6 functions as a negative regulator of the epithelial-mesenchymal transition; the expression levels of the epithelial markers ZO-1 and E-cadherin were increased, while the expression level of the mesenchymal marker Snail was decreased in a RASSF6 overexpressing DLD1 cell line. Additionally, rescue assays revealed that the activation of Wnt signalling by LiCl treatment impaired the inhibitory effect of RASSF6 on the proliferation and metastasis of colorectal cancer cells, which implies that RASSF6 suppresses the tumorigenicity of colorectal cancer cells at least in part through inhibiting Wnt signalling pathway. Collectively, these findings provide new perspectives for the future study of RASSF6 as a therapeutic target for colorectal cancer. PMID- 28903411 TI - Efficacy and safety of Re-Du-Ning injection in the treatment of seasonal influenza: results from a randomized, double-blinded, multicenter, oseltamivir controlled trial. AB - OBJECTIVE: To assess the efficacy and safety of RDNI in the treatment of seasonal influenza. RESULTS: 1575 participants were screened and 229 completed the study and had a RT-PCR laboratory confirmation of influenza virus infection. Fever alleviation time was 2 and 6 hours, and fever clearance time was 27 and 47 in RDNI and oseltamivir, with significant difference between two groups. Total scores of influenza symptoms descended more in RDNI than oseltamivir on day 2 and day 3. Single symptom such as fever, aversion to cold, sore throat and nasal obstruction score descended more in RDNI than oseltamivir on different days. 20 subjects used aspirin during the trial, and there was no significant difference between two groups. MATERIALS AND METHODS: We conducted a randomized, double blind, double-dummy, oseltamivir controlled clinical trial. Patients with a positive influenza rapid test diagnosis were enrolled and randomized to receive RDNI or oseltamivir. Primary outcome was the median fever alleviation and clearance time. Secondary outcomes were total 8 influenza symptom scores, the single influenza symptom score, and the frequency of aspirin usage. CONCLUSIONS: The effect of RDNI was not worse than oseltamivir on the alleviation of influenza symptoms. RDNI was well tolerated, with no serious adverse events noted during the study period. PMID- 28903412 TI - Acute atorvastatin treatment restores the cardioprotective effects of ischemic postconditioning in hyperlipidemic rats. AB - BACKGROUND: Ischemic Postconditioning (IPC) reduces ischemia/reperfusion (I/R) injury under normal conditions. HMG-CoA reductase inhibitors (statins), which inhibit the synthesis of mevalonate, can interfere with the cardioprotective effect of IPC. However, the beneficial role of IPC in hyperlipidemic patients, post-acute administration of statins remains unknown. This study was to determine if acute administration of atorvastatin affect the infarct size-limiting effect of IPC in hyperlipidemic rats. RESULTS: Compared to control group, infarct size decreased more significantly in atorvastatin+IPC and atorvastatin+IPC+wortmannin groups than IPC or atorvastatin+IPC+PD98059 groups. Phosphorylation of PI3K/Akt was attenuated in atorvastatin + IPC+ wortmannin group, phosphorylation of P42 MAPK/ERK was increased in atorvastatin+IPC and atorvastatin+IPC+wortmannin groups. MATERIALS AND METHODS: Ninety four-weeks old male SD rats fed with cholesterol enriched diet for six weeks were randomized into nine groups (n = 10/group) - sham group, control group, IPC group, atorvastatin group, wortmannin group, PD98059 group, atorvastatin+IPC group, atorvastatin+IPC+wortmannin group and atorvastatin+IPC+PD98059 group. Atorvastatin was administered orally 12 hours before myocardial reperfusion. CONCLUSIONS: Post-translational activation of P42 MAPK/ERK, rather than PI3K/Akt, participates in the net protective effect of IPC and atorvastatin in hyperlipidemia. PMID- 28903413 TI - A novel heterozygous germline deletion in MSH2 gene in a five generation Chinese family with Lynch syndrome. AB - Lynch syndrome (LS) is one of the most common familial forms of colorectal cancer predisposing syndrome with an autosomal dominant mode of inheritance. LS is caused by the germline mutations in DNA mismatch repair (MMR) genes including MSH2, MLH1, MSH6 and PMS2. Clinically, LS is characterized by high incidence of early-onset colorectal cancer as well as endometrial, small intestinal and urinary tract cancers, usually occur in the third to fourth decade of the life. Here we describe a five generation Chinese family with LS clinically diagnosed according to the Amsterdam II criteria. Immuno-histochemical staining of MSH2 and MSH6 shows only foci nuclear positive on the surface of the tumor with strong expression of MLH1 and PMS2 with diffuse immunoreactivity. In order to dig into the molecular basis of this LS pedigree, we collected the proband's blood sample, extracted the genomic DNA and applied the genetic screening. As a result, we identified a novel heterozygous deletion in MSH2 gene by targeted next generation sequencing, which is also proved to be co-segregated among other affected family members by following validation. To our knowledge, this novel heterozygous deletion (c.1676_1679 delTAAA) in MSH2 gene causes frameshift mutation (p.Asn560Lysfs*29) and leads to the formation of a truncated MSH2 protein which is confirmed to be a deleterious mutation according to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG). Identification of novel DNA mismatch repair (MMR) gene mutations can definitely benefit to the clinical diagnosis and management. PMID- 28903414 TI - Micro-HCCs in rats with liver cirrhosis: paradoxical targeting effects with vascular disrupting agent CA4P. AB - We sought to investigate anticancer efficacy of a vascular disrupting agent (VDA) combretastatin A-4 phosphate (CA4P) in relation to tumor size among hepatocellular carcinomas (HCCs) in rats using magnetic resonance imaging (MRI) and postmortem techniques. Nineteen rats with 43 chemically-induced HCCs of 2.8 20.9 mm in size on liver cirrhosis received CA4P intravenously at 10 mg/kg. Tumor diameter was measured by T2-weighted imaging (T2WI) to define microcancers (< 5 mm) versus larger HCCs. Vascular responses and tissue necrosis were detected by diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (CE-T1WI) and dynamic contrast enhanced (DCE-) MRI, which were validated by microangiography and histopathology. MRI revealed nearly complete necrosis in 5 out of 7 micro-HCCs, but diverse therapeutic necrosis in larger HCCs with a positive correlation with tumor size. Necrosis in micro-HCCs was 36.9% more than that in larger HCCs. While increased diffusion coefficient (ADCdiff) suggested tumor necrosis, perfusion coefficient (ADCperf) indicated sharply decreased blood perfusion in cirrhotic liver together with a reduction in micro-HCCs. DCE revealed lowered tumor blood flow from intravascular into extravascular extracellular space (EES). Microangiography and histopathology revealed hypo- and hypervascularity in 4 and 3 micro-HCCs, massive, partial and minor degrees of tumoral necrosis in 5, 1 and 1 micro-HCCs respectively, and patchy necrotic foci in cirrhotic liver. CD34-PAS staining implicated that poorly vascularized micro HCCs growing on liver cirrhosis tended to respond better to CA4P treatment. In this study, more complete CA4P-response occurred unexpectedly in micro-HCCs in rats, along with CA4P-induced necrotic foci in cirrhotic liver. These may help to plan clinical applications of VDAs in patients with HCCs and liver cirrhosis. PMID- 28903415 TI - A missense mutation in TCN2 is associated with decreased risk for congenital heart defects and may increase cellular uptake of vitamin B12 via Megalin. AB - Deregulation of folate and vitamin B12 (VB12) metabolism contributes to the risk of congenital heart defects (CHDs). Transcobalamin (TCN2) is essential for transporting VB12 from blood to cells as TCN2-bound VB12 (holo-TC) is the only form for somatic cellular uptake. In this study, we performed an association study between common polymorphisms in 46 one carbon metabolism genes and CHD in 412 CHDs and 213 controls. Only two significant association signals in coding regions were identified: FTCD c.1470C>T & TCN2 c.230A>T. The only missense mutation, TCN2 c.230A>T, was further validated in 412 CHDs and 1177 controls. TCN2 c.230T is significantly associated with reduced CHD risk in North Chinese (odds ratio = 0.67, P = 4.62e-05), compared with the 230A allele. Interestingly, the mean level of plasma holo-TC in women with the TA genotype was 1.77-fold higher than that in women with the AA genotype. Further analysis suggested that c.230A>T enhanced the cellular uptake of holo-TC via the LRP2 receptor. Our results determined that a functional polymorphism in TCN2 contributes to the prevalence of CHDs. TCN2 c.230A>T is significantly associated with a reduced CHD risk, likely due to TCN2 c.230T improving the interaction between holo-TC and its LRP2 receptor. PMID- 28903416 TI - Overriding TKI resistance of renal cell carcinoma by combination therapy with IL 6 receptor blockade. AB - Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFkappaB, HIF-2alpha and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis. Our findings suggest that a combination therapy of IL 6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment. PMID- 28903417 TI - Disruption of DNA repair in cancer cells by ubiquitination of a destabilising dimerization domain of nucleotide excision repair protein ERCC1. AB - DNA repair pathways present in all cells serve to preserve genome stability, but in cancer cells they also act reduce the efficacy of chemotherapy. The endonuclease ERCC1-XPF has an important role in the repair of DNA damage caused by a variety of chemotherapeutic agents and there has been intense interest in the use of ERCC1 as a predictive marker of therapeutic response in non-small cell lung carcinoma, squamous cell carcinoma and ovarian cancer. We have previously validated ERCC1 as a therapeutic target in melanoma, but all small molecule ERCC1 XPF inhibitors reported to date have lacked sufficient potency and specificity for clinical use. In an alternative approach to prevent the repair activity of ERCC1-XPF, we investigated the mechanism of ERCC1 ubiquitination and found that the key region was the C-terminal (HhH)2 domain which heterodimerizes with XPF. This ERCC1 region was modified by non-conventional lysine-independent, but proteasome-dependent polyubiquitination, involving Lys33 of ubiquitin and a linear ubiquitin chain. XPF was not polyubiquitinated and its expression was dependent on presence of ERCC1, but not vice versa. To our surprise we found that ERCC1 can also homodimerize through its C-terminal (HhH)2 domain. We exploited the ability of a peptide containing this C-terminal domain to destabilise both endogenous ERCC1 and XPF in human melanoma cells and fibroblasts, resulting in reductions of up to 85% in nucleotide excision repair and near two-fold increased sensitivity to DNA damaging agents. We suggest that the ERCC1 (HhH)2 domain could be used in an alternative strategy to treat cancer. PMID- 28903418 TI - Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection. AB - Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were "DNA methylation-sensitive" genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A. The other half were "DNA methylation-resistant" genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site. PMID- 28903419 TI - Development of zebrafish medulloblastoma-like PNET model by TALEN-mediated somatic gene inactivation. AB - Genetically engineered animal tumor models have traditionally been generated by the gain of single or multiple oncogenes or the loss of tumor suppressor genes; however, the development of live animal models has been difficult given that cancer phenotypes are generally induced by somatic mutation rather than by germline genetic inactivation. In this study, we developed somatically mutated tumor models using TALEN-mediated somatic gene inactivation of cdkn2a/b or rb1 tumor suppressor genes in zebrafish. One-cell stage injection of cdkn2a/b-TALEN mRNA resulted in malignant peripheral nerve sheath tumors with high frequency (about 39%) and early onset (about 35 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Injection of rb1-TALEN mRNA also led to the formation of brain tumors at high frequency (58%, 31 weeks of age) in F0 tp53e7/e7 mutant zebrafish. Analysis of each tumor induced by somatic inactivation showed that the targeted genes had bi-allelic mutations. Tumors induced by rb1 somatic inactivation were characterized as medulloblastoma-like primitive neuroectodermal tumors based on incidence location, histopathological features, and immunohistochemical tests. In addition, 3' mRNA Quanti-Seq analysis showed differential activation of genes involved in cell cycle, DNA replication, and protein synthesis; especially, genes involved in neuronal development were up-regulated. PMID- 28903420 TI - High expression of Ki-67 is an independent favorable prognostic factor for esophageal small cell carcinoma. AB - BACKGROUND: The prognostic value of Ki-67 expression in small cell carcinoma of the esophagus (SCCE) has not been explored in any previous studies. Therefore, we conducted this retrospective study to investigate the prognostic role of Ki-67 in SCCE for the first time. RESULTS: A total of 44 patients were included for analysis. The baseline clinicopathological data of these SCCE patients shared similar characteristics with previous studies. Ten patients were at stage I, 17 at stage II, and the remaining 17 were at stage III. Postoperatively, 23 patients received adjuvant therapy. Twenty-eight patients were found to have a high expression of Ki-67 (> 50%). After a median follow-up time of 54.8 months, the median survival time of those patients was 22.1 months. Early TNM stage, application of adjuvant therapy, and high expression of Ki-67 (Hazard Ratio = 0.314, 95% CI: 0.127-0.774; P = 0.012) were found to be favorable prognostic factors of patients with SCCE. In subgroup analysis, adjuvant therapy could only bring significant survival benefit for patients with high expression of Ki-67 (P = 0.008). MATERIALS AND METHODS: Patients undergoing esophagectomy with lymphadenectomy for SCCE from January 2009 to January 2015 in our department were retrospectively analyzed. Data for analysis included demographic data, pathologic findings, tumor stage, adjuvant therapy, and survival time as well as Ki-67 index. CONCLUSIONS: This study suggested that high expression of Ki-67 may not only serve as a favorable prognostic factor of SCCE but also an indication of providing adjuvant therapy for SCCE patients with surgical resection. PMID- 28903421 TI - Development and validation of a preoperative prediction model for colorectal cancer T-staging based on MDCT images and clinical information. AB - OBJECTIVES: This study aimed to establish and evaluate the efficacy of a prediction model for colorectal cancer T-staging. RESULTS: T-staging was positively correlated with the level of carcinoembryonic antigen (CEA), expression of carbohydrate antigen 19-9 (CA19-9), wall deformity, blurred outer edges, fat infiltration, infiltration into the surrounding tissue, tumor size and wall thickness. Age, location, enhancement rate and enhancement homogeneity were negatively correlated with T-staging. The predictive results of the model were consistent with the pathological gold standard, and the kappa value was 0.805. The total accuracy of staging improved from 51.04% to 86.98% with the proposed model. MATERIALS AND METHODS: The clinical, imaging and pathological data of 611 patients with colorectal cancer (419 patients in the training group and 192 patients in the validation group) were collected. A spearman correlation analysis was used to validate the relationship among these factors and pathological T staging. A prediction model was trained with the random forest algorithm. T staging of the patients in the validation group was predicted by both prediction model and traditional method. The consistency, accuracy, sensitivity, specificity and area under the curve (AUC) were used to compare the efficacy of the two methods. CONCLUSIONS: The newly established comprehensive model can improve the predictive efficiency of preoperative colorectal cancer T-staging. PMID- 28903422 TI - CDK4/6 inhibition is more active against the glioblastoma proneural subtype. AB - Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17~92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy. PMID- 28903423 TI - Mitochondria sustain store-operated currents in colon cancer cells but not in normal colonic cells: reversal by non-steroidal anti-inflammatory drugs. AB - Tumor cells undergo a critical remodeling of intracellular Ca2+ homeostasis that contribute to important cancer hallmarks. Store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway modulated by mitochondria, is dramatically enhanced in colon cancer cells. In addition, most cancer cells display the Warburg effect, a metabolic switch from mitochondrial metabolism to glycolysis that provides survival advantages. Accordingly, we investigated mitochondria control of store operated currents (SOCs) in two cell lines previously selected for representing human normal colonic cells and colon cancer cells. We found that, in normal cells, mitochondria are important for SOCs activity but they are unable to prevent current inactivation. In contrast, in colon cancer cells, mitochondria are dispensable for SOCs activation but are able to prevent the slow, Ca2+ dependent inactivation of SOCs. This effect is associated to increased ability of tumor cell mitochondria to take up Ca2+ due to increased mitochondrial potential (DeltaPsi) linked to the Warburg effect. Consistently with this view, selected non-steroidal anti-inflammatory drugs (NSAIDs) depolarize mitochondria, inhibit mitochondrial Ca2+ uptake and promote SOC inactivation, leading to inhibition of both SOCE and cancer cell proliferation. Thus, mitochondria sustain store operated currents in colon cancer cells but not in normal colonic cells and this effect is counteracted by selected NSAIDs providing a mechanism for cancer chemoprevention. PMID- 28903424 TI - Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient. AB - In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors. As suggested by other pieces of evidence, entrectinib - an orally available pan-TRK, ROS1 and ALK inhibitor - may have particular efficacy in patients with NTRK rearrangements. Therefore, screening for rearrangements involving NTRK genes may help identifying a subset of patients able to derive benefit from treatment with entrectinib or other targeted inhibitors. PMID- 28903425 TI - Pasireotide is more effective than octreotide, alone or combined with everolimus on human meningioma in vitro. AB - Pasireotide is a somatostatin analog (SSA) that targets somatostatin receptor subtype 1 (SST1), SST2, SST3, and SST5 with a high affinity. Pasireotide has a better antisecretory effect in acromegaly, Cushing's disease, and neuroendocrine tumors than octreotide. In this study, we compared the effects of pasireotide to those of octreotide in vitro on meningioma primary cell cultures, both alone and in combination with the mTOR inhibitor everolimus. Significant mRNA expression levels of SST1, SST2, and SST5 were observed in 40.5%, 100%, and 35% of meningioma samples, respectively. Pasireotide had a significantly stronger inhibitory effect on cell proliferation than octreotide. The effect of pasireotide, but not of octreotide, was significantly stronger in the group expressing the highest level of SST1 mRNA. Combined treatment with pasireotide and everolimus induced a higher reduction in cell viability than that with octreotide plus everolimus. Moreover, pasireotide decreased Akt phosphorylation and reversed everolimus-induced Akt hyperphosphorylation to a higher degree than octreotide. Using 4E-BP1 siRNA (si4E-BP), we demonstrated that 4E-BP1 protein silencing significantly reversed the response to everolimus, both alone and in combination with SSAs. Moreover, si4E-BP completely reversed the inhibition of cyclin D1 expression level and the increase in p27kip1 induced by SSAs, both alone and in combination with everolimus. Our results strongly support the need for further studies on the combination of pasireotide and everolimus in medical therapy for meningiomas. PMID- 28903426 TI - The prognostic implication of intraductal carcinoma of the prostate in metastatic castration-resistant prostate cancer and its potential predictive value in those treated with docetaxel or abiraterone as first-line therapy. AB - Intraductal carcinoma of the prostate (IDC-P) is recognized as a newly pathological entity in 2016 WHO classification. It's role in metastatic castration-resistant prostate cancer (CRPC) remains obscure. We aimed to explore the association of IDC-P with clinical outcome and to further identify its potential predictive role in making first-line treatment decisions for mCRPC. We retrospectively analyzed data of 131 mCRPC patients. IDC-P was diagnosed by re biopsy at the time of mCRPC. Among total patients, 45 and 41 received abiraterone or docetaxel as first-line therapies, respectively. PSA response, PSA progression free survival (PSA-PFS) and overall survival (OS) from mCRPC to death were analyzed using Kaplan-Meier curves, Log-rank test, Cox regression models and Harrell's C-index. The incidence of IDC-P in mCRPC reached 47.3%. IDC-P was not only related to rapid PSA progression, but also associated with a 20-month decrease in OS. Among IDC-P(-) patients, PSA response, PSA-PFS and OS were comparable in abiraterone-treated and docetaxel-treated groups. In contrast, among IDC-P(+) patients, PSA response rate is higher in abiraterone-treated group vs. docetaxel-treated group (52.4% vs. 21.7%; p = 0.035). Also, PSA-PFS and OS were much longer in the IDC-P(+) abiraterone-treated group vs. the docetaxel treated group (PSA-PFS: 13.5 vs.6.0 months, p = 0.012; OS: not reach vs.14.7 months, p = 0.128). Overall, IDC-P in mCRPC from re-biopsy was an independent prognosticator for clinical outcome. Abiraterone was observed having a better therapeutic efficacy than docetaxel as the first-line therapy in IDC-P(+) mCRPC patients. Thus, we suggest IDC-P should be considered as a novel predictive marker helping physicians making treatment decisions for mCRPC. PMID- 28903427 TI - Ginsenoside Rg1 attenuates adjuvant-induced arthritis in rats via modulation of PPAR-gamma/NF-kappaB signal pathway. AB - Ginsenoside Rg1, the main active compound in Panax ginseng, has already been shown to have anti-inflammatory effects. However, the protective effects of Rg1 on rheumatoid arthritis (RA) remain unclear. The aim of the present study was to investigate the effects and mechanisms of Rg1 on adjuvant-induced arthritis (AIA) in rats. AIA rats were given Rg1 at doses of 5, 10, and 20 mg/kg intraperitoneally for 14 days to observe the anti-arthritic effects. The results showed that Rg1 significantly alleviated joint swelling and injuries. Rg1 can also significantly reduce the level of TNF-alpha and IL-6, increase PPAR-gamma protein expression, inhibit IkappaBalpha phosphorylation and NF-kappaB nuclear translocation in the inflammatory joints of AIA rats and RAW264.7 cells stimulated by lipopolysaccharide (LPS). The results indicate that Rg1 has therapeutic effects on AIA rats, and the mechanism might be associated with its anti-inflammatory effects by up-regulating PPAR-gamma and subsequent inhibition of NF-kappaB signal pathway. PMID- 28903428 TI - Comparison of clinical utilities of the platelet count and platelet-lymphocyte ratio for predicting survival in patients with cervical cancer: a single institutional study and literature review. AB - OBJECTIVE: To compare the clinical utilities of the platelet count and platelet lymphocyte ratio (PLR) for predicting survival in patients with cervical cancer. RESULTS: Multivariate analyses demonstrated that thrombocytosis and elevated PLR were found to be independent prognostic factors for progression-free survival (PFS, P = 0.0077, P = 0.044) and overall survival (OS, P = 0.025, P = 0.019) in separate Multivariate analyses. In the ROC analysis, the platelet count showed a significantly greater area under the ROC curve (AUC) value than that of PLR for predicting patient recurrence (0.5941 versus 0.5331, p = 0.018) and survival (0.6139 versus 0.5468, p = 0.029). In patients without thrombocytosis, elevated PLR correlated with shorter survival (PFS, P = 0.041; OS, P = 0.017). In contrast, PLR in patients with thrombocytosis did not provide prognostic information. We divided patients into 3 prognostic groups using platelet counts and PLR: high-risk (thrombocytosis with any PLR); intermediate-risk (elevated PLR without thrombocytosis); low-risk (none of the above), which allowed for individualized and accurate survival estimates. MATERIALS AND METHODS: The baseline characteristics and clinical outcomes of cervical cancer patients were identified. Patients were grouped according to their pretreatment platelet counts or PLR, and clinicopathological characteristics and patient survival were then compared between these groups. The clinical utilities of the platelet count and PLR were compared using a time-dependent receiver operating characteristic (ROC) analysis. CONCLUSIONS: Pretreatment thrombocytosis and elevated PLR were identified as independent predictors in cervical cancer patients. Platelet counts were superior to PLR for predicting the prognosis of uterine cervical cancer patients. Our prognostic model consisting of platelet counts and PLR offers individualized survival estimates. PMID- 28903429 TI - Lenalidomide restores the osteogenic differentiation of bone marrow mesenchymal stem cells from multiple myeloma patients via deactivating Notch signaling pathway. AB - Multiple myeloma (MM) always presents osteolytic bone lesions, resulting from the abnormal osteoblastic and osteoclastic function in patients. MM patients exhibit the impairment of osteogenic differentiation of BMMSCs (bone marrow mesenchymal stem cells) and osteoblast deficiency. Effects of the drug, lenalidomide on the osteoblastic functions and the involved mechanisms remain unexplored. In the present study, it is observed that the osteogenic differentiation of BMMSCs from MM patients (MM-MSCs) is impaired and activation of Notch signaling pathway in MM MSCs is abnormal. Notch signaling activation inhibits BMMSCs osteogenesis. Knockdown of Notch1 expression and DAPT application reverse the osteogenic differentiation from MM-MSCs. Furthermore, it is shown that the gene expression of Notch signaling molecules, including receptors, ligands and downstream factors are significantly decreased in MM-MSCs following lenalidomide treatment, compared with non-treated MM-MSCs. Taken together, treatment with lenalidomide restores the osteogenic differentiation of MM-MSCs via deactivating Notch signaling pathway. PMID- 28903431 TI - Detection of specific Chlamydia pneumoniae and cytomegalovirus antigens in human carotid atherosclerotic plaque in a Chinese population. AB - To explore the relationship between certain pathogens, such as chlamydia pneumonia (Cpn) and cytomegalovirus (CMV), and carotid atherosclerosis (AS) in a Chinese population.Twenty-five carotid atherosclerotic stenosis patients from the Beijing Tiantan Hospital (affiliated with Capital Medical University) participated in the study. After undergoing digital subtraction angiography (DSA) and/or computed tomography angiography (CTA), the degree of carotid artery stenosis was over 70% in all cases, and the patients underwent carotid endarterectomy. Plaque specimens were obtained during surgery. The streptavidin peroxidase (SP) method was used to test the Cpn and CMV antigens in the specimens, and the relationship between the Cpn and CMV pathogen infections and AS was analyzed based on the test results. In the group of 25 carotid atherosclerotic specimens, the detection rate of the Cpn-specific antigens was 84.0% (21/25). In the control group, the detection rate was 13.3% (2/15) in the ascending aortic intima. Thus, the between-group difference was significant (P<0.01). The CMV-specific antigen detection rate was 72.0% (18/25) using the same experimental group specimens, and the detection rate was zero in the control group. Thus, there were significant between-group differences (P<0.01). Due to the high detection rate of Cpn- and CMV-specific antigens in carotid atherosclerotic plaque in a Chinese population, it can be inferred that pathogens such as Cpn and CMV are one factor associated with carotid atherosclerosis. PMID- 28903430 TI - Resveratrol inhibits age-dependent spontaneous tumorigenesis by SIRT1-mediated post-translational modulations in the annual fish Nothobranchius guentheri. AB - Resveratrol, SIRT1 activator, inhibits carcinogenesis predominantly performed in transgenic animal models, orthotopic cancers of nude mice or different cancer cell lines, but its effects during process of spontaneous tumors using vertebrate models remain untested. Spontaneous liver neoplasm is an age-related disease and is inhibited by resveratrol in the annual fish Nothobranchius guentheri, which indicates that the fish can act as an excellent model to study spontaneous tumorigenesis. Totally, 175 fish were fed with resveratrol and another 175 fish for controls. Treated fish were fed with resveratrol (25 MUg/fish/day) from sexual maturity (4-month-old) until they were sacrificed at 6-, 9- and 12-month old. Immunoblot, immunohistochemistry and co-immunoprecipitation were employed to investigate the underlying mechanisms that resveratrol inhibited age-dependent spontaneous tumorigenesis in the fish. Results showed that resveratrol increased protein level of SIRT1 and alleviated age-associated tumorigenesis in liver. With SIRT1 up-regulation, resveratrol reduced proliferation by deacetylating K-Ras and inactivating K-Ras/PI3K/AKT pathway; and promoted apoptosis through deacetylation and dephosphorylation of FoxOs, up-regulation of DLC1 and interaction between SIRT1 and DLC1, and dephosphorylation of DLC1 in spontaneous neoplasms. We established a novel short-lived fish model for understanding the molecular mechanisms of drugs on age-dependent spontaneous tumorigenesis. PMID- 28903432 TI - Genetic variation and forensic characteristic analysis of 25 STRs of a novel fluorescence co-amplification system in Chinese Southern Shaanxi Han population. AB - We analyzed the genetic polymorphisms of 15 autosomal and 10 Y-chromosomal STR loci in 214 individuals of Han population from Southern Shaanxi of China and studied the genetic relationships between Southern Shaanxi Han and other populations. We observed a total of 150 alleles at 15 autosomal STR loci with the corresponding allelic frequencies ranging from 0.0023 to 0.5210, and the combined power of discrimination and exclusion for the 15 autosomal STR loci were 0.99999999999999998866 and 0.999998491, respectively. For the 10 Y-STR loci, totally 100 different haplotypes were obtained, of which 94 were unique. The discriminatory capacity and haplotype diversity values of the 10 Y-STR loci were 0.9259 and 0.998269, respectively. The results demonstrated high genetic diversities of the 25 STR loci in the population for forensic applications. We constructed neighbor-joining tree and conducted principal component analysis based on 15 autosomal STR loci and conducted multidimensional scaling analysis and constructed neighbor-joining tree based on 10 Y-STR loci. The results of population genetic analyses based on both autosomal and Y-chromosome STRs indicated that the studied Southern Shaanxi Han population had relatively closer genetic relationship with Eastern Han population, and distant relationships with Croatian, Serbian and Moroccan populations. PMID- 28903433 TI - microRNA-451-modulated hnRNP A1 takes a part in granulocytic differentiation regulation and acute myeloid leukemia. AB - Myelopoiesis is under the control of a complex network containing various regulation factors. Deregulation of any important regulation factors may result in serious consequences including acute myeloid leukemia (AML). In order to find out the genes that may take a part in AML development, we analyzed data from AML cDNA microarray (GSE2191) in the NCBI data pool and noticed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is abnormally over-expressed in AML patients. Then we investigated the function and mechanisms of hnRNP A1 in myeloid development. A gradually decreased hnRNP A1 expression was detected during granulocytic differentiation in ATRA-induced-NB4 and HL-60 cells and cytokines induced hematopoietic stem and progenitor cells. By function-loss and winning experiments we demonstrated hnRNP A1's inhibition role via inhibiting expression of C/EBPalpha, a key regulator of granulocytic differentiation, in the granulocytic differentiation. During granulocytic differentiation the decrease of hnRNP A1 reduces inhibition on C/EBPalpha expression, and the increased C/EBPalpha promotes the differentiation. We also demonstrated that miR-451 promotes granulocytic differentiation via targeting to and down-regulating hnRNP A1, and hnRNP A1 positively regulates c-Myc expression. Summarily, our results revealed new function and mechanisms of hnRNP A1 in normal granulocytiesis and the involvement of a feed-back loop comprising c-Myc, miR-451 and hnRNP A1 in AML development. PMID- 28903434 TI - Total fluid consumption and risk of bladder cancer: a meta-analysis with updated data. AB - With meta-analysis we tented to reveal the potential relationship between daily fluid consumption and bladder cancer risk, and to find out a recommendation on daily fluid intake. Databases of the Web of Science, PubMed and EMBASE were searched then 21 case-control and 5 cohort studies were included. Stratified analyses on gender, region, time of subjects recruiting and fluid quantity were performed as well as dose-response meta-analysis. Comparing the highest exposure category with the lowest in each study, no association appeared when all data pooled together (p=0.50), but a significant OR of 1.46 (1.02-2.08, p=0.04) was found in male subgroup. For different regions, the summarized OR was 1.44 (1.10 1.89) in American case-control studies, 1.87 (1.20-2.90) in European male subgroup and 0.24 (0.10-0.60) in Asia. There was a significant relationship that each increment 1000ml daily consumption would increase the risk by 28.6% in European male (p=0.007). Similarly every additional 1000ml consumption may increase the OR by 14.9% in American people but the association wasn't that strong (p=0.057). Stratified analyses showed fluid consumption over 3000ml/day in American residents and 2000ml/day in European male resulted in OR>1 with statistical significance. In conclusion, a relationship between higher fluid intake and higher bladder cancer risk was observed in European male and American residents and a limitation to <2000ml and <3000ml per day are recommended respectively. PMID- 28903435 TI - Effects of metformin on survival outcomes of pancreatic cancer: a meta-analysis. AB - BACKGROUND AND AIM: Recent epidemiological studies indicated that metformin might improve the survival of various cancers. However, its benefit on pancreatic cancer was controversial. METHODS: We performed this meta-analysis to investigate the benefit of metformin on pancreatic cancer. A comprehensive literature search was performed through PubMed, Cochrane Library and Embase. Relative risk (RR) and hazard ratio (HR) with 95% confidence interval (CI) were pooled. RESULTS: The meta-analysis of 2 randomized controlled trials including181 pancreatic patients, revealed that metformin use was not associated with an improved overall survival at 6 months (RR=0.90, 95% CI=0.67-1.21), overall survival (HR=1.19, 95% CI=0.86 1.63) and progression-free survival (HR=1.39, 95% CI=0.97-1.99). But the meta analysis of 8 cohorts, involving 2805 pancreatic patients with diabetes, demonstrated a favorable result with improved overall survival (HR=0.78, 95% CI=0.66-0.92). CONCLUSIONS: Observations in the cohort studies supported a favorable role of metformin while the data from randomized controlled trials did not support that. Therefore, more high-quality RCTs are warranted. PMID- 28903437 TI - Meta-analysis of microRNAs expression in head and neck cancer: uncovering association with outcome and mechanisms. AB - Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, incurring significant high mortality and morbidity. This review explored the risk stratification of miRNAs, and investigated the impact of miRNA networking in HNSCC prognostication. We performed a meta-analysis and a systematic literature search on online databases for papers published prior to December 1, 2016. The list of miRNAs was uploaded to MetacoreTM to construct a protein-protein interaction network, which was used to identify targets of the miRNAs and potential drugs. In addition, a representative network was further validated by immunohistochemistry in a cohort of 100 patients. We found 116 studies that included 8,194 subjects, in which the relationship between miRNA expression and prognosis of HNSCC were analyzed. Significant elevated expressions of 27 miRNAs and decreased expression of 26 miRNAs were associated with poor outcome. After excluding the studies causing heterogeneity, a fixed model was applied, which showed a statistically significant association between increased expression of miR-21 and poor survival (Pooled HR = 1.81,95% CI = 0.66-2.95, P < 0.005). We identified four networks affected by the miRNAs expression and enriched in genes related to metabolic processes and regulation of cell mitogenesis in response to extracellular stimuli. One network point out to 16 miRNAs directly or indirectly involved in the regulation of androgen-receptor (AR). Evaluation of AR protein expression in our cohort revealed that patients with upregulation of AR had poor survival rates (log-rank test, P < 0.005). This study showed that miRNAs have potential prognostic value to serve as screening tool for HNSCC during the follow-up. In addition, the implementation of a network based analysis may reveal proteins with potential to be used as a biomarker. PMID- 28903438 TI - A novel prognostic index for oral squamous cell carcinoma patients with surgically treated. AB - This study aims to develop an applicable prognostic index with conventional factors for predicting outcome of patients with oral squamous cell carcinoma (OSCC). We performed a prospective study in a large cohort of 892 OSCC patients in Fujian, China. All patients were randomly divided into a discovery group and validation group. A prognostic index was developed based on beta value of each significant variable obtained from the multivariate Cox regression model. The results from discovery and validation set demonstrated thatthe model-4(included clinical stage, tumor differentiation, ill-fitting denture, oral hygiene and cigarette smoking) was the optimal model. The optimal cutoff points of prognostic index (1.88 and 2.80) were determined by X-tile program which categorized all subjects into low, middle and high risk subsets. Patients in high risk group were at the greatest risk of death compared with those in low risk group (HR: 6.02; 95%CI: 4.33-8.38). Moreover, there was a significant tendency of the worse overall survival with the higher prognostic index (Ptrend <0.001). The discriminatory capacity of prognostic index was 0.661(95%CI: 0.621-0.701). This study developed and validated a prognostic index that is an economical and useful tool for predicting the clinical outcomes of OSCC patients in Southeast China. Future randomized trials with larger cohort are required to confirm our results. PMID- 28903436 TI - Prognostic value of microRNAs in gastric cancer: a meta-analysis. AB - BACKGROUND: Previous articles have reported that expression levels of microRNAs (miRNAs) are associated with survival time of patients with gastric cancer (GC). A systematic review and meta-analysis was performed to study the outcome of it. DESIGN: Meta-analysis. METHODS: English studies estimating expression levels of miRNAs with any of survival curves in GC were identified up till March 19, 2017 through performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two authors independently. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). RESULTS: Sixty nine relevant articles about 26 miRNAs with 6148 patients were ultimately included. GC patients with high expression of miR-20b (HR=2.38, 95%CI=1.16-4.87), 21 (HR=1.77, 95%CI=1.01-3.08), 106b (HR=1.84, 95%CI=1.15-2.94), 196a (HR=2.66, 95%CI=1.94-3.63), 196b (HR=1.67, 95%CI=1.38-2.02), 214 (HR=1.84, 95%CI=1.27-2.67) or low expression of miR-125a (HR=2.06, 95%CI=1.26-3.37), 137 (HR=3.21, 95%CI=1.68-6.13), 141 (HR=2.47, 95%CI=1.34-4.56), 145 (HR=1.62, 95%CI=1.07-2.46), 146a (HR=2.60, 95%CI=1.63-4.13), 206 (HR=2.85, 95%CI=1.73-4.70), 218 (HR=2.61, 95%CI=1.74-3.92), 451 (HR=1.73, 95%CI=1.19-2.52), 486-5p (HR=2.45, 95%CI=1.65 3.65), 506 (HR=2.07, 95%CI=1.33-3.23) have significantly poor OS (P<0.05). CONCLUSIONS: In summary, miR-20b, 21, 106b, 125a, 137, 141, 145, 146a, 196a, 196b, 206, 214, 218, 451, 486-5p and 506 demonstrate significantly prognostic value. Among them, miR-20b, 125a, 137, 141, 146a, 196a, 206, 218, 486-5p and 506 are strong biomarkers of prognosis in GC. PMID- 28903439 TI - Lymph node status in different molecular subtype of breast cancer: triple negative tumours are more likely lymph node negative. AB - BACKGROUND AND OBJECTIVES: To investigate the association between different molecular subtype (MST) and the axillary lymph nodal (ALN) status. MATERIALS AND METHODS: A total of 528 female patients with primary breast cancer were collected. Survival estimates were calculated using the Kaplan-Meier method, univariate and multivariate logistic regression models. RESULTS: Triple negative and Luminal A breast cancers were more frequently node-negative (N0) when compared to Luminal B and Her-2 positive cancers (77.4% and 73.4% vs. 45.3% and 40.0%, respectively; P < 0.0001). We observed a clearly significant difference among ALN status in patients with Her-2 positive (P = 0.001) and Luminal B (P < 0.0001) breast cancer. While no significant prognostic diffreence among different LN status was detected in the Triple negative (P = 0.070) and Luminal A subtype (P = 0.660). On the other hand, we detected no prognostic diffreence among different MST in N1 and N3 subgroups (P = 0.569 and P = 0.484, respectively). Multivariate analysis showed that lymph node status (P < 0.01), molecular subtype (P < 0.01), and tumor size (P < 0.01) were significantly and independently prognostic factors. The c-index of the prognosis nomogram for recurrence prediction was 0.70. CONCLUSION: Triple negative breast cancer is not associated more frequently with a higher number of involved nodes. The prognosis nomogram can predict the probability of recurrence patients within 3 or 5 years. PMID- 28903440 TI - Evaluation of pituitary uptake incidentally identified on 18F-FDG PET/CT scan. AB - The clinical significance of pituitary uptake on routine whole body 18F fluorodeoxyglucose (FDG) positron emission tomography/computer tomography (PET/CT) is not completely characterized. We seek to assess the potential differential diagnosis/underlying etiology of pituitary FDG uptake incidentally identified on routine PET/CT scans. A total of 24,007 PET/CT whole body scans in recent 5 years were retrospectively reviewed. Patients with maximum standardized uptake value (SUVmax) > 4.1 in the pituitary glands were identified. Cases with a known history of pituitary disorders were excluded. Nineteen cases were identified with incidental pituitary FDG uptake which all had a final pathological diagnosis/clinical follow up. Among them, there were 9 primary pituitary tumors, with SUVmax ranging from 4.7 to 29.3 (13.6 +/- 9.8); 3 metastatic malignancy with SUVmax ranging from 7.3 to 32.3 (16.0 +/- 10.6); 3 Langerhans cell histiocytosis (LCH) with SUVmax ranging from 6.0 to 26.0 (15.0 +/ 10.2); 1 pituitary lymphocytic hypophysitis with SUVmax of 4.7. Of note, 3 cases with SUVmax of 7.5,7.9 and 9.6 showed no relevant clinical symptoms with negative results on subsequent magnetic resonance (MR) and were counted as benign physiologic uptake. The most common differential diagnosis of incidental pituitary uptake on routine whole body PET/CT scans was primary pituitary tumors, followed by metastatic malignancy, Langerhans cell histiocytosis, and inflammatory lymphocytic hypophysitis. Of note, benign physiologic uptake without corresponding lesions could also occur in our population. PMID- 28903441 TI - Loss of steroid hormone receptors is common in malignant pleural and peritoneal effusions of breast cancer patients treated with endocrine therapy. AB - Discordance in estrogen receptor alpha (ERalpha), progesterone receptor (PR), androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) status between primary breast cancers and solid distant metastases ("conversion") has been reported previously. Even though metastatic spread to the peritoneal and pleural cavities occurs frequently and is associated with high mortality, the rate of receptor conversion and the prognostic implications thereof remain elusive. We therefore determined receptor conversion in 91 effusion metastases (78 pleural, 13 peritoneal effusions) of 69 patients by immunohistochemistry (IHC) and in situ hybridization. Data were coupled to clinical variables and treatment history. ERalpha, PR and AR receptor status converted from positive in the primary tumor to negative in the effusion metastases or vice versa in 25-30%, 30-35% and 46-51% of cases for the 1% and 10% thresholds for positivity, respectively. 19-25% of patients converted clinically relevant from "ERalpha+ or PR+" to ERalpha-/PR- and 3-4% from ERalpha-/PR- to "ERalpha+ or PR+". For HER2, conversion was observed in 6% of cases. Importantly, receptor conversion for ERalpha (p = 0.058) and AR (p < 0.001) was more often seen in patients adjuvantly treated with endocrine therapy. Analogous to this observation, HER2-loss was more frequent in patients adjuvantly treated with trastuzumab (p < 0.001). Alike solid distant metastases, receptor conversion for ERalpha, PR, AR and HER2 is a frequent phenomenon in peritoneal and pleural effusion metastases. Adjuvant endocrine and trastuzumab therapy imposes an evolutionary selection pressure on the tumor, leading to receptor loss in effusion metastases. Determination of receptor status in malignant effusion specimens will facilitate endocrine treatment decision-making at this lethal state of the disease, and is hence recommended whenever possible. PMID- 28903442 TI - Association between coronary heart disease and erectile dysfunction in Chinese Han population. AB - To investigate the association between coronary heart disease (CHD) and erectile dysfunction (ED) in Chinese Han population. Patients who went to the andrological out-patient clinic of our hospital between August 1, 2015 and May 1, 2016 and met all eligible criteria were enrolled in this study. The patients diagnosed as ED using self-administered International Index of Erectile Function-5 (IIEF-5) questionnaire were considered as case group and others were considered as control. The cases were categorized as mild, moderate, and severe ED. Subjects were interviewed for the history of CHD. Uni- and multivariate logistic regression models were used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using the SPSS 18.0 software. A total of 240 participants (56 ED patients and 184 controls) were enrolled. CHD prevalence was higher in cases without statistical significance (OR = 1.20, 95%CI = 0.63-2.29; p = 0.58). Results of adjusted analysis also showed a non-significantly increased risk (OR = 1.25, 95%CI = 0.55-2.85; p = 0.59). Stratified analysis by severity of ED revealed similar results. This study suggests no significant association exists between CHD and ED in Chinese Han population. PMID- 28903443 TI - Radioligand therapy of metastatic prostate cancer using 177Lu-PSMA-617 after radiation exposure to 223Ra-dichloride. AB - Radioligand therapy with 177Lu-PSMA-617 is an innovative and effective therapy for castrate-resistant metastatic prostate cancer patients. For patients with symptomatic bone metastases without visceral metastases, the guidelines recommend radionuclide therapy with 223Ra-dichloride as a single therapeutic agent or in combination with hormone therapy. The aim of this study was to evaluate the safety of repeated cycles of 177Lu-PSMA-617 after exposure to more cycles of 223Ra. Forty-nine patients were treated with three cycles of Lu-PSMA-617 divided into two groups subjected to a history of therapy with 223Ra. Group 1 included 20 patients, who had received therapy with 223Ra prior to Lu-PSMA-617 therapy. Group 2, which was the control group regarding hematotoxicity, comprised 29 patients without any history of a bone-targeted radionuclide therapy. No CTC 4 degrees hematotoxicity was observed in the entire study population. There was no CTC 3 degrees or CTC 4 degrees leucopenia in either group. One and three patients from group 1 and 2, respectively, showed CTC 3 degrees anemia. In group 1 there was significantly more CTC 2 degrees anemia (50% vs. 6.9%) (p=0.008). One patient from group 1 (5%) showed a CTC 3 degrees thrombocytopenia without any concurrent anemia, and two patients from group 2 (7%) showed a CTC 3 degrees thrombocytopenia, one with CTC 3 degrees anemia and one without any anemia. There were no significant differences between the two groups regarding leucopenia and thrombocytopenia. These results confirmed that performing repeated cycles of Lu-PSMA-617 after 223Ra seems to be safe with a very small probability of hematotoxicity. PMID- 28903444 TI - Early tumour shrinkage as a survival predictor in patients with recurrent glioblastoma treated with bevacizumab in the AVAREG randomized phase II study. AB - BACKGROUND: Disease assessment for recurrent glioblastoma (GBM) represents a challenge, especially with the use of antiangiogenic agents. Moreover, validated neuroradiological predictors of outcome are lacking. Recently, the concept of early tumor shrinkage (ETS) has been developed to better assess the ability of treatments in determining a rapid and remarkable tumor response. The aim of the study was to evaluate the role of ETS in predicting survival of GBM patients treated with BEV. METHODS: We examined the radiological data of patients with recurrent GBM treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG trial (EudraCT: 2011-001363-46). Radiologic assessments at first disease assessment (day 46) were used to calculate the relative change in the sum of the products of perpendicular diameters of all measurable lesions determined by either T1 contrast and T2/FLAIR. RESULTS: In patients treated with BEV, the best ETS cut-off was reduction of 15% with T1 contrast and of 40% with T2/FLAIR. Adopting this cut-off for T1 contrast radiological changes, ETS was a significant predictor of OS for patients treated with BEV (HR = 0.511, 95%CI:0.269-0.971, p = 0.040). The cut-off obtained for T2/FLAIR was not significantly correlated with OS (p = 0.102), but we found a trend for correlation with survival when considering the variable as continuous (p = 0.058). CONCLUSIONS: ETS evaluating T1 contrast reduction is a helpful predictor of survival in patients with recurrent GBM treated with BEV, and if validated in a larger prospective trial could be a helpful surrogate endpoint. PMID- 28903445 TI - Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study. AB - BACKGROUND: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. METHODS: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. RESULTS: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). CONCLUSION: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies. PMID- 28903446 TI - Application of embolization microspheres in interventional therapy of malignant non-hypervascular tumor of liver. AB - OBJECTIVE: To investigate the efficacy and safety of transarterial embolization (TAE) using embolization microspheres in the treatment of non-hypervascular malignant liver tumors. METHODS: Patients with malignant non-hypervascular liver tumors, who were treated with TAE using embolization microspheres, were selected and analyzed retrospectively. The technical success rate, tumor response, and complications were assessed. RESULTS: Six patients were included in the study: 1 patient each with hepatocellular-cholangiocarcinoma, intrahepatic cholangiocarcinoma, hepatic metastasis after resection of common bile duct carcinoma, liver metastasis from colon cancer, liver metastasis from esophageal cancer, and liver metastasis from pancreatic cancer. The technical success rate was 100%. At 1 and 3 months after TAE, tumor local reactions were seen in 6/6 and 2/6 patients, respectively, and the tumor necrosis rates were 48%-73% and 22% 68%, respectively. The main complications were those related to the embolization syndrome, including 1 case of liver abscess and 1 case of severe pain on the first day after embolization. CONCLUSION: TAE with embolization microspheres is safe and effective in non-hypervascular liver tumors. It is a feasible option for palliative therapy of these tumors. PMID- 28903447 TI - Locoregionally recurrent head and neck squamous cell carcinoma: incidence, survival, prognostic factors, and treatment outcomes. AB - PURPOSE: For locoregionally recurrent head and neck squamous cell carcinoma (HNSCC), appropriate therapeutic decisions remain unclear. We examined the treatment outcomes of a national cohort to determine suitable treatments for and prognostic factors in patients with locoregionally recurrent HNSCCs at different stages and sites. PATIENTS AND METHODS: We analyzed data of >20-year-old patients with HNSCC at American Joint Committee on Cancer clinical stages I-IV without metastasis from Taiwan National Health Insurance and cancer registry databases. The index date was the date of recurrent HNSCC diagnosis. Recurrent HNSCC was defined as the annotation of locoregional recurrence with tissue proof in cancer registry databases. The enrolled patients were categorized into three groups: Group 1 comprised those undergoing chemotherapy (CT) alone; Group 2 comprised those receiving reirradiation (re-RT) alone (total radiation dose >= 60 Gy through intensity modulation radiation therapy [IMRT]); Group 3 comprised those receiving concurrent chemoradiotherapy (CCRT) alone (irradiation total dose >=60 Gy through IMRT); and Group 4 comprised those receiving salvage surgery with or without RT or CT. RESULTS: We enrolled 4,839 and 28,664 HNSCC patients with and without locoregional recurrence, respectively (median follow-up, 3.25 years). Locoregional recurrence rate and incidence were 14.44% and 40.73 per 1,000 person years, respectively. Age >= 65 years, Charlson comorbidity index (CCI) score > 6, advanced clinical stage at first diagnosis, and recurrence-free interval < 1 year were significant independent prognostic risk factors for overall survival as per univariate and multivariate Cox regression analyses. After adjusting for age, sex, CCI scores, clinical stage at first diagnosis, and recurrence-free interval, adjusted hazard ratios (aHRs; 95% confidence intervals [CIs]) for overall mortality in recurrent clinical stages I and II were 0.63 (0.45-0.89, p = 0.009), 0.65 (0.52-0.83, p < 0.001), and 0.32 (0.26-0.40, p < 0.001) in Groups 2, 3, and 4, respectively, whereas they were 1.23 (0.99-1.52, p = 0.062), 0.69 (0.60-0.79, p < 0.001), and 0.39 (0.34-0.44, p < 0.001) for Groups 2, 3, and 4, respectively, for overall mortality in recurrent clinical stage III and IV. CONCLUSIONS: Age, CCI score, clinical stage at first diagnosis, and recurrence-free interval are significant independent prognostic factors for overall survival of recurrent HNSCC patients. Regardless of recurrence stage or site, salvage surgery is the recommended first recurrent HNSCC treatment choice. Re-RT alone and CCRT are more suitable for inoperable recurrent early-stage oral and nonoral cavity recurrent HNSCCs, respectively. PMID- 28903448 TI - Positive expression of Y-box binding protein 1 and prognosis in non-small cell lung cancer: a meta-analysis. AB - BACKGROUND: Y-box binding protein 1 (YB-1) belongs to the cold shock domain protein family involved in transcription and translation. We conducted a meta analysis of the association between YB-1 expression and the survival and clinicopathological features in NSCLC. METHODS: PubMed and Embase were searched to identify studies that evaluated the YB-1 expression (by immunohistochemistry) and overall survival (OS) in NSCLC. Hazard ratios (HRs) and 95% confidence intervals (CI) of OS were pooled. Odds ratios (ORs) of clinicopathological features were computed. Meta-analysis was performed using STATA 12.0 software. RESULTS: Data on 692 NSCLC patients were collected from six eligible studies. Meta-analysis revealed that YB-1 was associated with worse OS (HR = 1.59, 95% CI [1.27, 2.00], P < 0.001, fixed effect), tumor stage (OR = 0.43, 95% CI [0.22 0.82], P = 0.01, random effect), and depth of invasion (OR = 0.37, 95%CI [0.22 0.63], P < 0.001, fixed effect). A subgroup was analyzed by IHC staining to determine the location of YB-1 positive expression. Poor OS was observed in nucleus staining (pooled HR = 1.86, 95% CI [1.41, 2.45], P < 0.001). However, no statistical significance was observed in combined cytoplasmic and nuclear staining (pooled HR = 1.14, 95% CI [0.76, 1.72], P = 0.536). CONCLUSIONS: Meta analysis indicated that YB-1 overexpression is correlated with worse OS and clinicopathological features in NSCLC. Subgroup analysis revealed that the nucleus expression of YB-1 may be more closely associated with NSCLC prognosis than cytoplasmic expression. PMID- 28903449 TI - Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. AB - OBJECTIVES: The objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM). METHODS: We systemically searched the following databases for studies published between the databases' dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis. RESULTS: A total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642~0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC. CONCLUSIONS: The risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy. PMID- 28903450 TI - Clinical and biological significance of circulating tumor cells, circulating tumor DNA, and exosomes as biomarkers in colorectal cancer. AB - Colorectal cancer (CRC) has been the fourth leading cause of cancer-related mortality worldwide. Owing to clonal evolution and selection, CRC treatment needs multimodal therapeutic approaches and due monitoring of tumor progression and therapeutic efficacy. Liquid biopsy, involving the use of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes, may offer a promising noninvasive alternative for diagnosis and for real-time monitoring of tumor evolution and therapeutic response compared to traditional tissue biopsy. Monitoring of the disease processes can enable clinicians to readily adopt a strategy based on optimal therapeutic decision-making. This article provides an overview of the significant advances and the current clinical and biological significance of CTCs, ctDNA, and exosomes in CRC, as well as a comparison of the main merits and demerits of these three components. The hurdles that need to be resolved and potential directions to be followed with respect to liquid biopsies for detection and therapy of CRC are also discussed. PMID- 28903451 TI - The correlation of sperm morphology with unexplained recurrent spontaneous abortion: A systematic review and meta-analysis. AB - Sperm morphology displays a potential impact on sperm function and may ultimately impact reproductive function. Current studies have investigated the correlation between sperm morphology with unexplained recurrent spontaneous abortion (RSA) but have shown inconsistent results. Hence, we systematically searched MEDLINE, EMBASE, CNKI databases, as well as the Cochrane Library for studies that examined the association between sperm morphology and unexplained RSA. Fifteen studies were identified, including 883 cases and 530 controls. Our meta-analysis results indicated that the percentage of normal sperm morphology from men with RSA partners was significantly lower than those from normal controls(SMD [95% CI]: - 0.60 [-0.81, -0.40]; P<0.00001) and the percentage of sperm morphologic alterations was significantly higher in patients with RSA compared with the control group (SMD [95% CI]: 0.92 [0.42, 1.43]; P=0.0004). The present study suggested that the percentage of normal sperm morphology may indeed decrease in men from RSA group compared with controls. However, there were some limitations in the study such as the differences in stain techniques and classification criteria. Further evidences are needed to better elucidate the relationship between sperm morphology and unexplained RSA. PMID- 28903452 TI - Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival for peritoneal carcinomatosis from colorectal cancer: a systematic review and meta-analysis of current evidence. AB - OBJECTIVES: The therapeutic efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is still under debate. This meta analysis and systematic review of published literature on this comprehensive strategy aims to evaluate its efficacy on CRC patients with PC. METHODS: A systemic review with meta-analysis of published literatures on treatment of CRS plus HIPEC for patients with PC from CRC was performed. In addition, a summary of study results of published literatures concerning CRS plus HIPEC treating patients with PC from CRC was also conducted. RESULTS: A total of 76 studies were selected, including 1 randomized controlled trial, 14 non-randomized controlled studies, and 61 non-controlled studies. The pooled hazard ratios (HRs) for overall survival (OS) in the 15 researches for meta-analysis was 2.67 (95% CI, 2.21-3.23, I2= 0%, P < 0.00001), and no significant evidence of publication bias was found. The difference of chemotherapy regimens of HIPEC was not associated with OS and DFS (disease-free survival) after CRS and HIPEC, with no significant difference of heterogeneity (P = 0.27, I2 = 24.1%). In both groups of mitomycin C based HIPEC group and oxaliplatin group, patients received HIPEC had significant better survival (P < 0.00001). The mean mortality and morbidity for HIPEC program were 2.8% and 33.0%, respectively. CONCLUSIONS: This meta-analysis revealed that comprehensive therapeutic strategy of CRS plus HIPEC could bring survival benefit for selected patients with PC from CRC with acceptable safety. PMID- 28903454 TI - Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy. AB - Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients. PMID- 28903455 TI - Targeting EIF4F complex in non-small cell lung cancer cells. AB - Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, which represents the leading cause of cancer-related death in the world. The majority of lung cancer patients doesn't respond well to conventional chemo /radio-therapeutic regimens and have a poor prognosis. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but their outcome/prognosis is far from satisfactory. The translation initiation EIF4F complex has been shown to play important roles in cancer progression, but its functional role and therapeutic effect in lung cancers especially NSCLC remain largely unknown. In this current review, we summarize recent findings regarding the role of EIF4F complex in NSCLC progression and targeted therapy potentials. We also discuss the unanswered questions and future directions in this field. PMID- 28903456 TI - Tumor reductive therapies and antitumor immunity. AB - Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought. In many cases, the effectiveness of classic therapies is heavily influenced by the status of the underlying antitumor-immunity. On the other hand, immunotherapies have shown better outcome when combined with tumor reductive therapies, not only due to the combined effects of tumor killing by each therapy but also because of a synergy between the two. Many clinical observations can be explained once we start to look at these classic therapies from an immunity standpoint. We have seen their direct effect on tumor antigen in vivo that they impact antitumor immunity more than we have realized. In turn, antitumor immunity contributes to tumor control and destruction as well. This review will take the immunological view of the classic therapies and summarize historical as well as recent findings in animal and clinical studies to make the argument that most of the cancer treatments exert their ultimate efficacy through antitumor immunity. PMID- 28903453 TI - The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells. AB - By gating the traffic of molecules and cells across the vessel wall, endothelial cells play a central role in regulating cardiovascular functions and systemic homeostasis and in modulating pathophysiological processes such as inflammation and immunity. Accordingly, the loss of endothelial cell integrity is associated with pathological disorders that include atherosclerosis and cancer. The p38 mitogen-activated protein kinase (MAPK) cascades are major signaling pathways that regulate several functions of endothelial cells in response to exogenous and endogenous stimuli including growth factors, stress and cytokines. The p38 MAPK family contains four isoforms p38alpha, p38beta, p38gamma and p38delta that are encoded by four different genes. They are all widely expressed although to different levels in almost all human tissues. p38alpha/MAPK14, that is ubiquitously expressed is the prototype member of the family and is referred here as p38. It regulates the production of inflammatory mediators, and controls cell proliferation, differentiation, migration and survival. Its activation in endothelial cells leads to actin remodeling, angiogenesis, DNA damage response and thereby has major impact on cardiovascular homeostasis, and on cancer progression. In this manuscript, we review the biology of p38 in regulating endothelial functions especially in response to oxidative stress and during the metastatic process. PMID- 28903459 TI - Correction: A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01). AB - [This corrects the article DOI: 10.18632/oncotarget.13056.]. PMID- 28903458 TI - Epidermal growth factor receptor-mutant lung cancer in Down syndrome: a case presentation and review of the literature. AB - BACKGROUND: Solid tumors have a markedly decreased incidence in individuals with Down syndrome (DS), including lung cancers. METHODS: The clinical presentation of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) in DS was reported and literature on the subject reviewed. RESULTS: In individuals with DS, the risk of lung cancer appears markedly lower. EGFR mutation and EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance also exist in DS with lung cancer. CONCLUSIONS: Clinicians should consider EGFR mutation and EGFR-TKIs resistance in lung cancer patients with DS. PMID- 28903457 TI - The lifecycle of the Ebola virus in host cells. AB - Ebola haemorrhagic fever causes deadly disease in humans and non-human primates resulting from infection with the Ebola virus (EBOV) genus of the family Filoviridae. However, the mechanisms of EBOV lifecycle in host cells, including viral entry, membrane fusion, RNP formation, GP-tetherin interaction, and VP40 inner leaflet association remain poorly understood. This review describes the biological functions of EBOV proteins and their roles in the lifecycle, summarizes the factors related to EBOV proteins or RNA expression throughout the different phases, and reviews advances with regards to the molecular events and mechanisms of the EBOV lifecycle. Furthermore, the review outlines the aspects remain unclear that urgently need to be solved in future research. PMID- 28903460 TI - Correction: Increased expression of SKP2 is an independent predictor of locoregional recurrence in cervical cancer via promoting DNA-damage response after irradiation. AB - [This corrects the article DOI: 10.18632/oncotarget.10057.]. PMID- 28903461 TI - Comparative Genomics Reveals Two Major Bouts of Gene Retroposition Coinciding with Crucial Periods of Symbiodinium Evolution. AB - Gene retroposition is an important mechanism of genome evolution but the role it plays in dinoflagellates, a critical player in marine ecosystems, is not known. Until recently, when the genomes of two coral-symbiotic dinoflagellate genomes, Symbiodinium kawagutii and S. minutum, were released, it has not been possible to systematically study these retrogenes. Here we examine the abundant retrogenes (~23% of the total genes) in these species. The hallmark of retrogenes in the genome is the presence of DCCGTAGCCATTTTGGCTCAAG, a spliced leader (DinoSL) constitutively trans-spliced to the 5'-end of all nucleus-encoded mRNAs. Although the retrogenes have often lost part of the 22-nt DinoSL, the putative promoter motif from the DinoSL, TTT(T/G), is consistently retained in the upstream region of these genes, providing an explanation for the high survival rate of retrogenes in dinoflagellates. Our analysis of DinoSL sequence divergence revealed two major bursts of retroposition in the evolutionary history of Symbiodinium, occurring at ~60 and ~6 Ma. Reconstruction of the evolutionary trajectory of the Symbiodinium genomes mapped these 2 times to the origin and rapid radiation of this dinoflagellate lineage, respectively. GO analysis revealed differential functional enrichment of the retrogenes between the two episodes, with a broad impact on transport in the first bout and more localized influence on symbiosis related processes such as cell adhesion in the second bout. This study provides the first evidence of large-scale retroposition as a major mechanism of genome evolution for any organism and sheds light on evolution of coral symbiosis. PMID- 28903463 TI - Curriculum vitae writing and the academic job search. PMID- 28903462 TI - Distribution, Diversity, and Long-Term Retention of Grass Short Interspersed Nuclear Elements (SINEs). AB - Instances of highly conserved plant short interspersed nuclear element (SINE) families and their enrichment near genes have been well documented, but little is known about the general patterns of such conservation and enrichment and underlying mechanisms. Here, we perform a comprehensive investigation of the structure, distribution, and evolution of SINEs in the grass family by analyzing 14 grass and 5 other flowering plant genomes using comparative genomics methods. We identify 61 SINE families composed of 29,572 copies, in which 46 families are first described. We find that comparing with other grass TEs, grass SINEs show much higher level of conservation in terms of genomic retention: The origin of at least 26% families can be traced to early grass diversification and these families are among most abundant SINE families in 86% species. We find that these families show much higher level of enrichment near protein coding genes than families of relatively recent origin (51%:28%), and that 40% of all grass SINEs are near gene and the percentage is higher than other types of grass TEs. The pattern of enrichment suggests that differential removal of SINE copies in gene poor regions plays an important role in shaping the genomic distribution of these elements. We also identify a sequence motif located at 3' SINE end which is shared in 17 families. In short, this study provides insights into structure and evolution of SINEs in the grass family. PMID- 28903464 TI - Characterization of the contaminant bacterial communities in sugarcane first generation industrial ethanol production. AB - The industrial ethanolic fermentation process is operated in distilleries, either in fed-batch or continuous mode. A consequence of the large industrial ethanol production is bacterial contamination in the fermentation tanks, which is responsible for significant economic losses. To investigate this community, we accessed the profile of bacterial contaminant from two distilleries in Brazil, each operating a different fermentation mode, throughout sugarcane harvest of 2013-2014. Bacterial communities were accessed through Illumina culture independent 16S rDNA gene sequencing, and qPCR was used to quantify total bacteria abundance. Both ethanol production modes showed similar bacterial abundance, around 105 gene copies/mL. 16S rDNA sequencing showed that 92%-99% of the sequences affiliated to Lactobacillus genus. Operational taxonomic units differently represented belonged mainly to Lactobacillus, but also to Weissella, Pediococcus, Acetobacter and Anaeosporobacter, although in lower abundance. Alpha diversity only showed a correlation through the fermentation tanks in continuous mode, where it was always higher in the second and third tanks. Beta-diversity clearly separated the two distilleries and metagenome prediction reinforces clusterization within distilleries. Despite certain variations between bacterial community in the distilleries throughout harvest season, Lactobacillus were the main genera reported in both distilleries and bacterial community seemed to persist along time, suggesting bacterial reinfestation. PMID- 28903465 TI - Role of host cell integrins in the microsporidium Encephalitozoon intestinalis adherence and infection in vitro. AB - Microsporidia are obligate intracellular, spore-forming, fungal-related pathogens that employ a unique organelle, the polar tube, to transfer infectious spore contents into host cells to initiate infection. Spore adherence to host cells may provide the proximity required for polar tube/host cell interaction during in vivo infection. In previous in vitro studies, host sulfated glycosaminoglycans (GAGs) or recombinant microsporidia endospore protein (EnP1) was implicated in the pathogen adherence and infection process; however, complete ablation of spore adherence and infection could not be achieved, suggesting that additional or alternative spore and host cell determinants of adherence and infection may exist. Analysis of the Encephalitozoon intestinalis genome revealed about 100 predicted proteins containing the canonical integrin-binding motif arginine glycine-aspartic acid (RGD); and, many pathogens have been shown to engage integrin molecules on cell surfaces. We hypothesized that host cell integrins play a role in microsporidia adherence and infection. In this study, we demonstrated that addition of exogenous integrin ligands or recombinant alpha 3 beta 1 integrin or alpha 5 beta 1 integrin to assays of E. intestinalis adherence and infection significantly reduced spore adherence and infection of host cells, supporting our hypothesis and implicating these specific integrins as putative host cell receptors for E. intestinalis spores. PMID- 28903466 TI - Doxycycline enhances adsorption and inhibits early-stage replication of porcine reproductive and respiratory syndrome virus in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has an important impact on the pig industry. Doxycycline (Dox) is a second-generation tetracycline widely used for treating bacterial infections. We evaluated the antiviral effect of Dox against PRRSV infection in Marc-145 cells that were susceptible to PRRSV infection. Dox significantly reduced the PRRSV-induced cytopathic effect and effectively restrained PRRSV replication in a dose-dependent manner. The 50% effective concentration of Dox was approximately 0.25 +/- 0.05 MUg/ml. We also determined the stage at which Dox influenced PRRSV replication, and showed that Dox enhanced PRRSV adsorption and inhibited the early stage of PRRSV replication after viral entry into host cells. These observations demonstrate that Dox is able to restrain PRRSV infection in cultured cells. PMID- 28903468 TI - A case for the protection of saline and hypersaline environments: a microbiological perspective. AB - Saline and hypersaline environments are known for their unique geochemical properties, microbial populations and aesthetic appeal. Microbial activities and a spectrum of diversity seen in hypersaline environments are distinct with many novel species being identified and reported on a regular basis. Many distinguishing characteristics about the adaptation, morphology, evolutionary history, and potential environmental and biotechnological applications of these organisms are continually investigated. An abundance of interdisciplinary activities and opportunities exist to explore and understand the importance of these environments that potentially hold promising solutions for current and future global issues. Therefore, it is critical to conserve these unique environments and limit the damage inflicted by anthropogenic influences. Increased salinization due to water diversions, undesired freshening, extensive mineral extraction, sewage effluents, pollution due to agricultural runoff and industrial processes, urbanization, and global climate change are factors negatively affecting hypersaline lakes and their surrounding environments. If these harmful effects continue to proceed at the current or even accelerated rates, irrevocable consequences for these environments will occur, resulting in the loss of potential opportunities to gain new knowledge of the biogeochemistry as well as beneficial microbial populations closely associated with these unique and interesting environments. PMID- 28903467 TI - Development and characterization of a synthetic DNA, NUversa, to be used as a standard in quantitative polymerase chain reactions for molecular pneumococcal serotyping. AB - Identification of Streptococcus pneumoniae and its more than 90 serotypes is routinely conducted by culture and Quellung reactions. Quantitative polymerase chain reactions (qPCRs) have been developed for molecular detection, including a pan-pneumococcus lytA assay, and assays targeting 79 serotypes. Reactions require genomic DNA from every target to prepare standards, which can be time consuming. In this study, we have developed a synthetic DNA molecule as a surrogate for genomic DNA and present new single-plex qPCR reactions to increase molecular detection to 94 pneumococcal serotypes. Specificity of these new reactions was confirmed with a limit of detection between 2 and 20 genome equivalents/reaction. A synthetic DNA (NUversa, ~8.2 kb) was then engineered to contain all available qPCR targets for serotyping and lytA. NUversa was cloned into pUC57-Amp-modified to generate pNUversa (~10.2 kb). Standards prepared from pNUversa and NUversa were compared against standards made out of genomic DNA. Linearity [NUversa (R2 > 0.982); pNUversa (R2 > 0.991)] and efficiency of qPCR reactions were similar to those utilizing chromosomal DNA (R2 > 0.981). Quantification with plasmid pNUversa was affected, however, whereas quantification with synthetic NUversa was comparable to that of genomic DNA. Therefore, NUversa may be utilized as DNA standard in single-plex assays of the currently known 94 pneumococcal serotypes. PMID- 28903469 TI - Signatures in the gut microbiota of Japanese infants who developed food allergies in early childhood. AB - Bacterial colonization in infancy is considered crucial for the development of the immune system. Recently, there has been a drastic increase in childhood allergies in Japan. Therefore, we conducted a prospective study with 56 infants on the relationship between gut microbiota in the first year of life and the development of allergies during the first 3 years. In the lactation period, organic acid producers such as Leuconostoc, Weissella and Veillonella tended to be underrepresented in subjects who developed food allergies (FA, n = 14) within the first two years. In the weaning period, children in the FA group were highly colonized by unclassified Enterobacteriaceae and two Clostridium species closely related to Clostridium paraputrificum and C. tertium, and the whole tree phylogenetic diversity index was significantly lower in the FA group. All of these differences in the weaning period were statistically significant, even after adjusting for potential confounding factors. A higher abundance of unclassified Enterobacteriaceae was also found in the other allergic group (n = 15), whereas the two Clostridium species were highly specific to the FA group. The mode of action of these Clostridium species in childhood food allergies remains unknown, warranting further investigation. PMID- 28903470 TI - A Decade of Information on the Use of Cardiac Implantable Electronic Devices and Interventional Electrophysiological Procedures in the European Society of Cardiology Countries: 2017 Report from the European Heart Rhythm Association. AB - Aims: The aim of this analysis was to provide comprehensive information on invasive cardiac arrhythmia therapies in the European Society of Cardiology (ESC) area over the past 10 years. Methods and results: The European Heart Rhythm Association (EHRA) has collected data on invasive arrhythmia therapies since 2008. This year 53 of the 56 ESC member countries provided data for the EHRA White Book. Here we present updated data on procedure rates together with information on demographics, economy, vital statistics, local healthcare systems and training activities. Considerable heterogeneity in the access to invasive arrhythmia therapies still exists across the five geographical ESC regions. In 2016, the device implantation rates per million population were 3-6 times higher in the Western region than in the non-European and Eastern ESC member countries. Catheter ablation activity was highest in the Western countries followed by the Northern and Southern areas. In the non-European countries, atrial fibrillation ablation rate was more than tenfold lower than in the European countries. On the other hand, the growth rate over the past ten years was highest in the non European and Eastern countries. In some Eastern European countries with relative low gross domestic product the procedure rates exceeded the average values. Conclusion: It was encouraging to note that during the past decade the growth in invasive arrhythmia therapies was greatest in the areas historically with relatively low activity. Nevertheless, there is substantial disparity and continued efforts are needed to improve harmonization of cardiac arrhythmia therapies in the ESC area. PMID- 28903471 TI - The role of TGF-beta in the pathophysiology of peritoneal endometriosis. AB - BACKGROUND: Endometriosis is estimated to affect 6-10% of women of reproductive age and it is associated with chronic pelvic pain, dysmenorrhoea and subfertility. It is currently managed surgically or medically but symptoms recur in up to 75% of cases and available medical treatments have undesirable side effects. Endometriosis is defined as the presence of endometrial tissue outside the uterus with lesions typically found on the peritoneum. The aetiology of endometriosis is uncertain but there is increasing evidence that transforming growth factor (TGF)-beta plays a major role. OBJECTIVE AND RATIONALE: A descriptive review was undertaken of the published literature on the expression pattern of TGF-beta ligands and signalling molecules in women with and without endometriosis, and on the potential roles of TGF-beta signalling in the development and progression of peritoneal endometriosis. The current understanding of the TGF-beta signalling pathway is summarized. SEARCH METHODS: We searched the Pubmed database using the terms 'transforming growth factor beta' and 'endometriosis' for studies published between 1995 and 2016. The initial search identified 99 studies and these were used as the basic material for this review. We also extended our remit for important older publications. In addition, we searched the reference lists of studies used in this review for additional studies we judged as relevant. Studies which were included in the review focused on peritoneal endometriosis only as increasing evidence suggests that ovarian and deep endometriosis may have a differing pathophysiology. Thus, a final 95 studies were included in the review. OUTCOMES: TGF-beta1 is reported to be increased in the peritoneal fluid, serum, ectopic endometrium and peritoneum of women with endometriosis compared to women without endometriosis, and TGF-beta1-null mice have reduced endometriosis lesion growth when compared to their wild-type controls. Studies in mice and women have indicated that increasing levels of TGF beta ligands are associated with decreased immune cell activity within the peritoneum, together with an increase in ectopic endometrial cell survival, attachment, invasion and proliferation, during endometriosis lesion development. TGF-beta1 has been associated with changes in ectopic endometrial and peritoneal cell metabolism and the initiation of neoangiogenesis, further fuelling endometriosis lesion development. WIDER IMPLICATIONS: Together these studies suggest that TGF-beta1 plays a major role in the development of peritoneal endometriosis lesions and that targeting this pathway may be of therapeutic potential. PMID- 28903472 TI - GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. AB - BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF population, women with PCOS and women with poor ovarian response. Pre-planned subgroup analyses were performed for various antagonist treatment schedules. OUTCOMES: We included 50 studies. Of these, 34 studies reported on general IVF patients, 10 studies reported on PCOS patients and 6 studies reported on poor responders. In general IVF patients, ongoing pregnancy rate was significantly lower in the antagonist group compared with the agonist group (RR 0.89, 95% CI 0.82-0.96). In women with PCOS and in women with poor ovarian response, there was no evidence of a difference in ongoing pregnancy between the antagonist and agonist groups (RR 0.97, 95% CI 0.84-1.11 and RR 0.87, 95% CI 0.65 1.17, respectively). Subgroup analyses for various antagonist treatment schedules compared to the long protocol GnRH agonist showed a significantly lower ongoing pregnancy rate when the oral hormonal programming pill (OHP) pretreatment was combined with a flexible protocol (RR 0.74, 95% CI 0.59-0.91) while without OHP, the RR was 0.84, 95% CI 0.71-1.0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP (RR 0.94, 95% CI 0.79-1.12 and RR 0.94, 95% CI 0.83-1.05, respectively). Antagonists resulted in significantly lower OHSS rates both in the general IVF patients and in women with PCOS (RR 0.63, 95% CI 0.50-0.81 and RR 0.53, 95% CI 0.30-0.95, respectively). No data on OHSS was available from trials in poor responders. WIDER IMPLICATIONS: In a general IVF population, GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists, but also with lower OHSS rates. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with PCOS and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as standard treatment. PMID- 28903473 TI - Baseline anatomical assessment of the uterus and ovaries in infertile women: a systematic review of the evidence on which assessment methods are the safest and most effective in terms of improving fertility outcomes. AB - BACKGROUND: This review focuses on the initial presentation of women who suspect that they are infertile, and how best to assess the anatomy of their uterus and ovaries in order to investigate the cause of their infertility, and potentially improve desired fertility outcomes. This review was undertaken as part of a World Health Organization initiative to assess the evidence available to address guidance for the diagnosis and treatment of infertility within a global context. Providing access to care for infertile women will help to ease the psycho-social burdens, such as ostracization, intimate partner violence and other negative consequences of being involuntarily childless or unable to become pregnant despite desiring a biological child or children. OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the diagnostic and prognostic value of various investigations used for detecting uterine and/or ovarian pathology in women presenting at fertility clinics for their initial assessment. SEARCH METHODS: We performed a comprehensive search of relevant studies on 28 August and 10 September 2014. A further search was performed on 6 June 2016 to ensure all possible studies were captured. These strategies were not limited by date or language. The search returned 3968 publications in total; 63 full text articles were retrieved and 10 additional studies were found through hand searching. After excluding 54, a total of 19 studies were analysed. We extracted and tabulated data on the characteristics, quality and results of each eligible study and combined the findings in a narrative synthesis. Risk of bias was assessed according to article type using tools such as assessment of the methodological quality of systematic reviews, Newcastle Ottawa Scale, Cochrane risk of bias tool, quality assessment tool for diagnostic accuracy studies and quality in prognostic studies. Nineteen studies were selected as being the best evidence available. A narrative synthesis of the data was undertaken. Discussion of the data, and resultant consensus for best practice were accomplished in a consensus expert consultation in Geneva, October 2015. An independent expert review process concerning this work and outcomes was conducted during 2016. OUTCOMES: The draft recommendations presented here apply to infertile women whether or not they are undergoing fertility treatment. Transvaginal ultrasound (TVUS) should be offered to all infertile women with symptoms or signs of anatomic pelvic pathology. TVUS should not be offered routinely to women without symptoms of pelvic pathology. Hysteroscopy should be offered if intrauterine pathology is suspected by TVUS. Hysteroscopy should not be routinely offered to infertile women who have normal TVUS findings. In women who have normal TVUS findings and are undergoing IVF, hysteroscopy does not improve the outcome. Good practice points recommend that providers of fertility care should confirm that all infertile women have a recent pelvic examination, recent cervical screening and well-woman screening in line with local guidelines. Additionally, hystero contrast salpingography in infertile women does not improve clinical pregnancy rates with expectant management in heterosexual couples and should not be offered as a therapeutic procedure. Most of the findings of this review on diagnosis are based on a low, or very low, quality of evidence, according to GRADE Working Group (grading of recommendations, assessment, development and evaluation) criteria. A low quality grading indicates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, while a very low grade indicates that any estimate of effect is very uncertain. WIDER IMPLICATIONS: This review provides the most reliable evidence available to guide clinicians worldwide in the initial, evidence-based investigation of women with fertility problems in order to undertake the most useful investigation and avoid the burden of unnecessary tests. PMID- 28903475 TI - Non-Newtonian pulsatile shear stress assessment: a method to differentiate bioresorbable scaffold platforms. PMID- 28903474 TI - Nitric oxide-heat shock protein axis in menopausal hot flushes: neglected metabolic issues of chronic inflammatory diseases associated with deranged heat shock response. AB - BACKGROUND: Although some unequivocal underlying mechanisms of menopausal hot flushes have been demonstrated in animal models, the paucity of similar approaches in humans impedes further mechanistic outcomes. Human studies might show some as yet unexpected physiological mechanisms of metabolic adaptation that permeate the phase of decreased oestrogen levels in both symptomatic and asymptomatic women. This is particularly relevant because both the severity and time span of hot flushes are associated with increased risk of chronic inflammatory disease. On the other hand, oestrogen induces the expression of heat shock proteins of the 70 kDa family (HSP70), which are anti-inflammatory and cytoprotective protein chaperones, whose expression is modulated by different types of physiologically stressful situations, including heat stress and exercise. Therefore, lower HSP70 expression secondary to oestrogen deficiency increases cardiovascular risk and predisposes the patient to senescence associated secretory phenotype (SASP) that culminates in chronic inflammatory diseases, such as obesities, type 2 diabetes, neuromuscular and neurodegenerative diseases. OBJECTIVE AND RATIONALE: This review focuses on HSP70 and its accompanying heat shock response (HSR), which is an anti-inflammatory and antisenescent pathway whose intracellular triggering is also oestrogen-dependent via nitric oxide (NO) production. The main goal of the manuscript was to show that the vasomotor symptoms that accompany hot flushes may be a disguised clue for important neuroendocrine alterations linking oestrogen deficiency to the anti inflammatory HSR. SEARCH METHODS: Results from our own group and recent evidence on hypothalamic control of central temperature guided a search on PubMed and Google Scholar websites. OUTCOMES: Oestrogen elicits rapid production of the vasodilatory gas NO, a powerful activator of HSP70 expression. Whence, part of the protective effects of oestrogen over cardiovascular and neuroendocrine systems is tied to its capacity of inducing the NO-elicited HSR. The hypothalamic areas involved in thermoregulation (infundibular nucleus in humans and arcuate nucleus in other mammals) and whose neurons are known to have their function altered after long-term oestrogen ablation, particularly kisspeptin-neurokinin B dynorphin neurons, (KNDy) are the same that drive neuroprotective expression of HSP70 and, in many cases, this response is via NO even in the absence of oestrogen. From thence, it is not illogical that hot flushes might be related to an evolutionary adaptation to re-equip the NO-HSP70 axis during the downfall of circulating oestrogen. WIDER IMPLICATIONS: Understanding of HSR could shed light on yet uncovered mechanisms of menopause-associated diseases as well as on possible manipulation of HSR in menopausal women through physiological, pharmacological, nutraceutical and prebiotic interventions. Moreover, decreased HSR indices (that can be clinically determined with ease) in perimenopause could be of prognostic value in predicting the moment and appropriateness of starting a HRT. PMID- 28903477 TI - Chronic refractory angina pectoris: recent progress and remaining challenges. PMID- 28903478 TI - Thomas F. Luscher moves to London. PMID- 28903476 TI - Adenoviral intramyocardial VEGF-DDeltaNDeltaC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. AB - Aims: We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DDeltaNDeltaC gene therapy in patients with refractory angina. Methods and results: Thirty patients were randomized to AdVEGF DDeltaNDeltaC (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00 +/- 0.36) at 3 months (1.31 +/- 0.46, P = 0.045) and 12 months (1.44 +/- 0.48, P = 0.009) whereas MPR in the reference area tended to decrease (2.05 +/- 0.69, 1.76 +/- 0.62, and 1.87 +/- 0.69; baseline, 3 and 12 months, respectively, P = 0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months (1.26 +/- 0.37, 1.57 +/- 0.55, and 1.48 +/- 0.48; respectively, P = 0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94 +/- 0.32 and 1.76 +/- 0.41 baseline and 12 months, respectively, P = 0.023). Conclusion: AdVEGF-DDeltaNDeltaC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy. PMID- 28903479 TI - Record high EHJ Impact Factor 2016. PMID- 28903480 TI - Royal Brompton Hospital, London. PMID- 28903482 TI - Record EHJ Impact Factor 20.213 in 2016. PMID- 28903481 TI - What Academic Research Captured the Public's Imagination in 2016? PMID- 28903483 TI - Frontiers in the management of coronary artery disease: bioabsorable scaffolds, regenerative medicine, and gene therapy. PMID- 28903484 TI - Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. AB - Background: Circular RNAs (circRNAs) are RNA transcripts that are widespread in the eukaryotic genome. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. However, whether circRNAs encode functional proteins remains elusive, although translation of several circRNAs was recently reported. Methods: CircRNA deep sequencing was performed by using 10 pathologically diagnosed glioblastoma samples and their paired adjacent normal brain tissues. Northern blotting, Sanger sequencing, antibody, and liquid chromatograph Tandem Mass Spectrometer were used to confirm the existence of circ-FBXW7 and its encoded protein in in two cell lines. Lentivirus-transfected stable U251 and U373 cells were used to assess the biological functions of the novel protein invitro and invivo (five mice per group). Clinical implications of circ-FBXW7 were assessed in 38 pathologically diagnosed glioblastoma samples and their paired periphery normal brain tissues by using quantitative polymerase chain reaction (two-sided log-rank test). Results: Circ-FBXW7 is abundantly expressed in the normal human brain (reads per kilobase per million mapped reads [RPKM] = 9.31). The spanning junction open reading frame in circ-FBXW7 driven by internal ribosome entry site encodes a novel 21-kDa protein, which we termed FBXW7-185aa. Upregulation of FBXW7-185aa in cancer cells inhibited proliferation and cell cycle acceleration, while knockdown of FBXW7 185aa promoted malignant phenotypes invitro and invivo. FBXW7-185aa reduced the half-life of c-Myc by antagonizing USP28-induced c-Myc stabilization. Moreover, circ-FBXW7 and FBXW7-185aa levels were reduced in glioblastoma clinical samples compared with their paired tumor-adjacent tissues (P < .001). Circ-FBXW7 expression positively associated with glioblastoma patient overall survival (P = .03). Conclusions: Endogenous circRNA encodes a functional protein in human cells, and circ-FBXW7 and FBXW7-185aa have potential prognostic implications in brain cancer. PMID- 28903485 TI - Editor's Highlight: Mechanistic Toxicity Tests Based on an Adverse Outcome Pathway Network for Hepatic Steatosis. AB - Risk assessors use liver endpoints in rodent toxicology studies to assess the safety of chemical exposures. Yet, rodent endpoints may not accurately reflect human responses. For this reason and others, human-based invitro models are being developed and anchored to adverse outcome pathways to better predict adverse human health outcomes. Here, a networked adverse outcome pathway-guided selection of biology-based assays for lipid uptake, lipid efflux, fatty acid oxidation, and lipid accumulation were developed. These assays were evaluated in a metabolically competent human hepatocyte cell model (HepaRG) exposed to compounds known to cause steatosis (amiodarone, cyclosporine A, and T0901317) or activate lipid metabolism pathways (troglitazone, Wyeth-14,643, and 22(R)-hydroxycholesterol). All of the chemicals activated at least one assay, however, only T0901317 and cyclosporin A dose-dependently increased lipid accumulation. T0901317 and cyclosporin A increased fatty acid uptake, decreased lipid efflux (inferred from apolipoprotein B100 levels), and increased fatty acid synthase protein levels. Using this biologically-based evaluation of key events regulating hepatic lipid levels, we demonstrated dysregulation of compensatory pathways that normally balance hepatic lipid levels. This approach may provide biological plausibility and data needed to increase confidence in linking invitro-based measurements to chemical effects on adverse human health outcomes. PMID- 28903487 TI - From the Cover: Arsenic Induces Hippocampal Neuronal Apoptosis and Cognitive Impairments via an Up-Regulated BMP2/Smad-Dependent Reduced BDNF/TrkB Signaling in Rats. AB - Arsenic promotes hippocampal neuronal damage inducing cognitive impairments. However, mechanism arbitrating arsenic-mediated cognitive deficits remains less known. Here, we identified that chronic exposure to environmentally relevant doses of arsenic increased apoptosis, characterized by caspase-3 activation, poly(ADP-ribose) polymerase cleavage and Terminal deoxynucleotidyl transferase dUTP nick-end labeling of rat hippocampal neurons, marked by NeuN. Investigating apoptotic mechanism through invivo and invitro studies revealed that arsenic promoted bone morphogenetic protein-2 (BMP2) expression, supported by increased BMP-receptor2 (BMPR2) and p-Smad1/5 in hippocampal neurons. BMP2-silencing and treatment with BMP antagonist, noggin, attenuated the arsenic-induced apoptosis and loss in hippocampal neurons. We then investigated whether BMP2/Smad signaling stimulated neuronal apoptosis independently or required other intermediate pathways. We hypothesized participation of brain-derived neurotrophic factor (BDNF) that promotes neuronal survival. We identified an arsenic-mediated attenuation of BDNF-dependent TrkB signaling, and observed that co-treatment with recombinant-BDNF reinstated BDNF/TrkB and reduced neuronal apoptosis. To probe whether BMP2/Smad and BDNF/TrkB pathways could be linked, we co-treated arsenic with noggin or recombinant BDNF. We detected a noggin-mediated restored BDNF/TrkB, while recombinant-BDNF failed to affect BMP2/Smad signaling. In addition, we found that TrkB-inhibitor, K252a, nullified noggin-induced protection, proving the necessity of a downstream reduced BDNF/TrKB signaling for BMP2/Smad-mediated apoptosis in arsenic-treated neurons. We further related our observations with cognitive performances, and detected noggin-mediated restoration of transfer latency time and learning-memory ability for passive avoidance and Y-Maze tests respectively in arsenic-treated rats. Overall, our study proves that arsenic promotes hippocampal neuronal apoptosis through an up regulated BMP2/Smad-dependent attenuation of BDNF/TrkB pathway, inducing cognitive deficits. PMID- 28903486 TI - Nonalcoholic Fatty Liver Disease Is a Susceptibility Factor for Perchloroethylene Induced Liver Effects in Mice. AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent pathological liver condition in developed countries. NAFLD results in severe alterations in liver function, including xenobiotic metabolism. Perchloroethylene (PERC) is a ubiquitous environmental pollutant, a known hepatotoxicant in rodents, and a probable human carcinogen. It is known that PERC disposition and metabolism are affected by NAFLD in mice; here, we examined how NAFLD changes PERC-associated liver effects. Male C57Bl6/J mice were fed a low-fat diet (LFD), high-fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, or mild and severe forms of NAFLD, respectively. After 8 weeks on diets, mice were orally administered PERC (300 mg/kg/day) or vehicle (5% aqueous Alkamuls-EL620) for 5 days. PERC-induced liver effects were exacerbated in both NAFLD groups. PERC exposure was associated with up-regulation of genes involved in xenobiotic, lipid, and glutathione metabolism, and down-regulation of the complement and coagulation cascades, regardless of the diet. Interestingly, HFD fed mice, not MCD-fed mice, were generally more sensitive to PERC-induced liver effects. This was indicated by histopathology and transcriptional responses, where induction of genes associated with cell cycle and inflammation were prominent. Liver effects positively correlated with diet-specific differences in liver concentrations of PERC. We conclude that NAFLD alters the toxicodynamics of PERC and that NAFLD is a susceptibility factor that should be considered in future risk management decisions for PERC and other chlorinated solvents. PMID- 28903488 TI - An Analysis of the Relationship Between Preclinical and Clinical QT Interval Related Data. AB - There has been significant focus on drug-induced QT interval prolongation caused by block of the human ether-a-go-go-related gene (hERG)-encoded potassium channel. Regulatory guidance has been implemented to assess QT interval prolongation risk: preclinical guidance requires a candidate drug's potency as a hERG channel blocker to be defined and also its effect on QT interval in a non rodent species; clinical guidance requires a "Thorough QT Study" during development, although some QT prolonging compounds are identified earlier via a Phase I study. Clinical, heart rate-corrected QT interval (QTc) data on 24 compounds (13 positives; 11 negatives) were compared with their effect on dog QTc and the concentration of compound causing 50% inhibition (IC50) of hERG current. Concordance was assessed by calculating sensitivity and specificity across a range of decision thresholds, thus yielding receiver operating characteristic curves of sensitivity versus (1-specificity). The area under the curve of ROC curves (for which 0.5 and 1 indicate chance and perfect concordance, respectively) was used to summarize concordance. Three aspects of preclinical data were compared with the clinical outcome (receiver operating characteristic area under the curve values shown in brackets): absolute hERG IC50 (0.78); safety margin between hERG IC50 and clinical peak free plasma exposure (0.80); safety margin between QTc effects in dogs and clinical peak free plasma exposure (0.81). Positive and negative predictive values of absolute hERG IC50 indicated that from an early drug discovery perspective, low potency compounds can be progressed on the basis of a low risk of causing a QTc increase. PMID- 28903489 TI - From the Cover: Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants Decreased p-beta-Cateninser675 Expression and Its Interaction With E-Cadherin in the Mammary Glands of Lactating Rats. AB - Proper mammary gland development and function require precise hormonal regulation and bidirectional cross talk between cells provided by means of paracrine factors as well as intercellular junctions; exposure to environmental endocrine disruptors can disturb these processes. Exposure to one such family of chemicals, the brominated flame retardants (BFRs), is ubiquitous. Here, we tested the hypothesis that BFR exposures disrupt signaling pathways and intercellular junctions that control mammary gland development. Before mating, during pregnancy and throughout lactation, female Sprague-Dawley rats were fed diets containing that BFR mixture based on house dust, delivering nominal exposures of BFR of 0 (control), 0.06, 20, or 60 mg/kg/d. Dams were euthanized and mammary glands collected on postnatal day 21. BFR exposure had no significant effects on mammary gland/body weight ratios or the levels of proteins involved in milk synthesis, epithelial-mesenchymal transition, cell-cell interactions, or hormone signalling. However, BFR exposure (0.06 mg/kg/d) down-regulated phospho-ser675 beta-catenin (p-beta-catSer675) levels in the absence of any effect on total beta-catenin levels. Levels of p-CREB were also down-regulated, suggesting that PKA inhibition plays a role. p-beta-catSer675 co-localized with beta-catenin at the mammary epithelial cell membrane, and its expression was decreased in animals from the 0.06 and 20 mg/kg/d BFR treatment groups. Although beta-Catenin signaling was not affected by BFR exposure, the interaction between p-beta-catSer675 and E-cadherin was significantly reduced. Together, our results demonstrate that exposure to an environmentally relevant mixture of BFR during pregnancy and lactation decreases p-beta-catser675 at cell adhesion sites, likely in a PKA-dependant manner, altering mammary gland signaling. PMID- 28903490 TI - Estimating Methylmercury Intake for the General Population of South Korea Using Physiologically Based Pharmacokinetic Modeling. AB - The Korean National Environmental Health Survey (KoNEHS 2009-2011) tracks levels of environmental pollutants in biological samples from the adult Korean population (age 19-88). Recent survey results for blood mercury (Hg) suggest some exceedance above existing blood Hg reference levels. Because total blood Hg represents both organic and inorganic forms, and methylmercury (MeHg) has been specifically linked to several adverse health outcomes, a need exists to quantify MeHg intake for this population. Gender, age, and frequency of fish consumption were first identified as important predictors of KoNEHS blood Hg levels using generalized linear models. Stratified distributions of total blood Hg were then used to estimate distributions of blood MeHg using fractions of MeHg to total Hg from the literature. Next, a published physiologically based pharmacokinetic (PBPK) model was used to predict distributions of blood MeHg as a function of MeHg intake; ratios of MeHg intake to model-predicted blood MeHg were then combined with KoNEHS-based blood MeHg values to produce MeHg intake estimates. These intake estimates were ultimately compared with the Reference Dose (RfD) for MeHg (0.1 ug/kg/day) and reported as margin of exposure (MOE) estimates for specific KoNEHS subgroups. The derived MOEs across all subgroups, based on estimated geometric mean intake, ranged from 1.6 to 4.1. These results suggest MeHg exposures approaching the RfD for several subgroups of the Korean population, and not just for specific subgroups (eg, those who eat fish very frequently). PMID- 28903491 TI - Use of Rat Primary Mesenteric Cells for the Prediction of PDE4 Inhibitor Drug Induced Vascular Injury. AB - Drug-induced vascular injury (DIVI) in preclinical studies can delay, if not terminate, a drug development program. Clinical detection of DIVI can be very difficult as there are no definitive biomarkers known to reliably detect this disorder in all instances. The preclinical identification of DIVI requires detailed microscopic examination of a wide range of tissues although one of the most commonly affected areas in rats is the mesenteric vasculature. The reason for this predisposition of mesenteric arteries in rats as well as the exact mechanism and cell types involved in the initial development of these lesions have not been fully elucidated. We hypothesized that by using a mixed culture of cells from rat mesenteric tissue, we would be able to identify an RNA expression signature that could predict the invivo development of DIVI. Five compounds designed to inhibit Phosphodiesterase 4 activity (PDE4i) were chosen as positive controls. PDE4i's are well known to induce DIVI in the mesenteric vasculature of rats and there is microscopic evidence that this is associated, at least in part, with a proinflammatory mechanism. We surveyed, by qRT-PCR, the expression of 96 genes known to be involved in inflammation and using a Random-Forest model, identified 12 genes predictive of invivo DIVI outcomes in rats. Using these genes, we were able to cross-validate the ability of the Random-Forest modeling to predict the concentration at which PDE4i caused DIVI invivo. PMID- 28903493 TI - Editor's Highlight: Formulation and Toxicology Evaluation of the Intrathecal AYX1 DNA-Decoy in Sprague Dawley Rats. AB - The longevity of pain after surgery is debilitating and limits the recovery of patients. AYX1 is a double-stranded, unprotected, 23 base-pair oligonucleotide designed to reduce acute post-surgical pain and prevent its chronification with a single intrathecal perioperative dose. AYX1 mimics the DNA sequence normally bound by EGR1 on chromosomes, a transcription factor transiently induced in the dorsal root ganglia-spinal cord network following a noxious input. AYX1 binds to EGR1 and prevents it from launching waves of gene regulation that are necessary to maintain pain over time. A formulation suitable for an intrathecal injection of AYX1 was developed, including a specific ratio of AYX1 and calcium so the ionic homeostasis of the cerebrospinal fluid is maintained and no impact on neuromuscular control is produced upon injection. A GLP toxicology study in naive Sprague Dawley rats was conducted using 3 dose levels up to the maximum feasible dose. Clinical observations, neurobehavioral observations, clinical pathology and histopathology of the nervous system and peripheral tissues were conducted. An additional nonGLP study was conducted in the spared nerve injury model of chronic neuropathic pain in which EGR1 is induced in the dorsal root ganglia and spinal cord. Similar testing was performed, including a modified Irwin test to assess a potential impact of AYX1 on autonomic nervous system responses, locomotion, activity, arousal, sensorimotor, and neuromuscular function. No AYX1-related adverse events were observed in any of the studies and the no-observed-adverse effect-level was judged to be the maximum feasible dose. PMID- 28903492 TI - Editor's Highlight: Nlrp3 Is Required for Inflammatory Changes and Nigral Cell Loss Resulting From Chronic Intragastric Rotenone Exposure in Mice. AB - Complex interactions between genetic and environmental factors are widely believed to underlie the incidence and progression of Parkinson's disease (PD). Rotenone is a naturally occurring metabolic toxin employed as an insecticide and piscicide identified as a risk factor for the development of PD in agricultural workers. The Nlrp3 inflammasome is an intracellular mediator that can initiate an inflammatory cascade in response to cellular stress. Reports by others indicating that NLRP3 expression was detectable in tissues obtained from Alzheimer's disease patients and that the PD-associated protein alpha-synuclein could activate inflammasomes in cultured glial cells, prompted us to test the prediction that Nlrp3 was required for the development of Parkinson's-like changes resulting from rotenone exposure in mice. We exposed wild type and Nlrp3-/- mice to chronic low doses of intragastric rotenone and conducted longitudinal behavioral and serum cytokine analysis followed by evaluation of neuroinflammatory and neurodegenerative endpoints in brain tissues. We observed progressive rotenone dependent changes in serum cytokine levels and circulating leukocytes in wild type mice not observed in Nlrp3-/- mice. Analysis of brain tissues revealed Nlrp3 dependent neuroinflammation and nigral cell loss in mice exposed to rotenone as compared with mice exposed to vehicle alone. Together, our findings provide compelling evidence of a role for Nlrp3 in nigral degeneration and neuroinflammation resulting from systemic rotenone exposure and suggest that the suppression of NLRP3 activity may be a rational neuroprotective strategy for toxin-associated PD. PMID- 28903494 TI - Optimization of the Ocular Treatment Following Organophosphate Nerve Agent Insult. AB - Eye exposure to organophosphate (OP) irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. The aim of this study was to find an anticholinergic antidote, which would counteract miosis and visual impairment induced by the nerve agents sarin and VX with minimal untoward side-effects. Rat pupil width and light reflex were evaluated from 15 min up to 2 weeks following topical OP exposure with or without topical ocular treatment of atropine or homatropine or with a combined intramuscular treatment of trimedoxime (TMB-4) and atropine (TA). Visual function following insult and treatment was assessed using a cued Morris water maze task. Topical VX exposure showed a dose-dependent miosis with a significant reduction in visual function similar to the effect seen following sarin exposure. Homatropine (2%; w/v) and atropine (0.1%; w/v) treatment ameliorated both sarin and VX-induced miosis and the resulting visual impairment. TA treatment was sufficient in ameliorating the sarin-induced ocular impairment while an additional ocular treatment with either 0.1% atropine or 2% homatropine was necessary following VX exposure. To conclude the use of 0.1% atropine or 2% homatropine was beneficial in ameliorating the ocular insult following VX or sarin ocular exposure and thus should be considered as universal treatments against this intoxication. The findings also emphasize the necessity of additional ocular treatment to the systemic treatment in visually impaired casualties following VX exposure. PMID- 28903495 TI - RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations. AB - Lead (Pb) is a well-known toxicant, especially for the developing nervous system, albeit the mechanism is largely unknown. In this study, we use time series RNA seq to conduct a genome-wide survey of the transcriptome response of human embryonic stem cell-derived neural progenitor cells to lead treatment. Using a dynamic time warping algorithm coupled with statistical tests, we find that lead can either accelerate or decelerate the expression of specific genes during the time series. We further show that lead disrupts a neuron- and brain-specific splicing factor NOVA1 regulated splicing network. Using lead induced transcriptome change signatures, we predict several known and novel disease risks under lead exposure. The findings in this study will allow a better understanding of the mechanism of lead toxicity, facilitate the development of diagnostic biomarkers and treatment for lead exposure, and comprise a highly valuable resource for environmental toxicology. Our study also demonstrates that a human (embryonic stem) cell-derived system can be used for studying the mechanism of toxicants, which can be useful for drug or compound toxicity screens and safety assessment. PMID- 28903496 TI - Editor's Highlight: Development of Novel Neural Embryonic Stem CellTests for High Throughput Screening of Embryotoxic Chemicals. AB - There is a great demand for appropriate alternative methods to rapidly evaluate the developmental and reproductive toxicity of a wide variety of chemicals. We used the differentiation of mouse embryonic stem cells (mESCs) into cardiomyocytes as a basis for establishing a rapid and highly reproducible invitro embryotoxicity test known as the Hand1-Luc Embryonic Stem Cell Test (Hand1-Luc EST). In this study, we developed novel neural-Luc ESTs using two marker genes for neural development, tubulin beta-3 (Tubb3) and Reelin (Reln), and evaluated the capacity of these tests to predict developmental toxicity. In addition, we tested whether an integrated approach (a combination of neural-Luc ESTs and the Hand1-Luc EST) improved developmental toxicant detection. To perform our neural-Luc ESTs, we needed to generate stable transgenic mESCs with individual promoters linked to the luciferase gene, and to establish that similar changes in promoter activities and mRNA expression levels occur during neural differentiation. Based on the concentration-response curves of 15 developmental toxicants and 17 non-developmental toxic chemicals, we derived a prediction formula and assessed the capacity of this formula to predict developmental toxicity. Although both were highly sensitive and specific for predicting developmental toxicity, neural-Luc ESTs had similar predictive capacities. In contrast, neural-Luc ESTs and Hand1-Luc EST had significantly different predictive powers. As expected, the combination of these ESTs increased the sensitivity of developmental toxicant detection. These results demonstrate the convenience and the usefulness of this combination of ESTs as an alternative assay system for future toxicological and mechanistic studies of developmental toxicity. PMID- 28903497 TI - Downregulation of TMEM70 in Rat Liver Cells After Hepatocarcinogen Treatment Related to the Warburg Effect in Hepatocarcinogenesis Producing GST-P-Expressing Proliferative Lesions. AB - We previously observed downregulation of mitochondrial oxidative phosphorylation related protein, TMEM70, which is suggestive of disrupted cellular senescence, in GST-P-expressing (+) proliferative lesions from early hepatocarcinogenesis stages in rats. The present study investigated the immunohistochemical relationship between TMEM70 downregulation and cellular metabolic changes in carcinogenic processes, as well as the onset of the liver cell respiratory changes after repeated hepatocarcinogen treatment in rats. At the early hepatocarcinogenesis stage in a 2-stage model, GST-P+ preneoplastic lesions showing TMEM70 downregulation also downregulated the mitochondrial ATPase, ATPB, but upregulated glycolysis-related glucose transporter member 1 (GLUT1) and glucose-6-phosphate dehydrogenase, suggesting a metabolic shift from oxidative phosphorylation to glycolysis, known as the Warburg effect. Combined downregulation of TMEM70 and ATPB increased proliferation activity in GST-P+ preneoplastic lesions, suggesting cell proliferation facilitation by reducing mitochondrial respiration. Concurrent GLUT1-upregulation and TMEM70-downregulation increased nuclear phosphorylated c MYC+ cells in GST-P+ preneoplastic lesions, suggesting c-MYC-mediated transcription facilitation to promote glycolysis and cell proliferation. The TMEM70-related metabolic shift was enhanced in GST-P+ neoplastic lesions, suggesting a contribution to tumor progression. Conversely, the TMEM70-related metabolic shift was lacking in peroxisome proliferator-activated receptor-alpha agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs. Transcript expression analysis following 28- and 90-day repeated hepatocarcinogen treatment showed downregulation of Tmem70 from day 28 and upregulation of Pkm and Myc at day 90, suggesting early onset of a catastrophic cellular senescence-related metabolic shift beginning from depressed mitochondrial respiration in the liver. These results suggest a contribution of TMEM70 downregulation to the Warburg effect, which directs tumor promotion and progression in GST-P+-linked hepatocarcinogenesis in rats. PMID- 28903498 TI - From the Cover: Lifelong Exposure of C57bl/6n Male Mice to Bisphenol A or Bisphenol S Reduces Recovery From a Myocardial Infarction. AB - Bisphenol A (BPA) leaches from plastics to contaminate foodstuffs. Analogs, such as bisphenol S (BPS), are now used increasingly in manufacturing. Greater BPA exposure has been correlated with exacerbation of cardiovascular disease, including myocardial infarction (MI). To test the hypothesis that bisphenol exposure impairs cardiac healing, we exposed C57bl/6n mice to water containing 25ng/ml BPA or BPS from conception and surgically induced an MI in adult male progeny. Increased early death and cardiac dilation, and reduced cardiac function were found post-MI in BPA- and BPS-exposed mice. Flow cytometry revealed increased monocyte and macrophage infiltration that correlated with increased chemokine C-C motif ligand-2 expression in the infarct. In vitro BPA and BPS addition increased matrix metalloproteinase-9 (MMP) protein and secreted activity in RAW264.7 macrophage cells suggesting that invivo increases in MMP2 and MMP9 in exposed infarcts were myeloid-derived. Bone marrow-derived monocytes isolated from exposed mice had greater expression of pro-inflammatory polarization markers when chemokine stimulated indicating an enhanced susceptibility to develop a pro inflammatory monocyte population. Chronic BPA exposure of estrogen receptor beta (ERbeta) deficient mice did not worsen early death, cardiac structure/function, or expression of myeloid markers after an MI. In contrast, BPS exposure of ERbeta deficient mice resulted in greater death and expression of myeloid markers. We conclude that lifelong exposure to BPA or BPS augmented the monocyte/macrophage inflammatory response and adverse remodeling from an MI thereby reducing the ability to survive and successfully recover, and that the adverse effect of BPA, but not BPS, is downstream of ERbeta signaling. PMID- 28903500 TI - Intrinsic Xenobiotic Metabolizing Enzyme Activities in Early Life Stages of Zebrafish (Danio rerio). AB - Early life stages of zebrafish (Danio rerio, zf) are gaining attention as an alternative invivo test system for drug discovery, early developmental toxicity screenings and chemical testing in ecotoxicological and toxicological testing strategies. Previous studies have demonstrated transcriptional evidence for xenobiotic metabolizing enzymes (XME) during early zf development. However, elaborate experiments on XME activities during development are incomplete. In this work, the intrinsic activities of representative phase I and II XME were monitored by transformation of putative zf model substrates analyzed using photometry and high pressure liquid chromatography techniques. Six different defined stages of zf development (between 2.5 h postfertilization (hpf) to 120 hpf) were investigated by preparing a subcellular fraction from whole organism homogenates. We demonstrated that zf embryos as early as 2.5 hpf possess intrinsic metabolic activities for esterase, Aldh, Gst, and Cyp1a above the methodological detection limit. The activities of the enzymes Cyp3a and Nat were measurable during later stages in development. Activities represent dynamic patterns during development. The role of XME activities revealed in this work is relevant for the assessing toxicity in this test system and therefore contributes to a valuable characterization of zf embryos as an alternative testing organism in toxicology. PMID- 28903499 TI - The Long-Lasting Rodenticide Brodifacoum Induces Neuropathology in Adult Male Rats. AB - Superwarfarins are very long-lasting rodenticides effective in warfarin-resistant rodents at extremely low doses. The consequences of chronic superwarfarin levels in tissues, due to biological half-lives on the order of 20 days, have not been examined. We now characterized the neurological effects of brodifacoum (BDF), one of the most widely used superwarfarins, in adult male Sprague Dawley rats. Dosing curves established the acute oral lethal dose for BDF as 221 +/- 14 MUg/kg. Measurement of tissue BDF levels showed accumulation throughout the body, including the central nervous system, with levels diminishing over several days. Immunocytochemical staining showed that both astrocyte and microglial activation was increased 4 days after BDF administration, as were levels of carbonylated proteins, and neuronal damage assessed by fluorojade B staining. Direct toxic effects of BDF on neurons and glia were observed using enriched cultures of cerebellar neurons and cortical astrocytes. Proteomic analysis of cerebellar lysates revealed that BDF altered expression of 667 proteins in adult rats. Gene ontology and pathway analysis identified changes in several functional pathways including cell metabolism, mitochondria function, and RNA handling with ribosomal proteins comprising the largest group. In vitro studies using primary astrocytes showed that BDF suppressed de novo protein synthesis. These findings demonstrate that superwarfarin accumulation increases indices of neuroinflammation and neuropathology in adult rodents, suggesting that methods which minimize BDF toxicity may not address delayed neurological sequelae. PMID- 28903501 TI - Sex-Differential Responses of Tumor Promotion-Associated Genes and Dysregulation of Novel Long Noncoding RNAs in Constitutive Androstane Receptor-Activated Mouse Liver. AB - Xenobiotic agonists of constitutive androstane receptor (CAR) induce many hepatic drug metabolizing enzymes, but following prolonged exposure, promote hepatocellular carcinoma, most notably in male mouse liver. Here, we used nuclear RNA-seq to characterize global changes in the mouse liver transcriptome following exposure to the CAR-specific agonist ligand 1,4-bis-[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP), including changes in novel long noncoding RNAs that may contribute to xenobiotic-induced pathophysiology. Protein-coding genes dysregulated by 3 h TCPOBOP exposure were strongly enriched in KEGG pathways of xenobiotic and drug metabolism, with stronger and more extensive gene responses observed in female than male liver. After 27 h TCPOBOP exposure, the number of responsive genes increased >8-fold in males, where the top enriched pathways and their upstream regulators expanded to include factors implicated in cell cycle dysregulation and hepatocellular carcinoma progression (cyclin-D1, oncogenes E2f, Yap, Rb, Myc, and proto-oncogenes beta-catenin, FoxM1, FoxO1, all predicted to be activated by TCPOBOP in male but not female liver; and tumor suppressors p21 and p53, both predicted to be inhibited). Upstream regulators uniquely associated with 3 h TCPOBOP-exposed females include TNF/NFkB pathway members, which negatively regulate CAR-dependent proliferative responses and may contribute to the relative resistance of female liver to TCPOBOP-induced tumor promotion. These responses may be modified by the many long noncoding liver RNAs we show are dysregulated by TCPOBOP or pregnane-X-receptor agonist exposure, including lncRNAs proximal to CAR target genes Cyp2b10, Por, and Alas1. These data provide a comprehensive view of the CAR-regulated transcriptome and give insight into the mechanism of sex-biased susceptibility to CAR-dependent mouse liver tumorigenesis. PMID- 28903505 TI - Erratum. PMID- 28903503 TI - Identifying Gaps in Respiratory Syncytial Virus Disease Epidemiology in the United States Prior to the Introduction of Vaccines. AB - Respiratory syncytial virus (RSV) causes lower respiratory tract illness frequently. No effective antivirals or vaccines for RSV are approved for use in the United States; however, there are at least 50 vaccines and monoclonal antibody products in development, with those targeting older adults and pregnant women (to protect young infants) in phase 2 and 3 clinical trials. Unanswered questions regarding RSV epidemiology need to be identified and addressed prior to RSV vaccine introduction to guide the measurement of impact and future recommendations. The Centers for Disease Control and Prevention (CDC) convened a technical consultation to gather input from external subject matter experts on their individual perspectives regarding evidence gaps in current RSV epidemiology in the United States, potential studies and surveillance platforms needed to fill these gaps, and prioritizing efforts. Participants articulated their individual views, and CDC staff synthesized individuals' input into this report. PMID- 28903504 TI - Spontaneous Viral Load Decline and Subsequent Clearance of Chronic Hepatitis C Virus in Postpartum Women Correlates With Favorable Interleukin-28B Gene Allele. AB - Background: Postpartum hepatitis C viral (HCV) load decline followed by spontaneous clearance has been previously described. Herein we identify predictors for viral decline in a cohort of HCV-infected postpartum women. Methods: Pregnant women at Cairo University were screened for anti-HCV antibodies and HCV RNA, and viremic women were tested for quantitative HCV RNA at 3, 6, 9, and 12 months postpartum. Spontaneous clearance was defined as undetectable viremia twice at least 6-months apart. Associations between viral load and demographic, obstetrical, HCV risk factors, and interleukin-28B gene (IL28B) polymorphism (rs12979860) were assessed. Results: Of 2514 women, 97 (3.9%) had anti-HCV antibodies, 54 (2.1%) were viremic and of those, 52 (2.1%) agreed to IL28B testing. From pregnancy until 12 months postpartum, IL28B-CC allele women had a significant viral decline (P = .009). After adjusting, the IL28B-CC allele had a near significant difference compared to the CT allele (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.75,1.00; P = .05), but not the TT allele (OR, 0.91; 95% CI, 0.61,1.38; P = .64). All 14/52 (26.9%) women who subsequently cleared were among the 15 with undetectable viremia at 12 months, making that time point a strong predictor of subsequent clearance (sensitivity = 100%, specificity = 97.4%, positive predictive value = 93.3%, negative predictive value = 100%). Conclusions: IL28B-CC genotype and 12-month postpartum undetectable viremia were the best predictors for viral decline and subsequent clearance. These 2 predictors should influence clinical decision making. PMID- 28903506 TI - A Population-Based Assessment of the Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines on Macrolide-Resistant Invasive Pneumococcal Disease: Emergence and Decline of Streptococcus pneumoniae Serotype 19A (CC320) With Dual Macrolide Resistance Mechanisms. AB - Background: Macrolide efflux encoded by mef(E)/mel and ribosomal methylation encoded by erm(B) confer most macrolide resistance in Streptococcus pneumoniae. Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 reduced macrolide-resistant invasive pneumococcal disease (MR-IPD) due to PCV7 serotypes (6B, 9V, 14, 19F, and 23F). Methods: In this study, the impact of PCV7 and PCV13 on MR-IPD was prospectively assessed. A 20-year study of IPD performed in metropolitan Atlanta, Georgia, using active, population-based surveillance formed the basis for this study. Genetic determinants of macrolide resistance were evaluated using established techniques. Results: During the decade of PCV7 use (2000-2009), MR-IPD decreased rapidly until 2002 and subsequently stabilized until the introduction of PCV13 in 2010 when MR-IPD incidence decreased further from 3.71 to 2.45/100000 population. In 2003, serotype 19A CC320 isolates containing both mef(E)/mel and erm(B) were observed and rapidly expanded in 2005 2009, peaking in 2010 (incidence 1.38/100000 population), accounting for 36.1% of MR-IPD and 11.7% of all IPD isolates. Following PCV13 introduction, dual macrolide-resistant IPD decreased 74.1% (incidence 0.32/100000 in 2013). However, other macrolide-resistant serotypes (eg, 15A and 35B) not currently represented in PCV formulations increased modestly. Conclusions: The selective pressures of widespread macrolide use and PCV7 and PCV13 introductions on S. pneumoniae were associated with changes in macrolide resistance and the molecular basis over time in our population. Durable surveillance and programs that emphasize the judicious use of antibiotics need to continue to be a focus of public health strategies directed at S. pneumoniae. PMID- 28903507 TI - CD4:CD8 Ratio and CD8 Count as Prognostic Markers for Mortality in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC). AB - Background: We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count. Methods: We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy (ART) naive adults who started ART during 1996-2010, who were followed from the date they had CD4 count >=350 cells/MUL and were virologically suppressed (baseline). We used stratified Cox models to estimate unadjusted and adjusted (for sex, people who inject drugs, ART initiation year, and baseline age, CD4 count, AIDS, duration of ART) all-cause and cause-specific mortality hazard ratios for tertiles of CD4:CD8 ratio (0-0.40, 0.41-0.64 [reference], >0.64) and CD8 count (0 760, 761-1138 [reference], >1138 cells/MUL) and examined the shape of associations using cubic splines. Results: During 276526 person-years, 1834 of 49865 patients died (249 AIDS-related; 1076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11 (95% confidence interval [CI], 1.00-1.25). The association of CD8 count with all-cause mortality was U-shaped: aHR for higher vs middle tertile was 1.13 (95% CI, 1.01-1.26). AIDS related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. There was little evidence that CD4:CD8 ratio or CD8 count was prognostic for non-AIDS mortality. Conclusions: In this large cohort collaboration, the magnitude of adjusted associations of CD4:CD8 ratio or CD8 count with mortality was too small for them to be useful as independent prognostic markers in virally suppressed patients on ART. PMID- 28903508 TI - Effect of Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir and Ledipasvir/Sofosbuvir Regimens on Survival Compared With Untreated Hepatitis C Virus-Infected Persons: Results From ERCHIVES. AB - Background: Interferon-based regimens are associated with a substantial survival benefit for persons infected with hepatitis C virus (HCV). Survival data with direct-acting antiviral agents are not available. We conducted this study to quantify the effect of paritaprevir/ritonavir, ombitasvir, dasabuvir (PrOD) and ledipasvir/sofosbuvir (LDV/SOF) regimens upon mortality. Methods: In the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a well established national cohort of HCV-infected Veterans, we identified HCV-infected persons initiated on PrOD or LDV/SOF, excluding those with human immunodeficiency virus, hepatitis B surface antigen positivity, hepatocellular carcinoma, or missing HCV RNA or FIB-4 scores. For each case, we identified a propensity score matched control never initiated on treatment. Primary outcome was survival. Outcomes were assessed using frequency of events, Kaplan-Meier curves, and Cox proportional hazards regression analyses. Results: We identified 1473 persons on PrOD, 5497 on LDV/SOF, and 6970 propensity score-matched untreated persons. Treated persons were more likely to be obese and have cirrhosis, but less likely to have stage 3-5 chronic kidney disease (CKD), alcohol or drug abuse or dependence diagnosis, and anemia. The proportion of persons who died was higher in the untreated group compared with either treatment group (PrOD, 0.3%; LDV/SOF, 1.4%; untreated controls, 2.5%; P < .001). A significantly larger percentage of treated patients survived to 18 months of follow-up, compared with untreated controls (P < .001). In multivariable Cox regression analysis, treatment with either regimen (hazard ratio [HR], 0.43; 95% confidence interval [CI], .33-.57) and attainment of sustained virologic response (SVR) were associated with significantly lower mortality (HR, 0.57; 95% CI, .33-.99). Conclusions: Treatment with PrOD or LDV/SOF and SVR are associated with a significant mortality benefit, apparent within the first 18 months of treatment. PMID- 28903512 TI - Erratum. PMID- 28903510 TI - Changes in Liver Steatosis After Switching From Efavirenz to Raltegravir Among Human Immunodeficiency Virus-Infected Patients With Nonalcoholic Fatty Liver Disease. AB - Background: Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues. Methods: HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values >=238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP. Results: Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1-Q3, 221-277) dB/m and 286 (Q1-Q3, 269-314) dB/m for the EFV group (P = .035). The median decrease in CAP values was -20 (Q1-Q3, -67 to 15) dB/m for the RAL arm and 30 (Q1-Q3, -17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029). Conclusions: After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL. Clinical Trials Registration: NCT01900015. PMID- 28903511 TI - Fatal Deer Tick Virus Infection in Maine. AB - Deer tick virus (DTV), a genetic variant (lineage II) of Powassan virus, is a rare cause of encephalitis in North America. We report a fatal case of DTV encephalitis following a documented bite from an Ixodes scapularis tick and the erythema migrans rash associated with Lyme disease. PMID- 28903514 TI - Impact of an Antimicrobial Stewardship Program on Antibiotic Use at a Nonfreestanding Children's Hospital. AB - Background: Pediatric stewardship programs have been successful at reducing unnecessary antibiotic use. Data from nonfreestanding children's hospitals are currently limited. This study is an analysis of antibiotic use after implementation of an antimicrobial stewardship program at a community nonfreestanding children's hospital. Methods: In April 2013, an antimicrobial stewardship program that consisted of physician-group engagement and pharmacist prospective auditing and feedback was initiated. We compared antibiotic use in the preintervention period (April 2012 to March 2013) with that in the postintervention period (April 2013 to March 2015) in all units except the neonatal intensive care unit and the emergency department. In addition, drug acquisition costs, antibiotic-specific use, death, length of stay, and case-mix index were examined. Results: Antibiotic use decreased by 16.8% (95% confidence interval, 18.0% to -9.2%; P < .001) in the postintervention period. Vancomycin use decreased by 38% (P = .001), whereas antipseudomonal beta-lactam use was unaltered. Drug-acquisition cost savings were estimated to be $67 000/year over the 2-year postintervention period. Lengths of stay and mortality rates were unchanged in the postintervention period after adjusting for case-mix index. Conclusions: Implementation of a simple stewardship initiative with limited resources at a community nonfreestanding children's hospital effectively reduced antibiotic use without an overt negative impact on overall clinical outcomes. The results of this study suggest that nonfreestanding children's hospitals can achieve substantial reductions in antibiotic use despite limited resources. PMID- 28903515 TI - Update From the Advisory Committee on Immunization Practices. AB - The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts, meets 3 times per year to develop recommendations for vaccine use in the United States. The group has 15 voting members, and each member's term is 4 years. ACIP members and Centers for Disease Control and Prevention (CDC) staff discuss the epidemiology of vaccine-preventable diseases and vaccine research, effectiveness, safety data, and clinical trial results. Representatives from the American Academy of Pediatrics (C. L. B. and Y. A. M.) and the Pediatric Infectious Diseases Society (S. T. O.) are present as liaisons to the ACIP. The ACIP met February 22 and 23, 2017, to discuss proposed recommendations regarding vaccination for unprotected infants born to hepatitis B surface antigen (HBsAg)-positive mothers; topics included cost analysis, influenza surveillance, influenza vaccine effectiveness, herpes zoster vaccine, and considerations for meningococcal serogroup B booster doses in groups at increased risk. Updates on mumps epidemiology, Dengue virus vaccines, Zika virus vaccines, adult immunization, and yellow fever vaccine were also provided. PMID- 28903516 TI - Gradenigo Syndrome and Cavitary Lung Lesions in a 5-Year-Old With Recurrent Otitis Media. PMID- 28903517 TI - Association of Vancomycin Trough Concentration With Response to Treatment for Acute Pulmonary Exacerbation of Cystic Fibrosis. AB - Background: Our goal was to determine the relationship between serum vancomycin trough concentrations (VTCs) and changes in pulmonary function among individuals with an acute pulmonary exacerbation (APE) of cystic fibrosis (CF). Methods: We included subjects who were >=6 years of age, were hospitalized for an APE of CF between May 1, 2012, and April 30, 2014, were administered vancomycin for >=48 hours, and had a history of airway infection with methicillin-resistant Staphylococcus aureus. Pearson correlations were performed to characterize the relationship between VTC and pulmonary function. Results: The mean final VTC (+/- standard deviation) was 12.6 +/- 3.3 ug/mL; 40 (81.6%) of 49 final VTCs were in the range of 10 to <15 ug/mL. The mean change in forced expiratory volume in 1 second (FEV1) between admission and discharge was 24.5% +/- 24.4% (P < .001) of predicted values. Forty-two (85.7%) patients returned to their baseline FEV1. No correlation between the change in FEV1 and VTC (Pearson r = -0.10; P = .49) was identified. Similarly, VTC, daily weight-adjusted vancomycin dose, and vancomycin area under the concentration-time curve normalized to the minimum inhibitory concentration (AUC/MIC) were not significant predictors of change in FEV1 or return to baseline FEV1 on multivariate analysis. One (2%) subject experienced acute kidney injury. Conclusions: The majority of patients experienced improvement in pulmonary function and a return to their baseline FEV1 while achieving a VTC in the range of 10 to <15 ug/mL. We were unable to identify a correlation between markers of vancomycin exposure and change in pulmonary function test results. Additional studies are needed to reinforce the efficacy of VTCs of 10 to 15 ug/mL for treating APEs of CF. PMID- 28903518 TI - Recurrent Fever and Mouth Ulcers in a Healthy Child. PMID- 28903519 TI - Septic Shock Secondary to Chikungunya Virus in a 3-Month-Old Traveler Returning From Honduras. PMID- 28903521 TI - Treatment-Related Complications in Children Hospitalized With Disseminated Lyme Disease. AB - We describe here treatment approaches and treatment-related complications in 138 hospitalized children with disseminated Lyme disease. The patients who received parenteral antibiotics had a higher rate of complications than those who received oral therapy (15.4 vs 4.2 per 1000 days of therapy, respectively; P < .05). Oral therapy should be used preferentially if either route is supported by current guidelines. PMID- 28903520 TI - Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy. AB - Background: Data on long-term toxicity of antiretroviral therapy (ART) in HIV infected children are sparse. PENPACT-1 was an open-label trial in which HIV infected children were assigned randomly to receive protease inhibitor (PI)- or nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. Methods: We examined changes in clinical, immunologic, and inflammatory markers from baseline to year 4 in the subset of children in the PENPACT-1 study who experienced viral suppression between week 24 and year 4 of ART. Liver enzyme, creatinine, and cholesterol levels and hematologic parameters were assessed during the trial. Cystatin C, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), d dimer, and soluble CD14 (sCD14) were assayed from cryopreserved specimens. Results: Ninety-nine children (52 on PI-based and 47 on NNRTI-based ART) met inclusion criteria. The median age at initiation of ART was 6.5 years (interquartile range [IQR], 3.7-13.4 years), and 22% were aged <3 years at ART initiation; 56% of the PI-treated children received lopinavir/ritonavir, and 70% of NNRTI-treated children received efavirenz initially. We found no evidence of significant clinical toxicity in either group; growth, liver, kidney, and hematologic parameters either remained unchanged or improved between baseline and year 4. Total cholesterol levels increased modestly, but no difference between the groups was found. IL-6 and hs-CRP levels decreased more after 4 years in the NNRTI-based ART group. The median change in IL-6 level was -0.35 pg/ml in the PI based ART group and -1.0 in the NNRTI-based ART group (P = .05), and the median change in hs-CRP level was 0.25 ug/ml in the PI-based ART group and -0.95 ug/ml in the NNRTI-based ART group (P = .005). Conclusion: These results support the safety of prolonged ART use in HIV-infected children and suggest that suppressive NNRTI-based regimens can be associated with lower levels of systemic inflammation. PMID- 28903522 TI - Retrospective Analysis of Posaconazole Suspension Dosing Strategies in a Pediatric Oncology Population: Single-Center Experience. AB - Limited data on optimal posaconazole dosing strategies for pediatric patients exist. In this study, we found that the median initial dose in patients who achieved a posaconazole plasma concentration of 0.7 MUg/mL was 22.8 mg/kg per day whereas the median initial dose in those who did not reach the target concentration was 15.8 mg/kg per day; this result suggests that higher initial doses might be warranted. PMID- 28903523 TI - Fungal Infections of the Central Nervous System in Children. AB - Although uncommon in children, fungal infections of the central nervous system can be devastating and difficult to treat. A better understanding of basic mycologic, immunologic, and pharmacologic processes has led to important advances in the diagnosis and management of these diseases, but their mortality rates remain unacceptably high. In this focused review, we examine the epidemiology and clinical features of the most common fungal pathogens of the central nervous system in children and explore recent advances in diagnosis and antifungal therapy. PMID- 28903524 TI - Pediatric Dental Clinic-Associated Outbreak of Mycobacterium abscessus Infection. AB - Background: Mycobacterium abscessus is an uncommon cause of invasive odontogenic infection. Methods: M abscessus-associated odontogenic infections occurred in a group of children after they each underwent a pulpotomy. A probable case-child was defined as a child with facial or neck swelling and biopsy-confirmed granulomatous inflammation after a pulpotomy between October 1, 2013, and September 30, 2015. M abscessus was isolated by culture in confirmed case children. Clinical presentation, management, and outcomes were determined by medical record abstraction. Results: Among 24 children, 14 (58%) were confirmed case-children. Their median age was 7.3 years (interquartile range, 5.8-8.2 years), and the median time from pulpotomy to symptom onset was 74 days (range, 14-262 days). Clinical diagnoses included cervical lymphadenitis (24 [100%] of 24), mandibular or maxillary osteomyelitis (11 [48%] of 23), and pulmonary nodules (7 [37%] of 19). Each child had >=1 hospitalization and a median of 2 surgeries (range, 1-6). Of the 24 children, 12 (50%) had surgery alone and 11 (46%) received intravenous (IV) antibiotics. Nineteen of the 24 (79%) children experienced complications, including vascular access malfunction (7 [64%] of 11), high-frequency hearing loss (5 [56%] of 9), permanent tooth loss (11 [48%] of 23), facial nerve palsy (7 [29%] of 24), urticarial rash (3 [25%] of 12), elevated liver enzyme levels (1 [20%] of 5), acute kidney injury (2 [18%] of 11), incision dehiscence/fibrosis (3 [13%] of 24), and neutropenia (1 [9%] of 11). Conclusions: M abscessus infection was associated with significant medical morbidity and treatment complications. Unique manifestations included extranodal mandibular or maxillary osteomyelitis and pulmonary nodules. Challenges in the identification of case-children resulted from an extended incubation period and various clinical manifestations. Clinicians should consider the association between M abscessus infection and pulpotomy in children who present with subacute cervical lymphadenitis. The use of treated/sterile water during pulpotomy might prevent further outbreaks. PMID- 28903525 TI - The interactive impact of root branch order and soil genetic horizon on root respiration and nitrogen concentration. AB - In general, respiration (RS) is highly correlated with nitrogen concentration (N) in plant organs, including roots, which exhibit a positive N-RS relationship. Less is known, however, about the relationship between N and RS in roots of different branch orders within an individual tree along a vertical soil profile; this is especially true in trees with contrasting life strategies, such as pioneer Scots pine (Pinus sylvestris L.) vs mid-successional sessile oak (Quercus petraea Liebl.). In the present research, the impact of root branch order, as represented by those with absorptive vs transporting ability, and soil genetic horizon on root N, RS and the N-RS relationship was examined. Mean RS and total N concentration differed significantly among root branch orders and was significantly higher in absorptive roots than in transporting roots. The soil genetic horizon differentially affected root RS in Scots pine vs sessile oak. The genetic horizon mostly affected RS in absorptive roots of Scots pine and transporting roots in sessile oak. Root N was the highest in absorptive roots and most affected by soil genetic horizon in both tree species. Root N was not correlated with soil N, although N levels were higher in roots growing in fertile soil genetic horizons. Overall, RS in different root branch orders was positively correlated with N in both species. The N-RS relationship in roots, pooled by soil genetic horizon, was significant in both species, but was only significant in sessile oak when roots were pooled by root branch order. In both tree species, a significant interaction was found between the soil genetic horizon and root branch order with root function; however, species-specific responses were found. Both root N, which was unaffected by soil N, and the positive N-RS relationship consistently observed in different genetic horizons suggest that root function prevails over environmental factors, such as soil genetic horizon. PMID- 28903526 TI - Drought reduces growth and stimulates sugar accumulation: new evidence of environmentally driven non-structural carbohydrate use. PMID- 28903528 TI - Leptomeningeal metastases of lung adenocarcinoma detected by 18F-FDG PET/CT. PMID- 28903527 TI - Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial. AB - Objective: The rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma is high. Seeding upper urinary tract urothelial carcinoma cells onto the damaged bladder wall is considered to be one of the causes of intravesical recurrence after radical nephroureterectomy. We evaluated the utility of early ureteral ligation in preventing the intravesical recurrence. Methods: This prospective single-arm clinical trial included patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma in the Tohoku Urological Evidence-Based Medicine Study Group between 2012 and 2013. Early ureteral ligation was defined as ligation of the ureter as quickly as possible after expanding the retroperitoneal space. A historical control was extracted from 454 patients who underwent radical nephroureterectomy in the same group, using propensity score-matched analysis. Intravesical recurrence-free survival rates were analyzed using Kaplan-Meier curves. Factors predicting intravesical recurrence were assessed using multivariate analyses. Results: Seventy-four patients underwent early ureteral ligation. Seventeen (23%) patients had intravesical recurrence with a median follow-up period of 24 months. The 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 81% and 76%, and in the control group 75% and 63%, respectively (P = 0.160). In patients with renal pelvic cancer, the 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 89% and 86%, but in the control group 74% and 64%, respectively (P = 0.025). However, intravesical recurrence-free survival rates were similar in patients with ureteral cancer. Multivariate analyses of a subset of patients with renal pelvic cancer identified early ureteral ligation as an independent predictor of intravesical recurrence. Conclusions: Early ureteral ligation decreases the rate of intravesical recurrence after radical nephroureterectomy in patients with renal pelvic cancer. Thus, early ureteral ligation might help in prevention of intravesical recurrence for renal pelvic cancer. PMID- 28903529 TI - Retrospective analysis of definitive radiotherapy for neck node metastasis from unknown primary tumor: Japanese Radiation Oncology Study Group study. AB - Objective: To investigate the optimal treatment method and risk factor of neck node metastasis from unknown primary tumors (NUP) treated by radiotherapy. Methods: Retrospective case study based on a multi-institutional survey was conducted by the Japanese Radiation Oncology Study Group. Patients pathologically diagnosed as having NUP from 1998 to 2007 were identified. Univariate and multivariate analyses of overall survival (OS), progression free survival (PFS), neck progression free survival (NPFS) and mucosal progression free survival (MPFS) were evaluated. Results: In total, 130 patients with median age of 65 years were included. Nodal stages N1, N2a, N2b and N2c were observed for 10, 26, 43, 12 and 39 patients, respectively. All the patients received radiotherapy (RT) with neck dissection in 60 and with chemotherapy in 67 cases. The median doses to the metastatic nodes, prophylactic neck and prophylactic mucosal sites were 60.0, 50.4 and 50.4 Gy, respectively. The median follow-up period for surviving patients was 42 months. Among 12 patients, occult primary tumors in the neck region developed after radiotherapy. The 5-year OS, PFS, NPFS and MPFS were 58.1%, 42.4%, 47.3% and 54.9%, respectively. Univariate analysis showed that lower N stage (N1-2b), non-bulky node (<6 cm) and negative extracapsular extension (ECE) status were the factors associated with favorable OS, PFS, NPFS and MPFS. Radical surgery proved to be a favorable factor of OS, NPFS and MPFS. On multivariate analysis, lower N stage and negative ECE status were correlated with improved survival. Conclusions: Lower nodal stage and negative ECE status showed a favorable impact on survival and disease control in patients with NUP treated by radiotherapy. PMID- 28903530 TI - Antitumor activity of iNGR-GRIM-19 in colorectal cancer. AB - Background: Gene associated with retinoid-interferon induced mortality-19 (GRIM 19) plays crucial roles in carcinogenesis. Objective: To explore the antitumor activity of internalizing NGR (iNGR) gene associated with GRIM-19 in colorectal cancer. Methods: Cells were incubated with fluorescein isothiocyanate-labeled fusion proteins followed by fluorescence microscopic analysis. Cell proliferation was determined by MTT assay. Cell cycle was analyzed by flow cytometric analysis. Cell migration and invasion capacity were evaluated by wound scratch and Transwell assays, respectively. Apoptosis was measured by Annexin V/PI staining and TUNEL assay. Gene expressions were determined by RT-PCR and Western blotting. Nude mice bearing colorectal cancer received vehicle, GRIM-19, or iNGR-GRIM-19 fusion protein injection, and the in vivo antitumor capacity of the fusion proteins was examined. Results: iNGR-GRIM-19 was specifically taken up by human colorectal cancer Colo205 cells, but not corneal epithelial (HCEpic) cells, whereas GRIM-19 was not internalized by either cell type. Unlike GRIM-19, incubation with iNGR-GRIM-19 dose-dependently inhibited proliferation, induced G1 phase arrest, suppressed cell migration and invasion, and caused apoptosis in Colo205 cells. Additionally, injection of iNGR-GRIM-19 extended the lifespan of colorectal cancer-bearing nude mice and reduced in vivo tumor growth as compared with vehicle or GRIM-19 treatment. iNGR-GRIM-19 was localized only in the tumor mass, without affecting other tissues, such as liver or kidney. iNGR-GRIM-19 injection led to G1 phase arrest and induced cell apoptosis in xenografted colorectal cancer tissues. Conclusions: iNGR-GRIM-19 has an efficient antitumor activity in vitro and in vivo, and might be a promising agent for the treatment of colorectal cancer. PMID- 28903531 TI - Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer. AB - Background: Radiotherapy is an effective treatment for the postoperative loco regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer. Methods: We retrospectively investigated 35 patients treated for a postoperative loco-regional recurrence of esophageal cancer with local field radiotherapy between December 2008 and March 2016. The median irradiation dose was 60 Gy (range: 50-67.5 Gy). Thirty-one (88.6%) patients received concurrent chemotherapy. Results: The median follow-up period was 18 months (range: 5-94 months). The 2-year overall survival was 55.7%, with a median survival time of 29.9 months. In the univariate analysis, the maximal diameter <=20 mm (P = 0.0383), solitary lesion (P = 0.0352), and the complete remission after treatment (P = 0.00411) had a significantly better prognosis. A total of 27 of 35 patients (77.1%) had progressive disease (loco-regional failure [n = 9], distant metastasis [n = 7], and both loco-regional failure and distant metastasis [n = 11]). No patients had Grade 3 or greater mucositis. Conclusion: Local field radiotherapy is a considerable treatment option for postoperative loco-regional recurrence of esophageal cancer. PMID- 28903532 TI - Sex differences in lung cancer survival: long-term trends using population-based cancer registry data in Osaka, Japan. AB - Objective: Several studies of sex differences in lung cancer survival have been reported. However, large-size population-based studies based on long-term observation are scarce. We investigated long-term trends in sex differences in lung cancer survival using population-based cancer registry data from Osaka, Japan. Methods: We analyzed 79 330 cases from the Osaka Cancer Registry (OCR) diagnosed between 1975 and 2007. We calculated 5-year relative survival in the six periods (1975-1980, 1981-1986, 1987-1992, 1993-1997, 1998-2002 and 2003 2007). To estimate the trends in sex differences in lung cancer survival throughout the study period, we applied a multivariate excess hazard model to control for confounders. Results: The proportion of adenocarcinoma (ADC) and 5 year relative relative survival have increased for both sexes. Sex differences in lung cancer survival have widened over the period, especially in ADC and since the late 1990s. The excess hazard ratio of death within 5 years for males was 1.19 (95% CI: 1.16-1.21), adjusting for period at diagnosis, histologic type, stage, age group and treatment. Conclusion: We reported that females have better prognosis in lung cancer than males and the sex differences in lung cancer survival have become wider in Osaka, Japan. This can be partly explained by the sex differences in the proportions of histologic type and stage. Further studies considering other factors that influence sex differences in lung cancer survival are needed. PMID- 28903533 TI - Joint Symposium of Korean Cancer Association & UICC-ARO-Cross-boundary cancer studies: cancer and Universal Health Coverage (UHC) in Asia. AB - On 16 June 2016, the Korean Cancer Association (KCA) and Union for International Cancer Control-Asia Regional Office (UICC-ARO) organized a joint symposium as part of the official program of the 42nd Annual Meeting of the Korean Cancer Association to discuss the topic 'Cross-boundary Cancer Studies: Cancer and Universal Health Coverage (UHC) in Asia.' Universal Health Coverage is included in the Sustainable Development Goals adopted by the United Nations as part of the 2030 Agenda for Sustainable Development. The objectives of UHC are to ensure that all people can receive high-quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in controlling cancer in the region. Representatives from Korea, Japan and Indonesia reported on the status of UHC in their countries and the challenges that are being faced, many of which are common to other countries in Asia. In addition to country-specific presentations about the progress of and challenges facing UHC, there were also presentations from WHO Kobe Centre concerning advancing UHC in non-communicable diseases and prospects for further collaboration and research on UHC. A presentation from the University of Tokyo also highlighted the need to focus on multidisciplinary studies in an age of globalization and digitization. PMID- 28903534 TI - The estimates of 5-year lung cancer prevalence in adult population in 2012. PMID- 28903535 TI - Modeling the Multiple Facets of Speciation-with-Gene-Flow toward Inferring the Divergence History of Lake Whitefish Species Pairs (Coregonus clupeaformis). AB - Parallel divergence across replicated species pairs occurring in similar environmental contrasts may arise through distinct evolutionary scenarios. Deciphering whether such parallelism actually reflects repeated parallel divergence driven by divergent selection or a single divergence event with subsequent gene flow needs to be ascertained. Reconstructing historical gene flow is therefore of fundamental interest to understand how demography and selection jointly shaped genomic divergence during speciation. Here, we use an extended modeling framework to explore the multiple facets of speciation-with-gene-flow with demo-genetic divergence models that capture both temporal and genomic variation in effective population size and migration rate. We investigate the divergence history of replicate sympatric species pairs of Lake Whitefish (normal benthic and dwarf limnetic) characterized by variable degrees of ecological divergence and reproductive isolation. Genome-wide SNPs were used to document the extent of genetic differentiation in each species pair, and 26 divergence models were fitted and compared with the unfolded joint allele frequency spectrum of each pair. We found evidence that a recent (circa 3,000-4,000 generations) asymmetrical secondary contact between expanding postglacial populations has accompanied Whitefish diversification. Our results suggest that heterogeneous genomic differentiation has emerged through the combined effects of linked selection generating variable rates of lineage sorting across the genome during geographical isolation, and heterogeneous introgression eroding divergence at different rates across the genome upon secondary contact. This study thus provides a new retrospective insight into the historical demographic and selective processes that shaped a continuum of divergence associated with ecological speciation. PMID- 28903536 TI - An Alternative Strategy for Trypanosome Survival in the Mammalian Bloodstream Revealed through Genome and Transcriptome Analysis of the Ubiquitous Bovine Parasite Trypanosoma (Megatrypanum) theileri. AB - There are hundreds of Trypanosoma species that live in the blood and tissue spaces of their vertebrate hosts. The vast majority of these do not have the ornate system of antigenic variation that has evolved in the small number of African trypanosome species, but can still maintain long-term infections in the face of the vertebrate adaptive immune system. Trypanosoma theileri is a typical example, has a restricted host range of cattle and other Bovinae, and is only occasionally reported to cause patent disease although no systematic survey of the effect of infection on agricultural productivity has been performed. Here, a detailed genome sequence and a transcriptome analysis of gene expression in bloodstream form T. theileri have been performed. Analysis of the genome sequence and expression showed that T. theileri has a typical kinetoplastid genome structure and allowed a prediction that it is capable of meiotic exchange, gene silencing via RNA interference and, potentially, density-dependent growth control. In particular, the transcriptome analysis has allowed a comparison of two distinct trypanosome cell surfaces, T. brucei and T. theileri, that have each evolved to enable the maintenance of a long-term extracellular infection in cattle. The T. theileri cell surface can be modeled to contain a mixture of proteins encoded by four novel large and divergent gene families and by members of a major surface protease gene family. This surface composition is distinct from the uniform variant surface glycoprotein coat on African trypanosomes providing an insight into a second mechanism used by trypanosome species that proliferate in an extracellular milieu in vertebrate hosts to avoid the adaptive immune response. PMID- 28903538 TI - POSSUM: a bioinformatics toolkit for generating numerical sequence feature descriptors based on PSSM profiles. AB - Summary: Evolutionary information in the form of a Position-Specific Scoring Matrix (PSSM) is a widely used and highly informative representation of protein sequences. Accordingly, PSSM-based feature descriptors have been successfully applied to improve the performance of various predictors of protein attributes. Even though a number of algorithms have been proposed in previous studies, there is currently no universal web server or toolkit available for generating this wide variety of descriptors. Here, we present POSSUM ( Po sition- S pecific S coring matrix-based feat u re generator for m achine learning), a versatile toolkit with an online web server that can generate 21 types of PSSM-based feature descriptors, thereby addressing a crucial need for bioinformaticians and computational biologists. We envisage that this comprehensive toolkit will be widely used as a powerful tool to facilitate feature extraction, selection, and benchmarking of machine learning-based models, thereby contributing to a more effective analysis and modeling pipeline for bioinformatics research. Availability and implementation: http://possum.erc.monash.edu/ . Contact: trevor.lithgow@monash.edu or jiangning.song@monash.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28903539 TI - Kollector: transcript-informed, targeted de novo assembly of gene loci. PMID- 28903537 TI - Evolutionary Origins of Pax6 Control of Crystallin Genes. AB - The birth of novel genes, including their cell-specific transcriptional control, is a major source of evolutionary innovation. The lens-preferred proteins, crystallins (vertebrates: alpha- and beta/gamma-crystallins), provide a gateway to study eye evolution. Diversity of crystallins was thought to originate from convergent evolution through multiple, independent formation of Pax6/PaxB-binding sites within the promoters of genes able to act as crystallins. Here, we propose that alphaB-crystallin arose from a duplication of small heat shock protein (Hspb1-like) gene accompanied by Pax6-site and heat shock element (HSE) formation, followed by another duplication to generate the alphaA-crystallin gene in which HSE was converted into another Pax6-binding site. The founding beta/gamma-crystallin gene arose from the ancestral Hspb1-like gene promoter inserted into a Ca2+-binding protein coding region, early in the cephalochordate/tunicate lineage. Likewise, an ancestral aldehyde dehydrogenase (Aldh) gene, through multiple gene duplications, expanded into a multigene family, with specific genes expressed in invertebrate lenses (Omega crystallin/Aldh1a9) and both vertebrate lenses (eta-crystallin/Aldh1a7 and Aldh3a1) and corneas (Aldh3a1). Collectively, the present data reconstruct the evolution of diverse crystallin gene families. PMID- 28903540 TI - Molecular signatures that can be transferred across different omics platforms. PMID- 28903541 TI - Addressing unmet clinical needs: the potential of biosimilars in the treatment of rheumatic diseases. PMID- 28903543 TI - Biosimilars in rheumatology: A review of the evidence and their place in the treatment algorithm. AB - Determining biosimilarity involves a comprehensive exercise with a focus on determining the comparability of the molecular characteristics and preclinical profile of the biosimilar and reference product, such that there is less need for extensive clinical testing to assure comparability of clinical outcomes. Three anti-TNF biosimilar agents are approved for patients with rheumatic diseases in the European Union. The infliximab (Remicade(r)) biosimilars CT-P13 (Remsima(r) and Inflectra(r)) and SB2 (Flixabi(r)) and the etanercept (Enbrel(r)) biosimilar SB4 (Benepali(r)) have shown close comparability to their reference medicinal products, having undergone extensive evaluations. Guidelines on the treatment of rheumatic diseases have acknowledged that biosimilars and biologic DMARDs (bDMARDs) are interchangeable in clinical practice, except when patients experience lack of efficacy or tolerability with the reference agent. Given that cost is a barrier to effective bDMARD use, the introduction of less costly biosimilars is likely to widen access and dissipate treatment inequalities. Physicians faced with prescribing decisions should be reassured by the robust and exhaustive process that is involved in assuring comparability of biosimilars with their reference agents. De novo usage of a biosimilar and switching to a biosimilar following lack of efficacy or tolerability with a different reference biologic agent are likely to be strategies most easily adopted, although switching during successful treatment should also be considered given the potential cost implications. The introduction of biosimilar bDMARDs has the potential to improve patient access to effective biologic therapy, to better accommodate restraints within healthcare budgets and to improve overall patient outcomes. PMID- 28903542 TI - Reviewing the evidence for biosimilars: key insights, lessons learned and future horizons. AB - Biologic therapies have become central to the long-term management of many chronic diseases, including inflammatory rheumatic diseases. Over recent years, the development and licensing pathways for biosimilars have become more standardized, and several biosimilars have been made available for patients with inflammatory rheumatic diseases, such as RA. Pre-licensing requirements for biosimilars mandate the demonstration of comparability with reference products in terms of clinical activity, safety and immunogenicity, whereas post-marketing surveillance and risk minimization requirements are set in place to ensure that long-term, real-world safety data are collected to assess biosimilars in clinical practice. These measures should provide a foundation for physician confidence in biosimilars, which can be established further through clinical experience. Biosimilars may help to fill an unmet need by improving patient access to effective biologic treatments for chronic diseases. Greater access may result in additional clinical benefits, with appropriate use of biologic therapies according to treatment guidelines being associated with improved outcomes and the potential for reduced costs of care. Key challenges for the integration of biosimilars into everyday practice include questions about interchangeability, switching and automatic substitution. Several switching studies have shown that biosimilars can be used in place of reference products while maintaining efficacy and safety. Additional ongoing studies and registries may help to optimize the process of switching, and different funding models are examining the optimal mechanisms to ensure effective uptake of these new treatments. PMID- 28903544 TI - The process defines the product: what really matters in biosimilar design and production? AB - Biologic drugs are highly complex molecules produced by living cells through a multistep manufacturing process. The key characteristics of these molecules, known as critical quality attributes (CQAs), can vary based on post-translational modifications that occur in the cellular environment or during the manufacturing process. The extent of the variation in each of the CQAs must be characterized for the originator molecule and systematically matched as closely as possible by the biosimilar developer to ensure bio-similarity. The close matching of the originator fingerprint is the foundation of the biosimilarity exercise, as the analytical tools designed to measure differences at the molecular level are far more sensitive and specific than tools available to physicians during clinical trials. Biosimilar development, therefore, has a greater focus on preclinical attributes compared with the development of an original biological agent. As changes in CQAs can occur at different stages of the manufacturing process, even small modifications to the process can alter biosimilar attributes beyond the point of similarity and impact clinical effectiveness and safety. The manufacturer's ability to provide consistent production and quality control will greatly influence the acceptance of biosimilars. To this end, preventing drift from the required specifications over time and avoiding the various implications brought by product shortage will enhance biosimilar integration into daily practice. As most prescribers are not familiar with this new drug development paradigm, educational programmes will be needed so that prescribers see biosimilars as fully equivalent, efficacious and safe medicines when compared with originator products. PMID- 28903545 TI - The road from development to approval: evaluating the body of evidence to confirm biosimilarity. AB - Biosimilars are products that contain a similar version of the active substance of an already authorized original biologic medicinal product (reference medicinal product). Their development requires special consideration, as similarity to the reference agent needs to be established through a comprehensive comparability exercise. Given the complex nature of these agents, minor structural differences may emerge, but the process of biosimilarity determination is designed to ascertain that the nature and impact of these differences are not clinically significant. Determination of biosimilarity should follow quality-by-design principles, which provide a deep understanding of the product development process, guided by pre-defined objectives, process control and risk management. Compared with novel biologic development, biosimilar development places greater emphasis on establishing preclinical quality characteristics. Determination of comparability of quality characteristics includes assessment of physicochemical properties, biological activity, immunochemical properties, purity, impurity and quantity, with appropriate in vivo pharmacology studies being conducted thereafter. Head-to-head comparisons are then conducted to determine pharmacokinetic and pharmacodynamic characteristics, and efficacy, safety and tolerability in phase I and phase III clinical studies. Post-approval risk management requirements include implementation of pharmacovigilance systems and risk management through, for example, the conduct of pharmacoepidemiological studies. There are several biosimilars used in the field of rheumatology that are available in the European Union, or in development, that offer the potential to increase affordability/accessibility of biological treatment. The role of these agents in rheumatology will be determined by the confidence placed in them by rheumatologists. These prescribers should expect high-quality data evaluated by an extensive assessment process. PMID- 28903546 TI - Cellular and molecular mechanisms of viral infection in the human placenta. AB - The placenta is a highly specialized organ that is formed during human gestation for conferring protection and generating an optimal microenvironment to maintain the equilibrium between immunological and biochemical factors for fetal development. Diverse pathogens, including viruses, can infect several cellular components of the placenta, such as trophoblasts, syncytiotrophoblasts and other hematopoietic cells. Viral infections during pregnancy have been associated with fetal malformation and pregnancy complications such as preterm labor. In this minireview, we describe the most recent findings regarding virus-host interactions at the placental interface and investigate the mechanisms through which viruses may access trophoblasts and the pathogenic processes involved in viral dissemination at the maternal-fetal interface. PMID- 28903547 TI - ERK signalling as a regulator of cell motility. AB - Cell motility is regulated by multiple processes, including cell protrusion, cell retraction, cell-matrix adhesion, polarized exocytosis and polarized vesicle trafficking, each of which is spatiotemporally controlled by various intracellular signalling pathways. Dysregulation of cell motility leads to pathological conditions, such as tumour invasion and metastasis. Accumulating evidence has revealed that extracellular signal-regulated kinase (ERK) signalling is one of the critical regulators of cell motility, although it is classically known as an important regulator of cell proliferation, differentiation and survival through regulation of gene expression. ERK and its downstream kinase, p90 ribosomal S6 kinase (RSK), dynamically regulate cell motility mainly through direct phosphorylation of various molecules that are not necessarily involved in the regulation of gene transcription and translation. In this review, we summarize how ERK signalling regulates cell motility by focusing on the components of the cell motility machinery that are directly regulated by ERK or RSK. PMID- 28903548 TI - Role of the unfolded protein response in the development of central nervous system. AB - The unfolded protein response (UPR) is an intracellular homeostatic signalling pathway that is induced by accumulated misfolded/unfolded proteins in the endoplasmic reticulum (ER). The UPR is closely associated with the development of disease in several tissues, including the central nervous system (CNS), in response to ER stress. More recently, the unique features and importance of the UPR have been revealed in neural stem cells (NSCs) and differentiated CNS cells [neurons and glial cells (astrocytes and oligodendrocytes)]. Although several UPR signalling pathways dynamically change in each CNS cell during brain development, the role of UPR signalling in CNS cells (especially NSCs and glial cells) under pathological or physiological conditions is poorly understood. Here, we discuss and summarize the recent progress in understanding how the UPR regulates the proliferation, differentiation, maturation and viability of CNS cells. PMID- 28903549 TI - NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia. AB - Purpose: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). Materials and Methods: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. Results: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. Conclusion: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels. PMID- 28903550 TI - Combination of Tumor Volume and Epstein-Barr Virus DNA Improved Prognostic Stratification of Stage II Nasopharyngeal Carcinoma in the Intensity Modulated Radiotherapy Era: A Large-Scale Cohort Study. AB - Purpose: Little is known about combination of the circulating Epstein-Barr viral (EBV) DNA and tumor volume in prognosis of stage II nasopharyngeal carcinoma (NPC) patients in the intensity modulated radiotherapy (IMRT) era. We conducted this cohort study to evaluate the prognostic values of combining these two factors. Materials and Methods: By Kaplan-Meier, we compare the differences of survival curves between 385 patients with different EBV DNA or tumor volume levels, or with the combination of two biomarkers mentioned above. Results: Gross tumor volume of cervical lymph nodes (GTVnd, p < 0.001) and total tumor volume (GTVtotal, p < 0.001) were both closely related to pretreatment EBV DNA, while gross tumor volume of nasopharynx (GTVnx, p=0.047) was weakly related to EBV DNA. EBV DNA was significantly correlated with progress-free survival (PFS, p=0.005), locoregional-free survival (LRFS, p=0.039), and distant metastasis-free survival (DMFS, p=0.017), while GTVtotal, regardless of GTVnx and GTVnd, had a significant correlation with PFS and LRFS. The p-values of GTVtotal for PFS and LRFS were 0.008 and 0.001, respectively. According to GTVtotal and pretreatment EBV DNA level, patients were divided into a low-risk group (EBV DNA 0 copy/mL, GTVtotal < 30 cm3; EBV DNA 0 copy/mL, GTVtotal >= 30 cm3; or EBV DNA > 0 copy/mL, GTVtotal < 30 cm3) and a high-risk group (EBV DNA > 0 copy/mL, GTVtotal >= 30 cm3). When patients in the low-risk group were compared with those in the high-risk group, 3 year PFS (p=0.003), LRFS (p=0.010), and DMFS (p=0.031) rates were statistically significant. Conclusion: Pretreatment plasma EBV DNA and tumor volume were both closely correlated with prognosis of stage II NPC patients in the IMRT era. Combination of EBV DNA and tumor volume can refine prognosis and indicate for clinical therapy. PMID- 28903551 TI - The Generation and Application of Patient-Derived Xenograft Model for Cancer Research. AB - Establishing an appropriate preclinical model is crucial for translational cancer research. The most common way that has been adopted by far is grafting cancer cell lines, derived from patients. Although this xenograft model is easy to generate, but has several limitations because this cancer model could not represent the unique features of each cancer patient sufficiently. Moreover, accumulating evidences demonstrate cancer is a highly heterogeneous disease so that a tumor is comprised of cancer cells with diverse characteristics. In attempt to avoid these discrepancies between xenograft model and patients' tumor, a patient-derived xenograft (PDX) model has been actively generated and applied. The PDX model can be developed by the implantation of cancerous tissue from a patient's tumor into an immune-deficient mouse directly, thereby it preserves both cell-cell interactions and tumor microenvironment. In addition, the PDX model has shown advantages as a preclinical model in drug screening, biomarker development and co-clinical trial. In this review, we will summarize the methodology and applications of PDX in detail, and cover critical issues for the development of this model for preclinical research. PMID- 28903552 TI - Impact of Body Mass Index on the Quality of Life after Total Gastrectomy for Gastric Cancer. AB - Purpose: We evaluated the impact of postoperative body mass index (BMI) shifts on the quality of life (QoL) following total gastrectomy in patients with gastric cancer. Materials and Methods: QoL data collected from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and QLQ-STO22 questionnaires were obtained from 417 patients preoperatively and 1 year after surgery. Patients were divided into two groups based on changes in BMI: group 1 comprised patientswhose BMIrange category dropped, and group 2 included patients who maintained or rose to a higher category compared to their preoperative BMI category. Results: There were 276 patients in group 1 and 141 in group 2. QoLs with respect to the global health status and functional scales were not significantly different between the groups 1 year after surgery. However, there were significantly greater decreases in QoL in group 1 due to gastrointestinal symptoms, such as nausea and vomiting (p=0.008), appetite loss (p=0.001), and constipation (p=0.038). Of the QLQ-STO22 parameters, dysphagia (p=0.013), pain (p=0.012), reflux symptoms (p=0.017), eating restrictions (p=0.007), taste (p=0.009), and body image (p=0.009) were associated with significantly worse QoL in group 1 than in group 2 1 year after surgery. Conclusion: Patients have significantly different QoLs depending on the BMI shift after total gastrectomy. Efforts to reduce the gap in QoL should include intensive nutritional support and restoration of dietary behaviors. Appropriate clinical and institutional approaches, plus active medical interventions, are required for maintaining patients' BMIs after surgery. PMID- 28903553 TI - Monitoring Microbial Mineralization Using Reverse Stable Isotope Labeling Analysis by Mid-Infrared Laser Spectroscopy. AB - Assessing the biodegradation of organic compounds is a frequent question in environmental science. Here, we present a sensitive, inexpensive, and simple approach to monitor microbial mineralization using reverse stable isotope labeling analysis (RIL) of dissolved inorganic carbon (DIC). The medium for the biodegradation assay contains regular organic compounds and 13C-labeled DIC with 13C atom fractions (x(13C)DIC) higher than natural abundance (typically 2-50%). The produced CO2 (x(13C) ~ 1.11%) gradually dilutes the initial x(13C)DIC allowing to quantify microbial mineralization using mass-balance calculations. For 13C-enriched CO2 samples, a newly developed isotope ratio mid-infrared spectrometer was introduced with a precision of x(13C) < 0.006%. As an example for extremely difficult and slowly degradable compounds, CO2 production was close to the theoretical stoichiometry for anaerobic naphthalene degradation by a sulfate-reducing enrichment culture. Furthermore, we could measure the aerobic degradation of dissolved organic carbon (DOC) adsorbed to granular activated carbon in a drinking water production plant, which cannot be labeled with 13C. Thus, the RIL approach can be applied to sensitively monitor biodegradation of various organic compounds under anoxic or oxic conditions. PMID- 28903554 TI - Mechanisms of Furfural Reduction on Metal Electrodes: Distinguishing Pathways for Selective Hydrogenation of Bioderived Oxygenates. AB - Electrochemical reduction of biomass-derived platform molecules is an emerging route for the sustainable production of fuels and chemicals. However, understanding gaps between reaction conditions, underlying mechanisms, and product selectivity have limited the rational design of active, stable, and selective catalyst systems. In this work, the mechanisms of electrochemical reduction of furfural, an important biobased platform molecule and model for aldehyde reduction, are explored through a combination of voltammetry, preparative electrolysis, thiol-electrode modifications, and kinetic isotope studies. It is demonstrated that two distinct mechanisms are operable on metallic Cu electrodes in acidic electrolytes: (i) electrocatalytic hydrogenation (ECH) and (ii) direct electroreduction. The contributions of each mechanism to the observed product distribution are clarified by evaluating the requirement for direct chemical interactions with the electrode surface and the role of adsorbed hydrogen. Further analysis reveals that hydrogenation and hydrogenolysis products are generated by parallel ECH pathways. Understanding the underlying mechanisms enables the manipulation of furfural reduction by rationally tuning the electrode potential, electrolyte pH, and furfural concentration to promote selective formation of important biobased polymer precursors and fuels. PMID- 28903555 TI - Aldehyde and Ketone Photoproducts from Solar-Irradiated Crude Oil-Seawater Systems Determined by Electrospray Ionization-Tandem Mass Spectrometry. AB - Aldehyde and ketone photoproducts were observed in the aqueous phase under oil exposed to simulated sunlight by using 2,4-dinitrophenylhydrazine (DNPH) derivatization and electrospray ionization-tandem mass spectrometry (ESI-MS/MS). Oil samples were spread over seawater in a jacketed beaker held at 27.0 degrees C and exposed to simulated sunlight. The aqueous phase was collected after irradiation and derivatized with DNPH, which selectively reacts with aldehydes and ketones. The derivatized hydrazones (aldehyde- and ketone-DNPH derivatives) were washed and enriched with a solid-phase extraction cartridge prior to analysis by ESI-MS/MS in negative ion mode. Over 80 aldehyde and ketone photoproducts were observed from scan range 200-1000 atomic mass units (amu) in the aqueous phase after irradiation but were absent in dark controls. Based on the MS/MS fragmentation of the aldehyde- and ketone-DNPH derivatives, most of the aldehyde and ketone photoproduct mass spectra observed from the aqueous phase were determined to be consistent with dicarbonyls, hydroxycarbonyls, and oxo carboxylic acids. The formation of the photoproducts can be attributed to photoinduced oxidation of oil. The approach in this study allows the easy identification of molar mass and other structural features of aldehyde and ketone photoproducts without interference from the many tens of thousands of parent compounds in the oil. These results will provide insight into the impact of photochemistry on the fate of oil in environmental systems and will have implications for oil-spill response decisions. PMID- 28903556 TI - 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals. AB - The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions. PMID- 28903558 TI - Mustard Gas Surrogate Interactions with Modified Porous Carbon Fabrics: Effect of Oxidative Treatment. AB - Removal of chemical warfare agent (CWA) surrogates by highly porous carbon textiles was investigated. The carbon cloth was modified by oxidation in a mixture of concentrated sulfuric and nitric acid. This process did not affect textile structural integrity. The surface properties of the modified textiles were investigated, and their capabilities to remove 2-chloroethyl ethyl sulfide (CEES) and diethylsulfide (EES), two mustard gas surrogates, were evaluated. The oxidized carbon textiles have a highly active surface that has the ability to form radical species. This enhances the degradation of the surrogates, and so the detoxification efficiency. The reaction products detected suggest differences in degradation mechanisms which depend on the type of fabric surface features. Thus, the oxidized surfaces eliminate CEES mainly through dehydrohalogenation, while the nonoxidized surfaces act via hydrolysis. Only the oxidized carbon has a surface active enough to react with the less reactive surrogate EES, by cleavage of the C-S bond. The surface functional groups promote not only the radical formation but also contribute to a strong adsorption of the CWA surrogates, which enhance the decomposition of these toxic species. PMID- 28903557 TI - A Rheological Study of the Association and Dynamics of MUC5AC Gels. AB - The details of how a mucus hydrogel forms from its primary structural component, mucin polymers, remain incompletely resolved. To explore this, we use a combination of macrorheology and single-particle tracking to investigate the bulk and microscopic mechanical properties of reconstituted MUC5AC mucin gels. We find that analyses of thermal fluctuations on the length scale of the micrometer-sized particles are not predictive of the linear viscoelastic response of the mucin gels, and that taken together, the results from both techniques help to provide complementary insight into the structure of the network. In particular, we show that macroscopic stiffening of MUC5AC gels can be brought about in different ways by targeting specific associations within the network using environmental triggers such as modifications to the pH, surfactant, and salt concentration. Our work may be important for understanding how environmental factors, including pathogens and therapeutic agents, alter the mechanical properties of fully constituted mucus. PMID- 28903559 TI - Three Faces of N-Acetylaspartate: Activator, Substrate, and Inhibitor of Human Aspartoacylase. AB - Hydrolysis of N-acetylaspartate (NAA), one of the most concentrated metabolites in brain, catalyzed by human aspartoacylase (hAsp) shows a remarkable dependence of the reaction rate on substrate concentration. At low NAA concentrations, sigmoidal shape of kinetic curve is observed, followed by typical rate growth of the enzyme-catalyzed reaction, whereas at high NAA concentrations self-inhibition takes place. We show that this rate dependence is consistent with a molecular model, in which N-acetylaspartate appears to have three faces in the enzyme reaction, acting as activator at low concentrations, substrate at moderate concentrations, and inhibitor at high concentrations. To support this conclusion we identify binding sites of NAA at the hAsp dimer including those on the protein surface (activating sites) and at the dimer interface (inhibiting site). Using the Markov state model approach we demonstrate that population of either activating or inhibiting site shifts the equilibrium between the hAsp dimer conformations with the open and closed gates leading to the enzyme active site buried inside the protein. These conclusions are in accord with the calculated values of binding constants of NAA at the hAsp dimer, indicating that the activating site with a higher affinity to NAA should be occupied first, whereas the inhibiting site with a lower affinity to NAA should be occupied later. Application of the dynamical network analysis shows that communication pathways between the regulatory sites (activating or inhibiting) and the gates to the active site do not interfere. These considerations allow us to develop a kinetic mechanism and to derive the equation for the reaction rate covering the entire NAA concentration range. Perfect agreement between theoretical and experimental kinetic data provides strong support to the proposed catalytic model. PMID- 28903560 TI - Hot and Cold Charge-Transfer Mechanisms in Organic Photovoltaics: Insights into the Excited States of Donor/Acceptor Interfaces. AB - The evolution of the excited-state manifold in organic D/A aggregates (e.g., the prototypical P3HT/PCBM) is investigated through a bottom-up approach via first principles calculations. We show how the excited-state energies, the charge transfer (CT) states, and the electron-hole density distributions are strongly influenced by the size, the orientation, and the position (i.e., on-top versus on edge phases) of P3HT/PCBM domains. We discuss how the structural order influences the excited-state electronic structure, providing an atomistic interpretation of the photophysics of organic blends. We show how the simultaneous presence of on top and on-edge phases does not alter the optical absorption spectrum of the blend but does affect the photophysics. Photovoltaic processes such as (i) the simultaneous charge generation obtained from hot and cold excitations, (ii) the instantaneous and delayed charge separation, and (iii) the pump-push-probe charge generation can be interpreted based on our study. PMID- 28903562 TI - Spontaneous Octahedral Tilting in the Cubic Inorganic Cesium Halide Perovskites CsSnX3 and CsPbX3 (X = F, Cl, Br, I). AB - The local crystal structures of many perovskite-structured materials deviate from the average space-group symmetry. We demonstrate, from lattice-dynamics calculations based on quantum chemical force constants, that all of the cesium lead and cesium-tin halide perovskites exhibit vibrational instabilities associated with octahedral titling in their high-temperature cubic phase. Anharmonic double-well potentials are found for zone-boundary phonon modes in all compounds with barriers ranging from 108 to 512 meV. The well depth is correlated with the tolerance factor and the chemistry of the composition, but is not proportional to the imaginary harmonic phonon frequency. We provide quantitative insights into the thermodynamic driving forces and distinguish between dynamic and static disorder based on the potential-energy landscape. A positive band gap deformation (spectral blue shift) accompanies the structural distortion, with implications for understanding the performance of these materials in applications areas including solar cells and light-emitting diodes. PMID- 28903561 TI - Enhanced Sampling of Intrinsic Structural Heterogeneity of the BH3-Only Protein Binding Interface of Bcl-xL. AB - Antiapoptotic Bcl-xL plays central roles in regulating programed cell death. Partial unfolding of Bcl-xL has been observed at the interface upon specific binding to the pro-apoptotic BH3-only protein PUMA, which in turn disrupts the interaction of Bcl-xL with tumor suppressor p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures and atomistic molecular dynamics (MD) simulations have suggested that substantial intrinsic structure heterogeneity exists at the BH3-only protein binding interface of Bcl-xL to facilitate its conformational transitions upon binding. In this study, enhanced sampling is applied to further characterize the interfacial conformations of unbound Bcl-xL in explicit solvent. Extensive replica exchange with solute tempering (REST) simulations, with a total accumulated time of 16 MUs, were able to cover much wider conformational spaces for the interfacial region of Bcl-xL. The resulting structural ensembles are much better converged, with local and long-range structural features that are highly consistent with existing NMR data. These simulations further demonstrate that the BH3-only protein binding interface of Bcl-xL is intrinsically disordered and samples many rapidly interconverting conformations. Intriguingly, all previously observed conformers are well represented in the unbound structure ensemble. Such intrinsic structural heterogeneity and flexibility may be critical for Bcl-xL to undergo partial unfolding induced by PUMA binding, and likely provide a robust basis that allows Bcl-xL to respond sensitively to binding of various ligands in cellular signaling and regulation. PMID- 28903563 TI - Three-fold Symmetric Doping Mechanism in GaAs Nanowires. AB - A new dopant incorporation mechanism in Ga-assisted GaAs nanowires grown by molecular beam epitaxy is reported. Off-axis electron holography revealed that p type Be dopants introduced in situ during molecular beam epitaxy growth of the nanowires were distributed inhomogeneously in the nanowire cross-section, perpendicular to the growth direction. The active dopants showed a remarkable azimuthal distribution along the (111)B flat top of the nanowires, which is attributed to preferred incorporation along 3-fold symmetric truncated facets under the Ga droplet. A diffusion model is presented to explain the unique radial and azimuthal variation of the active dopants in the GaAs nanowires. PMID- 28903564 TI - Impact of an Artificial Digestion Procedure on Aluminum-Containing Nanomaterials. AB - Aluminum has gathered toxicological attention based on relevant human exposure and its suspected hazardous potential. Nanoparticles from food supplements or food contact materials may reach the human gastrointestinal tract. Here, we monitored the physicochemical fate of aluminum-containing nanoparticles and aluminum ions when passaging an in vitro model of the human gastrointestinal tract. Small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), ion beam microscopy (IBM), secondary ion beam mass spectrometry (TOF SIMS), and inductively coupled plasma mass spectrometry (ICP-MS) in the single particle mode were employed to characterize two aluminum-containing nanomaterials with different particle core materials (Al0, gammaAl2O3) and soluble AlCl3. Particle size and shape remained unchanged in saliva, whereas strong agglomeration of both aluminum nanoparticle species was observed at low pH in gastric fluid together with an increased ion release. The levels of free aluminum ions decreased in intestinal fluid and the particles deagglomerated, thus liberating primary particles again. Dissolution of nanoparticles was limited and substantial changes of their shape and size were not detected. The amounts of particle-associated phosphorus, chlorine, potassium, and calcium increased in intestinal fluid, as compared to nanoparticles in standard dispersion. Interestingly, nanoparticles were found in the intestinal fluid after addition of ionic aluminum. We provide a comprehensive characterization of the fate of aluminum nanoparticles in simulated gastrointestinal fluids, demonstrating that orally ingested nanoparticles probably reach the intestinal epithelium. The balance between dissolution and de novo complex formation should be considered when evaluating nanotoxicological experiments. PMID- 28903565 TI - Liquid Biopsies - the Clinics and the Molecules. AB - Unlike bone marrow biopsies, liquid biopsies represent a gentler, more accessible, less painful, repeatable and more comprehensive approach to get biologically relevant information about the entire tumor but also about treatment response and level of minimal residual disease. This is all possible since peripheral blood contains not only circulating tumor cells but also many circulating molecules of nucleic acids (microRNA, cell-free DNA, long non-coding RNA etc.). Multiple myeloma is a genetically heterogeneous disease characterized by multifocal tumor deposits in the bone marrow but also focal lesions elsewhere. Single-site biopsy of the bone marrow creates a sampling bias that provides a limited molecular profile as the biopsy cannot capture all subclones. Moreover, during disease progression and treatment, molecular profile is changed and subclones of multiple myeloma cells resistant to treatment are formed. Likewise, various clones found in extramedullary sites that are not present in the bone marrow respond differently to treatment directly influencing survival of patients. Thus, liquid biopsies seem to be a relevant and necessary next step for diseases such as multiple myeloma.Key words: multiple myeloma - minimal residual disease - prognosis - liquid biopsies - cell-free DNA - non-coding RNA. PMID- 28903566 TI - Biobanking - the First Step to Successful Liquid Biopsy Experiments. AB - BACKGROUND: Archiving of biological materials in biobanks is considered to be the initial crucial part of research activities. Most often, biobanks are founded for research purposes since they allow collection of sufficient material for analysis of new or testing of previously identified biomarkers. Biobanking needs to quickly react to current needs of researchers as well as clinicians, it is not a rigid system. Laboratory analyses of monoclonal gammopathies are based on separation of plasma cells from bone marrow of patients. A specific problem is usually a lack of tumor cell fraction, which is due to location of tumor cell in bone marrow in combination with low infiltration. One of the challenges in clinical research is the necessity of changes in biobanking for samples allowing detection of minimal residual disease in the bone marrow but also from peripheral blood by the so-called liquid biopsies. AIM: The aim of this review is to show the importance of archiving biological material in the Czech Republic and to show concrete examples of its usage in hematooncology. CONCLUSION: A general problem in solving many research questions is the availability of a critical amount of specimens for statistical analysis. Obtaining critical amount of specimens of biological material can be quickly archived by cooperation of biobanks sharing both methodological standards and informations about the availability of samples for research projects.Key words: archiving - biological material - informed consent - multiple myeloma - plasma cells. PMID- 28903567 TI - Minimal Residual Disease Assessment in Multiple Myeloma by Multiparametric Flow Cytometry. AB - BACKGROUND: Progress in treatment of multiple myeloma extensively increased patient remission rates, so minimal residual disease (MRD) detection becomes essential to assess the effectivity of treatment and depth of complete response. Nowadays, multiparametric flow cytometry (MFC) is the most used method for monitoring of MRD presence in the bone marrow of multiple myeloma patients; however, detection on molecular level can be used as well. It is evident that choice of protocol used for MFC-MRD assessment can significantly affect required results; nevertheless, standardized and highly sensitive approach of "next generation flow" is already available. Although benefit of MRD assessment as an independent predictor of progression-free survival and overall survival is known, very recent research showed that MRD-negative status surpasses the prognostic value of complete response achievement for progression-free survival and overall survival. AIM: This review is focused on use MFC in MRD assessment in multiple myeloma. The technical aspects and clinical benefits of this approach are mentioned as well. CONCLUSION: The information about MRD level detected by highly sensitive and reproducible MFC can be potentially used as a biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions and act as a surrogate for overall survival in multiple myeloma patients.Key words: multiple myeloma - minimal residual disease - flow cytometry - plasma cells. PMID- 28903568 TI - Circulating Plasma Cells in Monoclonal Gammopathies. AB - BACKGROUND: Monoclonal gammopathies are characterized by presence of clonal plasma cells in the bone marrow, although peripheral blood circulating plasma cells can be found in a significant proportion of patients. The number of circulating plasma cells is an independent prognostic marker associated with shorter survival, but it can also help to predict early relapse. The reason and mechanism of plasma cell expansion from the bone marrow to enter peripheral blood is still not entirely clear, but possible changes in the expression of adhesion molecules are probably involved. Multiparametric flow cytometry allows simple and exact enumeration of circulating plasma cells in different types of cell suspensions, even in their low quantity. The phenotype profile and confirmation of clonality regarding to their bone marrow clonal counterparts should be verified as well. There is no uniform method used in clinical laboratories for circulating plasma cells analyses at this moment. AIM: Review is focused on use of multiparametric flow cytometry for circulating plasma cells analysis in peripheral blood. It is comparing possibilities of their detection by different methods and on clinical relevance of that assessment. The standardization of analyses is the main goal. CONCLUSION: Multiparametric flow cytometry is a very sensitive method for detection of circulating plasma cells, so using a standardized approach can lead to determination and implementation of the flow cytometry diagnostic threshold in plasma cell leukemia suspicious cases as well as in prognostication of monoclonal gammopathies patients. Moreover, analysis of plasma cells phenotypic profile could probably clarify their future behaviour.Key words: monoclonal gammopathies - circulating plasma cells - plasma cell leukemia flow cytometry. PMID- 28903569 TI - Epidemiology of Multiple Myeloma in the Czech Republic. AB - BACKGROUND: Multiple myeloma (MM) is a cancer of plasma cells with an incidence of 4.8 cases per 100,000 population in the Czech Republic in 2014; the burden of MM in the Czech Republic is moderate when compared to other European countries. This work brings the latest information on MM epidemiology in the Czech population. MATERIAL AND METHODS: The Czech National Cancer Registry is the basic source of data for the population-based evaluation of MM epidemiology. This database also makes it possible to assess patient survival and to predict probable short-term as well as long-term trends in the treatment burden of the entire population. RESULTS: According to the latest Czech National Cancer Registry data, there were 504 new cases of MM and 376 deaths from MM in 2014. Since 2004, there has been a 26.9% increase in MM incidence and an 8.3% increase in MM mortality. In 2014, there were 1,982 persons living with MM or a history of MM, corresponding to a 74.4% increase when compared to MM prevalence in 2004. The 5-year survival of patients treated in the period 2010-2014 was nearly 40%. CONCLUSION: The available data make it possible to analyse long-term trends in MM epidemiology and to predict the future treatment burden as well as treatment results.Key words: multiple myeloma - epidemiology - Czech National Cancer Registry - Registry of Monoclonal Gammopathies - Czech Republic. PMID- 28903570 TI - Czech Registry of Monoclonal Gammopathies - Technical Solution, Data Collection and Visualisation. AB - BACKGROUND: The Registry of Monoclonal Gammopathies (RMG) was established by the Czech Myeloma Group in 2007. RMG is a registry designed for the collection of clinical data concerning diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies. Data on patients with monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom macroglobulinaemia (WM), multiple myeloma (MM) or primary AL ("amyloid light-chain") amyloidosis are collected in the registry. DATA: Nineteen Czech centres and four Slovak centres currently contribute to the registry. The registry currently contains records on more than 5,000 patients with MM, almost 3,000 patients with MGUS, 170 patients with WM and 26 patients with primary AL amyloidosis, i.e. more than 8,000 records on patients with monoclonal gammopathies altogether. RESULTS: This paper describes technology employed for the collection, storage and subsequent online visualisation of data. The CLADE-IS platform is introduced as a new system for the collection and storage of data from the registry. The form structure and functions of the new system are described for all diagnoses in general; these functions facilitate data entry to the registry and minimise the error rate in data. Publicly available online visualisations of data on patients with MGUS, WM, MM or primary AL amyloidosis from all Czech or Slovak centres are introduced, together with authenticated visualisations of data on patients with MM from selected centres. CONCLUSION: The RMG represents a data basis that makes it possible to monitor the disease course in patients with monoclonal gammopathies on the population level.Key words: Registry of Monoclonal Gammopathies - RMG - registries - monoclonal gammopathies - CLADE-IS - data visualisation - database. PMID- 28903571 TI - Asymptomatic and Treatment-requiring Multiple Myeloma - Data from the Czech Registry of Monoclonal Gammopathies. AB - BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) are premalignant stages of multiple myeloma (MM). MM is a malignancy of plasma cells, which is associated with a median overall survival of 5 to 7 years. MM accounts for approximately 10% of hematological malignancies. PATIENTS AND METHODS: Descriptive analysis of data from 19 Czech centres collected in the Registry of Monoclonal Gammopathies (RMG) was performed. RESULTS: Over the last 10 years of prospective collection of data, together with retrospectively recorded data on patients diagnosed before the registry establishment, data on 7,467 patients with either asymptomatic or symptomatic form of MM have been gathered. Validation criteria for the analysis were met by 2,506 MGUS patients, 400 SMM patients and 4,738 MM patients. The median duration of follow-up was 4.3 years in MGUS patients and 2.4 years in SMM patients. The overall risk of progression from MGUS to malignancy was 1.7% per year. The risk of progression from SMM to MM was highest in the 1st years after diagnosis: overall, this risk was 16.6% per year. The median duration of follow up was 2.8 years in MM patients. The median overall survival from the diagnosis was 5.7 years. The median OS from treatment initiation/progression-free survival decreased from 60.5/21.0 months in the 1st line therapy to 34.3/12.4 months in the 2nd line therapy, 22.6/8.9 months in the 3rd line therapy and 13.8/5.8 months in the 4th or higher line therapies. Thanks to the availability of novel drugs for MM treatment in the Czech Republic, treatment strategies have changed dramatically over the last decade. CONCLUSION: RMG is a registry designated for the collection of data on diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies in the long-term follow-up. RMG is a valuable source of data from real clinical practice.Key words: registries - monoclonal gammopathy of undetermined significance - smouldering multiple myeloma - multiple myeloma - progression - treatment - survival. PMID- 28903572 TI - Biomarkers in Immunoglobulin Light Chain Amyloidosis. AB - Immunoglobulin light chain amyloidosis (AL amyloidosis - ALA) is a monoclonal gammopathy characterized by presence of aberrant plasma cells producing amyloidogenic immunoglobulin light chains. This leads to formation of amyloid fibrils in various organs and tissues, mainly in heart and kidney, and causes their dysfunction. As amyloid depositing in target organs is irreversible, there is a big effort to identify biomarker that could help to distinguish ALA from other monoclonal gammopathies in the early stages of disease, when amyloid deposits are not fatal yet. High throughput technologies bring new opportunities to modern cancer research as they enable to study disease within its complexity. Sophisticated methods such as next generation sequencing, gene expression profiling and circulating microRNA profiling are new approaches to study aberrant plasma cells from patients with light chain amyloidosis and related diseases. While generally known mutation in multiple myeloma patients (KRAS, NRAS, MYC, TP53) were not found in ALA, number of mutated genes is comparable. Transcriptome of ALA patients proves to be more similar to monoclonal gammopathy of undetermined significance patients, moreover level of circulating microRNA, that are known to correlate with heart damage, is increased in ALA patients, where heart damage in ALA typical symptom.Key words: amyloidosis - plasma cell - genome - transcriptome - microRNA. PMID- 28903573 TI - CRISPR in Research and Treatment of Multiple Myeloma. AB - In the recent years, there was a remarkable advance in research and clinical implementation of the genome editing technologies. The most remarkable was a discovery of the bacterial adaptive immune system called CRISPR and its rapid transformation into a robust and broadly applicable technology that completely revolutionized both basic and applied biomedical research. Implementation of CRISPR makes genome modification easier, faster and significantly cheaper compare to any other currently available technology. It also offers a tremendous potential for desiging novel research approaches and future treatment options for various genetic diseases including multiple myeloma. The hightroughput use of CRISPR in pooled screen formats promises faster identification and validation of valuable drug targets together with revealing high-confidence biomarkers and unknown resistance mechanisms. This can provide clinicians with new diagnostic and prognostic tolls and ultimately allow more accurate patient stratification for personalised treatment with better eficacy. In this review, we summarize current knowledge about the CRISPR technology and focus especially on its impact in exploring gene functions, screening for novel drug targets, diagnostic markers and genes involved in resistance to commonly used drug in the treatment of multiple myeloma. Finally, we also highlight a potential future use of CRISPR in actual clinical practise.Key words: multiple myeloma - CRISPR - therapeutics. PMID- 28903574 TI - Whole Exome Sequencing of Aberrant Plasma Cells in a Patient with Multiple Myeloma Minimal Residual Disease. AB - Multiple myeloma is a plasma cell dyscrasia. It is the second most common hematological malignancy which is characterized by proliferation of clonal plasma cells producing harmful monoclonal immunoglobulin. Despite treatment modalities greatly evolved during the last decade, small amount of aberrant residual cells reside in patients after therapy and can cause relapse of the disease. Characterization of the residual, resistant clones can help to reveal important therapeutic targets for application of effective and precious treatment. We use CD38, CD45, CD56 and CD19 sorted aberrant plasma cells to perform next generation sequencing of their exome. Among the 213 genes in which at least one variant was present, the most interesting was found gene NRAS, one of the most often mutated gene in multiple myeloma, and homologs of 88 gene panel previously used for multiple myeloma sequencing among which was a gene previously identified as gene meaningful in bortezomib resistance. Nevertheless, the results of next generation exome sequencing need to be interpreted with caution, since they rely on bioinformatical analysis, which is still being optimized. The results of next generation sequencing will also have to be confirmed by Sanger sequencing. Final results supported by larger cohort of patients will be published soon.Key words: multiple myeloma - minimal residual disease - exome - next generation sequencing. PMID- 28903575 TI - Diagnostic Tools of Waldenstroms Macroglobulinemia - Best Possibilities for Non invasive and Long-term Disease Monitoring. AB - Waldenstroms macroglobulinemia (WM) is a B-cell malignancy characterized by high level of monoclonal immunoglobulin M (IgM) paraprotein in blood serum and associated with the bone marrow infiltration by malignant cells with lymphoplasmacytic differentiation. WM remains incurable advances in therapy. Most of WM cases are associated with a somatic point mutation L265P in MYD88. Significantly higher risk of progression from the IgM monoclonal gammopathy of undetermined significance (IgM MGUS) to WM for patients with mutated MYD88 gene suggests that this mutation is an early oncogenic event and plays a central role in development of malignant clones. The second, most prevalent mutation in WM is found in the CXCR4 gene and is often associated with drug resistance and aggressive disease presentation. Therefore, detection of these mutations (MYD88L265P and CXCR4S338X) could be useful diagnostic and prognostic tool for the patients with WM. While detection of these mutations in bone marrow sample is common, the aim of our study was to compare sensitivity of detection of mutation from different cell fraction from peripheral blood and bone marrow. The results show possibility to describe MYD88 and CXCR4 mutation status even from peripheral blood sample (sensitivity for MYD88L265P was 100%, for CXCR4S338X 91%), which significantly facilitate material collection. Moreover, comparable detection sensitivity of these mutations in bone marrow and peripheral blood samples examined before and during the therapy offers a promising tool for more routine diagnostic and monitoring of disease progression.Key words: Waldenstrom macroglobulinemia - hematology - neoplasms - lymphoma - mutation - MYD88 - CXCR4. PMID- 28903576 TI - Mitigating intimate partner violence among South African women testing HIV positive during mobile counseling and testing. AB - South African women continue to suffer disproportionately from the interlinked epidemics of HIV and intimate partner violence (IPV). Effective strategies are needed to mitigate HIV-related IPV, which often creates barriers to successful engagement along the HIV continuum of care. More information is needed on how IPV impacts women's safety following mobile HCT diagnosis, and the HIV IPV Risk Assessment & Safety-planning (HIRS) protocol was developed to address several related gaps in knowledge. The sample included 255 black South African women experiencing IPV and testing HIV+ during mobile HCT in Gauteng province. Outcomes were compared between a standard of care (SOC) group and an Experimental group with two dosage levels (D1, D2). Of the total sample and in the last year, 99.2% had experienced non-violent control, 40.7% physical abuse, 44.8% sexual abuse, and 67.3% physical or sexual abuse. There were no significant differences in pre/post safety scores, or for satisfaction or acceptability items. The overall linkage rate was 45.8% (M = 12.97 days), and the Experimental group had more links to care in certain age groups-the highest in those aged <=23 years in D1 (70%). The lowest linkage rate was for those aged 33-43 years in the SOC (22.2%). Almost two thirds of participants reported using the safety plan (61.9%), with 80% reporting it was helpful, and 80% using >=1 safety strategy. The Experimental group reported significantly less violence upon partner notification of serostatus, but all groups felt significantly less safe getting to medical appointments by post-test. Overall, the study indicates the HIRS protocol is safe and helpful, brief to administer, and may mitigate violence during partner notification of serostatus, but further investigation is needed before implementing it as a standard of care. PMID- 28903577 TI - A 2-4-Amino Acid Deletion in the V5 Region of HIV-1 Env gp120 Confers Viral Resistance to the Broadly Neutralizing Human Monoclonal Antibody, VRC01. AB - The envelope glycoprotein (Env) gp120 of human immunodeficiency virus type 1 (HIV 1) plays a critical role in viral entry into host cells. The broadly neutralizing human monoclonal antibody VRC01, which recognizes the CD4 binding site on gp120, neutralizes more than 90% of HIV-1 isolates. However, some of the CRF01_AE viruses prevalent in Southeast Asia are resistant to VRC01-mediated neutralization. We previously reported that 3 amino acid residues at positions 185, 186, and 197 of gp120 played an important role in the VRC01 resistance of CRF01_AE Env (AE-Env) clones isolated from HIV-infected Thai individuals. However, the VRC01 susceptibility of AE-Env clones was not fully explained by mutations at these 3 residues. In the present study, we examined other factors involved in the acquisition of viral VRC01 resistance. Neutralization tests using lentiviral vectors expressing a series of mutant AE-Env clones revealed that the deletion of 2-4 amino acid residues on the loop structure in the V5 region of gp120 conferred VRC01 resistance to several AE-Env clones. Our results provide novel insights into the mechanisms underlying viral VRC01 resistance. PMID- 28903578 TI - Mental Health Services Use Trends in Canadian Veterans: A Population-Based Retrospective Cohort Study in Ontario. AB - OBJECTIVE: A substantial evidence base in the peer-reviewed literature exists investigating mental illness in the military, but relatively less is documented about mental illness in veterans. This study uses provincial, administrative data to study the use of mental health services by Canadian veterans in Ontario. METHOD: This was a retrospective cohort study of Canadian Armed Forces and Royal Canadian Mounted Police veterans who were released between 1990 and 2013 and resided in Ontario. Mental health-related primary care physician, psychiatrist, emergency department (ED) visits, and psychiatric hospitalisations were counted. Repeated measures were presented in 5-year intervals, stratified by age at release. RESULTS: The cohort included 23,818 veterans. In the first 5 years following entry into the health care system, 28.9% of veterans had >=1 mental health-related primary care physician visit, 5.8% visited a psychiatrist at least once, and 2.4% received acute mental health services at an ED. The use of mental health services was consistent over time. Almost 8% of veterans aged 30 to 39 years saw a psychiatrist in the first 5 years after release, compared to 3.5% of veterans aged >=50 years at release. The youngest veterans at release (<30 years) were the most frequent users of ED services for a mental health-related reason (5.1% had at least 1 ED visit). CONCLUSION: Understanding how veterans use the health care system for mental health problems is an important step to ensuring needs are met during the transition to civilian life. PMID- 28903580 TI - Reliability of parent recall of symptom onset and timing in autism spectrum disorder. AB - Past events are often reported as occurring more recently than they actually took place, an error called forward telescoping. This study examined whether forward telescoping was evident in parent reports of autism spectrum disorder symptom emergence and onset classification. Parents were interviewed when their child was 2-3 years old (Time 1) and approximately 6 years old (Time 2). Significant forward telescoping was found in both age of social regression and age when language milestones were achieved, but not age of language regression. The correspondence between Time 1 and Time 2 onset report was low ( kappa = 0.38). Approximately one-quarter of the sample changed onset categories, most often due to parents not recalling a regression at Time 2 that they had reported at Time 1. These results challenge the use of retrospective methods in determining onset patterns. PMID- 28903581 TI - Geriatric Assessment Can Predict Outcomes of Endoscopic Surgery for Benign Prostatic Hyperplasia in Elderly Patients. AB - : Ojectives: Surgical management of benign prostatic hyperplasia (BPH) in elderly patients is associated with higher morbidity and mortality rate. This raises the question of benefice and risk balance. We conducted a prospective observational study to evaluate the results of endoscopic surgery for BPH in elderly patients, according to geriatric assessment. PATIENTS AND METHODS: We included prospectively 60 patients older than 75 years, with an indwelling catheter for acute or chronic retention, who were candidates to endoscopic surgery for BPH. Patients underwent the brief geriatric assessment (BGA) and the comprehensive geriatric assessment (CGA) to classify them into three groups: "vigorous," "vulnerable," and "sick." Success was defined by the bladder catheter withdrawal after surgery. RESULTS: After geriatric assessment, 33 patients were classified in the "vigorous" group (55%), 25 in the "vulnerable" group (42%), and 2 in the "sick" group (3%). The success rate immediately after surgery was 85% and 41% in the "vigorous patient" group and the "vulnerable and sick" patient group, respectively (p < 0.05). The success rate at 3 months after surgery was 94% and 55% (p < 0.05). The morbidity was higher for the "vulnerable and sick" group (44%) compared with the "vigorous" group (15%) (p < 0.05). The BGA also allowed predicting a higher risk of failure in patients with a score >=3 immediately after surgery (odds ratio 5.9, confidence interval [95% CI] 1.61, 29.9) and 3 months after surgery (odds ratio 6.9, 95% CI 1.31, 70.8). CONCLUSION: Geriatric assessment can predict the outcome of endoscopic surgery for BPH for patients in retention older than 75 years. "Vulnerable and sick" patients had a higher risk to keep their indwelling catheter after the surgery compared with "vigorous" patients. The complication rate is also higher. The BGA can although predict a poor result of surgery when its score is equal or above 3/6. PMID- 28903582 TI - Methylprednisolone for prevention of ovarian hyperstimulation syndrome in patients with polycystic ovarian syndrome undergoing in-vitro fertilisation: a randomised controlled trial. AB - This study aimed to evaluate the effect of methylprednisolone on prevention of ovarian hyperstimulation syndrome (OHSS) in polycystic ovarian syndrome (PCOS) patients undergoing in-vitro fertilisation (IVF). This randomised controlled trial was carried out between November 2009 and December 2013. A total of 219 eligible patients were randomly allocated for treatment (n = 108) or control groups (n = 111). The treatment group received oral methylprednisolone starting from the first day of stimulation. These patients also received an intravenous dose of methylprednisolone on the days of egg collection and embryo transfer. The control group received no glucocorticoid treatment to prevent OHSS. Nineteen percent of patients (18/93) who received methylprednisolone developed OHSS compared with 16.5% (15/91) in the control group and no significant difference was found (p = .61). There were no significant differences between treatment and control groups in the rates of implantation (10% versus 11%, p = .77) and clinical pregnancy (23.2% versus 17.7%, p = .46). Methylprednisolone did not reduce the incidence and severity of OHSS in PCOS patients undergoing IVF and no improvement in clinical outcomes was observed. Impact statement No significant differences were found in OHSS incidence and clinical outcomes between women who received methylprednisolone and control group. There seems to be no benefit for the routine use of glucocorticoids in IVF/ICSI treatments. PMID- 28903579 TI - Loneliness, Social Isolation, and Cardiovascular Health. AB - SIGNIFICANCE: Social and demographic changes have led to an increased prevalence of loneliness and social isolation in modern society. Recent Advances: Population based studies have demonstrated that both objective social isolation and the perception of social isolation (loneliness) are correlated with a higher risk of mortality and that both are clearly risk factors for cardiovascular disease (CVD). Lonely individuals have increased peripheral vascular resistance and elevated blood pressure. Socially isolated animals develop more atherosclerosis than those housed in groups. CRITICAL ISSUES: Molecular mechanisms responsible for the increased cardiovascular risk are poorly understood. In recent reports, loneliness and social stress were associated with activation of the hypothalamic pituitary-adrenocortical axis and the sympathetic nervous system. Repeated and chronic social stress leads to glucocorticoid resistance, enhanced myelopoiesis, upregulated proinflammatory gene expression, and oxidative stress. However, the causal role of these mechanisms in the development of loneliness-associated CVD remains unclear. FUTURE DIRECTIONS: Elucidation of the molecular mechanisms of how CVD is induced by loneliness and social isolation requires additional studies. Understanding of the pathomechanisms is essential for the development of therapeutic strategies to prevent the detrimental effects of social stress on health. Antioxid. Redox Signal. 28, 837-851. PMID- 28903583 TI - Prenatal genetic diagnosis of Neu-Laxova syndrome. PMID- 28903584 TI - Re: "How Mohs Surgery Transformed Into a First-Line Treatment of Skin Cancer". PMID- 28903585 TI - Reconsidering Accuracy of Acne Self-Reports. PMID- 28903589 TI - The Struggle for Supremacy in Wagner's Der Ring Des Nibelungen: The Breaking of the Father's Authority. PMID- 28903586 TI - JCMS, CME, and You / Le JCMS, le DPC et vous. PMID- 28903591 TI - Negative Self-Evaluating Emotions as Mediator in the Relationship Between Childhood Emotional Trauma and Alexithymia in Adulthood. PMID- 28903595 TI - Religious Coping and Defense Style in a Sample of Persons with Cognitive Complaints. PMID- 28903596 TI - Changes in Self-Representations Following Psychoanalytic Psychotherapy for Young Adults: A Comparative Typology. AB - Changes in dynamic psychological structures are often a treatment goal in psychotherapy. The present study aimed at creating a typology of self representations among young women and men in psychoanalytic psychotherapy, to study longitudinal changes in self-representations, and to compare self representations in the clinical sample with those of a nonclinical group. Twenty five women and sixteen men were interviewed according to Blatt's Object Relations Inventory pretreatment, at termination, and at a 1.5-year follow-up. In the comparison group, eleven women and nine men were interviewed at baseline, 1.5 years, and three years later. Typologies of the 123 self-descriptions in the clinical group and 60 in the nonclinical group were constructed by means of ideal type analysis for men and women separately. Clusters of self-representations could be depicted on a two-dimensional matrix with the axes Relatedness-Self definition and Integration-Nonintegration. In most cases, the self-descriptions changed over time in terms of belonging to different ideal-type clusters. In the clinical group, there was a movement toward increased integration in self representations, but above all toward a better balance between relatedness and self-definition. The changes continued after termination, paralleled by reduced symptoms, improved functioning, and higher developmental levels of representations. No corresponding tendency could be observed in the nonclinical group. PMID- 28903597 TI - The Relationship Between Defense Style and Intelligence. PMID- 28903598 TI - Healthcare providers' attitude and knowledge regarding medication use in breastfeeding women: a Jordanian national questionnaire study. AB - : Medication use among women who have recently given birth is unavoidable in some situations. The aim of this study was to assess the attitude and knowledge of healthcare providers (HCPs) in Jordan about the safe use of medications during breastfeeding. The data were collected from HCPs in maternal and children care centres and hospitals from April 2015 to January 2016, using a self-administered questionnaire. A total of 904 HCPs (79.3%) were enrolled in the study. Half of the participants followed the World Health Organisation's and American Academy of Pediatrics' recommendations. The awareness of HCPs regarding these recommendations was lower among nurses (OR 0.212, 95%CI 0.132-0.338, p < .001) and pharmacists (OR 0.476, 95%CI 0.297-0.763, p = .002) than physicians. The majority of participants (80%) had low level of knowledge and nurses were more likely to have low knowledge than physicians (OR 0.099, 95%CI 0.050-0.197, p < .001). Professional continuous education programmes were highly encouraged. Impact statement What is already known on this subject: Use of medications among women who have recently given birth is unavoidable in some situations and most of them are safe to be given during breastfeeding. What the results of this study add: Healthcare providers in Jordan have variable attitudes regarding the safety of medication use during breastfeeding. The majority of healthcare providers have a low level of knowledge regarding the safe use of medication during breastfeeding. Nurses are more likely to have low knowledge as compared to physicians. IMPLICATIONS FOR CLINICAL PRACTICE: Healthcare providers should be encouraged to seek information regarding compatibility of medication use during breastfeeding from reliable sources. Professional continuing education programmes concerning the safety of medication use during breastfeeding period are needed to target all involved HCPs. More attention should be directed toward medical schools' curricula to widen the knowledge of medication use and focus on practice based clinical experience. PMID- 28903599 TI - An Open Letter to Health Canada. PMID- 28903600 TI - Basal Cell Carcinoma in Erythropoietic Protoporphyria: All About Ultraviolet Light? PMID- 28903601 TI - "The Good Physician Treats the Disease; the Great Physician Treats the Patient Who Has the Disease" / "Le bon medecin traite la maladie; le grand medecin traite le patient atteint de la maladie". PMID- 28903602 TI - Role of maternal serum ferritin in prediction of preterm labour. AB - The aim of this study was to evaluate the value of measurement of serum ferritin level in pregnant women to predict preterm labour. The study included 236 women whose haemoglobin (Hb) levels were >=10.5 gm/dl and gestational age (GA) was less than 30 weeks. Serum ferritin levels were measured at 30 weeks of gestational age. At the end of the study, 23 women delivered with preterm premature rupture of membrane (PPROM) and 17 women delivered before 37 weeks but without PROM (study group). The rest of the pregnant women (196 women) delivered between 37 and 40 weeks (control group). We found a significant difference between the two groups with respect to serum ferritin level. The cut off value of serum ferritin between the two groups was 31 ng/ml with sensitivity 92.8%, specificity 99.4%, positive predictive value 97.5%, negative predictive value 98.4% and accuracy 98.3%. Impact statement What is already known on this subject: maternal serum ferritin has been found to be elevated in women who delivered preterm. What the results of this study add: In this study, we have shown that serum ferritin 31 ng/ml is the optimal cut-point between preterm and full-term women. What the implications are of these findings for clinical practice and/or further research: Serum ferritin 31 ng/ml could be proposed as a potential helpful marker to predict preterm labour. PMID- 28903603 TI - Reconsideration ICF scheme. PMID- 28903605 TI - In honour of Professor Ruth Duncan, recipient of the Journal of Drug Targeting's Lifetime Achievement Award for 2017. PMID- 28903604 TI - Remediation of contaminated soils by biotechnology with nanomaterials: bio behavior, applications, and perspectives. AB - Soil contamination caused by heavy metals and organic pollutants has drawn world wide concern. Biotechnology has been applied for many years to the decontamination of soils polluted with organic and inorganic contaminants, and novel nanomaterials (NMs) has attracted much concern due to their high capacity for the removal/stabilization/degradation of pollutants. Recently, developing advanced biotechnology with NMs for the remediation of contaminated soils has become a hot research topic. Some researchers found that bioremediation efficiency of contaminated soils was enhanced by the addition of NMs, while others demonstrated that the toxicity of NMs to the organism negatively influenced the repair capacity of polluted soils. This paper reviews the application of biotechnology and NMs in soil remediation, and further provides a critical view of the effects of NMs on the phytoremediation and micro-remediation of contaminated soils. This review also discusses the future research needs for the combined application of biotechnology and NMs in soil remediation. PMID- 28903606 TI - Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects. AB - Anxiolytic drugs, namely benzodiazepines, are the most commonly used psychoactive substances since anxiety disorders are prevalent mental disorders particularly in the Western world. Oxazepam is a short-acting benzodiazepine and one of the most frequently prescribed anxiolytic drugs. It is also the active metabolite of a wide range of other benzodiazepines, such as diazepam, ketazolam, temazepam, chlordiazepoxide, demoxazepam, halazepam, medazepam, prazepam, pinazepam, and chlorazepate. Therefore, relevant clinical and forensic outocomes may arise, namely those related to interference in driving performance. It is clinically available as a racemic formulation, with S-enantiomer being more active than R enantiomer. In humans, it is mainly polimorphically metabolized by glucuronide conjugation at the 3-carbon hydroxyl group, yielding stable diastereomeric glucuronides (R- and S-oxazepam glucuronide). Relevant metabolic and stereoselective interspecies differences have been reported. In this work, the pharmacokinetics of oxazepam with particular focus on metabolic pathways is fully reviewed. Moreover, the metabolic profile of other prescribed benzodiazepines that produce oxazepam as a metabolite is also discussed. It is aimed that knowing the metabolism of oxazepam and related benzodiazepines may lead to the development of new analytical strategies for its early detection and help in further toxicological and clinical interpretations. PMID- 28903607 TI - Candida endocarditis: systematic literature review from 1997 to 2014 and analysis of 29 cases from the Italian Study of Endocarditis. AB - INTRODUCTION: Candida Endocarditis (CE) is a deadly disease. It is of paramount importance to assess risk factors for acquisition of both Candida native (NVE) and prosthetic (PVE) valve endocarditis and relate clinical features and treatment strategies with the outcome of the disease. Areas covered: We searched the literature using the Pubmed database. Cases of CE from the Italian Study on Endocarditis (SEI) were also included. Overall, 140 cases of CE were analyzed. Patients with a history of abdominal surgery and antibiotic exposure had higher probability of developing NVE than PVE. In the PVE group, time to onset of CE was significantly lower for biological prosthesis compared to mechanical prosthesis. In the whole population, greater age and longer time to diagnosis were associated with increased likelihood of death. Patients with effective anti-biofilm treatment, patients who underwent cardiac surgery and patients who were administered chronic suppressive antifungal treatment showed increased survival. For PVE, moderate active anti-biofilm and highly active anti-biofilm treatment were associated with lower mortality. Expert commentary: Both NVE and PVE could be considered biofilm-related diseases, pathogenetically characterized by Candida intestinal translocation and initial transient candidemia. Cardiac surgery, EAB treatment and chronic suppressive therapy might be crucial in increasing patient survival. PMID- 28903608 TI - Influence of substrates on the in vitro kinetics of steviol glucuronidation and interaction between steviol glycosides metabolites and UGT2B7. AB - Steviol glycosides, a natural sweetener, may perform bioactivities via steviol, their main metabolite in human digestion. The metabolising kinetics, i.e. glucuronidation kinetics and interaction between steviol glycosides or their metabolites and metabolising enzyme, are important for understanding the bioactivity and cytotoxicity. The present study investigated kinetics of steviol glucuronidation in human liver microsome and a recombinant human UDP glucuronosyltransferases isomer, UGT2B7, along with molecular docking to analyse interaction between UGT2B7 and steviol or glucose. The active pocket of UGT2B7 is consisted of Arg352, Leu347, Lys343, Phe339, Tyr354, Lys355 and Leu353. The influence of stevioside, rebaudioside A, glucose and some chemotherapy reagents on the glucuronidation was also studied. The predicted hepatic clearence suggested that steviol could be classified as high-clearence drug. The steviol glycosides did not affect the glucuronidation of steviol notably. PMID- 28903609 TI - Erratum. PMID- 28903610 TI - A broad ligament pregnancy successfully managed by laparoscopy. PMID- 28903611 TI - Maternal leukocytosis after antenatal corticosteroid administration: a systematic review and meta-analysis. AB - Although it is known that corticosteroid administration causes leukocytosis, the magnitude and length of time this leukocytosis persists is unknown during pregnancy. This study aimed to establish the expected range of maternal leukocytosis in healthy pregnant women at risk for preterm delivery after antenatal corticosteroid administration. PubMed, Embase and ClinicalTrials.gov were searched to identify the studies in healthy women at risk for preterm delivery without signs of clinical infection that reported white blood cell values preceding and after antenatal corticosteroid administration. The inverse variance weighting technique was used to calculate the weighted means and the standard deviation from the mean for each time period. Six studies met inclusion criteria and included 524 patients and 1406 observations. Mean +/- standard deviation maternal white blood cell count values prior to antenatal corticosteroid administration and up to 24, 48, 72 and 96 hours after corticosteroid administration were 10.4 +/- 2.4, 13.6 +/- 3.6, 12.1 +/- 3.0, 11.5 +/- 2.9 and 11.1 +/- 2.5 * 109/L, respectively. Leukocytosis in healthy, non infected women is expected to peak 24 hours after antenatal corticosteroid administration and the magnitude of increase is small. Impact statement What is already known on this subject: While it is well known that administration of antenatal corticosteroids causes leukocytosis, it is currently unknown the magnitude and length of time the leukocytosis persists. What the results of this study add: This study establishes the expected range and the temporal progression and regression with antenatal corticosteroid administration in healthy pregnant women at risk for preterm delivery without clinical signs of infection. What the implications are of these findings for clinical practice and/or further research: Clinicians may wish to consider further investigation into the clinical cause, whether infectious or non-infectious, for absolute values and changes outside this range. PMID- 28903612 TI - Corrigendum. PMID- 28903613 TI - A survey to explore what information, advice and support community-dwelling people with stroke currently receive to manage instability and falls. AB - PURPOSE: To describe and determine the benefits of the information and support services currently offered to people with stroke experiencing instability and falls. METHODS: A cross-sectional survey study. Two hundred and fifty-six surveys were sent out to community stroke groups in Hampshire and the Isle of Wight, as well as to people with stroke on a patient register. RESULTS: One hundred and twenty-five surveys were returned. A total of 107 participants (86%) reported instability and 62 (50%) had experienced a fall in the preceding year; 29 (28%) had reportedly received information on falls prevention. Forty-four participants (43%) sought help from health professionals following instability and falls; just over half reported that the information they received was useful. One quarter (n = 11) of those seeking help were referred on to falls clinics; all attended and 86% felt attending had been beneficial. However, only one participant was followed up by these clinics. CONCLUSIONS: Findings suggest that the majority of people with stroke who have experienced instability and falls did not receive any information and support, with very few referred on to falls clinics. Health professionals play a key role in information provision and facilitating access to falls prevention programs. Further research is required to determine the most effective ways to implement current guidelines to manage instability and falls in this high-risk group. Implications for rehabilitation: Many community-dwelling people with stroke did not receive any information, help or support after experiencing instability and falls. Clinicians must stress that falls are a complication, not an expectation, post-stroke. Information on falls prevention and available support services should be offered to individuals prior to discharge from hospital, in GP practices and in rehabilitation settings. All individuals with stroke seeking health professional help following instability and falls should be referred on to falls clinics for individualized multifactorial assessment and intervention to comply with current guidelines. PMID- 28903614 TI - Context-specific food-based approach for ensuring nutrition security in developing countries: a review. AB - Sustainable food strategies for meeting nutrient needs in developing countries are not well established. The available evidence shows that more than one-third of the world's population is facing under-nutrition, of which the most affected individuals are children and mothers from poor countries. In most developing countries, losses resulting from malnutrition are between 3 and 16% of the gross domestic product. This burden is far larger than the donor-driven and government programmes can tackle alone. As such, an innovative approach, which is independent and not donor-based, is needed to reduce the burden of malnutrition in low-income countries. In this review, we describe a context specific food based approach for addressing malnutrition in developing countries. The approach deploys the hybrid public-private delivery model that enables cost sharing and efficiency gains in resource-poor countries. The model influences players to consider consumers' perspectives, which often are neglected and truly engage them as key stakeholders. PMID- 28903615 TI - A study of oxidative stress in migraine with special reference to prophylactic therapy. AB - OBJECTIVE: The role of oxidative stress markers in migraine and effect of treatment on these has been reported. SUBJECTS AND METHODS: One hundred and fifty patients having > four attacks of migraine headache/month were included. Headache severity, Migraine Index (MI) and frequency of headache were noted. 120 patients received repetitive transcranial magnetic stimulation (rTMS) therapy and 30 patients received Amitriptyline (AMT). Recovery was defined by 50% improvement in frequency, severity or reduction in MI. Oxidative stress and antioxidant markers have been estimated in patients before and after treatment and correlate the clinical and outcome parameters. RESULTS: Glutathione (GSH) (P < 0.001), glutathione-S-transferase (GST) (P = 0.049) and total antioxidant activity (TAC) (P < 0.001) level were significantly reduced in migraine patients. GSH (P = 0.02), GST (P = 0.05) and TAC (P < 0.001) were reduced in ictal migraineurs compared to controls. GSH (P < 0.001) and TAC (P = 0.003) levels increased after treatment compared to the base line. There is an increase in GSH levels in the patients who had improved following rTMS (P = 0.003); placebo (P = 0.001) and AMT (P = 0.013). TAC levels were also increased following rTMS (P = 0.009) and AMT (P = 0.020). CONCLUSION: There is evidence of oxidative stress in migraine pathophysiology. Following treatment, oxidative stress declined following both pharmacological and rTMS. PMID- 28903616 TI - Circulating dehydroepiandrosterone-sulphate decreases even with a slight change in oestradiol. AB - The aim of this study was to determine the effect of hormone replacement therapy (HRT) on changes in circulating dehydroepiandrosterone-sulphate (DHEA-S) with focus on the relationship between oestrogen level and change in DHEA-S. Forty-two women were enrolled in this longitudinal study. Nineteen women received oral oestradiol and twenty-three women received transdermal oestradiol continuously. Twenty women received progesterone continuously except for women who had undergone hysterectomy. Circulating oestradiol, follicle-stimulating hormone, luteinising hormone and DHEA-S levels before and at 3 months after commencement of HRT were measured. Circulating DHEA-S level was significantly decreased at 3 months (p < .001). Oestradiol level at 3 months ranged from 6.5 pg/ml to 159 pg/ml. There was no significant correlation of DeltaDHEA-S (DHEAS level at 3 months-DHEA-S level at baseline) with Deltaoestradiol (r = 0.114, p = .471). Circulating DHEA-S level was significantly decreased at 3 months in all the four quartiles and divided according to Deltaoestradiol, and DeltaDHEA-S did not show significant differences. In conclusion, circulating DHEA-S decreases even with a slight increase in oestradiol level. Impact statement What is already known on this subject: A transient increase in DHEA-S in women during the menopausal transition may be involved in the occurrence of menopausal symptoms and/or unfavourable metabolic changes. Hormone replacement therapy decreases circulating DHEA-S level. However, dose dependency of the change in DHEA-S on oestrogen has not been reported. What the results of this study add: Circulating DHEA-S decreases even with a slight increase in oestradiol level. What the implications are of these findings for clinical practice and/or further research: Adrenal function may respond to a small change in oestrogen. PMID- 28903617 TI - Review of egg-related salmonellosis and reduction strategies in United States, Australia, United Kingdom and New Zealand. AB - Globally, Salmonella enterica subsp. enterica is one of the most commonly reported causes of foodborne illness in humans. Contaminated food products of animal origin, particularly egg and egg products are frequently implicated in outbreaks of human salmonellosis. Salmonella enteritidis is frequently involved in egg and egg products-associated foodborne outbreaks in the USA and UK. However, in Australia and New Zealand, human infections caused by this serovar occur as a result of infection acquired while overseas travel, with Salmonella typhimurium being a predominant cause of local foodborne outbreaks. In this paper, an overview of Salmonella epidemiology on laying farms, egg-related Salmonella outbreaks in humans, and regulatory practises to control Salmonella across USA, UK, Australia and New Zealand is provided. Considering the estimated production of eggs in the USA, UK, Australia and New Zealand in 2015, the risk of foodborne illness in general is quite low for humans consuming eggs. Salmonella diagnostics, reporting and surveillance systems have improved over the years and will continue to improve in the years to come. However, given the number of different emerging Salmonella serovars a regular review of Salmonella control strategies from farm to fork is required. PMID- 28903618 TI - Biomaterial Cues Regulate Epigenetic State and Cell Functions-A Systematic Review. AB - Biomaterial cues can act as potent regulators of cell niche and microenvironment. Epigenetic regulation plays an important role in cell functions, including proliferation, differentiation, and reprogramming. It is now well appreciated that biomaterials can alter epigenetic states of cells. In this study, we systematically reviewed the underlying epigenetic mechanisms of how different biomaterial cues, including material chemistry, topography, elasticity, and mechanical stimulus, influence cell functions, such as nuclear deformation, cell proliferation, differentiation, and reprogramming, to summarize the differences and similarities among each biomaterial cues and their mechanisms, and to find common and unique properties of different biomaterial cues. Moreover, this work aims to establish a mechanogenomic map facilitating highly functionalized biomaterial design, and renders new thoughts of epigenetic regulation in controlling cell fates in disease treatment and regenerative medicine. PMID- 28903619 TI - The volume of PET-defined, active bone marrow spared predicts acute hematologic toxicities in anal cancer patients receiving concurrent chemoradiotherapy. PMID- 28903620 TI - Phylogenetic relationships of three representative sea krait species (genus Laticauda; elapidae; serpentes) based on 13 mitochondrial genes. AB - To investigate the phylogenetic relationships of the genus Laticauda to related higher taxa, we compared the sequences of four mitochondrial genes (12S rRNA, 16S rRNA, ND4, Cytb) from three Laticauda species (L. colubrina, L. laticaudata, and L. semifasciata) with those of 55 Asian and Australo-Melanesian elapid species. We also characterized the complete mitogenomes of the three Laticauda species and compared the sequences of 13 mitochondrial genes from Laticauda species with five terrestrial elapid and one viperid species to estimate phylogenetic relationships and divergence times. Our results showed that the genus Laticauda is paraphyletic to terrestrial elapids and diverged from the Asian elapids approximately 16.23 Mya. The mitogenomes of the three Laticauda species commonly encoded 13 proteins, 22 tRNAs, 12S and 16S rRNAs and two control regions and ranged from 17,170 and 17,450 bp in size. The L. colubrina mitogenome was more similar to that of L. laticaudata than that of L. semifasciata. The divergence time among the three Laticauda clades was estimated at 8-10 Mya, and a close phylogenetic relationship between L. colubrina and L. laticaudata was found. Our results contribute to our understanding of the evolutionary history of sea kraits. PMID- 28903621 TI - Virtual environments as an assessment modality with pediatric ASD populations: a brief report. AB - Virtual environments (VEs) have demonstrated promise as a neuropsychological assessment modality and may be well suited for the evaluation of children suspected of having an autism spectrum disorder (ASD). Some recent studies indicate their potential for enhancing reliability, ecologically validity, and sensitivity over traditional neuropsychological evaluation measures. Although research using VEs with ASD is increasing to the degree that several reviews of the literature have been conducted, the reviews to date lack rigor and are not necessarily specific to cognitive or neuropsychological assessment as many focus on intervention. The aim of this project was to comprehensively examine the current literature status of neuropsychological assessment in pediatric ASD using VEs by conducting a systematic review. Specifically, psychometric comparisons of VEs to traditional neuropsychological assessment measures that examined reliability, validity, and/or diagnostic accuracy for pediatric individuals, age 18 and below, with ASD were sought. The search using key words yielded 899 manuscripts, 894 of which were discarded for not meeting inclusion criteria. The remaining five met exclusion criteria. Therefore, the systematic review was modified to a brief report. These findings (or lack thereof) indicate a significant gap in the literature in that psychometric comparisons of these tools for the neuropsychological assessment of pediatric individuals with ASD are lacking. An important future direction of research will be extending the demonstrated incremental validity of VE neuropsychological assessment with other neurodevelopmental (e.g., attention-deficit/hyperactivity disorder) and adult populations to pediatric ASD populations. PMID- 28903622 TI - Maternal dietary n-6 polyunsaturated fatty acid deprivation does not exacerbate post-weaning reductions in arachidonic acid and its mediators in the mouse hippocampus. AB - OBJECTIVES: The present study examines how lowering maternal dietary n-6 polyunsaturated fatty acids (PUFA) (starting from pregnancy) compared to offspring (starting from post-weaning) affect the levels of n-6 and n-3 fatty acids in phospholipids (PL) and lipid mediators in the hippocampus of mice. METHODS: Pregnant mice were randomly assigned to consume either a deprived or an adequate n-6 PUFA diet during pregnancy and lactation (maternal exposure). On postnatal day (PND) 21, half of the male pups were weaned onto the same diet as their dams, and the other half were switched to the other diet for 9 weeks (offspring exposure). At PND 84, upon head-focused high-energy microwave irradiation, hippocampi were collected for PL fatty acid and lipid mediator analyses. RESULTS: Arachidonic acid (ARA) concentrations were significantly decreased in both total PL and PL fractions, while eicosapentaenoic acid (EPA) concentrations were increased only in PL fractions upon n-6 PUFA deprivation of offspring, regardless of maternal exposure. Several ARA-derived eicosanoids were reduced, while some of the EPA-derived eicosanoids were elevated by n-6 PUFA deprivation in offspring. There was no effect of diet on docosahexaenoic acid (DHA) or DHA-derived docosanoids concentrations under either maternal or offspring exposure. DISCUSSION: These results indicate that the maternal exposure to dietary n-6 PUFA may not be as important as the offspring exposure in regulating hippocampal ARA and some lipid mediators. Results from this study will be helpful in the design of experiments aimed at testing the significance of altering brain ARA levels over different stages of life. PMID- 28903623 TI - Endovascular stenting of mid-aortic syndrome due to Takayasu arteritis. AB - Introduction-patients: Takayasu arteritis may involve various parts of the aorta and its major branches. It leads to occlusive or aneurysmal disease of the vessel. It can be treated either with surgery or percutaneous intervention. We report a successful endovascular treatment of stenosis of the descending thoracic and abdominal aorta in a 19-year-old female. Methods-results-conclusions: Self expandable nitinol stent was deployed and adequate opening of the aorta was obtained in this patient. Long-term durability of endovascular approach is a matter of debate. We also reviewed the sufficiency of endovascular treatment versus surgery. PMID- 28903624 TI - Repair of Calvarial Bone Defect Using Jarid1a-Knockdown Bone Mesenchymal Stem Cells in Rats. AB - Histone methylation is regarded as an important epigenetic event during stem cell differentiation. Jumonji AT-rich interactive domain 1A (Jarid1a) is a histone demethylase that specifically catalyzes demethylation of dimethyl or trimethyl histone H3K4me3, which is normally associated with transcriptionally active genes. Runt-related transcription factor 2 (Runx2) has been identified as a key transcription factor in the early stage of osteogenesis. A better understanding of this epigenetic mechanism that governs osteogenic differentiation of bone mesenchymal stem cells (BMSCs) can provide new insights into BMSC-based bone tissue engineering. To define the function and regulatory mechanisms of Jarid1a in the osteogenic differentiation of BMSCs, we compared the expression of Jarid1a between undifferentiated and osteoinductive BMSCs. The expression of osteogenic transcriptional factors in BMSCs after Jarid1a knockdown was explored using western blot. To determine whether Jarid1a was associated with Runx2 during osteogenic differentiation, endogenous coimmunoprecipitation (co-IP) experiments were performed with osteoinductive BMSCs extracts. Then, we systematically evaluated the function of si-Jarid1a in enhancing BMSCs osteogenesis and the therapeutic potential of si-Jarid1a-modified BMSCs in a rat calvarial bone defect model with beta-tricalcium phosphate scaffolds. Knockdown of Jarid1a by small interfering RNA enhanced osteogenic differentiation of BMSCs in vitro. Knockdown of Jarid1a significantly improved the mRNA and protein expression of bone specific factors. Furthermore, co-IP in BMSCs lysate suggested that Jarid1a was physically and functionally associated with Runx2. The repair potential of bone defect was dramatically improved by Jarid1a-knockdown BMSCs, including increased bone volume, increased bone mineral density, and decreased scaffold residue in vivo. Altogether, this study explores the functional and regulatory role of Jarid1a in osteogenic differentiation and bone regeneration of BMSCs, and provides a new approach for bone defect repairing using epigenetic modification in vitro and in vivo. PMID- 28903625 TI - Radioprotective activity of curcumin-encapsulated liposomes against genotoxicity caused by Gamma Cobalt-60 irradiation in human blood cells. AB - PURPOSE: While the radioprotective activity of curcumin against genotoxicity has been well established, its poor oral bioavailability has limited its successful clinical applications. Nanoscale formulations, including liposomes, have been demonstrated to improve curcumin bioavailability. The objective of the present work was (1) to prepare and characterize curcumin-encapsulated liposomes (i.e. size, colloidal stability, encapsulation efficiency, and payload), and (2) subsequently to evaluate their radioprotective activity against genotoxicity in human blood cells caused by Gamma Cobalt-60 irradiation. MATERIALS AND METHODS: The curcumin-encapsulated liposomes were prepared by lipid-film hydration method using commercial phosphatidylcholine (i.e. Phospholipon(r) 90G). The blood cells were obtained from healthy male donors (n = 3) under an approved ethics protocol. The cell uptake and the radioprotective activity of the curcumin-encapsulated liposomes were characterized by fluorescence microscopy and micronucleus assay, respectively. RESULTS: Nanoscale curcumin-encapsulated liposomes exhibiting good physical characteristics and successful uptake by the human blood cells were successfully prepared. The radioprotective activity of the curcumin-encapsulated liposomes was found to be dependent on the curcumin concentration, where an optimal concentration existed (i.e. 30 MUg/mL) independent of the irradiation dose, above which the radioprotective activity had become stagnant (i.e. no more reduction in the micronuclei frequency). CONCLUSIONS: The present results established for the first time the radioprotective activity of curcumin encapsulated liposomes in human blood cells, which coupled by its well established bioavailability, boded well for its potential application as a nanoscale delivery system of other radioprotective phytochemicals. PMID- 28903626 TI - Light Dominates Peripheral Circadian Oscillations in Drosophila melanogaster During Sensory Conflict. AB - In Drosophila, as in other animals, the circadian clock is a singular entity in name and concept only. In reality, clock functions emerge from multiple processes and anatomical substrates. One distinction has conventionally been made between a central clock (in the brain) and peripheral clocks (e.g., in the gut and the eyes). Both types of clock generate robust circadian oscillations, which do not require external input. Furthermore, the phases of these oscillations remain exquisitely sensitive to specific environmental cues, such as the daily changes of light and temperature. When these cues conflict with one another, the central clock displays complex forms of sensory integration; how peripheral clocks respond to conflicting input is unclear. We therefore explored the effects of light and temperature misalignments on peripheral clocks. We show that under conflict, peripheral clocks preferentially synchronize to the light stimulus. This photic dominance requires the presence of the circadian photoreceptor, Cryptochrome. PMID- 28903627 TI - Reliability and minimal detectable change of a new treadmill-based progressive workload incremental test to measure cardiorespiratory fitness in manual wheelchair users. AB - BACKGROUND: Cardiorespiratory fitness training is commonly provided to manual wheelchair users (MWUs) in rehabilitation and physical activity programs, emphasizing the need for a reliable task-specific incremental wheelchair propulsion test. OBJECTIVE: Quantifying test-retest reliability and minimal detectable change (MDC) of key cardiorespiratory fitness measures following performance of a newly developed continuous treadmill-based wheelchair propulsion test (WPTTreadmill). METHODS: Twenty-five MWUs completed the WPTTreadmill on two separate occasions within one week. During these tests, participants continuously propelled their wheelchair on a motorized treadmill while the exercise intensity was gradually increased every minute until exhaustion by changing the slope and/or speed according to a standardized protocol. Peak oxygen consumption (VO2peak), carbon dioxide production (VCO2peak), respiratory exchange ratio (RERpeak), minute ventilation (VEpeak) and heart rate (HRpeak) were computed. Time to exhaustion (TTE) and number of increments completed were also measured. Intra-class correlation coefficients (ICC) were calculated to determine test retest reliability. Standard error of measurement (SEM) and MDC90% values were calculated. RESULTS: Excellent test-retest reliability was reached for almost all outcome measures (ICC=0.91-0.76), except for RERpeak (ICC=0.58), which reached good reliability. TTE (ICC=0.89) and number of increments (ICC=0.91) also reached excellent test-retest reliability. For the main outcome measures (VO2peak and TTE), absolute SEM was 2.27 mL/kg/min and 0.76 minutes, respectively and absolute MDC90% was 5.30 mL/kg/min and 1.77 minutes, respectively. CONCLUSION: The WPTTreadmill is a reliable test to assess cardiorespiratory fitness among MWUs. TTE and number of increments could be used as reliable outcome measures when VO2 measurement is not possible. PMID- 28903628 TI - What motivates serodiscordant couples to prevent HIV transmission within their relationships: findings from a PrEP implementation study in Kenya. AB - With the planned scale-up of pre-exposure prophylaxis (PrEP) for HIV prevention among serodiscordant couples in resource-limited settings, gaining an understanding of what motivates serodiscordant couples to prevent HIV is critical. We conducted 44 semi-structured, in-depth individual or couple interviews with 63 participants (33 HIV-infected and 30 HIV-uninfected participants) enrolled in a prospective implementation study of oral antiretroviral-based prevention in Kisumu, Kenya. Transcripts were iteratively analysed using inductive content analysis. Findings point to the importance of maintaining the emotional and economic stability of the partnership and family as motivators in preventing HIV transmission. Female participants identified fear of blame or potential violence for transmitting HIV as a motivator. Furthermore, couples primarily held the HIV-infected individual responsible for HIV prevention, but also held women more accountable for the use of prevention methods such as condoms. These themes substantiate traditional gender norms but also reveal how dyadic interdependence challenges these norms. As programmes in resource-limited settings scale up PrEP access, they should simultaneously capitalise on HIV serodiscordant couples' motivations for HIV prevention and address gender norms so women do not find themselves unduly responsible for the prevention of HIV transmission. PMID- 28903629 TI - A multidisciplinary approach for developing an assessment tool for touch screen devices. AB - AIM: The aim of this study was to describe the processes of reaching consensus regarding the assessment of the user's skills required to operate various touch screen devices. A five-step procedure was used to collect and validate the required skills by a multidisciplinary team of 52 experts. Content validity was calculated to determine the agreement levels between the experts. A comparison was made between the discipline groups in order to test correlation between each group and their choice of specific clusters of tasks. METHODS: The final consensus set by the experts' recommendations included 15 domains and 50 skills/measurements. The result of Cronbach's alpha test for the final assessment questionnaire (50 skills/measurements) was 0.94, which indicates a high degree of internal consistency. The results of Kruskal-Wallis's test showed the lack of any significant difference between agreements of the clinicians and the technicians groups, but significant differences were found between the educators and the clinicians groups. CONCLUSION: The assessment questionnaire, in its current form, can be used by clinicians and it is expected to help in developing an objective assessment tool to quantify the performance and touch characteristics of individuals with varying abilities and disabilities, in order to enhance accessibility of touch screen technology. Implications for Rehabilitation Collecting and creating the required knowledge needed for assessing the user's skills for operating touch screen devices. The created knowledge helps clinicians to focus on the essential skills and measurements needed for a comprehensive assessment of the individual's abilities and disabilities while operating touch screen devices. The results of the assessment can be used as recommendations for enhancing accessibility of touch screen devices for various disabilities. This knowledge is expected to help in developing an application that provides an objective assessment tool. The study emphasizes the importance of close collaboration with multidisciplinary teams for creating a valid assessment tool. PMID- 28903630 TI - Comparison of results of Bakri balloon tamponade and caesarean hysterectomy in management of placenta accreta and increta: a retrospective study. AB - The aim of this study was to compare the postoperative results of the patients who were treated with Bakri balloon tamponade or hysterectomy for placenta accreta and increta. Patients who were diagnosed with placenta accreta or increta preoperatively and intraoperatively and treated with Bakri balloon tamponade (Group 1) or caesarean hysterectomy (Group 2) were compared in regards to the postoperative results. Among the 36 patients diagnosed with placenta accreta or increta, 19 patients were treated with Bakri balloon tamponade while 17 cases were treated with hysterectomy. Intraoperative blood loss amount was 1794 +/- 725 ml in G1, which was lower than that in G2 (2694 +/- 893 ml). Blood transfusion amount was 2.7 +/- 2.6 units in G1, lower than that in G2 (5.7 +/- 2.4 units), too. Operation time was 64.5 +/- 29 min and 140 +/- 51 min in G1 and G2, respectively, showing significant differences between two groups. The success rate of Bakri balloon was determined as 84.21%. In conclusion, cases with placenta accreta/increta, with predicted placental detachment who are willing to preserve fertility, application of uterine balloon tamponade devices before the hysterectomy is encouraging with its advantages compared with the hysterectomy. Impact statement What is already known on this subject: Invasive placental anomalies are the most common indication of postpartum hysterectomy. Recently, uterine balloon tamponade was also included in the treatment modalities of postpartum haemorrhage.This study aimed to compare the postoperative results of UBT or hysterectomy for patients with placenta accreta and increta. What the results of this study add: In this study, the total amount of blood loss was higher in the caesarean hysterectomy group when compared with the Bakri balloon tamponade group. The mean transfusion requirement, mean operation time and hospitalisation period was significantly longer in the caesarean hysterectomy group. The success rate of the Bakri balloon was determined as 84.21%. Two patients who were treated with balloon application had a successful pregnancy and delivery later. Maternal mortality was reported in neither balloon nor hysterectomy groups. What the implications are of these findings for clinical practice and/or further research: In conclusion, patients diagnosed with placenta accreta/increta with ultrasound should be taken into the operation in elective conditions, if possible, on lithotomy position. In cases with predicted placental detachment that are willing to preserve fertility, application of uterine balloon tamponade devices before the hysterectomy has advantages compared with the hysterectomy. PMID- 28903631 TI - Evaluation of overactive bladder and nocturia as a risk factor for hip fracture in climacteric women: a matched pair case control study. AB - The aim of this study was to investigate whether overactive bladder (OAB) influences hip fractures in climacteric women by comparing the frequency of OAB and nocturia symptoms in patients with hip fractures and their age-matched controls in pre-fracture period. A total of 30 climacteric patients with a history of hip fracture were compared to a control group of 51 women in terms of OAB, nocturia and nocturia-QoL. A questionnaire composed of structured questions and Turkish validated versions of the specific questionnaires for OAB, OAB Quality of Life (OAB-q) and nocturia-QoL was directed to the two groups. We did not detect statistically relevant differences between the groups for the presence or severity of OAB and OAB-q (p > .05). However, Nocturia-QoL was worse in the group with hip fracture (p = .022). Overactive bladder has no contribution to the overall risk of hip fracture, whereas, the severity of nocturia seems to play a role as a risk factor in the formation of hip fracture. Impact statement What is already known on this subject: Hip fracture is associated with high morbidity, mortality and the cost. Prevention of hip fracture is a high priority for the patients, physicians and the public health. Several studies and consensus opinions have investigated the risk factors for the hip fractures. What the results of this study add: Although urinary symptoms were not evaluated in previous studies as a risk factor, desire of urination makes people stand up and move to their toilet, and may put them in a hurry if it is sudden and uncontrollable one. Therefore, we hypothesised that overactive bladder (OAB) and nocturia may be a risk factor in the formation of hip fractures. Our study showed that Nocturia Quality of Life is worse in patients with the hip fracture. Therefore, overactive bladder may not have a role on the overall risk of hip fracture, but the severity of nocturia seems as a risk factor in the fracture process. What the implications are of these findings for clinical practice and/or further research: The getting up from the bed would probably be harder than getting up from a chair in elderly, and life style modifications such as illumination bedroom and organisation of living place may be helpful to minimise the risks. PMID- 28903632 TI - Maximization Paradox: Result of Believing in an Objective Best. AB - The results from four studies provide reliable evidence of how beliefs in an objective best influence the decision process and subjective feelings. A belief in an objective best serves as the fundamental mechanism connecting the concept of maximizing and the maximization paradox (i.e., expending great effort but feeling bad when making decisions, Study 1), and randomly chosen decision makers operate similar to maximizers once they are manipulated to believe that the best is objective (Studies 2A, 2B, and 3). In addition, the effect of a belief in an objective best on the maximization paradox is moderated by the presence of a dominant option (Study 3). The findings of this research contribute to the maximization literature by demonstrating that believing in an objective best leads to the maximization paradox. The maximization paradox is indeed the result of believing in an objective best. PMID- 28903633 TI - Collective Self-Determination: How the Agent of Help Promotes Pride, Well-Being, and Support for Intergroup Helping. AB - This research integrates self-determination theory and the social identity approach to investigate the notion of collective (group level) self determination, and to test how the agent of intergroup help (helping initiated by a group representative versus group members) shapes group members' motives and support for intergroup helping. Study 1 ( N = 432) demonstrates that collective self-determination predicts support for intergroup helping, group pride, and well being, over and above individual-level self-determined motivation. Study 2 ( N = 216) confirmed that helping by group members was seen as more collectively self determined than helping by a group representative, producing effects on pride, well-being, and support. Study 3 ( N = 124) explores a qualifier of these effects: People who identify more strongly with the leader who is providing the help also experience representative helping as more collectively self-determined, thereby promoting well-being, group pride, and support. Findings highlight the value of integrating self-determination theory with intergroup theories to consider collective aspects of self-determination. PMID- 28903634 TI - The Dynamics of Compensation: When Ingroup Favoritism Paves the Way for Outgroup Praise. AB - Compensation research suggests that when people evaluate their own and another group, the search for positive differentiation fuels the emergence of compensatory ratings on the two fundamental dimensions of social perception, competence and warmth. In two experiments, we tested whether obstacles to positive differentiation on the preferred dimension disrupted compensation. Both experiments showed that high-status (low-status) group members grant the outgroup a higher standing on warmth (competence) when positive differentiation can be achieved on the orthogonal dimension, competence (warmth). Moreover, and in line with the " noblesse oblige" effect, Experiment 2 confirmed that, among high status group members, perceived higher pressures toward nondiscrimination were linked to outgroup bias on warmth only when ingroup bias on competence had been secured. The discussion focuses on compensation as one of the factors contributing to cooperative intergroup relations. PMID- 28903635 TI - Nothing Changes, Really: Why Women Who Break Through the Glass Ceiling End Up Reinforcing It. AB - Two correlational studies conducted in Switzerland ( N = 222) and Albania ( N = 156) explained the opposition of female managers to gender quotas by examining the origins and consequences of the "Queen Bee (QB)-phenomenon," whereby women who have been successful in male-dominated organizations do not support the advancement of junior women. Results disconfirm previous accounts of the QB phenomenon as indicating competitiveness among women. Instead, the tendency of women managers to consider themselves as different from other women, and their opposition to gender quotas, emerged when junior women were addressed but not when they considered their direct competitors, other women managers. Personal sacrifices women managers reported having made for career success predicted self distancing from junior women and opposition to gender quotas targeting these women. We provide a more nuanced picture of what the QB-response is really about, explaining why women managers oppose quotas for junior women, while supporting quotas for women in the same rank. PMID- 28903636 TI - A Brief Mindfulness Exercise Promotes the Correspondence Between the Implicit Affiliation Motive and Goal Setting. AB - People often choose to pursue goals that are dissociated from their implicit motives, which jeopardizes their motivation and well-being. We hypothesized that mindfulness may attenuate this dissociation to the degree that it increases sensitivity to internal cues that signal one's implicit preferences. We tested this hypothesis with a longitudinal repeated measures experiment. In Session 1, participants' implicit affiliation motive was assessed. In Session 2, half of the participants completed a mindfulness exercise while the other half completed a control task before indicating their motivation toward pursuing affiliation and nonaffiliation goals. In Session 3, this procedure was repeated with reversed assignment to conditions. The results confirmed our hypothesis that, irrespective of the order of the conditions, the implicit affiliation motive predicted a preference to pursue affiliation goals immediately after the mindfulness exercise, but not after the control task. We discuss implications of these findings for satisfaction and well-being. PMID- 28903637 TI - Helping Others Regulate Emotion Predicts Increased Regulation of One's Own Emotions and Decreased Symptoms of Depression. AB - Although much research considers how individuals manage their own emotions, less is known about the emotional benefits of regulating the emotions of others. We examined this topic in a 3-week study of an online platform providing training and practice in the social regulation of emotion. We found that participants who engaged more by helping others (vs. sharing and receiving support for their own problems) showed greater decreases in depression, mediated by increased use of reappraisal in daily life. Moreover, social regulation messages with more other focused language (i.e., second-person pronouns) were (a) more likely to elicit expressions of gratitude from recipients and (b) predictive of increased use of reappraisal over time for message composers, suggesting perspective-taking enhances the benefits of practicing social regulation. These findings unpack potential mechanisms of socially oriented training in emotion regulation and suggest that by helping others regulate, we may enhance our own regulatory skills and emotional well-being. PMID- 28903638 TI - Trait Perception Accuracy and Acquaintance Within Groups: Tracking Accuracy Development. AB - Previous work on trait perception has evaluated accuracy at discrete stages of relationships (e.g., strangers, best friends). A relatively limited body of literature has investigated changes in accuracy as acquaintance within a dyad or group increases. Small groups of initially unacquainted individuals spent more than 30 hr participating in a wide range of activities designed to represent common interpersonal contexts (e.g., eating, traveling). We calculated how accurately each participant judged others in their group on the big five traits across three distinct points within the acquaintance process: zero acquaintance, after a getting-to-know-you conversation, and after 10 weeks of interaction and activity. Judgments of all five traits exhibited accuracy above chance levels after 10 weeks. An examination of the trait rating stability revealed that much of the revision in judgments occurred not over the course of the 10-week relationship as suspected, but between zero acquaintance and the getting-to-know you conversation. PMID- 28903639 TI - When Silence Is Not Golden: Why Acknowledgment Matters Even When Being Excluded. AB - Following ostracism, individuals are highly sensitive to social cues. Here we investigate whether and when minimal acknowledgment can improve need satisfaction following an ostracism experience. In four studies, participants were either ostracized during Cyberball (Studies 1 and 2) or through a novel apartment application paradigm (Studies 3 and 4). To signal acknowledgment following ostracism, participants were either thrown a ball a few times at the end of the Cyberball game, or received a message that was either friendly, neutral, or hostile in the apartment-application paradigm. Both forms of acknowledgment increased need satisfaction, even when the acknowledgment was hostile (Study 4), emphasizing the beneficial effect of any kind of acknowledgment following ostracism. Reinclusion buffered threat immediately, whereas acknowledgment without reinclusion primarily aided recovery. Our results suggest that minimal acknowledgment such as a few ball throws or even an unfriendly message can reduce the sting of ostracism. PMID- 28903640 TI - It's All About the Money (For Some): Consequences of Financially Contingent Self Worth. AB - Financial success is an important goal, yet striving for it is often associated with negative outcomes. One reason for this paradox is that financial pressures may be tied to basing self-worth on financial success. Studies 1a to 1c developed a measure of Financial Contingency of Self-Worth (Financial CSW), and found that it predicted more financial social comparisons, financial hassles, stress, anxiety, and less autonomy. In response to a financial (vs. academic) threat, higher Financial CSW participants experienced less autonomy, perceived financial problems more negatively, and disengaged from their financial problems (Study 2). When given an opportunity to self-affirm, however, Financial CSW participants did not show diminished autonomy in response to a financial (vs. academic) threat (Study 3). Finally, participants with higher Financial CSW were less likely to make extravagant spending decisions following a financial (vs. health) threat (Study 4). Together, these studies demonstrate the many consequences of staking self-worth on financial success. PMID- 28903641 TI - Sex Unleashes Your Tongue: Sexual Priming Motivates Self-Disclosure to a New Acquaintance and Interest in Future Interactions. AB - Research has demonstrated the contribution of sexual activity to the quality of ongoing relationships. Nevertheless, less attention has been given to how activation of the sexual system affects relationship-initiation processes. Three studies used complementary methodologies to examine the effect of sexual priming on self-disclosure, a relationship-promoting behavior. In Study 1, participants were subliminally exposed to sexual stimuli (vs. neutral stimuli), and then disclosed over Instant Messenger a personal event to an opposite-sex stranger. Results showed that merely thinking about sex, even without being aware of it, encouraged self-disclosure. Study 2 replicated these findings in relatively naturalistic conditions (live face-to-face interactions following supraliminal video priming). Study 3 extended these findings, indicating that sexual priming facilitated self-disclosure, which, in turn, increased interest in future interactions with the stranger. Together, these findings suggest that activation of the sexual system encourages the use of strategies that allow people to become closer to potential partners. PMID- 28903642 TI - The Self-Control Irony: Desire for Self-Control Limits Exertion of Self-Control in Demanding Settings. AB - Self-control is a highly adaptive human capacity. Accordingly, development of self-control is widely encouraged. Whereas the benefits of having self-control are well documented, little is known about the impact of wanting self-control. The present investigation fills this void by exploring the effect of desire for self-control on the ability to exert self-control. It was expected that in the context of demanding self-control challenges, a desire for self-control will highlight a discrepancy between one's goals and perceived performance potential, leading to reduced efficacy beliefs and task disengagement. Four studies ( N = 635) supported the prediction. Study 1 showed that a strong desire impaired performance on a demanding task but not on a simple task. Study 2 conceptually replicated the decrement in performance and established causality by experimentally manipulating desire for self-control. Studies 3 and 4 showed that reduction in efficacy beliefs mediate the effect. Implications of the findings are discussed. PMID- 28903644 TI - The Curvilinear Relationship Between Attitude Certainty and Attitudinal Advocacy. AB - Do people advocate more on behalf of their own attitudes and opinions when they feel certain or uncertain? Although considerable past research suggests that people are more likely to advocate when they feel highly certain, there also is evidence for the opposite effect-that people sometimes advocate more when they experience a loss of certainty. The current research seeks to merge these insights. Specifically, we explore the possibility that the relationship between attitude certainty and attitudinal advocacy is curvilinear. Consistent with this hypothesis, we find evidence for a J-shaped curve: Advocacy intentions (and behavior) peak under high certainty, bottom out under moderate certainty, and show an uptick under low (relative to moderate) certainty. We document this relationship and investigate its potential mechanisms in three studies by examining advocacy intentions and the actual advocacy messages participants write when they feel high, moderate, or low certainty. PMID- 28903643 TI - A new measurement of an indirect measure of condom use and its relationships with barriers. AB - One of the challenges facing researchers in the domain of human immunodeficiency virus prevention is the assessment of condom use in an unbiased self-reported manner. The current study presents the development and preliminary validation of an indirect condom use test (I-CUTE), designed to assess condom use tendencies and to overcome self-report biases. Two samples were included using correlational designs. In sample 1, 88 students from European university completed the I-CUTE with questionnaires of condom use barriers, social desirability, and condom use negotiation self-efficacy. In sample 2, 212 students from sub-Saharan universities completed the I-CUTE with questionnaires of condom use barriers and knowledge. The I-CUTE included 17 pictures of human figures in relation to condom use, where participants had to choose one of the four a-priori given sentences reflecting the figures' thoughts. This represented a semi-projective, yet standardized test. In sample 1, I-CUTE scores were inversely related to barriers, positively correlated with condom use negotiation self-efficacy and unrelated to social desirability. In sample 2, I-CUTE scores were inversely related to barriers and unrelated to knowledge scores. In a multiple regression, condom use barriers had a unique contribution to explaining variance in I-CUTE scores, beyond the contribution of background variables and knowledge. These results support the preliminary reliability and validity of the I-CUTE tool in a variety of cultures, and reveal its lack of bias by social desirability and the importance of condom use barriers in condom use tendencies. PMID- 28903645 TI - Self-Expression on Social Media: Do Tweets Present Accurate and Positive Portraits of Impulsivity, Self-Esteem, and Attachment Style? AB - Self-expression values are at an all-time high, and people are increasingly relying upon social media platforms to express themselves positively and accurately. We examined whether self-expression on the social media platform Twitter elicits positive and accurate social perceptions. Eleven perceivers rated 128 individuals (targets; total dyadic impressions = 1,408) on their impulsivity, self-esteem, and attachment style, based solely on the information provided in targets' 10 most recent tweets. Targets were on average perceived normatively and with distinctive self-other agreement, indicating both positive and accurate social perceptions. There were also individual differences in how positively and accurately targets were perceived, which exploratory analyses indicated may be partially driven by differential word usage, such as the use of positive emotion words and self- versus other-focus. This study demonstrates that self-expression on social media can elicit both positive and accurate perceptions and begins to shed light on how to curate such perceptions. PMID- 28903646 TI - Communal and Agentic Interpersonal and Intergroup Motives Predict Preferences for Status Versus Power. AB - Seven studies involving 1,343 participants showed how circumplex models of social motives can help explain individual differences in preferences for status (having others' admiration) versus power (controlling valuable resources). Studies 1 to 3 and 7 concerned interpersonal motives in workplace contexts, and found that stronger communal motives (to have mutual trust, support, and cooperation) predicted being more attracted to status (but not power) and achieving more workplace status, while stronger agentic motives (to be firm, decisive, and influential) predicted being more attracted to and achieving more workplace power, and experiencing a stronger connection between workplace power and job satisfaction. Studies 4 to 6 found similar effects for intergroup motives: Stronger communal motives predicted wanting one's ingroup (e.g., country) to have status-but not power-relative to other groups. Finally, most people preferred status over power, and this was especially true for women, which was partially explained by women having stronger communal motives. PMID- 28903647 TI - Intergroup Contact and Social Change: Implications of Negative and Positive Contact for Collective Action in Advantaged and Disadvantaged Groups. AB - Previous research has shown that (a) positive intergroup contact with an advantaged group can discourage collective action among disadvantaged-group members and (b) positive intergroup contact can encourage advantaged-group members to take action on behalf of disadvantaged outgroups. Two studies investigated the effects of negative as well as positive intergroup contact. Study 1 ( n = 482) found that negative but not positive contact with heterosexual people was associated with sexual-minority students' engagement in collective action (via group identification and perceived discrimination). Among heterosexual students, positive and negative contacts were associated with, respectively, more and less LGB (lesbian, gay, bisexual) activism. Study 2 ( N = 1,469) found that only negative contact (via perceived discrimination) predicted LGBT (lesbian, gay, bisexual, and transgender) students' collective action intentions longitudinally while only positive contact predicted heterosexual/cisgender students' LGBT activism. Implications for the relationship between intergroup contact, collective action, and social change are discussed. PMID- 28903648 TI - Using Groups to Measure Intergroup Prejudice. AB - Implicit measures of racial attitudes often assess reactions to images of individuals to infer attitudes toward an entire social category. However, an increasing amount of research indicates that responses to individuals are highly dependent on context and idiosyncratic features of individual exemplars. Thus, using images of individuals to assess beliefs about a whole social category may not be ideal. Across three time points, we predicted that using images of groups would mitigate the influence of idiosyncratic features of individual targets and, thus, provide a better measurement tool to assess beliefs about a category to which all group members belong. Results revealed that an implicit measure that presented images of Black and White groups had greater construct validity, test retest reliability, and predictive validity as compared with an implicit measure that presented the same exemplars individually. We conclude that groups provide a window into existing beliefs about social categories. PMID- 28903649 TI - Backlash: The Politics and Real-World Consequences of Minority Group Dehumanization. AB - Research suggests that members of advantaged groups who feel dehumanized by other groups respond aggressively. But little is known about how meta-dehumanization affects disadvantaged minority group members, historically the primary targets of dehumanization. We examine this important question in the context of the 2016 U.S. Republican Primaries, which have witnessed the widespread derogation and dehumanization of Mexican immigrants and Muslims. Two initial studies document that Americans blatantly dehumanize Mexican immigrants and Muslims; this dehumanization uniquely predicts support for aggressive policies proposed by Republican nominees, and dehumanization is highly associated with supporting Republican candidates (especially Donald Trump). Two further studies show that, in this climate, Latinos and Muslims in the United States feel heavily dehumanized, which predicts hostile responses including support for violent versus non-violent collective action and unwillingness to assist counterterrorism efforts. Our results extend theorizing on dehumanization, and suggest that it may have cyclical and self-fulfilling consequences. PMID- 28903650 TI - Is Comparison the Thief of Joy? Sexual Narcissism and Social Comparisons in the Domain of Sexuality. AB - Are people who are high in sexual narcissism more sensitive to information comparing their sex lives with the sex lives of others? Does this sensitivity explain narcissists' lower sexual and relationship satisfaction? We conducted three studies to address this question. Participants completed the Sexual Narcissism Scale (Widman & McNulty, 2010), and then either recalled (Study 1), imagined (Study 2), or actually made (Study 3) a sexual comparison. We found that people high in sexual narcissism (compared with those lower in sexual narcissism) were more bothered when comparing themselves with someone with a higher sexual frequency and felt better about a comparison with someone with a lower sexual frequency. In turn, narcissists' greater sensitivity to upward social comparisons predicted lower sexual and relationship satisfaction. These results suggest that those high in sexual narcissism may use downward sexual comparisons to maintain their grandiose self-views and be particularly sensitive to upward sexual comparisons. PMID- 28903651 TI - For the Sake of the Eternal Group: Perceiving the Group as Trans-Generational and Endurance of Ingroup Suffering. AB - We introduce the distinction between perceiving the group as Intra-Generational (IG; including only the present generation of group members) and Trans Generational (TG; including all past, present, and future generations of the group). In four studies ( N = 1,265) administered to Jewish Israeli, Palestinian Israeli, American, and Swedish samples, we demonstrate that a tendency to perceive the group as TG is related to willingness to endure ingroup suffering and that this relationship is mediated by the degree to which the interest of the group as a whole is given primacy over the interest of the group as a collection of group members (Primacy of Interest). Furthermore, experimentally raising the salience of the group as TG leads to increased willingness to endure ingroup suffering as compared with raising the salience of the group as IG, and the effect of the TG salience manipulation is mediated by Primacy of Interest. PMID- 28903652 TI - Salient Multiculturalism Enhances Minority Group Members' Feelings of Power. AB - The present research examined how messages advocating different intergroup ideologies affect outcomes relevant to minority group members' ability to exert power in exchanges with dominant group members. We expected that salient multiculturalism would have positive implications for minority group members' feelings of power by virtue of highlighting essential contributions they make to society, and that no such empowering effect would be evident for them in connection with alternative ideologies such as color-blindness or for dominant group members. Results across four studies involving different participant populations, operationalizations of ideology, ethnic minority groups, and experimental settings were consistent with these hypotheses and further indicated that the effects of salient multiculturalism on feelings of power had downstream implications for expectations of control in an ostensibly upcoming intergroup interaction and general goal-directed cognition. PMID- 28903653 TI - Corrigendum. AB - Fuesting, M. A., & Diekman, A. B. (2017). Not by success alone: Role models provide pathways to communal opportunities in STEM. Personality and Social Psychology Bulletin, 43(2), 163-176. PMID- 28903654 TI - Cultivating Effective Social Support Through Abstraction: Reframing Social Support Promotes Goal-Pursuit. AB - Social support, in theory, should promote individual goal-pursuit. However, a growing number of studies shows that receiving support can undermine goal pursuit. Addressing this paradox, we investigated a novel idea of the effects of how people think about their social support on their goal-pursuit. Four experiments showed that participants who were led to think abstractly (vs. concretely) about their social support showed higher intent to pursue their goal (Studies 1-3) and worked harder toward their goal (Study 4). The benefits of abstracting one's social support occurred over a variety of personal goals, support types, and support-providers, indicating the generalizability and robustness of our findings. These results demonstrate that how people think about their social support influences goal-pursuit and suggest ways in which support recipients can maximize their social support. PMID- 28903655 TI - Being Your Actual or Ideal Self? What It Means to Feel Authentic in a Relationship. AB - Relational authenticity-which refers to subjective feelings of authenticity in a specific relationship-confers well-being; yet little is known about what gives rise to it. The present research tested competing hypotheses about the basis of relational authenticity, whether it arises from being one's actual self in a relationship (actual-relational selves overlap), ideal self (relational-ideal selves overlap), or both. A pilot study examined lay beliefs about the basis of relational authenticity. Study 1 then showed that relational-ideal, but not actual-relational, overlap predicts relational authenticity. The remaining studies experimentally manipulated relational-ideal overlap, and showed that low overlap reduced relational authenticity compared with a control condition (Study 2), with varying actual-relational overlap (Study 3), and with varying actual ideal overlap (Study 4). Several alternative accounts (e.g., negative general relationship perceptions) were addressed. We conclude that relational authenticity emanates largely from being one's ideal self in the relevant relationship, and discuss implications and future directions. PMID- 28903656 TI - On the Attitudinal Consequences of Being Mindful: Links Between Mindfulness and Attitudinal Ambivalence. AB - A series of studies examined whether mindfulness is associated with the experience of attitudinal ambivalence. Studies 1A and 1B found that mindful individuals expressed greater comfort holding ambivalent views and reported feeling ambivalent less often. More mindful individuals also responded more positively to feelings of uncertainty (as assessed in Study 1B). Study 2 replicated these effects and demonstrated that mindful individuals had lower objective and subjective ambivalence across a range of attitude objects but did not differ in attitude valence, extremity, positivity/negativity, strength, or the need to evaluate. Study 3 showed that the link between greater ambivalence and negative affect was buffered by mindfulness, such that there was no link between the amount of ambivalence and negative affect among more mindful individuals. The results are discussed with respect to the benefits of mindfulness in relation to ambivalence and affect. PMID- 28903657 TI - When Wanting the Best Goes Right or Wrong: Distinguishing Between Adaptive and Maladaptive Maximization. AB - Researchers have often disagreed on how to define maximization, leading to conflicting conclusions about its potential benefits or drawbacks. Drawing from motivation research, we distinguish between the goals (i.e., wanting the best) and strategies (e.g., alternative search) associated with maximizing. Three studies illustrate how this differentiation offers insight into when maximizers do or do not experience affective costs when making decisions. In Study 1, we show that two motivational orientations, promotion focus and assessment mode, are both associated with the goal of wanting the best, yet assessment (not promotion) is related to the use of alternative search strategies. In Study 2, we demonstrate that alternative search strategies are associated with frustration on a discrete decision task. In Study 3, we provide evidence that one reason for this link may be due to reconsideration of previously dismissed options. We discuss the potential of this approach to integrate research in this area. PMID- 28903658 TI - A Social Recognition Approach to Autonomy: The Role of Equality-Based Respect. AB - Inspired by philosophical reasoning about the connection between equality and freedom, we examined whether experiences of (equality-based) respect increase perceived autonomy. This link was tested with generalized experiences of respect and autonomy people make in their daily lives (Study 1) and with more specific experiences of employees at the workplace (Study 2). In both studies, respect strongly and independently contributed to perceived autonomy over and above other forms of social recognition (need-based care and achievement-based social esteem) and further affected (life/work) satisfaction. Study 3 experimentally confirmed the hypothesized causal influence of respect on perceived autonomy and demonstrated that this effect further translates into social cooperation. The respect-cooperation link was simultaneously mediated by perceived autonomy and superordinate collective identification. We discuss how the recognition approach, which differentiates between respect, care, and social esteem, can enrich research on autonomy. PMID- 28903659 TI - Sage on the Stage: Women's Representation at an Academic Conference. AB - Who presents at conferences matters. Presenting research benefits speakers, and presenters shape the conclusions audiences draw about who can succeed in a field. This is particularly important for members of historically underrepresented or disadvantaged groups, such as women. We investigated gender representation over a 13-year period among speakers at the largest social and personality psychology conference. On average, women were underrepresented as speakers, though this effect diminished over time. Chairs appeared to serve as gatekeepers: In symposia chaired by women, almost half of the invited speakers were women, whereas in symposia chaired by men, it was a third. The representation of women as speakers varied significantly by academic rank, with women underrepresented at lower ranks but not as full professors, and by topic. Women also tended to present with a smaller, less varied array of individuals than men, though this could be explained by women's lower average academic rank. PMID- 28903661 TI - Social Identification in Sports Teams: The Role of Personal, Social, and Collective Identity Motives. AB - Based on motivated identity construction theory (MICT; Vignoles, 2011), we offer an integrative approach examining the combined roles of six identity motives (self-esteem, distinctiveness, belonging, meaning, continuity, and efficacy) instantiated at three different motivational levels (personal, social, and collective identity) as predictors of group identification. These identity processes were investigated among 369 members of 45 sports teams from England and Italy in a longitudinal study over 6 months with four time points. Multilevel change modeling and cross-lagged analyses showed that satisfaction of four personal identity motives (individuals' personal feelings of self-esteem, distinctiveness, meaning, and efficacy derived from team membership), three social identity motives (individuals' feelings that the team identity carries a sense of belonging, meaning, and continuity), and one collective identity motive (a shared belief in group distinctiveness) significantly predicted group identification. Motivational processes underlying group identification are complex, multilayered, and not reducible to personal needs. PMID- 28903660 TI - The Process of Disengagement From Personal Goals: Reciprocal Influences Between the Experience of Action Crisis and Appraisals of Goal Desirability and Attainability. AB - To date, it is not well understood how individuals disengage from goals. A recent approach suggests that disengagement is often preceded by an action crisis, a motivational conflict in which the individual is torn between holding on to and letting go of a personal goal. We postulate that a dynamic interplay between the experience of action crisis and appraisals of goal desirability and attainability shapes the disengagement process from personal goals. In two longitudinal studies ( N = 364), an action crisis in the goal to complete a university degree predicted devaluations of its desirability and attainability, and reversely, low goal attainability (but not desirability) predicted an increase in action crisis. Moreover, studies provided first evidence that devaluing goal desirability might be functional for well-being in an action crisis. Studies strengthen the view that disengagement is shaped by reciprocal processes between the experience of action crisis and changes in goal appraisal. PMID- 28903662 TI - Looking Backward to Move Forward: Effects of Acknowledgment of Victimhood on Readiness to Compromise for Peace in the Protracted Israeli-Palestinian Conflict. AB - Two large-scale surveys conducted in Israel (Study 1A) and the Palestinian Authority (Study 1B) show that the belief by group members that people in the "enemy" group acknowledge their victimhood (i.e., Holocaust and Nakba for Jews and Palestinians, respectively) is associated with Israeli-Jews' readiness to accept responsibility for Palestinian sufferings and offer apologies. For Palestinians, this belief is linked to a perceived higher likelihood of a reconciled future with Israelis. Three field experiments demonstrate that a manipulated high level of acknowledgment of Jewish victimhood by Palestinians (Studies 2 and 4) and of Palestinian victimhood by Israeli-Jews (Study 3) caused greater readiness to make concessions for the sake of peace on divisive issues (e.g., Jerusalem, the 1967 borders, the right of return) and increased conciliatory attitudes. Additional analyses indicate the mediating role of increased trust and reduced emotional needs in these relationships. PMID- 28903663 TI - The Shadows of the Past: Effects of Historical Group Trauma on Current Intergroup Conflicts. AB - We examined associations between two orientations based on historical group trauma, a form of enduring group victimhood (Perpetual Ingroup Victimhood Orientation [PIVO]) and the belief that one's group might itself become a victimizer (Fear of Victimizing [FOV]), and attitudes, cognitions, and emotions related to intergroup conflicts. PIVO was positively and FOV was negatively related to aggressive attitudes and emotions toward the outgroup (Studies 1a-1c, Israeli-Palestinian conflict), and to the attribution of responsibility for a series of hostilities to the outgroup (Study 3, Israeli-Palestinian conflict). PIVO was negatively and FOV positively related to support for forgiveness and reconciliation (Study 2, Northern Ireland conflict). In Experimental Study 4, FOV predicted greater accuracy in remembering harm, regardless of victims' group identity, whereas PIVO was associated with reduced accuracy only when victims were Palestinians (outgroup members). Taken together, these findings indicate that both orientations have a significant impact on intergroup conflicts and their resolution. PMID- 28903664 TI - Preferences and actual chemotherapy decision-making in the greater plains collaborative breast cancer study. AB - INTRODUCTION: There is renewed interest in identifying breast cancer patients' participation in decision-making about adjuvant chemotherapy. There is a gap in the literature regarding the impact of these decisions on quality of life (QOL) and quality of care (QOC). Our aims were to determine similarities and differences in how patients diagnosed with breast cancer preferred to make decisions with providers about cancer treatment, to examine the patient's recall of her role when the decision was made about chemotherapy and to determine how preferred and actual roles, as well as congruence between them, relate to QOL and perceived QOC. MATERIAL AND METHODS: Greater Plains Collaborative clinical data research network of PCORnet conducted the 'Share Thoughts on Breast Cancer' survey among women 12-18 months post-diagnosis at eight sites in seven Midwestern United States. Patients recalled their preferred and actual treatment decision making roles and three new shared decision-making (SDM) variables were created. Patients completed QOL and QOC measurements. Correlations and t-tests were used. RESULTS: Of 1235 returned surveys, 873 (full sample) and 329 (subsample who received chemotherapy) were used. About one-half of women in both the full (50.7%) and subsample (49.8%,) preferred SDM with providers about treatment decisions, but only 41.2% (full) and 42.6% (subsample) reported experiencing SDM. Significant differences were found between preferred versus actual roles in the full (p < .001) and subsample (p < .004). In the full sample, there were no relationships between five decision-making variables with QOL, but there was an association with QOC. The subsample's decision-making variables related to several QOL scales and QOC items, with a more patient-centered decision than originally preferred related to higher physical and social/family well-being, overall QOL and QOC. CONCLUSIONS: Patients benefit from providers' efforts to identify patient preferences, encourage an active role in SDM, and tailor decision making to their desired choice. PMID- 28903665 TI - Erratum. PMID- 28903666 TI - Who Represents Our Group? The Effects of Prototype Content on Perceived Status Dispersion and Social Undermining. AB - Group identity may be embodied in more typical or extreme member attributes. The present research suggests that individuals' perceptions of the group identity prototype predict their beliefs about the status hierarchy and, in turn, the prevalence of social undermining behavior. Across four studies using both experimental and field data, we find that perceiving that the group prototype is focused on the ideal rather than the central tendency is associated with greater levels of perceived status dispersion and social undermining, and that perceived status dispersion mediates the relationship between members' perception of the group prototype and social undermining behavior. We also find that social context specifically, salient group achievement goals elicited by intergroup competition and common ingroup identity-attenuates the effect of ideal prototypes on perceived social undermining. Theoretical implications for the social identity, status, and social undermining literatures are discussed. PMID- 28903667 TI - Identity and Professional Networking. AB - Despite evidence that large professional networks afford a host of financial and professional benefits, people vary in how motivated they are to build such networks. To help explain this variance, the present article moves beyond a rational self-interest account to examine the possibility that identity shapes individuals' intentions to network. Study 1 established a positive association between viewing professional networking as identity-congruent and the tendency to prioritize strengthening and expanding one's professional network. Study 2 revealed that manipulating the salience of the self affects networking intentions, but only among those high in networking identity-congruence. Study 3 further established causality by experimentally manipulating identity-congruence to increase networking intentions. Study 4 examined whether identity or self interest is a better predictor of networking intentions, providing support for the former. These findings indicate that identity influences the networks people develop. Implications for research on the self, identity-based motivation, and professional networking are discussed. PMID- 28903668 TI - The Mandate of the Collective: Apology Representativeness Determines Perceived Sincerity and Forgiveness in Intergroup Contexts. AB - The sincerity of an apology is often critical for it to be viewed positively by victims. For collective apologies, we argue that sincerity takes on a particular meaning: It is a function of the apology's perceived representativeness for the offender group's will or sentiment. Consistent with this notion, when an apologetic (vs. nonapologetic) message was democratically chosen (Study 1) or explicitly endorsed by the majority of the offending outgroup (Study 2), it was considered more sincere and, through this, led to more forgiveness. Furthermore, while disagreement about an apology within the offender group reduced its perceived representativeness and sincerity, this was less so when the dissenters could be subtyped: when disagreement was correlated with an existing subgroup within the offending outgroup (Study 3) and in line with expectations for that subgroup (Study 4). This research shows that victim group members consider intragroup processes within the offending outgroup for attributions of sincerity. PMID- 28903669 TI - The Evil Animal: A Terror Management Theory Perspective on the Human Tendency to Kill Animals. AB - This research tested whether support for the killing of animals serves a terror management function. In five studies, death primes caused participants to support the killing of animals more than control primes, unless the participants' self esteem had been elevated (Study 4). This effect was not moderated by gender, preexisting attitudes toward killing animals or animal rights, perceived human animal similarity, religiosity, political orientation, or by the degree to which the killing was justified. Support for killing animals after subliminal death primes was also associated with an increased sense of power and invulnerability (Study 5). Implications and future directions are discussed. PMID- 28903670 TI - Daily Autonomy Support and Sexual Identity Disclosure Predicts Daily Mental and Physical Health Outcomes. AB - Using a daily diary methodology, we examined how social environments support or fail to support sexual identity disclosure, and associated mental and physical health outcomes. Results showed that variability in disclosure across the diary period related to greater psychological well-being and fewer physical symptoms, suggesting potential adaptive benefits to selectively disclosing. A multilevel path model indicated that perceiving autonomy support in conversations predicted more disclosure, which in turn predicted more need satisfaction, greater well being, and fewer physical symptoms that day. Finally, mediation analyses revealed that disclosure and need satisfaction explained why perceiving autonomy support in a conversation predicted greater well-being and fewer physical symptoms. That is, perceiving autonomy support in conversations indirectly predicted greater wellness through sexual orientation disclosure, along with feeling authentic and connected in daily interactions with others. Discussion highlights the role of supportive social contexts and everyday opportunities to disclose in affecting sexual minority mental and physical health. PMID- 28903671 TI - Humor Use Moderates the Relation of Stressful Life Events With Psychological Distress. AB - Three studies examined humor and adjustment to stressful events. In Study 1, patients with fibromyalgia syndrome ( N = 22) reported on mental and physical adjustment, social interaction, and reappraisal of their illness. Dispositional humor was associated with reduced distress and fewer physical symptoms. Study 2 ( N = 109) examined undergraduates' reports of stressful events. Dispositional, self-enhancing, affiliative, and self-defeating humor showed direct effects on distress, which were mediated by social interaction and reappraisal. Moreover, dispositional and aggressive humor showed stress-buffering effects. Study 3 ( N = 105) examined undergraduates' adjustment to the September 11, 2001, attacks at 1 and 3 months postattack. At T1, affiliative humor showed a stress-buffering effect on distress. Social interaction mediated the relation of self-enhancing humor with reduced T1 distress, and mediated relations of aggressive and self defeating humor with greater distress. Relations of T1 dispositional and self defeating humor to changes in T2 distress were mediated by reappraisal. PMID- 28903672 TI - Cognitive and Interpersonal Features of Intellectual Humility. AB - Four studies examined intellectual humility-the degree to which people recognize that their beliefs might be wrong. Using a new Intellectual Humility (IH) Scale, Study 1 showed that intellectual humility was associated with variables related to openness, curiosity, tolerance of ambiguity, and low dogmatism. Study 2 revealed that participants high in intellectual humility were less certain that their beliefs about religion were correct and judged people less on the basis of their religious opinions. In Study 3, participants high in intellectual humility were less inclined to think that politicians who changed their attitudes were "flip-flopping," and Study 4 showed that people high in intellectual humility were more attuned to the strength of persuasive arguments than those who were low. In addition to extending our understanding of intellectual humility, this research demonstrates that the IH Scale is a valid measure of the degree to which people recognize that their beliefs are fallible. PMID- 28903673 TI - Affective and Cognitive Orientations in Intergroup Perception. AB - Three studies examined the role of need for affect (NFA) and need for cognition (NFC) in intergroup perception. We hypothesized that NFA predicts a preference for stereotypically warm groups over stereotypically cold groups, whereas NFC predicts a preference for stereotypically competent groups over stereotypically incompetent groups. Study 1 supported these hypotheses for attitudes toward stereotypically ambivalent groups, which are stereotyped as high on one of the trait dimensions (e.g., high warmth) and low on the other (e.g., low competence), but not for stereotypically univalent groups, which are seen as high or low on both dimensions. Studies 2 and 3 replicated this pattern for stereotypically ambivalent groups, and yielded provocative evidence regarding several putative mechanisms underlying these associations. Together, these findings help integrate and extend past evidence on attitude-relevant individual differences with research on intergroup perception. PMID- 28903674 TI - Social Traces of Generic Humans Increase the Value of Everyday Objects. AB - Past research finds that people behave as though the particular qualities of specific, strongly valenced individuals "rub off" on objects. People thus value a sweater worn by George Clooney but are disgusted by one worn by Hitler. We hypothesized that social traces of generic humans can also adhere to objects, increasing their value. Experiments 1 and 2 found that simply marking that consumer products (mugs, giftwrap) were made by generic strangers (e.g., "by people using machines" vs. "by machines run by people") increased their perceived value. Experiment 3 demonstrated that this effect was mediated by thoughts about attention the object received from other people, which, in turn, led people to see the object as possessing more positive social qualities (e.g., friendly), increasing valuation. The results suggest that generic humans are perceived positively, possessing warm social qualities, and these can "rub off" and adhere to everyday objects increasing their value. PMID- 28903675 TI - Interactive Effects of Obvious and Ambiguous Social Categories on Perceptions of Leadership: When Double-Minority Status May Be Beneficial. AB - Easily perceived identities (e.g., race) may interact with perceptually ambiguous identities (e.g., sexual orientation) in meaningful but elusive ways. Here, we investigated how intersecting identities impact impressions of leadership. People perceived gay Black men as better leaders than members of either single-minority group (i.e., gay or Black). Yet, different traits supported judgments of the leadership abilities of Black and White targets; for instance, warmth positively predicted leadership judgments for Black men but dominance positively predicted leadership judgments for White men. These differences partly occurred because of different perceptions of masculinity across the intersection of race and sexual orientation. Indeed, both categorical (race and sex) and noncategorical (trait) social information contributed to leadership judgments. These findings highlight differences in the traits associated with leadership in Black and White men, as well as the importance of considering how intersecting cues associated with obvious and ambiguous groups moderate perceptions. PMID- 28903676 TI - The Influence of Effortful Thought and Cognitive Proficiencies on the Conjunction Fallacy: Implications for Dual-Process Theories of Reasoning and Judgment. AB - Human judgment often violates normative standards, and virtually no judgment error has received as much attention as the conjunction fallacy. Judgment errors have historically served as evidence for dual-process theories of reasoning, insofar as these errors are assumed to arise from reliance on a fast and intuitive mental process, and are corrected via effortful deliberative reasoning. In the present research, three experiments tested the notion that conjunction errors are reduced by effortful thought. Predictions based on three different dual-process theory perspectives were tested: lax monitoring, override failure, and the Tripartite Model. Results indicated that participants higher in numeracy were less likely to make conjunction errors, but this association only emerged when participants engaged in two-sided reasoning, as opposed to one-sided or no reasoning. Confidence was higher for incorrect as opposed to correct judgments, suggesting that participants were unaware of their errors. PMID- 28903677 TI - Considering Roads Taken and Not Taken: How Psychological Distance Influences the Framing of Choice Events. AB - After people make choices, they can frame the choice event in terms of what they chose, or in terms of what they did not choose. The current research proposes psychological distance as one factor influencing this framing and suggests implications. Three experiments manipulated dimensions of distance to demonstrate people's greater tendency to frame choice events in terms of chosen options at greater psychological distances. Additional findings demonstrate that these effects occur regardless of whether the decision turned out well or poorly. In a final experiment, framing a decision in terms of choosing (versus not choosing) a task made people more likely to believe their choice reflected their liking for the chosen task, which led to more favorable expectations for it. The discussion focuses on possible implications of these findings for understanding prior work on self-other differences in decision making, motivations for past decisions, reactions to decision outcomes, and counterfactual thinking. PMID- 28903678 TI - Is Education a Fundamental Right? People's Lay Theories About Intellectual Potential Drive Their Positions on Education. AB - Does every child have a fundamental right to receive a high-quality education? We propose that people's beliefs about whether "nearly everyone" or "only some people" have high intellectual potential drive their positions on education. Three studies found that the more people believed that nearly everyone has high potential, the more they viewed education as a fundamental human right. Furthermore, people who viewed education as a fundamental right, in turn (a) were more likely to support the institution of free public education, (b) were more concerned upon learning that students in the country were not performing well academically compared with students in peer nations, and (c) were more likely to support redistributing educational funds more equitably across wealthier and poorer school districts. The studies show that people's beliefs about intellectual potential can influence their positions on education, which can affect the future quality of life for countless students. PMID- 28903679 TI - Distinctive Facial Cues Predict Leadership Rank and Selection. AB - Facial appearance correlates with leadership, both in terms of who is chosen (leader selection) and how they do (leader success). Leadership theories suggest that exceptional individuals acquire positions as leaders. Exceptional traits can differ between domains, however, and so the qualities valued in leaders in one occupation may not match those valued among leaders in another. To test this, we compared the relationship between facial appearance and leadership across two domains: law firms and mafia families. Perceptions of power correlated with leadership among law executives whereas social skill correlated with leadership in organized crime. Critically, these traits were distinctive within their respective groups. Furthermore, an experimental test showed that the relative frequency of facial traits in a group can render them either an asset or liability. Perceived leadership ability is therefore enhanced by characteristics that appear unique among individuals who satisfy the basic criteria for their group. PMID- 28903680 TI - Exaggerating Accessible Differences: When Gender Stereotypes Overestimate Actual Group Differences. AB - Stereotypes are often presumed to exaggerate group differences, but empirical evidence is mixed. We suggest exaggeration is moderated by the accessibility of specific stereotype content. In particular, because the most accessible stereotype contents are attributes perceived to differ between groups, those attributes are most likely to exaggerate actual group differences due to regression to the mean. We tested this hypothesis using a highly accessible gender stereotype: that women are more socially sensitive than men. We confirmed that the most accessible stereotype content involves attributes perceived to differ between groups (pretest), and that these stereotypes contain some accuracy but significantly exaggerate actual gender differences (Experiment 1). We observe less exaggeration when judging less accessible stereotype content (Experiment 2), or when judging individual men and women (Experiment 3). Considering the accessibility of specific stereotype content may explain when stereotypes exaggerate actual group differences and when they do not. PMID- 28903681 TI - Hedonic Benefits of Close and Distant Interaction Partners: The Mediating Roles of Social Approval and Authenticity. AB - The current research utilized ecological momentary assessment methodology to examine affective responses to interacting with close versus distant interaction partners during naturally occurring social interactions, and to test predictions regarding the mediating roles of perceived social approval and authenticity. Analysis of 4,602 social interactions reported by 176 participants suggested that, relative to interactions with distant partners, interactions with close partners were characterized by more positive affect. This effect was mediated by perceived social approval and authenticity. These findings suggest that social interactions with close others confer greater hedonic benefits relative to interactions with distant partners due to greater confidence in social approval and feelings of authenticity. Exploratory analyses suggested that interactions with close partners featured warmer and less shy behavior, and that participants who placed more importance on close relationships (as measured by high relational interdependent self-construal) experienced more approval and authenticity in their interactions, particularly with distant partners. PMID- 28903682 TI - Differential and Domain-Specific Associations Among Right-Wing Authoritarianism, Social Dominance Orientation, and Adolescent Delinquency. AB - Using a dual-process model (DPM) framework, this research examined whether right wing authoritarianism (RWA) and social dominance orientation (SDO) are differentially associated with adolescent delinquency. In Study 1 ( N = 847; Mage = 15.96) and Study 2 ( N = 340; Mage = 16.64), adolescents completed measures of RWA, SDO, and engagement in different forms of delinquency. In Study 2, adolescents also reported their beliefs about obeying different laws. Across both studies, adolescents who endorsed greater RWA engaged in lower levels of delinquency and those who endorsed greater SDO engaged in higher levels of delinquency. Findings from Study 2 suggest that these associations are contingent on the domain-specific purpose of the law being violated and are also present with adolescents' beliefs about their obligation to obey laws. These results extend the DPM, demonstrating that RWA and SDO are differentially linked with youth delinquency. PMID- 28903683 TI - Individual Perceptions of Self-Actualization: What Functional Motives Are Linked to Fulfilling One's Full Potential? AB - Maslow's self-actualization remains a popular notion in academic research as well as popular culture. The notion that life's highest calling is fulfilling one's own unique potential has been widely appealing. But what do people believe they are doing when they pursue the realization of their full, unique potentials? Here, we examine lay perceptions of self-actualization. Self-actualizing, like any drive, is unlikely to operate without regard to biological and social costs and benefits. We examine which functional outcomes (e.g., gaining status, making friends, finding mates, caring for kin) people perceive as central to their individual self-actualizing. Three studies suggest that people most frequently link self-actualization to seeking status, and, concordant with life history theory, what people regard as self-actualizing varies in predictable ways across the life span and across individuals. Contrasting with self-actualization, people do not view other types of well-being-eudaimonic, hedonic, subjective-as furthering status-linked functional outcomes. PMID- 28903684 TI - The "Wallpaper Effect" Revisited: Divergent Findings on the Effects of Intergroup Contact on Attitudes in Diverse Versus Nondiverse Contexts. AB - This article reexamines the so-called "wallpaper effect" of intergroup contact, which contends that for minority group members living in areas more densely populated by majority group members, intergroup contact fails to reduce prejudice. We tested this claim in five studies, using data from five countries, two types of contexts, a range of measures, and involving different minority versus majority groups. Using multilevel cross-level interaction models, we considered whether effects of contact on outgroup attitudes were moderated by relative outgroup size. Results failed to replicate the previously reported findings, revealing, by and large, nonsignificant cross-level moderation effects; instead, we witnessed consistent positive contact effects on attitudes. Findings are discussed against the backdrop of recent research on the consequences of diversity, as well as context-based considerations regarding minority versus majority constellations. We also discuss some exceptions to our findings that emerged for some respondent groups and contexts across the five studies. PMID- 28903685 TI - Evaluating the Dimensionality of Self-Determination Theory's Relative Autonomy Continuum. AB - We conducted a theoretical and psychometric evaluation of self-determination theory's "relative autonomy continuum" (RAC), an important aspect of the theory whose validity has recently been questioned. We first derived a Comprehensive Relative Autonomy Index (C-RAI) containing six subscales and 24 items, by conducting a paired paraphrase content analysis of existing RAI measures. We administered the C-RAI to multiple U.S. and Russian samples, assessing motivation to attend class, study a major, and take responsibility. Item-level and scale level multidimensional scaling analyses, confirmatory factor analyses, and simplex/circumplex modeling analyses reaffirmed the validity of the RAC, across multiple samples, stems, and studies. Validation analyses predicting subjective well-being and trait autonomy from the six separate subscales, in combination with various higher order composites (weighted and unweighted), showed that an aggregate unweighted RAI score provides the most unbiased and efficient indicator of the overall quality of motivation within the behavioral domain being assessed. PMID- 28903686 TI - * Engineering Membranes for Bone Regeneration. AB - This review is focused on the use of membranes for the specific application of bone regeneration. The first section focuses on the relevance of membranes in this context and what are the specifications that they should possess to improve the regeneration of bone. Afterward, several techniques to engineer bone membranes by using "bulk"-like methods are discussed, where different parameters to induce bone formation are disclosed in a way to have desirable structural and functional properties. Subsequently, the production of nanostructured membranes using a bottom-up approach is discussed by highlighting the main advances in the field of bone regeneration. Primordial importance is given to the promotion of osteoconductive and osteoinductive capability during the membrane design. Whenever possible, the films prepared using different techniques are compared in terms of handability, bone guiding ability, osteoinductivity, adequate mechanical properties, or biodegradability. A last chapter contemplates membranes only composed by cells, disclosing their potential to regenerate bone. PMID- 28903687 TI - Post-Fight Respect Signals Valuations of Opponent's Fighting Performance. AB - The current research explores whether humans process inputs about combat (e.g., assessments of formidability) that produce outputs of post-fight respect (e.g., shaking an opponent's hand when the fight ends). Using an online questionnaire (Study 1, n = 132), an in-person questionnaire (Study 2, n = 131), and an in-lab fight simulation (Study 3, n = 58), we investigated whether participants were more likely to receive (Studies 1 and 3) and display (Studies 2 and 3) post-fight respect as a function of the fight outcome (Hypothesis 1), use of fight tactics (Hypothesis 2), fighter asymmetries (Hypothesis 3), fighter ranking (Hypothesis 4), and the presence of witnesses (Hypothesis 5). The results support Hypotheses 1 to 4 concerning expectations of receiving post-fight respect, and support only Hypotheses 2 and 3 concerning displays of post-fight respect. We suggest that post-fight respect signals positive valuations of fighting performance that may function to maintain valuable relationships within the social group. PMID- 28903688 TI - More Than Just Sex: Affection Mediates the Association Between Sexual Activity and Well-Being. AB - Positive interpersonal interactions such as affection are central to well-being. Sex is associated with greater individual well-being, but little is known about why this occurs. We predicted that experienced affection would account for the association between sex and well-being. Cross-sectional results indicated that affection mediated the association between sex and both life satisfaction (Study 1) and positive emotions (however, among men only in Study 2). In Study 3, an experience sampling study with 106 dual-earner couples with children, affection mediated the association between sex and increased positive affect in daily life. Cross-lagged analyses in Study 3 to 4 supported the predicted direction of the associations. Moreover, the strength of the daily association between sex and positive affect predicted both partners' relationship satisfaction 6 months later. Our findings underscore the importance of affection and positive affect for understanding how sex promotes well-being and has long-term relational benefits. PMID- 28903689 TI - Temporal Stability of Implicit and Explicit Measures: A Longitudinal Analysis. AB - A common assumption about implicit measures is that they reflect early experiences, whereas explicit measures are assumed to reflect recent experiences. This assumption subsumes two distinct hypotheses: (a) Implicit measures are more resistant to situationally induced changes than explicit measures; (b) individual differences on implicit measures are more stable over time than individual differences on explicit measures. Although the first hypothesis has been the subject of numerous studies, the second hypothesis has received relatively little attention. The current research addressed the second hypothesis in two longitudinal studies that compared the temporal stability of individual differences on implicit and explicit measures in three content domains (self concept, racial attitudes, political attitudes). In both studies, implicit measures showed significantly lower stability over time (weighted average r = .54) than conceptually corresponding explicit measures (weighted average r = .75), despite comparable estimates of internal consistency. Implications for theories of implicit social cognition and interpretations of implicit and explicit measures are discussed. PMID- 28903690 TI - How Moral Perceptions Influence Intergroup Tolerance: Evidence From Lebanon, Morocco, and the United States. AB - Intergroup boundaries are often associated with differences in moral codes. How does the perception of similarity and dissimilarity in moral worldviews influence tolerant relationships between members of different groups? We theorized that the relationship between perceived moral similarity and intergroup tolerance is domain specific. Specifically, because people treat autonomy values (e.g., caring for others, being fair) as denoting universal rights and obligations, but binding values (e.g., purity) as denoting rights and obligations that apply preferentially for their own group, perceived similarity on autonomy values should be more relevant than perceived similarity on binding values to intergroup tolerance. Here, we describe correlational and experimental evidence to support these predictions from studies carried out in Lebanon (with sectarian groups), in Morocco (with ethnic groups), and in the United States (with ideological groups). Implications for understanding intergroup relations and theories of morality are discussed. PMID- 28903691 TI - Sadism, the Intuitive System, and Antisocial Punishment in the Public Goods Game. AB - In public goods situations, a specific destructive behavior emerges when individuals face the possibility of punishing others: antisocial punishment, that is, costly punishing cooperative individuals. So far, little is known about the (intuitive or reflective) processes underlying antisocial punishment. Building on the Social Heuristics Hypothesis and arguing that antisocial punishment reflects the basic characteristics of sadism, namely, aggressive behavior to dominate and to harm other individuals it is assumed that everyday sadists intuitively engage in antisocial punishment. Two studies document that activating (Study 1) and inhibiting (Study 2) the intuitive system when a punishment option can be realized in one-shot iterated public goods games increased (Study 1) and reduced (Study 2) antisocial punishment, in particular among individuals who reported a proneness to sadism. In sum, the present research suggests that sadistic tendencies executed intuitively play a crucial role regarding antisocial punishment in public goods situations. PMID- 28903692 TI - Authoritarianism, Institutional Confidence, and Willingness to Engage in Collective Action: A Multinational Analysis. AB - The antecedents of collective action have received considerable attention in psychology, political science, and sociology. However, few studies have addressed the extent to which individual differences in psychological needs, motives, and traits predict collective action tendencies. In the present study, we focus on an especially important individual difference: authoritarianism. We examined three key hypotheses: (1) that authoritarianism would be associated with lower willingness to engage in collective action (net of other factors known to predict protest), (2) that the negative relationship between authoritarianism and collective action would be stronger among the politically engaged; and (3) that the negative relationship between authoritarianism and collective action would be weaker among those who lacked confidence in major social institutions. Using data from three independent waves of the World Values Survey, we find cross-national evidence supporting all three hypotheses. PMID- 28903693 TI - Societal Conditions and the Gender Difference in Well-Being: Testing a Three Stage Model. AB - Findings from a meta-analysis on gender differences in self-esteem (Zuckerman et al., 2016) suggest that the relation between the degree to which societal conditions are favorable to women and gender difference in self-esteem might be quadratic; when conditions improve, women's self-esteem (relative to that of men) trends downward but when conditions continue to improve, women's self-esteem begins to trend upward. Testing whether these relations generalize to subjective well-being, the present study found a quadratic relation between improving societal conditions and the gender difference in life satisfaction and positive affect (women are lower than men when societal conditions are moderately favorable compared to when they are at their worst and at their best); the relation was linear for negative emotion (women report more negative emotions than men when societal conditions are better). Directions for future research that will address potential explanations for these results are proposed. PMID- 28903694 TI - Attachment and Self-Regulation. AB - Close relationships and self-regulation are inextricably intertwined, yet many of the details regarding how interpersonal processes influence self-regulation are not well understood. To gain a better understanding of this link, we investigated the association between attachment styles and self-regulatory mode orientations. According to regulatory mode theory, locomotors are concerned with initiating goal-directed movement, whereas assessors are concerned with appraising potential means and goals. We predicted that the presence of an attachment figure with whom one has an anxious attachment would be associated with higher assessment tendencies. In addition, we predicted that the presence of an attachment figure with whom one has an avoidant attachment would be associated with lower locomotion tendencies. Five studies ( N = 1,434) supported our predictions, and demonstrated that attachment styles and self-regulatory mode orientations covary across interaction partners. PMID- 28903695 TI - Toward a Comprehensive Understanding of Intergroup Contact: Descriptions and Mediators of Positive and Negative Contact Among Majority and Minority Groups. AB - Positive contact predicts reduced prejudice, but negative contact may increase prejudice at a stronger rate. The current project builds on this work in four ways: establishing an understanding of contact that is grounded in subjective experience, examining the affective mediators involved in the negative contact prejudice relationship, extending research on the effects of positive and negative contact to minority groups, and examining the contact asymmetry experimentally. Study 1 introduced anger as a mediator of the relationships between positive and negative contact and prejudice among White Americans ( N = 371), using a contact measure that reflected the frequency and intensity of a wide range of experiences. Study 2 found a contact asymmetry among Black and Hispanic Americans ( N = 365). Study 3 found initial experimental evidence of a contact asymmetry ( N = 309). We conclude by calling for a more nuanced understanding of intergroup contact that recognizes its multifaceted and subjective nature. PMID- 28903696 TI - Permeability of Group Boundaries: Development of the Concept and a Scale. AB - The perceived possibility of movement between groups, referred to as permeability of group boundaries, is considered a key factor in explaining intergroup relations. However, so far, permeability has been conceptualized in different ways and there exists no validated measure. Integrating different conceptualizations, we developed a scale distinguishing membership permeability (e.g., a person changing from one sport team to another) versus status permeability (e.g., a person acquiring a higher social status). Scale validation occurred across samples representing five lower status groups (older adults, women, obese, lower educated, ethnic minorities). Our scale was related to central indicators of intergroup relations such as self-reported intergroup attitudes (e.g., identification) and endorsement of behavioral strategies (individual mobility, collective action). Moreover, it distinguished permeability characteristics of different types of social groups. The scale provides a novel theoretical conceptualization of permeability and can be used to examine levels and correlates of permeability perceptions across social groups. PMID- 28903697 TI - Foundational Tests of the Need-Support Model: A Framework for Bridging Regulatory Focus Theory and Self-Determination Theory. AB - This article introduces the need-support model, which proposes that regulatory focus can affect subjective support for the needs proposed by self-determination theory (autonomy, competence, and relatedness), and support of these needs can affect subjective labeling of experiences as promotion-focused and prevention focused. Three studies tested these hypotheses ( N = 2,114). Study 1 found that people recall more need support in promotion-focused experiences than in prevention-focused experiences, and need support in their day yesterday (with no particular regulatory focus) fell in between. Study 2 found that experiences of higher need support were more likely to be labeled as promotion-focused rather than prevention-focused, and that each need accounted for distinct variance in the labeling of experiences. Study 3 varied regulatory focus within a performance task and found that participants in the promotion condition engaged in need support inflation, whereas participants in the prevention condition engaged in need-support deflation. Directions for future research are discussed. PMID- 28903698 TI - Media Violence and Other Aggression Risk Factors in Seven Nations. AB - Cultural generality versus specificity of media violence effects on aggression was examined in seven countries (Australia, China, Croatia, Germany, Japan, Romania, the United States). Participants reported aggressive behaviors, media use habits, and several other known risk and protective factors for aggression. Across nations, exposure to violent screen media was positively associated with aggression. This effect was partially mediated by aggressive cognitions and empathy. The media violence effect on aggression remained significant even after statistically controlling a number of relevant risk and protective factors (e.g., abusive parenting, peer delinquency), and was similar in magnitude to effects of other risk factors. In support of the cumulative risk model, joint effects of different risk factors on aggressive behavior in each culture were larger than effects of any individual risk factor. PMID- 28903699 TI - Corrigendum. PMID- 28903700 TI - Motivational Differences in Seeking Out Evaluative Categorization Information. AB - Previous research shows that people draw finer evaluative distinctions when rating liked versus disliked objects (e.g., wanting a 5-point scale to evaluate liked cuisines and a 3-point scale to rate disliked cuisines). Known as the preference-categorization effect, this pattern may exist not only in how individuals form evaluative distinctions but also in how individuals seek out evaluative information. The current research presents three experiments that examine motivational differences in evaluative information seeking (rating scales and attributes). Experiment 1 found that freedom of choice (the ability to avoid undesirable stimuli) and sensitivity to punishment (as measured by the Behavior Inhibition System/Behavioral Approach System [BIS/BAS] scale) influenced preferences for desirable and undesirable evaluative information in a health related decision. Experiment 2 examined choice optimization, finding that maximizers prefer finer evaluative information for both liked and disliked options in a consumer task. Experiment 3 found that this pattern generalizes to another type of evaluative categorization, attributes. PMID- 28903701 TI - When Praising Yourself Insults Others: Self-Superiority Claims Provoke Aggression. AB - We tested the prediction, derived from the hubris hypothesis, that bragging might serve as a verbal provocation and thus enhance aggression. Experiments 1 and 2 were vignette studies where participants could express hypothetical aggression; Experiment 3 was an actual decision task where participants could make aggressive and/or prosocial choices. Observers disliked an explicit braggart (who claimed to be "better than others") or a competence braggart as compared with an implicit braggart (who claimed to be "good") or a warmth braggart, respectively. Showing that explicit and competence bragging function as verbal provocations, observers responded more aggressively to the explicit and competence braggart than to the implicit and warmth braggart, respectively. They did so because they inferred that an explicit and a competence braggart viewed other people and them negatively, and therefore disliked the braggart. Rather than praising the self, braggarts are sometimes viewed as insulting others. PMID- 28903702 TI - Information-Acquisition Processes in Moral Judgments of Blame. AB - When people make moral judgments, what information do they look for? Despite its theoretical and practical implications, this question has largely been neglected by prior literature. The recent Path Model of Blame predicts a canonical order in which people acquire information when judging blame. Upon discovering a negative event, perceivers consider information about causality, then intentionality, then (if the event is intentional) reasons or (if the event is unintentional) preventability. Three studies, using two novel paradigms, assessed and found support for these predictions: In constrained (Study 1) and open-ended (Study 2) information-acquisition contexts, participants were most likely, and fastest, to seek information in the canonical order, even when under time pressure (Study 3). These findings indicate that blame relies on a set of information components that are processed in a systematic order. Implications for moral judgment models are discussed, as are potential roles of emotion and motivated reasoning in information acquisition. PMID- 28903703 TI - Motivated Use of Numerical Anchors for Judgments Relevant to the Self. AB - The anchoring effect has been replicated so extensively that it is generally thought to be ubiquitous. However, anchoring has primarily been tested in domains in which people are motivated to reach accurate conclusions rather than biased conclusions. Is the anchoring effect robust even when the anchors are threatening? In three studies, participants made a series of probability judgments about their own futures paired with either optimistic anchors (e.g., "Do you think that the chances that your current relationship will last a lifetime are more or less than 95%?"), pessimistic anchors (e.g., "more or less than 10%?"), or no anchors. A fourth study experimentally manipulated motivation to ignore the anchor with financial incentives. Across studies, anchors that implied high probabilities of unwanted events occurring were ineffective. Together, these studies suggest that anchoring has an important boundary condition: Personally threatening anchors are ignored as a result of motivated reasoning processes. PMID- 28903704 TI - Emotion Decoding and Incidental Processing Fluency as Antecedents of Attitude Certainty. AB - Previous research demonstrates that attitude certainty influences the degree to which an attitude changes in response to persuasive appeals. In the current research, decoding emotions from facial expressions and incidental processing fluency, during attitude formation, are examined as antecedents of both attitude certainty and attitude change. In Experiment 1, participants who decoded anger or happiness during attitude formation expressed their greater attitude certainty, and showed more resistance to persuasion than participants who decoded sadness. By manipulating the emotion decoded, the diagnosticity of processing fluency experienced during emotion decoding, and the gaze direction of the social targets, Experiment 2 suggests that the link between emotion decoding and attitude certainty results from incidental processing fluency. Experiment 3 demonstrated that fluency in processing irrelevant stimuli influences attitude certainty, which in turn influences resistance to persuasion. Implications for appraisal-based accounts of attitude formation and attitude change are discussed. PMID- 28903705 TI - Perceptions of Active Versus Passive Risks, and the Effect of Personal Responsibility. AB - Not getting vaccinated or not backing up computer files are examples of passive risk taking: risk brought on or magnified by inaction. We suggest the difficulty in paying attention to absences, together with the reduced agency and responsibility that is associated with passive choices, leads to the perception of passive risks as being less risky than equivalent active risks. Using scenarios in which risk was taken either actively or passively, we demonstrate that passive risks are judged as less risky than equivalent active risks. We find the perception of personal responsibility mediates the differences between the perception of passive and active risks. The current research offers an additional explanation for omission or default biases: The passive nature of these choices causes them to appear less risky than they really are. PMID- 28903706 TI - Cross-Situational Self-Consistency in Nine Cultures: The Importance of Separating Influences of Social Norms and Distinctive Dispositions. AB - We assessed self-consistency (expressing similar traits in different situations) by having undergraduates in the United States ( n = 230), Australia ( n = 220), Canada ( n = 240), Ecuador ( n = 101), Mexico ( n = 209), Venezuela ( n = 209), Japan ( n = 178), Malaysia ( n = 254), and the Philippines ( n = 241) report the traits they expressed in four different social situations. Self-consistency was positively associated with age, well-being, living in Latin America, and not living in Japan; however, each of these variables showed a unique pattern of associations with various psychologically distinct sources of raw self consistency, including cross-situationally consistent social norms and injunctions. For example, low consistency between injunctive norms and trait expressions fully explained the low self-consistency in Japan. In accord with trait theory, after removing normative and injunctive sources of consistency, there remained robust distinctive noninjunctive self-consistency (reflecting individuating personality dispositions) in every country, including Japan. The results highlight how clarifying the determinants and implications of self consistency requires differentiating its distinctive, injunctive, and noninjunctive components. PMID- 28903707 TI - Putting Yourself on the Line: Self-Esteem and Expressing Affection in Romantic Relationships. AB - Although expressing affection is an important way to connect to a romantic partner, it also involves putting yourself on the line-revealing dependence on your partner. Extending the risk-regulation model, we hypothesized that individuals with lower self-esteem (SE), who are concerned about vulnerability in relationships, experience less rewarding reactions to expressing affection, and believe that their partners respond less positively to receiving affection. We assessed these predictions across two studies that measured retrospective reports, reactions to an in vivo exchange and responses in daily life. We found that participants with lower SE expressed less affection and experienced less positive emotional, cognitive, and physiological reactions when doing so. Participants with lower SE believed that their partners derived fewer benefits from their affection despite that their partners experienced normative boosts in positive emotion and relationship satisfaction during these exchanges. The consequences of these findings for relationship functioning and SE are discussed. PMID- 28903708 TI - United and Divided by Stress: How Stressors Differentially Influence Social Support in African American Couples Over Time. AB - The factors that allow people to be good support providers in relationships are not fully understood. We examined how support providers' stressful experiences (financial strain and racial discrimination) differentially influence their supportiveness, using longitudinal data from two samples of African American couples. Among couples that provided observational data ( N = 163 couples), providers who experienced high chronic financial strain behaved less supportively toward their partners, while those who experienced frequent racial discrimination behaved more supportively over a 2-year period. In a second sample of 213 couples over a 3-year period, support providers who experienced financial strain were perceived by their partners as slightly less supportive, while providers who experienced frequent racial discrimination were perceived by their partners as more supportive. Findings suggest that supportiveness in relationships may be differentially shaped by the specific stresses and strains that partners face. PMID- 28903710 TI - Are Some Attitudes More Self-Defining Than Others? Assessing Self-Related Attitude Functions and Their Consequences. AB - Attitudes serve multiple functions, some related to the self-concept. We call attitudes that help people define who they are "self-defining." Across four studies, we tested a brief self-report measure of the extent to which an attitude is self-defining. Studies 1 and 2 showed that self-defining attitudes tend to be extreme, positive, and unambivalent. Studies 3 and 4 produced two main findings. First, self-definition was related to, but not redundant with, a number of other characteristics of the attitude (e.g., attitude certainty). Second, self definition predicted participants' intentions to spontaneously advocate and, in Study 4, their reactions to an opportunity to advocate behaviorally (i.e., writing about their attitude in an optional response box) following a self threat. Overall, the results highlight the utility of this approach and, more broadly, demonstrate the value of considering the role of the self in attitudinal processes, and vice versa. PMID- 28903709 TI - The Influence of Daily Coping on Anxiety Under Examination Stress: A Model of Interindividual Differences in Intraindividual Change. AB - Although much is known about people's attempts to cope with stressors, unmeasured heterogeneity in these stressors has made it difficult to assess the effectiveness of coping attempts. We remedied this problem by focusing on coping effectiveness in people preparing for a major, planned, uniform stressor, the Bar Examination. Within-person analyses of longitudinal data on anxiety in 321 persons over 35 days provided evidence on (a) coping effectiveness for the typical person, (b) how effectiveness changed across time, and (c) the extent to which individuals differed in their effectiveness. For the typical person, active coping and positive reinterpretation on one day were associated with reduced anxiety the next morning, whereas practical support seeking, venting, and mental disengagement were associated with increased anxiety. The effectiveness of planning, acceptance, and disengagement varied as a function of time to the stressful event. Finally, there were large individual differences in coping effectiveness across the sample. PMID- 28903711 TI - Authoritarianism and National Identity: Examining the Longitudinal Effects of SDO and RWA on Nationalism and Patriotism. AB - The resurgence of right-wing political parties across the globe raises questions about the origins of national identity. Based on the Dual Process Model of Ideology and Prejudice, we argue that people's tendency to submit to ingroup authorities (Right-Wing Authoritarianism [RWA]) and preference for group-based hierarchy (Social Dominance Orientation [SDO]) underlie people's belief in the superiority of their nation (nationalism) and attachment to their homeland (patriotism). We examine these hypotheses using three waves of data from an annually conducted national longitudinal panel study of New Zealanders ( N = 3,838). As predicted, RWA had positive cross-lagged effects on nationalism and patriotism. Conversely, SDO had a positive cross-lagged effect on nationalism, but a negative cross-lagged effect on patriotism. Little evidence of reciprocal cross-lagged effects (i.e., national identity on authoritarianism) was found. These results demonstrate that nationalism and patriotism are related, albeit distinct, ways of identifying with one's nation that are ultimately rooted in authoritarianism. PMID- 28903713 TI - Is It a Dangerous World Out There? The Motivational Bases of American Gun Ownership. AB - Americans are the world's best armed citizens and public polling suggests protection/self-defense is their main reason for gun ownership. However, there is virtually no psychological research on gun ownership. The present article develops the first psychological process model of defensive gun ownership specifically, a two-component model that considers both the antecedents and consequences of owning a gun for protection/self-defense. We demonstrate that different levels of threat construal-the specific perceived threat of assault and a diffuse threat of a dangerous world-independently predict handgun ownership; we also show how utility judgments can explain the motivated reasoning that drives beliefs about gun rights. We tested our model in two independent samples of gun owners (total N = 899), from just before and after the Orlando mass shooting. This study illustrates how social-cognitive theories can help explain what motivates Americans to own handguns and advocate for broad rights to carry and use them. PMID- 28903712 TI - Power Moves Beyond Complementarity: A Staring Look Elicits Avoidance in Low Power Perceivers and Approach in High Power Perceivers. AB - Sustained, direct eye-gaze-staring-is a powerful cue that elicits strong responses in many primate and nonprimate species. The present research examined whether fleeting experiences of high and low power alter individuals' spontaneous responses to the staring gaze of an onlooker. We report two experimental studies showing that sustained, direct gaze elicits spontaneous avoidance tendencies in low power perceivers and spontaneous approach tendencies in high power perceivers. These effects emerged during interactions with different targets and when power was manipulated between-individuals (Study 1) and within-individuals (Study 2), thus attesting to a high degree of flexibility in perceivers' reactions to gaze cues. Together, the present findings indicate that power can break the cycle of complementarity in individuals' spontaneous responding: Low power perceivers complement and move away from, and high power perceivers reciprocate and move toward, staring onlookers. PMID- 28903714 TI - Less Evil Than You: Bounded Self-Righteousness in Character Inferences, Emotional Reactions, and Behavioral Extremes. AB - Recent research suggests that self-righteousness is bounded, arising more reliably in evaluations of immoral actions than in evaluations of moral actions. Here, we test four implications of this asymmetry in self-righteousness and the mechanism explaining it. We find that people are less likely to make negative character inferences from their own unethical behavior than from others' unethical behavior (Experiment 1), believe they would feel worse after an unethical action than others (Experiment 2), and believe they are less capable of extreme unethical behavior than others (Experiment 3). We observe weaker self other differences in evaluations of ethical actions. This occurs partly because people base evaluations of themselves on their own moral intentions, leading to predictable individual differences. People more likely to ascribe cynical motives to their own behavior exhibit a smaller asymmetry in self-righteousness (Experiment 4). Self-righteousness seems better characterized as feeling "less evil than thou" than feeling "holier than thou." PMID- 28903715 TI - Reciprocal Influences Between Loneliness and Self-Centeredness: A Cross-Lagged Panel Analysis in a Population-Based Sample of African American, Hispanic, and Caucasian Adults. AB - Loneliness has been posited to increase the motivation to repair or replace deficient social relationships and, seemingly paradoxically, to increase the implicit motivation for self-preservation. In the current research, we report a cross-lagged panel analysis of 10 waves of longitudinal data ( N = 229) on loneliness and self-centeredness (as gauged by Feeney and Collins's measure of chronic self-focus) in a representative sample of middle-aged and older adults. As predicted by the proposition that loneliness increases the implicit motivation for self-preservation, loneliness in the current year predicts self-centeredness in the subsequent year beyond what is explained by current-year demographic variables, self-centeredness, depressive symptomatology, and overall negative mood. Analyses also show that self-centeredness in the current year (net covariates) predicts loneliness in the subsequent year, a reciprocal relationship that could potentially contribute to the maintenance of loneliness. Theoretical and practical implications are discussed. PMID- 28903716 TI - Predicting the Pursuit and Support of Challenging Life Opportunities. AB - Deciding to embrace challenging opportunities may present one life context through which individuals may thrive, and these decisions may be influenced by one's significant relationships. Married couples were unobtrusively videotaped as one couple-member was presented with a challenging opportunity and decided whether to accept it. We assessed interpersonal predictors of the decision to accept or forgo the opportunity, predictors of the spouse's support during decision-making, and follow-up thriving outcomes 6 months later. Results indicated that specific support behaviors enacted by the spouse-relational catalyst (RC) support provision-encouraged decision-makers to accept the challenge and that this decision predicted long-term thriving outcomes for the decision-maker. Results also indicated that the spouse's support behavior was influenced by both chronic and experimentally manipulated motivations for providing support, and these motives provide pathways by which relationship satisfaction and attachment security predict the provision of RC support. Implications and directions for future research are discussed. PMID- 28903717 TI - Subjective Importance as a Cue for Self-Reference. AB - We investigated whether people's judgments of self-reference could be influenced by cues of importance. Our investigation builds on evidence that information related to the self is processed in specialized ways and that implicit attributions affect how stimuli are interpreted. We hypothesized that the more important a trait descriptor was, the more likely participants would be to misremember it as having been presented in a self-referential manner. This hypothesis was tested using a source-memory task; subjective ratings of importance served as predictors of accuracy. In two experiments, logistic multilevel analyses supported our predictions, indicating that people use cues of importance when deciding if stimuli are self-referential. The results show that people do not rely solely on valence when making self-referential judgments; importance also can bias self-referential attributions. These findings have implications for social and autobiographical memory, including how people may assign responsibility for jointly produced actions. PMID- 28903718 TI - Understanding the MBA Gender Gap: Women Respond to Gender Norms by Reducing Public Assertiveness but Not Private Effort. AB - Women's underperformance in MBA programs has been the subject of recent debate and policy interventions, despite a lack of rigorous evidence documenting when and why it occurs. The current studies document a performance gap, specifying its contours and contributing factors. Two behaviors by female students that may factor into the gap are public conformity and private internalization. We predicted that women conform to the norm associating maleness with technical prowess by minimizing their public assertiveness in class discussions and meetings, but that they do not internalize the norm by reducing private effort. Data from multiple cohorts of a top-ranked MBA program reveal female underperformance occurred in technical subjects (e.g., accounting), but not social subjects (e.g., marketing). As predicted, the gender effect ran not through private effort but through public assertiveness, even controlling for gender differences in interests and aptitudes. These findings support some current policy interventions while casting doubt on others. PMID- 28903719 TI - Social Support in Intimate Relationships: The Role of Relationship Autonomy. AB - Prior research on effective support interactions in intimate relationships often focuses on support provision rather than how people seek support. The current study investigated how differences in relationship autonomy-authentic and self determined relationship motivations-predicted the behavior and outcomes of couples ( N = 80) in support interactions. Results indicated that support seekers' motivation and behavior were the primary contributor to effective support interactions. Support seekers who were autonomously motivated tended to seek support in a more direct and positive manner, which in turn promoted greater levels of emotional, informational, and tangible support from their partners. The relationship autonomy of both the support provider and the support seeker also predicted better subjective experiences regardless of behavior, such as perceiving the interaction as more supportive. These results illustrate how relationship autonomy promotes well-being in relationships via support seeking behaviors, as well as positive interpretations and experiences of important relationship interactions. PMID- 28903720 TI - Editorial: Personalized Medicine: A Positional Point of View about Precision Medicine and Clarity for Ethics of Public Health. PMID- 28903721 TI - Erratum to: Using technology to engage hospitalised patients in their care: a realist review. PMID- 28903722 TI - EEG power at 3 months in infants at high familial risk for autism. AB - BACKGROUND: Alterations in brain development during infancy may precede the behavioral manifestation of developmental disorders. Infants at increased risk for autism are also at increased risk for other developmental disorders, including, quite commonly, language disorders. Here we assess the extent to which electroencephalographic (EEG) differences in infants at high versus low familial risk for autism are present by 3 months of age, and elucidate the functional significance of EEG power at 3 months in predicting later development. METHODS: EEG data were acquired at 3 months in infant siblings of children with autism (high risk; n = 29) and infant siblings of typically developing children (low risk; n = 19) as part of a prospective, longitudinal investigation. Development across multiple domains was assessed at 6, 9, 12, 18, 24, and 36 months. Diagnosis of autism was determined at 18-36 months. We assessed relationships between 3-month-olds' frontal EEG power and autism risk, autism outcome, language development, and development in other domains. RESULTS: Infants at high familial risk for autism had reduced frontal power at 3 months compared to infants at low familial risk for autism, across several frequency bands. Reduced frontal high alpha power at 3 months was robustly associated with poorer expressive language at 12 months. CONCLUSIONS: Reduced frontal power at 3 months may indicate increased risk for reduced expressive language skills at 12 months. This finding aligns with prior studies suggesting reduced power is a marker for atypical brain function, and infants at familial risk for autism are also at increased risk for altered developmental functioning in non-autism-specific domains. PMID- 28903723 TI - Domains associated with successful quality improvement in healthcare - a nationwide case study. AB - BACKGROUND: There is a distinct difference between what we know and what we do in healthcare: a gap that is impairing the quality of the care and increasing the costs. Quality improvement efforts have been made worldwide by learning collaboratives, based on recognized continual improvement theory with limited scientific evidence. The present study of 132 quality improvement projects in Norway explores the conditions for improvement from the perspectives of the frontline healthcare professionals, and evaluates the effectiveness of the continual improvement method. METHODS: An instrument with 25 questions was developed on prior focus group interviews with improvement project members who identified features that may promote or inhibit improvement. The questionnaire was sent to 189 improvement projects initiated by the Norwegian Medical Association, and responded by 70% (132) of the improvement teams. A sub study of their final reports by a validated instrument, made us able to identify the successful projects and compare their assessments with the assessments of the other projects. A factor analysis with Varimax rotation of the 25 questions identified five domains. A multivariate regression analysis was used to evaluate the association with successful quality improvements. RESULTS: Two of the five domains were associated with success: Measurement and Guidance (p = 0.011), and Professional environment (p = 0.015). The organizational leadership domain was not associated with successful quality improvements (p = 0.26). CONCLUSION: Our findings suggest that quality improvement projects with good guidance and focus on measurement for improvement have increased likelihood of success. The variables in these two domains are aligned with improvement theory and confirm the effectiveness of the continual improvement method provided by the learning collaborative. High performing professional environments successfully engaged in patient-centered quality improvement if they had access to: (a) knowledge of best practice provided by professional subject matter experts, (b) knowledge of current practice provided by simple measurement methods, assisted by (c) improvement knowledge experts who provided useful guidance on measurement, and made the team able to organize the improvement efforts well in spite of the difficult resource situation (time and personnel). Our findings may be used by healthcare organizations to develop effective infrastructure to support improvement and to create the conditions for making quality and safety improvement a part of everyone's job. PMID- 28903724 TI - Resting heart rate and impaired glucose regulation in middle-aged and elderly Chinese people: a cross-sectional analysis. AB - BACKGROUND: Elevated resting heart rate (RHR) has been reported to be associated with metabolic syndrome and type 2 diabetes. The aim of this study was to explore whether a positive relationship exists between RHR and impaired glucose regulation (IGR) among middle-aged and older Chinese individuals. METHODS: We conducted a cross-sectional analysis that included a total of 9898 subjects (3194 men and 6704 women) in a Chinese population. The RHRs were derived from ECG recordings, and the subjects were stratified based on RHR quartiles. RESULTS: RHR levels were significantly higher in the subjects with isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), IFG + IGT and diabetes than in those with normal glucose regulation. When multivariate logistic regression analyses were performed, the odds ratios were substantially higher for the subjects with IGR (odds ratio 2.19, 95% confidence interval 1.85-2.58) in the fourth RHR quartile compared with those in the first quartile after adjustment for potential confounding covariates, and the corresponding OR for the combined IGR and type 2 diabetes group was 2.56 (95% CI 2.20-2.98, p < 0.001). Multiple regression analyses demonstrated that RHR was significantly associated with fasting plasma glucose, 2-h OGTT plasma glucose and A1c. CONCLUSIONS: Our cross sectional findings provide evidence that high RHR is associated with existing IGR among middle-aged and older Chinese individuals. PMID- 28903725 TI - Reporting of the translation and cultural adaptation procedures of the Addenbrooke's Cognitive Examination version III (ACE-III) and its predecessors: a systematic review. AB - BACKGROUND: The ACE-III, a gold standard for screening cognitive impairment, is restricted by language and culture, with no uniform set of guidelines for its adaptation. To develop guidelines a compilation of all the adaptation procedures undertaken by adapters of the ACE-III and its predecessors is needed. METHODS: We searched EMBASE, Medline and PsychINFO and screened publications from a previous review. We included publications on adapted versions of the ACE-III and its predecessors, extracting translation and cultural adaptation procedures and assessing their quality. RESULTS: We deemed 32 papers suitable for analysis. 7 translation steps were identified and we determined which items of the ACE-III are culturally dependent. CONCLUSIONS: This review lists all adaptations of the ACE, ACE-R and ACE-III, rates the reporting of their adaptation procedures and summarises adaptation procedures into steps that can be undertaken by adapters. PMID- 28903726 TI - A novel diagnostic method for malaria using loop-mediated isothermal amplification (LAMP) and MinIONTM nanopore sequencer. AB - BACKGROUND: A simple and accurate molecular diagnostic method for malaria is urgently needed due to the limitations of conventional microscopic examination. In this study, we demonstrate a new diagnostic procedure for human malaria using loop mediated isothermal amplification (LAMP) and the MinIONTM nanopore sequencer. METHODS: We generated specific LAMP primers targeting the 18S-rRNA gene of all five human Plasmodium species including two P. ovale subspecies (P. falciparum, P. vivax, P. ovale wallikeri, P. ovale curtisi, P. knowlesi and P. malariae) and examined human blood samples collected from 63 malaria patients in Indonesia. Additionally, we performed amplicon sequencing of our LAMP products using MinIONTM nanopore sequencer to identify each Plasmodium species. RESULTS: Our LAMP method allowed amplification of all targeted 18S-rRNA genes of the reference plasmids with detection limits of 10-100 copies per reaction. Among the 63 clinical samples, 54 and 55 samples were positive by nested PCR and our LAMP method, respectively. Identification of the Plasmodium species by LAMP amplicon sequencing analysis using the MinIONTM was consistent with the reference plasmid sequences and the results of nested PCR. CONCLUSIONS: Our diagnostic method combined with LAMP and MinIONTM could become a simple and accurate tool for the identification of human Plasmodium species, even in resource-limited situations. PMID- 28903727 TI - Uptake of health services among truck drivers in South Africa: analysis of routine data from nine roadside wellness centres. AB - BACKGROUND: Long-distance truck drivers are occupationally susceptible to poor health outcomes. Their patterns of healthcare utilisation and the suitability of healthcare services available to them are not well documented. We report on truck driver healthcare utilisation across South Africa and characterise the client population of the clinics serving them for future service development. METHODS: We analysed anonymised data routinely collected over a two-year period at nine Roadside Wellness Centres. Associations between services accessed and socio demographic characteristics were assessed using univariable and multivariable logistic regression models. RESULTS: We recorded 16,688 visits by 13,252 individual truck drivers (average of 1.26 visits/person) who accessed 17,885 services for an average of 1.07 services/visit and 1.35 services/person. The mean age of truck drivers was 39 years. Sixty-seven percent reported being in stable relationships. The most accessed services were primary healthcare (PHC)(62%) followed by HIV (32%). Low proportions (<=6%) accessed STI,TB and malaria services. Most visits were characterised by only one service being accessed (93%, n = 15,523/16,688). Of the remaining 7% of visits, up to five services were accessed per visit and the combination of TB /HIV services in one visit remained extremely low (<1%, n = 14/16,688). Besides PHC services at the beginning of the reporting period, all service categories displayed similar seasonal utilisation trends(i.e. service utilisation peaked in the immediate few months post clinics opening and substantially decreased before holidays). Across all service categories, younger truck drivers, those with a stable partner currently, and those of South African origin were the main clinic attendees. Older truck drivers (>=40 years) were more likely to access TB and PHC services, yet less likely to access HIV and STI services. Those with stable partners were less likely to access STI and TB services but more likely to access malaria and PHC services. South African attendees were more likely to access PHC, while attendees from other nationalities were more likely to access HIV and malaria services. CONCLUSIONS: This utilisation analysis shows that tailored services assist in alleviating healthcare access challenges faced by truck drivers, but it underscores the importance of ensuring that service packages and clinics speak to truck drivers' needs in terms of services offered and clinic location. PMID- 28903728 TI - Increased survival and proliferation of the epidemic strain Mycobacterium abscessus subsp. massiliense CRM0019 in alveolar epithelial cells. AB - BACKGROUND: Outbreaks of infections caused by rapidly growing mycobacteria have been reported worldwide generally associated with medical procedures. Mycobacterium abscessus subsp. massiliense CRM0019 was obtained during an epidemic of postsurgical infections and was characterized by increased persistence in vivo. To better understand the successful survival strategies of this microorganism, we evaluated its infectivity and proliferation in macrophages (RAW and BMDM) and alveolar epithelial cells (A549). For that, we assessed the following parameters, for both M. abscessus CRM0019 as well as the reference strain M. abscessus ATCC 19977: internalization, intracellular survival for up 3 days, competence to subvert lysosome fusion and the intracellular survival after cell reinfection. RESULTS: CRM0019 and ATCC 19977 strains showed the same internalization rate (approximately 30% after 6 h infection), in both A549 and RAW cells. However, colony forming units data showed that CRM0019 survived better in A549 cells than the ATCC 19977 strain. Phagosomal characteristics of CRM0019 showed the bacteria inside tight phagosomes in A549 cells, contrasting to the loosely phagosomal membrane in macrophages. This observation holds for the ATCC 19977 strain in both cell types. The competence to subvert lysosome fusion was assessed by acidification and acquisition of lysosomal protein. For M. abscessus strains the phagosomes were acidified in all cell lines; nevertheless, the acquisition of lysosomal protein was reduced by CRM0019 compared to the ATCC 19977 strain, in A549 cells. Conversely, in macrophages, both M. abscessus strains were located in mature phagosomes, however without bacterial death. Once recovered from macrophages M. abscessus could establish a new intracellular infection. Nevertheless, only CRM0019 showed a higher growth rate in A549, increasing nearly 10-fold after 48 and 72 h. CONCLUSION: M. abscessus CRM0019 creates a protective and replicative niche in alveolar epithelial cells mainly by avoiding phagosome maturation. Once recovered from infected macrophages, CRM0019 remains infective and displays greater intracellular growth in A549 cells compared to the ATCC 19977 strain. This evasion strategy in alveolar epithelial cells may contribute to the long survival of the CRM0019 strain in the host and thus to the inefficacy of in vivo treatment. PMID- 28903729 TI - Dynamic-ETL: a hybrid approach for health data extraction, transformation and loading. AB - BACKGROUND: Electronic health records (EHRs) contain detailed clinical data stored in proprietary formats with non-standard codes and structures. Participating in multi-site clinical research networks requires EHR data to be restructured and transformed into a common format and standard terminologies, and optimally linked to other data sources. The expertise and scalable solutions needed to transform data to conform to network requirements are beyond the scope of many health care organizations and there is a need for practical tools that lower the barriers of data contribution to clinical research networks. METHODS: We designed and implemented a health data transformation and loading approach, which we refer to as Dynamic ETL (Extraction, Transformation and Loading) (D ETL), that automates part of the process through use of scalable, reusable and customizable code, while retaining manual aspects of the process that requires knowledge of complex coding syntax. This approach provides the flexibility required for the ETL of heterogeneous data, variations in semantic expertise, and transparency of transformation logic that are essential to implement ETL conventions across clinical research sharing networks. Processing workflows are directed by the ETL specifications guideline, developed by ETL designers with extensive knowledge of the structure and semantics of health data (i.e., "health data domain experts") and target common data model. RESULTS: D-ETL was implemented to perform ETL operations that load data from various sources with different database schema structures into the Observational Medical Outcome Partnership (OMOP) common data model. The results showed that ETL rule composition methods and the D-ETL engine offer a scalable solution for health data transformation via automatic query generation to harmonize source datasets. CONCLUSIONS: D-ETL supports a flexible and transparent process to transform and load health data into a target data model. This approach offers a solution that lowers technical barriers that prevent data partners from participating in research data networks, and therefore, promotes the advancement of comparative effectiveness research using secondary electronic health data. PMID- 28903730 TI - Routine monitoring and assessment of adults living with HIV: results of the British HIV Association (BHIVA) national audit 2015. AB - BACKGROUND: The clinical care of people living with HIV changed fundamentally as a result of the development of effective antiretroviral therapy (ART). HIV infection is now a long-term treatable condition. We report a national audit to assess adherence to British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals. METHODS: All UK sites known as providers of adult HIV outpatient services were invited to complete a case-note review and a brief survey of local clinic practices. Participating sites were asked to randomly select 50-100 adults, who attended for specialist HIV care during 2014 and/or 2015. Each site collected data electronically using a self-audit spreadsheet tool. This included demographic details (gender, ethnicity, HIV exposure, and age) and whether 22 standardised and pre-defined clinical audited outcomes had been recorded. RESULTS: Data were collected on 8258 adults from 123 sites, representing approximately 10% of people living with HIV reported in public health surveillance as attending UK HIV services. Sexual health screening was provided within 96.4% of HIV services, cervical cytology and influenza vaccination within 71.4% of HIV services. There was wide variation in resistance testing across sites. Only 44.9% of patients on ART had a documented 10-year CVD risk within the past three years and fracture risk had been assessed within the past three years for only 16.7% patients aged over 50 years. CONCLUSIONS: There was high participation in the national audit and good practice was identified in some areas. However improvements can be made in monitoring of cardiovascular risk, bone and sexual health. PMID- 28903731 TI - Phytochemical-rich foods inhibit the growth of pathogenic trichomonads. AB - BACKGROUND: Plants produce secondary metabolites that often possess widespread bioactivity, and are then known as phytochemicals. We previously determined that several phytochemical-rich food-derived preparations were active against pathogenic foodborne bacteria. Trichomonads produce disease (trichomoniasis) in humans and in certain animals. Trichomonads are increasingly becoming resistant to conventional modes of treatment. It is of interest to test bioactive, natural compounds for efficacy against these pathogens. METHODS: Using a cell assay, black tea, green tea, grape, pomegranate, and jujube extracts, as well as whole dried jujube were tested against three trichomonads: Trichomonas vaginalis strain G3 (found in humans), Tritrichomonas foetus strain D1 (found in cattle), and Tritrichomonas foetus-like organism strain C1 (found in cats). The most effective of the test substances was subsequently tested against two metronidazole resistant Trichomonas vaginalis strains, and on normal mucosal flora. RESULTS: Black tea extract inhibited all the tested trichomonads, but was most effective against the T. vaginalis organisms. Inhibition by black tea was correlated with the total and individual theaflavin content of the two tea extracts determined by HPLC. Metronidazole-resistant Trichomonas vaginalis strains were also inhibited by the black tea extract. The response of the organisms to the remaining preparations was variable and unique. We observed no effect of the black tea extract on common normal flora bacteria. CONCLUSIONS: The results suggest that the black tea, and to a lesser degree green tea, grape seed, and pomegranate extracts might present possible natural alternative therapeutic agents to treat Trichomonas vaginalis infections in humans and the related trichomonad infections in animals, without negatively affecting the normal flora. PMID- 28903732 TI - A comparison of sequencing platforms and bioinformatics pipelines for compositional analysis of the gut microbiome. AB - BACKGROUND: Advancements in Next Generation Sequencing (NGS) technologies regarding throughput, read length and accuracy had a major impact on microbiome research by significantly improving 16S rRNA amplicon sequencing. As rapid improvements in sequencing platforms and new data analysis pipelines are introduced, it is essential to evaluate their capabilities in specific applications. The aim of this study was to assess whether the same project specific biological conclusions regarding microbiome composition could be reached using different sequencing platforms and bioinformatics pipelines. RESULTS: Chicken cecum microbiome was analyzed by 16S rRNA amplicon sequencing using Illumina MiSeq, Ion Torrent PGM, and Roche 454 GS FLX Titanium platforms, with standard and modified protocols for library preparation. We labeled the bioinformatics pipelines included in our analysis QIIME1 and QIIME2 (de novo OTU picking [not to be confused with QIIME version 2 commonly referred to as QIIME2]), QIIME3 and QIIME4 (open reference OTU picking), UPARSE1 and UPARSE2 (each pair differs only in the use of chimera depletion methods), and DADA2 (for Illumina data only). GS FLX+ yielded the longest reads and highest quality scores, while MiSeq generated the largest number of reads after quality filtering. Declines in quality scores were observed starting at bases 150-199 for GS FLX+ and bases 90-99 for MiSeq. Scores were stable for PGM-generated data. Overall microbiome compositional profiles were comparable between platforms; however, average relative abundance of specific taxa varied depending on sequencing platform, library preparation method, and bioinformatics analysis. Specifically, QIIME with de novo OTU picking yielded the highest number of unique species and alpha diversity was reduced with UPARSE and DADA2 compared to QIIME. CONCLUSIONS: The three platforms compared in this study were capable of discriminating samples by treatment, despite differences in diversity and abundance, leading to similar biological conclusions. Our results demonstrate that while there were differences in depth of coverage and phylogenetic diversity, all workflows revealed comparable treatment effects on microbial diversity. To increase reproducibility and reliability and to retain consistency between similar studies, it is important to consider the impact on data quality and relative abundance of taxa when selecting NGS platforms and analysis tools for microbiome studies. PMID- 28903733 TI - Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling. AB - BACKGROUND: Screening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions. METHODS: One hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information. RESULTS: PCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients. CONCLUSION: While our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics. PMID- 28903734 TI - Transcriptomic profiling of genes in matured dimorphic seeds of euhalophyte Suaeda salsa. AB - BACKGROUND: Suaeda salsa (S. salsa) is a euhalophyte with high economic value. S. salsa can produce dimorphic seeds. Brown seeds are more salt tolerant, can germinate quickly and maintain the fitness of the species under high saline conditions. Black seeds are less salt tolerant, may become part of the seed bank and germinate when soil salinity is reduced. Previous reports have mainly focused on the ecophysiological traits of seed germination and production under saline conditions in this species. However, there is no information available on the molecular characteristics of S. salsa dimorphic seeds. RESULTS: In the present study, a total of 5825 differentially expressed genes were obtained; and 4648 differentially expressed genes were annotated based on a sequence similarity search, utilizing five public databases by transcriptome analysis. The different expression of these genes may be associated with embryo development, fatty acid, osmotic regulation substances and plant hormones in brown and black seeds. Compared to black seeds, most genes may relate to embryo development, and various genes that encode fatty acid desaturase and are involved in osmotic regulation substance synthesis or transport are upregulated in brown seeds. A large number of differentially expressed genes related to plant hormones were found in brown and black seeds, and their possible roles in regulating seed dormancy/germination were discussed. CONCLUSIONS: Upregulated genes involved in seed development and osmotic regulation substance accumulation may relate to bigger seed size and rapid seed germination in brown seeds, compared to black seeds. Differentially expressed genes of hormones may relate to seed dormancy/germination and the development of brown and black seeds. The transcriptome dataset will serve as a valuable resource to further understand gene expression and functional genomics in S. salsa dimorphic seeds. PMID- 28903735 TI - FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-beta/Smad2/3 signaling pathway. AB - BACKGROUND: FOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in human hepatocellular carcinoma (HCC). METHODS: Expression profile of FOXP3 was analyzed using real-time RT-PCR, western blotting and immunofluorescence on HCC cell lines, and immunostaing of a tissue microarray containing of 240 primary HCC samples. The potential regulatory roles of FOXP3 were dissected by an integrated approach, combining biochemical assays, analysis of patient survival, genetic manipulation of HCC cell lines, mouse xenograft tumor models and chromatin immunoprecipitation (ChIP) sequencing. RESULTS: FOXP3 was constitutively expressed in HCC cells with the existence of splice variants (especially exon 3 and 4 deleted, Delta3,4-FOXP3). High expression of FOXP3 significantly correlated with low serum alpha-fetoprotein (AFP) level, absence of vascular invasion and early TNM stage. Survival analyses revealed that increased FOXP3 expression was significantly associated with better survival and reduced recurrence, and served as an independent prognosticator for HCC patients. Furthermore, FOXP3 could potently suppress the proliferation and invasion of HCC cells in vitro and reduce tumor growth in vivo. However, Delta3,4-FOXP3 showed a significant reduction in the tumor-inhibiting effect. The inhibition of FOXP3 on HCC aggressiveness was acted probably by enhancing the TGF-beta/Smad2/3 signaling pathway. CONCLUSION: Our findings suggest that FOXP3 suppresses tumor progression in HCC via TGF beta/Smad2/3 signaling pathway, highlighting the role of FOXP3 as a prognostic factor and novel target for an optimal therapy against this fatal malignancy. PMID- 28903736 TI - Factors associated with syphilis treatment failure and reinfection: a longitudinal cohort study in Shenzhen, China. AB - BACKGROUND: The treatment failure and reinfection rates among syphilis patients are high, and relevant studies in China are limited. The aim of this study was to detect the rates of treatment failure and reinfection after syphilis treatment and to explore the potential associated factors. METHODS: We conducted a longitudinal cohort study in a sexually transmitted disease clinic, the Department of Dermatology and Venereology in Nanshan Center for Chronic Disease Control. Serological testing was performed at baseline and throughout the 2-year follow-up for syphilis patients. To identify potential predictors of treatment outcomes, multivariate logistics analyses were utilized to compare the demographic and clinical characteristics of patients with serological failure/reinfection to those with serological cure/serofast. RESULTS: From June 2011 to June 2016, a total of 1133 patients were screened for syphilis. Among the 770 patients who completed the 2-year follow-up, 510 first-diagnosed patients were included in the final analysis. Multivariate logistics analysis revealed the stage of syphilis (secondary syphilis VS. primary syphilis: adjusted odds ratio, 3.50; 95% confidence interval, 1.11-15.47; p = 0.04), HIV status (positive VS. negative: adjusted odds ratio, 3.06; 95% confidence interval, 1.15-8.04; p = 0.02) and frequency of condom use (always use VS. never use: adjusted odds ratio, 0.28; 95% confidence interval 0.08-0.75; p = 0.02) were significantly associated with the serological outcome. CONCLUSIONS: The clinical implications of our findings suggest that it is very important to perform regular clinical and serologic evaluations after treatment. Health counseling and safety education on sex activity should be intensified among HIV-infected patients and secondary syphilis patients after treatment. PMID- 28903737 TI - Experiences with out-patient hospital service utilisation among older persons in the Asante Akyem North District- Ghana. AB - BACKGROUND: Though ageing is not a disease, it has been associated with the occurrence of conditions which require health service utilisation. Ghana's population is characterised by a steady growth in the number of older adults and previous studies have noted limited levels regarding utilisation by older persons. METHODS: Thus, this study utilised a qualitative approach to explore older persons' experiences regarding out-patient hospital service utilisation in the Asante Akyem North District of Ghana. The aim was to generate findings that will guide future policies. Sixteen semi-structured interviews were conducted and thematic analysis executed. The Andersen's Behavioural Model was used as a guiding framework. RESULTS: Medical condition was noted to characterise the need component of utilisation. Also, perceived effects of ageing, beliefs and past health status predisposed an older person to utilise available services. Beliefs were noted to make an older person utilise either orthodox or herbal services. Despite these, family support (in the form of financial assistance), accessibility (health facility, health professional, medication and information) and health care costs either enabled or prevented an older person from utilising services. Despite the existence of the National Health Insurance Scheme, health care costs are high and that delayed utilisation or made others avoid the services altogether. The care processes were noted to be cumbersome and involved long hours; though these features were noted to be absent whilst utilising traditional medicine services and this provides an avenue for further research in assessing patient outcomes associated with traditional medicine usage. These findings might be contributing factors to why other studies identified limited usage of health services among older persons in Ghana. CONCLUSION: Though older persons in the district may feel the need to utilise health services on outpatient basis, the enabling factors (notably finance) appeared to be a driving force to actual utilisation. Thus, more innovative health care financing strategies are needed to enhance the coverage of health services for older persons in the district. PMID- 28903738 TI - A randomized controlled trial of physical activity with individual goal-setting and volunteer mentors to overcome sedentary lifestyle in older adults at risk of cognitive decline: the INDIGO trial protocol. AB - BACKGROUND: Increasing physical activity (PA) effectively in those who are inactive is challenging. For those who have subjective memory complaints (SMC) or mild cognitive impairment (MCI) this is a greater challenge necessitating the need for more engaging and innovative approaches. The primary aim of this trial is to determine whether a home-based 6-month PA intervention with individual goal setting and peer mentors (GM-PA) can significantly increase PA levels in insufficiently active older adults at increased risk of developing Alzheimer's disease (AD). METHODS: Community living 60-80 year olds with SMC or MCI who do not engage in more than 60 min per week of moderate intensity PA will be recruited from memory clinics and the community via media advertisements to participate in this randomized, single-blind controlled trial. All participants will receive an individually tailored home-based PA program of 150 min of moderate intensity walking/week for 6 months. The intervention group will undertake individual goal-setting and behavioral education workshops with mentor support via telephone (GM-PA). Those randomized to the control group will have standard education workshops and Physical Activity Liaison (PAL) contact via telephone (CO-PA). Increase in PA is the primary outcome, fitness, cognitive, personality, demographic and clinical parameters will be measured and a health economic analysis performed. A saliva sample will be collected for APOE e4 genotyping. All participants will have a goal-setting interview to determine their PA goals. Active volunteers aged 50-85 years will be recruited from the community randomized and trained to provide peer support as mentors (intervention group) or PALS (control group) for the 6-month intervention. Mentors and PALS will have PA, exercise self-efficacy and mentoring self-efficacy measured. Participants in both groups are asked to attend 3 workshops in 6 months. At the first workshop, they will meet their allocated Mentor or PAL who will deliver their respective programs and support via 6 telephone calls during the intervention. DISCUSSION: If the GM-PA program is successful in increasing the PA levels of the target group it will potentially provide another strategy and community resource that can be translated into practice. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12613001181796 . (29/10/2013) retrospectively registered. PMID- 28903740 TI - Erratum to: Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family. PMID- 28903739 TI - Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis. AB - BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance. RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p. CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential. PMID- 28903741 TI - Is economic dependence on the husband a risk factor for intimate partner violence against female factory workers in Nepal? AB - BACKGROUND: Violence related injury is a serious public health issue all over the world. This study aims to assess the association between several socio-economic factors and intimate partner violence (IPV) in Nepal. METHODS: A cross-sectional study was conducted among 236 women working in carpet and garment factories in Kathmandu, Nepal. Interviews were conducted to collect quantitative data on three forms of IPV, namely physical violence, psychological violence and sexual violence, as well as on a number of potentially associated factors. RESULTS: Twenty-two percent of women experienced sexual IPV, 28% physical IPV and 35% psychological IPV at least once in the last 12 months. The variables independently associated with at least one form of IPV were: age of the woman >29 years [OR = 4.23, p = 0.025 for physical IPV; OR = 6.94, p = 0.008 for sexual IPV; OR = 3.42, p = 0.043 for psychological IPV], alcohol consumption of the husband [OR = 9.97, p < 0.001 for physical IPV; OR = 3.76, p = 0.004 for sexual IPV; OR = 4.85, p < 0.001 for psychological IPV], education of the husband above primary level [OR = 0.43, p = 0.013 for physical IPV; OR = 0.51, p = 0.033 for psychological IPV], and economic dependency of the woman on the husband [OR = 3.04, p = 0.021 for physical IPV; OR = 2.97, p = 0.008 for psychological IPV]. CONCLUSIONS: This study identified various factors associated with IPV and showed that economic dependence of wives on their husband was among the most important ones. Thus, for the prevention of IPV against women, long term strategies aiming at livelihood and economic empowerment as well as independence of women would be suggested. PMID- 28903743 TI - A socio-ecological analysis of barriers to the adoption, sustainablity and consistent use of sanitation facilities in rural Ethiopia. AB - BACKGROUND: Despite evidence showing that access to and use of improved sanitation is associated with healthier households and communities, barriers influencing the adoption and sustainablity of sanitation facilities remain unclear. We conducted a qualitative case study to explore barriers influencing the adoption, sustainablity and consistent use of sanitation facilities in rural Ethiopia. METHODS: A qualitative study was conducted in the rural district of Becho, in central Ethiopia, from June to August 2016. A socio-ecological model and Integrated Behavioural Model (IBM) for a Water Hygiene and Sanitation (WASH) framework were employed to design the study and analyse data. A total of 10 in depth interviews (IDI) were conducted with latrine adopters (n = 3), latrine non adopters (n = 3), health extension workers (n = 3) and the district WASH coordinator (n = 1). Eight Focus Group Discussions (FGD) were undertaken with 75 participants, of which 31 were women. The FGDs and IDIs were tape-recorded, transcribed verbatim and translated into English. The analysis was supported using Nvivo version 10 software. RESULTS: Barriers to sustained adoption and use of sanitation facilities were categorized into 1) individual level factors (e.g., past latrine experience, lack of demand and perceived high cost to improved latrines), 2) household level factors (e.g., unaffordability, lack of space and absence of a physically strong family member), 3) community level factors (e.g., lack of access to public latrines, lack of shared rules against open defecation, lack of financial access for the poor), and 4) societal level factors (e.g., lack of strong local leadership, flooding, soil conditions, lack of appropriate sanitation technology, lack of promotion and demand creation for improved latrines). CONCLUSION: The use of the socio-ecological model and IBM-WASH framework helped to achieve a better understanding of multi-level and multi dimensional barriers to sustained latrine adoption. The results indicate that there is a need to consider interventions that address multi-level factors concurrently. PMID- 28903742 TI - Can you un-ring the bell? A qualitative study of how affect influences cancer screening decisions. AB - BACKGROUND: The belief that early detection is the best protection against cancer underlies cancer screening. Emerging research now suggests harms associated with early detection may sometimes outweigh the benefits. Governments, cancer agencies, and organizations that publish screening guidelines have found it is difficult to "un-ring the bell" on the message that "early detection is your best protection" because of its widespread communication and enduring resonance. This study explores affective factors-and their interplay with relevant analytical factors-in public/laypersons' decision making about cancer screening. METHODS: A total of 93 people (47 men, 46 women) attended focus groups about, respectively, prostate cancer screening and breast cancer screening in two Canadian cities. RESULTS: Affective factors were a major influence on many focus group participants' decision making about cancer screening, including fear of cancer and a generalized enthusiasm for prevention/screening, and they were often inspired by anecdotes about the cancer experiences of family and friends. Affect also existed alongside more analytical factors including assessments of reduced risk in the management of any cancer diagnosis if caught early, and, for men, the belief that an unreliable test is "better than nothing," and that men deserve prostate cancer screening because women have breast and cervical cancer screening. Affective factors were particularly noticeable in the sub-groups most supportive of screening and the "early detection" message: older women who felt that mammogram screening should begin at age 40 rather than 50, and older men who felt that prostate cancer screening should be expanded beyond its current unorganized, opportunistic usage. In contrast, younger participants displayed less affective attachments to "early detection" messages and had greater concerns about harms of screening and were more receptive to nuanced messages informed by evidence. CONCLUSION: Policymakers attempting to communicate more nuanced versions of the "early detection" message need to understand the role of affect alongside other judgments brought into laypersons' decision making processes and anticipate how affective responses to their messages will be shaped, transformed, and potentially subverted by external forces beyond their control. Particularly overt external factors are campaigns by cancer advocacy organizations actively promoting breast and prostate cancer awareness and screening to younger women and men using affectively-charged messages. PMID- 28903744 TI - Renin-angiotensin system gene polymorphisms and high blood pressure in Lithuanian children and adolescents. AB - BACKGROUND: Epidemiological studies have demonstrated the influence of environmental factors on HBP in the population of Lithuanian children, although the role of genetic factors in hypertension has not yet been studied. The aim of this study was to assess the distribution of AGTR1, AGT, and ACE genotypes in the Lithuanian child population and to determine whether these genotypes have an impact on HBP in childhood. METHODS: This cross-sectional study enrolled 709 participants aged 12-15 years. The subjects were genotyped for AGT (M235 T, rs699), AGTR1 (A1166C, rs5186), and ACE (rs4340) gene polymorphisms using real time and conventional polymerase chain reactions. Blood pressure and anthropometric parameters were measured. RESULTS: The prevalence of HBP was 38.6% and was more frequently detected in boys than in girls (47.9% vs. 29.5%; p < 0.001). No significant differences in the frequencies of the AGT or AGTR1 genotypes or alleles between boys and girls were observed, except for ACE genotypes. The mean SBP value was higher in HBP subjects with ACE ID genotype compared to those with ACE II homozygotes (p = 0.04). No significant differences in BP between different AGT and AGTR1 genotype groups were found. Boys who carried the ACE ID + DD genotypes had higher odds of having HBP than carriers of the ACE II genotype did (controlling for the body mass index (BMI): ORMH = 1.83; 95% CI, 1.11-3.02, p = 0.024; and controlling for waist circumference (WC): ORMH = 1.76; 95% CI, 1.07-2.92, p = 0.035). These associations were not significant among girls. The same trend was observed in the multivariate analysis - after adjustment for BMI and WC, only boys with ACE ID genotype and ACE ID + DD genotypes had statistically significantly increased odds of HBP (aOR = 2.05; 95% CI, 1.19-3.53 (p = 0.01) and aOR = 1.82; 95% CI, 1.09-3.04 (p = 0.022), respectively). CONCLUSIONS: The evaluated polymorphisms of the AGT and AGTR1 genes did not contribute to the presence of HBP in the present study and may be seen as predisposing factors, while ACE ID genotypes were associated with significantly increased odds for the development of HBP in the Lithuanian child and adolescent population - especially in boys. PMID- 28903746 TI - Correlation between patients' reasons for encounters/health problems and population density in Japan: a systematic review of observational studies coded by the International Classification of Health Problems in Primary Care (ICHPPC) and the International Classification of Primary care (ICPC). AB - BACKGROUND: The Japanese health care system has yet to establish structured training for primary care physicians; therefore, physicians who received an internal medicine based training program continue to play a principal role in the primary care setting. To promote the development of a more efficient primary health care system, the assessment of its current status in regard to the spectrum of patients' reasons for encounters (RFEs) and health problems is an important step. Recognizing the proportions of patients' RFEs and health problems, which are not generally covered by an internist, can provide valuable information to promote the development of a primary care physician-centered system. METHODS: We conducted a systematic review in which we searched six databases (PubMed, the Cochrane Library, Google Scholar, Ichushi-Web, JDreamIII and CiNii) for observational studies in Japan coded by International Classification of Health Problems in Primary Care (ICHPPC) and International Classification of Primary Care (ICPC) up to March 2015. We employed population density as index of accessibility. We calculated Spearman's rank correlation coefficient to examine the correlation between the proportion of "non-internal medicine-related" RFEs and health problems in each study area in consideration of the population density. RESULTS: We found 17 studies with diverse designs and settings. Among these studies, "non-internal medicine-related" RFEs, which was not thought to be covered by internists, ranged from about 4% to 40%. In addition, "non-internal medicine-related" health problems ranged from about 10% to 40%. However, no significant correlation was found between population density and the proportion of "non-internal medicine-related" RFEs and health problems. CONCLUSIONS: This is the first systematic review on RFEs and health problems coded by ICHPPC and ICPC undertaken to reveal the diversity of health problems in Japanese primary care. These results suggest that primary care physicians in some rural areas of Japan need to be able to deal with "non-internal-medicine-related" RFEs and health problems, and that curriculum including practical non-internal medicine-related training is likely to be important. PMID- 28903745 TI - Acceptance of guidance to care at the emergency department following attempted suicide. AB - BACKGROUND: Research, aimed at improving the continuity of care after hospital discharge following attempted suicide focuses on the effectiveness of the interventions. Little attention has been paid to patients who immediately decline guidance to advised post-discharge care. We aimed to identify differences between accepters and decliners of guidance to care (GtC) in relation to the characteristics of patients who presented at the emergency department (ED) of an urban hospital in the Netherlands after attempted suicide. METHOD: This cross sectional study included all patients who presented at the ED of OLVG-West Amsterdam with a suicide attempt or intentional self-harm and were referred for psychiatric evaluation. Data were collected over a period of twenty months using a semi-structured questionnaire. Subgroups were described in relation the acceptance of GtC using univariate and multivariate logistic regression analyses. RESULTS: In total, 257 patients were included. GtC was accepted by 77%. Suicide attempters who reported loneliness as reason for the attempt showed a positive relation to acceptance. No indication was found that patients at higher risk for suicide are more reluctant to accept GtC. Suicide attempters with a non-Western ethnicity, especially patients with a Turkish/Moroccan ethnicity, declined contact by the GtC nurse significantly more often. In addition, patients who currently did not receive care were significantly more often of non-Western ethnicity and younger than 25. CONCLUSION: Acceptance of GtC is high among patients who presented at the ED after attempted suicide. The patients who were the most reluctant to accept GtC were young suicide attempters of non-Western ethnicity who were not in current care. As this study is the first to address the acceptance of GtC, we point out two lines of inquiry for further research. First, reasons to accept or decline need to be investigated further since only interventions that are accepted by patients have a chance to improve clinically relevant outcome. Second, follow-up research is warranted comparing the adherence to advised post-discharge care and attempted or completed suicide among accepters versus decliners of GtC in various ethnic and sociodemographic subgroups. PMID- 28903747 TI - Antenatal magnesium sulphate administration for fetal neuroprotection: a French national survey. AB - BACKGROUND: Magnesium sulphate (MgSO4) is the only treatment approved for fetal neuroprotection. No information on its use is available in the absence of a national registry of neonatal practices. The objective of our study was to evaluate the use of MgSO4 for fetal neuroprotection in French tertiary maternity hospitals (FTMH). METHODS: Online and phone survey of all FTMH between August 2014 and May 2015. A participation was expected from one senior obstetrician, one senior anaesthetist and one senior neonatologist from each FTMH. Information was obtained from 63/63 (100%) FTMH and 138/189 (73%) physicians. Use of MgSO4 for fetal neuroprotection, regimen and injection protocols, reasons for non-use were the main outcome measures. RESULTS: 60.3% of FTMH used MgSO4 for fetal neuroprotection. No significant difference was observed between university and non-university hospitals or according to the annual number of births. Protocols differed especially in terms of the maximum gestational age (3% <28 WG, 71% <33 WG, 18% <34 WG and 8% < 35 WG). Eighty seven percent of centers using MgSO4 prescribed retreatment when necessary, but according to non-consensual modalities in terms of number of treatments or between-treatment intervals. Injections and monitoring were mostly performed in the delivery room (97%) but also in the recovery room in one half of hospitals. Lack of experience (52%), absence of a written protocol (49%) and national guidelines (46%) were the reasons most commonly reported to explain non-use of MgSO4 as a neuroprotective agent. CONCLUSIONS: Sixty percent of FTMH used MgSO4 for fetal neuroprotection, but according to heterogeneous regimens. National guidelines could allow standardization of practices and better MgSO4 coverage. PMID- 28903748 TI - Costs associated with adverse events among acute patients. AB - BACKGROUND: The aim of this study was to analyse the additional treatment costs of acute patients admitted to a Danish hospital who suffered an adverse event (AE) during in-hospital treatment. METHODS: A matched case-control design was utilised. Using a combination of trigger words and patient record reviews 91 patients exposed to AEs were identified. Controls were identified among patients admitted to the same department during the same 20-month period. The matching was based on age, gender, and main diagnosis. Cost data was extracted from the Danish National Cost Database for four different periods after beginning of the admission. RESULTS: Patients exposed to an AE were associated with higher mean cost of EUR 9505 during their index admission (p = 0.014). For the period of 6 months from the beginning of the admission minus the admission itself they were associated with higher mean cost of EUR 4968 (p = 0.016). For the period from the 7th month until the end of the 12th month there was no statistically significant difference (p = 0.104). For the total period of 12 month, patients exposed to an AE were associated with statistically significant higher mean cost of EUR 13,930 (p = 0.001). CONCLUSIONS: AEs are associated with significant hospital costs. Our findings suggest that a follow-up period of 6 months is necessary when investigating the costs associated with AEs among acute patients. Further research of specific types of AEs and the costs of preventing these types of AEs would improve the understanding of the relationship between adverse events and costs. PMID- 28903749 TI - Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b. AB - BACKGROUND: Haemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of primary vaccine doses and an optimal schedule for the booster dose. We sought to evaluate the effect of a booster dose after receiving the primary series on the long-term disease incidence. METHODS: A stochastic model of Hib transmission dynamics was constructed to compare the long term impact of a booster vaccination and different booster schedules after receiving the primary series on the incidence of carriage and symptomatic disease. We parameterized the model with available estimates for the efficacy of Hib conjugate vaccine and durations of both vaccine-induced and naturally acquired immunity. RESULTS: We found that administering a booster dose substantially reduced the population burden of Hib disease compared to the scenario of only receiving the primary series. Comparing the schedules, the incidence of carriage for a 2-year delay (on average) in booster vaccination was comparable or lower than that observed for the scenario of booster dose within 1 year after primary series. The temporal reduction of symptomatic disease was similar in the two booster schedules, suggesting no superiority of one schedule over the other in terms of reducing the incidence of symptomatic disease. CONCLUSIONS: The findings underscore the importance of a booster vaccination for continued decline of Hib incidence. When the primary series provides a high level of protection temporarily, delaying the booster dose (still within the average duration of protection conferred by the primary series) may be beneficial to maintain longer-term protection levels and decelerate the decline of herd immunity in the population. PMID- 28903750 TI - Cancer survival disparities worsening by socio-economic disadvantage over the last 3 decades in new South Wales, Australia. AB - BACKGROUND: Public concerns are commonly expressed about widening health gaps. This cohort study examines variations and trends in cancer survival by socio economic disadvantage, geographical remoteness and country of birth in an Australian population over a 30-year period. METHODS: Data for cases diagnosed in New South Wales (NSW) in 1980-2008 (n = 651,245) were extracted from the population-based NSW Cancer Registry. Competing risk regression models, using the Fine & Gray method, were used for comparative analyses to estimate sub-hazard ratios (SHR) with 95% confidence intervals (CI) among people diagnosed with cancer. RESULTS: Increased risk of cancer death was associated with living in the most socio-economically disadvantaged areas compared with the least disadvantaged areas (SHR 1.15, 95% CI 1.13-1.17), and in outer regional/remote areas compared with major cities (SHR 1.05, 95% CI 1.03-1.06). People born outside Australia had a similar or lower risk of cancer death than Australian-born (SHR 0.99, 95% CI 0.98-1.01 and SHR 0.91, 95% CI 0.90-0.92 for people born in other English and non English speaking countries, respectively). An increasing comparative risk of cancer death was observed over time when comparing the most with the least socio economically disadvantaged areas (SHR 1.07, 95% CI 1.04-1.10 for 1980-1989; SHR 1.14, 95% CI 1.12-1.17 for 1990-1999; and SHR 1.24, 95% CI 1.21-1.27 for 2000 2008; p < 0.001 for interaction between disadvantage quintile and year of diagnosis). CONCLUSIONS: There is a widening gap in comparative risk of cancer death by level of socio-economic disadvantage that warrants a policy response and further examination of reasons behind these disparities. PMID- 28903751 TI - RNA-seq comparative analysis of Peking ducks spleen gene expression 24 h post infected with duck plague virulent or attenuated virus. AB - Duck plague virus (DPV), a member of alphaherpesvirus sub-family, can cause significant economic losses on duck farms in China. DPV Chinese virulent strain (CHv) is highly pathogenic and could induce massive ducks death. Attenuated DPV vaccines (CHa) have been put into service against duck plague with billions of doses in China each year. Researches on DPV have been development for many years, however, a comprehensive understanding of molecular mechanisms underlying pathogenicity of CHv strain and protection of CHa strain to ducks is still blank. In present study, we performed RNA-seq technology to analyze transcriptome profiling of duck spleens for the first time to identify differentially expressed genes (DEGs) associated with the infection of CHv and CHa at 24 h. Comparison of gene expression with mock ducks revealed 748 DEGs and 484 DEGs after CHv and CHa infection, respectively. Gene pathway analysis of DEGs highlighted valuable biological processes involved in host immune response, cell apoptosis and viral invasion. Genes expressed in those pathways were different in CHv infected duck spleens and CHa vaccinated duck spleens. The results may provide valuable information for us to explore the reasons of pathogenicity caused by CHv strain and protection activated by CHa strain. PMID- 28903752 TI - Measurement of cortisol in saliva: a comparison of measurement error within and between international academic-research laboratories. AB - OBJECTIVE: Hundreds of scientific publications are produced annually that involve the measurement of cortisol in saliva. Intra- and inter-laboratory variation in salivary cortisol results has the potential to contribute to cross-study inconsistencies in findings, and the perception that salivary cortisol results are unreliable. This study rigorously estimates sources of measurement variability in the assay of salivary cortisol within and between established international academic-based laboratories that specialize in saliva analyses. One hundred young adults (Mean age: 23.10 years; 62 females) donated 2 mL of whole saliva by passive drool. Each sample was split into multiple- 100 uL aliquots and immediately frozen. One aliquot of each of the 100 participants' saliva was transported to academic laboratories (N = 9) in the United States, Canada, UK, and Germany and assayed for cortisol by the same commercially available immunoassay. RESULTS: 1.76% of the variance in salivary cortisol levels was attributable to differences between duplicate assays of the same sample within laboratories, 7.93% of the variance was associated with differences between laboratories, and 90.31% to differences between samples. In established-qualified laboratories, measurement error of salivary cortisol is minimal, and inter laboratory differences in measurement are unlikely to have a major influence on the determined values. PMID- 28903753 TI - Acquisition of resistance to avian leukosis virus subgroup B through mutations on tvb cysteine-rich domains in DF-1 chicken fibroblasts. AB - Avian leukosis virus (ALV) is a retrovirus that causes tumors in avian species, and its vertical and horizontal transmission in poultry flocks results in enormous economic losses. Despite the discovery of specific host receptors, there have been few reports on the modulation of viral susceptibility via genetic modification. We therefore engineered acquired resistance to ALV subgroup B using CRISPR/Cas9-mediated genome editing technology in DF-1 chicken fibroblasts. Using this method, we efficiently modified the tumor virus locus B (tvb) gene, encoding the TVB receptor, which is essential for ALV subgroup B entry into host cells. By expanding individual DF-1 clones, we established that artificially generated premature stop codons in the cysteine-rich domain (CRD) of TVB receptor confer resistance to ALV subgroup B. Furthermore, we found that a cysteine residue (C80) of CRD2 plays a crucial role in ALV subgroup B entry. These results suggest that CRISPR/Cas9-mediated genome editing can be used to efficiently modify avian cells and establish novel chicken cell lines with resistance to viral infection. PMID- 28903754 TI - Supporting research readiness in social enterprise health services. AB - Health-based social enterprises are spun out of the NHS, yet continue to provide NHS-funded services. With the spin-out, however, formal processes for research governance were lost. Patients have a right to take part in research, regardless of where they access healthcare. This paper discusses the barriers to social enterprises undertaking applied health research and makes recommendations to address the need for equivalence of governance processes with NHS trusts. PMID- 28903755 TI - Prevalence of K13 mutation and Day-3 positive parasitaemia in artemisinin resistant malaria endemic area of Cambodia: a cross-sectional study. AB - BACKGROUND: The presence of artemisinin-resistant malaria parasites was confirmed in western Cambodia in 2009. In 2013, mutations in the propeller domain of the kelch protein K13 was found to be associated with artemisinin resistance. A cross sectional study was conducted to determine the prevalence of Day-3 parasitaemia, estimate the frequency of k13 molecular marker and assess their relationship in the context of operational research. METHODS: Blood smears and filter paper blood spots were collected from febrile patients in Kravanh District, Pursat Province. The blood smears were examined by microscopy, and blood spots by a k13 mutation assay. RESULTS: Data from 92 patients were analysed. Only one was positive for Day-3 parasitaemia. Results of the k13 assay were interpretable for 76 of the 92 samples. The findings were: wild type: 9 (12%), C580Y: 64 (84%), Y493H: 3 (4%). Therefore, despite the high prevalence of k13 mutants (67/76: 88%), only 1 of the 92 patients remained blood smear positive for Plasmodium falciparum on Day-3. CONCLUSIONS: These preliminary findings suggest good potency of artemisinin despite the dominance of k13 mutation in Kravanh, but the result is not necessarily representative of the western part of Cambodia. Further investigation should be made to determine if k13 marker remains useful as a tool for tracking artemisinin resistance and predicting the trend of the efficacy of artemisinin combination therapy once the mutant alleles have been well established in the population. PMID- 28903756 TI - Could the use of bedside lung ultrasound reduce the number of chest x-rays in the intensive care unit? AB - BACKGROUND: Lung ultrasound can be used as an alternative to chest radiography (CXR) for the diagnosis and follow-up of various lung diseases in the intensive care unit (ICU). Our aim was to evaluate the influence that introducing a routine daily use of lung ultrasound in critically ill patients may have on the number of CXRs and as a consequence, on medical costs and radiation exposure. METHODS: Data were collected by conducting a retrospective evaluation of the medical records of adult patients who needed thoracic imaging and were admitted to our academic polyvalent ICU. We compared the number of CXRs and relative costs before and after the introduction of lung ultrasound in our ICU. RESULTS: A total of 4134 medical records were collected from January 2010 to December 2014. We divided our population into two groups, before (Group A, 1869 patients) and after (Group B, 2265 patients) the introduction of a routine use of LUS in July 2012. Group A performed a higher number of CXRs compared to Group B (1810 vs 961, P = 0.012), at an average of 0.97 vs 0.42 exams per patient. The estimated reduction of costs between Groups A and B obtained after the introduction of LUS, was 57%. No statistically significant difference between the outcome parameters of the two groups was observed. CONCLUSIONS: Lung ultrasound was effective in reducing the number of CXRs and relative medical costs and radiation exposure in ICU, without affecting patient outcome. PMID- 28903757 TI - Access to medicines and hepatitis C in Africa: can tiered pricing and voluntary licencing assure universal access, health equity and fairness? AB - BACKGROUND: The recent introduction of Direct Acting Antivirals (DAAs) for treating Hepatitis C Virus (HCV) can significantly assist in the world reaching the international target of elimination by 2030. Yet, the challenge facing many individuals and countries today lies with their ability to access these treatments due to their relatively high prices. Gilead Sciences applies differential pricing and licensing strategies arguing that this provides fairer and more equitable access to these life-saving medicines. This paper analyses the implications of Gilead's tiered pricing and voluntary licencing strategy for access to the DAAs. METHODS: We examined seven countries in Africa (Egypt, Ethiopia, Nigeria, Democratic Republic of Congo, Cameroon, Rwanda and South Africa) to assess their financial capacity to provide DAAs for the treatment of HCV under present voluntary licensing and tiered-pricing arrangements. These countries have been selected to explore the experience of countries with a range of different burdens of HCV and shared eligibility for supply by licensed generic producers or from discounted Gilead prices. RESULTS: The cost of 12-weeks of generic DAA varies from $684 per patient treated in Egypt to $750 per patient treated in other countries. These countries can also procure the same DAA for 12 weeks of treatment from the originator, Gilead, at a cost of $1200 per patient. The current prices of DAAs (both from generic and originator manufacturers) are much more than the median annual income per capita and the annual health budget of most of these countries. If governments alone were to bear the costs of universal treatment coverage, then the required additional health expenditure from present rates would range from a 4% increase in South Africa to a staggering 403% in Cameroon. CONCLUSION: The current arrangements for increasing access to DAAs, towards elimination of HCV, are facing challenges that would require increases in expenditure that are either too burdensome to governments or potentially so to individuals and families. Countries need to implement the flexibilities in the Doha Declaration on Trade Related Intellectual Property Rights agreement, including compulsory licensing and patent opposition. This also requires political commitment, financial will, global solidarity and civil society activism. PMID- 28903758 TI - Factors associated with malaria microscopy diagnostic performance following a pilot quality-assurance programme in health facilities in malaria low transmission areas of Kenya, 2014. AB - BACKGROUND: Malaria accounts for ~21% of outpatient visits annually in Kenya; prompt and accurate malaria diagnosis is critical to ensure proper treatment. In 2013, formal malaria microscopy refresher training for microscopists and a pilot quality-assurance (QA) programme for malaria diagnostics were independently implemented to improve malaria microscopy diagnosis in malaria low-transmission areas of Kenya. A study was conducted to identify factors associated with malaria microscopy performance in the same areas. METHODS: From March to April 2014, a cross-sectional survey was conducted in 42 public health facilities; 21 were QA pilot facilities. In each facility, 18 malaria thick blood slides archived during January-February 2014 were selected by simple random sampling. Each malaria slide was re-examined by two expert microscopists masked to health-facility results. Expert results were used as the reference for microscopy performance measures. Logistic regression with specific random effects modelling was performed to identify factors associated with accurate malaria microscopy diagnosis. RESULTS: Of 756 malaria slides collected, 204 (27%) were read as positive by health facility microscopists and 103 (14%) as positive by experts. Overall, 93% of slide results from QA-pilot facilities were concordant with expert reference compared to 77% in non-QA pilot facilities (p < 0.001). Recently trained microscopists in QA-pilot facilities performed better on microscopy performance measures with 97% sensitivity and 100% specificity compared to those in non-QA pilot facilities (69% sensitivity; 93% specificity; p < 0.01). The overall inter reader agreement between QA-pilot facilities and experts was kappa = 0.80 (95% CI 0.74-0.88) compared to kappa = 0.35 (95% CI 0.24-0.46) between non-QA pilot facilities and experts (p < 0.001). In adjusted multivariable logistic regression analysis, recent microscopy refresher training (prevalence ratio [PR] = 13.8; 95% CI 4.6-41.4), >=5 years of work experience (PR = 3.8; 95% CI 1.5-9.9), and pilot QA programme participation (PR = 4.3; 95% CI 1.0-11.0) were significantly associated with accurate malaria diagnosis. CONCLUSIONS: Microscopists who had recently completed refresher training and worked in a QA-pilot facility performed the best overall. The QA programme and formal microscopy refresher training should be systematically implemented together to improve parasitological diagnosis of malaria by microscopy in Kenya. PMID- 28903759 TI - Knowledge, access and utilization of bed-nets among stable and seasonal migrants in an artemisinin resistance containment area of Myanmar. AB - BACKGROUND: Myanmar lies in the Greater Mekong sub-region of South-East Asia faced with the challenge of emerging resistance to artemisinin combination therapies (ACT). Migrant populations are more likely than others to spread ACT resistance. A vital intervention to reduce malaria transmission, resistance spread and eliminate malaria is the use of bed nets. Among seasonal and stable migrants in an artemisinin resistance containment region of Myanmar, we compared a) their household characteristics, b) contact with health workers and information material, and c) household knowledge, access and utilization of bed nets. METHODS: Secondary data from community-based surveys on 2484 migrant workers (2013 and 2014, Bago Region) were analyzed of which 37% were seasonal migrants. Bed net access and utilization were assessed using a) availability of at least one bed net per household, and b) one bed net per two persons, and c) proportion of household members who slept under abed net during the previous night (Indicator targets = 100%). RESULTS: Over 70% of all migrants were from unstable work settings with short transitory stays. Average household size was five (range 1-25) and almost half of all households had children under-five years. Roughly 10 % of migrants were night-time workers. Less than 40% of households had contact with health workers and less than 30% had exposure to information education and communication (IEC) materials, the latter being significantly lower among seasonal migrants. About 70% of households were aware of the importance of insecticide-treated bed-nets/long-lasting insecticidal nets (ITNs/LLINs), but knowledge on insecticide impregnation and retreatment of ITNs was poor (< 10%). Although over 95% of households had access to at least one bed net, the number with one bed net per two persons was grossly inadequate (13% for stable migrants and 9% for seasonal migrants, P = 0.001). About half of all household members slept under a bed net during the previous night. CONCLUSIONS: This study reveals important short-falls in knowledge, access and utilization of bed nets among migrants in Myanmar. Possible ways forward include frequent distribution campaigns to compensate for short transitory stays, matching household distributions to household size, enhanced information campaigns and introducing legislation to make mosquito repellents available for night-time workers at plantations and farms. Better understanding through qualitative research is also merited. PMID- 28903760 TI - Feasibility of detecting myocardial infarction in the sheep fetus using late gadolinium enhancement CMR imaging. AB - BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging has enabled the accurate assessment of myocardial infarction (MI). However, LGE CMR has not been performed successfully in the fetus, where it could be useful for animal studies of interventions to promote cardiac regeneration. We believe that LGE imaging could allow us to document the presence, extent and effect of MI in utero and would thereby expand our capacity for conducting fetal sheep MI research. We therefore aimed to investigate the feasibility of using LGE to detect MI in sheep fetuses. METHODS: Six sheep fetuses underwent a thoracotomy and ligation of a left anterior descending (LAD) coronary artery branch; while two fetuses underwent a sham surgery. LGE CMR was performed in a subset of fetuses immediately after the surgery and three days later. Early gadolinium enhancement (EGE) CMR was also performed in a subset of fetuses on both days. Cine imaging of the heart was performed to measure ventricular function. RESULTS: The imaging performed immediately after LAD ligation revealed no evidence of infarct on LGE (n=3). Two of four infarcted fetuses (50%) showed hypoenhancement at the infarct site on the EGE images. Three days after the ligation, LGE images revealed a clear, hyper-enhanced infarct zone in four of the five infarcted fetuses (80%). No hyper-enhanced infarct zone was seen on the one sham fetus that underwent LGE CMR. No hypoenhancement could be seen in the EGE images in either the sham (n=1) or the infarcted fetus (n=1). No regional wall motion abnormalities were apparent in two of the five infarcted fetuses. CONCLUSION: LGE CMR detected the MI three days after LAD ligation, but not immediately after. Using available methods, EGE imaging was less useful for detecting deficits in perfusion. Our study provides evidence for the ability of a non-invasive tool to monitor the progression of cardiac repair and damage in fetuses with MI. However, further investigation into the optimal timing of LGE and EGE scans and improvement of the sequences should be pursued with the aim of expanding our capacity to monitor cardiac regeneration after MI in fetal sheep. PMID- 28903761 TI - Protective effects of grape seed and skin extract against high-fat-diet-induced lipotoxicity in rat lung. AB - BACKGROUND: Obesity is a public health problem characterized by increased fat accumulation in different tissues. Obesity is directly linked to breathing problems and medical complications with lung, including obstructive sleep apnea syndrome, obesity hypoventilation syndrome, chronic obstructive pulmonary disease, asthma....In the present work, we aimed to investigate the effect of high fat diet (HFD) on lung lipotoxicity, oxidative stress, fatty acid composition and proportions in lung and implication in asthma development. The likely protection provided by grape seed extract (GSSE) was also investigated. METHODS: In order to assess HFD effect on lung and GSSE protection we used a rat model. We analyzed the lipid plasma profile, lung peroxidation and antioxidant activities (SOD, CAT and POD). We also analyzed transition metals (Ca2+, Mg2+, Zn2+ and iron) and lung free fatty acids using gas chromatography coupled to mass spectrometry (GC-MS). RESULTS: HFD induced lipid profile imbalance increasing cholesterol and VLDL-C. HFD also induced an oxidative stress assessed by elevated MDA level and the drop of antioxidant activities such as SOD, CAT and POD. Moreover, HFD induced mineral disturbances by decreasing magnesium level and increasing Calcium and iron levels. HFD induced also disturbances in lung fatty acid composition by increasing oleic, stearic and arachidonic acids. Interestingly, GSSE alleviated all these deleterious effects of HFD treatment. CONCLUSION: As a whole, GSSE had a significant preventive effect against HFD induced obesity, and hence may be used as an anti-obesity agent, and a benefic agent with potential applications against damages in lung tissue. PMID- 28903762 TI - Mesh penetrating the cecum and bladder following inguinal hernia surgery: a case report. AB - BACKGROUND: Tension-free repair using mesh is a common inguinal hernia surgical procedure. However, various complications such as mesh-related infection and recurrence may develop as a result. Moreover, although rare, there are also reports of intestinal obstruction caused by adhesion of the mesh to the intestinal wall and cases of mesh migration into various organs. Here, we report our experience with a patient in whom mesh extraction was performed due to migration of mesh into the intestinal tract following inguinal hernia surgery and formation of a fistula with the bladder. CASE PRESENTATION: Our patient was a 63 year-old Japanese man who had a history of operative treatment for right inguinal hernia during early childhood. Because a relapse subsequently occurred, he was diagnosed as having recurrent right inguinal hernia at the age of 56 years for which operative treatment (the Kugel method) was performed. He presented to our hospital 6 years later with the chief complaint of lower abdominal pain. Computed tomography findings revealed a mass shadow in contact with his bladder and cecal walls, and enteric bacteria were detected in his urine. Furthermore, because lower gastrointestinal endoscopic findings confirmed mesh in the cecum, we performed operative treatment. The mesh had migrated into the cecum and a fistula with his bladder had formed. We removed the mesh through ileocecal resection and partial cystectomy. CONCLUSIONS: It appeared that a peritoneal defect occurred when the mesh was placed, allowing the mesh to migrate into our patient's intestinal tract. Because contact between the mesh and the cecum resulted in inflammation, a fistula formed in his bladder. It is important to completely close the peritoneum when placing the mesh. PMID- 28903763 TI - Troponin as ischemic biomarker is related with all three echocardiographic risk factors for sudden death in hypertrophic cardiomyopathy (ESC Guidelines 2014). AB - BACKGROUND: Sudden cardiac death (SCD) risk stratification is the most important preventive action in patients with hypertrophic cardiomyopathy (HCM). The identification of the ischemia biomarker high sensitive troponin I (hs-TnI) role for this arrhythmic disease may provide additional information for SCD risk stratification. The aim of the study was to compare echocardiographic parameters (prognostic for risk stratification of SCD in HCM) among two subgroups of HCM patients: with elevated hs-TnI versus non-elevated hs-TnI level. METHODS: In 51 HCM patients (mean age 39 +/- 8 years, 31 males and 20 females) an echocardiographic examination, including the stimulating maneuvers to provoke maximized LVOT gradient, was performed. The hs-TnI was measured 24 h later. RESULTS: By comparing two subgroups of patients, 26 members with hs-TnI positive versus 25 with hs-TnI negative, the study showed that the values of all three parameters were greater: provocable left ventricular outflow tract gradient (LVOTG) - 49.1 +/- 45.9 vs 25.5 +/- 24.8 mmHg, p = 0.019; left atrial diameter - 50.1 +/- 9.6 vs 43.9 +/- 9.8 mmHg, p = 0.041; maximal LV thickness - 22.1 +/- 5.3 vs 19.9 +/- 34 mm, p = 0.029. CONCLUSION: The increased value of all three echocardiographic parameters used as risk factors for SCD (ESC Guidelines) is related to the elevated level of hs-TnI in HCM. Due to the high LVOTG - great hs TnI relationship, exercise stress, both diagnostic and even rehabilitation/training, should be monitored by biomarker control. PMID- 28903764 TI - Comparative assessment of fermentative capacity of different xylose-consuming yeasts. AB - BACKGROUND: Understanding the effects of oxygen levels on yeast xylose metabolism would benefit ethanol production. In this work, xylose fermentative capacity of Scheffersomyces stipitis, Spathaspora passalidarum, Spathaspora arborariae and Candida tenuis was systematically compared under aerobic, oxygen-limited and anaerobic conditions. RESULTS: Fermentative performances of the four yeasts were greatly influenced by oxygen availability. S. stipitis and S. passalidarum showed the highest ethanol yields (above 0.44 g g-1) under oxygen limitation. However, S. passalidarum produced 1.5 times more ethanol than S. stipitis under anaerobiosis. While C. tenuis showed the lowest xylose consumption rate and incapacity to produce ethanol, S. arborariae showed an intermediate fermentative performance among the yeasts. NAD(P)H xylose reductase (XR) activity in crude cell extracts correlated with xylose consumption rates and ethanol production. CONCLUSIONS: Overall, the present work demonstrates that the availability of oxygen influences the production of ethanol by yeasts and indicates that the NADH dependent XR activity is a limiting step on the xylose metabolism. S. stipitis and S. passalidarum have the greatest potential for ethanol production from xylose. Both yeasts showed similar ethanol yields near theoretical under oxygen limited condition. Besides that, S. passalidarum showed the best xylose consumption and ethanol production under anaerobiosis. PMID- 28903765 TI - Antimicrobial resistance among pathogenic bacteria from mink (Neovison vison) in Denmark. AB - BACKGROUND: For proper treatment of bacterial infections in mink, knowledge of the causative agents and their antimicrobial susceptibility patterns is crucial. The used antimicrobials are in general not registered for mink, i.e. most usage is "off-label". In this study, we report the patterns of antimicrobial resistance among pathogenic bacteria isolated from Danish mink during the period 2014-2016. The aim of this investigation was to provide data on antimicrobial resistance and consumption, to serve as background knowledge for new veterinary guidelines for prudent and optimal antimicrobial usage in mink. RESULTS: A total number of 308 Escherichia coli isolates, 41 Pseudomonas aeruginosa, 36 Streptococcus canis, 30 Streptococcus dysgalactiae, 55 Staphylococcus delphini, 9 Staphylococcus aureus, and 20 Staphylococcus schleiferi were included in this study. Among E. coli, resistance was observed more frequently among the hemolytic isolates than among the non-hemolytic ones. The highest frequency of resistance was found to ampicillin, 82.3% and 48.0% of the hemolytic of the non-hemolytic isolates, respectively. The majority of the P. aeruginosa isolates were only sensitive to ciprofloxacin and gentamicin. Among the Staphylococcus spp., the highest occurrence of resistance was found for tetracycline. Regarding the nine S. aureus, one isolate was resistant to cefoxitin indicating it was a methicillin resistant Staphylococcus aureus. Both beta-hemolytic Streptococcus species showed high levels of resistance to tetracycline and erythromycin. The antimicrobial consumption increased significantly during 2007-2012, and fluctuated at a high level during 2012-2016, except for a temporary drop in 2013-2014. The majority of the prescribed antimicrobials were aminopenicillins followed by tetracyclines and macrolides. CONCLUSIONS: The study showed that antimicrobial resistance was common in most pathogenic bacteria from mink, in particular hemolytic E. coli. There is a need of guidelines for prudent use of antimicrobials for mink. PMID- 28903766 TI - Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subrachnoid hemorrhage in rats. AB - BACKGROUND: The NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL 1beta and IL-18. Fluoxetine has been shown to have the anti-inflammatory properties in many disease models. However, the effects and mechanisms of these effects of fluoxetine in early brain injury after subarachnoid hemorrhage (SAH) have not been defined. METHODS: The SAH model was induced by an endovascular perforation in adult male Sprague-Dawley (SD) rats weighing 300-320 g. N-Ac-Tyr Val-Ala-Asp-chloromethyl ketone (AC-YVAD-CMK) was injected intraperitoneally (5 mg/kg) 1 h after SAH. Fluoxetine was administered via intravenous route 6 h after SAH. 3-Methyladenine (3-MA) was intracerebroventricularly injected 20 min before SAH. SAH grade, neurological function, brain water content, propidium iodide (PI) staining, western blot, double immunostaining, and transmission electron microscopy were performed. RESULTS: Expression of caspase-1 increased and peaked at 24 h after SAH. Caspase activation was along with the increased necrotic cells, which occurred mainly in neurons. Necrotic cell death of microglia and astrocyte were also found. Administration of AC-YVAD-CMK, a caspase-1 inhibitor, reduced the expression of IL-1beta and IL-18 and the number of PI-positive cells, attenuated brain edema, and improved neurological function, which was also observed in fluoxetine-treated rats. Furthermore, fluoxetine treatment significantly decreased the expression of NLRP3 and cleaved caspase-1 and upregulated the expression of beclin-1, a marker for autophagy. Finally, the effects of fluoxetine in NLRP3 inflammasome activation were reversed by additional 3-MA administration. CONCLUSIONS: Together, our present study indicated that NLRP3 inflammasome and caspase-1 activation play a deleterious role in early brain injury and fluoxetine mitigates NLRP3 inflammasome and caspase-1 activation through autophagy activation after SAH, providing a potential therapeutic agent for SAH treatment. PMID- 28903768 TI - Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research. AB - The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically track tumor evolution and to adapt molecularly targeted therapy according to the emergence of tumor clonal variants is shaping modern medical oncology., In order to better describe this new therapeutic paradigm we propose the term "Liquid dynamic medicine" in the place of "Personalized or Precision medicine". Clinical validation of the "Liquid dynamic medicine" approach is best captured by N-of-1 trials where each patient acts as tester and control of truly personalized therapies. PMID- 28903767 TI - Treatment of biofilms in bacterial vaginosis by an amphoteric tenside pessary clinical study and microbiota analysis. AB - BACKGROUND: Bacterial vaginosis (BV) is the most common vaginal syndrome among women in their reproductive years. It is associated with an increased risk of acquiring sexually transmitted infections and complications like preterm labor. BV is characterized by a high recurrence rate for which biofilms frequently found on vaginal epithelial cells may be a reason. RESULTS: Here, we report a controlled randomized clinical trial that tested the safety and effectiveness of a newly developed pessary containing an amphoteric tenside (WO3191) to disrupt biofilms after metronidazole treatment of BV. Pessaries containing lactic acid were provided to the control group, and microbial community composition was determined via Illumina sequencing of the V1-V2 region of the 16S rRNA gene. The most common community state type (CST) in healthy women was characterized by Lactobacillus crispatus. In BV, diversity was high with communities dominated by either Lactobacillus iners, Prevotella bivia, Sneathia amnii, or Prevotella amnii. Women with BV and proven biofilms had an increased abundance of Sneathia sanguinegens and a decreased abundance of Gardnerella vaginalis. Following metronidazole treatment, clinical symptoms cleared, Nugent score shifted to Lactobacillus dominance, biofilms disappeared, and diversity (Shannon index) was reduced in most women. Most of the patients responding to therapy exhibited a L. iners CST. Treatment with WO 3191 reduced biofilms but did not prevent recurrence. Women with high diversity after antibiotic treatment were more likely to develop recurrence. CONCLUSIONS: Stabilizing the low diversity healthy flora by promoting growth of health-associated Lactobacillus sp. such as L. crispatus may be beneficial for long-term female health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02687789. PMID- 28903769 TI - Specific barriers to the conduct of randomised clinical trials on medical devices. AB - BACKGROUND: Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. METHODS: Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. CONCLUSIONS: The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices. PMID- 28903770 TI - A novel bi-directional promoter system allows tunable recombinant protein production in Pichia pastoris. AB - BACKGROUND: The methylotrophic yeast Pichia pastoris is a well-studied host organism for recombinant protein production, which is usually regulated either by a constitutive promoter (e.g. promoter of glyceraldehyde-3-phosphate dehydrogenase; PGAP) or an inducible promoter (e.g. promoter of alcohol oxidase 1; PAOX1). Both promoter systems have several advantages and disadvantages; with one of the main disadvantages being their lack of tunability. Various novel promoter systems, which are either inducible or de-repressed, allowing higher degrees of freedom, have been reported. Recently, bi-directional promoter systems in P. pastoris with two promoter systems regulating recombinant expression of one or more genes were developed. In this study, we introduce a novel bi-directional promoter system combining a modified catalase promoter system (PDC; derepressible and inducible) and the traditional PAOX1, allowing tunable recombinant protein production. RESULTS: We characterized a recombinant P. pastoris strain, carrying the novel bi-directional promoter system, during growth and production in three dynamic bioreactor cultivations. We cloned the model enzyme cellobiohydralase downstream of either promoter and applied different feeding strategies to determine the physiological boundaries of the strain. We succeeded in demonstrating tunability of recombinant protein production solely in response to the different feeding strategies and identified a mixed feed regime allowing highest productivity. CONCLUSION: In this feasibility study, we present the first controlled bioreactor experiments with a recombinant P. pastoris strain carrying a novel bi-directional promotor combination of a catalase promoter variant (PDC) and the traditional PAOX1. We demonstrated that this bi-directional promoter system allows tunable recombinant protein expression only in response to the available C-sources. This bi-directional promoter system offers a high degree of freedom for bioprocess design and development, making bi-directional promoters in P. pastoris highly attractive for recombinant protein production. PMID- 28903771 TI - Novel spatiotemporal analysis of gait changes in body weight supported treadmill trained rats following cervical spinal cord injury. AB - BACKGROUND: Common gait measures such as stride length, cycle time, and step height are not independent variables, but different aspects of the same multidimensional step. This complicates comparisons between experimental groups. Here we present a novel multidimensional gait analysis method and use this method to assess the ability of body weight supported treadmill training (BWSTT) to improve rodent stepping after spinal cord injury (SCI). METHODS: In lieu of reducing a step to a collection of gait measures and comparing the means of several of these, we developed a multidimensional analysis technique that compares the step as a whole. While in a passive robotic gait training device, the pre-injury hindlimb stepping of 108 rats was recorded while they walked in a quadrupedal posture at 8 cm/s. Following a C4/5 over-hemisection spinal cord injury the weekly changes in stepping were tracked for 17 untrained and 10 BWSTT animals for 7 weeks. The performance of trained rats was recorded during training with BWS, as well as at the end of the training week without BWS. An additional six uninjured rats were trained for 5 weeks. RESULTS: Our novel multidimensional analysis shows that stepping is asymmetrically altered 1 week after SCI. The differences in stepping change over the following weeks, with the less impaired left hindlimb deviating further away from pre-injury than the more impaired right hindlimb. Uninjured rats do not significantly alter their stepping over 5 weeks. BWSTT improves the stepping of the right hindlimb, but only when the BWS is active. If the BWS is not present, the performance of trained animals is worse than untrained rats. The left hindlimb performance of BWSTT rats is worse than untrained rats, during both training sessions and weekly assessments. CONCLUSIONS: We feel that our novel multidimensional analysis is a more appropriate method to address the inter-dependencies of gait measures. Untrained rats exhibit both initial impairments as well as the development of compensatory techniques. BWSTT does not improve this spontaneous recovery, but exacerbates it, particularly in the less impaired left hindlimb. PMID- 28903772 TI - Transcranial direct current stimulation (tDCS) for improving capacity in activities and arm function after stroke: a network meta-analysis of randomised controlled trials. AB - BACKGROUND: Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving capacity in activities of daily living (ADL) and upper limb function after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types. METHODS: We performed a systematic review of randomised trials using network meta-analysis (NMA), searching the following databases until 5 July 2016: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of ADL capacity, versus control, after stroke. PROSPERO ID: CRD42016042055. RESULTS: We included 26 studies with 754 participants. Our NMA showed evidence of an effect of cathodal tDCS in improving our primary outcome, that of ADL capacity (standardized mean difference, SMD = 0.42; 95% CI 0.14 to 0.70). tDCS did not improve our secondary outcome, that of arm function, measured by the Fugl-Meyer upper extremity assessment (FM-UE). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events. CONCLUSION: Comparing different forms of tDCS shows that cathodal tDCS is the most promising treatment option to improve ADL capacity in people with stroke. PMID- 28903773 TI - Nutritional quality of meals and snacks assessed by the Food Standards Agency nutrient profiling system in relation to overall diet quality, body mass index, and waist circumference in British adults. AB - BACKGROUND: Studies examining meal and snack eating behaviors in relation to overall diet and health markers are limited, at least partly because there is no definitive consensus about what constitutes a snack, a meal, or an eating occasion. This cross-sectional study examined how nutritional quality of meals and snacks is associated with overall diet quality, body mass index (BMI), and waist circumference. METHODS: Based on 7-d weighed dietary record data, all eating occasions were divided into meals or snacks based on time (meals: 0600 1000, 1200-1500, and 1800-2100 h; snacks: others) or contribution to energy intake (EI) (meals: >=15%; snacks: <15%) in 1451 British adults aged 19-64 years participating in the National Diet and Nutrition Survey. Nutritional quality of meals and snacks was assessed as the arithmetic EI-weighted means of the British Food Standards Agency (FSA) nutrient profiling system score of each food and beverage consumed, based on the contents of energy, saturated fatty acid, total sugar, sodium, fruits/vegetables/nuts, dietary fiber, and protein per 100 g. RESULTS: Irrespective of the definition of meals and snacks, higher FSA scores (lower nutritional quality) of both meals and snacks were associated with unfavorable profiles of individual components of overall diet, including lower intakes of fruits/vegetables/nuts and higher intakes of biscuits/cakes/pastries, total fat, and saturated fatty acid. The FSA scores of meals and snacks were also inversely associated with overall diet quality assessed by the healthy diet indicator (regression coefficient (beta) = -0.22 to -0.17 and -0.06 to -0.03, respectively) and Mediterranean diet score (beta = -0.25 to -0.19 and -0.08 to 0.05, respectively) in both sexes (P <= 0.005). However, the associations were stronger for meals, mainly due to their larger contribution to total EI (64% to 84%). After adjustment for potential confounders, only the FSA score of snacks based on EI contribution was positively associated with BMI and waist circumference in women (P <= 0.005). CONCLUSIONS: Although lower nutritional quality of both meals and snacks assessed by the FSA score was associated with adverse profiles of overall diet quality (but not necessarily adiposity measures), stronger associations were observed for nutritional quality of meals. PMID- 28903774 TI - Triglyceride and glucose (TyG) index as a predictor of incident hypertension: a 9 year longitudinal population-based study. AB - BACKGROUND: Hypertension and the triglyceride and glucose index both have been associated with insulin resistance; however, the longitudinal association remains unclear. This study was designed to investigate the longitudinal association between the triglyceride and glucose index and incident hypertension among the Chinese population. METHODS: We studied 4686 subjects (3177 males and 1509 females) and followed up for 9 years. The subjects were divided into four groups based on the triglyceride and glucose index. Univariate and multivariate Cox regression models were used to analyse the risk factors of hypertension. RESULTS: After 9 years of follow-up, 2047 subjects developed hypertension. The overall 9 year cumulative incidence of hypertension was 43.7%, ranging from 28.5% in quartile 1 to 36.9% in quartile 2, 49.2% in quartile 3 and 59.8% in quartile 4 (p for trend < 0.001). Cox regression analyses indicated that higher triglyceride and glucose index was associated with an increased risk of subsequent incident hypertension. CONCLUSION: The triglyceride and glucose index can predict the incident hypertension among the Chinese population. PMID- 28903775 TI - Nonclinical and clinical pharmacology evidence for cardiovascular safety of saxagliptin. AB - BACKGROUND: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. METHODS: In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo controlled single-ascending-dose study (up to 100 mg); one randomized, double blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). RESULTS: Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment emergent adverse events suggestive of heart failure or myocardial damage were reported. CONCLUSIONS: The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR. PMID- 28903776 TI - Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes. AB - BACKGROUND: To evaluate the effect of insulin treatment on the incidence and/or severity of hepatocellular carcinoma (HCC) in a mouse model of HCC based on diabetes. METHODS: We recently reported that neonatal streptozotocin (STZ) treatment causes type 1 diabetes and subsequent HCC in ddY, Institute for Animal Reproduction (DIAR) mice. Newborn male DIAR mice were divided into three groups based on STZ and insulin (INS) treatment. STZ was subcutaneously injected (60 mg/g) into the STZ-treated group (DIAR-nSTZ mice, N = 13) and the STZ/insulin treated group (DIAR-nSTZ/INS mice, N = 20). A physiologic solution was injected into the control group (DIAR-control mice, N = 8) 1.5 days after birth. Insulin was subcutaneously injected into the DIAR-nSTZ/INS mice according to the following protocol: 2 IU/day at 4-5 weeks of age, 3 IU/day at 5-7 weeks of age, and 4 IU/day at 7-12 weeks of age. All mice were fed a normal diet and were subjected to physiological and histopathological assessments at 12 weeks of age. RESULTS: DIAR-nSTZ mice had significantly lower body weight and higher blood glucose levels than DIAR-control mice, whereas no significant differences were observed between DIAR-nSTZ/INS mice and control mice. At 12 weeks of age, lower weight of paratesticular fat and higher levels of total cholesterol, triglyceride, and free fatty acids were observed in DIAR-nSTZ mice compared to DIAR-control mice, whereas there were no significant differences between DIAR nSTZ/INS mice and DIAR-control mice. In the livers of DIAR-nSTZ mice, HCC was observed in 15% of cases, and dysplastic nodules were observed in 77% of cases. In the livers of DIAR-nSTZ/INS mice, HCC was observed in 39% of cases and dysplastic nodules were observed in 61% of cases (p = 0.011). Moreover, the average tumor size was significantly larger in STZ/INS-treated mice than in STZ treated mice. Immunohistochemical analysis demonstrated that the expression of ERK1/2, downstream substrates of insulin signaling that activate cell proliferation, was significantly higher in STZ/INS-treated mice compared to STZ treated mice. CONCLUSIONS: Insulin treatment promoted, rather than inhibited, the progression of liver carcinogenesis in DIAR-nSTZ mice. Hyperinsulinemia rather than hyperglycemia can accelerate the progression of HCC via insulin signaling. PMID- 28903777 TI - Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial. AB - BACKGROUND: A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains. METHODS: We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones. RESULTS: NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation. CONCLUSIONS: Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection. TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov, under identifier NCT02098590 . PMID- 28903778 TI - JTM advances in uncharted territories: diseases and disorders of unknown etiology. AB - We are delighted to announce a new section in the Journal of Translational Medicine, 'Illnesses of Unknown Etiology'. This section aims to provide a translational medicine forum for the publication of research on illnesses, multisystem diseases and syndromes of unknown etiology. Examples of these include Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia Syndrome. PMID- 28903779 TI - Hepatitis delta: virological and clinical aspects. AB - There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels. PMID- 28903780 TI - Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. AB - BACKGROUND: The accumulation of MWCNTs in the lung environment leads to inflammation and the development of disease similar to pulmonary fibrosis in rodents. Adverse Outcome Pathways (AOPs) are a framework for defining and organizing the key events that comprise the biological changes leading to undesirable events. A putative AOP has been developed describing MWCNT-induced pulmonary fibrosis; inflammation and the subsequent healing response induced by inflammatory mechanisms have been implicated in disease progression. The objective of the present study was to address a key data gap in this AOP: empirical data supporting the essentiality of pulmonary inflammation as a key event prior to fibrosis. Specifically, Interleukin-1 Receptor1 (IL-1R1) and Signal Transducer and Activator of Transcription 6 (STAT6) knock-out (KO) mice were employed to target inflammation and the subsequent healing response using MWCNTs as a model pro-fibrotic stressor to determine whether this altered the development of fibrosis. RESULTS: Wild type (WT) C57BL/6, IL-1R1 (KO) or STAT6 KO mice were exposed to a high dose of Mitsui-7 MWCNT by intratracheal administration. Inflammation was assessed 24 h and 28 days post MWCNT administration, and fibrotic lesion development was assessed 28 days post MWCNT administration. MWCNT-induced acute inflammation was suppressed in IL-1R1 KO mice at the 24 h time point relative to WT mice, but this suppression was not observed 28 days post exposure, and IL-1R1 KO did not alter fibrotic disease development. In contrast, STAT6 KO mice exhibited suppressed acute inflammation and attenuated fibrotic disease in response to MWCNT administration compared to STAT6 WT mice. Whole genome analysis of all post-exposure time points identified a subset of differentially expressed genes associated with fibrosis in both KO mice compared to WT mice. CONCLUSION: The findings support the essentiality of STAT6-mediated signaling in the development of MWCNT-induced fibrotic disease. The IL-1R1 KO results also highlight the nature of the inflammatory response associated with MWCNT exposure, and indicate a system with multiple redundancies. These data add to the evidence supporting an existing AOP, and will be useful in designing screening strategies that could be used by regulatory agencies to distinguish between MWCNTs of varying toxicity. PMID- 28903781 TI - Transmission of alpha-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? AB - Parkinson's disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein alpha-synuclein (alpha-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic alpha-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain alpha syn concentrations ~1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic alpha-syn. Here, we demonstrate that erythrocytes produce alpha-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to alpha-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS alpha-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis. PMID- 28903783 TI - The purification of reduced beta2-glycoprotein I showed its native activity in vitro. AB - BACKGROUND: New evidence has shown that reduced beta2-glycoprotein I (beta2GPI) has anti-oxidative stress and anti-inflammatory activity. However, the details are still poorly understood. This study aims to prepare stable reduced beta2GPI with its native bioactivity in vitro. METHODS: Human beta2GPI was purified from plasma first with perchloric acid precipitation and then purified with a series of chromatography methods including Sephadex G-25 desalting, SP HP, AF-heparin HC 650 M, and Sephacryl S-200. The purified human beta2GPI was reduced with thioredoxin-1 (TRX-1) activated by DL-dithiothreitol (DTT). Glutathione (GSH) was selected to block the free thiols in reduced beta2GPI. LC/MS was used to verify the location of free thiols. Western blot analysis was used to detect beta2GPI immunoreactivity. MTS and flow cytometry were conducted to investigate its biological effect on oxidative-stress-induced death of human umbilical vein endothelial cells (HUVECs). The levels of tumour necrosis factor-alpha (TNF alpha),interleukin-6 (IL-6) interleukin-10 (IL-10),interleukin-12P70 (IL 12P70),interferon-gamma (IFN-gamma) and monocyte chemoattractant protein -1(MCP 1) in mouse serum were quantified to assess its anti-inflammatory activity in lipopolysaccharide (LPS)-mediated systemic inflammation. RESULTS: We obtained approximately 10 mg beta2GPI (purity 98.7%) from 200 ml plasma. The protein yield was 0.05 mg/ml plasma. beta2GPI was then reduced by TRX-1/DTT in vitro; the free thiols were detected on Cys288 and Cys326 in domain V of beta2GPI. The GSH blockage stabilized the reduced beta2GPI in vitro. This reduced beta2GPI can be recognized by the anti-beta2GPI antibody, can significantly reduce the death of HUVECs after H2O2 treatment and can significantly decrease the levels of TNF alpha, IL-6,IFN-gamma and MCP-1 in mice upon LPS stimulation. CONCLUSION: Stable reduced beta2GPI can be obtained in vitro by TRX-1 deoxidation followed by the blockage of thiols with GSH. This reduced beta2GPI maintains the same immunological activity as oxidized beta2GPI and has the ability to counter the oxidative stress induced by H2O2 in HUVECs and inflammation in LPS-mediated inflammation in mice. PMID- 28903784 TI - Outbreaks attributed to pork in the United States, 1998-2015. AB - Each year in the United States, an estimated 525 000 infections, 2900 hospitalizations, and 82 deaths are attributed to consumption of pork. We analyzed the epidemiology of outbreaks attributed to pork in the United States reported to the Centers for Disease Control and Prevention (CDC) 1998-2015. During that period, 288 outbreaks were attributed to pork, resulting in 6372 illnesses, 443 hospitalizations, and four deaths. The frequency of outbreaks attributed to pork decreased by 37% during this period, consistent with a decline in total foodborne outbreaks. However, outbreaks attributed to pork increased by 73% in 2015 (19 outbreaks) compared with the previous 3 years (average of 11 outbreaks per year), without a similar increase in total foodborne outbreaks. Most (>99%) of these outbreaks occurred among people exposed in the same state. The most frequent etiology shifted from Staphylococcus aureus toxin during 1998 2001 (19%) to Salmonella during 2012-2015 (46%). Outbreaks associated with ham decreased from eight outbreaks per year during 1998-2001, to one per year during 2012-2015 (P < 0.01). Additional efforts are necessary to reduce outbreaks and sporadic illnesses associated with pork products. PMID- 28903785 TI - Food insecurity and emotional health in the USA: a systematic narrative review of longitudinal research. AB - OBJECTIVE: To examine the causal directionality in the relationship between food insecurity and emotional well-being among US-based populations. DESIGN: Systematic literature review from January 2006 to July 2016 using MEDLINE (PubMed), PsychInfo, Web of Science and CINHAL. Inclusion criteria were: written in English; examined a longitudinal association between food insecurity and emotional well-being. SETTING: The USA. SUBJECTS: Children and adults. RESULTS: Twelve out of 4161 peer-reviewed articles met inclusion criteria. Three articles examined the effect of emotional well-being on food insecurity, five studies examined the effect of food insecurity on emotional well-being, and four studies examined a bidirectional relationship. Most studies (83 %) reported a positive relationship between negative emotional well-being and food insecurity over time. CONCLUSIONS: Findings suggest a bidirectional association whereby food insecurity increases the risk of poor emotional health, and poor emotional health increases the risk of food insecurity. Better-constructed studies are needed to follow cohorts at risk for both food insecurity and poor emotional health to further understand the mediators and moderators of the relationships. Intervention studies designed to mitigate or reverse risks are also needed to determine best evidence for practice and policy. PMID- 28903782 TI - Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy. AB - BACKGROUND: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. RESULTS: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. CONCLUSIONS: RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. PMID- 28903786 TI - Identifying foods with good nutritional quality and price for the Opticourses intervention research project. AB - OBJECTIVE: People on a limited budget want to know the 'good price' of foods. Here we report the methodology used to produce an educational tool designed to help recognize foods with good nutritional quality and price, and assess the validity and relevancy of the tool. DESIGN: A 'Good Price Booklet' presenting a list of foods with good nutritional quality and price was constructed. The validity of the in-booklet prices was assessed by comparing them with prices actually paid by households from the Opticourses project. The relevancy of the booklet tool was assessed by semi-structured interviews with Opticourses participants. SETTING: Socio-economically disadvantaged neighbourhoods of Marseille, France. SUBJECTS: Ninety-one participants collected household food purchase receipts over a 1-month period. RESULTS: Based on the French food database, foods with higher-than-median nutritional quality were identified. After grouping similar foods, 100 foods were selected and their corresponding in booklet prices were derived based on the distribution of average national prices by food group. Household food purchases data revealed that of the 2386 purchases of foods listed in the booklet, 67.1 % were bought at prices lower than the in booklet prices. Nineteen semi-structured interviews showed that participants understood the tool and most continued using it more than a month after the intervention. CONCLUSIONS: A method was developed to ease the identification of foods with good nutritional quality and price. The Good Price Booklet is an effective tool to help guide people shopping on a low budget. PMID- 28903787 TI - A Preliminary Investigation of Metacognitive Therapy and Habit Reversal as a Treatment for Trichotillomania. AB - BACKGROUND: Not all patients suffering from trichotillomania (TTM) recover completely using CBT and of those that do, only a few maintain their recovery over time. AIMS: The purpose of the present study was to investigate the effectiveness of metacognitive methods combined with habit reversal (MCT/HRT) in trichotillomania with a relatively long-term follow-up. METHOD: A case series (n = 8) and a randomized wait-list controlled trial (n = 34) design were conducted in this study. In the case series, three of the eight patients dropped out of the study. Therefore, TTM-related symptoms were evaluated in five patients suffering from TTM before and after brief metacognitive plus habit reversal therapy during 1-month, 6-month, and 12-month follow-ups. The treatment consisted of detached mindfulness (DM) techniques, ritual postponement and habit reversal training (HRT) in eight sessions. RESULTS: All patients were responders at post-treatment in case series. After the 12-month follow-up, the results were associated with higher pre-treatment levels of self-esteem and global functioning and lower pre treatment levels of depression and anxiety with nearly complete abstinence from hair pulling immediately after treatment. A randomized wait-list controlled trial with experimental (n = 17) and waiting list group (n = 17) was then conducted to confirm the case series results. There were significant differences between the two groups regarding changes in MGH-HPS, Y-BOCS-TM, RSES, GAF, BDI, BAI and self monitoring. Therefore, the MCT/HRT treatment was found to be more effective than the waiting list group. CONCLUSIONS: A combined treatment including metacognitive and habit reversal techniques is remarkably effective in patients with TTM. PMID- 28903788 TI - Vitamin D serostatus and dengue fever progression to dengue hemorrhagic fever/dengue shock syndrome. AB - Vitamin D could modulate pathways leading to dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). We examined the associations of serum total 25-hydroxy vitamin D [25(OH)D] and vitamin D binding protein (VDBP) concentrations in patients with uncomplicated dengue fever (DF) with risk of progression to DHF/DSS. In a case-control study nested in a cohort of DF patients who were followed during the acute episode in Bucaramanga, Colombia, we compared 25(OH)D and VDBP at onset of fever between 110 cases who progressed to DHF/DSS and 235 DF controls who did not progress. 25(OH)D concentrations were also compared between the acute sample and a sample collected >1 year post-convalescence in a subgroup. Compared with 25(OH)D ?75 nmol/l, adjusted odds ratios (95% CI) for progression were 0.44 (0.22-0.88) and 0.13 (0.02-1.05) for 50 to 75 nmol/l (vitamin D insufficiency) and <50 nmol/l (vitamin D deficiency), respectively (P, trend = 0.003). Mean 25(OH)D concentrations were much lower post-convalescence compared with the acute episode, regardless of case status. Compared with controls, mean VDBP was non-significantly lower in cases. We conclude that low serum 25(OH)D concentrations in DF patients predict decreased odds of progression to DHF/DSS. PMID- 28903789 TI - The mind of suicide terrorists. AB - After reviewing the available literature about the main hypotheses on suicide terrorism and the psychological characteristics of terrorists that have been proposed throughout the years, the present authors have put forward some personal considerations on what the distinctive traits of today's suicide bombers might be. In spite of the heterogeneity and paucity of "real" data, it is evident that there is no peculiar familial, educational, or socioeconomic factors that may account for religious radicalization leading to suicide terrorism. On the contrary, some common psychological features can be highlighted: such as isolation, feelings of emptiness, cold rationality, a lack of empathy, and a lust for martyrdom and death. To die to kill: this is the core feature, a sort of organizer that can twist higher cognitive and emotional processes, resulting in the supreme and highly rewarding suicidal and killing behaviors. PMID- 28903790 TI - Virtual Reality Exposure Therapy for the Treatment of Dental Phobia: A Controlled Feasibility Study. AB - BACKGROUND: Virtual reality exposure therapy (VRET) has been used to treat a variety of fears and phobias. AIM: To determine the feasibility (i.e. safety and efficacy) of using VRET to treat dental phobia. METHOD: Safety was evaluated by determining any adverse events or symptom exacerbation. Efficacy of VRET was evaluated by comparing the reduction in dental anxiety scores (measured 16 times within a 14-week study period, and at 6-month follow-up), and its behavioural effects with that of an informational pamphlet (IP) on ten randomized patients with dental phobia using a controlled multiple baseline design. Participants' heart rate response during VRET, and their experience post-VRET, were indexed. RESULTS: No personal adverse events or symptom exacerbation occurred. Visual analysis and post-hoc intention-to-treat analysis showed a significantly greater decrease in dental anxiety scores [higher PND (percentage of non-overlap data) scores of 100% and lower POD (percentage of overlap data) of 0%, Modified Dental Anxiety Scale, F (1,8) = 8.61, p = 0.019, and Dental Fear Scale, F (1,8) = 10.53, p = 0.012], and behavioural avoidance in the VRET compared with the IP group [d = 4.2 and -1.4, respectively). There was no increase in average heart rate during VRET. Of the nine treatment completers, six (four from the VRET group and two from the IP group) no longer had dental phobia at 6-month follow-up. Four of the five VRET participants, but none of the IP participants, scheduled a dental treatment appointment following the intervention. CONCLUSION: VRET is a feasible alternative for patients with dental phobia. PMID- 28903791 TI - An outbreak of mumps with genetic strain variation in a highly vaccinated student population in Scotland. AB - An outbreak of mumps within a student population in Scotland was investigated to assess the effect of previous vaccination on infection and clinical presentation, and any genotypic variation. Of the 341 cases, 79% were aged 18-24. Vaccination status was available for 278 cases of whom 84% had received at least one dose of mumps containing vaccine and 62% had received two. The complication rate was 5.3% (mainly orchitis), and 1.2% were admitted to hospital. Genetic sequencing of mumps virus isolated from cases across Scotland classified 97% of the samples as genotype G. Two distinct clusters of genotype G were identified, one circulating before the outbreak and the other thereafter, suggesting the virus that caused this outbreak was genetically different from the previously circulating virus. Whilst the poor vaccine effectiveness we found may be due to waning immunity over time, a contributing factor may be that the current mumps vaccine is less effective against some genotypes. Although the general benefits of the measles mumps-rubella (MMR) vaccine should continue to be promoted, there may be value in reassessing the UK vaccination schedule and the current mumps component of the MMR vaccine. PMID- 28903792 TI - The Relationship between Competence and Patient Outcome with Low-Intensity Cognitive Behavioural Interventions. AB - BACKGROUND: Little is understood about the relationship between therapist competence and the outcomes of patients treated for common mental health disorders. Furthermore, the evidence is yet to extend to competence in the delivery of low-intensity cognitive behavioural interventions. Understanding this relationship is essential to the dissemination and implementation of low intensity cognitive behavioural interventions. AIMS: The aim of this study was to explore the relationship between Psychological Well-being Practitioner (PWP) competence and patient outcome within the framework of the British government's Improving Access to Psychological Therapies (IAPT) initiative. METHOD: Forty seven PWPs treating 3688 patients participated. Relationships between PWP scores on three observed standardized clinical examinations and reliable change in patients' symptoms of anxiety and depression were explored at two time points: during the year-long training phase, and over a 12-month follow-up. RESULTS: Results indicated that patients treated by qualified PWPs achieved superior outcomes than those treated by trainees. Little support was found for a general association between practitioner competence in delivering low-intensity cognitive behavioural interventions and patient outcome, either during or post-training; however, significantly more patients of the most competent PWPs demonstrated reliable improvement in their symptoms of anxiety and depression than would be expected by chance alone and fewer deteriorated compared with those treated by the least competent PWPs. CONCLUSION: Results were indicative of a complex, non linear relationship, with patient outcome affected by PWP status (trainee or qualified) and by competence at its extremes. The implications of these results for the dissemination and implementation of low-intensity cognitive behavioural interventions are discussed. PMID- 28903793 TI - How Supervisees on a Foundation Course in CBT Perceive a Supervision Session and what they Bring Forward to the Next Therapy Session. AB - BACKGROUND: There is limited research into the effect of supervision in cognitive behavioural therapy (CBT) from the supervisees' perspective. AIMS: The aim of the study was to acquire knowledge from the supervisees' perspective as to what in particular in the supervision process contributes to the therapy process. METHOD: Fourteen supervisees on a foundation course participated in the study. A qualitative approach was used with thematic analysis of the participants' written diaries after supervision and therapy sessions. RESULTS: Analyses of supervisees' experiences suggested that a variety of therapeutic interventions were easier to implement if one had the supervisor's support and felt free to decide if and when the suggested interventions could best be implemented. Evaluation in the form of positive feedback from the supervisor indicating that the supervisee was 'doing the right thing' was perceived to be important. A unifying theme when supervisees felt they were not getting anything out of the supervision was that the supervisees did not have a supervision question. CONCLUSIONS: The results of this research suggest that the supervisor's support during training is perceived to be important for the supervisee. Receiving positive feedback from one's supervisor in an evaluation is perceived to have a great impact on whether the therapist implements the suggested therapeutic interventions discussed in the previous supervision. PMID- 28903794 TI - Effect of dietary nutrients on ileal endogenous losses of threonine, cysteine, methionine, lysine, leucine and protein in broiler chicks. AB - An isotope dose technique was utilized (i) to determine endogenous amino acid (AA) and protein losses and (ii) to propose adjusted values for AA requirements. The endogenous flow rate was calculated from the pool of enrichment in plasma AA, assuming similitude to enrichment of endogenous AA. In experiment 1, chicks were orally administered D4-lysine at 2% of estimated lysine intake from 16 to 24 days to find the isotopic steady state of the atom percent excess (APE) of lysine for plasma and jejunal and ileal digesta. The APE of D4-lysine in plasma, jejunal digesta and ileal digesta reached the isotopic steady state at 5.5, 3.4 and 2.0 days, respectively, by using the broken-line model. It was assumed that the isotopic steady state at 5 days identified for D4-lysine is also representative for the 15N-labeled AA. In experiment 2, chicks were fed diets from 1 to 21 days with increasing levels of fat (6%, 8%, 12%, 13% extract ether), protein (26%, 28.5%, 31% CP) or fiber (14%, 16%, 18% NDF) by adding poultry fat, soybean meal, blended animal protein or barley. Chicks were orally administered 15N-threonine, 15N-cysteine, 15N-methionine, 15N-lysine and 15N-leucine at 2% of estimated daily intake for 5 days from 17 to 21 days of age. Dietary nutrients influenced endogenous losses (EL), where dietary fat stimulated EL of lysine (P=0.06), leucine and protein (P=0.07); dietary protein enhanced EL of leucine and protein; and finally the dietary fiber increased EL of leucine. Dietary nutrients also affected apparent ileal digestibility (AID). Dietary fat increased AID of cysteine but decreased AID of lysine. Dietary protein reduced AID of protein, threonine, lysine and leucine, and similarly dietary fiber decreased AID of protein, threonine, methionine, lysine and leucine. In contrast, dietary fat or protein did not affect real ileal digestibility (RID) of protein and AA except threonine and leucine. The dietary fiber reduced the RID of protein, threonine and leucine. This indicate that variations of some endogenous AA and protein losses due to dietary nutrients almost eliminates the effects of RID, and thus the EL coming from the body should be utilized to adjust the AA requirement instead of changing the true digestible nutrients of ingredients. The present data suggest that 5 days' feeding labeled AA was enough to reach the isotopic steady state and AA requirements should be adjusted when additional dietary protein, fat or fiber is fed. PMID- 28903795 TI - Rapid Triage of Mental Health Risk in Emergency Medical Workers: Findings From Typhoon Haiyan. AB - OBJECTIVE: To determine the ability of a novel responder mental health self triage system to predict post-traumatic stress disorder (PTSD) in emergency medical responders after a disaster. METHODS: Participants in this study responded to Typhoon Haiyan, which struck the Philippines in November 2013. They completed the Psychological Simple Triage and Rapid Treatment (PsySTART) responder triage tool, the PTSD Checklist (PCL-5) and the Patient Health Questionnaire-8 (PHQ-8) shortly after responding to this disaster. The relationships between these 3 tools were compared to determine the association between different risk exposures while providing disaster medical care and subsequent levels of PTSD or depression. RESULTS: The total number of PsySTART responder risk factors was closely related to PCL-5 scores >=38, the threshold for clinical PTSD. Several of the PsySTART risk factors were predictive of clinical levels of PTSD as measured by the PCL-5 in this sample of deployed emergency medical responders. CONCLUSIONS: The presence of a critical number and type of PsySTART responder self-triage risk factors predicted clinical levels of PTSD and subclinical depression in this sample of emergency medical workers. The ability to identify these disorders early can help categorize an at-risk subset for further timely "stepped care" interventions with the goals of both mitigating the long-term consequences and maximizing the return to resilience. (Disaster Med Public Health Preparedness. 2018;12:19-22). PMID- 28903796 TI - Measurement of Fall Prevention Awareness and Behaviours among Older Adults at Home. AB - This study surveyed awareness of, and adherence to, six national fall prevention recommendations among community-dwelling older adults (n = 1050) in Ottawa. Although 76 per cent of respondents agreed falling is a concern and preventable, fewer perceived susceptibility to falling (63%). Respondents had high awareness that home modifications and physical activity can prevent falls. Reported modifications included grab bars (50%), night lights (44%), and raised toilet seats (19%). Half met aerobic activity recommendations; 38 per cent met strength recommendations. Respondents had lower awareness that an annual medication review, annual eye and physical examination, and daily vitamin D supplementation could reduce fall risk. However, reported annual medication review (79%) and eye examination (75%) was high. Nearly half met recommendations for vitamin D intake. These findings suggest a gap in knowledge of awareness and adherence to national recommendations, highlighting the ones that may require attention from those who work to prevent falls. PMID- 28903798 TI - What's the Twist? Twiddler's Syndrome in Deep Brain Stimulation. PMID- 28903797 TI - Prevalence of anti-hepatitis B surface antibodies among children and adolescents vaccinated in infancy and effect of booster dose administered within a pilot study. AB - We determined the prevalence of anti-hepatitis B surface antibodies (anti-HBs) among children and adolescents vaccinated for hepatitis B virus in infancy as part of the routine vaccination programme. A representative serum sample of the Israeli population age 0-19 was tested. In a separate pilot study, a booster dose of hepatitis B vaccine was administered to 31 candidates for national service, who were fully vaccinated in infancy and tested negative for hepatitis B surface antibodies at age 17-19 years and anti-HBs antibodies were assessed 8 weeks later. Of the 1273 samples tested, 631 (49.6%) were positive to anti-HBs antibodies. Seropositivity rates were 89.5% among infants aged 6-12 months and declined significantly with age to 20.7% at age 19 years. No differences in seropositivity rates were observed between Jews and Arabs, males and females and those born in Israel and in other countries. Seroconversion rate among the 31 individuals who received a booster dose was 90.3% (95% CI: 75.1-96.6%). We recommend a booster dose for healthcare personnel before starting to work at the health care facility. PMID- 28903799 TI - A comparison of outcomes according to different diagnostic systems for delirium (DSM-5, DSM-IV, CAM, and DRS-R98). AB - ABSTRACTStudies indicate that DSM-5 criteria for delirium are relatively restrictive, and identify different cases of delirium compared with previous systems. We evaluate four outcomes of delirium (mortality, length of hospital stay, institutionalization, and cognitive improvement) in relation to delirium defined by different DSM classification systems.Prospective, longitudinal study of patients aged 70+ admitted to medical wards of a general hospital. Participants were assessed up to a maximum of four times during two weeks, using DSM-5 and DSM-IV criteria, DRS-R98 and CAM scales as proxies for DSM III-R and DSM III.Of the 200 assessed patients (mean age 81.1, SD = 6.5; and 50% female) during hospitalization, delirium was identified in 41 (20.5%) using DSM-5, 45 (22.5%) according to DSM-IV, 46 (23%) with CAM positive, and 37 (18.5%) with DRS R98 severity score >15. Mortality was significantly associated with delirium according to any classification system, but those identified with DSM-5 were at greater risk. Length of stay was significantly longer for those with DSM-IV delirium. Discharge to a care home was associated only with DRS-R98 defined delirium. Cognitive improvement was only associated with CAM and DSM-IV. Different classification systems for delirium identify populations with different outcomes. PMID- 28903800 TI - Predicting treatment failure, death and drug resistance using a computed risk score among newly diagnosed TB patients in Tamaulipas, Mexico. AB - The purpose of this study was to develop a method for identifying newly diagnosed tuberculosis (TB) patients at risk for TB adverse events in Tamaulipas, Mexico. Surveillance data between 2006 and 2013 (8431 subjects) was used to develop risk scores based on predictive modelling. The final models revealed that TB patients failing their treatment regimen were more likely to have at most a primary school education, multi-drug resistance (MDR)-TB, and few to moderate bacilli on acid fast bacilli smear. TB patients who died were more likely to be older males with MDR-TB, HIV, malnutrition, and reporting excessive alcohol use. Modified risk scores were developed with strong predictability for treatment failure and death (c-statistic 0.65 and 0.70, respectively), and moderate predictability for drug resistance (c-statistic 0.57). Among TB patients with diabetes, risk scores showed moderate predictability for death (c-statistic 0.68). Our findings suggest that in the clinical setting, the use of our risk scores for TB treatment failure or death will help identify these individuals for tailored management to prevent these adverse events. In contrast, the available variables in the TB surveillance dataset are not robust predictors of drug resistance, indicating the need for prompt testing at time of diagnosis. PMID- 28903801 TI - S. aureus Infections in Chicago, 2006-2014: Increase in CA MSSA and Decrease in MRSA Incidence. AB - OBJECTIVE To examine trends in Staphylococcus aureus infections in adults and children at a single academic center in 2006-2014. DESIGN Retrospective cohort study. SETTING Inpatient, outpatient, and emergency department settings in a private, tertiary referral center. PATIENTS Patients with an infection culture that grew S. aureus in January 1, 2006, through March 31, 2014. METHODS The first isolate per year for each patient was classified as community-associated (CA-), healthcare-associated (HA-), or HA-community-onset S. aureus. The incidence density of S. aureus, methicillin-susceptible S. aureus (MSSA), and methicillin resistant S. aureus (MRSA) infections were calculated per quarter year. RESULTS Overall, 5,491 MRSA and 5,398 MSSA isolates were included. MRSA infections decreased by an average of 5.2% annually (P<.001). MRSA skin and soft-tissue infection (SSTI) incidence density decreased in adults (-3.5%; P<.001) and children (-2.9%; P=.004). MSSA infections at all anatomic sites increased by an average of 1.9% annually (P=.007) in adults and decreased 5.1% annually (P<.001) in children. MSSA SSTI incidence density increased in adults (+3.8%; P<.001) and children (+5.6%; P<.001). For MRSA and MSSA SSTI isolates, susceptibility to tetracycline and clindamycin decreased significantly. CONCLUSIONS In 2006-2014, MRSA SSTI incidence decreased among children and adults. MSSA SSTI incidence density increased in children and adults, suggesting that current empiric SSTI treatment recommendations may not be optimal. Adults experienced an overall increase in MSSA infections, which may prompt consideration of the need for horizontal infection control practices to decrease MSSA infection risk. Infect Control Hosp Epidemiol 2017;38:1226-1234. PMID- 28903802 TI - Can National Healthcare-Associated Infections (HAIs) Data Differentiate Hospitals in the United States? AB - OBJECTIVE To determine whether patients using the Centers for Medicare and Medicaid Services (CMS) Hospital Compare website (http://medicare.gov/hospitalcompare) can use nationally reported healthcare associated infection (HAI) data to differentiate hospitals. DESIGN Secondary analysis of publicly available HAI data for calendar year 2013. METHODS We assessed the availability of HAI data for geographically proximate hospitals (ie, hospitals within the same referral region) and then analyzed these data to determine whether they are useful to differentiate hospitals. We assessed data for the 6 HAIs reported by hospitals to the Centers for Disease Control and Prevention (CDC). RESULTS Data were analyzed for 4,561 hospitals representing 88% of registered community and federal government hospitals in the United States. Healthcare-associated infection data are only useful for comparing hospitals if they are available for multiple hospitals within a geographic region. We found that data availability differed by HAI. Clostridium difficile infections (CDI) data were most available, with 82% of geographic regions (ie, hospital referral regions) having >50% of hospitals reporting them. In contrast, 4% of geographic regions had >50% of member hospitals reporting surgical site infections (SSI) for hysterectomies, which had the lowest availability. The ability of HAI data to differentiate hospitals differed by HAI: 72% of hospital referral regions had at least 1 pair of hospitals with statistically different risk-adjusted CDI rates (SIRs), compared to 9% for SSI (hysterectomy). CONCLUSIONS HAI data generally are reported by enough hospitals to meet minimal criteria for useful comparisons in many geographic locations, though this varies by type of HAI. CDI and catheter associated urinary tract infection (CAUTI) are more likely to differentiate hospitals than the other publicly reported HAIs. Infect Control Hosp Epidemiol 2017;38:1167-1171. PMID- 28903803 TI - A Blueprint for Targeted Antimicrobial Stewardship in Neonatal Intensive Care Units. PMID- 28903805 TI - Recombinant human C1 esterase inhibitor for acute hereditary angioedema attacks with upper airway involvement. AB - BACKGROUND: Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treatment of hereditary angioedema (HAE) in adolescents and adults. HAE attacks that involve the upper airway can be life threatening, and data on the administration of rhC1-INH for these types of attacks are currently limited. OBJECTIVE: To evaluate the efficacy and safety of rhC1-INH for treatment of acute HAE attacks with upper airway involvement. METHODS: A pooled analysis of data from three clinical trials with open-label extensions examined rhC1-INH for treatment of acute HAE attacks with upper airway involvement. Patients with functional plasma C1 esterase inhibitor <50% of normal who had experienced an acute upper airway HAE attack and received rhC1-INH were identified retrospectively based on severity of breathing or swallowing symptoms. The primary end point was the time to beginning of relief (time at which the overall visual analog scale score [0-100 mm] decreased from baseline by >=20 mm for two consecutive time points [persistence]). RESULTS: Of 683 acute HAE attacks treated with rhC1-INH, data for 45 attacks with upper airway involvement were included. The median time to the beginning of symptom relief was 67 minutes (95% confidence interval, 60-120 minutes) and did not differ by attack number or by baseline breathing or swallowing symptom severity. Most attacks (91.1%) achieved the beginning of relief within 4 hours of rhC1-INH treatment. All attacks resolved without the need for any additional medication, and no patients required intubation or tracheostomy. Treatment with rhC1-INH was well tolerated, with no adverse events reported in more than one patient (except HAE reported as an adverse event [n = 2]). CONCLUSION: This pooled analysis of clinical trial data supports the efficacy of rhC1-INH for treatment of acute HAE attacks with upper airway involvement. PMID- 28903804 TI - Beyond the dinner table: who's having breakfast, lunch and dinner family meals and which meals are associated with better diet quality and BMI in pre-school children? AB - OBJECTIVE: Having frequent family dinners is associated with better diet quality in children; however, it is unknown whether the frequency of certain family meal types (i.e. dinner) is more strongly associated with better child weight and diet quality compared with other meal types (i.e. breakfast, lunch). Thus, the current study examined the frequency of eating breakfast, lunch or dinner family meals and associations with pre-school children's overall diet quality (HEI-2010) and BMI percentile. DESIGN: Cross-sectional baseline data (2012-2014) from two randomized controlled childhood obesity prevention trials, NET-Works and GROW, were analysed together. SETTING: Studies were carried out in community and in home settings in urban areas of Minnesota and Tennessee, USA. SUBJECTS: Parent child (ages 2-5 years) pairs from Minnesota (n 222 non-Hispanics; n 312 Hispanics) and Tennessee (n 545 Hispanics; n 55 non-Hispanics) participated in the study. RESULTS: Over 80 % of families ate breakfast or lunch family meals at least once per week. Over 65 % of families ate dinner family meals >=5 times/week. Frequency of breakfast family meals and total weekly family meals were significantly associated with healthier diet quality for non-Hispanic pre school children (P<0.05), but not for Hispanic children. Family meal frequency by meal type was not associated with BMI percentile for non-Hispanic or Hispanic pre school children. CONCLUSIONS: Breakfast family meal frequency and total weekly family meal frequency were associated with healthier diet quality in non-Hispanic pre-school children but not in Hispanic children. Longitudinal research is needed to clarify the association between family meal type and child diet quality and BMI percentile. PMID- 28903806 TI - Development of an Accurate and Sensitive Analytical Method for the Determination of Cadmium at Trace Levels Using Dispersive Liquid-Liquid Microextraction Based on the Solidification of Floating Organic Drops Combined with Slotted Quartz Tube Flame Atomic Absorption Spectrometry. AB - A dispersive liquid-liquid microextraction (DLLME) technique based on a solidification-of-floating-organic-drop (SFOD) procedure was developed for the determination of trace amounts of cadmium (Cd) by using a flame atomic absorption spectrometer (FAAS) fitted with a slotted quartz tube (SQT). The extraction of Cd was achieved by forming a complex with diphenylcarbazone. Parameters affecting the formation of complex and extraction outputs were carefully optimized to obtain high-absorbance signals to achieve lower LODs. An SQT was fitted on top of the flame burner head to further enhance the absorbance of the signals recorded by the FAAS. Coupling the DLLME-SFOD procedure with SQT-FAAS produced an enhancement factor of about 183. The LOD of the method was 0.23 ug/L with an RSD of 3.8%. Matrix-matching was used to overcome any low recovery results obtained with tap water and municipal wastewater. PMID- 28903807 TI - Editorial. PMID- 28903808 TI - Active-shooter events in the workplace: Findings and policy implications. AB - Employees and citizens generally view places of business as inherently safe. Business leaders sometimes make hasty security decisions in hopes of protecting their employees and customers. Leadership should have empirical data to aid in the decision-making process. This paper provides an exhaustive breakdown of active-shooter events in the workplace. The data are disaggregated by business function (eg retail, factory/warehouse, and office space) and include information on the shooter, the event itself, and how the event was resolved. The analyses are followed up by an in-depth discussion of potential policy changes supported by the data. PMID- 28903809 TI - Decision-making in crisis: Applying a healthcare triage methodology to business continuity management. AB - The concept of triage in healthcare has been around for centuries and continues to be applied today so that scarce resources are allocated according to need. A business impact analysis (BIA) is a form of triage in that it identifies which processes are most critical, which to address first and how to allocate limited resources. On its own, however, the BIA provides only a roadmap of the impacts and interdependencies of an event. When disaster strikes, organisational decision makers often face difficult decisions with regard to allocating limited resources between multiple 'mission-critical' functions. Applying the concept of triage to business continuity provides those decision-makers navigating a rapidly evolving and unpredictable event with a path that protects the fundamental priorities of the organisation. A business triage methodology aids decision-makers in times of crisis by providing a simplified framework for decision-making based on objective, evidence-based criteria, which is universally accepted and understood. When disaster strikes, the survival of the organisation depends on critical decision-making and quick actions to stabilise the incident. This paper argues that organisations need to supplement BIA processes with a decision-making triage methodology that can be quickly applied during the chaos of an actual event. PMID- 28903810 TI - Effective crisis decision-making. AB - When an organisation's reputation is at stake, crisis decision-making (CDM) is challenging and prone to failure. Most CDM schemes are strong at certain aspects of the overall CDM process, but almost none are strong at all of them. This paper defines criteria for good CDM schemes, analyses common approaches and introduces an alternative, stakeholder-driven scheme. Focusing on the most important stakeholders and directing any actions to preserve the relationships with them is crucial. When doing so, the interdependencies between the stakeholders must be identified and considered. Without knowledge of the sometimes less than obvious links, wellmeaning actions can cause adverse effects, so a cross-check for the impacts of potential options is recommended before making the final decision. The paper also gives recommendations on how to implement these steps at any organisation in order to enhance the quality of CDM and thus protect the organisation's reputation. PMID- 28903811 TI - Does integration matter? A holistic model for building community resilience in Pakistan. AB - This paper analyses an integrated communitybased risk reduction model adopted by the Pakistan Red Crescent. The paper analyses the model's constructs and definitions, and provides a conceptual framework and a set of practical recommendations for building community resilience. The study uses the process of outcome-based resilience index to assess the effectiveness of the approach. The results indicate that the integrated programming approach is an effective way to build community resilience as it offers a number of tangible and longlasting benefits, including effective and efficient service delivery, local ownership, sustainability of results, and improved local resilience with respect to the shock and stress associated with disaster. The paper also outlines a set of recommendations for the effective and efficient use of the model for building community resilience in Pakistan. PMID- 28903812 TI - The capability and constraint model of recoverability: An integrated theory of continuity planning. AB - While there are best practices, good practices, regulations and standards for continuity planning, there is no single model to collate and sort their various recommended activities. To address this deficit, this paper presents the capability and constraint model of recoverability - a new model to provide an integrated foundation for business continuity planning. The model is non-linear in both construct and practice, thus allowing practitioners to remain adaptive in its application. The paper presents each facet of the model, outlines the model's use in both theory and practice, suggests a subsequent approach that arises from the model, and discusses some possible ramifications to the industry. PMID- 28903813 TI - Rebooting healthcare information technology downtime management. AB - Healthcare, like many other industries, has become reliant on technology to manage daily operations. Often, technology downtimes are managed within the information technology departments to ensure the technical staff can return the hardware or software to the end users as quickly as possible. However, if managed strictly through IT departments, such incidents lack critical communication components and an understanding of the impact on end users. This paper argues that such technological incidents need to be managed not just rapidly but also in conjunction with the emergency preparedness department. It presents the example of a healthcare system from the US Midwest where the IT department has worked closely with the emergency preparedness department to design a major incident management system that closely resembles the hospital incident command structure. The development and implementation of this process has improved several metrics, including time to declare (declaration of an incident) and mean time to restore (returning the technology back to the end users). This paper will describe how this collaboration between information technology and emergency preparedness has improved the impact on healthcare operations, and will highlight the metrics used to monitor success. PMID- 28903814 TI - Academic continuity planning in higher education. AB - Crisis planning in institutions of higher learning has focused largely on emergency management, physical safety and technology recovery. While these are clearly important, many aspects of planning for continuity have largely been ignored, including planning for the post-secondary education sector's core business, that is, the delivery of graduate and undergraduate academic programmes. Use of the term 'academic continuity' as a component of institutional planning is relatively new in higher education. Discussions on academic continuity have often centred on the use of technology-enhanced education and online teaching in the event of crisis or disaster affecting campuses. However, online approaches are only one aspect of academic continuity planning. Using examples of two different crisis situations encountered at a large urban university spanning three campuses, this paper presents an approach to academic continuity planning that can potentially serve as a model for other institutions. PMID- 28903816 TI - Publication of Negative Data Contributes to Sound Science. PMID- 28903815 TI - Determining the appropriate strategies for emergency planning through AHP-SWOT. AB - During an unexpected incident, companies should demonstrate appropriate behaviour based on predetermined and rehearsed emergency strategies. This paper describes how to select the proper strategies for emergency situations via means of the AHP SWOT tool, where the initial SWOT analysis is conducted for the emergency management system, and the final strategies are selected via the analytic hierarchy process (AHP). Alternative response strategies comprise internal, shared and external responses. Most of the scenarios investigated for this study demanded a shared response. These findings highlight the importance of mutual aid agreements, cooperative exercises and the improvement of communication systems. Organisations can take advantage of integrated approaches to select the best strategies and tactics for normal situations in general and emergency situations in particular. PMID- 28903817 TI - Properly Describing Individually Ventilated Caging Systems in Scientific Manuscripts. PMID- 28903818 TI - Responses to Drs Perkins' and Lipman's Letter to the Editor. PMID- 28903819 TI - Review of CO2 as a Euthanasia Agent for Laboratory Rats and Mice. AB - Selecting an appropriate, effective euthanasia agent is controversial. Several recent publications provide clarity on the use of CO2 in laboratory rats and mice. This review examines previous studies on CO2 euthanasia and presents the current body of knowledge on the subject. Potential areas for further investigation and recommendations are provided. PMID- 28903820 TI - Considerations When Writing and Reviewing a Higher Education Teaching Protocol Involving Animals. AB - The targeted use of animals in teaching at institutions of higher learning is fundamental to educating the next generation of professionals in the biologic and animal sciences. As with animal research, universities and colleges that use animals in teaching are subject to regulatory oversight. Instructors must receive approval from their IACUC before using animals in their teaching. However, the questions asked on many institutions' animal care and use protocol (ACUP) are often geared more toward the use of animals for research. These questions may not be wholly appropriate in evaluating a teaching protocol; some questions are not applicable (for example, power analysis to justify animal numbers) whereas other important questions may be missing. This article discusses the issues surrounding the rationale for animal use in teaching; it also proposes a framework that instructors and IACUC members alike can use when writing and reviewing teaching ACUP. We hope this framework will help to ensure the most appropriate IACUC review of the ethical use of animals in higher education. PMID- 28903821 TI - Age- and Sex-associated Differences in Phenotypic and Functional Characteristics of Peripheral Blood Lymphocytes in Chimpanzees (Pan troglodytes). AB - Chimpanzees are the closest phylogenetic relatives to humans, sharing more than 98% genetic sequence identity. These genetic similarities prompted the belief that chimpanzees can serve as an ideal model for human disease conditions and vaccine development. However, in light of the recent NIH decision to phase out biomedical research in chimpanzees and retire NIH-supported chimpanzees, data from the present study will continue to provide value for the care of aged and sick chimpanzees located in zoos, sanctuaries, and primate centers. Surprisingly little information has been published regarding the normal chimpanzee immune system, and most extant studies have been based on small numbers of animals. In the current study, we provide a better understanding of the chimpanzee immune system with regard to age and sex. We examined immune parameters of chimpanzees (n = 94; 51 female, 43 male; age, 6 to 47 y) by using flow cytometry, immune function analysis, and cytokine analysis. Because lymphocytes are key mediators of cellular immune responses, particularly to intracellular pathogens such as viruses, we surveyed the phenotypic and functional attributes of T and B lymphocytes in this healthy and age-stratified population of chimpanzees. We noted a significantly higher percentage of CD16+T cells in male compared with female chimpanzees but no significant changes in percentages of CD3+, CD4+, CD8+, or CD4+CD8+ T cells with age or sex. In addition, aging was associated with decreased proliferative responses to mitogens in both sexes. Sex-specific differences also were present in the percentage of NK cells but not in their cytotoxic activity and in circulating cytokine levels in plasma. Going forward, the data presented here regarding immune cell changes associated with aging in healthy chimpanzees will serve to enhance the care of geriatric and ill animals. PMID- 28903822 TI - Evaluation of a Zinc Gluconate Neutralized with Arginine Product as a Nonsurgical Method for Sterilization of Rhesus Macaques (Macaca mulatta). AB - Because rhesus macaques (Macaca mulatta) are prolific breeders, overpopulation can be problematic in both research and feral populations. Currently, the most effective contraceptive methods are hormonal control in female macaques and vasectomies in males. These methods each come with innate challenges, the foremost being the alteration of necessary hormonal patterns. In this study, we assessed the use of zinc gluconate neutralized with arginine as a novel, nonsurgical alternative to male contraception in 12 rhesus macaques. This FDA approved product for dogs is given as a one-time, intratesticular injection to cause permanent infertility yet theoretically spare the testosterone-producing Leydig cells of the testis. CBC counts, serum biochemistry analyses, testosterone levels, and testicular widths were evaluated at the time of injection and at 1 wk, 1 mo, 2 mo, or 3 mo afterward. Daily postinjection observations revealed transient scrotal enlargement in 8 of the 12 macaques but no indications of pain. In addition, full necropsies including testicular histopathology were assessed at study endpoints. Although some portion of every testis had evidence of seminiferous tubule loss, normal spermatogenesis was present in 22 of the 24 testes. In conclusion, chemical castration with the tested zinc gluconate neutralized with arginine product is not an effective method for sterilization of male rhesus macaques. PMID- 28903823 TI - Results of Survey Regarding Prevalence of Adventitial Infections in Mice and Rats at Biomedical Research Facilities. AB - Control of rodent adventitial infections in biomedical research facilities is of extreme importance in assuring both animal welfare and high-quality research results. Sixty-three U.S. institutions participated in a survey reporting the methods used to detect and control these infections and the prevalence of outbreaks from 1 January 2014 through 31 December 2015. These results were then compared with the results of 2 similar surveys published in 1998 and 2008. The results of the current survey demonstrated that the rate of viral outbreaks in mouse colonies was decreasing, particularly in barrier facilities, whereas the prevalence of parasitic outbreaks has remained constant. These results will help our profession focus its efforts in the control of adventitial rodent disease outbreaks to the areas of the greatest needs. PMID- 28903824 TI - Pharmacokinetic Profiles of Nalbuphine after Intraperitoneal and Subcutaneous Administration to C57BL/6 Mice. AB - Mice undergo a variety of procedures that necessitate the use of analgesic agents. Opioids are often essential to successful pain management plans, but most are controlled substances, and their use requires appropriate federal and state registrations. Nalbuphine is a potentially effective opioid analgesic for mice that is not currently classified as a controlled substance. This compound has received little attention as an analgesic for mice, and standard dosage regimens have not been developed. Here we compared the pharmacokinetic profiles of 10 mg/kg nalbuphine in male C57BL/6 mice subcutaneous or intraperitoneal administration. Blood was collected from 3 mice per treatment at 5, 10, 20, and 30 min and 1, 2, 3, 6, 12, and 24 h after administration. Plasma concentrations were measured, and standard pharmacokinetic parameters were calculated. Profile characteristics for each route of administration were similar, with significant differences in plasma concentration at 5 and 30 min and 1 and 3 h. Nalbuphine was absorbed more quickly when administered subcutaneously (Tmax, 5 min) than intraperitoneally (Tmax, 10 min), whereas the drug's half-life was similar between the intraperitoneal (0.94 h) and subcutaneous (1.12 h) routes. The AUC0 tldc and AUC0-inf were higher but the apparent clearance and apparent volume of distribution were lower after subcutaneous administration compared with intraperitoneal dosing. Plasma concentrations were below the level of detection by 12 h. These results suggest that nalbuphine is absorbed in and eliminated quickly from mice, making it a possible candidate for acute pain management. PMID- 28903825 TI - Pharmacokinetics of Single-dose Subcutaneous Meloxicam Injections in Black-tailed Prairie Dogs (Cynomys ludovicianus). AB - This study evaluated the pharmacokinetic profile of a single dose of meloxicam (1.0 mg/kg) administered subcutaneously (n = 6) or intravenously (n = 2) to black tailed prairie dogs (Cynomys ludovicianus). Blood was collected immediately before (time 0) and at 0.5, 1, 2, 4, 8, 12 and 24 h after drug administration. Plasma meloxicam concentrations were quantified with HPLC-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. The peak plasma concentrations, time to peak plasma concentration, and terminal half-life of meloxicam after subcutaneous administration (median [minimum-maximum]) were 4.30 (3.00-4.89) MUg/mL, 2.00 (0.62-4.00) h, and 11.88 (7.35-18.64) h, respectively. Plasma concentrations of meloxicam for prairie dogs in the present study showed high absorption and slow elimination after drug administration. The results of this study suggest that a 1.0-mg/kg SC dose of meloxicam administered every 24 h might be excessive for prairie dogs, although the ideal therapeutic dose in terms of safety and efficacy is unknown in this species. PMID- 28903826 TI - Comparison of 6 Injectable Anesthetic Regimens and Isoflurane in Gray Short tailed Opossums (Monodelphis domestica). AB - Gray short-tailed opossums are used in a wide variety of research in the areas of developmental biology, oncology, immunology, and comparative biology. Despite many frequent experimental manipulations of these animals under anesthesia, few studies to date have characterized the effects of anesthesia in this species. Our aim was to identify safe and effective injectable anesthetic combinations using ketamine and xylazine or ketamine and dexmedetomidine at doses of 40 mg/kg to 100 mg/kg for ketamine, 5 mg/kg to 10 mg/kg for xylazine, and 0.05 mg/kg to 0.1 mg/kg for dexmedetomidine. Effects of the proposed regimens ranged from light sedation to surgical anesthesia, but only 100 mg/kg ketamine + 0.1 mg/kg dexmedetomidine induced surgical anesthesia in all opossums, with a mean duration of 25.4 min. The 2 lowest doses of ketamine and xylazine (40 mg/kg ketamine + 5 mg/kg xylazine and 40 mg/kg ketamine + 10 mg/kg xylazine) achieved sedation to light anesthesia in all animals but did not produce a surgical plane of anesthesia in any animal. All regimens that induced a surgical plane of anesthesia caused bradycardia and bradypnea, and 75 mg/kg ketamine + 10 mg/kg xylazine and 100 mg/kg ketamine + 0.1 mg/kg dexmedetomidine caused the greatest decreases in SpO2. Except for one opossum that died of unknown causes, all animals remained healthy and apparently free of anesthetic complications. Among all treatments, isoflurane delivered by a precision vaporizer provided the most consistent and reliable anesthesia; therefore, we recommend inhalant anesthesia over the injectable combinations used in this study. PMID- 28903827 TI - Pharmacokinetics of a Transdermal Fentanyl Solution in Suffolk Sheep (Ovis aries). AB - Sheep used as surgical models require appropriate pain management, and the commonly used transdermal fentanyl patches require a long predosing period to achieve adequate plasma concentrations. The aim of this study was to assess the pharmacokinetic parameters of an FDA-approved transdermal fentanyl solution (TFS) that has yet to be tested in sheep. In this study, we compared TFS at 2.7 mg/kg (n = 2), 1.7 mg/kg (n = 3), and 0.5 mg/kg (n = 3) with the control fentanyl patch at 2 MUg/kg/h (n = 1); both products were applied topically to the intrascapular region. Plasma concentrations showed significant interanimal variability. Severe adverse effects occurred at both 2.7 and 1.7 mg/kg TFS and mild to moderate adverse effects were noted at 0.5 mg/kg. At all 3 doses, TFS had greater maximal concentration, clearance rate, and volume of distribution; shorter time to maximal concentration; and similar half-lives to those of the patch. In addition, we validated the use of a commercial human fentanyl ELISA kit, which positively correlated with the liquid chromatography-mass spectroscopy data, but absolute values did not match. Overall, at all 3 dosages tested (0.5, 1.7, and 2.7 mg/kg), TFS delivered fentanyl plasma concentrations that exceeded the minimal effective concentration; however, adverse effects were noted at all 3 dosages. Caution and further study are required before the use of TFS in sheep can be recommended fully. PMID- 28903828 TI - Pharmacokinetics of Single-bolus Subcutaneous Cefovecin in C57BL/6 Mice. AB - Because of its extended half-life, cefovecin is a broad-spectrum cephalosporin antibiotic commonly used to treat dermatitis in dogs and cats. A single injection in dogs can yield an effective plasma concentration for as long as 14 d, depending on the strain of Staphylococcus and for as long as 7 d in cats for the treatment of Pasteurella multocida. In the laboratory animal setting, C57BL/6 mice are commonly affected with dermatologic conditions that make these animals unsuitable for experiments. Therefore, we performed this pharmacokinetic study to determine whether cefovecin would be of benefit in mice. Plasma levels of the drug were determined by HPLC. For this study, single-bolus subcutaneous dosages of 8 and 40 mg/kg were assessed. The results showed that the dosage of 40 mg/kg achieved a maximal plasma concentration of 411.54 MUg/mL with a half-life of 0.84 h, whereas 8 mg/kg yielded 78.18 MUg/mL and 1.07 h respectively. The pharmacokinetic results suggest that cefovecin is not suitable as a long-acting antibiotic after a single subcutaneous bolus injection in mice for the treatment of dermatitis or any other bacteria sensitive to this medication. PMID- 28903829 TI - Quantification of Induced Hypothermia from Aseptic Scrub Applications during Rodent Surgery Preparation. AB - Laboratory mice (Mus musculus) are prone to develop hypothermia during anesthesia for surgery, thus potentially impeding anesthetic recovery, wound healing, and future health. The core body temperatures of isoflurane-anesthetized mice are influenced by the choice of supplemental heat sources; however, the contribution of various surgical scrubs on the body temperatures of mice under gas anesthesia has not been assessed. We sought to quantify the effect of using alcohol (70% isopropyl alcohol [IPA]) compared with saline to rinse away surgical scrub on the progression of hypothermia in anesthetized mice (n = 47). IPA, room-temperature saline, or warmed saline (37 degrees C) was combined with povidone-iodine and then assessed for effects on core (rectal) and surface (infrared) temperatures. Agents were applied to a 2*2-cm shaved abdominal area of mice maintained on a water-recirculating blanket (at 38 degrees C) under isoflurane anesthesia (1.5% to 2.0% at 0.6 L/min) for 30 min. Although all scrub regimens significantly decreased body temperature at the time of application, treatments that included povidone-iodine led to the coldest core temperatures, which persisted while mice were anesthetized. Compared with room-temperature saline and when combined with povidone-iodine, warming of saline did not ameliorate heat loss. IPA alone demonstrated the most dramatic cooling of both surface and core readings at application but generated an unanticipated warming (rebound) phase during which body temperatures equilibrated with those of controls within minutes of application. Although alcohol is inappropriate as a stand-alone agent for surgical skin preparation, IPA is a viable alternative to saline-based rinses in this context, and its use should be encouraged within institutional guidance for rodent surgical procedures without concern for prolonged hypothermia in mice. PMID- 28903831 TI - Abstracts of Scientific Papers 2017 AALAS National Meeting. PMID- 28903830 TI - An Efficient, Simple, and Noninvasive Procedure for Genotyping Aquatic and Nonaquatic Laboratory Animals. AB - Various animal models are indispensible in biomedical research. Increasing awareness and regulations have prompted the adaptation of more humane approaches in the use of laboratory animals. With the development of easier and faster methodologies to generate genetically altered animals, convenient and humane methods to genotype these animals are important for research involving such animals. Here, we report skin swabbing as a simple and noninvasive method for extracting genomic DNA from mice and frogs for genotyping. We show that this method is highly reliable and suitable for both immature and adult animals. Our approach allows a simpler and more humane approach for genotyping vertebrate animals. PMID- 28903832 TI - Validation of Modifications to the ANSR for Listeria Method for Improved Internal Positive Control Performance. AB - A study was conducted to validate a minor reagent formulation change to the ANSR for Listeria method, Performance Tested MethodSM 101202. This change involves increasing the master mix volume prelyophilization by 40% and addition of salmon sperm DNA (nontarget DNA) to the master mix. These changes improve the robustness of the internal positive control response and reduce the possibility of obtaining invalid results due to weak-positive control curves. When three foods (hot dogs, Mexican-style cheese, and cantaloupe) and sponge samples taken from a stainless steel surface were tested, no significant differences in performance between the ANSR and U.S. Food and Drug Administration Bacteriological Analytical Manual or U.S. Department of Agriculture-Food Safety and Inspection Service Microbiology Laboratory Guidebook reference culture procedures were observed for any of the matrixes as determined by probability of detection analysis. Inclusivity and exclusivity testing yielded 100% expected results for target and nontarget bacteria. Accelerated stability testing was carried out over a 7 week period and showed no decrease in assay performance over time. PMID- 28903833 TI - Resolution and Quantitation of Triamcinolone Acetonide and Its Coformulated Drug in the Presence of Its Impurities and Degradation Products by HPTLC and HPLC. AB - Two specific, sensitive, and precise stability-indicating chromatographic methods have been developed for the determination of triamcinolone acetonide (TMC) and its coformulated drug, econazole nitrate (ECZ), in the presence of TMC impurities and degradation products. The first method was based on HPTLC-spectrodensitometry in which resolution and quantitation was achieved by using silica gel 60 F254 HPTLC plates and an ethyl acetate-tetrahydrofuran-ammonia mobile phase (10.0 + 7.0 + 0.1, v/v/v). The second method was a reversed-phase HPLC method in which separation was achieved using an acetonitrile-methanol-0.05 M potassium dihydrogen phosphate mobile phase, pH 3.0 (25.0 + 15.0 + 60.0, v/v/v). In both methods, the separated components were detected at 225 nm. Validation of both methods was conducted in compliance with International Conference on Harmonization (ICH) guidelines, and system suitability was confirmed. The linearity ranges were 0.20-28.00 and 0.50-55.00 ug/band for TMC and ECZ by HPTLC, whereas for HPLC, the range was 0.05-30.00 and 1.00-40.00 ug/mL for both drugs, respectively. The methods were successfully applied for the analysis of a pharmaceutical formulation and were compared with the reported method with no significant difference. PMID- 28903834 TI - Radiologic Surveillance of Patients with Viral Hepatitis. PMID- 28903835 TI - Soyabean Oil Supplementation Effects on Perivascular Inflammation in Lungs Induced by Bisphenol A: A Histological Study. AB - OBJECTIVE: To determine the effect of soyabean oil supplementation on perivascular inflammation in lungs of adult mice induced by Bisphenol A(BPA). STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Anatomy, Army Medical College, Rawalpindi, in collaboration with the Animal House, National Institute of Health, Islamabad, from June to November 2016. METHODOLOGY: Thirty male and female BALB/c mice were divided into three groups, of 10 animals each. Group Aanimals served as control. Group B animals were given BPAat a dose of 50 mg/Kg body weight/day. Group C animals were given BPAand soyabean oil at doses of 50 mg/Kg body weight/day and 500 mg/day, respectively. All treatments were given once daily for a period of eight weeks. Animals were dissected 24 hours after receiving the last dose. Lung tissue specimen processing and H&E staining was carried out for routine histological study. Perivascular inflammation was morphometrically graded and statistically analysed using Chi square test with p<0.05. RESULTS: Grade 2 inflammation was recorded in two (20%) animals and grade 3 perivascular inflammation in 80% specimens in Group B; whereas 20% specimens of Group C had grade 2 inflammation and eight (80%) showed grade 1 inflammation. None of the control animals showed any inflammation. All groups were significantly different at p<0.001. CONCLUSION: BPAproduced perivascular inflammation and con-commitant administration of soyabean oil diet protected against it in rodent. PMID- 28903836 TI - Reconsidering a Lower Level of Follicle-Stimulating Hormone as Abnormal in Sub Fertile Males of Pakistan. AB - OBJECTIVE: To assess the association between Follicle-Stimulating Hormone (FSH) and semen parameters in order to evaluate whether the current laboratory reference for abnormal FSH levels should be readjusted. STUDY DESIGN: Observational, cross-sectional study. PLACE AND DURATION OF STUDY: Infertility Clinic of Gynecology Unit 1, Civil Hospital, Karachi, from May 2015 to April 2016. METHODOLOGY: The study included 100 sub-fertile males inducted from the clinic. Those above 45 years of age, with hypo gonadotrophic hypogonadism, and those on anabolic steroids were excluded. After history and examination, semen parameters and FSH levels were tested. Abnormal semen values were based on WHO 1999 criteria. Data was analyzed by SPSS 17 and mean, frequencies and percentages were calculated. Chi-square test was applied to check association between variables. RESULTS: The FSH levels had a significant association with abnormal semen sperm concentration, motility and morphology but not with semen volume (p=0.246). The mean FSH level was 5.8 +/-1.80 IU/Lwith two-thirds of individuals having value >4.5 IU/L. Frequency of semen abnormalities increased as the level of FSH increased. CONCLUSION: There is significantly an increased possibility of abnormal semen characteristics at FSH levels >4.5, so the current reference level should be lowered down and adjusted again. PMID- 28903837 TI - Impact of Different Treatment Modalities on the Outcome of Pancreatic Cancer. AB - OBJECTIVE: To analyze overall survival patterns of our pancreatic cancer patient population managed with a curative or palliative intent. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from January 2000 till February 2015. METHODOLOGY: Aretrospective review of the data of all of our pancreatic cancer patients was performed, using the hospital information system. Patients with tumor other than adenocarcinoma or a histopathologic diagnosis not made at our hospital are excluded from the study, along with patients having an incomplete medical record for all included variables. The main outcome measure was overall survival in months from the date of diagnosis. All results were segregated and analyzed according to the intervention modality used, i.e. group A: surgery with curative intent, group B: Palliative chemotherapy, and group C: Supportive care. Results were controlled for the confounding variables including age, gender, significant comorbid conditions, stage of disease at initial presentation, tumor location, and histological grade. RESULTS: Among the 197 patients fulfilling the inclusion criteria, 21 (10.7%) were excluded as they were lost to follow-up. Overall Kaplan Meier survival analysis gave a 56% one-year survival, 22% at 3- and 16% at 5 year. The subset analysis on Cox-regression survival plot showed inferior survival with advancing stage of the disease and a treatment less than definitive surgical resection and adjuvant chemotherapy. On Cox-proportional regression analysis, stage of the disease and treatment modality were only independent predictive factors for overall survival (p < 0.01). CONCLUSION: Stage for stage, surgery with curative intent (group A) or palliative chemotherapy (group B) showed a trend towards improved survival as compared to supportive management (group C) alone. The results were more significant for surgical resection arm. PMID- 28903838 TI - Prognostic Potential of N-Cadherin in Oral Squamous Cell Carcinoma via Immunohistochemical Methods. AB - OBJECTIVE: To assess the prognostic potential for N-cadherin in oral squamous cell carcinoma and oral epithelial dysplasia. STUDY DESIGN: Across-sectional study, analytical study. PLACE AND DURATION OF STUDY: Maharishi Markandeshwar College of Dental Science Research (MMCDSR), Ambala, India, from 2011 to 2014. METHODOLOGY: Immunohistochemistry was used to observe the N-cadherin expression in 100 cases having epithelium with normal oral mucosa, oral epithelial dysplastic lesions and oral squamous cell carcinoma (OSCC). For statistical significance, SPSS 13.0 was used to calculate the data by Mann-Whitney and Kruskal-Wallis tests. RESULTS: In OSCC, N-cadherin expression was more evident than in oral epithelial dysplasia followed by the normal oral epithelium that did not show any dysplastic changes (p=0.001). Conversely, N-cadherin expression was not significant among the histological grade of OSCC. CONCLUSION: N-cadherin can be used as a potential biomarker for early diagnosis of OSCC. However, the N cadherin expression did not show any correlation with the histological grade of OSCC. PMID- 28903839 TI - Comparison of Cognitive Professionalism in Residents of Public and Private Hospitals of Karachi. AB - OBJECTIVE: To evaluate and compare the cognitive professionalism in resident medical officers (RMOs) of public and private hospitals of Karachi. STUDY DESIGN: Across-sectional survey. PLACE AND DURATION OF STUDY: Civil Hospital and Ziauddin Medical University Clifton Campus, Karachi, from August to December 2014. METHODOLOGY: This survey was conducted in one public and one private medical college. All residents from Gynecology and Obstetrics, Medicine and Surgery departments were included with non-probability purposive sampling. Avalidated tool (Barry Challenges to Professionalism questionnaire) was used to assess professionalism, containing six challenges to professionalism (acceptance of gifts, conflict of interest, confidentiality, physician impairment, sexual harassment, and honesty) with multiple-choice responses. Data was analyzed with SPSS version 17 and chi-square test was used for determining significant difference between public and private institutes. RESULTS: Forty-three residents from both the places responded. The frequency of acceptable answers to the six scenarios ranged from 0% to 55.8%. Acceptable responses were more from private sector institute residents than public-sector residents, but no statistical significant difference was seen. CONCLUSION: Most residents did not provide appropriate responses to professional challenges. The postgraduate training programs are very stringent on medical knowledge and skills. However, it is needed to address formally professional attitudes and behaviors and include them as a competency in the training program. PMID- 28903840 TI - Burr Hole Aspiration of Brain Abscess in Children with Cyanotic Heart Disease. AB - OBJECTIVE: To determine the efficacy of burr hole aspiration of brain abscess in children with cyanotic heart disease in terms of number of aspirations and residual abscess. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Pediatric Neurosurgery at The Children's Hospital and The Institute of Child Health, Multan, from July 2010 to June 2014. METHODOLOGY: Pediatric patients of cyanotic heart disease with brain abscess were admitted. After taking history, clinical examination and necessary investigation, aspiration of abscess through a burr hole was performed. Data was collected through pre-designed proforma. Analysis of results was performed and comparison was made through statistical package for social sciences (SPSS-20). RESULTS: Total number of patients were 50 with 31 (62%) male and 19 (38%) female children. Patients' age ranged from 5-10 years with mean age of 7.44 +/-1.11 years. Single abscess in supra tentorial was commonly found in 44 (88%) patients. Multiple abscesses were present in 4 (8%) patients. Cerebellum was involved in 2 (4%) patients. Abscess was completely aspirated in single attempt in 37 (74%) patients, two attempts in 9 (18%) patients, and three attempts in 4 (8%) patients. No bacterial growth on culture was reported in 32 (64%) patients. Culture was positive in 18 (36%) patients. Postoperative hematoma developed in 2 (4%) patients. No mortality was reported in early postoperative period. CONCLUSION: Aspiration of brain abscess in children with cyanotic heart disease through a burr hole is safe and successful. PMID- 28903841 TI - Anatomical Outcome Following Indocyanine Green Assisted Internal Limiting Membrane Peeling for Stage 3 and 4 Macular Hole Surgery. AB - OBJECTIVE: To evaluate the anatomical success of stage 3 and 4 macular hole surgery after removal of internal limiting membrane (ILM) with the help of Indocyanine green (ICG). STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: LRBTTertiary Care Eye Hospital, Karachi, October 2015 to August 2016. METHODOLOGY: Twenty patients with stage 3 and 4 macular hole (confirmed by spectral domain optical coherence tomography) underwent standard 3 ports pars plana vitrectomy. Staining of ILM was performed with the help of 0.5% ICG to aid in visualization. ILM was removed by using intraocular forceps in circular fashion. Finally, gas fluid exchange with internal tamponade of SF6 20% was performed. Postoperative face down posture was maintained for seven days. Patients were followed-up for 8 months and assessment of macular hole closure was done using SD-OCT. RESULTS: After a follow-up of 8 months, macular hole was closed in 17 eyes (85%) and vision had improved in 6 patients. Postoperative complications included cataract, hyphema and vitreous hemorrhage. CONCLUSION: Surgery for stage 3 and 4 macular hole with ILM peeling has high anatomical success rate. Final visual acuity is dependent on preoperative macular hole stage and visual acuity at presentation. PMID- 28903842 TI - Effect of Early <= 3 Mets (Metabolic Equivalent of Tasks) of Physical Activity on Patient's Outcome after Cardiac Surgery. AB - OBJECTIVE: To determine the effect of <3 Mets (Metabolic Equivalent of Tasks) of physical activity on zero postoperative days for improving hemodynamic and respiratory parameters of patients after cardiac surgeries. STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: BARMWTHospital, Rawalpindi, from March to August 2015. METHODOLOGY: Arandomized controlled trial was conducted on 174 CABG and valvular heart disease patients undergoing cardiac surgical procedures. After selection of sample via non-probability purposive sampling, they were randomly allocated into interventional group (n=87) and control group (n=87). Treatment protocol for experimental group was <=3 Mets of physical activity, i.e. chest physiotherapy, sitting over edge of bed, standing and sitting on chair at bedside, on zero postoperative day but the control group was treated with conventional treatment on first postoperative day. Pre- and post treatment assessment was done in control and interventional groups on both zero and first postoperative days. Data was analyzed on SPSS version 21. RESULTS: The patients' mean age was 51.86 +/-13.76 years. Male to female ratio was 132:42. Statistically significant differences in respiratory rate and SpO2 (p=0.000 and 0.000, respectively) were found between both groups. Among ABG's, PCO2 and pH showed significant differences with p values of 0.039 and <0.001, respectively. No significant differences were observed between both groups regarding electrolytes (Na+, K+, Cl-, p-values of 0.361, 0.575 and 0.120 respectively) and creatinine (p=0.783). Marked improvement in oxygen saturation, dyspnea and a fall in systolic BPwas seen in interventional group. There was also observed to be a reduction in the length of ICU stay among interventional group patients as frequency with percentage of total stay was compared to control group. CONCLUSION: Early physical activity (<=3 METS) post-cardiac surgeries prevent respiratory complications through improvement in dyspnea, respiratory rate, and oxygen saturation. PMID- 28903843 TI - Causes and Adverse Impact of Physician Burnout: A Systematic Review. AB - OBJECTIVE: To review the significant causes and effects of physician burnout in published literature. METHODOLOGY: Asystematic review was conducted for searching published literature on the causes and effects of burnout in three online databases. Inclusion and exclusion criteria were developed for final selection of papers. The selected papers were critically appraised and thematic analysis was done to identify major themes related to physician burnout. RESULTS: Thirty-one papers were finally selected among the 2,828 identified studies. The thematic analysis revealed demographic factors, e.g. age, gender, marital status, specialty and job position; and organizational factors, e.g. workload, interpersonal demands, job insecurity and lack of resources, as significant causes of burnout. The consequences of burnout included individual and organizational effects. The individual effects of burnout included physical health problems; while organizational effects included poor job performance, low organizational commitment, and turnover intentions. CONCLUSION: Burnout is a recognized workplace hazard in the healthcare sector. The individual characteristics of physicians and working environment within hospitals are contributory factors of burnout. Therefore, proactive interventions should be taken at individual and institutional levels for preventing physician burnout by improving the personal lifestyle of physician and working environment in hospitals. PMID- 28903844 TI - Bone Marrow Involvement in Metastatic Pediatric Ewing Sarcoma. AB - OBJECTIVE: To evaluate the frequency of bone marrow involvement with metastatic lung and bone sites in newly-diagnosed pediatric patients with Ewing sarcoma (ES). STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan, from January 2010 to October 2015. METHODOLOGY: Newly-diagnosed pediatric-age patients with ES were inducted. Ten patients were excluded because bone marrow aspiration/biopsy (BMAB) was not done. Patients'medical records were reviewed for data collection of age, diagnosis, tumor volume, bone marrow diagnosis, metastatic work-up and outcomes. RESULTS: Atotal of 139 patients with median age of 12 years were identified. The median volume of tumors was 529 ml. Eleven patients had bone marrow (BM) disease involvement. Five (45.5%) had bone metastatic disease and 1 (9%) had both pulmonary and bone metastases. Four patients (31.1%) with positive BM had primary limb disease. CONCLUSION: Ewing sarcoma patients with bone metastatic disease have a higher frequency of BM involvement. However, BM can be involved without metastatic disease. BMAB should still be considered at staging for newly diagnosed pediatric patients with localized ES. PMID- 28903845 TI - New Maneuver in Robotic Single-Port Cholecystectomy. AB - The need to integrate aspects of functional, psychosocial and cosmetic impairment into medical care is increasingly accepted among the physicians and the patients. For these reasons, single-port robotic surgery emerges as the most advanced approach using the technology. In this study, authors used a new robotic dissector with monopolar electrocautery feature in order to determine the device's safety and efficacy. Between January 2015 and February 2016, 10 out of 11 consecutive cholecystectomies were included in the study. There was no significant differences in port placement and docking time between two groups (p=0.382, p=0.789). The time spent by surgeon was significantly shorter in group 2 (p=0.005). Using robotic dissector with monopolar cautery significantly shortened the console time. This new instrument (Maryland monopolar dissector) provides more feasible and faster dissection of the Calot's triangle, supporting further the advantages of robotic single-site cholecystectomy. PMID- 28903846 TI - Ileocolonic Basidiobolomycosis in a Child: An Unusual Fungal Infection. AB - Systemic basidiobolomycosis is a rare fungal infection caused by Basidiobolus rararum (B. rararum). The clinical presentation is non-specific and is similar to many gastrointestinal conditions such as Crohn's disease (CD). The most consistent findings of basidiobolomycosis are recurrent abdominal pain, weight loss, fever and peripheral eosinophilia. Most of the patients are diagnosed on surgical resection of the involved region along with compatible histopathological findings like transmural inflammation, granulomas with eosinophilic infiltration (Splendore-Hoeppli phenomenon) and more specifically detection of fungal hyphae on fungal stains. Effective and curative treatment for systemic basidiobolomycosis is available, if diagnosed and managed properly in time. We report here a Saudi boy who had ileo-caecal basidiobolomycosis, but diagnosed after a prolonged course of illness. PMID- 28903847 TI - Dengue Hemorrhagic Fever: ARare Cause of Acute Liver Failure. AB - Acute liver failure (ALF) is an acute medical emergency which carries high mortality without liver transplantation. Various hepatotropic viruses, drug induced liver injury, auto immune hepatitis, and metabolic liver diseases are the commonly implicated etiologic agents. Liver involvement in dengue hemorrhagic fever (DHF) is quite common, but acute liver failure is its rare complication. Neurological complications are also commonly seen in DHF. Ateenage girl presented with high grade fever and subconjunctival hemorrhage, and later developed jaundice due to acute liver failure. Liver transplantation could not be offered due to fungemia. During hospital stay, she had seizures and intracranial hemorrhage culminating in brain death. ALF with neurological involvement is a rare but very important and fatal complication of DHF; and it should be considered as a cause of acute liver failure, especially in endemic areas. PMID- 28903848 TI - Prosthetic Rehabilitation of a Partially Edentulous Patient with Maxillary Acquired Defect by a Two-Piece Hollow Bulb Obturator (Using a Dentogenic Concept). AB - Patients may face functional, aesthetic, and social distress because of the palatal defects. Prosthetic rehabilitation of maxillectomy or developmental defect can be challenging for prosthodontists. Prognosis of the prosthetic appliances can be affected not only by patients' own ability to adapt to the prosthesis but also by the factors like the remaining teeth, bony structure, and existing mucosa. Maxillary defects are usually developed by surgical intercession of the benign or malignant conditions and trauma cases. Speech, mastication and aesthetics can be hampered by any extent of palatal defect. During obturation of palatal/maxillectomy defects, the primary intent of the prosthodontist should be the shutting of the maxillectomy defect and parting of the oral cavity from the sinonasal openings by use of different bulb designs. In the present case, dentogenic concept has been applied while fabricating the two-piece hollow bulb obturator for restoration of the defect. Well known fact about the gravitational force is that it acts on maxillary obturator and reduces its retentive qualities, this can be counteracted to some extent by making the obturator hollow. Dentogenic concept is the skill, training, and procedure of generating the chimera of natural teeth in artificial teeth during prosthodontic restorations. PMID- 28903849 TI - Acute Complete Adult-onset Kawasaki Disease in a Middle-Aged Woman. AB - A 55-year-old Chinese lady was diagnosed with acute complete Kawasaki disease (KD) in January 2015. To our knowledge, this patient was the first described woman who was over 50 years and fulfilled all the characteristics of acute complete KD. The patient had a striking result on the 26th day since this disease onset after the initiation of treatment of immunoglobulin (IG) and aspirin; and did not have any complications up to now. The purpose of this case report was to raise the awareness of KD in the middle-aged persons and the therapeutic schedules, as there is no valid therapeutic therapeutic for adults with KD. PMID- 28903851 TI - Circulation of RNY-Derived Small RNAs: Novel Diagnostic Biomarker for CAD. PMID- 28903850 TI - Comparison of Oxacillin and Cefoxitin for the Detection of mecAGene to Determine Methicillin Resistance in Coagulase Negative Staphylococci(CoNs). AB - The aim of the study was to compare the effectiveness of Cefoxitin with that of Methicillin/Oxacillin in the determination of mecAgene in Methicillin resistant Coagulase-negative staphylococci(CoNS). We assessed 57 CoNS isolates for mecA gene via PCR, which were subsequently subjected to Methicillin/Oxacillin and Cefoxitin disc diffusion test. These methods are simple, inexpensive and easily available compared to PCR despite less specificity. Out of 41 mecApositive species, 33 (80.5%) were resistant to Methicillin/Oxacillin. Cefoxitin-resistance was seen in all 41 (100%) mecApositive samples. Two (12.5%) mecAnegative isolates of S.saprophyticuswere Methicillin/Oxacillin resistant, but were Cefoxitin sensitive. Four (9.7%) isolates of S.saprophyticus, three (7.3%) of S.epidermidisspecies, and one (2.4%) S.haemolyticusthat were mecApositive were sensitive to Methicillin/Oxacillin but resistant to Cefoxitin. Cefoxitin resistance provides a more accurate picture of mecAgene positivity as compared to Methicillin and Oxacillin. PMID- 28903852 TI - Prilocaine-induced Methemoglobinemia. PMID- 28903853 TI - Single Umbilical Artery. PMID- 28903854 TI - Controversies in Management of Hemorrhagic Stroke and Rehabilitation Challenges in Pakistan. PMID- 28903855 TI - Acute Copper Sulphate Poisoning. PMID- 28903856 TI - Triphenylamine-based hypercrosslinked organic polymer as adsorbent for the extraction of phenylurea herbicides. AB - A hypercrosslinked organic polymer material (named as PPTPA) was prepared by a simple one-step self-polycondensation of triphenylamine. A series of characterization experiments, including N2 adsorption, scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectra, and thermogravimetric analysis, were carried out to evaluate the morphology, structure and other intrinsic properties of the PPTPA. To investigate its adsorption performance, the PPTPA was used as the solid-phase extraction adsorbent for the extraction of phenylurea herbicides from water, milk and tomato juice samples followed by high-performance liquid chromatographic analysis. Under optimum conditions, good linearity for the analytes was observed in the range of 0.05-40.0ngmL-1, 0.1-40.0ngmL-1 and 0.5-40.0ngmL-1 for water, milk and tomato juice samples, respectively. The established method also showed low limits of detection (S/N=3) in the range of 0.008-0.01ngmL-1, 0.01-0.03ngmL-1 and 0.05 0.1ngmL-1 for water, milk and tomato juice samples, respectively. The possible adsorption mechanism of the PPTPA towards the analytes was investigated, and the results demonstrated that the hydrogen bonding was the main interaction force between the PPTPA and the analytes. It suggests that the PPTPA can serve as a promisingadsorbent for the efficient pre-enrichment of organic compounds with more hydrogen-bonding donor sites. PMID- 28903857 TI - Commentary on: Treatment of laryngopharyngeal reflux using a sleep positioning device: A prospective cohort study. PMID- 28903858 TI - Submarine canyons along the upper Sardinian slope (Central Western Mediterranean) as repositories for derelict fishing gears. AB - By means of ROV surveys, we assessed the quantity, composition and bathymetric distribution of marine litter in 17 sites along the Sardinian continental margin (Central Western Mediterranean) at depths ranging from 100 to 480m. None of the investigated sites was litter free, but the mean density of litter (0.0175+/ 0.0022itemsm-2) was lower than that reported from other Tyrrhenian regions. The difference in the total litter density among sites was negligible, but the density of derelict fishing gear (DFG) items (most of which ascribable to small scale fishery) in submarine canyons was higher in submarine canyons than in other habitats. Our result suggest that submarine canyons (known to be highly vulnerable ecosystems) act as major repositories of DFGs, and, therefore, we anticipate the need of specific measures aimed at minimizing the loss and abandonment of DFGs in submarine canyons. PMID- 28903859 TI - Immune-mediated neurological syndromes: Old meets new. PMID- 28903860 TI - A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements. AB - To date, there are 80 synthetic PDE-5i found as adulterants in dietary supplements. Analogues of sildenafil remain as the top list with 50 (62%) and are followed by analogues of tadalafil, 21 (26%), analogues of vardenafil, 7 (9%) and others, 2 (3%). The sildenafil group can be sub-categorized into sulphonamide bonded (24, 48%), acetyl-bonded (11, 22%), carbonyl or thiocarbonyl-bonded (8, 16%) and other types (7, 14%) based on the functional group linked to pyrazolopyrimidine-one moieties. Meanwhile, analogues of tadalafil have become popularly found as adulterants in dietary supplements like beverages and herbal extracts from 2015 to 2016. The uptrend has been observed with the increase in number and complexity with more trans-oriented and dimerized tadalafil analogues being reported. Interestingly, there is no much increase for analogues of vardenafil. About two thirds of analogues have been reported from the Asian countries (67%), followed by Europe (22%) and North America (11%). South Korea and Singapore have reported the most number of analogues with a total number of 40 (50%). One plausible contributing factor to this trend is the convenient purchase of sexual enhancement dietary supplements, especially the on-line purchase. In terms of analytical methodologies, high performance liquid chromatography (HPLC) hyphenated to ultra-violet (UV) and/or mass spectrometry (MS) detection have been preferred in the screening analysis, i.e. 70 out of 77 compounds have been analysed by HPLC-UV. In addition, the electrospray ionization multistage fragmentation experiments (ESI-MSn) for acquiring low- and high resolution mass spectra have been successfully applied to detect and quantify PDE 5i in adulterated products simultaneously. Nuclear magnetic resonance (NMR) is another important technique in the structural elucidation of novel analogues. PMID- 28903861 TI - A decision support system and rule-based algorithm to augment the human interpretation of the 12-lead electrocardiogram. AB - BACKGROUND: The 12-lead Electrocardiogram (ECG) has been used to detect cardiac abnormalities in the same format for more than 70years. However, due to the complex nature of 12-lead ECG interpretation, there is a significant cognitive workload required from the interpreter. This complexity in ECG interpretation often leads to errors in diagnosis and subsequent treatment. We have previously reported on the development of an ECG interpretation support system designed to augment the human interpretation process. This computerised decision support system has been named 'Interactive Progressive based Interpretation' (IPI). In this study, a decision support algorithm was built into the IPI system to suggest potential diagnoses based on the interpreter's annotations of the 12-lead ECG. We hypothesise semi-automatic interpretation using a digital assistant can be an optimal man-machine model for ECG interpretation. OBJECTIVES: To improve interpretation accuracy and reduce missed co-abnormalities. METHODS: The Differential Diagnoses Algorithm (DDA) was developed using web technologies where diagnostic ECG criteria are defined in an open storage format, Javascript Object Notation (JSON), which is queried using a rule-based reasoning algorithm to suggest diagnoses. To test our hypothesis, a counterbalanced trial was designed where subjects interpreted ECGs using the conventional approach and using the IPI+DDA approach. RESULTS: A total of 375 interpretations were collected. The IPI+DDA approach was shown to improve diagnostic accuracy by 8.7% (although not statistically significant, p-value=0.1852), the IPI+DDA suggested the correct interpretation more often than the human interpreter in 7/10 cases (varying statistical significance). Human interpretation accuracy increased to 70% when seven suggestions were generated. CONCLUSION: Although results were not found to be statistically significant, we found; 1) our decision support tool increased the number of correct interpretations, 2) the DDA algorithm suggested the correct interpretation more often than humans, and 3) as many as 7 computerised diagnostic suggestions augmented human decision making in ECG interpretation. Statistical significance may be achieved by expanding sample size. PMID- 28903862 TI - In a stable battlefield, avoid using austere surgical units to meet the golden hour of trauma time to care goal. PMID- 28903863 TI - Effectiveness trials in asthma: time to SaLSA? PMID- 28903865 TI - Economic evaluation of the eradication program for bovine viral diarrhea in the Swiss dairy sector. AB - Since 2008, the Swiss veterinary service has been running a mandatory eradication program for Bovine Viral Diarrhea (BVD) that is focused on detecting and eliminating persistently infected (PI) animals. Detection was initially based on antigen testing from ear tag samples of the entire cattle population, followed by antigen testing of all newborn calves until 2012. Since then, bulk milk serology (dairy herds) and blood sample serology (beef herds) have been used for the surveillance of disease-free herds. From 2008 to 2012, the proportion of newborn PI calves decreased from 1.4% to less than 0.02%. However, this success was associated with substantial expenditures. The aim of this study was to conduct an economic evaluation of the BVD eradication program in the Swiss dairy sector. The situation before the start of the program (herd-level prevalence: 20%) served as a baseline scenario. Production models for three dairy farm types were used to estimate gross margins as well as net production losses and expenditures caused by BVD. The total economic benefit was estimated as the difference in disease costs between the baseline scenario and the implemented eradication program and was compared to the total eradication costs in a benefit-cost analysis. Data on the impact of BVD virus (BVDV) infection on animal health, fertility and production parameters were obtained empirically in a retrospective epidemiological case-control study in Swiss dairy herds and complemented by literature. Economic and additional production parameters were based on benchmarking data and published agricultural statistics. The eradication costs comprised the cumulative expenses for sampling and diagnostics. The economic model consisted of a stochastic simulation in @Risk for Excel with 20,000 iterations and was conducted for a time period of 14 years (2008-2021). The estimated annual financial losses in BVDV infected herds were CHF 85-89 per dairy cow and CHF 1337-2535 for an average farm, depending on the production type. The median net present value (NPV) was estimated at CHF 44.9 million (90% central range: CHF 13.4 million-69.4 million) and the break-even point to have been reached in 2015. Overall, the outcomes demonstrate that the Swiss BVD eradication program results in a net benefit for the dairy sector. These findings are relevant for planning similar BVD control programs in other countries. PMID- 28903866 TI - A Bayesian latent class model to estimate the accuracy of pregnancy diagnosis by transrectal ultrasonography and laboratory detection of pregnancy-associated glycoproteins in dairy cows. AB - Accurate diagnosis of pregnancy is an essential component of an effective reproductive management plan for dairy cattle. Indirect methods of pregnancy detection can be performed soon after breeding and offer an advantage over traditional direct methods in not requiring an experienced veterinarian and having potential for automation. The objective of this study was to estimate the sensitivity and specificity of pregnancy-associated glycoprotein (PAG) detection ELISA and transrectal ultrasound (TRUS) in dairy cows of South Africa using a Bayesian latent class approach. Commercial dairy cattle from the five important dairy regions in South Africa were enrolled in a short-term prospective cohort study. Cattle were examined at 28-35days after artificial insemination (AI) and then followed up 14days later. At both sampling times, TRUS was performed to detect pregnancy and commercially available PAG detection ELISAs were performed on collected serum and milk. A total of 1236 cows were sampled and 1006 had complete test information for use in the Bayesian latent class model. The estimated sensitivity (95% probability interval) and specificity for PAG detection serum ELISA were 99.4% (98.5, 99.9) and 97.4% (94.7, 99.2), respectively. The estimated sensitivity and specificity for PAG detection milk ELISA were 99.2% (98.2, 99.8) and 93.4% (89.7, 96.1), respectively. Sensitivity of veterinarian performed TRUS at 28-35days post-AI varied between 77.8% and 90.5% and specificity varied between 94.7% and 99.8%. In summary, indirect detection of pregnancy using PAG ELISA is an accurate method for use in dairy cattle. The method is descriptively more sensitive than veterinarian-performed TRUS and therefore could be an economically viable addition to a reproductive management plan. PMID- 28903864 TI - Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised controlled trial. AB - BACKGROUND: Evidence for management of asthma comes from closely monitored efficacy trials done in highly selected patient groups. There is a need for randomised trials that are closer to usual clinical practice. METHODS: We did an open-label, randomised, controlled, two-arm effectiveness trial at 74 general practice clinics in Salford and South Manchester, UK. Patients aged 18 years or older with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy were randomly assigned to initiate treatment with a once-daily inhaled combination of either 100 MUg or 200 MUg fluticasone furoate with 25 MUg vilanterol or optimised usual care and followed up for 12 months. The primary endpoint was the percentage of patients who achieved an asthma control test (ACT) score of 20 or greater or an increase in ACT score from baseline of 3 or greater at 24 weeks (termed responders), in patients with a baseline ACT score less than 20 (the primary effectiveness analysis population). All effectiveness analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01706198. FINDINGS: Between Nov 12, 2012, and Dec 16, 2016, 4725 patients were enrolled and 4233 randomly assigned to initiate treatment with fluticasone furoate and vilanterol (n=2114) or usual care (n=2119). 1207 patients (605 assigned to usual care, 602 to fluticasone furoate and vilanterol) had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1399 in the usual care group; odds ratio [OR] 2.00 [95% CI 1.70-2.34], p<0.0001). At week 24, the adjusted mean ACT score increased by 4.4 points from baseline in patients initiated with fluticasone furoate and vilanterol, compared with 2.8 points in the usual care group (difference 1.6 [95% CI 1.3-2.0], p<0.0001). This result was consistent for the duration of the study. Pneumonia was uncommon, with no differences between groups; there was no difference in other serious adverse events between the groups. INTERPRETATION: In patients with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined fluticasone furoate and vilanterol improved asthma control without increasing the risk of serious adverse events when compared with optimised usual care. FUNDING: GlaxoSmithKline. PMID- 28903867 TI - Detection accuracy of Renibacterium salmoninarum in Chinook salmon, Oncorhynchus tshawytscha (Walbaum) from non-lethally collected samples: Effects of exposure route and disease severity. AB - Bacterial kidney disease (BKD), caused by Renibacterium salmoninarum, threatens salmonid populations throughout the Northern hemisphere. Many fishery regulatory authorities require ongoing disease monitoring in hatcheries and spawning runs prior to gamete collection to prevent BKD outbreaks and spread. According to diagnostic protocols of the American Fisheries Society-Fish Health Section, monitoring for R. salmoninarum generally consists of lethal sampling of visceral organs from fish. However, non-lethal sampling would be preferable, especially for valuable broodstock or endangered species. In this study, non-lethal sampling methods were evaluated for their ability to detect R. salmoninarum in Chinook salmon (Oncorhynchus tshawytscha) that were experimentally infected via two different routes (e.g., intraperitoneal injection and waterborne immersion) to mimic acute and chronic disease courses. Non-lethal (e.g., blood, mucus, and a urine/feces mixture) and lethal (e.g., kidney and spleen homogenate) samples were collected from challenged and mock-challenged Chinook salmon and the presence of R. salmoninarum was assessed by culture on modified kidney disease medium, nested polymerase chain reaction (nPCR), and semi-quantitative enzyme-linked immunosorbent assay (ELISA). Sensitivity, specificity, and accuracy of lethal and non-lethal samples in detecting R. salmoninarum were calculated using receiver operating characteristic (ROC) analyses. For ROC analyses, true disease status was evaluated under two different assumptions: 1) that lethal samples represented the true disease status and 2) that all experimentally challenged fish were truly infected. We found that sensitivity and specificity of non-lethal samples depended upon time of sampling after experimental infection, sample type, and R. salmoninarum exposure route. Uro-fecal samples had the greatest potential as non lethal samples compared to mucus and blood. In terms of future monitoring, combining lethal samples tested by ELISA assay with uro-fecal samples tested by nPCR could be the best strategy for detecting R. salmoninarum prevalence in a population as it reduces the overall number of fish required for sampling. PMID- 28903868 TI - Predicting farm-level animal populations using environmental and socioeconomic variables. AB - Accurate information on the geographic distribution of domestic animal populations helps biosecurity authorities to efficiently prepare for and rapidly eradicate exotic diseases, such as Foot and Mouth Disease (FMD). Developing and maintaining sufficiently high-quality data resources is expensive and time consuming. Statistical modelling of population density and distribution has only begun to be applied to farm animal populations, although it is commonly used in wildlife ecology. We developed zero-inflated Poisson regression models in a Bayesian framework using environmental and socioeconomic variables to predict the counts of livestock units (LSUs) and of cattle on spatially referenced farm polygons in a commercially available New Zealand farm database, Agribase. Farm level counts of cattle and of LSUs varied considerably by region, because of the heterogeneous farming landscape in New Zealand. The amount of high quality pasture per farm was significantly associated with the presence of both cattle and LSUs. Internal model validation (predictive performance) showed that the models were able to predict the count of the animal population on groups of farms that were located in randomly selected 3km zones with a high level of accuracy. Predicting cattle or LSU counts on individual farms was less accurate. Predicted counts were statistically significantly more variable for farms that were contract grazing dry stock, such as replacement dairy heifers and dairy cattle not currently producing milk, compared with other farm types. This analysis presents a way to predict numbers of LSUs and cattle for farms using environmental and socio-economic data. The technique has the potential to be extrapolated to predicting other pastoral based livestock species. PMID- 28903869 TI - Interventions to reduce non-typhoidal Salmonella in pigs during transport to slaughter and lairage: Systematic review, meta-analysis, and research synthesis based infection models in support of assessment of effectiveness. AB - A systematic review of the effectiveness of interventions to reduce Salmonella prevalence or concentration in pork was undertaken. A broad search was conducted in two electronic databases. Each citation was appraised using screening tools designed and tested a priori. Level 1 relevance screening excluded irrelevant citations; level 2 confirmed relevance and categorized. Data were then extracted, and intervention categories were descriptively summarized. Meta-analysis was performed to provide a summary estimate of treatment effect where two or more studies investigated the same intervention in comparable populations. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to assess the confidence in the estimated summary measures of intervention effect for each data subgroup. Data were also extracted from the control groups of 25 challenge trials captured by the review, to fit logistic regression models of Salmonella infection in pigs, using odds of infection as the outcome measure. The only intervention captured by the review which was significantly associated with reduced risk of Salmonella in field settings, was elimination of lairage, which is not currently feasible commercially. The logistic regression model for fecal Salmonella shedding in pigs with a random intercept for trial yielded the following predictors significantly associated with increased odds of infection: oral challenge route relative to intra-nasal, log increase in challenge dose, and elapsed time post-challenge. Univariable exact logistic regression modeling lymph node contamination post-challenge yielded the following predictors significantly associated with increased odds of Salmonella infection: younger animals relative to older ones; intra-nasal challenge route relative to oral route; and animals sampled within the first 7days post-challenge relative to those sampled at 14 or 21days. We hypothesize that the presence of absence of one or more of these predictors across studies could help to explain the inconsistent and/or non significant findings reported for some interventions applied at lairage. PMID- 28903870 TI - Spatial distribution of bovine cysticercosis-A retrospective study in Brazil from 2010 through 2015. AB - Geographical Information Systems (GIS) is frequently used in the control of animal diseases. In Brazil, the most impacting economical loss in the beef supply chain is bovine cysticercosis. This study focused on assessing the prevalence and geospatial distribution of bovine cysticercosis in 19 Brazilian states. To this, we gathered data from 146,346,244 bovines slaughtered between the years of 2010 and 2015. The observed prevalence was 0.62% (C.I. 0.62-0.63). In total, 30.86% cysticerci were viable, while 69.14% were unviable. Bovine cysticercosis cases had a significant decrease (p<0.05) during this period. The states of Parana (2.01%; C.I. 2.00-2.02), Santa Catarina (1.96%; C.I. 1.93-2.00), Sao Paulo (1.77%; C.I. 1.76-1.77), Rio Grande do Sul (1.63%; C.I. 1.60-1.63) and Mato Grosso do Sul (0.80%; C.I. 0.80-0.80) had the highest prevalence values. In some states a significant (p<0.05) decreasing trend was detected in the prevalence. In conclusion, Taenia-saginata-cysticercosis remains endemic in Brazil and interventions are necessary to maintain Brazilian beef competitive in the international food market and improve food safety to population. PMID- 28903871 TI - Prevalence and risk factors for transition period diseases in grazing dairy cows in Brazil. AB - The aim of this cross-sectional study was to describe the incidence risk of dystocia, retained placenta (RP), pathological recumbence (down cow), the prevalence of metritis and subclinical ketosis (SCK), and the risk factors for SCK, metritis, and RP in grazing dairy herds in Southern Brazil. Fifty-three herds were visited 2-6 times from February to October of 2015. Body condition score (BCS), breed, days in milk (DIM), parity and disease status were recorded for each cow that was between 3 and 21 DIM at the time of the visits. Management practices were determined using a survey and environmental inspection was performed on each visit. SCK was identified if blood beta-hydroxybutyrate was >=1.2mmol/L and metritis by inspection of the vaginal discharge; cows were assessed once between 3 and 21 DIM. Multilevel logistic regression models, controlling for farm as a random effect, were built to identify risk factors for each disease and to assess the proportion of variance at the herd and cow levels. Models were constructed based on causal diagrams and variable screening. Overall, prevalence of SCK and metritis and incidence risk of RP were 21, 11 and 14%, respectively. Reported incidence risk of down cow was 6% and displaced abomasum was 1%. The odds (OR; 95% CI) of a cow having SCK were higher in herds with high (>10%) incidence of down cows (2.7; 1.4-5.0), limited access to water (1.9; 1.1 3.1), Jersey cows (OR: 2.2; 1.2-4.1) and in cows that were in third or greater lactation (2.9; 1.4-5.5). BCS 3.0-3.5 decreased the odds (0.4; 0.2-0.8) of metritis, while DIM, RP and being in a herd with a dirty holding area increased the odds of metritis by 1.1 (1.1-1.2), 19.5 (9.9-38.3) and 2.1 (1.0-4.2) fold, respectively. Parity >2 and dystocia increased the odds of RP by 2.4 (1.2-4.6) and 3.0 (1.6-5.4) fold, respectively. Jersey breed, use of a maternity pen and keeping the newborn calf with the cow >12h decreased the odds of having RP by 0.1 (0.0-0.4), 0.5 (0.3-1.0) and 0.4 (0.2-0.8) times, respectively. The variation in disease occurrence was largely dependent on cow-level factors. However, herd level risk factors also influenced disease occurrence and should be considered in order to design better preventive transition period diseases protocols. PMID- 28903872 TI - Prevalence of subclinical mastitis and associated risk factors at cow and herd level in dairy farms in North-West Ethiopia. AB - Knowledge of mastitis pathogens and their predominance as well as understanding of risk factors are prerequisites to improve udder health in a herd, region or country. In Ethiopia, such information is scarce, despite the fact that mastitis is an important cattle disease in the country. A cross-sectional study that describes prevalence and causative agents of subclinical mastitis (SCM) as well as risk factors at cow and herd level was conducted on 167 dairy farms in North West Ethiopia. On average, 33% of the quarters and 62% of the cows were California Mastitis Test (CMT) positive, but the within herd quarter level prevalence ranged between 0 and 100%. A total of 1543 milk samples, being 27 quarters that showed signs of CM, 606 CMT positive quarters and 910 CMT negative quarters were cultured, respectively 40%, 67% and 47% was positive on bacteriological culture. Coagulase negative staphylococci (CNS) (31%) followed by Staphylococcus aureus (9%) were the pathogens most frequently isolated. Based on face-to-face questionnaire data, 35 herd level and 13 cow level factors were evaluated for their association with SCM (based on CMT) and with a positive culture for any bacteria, CNS or S. aureus. Cows with a history of CM, of higher parity, >150days in milk (DIM) and herds with owners that have >10th grade level of education had higher odds of SCM. The odds of being culture positive for any bacteria was higher in cows with >=25% Holstein Friesian blood level (HBL), >150 DIM, housed on cemented floors, and milked by squeezing rather than stripping. Similarly, the odds of culturing CNS was higher in cows with 25-50% HBL, >150 DIM, and milked by squeezing. Staphylococcus aureus was more often found in cows with a history of CM and in larger herds. Checking the udder for mastitis, feeding cows according to their requirements and allowing calves to suckle the cows were negatively associated with SCM, with culturing any bacteria and with culturing CNS, respectively. Higher odds of SCM and of culturing CNS were found in herds owned by members of a dairy cooperative. In summary, we identified a high prevalence of SCM and intramammary infections with substantial variation between farms, and we found a number of risk factors explaining this variation. The risk factors for mastitis that were identified in this study can form the basis of an udder health control program specific for the dairy industry in North West Ethiopia. PMID- 28903873 TI - Validation of a model for ranking aquaculture facilities for risk-based disease surveillance. AB - A semi-quantitative model for risk ranking of aquaculture facilities in Switzerland with regard to the introduction and spread of Viral Haemorrhagic Septicaemia (VHS) and Infectious Haematopoietic Necrosis (IHN) was developed in a previous study (Diserens et al., 2013). The objective of the present study was to validate this model using data collected during field visits on aquaculture sites in four Swiss cantons compared to data collected through a questionnaire in the previous study. A discrepancy between the values obtained with the two different methods was found in 32.8% of the parameters, resulting in a significant difference (p<0.001) in the risk classification of the facilities. As data gathered exclusively by means of a questionnaire are not of sufficient quality to perform a risk-based surveillance of aquaculture facilities a combination of questionnaires and farm inspections is proposed. A web-based reporting system could be advantageous for the factors which were identified as being more likely to vary over time, in particular for factors considering fish movements, which showed a marginally significant difference in their risk scores (p>=0.1) within a six- month period. Nevertheless, the model proved to be stable over the considered period of time as no substantial fluctuations in the risk categorisation were observed (Kappa agreement of 0.77).Finally, the model proved to be suitable to deliver a reliable risk ranking of Swiss aquaculture facilities according to their risk of getting infected with or spreading of VHS and IHN, as the five facilities that tested positive for these diseases in the last ten years were ranked as medium or high risk. Moreover, because the seven fish farms that were infected with Infectious Pancreatic Necrosis (IPN) during the same period also belonged to the risk categories medium and high, the classification appeared to correlate with the occurrence of this third viral fish disease. PMID- 28903874 TI - Mortality in Danish Swine herds: Spatio-temporal clusters and risk factors. AB - The aim of this study was to explore spatio-temporal mortality patterns in Danish swine herds from December 2013 to October 2015, and to discuss the use of mortality data for syndromic surveillance in Denmark. Although it has previously been assessed within the context of syndromic surveillance, the value of mortality data generated on a regular and mandatory basis from all swine herds remains unexplored in terms of swine surveillance in Denmark. A total of 5010 farms were included in the analysis, corresponding to 1896 weaner herds, 1490 sow herds and 3839 finisher herds. The spatio-temporal analysis included data description for spatial, temporal, and spatio-temporal cluster analysis for three age groups: weaners (up to 30kg), sows and finishers. Logistic regression models were used to assess the potential factors associated with finisher and weaner herds being included within multiple-herd clusters. The spatio-temporal distribution of mortality changed over time, and suggested a general increase in mortality for the months of January and July for the three age groups. A large number of single-herd clusters (i.e. clusters with only one herd), and fewer multiple-herd clusters (i.e. clusters with at least two herds) were found. The herd size affected whether weaner herds were within multiple-herd clusters, and factors such farm type, SPF status and presence of atrophic rhinitis had an impact on finisher herds being inside vs. outside multiple-herd clusters in the univariable analysis. However, due to a strong correlation between variables, only farm type remained in the multivariable analysis for the finisher herds. The higher mortality observed for the months of January and July could be linked to infrequent updates of the data used to calculate mortality. The presence of single-herd clusters might indicate welfare and disease issues, while multiple herd clusters could suggest the presence of infectious diseases within the cluster area. The impact of farm type is linked to the fact that larger farms specialize in only one age group, with high biosecurity and more specialized personnel, and subsequently a lower mortality. Mortality data have a potential use in disease surveillance. However, detected clusters might not be due to disease, but the result of changes such as herd management practices. Further analysis to explore other spatio-temporal monitoring methods is needed before mortality data can be incorporated into a Danish disease monitoring system. PMID- 28903875 TI - Risk assessment of the entry of canine-rabies into Papua New Guinea via sea and land routes. AB - Canine-rabies is endemic in parts of Indonesia and continues to spread eastwards through the Indonesian archipelago. Papua New Guinea (PNG) has a land border with Papua Province, Indonesia, as well as logging and fishing industry connections throughout Asia. PNG has a Human Development Index of 0.505; therefore, an incursion of canine-rabies could have devastating impacts on human (7.5 million) and animal populations. Given the known difficulties of rabies elimination in resource-scarce environments, an incursion of rabies into PNG would also likely compromise the campaign for global elimination of rabies. A previous qualitative study to determine routes for detailed risk assessment identified logging, fishing and three land-routes (unregulated crossers ["shopper-crossers"], traditional border crossers and illegal hunters) as potential high risk routes for entry of rabies-infected dogs into PNG. The objective of the current study was to quantify and compare the probability of entry of a rabies-infected dog via these routes into PNG and to identify the highest risk provinces and border districts to target rabies prevention and control activities. Online questionnaires were used to elicit expert-opinion about quantitative model parameter values. A quantitative, stochastic model was then used to assess risk, and parameters with the greatest influence on the estimated mean number of rabies infected dogs introduced/year were identified via global sensitivity analysis (Sobol method). Eight questionnaires - including 7 online - were implemented and >220 empirical distributions were parameterised using >2900 expert-opinions. The highest risk provinces for combined sea routes were West Sepik, Madang and Western Province, driven by the number of vessels and the probability of bringing dogs. The highest risk border districts for combined land routes were Vanimo Green River and South Fly, driven by the number of people crossing the border and the number of dogs (with hunters). Overall, the risk posed by land routes was much higher than the risk of rabies introduction by sea routes. This study provides a foundation to develop targeted border control measures, surveillance and response strategies for canine-rabies for the highest risk routes and regions in PNG. Sensitivity analysis using the Sobol method played a key role in this study and directed further data collection to refine risk estimates. The ease of expert-elicitation using online methods demonstrates the feasibility of using such methods for animal and human disease surveillance in PNG. PMID- 28903876 TI - Persistence of Mycoplasma hyopneumoniae sequence types in spite of a control program for enzootic pneumonia in pigs. AB - Enzootic pneumonia (EP) in pigs caused by Mycoplasma (M.) hyopneumoniae has successfully been combatted in Switzerland. A control program was fully implemented in 2004 which is based on total depopulation strategies of affected fattening farms as well as partial depopulation on breeding farms. Thereby, the number of cases has dropped drastically from more than 200 in 2003 to two cases in 2013. Currently monitoring is done based on clinical observation and subsequent diagnostic of coughing pigs. Moreover, in case of more than 10% gross pathological lesions per slaughter batch laboratory confirmation for EP is compulsory. Despite these strict measures it was not possible to eliminate M. hyopneumoniae from Swiss pig production. In fact, during the last few years the number of EP cases has slightly increased. Therefore, genotyping of the involved M. hyopneumoniae strains was conducted in order to elucidate possible sources and routes of infection. All available and typeable samples from totally 22 cases during the period 2014-2016 were investigated by extended multilocus sequence typing (MLST). A total of 16 cases, including eight from 2014, five from 2015 and three from 2016 could thereby be included in the study. MLST revealed that the majority of cases in 2014/2015 were due to two major spread scenarios, i.e. two M. hyopneumoniae sequence types, each scenario involving six individual production farms in five to six different Cantons (states), respectively. Moreover, by comparison of archived sequences some sequence types were observed over ten years demonstrating their persistence over a long time and the possible partial failure of elimination measures in Switzerland. Insufficient sanitation on affected farms and subsequent animal transport of symptomless infected pigs could lead to recurrent cases. Wild boar harbor identical strains found with EP but solid data are missing to assign a role as reservoir to this wild animal. Implementing a monitoring scheme for M. hyopneumoniae in wild boar in combination with genotyping of all available samples from domestic pigs could direct responsible authorities to possible gaps and deficiencies of control measures taken for combating enzootic pneumonia. With the newly installed PubMLST database sequence types for M. hyopneumoniae are now available and allow tracing back strains on the international level. PMID- 28903877 TI - Exploring the role of small-scale livestock keepers for national biosecurity-The pig case. AB - Small-scale keepers are less likely to engage with production organisations and may therefore be less aware of legislation, rules and biosecurity practices which are implemented in the livestock sector. Their role in the transmission of endemic and exotic diseases is not well studied, but is believed to be important. The authors use small-scale pig keepers in Scotland as an example of how important small-scale livestock keepers might be for national biosecurity. In Scotland more than two thirds of pig producers report that they keep less than 10 pigs, meaning that biosecurity practices and pig health status on a substantial number of holdings are largely unknown; it is considered important to fill this knowledge gap. A questionnaire was designed and implemented in order to gather some of this information. The questionnaire comprised a total of 37 questions divided into seven sections (location of the enterprise, interest in pigs, details about the pig enterprise, marketing of pigs, transport of pigs, pig husbandry, and pig health/biosecurity). Over 610 questionnaires were sent through the post and the questionnaire was also available online. The questionnaire was implemented from June to October 2013 and 135 questionnaires were returned by target respondents. The responses for each question are discussed in detail in this paper. Overall, our results suggest that the level of disease identified by small-scale pig keepers is low but the majority of the small-scale pig keepers are mixed farms, with associated increased risk for disease transmission between species. Almost all respondents implemented at least one biosecurity measure, although the measures taken were not comprehensive in the majority of cases. Overall as interaction between small-scale keepers and commercial producers exists in Scotland the former can pose a risk for commercial production. This investigation fills gaps in knowledge which will allow industry stakeholders and policy makers to adapt their current disease programmes and contingency plans to the reality of small-scale pig-keeping enterprises' health and biosecurity status. We predict that some conclusions from this work will be relevant to countries with similar pig production systems and importantly some of these findings will relate to small-scale producers in other livestock sectors. PMID- 28903878 TI - Thermal Inactivation of avian influenza virus in poultry litter as a method to decontaminate poultry houses. AB - Removal of contaminated material from a poultry house during recovery from an avian influenza virus (AIV) outbreak is costly and labor intensive. Because AIV is not environmentally stable, heating poultry houses may provide an alternative disinfection method. The objective was to determine the time necessary to inactivate AIV in poultry litter at temperatures achievable in a poultry house. Low pathogenic (LP) AIV inactivation was evaluated between 10.0 degrees -48.9 degrees C, at ~5.5 degrees C intervals and highly pathogenic (HP) AIV inactivation was evaluated between 10.0 degrees -43.3 degrees C, at ~11 degrees C intervals. Samples were collected at numerous time points for each temperature. Virus isolation in embryonating chicken eggs was conducted to determine if viable virus was present. Each sample was also tested by real-time RT-PCR. Low pathogenicity AIV was inactivated at 1day at 26.7 degrees C or above. At 10.0, 15.6 and 21.1 degrees C, inactivation times increased to 2-5days. Highly pathogenic AIV followed a similar trend; the virus was inactivated after 1day at 43.3 degrees C and 32.2 degrees C, and required 2 and 5days for inactivation at 21.1 degrees C and 10.0 degrees C respectively. While low pathogenicity AIV appeared to be inactivated at a lower temperature than high pathogenicity AIV, this was not due to any difference in the strains, but due to fewer temperature points being evaluated for high pathogenicity. Endpoints for detection by real time RT-PCR were not found even weeks after the virus was inactivated. This provides a guideline for the time required, at specific temperatures to inactivate AIV in poultry litter and likely on surfaces within the house. Heat treatment will provide an added level of safety to personnel and against further spread by eliminating infectious virus prior to cleaning a house. PMID- 28903879 TI - Salmonella enterica subsp. diarizonae serotype 61:k:1,5,(7) associated with chronic proliferative rhinitis and high nasal colonization rates in a flock of Texel sheep in Switzerland. AB - Salmonella (S.) enterica subspecies diarizonae (IIIb) serovar 61:(k):1,5,(7) (S. IIIb 61:(k):1,5,(7)) is considered to be host adapted to sheep and is found regularly in feces of healthy carriers and of sheep with salmonellosis. A few cases of chronic proliferative rhinitis (CPR) in sheep have been described as a new disease in association with S. IIIb 61:k:1,5,(7) in the USA, in Spain and now for the first time in Switzerland. Three animals of a flock of Texel sheep suffering from chronic nasal discharge and dyspnea with subsequent death were necropsied. The pathological lesions are consistent with a severe proliferation of the nasal mucosae of the turbinates in association with severe chronic inflammation. S. IIIb 61:(k):1,5,(7) was isolated from the lesions by direct bacteriological culture and the presence of Salmonella spp. was confirmed by immunohistochemistry. The affected flock was systematically tested after the first occurrence of the disease. Clinical examination of the flock revealed approx. 20% of the adult sheep to show nasal discharge, approx. 5% having severe dyspnea and approx. 5% having chronic intermittent diarrhea. Lambs (n=28) showed no clinical signs at all. High positivity of nasal mucosa (46%), but low prevalence in feces (6%) for S. IIIb 61:k:1,5,(7) was found. The results lead to the assumption of a direct animal to animal transmission by nasal discharge followed by a chronic disease leading to death after several months to years. Animals tested positive for S. IIIb 61:k:1,5,(7) were all >1year old. CPR represents a chronic disease in adult sheep posing a risk for spreading S. IIIb 61:k:1,5,(7) between flocks and with a zoonotic potential. PMID- 28903880 TI - Sampling pig farms at the abattoir in a cross-sectional study - Evaluation of a sampling method. AB - A cross-sectional study design is relatively inexpensive, fast and easy to conduct when compared to other study designs. Careful planning is essential to obtaining a representative sample of the population, and the recommended approach is to use simple random sampling from an exhaustive list of units in the target population. This approach is rarely feasible in practice, and other sampling procedures must often be adopted. For example, when slaughter pigs are the target population, sampling the pigs on the slaughter line may be an alternative to on site sampling at a list of farms. However, it is difficult to sample a large number of farms from an exact predefined list, due to the logistics and workflow of an abattoir. Therefore, it is necessary to have a systematic sampling procedure and to evaluate the obtained sample with respect to the study objective. We propose a method for 1) planning, 2) conducting, and 3) evaluating the representativeness and reproducibility of a cross-sectional study when simple random sampling is not possible. We used an example of a cross-sectional study with the aim of quantifying the association of antimicrobial resistance and antimicrobial consumption in Danish slaughter pigs. It was not possible to visit farms within the designated timeframe. Therefore, it was decided to use convenience sampling at the abattoir. Our approach was carried out in three steps: 1) planning: using data from meat inspection to plan at which abattoirs and how many farms to sample; 2) conducting: sampling was carried out at five abattoirs; 3) evaluation: representativeness was evaluated by comparing sampled and non-sampled farms, and the reproducibility of the study was assessed through simulated sampling based on meat inspection data from the period where the actual data collection was carried out. In the cross-sectional study samples were taken from 681 Danish pig farms, during five weeks from February to March 2015. The evaluation showed that the sampling procedure was reproducible with results comparable to the collected sample. However, the sampling procedure favoured sampling of large farms. Furthermore, both under-sampled and over-sampled areas were found using scan statistics. In conclusion, sampling conducted at abattoirs can provide a spatially representative sample. Hence it is a possible cost effective alternative to simple random sampling. However, it is important to assess the properties of the resulting sample so that any potential selection bias can be addressed when reporting the findings. PMID- 28903882 TI - Structural modeling and mutagenesis of endo-beta-N-acetylglucosaminidase from Ogataea minuta identifies the importance of Trp295 for hydrolytic activity. AB - Endo-beta-N-acetylglucosaminidase from the methylotrophic yeast Ogataea minuta (Endo-Om) is a glycoside hydrolase family 85 enzyme that has dual catalytic activity in the hydrolysis and transglycosylation of complex N-glycans, in common with the enzymes from the eukaryotic species. In this study, we have conducted mutagenesis of Endo-Om at Trp295, to determine the effect on hydrolytic activity. Structural modeling predicted that Trp295 forms an important interaction with the alpha-1,3-linked mannose residue of the trimannosyl N-glycan core, rather than being directly involved in catalytic activity. Our results showed that an aromatic amino acid is required at position 295 for the hydrolytic activity of this enzyme. Notably, the tryptophan residue is highly conserved in eukaryotic endo-beta-N-acetylglucosaminidases that show activity toward complex oligosaccharides. Accordingly, our results strongly suggested that Trp295 is involved in the recognition of oligosaccharide substrates by Endo-Om. PMID- 28903883 TI - The natural history of the patients with Duchenne muscular dystrophy in Taiwan: A medical center experience. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common hereditary muscular dystrophy and caused by DMD gene mutation. In addition to progressive proximal muscle weakness, respiratory, orthopedic, and gastrointestinal complications are often observed in DMD. The natural history of patients with DMD in Taiwan has not been reported thus far. METHODS: Medical records of 39 patients who received a diagnosis of DMD between 1999 and 2016 at Kaohsiung Medical University Hospital were reviewed. The diagnosis of DMD was confirmed through muscle biopsy or DMD genetic analysis. RESULTS: The mean onset age and mean follow-up period were 2.75 years and 6.76 years, respectively. Seventeen patients (43.5%) had a family history of DMD. The mean full intelligence quotient of the patients was 71.08, and the mean age of walking ability loss was 9.7 years (25 patients). The mean onset age of respiratory insufficiency was 10.64 years with a decline rate of 5.18% per year (25 patients). The mean onset age of cardiomyopathy was 14.69 years (seven patients). The mean onset age of scoliosis was 13.29 years with a progression rate of 11.48 degrees per year (14 patients). Eleven (28.2%) and eight (20.5%) patients had deletions and duplications of DMD, respectively. Fourteen patients (35.9%) had point mutations or small deletions or insertions. Five patients received only multiplex ligation-dependent probe amplification (MLPA) analysis and exhibited neither deletion nor duplication. No mutation was identified in one patient through both MLPA and exon sequencing. CONCLUSION: The clinical phenotypes and disease course in our cohort were consistent with that reported in previous studies. However, the proportion of point mutations or small deletions or insertions in our study was considerably higher than that in reports from other populations. Cardiac ejection fraction was found not a reliable biomarker for identifying cardiac problems, discovering a better parameter is necessary. PMID- 28903881 TI - Factors affecting the cost-effectiveness of on-farm culture prior to the treatment of clinical mastitis in dairy cows. AB - The objective of this study was to use probabilistic sensitivity analysis to evaluate the cost-effectiveness of using an on-farm culture (OFC) approach to the treatment of clinical mastitis in dairy cows and compare this to a 'standard' treatment approach. A specific aim was to identify the herd circumstances under which an OFC approach would be most likely to be cost-effective. A stochastic Monte Carlo model was developed to simulate 5000 cases of clinical mastitis at the cow level and to calculate the associated costs simultaneously when treated according to 2 different treatment protocols; i) a 'conventional' approach (3 tubes of intramammary antibiotic) and ii) an OFC programme, whereby cows are treated according to the results of OFC. Model parameters were taken from recent peer reviewed literature on the use of OFC prior to treatment of clinical mastitis. Spearman rank correlation coefficients were used to evaluate the relationships between model input values and the estimated difference in cost between the standard and OFC treatment protocols. The simulation analyses revealed that both the difference in the bacteriological cure rate due to a delay in treatment when using OFC and the proportion of Gram-positive cases that occur on a dairy unit would have a fundamental impact on whether OFC would be cost effective. The results of this study illustrated that an OFC approach for the treatment of clinical mastitis would probably not be cost-effective in many circumstances, in particular, not those in which Gram-positive pathogens were responsible for more than 20% of all clinical cases. The results highlight an ethical dilemma surrounding reduced use of antimicrobials for clinical mastitis since it may be associated with financial losses and poorer cow welfare in many instances. PMID- 28903884 TI - Successful Outcome of Severe Intra-cerebral Bleeding Associated with Acquired Factor V Inhibition: Utilization of Multiple Therapeutic Agents. AB - BACKGROUND: Acquired coagulation factor inhibitors are antibodies that either inhibit activity or increase the clearance of a clotting factor and lead to an increased risk of bleeding. Most of the time, the disorder is attributed to factor VIII inhibition (acquired haemophilia A); however, other coagulation factors could also be implicated. CASE REPORT: Herein, we report an interesting case of a patient who underwent coronary artery bypass grafting and received antibiotic treatment after surgery with third generation cephalosporin. A month later, he presented with extreme bleeding diathesis and cerebral haemorrhage. Following a thorough clinical and laboratory investigation, an acquired factor V inhibitor was diagnosed. The patient received treatment with corticosteroids, intravenous immunoglobulins, anti-CD20 monoclonal antibodies (rituximab), cyclophosphamide and recombinant factor VIIa. Finally, despite the poor initial prognosis, the patient managed to achieve a full recovery. CONCLUSION: As there are no clear guidelines on acquired coagulation inhibitor treatment, reports of such cases could offer insight for future therapy choices. The case was unique because the treatment regimen included a combination of multiple therapeutic agents including rituximab. PMID- 28903885 TI - The Effects of Baicalin on Myoglobinuric Acute Renal Failure in Rats. AB - BACKGROUND: Myoglobinuric acute kidney injury is a uremic syndrome that develops due to damage of skeletal muscle. Free radicals and nitric oxide play an important role in the pathogenesis of myoglobinuric acute kidney injury. Baicalin has multiple bioactivities, including antimicrobial, anti-inflammatory and antioxidant properties and is a potent free radical scavenger. AIMS: To investigate the nephroprotective mechanism of baicalin on myoglobinuric acute kidney injury. STUDY DESIGN: Animal experimentation. METHODS: In our study, male Sprague Dawley rats were divided into 4 groups. Control (n=8), Baicalin (n=8), myoglobinuric acute kidney injury (n=10) and myoglobinuric acute kidney injury + baicalin (n=10). The rats were deprived of water for 24 hours before receiving intramuscular injection. The control and baicalin groups were injected intramuscularly with saline (8 ml/kg), and the myoglobinuric acute kidney injury and myoglobinuric acute kidney injury + baicalin groups were given 50% glycerol 8 ml/kg. One hour later, the control and myoglobinuric acute kidney injury groups received saline intraperitoneally, and the baicalin and myoglobinuric acute kidney injury + baicalin groups were given 200 mg/kg baicalin. Twenty-four hours after the glycerol injection, urine and blood samples were taken, and the kidneys of the rats were harvested under intraperitoneally injections of anaesthesia. RESULTS: We found that the levels of creatinine, urea, nitric oxide, alanine transaminase, aspartate aminotransferase, creatine kinase in serum samples, malondialdehyde, nitric oxide, inducible nitric oxide synthase, and endothelial nitric oxide synthase concentrations in renal tissue were increased in the myoglobinuric acute kidney injury group compared with the control group (p<0.05). The nitric oxide and glutathione levels in the kidney were significantly decreased in the myoglobinuric acute kidney injury + baicalin group compared with the myoglobinuric acute kidney injury group (p<0.05). There were no significant differences between any other parameters. CONCLUSION: Our results did not show any protective effect of baicalin on myoglobinuric acute kidney injury, possibly because the different effective factors in the pathogenesis of experimental myoglobinuric acute kidney injury used in this experiment deviate from other experimental models. Moreover, detailed studies are needed to clarify the effects of baicalin in different doses and treatment durations in glycerol-induced acute kidney injury model. PMID- 28903886 TI - Patient Privacy in the Era of Big Data. AB - Privacy was defined as a fundamental human right in the Universal Declaration of Human Rights at the 1948 United Nations General Assembly. However, there is still no consensus on what constitutes privacy. In this review, we look at the evolution of privacy as a concept from the era of Hippocrates to the era of social media and big data. To appreciate the modern measures of patient privacy protection and correctly interpret the current regulatory framework in the United States, we need to analyze and understand the concepts of individually identifiable information, individually identifiable health information, protected health information, and de-identification. The Privacy Rule of the Health Insurance Portability and Accountability Act defines the regulatory framework and casts a balance between protective measures and access to health information for secondary (scientific) use. The rule defines the conditions when health information is protected by law and how protected health information can be de identified for secondary use. With the advents of artificial intelligence and computational linguistics, computational text de-identification algorithms produce de-identified results nearly as well as those produced by human experts, but much faster, more consistently and basically for free. Modern clinical text de-identification systems now pave the road to big data and enable scientists to access de-identified clinical information while firmly protecting patient privacy. However, clinical text de-identification is not a perfect process. In order to maximize the protection of patient privacy and to free clinical and scientific information from the confines of electronic healthcare systems, all stakeholders, including patients, health institutions and institutional review boards, scientists and the scientific communities, as well as regulatory and law enforcement agencies must collaborate closely. On the one hand, public health laws and privacy regulations define rules and responsibilities such as requesting and granting only the amount of health information that is necessary for the scientific study. On the other hand, developers of de-identification systems provide guidelines to use different modes of operations to maximize the effectiveness of their tools and the success of de-identification. Institutions with clinical repositories need to follow these rules and guidelines closely to successfully protect patient privacy. To open the gates of big data to scientific communities, healthcare institutions need to be supported in their de identification and data sharing efforts by the public, scientific communities, and local, state, and federal legislators and government agencies. PMID- 28903887 TI - Seasonal Influenza Vaccine Effectiveness in Preventing Laboratory Confirmed Influenza in 2014-2015 Season in Turkey: A Test-Negative Case Control Study. AB - BACKGROUND: Influenza has an important public health impact worldwide with its considerable annual morbidity among persons with or without risk factors and its serious complications among persons in high-risk groups. The seasonal influenza vaccine is essential for preventing the burden of influenza in a population. Since the vaccine is reformulated each season according to the virus serotypes in circulation, its effectiveness can vary from season to season. Vaccine effectiveness is defined as the relative risk reduction in vaccinated individuals in observational studies. AIMS: To calculate influenza vaccine effectiveness in preventing laboratory-confirmed influenza in the Turkish population for the first time using the national sentinel surveillance data in the 2014-2015 influenza season. STUDY DESIGN: Test-negative case-control study. METHODS: We compared vaccination odds of influenza positive cases to influenza negative controls in the national influenza surveillance in Turkey to estimate influenza vaccine effectiveness. RESULTS: The influenza vaccine effectiveness against influenza A (H1N1) (68.4%, 95% CI: -2.9 to 90.3) and B (44.6%, 95% CI: -27.9 to 66.6) were moderate, and the influenza vaccine effectiveness against influenza A (H3N2) (75.0%, 95% CI: -86.1 to 96.7) was relatively high; all had low precision given the low vaccination coverage. Overall, the influenza vaccination coverage rate was 4.2% (95% CI: 3.5 to 5.0), which is not sufficient to control the burden of influenza. CONCLUSION: In Turkey, national surveillance for influenza should be strengthened and utilised annually for the assessment of influenza vaccine effectiveness with more precision. Annual influenza vaccine effectiveness in Turkey should continue to be monitored as part of the national sentinel influenza surveillance. PMID- 28903888 TI - Serum Angiogenic and Anti-angiogenic Markers in Pregnant Women with Placenta Percreta. AB - BACKGROUND: Placenta percreta is the morbidly adherent form of all the placental invasion abnormalities. The pathology that underlies placenta percreta is poorly understood. AIMS: To compare the levels of circulating vascular endothelial growth factor, placental growth factor and soluble fms-like tyrosine kinase 1 in pregnant women with placenta percreta to a control group. STUDY DESIGN: Case control study. METHODS: Twenty-two women who underwent caesarean section due to placenta percreta and 22 women who underwent caesarean section for other obstetric reasons were included in this study. The diagnosis of placenta percreta was defined as extreme trophoblastic invasion involving serosa of the uterus. Venous blood samples were collected for biochemical comparison of circulating vascular endothelial growth factor, placental growth factor and soluble fms-like tyrosine kinase 1 from all pregnant women. RESULTS: Women with placenta percreta were significantly older, had higher gravidity, received more frequent antenatal steroids and blood transfusions and delivered at an earlier gestational age when compared to the control group. In women with placenta percreta, preoperative circulating levels of vascular endothelial growth factor, placental growth factor and soluble fms-like tyrosine kinase 1 were lower than the controls (p<0.001, p<0.001 and p<0.05, respectively). While the postoperative levels of vascular endothelial growth factorand soluble fms-like tyrosine kinase 1 levels were higher in placenta percreta (p=0.001 and p<0.001, respectively), placental growth factor levels were similar in both groups. CONCLUSION: The findings of this study suggest that a decrease in vascular endothelial growth factor, placental growth factor and soluble fms-like tyrosine kinase 1 levels may be related to placenta percreta etiopathogenesis. PMID- 28903889 TI - GDF9 and BMP15 Expressions and Fine Structure Changes During Folliculogenesis in Polycystic Ovary Syndrome. AB - BACKGROUND: Polycystic ovary syndrome is the most frequently seen endocrine disorder in women of reproductive age with a prevalence of about 10%. AIMS: To investigate the efficiency of growth differentiation factor 9 and bone morphogenetic protein 15 during folliculogenesis in a dehydroepiandrosterone induced mouse Polycystic ovary syndrome model. STUDY DESIGN: Animal experimentation. METHODS: Mice were divided into 3 groups: control, vehicle and Polycystic ovary syndrome. Polycystic ovary syndrome model mice were developed by the injection of dehydroepiandrosterone dissolved in 0.1 mL of sesame oil. Ovarian tissues were examined for growth differentiation factor 9 and bone morphogenetic protein 15 using immunofluorescent labelling and electron microscopic examinations. RESULTS: The immunoreactivity of growth differentiation factor 9 and bone morphogenetic protein 15 proteins decreased (p<0.05) in the Polycystic ovary syndrome group (27.73+/-8.43 and 24.85+/-7.03, respectively) compared with the control group (33.72+/-11.22 and 31.12+/-11.05, respectively) and vehicle group (33.95+/-10.75 and 29.99+/-10.72, respectively). Apoptotic changes were observed in granulosa cells, lipid vacuoles increased in Theca cells and thickening and irregularities were noted in the basal lamina of granulosa cells. An increased electron density in the zona pellucida in some of the multilaminar primary and secondary follicles in the Polycystic ovary syndrome model was also observed at the ultrastructural level. CONCLUSION: These results suggest that the decrease in the growth differentiation factor 9 and bone morphogenetic protein 15 expression initiated at the primary follicle stage effect the follicle development and zona pellucida structure and may cause subfertility or infertility in Polycystic ovary syndrome. PMID- 28903890 TI - Human Parasitic Diseases in Bulgaria in Between 2013-2014. AB - BACKGROUND: In Bulgaria, more than 20 autochthonous human parasitic infections have been described and some of them are widespread. Over 50 imported protozoan and helminthic infections represent diagnostic and therapeutic challenges and pose epidemiological risks due to the possibility of local transmission. AIMS: To establish the distribution of autochthonous and imported parasitic diseases among the population of the country over a 2-year period (2013-2014) and to evaluate their significance in the public health system. STUDY DESIGN: Cross sectional study. METHODS: We used the annual reports by regional health inspectorates and data from the National Reference Laboratory at the National Centre of Infectious and Parasitic Diseases on all individuals infected with parasitic diseases in the country. Prevalence was calculated for parasitic diseases with few or absent clinical manifestations (oligosymptomatic or asymptomatic infections). Incidence per 100.000 was calculated for diseases with an overt clinical picture or those that required hospitalisation and specialised medical interventions (e.g. surgery). RESULTS: During the research period, parasitological studies were conducted on 1441.244 persons, and parasitic infections were diagnosed in 22.039 individuals. Distribution of various parasitic pathogens among the population displayed statistically significant differences in prevalence for some intestinal parasites (enterobiasis 0.81%, giardiasis 0.34% and blastocystosis 0.22%). For certain zoonotic diseases such as cystic echinococcosis (average incidence of 3.99 per 100.000) and trichinellosis (average incidence of 0.8 per 100.000), the incidence exceeds several times the annual incidence recorded in the European Union. CONCLUSION: Parasitic diseases still pose a substantial problem with social and medical impacts on the residents of our country. Improved efficiency regarding autochthonous and imported parasitic diseases is essential in providing the public health system the tools it needs to combat these diseases. Attention should be focused on the various imported vector-borne parasitic diseases (e.g. malaria and cutaneous leishmaniasis) for which the country is potentially endemic. PMID- 28903891 TI - Health Information National Trends Survey in American Sign Language (HINTS-ASL): Protocol for the Cultural Adaptation and Linguistic Validation of a National Survey. AB - BACKGROUND: The Health Information National Trends Survey (HINTS) collects nationally representative data about the American's public use of health-related information. This survey is available in English and Spanish, but not in American Sign Language (ASL). Thus, the exclusion of ASL users from these national health information survey studies has led to a significant gap in knowledge of Internet usage for health information access in this underserved and understudied population. OBJECTIVE: The objectives of this study are (1) to culturally adapt and linguistically translate the HINTS items to ASL (HINTS-ASL); and (2) to gather information about deaf people's health information seeking behaviors across technology-mediated platforms. METHODS: We modified the standard procedures developed at the US National Center for Health Statistics Cognitive Survey Laboratory to culturally adapt and translate HINTS items to ASL. Cognitive interviews were conducted to assess clarity and delivery of these HINTS-ASL items. Final ASL video items were uploaded to a protected online survey website. The HINTS-ASL online survey has been administered to over 1350 deaf adults (ages 18 to 90 and up) who use ASL. Data collection is ongoing and includes deaf adult signers across the United States. RESULTS: Some items from HINTS item bank required cultural adaptation for use with deaf people who use accessible services or technology. A separate item bank for deaf-related experiences was created, reflecting deaf-specific technology such as sharing health-related ASL videos through social network sites and using video remote interpreting services in health settings. After data collection is complete, we will conduct a series of analyses on deaf people's health information seeking behaviors across technology mediated platforms. CONCLUSIONS: HINTS-ASL is an accessible health information national trends survey, which includes a culturally appropriate set of items that are relevant to the experiences of deaf people who use ASL. The final HINTS-ASL product will be available for public use upon completion of this study. PMID- 28903892 TI - Effectiveness of SmartMoms, a Novel eHealth Intervention for Management of Gestational Weight Gain: Randomized Controlled Pilot Trial. AB - BACKGROUND: Two-thirds of pregnant women exceed gestational weight gain (GWG) recommendations. Because excess GWG is associated with adverse outcomes for mother and child, development of scalable and cost-effective approaches to deliver intensive lifestyle programs during pregnancy is urgent. OBJECTIVE: The aim of this study was to decrease the proportion of women who exceed the Institute of Medicine (IOM) 2009 GWG guidelines. METHODS: In a parallel-arm randomized controlled trial, 54 pregnant women (age 18-40 years) who were overweight (n=25) or obese (n=29) were enrolled to test whether an intensive lifestyle intervention (called SmartMoms) decreased the proportion of women with excess GWG, defined as exceeding the 2009 IOM guidelines, compared to no intervention (usual care group). The SmartMoms intervention was delivered through mobile phone (remote group) or in a traditional in-person, clinic-based setting (in-person group), and included a personalized dietary intake prescription, self monitoring weight against a personalized weight graph, activity tracking with a pedometer, receipt of health information, and continuous personalized feedback from counselors. RESULTS: A significantly smaller proportion of women exceeded the IOM 2009 GWG guidelines in the SmartMoms intervention groups (in-person: 56%, 10/18; remote: 58%, 11/19) compared to usual care (85%, 11/13; P=.02). The remote intervention was a lower cost to participants (mean US $97, SD $6 vs mean US $347, SD $40 per participant; P<.001) and clinics (US $215 vs US $419 per participant) and with increased intervention adherence (76.5% vs 60.8%; P=.049). CONCLUSIONS: An intensive lifestyle intervention for GWG can be effectively delivered via a mobile phone, which is both cost-effective and scalable. TRIAL REGISTRATION: Clinicaltrials.gov NCT01610752; https://clinicaltrials.gov/ct2/show/NCT01610752 (Archived by WebCite at http://www.webcitation.org/6sarNB4iW). PMID- 28903893 TI - User Acceptance of Computerized Cognitive Behavioral Therapy for Depression: Systematic Review. AB - BACKGROUND: Computerized cognitive behavioral therapy (cCBT) has been proven to be effective in depression care. Moreover, cCBT packages are becoming increasingly popular. A central aspect concerning the take-up and success of any treatment is its user acceptance. OBJECTIVE: The aim of this study was to update and expand on earlier work on user acceptance of cCBT for depression. METHODS: This paper systematically reviewed quantitative and qualitative studies regarding the user acceptance of cCBT for depression. The initial search was conducted in January 2016 and involved the following databases: Web of Science, PubMed, the Cochrane Library, and PsycINFO. Studies were retained if they described the explicit examination of the user acceptance, experiences, or satisfaction related to a cCBT intervention, if they reported depression as a primary outcome, and if they were published in German or English from July 2007 onward. RESULTS: A total of 1736 studies were identified, of which 29 studies were eligible for review. User acceptance was operationalized and analyzed very heterogeneously. Eight studies reported a very high level of acceptance, 17 indicated a high level of acceptance, and one study showed a moderate level of acceptance. Two qualitative studies considered the positive and negative aspects concerning the user acceptance of cCBT. However, a substantial proportion of reviewed studies revealed several methodical shortcomings. CONCLUSIONS: In general, people experience cCBT for depression as predominantly positive, which supports the potential role of these innovative treatments. However, methodological challenges do exist in terms of defining user acceptance, clear operationalization of concepts, and measurement. PMID- 28903894 TI - Prototype Development: Context-Driven Dynamic XML Ophthalmologic Data Capture Application. AB - BACKGROUND: The capture and integration of structured ophthalmologic data into electronic health records (EHRs) has historically been a challenge. However, the importance of this activity for patient care and research is critical. OBJECTIVE: The purpose of this study was to develop a prototype of a context-driven dynamic extensible markup language (XML) ophthalmologic data capture application for research and clinical care that could be easily integrated into an EHR system. METHODS: Stakeholders in the medical, research, and informatics fields were interviewed and surveyed to determine data and system requirements for ophthalmologic data capture. On the basis of these requirements, an ophthalmology data capture application was developed to collect and store discrete data elements with important graphical information. RESULTS: The context-driven data entry application supports several features, including ink-over drawing capability for documenting eye abnormalities, context-based Web controls that guide data entry based on preestablished dependencies, and an adaptable database or XML schema that stores Web form specifications and allows for immediate changes in form layout or content. The application utilizes Web services to enable data integration with a variety of EHRs for retrieval and storage of patient data. CONCLUSIONS: This paper describes the development process used to create a context-driven dynamic XML data capture application for optometry and ophthalmology. The list of ophthalmologic data elements identified as important for care and research can be used as a baseline list for future ophthalmologic data collection activities. PMID- 28903895 TI - Putting the Focus Back on the Patient: How Privacy Concerns Affect Personal Health Information Sharing Intentions. AB - BACKGROUND: Health care providers are driven by greater participation and systemic cost savings irrespective of benefits to individual patients derived from sharing Personal Health Information (PHI). Protecting PHI is a critical issue in the sharing of health care information systems; yet, there is very little literature examining the topic of sharing PHI electronically. A good overview of the regulatory, privacy, and societal barriers to sharing PHI can be found in the 2009 Health Information Technology for Economic and Clinical Health Act. OBJECTIVE: This study investigated the factors that influence individuals' intentions to share their PHI electronically with health care providers, creating an understanding of how we can represent a patient's interests more accurately in sharing settings, instead of treating patients like predetermined subjects. Unlike privacy concern and trust, patient activation is a stable trait that is not subject to change in the short term and, thus, is a useful factor in predicting sharing behavior. We apply the extended privacy model in the health information sharing context and adapt this model to include patient activation and issue involvement to predict individuals' intentions. METHODS: This was a survey-based study with 1600+ participants using the Health Information National Trends Survey (HINTS) data to validate a model through various statistical techniques. The research method included an assessment of both the measurement and structural models with post hoc analysis. RESULTS: We find that privacy concern has the most influence on individuals' intentions to share. Patient activation, issue involvement, and patient-physician relationship are significant predictors of sharing intention. We contribute to theory by introducing patient activation and issue involvement as proxies for personal interest factors in the health care context. CONCLUSIONS: Overall, this study found that although patients are open to sharing their PHI, they still have concerns over the privacy of their PHI during the sharing process. It is paramount to address this factor to increase information flow and identify how patients can assure that their privacy is protected. The outcome of this study is a set of recommendations for motivating the sharing of PHI. The goal of this research is to increase the health profile of the patients by integrating the testing and diagnoses of various doctors across health care providers and, thus, bring patients closer to the physicians. PMID- 28903896 TI - The regulatory functions of piRNA/PIWI in spermatogenesis. AB - A class of 24-32 nt PIWI-binding small noncoding RNAs (sncRNAs) termed as PIWI interacting RNAs (piRNAs) have been identified in animal germline. Recent studies suggest that piRNA/PIWI pathway plays a critical role in both silencing of transposons and posttranscriptional regulation of mRNAs in animal germline. A study from Dr. Mofang Liu's lab in Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, reveals the physiological and pathological importance of PIWI metabolism (mouse PIWI as known as MIWI; human PIWI as HIWI) in mammalian spermatogenesis. Here, we summarize our current understanding of the piRNA/PIWI pathway in mammals (focusing on mouse and human), which is emerging as a fundamental component of spermatogenesis that ensures male fertility and genome integrity. PMID- 28903897 TI - Ubiquitination modification precisely modulates the ABA signaling pathway in plants. AB - Protein post-translational modification by ubiquitination is essential for the activity and stability of proteins in the eukaryotic life cycle. In the past few years, it has been found that ubiquitination subtly modulates the abscisic acid (ABA) signaling pathway to regulate plant growth, development and stress responses, such as drought, salinity and cold stress responses. In this review, how the ubiquitin-proteasome system and ubiquitination-related membrane trafficking pathway affect ABA synthesis and signal transduction will be addressed and analysed. Also, the challenging questions in this field will be raised. These comprehensive views on the regulatory role of ubiquitination modification in the ABA pathway will shed light on future researches on how the ubiquitination-related process affects other hormone signaling pathways. PMID- 28903898 TI - Current status of pathway analysis in genome-wide association study. AB - Since the first publication in 2005, the genome-wide association study (GWAS) strategy has contributed significantly to the understanding of the mechanisms of human genetic diseases. Integrations of statistical methods and systematic biology are important means to explore the GWAS data. Pathway analysis establishes the importance of genetic variants from GWAS and provides insights into their biological significance. It is conducive in correlating the genetic variants, which have only small but interactive changes, to their importance in the biological pathways. At present, pathway analysis has been widely applied to studies of GWAS data, with relatively good results. In the meantime, various analytical methods are being developed and adapted for research on more types of complex data. In this review, we summarize the statistical methods of pathway analysis on GWAS data, and divide them into non-kernel methods and kernel methods. The non-kernel methods include gene set enrichment analysis (GSEA) and hierarchical Bayes prioritization (HBP) analysis, while kernel methods include linear kernel (LIN), identity-by-status kernel (IBS) and powered exponential kernel. We have summarized the calculation principles and features of these statistical methods to provide insights for further developments of new algorithms in GWAS research. PMID- 28903899 TI - The application of next-generation sequencing techniques in studying transcriptional regulation in embryonic stem cells. AB - The mechanism of transcriptional regulation has been the focus of many studies in the post-genomic era. The development of sequencing-based technologies for chromatin profiling enables current researchers to experimentally measure chromatin properties. Moreover, many studies aim at annotating the state of the chromatin into broad categories based on observed chromatin features and/or DNA sequences, then associating the resultant distal regulatory regions with the correct target genes based on DNA sequences, and predicting the dependence of epigenetic features on genetic variation. Stem cell biology has many applications in the area of regenerative medicine and tumorigenesis. In this review, we summarize recent research progresses on the application of next-generation sequencing techniques in studying transcriptional regulation in embryonic stem cells. This review mainly focuses on four areas: (1) microarray or RNA-seq; (2) chromatin immunoprecipitation (ChIP); (3) Dnase I hypersensitive sites (DHSs); (4) high-throughput chromosome conformation capture (Hi-C). These technologies have been utilized in studying chromatin on three levels, i.e., gene expression, transcription factor binding and genome three-dimensional structure. We especially emphasize three master transcription factors of pluripotency: Oct4, Sox2 and Nanog. We aim to track the frontier of stem cell transcriptional regulation research and share important progresses in this field. PMID- 28903900 TI - Genetics association study and functional analysis on osteoporosis susceptibility gene BDNF. AB - To explore the relationship between brain-derived neurotrophic factor (BDNF) gene and bone mineral density (BMD) in Chinese Han population, we performed association analysis of 14 tag SNPs on BDNF gene with hip/spine BMD in 1300 Han Chinese samples from Shaanxi Province. We found that 8 of the 14 SNPs were significantly associated with hip or spine BMD (P < 0.05). Moreover, the SNP rs16917237 was significantly associated with both hip and spine BMD, with significant Bonferroni correlation (P value 0.05/14 = 0.0036) in hip BMD. To further explore the regulatory mechanism of BDNF gene in osteoporosis, we further performed a set of data analyses, including linkage disequilibrium and haplotype analysis, epigenetic annotation, expression quantitative trait locus (eQTL) analysis and metabolic pathway analysis. Further, we have established a mouse pre osteoblasts differentiation cell model (MC3T3-E1) by recombination human bone morphogenetic protein (rh-BMP2) induction. siRNA- mediated knock down of BDNF in this cell model showed that all 14 SNPs are in the same haplotype block. Strong signals of active histone H3K4me1, H3K4me3, H3K27ac modifications and P300 binding were observed in osteoblasts, in the region surrounding the most significant SNP rs16917237, suggesting that this SNP might have a regulatory function in osteoblasts. Furthermore, analysis of genotype data of rs16917237 and BDNF expression in multiple tissues from GTEx showed that rs16917237 SNP could significantly affect the expression of BDNF in 11 tissues. Through analysis of the various BDNF pathways, we showed that BDNF participates in the MAPK pathway, which is a vital and well-established pathway affecting osteoblasts proliferation and differentiation. siRNA knock down of BDNF significantly decreased the mRNA and protein levels of CREB, which is important in the MAPK pathway in osteoblast differentiation. These findings suggest that BDNF might affect osteoblast differentiation via regulation of CREB expression. In conclusion, our results from combined genetic association and functional analyses show that BDNF is a vital osteoporosis susceptibility gene, which can affect BMD not only in Chinese Han but also likely in other populations. PMID- 28903901 TI - Genome-wide analysis of the GST gene family in Gossypium hirsutum L. AB - Glutathione-S-transferase (GST) is a ubiquitous multi-functional protein superfamily that plays important roles in plant primary and secondary metabolism, stress and intercellular signal transduction. Concomitantly, it also functions as a ligand in the metabolism of plant hormones and substance transport. In order to understand the GST gene family in upland cotton (Gossypium hirsutum L.), herein we analyzed the species, evolutionary relationship, physical location, gene structure, conserved motifs and expression patterns. We identified 70 GST genes in the whole genome of upland cotton, and divided them into U, F, T, Z, EF1Bgamma and TCHQD groups by phylogenetic tree and gene structure analyses. The gene mapping analysis indicated that the GST genes were on every chromosome except chromosome AD/At2, AD/At4, AD/At5, AD/Dt5 and AD/Dt10. Moreover, the GST gene cluster appeared on four chromosomes (AD/At9, AD/Dt7, AD/Dt12 and AD/Dt13). qRT PCR assays showed that eight genes (GhGSTF2-9) were expressed in the root, stem, leave and fiber of different developmental stages while GhGSTF1 might be a pseudogene. Combining qRT-PCR and bioinformatic analysis, we speculated that GhGSTF8 might be involved in the transport and accumulation of proanthocyanidins/anthocyanins; GhGSTF4, 6 and 9 might play roles in regulating the growth and stress response of upland cotton; the function of GhGSTF2, 3, 5 and 7 remains to be further investigated. Our work provides a theoretical basis for further studies on the molecular evolution and function of the GST gene family in upland cotton. PMID- 28903902 TI - Single-cell gene variation analysis method for single gland. AB - Single-cell analysis of heterogeneity has become the cutting-edge technology for profound understandings of relationships between cell populations. At present, common methods used in single cellular genomic research are mainly microfluidic technologies (Fluidigm) or based on microwells, both requiring a uniform size of cells at the entrance. However, the size of cells in specific tissues can vary from type to type. To address this issue, we need to establish a method to identify genomic features of individual cells of different sizes. In this paper, we developed a robust method in the analysis of single cellular genomic mutations among gastric tissues. Briefly, the single gastric gland was isolated from the whole tissue, and further enzymatically digested into single cells of various sizes by trypsin. These single cells were then spread on the polyethylene naphthalene slides and selected by the laser microdissection method. Whole genome amplification (WGA) and capillary electrophoresis were performed subsequently to detect single cell microsatellite. This method enabled us to detect the existence of microsatellite instability (MSI) of each single cell within the intestinal metaplasia, and to carry out a flexible and fine analysis of single cells with different sizes in tissues and glands. This reliable and practical method is well performed in both low and high-throughput genome analysis when combined with cell labeling methods, thus providing a novel and highly flexible way to study tissue heterogeneity on the single cell scale. PMID- 28903903 TI - Utilization of Caenorhabditis elegans in laboratory teaching of genetics. AB - Caenorhabditis elegans is one of the most important model organisms in the study of biology. It is ideal for laboratory teaching due to its short life cycle and low cost. It enriches the teaching content and can motivate students' interest of learning. In this article, we have shown cased C. elegans for the observation of life cycle and mating, as well as the investigation of single nucleotide polymorphism (SNP) and RNA interfere. In addition, we also discuss the details of the experimental design, basic requirement, preparations and related information. We conclude that C. elegans can be used as the experimental materials for teaching college laboratory courses, such as genetic, cell biology, model biology and developmental biology. PMID- 28903904 TI - Insights of sex determination and differentiation from medaka as a teleost model. AB - The mechanisms of sex determination and differentiation in fish are highly divergent with a broad range of gonadal differentiation types from hermaphroditism to gonochorism. Multiple triggers regulate the process of sexual differentiation including genetic or environmental factors (temperature, light, hormones and/or pH value, etc.). In recent years, with the advances of molecular technologies and genetic engineering approaches, there are significant breakthroughs in identifying the master genes of vertebrate sex determination and differentiation. In this review, we explore the fundamental and molecular mechanisms underlying the sexual differentiation in teleost fish, using medaka (Oryzias latipes) as a model. We focus on the male pathways and factors, particularly on dmrt1, gsdf and amh genes involved in testicular differentiation, sexual reversal and plasticity. It is anticipated that new techniques will likely be developed in the field of sex manipulations and monosex breeding for fish aquaculture in the future. PMID- 28903905 TI - The pathogenicity of genomic/genetic variant of X-chromosomal genes in males with intellectual disability. AB - Intellectual Disability (ID, previously named mental retardation) is a group of common pediatric neurology disorders characterized by extensive genetic and phenotypic heterogeneity. About 25%-50% of ID was caused by genomic/genetic variants, in which genomic/genetic variants of X-chromosome are one of key pathogenic causation (25%-30%), resulting in X-linked ID (XLID). The epidemiological data showed that the male to female ratio is 1.3: 1 in ID patients. The prevalence of XLID in the whole ID population is 10%-15%, and this prevalence reaches 20%-25% in the male ID population. This sex-related differential proportion of ID may be attributed to hemizygosity of X chromosomes in males. A quick detection of genomic/genetic aberrations of X chromosome is feasible and available now due to the overwhelming development of next-generation genomic techniques and their clinical applications; in particular, whole exome sequencing, customer-designed whole genomic chip for the X chromosome, high density target sequencing and whole X chromosomal sequencing are used widely for clinical diagnosis. In this review, we systematically summarize the pathogenicity and characteristics of X-chromosomal genomic/genetic aberrations in the male patients with ID, and how the new technologies have been used to detect X chromosomal abnormalities. This review will help researchers understand the pathogenicity of X-chromosomal variations in male ID patients from the view of whole genome, refresh the knowledge about the genomic/genetic etiology of ID, and further provide a theoretical basis for genetic counseling and prenatal diagnosis in the future. PMID- 28903906 TI - The roles of Fanconi anemia genes in the regulation of follicle development. AB - Fanconi anemia (FA) is a rare recessive autosomal or X-linked genetic disease caused by the mutations of the FA genes. The FA genes are involved in the homologous recombination repair processes of damaged interstrand crosslinks in DNA. Premature ovarian insufficiency (POI) is commonly observed in female FA patients and in mice of experimental FA models with serious deficiency of germ cells, suggesting that FA genes could play an important role(s) in follicle development in mammals. Studies have showed that FA genes play significant functions in promoting the proliferation of primordial germ cell, maintaining normal meiosis of the oocytes, participating in the gonadotropin regulation of oocytes and granular cell growth, and other aspects of regulation of follicular development. In this review, we summarize the roles and molecular mechanisms of FA genes in the development of mammalian follicle, which may provide some insights on the genetic basis for the etiology of POI. PMID- 28903907 TI - Research progress on genetic heterogeneity between primary and paired metastatic colorectal cancer. AB - Colorectal cancer (CRC) is one of the leading causes of cancer deaths in China. A standard practice in treating metastatic CRC (mCRC) is to predict benefits of the anti-EGFR monoclonal antibody treatment based on the somatic mutation spectrum. Because metastatic samples are difficult to obtain clinically, primary tumors are normally used instead. However, due to the genetic heterogeneity between primary and paired metastatic tumors, primary site biopsy always underrepresents the mutational landscape of metastatic sites. Currently, the extent of genetic heterogeneity between primary and paired mCRC is still under debate. Here, we review comparative studies of primary and matched mCRC and discuss the underlying causes and potential strategies. PMID- 28903908 TI - Advances in genome-wide association studies for important traits in sheep and goats. AB - Genome-wide association study (GWAS), an effective strategy to identify genetic variants associated with complex traits, has been used to study candidate genes of economical traits in animals. With the recent completion of sheep and goat genomes, single nucleotide polymorphism (SNP) chips of different densities are developed and commercialized. All these advances have enlarged the collection of molecular markers and also shed new light on the genetics of traits of interest in sheep and goats. In this review, we focus on the adoption of GWAS for important traits in sheep and goats, such as horn types, wool, dairy, growth and meat, reproduction and disease types, etc., and summarize the populations, major statistical methods and results of the GWAS analysis. Moreover, we also discuss the current state of GWAS, aiming to provide a reference for further studies on the genetic background of the important traits of sheep and goats by GWAS. PMID- 28903909 TI - Identification of differentially expressed genes between subcutaneous and intramuscular adipose tissue of Large White pig using RNA-seq. AB - To explore the molecular mechanisms of lipid accumulation in different types of adipose tissue, the transcriptomes of the subcutaneous and intramuscular adipose tissues from the Large White pig were determined using RNA-seq technology and bioinformatics methods. The differential gene expression profiles were identified and analyzed with the Gene Ontology, KEGG pathway and protein-protein interaction network strategies. There were 180 differentially expressed genes between the two adipose tissues. The genes up-regulated in the subcutaneous, as compared to intramuscular, adipose tissues were mainly involved in the biological processes related to lipid metabolism. The down-regulated genes were significantly enriched in MAPK signaling pathway, suggesting that this signaling pathway could have an important regulatory role(s) in adipocyte differentiation. In summary, differentially expressed genes between the subcutaneous and intramuscular adipose tissues were predominantly involved in lipid metabolism/accumulation and regulation of adipogenesis in the Large White pig. PMID- 28903910 TI - Genome-wide identification, subcellular localization and gene expression analysis of the members of CESA gene family in common tobacco (Nicotiana tabacum L.). AB - Cellulose-synthase proteins (CESAs) are membrane localized proteins and they form protein complexes to produce cellulose in the plasma membrane. CESA proteins play very important roles in cell wall construction during plant growth and development. In this study, a total of 21 NtCESA gene sequences were identified by using PF03552 conserved protein sequence and 10 AtCESA protein sequences of Arabidopsis thaliana to blast against the common tobacco (Nicotiana tabacum L.) genome database with TBLASTN protocol. We analyzed the physical and chemical properties of protein sequences based on some software or on-line analysis tools. The results showed that there were no significant variances in terms of the physical and chemical properties of the 21 NtCESA proteins. First, phylogenetic tree analysis showed that 21 NtCESA genes and 10 AtCESA genes were clustered into five groups, and the gene structures were similar among the genes that are clustered into the same group. Second, in all of the 21 NtCESA proteins the conserved zinc finger domain was identified in the N-terminus, transmembrane domains were identified in the C-terminus and the DDD-QXXRW conserved domains were also identified. Third, gene expression analysis results indicated that most NtCESA genes were expressed in roots and leaves of seedling or mature tissues of tobacco, seeds and callus tissues. The genes that clustered into the same group share similar expression patterns. Importantly, NtCESA proteins that are involved in secondary cell wall cellulose synthesis have two extra transmembrane domains compared with that involved in primary cell wall cellulose biosynthesis. In addition, subcellular localization results showed that NtCESA9 and NtCESA14 were two plasma membrane anchored proteins. This study will lay a foundation for further functional characterization of these NtCESA genes. PMID- 28903911 TI - A visual multiplex PCR microchip with easy sample loading. AB - There is an urgent demand for affordable, rapid and easy-to-use technology to simultaneously detect many different DNA targets within one reaction. Conventional multiplex PCR is an effective methodology to simultaneously amplify different DNA targets. However, its multiplicity is limited due to the intrinsic interference and competition among primer pairs within one tube. Here, we present an easy multiplex PCR microchip system, which can simultaneously detect 54 targets. The design of the microchip is quite simple. There is a microchannel connected with multiple underlying parallel microwells. And every microchannel has an inlet/outlet for loading PCRmix. The surface of the microchannel is hydrophobic and the inner surface of the microwell is hydrophilic, which enables us to load and separate the PCRmix into different microwells simultaneously. Different primer pairs and low melting agarose are pre-fixed in different microwells, and the microchip is assembled with top glass. The PCRmix is loaded into inlets and then mineral oil is sequentially pipetted into channels to push the PCRmix into all microwells and subsequently mineral oil fills the channels to avoid cross contaminations. After the PCRmix is loaded, it would be placed on a plat thermal cycler for PCR. During PCR, the low melting gel in the well is liquid and after PCR it would be solidified due to temperature changes. When PCR is completed, a nucleic acid dye is introduced into channels and then results are visualized by a home-made, potable UV detector. In our platform we successfully detected seven frequently used targets of genetically modified (GM) organisms. The results demonstrate that our platform has high flexibility and specificity. Due to the excellent performance of this technology, we believe that it can be applied to multiple nucleic acid detection fields including GM organisms. PMID- 28903912 TI - Corrigendum. PMID- 28903913 TI - Hurricane Harvey and pharmacy's call to action. PMID- 28903914 TI - Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. AB - Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol 314: R71-R83, 2018. First published September 13, 2017; doi: 10.1152/ajpregu.00157.2017 .-Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS R1a) in the pancreas has raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signaling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [d-Lys3]-growth hormone-releasing peptide (GHRP)-6, on glucose homeostasis, food intake, and indirect calorimetric parameters in nonobese diabetic MKR mice. Our results showed that [d-Lys3]-GHRP-6 (200 nmol/mouse) reduced pulsatile growth hormone secretion and body fat mass as expected but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and C-peptide levels were observed in MKR mice following long-term [d-Lys3]-GHRP-6 treatment, suggesting a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin-positive cells and a decrease in insulin positive cells in [d-Lys3]-GHRP-6-treated mice. Furthermore, [d-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of proopiomelanocortin gene expression and antagonized GH secretion via reduced growth hormone-releasing hormone gene expression in hypothalamus. These results demonstrate that [d-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes. PMID- 28903916 TI - Beating type 2 diabetes into remission. PMID- 28903917 TI - Screening for glaucoma using intraocular pressure alone. PMID- 28903915 TI - Obesity modulates diaphragm curvature in subjects with and without COPD. AB - Obesity is a common comorbidity of chronic obstructive pulmonary disease (COPD) and has been associated with worse outcomes. However, it is unknown whether the interaction between obesity and COPD modulates diaphragm shape and consequently its function. The body mass index (BMI) has been used as a correlate of obesity. We tested the hypothesis that the shape of the diaphragm muscle and size of the ring of its insertion in non-COPD and COPD subjects are modulated by BMI. We recruited 48 COPD patients with postbronchiodilator forced expiratory volume in 1 s (FEV1)-to-forced vital capacity (FVC) < 0.7 and 29 age-matched smoker/exsmoker control (non-COPD) subjects, who underwent chest computed tomography (CT) at lung volumes ranging from functional residual capacity (FRC) to total lung capacity (TLC). We then computed maximum principal diaphragm curvature in the midcostal region of the left hemidiaphragm at the end of inspiration during quiet breathing (EI) and at TLC. The radius of maximum curvature of diaphragm muscle increased with BMI in both COPD and non-COPD subjects. The size of diaphragm ring of insertion on the chest wall also increased significantly with increasing BMI. Surprisingly, COPD severity did not appear to cause significant alteration in diaphragm shape except in normal-weight subjects at TLC. Our data uncovered important factors such as BMI, the size of the diaphragm ring of insertion, and disease severity that modulate the structure of the ventilatory pump in non-COPD and COPD subjects. PMID- 28903919 TI - Mary Black: Likely to change the rules. PMID- 28903918 TI - (Pro)renin receptor mediates albumin-induced cellular responses: role of site-1 protease-derived soluble (pro)renin receptor in renal epithelial cells. AB - Proteinuria is a characteristic of chronic kidney disease and also a causative factor that promotes the disease progression, in part, via activation of the intrarenal renin-angiotensin system (RAS). (Pro)renin receptor (PRR), a newly discovered component of the RAS, binds renin and (pro)renin to promote angiotensin I generation. The present study was performed to test the role of soluble PRR (sPRR) in albumin overload-induced responses in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells. Bovine serum albmuin (BSA) treatment for 24 h at 20 mg/ml induced renin activity and inflammation, both of which were attenuated by a PRR decoy inhibitor PRO20. BSA treatment induced a more than fivefold increase in medium sPRR due to enhanced cleavage of PRR. Surprisingly, this cleavage event was unaffected by inhibition of furin or a disintegrin and metalloproteinase 19. Screening for a novel cleavage enzyme led to the identification of site-1 protease (S1P). Inhibition of S1P with PF-429242 or siRNA remarkably suppressed BSA-induced sPRR production, renin activity, and inflammatory response. Administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. In HK-2 cells overexpressing PRR, mutagenesis of the S1P, but not furin cleavage site, reduced sPRR levels. Together, these results suggest that PRR mediates albumin-induced cellular responses through S1P-derived sPRR. PMID- 28903920 TI - Should Google offer an online screening test for depression? PMID- 28903921 TI - Opioid prescriptions in England doubled over 12 years, study shows. PMID- 28903923 TI - Violent crime at GP surgeries is on the rise, figures show. PMID- 28903922 TI - Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials. AB - Objectives To examine the risk of relapse and time to relapse after discontinuation of antidepressants in patients with anxiety disorder who responded to antidepressants, and to explore whether relapse risk is related to type of anxiety disorder, type of antidepressant, mode of discontinuation, duration of treatment and follow-up, comorbidity, and allowance of psychotherapy.Design Systematic review and meta-analyses of relapse prevention trials.Data sources PubMed, Cochrane, Embase, and clinical trial registers (from inception to July 2016).Study selection Eligible studies included patients with anxiety disorder who responded to antidepressants, randomised patients double blind to either continuing antidepressants or switching to placebo, and compared relapse rates or time to relapse.Data extraction Two independent raters selected studies and extracted data. Random effect models were used to estimate odds ratios for relapse, hazard ratios for time to relapse, and relapse prevalence per group. The effect of various categorical and continuous variables was explored with subgroup analyses and meta-regression analyses respectively. Bias was assessed using the Cochrane tool.Results The meta-analysis included 28 studies (n=5233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n=3002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n=11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n=28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n=28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n=27 studies).Conclusions Up to one year of follow-up, discontinuation of antidepressant treatment results in higher relapse rates among responders compared with treatment continuation. The lack of evidence after a one year period should not be interpreted as explicit advice to discontinue antidepressants after one year. Given the chronicity of anxiety disorders, treatment should be directed by long term considerations, including relapse prevalence, side effects, and patients' preferences. PMID- 28903925 TI - Brenda Fitzgerald: Trump's public health chief wants to partner with industry. PMID- 28903926 TI - Working when exhausted is unacceptable. PMID- 28903924 TI - Multivariate and network meta-analysis of multiple outcomes and multiple treatments: rationale, concepts, and examples. PMID- 28903927 TI - Patient Commentary: Online screening for depression-old (paternalistic) wine in new (digital) bottles. PMID- 28903928 TI - Allergan transfers Restasis patent to Mohawk tribe to deter challenges from generics. PMID- 28903929 TI - What it feels like to have a facial disfigurement. PMID- 28903930 TI - Generations of care. PMID- 28903931 TI - When doctors disagree, how do patients decide? PMID- 28903932 TI - NHS is warned to be on high alert for flu this winter. PMID- 28903933 TI - Antibiotics are recommended in preterm labour to stop group B streptococcal transmission. PMID- 28903934 TI - STP savings plans are "not credible," think tanks warn. PMID- 28903935 TI - Glaucoma and intraocular pressure in EPIC-Norfolk Eye Study: cross sectional study. AB - Objectives To report the distribution of intraocular pressure (IOP) by age and sex and the prevalence of glaucoma.Design Community based cross sectional observational study.Setting EPIC-Norfolk cohort in Norwich and the surrounding rural and urban areas.Participants 8623 participants aged 48-92 recruited from the community who underwent ocular examination to identify glaucoma.Main outcome measures Prevalence and characteristics of glaucoma, distribution of IOP, and the sensitivity and specificity of IOP for case finding for glaucoma.Results The mean IOP in 8401 participants was 16.3 mm Hg (95% confidence interval 16.2 mm Hg to 16.3 mm Hg; SD 3.6 mm Hg). In 363 participants (4%), glaucoma was present in either eye; 314 (87%) had primary open angle glaucoma. In the remaining participants, glaucoma was suspected in 607 (7%), and 863 (10.0%) had ocular hypertension. Two thirds (242) of those with glaucoma had previously already received the diagnosis. In 76% of patients with newly diagnosed primary open angle glaucoma (83/107), the mean IOP was under the threshold for ocular hypertension (21 mm Hg). No one IOP threshold provided adequately high sensitivity and specificity for diagnosis of glaucoma.Conclusions In this British community, cases of glaucoma, suspected glaucoma, and ocular hypertension represent a large number of potential referrals to the hospital eye service. The use of IOP for detection of those with glaucoma is inaccurate and probably not viable. PMID- 28903936 TI - Aortic Valve Stenosis Alters Expression of Regional Aortic Wall Shear Stress: New Insights From a 4-Dimensional Flow Magnetic Resonance Imaging Study of 571 Subjects. AB - BACKGROUND: Wall shear stress (WSS) is a stimulus for vessel wall remodeling. Differences in ascending aorta (AAo) hemodynamics have been reported between bicuspid aortic valve (BAV) and tricuspid aortic valve patients with aortic dilatation, but the confounding impact of aortic valve stenosis (AS) is unknown. METHODS AND RESULTS: Five hundred seventy-one subjects underwent 4-dimensional flow magnetic resonance imaging in the thoracic aorta (210 right-left BAV cusp fusions, 60 right-noncoronary BAV cusp fusions, 245 tricuspid aortic valve patients with aortic dilatation, and 56 healthy controls). There were 166 of 515 (32%) patients with AS. WSS atlases were created to quantify group-specific WSS patterns in the AAo as a function of AS severity. In BAV patients without AS, the different cusp fusion phenotypes resulted in distinct differences in eccentric WSS elevation: right-left BAV patients exhibited increased WSS by 9% to 34% (P<0.001) at the aortic root and along the entire outer curvature of the AAo whereas right-noncoronary BAV patients showed 30% WSS increase (P<0.001) at the distal portion of the AAo. WSS in tricuspid aortic valve patients with aortic dilatation patients with no AS was significantly reduced by 21% to 33% (P<0.01) in 4 of 6 AAo regions. In all patient groups, mild, moderate, and severe AS resulted in a marked increase in regional WSS (P<0.001). Moderate-to-severe AS further increased WSS magnitude and variability in the AAo. Differences between valve phenotypes were no longer apparent. CONCLUSIONS: AS significantly alters aortic hemodynamics and WSS independent of aortic valve phenotype and over-rides previously described flow patterns associated with BAV and tricuspid aortic valve with aortic dilatation. Severity of AS must be considered when investigating valve-mediated aortopathy. PMID- 28903937 TI - Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes, macrophages, and endothelial cells of capillaries but not arteries. FABP4 is secreted from adipocytes in association with lipolysis, and an elevated circulating FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the link between FABP4 and endovascular injury. We investigated the involvement of ectopic FABP4 expression in endothelial cells in neointima hyperplasia after vascular injury. METHODS AND RESULTS: Femoral arteries of 8-week-old male mice were subjected to wire-induced vascular injury. After 4 weeks, immunofluorescence staining showed that FABP4 was ectopically expressed in endothelial cells of the hyperplastic neointima. Neointima formation determined by intima area and intima to media ratio was significantly decreased in FABP4-defficient mice compared with that in wild-type mice. Adenovirus-mediated overexpression of FABP4 in human coronary artery endothelial cells (HCAECs) in vitro increased inflammatory cytokines and decreased phosphorylation of nitric oxide synthase 3. Furthermore, FABP4 was secreted from HCAECs. Treatment of human coronary smooth muscle cells or HCAECs with the conditioned medium of Fabp4-overexpressed HCAECs or recombinant FABP4 significantly increased gene expression of inflammatory cytokines and proliferation- and adhesion-related molecules in cells, promoted cell proliferation and migration of human coronary smooth muscle cells, and decreased phosphorylation of nitric oxide synthase 3 in HCAECs, which were attenuated in the presence of an anti-FABP4 antibody. CONCLUSIONS: Ectopic expression and secretion of FABP4 in vascular endothelial cells contribute to neointima formation after vascular injury. Suppression of ectopic FABP4 in the vascular endothelium would be a novel strategy against post-angioplasty vascular restenosis. PMID- 28903938 TI - Atrial Fibrillation in Acute Obstructive Sleep Apnea: Autonomic Nervous Mechanism and Modulation. AB - BACKGROUND: The mechanisms of atrial fibrillation (AF) induced by obstructive sleep apnea (OSA) are not completely understood. This study investigated the roles of the intrinsic and extrinsic cardiac autonomic nervous system in OSA induced AF and provided noninvasive autonomic nervous modulation for the suppression of OSA-induced AF by using low-level transcutaneous electrical stimulation (LL-TS) of the auricular branch of the vagus nerve at the tragus. METHODS AND RESULTS: Eighteen dogs received tracheostomy under general anesthesia and were randomly divided into 3 groups: the OSA group (OSA was simulated via clamping of the endotracheal tube at end expiration for 1.5 minutes every 10 minutes, n=6), the LL-TS + OSA group (simulated OSA plus LL-TS, at 80% of the slowing sinus rate, n=6), and the control group (sham surgery without stimulation, n=6). The effective refractory period was significantly shortened after 1 hour of simulated OSA, and the window of vulnerability and plasma norepinephrine levels were both markedly increased in the OSA group. OSA dramatically increased the neural function and activity of the intrinsic and extrinsic cardiac autonomic nervous system, including the superior left ganglionated plexus, the left stellate ganglion, and the left renal sympathetic nerve. OSA also significantly upregulated the expression levels of c-fos and nerve growth factor in the superior left ganglionated plexus and the left stellate ganglion. However, LL-TS markedly improved these parameters. CONCLUSIONS: These findings suggest that the intrinsic and extrinsic cardiac autonomic nervous system plays crucial roles in the acute stage of OSA-induced AF. Noninvasive LL-TS suppressed shortening of atrial refractoriness and autonomic remodeling, which prevented OSA-induced AF. PMID- 28903939 TI - Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Chronic Total Coronary Occlusion With Well-Developed Collaterals. AB - BACKGROUND: The impact of percutaneous coronary intervention (PCI) on chronic total occlusion in patients with well-developed collaterals is not clear. METHODS AND RESULTS: A total of 640 chronic total occlusion patients with collateral flow grade >=2 were divided into 2 groups; chronic total occlusion patients either treated with PCI (the PCI group; n=305) or optimal medical therapy (the optimal medical therapy group; n=335). To adjust for potential confounders, a propensity score matching analysis was performed. Major clinical outcomes were compared between the 2 groups up to 5 years. In the entire population, the PCI group had a lower hazard of myocardial infarction (hazard ratio [HR], 0.177; P=0.039; 95% confidence interval [CI], 0.03-0.91) and the composite of total death or myocardial infarction (HR, 0.298; P=0.017; 95% CI, 0.11-0.80); however, it showed higher hazard of target lesion revascularization (HR, 3.942; P=0.003; 95% CI, 1.58-9.81) and target vessel revascularization (HR, 4.218; P=0.001; 95% CI, 1.85 9.60). After propensity score matching, a total of 158 matched pairs were generated. Although the PCI group showed a higher hazard of target lesion revascularization (HR, 2.868; P=0.027; 95% CI, 1.13-7.31) and target vessel revascularization (HR=2.62; P=0.022; 95% CI, 1.15-5.97), it still exhibited a lower incidence of the composite of total death or myocardial infarction (HR, 0.263; P=0.017; 95% CI, 0.087-0.790). The mean ejection fraction was improved from 47.8% to 51.6% (P<0.001) after PCI. CONCLUSIONS: In our study, successful revascularization by PCI for chronic total occlusion lesions with well-developed collaterals was associated with lower incidence of death and myocardial infarction, improved left ventricular function, but increased repeat revascularization rate. PMID- 28903940 TI - Secondary Open Aortic Procedure Following Thoracic Endovascular Aortic Repair: Meta-Analytic State of the Art. AB - BACKGROUND: Thoracic endovascular aortic repair is characterized by a substantial need for reintervention. Secondary open aortic procedure becomes necessary when further endoluminal options are exhausted. This synopsis and quantitative analysis of available evidence aims to overcome the limitations of institutional cohort reports on secondary open aortic procedure. METHODS AND RESULTS: Electronic databases were searched from 1994 to the present date with a prospectively registered protocol. Pooled quantification of pre/intraoperative variables, and proportional meta-analysis with random effect model of early and midterm outcomes were performed. Subgroup analysis was conducted for patients who had early mortality. Fifteen studies were elected for final analysis, encompassing 330 patients. The following values are expressed as "pooled mean, 95% confidence interval." Type B dissection was the most common pathology at index thoracic endovascular aortic repair (51.2%, 44.4-57.9). The most frequent indication for secondary open aortic procedure was endoleak (39.7%, 34.6-45.1). More than half of patients had surgery on the descending aorta (51.2%, 45.8 56.6), and one fourth on the arch (25.2%, 20.8-30.1). Operative mortality was 10.6% (7.4-14.9). Neurological morbidity was substantial between stroke (5.1%, 2.8-9.1) and paraplegia (8.3%, 5.2-13.1). At 2-year follow-up, mortality (20.4%, 11.5-33.5) and aortic adverse event (aortic death 7.7%, 4.3-13.3, tertiary aortic open procedure 7.4%, 4.0-13.2) were not negligible. CONCLUSIONS: In the secondary open aortic procedure population, type B dissection was both the most common pathology and the one associated with the lowest early mortality, whereas aortic infection and extra-anatomical bypass were associated with the most ominous prognosis. PMID- 28903941 TI - Increased Hazard of Myocardial Infarction With Insulin-Provision Therapy in Actively Smoking Patients With Diabetes Mellitus and Stable Ischemic Heart Disease: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) Trial. AB - BACKGROUND: In the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, randomization of diabetic patients with stable ischemic heart disease to insulin provision (IP) therapy, as opposed to insulin sensitization (IS) therapy, resulted in biochemical evidence of impaired fibrinolysis but no increase in adverse clinical outcomes. We hypothesized that the prothrombotic effect of IP therapy in combination with the hypercoagulable state induced by active smoking would result in an increased risk of myocardial infarction (MI). METHODS AND RESULTS: We analyzed BARI 2D patients who were active smokers randomized to IP or IS therapy. The primary end point was fatal or nonfatal MI. PAI-1 (plasminogen activator inhibitor 1) activity was analyzed at 1, 3, and 5 years. Of 295 active smokers, MI occurred in 15.4% randomized to IP and in 6.8% randomized to IS over the 5.3 years (P=0.023). IP therapy was associated with a 3.2-fold increase in the hazard of MI compared with IS therapy (hazard ratio: 3.23; 95% confidence interval, 1.43-7.28; P=0.005). Baseline PAI-1 activity (19.0 versus 17.5 Au/mL, P=0.70) was similar in actively smoking patients randomized to IP or IS therapy. However, IP therapy resulted in significantly increased PAI-1 activity at 1 year (23.0 versus 16.0 Au/mL, P=0.001), 3 years (24.0 versus 18.0 Au/mL, P=0.049), and 5 years (29.0 versus 15.0 Au/mL, P=0.004) compared with IS therapy. CONCLUSIONS: Among diabetic patients with stable ischemic heart disease who were actively smoking, IP therapy was independently associated with a significantly increased hazard of MI. This finding may be explained by higher PAI 1 activity in active smokers treated with IP therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305. PMID- 28903942 TI - WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly. PMID- 28903943 TI - Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies. AB - Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD) based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19 expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 MUg/kg (3 MUg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 MUg/kg (1 MUg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20+ B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT02702141. PMID- 28903945 TI - Complement C5a receptors C5L2 and C5aR in renal fibrosis. AB - Complement factor C5a has two known receptors, C5aR, which mediates proinflammatory effects, and C5L2, a potential C5a decoy receptor. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury. Expression of key proinflammatory mediators, however, significantly increased in C5L2- compared with C5aR-deficient mice, but this had no effect on the number of renal infiltrating macrophages or T cells. Moreover, in C5L2-/- mice, the cytokine and matrix metalloproteinase-inhibitor tissue inhibitor of matrix metalloproteinase-1 was specifically enhanced. Consequently, in C5L2-/- mice the degree of renal fibrosis was similar to wild type (WT), albeit with reduced mRNA expression of some fibrosis-related genes. In contrast, C5aR-/- mice had significantly reduced renal fibrosis compared with WT and C5L2-/- mice in UUO. In vitro experiments with primary tubular cells demonstrated that deficiency for either C5aR or C5L2 led to a significantly reduced expression of tubular injury and fibrosis markers. Vice versa, stimulation of WT tubular cells with C5a significantly induced the expression of these markers, whereas the absence of either receptor abolished this induction. In conclusion, in experimental renal fibrosis C5L2 and C5aR both contribute to tubular injury, and, while C5aR acts profibrotic, C5L2 does not play a role in extracellular matrix accumulation, arguing against C5L2 functioning simply as a decoy receptor. PMID- 28903944 TI - A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth. AB - To uncover the role of Vps34, the sole class III phosphoinositide 3-kinase (PI3K), in megakaryocytes (MKs) and platelets, we created a mouse model with Vps34 deletion in the MK/platelet lineage (Pf4-Cre/Vps34lox/lox). Deletion of Vps34 in MKs led to the loss of its regulator protein, Vps15, and was associated with microthrombocytopenia and platelet granule abnormalities. Although Vps34 deficiency did not affect MK polyploidisation or proplatelet formation, it dampened MK granule biogenesis and directional migration toward an SDF1alpha gradient, leading to ectopic platelet release within the bone marrow. In MKs, the level of phosphatidylinositol 3-monophosphate (PI3P) was significantly reduced by Vps34 deletion, resulting in endocytic/trafficking defects. In platelets, the basal level of PI3P was only slightly affected by Vps34 loss, whereas the stimulation-dependent pool of PI3P was significantly decreased. Accordingly, a significant increase in the specific activity of Vps34 lipid kinase was observed after acute platelet stimulation. Similar to Vps34-deficient platelets, ex vivo treatment of wild-type mouse or human platelets with the Vps34-specific inhibitors, SAR405 and VPS34-IN1, induced abnormal secretion and affected thrombus growth at arterial shear rate, indicating a role for Vps34 kinase activity in platelet activation, independent from its role in MKs. In vivo, Vps34 deficiency had no impact on tail bleeding time, but significantly reduced platelet prothrombotic capacity after carotid injury. This study uncovers a dual role for Vps34 as a regulator of platelet production by MKs and as an unexpected regulator of platelet activation and arterial thrombus formation dynamics. PMID- 28903947 TI - Fight, flight or finished: forced fitness behaviours in Game of Thrones. PMID- 28903946 TI - PPARalpha agonist fenofibrate enhances fatty acid beta-oxidation and attenuates polycystic kidney and liver disease in mice. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear hormone receptor that promotes fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARalpha and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARalpha and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARalpha and FAO/OXPHOS genes is downregulated, and in vivo beta-oxidation rate of 3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARalpha, we conducted a 5 mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARalpha agonist. Fenofibrate treatment resulted in increased expression of PPARalpha and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher beta-oxidation rates in Pkd1RC/RC kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared with untreated littermate Pkd1RC/RC mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells, including M2 like macrophages. Finally, fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPARalpha activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD. PMID- 28903948 TI - Bright spots, physical activity investments that work-Complete Streets: redesigning the built environment to promote health. PMID- 28903950 TI - Hearing the voices of children and young people to develop and test a patient reported experience measure in a specialist paediatric setting. AB - OBJECTIVE: To develop and test patient-reported experience measures (PREMs) for children and young people in a specialist paediatric hospital setting. DESIGN: Six PREMs were developed and tested by children and young people for children and young people aged 8-11, 12-13 and 14-16 years in inpatient and outpatient settings. A week-long pilot was implemented across inpatient wards and outpatient clinics to identify facilitators and barriers to the routine use of PREMs in a real-time setting across our organisation. SETTING: Tertiary paediatric hospital. MAIN OUTCOME MEASURES: Final PREMs; identified facilitators and barriers to implementation. PARTICIPANTS: 543 children and young people aged 8-16 years attending outpatient clinics or inpatient wards across a range of specialties. RESULTS: Three key themes about hospital experience were identified during focus groups: facilities, treatment and tests and people working at the hospital, and these provided the structure for the questionnaires. During cognitive testing the questionnaires were generally understood but some revisions to language and length of the questionnaires were required. Two designs were selected for the final PREMs. During acceptability and feasibility testing it was evident that children and young people liked the PREMs and wanted to give feedback on their hospital experience. Particular challenges for routine use of the PREMs focused on sustainability and resources. CONCLUSIONS: The new PREMs will provide children and young people receiving care in specialist paediatric hospitals with the opportunity to provide feedback on their experience. Sustainability and ensuring that feedback results in improvements need to be addressed in future work. PMID- 28903949 TI - Intramuscular tendon involvement on MRI has limited value for predicting time to return to play following acute hamstring injury. AB - BACKGROUND: Hamstring injury with intramuscular tendon involvement is regarded as a serious injury with a delay in return to play (RTP) of more than 50 days and reinjury rates up to 63%. However, this reputation is based on retrospective case series with high risk of bias. OBJECTIVE: Determine whether intramuscular tendon involvement is associated with delayed RTP and elevated rates of reinjury. METHODS: MRI of male athletes with an acute hamstring injury was obtained within 5 days of injury. Evaluation included standardised MRI scoring and scoring of intramuscular tendon involvement. Time to RTP and reinjury rate were prospectively recorded. RESULTS: Out of 70 included participants, intramuscular tendon disruption was present in 29 (41.4%) injuries. Injuries without intramuscular tendon disruption had a mean time to RTP of 22.2+/-7.4 days. Injuries with <50%, 50%-99% and 100% disruption of tendon cross-sectional area had a mean time to RTP of 24.0+/-9.7, 25.3+/-8.6 and 31.6+/-10.9 days, respectively. Injuries with full-thickness disruption took longer to RTP compared with injuries without disruption (p=0.025). Longitudinal intramuscular tendon disruption was not significantly associated with time to RTP. Waviness was present in 17 (24.3%) injuries. Mean time to RTP for injuries without and with waviness was 22.6+/-7.5 and 30.2+/-10.8 days (p=0.014). There were 11 (15.7%) reinjuries within 12 months, five (17.2%) in the group with intramuscular tendon disruption and six (14.6%) in the group without intramuscular tendon disruption. CONCLUSION: Time to RTP for injuries with full-thickness disruption of the intramuscular tendon and waviness is significantly longer (by slightly more than 1 week) compared with injuries without intramuscular tendon involvement. However, due to the considerable overlap in time to RTP between groups with and without intramuscular tendon involvement, its clinical significance for the individual athlete is limited. PMID- 28903951 TI - Managing problematic severe asthma: beyond the guidelines. AB - This review discusses issues related to managing problematic severe asthma in children and young people. A small minority of children have genuinely severe asthma symptoms which are difficult to control. Children with genuinely severe asthma need investigations and treatments beyond those described within conventional guidelines. However, the majority of children with poor symptom control despite high-intensity treatment achieve improvement in their asthma control once attention has been paid to the basics of asthma management. Basic asthma management requires optimisation of inhaler technique and treatment adherence, avoidance of environmental triggers and self-management education. It is also important that clinicians recognise risk factors that predispose patients to asthma exacerbations and potentially life-threatening attacks. These correctable issues need to be tackled in partnership with children and young people and their families. This requires a coordinated approach between professionals across healthcare settings. Establishing appropriate infrastructure for coordinated asthma care benefits not only those with problematic severe asthma, but also the wider asthma population as similar correctable issues exist for children with asthma of all severities. Investigation and management of genuine severe asthma requires specialist multidisciplinary expertise and a systematic approach to characterising patients' asthma phenotypes and delivering individualised care. While inhaled corticosteroids continue to play a leading role in asthma therapy, new treatments on the horizon might further support phenotype-specific therapy. PMID- 28903952 TI - Humidified high-flow nasal cannula oxygen for bronchiolitis: should we go with the flow? PMID- 28903953 TI - Looking after each other when a child dies. PMID- 28903954 TI - Quantity and source of dietary protein influence metabolite production by gut microbiota and rectal mucosa gene expression: a randomized, parallel, double blind trial in overweight humans. AB - Background: Although high-protein diets (HPDs) are frequently consumed for body weight control, little is known about the consequences for gut microbiota composition and metabolic activity and for large intestine mucosal homeostasis. Moreover, the effects of HPDs according to the source of protein need to be considered in this context.Objective: The objective of this study was to evaluate the effects of the quantity and source of dietary protein on microbiota composition, bacterial metabolite production, and consequences for the large intestinal mucosa in humans.Design: A randomized, double-blind, parallel-design trial was conducted in 38 overweight individuals who received a 3-wk isocaloric supplementation with casein, soy protein, or maltodextrin as a control. Fecal and rectal biopsy-associated microbiota composition was analyzed by 16S ribosomal DNA sequencing. Fecal, urinary, and plasma metabolomes were assessed by 1H-nuclear magnetic resonance. Mucosal transcriptome in rectal biopsies was determined with the use of microarrays.Results: HPDs did not alter the microbiota composition, but induced a shift in bacterial metabolism toward amino acid degradation with different metabolite profiles according to the protein source. Correlation analysis identified new potential bacterial taxa involved in amino acid degradation. Fecal water cytotoxicity was not modified by HPDs, but was associated with a specific microbiota and bacterial metabolite profile. Casein and soy protein HPDs did not induce inflammation, but differentially modified the expression of genes playing key roles in homeostatic processes in rectal mucosa, such as cell cycle or cell death.Conclusions: This human intervention study shows that the quantity and source of dietary proteins act as regulators of gut microbiota metabolite production and host gene expression in the rectal mucosa, raising new questions on the impact of HPDs on the large intestine mucosa homeostasis. This trial was registered at clinicaltrials.gov as NCT02351297. PMID- 28903956 TI - Closer to clarity on the effect of lipid consumption on fat-soluble vitamin and carotenoid absorption: do we need to close in further? PMID- 28903955 TI - In the elderly, meat protein assimilation from rare meat is lower than that from meat that is well done. AB - Background: Meat cooking conditions in in vitro and in vivo models have been shown to influence the rate of protein digestion, which is known to affect postprandial protein metabolism in the elderly.Objective: The present study was conducted to demonstrate the effect of cooking conditions on meat protein assimilation in the elderly. We used a single-meal protocol to assess the meat protein absorption rate and estimate postprandial meat protein utilization in elderly subjects.Design: The study recruited 10 elderly volunteers aged 70-82 y. Each received, on 2 separate occasions, a test meal exclusively composed of intrinsically 15N-labeled bovine meat (30 g protein), cooked at 55 degrees C for 5 min [rare meat (RM)] or at 90 degrees C for 30 min [fully cooked meat (FCM)], and minced. Whole-body fluxes of leucine, before and after the meal, were determined with the use of a [1-13C]leucine intravenous infusion. Meat protein absorption was recorded with the use of 15N enrichment of amino acids.Results: Postprandial time course observations showed a lower concentration in the plasma of indispensable amino acids (P < 0.01), a lower entry rate of meat leucine in the plasma (P < 0.01), and a lower contribution of meat nitrogen to plasma amino acid nitrogen (P < 0.001), evidencing lower peripheral bioavailability of meat amino acids with RM than with FCM. This was associated with decreased postprandial whole-body protein synthesis with RM than with FCM (40% compared with 56% of leucine intake, respectively; P < 0.01).Conclusions: Whereas meat cooking conditions have little effect on postprandial protein utilization in young adults, the present work showed that the bioavailability and assimilation of meat amino acids in the elderly is lower when meat is poorly cooked. In view to preventing sarcopenia, elderly subjects should be advised to favor the consumption of well-cooked meat. This trial was registered at clinicaltrials.gov as NCT02157805. PMID- 28903958 TI - Can changes in the plasma lipidome help explain the cardiovascular benefits of the Mediterranean diet? PMID- 28903957 TI - Within-day protein distribution does not influence body composition responses during weight loss in resistance-training adults who are overweight. AB - Background: Emerging research suggests that redistributing total protein intake from 1 high-protein meal/d to multiple moderately high-protein meals improves 24 h muscle protein synthesis. Over time, this may promote positive changes in body composition.Objective: We sought to assess the effects of within-day protein intake distribution on changes in body composition during dietary energy restriction and resistance training.Design: In a randomized parallel-design study, 41 men and women [mean +/- SEM age: 35 +/- 2 y; body mass index (in kg/m2): 31.5 +/- 0.5] consumed an energy-restricted diet (750 kcal/d below the requirement) for 16 wk while performing resistance training 3 d/wk. Subjects consumed 90 g protein/d (1.0 +/- 0.03 g . kg-1 . d-1, 125% of the Recommended Dietary Allowance, at intervention week 1) in either a skewed (10 g at breakfast, 20 g at lunch, and 60 g at dinner; n = 20) or even (30 g each at breakfast, lunch, and dinner; n = 21) distribution pattern. Body composition was measured pre- and postintervention.Results: Over time, whole-body mass (least-squares mean +/- SE: -7.9 +/- 0.6 kg), whole-body lean mass (-1.0 +/- 0.2 kg), whole-body fat mass (-6.9 +/- 0.5 kg), appendicular lean mass (-0.7 +/- 0.1 kg), and appendicular fat mass (-2.6 +/- 0.2 kg) each decreased. The midthigh muscle area (0 +/- 1 cm2) did not change over time, whereas the midcalf muscle area decreased (-3 +/- 1 cm2). Within-day protein distribution did not differentially affect these body-composition responses.Conclusion: The effectiveness of dietary energy restriction combined with resistance training to improve body composition is not influenced by the within-day distribution of protein when adequate total protein is consumed. This trial was registered at clinicaltrials.gov as NCT02066948. PMID- 28903960 TI - Biomarkers of food intake and nutrient status are associated with glucose tolerance status and development of type 2 diabetes in older Swedish women. AB - Background: Diet is frequently associated with both the development and prevention of type 2 diabetes (T2D), but there is a lack of objective tools for assessing the relation between diet and T2D. Biomarkers of dietary intake are unconfounded by recall and reporting bias, and using multiple dietary biomarkers could help strengthen the link between a healthy diet and the prevention of T2D.Objective: The objective of this study was to explore how diet is related to glucose tolerance status (GTS) and to future development of T2D irrespective of common T2D and cardiovascular disease risk factors by using multiple dietary biomarkers.Design: Dietary biomarkers were measured in plasma from 64-y-old Swedish women with different GTS [normal glucose tolerance (NGT; n = 190), impaired glucose tolerance (IGT; n = 209), and diabetes (n = 230)]. The same subjects were followed up after 5 y to determine changes in glucose tolerance (n = 167 for NGT, n = 174 for IGT, and n = 159 for diabetes). ANCOVA and logistic regression were used to explore baseline data for associations between dietary biomarkers, GTS, and new T2D cases at follow-up (n = 69).Results: Of the 10 dietary biomarkers analyzed, beta-alanine (beef) (P-raw < 0.001), alkylresorcinols C17 and C19 (whole-grain wheat and rye) (P-raw = 0.003 and 0.011), eicosapentaenoic acid (fish) (P-raw = 0.041), 3-carboxy-4-methyl-5-propyl 2-furanpropanoic acid (CMPF) (fish) (P-raw = 0.002), linoleic acid (P-raw < 0.001), oleic acid (P-raw = 0.003), and alpha-tocopherol (margarine and vegetable oil) (P-raw < 0.001) were associated with GTS, and CMPF (fish) (OR: 0.72; 95% CI: 0.56, 0.93; P-raw = 0.013) and alpha-tocopherol (OR: 0.71; 95% CI: 0.51, 0.98; P raw = 0.041) were inversely associated with future T2D development.Conclusions: Several circulating dietary biomarkers were strongly associated with GTS after correction for known T2D risk factors, underlining the role of diet in the development and prevention of T2D. To our knowledge, this study is the first to use multiple dietary biomarkers to investigate the link between diet and disease risk. PMID- 28903959 TI - Effect of prior meal macronutrient composition on postprandial glycemic responses and glycemic index and glycemic load value determinations. AB - Background: The potential impact of prior meal composition on the postprandial glycemic response and glycemic index (GI) and glycemic load (GL) value determinations remains unclear.Objective: We determined the effect of meals that varied in macronutrient composition on the glycemic response and determination of GI and GL values of a subsequent standard test food.Design: Twenty healthy participants underwent 6 test sessions within 12 wk. The subjects received each of 3 isocaloric breakfast meals (i.e., high carbohydrate, high fat, or high protein) on separate days in a random order, which was followed by a standard set of challenges (i.e., white bread and a glucose drink) that were tested on separate days in a random order 4 h thereafter. Each challenge provided 50 g available carbohydrate. Arterialized venous blood was sampled throughout the 2-h postchallenge period. GI, GL, and insulin index (II) values were calculated with the use of the incremental area under the curve (AUCi) method, and serum lipids were determined with the use of standard assays.Results: The consumption of the high-protein breakfast before the white-bread challenge attenuated the rise in the postprandial serum glucose response (P < 0.0001) and resulted in lower glucose AUCi (P < 0.0001), GI (P = 0.0096), and GL (P = 0.0101) values than did the high-carbohydrate and high-fat breakfasts. The high-protein breakfast resulted in a lower insulin AUCi (P = 0.0146) for white bread than did the high fat breakfast and a lower II value (P = 0.0285) than did the high-carbohydrate breakfast. The 3 breakfasts resulted in similar serum lipid responses to the white-bread challenge.Conclusions: These data indicate that the macronutrient composition of the prior meal influences the glycemic response and the determination of GI and GL values for white bread. Future studies are needed to determine whether the background food macronutrient composition influences mean dietary GI and GL values that are calculated for eating patterns, which may alter the interpretation of the associations between these values and chronic disease risk. This trial was registered at clinicaltrials.gov as NCT01023646. PMID- 28903961 TI - Paediatric optic neuritis: factors leading to unfavourable outcome and relapses. AB - OBJECTIVES: To identify prognostic factors associated with poor visual recovery and chronic relapsing diseases, for example, multiple sclerosis (MS), in children with optic neuritis (ON) at onset. METHODS: This multicentre retrospective study included 102 children with a first ON episode between 1990 and 2012. The primary criterion was poor visual recovery determined by visual acuity, and the secondary was relapses following ON. RESULTS: Median age was 11 years, 66% were girls and mean follow-up was 24 months. 58% of children were diagnosed with idiopathic isolated ON, 22% had MS, 5% had Devic's neuromyelitis optica and 6% chronic relapsing inflammatory ON. Complete visual acuity recovery rate was 57% (95% CI=[46%-69%]) at 6 months and 71% (95% CI=[60%-81%]) at 1 and 2 years but was lower in MS (p<0.01), with recovery rate of only 27% (95% CI=[12%-54%]) at 1 year. Age >=10 years, optic disc pallor at funduscopy and MS were the principal factors associated with poor visual recovery. Age >=10 years, abnormal brain MRI at onset and oligoclonal banding were significantly associated with MS (p<0.01). CONCLUSION: Age >=10, optic disc pallor and MS were associated with poor recovery. Better identification of these patients may help to adapt treatment and lead to a prospective treatment study. PMID- 28903962 TI - An evaluation of intracameral mydriasis for routine cataract surgery. AB - BACKGROUND: Intracameral Mydrane might facilitate a more streamlined cataract service and improve the patient experience. There is limited 'real-world' evidence of its use in a UK setting. METHODS: As part of a local evaluation of cataract surgery using intracameral Mydrane (group 2; n=60), data were collected on intraoperative pupil size and postoperative visual acuity (VA), as well as the rate of mechanical pupil dilation, intraoperative floppy iris syndrome (IFIS) and complications. Preoperative and theatre turnaround time was recorded and patients completed a validated measure of satisfaction postoperatively. Data were compared with a previous cohort subjected to the existing standard regime of preoperative topical mydriatics (group 1; n=60). RESULTS: Postoperative VA was comparable between groups (0.09+/-0.16 vs 0.08+/-0.15; p=0.59). Pupil size in group 2 was 7.0+/-1.0 mm prior to capsulorhexis and 6.5+/-0.29 mm after cortical aspiration, with a smaller pupil in patients on alpha-antagonists (4.7+/-1.1 mm; p=0.004) at this later time point. Comparing group 2 with group 1, preoperative waiting was less (87 vs 146 min; p<0.0001) and satisfaction was higher (76.0+/-11.2 vs 66.3+/ 8.6; p<0.0001), although theatre turnaround time was longer (25 min vs 22 min). CONCLUSION: Intracameral mydriasis was clinically effective in most patients undergoing cataract surgery and might be associated with an improved patient experience and a more streamlined preoperative flow. Mydrane represents a licensed alternative to the off-label use of other intracameral mydriatic agents, but was not judged to be a cost-effective intervention for routine use in this particular setting. PMID- 28903963 TI - Predictors of radio-induced visual impairment after radiosurgery for uveal melanoma. AB - AIMS: The aim of the present work is to assess the main predictors of the most clinically relevant radio-induced effects after Gamma Knife stereotactic radiosurgery (GKRS) for uveal melanoma (UM). MATERIALS AND METHODS: Medical records and three-dimensional dosimetry data of critical structures of 66 patients were retrospectively reviewed. Cox's proportional hazard model was used to identify clinical and dosimetric variables as independent risk factor for GKRS related complications. RESULTS: The fraction of the posterior segment receiving more than 20Gy (V20), Bruch's membrane rupture and tumour thickness were significant prognostic factors for neovascular glaucoma. A clear relationship with the dose received by 1% of the optic nerve (D1%) was found for radiation retinopathy and papillopathy. Multivariables models resulted for visual acuity (VA) reduction >20% of the basal value and for complete VA loss, both including largest tumour diameter and D1% to the optic nerve. The predictive model for complete VA loss includes also Bruch's membrane rupture. An alternative model for complete visual acuity loss, including the optic nerve-prescription isodose minimum distance, was also suggested. CONCLUSIONS: We found clinical and dosimetric variables to clearly predict the risk of the main side effects after GKRS for UM. These results may provide dose constraints to critical structures, potentially able to reduce side effects. Constraining D1% to the optic nerve below 12-13Gy may result in a dramatic reduction of blindness risk, while reducing V20 of the posterior segment of the bulb could limit the neovascular glaucoma onset. PMID- 28903964 TI - Clinical profile of pythium keratitis: perioperative measures to reduce risk of recurrence. AB - PURPOSE: To report the clinical profile and role of perioperative adjunctive measures to reduce the risk of recurrence in Pythium insidiosum keratitis. METHODS: Retrospective analysis of 10 eyes of 10 patients with P. insidiosum keratitis. Diagnosis was confirmed by PCR DNA sequencing. RESULTS: 7out of 10 patients were from urban locales, and none had any obvious history of injury with vegetative matter and were being treated for fungal keratitis. 6 eyes presented with central full thickness infiltrates with subepithelial and superficial stromal infiltrates radiating in a reticular pattern. Corneal scraping in all eyes revealed sparsely septate fungal-like filaments on potassium hydroxide/Calcofluor. All eyes underwent the first therapeutic penetrating keratoplasty (TPK) based on worsening or non-responsiveness of clinical features to the antifungal regimen. Recurrence was noted in 7 out of 10 eyes of which 2 eyes underwent evisceration. Of the six eyes that underwent cryotherapy following confirmation of microbiological diagnosis of Pythium (along with primary TPK-1, with re-TPK-5), only one eye had a recurrence and had to be eviscerated. Of the two eyes that did not undergo cryotherapy during re-TPK, following microbiological diagnosis, one eye had a recurrence and had to be eviscerated. In two eyes with adjoining scleritis, the host bed was swabbed using absolute alcohol of which one eye was salvaged. CONCLUSION: This series highlights the need to be aware of this entity in the management of refractory fungal keratitis. It also brings to fore the adjunctive measures that could have a beneficial role in the management of pythium keratitis. PMID- 28903965 TI - Enteric-coated mycophenolate sodium in the treatment of non-infectious intermediate uveitis: results of a prospective, controlled, randomised, open label, early terminated multicentre trial. AB - BACKGROUND/AIMS: To evaluate the efficacy, safety and tolerability of enteric coated mycophenolate sodium (EC-MPS) in combination with low-dose corticosteroids compared with a monotherapy with low-dose corticosteroids in subjects with non infectious intermediate uveitis (IU). METHODS: Open-label, prospective, controlled, randomised multicentre trial. Patients were randomised in a 1:1 ratio to either the treatment group (prednisolone plus EC-MPS) or control group (prednisolone monotherapy). Patients in the control group who relapsed within 6 months changed to the crossover group (prednisolone plus EC-MPS). Maximum treatment duration was 15 months. The primary endpoint was the time to first relapse in the treatment group and control group. RESULTS: Forty-one patients at eight sites were analysed. Twenty-two patients were allocated to the treatment group, with 19 patients in the control group. A first relapse occurred in 9 patients (40.9%) in the treatment group and 15 patients (78.9%) in the control group (p=0.03). The median time to the first relapse was >15 months for the treatment group and 2.8 months for the control group (p=0.07). The probability of relapse-free survival at month 15 was estimated to be 52.9% in the treatment group and 19.7% in the control group (p=0.01). 15 patients changed to the crossover group. Of these, only four patients developed a second relapse. No safety concerns arose during the trial. Only one patient had to discontinue EC MPS due to increased liver enzymes. CONCLUSION: EC-MPS can be considered an effective and well-tolerated immunosuppressive drug to prevent relapses in patients with chronic IU. TRIAL REGISTRATION NUMBER: EUDRACT number: 2009-009998 10, Results. PMID- 28903966 TI - Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. A multicentre, randomised controlled trial: design and methodology. AB - PURPOSE: The Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial aims to establish whether initial treatment with selective laser trabeculoplasty (SLT) is superior to initial treatment with topical medication for primary open-angle glaucoma (POAG) or ocular hypertension (OHT). DESIGN: The LiGHT Trial is a prospective, unmasked, multicentre, pragmatic, randomised controlled trial. 718 previously untreated patients with POAG or OHT were recruited at six collaborating centres in the UK between 2012 and 2014. The trial comprises two treatment arms: initial SLT followed by conventional medical therapy as required, and medical therapy without laser therapy. Randomisation was provided online by a web-based randomisation service. Participants will be monitored for 3 years, according to routine clinical practice. The target intraocular pressure (IOP) was set at baseline according to an algorithm, based on disease severity and lifetime risk of loss of vision at recruitment, and subsequently adjusted on the basis of IOP control, optic disc and visual field. The primary outcome measure is health related quality of life (HRQL) (EQ-5D five-level). Secondary outcomes are treatment pathway cost and cost-effectiveness, Glaucoma Utility Index, Glaucoma Symptom Scale, Glaucoma Quality of Life, objective measures of pathway effectiveness, visual function and safety profiles and concordance. A single main analysis will be performed at the end of the trial on an intention-to-treat basis. CONCLUSIONS: The LiGHT Trial is a multicentre, pragmatic, randomised clinical trial that will provide valuable data on the relative HRQL, clinical effectiveness and cost-effectiveness of SLT and topical IOP-lowering medication. TRIAL REGISTRATION NUMBER: ISRCTN32038223, Pre-results. PMID- 28903967 TI - Long-term follow-up of benign positional vertical opsoclonus in infants: retrospective cohort. AB - BACKGROUND/AIMS: Benign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon. METHODS: This retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012-2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation. RESULTS: The cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from <10 to dozens per day. In five infants, symptoms occurred in the supine position. There was a wide variability in the work-up without any pathological findings. Follow-up ranged from 1 to 2.5 years. Ocular symptoms gradually decreased until resolution. Infants reached normal developmental milestones. CONCLUSIONS: Our identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary. PMID- 28903968 TI - What factors are associated with reporting lacking interest in sex and how do these vary by gender? Findings from the third British national survey of sexual attitudes and lifestyles. AB - OBJECTIVES: To investigate factors associated with reporting lacking interest in sex and how these vary by gender. SETTING: British general population. DESIGN: Complex survey analyses of data collected for a cross-sectional probability sample survey, undertaken 2010-2012, specifically logistic regression to calculate age-adjusted OR (AOR) to identify associated factors. PARTICIPANTS: 4839 men and 6669 women aged 16-74 years who reported >=1 sexual partner (opposite-sex or same-sex) in the past year for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). MAIN OUTCOME MEASURE: Lacking interest in sex for >=3 months in the past year. RESULTS: Overall, 15.0% (13.9 16.2) of men and 34.2% (32.8-35.5) of women reported lacking interest in sex. This was associated with age and physical and mental health for both men and women, including self-reported general health and current depression. Lacking interest in sex was more prevalent among men and women reporting sexually transmitted infection diagnoses (ever), non-volitional sex (ever) and holding sexual attitudes related to normative expectations about sex. Some gender similarities in associated relationship and family-related factors were evident, including partner having had sexual difficulties in the last year (men: AOR 1.41 (1.07-1.86); women: AOR 1.60 (1.32-1.94)), not feeling emotionally close to partner during sex (men: 3.74 (1.76-7.93); women: 4.80 (2.99-7.69) and ease of talking about sex (men: 1.53 (1.23-1.90);women: 2.06 (1.77-2.39)). Among women only, lack of interest in sex was higher among those in a relationship of >1 year in duration and those not sharing the same level of interest (4.57 (3.87-5.38)) or preferences (2.91 (2.22-3.83)) with a partner. CONCLUSIONS: Both gender similarities and differences were found in factors associated with lacking interest in sex, with the most marked differences in relation to some relationship variables. Findings highlight the need to assess, and if appropriate, treat lacking interest in sex in a holistic and relationship specific way. PMID- 28903969 TI - Healing journey: a qualitative analysis of the healing experiences of Americans suffering from trauma and illness. AB - OBJECTIVES: To elucidate pathways to healing for people having suffered injury to the integrity of their function as a human being. METHODS: A team of physician analysts conducted thematic analyses of in-depth interviews of 23 patients who experienced healing, as identified by six primary care physicians purposefully selected as exemplary healers. RESULTS: People in the sample experienced healing journeys that spanned a spectrum from overcoming unspeakable trauma and then becoming healers themselves to everyday heroes functioning well despite ongoing serious health challenges.The degree and quality of suffering experienced by each individual is framed by contextual factors that include personal characteristics, timing of their initial or ongoing wounding in the developmental life cycle and prior and current relationships.In the healing journey, bridges from suffering are developed to healing resources/skills and connections to helpers outside themselves. These bridges often evolve in fits and starts and involve persistence and developing a sense of safety and trust.From the iteration between suffering and developing resources and connections, a new state emerges that involves hope, self-acceptance and helping others. Over time, this leads to healing that includes a sense of integrity and flourishing in the pursuit of meaningful goals and purpose. CONCLUSION: Moving from being wounded, through suffering to healing, is possible. It is facilitated by developing safe, trusting relationships and by positive reframing that moves through the weight of responsibility to the ability to respond. PMID- 28903970 TI - Urinary Fibrinogen as a Predictor of Progression of CKD. AB - BACKGROUND AND OBJECTIVES: Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 402 patients with CKD and kidney biopsies, including 101 with diabetic nephropathy, 94 with idiopathic membranous nephropathy, 55 with idiopathic FSGS, and 152 with IgA nephropathy. We quantified urinary fibrinogen by ELISA and tested associations with kidney histology and progression to ESRD. RESULTS: Median (interquartile range) urinary fibrinogen-to-creatinine ratio was 536 (191 1461) ng/mg for patients with CKD, significantly higher than 2 (2-3) ng/mg for healthy controls (P<0.001). Urinary fibrinogen was positively correlated with urine protein (r=0.64; P<0.001) and interstitial fibrosis and tubular atrophy (r=0.10; P=0.04), and it was negatively correlated with eGFR (r=-0.20; P<0.001). Over a median follow-up period of 35 months (interquartile range, 24-78 months), 68 of 402 patients (17%) developed ESRD. Higher urinary fibrinogen level was associated with increased risk of ESRD (hazard ratio, 2.12; 95% confidence interval, 1.31 to 3.26) per log10 higher urinary fibrinogen-to-creatinine ratio (P=0.003) adjusting for age, sex, BP, urine protein, disease type, eGFR, and interstitial fibrosis and tubular atrophy. For prediction of ESRD, the addition of urinary fibrinogen to eGFR, urine protein, and BP increased the area under the receiver operating curve from 0.73 to 0.76, and the Akaike information criterion improved from 333.6 to 327.0. CONCLUSIONS: Urinary fibrinogen correlated with interstitial fibrosis and tubular atrophy and was an independent risk factor for progression of CKD to ESRD. PMID- 28903971 TI - Extracellular S100A9 Protein in Bone Marrow Supports Multiple Myeloma Survival by Stimulating Angiogenesis and Cytokine Secretion. AB - Dysregulated expression of S100 protein family members is associated with cancer proliferation, invasion, angiogenesis, and inflammation. S100A9 induces myeloid derived suppressor cell (MDSC) accumulation and activity. MDSCs, immunosuppressive cells that contribute to tumor immune escape, are the main producers of S100A9. In this study, we evaluated the role of extracellular S100A9 and the therapeutic relevance of S100A9 inhibition in multiple myeloma (MM), using the immunocompetent murine 5T33MM model. We demonstrated the presence of S100A9 and its receptor TLR4 in both monocytic and granulocytic MDSCs in human and mouse samples. We showed that S100A9 acted as a chemoattractant for MM cells and induced MDSCs to express and secrete inflammatory and pro-myeloma cytokines, including TNFalpha, IL6, and IL10. Blocking S100A9 interactions in vivo with the small molecule ABR-238901 did not directly affect MDSC accumulation but did reduce IL6 and IL10 cytokine expression by MDSC. ABR-238901 treatment in vivo reduced angiogenesis but had only minor effects on tumor load as single agent (6% reduction). However, ABR-238901 treatment in combination with bortezomib resulted in an increased reduction in tumor load compared with single treatments (50% relative reduction compared with bortezomib alone). Our data suggest that extracellular S100A9 promotes MM and that inhibition of S100A9 may have therapeutic benefit. Cancer Immunol Res; 5(10); 839-46. (c)2017 AACR. PMID- 28903972 TI - Lactobacillus: the not so friendly bacteria. AB - We present a 65-year-old diabetic patient with a complex liver abscess and bacteraemia from Lactobacillus paracasei The abscess resulted in a prolonged hospital stay due to ongoing sepsis despite ultrasound-guided drainage and broad spectrum antibiotics. Furthermore, the patient developed several secondary complications including a right-sided pleural effusion, an inferior vena cava thrombus and septic lung emboli. The abscess was eventually managed successfully with a prolonged course of antibiotics and multiple ultrasound-guided drainage procedures.To our knowledge, this is the first reported case of probiotic consumption, confirmed by strain identification, as the likely source of a liver abscess. Probiotic products have been widely used for many years and are advocated to the general public for their health benefits with no warning of side effects. Lactobacilli are one group of bacteria commonly used in these products. Although rare, complications have been reported. Susceptible patients, such as those who are immunocompromised, should be advised against excessive consumption. PMID- 28903973 TI - Cranial fasciitis of childhood (CFC): an unusual clinical case of a rare disease. AB - Cranial fasciitis of childhood (CFC) is a very uncommon tumour of the scalp, which is almost exclusively observed in the first years of life. It is a benign proliferation of fibroblasts, but its rapid growth rate may resemble a malignant disease. This disease may be suspected from clinical and radiological features, but a definitive diagnosis may be achieved only by pathological examination. We report a case whose onset was in late childhood and whose clinical and radiological characteristics were atypical. PMID- 28903974 TI - Ultrawide field imaging and sonography of a radial buckle. PMID- 28903975 TI - Proximal avulsion rupture of the flexor digitorum longus tendon associated with a medial malleolus ankle fracture. PMID- 28903976 TI - Working hard but working differently: a qualitative study of the impact of generational change on rural health care. AB - BACKGROUND: There is limited literature evaluating generational change in the physician workforce and the adjustments required of practices, practitioners and the health care system as a whole. The purpose of this study was to explore rural practitioners' experiences of their current contexts relevant to recruitment and retention and to determine how practices are responding to changing aspirations of new practitioners. METHODS: We used qualitative methods. Participants were selected to ensure diversity of career stage. Semistructured interviews conducted with 39 physicians, 2 nurses and 1 practice administrator from rural northwestern Canada (British Columbia, the Yukon Territory and the Northwest Territories) between June and October 2016 sought participants' views on research, training, recruitment and retention in the rural setting. Interviews lasted 30-50 minutes with the exception of 4 group interviews (45-90 min). Interviews were then conducted with 4 rural practitioners on Vancouver Island to confirm emerging themes. The interviews were recorded and analyzed interpretively. RESULTS: Three themes were identified that showed the interplay among practitioners, patients and resources within a rural health environment: 1) scope of practice and the changing concept of generalism, 2) connectivity and relationships and 3) divergent career aspirations. Within these themes, generational differences between early-career physicians and established practitioners influenced changes under way in rural practice in terms of adapting the practice environment to enhance recruitment and retention. INTERPRETATION: Some rural practices are beginning to adapt in ways that reflect changing generational aspirations. Specifically, they provide environments that support and nurture young physicians, encourage collaborative working and include flexible working arrangements, with varying support and financial models. Rural practices that were responsive to changing aspirations reported success in recruitment and retention. PMID- 28903977 TI - WHO Mental Health Gap Action Programme (mhGAP) Intervention Guide: a systematic review of evidence from low and middle-income countries. AB - QUESTION: Despite mental, neurological and substance use (MNS) disorders being highly prevalent, there is a worldwide gap between service need and provision. WHO launched its Mental Health Gap Action Programme (mhGAP) in 2008, and the Intervention Guide (mhGAP-IG) in 2010. mhGAP-IG provides evidence-based guidance and tools for assessment and integrated management of priority MNS disorders in low and middle-income countries (LMICs), using clinical decision-making protocols. It targets a non-specialised primary healthcare audience, but has also been used by ministries, non-governmental organisations and academics, for mental health service scale-up in 90 countries. This review aimed to identify evidence to date for mhGAP-IG implementation in LMICs. STUDY SELECTION AND ANALYSIS: We searched MEDLINE, Embase, PsycINFO, Web of Knowledge/Web of Science, Scopus, CINAHL, LILACS, SciELO/Web of Science, Cochrane, Pubmed databases and Google Scholar for studies reporting evidence, experience or evaluation of mhGAP-IG in LMICs, in any language. Data were extracted from included papers, but heterogeneity prevented meta-analysis. FINDINGS: We conducted a systematic review of evidence to date, of mhGAP-IG implementation and evaluation in LMICs. Thirty three included studies reported 15 training courses, 9 clinical implementations, 3 country contextualisations, 3 economic models, 2 uses as control interventions and 1 use to develop a rating scale. Our review identified the importance of detailed reports of contextual challenges in the field, alongside detailed protocols, qualitative studies and randomised controlled trials. CONCLUSIONS: The mhGAP-IG literature is substantial, relative to other published evaluations of clinical practice guidelines: an important contribution to a neglected field. PMID- 28903978 TI - Antihyperglycemic Medications: A Claims-Based Estimate of First-line Therapy Use Prior to Initialization of Second-line Medications. AB - OBJECTIVE: The American Diabetes Association recommends metformin as first-line therapy for type 2 diabetes. However, nonadherence to antihyperglycemic medication is common, and a clinician could confuse nonadherence with pharmacologic failure, potentially leading to premature prescribing of second line therapies. We measured metformin use prior to second-line therapy initialization. RESEARCH DESIGN AND METHODS: This retrospective cross-sectional study used unidentifiable member claims data from individuals covered from 2010 to 2015 by Aetna, a U.S. health benefits company. Beneficiaries with two physician claims or one hospitalization with a type 2 diabetes diagnosis were included. Recommended use of metformin was measured by the proportion of days covered over 60 days. Through sensitivity analysis, we varied estimates of the percentage of beneficiaries who used low-cost generic prescription medication programs. RESULTS: A total of 52,544 individuals with type 2 diabetes were eligible. Of 22,956 patients given second-line treatment, only 1,875 (8.2%) had evidence of recommended use of metformin in the prior 60 days, and 6,441 (28.0%) had no prior claims evidence of having taken metformin. At the top range of sensitivity, only 49.5% patients could have had recommended use. Patients were more likely to be given an additional second-line antihyperglycemic medication or insulin if they were given their initial second-line medication without evidence of recommended use of metformin (P < 0.001). CONCLUSIONS: Despite published guidelines, second-line therapy often is initiated without evidence of recommended use of first-line therapy. Apparent treatment failures, which may in fact be attributable to nonadherence to guidelines, are common. Point-of-care and population-level processes are needed to monitor and improve guideline adherence. PMID- 28903980 TI - Uniform gene expression in embryos is achieved by temporal averaging of transcription noise. AB - Transcription is often stochastic. This is seemingly incompatible with the importance of gene expression during development. Here we show that during zebrafish embryogenesis, transcription activation is stochastic due to (1) genes acquiring transcriptional competence at different times in different cells, (2) differences in cell cycle stage between cells, and (3) the stochastic nature of transcription. Initially, stochastic transcription causes large cell-to-cell differences in transcript levels. However, variability is reduced by lengthening cell cycles and the accumulation of transcription events in each cell. Temporal averaging might provide a general context in which to understand how embryos deal with stochastic transcription. PMID- 28903979 TI - Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. AB - Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked beta-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis. PMID- 28903981 TI - Serotonin Drives Predatory Feeding Behavior via Synchronous Feeding Rhythms in the Nematode Pristionchus pacificus. AB - Feeding behaviors in a wide range of animals are regulated by the neurotransmitter serotonin, although the exact neural circuits and associated mechanism are often unknown. The nematode Pristionchus pacificus can kill other nematodes by opening prey cuticles with movable teeth. Previous studies showed that exogenous serotonin treatment induces a predatory-like tooth movement and slower pharyngeal pumping in the absence of prey; however, physiological functions of serotonin during predation and other behaviors in P. pacificus remained completely unknown. Here, we investigate the roles of serotonin by generating mutations in Ppa-tph-1 and Ppa-bas-1, two key serotonin biosynthesis enzymes, and by genetic ablation of pharynx-associated serotonergic neurons. Mutations in Ppa-tph-1 reduced the pharyngeal pumping rate during bacterial feeding compared with wild-type. Moreover, the loss of serotonin or a subset of serotonergic neurons decreased the success of predation, but did not abolish the predatory feeding behavior completely. Detailed analysis using a high-speed camera revealed that the elimination of serotonin or the serotonergic neurons disrupted the timing and coordination of predatory tooth movement and pharyngeal pumping. This loss of synchrony significantly reduced the efficiency of successful predation events. These results suggest that serotonin has a conserved role in bacterial feeding and in addition drives the feeding rhythm of predatory behavior in Pristionchus. PMID- 28903982 TI - Mapping Loci That Control Tuber and Foliar Symptoms Caused by PVY in Autotetraploid Potato (Solanum tuberosum L.). AB - Potato tuber necrotic ringspot disease (PTNRD) is a tuber deformity associated with infection by the tuber necrotic strain of Potato virus Y (PVYNTN). PTNRD negatively impacts tuber quality and marketability, and poses a serious threat to seed and commercial potato production worldwide. PVYNTN symptoms differ in the cultivars Waneta and Pike: Waneta expresses severe PTNRD and foliar mosaic with vein and leaf necrosis, whereas Pike does not express PTNRD and mosaic is the only foliar symptom. To map loci that influence tuber and foliar symptoms, 236 F1 progeny of a cross between Waneta and Pike were inoculated with PVYNTN isolate NY090029 and genotyped using 12,808 potato SNPs. Foliar symptom type and severity were monitored for 10 wk, while tubers were evaluated for PTNRD expression at harvest and again after 60 d in storage. Pairwise correlation analyses indicate a strong association between PTNRD and vein necrosis (tau = 0.4195). QTL analyses revealed major-effect QTL on chromosomes 4 and 5 for mosaic, 4 for PTNRD, and 5 for foliar necrosis symptoms. Locating QTL associated with PVY-related symptoms provides a foundation for breeders to develop markers that can be used to eliminate potato clones with undesirable phenotypes, e.g., those likely to develop PTNRD or to be symptomless carriers of PVY. PMID- 28903983 TI - Ivabradine in Heart Failure: The Representativeness of SHIFT (Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial) in a Broad Population of Patients With Chronic Heart Failure. AB - BACKGROUND: The sinus node inhibitor ivabradine was approved for patients with heart failure (HF) after the ivabradine and outcomes in chronic HF (SHIFT [Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial]) trial. Our objective was to characterize the proportion of patients with HF eligible for ivabradine and the representativeness of the SHIFT trial enrollees compared with those in the Swedish Heart Failure Registry. METHODS AND RESULTS: We examined 26 404 patients with clinical HF from the Swedish Heart Failure Registry and divided them into SHIFT type (left ventricular ejection fraction <40%, New York Heart Association class II-IV, sinus rhythm, and heart rate >=70 beats per minute) and non-SHIFT type. Baseline characteristics and medication use were compared and change in eligibility over time was reported at 6 months and 1 year in a subset of patients. Overall, 14.2% (n=3741) of patients were SHIFT type. These patients were more likely to be younger, men, have diabetes mellitus, ischemic heart disease, lower left ventricular ejection fraction, and more recent onset HF (<6 months; all, P<0.001). Although 88.9% of SHIFT type and 88.5% of non-SHIFT type (P=0.421) were receiving selected beta-blockers, only 58.8% and 67.3% (P<0.001) were on >50% of target dose. From those patients who had repeated visits within 6 months (n=5420) and 1 year (n=6840), respectively, 10.2% (n=555) and 10.6% (n=724) of SHIFT-type patients became ineligible, 77.3% (n=4188) and 77.3% (n=5287) remained ineligible, and 4.6% (n=252) and 4.9% (n=335) of non-SHIFT-type patients became eligible for initiation of ivabradine. CONCLUSIONS: From the Swedish Heart Failure Registry, 14.2% of patients with HF were eligible for ivabradine. These patients more commonly were not receiving target beta-blocker dose. Over time, a minority of patients became ineligible and an even smaller minority became eligible. PMID- 28903984 TI - How Many Heart Failure Patients Might We SHIFT to a Lower Heart Rate? PMID- 28903986 TI - Correction for Perry, "A Decade of Development of Chromogenic Culture Media for Clinical Microbiology in an Era of Molecular Diagnostics". PMID- 28903985 TI - Molecular Tools for the Detection and Deduction of Azole Antifungal Drug Resistance Phenotypes in Aspergillus Species. AB - The incidence of azole resistance in Aspergillus species has increased over the past years, most importantly for Aspergillus fumigatus. This is partially attributable to the global spread of only a few resistance alleles through the environment. Secondary resistance is a significant clinical concern, as invasive aspergillosis with drug-susceptible strains is already difficult to treat, and exclusion of azole-based antifungals from prophylaxis or first-line treatment of invasive aspergillosis in high-risk patients would dramatically limit drug choices, thus increasing mortality rates for immunocompromised patients. Management options for invasive aspergillosis caused by azole-resistant A. fumigatus strains were recently reevaluated by an international expert panel, which concluded that drug resistance testing of cultured isolates is highly indicated when antifungal therapy is intended. In geographical regions with a high environmental prevalence of azole-resistant strains, initial therapy should be guided by such analyses. More environmental and clinical screening studies are therefore needed to generate the local epidemiologic data if such measures are to be implemented on a sound basis. Here we propose a first workflow for evaluating isolates from screening studies, and we compile the MIC values correlating with individual amino acid substitutions in the products of cyp51 genes for interpretation of DNA sequencing data, especially in the absence of cultured isolates. PMID- 28903987 TI - Heat Shock Proteins in Histoplasma and Paracoccidioides. AB - Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of Histoplasma and Paracoccidioides and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi. PMID- 28903989 TI - Liquid Biopsy Technique May Allow Early Screening. AB - Researchers have developed a new liquid biopsy technique that may allow screening for certain types of cancer. The technique can detect tumor mutations from the small amount of blood DNA present early in the disease. In four types of cancer, the technique's overall sensitivity was between 56% and 83%, and it could pinpoint 62% of patients with early-stage cancer. PMID- 28903988 TI - The Use of Reverse Vaccinology in the Design and Construction of Nano glycoconjugate Vaccines against Burkholderia pseudomallei. AB - Burkholderia pseudomallei (Bpm) is a Gram negative, facultative intracellular pathogen that causes the disease melioidosis in humans and other mammals. Respiratory infection with B. pseudomallei leads to a fulminant and often fatal disease. It has previously been shown that glycoconjugate vaccines can provide significant protection against lethal challenge; however, the limited number of known Burkholderia antigens has slowed progress towards vaccine development. The objective of this study was to identify novel antigens and evaluate their protective capacity when incorporated into a nano-glycoconjugate vaccine platform. First, an in silico approach to identify antigens with strong predicted immunogenicity was developed. Protein candidates were screened and ranked according to predicted subcellular localization, transmembrane domains, adhesive properties and ability to interact with Major Histocompatibility Complex (MHC) I and II. From these in silico predictions, we identified seven "high priority" proteins that demonstrated seroreactivity with anti-Bpm murine sera and convalescent human melioidosis sera, providing validation of our methods. Two novel proteins, together with Hcp1, were linked to lipopolysaccharide (LPS) and incorporated onto the surface of a gold nanoparticle (AuNP). Animals receiving AuNP-glycoconjugate vaccines generated high protein- and polysaccharide-specific antibody titers. Importantly, immunized animals receiving the AuNP-FlgL-LPS alone or as a combo demonstrated up to 100% survival and reduced lung colonization following lethal challenge with Bpm. Together, this study provides a rational approach to vaccine design that can be adapted for other complex pathogens, and provides rationale for further pre-clinical testing of AuNP-glycoconjugate in animal models of infection. PMID- 28903990 TI - The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History on the Progression From Multiple Autoantibodies to Type 1 Diabetes: A TEDDY Study Report. AB - This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086_A [P = 0.03], rs1534422_G [P = 0.006], and rs2327832_G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446_A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied. PMID- 28903992 TI - Importance of the valve durability-life expectancy ratio in selection of a prosthetic aortic valve. PMID- 28903993 TI - Mitral regurgitation in patients with severe aortic stenosis: diagnosis and management. AB - Severe aortic stenosis (AS) and mitral regurgitation (MR) frequently coexist. Although some observational studies have reported that moderate or severe MR is associated with higher mortality, the optimal management of such patients is still unclear. Simultaneous replacement of both aortic and mitral valves is linked to significantly higher morbidity and mortality. Recent advances in minimally invasive surgical or transcatheter therapies for MR allow for staged procedures in which surgical or transcatheter aortic valve replacement (SAVR/TAVR) is done first and MR severity re-evaluated afterwards. Current evidence suggests MR severity improves in some patients after SAVR or TAVR, depending on several factors (MR aetiology, type of valve used for TAVR, presence/absence of atrial fibrillation, residual aortic regurgitation, etc). However, as of today, the absence of randomised clinical trials does not allow for evidence-based recommendations about whether or not MR should be addressed at the time of SAVR or TAVR. A careful patient evaluation and clinical judgement are recommended to distinguish patients who might benefit from a double valve intervention from those in which MR should be left alone. The aim of this review is to report and critique the available data on this subject in order to help guide the clinical decision making in this challenging subset of patients. PMID- 28903991 TI - Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium. AB - Background: African American (AA) women have higher incidence of aggressive, young-onset (<40 years) breast cancers. Young- and older-onset disease may have distinct tumor biologies and etiologies; however, studies investigating age differences among AA women have been rare and generally underpowered.Methods: We examined tumor characteristics and breast cancer risk factors associated with premenopausal young (<40) vs. older (>=40) AA women's breast cancer in the African American Breast Cancer Epidemiology and Risk Consortium (2,008 cases and 5,144 controls). Unconditional logistic regression models assessed heterogeneity of tumor biology and risk factor associations by age, overall, and by estrogen receptor status.Results: Premenopausal AA women <40 years had higher frequency of poorer-prognosis tumor characteristics compared with older women, including negative estrogen and progesterone receptor status, triple-negative subtype, higher grade, higher stage, and larger tumors. Adiposity (i.e., waist-to-hip ratio) and family history of breast cancer were more strongly associated with young-onset disease [case-control OR = 1.46, 95% confidence interval (CI) = 1.04 2.05; OR = 3.10, 95% CI = 2.08-4.63, respectively] compared with older-onset disease (OR = 1.11, 95% CI = 0.91-1.35; OR = 1.57, 95% CI = 1.26-1.94). Breastfeeding showed a slight inverse risk association among young women (OR = 0.70, 95% CI = 0.43-1.16). Oral contraceptive use was associated with increased risk regardless of age. Considering various cutoff points for young age (<40, <45, <50), age-related heterogeneity was greatest when <40 was used.Conclusions: Among premenopausal AA women, diagnosis before age 40 is associated with more aggressive breast tumor biology and some etiologic differences.Impact: Modifiable risk factors including breastfeeding, adiposity, and oral contraceptive use may be important targets for mitigating harms of young-onset breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1722-9. (c)2017 AACR. PMID- 28903994 TI - The level of heparin-induced antibodies in correlation with the result of the flow cytometric functional assay in the patients with suspected HIT. AB - Heparin can induce the formation of antibodies against a heparin complex with a platelet factor 4 (PF4), leading to platelet activation and the development of heparin-induced thrombocytopaenia (HIT). Because screening ELISA does not discriminate between platelet activating and non-activating anti-heparin/PF4 antibodies, each positive result is confirmed by an additional functional assay. We analysed 1004 sera of patients with suspected HIT. Optical density (OD) values of ELISA-positive results were correlated with the risk for a positive result with our functional flow cytometric assay. Only 10.7% were ELISA positive and 59.8% of those were positive with the functional assay. The positive functional assay was found in 23.4% of patients with OD<1.0, in 57.7% with 1.02.0. Although our results showed that higher ELISA OD values increasethe possibility of the presence of platelet-activating anti-heparin/PF4 antibodies , there is no need for improving ELISA cut-off value for positive result. PMID- 28903995 TI - ROS1 [corrected]. AB - ROS1 is a receptor tyrosine kinase that has recently been shown to undergo gene rearrangements in~1%-2% of non-small cell lung carcinoma (NSCLC) and in a variety of other tumours including cholangiocarcinoma, gastric carcinoma, colorectal carcinoma and in spitzoid neoplasms, glioblastoma and inflammatory myofibroblastic tumours. The ROS1 gene fusion undergoes constitutive activation, regulates cellular proliferation and is implicated in carcinogenesis. ROS1 fusions can be detected by fluorescence in situ hybridisation, real-time PCR, sequencing-based techniques and immunohistochemistry-based methods in clinical laboratories. The small molecule tyrosine kinase inhibitor, crizotinib has been shown to be an effective inhibitor of ROS1 and has received Food and Drug Administration approval for treatment of advanced NSCLC. The current review is an update on the clinical findings and detection methods of ROS1 in clinical laboratories in NSCLC and other tumours. PMID- 28903996 TI - Crouching tiger, hidden dragon. PMID- 28903997 TI - Mitotic post-translational modifications of histones promote chromatin compaction in vitro. AB - How eukaryotic chromosomes are compacted during mitosis has been a leading question in cell biology since the nineteenth century. Non-histone proteins such as condensin complexes contribute to chromosome shaping, but appear not to be necessary for mitotic chromatin compaction. Histone modifications are known to affect chromatin structure. As histones undergo major changes in their post translational modifications during mitotic entry, we speculated that the spectrum of cell-cycle-specific histone modifications might contribute to chromosome compaction during mitosis. To test this hypothesis, we isolated core histones from interphase and mitotic cells and reconstituted chromatin with them. We used mass spectrometry to show that key post-translational modifications remained intact during our isolation procedure. Light, atomic force and transmission electron microscopy analysis showed that chromatin assembled from mitotic histones has a much greater tendency to aggregate than chromatin assembled from interphase histones, even under low magnesium conditions where interphase chromatin remains as separate beads-on-a-string structures. These observations are consistent with the hypothesis that mitotic chromosome formation is a two stage process with changes in the spectrum of histone post-translational modifications driving mitotic chromatin compaction, while the action of non histone proteins such as condensin may then shape the condensed chromosomes into their classic mitotic morphology. PMID- 28903998 TI - Shape, form, function and Leishmania pathogenicity: from textbook descriptions to biological understanding. AB - The shape and form of protozoan parasites are inextricably linked to their pathogenicity. The evolutionary pressure associated with establishing and maintaining an infection and transmission to vector or host has shaped parasite morphology. However, there is not a 'one size fits all' morphological solution to these different pressures, and parasites exhibit a range of different morphologies, reflecting the diversity of their complex life cycles. In this review, we will focus on the shape and form of Leishmania spp., a group of very successful protozoan parasites that cause a range of diseases from self-healing cutaneous leishmaniasis to visceral leishmaniasis, which is fatal if left untreated. PMID- 28904000 TI - Correction: Dynamics of in vivo ASC speck formation. PMID- 28903999 TI - Cdc42 regulates junctional actin but not cell polarization in the Caenorhabditis elegans epidermis. AB - During morphogenesis, adherens junctions (AJs) remodel to allow changes in cell shape and position while preserving adhesion. Here, we examine the function of Rho guanosine triphosphatase CDC-42 in AJ formation and regulation during Caenorhabditis elegans embryo elongation, a process driven by asymmetric epidermal cell shape changes. cdc-42 mutant embryos arrest during elongation with epidermal ruptures. Unexpectedly, we find using time-lapse fluorescence imaging that cdc-42 is not required for epidermal cell polarization or junction assembly, but rather is needed for proper junctional actin regulation during elongation. We show that the RhoGAP PAC-1/ARHGAP21 inhibits CDC-42 activity at AJs, and loss of PAC-1 or the interacting linker protein PICC-1/CCDC85A-C blocks elongation in embryos with compromised AJ function. pac-1 embryos exhibit dynamic accumulations of junctional F-actin and an increase in AJ protein levels. Our findings identify a previously unrecognized molecular mechanism for inhibiting junctional CDC-42 to control actin organization and AJ protein levels during epithelial morphogenesis. PMID- 28904002 TI - Assessing Microvascular Function in Humans from a Chronic Disease Perspective. AB - Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied. This reactivity depends on the balance between various mediators, including nitric oxide, endothelin, and prostanoids, among others. The measurement of microvascular (endothelial) function is important to understand the pathophysiologic mechanisms that contribute to MVD and the role of MVD in the development and progression of cardiometabolic/renal disease. Here, we review a selection of direct, noninvasive techniques for measuring human microcirculation, with a focus on methods, interpretation, and limitations from the perspective of chronic cardiometabolic and renal disease. PMID- 28904004 TI - Jadomycins Inhibit Type II Topoisomerases and Promote DNA Damage and Apoptosis in Multidrug-Resistant Triple-Negative Breast Cancer Cells. AB - Jadomycins are natural products that kill drug-sensitive and multidrug-resistant (MDR) breast cancer cells. To date, the cytotoxic activity of jadomycins has never been tested in MDR breast cancer cells that are also triple negative. Additionally, there is only a rudimentary understanding of how jadomycins cause cancer cell death, which includes the induction of intracellular reactive oxygen species (ROS). We first created a paclitaxel-resistant, triple-negative breast cancer cell line [paclitaxel-resistant MDA-MB-231 breast cancer cells (231-TXL)] from drug-sensitive control MDA-MB-231 cells (231-CON). Using thiazolyl blue methyltetrazolium bromide cell viability-measuring assays, jadomycins B, S, and F were found to be equipotent in drug-sensitive 231-CON and MDR 231-TXL cells; and using ROS-detecting assays, these jadomycins were determined to increase ROS activity in both cell lines by up to 7.3-fold. Jadomycins caused DNA double strand breaks in 231-CON and 231-TXL cells as measured by gammaH2AX Western blotting. Coincubation with the antioxidant N-acetyl cysteine or pro-oxidant auranofin did not affect jadomycin-mediated DNA damage. Jadomycins induced apoptosis in 231-CON and 231-TXL cells as measured by annexin V affinity assays, a process that was retained when ROS were inhibited. This indicated that jadomycins are capable of inducing MDA-MB-231 apoptotic cell death independently of ROS activity. Using quantitative polymerase chain reaction, Western blotting, and direct topoisomerase inhibition assays, it was determined that jadomycins inhibit type II topoisomerases and that jadomycins B and F selectively poison topoisomerase IIbeta We therefore propose novel mechanisms through which jadomycins induce breast cancer cell death independently of ROS activity, through inhibition or poisoning of type II topoisomerases and the induction of DNA damage and apoptosis. PMID- 28904003 TI - Preclinical Pharmacology and Pharmacokinetics of Inhaled Hexadecyl-Treprostinil (C16TR), a Pulmonary Vasodilator Prodrug. AB - This article describes the preclinical pharmacology and pharmacokinetics (PK) of hexadecyl-treprostinil (C16TR), a prodrug of treprostinil (TRE), formulated in a lipid nanoparticle (LNP) for inhalation as a pulmonary vasodilator. C16TR showed no activity (>10 uM) in receptor binding and enzyme inhibition assays, including binding to prostaglandin E2 receptor 2, prostaglandin D2 receptor 1, prostaglandin I2 receptor, and prostaglandin E2 receptor 4; TRE potently bound to each of these prostanoid receptors. C16TR had no effect (up to 200 nM) on platelet aggregation induced by ADP in rat blood. In hypoxia-challenged rats, inhaled C16TR-LNP produced dose-dependent (0.06-6 ug/kg), sustained pulmonary vasodilation over 3 hours; inhaled TRE (6 ug/kg) was active at earlier times but lost its effect by 3 hours. Single- and multiple-dose PK studies of inhaled C16TR LNP in rats showed proportionate dose-dependent increases in TRE Cmax and area under the curve (AUC) for both plasma and lung; similar results were observed for dog plasma levels in single-dose PK studies. In both species, inhaled C16TR-LNP yielded prolonged plasma TRE levels and a lower plasma TRE Cmax compared with inhaled TRE. Inhaled C16TR-LNP was well tolerated in rats and dogs; TRE-related side effects included cough, respiratory tract irritation, and emesis and were seen only after high inhaled doses of C16TR-LNP in dogs. In guinea pigs, inhaled TRE (30 ug/ml) consistently produced cough, but C16TR-LNP (30 ug/ml) elicited no effect. These results demonstrate that C16TR-LNP provides long-acting pulmonary vasodilation, is well tolerated in animal studies, and may necessitate less frequent dosing than inhaled TRE with possibly fewer side effects. PMID- 28904001 TI - Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance. AB - The intrinsic electrical characteristics of different types of neurons are shaped by the K+ channels they express. From among the more than 70 different K+ channel genes expressed in neurons, Kv3 family voltage-dependent K+ channels are uniquely associated with the ability of certain neurons to fire action potentials and to release neurotransmitter at high rates of up to 1,000 Hz. In general, the four Kv3 channels Kv3.1-Kv3.4 share the property of activating and deactivating rapidly at potentials more positive than other channels. Each Kv3 channel gene can generate multiple protein isoforms, which contribute to the high-frequency firing of neurons such as auditory brain stem neurons, fast-spiking GABAergic interneurons, and Purkinje cells of the cerebellum, and to regulation of neurotransmitter release at the terminals of many neurons. The different Kv3 channels have unique expression patterns and biophysical properties and are regulated in different ways by protein kinases. In this review, we cover the function, localization, and modulation of Kv3 channels and describe how levels and properties of the channels are altered by changes in ongoing neuronal activity. We also cover how the protein-protein interaction of these channels with other proteins affects neuronal functions, and how mutations or abnormal regulation of Kv3 channels are associated with neurological disorders such as ataxias, epilepsies, schizophrenia, and Alzheimer's disease. PMID- 28904005 TI - The coefficient of determination R2 and intra-class correlation coefficient from generalized linear mixed-effects models revisited and expanded. AB - The coefficient of determination R2 quantifies the proportion of variance explained by a statistical model and is an important summary statistic of biological interest. However, estimating R2 for generalized linear mixed models (GLMMs) remains challenging. We have previously introduced a version of R2 that we called [Formula: see text] for Poisson and binomial GLMMs, but not for other distributional families. Similarly, we earlier discussed how to estimate intra class correlation coefficients (ICCs) using Poisson and binomial GLMMs. In this paper, we generalize our methods to all other non-Gaussian distributions, in particular to negative binomial and gamma distributions that are commonly used for modelling biological data. While expanding our approach, we highlight two useful concepts for biologists, Jensen's inequality and the delta method, both of which help us in understanding the properties of GLMMs. Jensen's inequality has important implications for biologically meaningful interpretation of GLMMs, whereas the delta method allows a general derivation of variance associated with non-Gaussian distributions. We also discuss some special considerations for binomial GLMMs with binary or proportion data. We illustrate the implementation of our extension by worked examples from the field of ecology and evolution in the R environment. However, our method can be used across disciplines and regardless of statistical environments. PMID- 28904006 TI - The CRASH report: emergency management dilemmas facing acute physicians in patients with pulmonary arterial hypertension. AB - Treatment of acute emergencies in patients with pulmonary arterial hypertension (PAH) can be challenging. In the UK and Ireland, management of adult patients with PAH is centred in eight nationally designated pulmonary hypertension (PH) centres. However, many patients live far from these centres and physicians in local hospitals are often required to manage PAH emergencies. A committee of physicians from nationally designated PH centres identified the 'most common' emergency clinical scenarios encountered in patients with PAH. Thereafter, a review of the literature was performed centred on these specified topics and a management approach was developed based on best available evidence and expert consensus. Management protocols were developed on the following PAH emergencies: chest pain (including myocardial ischaemia), right ventricular failure, arrhythmias, sepsis, haemoptysis ('CRASH'), as well as considerations relevant to surgery, anaesthesia and pregnancy. Emergencies are not uncommon in PAH. While expertise in PAH management is essential, all physicians involved in acute care should be aware of the principles of acute management of PAH emergencies. A multidisciplinary approach is necessary, with physicians from tertiary PH centres supporting care locally and planning safe transfer of patients to PH centres when appropriate. PMID- 28904007 TI - Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance Linked ATP-Binding Cassette Transporter ABCG2. AB - Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells. PMID- 28904008 TI - MECHANISMS IN ENDOCRINOLOGY: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism. AB - Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized. PMID- 28904010 TI - Vitamin D supplementation to palliative cancer patients: protocol of a double blind, randomised controlled trial 'Palliative-D'. AB - BACKGROUND: According to a small pilot study on palliative cancer patients at our ward, vitamin D supplementation had beneficial effects on pain (measured as opioid consumption), infections and quality of life (QoL) without having any significant side effects. OBJECTIVE: The primary objective of the 'Palliative-D' study is to test the hypothesis that vitamin D supplementation for 12 weeks reduces opioid consumption. The secondary objectives are to study if reduction of antibiotic consumption and fatigue as well as improvement in QoL assessments can be observed. Effect on the 25-hydroxy vitamin D (25-OHD) levels in serum after 12 weeks of treatment will be studied, as well as the change in opioid dose in relation to genetic polymorphism in genes involved in the effect and metabolism of vitamin D. METHOD: A randomised, double-blind placebo-controlled multicentre trial has been designed. The trial will include 254 adult palliative cancer patients with 25-OHD levels <50 nmol/L and a life expectancy of more than 3 months recruited from two advanced palliative home care centres in Stockholm. Included patients will be randomly assigned to 12 weeks of treatment with cholecalciferol (vitamin D3) 4000 IU/day or placebo. The study will start in November 2017 and will finish in December 2019. The study is approved by the Regional Ethical Committee, Dnr2017/405-31/1, by the Swedish Medical Products Agency, EudraCT: 2017-000268-14, and is registered at Clinicaltrial.gov: NCT03038516. The study is financed with research grants from the Swedish Cancer Society and the Stockholm County Council. PMID- 28904009 TI - DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? AB - Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18 hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17alpha-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effective in vivo In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18 oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism. PMID- 28904011 TI - Continuation of non-essential medications in actively dying hospitalised patients. AB - OBJECTIVE: The objective of this analysis was to examine the use of 11 non essential medications in actively dying patients. METHODS: This was a planned secondary analysis of data from the Best Practices for End-of-Life Care for Our Nation's Veterans trial, a multicentre implementation trial of an intervention to improve processes of end-of-life care in inpatient settings. Supported with an electronic comfort care decision support tool, intervention included training hospital staff to identify actively dying patients, communicate the prognosis to patients/families and implement best practices of traditionally home-based hospice care. Data on medication use before and after intervention were derived from electronic medical records of 5476 deceased veterans. RESULTS: Five non essential medications, clopidogrel, donepezil, glyburide, metformin and propoxyphene, were ordered in less than 5% of cases. More common were orders for simvastatin (15.8%/15.1%), calcium tablets (8.4%/7.9%), multivitamins (11.6%/10.8%), ferrous sulfate (9.1%/7.6%), diphenhydramine (7.2%/5.1%) and subcutaneous heparin (29.9%/27.5%). Significant decreases were found for donepezil (2.5%/1.3%; p=0.001), propoxyphene (0.8%/0.1%; p=0.001), metformin (0.8%/0.3%; p=0.007) and multivitamins (11.6%/10.8%; p=0.01). Orders for one or more non-essential medications were less likely to occur in association with palliative care consultation (adjusted OR (AOR)=0.64, p<0.001), do-not resuscitate orders (AOR=0.66, p=0.001) and orders for death rattle medication (AOR=0.35, p<0.001). Patients who died in an intensive care unit were more likely to receive a non-essential medication (AOR=1.60, p=0.009), as were older patients (AOR=1.12 per 10 years, p=0.002). CONCLUSIONS: Non-essential medications continue to be administered to actively dying patients. Discontinuation of these medications may be facilitated by interventions that enhance recognition and consideration of patients' actively dying status. PMID- 28904012 TI - Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity. AB - The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53. We set out to address this problem by generating multiple genomic data sets for three different cancer cell lines, allowing the identification of distinct sets of TP53-regulated genes, from early transcriptional targets through to late targets controlled at the translational level. We found that although TP53 elicits vastly divergent signaling cascades across cell lines, it directly activates a core transcriptional program of ~100 genes with diverse biological functions, regardless of cell type or cellular response to TP53 activation. This core program is associated with high-occupancy TP53 enhancers, high levels of paused RNA polymerases, and accessible chromatin. Interestingly, two different shRNA screens failed to identify a single TP53 target gene required for the anti proliferative effects of TP53 during pharmacological activation in vitro. Furthermore, bioinformatics analysis of thousands of cancer genomes revealed that none of these core target genes are frequently inactivated in tumors expressing wild-type TP53. These results support the hypothesis that TP53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular contexts. PMID- 28904013 TI - Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation. AB - Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Transcriptional activation correlated with the highest increases in MYC binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in MYC binding. Altogether, the relative abundance (henceforth, "share") of MYC at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over MYC's association with the corepressor ZBTB17 (also known as MIZ1). MYC activation elicited immediate loading of RNA polymerase II (RNAPII) at activated promoters, followed by increases in pause-release, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the MYC share, suggesting that repression by MYC may be partly indirect, owing to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at MYC regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle and the resulting transcriptional response. PMID- 28904016 TI - lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle development by attenuating the function of miR-30c. AB - Long noncoding RNAs (lncRNAs) have been reported to play diverse roles in biologic and pathologic processes, including myogenesis. We found that lncRNA AK017368 is highly expressed in skeletal muscle cells. Functional analyses showed that overexpression of AK017368 promoted proliferation and restrained differentiation of myoblasts; whereas inhibition of AK017368 had completely opposite effects in vitro In mice, knockdown of AK017368 promoted muscle hypertrophy in vivo RNA molecules of AK017368 acted mechanistically as competing endogenous RNAs to target micro-RNA (miR)-30c, which was supported by the results of bioinformatics analyses and dual-luciferase reporter assays. It has been shown that lncRNA AK017368 competes with trinucleotide repeat containing-6A (Tnrc6a) for miR-30c. Tnrc6a was previously reported to promote proliferation and inhibit differentiation of myoblast cells, whereas miR-30c targets the 3'-UTR of Tnrc6a mRNA to weaken its function. Taken together, lncRNA AK017368 promotes proliferation and inhibits differentiation of myoblast cells by attenuating function of miR-30c.-Liang, T., Zhou, B., Shi, L., Wang, H., Chu, Q., Xu, F., Li, Y., Chen, R., Shen, C., Schinckel, A. P. lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle development by attenuating the function of miR-30c. PMID- 28904015 TI - Sasquatch: predicting the impact of regulatory SNPs on transcription factor binding from cell- and tissue-specific DNase footprints. AB - In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor binding. Sasquatch performs a comprehensive k-mer-based analysis of DNase footprints to determine any k-mer's potential for protein binding in a specific cell type and how this may be changed by sequence variants. Therefore, Sasquatch uses an unbiased approach, independent of known transcription factor binding sites and motifs. Sasquatch only requires a single DNase-seq data set per cell type, from any genotype, and produces consistent predictions from data generated by different experimental procedures and at different sequence depths. Here we demonstrate the effectiveness of Sasquatch using previously validated functional SNPs and benchmark its performance against existing approaches. Sasquatch is available as a versatile webtool incorporating publicly available data, including the human ENCODE collection. Thus, Sasquatch provides a powerful tool and repository for prioritizing likely regulatory SNPs in the noncoding genome. PMID- 28904014 TI - Redundant and incoherent regulations of multiple phenotypes suggest microRNAs' role in stability control. AB - Each microRNA (miRNA) represses a web of target genes and, through them, controls multiple phenotypes. The difficulties inherent in such controls cast doubt on how effective miRNAs are in driving phenotypic changes. A "simple regulation" model posits "one target-one phenotype" control under which most targeting is nonfunctional. In an alternative "coordinate regulation" model, multiple targets are assumed to control the same phenotypes coherently, and most targeting is functional. Both models have some empirical support but pose different conceptual challenges. Here, we concurrently analyze multiple targets and phenotypes associated with the miRNA-310 family (miR310s) of Drosophila Phenotypic rescue in the mir310s knockout background is achieved by promoter-directed RNA interference that restores wild-type expression. For one phenotype (eggshell morphology), we observed redundant regulation, hence rejecting "simple regulation" in favor of the "coordinate regulation" model. For other phenotypes (egg-hatching and male fertility), however, one gene shows full rescue, but three other rescues aggravate the phenotype. Overall, phenotypic controls by miR310s do not support either model. Like a thermostat that controls both heating and cooling elements to regulate temperature, redundancy and incoherence in regulation generally suggest some capacity in stability control. Our results therefore support the published view that miRNAs play a role in the canalization of transcriptome and, hence, phenotypes. PMID- 28904017 TI - Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics. AB - We recently reported the aptitude of a membrane-active lipopeptide (C10OOc12O) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared Escherichia coli sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis-sepsis model for mono- and combination therapies. We found that by altering permeability of both outer and inner membranes, subinhibitory concentrations of C10OOc12O can transiently sensitize GNB to diverse cytoplasm-targeting antibiotics in simple media. Sensitization was maintained in plasma, where C10OOc12O instigated greater bactericidal activities, including in the presence of a bacteriostatic antibiotic (erythromycin). Single-dose administrations of rifampin and C10OOc12O to E. coli infected mice resulted in 55% vs. 0, and 36% viability, respectively, for combined and individual treatments. Combining C10OOc12O and erythromycin has similarly improved mice protection from developing fatal sepsis. Consequently, the data confirmed that C10OOc12O renders GNB sensitive to both endogenous and exogenous antibacterials, and suggested that the tripartite concomitant presence increases therapeutic efficacy synergistically. This approach might expand the available treatment options to comprise antimicrobials with low permeability and/or efflux issues.-Jammal, J., Zaknoon, F., Mor, A. Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics. PMID- 28904018 TI - Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. AB - Mitochondrial trafficking plays a central role in dorsal root ganglion (DRG) neuronal cell survival and neurotransmission by transporting mitochondria from the neuronal cell body throughout the bundles of DRG axons. In type 2 diabetes (T2DM), dyslipidemia and hyperglycemia damage DRG neurons and induce mitochondrial dysfunction; however, the impact of free fatty acids and glucose on mitochondrial trafficking in DRG neurons remains unknown. To evaluate the impact of free fatty acids compared to hyperglycemia on mitochondrial transport, primary adult mouse DRG neuron cultures were treated with physiologic concentrations of palmitate and glucose and assessed for alterations in mitochondrial trafficking, mitochondrial membrane potential, and mitochondrial bioenergetics. Palmitate treatment significantly reduced the number of motile mitochondria in DRG axons, but physiologic concentrations of glucose did not impair mitochondrial trafficking dynamics. Palmitate-treated DRG neurons also exhibited a reduction in mitochondrial velocity, and impaired mitochondrial trafficking correlated with mitochondrial depolarization in palmitate-treated DRG neurons. Finally, we found differential bioenergetic effects of palmitate and glucose on resting and energetically challenged mitochondria in DRG neurons. Together, these results suggest that palmitate induces DRG neuron mitochondrial depolarization, inhibiting axonal mitochondrial trafficking and altering mitochondrial bioenergetic capacity.-Rumora, A. E., Lentz, S. I., Hinder, L. M., Jackson, S. W., Valesano, A., Levinson, G. E., Feldman, E. L. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. PMID- 28904019 TI - Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels. AB - Cathepsin B (CtsB) contributes to atherosclerosis and cancer progression by processing the extracellular matrix and promoting angiogenesis. Although CtsB was reported to promote and reduce angiogenesis, there is no mechanistic explanation that reconciles this apparent discrepancy. CtsB cleaves CD18 from the surface of immune cells, but its contribution to angiogenesis has not been studied. We developed an in vivo technique for visualization of immune cell transmigration from corneal vessels toward implanted cytokines. Wild-type (WT) leukocytes extravasated from limbal vessels, angiogenic stalks, and growing tip vessels and migrated toward the cytokines, indicating immune competence of angiogenic vessels. Compared to WT leukocytes, CtsB-/- leukocytes accumulated in a higher number in angiogenic vessels, but extravasated less toward the implanted cytokine. The accumulated CtsB-/- leukocytes in angiogenic vessels expressed more CD18. CD18-/- leukocytes extravasated later than WT leukocytes. However, once extravasated, CD18-/- leukocytes transmigrated more rapidly than their WT counterparts. These results suggest that, although CD18 facilitates efficient extravasation, outside of the vessel CD18 interaction with the extracellular matrix, it reduced transmigration velocity. Our results reveal an unexpected role for CtsB in leukocyte extravasation and transmigration, which advances our understanding of the complex contribution of CtsB to angiogenesis.-Nakao, S., Zandi, S., Sun, D., Hafezi-Moghadam, A. Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels. PMID- 28904020 TI - GTRAP3-18 regulates food intake and body weight by interacting with pro opiomelanocortin. AB - Pro-opiomelanocortin (POMC)-expressing neurons provide alpha-melanocyte stimulating hormone (alpha-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. alpha-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter-associated protein 3-18 (GTRAP3-18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical regulator of food intake and body weight by interacting with POMC. GTRAP3-18-deficient mice showed hypophagia, lean bodies, and lower blood glucose, insulin, and leptin levels with increased serum and brain alpha-MSH levels, leading to AMPK inhibition. Intraperitoneal glucose tolerance tests revealed significantly decreased blood glucose levels and areas under the curve in GTRAP3-18-deficient mice compared to wild-type mice. An intracerebroventricular infusion of a selective melanocortin 4 receptor antagonist to GTRAP3-18-deficient mice significantly increased their food intake and body weight. A fluorescence resonance energy transfer study showed an interaction between GTRAP3-18 and POMC in vitro These findings suggest that activation of the melanocortin pathway by modulating GTRAP3-18/POMC interaction could be an alternative strategy for obesity and/or type 2 diabetes.-Aoyama, K., Bhadhprasit, W., Watabe, M., Wang, F., Matsumura, N., Nakaki, T. GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin. PMID- 28904021 TI - BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility. AB - Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant and carcinogen that is frequently found in particulate matter, with a diameter of <=2.5 MUm (PM2.5). It has been reported to interrupt the normal reproductive system, but the exact molecular basis has not been clearly defined. To understand the underlying mechanisms regarding how BaP exposure disrupts female fertility, we evaluated oocyte quality by assessing the critical regulators and events during oocyte meiotic maturation and fertilization. We found that BaP exposure compromised the mouse oocyte meiotic progression by disrupting normal spindle assembly, chromosome alignment, and kinetochore-microtubule attachment, consequently leading to the generation of aneuploid eggs. In addition, BaP administration significantly decreased the fertilization rate of mouse eggs by reducing the number of sperm binding to the zona pellucida, which was consistent with the premature cleavage of N terminus of zona pellucida sperm-binding protein 2 and precocious exocytosis of ovastacin. Furthermore, BaP exposure interfered with the gamete fusion process by perturbing the localization and protein level of Juno. Notably, we found that BaP exposure induced oxidative stress with an increased level of reactive oxygen species and apoptosis in oocytes and thereby led to the deterioration of critical regulators and events during oocyte meiotic progression and fertilization. Our data document that BaP exposure reduces female fertility via impairing oocyte maturation and fertilization ability induced by oxidative stress and early apoptosis in murine models.-Zhang, M., Miao, Y., Chen, Q., Cai, M., Dong, W., Dai, X., Lu, Y., Zhou, C., Cui, Z., Xiong, B. BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility. PMID- 28904022 TI - PI3Kgamma ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic beta-cell apoptosis. AB - PI3Kgamma has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3Kgamma activity in pancreatic beta cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic beta-cell function is a major concern for the pharmacologic inhibition of PI3Kgamma. To address this issue, we investigated the effects of PI3Kgamma ablation in db/db diabetic mice, a genetic model of obesity-driven beta-cell failure and diabetes. Mice that lacked PI3Kgamma were backcrossed into db/+ mice C57BL/KS (>10 generations) to obtain db/db-PI3Kgamma-/- mice. db/db-PI3Kgamma-/- mice and control db/db mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic beta-cell apoptosis and proliferation were also evaluated. db/db-PI3Kgamma -/- mice and control db/db mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, db/db-PI3Kgamma-/- mice displayed improved insulin tolerance, higher levels of fasting serum insulin, and lower pancreatic insulin content. In db/db-PI3Kgamma-/- mice, the number of adipose tissue macrophages was similar to control, but displayed reduced adipose tissue neutrophils and M2-polarized adipose tissue gene expression. Finally, db/db PI3Kgamma-/- mice have more pancreatic beta cells and larger islets than db/db mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced beta-cell apoptosis in db/db-PI3Kgamma-/- mice compared with control db/db mice. Our results are consistent with the concept that the beneficial action of PI3Kgamma ablation in obesity-driven glucose intolerance is largely a result of its leptin-dependent effects on adiposity and, to a lesser extent, the promotion of adipose tissue neutrophil recruitment and M1 polarization of gene expression. Of importance, our data challenge the concept that PI3Kgamma is required for insulin secretion in response to glucose in vivo, and indicate that PI3Kgamma ablation protects db/db mice from beta-cell apoptosis and improves fasting insulin levels. We conclude that PI3Kgamma inhibition in obese patients who are predisposed to beta-cell failure is not expected to produce adverse effects on insulin secretion.-Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. PI3Kgamma ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic beta-cell apoptosis. PMID- 28904023 TI - alpha-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40. AB - Among dietary fatty acids with immunologic effects, omega-3 polyunsaturated fatty acids, such as alpha-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo 9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC beta and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. alpha-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40. PMID- 28904025 TI - What is a medical journal good for? PMID- 28904026 TI - ? PMID- 28904024 TI - Polyamines and Their Role in Virus Infection. AB - Polyamines are small, abundant, aliphatic molecules present in all mammalian cells. Within the context of the cell, they play a myriad of roles, from modulating nucleic acid conformation to promoting cellular proliferation and signaling. In addition, polyamines have emerged as important molecules in virus host interactions. Many viruses have been shown to require polyamines for one or more aspects of their replication cycle, including DNA and RNA polymerization, nucleic acid packaging, and protein synthesis. Understanding the role of polyamines has become easier with the application of small-molecule inhibitors of polyamine synthesis and the use of interferon-induced regulators of polyamines. Here we review the diverse mechanisms in which viruses require polyamines and investigate blocking polyamine synthesis as a potential broad-spectrum antiviral approach. PMID- 28904027 TI - Competing demands and opportunities in primary care. PMID- 28904028 TI - Spinal manipulative therapy for low back pain-time for an update. PMID- 28904029 TI - Response. PMID- 28904030 TI - Approach to advanced heart failure at the end of life. AB - OBJECTIVE: To outline symptom management in, as well as offer a home-based protocol for, patients with advanced heart failure (HF). SOURCES OF INFORMATION: The terms palliative care and heart failure were searched in PubMed and relevant databases. All articles were reviewed. The specific medical management protocol was developed by the "HeartFull" collaborative team at the Temmy Latner Centre for Palliative Care in Toronto, Ont. MAIN MESSAGE: Educating patients about advanced HF and helping them understand their illness and illness trajectory can foster end-of-life discussions. Home-based care of patients with advanced HF that includes optimizing diuresis can lead to improved symptom management. It is also hoped that it can reduce both patient and health care system burden and result in greater health-related quality of life for patients with advanced HF. CONCLUSION: This article provides an overview of how to manage common symptoms in patients with advanced HF. The home diuresis protocol with guidelines for oral and intravenous diuretic therapy is available at CFPlus. PMID- 28904031 TI - Shared decision making in preventive health care: What it is; what it is not. PMID- 28904032 TI - Antibiotic therapy for children with acute otitis media. AB - Question Acute otitis media is one of the most common infections in childhood. Routine prescription of antibiotics has led to adverse events and bacterial resistance to antibiotics. I have heard that "watchful waiting" is a good strategy to reduce this potential problem in children older than 6 months of age. Should I apply this strategy in my clinical practice? Answer Watchful waiting can be applied in selected children with nonsevere acute otitis media by withholding antibiotics and observing the child for clinical improvement. Antibiotics should be promptly provided if the child's infection worsens or fails to improve within 24 to 48 hours. Guidelines and most ongoing studies support these recommendations. Correct choice of regimen, dose, frequency, and length of treatment are all important. PMID- 28904033 TI - ? PMID- 28904034 TI - Clinical Institute Withdrawal Assessment for Alcohol-Revised might be an unreliable tool in the management of alcohol withdrawal. PMID- 28904035 TI - Choosing Wisely Canada recommendations: Interview with Dr Caroline Laberge. PMID- 28904036 TI - Sacubitril-valsartan: novel therapy for heart failure. PMID- 28904037 TI - ? PMID- 28904038 TI - Facilitated access to an integrated model of care for arthritis in an urban Aboriginal population. AB - OBJECTIVE: To evaluate a model of care to improve arthritis detection and treatment in an urban Aboriginal population. DESIGN: Cohort study. SETTING: The Elbow River Healing Lodge in Calgary, Alta. PARTICIPANTS: A total of 26 participants with noninflammatory arthritis and 12 with inflammatory arthritis. INTERVENTION: A monthly rheumatology clinic was embedded in the primary health care service and received referrals from primary care providers and allied health care professionals, or self-referrals. All participants had a standardized assessment to determine their diagnosis. Those with noninflammatory musculoskeletal conditions were returned to primary care management and those with inflammatory arthritis conditions were followed by the rheumatologist. MAIN OUTCOME MEASURES: Accessibility, acceptability, effectiveness, and cultural safety were evaluated as measures of quality for the model of care. RESULTS: Nearly all participants (87%) thought the services were very easy or easy to obtain, and overall satisfaction with the model of care was high (89% were very satisfied or satisfied). For inflammatory arthritis patients, the swollen and tender joint counts improved over time (both P < .01) and patient safety was assured. A high degree of cultural safety was provided, with 95% of participants responding that they did not perceive discrimination on the basis of race. CONCLUSION: This model of care facilitated access for diagnosis and return to care of inflammatory arthritis conditions, and was acceptable to participants. This model of care removes the complexities of access to non-family physician specialty care while providing health care in a setting valued by Aboriginal patients. PMID- 28904039 TI - Patient of steel. PMID- 28904040 TI - Courage, relationships, and applicability: Big research from small places. PMID- 28904041 TI - Engagement of people with lived experience in primary care research: Living with HIV Innovation Team Community Scholar Program. PMID- 28904043 TI - ? PMID- 28904042 TI - Serving vulnerable communities. PMID- 28904044 TI - ? PMID- 28904045 TI - Cultural competence and the Besrour Centre. PMID- 28904046 TI - ? PMID- 28904047 TI - ? PMID- 28904048 TI - What can organizations do to improve family physicians' interprofessional collaboration? Results of a survey of primary care in Quebec. AB - OBJECTIVE: To assess the degree of collaboration in primary health care organizations between FPs and other health care professionals; and to identify organizational factors associated with such collaboration. DESIGN: Cross sectional survey. SETTING: Primary health care organizations in the Montreal and Monteregie regions of Quebec. PARTICIPANTS: Physicians or administrative managers from 376 organizations. MAIN OUTCOME MEASURES: Degree of collaboration between FPs and other specialists and between FPs and nonphysician health professionals. RESULTS: Almost half (47.1%) of organizations reported a high degree of collaboration between FPs and other specialists, but a high degree of collaboration was considerably less common between FPs and nonphysician professionals (16.5%). Clinic collaboration with a hospital and having more patients with at least 1 chronic disease were associated with higher FP collaboration with other specialists. The proportion of patients with at least 1 chronic disease was the only factor associated with collaboration between FPs and nonphysician professionals. CONCLUSION: There is room for improvement regarding interprofessional collaboration in primary health care, especially between FPs and nonphysician professionals. Organizations that manage patients with more chronic diseases collaborate more with both non-FP specialists and nonphysician professionals. PMID- 28904049 TI - Use of thyroid-stimulating hormone tests for identifying primary hypothyroidism in family medicine patients. AB - OBJECTIVE: To assess the use of thyroid-stimulating hormone (TSH) tests for identifying primary hypothyroidism in 2 academic family medicine settings. DESIGN: Descriptive study involving a retrospective electronic chart review of family medicine patients who underwent TSH testing. SETTING: Two academic family practice sites: one site is within a tertiary hospital in Toronto, Ont, and the other is within a community hospital in Newmarket, Ont. PARTICIPANTS: A random sample of 205 adult family medicine patients who had 1 or more TSH tests for identifying potential primary hypothyroidism between July 1, 2009, and September 15, 2013. Exclusion criteria included a previous diagnosis of any thyroid condition or abnormality, as well as pregnancy or recent pregnancy within the year preceding the study period. MAIN OUTCOME MEASURES: The proportion of normal TSH test results and the proportion of TSH tests that did not conform to test ordering guidelines. RESULTS: Of the 205 TSH test results, 200 (97.6%, 95% CI 94.4% to 99.2%) showed TSH levels within the normal range. All 5 patients with abnormal TSH test results had TSH levels above the upper reference limits. Nearly one-quarter (22.4%, 95% CI 16.9% to 28.8%) of tests did not conform to test ordering guidelines. All TSH tests classified as not conforming to test-ordering guidelines showed TSH levels within normal limits. There was a significant difference (P < .001) between the proportions of nonconforming TSH tests at the tertiary site (14.3%, 95% CI 8.2% to 22.5%) and the community site (31.0%, 95% CI 22.1% to 41.0%). Preliminary analyses examining which variables might be associated with abnormal TSH levels showed that only muscle cramps or myalgia (P = .0286) and a history of an autoimmune disorder (P = .0623) met or approached statistical significance. CONCLUSION: In this study, the proportion of normal TSH test results in the context of primary hypothyroidism case finding and screening was high, and the overall proportion of TSH tests that did not conform to test ordering guidelines was relatively high as well. These results highlight a need for more consistent TSH test-ordering guidelines for primary hypothyroidism and perhaps some educational interventions to help curtail the overuse of TSH tests in the family medicine setting. PMID- 28904051 TI - ? PMID- 28904050 TI - Defining "high-frequency" emergency department use: Does one size fit all for urban and rural areas? AB - OBJECTIVE: To suggest a functional definition for identification of "high frequency" emergency department (ED) users in rural areas. DESIGN: Retrospective analysis of secondary data. SETTING: Sioux Lookout Meno Ya Win Health Centre in northwestern Ontario. PARTICIPANTS: All ED visitors (N = 7121) in 2014 (N = 17 911 visits) in one rural hospital. MAIN OUTCOME MEASURES: The number of patients and visits identified using different definitions of high-frequency use. RESULTS: By using the most common definition of high-frequency use (>= 4 annual visits) for our hospital data, we identified 16.7% of ED patients. Using 6 or more annual visits as the definition, we identified 7.9% of ED patients; these patients accounted for 31.3% of the ED visit workload. Using the definition of 6 or more identifies less than 10% of the patients, which is a similar result to using the lower visit standard (>= 4) in urban centres. CONCLUSION: We suggest that the definition for high-frequency visitors to a rural ED should be 6 or more annual visits. Other useful subsets might include very high-frequency users (12 to 19 annual visits) and super users (>= 20 annual visits). PMID- 28904052 TI - DNA Breathing Enables Closed-Tube Mutant Allele Enrichment for Circulating Tumor DNA Analysis. PMID- 28904053 TI - Cardiovascular Biomarkers in Hypertensive Patients with Medical Treatment-Results from the Randomized TEAMSTA Protect I Trial. AB - BACKGROUND: High blood pressure (BP) is associated with an increased rate of cardiovascular events and mortality. Cardiovascular biomarkers are able to predict long-term risk in the general population, particularly in diseased cohorts. We undertook an investigation of the effect of 2 different antihypertensive treatments on cardiovascular biomarkers in a randomized trial. METHODS: The TEAMSTA study included 481 hypertensive patients. They were randomized to either 80-mg telmisartan + 5-mg amlodipine (TA) or 40-mg olmesartan + 12.5-mg hydrochlorothiazide (OH). The trial was performed as a prospective, randomized, double-blinded, controlled, single-center study. We measured BP, high sensitivity cardiac troponin I (hs-cTnI), high-sensitivity cardiac troponin T (hs cTnT), B-type natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-proBNP) before randomization and after 6 months. RESULTS: Individuals were randomized into 2 groups: 230 individuals to the OH-group and 251 to the TA-group. After 6 months of treatment, a reduction in BP (systolic/diastolic) was seen, from 135.2/85.2 mmHg to 122.5/75.7 mmHg with similar effects in both groups. hs-cTnT concentrations were measureable in 26.2% of the study population, while hs-cTnI was detected in 98.3%. hs-cTnI concentrations were significantly reduced from 4.6 to 4.2 ng/L in the overall population, from 4.7 to 4.4 ng/L in the OH-group, and from 4.6 to 4.0 ng/L in the TA-group (all P < 0.001). No significant changes of hs-cTnT were observed. BNP and NT-proBNP concentrations decreased from 15.0 to 12.4 ng/L (P < 0.001) and from 64.8 to 53.3 ng/L (P < 0.001), respectively, after 6 months. CONCLUSIONS: The reduction in BP was associated with a decrease of high sensitivity troponin I, BNP, and NT-proBNP concentrations, which might represent a cardiovascular risk reduction. CLINICAL TRIAL REGISTRATION: EudraCT 2009-017010 68. PMID- 28904054 TI - A 13-Steroid Serum Panel Based on LC-MS/MS: Use in Detection of Adrenocortical Carcinoma. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy, with an annual incidence of 1 or 2 cases per million. Biochemical diagnosis is challenging because up to two-thirds of the carcinomas are biochemically silent, resulting from de facto enzyme deficiencies in steroid hormone biosynthesis. Urine steroid profiling by GC-MS is an effective diagnostic test for ACC because of its capacity to detect and quantify the increased metabolites of steroid pathway synthetic intermediates. Corresponding serum assays for most steroid pathway intermediates are usually unavailable because of low demand or lack of immunoassay specificity. Serum steroid analysis by LC-MS/MS is increasingly replacing immunoassay, in particular for steroids most subject to cross-reaction. METHODS: We developed an LC-MS/MS method for the measurement of serum androstenedione, corticosterone, cortisol, cortisone, 11-deoxycorticosterone, 11 deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, pregnenolone, 17 hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, and testosterone. Assay value in discriminating ACC from other adrenal lesions (phaeochromocytoma/paraganglioma, cortisol-producing adenoma, and lesions demonstrating no hormonal excess) was then investigated. RESULTS: In ACC cases, between 4 and 7 steroids were increased (median = 6), and in the non-ACC groups, up to 2 steroids were increased. 11-Deoxycortisol was markedly increased in all cases of ACC. All steroids except testosterone in males and corticosterone and cortisone in both sexes were of use in discriminating ACC from non-ACC adrenal lesions. CONCLUSIONS: Serum steroid paneling by LC-MS/MS is useful for diagnosing ACC by combining the measurement of steroid hormones and their precursors in a single analysis. PMID- 28904055 TI - Toward Noninvasive Probing of Maternal-Fetal-Microbial Interactions during Pregnancy. PMID- 28904056 TI - Simultaneously Monitoring Immune Response and Microbial Infections during Pregnancy through Plasma cfRNA Sequencing. AB - BACKGROUND: Plasma cell-free RNA (cfRNA) encompasses a broad spectrum of RNA species that can be derived from both human cells and microbes. Because cfRNA is fragmented and of low concentration, it has been challenging to profile its transcriptome using standard RNA-seq methods. METHODS: We assessed several recently developed RNA-seq methods on cfRNA samples. We then analyzed the dynamic changes of both the human transcriptome and the microbiome of plasma during pregnancy from 60 women. RESULTS: cfRNA reflects a well-orchestrated immune modulation during pregnancy: an up-regulation of antiinflammatory genes and an increased abundance of antimicrobial genes. We observed that the plasma microbiome remained relatively stable during pregnancy. The bacteria Ureaplasma shows an increased prevalence and increased abundance at postpartum, which is likely to be associated with postpartum infection. We demonstrated that cfRNA-seq can be used to monitor viral infections. We detected a number of human pathogens in our patients, including an undiagnosed patient with a high load of human parvovirus B19 virus (B19V), which is known to be a potential cause of complications in pregnancy. CONCLUSIONS: Plasma cfRNA-seq demonstrates the potential to simultaneously monitor immune response and microbial infections during pregnancy. PMID- 28904057 TI - Prevalence of Rare Hemoglobin Variants Identified During Measurements of Hb A1c by Capillary Electrophoresis. PMID- 28904058 TI - Evaluation of Lipoprotein(a) Electrophoretic and Immunoassay Methods in Discriminating Risk of Calcific Aortic Valve Disease and Incident Coronary Heart Disease: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: A number of lipoprotein(a) [Lp(a)] analytical techniques are available that quantify distinct particle components, yet their clinical efficacy has not been comprehensively evaluated. This study determined whether Lp(a) mass [Lp(a)-M], Lp(a) cholesterol content [Lp(a)-C], and particle concentration [Lp(a) P] differentially discriminated risk of calcific aortic valve disease (CAVD) or incident coronary heart disease (CHD) among 4679 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Lp(a)-M, Lp(a)-C, and Lp(a)-P were measured in individuals without clinical evidence of CHD at baseline. Relative risk regression and Cox proportional analysis determined associations between Lp(a) and the presence of CAVD or 12-year risk of CHD, respectively. To control for the relatively high lower limits of quantification for Lp(a)-C and Lp(a)-P assays, the upper 25th and 15th percentiles were selected as analytical cutoff points. RESULTS: Regardless of method or analytical cutoff, high Lp(a) concentrations were significantly associated with CAVD and CHD in MESA participants following adjustment for typical cardiovascular risk factors. Stratifying by race/ethnicity rendered most associations nonsignificant after correction for multiple comparisons, but Lp(a) remained associated with CAVD in whites irrespective of method (all P < 0.0001). CONCLUSIONS: Associations of Lp(a)-C, Lp(a)-P, and Lp(a)-M with CAVD or incident CHD were similar in this entire MESA sample using a dichotomized statistical approach. However, the high lower limits of quantification and imprecision of the Lp(a)-C and Lp(a)-P assays limited their usefulness in our analyses and would likely do so in research and clinical settings. PMID- 28904059 TI - Gene Methylation Biomarkers in Sputum and Plasma as Predictors for Lung Cancer Recurrence. AB - Detection of methylated genes in exfoliated cells from the lungs of smokers provides an assessment of the extent of field cancerization, is a validated biomarker for predicting lung cancer, and provides some discrimination when interrogated in blood. The potential utility of this 8-gene methylation panel for predicting tumor recurrence has not been assessed. The Eastern Cooperative Oncology Group initiated a prevention trial (ECOG-ACRIN5597) that enrolled resected stage I non-small cell lung cancer patients who were randomized 2:1 to receive selenized yeast versus placebo for 4 years. We conducted a correlative biomarker study to assess prevalence for methylation of the 8-gene panel in longitudinally collected sputum and blood after tumor resection to determine whether selenium alters their methylation profile and whether this panel predicts local and/or distant recurrence. Patients (N = 1,561) were enrolled into the prevention trial; 565 participated in the biomarker study with 122 recurrences among that group. Assessing the association between recurrence and risk of gene methylation longitudinally for up to 48 months showed a 1.4-fold increase in OR for methylation in sputum in the placebo group independent of location (local or distant). Kaplan-Meier curves evaluating the association between number of methylated genes and time to recurrence showed no increased risk in sputum, while a significant HR of 1.5 was seen in plasma. Methylation detection in sputum and blood is associated with risk for recurrence. Cancer Prev Res; 10(11); 635-40. (c)2017 AACR. PMID- 28904060 TI - Early Exposure to a High Fat/High Sugar Diet Increases the Mammary Stem Cell Compartment and Mammary Tumor Risk in Female Mice. AB - Obesity and alterations in metabolic programming from early diet exposures can affect the propensity to disease in later life. Through dietary manipulation, developing mouse pups were exposed to a hyperinsulinemic, hyperglycemic milieu during three developmental phases: gestation, lactation, and postweaning. Analyses showed that a postweaning high fat/high sugar (HF/HS) diet had the main negative effect on adult body weight, glucose tolerance, and insulin resistance. However, dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis revealed that animals born to a mother fed a HF/HS gestation diet, nursed by a mother on a mildly diet-restricted, low fat/low sugar diet (DR) and weaned onto a HF/HS diet (HF/DR/HF) had the highest mammary tumor incidence, while HF/HF/DR had the lowest tumor incidence. Cox proportional hazards analysis showed that a HF/HS postweaning diet doubled mammary cancer risk, and a HF/HS diet during gestation and postweaning increased risk 5.5 times. Exposure to a HF/HS diet during gestation, when combined with a postweaning DR diet, had a protective effect, reducing mammary tumor risk by 86% (HR = 0.142). Serum adipocytokine analysis revealed significant diet-dependent differences in leptin/adiponectin ratio and IGF-1. Flow cytometry analysis of cells isolated from mammary glands from a high tumor incidence group, DR/HF/HF, showed a significant increase in the size of the mammary stem cell compartment compared with a low tumor group, HF/HF/DR. These results indicate that dietary reprogramming induces an expansion of the mammary stem cell compartment during mammary development, increasing likely carcinogen targets and mammary cancer risk. Cancer Prev Res; 10(10); 553-62. (c)2017 AACRSee related editorial by Freedland, p. 551-2. PMID- 28904061 TI - A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer. AB - Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50-55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention (P = 0.05), but had no effect in older women (Pinteraction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol-O-methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710-8. (c)2017 AACR. PMID- 28904062 TI - Optical Coherence Tomography Detects Necrotic Regions and Volumetrically Quantifies Multicellular Tumor Spheroids. AB - Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anticancer drug development. However, currently available imaging approaches used in high-throughput screening drug discovery platforms, for example, bright-field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (>50 MUm) tumor spheroids. In this study, we established a label-free, noninvasive optical coherence tomography (OCT) imaging platform to characterize 3D morphologic and physiologic information of multicellular tumor spheroids (MCTS) growing from approximately 250 to 600 MUm in height over 21 days. In particular, tumor spheroids of two cell lines, glioblastoma (U-87MG) and colorectal carcinoma (HCT116), exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphologic and physiologic features of MCTS, showing great potential for high-throughput drug screening. Cancer Res; 77(21); 6011-20. (c)2017 AACR. PMID- 28904063 TI - Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance. AB - Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628-38. (c)2017 AACR. PMID- 28904064 TI - Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors. AB - Many estrogen receptor alpha (ERalpha)-positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER containing MCF7 and T47D cells revealed that AE responses were compound, cell type, and ERalpha-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy-resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602-13. (c)2017 AACR. PMID- 28904065 TI - ANGPTL1 Interacts with Integrin alpha1beta1 to Suppress HCC Angiogenesis and Metastasis by Inhibiting JAK2/STAT3 Signaling. AB - Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here, we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis, and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility, and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2-mediated antiapoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, ANGPTL1 inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin alpha1beta1 receptor to suppress the downstream FAK/Src JAK-STAT3 signaling pathway. Taken together, these results suggest ANGPTL1 as a prognostic biomarker and novel therapeutic agent in HCC. Cancer Res; 77(21); 5831 45. (c)2017 AACR. PMID- 28904067 TI - Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency. AB - Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755-62. (c)2017 AACR. PMID- 28904066 TI - PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. AB - Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-gamma secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. (c)2017 AACR. PMID- 28904068 TI - Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. AB - BACKGROUND: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. METHODS: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) >=30 mL.min-1.1.73 m-2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL.min-1.1.73 m-2 and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45-<60, 60-<90, >=90 mL.min-1.1.73 m-2) and baseline urine albumin-creatinine ratio (>300, 30-<=300, <30 mg/g). RESULTS: Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42 0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72 0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL.min-1.1.73 m-2 was consistent with the overall trial population. CONCLUSIONS: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676. PMID- 28904071 TI - Assessing the Febrile Child for Serious Infection: A Step Closer to Meaningful Rapid Results. PMID- 28904069 TI - Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. AB - BACKGROUND: Preeclampsia is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in preeclampsia. Our study aims to investigate whether disturbed imprinting contributes to preeclampsia. METHODS: We first aimed to confirm that preeclampsia is a disease of the placenta by generating and analyzing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from healthy controls and patients with preeclampsia. Next, we identified differentially expressed genes in preeclamptic placentas and intersected them with the list of human imprinted genes. We used bioinformatics/statistical analyses to confirm association between imprinting and preeclampsia and to predict biological processes affected in preeclampsia. Validation included epigenetic and cellular assays. In terms of human specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque, and mouse preimplantation embryogenesis. RESULTS: We found disturbed placental imprinting in preeclampsia and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with preeclampsia. As a result of loss of imprinting, DLX5 was upregulated in 69% of preeclamptic placentas. Levels of DLX5 correlated with classic preeclampsia markers. DLX5 is expressed in human but not in murine trophoblast. The DLX5high phenotype resulted in reduced proliferation, increased metabolism, and endoplasmic reticulum stress-response activation in trophoblasts in vitro. The transcriptional profile of such cells mimics the transcriptome of preeclamptic placentas. Pan-mammalian comparative analysis identified DLX5 as part of the human-specific regulatory network of trophoblast differentiation. CONCLUSIONS: Our analysis provides evidence of a true association among disturbed imprinting, gene expression, and preeclampsia. As a result of disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in preeclampsia research. Human-specific regulatory circuitry of DLX5 might help explain certain aspects of preeclampsia. PMID- 28904070 TI - Antiarrhythmic Drugs for Nonshockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) commonly presents with nonshockable rhythms (asystole and pulseless electric activity). It is unknown whether antiarrhythmic drugs are safe and effective when nonshockable rhythms evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia [VF/VT]) during resuscitation. METHODS: Adults with nontraumatic OHCA, vascular access, and VF/VT anytime after >=1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine, or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a prespecified analysis in a separate cohort that initially presented with nonshockable OHCA and was randomized on subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge. Secondary outcomes included discharge functional status and adverse drug-related effects. RESULTS: Of 37 889 patients with OHCA, 3026 with initial VF/VT and 1063 with initial nonshockable-turned-shockable rhythms were treatment-eligible, were randomized, and received their assigned drug. Baseline characteristics among patients with nonshockable-turned-shockable rhythms were balanced across treatment arms, except that recipients of a placebo included fewer men and were less likely to receive bystander cardiopulmonary resuscitation. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug, and ancillary antiarrhythmic drugs than recipients of a placebo (P<0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine, and 6 (1.9%) placebo-treated patients survived to hospital discharge (P=0.24). No significant interaction between treatment assignment and discharge survival occurred with the initiating OHCA rhythm (asystole, pulseless electric activity, or VF/VT). Survival in each of these categories was consistently higher with active drugs, although the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from nonshockable-turned-shockable arrhythmias with amiodarone versus placebo were 2.3% (-0.3, 4.8), P=0.08, and for lidocaine versus placebo 1.2% (-1.1, 3.6), P=0.30. More than 50% of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent. CONCLUSIONS: Outcome from nonshockable-turned-shockable OHCA is poor but not invariably fatal. Although not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01401647. PMID- 28904072 TI - Validation of a Novel Assay to Distinguish Bacterial and Viral Infections. AB - BACKGROUND: Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein-10, and C-reactive protein [CRP]) was developed to assist in differentiation between bacterial and viral disease. METHODS: We performed double-blind, multicenter assay evaluation using serum remnants collected at 5 pediatric emergency departments and 2 wards from children >=3 months to <=18 years without (n = 68) and with (n = 529) suspicion of acute infection. Infectious cohort inclusion criteria were fever >=38 degrees C and symptom duration <=7 days. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results. Assay performers were blinded to the reference standard. Assay cutoffs were predefined. RESULTS: Of 529 potentially eligible patients with suspected acute infection, 100 did not fulfill infectious inclusion criteria and 68 had insufficient serum. The resulting cohort included 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The assay distinguished between bacterial and viral patients with 93.8% sensitivity (95% confidence interval: 87.8%-99.8%) and 89.8% specificity (85.6%-94.0%); 11.7% had an equivocal assay outcome. The assay outperformed CRP (cutoff 40 mg/L; sensitivity 88.2% [80.4%-96.1%], specificity 73.2% [67.6%-78.9%]) and procalcitonin testing (cutoff 0.5 ng/mL; sensitivity 63.1% [51.0%-75.1%], specificity 82.3% [77.1%-87.5%]). CONCLUSIONS: Double-blinded evaluation confirmed high assay performance in febrile children. Assay was significantly more accurate than CRP, procalcitonin, and routine laboratory parameters. Additional studies are warranted to support its potential to improve antimicrobial treatment decisions. PMID- 28904073 TI - Wounding Triggers Callus Formation via Dynamic Hormonal and Transcriptional Changes. AB - Wounding is a primary trigger of organ regeneration, but how wound stress reactivates cell proliferation and promotes cellular reprogramming remains elusive. In this study, we combined transcriptome analysis with quantitative hormonal analysis to investigate how wounding induces callus formation in Arabidopsis (Arabidopsis thaliana). Our time course RNA-seq analysis revealed that wounding induces dynamic transcriptional changes, starting from rapid stress responses followed by the activation of metabolic processes and protein synthesis and subsequent activation of cell cycle regulators. Gene ontology analyses further uncovered that wounding modifies the expression of hormone biosynthesis and response genes, and quantitative analysis of endogenous plant hormones revealed accumulation of cytokinin prior to callus formation. Mutants defective in cytokinin synthesis and signaling display reduced efficiency in callus formation, indicating that de novo synthesis of cytokinin is critical for wound induced callus formation. We further demonstrate that type-B ARABIDOPSIS RESPONSE REGULATOR-mediated cytokinin signaling regulates the expression of CYCLIN D3;1 (CYCD3;1) and that mutations in CYCD3;1 and its homologs CYCD3;2 and 3 cause defects in callus formation. In addition to these hormone-mediated changes, our transcriptome data uncovered that wounding activates multiple developmental regulators, and we found novel roles of ETHYLENE RESPONSE FACTOR 115 and PLETHORA3 (PLT3), PLT5, and PLT7 in callus generation. All together, these results provide novel mechanistic insights into how wounding reactivates cell proliferation during callus formation. PMID- 28904074 TI - MiR408 Regulates Grain Yield and Photosynthesis via a Phytocyanin Protein. AB - Increasing grain yield is the most important object of crop breeding. Here, we report that the elevated expression of a conserved microRNA, OsmiR408, could positively regulate grain yield in rice (Oryza sativa) by increasing panicle branches and grain number. We further showed that OsmiR408 regulates grain yield by down-regulating its downstream target, OsUCL8, which is an uclacyanin (UCL) gene of the phytocyanin family. The knock down or knock out of OsUCL8 also increases grain yield, while the overexpression of OsUCL8 results in an opposite phenotype. Spatial and temporal expression analyses showed that OsUCL8 was highly expressed in pistils, young panicles, developing seeds, and inflorescence meristem and was nearly complementary to that of OsmiR408. Interestingly, the OsUCL8 protein was localized to the cytoplasm, distinct from a majority of phytocyanins, which localize to the plasma membrane. Further studies revealed that the cleavage of OsUCL8 by miR408 affects copper homeostasis in the plant cell, which, in turn, affects the abundance of plastocyanin proteins and photosynthesis in rice. To our knowledge, this is the first report of the effects of miR408-OsUCL8 in regulating rice photosynthesis and grain yield. Our study further broadens the perspective of microRNAs and UCLs and provides important information for breeding high-yielding crops through genetic engineering. PMID- 28904075 TI - Association Between Living in Food Deserts and Cardiovascular Risk. AB - BACKGROUND: Food deserts (FD), neighborhoods defined as low-income areas with low access to healthy food, are a public health concern. We evaluated the impact of living in FD on cardiovascular risk factors and subclinical cardiovascular disease (CVD) with the hypothesis that people living in FD will have an unfavorable CVD risk profile. We further assessed whether the impact of FD on these measures is driven by area income, individual household income, or area access to healthy food. METHODS AND RESULTS: We studied 1421 subjects residing in the Atlanta metropolitan area who participated in the META-Health study (Morehouse and Emory Team up to Eliminate Health Disparities; n=712) and the Predictive Health study (n=709). Participants' zip codes were entered into the United States Food Access Research Atlas for FD status. Demographic data, metabolic profiles, hs-CRP (high-sensitivity C-reactive protein) levels, oxidative stress markers (glutathione and cystine), and arterial stiffness were evaluated. Mean age was 49.4 years, 38.5% male and 36.6% black. Compared with those not living in FD, subjects living in FD (n=187, 13.2%) had a higher prevalence of hypertension and smoking, higher body mass index, fasting glucose, and 10-year risk for CVD. They also had higher hs-CRP (P=0.014), higher central augmentation index (P=0.015), and lower glutathione level (P=0.003), indicative of increased oxidative stress. Area income and individual income, rather than food access, were associated with CVD risk measures. In a multivariate analysis that included food access, area income and individual income, both low-income area and low individual household income, were independent predictors of a higher 10-year risk for CVD. Only low individual income was an independent predictor of higher hs-CRP and augmentation index. CONCLUSIONS: Although living in FD is associated with a higher burden of cardiovascular risk factors and preclinical indices of CVD, these associations are mainly driven by area income and individual income rather than access to healthy food. PMID- 28904077 TI - Food Deserts: Limited Healthy Foods in the Land of Plenty. PMID- 28904076 TI - Residual Angina After Elective Percutaneous Coronary Intervention in Patients With Diabetes Mellitus. AB - BACKGROUND: Previous studies suggest that among patients with stable coronary artery disease, patients with diabetes mellitus (DM) have less angina and more silent ischemia when compared with those without DM. However, the burden of angina in diabetic versus nondiabetic patients after elective percutaneous coronary intervention (PCI) has not been recently examined. METHODS AND RESULTS: In a 10-site US PCI registry, we assessed angina before and at 1, 6, and 12 months after elective PCI with the Seattle Angina Questionnaire angina frequency score (range, 0-100, higher=better). We also examined the rates of antianginal medication prescriptions at discharge. A multivariable, repeated-measures Poisson model was used to examine the independent association of DM with angina over the year after treatment. Among 1080 elective PCI patients (mean age, 65 years; 74.7% men), 34.0% had DM. At baseline and at each follow-up, patients with DM had similar angina prevalence and severity as those without DM. Patients with DM were more commonly prescribed calcium channel blockers and long-acting nitrates at discharge (DM versus not: 27.9% versus 20.9% [P=0.01] and 32.8% versus 25.5% [P=0.01], respectively), whereas beta-blockers and ranolazine were prescribed at similar rates. In the multivariable, repeated-measures model, the risk of angina was similar over the year after PCI in patients with versus without DM (relative risk, 1.04; range, 0.80-1.36). CONCLUSIONS: Patients with stable coronary artery disease and DM exhibit a burden of angina that is at least as high as those without DM despite more antianginal prescriptions at discharge. These findings contradict the conventional teachings that patients with DM experience less angina because of silent ischemia. PMID- 28904078 TI - Toward a systems approach to the human cytochrome P450 ensemble: interactions between CYP2D6 and CYP2E1 and their functional consequences. AB - Functional cross-talk among human drug-metabolizing cytochrome P450 through their association is a topic of emerging importance. Here, we studied the interactions of human CYP2D6, a major metabolizer of psychoactive drugs, with one of the most prevalent human P450 enzymes, ethanol-inducible CYP2E1. Detection of P450-P450 interactions was accomplished through luminescence resonance energy transfer between labeled proteins incorporated into human liver microsomes and the microsomes of insect cells containing NADPH-cytochrome P450 reductase. The potential of CYP2D6 to form oligomers in the microsomal membrane is among the highest observed with human cytochrome P450 studied up to date. We also observed the formation of heteromeric complexes of CYP2D6 with CYP2E1 and CYP3A4, and found a significant modulation of these interactions by 3,4 methylenedioxymethylamphetamine, a widespread drug of abuse metabolized by CYP2D6. Our results demonstrate an ample alteration of the catalytic properties of CYP2D6 and CYP2E1 caused by their association. In particular, we demonstrated that preincubation of microsomes containing co-incorporated CYP2D6 and CYP2E1 with CYP2D6-specific substrates resulted in considerable time-dependent activation of CYP2D6, which presumably occurs via a slow substrate-induced reorganization of CYP2E1-CYP2D6 hetero-oligomers. Furthermore, we demonstrated that the formation of heteromeric complexes between CYP2E1 and CYP2D6 affects the stoichiometry of futile cycling and substrate oxidation by CYP2D6 by means of decreasing the electron leakage through the peroxide-generating pathways. Our results further emphasize the role of P450-P450 interactions in regulatory cross talk in human drug-metabolizing ensemble and suggest a role of interactions of CYP2E1 with CYP2D6 in pharmacologically important instances of alcohol-drug interactions. PMID- 28904079 TI - Ascorbic acid promotes a TGFbeta1-induced myofibroblast phenotype switch. AB - l-Ascorbic acid (AA), generally known as vitamin C, is a crucial cofactor for a variety of enzymes, including prolyl-3-hydroxylase (P3H), prolyl-4-hydroxylase (P4H), and lysyl hydroxylase (LH)-mediated collagen maturation. Here, we investigated whether AA has additional functions in the regulation of the myofibroblast phenotype, besides its function in collagen biosynthesis. We found that AA positively influences TGFbeta1-induced expression of COL1A1, ACTA2, and COL4A1 Moreover, we demonstrated that AA promotes alphaSMA stress fiber formation as well as the synthesis and deposition of collagens type I and IV Additionally, AA amplified the contractile phenotype of the myofibroblasts, as seen by increased contraction of a 3D collagen lattice. Moreover, AA increased the expression of several TGFbeta1-induced genes, including DDR1 and CCN2 Finally, we demonstrated that the mechanism of AA action seems independent of Smad2/3 signaling. PMID- 28904080 TI - Pressure and stretch differentially affect proliferation of renal proximal tubular cells. AB - Renal obstruction is frequently found in adults and children. Mechanical stimuli, including pressure and stretch in the obstructed kidney, contribute to damage; animal models of obstruction are characterized by increased cellular proliferation. We were interested in the direct effects of pressure and stretch on renal tubular cell proliferation. Human HKC-8 or rat NRK-52E proximal tubule cells were subjected to either pressure [0, 60 or 90 mmHg] or static stretch [0 or 20%] for 24 or 48 h. Cell proliferation was measured by cell counting, cell cycle analyzed by flow cytometry, and PCNA and Skp2 expression were determined by qPCR or western blot. Blood gases were determined in an iSTAT system. Proliferation was also assessed in vivo after 24 h of ureteral obstruction. There was a significant increase in HKC-8 cell number after 48 h of exposure to either 60 or 90 mmHg pressure. Western blot and qPCR confirmed increased expression of PCNA and Skp2 in pressurized cells. Cell cycle measurements demonstrated an increase in HKC-8 in S phase. Mechanical stretching increased PCNA protein expression in HKC-8 cells after 48 h while no effect was observed on Skp2 and cell cycle measurements. Increased PCNA expression was found at 24 h after ureteral obstruction. We demonstrate direct transduction of pressure into a proliferative response in HKC-8 and NRK-52E cells, measured by cell number, PCNA and Skp2 expression and increase in cells in S phase, whereas stretch had a less robust effect on proliferation. PMID- 28904081 TI - Variable setpoint as a relaxing component in physiological control. AB - Setpoints in physiology have been a puzzle for decades, and especially the notion of fixed or variable setpoints have received much attention. In this paper, we show how previously presented homeostatic controller motifs, extended with saturable signaling kinetics, can be described as variable setpoint controllers. The benefit of a variable setpoint controller is that an observed change in the concentration of the regulated biochemical species (the controlled variable) is fully characterized, and is not considered a deviation from a fixed setpoint. The variation in this biochemical species originate from variation in the disturbances (the perturbation), and thereby in the biochemical species representing the controller (the manipulated variable). Thus, we define an operational space which is spanned out by the combined high and low levels of the variations in (1) the controlled variable, (2) the manipulated variable, and (3) the perturbation. From this operational space, we investigate whether and how it imposes constraints on the different motif parameters, in order for the motif to represent a mathematical model of the regulatory system. Further analysis of the controller's ability to compensate for disturbances reveals that a variable setpoint represents a relaxing component for the controller, in that the necessary control action is reduced compared to that of a fixed setpoint controller. Such a relaxing component might serve as an important property from an evolutionary point of view. Finally, we illustrate the principles using the renal sodium and aldosterone regulatory system, where we model the variation in plasma sodium as a function of salt intake. We show that the experimentally observed variations in plasma sodium can be interpreted as a variable setpoint regulatory system. PMID- 28904082 TI - A relative L-arginine deficiency contributes to endothelial dysfunction across the stages of the menopausal transition. AB - Vascular endothelial function declines across the menopause transition in women. We tested the hypothesis that reduced availability of the endothelial nitric oxide synthase [eNOS] substrate L-arginine is an underlying mechanism to vascular endothelial dysfunction across menopause stages. Endothelial function (brachial artery flow-mediated dilation [FMD]) and plasma markers of L-arginine metabolism (citrulline, NG-mono-methyl-?-arginine [L-NMMA] asymmetric dimethylarginine [ADMA] and NG-N'G-dimethyl-l-arginine [SDMA]), were measured in 129 women: 36 premenopausal (33 +/- 7 years), 16 early- (49 +/- 3 years) or 21 late- (50 +/- 4 years) perimenopausal, and 21 early- (55 +/- 3 years) or 35 late- (61 +/- 4 years) postmenopausal. FMD was progressively reduced across menopause stages (P < 0.001). Menopause stage was associated with L-arginine concentrations (P = 0.012), with higher levels in early postmenopausal compared to early and late perimenopausal women (P < 0.05). The methylarginine and eNOS inhibitor L-NMMA was higher in early and late postmenopausal women compared to premenopausal and early and late perimenopausal women (all P < 0.001), and was inversely correlated with FMD (r = -0.30, P = 0.001). The L-arginine/L-NMMA ratio, a potential biomarker of relative L-arginine levels, was lower in postmenopausal compared to either premenopausal or perimenopausal women (both P < 0.001), and was positively correlated with FMD (r = 0.33, P < 0.001). There were no differences in plasma citrulline, ADMA or SDMA across groups. These data suggest that a relative L arginine deficiency may be a mechanism underlying the decline in endothelial function with the menopause transition in women. The relative L-arginine deficiency may be related to elevated levels of the methylarginine L-NMMA, which would compete with L-arginine for eNOS and for intracellular transport, reducing NO biosynthesis. PMID- 28904084 TI - Relevance of supraventricular runs detected after cerebral ischemia. AB - OBJECTIVE: Prolonged ECG monitoring after stroke frequently reveals short paroxysmal atrial fibrillation (pAF) and supraventricular (SV) runs. The minimal duration of atrial fibrillation (AF) required to induce cardioembolism, the relevance of SV runs, and whether short pAF results from cerebral damage itself are currently being debated. We aimed to study the relevance of SV runs and short pAF detected by prolonged Holter ECG after cerebral ischemia during long-term follow-up. METHODS: Analysis is from the prospective Find-AF trial (ISRCTN46104198). We included patients with acute cerebral ischemia. Those without AF on admission received 7-day Holter ECG monitoring. We differentiated patients with AF on admission (AF-adm), with pAF (>30 seconds), with SV runs (>5 beats but <30 seconds in a 24-hour ECG interval), and without SV runs (controls). During follow-up, those with baseline pAF received another 7-day Holter ECG to examine AF persistence. RESULTS: A total of 254 of 281 initially included patients were analyzed (mean age 70.0 years, 45.3% female). Forty-three (16.9%) had AF-adm. A total of 211 received 7-day Holter ECG monitoring: 27 (12.8%) had pAF, 67 (31.8%) had SV runs, and 117 (55.5%) were controls. During a mean 3.7 years of follow-up, the SV runs group had more recurrent strokes (p = 0.04) and showed numerically more novel AF (12% vs 5%, p = 0.09) than the controls. Seventy five percent of the patients with manifest pAF detected after cerebral ischemia still had AF during follow-up (50% paroxysmal, 50% persisting/permanent). CONCLUSIONS: Patients with cerebral ischemia and SV runs had more recurrent strokes and numerically more novel AF during follow-up and could benefit from further prolonged ECG monitoring. pAF detected after stroke is not a temporal phenomenon. PMID- 28904083 TI - Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography. AB - The effects of mitofusin 2 (MFN2) deficiency, on mitochondrial morphology and the mitochondria-junctional sarcoplasmic reticulum (jSR) complex in the adult heart, have been previously investigated using 2D electron microscopy, an approach which is unable to provide a 3D spatial assessment of these imaging parameters. Here, we use 3D electron tomography to show that MFN2-deficient mitochondria are larger in volume, more elongated, and less rounded; have fewer mitochondria-jSR contacts, and an increase in the distance between mitochondria and jSR, when compared to WT mitochondria. In comparison to 2D electron microscopy, 3D electron tomography can provide further insights into mitochondrial morphology and the mitochondria-jSR complex in the adult heart. PMID- 28904085 TI - Preventing multiple sclerosis: To (take) vitamin D or not to (take) vitamin D? PMID- 28904087 TI - Striving to improve the quality of stroke care in the USA. PMID- 28904088 TI - Quality improvement in neurology: Stroke and Stroke Rehabilitation Quality Measurement Set update. PMID- 28904089 TI - Some light in the shadows of atrial fibrillation and stroke: To look or not to look. PMID- 28904086 TI - Cognitive trajectories over 4 years among HIV-infected women with optimal viral suppression. AB - OBJECTIVE: To determine whether persistent viral suppression alters cognitive trajectories among HIV-infected (HIV+) women on combination antiretroviral therapy (cART) by investigating performance longitudinally in uninfected (HIV-) and 3 groups of HIV+ women: those with consistent viral suppression after continuous cART use (VS), those without consistent virologic suppression despite continuous cART use (NVS), and those without consistent virologic suppression after intermittent cART use (Int NVS). METHODS: Two hundred thirty-nine VS, 220 NVS, 172 Int NVS, and 301 HIV- women from the Women's Interagency HIV Study (WIHS) completed neuropsychological testing every 2 years for 3 visits between 2009 and 2013. Mixed-effects regressions were used to examine group differences on continuous T scores and categorical measures of impairment (T score <40). RESULTS: On global function, VS women demonstrated lower scores and were more likely to score in the impaired range than HIV- women (p = 0.01). These differences persisted over time (group * time, p > 0.39). VS women demonstrated lower learning and memory scores than HIV- women (p < 0.05) and lower attention/working memory and fluency scores than HIV- and NVS women (p < 0.05). Group differences in scores persisted over time. Categorically, VS women were more likely to be impaired on attention/working memory and executive function than HIV- women (p < 0.05). On motor skills, VS and NVS women showed a greater decline and were more likely to be impaired than HIV- women (p < 0.05). CONCLUSIONS: Cognitive difficulties remain among HIV+ women despite persistent viral suppression. In some instances, VS women are worse than NVS women, reinforcing the need for novel adjunctive therapies to attenuate cognitive problems. PMID- 28904090 TI - HIV-related cognitive decline despite viral suppression and complex confounds in American women. PMID- 28904091 TI - 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. AB - OBJECTIVE: To determine whether and to what extent vitamin D deficiency is associated with multiple sclerosis (MS) risk. METHODS: We conducted a prospective nested case-control study among women in the Finnish Maternity Cohort (FMC). The FMC had 1.8 million stored serum samples taken during the pregnancies of over 800,000 women at the time of this study. Through linkages with hospital and prescription registries, we identified 1,092 women with MS diagnosed between 1983 and 2009 with at least 1 serum sample collected prior to date of MS diagnosis; >=2 serum samples were available for 511 cases. Cases were matched to up to 3 controls (n = 2,123) on date of birth (+/-2 years) and area of residence. 25 Hydroxyvitamin D (25[OH]D) levels were measured using a chemiluminescence assay. We used conditional logistic regression adjusted for year of sample collection, gravidity, and parity to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: A 50 nmol/L increase in 25(OH)D was associated with a 39% reduced risk of MS (RR 0.61, 95% CI 0.44-0.85), p = 0.003. Women with 25(OH)D levels <30 nmol/L had a 43% higher MS risk (RR 1.43, 95% CI 1.02-1.99, p = 0.04) as compared to women with levels >=50 nmol/L. In women with >=2 samples, MS risk was 2-fold higher in women with 25(OH)D <30 nmol/L as compared to women with 25(OH)D >=50 nmol/L (RR 2.02, 95% CI 1.18-3.45, p = 0.01). CONCLUSIONS: These results directly support vitamin D deficiency as a risk factor for MS and strengthen the rationale for broad public health interventions to improve vitamin D levels. PMID- 28904092 TI - MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor Intracellular Trapping. AB - The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission.SIGNIFICANCE STATEMENT The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission. PMID- 28904093 TI - Sodium Dynamics in Pyramidal Neuron Dendritic Spines: Synaptically Evoked Entry Predominantly through AMPA Receptors and Removal by Diffusion. AB - Dendritic spines are key elements underlying synaptic integration and cellular plasticity, but many features of these important structures are not known or are controversial. We examined these properties using newly developed simultaneous sodium and calcium imaging with single-spine resolution in pyramidal neurons in rat hippocampal slices from either sex. Indicators for both ions were loaded through the somatic patch pipette, which also recorded electrical responses. Fluorescence changes were detected with a high-speed, low-noise CCD camera. Following subthreshold electrical stimulation, postsynaptic sodium entry is almost entirely through AMPA receptors with little contribution from entry through NMDA receptors or voltage-gated sodium channels. Sodium removal from the spine head is through rapid diffusion out to the dendrite through the spine neck with a half-removal time of ~16 ms, which suggests the neck has low resistance. Peak [Na+]i changes during single EPSPs are ~5 mm Stronger electrical stimulation evoked small plateau potentials that had significant longer-lasting localized [Na+]i increases mediated through NMDA receptors.SIGNIFICANCE STATEMENT Dendritic spines, small structures that are difficult to investigate, are important elements in the fundamental processes of synaptic integration and plasticity. The main tool for examining these structures has been calcium imaging. However, the kinds of information that calcium imaging reveals is limited. We used newly developed, high-speed, simultaneous sodium and calcium imaging to examine ion dynamics in spines in hippocampal pyramidal neurons. We found that following single subthreshold synaptic activation most sodium entry was through AMPA receptors and not through NMDA receptors or through voltage-gated sodium channels and that the spine neck is not a significant resistance barrier. Most spine mechanisms are linear. However, regenerative NMDA conductances can be activated with stronger stimulation. PMID- 28904094 TI - Favored local structures in amorphous colloidal packings measured by microbeam X ray diffraction. AB - Local structure and symmetry are keys to understanding how a material is formed and the properties it subsequently exhibits. This applies to both crystals and amorphous and glassy materials. In the case of amorphous materials, strong links between processing and history, structure and properties have yet to be made because measuring amorphous structure remains a significant challenge. Here, we demonstrate a method to quantify proportions of the bond-orientational order of nearest neighbor clusters [Steinhardt, et al. (1983) Phys Rev B 28:784-805] in colloidal packings by statistically analyzing the angular correlations in an ensemble of scanning transmission microbeam small-angle X-ray scattering (MUSAXS) patterns. We show that local order can be modulated by tuning the potential between monodisperse, spherical colloidal silica particles using salt and surfactant additives and that more pronounced order is obtained by centrifugation than sedimentation. The order in the centrifuged glasses reflects the ground state order in the dispersion at lower packing fractions. This diffraction-based method can be applied to amorphous systems across decades in length scale to connect structure to behavior in disordered systems with a range of particle interactions. PMID- 28904095 TI - Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS. AB - Mutations in autophagy genes can cause familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of autophagy in ALS pathogenesis is poorly understood, in part due to the lack of cell type-specific manipulations of this pathway in animal models. Using a mouse model of ALS expressing mutant superoxide dismutase 1 (SOD1G93A), we show that motor neurons form large autophagosomes containing ubiquitinated aggregates early in disease progression. To investigate whether this response is protective or detrimental, we generated mice in which the critical autophagy gene Atg7 was specifically disrupted in motor neurons (Atg7 cKO). Atg7 cKO mice were viable but exhibited structural and functional defects at a subset of vulnerable neuromuscular junctions. By crossing Atg7 cKO mice to the SOD1G93A mouse model, we found that autophagy inhibition accelerated early neuromuscular denervation of the tibialis anterior muscle and the onset of hindlimb tremor. Surprisingly, however, lifespan was extended in Atg7 cKO; SOD1G93A double-mutant mice. Autophagy inhibition did not prevent motor neuron cell death, but it reduced glial inflammation and blocked activation of the stress-related transcription factor c-Jun in spinal interneurons. We conclude that motor neuron autophagy is required to maintain neuromuscular innervation early in disease but eventually acts in a non-cell-autonomous manner to promote disease progression. PMID- 28904097 TI - Network approach to patterns in stratocumulus clouds. AB - Stratocumulus clouds (Sc) have a significant impact on the amount of sunlight reflected back to space, with important implications for Earth's climate. Representing Sc and their radiative impact is one of the largest challenges for global climate models. Sc fields self-organize into cellular patterns and thus lend themselves to analysis and quantification in terms of natural cellular networks. Based on large-eddy simulations of Sc fields, we present a first analysis of the geometric structure and self-organization of Sc patterns from this network perspective. Our network analysis shows that the Sc pattern is scale invariant as a consequence of entropy maximization that is known as Lewis's Law (scaling parameter: 0.16) and is largely independent of the Sc regime (cloud-free vs. cloudy cell centers). Cells are, on average, hexagonal with a neighbor number variance of about 2, and larger cells tend to be surrounded by smaller cells, as described by an Aboav-Weaire parameter of 0.9. The network structure is neither completely random nor characteristic of natural convection. Instead, it emerges from Sc-specific versions of cell division and cell merging that are shaped by cell expansion. This is shown with a heuristic model of network dynamics that incorporates our physical understanding of cloud processes. PMID- 28904096 TI - RIPK1 mediates a disease-associated microglial response in Alzheimer's disease. AB - Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Abeta in vitro. We characterized the transcriptional profiles of adult microglia from APP/PS1 mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD. PMID- 28904098 TI - Characterization of ion channels and O2 sensitivity in gill neuroepithelial cells of the anoxia-tolerant goldfish (Carassius auratus). AB - The neuroepithelial cell (NEC) of the fish gill is an important model for O2 sensing in vertebrates; however, a complete picture of the chemosensory mechanisms in NECs is lacking, and O2 chemoreception in vertebrates that are tolerant to anoxia has not yet been explored. Using whole cell patch-clamp recording, we characterized four types of ion channels in NECs isolated from the anoxia-tolerant goldfish. A Ca2+-dependent K+ current (IKCa) peaked at ~20 mV, was potentiated by increased intracellular Ca2+, and was reduced by 100 MUM Cd2+ A voltage-dependent inward current in Ba2+ solution, with peak at 0 mV, confirmed the presence of Ca2+ channels. A voltage-dependent K+ current (IKV) was inhibited by 20 mM tetraethylammonium and 5 mM 4-aminopyridine, revealing a background K+ current (IKB) with open rectification. Mean resting membrane potential of -45.2 +/- 11.6 mV did not change upon administration of hypoxia (Po2 = 11 mmHg), nor were any of the K+ currents sensitive to changes in Po2 during whole cell recording. By contrast, when the membrane and cytosol were left undisturbed during fura-2 or FM 1-43 imaging experiments, hypoxia increased intracellular Ca2+ concentration and initiated synaptic vesicle activity. 100 MUM Cd2+ and 50 MUM nifedipine eliminated uptake of FM 1-43. We conclude that Ca2+ influx via L type Ca2+ channels is correlated with vesicular activity during hypoxic stimulation. In addition, we suggest that expression of IKCa in gill NECs is species specific and, in goldfish, may contribute to an attenuated response to acute hypoxia.NEW & NOTEWORTHY This study provides the first physiological characterization of oxygen chemoreceptors from an anoxia-tolerant vertebrate. Neuroepithelial cells (NECs) from the gills of goldfish displayed L-type Ca2+ channels and three types of K+ channels, one of which was dependent upon intracellular Ca2+ Although membrane currents were not inhibited by hypoxia during patch-clamp recording, this study is the first to show that NECs with an undisturbed cytosol responded to hypoxia with increased intracellular Ca2+ and synaptic vesicle activity. PMID- 28904099 TI - Spasticity may obscure motor learning ability after stroke. AB - Previous motor learning studies based on adapting movements of the hemiparetic arm in stroke subjects have not accounted for spasticity occurring in specific joint ranges (spasticity zones), resulting in equivocal conclusions about learning capacity. We compared the ability of participants with stroke to rapidly adapt elbow extension movements to changing external load conditions outside and inside spasticity zones. Participants with stroke ( n = 12, aged 57.8 +/- 9.6 yr) and healthy age-matched controls ( n = 8, 63.5 +/- 9.1 yr) made rapid 40 degrees 50 degrees horizontal elbow extension movements from an initial (3 degrees ) to a final (6 degrees ) target. Sixteen blocks (6-10 trials/block) consisting of alternating loaded (30% maximal voluntary contraction) and nonloaded trials were made in one (controls) or two sessions (stroke; 1 wk apart). For the stroke group, the tonic stretch reflex threshold angle at which elbow flexors began to be activated during passive elbow extension was used to identify the beginning of the spasticity zone. The task was repeated in joint ranges that did or did not include the spasticity zone. Error correction strategies were identified by the angular positions before correction and compared between groups and sessions. Changes in load condition from no load to load and vice versa resulted in undershoot and overshoot errors, respectively. Stroke subjects corrected errors in 1-4 trials compared with 1-2 trials in controls. When movements did not include the spasticity zone, there was an immediate decrease in the number of trials needed to restore accuracy, suggesting that the capacity to learn may be preserved after stroke but masked by the presence of spasticity. NEW & NOTEWORTHY When arm movements were made outside, instead of inside, the range affected by spasticity, there was an immediate decrease in the number of trials needed to restore accuracy in response to a change in the external load. This suggests that motor learning processes may be preserved in patients with stroke but masked by the presence of spasticity in specific joint ranges. This has important implications for designing rehabilitation interventions predicated on motor learning principles. PMID- 28904100 TI - Influence of biases in numerical magnitude allocation on human prosocial decision making. AB - Over the past decade neuroscientific research has attempted to probe the neurobiological underpinnings of human prosocial decision making. Such research has almost ubiquitously employed tasks such as the dictator game or similar variations (i.e., ultimatum game). Considering the explicit numerical nature of such tasks, it is surprising that the influence of numerical cognition on decision making during task performance remains unknown. While performing these tasks, participants typically tend to anchor on a 50:50 split that necessitates an explicit numerical judgement (i.e., number-pair bisection). Accordingly, we hypothesize that the decision-making process during the dictator game recruits overlapping cognitive processes to those known to be engaged during number-pair bisection. We observed that biases in numerical magnitude allocation correlated with the formulation of decisions during the dictator game. That is, intrinsic biases toward smaller numerical magnitudes were associated with the formulation of less favorable decisions, whereas biases toward larger magnitudes were associated with more favorable choices. We proceeded to corroborate this relationship by subliminally and systematically inducing biases in numerical magnitude toward either higher or lower numbers using a visuo-vestibular stimulation paradigm. Such subliminal alterations in numerical magnitude allocation led to proportional and corresponding changes to an individual's decision making during the dictator game. Critically, no relationship was observed between neither intrinsic nor induced biases in numerical magnitude on decision making when assessed using a nonnumerical-based prosocial questionnaire. Our findings demonstrate numerical influences on decisions formulated during the dictator game and highlight the necessity to control for confounds associated with numerical cognition in human decision-making paradigms.NEW & NOTEWORTHY We demonstrate that intrinsic biases in numerical magnitude can directly predict the amount of money donated by an individual to an anonymous stranger during the dictator game. Furthermore, subliminally inducing perceptual biases in numerical magnitude allocation can actively drive prosocial choices in the corresponding direction. Our findings provide evidence for numerical influences on decision making during performance of the dictator game. Accordingly, without the implementation of an adequate control for numerical influences, the dictator game and other tasks with an inherent numerical component (i.e., ultimatum game) should be employed with caution in the assessment of human behavior. PMID- 28904101 TI - Methodological considerations for a chronic neural interface with the cuneate nucleus of macaques. AB - While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult-to-access brain stem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implanting arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brain stem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.NEW & NOTEWORTHY In primates, the neural basis of touch and of our sense of limb posture and movements has been studied in the peripheral nerves and in somatosensory cortex, but coding in the cuneate and external cuneate nuclei, the first processing stage for these signals in the central nervous system, remains an enigma. We have developed a method to record from these nuclei, thereby paving the way to studying how sensory information from the limb is encoded there. PMID- 28904102 TI - Stability of hand force production. I. Hand level control variables and multifinger synergies. AB - We combined the theory of neural control of movement with referent coordinates and the uncontrolled manifold hypothesis to explore synergies stabilizing the hand action in accurate four-finger pressing tasks. In particular, we tested a hypothesis on two classes of synergies, those among the four fingers and those within a pair of control variables, stabilizing hand action under visual feedback and disappearing without visual feedback. Subjects performed four-finger total force and moment production tasks under visual feedback; the feedback was later partially or completely removed. The "inverse piano" device was used to lift and lower the fingers smoothly at the beginning and at the end of each trial. These data were used to compute pairs of hypothetical control variables. Intertrial analysis of variance within the finger force space was used to quantify multifinger synergies stabilizing both force and moment. A data permutation method was used to quantify synergies among control variables. Under visual feedback, synergies in the spaces of finger forces and hypothetical control variables were found to stabilize total force. Without visual feedback, the subjects showed a force drift to lower magnitudes and a moment drift toward pronation. This was accompanied by disappearance of the four-finger synergies and strong attenuation of the control variable synergies. The indexes of the two types of synergies correlated with each other. The findings are interpreted within the scheme with multiple levels of abundant variables.NEW & NOTEWORTHY We extended the idea of hierarchical control with referent spatial coordinates for the effectors and explored two types of synergies stabilizing multifinger force production tasks. We observed synergies among finger forces and synergies between hypothetical control variables that stabilized performance under visual feedback but failed to stabilize it after visual feedback had been removed. Indexes of two types of synergies correlated with each other. The data suggest the existence of multiple mechanisms stabilizing motor actions. PMID- 28904103 TI - Surface electrodes record and label brain neurons in insects. AB - We used suction electrodes to reliably record the activity of identified ascending auditory interneurons from the anterior surface of the brain in crickets. Electrodes were gently attached to the sheath covering the projection area of the ascending interneurons and the ringlike auditory neuropil in the protocerebrum. The specificity and selectivity of the recordings were determined by the precise electrode location, which could easily be changed without causing damage to the tissue. Different nonauditory fibers were recorded at other spots of the brain surface; stable recordings lasted for several hours. The same electrodes were used to deliver fluorescent tracers into the nervous system by means of electrophoresis. This allowed us to retrograde label the recorded auditory neurons and to reveal their cell body and dendritic structure in the first thoracic ganglion. By adjusting the amount of dye injected, we specifically stained the ringlike auditory neuropil in the brain, demonstrating the clusters of cell bodies contributing to it. Our data provide a proof that surface electrodes are a versatile tool to analyze neural processing in small brains of invertebrates.NEW & NOTEWORTHY We show that surface suction electrodes can be used to monitor the activity of auditory neurons in the cricket brain. They also allow delivering electrophoretically a fluorescent tracer to label the structure of the recorded neurons and the local neuropil to which the electrode was attached. This new extracellular recording and labeling technique is a versatile and useful method to explore neural processing in invertebrate sensory and motor systems. PMID- 28904104 TI - The superior colliculus and the steering of saccades toward a moving visual target. AB - Following the suggestion that a command encoding current target location feeds the oculomotor system during interceptive saccades, we tested the involvement of the deep superior colliculus (dSC). Extracellular activity of 52 saccade-related neurons was recorded in three monkeys while they generated saccades to targets that were static or moving along the preferred axis, away from (outward) or toward (inward) a fixated target with a constant speed (20 degrees /s). Vertical and horizontal motions were tested when possible. Movement field (MF) parameters (boundaries, preferred vector, and firing rate) were estimated after spline fitting of the relation between the average firing rate during the motor burst and saccade amplitude. During radial target motions, the inner MF boundary shifted in the motion direction for some, but not all, neurons. Likewise, for some neurons, the lower boundaries were shifted upward during upward motions and the upper boundaries downward during downward motions. No consistent change was observed during horizontal motions. For some neurons, the preferred vectors were also shifted in the motion direction for outward, upward, and "toward the midline" target motions. The shifts of boundary and preferred vector were not correlated. The burst firing rate was consistently reduced during interceptive saccades. Our study demonstrates an involvement of dSC neurons in steering the interceptive saccade. When observed, the shifts of boundary in the direction of target motion correspond to commands related to past target locations. The absence of shift in the opposite direction implies that dSC activity does not issue predictive commands related to future target location.NEW & NOTEWORTHY The deep superior colliculus is involved in steering the saccade toward the current location of a moving target. During interceptive saccades, the active population consists of a continuum of cells ranging from neurons issuing commands related to past locations of the target to neurons issuing commands related to its current location. The motor burst of collicular neurons does not contain commands related to the future location of a moving target. PMID- 28904105 TI - Contribution of sensory feedback to plantar flexor muscle activation during push off in adults with cerebral palsy. AB - Exaggerated sensory activity has been assumed to contribute to functional impairment following lesion of the central motor pathway. However, recent studies have suggested that sensory contribution to muscle activity during gait is reduced in stroke patients and children with cerebral palsy (CP). We investigated whether this also occurs in CP adults and whether daily treadmill training is accompanied by alterations in sensory contribution to muscle activity. Seventeen adults with CP and 12 uninjured individuals participated. The participants walked on a treadmill while a robotized ankle-foot orthosis applied unload perturbations at the ankle, thereby removing sensory feedback naturally activated during push off. Reduction of electromyographic (EMG) activity in the soleus muscle caused by unloads was compared and related to kinematics and ankle joint stiffness measurements. Similar measures were obtained after 6 wk of gait training. We found that sensory contribution to soleus EMG activation was reduced in CP adults compared with uninjured adults. The lowest contribution of sensory feedback was found in participants with lowest maximal gait speed. This was related to increased ankle plantar flexor stiffness. Six weeks of gait training did not alter the contribution of sensory feedback. We conclude that exaggerated sensory activity is unlikely to contribute to impaired gait in CP adults, because sensory contribution to muscle activity during gait was reduced compared with in uninjured individuals. Increased passive stiffness around the ankle joint is likely to diminish sensory feedback during gait so that a larger part of plantar flexor muscle activity must be generated by descending motor commands.NEW & NOTEWORTHY Findings suggest that adults with cerebral palsy have less contribution of sensory feedback to ongoing soleus muscle activation during push off than uninjured individuals. Increased passive stiffness around the ankle joint is likely to diminish sensory feedback during gait, and/or sensory feedback is less integrated with central motor commands in the activation of spinal motor neurons. Consequently, muscle activation must to a larger extent rely on descending drive, which is already decreased because of the cerebral lesion. PMID- 28904106 TI - Diversity in spatial scope of contrast adaptation among mouse retinal ganglion cells. AB - Retinal ganglion cells adapt to changes in visual contrast by adjusting their response kinetics and sensitivity. While much work has focused on the time scales of these adaptation processes, less is known about the spatial scale of contrast adaptation. For example, do small, localized contrast changes affect a cell's signal processing across its entire receptive field? Previous investigations have provided conflicting evidence, suggesting that contrast adaptation occurs either locally within subregions of a ganglion cell's receptive field or globally over the receptive field in its entirety. Here, we investigated the spatial extent of contrast adaptation in ganglion cells of the isolated mouse retina through multielectrode-array recordings. We applied visual stimuli so that ganglion cell receptive fields contained regions where the average contrast level changed periodically as well as regions with constant average contrast level. This allowed us to analyze temporal stimulus integration and sensitivity separately for stimulus regions with and without contrast changes. We found that the spatial scope of contrast adaptation depends strongly on cell identity, with some ganglion cells displaying clear local adaptation, whereas others, in particular large transient ganglion cells, adapted globally to contrast changes. Thus, the spatial scope of contrast adaptation in mouse retinal ganglion cells appears to be cell-type specific. This could reflect differences in mechanisms of contrast adaptation and may contribute to the functional diversity of different ganglion cell types.NEW & NOTEWORTHY Understanding whether adaptation of a neuron in a sensory system can occur locally inside the receptive field or whether it always globally affects the entire receptive field is important for understanding how the neuron processes complex sensory stimuli. For mouse retinal ganglion cells, we here show that both local and global contrast adaptation exist and that this diversity in spatial scope can contribute to the functional diversity of retinal ganglion cell types. PMID- 28904107 TI - Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds. AB - Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90-100 ms was significantly increased in lower threshold sensory axons times (F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold (I/V) gradient was significantly increased in lower threshold axons (F = 3.191, P < 0.05). The minimum I/V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets.NEW & NOTEWORTHY Hyperpolarization activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents (Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases. PMID- 28904109 TI - A wound-healing program is hijacked to promote cancer metastasis. AB - In this issue of JEM, Sundaram et al. (https://doi.org/10.1084/jem.20170354) report a mechanism by which the normal epithelial wound healing response is "hijacked" to promote invasion and metastasis in head and neck squamous carcinomas (HNSCCs), a finding that unveils new markers of poor outcomes and potential targets for therapeutic intervention. PMID- 28904108 TI - Comparison of three models of saccade disconjugacy in strabismus. AB - In pattern strabismus the horizontal and vertical misalignments vary with eye position along the orthogonal axis. The disorder is typically described in terms of overaction or underaction of oblique muscles. Recent behavioral studies in humans and monkeys, however, have reported that such actions are insufficient to fully explain the patterns of directional and amplitude disconjugacy of saccades. There is mounting evidence that the oculomotor abnormalities associated with strabismus are at least partially attributable to neurophysiological abnormalities. A number of control systems models have been developed to simulate the kinematic characteristics of saccades in normal primates. In the present study we sought to determine whether these models could simulate the abnormalities of saccades in strabismus by making two assumptions: 1) in strabismus the burst generator gains differ for the two eyes and 2) abnormal crosstalk exists between the horizontal and vertical saccadic circuits in the brain stem. We tested three models, distinguished by the location of the horizontal-vertical crosstalk. All three models were able to simulate amplitude and directional saccade disconjugacy, postsaccadic drift, and a pattern strabismus for static fixation, but they made different predictions about the dynamics of saccades. By assuming that crosstalk occurs at multiple nodes, the Distributed Crosstalk Model correctly predicted the dynamics of saccades. These new models make additional predictions that can be tested with future neurophysiological experiments.NEW & NOTEWORTHY Over the past several decades, numerous control systems models have been devised to simulate the known kinematic features of saccades in normal primates. These models have proven valuable to neurophysiology, as a means of generating testable predictions. The present manuscript, as far as we are aware, is the first to present control systems models to simulate the known abnormalities of saccades in strabismus. PMID- 28904111 TI - A Literature Review of the Effect of Malaria on Stunting. AB - Background: The current version of the Lives Saved Tool (LiST) maternal and child health impact modeling software does not include an effect of malaria on stunting.Objective: This literature review was undertaken to determine whether such a causal link should be included in the LiST model.Methods: The PubMed, Embase, and Scopus databases were searched by using broad search terms. The searches returned a total of 4281 documents. Twelve studies from among the retrieved documents were included in the review according to the inclusion and exclusion criteria.Results: There was mixed evidence for an effect of malaria on stunting among longitudinal observational studies, and none of the randomized controlled trials of malaria interventions found an effect of the interventions on stunting.Conclusions: There is insufficient evidence to include malaria as a determinant of stunting or an effect of malaria interventions on stunting in the LiST model. The paucity and heterogeneity of the available literature were a major limitation. In addition, the studies included in the review consistently fulfilled their ethical responsibility to treat children under observation for malaria, which may have interfered with the natural history of the disease and prevented any observable effect on stunting or linear growth. PMID- 28904110 TI - The chromatin accessibility signature of human immune aging stems from CD8+ T cells. AB - Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-kappaB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency. PMID- 28904112 TI - Modeling the Impact of Nutrition Interventions on Birth Outcomes in the Lives Saved Tool (LiST). AB - Background: Negative birth outcomes [small-for-gestational age (SGA) and preterm birth (PTB)] are common in low- and middle-income countries and have important subsequent health and developmental impacts on children. There are numerous nutritional and non-nutritional interventions that can decrease the risk of negative birth outcomes and reduce subsequent risk of mortality and growth faltering.Objective: The objective of this article was to review the current evidence for the impact of nutritional interventions in pregnancy [calcium supplementation, iron and folic acid supplementation, multiple micronutrient (MMN) supplementation, and balanced energy supplementation (BES)] and risk factors (maternal anemia) on birth outcomes, with the specific goal of determining which intervention-outcome linkages should be included in the Lives Saved Tool (LiST) software.Methods: A literature search was conducted by using the WHO e-Library of Evidence for Nutrition Actions as the starting point. Recent studies, meta-analyses, and systematic reviews were reviewed for inclusion on the basis of their relevance to LiST.Results: On the basis of the available scientific evidence, the following linkages were found to be supported for inclusion in LiST: calcium supplementation on PTB (12% reduction), MMN supplementation on SGA (9% reduction), and BES on SGA (21% reduction among food insecure women).Conclusions: The inclusion of these linkages in LiST will improve the utility of the model for users who seek to estimate the impact of antenatal nutrition interventions on birth outcomes. Scaling up these interventions should lead to downstream impacts in reducing stunting and child mortality. PMID- 28904113 TI - Complementary Feeding Interventions Have a Small but Significant Impact on Linear and Ponderal Growth of Children in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis. AB - Background: World Health Assembly member states have committed to ambitious global targets for reductions in stunting and wasting by 2025. Improving complementary diets of children aged 6-23 mo is a recommended approach for reducing stunting in children <5 y old. Less is known about the potential of these interventions to prevent wasting.Objective: The aim of this article was to review and synthesize the current literature for the impact of complementary feeding interventions on linear [length-for-age z score (LAZ)] and ponderal [weight-for-length z score (WLZ)] growth of children aged 6-23 mo, with the specific goal of updating intervention-outcome linkages in the Lives Saved Tool (LiST).Methods: We started our review with studies included in the previous LiST review and searched for articles published since January 2012. We identified longitudinal trials that compared children aged 6-23 mo who received 1 of 2 types of complementary feeding interventions (nutrition education or counseling alone or complementary food supplementation with or without nutrition education or counseling) with a no-intervention control. We assessed study quality and generated pooled estimates of LAZ and WLZ change, as well as length and weight gain, for each category of intervention.Results: Interventions that provided nutrition education or counseling had a small but significant impact on linear growth in food-secure populations [LAZ standardized mean difference (SMD): 0.11; 95% CI: 0.01, 0.22] but not on ponderal growth. Complementary food supplementation interventions with or without nutrition education also had a small, significant effect in food-insecure settings on both LAZ (SMD: 0.08; 95% CI: 0.04, 0.13) and WLZ (SMD: 0.05; 95% CI: 0.01, 0.08).Conclusions: Nutrition education and complementary feeding interventions both had a small but significant impact on linear growth, and complementary feeding interventions also had an impact on ponderal growth of children aged 6-23 mo in low- and middle income countries. The updated LiST model will support nutrition program planning and evaluation efforts by allowing users to model changes in intervention coverage on both stunting and wasting. PMID- 28904114 TI - The Lives Saved Tool (LiST) as a Model for Prevention of Anemia in Women of Reproductive Age. AB - Background: Anemia in women is a major public health burden worldwide, particularly in low- and middle-income countries (LMICs). It is a complex condition with multiple nutritional and non-nutritional causes, and geographic heterogeneity of burden. The World Health Assembly has set a target of a 50% reduction in anemia among women of reproductive age (WRA) by 2025.Objective: This article seeks to identify the leading causes of anemia among women in LMICs, review the evidence supporting interventions to address anemia in these settings, and ultimately use this information to decide which interventions should be included in the Lives Saved Tool (LiST) model of anemia. It also seeks to examine the link between anemia and cause-specific maternal mortality.Methods: The leading causes of anemia in WRA were inventoried to identify preventive and curative interventions available for implementation at the public health scale. A literature review was then conducted for each identified intervention, as well as for the link between anemia and maternal mortality.Results: The interventions for which data were available fell into the following categories: provision of iron, malaria prevention, and treatment of parasitic infestation. Ultimately, 5 interventions were included in the LiST model for anemia: blanket iron supplementation or fortification, iron and folic acid supplementation in pregnancy, multiple micronutrient supplementation in pregnancy, intermittent preventive treatment of malaria in pregnancy, and household ownership of an insecticide-treated bednet. In addition, anemia was linked in the model with risk of maternal mortality due to hemorrhage.Conclusion: The updated LiST model for anemia reflects the state of the current scientific evidence and should be of use to researchers, program managers, and policymakers who seek to model the impact of scaling up nutrition and health interventions on anemia, and ultimately on maternal mortality. PMID- 28904115 TI - New Option in the Lives Saved Tool (LiST) Allows for the Conversion of Prevalence of Small-for-Gestational-Age and Preterm Births to Prevalence of Low Birth Weight. AB - Background: The Lives Saved Tool (LiST) is a software model that estimates the health impact of scaling up interventions on maternal and child health. One of the outputs of the model is an estimation of births by fetal size [appropriate for-gestational-age (AGA) or small-for-gestational-age (SGA)] and by length of gestation (term or preterm), both of which influence birth weight. LiST uses prevalence estimates of births in these categories rather than of birth weight categories, because the causes and health consequences differ between SGA and preterm birth. The World Health Assembly nutrition plan, however, has set the prevalence of low birth weight (LBW) as a key indicator, with a specific goal of a 30% reduction in LBW prevalence by 2025.Objective: The objective of the study is to develop an algorithm that will allow LiST users to estimate changes in prevalence of LBW on the basis of changes in coverage of interventions and the resulting impact on prevalence estimates of SGA and preterm births.Methods: The study used 13 prospective cohort data sets from low- and middle-income countries (LMICs; 4 from sub-Saharan Africa, 5 from Asia, and 4 from Latin America), with reliable measures of gestational age and birth weight. By calculating the proportion of LBW births among SGA and preterm births in each data set and meta analyzing those estimates, we calculated region-specific pooled rates of LBW among SGA and preterm births.Results: In Africa, 0.4% of term-AGA, 36.7% of term SGA, 49.3% of preterm-AGA, and 100.0% of preterm-SGA births were LBW. In Asia, 1.0% of term-SGA, 47.0% of term-SGA, 36.7% of preterm-AGA, and 100.0% of preterm SGA births were LBW. In Latin America, 0.4% of term-AGA, 34.4% of term-SGA, 32.3% of preterm-AGA, and 100.0% of preterm-SGA births were LBW.Conclusions: The simple conversion factor proposed here allows for the estimation of LBW within LiST for most LMICs. This will allow LiST users to approximate the impact of their health programs on LBW prevalence via the impact on SGA and preterm prevalence. PMID- 28904116 TI - Integrated Interventions Delivered in Health Systems, Home, and Community Have the Highest Impact on Breastfeeding Outcomes in Low- and Middle-Income Countries. AB - Background: Improving breastfeeding rates is critical. In low- and middle-income countries (LMICs), only subtle improvements in breastfeeding rates have been observed over the past decade, which highlights the need for accelerating breastfeeding promotion interventions.Objective: The objective of this article is to update evidence on the effect of interventions on early initiation of and exclusive (<1 and 1-5 mo) and continued (6-23 mo) breastfeeding rates in LMICs when delivered in health systems, in the home or in community environments, or in a combination of settings.Methods: A systematic literature search was conducted in PubMed, Cochrane, and CABI databases to identify new articles relevant to our current review, which were published after the search date of our earlier meta analysis (October 2014). Nine new articles were found to be relevant and were included, in addition to the other 52 studies that were identified in our earlier meta-analysis. We reported the pooled ORs and corresponding 95% CIs as our outcome estimates. In cases of high heterogeneity, random-effects models were used and causes were explored by subgroup analysis and meta-regression.Results: Early initiation of and exclusive (<1 and 1-5 mo) and continued (6-23 mo) breastfeeding rates in LMICs improved significantly as a result of interventions delivered in health systems, in the home or community, or a combination of these. Interventions delivered concurrently in a combination of settings were found to show the largest improvements in desired breastfeeding outcomes. Counseling provided in any setting and baby-friendly support in health systems appear to be the most effective interventions to improve breastfeeding.Conclusions: Improvements in breastfeeding practices are possible in LMICs with judicious use of tested interventions, particularly when delivered in a combination of settings concurrently. The findings can be considered for inclusion in the Lives Saved Tool model. PMID- 28904117 TI - Estimating Lives Saved by Achieving Dietary Micronutrient Adequacy, with a Focus on Vitamin A Intervention Programs in Cameroon. AB - Background: We previously compared the potential effects of different intervention strategies for achieving dietary vitamin A (VA) adequacy. The Lives Saved Tool (LiST) permits estimates of lives saved through VA interventions but currently only considers periodic VA supplements (VASs).Objective: We aimed to adapt the LiST method for estimating the mortality impact of VASs to estimate the impact of other VA interventions (e.g., food fortification) on child mortality and to estimate the number of lives saved by VA interventions in 3 macroregions in Cameroon.Methods: We used national dietary intake data to predict the effects of VA intervention programs on the adequacy of VA intake. LiST parameters of population affected fraction and intervention coverage were replaced with estimates of prevalence of inadequate intake and effective coverage (proportion achieving adequate VA intake). We used a model of liver VA stores to derive an estimate of the mortality reduction from achieving dietary VA adequacy; this estimate and a conservative assumption of equivalent mortality reduction for VAS and VA intake were applied to projections for Cameroon.Results: There were 2217 3048 total estimated VA-preventable deaths in year 1, with 58% occurring in the North macroregion. The relation between effective coverage and lives saved differed by year and macroregion due to differences in total deaths, diarrhea burden, and prevalence of low VA intake. Estimates of lives saved by VASs (the intervention common to both methods) were similar with the use of the adapted method (in 2012: North, 743-1021; South, 280-385; Yaounde and Douala, 146-202) and the "usual" LiST method (North: 697; South: 381; Yaounde and Douala: 147).Conclusions: Linking effective coverage estimates with an adapted LiST method permits estimation of the effects of combinations of VA programs (beyond VASs only) on child mortality to aid program planning and management. Rigorous program monitoring and evaluation are necessary to confirm predicted impacts. PMID- 28904118 TI - Nutrition Interventions in the Lives Saved Tool (LiST). AB - The Lives Saved Tool (LiST) was initially developed in 2003 to estimate the impact of increasing coverage of efficacious interventions on under-5 mortality. Over time, the model has been expanded to include more outcomes (neonatal mortality, maternal mortality, stillbirths) and interventions. The model has also added risk factors, such as stunting and wasting, and over time has attempted to capture a full range of nutrition and nutrition-related interventions (e.g., antenatal supplementation, breastfeeding promotion, child supplemental feeding, acute malnutrition treatment), practices (e.g., age-appropriate breastfeeding), and outcomes (e.g., stunting, wasting, birth outcomes, maternal anemia). This article reviews the overall nutrition-related structure, assumptions, and outputs that are currently available in LiST. This review focuses on the new assumptions and structure that have been added to the model as part of the current effort to expand and improve the nutrition modeling capability of LiST. It presents the full set of linkages in the model that relate to nutrition outcomes, as well as the research literature used to support those linkages. PMID- 28904119 TI - Metrics for Identifying Food Security Status and the Population with Potential to Benefit from Nutrition Interventions in the Lives Saved Tool (LiST). AB - Background: The Lives Saved Tool (LiST) uses the poverty head-count ratio at $1.90/d as a proxy for food security to identify the percentage of the population with the potential to benefit from balanced energy supplementation and complementary feeding (CF) interventions, following the approach used for the Lancet's 2008 series on Maternal and Child Undernutrition. Because much work has been done in the development of food security indicators, a re-evaluation of the use of this indicator was warranted.Objective: The aim was to re-evaluate the use of the poverty head-count ratio at $1.90/d as the food security proxy indicator in LiST.Methods: We carried out a desk review to identify available indicators of food security. We identified 3 indicators and compared them by using scatterplots, Spearman's correlations, and Bland-Altman plot analysis. We generated LiST projections to compare the modeled impact results with the use of the different indicators.Results: There are many food security indicators available, but only 3 additional indicators were identified with the data availability requirements to be used as the food security indicator in LiST. As expected, analyzed food security indicators were significantly positively correlated (P < 0.001), but there was generally poor agreement between them. The disparity between the indicators also increases as the values of the indicators increase. Consequently, the choice of indicator can have a considerable effect on the impact of interventions modeled in LiST, especially in food-insecure contexts.Conclusions: There was no single indicator identified that is ideal for measuring the percentage of the population who is food insecure for LiST. Thus, LiST will use the food security indicators that were used in the meta-analyses that produced the effect estimates. These are the poverty head-count ratio at $1.90/d for CF interventions and the prevalence of a low body mass index in women of reproductive age for balanced energy supplementation interventions. PMID- 28904120 TI - Introduction to Nutrition Modeling in the Lives Saved Tool (LiST). PMID- 28904121 TI - Establishment of a Meal Coding System for the Characterization of Meal-Based Dietary Patterns in Japan. AB - Background: Most studies on dietary patterns to date have focused on the daily intake of individual foods, rather than the combination of foods simultaneously consumed during specific eating occasions (breakfast, lunch, dinner, and snacks).Objective: We aimed to establish a meal coding system for characterizing meal-based dietary patterns in Japan.Methods: Dietary data used were from the 2012 National Health and Nutrition Survey, Japan, in which 1-d weighed dietary records were collected from 26,361 adults aged >=20 y. The food diary was based on a typical Japanese eating pattern, which comprised breakfast, lunch, dinner, and snacks; these eating occasions were prescribed in the diary. A total of 94,439 eating occasions (25,187 breakfasts, 25,888 lunches, 26,248 dinners, and 17,116 snacks) were identified. For all meal types, common food group combinations were identified to produce a range of generic meals. These generic meals were then used in principal components analysis to establish meal patterns.Results: In total, 94 generic meals (24 breakfasts, 27 lunches, 26 dinners, and 17 snacks) were identified. The most frequently identified food group combination for all 3 main meals was "rice and vegetables" (9 generic meals for breakfast, 12 for lunch, and 16 for dinner), whereas "confectioneries and nonalcoholic and noncaloric beverages" was the most prevalent combination for snacks (3 generic meals). In total, 19 meal patterns were established by using principal components analysis, which accounted for 24.1% of total variance. Patterns ranged considerably with regard to meal-type inclusion and the selection of staple foods (rice, bread, and noodles) and beverages, as well as with regard to meal constituents.Conclusions: With the use of a meal coding system, we identified a wide range of meal-based dietary patterns in Japanese adults. This meal coding system may be useful in capturing and investigating the complex nature of Japanese meals and food combination patterns. PMID- 28904123 TI - Unveiling the Peptide Motifs of HLA-C and HLA-G from Naturally Presented Peptides and Generation of Binding Prediction Matrices. AB - The classical HLA-C and the nonclassical HLA-E and HLA-G molecules play important roles both in the innate and adaptive immune system. Starting already during embryogenesis and continuing throughout our lives, these three Ags exert major functions in immune tolerance, defense against infections, and anticancer immune responses. Despite these important roles, identification and characterization of the peptides presented by these molecules has been lacking behind the more abundant HLA-A and HLA-B gene products. In this study, we elucidated the peptide specificities of these HLA molecules using a comprehensive analysis of naturally presented peptides. To that end, the 15 most frequently expressed HLA-C alleles as well as HLA-E*01:01 and HLA-G*01:01 were transfected into lymphoblastoid C1R cells expressing low endogenous HLA. Identification of naturally presented peptides was performed by immunoprecipitation of HLA and subsequent analysis of HLA-bound peptides by liquid chromatographic tandem mass spectrometry. Peptide motifs of HLA-C unveil anchors in position 2 or 3 with high variances between allotypes, and a less variable anchor at the C-terminal end. The previously reported small ligand repertoire of HLA-E was confirmed within our analysis, and we could show that HLA-G combines a large ligand repertoire with distinct features anchoring peptides at positions 3 and 9, supported by an auxiliary anchor in position 1 and preferred residues in positions 2 and 7. The wealth of HLA ligands resulted in prediction matrices for octa-, nona-, and decamers. Matrices were validated in terms of their binding prediction and compared with the latest NetMHC prediction algorithm NetMHCpan-3.0, which demonstrated their predictive power. PMID- 28904122 TI - Evolution of polymer formation within the actin superfamily. AB - While many are familiar with actin as a well-conserved component of the eukaryotic cytoskeleton, it is less often appreciated that actin is a member of a large superfamily of structurally related protein families found throughout the tree of life. Actin-related proteins include chaperones, carbohydrate kinases, and other enzymes, as well as a staggeringly diverse set of proteins that use the energy from ATP hydrolysis to form dynamic, linear polymers. Despite differing widely from one another in filament structure and dynamics, these polymers play important roles in ordering cell space in bacteria, archaea, and eukaryotes. It is not known whether these polymers descended from a single ancestral polymer or arose multiple times by convergent evolution from monomeric actin-like proteins. In this work, we provide an overview of the structures, dynamics, and functions of this diverse set. Then, using a phylogenetic analysis to examine actin evolution, we show that the actin-related protein families that form polymers are more closely related to one another than they are to other nonpolymerizing members of the actin superfamily. Thus all the known actin-like polymers are likely to be the descendants of a single, ancestral, polymer-forming actin-like protein. PMID- 28904124 TI - Cutting Edge: Endogenous IFN-beta Regulates Survival and Development of Transitional B Cells. AB - The transitional stage of B cell development is a formative stage in the spleen where autoreactive specificities are censored as B cells gain immune competence, but the intrinsic and extrinsic factors regulating survival of transitional stage 1 (T1) B cells are unknown. We report that B cell expression of IFN-beta is required for optimal survival and TLR7 responses of transitional B cells in the spleen and was overexpressed in T1 B cells from BXD2 lupus-prone mice. Single cell gene expression analysis of B6 Ifnb+/+ versus B6 Ifnb-/- T1 B cells revealed heterogeneous expression of Ifnb in wild-type B cells and distinct gene expression patterns associated with endogenous IFN-beta. Single-cell analysis of BXD2 T1 B cells revealed that Ifnb is expressed in early T1 B cell development with subsequent upregulation of Tlr7 and Ifna1 Together, these data suggest that T1 B cell expression of IFN-beta plays a key role in regulating responsiveness to external factors. PMID- 28904125 TI - Enhancing Vaccine Efficacy by Engineering a Complex Synthetic Peptide To Become a Super Immunogen. AB - Peptides offer enormous promise as vaccines to prevent and protect against many infectious and noninfectious diseases. However, to date, limited vaccine efficacy has been reported and none have been licensed for human use. Innovative ways to enhance their immunogenicity are being tested, but rational sequence modification as a means to improve immune responsiveness has been neglected. Our objective was to establish a two-step generic protocol to modify defined amino acids of a helical peptide epitope to create a superior immunogen. Peptide variants of p145, a conserved helical peptide epitope from the M protein of Streptococcus pyogenes, were designed by exchanging one amino acid at a time, without altering their alpha-helical structure, which is required for correct antigenicity. The immunogenicities of new peptides were assessed in outbred mice. Vaccine efficacy was assessed in a skin challenge and invasive disease model. Out of 86 variants of p145, seven amino acid substitutions were selected and made the basis of the design for 18 new peptides. Of these, 13 were more immunogenic than p145; 7 induced Abs with significantly higher affinity for p145 than Abs induced by p145 itself; and 1 peptide induced more than 10,000-fold greater protection following challenge than the parent peptide. This peptide also only required a single immunization (compared with three immunizations with the parent peptide) to induce complete protection against invasive streptococcal disease. This study defines a strategy to rationally improve the immunogenicity of peptides and will have broad applicability to the development of vaccines for infectious and noninfectious diseases. PMID- 28904126 TI - NLRP3 and Potassium Efflux Drive Rapid IL-1beta Release from Primary Human Monocytes during Toxoplasma gondii Infection. AB - IL-1beta is produced by myeloid cells and acts as a critical mediator of host defense during infection and injury. We found that the intracellular protozoan parasite Toxoplasma gondii induced an early IL-1beta response (within 4 h) in primary human peripheral blood monocytes isolated from healthy donors. This process involved upregulation of IL-1beta, IL-1RN (IL-1R antagonist), and NLRP3 transcripts, de novo protein synthesis, and the release of pro- and mature IL 1beta from infected primary monocytes. The released pro-IL-1beta was cleavable to mature bioactive IL-1beta in the extracellular space by the protease caspase-1. Treatment of primary monocytes with the NLRP3 inhibitor MCC950 or with extracellular potassium significantly reduced IL-1beta cleavage and release in response to T. gondii infection, without affecting the release of TNF-alpha, and indicated a role for the inflammasome sensor NLRP3 and for potassium efflux in T. gondii-induced IL-1beta production. Interestingly, T. gondii infection did not induce an IL-1beta response in primary human macrophages derived from the same blood donors as the monocytes. Consistent with this finding, NLRP3 was downregulated during the differentiation of monocytes to macrophages and was not induced in macrophages during T. gondii infection. To our knowledge, these findings are the first to identify NLRP3 as an inflammasome sensor for T. gondii in primary human peripheral blood cells and to define an upstream regulator of its activation through the release of intracellular potassium. PMID- 28904127 TI - Therapeutic Effects of Monoclonal Antibody against Dengue Virus NS1 in a STAT1 Knockout Mouse Model of Dengue Infection. AB - Dengue virus (DENV) is the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome and is endemic to tropical and subtropical regions of the world. Our previous studies showed the existence of epitopes in the C-terminal region of DENV nonstructural protein 1 (NS1) which are cross reactive with host Ags and trigger anti-DENV NS1 Ab-mediated endothelial cell damage and platelet dysfunction. To circumvent these potentially harmful events, we replaced the C-terminal region of DENV NS1 with the corresponding region from Japanese encephalitis virus NS1 to create chimeric DJ NS1 protein. Passive immunization of DENV-infected mice with polyclonal anti-DJ NS1 Abs reduced viral Ag expression at skin inoculation sites and shortened DENV-induced prolonged bleeding time. We also investigated the therapeutic effects of anti-NS1 mAb. One mAb designated 2E8 does not recognize the C-terminal region of DENV NS1 in which host-cross-reactive epitopes reside. Moreover, mAb 2E8 recognizes NS1 of all four DENV serotypes. We also found that mAb 2E8 caused complement-mediated lysis in DENV-infected cells. In mouse model studies, treatment with mAb 2E8 shortened DENV-induced prolonged bleeding time and reduced viral Ag expression in the skin. Importantly, mAb 2E8 provided therapeutic effects against all four serotypes of DENV. We further found that mAb administration to mice as late as 1 d prior to severe bleeding still reduced prolonged bleeding time and hemorrhage. Therefore, administration with a single dose of mAb 2E8 can protect mice against DENV infection and pathological effects, suggesting that NS1-specific mAb may be a therapeutic option against dengue disease. PMID- 28904128 TI - Integration of Kinase and Calcium Signaling at the Level of Chromatin Underlies Inducible Gene Activation in T Cells. AB - TCR signaling pathways cooperate to activate the inducible transcription factors NF-kappaB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ~2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression. We found that these regions typically function as inducible enhancers. Many of these elements contain composite NFAT/AP-1 sites, which typically support cooperative binding, thus further reinforcing the need for cooperation between calcium and kinase signaling in the activation of genes in T cells. In contrast, treatment with PMA or ionomycin alone induces chromatin remodeling at far fewer regions (~600 and ~350, respectively), which mostly represent a subset of those induced by costimulation. This suggests that the integration of TCR signaling largely occurs at the level of chromatin, which we propose plays a crucial role in regulating T cell activation. PMID- 28904130 TI - CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development. AB - Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4+CD25+CCR5+, CD4+CD25-CCR5+ or CD8+CCR5+ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4+CD25+CCR5+ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8+ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. Mol Cancer Ther; 16(12); 2871-80. (c)2017 AACR. PMID- 28904129 TI - T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell-Cell Contact Mediated through SLAMF6 and SAP. AB - The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, proliferation, and apoptosis. In this study, we focused on the role of T cells in the maintenance/survival of the mature naive peripheral B cell population. We show that naive B and T cells interact via the signaling lymphocyte activation molecule (SLAM) family receptor, SLAMF6. This interaction induces cell type-specific signals in both cell types, mediated by the SLAM associated protein (SAP) family of adaptors. This signaling results in an upregulation of the expression of the cytokine migration inhibitory factor in the T cells and augmented expression of its receptor CD74 on the B cell counterparts, consequently enhancing B cell survival. Furthermore, in X-linked lymphoproliferative disease patients, SAP deficiency reduces CD74 expression, resulting in the perturbation of B cell maintenance from the naive stage. Thus, naive T cells regulate B cell survival in a SLAMF6- and SAP-dependent manner. PMID- 28904131 TI - Superior Properties of Fc-comprising scTRAIL Fusion Proteins. AB - The TNF-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In this study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of EGF receptor (EGFR)-targeting dimeric scTRAIL fusion proteins [Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL] as well as two nontargeted dimeric scTRAIL molecules (EHD2 scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on antitumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro, exceeding the activity of the respective nontargeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent antitumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable antitumor activities were found for the EGFR targeting scFv-Fc-scTRAIL and the nontargeting Fc-scTRAIL in vivoMol Cancer Ther; 16(12); 2792-802. (c)2017 AACR. PMID- 28904132 TI - Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer. AB - Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition (EMT) in AXL mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments (P < 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 2881-91. (c)2017 AACR. PMID- 28904133 TI - Comparing physical and social cognitive skills in macaque species with different degrees of social tolerance. AB - Contemporary evolutionary theories propose that living in groups drives the selection of enhanced cognitive skills to face competition and facilitate cooperation between individuals. Being able to coordinate both in space and time with others and make strategic decisions are essential skills for cooperating within groups. Social tolerance and an egalitarian social structure have been proposed as one specific driver of cooperation. Therefore, social tolerance is predicted to be associated with enhanced cognitive skills that underpin communication and coordination. Social tolerance should also be associated with enhanced inhibition, which is crucial for suppressing automatic responses and permitting delayed gratification in cooperative contexts. We tested the performance of four closely related non-human primate species (genus Macaca) characterized by different degrees of social tolerance on a large battery of cognitive tasks covering physical and social cognition, and on an inhibitory control task. All species performed at a comparable level on the physical cognition tasks but the more tolerant species outperformed the less tolerant species at a social cognition task relevant to cooperation and in the inhibitory control task. These findings support the hypothesis that social tolerance is associated with the evolution of sophisticated cognitive skills relevant for cooperative social living. PMID- 28904134 TI - An ant-plant mutualism through the lens of cGMP-dependent kinase genes. AB - In plant-animal mutualisms, how an animal forages often determines how much benefit its plant partner receives. In many animals, foraging behaviour changes in response to foraging gene expression or activation of the cGMP-dependent protein kinase (PKG) that foraging encodes. Here, we show that this highly conserved molecular mechanism affects the outcome of a plant-animal mutualism. We studied the two PKG genes of Allomerus octoarticulatus, an Amazonian ant that defends the ant-plant Cordia nodosa against herbivores. Some ant colonies are better 'bodyguards' than others. Working in the field in Peru, we found that colonies fed with a PKG activator recruited more workers to attack herbivores than control colonies. This resulted in less herbivore damage. PKG gene expression in ant workers correlated with whether an ant colony discovered an herbivore and how much damage herbivores inflicted on leaves in a complex way; natural variation in expression levels of the two genes had significant interaction effects on ant behaviour and herbivory. Our results suggest a molecular basis for ant protection of plants in this mutualism. PMID- 28904135 TI - Bird and bat species' global vulnerability to collision mortality at wind farms revealed through a trait-based assessment. AB - Mitigation of anthropogenic climate change involves deployments of renewable energy worldwide, including wind farms, which can pose a significant collision risk to volant animals. Most studies into the collision risk between species and wind turbines, however, have taken place in industrialized countries. Potential effects for many locations and species therefore remain unclear. To redress this gap, we conducted a systematic literature review of recorded collisions between birds and bats and wind turbines within developed countries. We related collision rate to species-level traits and turbine characteristics to quantify the potential vulnerability of 9538 bird and 888 bat species globally. Avian collision rate was affected by migratory strategy, dispersal distance and habitat associations, and bat collision rates were influenced by dispersal distance. For birds and bats, larger turbine capacity (megawatts) increased collision rates; however, deploying a smaller number of large turbines with greater energy output reduced total collision risk per unit energy output, although bat mortality increased again with the largest turbines. Areas with high concentrations of vulnerable species were also identified, including migration corridors. Our results can therefore guide wind farm design and location to reduce the risk of large-scale animal mortality. This is the first quantitative global assessment of the relative collision vulnerability of species groups with wind turbines, providing valuable guidance for minimizing potentially serious negative impacts on biodiversity. PMID- 28904136 TI - Neural evidence supports a dual sensory-motor role for insect wings. AB - Flying insects use feedback from various sensory modalities including vision and mechanosensation to navigate through their environment. The rapid speed of mechanosensory information acquisition and processing compensates for the slower processing times associated with vision, particularly under low light conditions. While halteres in dipteran species are well known to provide such information for flight control, less is understood about the mechanosensory roles of their evolutionary antecedent, wings. The features that wing mechanosensory neurons (campaniform sensilla) encode remains relatively unexplored. We hypothesized that the wing campaniform sensilla of the hawkmoth, Manduca sexta, rapidly and selectively extract mechanical stimulus features in a manner similar to halteres. We used electrophysiological and computational techniques to characterize the encoding properties of wing campaniform sensilla. To accomplish this, we developed a novel technique for localizing receptive fields using a focused IR laser that elicits changes in the neural activity of mechanoreceptors. We found that (i) most wing mechanosensors encoded mechanical stimulus features rapidly and precisely, (ii) they are selective for specific stimulus features, and (iii) there is diversity in the encoding properties of wing campaniform sensilla. We found that the encoding properties of wing campaniform sensilla are similar to those for haltere neurons. Therefore, it appears that the neural architecture that underlies the haltere sensory function is present in wings, which lends credence to the notion that wings themselves may serve a similar sensory function. Thus, wings may not only function as the primary actuator of the organism but also as sensors of the inertial dynamics of the animal. PMID- 28904137 TI - Seasonal variation in nutrient utilization shapes gut microbiome structure and function in wild giant pandas. AB - Wild giant pandas use different parts of bamboo (shoots, leaves and stems) and different bamboo species at different times of the year. Their usage of bamboo can be classified temporally into a distinct leaf stage, shoot stage and transition stage. An association between this usage pattern and variation in the giant panda gut microbiome remains unknown. Here, we found associations using a gut metagenomic approach and nutritional analyses whereby diversity of the gut microbial community in the leaf and shoot stages was significantly different. Functional metagenomic analysis showed that in the leaf stage, bacteria species over-represented genes involved in raw fibre utilization and cell cycle control. Thus, raw fibre utilization by the gut microbiome was guaranteed during the nutrient-deficient leaf stage by reinforcing gut microbiome robustness. During the protein-abundant shoot stage, the functional capacity of the gut microbiome expanded to include prokaryotic secretion and signal transduction activity, suggesting active interactions between the gut microbiome and host. These results illustrate that seasonal nutrient variation in wild giant pandas substantially influences gut microbiome composition and function. Nutritional interactions between gut microbiomes and hosts appear to be complex and further work is needed. PMID- 28904138 TI - A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation. AB - Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entree into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material. PMID- 28904139 TI - An edrioasteroid from the Silurian Herefordshire Lagerstatte of England reveals the nature of the water vascular system in an extinct echinoderm. AB - Echinoderms are unique in having a water vascular system with tube feet, which perform a variety of functions in living forms. Here, we report the first example of preserved tube feet in an extinct group of echinoderms. The material, from the Silurian Herefordshire Lagerstatte, UK, is assigned to a new genus and species of rhenopyrgid edrioasteroid, Heropyrgus disterminus The tube feet attach to the inner surface of compound interradial plates and form two sets, an upper and a lower, an arrangement never reported previously in an extant or extinct echinoderm. Cover plates are absent and floor plates are separated creating a large permanent entrance to the interior of the oral area. The tube feet may have captured food particles that entered the oral area and/or enhanced respiration. The pentameral symmetry of the oral surface transitions to eight columns in which the plates are vertically offset resulting in a spiral appearance. This change in symmetry may reflect flexibility in the evolutionary development of the axial and extraxial zones in early echinoderm evolution. PMID- 28904140 TI - Quantitative study of developmental biology confirms Dickinsonia as a metazoan. AB - The late Ediacaran soft-bodied macroorganism Dickinsonia (age range approx. 560 550 Ma) has often been interpreted as an early animal, and is increasingly invoked in debate on the evolutionary assembly of eumetazoan body plans. However, conclusive positive evidence in support of such a phylogenetic affinity has not been forthcoming. Here we subject a collection of Dickinsonia specimens interpreted to represent multiple ontogenetic stages to a novel, quantitative method for studying growth and development in organisms with an iterative body plan. Our study demonstrates that Dickinsonia grew via pre-terminal 'deltoidal' insertion and inflation of constructional units, followed by a later inflation dominated phase of growth. This growth model is contrary to the widely held assumption that Dickinsonia grew via terminal addition of units at the end of the organism bearing the smallest units. When considered alongside morphological and behavioural attributes, our developmental data phylogenetically constrain Dickinsonia to the Metazoa, specifically the Eumetazoa plus Placozoa total group. Our findings have implications for the use of Dickinsonia in developmental debates surrounding the metazoan acquisition of axis specification and metamerism. PMID- 28904141 TI - Extreme diel dissolved oxygen and carbon cycles in shallow vegetated lakes. AB - A common perception in limnology is that shallow lakes are homogeneously mixed owing to their small water volume. However, this perception is largely gained by downscaling knowledge from large lakes to their smaller counterparts. Here we show that shallow vegetated lakes (less than 0.6 m), in fact, undergo recurring daytime stratification and nocturnal mixing accompanied by extreme chemical variations during summer. Dense submerged vegetation effectively attenuates light and turbulence generating separation between warm surface waters and much colder bottom waters. Photosynthesis in surface waters produces oxygen accumulation and CO2 depletion, whereas respiration in dark bottom waters causes anoxia and CO2 accumulation. High daytime pH in surface waters promotes precipitation of CaCO3 which is re-dissolved in bottom waters. Nocturnal convective mixing re-introduces oxygen into bottom waters for aerobic respiration and regenerated inorganic carbon into surface waters, which supports intense photosynthesis. Our results reconfigure the basic understanding of local environmental gradients in shallow lakes, one of the most abundant freshwater habitats globally. PMID- 28904142 TI - Trophic dynamics of a simple model ecosystem. AB - We have constructed a model of community dynamics that is simple enough to enumerate all possible food webs, yet complex enough to represent a wide range of ecological processes. We use the transition matrix to predict the outcome of succession and then investigate how the transition probabilities are governed by resource supply and immigration. Low-input regimes lead to simple communities whereas trophically complex communities develop when there is an adequate supply of both resources and immigrants. Our interpretation of trophic dynamics in complex communities hinges on a new principle of mutual replenishment, defined as the reciprocal alternation of state in a pair of communities linked by the invasion and extinction of a shared species. Such neutral couples are the outcome of succession under local dispersal and imply that food webs will often be made up of suites of trophically equivalent species. When immigrants arrive from an external pool of fixed composition a similar principle predicts a dynamic core of webs constituting a neutral interchange network, although communities may express an extensive range of other webs whose membership is only in part predictable. The food web is not in general predictable from whole-community properties such as productivity or stability, although it may profoundly influence these properties. PMID- 28904143 TI - Hierarchical structure of ecological and non-ecological processes of differentiation shaped ongoing gastropod radiation in the Malawi Basin. AB - Ecological processes, non-ecological processes or a combination of both may cause reproductive isolation and speciation, but their specific roles and potentially complex interactions in evolutionary radiations remain poorly understood, which defines a central knowledge gap at the interface of microevolution and macroevolution. Here I examine genome scans in combination with phenotypic and environmental data to disentangle how ecological and non-ecological processes contributed to population differentiation and speciation in an ongoing radiation of Lanistes gastropods from the Malawi Basin. I found a remarkable hierarchical structure of differentiation mechanisms in space and time: neutral and mutation order processes are older and occur mainly between regions, whereas more recent adaptive processes are the main driver of genetic differentiation and reproductive isolation within regions. The strongest differentiation occurs between habitats and between regions, i.e. when ecological and non-ecological processes act synergistically. The structured occurrence of these processes based on the specific geographical setting and ecological opportunities strongly influenced the potential for evolutionary radiation. The results highlight the importance of interactions between various mechanisms of differentiation in evolutionary radiations, and suggest that non-ecological processes are important in adaptive radiations, including those of cichlids. Insight into such interactions is critical to understanding large-scale patterns of organismal diversity. PMID- 28904144 TI - Low recruitment due to altered settlement substrata as primary constraint for coral communities under ocean acidification. AB - The future of coral reefs under increasing CO2 depends on their capacity to recover from disturbances. To predict the recovery potential of coral communities that are fully acclimatized to elevated CO2, we compared the relative success of coral recruitment and later life stages at two volcanic CO2 seeps and adjacent control sites in Papua New Guinea. Our field experiments showed that the effects of ocean acidification (OA) on coral recruitment rates were up to an order of magnitude greater than the effects on the survival and growth of established corals. Settlement rates, recruit and juvenile densities were best predicted by the presence of crustose coralline algae, as opposed to the direct effects of seawater CO2 Offspring from high CO2 acclimatized parents had similarly impaired settlement rates as offspring from control parents. For most coral taxa, field data showed no evidence of cumulative and compounding detrimental effects of high CO2 on successive life stages, and three taxa showed improved adult performance at high CO2 that compensated for their low recruitment rates. Our data suggest that severely declining capacity for reefs to recover, due to altered settlement substrata and reduced coral recruitment, is likely to become a dominant mechanism of how OA will alter coral reefs. PMID- 28904146 TI - Correction to 'The evolution of dual meat and milk cattle husbandry in Linearbandkeramik societies'. PMID- 28904145 TI - Older fathers' children have lower evolutionary fitness across four centuries and in four populations. AB - Higher paternal age at offspring conception increases de novo genetic mutations. Based on evolutionary genetic theory we predicted older fathers' children, all else equal, would be less likely to survive and reproduce, i.e. have lower fitness. In sibling control studies, we find support for negative paternal age effects on offspring survival and reproductive success across four large populations with an aggregate N > 1.4 million. Three populations were pre industrial (1670-1850) Western populations and showed negative paternal age effects on infant survival and offspring reproductive success. In twentieth century Sweden, we found minuscule paternal age effects on survival, but found negative effects on reproductive success. Effects survived tests for key competing explanations, including maternal age and parental loss, but effects varied widely over different plausible model specifications and some competing explanations such as diminishing paternal investment and epigenetic mutations could not be tested. We can use our findings to aid in predicting the effect increasingly older parents in today's society will have on their children's survival and reproductive success. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time periods. PMID- 28904149 TI - Correction to: Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt-Induced Hypertension. PMID- 28904147 TI - Long-legged bees make adaptive leaps: linking adaptation to coevolution in a plant-pollinator network. AB - Adaptation is evolution in response to natural selection. Hence, an adaptation is expected to originate simultaneously with the acquisition of a particular selective environment. Here we test whether long legs evolve in oil-collecting Rediviva bees when they come under selection by long-spurred, oil-secreting flowers. To quantify the selective environment, we drew a large network of the interactions between Rediviva species and oil-secreting plant species. The selective environment of each bee species was summarized as the average spur length of the interacting plant species weighted by interaction frequency. Using phylogenetically independent contrasts, we calculated divergence in selective environment and evolutionary divergence in leg length between sister species (and sister clades) of Rediviva We found that change in the selective environment explained 80% of evolutionary change in leg length, with change in body size contributing an additional 6% of uniquely explained variance. The result is one of four proposed steps in testing for plant-pollinator coevolution. PMID- 28904150 TI - Emotional Intelligence Throughout the Lifecycle of Australian Radiographers. AB - PURPOSE: To measure global and domain trait emotional intelligence (EI) throughout the professional lifecycle of Australian radiographers and report the trends. METHODS: A combination retrospective and prospective cross-sectional multiple-cohort study using the Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF) was designed to collect global and domain trait EI scores of several populations, including radiography students (n = 95), inexperienced radiographers (0-5 years' experience; n = 94), experienced radiographers (>= 6 years' experience; n = 451), chief radiographers (n = 107), clinical educators (n = 24), application specialists (n = 24), and radiographers working in education (n = 15). Mean EI scores were calculated and statistical tests were performed to determine whether significant differences existed among the groups. RESULTS: Statistically significant differences were found among populations for global EI and the domains of self-control and well-being, with students demonstrating consistently lower scores than qualified radiographers (P >= .001). Chief radiographers demonstrated higher scores for well-being than inexperienced radiographers, radiographers working in education, and students (P < .001). Global EI scores increased steadily throughout the professional lifecycle of Australian radiographers, plateauing at 10 years of clinical experience. DISCUSSION: Chief radiographers demonstrated the highest scores for well-being, which is consistent with prior research acknowledging the importance of EI in organizational leadership. Students demonstrated lower EI scores likely because they are at the beginning of their careers and might not yet perceive themselves as confident or successful. Higher EI scores are expected in normal career advancement, plateauing at about 10 years of clinical experience. CONCLUSION: A statistically significant difference exists between global and domain trait EI scores throughout the professional lifecycle of Australian radiologic technologists. Global trait EI scores showed a marked increase after 6 years of clinical experience, indicating that clinical experience might have an effect on trait EI scores. PMID- 28904151 TI - Radiography Student Participation in Professional Organizations. AB - PURPOSE: To gather data on educational program requirements for student membership in a state or national professional society, organization, or association. METHODS: A 10-question online survey about student involvement in professional societies was emailed to 616 directors of Joint Review Committee on Education in Radiologic Technology (JRCERT)-accredited radiography programs. RESULTS: A total of 219 responses were received, for a 36% response rate. Of these, 89 respondents (41%) answered that their programs require students to join a professional organization. The society respondents most often required (70%) was a state radiography society. Sixty respondents (68%) answered that students join a society at the beginning of the radiography program (from matriculation to 3 months in). Of programs requiring student membership in professional societies, 42 (49%) reported that their students attend the state or national society annual conference; however, participation in activities at the conferences and in the society throughout the year is lower than conference attendance. DISCUSSION: Some directors stated that although their programs' policies do not allow membership mandates, they encourage students to become members, primarily so that they can access webinars and other educational materials or information related to the profession. CONCLUSION: Survey data showed that most JRCERT-accredited radiography programs support but do not require student membership in professional organizations. The data reveal that more programs have added those requirements in recent years. Increased student participation could be realized if programs mandated membership and supported it financially. PMID- 28904152 TI - Imaging Atlantooccipital and Atlantoaxial Traumatic Injuries. AB - Cervical spine injuries, specifically the atlantooccipital joint and atlantoaxial joint, often involve the spinal canal or large blood vessels that supply blood to the brain. Patient handling, transport, and positioning for imaging plays an important role in diagnosis, treatment, and patient prognosis. This article discusses cervical spine anatomy, specific traumatic spinal injuries, and radiography's role in treating these injuries. Treatment options and imaging before and after treatment also are discussed, and a description of dose reduction techniques is included. PMID- 28904153 TI - Imaging and Diagnosis of Physical Child Abuse. AB - Child abuse involves grave and disturbing acts of violence that can have lasting physical and emotional consequences for children and their families. The diagnosis of child abuse is emotionally difficult for those involved, and an error in judgment either way can have a detrimental effect on the health and safety of the child. Physicians rely on the skills of the imaging team to produce high-quality images that assist in differentiating inflicted injuries from accidental trauma. This article explores the significance of imaging in child abuse by discussing the types of injuries that occur and the imaging studies that aid in diagnosing physical child abuse. PMID- 28904154 TI - Visualizing the Future. PMID- 28904159 TI - Pediatric Elbow Fracture Diagnosis Using 3-D MR Imaging. PMID- 28904160 TI - A Picture Is Worth a Thousand Words: Visualization in Data Analysis. PMID- 28904161 TI - Domestic Violence, Concussion Injuries, and the Imaging Professional's Role in Identifying Traumatic Brain Injury. PMID- 28904162 TI - Keeping Up With Technology. PMID- 28904163 TI - Minimizing Incivility in the Online Classroom. PMID- 28904164 TI - Diagnostic Challenges of Postsurgical Breast Cancer Recurrence. PMID- 28904165 TI - The Importance of Precision Assessments When Serial Scanning. PMID- 28904166 TI - Reducing Occurrences of MR-related Claustrophobia in Patients With PTSD. PMID- 28904167 TI - Styrofoam Model Heads: A Tool for Learning Positioning and Anatomy. PMID- 28904168 TI - Dissemination of Translational Research. PMID- 28904169 TI - The Clinical Experience: A Student's Testimonial. PMID- 28904171 TI - Breast Sonography and Mammography: Complementarity and Correlation. AB - Mammography is a proven tool for detecting breast cancer and reducing breast cancer mortality, but breast sonography plays an important role in promoting breast health, too. These modalities can complement each other, especially when images are correlated to examine an abnormality or suspicious area. This article discusses how breast sonography supplements mammography as a screening and diagnostic technique, how mammographic and sonographic images are correlated, and how some common breast diseases and conditions appear on the 2 modalities. The limitations of both breast imaging modalities also are discussed. PMID- 28904172 TI - FDA Approval Summary: Daratumumab for Treatment of Multiple Myeloma After One Prior Therapy. AB - : On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on two randomized, open-label trials in which daratumumab was added to these backbone therapies. The MMY3003 trial demonstrated substantial improvement in progression free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.27-0.52; p < .0001), representing a 63% reduction in the risk of disease progression or death. Similar results were observed in the MMY3004 trial comparing the combination of daratumumab, bortezomib, and dexamethasone with bortezomib and dexamethasone. The estimated median PFS was not reached in the daratumumab arm and was 7.2 months in the control arm (HR = 0.39; 95% CI: 0.28-0.53; p < .0001), representing a 61% reduction in the risk of disease progression or death. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3003 were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough, and dyspnea. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3004 were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, and peripheral sensory neuropathy. Neutropenia and thrombocytopenia have been added to the Warnings and Precautions of the drug label. IMPLICATIONS FOR PRACTICE: Daratumumab, the first monoclonal antibody targeted against CD38, received U.S. Food and Drug Administration accelerated approval in 2015 based on data from single-agent, single-arm trials that provided response rate information. Results of the MMY3003 and MMY3004 trials established that daratumumab can be combined synergistically with some of the most highly active agents used to treat multiple myeloma, leading to daratumumab's regular approval in 2016. Daratumumab added to lenalidomide and dexamethasone, or bortezomib and dexamethasone, provides a substantial improvement in progression-free survival in previously treated patients with multiple myeloma. These combinations will likely improve the survival outlook for patients with multiple myeloma. PMID- 28904173 TI - Impact of Metastasectomy in the Multimodality Approach for BRAF V600E Metastatic Colorectal Cancer: The Mayo Clinic Experience. AB - BACKGROUND: BRAF V600E mutations are present in 8%-10% of patients with metastatic colorectal cancer (mCRC) and portend poor prognosis. This study investigated the impact of metastasectomy for patients with BRAF V600E mCRC. SUBJECTS, MATERIALS, AND METHODS: Using prospective clinical and molecular data, patients with BRAF V600E mCRC were analyzed for clinical characteristics and survival. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazard models. RESULTS: Fifty-two patients were identified between July 1, 2008, and January 4, 2016. Patient characteristics included median age 65 years, 61% female, Eastern Cooperative Oncology Group performance status <=1, 71% with right-sided tumors, and 28% with liver-limited metastasis. In the first-line setting, 7% (4/52) received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (BEV) and 81% were treated with doublet chemotherapy consisting of fluoropyrimidine, oxaliplatin, and BEV. Median overall survival (OS) for all 52 patients was 25 months with median progression-free survival (PFS) of 9.3 months. With median follow-up of 18.3 months, 21 patients underwent metastasectomy with longer OS (29.1 months vs. 22.7 months, hazard ratio [HR] = 0.33; confidence interval [CI], 0.12-0.78; p = .01) and PFS (13.6 months vs. 6.2 months, HR = 0.53, CI, 0.28-0.97; p = .03) compared with the non-metastasectomy cohort. In multivariate analysis, metastasectomy remained significant for improved survival outcomes (HR = 0.52; 95% CI, 0.07 1.02; p = .02). Median disease-free survival after metastasectomy was 9.7 months (95% CI, 5.5-19.5). Two patients remain disease-free at the time of last follow up, with one patient without relapse for greater than 2 years (28.9 months). CONCLUSION: Multimodality therapy incorporating metastasectomy for BRAF V600E mCRC should be considered and might be associated with improved overall survival in select patients. IMPLICATIONS FOR PRACTICE: BRAF V600E metastatic colorectal cancer (mCRC) represents an extremely difficult molecular subset of colorectal cancer to treat. To date, this subset remains refractory to standard chemotherapies, prompting extensive clinical investigation regarding novel treatment approaches and targeted modalities. While the use of metastasectomy for expanded RAS wild-type and RAS mutated mCRC has resulted in improved overall survival for select patients, utilization of metastasectomy in patients with BRAF V600E mCRC remains controversial. This article explores the authors' experience with BRAF V600E mCRC to ascertain whether a multidisciplinary approach incorporating metastasectomy for well-selected patients improves overall survival. PMID- 28904174 TI - In-Hospital Outcomes of Tumor Lysis Syndrome: A Population-Based Study Using the National Inpatient Sample. AB - The epidemiology and outcomes of tumor lysis syndrome (TLS) are understudied. We used the National Inpatient Sample (NIS), a nationally representative weighted sample of all U.S. hospital discharges, to study outcomes and predictors of mortality in hospitalized patients with TLS. The NIS was queried for patients with a discharge diagnosis of TLS (ICD-9 code 277.88) from 2010-2013. Baseline characteristics and outcomes were analyzed. A multivariable logistic regression analysis was performed to identify predictors of mortality. From 2010-2013, 28,370 patients were discharged with a diagnosis of TLS. The most common malignancies were non-Hodgkin lymphoma (30%), solid tumors (20%), acute myeloid leukemia (19%), and acute lymphocytic leukemia (13%). Overall in-hospital mortality was 21%. The median length of stay was 10 days (IQR 5-22). Sixty-nine percent of patients experienced a severe complication, including sepsis (22%, 95% confidence interval [CI] 21-23), dialysis (15%, 95% CI 14-16), acute respiratory failure (23%, 95% CI 22-24), mechanical ventilation (16%, 95% CI 15-17), gastrointestinal hemorrhage (6%, 95% CI 5-7), cerebral hemorrhage (2%, 95% CI 2 3), seizures (1%, 95% CI 0.6-1), and cardiac arrest (2%, 95% CI 2-3). Predictors of mortality were derived from a multivariable logistic regression and included age, Elixhauser comorbidity score, insurance status, teaching versus nonteaching hospital, and cancer type. Predictors of increased length of stay included age, race, teaching versus nonteaching hospital, and cancer type. In the U.S., many patients with TLS develop life-threatening complications and a quarter die during hospitalization. As more cancer treatments become available, strategies to improve the supportive care of patients with TLS should be a priority. PMID- 28904175 TI - Splice variants of cytosolic polyadenylation element-binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis. AB - The translational regulator cytosolic polyadenylation element-binding protein 2 (CPEB2) has two isoforms, CPEB2A and CPEB2B, derived by alternative splicing of RNA into a mature form that either includes or excludes exon 4. Previously, we reported that this splicing event is highly dysregulated in aggressive forms of breast cancers, which overexpress CPEB2B. The loss of CPEB2A with a concomitant increase in CPEB2B was also required for breast cancer cells to resist cell death because of detachment (anoikis resistance) and metastasize in vivo To examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes, we used next generation sequencing of triple negative breast cancer cells in which the isoforms were specifically down-regulated. Down-regulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition and hypoxic response, whereas down-regulation of the CPEB2A isoform did not have this effect. Examining key nodes of these pathways showed that CPEB2B induced the expression of regulatory DNA trans-factors (e.g. HIF1alpha and TWIST1). Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1alpha. Functional studies showed that specific down-regulation of either HIF1alpha or TWIST1 inhibited the ability of CPEB2B to induce the acquisition of anoikis resistance and drive metastasis. Overall, this study demonstrates that CPEB2 alternative splicing is a major regulator of key cellular pathways linked to anoikis resistance and metastasis. PMID- 28904176 TI - The crystal structure of the AhRR-ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related compounds are extraordinarily potent environmental toxic pollutants. Most of the 2,3,7,8-tetrachlorodibenzo-p dioxin toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand dependent transcription factor belonging to the basic helix-loop-helix (bHLH) Per ARNT-Sim (PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, because of the lack of structural information. Here, we determined the structure of the AhRR-ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR-ARNT and AhR-ARNT were similar in the bHLH-PAS-A region, whereas the PAS-B of ARNT in the AhRR-ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA and further suggested the existence of an AhRR-ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription. PMID- 28904178 TI - Offspring telomere length in the long lived Alpine swift is negatively related to the age of their biological father and foster mother. AB - A growing body of studies is showing that offspring telomere length (TL) can be influenced by the age of their parents. Such a relationship might be explained by variation in TL at conception (gamete effect) and/or by alteration of early growth conditions in species providing parental care. In a long-lived bird with bi-parental care, the Alpine swift (Apus melba), we exchanged an uneven number of 2 to 4-day-old nestlings between pairs as part of a brood size manipulation. Nestling TL was measured at 50 days after hatching, which allowed investigation of the influence of the age of both their biological and foster parents on offspring TL, after controlling for the manipulation. Nestling TL was negatively related to the age of their biological father and foster mother. Nestling TL did not differ between enlarged and reduced broods. These findings suggest that offspring from older males were fertilized by gametes with shorter telomeres, presumably due to a greater cell division history or a longer accumulation of damage, and that older females may have provided poorer parental care to their offspring. PMID- 28904177 TI - Limited proteolysis as a tool to probe the tertiary conformation of dysferlin and structural consequences of patient missense variant L344P. AB - Dysferlin is a large transmembrane protein that plays a key role in cell membrane repair and underlies a recessive form of inherited muscular dystrophy. Dysferlinopathy is characterized by absence or marked reduction of dysferlin protein with 43% of reported pathogenic variants being missense variants that span the length of the dysferlin protein. The unique structure of dysferlin, with seven tandem C2 domains separated by linkers, suggests dysferlin may dynamically associate with phospholipid membranes in response to Ca2+ signaling. However, the overall conformation of the dysferlin protein is uncharacterized. To dissect the structural architecture of dysferlin, we have applied the method of limited proteolysis, which allows nonspecific digestion of unfolded peptides by trypsin. Using five antibodies spanning the dysferlin protein, we identified a highly reproducible jigsaw map of dysferlin fragments protected from digestion. Our data infer a modular architecture of four tertiary domains: 1) C2A, which is readily removed as a solo domain; 2) midregion C2B-C2C-Fer-DysF, commonly excised as an intact module, with subdigestion to different fragments suggesting several dynamic folding options; 3) C-terminal four-C2 domain module; and 4) calpain cleaved mini-dysferlinC72, which is particularly resistant to proteolysis. Importantly, we reveal a patient missense variant, L344P, that largely escapes proteasomal surveillance and shows subtle but clear changes in tertiary conformation. Accompanying evidence from immunohistochemistry and flow cytometry using antibodies with conformationally sensitive epitopes supports proteolysis data. Collectively, we provide insight into the structural topology of dysferlin and show how a single missense mutation within dysferlin can exert local changes in tertiary conformation. PMID- 28904179 TI - Phylogenomic analyses of more than 4000 nuclear loci resolve the origin of snakes among lizard families. AB - Squamate reptiles (lizards and snakes) are the most diverse group of terrestrial vertebrates, with more than 10 000 species. Despite considerable effort to resolve relationships among major squamates clades, some branches have remained difficult. Among the most vexing has been the placement of snakes among lizard families, with most studies yielding only weak support for the position of snakes. Furthermore, the placement of iguanian lizards has remained controversial. Here we used targeted sequence capture to obtain data from 4178 nuclear loci from ultraconserved elements from 32 squamate taxa (and five outgroups) including representatives of all major squamate groups. Using both concatenated and species-tree methods, we recover strong support for a sister relationship between iguanian and anguimorph lizards, with snakes strongly supported as the sister group of these two clades. These analyses strongly resolve the difficult placement of snakes within squamates and show overwhelming support for the contentious position of iguanians. More generally, we provide a strongly supported hypothesis of higher-level relationships in the most species rich tetrapod clade using coalescent-based species-tree methods and approximately 100 times more loci than previous estimates. PMID- 28904180 TI - Females can solve the problem of low signal reliability by assessing multiple male traits. AB - Male signals that provide information to females about mating benefits are often of low reliability. It is thus not clear why females often express strong signal preferences. We tested the hypothesis that females can distinguish between males with preferred signals that provide lower and higher quality direct benefits. In the field cricket, Gryllus lineaticeps, females usually prefer higher male chirp rates, but chirp rate is positively correlated with the fecundity benefits females will receive from males only for males that have experienced low quality diets. We paired females with muted males that were maintained on low or high nutrition diets, during the interactions we broadcast a replacement high chirp rate, and we observed whether females mated with the assigned male. Females were more likely to mate when paired with low nutrition males. These results suggest that females have evolved assessment mechanisms that allow them distinguish between males with preferred signals that provide high quality benefits (low nutrition males with high chirp rates) and males with preferred signals that provide low quality benefits (high nutrition males with high chirp rates). PMID- 28904181 TI - Progress and Challenges towards Point-of-Care Diagnostic Development for Dengue. AB - Dengue detection strategies involve viral RNA, antigen, and/or antibody detection. Each strategy has its advantages and disadvantages. Optimal, user friendly, rapid diagnostic tests based on immunochromatographic assays are pragmatic point-of-care tests (POCTs) in regions where dengue is endemic where there are limited laboratory capabilities and optimal storage conditions. Increasingly, there is a greater public health significance for a multiplexing assay that differentiates dengue from Zika or pathogens with similar clinical presentations. Although there have been many assay/platform developments toward POCTs, independent validation and implementation remain very limited. This review highlights the current key progress and challenges toward the development of a dengue POCT. PMID- 28904182 TI - Finegoldia magna Isolated from Orthopedic Joint Implant-Associated Infections. AB - The anaerobic Gram-positive coccus Finegoldia magna is a rare cause of infections of bone and joints. The aim of this study was to describe the microbiological and clinical characteristics of orthopedic implant-associated infections caused by F. magna We retrospectively analyzed samples consisting of anaerobic Gram-positive cocci and samples already identified as F. magna from patients with orthopedic infections. The isolates found were determined to the species level using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The antibiotic susceptibility pattern was determined by Etest. Whole-genome sequencing (WGS) was performed. Clinical data were extracted from each patient's journal. In nine patients, orthopedic joint implant-associated infections were identified as being caused by F. magna The isolates were susceptible to most of the antibiotics tested, with the exception of rifampin and moxifloxacin in a few cases. Five of the nine infections were monomicrobial. The most common antibiotic used to treat the infection was penicillin V, but five of the nine patients received a combination of antibiotics. Eight patients underwent surgical treatment, with extraction of the implant performed in seven cases and reimplantation in only two cases. The WGS showed a relatively small core genome, with 126,647 single nucleotide polymorphisms identified within the core genome. A phylogenomic analysis revealed that the isolates clustered into two distinct clades. Orthopedic implant-associated infections caused by F. magna are rare, but the bacteria are generally susceptible to antibiotics. Despite this, surgical treatment combined with long-term antibiotics is often necessary. The WGS analysis revealed a high heterogeneity and suggested the existence of at least two different Finegoldia species. PMID- 28904184 TI - Improved Bactec MGIT 960 Pyrazinamide Test Decreases Detection of False Mycobacterium tuberculosis Pyrazinamide Resistance. PMID- 28904183 TI - The TB Portals: an Open-Access, Web-Based Platform for Global Drug-Resistant Tuberculosis Data Sharing and Analysis. AB - The TB Portals program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug resistant tuberculosis working with data scientists and information technology professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), 976 (75.1%) of which are multidrug or extensively drug resistant and 38.2%, 51.9%, and 36.3% of which contain X-ray, computed tomography (CT) scan, and genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and single nucleotide polymorphisms (SNPs) that confer resistance to isoniazid, rifampin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations to our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at https://tbportals.niaid.nih.gov/. PMID- 28904185 TI - Thinking beyond the Common Candida Species: Need for Species-Level Identification of Candida Due to the Emergence of Multidrug-Resistant Candida auris. AB - Candida species are one of the leading causes of nosocomial infections. Because much of the treatment for Candida infections is empirical, some institutions do not identify Candida to species level. With the worldwide emergence of the multidrug-resistant species Candida auris, identification of Candida to species level has new clinical relevance. Species should be identified for invasive candidiasis isolates, and species-level identification can be considered for selected noninvasive isolates to improve detection of C. auris. PMID- 28904186 TI - Stool Culture for Diagnosis of Pulmonary Tuberculosis in Children. AB - Bacteriological confirmation of Mycobacterium tuberculosis is achieved in the minority of young children with tuberculosis (TB), since specimen collection is resource intensive and respiratory secretions are mostly paucibacillary, leading to limited sensitivity of available diagnostic tests. Although molecular tests are increasingly available globally, mycobacterial culture remains the gold standard for diagnosis and determination of drug susceptibility and is more sensitive than molecular methods for paucibacillary TB. We evaluated stool culture as an alternative to respiratory specimens for the diagnosis of suspected intrathoracic TB in a subgroup of 188 children (median age, 14.4 months; 15.4% HIV infected) enrolled in a TB diagnostic study at two local hospitals in Cape Town, South Africa. One stool culture was compared to overall bacteriological confirmation by stool Xpert and by Xpert and culture of multiple respiratory specimens. After decontamination/digestion with NALC (N-acetyl-l-cysteine)-NaOH (1.25%), concentrated fluorescent smear microscopy, Xpert MTB/RIF, and liquid culture were completed for all specimens. Culture contamination of stool specimens was high at 41.5%. Seven of 90 (7.8%) children initiating TB treatment were stool culture positive for M. tuberculosis Excluding contaminated cultures, the sensitivity of stool culture versus confirmed TB was 6/25 (24.0%; 95% confidence interval [CI] = 9.4 to 45.1%). In addition, stool culture detected TB in 1/93 (1.1%) children with "unconfirmed TB." Testing the same stool by Xpert increased sensitivity to 33.3% (95% CI = 18.0 to 51.8%). In conclusion, stool culture had low sensitivity for M. tuberculosis detection in children with intrathoracic TB. Reducing culture contamination through improved laboratory protocols may enable more reliable estimates of its diagnostic utility. PMID- 28904187 TI - Genomic Characterization of Urethritis-Associated Neisseria meningitidis Shows that a Wide Range of N. meningitidis Strains Can Cause Urethritis. AB - Neisseria meningitidis, typically a resident of the oro- or nasopharynx and the causative agent of meningococcal meningitis and meningococcemia, is capable of invading and colonizing the urogenital tract. This can result in urethritis, akin to the syndrome caused by its sister species, N. gonorrhoeae, the etiologic agent of gonorrhea. Recently, meningococcal strains associated with outbreaks of urethritis were reported to share genetic characteristics with the gonococcus, raising the question of the extent to which these strains contain features that promote adaptation to the genitourinary niche, making them gonococcus-like and distinguishing them from other N. meningitidis strains. Here, we analyzed the genomes of 39 diverse N. meningitidis isolates associated with urethritis, collected independently over a decade and across three continents. In particular, we characterized the diversity of the nitrite reductase gene (aniA), the factor H binding protein gene (fHbp), and the capsule biosynthetic locus, all of which are loci previously suggested to be associated with urogenital colonization. We observed notable diversity, including frameshift variants, in aniA and fHbp and the presence of intact, disrupted, and absent capsule biosynthetic genes, indicating that urogenital colonization and urethritis caused by N. meningitidis are possible across a range of meningococcal genotypes. Previously identified allelic patterns in urethritis-associated N. meningitidis strains may reflect genetic diversity in the underlying meningococcal population rather than novel adaptation to the urogenital tract. PMID- 28904188 TI - Characterization of Antigenic Relatedness between GII.4 and GII.17 Noroviruses by Use of Serum Samples from Norovirus-Infected Patients. AB - A novel GII.17 norovirus variant caused major gastroenteritis epidemics in China in 2014 to 2016. To explore the host immune factors in selection of the emergence of this new variant, we characterized its antigenic relatedness with the GII.4 noroviruses that have dominated in China for decades. Through an enzyme-linked immunosorbent assay (ELISA) and a histo-blood group antigen (HBGA) blocking assay using sera from GII.4 and the GII.17 variant-infected patients, respectively, we observed limited cross-immune reactivity by the ELISA but little reactivity by the HBGA blocking assay between GII.4 norovirus and the new GII.17 variant. Our data suggest that, among other possible factors, GII.4-specific herd immunity had little role in the emergence of the new GII.17 variant. Thus, GII.17 may be an important active antigenic type or immunotype that needs to be considered for future vaccine strategies against human noroviruses. PMID- 28904189 TI - Comparison of Automated Antimicrobial Susceptibility Testing Systems To Detect mecC-Positive Methicillin-Resistant Staphylococcus aureus. PMID- 28904190 TI - Exploring the Human-Nipah Virus Protein-Protein Interactome. AB - Nipah virus is an emerging, highly pathogenic, zoonotic virus of the Paramyxoviridae family. Human transmission occurs by close contact with infected animals, the consumption of contaminated food, or, occasionally, via other infected individuals. Currently, we lack therapeutic or prophylactic treatments for Nipah virus. To develop these agents we must now improve our understanding of the host-virus interactions that underpin a productive infection. This aim led us to perform the present work, in which we identified 101 human-Nipah virus protein protein interactions (PPIs), most of which (88) are novel. This data set provides a comprehensive view of the host complexes that are manipulated by viral proteins. Host targets include the PRP19 complex and the microRNA (miRNA) processing machinery. Furthermore, we explored the biologic consequences of the interaction with the PRP19 complex and found that the Nipah virus W protein is capable of altering p53 control and gene expression. We anticipate that these data will help in guiding the development of novel interventional strategies to counter this emerging viral threat.IMPORTANCE Nipah virus is a recently discovered virus that infects a wide range of mammals, including humans. Since its discovery there have been yearly outbreaks, and in some of them the mortality rate has reached 100% of the confirmed cases. However, the study of Nipah virus has been largely neglected, and currently we lack treatments for this infection. To develop these agents we must now improve our understanding of the host-virus interactions that underpin a productive infection. In the present work, we identified 101 human-Nipah virus protein-protein interactions using an affinity purification approach coupled with mass spectrometry. Additionally, we explored the cellular consequences of some of these interactions. Globally, this data set offers a comprehensive and detailed view of the host machinery's contribution to the Nipah virus's life cycle. Furthermore, our data present a large number of putative drug targets that could be exploited for the treatment of this infection. PMID- 28904191 TI - Dose of Retroviral Infection Determines Induction of Antiviral NK Cell Responses. AB - Natural killer (NK) cells are part of the innate immune system and recognize virus-infected cells as well as tumor cells. Conflicting data about the beneficial or even detrimental role of NK cells in different infectious diseases have been described previously. While the type of pathogen strongly influences NK cell functionality, less is known about how the infection dose influences the quality of a NK cell response against retroviruses. In this study, we used the well-established Friend retrovirus (FV) mouse model to investigate the impact of virus dose on the induction of antiviral NK cell functions. High-dose virus inoculation increased initial virus replication compared to that with medium- or low-dose viral challenge and significantly improved NK cell activation. Antiviral NK cell activity, including in vivo cytotoxicity toward infected target cells, was also enhanced by high-dose virus infection. NK cell activation following high dose viral challenge was likely mediated by activated dendritic cells (DCs) and macrophages and the NK cell-stimulating cytokines interleukin 15 (IL-15) and IL 18. Neutralization of these cytokines decreased NK cell functions and increased viral loads, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we demonstrate that virus dose positively correlates with antiviral NK cell activity and function, which are at least partly driven by IL-15 and IL-18. Our results suggest that NK cell activity may be therapeutically enhanced by administering IL 15 and IL-18 in virus infections that inadequately activate NK cells.IMPORTANCE In infections with retroviruses, like HIV and FV infection of mice, NK cells clearly mediate antiviral activities, but they are usually not sufficient to prevent severe pathology. Here we show that the initial infection dose impacts the induction of an antiviral NK cell response during an acute retroviral infection, which had not investigated before. High-dose infection resulted in a strong NK cell functionality, whereas no antiviral activities were detected after low- or medium-dose infection. Interestingly, DCs and macrophages were highly activated after high-dose FV challenge, which corresponded with increased levels of NK cell-stimulating cytokines IL-15 and IL-18. IL-15 and IL-18 neutralization decreased NK cell functions, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we show the importance of cytokines for NK cell activation in retroviral infections; our findings suggest that immunotherapy combining the well tolerated cytokines IL-15 and IL-18 might be an interesting approach for antiretroviral treatment. PMID- 28904192 TI - Role of Herpes Simplex Virus 1 gamma34.5 in the Regulation of IRF3 Signaling. AB - During viral infection, pattern recognition receptors (PRRs) and their associated adaptors recruit TANK-binding kinase 1 (TBK1) to activate interferon regulatory factor 3 (IRF3), resulting in production of type I interferons (IFNs). ICP0 and ICP34.5 are among the proteins encoded by herpes simplex virus 1 (HSV-1) that modulate type I IFN signaling. We constructed a recombinant virus (DeltaXX) that lacks amino acids 87 to 106, a portion of the previously described TBK1-binding domain of the gamma34.5 gene (D. Verpooten, Y. Ma, S. Hou, Z. Yan, and B. He, J Biol Chem 284:1097-1105, 2009, https://doi.org/10.1074/JBC.M805905200). These 20 residues are outside the gamma34.5 beclin1-binding domain (BBD) that interacts with beclin1 and regulates autophagy. Unexpectedly, DeltaXX showed no deficit in replication in vivo in a variety of tissues and showed virulence comparable to that of wild-type and marker-rescued viruses following intracerebral infection. DeltaXX was fully capable of mediating the dephosphorylation of eIF2alpha, and the virus was capable of controlling the phosphorylation of IRF3. In contrast, a null mutant in gamma34.5 failed to control IRF3 phosphorylation due to an inability of the mutant to sustain expression of ICP0. Our data show that while gamma34.5 regulates IRF3 phosphorylation, the TBK1-binding domain itself has no impact on IRF3 phosphorylation or on replication and pathogenesis in mice.IMPORTANCE Interferons (IFNs) are potent activators of a variety of host responses that serve to control virus infections. The Herpesviridae have evolved countermeasures to IFN responses. Herpes simplex virus 1 (HSV-1) encodes the multifunctional neurovirulence protein ICP34.5. In this study, we investigated the biological relevance of the interaction between ICP34.5 and TANK-binding kinase 1 (TBK1), an activator of IFN responses. Here, we establish that although ICP34.5 binds TBK1 under certain conditions through a TBK1-binding domain (TBD), there was no direct impact of the TBD on viral replication or virulence in mice. Furthermore, we showed that activation of IRF3, a substrate of TBK1, was independent of the TBD. Instead, we provided evidence that the ability of ICP34.5 to control IRF3 activation is through its ability to reverse translational shutoff and sustain the expression of other IFN inhibitors encoded by the virus. This work provides new insights into the immunomodulatory functions of ICP34.5. PMID- 28904193 TI - Mutations in the Fusion Protein of Measles Virus That Confer Resistance to the Membrane Fusion Inhibitors Carbobenzoxy-d-Phe-l-Phe-Gly and 4-Nitro-2 Phenylacetyl Amino-Benzamide. AB - The inhibitors carbobenzoxy (Z)-d-Phe-l-Phe-Gly (fusion inhibitor peptide [FIP]) and 4-nitro-2-phenylacetyl amino-benzamide (AS-48) have similar efficacies in blocking membrane fusion and syncytium formation mediated by measles virus (MeV). Other homologues, such as Z-d-Phe, are less effective but may act through the same mechanism. In an attempt to map the site of action of these inhibitors, we generated mutant viruses that were resistant to the inhibitory effects of Z-d-Phe l-Phe-Gly. These 10 mutations were localized to the heptad repeat B (HRB) region of the fusion protein, and no changes were observed in the viral hemagglutinin, which is the receptor attachment protein. Mutations were validated in a luciferase-based membrane fusion assay, using transfected fusion and hemagglutinin expression plasmids or with syncytium-based assays in Vero, Vero SLAM, and Vero-Nectin 4 cell lines. The changes I452T, D458N, D458G/V459A, N462K, N462H, G464E, and I483R conferred resistance to both FIP and AS-48 without compromising membrane fusion. The inhibitors did not block hemagglutinin protein mediated binding to the target cell. Edmonston vaccine/laboratory and IC323 wild type strains were equally affected by the inhibitors. Escape mutations were mapped upon a three-dimensional (3D) structure modeled from the published crystal structure of parainfluenzavirus 5 fusion protein. The most effective mutations were situated in a region located near the base of the globular head and its junction with the alpha-helical stalk of the prefusion protein. We hypothesize that the fusion inhibitors could interfere with the structural changes that occur between the prefusion and postfusion conformations of the fusion protein.IMPORTANCE Due to lapses in vaccination worldwide that have caused localized outbreaks, measles virus (MeV) has regained importance as a pathogen. Antiviral agents against measles virus are not commercially available but could be useful in conjunction with MeV eradication vaccine programs and as a safeguard in oncolytic viral therapy. Three decades ago, the small hydrophobic peptide Z-d Phe-l-Phe-Gly (FIP) was shown to block MeV infections and syncytium formation in monkey kidney cell lines. The exact mechanism of its action has yet to be determined, but it does appear to have properties similar to those of another chemical inhibitor, AS-48, which appears to interfere with the conformational change in the viral F protein that is required to elicit membrane fusion. Escape mutations were used to map the site of action for FIP. Knowledge gained from these studies could help in the design of new inhibitors against morbilliviruses and provide additional knowledge concerning the mechanism of virus-mediated membrane fusion. PMID- 28904194 TI - Distinct Mechanism for the Formation of the Ribonucleoprotein Complex of Tomato Spotted Wilt Virus. AB - The Tomato spotted wilt virus (TSWV) belongs to the Tospovirus genus of the Bunyaviridae family and represents the sole plant-infecting group within bunyavirus. TSWV encodes a nucleocapsid protein (N) which encapsidates the RNA genome to form a ribonucleoprotein complex (RNP). In addition, the N has multiple roles during the infection of plant cells. Here, we report the crystal structure of the full-length TSWV N. The N features a body domain consisting of an N-lobe and a C-lobe. These lobes clamp a positively charged groove which may constitute the RNA binding site. Furthermore, the body domains are flanked by N- and C terminal arms which mediate homotypic interactions to the neighboring subunits, resulting in a ring-shaped N trimer. Interestingly, the C terminus of one protomer forms an additional interaction with the protomer of an adjacent trimer in the crystal, which may constitute a higher-order oligomerization contact. In this way, this study provides insights into the structure and trimeric assembly of TSWV N, which help to explain previous functional findings, but also suggests distinct N interactions within a higher-order RNP.IMPORTANCE TSWV is one of the most devastating plant pathogens that cause severe diseases in numerous agronomic and ornamental crops worldwide. TSWV is also the prototypic member of the Tospovirus genus, which is the sole group of plant-infecting viruses in the bunyavirus family. This study determined the structure of full-length TSWV N in an oligomeric state. The structural observations explain previously identified biological properties of TSWV N. Most importantly, the additional homotypic interaction between the C terminus of one protomer with another protomer indicates that there is a distinct mechanism of RNP formation in the bunyavirus family, thereby enhancing the current knowledge of negative-sense single-stranded RNA virus-encoded N. TSWV N is the last remaining representative N with an unknown structure in the bunyavirus family. Combined with previous studies, the structure of TSWV N helps to build a complete picture of the bunyavirus-encoded N family and reveals a close evolutionary relationship between orthobunyavirus, phlebovirus, hantavirus, and tospovirus. PMID- 28904195 TI - Vector order determines protection against pathogenic simian immunodeficiency virus infection in a triple component vaccine by balancing CD4+ and CD8+ T-cell responses. AB - An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4+ T cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single cycle immunodeficiency virus, followed by two mucosal boosts either with recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose, intrarectal challenge with pathogenic SIVmac251 resulting in a vaccine efficacy (i.e. risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8+ T cells and Gag-specific IFN-gamma secreting CD8+ cells, low virus-specific CD4+ T cell responses and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4+ T cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4+ T cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69+ CD8+ T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by this vaccine regimen.IMPORTANCE A failed phase II AIDS vaccine trial led to the hypothesis that CD4+ T cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4+ T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4+ T cells in combination with high levels of activated CD8+ T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env-antibody titers. Moreover, we show that both, the vector and the route of immunization affected the level of CD4+ T cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered as potent prime in prime-boost vaccination protocols. PMID- 28904196 TI - Vaccinia Virus Encodes a Novel Inhibitor of Apoptosis That Associates with the Apoptosome. AB - Apoptosis is an important antiviral host defense mechanism. Here we report the identification of a novel apoptosis inhibitor encoded by the vaccinia virus (VACV) M1L gene. M1L is absent in the attenuated modified vaccinia virus Ankara (MVA) strain of VACV, a strain that stimulates apoptosis in several types of immune cells. M1 expression increased the viability of MVA-infected THP-1 and Jurkat cells and reduced several biochemical hallmarks of apoptosis, such as PARP 1 and procaspase-3 cleavage. Furthermore, ectopic M1L expression decreased staurosporine-induced (intrinsic) apoptosis in HeLa cells. We then identified the molecular basis for M1 inhibitory function. M1 allowed mitochondrial depolarization but blocked procaspase-9 processing, suggesting that M1 targeted the apoptosome. In support of this model, we found that M1 promoted survival in Saccharomyces cerevisiae overexpressing human Apaf-1 and procaspase-9, critical components of the apoptosome, or overexpressing only conformationally active caspase-9. In mammalian cells, M1 coimmunoprecipitated with Apaf-1-procaspase-9 complexes. The current model is that M1 associates with and allows the formation of the apoptosome but prevents apoptotic functions of the apoptosome. The M1 protein features 14 predicted ankyrin (ANK) repeat domains, and M1 is the first ANK-containing protein reported to use this inhibitory strategy. Since ANK containing proteins are encoded by many large DNA viruses and found in all domains of life, studies of M1 may lead to a better understanding of the roles of ANK proteins in virus-host interactions.IMPORTANCE Apoptosis selectively eliminates dangerous cells such as virus-infected cells. Poxviruses express apoptosis antagonists to neutralize this antiviral host defense. The vaccinia virus (VACV) M1 ankyrin (ANK) protein, a protein with no previously ascribed function, inhibits apoptosis. M1 interacts with the apoptosome and prevents procaspase-9 processing as well as downstream procaspase-3 cleavage in several cell types and under multiple conditions. M1 is the first poxviral protein reported to associate with and prevent the function of the apoptosome, giving a more detailed picture of the threats VACV encounters during infection. Dysregulation of apoptosis is associated with several human diseases. One potential treatment of apoptosis-related diseases is through the use of designed ANK repeat proteins (DARPins), similar to M1, as caspase inhibitors. Thus, the study of the novel antiapoptosis effects of M1 via apoptosome association will be helpful for understanding how to control apoptosis using either natural or synthetic molecules. PMID- 28904198 TI - Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium. AB - Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied in vivo Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alert mice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c+ cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I based interventions to reduce host colonization.IMPORTANCE Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon based therapeutic intervention. PMID- 28904197 TI - Differential Inhibitory Receptor Expression on T Cells Delineates Functional Capacities in Chronic Viral Infection. AB - Inhibitory receptors have been extensively described for their importance in regulating immune responses in chronic infections and cancers. Blocking the function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 has shown promise for augmenting CD8 T cell activity and boosting pathogen-specific immunity. However, the prevalence of inhibitory receptors on CD4 T cells and their relative influence on CD4 T cell functionality in chronic HIV infection remains poorly described. We therefore determined and compared inhibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus specific CD4 and CD8 T cells in relation to their functional T cell profile. In chronic HIV infection, inhibitory receptor distribution differed markedly between cytokine-producing T cell subsets with, gamma interferon (IFN-gamma)- and tumor necrosis factor alpha (TNF-alpha)-producing cells displaying the highest and lowest prevalence of inhibitory receptors, respectively. Blockade of inhibitory receptors differentially affected cytokine production by cells in response to staphylococcal enterotoxin B stimulation. CTLA-4 blockade increased IFN-gamma and CD40L production, while PD-1 blockade strongly augmented IFN-gamma, interleukin-2 (IL-2), and TNF-alpha production. In a Friend retrovirus infection model, CTLA-4 blockade in particular was able to improve control of viral replication. Together, these results show that inhibitory receptor distribution on HIV specific CD4 T cells varies markedly with respect to the functional subset of CD4 T cells being analyzed. Furthermore, the differential effects of receptor blockade suggest novel methods of immune response modulation, which could be important in the context of HIV vaccination or therapeutic strategies.IMPORTANCE Inhibitory receptors are important for limiting damage by the immune system during acute infections. In chronic infections, however, their expression limits immune system responsiveness. Studies have shown that blocking inhibitory receptors augments CD8 T cell functionality in HIV infection, but their influence on CD4 T cells remains unclear. We assessed the expression of inhibitory receptors on HIV-specific CD4 T cells and their relationship with T cell functionality. We uncovered differences in inhibitory receptor expression depending on the CD4 T cell function. We also found differences in functionality of CD4 T cells following blocking of different inhibitory receptors, and we confirmed our results in a Friend virus retroviral model of infection in mice. Our results show that inhibitory receptor expression on CD4 T cells is linked to CD4 T cell functionality and could be sculpted by blockade of specific inhibitory receptors. These data reveal exciting possibilities for the development of novel treatments and immunotherapeutics. PMID- 28904199 TI - Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells. AB - The neuroimmune dialogue between peripheral neurons and Langerhans cells (LCs) within mucosal epithelia protects against incoming pathogens. LCs rapidly internalize human immunodeficiency virus type 1 (HIV-1) upon its sexual transmission and then trans-infect CD4+ T cells. We recently found that the neuropeptide calcitonin gene-related peptide (CGRP), secreted mucosally from peripheral neurons, inhibits LC-mediated HIV-1 trans-infection. In this study, we investigated the mechanism of CGRP-induced inhibition, focusing on HIV-1 degradation in LCs and its interplay with trans-infection. We first show that HIV 1 degradation occurs in endolysosomes in untreated LCs, and functionally blocking such degradation with lysosomotropic agents results in increased trans-infection. We demonstrate that CGRP acts via its cognate receptor and at a viral postentry step to induce faster HIV-1 degradation, but without affecting the kinetics of endolysosomal degradation. We reveal that unexpectedly, CGRP shifts HIV-1 degradation from endolysosomes toward the proteasome, providing the first evidence for functional HIV-1 proteasomal degradation in LCs. Such efficient proteasomal degradation significantly inhibits the first phase of trans infection, and proteasomal, but not endolysosomal, inhibitors abrogate CGRP induced inhibition. Together, our results establish that CGRP controls the HIV-1 degradation mode in LCs. The presence of endogenous CGRP within innervated mucosal tissues, especially during the sexual response, to which CGRP contributes, suggests that HIV-1 proteasomal degradation predominates in vivo Hence, proteasomal, rather than endolysosomal, HIV-1 degradation in LCs should be enhanced clinically to effectively restrict HIV-1 trans-infection.IMPORTANCE During sexual transmission, HIV-1 is internalized and degraded in LCs, the resident antigen-presenting cells in mucosal epithelia. Yet during trans infection, infectious virions escaping degradation are transferred to CD4+ T cells, the principal HIV-1 targets. We previously found that the neuroimmune dialogue between LCs and peripheral neurons, innervating mucosal epithelia, significantly inhibits trans-infection via the action of the secreted neuropeptide CGRP on LCs. In this study, we investigated whether CGRP-induced inhibition of trans-infection is linked to CGRP-controlled HIV-1 degradation in LCs. We show that in untreated LCs, HIV-1 is functionally degraded in endolysosomes. In sharp contrast, we reveal that in CGRP-treated LCs, HIV-1 is diverted toward and degraded via another cytosolic protein degradative pathway, namely, the proteasome. These results establish that CGRP regulates HIV-1 degradation in LCs. As CGRP contributes to the sexual response and present within mucosal epithelia, HIV-1 proteasomal degradation in LCs might predominate in vivo and should be enhanced clinically. PMID- 28904200 TI - Epstein-Barr Virus BKRF4 Gene Product Is Required for Efficient Progeny Production. AB - Epstein-Barr virus (EBV), a member of human gammaherpesvirus, infects mainly B cells. EBV has two alternative life cycles, latent and lytic, and is reactivated occasionally from the latent stage to the lytic cycle. To combat EBV-associated disorders, understanding the molecular mechanisms of the EBV lytic replication cycle is also important. Here, we focused on an EBV lytic gene, BKRF4. Using our anti-BKRF4 antibody, we revealed that the BKRF4 gene product is expressed during the lytic cycle with late kinetics. To characterize the role of BKRF4, we constructed BKRF4-knockout mutants using the bacterial artificial chromosome (BAC) and CRISPR/Cas9 systems. Although disruption of the BKRF4 gene had almost no effect on viral protein expression and DNA synthesis, it significantly decreased progeny virion levels in HEK293 and Akata cells. Furthermore, we show that BKRF4 is involved not only in production of progeny virions but also in increasing the infectivity of the virus particles. Immunoprecipitation assays revealed that BKRF4 interacted with a virion protein, BGLF2. We showed that the C terminal region of BKRF4 was critical for this interaction and for efficient progeny production. Immunofluorescence analysis revealed that BKRF4 partially colocalized with BGLF2 in the nucleus and perinuclear region. Finally, we showed that BKRF4 is a phosphorylated, possible tegument protein and that the EBV protein kinase BGLF4 may be important for this phosphorylation. Taken together, our data suggest that BKRF4 is involved in the production of infectious virions.IMPORTANCE Although the latent genes of EBV have been studied extensively, the lytic genes are less well characterized. This study focused on one such lytic gene, BKRF4, which is conserved only among gammaherpesviruses (ORF45 of Kaposi's sarcoma-associated herpesvirus or murine herpesvirus 68). After preparing the BKRF4 knockout virus using B95-8 EBV-BAC, we demonstrated that the BKRF4 gene was involved in infectious progeny particle production. Importantly, we successfully generated a BKRF4 knockout virus of Akata using CRISPR/Cas9 technology, confirming the phenotype in this separate strain. We further showed that BKRF4 interacted with another virion protein, BGLF2, and demonstrated the importance of this interaction in infectious virion production. These results shed light on the elusive process of EBV progeny maturation in the lytic cycle. Notably, this study describes a successful example of the generation and characterization of an EBV construct with a disrupted lytic gene using CRISPR/Cas9 technology. PMID- 28904201 TI - Heterogeneity of the Epstein-Barr Virus (EBV) Major Internal Repeat Reveals Evolutionary Mechanisms of EBV and a Functional Defect in the Prototype EBV Strain B95-8. AB - Epstein-Barr virus (EBV) is a ubiquitous pathogen of humans that can cause several types of lymphoma and carcinoma. Like other herpesviruses, EBV has diversified through both coevolution with its host and genetic exchange between virus strains. Sequence analysis of the EBV genome is unusually challenging because of the large number and lengths of repeat regions within the virus. Here we describe the sequence assembly and analysis of the large internal repeat 1 of EBV (IR1; also known as the BamW repeats) for more than 70 strains. The diversity of the latency protein EBV nuclear antigen leader protein (EBNA-LP) resides predominantly within the exons downstream of IR1. The integrity of the putative BWRF1 open reading frame (ORF) is retained in over 80% of strains, and deletions truncating IR1 always spare BWRF1. Conserved regions include the IR1 latency promoter (Wp) and one zone upstream of and two within BWRF1. IR1 is heterogeneous in 70% of strains, and this heterogeneity arises from sequence exchange between strains as well as from spontaneous mutation, with interstrain recombination being more common in tumor-derived viruses. This genetic exchange often incorporates regions of <1 kb, and allelic gene conversion changes the frequency of small regions within the repeat but not close to the flanks. These observations suggest that IR1-and, by extension, EBV-diversifies through both recombination and breakpoint repair, while concerted evolution of IR1 is driven by gene conversion of small regions. Finally, the prototype EBV strain B95-8 contains four nonconsensus variants within a single IR1 repeat unit, including a stop codon in the EBNA-LP gene. Repairing IR1 improves EBNA-LP levels and the quality of transformation by the B95-8 bacterial artificial chromosome (BAC).IMPORTANCE Epstein-Barr virus (EBV) infects the majority of the world population but causes illness in only a small minority of people. Nevertheless, over 1% of cancers worldwide are attributable to EBV. Recent sequencing projects investigating virus diversity to see if different strains have different disease impacts have excluded regions of repeating sequence, as they are more technically challenging. Here we analyze the sequence of the largest repeat in EBV (IR1). We first characterized the variations in protein sequences encoded across IR1. In studying variations within the repeat of each strain, we identified a mutation in the main laboratory strain of EBV that impairs virus function, and we suggest that tumor-associated viruses may be more likely to contain DNA mixed from two strains. The patterns of this mixing suggest that sequences can spread between strains (and also within the repeat) by copying sequence from another strain (or repeat unit) to repair DNA damage. PMID- 28904202 TI - Discrete Dynamical Modeling of Influenza Virus Infection Suggests Age-Dependent Differences in Immunity. AB - Immunosenescence, an age-related decline in immune function, is a major contributor to morbidity and mortality in the elderly. Older hosts exhibit a delayed onset of immunity and prolonged inflammation after an infection, leading to excess damage and a greater likelihood of death. Our study applies a rule based model to infer which components of the immune response are most changed in an aged host. Two groups of BALB/c mice (aged 12 to 16 weeks and 72 to 76 weeks) were infected with 2 inocula: a survivable dose of 50 PFU and a lethal dose of 500 PFU. Data were measured at 10 points over 19 days in the sublethal case and at 6 points over 7 days in the lethal case, after which all mice had died. Data varied primarily in the onset of immunity, particularly the inflammatory response, which led to a 2-day delay in the clearance of the virus from older hosts in the sublethal cohort. We developed a Boolean model to describe the interactions between the virus and 21 immune components, including cells, chemokines, and cytokines, of innate and adaptive immunity. The model identifies distinct sets of rules for each age group by using Boolean operators to describe the complex series of interactions that activate and deactivate immune components. Our model accurately simulates the immune responses of mice of both ages and with both inocula included in the data (95% accurate for younger mice and 94% accurate for older mice) and shows distinct rule choices for the innate immunity arm of the model between younger and aging mice in response to influenza A virus infection.IMPORTANCE Influenza virus infection causes high morbidity and mortality rates every year, especially in the elderly. The elderly tend to have a delayed onset of many immune responses as well as prolonged inflammatory responses, leading to an overall weakened response to infection. Many of the details of immune mechanisms that change with age are currently not well understood. We present a rule-based model of the intrahost immune response to influenza virus infection. The model is fit to experimental data for young and old mice infected with influenza virus. We generated distinct sets of rules for each age group to capture the temporal differences seen in the immune responses of these mice. These rules describe a network of interactions leading to either clearance of the virus or death of the host, depending on the initial dosage of the virus. Our models clearly demonstrate differences in these two age groups, particularly in the innate immune responses. PMID- 28904203 TI - Three Conserved Regions in Baculovirus Sulfhydryl Oxidase P33 Are Critical for Enzymatic Activity and Function. AB - Baculoviruses encode a conserved sulfhydryl oxidase, P33, which is necessary for budded virus (BV) production and multinucleocapsid occlusion-derived virus (ODV) formation. Here, the structural and functional relationship of P33 was revealed by X-ray crystallography, site-directed mutagenesis, and functional analysis. Based on crystallographic characterization and structural analysis, a series of P33 mutants within three conserved regions, i.e., the active site, the dimer interface, and the R127-E183 salt bridge, were constructed. In vitro experiments showed that mutations within the active site and dimer interface severely impaired the sulfhydryl oxidase activity of P33, while the mutations in the salt bridge had a relatively minor influence. Recombinant viruses containing mutated P33 were constructed and assayed in vivo Except for the active-site mutant AXXA, all other mutants produced infectious BVs, although certain mutants had a decreased BV production. The active-site mutant H114A, the dimer interface mutant H227D, and the salt bridge mutant R127A-E183A were further analyzed by electron microscopy and bioassays. The occlusion bodies (OBs) of mutants H114A and R127A E183A had a ragged surface and contained mostly ODVs with a single nucleocapsid. The OBs of all three mutants contained lower numbers of ODVs and had a significantly reduced oral infectivity in comparison to control virus. Crystallographic analyses further revealed that all three regions may coordinate with one another to achieve optimal function of P33. Taken together, our data revealed that all the three conserved regions are involved in P33 activity and are crucial for virus morphogenesis and peroral infectivity.IMPORTANCE Sulfhydryl oxidase catalyzes disulfide bond formation of substrate proteins. P33, a baculovirus-encoded sulfhydryl oxidase, is different from other cellular and viral sulfhydryl oxidases, bearing unique features in tertiary and quaternary structure organizations. In this study, we found that three conserved regions, i.e., the active site, dimer interface, and the R127-E183 salt bridge, play important roles in the enzymatic activity and function of P33. Previous observations showed that deletion of p33 results in a total loss of budded virus (BV) production and in morphological changes in occlusion-derived virus (ODV). Our study revealed that certain P33 mutants lead to occlusion bodies (OBs) with a ragged surface, decreased embedded ODVs, and reduced oral infectivity. Interestingly, some P33 mutants with impaired ODV/OB still retained BV productivity, indicating that the impacts on BV and on ODV/OB are two distinctly different functions of P33, which are likely to be performed via different substrate proteins. PMID- 28904204 TI - Distinct roles of the polarity factors Boi1 and Boi2 in the control of exocytosis and abscission in budding yeast. AB - Boi1 and Boi2 (Boi1/2) are budding yeast plasma membrane proteins that function in polarized growth, and in cytokinesis inhibition in response to chromosome bridges via the NoCut abscission checkpoint. How Boi1/2 act in these two distinct processes is not understood. We demonstrate that Boi1/2 are required for a late step in the fusion of secretory vesicles with the plasma membrane of the growing bud. Cells lacking Boi1/2 accumulate secretory vesicles and are defective in bud growth. In contrast, Boi2 is specifically required for abscission inhibition in cells with chromatin bridges. The SH3 domain of Boi2, which is dispensable for bud growth and targets Boi2 to the site of abscission, is necessary and sufficient for abscission inhibition. Gain of function of the exocyst, a conserved protein complex involved in tethering of exocytic vesicles to the plasma membrane, rescued secretion and bud growth defects in boi mutant cells, and abrogated NoCut checkpoint function. Thus Boi2 functions redundantly with Boi1 to promote the fusion of secretory vesicles with the plasma membrane at sites of polarized growth, and acts as an abscission inhibitor during cytokinesis in response to chromatin bridges. PMID- 28904205 TI - Hemodynamic forces can be accurately measured in vivo with optical tweezers. AB - Force sensing and generation at the tissue and cellular scale is central to many biological events. There is a growing interest in modern cell biology for methods enabling force measurements in vivo. Optical trapping allows noninvasive probing of piconewton forces and thus emerged as a promising mean for assessing biomechanics in vivo. Nevertheless, the main obstacles lie in the accurate determination of the trap stiffness in heterogeneous living organisms, at any position where the trap is used. A proper calibration of the trap stiffness is thus required for performing accurate and reliable force measurements in vivo. Here we introduce a method that overcomes these difficulties by accurately measuring hemodynamic profiles in order to calibrate the trap stiffness. Doing so, and using numerical methods to assess the accuracy of the experimental data, we measured flow profiles and drag forces imposed to trapped red blood cells of living zebrafish embryos. Using treatments enabling blood flow tuning, we demonstrated that such a method is powerful in measuring hemodynamic forces in vivo with accuracy and confidence. Altogether this study demonstrates the power of optical tweezing in measuring low range hemodynamic forces in vivo and offers an unprecedented tool in both cell and developmental biology. PMID- 28904206 TI - A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal. AB - Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the CAV1 gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in CAV1, P158PfsX22, on caveolae assembly and function. We show that C-terminus of the CAV1 P158 protein contains a functional ER-retention signal that inhibits ER exit and caveolae formation and accelerates CAV1 turnover in Cav1-/- MEFs. Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1-/- MEFs, CAV1-P158 functions as a dominant negative by partially disrupting WT CAV1 trafficking. In patient skin fibroblasts, CAV1 and caveolar accessory protein levels are reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical abnormalities. Patient fibroblasts also exhibit decreased resistance to a hypo-osmotic challenge, suggesting the function of caveolae as membrane reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces a gain of function that gives rise to a dominant negative form of CAV1, defining a new mechanism by which disease-associated mutations in CAV1 impair caveolae assembly. PMID- 28904207 TI - Two kinesins drive anterograde neuropeptide transport. AB - Motor-dependent anterograde transport, a process that moves cytoplasmic components from sites of biosynthesis to sites of use within cells, is crucial in neurons with long axons. Evidence has emerged that multiple anterograde kinesins can contribute to some transport processes. To test the multi-kinesin possibility for a single vesicle type, we studied the functional relationships of axonal kinesins to dense core vesicles (DCVs) that were filled with a GFP-tagged neuropeptide in the Drosophila nervous system. Past work showed that Unc-104 (a kinesin-3) is a key anterograde DCV motor. Here we show that anterograde DCV transport requires the well-known mitochondrial motor Khc (kinesin-1). Our results indicate that this influence is direct. Khc mutations had specific effects on anterograde run parameters, neuron-specific inhibition of mitochondrial transport by Milton RNA interference had no influence on anterograde DCV runs, and detailed colocalization analysis by superresolution microscopy revealed that Unc-104 and Khc coassociate with individual DCVs. DCV distribution analysis in peptidergic neurons suggest the two kinesins have compartment specific influences. We suggest a mechanism in which Unc-104 is particularly important for moving DCVs from cell bodies into axons, and then Unc 104 and kinesin-1 function together to support fast, highly processive runs toward axon terminals. PMID- 28904208 TI - Genome-wide screen of gamma-secretase-mediated intramembrane cleavage of receptor tyrosine kinases. AB - Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is unknown whether they can exploit this new signaling mechanism. Here we used a system-wide screen to address the frequency of susceptibility to gamma secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all nine previously published gamma-secretase substrates. We biochemically validated the screen by demonstrating that the release of a soluble intracellular fragment from endogenous AXL was dependent on the sheddase disintegrin and metalloprotease 10 (ADAM10) and the gamma-secretase component presenilin-1. Functional analysis of the cleavable RTKs indicated that proliferation promoted by overexpression of the TAM family members AXL or TYRO3 depends on gamma-secretase cleavage. Taken together, these data indicate that gamma-secretase-mediated cleavage provides an additional signaling mechanism for numerous human RTKs. PMID- 28904209 TI - Drosophila MIC60/mitofilin conducts dual roles in mitochondrial motility and crista structure. AB - MIC60/mitofilin constitutes a hetero-oligomeric complex on the inner mitochondrial membranes to maintain crista structure. However, little is known about its physiological functions. Here, by characterizing Drosophila MIC60 mutants, we define its roles in vivo. We discover that MIC60 performs dual functions to maintain mitochondrial homeostasis. In addition to its canonical role in crista membrane structure, MIC60 regulates mitochondrial motility, likely by influencing protein levels of the outer mitochondrial membrane protein Miro that anchors mitochondria to the microtubule motors. Loss of MIC60 causes loss of Miro and mitochondrial arrest. At a cellular level, loss of MIC60 disrupts synaptic structure and function at the neuromuscular junctions. The dual roles of MIC60 in both mitochondrial crista structure and motility position it as a crucial player for cellular integrity and survival. PMID- 28904210 TI - Membrane mechanics govern spatiotemporal heterogeneity of endocytic clathrin coat dynamics. AB - Dynamics of endocytic clathrin-coated structures can be remarkably divergent across different cell types, cells within the same culture, or even distinct surfaces of the same cell. The origin of this astounding heterogeneity remains to be elucidated. Here we show that cellular processes associated with changes in effective plasma membrane tension induce significant spatiotemporal alterations in endocytic clathrin coat dynamics. Spatiotemporal heterogeneity of clathrin coat dynamics is also observed during morphological changes taking place within developing multicellular organisms. These findings suggest that tension gradients can lead to patterning and differentiation of tissues through mechanoregulation of clathrin-mediated endocytosis. PMID- 28904212 TI - Distinct Phases of Tau, Amyloid, and Functional Connectivity in Healthy Older Adults. PMID- 28904211 TI - Zonda is a novel early component of the autophagy pathway in Drosophila. AB - Autophagy is an evolutionary conserved process by which eukaryotic cells undergo self-digestion of cytoplasmic components. Here we report that a novel Drosophila immunophilin, which we have named Zonda, is critically required for starvation induced autophagy. We show that Zonda operates at early stages of the process, specifically for Vps34-mediated phosphatidylinositol 3-phosphate (PI3P) deposition. Zonda displays an even distribution under basal conditions and, soon after starvation, nucleates in endoplasmic reticulum-associated foci that colocalize with omegasome markers. Zonda nucleation depends on Atg1, Atg13, and Atg17 but does not require Vps34, Vps15, Atg6, or Atg14. Zonda interacts physically with Atg1 through its kinase domain, as well as with Atg6 and Vps34. We propose that Zonda is an early component of the autophagy cascade necessary for Vps34-dependent PI3P deposition and omegasome formation. PMID- 28904213 TI - The Medial Premotor Cortex as a Bridge from Internal Timekeeping to Action. PMID- 28904215 TI - Everyday Exotropia: Learning from the Littlest. AB - BACKGROUND AND PURPOSE: Early onset exodeviations in systemically and ocularly healthy young children, diagnosed at less than 1 year of age, may be of the constant, "infantile XT" type, or early X(T) type. The onset of common childhood X(T) is not clearly known. The purpose of this lecture is to discuss theories and characteristics of early onset exodeviations, and report on our observations of infantile XT and early X(T) at Children's Eye Care in Michigan. PATIENTS AND METHODS: A retrospective review of 470 cases of childhood exodeviations (ages 6 months to 15 years) were reviewed and met inclusion criteria of no prior surgical treatment, no ocular, CNS or craniofacial disease, and no significant prematurity. Thirty-nine cases were diagnosed at less than 1 year of age: thirty five patients with early X(T) and four patients with infantile XT, based upon a motility evaluation at 6 m and 1/3 m fixation using dissociative methods. The clinical characteristics and outcomes of these two groups were described and compared. RESULTS: Comparing infantile XT and early X(T) groups, reported onset by caregivers was significantly younger in the infantile XT group (3 months vs. 6 months), and size of the deviation at both distance and near fixation ranges was significantly larger in the infantile XT group (XT-43/XT'-48Delta vs. X(T) 25/X(T)'-23Delta). Three of 4 infantile XT patients received surgery, one spontaneously resolved, and all resulted in small, residual XT, and DVD without measurable stereoacuity. Many patients with early X(T) demonstrated good/excellent control at near range and fair/poor control at distance range. Four early X(T) patients who did not receive surgical correction either resolved, remained the same, or decompensated. Surgical correction for X(T) resulted in a 50% success rate for one procedure with a minimum of 2 years postoperative follow up. Stereoacuity outcomes did not appear to correlate with quality of control. CONCLUSIONS: Most healthy children with X(T) are diagnosed by age 5 years, although many have a reported onset by caregivers of less than 1 year of age. Good control of X(T) at near range may preclude early examinations. Motility evaluation by dissociative methods at near and far-range fixation may facilitate early diagnosis. Infantile XT is less common than early X(T), by a ratio of 1:10. Characteristics of infantile XT and early X(T) have significant differences in report onset, deviation size, and outcomes with and without surgical intervention. Patients with either infantile XT or early X(T) may spontaneously resolve over time. PMID- 28904214 TI - After Nerve Injury, Lineage Tracing Shows That Myelin and Remak Schwann Cells Elongate Extensively and Branch to Form Repair Schwann Cells, Which Shorten Radically on Remyelination. AB - There is consensus that, distal to peripheral nerve injury, myelin and Remak cells reorganize to form cellular columns, Bungner's bands, which are indispensable for regeneration. However, knowledge of the structure of these regeneration tracks has not advanced for decades and the structure of the cells that form them, denervated or repair Schwann cells, remains obscure. Furthermore, the origin of these cells from myelin and Remak cells and their ability to give rise to myelin cells after regeneration has not been demonstrated directly, although these conversions are believed to be central to nerve repair. Using genetic lineage-tracing and scanning-block face electron microscopy, we show that injury of sciatic nerves from mice of either sex triggers extensive and unexpected Schwann cell elongation and branching to form long, parallel processes. Repair cells are 2- to 3-fold longer than myelin and Remak cells and 7 to 10-fold longer than immature Schwann cells. Remarkably, when repair cells transit back to myelinating cells, they shorten ~7-fold to generate the typically short internodes of regenerated nerves. The present experiments define novel morphological transitions in injured nerves and show that repair Schwann cells have a cell-type-specific structure that differentiates them from other cells in the Schwann cell lineage. They also provide the first direct evidence using genetic lineage tracing for two basic assumptions in Schwann cell biology: that myelin and Remak cells generate the elongated cells that build Bungner bands in injured nerves and that such cells can transform to myelin cells after regeneration.SIGNIFICANCE STATEMENT After injury to peripheral nerves, the myelin and Remak Schwann cells distal to the injury site reorganize and modify their properties to form cells that support the survival of injured neurons, promote axon growth, remove myelin-associated growth inhibitors, and guide regenerating axons to their targets. We show that the generation of these repair-supportive Schwann cells involves an extensive cellular elongation and branching, often to form long, parallel processes. This generates a distinctive repair cell morphology that is favorable for the formation of the regeneration tracks that are essential for nerve repair. Remyelination, conversely, involves a striking cell shortening to form the typical short myelin cells of regenerated nerves. We also provide evidence for direct lineage relationships between: (1) repair cells and myelin and Remak cells of uninjured nerves and (2) remyelinating cells in regenerated nerves. PMID- 28904216 TI - Anterior Segment Optical Coherence Tomography of Previously Operated Extraocular Muscles. AB - BACKGROUND AND PURPOSE: To assess the possibility of determining the insertion distance from the limbus of previously operated extraocular rectus muscles (EOM) with the Heidelberg Spectralis anterior segment optical coherence tomography (AS OCT). PATIENT AND METHOD: Subjects with a history of previous strabismus surgery underwent AS-OCT of the EOM before planned additional strabismus surgery. The EOM insertion distances from the limbus were measured pre-operatively on the AS-OCT and compared to the caliper distance measured during the strabismus surgery. RESULTS: Ten previously operated muscles on nine subjects underwent AS-OCT before subsequent additional strabismus surgery. Four additional un-operated muscles subsequently operated on, were also imaged with the AS-OCT pre-operatively. Subject ages ranged from 13-52 years old (mean +/- SD; 27.9 +/- 13.2). The muscle insertion could be definitely identified in 6/10 muscles previously operated and 4/4 un-operated muscles. The difference between the two measurements of limbus to insertion in previously operated muscles was <=1mm in 3/6, and <=1.5mm in 6/6; <1mm in 4/4 un-operated muscles. Of the four insertions not readily identifiable, two revealed the presence of the muscle with scar tissue; the other two, the muscle insertions, were not visible, which showed that the muscle was at least a minimal amount from the limbus. CONCLUSION: Our study showed that the Heidelberg AS-OCT is capable of imaging previously operated EOM, which can give valuable information to the strabismus surgeon. The information from the AS-OCT was useful in all cases. The insertion to limbus measurements between pre-operative and intra-operative were within 1.5mm in all of the cases that the muscle insertion was able to be identified. The ability to accurately image EOM insertions has significant implications for the pre-operative procedure planning in previously operated and complicated strabismus patients. PMID- 28904217 TI - Two Orthoptic Treatments in Dragged-Fovea Diplopia Syndrome. AB - BACKGROUND: "Dragged-fovea diplopia syndrome" is a type of central binocular diplopia that is secondary to a foveal displacement, caused by epiretinal membranes (ERMs) or other macular diseases. Its management is difficult, because prisms are not effective. CASE REPORTS: Two cases of dragged-fovea diplopia syndrome were presented. Both patients were affected with a unilateral epiretinal membrane. Therefore, the pathophysiology underlying their diplopia was the conflict between central and peripheral fusion mechanisms. CONCLUSIONS: Diplopia caused by ERM "shift" deserves a complex management. We suggest to be careful about subjective symptoms and to optimize the residual visual function to customize the orthoptic management. A strict cooperation between ophthalmologists and orthoptists could lead to a successful outcome. PMID- 28904218 TI - Early Onset Sixth-Nerve Palsy with Eccentric Fixation. AB - PURPOSE: To report four cases of early onset sixth-nerve palsy all of whom had eccentric fixation. METHODS: A retrospective case note review was undertaken of all cases presenting to the senior author's private and NHS practice with early onset sixth palsy between 2006 and 2012. As well as demographic information, details of ophthalmic, orthoptic, electrophysiological examinations, and radiological investigations that were extracted from the records. RESULTS: Four children with unilateral or asymmetric early onset sixth-nerve palsy were identified, of which three were congenital. All four had MRI and only one had a normal MRI. Age at presentation ranged from 14-42 months, but all four had marked esotropia and poor visual acuities in the worst affected eye with eccentric fixation, which became more easily or only noticeable after surgical correction. Three patients with congenital sixth-nerve palsy underwent vertical muscle transposition with Botulinum Toxin A (BTXA) to the ipsilateral medial rectus, and two of these patients also had Foster sutures to the transposed vertical muscles. The fourth patient had unilateral medial rectus recession and lateral rectus resection. The mean preoperative measurement was 55Delta ET (range 50-60Delta), and the mean postoperative measurement was 11Delta ET (range 16XT-25ET) at near, and 2Delta XT (range 15XT-14ET) at distance. CONCLUSIONS: We speculate that early onset paralytic strabismus due to congenital sixth-nerve palsy results in an inability to cross fixate which results in the development of eccentric fixation. Attempts to use reverse occlusion to negate the eccentric fixation failed. We therefore recommend early surgery for this condition to avoid this sequelae. PMID- 28904219 TI - Alfred Bielschowsky, 1871-1940: Ophthalmologist, Innovative Scientist, and Influential Teacher. PMID- 28904220 TI - Congenital Cranial Dysinnervation Disorders: A Literature Review. AB - Congenital cranial dysinnervation disorders (CCDD) is a new term describing a collection of non-progressive neurogenic syndromes. Initially referred to as congenital fibrosis syndrome, it was thought that the primary problem was extraocular muscular maldevelopment. Recent advancements in genetics and neuro radiology have now determined the initial observation of fibrotic muscles is secondary to a primary lack of innervation from deficient, absent, or misguided cranial nerves. This presentation provides an overview of the known genes and phenotypes currently recognized within the CCDD domain. It will also highlight areas of current research being done in the area of cranial nerve development. Increased knowledge and awareness of these disorders has resulted in more research being conducted. These studies have provided a more complete understanding of efferent motor system development and are leading to improved treatment strategies for patients. PMID- 28904221 TI - Editorial. PMID- 28904222 TI - Editorial. PMID- 28904223 TI - Editorial. PMID- 28904224 TI - Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. AB - Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease. PMID- 28904225 TI - Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. AB - Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln-/- and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln-/- mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders. PMID- 28904226 TI - Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. AB - In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3) blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naive T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naive T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response. PMID- 28904228 TI - Anesthesia-Related Outcomes for Endovascular Stroke Revascularization: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: There is currently controversy on the ideal anesthesia strategy during mechanical thrombectomy for acute ischemic stroke. We performed a systematic review and meta-analysis of studies comparing clinical and angiographic outcomes of patients undergoing general anesthesia (GA group) and those receiving either local anesthesia or conscious sedation (non-GA group). METHODS: A literature search on anesthesia and endovascular treatment of acute ischemic stroke was performed. Using random-effects meta-analysis, we evaluated the following outcomes: recanalization rate, good functional outcome at 90 days (modified Rankin Score<=2), symptomatic intracranial hemorrhage, death, vascular complications, respiratory complications, procedure time, and time to groin puncture. RESULTS: Twenty-two studies (3 randomized controlled trials and 19 observational studies), including 4716 patients (1819 GA and 2897 non-GA) were included. In the nonadjusted analysis, patients in the GA group had higher odds of death (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.66-2.45) and respiratory complications (OR, 1.70; 95% CI, 1.22-2.37) and lower odds of good functional outcome (OR, 0.58; 95% CI, 0.48-0.64) compared with the non-GA group. There was no difference in procedure time between the 2 primary comparison groups. When adjusting for baseline National Institutes of Health Stroke Scale, GA was still associated with lower odds of good functional outcome (OR, 0.59; 95% CI, 0.29-0.94). When considering studies performed in the stent retriever/aspiration era, there was no significant difference in good neurological outcome rates (OR, 0.84; 95% CI, 0.67-1.06). CONCLUSIONS: Acute ischemic stroke patients undergoing intra-arterial therapy may have worse outcomes when treated with GA as compared with conscious sedation/local anesthesia. However, major limitations of current evidence (ie, retrospective studies and selection bias) indicate a need for adequately powered, multicenter randomized controlled trials to answer this question. PMID- 28904227 TI - Peptide probes detect misfolded transthyretin oligomers in plasma of hereditary amyloidosis patients. AB - Increasing evidence supports the hypothesis that soluble misfolded protein assemblies contribute to the degeneration of postmitotic tissue in amyloid diseases. However, there is a dearth of reliable nonantibody-based probes for selectively detecting oligomeric aggregate structures circulating in plasma or deposited in tissues, making it difficult to scrutinize this hypothesis in patients. Hence, understanding the structure-proteotoxicity relationships driving amyloid diseases remains challenging, hampering the development of early diagnostic and novel treatment strategies. We report peptide-based probes that selectively label misfolded transthyretin (TTR) oligomers circulating in the plasma of TTR hereditary amyloidosis patients exhibiting a predominant neuropathic phenotype. These probes revealed that there are much fewer misfolded TTR oligomers in healthy controls, in asymptomatic carriers of mutations linked to amyloid polyneuropathy, and in patients with TTR-associated cardiomyopathies. The absence of misfolded TTR oligomers in the plasma of cardiomyopathy patients suggests that the tissue tropism observed in the TTR amyloidoses is structure based. Misfolded oligomers decrease in TTR amyloid polyneuropathy patients treated with disease-modifying therapies (tafamidis or liver transplant-mediated gene therapy). In a subset of TTR amyloid polyneuropathy patients, the probes also detected a circulating TTR fragment that disappeared after tafamidis treatment. Proteomic analysis of the isolated TTR oligomers revealed a specific patient-associated signature composed of proteins that likely associate with the circulating TTR oligomers. Quantification of plasma oligomer concentrations using peptide probes could become an early diagnostic strategy, a response-to-therapy biomarker, and a useful tool for understanding structure-proteotoxicity relationships in the TTR amyloidoses. PMID- 28904230 TI - Why Is It Worthwhile to Get Involved in Stroke Organizations? PMID- 28904229 TI - Eosinophil Cationic Protein, Carotid Plaque, and Incidence of Stroke. AB - BACKGROUND AND PURPOSE: ECP (eosinophil cationic protein) is a marker of eosinophil activity and degranulation, which has been linked to atherosclerosis and cardiovascular disease. We examined the relationship between ECP, carotid plaque, and incidence of stroke in a prospective population-based cohort. METHODS: The subjects participated in the Malmo Diet and Cancer Study between 1991 and 1994. A total of 4706 subjects with no history of stroke were included (40% men; mean age, 57.5 years). Carotid plaque was determined by B-mode ultrasound of the right carotid artery. Incidence of stroke was followed up during a mean period of 16.5 years in relation to plasma ECP levels. RESULTS: Subjects in the third tertile (versus first tertile) of ECP tended to have higher prevalence of carotid plaque (odds ratio: 1.18; 95% confidence interval: 1.003 1.39; P=0.044 after multivariate adjustments). A total of 258 subjects were diagnosed with ischemic stroke (IS) during follow-up. ECP was associated with increased incidence of IS after risk factor adjustment (hazard ratio, 1.57; 95% confidence interval: 1.13-2.18; for third versus first tertile; P=0.007). High ECP was associated with increased risk of IS in subjects with carotid plaque. The risk factor-adjusted hazard ratio for IS was 1.86 (95% confidence interval: 1.32 2.63) in subjects with carotid plaque and ECP in the top tertile, compared with those without plaque and ECP in the first or second tertiles. CONCLUSIONS: High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque. PMID- 28904231 TI - Interactions Between the Corticospinal Tract and Premotor-Motor Pathways for Residual Motor Output After Stroke. AB - BACKGROUND AND PURPOSE: Brain imaging has continuously enhanced our understanding how different brain networks contribute to motor recovery after stroke. However, the present models are still incomplete and do not fit for every patient. The interaction between the degree of damage of the corticospinal tract (CST) and of corticocortical motor connections, that is, the influence of the microstructural state of one connection on the importance of another has been largely neglected. METHODS: Applying diffusion-weighted imaging and probabilistic tractography, we investigated cross-network interactions between the integrity of ipsilesional CST and ipsilesional corticocortical motor pathways for variance in residual motor outcome in 53 patients with subacute stroke. RESULTS: The main finding was a significant interaction between the CST and corticocortical connections between the primary motor and ventral premotor cortex in relation to residual motor output. More specifically, the data indicate that the microstructural state of the connection primary motor-ventral premotor cortex plays only a role in patients with significant damage to the CST. In patients with slightly affected CST, this connection did not explain a relevant amount of variance in motor outcome. CONCLUSIONS: The present data show that patients with stroke with different degree of CST disruption differ in their dependency on structural premotor-motor connections for residual motor output. This finding might have important implications for future research on recovery prediction models and on responses to treatment strategies. PMID- 28904232 TI - Effects of High- Versus Moderate-Intensity Training on Neuroplasticity and Functional Recovery After Focal Ischemia. AB - BACKGROUND AND PURPOSE: This study was designed to compare the effects of high intensity interval training (HIT) and moderate-intensity aerobic training (MOD) on functional recovery and cerebral plasticity during the first 2 weeks after cerebral ischemia. METHODS: Rats were randomized as follows: control (n=15), SHAM (n=9), middle cerebral artery occlusion (n=13), middle cerebral artery occlusion at day 1 (n=7), MOD (n=13), and HIT (n=13). Incremental tests were performed at day 1 (D1) and 14 (D14) to identify the running speed associated with the lactate threshold (SLT) and the maximal speed (Smax). Functional tests were performed at D1, D7, and D14. Microglia form, cytokines, p75NTR (pan-neurotrophin receptor p75), potassium-chloride cotransporter type 2, and sodium-potassium-chloride cotransporter type 1 expression were made at D15. RESULTS: HIT was more effective to improve the endurance performance than MOD and induced a fast recovery of the impaired forelimb grip force. The ionized calcium binding adaptor molecule 1 (Iba 1)-positive cells with amoeboid form and the pro- and anti-inflammatory cytokine expression were lower in HIT group, mainly in the ipsilesional hemisphere. A p75NTR overexpression is observed on the ipsilesional side together with a restored sodium-potassium-chloride cotransporter type 1/potassium-chloride cotransporter type 2 ratio on the contralesional side. CONCLUSIONS: Low-volume HIT based on lactate threshold seems to be more effective after cerebral ischemia than work-matched MOD to improve aerobic fitness and grip strength and might promote cerebral plasticity. PMID- 28904233 TI - Hemorrhagic Transformation After Large Cerebral Infarction in Rats Pretreated With Dabigatran or Warfarin. AB - BACKGROUND AND PURPOSE: It is uncertain whether hemorrhagic transformation (HT) after large cerebral infarction is less frequent in dabigatran users than warfarin users. We compared the occurrence of HT after large cerebral infarction among rats pretreated with dabigatran, warfarin, or placebo. METHODS: This was a triple-blind, randomized, and placebo-controlled experiment. After treatment with warfarin (0.2 mg/kg), dabigatran (20 mg/kg), or saline for 7 days, Wistar rats were subjected to transient middle cerebral artery occlusion. As the primary outcome, HT was determined by gradient-recalled echo imaging. For the secondary outcome, intracranial hemorrhage was assessed via gradient-recalled echo imaging in surviving rats and via autopsy for dead rats. RESULTS: Of 62 rats, there were 33 deaths (53.2%, 17 technical reasons). Of the intention-to-treat population, 33 rats underwent brain imaging. HT was less frequent in the dabigatran group than the warfarin group (placebo 2/14 [14%], dabigatran 0/10 [0%], and warfarin 9/9 [100%]; dabigatran versus warfarin; P<0.001). In all 62 rats, compared with the placebo (2/14 [14.3%]), the incidence of intracranial hemorrhage was significantly higher in the warfarin group (19/29 [65.5%]; P=0.003), but not in the dabigatran group (6/19 [31.6%]; P=0.420). Mortality was significantly higher in the warfarin group than the dabigatran group (79.3% versus 47.4%; P=0.022), but not related to the hemorrhage frequency. CONCLUSIONS: The risk of HT after a large cerebral infarction was significantly increased in rats pretreated with warfarin than those with dabigatran. However, the results here may not have an exact clinical translation. PMID- 28904234 TI - Fibrin Clot Permeability as a Predictor of Stroke and Bleeding in Anticoagulated Patients With Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: Formation of denser fiber networks has been reported in atrial fibrillation and ischemic stroke. In this longitudinal cohort study, we evaluated whether fibrin clot density may predict thromboembolic and bleeding risk in patients with atrial fibrillation on vitamin K antagonists. METHODS: In 236 patients with atrial fibrillation receiving vitamin K antagonists treatment, we measured ex vivo plasma clot permeability (Ks), a measure of the pore size in fibrin networks. RESULTS: During a median follow-up of 4.3 (interquartile range, 3.7-4.8) years, annual rates of ischemic stroke or transient ischemic attack and major bleeds were 2.96% and 3.45%, respectively. In multivariate Cox regression analysis, patients with lower Ks (<6.8 cm2*10-9, median) had increased risk of ischemic stroke or transient ischemic attack (hazard ratio [HR], 6.55; 95% confidence interval [CI], 2.17-19.82) and major bleeds (HR, 10.65; 95% CI, 3.52 32.22). Patients with elevated Ks (>=6.8 cm2*10-9) had an increased rate of minor bleeding compared with the remainder (11.63% per year versus 3.55% per year; P<0.0001). The independent predictors of stroke or transient ischemic attack were low Ks (<6.8 cm2*10-9; HR, 7.24; 95% CI, 2.53-20.76), age (HR, 1.05; 95% CI, 1.01 1.10), and treatment with angiotensin-converting enzyme inhibitors (HR, 2.27; 95% CI, 1.08-4.77). Major bleeds were predicted by low Ks (<6.8 cm2*10-9; HR, 8.48; 95% CI, 2.99-24.1) and HAS-BLED score >=3 (HR, 2.22; 95% CI, 1.12-4.38). CONCLUSIONS: This study is the first to show that unfavorable fibrin properties reflected by formation of denser fibrin networks determine, in part, the efficacy and safety of anticoagulation with vitamin K antagonists in patients with atrial fibrillation. PMID- 28904235 TI - Response by Yoo et al to Letter Regarding Article, "Impact of Thrombus Length on Outcomes After Intra-Arterial Aspiration Thrombectomy in the THERAPY Trial". PMID- 28904236 TI - Letter by Li and Chen Regarding Article, "Impact of Thrombus Length on Outcomes After Intra-Arterial Aspiration Thrombectomy in the THERAPY Trial". PMID- 28904237 TI - Labetalol Use Is Associated With Increased In-Hospital Infection Compared With Nicardipine Use in Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Increased sympathetic tone causes hypertension after intracerebral hemorrhage, and blood pressure reduction has been studied as a way to decrease hemorrhage growth and improve outcomes. It is unknown if the antihypertensive used to achieve blood pressure goals influences either. Because sympatholytic drugs reduce death and infection in animal models, we hypothesized that labetalol would improve outcomes compared with nicardipine. METHODS: Prospective data from a single center were retrospectively reviewed. Patients receiving labetalol, nicardipine, or both during their first 3 days of hospitalization were included. Outcomes included in-hospital death; discharge modified Rankin Score >2; and in-hospital urinary tract infection, pneumonia, or bacteremia. Patients were compared with propensity scoring and analyzed with linear models adjusted for significant confounders. RESULTS: Of 1066 admissions, 525 were treated with labetalol or nicardipine and are included; 229 (43.6%) received labetalol, 107 (20.4%) received nicardipine, and 189 (36.0%) received both. Mortality and infection rates were 40.2% and 15.8%, respectively, 77.2% had a modified Rankin Score >2. After adjustment, compared with nicardipine alone, labetalol alone was associated with infection (odds ratio, 3.12; confidence interval, 1.27-7.64; P=0.013) but not when combined with nicardipine (odds ratio, 2.44; confidence interval, 0.98-6.07; P=0.055). Labetalol, with or without nicardipine, was not associated with death or discharge modified Rankin Score >2. CONCLUSIONS: Compared with nicardipine, labetalol was associated with increased in-hospital infections, but not mortality or modified Rankin Score >2. These findings do not support our hypothesis that labetalol use improves outcomes relative to nicardipine in intracerebral hemorrhage. PMID- 28904238 TI - gamma-Glutamyl Transferase as a Risk Factor for All-Cause or Cardiovascular Disease Mortality Among 5912 Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The aim of the study was to evaluate the association of the measurement of serum gamma-glutamyl transferase (GGT) concentrations at admission with 1-year all-cause or cardiovascular disease (CVD) mortality in patients with acute ischemic stroke. METHODS: This prospective, multicenter cohort study was conducted in 4 stroke centers in China. Baseline GGT measurements were tested. The relationship of GGT to the risk of death from all cause or CVD was examined among 1-year follow-up patients. RESULTS: We recorded results from 5912 patients with stroke. In those patients, 51.0% were men, and the median age was 61 years. In both men and women, high GGT was significantly associated with total mortality from all-cause or CVD (P<0.001). The elevated GGT revealed adjusted hazard ratios (95% confidence interval) of 3.03 (1.99-4.54) and 3.24 (2.14-4.92) for mortality from all-cause and CVD, respectively. With an area under the curve of 0.69 (95% confidence interval, 0.66-0.73), GGT showed a significantly greater discriminatory ability to predict all-cause mortality as compared with others factors. GGT improved the National Institutes of Health Stroke Scale score (area under the curve of the combined model, 0.75 [95% confidence interval, 0.73-0.78]; P<0.01). CONCLUSIONS: This study demonstrates that GGT is independently associated with all-cause and CVD mortality in patients with ischemic stroke. PMID- 28904239 TI - Stereotactic Catheter Ventriculocisternostomy for Clearance of Subarachnoid Hemorrhage: A Matched Cohort Study. AB - BACKGROUND AND PURPOSE: Delayed cerebral infarction (DCI) is a major source of morbidity and mortality after aneurysmal subarachnoid hemorrhage. We report a novel intervention-stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage therapy-for DCI prevention. Outcomes of 20 consecutive patients are compared with 60 matched controls. METHODS: On the basis of individual treatment decisions, STX-VCS was performed in 20 high-risk aneurysmal subarachnoid hemorrhage patients admitted to our department between September 2015 and October 2016. Three controls matched for age, sex, aneurysm treatment method, and admission Hunt and Hess grade were assigned to each case treated by STX-VCS. DCI was the primary outcome. Mortality and mRS at rehabilitation discharge were secondary outcome parameters. The association between STX-VCS and DCI, mortality, and mRS was assessed by conditional logistic regression. RESULTS: Stereotactic procedures were performed without surgical complications. Continuous cisternal lavage was feasible in 17 of 20 patients (85%). One adverse event because of cisternal lavage was without sequelae. DCI occurred in 25 of 60 (42%) controls and 3 of 20 (15%) patients with STX-VCS (odds ratio, 0.15; 95% confidence interval, 0.04-0.64). Mortality occurred in 20 of 60 (33%) controls and 1 of 20 (5%) patients with STX-VCS, respectively (odds ratio, 0.08; 95% confidence interval, 0.01 - 0.66). Favorable outcome (mRS<=3) at rehabilitation discharge was observed in 12 of 20 patients with STX-VCS (60%) versus 21 of 60 (35%) matched controls (odds ratio, 0.26; 95% confidence interval, 0.8-0.86). CONCLUSIONS: STX-VCS was feasible and safe in patients with severe aneurysmal subarachnoid hemorrhage. Initial results indicate that DCI and mortality can be reduced, and neurological outcome may be improved with this method. PMID- 28904241 TI - Autophagic responses compensate mitochondrial impairments. PMID- 28904243 TI - Solitary Fibrous Tumour A rare cause of acute abdomen. AB - : Solitary Fibrous Tumours(SFT), previously known as haemangiopericytoma, are rarely encountered in surgery. They arise from mesenchyme tissue and can occur at several sites in the body - head and neck, extremities, thorax, abdomen and retroperitoneal space. In the thorax, where they arise from the pleura, and abdomen they may attain a large size before giving rise to symptoms. Most SFT behave in a benign manner. However a number of them recur locally or metastasize. Recurrences can occur several years after excision of the primary tumour. Complete surgical excision remains the primary modality of treatment. But, in sites where complete excision is not possible, other modalities have been tried with varying success. Here, we describe a SFT of the mesentery of the small intestine, an uncommon manifestation of the tumour, recurring after a period of 19 years in a 55 year old female, and presenting to the Emergency Department as an acute abdomen caused by acute intestinal obstruction. Surgical excision of the tumour was performed together with primary anastomosis of the small intestine. KEY WORDS: Acute abdomen, Late recurrence, Mesentery, Solitary Fibrous tumour. PMID- 28904242 TI - The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons. AB - The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G quadruplexes could represent a new avenue for neurodegeneration and brain aging research. PMID- 28904244 TI - Tracheobronchopathia osteochondroplastica in recurrent retrosternal goiter. Surgical management. AB - : Tracheobronchopathia osteochondroplastica (TPO) is a rare pathology characterized by a progressive segmentary stenosis of the respiratory tract due to proliferation of osteocartilagineous nodules in the lumen of the distal part of the trachea and large bronchial trunks. Prognosis is usually benign, but some cases with an acute progression and a lethal outcome have been described. Clinical presentation is non specific, the chest x-ray is generally normal and there are not typical radiological signs of suspicion: diagnosis of TPO is usually incidental. We report a case of TPO associated with a retrosternal recurrent goiter. The CT scan conducted to evaluate the extension and the vascular relationships showed the characteristic lesions of the TPO with a segmental stenosis of the trachea greater than 70%. A bronchofiberoscopy confirmed the suspect of TPO. To date, the clinical studies carried out do not show a certain etiology, but all agree that chronic damage or chronic inflammations could be the cause of the onset of structural anomalies of the respiratory tract In literature, there is only a report which describes an association between TPO and thyroid pathology. It is obscure whatever these disease could be etiologically or fortuitously associated but a relationship cannot be completely excluded. Surgeons, anesthetists and radiologists which deal with thyroid pathology must recognize the disease, especially in the presence of bulky retrosternal goiters, to make a correct diagnosis and provide adequate perioperative management. KEY WORDS: Mediastinal goiter, Osteocartilagineous Nodules, Tracheal Stenosis, Total Thyroidectomy, Tracheobronchopathia Osteochondroplastica. PMID- 28904245 TI - Gallstone ileus in an ederly patient Case report. AB - AIM: To report an another case of gallstone ileus in ederly patient that was treated with simple enterolithotomy. MATERIAL OF STUDY: We report a case of 84 years old female that was admitted with intestinal obstruction. A CT scan suggested small bowel obstruction secondary to gallstone ileus. In relation to the overall clinical condition, we decided to perform a simple enterolithotomy. DISCUSSION: The first case of a cholecysto intestinal fistula with a gallstone within the gastro intestinal tract was described n 1654 by, Thomas Bartholin in a necropsy study. It constitutes the etiologic factor in less than 5% of cases of intestinal obstruction, but up to one quarter of nonstrangulated small bowel obstructions in elderly patients. CONCLUSION: In conclusion gallstone ileus is increasingly common, especially in the context of an aging population in developed helthcare system. It is an important differential diagnosis in ederly patients presenting with small bowel obstruction because it has a high mortality rate. KEY WORDS: Enterolithotomy, Gallstone ileus, Intestinal obstruction. PMID- 28904246 TI - Questions from and answers to a patient with groin hernia. AB - : Inguinal hernia surgical treatment are the most commonly performed operations in general surgery practice. There is a need for detailed anatomical knowledge and surgical skills to satisfactorily treat this disease. In this review, we aimed to present up-to-date information and approaches on basic diagnosis, treatment, complications and management of inguinal hernias in our institution. KEY WORDS: Chronic pain, Groin hernia, Inguinal hernia, Recurrence, Surgery. PMID- 28904247 TI - Efficacy and safety of subgroup analysis stratified by baseline HbA1c in a Japanese phase 3 study of dulaglutide 0.75 mg compared with insulin glargine in patients with type 2 diabetes. AB - The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) compared with once-daily insulin glargine (glargine) in Japanese patients with type 2 diabetes were evaluated according to subgroups stratified by baseline glycated hemoglobin (HbA1c) (<=8.5% or >8.5%). This exploratory analysis of a randomized, open-label, phase 3 study included 361 patients. In both HbA1c subgroups (patients with baseline HbA1c <=8.5% or >8.5%), a statistically significantly greater reduction in HbA1c was observed in dulaglutide-treated patients compared with glargine-treated patients after 26 weeks of treatment (HbA1c <=8.5%: dulaglutide, -1.27%; glargine, -0.72%; HbA1c >8.5%: dulaglutide, -2.04%; glargine, -1.47%; p < 0.001 for both). Mean body weight was decreased from baseline in both subgroups of the dulaglutide group and increased in both subgroups of the glargine group; there were statistically significant differences between the treatment groups in both subgroups (p < 0.05 for both). In both subgroups, similar reductions in fasting blood glucose were observed for dulaglutide- and glargine-treated patients, and a greater reduction in postprandial blood glucose was observed for dulaglutide-treated patients compared with glargine-treated patients. Although dulaglutide increased gastrointestinal adverse events compared with glargine in both subgroups, all gastrointestinal events of diarrhea, nausea, constipation, and vomiting in dulaglutide-treated patients were mild in intensity and well tolerated. In both subgroups, there was a lower incidence of hypoglycemia with dulaglutide than with glargine. Dulaglutide demonstrated significantly greater HbA1c reduction compared with glargine, with an acceptable safety profile, regardless of baseline HbA1c. PMID- 28904248 TI - [The System and Human Resources for Occupational Health in Republic Of Indonesia for Japanese Enterprises to Manage Proper Occupational Health Activities at Overseas Workplaces]. AB - OBJECTIVES: To consider the appropriate occupational health system for Japanese enterprises in Indonesia with information on the regulations and development of the specialists. METHODS: In this study, we used the information-gathering checklist developed by Kajiki et al. Along with literature and internet surveys, we surveyed local corporations owned and operated by Indonesians, central government agencies in charge of medical and health issues, a Japanese independent administrative agency supporting subsidiaries of overseas Japanese enterprises, and an educational institution formulating specialized occupational physician training curricula. RESULTS: In Indonesia, the Ministry of Manpower and the Ministry of Health administer occupational health matters. The act No. 1 on safety serves as the fundamental regulation. We confirmed at least 40 respective regulations in pertinent areas, such as the placement of medical and health professionals, health examinations, occupational disease, and occupational health service agencies. There are some regulations that indicate only an outline of activities but not details. Occupational physicians and safety officers are the two professional roles responsible for occupational health activities. A new medical insurance system was started in 2014, and a workers' compensation system was also established in 2017 in Indonesia according to the National Social Security System Act. DISCUSSION: Although safety and health laws and regulations exist in Indonesia, their details are unclear and the quality of expert human resources needed varies. To conduct high-quality occupational health activities from the standpoint of Japanese companies' headquarters, the active promotion of employing highly specialized professionals and cooperation with educational institutions is recommended. PMID- 28904249 TI - Relationship between Serum Uric Acid and Vascular Function and Structure Markers and Gender Difference in a Real-World Population of China-From Beijing Vascular Disease Patients Evaluation Study (BEST) Study. AB - AIM: The study was done to establish the relationship between serum uric acid (UA) and vascular function and structure parameters including carotid femoral pulse wave velocity (CF-PWV), carotid radial pulse wave velocity (CR-PWV), cardio ankle vascular index (CAVI), ankle brachial index (ABI), and carotid intima-media thickness (CIMT), and the gender difference in a real-world population from China. METHODS: A total of 979 subjects were enrolled (aged 60.86+/-11.03 years, male 416 and female 563). Value of UA was divided by 100 (UA/100) for analysis. RESULTS: Body mass index (BMI), diastolic blood pressure (DBP), fasting plasma glucose (FPG), UA, and UA/100 were significantly higher in males compared with females (all p<0.05); pulse pressure (PP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were lower in males than females (all p<0.05). All vascular parameters including CF-PWV, CR-PWV, CAVI, ABI, and CIMT were higher in males than females (all p<0.05). Multiple linear regression analysis showed that UA/100 was independently positively linearly correlated with CAVI (B=0.143, p=0.001) and negatively correlated with ABI in the male population (B=-0.012, p=0.020). In people with higher UA, the risk of higher CF-PWV was 1.593 (p<0.05). CONCLUSIONS: 1. All vascular parameters were higher in males than females. There was no gender difference in the relationship between UA and vascular markers except in ABI. 2. UA was independently linearly correlated with CAVI. 3. In people with higher UA level, the risk of higher CF-PWV increased. Therefore, higher UA may influence the vascular function mainly instead of vascular structure. PMID- 28904250 TI - Building a complete image of genome regulation in the model organism Escherichia coli. AB - The model organism, Escherichia coli, contains a total of more than 4,500 genes, but the total number of RNA polymerase (RNAP) core enzyme or the transcriptase is only about 2,000 molecules per genome. The regulatory targets of RNAP are, however, modulated by changing its promoter selectivity through two-steps of protein-protein interplay with 7 species of the sigma factor in the first step, and then 300 species of the transcription factor (TF) in the second step. Scientists working in the field of prokaryotic transcription in Japan have made considerable contributions to the elucidation of genetic frameworks and regulatory modes of the genome transcription in E. coli K-12. This review summarizes the findings by this group, first focusing on three sigma factors, the stationary-phase sigma RpoS, the heat-shock sigma RpoH, and the flagellar chemotaxis sigma RpoF, as examples. It also presents an overview of the current state of the systematic research being carried out to identify the regulatory functions of all TFs from a single and the same bacterium E. coli K-12, using the genomic SELEX and PS-TF screening systems. All these studies have been undertaken with the aim of understanding the genome regulation in E. coli K-12 as a whole. PMID- 28904251 TI - Effects of the deletion of hup genes encoding the uptake hydrogenase on the activity of hydrogen production in the purple photosynthetic bacterium Rubrivivax gelatinosus IL144. AB - The efficiency of hydrogen gas production by nitrogenase in bacteria has been improved by the inhibition of antagonistic activity by the uptake hydrogenase. In this study, a mutant lacking the gene coding for the uptake hydrogenase was generated from the photosynthetic beta-proteobacterium Rubrivivax gelatinosus IL144 to explore new ways of hydrogen gas production driven by light energy. The mutant cells produced 25-30% higher amounts of molecular hydrogen than the wild type cells under nitrogen-deficient conditions under light. Furthermore, by the addition of 5 mM glutamate, the photosynthetic growth rate was greatly enhanced, and the hydrogen gas production activity reached 41.1 (mmol/l) in the mutant. PMID- 28904252 TI - Functional comparison of methionine sulphoxide reductase A and B in Corynebacterium glutamicum. AB - Methionine sulphoxide reductases (Msr) are able to reduce methionine sulfoxide to methionine and protect bacteria against reactive oxygen species (ROS). Many organisms express both methionine sulphoxide reductase A (MsrA), specific for methionine-S-sulfoxide and methionine sulphoxide reductase B (MsrB), active against methionine-R-sulfoxide. Corynebacterium glutamicum expresses MsrA, the function of which has been well defined; however, the function of MsrB has not been studied. Whether MsrB and MsrA play an equally important role in the antioxidant process is also poorly understood. In this study, we identified MsrB encoded by ncgl1823 in C. glutamicum, investigated its function and made a comparison with MsrA. The msrB gene showed a slight effect on utilizing methionine sulfoxide (MetO) as the sole Met source; however, the survival rates showed no sensitivity to oxidants. MsrB showed catalytic activity using thioredoxin/thioredoxin reductase (Trx/TrxR) reducing system as electron donors, but independent from the mycoredoxin 1/mycothione reductase/mycothiol (Mrx1/Mtr/MSH) system. Therefore, MsrB plays a limited role in resisting oxidative stress and it could reduce MetO to Met by the Trx/TrxR reducing system, which is useful for expanding the understanding of the functions of Msr in this important industrial microbe. PMID- 28904254 TI - Psychological Distress among Individuals Whose Partners Have Cancer. AB - Cancer diagnosis influences both patients and their closest relatives. This cross sectional study examined psychological distress among individuals whose partners had cancer in a population-based sample. Participants in the survey were citizens residing in Ohsaki City, Miyagi, Japan. Spouse pairs were identified by information of participants' relationship to the householder and address provided by municipality, and we collected self-report information on cancer history and current pain (but not the cause of pain). Psychological distress was evaluated using the Kessler 6 scale (K6). We identified 29,410 potential participants (14,705 couples), of which 23,766 (11,690 men and 12,076 women) were included in the analyses. A total of 1,374 participants (581 male and 793 female participants) had partners with history of cancer. Logistic regression analyses revealed that these participants, regardless of sex, did not show significantly higher risk of psychological distress (K6 score >= 13). When stratifying the analysis by partners' current pain, men whose partners had cancer and pain showed greater odds of psychological distress (odds ratio = 1.5, p = 0.04), compared with men whose partners had no cancer and had pain. However, male subjects whose partners had cancer but no pain did not show greater odds of psychological distress compared with men whose partners had no cancer and no pain. By contrast, in women whose partners had cancer, psychological distress was not associated with pain status. In conclusion, men whose partners had cancer and pain have higher risk of psychological distress, and its screening to these individuals may reduce the risk. PMID- 28904255 TI - Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease. AB - BACKGROUND: The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment.Methods and Results:This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjogren's syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants. CONCLUSIONS: Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short- and long-term outcomes. PMID- 28904253 TI - Genetic Variants of RAMP2 and CLR are Associated with Stroke. AB - AIM: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions. METHODS: Using cross-sectional data from the Japan Multi Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis. RESULTS: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076-0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke. CONCLUSIONS: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human. PMID- 28904256 TI - Current Surgical Outcomes of Congenital Heart Surgery for Patients With Down Syndrome in Japan. AB - BACKGROUND: Current surgical outcomes of congenital heart surgery for patients with Down syndrome are unclear.Methods and Results:Of 29,087 operations between 2008 and 2012 registered in the Japan Congenital Cardiovascular Surgery Database (JCCVSD), 2,651 were carried out for patients with Down syndrome (9%). Of those, 5 major biventricular repair procedures [ventricular septal defect repair (n=752), atrioventricular septal defect repair (n=452), patent ductus arteriosus closure (n=184), atrial septal defect repair (n=167), tetralogy of Fallot (TOF) repair (n=108)], as well as 2 major single ventricular palliations [bidirectional Glenn (n=21) and Fontan operation (n=25)] were selected and their outcomes were compared. The 90-day and in-hospital mortality rates for all 5 major biventricular repair procedures and bidirectional Glenn were similarly low in patients with Down syndrome compared with patients without Down syndrome. On the other hand, mortality after Fontan operation in patients with Down syndrome was significantly higher than in patients without Down syndrome (42/1,558=2.7% vs. 3/25=12.0%, P=0.005). CONCLUSIONS: Although intensive management of pulmonary hypertension is essential, analysis of the JCCVSD revealed favorable early prognostic outcomes after 5 major biventricular procedures and bidirectional Glenn in patients with Down syndrome. Indication of the Fontan operation for patients with Down syndrome should be carefully decided. PMID- 28904257 TI - Prognostic Significance of Blood Urea Nitrogen in Acute Ischemic Stroke. AB - BACKGROUND: Prior studies have shown an association between high blood urea nitrogen (BUN) and an elevated risk of mortality in heart failure patients, but data on the prognostic significance of BUN and other markers of kidney function in acute ischemic stroke (AIS) patients are sparse.Methods and Results:A total of 3,355 AIS patients were enrolled from December 2013 to May 2014, across 22 hospitals. Admission BUN was divided into quartiles (Q1, <4.39 mmol/L; Q2, >=4.39 and <5.40 mmol/L; Q3, >=5.40 and <6.70 mmol/L and Q4, >=6.70 mmol/L) and estimated glomerular filtration rate (eGFR), creatinine (Cr) and BUN/Cr were also categorized. Cox proportional hazard and logistic regression models were used to estimate the effect of BUN, eGFR, Cr and BUN/Cr on all-cause in-hospital mortality and poor outcome on discharge (modified Rankin Scale score >=3) in AIS patients. During hospitalization, 120 patients (3.6%) died from all causes and 1,287 (38.4%) had poor outcome at discharge. BUN was independently associated with all-cause in-hospital mortality (adjusted HR for Q4 vs. Q1, 3.75; 95% CI: 1.53-9.21; P-trend=0.003) but not poor outcome at discharge (P-trend=0.229). No significant association was found, however, between reduced eGFR, increased Cr and BUN/Cr and all-cause in-hospital mortality and poor outcome at discharge (all P-trend >=0.169). CONCLUSIONS: Increased BUN at admission is a significant prognostic factor associated with in-hospital mortality in AIS patients, but not with poor discharge outcome. PMID- 28904258 TI - Prevalence of work-related musculoskeletal disorders among sonographers in China: results from a national web-based survey. AB - OBJECTIVES: The aims of present study were to determine the prevalence of work related musculoskeletal disorders (WRMSDs) among sonographers in China and to provide evidence for appropriate intervention measures to be taken. METHODS: A self-reported questionnaire was used to screen WRMSDs experienced by sonographers during the past 12 months. This questionnaire survey was created and hosted on the WeChat official account platform for sonographers. RESULTS: In the present study, 567 sonographers from 521 medical institutions completed the questionnaire. The vast majority (99.3%) of respondents reported experiencing symptoms of WRMSDs for at least one body region during the past 12 months. Work related musculoskeletal pain or discomfort was most frequently reported for the neck (95.1%), right shoulder (84.1%), lower back (82.4%), right wrist/hand (81.0%), upper back (78.1%), right forearm/elbow (72.0%), and left shoulder (66.1%). Scanning hours per day, number of patients per day, and years of experience were positively associated with the occurrence and frequency of experiencing WRMSDs of some common and specific anatomical regions. Taking a regular rest break during the scanning working day was associated with a reduction of WRMSDs of the right shoulder and right wrist/hand. Adopting a sitting posture while performing scanning was associated with a reduction of WRMSDs, particularly for the lower back and the neck. Performing regular physical activity during leisure time was associated with a reduction of WRMSDs of the neck. CONCLUSIONS: The prevalence of WRMSDs among sonographers in China was extremely high. It is necessary and essential to reduce the number of scanning hours and patients per day, adopt a sitting posture while performing scanning, schedule regular rest breaks during the scanning working day, and encourage performance of regular physical activity during leisure time to alleviate this WRMSD issue experienced by sonographers. PMID- 28904259 TI - Prevalence and risk factors of needle stick and sharp injury among tertiary hospital workers, Vientiane, Lao PDR. AB - OBJECTIVES: Health care workers (HCWs) face risks of needle stick and sharp injuries (NSIs). Most NSIs occur in developing countries, however, no epidemiological study on NSIs is publicly available in Lao PDR. The objective of this study is to identify the prevalence and risk factors of NSIs among HCWs in Lao PDR. METHODS: This cross-sectional study was designed to determine the prevalence and risk factors of NSIs among four tertiary hospitals in Vientiane, Lao People's Democratic Republic. RESULTS: Six months before the survey, 11.4% (106/932) of hospital staff had experienced NSIs, while 42.1% did in their entire career. Key protective factors of NSIs among nurses included adequate availability of needles, syringes, and sharp equipment (p = 0.042; odds ratio [OR], 0.47) and attendance to educational or refresher courses on safety regarding NSIs (p = 0.038; OR, 0.50). As an on-site practice, single-handed recapping was prevalent (46.7%, 257/550) among participants. CONCLUSIONS: The result showed that high rates of NSIs persist among HCWs. The findings of this research call for comprehensive health and injection safety programs for HCWs involved in clinical practice. PMID- 28904260 TI - Impaired beta-cell function and decreased insulin sensitivity in subjects with normal oral glucose tolerance but isolated high glycosylated hemoglobin. AB - The pathophysiology is distinct in various state of glucose metabolism abnormalities. As the defect of individuals with normal oral glucose tolerance (NGT) but isolated high glycosylated hemoglobin (HbA1c), i.e. iHH, was ambiguous, we aimed to investigate the insulin sensitivity and beta-cell function of iHH. According to the ADA criteria of HbA1c cut-off point (5.7%), 3,517 subjects with NGT screened from a total of 7,855 middle-aged and elderly Chinese without known diabetes were divided into two groups, 1,877 subjects with HbA1c < 5.7% and 1,640 with HbA1c >= 5.7% (i.e. iHH). A variety of indexes from blood glucose and insulin levels of oral glucose tolerance were calculated to evaluate insulin sensitivity and beta-cell function. Compared with subjects with HbA1c < 5.7%, individuals with iHH had increased homeostasis model assessment of insulin resistance (HOMA-IR), early-phase and total insulin release indexes (insulin release index 30 min and 120 min, i.e. INRS30 and INSR120), and decreased Matsuda insulin sensitivity index (Matsuda ISI) and early-phase disposition index (DI30). After adjustment for confounding factors, the significant difference of HOMA-IR and INSR30 between the two groups vanished, however, Matsuda ISI and DI30 remained significantly lower and INSR120 was still higher in iHH group compared with HbA1c < 5.7%. In conculsion, subjects with NGT may not be perfectly healthy in glycometabolism, those with iHH have impaired early-phase beta-cell function and decreased insulin sensitivity. PMID- 28904261 TI - Chemical immobilization of free-ranging and captive Sunda clouded leopards (Neofelis diardi) with two anesthetic protocols: medetomidine-ketamine and tiletamine-zolazepam. AB - There is currently no available information regarding the veterinary management of Sunda clouded leopards (Neofelis diardi), either in captivity or in the wild. In this study, 12 Sunda clouded leopards were anesthetized between January 2008 and February 2014 for medical exams, and/or GPS-collaring. Seven wild-caught individuals were kept in captivity and 5 free-ranging animals were captured by cage traps. Two anesthesia combinations were used: medetomidine-ketamine (M-K) or tiletamine-zolazepam (T-Z). Atipamezole (0.2 mg/kg im) was used as an antagonist for medetomidine. Medetomidine (range: 0.039-0.054 mg/kg) and ketamine (range: 3 4.39 mg/kg) were administered during 5 immobilizations, resulting in median induction times of 7 min. After a median anesthesia time of 56 min, atipamezole was injected, observing effects of antagonism at a median time of 12 min. T-Z (range: 6.8-10.8 mg/kg) was administered on 7 occasions. Median induction times observed with this combination were shorter than with M-K (4 min vs 7 min; P=0.04), and anesthesia and recovery times were significantly longer (244 and 35 min vs 56 and 16 min, respectively; P=0.02). Lower heart rates were measured in the M-K group, while lower rectal temperatures were found in the T-Z group. Both combinations resulted in safe and reliable immobilizations, although given the favorable anesthesia and recovery times of M-K, we recommend this approach over T Z for the veterinary handling of Sunda clouded leopards. PMID- 28904263 TI - Concerning Increase in Antimicrobial Resistance in Shiga Toxin-Producing Escherichia coli Isolated from Young Animals during 1980-2016. AB - This study was conducted in order to assess the antimicrobial resistance patterns of E. coli isolated from young animals affected between 1980 and 2016. The selected isolates for this study (n=175) carried stx1/stx2 genes and the most prevalent type of pathogenic E. coli found belonged to serogroup O101, antigen (K99)-F41 positive. All STEC-positive isolates were tested for susceptibility to 11 antimicrobials. Multidrug resistance (MDR) increased from 11% during the 1980s to 40% between 2000 and 2016. Resistance to tetracycline and streptomycin was the most frequent co-resistance phenotype (37%). Co-resistance to tetracycline and sulfonamide was found in 21% of E. coli isolates, while the MDR pattern to tetracycline, sulfonamide, and streptomycin was observed in 12% of the strains tested. Only 8% of isolates were co-resistant to tetracycline, ampicillin, streptomycin, and sulfonamide. The most common resistance genes found were those encoding for tetracycline, sulphonamides, and streptomycin, with 54% (n=95) of the tested isolates containing at least one of the genes encoding tetracycline resistance. A total of 87% of E. coli that tested positive for tetracycline (tetA, tetB, and tetC) and sulphonamide (sul1) resistance genes were isolated between 2000 and 2016. A large number of isolates (n=21) carried int1 and a nucleotide sequence analysis revealed that all class 1 integron gene cassettes carried sul1, tet, and dfrA1 resistance genes. An increase was observed in the level of resistance to antimicrobials in Romania, highlighting the urgent need for a surveillance and prevention system for antimicrobial resistance in livestock in Eastern Europe. PMID- 28904262 TI - Biodegradation of Volatile Organic Compounds and Their Effects on Biodegradability under Co-Existing Conditions. AB - Volatile organic compounds (VOCs) are major pollutants that are found in contaminated sites, particularly in developed countries such as Japan. Various microorganisms that degrade individual VOCs have been reported, and genomic information related to their phylogenetic classification and VOC-degrading enzymes is available. However, the biodegradation of multiple VOCs remains a challenging issue. Practical sites, such as chemical factories, research facilities, and illegal dumping sites, are often contaminated with multiple VOCs. In order to investigate the potential of biodegrading multiple VOCs, we initially reviewed the biodegradation of individual VOCs. VOCs include chlorinated ethenes (tetrachloroethene, trichloroethene, dichloroethene, and vinyl chloride), BTEX (benzene, toluene, ethylbenzene, and xylene), and chlorinated methanes (carbon tetrachloride, chloroform, and dichloromethane). We also summarized essential information on the biodegradation of each kind of VOC under aerobic and anaerobic conditions, together with the microorganisms that are involved in VOC-degrading pathways. Interactions among multiple VOCs were then discussed based on concrete examples. Under conditions in which multiple VOCs co-exist, the biodegradation of a VOC may be constrained, enhanced, and/or unaffected by other compounds. Co metabolism may enhance the degradation of other VOCs. In contrast, constraints are imposed by the toxicity of co-existing VOCs and their by-products, catabolite repression, or competition between VOC-degrading enzymes. This review provides fundamental, but systematic information for designing strategies for the bioremediation of multiple VOCs, as well as information on the role of key microorganisms that degrade VOCs. PMID- 28904264 TI - Zoonotic Potential and Antibiotic Resistance of Escherichia coli in Neonatal Calves in Uruguay. AB - Escherichia coli is one of the main etiological agents of neonatal calf diarrhea (NCD). The objective of this study was to assess the presence of virulence genes, genetic diversity, and antibiotic resistance mechanisms in E. coli associated with NCD in Uruguay. PCR was used to assess the presence of intimin, Shiga-like toxin, and stable and labile enterotoxin genes. Resistance to fluoroquinolones and oxyimino-cephalosporins was estimated on Muller-Hinton agar plates. Further antibiotic disc-diffusion tests were performed to assess bacterial multi resistance. The presence of PMQR, ESBL, MCR-1, and integron genes was evaluated. Isolates were typed using ERIC-PCR, and 20 were selected for MLST, adhesion to Hep-2 cells, in vitro biofilm formation, and eukaryotic cytotoxicity. The prevalence of ETEC genes was lower than 3% in each case (estA and elt). Six isolates were EPEC (eae+) and 2 were EHEC/STEC (eae+/stx1+). The results of a diversity analysis showed high genetic heterogenicity among isolates. Additionally, different sequence types, including ST10, ST21, and ST69, were assigned to selected isolates. Thirty-six percent (96/264) of the isolates were fluoroquinolone-resistant, with 61/96 (63.5%) being multidrug-resistant. Additionally, 6 were oxyimino-cephalosporin-resistant. The qnrB, qnrS1, and blaCTX-M-14 genes were detected, whereas no isolates carried the mcr-1 gene. Isolates had the ability to adhere to Hep-2 cells and form biofilms. Only 1 isolate expressed toxins in vitro. E. coli from NCD cases in Uruguay are very diverse, potentially virulent, and may interact with eukaryotic cells. Zoonotic potential, together with resistance traits and the presence of horizontal transfer mechanisms, may play a significant role in infections caused by these microorganisms. PMID- 28904265 TI - Changes in Gut Microbial Ecology and Immunological Responses of Mice Fed the Insoluble Fraction of Brassica rapa L. that was Fermented or Not. AB - We aimed to investigate the effects of feeding fermented Brassica rapa L. on ecological and immunological changes in the mouse gut using in vitro cultivation tests and in vivo experiments in normal mice. In the preliminary in vitro study, two B. rapa L. products from different fermentation periods (one d [SF] or six months [LF]) were evaluated along with non-fermented vegetables (NF). Among the components of each product, the insoluble fraction resulted in the most prominent change such as a relative increase in butyrate production during a cultivation inoculated with mouse cecum contents. Based on this result, the boiled water insoluble fractions of B. rapa L. (SF, LF, and NF samples) were selected as test materials for the subsequent in vivo experiment. Male C57BL/6J mice were divided into four groups and fed either a control diet (CON) or control diet plus one of the insoluble fractions for two weeks. The NF and LF groups had higher relative populations of Faecalibacterium prausnitzii than the CON group. Therefore, colonic butyrate concentrations were higher in the NF and LF groups than in the CON group. The oral administration of B. rapa L. extract induced immune regulatory effects, even when mice were fed NF and SF, but not LF, as assessed by an increase in regulatory T cell numbers. Our results indicate that feeding a purified insoluble fraction from B. rapa L. affects enteric short-chain fatty acid production and immunological responses in the mouse gut in a similar manner, regardless of the fermentation status. PMID- 28904266 TI - Clinical Impact of Main Pulmonary Artery Dilatation on Outcome in Pediatric Idiopathic and Heritable Pulmonary Arterial Hypertension. AB - BACKGROUND: Few studies have investigated the clinical impact of pulmonary artery (PA) dilatation on outcomes in pediatric pulmonary arterial hypertension (PAH).Methods and Results:This study investigated the clinical outcomes of idiopathic or heritable PAH in 66 children aged <18 years at diagnosis. Main PA/thorax (MPA/T) ratio was measured on chest radiography in PAH patients. Patients were divided into 2 groups based on MPA/T ratio, and compared with a control group of 166 age- and gender-matched healthy children. Group A had higher MPA/T ratio than normal, and group B had normal MPA/T ratio. Composite outcomes included cardiac death, lung transplantation, and hospitalization due to heart failure. Group A consisted of 27 patients and group B, 39 patients. At diagnosis, group A had significantly higher brain natriuretic peptide (BNP), cardiothoracic ratio, PA pressure, and pulmonary vascular resistance index compared with group B. The number of patients with New York Heart Association (NYHA) functional class III and IV was significantly higher in group A than in group B. Cumulative event free survival rate was significantly lower in group A. CONCLUSIONS: MPA dilatation correlated with BNP, NYHA functional class, and hemodynamics with regard to disease severity, and may be a potential prognostic factor in pediatric idiopathic and heritable PAH. PMID- 28904267 TI - Trends in Hospitalizations for Cardiac Sarcoidosis in the United States, 2005 2011. AB - BACKGROUND: Cardiac sarcoidosis (CS) is a life-threatening disease that is frequently under-diagnosed.Methods and Results:We used a nationwide inpatient sample to identify CS patients from 2005 to 2011 in the USA. The annual admissions of CS increased from 1,108 in 2005 to 2,182 in 2011, representing a 2 fold rise over a short time. The proportions of CS patients with severe comorbidities, ventricular tachycardia, ventricular fibrillation and heart failure all increased from 2005 to 2011. However, the in-hospital mortality rate declined. CONCLUSIONS: An increasing trend of CS was observed. Cardiologists should notice that CS is not as rare as thought. PMID- 28904269 TI - The Effectiveness of Specific Risk Mitigation Techniques Used in the Production and Handling of Manufactured Nanomaterials: A Systematic Review. AB - Many kinds of manufactured nanomaterials (MNMs) have been developed and used as basic materials of industrial products, and they may pose health risks for workers in not only developed countries but also in developing countries. Few studies have looked at the evidence for effects of controls that mitigate the risk of exposure to MNMs. Therefore, we systematically searched the literature from the year 2000 to 2015. We included studies that compared the use of an exposure control to the situation without such a technique and those that measured the exposure to MNMs as the outcome. In order to evaluate the effectiveness of these controls, we used their "protection factor", defined as the ratio between concentrations without and with the control. We located 1,131 references in PubMed and other lists, and out of these references, 41 studies fulfilled our inclusion criteria. We categorized them as engineering controls such as enclosure, local exhaust ventilation or process automation, and as personal protective equipment (PPE). For enclosure systems we found a protection factor beyond 100. For other engineering controls, the better controls scored 10 to 20, but many cases of local exhaust ventilation had a protection factor of less than 10 and some cases even increased exposure. PPE such as N95 or equivalent filtering respirators had a protection factor of approximately 10 tested with nano-sized aerosols. We conclude that there is low quality evidence that specific engineering controls can reduce exposure to MNMs but that enclosure is considerably more effective. For respiratory protection the evidence is of very low quality due to the lack of field studies. This information can be used to decide about controls when exposure to MNMs exceeds proposed occupational exposure limits or when no toxicological information is available for a MNM. PMID- 28904270 TI - Comparison of Chemicals in Mainstream Smoke in Heat-not-burn Tobacco and Combustion Cigarettes. AB - Because of the health effects of secondhand smoke, the Japanese government is trying to establish an effective law for total avoidance of secondhand smoke in indoor environments for tobacco-free Tokyo Olympic and Paralympic games 2020, as requested by the International Olympic Committee (IOC) and the World Health Organization (WHO). Meanwhile, Philip Morris International has begun selling a new heat-not-burn tobacco, iQOS, which it claims is designed not to produce secondhand smoke. There is little scientific data, however, of the hazards and toxicity of iQOS. In this study, we evaluated several harmful compounds (nicotine, tar, carbon monoxide (CO) and tobacco-specific nitrosamines (TSNAs)) in the mainstream smoke and fillers of iQOS, and compared their concentrations with those from conventional combustion cigarettes. The concentrations of nicotine in tobacco fillers and the mainstream smoke of iQOS were almost the same as those of conventional combustion cigarettes, while the concentration of TSNAs was one fifth and CO was one hundredth of those of conventional combustion cigarettes. These toxic compounds are not completely removed from the mainstream smoke of iQOS, making it necessary to consider the health effects and regulation of iQOS. PMID- 28904271 TI - Frequent Oxygen Desaturation During Sleep on the Day of Bronchoscopy Evaluated by Continuous Pulse Oximeter Monitoring. AB - To perform a bronchoscopy safely, it is very important to make a risk assessment before and after the procedure. There have been no reports of hypoxemia during sleep on the day after a bronchoscopic examination; therefore, we evaluated the oxygen saturation status during sleep on the days before and after bronchoscopy. Thirty patients that underwent bronchoscopy were studied. Continuous pulse oximetry monitoring was performed on the day before bronchoscopy and the day when the bronchoscopy was performed. The average oxygen saturation levels and the oxygen desaturation index (ODI) were evaluated. There was a significant increase (P < 0.05) in the ODI-3% during sleep on the day of the bronchoscopy compared to the day before the bronchoscopy. Clinicians should pay careful attention to hypoxia not only during bronchoscopy, but also during sleep on the night following the procedure. PMID- 28904272 TI - The Reliability and Validity of the Japanese Version of the Stroke Impact Scale Version 3.0. AB - It is important to evaluate body functions and structures, activity, and participation in stroke rehabilitation. The Stroke Impact Scale (SIS), a new stroke-specific self-report measure that was developed by Duncan et al, is widely used to measure multidimensional consequences about health-related quality of life. The SIS version 3.0 includes 9 domains (strength, hand function, activity of daily living and instrumental activity of daily living, mobility, communication, emotion, memory and thinking, participation, and recovery). Patients are asked to make a percentage rating of their recovery since their stroke on a visual analog scale of 0 to 100 for the stroke recovery domain. Each item in the 8 domains other than stroke recovery are scored in a range of 1 to 5 as a raw score and calculated using the manual to a final score. We developed a Japanese version of the SIS version 3.0 and assessed its reliability and validity in 32 chronic stroke survivors. The internal consistency (Cronbach's alpha < 0.70) was satisfactory. The test-retest reliability (ICC, 0.86 to 0.96) was also satisfactory. Regarding convergent validity, a significant correlation (Spearman's correlation coefficient, P < 0.05) was found between the SIS physical domain score and Brunnstrom stage (r, 0.49 to 0.53) and short form 8 (r = 0.82). The Japanese version of the SIS version 3.0 is valid, reliable, and clinically useful for stroke survivors. PMID- 28904273 TI - A Review of 7 Cases of Laparoscopic Cholecystectomy for Pediatric Cholecystolithiasis. AB - Pediatric cholecystolithiasis is a relatively rare disease, but it is recently increasing in Japan. Laparoscopic cholecystectomy (LC) is a standard procedure for cholecystolithiasis not only in adults but also in children, and we are aggressively introducing single-incision laparoscopic cholecystectomy (SILC) at our hospital. We reviewed the patient characteristics, operation procedures and outcomes of 7 children (15 years old and under) with cholecystolithiasis who underwent LC in our hospital between August 1995 and December 2015. The 7 patients included 5 males and 2 females, with a mean age of 8 years 6 months. Underlying diseases were found in 5 patients (cerebral palsy in 2 patients, pancreaticobiliary maljunction with common bile duct stones in 1, acute lymphocytic leukemia in 1, hereditary stomatocytosis in 1), and none were found in the other 2. LC (3 conventional LC and 2 SILC) was performed in 5 of the patients. Laparoscopic choledocholithotomy was performed in 1 patient and laparoscopic splenectomy (LS) was performed in 1 patient at the same time. The mean operative time in all the cases of LC was 108 (70-140) minutes (conventional LC 113 (70-140) min, SILC 100 (90-100) min). Intraoperative cholangiography was performed in 4 cases and omitted in 3 cases. The only postoperative complication was a wound infection in 1 patient. The umbilical skin incision length in the SILC was 2.0 cm. We conclude that LC can be safely performed for children with cholecsytolithiasis, and that SILC is feasible and advantageous in terms of its improved cosmesis. PMID- 28904274 TI - Factors Relating to Self-Efficacy Among Psychiatric Nurses. AB - This study aimed to clarify the factors related to self-efficacy experienced by psychiatric nurses. Analysis of qualitative descriptive data from a free self description questionnaire administered to 16 psychiatric nurses working in psychiatric hospitals revealed 24 codes across the following 8 categories as factors that increase self-efficacy: A1. possibility of practical use in nursing, A2. nursing judgment, A3. improvement of psychiatric symptoms, A4. the patients presenting a positive attitude, A5. building a relationship of trust with the patients, A6. building a relationship of trust with other nurses, A7. work progressing according to plan and A8. team medical practice. Twenty-five codes across the following 10 categories were identified as factors that decrease self efficacy: B1. lack of communication, B2. uncertainty in caregiving, B3. recurrence of psychiatric symptoms, B4. feeling overpowered by a patient, B5. sense of being too busy to work adequately, B6. difficulty in bringing about self improvement, B7. sense of loss regarding one's role as a nurse, B8. lack of physical strength, B9. mechanical performance of nursing and B10. fluctuating view of nursing due to mistakes. These factors require intervention for psychiatric nurses' self-efficacy. PMID- 28904275 TI - Family-Centered Care in Neonatal Intensive Care Units: Combining Intensive Care and Family Support. AB - Advances in treatment in neonatal intensive care units (NICU) for preterm and sick newborns have improved the mortality rate of patients, but admission to the NICU may disrupt parent-infant interaction, with adverse consequences for infants and their families because of physical, psychological, and emotional separation. The concept of family centered care (FCC), in which family members are part of the care team and infants are close to the family, is important and has become popular in NICU. In 2013, we created a team called "Kodomo-Kazoku Mannaka" to promote FCC in Japan, and visited the NICU at Uppsala University Hospital in Sweden, which is internationally famous for FCC. Since this fruitful visit, we have been promoting FCC in Japan by exhibitions and presentations of the FCC ideas at academic conferences and using internet services. A questionnaire survey conducted in 2015 revealed that the importance and the benefits of FCC in NICU are recognized, although there are some barriers to FCC in each facility. It is hard to change facilities and social systems right away, but it is easier and more important to change people's minds. Our role is to spread the concept of FCC and to help each facility find its own way to adopt it. We will continue to make efforts encourage to promote FCC in Japan. PMID- 28904276 TI - A Case of Acromegaly in which a Pituitary Gland Tumor was Reduced Significantly by Administering Octreotide Long Acting Release (LAR) and Could Be Removed Surgically. AB - A 54-year-old woman was admitted to our hospital for detailed examination of acromegaly because she noticed bilateral hand and finger swelling at the age of 43 and plantar thickening, facial changes and unclear articulation at the age of 49. She had prominent brow ridges, mandibular protrusion, and enlargement of the hands, feet, nasal wings, lips and tongue. Her growth hormone (GH) level was 39.8 ng/ml, insulin-like growth factor-1 (IGF-1) level was 717 ng/ml, GH level was not suppressed (22.9 ng/ml) during a 75-g oral glucose tolerance test (OGTT). Radiography showed cauliflower-like enlargement of the distal phalanx of the fingers, thickening/enlargement of the plantar soft tissues, and increased antero posterior diameter of the sella turcica. Magnetic resonance imaging showed a mass (21*17 mm) growing towards the right suprasellar region and invading the cavernous sinus. She was diagnosed with acromegaly based on the characteristic physical findings, GH excess, high IGF-1, lack of GH suppression during the 75-g OGTT, and the presence of a pituitary tumor. She was started on octreotide long acting release (Oct-LAR) 20 mg/4w for tumor shrinkage. After three doses, her GH and IGF-1 levels decreased to 2.19 ng/ml (1.69 during the 75-g OGTT) and 205 ng/ml, respectively, meeting cure criteria for acromegaly. In this case, a decrease in GH and IGF-1 levels, tumor shrinkage, and resolution of cavernous sinus invasion allowed the patient to undergo surgery with curative intent (the first-line treatment for acromegaly) without postoperative complications. Thus, preoperative Oct-LAR administration has the potential to improve treatment outcomes of acromegaly. PMID- 28904277 TI - Announcement of the 35th Annual Meeting of the UOEH Association of Health Sciences and the 29th National Conference of the Research Association for the Promotion of Occupational Medicine. PMID- 28904278 TI - ALLERGIC CONJUNCTIVAL DISORDERS AND THE BARRIER FUNCTION OF CONJUNCTIVA, FOCUSING ON TEARS AND CALT. PMID- 28904279 TI - ENDOTYPES OF NEUTROPHILIC AIRWAY INFLAMMATION. PMID- 28904280 TI - FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS DUE TO INGESTION OF MIKAN (CITRUS UNSHIU). AB - A 12-year-old girl was referred to our hospital owing to repeated anaphylactic reactions induced by exercise after meals. Food-dependent exercise-induced anaphylaxis (FDEIAn) was suspected. However, sequential tests of typical foods, including egg, milk, soy, and wheat, in combination with exercise, were all negative.The results of the skin prick test (SPT) for Citrus unshiu and specific IgE test for orange and grapefruit were positive. Although no symptoms were noted after an exercise challenge combined with the ingestion of only Citrus unshiu, an anaphylactic reaction was induced by additional acetyl-salicylic acid. From these results, she was diagnosed with FDEIAn due to the ingestion of Citrus unshiu. Because the SPT results for other citrus fruits (including orange, grapefruit, lemon, yuzu, sudachi, ponkan, and iyokan) were all positive, it was suggested that these fruits demonstrate cross-reactivity with each other. Since the girl eliminated citrus fruits from her diet, she has not developed any anaphylactic symptoms. Citrus fruits are not known to cause FDEIAn, but the findings of this case suggest that it is necessary to recognize them as a causative allergen of FDEIAn. PMID- 28904281 TI - YKL-40. PMID- 28904282 TI - Autophagy. PMID- 28904283 TI - RELATION BETWEEN ADULT ASTHMA AND UNDERWEIGHT-NECESSITY TO REVEAL ITS MECHANISM. PMID- 28904284 TI - OBESITY AND ASTHMA IN CHILDHOOD. PMID- 28904285 TI - OBESITY AND ATOPIC DERMATITIS, ALLERGIC RHINITIS. PMID- 28904286 TI - THE BRIEF COMMENTARY ON GUIDELINES FOR THE MANAGEMENT OF ATOPIC DERMATITIS 2015 - FORCUSING ON THE BIOMARKER AND SKIN CARE. PMID- 28904287 TI - SKIN BARRIER AND EPIDERMAL DENDRITIC CELLS IN ATOPIC DERMATITIS. PMID- 28904288 TI - Alpha-PVP induces the rewarding effect via activating dopaminergic neuron. AB - A synthetic cathinone, 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP), was occasionally found in the "bath salt" type of designer drugs, as an active ingredient. It has been reported that drivers who consumed alpha-PVP were in an excited state and incapable of controlling their behavior, causing traffic accidents. Despite its acute excitatory effects, there is no information on the psychological dependency elicited by alpha-PVP use. The purpose of the present study was to clarify whether the reward pathway is activated with repeated doses of alpha-PVP in experimental animals. Treatment of male C57BL/6j mice with alpha PVP (25 mg/kg, i.p.), once a day, for 3 days significantly increased the conditioned place preference scores. Therefore, repeated doses of alpha-PVP were shown to induce palatability in mice. alpha-PVP increases extracellular dopamine levels in the nucleus accumbens shell immediately after administration. The number of cells immunopositive for phosphorylated cAMP-regulatory element binding protein (CREB) was significantly increased in the alpha-PVP-treated mice in our study. These results indicate that the administration of alpha-PVP activates the phosphorylation of CREB in the nucleus accumbens shell. Our results suggest that alpha-PVP stimulates the reward pathway by increasing the extracellular dopamine levels and CREB phosphorylation in the nucleus accumbens shell, eventually causing positive reinforcement in mice. PMID- 28904289 TI - Restoration of YAP activation rescues HL-1 cardiomyocytes from apoptotic death by ethanol. AB - We reported previously that when mouse atrium-derived HL-1 cardiomyocytes undergo apoptosis upon exposure to 2% ethanol, the cellular cytoskeleton is severely disrupted and the anti-apoptotic transcriptional co-activator Yes-associated protein (YAP) is inactivated. Consistent with our previous observations, the expression of connective tissue growth factor (CTGF), an anti-apoptotic growth factor and a target of YAP, decreases in a time-dependent manner during exposure to 2% ethanol. The restoration of YAP activation rescues the cells from apoptosis: both the retrovirus-mediated expression of constitutively active YAP and the stabilization of the actomyosin cytoskeleton by jasplakinolide prevent cell death. In contrast, YAP inhibitors have no effect on cell death, confirming the inactivation of YAP in ethanol-exposed cells. Thus, a decrease in actin tension and YAP inactivation should be crucially involved in the cytotoxicity of ethanol on HL-1 cardiomyocytes. PMID- 28904290 TI - Copper diethyldithiocarbamate as an inhibitor of tissue plasminogen activator synthesis in cultured human coronary endothelial cells. AB - Recent developments have shown that organic-inorganic hybrid molecules have the potential to provide useful tools for analyzing biological systems. In the case of fibrinolysis, which is the phenomenon whereby fibrin is degraded by plasmin that has been converted from plasminogen via tissue plasminogen activator (t-PA) secreted from vascular endothelial cells, we hypothesized that there may be organic-inorganic hybrid molecules that could be used to analyze the mechanisms by which endothelial fibrinolysis is regulated. In our present study, we found that a copper complex - copper diethyldithiocarbamate (Cu10) - reduces t-PA activity in a conditioned medium of cultured human coronary endothelial cells by inhibiting the t-PA synthesis without changing the synthesis of plasminogen activator inhibitor type 1, which is a t-PA inhibitor. Copper sulfate, the Cu10 ligand, and zinc/iron complexes with the same Cu10 ligand, did not exhibit such biological activity. These results indicate that Cu10 has the potential to provide a useful tool for finding alternative pathways that downregulate endothelial t-PA synthesis. PMID- 28904291 TI - Concentration-dependent roles of DMT1 and ZIP14 in cadmium absorption in Caco-2 cells. AB - Intestinal absorption of cadmium (Cd) is considered to be mediated mainly by the ferrous iron transporter DMT1, or the calcium transporter CaT1. The roles of zinc transporters such as ZIP8 and ZIP14 remain unclear, and the roles of these four transporters in the intestinal uptake of Cd under physiological conditions have not been compared. Here, we used a trans-well cell culture system to investigate the effects of the down-regulation of these four transporters on the uptake of Cd from the apical side of enterocytes. We used a Caco-2-kh cell line that can form tight junctions within a few days. The transfection of DMT1 siRNA significantly decreased the Cd uptake from the apical side at 5 MUM, but not at 0.1 or 1 MUM. The transfection of ZIP14 siRNA markedly decreased the Cd uptake at 0.1 and 1 MUM, but not at 5 MUM. The transfection of siRNA of CaT1 or ZIP8 did not alter the Cd uptake at any concentrations of Cd examined. These results suggest that DMT1 and ZIP14 play different roles in intestinal Cd absorption depending on the concentration of Cd. PMID- 28904292 TI - Development of a modified 3T3 Neutral Red Uptake Phototoxicity Test protocol for evaluation of poorly water-soluble substances. AB - The 3T3 neutral red uptake phototoxicity test (OECD TG432) is an alternative phototoxicity test method that is relatively easy and rapid to implement, with results obtainable in a short time, and is reported to have high reproducibility compared with in vivo assay methods. However, this method has been shown to be unsuitable for testing poorly water-soluble substances, which tend to separate out when mixed with the assay buffer solution. This causes difficulties in determining the dose dependency of substances and subsequent determination of the photoirritation factor because the ratio of cell viability, expressed as the half maximal inhibitory concentration (IC50) in the presence or absence of light, is not calculable. In this study, we investigated the optimum conditions for the evaluation of poorly water-soluble substances. In the conventional method, the final solvent concentration was 1% and the pre-incubation time was 60 min, but in the modified method, 10% and 5 min were used, respectively. Next, the results from the conventional method were compared with those of our modified method, which was found to be viable and comparable with the conventional method. Moreover, the false positive results frequently obtained with poorly water soluble substances in the conventional method were not evident with the modified method, thus confirming its usefulness for the evaluation of such substances. We therefore propose that the modified method can be used for the in vitro testing of poorly water-soluble substances in phototoxicity evaluations. PMID- 28904293 TI - Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes. AB - The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval. PMID- 28904294 TI - Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver. AB - It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Drug-induced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity. In this study, we examined whether chimeric mice can reveal species differences in DIPL. Changes in various phosphatidylcholine (PhC) molecules were investigated in the liver of chimeric mice after administering amiodarone, which induces phospholipidosis. Liquid chromatography-tandem mass spectrometry revealed that levels of PhCs tended to increase in the liver after administration of amiodarone. The liver of chimeric mice consists of human hepatocytes and residual mouse hepatocytes. We used imaging mass spectrometry (IMS) to evaluate the increase of PhCs in human and mouse hepatocytes after administration of amiodarone. IMS visualizes localization of endogenous and exogenous molecules in tissues. The IMS analysis suggested that the localized levels of several PhCs tended to be higher in the human hepatocytes than those in mouse hepatocytes, and PhC levels changed in response to amiodarone. Chimeric mice with a humanized liver will be useful to evaluate species differences in DIPL between mice and humans. PMID- 28904295 TI - Multidirectional analyses of hepatic chronotoxicity induced by cadmium in mice. AB - The expression levels or activities of biological defense factors can fluctuate daily following biological rhythms. We have focused on the relationship between injection timing and the degree of toxicity of cadmium (Cd) to promote the concept of "chronotoxicology," which introduces chronobiology to the field of toxicology. Our previous studies have clearly indicated that Cd may be subject to chronotoxicity. In this report, to confirm the character of the Cd-induced chronotoxicity, we performed multidirectional examinations. Male C57BL/6J mice that received a single intraperitoneal injection of CdCl2 at ZT6 showed drastic hepatic injury estimated by histopathological analyses, i.e., nuclear condensations, fatty degenerations, and hemorrhages, but showed no injury when injected at ZT18. This difference was supported by several biochemical analyses that were indicators of hepatic injury (levels of alanine aminotransferase, aspartate aminotransferase, and malondialdehyde). The chronotoxicity of Cd was also observed in multiple strains (ICR and Balb/c), in a different injection route (subcutaneous), and in multiple injections (5 injections). Based on these results, we propose that chronotoxicology may provide important information not only for toxicology but also for occupational health, i.e., the importance of injection timing for toxicity evaluation tests, the reproducibility of animal experiments, and the improvement in the quality of risk assessments for night shift workers who may be exposed to toxic substances at various times of the day. PMID- 28904296 TI - Developmental changes in drug-metabolizing enzyme expression during metamorphosis of Xenopus tropicalis. AB - A large number of chemicals are routinely detected in aquatic environments, and these chemicals may adversely affect aquatic organisms. Accurate risk assessment requires understanding drug-metabolizing systems in aquatic organisms because metabolism of these chemicals is a critical determinant of chemical bioaccumulation and related toxicity. In this study, we evaluated mRNA expression levels of nuclear receptors and drug-metabolizing enzymes as well as cytochrome P450 (CYP) activities in pro-metamorphic tadpoles, froglets, and adult frogs to determine how drug-metabolizing systems are altered at different life stages. We found that drug-metabolizing systems in tadpoles were entirely immature, and therefore, tadpoles appeared to be more susceptible to chemicals compared with metamorphosed frogs. On the other hand, cyp1a mRNA expression and CYP1A-like activity were higher in tadpoles. We found that thyroid hormone (TH), which increases during metamorphosis, induced CYP1A-like activity. Because endogenous TH concentration is significantly increased during metamorphosis, endogenous TH would induce CYP1A-like activity in tadpoles. PMID- 28904297 TI - Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats. AB - Urinary biomarkers have been used widely in preclinical toxicity studies to detect dysfunctions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on urinary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excretion levels of leucine aminopeptidase (LAP), gamma-glutamyl transpeptidase (gammaGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and beta2-microglobulin (beta2 MG), and lower excretion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, gammaGTP, N-acetyl-beta-D glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, beta2-MG and neutrophil gelatinase-associated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excretion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, gammaGTP, total protein, L-FABP, Cys-C, and beta2 MG, may closely relate to the endogenous testosterone. PMID- 28904298 TI - Usefulness of urinary biomarkers for nephrotoxicity in cynomolgus monkeys treated with gentamicin, cisplatin, and puromycin aminonucleoside. AB - The objective of this study was to investigate the availability of novel urinary biomarkers (BMs) such as total protein, albumin, beta2-microglobulin, clusterin, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL) for the detection of acute nephrotoxicity in cynomolgus monkeys. Animals (total 9 males/3 groups) were administered gentamicin (GM) subcutaneously at 40 mg/kg for 7 days, cisplatin (CDDP) intravenously at 3 mg/kg once and puromycin aminonucleoside (PAN) intravenously at 20 mg/kg for 7 days. Two-hr urine on Days 0, 3, and 6, and 16-hr urine and blood on Days 1, 4, and 7 were collected. Novel urinary BMs and conventional clinical pathology parameters were evaluated in parallel to histopathological and electron microscopic examinations on the kidneys at termination. Urinary BMs and enzymes increased earlier than serum creatinine and blood urea nitrogen, particularly in 2-hr urine after dosing on Day 0, urinary albumin was increased in all groups and urinary NGAL with the highest magnitude of change rate among urinary BMs was observed in the GM and CDDP groups. Degeneration/necrosis and hyaline droplet of renal tubule, cellular cast and dilatation of renal tubule, and hypertrophy of podocytes were observed in the GEN, CDDP, and PAN groups, respectively. These results showed that the increases of urinary BMs reflected the agent-specific renal damages and these urinary BMs could be useful for the detection of segment-specific nephrotoxicity. Urinary albumin and NGAL are the most useful BMs to estimate glomerular and distal tubular damages, respectively, as well as proximal tubular damage in cynomolgus monkeys. PMID- 28904299 TI - A cell-based assay using HepaRG cells for predicting drug-induced phospholipidosis. AB - The utility of HepaRG cells as an in vitro cell-based assay system for predicting drug-induced phospholipidosis (PLD) was investigated. In experiment 1, 10 PLD positive compounds and 11 PLD-negative compounds were selected. HepaRG cells were treated with each compound for 48 hr. In experiment 2, loratadine and desloratadine, a major metabolite of loratadine, were used to assess metabolic activation for PLD. HepaRG cells were treated with loratadine and desloratadine in the presence or absence of 500 MUM 1-aminobenzotriazole (ABT), a broad CYP inhibitor, for 48 hr. After treatment with compounds in experiments 1 and 2, the relative fluorescence intensity (RFI) was measured using LYSO-ID Red dye to assess the PLD induction. In experiment 1, our cell-based assay system using HepaRG cells exhibited 100% sensitivity and 100% specificity for predicting drug induced PLD. In experiment 2, loratadine increased the RFI in the PLD assay. However, the increase in the RFI was not observed in co-treatment with loratadine and ABT. In addition, desloratadine increased the RFI in the presence and absence of ABT. These results suggested that metabolic activation of loratadine may contribute to PLD in HepaRG cells. We newly demonstrated that HepaRG cells have a high ability for predicting drug-induced PLD. In addition, we newly showed that HepaRG cells may predict drug-induced PLD mediated by metabolic activation of loratadine. Thus, a cell-based assay system using HepaRG cells is a useful model for predicting drug-induced PLD. PMID- 28904300 TI - Hair mercury levels in relation to fish consumption among Vietnamese in Hanoi. AB - People are exposed to methylmercury (MeHg) mainly through fish consumption, which is increasing in Vietnam. However, little information is available on estimating the health risk of MeHg exposure through fish consumption in Vietnam. The present study examined the association between mercury (Hg) levels in hair and selenium (Se) levels in toenails of 196 Vietnamese people and their fish consumption, using a dietary questionnaire to obtain information pertinent for assessing health risk owing to MeHg exposure. The geometric mean of Hg levels in the hair of males and females was 617 ng/g and 575 ng/g, respectively. We found that Hg levels in the hair of 98% of the Vietnamese study subjects were lower than the provisional tolerable weekly intake for MeHg (1.6 ug Hg/kg body weight; which is equivalent to a hair Hg concentration of approximately 2,300 ng/g, with an uncertainty factor of 6.4). There were significant differences in the age adjusted geometric mean of Hg levels found in hair from females related to their frequency of freshwater fish consumption. The levels of Hg in hair and Se in toenails increased with an increased frequency of marine fish consumption, and both showed a significant positive correlation in subjects who consumed marine fish >= once/week. This is the first cross-sectional study to investigate the association between hair Hg levels and fish consumption in Vietnam. These findings provide valuable information for future assessments of the health risk of MeHg exposure through fish consumption in Vietnam. PMID- 28904301 TI - A case of gastric lipoma resected by endoscopic submucosa dissection with difficulty in preoperative diagnosis. AB - A 66-year-old man was referred to our hospital with an increasing subepithelial lesion in the gastric antrum. Using esophagogastroduodenoscopy, a tumor with a steep, 20-mm-high rise protruding in the lumen was observed. The mucosal surface of the tumor was reddish, with ulcers forming at the base. Moreover, the tumor was mobile and soft. A biopsy specimen was taken from the ulcer, but tumor tissue was not collected from the submucosa. Endoscopic ultrasonography (EUS) showed a high echoic mass in the submucosa. However, because the mucosal surface of the ulceration was red, the mesenchymal tumor with internal bleeding was inferred to be lipoma. Additionally, because the tumor was small, flexible, and soft, collecting tumor tissue under EUS-guided fine-needle aspiration was inferred as difficult. We were unable to make a final diagnosis because the lesion showed a small tumor with atypical macroscopic morphology. Therefore, endoscopic submucosa dissection (ESD) was chosen for the diagnostic treatment. Sodium hyaluronate sufficient for separation from the muscular layer was injected into the submucosa. Then submucosal dissection was performed just above the muscle layer. Results demonstrate the possibility of removing the tumor reliably without perforation. Pathological evaluation of the ESD specimen indicated a diagnosis of gastric lipoma. PMID- 28904303 TI - Symposiums (S1-1 - S4-6). PMID- 28904302 TI - The incidence and severity of IgA vasculitis with nephritis over a 10-year period in our hospital. AB - BACKGROUND: To evaluate the recent frequency of onset and severity of IgA vasculitis with nephritis (IgAVN) in Fukushima Prefecture, we examined the epidemiology and clinico-pathological manifestations of IgAVN in our hospital over a 10-year period. METHODS: We enrolled 18 patients with IgAVN treated between 2004 and 2013 in the Department of Pediatrics, Fukushima Medical University School of Medicine. These patients were divided into two groups; Group 1 consisted of 12 patients with IgAVN hospitalized between 2004 and 2008 and Group 2 consisted of 6 patients with IgAVN hospitalized between 2009 and 2013. The epidemiology, clinical features, laboratory data, pathological findings, and outcome were retrospectively compared between the two groups. RESULTS: The numbers of patients with IgAVN per year in Group 2 were lower than that in Group 1. The frequency of patients with higher than grade IIIb disease in Group 2 (50%) was lower than that in Group 1 (94%); furthermore, the frequency of patients with higher than grade IV disease in Group 2 (0%) was lower than that in Group 1 (50%). CONCLUSIONS: Our findings suggest that the incidence of onset and severity of IgAVN in patients diagnosed between 2009 and 2013 were lower than those in patients diagnosed between 2004 and 2008. PMID- 28904304 TI - Workshops (PW-1 - WS10-7). PMID- 28904305 TI - General sessions (1A-01 - 3E-12). PMID- 28904306 TI - Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a single-institutional experience in Japan. AB - Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). To date, no studies on NIFTP have been reported in Japan. This study aimed to evaluate the clinical, cytological, and pathological findings of 54 cases of NIFTP from a single center in Japan, and compare them with those in the western countries. There were no significant differences in age, sex, or tumor size between patients with NIFTP and those with invasive encapsulated follicular variant -PTC. Ultrasound investigation showed a high suspicion lesion in 6.5% of NIFTP and 44.1% of invasive encapsulated follicular variant -PTC (p<0.001). On fine needle aspiration cytology, 75.7% of NIFTP cases were reported as suspicious for malignancy or malignant. Nuclear grooves and irregular-shaped nuclei were observed in 94.6% of cases of NIFTP. Pathologically, 27.8% cases of NIFTP and 13.0% cases of invasive encapsulated follicular variant PTC had been originally diagnosed as macrofollicular variants of PTC. There were no NIFTP cases with nodal metastasis. We concluded that NIFTP should be renounced noninvasive encapsulated follicular variant -PTC, and should be considered as a malignant tumor with exceeding indolent behavior, and lobectomy alone should be satisfactory for the diagnosis and treatment. PMID- 28904307 TI - Irisin is a biomarker for metabolic syndrome in prepubertal children. AB - The aim of the present study was to evaluate the association of irisin with obesity and metabolic syndrome (MetS) in Korean prepubertal children. A total of 96 children and adolescents aged 6 to 10 years (56 males) were included in this study. Subjects were divided into 3 groups: normal weight (n = 54), overweight (n = 16), and obese (n = 26). In the subgroup analyses, overweight/obese children were further divided based on their MetS status (with MetS vs. without MetS). Children with obesity tended to exhibit a lower mean irisin concentration compared to those with normal weight (p = 0.028). Using Pearson's correlation coefficient to compare all the children in the study, there was a significant inverse correlation between irisin and body mass index (BMI) standard deviation scores (SDS) (r = -0.210, p = 0.041), waist circumference SDS (r = -0.203, p = 0.049), and glucose (r = -0.296, p = 0.004). In the subgroup analyses of overweight/obese children, irisin exhibited a significant inverse correlation with glucose (r = -0.507, p = 0.001) and triglycerides (r = -0.331, p = 0.033). Children with MetS exhibited lower irisin concentrations than those without MetS (14.70 ng/mL vs. 22.02 ng/mL, p = 0.001), and these associations were significant after adjusting for age, gender, and BMI SDS (14.51 ng/mL vs. 22.06 ng/mL, p = 0.002). The irisin level of 15.43 ng/mL was determined to be a possible cutoff to distinguish children with metabolic syndrome from overweight/obese children, with a sensitivity of 75% and a specificity of 94% (p < 0.001). Our results suggest that decreased irisin levels may be associated with MetS in prepubertal children and that irisin might be a biomarker for MetS in prepubertal children. PMID- 28904308 TI - Aging Modulates the Substrate and Triggers Remodeling in Atrial Fibrillation. AB - Aging plays a critical role in the genesis of atrial fibrillation (AF) and also increases the risks of cardiac dysfunction and stroke in AF patients. AF is caused by increased AF triggering from abnormalities of the thoracic vein and/or modulated substrate (atrial) with enhancement of AF maintenance. Clinical and laboratory evidence indicates that aging is significant in the creation of atrial electrical and structural remodeling that leads to increased susceptibility to AF occurrence. Aging is commonly associated with cardiovascular comorbidities, oxidative stress, calcium dysregulation, atrial myopathy with apoptosis, and fibrosis, which all contribute to the genesis of AF. This review updates the current understanding of the effects of aging on the pathophysiology of AF. PMID- 28904309 TI - Evaluation of black spaces between maxillary central incisors by dentistry students and laypeople. AB - This study aimed to compare the perception of smile esthetics and alterations among dentistry degree students and laypeople to identify differences in the esthetic perception of black spaces between the maxillary central incisors among Turkish laypeople and students in different study years. Photographs altered to include black spaces of various sizes at the midline were evaluated by 208 dentistry students in years 1-5 and 45 Turkish laypeople. Perceptional differences in different photographs were statistically significant. The students in years 2-5 were more aware of differences between photographs than year 1 students and laypeople. The proportion of participants who decided the most attractive photograph as A was highest among 3rd year students, followed by 5th year students. However, the proportion of students agreeing on the least attractive image was highest among 4th year students, followed by 3rd year students. Photographs A and H were selected as the most and least attractive, respectively, by all participants. The esthetic perception of 1st and 2nd year dentistry students was very different from that of laypeople. To increase esthetic perception among dentistry students, specific lessons with clinical photography should be included in dental education. PMID- 28904310 TI - Efficacy of botulinum toxin therapy in treatment of myofascial pain. AB - The present study aimed to assess the efficacy of using botulinum toxin (BTX) in temporomandibular joint disorders, particularly pertaining to myofascial pain from masseter and temporal muscles. The study included 11 patients who were diagnosed with masseter and temporalis myofascial pain. Visual analog scale for pain and pressure algometry were conducted initially, after 1 month of conservative therapy (control group), and after 1 month of BTX type A injections (study group). Data were statistically analyzed (analysis of variance and Wilcoxon's test) to determine intergroup differences. Both conservative therapy and BTX injections showed reduction in pain scores and increase in pain threshold compared with baseline, and statistically significant differences were noted between both groups. Thus, BTX injections appear to be effective in management of chronic myofascial pain targeting masseter and temporalis muscles. PMID- 28904311 TI - Retrospective cohort clinical investigation of a dental implant with a narrow diameter and short length for the partial rehabilitation of extremely atrophic jaws. AB - We investigated the short-term clinical outcomes of narrow-diameter short-length implants for the fixed-prosthetic partial rehabilitation of extremely resorbed jaws. Twenty-three patients requiring partial rehabilitations with narrow platform short-length implants in any jaw were included in this study. In total, 30 implants 3.3 mm in diameter and 7 (n = 15 implants) or 8.5 (n = 15 implants) mm in length were inserted. The primary outcome measure was implant cumulative survival rate (CSR); the secondary outcome measures were marginal bone resorption at 1 and 3 years and the incidence of biologic and mechanical complications. Five patients (21.7%) with six implants (20%) were lost to follow-up. Two implants failed in two patients, yielding a CSR at 3 years of follow-up of 93.4%. The average (standard deviation) marginal bone resorption was 1.34 mm (0.95 mm) after the first year and 1.38 mm (0.78 mm) after the third year. Biologic complications occurred in three patients; mechanical complications occurred in three patients. Despite the limitations of the study, our findings show that the use of new narrow-diameter short-length implants for the rehabilitation of extremely atrophic regions is viable in the short-term, and can be considered a treatment alternative in extremely resorbed jaws. PMID- 28904312 TI - Adhesion of human periodontal ligament cells by three-dimensional culture to the sterilized root surface of extracted human teeth. AB - Residual periodontal ligament (PDL) and cement mass on the roots of extracted teeth are factors that considerably affect tooth transplantation. Therefore, when normal extracted teeth are used for autologous transplantation, it is necessary to regenerate the PDL of the root surface. Here we describe a method to examine human PDL cell adhesion on sterilized root surfaces. Sample teeth were extracted during orthodontic treatment. PDL cells were obtained from healthy periodontal tissue explants from teeth extracted for orthodontic reasons. We developed a method for adhering PDL cells to sterile root surfaces using three-dimensional culture for 3 weeks. We evaluated the adhesion of human PDL cells to the sterilized root surfaces biochemically and histologically. The adherent PDL cells presented new projections on the sterile root surfaces. Therefore, PDL cells can adhere to sterile root surfaces. PMID- 28904313 TI - Immune receptors CD40 and CD86 in oral keratinocytes and implications for oral lichen planus. AB - Lichen planus (LP) is a chronic T-cell-mediated mucocutaneous inflammatory disease that targets stratified epithelia, including those lining the oral cavity. The intraoral variant of LP (OLP) is associated with interferon (IFN) gamma production by infiltrating T lymphocytes; however, the role of epithelial cells in the etiopathogenesis OLP is not completely understood. There is however a growing body of evidence regarding the involvement of epithelial-derived cytokines, immune receptors, and costimulatory molecules in the pathobiological processes that promote and sustain OLP. In the present study, we used a reverse transcriptase-polymerase chain reaction assay to assess whether CD40-a receptor found mainly on antigen presenting cells-and the costimulatory molecule CD86 were expressed in oral keratinocytes (three strains of primary normal oral keratinocytes and the H357 cell line) in the presence or absence of IFN-gamma. To further characterize the involvement of CD40 in OLP, expression and distribution of receptor and ligand (CD40/CD154) in tissues from OLP were evaluated by immunohistochemistry. The present results are the first to show that both CD40 and CD86 are constitutively expressed at low levels in oral keratinocytes and that their expression was enhanced by IFN-gamma stimulation. The intensity of CD40 staining in OLP tissues was strong. Taken together, the results strongly suggest that CD40 and CD86 play a role in the pathophysiology of oral inflammatory diseases such as OLP. PMID- 28904314 TI - Effects of tannin-fluoride and milk-fluoride mixture on human enamel erosion from inappropriately chlorinated pool water. AB - This in vitro study aimed to investigate the efficacy of tannin-fluoride and milk fluoride mixtures on human enamel erosion after exposure to inappropriately chlorinated pool water. Enamel specimens were immersed in swimming pool water (pH 2.7) for 30 min and in each test reagent for 4 min once a day for 60 consecutive days (group I: control, group II: tannin-fluoride, group III: milk-fluoride, group IV: tannin-fluoride before and milk-fluoride after erosive challenge, and group V: milk containing tannin-fluoride before and after erosive exposure). Surface microhardness was assessed on days 0, 30, and 60. Scanning electron microscopy (SEM) and electron probe microanalysis (EPMA) were performed after treatment of samples for 60 days. Surface microhardness of experimental groups was ranked as follows: group III > group IV-group V > group II > group I (P < 0.05). Moreover, SEM images revealed deposition of substances on erosive enamel surface after treatment with tannin-fluoride and milk-fluoride mixtures. Furthermore, EPMA profiles showed decrease of phosphorus and increase of fluoride content in groups II and IV. In conclusion, we demonstrated that treatment with fluoridated milk with or without tannin-fluoride has protective effects against enamel erosion caused by low-pH swimming pool water. PMID- 28904315 TI - Microbiological assessment of effects of clinical mouth rinses on common oral microbes. AB - Dry mouth occurs frequently in aged individuals, as well as in patients who are hospitalized, receiving multiple drugs, undergoing radiation treatment to the head and neck, or wearing a removable denture prosthesis, use of mouth rinse being often an option for relief. In the present study, we performed microbiological assessments of subjects given three different commercially available mouth rinses commonly employed in clinical practice (Peptisal, Biotene, ConCool) to determine their effects. For bacterial clearance in vitro, Peptisal showed the highest level of suppression of oral indigenous bacteria found in both planktonic formations and biofilm. Furthermore, the inhibitory effects of these agents on biofilm formation on acrylic resin plates were examined using scanning electron microscopy. Again, Peptisal proved superior, because acquisition of resistance to antimicrobial peptides by a sensitive microbial strain was rarely observed. We conclude that Peptisal is an effective mouth rinse for clearance of planktonic and biofilm microorganisms present in the oral cavity. PMID- 28904316 TI - Assessment of local and systemic 25-hydroxy-vitamin D, RANKL, OPG, and TNF levels in patients with rheumatoid arthritis and periodontitis. AB - The present study aimed to evaluate proinflammatory cytokine and vitamin D levels in rheumatoid arthritis (RA) and chronic periodontitis (CP) patients and healthy individuals before and after initial periodontal treatment. Overall, 17 CP patients with RA (RA + CP), 18 systemically healthy CP patients (CP), and 18 healthy controls (C) were included. Clinical periodontal measurements were recorded and gingival crevicular fluid (GCF) and blood samples were recorded. RA + CP and CP patients received nonsurgical periodontal treatment. Vitamin D, tumor necrosis factor (TNF)-alpha, receptor activator of nuclear factor-KB ligand (RANKL), and OPG levels were determined in GCF and serum. Baseline clinical parameters were similar in all periodontitis groups (P > 0.05) but were higher than that in controls (P < 0.05). Periodontal treatment improved clinical parameters in all periodontitis groups (P < 0.05). GCF vitamin D levels were higher in RA + CP and CP groups than in healthy controls, but these levels decreased in the RA + CP group after periodontal treatment (P < 0.05). Serum RANKL and GCF TNF-alpha levels in RA patients decreased after periodontal treatment (P < 0.05). Within the limitations of this study, the results suggested that GCF vitamin D levels are increased in RA patients and decrease after periodontal treatment; therefore, local vitamin D levels might be an important indicator of periodontal bone loss. PMID- 28904317 TI - Notch signaling partly regulates the osteogenic differentiation of retinoic acid treated murine induced pluripotent stem cells. AB - Notch signaling is involved in osteogenic differentiation; however, its role differs depending on cell type and differentiation stage. Here, we investigated the involvement of Notch signaling in the osteogenic differentiation of retinoic acid-treated embryoid bodies derived from mouse gingival fibroblast-derived induced pluripotent stem cells (mGF-iPSCs). When cultured in osteogenic media, mGF-iPSCs showed an increase in their expression of osteogenic marker genes and deposited a mineralized matrix. Furthermore, increased levels of mRNA for Notch1, Notch2, and Hey1 were observed. In the presence of DAPT, a Notch signaling inhibitor, during osteogenic induction, mRNA levels for osteogenic marker genes were significantly decreased; however, no difference was noted in mineral deposition. Moreover, activation of Notch signaling using Jagged1-immobilized surfaces resulted in a slight increase of in vitro mineralization on days 3 and 7 of osteogenic induction. Significant upregulation of Dlx5, Bsp, and Col I mRNA expression was observed in mGF-iPSCs cultured on Jagged1 surfaces. In conclusion, inhibition and activation of Notch signaling was shown to decrease and increase mGF-iPSC osteogenic differentiation, respectively. However, the responses were not robust, suggesting the involvement of additional signaling pathways. PMID- 28904318 TI - CAY10591, a SIRT1 activator, suppresses cell growth, invasion, and migration in gingival epithelial carcinoma cells. AB - SIRT1 is a NAD-dependent histone deacetylase that is important in a wide variety of physiological and pathophysiological processes. Although many studies have examined the relationship between SIRT1 and cancer, the role of SIRT1 in tumor malignancy is controversial. Here, we examined the effects of the SIRT1 activator CAY10591 in gingival epithelial carcinoma Ca9-22 cells. CAY10591 treatment dose- and time-dependently increased SIRT1 level and activity. The treatment decreased cell growth and induced cell-cycle repressor p21 levels. In addition, dimethyl sulfoxide significantly reduced cellular invasion and migration, and CAY10591 enhanced this decrease. Quantitative PCR analysis showed that CAY10591 decreased expression of several invasion/migration promoter genes and induced repressor genes. Our findings suggest that CAY10591 suppresses cell growth and invasion/migration activity in gingival squamous cell carcinoma Ca9-22 cells. PMID- 28904319 TI - In vivo study of antifungal effects of low-molecular-weight chitosan against Candida albicans. AB - This study investigated the antifungal effects of low-molecular-weight chitosan solution on Candida albicans in denture stomatitis in comparison with nystatin suspension. This randomized, sing-leblind clinical trial included 40 patients diagnosed with denture stomatitis. Patients were divided into two groups, wherein one was treated with chitosan and the other with nystatin for 2 weeks. Changes in the erythematous area were recorded during and after treatment. A palatal smear was obtained for each patient before and after treatment to determine the number of blastospores and mycelia of C. albicans. The results were compared using the Mann-Whitney U test, revealing that the chitosan solution significantly decreased the erythematous surface area, burning sensation, time required for clinical improvement, and number of blastospores and mycelia. The antifungal efficacy of chitosan along with its inherent biocompatibility makes it a promising candidate for use as an antifungal mouthwash. PMID- 28904320 TI - Geometrical effects of conventional and digital prosthodontic planning wax-ups on lateral occlusal contact number, contact area, and steepness. AB - This study evaluated and compared the effect of conventional and digital wax-ups on three lateral occlusion variables: contact number, contact area, and steepness. Dental casts of 10 patients with Angle Class I relationship were included in the study. All patients required fixed prosthodontic treatment that would affect lateral occlusion. The casts of all patients received conventional and digital wax-ups. For pretreatment, conventional wax-up, and digital wax-up casts, contact number, contact area, and occlusion steepness were measured at four lateral positions, that is, at excursions of 0.5, 1.0, 2.0, and 3.0 mm from maximal intercuspation. Lateral occlusion scheme variables were affected by use of diagnostic wax-ups. For all types of casts, contact number decreased as excursion increased. The two types of wax-ups had similar contact number patterns, and contact number was significantly greater for these casts than for pretreatment casts in the earlier stages of excursion. Similarly, contact area gradually decreased with increasing excursion in the pretreatment and conventional and digital wax-up casts. There was only a minimal decrease in occlusion steepness as excursion increased. However, lateral occlusion was generally steeper for digital wax-up casts. PMID- 28904321 TI - Altered expression of mitochondrial antioxidants in oral squamous cell carcinoma. AB - Reactive oxygen species, if produced in excess by oxidative phosphorylation, contributes to mitochondrial DNA damage and progressive respiratory chain dysfunction, leading to various diseases including carcinogenesis. Mitochondria are susceptible to oxidative stress (OS) owing to lack of introns, protective histones, and DNA repair enzymes. However, mitochondria are protected from OS by numerous antioxidants such as superoxide dismutase 2 (SOD2), catalase, glutaredoxin 2 (GLRX2), reduced glutathione (GSH), glutathione peroxidase (GPX), and thioredoxin 2 (TXN2). To obtain insights regarding expression of these mitochondrial antioxidants in oral squamous cell carcinoma (OSCC), we performed qualitative and quantitative estimations of key molecular players of mitochondrial antioxidants during various stages of OSCC by immunoblotting with specific antibodies against antioxidant enzymes and/or biochemical assays. Different mitochondrial antioxidants varied in their expression levels as OSCC progressed. The levels of GPX1, GPX4, and catalase reduced with progression of OSCC. However, GLRX2, PXR3, TXN2, and reduced GSH gradually increased. Expression of SOD2 decreased initially in Stages II and III of OSCC but increased in Stage IV. In conclusion, our findings indicate a complex interplay of various mitochondrial antioxidants in different stages of OSCC, and further insights regarding these molecular players can help us better understand the pathogenesis of OSCC in context of mitochondrial redox status. PMID- 28904322 TI - A preliminary study of effects of low-intensity pulsed ultrasound (LIPUS) irradiation on dentoalveolar ankylosis. AB - The purpose of this experiment was to investigate whether low-intensity pulsed ultrasound (LIPUS) irradiation can inhibit dentoalveolar ankylosis in transplanted rat teeth. LIPUS irradiation (the pulsed ultrasound signal had a frequency of 3.0 MHz, a spatial average intensity of 30 mW/cm2, and a pulse ratio of 1:4) was performed on the face over the re-planted teeth of rats for 4 weeks. After the rats were euthanized, we measured mobility (Periotest value [PTV]) of the transplanted and control teeth using a Periotest. Finally, we performed histological evaluation to detect ankylosis. PTVs tended to be significantly lower for re-planted teeth than for control teeth. Histological evaluation revealed that the roots of all re-planted teeth were coalescent with alveolar bone. Furthermore, no ankylosis was observed in three-fifths of the re-planted teeth following LIPUS irradiation. These results indicate the potential efficacy of LIPUS to inhibit dentoalveolar ankylosis. PMID- 28904323 TI - Effects of bittern water on cariogenic bacteria and saliva secretion. AB - The effects of bittern water (BW), obtained from the ocean floor, on cariogenic bacteria and saliva secretion were examined. Streptococcus mutans was mixed with BW for 1, 3, 5, 10, and 20 min to explore the bactericidal effects of BW against cariogenic bacteria. Bacterial viability was calculated by counting the number of colony-forming units on Brain Heart Infusion agar plates. The results indicated a bacterial viability of more than 35% even after 20 min of incubation. Subsequently, the effects of BW on saliva secretion and the salivary concentration of secretory IgA (sIgA) were examined. Gargling with BW significantly augmented saliva secretion. Although the sIgA concentration was reduced, the total sIgA secreted into saliva was increased significantly. Our findings indicate that the use of BW may be a new strategy for the treatment of various oral diseases, including dry mouth. PMID- 28904324 TI - Management of developmental enamel defects in the primary dentition. AB - This study attempted to identify appropriate materials for restoration of enamel defects in the primary dentition, which were classified by severity and region with the modified developmental defects of enamel index. To identify the most appropriate materials, we used restorative materials to protect teeth and evaluated clinical outcomes of restoration. Three materials were used for restoration or repair after dislodgement of restorations. Our findings in this case suggest that, because of its durability and esthetic advantages, adhesive resin is beneficial for patients with enamel defects, particularly for restorations of less than two-thirds of the extent of the defect. PMID- 28904325 TI - New medical education reform in China: Towards healthy China 2030. AB - On July 11, 2017, the State Council of China issued a bold plan to revolutionize medical education and promote collaboration between medical education and practice. The cornerstone of the plan is training more qualified medical professionals to improve public healthcare on the path to Healthy China 2030. According to this plan, a "5+3" training system will be instituted to train medical professionals in China, and top medical colleges will be encouraged to recruit more students. However, given the less-than-ideal professional status of Chinese doctors, the frequent incidents of violence against them, long working hours and a heavy workload, and an unsatisfactory income, attracting personnel to work in medicine and health care has become a challenge. Prior to the end of 2016, there were 3.19 million practicing (assistant) physicians in China, amount to 2.31 per thousand population. The average workload of physicians was 7.3 outpatient visits per day and 2.6 beds per day, and these figures are much higher for physicians working in tertiary hospitals. Studies have found that 78% of physicians work more than 8 hours a day and 7% of physicians work more than 12 hours a day, but the average annual income of physicians in 2015 was 77,000 yuan (about $12,360), in contrast to an average annual income of $294,000 for physicians in the United States. Medical humanities education is also emphasized by the new medical education reform to foster the humanistic spirts of medical students in order to improve public healthcare in China. In the face of a mindset that "medical technology comes first" and growing expectations among the public, public education is needed to provide the public with a more comprehensive view by explaining the limitations of modern medicine since "medicine is not a panacea". Additional efforts should be undertaken by the Government, organizations, physicians, patients, and the public to create a virtuous cycle of healthcare in China. PMID- 28904326 TI - Intravenous polymyxins: Revival with puzzle. AB - With the increasing incidence of multi-drug resistant strains, especially carbapenem resistant strains, polymyxsins (mainly colistin and polymyxin B) based regimens seem to be a revival as an effective treatment of last resort in these infections. Evidence from 47 clinical trials or case series we reviewed showed that polymyxins based regimens are effective and have less toxicity compared with previous trials. When used alone, the mortality of intravenous polymyxsins ranged from 0% to 74.3%, clinical response (cure and improvement) rate was 7-82.1%, and microbiological eradication was 27.3-73.9%. The main reasons for the combination therapy are to get potential synergistic effects and to prevent the selection of heteroresistant strains. Several studies showed combination therapy seemed to be more effective than monotherapy, though a few doubts remain. Clinically, polymyxsins can be used in combination with several antibiotics, such as carberpenem, sulbactam, tigecycline, fosfomycin, glycopeptide, rifampicin and so on, but the optimal combination regimen is yet to be confirmed. The optimal dose of polymyxins is also controversial. With the limited clinical evidence, it's suggested loading dose regimens may be more effective, but more attention should be paid to adverse effects. Although recommended in some studies, high dose polymxins regimens with inconsistent clinical evidence need more trials to confirm. It is important to note that concerning dosing regimens, colistin and polymyxin B are not quite the same. In renal impaired patients polymyxin B should be prescribed without dosing adjustment. Risk of renal failure may increase in the following situations, such as the combination of intravenous colistin plus intravenous vancomycin, higher doses-colistin, and intravenous colistin combined with inhalational colistin. In conclusion, there're still controversies in combination regimens, dosing strategies and so on. Prospective trials of lager sample size are needed. PMID- 28904327 TI - The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. In this review, we made a review on current guidelines published from January 2001 to June 2017 worldwide with a focus on the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and the Japanese CiNii were systematically searched. A total of 18 characteristic guidelines for HCC management were finally included, including 8 guidelines from Asia, 5 from Europe, and 5 from the United States of America (USA). If guidelines were published in multiple versions, the most recent update was included, and surveillance, diagnosis, and treatment were compared. The composition of and recommendations in current guidelines on HCC varied, so these guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories of a "Size-based pathway" and a "Non-size-based pathway." The treatment criteria were divided into 4 categories: i) Criteria based on the Barcelona Clinic Liver Cancer staging system; ii) Criteria based on the modified Union of International Cancer Control staging system; iii) Criteria based on the Child-Pugh class of liver function; and iv) Criteria based on tumor resectability. Findings from comparison of current guidelines might help target and concentrate efforts to improve the clinical management of HCC. However, further studies are needed to improve the management and outcomes of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions in the treatment of HCC in the future. PMID- 28904328 TI - A narrative review of non-operative treatment, especially traditional Chinese medicine therapy, for lumbar intervertebral disc herniation. AB - Lumbar intervertebral disc herniation (LIDH), as the main contributor to low back pain and sciatica, imposes a heavy burden on both the individual and society. Non operative treatment or conservative treatment has proven effective in alleviation of the symptoms of LIDH and are considered to be a first-line choice for most cases. Active lifestyle, physical therapy, complementary and alternative medicine therapy or Traditional Chinese medicine (TCM) therapy, and pharmacotherapy are routinely used as effective non-operative treatment for LIDH patients. However, how to choose one or several conservative treatments with higher efficacy, less side effects, minimal injury, and low cost is still a challenge for doctors and LIDH patients. Furthermore, there are some national characteristics for some conservative treatments in different countries, which bring difficulties for the widespread use of these methods. Here we initiated a search on the non-operative treatment especially TCM therapy for LIDH mainly using PubMed, Web of Science, China National Knowledge Internet (CNKI), and Chinese biomedicine database since the 1980s with no restriction of language. According to these related references, we gave a narrative review which emphasizes up-to-date knowledge regarding the effectiveness and safety of various conservative methods with special consideration for TCM therapy including acupuncture, autonomy, Chinese massage, and Chinese herbal medicines, for LIDH treatment. We hope this review will further contribute to an understanding of conservative treatment as an important choice for LIDH patients and provide useful information for the development of more effective conservative methods for LIDH treatment. PMID- 28904329 TI - Latest advances in the efficacy, tolerability, and monotherapy of integrase inhibitors. AB - More than 30 drugs for antiretroviral therapy (ART), including integrase inhibitors (INIs), have been approved by the U.S. Food and Drug Administration (FDA) as of 2017. Integrase is the third essential enzyme in the cycle of human immunodeficiency virus (HIV) replication. INIs can effectively inhibit the replication of HIV and HIV is less prone to develop resistance to INIs clinically. Previous studies based on 7 phase III clinic trials indicate that INIs have satisfactory efficacy and tolerability in patients infected with HIV. The latest advances in INIs indicate that: i) dolutegravir (DTG)-based regimens are more efficacious, tolerable, and safer forms of first-, second-, and third Line ART; ii) current studies have indicated that DTG monotherapy fails both virologically and clinically; and iii) whether the most cost-effective treatment for DTG is to replace efavirenz (EFV) as a first-line ART, to replace protease inhibitors (PIs) in second-line ART, or to replace both as a monotherapy is unclear. Given these circumstances, further study of INIs in terms of drug interactions, dose reduction, drug convenience, and drug costs is warranted. PMID- 28904330 TI - Analysis of Mucosa-Associated Microbiota in Colorectal Cancer. AB - BACKGROUND The aim of this study was to compare the microbiota community structure, assess differences in intestinal bacterial types, and identify metagenomic biomarkers for disparate stages of colorectal cancer formation. MATERIAL AND METHODS A total of 160 individuals were recruited: 61 cases with non tumor colon were regarded as the normal group, 47 cases with histology substantiated colorectal adenomas were regarded as the adenoma group, and 52 cases with invasive adenocarcinomas were regarded as the cancer group. Biopsy on the mucosa was performed on each subject. USEARCH was used to process the sequences data and generate OTUs. Gut mucosal microbiota from healthy controls, adenoma patients, and carcinoma patients were analyzed. RESULTS Principal coordinate analysis of unweighted and weighted UniFrac distance showed a separation in composition of microbiota in the 3 groups. Bacteria with potential tumorigenesis, like Bacteroides fragilis and Fusobacterium, were more common in the carcinoma group, while some SCFA (short chain fatty acids) - producing microbes were enriched in the normal group. The commensal Escherichia were more abundant in adenoma patients. CONCLUSIONS Our study provides insights into possible function of gut microbiota in diagnosis and treatment of colorectal cancer. Some bacteria, such as Butyricicoccus, E. coli, and Fusobacterium, can be used as potential biomarkers for normal, adenoma, and cancer groups, respectively. PMID- 28904331 TI - Angiomyolipoma of the Adrenal Gland: A Report of Two Cases and Review of the Literature. AB - BACKGROUND Angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle cells, and adipose tissue and has been described as belonging to the group of tumors of perivascular epithelioid cell origin (PEComa), commonly found in the kidneys and strongly associated with tuberous sclerosis. Only a few cases of extra-renal angiomyolipoma have previously been reported in the literature, most commonly in the liver. Adrenal angiomyolipoma is very rare, is usually asymptomatic, and is often found incidentally, with only 14 previously reported cases identified in the literature. CASE REPORT We report two cases of adrenal angiomyolipoma that were identified by abdominal computed tomography (CT). The first case presented in a 36-year-old man and was an oval-shaped adrenal mass, measuring 5.2*4.2*3.1 cm. The second case presented in a 61-year-old woman and was a round-shaped mass measuring 8.6*9.5*8.1 cm. Both patients underwent adrenalectomy. Histopathology and immunohistochemistry confirmed the diagnosis of benign angiomyolipoma composed of adipose tissues, blood vessels, and smooth muscle cells. CONCLUSIONS We present two rare cases of adrenal angiomyolipoma. We have reviewed the literature and identified 14 other cases of adrenal angiomyolipoma, and discuss the clinical, radiological, and pathological features of this rare tumor. PMID- 28904332 TI - Identification of sites of 2'-O-methylation vulnerability in human ribosomal RNAs by systematic mapping. AB - Ribosomal RNA modifications are important in optimizing ribosome function. Sugar 2'-O-methylation performed by fibrillarin-associated box C/D antisense guide snoRNAs impacts all steps of translation, playing a role in disease etiology (cancer). As it renders adjacent phosphodiester bonds resistant to alkaline treatment, 2'-O-methylation can be monitored qualitatively and quantitatively by applying next-generation sequencing to fragments of randomly cleaved RNA. We remapped all sites of 2'-O-methylation in human rRNAs in two isogenic diploid cell lines, one producing and one not producing the antitumor protein p53. We identified sites naturally modified only partially (confirming the existence in cells of compositionally distinct ribosomes with potentially specialized functions) and sites whose 2'-O-methylation is sensitive to p53. We mapped sites particularly vulnerable to a reduced level of the methyltransferase fibrillarin. The remarkable fact that these are largely sites of natural hypomodification provides initial insights into the mechanism of partial RNA modification. Sites where methylation appeared vulnerable lie peripherally on the 3-D structure of the ribosomal subunits, whereas the numerous modifications present at the core of the subunits, where the functional centers lie, appeared robustly made. We suggest that vulnerable sites of 2'-O-methylation are highly likely to undergo specific regulation during normal and pathological processes. PMID- 28904334 TI - The first physical evidence of subglacial volcanism under the West Antarctic Ice Sheet. AB - The West Antarctic ice sheet (WAIS) is highly vulnerable to collapsing because of increased ocean and surface temperatures. New evidence from ice core tephra shows that subglacial volcanism can breach the surface of the ice sheet and may pose a great threat to WAIS stability. Micro-CT analyses on englacial ice core tephra along with detailed shard morphology characterization and geochemical analysis suggest that two tephra layers were derived from subglacial to emergent volcanism that erupted through the WAIS. These tephra were erupted though the center of the ice sheet, deposited near WAIS Divide and preserved in the WDC06A ice core. The sources of these tephra layers were likely to be nearby subglacial volcanoes, Mt. Resnik, Mt. Thiel, and/or Mt. Casertz. A widespread increase in ice loss from WAIS could trigger positive feedback by decreasing ice mass and increasing decompression melting under the WAIS, increasing volcanism. Both tephra were erupted during the last glacial period and a widespread increase in subglacial volcanism in the future could have a considerable effect on the stability of the WAIS and resulting sea level rise. PMID- 28904333 TI - The Ino80 complex mediates epigenetic centromere propagation via active removal of histone H3. AB - The centromere is the chromosomal locus at which the kinetochore is assembled to direct chromosome segregation. The histone H3 variant, centromere protein A (CENP A), is known to epigenetically mark active centromeres, but the mechanism by which CENP-A propagates at the centromere, replacing histone H3, remains poorly understood. Using fission yeast, here we show that the Ino80 adenosine triphosphate (ATP)-dependent chromatin-remodeling complex, which removes histone H3-containing nucleosomes from associated chromatin, promotes CENP-ACnp1 chromatin assembly at the centromere in a redundant manner with another chromatin remodeling factor Chd1Hrp1. CENP-ACnp1 chromatin actively recruits the Ino80 complex to centromeres to elicit eviction of histone H3-containing nucleosomes. Artificial targeting of Ino80 subunits to a non-centromeric DNA sequence placed in a native centromere enhances the spreading of CENP-ACnp1 chromatin into the non-centromeric DNA. Based on these results, we propose that CENP-ACnp1 chromatin employs the Ino80 complex to mediate the replacement of histone H3 with CENP ACnp1, and thereby reinforces itself.The histone variant CENP-A marks active centromeres and replaces H3 at centromeres through a poorly understood mechanism. Here, the authors provide evidence that the chromatin remodeller Ino80 promotes CENP-A chromatin assembly at the centromere in fission yeast. PMID- 28904335 TI - BRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination. AB - Mutations in the tumor suppressor BRCA2 predominantly predispose to breast cancer. Paradoxically, while loss of BRCA2 promotes tumor formation, it also causes cell lethality, although how lethality is triggered is unclear. Here, we generate BRCA2 conditional non-transformed human mammary epithelial cell lines using CRISPR-Cas9. Cells are inviable upon BRCA2 loss, which leads to replication stress associated with under replication, causing mitotic abnormalities, 53BP1 nuclear body formation in the ensuing G1 phase, and G1 arrest. Unexpected from other systems, the role of BRCA2 in homologous recombination, but not in stalled replication fork protection, is primarily associated with supporting human mammary epithelial cell viability, and, moreover, preventing replication stress, a hallmark of pre-cancerous lesions. Thus, we uncover a DNA under replication 53BP1 nuclear body formation-G1 arrest axis as an unanticipated outcome of homologous recombination deficiency, which triggers cell lethality and, we propose, serves as a barrier that must be overcome for tumor formation.BRCA2 mutations promote tumour formation while also paradoxically causing cell lethality. Here the authors generate conditional BRCA2 loss in a non-transformed human mammary cell line and see increased replication stress due to under replication of DNA. PMID- 28904336 TI - The relation between cesarean birth and child cognitive development. AB - This is the first detailed study of the relation between cesarean birth and child cognitive development. We measure differences in child cognitive performance at 4 to 9 years of age between cesarean-born and vaginally-born children (n = 3,666) participating in the Longitudinal Study of Australian Children (LSAC). LSAC is a nationally representative birth cohort surveyed biennially. Using multivariate regression, we control for a large range of confounders related to perinatal risk factors and the socio-economic advantage associated with cesarean-born children. Across several measures, we find that cesarean-born children perform significantly below vaginally-born children, by up to a tenth of a standard deviation in national numeracy test scores at age 8-9. Estimates from a low-risk sub-sample and lower-bound analysis suggest that the relation is not spuriously related to unobserved confounding. Lower rates of breastfeeding and adverse child and maternal health outcomes that are associated with cesarean birth are found to explain less than a third of the cognitive gap, which points to the importance of other mechanisms such as disturbed gut microbiota. The findings underline the need for a precautionary approach in responding to requests for a planned cesarean when there are no apparent elevated risks from vaginal birth. PMID- 28904338 TI - Aqueous synthesis of functionalized copper sulfide quantum dots as near-infrared luminescent probes for detection of Hg2+, Ag+ and Au3. AB - Stable water-soluble copper sulfide(Cu2S) quantum dots(QDs) with near-infrared emission were synthesized using N-acetyl-L-cysteine(NAC) as a modifier in aqueous solution and nitrogen atmosphere at room temperature. The product was characterized by TEM, XRD, XPS, FT-IR, FL and UV-VIS spectrometers. Effects of preparation conditions such as pH values, the molar ratio of reactants, temperature, and metal ions on the fluorescence properties of Cu2S QDs were discussed. Under optimal conditions, the prepared Cu2S QDs with average diameter about 2-5 nm show a near-infrared emission at 770 nm with the excitation wavelength of 466 nm, and have a good detection sensitivity for ions of Hg2+, Ag+ and Au3+, based on the characteristic of fluorescence quenching. The fluorescence quenching mechanism was proposed via electron transfer with cation exchange, which based on the theory of Hard-Soft-Acid-Base (HSAB) and Ksp value of metal sulfide. PMID- 28904339 TI - A Plastid-Localized Pentatricopeptide Repeat Protein is Required for Both Pollen Development and Plant Growth in Rice. AB - Several mitochondrial-targeted pentatricopeptide repeat (PPR) proteins involved in pollen development have been reported to be fertility restorer (Rf) proteins. However, the roles of plastid-localized PPR proteins in plant male reproduction are poorly defined. Here, we described a plastid-localized PPR-SMR protein, OsPPR676, which is required for plant growth and pollen development in rice. In this study, OsPPR676 was confirmed to be an interacted protein with Osj10gBTF3, beta-subunit of nascent polypeptide-associated complex (beta-NAC), by bimolecular fluorescence complementation assays, indicating that both proteins are probably involved in the same regulatory pathway of pollen development. Compared with other chloroplast-rich tissues, OsPPR676 was only weakly expressed in anther, but in the Mei and YM stages of pollen development, its expression was relatively strong in the tapetum. Disruption of OsPPR676 resulted in growth retardation of plants and partial sterility of pollens. Phenotypic analysis of different osppr676 mutant lines implied that the SMR domain was not essential for the function of OsPPR676. We further demonstrated that OsPPR676 is essential for production of plastid atpB subunit, and then plays crucial roles in biosynthesis of fatty acids, carbohydrates, and other organic matters via affecting activity of ATP synthase. PMID- 28904340 TI - MicroRNA-196b inhibits late apoptosis of pancreatic cancer cells by targeting CADM1. AB - Pancreatic cancer (PC), as the leading cause of cancer death worldwide, is one of the deadliest tumors with a very low 5-year survival rate. Therefore, it is urgent to seek new biomarkers of PC for more accurate and reliable treatments. To identify the differentially expressed miRNAs (DEM) in PC tissues, we performed the systematic microarray and qRT-PCR analyses. We found miR-196b was the top dysregulated DEM in PC tissues as compared with the corresponding adjacent tissues, and positively correlated with poor differentiation, tumor size, lymphatic invasion and TNM stage. Furthermore, the late apoptosis rate was significantly reduced, while the cell proliferation was increased in PANC-1 and ASPC-1 cell-lines after treatment with miR-196b mimics. The qRT-PCR and Western blot analysis demonstrated that the level of CADM1 in PANC-1 cells response to the alteration of miR-196b. Moreover, blockade of CADM1 could decrease the late apoptosis in PANC-1 cells as up-regulated by inhibition of miR-196b. Finally, luciferase report assay confirmed that CADM1 was the direct target gene of miR 196b. Overexpression of miR-196b in PC tissues can increase the late apoptosis of pancreatic cancer cells by targeting CADM1. These findings suggested miR-196b is a potential target for diagnosis and therapeutics of human pancreatic cancer. PMID- 28904341 TI - Erratum: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28904337 TI - Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer. AB - One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a comprehensive systems analysis of the infected brain: We identified susceptibility genes for congenital toxoplasmosis in our cohort of infected humans and found these genes are expressed in human brain. Transcriptomic and quantitative proteomic analyses of infected human, primary, neuronal stem and monocytic cells revealed effects on neurodevelopment and plasticity in neural, immune, and endocrine networks. These findings were supported by identification of protein and miRNA biomarkers in sera of ill children reflecting brain damage and T. gondii infection. These data were deconvoluted using three systems biology approaches: "Orbital-deconvolution" elucidated upstream, regulatory pathways interconnecting human susceptibility genes, biomarkers, proteomes, and transcriptomes. "Cluster-deconvolution" revealed visual protein-protein interaction clusters involved in processes affecting brain functions and circuitry, including lipid metabolism, leukocyte migration and olfaction. Finally, "disease-deconvolution" identified associations between the parasite-brain interactions and epilepsy, movement disorders, Alzheimer's disease, and cancer. This "reconstruction-deconvolution" logic provides templates of progenitor cells' potentiating effects, and components affecting human brain parasitism and diseases. PMID- 28904342 TI - Evolution of T Cell Responses during Measles Virus Infection and RNA Clearance. AB - Measles is an acute viral disease associated both with immune suppression and development of life-long immunity. Clearance of measles virus (MeV) involves rapid elimination of infectious virus during the rash followed by slow elimination of viral RNA. To characterize cellular immune responses during recovery, we analyzed the appearance, specificity and function of MeV-specific T cells for 6 months after respiratory infection of rhesus macaques with wild type MeV. IFN-gamma and IL-17-producing cells specific for the hemagglutinin and nucleocapsid proteins appeared in circulation in multiple waves approximately 2 3, 8 and 18-24 weeks after infection. IFN-gamma-secreting cells were most abundant early and IL-17-secreting cells late. Both CD4+ and CD8+ T cells were sources of IFN-gamma and IL-17, and IL-17-producing cells expressed RORgammat. Therefore, the cellular immune response evolves during MeV clearance to produce functionally distinct subsets of MeV-specific CD4+ and CD8+ T cells at different times after infection. PMID- 28904343 TI - Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors. AB - The absence of an adequate reversal strategy to prevent and stop potential life threatening bleeding complications is a major drawback to the clinical use of the direct oral inhibitors of blood coagulation factor Xa. Here we show that specific modifications of the substrate-binding aromatic S4 subpocket within the factor Xa active site disrupt high-affinity engagement of the direct factor Xa inhibitors. These modifications either entail amino-acid substitution of S4 subsite residues Tyr99 and/or Phe174 (chymotrypsinogen numbering), or extension of the 99-loop that borders the S4 subsite. The latter modifications led to the engineering of a factor Xa variant that is able to support coagulation in human plasma spiked with (supra-)physiological concentrations of direct factor Xa inhibitors. As such, this factor Xa variant has the potential to be employed to bypass the direct factor Xa inhibitor-mediated anticoagulation in patients that require restoration of blood coagulation.A major drawback in the clinical use of the oral anticoagulants that directly inhibit factor Xa in order to prevent blood clot formation is the potential for life threatening bleeding events. Here the authors describe factor Xa variants that are refractory to inhibition by these anticoagulants and could serve as rescue agents in treated patients. PMID- 28904344 TI - Perturbed cholesterol and vesicular trafficking associated with dengue blocking in Wolbachia-infected Aedes aegypti cells. AB - Wolbachia are intracellular maternally inherited bacteria that can spread through insect populations and block virus transmission by mosquitoes, providing an important approach to dengue control. To better understand the mechanisms of virus inhibition, we here perform proteomic quantification of the effects of Wolbachia in Aedes aegypti mosquito cells and midgut. Perturbations are observed in vesicular trafficking, lipid metabolism and in the endoplasmic reticulum that could impact viral entry and replication. Wolbachia-infected cells display a differential cholesterol profile, including elevated levels of esterified cholesterol, that is consistent with perturbed intracellular cholesterol trafficking. Cyclodextrins have been shown to reverse lipid accumulation defects in cells with disrupted cholesterol homeostasis. Treatment of Wolbachia-infected Ae. aegypti cells with 2-hydroxypropyl-beta-cyclodextrin restores dengue replication in Wolbachia-carrying cells, suggesting dengue is inhibited in Wolbachia-infected cells by localised cholesterol accumulation. These results demonstrate parallels between the cellular Wolbachia viral inhibition phenotype and lipid storage genetic disorders. Wolbachia infection of mosquitoes can block dengue virus infection and is tested in field trials, but the mechanism of action is unclear. Using proteomics, Geoghegan et al. here identify effects of Wolbachia on cholesterol homeostasis and dengue virus replication in Aedes aegypti. PMID- 28904345 TI - Vdelta2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. AB - Vdelta2+ gammadelta T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naive adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vdelta2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vdelta2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vdelta2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vdelta2+ T cell pro-inflammatory cytokine production. Higher Vdelta2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vdelta2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria. PMID- 28904346 TI - Brain damage and behavioural disorders in fish induced by plastic nanoparticles delivered through the food chain. AB - The tremendous increases in production of plastic materials has led to an accumulation of plastic pollution worldwide. Many studies have addressed the physical effects of large-sized plastics on organisms, whereas few have focused on plastic nanoparticles, despite their distinct chemical, physical and mechanical properties. Hence our understanding of their effects on ecosystem function, behaviour and metabolism of organisms remains elusive. Here we demonstrate that plastic nanoparticles reduce survival of aquatic zooplankton and penetrate the blood-to-brain barrier in fish and cause behavioural disorders. Hence, for the first time, we uncover direct interactions between plastic nanoparticles and brain tissue, which is the likely mechanism behind the observed behavioural disorders in the top consumer. In a broader perspective, our findings demonstrate that plastic nanoparticles are transferred up through a food chain, enter the brain of the top consumer and affect its behaviour, thereby severely disrupting the function of natural ecosystems. PMID- 28904347 TI - Oscillatory dynamics of p38 activity with transcriptional and translational time delays. AB - Recent experimental evidence reports that oscillations of p38 MAPK (p38) activity would efficiently induce pro-inflammatory gene expression, which might be deleterious to immune systems and may even cause cellular damage and apoptosis. It is widely accepted now that transcriptional and translational delays are ubiquitous in gene expression, which can typically result in oscillatory responses of gene regulations. Consequently, delay-driven sustained oscillations in p38 activity (p38*) could in principle be commonplace. Nevertheless, so far the studies of the impact of such delays on p38* have been lacking both experimentally and theoretically. Here, we use experimental data to develop a delayed mathematical model, with the aim of understanding how such delays affect oscillatory behaviour on p38*. We analyze the stability and oscillation of the model with and without explicit time delays. We show that a sufficiently input stimulation strength is prerequisite for generating p38* oscillations, and that an optimal rate of model parameters is also essential to these oscillations. Moreover, we find that the time delays required for transcription and translation in mitogen-activated protein kinase phosphatase-1 (MKP-1) gene expression can drive p38* to be oscillatory even when the concentration of p38* level is at a stable state. Furthermore, the length of these delays can determine the amplitude and period of the oscillations and can enormously extend the oscillatory ranges of model parameters. These results indicate that time delays in MKP-1 synthesis are required, albeit not sufficient, for p38* oscillations, which may lead to new insights related to p38 oscillations. PMID- 28904349 TI - Cross-polarization coupling terahertz time-domain spectroscopy in a semiconductor based on the Hall effect. AB - We propose a new type of terahertz time-domain spectroscopy in an isotropic semiconductor wafer applied by a magnetic field in which two cross-polarization THz pulses couple with each other via the Hall effect. We built a classic theoretic model to describe cross-polarization coupling THz spectroscopy (CPCTS). Numerical simulations show that the magnetic field can clearly affect the spectral features of the two THz pulses via the Hall effect in which both the magnitude and direction of the magnetic field and the thickness of the wafer play important roles. Using CPCTS, we present an improved method that is non-contact to measure the material parameters, such as the damping constant and carrier density of a semiconductor wafer, and discuss the possibility of THz functional devices. Finally, we describe an experimental scheme to guide CPCTS. PMID- 28904348 TI - Transcriptome profiling of genes involved in induced systemic salt tolerance conferred by Bacillus amyloliquefaciens FZB42 in Arabidopsis thaliana. AB - Plant growth-promoting Bacillus amyloliquefaciens FZB42 induces systemic salt tolerance in Arabidopsis and enhances the fresh and dry weight. However, the underlying molecular mechanism that allows plants to respond to FZB42 and exhibit salt tolerance is largely unknown. Therefore, we performed large-scale transcriptome sequencing of Arabidopsis shoot tissues grown under salt stress with or without FZB42 inoculation by using Illumina sequencing to identify the key genes and pathways with important roles during this interaction. In total, 1461 genes were differentially expressed (FZB42-inoculated versus non-inoculated samples) at 0 mM NaCl, of which 953 were upregulated and 508 downregulated, while 1288 genes were differentially expressed at 100 mM NaCl, of which 1024 were upregulated and 264 were downregulated. Transcripts associated with photosynthesis, auxin-related, SOS scavenging, Na+ translocation, and osmoprotectant synthesis, such as trehalose and proline, were differentially expressed by FZB42 inoculation, which reduced the susceptibility to salt and facilitated salt adaptation. Meanwhile, etr1-3, eto1, jar1-1, and abi4-102 hormone-related mutants demonstrated that FZB42 might induce plant salt tolerance via activating plants ET/JA signaling but not ABA-dependent pathway. The results here characterize the plant transcriptome under salt stress with plant growth promoting bacteria inoculation, thereby providing insights into the molecular mechanisms responsible for induced salt tolerance. PMID- 28904351 TI - Localized-itinerant dichotomy and unconventional magnetism in SrRu2O6. AB - Electron correlations tend to generate local magnetic moments that usually order if the lattices are not too frustrated. The hexagonal compound SrRu2O6 has a relatively high Neel temperature but small local moments, which seem to be at odds with the nominal valence of Ru5+ in the [Formula: see text] configuration. Here, we investigate the electronic property of SrRu2O6 using density functional theory (DFT) combined with dynamical-mean-field theory (DMFT). We find that the strong hybridization between Ru d and O p states results in a Ru valence that is closer to +4, leading to the small ordered moment ~1.2 MU B . While this is consistent with a DFT prediction, correlation effects are found to play a significant role. The local moment per Ru site remains finite ~2.3 MU B in the whole temperature range investigated. Due to the lower symmetry, the t 2g manifold is split and the quasiparticle weight is renormalized significantly in the a 1g state, while the renormalization in [Formula: see text] states is about a factor of 2-3 weaker. Our theoretical Neel temperature ~700 K is in reasonable agreement with experimental observations. SrRu2O6 is a unique system in which localized and itinerant electrons coexist with the proximity to an orbitally selective Mott transition within the t 2g sector. PMID- 28904350 TI - Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells. AB - Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis in a CAP-independent manner. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.Sequestering mRNA in cytoplasmic stress granules is a mechanism for translational repression. Here the authors find that p53 mRNA, present in stress granules in activated B lymphocytes, is released upon DNA damage and is translated in a CAP-independent manner. PMID- 28904352 TI - Polyphenols journey through blood-brain barrier towards neuronal protection. AB - Age-related complications such as neurodegenerative disorders are increasing and remain cureless. The possibility of altering the progression or the development of these multifactorial diseases through diet is an emerging and attractive approach with increasing experimental support. We examined the potential of known bioavailable phenolic sulfates, arising from colonic metabolism of berries, to influence hallmarks of neurodegenerative processes. In silico predictions and in vitro transport studies across blood-brain barrier (BBB) endothelial cells, at circulating concentrations, provided evidence for differential transport, likely related to chemical structure. Moreover, endothelial metabolism of these phenolic sulfates produced a plethora of novel chemical entities with further potential bioactivies. Pre-conditioning with phenolic sulfates improved cellular responses to oxidative, excitotoxicity and inflammatory injuries and this attenuation of neuroinflammation was achieved via modulation of NF-kappaB pathway. Our results support the hypothesis that these small molecules, derived from dietary (poly)phenols may cross the BBB, reach brain cells, modulate microglia-mediated inflammation and exert neuroprotective effects, with potential for alleviation of neurodegenerative diseases. PMID- 28904353 TI - Toll-like receptor 2 induced cytotoxic T-lymphocyte-associated protein 4 regulates Aspergillus-induced regulatory T-cells with pro-inflammatory characteristics. AB - Patients with cystic fibrosis, chronic obstructive pulmonary disease, severe asthma, pre-existing pulmonary lesions, and severely immunocompromised patients are susceptible to develop infections with the opportunistic pathogenic fungus Aspergillus fumigatus, called aspergillosis. Infections in these patients are associated with persistent pro-inflammatory T-helper (TH)2 and TH17 responses. Regulatory T-cells, natural suppressor cells of the immune system, control pro inflammatory T-cell responses, but can also contribute to disease by shifting to a pro-inflammatory TH17-like phenotype. Such a shift could play an important role in the detrimental immunopathology that is seen in aspergillosis. Our study demonstrates that Aspergillus fumigatus induces regulatory T-cells with a TH17 like phenotype. We also demonstrate that these regulatory T-cells with a pro inflammatory TH17-like phenotype can be reprogrammed to their "classical" anti inflammatory phenotype by activating Toll-like receptor 2 (TLR2), which regulates the induction of cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Similarly, soluble CTLA4 could reverse the pro-inflammatory phenotype of Aspergillus-induced regulatory T-cells. In conclusion, our results suggest a role for regulatory T cells with a pro-inflammatory TH17-like phenotype in Aspergillus-associated immunopathology, and identifies key players, i.e. TLR2 and CTLA4, involved in this mechanism. PMID- 28904354 TI - Identification and characterization of the novel reversible and selective cathepsin X inhibitors. AB - Cathepsin X is a cysteine peptidase involved in the progression of cancer and neurodegenerative diseases. Targeting this enzyme with selective inhibitors opens a new possibility for intervention in several therapeutic areas. In this study triazole-based reversible and selective inhibitors of cathepsin X have been identified. Their selectivity and binding is enhanced when the 2,3 dihydrobenzo[b][1,4]dioxine moiety is present as the R1 substituent. Of a series of selected triazole-benzodioxine derivatives, compound 22 is the most potent inhibitor of cathepsin X carboxypeptidase activity (Ki = 2.45 +/- 0.05 MUM) with at least 100-fold greater selectivity in comparison to cathepsin B or other related cysteine peptidases. Compound 22 is not cytotoxic to prostate cancer cells PC-3 or pheochromocytoma PC-12 cells at concentrations up to 10 MUM. It significantly inhibits the migration of tumor cells and increases the outgrowth of neurites, both processes being under the control of cathepsin X carboxypeptidase activity. Compound 22 and other characterized triazole-based inhibitors thus possess a great potential for further development resulting in several in vivo applications. PMID- 28904355 TI - Highly potent antimicrobial modified peptides derived from the Acinetobacter baumannii phage endolysin LysAB2. AB - The increase in the prevalence of multidrug-resistant Acinetobacter baumannii (MDRAB) strains is a serious public health concern. Antimicrobial peptides (AMPs) are a possible solution to this problem. In this study, we examined whether AMPs could be derived from phage endolysins. We synthesized four AMPs based on an amphipathic helical region in the C-terminus of endolysin LysAB2 encoded by the A. baumannii phage PhiAB2. These peptides showed potent antibacterial activity against A. baumannii (minimum inhibitory concentration, 4-64 MUM), including some MDR and colistin-resistant A. baumannii. Of the four peptides, LysAB2 P3, with modifications that increased its net positive charge and decreased its hydrophobicity, showed high antibacterial activity against A. baumannii but little haemolytic and no cytotoxic activity against normal eukaryotic cells. The results of electron microscopy experiments and a fluorescein isothiocyanate staining assay indicated that this peptide killed A. baumannii through membrane permeabilization. Moreover, in a mouse intraperitoneal infection model, at 4 h after the bacterial injection, LysAB2 P3 decreased the bacterial load by 13-fold in ascites and 27-fold in blood. Additionally, LysAB2 P3 rescued sixty percent of mice heavily infected with A. baumannii from lethal bacteremia. Our results confirmed that bacteriophage endolysins are a promising resource for developing effective AMPs. PMID- 28904356 TI - Extremely high electrical conductance of microporous 3D graphene-like zeolite templated carbon framework. AB - We report the remarkably high electrical conductance of microporous 3D graphene like carbons that were formed using lanthanum (La)-catalyzed synthesis in a Y zeolite (LaY) template investigated using conductive atomic force microscopy (C AFM) and theoretical calculations. To uncover the relation between local electrical conductance and the microporous structures, we tuned the crystallographic ordering of LaY-templated carbon systems by changing the heating temperature. The structure of the LaY-templated carbon prepared at the higher temperature has graphene-like sp 2 hybridized bonds, which was confirmed using high-resolution transmission electron microscopy and X-ray diffraction measurements. C-AFM current-voltage spectroscopy revealed that the local current flow in the LaY-templated carbon depends on the quantity of C-C bonds within the narrow neck between the closed supercages (i.e. there are three types of carbon: carbon with heat treatment, carbon without heat treatment, and carbon synthesized at low temperature). The difference in electrical conductance on the LaY templated carbon was also confirmed via theoretical computation using the Boltzmann transport theory and the deformation potential theory based on the density functional theory. These results suggest that the degree of order of the pores in the 3D zeolite-templated carbon structures is directly related to electrical conductance. PMID- 28904357 TI - Social-demographic shift in drug users at the first-ever- methadone maintenance treatment in Wuhan, China. AB - The methadone maintenance treatment (MMT) has been initiated in Wuhan, China since early 2006. To understand the social-demographic, behavioral, and infectious diseases characteristics of drug users enrolled in their first-ever MMT between 2006 and 2015, a retrospective observational study was implemented to also provide evidence for health policy-decisions to reduce harm and control disease. Pearson chi-square tests and t-tests were used to assess significant differences between two 5-year periods, 2006-2010 and 2011-2015. We observed increases in the mean age (38.65 vs. 42.43 years, P < 0.001), mean age of initial opioid drug use (28.18 vs. 31.07 years, P < 0.001), employment (11.9% vs. 30.7%, P < 0.001), married/co-habiting (42.4% vs. 47.8%, P < 0.001), and declines in higher education level (93.6% vs. 84.8%, P < 0.001), injection (82.3% vs. 75.1%, P < 0.001), syringe sharing (27.7% vs. 9.9%, P < 0.001), HCV infection rates (72.9% vs. 70.5%, P = 0.017). The number of drug users enrolling each year reduced following a continuous rapid growth in the first 3 years. The findings imply for adjusting in treatment services and allocation of resources to respond to emerging trends. In addition, the data will also be helpful for identifying needs and getting a baseline insight of the social-demographic and behavioral characteristics of the opioid abusers in the area. PMID- 28904358 TI - Monitoring osteoarthritis progression using near infrared (NIR) spectroscopy. AB - We demonstrate in this study the potential of near infrared (NIR) spectroscopy as a tool for monitoring progression of cartilage degeneration in an animal model. Osteoarthritic degeneration was artificially induced in one joint in laboratory rats, and the animals were sacrificed at four time points: 1, 2, 4, and 6 weeks (3 animals/week). NIR spectra were acquired from both (injured and intact) knees. Subsequently, the joint samples were subjected to histological evaluation and glycosaminoglycan (GAG) content analysis, to assess disease severity based on the Mankin scoring system and to determine proteoglycan loss, respectively. Multivariate spectral techniques were then employed for classification (principal component analysis and support vector machines) and prediction (partial least squares regression) of the samples' Mankin scores and GAG content from their NIR spectra. Our results demonstrate that NIR spectroscopy is sensitive to degenerative changes in articular cartilage, and is capable of distinguishing between mild (weeks 1&2; Mankin <=2) and advanced (weeks 4&6; Mankin =>3) cartilage degeneration. In addition, the spectral data contains information that enables estimation of the tissue's Mankin score (error = 12.6%, R2 = 86.2%) and GAG content (error = 7.6%, R2 = 95%). We conclude that NIR spectroscopy is a viable tool for assessing cartilage degeneration post-injury, such as, post traumatic osteoarthritis. PMID- 28904359 TI - Structured illumination microscopy and automatized image processing as a rapid diagnostic tool for podocyte effacement. AB - The morphology of podocyte foot processes is obligatory for renal function. Here we describe a method for the superresolution-visualization of podocyte foot processes using structured illumination microscopy of the slit diaphragm, which before has only been achieved by electron microscopy. As a proof of principle, we measured a mean foot process width of 0.249 +/- 0.068 um in healthy kidneys and a significant higher mean foot process width of 0.675 +/- 0.256 um in minimal change disease patients indicating effacement of foot processes. We then hypothesized that the slit length per glomerular capillary surface area (slit diaphragm density) could be used as an equivalent for the diagnosis of effacement. Using custom-made software we measured a mean value of 3.10 +/- 0.27 um-1 in healthy subjects and 1.83 +/- 0.49 um-1 in the minimal change disease patients. As foot process width was highly correlated with slit diaphragm density (R2 = 0.91), we concluded that our approach is a valid method for the diagnosis of foot process effacement. In summary, we present a new technique to quantify podocyte damage, which combines superresolution microscopy with automatized image processing. Due to its diverse advantages, we propose this technique to be included into routine diagnostics of glomerular histopathology. PMID- 28904360 TI - Comparison of prognostic, clinical, and renal histopathological characteristics of overlapping idiopathic membranous nephropathy and IgA nephropathy versus idiopathic membranous nephropathy. AB - Overlapping idiopathic membranous nephropathy (IMN) and immunoglobulin A nephropathy (IgAN) is rare. This study aims to investigate the unique prognostic, clinical, and renal histopathological characteristics of IMN+IgAN. This retrospective observational study included 73 consecutive cases of IMN+IgAN and 425 cases of IMN treated between September 2006 and November 2015. Prognostic and baseline clinical and histopathological data were compared between the two patient groups. Poor prognostic events included a permanent 50% reduction in eGFR, end-stage renal disease, and all-cause mortality. Renal histopathology demonstrated that the patients with IMN+IgAN presented with significantly increased mesangial cell proliferation and matrix expansion, increased inflammatory cell infiltration, and higher proportions of arteriole hyalinosis and lesions than the patients with IMN (all P < 0.05). Kaplan-Meier analysis showed that the patients with IMN+IgAN had significantly higher cumulative incidence rates of partial or complete remission (PR or CR, P = 0.0085). Multivariate Cox model analysis revealed that old age at biopsy and high baseline serum creatinine and uric acid levels were significantly associated with poor prognosis (all P < 0.05), and increased IgA expression correlated significantly with PR or CR (P < 0.05). The present study found that overlapping IMN and IgAN presents with unique renal histopathology and appears not to cause a poorer prognosis than IMN. PMID- 28904361 TI - Intrafascial versus interfascial nerve sparing in radical prostatectomy for localized prostate cancer: a systematic review and meta-analysis. AB - The present study aimed to systematically evaluate the effectiveness and safety of the intrafascial and interfascial nerve sparing (ITR-NS and ITE-NS) radical prostatectomy. PubMed, Embase, and Cochrane Library databases were searched for eligible studies. Meta-analysis with random-effects model was performed. Six comparative trials were selected and embraced in this research, including one randomized controlled trial, three prospective comparative trials, and two retrospective comparative trials. With regard to perioperative parameters, no significant association of operative time, blood loss, transfusion rates, duration of catheterization, and hospital stay existed between ITR-NS and ITE-NS. With respect to the functional results, ITR-NS had advantages in terms of both continence and potency recovery compared with ITE-NS. In reference to the oncologic results, the ITR-NS showed lower overall positive surgical margin (PSM) compared with ITE-NS but pT2 PSM and biochemical recurrence free rates were similar to the two surgical types. This study demonstrates that ITR-NS has better continence at 6 mo and 36 mo and better potency recovery at 6 mo and 12 mo postoperatively, regardless of the surgical technique. The cancer control of ITR NS was also better than that of ITE-NS. This may be explained by the fact that patients in ITE-NS group present higher risk cancer than patients in ITR-NS group. PMID- 28904362 TI - Detailed Balance Limit of Efficiency of Broadband-Pumped Lasers. AB - Broadband light sources are a wide class of pumping schemes for lasers including LEDs, sunlight and flash lamps. Recently, efficient coupling of broadband light to high-quality micro-cavities has been demonstrated for on-chip applications and low-threshold solar-pumped lasers via cascade energy transfer. However, the conversion of incoherent to coherent light comes with an inherent price of reduced efficiency, which has yet to be assessed. In this paper, we derive the detailed balance limit of efficiency of broadband-pumped lasers and discuss how it is affected by the need to maintain a threshold population inversion and thermodynamically dictated minimal Stokes' shift. We show that lasers' slope efficiency is analogous to the nominal efficiency of solar cells, limited by thermalisation losses and additional unavoidable Stokes' shift. The lasers' power efficiency is analogous to the detailed balance limit of efficiency of solar cells, affected by the cavity mirrors and impedance matching factor, respectively. As an example we analyze the specific case of solar-pumped sensitized Nd3+:YAG-like lasers and define the conditions to reach their thermodynamic limit of efficiency. Our work establishes an upper theoretical limit for the efficiency of broadband-pumped lasers. Our general, yet flexible model also provides a way to incorporate other optical and thermodynamic losses and, hence, to estimate the efficiency of non-ideal broadband-pumped lasers. PMID- 28904363 TI - Calcitriol reduces kidney development disorders in rats provoked by losartan administration during lactation. AB - Calcitriol has important effects on cellular differentiation and proliferation, as well as on the regulation of the renin gene. Disturbances in renal development can be observed in rats exposed to angiotensin II (AngII) antagonists during lactation period. The lack of tubular differentiation in losartan-treated rats can affect calcitriol uptake. This study evaluated the effect of calcitriol administration in renal development disturbances in rats provoked by losartan (AngII type 1 receptor antagonist) administration during lactation. Animals exposed to losartan presented higher albuminuria, systolic blood pressure, increased sodium and potassium fractional excretion, and decreased glomerular filtration rate compared to controls. These animals also showed a decreased glomerular area and a higher interstitial relative area from the renal cortex, with increased expression of fibronectin, alpha-SM-actin, vimentin, and p-JNK; and an increased number of macrophages, p-p38, PCNA and decreased cubilin expression. Increased urinary excretion of MCP-1 and TGF-beta was also observed. All these alterations were less intense in the losartan + calcitriol group.The animals treated with calcitriol showed an improvement in cellular differentiation, and in renal function and structure. This effect was associated with reduction of cell proliferation and inflammation. PMID- 28904364 TI - Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth. AB - Caffeine is a widely consumed psychoactive substance, but little is known about the effects of caffeine stimulation on global gene expression changes in neurons. Here, we conducted gene expression profiling of human neuroepithelial stem cell derived neurons, stimulated with normal consumption levels of caffeine (3 MUM and 10 MUM), over a period of 9 h. We found dosage-dependent activation of immediate early genes after 1 h. Neuronal projection development processes were up regulated and negative regulation of axon extension processes were down-regulated at 3 h. In addition, genes involved in extracellular matrix organization, response for wound healing, and regulation of immune system processes were down regulated by caffeine at 3 h. This study identified novel genes within the neuronal projection guidance pathways that respond to acute caffeine stimulation and suggests potential mechanisms for the effects of caffeine on neuronal cells. PMID- 28904365 TI - RNAi-mediated silencing of a pyruvate dehydrogenase kinase enhances triacylglycerol biosynthesis in the oleaginous marine alga Nannochloropsis salina. AB - Oleaginous microalgae have been emerging as the third-generation feedstocks for biofuel production. Genetic manipulation for improving triacylglycerol (TAG) accumulation represents a promising approach towards the economics of microalgal biofuels. Acetyl-CoA, the essential carbon precursor for de novo fatty acid biosynthesis, can be derived from pyruvate catalyzed by pyruvate dehydrogenase, which is negatively regulated by pyruvate dehydrogenase kinase (PDK). In the present study, we characterized a PDK gene (NsPDK) from Nannochloropsis salina. Subcellular localization assay assisted by green fluorescence protein (GFP) fusion indicated the localization of NsPDK in mitochondria of N. salina cells. NsPDK knockdown via RNA interference strategy attenuated NsPDK expression at the mRNA level and its enzymatic activity in vivo, leading to faster TAG accumulation without compromising cell growth under high light stress conditions. Interestingly, the TAG increase was accompanied by a decline in membrane polar lipids. NsPDK knockdown also altered fatty acid profile in N. salina. Furthermore, transcriptional analysis suggested that the carbon metabolic pathways might be influenced by NsPDK knockdown leading to diverted carbon flux towards TAG synthesis. Taken together, our results demonstrate the role of NsPDK in regulating TAG accumulation and provide valuable insights into future manipulation of oleaginous microalgae for improving biofuel production. PMID- 28904366 TI - Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis. AB - Craniosynostosis is a bone developmental disease where premature ossification of the cranial sutures occurs leading to fused sutures. While biomechanical forces have been implicated in craniosynostosis, evidence of the effect of microenvironmental stiffness changes in the osteogenic commitment of cells from the sutures is lacking. Our aim was to identify the differential genetic expression and osteogenic capability between cells from patent and fused sutures of children with craniosynostosis and whether these differences are driven by changes in the stiffness of the microenvironment. Cells from both sutures demonstrated enhanced mineralisation with increasing substrate stiffness showing that stiffness is a stimulus capable of triggering the accelerated osteogenic commitment of the cells from patent to fused stages. The differences in the mechanoresponse of these cells were further investigated with a PCR array showing stiffness-dependent upregulation of genes mediating growth and bone development (TSHZ2, IGF1), involved in the breakdown of extracellular matrix (MMP9), mediating the activation of inflammation (IL1beta) and controlling osteogenic differentiation (WIF1, BMP6, NOX1) in cells from fused sutures. In summary, this study indicates that stiffer substrates lead to greater osteogenic commitment and accelerated bone formation, suggesting that stiffening of the extracellular environment may trigger the premature ossification of the sutures. PMID- 28904367 TI - Changing smoking-mortality association over time and across social groups: National census-mortality cohort studies from 1981 to 2011. AB - The difference in mortality between current and never-smokers varies over time, affecting future projections of health gains from tobacco control. We examine this heterogeneity by sex, ethnicity and cause of death on absolute and relative scales using New Zealand census data. These data included smoking status, and were linked to subsequent mortality records in 1981-84, 1996-99 and 2006-11 for 25-74 year olds (16.1 million person-years of follow-up). Age-standardised mortality rates and rate differences (SRDs) were calculated comparing current to never-smokers, and Poisson regression was used to adjust for multiple socioeconomic factors and household smoking. We found that mortality declined over time in never-smokers; however, mortality trends in current-smokers varied by sex, ethnicity and cause of death. SRDs were stable over time in European/Other men, moderately widened in European/Other women and markedly increased in Maori men and women (Indigenous population). Poisson smoking mortality rate ratios (RRs) increased from 1981-84 to 1996-99 with a moderate increase from 1996-99 to 2006-11 (RRs 1.48, 1.77, 1.79 in men and 1.51, 1.80, 1.90 in women). Socioeconomic confounding increased over time. In summary, this marked heterogeneity in smoking-mortality RRs over time has implications for estimating the future health and inequality impacts of tobacco control interventions. PMID- 28904368 TI - Polycystin-1 inhibits eIF2alpha phosphorylation and cell apoptosis through a PKR eIF2alpha pathway. AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 which encodes polycystin-1 (PC1) and polycystin-2, respectively. PC1 was previously shown to slow cell proliferation and inhibit apoptosis but the underlying mechanisms remain elusive or controversial. Here we showed in cultured mammalian cells and Pkd1 knockout mouse kidney epithelial cells that PC1 and its truncation mutant comprising the last five transmembrane segments and the intracellular C-terminus (PC1-5TMC) down-regulate the phosphorylation of protein kinase R (PKR) and its substrate eukaryotic translation initiation factor 2 alpha (eIF2alpha). PKR is known to be activated by interferons and dsRNAs, inhibits protein synthesis and induces apoptosis. By co-immunoprecipitation experiments we found that PC1 truncation mutants associate with PKR, or with PKR and its activator PACT. Further experiments showed that PC1 and PC1-5TMC reduce phosphorylation of eIF2alpha through inhibiting PKR phosphorylation. Our TUNEL experiments using tunicamycin, an apoptosis inducer, and GADD34, an inhibitor of eIF2alpha phosphorylation, demonstrated that PC1-5TMC inhibits apoptosis of HEK293T cells in a PKR-eIF2alpha-dependent manner, with concurrent up- and down regulation of Bcl-2 and Bax, respectively, revealed by Western blotting. Involvement of PC1-regulated eIF2alpha phosphorylation and a PKR-eIF2alpha pathway in cell apoptosis may be an important part of the mechanism underlying ADPKD pathogenesis. PMID- 28904369 TI - Antimutagenic and antioxidant activity of the essential oils of Citrus sinensis and Citrus latifolia. AB - The essential oils of Citrus sinensis and Citrus latifolia showed antimycotic activity against Candida spp. isolated from the oral cavity; they are neither mutagenic on the Ames test nor cytotoxic. Their main components are R-(+) limonene, beta-thujene, alpha-myrcene and gamma-terpinene. The aim of this work was to evaluate their antimutagenic and antioxidant capacities. Antimutagenic properties were evaluated against MNNG and ENNG on S. typhimurium TA100; against 2AA on strain TA98 and in front of 4NQO and NOR on strain TA102. Both were antimutagenic against MNNG (p < 0.001) but only C. latifolia was antimutagenic against ENNG (p < 0.001). Both presented antimutagenic activity against 2AA (p < 0.001). They were antioxidant against the ROS-generating compound 4NQO (p < 0.001) and the antibiotic NOR (p < 0.001). In the antioxidant evaluation, the activity in DPPH assay was in a range of 6-23% for C. sinensis and of 22-71% for C. latifolia. Both were antioxidant compared with BHT in beta-carotene bleaching assay and were able to decreased apoptosis in HaCat cells stimulated with H2O2. The levels of intracellular superoxide ion were lower in the presence of both oils. In conclusion, the essential oils of C. sinensis and C. latifolia are antimutagenic against at least three types of mutagens and have antioxidants properties. PMID- 28904370 TI - In planta expression of hyperthermophilic enzymes as a strategy for accelerated lignocellulosic digestion. AB - Conversion of lignocellulosic biomass to biofuels and biomaterials suffers from high production costs associated with biomass pretreatment and enzymatic hydrolysis. In-planta expression of lignocellulose-digesting enzymes is a promising approach to reduce these cost elements. However, this approach faces a number of challenges, including auto-hydrolysis of developing cell walls, plant growth and yield penalties, low expression levels and the limited stability of expressed enzymes at the high temperatures generally used for biomass processing to release fermentable sugars. To overcome these challenges we expressed codon optimized recombinant hyperthermophilic endoglucanase (EG) and xylanase (Xyn) genes in A. thaliana. Transgenic Arabidopsis lines expressing EG and Xyn enzymes at high levels without any obvious plant growth or yield penalties were selected for further analysis. The highest enzyme activities were observed in the dry stems of transgenic lines, indicating that the enzymes were not degraded during stem senescence and storage. Biomass from transgenic lines exhibited improved saccharification efficiency relative to WT control plants. We conclude that the expression of hyperthermophilic enzymes in plants is a promising approach for combining pretreatment and enzymatic hydrolysis processes in lignocellulosic digestion. This study provides a valid foundation for further studies involving in planta co-expression of core and accessory lignocellulose-digesting enzymes. PMID- 28904371 TI - Acute interaction between hydrocortisone and insulin alters the plasma metabolome in humans. AB - With the aim of identifying biomarkers of glucocorticoid action and their relationship with biomarkers of insulin action, metabolomic profiling was carried out in plasma samples from twenty healthy men who were administered either a low or medium dose insulin infusion (n = 10 each group). In addition, all subjects were given metyrapone (to inhibit adrenal cortisol secretion) + /- hydrocortisone (HC) in a randomised crossover design to produce low, medium and high glucocorticoid levels. The clearest effects of insulin were to reduce plasma levels of the branched chain amino acids (BCAs) leucine/isoleucine and their deaminated metabolites, and lowered free fatty acids and acylcarnitines. The highest dose of hydrocortisone increased plasma BCAs in both insulin groups but increased free fatty acids only in the high insulin group, however hydrocortisone did not affect the levels of acyl carnitines in either group. The clearest interaction between HC and insulin was that hydrocortisone produced an elevation in levels of BCAs and their metabolites which were lowered by insulin. The direct modulation of BCAs by glucocorticoids and insulin may provide the basis for improved in vivo monitoring of glucocorticoid and insulin action. PMID- 28904373 TI - Spatial and temporal distribution of phase slips in Josephson junction chains. AB - The Josephson effect, tunnelling of a supercurrent through a thin insulator layer between two superconducting islands, is a phenomena characterized by a spatially distributed phase of the superconducting condensate. In recent years, there has been a growing focus on Josephson junction devices particularly for the applications of quantum metrology and superconducting qubits. In this study, we report the development of Josephson junction circuit formed by serially connecting many Superconducting Quantum Interference Devices, SQUIDs. We present experimental measurements as well as numerical simulations of a phase-slip center, a SQUID with weaker junctions, embedded in a Josephson junction chain. The DC transport properties of the chain are the result of phase slips which we simulate using a classical model that includes linear external damping, terminating impedance, as well as internal nonlinear quasiparticle damping. We find good agreement between the simulated and the experimental current voltage characteristics. The simulations allow us to examine the spatial and temporal distribution of phase-slip events occurring across the chains and also the existence of travelling voltage pulses which reflect at the chain edges. PMID- 28904372 TI - Butyrate-producing bacteria supplemented in vitro to Crohn's disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity. AB - The management of the dysbiosed gut microbiota in inflammatory bowel diseases (IBD) is gaining more attention as a novel target to control this disease. Probiotic treatment with butyrate-producing bacteria has therapeutic potential since these bacteria are depleted in IBD patients and butyrate has beneficial effects on epithelial barrier function and overall gut health. However, studies assessing the effect of probiotic supplementation on microbe-microbe and host microbe interactions are rare. In this study, butyrate-producing bacteria (three mono-species and one multispecies mix) were supplemented to the fecal microbial communities of ten Crohn's disease (CD) patients in an in vitro system simulating the mucus- and lumen-associated microbiota. Effects of supplementation in short chain fatty acid levels, bacterial colonization of mucus environment and intestinal epithelial barrier function were evaluated. Treatment with F. prausnitzii and the mix of six butyrate-producers significantly increased the butyrate production by 5-11 mol%, and colonization capacity in mucus- and lumen associated CD microbiota. Treatments with B. pullicaecorum 25-3T and the mix of six butyrate-producers improved epithelial barrier integrity in vitro. This study provides proof-of-concept data for the therapeutic potential of butyrate producing bacteria in CD and supports the future preclinical development of a probiotic product containing butyrate-producing species. PMID- 28904374 TI - Corrigendum: High-throughput screening of metal-porphyrin-like graphenes for selective capture of carbon dioxide. AB - This corrects the article DOI: 10.1038/srep21788. PMID- 28904375 TI - A rechargeable iodine-carbon battery that exploits ion intercalation and iodine redox chemistry. AB - Graphitic carbons have been used as conductive supports for developing rechargeable batteries. However, the classic ion intercalation in graphitic carbon has yet to be coupled with extrinsic redox reactions to develop rechargeable batteries. Herein, we demonstrate the preparation of a free standing, flexible nitrogen and phosphorus co-doped hierarchically porous graphitic carbon for iodine loading by pyrolysis of polyaniline coated cellulose wiper. We find that heteroatoms could provide additional defect sites for encapsulating iodine while the porous carbon skeleton facilitates redox reactions of iodine and ion intercalation. The combination of ion intercalation with redox reactions of iodine allows for developing rechargeable iodine-carbon batteries free from the unsafe lithium/sodium metals, and hence eliminates the long standing safety issue. The unique architecture of the hierarchically porous graphitic carbon with heteroatom doping not only provides suitable spaces for both iodine encapsulation and cation intercalation but also generates efficient electronic and ionic transport pathways, thus leading to enhanced performance.Carbon-based electrodes able to intercalate Li+ and Na+ ions have been exploited for high performing energy storage devices. Here, the authors combine the ion intercalation properties of porous graphitic carbons with the redox chemistry of iodine to produce iodine-carbon batteries with high reversible capacities. PMID- 28904376 TI - Erratum: Identification of a six-lncRNA signature associated with recurrence of ovarian cancer. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28904377 TI - Kleptoplasty does not promote major shifts in the lipidome of macroalgal chloroplasts sequestered by the sacoglossan sea slug Elysia viridis. AB - Sacoglossan sea slugs, also known as crawling leaves due to their photosynthetic activity, are highly selective feeders that incorporate chloroplasts from specific macroalgae. These "stolen" plastids - kleptoplasts - are kept functional inside animal cells and likely provide an alternative source of energy to their host. The mechanisms supporting the retention and functionality of kleptoplasts remain unknown. A lipidomic mass spectrometry-based analysis was performed to study kleptoplasty of the sacoglossan sea slug Elysia viridis fed with Codium tomentosum. Total lipid extract of both organisms was fractionated. The fraction rich in glycolipids, exclusive lipids from chloroplasts, and the fraction rich in betaine lipids, characteristic of algae, were analysed using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-LC-MS). This approach allowed the identification of 81 molecular species, namely galactolipids (8 in both organisms), sulfolipids (17 in C. tomentosum and 13 in E. viridis) and betaine lipids (51 in C. tomentosum and 41 in E. viridis). These lipid classes presented similar lipidomic profiles in C. tomentosum and E. viridis, indicating that the necessary mechanisms to perform photosynthesis are preserved during the process of endosymbiosis. The present study shows that there are no major shifts in the lipidome of C. tomentosum chloroplasts sequestered by E. viridis. PMID- 28904378 TI - End-Cretaceous akaganeite as a mineral marker of Deccan volcanism in the sedimentary record. AB - An enigmatic chloride-rich iron (oxyhydr)oxide has been recently identified together with mercury anomalies in End-Cretaceous marine sediments coeval with the Deccan Traps eruptions. The mineral was observed in Bidart (France) and Gubbio (Italy), suggesting a widespread phenomenon. However, the exact nature and origin of this Cl-bearing mineral remained speculative. Here, we characterized the accurate composition and nanostructure of this chloride-rich phase by using micro-Raman spectroscopy, Transmission (TEM) and Scanning (SEM) Electron Microscopy on Focused Ion Beam foils. We also provide new evidence of its occurrence in Zumaia, a reference KPg section from Spain. Results confirm akaganeite (beta-FeOOH) as the main phase, with chloride content of 3-5 atomic weight %. Akaganeite particles are constituted by the aggregation of nanorods of akaganeite. Internal structures contain empty spaces, suggesting formation in a low-density (atmospheric) environment. This new mineralogical evidence supports the hypothesis that the observed akaganeite was formed in the Deccan volcanic plume and was transported to the Atlantic and Tethysian realms through the stratosphere. Therefore, akaganeite provides a potential new sedimentary marker to identify the imprint of the Deccan eruptions in the stratigraphic record and is evidence of volcanic halogen degassing and its potential role for the Cretaceous-Tertiary mass extinction. PMID- 28904379 TI - A Screening Mechanism Differentiating True from False Pain during Empathy. AB - Empathizing with another's suffering is important in social interactions. Empathic behavior is selectively elicited from genuine, meaningful pain but not from fake, meaningless scenarios. However, the brain's screening mechanism of false information from meaningful events and the time course for the screening process remains unclear. Using EEG combined with principle components analysis (PCA) techniques, here we compared temporal neurodynamics between the observation of pain and no-pain pictures as well as between true (painful expressions and needle-penetrated arms) and false (needle-penetrated faces with neutral expressions) pain pictures. The results revealed that pain vs. no-pain information is differentiated in the very early ERP components, i.e., the N1/P1 for the face and arm pictures categories and the VPP/N170 for the facial expression category while the mid-latency ERP components, N2 and P3, played key roles in differentiating true from false situations. The complex of N2 and P3 components may serve as a screening mechanism through which observers allocate their attentions to more important or relevant events and screen out false environmental information. This is the first study to describe and provide a time course of the screening process during pain empathy. These findings shed new light on the understanding of empathic processing. PMID- 28904380 TI - Transfer of labile organic matter and microbes from the ocean surface to the marine aerosol: an experimental approach. AB - Surface ocean bubble-bursting generates aerosols composed of microscopic salt water droplets, enriched in marine organic matter. The organic fraction profoundly influences aerosols' properties, by scattering solar radiations and nucleating water particles. Still little is known on the biochemical and microbiological composition of these organic particles. In the present study, we experimentally simulated the bursting of bubbles at the seawater surface of the North-Eastern Atlantic Ocean, analysing the organic materials and the diversity of the bacteria in the source-seawaters and in the produced aerosols. We show that, compared with seawater, the sub-micron aerosol particles were highly enriched in organic matter (up to 140,000x for lipids, 120,000x for proteins and 100,000x for carbohydrates). Also DNA, viruses and prokaryotes were significantly enriched (up to 30,000, 250 and 45x, respectively). The relative importance of the organic components in the aerosol did not reflect those in the seawater, suggesting their selective transfer. Molecular analyses indicate the presence of selective transfers also for bacterial genotypes, highlighting higher contribution of less abundant seawater bacterial taxa to the marine aerosol. Overall, our results open new perspectives in the study of microbial dispersal through marine aerosol and provide new insights for a better understanding of climate-regulating processes of global relevance. PMID- 28904381 TI - Sexual-size dimorphism modulates the trade-off between exploiting food and wind resources in a large avian scavenger. AB - Animals are expected to synchronize activity routines with the temporal patterns at which resources appear in nature. Accordingly, species that depend on resources showing temporally mismatched patterns should be expected to schedule routines that balance the chances of exploiting each of them. Large avian scavengers depend on carcasses which are more likely available early in the morning, but they also depend on wind resources (i.e. uplifts) to subside flight which are stronger in afternoon hours. To understand how these birds deal with this potential trade-off, we studied the daily routines of GPS-tagged individuals of the world's largest terrestrial soaring scavenger, the Andean condor (Vultur gryphus). Andean condors vary largely in weight and show a huge sexual dimorphism that allowed us to evaluate the effect of sex and body size on their daily routines. We found that condors use an intermediate solution strategy between the best times to exploit carcasses and uplifts, with this strategy changing over the year. Bigger males scheduled earlier routines that aligned more closely with uplift availability compared to smaller females, resulting in a partial temporal segregation between sexes. Condors' routines reflect a sexual-size dependent trade-off that may underpin ecological and sociobiological traits of the studied population. PMID- 28904382 TI - Multidimensional encoding of brain connectomes. AB - The ability to map brain networks in living individuals is fundamental in efforts to chart the relation between human behavior, health and disease. Advances in network neuroscience may benefit from developing new frameworks for mapping brain connectomes. We present a framework to encode structural brain connectomes and diffusion-weighted magnetic resonance (dMRI) data using multidimensional arrays. The framework integrates the relation between connectome nodes, edges, white matter fascicles and diffusion data. We demonstrate the utility of the framework for in vivo white matter mapping and anatomical computing by evaluating 1,490 connectomes, thirteen tractography methods, and three data sets. The framework dramatically reduces storage requirements for connectome evaluation methods, with up to 40x compression factors. Evaluation of multiple, diverse datasets demonstrates the importance of spatial resolution in dMRI. We measured large increases in connectome resolution as function of data spatial resolution (up to 52%). Moreover, we demonstrate that the framework allows performing anatomical manipulations on white matter tracts for statistical inference and to study the white matter geometrical organization. Finally, we provide open-source software implementing the method and data to reproduce the results. PMID- 28904383 TI - Effects of Coarse Graining and Saturation of Hydrocarbon Chains on Structure and Dynamics of Simulated Lipid Molecules. AB - Molecular dynamics simulations are used extensively to study the processes on biological membranes. The simulations can be conducted at different levels of resolution: all atom (AA), where all atomistic details are provided; united atom (UA), where hydrogen atoms are treated inseparably of corresponding heavy atoms; and coarse grained (CG), where atoms are grouped into larger particles. Here, we study the behavior of model bilayers consisting of saturated and unsaturated lipids DOPC, SOPC, OSPC and DSPC in simulations performed using all atom CHARMM36 and coarse grained Martini force fields. Using principal components analysis, we show that the structural and dynamical properties of the lipids are similar, both in AA and CG simulations, although the unsaturated molecules are more dynamic and favor more extended conformations. We find that CG simulations capture 75 to 100% of the major collective motions, overestimate short range ordering, result in more flexible molecules and 5-7 fold faster sampling. We expect that the results reported here will be useful for comprehensive quantitative comparisons of simulations conducted at different resolution levels and for further development and improvement of CG force fields. PMID- 28904384 TI - Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. AB - Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21 activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL. PMID- 28904386 TI - Skewed X inactivation in Lesch-Nyhan disease carrier females. AB - X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT deficiency carrier females. As a group, 75% of HPRT-deficiency carrier females presented skewed XCI. Moreover, skewed XCI is significantly more frequent in LND carriers (83%) than in LNV (0-50%, depending on the phenotype severity). The ratios of the preferentially inactivated allele of carrier females were significantly higher than the ratios of the preferentially inactivated allele of noncarrier females (89.4+/-15, n=52 vs 65.2+/-12, n=52; P<0.0001). For carrier diagnosis, the presence of skewed XCI presents a sensitivity of 75% with a specificity of 85%. In LND families, the presence of skewed XCI is more sensitive for carrier diagnosis than in LNV families; however, we believe that this test is not accurate for carrier diagnostic purposes. PMID- 28904385 TI - Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species. AB - In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans. PMID- 28904387 TI - Bacterial distributions and prognosis of bloodstream infections in patients with liver cirrhosis. AB - Bloodstream infections (BSIs) are a frequently observed complication in liver cirrhosis patients. This study aimed to investigate the microbiological characteristics and outcomes of BSIs in patients with liver cirrhosis. We retrospectively studied 852 patients with liver cirrhosis who developed a BSI. Patient outcome was evaluated using 30-day mortality and assessed using multivariate stepwise logistic regression analysis. Antibiotic sensitivity of the pathogens was tested. Gram-negative bacteria were responsible for 59.6% of BSIs, and Gram-positive bacteria caused 40.4% of the episodes among liver cirrhosis patients. The bacterial distribution significantly differed between hospital acquired and community-acquired infections, especially in cases caused by Gram negative pathogens. The results of the drug sensitivity test suggested that amikacin, cefoperazone/sulbactam, and piperacillin/tazobactam highly suppressed Gram-negative infections, while vancomycin and teicoplanin strongly inhibited Gram-positive BSIs. Liver failure, liver cancer, complications, Child-Pugh grade, septic shock, administration of appropriate antibiotics within 24 h, ICU admission, nosocomial infection, and Gram nature of the bacteria were independent risk factors for 30-day mortality (P < 0.05). The choice of initial empirical antibiotics should be based on the type, severity and origin of infection and on the local epidemiological data on antibiotic resistance. Accurate evaluation of risk factors for mortality may improve appropriate therapeutic choice. PMID- 28904389 TI - High wettability of liquid caesium iodine with solid uranium dioxide. AB - In March 2011, the Fukushima Daiichi Nuclear Power Plant accident caused nuclear fuel to melt and the release of high-volatility fission products into the environment. Caesium and iodine caused environmental contamination and public exposure. Certain fission-product behaviours remain unclear. We found experimentally that liquid CsI disperses extremely favourably toward solid UO2, exhibiting a contact angle approaching zero. We further observed the presence of CsI several tens of micrometres below the surface of the solid UO2 sample, which would be caused by the infiltration of pores network by liquid CsI. Thus, volatile fission products released from molten nuclear fuels with complex internal composition and external structure migrate or evaporate to varying extents, depending on the nature of the solid-liquid interface and the fuel material surface, which becomes the pathway for the released fission products. Introducing the concept of the wettability of liquid chemical species of fission products in contact with solid fuels enabled developing accurate behavioural assessments of volatile fission products released by nuclear fuel. PMID- 28904388 TI - Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells. AB - alpha-synuclein-induced neurotoxicity is a core pathogenic event in neurodegenerative synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. There is currently no disease-modifying therapy available for these diseases. We screened 1,600 FDA-approved drugs for their efficacy to protect LUHMES cells from degeneration induced by wild-type alpha-synuclein and identified dipyridamole, a non-selective phosphodiesterase inhibitor, as top hit. Systematic analysis of other phosphodiesterase inhibitors identified a specific phosphodiesterase 1 inhibitor as most potent to rescue from alpha-synuclein toxicity. Protection was mediated by an increase of cGMP and associated with the reduction of a specific alpha-synuclein oligomeric species. RNA interference experiments confirmed PDE1A and to a smaller extent PDE1C as molecular targets accounting for the protective efficacy. PDE1 inhibition also rescued dopaminergic neurons from wild-type alpha-synuclein induced degeneration in the substantia nigra of mice. In conclusion, this work identifies inhibition of PDE1A in particular as promising target for neuroprotective treatment of synucleinopathies. PMID- 28904390 TI - Quantum interference in the presence of a resonant medium. AB - Interaction of light with media often occurs with a femtosecond response time. Its measurement by conventional techniques requires the use of femtosecond lasers and sophisticated time-gated optical detection. Here we demonstrate that by exploiting quantum interference of entangled photons it is possible to measure the dephasing time of a resonant media on the femtosecond time scale (down to 100 fs) using accessible continuous wave laser and single-photon counting. We insert a sample in the Hong-Ou-Mandel interferometer and observe the modification of the two-photon interference pattern, which is driven by the coherent response of the medium, determined by the dephasing time. The dephasing time is then inferred from the observed pattern. This effect is distinctively different from the basic effect of spectral filtering, which was studied in earlier works. In addition to its ease of use, our technique does not require compensation of group velocity dispersion and does not induce photo-damage of the samples. Our technique will be useful for characterization of ultrafast phase relaxation processes in material science, chemistry, and biology. PMID- 28904391 TI - Exposure to genetically engineered olive fly (Bactrocera oleae) has no negative impact on three non-target organisms. AB - Bactrocera oleae (Diptera: Tephritidae) remains a major pest of olive fruit production worldwide. Current pest management programs largely depend on chemical insecticides, resulting in high economic and environmental costs. Alternative pest control approaches are therefore highly desirable. We have created a conditional female-specific self-limiting strain of B. oleae (OX3097D-Bol) that could be applied for sustainable pest control. OX3097D-Bol olive fly carries a fluorescent marker (DsRed2) for identification and a self-limiting genetic trait that is repressed by tetracycline. In the absence of tetracycline, the tetracycline transactivator (tTAV) accumulates, resulting in female death at larvae and early pupal stages. The aim of this study was to evaluate the impact of genetically engineered OX3097D-Bol olive fly on three non-target organisms that either predate or parasitize olive flies, one from the guild of parasitoids (Psyttalia concolor) and two from the guild of predators (Pardosa spider species and the rove beetle Aleochara bilineata). No significant negative effect was observed on life history parameters, mortality and reproductive capacity of the non-target organisms studied. These results suggest that potential exposure to DsRed2 and tTAV gene products (e.g. mRNA and encoded proteins) would have a negligible impact on on-target organisms in the guilds or predators and parasitoids. PMID- 28904392 TI - Emergent spectral properties of river network topology: an optimal channel network approach. AB - Characterization of river drainage networks has been a subject of research for many years. However, most previous studies have been limited to quantities which are loosely connected to the topological properties of these networks. In this work, through a graph-theoretic formulation of drainage river networks, we investigate the eigenvalue spectra of their adjacency matrix. First, we introduce a graph theory model for river networks and explore the properties of the network through its adjacency matrix. Next, we show that the eigenvalue spectra of such complex networks follow distinct patterns and exhibit striking features including a spectral gap in which no eigenvalue exists as well as a finite number of zero eigenvalues. We show that such spectral features are closely related to the branching topology of the associated river networks. In this regard, we find an empirical relation for the spectral gap and nullity in terms of the energy dissipation exponent of the drainage networks. In addition, the eigenvalue distribution is found to follow a finite-width probability density function with certain skewness which is related to the drainage pattern. Our results are based on optimal channel network simulations and validated through examples obtained from physical experiments on landscape evolution. These results suggest the potential of the spectral graph techniques in characterizing and modeling river networks. PMID- 28904395 TI - SECOND SPECIAL ISSUE: HERITAGE OF A PSYCHOANALYTIC MIND. FERENCZI INTERNATIONAL CONFERENCE IN TORONTO. PMID- 28904393 TI - MicroRNA pharmacogenomics based integrated model of miR-17-92 cluster in sorafenib resistant HCC cells reveals a strategy to forestall drug resistance. AB - Among solid tumors, hepatocellular carcinoma (HCC) emerges as a prototypical therapy-resistant tumor. Considering the emerging sorafenib resistance crisis in HCC, future studies are urgently required to overcome resistance. Recently noncoding RNAs (ncRNAs) have emerged as significant regulators in signalling pathways involved in cancer drug resistance and pharmacologically targeting these ncRNAs might be a novel stratagem to reverse drug resistance. In the current study, using a hybrid Petri net based computational model, we have investigated the harmonious effect of miR-17-92 cluster inhibitors/mimics and circular RNAs on sorafenib resistant HCC cells in order to explore potential resistance mechanisms and to identify putative targets for sorafenib-resistant HCC cells. An integrated model was developed that incorporates seven miRNAs belonging to miR-17-92 cluster (hsa-miR-17-5p, hsa-miR-17-3p, hsa-miR-19a, hsa-miR-19b, hsa-miR-18a, hsa-miR-20a and hsa-miR-92) and crosstalk of two signaling pathways (EGFR and IL-6) that are differentially regulated by these miRNAs. The mechanistic connection was proposed by the correlation between members belonging to miR-17-92 cluster and corresponding changes in the protein levels of their targets in HCC, specifically those targets that have verified importance in sorafenib resistance. Current findings uncovered potential pathway features, underlining the significance of developing modulators of this cluster to combat drug resistance in HCC. PMID- 28904394 TI - Ultraviolet B Light Emitting Diodes (LEDs) Are More Efficient and Effective in Producing Vitamin D3 in Human Skin Compared to Natural Sunlight. AB - Vitamin D, the sunshine vitamin is important for health. Those with fat malabsorption disorders malabsorb vitamin D and thus must rely on cutaneous production of vitamin D3. Vitamin D3 is generated secondary to exposure to ultraviolet B (UVB) radiation (whether from the sun or from an artificial source). Light emitting diodes (LEDs) have been developed to emit ultraviolet radiation. Little is known about the efficiency of UVB emitting LEDs tuned to different wavelengths for producing vitamin D3 in human skin. Ampoules containing 7-dehydrocholesterol were exposed to a LED that emitted a peak wavelength at 293, 295, 298 or 305 nm to determine their efficiency to produce previtamin D3. The 293 nm LED was best suited for evaluating its effectiveness for producing vitamin D in human skin due to the shorter exposure time. This LED was found to be 2.4 times more efficient in producing vitamin D3 in human skin than the sun in less than 1/60th the time. This has significant health implications for medical device development in the future that can be used for providing vitamin D supplementation to patients with fat malabsorption syndromes as well as patients with other metabolic abnormalities including patients with chronic kidney disease. PMID- 28904396 TI - The Failure of Clara Thompson's Ferenczian (Proxy) Analysis of Harry Stack Sullivan. AB - After hearing Ferenczi's talks on theory and practice in New York in 1926, psychiatrist Harry Stack Sullivan urged his friend and colleague Clara Thompson to get analyzed by Ferenczi so they could learn his technique. After saving for 2 years Thompson was a patient of Ferenczi for three summers and then moved to Budapest full-time for analysis until Ferenczi's death. Two years after she returned to New York she attempted to analyze Sullivan. Analysis was broken off in anger by Sullivan after 14 months. Before the promised Ferenczian analysis began Thompson discovered Wilhelm Reich's Character Analysis (1933) and she tried an aggressive attack on character with Sullivan rather than Ferenczian trauma oriented "relaxation" and "neocathartic" therapy. Sullivan could not tolerate this. Because of their own unhealed trauma both individually and in relation to each other, neither Thompson nor Sullivan was able to advance Ferenczi's views on trauma or its healing in America. PMID- 28904397 TI - Study of the link between dopamine transporter gene polymorphisms and response to paroxetin and escitalopram in patients with lifelong premature ejaculation. AB - We evaluated the role of dopamine (DA) transporter gene polymorphism in lifelong premature ejaculation (LPE) and its role in determining the response to paroxetine and escitalopram. Eighty consecutive patients and controls were recruited. Sixty of them suffered from LPE. They were divided into two equal groups. One group received paroxetine 20 mg daily for 3 months and the other one received ecistalopram 20 mg daily for 3 months. Their wives were instructed to measure the intra-vaginal ejaculation latency time using stopwatch. Five milliliters of blood was withdrawn from patients and controls for PCR analysis. The present study revealed that the mean ages of the patients and controls were 41.42 and 36.4 years, respectively. The majority of the patients were of (10R/10R) genotypes of the DA transporter gene polymorphism, whereas the controls were of (6R/6R) genotypes and this revealed statistically significant result (P value=0.001). Both paroxitine and escitalopram significantly delayed ejaculation in the responders (P-values=0.001 and 0.001, respectively). The study revealed significant association between such response and DA transporter gene polymorphism (P-values of fold increase and log FI were 0.019 and 0.010, respectively). To the best of our knowledge, this is the first report to demonstrate a highly significant association between such response and DA transporter gene polymorphism in patients with LPE. PMID- 28904398 TI - Genetic variants in PPP2CA are associated with gastric cancer risk in a Chinese population. AB - Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02-1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 * 10-6), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population. PMID- 28904400 TI - Enhanced Bandwidth of High Directive Emission Fabry-Perot Resonator Antenna with Tapered Near-Zero Effective Index Using Metasurface. AB - In this paper, a novel explanation on high directive emission of Fabry-Perot resonator antenna with subwavelength metasurface is proposed. Based on image theory and effective constitutive parameter retrieval, the whole Fabry-Perot resonant cavity structure composed of a single-layer metasurface with square ring element and a PEC ground plate can be acted as an effective metamaterial media with very low refractive index (near zero index). According to Snell's theory, this property can be used to enhance the directive emission. Based on this, with tapered size square ring unitcell, the overlapped bandwidth in which the effective refractive index is near to zero is obtained to widen the bandwidth of high directive emission. It is demonstrated that the maximum of directivity is nearly approaching to 19 dBi, and its 3-dB bandwidth can be improved to 19.5%. A final prototype has been fabricated and measured to validate the proposed design concept. The measured 3-dB gain bandwidth is approximately 20.3% with a peak gain of 17.9 dBi. These results indicate the feasibility of such kind of antenna for broadband and high directivity applications simultaneously. PMID- 28904399 TI - Semaphorin 3 C drives epithelial-to-mesenchymal transition, invasiveness, and stem-like characteristics in prostate cells. AB - Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leader in cancer-related deaths. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease underscoring the need to identify mechanisms mediating PCa progression. The semaphorins are a large grouping of membrane-associated or secreted signalling proteins whose normal roles reside in embryogenesis and neuronal development. In this context, semaphorins help establish chemotactic gradients and direct cell movement. Various semaphorin family members have been found to be up- and down-regulated in a number of cancers. One family member, Semaphorin 3 C (SEMA3C), has been implicated in prostate, breast, ovarian, gastric, lung, and pancreatic cancer as well as glioblastoma. Given SEMA3C's roles in development and its augmented expression in PCa, we hypothesized that SEMA3C promotes epithelial-to-mesenchymal transition (EMT) and stem-like phenotypes in prostate cells. In the present study we show that ectopic expression of SEMA3C in RWPE-1 promotes the upregulation of EMT and stem markers, heightened sphere-formation, and cell plasticity. In addition, we show that SEMA3C promotes migration and invasion in vitro and cell dissemination in vivo. PMID- 28904401 TI - Identification of Genetically Important Individuals of the Rediscovered Floreana Galapagos Giant Tortoise (Chelonoidis elephantopus) Provide Founders for Species Restoration Program. AB - Species are being lost at an unprecedented rate due to human-driven environmental changes. The cases in which species declared extinct can be revived are rare. However, here we report that a remote volcano in the Galapagos Islands hosts many giant tortoises with high ancestry from a species previously declared as extinct: Chelonoidis elephantopus or the Floreana tortoise. Of 150 individuals with distinctive morphology sampled from the volcano, genetic analyses revealed that 65 had C. elephantopus ancestry and thirty-two were translocated from the volcano's slopes to a captive breeding center. A genetically informed captive breeding program now being initiated will, over the next decades, return C. elephantopus tortoises to Floreana Island to serve as engineers of the island's ecosystems. Ironically, it was the haphazard translocations by mariners killing tortoises for food centuries ago that created the unique opportunity to revive this "lost" species today. PMID- 28904403 TI - An in planta biolistic method for stable wheat transformation. AB - The currently favoured method for wheat (Triticum aestivum L.) transformation is inapplicable to many elite cultivars because it requires callus culture and regeneration. Here, we developed a simple, reproducible, in planta wheat transformation method using biolistic DNA delivery without callus culture or regeneration. Shoot apical meristems (SAMs) grown from dry imbibed seeds were exposed under a microscope and subjected to bombardment with different-sized gold particles coated with the GFP gene construct, introducing DNA into the L2 cell layer. Bombarded embryos were grown to mature, stably transformed T0 plants and integration of the GFP gene into the genome was determined at the fifth leaf. Use of 0.6-um particles and 1350-psi pressure resulted in dramatically increased maximum ratios of transient GFP expression in SAMs and transgene integration in the fifth leaf. The transgene was integrated into the germ cells of 62% of transformants, and was therefore inherited in the next generation. We successfully transformed the model wheat cultivar 'Fielder', as well as the recalcitrant Japanese elite cultivar 'Haruyokoi'. Our method could potentially be used to generate stable transgenic lines for a wide range of commercial wheat cultivars. PMID- 28904404 TI - Response to 'Non-invasive high frequency ventilation and the errors from the past: designing simple trials neglecting complex respiratory physiology'. PMID- 28904402 TI - Power frequency magnetic field promotes a more malignant phenotype in neuroblastoma cells via redox-related mechanisms. AB - In accordance with the classification of the International Agency for Research on Cancer, extremely low frequency magnetic fields (ELF-MF) are suspected to promote malignant progression by providing survival advantage to cancer cells through the activation of critical cytoprotective pathways. Among these, the major antioxidative and detoxification defence systems might be targeted by ELF-MF by conferring cells significant resistance against clinically-relevant cytotoxic agents. We investigated whether the hyperproliferation that is induced in SH-SY5Y human neuroblastoma cells by a 50 Hz, 1 mT ELF magnetic field was supported by improved defence towards reactive oxygen species (ROS) and xenobiotics, as well as by reduced vulnerability against both H2O2 and anti-tumor ROS-generating drug doxorubicin. ELF-MF induced a proliferative and survival advantage by activating key redox-responsive antioxidative and detoxification cytoprotective pathways that are associated with a more aggressive behavior of neuroblastoma cells. This was coupled with the upregulation of the major sirtuins, as well as with increased signaling activity of the erythroid 2-related nuclear transcription factor 2 (NRF2). Interestingly, we also showed that the exposure to 50 Hz MF as low as 100 uT may still be able to alter behavior and responses of cancer cells to clinically-relevant drugs. PMID- 28904405 TI - Noninvasive high-frequency ventilation and the errors from the past: designing simple trials neglecting complex respiratory physiology. PMID- 28904406 TI - Response dynamics of rat barrel cortex neurons to repeated sensory stimulation. AB - Neuronal adaptation is a common feature observed at various stages of sensory processing. Here, we quantified the time course of adaptation in rat somatosensory cortex. Under urethane anesthesia, we juxta-cellularly recorded single neurons (n = 147) while applying a series of whisker deflections at various frequencies (2-32 Hz). For ~90% of neurons, the response per unit of time decreased with frequency. The degree of adaptation increased along the train of deflections and was strongest at the highest frequency. However, a subset of neurons showed facilitation producing higher responses to subsequent deflections. The response latency to consecutive deflections increased both for neurons that exhibited adaptation and for those that exhibited response facilitation. Histological reconstruction of neurons (n = 45) did not reveal a systematic relationship between adaptation profiles and cell types. In addition to the periodic stimuli, we applied a temporally irregular train of deflections with a mean frequency of 8 Hz. For 70% of neurons, the response to the irregular stimulus was greater than that of the 8 Hz regular. This increased response to irregular stimulation was positively correlated with the degree of adaptation. Altogether, our findings demonstrate high levels of diversity among cortical neurons, with a proportion of neurons showing facilitation at specific temporal intervals. PMID- 28904407 TI - Syk-dependent tyrosine phosphorylation of 3BP2 is required for optimal FcRgamma mediated phagocytosis and chemokine expression in U937 cells. AB - The adaptor protein c-Abl SH3 domain binding protein-2 (3BP2) is tyrosine phosphorylated by Syk in response to cross-linking of antigen receptors, which in turn activates various immune responses. Recently, a study using the mouse model of cherubism, a dominant inherited disorder caused by mutations in the gene encoding 3BP2, showed that 3BP2 is involved in the regulation of phagocytosis mediated by Fc receptor for IgG (FcgammaR) in macrophages. However, the molecular mechanisms underlying 3BP2-mediated regulation of phagocytosis and the physiological relevance of 3BP2 tyrosine phosphorylation remains elusive. In this study, we established various gene knockout U937 cell lines using the CRISPR/Cas9 system and found that 3BP2 is rapidly tyrosine phosphorylated by Syk in response to cross-linking of FcgammaRI. Depletion of 3BP2 caused significant reduction in the Fc receptor gamma chain (FcRgamma)-mediated phagocytosis in addition to the FcgammaRI-mediated induction of chemokine mRNA for IL-8, CCL3L3 and CCL4L2. Syk dependent tyrosine phosphorylation of 3BP2 was required for overcoming these defects. Finally, we found that the PH and SH2 domains play important roles on FcgammaRI-mediated tyrosine phosphorylation of 3BP2 in HL-60 cells. Taken together, these results indicate that Syk-dependent tyrosine phosphorylation of 3BP2 is required for optimal FcRgamma-mediated phagocytosis and chemokine expression. PMID- 28904408 TI - Schismatoglottis and Apoballis (Araceae: Schismatoglottideae): A new example for the significance of pollen morphology in Araceae systematics. AB - Pollen characters in Araceae accord well with recent DNA-based phylogenies, and here we provide a new example of "compass needle" quality in Araceae on the basis of two closely related genera, Schismatoglottis and Apoballis. All investigated Schismatoglottis pollen is psilate (smooth pollen surface) with calcium crystals covering the pollen surface. By contrast, pollen of species transferred to recently resurrected Apoballis (Apoballis acuminatissima and A. mutata) is distinctively echinate (spiny). A unique layer covers the endexine of Schismatoglottis, and the whole pollen surface of Apoballis. Our findings strongly suggest that "Schismatoglottis" species with echinate pollen fall into the genus Apoballis. Moreover, all schismatoglottid taxa perform spathe movements during anthesis to control the movement of pollinators. The spathe movements of Apoballis acuminatissima clearly differ from those known in Schismatoglottis species, and indeed are so far unique for the entire family. This, together with differences in floral odour is strongly suggestive of differences in pollination ecology between the genera Schismatoglottis and Apoballis. PMID- 28904409 TI - Biomedical Applications of Polyhydroxyalkanoates. AB - Polyhydroxyalkanoates (PHA) are produced by a large number of microbes under stress conditions such as high carbon (C) availability and limitations of nutrients such as nitrogen, potassium, phosphorus, magnesium, and oxygen. Here, microbes store C as granules of PHAs-energy reservoir. PHAs have properties, which are quite similar to those of synthetic plastics. The unique properties, which make them desirable materials for biomedical applications is their biodegradability, biocompatibility, and non-toxicity. PHAs have been found suitable for various medical applications: biocontrol agents, drug carriers, biodegradable implants, tissue engineering, memory enhancers, and anticancer agents. PMID- 28904410 TI - Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae. AB - Ergosterol, an important component of the fungal cell membrane, is not only essential for fungal growth and development but also very important for adaptation to stress in fungi. Ergosterol is also a direct precursor for steroid drugs. The biosynthesis of ergosterol can be divided into three modules: mevalonate, farnesyl pyrophosphate (farnesyl-PP) and ergosterol biosynthesis. The regulation of ergosterol content is mainly achieved by feedback regulation of ergosterol synthase activity through transcription, translation and posttranslational modification. The synthesis of HMG-CoA, catalyzed by HMGR, is a major metabolic check point in ergosterol biosynthesis. Excessive sterols can be subsequently stored in lipid droplets or secreted into the extracellular milieu by esterification or acetylation to avoid toxic effects. As sterols are insoluble, the intracellular transport of ergosterol in cells requires transporters. In recent years, great progress has been made in understanding ergosterol biosynthesis and its regulation in Saccharomyces cerevisiae. However, few reviews have focused on these studies, especially the regulation of biosynthesis and intracellular transport. Therefore, this review summarizes recent research progress on the physiological functions, biosynthesis, regulation of biosynthesis and intracellular transportation of ergosterol in S. cerevisiae. PMID- 28904411 TI - Structural and Functional Properties, Biosynthesis, and Patenting Trends of Bacterial Succinoglycan: A Review. AB - The exopolysaccharide succinoglycan is produced mainly by a large number of soil microbes of Agrobacterium, Rhizobium or Pseudomonas genera etc. Structural properties of succinoglycan are unique in terms of its thermal stability and superior viscosifying property. Unlike the other highly commercialized bacterial exopolysaccharides like dextran or xanthan, mass scale application of succinoglycan has not been that much broadly explored yet. Bacterial succinoglycan is found suitable as a viscosifying and emulsifying agent in food industry, in gravel packing or fluid-loss control agent etc. In this present review, the key aspects of succinoglycan study, in particular, developments in structural characterizations, exo/exs operon system involved in biosynthesis pathway, commercial applications in food and other industries and patenting trends have been discussed. PMID- 28904412 TI - Bio-prospecting Bacterial Diversity of Hot Springs in Northern Himalayan Region of India for Laccases. AB - Bacterial diversity of hot springs of northern Himalayan region of India was studied and explored for laccases, the multicopper enzymes applicable in a large number of industries due to their ability to utilize a wide range of substrates. 220 operational taxonomic units (OTUs) out of 5551 sequence reads for bacterial diversity and 3 OTUs out of 19 sequence reads for Laccase like multicopper oxidases (LMCOs) diversity were generated. Bacteroidetes (74.28%) was the most abundant phylum including genus Paludibacter (66.96%), followed by phylum Proteobacteria (24.53%) including genera Chitinilyticum (7.55%) and Cellvibrio (6.14%). In case of laccase diversity, three LMCO sequences showed affiliation with proteobacteria and one with two domain laccase from uncultivable bacteroidetes. LMCO sequences belonged to H and N families. PMID- 28904413 TI - Hexavalent Chromium Reduction from Pollutant Samples by Achromobacter xylosoxidans SHB 204 and its Kinetics Study. AB - Cr(VI) is most toxic heavy metal and second most widespread hazardous metal compound worldwide. Present work focused on Cr(VI) reduction from synthetic solutions and polluted samples by Achromobacter xylosoxidans SHB 204. It could tolerate Cr(VI) up to 1600 ppm and reduce 500 ppm with 4.5 chromium reductase enzyme units (U) having protein size 30 kDa. Changes in morphology of cells on interaction with Cr(VI) metal ion was also studied using SEM-EDX and FTIR. Microcosm studies in pollutant samples for Cr(VI) reduction and adsorption isotherm with biomass of bacterium was best fitted with Langmuir model along with kinetic studies. This study focuses on significance of Cr reduction from synthetic solutions and polluted samples by A. xylosoxidans SHB 204 and its potential for bioremediation. PMID- 28904414 TI - Identification of Arsenic Resistance Genes from Marine Sediment Metagenome. AB - A metagenomic library of sea sediment metagenome containing 245,000 recombinant clones representing ~ 2.45 Gb of sea sediment microbial DNA was constructed. Two unique arsenic resistance clones, A7 and A12, were identified by selection on sodium arsenite containing medium. Clone A7 showed a six-fold higher resistance to arsenate [As(V)], a three-fold higher resistance to arsenite [As(III)] and significantly increased resistance to antimony [Sb(III)], while clone A12 showed increased resistance only to sodium arsenite and not to the other two metalloids. The clones harbored inserts of 8.848 Kb and 6.771 Kb, respectively. Both the clones possess A + T rich nucleotide sequence with similarity to sequences from marine psychrophilic bacteria. Sequence and transposon-mutagenesis based analysis revealed the presence of a putative arsenate reductase (ArsC), a putative arsenite efflux pump (ArsB/ACR) and a putative NADPH-dependent FMN reductase (ArsH) in both the clones and also a putative transcriptional regulatory protein (ArsR) in pA7. The increased resistance of clone A7 to As(V), As(III) and Sb(III) indicates functional expression of ArsC and ArsB proteins from pA7. The absence of increased As(V) resistance in clone A12 may be due to the expression of a possible inactive ArsC, as conserved Arg60 residue in this protein was replaced by Glu60, while the absence of Sb(III) resistance may be due to the presence of an ACR3p-type arsenite pump, which is known to lack antimony transport ability. PMID- 28904415 TI - Targeted Metagenome Based Analyses Show Gut Microbial Diversity of Inflammatory Bowel Disease patients. AB - Inflammatory bowel disease (IBD) is a multifactorial disease including both genetic and environmental factors. We compared the diversity of intestinal microbesamong a cohort of IBD patients to study the microbial ecological effects on IBD. Fecal samples from patients were sequenced with next generation sequence technology at 16S rDNA region. With statistical tools, microbial community was investigated at different level. The gut microbial diversity of Crohn's disease (CD) patients and colonic polyp (CP) patients significantly different from each other. However, the character of ulcerative colitis (UC) patients has of both CD and CP features. The microbial community from IBD patients can be very different (CD patient) or somewhat similar (UC patients) to non-IBD patients. Microbial diversity can be an important etiological factor for IBD clinical phenotype. PMID- 28904416 TI - Knockout of pprM Decreases Resistance to Desiccation and Oxidation in Deinococcus radiodurans. AB - Deinococcus radiodurans has attracted a great interest in the past decades due to its extraordinary resistance to ionizing radiation and highly efficient DNA repair system. Recent studies indicated that pprM is a putative pleiotropic gene in D. radiodurans and plays an important role in radioresistance and antioxidation, but its underlying mechanisms are poorly elucidated. In this study, pprM mutation was generated to investigate resistance to desiccation and oxidative stress. The result showed that the survival of pprM mutant under desiccation was markedly retarded compared to the wild strain from day 7-28. Furthermore, knockout of pprM increases the intercellular accumulation of ROS and the sensibility to H2O2 stress in the bacterial growth inhibition assay. The absorbance spectrum experiment for detecting the carotenoid showed that deinoxanthin, a carotenoid that peculiarly exists in Deinococcus, was reduced in the pprM mutant in the pprM mutant. Quantitative real time PCR showed decreased expression of three genes viz. CrtI (DR0861, 50%),CrtB (DR0862, 40%) and CrtO (DR0093, 50%), which are involved in deinoxanthin synthesis, and of Dps (DNA protection during starving) gene (DRB0092) relevant to ion combining and DNA protection in cells. Our results suggest that pprM may affect antioxidative ability of D. radiodurans by regulating the synthesis of deinoxanthin and the concentration of metal ions. This may provide new clues for the treatment of antioxidants. PMID- 28904417 TI - Itaconic Acid Production by Filamentous Fungi in Starch-Rich Industrial Residues. AB - Several fungi and starch-rich industrial residues were screened for itaconic acid (IA) production. Out of 15 strains, only three fungal strains were found to produce IA, which was confirmed by HPLC and GC-MS analysis. These strains were identified as Aspergillus terreus strains C1 and C2, and Ustilago maydis strain C3 by sequencing of 18S rRNA gene and internal transcribed spacer regions. Cis aconitate decarboxylase (cad) gene, which encodes a key enzyme in IA production in A. terreus, was characterized from strains C1 and C2. C1 and C2 cad gene sequences showed about 96% similarity to the only available GenBank sequence of A. terreus cad gene. 3-D structure and cis-aconitic acid binding pocket of Cad enzyme were predicted by structural modeling. Rice, corn and potato starch wastes were screened for IA production. These materials were enzymatically hydrolyzed under experimentally optimized conditions resulting in the highest glucose production of 230 mg/mL from 20% potato waste. On comparing the production potential of selected strains with different wastes, the best IA production was achieved with strain C1 (255.7 mg/L) using potato waste. Elemental composition as well as batch-to-batch variation in waste substrates were analyzed. The difference in IA production from two different batches of potato waste was found to inversely correlate with their phosphorus content, which indicated that A. terreus produced IA under phosphate limiting condition. The potato waste hydrolysate was deionized to remove inhibitory ions like phosphate, resulting in improved IA production of 4.1 g/L by C1 strain, which is commercially competitive. PMID- 28904418 TI - Leaf Extracts of Selected Gardening Trees Can Attenuate Quorum Sensing and Pathogenicity of Pseudomonas aeruginosa PAO1. AB - An increasing concern on resistance to multiple-antibiotics has led to the discovery of novel agents and the establishment of new precaution strategy. Numerous plant sources have been widely studied to reduce virulence of pathogenic bacteria by interfering cell-to-cell based communication called quorum sensing (QS). Leaf extracts of 17 gardening trees were collected and investigated for their anti-QS effects using a sensor strain Chromobacterium violaceum CV026. Methanolic extracts of K4 (Acer palmatum), K9 (Acer pseudosieboldianum) and K13 (Cercis chinensis) leaves were selected for further experiments based on their antagonism effect on QS without inhibiting C. violaceum CV026 growth. Subsequently, the leaf extracts on QS-mediated virulence of Pseudomonas aeruginosa PAO1 involved in biofilm formation, motility, bioluminescence, pyocyanin production, QS molecules production, and Caenorhabditis elegans killing activity were evaluated. The biofilm formation ability and swarming motility of P. aeruginosa PAO1 were decreased approximately 50% in the presence of these leaf extracts at a concentration of 1 mg/mL. The expression level of lecA::lux of P. aeruginosa PAO1 and pyocyanin production were also reduced. The three leaf extracts also decreased autoinducer (AI) production in P. aeruginosa PAO1 without direct degradation, suggesting that AI synthesis might have been suppressed by these extracts. The three leaf extracts also showed anti-infection activity in C. elegans model. Taken together, these results suggest that methanolic leaf extracts of K4, K9 and K13 have the potential to attenuate the virulence of P. aeruginosa PAO1. PMID- 28904419 TI - Fish Scales as Potential Substrate for Production of Alkaline Protease and Amino Acid Rich Aqua Hydrolyzate by Bacillus altitudinis GVC11. AB - Fish processing industries generate large quantities of fish scales as processing waste, if not treated leading to environmental pollution. Fish scales are hard to degrade, hence cause difficulty in waste management. In this context present study was made to utilize fish scales as substrate for the production of alkaline protease by Bacillus altitudinis GVC11 and subsequently amino acid rich aqua hydrolyzate. B. altitudinis GVC11 efficiently utilized five types of fish scales as substrates and produced maximum alkaline protease using Labeo rohita (28,150 U/mL) followed by Catla catla (23,320 U/mL) at 48 h and Cyprinus carpio (17,146 U/mL) Mugil cephalus (18,917 U/mL), Cirrhinus mrigala (12,430 U/mL) at 72 h. The HPLC analysis of protein hydrolyzate obtained after fermentation was enriched in essential amino acids, leucine, isoleucine, phenylalanine, lysine and non essential amino acids, tyrosine, arginine and cysteine which can be used as animal feed supplement and organic fertilizer. PMID- 28904420 TI - Oxygen Reduction Reaction Affected by Sulfate-Reducing Bacteria: Different Roles of Bacterial Cells and Metabolites. AB - Sulfate-reducing bacteria (SRB) were found to be capable of tolerating a certain amount of oxygen (O2), but how they affect oxygen reduction reaction (ORR) has not been clear. The present work investigated the impact of SRB on ORR in 3.5 wt% sodium chloride solution with the cyclic voltammetry method. The addition of SRB culture solution hampered both the reduction of O2 to superoxide (O2.-) and hydrogen peroxide (H2O2) to water (H2O), and the influence of SRB metabolites was much larger than that of bacterial cells. Sulfide and extracellular polymeric substances (EPS), typical inorganic and organic metabolic products, had great impact on ORR. Sulfide played an important role in the decrease of cathodic current for H2O2 reduction due to its hydrolysis and chemical reaction activity with H2O2. EPS were sticky, easy to adsorb on the electrode surface and abundant in functional groups, which hindered the transformation of O2 into O2.- and favored the reduction of H2O2 to H2O. PMID- 28904421 TI - Impact of Preservation Conditions on Fatty Acids, Xanthan Gum Production and Other Characteristics of Xanthomonas campestris pv. mangiferaeindicae IBSBF 2103. AB - The conditions of storage, cultivation and maintenance of microbial cultures should preserve the microbiological homogeneity, phenotypic and genotypic characteristics to ensure better reproducibility of metabolic production. To evaluate the influence of the storage condition on the composition of cell fatty acids, genetic profile and biochemical characteristics of Xanthomonas campestris pv. mangiferaeindicae IBSBF 2103, as well as, to identify its relationship with the yielding and viscosity of the xanthan gum produced, this study monitored the strain preserved in two simple and widely used conditions, ultra-freezer (-80 degrees C) and refrigeration (3-8 degrees C) during 5 months. Were identified and quantified 13 fatty acids. The cells preserved at -80 degrees C showed more stable concentration of all fatty acids, producing more xanthan gum and with higher viscosity. The chromosomal analysis obtained with the enzyme XbaI revealed 17 distinct fragments with maximum size of 485 kilobases, without variations among the subcultures maintained in both storage conditions. The X. campestris pv. mangiferaeindicae subcultures preserved at -80 degrees C showed less pronounced phenotypic variations, which had positive influence in the qualitative and quantitative characteristics of the xanthan gum produced. PMID- 28904422 TI - Melioration in Anti-staphylococcal Activity of Conventional Antibiotic(s) by Organic Acids Present in the Cell Free Supernatant of Lactobacillus paraplantarum. AB - In view of emerging drug resistance in pathogens, there is a need to explore alternative strategies to combat infections. Use of probiotics is one such option. In this regard, efficacy of Lactobacillus plantarum has been reported against Staphylococcus aureus. Here, we propose that cell free supernatant (CFS) of Lactobacillus paraplantarum when used in combination with conventional antibiotics viz. ampicillin and oxacillin [to which the methicillin resistant Staphylococcus aureus (MRSA) strains were originally resistant] reduce the minimum inhibitory concentrations of these antibiotics, rendering the combination either synergistic or additive against the tested MRSA strain. The anti staphylococcal activity was observed to be due to organic acids (acetic acid and lactic acid as confirmed by HPLC analysis) present in the CFS, as neutralization of the CFS with an alkali, sodium hydroxide (NaOH), caused the complete abrogation of its activity. The role of H2O2 and bacteriocin present in the CFS was also ruled out. The findings of this study suggest that cell free supernatant and ampicillin/oxacillin combination(s) might help in rejuvenating the use of conventional anti-staphylococcal antibiotics for the treatment of multi-drug resistant strains. PMID- 28904423 TI - Ultra-High Efficient Colony PCR for High Throughput Screening of Bacterial Genes. AB - Current colony PCR methods are not suitable for screening genes encoded in genomic DNA and are limited to E. coli host strains. Here, we describe an ultra high efficient colony PCR method for high throughput screening of bacterial genes embedded in the genomic DNA of any bacterial species. This new technique expands colony PCR method to several hosts as well as offers a rapid, less expensive and reliable bacterial genomic DNA extraction. PMID- 28904424 TI - Uncommon pollen walls: reasons and consequences). AB - : The mature pollen wall of gymnosperms and angiosperms consists in principle of two fundamentally different layers, the complex, thick sporopolleninous exine and the homogeneous, thin, single-layered pectocellulosic intine. In angiosperms, the typical exine is usually formed by a tectum, columellae, a foot layer, and an endexine. An exine reduction (minimally up to the complete absence) occurs in many unrelated seed plants, without consequences for pollen viability. The intine sometimes also deviates from its common form, being either extremely thick or appearing two- or even three-layered. Environmental factors or developmental constraints are highlighted as being responsible for the various deviating exine and intine forms. PACINI E & HESSE M 2012 UNKOMPLETTE POLLENWAND - GRUNDE UND KONSEQUENZEN: Die fertige Pollenwand der Gymnospermen und der Angiospermen besteht im Prinzip aus zwei fundamental verschiedenen Lagen, aus der komplexen, dicken und sporopolleninhaltigen Exine, und der homogenen, dunnen, einschichtigen und uberwiegend zellulosehaltigen Intine. Bei Angiospermen ist die typische Exine aus einem Tectum, aus Columellae, aus einem Foot Layer und zumeist noch aus einer Endexine geformt. In vielen, nicht miteinander verwandten Angiospermen (seltener bei Gymnospermen) is die Exine mehr oder weniger stark reduziert, was allerdings keinen Einflubeta auf die Keimungsfahigkeit des Pollens hat. Auch die Intine weicht manchmal von ihrer ublichen Ausbildung ab, ist entweder auffallend dick oder zwei bis dreischichtig. Sowohl Umweltfaktoren als auch embryologisch und entwicklungsgeschichtlich bedingte Hemmungen sind fur die abweichenden Exine- und Intineformen verantwortlich. PMID- 28904425 TI - Wait Up!: Attachment and Sovereign Power. AB - Sociologists and feminist scholars have, over many decades, characterised attachment as a social construction that functions to support political and gender conservatism. We accept that attachment theory has seen use to these ends and consider recent deployments of attachment theory as justification for a minimal State within conservative political discourse in the UK since 2009. However, we contest that attachment is reducible to its discursive construction. We consider Judith Butler's depiction of the infant attached to an abusive caregiver as a foundation and parallel to the position of the adult citizen subjected to punitive cultural norms and political institutions. We develop and qualify Butler's account, drawing on the insights offered by the work of Lauren Berlant. We also return to Foucault's Psychiatric Power lectures, in which familial relations are situated as an island of sovereign power within the sea of modern disciplinary institutions. These reflections help advance analysis of three important issues: the social and political implications of attachment research; the relationship between disciplinary and sovereign power in the affective dynamic of subjection; and the political and ethical status of professional activity within the psy disciplines. PMID- 28904426 TI - Recurrent Crescentic Immunoglobulin A Nephropathy in the Graft Kidney. PMID- 28904427 TI - MicroRNAs Involvement in Renal Pathophysiology: A Bird's Eye View. AB - MicroRNAs (miRNAs) are known to suppress gene expression by binding to messenger RNAs and in turn regulate different pathophysiological processes. Transforming growth factor-beta, mitogen-activated protein kinase signaling, and Wnt signaling like major pathways associated with miRNAs are involved with kidney diseases. The discovery of miRNAs has provided new insights into kidney pathologies and may provide effective therapeutic strategies. Research has demonstrated the role of miRNAs in a variety of kidney diseases including diabetic nephropathy, lupus nephritis, hypertension, nephritic syndrome, acute kidney injury, renal cell carcinoma, and renal fibrosis. miRNAs are implicated as playing a role in these diseases due to their role in apoptosis, cell proliferation, differentiation, and development. As miRNAs have been detected in a stable condition in different biological fluids, they have the potential to be tools to study the pathogenesis of human diseases with a great potential to be used in disease diagnosis and prognosis. The purpose of this review is to examine the role of miRNA in kidney disease. PMID- 28904428 TI - Collapsing Glomerulopathy- A Troublemaker for the Renal Allograft: Lessons Learnt. AB - Collapsing glomerulopathy (CG) is a well-recognized distinct morphological pattern of proliferative parenchymal injury leading to rapid graft failure. We conducted a single-center retrospective study to evaluate the prevalence, clinicopathological features, and prognosis of CG in renal transplant recepient. We analyzed 2518 renal allograft biopsies performed from 2007 to 2015 and correlated their clinicopathological features. The prevalence of CG was 0.83% (21 out of 2518) of allograft biopsies with a higher prevalence of 1.4% during the period from 2012 to 2015. Out of 21 patients, 18 (85.71%) patients had undergone live donor and 3 (14.28%) patients had undergone deceased donor renal transplant. Hypertension was observed in 3 (14.28%) patients. The mean duration of diagnosis for CG was 1.85 +/- 1.91 years. Urinalysis revealed microhematuria in 5 (23.8%) patients. The mean 24 h urinary protein excretion was 4.77 +/- 5.3 g and serum creatinine was 2.12 +/- 1.5 mg/dl. The predominant native kidney diseases in recipients were chronic glomerulonephritis of unknown etiology in 12 (57.14%) patients and hypertensive nephropathy in 3 (14.28%) patients. CG was associated with rejection in 9 (42.85%), calcineurin-inhibitor toxicity in 2 (9.5%), and BK virus nephropathy in 1 patient. All patients received standard triple immunosuppression. Eleven (52.38%) patients developed graft failure over a mean period of 2.2 +/- 1.7 years and 6 (28.57%) patients recovered with stable graft function. CG can coexist with viral infection, drug toxicity, rejection, microvascular injury, etc. CG usually presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients. PMID- 28904429 TI - Correlation of Pretransplant Donor-specific Antibody Assay Using Luminex Crossmatch with Graft Outcome in Renal Transplant Patients. AB - The significance of pretransplant anti-human leukocyte antigen antibody levels that are detectable by more sensitive platforms (including the Luminex platform) yet undetected by complement-dependent cytotoxicity (CDC) assay remains unclear. The aim of this study was to determine the clinical significance of the donor specific antibody (DSA) assay Luminex crossmatch and its impact on short-term renal graft outcome such as acute rejections, graft survival, and graft function. The results of pretransplant DSA-lymphocyte crossmatching (LCXM) assay in 126 renal allograft recipients whose CDCs crossmatches were negative were retrospectively analyzed for correlation with posttransplant outcomes. Of the 126 recipients, 32 (25.4%) had pretransplant DSA positive. Statistically significant association was found between DSA-LCXM positivity with 14th day estimated glomerular filtration rate (eGFR) (P = 0.05), DSA Class I with 3rd (P = 0.014) and 6th month (P = 0.02) eGFR, DSA Class II with 14th day (P = 0.06) and 1st month (P = 0.10) eGFR, mean fluorescent intensity (MFI) DSA with 7th day (P = 0.08) and 14th day (P = 0.09) eGFR, and maximum MFI DSA with 7th day eGFR (P = 0.09). The posttransplant eGFR was higher at various time intervals in DSA-LCXM negative patients as compared to DSA-positive patients. However, pretransplant DSA-LCXM results did not predict the rejection episodes, graft loss, and 1-year posttransplant 24 h urine protein. Pretransplant DSA detected by LCXM in patients with a negative CDC does not predict adverse short-term outcomes. However, the difference in posttransplant eGFR supports further investigation in long-term effects. PMID- 28904430 TI - Immunohistochemical Analysis of Anti-phospholipase A2 Receptor Antibody on Renal Biopsies: A Single Tertiary Care Center Study. AB - Membranous nephropathy (MN) is one of the common cause of nephrotic syndrome. The discrimination between primary MN (iMN) and secondary MN is essential because of treatment implications. Immunohistochemical (IHC) evaluation with the help of anti-phospholipase A2 receptor (PLA2R) antibody helps in tissue evaluation of iMN, which is an easy, cost-effective, and pathologist-friendly technique. The study included 82 cases of MN over a period of 3 years. IHC using PLA2R antibody was performed on iMN and secondary cases with adequate tissue. Cases of minimal change disease (MCD) were included as control. Granular staining along the basement membrane in the absence of staining of podocytes was considered positive. Medical records were verified for clinical information, baseline biochemical parameters, details of viral markers, connective tissue disease profile, and basic imaging workup. Of the 82 cases of MN, 51 were iMN and 31 secondary MN (sMN). Thirteen MCD cases were included as control. IHC with PLA2R antibody showed a sensitivity of 91.8% and specificity of 95.1%, positive predictive value of 95.7%, and negative predictive value of 90.7% in the diagnosis of iMN. The other parameters, either clinical or laboratory, did not show significant differences between iMN and sMN groups. The results of PLA2R staining by IHC were comparable with other studies and showed a higher sensitivity (91.8%) and specificity (95.1%). IHC with anti-PLA2R antibody can be considered as the standard diagnostic approach to identify iMN and offer scope for individualized treatment. PMID- 28904431 TI - Role of Gut-derived Uremic Toxins on Oxidative Stress and Inflammation in Patients with Chronic Kidney Disease. AB - Several cardiovascular disease (CVD) risk factors have been identified among patients with chronic kidney disease (CKD). Gut-derived uremic toxins (GDUT) are important modifiable contributors in this respect. There are very few Indian studies on GDUT changes in CKD. One hundred and twenty patients older than 18 years diagnosed with CKD were enrolled along with forty healthy subjects. The patients were classified into three groups of forty patients based on stage of CKD. Indoxyl sulfate (IS), para cresyl sulfate (p-CS), indole acetic acid (IAA), and phenol were estimated along with the assessment of oxidative stress (OS), inflammatory state, and bone mineral disturbance. All the GDUT increased across the three groups of CKD. All patients had higher levels of malondialdehyde (MDA), ferric reducing ability of plasma (FRAP), high-sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6) as compared to controls. IS and IAA showed positive association with MDA/FRAP corrected for uric acid, whereas IS and p-CS showed positive association with IL-6. IS, IAA, and phenol showed a positive association with calcium * phosphorus product. GDUT increase OS and inflammatory state in CKD and may contribute to CVD risk. PMID- 28904432 TI - Impact of Steroids on the Inflammatory Response after Ischemic Acute Kidney Injury in Rats. AB - Inflammation plays a crucial role in acute kidney injury (AKI). The current study was designed to analyze the influence of prednisolone treatment on the inflammatory reaction during the first 96 h after AKI induction in a rat model. AKI was induced by unilateral clipping of the renal vessels. The treatment group received prednisolone 5 mg/kg s.c. daily. Infiltration rates of macrophages, leukocytes, and T-cells (24, 96 h) as well as plasma concentrations of the inflammatory markers intercellular adhesion molecule, interleukin-1 beta (IL 1beta), IL-18, IL-6, and tumor necrosis factor-alpha (0, 6, 24, 96 h) were determined by fluorescence-activated cell sorting (FACS) analysis only. Ninety six hours after AKI induction, the prednisolone group demonstrated significantly lower creatinine concentrations compared to the control group (P < 0.05). Twenty four hours after induction of AKI, a significantly higher rate of infiltrating leukocytes was detectable with FACS analysis in the control group (P < 0.01) with a corresponding significantly higher rate of macrophages after 96 h (P < 0.01). IL-6 and IL-1beta demonstrated a peak after 6 h with a significantly higher release in the control group (IL-6: P < 0.01; IL-1beta: P < 0.05). In contrast to the control group, the prednisolone group demonstrated no further incline of IL 18 after 24 h. The results demonstrate the importance of stretching the observation period in an ischemia-reperfusion-induced AKI setting beyond the first 24 h. Despite the demonstrated protective effects of a continuous prednisolone application, it seems that this single anti-inflammatory agent will not be able to completely suppress the inflammatory response after an ischemia reperfusion-induced AKI. PMID- 28904433 TI - Risk Factors for Urinary Tract Infections in Renal Allograft Recipients: Experience of a Tertiary Care Center in Hyderabad, South India. AB - Renal transplantation is an effective and commonly performed procedure for end stage renal disease. Urinary tract infections are a major cause of morbidity and mortality in renal transplant patients. As data on postrenal transplant urinary tract infections from the Indian subcontinent are limited, the present study was conducted to estimate the burden of urinary tract infections in this vulnerable group of patients. This was a prospective study on patients undergoing renal transplantation in 2014 at our tertiary hospital in South India with a follow-up of 2 years to evaluate the risk factors for urinary tract infections. The prevalence of urinary tract infections was 41.9% with a male preponderance of 76.9%. Mean age of the 31 patients was 32.4 +/- 10.2 years (range: 16-55 years). Gram-negative bacilli were the most common isolates with Escherichia coli being the predominant pathogen (53.3%). All the infections occurred within 1 year of transplantation with delayed graft function (P < 0.001; confidence interval [CI]: 29.0-96.3) and prolonged hospital stay (P = 0.0281; CI: 42.1-99.6) being the significant risk factors for acquiring urinary tract infections. Carbapenemase production was noted in 33.3% of isolates and all the Gram-negative organisms isolated in the 1st month of transplantation were carbapenem-resistant (CR) E. coli. The high rate of carbapenem-resistant organisms in the early posttransplant period is a point of concern, especially with cadaver transplants. Infection control practices and catheter care need to be strictly monitored to minimize the risk for UTI in the immediate posttransplant period. PMID- 28904434 TI - Effect of Double Filtration Plasmapheresis on Various Plasma Components and Patient Safety: A Prospective Observational Cohort Study. AB - Double filtration plasmapheresis (DFPP) was historically used for blood group incompatible renal transplantation. Very few studies are available worldwide regarding its efficiency in removing specific plasma components, and safety. We conducted a prospective observational cohort study over 1 year on patients undergoing DFPP for various renal indications. There were 15 patients with 39 sessions. The pre- and post-procedure plasma samples of serum IgG, IgA, IgM, fibrinogen, calcium, phosphate, potassium, and magnesium were analyzed. The effluent albumin concentration was also measured, and complications during the hospital stay were recorded. Cumulative removal of serum IgG, IgA, IgM, fibrinogen, and albumin at the end of four sessions were 72%, 89%, 96%, 88.5%, and 21.3%, respectively and effluent albumin concentration was 1.75 - 2.0 times (range: 6.3 g/dl - 7.2 g/dl; mean +/- standard deviation (SD) - 7 g/dl +/- 0.3 g/dl) the preprocedural serum albumin (mean +/- SD - 3.5 g/dl +/- 0.5 g/dl). Removal of other plasma components were not statistically significant. Hypotensive episodes were observed only 16.6%, with the usage of effluent concentration albumin as replacement fluid despite an average 2.4 (mean +/- SD - 2.4 +/- 0.4 l) liters of plasma volume processing each session. DFPP removes IgG, IgA, IgM, fibrinogen, and albumin. The cumulative removal IgG (72%) is suboptimal, whereas IgA (89%) and IgM (96%) are comparable to historical controls. We observed lesser episodes (12.5%) of hypotension with effluent albumin concentration as replacement fluid, and all bleeding complications were observed when serum fibrinogen level was <50 mg/dl. PMID- 28904435 TI - Employment Status of Patients Receiving Maintenance Dialysis - Peritoneal and Hemodialysis: A Cross-sectional Study. AB - The long-term dialysis therapy for end-stage renal disease takes a heavy toll of quality of life of the patient. Several factors such as fatigue and decreased physical capability, impaired social and mental functioning, contribute to this forlorn state. To meld maintenance dialysis treatment with a regular employment can be a serious test. A cross-sectional study of employment of patients on hemodialysis and peritoneal dialysis in a state government tertiary institute in South India was performed between June 2015 and December 2015. Patients who completed 3 months of regular dialysis were only included in the study. The number of patients on hemodialysis was 157 and on peritoneal dialysis was 69. The employment status before the initiation of dialysis was 60% (93 out of 155) and 63.7% (44 out of 69) in hemodialysis and peritoneal dialysis, respectively. After initiation, the loss of employment was observed in 44% (41 out of 93) in hemodialysis and 51.2% (26 out of 44) in peritoneal dialysis (P = 0.2604). Even though there was fall of absolute number of job holders in both the blue and white collar jobs, the proportion of jobholders in the white collar job holders improved. On univariate analysis, the factors which influenced the loss of employment were males, age between 50 and 60 years, number of comorbidities >2, illiteracy and blue collar versus white collar job before the initiation of dialysis. The majority of patients had the scores above 80 on Karnofsky performance scale and the majority belonged upper and middle classes than lower classes on modified Kuppuswamy's socioeconomic status scale; however, the loss of employment was also disproportionately high. There appeared a substantial difference in the attitude of the patients toward the employment. There was no difference between hemodialysis and peritoneal dialysis in the loss of employment of our patients. PMID- 28904436 TI - Strongyloid Hyperinfection in a Patient with Immunocompromised Chronic Kidney Disease. AB - Strongyloid hyperinfection is seen in immunocompromised individuals with underlying lung disease. The use of immunosuppressive drugs is an important risk factor. We report a case of IgA nephropathy with crescent, started on glucocorticoid and mycophenolate mofetil. He presented with bilateral lung opacities with breathlessness. As the breathlessness was not improving, despite adequate ultrafiltration, bronchoscopy was done. Bronchoalveolar lavage fluid examination showed the presence of strongyloid larvae, which was later demonstrated in stool also. He responded to antihelminthic treatment with disappearance of larvae from stool but later developed secondary bacterial infections. PMID- 28904437 TI - Cryptococcal Infection in Transplant Kidney Manifesting as Chronic Allograft Dysfunction. AB - Invasive fungal infections (IFIs) are a significant cause of morbidity in solid organ transplant (SOT) recipients. Common causes among them are Aspergillus, Candida, and Cryptococcus. Antifungal prophylaxis has led to decrease in overall incidence of IFI; however, there is very little decline in the incidence of Cryptococcal infections of SOT recipients because effective prophylaxis is not available against this infectious agent. Spectrum of manifestation of Cryptococcal infection varies in immunocompetent and immunocompromised host with subclinical and self-limiting with lungs being the primary site in immunocompetent and central nervous system as the most common site in an immunocompromised host. Other preferred sites are cutaneous, pulmonary, urinary tract (prostate) and the bone. Herein, we describe a young adult renal transplant recipient male diagnosed as a rare case of biopsy proven Cryptococcal infection in transplant kidney manifesting as chronic allograft dysfunction. PMID- 28904438 TI - Plasma Cell Infiltration of the Kidney as a Manifestation of Myeloma: A Report of Three Cases. AB - Infiltration of renal parenchyma by neoplastic plasma cells in myeloma patients is an unusual finding. We report 3 cases of myeloma, with renal biopsy being the first clue to the diagnosis in one. The plasma cell infiltrate in other two cases was not so evident but immunofluorescence (IF) and immunohistochemical (IHC) stains for light chains helped establish the monoclonal nature of the infiltrate. We surmise that plasma cell infiltration in the kidney can be an important clue to the diagnosis of an underlying myeloma and could in future be regarded as a myeloma-defining event (MDE) if monoclonality is confirmed. This finding could directly affect the prognosis and be a direct indicator of the tumor burden. Further studies are however required to determine the exact prognostic value and precise relationship of such a finding with deranged renal functions in myeloma. PMID- 28904439 TI - Association of Amelogenesis Imperfecta and Bartter's Syndrome. AB - Bartter's syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure. Bartter's syndrome is associated with hypercalciuria and nephrocalcinosis. Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect dental enamel. AI could be part of several syndromes. The enamel renal syndrome is the association of AI and nephrocalcinosis. We report two patients of AI with Bartter's syndrome. PMID- 28904440 TI - Primary Hyperoxaluria Type 1 with Homozygosity for a Double-mutated AGXT Allele in a 2-year-old Child. AB - Primary hyperoxaluria (PH) Type 1 is a rare, genetic disorder caused by deficiency of the liver enzyme alanine-glyoxylate aminotransferase, which is encoded by AGXT gene. We report a 2-year-old South Indian Tamil child with nephrocalcinosis due to PH Type 1, in whom a homozygous genotype for two missense mutations in the AGXT gene was found: first, a C to G transversion (c. 32C>G) in exon 1 resulting in the amino acid substitution p.Pro11Arg; second, a T to A transversion (c. 167T>A) in exon 2 resulting in p.Ile56Asn. A therapy based on potassium citrate and pyridoxine was started. This is the first report of molecular testing-proven childhood onset-PH Type 1 from South India and is notable for the co-occurrence of two missense mutations in one AGXT allele, which might lead to different and more severe phenotype than each mutation alone. To the best of our knowledge, AGXT allele carrying two already known mutations has not been previously reported. PMID- 28904441 TI - Everolimus-associated Acute Kidney Injury in Patients with Metastatic Breast Cancer. AB - Recently, everolimus (Evl) has been introduced in the management of hormone receptor-positive metastatic breast cancer, in combination with aromatase inhibitors. Evl-induced acute kidney injury has hitherto been described in other malignancies, especially renal cell cancer, but only once before in a patient with breast cancer. We describe two cases of Evl-associated nephrotoxicity in patients with breast cancer, one of whom underwent a renal biopsy showing acute tubular necrosis. Both our patients improved after withdrawal of the offending agent and have normal renal functions on follow-up. PMID- 28904442 TI - Renal Cysts and Nephrocalcinosis in 11 Beta-hydroxylase Deficiency. PMID- 28904443 TI - To Compare Acute Peritoneal Dialysis with Sustained Low-efficiency Dialysis in Critically Ill Patients Requiring Renal Replacement Therapy. PMID- 28904444 TI - Utility of Determining Autoantibodies to M-type Phospholipase A2 Receptor in Diagnosing Primary Membranous Nephropathy: An Ideal Setting. PMID- 28904446 TI - Levodopa: History and Therapeutic Applications. AB - Levodopa - the aromatic amino acid L-3,4-dihydroxy phenylalanine has held the attention of neurologists and pharmacologists alike for more than half a century. Even though extensive research has been done across the globe in treatment of Parkinson's disease, with different molecules, none could replace the gold standard treatment or provide complete relief for the debilitated. Although research brought us better tips and tricks to modulate the dopamine blood levels to balance between the desired and deleterious effects, it could never replace the basic substrate. From simple oral preparation to more advanced treatment like duodenal dopa administration for better efficacy and compliance, L-dopa has sure undergone scrutiny and stayed strong as the fundamental neurotransmitter replacement therapy to pave path for many more new therapeutic strategies. So as a token of gratitude to the revolutionary agent and pioneers behind it, a trip down the memory lane is in order. PMID- 28904445 TI - Epidemiology of Peripheral Neuropathy: An Indian Perspective. AB - Peripheral neuropathy (PN) is a common disorder and presents as diagnostic and therapeutic challenge to physicians and neurologists. In epidemiological studies from India from various regions the overall prevalence of PN varied from 5 to 2400 per 10,000 population in various community studies. India is composed of a multiethnic, multicultural population who are exposed to different adverse environmental factors such as arsenic and lead. Use of different chemotherapeutic agents with propensity to affect peripheral nerves, increasing methods of diagnosis of connective tissue disorders and use of immunomodulating drugs, growing aging population is expected to change the spectrum and burden of peripheral neuropathy in the community. The other important aspect of peripheral neuropathies is in terms of the geographical and occupational distribution especially of toxic neuropathies like arsenic which is common in eastern belt; lead, mercury and organo-phosphorous compounds where occupational exposures are major sources. Inflammatory neuropathies either due to vasculitis or G B Syndrome, chronic inflammatory polyradiculopathies are another major group of neuropathies which is increasing due to increase longevity of Indian subjects and immunological impairment, also adds to morbidity of the patients and are potentially treatable. Leprous neuropathy is common in India and although its frequency is significantly decreasing because of national control program yet pure neuritic form still remains a cause of concern and similar is the case with another infective cause like diptheric neurpathy. Thus this article is an attempt to cover major categories and also highlight the areas where further studies are needed. PMID- 28904447 TI - Levodopa-induced Dyskinesia: Clinical Features, Pathophysiology, and Medical Management. AB - Levodopa-induced dyskinesia (LID) is commonly seen in Parkinson's disease patients treated with levodopa. This side effect is usually encountered after long duration of treatment, but occasionally, this may be seen even after few days or months of treatment. LID is broadly classified as peak-dose dyskinesia, wearing-off or off-period dyskinesia, and diphasic dyskinesia. Pathogenesis of LID is complex, and different neurotransmitters such as dopamine, glutamine, adenosine, and gamma-aminobutyric acid play important role altering the normal physiology of direct and indirect pathway of cortico-basal ganglia-thalamic loop responsible for fine motor control. Treatment of LID requires careful history taking and clinical examination to find the type of dyskinesia as different approach is required for different types. Changes in dopaminergic medication including continuous dopaminergic stimulation are very helpful in the management of peak-dose dyskinesia. Different types of surgical approaches including unilateral pallidotomy and deep brain stimulation have given very good result in patients, who cannot be managed by medications alone. The surgical management of LID is dealt with in detail in another review in this series. PMID- 28904449 TI - James Wenceslaus Papez, His Circuit, and Emotion. AB - James Papez worked on the anatomical substrates of emotion and described a circuit, mainly composed of the hippocampus, thalamus and cingulum, and published his observations in 1937. However, such an idea existed before him, as evidenced by the rudimentary indications from Paul Broca, and Paul MacLean added some other structures like, septum, amygdala, and hypothalamus in its ambit and called it the limbic system. Paul Ivan Yakovlev, proposed a circuit which also referred to orbitofrontal, insular, anterior temporal lobe, and other nuclei of thalamus. Further works hinted at cerebellar projections into this system and the clinical picture of aggression, arousal and positive feeding responses with stimulation of cerebellar nuclei, attests its possible role. Finally, the work of Heinrich Kluver and Paul Bucy of the United States of America on ablating the temporal lobes and amygdala and the resultant behaviour of the animals, almost incontrovertibly adduced evidence for the operation of a neural circuitry in the genesis of emotion. Additionally, Papez circuit may also be concerned with memory and damage to its various components in Parkinson's disease, Alzheimer's disease, Korsakoff's syndrome, semantic dementia, and global amnesia, where cognitive disturbance is almost universal, lends credence to its putative role. PMID- 28904448 TI - Surgical Treatment of Levodopa-induced Dyskinesia in Parkinson's Disease. AB - The treatment of motor manifestations of Parkinson's disease (PD) is essentially a trade-off between adequate relief of motor symptoms and prevention and control of motor complications, particularly levodopa-induced dyskinesia (LID). Progression of PD is paralleled by a progressive difficulty in achieving the balance. Functional neurosurgical procedures provide sustained relief of LID in carefully selected patients when further tailoring of medical therapy fails to achieve this goal. Though deep brain stimulation (DBS) has superseded lesioning surgeries, pallidotomy still has a role in those patients in whom DBS is not feasible for financial or other reasons. PMID- 28904450 TI - Acute Ischemic Stroke Treatment Using Mechanical Thrombectomy: A Study of 137 Patients. AB - BACKGROUND: Mechanical thrombectomy (MT) is the most effective treatment in large vessel occlusion (LVO). We have analyzed our initial experience of MT of 137 patients in anterior circulation (AC) and posterior circulation (PC) LVO using Solitaire stent retriever device. METHODS: Retrospective cohort analysis of 112 AC and 25 PC acute ischemic strokes was done considering various baseline characteristics, risk factors, National Institute of Health Stroke Scale (NIHSS) change, revascularization rate, complications, and functional outcome at 3 months using modified Rankin score. RESULTS: Out of 137 patients, occlusion was found in M1 segment (44.5%), carotid T occlusion (37.2%), and basilar artery (18.2%). Atrial fibrillation was important risk factor for Carotid T occlusion. 50.4% patients received intravenous thrombolysis. Baseline mean NIHSS in AC was 15.5 (+/-4.32), and PC was 19 (+/-5.5). Tandem lesions were noted in 14.6%. There was significant difference in mean door-to-needle time for AC and PC (220 +/- 80.6 and 326 +/- 191.8 min, respectively). Mean time to revascularization for AC (39.5 +/- 14.1) and PC (42.2 +/- 19.4) was similar. Procedural success (modified thrombolysis in cerebral infarction >=2b) observed in AC and PC was 92.9% and 84%, respectively (P = 0.154). NIHSS at admission between 5 and 15 and immediate postprocedure NIHSS improvement >4 was associated with significant better clinical outcome at 3 months. Overall complication rate was about 15.3% including symptomatic intracranial hemorrhage in 8.1% and 6.6% deaths. CONCLUSION: MT is safe treatment and equally effective for both AC and PC LVO. With careful patient selection, clinical outcome in PC was comparable to AC despite delayed presentation and higher baseline NIHSS. PMID- 28904451 TI - Short Version of the Bilingual Aphasia Test in Malayalam. AB - BACKGROUND: Brain damage can impair the use of all languages in bilingual persons. For effective management of aphasia (i.e., impaired language) in such persons, assessment of all languages is essential. The most widely used test for this purpose - the Bilingual Aphasia Test (BAT) - is cumbersome and requires a considerable amount of time for administration. To overcome this limitation, a short version of the BAT has been recommended. OBJECTIVE: The objective of this study was to derive a short version of BAT for Malayalam-English bilingual persons with aphasia and to establish the test-retest reliability as well as the content and construct validities of this version. METHODS: Following the recommendations of the test developers, we used seven subtests from the draft of an adapted full version of Malayalam BAT. These subtests in Malayalam and their counterparts in English were administered on a group of 22 Malayalam-English bilingual participants with aphasia. The scores obtained from these two languages were used to establish content and construct validities of the short version of the BAT in Malayalam. Further, we readministered the short version of BAT in a group of ten participants with aphasia to examine the test-retest reliability within 14 days from the date of first administration. RESULTS: The short version of BAT in Malayalam revealed high test-retest reliability as well as content and construct validities. The administration time ranged between 30 and 45 min. CONCLUSIONS: Thus, the short version of the BAT in Malayalam can be considered a valid and reliable language test that can be quickly administered in Malayalam English bilingual persons with aphasia. PMID- 28904452 TI - Long-term Response of Cerebrospinal Fluid Pressure in Patients with Idiopathic Intracranial Hypertension - A Prospective Observational Study. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is increased intracranial pressure (ICP) with normal cerebrospinal fluid (CSF) contents, in the absence of an intracranial mass, hydrocephalus, or other identifiable causes. The current knowledge of the treatment outcome of IIH is limited, and the data on the natural history of this entity are scant. OBJECTIVE: The objective of the study is to study the treatment response of IIH by serially measuring the CSF opening pressure and to delineate the factors influencing the same. MATERIALS AND METHODS: A prospective observational study in a cohort of fifty patients with IIH in whom CSF opening pressure was serially measured at pre-specified intervals. RESULTS: The mean CSF opening pressure at baseline was 302.4 +/- 51.69 mm of H2O (range: 220-410). Even though a higher body mass index (BMI) showed a trend toward a higher CSF opening pressure, the association was not significant (P = 0.168). However, the age of the patient had a significant negative correlation with the CSF pressure (P = 0.006). The maximum reduction in CSF pressure occurred in the first 3 months of treatment, and thereafter it plateaued. Remission was attained in 12 (24%) patients. BMI had the strongest association with remission (P = 0.001). CONCLUSIONS: In patients with IIH, treatment response is strongly related to BMI. However, patients with normal BMI are also shown to relapse and hence should have continuous, long-term follow-up. The reduction in CSF pressure attained in the first 3 months could reflect the long-term response to treatment. PMID- 28904453 TI - Hospital-based Retrospective Study of Cryptococcal Meningitis in a Large Cohort from India. AB - BACKGROUND: Cryptococcal meningitis is an important and a fatal neuroinfection. Early diagnosis and treatment is of utmost importance in reducing morbidity and mortality. MATERIALS AND METHODS: Data of patients with laboratory-confirmed cryptococcal meningitis seen in tertiary care hospital were reviewed. Details of demographic profile, clinical data, laboratory parameters, complications, and in hospital mortality were studied. RESULTS: Among 97 patients with cryptococcal meningitis (79 men, 18 women), 88 were HIV-positive, two were diabetic, and seven were sporadic. Their age ranged from 23 to 67 years (39.16 +/- 9.49). Additional pathogens for meningitis were identified in 24 patients. Headache was the most common symptom (91%) followed by fever (66%), vomiting (51%), altered sensorium (31%), and seizures (20%). Neurological deficits included cranial nerve palsies (28), motor deficits (11), sphincter disturbances (5), and sensory involvement in four patients. Complications included renal dysfunction (20%), dyselectrolytemia (20%), seizures (16%), hypersensitivity (7%), and hepatic dysfunction (5%). Favorable outcome was seen in 72 patients, 13 remained unchanged, and 12 died. Rapid clinical progression, low cerebrospinal fluid (CSF) cell count and protein were associated with higher mortality. CSF cell count and protein were lower in patients who had isolated cryptococcal meningitis compared to those with additional pathogen. Mean sugar levels were higher and duration of illness was shorter in HIV-negative individuals. CONCLUSION: Cryptococcal meningitis is common in patients with AIDS. Effective and early antifungal treatment carries a good prognosis. On rapid evolution of the disease, decreased CSF cell count and protein heralds poor prognosis and warrants initiation of early specific treatment. PMID- 28904454 TI - Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience. AB - BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients. OBJECTIVES: The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario. METHODS: This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study. RESULTS: In the study, mean ARR reduced from 2.61 to 0.09 after therapy (P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted. CONCLUSIONS: The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated. PMID- 28904455 TI - Stigma and Polytherapy: Predictors of Quality of Life in Patients with Epilepsy from South India. AB - BACKGROUND: Apart from unpredictable seizures and consequent injuries, people with epilepsy (PWE) confront with psychosocial adjustments. Quality of life (QOL) varies with culture and socioeconomic milieu. Identification of predictors for QOL enables comprehensive and effective care. OBJECTIVE: The objective of this study was to investigate the role of stigma, demographic, socioeconomic, and clinical factors in QOL among PWE. SUBJECTS AND METHODS: In this prospective observational study, 170 PWE answered QOL in epilepsy-31 (QOLIE-31) and stigma questionnaire. Internal consistency of instruments was evaluated by Cronbach's alpha and reproducibility by intracorrelation coefficient (ICC). Descriptive statistics were calculated, and predictors were identified by regression analysis. RESULTS: Mean age of the PWE was 34.39 +/- 11.49. Cronbach's alpha and ICC of the QOLIE-31 were 0.946 and 0.974 and stigma scale was 0.903 and 0.954, respectively. Mean total QOL was 60.29 +/- 14.12. Highest and lowest scores of subscales of QOL were observed in medication effects and social functioning. Mean stigma score of PWE was 22.21 +/- 14.64. Majority of PWE had mild stigma (75%) followed by moderate (22%) and high stigma (1%). Stigma score correlated with total and subscales of QOL (P < 0.01). Statistically significant decrease in scores of total and subscales of QOL was observed in high and moderate stigma when compared to mild stigma (P < 0.01). Stigma (standardized beta coefficient = 0.652, P < 0.00) and polytherapy (standardized beta coefficient = -0.180, P < 0.02) were found to be the significant predictors of QOL. Significant decrease in total and subscale scores of QOL was observed in PWE under polytherapy when compared to monotherapy and also in seizure frequent against seizure-free PWE (P < 0.01). CONCLUSIONS: Besides control of seizures, encouragement of monotherapy and destigmatization campaigns may improve the QOL of PWE. PMID- 28904456 TI - Association of Serum 25-hydroxyvitamin D in Carotid Intima-media Thickness: A Study from South India. AB - BACKGROUND: Abnormal carotid intima-media thickness (IMT) is a marker of carotid atherosclerosis which is a risk factor for cerebrovascular and cardiovascular diseases. Recent studies have found an association of 25-hydroxyvitamin D deficiency with abnormal carotid IMT. PURPOSE: The purpose of the study was to investigate the association of serum 25-hydroxyvitamin D levels with carotid IMT in Indian participants. MATERIALS AND METHODS: We prospectively recruited 300 participants at Yashoda Hospital, Hyderabad, during the study period between January 2012 and December 2014. All participants were assessed for fasting blood sugar, lipid profile, C-reactive protein (CRP), serum alkaline phosphatase, serum calcium, serum phosphorous, serum 25-hydroxyvitamin D levels, and carotid Doppler examination. RESULTS: Among the 300 participants, men were 190 (63.3%) and mean age was 51.9 +/- 7.7 years with a range from 35 to 64 years. On risk factors evaluation, 105 (35%) were hypertensive, 79 (26.3%) diabetics, 63 (21%) smokers, and 56 (18.6%) were alcoholics. On evaluation of biochemical parameters, 81 (27%) had dyslipidemia, 120 (40%) had elevated CRP levels, 119 (39.6%) had 25 hydroxyvitamin D deficiency, mean alkaline phosphatase was 93.9 +/- 14.9 IU/L, serum calcium (mg/dL) was 9.2 +/- 2.3, and serum phosphorous 4.4 +/- 1.2 mg/dL. On carotid imaging, 121 (40.3%) had abnormal IMT. After multivariate analysis, 25 hydroxyvitamin D deficiency (odds ratio [OR]: 2.14; 95% confidence interval [CI]: 1.29-3.55), dyslipidemia (OR: 2.53; 95% CI: 1.46-4.40), elevated CRP (OR: 2.27; 95% CI: 1.37-3.76), smoking (OR: 2.09; 95% CI: 1.16-3.77), and diabetes (OR: 1.84; 95% CI: 1.05-3.21) were independently associated with abnormal IMT. CONCLUSION: In our study, we established 25-hydroxyvitamin D deficiency as an independently associated with abnormal IMT in Indian participants. PMID- 28904457 TI - Delayed Orthostatic Hypotension: A Pilot Study from India. AB - INTRODUCTION: Orthostatic hypotension is defined as a sustained decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing compared with blood pressure from the sitting or supine position or by head-up tilt-table testing (1). When sustained blood pressure (BP) drop is after three minutes of upright posture it is called delayed orthostatic hypotension (delayed OH) (2). AIM OF THE STUDY: To detect the incidence of delayed orthostatic hypotension in patients referred to our autonomic lab. MATERIALS AND METHOD: BP was measured noninvasively at 1-minute intervals with an automated cuff sphygmomanometer over the right brachial artery for 45 minutes. The onset and duration of falls in blood pressure either systolic or diastolic or both were documented, and any associated symptoms were recorded. Only patients with sustained falls in BP were included. Drugs causing OH was stopped 48 hours before testing as per protocol followed in lab. We also looked into other autonomic function test abnormalities in patients with delayed OH. INCLUSION CRITERIA: Patients above age of 18 years referred for evaluation of autonomic function tests. EXCLUSION CRITERIA: Patients with severe cardiac failure and cardiac arrhythmias were excluded and patients with rapid fall in BP and bradycardia (Neurally mediated syncope) were excluded. RESULTS: Total 170 patients underwent tilt table testing. Orthostatic hypotension was seen within 3 minutes in seventy patients, fifty patients had delayed OH (BP fall after 3 minutes). There were twenty seven males and twenty three females in this group. Twenty nine of the 50 patients with delayed orthostatic hypotension, had symptoms during the tilt table procedure. Asymptomatic OH was more common in patients who developed OH after 10 minutes. CONCLUSION: This is a pilot study, first in India where we looked into the incidence of delayed orthostatic hypotension in patients undergoing tilt table testing in our autonomic lab. We found that fifty patients had delayed orthostatic hypotension which could have been missed on clinical evaluation. High clinical suspicion is needed to detect this disorder and tilt table testing should be done in suspicious cases since orthostatic hypotension is cause of high morbidity. PMID- 28904458 TI - Can Transcranial Color Doppler Spectral Signatures be a Novel Biomarker for Monitoring Cerebrovascular Autoregulation and Intracranial Pressure? A Speculative Synthesis. AB - BACKGROUND: Trans Cranial Colour Doppler (TCCD) has been extensively used in various neurological and neurosurgical conditions causing severe raise in the intracranial pressure (ICP). MATERIAL AND METHOD: Our study explores the sequential evolution of TCCD flow pattern by correlating with pupillary reactivity, Glasgow coma scale (GCS), and imaging. Our cohort consisted of thirty patients with ten patients in each subgroup admitted to the neuro-Intensive Care Unit (NICU) for various neurological and neurosurgical causes. Middle cerebral artery was insonated through the transtemporal window at the time of admission to NICU. Doppler waveform and parameters such as peak systolic velocity, end diastolic velocity, systolic by diastolic ratio, pulsatility index, and resistivity index were recorded. The clinical variables for evaluating the degree of raised ICP were the GCS and pupil size. Other systemic parameters such as mean arterial pressure, heart rate, and respiratory rate were also considered and these results were further correlated with TCCD findings. The groups were divided into three groups based on GCS, pupillary reactivity, and imaging. Imaging was done to indicate the etiology for ICP changes and also to look for signs of raised ICP. RESULTS: Ten distinct types of waveform patterns were noted, and these waveforms correlated with various physiological parameters suggestive of raised ICP. CONCLUSION: The sequential evolution of distinct patterns of Doppler waveform with increasing degree of raise in ICP has been described and can act as a quick screening tool in NICU and helps stratify patients for treatment and prognostication. PMID- 28904459 TI - Clinical, Biochemical Characteristics and Hospital Outcome of Acute Intermittent Porphyria Patients: A Descriptive Study from North India. AB - INTRODUCTION: Acute intermittent porphyria (AIP) is an inherited metabolic disease characterized by disordered heme biosynthesis. There is no recent study reported from India. MATERIALS AND METHODS: It was a retrospective, observational study. Clinical records of patients of AIP with acute porphyric attacks admitted from April 2008 to December 2016 were analyzed. RESULTS: Fifteen AIP patients constituted of eight females and seven males were analyzed. Mean age at presentation was 34.33 +/- 15.86 years. Thirteen patients (86.67%) had acute flaccid paralysis (AFP). All of them had peripheral neuropathy. These patients concomitantly had abdominal pain, seizure, encephalopathy, autonomic hyperactivity, history of passage of dark urine, and electrolyte abnormality (hyponatremia) in various combinations. Abdominal pain was the presenting symptom in 11 (73.33%) patients. Seven (46.67%) patients had seizure episodes. Five patients (33.33%) had hyponatremia at presentation. Significantly higher percentage of them had seizure at presentation or during hospital stay (P = 0.007). These patients also had evidence of autonomic hyperactivity in the form of higher pulse rate, systolic and diastolic blood pressure at presentation. They had prolonged duration of hospital stay as well (P = 0.016). Eleven patients had partial recovery and rest four patients (26.67%) had in-hospital mortality. CONCLUSION: Patients had severe neurological involvement manifesting mainly as AFP and seizure episodes. We recommend screening for AIP in patients presenting with features of AFP along with any combination of clinical/laboratory manifestations such as abdominal pain, seizure, encephalopathy, autonomic hyperactivity, passage of dark urine, and hyponatremia. Electrolyte abnormality in the form of hyponatremia was an important severity marker. PMID- 28904460 TI - Juvenile Myoclonic Epilepsy with Frontal Executive Dysfunction is Associated with Reduced Gray Matter Volume by Voxel-based Morphometry. AB - OBJECTIVE: Frontal executive dysfunction (FED) and abnormalities in volumetric magnetic resonance imaging (MRI) have been described in juvenile myoclonic epilepsy (JME). We aimed to compare JME patients with and without FED by group analysis of voxel-based morphometric (VBM) estimates of brain volume in MRI. SUBJECTS AND METHODS: We studied frontal executive functions in patients with JME and analyzed the possible association of FED with their demographic, clinical, and electrographic characteristics. We aimed to do group analysis of the VBM MRI brain data to compare the gray matter (GM) volumes of JME patients with and without FED. RESULTS: We recruited 34 patients (20 women) with JME (mean age 23.7 +/- 4.58 years) from the epilepsy outpatient services. FED was detected in twenty patients (58.8%). Group analysis of VBM MRI brain showed significant (P < 0.001) reduction in GM volume in dorsolateral prefrontal cortex (left Brodmann area [BA] 10, 46, 9, Z-score 3.36, 2.91, 2.03, respectively, and right BA 10 and BA 45, Z score 2.98 and 3.36, respectively), left insula (BA 13, Z-score 2.14), temporal lobe (BA 38, Z-score 2.76), in the subgroup of JME with FED. INFERENCE: JME with FED has an anatomical correlate in the form of reduced GM volume in dorsolateral prefrontal cortex. PMID- 28904461 TI - The Prevalence and Severity of Autonomic Dysfunction in Chronic Inflammatory Demyelinating Polyneuropathy. AB - INTRODUCTION: In chronic inflammatory demyelinating polyneuropathy (CIDP), emphasis has been on motor disabilities, and autonomic dysfunction in these patients has not been addressed systematically. MATERIALS AND METHODS: Autonomic function was prospectively analyzed in 38 patients with CIDP. Quantitative autonomic function testing was done using Finometer(r) PRO and severity of adrenergic and cardiovagal dysfunction graded according to composite autonomic severity score and sudomotor dysfunction assessed using sympathetic skin response. RESULTS: Thirty-four (89%) patients had features of autonomic dysfunction. Thirty-three (86%) patients had cardiovagal dysfunction, 21 (55%) had adrenergic dysfunction, and 24 (63%) had sudomotor dysfunction. Autonomic dysfunction was mild to moderate in the majority (86%). CONCLUSIONS: Autonomic dysfunction in CIDP is underreported and potentially amenable to therapy. Our cohort had a high proportion of adrenergic dysfunction compared to previous studies. PMID- 28904462 TI - Clinical Spectrum, Therapeutic Outcomes, and Prognostic Predictors in Sjogren's Syndrome-associated Neuropathy. AB - OBJECTIVES: There are limited data regarding long-term follow-up and therapeutic outcomes in Sjogren's syndrome (SS)-associated peripheral neuropathy. In this study, we aim to study the clinical, electrophysiological spectrum and therapeutic responses among the different subtypes of SS-associated neuropathy. The predictors of suboptimal treatment response will be identified. METHODS: The study included a retrospective cohort of patients with SS-associated neuropathy between January 2012 and November 2015. Baseline clinical, laboratory, electrophysiological data and details of treatment were noted. Therapeutic outcomes were assessed at follow-up and compared among the different subtypes. Prognostic predictors were determined using logistic regression analysis. RESULTS: Fifty-four patients were included in the study. Sensory ataxic neuropathy (17, including 9 with sensory ganglionopathy) and radiculoneuropathy (11) were the main subtypes. Notable atypical presentations included acute neuropathies, pure motor neuropathies, and hypertrophic neuropathy. Concomitant autoimmune disorders were present in 24 (44.4%) patients. Most presentations were subacute-chronic (51, 94.4%). Minor salivary gland biopsy had a higher yield compared to serological markers (81.5 vs. 44.4%). Sensory ataxic neuropathy was associated with greater severity and autonomic dysfunction. Improvement was noted in 33 (61%) patients. Cranial neuropathy and radiculoneuropathy subtypes were associated with the best treatment responses. Chronicity, orthostatic hypotension, baseline severity, and marked axonopathy (nerve biopsy) were predictive of a suboptimal therapeutic response. CONCLUSIONS: The study highlights the heterogeneous spectrum, atypical presentations, and differential therapeutic responses. SS-associated neuropathy remains underdiagnosed. Early diagnosis and prompt initiation of immunotherapy before worsening axonal degeneration is paramount. SS-associated neuropathy need not necessarily be associated with a poor prognosis. PMID- 28904463 TI - Relationship between Factor V Leiden Gene Variant and Risk of Ischemic Stroke: A Case-Control Study. AB - BACKGROUND: Factor V Leiden is the most common genetic variation among the blood coagulation pathway which leads to prothrombotic state, therefore, is considered an important gene for understating the stroke mechanism. AIM: The aim of the present study is to determine the relationship between single nucleotide polymorphism at G1691A position of Factor V gene and risk of ischemic stroke (IS) in North Indian population. MATERIALS AND METHODS: In a retrospective case control study, 250 patients with IS and 250 age- and gender-matched controls were enrolled in the period of October 2012 to September 2014 from in- and out-patient department of Neurology, All India Institute of Medical Sciences, New Delhi, India. Deoxyribonucleic acid for each case and control was isolated from peripheral blood using phenol-chloroform extraction method. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine the polymorphism. Data were analyzed using STATA Software Version 13. RESULTS: The mean age of IS patient was 52.8 +/- 12.5 years and in control group was 50.97 +/- 12.7 years. Genotypic frequency distributions were in accordance with Hardy Weinberg equilibrium in both cases and controls. As expected hypertension, diabetes, dyslipidemia, smoking, heavy alcohol intake, family history of stroke, and poor economic status were significantly associated with the risk of IS. Multivariate analysis revealed 5.17 times higher odds for developing the risk of large vessel subtype of IS in patients carrying Factor V Leiden G1691A gene variation as compared to control subjects (OR, 5.17; 95% CI, 1.32-20.3, P = 0.01). CONCLUSION: The present study suggests that Factor V Leiden G1691A polymorphism may be significantly associated with the risk of large vessel subtype of IS. Large sample size studies using prospective cohort designs are required to corroborate the present findings. PMID- 28904464 TI - Clinical Features, Risk Factors, and Short-term Outcome of Ischemic Stroke, in Patients with Atrial Fibrillation: Data from a Population-based Study. AB - OBJECTIVES: Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder associated with stroke. This study was done to describe risk factors, clinical features, and short-term outcomes of stroke patients with AF. MATERIALS AND METHODS: This study was a part of the Indian Council of Medical Research funded "Ludhiana urban population based Stroke Registry." Data were collected using WHO STEPS stroke method. All patients >=18 years of age, who developed ischemic stroke between March 26, 2011, and March 25, 2013, were included in this study. Data about demographic details, clinical features, and risk factors were collected. The outcome was assessed at 28 days using modified Rankin scale (mRs) (good outcome: mRS <=2; poor outcome >2). The statistical measures calculated were descriptive statistics, Chi-square test, Fischer's exact test, and independent t-test. RESULTS: Of the total 7199 patients enrolled in the registry, data of 1942 patients who fulfilled inclusion criteria were analyzed, and AF was seen in 203 (10%) patients. AF patients were older (AF 62 +/- 14 vs. non-AF 60 +/ 15 years, P = 0.01), had more hypertension (AF 176 [87%] vs. non-AF 1396 [80%], P = 0.03), hyperlipidemia (AF 60 [32%] vs. non-AF 345 [21%], P = 0.001), coronary artery disease (AF 60 [30%] vs. non-AF 195 [11%], P < 0.0001), and carotid stenosis (AF 14 [7%] vs. non-AF 57 (3%), P = 0.02). They had worse outcome (mRS >2; AF 90 [50%] vs. non-AF 555 [37%], P = 0.001). CONCLUSIONS: Ten percent of stroke patients had AF. They were older, had multiple risk factors and worse outcome. There was no gender difference in this large cohort. PMID- 28904465 TI - Spectrum of Visual Impairment in Cerebral Venous Thrombosis: Importance of Tailoring Therapies Based on Pathophysiology. AB - Visual impairment can complicate cerebral venous thrombosis (CVT). Here, we describe the various pathophysiological mechanisms and treatments available. A retrospective chart review of all patients treated for CVT in a large quaternary teaching hospital was done, and cases with visual impairment due to CVT were identified. The various mechanisms causing visual impairment in CVT were (1) raised intracranial pressure (ICP) caused by venous thrombosis without venous infarcts resulting in a benign intracranial hypertension-like presentation of CVT, (2) venous infarcts involving the occipital cortex, (3) raised ICP following the development of a secondary dural arteriovenous (AV) fistula, and (4) arterial occipital infarcts due to posterior cerebral artery compression secondary to herniation in large venous infarcts. Apart from using systemic anticoagulants to attempt recanalization and drugs with carbonic anhydrase inhibitor activity to reduce the ICPs, treatment modalities employed to save vision were (1) recanalization by local thrombolysis, stenting, or mechanical devices; (2) cerebrospinal fluid diversion procedures such as theco-periotoneal shunting; (3) optic nerve sheath fenestration; and (4) specific treatment for conditions such as dural AV fistula occurring as a late complication. CVT can cause visual impairment through different pathophysiological mechanisms. Depending on the mechanism, treatment strategies need to be tailored. Furthermore, very close monitoring is needed both in the acute and in the follow-up period, as new pathophysiological mechanisms can arise, compromising the vision. This may require a different treatment approach. Literature on this aspect of CVT is lacking. PMID- 28904467 TI - Post bariatric Surgery Acute Axonal Polyneuropathy: Doing Your Best is Not Always Enough. AB - Neurological complications are frequently recognized with weight reduction surgeries for morbid obesity. The spectrum of peripheral neuropathies complicating the weight loss surgery is wide, and among them, the acute axonal peripheral neuropathy resembling Guillain-Barre syndrome is rare and only less than a dozen cases are reported. We present three cases, which after bariatric surgery developed acute polyneuropathy that rapidly progressed over 4 weeks from the onset. All patients responded to aggressive parenteral Vitamin B1 and B12 replacement therapy. These cases highlight the fact that bariatric surgery although is a promising option to treat morbid obesity; it is certainly not devoid of potential neurological complications due to micronutrient deficiencies. Delay in the diagnosis of acute polyneuropathy may worsen its long-term sequelae. A multidisciplinary team management with careful nutritional monitoring at regular interval is crucial in all patients for early recognition and intervention to avoid these complications after bariatric surgery. PMID- 28904466 TI - Detection of Dysferlin Gene Pathogenic Variants in the Indian Population in Patients Predicted to have a Dysferlinopathy Using a Blood-based Monocyte Assay and Clinical Algorithm: A Model for Accurate and Cost-effective Diagnosis. AB - BACKGROUND: Limb-girdle muscular dystrophy (LGMD) is the most common adult-onset class of muscular dystrophies in India, but a majority of suspected LGMDs in India remain unclassified to the genetic subtype level. The next-generation sequencing (NGS)-based approaches have allowed molecular characterization and subtype diagnosis in a majority of these patients in India. MATERIALS AND METHODS: (I) To select probable dysferlinopathy (LGMD2B) cases from other LGMD subtypes using two screening methods (i) to determine the status of dysferlin protein expression in blood (peripheral blood mononuclear cell) by monocyte assay (ii) using a predictive algorithm called automated LGMD diagnostic assistant (ALDA) to obtain possible LGMD subtypes based on clinical symptoms. (II) Identification of gene pathogenic variants by NGS for 34 genes associated with LGMD or LGMD like muscular dystrophies, in cases showing: absence of dysferlin protein by the monocyte assay and/or a typical dysferlinopathy phenotype, with medium to high predictive scores using the ALDA tool. RESULTS: Out of the 125 patients screened by NGS, 96 were confirmed with two dysferlin variants, of which 84 were homozygous. Single dysferlin pathogenic variants were seen in 4 patients, whereas 25 showed no variants in the dysferlin gene. CONCLUSION: In this study, 98.2% of patients with absence of the dysferlin protein showed one or more variants in the dysferlin gene and hence has a high predictive significance in diagnosing dysferlinopathies. However, collection of blood samples from all over India for protein analysis is expensive. Our analysis shows that the use of the "ALDA tool" could be a cost-effective alternative method. Identification of dysferlin pathogenic variants by NGS is the ultimate method for diagnosing dysferlinopathies though follow-up with the monocyte assay can be useful to understand the phenotype in relation to the dysferlin protein expression and also be a useful biomarker for future clinical trials. PMID- 28904468 TI - Gyriform Infarction in Cerebral Air Embolism: Imaging Mimicker of Status Epilepticus. AB - Cerebral air embolism (CAE) is a potentially fatal iatrogenic complication related to common procedures including central venous catheter (CVC) removal. We report an interesting case of CAE related to CVC removal that was further complicated with status epilepticus. Neuroimaging of CAE and status epilepticus could pose diagnostic dilemmas and require consideration of wide diagnostic differentials. We discuss the clinical presentation, mechanism, and diagnostic approach, especially neuroimaging to differentiate various etiologies in CAE patients. PMID- 28904469 TI - Hyper Acute Demyelinating Encephalomyelitis of Childhood: A Rare Entity. AB - A young child with catastrophic neurological illness diagnosed as a rare variant of acute demyelinating encephalomyelitis (ADEM). She succumbed to her illness despite of aggressive and appropriate management. Malignant demyelinating encephalomyelitis should be considered in children who are refractory to the treatment of ADEM. PMID- 28904470 TI - Susceptibility-weighted Imaging Torch Fire Sign in a Patient with Dystonia due to Hypoxic-ischemic Injury. PMID- 28904471 TI - Leptomeningeal Carcinomatosis Presenting as Cauda Equina Syndrome. PMID- 28904472 TI - A Rare but Treatable Cause of Paroxysmal Nonkinesigenic Choreoathetosis. PMID- 28904473 TI - Surgical Interventions for Task-specific Dystonia (Writer's Dystonia). AB - OBJECTIVES: Writer's cramp is a focal dystonia producing abnormal postures during selective motor activities. Thalamotomy or globus pallidus internus deep brain stimulation (GPi DBS) has been used as a surgical treatment in patients not responding to medical treatment. MATERIALS AND METHODS: Eight patients (all men, age 16-47 years) with refractory focal hand dystonia underwent either ventrooralis (Vo) thalamotomy (seven patients) or GPi DBS (one patient) using stereotactic techniques. Preoperative video recordings, Writing movment score for dystonic posture and latency of dystonia (WMS), and symptom severity scores (SSSs) were evaluated at baseline and latest follow-up ranging from 1 to 4 years. RESULTS: All patients had difficulty in performing their most common tasks. The duration of symptoms ranged from 6 months to 12 years. All patients obtained immediate postoperative relief from the dystonic symptoms, and the effect was sustained during the follow-up period. The WMS (range 0-28) improved from a mean of 14.5 before surgery to 2, whereas the SSS (maximum 43 and minimum 10) improved from a mean of 15.3 before surgery to 2 at the last follow-up. There were no surgical complications, morbidity, or mortality. CONCLUSION: Vo thalamotomy or GPi DBS offers successful symptom relief in patients with task-specific dystonia. PMID- 28904474 TI - Mitochondrial Neurogastrointestinal Encephalomyopathy Syndrome with an Unusual Pattern of Inheritance. PMID- 28904475 TI - Stroke in a Child with Dengue Encephalopathy. PMID- 28904476 TI - A Methodological Study to Develop a Standard Operational Protocol for Nurses on Central Line Catheter Care of Patients in Selected Intensive Care Units. AB - AIM: This study aims to develop a standard operational protocol (SOP) for central line catheter care for nurses. MATERIALS AND METHODS: A preliminary draft of protocol based on extensive review of the literature was developed. The current practices of the nurses regarding central line catheter care were observed. Focus group discussions (FGD) were conducted with the nurses to identify the problems encountered by them during care of central line. Four rounds of Delphi were conducted to validate the protocol. The protocol was found to be feasible in terms of understanding, clarity and easy implementation after conducting a pilot study. An observation checklist was developed from the final draft of the protocol. The nurses were taught regarding the central line catheter care as per the protocol. 30 nurses were observed during central line catheter care by the researcher. After implementation of the protocol, feedback of the nurses was taken by conducting FGDs. RESULTS: Content validity index of each item in the protocol was acceptable. The overall Cronbach's alpha value of the checklist was 0.75. It was concluded that the checklist is reliable and each item has a contribution in the checklist. CONCLUSION: This protocol addresses interventions to enable staff to provide proper care of the central line catheter to prevent CLABSI. PMID- 28904477 TI - Studying the Power of the Integrative Weaning Index in Predicting the Success Rate of the Spontaneous Breathing Trial in Patients under Mechanical Ventilation. AB - BACKGROUND AND AIMS: The use of weaning predictive indicators can avoid early extubation and wrongful prolonged mechanical ventilation. This study aimed to determine the power of the integrative weaning index (IWI) in predicting the success rate of the spontaneous breathing trial (SBT) in patients under mechanical ventilation. MATERIALS AND METHODS: In this prospective study, 105 patients undergoing mechanical ventilation for over 48 h were enrolled. Before weaning initiation, the IWI was calculated and based on the defined cutoff point (>=25), the success rate of the SBT was predicted. In case of weaning from the device, 2-h SBT was performed and the physiologic and respiratory indices were continuously studied while being intubated. If they were in the normal range besides the patient's tolerance, the test was considered as a success. The result was then compared with the IWI and further analyzed. RESULTS: The SBT was successful in 90 (85.7%) and unsuccessful in 15 (14.3%) cases. The difference between the true patient outcome after SBT, and the IWI prediction was 0.143 according to the Kappa agreement coefficient (P < 0.001). Moreover, regarding the predictive power, IWI had high sensitivity (95.6%), specificity (40%), positive and negative predictive values (90.5% and 60), positive and negative likelihood ratios (1.59 and 0.11), and accuracy (86.7%). CONCLUSION: The IWI as a more objective indicator has acceptable accuracy and power for predicting the 2-h SBT result. Therefore, in addition to the reliable prediction of the final weaning outcome, it has favorable power to predict if the patient is ready to breathe spontaneously as the first step to weaning. PMID- 28904478 TI - How Useful is Extravascular Lung Water Measurement in Managing Lung Injury in Intensive Care Unit? AB - CONTEXT: The primary goal of septic shock management is optimization of organ perfusion, often at the risk of overloading the interstitium and causing pulmonary edema. The conventionally used end points of resuscitation do not generally include volumetric parameters such as extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI). AIMS: This study aimed to assess the prognostic value of EVLWI and PVPI by calculating their correlation with the severity of lung injury. SETTINGS AND DESIGN: This prospective observational study included twenty mechanically ventilated critically ill patients with Acute Physiology and Chronic Health Evaluation score (APACHE II) >20. SUBJECTS AND METHODS: EVLWI and PVPI were measured using transpulmonary thermodilution, and simultaneously, PaO2:FiO2 ratio, alveolar-arterial gradient of oxygen (AaDO2), and chest radiograph scores from two radiologists were obtained. STATISTICAL ANALYSIS: The correlation of EVLWI and PVPI with chest radiograph scores, PaO2:FiO2 ratio, and AaDO2 were calculated. The inter-observer agreement between the two radiologists was tested using kappa test. RESULTS: EVLWI and PVPI correlated modestly with PaO2:FiO2 (r = -0.32, P = 0.0004; r = 0.39, P = 0.0001). There was a better correlation of EVLWI and PVPI with PaO2:FiO2 ratio (r = -0.71, P < 0.0001; r = -0.58, P = 0.0001) in the acute respiratory distress syndrome (ARDS) subgroup. The EVLWI values correlated significantly with corresponding chest radiograph scores (r = 0.71, P < 0.0001 for observer 1 and r = 0.68, P < 0.0001 for observer 2). CONCLUSIONS: EVLWI and PVPI may have a prognostic significance in the assessment of lung injury in septic shock patients with ARDS. Further research is required to reveal the usefulness of EVLWI as an end point of fluid resuscitation in the management of septic shock with ARDS. PMID- 28904479 TI - Effect of Fat-based versus Carbohydrate-based Enteral Feeding on Glycemic Control in Critically Ill Patients: A Randomized Clinical Trial. AB - BACKGROUND AND AIMS: The aim of this study was to evaluate the preventive effects of high-fat enteral feeding on glycemic control and clinical outcomes in critically ill patients: a randomized clinical trial. MATERIALS AND METHODS: This study was done on 42 normoglycemic patients admitted to Intensive Care Unit (ICU). Patients were randomly classified into three groups of 14 each. Control group (A) received carbohydrate-based diet (protein: 20%, fat: 30%, and carbohydrate: 50%), study groups received two types of high-fat diet; Group B (protein: 20%, fat: 45% including half of olive oil and half sunflower oil, and carbohydrate: 35%); and Group C (protein: 20%, fat: 45% including sunflower oil, and carbohydrate: 35%) in the first 48 h of admission. RESULTS: Basal characteristics of participants were the same. After the feeding trial, there was no difference between the groups in mean plasma and capillary glucose levels and insulin requirements. Serum high density lipoprotein (HDL)-cholesterol level was increased significantly in Group B on day 10 compared to admission level (40.75 +/- 5.58 vs. 43.56 +/- 2.25, P = 0.05). We did not find any difference in organ failure involvement and mortality rate between groups. The number of ICU free days was significantly more in Group B compared to the control group (P = 0.04). CONCLUSION: High-fat diets have no preventive effect on stress hyperglycemia. High monounsaturated fat diet may increase serum HDL-cholesterol level and decrease the length of stay in ICU. PMID- 28904480 TI - Association of Massive Transfusion for Resuscitation in Gastrointestinal Bleeding with Transfusion-related Acute Lung Injury. AB - BACKGROUND AND AIMS: This study aimed to understand the use of massive transfusion (MT) for gastrointestinal bleeding (GIB). PATIENTS AND METHODS: We performed a retrospective analysis of patients admitted to our medical Intensive Care Unit (ICU) with GIB for the type of bleeding, quantity of blood products transfused, and risk of transfusion-related acute lung injury (TRALI) and death. MT was defined as transfusion of 10 or more units of red blood cell (RBC) within a 24-h period in a 1-unit RBC: 1-unit fresh frozen plasma: and 1-unit platelet ratio. TRALI was defined as development of acute lung injury (ALI), within 6 h of transfusion, with new bilateral pulmonary infiltrates, absence of circulatory overload, or other explanation for ALI. RESULTS: In a 43-month interval, 169 patients were admitted to the ICU with GIB and received blood products, of whom 13 received MT. Ten patients developed TRALI, of whom 7 (70%) had received MT. MT was associated with an increased risk of TRALI (odds ratio [OR]: 17.9, 95% confidence interval [CI]: 2.9-111.2, P = 0.002) after adjusting for age, sex, body mass index, baseline vitals, and laboratory data. Death was predicted by MT (OR: 5.6, 95% CI: 1.6-19.7, P = 0.007), TRALI (OR: 2.3, 95% CI: 1.1-4.6, P = 0.02), and Acute Physiologic Chronic Health Evaluation II score (OR: 1.17 per unit increase, 95% CI: 1.09-1.26, P < 0.001) after adjusting for age and sex. CONCLUSIONS: MT for GIB is associated with an increased risk of TRALI and death. Prospective studies assessing the use of MT in this population are needed to understand and improve outcomes. PMID- 28904481 TI - External Validation of Risk Prediction Scores for Invasive Candidiasis in a Medical/Surgical Intensive Care Unit: An Observational Study. AB - BACKGROUND: The aim of this study was to conduct external validation of risk prediction scores for invasive candidiasis. METHODS: We conducted a prospective observational study in a 12-bedded adult medical/surgical Intensive Care Unit (ICU) to evaluate Candida score >3, colonization index (CI) >0.5, corrected CI >0.4 (CCI), and Ostrosky's clinical prediction rule (CPR). Patients' characteristics and risk factors for invasive candidiasis were noted. Patients were divided into two groups; invasive candidiasis and no-invasive candidiasis. RESULTS: Of 198 patients, 17 developed invasive candidiasis. Discriminatory power (area under receiver operator curve [AUROC]) for Candida score, CI, CCI, and CPR were 0.66, 0.67, 0.63, and 0.62, respectively. A large number of patients in the no-invasive candidiasis group (114 out of 181) were exposed to antifungal agents during their stay in ICU. Subgroup analysis was carried out after excluding such patients from no-invasive candidiasis group. AUROC of Candida score, CI, CCI, and CPR were 0.7, 0.7, 0.65, and 0.72, respectively, and positive predictive values (PPVs) were in the range of 25%-47%, along with negative predictive values (NPVs) in the range of 84%-96% in the subgroup analysis. CONCLUSION: Currently available risk prediction scores have good NPV but poor PPV. They are useful for selecting patients who are not likely to benefit from antifungal therapy. PMID- 28904482 TI - Mathematics of Ventilator-induced Lung Injury. AB - Ventilator-induced lung injury (VILI) results from mechanical disruption of blood gas barrier and consequent edema and releases of inflammatory mediators. A transpulmonary pressure (PL) of 17 cmH2O increases baby lung volume to its anatomical limit, predisposing to VILI. Viscoelastic property of lung makes pulmonary mechanics time dependent so that stress (PL) increases with respiratory rate. Alveolar inhomogeneity in acute respiratory distress syndrome acts as a stress riser, multiplying global stress at regional level experienced by baby lung. Limitation of stress (PL) rather than strain (tidal volume [VT]) is the safe strategy of mechanical ventilation to prevent VILI. Driving pressure is the noninvasive surrogate of lung strain, but its relations to PL is dependent on the chest wall compliance. Determinants of lung stress (VT, driving pressure, positive end-expiratory pressure, and inspiratory flow) can be quantified in terms of mechanical power, and a safe threshold can be determined, which can be used in decision-making between safe mechanical ventilation and extracorporeal lung support. PMID- 28904483 TI - Fecal Carriage of Extended-spectrum Beta-lactamase-producing Enterobacteriaceae in Intensive Care Unit Patients. AB - BACKGROUND AND AIMS: Increasing and indiscriminate use of antibiotics has led the bacteria to develop resistance to most of the antibiotics. Beta-lactamase production is the mechanism of resistance to beta-lactams. Extended-spectrum beta lactamases (ESBLs) have been found in the members of Enterobacteriaceae such as Escherichia coli and Klebsiella spp. which are the common health-care-associated pathogens. The aim was to study the rate of fecal carriage of ESBL-producing Enterobacteriaceae in patients admitted to the Intensive Care Unit (ICU) of tertiary care hospital and follow them subsequently for the development of infections. MATERIALS AND METHODS: A hospital-based descriptive study was conducted in the department of microbiology of a tertiary care hospital for a period of 2 months from June 2016 to August 2016. Rectal swabs were collected from the patients admitted to the ICU after a period of 48 h. The swab was inoculated onto a special selective media (ChromID ESBL media). The results were noted according to the color of the colony produced. These patients are followed for the development of infection and the ESBL-producing organisms. RESULTS: A total of 60 rectal swabs were cultured, 39 (65%) showed a positive result. Out of which, 22 (56%) were ESBL-producing E. coli and 17 (43%) Klebsiella spp. Twenty three (38%) of the total patients screened were infected with ESBL-producing organisms. CONCLUSION: The study revealed high rates of carriage of ESBL producers in patients admitted to the ICU. PMID- 28904484 TI - Effectiveness of Humidification with Heat and Moisture Exchanger-booster in Tracheostomized Patients. AB - BACKGROUND: The two most commonly used types of humidifiers are heated humidifiers and heat and moisture exchange humidifiers. Heated humidifiers provide adequate temperature and humidity without affecting the respiratory pattern, but overdose can cause high temperatures and humidity resulting in condensation, which increases the risk of bacteria in the circuit. These devices are expensive. Heat and moisture exchanger filter is a new concept of humidification, increasing the moisture content in inspired gases. AIMS: This study aims to determine the effectiveness of the heat and moisture exchanger (HME)-Booster system to humidify inspired air in patients under mechanical ventilation. MATERIALS AND METHODS: We evaluated the humidification provided by 10 HME-Booster for tracheostomized patients under mechanical ventilation using Servo I respirators, belonging to the Maquet company and Evita 4. RESULTS: There was an increase in the inspired air humidity after 1 h with the humidifier. CONCLUSION: The HME-Booster combines the advantages of heat and moisture exchange minimizing the negatives. It increases the amount of moisture in inspired gas in mechanically ventilated tracheostomized patients. It is easy and safe to use. The type of ventilator used has no influence on the result. PMID- 28904485 TI - Temporary Left Ventricular Pacing: A Desperate Life-saving Measure in Emergency Situation. AB - Transcutaneous or transvenous pacing of the right ventricle is performed as a routine practice for patients received with symptomatic bradycardia or complete heart block with relative ease in cath lab. However, more and more patients are received with multiple comorbidities, critical condition, and difficult vascular access. In this article, we describe a patient with difficult venous access with tricuspid regurgitation and displaced the right ventricular pacemaker temporary lead undergoing coronary angiography who was managed with emergent nonconventional left ventricular pacing. PMID- 28904486 TI - Hemolytic-uremic Syndrome Complicating Acute Pancreatitis. AB - Hemolytic-uremic syndrome (HUS) is characterized by acute kidney injury with hemolytic anemia and thrombocytopenia. It has diverse etiologies, clinical manifestations, and risk factors. Acute pancreatitis as a cause of HUS is rare in adults. We report a case of 32-year-old male who presented with ethanol-induced acute pancreatitis complicated with hemolytic-uremic syndrome managed with hemodialysis and plasmapheresis. PMID- 28904487 TI - Hemodialysis for Lactic Acidosis. AB - Lactic acidosis (Type A) is common in critically ill patients and usually treated by correcting the underlying etiology. We present the case of a young female who presented with life-threatening lactic acidosis secondary to hematological malignancy. Timely initiation of hemodialysis was lifesaving. The case highlights the importance of considering Type B lactic acidosis (in this case secondary to a hematological malignancy) and also initiating renal replacement therapy when routine measures are ineffective. PMID- 28904488 TI - Thrombotic Thrombocytopenic Purpura or Disseminated Intravascular Coagulation? PMID- 28904489 TI - Does N-acetyl Cysteine Have Protective Effects in Acute Aluminum Phosphide Poisoning? PMID- 28904490 TI - Dengue and Thrombotic Thrombocytopenic Purpura. PMID- 28904491 TI - Vitamin D Deficiency in Critically Ill. PMID- 28904492 TI - From the Editor's Desk. PMID- 28904493 TI - Comparative Prospective Study of Hysterosalpingography and Hysteroscopy in Infertile Women. AB - AIM: To compare the findings and diagnostic accuracy of Hysterosalpingography (HSG) and hysteroscopy in infertile women. SETTING AND DESIGN: Prospective comparative study in a tertiary care Centre. MATERIAL AND METHODS: 108 women with primary or secondary infertility were recruited. In all women after basic infertility workup, both HSG and hysteroscopy were performed. RESULTS: Out of 108 women, in 3 women HSG couldn't be done and in one woman there was uterine perforation on hysteroscopy. HSG showed normal uterine cavity in 77.8% (81/105) women and abnormal in 22.85% (24/105). Hysteroscopy findings were normal in 70.09% (75/107) and abnormal in 29.91% (32/107). Hysteroscopy detected incidental findings in 15.38% (16/104) cases. HSG showed irregular uterine cavity in 14.15% (15/105) women but on hysteroscopy; normal cavity was present in 6 (40%) women and abnormality was detected in 9 (60%) women. The sensitivity, specificity, positive predictive and negative predictive value of HSG in evaluating uterine cavity abnormalities were 44.83% (95% confidence interval (CI); 0.26-0.64), 86.67% (95% CI; 0.76-0.93), 56.52% (95% CI; 0.34-0.76) and 80.25% (95%CI; 0.69 0.88). Positive likelihood ratio and negative likelihood ratio of HSG in detecting uterine cavity abnormality was 3.36 and 0.64 respectively. The agreement between HSG and hysteroscopy was 75%. This was statistically significant (P value = 0.001) with fair strength of agreement between HSG and hysteroscopy. (k value= 0.336). CONCLUSION: Hysteroscopy should be performed in all infertile patients as it can detect significant number of incidental findings missed by HSG. PMID- 28904494 TI - Vitamin D Deficiency Does Not Influence Reproductive Outcomes of IVF-ICSI: A Study of Oocyte Donors and Recipients. AB - BACKGROUND: Vitamin D and its active metabolite, 1,25-dihydroxy vitamin D (1,25 (OH)2D3), play a significant role in reproduction. AIM: To assess the effect of serum 25-hydroxy vitamin D level on oocyte quality and endometrial receptivity by studying oocyte donors and their recipients. MATERIALS AND METHODS: This prospective study consisted of two groups: Group A (recipient group) and Group B (donor group). All the participants of Groups A1 and B1 as well as Groups A2 and B2 were subcategorized into vitamin D-deficient (<20 ng/mL) and vitamin D replete insufficient (20 to >=30 ng/mL), respectively. RESULTS: In the recipient group, out of the 192 participants, 123 were in A1 group, and 69 were in A2 group. In donor group, out of the 99 participants, 54 were in B1 group, and 45 in B2 group. In the recipient group, Group A2 had a higher clinical pregnancy rate, implantation rate and ongoing pregnancy rate, and a lower abortion rate as compared to that of A1, but these are statistically insignificant. The difference in endometrial thickness and number of embryos transferred between both groups was insignificant. In the donor group, the total number of days of controlled ovarian hyperstimulation, the dose of gonadotropins, the number of oocytes retrieved, the percentage of mature oocytes, and the percentage of usable embryos were higher in Group B2 than those in Group B1, but these are statistically insignificant. The fertilization rate was statistically insignificant between Groups B1 and B2. CONCLUSION: Vitamin D deficiency leads to lower reproductive outcomes, though not statistically significant and, thereby, does not have a negative influence on in-vitro fertilization-intracytoplasmic sperm injection outcomes. PMID- 28904495 TI - To Study the Vitamin D Levels in Infertile Females and Correlation of Vitamin D Deficiency with AMH Levels in Comparison to Fertile Females. AB - CONTEXT: Human and animal data suggest that low vitamin D (25-hydroxyvitamin D) status is associated with impaired fertility, endometriosis, and polycystic ovary syndrome. Vitamin D regulates antimullerian hormone (AMH), FSH, mRNA, and expression of genes in reproductive tissues, implicating a role in female reproduction. AIMS: To study the vitamin D levels in infertile females and to know the correlation of vitamin D deficiency (VDD) with serum AMH in infertile females compare to fertile females. SETTINGS AND DESIGN: This prospective study was conducted in department of Maternal and Reproductive Health in between April 2014 and April 2016. MATERIALS AND METHODS: After matching inclusion and exclusion criteria out of total 70 infertile females, 45 were found to have VDD. Of these 35 patients were identified as cases; in whom, the AMH levels were assessed. As control 35 fertile normal females were taken, in which vitamin D and AMH were taken. In both groups, correlation of VDD with AMH was studied. STATISTICAL ANALYSIS USED: To analyze the correlation between vitamin D and AMH linear regression test and for comparison of both the groups, two sample t tests were used. RESULTS: The VDD was present in 64.28% of infertile females. In vitamin D deficient cases, the mean for vitamin D was 6.18 +/- 2.09 and AMH was 1.94 +/- 1.30. In vitamin D deficient controls, the mean for vitamin D was 4.85 +/- 3.02 and AMH was 3.47 +/- 2.59. On comparison, the vitamin D levels were lower in fertile than infertile females, which was significant (P = 0.04), and AMH levels were lower in cases than control group (P = 0.003). CONCLUSION: The VDD was present in 64.28% of infertile females. No significant correlation was found in between VDD and AMH levels in both the groups. PMID- 28904496 TI - Serum AMH Level to Predict the Hyper Response in Women with PCOS and Non-PCOS Undergoing Controlled Ovarian Stimulation in ART. AB - BACKGROUND: It is essential to determine the cut-off value of serum anti Mullerian hormone (AMH) to predict the hyper response in assisted reproductive technology (ART). There are few studies mentioning the cut-off value for the hyper response in infertile women but not specifically for polycystic ovary syndrome (PCOS) and non-PCOS groups. With this in background, this study was conducted. AIM: To determine the cut-off value of serum AMH to predict the hyper response in women with PCOS and non-PCOS undergoing a controlled ovarian stimulation (COS) in ART. OBJECTIVE: To compare the outcome of stimulation in PCOS and non-PCOS groups. MATERIALS AND METHODS: All 246 women enrolled for Intra Cytoplasmic Sperm Injection (ICSI) fulfilling the selection criteria were recruited. On the day 3 of the cycle, the serum AMH, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), estradiol and antral follicle count (AFC) were measured. They underwent COS as per the unit protocol. They were divided into PCOS and non-PCOS groups as per the Rotterdam's criteria. The mean age, duration of infertility, Body Mass Index (BMI), Ovarian reserve markers and outcome of stimulation were compared. Using the Statistical Package for the Social Sciences version 16.0 software, the significant difference was measured by multivariate analysis, as well as a one-way analysis of variance with Tukey's post-hoc test was used. RESULTS: Among 246 women, 31.3% were in PCOS group, and 68.7% were in non-PCOS group. Comparison of PCOS and non-PCOS groups showed a significant difference in the age with the mean age being 29.2 and 31.5 years, respectively. The mean AMH and AFC were 2-fold higher in PCOS group. The mean number of follicles, oocytes retrieved, MII and oocytes fertilised were significantly higher in PCOS group. The pregnancy rate was 52.6% in PCOS and 30.9% in non-PCOS group. In the PCOS group, 22.1% had ovarian hyper stimulation syndrome (OHSS), and only 4.7% had OHSS in non-PCOS group (P = 0.0005). Receiving Operator Curve (ROC) curve was plotted to predict the hyper response, which showed a cut-off value of 6.85 ng/ml with a sensitivity of 66.7% and a specificity of 68.7% for PCOS group and 4.85 ng/ml with a sensitivity of 85.7% and a specificity of 89.7% in non-PCOS group. CONCLUSION: The cut-off value of serum AMH to predict the hyper response in PCOS group is 6.85 ng/ml and in non-PCOS group is 4.85 ng/ml. PMID- 28904497 TI - The Effect of Metformin Treatment on the Serum Levels of Homocysteine, Folic Acid, and Vitamin B12 in Patients with Polycystic Ovary Syndrome. AB - BACKGROUND AND OBJECTIVE: Hyperhomocysteinemia is a well-known risk factor for cardiovascular disease. Although metformin therapy can increase homocysteine (Hcy) levels, it frequently is used as an oral medicine in women with polycystic ovary syndrome (PCOS), who might be at risk of catching diabetes mellitus. The aim of this study was to investigate the effect of metformin on the levels of serum Hcy, vitamin B12 (vit B12), and folic acid in patients with PCOS. MATERIALS AND METHODS: An interventional study was designed with 18 patients with PCOS at the Fatemehzahra infertility Hospital in Babol, Iran. Metformin treatment (500 mg twice daily) was initiated in all patients for a period of consecutive 6 months. The levels of serum Hcy, vit B12, and folic acid were measured in the participants before and after metformin treatment. RESULTS: The mean vit B12 level showed a significant decrease in patients after 6 months of metformin treatment (P = 0.002). However, there was no significant difference in serum folic acid levels. The mean Hcy levels increased after treatment, but this difference not was statistically significant. When patients were stratified into four subgroups by their insulin sensitivity and body mass index (BMI), relatively similar results were obtained in the subgroups, except that Hcy levels in the overweight/obesity group (BMI > 25 kg/m2) after treatment showed a significant increase (P = 0.01). CONCLUSION: These findings indicate that metformin increases the serum Hcy concentration in patients with PCOS especially in the women with BMI > 25 kg/m2. The possible mechanism for this effect would be the obvious reduction in the levels of vit B12. PMID- 28904498 TI - Correlation of Site of Embryo Transfer with IVF Outcome: Analysis of 743 Cycles from a Single Center. AB - OBJECTIVE: To investigate the influence of site of embryo transfer (ET) on reproductive outcome. MATERIALS AND METHODS: A retrospective analysis of 743 ultrasound-guided ET in fresh in vitro fertilization (IVF) cycles from a single center over a period of 4 years was conducted. The distance between the fundal endometrial surface and the air bubble was measured, and accordingly, patients were divided into four groups (<=10 mm; >10 and <=15 mm; >15 and 20 mm; >20 and <25 mm). SETTING: Tertiary Assisted Reproductive Technology (ART) center. PATIENTS: All patients enrolled in the IVF program undergoing ET. INTERVENTIONS: Controlled ovarian hyperstimulation (OS), IVF, and ET. MAIN OUTCOME MEASURES: Cleavage rate and clinical pregnancy rate. RESULTS: Clinical pregnancy rate was significantly more in groups 2 and 3 compared to the other groups. Logistic regression analysis showed that one unit increase in embryos transfer will enhance the pregnancy outcome about 3.7 (adjusted odds ratio) times with 95% confidence limits 2.6 to 5.4. Similarly, pregnancy outcome will be 3.1 (95% confidence limits: 1.5-6.4) times higher for distance group >15 and <20 mm compared to less than 10-mm distance group. Ectopic pregnancy rates were similar in all the four groups. CONCLUSION: The present study demonstrates that site of ET has significant difference on reproductive outcome. PMID- 28904499 TI - Does First Serum Beta-Human Chorionic Gonadotropin Value Prognosticate the Early Pregnancy Outcome in an In-Vitro Fertilisation Cycle? AB - BACKGROUND: Pregnancies achieved through in-vitro fertilisation (IVF) are associated with adverse first trimester outcomes in comparison to spontaneously achieved pregnancies. In view of this, it is imperative to predict the success as well as prognosticate the pregnancy outcome of an IVF cycle not only for the clinicians but also the couples undergoing IVF. Serum beta-human chorionic gonadotropin (beta-hCG) value has, thus, been used as a biomarker for pregnancy outcome after IVF and also an aid in counselling and management of the patient. AIM: The main objective of this study was to compare the predictive value of the first serum beta-hCG value and the pregnancy outcome after an IVF cycle (whether fresh or frozen embryo transfer) in the two subgroups of patients. SETTINGS AND DESIGN: The study was conducted at Assisted Reproductive Technology Centre of a tertiary care hospital, and it was a retrospective cohort study. METHODS AND MATERIALS: A retrospective study was performed for post-IVF pregnancies at a single IVF centre from March 2014 to February 2015 with serum beta-hCG values less than or equal to 1000 mIU/ml. The initial serum values of beta-hCG on the day 16 of embryo transfer were correlated with first trimester pregnancy outcome and ongoing pregnancy rate (>12 weeks gestation). RESULTS: Of the 208 post-IVF pregnancies included in the study, the group with beta-hCG more than 500 mIU/ml had statistically significant higher ongoing pregnancy rates and a lesser poor pregnancy outcome. CONCLUSION: The study concluded that an early serum beta-hCG value can be used as a predictor of a successful or an adverse first trimester pregnancy outcome helping in better counselling and monitoring of the high-risk precious IVF pregnancies. PMID- 28904500 TI - Retrospective Study of Factors Affecting Intrauterine Insemination Pregnancy Outcome: The Impact of Male Habits and Working Environment. AB - AIMS: This study is aimed at determining the prognostic factors influencing successful pregnancy following intrauterine insemination (IUI). SETTINGS AND DESIGN: Retrospective analysis. MATERIALS AND METHODS: A total of 2123 cycles undergone by 871 couples during the period of 5 years (2011-2015) were retrospectively studied. STATISTICAL ANALYSIS USED: Each of the factors was compared with pregnancy outcome (PO) using statistical analysis with a confidence interval of 95% in SPSS software version 19. Chi-square test and logistic regression analysis method were used to determine the significance of each factor with the PO. RESULTS: Among the various factors included in our study population, male habits (P = 0.004), male occupational environment (P = 0.025), male age (P = 0.002), and female age (P = 0.001) were found to significantly influence the PO following IUI. CONCLUSION: Our results indicate that avoiding smoking and alcohol consuming prior and during the IUI treatment along with working in low-heat generating environment might lead to better success following the treatment. PMID- 28904501 TI - Patient Experience with Conscious Sedation as a Method of Pain Relief for Transvaginal Oocyte Retrieval: A Cross Sectional Study. AB - AIM: The aim of the study was to measure patient's satisfaction level and acceptance of conscious sedation as a method of pain relief following transvaginal oocyte retrieval (TVOR) during assisted reproduction technology treatment. We also evaluated the factors that may influence the efficacy of conscious sedation method. SETTING AND DESIGN: A prospective cross-sectional study. MATERIALS AND METHODS: Prospective study was conducted from October 2015 to January 2016 at a university-level hospital and 100 women were recruited. Variables for analysis included woman age, duration of procedure, number of oocytes retrieved, and transmyometrial passage of the needle. Pain assessment was done by visual analog scale (VAS). Medical complications, and patient satisfaction score [Likert's score and client satisfaction questionnaire (CSQ)] were recorded. RESULTS: There was a moderate positive correlation between age and pain score on day 1 post-procedure. When the duration of procedure was >12 min, immediate post-procedure pain score was significantly higher compared to those whose procedure where duration was <12 min. There was no correlation between pain score and the number of oocytes retrieved (<=5, 6-15, and >=16) and transmyometrial passage of needle. The VAS 10-point score immediately post procedure, after 6 and 24 h post-procedure, and on day of embryo transfer was 2.83 (+/-1.67), 0.78 (+/-1.04), 0.39 (+/-1.09), and 0.14 (+/-0.58), respectively. The Likert's score was 3.65 (+/-0.82) and mean CSQ was 27.04 (+/-3.01). Majority of the women (86%) preferred the same pain relief method for future analgesia. There were no major complications. CONCLUSION: Conscious sedation was associated with high satisfaction level and acceptance rate among patients undergoing TVOR. PMID- 28904502 TI - Antispermatogenic Mechanism of Trona is Associated with Lipid Peroxidation but Not Testosterone Suppression. AB - BACKGROUND: About half of the cases of infertility in couples have been attributed to male factor. Despite the claim in folklore medicine that trona (a sesquicarbonate or hydrated carbonate of sodium) causes fetal loss, its effect on male reproductive function has not been investigated. AIM: This study sought to provide scientific evidence on the effect of trona on sperm characteristics, male reproductive hormones and organs, and lipid peroxidation. MATERIALS AND METHODS: Forty male Wistar rats of comparable weights were used for the study. Rats were randomized into four different groups. The control received 1 mL of distilled water orally, whereas those in groups 1, 2, and 3 (test groups) received orally, same volume of trona preparation corresponding to 100, 200, and 400 mg/kg body weight, respectively, for 28 days. Body weight was monitored throughout the study period, and at the end of the experiment, testicular morphometry, sperm characteristic, reproductive hormones, and malondialdehyde (MDA), an index of lipid peroxidation, were determined. RESULTS: Sperm count, motility, progressibility, and percentage of normal sperm were significantly decreased in the trona-treated rats (P < 0.05). The percentage of abnormal sperm, luteinizing hormone, follicle stimulating hormone, and MDA were significantly increased in the treated rats (P < 0.05). Body weight, testicular morphometry, and testosterone level were comparable across all groups (P > 0.05). CONCLUSION: The study showed that trona has a dose-dependent deleterious effect on sperm characteristic. The antispermatogenic effect of trona was associated with lipid peroxidation but not testosterone. PMID- 28904503 TI - An Experimental Study of the Effects of Combined Exposure to Microwave and Heat on Gene Expression and Sperm Parameters in Mice. AB - OBJECTIVES: Separate exposure to microwaves (MWs) or heat had effects on expression levels of Bax and Bcl-2 and sperm parameters in studied group. AIMS: The objectives of this research were to determine the effects of separate and combined exposure to 900-MHz MW (as representative of cell phone radiation) and heat on gene expression and spermogram of male mice. SETTINGS AND DESIGN: This experimental animal study was conducted in the school of public health. MATERIALS AND METHODS: The study was done on 12 male mice randomly divided into four groups (21-23 g): control, test group 1 with separate exposure to 900-MHz MW, test group 2 with separate exposure to hot and sultry climate, and test group 3 with simultaneous whole body exposures to 900-MHz MW and hot and sultry climate. In all studied groups, gene expression and sperm parameters were measured. RESULTS: Tissue samples in all test groups showed integrity of the seminiferous tubule followed by all types of germ line cells. Significant increases in the number of dead sperms in mice with separate exposure to heat were observed in comparison with the other studied groups (P < 0.05). The ratio of Bax expression was elevated to 0.015 +/- 0.006 in mice after combined exposures to 900-MHz MW and heat. CONCLUSION: Separate and combined exposure to 900-MHz MW and heat may induce adverse effects on sperm parameters and gene expression of studied male mice. PMID- 28904504 TI - Role of Serpine Gene Polymorphism in Recurrent Implantation Failure and Preeclampsia. AB - This is a rare case of serpine gene polymorphism causing thrombophilia and recurrent implantation failure following intrauterine insemination. SERPINE1 gene encodes plasminogen activator inhibitor type 1 and inhibits fibrinolysis, or clot dissolution. The 4G variant results in increased expression of SERPINE1 and consequently higher inhibition of fibrinolysis, thus leading to thrombophilia. The patient had unexplained primary infertility for 9 years. Ovulation induction was done with gonadotropin releasing hormone (GnRH) agonist long protocol. Recombinant follicle stimulating hormone (FSH) with step down protocol was used. Ovulation trigger was given with recombinant human chorionic gonadotrophin (HCG). Ovum pick up was done after 40 h of trigger. A total of 13 eggs were collected. Patient was put on Cabergoline to prevent ovarian hyperstimulation syndrome (OHSS). Four frozen embryos were transferred on day 14 after Laser-assisted hatching. EmbryoGlue was used to prevent implantation failure. Luteal phase support was given. She was put on enoxaparin and pregnancy has now been confirmed. The patient was on strict monitoring as this gene is also associated with preeclampsia during pregnancy. PMID- 28904505 TI - Embryo Cryopreservation Following In-Vitro Maturation for Fertility Preservation in a Woman with Mullerian Adenosarcoma: A Case Report. AB - In-vitro maturation (IVM) of the immature oocytes recovered from the surgically removed ovarian tissue has been considered as a process for fertility preservation in patients with cancer. Fertility preservation for a woman with Mullerian adenocarcinoma. A 37-year-old woman with Mullerian adenocarcinoma was a candidate for ovarian resection. The immature oocytes were retrieved after ovarian resection from a 37-year-old woman with Mullerian adenocarcinoma. The oocytes underwent IVM and were fertilized using intracytoplasmic sperm injection (ICSI). Two healthy embryos were cryopreserved for future use. The immature oocytes from the ovarian tissue can be matured with IVM for generation of embryos after ICSI. The embryos can be vitrified using routine methods for fertility preservation in young women with cancer. PMID- 28904506 TI - Erratum: Relationship between morphology, euploidy and implantation potential of cleavage and blastocyst stage embryos. AB - [This corrects the article on p. 49 in vol. 10, PMID: 28479756.]. PMID- 28904507 TI - Adjunctive Melatonin for Tardive Dyskinesia in Patients with Schizophrenia: A Meta-Analysis. AB - BACKGROUND: Tardive dyskinesia (TD) is characterized by abnormal and involuntary movements. Importantly, TD could cause considerable personal suffering and social and physical disabilities. AIMS: This meta-analysis based on randomized controlled trials (RCTs) systematically assessed the therapeutic effect and tolerability of melatonin for TD in schizophrenia. METHODS: A computerized and systematical search of both Chinese (Wanfang Data, Chinese National Knowledge Infrastructure (CNKI), SINOMED) and English (PubMed, PsycINFO, Embase, Cochrane Library databases) databases, from their inception until June 8, 2017, was conducted by two independent authors. The severity of TD symptoms were the primary outcome measure and analyzed using a random effects model by the Review Manager (RevMan) Version 5.3. Quality evaluation of included RCTs was conducted using the Cochrane risk of bias and Jadad scale. The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system recommendation grading method was used to assess the overall quality level of meta-analytic outcomes. RESULTS: Four RCTs (n=130) were identified and analyzed. Three RCTs used double blind and 1 RCT used masked assessors using the Cochrane risk of bias, and 3 RCTs were rated as high quality based on Jadad scale. Compared with the control group, adjunctive melatonin was superior in reducing the severity of TD as measured by the Abnormal Involuntary Movement Scale (AIMS) (4 RCTs, n=130, weighted mean difference (WMD): -1.52 (95% confidence intervals (CI): -3.24, 0.20), p=0.08; I2 =0%) although the improvement did not reach a significant level. The overall evidence quality of the improvement of TD symptoms, according to GRADE approach, was rated as "Low". The data on the ADRs and cognitive effect were limited. CONCLUSIONS: This meta-analysis shows that melatonin has potential for improving TD symptoms in schizophrenia. Future higher quality and larger RCTs are warranted to confirm the findings. PMID- 28904508 TI - Changes in Cognitive Function in Patients with Primary Insomnia. AB - BACKGROUND: Neuropsychological evidence is not sufficient concerning whether there is cognitive impairment in patients with primary insomnia. Further study is needed in this regard. AIMS: To measure the changes in cognitive functioning in patients with primary insomnia. METHODS: 40 patients with insomnia (insomnia group) and 48 normal sleepers (control group) were tested using the Pittsburgh Sleep Quality Index (PSQI), episodic memory test, and Montreal Cognitive Assessment (MoCA). RESULTS: The insomnia group had significantly lower scores than the control group in the naming (t=3.17, p=0.002), immediate memory (t=3.33, p=0.001), and delayed recall (t=6.05, p=0.001) sections of the MoCA, as well as a lower overall score on the MoCA (t=3.24, p=0.002). Participants with different degrees of insomnia also had significantly different scores in naming (F=7.56, p=0.001), language (F=3.22, p=0.045), total score (F=6.72, p=0.002), delayed memory (F=8.41, p=0.001), and delayed recall (F=22.67, p=0.001) sections of the MoCA. The age of primary insomnia patients was correlated to MoCA total score, immediate memory, delayed recall, and delayed recognition function, also with statistical significance. The years of education of primary insomnia patients was also significantly correlated to overall MoCA score, as well as visuospatial and executive function, naming, attention, language, and abstraction sections of the MoCA. CONCLUSION: Primary insomnia patients have cognitive impairment. The more severe the insomnia is, the wider the range of and the more serious the degree of cognitive impairment is. PMID- 28904509 TI - Peripheral SLC6A4 Gene Expression in Obsessive-Compulsive Disorder in the Han Chinese Population. AB - BACKGROUND: Serotonergic system dysfunction has been implicated in obsessive compulsive disorder (OCD). This study examined peripheral SLC6A4 gene expression in OCD patients and healthy controls to explore the relationship between SLC6A4 and OCD. METHODS: Participants included 50 first episode OCD patients and 60 age and gender-matched healthy controls. Relative SLC6A4 gene expression were examined by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in peripheral leukocytes of all the subjects. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess the severity and subtype of OCD. RESULTS: SLC6A4 gene expression, normalized by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), were not significantly different between the OCD patients and healthy controls(z=-0.79, p=0.428). Male OCD patients showed a tendency of low gene expression of SLC6A4 in peripheral blood (z=-1.66, p=0.096). We did not find a significant correlation between SLC6A4 expression and the severity and subtype of OCD. CONCLUSION: There is no correlation between SLC6A4 expression levels and the severity and subtype of OCD, but male OCD patients showed a tendency of low gene expression of SLC6A4 in peripheral blood. These results suggest that gene expression of SLC6A4 in peripheral blood may not be a useful biomarker of OCD in the Han Chinese population. PMID- 28904510 TI - Dysfunction of Cognition Patterns Measured by MATRICS Consensus Cognitive Battery (MCCB) among First Episode Schizophrenia Patients and Their Biological Parents. AB - BACKGROUND: Schizophrenia is characterized by abnormal perception, thinking, emotions, and behaviors. Cognitive dysfunction is acknowledged as one of the most pivotal symptoms in schizophrenia. In addition to positive or negative symptoms, which had been proposed by Gallhofer in the early 1970s, schizophrenia patients suffered from cognitive impairments as well. Many studies show that there is genetic susceptibility in the first grading kinship of patients with schizophrenia. Patients with schizophrenia have cognitive impairment not only in the acute phase but also in the stable phase. Studies also show that the healthy first-grading relatives of patients with schizophrenia suffer from cognitive defects. However, there is still a lack of studies about the cognitive features of biological parents of those with schizophrenia. In this study, we speculate the biological parents of schizophrenia patients have specific cognitive dysfunction. And we explore the patterns of cognition among both schizophrenia patients and their biological parents using the Chinese version of MATRICS Consensus Cognitive Battery (MCCB). AIMS: Cognitive features of patients with schizophrenia might be affected by the cognition mode of patients' biological parents. The dysfunctional cognitive patterns need to be characterized among the patients with schizophrenia and their parents. METHODS: We applied the MATRICS Consensus Cognitive Battery (MCCB, a novel measurement tool) to evaluate the cognitive function of 29 first-episode patients with schizophrenia (meeting ICD 10 diagnostic criteria for schizophrenia, aged between 17-45 years old), 58 cases of biological parents of schizophrenia patients (aged between 40-70 years old) and 46 healthy controls (aged between 40-70 years old). Furthermore, we explored the relationship between the cognitive dysfunction in patients with schizophrenia and their biological parents. All data were analyzed using SPSS18.0 statistical software. RESULTS: 1) Male patients with schizophrenia had obvious cognitive defects in six domains of cognitive function as measured by the MCCB (all except the social cognition domain) compared to their male parents. Female patients showed lower ability on both working memory and problem reasoning than their female parents. 2) The significant differences of both working memory and reasoning problems also existed between the patients' fathers and matched healthy controls. 3) Patients' mothers didn't show any significant difference on the problem reasoning domain compared with healthy controls. However, the visual learning domain appeared abnormal in patients' mothers compared with healthy controls. CONCLUSION: There are six dimensions of cognitive impairments in both first-episode schizophrenia patients and their biological parents. Compared with healthy controls, patients' biological parents have conspicuous dysfunction in domains of working memory, problem reasoning and visual learning as well. Further study is needed to explore the underlying mechanisms of similar cognitive dysfunction between first-episode schizophrenia patients and their biological parents. PMID- 28904511 TI - The Fantasmatic and Imaginary Child of the Pregnant Woman. AB - BACKGROUND: Pregnancy is a period of transition, which makes women more vulnerable and in unfavorable conditions may lead to psychopathology in both mother and infant. It is essential to outline factors adversely affecting the resolution of this period. Early interventions and why they matter: Interventions during pregnancy can provide important improvement in the outcome for both maternal and infant mental health. AIM: The aim of the study is to evaluate the risk factors of antenatal anxiety and depression focusing particularly on maternal representations of the relationship towards the fetus and her own parents during pregnancy and the early postpartum period. METHODS: The study is outlined using a quantifiable interview during pregnancy to evaluate the woman's ability to keep her child in mind, measured by reflective functioning. Reflective functioning provides information regarding the pregnant woman's relationship quality to her fetus and important people in her life. Primiparae in Stockholm around gestation week 20 are asked about their experience with respect to pregnancy, their relationship to their family, partner, and their unborn child. The women selected to the study are an at risk population, with high levels of stress, childhood adversity, and/or history of mental health. These women are more vulnerable to develop perinatal anxiety and depression. RESULTS: The pregnancy interview provides valuable insight into the pregnant women's psychic constitution. The quantifiable measure of their mental state, reflective functioning, serves as measure of quality of the mother's parenting capacity. The countertransference and transference of the interviewer towards the women during the interview enables a more profound understanding of the underlying dynamics and constructs of repression, aggression, mourning, and narcissistic defenses. CONCLUSION: A better understanding of the underlying mechanisms of the pregnant women's intrapsychic reorganization of motherhood and her relation to the unborn child shall facilitate specific early interventions. These interventions shall be targeted to specific risk groups and enable the prevention of adverse child outcomes. PMID- 28904512 TI - Is Depression the Result of Immune System Abnormalities? AB - The etiology of Major Depressive Disorder (MDD) is still unclear. We reviewed the literature for the relationship between inflammatory signaling and cytokines in the pathogenesis of MDD. In addition, we provid evidence for adjunctive treatment using anti-inflammatory drugs to improve the therapeutic effect and prognosis. Finally, we explore the possible relationship between the pathogenesis of MDD and immune disturbances. PMID- 28904513 TI - Autoimmune Thyroiditis Presenting as Psychosis. AB - Hashimoto's thyroiditis is a rare condition associated mainly with neurological symptoms. It contains an abundant amount of auto-antibodies in the blood. Only a few cases of behavioral symptoms without significant neurological disturbances have been recorded in the literature. In this view, our case is unique as it was not associated with overt hypothyroid manifestations. PMID- 28904514 TI - Hyponatremia with Olanzapine - A Suspected Association. AB - Hyponatremia is a rare, yet potentially life threatening complication of antipsychotics. Here, we report a case of a 45-year-old female diagnosed with schizophrenia who developed hyponatremia soon after addition of olanzapine to the existing treatment. This prompted us to evaluate the relationship between hyponatremia and olanzapine, as timely management is crucial. Naranjo algorithm established a "probable" causal relation between olanzapine and hyponatremia. Possible etiological reasons of this clinically significant and life threatening adverse event have been discussed. We report the case and the literature focusing on hyponatremia as a possible adverse event of olanzapine. Medical illnesses are often ignored or missed in patients with psychiatric disorders either due to patients' inability to report complaints or non-serious attitude of physicians towards such patients. A high index of suspicion should be kept while dealing with this probable complication. PMID- 28904515 TI - Psychogenic Polydipsia - Management Challenges. AB - Compulsive water drinking or psychogenic polydipsia is now increasingly seen in psychiatric populations. Effects of increased water intake can lead to hyponatremia causing symptoms of nausea, vomiting, seizures, delirium and can even be life threatening if not recognized and managed early. Here we present a 35-year old adult who was diagnosed with psychogenic polydipsia and was successfully managed with a combination of pharmacotherapy, fluid restriction and psychosocial management. PMID- 28904516 TI - The Differences and Similarities Between Two-Sample T-Test and Paired T-Test. AB - In clinical research, comparisons of the results from experimental and control groups are often encountered. The two-sample t-test (also called independent samples t-test) and the paired t-test are probably the most widely used tests in statistics for the comparison of mean values between two samples. However, confusion exists with regard to the use of the two test methods, resulting in their inappropriate use. In this paper, we discuss the differences and similarities between these two t-tests. Three examples are used to illustrate the calculation procedures of the two-sample t-test and paired t-test. PMID- 28904517 TI - On [Formula: see text]-Szasz-Mirakyan operators and their approximation properties. AB - In the present paper, we introduce a new modification of Szasz-Mirakyan operators based on [Formula: see text]-integers and investigate their approximation properties. We obtain weighted approximation and Voronovskaya-type theorem for new operators. PMID- 28904518 TI - Majorization, Csiszar divergence and Zipf-Mandelbrot law. AB - In this paper we show how the Shannon entropy is connected to the theory of majorization. They are both linked to the measure of disorder in a system. However, the theory of majorization usually gives stronger criteria than the entropic inequalities. We give some generalized results for majorization inequality using Csiszar f-divergence. This divergence, applied to some special convex functions, reduces the results for majorization inequality in the form of Shannon entropy and the Kullback-Leibler divergence. We give several applications by using the Zipf-Mandelbrot law. PMID- 28904519 TI - On homogeneous second order linear general quantum difference equations. AB - In this paper, we prove the existence and uniqueness of solutions of the beta Cauchy problem of second order beta-difference equations [Formula: see text] [Formula: see text], in a neighborhood of the unique fixed point [Formula: see text] of the strictly increasing continuous function beta, defined on an interval [Formula: see text]. These equations are based on the general quantum difference operator [Formula: see text], which is defined by [Formula: see text], [Formula: see text]. We also construct a fundamental set of solutions for the second order linear homogeneous beta-difference equations when the coefficients are constants and study the different cases of the roots of their characteristic equations. Finally, we drive the Euler-Cauchy beta-difference equation. PMID- 28904520 TI - Vapochromic Behaviour of Polycarbonate Films Doped with a Luminescent Molecular Rotor. AB - We report on vapochromic films suitable for detecting volatile organic compounds (VOCs), based on polycarbonate (PC) doped with 4-(triphenylamino)phthalonitrile (TPAP), a fluorescent molecular rotor sensitive to solvent polarity and viscosity. PC films of variable thickness (from 20 up to 80 um) and containing small amounts of TPAP (0.05 wt.%) were prepared and exposed to a saturated atmosphere of different VOCs. TPAP/PC films showed a gradual decrease and red shift of the emission during the exposure to solvents with high polarity index and favourable interaction with the polymer matrix such as THF, CHCl3, and acetonitrile. In the case of the most interacting solvents (THF and CHCl3), TPAP/PC films also showed a fluorescence increase at longer exposure times, as a consequence of an irreversible, solvent-induced crystallization process of the polymeric matrix. The vapochromism of TPAP/PC films is rationalized on the basis of alterations of the rotor intramolecular motion upon solvent uptake by PC and polarity effects of the microenvironment. Interestingly, the fluorescence response of the TPAP/PC films shows a non-trivial, tuneable dependence on film thickness during the second solvent-exposure stage. The latter effect is attributed to a variable extent of the crystallization process occurring in the PC films. This observation promptly suggests, in turn, an effective procedure to modulate the spectroscopic response in such functionalized polymeric materials through the precise control of the film thickness. PMID- 28904522 TI - Endoscopic Pilonidal Sinus Treatment: Long-Term Results of a Prospective Series. AB - BACKGROUND AND OBJECTIVES: Pilonidal sinus is a common problem in the sacrococcygeal region, especially in obese, sedentary young men. The ideal surgical solution is still under debate, and there is a high rate of recurrence. In the present study, we analyzed the long-term results of a video-assisted minimally invasive technique for the treatment of sacrococcygeal pilonidal disease: endoscopic pilonidal sinus treatment (EPSiT). METHODS: From October 2013 through November 2015, a total of 77 consecutive patients (69 Males and 8 Females, median age: 23 y) were referred to our colorectal units. Sixty-eight patients had a primary sacrococcygeal pilonidal sinus, and 9 had recurrent pilonidal sinus; all underwent EPSiT. A fistuloscope was introduced through an external opening and the sinus cavity was completely ablated under direct vision. Postoperative complications, wound infection rate, recurrence rate, time until return to work, and patient satisfaction score were recorded during follow-up or at the last interview. Clinical data were obtained at 7, 15, and 30 days and at 6, 12, and 24 months after surgery. RESULTS: All patients completed the follow-up (median follow-up was 25 (range, 17-40) months. Median operative time was 18 (range, 12-30) minutes. The median hospital stay was 6.5 (range, 5-9) hours, and the median time to return to work was 5 days. Median healing time was 26 (range, 15-45) days. There were no major or minor complications. Six patients experienced recurrence. The overall satisfaction rate was 97%. CONCLUSIONS: The ideal surgical treatment for pilonidal sinus disease should be simple and effective. In our experience, EPSiT can be performed as a day surgery, with early return to daily activities. This technique is an uneventful procedure, with good aesthetic results and a low recurrence rate. PMID- 28904521 TI - Mesh Displacement After Bilateral Inguinal Hernia Repair With No Fixation. AB - BACKGROUND AND OBJECTIVES: About 20% of patients with inguinal hernia present bilateral hernias in the diagnosis. In these cases, laparoscopic procedure is considered gold standard approach. Mesh fixation is considered important step toward avoiding recurrence. However, because of cost and risk of pain, real need for mesh fixation has been debated. For bilateral inguinal hernias, there are few specific data about non fixation and mesh displacement. We assessed mesh movement in patients who had undergone laparoscopic bilateral inguinal hernia repair without mesh fixation and compared the results with those obtained in patients with unilateral hernia. METHODS: From January 2012 through May 2014, 20 consecutive patients with bilateral inguinal hernia underwent TEP repair with no mesh fixation. Results were compared with 50 consecutive patients with unilateral inguinal hernia surgically repaired with similar technique. Mesh was marked with 3 clips. Mesh movements were measured by comparing initial radiography performed at the end of surgery, with a second radiographic scan performed 30 days later. RESULTS: Mean movements of all 3 clips in bilateral nonfixation (NF) group were 0.15-0.4 cm compared with 0.1-0.3 cm in unilateral NF group. Overall displacement of bilateral and unilateral NF groups did not show significant difference. Mean overall displacement was 1.9 cm versus 1.8 cm in the bilateral and unilateral NF groups, respectively (P = .78). CONCLUSIONS: TEP with no mesh fixation is safe in bilateral inguinal repairs. Early mesh displacement is minimal. This technique can be safely used in most patients with inguinal hernia. PMID- 28904523 TI - Music Listening Among Postoperative Patients in the Intensive Care Unit: A Randomized Controlled Trial with Mixed-Methods Analysis. AB - BACKGROUND: Music listening may reduce the physiological, emotional, and mental effects of distress and anxiety. It is unclear whether music listening may reduce the amount of opioids used for pain management in critical care, postoperative patients or whether music may improve patient experience in the intensive care unit (ICU). METHODS: A total of 41 surgical patients were randomized to either music listening or controlled non-music listening groups on ICU admission. Approximately 50-minute music listening interventions were offered 4 times per day (every 4-6 hours) during the 48 hours of patients' ICU stays. Pain, distress, and anxiety scores were measured immediately before and after music listening or controlled resting periods. Total opioid intake was recorded every 24 hours and during each intervention. RESULTS: There was no significant difference in pain, opioid intake, distress, or anxiety scores between the control and music listening groups during the first 4 time points of the study. However, a mixed modeling analysis examining the pre- and post-intervention scores at the first time point revealed a significant interaction in the Numeric Rating Scale (NRS) for pain between the music and the control groups (P = .037). The Numeric Rating Score decreased in the music group but remained stable in the control group. Following discharge from the ICU, the music group's interviews were analyzed for themes. CONCLUSIONS: Despite the limited sample size, this study identified music listening as an appropriate intervention that improved patients' post intervention experience, according to patients' self-report. Future mixed methods studies are needed to examine both qualitative patient perspectives and methodology to improve music listening in critical care units. PMID- 28904524 TI - Prevalence, Circumstances, and Management of Acute Pesticide Poisoning in Hospitals in Kampala City, Uganda. AB - This study was aimed at assessing prevalence, circumstance, and management of acute pesticide poisoning in hospitals in Kampala. It was a retrospective cross sectional study that involved reviewing of 739 poisoning patient records from 5 hospitals in Kampala. Of the 739 patients, 212 were due to pesticide poisoning resulting in a prevalence of 28.8%. About 91.4% (191/210) of the cases were due to organophosphate poisoning, 63.3% (133/210) were intentional, and 98.1% (206/210) were exposed through ingestion. Diagnosis was majorly based on poisoning history 91.2% (187/205), and clinical features such as airways, breathing, and circulation examination 48.0% (95/198); nausea and vomiting 42.9% (91/212); muscle weakness 29.7% (63/212); excessive salivation 23.1% (49/212); and confusion 20.3% (43/212). More than half of the patients admitted were treated using atropine 52.3% (113/212). The prevalence of acute pesticide poisoning was high with most managed based on physical and clinical examination. PMID- 28904525 TI - Knowing About Device Algorithms to Understand the Rhythm and Role of Managed Ventricular Pacing. AB - A 66-year-old patient with a DR pacemaker for intermittent atrioventricular block presented with an electrocardiogram (ECG) showing some P waves non followed by QRS complexes, raising suspicion of device dysfunction. The device was equipped with a special algorithm (Managed Ventricular Pacing; Medtronic), and the observed ECG tracing was a normal consequence of the function of such algorithms. Being aware of the function of specific algorithms is essential to adequately analyze rhythms. PMID- 28904526 TI - A Case of a Very Elongated Styloid Process. AB - Eagle syndrome is characterized by recurrent pain in the oropharynx and face due to an elongated styloid process or calcified stylohyoid ligament. In this article, we experienced a case of an elongated styloid process which is very rare in size and detailed treatment process. The patient was a 53-year-old Chinese woman with a chief complaint of frequent episodes of radiating pain in left preauricular region for 2 years. An intraoral approach was chosen to shorten part of her styloid process, and the chief complaint disappeared immediately after the operation. PMID- 28904527 TI - Cost effectiveness of vildagliptin versus glimepiride as add-on treatment to metformin for the treatment of diabetes mellitus type 2 patients in Greece. AB - OBJECTIVES: This study was designed to assess the cost-effectiveness of vildagliptin versus glimepiride as add-on to metformin in the management of type 2 diabetes mellitus (T2DM) patients in the Greek healthcare setting. METHODS: A cost-effectiveness model was designed, using MS Excel, to compare two treatment strategies. Strategy 1 consisted of first-line metformin, followed by metformin + vildagliptin in second-line, while strategy 2 consisted of first line metformin, followed by metformin + glimepiride in second line. Subsequent lines were the same in both strategies and consisted of metformin + basal insulin and metformin + basal + rapid insulin. Clinical data and utility decrements relating to diabetes complications were taken from the published literature. Only direct medical costs were included in the analysis (cost base year 2014), and consisted of drug, adverse events and comorbidity costs (taken from local officially published sources and the literature). The perspective adopted was that of the Social Insurance Fund. The time horizon was lifetime, and future costs and outcomes were discounted at 3.5% per annum. RESULTS: Adding vildagliptin to metformin increased drug costs compared with adding glimepiride to metformin (?2853 vs. ?2427, respectively). However, this increase was offset by a decrease in the costs of associated comorbidities (?4393 vs. ?4539) and adverse events (?2757 vs. ?3111), resulting in a lower total cost of ?74 in strategy 1 compared with strategy 2. Comorbidities were the largest cost component in both strategies, accounting for 43.9 and 45.0% in strategies 1 and 2, respectively. Strategy 1 was also associated with increased life-years (LYs, 0.11) and quality adjusted life-years (QALYs, 0.11) compared with strategy 2. Strategy 1 is therefore dominant, as it is associated with both lower overall costs and increased effectiveness. CONCLUSIONS: Vildagliptin as add-on treatment to metformin in the management of T2DM in Greece appears to be dominant versus. glimepiride in terms of both cost per LY and cost per QALY gained. PMID- 28904528 TI - Access criteria for anti-TNF agents in spondyloarthritis: influence on comparative 1-year cost-effectiveness estimates. AB - BACKGROUND: Anti-tumor necrosis factor (anti-TNF) agents are an effective, but costly, treatment for spondyloarthritis (SpA). Worldwide, multiple sets of access criteria aim to restrict anti-TNF therapy to patients with specific clinical characteristics, yet the influence of access criteria on anti-TNF cost effectiveness is unknown. Our objective was to use data from the DESIR cohort, a prospective study of early SpA patients in France, to determine whether the French anti-TNF access criteria are the most cost-effective in that setting relative to other potential restrictions. METHODS: We used data from the DESIR cohort to create five study populations of patients meeting anti-TNF access criteria from Canada, France, Germany, United Kingdom, and Hong Kong, respectively. For each study population, we calculated the costs and quality adjusted life years (QALYs) over 1 year of patients treated and not treated with anti-TNF therapy. To control for differences between anti-TNF users and non users, we used linear regression models to derive adjusted mean costs and QALYs. We calculated incremental cost-effectiveness ratios (ICERs) representing the incremental cost per additional QALY gained by treating with an anti-TNF within each of the five study populations, using bootstrapping to explore the range of uncertainty in costs and QALYs. A series of sensitivity analyses was conducted, including one to simulate the effect of a 24-week stopping rule for anti-TNF non responders. RESULTS: Anti-TNF access criteria from France were satisfied by the largest proportion of DESIR patients (27.8%), followed by Germany (25.1%), Canada (23.8%), the UK (12.1%) and Hong Kong (8.6%). Confidence intervals around incremental costs and QALYs in the basecase analysis were overlapping, indicating that anti-TNF cost-effectiveness estimates derived from each subset were similar. In the sensitivity analysis that examined the effect of excluding costs accumulated past 24 weeks by anti-TNF non-responders, the incremental cost per QALY was reduced by approximately 25% relative to the basecase analysis (France: ?857,992 vs. ?1,105,859; Canada: ? 626,459 vs. ?818,186; Germany: ? 422,568 vs. ?545,808); UK ?578,899 vs. ?766,217; Hong Kong ?335,418 vs. ?456,850). CONCLUSIONS: Anti-TNF cost-effectiveness is strongly affected by treatment continuation among non-responders. Access criteria could improve anti-TNF cost effectiveness by defining patients likely to respond. PMID- 28904529 TI - Complementarity in dietary supplements and foods: are supplement users vegetable eaters? AB - Background: The consumption of fruits, vegetables, and dietary supplements correlate. Most previous studies have aimed to identify the determinants of supplement uses or the distinct features of supplement users; this literature lacks a discussion on dietary supplement consumption as a predictor of fruit and vegetable consumption. Objective: This study examines how dietary supplement consumption correlates with fruit and vegetable consumption by combining scanner data and surveys of Korean household grocery shopping. Methods: Propensity score matching (PSM) is used to identify the relationship between dietary supplement consumption and fruit and vegetable consumption in a household. A logit regression using supplement consumption as the dependent variable is used. Then, the supplement takers (the treatment group) are matched with non-takers (the control group) based on the propensity scores estimated in the logit regression. The fruit and vegetable consumption levels of the groups are then compared. Results: We found that dietary supplement use is associated with higher fruit and vegetable consumption. This supports the health consciousness hypothesis based on attention bias, availability heuristics, the focusing effect, and the consumption episode effect. It rejects the health substitute hypothesis based on economic substitutes and mental accounting. Conclusions: Future research on the health benefits of dietary supplements should address the complementary consumption of fruits/vegetables and their health benefits to avoid misstating the health effects of supplements. PMID- 28904530 TI - Corrigendum. AB - [This corrects the article DOI: 10.1080/16546628.2017.1348865.]. PMID- 28904531 TI - Potential Therapeutic Mechanisms and Tracking of Transplanted Stem Cells: Implications for Stroke Treatment. AB - Stem cell therapy is a promising potential therapeutic strategy to treat cerebral ischemia in preclinical and clinical trials. Currently proposed treatments for stroke employing stem cells include the replacement of lost neurons and integration into the existing host circuitry, the release of growth factors to support and promote endogenous repair processes, and the secretion of extracellular vesicles containing proteins, noncoding RNA, or DNA to regulate gene expression in recipient cells and achieve immunomodulation. Progress has been made to elucidate the precise mechanisms underlying stem cell therapy and the homing, migration, distribution, and differentiation of transplanted stem cells in vivo using various imaging modalities. Noninvasive and safe tracer agents with high sensitivity and image resolution must be combined with long-term monitoring using imaging technology to determine the optimal therapy for stroke in terms of administration route, dosage, and timing. This review discusses potential therapeutic mechanisms of stem cell transplantation for the treatment of stroke and the limitations of current therapies. Methods to label transplanted cells and existing imaging systems for stem cell labeling and in vivo tracking will also be discussed. PMID- 28904532 TI - The Use of Adipose-Derived Stem Cells in Selected Skin Diseases (Vitiligo, Alopecia, and Nonhealing Wounds). AB - The promising results derived from the use of adipose-derived stem cells (ADSCs) in many diseases are a subject of observation in preclinical studies. ADSCs seem to be the ideal cell population for the use in regenerative medicine due to their easy isolation, nonimmunogenic properties, multipotential nature, possibilities for differentiation into various cell lines, and potential for angiogenesis. This article reviews the current data on the use of ADSCs in the treatment of vitiligo, various types of hair loss, and the healing of chronic wounds. PMID- 28904535 TI - Effect of Massage Therapy on Labor Pain Reduction in Primiparous Women: A Systematic Review and Meta-analysis of Randomized Controlled Clinical Trials in Iran. AB - BACKGROUND: Pain is a common experience for women during labor. Therefore, pain relief care for mothers during labor is very important. This meta-analysis was conducted to evaluate the efficacy of massage therapy on labor pain reduction in primiparous women. MATERIALS AND METHODS: In this meta-analysis, the databases of Web of Knowledge, PubMed, Scopus, Cochrane, Iranmedex, Scientific Information Database (SID), and Magiran were searched for published articles in English and Persian language up to January 2016. Among the studies, with regard to the inclusion and exclusion criteria, 10 studies were selected. Data were analyzed by using Stata software version 11, and standard mean difference (SMD) of effects of massage therapy was calculated. The heterogeneity among studies was evaluated by the Chi-square based Q-test and I2 statistics. RESULTS: The results of Chi-square based on Q-test and I2 statistics showed heterogeneity among studies in the latent phase (Q = 63.52, P value < 0.001 and I2 = 87.4%), active phase (Q = 26.42, P value < 0.001, and I2 = 77.3%), and transitional phase (Q = 104.84, P value <0.001, and I2 = 95.2%). Results showed that massage therapy reduces labor pain in the latent phase (SMD = -1.23, 95% CI: -1.73 to -0.74), active phase (SMD = -1.59, 95% CI: -2.06 to -1.12), and transitional phase (SMD = -1.90, 95% CI: 3.09 to -0.71). CONCLUSIONS: This study provides valid evidence for the effect of massage therapy in Iran for labor pain relief. Therefore, the use of massage therapy can be recommended in the primiparous women. PMID- 28904536 TI - Relationship between Differentiation of Self and Attitude Towards Physician-Nurse Relationship in Hospitals (Isfahan/Iran). AB - BACKGROUND: Attitude towards physician-nurse relationship is fundamental to achieve health care quality. Such attitude maybe determined by some personality traits such as differentiation of self. Hence, the present study aimed to investigate the relationship between differentiation of self and attitude to professional physician-nurse relationship. MATERIALS AND METHODS: This cross sectional study was done in three hospitals in Isfahan in 2015. The study included all nurses and physicians. In total, 400 participants were recruited through convenience-sampling method. Data gathering instruments included a three part questionnaire [demographic data sheet, Jefferson Scale of Attitudes toward Physician-Nurse Collaboration (JSAPNC) and differentiation of self-inventory (DSI)]. The data were analyzed through descriptive and inferential statistics [t test, analysis of variance (ANOVA), and multiple linear regression) by the Statistical Package for the Social Sciences (SPSS) version 16 software. RESULTS: The mean [standard deviation (SD)] of the scores of differentiation of self in physicians and nurses were 86.43 (9.62) and 159.28 (9.53), respectively. The results showed that the predicting model of attitudes towards physician-nurse relationship based on dimensions of differentiation of self both in nurses and physicians were significant. Moreover, the findings from linear regression analyses showed that predictor variables explained 0.18 and 0.14 of the variance of attitudes towards physician-nurse relationships in nurses and physicians, respectively. CONCLUSIONS: Considering the significant role of differentiation of self to predict attitudes towards physician-nurse relationship, it is worthwhile to suggest provision of training programs particularly in the nursing and medical students to enhance differentiation of self both in physicians and nurses to improve culture of interprofessional relationships and to achieve optimum professional relationships between doctors and nurses. PMID- 28904534 TI - Three-Dimensional Organoid System Transplantation Technologies in Future Treatment of Central Nervous System Diseases. AB - In recent years, scientists have made great achievements in understanding the development of human brain and elucidating critical elements of stepwise spatiotemporal control strategies in neural stem cell specification lineage, which facilitates successful induction of neural organoid in vitro including the cerebral cortex, cerebellar, neural tube, hippocampus cortex, pituitary, and optic cup. Besides, emerging researches on neural organogenesis promote the application of 3D organoid system transplantation in treating central nervous system (CNS) diseases. Present review will categorize current researches on organogenesis into three approaches: (a) stepwise, direct organization of region specific or population-enriched neural organoid; (b) assemble and direct distinct organ-specific progenitor cells or stem cells to form specific morphogenesis organoid; and (c) assemble embryoid bodies for induction of multilayer organoid. However, the majority of these researches focus on elucidating cellular and molecular mechanisms involving in brain organogenesis or disease development and only a few of them conducted for treating diseases. In this work, we will compare three approaches and also analyze their possible indications for diseases in future treatment on the basis of their distinct characteristics. PMID- 28904533 TI - Gut Microbial Influences on the Mammalian Intestinal Stem Cell Niche. AB - The mammalian intestinal epithelial stem cell (IESC) niche is comprised of diverse epithelial, immune, and stromal cells, which together respond to environmental changes within the lumen and exert coordinated regulation of IESC behavior. There is growing appreciation for the role of the gut microbiota in modulating intestinal proliferation and differentiation, as well as other aspects of intestinal physiology. In this review, we evaluate the diverse roles of known niche cells in responding to gut microbiota and supporting IESCs. Furthermore, we discuss the potential mechanisms by which microbiota may exert their influence on niche cells and possibly on IESCs directly. Finally, we present an overview of the benefits and limitations of available tools to study niche-microbe interactions and provide our recommendations regarding their use and standardization. The study of host-microbe interactions in the gut is a rapidly growing field, and the IESC niche is at the forefront of host-microbe activity to control nutrient absorption, endocrine signaling, energy homeostasis, immune response, and systemic health. PMID- 28904537 TI - The Effect of New Model PREPARED on Obtaining Informed Consent Skill in Midwifery Students of Shahid Sadoughi University of Medical Sciences. AB - BACKGROUND: Professional ethics culture should be taught to students appropriately. Studies have shown that midwifery students are not entirely familiar with the skill of obtaining informed consent. Using a new and applicable model to teach this skill to midwifery students is necessary. This study was conducted to determine the effect of a new standard model, PREPARED, on the skill of obtaining informed consent in midwifery students of Shahid Sadoughi University of Medical Sciences. MATERIALS AND METHODS: This interventional study was conducted on 37 5th semester midwifery students through a census method. After determining psychometric indices, in two phases with a 4-week interval (before and after the training), the PREPARED checklist was completed by the professors of the research team in the presence of students in the delivery room while they were performing midwifery care considering their compliance to the checklist. Descriptive statistics paired t-test were used for data analysis. RESULTS: The lowest mean score before the training belonged to alternative methods (1.00) and treatment expenses (1.00). After the training, treatment plan had the highest mean score (3.54 (0.69)). The mean and standard deviation of scores before and after training the students were 9.12 (2.00) and 30.6824 (5.25), respectively. Based on the results of the paired t-test (P = 0.001), the difference was statistically significant. CONCLUSION: Results showed that the implementation of the new model of PREPARED would increase the skill of obtaining informed consent in midwifery students and could be applied for educating students of other medical majors in Iran. PMID- 28904538 TI - The Effect of Group Cognitive Behavioral Therapy on Stress, Anxiety, and Depression of Women with Multiple Sclerosis. AB - BACKGROUND: One of the factors that could influence the quality of life in patients with multiple sclerosis, which is usually overlooked, is its psychological aspects. Considering the increasing acceptance of complementary medicine in the health system, this study was designed and conducted to determine the effect of group cognitive therapy on the stress, anxiety, and depression of women suffering from multiple sclerosis. MATERIALS AND METHODS: This clinical trial was conducted among 70 women suffering from multiple sclerosis who were referred to the health centers of Isfahan. Participants were randomly allocated into two groups of intervention and control, each containing 35 patients. The intervention group received cognitive behavioral therapy as 8 90-minute group sessions (a session per week), and the control group participated in 4 group sessions to express their feelings and experiences. Data were gathered using the Depression Anxiety Stress Scale (DASS-24). RESULTS: There was a significant difference between the mean score of stress (P = 0.03), anxiety (P = 0.02), and depression (P = 0.03) of the intervention and the control group immediately after and 1 month after the intervention. Least squares difference test showed that the mean score of stress (P = 0.02), anxiety (P = 0.02), and depression (P = 0.03) immediately and 1 month after the intervention was significantly lower in the intervention group. CONCLUSIONS: According to the results of the present study, cognitive behavioral therapy could decrease stress, anxiety, and depression in patients suffering from multiple sclerosis. PMID- 28904539 TI - The Relationship of Social Problem-Solving Skills and Dysfunctional Attitudes with Risk of Drug Abuse among Dormitory Students at Isfahan University of Medical Sciences. AB - BACKGROUND: Dormitory students encounter multiple social factors which cause pressure, such as new social relationships, fear of the future, and separation from family, which could cause serious problems such as tendency toward drug abuse. This research was conducted with the goal to determine social problem solving skills, dysfunctional attitudes, and risk of drug abuse among dormitory students of Isfahan University of Medical Sciences, Iran. MATERIALS AND METHODS: This was a descriptive-analytical, correlational, and cross-sectional research. The research sample consisted of 211 students living in dormitories. The participants were selected using randomized quota sampling method. The data collection tools included the Social Problem-Solving Inventory (SPSI), Dysfunctional Attitude Scale (DAS), and Identifying People at Risk of Addiction Questionnaire. RESULTS: The results indicated an inverse relationship between social problem-solving skills and risk of drug abuse (P = 0.0002), a direct relationship between dysfunctional attitude and risk of drug abuse (P = 0.030), and an inverse relationship between social problem-solving skills and dysfunctional attitude among students (P = 0.0004). CONCLUSIONS: Social problem solving skills have a correlation with dysfunctional attitudes. As a result, teaching these skills and the way to create efficient attitudes should be considered in dormitory students. PMID- 28904540 TI - Assessing Emergency Nurses' Clinical Competency: An Exploratory Factor Analysis Study. AB - BACKGROUND: Nursing as a clinical discipline is developing in the emergency wards. Health care systems should continuously assess and prioritize indicators of clinical competency in these wards. The lack of clear standards of clinical competency indicators challenges evaluation. The purpose of this study was to determine clinical competency indicators and its priority based on nurses' views in educational and therapeutic centers in Guilan. MATERIALS AND METHODS: The Q methodology was conducted in three phases, that is, phase I (determining the clinical competency indicators), phase II (classifying clinical competency indicators by an expert panel), and phase III (prioritizing clinical competency indicators). The subjects were selected by convenience sampling among nurses working in the emergency wards of teaching hospitals affiliated to Guilan in 2013. Finally, clinical competency indicators were prioritized using exploratory factor analysis. RESULTS: In the prioritizing phase, data were collected from 710 nurses over two months. Five factors with 30 general competencies were found in three domains: communication, professional maturity, and personality characteristics. Six factors with 37 specific competencies were also found in two domains: scientific and technical capabilities and basic clinical skills that can provide a structured instrument for assessing clinical competence in emergency nurses. CONCLUSIONS: Achieved competencies can be used as a reference for nursing education and practice in emergency. Further research on health care system is needed in order to achieve a reliable and valid instrument. PMID- 28904541 TI - The Effect of Interactive Text Message Follow-up on Health Promoting Lifestyle of Patients with Acute Coronary Syndrome. AB - BACKGROUND: Lifestyle modification is an essential factor in the promotion of health in patients with acute coronary syndrome (ACS). One of the interventions to promote lifestyle is interactive follow-up, which, according to the traditional methods, requires spending significant amount of time and cost. Therefore, this study aimed to determine the effectiveness of interactive text message follow-up on health promoting lifestyle of patients with ACS. MATERIALS AND METHODS: This was a randomized controlled trial among 100 patients suffering from ACS during October-February 2016. The participants were randomly assigned to the experimental and control groups. Collection of data on lifestyle was performed before, 3, and 4 months after the beginning of the intervention using Walker's Health Promoting lifestyle questionnaire. Six messages were sent to the intervention groups each week, and participants asked the questions by sending text message, each week 1 message were sent to the control group for 12 weeks. The statistical analysis of data was performed using independent t-test, Chi square, Mann-Whitney U test, and repeated measures analysis of variance (ANOVA). RESULTS: Before the intervention, there was no significant difference between the mean score of lifestyle of the two groups, however, 3 months and 4 months after the beginning of the intervention, the mean score of lifestyle in the intervention group was significantly higher than that of the control group (P < 0.001). CONCLUSION: The interactive text message follow-up is effective in promoting the lifestyle of patients with ACS and can be considered in the planning of follow-up of patients with ACS. PMID- 28904542 TI - Claims about Medical Malpractices Resulting in Maternal and Perinatal Mortality Referred to Iranian Legal Medicine Organization During 2011-2012. AB - BACKGROUND: Obstetricians, gynecologists, and midwives are the most common specialists of the medical sciences group against whom medical malpractices are claimed, many of which are avoidable and preventable. Therefore, the present study was conducted to investigate the causes of claims regarding medical malpractices resulting in maternal and perinatal mortality. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted and 7616 claims of medical malpractices in the field of obstetrics, gynecology, and midwifery that were referred from all 31 provinces to the central commission of legal medicine were studied during 2011-2012. Therefore, the present research is a national inclusive study covering all the provinces across Iran. To collect information from the transcript of medical malpractices cases, a researcher-made checklist was used, and the collected data were analyzed. RESULTS: The results of the present study showed that among all the medical malpractice claims regarding pregnancy and childbirth (42.24%), the majority concerned perinatal death (71.82%) and maternal death (28.16%). CONCLUSIONS: Medical malpractice complaints are increasing; although, most of these claims are preventable. To achieve this aim, it is necessary for obstetricians, gynecologists, and midwives to try to reduce the complaints by paying more attention to the signs and symptoms of diseases, performing all the diagnostic and therapeutic measures according to the scientific criteria, and fully document patients' records. In addition, patients' acquaintance with the importance of measurements and examinations, before and during pregnancy care and even after childbirth is crucial. PMID- 28904543 TI - The Application of the Transtheoretical Model to Identify Physical Activity Behavior in Women. AB - BACKGROUND: The low level of physical activity is a risk factor behind several chronic diseases. Evidence shows the level of physical activity is decreasing, especially in women. This study aimed to apply the transtheoretical model to identify physical activity behavior in women who referred to health centers of Isfahan. MATERIALS AND METHODS: This cross-sectional study was carried out among 400 women in Isfahan's health centers. Data were collected using a questionnaire including demographic factors, the standard of exercise behavior, stages-of change questionnaire, processes of change, self-efficacy, and decisional balance. Data were analyzed with the Statistical Package for the Social Sciences (SPSS) (version 16). Descriptive statistics, the Mann-Whitney test, one-way analysis of variance (ANOVA), and Pearson correlation were used. RESULTS: The mean (SD) of age was 31.46 (8.92); 81.5% of women were housewives and the others employees. The mean score of physical activity per day for women was 10.66 min. Ninety-six persons (24%) were classified in the pr-contemplation stage, 100 (33.3%) in the contemplation stage, 102 (25.5%) in the preparation stage, 29 (7.2%) in the action stage, and 40 (10%) in the maintenance stage. The results showed the stages of change significantly correlated with the decisional balance (P = 0.04), processes of change, and self-efficacy (P < 0.01). CONCLUSIONS: With regard to the low level of physical activity in women and the role of the stages-of-change model in determining effective factors behind behavior, there should be an attempt to develop continuous and organized educational programs to promote physical activity in women by using the transtheoretical model. PMID- 28904544 TI - Changing Beliefs and Behaviors Related to Sexually Transmitted Diseases in Vulnerable Women: A Qualitative Study. AB - BACKGROUND: The first step in health education is awareness of the people and their acceptance to change their behavior. Therefore, the aim of this study was to investigate the effects of empowerment program towards the concept of self care and prevention of sexually transmitted diseases (STDs) in women at risk of STDs. MATERIALS AND METHODS: The present study was conducted as a qualitative approach (step of action and observation of an action) by using conventional content analysis method. An empowerment program regarding STDs (Action) was performed among 32 (with convenient sample) drug user women with addicted husbands referring to the counseling center for vulnerable women (drop in enter) in Isfahan in 2015. The knowledge of quiddity, transmission, and prevention of STDs, as well as some items of life skills such as self-awareness, interpersonal communication, and assertive behavior were taught in an educational program. Teaching methods were lectures, group, and individual training and role play. The impact of the program on modified belief and behavior change regarding STDs was evaluated with structured interviews. RESULTS: Analysis of the obtained results yielded three categories. The categories were awareness of STD, believing in being at risk, and decision and change. CONCLUSIONS: Promoting self-care and prevention through education programs based on action research can make a significant reduction in the incidence of problems and cause a behavior change in women with the disease or those at risk for STDs. PMID- 28904545 TI - The Effects of Massage and Breastfeeding on Response to Venipuncture Pain among Hospitalized Neonates. AB - BACKGROUND: Untreated procedural pain leads to long-term and short-term complications in neonates. Preventing pain in sick infants and neonates, whose conditions are getting worse, not only is a professional and legal duty but also a prevention measure to decrease future psychological and even neurological complications. Therefore, nurses should prevent newborns' pain. The aim of this study was to compare the effects of massage and breastfeeding on the pain of the neonates. MATERIALS AND METHODS: This was a clinical trial conducted among 75 full-term and near-term infants who underwent venipuncture. The newborns were randomly allocated to the following groups (n = 25 for each): group 1, breastfeeding; group 2, massage; and group 3, control. In the first group, venipuncture was done 2 minutes after breastfeeding. In the second group, massage was done with effleurage technique for 3 minutes and venipuncture was done 2 minutes after massage. The Neonatal Infant Pain Scale (NIPS) was used for pain measurement in the first 30 seconds of venipuncture. Data were analyzed by t-test and one-way analysis of variance (ANOVA). RESULTS: The lowest mean pain score recorded in the massage group (0.92) whereas it was 4.84 in the breastfeeding group and 6.16 in the control group. ANOVA test and post-hoc statistics revealed that both interventions resulted in a significant reduction of the pain scores. CONCLUSIONS: According to the findings of this study, the lowest pain score was in massage group, then in breastfeeding group and control group accordingly. Considering the fact that massage and breastfeeding are natural, useful, and cost free interventions and do not need any special facility, these methods are suggested in pain management and pain control during painful procedures administrated for infants. PMID- 28904546 TI - Evidence-based Draft Guideline for Prevention of Midwifery Malpractices based on Referred Cases to the Forensic Medicine Commission and the Medical Council from 2006-2011. AB - BACKGROUND: Medical errors are the main concerns in health systems, which considering their ascending rate in the recent years, especially in the field of midwifery, have caused a medical crisis. Considering the importance of evidence based health services as a way to improve health systems, the aim of this study was to suggest a guideline for preventing malpractice in midwifery services. MATERIALS AND METHODS: In this cross-sectional study that was conducted in 2013, we investigated 206 cases that were referred to the Isfahan Legal Medicine Organization and Medical Council of Forensic Medicine from 2006-2011. Data were collected by a checklist and were analyzed using SPSS-16 software. Descriptive statistical tests (mean, maximum, minimum, standard deviation, frequency, and percentage agreement) were used to describe the data. Then, we used the Delphi technique with the participation from 17 experts in midwifery, gynecology, and legal medicine to provide an evidence-based draft guideline for prevention of midwifery errors. RESULTS: A total of 206 cases were reviewed. In 66 cases (32%) the verdict for malpractice in midwifery services was approved. A practical draft guideline for preventing clinical errors for midwifery in the fields of pregnancy, delivery, and postpartum period was developed. CONCLUSIONS: This evidence-based draft guideline can improve the attention of all the healthcare providers, especially midwives and physicians to prevent urgent problems and offer effective health services for mothers and infants. PMID- 28904547 TI - The Process of Transition to Hemodialysis: A Grounded Theory Research. AB - BACKGROUND: Transition is a passage or movement from one state, condition, or place to another. Patients with chronic disorders such as end-stage renal disease experience transitions. This study aims to explore the process of transition to hemodialysis. MATERIALS AND METHODS: This is a qualitative grounded theory of a doctoral dissertation. Twenty-four participants (19 patients on hemodialysis, 2 family members, 2 nurses, and a physician) were selected through purposive and theoretical sampling until data saturation. Data collection was conducted through semi-structured interviews, as well as field notes and memos. Data analysis was done concurrently with data collection in three levels of open, axial, and selective coding according to the Strauss and Corbin (1998) method. Core variable was appeared at the end of selecting coding stage. RESULTS: Confronting unexpected situation of hemodialysis, challenge of accepting hemodialysis, comprehensive and pervasive changes, efforts made to self-management, and integration of hemodialysis with everyday life were considered to be the main themes of the process of transition to hemodialysis. CONCLUSIONS: The results would increase evidence-based knowledge regarding the process of transition to hemodialysis. Through identification of this process, effective factors such as determining strategies for management would lead to facilitate more specialized care of people undergoing hemodialysis, appropriate nursing interventions and more effective training programs to prepare patients and their families during the process of transition to hemodialysis. These results can be used for conducting and preparing other qualitative and quantitative studies. PMID- 28904548 TI - Effect of Family-Patient Communication on the Incidence of Delirium in Hospitalized Patients in Cardiovascular Surgery ICU. AB - BACKGROUND: Cardiovascular diseases are the most important causes of morbidity and mortality in the world, and cardiac surgery is one of the treatments that have complication for patients. One of the most important current psychological complications after cardiac surgery is delirium. For its prevention and treatment, considerable attention should be paid to the role of family. This study has been conducted for assessing the effect of the relationship between the family and patient on the incidence of delirium in hospitalized patients in cardiovascular surgery intensive care unit (ICU) of Isfahan Shahid Chamran hospital. MATERIALS AND METHODS: This study is a two-group, single-blind (for the questioner) clinical trial that was conducted among 68 patients in the cardiac surgery ICU of Shahid Chamran hospital affiliated to the Isfahan University of Medical Science in 2013. Sampling was convenient sampling, and the patients were allocated to two groups (n = 34 patients) based on random numbers table. The day after the surgery, one of the family members in the intervention group who had received education the day before was allowed to visit the patient in the morning shift. In the control group, patients received routine care. Two groups were assessed for delirium twice a day for a total of three times (two times in the morning and one time in the evening) with use of Richmond Agitation Sedation Scale and Confusion Assessment Method -ICU (CAM - ICU) scale. RESULTS: In the intervention group, 41.18% patients were females and 58.82% patients were males, and in the control group, 29.42% patients were females and 70.58% were males. Mean and SD of patients' age in the intervention group was 55.11 (12.11) and in the control group 54.12 (13.11) years. Based on study results, incidence of delirium in the morning after surgery (second day) in intervention group was 11.76%, and in control group it was 23.53%. In the third day, it was 8.83% in intervention group and 20.58% in control group. Chi-square test showed a significant difference in incidence of delirium during the second (P = 0.04) and the third (P = 0.03) days of surgery in the two groups. In the control group, the incidence of delirium in the evening was 32.35%, which was more than that in the morning. Cochran test showed a significant difference in the morning and afternoon shifts in the control group (P = 0.004). CONCLUSIONS: Effective communication between the patient and family, as a nonmedical method, can reduce delirium after cardiac surgery, especially, at the end of the day; nurses should pay more attention to the prevention of delirium. PMID- 28904549 TI - Risk Factors Of Heart Disease in Nurses. AB - BACKGROUND: Identifying and correcting the modifiable risk factors reduces the prevalence of coronary artery disorders (CAD). Nurses, with regards to their employment conditions, can be prone to cardiovascular disease (CVD). This study aimed to determine the prevalence of cardiovascular risk factors among nurses. MATERIALS AND METHODS: In this cross-sectional study, census sampling was conducted among nurses of Jahrom, Iran, in 2014. Data were collected through interviews, blood pressure measurement, anthropometric parameters, and blood sample collection. To analyze the data, descriptive statistical analysis, and comparative (independent t-test) and correlation (Pearson) tests were used; the significance level was considered to be P < 0.05. RESULTS: In this study, 263 (89.76%) nurses participated, 79.8% of whom were women. The mean age of the participants was 31.04 (6.97). In terms of body mass index, 41.7% was the waist to-hip ratio, 16.7% was the waist-to-height ratio, and 63.1% were in the range of obesity. In addition, 5.7% had abnormal triglyceride, 4.9% had high cholesterol, and 15.1% had high blood pressure. The mean percentage of the Framingham risk score of the participants was 1.07 (1.84). CONCLUSIONS: In this study, the total mean percentage of the Framingham risk score of the nurses was 1.07, which showed a low risk of CAD in the study population over the next decade. PMID- 28904550 TI - Maoto, a Traditional Japanese Herbal Medicine, Inhibits Uncoating of Influenza Virus. AB - We previously reported in randomized controlled trials that maoto, a traditional herbal medicine, showed clinical and virological efficacy for seasonal influenza. In this study, a culturing system for influenza was used to test the effect of maoto. A549 cells in the culture were infected with influenza virus A (PR8) and followed after treatment with maoto; the virus titers in the culture supernatant, intracellular viral proteins, and viral RNA were determined. When infected cells were cultured with maoto for 24 hr, the virus titer and protein were significantly reduced compared with medium only. Other subtypes, A/H3N2, H1N1pdm, and B, were also inhibited by maoto. Proliferation of viral RNA in a 6 hr culture was inhibited by maoto in the early phase, especially in the first 30 min. Focusing on the entry step of the influenza virus, we found that endosomal pH, regulated by vacuolar-type H+ ATPase (V-ATPase) located in the membrane, was increased when treated with maoto. We also found that uncoating of influenza viruses was also inhibited by maoto, resulting in the increase of the number of virus particles in endosomes. These results strongly suggest that the inhibition of endosomal acidification by maoto results in blocking influenza virus entry to cytoplasm, probably through the inhibition of V-ATPase. The present study provides evidence that supports the clinical use of maoto for the treatment of influenza. PMID- 28904551 TI - Suppressive Effect of the n-Hexane Extract of Litsea japonica Fruit Flesh on Monosodium-Iodoacetate-Induced Osteoarthritis in Rats. AB - We examined the antiosteoarthritic effect of the n-hexane extract of Litsea japonica fruit flesh (LJF-HE) in a rat model of monosodium-iodoacetate- (MIA-) induced osteoarthritis. LJF-HE significantly reduced the difference in weight bearing capabilities of the hind paws between healthy and MIA-treated rats. Histological examination of the knee joints indicated that LJF-HE suppressed cartilage and bone destruction. Additionally, there were decreases in the expression of matrix metalloproteinase-2 and metalloproteinase-9 and cyclooxygenase-2 in the joints. The serum levels of deoxypyridinoline (DPD) and osteocalcin, which are markers of bone metabolism, also decreased. Furthermore, LJF-HE significantly suppressed infiltration of inflammatory cells into the synovium and inhibited the expression of proinflammatory cytokines such as tumor necrosis factor- (TNF-) alpha, interleukin- (IL-) 1, and IL-6 in the joints and serum. The serum levels of leukotriene B4 and lipoxygenase were also significantly lowered by LJF-HE. Finally, LJF-HE inhibited the production of nitric oxide, prostaglandin E2, IL-6, and TNF-alpha in lipopolysaccharide activated macrophages, which might be associated with inhibited phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. Our data suggest that LJF-HE has an anti-inflammatory effect and may have potential as an antiosteoarthritic agent. PMID- 28904552 TI - Antioxidant and Anti-Inflammatory Properties of Anacardium occidentale Leaf Extract. AB - In tropical America, principally in Northeastern Brazil, the leaf extract of Anacardium occidentale is traditionally used for treatment of different diseases. However, chemical and biological properties and activities of Anacardium occidentale are poorly investigated and known. Here, we evaluated the antioxidant and anti-inflammatory activities "in vitro" of leaf extract from Anacardium occidentale. Our results show that leaf extract exhibits antioxidant activity when used to treat RAW 264.7 macrophage cells. Antioxidant effects were observed by decrease in oxidative damage in macrophage cells treated with 0.5 ug/mL and 5 ug/mL of leaf extract. Moreover, leaf extract reversed oxidative damage and inflammatory parameters induced in LPS-stimulated RAW 264.7 macrophage cells. Leaf extract at 0.5 ug/mL and 5 ug/mL was able to inhibit release of TNF-alpha and IL-1beta in LPS-stimulated cells. Taken together, our results indicate antioxidant and anti-inflammatory effects of leaf extract from Anacardium occidentale and reveal the positive effects that intake of these products can mediate in biological system. PMID- 28904553 TI - Manual Acupuncture Suppresses the Expression of Proinflammatory Proteins Associated with the NLRP3 Inflammasome in the Hippocampus of SAMP8 Mice. AB - OBJECTIVE: To investigate the effect of manual acupuncture (MA) on NLRP3 inflammasome-related proteins. METHODS: SAMP8 mice were randomly divided into Alzheimer's disease (AD) group, the MA group, and the medicine (M) group. Mice in the M group were treated with donepezil hydrochloride at 0.65 MUg/g. In the MA group, MA was applied on Baihui (GV20) and Yintang (GV29) for 20 min and then pricked at Shuigou (GV26). The Morris water maze was applied to assess spatial learning and memory. Immunohistochemical staining and western blot analysis were used to observe the expression of NLRP3 inflammasome-related proteins. RESULTS: Compared with the normal (N) control group, spatial learning and the memory capabilities of the AD group significantly decreased (p < 0.01). The number of NLRP3, ASC, Caspase-1, and IL-1beta positively stained cells in the AD group was higher than the N group, and the relative expression levels of the above proteins were significantly higher than those in the N group (p < 0.01). These changes were reversed by both MA and donepezil (p < 0.01). CONCLUSION: MA can improve the learning and memory capabilities of SAMP8 mice. The negative regulation of the NLRP3/Caspase-1 pathway in the hippocampus may be a possible mechanism of MA in the treatment of AD. PMID- 28904555 TI - Acyclic Sesquiterpenes from the Fruit Pericarp of Sapindus saponaria Induce Ultrastructural Alterations and Cell Death in Leishmania amazonensis. AB - Previous studies reported antiprotozoal activities of Sapindus saponaria L. The aim of this work was the evaluation of antileishmanial activity and mechanism of action of extract and fractions of S. saponaria L. Hydroethanolic extract (EHA) obtained from fruit pericarps was fractionated using solid-phase extraction in a reversed phase, resulting in fractions enriched with saponins (SAP fraction) and acyclic sesquiterpene oligoglycosides (OGSA fraction). The activities of EHA, SAP, and OGSA were evaluated by antiproliferative assays with promastigote and intracellular amastigote forms. Cytotoxicity on macrophages and hemolytic activity were also analyzed. Morphological and ultrastructural changes in Leishmania amazonensis promastigotes were evaluated by electron microscopy. Flow cytometry was used to investigate mitochondrial dysfunction and phosphatidylserine exposure. OGSA was more selective for parasites than mammalian J774A1 macrophage cells, with selectivity indices of 3.79 and 7.35, respectively. Our results showed that only the OGSA fraction did not present hemolytic activity at its IC50 for promastigote growth. Electron microscopy revealed changes in parasite flagellum, cell body shape, and organelle size, mainly mitochondria. Flow cytometry analysis indicated mitochondrial membrane and cell membrane dysfunction. OGSA showed antileishmanial activity, resulting in several changes to protozoa cells, including mitochondrial depolarization and early phosphatidylserine exposure, suggesting a possible apoptotic induction. PMID- 28904557 TI - Ginger Ingredients Alleviate Diabetic Prostatic Complications: Effect on Oxidative Stress and Fibrosis. AB - Prostatic complications are common in patients with diabetes. This study investigated the effect of different ginger ingredients: zingerone, geraniol, and 6-gingerol on the prostate in diabetic rats. Diabetes was induced in Wistar rats by streptozotocin intraperitoneal injection (50 mg/kg), and the rats were left for 10 weeks to develop prostatic complications. In diabetic treated groups, rats received daily oral zingerone, geraniol, and 6-gingerol in doses of 20, 200, and 75 mg/kg, respectively, in the last 8 weeks. Treatment with the compounds caused changes in the ventral prostate of diabetic animals as indicated by the columnar ductal epithelium and dense secretions. There was an amelioration of oxidative stress as evidenced by the lowering of prostate malondialdehyde and elevating prostate oxidized to reduced glutathione (GSH/GSSG) ratios by geraniol and 6 gingerol. None of the three ginger ingredients affected the hyperglycemia, reduction in body weight gain, and testosterone deficiency seen in diabetic animals. Interleukin-1beta and interleukin-6 levels remained unchanged. However, zingerone and geraniol ameliorated the fibrosis in diabetic prostate through suppressing the elevated prostate transforming growth factor beta 1 (TGFbeta1) and collagen IV. Therefore, ginger ingredients could be beneficial in alleviating diabetic prostatic complications through suppressing oxidative stress and tissue fibrosis. PMID- 28904558 TI - Herbal Medicines: Personal Use, Knowledge, Attitude, Dispensing Practice, and the Barriers among Community Pharmacists in Gondar, Northwest Ethiopia. AB - BACKGROUND: Herbal medicine use is increasing and the global market is estimated to be US$107 billion by the year 2017. OBJECTIVES: This study aimed at assessing community pharmacists' personal use, knowledge, attitude, dispensing practice, and the barriers regarding herbal medicines. METHODS: Institution based cross sectional study was conducted among 47 community pharmacists in Gondar, Northwest Ethiopia, using a structured interviewing questionnaire. RESULTS: Nearly half of the respondents (n = 22, 46.8%) sometimes use herbal medicines. Although knowledge related to such preparations was self-rated as poor/acceptable (n = 34, 72.4%), majority (n = 44, 93.7%) of community pharmacists agree/strongly agree that herbal medicines have beneficial effects. Only 6 (12.7%) of them are sometimes/often engaged in dispensing herbal medicines and most of them (n = 34, 72.3%) rarely/never counseled clients regarding these preparations. Limited knowledge on and access to information regarding herbal medicines are the main barriers to the pharmacists' practice. CONCLUSION: Although community pharmacists in Gondar, Northwest Ethiopia, commonly use and demonstrated good attitude towards herbal medicines, they are less involved in dispensing such products. They are also challenged with limited knowledge on and access to herbal medicine information. Thus, pharmacy educators, professional organizations, and the government shall pay more attention to solve the problem. Regulatory provisions on herbal medicine dispensing must be enacted and communicated very well. PMID- 28904554 TI - Plants-Derived Neuroprotective Agents: Cutting the Cycle of Cell Death through Multiple Mechanisms. AB - Neuroprotection is the preservation of the structure and function of neurons from insults arising from cellular injuries induced by a variety of agents or neurodegenerative diseases (NDs). The various NDs including Alzheimer's, Parkinson's, and Huntington's diseases as well as amyotropic lateral sclerosis affect millions of people around the world with the main risk factor being advancing age. Each of these diseases affects specific neurons and/or regions in the brain and involves characteristic pathological and molecular features. Hence, several in vitro and in vivo study models specific to each disease have been employed to study NDs with the aim of understanding their underlying mechanisms and identifying new therapeutic strategies. Of the most prevalent drug development efforts employed in the past few decades, mechanisms implicated in the accumulation of protein-based deposits, oxidative stress, neuroinflammation, and certain neurotransmitter deficits such as acetylcholine and dopamine have been scrutinized in great detail. In this review, we presented classical examples of plant-derived neuroprotective agents by highlighting their structural class and specific mechanisms of action. Many of these natural products that have shown therapeutic efficacies appear to be working through the above-mentioned key multiple mechanisms of action. PMID- 28904556 TI - Medicinal Plants for the Treatment of Local Tissue Damage Induced by Snake Venoms: An Overview from Traditional Use to Pharmacological Evidence. AB - Snakebites are a serious problem in public health due to their high morbimortality. Most of snake venoms produce intense local tissue damage, which could lead to temporary or permanent disability in victims. The available specific treatment is the antivenom serum therapy, whose effectiveness is reduced against these effects. Thus, the search for complementary alternatives for snakebite treatment is relevant. There are several reports of the popular use of medicinal plants against snakebites worldwide. In recent years, many studies have been published giving pharmacological evidence of benefits of several vegetal species against local effects induced by a broad range of snake venoms, including inhibitory potential against hyaluronidase, phospholipase, proteolytic, hemorrhagic, myotoxic, and edematogenic activities. In this context, this review aimed to provide an updated overview of medicinal plants used popularly as antiophidic agents and discuss the main species with pharmacological studies supporting the uses, with emphasis on plants inhibiting local effects of snake envenomation. The present review provides an updated scenario and insights into future research aiming at validation of medicinal plants as antiophidic agents and strengthens the potentiality of ethnopharmacology as a tool for design of potent inhibitors and/or development of herbal medicines against venom toxins, especially local tissue damage. PMID- 28904559 TI - Cartilage Protection and Analgesic Activity of a Botanical Composition Comprised of Morus alba, Scutellaria baicalensis, and Acacia catechu. AB - Although there have been augmented advances in drug discovery, current OA management is inadequate due to the lack of successful therapies proven to be effective in modifying disease progression. For some, the risk outweighs the benefit. As a result, there is a desperate need for safe and efficacious natural alternatives. Here we evaluated a composition from Morus alba, Scutellaria baicalensis, and Acacia catechu in maintaining joint structural integrity and alleviating OA associated symptoms in monoiodoacetate- (MIA-) induced rat OA disease model. Study lasted for 6 weeks. 59.6%, 64.6%, 70.7%, 69.9%, and 70.3% reductions in pain sensitivity were observed for rats treated with the composition from week 1 to week 5, respectively. Statistically significant improvements in articular cartilage matrix integrity (maintained at 57.1% versus MIA + vehicle treated rats) were shown from the modified total Mankin score for animals treated with the composition. The composition showed a statistically significant reduction in uCTX-II level (54.1% reductions). The merit of combining these botanicals was also demonstrated in their synergistic analgesic activity. Therefore, the standardized blend of Morus alba, Scutellaria baicalensis, and Acacia catechu could potentially be considered as an alternative remedy from natural sources for the management of OA and/or its associated symptoms. PMID- 28904560 TI - Antidiabetic Effect of Tibetan Medicine Tang-Kang-Fu-San on High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats. AB - The aim of this study was to investigate the antidiabetic effects of a Tibetan medicine, Tang-Kang-Fu-San (TKFS), on experimental type 2 diabetes mellitus (T2DM) rats and to explore its underlying mechanisms. Firstly two major chemical compositions of TKFS, gallic acid and curcumin, were characterized by HPLC fingerprint analysis. Next T2DM in rats was induced by high-fat diet and a low dose streptozotocin (STZ 35 mg/kg). Then oral gavage administration of three different doses of TKFS (0.3 g/kg, 0.6 g/kg, and 1.2 g/kg) was given to T2DM rats. Experimental results showed that TKFS dramatically reduced the levels of fasting blood glucose, fasting blood insulin, triglyceride, total cholesterol, LDL cholesterol, and HDL cholesterol, even though it did not alter the animal body weight. The downregulation of phosphorylation-AKT (p-AKT) and glucose transporter-4 (GLUT4) in skeletal muscle of T2DM rats was restored and abnormal pathological changes in pancreas tissues were also improved. Our work showed that TKFS could alleviate diabetic syndromes, maintain the glucose homeostasis, and protect against insulin resistance in T2DM rats, and the improvement of AKT phosphorylation and GLUT4 translocation in skeletal muscle would be one of its possible underlying mechanisms. PMID- 28904561 TI - Understanding Mind-Body Interaction from the Perspective of East Asian Medicine. AB - OBJECTIVE: Attempts to understand the emotion have evolved from the perspective of an independent cognitive system of the mind to that of an interactive response involving the body. This study aimed to quantify and visualize relationships between different emotions and bodily organ systems from the perspective of East Asian medicine. METHODS: Term frequency-inverse document frequency (tf-idf) method was used to quantify the significance of Five Viscera and the gallbladder relative to seven different emotions through the classical medical text of DongUiBoGam. Bodily organs that corresponded to different emotions were visualized using a body template. RESULTS: The emotions had superior tf-idf values with the following bodily organs: anger with the liver, happiness with the heart, thoughtfulness with the heart and spleen, sadness with the heart and lungs, fear with the kidneys and the heart, surprise with the heart and the gallbladder, and anxiety with the heart and the lungs. Specific patterns between the emotions and corresponding bodily organ systems were identified. CONCLUSION: The present findings will further the current understanding of the relationship between the mind and body from the perspective of East Asian medicine. Western medicine characterizes emotional disorders using "neural" language while East Asian medicine uses "somatic" language. PMID- 28904562 TI - Proceedings from the CIHLMU 5th Infectious Diseases Symposium 2016 "Drug Resistant Tuberculosis: Old Disease - New Challenge". AB - The 5th CIHLMU Infectious Disease Symposium, Munich, Germany, March 12, 2016 brought together Tuberculosis Experts from developed and low middle-income countries to discuss the control of drug resistance Tuberculosis. The meeting featured 9 presentations: Tuberculosis history and current scenario, Tuberculosis and migration - current scenario in Germany, Mechanism of Tuberculosis resistance development, Epidemiology of resistance - transmission vs. new generation of resistance, The impact of diagnostic in patients beyond - sensitivity and specificity, The Bangladesh regimen - new hope trough old drugs, New drugs and regimens - an overview on studies and Multi and Extensively Drug Resistant Tuberculosis from Europe. The presentations were followed by a panel discussion. Serious Multidrug Resistance epidemic in some countries may jeopardize the progress in Tuberculosis control. In this meeting epidemiology, mechanism, immigration and screening, diagnosis, research and treatment of drug resistant tuberculosis were discussed. PMID- 28904563 TI - Bacillus coagulans MA-13: a promising thermophilic and cellulolytic strain for the production of lactic acid from lignocellulosic hydrolysate. AB - BACKGROUND: The transition from a petroleum-based economy towards more sustainable bioprocesses for the production of fuels and chemicals (circular economy) is necessary to alleviate the impact of anthropic activities on the global ecosystem. Lignocellulosic biomass-derived sugars are suitable alternative feedstocks that can be fermented or biochemically converted to value-added products. An example is lactic acid, which is an essential chemical for the production of polylactic acid, a biodegradable bioplastic. However, lactic acid is still mainly produced by Lactobacillus species via fermentation of starch containing materials, the use of which competes with the supply of food and feed. RESULTS: A thermophilic and cellulolytic lactic acid producer was isolated from bean processing waste and was identified as a new strain of Bacillus coagulans, named MA-13. This bacterium fermented lignocellulose-derived sugars to lactic acid at 55 degrees C and pH 5.5. Moreover, it was found to be a robust strain able to tolerate high concentrations of hydrolysate obtained from wheat straw pre treated by acid-catalysed (pre-)hydrolysis and steam explosion, especially when cultivated in controlled bioreactor conditions. Indeed, unlike what was observed in microscale cultivations (complete growth inhibition at hydrolysate concentrations above 50%), B. coagulans MA-13 was able to grow and ferment in 95% hydrolysate-containing bioreactor fermentations. This bacterium was also found to secrete soluble thermophilic cellulases, which could be produced at low temperature (37 degrees C), still retaining an optimal operational activity at 50 degrees C. CONCLUSIONS: The above-mentioned features make B. coagulans MA-13 an appealing starting point for future development of a consolidated bioprocess for production of lactic acid from lignocellulosic biomass, after further strain development by genetic and evolutionary engineering. Its optimal temperature and pH of growth match with the operational conditions of fungal enzymes hitherto employed for the depolymerisation of lignocellulosic biomasses to fermentable sugars. Moreover, the robustness of B. coagulans MA-13 is a desirable trait, given the presence of microbial growth inhibitors in the pre-treated biomass hydrolysate. PMID- 28904564 TI - The role of pre-reduction MRI in the management of complex cervical spine fracture-dislocations: an ongoing controversy? AB - BACKGROUND: Cervical spine fracture-dislocations in neurologically intact patients represent a surgical challenge due to the risk of inflicting iatrogenic spinal cord compression by closed reduction maneuvers. The use of MRI for early advanced imaging in these injuries remains controversially debated. CASE PRESENTATION: A 54-year old man sustained a fall over the handlebars of his racing bicycle. The helmeted patient sustained a fall on his head which resulted in a hyperflexion injury of the neck. He was neurologically intact on presentation. Initial CT imaging revealed a complex multisegmental cervical spine injury with a left-sided C6/C7 perched facet, a right sided C7/T1 fracture dislocation, and a right-sided C6 and C7 traumatic laminotomy. The initial management consisted of temporary external Halo fixator application without closed reduction maneuver, to mitigate the risk of a delayed spinal cord injury. Subsequent advanced imaging by MRI revealed an acute traumatic C7/T1 disc herniation, with the intervertebral disc completely extruded into the spinal canal. Definitive surgical management was then accomplished by employing a three stage anterior-posterior-anterior spinal decompression, realignment, fixation and fusion C4-T2 in one operative session. The patient recovered well and retained full neurological function. He resumed bicycle street racing within 10 months of the injury following successful spinal reconstruction. CONCLUSIONS: The diagnostic evaluation of cervical fracture-dislocations should include advanced imaging by MRI in order to fully understand the injury pattern prior to proceeding with spinal reduction maneuvers which may impose the imminent threat of a devastating iatrogenic injury to the spinal cord. The presented staged management by initial Halo fixation without attempts for spinal reduction, followed by a surgical decompression and multilevel fusion, appears to represent a feasible and safe strategy for patients at risk of a delayed neurological injury. PMID- 28904565 TI - Class 1 integrons and plasmid-mediated multiple resistance genes of the Campylobacter species from pediatric patient of a university hospital in Taiwan. AB - BACKGROUND: The Campylobacter species usually causes infection between humans and livestock interaction via livestock breeding. The studies of the Campylobacter species thus far in all clinical isolates were to show the many kinds of antibiotic phenomenon that were produced. Their integrons cause the induction of antibiotic resistance between bacterial species in the Campylobacter species. RESULTS: The bacterial strains from the diarrhea of pediatric patient which isolated by China Medical University Hospital storage bank. These isolates were identified by MALDI-TOF mass spectrometry. The anti-microbial susceptibility test showed that Campylobacter species resistant to cefepime, streptomycin, tobramycin and trimethoprim/sulfamethoxazole (all C. jejuni and C. coli isolates), ampicillin (89% of C. jejuni; 75% of C. coli), cefotaxime (78% of C. jejuni; 100% of C. coli), nalidixic acid (78% of C. jejuni; 100% of C. coli), tetracycline (89% of C. jejuni; 25% C. coli), ciprofloxacin (67% of C. jejuni; 50% C. coli), kanamycin (33% of C. jejuni; 75% C. coli) and the C. fetus isolate resisted to ampicillin, cefotaxime, nalidixic acid, tetracycline, ciprofloxacin, kanamycin by disc-diffusion method. The effect for ciprofloxacin and tetracycline of the Campylobacter species was tested using an E-test. The tet, erm, and integron genes were detected by PCR assay. According to the sequencing analysis (type I: dfr12-gcuF-aadA2 genes and type II: dfrA7 gene), the cassette type was identified. The most common gene cassette type (type I: 9 C. jejuni and 2 C. coli isolates; type II: 1 C. coli isolates) was found in 12 class I integrase-positive isolates. CONCLUSIONS: Our results suggested an important information in the latency of Campylobacter species with resistance genes, and irrational antimicrobial use should be concerned. PMID- 28904566 TI - Is Vitamin D Deficiency Implicated in Autonomic Dysfunction? AB - Dysautonomia, dysfunction of the autonomic nervous system, presents with heterogeneous clinical features from an imbalanced regulation of the sympathetic and parasympathetic nervous systems. Low Vitamin D levels can explain the heterogeneous clinical features of migraine headaches, cardiac and gastrointestinal dysfunction, and oxidative stress evident in dysautonomia patients. The role of Vitamin D in modulating pain sensitivity has been recently established. However, there is a lack of research and understanding regarding the association between Vitamin D deficiency and autonomic dysfunction. Vitamin D is a neuroactive hormone that modulates autonomic balance, regulating the sympathetic and parasympathetic nervous systems, and has multisystem benefits. The following review explores the literature and addresses the relationship between Vitamin D deficiency and autonomic dysfunction. Overall, this literature review implicates Vitamin D deficiency in autonomic dysfunction and elucidates the potential therapeutic role of Vitamin D in autonomic disorders. PubMed search was performed for English articles from 1996 to 2016. Following keywords: Vitamin D, autonomic dysfunction and orthostatic hypotension, Vitamin D receptor, migraine and traumatic brain injury, Vitamin D, cardiac and gastrointestinal disease, Vitamin D, glutathione, oxidative stress, and serotonin were included. Only articles reporting primary data relevant to the above question were included in the study. PMID- 28904567 TI - Intermittent Divergent Squint in Prematurity and Its Neurophysiological Aspects. AB - Intermittent distance exotropia is a deviation characterized by an exophoria at near fixation and manifest exotropia at distance fixation. There is normal binocular fusional vergence and stereoacuity at near fixation, but the eyes tend to diverge in bright sunlight, tiredness, day dreaming and the patient may close one eye in such circumstances. Prematurity is associated with numerous eye pathology, besides retinopathy of prematurity, amblyopia, refractive errors, it is also associated with a higher risk esotropia and exotropia. We report a case of a 5-year-old girl (preterm and very low birth weight) with an intermittent deviation of both eyes since three years. On her detailed ocular examination diagnosis of divergence excess intermittent exotropia with normal accommodative convergence to accommodation ratio was made. Bilateral lateral rectus recession was done using hang back technique. Postoperatively, the eyes were aligned normally thereby achieving orthotropia. This article reviews various neurophysiological aspects of intermittent divergent squint delineating the etiopathogenesis, classification system, and management options in intermittent exotropia. PMID- 28904568 TI - Pediatric Autoimmune Encephalitis. AB - Autoimmune (antibody mediated) encephalitis (AE) is emerging as a more common cause of pediatric encephalopathy than previously thought. The autoimmune process may be triggered by an infection, vaccine, or occult neoplasm. In the latter case, onconeural autoantibodies are directed against intracellular neuronal antigens, but a recent heterogeneous group of encephalitic syndromes has been found not to have underlying tumor but is associated with autoantibodies to the neuronal surface or synaptic antigens. Neuropsychiatric symptoms are very common in autoimmune encephalopathy; as a result, affected children may be initially present to psychiatrists. Neurological features are movement disorders, seizures, altered conscious level, and cognitive regression. Hypoventilation and autonomic features may be an aspect. Inflammatory findings in the cerebrospinal fluid may be present but are relatively nonspecific. Magnetic resonance imaging (MRI) may also demonstrate abnormalities that provide clues for diagnosis, particularly on fluid-attenuated inversion recovery or T2-weighted images. AE is well responsive to immune therapy, with prompt diagnosis and treatment strongly beneficial. Patients with paraneoplastic encephalitis are more refractory to treatment compared to those in whom no malignancy is identified. Herein, the authors present an update of literature data on the clinical presentation, laboratory and imaging findings, therapy, and outcomes for the most common autoimmune encephalitides. PMID- 28904569 TI - Serum Insulin and Leptin Levels in Children with Epilepsy on Valproate-associated Obesity. AB - BACKGROUND: Weight gain is a common adverse effect of sodium valproic acid (VPA) in children with epilepsy. Several mechanisms of VPA-induced obesity have been suggested such as increased appetite, facultative thermogenesis, and elevated insulin and leptin levels. In this study, we aimed to investigate the role of Insulin and Leptin in the pathogenesis of weight gain caused by VPA. MATERIALS AND METHODS: Body mass index (BMI) was calculated, and serum insulin and leptin levels were measured in 45 consecutive patients and 45 controls. RESULTS: The mean BMI of the cases and control group was 22.97 kg/m2 and 19.4 kg/m2, respectively, and it was significantly higher in cases (P < 0.001). Fasting serum insulin levels were higher in VPA group (26.3 MUU/ml) than in controls (15.83 MUU/ml), which was statistically significant (P < 0.001). Serum leptin levels were also found to be elevated significantly in VPA group (7.9 ng/ml) than in controls (1.6 ng/ml). CONCLUSION: Sodium VPA is associated with significant rise of BMI, hyperinsulinemia, raised insulin resistance, and increased leptin levels in children with epilepsy. PMID- 28904570 TI - Bone Mineral Status in Children with Epilepsy: Biochemical and Radiologic Markers. AB - OBJECTIVE: The aim of this study is to assess bone mineral status in children with epilepsy, on different antiepileptic drugs (AEDs) regimen, using dual-energy X-ray absorptiometry (DXA) and routine biochemical bone markers. PATIENTS AND METHODS: This is observational prospective controlled cohort study, conducted at Mansoura University Children Hospital, from January 2014 to June 2015. In this study, we had 152 participants with ages 3-13 years, 70 children diagnosed with epilepsy and 82 were controls. Children classified into two groups according to the duration of treatment, Group 1 children maintained on AEDs for 6-24 months, Group 2 children >=24 months. Bone mineral density (BMD) measured by DXA and biochemical markers includes serum calcium, phosphorus, alkaline phosphatase (ALP), and parathyroid hormone (PTH). RESULTS: In this study, we found that the serum level of calcium and phosphate were significantly low (P > 0.05) in total cases versus control. We found that the serum level of and ALP and PTH were significantly high (P > 0.05) in total cases versus control. Regarding the DXA markers, there was a significant decrease of BMD and Z-score for the total body and lumbar area in the total cases versus control (P > 0.05). CONCLUSION: The present study showed that all AEDs (new and old) affect bone mineral status in children receiving therapy for more than 6 months, altering both biochemical markers (serum calcium, phosphorus, ALP, and PTH) and radiologic markers (BMD assessed using DXA). Children on AEDs for a longer duration (>=2 years) showed more severe side effects on BMD. Children receiving multiple AEDs are more prone to altered bone mineral status, especially with long duration of therapy. The study also highlights the role of DXA as a safe noninvasive method to assess BMD in children on long-term AEDs. PMID- 28904571 TI - Transcranial Magnetic Stimulation as an Additional Diagnostic Tool in Children with Acute Inflammatory Demyelinating Polyneuropathy. AB - CONTEXT: The diagnosis of polyneuropathy may be challenging at the early stages of the disease. Despite electromyography (EMG) efficacy in the establishment of polyneuropathy diagnosis, in some cases, results are dubious and neurophysiologists may implement additional techniques to ensure that conduction is affected. AIMS: The aim of the study was to evaluate motor-evoked potential (MEP) characteristics in children with acute inflammatory demyelinating polyneuropathy (AIDP). SETTINGS AND DESIGN: The study was conducted at a pediatric research and clinical center for infectious diseases. SUBJECTS AND METHODS: Twenty healthy children (7-14 years old) without signs of neurological disorders were enrolled as controls. Thirty-seven patients (8-13 years old) with AIDP were enrolled as the main group. EMG and transcranial magnetic stimulation (TMS) were performed on the 3rd-7th days from the onset of the first symptoms. STATISTICAL ANALYSIS USED: Descriptive statistics and Student's t-test were used. Bonferroni method was applied to implement appropriate corrections for multiple comparisons. RESULTS: Significant differences between children with AIDP and controls on latencies of both cortical and lumbar MEPs were registered. Cortical MEP shapes were disperse in 100% of the cases and lumbar MEPs were disperse in 57% of the cases. CONCLUSIONS: Diagnostic TMS on the early stage of the AIDP in children may be implemented as the additional tool. The main finding in this population is lengthening of the latency of cortical and lumbar MEPs. Disperse shape of the lumbar MEPs may be used as the early sign of the acute demyelization. PMID- 28904572 TI - Outcome Predictors in Pediatric Head Trauma: A Study of Clinicoradiological Factors. AB - INTRODUCTION: Traumatic injuries are the leading cause of death and a major cause of disability among children. About 70%-80% of the accidental deaths in pediatric age group result directly from central nervous system lesions. METHODS: The purpose of our study was to study all the patients of <=18 years of age with head or spinal injury admitted in neurointensive care unit at our center, an apex trauma center in a developing country, between June 2009 and September 2011. We retrospectively analyzed various factors including type of injury, mode of injury, admission Glasgow coma score (in case of head injury), and mortality rate. OBSERVATIONS: The study population consisted of 264 injured children. Mean age was 8.3 +/- 5.6 years (range 5 months to 18 years). Forty percent of patients were within 1-5-year age group. Head injury accounted for 89% of cases and 11% of cases were spinal injury patients. Low-velocity trauma was the most common mode of injury, accounting for 74% of the cases. The percentage of patients with mild, moderate, and severe head injury were 38%, 15%, and 47%, respectively, in the head injury group. Mortality in head injury patients was 18% and in spinal injury patients was 9%. Operative intervention was done in 56% of patients. Predictors of mortality included severe head injury, hospital stay <7 days, pneumothorax, the presence of hypotension, and deranged coagulation parameters. CONCLUSIONS: Head injury is much more common than spinal injury in pediatric patients and fall from height being the most common mode of injury. Severe head injury, hospital stay <7 days, pneumothorax, presence of hypotension, and deranged coagulation parameters are predictors of poor outcome. PMID- 28904573 TI - Lissencephaly-pachygyria Masquerading as Leukodystrophy on Magnetic Resonance Imaging Brain. PMID- 28904574 TI - Multicentric Chordoma in a Child. AB - Chordomas are primary malignant bone tumors that arise in the axial skeleton, believed to originate from remnants of embryologic notochordal cell rests. Multicentric origin of chordoma is extremely rare. To our literature search, we found only three cases of multicentric chordoma in adults. We report a first case of multicentric chordoma in pediatric age group. A 14-month-old child presented with torticolis and left upper limb monoparesis, imaging showed expansile bony destructive lesion in clivus and dorsal spine simultaneously. The child underwent laminectomy, decompression of cord, excision of lesion, and histopathology was suggestive of chordoma. Pediatric chordomas are aggressive tumors, require multidisciplinary management with maximal safe resection followed by radiotherapy (conventional and/or proton). Even with multidisciplinary management, pediatric chordomas have high morbidity and mortality. PMID- 28904575 TI - Facial Palsy in Cerebral Venous Thrombosis: An Atypical Case in a Young Girl. AB - Cerebral venous thrombosis (CVT) is a rare and potentially life-threating cause of stroke. A number of etiologies and risk factors for CVT have been identified so far. These include head trauma, local and systemic infectious diseases, malignancies, autoimmune diseases, and oral contraceptive use. The most common clinical symptoms are headache and changes in consciousness. Cranial nerve palsy in CVT is uncommon, and there are very few reports of facial nerve palsy. This case report highlights an atypical manifestation in a CVT patient, who presented with peripheral facial palsy. The patient was successfully treated with anticoagulation. PMID- 28904576 TI - A Rare Complication of Subdural-peritoneal Shunt: Migration of Catheter Components through the Pelvic Inlet into the Subdural Space. AB - Subdural-peritoneal (SP) shunting is a simple procedure to treat subdural hygromas; however, several rare complications such as shunt migration exist. A 15 year-old boy presented with headache, nausea, and vomiting, and underwent SP shunting for left frontoparietal chronic subdural effusion. Six weeks later, radiographic examinations revealed total migration of the shunt through the pelvic inlet. The migrated shunt was replaced with a new SP shunt. Four weeks later, radiographic examinations revealed shunt migration into the subdural space. The shunt catheter was removed and the subdural effusion was evacuated. Shunt migration may result from pressure differences between the abdomen and the cranium or from head movement, and insufficient fixation and/or large burr holes can facilitate shunt migration. Double firm anchoring and small-sized burr holes can prevent this complication. SP shunt is a simple procedure, and its assumed complications can be prevented through precaution. PMID- 28904577 TI - Acute Necrotizing Encephalopathy of Childhood Secondary to Dengue Infection: A Case Report from Pakistan. AB - Acute necrotizing encephalopathy of childhood (ANEC) is a rare condition mainly affecting children with a distinct clinico-radiologic pattern. Initially thought to be secondary to respiratory viral infections, there have been more insights to the pathogenesis of ANEC including genetics. We present a case of a girl who developed this condition with classical clinico-radiologic findings of ANEC secondary to severe dengue infection and could not survive. We report this case with the aim to raise awareness about this fatal complication of dengue infection as dengue has become a global health-care problem. PMID- 28904578 TI - Rosette-forming Glioneuronal Tumor: A Rare Posterior Fossa Tumor in an Adolescent. AB - Rosette-forming glioneuronal tumor (RGNT) is a rare variety of slow growing mixed glioneuronal tumor involving primarily fourth ventricular region and occurring predominantly in young adults. We present a case of a 16-year-old boy who presented with dizziness and occipital headache. On radiological evaluation, a fairly large hypodense posterior fossa mass lesion in relation to the left side of the vermis, with a large cystic component was found. Surgical resection of the tumor was performed. Histopathological examination showed a biphasic tumor composed of bland neurocytic cells, arranged in the form of neurocytic rosettes along with glial areas resembling low-grade glioma. The neurocytic rich region shows strong synaptophysin positivity in the neuropil-rich core of the rosettes. Methylation-inhibited binding proliferative index was low (<1%). Based on these features, a diagnosis of RGNT was made. RGNT of the fourth ventricle should be considered in differential diagnosis of posterior fossa lesions, especially in relation to fourth ventricle and vermis in young adults. PMID- 28904579 TI - Dopa-responsive Dystonia in a Child Misdiagnosed as Cerebral Palsy. AB - Dopa-responsive dystonia also known as "Segawa's syndrome" was first described in 1976. The dystonia typically shows diurnal variations and is more marked toward the end of the day and improves in sleep. This entity is often misdiagnosed in the clinical setting, mostly due to the lack of awareness, and these patients are exposed to various treatment regimens and nonpharmacological measures. We present a boy being treated as dystonic cerebral palsy who showed significant improvement in dystonic symptoms with L-dopa therapy. PMID- 28904580 TI - Extradural Spinal Metastasis in Ovarian Mixed Germ Cell Tumor. AB - Ovarian germ cell tumors (GCTs) are rare and affect mainly young girls and women. Two histological groups are distinguished: dysgerminomas and nondysgerminomatous tumors. These tumors have initial good responses to surgery and chemotherapy in 80% cases, but >75% of patients die due to complications of disease progression. There are very few case reports of mixed GCT with extradural spine metastases. We report a rare case of a 17-year-old girl who had undergone left salpingo oophorectomy with omental and peritoneal biopsy for ovarian GCT with extradural spinal metastasis. PMID- 28904581 TI - Split Notochord Syndrome: A Rare Variant. AB - Split notochord syndrome represents an extremely rare and pleomorphic form of spinal dysraphism characterized by a persistent communication between the endoderm and the ectoderm, resulting in splitting or deviation of the notochord. It manifests as a cleft in the dorsal midline of the body through which intestinal loops are exteriorized and even myelomeningoceles or teratomas may occur at the site. A rare variant was diagnosed on autopsy of a 23+4-week-old fetus showing a similar dorsal enteric fistula and midline protruding intestinal loops in thoracolumbar region. The anteroposterior radiograph showed a complete midline cleft in the vertebral bodies from T11 to L5 region, and a split in the spinal cord was further confirmed by ultrasonography. Myelomeningocele was erroneously reported on antenatal ultrasound. Thus, awareness of this rare anomaly is necessary to thoroughly evaluate the cases of such spinal defects or suspected myelomeningoceles. PMID- 28904582 TI - Giant Intracerebral Tuberculoma with Complete Disappearance on Antitubercular Therapy Alone in a Pediatric Case: A Case Illustration with Review of Management Strategy. AB - The Central nervous system can be affected in extrapulmonary tuberculosis. The intracranial tuberculoma occurrence is a rare entity occurrence; most often occur in the form of discrete small multiple lesions. Rarely a large sized tuberculoma is observed with mass effects and usually managed surgically to provide rapid relief of mass effect, histopathological confirmation of diagnosis, reduction of pathological mass thereby increasing efficacy of medical therapy. Author reports an extremely rare case of giant tuberculoma occurring in a pediatric patient, which was managed with antituberculous medication along with cerebral decongestant. The patient was also advised surgical therapy in view of giant size of tuberculoma associated with significant mass effect; however, the parents were unwilling for any form of surgical intervention and finally choose to continue medical treatment alone. After 6 months of antitubercular medical therapy, magnetic resonance imaging brain showed completely vanishing of lesion and also amelioration of mass effect with marked subsidence of perilesional edema correlated very well with marked improvement in the clinical status. He received antituberculous therapy for 24 months. To the best knowledge of authors, the current case represents first case of its kind in the pediatric age group with giant intracerebral tuberculoma responding favorably with medication. Management of such rare case and pertinent literature is reviewed briefly. PMID- 28904583 TI - Giant Unruptured Middle Cerebral Artery Aneurysm Presenting with Complex Partial Seizure: A Short Review. AB - Intracranial aneurysm is a rare cause of seizure although few cases may develop new onset seizure following rupture of aneurysm. The causes of seizure in ruptured aneurysm may be caused due to presence of subarachnoid hemorrhage, intracerebral hematoma, infarct due to progressive vasospasm, worsening of hydrocephalus, or even after surgical craniotomy for clipping of aneurysm. However, incidental aneurysm solely presenting with complex partial seizure is not reported in literature. To the best of knowledge of authors, current case represents the first case as incidental aneurysm presenting with seizure and pertinent literature is briefly reviewed. PMID- 28904584 TI - Central Nervous System Inflammatory Myofibroblastic Tumor Masquerading as Chronic Suppurative Otitis Media. AB - Inflammatory myofibroblastic tumor (IMT) is a rare tumor in the central nervous system (CNS), mostly being extracranial. Approximately 100 sporadic cases have been reported in the literature. The rarity of the tumor, its various histopathological characteristics, and its variable aggressive course render it difficult to diagnose and treat. IMT is generally a histological diagnosis which is rarely suspected preoperatively. It mimics other intracranial tumors such as giant cell tumor, hemangiopericytoma, anaplastic meningioma, plasmacytoma, and lymphoma. Rarely, it can present with a clinical picture which mimics a benign infective process, Rosai-Dorfman disease, or an idiopathic hypertrophic pachymeningitis. High index of suspicion is required as total resection of this lesion is mandatory to prevent recurrence. Here, we describe a case of a 10-year old child which initially presented with clinical features mimicking chronic suppurative otitis media and radiological presentation of a small intracranial abscess. He was initially treated by an ENT surgeon who started him on intravenous antibiotics, but the patient was lost to follow up. He returned after 2 months with a large lesion at the same location. Histological examination revealed multiple spindle cells with plasma cells and lymphocytes scattered among these spindle cells. The spindle cells were immunopositive for smooth muscle actin and negative for epithelial membrane antigen, S100, and CD34. PMID- 28904585 TI - Is it the Monster "Teratoma" or Simply Meningomyelocele: Our Experience of "Histological Surprise". AB - Teratomas are one of the most common tumors in newborn with excellent prognosis arises from totipotent primordial germ cells harboring two or three germ cell layers. The tumor has been titled "Great masquerade." The teratomas of sacrococcygeal region present with lower limb weakness, urinary or bowel obstruction, and swelling at lower back or intrauterine mass in ultrasound or complicated delivery. A 2-month-old male child presented with complaints of swelling over lumbosacral region with discharging punctum since birth. Sagittal T2-weighted magnetic resonance imaging (MRI) of the spine showed myelocele at L5 level forming placode with central defect at L4-S1 and low-lying tethered cord up to L4-L5. The patient was operated, and histopathology surprisingly came to be mature teratoma. We followed the patient with serum beta human chorionic gonadotropin and alpha-fetoprotein markers and MRI. Literature supports complete surgical removal, including coccyx and tumor base. Mature teratoma is considered as benign disease thus even subtotal excision is appropriate but with aggressive follow-up. The difference in recurrence following total compared to subtotal resection is considered insignificant. In this article, we have discussed the management of teratoma in detail. Teratoma with meningomyelocele is a rare entity. There is still dilemma in managing cases and prognosticating parents in such patients. The provisional diagnosis of teratoma should also be considered when child presents as midline sacrococcygeal mass. PMID- 28904586 TI - Case of Childhood Ataxia with Central Nervous System Hypomyelination with a Novel Mutation in EIF2B3 gene. AB - A 4-year-old boy presented with loss of motor milestones following viral fever. On examination, the child had increased tone and exaggerated deep tendon reflexes. Magnetic resonance imaging of the brain showed white matter hyperintensities on T2-weighted images, which revealed partial inversion on fluid attenuated inversion recovery images. Clinical exome sequencing revealed a novel homozygous mutation c.1270T>G: pCys424Gly in exon 11 of the EIF2B3 gene. This novel mutation is reported in this article along with a literature review. PMID- 28904587 TI - Complete Resolution of Papilledema in Syndromic Craniosynostosis with Posterior Cranial Vault Distraction. AB - We report a case of surgical management of Crouzon syndrome with multisuture craniosynostosis presenting with increased intracranial pressure (ICP) manifesting with chronic papilledema without ventriculomegaly. A 12-month-old boy had complete resolution of papilledema after posterior cranial vault distraction followed by staged fronto-orbital advancement. Expansion of the cranial vault with posterior distraction osteogenesis posed an elegant treatment, obviating ventriculoperitoneal shunt placement for cerebrospinal fluid (CSF) diversion. Strategies for the management of elevated ICP without ventriculomegaly in craniosynostosis include CSF shunting and cranial vault expansion. Posterior calvarial vault distraction associated with resolved papilledema has not been previously reported. Addressing the craniocephalic disproportion for this child with chronic papilledema, without ventriculomegaly, allowed the possibility of shunt freedom. PMID- 28904588 TI - A Case of Epilepsia Partialis Continua Due to Linear Nevus Syndrome with Hemimegalencephaly. AB - Epilepsia partialis continua (EPC) is a form of focal status epilepticus often refractory to anticonvulsant therapy. A wide range of abnormalities such as inflammatory, vascular, metabolic-toxic, developmental malformations, and neoplasia cause EPC. Linear nevus syndrome with hemimegalencephaly is one of the developmental malformations that can present with EPC. PMID- 28904589 TI - Arterial Stroke as an Isolated Manifestation of Homocystinuria in an Infant. PMID- 28904590 TI - Psychology in the Post-Truth Era. PMID- 28904591 TI - Representations of Death Among Italian Vegetarians: An Ethnographic Research on Environment, Disgust and Transcendence. AB - This paper focuses on the motives for vegetarian choices in contemporary Italian food culture, with specific reference to the role of the representations of death. The study adopts a qualitative research design aimed at an in-depth exploration of the reasons for avoiding meat, following an ethnographic method. Twenty-two participants (55% women, 45% men) aged 19-74, all vegetarians or vegans, mainly from Northern and Central Italy, were involved. Data from the Interpretative Phenomenological Analysis were examined according to the qualitative thematic analysis: the results show the role of death in the construction of disgust towards meat, running parallel with an emphasis on spirituality, ethical treatment of animals and the environment as reasons for avoiding meat, in particular, the concern-generating disgust and its relationship with the representation of death as a contaminating essence. The basis of disgust lies in this connection, from which the idea that oral consumption of contaminants characterized by corruptive properties, passing through the flesh of dead animals to humans, derives. The role of anti-speciesism is considered as a latent perspective, which may influence the vegetarian and vegan choices. PMID- 28904592 TI - Measuring Teacher Job Satisfaction: Assessing Invariance in the Teacher Job Satisfaction Scale (TJSS) Across Six Countries. AB - Work and organizational psychology has long been concerned with measuring job satisfaction in organizational contexts, and this has carried across to the field of education, leading to a research focus on the work-related satisfaction of teachers. Today, a myriad of organizations continue to assess employees' job satisfaction on a routine basis (Liu, Borg, & Spector, 2004). Unfortunately, a sort of balkanization of the field has resulted in the production of dozens of specific measurement tools, making it difficult to cross-compare samples and contexts. The present paper tested the measurement invariance of the Teacher Job Satisfaction Scale (TJSS) in six international cohorts (Netherlands, United States, Russia China, Italy and Palestine) of in-service teachers (N = 2,819). Confirmatory factor analysis and multi-group invariance tests were applied. The TJSS-9 displayed robust psychometric proprieties and no substantial departures from measurement invariance (configural and metric). Future research is required to further test equivalence across additional countries, with view to developing a truly international tool for measuring job satisfaction in teaching. PMID- 28904593 TI - Criteria for the Transition to Adulthood, Developmental Features of Emerging Adulthood, and Views of the Future Among Greek Studying Youth. AB - This study investigated emerging adulthood and transition to adulthood in Greece, a highly underresearched issue in this country. Participants were 784 university students aged 17.5-27.5 years. Criteria for the transition to adulthood, developmental features of emerging adulthood, perceived adult status, views of the future (optimism), and sociodemographic variables were assessed. The results support the existence of emerging adulthood as a distinct life period in Greece. More than two thirds of the sample were self-perceived emerging adults. Most prevalent criteria were Norm compliance and Family capacities. Developmental features of emerging adulthood ranked high, especially Identity exploration, Experimentation/possibilities, and Feeling "in-between". Statistically significant variations emerged as a function of gender, age, living arrangement, job experience, and perceived adult status. Views of the future were cautiously optimistic. Similarities with existing data and differences related to the specific characteristics of the Southern European context are discussed. PMID- 28904594 TI - Psychological Well-Being in Italian Families: An Exploratory Approach to the Study of Mental Health Across the Adult Life Span in the Blue Zone. AB - Self-reported measures of psychological well-being and depressive symptoms were examined across differently aged family members, while controlling for the impact of marital status and personal satisfaction about family and non-family relations. Twenty-one grandchildren (i.e., ages 21-36 years) were recruited with their parents (i.e., 48-66 years old) and grandparents (i.e., 75-101 years of age) in the 'blue zone' of Ogliastra, an Italian area known for the longevity of its inhabitants. Each participant was individually presented a battery of questionnaires assessing their lifestyle and several perceived mental health indices, including the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS, Tennant et al., 2007), and the Center for Epidemiologic Studies Depression Scale (i.e., CES-D, Radloff, 1977). After assessing the level of concordance among adults sharing the same context, the Hierarchical Linear Modeling (HLM) approach was used to assess the nested dataset. It was found that family membership (i.e., grandchildren versus parents and grandparents) predicted the WEMWBS score but not the CES-D when the impact of marital status and personal satisfaction about social (i.e., family and non-family) ties was controlled for. Moreover, two separate repeated-measure Analyses of Variance (ANOVAs) documented similar level of personal satisfaction about social relationships across the three family groups. In conclusions, satisfying social ties with friends and family members together with an active socially oriented life style seems to contribute to the promotion of mental health in adult span. PMID- 28904595 TI - A Cross-Continental Study on Children's Drawings of Football Players: Implications for Understanding Key Issues and Controversies in Human Figure Drawings. AB - Professionals examine various aspects of girls' and boys' drawings as a way of understanding their intelligence, personality and emotional state. However, the extent to which such measures could be universally generalised or attributed to a specific cultural norm is still a debatable issue. In the present study five key features of children's drawings namely: the size (height) of the drawings, profile or full face, figure in action or static, shaded or non-shaded and the nature of additional details were examined from a cross-cultural perspective, and by providing a topic (football) for which children's drawing of a human figure could provide opportunities for the latter indices to manifest and flourish. Children from three countries; England, Iran and Brazil, representing three continents took part in this study. The participants were asked to draw a football player from their own country and from the other participating countries. The results showed that Brazilian children differ from Iranian and English children by drawing significantly smaller figures and putting more football action in the drawings. Shading of the figure drawn was more prevalent amongst English children. Such findings have implications for the interpretation of key aspects of children's drawings in educational, clinical and therapeutic settings and from a universal vs. culturally-specific viewpoint. PMID- 28904596 TI - A Psychobiographical Study of Intuition in a Writer's Life: Paulo Coelho Revisited. AB - Intuition is defined as a form of knowledge which materialises as awareness of thoughts, feelings and physical sensations. It is a key to a deeper understanding and meaningfulness. Intuition, used as a psychological function, supports the transmission and integration of perceptions from unconscious and conscious realms. This study uses a psychobiographical single case study approach to explore intuition across the life span of Paulo Coelho. Methodologically, the study is based on a single case study, using the methodological frame of Dilthey's modern hermeneutics. The author, Paulo Coelho, was chosen as a subject of research, based on the content analysis of first- and third-person perspective documents. Findings show that Paulo Coelho, as one of the most famous and most read contemporary authors in the world, uses his intuitions as a deeper guidance in life, for decision-making and self-development. Intuitive decision-making is described throughout his life and by referring to selected creative works. PMID- 28904597 TI - Machiavellianism, Relationship Satisfaction, and Romantic Relationship Quality. AB - Machiavellianism is characterised by a manipulative interpersonal style, willingness to exploit others, and a preference for emotionally detached relationships. The present studies investigate the extent to which Machiavellianism influences relationship satisfaction and romantic relationship quality. In Study 1, 194 heterosexual partnered women completed Machiavellianism and Relationship Satisfaction measures. Women with higher levels of Machiavellianism reported lower levels of relationship satisfaction. In Study 2, 132 heterosexual partnered women completed Machiavellianism, Trust, Commitment, Control, and Emotional Abuse scales. Women with higher levels of Machiavellianism perceived their partners to be less dependable, reported less faith in their partners, and were less willing to persist with the relationship than those with low levels of Machiavellianism. With regards to negative behavior, Machiavellianism predicted each form of control and emotional abuse investigated, such that those with high levels of Machiavellianism were more likely to engage in controlling behavior and emotional abuse. Findings have important implications for the prediction of romantic relationship quality and in particular for negative behavior such as control and abuse. PMID- 28904598 TI - Delusional Ideation, Cognitive Processes and Crime Based Reasoning. AB - Probabilistic reasoning biases have been widely associated with levels of delusional belief ideation (Galbraith, Manktelow, & Morris, 2010; Lincoln, Ziegler, Mehl, & Rief, 2010; Speechley, Whitman, & Woodward, 2010; White & Mansell, 2009), however, little research has focused on biases occurring during every day reasoning (Galbraith, Manktelow, & Morris, 2011), and moral and crime based reasoning (Wilkinson, Caulfield, & Jones, 2014; Wilkinson, Jones, & Caulfield, 2011). 235 participants were recruited across four experiments exploring crime based reasoning through different modalities and dual processing tasks. Study one explored delusional ideation when completing a visually presented crime based reasoning task. Study two explored the same task in an auditory presentation. Study three utilised a dual task paradigm to explore modality and executive functioning. Study four extended this paradigm to the auditory modality. The results indicated that modality and delusional ideation have a significant effect on individuals reasoning about violent and non-violent crime (p < .05), which could have implication for the presentation of evidence in applied setting such as the courtroom. PMID- 28904599 TI - The Effectiveness of a Parent-Training Program for Promoting Cognitive Performance in Preschool Children. AB - The study aims to evaluate the effectiveness of a parent training program for promoting cognitive performance of young children through enriching the parent child interactions among mothers of preschool-aged children in Mashhad, Iran. A total of 29 couples of mothers and their children were assigned to an experimental group (n = 16 couples) and a control group (n = 13 couples). Mothers in the experimental group participated in 12 weekly sessions and were trained how to enrich their daily parent-child interactions as such. Children's cognitive performance was assessed by three subscales of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). The results of the analysis of covariance (ANCOVA) indicated a significant difference between the experimental and control group. The findings support the effectiveness of the parent training program for enhancing cognitive performance in preschoolers. PMID- 28904600 TI - Psychological Functions of Semiotic Borders in Sense-Making: Liminality of Narrative Processes. AB - In this paper we discuss the semiotic functions of the psychological borders that structure the flow of narrative processes. Each narration is always a contextual, situated and contingent process of sensemaking, made possible by the creation of borders, such as dynamic semiotic devices that are capable of connecting the past and the future, the inside and the outside, and the me with the non-me. Borders enable us to narratively construct one's own experiences using three inherent processes: contextualization, intersubjective positioning and setting of pertinence. The narrative process - as a subjective articulation of signs in a contingent social context - involves several functions of semiotic borders: separation, differentiation, distinction-making, connection, articulation and relation-enabling. The relevant psychological aspect highlighted here is that a border is a semiotic device which is required for both maintaining stability and inducing transformation at the same time. The peculiar dynamics and the semiotic structure of borders generate a liminal space, which is characterized by instability, by a blurred space-time distinction and by ambiguities in the semantic and syntactic processes of sensemaking. The psychological processes that occur in liminal space are strongly affectively loaded, yet it is exactly the setting and activation of liminality processes that lead to novelty and creativity and enable the creation of new narrative forms. PMID- 28904601 TI - From Militant Voices to Militant Irony: Examining Identity, Memory and Conflict in the Basque Country. AB - Collective memory and identity so often go hand in hand with conflicts. Alongside the use of violence, conflicts unfold against the backdrop of different narratives about the past through which groups constantly remind themselves of the supposed origin of the conflict, and consequently, what position individuals are expected to take as members of the group. Narratives - as symbolic tools for interpreting the past and the present, as well as happenings that have yet to occur - simultaneously underpin, and are underpinned by, the position held by each warring faction. Drawing on previous works, this paper compares different versions of the 2016 truce period in the Basque Country stemming from three subjects identified, to varying degrees, with the main political actors involved in that conflict. These three cases have been selected from a total of 16 participants who were asked to define the Basque conflict and to provide an account of the 2006 truce period by using 23 documents taken from different Spanish newspapers. On the one hand, the results show two narratives reproducing the versions of two of the main political actors involved in the conflict, and on the other hand, a narrative characterized by a more personal and ironic appropriation of those versions. Results are discussed vis-a-vis the use of irony in history teaching in increasingly plural societies. PMID- 28904602 TI - There Is an 'Unconscious,' but It May Well Be Conscious. AB - Depth psychology finds empirical validation today in a variety of observations that suggest the presence of causally effective mental processes outside conscious experience. I submit that this is due to misinterpretation of the observations: the subset of consciousness called "meta-consciousness" in the literature is often mistaken for consciousness proper, thereby artificially creating space for an "unconscious." The implied hypothesis is that all mental processes may in fact be conscious, the appearance of unconsciousness arising from our dependence on self-reflective introspection for gauging awareness. After re-interpreting the empirical data according to a philosophically rigorous definition of consciousness, I show that two well-known phenomena corroborate this hypothesis: (a) experiences that, despite being conscious, aren't re represented during introspection; and (b) dissociated experiences inaccessible to the executive ego. If consciousness is inherent to all mentation, it may be fundamental in nature, as opposed to a product of particular types of brain function. PMID- 28904603 TI - Mindfulness-Based Treatment for Bipolar Disorder: A Systematic Review of the Literature. AB - Despite the increasing number of studies examining the effects of mindfulness interventions on symptoms associated with Bipolar Disorder (BD), the effectiveness of this type of interventions remains unclear. The aim of the present systematic review was to (i) critically review all available evidence on Mindfulness Based Cognitive Therapy (MBCT) as a form of intervention for BD; (ii) discuss clinical implications of MBCT in treating patients with BD; and (iii) provide a direction for future research. The review presents findings from 13 studies (N = 429) that fulfilled the following selection criteria: (i) included BD patients; (ii) presented results separately for BD patients and control groups (where a control group was available); (iii) implemented MBCT intervention; (iv) were published in English; (v) were published in a peer reviewed journal; and (vi) reported results for adult participants. Although derived from a relatively small number of studies, results from the present review suggest that MBCT is a promising treatment in BD in conjunction with pharmacotherapy. MBCT in BD is associated with improvements in cognitive functioning and emotional regulation, reduction in symptoms of anxiety depression and mania symptoms (when participants had residual manic symptoms prior to MBCT). These, treatment gains were maintained at 12 month follow up when mindfulness was practiced for at least 3 days per week or booster sessions were included. Additionally, the present review outlined some limitations of the current literature on MBCT interventions in BD, including small study sample sizes, lack of active control groups and idiosyncratic modifications to the MBCT intervention across studies. Suggestions for future research included focusing on factors underlying treatment adherence and understanding possible adverse effects of MBCT, which could be of crucial clinical importance. PMID- 28904605 TI - A novel approach to oxoisoaporphine alkaloids via regioselective metalation of alkoxy isoquinolines. AB - Oxoisoaporphine alkaloids are conveniently prepared via direct ring metalation of alkoxy-substituted isoquinolines at C-1, followed by reaction with iodine. Subsequent Suzuki cross-coupling of the resulting 1-iodoisoquinolines to methyl 2 (isoquinolin-1-yl)benzoates and intramolecular acylation of the corresponding carboxylic acids with Eaton's reagent afforded five alkaloids of the oxoisoaporphine type. The yield of the cyclization step strongly depends on the electrophilic properties of ring B. An alternative cyclization protocol via directed remote metalation of ester and amide intermediates was investigated thoroughly, but found to be not feasible. Two of the alkaloids showed strong cytotoxicity against the HL-60 tumor cell line. PMID- 28904604 TI - Chemical systems, chemical contiguity and the emergence of life. AB - Charting the emergence of living cells from inanimate matter remains an intensely challenging scientific problem. The complexity of the biochemical machinery of cells with its exquisite intricacies hints at cells being the product of a long evolutionary process. Research on the emergence of life has long been focusing on specific, well-defined problems related to one aspect of cellular make-up, such as the formation of membranes or the build-up of information/catalytic apparatus. This approach is being gradually replaced by a more "systemic" approach that privileges processes inherent to complex chemical systems over specific isolated functional apparatuses. We will summarize the recent advances in system chemistry and show that chemical systems in the geochemical context imply a form of chemical contiguity in the syntheses of the various molecules that precede modern biomolecules. PMID- 28904606 TI - Molecular recognition of N-acetyltryptophan enantiomers by beta-cyclodextrin. AB - The enantioselectivity of beta-cyclodextrin (beta-CD) towards L- and D-N acetyltryptophan (NAcTrp) has been studied in aqueous solution and the crystalline state. NMR studies in solution show that beta-CD forms complexes of very similar but not identical geometry with both L- and D-NAcTrp and exhibits stronger binding with L-NAcTrp. In the crystalline state, only beta-CD-L-NAcTrp crystallizes readily from aqueous solutions as a dimeric complex (two hosts enclosing two guest molecules). In contrast, crystals of the complex beta-CD-D NAcTrp were never obtained, although numerous conditions were tried. In aqueous solution, the orientation of the guest in both complexes is different than in the beta-CD-L-NAcTrp complex in the crystal. Overall, the study shows that subtle differences observed between the beta-CD-L,D-NAcTrp complexes in aqueous solution are magnified at the onset of crystallization, as a consequence of accumulation of many soft host-guest interactions and of the imposed crystallographic order, thus resulting in very dissimilar propensity of each enantiomer to produce crystals with beta-CD. PMID- 28904607 TI - New electroactive asymmetrical chalcones and therefrom derived 2-amino- / 2-(1H pyrrol-1-yl)pyrimidines, containing an N-[omega-(4-methoxyphenoxy)alkyl]carbazole fragment: synthesis, optical and electrochemical properties. AB - In this paper we present a synthetic approach to six new D-pi-A-D conjugated chromophores containing the N-[omega-(4-methoxyphenoxy)alkyl]carbazole fragment. Such readily functionalizable heterocycle as carbazole was used as a main starting compound for their preparation. The investigation of the optical properties has shown that the positive solvatochromism is inherent to the chromophores containing an electron-withdrawing prop-2-en-1-one fragment, while the compounds containing a 2-aminopyrimidine moiety exhibit both positive and negative solvatochromism. The fluorescence quantum yields were experimentally determined for some of the synthesized chromophores; e.g., 1-(5-arylthiophen-2 yl)ethanones quantum yields were found to lie in an interval of 60-80%. Electrochemical oxidation of the synthesized chromophores has resulted in the formation of colored thin oligomeric films that became possible due to the presence of carbazole or pyrrole fragments with free electron-rich positions. PMID- 28904609 TI - Encaging palladium(0) in layered double hydroxide: A sustainable catalyst for solvent-free and ligand-free Heck reaction in a ball mill. AB - In this paper, the synthesis of a cheap, reusable and ligand-free Pd catalyst supported on MgAl layered double hydroxides (Pd/MgAl-LDHs) by co-precipitation and reduction methods is described. The catalyst was used in Heck reactions under high-speed ball milling (HSBM) conditions at room temperature. The effects of milling-ball size, milling-ball filling degree, reaction time, rotation speed and grinding auxiliary category, which would influence the yields of mechanochemical Heck reactions, were investigated in detail. The characterization results of XRD, ICP-MS and XPS suggest that Pd/MgAl-LDHs have excellent textural properties with zero-valence Pd on its layers. The reaction results indicate that the catalyst could be utilized in HSBM systems to afford a wide range of Heck coupling products in satisfactory yields. Furthermore, this catalyst could be easily recovered and reused for at least five times without significant loss of catalytic activity. PMID- 28904610 TI - Correction: Dynamic behavior of rearranging carbocations - implications for terpene biosynthesis. AB - [This corrects the article DOI: 10.3762/bjoc.12.41.]. PMID- 28904608 TI - The chemistry and biology of mycolactones. AB - Mycolactones are a group of macrolides excreted by the human pathogen Mycobacterium ulcerans, which exhibit cytotoxic, immunosuppressive and analgesic properties. As the virulence factor of M. ulcerans, mycolactones are central to the pathogenesis of the neglected disease Buruli ulcer, a chronic and debilitating medical condition characterized by necrotic skin ulcers. Due to their complex structure and fascinating biology, mycolactones have inspired various total synthesis endeavors and structure-activity relationship studies. Although this review intends to cover all synthesis efforts in the field, special emphasis is given to the comparison of conceptually different approaches and to the discussion of more recent contributions. Furthermore, a detailed discussion of molecular targets and structure-activity relationships is provided. PMID- 28904611 TI - Oxidative dehydrogenation of C-C and C-N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds. AB - Nitrogen heteroarenes form an important class of compounds which can be found in natural products, synthetic drugs, building blocks etc. Among the diverse strategies that were developed for the synthesis of nitrogen heterocycles, oxidative dehydrogenation is extremely effective. This review discusses various oxidative dehydrogenation strategies of C-C and C-N bonds to generate nitrogen heteroarenes from their corresponding heterocyclic substrates. The strategies are categorized under stoichiometric and catalytic usage of reagents that facilitate such transformations. The application of these strategies in the synthesis of nitrogen heteroarene natural products and synthetic drug intermediates are also discussed. We hope this review will arouse sufficient interest among the scientific community to further advance the application of oxidative dehydrogenation in the synthesis of nitrogen heteroarenes. PMID- 28904612 TI - Block copolymers from ionic liquids for the preparation of thin carbonaceous shells. AB - This paper describes the controlled radical polymerization of an ionic-liquid monomer by RAFT polymerization. This allows the control over the molecular weight of ionic liquid blocks in the range of 8000 and 22000 and of the block-copolymer synthesis. In this work we focus on block copolymers with an anchor block. They can be used to control the formation of TiO2 nanoparticles, which are functionalized thereafter with a block of ionic-liquid polymer. Pyrolysis of these polymer functionalized inorganic nanoparticles leads to TiO2 nanoparticles coated with a thin carbonaceous shell. Such materials may, e.g., be interesting as battery materials. PMID- 28904613 TI - A recursive microfluidic platform to explore the emergence of chemical evolution. AB - We propose that a chemically agnostic approach to explore the origin of life, using an automated recursive platform based on droplet microfluidics, could be used to induce artificial chemical evolution by iterations of growth, speciation, selection, and propagation. To explore this, we set about designing an open source prototype of a fully automated evolution machine, comprising seven modules. These modules are a droplet generator, droplet transfer, passive and active size sorting, splitter, incubation chamber, reservoir, and injectors, all run together via a LabVIEWTM program integration system. Together we aim for the system to be used to drive cycles of droplet birth, selection, fusion, and propagation. As a proof of principle, in addition to the working individual modules, we present data showing the osmotic exchange of glycylglycine containing and pure aqueous droplets, showing that the fittest droplets exhibit higher osomolarity relative to their neighbours, and increase in size compared to their neighbours. This demonstrates the ability of our platform to explore some different physicochemical conditions, combining the efficiency and unbiased nature of automation with our ability to select droplets as functional units based on simple criteria. PMID- 28904614 TI - Theoretical simulation of the infrared signature of mechanically stressed polymer solids. AB - Mechanical stress leads to deformation of strands in polymer solids, including elongation of covalent bonds and widening of bond angles, which changes the infrared spectrum. Here, the infrared spectrum of solid polymer samples exposed to mechanical stress is simulated by density functional theory calculations. Mechanical stress is described with the external force explicitly included (EFEI) method. The uneven distribution of the external stress on individual polymer strands is accounted for by a convolution of simulated spectra with a realistic force distribution. N-Propylpropanamide and propyl propanoate are chosen as model molecules for polyamide and polyester, respectively. The effect of a specific force on the polymer backbone is a redshift of vibrational modes involving the C N and C-O bonds in the backbone, while the free C-O stretching mode perpendicular to the backbone is largely unaffected. The convolution with a realistic force distribution shows that the dominant effect on the strongest infrared bands is not a shift of the peak position, but rather peak broadening and a characteristic change in the relative intensities of the strongest bands, which may serve for the identification and quantification of mechanical stress in polymer solids. PMID- 28904615 TI - An effective Pd nanocatalyst in aqueous media: stilbene synthesis by Mizoroki Heck coupling reaction under microwave irradiation. AB - Aqueous Mizoroki-Heck coupling reactions under microwave irradiation (MW) were carried out with a colloidal Pd nanocatalyst stabilized with poly(N vinylpyrrolidone) (PVP). Many stilbenes and novel heterostilbenes were achieved in good to excellent yields starting from aryl bromides and different olefins. The reaction was carried out in a short reaction time and with low catalyst loading, leading to high turnover frequency (TOFs of the order of 100 h-1). The advantages like operational simplicity, high robustness, efficiency and turnover frequency, the utilization of aqueous media and simple product work-up make this protocol a great option for stilbene syntheses by Mizoroki-Heck reaction. PMID- 28904616 TI - Mechanochemical enzymatic resolution of N-benzylated-beta3-amino esters. AB - The use of mechanochemistry to carry out enantioselective reactions has been explored in the last ten years with excellent results. Several chiral organocatalysts and even enzymes have proved to be resistant to milling conditions, which allows for rather efficient enantioselective transformations under ball-milling conditions. The present article reports the first example of a liquid-assisted grinding (LAG) mechanochemical enzymatic resolution of racemic beta3-amino esters employing Candida antarctica lipase B (CALB) to afford highly valuable enantioenriched N-benzylated-beta3-amino acids in good yields. Furthermore the present protocol is readily scalable. PMID- 28904617 TI - An efficient Pd-NHC catalyst system in situ generated from Na2PdCl4 and PEG functionalized imidazolium salts for Mizoroki-Heck reactions in water. AB - Three PEG-functionalized imidazolium salts L1-L3 were designed and prepared from commercially available materials via a simple method. Their corresponding water soluble Pd-NHC catalysts, in situ generated from the imidazolium salts L1-L3 and Na2PdCl4 in water, showed impressive catalytic activity for aqueous Mizoroki-Heck reactions. The kinetic study revealed that the Pd catalyst derived from the imidazolium salt L1, bearing a pyridine-2-methyl substituent at the N3 atom of the imidazole ring, showed the best catalytic activity. Under the optimal conditions, a wide range of substituted alkenes were achieved in good to excellent yields from various aryl bromides and alkenes with the catalyst TON of up to 10,000. PMID- 28904618 TI - Mechanochemical N-alkylation of imides. AB - The mechanochemical N-alkylation of imide derivatives was studied. Reactions under solvent-free conditions in a ball mill gave good yields and could be put in place of the classical solution conditions. The method is general and can be applied to various imides and alkyl halides. Phthalimides prepared under ball milling conditions were used in a mechanochemical Gabriel synthesis of amines by their reaction with 1,2-diaminoethane. PMID- 28904619 TI - Chiral phase-transfer catalysis in the asymmetric alpha-heterofunctionalization of prochiral nucleophiles. AB - Chiral phase-transfer catalysis is one of the major catalytic principles in asymmetric catalysis. A broad variety of different catalysts and their use for challenging applications have been reported over the last decades. Besides asymmetric C-C bond forming reactions the use of chiral phase-transfer catalysts for enantioselective alpha-heterofunctionalization reactions of prochiral nucleophiles became one of the most important field of application of this catalytic principle. Based on several highly spectacular recent reports, we thus wish to discuss some of the most important achievements in this field within the context of this review. PMID- 28904620 TI - 18-Hydroxydolabella-3,7-diene synthase - a diterpene synthase from Chitinophaga pinensis. AB - The product obtained in vitro from a diterpene synthase encoded in the genome of the bacterium Chitinophaga pinensis, an enzyme previously reported to have germacrene A synthase activity during heterologous expression in Escherichia coli, was identified by extensive NMR-spectroscopic methods as 18 hydroxydolabella-3,7-diene. The absolute configuration of this diterpene alcohol and the stereochemical course of the terpene synthase reaction were addressed by isotopic labelling experiments. Heterologous expression of the diterpene synthase in Nicotiana benthamiana resulted in the production of 18-hydroxydolabella-3,7 diene also in planta, while the results from the heterologous expression in E. coli were shown to be reproducible, revealing that the expression of one and the same terpene synthase in different heterologous hosts may yield different terpene products. PMID- 28904621 TI - Conformational impact of structural modifications in 2-fluorocyclohexanone. AB - 2-Haloketones are building blocks that combine physical, chemical and biological features of materials and bioactive compounds, while organic fluorine plays a fundamental role in the design of performance organic molecules. Since these features are dependent on the three-dimensional chemical structure of a molecule, simple structural modifications can affect its conformational stability and, consequently, the corresponding physicochemical/biological property of interest. In this work, structural changes in 2-fluorocyclohexanone were theoretically studied with the aim at finding intramolecular interactions that induce the conformational equilibrium towards the axial or equatorial conformer. The interactions evaluated were hydrogen bonding, hyperconjugation, electrostatic and steric effects. While the gauche effect, originated from hyperconjugative interactions, does not appear to cause some preferences for the axial conformation of organofluorine heterocycles, more classical effects indeed rule the conformational equilibrium of the compounds. Spectroscopic parameters (NMR chemical shifts and coupling constants), which can be useful to determine the stereochemistry and the interactions operating in the series of 2 fluorocyclohexanone derivatives, were also calculated. PMID- 28904622 TI - Selective enzymatic esterification of lignin model compounds in the ball mill. AB - A lipase-catalyzed esterification of lignin model compounds in the ball mill was developed combining the advantages of enzyme catalysis and mechanochemistry. Under the described conditions, the primary aliphatic hydroxy groups present in the substrates were selectively modified by the biocatalyst to afford monoesterified products. Amongst the tested lipases, CALB proved to be the most effective biocatalyst for these transformations. Noteworthy, various acyl donors of different chain lengths were tolerated under the mechanochemical conditions. PMID- 28904623 TI - Ni nanoparticles on RGO as reusable heterogeneous catalyst: effect of Ni particle size and intermediate composite structures in C-S cross-coupling reaction. AB - The present work demonstrates the C-S cross-coupling reaction between aryl halides and thiols using nickel nanoparticles (Ni NPs) supported on reduced graphene oxide (Ni/RGO) as a heterogeneous catalyst. It is observed that the uniformly dispersed Ni NPs supported on RGO could exhibit excellent catalytic activity in C-S cross-coupling reactions and the catalytic application is generalized with diverse coupling partners. Although the electron-rich planar RGO surface helps in stabilizing the agglomeration-free Ni NPs, the catalytic process is found to occur involving Ni(II) species and the recovered catalyst containing both Ni(0)/Ni(II) species is equally efficient in recycle runs. A correlation of loading of Ni species, size of NPs and the intermediate Ni-related heterostructures formed during the catalytic process has been established for the first time, and found to be best in the C-S cross-coupling reaction for Ni(0) and Ni(II) NPs of the average sizes 11-12 nm and 4 nm, respectively. PMID- 28904624 TI - Pd(OAc)2/Ph3P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles. AB - The palladium-catalyzed dimerization of isoprene is a practical approach of synthesizing monoterpenes. Though several highly selective methods have been reported, most of them still required pressure or costly ligands for attaining the active system and desired selectivity. Herein, we present a simple and economical procedure towards the tail-to-tail dimer using readily available Pd(OAc)2 and inexpensive triphenylphosphine as ligand. Furthermore, simple screw cap vials are employed, allowing carrying out the reaction at low pressure. In addition, the potential of the dimer as a chemical platform for the preparation of heterocyclic terpenes by subsequent (hetero)-Diels-Alder or [4 + 1] cycloadditions with nitrenes is also depicted. PMID- 28904625 TI - NHC-catalyzed cleavage of vicinal diketones and triketones followed by insertion of enones and ynones. AB - Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The diketones gave alpha,beta-double acylation products via unique Breslow intermediates isolable as acid salts, whereas the triketones formed stable adducts with the NHC instead of the coupling products. PMID- 28904626 TI - Iodoarene-catalyzed cyclizations of N-propargylamides and beta-amidoketones: synthesis of 2-oxazolines. AB - Two complementary iodoarene-catalyzed methods for the preparation of 2-oxazolines are presented. The first involves the cyclization of N-propargylamides and the second involves the cyclization of beta-amidoketones. These are proposed to proceed through different mechanisms and have different substrate scopes. PMID- 28904627 TI - Mechanochemical synthesis of thioureas, ureas and guanidines. AB - In this review, the recent progress in the synthesis of ureas, thioureas and guanidines by solid-state mechanochemical ball milling is highlighted. While the literature is abundant on their preparation in conventional solution environment, it was not until the advent of solvent-free manual grinding using a mortar and pestle and automated ball milling that new synthetic opportunities have opened. The mechanochemical approach not only has enabled the quantitative synthesis of (thio)ureas and guanidines without using bulk solvents and the generation of byproducts, but it has also been established as a means to develop "click-type" chemistry for these classes of compounds and the concept of small molecule desymmetrization. Moreover, mechanochemistry has been demonstrated as an effective tool in reaction discovery, with emphasis on the reactivity differences in solution and in the solid state. These three classes of organic compounds share some structural features which are reflected in their physical and chemical properties, important for application as organocatalysts and sensors. On the other hand, the specific and unique nature of each of these functionalities render (thio)ureas and guanidines as the key constituents of pharmaceuticals and other biologically active compounds. PMID- 28904628 TI - Tibial derotational osteotomies in two neuromuscular populations: comparing cerebral palsy with myelomeningocele. AB - PURPOSE: To review the outcomes of tibial derotational osteotomies (TDOs) as a function of complication and revision surgery rates comparing a cohort of children with myelodysplasia to a cohort with cerebral palsy (CP). METHODS: A chart review was completed on TDOs performed in a tertiary referral centre on patients with myelodysplasia or CP between 1985 and 2013 in patients aged > 5 years with > 2 years follow-up. Charts were reviewed for demographics, direction/degree of derotation, complications and need for re-derotation. Two sample T-tests were used to compare the characteristics of the two groups. Two tailed chi-square tests were used to compare complications. Generalised linear logit models were used to identify independent risk factors for complication and re-rotation. RESULTS: The 153 patients (217 limbs) were included. Average follow up was 7.83 years. Overall complication incidence was 10.14%, including removal of hardware for any reason, with a 4.61% major complication incidence (fracture, deep infection, hardware failure). After adjusting for gender and age, the risk of complication was not statistically significantly different between groups (p = 0.42) nor was requiring re-derotation (p = 0.09). The probability of requiring re derotation was 31.9% less likely per year increase in age at index surgery (p = 0.005). CONCLUSION: With meticulous operative technique, TDO in children with neuromuscular disorders is a safe and effective treatment for tibial torsion, with an acceptable overall and major complication rate. The risk of re-operation decreases significantly in both groups with increasing age. The association between age at initial surgery and need for re-derotation should help guide the treatment of children with tibial torsion. PMID- 28904629 TI - Reliability of patellar height indices in children with cerebral palsy and spina bifida. AB - BACKGROUND: The Koshino (KI) and Caton-Deschamps (CDI) indices are used to measure patellar height in children, with the CDI showing excellent reliability in typically developing (TD) children. Reliability of such measures in children with cerebral palsy (CP) and spina bifida (SB) is unknown. METHODS: Lateral knee radiographs were reviewed retrospectively for children with TD (n = 49), CP (n = 48) and SB (n = 42). Five raters took measurements from radiographs twice, at least two weeks apart. Measurements included the CDI, Insall-Salvati Index (ISI) and KI. Systematic variability (bias) and random variability were examined using repeated measures ANOVA, 95% limits of agreement (LOA) and coefficients of variation (CV). RESULTS: Mean values of all three indices differed among raters (p < 0.0001). A significant difference was seen between the first and second measurements for CDI and KI indicating a learning effect. LOA ranges were large for the CDI (intra-rater: 0.37-0.95, inter-rater: 0.60-1.04) and ISI (intra rater: 0.25-0.49, inter-rater: 0.51-0.57) for all patient groups. The KI showed a clinically acceptable range for TD participants (intra-rater: 0.14-0.16, inter rater: 0.11-0.14) with larger ranges for CP (intra-rater: 0.26-0.33, inter-rater 0.0.2-0.35) and SB patients (intra-rater: 0.23-0.27, inter-rater: 0.19-0.25). CVs were lowest (best) for KI (3.8% to 7.4%) and highest (worst) for CDI (14.7% to 23.1%) for all three groups. Results were similar for patients with both open and closed physes. CONCLUSIONS: The KI is the most reliable patellar height measure for paediatric patients with TD, CP and SB, with either open or closed physes. The KI is more complex and experience may be important for valid, reliable measurement. PMID- 28904630 TI - Inter- and intra-rater reliability of the head-shaft angle in children with cerebral palsy. AB - PURPOSE: Children with cerebral palsy (CP) are at increased risk for hip dislocation. This can be prevented in most cases using surveillance programmes that include radiographic examinations. Known risk factors for hip dislocation include young age, high Gross Motor Function Classification System (GMFCS) level and high migration percentage (MP). The head-shaft angle (HSA) has recently been described as an additional risk factor. The study aim was to determine inter- and intra-rater reliability of the HSA in a surveillance programme for children with CP. METHODS: We included hip radiographs from the CP surveillance programme CPUP in southern Sweden during the first half of 2016. Fifty radiographs were included from children at GMFCS levels II-V, with a mean age of 6.6 (SD 3.2) years. Three raters measured the HSA of one hip (left or right) at baseline and four weeks later; intraclass correlation coefficient (ICC) was used to estimate inter- and intra-rater reliability. RESULTS: Inter- and intra-rater reliability were excellent for the HSA, with ICC 0.92 (95% CI 0.87-0.96) and ICC 0.99 (95% CI 0.98 0.99), respectively. CONCLUSION: The HSA showed excellent inter- and intra-rater reliability for children with CP, providing further evidence for use of the HSA as an additional factor for identifying risk for further hip displacement or dislocation. PMID- 28904631 TI - Do research papers provide enough information on design and material used in ankle foot orthoses for children with cerebral palsy? A systematic review. AB - OBJECTIVES: The purpose of this article is to determine how many of the current peer-reviewed studies of ankle foot or-thoses (AFOs) on children with cerebral palsy (CP) have included adequate details of the design and material of the AFO, to enable the study to be reproduced and outcomes clearly understood. METHODS: A thorough search of studies published in English was conducted in March 2015, with no restriction on dates, within all major databases using relevant phrases. These searches were then supplemented by tracking all key references from the appropriate articles identified. STUDY SELECTION: The inclusion criteria were as follows: (1) population - children with CP; (2) intervention - AFOs; and (3) outcome measure. One reviewer extracted data regarding the characteristics of the included studies, with the extracted data checked for accuracy and completeness by a second reviewer. None of the studies reviewed gave adequate details of the AFOs. Only 3.6% (n = 2) of papers tested the stiffness. Many studies (54.5%) did not describe the material used nor the material thickness (72.7 %). None of them gave any clinical justification for the chosen design of AFO. CONCLUSIONS: There is a clear paucity of detail regarding the design and material used in AFOs on studies involving children with CP. Such a lack of detail has the potential to affect the validity of the reported outcomes, the ability to reproduce the studies and may misinform clinical practice. PMID- 28904632 TI - Incidence of acetabular dysplasia in breech infants following initially normal ultrasound: the effect of variable diagnostic criteria. AB - PURPOSE: This study aimed to determine the incidence of acetabular dysplasia at six months of age in patients with breech presentation and previously normal hip ultrasounds, reporting primary radiographic measurements to allow for comparison with other patient cohorts. METHODS: A retrospective analysis of breech infants with initially normal clinical examinations and hip ultrasounds was performed to determine the rate of subsequent acetabular dysplasia and to characterise the distribution of acetabular index (AI). At approximately six months of age, AI was measured bilaterally on anteroposterior (AP) pelvic radiographs and reported using descriptive statistics. RESULTS: A total of 94 hips in 47 breech infants were eligible for analysis. All infants demonstrated normal ultrasound findings at a mean age of 6.9 +/- 1.7 weeks and returned for follow-up at a mean age of 6.4 +/- 0.5 months. On AP pelvic radiographs, mean right hip AI was 25.0 degrees , with an interquartile range (IQR) (25th -75th percentile) of 23 degrees to 27 degrees and mean left hip AI was 25.5 degrees , with an IQR of 22 degrees to 28 degrees . If one applies a single commonly used threshold value for defining dysplasia (AI >= 30 degrees ), 10/94 hips (10.6%) meet diagnostic criteria. Alternatively, strict adherence to previously established normative AI values stratified by gender and laterality results in 4/94 hips (4.3%) qualifying as significantly dysplastic. CONCLUSIONS: The proportion of breech infants who, despite normal initial ultrasound findings, were diagnosed with dysplasia at six months supports observation of breech-born patients beyond six weeks. Reliance on different threshold values for diagnosing acetabular dysplasia can lead to discrepancies in incidence rates. PMID- 28904633 TI - An improved method for measuring hip abduction in spica after surgical reduction for developmental dysplasia of the hip. AB - PURPOSE: Excessive in-spica abduction is a risk factor for oste-onecrosis after surgical reduction for developmental dysplasia of the hip (DDH). The traditional method for radiographically measuring hip abduction using axial imaging does not reflect the true angle, which usually lies in an oblique plane. The purpose of this study was to describe a novel method for measuring true hip position using advanced imaging. METHODS: A trigonometric model was derived to define hip position based upon the femoral axis angular deviation from midline as measured on axial and coronal sequences of MRI studies. In-spica MRIs of 28 hips having undergone surgery for DDH were reviewed. On two separate occasions, the same three raters measured the femoral axis deviation from mid-line on axial and coronal imaging. Abduction was estimated using the traditional method of measurement and our novel method. Intra- and inter-rater reliability were assessed. RESULTS: The methods yielded different estimates (p < 0.001). Inter- and intra-rater reliability were excellent for both methods (inter-rater ICC > 0.922, intra-rater ICC > 0.919). The traditional method is accurate at 90 degrees of flexion, but it increasingly overestimates abduction as hip flexion decreases. All cases where hip flexion was <= 40 degrees exhibited >= 10 degrees of error. CONCLUSIONS: Decreasing hip flexion in spica modifies the perceived angle of abduction as measured using axial imaging. This inaccuracy can be overcome through assessment of orthogonal views using our new approach, which is accurate and reliable. It should be considered for future research investigating the effects of in-spica hip position on outcomes of DDH treatment. PMID- 28904634 TI - Treatment of chronic, stable slipped capital femoral epiphysis via surgical hip dislocation with combined osteochondroplasty and Imhauser osteotomy. AB - PURPOSE: Treatment of slipped capital femoral epiphysis (SCFE), including the modified Dunn procedure, restores anatomy with significant risk for avascular necrosis (AVN), if performed in the setting of moderate to severe, stable SCFE. The Imhauser osteotomy has been shown to be an effective way to correct residual deformity without the risk of AVN. We sought to evaluate the effectiveness and safety of a combined Imhauser osteotomy and osteochondroplasty, performed via a surgical hip dislocation approach for the acute and delayed treatment of stable SCFE. METHODS: A retrospective review was performed on a series of patients who underwent Imhauser osteotomy and osteochondroplasty via surgical hip dislocation for treatment of chronic, stable SCFE. Patients were divided into acute or delayed treatment groups based on whether osteotomy was performed as the initial slip treatment. RESULTS: In total 19 patients (15 male, four female, average age 13.7 years) were reviewed. Six osteotomies were performed acutely in combination with in situ pinning, 13 were delayed at least six months after in situ pinning (average 21.7 months). Two hips had labral tears that required repair. The mean follow-up was 61 months (23 to 120) (delayed) and 53 months (27 to 61) (acute). The average improvement in slip angle was 40.7 degrees (delayed) and 50.2 degrees (acute) (p = 0.0916), final post-operative slip angle averaged 15.8 degrees (delayed) and 17.8 degrees (acute) (p = 0.544). Femoral neck length and greater trochanteric height were similar between both groups. Average alpha angle at final follow-up measured 55.8 degrees (delayed) and 60.8 degrees (acute) (p = 0.542). No cases of AVN were identified. CONCLUSION: Imhauser osteotomy combined with osteochondroplasty via surgical hip dislocation approach is a safe and effective treatment of moderate to severe, stable SCFE performed in both the acute and delayed setting. PMID- 28904636 TI - The orthopaedic management of lower limb deformity in hypophosphataemic rickets. AB - BACKGROUND: Many patients with X-linked hypophosphataemic rickets (X-LHPR) demonstrate significant lower limb deformity despite optimal medical management. This study evaluates the use of guided growth by means of hemi-epiphysiodesis to address coronal plane deformity in the skeletally immature child. METHODS: Since 2005, 24 patients with X-LHPR have been referred to our orthopaedic unit for evaluation. All patients had standardised long leg radiographs that were analysed sequentially before and after surgery if any was performed. The rate of correction of deformity was calculated based on peri-articular angles and diaphyseal deformity angles measured at regular intervals using Traumacad software. Clinical records were reviewed to obtain relevant clinical and demographic details. Statistical analysis was performed using SPSS 23 (SPSS Inc., Chicago, IL, USA). RESULTS: The indication for surgical intervention was a mechanical axis progressing through Zone 2 or in Zone 3 despite one year of optimised medical treatment. The 15 patients underwent 16 episodes of guided growth (30 limbs, 38 segments) at a mean age of 10.3 years. In four limbs, surgery has only taken place recently; and in three limbs, correction is ongoing. Neutral mechanical axis was restored in 16/23 (70%) limbs: six improved and one limb (one segment) required osteotomy for residual deformity. The mean rate of angular correction per month was 0.3 degrees for the proximal tibia and 0.7 degrees for the distal femur. Patients with >= 3 years of growth remaining responded significantly better than older patients (p = 0.004). Guided growth was more successful in correcting valgus than varus deformity (p = 0.007). In younger patients, diaphyseal deformity corrected at a rate of 0.2 degrees and 0.6 degrees per month for the tibia and the femur, respectively. There has been one case of recurrent deformity. Patients with corrected coronal plane alignment did not complain of significant residual torsional malalignment. Serum phosphate and alkaline phosphatase levels did not affect response to surgery. CONCLUSIONS: Guided growth is a successful, minimally invasive method of addressing coronal plane deformity in X-LHPR. If coronal plane deformity is corrected early in patients with good metabolic control, osteotomy can be avoided. PMID- 28904635 TI - Does orthopaedic surgery improve quality of life and function in patients with mucopolysaccharidoses? AB - PURPOSE: Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders associated with involvement of multiple organs along with a generalised skeletal dysplasia. Both haematopoetic stem cell transplant and enzyme replacement therapy have improved the outlook for patients while surgery remains high-risk and there is little information on clinical or functional outcome to justify many of the surgical procedures performed. This paper aims to summarise the orthopaedic surgical procedures in MPS patients for which quality of life (QoL) and functional data are available and to describe additional QoL and functional measurement tools of relevance to the assessment of orthopaedic outcomes in MPS. METHODS: We reviewed the available literature to look for reported outcomes of orthopaedic surgery to lower and upper limbs and the spine. In addition, we describe the general and MPS-specific health measures that might be of relevance to the orthopaedic surgeon. RESULTS: There is some evidence in the literature that orthopaedic surgery may improve QoL and function in some specific aspects of the MPS condition (in relation to genu valgum, carpal tunnel syndrome and trigger digits); however, the literature is sparse and consists of level 4/5 studies only. Further studies of these conditions should include QoL and functional assessment in order to confirm or refute these reports. In other areas (spine and hip), outcomes are judged largely on radiographic appearances with little clinical correlation and short follow-up; however, one long-term study of function following hip dysplasia surgery suggests poor outcomes. Anaesthetic morbidity/mortality is not insignificant in these complex patients with multi-organ involvement. Careful assessment is required, particularly when there is neurological involvement. CONCLUSIONS: Orthopaedic surgeons involved with MPS patients should be encouraged to use and report measures of QoL and function with respect to musculoskeletal manifestations and response to surgery, recognising that such assessments in these complex and challenging patients may require a multidisciplinary approach. PMID- 28904637 TI - The emerging trend of non-operative treatment in paediatric type I open forearm fractures. AB - PURPOSE: Open fractures are considered an orthopaedic emergency and are generally an indication for operative debridement. Recent studies have questioned this approach for the management of Gustilo-Anderson Type I open fractures in the paediatric population. This meta-analysis studies the non-operative management of Type I open paediatric forearm fractures. METHODS: An Ovid MEDLINE and PubMed database literature search was performed for studies that involved a quantified number of Gustilo-Anderson Type I open forearm fractures in the paediatric population, which were treated without operative intervention. A fixed-effect meta-analysis, weighting each study based on the number of patients, and a pooled estimate of infection risk (with 95% confidence interval (CI)) was performed. RESULTS: The search results yielded five studies that were eligible for inclusion. No included patients had operative debridement and all were treated with antibiotics. The number of patients in each study ranged from 3 to 45, with a total of 127 paediatric patients in the meta-analysis. The infection rate was 0% for all patients included. The meta-analysis estimated a pooled infection risk of 0% (95% CI 0 to 2.9). CONCLUSIONS: The five included studies had a total of 127 patients with no cases of infection after non-operative management of Type I open paediatric forearm fractures. The infection rate of Type I fractures among operatively managed patients is 1.9%. The trend in literature towards non operative treatment of paediatric Type I open fractures holds true in this meta analysis. PMID- 28904638 TI - Functional outcomes following non-operative versus operative treatment of clavicle fractures in adolescents. AB - PURPOSE: Superiority of non-operative versus operative treatment of clavicle shaft fractures remains unclear. We aimed to assess shoulder function in adolescents following shortened clavicle fracture and compare operative versus non-operative treatment. METHODS: Patients aged 12 to 18 years at the time of fracture and minimum 1.5 years post injury were identified for this institutional review board (IRB)-approved study. For this retrospective cohort study, patients were frequency-matched for age, gender, shortening of the clavicle fracture and activity level. The dominant arm was controlled in the statistical model. Initial radiographs were used to measure clavicle shortening. At follow-up, isokinetic testing of both shoulders was performed in flexion, external rotation and the plane of scapular motion. Maximum number of isotonic repetitions and average isometric torque were recorded, as were ASES and DASH scores. Data were analysed comparing non-operative and operative groups and involved and uninvolved shoulders. RESULTS: Twenty patients were recruited (18 male, 2 female), with ten in each group. Median clavicle shortening was 17.5 mm (11.4 to 23.6). There was no statistical difference in average ASES (100 vs 99; p = 0.84) or DASH (0.0 vs 1.7; p = 0.08) between non-operative and operative groups, respectively. Results of isokinetic testing comparison between non-operative and operative groups showed no statistical difference for any individual association, controlling for the dominant arm. Among the non-operative group, the involved arm had decreased functional measures compared with the uninvolved arm on all measures, when controlling for dominant arm, and there was increased variability of the functional estimate. CONCLUSIONS: The increased variability in functional measures for the non-operative group suggests some patients may have dysfunction. PMID- 28904639 TI - A comparison of functional outcome between amputation and extension prosthesis in the treatment of congenital absence of the fibula with severe limb deformity. AB - PURPOSE: Complete fibula absence often presents with significant lower-limb deformity. Parental counselling regarding management is paramount in achieving the optimum functional outcome. Amputation offers a single surgical event with minimal complications. This study compares outcomes with an amputation protocol to those using an extension prosthesis. METHOD: Thirty-two patients were identified. Nine patients (2 males, 7 females; median age at assessment of 23.5 years) used an extension prosthesis. Twenty-three patients (16 males, 7 females; median age at assessment of eight years) underwent 25 amputations during childhood. Mobility was assessed using SIGAM and K scores. Quality of life was assessed using the PedsQL inventory questionnaire; pain by a verbal severity score. RESULTS: The 19 Syme and one Boyd amputation in 19 patients were performed early (mean age 15 months). Four Syme and one trans-tibial amputation in four patients took place in older children (mean age 6.6 years). Only two underwent tibial kyphus correction to aid prosthetic fitting. K scores were significantly higher (mean 4 vs 2) and pain scores lower in the amputation group allowing high impact activity compared with community ambulation with an extension prosthesis. The SIGAM and PedsQL scores were all better in the amputation group, but not significantly so. CONCLUSION: Childhood amputation for severe limb length inequality and foot deformity in congenital fibula absence offers excellent short term functional outcome with prosthetic support. The tibial kyphus does not need routine correction and facilitates prosthetic suspension. Accommodative extension prostheses offer reasonable long-term function but outcome scores are lower. PMID- 28904642 TI - Focus on endeavor for creation of materials-tissues intelligent interface. PMID- 28904640 TI - Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology. AB - BACKGROUND: Methionine, a central molecule in one-carbon metabolism, is an essential amino acid required for normal growth and development. Despite its importance to biological systems, methionine is toxic when administered at supra physiological levels. The aim of this study was to investigate the effects of short-term methionine dietary modulation on the proximal jejunum, the section of the gut specifically responsible for amino acid absorption, in a mouse model. Eight-week-old CBA/J male mice were fed methionine-adequate (MAD; 6.5 g/kg) or methionine-supplemented (MSD; 19.5 g/kg) diets for 3.5 or 6 days (average food intake 100 g/kg body weight). The study design was developed in order to address the short-term effects of the methionine supplementation that corresponds to methionine dietary intake in Western populations. Biochemical indices in the blood as well as metabolic, epigenetic, transcriptomic, metagenomic, and histomorphological parameters in the gut were evaluated. RESULTS: By day 6, feeding mice with MSD (protein intake <10% different from MAD) resulted in increased plasma (2.3-fold; p < 0.054), but decreased proximal jejunum methionine concentrations (2.2-fold; p < 0.05) independently of the expression of neutral amino acid transporters. MSD has also caused small bowel bacteria colonization, increased the abundance of pathogenic bacterial species Burkholderiales and decreased the gene expression of the intestinal transmembrane proteins-Cldn8 (0.18-fold, p < 0.05), Cldn9 (0.24-fold, p < 0.01) and Cldn10 (0.05-fold, p < 0.05). Feeding MSD led to substantial histomorphological alterations in the proximal jejunum exhibited as a trend towards decreased plasma citrulline concentrations (1.8-fold, p < 0.07), as well as loss of crypt depth (by 28%, p < 0.05) and mucosal surface (by 20%, p < 0.001). CONCLUSIONS: Together, these changes indicate that short-term feeding of MSD substantially alters the normal gut physiology. These effects may contribute to the pathogenesis of intestinal inflammatory diseases and/or sensitize the gut to exposure to other stressors. PMID- 28904643 TI - Rolling Circle Mutagenesis of GST-mCherry to Understand Mutation, Gene Expression, and Regulation. AB - Undergraduates are often familiar with textbook examples of human mutations that affect coding regions and the subsequent disorders, but they may struggle with understanding the implications of mutations in the regulatory regions of genes. We have designed a laboratory sequence that will allow students to explore the effect random mutagenesis can have on protein function, expression, and ultimately phenotype. Students design and perform a safe and time-efficient random mutagenesis experiment using error-prone rolling circular amplification of a plasmid expressing the inducible fusion protein glutathione S-transferase (GST) mCherry. Mutagenized and wild-type control plasmid DNA, respectively, are then purified and transformed into bacteria to assess phenotypic changes. While bacteria transformed with the wild type control should be pink, some bacterial colonies transformed with mutagenized plasmids will exhibit a different color. Students attempt to identify their mutations by isolating plasmid from these mutant colonies, sequencing, and comparing their mutant sequence to the wild-type sequence. Additionally, students evaluate the potential effects of mutations on protein production by inducing GST-mCherry expression in cultures, generating cell lysates, and analyzing them using SDS-PAGE. Students who have a phenotypic difference but do not obtain a coding region mutation will be able to think critically about plasmid structure and regulation outside of the gene sequence. Students who do not obtain bacterial transformants have the chance to contemplate how mutation of antibiotic resistance genes or replication origins may have contributed to their results. Overall, this series of laboratories exposes students to basic genetic techniques and helps them conceptualize mutation beyond coding regions. PMID- 28904641 TI - Histone code and long non-coding RNAs (lncRNAs) aberrations in lung cancer: implications in the therapy response. AB - Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer. Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy. Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lncRNAs expression levels and patterns in human lung carcinomas in cancer drug-based treatments, as an important comprehensive knowledge focusing on better oncological therapies. In addition, a new future direction must be refocusing on several gene target therapies, mainly on pharmaceutical EGFR-TKIs compounds, widely applied in lung cancer, currently the leading cause of death by malignant diseases. PMID- 28904644 TI - Teaching the History of Microbiology and the Transformation of the Laboratory: A Study in Miniature. AB - This article presents a technique for bringing the history of microbiology to life in an exciting way. Eight miniature models were created, based on photographs or drawings, showing scientists at work in their labs. The models chosen represent important discoveries in microbiology, illustrating changes and advances in techniques and tools over the history of the discipline from 1600 through 2000. They serve as a novel and engaging teaching tool. While the instructor still presents the historic facts, the use of models provides the feeling of being there! They can also serve as a record for the future. PMID- 28904645 TI - Fitness of Antibiotic-Resistant Bacteria in the Environment: A Laboratory Activity. AB - In this laboratory experiment, we propose an opportunity for students to broaden their understanding of the ecology of antibiotic-resistant and sensitive waterborne bacteria. Antibiotics can be found in rivers or soil as a consequence of agricultural practices or as a result of human use. Concentrations of antibiotics in the environment may range from a few ng to MUg L-1. Such concentrations can affect the selection and fitness of resistant bacteria. In this laboratory activity, students learn how to set up a fitness experiment by using an isogenic pair of antibiotic-resistant and sensitive bacteria in the presence or absence of selective pressure. Microcosms were generated by using filtered river water containing populations of resistant and sensitive bacteria. Competition of both populations was measured in the presence or absence of antibiotics. Students appreciated the use of microcosms for in vitro experiments and the extent to which the fitness of resistant and sensitive bacteria changed in the presence and/or absence of a selective pressure in river water. Student learning was measured by using different types of assessments: multiple-choice, true/false, fill in the blanks, laboratory skills observations, and laboratory reports. After the laboratory activity, the percentage of correct answers significantly rose from ~20% to ~85%. Laboratory skills were also evaluated during the exercises, showing no major issues during the experiment. Students showed proficiency in analyzing the complexity of fitness data by reaching a mean of 5.57 (standard error 0.57) over a maximum score of 7 points. PMID- 28904646 TI - Participation in a Year-Long CURE Embedded into Major Core Genetics and Cellular and Molecular Biology Laboratory Courses Results in Gains in Foundational Biological Concepts and Experimental Design Skills by Novice Undergraduate Researchers. AB - This two-year study describes the assessment of student learning gains arising from participation in a year-long curriculum consisting of a classroom undergraduate research experience (CURE) embedded into second-year, major core Genetics and Cellular and Molecular Biology (CMB) laboratory courses. For the first course in our CURE, students used micro-array or RNAseq analyses to identify genes important for environmental stress responses by Saccharomyces cerevisiae. The students were tasked with creating overexpressing mutants of their genes and designing their own original experiments to investigate the functions of those genes using the overexpression and null mutants in the second CURE course. In order to evaluate student learning gains, we employed three validated concept inventories in a pretest/posttest format and compared gains on the posttest versus the pretest with student laboratory final grades. Our results demonstrated that there was a significant correlation between students earning lower grades in the Genetics laboratory for both years of this study and gains on the Genetics Concept Assessment (GCA). We also demonstrated a correlation between students earning lower grades in the Genetics laboratory and gains on the Introductory Molecular and Cell Biology Assessment (IMCA) for year 1 of the study. Students furthermore demonstrated significant gains in identifying the variable properties of experimental subjects when assessed using the Rubric for Experimental (RED) design tool. Results from the administration of the CURE survey support these findings. Our results suggest that a year-long CURE enables lower performing students to experience greater gains in their foundational skills for success in the STEM disciplines. PMID- 28904647 TI - Measuring and Advancing Experimental Design Ability in an Introductory Course without Altering Existing Lab Curriculum. AB - Introductory biology courses provide an important opportunity to prepare students for future courses, yet existing cookbook labs, although important in their own way, fail to provide many of the advantages of semester-long research experiences. Engaging, authentic research experiences aid biology students in meeting many learning goals. Therefore, overlaying a research experience onto the existing lab structure allows faculty to overcome barriers involving curricular change. Here we propose a working model for this overlay design in an introductory biology course and detail a means to conduct this lab with minimal increases in student and faculty workloads. Furthermore, we conducted exploratory factor analysis of the Experimental Design Ability Test (EDAT) and uncovered two latent factors which provide valid means to assess this overlay model's ability to increase advanced experimental design abilities. In a pre-test/post-test design, we demonstrate significant increases in both basic and advanced experimental design abilities in an experimental and comparison group. We measured significantly higher gains in advanced experimental design understanding in students in the experimental group. We believe this overlay model and EDAT factor analysis contribute a novel means to conduct and assess the effectiveness of authentic research experiences in an introductory course without major changes to the course curriculum and with minimal increases in faculty and student workloads. PMID- 28904648 TI - Metacognition Modules: A Scaffolded Series of Online Assignments Designed to Improve Students' Study Skills. AB - Many first-year biology students begin college with high aspirations but limited skills in terms of those needed for their success. Teachers are increasingly focused on students' lack of metacognitive awareness combined with students' inability to self-regulate learning behaviors. To address this need, we have designed a series of out-of-class assignments to provide explicit instruction on memory and learning. Our metacognition modules consist of six video assignments with reflective journaling prompts, allowing students to explore the relationship between the learning cycle, neuroplasticity, memory function, expert and novice thinking, and effective study strategies. By setting lessons on improving study behavior within a biological context, we help students grasp the reason for changing their behavior based on an understanding of biological functions and their application to learning. Students who complete these scaffolded journaling assignments show a shift toward a growth mindset and a consistent ability to evaluate the efficacy of their own study behaviors. In this article, we discuss the modules and student assignments, as well as provide in depth support for faculty who wish to adopt the modules for their own courses. PMID- 28904649 TI - Harnessing Whole Genome Sequencing in Medical Mycology. AB - PURPOSE OF REVIEW: Comparative genome sequencing studies of human fungal pathogens enable identification of genes and variants associated with virulence and drug resistance. This review describes current approaches, resources, and advances in applying whole genome sequencing to study clinically important fungal pathogens. RECENT FINDINGS: Genomes for some important fungal pathogens were only recently assembled, revealing gene family expansions in many species and extreme gene loss in one obligate species. The scale and scope of species sequenced is rapidly expanding, leveraging technological advances to assemble and annotate genomes with higher precision. By using iteratively improved reference assemblies or those generated de novo for new species, recent studies have compared the sequence of isolates representing populations or clinical cohorts. Whole genome approaches provide the resolution necessary for comparison of closely related isolates, for example, in the analysis of outbreaks or sampled across time within a single host. SUMMARY: Genomic analysis of fungal pathogens has enabled both basic research and diagnostic studies. The increased scale of sequencing can be applied across populations, and new metagenomic methods allow direct analysis of complex samples. PMID- 28904650 TI - Dermatologic Microsutures Using Human Hair: A Useful Technique in Cutaneous Stitching. AB - Background: Facial wounds are challenging for dermatologic surgeons, particularly traumatic facial wounds, because they can yield disfiguring scars. To obtain good results, narrow needles and sutures are needed. Hair filaments have a very small diameter (0.06-0.1 mm) and could serve as suture threads for facial wounds. Objective: To determine the aesthetic outcomes by using autologous hair to suture facial wounds. Patients and Methods: This case series study examined the aesthetic outcomes of all consecutive female patients with traumatic facial wounds who underwent autologous hair-based stitching in 2009-2016. Autologous hair ampoules were generated from an insulin needle. Micro instruments were used for wound stitching. Results: In total, 54 females (mean age, 10.8; range, 3-45) years had 56 traumatic wounds. Mean wound length was 3.6 (range, 1-12) cm. Injury depth varied from cutaneous-only to muscle involvement. Suturing yielded good edge coaptation, nice healing, and excellent aesthetic outcomes; the scars were often scarcely visible. Suture marks were not detected. Cutaneous reactions did not occur. Conclusion: Autologous hair can serve as a thread for closing facial wounds. It is low cost and thus suitable in settings characterized by facility and equipment limitations. It is also suitable for the battlefield. PMID- 28904651 TI - [Primary cerebral gliosarcoma: about two cases and review of the literature]. AB - Gliosarcoma is a very rare brain tumor accounting for 1.8 -8% of all glial tumors. It has been classified by the World Health Organization as a variant of glioblastoma. It is a tumor with double glial and sarcomatous component. Patient's clinical picture is polymorphic, imaging data are evocative, diagnosis is based on histology. Treatment is always surgical. Prognosis is closely linked to the quality of resection. We here report two clinical cases with the aim of assessing the diagnostic, therapeutic and prognostic features of this rare entity. PMID- 28904652 TI - [Role of Trauma Damage Control Orthopaedic in polytraumas: a case of pelvic disjunction associated with hip dislocation with vascular injury]. AB - The knowledge of the pathophysiology of patients with severe trauma and the hemodynamic and inflammatory consequences of initial surgical management has led many surgeons to change their approach to the treatment of patients with severe polytraumas associated with lesions of the pelvis or of limbs by integrating the principles of sequential treatment or Trauma Damage Control Orthopaedic (TDCO). We report the case of a patient involved in a public road accident, admitted to hospital in a state of shock with pelvic disjunction and hip dislocation complicated by vascular injury in the same limb. Our approach was based on TDCO concepts by favoring external fixation of the pelvis after hip dislocation reduction. The timeliness of our apprach allowed early limb revascularization while avoiding the hemodynamic and inflammatory complications of open surgery. PMID- 28904653 TI - [Pure internal subtalar dislocation: about a case]. AB - Pure subtalar dislocation is a rare condition. We here report the case of a young patient presenting with pure internal subtalar dislocation as a result of a sport accident. He underwent orthopedic therapy achieving a good functional outcome. PMID- 28904654 TI - [Primary squamous cell carcinoma of the colon: about a case]. AB - Primary squamous cell carcinoma (SCC) of the colon is an exceptional tumor. Less than 150 cases have been reported in the literature up to the year 2014. In addition to its rarity, it is distinguished by its frequent association with other digestive neoplasias. We report the case of a 54-year old patient with primary SCC of the colon. In the light of this case study, we will discuss the anatomo-clinical and therapeutic features as well as the etiopathogenic assumptions of this unusual entity. PMID- 28904656 TI - Reversal of tenofovir induced nephrotoxicity: case reports of two patients. AB - The use of the antiretroviral drug tenofovir has been associated with nephrotoxicity. However, the overall impact of this adverse effect has not comprehensively evaluated. Some researchers have reported that it is quite severe to warrant monitoring for renal toxicity, while others have concluded that the magnitude may not be that significant. We report two clinical cases seen in our renal clinic with high creatinine levels suggestive of nephrotoxicity who reverted back to normality upon withdrawal of tenofovir. PMID- 28904655 TI - Assessment of potentially preventable hospitalizations in the regional hospital of Saint-Louis, Senegal. AB - INTRODUCTION: The "potentially preventable hospitalizations (PPH)'' are hospital admissions that could have been avoided through effective primary care given at the appropriate time. Non-communicable diseases (NCDs), causes of PPH, are the leading cause of death worldwide with significant socioeconomic consequences especially in developing countries. This study aimed to assess the burden of potentially preventable hospitalizations in the St. Louis regional hospital. METHODS: This was a descriptive cross-sectional study. The surveyed population consisted of all patients older than one year, admitted to St. Louis hospital for more than four (04) hours time between January 20 and April 30, 2015. Patients hospitalized in surgery (general surgery, ENT, ophthalmology), maternity and neonatology, as well as those who refused or were unable to participate in the study were excluded. RESULTS: The study included one hundred forty four (144) individuals with an average age of 54.68+/-15 years (17-88 years) and sex ratio woman/man of 1.21. The PPH represented 54% of all hospitalizations. The main causes of hospitalizations were diabetes with 22.1%, chronic kidney disease 12%, hypertension 10.9%, Stroke 6.4% and finally broncho-pulmonary diseases 2.6%. The average length of stay was 6.68+/-5.51 days. The average distance between the residence and the hospital was 26.51+/-60KM with a median of 3.5KM. The average cost of care was Euros 104.583 +/-83.51. For 61.10%, it was a first hospitalization and for 30.60%, a second one. The Knowledge about signs of disease severity had changed significantly at the end of hospitalization, from 29% at the beginning to 98% at the end of stay in hospital. As for the means of prevention, 30.55% reported knowing them before their hospitalization and 68% after hospitalization. CONCLUSION: Potentially preventable hospitalizations are a heavy burden for the population of St. Louis. Their negative social and economic impacts may hinder health policies initiated to relieve vulnerable groups. Their prevention should be a national priority. PMID- 28904657 TI - Risk factors for postoperative throat pain after general anaesthesia with endotracheal intubation at the University of Gondar Teaching Hospital, Northwest Ethiopia, 2014. AB - INTRODUCTION: Postoperative sore throat is listed from the top as patients' most undesirable outcome in the postoperative period. It is believed to originate from mucosal dehydration or edema, tracheal ischemia secondary to the pressure of endotracheal tube cuffs, aggressive oropharyngeal suctioning, and mucosal erosion from friction between delicate tissues and the endotracheal tube. Even if the problem was indicated in many literatures, it has never been studied in our country. The study aimed to assess prevalence and factors associated with postoperative sore throat among patients who were operated under general anesthesia with endotracheal intubation. METHODS: Hospital based cross sectional study was conducted from February 25 - April 10, 2014 in Gondar University hospital. Patient interview and chart review were employed for data collection. Bivariate and multivariate logistic regressions were used to determine the association. RESULTS: A total of 240 out of 299 patients were included in this study with a response rate of 80.3%. The prevalence of postoperative sore throat within 48 hours after operation was 59.6%. Factors which had association with postoperative sore throat from the multivariate logistic regression were female sex (AOR = 3.3, 95% CI: 1.07, 10.375), repeated number of attempts to intubate (AOR = 3.291, 95% CI: 1.658, 6.531), and the use of nasogastric tube (AOR = 0.41, 95% CI: 0.174, 0.965) respectively. CONCLUSION: The prevalence of postoperative sore throat was high in Gondar University Hospital. Awareness creation about the problem should be made for health professionals and postoperative sore throat management protocol need to be introduced. PMID- 28904658 TI - Prenatal diagnosis of caudal regression syndrome and omphalocele in a fetus of a diabetic mother. AB - The caudal regression syndrome is defined as total or partial agenesis of the sacrum and lumbar spine, frequently associated with other developmental malformations (orthopedic, neurological, genito-urinary, gastrointestinal...). Prenatal diagnosis is possible through fetal ultrasound (US) and magnetic resonance imaging (MRI). A case of fetal caudal regression syndrome with omphalocele from a diabetic mother is presented, demonstrating the sonographic, MRI, CT and X-Ray features diagnostic. We will also discuss neonatal findings, risk factors and prognosis of this condition. PMID- 28904659 TI - [Pulmonary embolism at the University Hospital Campus of Lome (Togo): a retrospective study about 51 cases]. AB - INTRODUCTION: This study provides an analysis of the evolutionary, clinical and epidemiological aspects of pulmonary embolism at the University Hospital Campus of Lome. METHODS: We conducted a retrospective, analytic and descriptive study over a period of 39 months (November 1 , 2011- January 31, 2015). All the medical records of patients hospitalized for PE in the Department of Cardiology at the University Hospital Campus were analyzed. RESULTS: The prevalence of PE was 3.1%. Female/male sex ratio was 2.2. The average age was 52.7 +/- 14.4 years. Risk factors for venous thromboembolic disease VTD were dominated by: obesity (54.9%), bedrest (25.5%) and long journey (17.6%). The main symptoms were: dyspnoea (98.0%), chest pain (78.4%) and cough (60.8%). Wells' score was high in 29.4% of cases. ECG showed: tachycardia (78.4%), right ventricular hypertrophy (RVH)(49.0%), S1Q3T3 aspect (47.1%) and right block (39.2%). Transthoracic Doppler echocardiogram showed right cavitary dilation and right intraventricular thrombus in 5.6% of cases. Thoracic angioscanner was normal in 9.8% of cases and showed embolus in 82.4% of cases. Treatment was based on Low Molecular Weight Heparin (LMWH) at therapeutic doses with antivitamin K (AVK) relay. Thrombolysis was performed in 8 patients. Evolution was favorable in 86.3% of cases. Case fatality rate was 13.7%. CONCLUSION: The prevalence of PE is relatively low in our area but it is probably underestimated. PE is a therapeutic problem in Togo because of the high cost of complementary examinations and thrombolysis. Prevention is therefore the only effective weapon. PMID- 28904660 TI - [Ulceronecrotic cancer of the vulva]. PMID- 28904661 TI - [Occlusion secondary to congenital internal transmesenteric hernia: about 2 cases]. AB - Internal hernia due to mesenteric defect or transmesenteric hernia is a rare cause of acute intestinal obstruction. Its diagnosis is most often done during surgery. The knowledge of its clinical peculiarities allows the preoperative diagnosis. We here report 2 cases of acute intestinal obstruction secondary to congenital transmesenteric hernia in two adult patients. This study aims to highlight the clinical peculiarities of this rare form of internal hernia. PMID- 28904662 TI - Long-term results of retromuscular hernia repair: a single center experience. AB - INTRODUCTION: Incisional hernia (IH) is one of the most frequent postoperative complications after abdominal surgery. There are multiple surgical techniques described for IH repair. The aim of the study is to evaluate the effect of primary fascial closure on long-term results in retromuscular hernia repair (RHR) for incisional hernias. METHODS: A total of 132 patients underwent RHR for IH were included in our study. 109 patients were evaluated in 2009 and 55 patients in 2015 for short and long-term results. RESULTS: Among 132 patients perfromed RHR, fascia was closed in 107 (81%) and left open in 25 (19%) patients. The mean age of patients was 57.9 +/- 11.8 years. Average mesh area was 439.8 +/- 194.6 cm2, hernia area was 112 +/- 77.5 cm2 and open area after repair was 40.8 +/- 43.3 cm2. Mean follow-up of 104 patients regarding postoperative complications evaluated in 2009 was 30.7 +/- 14.1 months. Recurrent IH was observed in 6 (4.5%) patients according to data collected in 2009. Long-term results were; mean follow up period was 91 +/- 20.2 months (20-112 months) and recurrent IH was observed in 4 (7.3%) patients. CONCLUSION: Retromuscular repair for incisional hernia regardless of the fascial closure gives high patient satisfaction, less recurrence rates and complications in long-term follow-up. PMID- 28904663 TI - [Direct medical costs of hospital treatment of fractures of the upper extremity of the femur]. AB - Fractures of the upper extremity of the femur are serious because of their morbidity and social and/or economic consequences. They have been the subject of several studies of world literature concerning their hospital treatment, evolution and prevention. The increase in the incidence of this pathology seems unavoidable due to population ageing and to the lengthening life expectancy; it is posing a real long-term public health problem whose importance will be further increased by the need to control health care costs. The results of this study show that the average age of onset of fracture of the proximal extremity of the femur is 68,13 +/- 16.9 years, with a male predominance and a sex ratio of 1.14. In our study pertrochanterian fractures represented 69.4% of cases. Direct medical costs of the hospital treatment of fractures of the upper extremity of the femur at the Hassan II University Hospital were L387 714,38 in 222 cases, with an average cost of L1757,4 , including costs for patient's stay in hospital, which represented the majority of expenses ( 77% of total costs). It is desirable to raise staff awareness of the costs of consumables in order to reduce treatment costs and to adopt cost-oriented behaviour. Length of stay should be limited to the maximum extent because it only allows to reduce staff and accommodation costs. PMID- 28904664 TI - [Pregnancy and delivery in patients with a personal history of cesarean section in Dakar: epidemiological, clinical, therapeutic and prognostic aspects]. AB - The aim of our study was to determine hospitalization rate for vaginal birth after cesarean section in Pikine, to evaluate the quality of the management of pregnant women with previous cesarean section and to determine prognostic factors of the outcome of a trial of scar. We conducted a retrospective study based on medical records and operational protocols of patients who underwent vaginal birth after cesarean section over the period 1 January 2010 - 31 December 2011. We analyzed socio-demographic data, pregnancy follow-up, therapeutic modalities and prognosis. Data were collected and analyzed using Microsoft Office Excel 2007 software and SPSS software 17.0. The frequency of vaginal births after cesarean section was 9.6%. The average age of our patients was 29.4 years. Primiparous women accounted for 54%. Short spacing interval between births was found in 52.6% of cases. Based on the number of cesarean sections, the breakdown was as follows: patients with a history of one previous cesarean section (79.8%), patients with a history of two previous caesarean sections (17.9%) and patients with a history of three previous caesarean sections (2.3%). The number of antenatal consultations performed was greater than or equal to 3 in 79.8% of cases. Patients undergoing evacuation accounted for 54.2% and they were already in labor at the time of admission in 81.7% of cases. Trial of scar was authorized in 177 patients (34.3%) and, at the end of this test, 147 patients (83%) had vaginal birth, of whom 21.7% by vacuum extraction. Cesarean section was performed in 71.4% of cases with 245 emergency cesarean sections and 93 scheduled cesarean sections. A history of vaginal birth was a determining factor in normal delivery (p = 0.0001). There was also a significant relationship between mode of admission and decision to perform a cesarean section (p = 0.0001). Maternal mortality was 0.4%. Perinatal mortality rate was 28.20/00 of live births. We are witnessing a dramatic increase of deliveries after cesarean section in our SONUC Health Centre. The quality of management should be enhanced through a better strategy in preparation for delivery. Trial of scar is a procedure to encourage in order to reduce the rate of iterative cesarean sections. PMID- 28904665 TI - [Idiopathic gastric perforation in neonates: about a case]. AB - Spontaneous neonatal gastric perforation is rare. We report the case of a newborn without any abnormality identified at delivery and whose mother had problem-free pregnancy. On the third day of life, he had a sudden onset of severe abdominal distension followed by bilious vomiting. Abdominal X-rays without treatment showed massive pneumoperitoneum and laparotomy showed a perforation at the level of the anterior gastric wall closed in a single layer closure. Postoperative course was uneventful. Spontaneous neonatal gastric perforation usually has a favorable outcome. Hence the importance of early diagnosis and patient management. PMID- 28904667 TI - Beaver in the liver. PMID- 28904666 TI - Detection of Human Herpes Virus 8 in Kaposi's sarcoma tissues at the University Teaching Hospital, Lusaka, Zambia. AB - INTRODUCTION: Human herpes virus-8, a gamma2-herpes virus, is the aetiological agent of Kaposi sarcoma. Recently, Kaposi's sarcoma cases have increased in Zambia. However, the diagnosis of this disease is based on morphological appearance of affected tissues using histological techniques, and the association with its causative agent, Human Herpes virus 8 is not sought. This means poor prognosis for affected patients since the causative agent is not targeted during diagnosis and KS lesions may be mistaken for other reactive and neoplastic vascular proliferations when only histological techniques are used. Therefore, this study was aimed at providing evidence of Human Herpes virus 8 infection in Kaposi's sarcoma tissues at the University Teaching Hospital in Lusaka, Zambia. METHODS: One hundred and twenty suspected Kaposi's sarcoma archival formalin fixed paraffin-wax embedded tissues stored from January 2013 to December 2014 in the Histopathology Laboratory at the University Teaching Hospital, Lusaka, Zambia were analysed using histology and Polymerase Chain Reaction targeting the ORF26 gene of Human Herpes virus 8. RESULTS: The predominant histological type of Kaposi's sarcoma detected was the Nodular type (60.7%) followed by the plaque type (22.6%) and patch type (16.7%). The nodular lesion was identified mostly in males (40.5%, 34/84) than females (20.2%, 17/84) (p=0.041). Human Herpes virus 8 DNA was detected in 53.6% (45/84) and mostly in the nodular KS lesions (60%, 27/84) (p=0.035). CONCLUSION: The findings in this study show that the Human Herpes virus-8 is detectable in Kaposi's sarcoma tissues, and, as previously reported in other settings, is closely associated with Kaposi's sarcoma. The study has provided important baseline data for use in the diagnosis of this disease and the identification of the virus in the tissues will aid in targeted therapy. PMID- 28904668 TI - [Squamous cell carcinoma complicating Verneuil's disease]. PMID- 28904669 TI - An unexpected guest. PMID- 28904670 TI - Vanishing lung syndrome in a patient with HIV infection and recurrent pneumothorax. PMID- 28904671 TI - [Idiopathic intracranial hypertension: a rare case related to pregnancy]. AB - We report the case of a 25-year old primipara whose pregnancy was complicated by idiopathic intracranial hypertension (ICHT) associated with visual impairment in the first quarter. She underwent lumboperitoneal shunt without obstetric consequences. This study aimed to determine the features of this rare pathological entity whose pathophysiological mechanism is poorly elucidated. It would be caused by poor absorption of cerebrospinal fluid (CSF) through the arachnoid granulations. Major risk factors are: obesity, polycystic ovary syndrome, thrombophilia and hyperfibrinolyse. Diagnosis is based on modified Dandy criteria after negative clinico-biological and radiological assessment. Visual prognosis is compromised, as in the case of " classical " ICHT. However, there is no risk for cerebral involvements which could be life-threatening. In addition, this disease does not influence pregnancy outcome. This said, rapid and effective treatment should be implemented in order to preserve visual function in these patients. PMID- 28904672 TI - [Kikuchi-Fujimoto disease: about a case]. AB - Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare cause of benign cervical adenopathies. It is an anatomoclinic entity of unknown cause. Diagnosis is based on histologic examination of the lymph nodes. Patient's evolution is generally favorable with spontaneous healing after a few weeks. We here report the case of a 9-year old girl presenting with cervical lymphadenopathy associated with fever. Cervical lymph node biopsy showed Kikuchi Fujimoto disease. Patient's evolution was marked by regression of adenopathies without receiving any treatment. PMID- 28904674 TI - [A rare cause of exertional dry cough: agenesis of the left pulmonary artery associated with pulmonary hypoplasia]. AB - Agenesis of the left pulmonary artery associated with hypoplasia of the ipsilateral lung is a rare congenital malformation in children; it can be discovered fortuitously or because of the presence of recurrent respiratory infections. Diagnosis is based on thoracic angioscanner. Treatment is essentially conservative. We report the case of a 6-year old child with agenesis of the left pulmonary artery associated with hypoplasia of the ipsilateral lung detected because of exertional dry cough. PMID- 28904673 TI - Mutations in rpoB and katG genes of multidrug resistant mycobacterium tuberculosis undetectable using genotyping diagnostic methods. AB - INTRODUCTION: Tuberculosis remains the leading causes of death worldwide with frequencies of mutations in rifampicin and isoniazid resistant Mycobacterium tuberculosis isolates varying according to geographical location. There is limited information in Zimbabwe on specific antibiotic resistance gene mutation patterns in MTB and hence, increased rate of discordant results and mortality due to inappropriate antibiotic prescriptions. The rpoB and katG genes molecular markers are used for detecting rifampicin and isoniazid resistance respectively. Some mutations within these gene sequences are associated with drug resistance as they directly alter gene function. The objectives of this research was to determine the drug resistance profiles in M. tuberculosis isolates that are phenotypically resistant but not detected by the GeneXpert and MTBDRplus kit and also to detect mutations in the rpoB and katG genes which are not detected by the Hain Genotype MTBDRplus kit and GeneXpert diagnosis. METHODS: PCR was used for the amplification of the rpoB and katG genes from MTB isolates collected from human clinical samples between 2008 and 2015. The genes were sequenced and compared to the wild type MTB H37Rv rpoB (accession number L27989) and kat G genes (KP46920), respectively. Sequence analysis results were compared to genotyping results obtained from molecular assays and culture results of all isolates. RESULTS: The most frequent mutation responsible for rifampicin resistance was (25/92) S531L that was detected by using all molecular assays. Some inconsistencies were observed between phenotypic and genotypic assay results for both katG and rpoB genes in 30 strains. For these, eight codons; G507S, T508A, L511V, del513-526, P520P, L524L, R528H, R529Q and S531F were novel mutations. In addition, the I572P/F, E562Q, P564S, and Q490Y mutations were identified as novel mutations outside the rifampicin resistance determining region. In katG gene, amino acid changes to threonine, asparagine and isoleucine exhibited high degrees of polymorphism such as V473N, D311N, and L427I. The R463L (20/92) amino acid substitution was most common but was not associated with isoniazid resistance. CONCLUSION: These finding indicate that molecular assay kit diagnosis that is based on the rpoB and katG genes should be improved to cater for the genetic variations associated with the geographic specificity of the target genes and be able to detect most prevalent mutations in different areas. PMID- 28904675 TI - Von Willebrand's disease: case report and review of literature. AB - Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner face of the lower lip that caused an external acute bleeding loss. The laboratory data showed unfortunately, the most severe form of Von Willebrand's Disease; Type 3. The management was based on erythrocyte and fresh-frozen plasma (FFP) transfusions with administration of factor VII with good evolution. PMID- 28904676 TI - [Gestational diabetes revealed by inaugural diabetic ketoacidosis: about a case]. AB - Ketoacidosis complicating gestational diabetes is rare and responsible for severe maternal-fetal mortality. It is an acute metabolic emergency whose management is multidisciplinary. Early diagnosis and treatment affect the vital prognosis of both the mother and the fetus. We report the case of a 27-year old pregnant woman at term, with a family history of diabetes, admitted to the emergency obstetric care with alertness problems associated with dyspnoea. The diagnosis of inaugural ketoacidosis decompensated due to severe malaria associated with gestational diabetes was retained on the basis of patient's medical history, of clinical examination and paraclinical assessment. The patient received insulin therapy, rehydration therapy, correction of electrolyte imbalance as well as antimalarial treatment. She underwent emergency cesarean section under general anesthesia and a dead-born macrosome macerated male fetus was extracted. Patient's evolution was favorable, with return of consciousness and standardization of biological parameters. PMID- 28904677 TI - [Pulmonary nocardiosis in immunocompetent patients: about 2 cases]. AB - Nocardiosis is a rare but severe infection caused by bacteria of the genus nocardia, which belong to the order actinomycetales. If they can affect immunocompetent adult, nocardioses are pathologies affecting the individuals with weakened immune system. Pulmonary involvement is the most common manifestation, its correct management is based on diagnosis, which is often delayed due to non specific symptoms and inconclusive specimens. We here report two cases of nocardiosis in immunocompetent patients. The first case concerns a 24-year old man with a history of smoking and alcoholism, hospitalized for chest pain and hemoptysis of low abundance evolving for two months, associated with the occurrence of dorsal subcutaneous fistulized abscess. Radiological assessment showed right mediastino-pulmonary tissue mass associated with adjacent costal lysis and dissemination in rights paravertebral tissues. Bacteriological sampling remained negative motivating ultrasound-guided biopsy of the lesion, which confirmed the diagnosis of nocardia infection. The second case concerns a 22-year old man with a history of pleural tuberculosis treated 8 years ago and of relapse of tuberculosis in 2011 (mediastinal abscess). He was admitted to hospital due to suspicion of relapse of tuberculosis based on chronic cough with alteration of general state and hepatosplenomegaly. Chest CT scan showed alveolar condensations with pleurisy. During his hospitalization, purulent subcutaneous swellings occurred. Bacteriological analysis of the pus confirmed the diagnosis of nocardiosis. Nocardia strains were resistant to all antibiotics except for colistin and bactrim. This study aims to highlight the clinical and radiological aspects of pulmonary nocardiosis, focusing on diagnostic and therapeutic difficulties especially in a country with a high prevalence of tuberculosis and a very low incidence of nocardiosis. PMID- 28904678 TI - [Epidemiological profile of hemoglobinopathies: a cross-sectional and descriptive index case study]. AB - Hemoglobinopathies are congenital disorders resultimg from hemoglobin abnormalities. Major forms are often severe, their management is difficult and associated with a great psychosocial impact on patients and their families. They are classified as rare diseases and are still insufficiently known by health professionals. This lack of knowledge is at the origin of diagnostic errors, delay in their management and therefore high morbidity and mortality rate for these patients. In 2008, the World Health Organization (WHO) has published data on hemoglobinopathies epidemiology: more than 330.000 cases of hemoglobinopathy occur each year (83% of cases of sickle cell anemia, 17 % of cases of thalassemia). Hemoglobin disorders are responsible for approximately 3.4% of deaths among people under the age of 5. At the global level, approximately 7% of pregnant women would be carriers of a form of thalassemia and 1% of couples are at risk. However, they are relatively frequent in some regions of the globe where consanguineous marriages are common. We conducted a descriptive cross-sectional study based on two surveys, the first in May 2015 and the second in June of the same year. It was performed in the immunization days to deliver pneumococcal vaccine to the index cases and it was aimed to describe the epidemiological features of families at risk of hemoglobinopathies (index case study), whose index cases were treated in the Department of Pediatrics at the Provincial Hospital El Idrisi, Kenitra, Morocco. After having collected the epidemiological data from patients, laboratory tests were performed including: blood count with red blood cells morphological assessment using the MGG assay and automatic numbering of reticulocytes; hemoglobin electrophoresis at alkaline pH (8.8) and then at acid pH (5.4) on agarose gel and densitometric integration. 275 patients had laboratory profiles compatible with hemoglobinopathy. The majority of these patients were born to consanguineous marriages (83.1%) and came from the north regions of Morocco. This family survey allowed to identify families at risk with a high frequency of sickle cell anemia. Our results confirm the existence of hemoglobinopathies variants among Moroccan population. PMID- 28904680 TI - [A plantar nodule]. PMID- 28904679 TI - Knowledge, attitudes and screening practices regarding prostatic diseases among men older than 40 years: a population-based study in Southwest Nigeria. AB - INTRODUCTION: Despite the global increase in awareness of prostatic diseases resulting from widespread availability of screening tools, there is no evidence that the knowledge, attitudes and screening practices of Nigerian men have improved regarding prostatic diseases. METHODS: A descriptive cross-sectional study amongst 305 community-dwelling men. Respondents were selected using multi staged sampling techniques. Knowledge, attitudes and screening practices were determined based on responses to a semi-structured KAP questionnaire. Data were analyzed using SPSS version 18. Pearson's chi-square and Fisher's exact test (two tail) with level of significance set at 0.05 were used to determine the level of statistical significance. Pearson's correlation coefficient was used to establish correlation between variables. RESULTS: Mean age of respondents was 63.4+/-11.8 years. Slightly less than half, 145(47.5%) were aware of prostate cancer (PCa) while only 99(32.5%) and 91(29.8%) were aware of BPH and prostatitis respectively. About a quarter (25.1%) had heard of PSA. The main sources of information were radio and television. Overall, 143(46.9%) respondents had good knowledge while 162(53.1%) had poor knowledge. Sexually transmitted disease was the commonest misconception as the cause of prostatic diseases. Overall, 44.3% had good attitudes. Only 31(10.2%) respondents had ever carried out screening for PCa. Only educational and occupational status had significant associations with level of knowledge and attitudes of participants. The only factor that influenced screening practices was educational status. CONCLUSION: There is a poor level of knowledge, attitudes and screening practices regarding prostatic diseases in Nigeria. We recommend a widespread public health education to improve knowledge, attitudes and screening practices for prostatic diseases. PMID- 28904681 TI - Clinicopathological findings and outcome of lupus nephritis in Tunisian children: a review of 43 patients. AB - We report clinical and renal histological data, treatment modalities and outcome of 43 Tunisian children with biopsy-proven lupus nephritis seen over a 23-year period. There were 39 girls and 4 boys with a mean age of 12.5 years at diagnosis of lupus nephritis and followed for a mean period of 77 months. Renal symptoms included urinary abnormalities in all patients, hypertension in 40% of cases, nephrotic syndrome in 60% of cases and renal failure in 25% of cases. Class IV and class III nephritis were observed in 48.8 % and 30.2 % respectively. Corticosteroids were used in all cases, associated to immunosuppressive therapy in 23%. Overall survival was 86% at 5 years and 74% at 10 and 15 years. Renal survival was 83% at 5 and 10 years and 63% at 15 years. Initial renal failure and tubulointerstitial fibrosis were significantly increased risk for the development of end-stage renal disease in our study group. Renal histological findings provide the basis for treatment recommendations. Timely performed renal biopsy is greatly needed to accurately determine the prognosis and to guide treatment in children lupus nephritis. PMID- 28904682 TI - Severity of motor dysfunction in children with cerebral palsy seen in Enugu, Nigeria. AB - INTRODUCTION: Children with cerebral palsy (CP) have gross motor dysfunction (GMD) of varying degrees of severity. The Gross Motor Function Classification System (GMFCS) is widely used internationally to classify children with CP into functional severity levels. There are few reports on the use of GMFCS in Nigeria to determine the severity of motor dysfunction in children with CP. This study aims to classify children with CP in Enugu on the basis of severity of their GMD in order to ascertain their management needs. METHODS: The study was a cross sectional observational study and sample selection was by consecutive recruitment. One hundred (100) children with CP aged 9 - 96 months, attending two Pediatric Neurology Clinics in Enugu, were consecutively recruited. Relevant history was taken including modalities of treatment received. Neurological examination was done and the GMFCS manual was used to classify the children into levels of severity. RESULTS: GMD varied in severity in the patients from mild (47%) (GMFCS levels I & II) to moderate (7%) (GMFCS levels III) and to severe (46%) (GMFCS levels IV & V). Those in levels I - III (54%) were ambulatory while those in levels IV & V (46%) were non-ambulatory. Of the 53 that required mobility assistive device, only 6 (11.3%) were using one. CONCLUSION: More than half of CP patients seen in Enugu were ambulatory with mild to moderate motor dysfunction based on the GMFCS. Only a few of our patients are appropriately rehabilitated with augmentative interventions. PMID- 28904683 TI - [Pertrochanterian fracture revealing multiple myeloma: how is it treated?] AB - Skeletal involvement is the major clinical complication of multiple myelomas, resulting in pathological fractures. Proximal femoral fractures are very frequent during multiple myeloma evolution and they seriously compromise survival and quality of life of patients with cancer. Early surgical treatment allows mortality and morbidity improvement. Cervicomedullary Gamma locking nail osteosynthesis allows efficient, sustainable and stable fixation associated with early patient mobilization and survival improvement. However, prolonged survival imposes regular monitoring of the osteosynthesis in order to detect and to treat equipment failure. We should not overlook the fact that the recovery of independence after pertrochanterian fracture also influences myeloma control through the possibility to perform bone marrow autograft or not. PMID- 28904684 TI - Anaesthetic management for awake craniotomy in brain glioma resection: initial experience in Military Hospital Mohamed V of Rabat. AB - The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awake-awake-awake method. We describe our first experience with anesthetic management for awake craniotomy, which was a combination of these techniques with scalp nerve block, and propofol/remifentanil target controlled infusion. A 28-year-oldmale underwent an awake craniotomy for brain glioma resection. The scalp nerve block was performed and a low sedative state was maintained until removal of bone flap. During brain glioma resection, the patient awake state was maintained without any complications. Once, the tumorectomy was completed, the level of anesthesia was deepened and a laryngeal mask airway was inserted. A well psychological preparation, a reasonable choice of anesthetic techniques and agents, and continuous team communication were some of the key challenges for successful outcome in our patient. PMID- 28904685 TI - [Poorly tolerated broad QRS complex tachycardia in a newborn]. AB - Poorly tolerated broad QRS complex tachycardia in a newborn poses problems with its diagnosis and emergency management. We report the case of a 35-day-old newborn with broad QRS complex tachycardia admitted because of cardiocirculatory distress. Doppler echocardiography showed morphologically normal heart. The patient received a loading dose of amiodarone but it didn't attenuate tachycardia. Normal sinus rhythm was restored after cardioversion through Lifeline semi-automatic external defibrillator. Maintenance therapy was based on oral amiodarone. The patient had normal sinus rhythm at 03 months of follow-up. PMID- 28904686 TI - [Rare and severe complication of spinal anesthesia: bacterial meningitis (about a case and literature review)]. AB - Spinal anesthesia (SA) is the first locoregional anesthesia. It can cause side effects and carry risks that need to be avoided, prevented or treated early. We here report the case of a female patient operated under spinal anesthesia who had intense headache associated with nausea and vomiting evolving in the context of fever within a few days after surgeryLumbar puncture showed cloudy liquid revealing Gram + cocci on direct examination. This allowed the diagnosis of bacterial meningitis. Patient's evolution was favorable after antibiotic therapy. PMID- 28904687 TI - A case of reccuring giant condyloma of vulva in infant without sexual abuse successfully treated with electrocoagulation in Benin. AB - We report here a case of giant vulval condyloma in a two-year-old infant infected by her "baby sitter" without sexual abuse. Treated by surgical excision coupled with electrocoagulation, it was noted a rapid recurrence two weeks after treatment requiring a second electrocoagulation session. More than a year later, no lesion was noted, thus demonstrating therapeutic success. The unavailability of imiquimod in our context requires a systematic use of invasive treatment regardless of the age of the patient. PMID- 28904688 TI - Cellulitis in aged persons: a neglected infection in the literature. AB - Cellulitis is a frequent soft tissue and skin infection. The lower limbs are affected in 70 to 80% of cases. Cellulitis in aged persons is not yet well described in literature. A retrospective descriptive study conducted in the Internal Medicine Department of Sahloul hospital in Sousse in Tunisia. It included patients whose age was up to 65 years old admitted into hospital for cellulitis of the legs, the arms or the face. One hundred fifty eight patients with a mean age of 73 years old (range: 65 to 94 years old) were included. Female to male sex ratio was 0.68. Among them, we noted diabetes mellitus in 81 cases (50.6%). The infection was located in the lower limbs in 155 cases (98%), in the face in two cases (1.3%) and in the upper limb in one case (0.7%). Twenty one patients (13.3%) presented with severe cellulitis and one presented with necrotizing fasciitis. All patients received intra venous antibiotic therapy. Surgical treatment was indicated in 14 cases. Cefazolin was prescribed in 77 cases (48%). Favorable evolution was noted in 144 patients (91.1%). Forty four patients (27.8%) received prophylactic antibiotics. Prevention of skin and soft tissue infection is a crucial step to preserve health in aged persons. PMID- 28904689 TI - Severe neonatal cytomegalovirus infection: about a case. AB - Maternofoetal infection with Cytomegalovirus (CMV) is the most common congenital infection and a leading cause of mental retardation and sensori-neural hearing loss. Population-based studies indicate that at least 0.5% of all infants born alive have CMV of whom approximately 10% have clinically evident symptomsat birth. The Justification of systematic screening for foetal CMV infection is still controversial and is not recommended in most developed countries. This is mainly justified by the paucity of antenatal prognostic factors and the lack of established intrauterine treatment when foetal infection has been diagnosed. In case of congenital CMV infection, infants can be symptomatic or asymptomatic at birth. Mortality for such infants can reach 30%, and survivors can have mental retardation, sensorineural hearing loss, chorioretinitis, and other significant medical problems. A newborn symptomatic is defined by the existence of clinical and / or biological signs and / or neonatal imaging, the most frequent clinical signs are: hepatosplenomegaly (60%), microcephaly (53%), jaundice (67%), petechiae (76%), at least one neurological abnormality (68%). The frequency of biological abnormalities is as follows: increase in transaminases (83%), thrombocytopenia (77%), hyperbilirubinemia (69%), haemolysis (51%), hyperproteinorrachy (46%). The abnormalities of neonatal imaging are present in 70% of symptomatic newborns; intracerebral calcifications are the most frequent abnormalities. We report a case of newborn who presented a congenital infection by CMV, evoked on the intrauterine growth retardation, organs of the reticulo endothelial and haematological system were reached while nervous system was spared, and CMV PCR was very positive. indicating an antiviral treatment for 6weeks based on ganciclovir. PMID- 28904690 TI - [Mixed connective tissue disease: prevalence and clinical characteristics in African black, study of 7 cases in Gabon and review of the literature]. AB - The literature reports that mixed connective tissue disease seems more frequent in the black population and among Asians. This study aims to determine the prevalence of mixed connective tissue disease (MCTD) among connective tissue disorders and all rheumatologic pathologies in a hospital population in Gabon as well as to describe the clinical features of this disease. We conducted a retrospective study by reviewing the medical records of patients treated for mixed connective tissue disease (Kasukawa criteria) and other entities of connective tissue disorders (ACR criteria) in the Division of Rheumatology at the University Hospital in Libreville between January 2010 and December 2015. For each case of MCTD the parameters studied were articular and extra-articular manifestations, anti-U1RNP antibodies levels, patient's evolution. Over a period of 6 years, data were collected by medical records of 7 patients out of 6050 patients and 67 cases of connective tissue disorders, reflecting a prevalence of 0.11% and 10.44% respectively. the 7 patients were women (100%), with an average age of 39.5 years. Articular manifestations included: polyarthritis, myalgias, chubby fingers and Raynaud's phenomenon in 87.5%, 87.5%, 28.6% and 14% respectively. The 7 patients had high anti-U1RNP antibodies levels, ranging between 5 and 35N (N<= 7 IU). A case of death due to pulmonary arterial hypertension (PAH) was certified. This is the largest case series of MCTD reported in Black Africa. The disease seems to be rare among the black Africans; the reason could be genetic. The demographic and clinical aspects appear similar to those in Caucasians, Asians and Blacks except for a low frequency of Raynaud?s phenomenon among Blacks. PMID- 28904691 TI - IL-21 Augments Rapamycin in Expansion of Alpha Fetoprotein Antigen Specific Stem Cell-like Memory T Cells in vitro. AB - INTRODUCTION: Alloreactive tumor specific T cells are important arsenals of the adaptive immune system in the fight against tumors. However, stem cell-like memory T cells (Tscm) provide the key to effective elimination of tumor cells. Methods for generating these T cell subsets already exist. However, they could be made more efficient. Further, they are expensive and unattainable to the resource poor laboratories. In this regard, we are hereby describing a novel in vitro allogeneic co-culture method for raising allo-restricted tumor specific Tscm cells that we developed. METHODS: We started by obtaining PBLs that screened negative for HLA-A2 molecules from healthy donors followed by co-culture with T2/AFP cells to generate AFP peptide specific tumor-reactive T cells. Controls, IL-21 and/or rapamycin were applied to samples in 24 well plates. Samples were harvested and stained with anti-human CD3, CD8, CD44, CD62L, and HLA-A2/AFP dimer followed by flow cytometry analysis. Cell viability was measured by Trypan blue exclusion assay. One Way ANOVA and independent t test were used to compare the mean differences among and between groups where P values less than 0.05 were considered significant. RESULTS: Our results show that rapamycin arrests the differentiation of, and expands AFP specific Tscm cells. Further, the expansion of Tscm cells is augmented in the presence of IL-21. CONCLUSION: IL-21 and Rapamycin can be used concurrently to raise and maintain antigen specific Tscm cells in vitro for purposes of augmenting immunotherapy strategies against cancers. PMID- 28904692 TI - Evaluation of bacterial meningitis surveillance data of the northern region, Ghana, 2010-2015. AB - INTRODUCTION: Bacterial meningitis is a disease of major public health importance especially for countries such as Ghana; whose northern part lies within the meningitis belt. The Northern region of Ghana has been recording cases with outbreaks over the years. In order to generate evidence to improve surveillance, we described the epidemiology of bacterial meningitis using surveillance data of the northern region. METHODS: Bacterial meningitis datasets from January 2010 to December 2015 for all the 26 districts of the Northern region were retrieved from line lists. Data were analyzed in terms of person, place, time, and identity of causative organisms using descriptive statistics. The results were presented as proportions, rates, tables and graphs. RESULTS: A total of 1,176 cases were reported. Of these, 53.5% (629/1,176) were males. The proportion of cases aged 0 to 29 years was 77.4%. The Overall Case Fatality Rate (CFR) was 9.7% (114/1,176). About 65% of all cases were recorded from January to April. Only 23.7% (279/1,176) of cases were laboratory-confirmed. Neisseria meningitides and Streptococcus pneumonia accounted for 91.4% of confirmed cases. Over the period, the incidence reduced from 9.0/100,000 population to 3.8/100,000 population and CFR reduced from 16.6% to 5.7%. CONCLUSION: Most cases of bacterial meningitis were recorded in the dry season and in persons younger than 30 years. Less than a quarter of cases were laboratory confirmed, and no new bacteria species were identified. Both morbidity and mortality rates were on the decline. There is the need to consolidate these gains by intensifying meningitis surveillance and improving on the rate of laboratory case confirmation. PMID- 28904693 TI - [Gastrointestinal Stromal Tumors "GIST": status and news through our experience on 54 cases and review of literature]. AB - Tumors Gastrointestinal Stromal "GIST" are a very rare form of digestive tract cancers belonging to the family of sarcomas. The aim of this study is to establish the epidemiological profile, the diagnostic and therapeutic difficulties of this malignancy supported in a developing country. A retrospective study spread over 8 years from January 2002 to March 2010, was conducted at the Department of Radiotherapy and Oncology of Casablanca (Morocco) have collated 54 cases of Gastrointestinal Stromal tumors. The average age of our patients was 55 years. The average time of evolution was 11 months (0-72 months). The biopsy confirmed the diagnosis in 14 cases and surgery in 40 cases. The main histological form was fusiform (92.6%). GIST in our series had an average tumor size of 12.5 cm with a positive C-Kit in 52 cases. The risk of progression was established in 47 cases of which 39 were high risk. Surgery was the main treatment of patients in our study. After a mean fellow of 31 months, half of evaluable patients in our series (n = 19) is maintained complete remission, one third (n= 13) died while a quarter (n= 8) has a local recurrence and / or metastatic. Although the recommendations are published for the treatment of these tumors, these still present many problems both diagnostic and therapeutic in our context. PMID- 28904694 TI - [Bellini duct carcinoma: a new case study and literature review]. AB - Bellini duct carcinoma is a very rare type of renal cell carcinoma (RCC), accounting for less than 1%. It arises from the distal nephron, more specifically from the collecting duct. Its morphological features are extremely variable, making its diagnosis difficult. We report the case of a 62-year old patient admitted with a painless progressive left flank swelling. CT scan showed a huge mass occupying the upper portion of the left kidney. The patient underwent radical nephrectomy. Anatomopathological examination showed collecting duct carcinoma of the kidney. Patient's evolution was exceptionally favorable: no recurrence, no locoregional metastasis and no distant metastasis. PMID- 28904695 TI - A case of gestational gigantomastia in a 37-years-old woman associated with elevated ANA: a casual linkage? AB - Hypertrophy of the breast (macromastia and gigantomastia) is a rare medical condition of the breast connective tissues. The etiology of this condition is still not clear; rarely, gigantomastia has been reported to develop in the setting of an autoimmune illness. We reported a case of a 37-years-old woman with undifferentiated connective tissue disease of 2-years duration presented with enlargement of breasts. The breast enlargment started at 5 months of gestation. She successfully underwent reduction mammoplasty with free nipple graft. In the succeeding months the level of antinuclear ANA remained stable. It is uncertain whether a positive antinuclear antibodies in gigantomastia is a casuative agent or an effect. PMID- 28904696 TI - Health worker attrition at a rural district hospital in Rwanda: a need for improved placement and retention strategies. AB - INTRODUCTION: The shortage and maldistribution of health care workers in sub Saharan Africa is a major concern for rural health facilities. Rural areas have 63% of sub-Saharan Africa population but only 37% of its doctors. Although attrition of health care workers is implicated in the human resources for health crisis in the rural settings, few studies report attrition rates and risk factors for attrition in rural district hospitals in sub-Saharan Africa. METHODS: We assessed attrition of health care workers at a Kirehe District Hospital in rural Rwanda. We included all hospital staff employed as of January 1, 2013 in this retrospective cohort study. We report the proportion of staff that left employment during 2013, and used a logistic regression to assess individual characteristics associated with attrition. RESULTS: Of the 142 staff employed at Kirehe District Hospital at the start of 2013, 31.7% (n=45) of all staff and 81.8% (n=9) of doctors left employment in 2013. Being a doctor (OR=10.0, 95% CI: 1.9-52.1, p=0.006) and having up to two years of experience at the hospital (OR=5.3, 95% CI: 1.3-21.7, p=0.022) were associated with attrition. CONCLUSION: Kirehe District Hospital experienced high attrition rates in 2013, particularly among doctors. Opportunities for further training through Rwanda's Human Resources for Health program in 2013 and a two-year compulsory service program for doctors that is not linked to interventions for rural retention may have driven these patterns. Efforts to link these programs with rural placement and retention strategies are recommended. PMID- 28904697 TI - [Acromegaly features in the aging population]. AB - Somatotroph adenomas are rare in the aging population. Diagnosis of somatotroph adenomas is often long delayed and they are characterized by atypical clinical picture. Their diagnostic criteria are similar to those used for younger patients. Surgery, if possible, is the treatment of choice for acromegaly in the elderly. Somatostatin analogues have shown to be effective in these patients. Prognosis is inversely correlated with patient's age, duration of disease and last GH level under treatment. Beside evolution of disease, age is a major determinant of mortality. We report three cases of elderly patients with acromegaly aged 75, 70 and 66 years respectively with a literature review. PMID- 28904698 TI - HIV-related knowledge, attitude and practices of healthy adults in Cross River State Nigeria: a population based-survey. AB - INTRODUCTION: Human Immunodeficiency Virus (HIV) remains a global health problem disproportionately distributed across Nigeria. Cross river state (CRS), a tourist state, located in the Niger delta, has one of the highest prevalence rates. There is evidence that poor knowledge and stigmatization are obstacles to achieving universal access to HIV prevention programs. The objective of this study was to determine the Knowledge, Attitude and Practice (KAP) of HIV among adults resident in CRS, Nigeria. METHODS: A cross sectional descriptive survey design was employed. A total of 1,620 healthy adults were recruited. KAP towards HIV was assessed using a structured pre-tested questionnaire. Categorical variables were described as frequencies and continuous variables as median and interquartile range. Kruskal-Wallis test was used to determine relationship between variables and median KAP scores. P value < 0.05 was considered significant. All analyses were performed using Stata 12 statistical package. RESULTS: A total of 1,465 respondents completed the questionnaire correctly giving a response rate of 91%. The M: F ratio was 1:1.8. The median age was 38 years. Majority was married and had formal education. Knowledge of HIV and common routes of transmission was high (>80%). However, misconception that HIV can be transmitted through hugging, hand shake, mosquito bites and witch craft was also common (> 60%). The overall attitude and practice towards persons living with HIV infection was poor. CONCLUSION: This study showed misconceptions in the knowledge and consequences of HIV infection which is associated with negative attitude towards persons living with HIV. PMID- 28904699 TI - Primary spinal marginal zone lymphoma: an unusual cause of spinal cord compression. PMID- 28904700 TI - Descriptive epidemiology of a cholera outbreak in Kaduna State, Northwest Nigeria, 2014. AB - INTRODUCTION: Cholera is an acute gastrointestinal infection caused by Vibrio cholerae, which may lead to severe dehydration and death if not treated. This analysis is aimed at highlighting the magnitude, pattern and trend of cholera outbreak that occurred in Kaduna State in 2014. METHODS: We obtained the 2014 cholera line-list from the Kaduna State Disease Surveillance and Notification officer (DSNO). We described the outbreaks in time, place and person using Epi info 7 and Health Mapper. RESULTS: A total of 1468 case-patients and 54 deaths were recorded, giving a case fatality rate (CFR) of 3.68%. Female case-patients were 809(55.08%). The median age for case-patients was 15 years, with an age range of 0.04-90 years. Age specific case fatality rate (ASCFR) is highest among the > 60 years. Seven (30%) out of the 23 local government areas (LGAs) in Kaduna State were affected by the cholera outbreak in 2014. Igabi LGA has the highest attack rate (150.46 per 100,000 population) while Chikun LGA has the lowest attack rate (12.22 per 100,000 population). Chikun LGA records the highest CFR (17.54%). Cholera infection spread across LGAs sharing the same borders. The outbreak started from the first epidemic week of 2014 and lasted over 33 weeks. CONCLUSION: Our analysis revealed a protracted cholera outbreak that gradually increases in magnitude throughout the first half of 2014 and spread within contiguous LGAs. We recommended the strengthening of the state's diseases surveillance system towards timely detection and early response to disease outbreaks in the future. PMID- 28904701 TI - Laparoscopic evaluation and management of isolated gastric rupture in a boy after blunt abdominal injury. AB - Blunt abdominal injury in children can be a significant diagnostic and therapeutic challenge. The extent and localization of organ damage cannot be always thoroughly investigated noninvasively and in spite of modern imaging techniques and a laparotomy may be necessary for diagnosis, even though it carries a significant morbidity. We present a rare case of isolated gastric rupture after blunt abdominal injury in a 12 year old boy that sustained a bicycle accident. He was hemodynamically stable, had signs of acute abdomen and axial tomography was inconclusive as of the site of visceral perforation. Definitive diagnosis and treatment were carried out laparoscopically with excellent results. Laparoscopic surgery in cases of blunt abdominal injury with gastric rupture can serve both as a diagnostic and therapeutic modality with the additional advantage of being less traumatic. The accumulation of relevant experience is mandatory in order to establish this modality in the diagnostic and therapeutic protocols. PMID- 28904702 TI - [Leprosy in children in the region of Thies, Senegal: study determining whether or not it is a signal of recrudescence]. AB - Leprosy is an infectious and transmissible disease. According to the WHO, the number of new cases of leprosy in children in Senegal has risen moderately since 2013. This study aimed to analyze the epidemiological, clinical, therapeutic and evolutionary features of leprosy in children in the geographical areas of two social rehabilitation villages in the region of Thies. We conducted a retrospective study over a period of 3 years (2013-2015). All new cases of Hansen's disease aged 0 -15 years were included. Over the three year period, 39 children were included in the study, with a boy predominance (n=23, 59%). Among these children, 27 (66.7%) came from a social rehabilitation village for leprosy patients. One family member was affected by leprosy in 27 cases (69.2%). More than half of the children (23 cases, 58.9%) had multibacillary leprosy (lepromatous-lepromatous). All children underwent a 12-month treatment, at the end of which thirty-six (92.3%) children were healed. Leprosy is still present in Senegal despite the efforts made by the national programme to combat leprosy. In the light of these results, it is important to emphasize the role of active screening strategy targeted to children, which seems to have shown its effectiveness in the region. Early detection, contact tracing and early treatment are important factors in the reduction of the contagiousity of leprosy. PMID- 28904703 TI - Patient satisfaction with the perioperative surgical services and associated factors at a University Referral and Teaching Hospital, 2014: a cross-sectional study. AB - INTRODUCTION: Globally, increasing consideration has been given to the assessment of patient satisfaction as a method of monitor of the quality of health care provision in the health institutions. Perioperative patient satisfaction has been contemplated to be related with the level of postoperative pain intensity, patients' expectation of the outcome, patient health provider relationship, inpatient services, hospital facilities, access to care, waiting time, cost and helpfulness of treatments received. The study aimed to assess the level of patient satisfaction with perioperative surgical services and associated factors. METHODS: Hospital based quantitative cross-sectional study was conducted in University of Gondar teaching hospital from April1-30, 2014. Structured Amharic version questionnaire and checklist used for data collection. All patients who operated upon during the study period were included. Both bivariate and multivariate logistic regression model used to identify the variables which had association with the dependent variable. P-values < 0.05 were considered statistically significant. RESULTS: Two hundred and seventy eight patients underwent surgery during the study period. Nine patients were excluded due to refusal to participate in the study. A total of 269 out of 278 patients were included in the study with a response rate of 96.8%. The overall level of patient satisfaction with perioperative surgical services was 98.1%. The variables that had association with the outcome variable from the multivariate analysis were patient admission status (AOR=0.073, CI=0.007-0.765, P=0.029), information about the disease and operation (AOR=0.010, CI=0.001-0.140, P=0.001) and operation theatre staff attention to the patients complains (AOR=0.028, CI=0.002-0.390, P=0.008) respectively. CONCLUSION: The level of patient satisfaction with perioperative surgical services was high compared with previous studies conducted in the country and other countries in the world. Health professionals need to give emphasis for information on care provision processes, patients' health progress and patients' complaints. PMID- 28904704 TI - [Prolactin-secreting microadenoma in menopausal women]. AB - Prolactin-secreting adenoma is rare in elderly women. Patient's clinical picture may be confused with that of menopause, making diagnosis sometimes difficult. We report the case of a 57-year old woman with a 2-year history of secondary amenorrhea without hot flushes associated with galactorrhea in order to highlight the peculiarities of prolactin-secreting microadenomas. Physical examination confirmed the diagnosis of galactorrhoea and biology showed hyperprolactinemia at mIU/L, FSH = 15.1 IU/L and LH = 4,1 IU/L. Pituitary MRI showed left adenoma measuring 8 mm. Patient's evolution under dopaminergic treatment was marked by the recovery, for a transitional period, of mestrual cycles and the occurrence of hot flushes, normalization of prolactin levels and reduction of adenoma size. PMID- 28904705 TI - A study to determine the prevalence and factors associated with hypertension among employees working at a call centre Nairobi Kenya. AB - INTRODUCTION: Hypertension often referred to as Non Communicable Diseases (NCDs). Causes of hypertension are classified into modifiable and non-modifiable factors. The objective of the study was to determine the prevalence and other associated factors leading to the onset of hypertension among employees working at the call center. METHODS: This was a descriptive cross sectional study design. Data collection was done in two parts; part one comprised of clinical health assessments; weight and height to aid determine Body Mass Index and blood pressure measurement. Part two was by self-administered questionnaires to participants to aid identify behavioral risk factors and further elicit lifestyle practices. Data was collected from a sample population of 370 respondents. Descriptive statistical analysis was applied in univariate analysis. Further analysis included bivariate and multiple regression analysis; Odds Ratio with 95% confidence interval was used to determine the strength of association. RESULTS: The proportion of hypertension was significantly higher among overweight respondents (32.7%) (OR= 11.55; 95% CI= 4.44-30.07; P < 0.001) and obese respondents (60.2%) (OR= 36.02; 95% CI= 13.43-96.60; P < 0.001) compared to those respondents who were within normal range of weight (4.0%). Nine (9) factors that were associated with hypertension at bivariate analysis (P < 0.05) were all subjected to a multiple regression analysis or reduced model where four factors remained in the final analysis. Respondents who were classified as overweight had 10.6 times likelihood developing hypertension compared to those respondents with normal weight (AOR= 10.61; 95%CI= 3.98-28.32; P < 0.001). Likewise, obese respondents were 43.6 fold more likely to develop hypertension compared to those respondents within normal range of weight [OR=43.68; 95%CI=15.24-125.16; P<0.001]. Respondents not trying to reduce fat in their diet were highly predisposed having hypertension at (AOR=2.44; 95% CI=1.20-4.96; P= 0.014) than respondents who always tried to reduce fat in their diet. Respondents who sometimes engage on more physical exercises were 2.2 times likely to develop hypertension (AOR=2.22; 95%CI= 1.20-4.10; P= 0.011) compared to those who always engaged in more physical exercises. Respondents with parenting issues were about twice as likely to have hypertension (AOR= 2.15; 95% CI: 1.23-3.74; P= 0.007) than parents who did not have parenting issues. CONCLUSION: This study depicts rising cases of hypertension and an alarming rate of pre-hypertension among the working population. This vary based on the age, obesity, parental responsibility, unhealthy diet and lack of or reduced physical activity. These call for strategic interventions and greater emphasis on health promotion programs at the workplace alongside staff empowerment towards health seeking behaviors. PMID- 28904706 TI - [When the denture becomes dangerous!] AB - Although rare in adults, foreign body aspiration (FBA) is a serious accident which can be potentially life threatening or lead to significant sequelae. We report the case of a 50 year old patient without previous pathological history, presenting to the emergency department with chest pain, intermittent cough and exertional dyspnea occurring six days after the accidental aspiration of his plastic dental prosthesis during a meal. Clinical examination was unremarkable. Chest X-ray as well as abdominal x-ray requiring no prior preparation showed no abnormalities. Flexible bronchoscopy under general anesthesia showed FBA at the level of the intermediate trunk. Successful extraction was performed avoiding a much more invasive procedure. Standard X-ray can be useful to visualize radio opaque FBA or indirect signs suggesting the presence of FBA, but diagnostic and therapeutic bronchoscopyis is essential. PMID- 28904707 TI - Perspectives on utilization of community based health information systems in Western Kenya. AB - INTRODUCTION: Health information systems (HIS) are considered fundamental for the efficient delivery of high quality health care. However, a large number of legal and practical constraints influence the design and introduction of such systems. The inability to quantify and analyse situations with credible data and to use data in planning and managing service delivery plagues Africa. Establishing effective information systems and using this data for planning efficient health service delivery is essential to district health systems' performance improvement. Community Health Units in Kenya are central points for community data collection, analysis, dissemination and use. In Kenya, data tend to be collected for reporting purposes and not for decision-making at the point of collection. This paper describes the perspectives of local users on information use in various socio-economic contexts in Kenya. METHODS: Information for this study was gathered through semi-structured interviews. The interviewees were purposefully selected from various community health units and public health facilities in the study area. The data were organized and analysed manually, grouping them into themes and categories. RESULTS: Information needs of the community included service utilization and health status information. Dialogue was the main way of information utilization in the community. However, health systems and personal challenges impeded proper collection and use of information. CONCLUSION: The challenges experienced in health information utilization may be overcome by linkages and coordination between the community and the health facilities. The personal challenges can be remedied using a motivational package that includes training of the Community Health Workers. PMID- 28904708 TI - [Latissimus dorsi flap in reconstruction following treatment of giant tumor of the abdominal wall: about a rare case]. AB - We report the case of a 16-year old patient presenting with giant, multinodular, mesenchymal tumor of the abdominal wall occupying the left abdominal region and measuring 25 cm on the vertical axis, 20 cm on the transverse axis, mobile when compared with the deep structures and gradually increasing in volume over childhood and neglected. After small biopsy, which showed desmoid tumor, the patient underwent complete surgical resection of the tumor with immediate reconstruction by free muscolo skin flap of the latissimus dorsi attached to the large blood vessels of the inguinal fold (left iliac artery and left external iliac vein), connected by termino lateral anastomosis. Flap survival was correctly performed and reconstruction was successful. PMID- 28904709 TI - [Factor V congenital deficiency: about a case]. AB - Factor V congenital deficiency is a rare coagulation disorder initially described by Owren in 1947 and known as para hemophilia. It is transmitted through autosomal-recessive inheritance and homozygous cases are usually symptomatic. Factor V is an essential cofactor in the conversion of prothrombin to thrombin by activated factor X. In the absence of factor V, thrombin generation is slowed down and fibrin formation is delayed. This results in a bleeding tendency. We report a case of factor V congenital deficiency in an infant with recurrent epistaxis. PMID- 28904710 TI - Self-medication and its risk factors among women before and during pregnancy. AB - INTRODUCTION: Self-medication can cause significant challenges for the individuals and community, especially in women during pregnancy. This study was aimed to compare the prevalence of self-medication before and during pregnancy among women in Iran. METHODS: in this cross-sectional study, a total of 384 pregnant women were evaluated for the prevalence of self-medication and its associated factors before and during pregnancy. Stratified random sampling was used as the sampling method. Descriptive statistics and chi-square and logistic regression tests were used for statistical analysis of data. RESULTS: The results showed that the prevalence of self-medication, in women who had become ill at least once, was 63.9% before pregnancy and 43.5% and during pregnancy. Variables such as lack of insurance, high school education and not having a child increased odds ratio of self-medication before pregnancy, while the variables of lack of insurance, not having a child or fewer number of children and no history of abortion increased the odds ratio of self-medication during pregnancy. CONCLUSION: Although the prevalence of self-medication during pregnancy was less than that before pregnancy, but this prevalence during pregnancy was still significant. Therefore, it seems necessary to provide public trainings for all women of reproductive age and train them about the dangers and side effects of self-medication. PMID- 28904711 TI - Factors determining late antenatal care booking and the content of care among pregnant mother attending antenatal care services in East Wollega administrative zone, West Ethiopia. AB - INTRODUCTION: Antenatal care (ANC) is important for both maternal and fetal health. However, the existing evidence from developing countries indicates that most pregnant women attending ANC in their late pregnancy. Little is known about the factors determining ANC booking and the content of care among pregnant women in West part of Ethiopia. Therefore, the present study was conducted to identify factors determining late ANC booking and the content of care among pregnant mother attending antenatal care services in East Wollega administrative zone, West Ethiopia. METHODS: Institutional based cross-sectional study was conducted from July to September, 2014 among 421 pregnant women's attending ANC services in purposively selected health facilities, East Wollega zone, Ethiopia. The pretested-structured questionnaires were used to collect socio-demographic data and predictor factors of late initiation of ANC services. Five trained nurse working at ANC clinic at each health institution administered the questionnaire. The collected data was analysed using SPSS version 20. RESULTS: The prevalence of late ANC booking was 81.5% (343/421) in the study area. Being from Oromo ethnic group (AOR 4.27, (95% CI, 1.48-12.33)), maternal age equal or more than 25 year old (AOR 3.09 (95% CI, 1.53-6.27)), second trimester (AOR 6.05(95% CI, 3.08 11.88)) and third trimester (AOR 7.97 (95% CI, 3.92-16.23)) were main factors identified as contributing (favoring factors) for the likely occurrence of late booking for ANC whereas; monthly income more than and/or equal to 15000 Ethiopian birrs (AOR 0.38 (95% CI, 0.18-084)) were factors compromising (decreasing) the chances for late attendance for the services among the pregnant women. CONCLUSION: Late ANC initiation is high in the study area despite the services is provided free of charge. Hence, it is important to provide health education on the timing of ANC among women with reproductive age. Community's awareness on importance of receiving early ANC also needs to be promoted. PMID- 28904712 TI - [Colonic gallstone ileus: a rare cause of colonic obstruction]. AB - Bile ileus with migration of the gallstone into the colon through cholecystocolonic fistula is rare. The diagnosis is difficult and often late. We here report the case of a 89-year old patient with a history of sigmoid diverticular disease presenting with colonic obstruction associated with bile ileus caused by migration of a large gallstone through cholecystocolonic fistula. Abdominal CT scan allowed the diagnosis. The patient underwent surgical extraction of the gallstone with sigmoidotomy followed by sigmoidostomy with subsequent recovery of the digestive continuity. The cholecystocolonic fistula wasn't identified. PMID- 28904713 TI - [Chase's amputation in a patient with melanoma on the index finger: about a case]. AB - We report the case of a 40-year old patient referred by the Depatment of Dermatology at the Ibn Sina Hospital in Rabat for amputation of the index finger as a result of a melanoma diagnosed by biopsy. The amputation was performed according to Chase's method. Aesthetic and functional outcome was very good six months following surgical treatment. PMID- 28904714 TI - [The overweight, the obesity and the glycemic control among diabetics of the provincial reference center of diabetes (CRD), Kenitra, Morocco]. AB - INTRODUCTION: Diabetes is a disorder of assimilation, use and storage of sugars provided in the diet. Its management is based on follow-up of overweight and obese patients and on regular glycemic control. This study aimed to analyze overweight, obesity and glycemic control in 2227 patients with different types of diabetes (type 1, 2 and gestational) presenting to the Provincial referral center of diabetes (RCD) in Kenitra, Morocco. METHODS: We conducted a study over the period January-December 2015. Overweight and obesity assessment was performed using Body Mass Index calculator (BMI = weight/height2 (kg/m2). Overweight and obesity were defined by BMI > 25 kg/m2and BMI > 30 kg/m2 respectively; the weight and the height were measured according to World Health Organization's recommendations. Glycemic control was based on glycated hemoglobin levels and fasting blood glucose test. Current guidelines recommend a glycosylated hemoglobin level of 7% and a fasting blood glucose of 0.70g/l - 1.10g/L. RESULTS: The age of patients ranged from 8 months to 80 years, with a prevalence of diabetic patients from the urban environment (74%) compared to those from the rural areas (26%). The entire study population was overweight. The average BMI of women showed a trend toward obesity (BMI~30): (29.21 kg/m2 +/- 3,1) in patients with gestational diabetes and (29.15 kg/m2 +/- 3.2) in patients with type 2 diabetes. Blood sugar levels were above the standards: 8.5% +/- 2.6 > 7% for glycosylated hemoglobin and 1.5 g/L +/- 1.3>1.10g/L for fasting blood glucose. The difference between glycosylated hemoglobin levels between men (8.57% +/- 2.6) and women (8.1% +/- 2.3) were not significant (p > 0.05), it was the same with fasting blood glucose: men (1.44 g/L +/- 1,1) and women (1.43 g/L +/- 1.2). Pearson's correlation coefficients were highly significant (p<0.005); on the one hand between BMI and fasting blood glucose(r = 0.5) and on the other hand between BMI and glycosylated hemoglobin levels (r = 0.4). CONCLUSION: The entire study population had BMI and glycaemic control levels above the standards. More research is needed on diabetic patients in order to develop a remediation plan. PMID- 28904715 TI - Awareness of hypertension and its impact on blood pressure control among elderly nigerians: report from the Ibadan study of aging. AB - INTRODUCTION: Hypertension is highly prevalent among the elderly. Its awareness has a direct influence on control through drug adherence. Earlier studies have shown that awareness of hypertension is low among sub-Saharan African populations but only a few studies have looked at the prevalence and awareness of hypertension among the elderly. METHODS: The Ibadan Study of Ageing is a longitudinal cohort study of the mental and physical health status as well as the functioning of elderly persons residing in the Yoruba-speaking areas of Nigeria. Study was conducted in multiple waves from 2003/2004 to 2009. This report is based on the sample studied in 2007 (N = 1469). Respondents, aged >= 65 years, were assessed for the presence of hypertension, its awareness, receipt of and adherence to medication for the condition, and effectiveness of treatment on the control of blood pressure. Blood pressure was measured with the use of digital monitors (Omron MS - 2 Basic Model). Awareness of the diagnosis of hypertension was ascertained by self-reports. We explored social, economic, demographic and clinical correlates of the presence of hypertension, its awareness and control using multiple logistic regression analyses. RESULTS: The sample was composed of 809 (55.1%) females and 666 (44.9%) males. The mean age of the participants was 76.9 +/- 8.4 years. Hypertension (defined as previous diagnosis by a health provider or a measured blood pressure higher than or equal to 140/90 mm Hg) was recorded in 973 (62.2%) participants, with females having a prevalence of 61.4% and males that of 70.1%. Other than female gender, residing in urban/semi urban areas and being overweight or obesity were associated with the occurrence of hypertension. Among those assessed to have hypertension, 78% were not previously aware of its presence. Factors independently associated with lack of awareness of hypertension included low socioeconomic class (OR 8.21, 95% CI 3.72-18.11, P < 0.001), and BMI >25kg/m2 (OR 3.11, 95% CI 1.36-7.09, P < 0.009). Among those who were aware of the presence of hypertension and were on treatment, 77.3% still had uncontrolled hypertension. Only obesity or overweight (OR 5.56, 95% CI 1.35 - 22.83, P < 0.016) was independently associated with poor blood pressure control. CONCLUSION: The prevalence of hypertension among elderly Nigerians is high and those affected are often not aware of having the condition. Only a minority of those who receive treatment for the condition have adequate blood pressure control. The findings highlight the need for improved healthcare for the growing population of elderly persons, with particular attention to early detection and effective control of the condition. PMID- 28904716 TI - [Supracricoid partial laryngectomy (SCPL) with either cricohyoidoepiglottopexy (CHEP): our experience with 16 cases]. AB - Partial laryngectomy with either cricohyoidoepiglottopexy (CHEP) are mainly used to treat glottic cancers becuse they ensure a satisfactory preservation of physiological functions and satisfactory local carcinologic control. Our study aimed to analyze the functional and carcinologic results of this surgical technique. We conducted a retrospective study of patients undergoing partial laryngectomy with either cricohyoidoepiglottopexy in our Hospital between 2011 and 2014. We analyzed the epidemiological data, the surgical peculiarities, the functional outcomes and the carcinologic control of the disease. A total of 16 patients were included in this study. All our patients had T1 or T2 glottis squamous cell carcinoma. Functional outcomes were generally simple, especially in cases where the preservation of the 2 cricoarytenoid units was possible (75% of cases). However post-operative complications were reported in 31.25%. Carcinologic control was satisfactory, only one patient experienced local recurrence. Partial laryngectomy with either cricohyoidoepiglottopexy (CHEP) is a safe surgery preserving physiological functions and ensuring satisfactory quality of life. It also allows for good carcinologic control (it is subject of course to compliance with surgical indications). PMID- 28904717 TI - Aseptic meningitis following a bupivacaine spinal anesthesia. AB - Spinal anesthesia complicated by meningitis is rare. The diagnosis is difficult and the clinical signs are unspecific. There is a subgroup called aseptic meningitis of a different mechanism (hypersensitive reaction and irritation of the meninges), which must be identified for appropriate care. We report the case of aseptic meningitis resulting from bupivacaine use complicating spinal anesthesia. She is 31 years old and was admitted to the intensive care unit for meningitis following a Caesarean delivery. 10 hours after the procedure, she was found to have severe headache, neck stiffness and was found restless. She lost consciousness; she was treated by attending physicians. A CT scan have been performed and was found normal. 24 hours after intubation, the patient woke up. The clinical and biological valuations were normal, allowing for the elimination of the other causes of meningitis. PMID- 28904718 TI - [Intrauterine device: about a rare complication and literature review]. AB - The intrauterine device (IUD) is the most common contraceptive method used in the world. Transuterine migration is a rare complication, accounting for 1/350 - 1/10000 insertions in the literature. We report the case of a 40-year old patient, who had had an IUD insertion 12-year before, presenting with pelvic and right lower back pain associated with intermittent hematuria and burning during urination. Radiological assessment showed calcific deposits on intra bladder IUD. The patient underwent cystostomy, without any difficulty, allowing stone and IUD extraction. A urinary catheter was left in place for 5 days and then withdrawn. The postoperative course was uneventful. PMID- 28904719 TI - About a rare complication of spondyloarthritis. PMID- 28904720 TI - Lodox reveals the ideal body. PMID- 28904721 TI - Septal alcoholization in hypertrophic cardiomyopathy: about 11 cases. AB - Outcomes of septal alcoholization in hypertrophic obstructive cardiomyopathy are not enough studied in all centers. The purpose of this study was to determine the outcomes of septal alcoholization in hypertrophic obstructive cardiomyopathy in our hospital. A retrospective and prospective descriptive study focused on all patients aged at least 18 years treated by alcohol septal ablation between July 2005 and June 2010 in the cardiology unit of Clermont-Ferrand teaching Hospital. The inclusion criteria were, hypertrophic obstructive cardiomyopathy with left ventricular outflow tract obstruction >= 50 mmHg, symptomatic despite optimal medical therapy. The clinical, paraclinical data and the results of alcohol ablation were collected from medical records of patients and a telephone conversation with the patients or their physicians. These data were analyzed by EPI info 6.04. Eleven patients with average age of 56.27 +/- 15, 83 were included of which 81.8% of men. The main indications of alcohol septal were dyspnea stage NYHA II-IV (45.5%), lipothymia (18.2%) and invalidating angina (18.2%). Main electrocardiographic abnormalities were left ventricular hypertrophy and disorders of repolarization with 72.7% each. Minor conductive disorders were found in 45.5% of the cases. The left ventricular outflow tract obstruction was 98.18 +/- 25.93 mmHg before alcohol septal ablation and 18.91 +/- 31.97 mmHg after a follow-up of 25.64 +/- 21.97 months. The success rate was 81.8%. Conductive disorders (45.5%) required the establishment of a definitive pacemaker in 36.4% of the patients. A cardiac defibrillator was implanted at 27.3%. Septal alcoholization was succesful. PMID- 28904722 TI - [Normal adnexal torsion and pregnancy: about a case]. AB - Normal adnexal torsion is rare during pregnancy. We here report the case of a 22 year old patient presenting with acute lateropelvic pain associated with a 2 month history amenorrhea. Exploratory laparotomy showed severe ischemia due to torsion in a normal ovary. The patient underwent adnexal detorsion without ovarian pexy. The postoperative course was uneventful. Ultrasound examination after 3 weeks showed normal pregnancy. Ovarian torsion is an emergency that should not be ignored in pregnant women with acute pelvic pain. Conservative treatment is the gold standard and proper management is necessary to avoid possible maternal and fetal complications. PMID- 28904723 TI - Osteogenesis imperfecta Type IV: a newly identified variant at position c.560 (G > T; p.Gly187Val) in the COL1A2 gene. AB - Osteogenesis imperfecta is a clinically heterogenous disease caused by defective collagen syntesis associated with a mutation in the COL1A1 or COL1A2 genes. In this report, we present a case of osteogenesis imperfecta (OI) type IV, seen in a female fetus with incurved femurs at 18 weeks of gestation. Molecular analysis of the newborn revealed a novel mutation at position c.560 (c.560 G > T) of the exon 12 in the COL1A2 gene; which lead to the glycine modification with valine (p.Gly187Val) at codon 187. The pregnancy follow-up was uneventful. After delivery, the newborn underwent biphosponat therapy and no fracture was detected until 1 year old. PMID- 28904724 TI - Treatment of high-energy pilon fractures using the ILIZAROV treatment. AB - The management of high-energy pilon fractures is still controversial. Open reduction and internal fixation are often associated with serious complications. Various methods have been used to treat these injuries, with variable results. The aim of this retrospective study was to analyze the clinical and radiographic outcome of the ILIZAROV technique in patients with high-energy pilon fractures. Thirty cases of distal tibia epiphysis fractures (pilon fractures) were managed from 1999 to 2012. The study group included 5 cases of open fractures. The mean age was 47 years. According to Ruedi and Algower classification; 11 fractures were type II, and 19 type III. All fractures were a consequence of high-energy trauma. Fractures of the lower fibula were present in 28 of the patients. An external Fixator was applied for open fractures. Closed injuries were operated on 3 to 13 days after injury, with an average of 8 days. The mean follow-up was 48 months. All fractures united. The external fixator was removed after a mean of 22 weeks (10 - 28 weeks). Two patients with a type III fracture had a delayed union and were treated with corticotomy and dynamisation of the ILIZAROV fixator. Only one secondary displacement of a type III fracture was noted after two months and was treated by adjuction of 2 olive wires. There were no cases of osteomyelitis or deep infections. Pin-tract infections occurred in ten patients. We had not any case of nervous injury due to introduction of the pins. Using radiological criteria for assessement of reduction of the articular fragments, there was excellent and good restoration of articular structure in 24 cases. The average American Orthopeadic Foot and Ankle Society ankle-hind foot score was excellent in 16, good in 6, fair in 6 and poor in 2. Soft tissue healing occurred without need for plastic surgery in all cases. The movements of the ankle ranged from 0 to 20 degrees of dorsiflexion and 5 degrees to 40 degrees of plantar flexion. Twenty patients had gone back to their preinjury profession. The ILIZAROV technique is a safe and a very effective treatment for severe pilon fractures with minimum complications and good healing results. PMID- 28904725 TI - [Hidradenitis suppurativa and psoriasis: manifestation of a hidden disease]. PMID- 28904726 TI - Radiographic determination of cardiomegaly using cardiothoracic ratio and transverse cardiac diameter: can one size fit all? Part one. AB - INTRODUCTION: The cardio-thoracic ratio (CTR) and the transverse cardiac diameter (TCD) on Plain chest radiography are the two parameters commonly used to diagnose cardiomegaly and heart disease. A CTR of greater than 50% on a PA film is abnormal and normally indicates cardiac or pericardial disease condition, whiles an increase of TCD from 1.5 to 2cm on two consecutive radiographs, taken at short interval, suggests possible cardiac pathology. The aim was to determine the suitability of using the same TCD and CTR to detect cardiomegaly for all age groups and genders respectively. METHODS: A retrospective study involved the review of 1047 radiological images of adults aged 21 to 80 years, who had plain postero-anterior chest radiographs between January 2012 and November 2013 by 3 radiologists. Data recorded included the transverse cardiac, thoracic diameter and the cardiothoracic ratios. Descriptive analyses were carried out using the Microsoft excel 2010. RESULTS: The mean age and standard deviation for the study population was 35.1 +/- 12.7. The mean and standard deviations for the transverse cardiac diameter, thoracic diameter, and the cardiothoracic ratios for male participants were 13.08cm +/- 1.2, 29.7cm +/- 2.7 and 46.6% +/- 3.9; and 12.9 cm +/- 1.3, 27.1 cm +/- 2.6, and 47.8% +/- 4.8 for females. An increase in TCD of 1cm resulted in a CTR of greater than 50.0% in all but the males aged 21-40 years. CONCLUSION: The study found that the same TCD and CTR values are not suitable in detecting cardiomegaly for all age groups and genders. PMID- 28904727 TI - Post-ivermectin encephalopathy in Senegal: a case report. AB - Ivermectin is an ant parasitic drug used for combating onchocerciasis and lymphatic filariasis. It works by inhibiting the function of neurons and muscles, thus causing paralysis of microfilariae. Side effects of this drug have been reported including post-ivermectin encephalopathy requiring emergency care in hospital. We report the case of a 35 years old patient living in rural areas of Senegal who presented two days after a mistake in administration of a second dose of ivermectin, headaches, altered consciousness and bilateral blindness. The workup revealed brain white matter lesions, abnormal liver function tests and biological inflammation without evidence of Loa loa microfilariae in blood and cerebrospinal fluid. Corticosteroid treatment was administered in emergency and patient recovered despite the persistence of bilateral blindness. Inflammatory process seems to have an important role in the pathophysiology of this encephalopathy. We should therefore carefully control the administration of this drugs. PMID- 28904728 TI - Evaluation of the acute flaccid paralysis (AFP) surveillance system, Gokwe North district, Zimbabwe, 2015: a descriptive cross sectional study. AB - INTRODUCTION: AFP surveillance was adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Gokwe North district with an estimated 119 655 children <15 years detected 2 cases, 4 cases and 1 case of AFP in 2012, 2013 and 2014 respectively against a target of 5 cases per year. We therefore set out to evaluate the system and find out why it was failing to detect at least 5 cases per year. METHODS: A descriptive cross sectional study was carried out. All three hospitals in the district were purposively selected. Twelve of the nineteen health facilities were randomly selected and forty nine health workers were purposively recruited. An interviewer administered questionnaire and key informant interview guide were used to collect data. Quantitative data was analysed using Epi info. RESULTS: Out of the 49 respondents, 17(34.7%) knew the target age group for AFP surveillance. Twelve (24.5%) knew the number of notification forms to be filled. Seven (14.3%) and ten (20.4%) respondents knew when to follow up an AFP case and when an AFP case should be followed up and completely notified and investigated respectively. Forty one (83.7%) respondents were not trained on AFP surveillance. Nineteen (39%) had AFP notification forms at the clinic and 33(67%) had displayed AFP case definitions. All the 22 health facilities in the district participate in AFP surveillance; however, all have hard to reach areas. Seventeen (34.7%) reportedly took public health actions based on AFP data. CONCLUSION: The system was found to be useful, simple, acceptable, timely, unstable, not representative and not sensitive. The system was threatened by lack of health worker knowledge and community active search. Advocacy, communication and social mobilization on AFP surveillance might improve the performance of the system in Gokwe North district. PMID- 28904729 TI - Evaluation of the maternal mortality surveillance system in Mutare district, Zimbabwe, 2014-2015: a cross sectional study. AB - INTRODUCTION: In Zimbabwe the integrated disease surveillance and response guidelines include maternal mortality as a notifiable event reported through the Maternal Mortality Surveillance System (MMSS). A preliminary review of the MMSS data for Mutare district for the period January to June 2014 revealed that there were some discrepancies in cases notified and those captured on the T5 monthly return form. There were also delays in reporting of some maternal deaths. Poor reporting indicated shortcomings in the MMSS in Mutare district and we therefore sought to assess the performance of the maternal mortality surveillance system in Mutare district. METHODS: A descriptive cross sectional study was conducted using Centers for Disease Control and Prevention updated guidelines for evaluating public health surveillance systems. A total of 64 health workers were enrolled into the study from 19 selected health facilities in Mutare district and 32 maternal death notification forms submitted in 2014 to the provincial office were reviewed to assess the quality of information on the forms. Interviewer administered questionnaires were used to collect information from enrolled health workers, the system's attributes namely usefulness, acceptability, simplicity, stability, data quality, timeliness and completeness were assessed and a checklist was used to assess availability of resources for the implementation of the maternal mortality surveillance. We also determined the cost of reporting each maternal death in Mutare district. RESULTS: Half of the study participants gave the correct definition of a maternal death. All health workers participated and were willing to continue participating in the maternal mortality surveillance. Majority of health workers, 79.7% used data generated from the surveillance system and 59.5% found it easy to implement the system. A total of 32 death notification forms were reviewed and of these, 31 forms were forwarded to the national office and all did not reach the national office on time. Average completeness of notification forms was 76.0% and 53.1% of the forms had all the necessary accompanying documents. Reporting each maternal death was estimated to cost $28.65 in Mutare district. CONCLUSION: The strongest components of the maternal mortality surveillance system in Mutare district were usefulness and acceptability. Timeliness and completeness were the weaker components of the system. The system was found to be simple; however, resources were not adequately available in all health facilities. PMID- 28904730 TI - [Tuberculous meningoencephalitis revealed by psychiatric disorders: about a case]. AB - Tuberculous meningoencephalitis is fairly frequent in endemic countries and it is the most severe form of tuberculosis. Therapeutic failure is common because of diagnostic delay. This delay is primarily due to a wide clinical polymorphism and, in particular, to misleading forms. We here report a rare clinical case of tuberculous meningitis in a patient in prodromal phase of psychosis. PMID- 28904731 TI - [Management for esophageal foreign bodies: about 36 cases]. AB - Esophageal foreign bodies are a frequent reason for consultation in the Pediatric Emergency Department. However, they can occur at all ages. This study aims to highlight the clinical, paraclinical and therapeutic features of esophageal foreign bodies management at the Hospital in Mali. We conducted a prospective study of all cases of ingestion of foreign bodies between January 2011 and December 2014. A total of 36 patients underwent endoscopic or surgical treatment. The average age was 6 years (with a range from 14 months to 62 years). They mainly affected male patients with a sex ratio of 1.75. Foreign bodies were blocked in the cricopharyngeal shrinkage in 69.45% of cases, 22.22% of whom had subsequent aortic shrinkage. The average time of foreign body removal was 7.30 hours. Rigid fibroscopy allowed the removal of the foreign body in 88.89% of cases. Thoracotomy allowed the removal of the foreign body in 5.55%. Esophageal foreign bodies can occur at all ages but they are more frequent among children. Endoscopic removal is the gold standard treatment but surgical removal of a blocked esophageal foreign body, although rare, is the last resort, due to the nature of the foreign body and to the occurrence of complications. The best way to reduce accidents is prevention. PMID- 28904732 TI - [Type III Monteggia lesion: a rare association, about a case]. AB - Type III Monteggia lesion is very rare, usually occurring within a context of violent trauma and often going unnoticed. We report the case of a 11-year old boy presenting to the Emergency Department with blunt trauma of the upper limb. The radiological evaluation showed olecranon fracture and radial epiphyseal separation associated with dislocation of the radial head. The patient underwent orthopedic treatment with good outcome after a mean follow-up of 3 months. PMID- 28904733 TI - [Bone metastases from malignant melanoma detected on 18F-FDG PET in a patient with normal skeletal scintigraphy]. PMID- 28904734 TI - A 17-year-old male with a Small Bowel Neuroendocrine Tumor: flushing differential diagnosis. AB - BACKGROUND: Neuroendocrine tumors (NETs) are heterogeneous neoplasms that originate from cells with a secretory function. Small bowel NETs (SB-NETs) are related to serotonin hypersecretion which causes: flushing, diarrhea, abdominal pain, bronchoconstriction and heart involvement, also known as carcinoid syndrome (CS). CS can be confused with an allergic reaction and thus should be considered as a differential diagnosis in the allergy consult. We present the case of a pediatric patient initially referred under the suspicion of food allergies. CASE PRESENTATION: We present the case of a 17-year-old male with evanescent non pruriginous erythematous lesions- flushing that appeared with food consumption, associated with conjunctival injection, warmth and diaphoresis after the lesions disappeared. He denied abdominal pain, diarrhea, cough or wheezing. The 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion was elevated. The CT scan showed thickening of the distal ileum and multiple lesions on both hepatic lobules and the colonoscopy revealed a tumor in the ileocecal valve. Hepatic and intestinal biopsies reported a well-differentiated NET of the ileocecal valve with hepatic metastasis. He was started on octreotide and underwent a wide hepatectomy and right hemicolectomy with improvement of symptoms. CONCLUSIONS: NETs can present as carcinoid syndrome (flushing, diarrhea, abdominal pain, wheezing), which constitutes vague symptomatology and represents a challenging diagnosis for physicians. They can be confused with an allergic reaction and the allergist should consider it as a differential diagnosis. Accurate diagnostic tests will help to diagnose NETs earlier and potentially prevent carcinoid heart disease, bowel obstruction, and improve quality of life and mortality in these patients. PMID- 28904735 TI - Corrigendum to "Immune Profile of Obese People and In Vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells". AB - [This corrects the article DOI: 10.1155/2017/9210862.]. PMID- 28904736 TI - Beer Polyphenols and Menopause: Effects and Mechanisms-A Review of Current Knowledge. AB - Beer is one of the most frequently consumed fermented beverages in the world, and it has been part of the human diet for thousands of years. Scientific evidence obtained from the development of new techniques of food analysis over the last two decades suggests that polyphenol intake derived from moderate beer consumption may play a positive role in different health outcomes including osteoporosis and cardiovascular risk and the relief of vasomotor symptoms, which are commonly experienced during menopause and are an important reason why women seek medical care during this period; here, we review the current knowledge regarding moderate beer consumption and its possible effects on menopausal symptoms. The effect of polyphenol intake on vasomotor symptoms in menopause may be driven by the direct interaction of the phenolic compounds present in beer, such as 8-prenylnaringenin, 6-prenylnaringenin, and isoxanthohumol, with intracellular estrogen receptors that leads to the modulation of gene expression, increase in sex hormone plasma concentrations, and thus modulation of physiological hormone imbalance in menopausal women. Since traditional hormone replacement therapies increase health risks, alternative, safer treatment options are needed to alleviate menopausal symptoms in women. The present work aims to review the current data on this subject. PMID- 28904737 TI - Anticataractogenesis and Antiretinopathy Effects of the Novel Protective Agent Containing the Combined Extract of Mango and Vietnamese Coriander in STZ-Diabetic Rats. AB - The novel protectant against diabetic cataract and diabetic retinopathy is currently required due to the increased prevalence and therapeutic limitation. Based on the advantage of polyphenol on diabetic eye complications, we hypothesized that the combined extract of mango seed Vietnamese coriander (MPO), a polyphenol-rich substance, should possess anticataractogenesis and antiretinopathy in streptozotocin- (STZ-) diabetic rats. MPO at doses of 2, 10, and 50 mg/kg.BW were orally given to STZ-diabetic rats for 10 weeks. Lens opacity was evaluated every week throughout a study period whereas the evaluation of cataract severity and histological changes of both rat lens epithelium and retina together with the biochemical assays of oxidative stress status, aldose reductase, p38MAPK, ERK1/2, and VEGF were performed at the end of experiment. Our data showed that MPO improved cataract and retinopathy in STZ-diabetic rats. The improved oxidative stress status and the decreased p38MAPK, ERK1/2, and VEGF were also observed. Therefore, anticataractogenesis and antiretinopathy of MPO might occur partly via the decreased oxidative stress status and the suppression of aldose reductase, p38MAPK, ERK1/2, and VEGF. This study points out that MPO is the potential candidate protectant against diabetic cataract and diabetic retinopathy. However, the exploration for possible active ingredient (S) still requires further researches. PMID- 28904738 TI - Total Oxidant and Antioxidant Status in Prepubertal Children with Obesity. AB - AIMS: Obesity is accompanied by the formation of oxygen free radicals, whose intensified activity without effective defense mechanisms can lead to oxidative stress and related complications. We evaluated the presence of oxidative stress in obese prepubertal children. METHODS: The study included 83 healthy children aged 2-10 years (62 with obesity and 21 nonobese controls). Total oxidant capacity (TOC), total antioxidant capacity (TAC), oxidized low-density lipoprotein (ox-LDL), lipid parameters, glucose, and C-reactive protein (CRP) were measured in serum. Oxidative stress index (OSI) was calculated. RESULTS: Serum TOC concentration was significantly higher (p < 0.05) and TAC concentration was lower (p < 0.05) in obese children. OSI was higher (p < 0.01) in obese subjects compared with controls. CRP levels were normal in all children, but median CRP value was higher (p < 0.01) and HDL cholesterol levels were lower (p < 0.05) in the obese group. We found a significant negative correlation between TAC and ox-LDL concentrations (r = -0.27, p < 0.05) in obese children. Furthermore, obesity duration was positively correlated with TOC level (r = 0.32, p < 0.05) in this group. CONCLUSIONS: Obesity-related oxidative stress already occurs in prepubescence. Early obesity diagnosis and the necessary therapeutic activity implementation is a vital strategy for the prophylaxis of free radical damage and related multiorgan complications. PMID- 28904739 TI - Role of Oxidative Stress and Mitochondrial Dysfunction in Sepsis and Potential Therapies. AB - Sepsis is one of the most important causes of death in intensive care units. Despite the fact that sepsis pathogenesis remains obscure, there is increasing evidence that oxidants and antioxidants play a key role. The imbalance of the abovementioned substances in favor of oxidants is called oxidative stress, and it contributes to sepsis process. The most important consequences are vascular permeability impairment, decreased cardiac performance, and mitochondrial malfunction leading to impaired respiration. Nitric oxide is perhaps the most important and well-studied oxidant. Selenium, vitamin C, and 3N-acetylcysteine among others are potential therapies for the restoration of redox balance in sepsis. Results from recent studies are promising, but there is a need for more human studies in a clinical setting for safety and efficiency evaluation. PMID- 28904741 TI - Complete genome of Arthrobacter alpinus strain R3.8, bioremediation potential unraveled with genomic analysis. AB - Arthrobacter alpinus R3.8 is a psychrotolerant bacterial strain isolated from a soil sample obtained at Rothera Point, Adelaide Island, close to the Antarctic Peninsula. Strain R3.8 was sequenced in order to help discover potential cold active enzymes with biotechnological applications. Genome analysis identified various cold adaptation genes including some coding for anti-freeze proteins and cold-shock proteins, genes involved in bioremediation of xenobiotic compounds including naphthalene, and genes with chitinolytic and N-acetylglucosamine utilization properties and also plant-growth-influencing properties. In this genome report, we present a complete genome sequence of A. alpinus strain R3.8 and its annotation data, which will facilitate exploitation of potential novel cold-active enzymes. PMID- 28904740 TI - Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response. AB - We have hypothesized that the adaptive response to low doses of ionizing radiation (IR) is mediated by oxidized cell-free DNA (cfDNA) fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production), induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs) with low doses of IR (10 cGy) leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR. PMID- 28904742 TI - Draft genome sequence of the cellulolytic endophyte Chitinophaga costaii A37T2T. AB - Here we report the draft genome sequence of Chitinophaga costai A37T2T (=CIP 110584T, =LMG 27458T), which was isolated from the endophytic community of Pinus pinaster tree. The total genome size of C. costaii A37T2T is 5.07 Mbp, containing 4204 coding sequences. Strain A37T2T encoded multiple genes likely involved in cellulolytic, chitinolytic and lipolytic activities. This genome showed 1145 unique genes assigned into 109 Cluster of Orthologous Groups in comparison with the complete genome of C. pinensis DSM 2588T. The genomic information suggests the potential of the strain A37T2T to interact with the plant metabolism. As there are only a few bacterial genomes related to Pine Wilt Disease, this work provides a contribution to the field. PMID- 28904743 TI - Complete genome sequence of the sulfur-oxidizing chemolithoautotrophic Sulfurovum lithotrophicum 42BKTT. AB - A sulfur-oxidizing chemolithoautotrophic bacterium, Sulfurovum lithotrophicum 42BKTT, isolated from hydrothermal sediments in Okinawa, Japan, has been used industrially for CO2 bio-mitigation owing to its ability to convert CO2 into C5H8NO4- at a high rate of specific mitigation (0.42 g CO2/cell/h). The genome of S. lithotrophicum 42BKTT comprised of a single chromosome of 2217,891 bp with 2217 genes, including 2146 protein-coding genes and 54 RNA genes. Here, we present its complete genome-sequence information, including information about the genes encoding enzymes involved in CO2 fixation and sulfur oxidation. PMID- 28904744 TI - Clinical and surgical characteristics of infected diabetic foot ulcers in a tertiary hospital of Mexico. AB - Background: The objective of this study was to determine the clinical and surgical characteristics of diabetic foot ulcers in a tertiary level hospital in Mexico. Methods: We performed a longitudinal, descriptive study from July, 2012 to August, 2015 on a sample composed of 100 patients with type 2 diabetes mellitus and infected diabetic foot ulcers. We analyzed socio-demographic variables, comorbidities, characteristics of ulcers, and the applied treatment. Results: We found that the most affected areas were the forefoot (48%) and the plantar region (55%) of the foot. Also, most of the patients arrived with advanced stages of diabetic foot ulcers, since 93% of the lesions were of grades III-V according to the Wagner classification. Moreover, lesions usually present with advanced states of infection, since 60% of the lesions were of grades 3-4 in the PEDIS scale. In addition, the great majority of the patients are prone to complications because we found that 43% of the patients suffered from hypertension, 47% of the patients had chronic kidney disease, and 45% reported smoking. In fact, 45% of the patients eventually suffered an amputation. We also found that the situation is more difficult because the great majority of the patients (96%) have a low level of education and very low income and they do not have any health insurance. Nevertheless, we also found that an efficient treatment can help in avoiding amputations, since 53% of grade IV and 25% of grade V lesions according to the Wagner system did not suffer an amputation. Conclusions: Therefore, an effective antibiotic treatment and an education of the patient on the adequate care of their lesions are essential in increasing the welfare of patients, especially when they have a low level of education. PMID- 28904745 TI - Genome editing of the HIV co-receptors CCR5 and CXCR4 by CRISPR-Cas9 protects CD4+ T cells from HIV-1 infection. AB - BACKGROUND: The main approach to treat HIV-1 infection is combination antiretroviral therapy (cART). Although cART is effective in reducing HIV-1 viral load and controlling disease progression, it has many side effects, and is expensive for HIV-1 infected patients who must remain on lifetime treatment. HIV 1 gene therapy has drawn much attention as studies of genome editing tools have progressed. For example, zinc finger nucleases (ZFN), transcription activator like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 have been utilized to successfully disrupt the HIV-1 co-receptors CCR5 or CXCR4, thereby restricting HIV-1 infection. However, the effects of simultaneous genome editing of CXCR4 and CCR5 by CRISPR-Cas9 in blocking HIV-1 infection in primary CD4+ T cells has been rarely reported. Furthermore, combination of different target sites of CXCR4 and CCR5 for disruption also need investigation. RESULTS: In this report, we designed two different gRNA combinations targeting both CXCR4 and CCR5, in a single vector. The CRISPR-sgRNAs-Cas9 could successfully induce editing of CXCR4 and CCR5 genes in various cell lines and primary CD4+ T cells. Using HIV-1 challenge assays, we demonstrated that CXCR4-tropic or CCR5-tropic HIV-1 infections were significantly reduced in CXCR4- and CCR5-modified cells, and the modified cells exhibited a selective advantage over unmodified cells during HIV-1 infection. The off-target analysis showed that no non-specific editing was identified in all predicted sites. In addition, apoptosis assays indicated that simultaneous disruption of CXCR4 and CCR5 in primary CD4+ T cells by CRISPR-Cas9 had no obvious cytotoxic effects on cell viability. CONCLUSIONS: Our results suggest that simultaneous genome editing of CXCR4 and CCR5 by CRISPR-Cas9 can potentially provide an effective and safe strategy towards a functional cure for HIV-1 infection. PMID- 28904746 TI - Discovery and characterization of single nucleotide polymorphisms in two anadromous alosine fishes of conservation concern. AB - Freshwater habitat alteration and marine fisheries can affect anadromous fish species, and populations fluctuating in size elicit conservation concern and coordinated management. We describe the development and characterization of two sets of 96 single nucleotide polymorphism (SNP) assays for two species of anadromous alosine fishes, alewife and blueback herring (collectively known as river herring), that are native to the Atlantic coast of North America. We used data from high-throughput DNA sequencing to discover SNPs and then developed molecular genetic assays for genotyping sets of 96 individual loci in each species. The two sets of assays were validated with multiple populations that encompass both the geographic range and the known regional genetic stocks of both species. The SNP panels developed herein accurately resolved the genetic stock structure for alewife and blueback herring that was previously identified using microsatellites and assigned individuals to regional stock of origin with high accuracy. These genetic markers, which generate data that are easily shared and combined, will greatly facilitate ongoing conservation and management of river herring including genetic assignment of marine caught individuals to stock of origin. PMID- 28904747 TI - Linking the wintering and breeding grounds of warblers along the Pacific Flyway. AB - Long-distance migration is a behavior that is exhibited by many animal groups. The evolution of novel migration routes can play an important role in range expansions, ecological interactions, and speciation. New migration routes may evolve in response to selection in favor of reducing distance between breeding and wintering areas, or avoiding navigational barriers. Many migratory changes are likely to evolve gradually and are therefore difficult to study. Here, we attempt to connect breeding and wintering populations of myrtle warblers (Setophaga coronata coronata) to better understand the possible evolution of distinct migration routes within this species. Myrtle warblers, unlike most other warblers with breeding ranges primarily in eastern North America, have two disjunct overwintering concentrations-one in the southeastern USA and one along the Pacific Coast-and presumably distinct routes to-and-from these locations. We studied both myrtle and Audubon's warblers (S. c. auduboni) captured during their spring migration along the Pacific Coast, south of the narrow region where these two taxa hybridize. Using stable hydrogen isotopes and biometric data, we show that those myrtle warblers wintering along the southern Pacific Coast of North America are likely to breed at high latitudes in Alaska and the Yukon rather than in Alberta or further east. Our interpretation is that the evolution of this wintering range and migration route along the Pacific Coast may have facilitated the breeding expansion of myrtle warblers into northwestern North America. Moreover, these data suggest that there may be a migratory divide within genetically similar populations of myrtle warblers. PMID- 28904749 TI - Do you hear what I see? Vocalization relative to visual detection rates of Hawaiian hoary bats (Lasiurus cinereus semotus). AB - Bats vocalize during flight as part of the sensory modality called echolocation, but very little is known about whether flying bats consistently call. Occasional vocal silence during flight when bats approach prey or conspecifics has been documented for relatively few species and situations. Bats flying alone in clutter-free airspace are not known to forgo vocalization, yet prior observations suggested possible silent behavior in certain, unexpected situations. Determining when, why, and where silent behavior occurs in bats will help evaluate major assumptions of a primary monitoring method for bats used in ecological research, management, and conservation. In this study, we recorded flight activity of Hawaiian hoary bats (Lasiurus cinereus semotus) under seminatural conditions using both thermal video cameras and acoustic detectors. Simultaneous video and audio recordings from 20 nights of observation at 10 sites were analyzed for correspondence between detection methods, with a focus on video observations in three distance categories for which accompanying vocalizations were detected. Comparison of video and audio detections revealed that a high proportion of Hawaiian hoary bats "seen" on video were not simultaneously "heard." On average, only about one in three visual detections within a night had an accompanying call detection, but this varied greatly among nights. Bats flying on curved flight paths and individuals nearer the cameras were more likely to be detected by both methods. Feeding and social calls were detected, but no clear pattern emerged from the small number of observations involving closely interacting bats. These results may indicate that flying Hawaiian hoary bats often forgo echolocation, or do not always vocalize in a way that is detectable with common sampling and monitoring methods. Possible reasons for the low correspondence between visual and acoustic detections range from methodological to biological and include a number of biases associated with the propagation and detection of sound, cryptic foraging strategies, or conspecific presence. Silent flight behavior may be more prevalent in echolocating bats than previously appreciated, has profound implications for ecological research, and deserves further characterization and study. PMID- 28904748 TI - The complexity of mating decisions in stalk-eyed flies. AB - All too often, studies of sexual selection focus exclusively on the responses in one sex, on single traits, typically those that are exaggerated and strongly sexually dimorphic. They ignore a range of less obvious traits and behavior, in both sexes, involved in the interactions leading to mate choice. To remedy this imbalance, we analyze a textbook example of sexual selection in the stalk-eyed fly (Diasemopsis meigenii). We studied several traits in a novel, insightful, and efficient experimental design, examining 2,400 male-female pairs in a "round robin" array, where each female was tested against multiple males and vice versa. In D. meigenii, females exhibit strong mate preference for males with highly exaggerated eyespan, and so we deliberately constrained variation in male eyespan to reveal the importance of other traits. Males performing more precopulatory behavior were more likely to attempt to mate with females and be accepted by them. However, behavior was not a necessary part of courtship, as it was absent from over almost half the interactions. Males with larger reproductive organs (testes and accessory glands) did not make more mating attempts, but there was a strong tendency for females to accept mating attempts from such males. How females detect differences in male reproductive organ size remains unclear. In addition, females with larger eyespan, an indicator of size and fecundity, attracted more mating attempts from males, but this trait did not alter female acceptance. Genetic variation among males had a strong influence on male mating attempts and female acceptance, both via the traits we studied and other unmeasured attributes. These findings demonstrate the importance of assaying multiple traits in males and females, rather than focusing solely on prominent and exaggerated sexually dimorphic traits. The approach allows a more complete understanding of the complex mating decisions made by both males and females. PMID- 28904750 TI - Phenology of brown marmorated stink bug described using female reproductive development. AB - Temperature-based degree-day models describe insect seasonality and to predict key phenological events. We expand on the use of a temperature-based process defining timing of reproduction through the incorporation of female reproductive physiology for the invasive pentatomid species Halyomorpha halys, the brown marmorated stink bug. A five-stage ranking system based on ovary development was able to distinguish between the reproductive statuses of field-collected females. Application of this ranking method described aspects of H. halys' seasonality, overwintering biology, and phenology across geographic locations. Female H. halys were collected in the US from NJ, WV, NC, OR, and two sites in PA in 2006-2008 (Allentown, PA only) and 2012-2014. Results identify that H. halys enters reproductive diapause in temperate locations in the fall and that a delay occurs in developmental maturity after diapause termination in the spring. Modification of the Snyder method to identify biofix determined 12.7-hr photoperiod as the best fit to define initiation of reproduction in the spring. Applying the biofix, we demonstrated significant differences between locations for the rate at which the overwintering generation transition into reproductive status and the factors contributing to this difference require further study. For example, after including abiotic variables influencing development such as temperature and photoperiod (critical diapause cue), reproduction occurred earlier in OR and for an extended period in NJ. This data describe a method to investigate insect seasonality by incorporating physiological development across multiple regions that can clarify phenology for insects with overlapping generations. PMID- 28904751 TI - The thermal niche of Neotropical nectar-feeding bats: Its evolution and application to predict responses to global warming. AB - The thermal niche of a species is one of the main determinants of its ecology and biogeography. In this study, we determined the thermal niche of 23 species of Neotropical nectar-feeding bats of the subfamily Glossophaginae (Chiroptera, Phyllostomidae). We calculated their thermal niches using temperature data obtained from collection records, by generating a distribution curve of the maximum and minimum temperatures per locality, and using the inflection points of the temperature distributions to estimate the species optimal (STZ) and suboptimal (SRZ) zones of the thermal niche. Additionally, by mapping the values of the STZ and SRZ on a phylogeny of the group, we generated a hypothesis of the evolution of the thermal niches of this clade of nectar-feeding bats. Finally, we used the characteristics of their thermal niches to predict the responses of these organisms to climate change. We found a large variation in the width and limits of the thermal niches of nectar-feeding bats. Additionally, while the upper limits of the thermal niches varied little among species, their lower limits differ wildly. The ancestral reconstruction of the thermal niche indicated that this group of Neotropical bats evolved under cooler temperatures. The two clades inside the Glossophaginae differ in the evolution of their thermal niches, with most members of the clade Choeronycterines evolving "colder" thermal niches, while the majority of the species in the clade Glossophagines evolving "warmer" thermal niches. By comparing thermal niches with climate change models, we found that all species could be affected by an increase of 1 degrees C in temperature at the end of this century. This suggests that even nocturnal species could suffer important physiological costs from global warming. Our study highlights the value of scientific collections to obtain ecologically significant physiological data for a large number of species. PMID- 28904752 TI - Impacts of natural factors and farming practices on greenhouse gas emissions in the North China Plain: A meta-analysis. AB - Requirements for mitigation of the continued increase in greenhouse gas (GHG) emissions are much needed for the North China Plain (NCP). We conducted a meta analysis of 76 published studies of 24 sites in the NCP to examine the effects of natural conditions and farming practices on GHG emissions in that region. We found that N2O was the main component of the area-scaled total GHG balance, and the CH 4 contribution was <5%. Precipitation, temperature, soil pH, and texture had no significant impacts on annual GHG emissions, because of limited variation of these factors in the NCP. The N2O emissions increased exponentially with mineral fertilizer N application rate, with y = 0.2389e0.0058x for wheat season and y = 0.365e0.0071x for maize season. Emission factors were estimated at 0.37% for wheat and 0.90% for maize at conventional fertilizer N application rates. The agronomic optimal N rates (241 and 185 kg N ha-1 for wheat and maize, respectively) exhibited great potential for reducing N2O emissions, by 0.39 (29%) and 1.71 (56%) kg N2O-N ha-1 season-1 for the wheat and maize seasons, respectively. Mixed application of organic manure with reduced mineral fertilizer N could reduce annual N2O emissions by 16% relative to mineral N application alone while maintaining a high crop yield. Compared with conventional tillage, no tillage significantly reduced N2O emissions by ~30% in the wheat season, whereas it increased those emissions by ~10% in the maize season. This may have resulted from the lower soil temperature in winter and increased soil moisture in summer under no-tillage practice. Straw incorporation significantly increased annual N2O emissions, by 26% relative to straw removal. Our analysis indicates that these farming practices could be further tested to mitigate GHG emission and maintain high crop yields in the NCP. PMID- 28904753 TI - Connecting the dots: Stopover strategies of an intercontinental migratory songbird in the context of the annual cycle. AB - The phases of the annual cycle for migratory species are inextricably linked. Yet, less than five percent of ecological studies examine seasonal interactions. In this study, we utilized stable hydrogen isotopes to geographically link individual black-and-white warblers (Mniotilta varia) captured during spring migration with breeding destinations to understand a migrant's stopover strategy in the context of other phases of the annual cycle. We found that stopover strategy is not only a function of a bird's current energetic state, but also the distance remaining to breeding destination and a bird's time-schedule, which has previously been linked to habitat conditions experienced in the preceding phase of the annual cycle. Birds in close proximity to their breeding destination accumulate additional energy reserves prior to arrival on the breeding grounds, as reflected by higher migratory condition upon arrival, higher refueling rates measured via blood plasma metabolites, and longer stopover durations compared to birds migrating to breeding destinations farther from the stopover site. However, late birds near their breeding destination were more likely to depart on the day of arrival (i.e., transients), and among birds that stopped over at the site, the average duration of stopover was almost half the time of early conspecifics, suggesting late birds are trying to catch-up with the overall time-schedule of migration for optimal arrival time on the breeding grounds. In contrast, birds with long distances remaining to breeding destinations were more likely to depart on the day of arrival and primarily used stopover to rest before quickly resuming migration, adopting similar strategies regardless of a bird's time-schedule. Our study demonstrates that migrants adjust their en route strategies in relation to their time-schedule and distance remaining to their breeding destination, highlighting that strategies of migration should be examined in the context of other phases of the annual cycle. PMID- 28904754 TI - Interactive effects of leg autotomy and incline on locomotor performance and kinematics of the cellar spider, Pholcus manueli. AB - Leg autotomy can be a very effective strategy for escaping a predation attempt in many animals. In spiders, autotomy can be very common (5-40% of individuals can be missing legs) and has been shown to reduce locomotor speeds, which, in turn, can reduce the ability to find food, mates, and suitable habitat. Previous work on spiders has focused mostly on the influence of limb loss on horizontal movements. However, limb loss can have differential effects on locomotion on the nonhorizontal substrates often utilized by many species of spiders. We examined the effects of leg autotomy on maximal speed and kinematics while moving on horizontal, 45 degrees inclines, and vertical (90 degrees ) inclines in the cellar spider Pholcus manueli, a widespread species that is a denizen of both natural and anthropogenic, three-dimensional microhabitats, which frequently exhibits autotomy in nature. Maximal speeds and kinematic variables were measured in all spiders, which were run on all three experimental inclines twice. First, all spiders were run at all inclines prior to autotomization. Second, half of the spiders had one of the front legs removed, while the other half was left intact before all individuals were run a second time on all inclines. Speeds decreased with increasing incline and following autotomy at all inclines. Autotomized spiders exhibited a larger decrease in speed when moving horizontally compared to on inclines. Stride length decreased at 90 degrees but not after autotomy. Stride cycle time and duty factor increased after autotomy, but not when moving uphill. Results show that both incline and leg autotomy reduce speed with differential effects on kinematics with increasing incline reducing stride length, but not stride cycle time or duty factor, and vice versa for leg autotomy. The lack of a significant influence on a kinematic variable could be evidence for partial compensation to mitigate speed reduction. PMID- 28904755 TI - Effects of climate warming on net primary productivity in China during 1961-2010. AB - The response of ecosystems to different magnitudes of climate warming and corresponding precipitation changes during the last few decades may provide an important reference for predicting the magnitude and trajectory of net primary productivity (NPP) in the future. In this study, a process-based ecosystem model, Carbon Exchange between Vegetation, Soil and Atmosphere (CEVSA), was used to investigate the response of NPP to warming at both national and subregional scales during 1961-2010. The results suggest that a 1.3 degrees C increase in temperature stimulated the positive changing trend in NPP at national scale during the past 50 years. Regardless of the magnitude of temperature increase, warming enhanced the increase in NPP; however, the positive trend of NPP decreased when warming exceeded 2 degrees C. The largest increase in NPP was found in regions where temperature increased by 1-2 degrees C, and this rate of increase also contributed the most to the total increase in NPP in China's terrestrial ecosystems. Decreasing precipitation depressed the positive trend in NPP that was stimulated by warming. In northern China, warming depressed the increasing trend of NPP and warming that was accompanied by decreasing precipitation led to negative changing trends in NPP in large parts of northern China, especially when warming exceeded 2 degrees C. However, warming stimulated the increase in NPP until warming was greater than 2 degrees C, and decreased precipitation helped to increase the NPP in southern China. PMID- 28904756 TI - Phylogenetic conservatism and trait correlates of spring phenological responses to climate change in northeast China. AB - Climate change has resulted in major changes in plant phenology across the globe that includes leaf-out date and flowering time. The ability of species to respond to climate change, in part, depends on their response to climate as a phenological cue in general. Species that are not phenologically responsive may suffer in the face of continued climate change. Comparative studies of phenology have found phylogeny to be a reliable predictor of mean leaf-out date and flowering time at both the local and global scales. This is less true for flowering time response (i.e., the correlation between phenological timing and climate factors), while no study to date has explored whether the response of leaf-out date to climate factors exhibits phylogenetic signal. We used a 52-year observational phenological dataset for 52 woody species from the Forest Botanical Garden of Heilongjiang Province, China, to test phylogenetic signal in leaf-out date and flowering time, as well as, the response of these two phenological traits to both temperature and winter precipitation. Leaf-out date and flowering time were significantly responsive to temperature for most species, advancing, on average, 3.11 and 2.87 day/ degrees C, respectively. Both leaf-out and flowering, and their responses to temperature exhibited significant phylogenetic signals. The response of leaf-out date to precipitation exhibited no phylogenetic signal, while flowering time response to precipitation did. Native species tended to have a weaker flowering response to temperature than non-native species. Earlier leaf out species tended to have a greater response to winter precipitation. This study is the first to assess phylogenetic signal of leaf-out response to climate change, which suggests, that climate change has the potential to shape the plant communities, not only through flowering sensitivity, but also through leaf-out sensitivity. PMID- 28904757 TI - Social dilemma in the external immune system of the red flour beetle? It is a matter of time. AB - Sociobiology has revolutionized our understanding of interactions between organisms. Interactions may present a social dilemma where the interests of individual actors do not align with those of the group as a whole. Viewed through a sociobiological lens, nearly all interactions can be described regarding their costs and benefits, and a number of them then resemble a social dilemma. Numerous experimental systems, from bacteria to mammals, have been proposed as models for studying such dilemmas. Here, we make use of the external immune system of the red flour beetle, Tribolium castaneum, to investigate how the experimental duration can affect whether the external secretion comprises a social dilemma or not. Some beetles (secretors) produce a costly quinone-rich external secretion that inhibits microbial growth in the surrounding environment, providing the secretors with direct personal benefits. However, as the antimicrobial secretion acts in the environment of the beetle, it is potentially also advantageous to other beetles (nonsecretors), who avoid the cost of producing the secretion. We test experimentally if the secretion qualifies as a public good. We find that in the short term, costly quinone secretion can be interpreted as a public good presenting a social dilemma where the presence of secretors increases the fitness of the group. In the long run, the benefit to the group of having more secretors vanishes and becomes detrimental to the group. Therefore, in such seminatural environmental conditions, it turns out that qualifying a trait as social can be a matter of timing. PMID- 28904758 TI - Early-life foraging: Behavioral responses of newly fledged albatrosses to environmental conditions. AB - In order to survive and later recruit into a population, juvenile animals need to acquire resources through the use of innate and/or learnt behaviors in an environment new to them. For far-ranging marine species, such as the wandering albatross Diomedea exulans, this is particularly challenging as individuals need to be able to rapidly adapt and optimize their movement strategies in response to the highly dynamic and heterogeneous nature of their open-ocean pelagic habitats. Critical to this is the development and flexibility of dispersal and exploratory behaviors. Here, we examine the movements of eight juvenile wandering albatrosses, tracked using GPS/Argos satellite transmitters for eight months following fledging, and compare these to the trajectories of 17 adults to assess differences and similarities in behavioral strategies through time. Behavioral clustering algorithms (Expectation Maximization binary Clustering) were combined with multinomial regression analyses to investigate changes in behavioral mode probabilities over time, and how these may be influenced by variations in day duration and in biophysical oceanographic conditions. We found that juveniles appeared to quickly acquire the same large-scale behavioral strategies as those employed by adults, although generally more time was spent resting at night. Moreover, individuals were able to detect and exploit specific oceanographic features in a manner similar to that observed in adults. Together, the results of this study suggest that while shortly after fledging juvenile wandering albatrosses are able to employ similar foraging strategies to those observed in adults, additional skills need to be acquired during the immature period before the efficiency of these behaviors matches that of adults. PMID- 28904759 TI - Different facets of tree sapling diversity influence browsing intensity by deer dependent on spatial scale. AB - Browsing of tree saplings by deer hampers forest regeneration in mixed forests across Europe and North America. It is well known that tree species are differentially affected by deer browsing, but little is known about how different facets of diversity, such as species richness, identity, and composition, affect browsing intensity at different spatial scales. Using forest inventory data from the Hainich National Park, a mixed deciduous forest in central Germany, we applied a hierarchical approach to model the browsing probability of patches (regional scale) as well as the species-specific proportion of saplings browsed within patches (patch scale). We found that, at the regional scale, the probability that a patch was browsed increased with certain species composition, namely with low abundance of European beech (Fagus sylvatica L.) and high abundance of European ash (Fraxinus excelsior L.), whereas at the patch scale, the proportion of saplings browsed per species was mainly determined by the species' identity, providing a "preference ranking" of the 11 tree species under study. Interestingly, at the regional scale, species-rich patches were more likely to be browsed; however, at the patch scale, species-rich patches showed a lower proportion of saplings per species browsed. Presumably, diverse patches attract deer, but satisfy nutritional needs faster, such that fewer saplings need to be browsed. Some forest stand parameters, such as more open canopies, increased the browsing intensity at either scale. By showing the effects that various facets of diversity, as well as environmental parameters, exerted on browsing intensity at the regional as well as patch scale, our study advances the understanding of mammalian herbivore-plant interactions across scales. Our results also indicate which regeneration patches and species are (least) prone to browsing and show the importance of different facets of diversity for the prediction and management of browsing intensity and regeneration dynamics. PMID- 28904760 TI - Maintaining genetic integrity of coexisting wild and domestic populations: Genetic differentiation between wild and domestic Rangifer with long traditions of intentional interbreeding. AB - This study investigates the genetic effect of an indigenous tradition of deliberate and controlled interbreeding between wild and domestic Rangifer. The results are interpreted in the context of conservation concerns and debates on the origin of domestic animals. The study is located in Northeastern Zabaikal'e, Russia at approximately 57 degrees North latitude. Blood and skin samples, collected from wild and domestic Rangifer, are analyzed for their mtDNA and microsatellite signatures. Local husbandry traditions are documented ethnographically. The genetic data are analyzed with special reference to indigenous understandings of the distinctions between local domestic types and wild Rangifer. The genetic results demonstrate a strong differentiation between wild and domestic populations. Notably low levels of mtDNA haplotype sharing between wild and domestic reindeer, suggest mainly male-mediated gene flow between the two gene pools. The nuclear microsatellite results also point to distinct differences between regional domestic clusters. Our results indicate that the Evenki herders have an effective breeding technique which, while mixing pedigrees in the short term, guards against wholesale introgression between wild and domestic populations over the long term. They support a model of domestication where wild males and domestic females are selectively interbred, without hybridizing the two populations. Our conclusions inform a debate on the origins of domestication by documenting a situation where both wild and domestic types are in constant interaction. The study further informs a debate in conservation biology by demonstrating that certain types of controlled introgression between wild and domestic types need not reduce genetic diversity. PMID- 28904761 TI - Too hot to die? The effects of vegetation shading on past, present, and future activity budgets of two diurnal skinks from arid Australia. AB - Behavioral thermoregulation is an important mechanism allowing ectotherms to respond to thermal variations. Its efficiency might become imperative for securing activity budgets under future climate change. For diurnal lizards, thermal microhabitat variability appears to be of high importance, especially in hot deserts where vegetation is highly scattered and sensitive to climatic fluctuations. We investigated the effects of a shading gradient from vegetation on body temperatures and activity timing for two diurnal, terrestrial desert lizards, Ctenotus regius, and Morethia boulengeri, and analyzed their changes under past, present, and future climatic conditions. Both species' body temperatures and activity timing strongly depended on the shading gradient provided by vegetation heterogeneity. At high temperatures, shaded locations provided cooling temperatures and increased diurnal activity. Conversely, bushes also buffered cold temperature by saving heat. According to future climate change scenarios, cooler microhabitats might become beneficial to warm-adapted species, such as C. regius, by increasing the duration of daily activity. Contrarily, warmer microhabitats might become unsuitable for less warm-adapted species such as M. boulengeri for which midsummers might result in a complete restriction of activity irrespective of vegetation. However, total annual activity would still increase provided that individuals would be able to shift their seasonal timing towards spring and autumn. Overall, we highlight the critical importance of thermoregulatory behavior to buffer temperatures and its dependence on vegetation heterogeneity. Whereas studies often neglect ecological processes when anticipating species' responses to future climate change the strongest impact of a changing climate on terrestrial ectotherms in hot deserts is likely to be the loss of shaded microhabitats rather than the rise in temperature itself. We argue that conservation strategies aiming at addressing future climate changes should focus more on the cascading effects of vegetation rather than on shifts of species distributions predicted solely by climatic envelopes. PMID- 28904763 TI - Winter bait stations as a multispecies survey tool. AB - Winter bait stations are becoming a commonly used technique for multispecies inventory and monitoring but a technical evaluation of their effectiveness is lacking. Bait stations have three components: carcass attractant, remote camera, and hair snare. Our 22,975 km2 mountainous study area was stratified with a 5 * 5 km sampling grid centered on northern Idaho and including portions of Washington, Montana, and British Columbia. From 2010-14, we conducted 563 sampling sessions at 497 bait stations in 453 5 * 5 km cells. We evaluated the effectiveness of cameras and hair snare DNA collection at stations to detect species and individual animals, factors affecting DNA viability, the effectiveness of re visiting stations, and the influence of elevation, seasonality, and latency on species detections. Cameras were more effective at detecting multiple species than DNA hair snaring. Length of deployment time and elevation increased genetic species ID success but individual ID success rates were increased only by collecting hairs earlier in the season. Re-visiting stations did not change camera or genetic species detection results but did increase the number of individual genotypes identified. Marten and fisher were detected quickly while bobcat and coyote showed longer latency to detection. Seasonality significantly affected coyote and bobcat detections but not marten, fisher, or weasel. Multispecies bait station study design should incorporate mixed elevation sites with stratified seasonality. Priority should be given to including cameras as components of bait stations over hair snares, unless there is a specific genetic goal to the study. A hair snare component should be added, however, if individual ID or genetic data are necessary. Winter stations should be deployed a minimum of 45-60 days to allow for detection of low density species and species with long latency to detection times. Hair samples should be collected prior to DNA degrading late season rain events. Re-visiting stations does not change which species are detected at stations; therefore, studies with objectives to delineate species presence or distribution will be more effective if they focus on deploying more stations across a broader landscape in lieu of surveying the same site multiple times. PMID- 28904762 TI - Influences of thermal environment on fish growth. AB - Thermoregulation in ectothermic animals is influenced by the ability to effectively respond to thermal variations. While it is known that ectotherms are affected by thermal changes, it remains unknown whether physiological and/or metabolic traits are impacted by modifications to the thermal environment. Our research provides key evidence that fish ectotherms are highly influenced by thermal variability during development, which leads to important modifications at several metabolic levels (e.g., growth trajectories, microstructural alterations, muscle injuries, and molecular mechanisms). In Atlantic salmon (Salmo salar), a wide thermal range (DeltaT 6.4 degrees C) during development (posthatch larvae to juveniles) was associated with increases in key thermal performance measures for survival and growth trajectory. Other metabolic traits were also significantly influenced, such as size, muscle cellularity, and molecular growth regulators possibly affected by adaptive processes. In contrast, a restricted thermal range (DeltaT 1.4 degrees C) was detrimental to growth, survival, and cellular microstructure as muscle growth could not keep pace with increased metabolic demands. These findings provide a possible basic explanation for the effects of thermal environment during growth. In conclusion, our results highlight the key role of thermal range amplitude on survival and on interactions with major metabolism-regulating processes that have positive adaptive effects for organisms. PMID- 28904764 TI - The second Southern African Bird Atlas Project: Causes and consequences of geographical sampling bias. AB - Using the Southern African Bird Atlas Project (SABAP2) as a case study, we examine the possible determinants of spatial bias in volunteer sampling effort and how well such biased data represent environmental gradients across the area covered by the atlas. For each province in South Africa, we used generalized linear mixed models to determine the combination of variables that explain spatial variation in sampling effort (number of visits per 5' * 5' grid cell, or "pentad"). The explanatory variables were distance to major road and exceptional birding locations or "sampling hubs," percentage cover of protected, urban, and cultivated area, and the climate variables mean annual precipitation, winter temperatures, and summer temperatures. Further, we used the climate variables and plant biomes to define subsets of pentads representing environmental zones across South Africa, Lesotho, and Swaziland. For each environmental zone, we quantified sampling intensity, and we assessed sampling completeness with species accumulation curves fitted to the asymptotic Lomolino model. Sampling effort was highest close to sampling hubs, major roads, urban areas, and protected areas. Cultivated area and the climate variables were less important. Further, environmental zones were not evenly represented by current data and the zones varied in the amount of sampling required representing the species that are present. SABAP2 volunteers' preferences in birding locations cause spatial bias in the dataset that should be taken into account when analyzing these data. Large parts of South Africa remain underrepresented, which may restrict the kind of ecological questions that may be addressed. However, sampling bias may be improved by directing volunteers toward undersampled regions while taking into account volunteer preferences. PMID- 28904765 TI - The evolutionary consequences of habitat fragmentation: Body morphology and coloration differentiation among brook trout populations of varying size. AB - A reduction in population size due to habitat fragmentation can alter the relative roles of different evolutionary mechanisms in phenotypic trait differentiation. While deterministic (selection) and stochastic (genetic drift) mechanisms are expected to affect trait evolution, genetic drift may be more important than selection in small populations. We examined relationships between mature adult traits and ecological (abiotic and biotic) variables among 14 populations of brook trout. These naturally fragmented populations have shared ancestry but currently exhibit considerable variability in habitat characteristics and population size (49 < Nc < 10,032; 3 < Nb < 567). Body size, shape, and coloration differed among populations, with a tendency for more variation among small populations in both trait means and CV when compared to large populations. Phenotypic differences were more frequently and directly linked to habitat variation or operational sex ratio than to population size, suggesting that selection may overcome genetic drift at small population size. Phenotype-environment associations were also stronger in females than males, suggesting that natural selection due to abiotic conditions may act more strongly on females than males. Our results suggest that natural and sexual-selective pressures on phenotypic traits change during the process of habitat fragmentation, and that these changes are largely contingent upon existing habitat conditions within isolated fragments. Our study provides an improved understanding of the ecological and evolutionary consequences of habitat fragmentation and lends insight into the ability of some small populations to respond to selection and environmental change. PMID- 28904766 TI - Temporal degradation of data limits biodiversity research. AB - Spatial and/or temporal biases in biodiversity data can directly influence the utility, comparability, and reliability of ecological and evolutionary studies. While the effects of biased spatial coverage of biodiversity data are relatively well known, temporal variation in data quality (i.e., the congruence between recorded and actual information) has received much less attention. Here, we develop a conceptual framework for understanding the influence of time on biodiversity data quality based on three main processes: (1) the natural dynamics of ecological systems-such as species turnover or local extinction; (2) periodic taxonomic revisions, and; (3) the loss of physical and metadata due to inefficient curation, accidents, or funding shortfalls. Temporal decay in data quality driven by these three processes has fundamental consequences for the usage and comparability of data collected in different time periods. Data decay can be partly ameliorated by adopting standard protocols for generation, storage, and sharing data and metadata. However, some data degradation is unavoidable due to natural variations in ecological systems. Consequently, changes in biodiversity data quality over time need be carefully assessed and, if possible, taken into account when analyzing aging datasets. PMID- 28904768 TI - Herbivores alter plant-wind interactions by acting as a point mass on leaves and by removing leaf tissue. AB - In nature, plants regularly interact with herbivores and with wind. Herbivores can wound and alter the structure of plants, whereas wind can exert aerodynamic forces that cause the plants to flutter or sway. While herbivory has many negative consequences for plants, fluttering in wind can be beneficial for plants by facilitating gas exchange and loss of excess heat. Little is known about how herbivores affect plant motion in wind. We tested how the mass of an herbivore resting on a broad leaf of the tulip tree Liriodendron tulipifera, and the damage caused by herbivores, affected the motion of the leaf in wind. For this, we placed mimics of herbivores on the leaves, varying each herbivore's mass or position, and used high-speed video to measure how the herbivore mimics affected leaf movement and reconfiguration at two wind speeds inside a laboratory wind tunnel. In a similar setup, we tested how naturally occurring herbivore damage on the leaves affected leaf movement and reconfiguration. We found that the mass of an herbivore resting on a leaf can change that leaf's orientation relative to the wind and interfere with the ability of the leaf to reconfigure into a smaller, more streamlined shape. A large herbivore load slowed the leaf's fluttering frequency, while naturally occurring damage from herbivores increased the leaf's fluttering frequency. We conclude that herbivores can alter the physical interactions between wind and plants by two methods: (1) acting as a point mass on the plant while it is feeding and (2) removing tissue from the plant. Altering a plant's interaction with wind can have physical and physiological consequences for the plant. Thus, future studies of plants in nature should consider the effect of herbivory on plant-wind interactions, and vice versa. PMID- 28904767 TI - Genetic differentiation and inferred dynamics of a hybrid zone between Northern Spotted Owls (Strix occidentalis caurina) and California Spotted Owls (S. o. occidentalis) in northern California. AB - Genetic differentiation among Spotted Owl (Strix occidentalis) subspecies has been established in prior studies. These investigations also provided evidence for introgression and hybridization among taxa but were limited by a lack of samples from geographic regions where subspecies came into close contact. We analyzed new sets of samples from Northern Spotted Owls (NSO: S. o. caurina) and California Spotted Owls (CSO: S. o. occidentalis) in northern California using mitochondrial DNA sequences (mtDNA) and 10 nuclear microsatellite loci to obtain a clearer depiction of genetic differentiation and hybridization in the region. Our analyses revealed that a NSO population close to the northern edge of the CSO range in northern California (the NSO Contact Zone population) is highly differentiated relative to other NSO populations throughout the remainder of their range. Phylogenetic analyses identified a unique lineage of mtDNA in the NSO Contact Zone, and Bayesian clustering analyses of the microsatellite data identified the Contact Zone as a third distinct population that is differentiated from CSO and NSO found in the remainder of the subspecies' range. Hybridization between NSO and CSO was readily detected in the NSO Contact Zone, with over 50% of individuals showing evidence of hybrid ancestry. Hybridization was also identified among 14% of CSO samples, which were dispersed across the subspecies' range in the Sierra Nevada Mountains. The asymmetry of hybridization suggested that the hybrid zone may be dynamic and moving. Although evidence of hybridization existed, we identified no F1 generation hybrid individuals. We instead found evidence for F2 or backcrossed individuals among our samples. The absence of F1 hybrids may indicate that (1) our 10 microsatellites were unable to distinguish hybrid types, (2) primary interactions between subspecies are occurring elsewhere on the landscape, or (3) dispersal between the subspecies' ranges is reduced relative to historical levels, potentially as a consequence of recent regional fires. PMID- 28904769 TI - Identifying coevolving loci using interspecific genetic correlations. AB - Evaluating the importance of coevolution for a wide range of evolutionary questions, such as the role parasites play in the evolution of sexual reproduction, requires that we understand the genetic basis of coevolutionary interactions. Despite its importance, little progress has been made identifying the genetic basis of coevolution, largely because we lack tools designed specifically for this purpose. Instead, coevolutionary studies are often forced to re-purpose single species techniques. Here, we propose a novel approach for identifying the genes mediating locally adapted coevolutionary interactions that relies on spatial correlations between genetic marker frequencies in the interacting species. Using individual-based multi-locus simulations, we quantify the performance of our approach across a range of coevolutionary genetic models. Our results show that when one species is strongly locally adapted to the other and a sufficient number of populations can be sampled, our approach accurately identifies functionally coupled host and parasite genes. Although not a panacea, the approach we outline here could help to focus the search for coevolving genes in a wide variety of well-studied systems for which substantial local adaptation has been demonstrated. PMID- 28904770 TI - Islands, mainland, and terrestrial fragments: How isolation shapes plant diversity. AB - The fragmentation of natural habitats is a major threat for biodiversity. However, the impact and spatial scale of natural isolation mechanisms leading to species loss, compared to anthropogenic fragmentation, are not clear, mainly due to differences between fragments and islands, such as matrix permeability. We studied a 500 km2 Mediterranean region in France, including urban habitat fragments, continuous habitat, and continental-shelf islands. On the basis of 295 floristic releves, we built species-area relationships to compare isolation in fragments after urbanization, with continuous habitat and continental-shelf islands. We assumed either no dispersal, infinite dispersal, or estimated intermediate levels of habitat reachability through graph theory. Isolation mechanisms occurred in fragments but with a lower strength than in near-shore islands, and most importantly affected perennial plants. Annual plants were less affected, probably due to their smaller size and shorter life cycle. Isolation occurred at landscape level in fragments and at patch level in islands. The amount of reachable habitat (accounting for spatial configuration) explained local species richness in both systems, but the amount of habitat (no consideration of spatial configuration) was already a good predictor. These results suggest an important role of habitat amount around fragments in mitigating the isolation effects observed in near-shore islands, and the importance of carefully considering different functional groups. PMID- 28904771 TI - Sorting things out: Assessing effects of unequal specimen biomass on DNA metabarcoding. AB - Environmental bulk samples often contain many different taxa that vary several orders of magnitude in biomass. This can be problematic in DNA metabarcoding and metagenomic high-throughput sequencing approaches, as large specimens contribute disproportionately high amounts of DNA template. Thus, a few specimens of high biomass will dominate the dataset, potentially leading to smaller specimens remaining undetected. Sorting of samples by specimen size (as a proxy for biomass) and balancing the amounts of tissue used per size fraction should improve detection rates, but this approach has not been systematically tested. Here, we explored the effects of size sorting on taxa detection using two freshwater macroinvertebrate bulk samples, collected from a low-mountain stream in Germany. Specimens were morphologically identified and sorted into three size classes (body size < 2.5 * 5, 5 * 10, and up to 10 * 20 mm). Tissue powder from each size category was extracted individually and pooled based on tissue weight to simulate samples that were not sorted by biomass ("Unsorted"). Additionally, size fractions were pooled so that each specimen contributed approximately equal amounts of biomass ("Sorted"). Mock samples were amplified using four different DNA metabarcoding primer sets targeting the Cytochrome c oxidase I (COI) gene. Sorting taxa by size and pooling them proportionately according to their abundance lead to a more equal amplification of taxa compared to the processing of complete samples without sorting. The sorted samples recovered 30% more taxa than the unsorted samples at the same sequencing depth. Our results imply that sequencing depth can be decreased approximately fivefold when sorting the samples into three size classes and pooling by specimen abundance. Even coarse size sorting can substantially improve taxa detection using DNA metabarcoding. While high-throughput sequencing will become more accessible and cheaper within the next years, sorting bulk samples by specimen biomass or size is a simple yet efficient method to reduce current sequencing costs. PMID- 28904772 TI - Carbon and nitrogen allocation shifts in plants and soils along aridity and fertility gradients in grasslands of China. AB - Plant carbon (C) and nitrogen (N) stoichiometry play an important role in the maintenance of ecosystem structure and function. To decipher the influence of changing environment on plant C and N stoichiometry at the subcontinental scale, we studied the shoot and root C and N stoichiometry in two widely distributed and dominant genera along a 2,200-km climatic gradient in China's grasslands. Relationships between C and N concentrations and soil climatic variables factors were studied. In contrast to previous theory, plant C concentration and C:N ratios in both shoots and roots increased with increasing soil fertility and decreased with increasing aridity. Relative N allocation shifted from soils to plants and from roots to shoots with increasing aridity. Changes in the C:N ratio were associated with changes in N concentration. Dynamics of plant C concentration and C:N ratios were mainly caused by biomass reallocation and a nutrient dilution effect in the plant-soil system. Our results suggest that the shifted allocation of C and N to different ecosystem compartments under a changing environment may change the overall use of these elements by the plant soil system. PMID- 28904773 TI - A spatial theory for emergent multiple predator-prey interactions in food webs. AB - Predator-prey interaction is inherently spatial because animals move through landscapes to search for and consume food resources and to avoid being consumed by other species. The spatial nature of species interactions necessitates integrating spatial processes into food web theory and evaluating how predators combine to impact their prey. Here, we present a spatial modeling approach that examines emergent multiple predator effects on prey within landscapes. The modeling is inspired by the habitat domain concept derived from empirical synthesis of spatial movement and interactions studies. Because these principles are motivated by synthesis of short-term experiments, it remains uncertain whether spatial contingency principles hold in dynamical systems. We address this uncertainty by formulating dynamical systems models, guided by core habitat domain principles, to examine long-term multiple predator-prey spatial dynamics. To describe habitat domains, we use classical niche concepts describing resource utilization distributions, and assume species interactions emerge from the degree of overlap between species. The analytical results generally align with those from empirical synthesis and present a theoretical framework capable of demonstrating multiple predator effects that does not depend on the small spatial or temporal scales typical of mesocosm experiments, and help bridge between empirical experiments and long-term dynamics in natural systems. PMID- 28904774 TI - Phenotypic differentiation of the Solidago virgaurea complex along an elevational gradient: Insights from a common garden experiment and population genetics. AB - Plant species distributed along wide elevational or latitudinal gradients show phenotypic variation due to their heterogeneous habitats. This study investigated whether phenotypic variation in populations of the Solidago virgaurea complex along an elevational gradient is caused by genetic differentiation. A common garden experiment was based on seeds collected from nine populations of the S. virgaurea complex growing at elevations from 1,597 m to 2,779 m a.s.l. on Mt. Norikura in central Japan. Population genetic analyses with microsatellite markers were used to infer the genetic structure and levels of gene flow between populations. Leaf mass per area was lower, while leaf nitrogen and chlorophyll concentrations were greater for higher elevations at which seeds were originally collected. For reproductive traits, plants derived from higher elevations had larger flower heads on shorter stems and flowering started earlier. These elevational changes in morphology were consistent with the clines in the field, indicating that phenotypic variation along the elevational gradient would have been caused by genetic differentiation. However, population genetic analysis using 16 microsatellite loci suggested an extremely low level of genetic differentiation of neutral genes among the nine populations. Analysis of molecular variance also indicated that most genetic variation was partitioned into individuals within a population, and the genetic differentiation among the populations was not significant. This study suggests that genome regions responsible for adaptive traits may differ among the populations despite the existence of gene flow and that phenotypic variation of the S. virgaurea complex along the elevational gradient is maintained by strong selection pressure. PMID- 28904775 TI - How shrub encroachment under climate change could threaten pollination services for alpine wildflowers: A case study using the alpine skypilot, Polemonium viscosum. AB - : Under climate change, shrubs encroaching into high altitude plant communities disrupt ecosystem processes. Yet effects of encroachment on pollination mutualisms are poorly understood. Here, we probe potential fitness impacts of interference from encroaching Salix (willows) on pollination quality of the alpine skypilot, Polemonium viscosum. Overlap in flowering time of Salix and Polemonium is a precondition for interference and was surveyed in four extant and 25 historic contact zones. Pollinator sharing was ascertained from observations of willow pollen on bumble bees visiting Polemonium flowers and on Polemonium pistils. We probed fitness effects of pollinator sharing by measuring the correlation between Salix pollen contamination and seed set in naturally pollinated Polemonium. To ascertain whether Salix interference occurred during or after pollination, we compared seed set under natural pollination, conspecific pollen addition, and Salix pollen addition. In current and past contact zones Polemonium and Salix overlapped in flowering time. After accounting for variance in flowering date due to latitude, Salix and Polemonium showed similar advances in flowering under warmer summers. This trend supports the idea that sensitivity to temperature promotes reproductive synchrony in both species. Salix pollen is carried by bumble bees when visiting Polemonium flowers and accounts for up to 25% of the grains on Polemonium pistils. Salix contamination correlates with reduced seed set in nature and when applied experimentally. Postpollination processes likely mediate these deleterious effects as seed set in nature was not limited by pollen delivery. SYNTHESIS: As willows move higher with climate change, we predict that they will drive postpollination interference, reducing the fitness benefits of pollinator visitation for Polemonium and selecting for traits that reduce pollinator sharing. PMID- 28904777 TI - How relative size and abundance structures the relationship between size and individual growth in an ontogenetically piscivorous fish. AB - While individual growth ultimately reflects the quality and quantity of food resources, intra and interspecific interactions for these resources, as well as individual size, may have dramatic impacts on growth opportunity. Out-migrating anadromous salmonids make rapid transitions between habitat types resulting in large pulses of individuals into a given location over a short period, which may have significant impact on demand for local resources. We evaluated the spatial and temporal variation in IGF-1 concentrations (a proxy for growth rate) and the relationship between size and concentration for juvenile Chinook salmon in Puget Sound, WA, USA, as a function of the relative size and abundance of both Chinook salmon and Pacific herring, a species which commonly co-occurs with salmonids in nearshore marine habitats. The abundance of Chinook salmon and Pacific herring varied substantially among the sub-basins as function of outmigration timing and spawn timing, respectively, while size varied systematically and consistently for both species. Mean IGF-1 concentrations were different among sub-basins, although patterns were not consistent through time. In general, size was positively correlated with IGF-1 concentration, although the slope of the relationship was considerably higher where Pacific herring were more abundant than Chinook salmon; specifically where smaller individual herring, relative to Chinook salmon, were more abundant. Where Pacific herring were less abundant than Chinook salmon, IGF 1 concentrations among small and large Chinook salmon were more variable and showed no consistent increase for larger individuals. The noticeable positive effect of relative Pacific herring abundance on the relationship between size and individual growth rates likely represents a shift to predation based on increased IGF-1 concentrations for individual Chinook salmon that are large enough to incorporate fish into their diet and co-occur with the highest abundances of Pacific herring. PMID- 28904776 TI - Escaping introns in COI through cDNA barcoding of mushrooms: Pleurotus as a test case. AB - DNA barcoding involves the use of one or more short, standardized DNA fragments for the rapid identification of species. A 648-bp segment near the 5' terminus of the mitochondrial cytochrome c oxidase subunit I (COI) gene has been adopted as the universal DNA barcode for members of the animal kingdom, but its utility in mushrooms is complicated by the frequent occurrence of large introns. As a consequence, ITS has been adopted as the standard DNA barcode marker for mushrooms despite several shortcomings. This study employed newly designed primers coupled with cDNA analysis to examine COI sequence diversity in six species of Pleurotus and compared these results with those for ITS. The ability of the COI gene to discriminate six species of Pleurotus, the commonly cultivated oyster mushroom, was examined by analysis of cDNA. The amplification success, sequence variation within and among species, and the ability to design effective primers was tested. We compared ITS sequences to their COI cDNA counterparts for all isolates. ITS discriminated between all six species, but some sequence results were uninterpretable, because of length variation among ITS copies. By comparison, a complete COI sequences were recovered from all but three individuals of Pleurotus giganteus where only the 5' region was obtained. The COI sequences permitted the resolution of all species when partial data was excluded for P. giganteus. Our results suggest that COI can be a useful barcode marker for mushrooms when cDNA analysis is adopted, permitting identifications in cases where ITS cannot be recovered or where it offers higher resolution when fresh tissue is. The suitability of this approach remains to be confirmed for other mushrooms. PMID- 28904778 TI - The influence of herbivory and weather on the vital rates of two closely related cactus species. AB - Herbivory has long been recognized as a significant driver of plant population dynamics, yet its effects along environmental gradients are unclear. Understanding how weather modulates plant-insect interactions can be particularly important for predicting the consequences of exotic insect invasions, and an explicit consideration of weather may help explain why the impact can vary greatly across space and time. We surveyed two native prickly pear cactus species (genus Opuntia) in the Florida panhandle, USA, and their specialist insect herbivores (the invasive South American cactus moth, Cactoblastis cactorum, and three native insect species) for five years across six sites. We used generalized linear mixed models to assess the impact of herbivory and weather on plant relative growth rate (RGR) and sexual reproduction, and we used Fisher's exact test to estimate the impact of herbivory on survival. Weather variables (precipitation and temperature) were consistently significant predictors of vital rate variation for both cactus species, in contrast to the limited and varied impacts of insect herbivory. Weather only significantly influenced the impact of herbivory on Opuntia humifusa fruit production. The relationships of RGR and fruit production with precipitation suggest that precipitation serves as a cue in determining the trade-off in the allocation of resources to growth or fruit production. The presence of the native bug explained vital rate variation for both cactus species, whereas the invasive moth explained variation only for O. stricta. Despite the inconsistent effect of herbivory across vital rates and cactus species, almost half of O. stricta plants declined in size, and the invasive insect negatively affected RGR and fruit production. Given that fruit production was strongly size-dependent, this suggests that O. stricta populations at the locations surveyed are transitioning to a size distribution of predominantly smaller sizes and with reduced sexual reproduction potential. PMID- 28904779 TI - Discriminating patterns and drivers of multiscale movement in herpetofauna: The dynamic and changing environment of the Mojave desert tortoise. AB - Changes to animal movement in response to human-induced changes to the environment are of growing concern in conservation. Most research on this problem has focused on terrestrial endotherms, but changes to herpetofaunal movement are also of concern given their limited dispersal abilities and specialized thermophysiological requirements. Animals in the desert region of the southwestern United States are faced with environmental alterations driven by development (e.g., solar energy facilities) and climate change. Here, we study the movement ecology of a desert species of conservation concern, the Mojave desert tortoise (Gopherus agassizii). We collected weekly encounter locations of marked desert tortoises during the active (nonhibernation) seasons in 2013-2015, and used those data to discriminate movements among activity centers from those within them. We then modeled the probability of movement among activity centers using a suite of covariates describing characteristics of tortoises, natural and anthropogenic landscape features, vegetation, and weather. Multimodel inference indicated greatest support for a model that included individual tortoise characteristics, landscape features, and weather. After controlling for season, date, age, and sex, we found that desert tortoises were more likely to move among activity centers when they were further from minor roads and in the vicinity of barrier fencing; we also found that movement between activity centers was more common during periods of greater rainfall and during periods where cooler temperatures coincided with lower rainfall. Our findings indicate that landscape alterations and climate change both have the potential to impact movements by desert tortoises during the active season. This study provides an important baseline against which we can detect future changes in tortoise movement behavior. PMID- 28904780 TI - Spatial patterns of hypolithic cyanobacterial diversity in Northern Australia. AB - Photosynthetic microbial communities under translucent rocks (hypolithic) are found in many arid regions. At the global scale, there has been little intercontinental gene flow, and at a local scale, microbial composition is related to fine-scale features of the rocks and their environment. Few studies have investigated patterns of hypolithic community composition at intermediate distances. We examined hypolithic cyanobacterial diversity in semi-arid Australia along a 10-km transect by sampling six rocks from four adjacent 1 m2 quadrats ("distance zero") and from additional quadrats at 10, 100, 1,000, and 10,000 m to test the hypothesis that diversity would increase with the number of rocks sampled and distance. A total of 3,108 cyanobacterial operational taxonomic units (OTUs) were detected. Most were neither widespread nor abundant. The few that were widespread tended to be abundant. There was no difference in the community composition between the four sites at distance zero, but the samples 10 m away were significantly different, as were those at all other distances compared to distance zero. Many additional OTUs were recorded with increasing distance up to 100 m. These patterns of distribution are consistent with a colonization model involving dispersal from rock to rock. Our results indicate that distance was a significant factor that can be confounded by interrock differences. Most diversity was represented in the first 100 m of the transect, with an additional 1.5% of the total diversity added by the sample at 1 km, but only 0.2% added with the addition of the 10-km site. PMID- 28904781 TI - Sharing is caring? Measurement error and the issues arising from combining 3D morphometric datasets. AB - Geometric morphometrics is routinely used in ecology and evolution and morphometric datasets are increasingly shared among researchers, allowing for more comprehensive studies and higher statistical power (as a consequence of increased sample size). However, sharing of morphometric data opens up the question of how much nonbiologically relevant variation (i.e., measurement error) is introduced in the resulting datasets and how this variation affects analyses. We perform a set of analyses based on an empirical 3D geometric morphometric dataset. In particular, we quantify the amount of error associated with combining data from multiple devices and digitized by multiple operators and test for the presence of bias. We also extend these analyses to a dataset obtained with a recently developed automated method, which does not require human-digitized landmarks. Further, we analyze how measurement error affects estimates of phylogenetic signal and how its effect compares with the effect of phylogenetic uncertainty. We show that measurement error can be substantial when combining surface models produced by different devices and even more among landmarks digitized by different operators. We also document the presence of small, but significant, amounts of nonrandom error (i.e., bias). Measurement error is heavily reduced by excluding landmarks that are difficult to digitize. The automated method we tested had low levels of error, if used in combination with a procedure for dimensionality reduction. Estimates of phylogenetic signal can be more affected by measurement error than by phylogenetic uncertainty. Our results generally highlight the importance of landmark choice and the usefulness of estimating measurement error. Further, measurement error may limit comparisons of estimates of phylogenetic signal across studies if these have been performed using different devices or by different operators. Finally, we also show how widely held assumptions do not always hold true, particularly that measurement error affects inference more at a shallower phylogenetic scale and that automated methods perform worse than human digitization. PMID- 28904782 TI - Molecular phylogeny and phylogeography of genus Pseudois (Bovidae, Cetartiodactyla): New insights into the contrasting phylogeographic structure. AB - Blue sheep, Pseudois nayaur, is endemic to the Tibetan Plateau and the surrounding mountains, which are the highest-elevation areas in the world. Classical morphological taxonomy suggests that there are two subspecies in genus Pseudois (Bovidae, Artiodactyla), namely Pseudois nayaur nayaur and Pseudois nayaur szechuanensis. However, the validity and geographic characteristics of these subspecies have never been carefully discussed and analyzed. This may be partially because previous studies have mainly focused on the vague taxonomic status of Pseudois schaeferi (dwarf blue sheep). Thus, there is an urgent need to investigate the evolutionary relationship and taxonomy system of this genus. This study enriches a previous dataset by providing a large number of new samples, based on a total of 225 samples covering almost the entire distribution of blue sheep. Molecular data from cytochrome b and the mitochondrial control region sequences were used to reconstruct the phylogeny of this species. The phylogenetic inferences show that vicariance plays an important role in diversification within this genus. In terms of molecular dating results and biogeographic analyses, the striking biogeographic pattern coincides significantly with major geophysical events. Although the results raise doubt about the present recognized distribution range of blue sheep, they have corroborated the validity of the identified subspecies in genus Pseudois. Meanwhile, these results demonstrate that the two geographically distinct populations, the Helan Mountains and Pamir Plateau populations, have been significantly differentiated from the identified subspecies, a finding that challenges the conventional taxonomy of blue sheep. PMID- 28904783 TI - Making the most of survey data: Incorporating age uncertainty when fitting growth parameters. AB - Individual growth is an important parameter and is linked to a number of other biological processes. It is commonly modeled using the von Bertalanffy growth function (VBGF), which is regularly fitted to age data where the ages of the animals are not known exactly but are binned into yearly age groups, such as fish survey data. Current methods of fitting the VBGF to these data treat all the binned ages as the actual ages. We present a new VBGF model that combines data from multiple surveys and allows the actual age of an animal to be inferred. By fitting to survey data for Atlantic herring (Clupea harengus) and Atlantic cod (Gadus morhua), we compare our model with two other ways of combining data from multiple surveys but where the ages are as reported in the survey data. We use the fitted parameters as inputs into a yield-per-recruit model to see what would happen to advice given to management. We found that each of the ways of combining the data leads to different parameter estimates for the VBGF and advice for policymakers. Our model fitted to the data better than either of the other models and also reduced the uncertainty in the parameter estimates and models used to inform management. Our model is a robust way of fitting the VBGF and can be used to combine data from multiple sources. The model is general enough to fit other growth curves for any taxon when the age of individuals is binned into groups. PMID- 28904784 TI - Marine dock pilings foster diverse, native cryptobenthic fish assemblages across bioregions. AB - Anthropogenic habitats are increasingly prevalent in coastal marine environments. Previous research on sessile epifauna suggests that artificial habitats act as a refuge for nonindigenous species, which results in highly homogenous communities across locations. However, vertebrate assemblages that live in association with artificial habitats are poorly understood. Here, we quantify the biodiversity of small, cryptic (henceforth "cryptobenthic") fishes from marine dock pilings across six locations over 35 degrees of latitude from Maine to Panama. We also compare assemblages from dock pilings to natural habitats in the two southernmost locations (Panama and Belize). Our results suggest that the biodiversity patterns of cryptobenthic fishes from dock pilings follow a Latitudinal Diversity Gradient (LDG), with average local and regional diversity declining sharply with increasing latitude. Furthermore, a strong correlation between community composition and spatial distance suggests distinct regional assemblages of cryptobenthic fishes. Cryptobenthic fish assemblages from dock pilings in Belize and Panama were less diverse and had lower densities than nearby reef habitats. However, dock pilings harbored almost exclusively native species, including two species of conservation concern absent from nearby natural habitats. Our results suggest that, in contrast to sessile epifaunal assemblages on artificial substrates, artificial marine habitats can harbor diverse, regionally characteristic assemblages of vertebrates that follow macroecological patterns that are well documented for natural habitats. We therefore posit that, although dock pilings cannot function as a replacement for natural habitats, dock pilings may provide cost-effective means to preserve native vertebrate biodiversity, and provide a habitat that can be relatively easily monitored to track the status and trends of fish biodiversity in highly urbanized coastal marine environments. PMID- 28904785 TI - Genomic timetree and historical biogeography of Caribbean island ameiva lizards (Pholidoscelis: Teiidae). AB - The phylogenetic relationships and biogeographic history of Caribbean island ameivas (Pholidoscelis) are not well-known because of incomplete sampling, conflicting datasets, and poor support for many clades. Here, we use phylogenomic and mitochondrial DNA datasets to reconstruct a well-supported phylogeny and assess historical colonization patterns in the group. We obtained sequence data from 316 nuclear loci and one mitochondrial marker for 16 of 19 extant species of the Caribbean endemic genus Pholidoscelis. Phylogenetic analyses were carried out using both concatenation and species tree approaches. To estimate divergence times, we used fossil teiids to calibrate a timetree which was used to elucidate the historical biogeography of these lizards. All phylogenetic analyses recovered four well-supported species groups (clades) recognized previously and supported novel relationships of those groups, including a (P. auberi + P. lineolatus) clade (western + central Caribbean), and a (P. exsul + P. plei) clade (eastern Caribbean). Divergence between Pholidoscelis and its sister clade was estimated to have occurred ~25 Ma, with subsequent diversification on Caribbean islands occurring over the last 11 Myr. Of the six models compared in the biogeographic analyses, the scenario which considered the distance among islands and allowed dispersal in all directions best fit the data. These reconstructions suggest that the ancestor of this group colonized either Hispaniola or Puerto Rico from Middle America. We provide a well-supported phylogeny of Pholidoscelis with novel relationships not reported in previous studies that were based on significantly smaller datasets. We propose that Pholidoscelis colonized the eastern Greater Antilles from Middle America based on our biogeographic analysis, phylogeny, and divergence time estimates. The closing of the Central American Seaway and subsequent formation of the modern Atlantic meridional overturning circulation may have promoted dispersal in this group. PMID- 28904786 TI - Phylogenetic position and age of Lake Baikal candonids (Crustacea, Ostracoda) inferred from multigene sequence analyzes and molecular dating. AB - With 104 endemic species family Candonidae is one of the most diverse crustacean groups in Lake Baikal, yet their phylogenetic relationships and position in the family have not been addressed so far. Here, we study the phylogenetic position of Baikal candonids within the family and their evolutionary history using molecular markers for the first time since their original description. We choose 10 Baikal and 28 species from around the world, and three ribosomal RNA-s (18S, 28S, and 16S), and analyze individual and concatenated datasets using Bayesian Inference in MrBayes and BEAST. For molecular divergence time estimates, four fossil records are used to calibrate the root and three internal nodes. The 28S dataset is tested under the strict molecular clock, while for other data we use relaxed clocks. Resulting trees show incongruence between molecular and fossil divergence time estimates, with the former suggesting older ages. Strict molecular clock analysis results in narrower node age confidence intervals and younger time estimates than other analysis. All trees support at least two candonid lineages in Baikal, with two independent colonization events, and 28S suggests a major radiation between 12 and 5 Mya. This divergence time estimate mostly agrees with another, unrelated, ostracod group in the lake and other lake animals as well. Baikal candonid clades show a close phylogenetic relationship with Palearctic lineages, but their deep divergence is indicative of separate genera. Results also suggest a monophyly of tribes that today live exclusively in subterranean waters, and we offer several hypotheses of their evolutionary history. PMID- 28904787 TI - Spatiotemporal variability of soil respiration in a seasonal tropical forest. AB - We monitored soil CO 2 effluxes for over 3 years in a seasonally wet tropical forest in Central Panama using automated and manual measurements from 2013 to 2016. The measurements displayed a high degree of spatial and temporal variability. Temporal variability could be largely explained by surface soil water dynamics over a broad range of temporal scales. Soil moisture was responsible for seasonal cycles, diurnal cycles, intraseasonal variability such as rain-induced pulses following dry spells, as well as suppression during near saturated conditions, and ultimately, interannual variability. Spatial variability, which remains largely unexplained, revealed an emergent role of forest structure in conjunction with physical drivers such as soil temperature and topography. Mean annual soil CO 2 effluxes (+/-SE) amounted to 1,613 (+/-59) gC m-2 year-1 with an increasing trend in phase with an El Nino/Southern Oscillation (ENSO) cycle which culminated with the strong 2015-2016 event. We attribute this trend to a relatively mild wet season during which soil saturated conditions were less persistent. PMID- 28904789 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/ece3.2809.]. PMID- 28904788 TI - Biogeography and systematics of endemic island damselflies: The Nesobasis and Melanesobasis (Odonata: Zygoptera) of Fiji. AB - The study of island fauna has greatly informed our understanding of the evolution of diversity. We here examine the phylogenetics, biogeography, and diversification of the damselfly genera Nesobasis and Melanesobasis, endemic to the Fiji Islands, to explore mechanisms of speciation in these highly speciose groups. Using mitochondrial (COI, 12S) and nuclear (ITS) replicons, we recovered garli-part maximum likelihood and mrbayes Bayesian phylogenetic hypotheses for 26 species of Nesobasis and eight species/subspecies of Melanesobasis. Biogeographical patterns were explored using lagrange and bayes-lagrange and interpreted through beast relaxed clock dating analyses. We found that Nesobasis and Melanesobasis have radiated throughout Fiji, but are not sister groups. For Nesobasis, while the two largest islands of the archipelago-Viti Levu and Vanua Levu-currently host two distinct species assemblages, they do not represent phylogenetic clades; of the three major groupings each contains some Viti Levu and some Vanua Levu species, suggesting independent colonization events across the archipelago. Our beast analysis suggests a high level of species diversification around 2-6 Ma. Our ancestral area reconstruction (rasp-lagrange) suggests that both dispersal and vicariance events contributed to the evolution of diversity. We thus conclude that the evolutionary history of Nesobasis and Melanesobasis is complex; while inter-island dispersal followed by speciation (i.e., peripatry) has contributed to diversity, speciation within islands appears to have taken place a number of times as well. This speciation has taken place relatively recently and appears to be driven more by reproductive isolation than by ecological differentiation: while species in Nesobasis are morphologically distinct from one another, they are ecologically very similar, and currently are found to exist sympatrically throughout the islands on which they are distributed. We consider the potential for allopatric speciation within islands, as well as the influence of parasitic endosymbionts, to explain the high rates of speciation in these damselflies. PMID- 28904790 TI - Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in retail food in Singapore. AB - We characterised 227 Staphylococcus aureus isolates from retail food and food handlers' gloves samples obtained through food surveillance and risk assessment studies between 2011 and 2014. Of 227 isolates, five (2.2%) were methicillin resistant and belonged to sequence types ST80 (n = 3) and ST6 (n = 2). All five isolates belonged to SCCmec type IV, were Panton-Valentine leukocidin (pvl) negative and staphylococcal enterotoxin genes-positive. Resistance to azithromycin was found in ST80 isolates, in addition to resistance to beta lactams. Our finding of two clinically relevant methicillin-resistant S. aureus (MRSA) strains (ST80 and ST6) in ready-to-eat food and food contact surfaces at retail in Singapore suggests food and food contact surfaces as potential environmental sources of MRSA in the community. PMID- 28904791 TI - Brucellosis in livestock and wildlife: zoonotic diseases without pandemic potential in need of innovative one health approaches. AB - Human brucellosis remains the commonest zoonotic disease worldwide with more than 500 000 new cases annually. Understanding the biology of Brucella infections and the transmission patterns at the wildlife/livestock/human interface is of paramount importance before implementing any brucellosis control or eradication program in animals, even more so should interventions be justified within One Health. In addition to calling for transdisciplinary collaboration, One Health formally aims to conserve the environment and to promote the well-being of animals. In this opinion paper, the One Health approach of brucellosis is reviewed in the industrialized and the low and middle income countries, highlighting pitfalls and shortcomings of serological studies and discussing the role of urban and peri-urban farming for the re-emergence of brucellosis in the developing world. The role of wildlife as a potential reservoir is highlighted and different management strategies are discussed. Lastly, beyond its role in the control of brucellosis, the ethical dimension of culling wildlife to control disease emergence or spill-back of infections in livestock is discussed. Core transdisciplinary competencies such as values and ethics are critically important in guiding the development of One Health curricula and in continuing professional education, as they describe the knowledge, skills, and attitudes required to be effective. A conceptual framework needs to be developed from inception to knowledge translation. Importantly, transdisciplinary competencies should be developed as an adjunct to discipline-specific areas of expertise, not as a replacement. A profound understanding of the biology of infectious agents is and will always remain a pre-requisite for any sound One Health approach. PMID- 28904792 TI - Desmoplastic small round cell tumors of the pleura: a review of the clinical literature. AB - Desmoplastic small round cell tumor of the pleura is a rare malignancy, with only a few cases reported in the scientific literature. The aim of the present review is to discuss the demographic, pathological, clinical, and therapeutic features of this rare tumor. English-language articles published since 1989, when the first case of desmoplastic small round cell tumor of the pleura was described, were retrieved, and fifteen cases included in fourteen articles were revised. The mean age of the patients was 25.5 years, out of them 60% were males. Chest pain, pleural effusion, and dyspnea were the most common clinical manifestations, while chest roentgenogram and computed tomography were the imaging techniques most commonly used. Surgical biopsy was employed in 80% of the cases for diagnosis. A multidisciplinary approach consisting in a combination of surgery with chemotherapy and radiation therapy was adopted in most cases. Only two patients (13.3%) were alive at 3 years from diagnosis, reflecting the aggressiveness of the disease, and the poor outcomes of the treatments currently available. Desmoplastic small round cell tumors of the pleura are extremely aggressive and challenging to diagnose, because of their rarity and unspecific demographic, clinical, and radiological features. An in-depth knowledge of such features is necessary for the optimal management of patients with this rare malignancy. PMID- 28904793 TI - Relationship between engagement and level of functional status in older adults. AB - : Functional status is an important component of quality of life for older adults and for their caregivers. Factors associated with level of functional status include age, comorbidity, cognitive status, depression, social support, and activity. Of the types of activity linked with functional status, the strongest evidence is for physical exercise, with weaker evidence for social and productive activity. Engagement is a construct including motivation, commitment, and participation. OBJECTIVE: The objective of this study was to determine whether or not engagement is associated with level of functional status after controlling for age, comorbidity, and depression among older adults. METHODS: In all, 92 older adults were recruited from senior living centers and a university-based senior exercise group. The main independent variable was engagement. Other independent variables were age, comorbidity, and depression. The dependent variable was level of functional status. Two different measures of level of functional status were used: the Katz Activities of Daily Living Index and the Lawton-Brody Instrumental Activities of Daily Living Scale. RESULTS: Engagement was a significant predictor of Lawton-Brody Instrumental Activities of Daily Living Scale level of function in the Lawton-Brody model (odds ratio: 1.147 (1.011-1.302)) and age was a significant negative predictor (odds ratio: 0.838 (0.769-0.914)). There were no significant predictors in the Katz model. CONCLUSION: Engagement is a significant predictor of perfect Lawton-Brody Instrumental Activities of Daily Living Scale score after controlling for age, comorbidity, and depression. Health-care professionals should consider including engagement in their assessment of older clients, whether using formal instruments such as the Engagement with Meaningful Activity Survey or assessing informally. PMID- 28904794 TI - Dexmedetomidine provides less body motion and respiratory depression during sedation in double-balloon enteroscopy than midazolam. AB - OBJECTIVES: Patients undergoing double-balloon enteroscopy require sedatives such as midazolam; however, patient's body motion often hampers the outcome of double balloon enteroscopy. Recently, dexmedetomidine has been used for endoscopic sedation and was reported to effectively reduce body motion. This study aimed to evaluate the efficacy and safety of sedation with dexmedetomidine in double balloon enteroscopy (UMIN ID000015785). METHODS: A prospective, observational study was conducted in 81 patients who underwent 111 double-balloon enteroscopy from July to December 2015 (dexmedetomidine group). The medical records of 112 patients who underwent 166 double-balloon enteroscopy with midazolam and pentazocine sedation from January 1 to October 31, 2014, were used for comparison (midazolam group). After propensity score matching, 182 double-balloon enteroscopy (91 double-balloon enteroscopy for each group) were analyzed. RESULTS: There were 13 cases (11.7%) with body movements in the dexmedetomidine group. Comparison of the two groups matched by propensity score showed that the dexmedetomidine group had less body movement (12.1% vs 34.1%, p = 0.001) and less respiratory depression (50.5% vs 68.1%, p = 0.023). Hypotension (8.8% vs 4.4%, p = 0.232) and bradycardia (2.2% vs 0%, p = 0.497) were not significantly different in the two groups. CONCLUSION: Using dexmedetomidine for conscious sedation can reduce body motion and respiratory depression compared to our previous records. PMID- 28904795 TI - Cervical superficial myofibroblastoma: Case report and review of the literature. AB - Superficial myofibroblastoma of the lower female genital tract is a rare benign, recently recognized neoplasm that mostly affects the vulvovaginal area. Our report discusses a case of cervical superficial myofibroblastoma of the lower female genital tract in a 45-year-old patient who is presented with menometrorrhagia. On examination, she had multiple uterine fibroids and a circumscribed submucosal mass lesion involving the anterior lip of cervix. At hysterectomy, histopathological examination of the cervical mass revealed a relatively hypocellular tumor consisted of bland spindled and stellate cells. An immunohistochemistry evaluation revealed reactivity for CD34, desmin, and smooth muscle actin. This neoplasm should be included in the differential diagnosis of cervical mass lesions. This tumor also needs to be differentiated from other mesenchymal lesions of lower female genital tract. PMID- 28904796 TI - Endovascular management of symptomatic cerebral aneurysm thromboembolism due to pre-aneurysmal arterial stenosis. AB - BACKGROUND: Pre-aneurysmal internal carotid steno-occlusive disease resulting in cerebral intra-aneurysmal thrombosis and subsequent embolic infarction has not been previously described. CONCLUSION: Antithrombotic treatment for dissolution of the thrombus and pre-aneurysmal stent angioplasty followed by Pipeline embolization flow diverter placement through the aneurysm is a safe and feasible management option. PMID- 28904797 TI - A cross-validation-based approach for delimiting reliable home range estimates. AB - BACKGROUND: With decreasing costs of GPS telemetry devices, data repositories of animal movement paths are increasing almost exponentially in size. A series of complex statistical tools have been developed in conjunction with this increase in data. Each of these methods offers certain improvements over previously proposed methods, but each has certain assumptions or shortcomings that make its general application difficult. In the case of the recently developed Time Local Convex Hull (T-LoCoH) method, the subjectivity in parameter selection serves as one of the primary impediments to its more widespread use. While there are certain advantages to the flexibility it offers for question-driven research, the lack of an objective approach for parameter selection may prevent some users from exploring the benefits of the method. METHODS: Here we present a cross-validation based approach for selecting parameter values to optimize the T-LoCoH algorithm. We demonstrate the utility of the approach using a case study from the Etosha National Park anthrax system. RESULTS: Utilizing the proposed algorithm, rather than the guidelines in the T-LoCoH documentation, results in significantly different values for derived site fidelity metrics. CONCLUSIONS: Due to its basis in principles of cross-validation, the application of this method offers a more objective approach than the relatively subjective guidelines set forth in the T LoCoH documentation and enables a more accurate basis for the comparison of home ranges among individuals and species, as well as among studies. PMID- 28904798 TI - Patterns of residual HIV-1 RNA shedding in the seminal plasma of patients on effective antiretroviral therapy. AB - BACKGROUND: More and more HIV-1-infected men on effective antiretroviral treatment (ART) have unprotected sex in order to procreate. The main factor influencing transmission is seminal HIV shedding. While the risk of HIV transmission is very low, it is difficult to assess in individuals. Nevertheless, it should be quantified. RESULTS: We retrospectively analysed seminal plasma HIV 1 shedding by 362 treated HIV-infected men attending a medically assisted reproduction centre (1998-2013) in order to determine its frequency, the impact of the antiretroviral regimen on HIV shedding, and to identify shedding patterns. The HIV-1 virus loads in 1396 synchronized blood and semen samples were measured, and antiretroviral treatment, biological and epidemiological data were recorded. We detected isolated HIV-1 shedding into the seminal plasma in 5.3% of patients on efficient antiretroviral treatment, but there was no association with the HIV antiretroviral drug regimen or the CD4 cell count. These men had undergone more regimen changes since treatment initiation and had been on the ongoing drug regimen longer than the non-shedding men. The patterns of HIV seminal shedding among patients with undetectable HIV blood virus load varied greatly. HIV seminal shedding can occur as long as 5 years after starting antiretroviral treatment. CONCLUSIONS: The seminal HIV load was used to monitor risk for infertile HIV infected patients on an assisted reproductive technology program. This can still be recommended for patients who recently (6 months) started ART, or those with a poor history of adherence to ART but may also be usefull for some patients during counselling. Residual HIV seminal shedding is probably linked to breaks in adherence to antiretroviral treatment but local genital factors cannot be ruled out. PMID- 28904799 TI - Clinical significance of measuring plasminogen activator inhibitor-1 in sepsis. AB - BACKGROUND: Disseminated thrombotic process in the microcirculation is considered to be an important cause of multiple organ dysfunction in sepsis. The fundamental purpose of this prothrombotic change was believed to be in the host defense against microbial dissemination. In that process, antifibrinolytic property plays an important role. MAIN BODY: For the understanding of pathophysiology of sepsis, it is quite useful to grasp the alterations in coagulation/fibrinolytic parameters, i.e., plasminogen activator and plasminogen activator inhibitor-1. They play crucial roles in the development of clot formation and disseminated intravascular coagulation that leads to fatal organ dysfunction. Basically, fibrinolysis is a simple system compared to the complex coagulation cascade. Plasmin is the only factor that regulates fibrinolysis, and this enzyme is modulated by several factors including plasminogen activators and plasminogen activator inhibitor-1. However, recent studies have elucidated the complex regulation of the production, activation, and inactivation of these fibrinolytic factors. CONCLUSION: The dynamic change of the fibrinolytic system plays a crucial role in the pathophysiology of sepsis. In this commentary, we introduce the recent advances of the research regarding fibrinolytic system. PMID- 28904800 TI - Alterations in hematologic indices during long-duration spaceflight. AB - BACKGROUND: Although a state of anemia is perceived to be associated with spaceflight, to date a peripheral blood hematologic assessment of red blood cell (RBC) indices has not been performed during long-duration space missions. METHODS: This investigation collected whole blood samples from astronauts participating in up to 6-months orbital spaceflight, and returned those samples (ambient storage) to Earth for analysis. As samples were always collected near undock of a returning vehicle, the delay from collection to analysis never exceeded 48 h. As a subset of a larger immunologic investigation, a complete blood count was performed. A parallel stability study of the effect of a 48 h delay on these parameters assisted interpretation of the in-flight data. RESULTS: We report that the RBC and hemoglobin were significantly elevated during flight, both parameters deemed stable through the delay of sample return. Although the stability data showed hematocrit to be mildly elevated at +48 h, there was an in flight increase in hematocrit that was ~3-fold higher in magnitude than the anticipated increase due to the delay in processing. CONCLUSIONS: While susceptible to the possible influence of dehydration or plasma volume alterations, these results suggest astronauts do not develop persistent anemia during spaceflight. PMID- 28904801 TI - Hypnotics use in children 0-18 months: moderate agreement between mother-reported survey data and prescription registry data. AB - BACKGROUND: Different methods in pharmacoepidemiology can be used to study hypnotic use in children. But neither questionnaire-based data nor prescription records can be considered a "gold standard". This study aimed to investigate the agreement between mother-reported questionnaire-based data and prescription record data for hypnotic drugs in children aged 0-18 months. The agreement was compared to the agreement for a group of antiepileptic drugs. METHODS: Prescription record data were collected from the Norwegian prescription database for 47,413 children also surveyed in the Norwegian mother and child cohort between 2005 and 2009. Agreement between in the two data sources was calculated using Cohens Kappa. Multinomial logistic regression was used to calculate the effect of sociodemographic variables on discrepancies in data sources. RESULTS: The agreement between mother-reported and dispensed hypnotics was less than 50% for all hypnotics. Sensitivity of reporting increased with number of filled prescriptions. The agreement of antiepileptic drugs was 92.9% in the same population. Of several sociodemographic factors only paternal educational level and maternal work situation was significantly related to agreement between prescription record and survey data. CONCLUSION: There was a moderate agreement between reported use and dispensed hypnotic drugs for infants and toddlers. Results indicate that sociodemographic factors play only a minor role in explaining discrepancy. PMID- 28904802 TI - Analytical study of 226Ra activity concentration in market consuming foodstuffs of Ramsar, Iran. AB - BACKGROUND: Ramsar, a city of Iran located on the coast of the Caspian Sea, has been considered to be enormously important due to its high natural radioactivity levels. People living in High Level Natural Radiation Areas (HLNRAs) have been exposed by several sources, one of which could be foodstuff. However, many studies have been carried out to measure the environmental radioactivity in Ramsar, but no survey has been conducted in all stapled consumed foods yet. This study was dedicated to determine 226Ra activity concentration in the daily diets of Ramsar residents as a probable exposure. METHODS: Approximately 70 different market samples were collected during the four seasons based on the daily consumption patterns of residents which have the highest consumption and their availability in the seasons. All samples, after washing, drying and pretreatment, were analyzed for 226Ra radionuclide determination by alpha-spectrometry. RESULTS: The mean radioactivity concentration of 226Ra ranged between 7 +/- 1 mBq Kg-1 wet weight in meat, and 318 +/- 118 mBq Kg-1 for tea dry leaves. The 226Ra activity concentrations in collected samples varied from below the minimum detectable activity up to 530 +/- 30 mBq Kg-1. To compare the results with United Nations Scientific Committee on Effects of Atomic Radiation (UNSCEAR) reference values, the 226Ra activity concentrations concluded from the results appear to be higher in milk, chicken and eggs and less in grain products, vegetables, fruits and fish products. These results indicate that no significant 226Ra contamination is present in market foodstuffs and provide reference values for the foodstuffs in Ramsar. CONCLUSIONS: Of the total daily dietary 226Ra exposure from market consuming foodstuffs for adults in Ramsar, the largest percentage was from wheat. The residents consuming wheat and manufacturing wheat products such as bread, pasta, porridge, crackers, biscuits, pancakes, pies, pastries, cakes, cookies, muffins, rolls, doughnuts, breakfast cereals and so on may receive an elevated dose in the diet. In conclusion, with regards to presence of 226Ra in foodstuffs it is necessary to monitor regularly the activity of 226Ra in foodstuffs including market and local foods. PMID- 28904803 TI - Comparative transcriptome analysis during early fruit development between three seedy citrus genotypes and their seedless mutants. AB - Identification of genes with differential transcript abundance (GDTA) in seedless mutants may enhance understanding of seedless citrus development. Transcriptome analysis was conducted at three time points during early fruit development (Phase 1) of three seedy citrus genotypes: Fallglo (Bower citrus hybrid (Citrus reticulata*C. reticulata*C. paradisi)*Temple (C. reticulata*C. sinensis)), grapefruit (C. paradisi), Pineapple sweet orange (C. sinensis), and their seedless mutants. Seed abortion in seedless mutants was observed at 26 days post anthesis (Time point 2). Affymetrix transcriptomic analysis revealed 359 to 1077 probe sets with differential transcript abundance in the comparison of seedless versus seedy fruits for each citrus genotypes and time points. The GDTA identified by 18 microarray probe sets were validated by qPCR. Hierarchical clustering analysis revealed a range of GDTA associated with development, hormone and protein metabolism, all of which may reflect genes associated with seedless fruit development. There were 14, 9 and 12 genes found exhibiting similar abundance ratios in all three seedless versus seedy genotype comparisons at time point 1, 2 and 3, respectively. Among those genes were genes coding for an aspartic protease and a cysteine protease, which may play important roles in seedless fruit development. New insights into seedless citrus fruit development may contribute to biotech approaches to create seedless cultivars. PMID- 28904804 TI - Bringing new medicines to women with epithelial ovarian cancer: what is the unmet medical need? AB - BACKGROUND: Therapy for advanced epithelial ovarian cancer (OC) includes first line platinum/taxane-containing chemotherapy and re-treatment with platinum containing regimens for disease recurrence in patients likely to respond again. Single-agent, non-platinum, cytotoxic agents are commonly used to treat patients resistant to platinum retreatment, but these agents are associated with dose limiting toxicities and response rates below 20%. MAIN BODY: Recent advances have led to novel targeted treatments for recurrent OC that offer opportunities to improve response rates and prolong progression-free intervals. However, they also add complexity to the process of selecting treatment for individual patients at different stages of the disease process. Advanced and recurrent OC is rarely cured. Multiple lines of platinum combinations, and nonplatinum chemotherapeutics eventually fail to achieve clinical benefit, thus other active and tolerable systemic therapies are needed. Consequently, the US Food and Drug Administration has created a mechanism for "accelerated approval" of new medicines in situations of high unmet medical need. CONCLUSION: We review the clinical implications of recent key clinical studies in these settings and outline the path forward for study design and approval of novel therapeutics to treat recurrent OC. PMID- 28904805 TI - High-dose levothyroxine for the management of bipolar affective disorder: two case reports. AB - In this article, we report two cases from our centre: case A has the longest recovery period and case B is one of the most complex from a diagnostic and management perspective, highlighting how treatment resistance can be overcome depending on patient response and needs. PMID- 28904806 TI - Do clinicians receive adequate training to identify trafficked persons? A scoping review of NHS Foundation Trusts. AB - OBJECTIVE: We investigate whether physicians in secondary care in the English NHS receive adequate training to recognise and appropriately refer for services those persons suspected to be victims of human trafficking. DESIGN: Freedom of Information requests were sent to the 105 England's NHS Trusts delivering acute care in England. SETTING: NHS Trusts providing secondary care in England. PARTICIPANTS: English NHS Trusts. MAIN OUTCOME MEASURES: We requested data about the training provided on human trafficking to clinicians, including the nature, delivery, and format of any education, and any planned training. RESULTS: A total of 89.5% of the 105 Trusts responded. Of these Trusts, 69% provide education to physicians on human trafficking, and a further 6% provide training but did not specify who received it. The majority of Trusts providing training did so within wider safeguarding provision (91%). Only one trust reported that it provides stand-alone training on trafficking to all its staff, including physicians. Within training offered by Trusts, 54% observed best practice providing training on the clinical indicators of trafficking, while 16% referenced the National Referral Mechanism. Amongst those not providing training, 39% of Trusts report provision is in development. CONCLUSIONS: Our results find that 25% of NHS Foundation Trusts appear to lack training for physicians around human trafficking. It is also of concern that of the Trusts who currently do not provide training, only 39% are developing training or planning to do so. There is an urgent need to review and update the scope of available training and bring it into alignment with current legislation. PMID- 28904807 TI - The return of a former foe: syphilis with antiphospholipid syndrome as a cause of acute stroke. AB - This article highlights a rare complication of syphilis infection and the importance of including syphilis and antiphospholipid antibody testing in the acute stroke screen.. PMID- 28904808 TI - Intracardiac fistula: an unusual complication of catheter-related blood stream infection. AB - In end stage renal disease patients on dialysis, the use of catheter as a vascular access is associated with a significant risk of sepsis compared to an arterio-venous fistula. Our case emphasizes the importance of having high index of suspicion for unusual complications in patients presenting with possible catheter-related blood stream infection and early use of complementary tools such as trans-oesophageal echocardiography whenever applicable. PMID- 28904809 TI - Magnetic resonance imaging performance for diagnosis of ovarian torsion in pregnant women with stimulated ovaries. AB - BACKGROUND: To determine if asymmetric ovarian edema on non-contrast MRI can be used to distinguish torsed from non-torsed stimulated ovaries in pregnant women. METHODS: In this retrospective study, our radiology database was searched for women who were pregnant and who had undergone ovarian stimulation and underwent MRI abdomen/pelvis from 1/2000-12/2012. At our institution, ultrasound is typically performed as a first line study for pregnant women with pelvic pain, with MR for those patients with indeterminate findings. 64 pregnant women (gestational age range 3-37 weeks) were included. MRI indication, prospective interpretation, operative diagnosis, and follow-up were recorded. Two blinded radiologists (with a third radiologist tie-breaker) independently measured and described the ovaries, including the likelihood of torsion. If one or both ovaries/adnexa had an underlying lesion such as a dermoid, cystadenoma, or abscess, the patient was excluded from size and signal intensity comparison (N = 14). For the remaining 50 women, comparison was made of the ovaries in women with normal ovaries (N = 27), stimulated ovaries without torsion (N = 11), non stimulated ovaries with torsion (N = 3), and stimulated ovaries with torsion (N = 3). Patients with asymmetric ovarian edema without stimulation or torsion (N = 3) and with polycystic ovary syndrome (N = 3) were analyzed separately. RESULTS: Average normal ovarian length was 3.2 cm, compared to 4.5 cm for asymmetric edema and 5.6-8.8 cm for the other four groups. Average difference in greatest right and left ovarian diameter was 19% for normal ovaries compared to 24-37% for the other 5 groups. Asymmetric signal on T2-weighted imaging (T2WI) was seen in 12% (3/27) of normal ovaries compared to 9% (1/11) of stimulated patients without torsion, 33% (1/3) of patients with PCOS and 67% (2/3) of patients with torsion both without and with stimulation. The correct diagnosis of torsion was made prospectively in 5/6 cases but retrospectively in only 3/6 cases. In patients with stimulation, correct diagnosis of torsion was made in 2/3 cases prospectively (both with asymmetric T2 signal) and retrospectively in only 1/3 cases. In 13/64 patients, other acute gynecologic and non-gynecologic findings were diagnosed on MRI. CONCLUSIONS: Enlarged edematous ovary can be seen with ovarian stimulation, ovarian torsion, or both. Although asymmetric ovarian edema occurred more frequently in patients with torsion than without, in pregnant patients with stimulated ovaries referred for MRI (typically after non-diagnostic ultrasound), ovarian torsion could not be confidently diagnosed or excluded retrospectively with non-contrast MRI. PMID- 28904810 TI - Nasal high flow treatment in preterm infants. AB - Nasal High Flow (HF) is a mode of 'non-invasive' respiratory support for preterm infants, with several potential modes of action, including generation of distending airway pressure, washout of the nasopharyngeal dead space, reduction of work of breathing, and heating and humidification of inspired gas. HF has several potential advantages over continuous positive airway pressure (CPAP), the most commonly applied form of non-invasive support, such as reduced nasal trauma, ease of use, and infant comfort, which has led to its rapid adoption into neonatal care. In recent years, HF has become a well-established and commonly applied treatment in neonatal care. Recent trials comparing HF and CPAP as primary support have had differing results. Meta-analyses suggest that primary HF results in an increased risk of treatment failure, but that 'rescue' CPAP use in those infants with HF failure results in no greater risk of mechanical ventilation. Even in studies with higher rates of HF failure, the majority of infants were successfully treated with HF, and rates of important neonatal morbidities did not differ between treatment groups. Importantly, these studies have included only infants born at >=28 weeks' gestational age (GA). The decision whether to apply primary HF will depend on the value placed on its advantages over CPAP by clinicians, the approach to surfactant treatment, and the severity of respiratory disease in the relevant population of preterm infants. Post extubation HF use results in similar rates of treatment failure, mechanical ventilation, and adverse events compared to CPAP. Post-extubation HF appears most suited to infants >=28 weeks; there are few published data for infants below this gestation, and available evidence suggests that these infants are at high risk of HF failure, although rates of intubation and other morbidities are similar to those seen with CPAP. There is no evidence that using HF to 'wean' off CPAP allows for respiratory support to be ceased more quickly, but given its advantages it would appear to be a suitable alternative in infants who require ongoing non-invasive support. Safety data from randomised trials are reassuring, although more evidence in extremely preterm infants (<28 weeks' GA) is required. PMID- 28904811 TI - Which symptoms contribute the most to patients' perception of health in multiple sclerosis? AB - BACKGROUND: Multiple sclerosis is a polysymptomatic disease. Little is known about relative contributions of the different multiple sclerosis symptoms to self perception of health. OBJECTIVES: To investigate the relationship between symptom severity in 11 domains affected by multiple sclerosis and self-rated health. METHODS: Multiple sclerosis patients in two multiple sclerosis centers assessed self-rated health with a validated instrument and symptom burden with symptoMScreen, a validated battery of Likert scales for 11 domains commonly affected by multiple sclerosis. Pearson correlations and multivariate linear regressions were used to investigate the relationship between symptoMScreen scores and self-rated health. RESULTS: Among 1865 multiple sclerosis outpatients (68% women, 78% with relapsing-remitting multiple sclerosis, mean age 46.38 +/- 12.47 years, disease duration 13.43 +/- 10.04 years), average self-rated health score was 2.30 ('moderate to good'). Symptom burden (composite symptoMScreen score) highly correlated with self-rated health (r = 0.68, P < 0.0001) as did each of the symptoMScreen domain subscores. In regression analysis, pain (t = 7.00), ambulation (t = 6.91), and fatigue (t = 5.85) contributed the highest amount of variance in self-rated health (P < 0.001). CONCLUSIONS: Pain contributed the most to multiple sclerosis outpatients' perception of health, followed by gait dysfunction and fatigue. These findings suggest that 'invisible disability' may be more important to patients' sense of wellbeing than physical disability, and challenge the notion that physical disability should be the primary outcome measure in multiple sclerosis. PMID- 28904812 TI - Strongest grip on the rod: tarsal morphology and attachment of Japanese pine sawyer beetles. PMID- 28904813 TI - Seasonal affective disorder and non-seasonal affective disorders: results from the NESDA study. AB - BACKGROUND: Seasonal affective disorder (SAD) is considered to be a subtype of depression. AIMS: To compare the clinical picture of SAD to non-seasonal affective disorders (non-SADs). METHOD: Diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) were established in 2185 participants of the Netherlands Study of Depression and Anxiety. The Seasonal Pattern Assessment Questionnaire was administered to diagnose SAD. Symptoms of depression and anxiety were measured with the Inventory of Depressive Symptoms, the Beck Anxiety Inventory and the Fear Questionnaire. RESULTS: Participants with SAD, participants with a lifetime bipolar disorder and participants with a lifetime comorbid anxiety and depressive disorder scored highest in terms of psychopathology in the past year. The seasonal distribution of major depressive episodes was not different for participants with or without SAD. CONCLUSIONS: SAD may be a measure of severity of depression with a subjectively perceived worsening of symptoms in the winter months. DECLARATION OF INTEREST: Y.M. has received research funding and served as a consultant for Royal Philips Electronics NV and The Litebook Company Ltd. W.A.N. has received grants from the Netherlands Organization for Health Research and Development, the European Union, the Stanley Medical Research Institute, Astra Zeneca, Eli Lilly, GlaxoSmithKline and Wyeth; has received honoraria/speaker's fees from Astra Zeneca, Pfizer, Servier and Wyeth; and has served in advisory boards for Astra Zeneca, Pfizer and Servier. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28904814 TI - Factors impacting perceived safety among staff working on mental health wards. AB - BACKGROUND: Safety at work is a core issue for mental health staff working on in patient units. At present, there is a limited theoretical base regarding which factors may affect staff perceptions of safety. AIMS: This study attempted to identify which factors affect perceived staff safety working on in-patient mental health wards. METHOD: A cross-sectional design was employed across 101 forensic and non-forensic mental health wards, over seven National Health Service trusts nationally. Measures included an online staff survey, Ward Features Checklist and recorded incident data. Data were analysed using categorical principal components analysis and ordinal regression. RESULTS: Perceptions of staff safety were increased by ward brightness, higher number of patient beds, lower staff to patient ratios, less dayroom space and more urban views. CONCLUSIONS: The findings from this study do not represent common-sense assumptions. Results are discussed in the context of the literature and may have implications for current initiatives aimed at managing in-patient violence and aggression. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license. PMID- 28904815 TI - Predictors, help-seeking behaviour and treatment coverage for depression in adults in Sehore district, India. AB - BACKGROUND: National Mental Health Survey found that in India, the point prevalence of major depressive disorder (MDD) was 2.7% and the treatment gap was 85.2%, whereas in Madhya Pradesh the point prevalence of MDD was 1.4% and the treatment gap was 80%. AIMS: To describe the baseline prevalence of depression among adults, association of various demographic and socioeconomic variables with depression and estimation of contact coverage for the same. METHOD: Population based cross-sectional survey of 3220 adults in Sehore district of Madhya Pradesh, India. The outcome of interest was a probable diagnosis of depression that was measured using the Patient Health Questionnaire (PHQ-9) and the proportion of individuals with depression (PHQ-9>9) who sought care for the same. The data were analysed using simple and multiple log-linear regression. RESULTS: Low educational attainment, unemployment and indebtedness were associated with both moderate/severe depression (PHQ-9 score >9) and severe depression only (PHQ-9 score >14), whereas age, caste and marital status were associated with only moderate or severe depression. Religion, type of house, land ownership and amount of loan taken were not associated with either moderate/severe or only severe depression. The contact coverage for moderate/severe depression was 13.08% (95% CI 10.2-16.63). CONCLUSIONS: There is an urgent need to bridge the treatment gap by targeting individuals with social vulnerabilities and integrating evidence based interventions in primary care. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28904816 TI - Regulation of hnRNPA1 by microRNAs controls the miR-18a-K-RAS axis in chemotherapy-resistant ovarian cancer. AB - The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a 3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a 5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor. PMID- 28904817 TI - IHC-based subcellular quantification provides new insights into prognostic relevance of FLIP and procaspase-8 in non-small-cell lung cancer. AB - In this study, we developed an image analysis algorithm for quantification of two potential apoptotic biomarkers in non-small-cell lung cancer (NSCLC): FLIP and procaspase-8. Immunohistochemical expression of FLIP and procaspase-8 in 184 NSCLC tumors were assessed. Individual patient cores were segmented and classified as tumor and stroma using the Definiens Tissue Studio. Subsequently, chromogenic expression of each biomarker was measured separately in the nucleus and cytoplasm and reported as a quantitative histological score. The software package pROC was applied to define biomarker thresholds. Cox proportional hazards analysis was applied to generate hazard ratios (HRs) and associated 95% CI for survival. High cytoplasmic expression of tumoral (but not stromal) FLIP was associated with a 2.5-fold increased risk of death in lung adenocarcinoma patients, even when adjusted for known confounders (HR 2.47, 95% CI 1.14-5.35). Neither nuclear nor cytoplasmic tumoral procaspase-8 expression was associated with overall survival in lung adenocarcinoma patients; however, there was a significant trend (P for trend=0.03) for patients with adenocarcinomas with both high cytoplasmic FLIP and high cytoplasmic procaspase-8 to have a multiplicative increased risk of death. Notably, high stromal nuclear procaspase-8 expression was associated with a reduced risk of death in lung adenocarcinoma patients (adjusted HR 0.31, 95% CI 0.15-0.66). On further examination, the cells with high nuclear procaspase-8 were found to be of lymphoid origin, suggesting that the better prognosis of patients with tumors with high stromal nuclear procaspase-8 is related to immune infiltration, a known favorable prognostic factor. No significant associations were detected in analysis of lung squamous cell carcinoma patients. Our results suggest that cytoplasmic expression of FLIP in the tumor and nuclear expression of procaspase-8 in the stroma are prognostically relevant in non-small-cell adenocarcinomas but not in squamous cell carcinomas of the lung. PMID- 28904818 TI - NF-kappaB pathway link with ER stress-induced autophagy and apoptosis in cervical tumor cells. AB - Targeting endoplasmic reticulum (ER) stress is being investigated for its anticancer effect in various cancers, including cervical cancer. However, the molecular pathways whereby ER stress mediates cell death remain to be fully elucidated. In this study, we confirmed that ER stress triggered by compounds such as brefeldin A (BFA), tunicamycin (TM), and thapsigargin (TG) leads to the induction of the unfolded protein response (UPR) in cervical cancer cell lines, which is characterized by elevated levels of inositol-requiring kinase 1alpha, glucose-regulated protein-78, and C/EBP homologous protein, and swelling of the ER observed by transmission electron microscope (TEM). We found that BFA significantly increased autophagy in tumor cells and induced TC-1 tumor cell death in a dose-dependent manner. BFA increased punctate staining of LC3 and the number of autophagosomes observed by TEM in TC-1 and HeLa cells. The autophagic flux was also assessed. Bafilomycin, which blocked degradation of LC3 in lysosomes, caused both LC3I and LC3II accumulation. BFA initiated apoptosis of TC 1 tumor cells through activation of the caspase-12/caspase-3 pathway. At the same time, BFA enhanced the phosphorylation of IkappaBalpha protein and translocation into the nucleus of NF-kappaB p65. Quinazolinediamine, an NF-kappaB inhibitor, attenuated both autophagy and apoptosis induced by BFA; meanwhile, it partly enhances survival of cervical cancer cells following BFA treatment. In conclusion, our results indicate that the cross-talk between ER stress, autophagy, apoptosis, and the NF-kappaB pathways controls the fate of cervical cancer cells. Careful evaluation should be given to the addition of an NF-kappaB pathway inhibitor to treat cervical cancer in combination with drugs that induce ER stress-mediated cell death. PMID- 28904819 TI - Prdx6 retards senescence and restores trabecular meshwork cell health by regulating reactive oxygen species. AB - A progressive decline in antioxidant potential and accumulation of reactive oxygen species (ROS) are major causes of pathogenesis of several diseases, including glaucoma. Trabecular meshwork (TM) dysfunction resulting in higher intraocular pressure (IOP) is a hallmark of glaucoma, but its causes are unclear. Using human (h) TM cells derived from glaucomatous and normal subjects of different ages and cells facing oxidative-stress, we showed that specific loss of moonlighting antioxidant protein Peroxiredoxin (Prdx) 6 in aging or in glaucomatous TM cells caused ROS accumulation and pathobiological changes in TM cells. Prdx6 limits the levels of ROS, thus preventing overstimulation of genes and resultant deleterious effects. We found that Prdx6 levels declined in aging and were reduced dramatically in glaucomatous and aged TM cells. Biochemical assays revealed enhanced levels of ROS, and high expression/activation of TGFbetas and its responsive extracellular matrix genes alpha-SM, fibronectin, TGase2 and Tsp1 in aged or glaucomatous cells. Furthermore, hTM cells displayed typical features of the combined effects of TGFbetas and oxidative-stress-induced cellular changes, showing increased levels of lipid peroxidation, oxidative DNA damage, and senescence markers p16, p21 and SA-betagal activity, along with reduced levels of telomerase expression and activity. Exposure to oxidative stress (H2O2) or knocking down of Prdx6 (with antisense) accelerated this process. Importantly, Prdx6 delivery to sick or aged TM cells reversed the process. We propose Prdx6 as a potential therapeutic target to guard the TM from oxidative-stress and age-dependent accumulation of ROS by balancing redox homeostasis to prevent ocular disorders, like glaucoma. PMID- 28904820 TI - Successful cerebral thrombectomy for a nonagenarian with stroke in the subacute phase after transcatheter aortic valve implantation. AB - BACKGROUND: Thromboembolic events are infrequent but serious complications of transcatheter aortic valve implantation (TAVI), occurring in 2.3-10% of the patients. However, the cause of post-TAVI stroke is unclear. CASE DESCRIPTION: A 90-year-old female underwent transfemoral-TAVI for severe aortic stenosis. Ten days later, she presented with an ischemic stroke of the left middle cerebral artery territory due to new-onset atrial fibrillation (NOAF). She underwent emergent endovascular thrombectomy with good reperfusion approximately 6 hours after onset of symptoms. At hospital discharge, her National Institutes of Health Stroke Scale score was 11. CONCLUSIONS: Although NOAF is rare during the subacute phase of TAVI, in this patient it might be the cause of her stroke. This finding suggests that dual antiplatelet therapy alone may be insufficient in the prevention of stroke after TAVI. Nonetheless, this case demonstrates the efficacy and safety of endovascular thrombectomy in patients with acute ischemic stroke caused by NOAF after TAVI. PMID- 28904821 TI - Endoscopic transnasal suprasellar approach for anterior clinoidal meningioma: A case report and review of the literature. AB - BACKGROUND: Anterior clinoidal meningiomas (ACM) are traditionally approached through transcranial routes. Due to their tendency to extend laterally and their proximity to vital neurovascular structures, the endoscopic transnasal suprasellar approach is still questionable. We present and describe an ACM case that underwent an endoscopic transnasal suprasellar approach, and provide a review of the literature and operative technique. CASE DESCRIPTION: A 56 year-old lady who presented with chronic left-sided decreased vision. Brain imaging revealed a lesion measuring 9 * 10 * 11 mm attached to the left anterior clinoid process (ACP) and extending to the left optic canal. Lesion was compressing the left optic nerve (ON) and abutting the supraclinoid part of the left internal carotid artery (ICA). Utilizing the endoscopic transnasal suprasellar approach, the meningioma was resected and the optic canal was decompressed. Reconstruction was achieved using fascia lata, vomer bone, and nasoseptal flap. A lumbar drain was inserted perioperatively. Patient had no perioperative morbidity and retained vision in the affected eye. CONCLUSIONS: Resection of selected ACMs can be safely achieved utilizing the endoscopic transnasal suprasellar approach. Although the literature lacks long-term outcome comparison between the transnasal and the traditional transcranial approaches, specifically addressing ACMs, this technique is becoming more popular over the last decade. More efforts should be directed towards implementing and reporting the endoscopic transnasal suprasellar approach for meningiomas of the anterior clinoid process. PMID- 28904823 TI - A novel drainage approach in patients with cholesterol granuloma: From petrous apex to mastoid air cell. AB - BACKGROUND: Cholesterol granulomas (CG) of the petrous apex (CGPA) are benign lesions that have high recurrence rates after surgical intervention. We describe the use of a robust silicon drain between the petrous apex and mastoid air cells to allow constant aeration of the lesion for preventing recurrence. CASE DESCRIPTION: A retrospective analysis was performed using the data of four patients treated at the Maastricht University Medical Centre between 2014 and 2016. Using the middle fossa approach, the petrous apex was reached, the cyst was opened, and the content aspirated. Subsequently, a robust silicon drain was placed between the cyst and mastoid air cell system. The outcome measures were clinical improvement of the symptoms and radiological parameters. The patients were female (n = 2) and male (n = 2) with an age range between 33 and 53 years at the time of the operation. Computed tomography and magnetic resonance imaging scans were used to confirm CG diagnosis. The most common presenting symptoms in our population were diplopia and headaches. The symptoms improved after surgery and there were no complications. Thus far, no recurrence has been observed and imaging shows aeration in the lesion area. CONCLUSION: The use of a robust drain seems to be an effective, safe, and feasible option to prevent recurrences in patients with CG. PMID- 28904822 TI - A parental perspective concerning barriers to care for neural tube defects in China. AB - BACKGROUND: The People's Republic of China (PRC) has the highest incidence of neural tube defects (NTDs) in the world. NTDs remain a significant contributor to the global burden of disease amendable to surgical care; however, no studies to date have evaluated the patients' perspective regarding perceived barriers to care. METHODS: The study was conducted at the Shanghai Children's Medical Center (SCMC) between 6/11/2014 and 7/17/2014. Surveys were administered to families presenting to the clinic of the SCMC director for Pediatric Neurosurgery. Additionally, orphaned patients under the care of the Baobei Foundation were surveyed for comparison. Participants were allowed to mark as many barriers on the survey as they deemed relevant to their experience. RESULTS: A total of 69 patients were surveyed. The most frequently chosen barrier to care, with a P value < 10-5, was that the referring physician did not know enough about the child's condition. As compared to the Baobei Foundation orphans, surveyed patients presented at an older age for initial treatment (7 months versus 1 month, P value = 0.001), and visited more hospitals before reaching SCMC (3.14 versus 1.0, P value < 10-5). CONCLUSIONS: The results of this study highlight the referring physician as a primary barrier to care. The younger age at time of treatment for Baobei orphans born with NTDs supports this finding, as they essentially bypassed the referral process. An elaboration on reasons for this real or perceived barrier may provide insight into a means for expedited diagnosis and treatment of NTDs within the PRC. PMID- 28904824 TI - A case of unruptured aneurysm of the internal carotid artery presenting as olfactory hallucinations. AB - BACKGROUND: Olfactory hallucination, a symptom of medial temporal lobe epilepsy, is rarely associated with unruptured intracranial aneurysms. CASE DESCRIPTION: We encountered this situation in a 70-year-old woman with an unruptured aneurysm at the bifurcation of the internal carotid and posterior communicating artery. We were able to achieve epileptic control by craniotomy clipping and medial temporal lesionectomy. CONCLUSION: According to our knowledge, previous reports are limited to cases of large middle cerebral artery aneurysms compressing the lateral orbitofrontal cortex, and this is apparently the first report of a case where olfactory hallucinations occurred from direct stimulation of the entorhinal cortex by an internal carotid and posterior communicating artery bifurcation aneurysm. We examined the pathophysiology underlying the development of olfactory hallucinations. We found craniotomy clipping and focal resection to be useful from the standpoint of seizure control. Whether seizure control can also be obtained with intracranial aneurysm coiling should be investigated in the future. PMID- 28904825 TI - Angiographic and epidemiological characteristics associated with aneurysm remnants after microsurgical clipping. AB - BACKGROUND: Despite new techniques for the treatment of cerebral aneurysms, the percentage of aneurysm remnants after surgical intervention seems to be relatively constant. The objective of this study was to assess angiographic and epidemiological features associated with aneurysm remnants after microsurgical clipping. METHODS: This study was conducted from February 2009 to August 2012 on a series of 90 patients with 105 aneurysms referred to the Santa Casa of Belo Horizonte who were surgically treated and angiographically controlled. RESULTS: Surgical clipping was considered incomplete in 13.3% of the aneurysms. The mean age of cases with an aneurysm remnant was 57.5 years, whereas the mean age without aneurysm remnant was 49.7 years (P = 0.02). Aneurysm remnants were detected more frequently on the internal carotid artery, nevertheless, no statistically significant differences were verified when comparing the locations. Aneurysm size in the preoperative angiography verified that the mean size of aneurysms operated was 6.56 mm, such that in cases showing a postoperative remnant, the mean size was 9.7 mm and in cases with complete clipping it was 6.08 mm (P = 0.02). Postoperative angiography showed that, in cases with residual aneurysm, the number of clips used was higher - a mean of 1.8 for complete clipping and 3.1 for incomplete clipping (P < 0.001). CONCLUSIONS: Aneurysm size and patient age showed significant correlations with residual intracranial aneurysm. The mean number of clips used was higher in cases with incomplete occlusion. PMID- 28904827 TI - Horizontal distance of anterior communicating artery aneurysm neck from anterior clinoid process is critically important to predict postoperative complication in clipping via pterional approach. AB - BACKGROUND: The difficulty of clipping aneurysm of the anterior communicating artery (AcomA) depends on the size, direction, positional relationship with the parent artery, and height from the anterior frontal base. Cases of clipping unruptured AcomA aneurysm through pterional approach were analyzed to investigate the importance of the horizontal distance from the base of the anterior clinoid process. METHODS: Twenty-six consecutive unruptured AcomA aneurysms were treated by clipping through pterional approach in 10 males and 11 females aged 37-77 years (mean 61.8 years). Size and direction of the aneurysm, and vertical distance from the anterior frontal base and horizontal distance from the base of the anterior clinoid process were measured by preoperative three-dimensional computed tomography angiography (3D-CTA). Correlations with occurrence of clinical complications and computed tomography (CT) abnormalities after operation were investigated. RESULTS: The aneurysms had a mean size of 4.7 mm (range 2.1 8.9 mm). Three patients suffered complications and all had anosmia. Three patients had CT abnormality and all were contusion. The mean horizontal distance from the base of the anterior clinoid process was -4.7 mm (range -12.3-3.5 mm). The patients were divided into the anterior and posterior groups with the boundary set at -5 mm. There were no significant complications between two groups (P = 0.26). There were statistically significant CT abnormalities in posterior group (P = 0.025). CONCLUSION: The horizontal distance from the base of the anterior clinoid process is important to predict CT abnormalities and complications in clipping of AcomA aneurysm through pterional approach. PMID- 28904826 TI - Modified extradural temporopolar approach with mini-peeling of dura propria for paraclinoid and/or parasellar tumors: Operative technique and nuances. AB - BACKGROUND: Modified extradural temporopolar approach (EDTPA) with mini-peeling of the dura propria can provide extensive exposure of the anterior clinoid process and early exposure, as well as complete mobilization and decompression of the optic nerve and internal carotid artery, which can prevent intraoperative neurovascular injury for paraclinoid and/or parasellar lesions. The present study investigated the usefulness of this modified technique and discusses the operative nuances. METHODS: We retrospectively reviewed medical charts of 27 consecutive patients with neoplastic paraclinoid and/or parasellar lesions who underwent this modified approach between September 2009 and August 2016. RESULTS: Preoperative visual acuity worsened in 2 patients (7.4%), and worsening of visual field function occurred in 2 patients (7.4%). Postoperative outcome was good recovery in 25 patients (92.6%) and moderate disability in 2 (7.4%). No operation related mortality occurred in the series. CONCLUSIONS: The modified EDTPA is safe and recommended for surgical treatment of paraclinoid and/or parasellar tumors to reduce the risk of intraoperative optic neurovascular injury. PMID- 28904828 TI - Usefulness of dural surface tracing of the cortical vessels with indocyanine green videoangiography just prior to dural opening for various cerebrovascular diseases. AB - BACKGROUND: Indocyanine green (ICG) videoangiography can be used to delineate the locations of the cortical vessels just prior to dural opening, allowing safe and optimal dural opening. The present clinical series demonstrates the adjunct use of ICG videoangiography to optimize dural opening for the treatment of various cerebrovascular diseases. METHODS: A total of 45 patients underwent surgery for superficial temporal artery-middle cerebral artery bypass (40), arteriovenous malformation (2), and dural arteriovenous fistula (3) between January 2012 and December 2016. After the dura had been exposed, ICG (0.25 mg/kg) was administered intravenously from the peripheral vein as a bolus just prior to dural opening. The operating microscope equipped with a fluorescent filter was used to examine the illuminated field of interest, and real-time flow assessment of the underlying cortical vessels and/or dural sinus was performed. The target recipient arteries for anastomosis or vascular malformations were visualized through the dura and marked using a pyoktanin pen on the dura mater. RESULTS: The optimal dural opening was performed for anastomosis, and safety was ensured by locating the vascular malformations through the dura mater in all cases. The cortical vessel injury was avoided in all cases. No complication was related to this procedure. CONCLUSIONS: Dural surface tracing of the cortical vessels with ICG videoangiography just prior to dural opening is a useful technique, which allows optimal and safe dural opening for treatment of various cerebrovascular diseases. PMID- 28904829 TI - Cavernous angioma presenting with subarachnoid hemorrhage which was diffusely distributed in the basal cisterns and mimicked intracranial aneurysm rupture. PMID- 28904830 TI - Review of commercially available demineralized bone matrix products for spinal fusions: A selection paradigm. AB - BACKGROUND: Spinal fusions are commonly performed in the US each year for various spinal pathologies. There are multiple commercially available graft material options for these procedures, including an abundance of demineralized bone matrix (DBM) products. METHODS: This study reviews, clearly organizes, and puts forth meaningful information on select biological and physical properties of several commercially available DBM products. In addition, we provide an alternative classification method of DBM products by carrier. RESULTS: This review takes a closer look at the commercial and distributor practices of these products and companies in order to increase transparency between the consumer and source companies. CONCLUSIONS: We propose a novel patient-centered approach to DBM product selection. This requires prioritizing patient safety, product effectiveness, and product transparency. This review offers a practical paradigm to facilitate informed product choice for surgeons and hospital systems alike. PMID- 28904831 TI - Sagittal Normal Limits of Lumbosacral Spine in a Large Adult Population: A Quantitative Magnetic Resonance Imaging Analysis. AB - OBJECTIVES: The objective of this study was to determine, using magnetic resonance imaging (MRI) of the lumbosacral spine from L1 to S1, the values of the normal sagittal diameter of the spinal canal (SCD), sagittal diameter of the dural sac (DSD), and the normal values of dural sac ratio (DSR) in a large nonsymptomatic adult population and to discriminate whether a vertebral canal is pathological or nonpathological for dural ectasia and/or stenosis. MATERIALS AND METHODS: Six hundred and four patients were prospectively enrolled. All measurements were performed on MRI sagittal T1- and T2-weighted images. The 95% confidence interval (95% CI), defined as mean +/- 1.96 standard deviation, was determined for each metric. The upper limit of 95% CI was considered the cutoff value for the normal DSR; the lower limit of 95% CI was considered the cutoff value for the normal SCD. RESULTS: SCD cutoff values from L1 to S1 ranged from 14.5-10.1 mm (males) to 15.0-9.9 mm (females). DSD ratios at S1 and L4 level show a significant difference in male and female groups: 11% of S1/L4 values exceeded 1 in male group while only 4% of S1/L4 values exceeded 1 in female group. Mean DSR at each level was significantly higher in female patients than in male patients (P < 0.001), ranging from 0.70 to 0.56 (male) and from 0.82 to 0.63 (female). CONCLUSIONS: We determined the cutoff values for the normal DSR and for the normal SCD. Our findings show the relevant discrepancies with respect to literature data for diagnosis of lumbar stenosis and/or dural ectasia. PMID- 28904832 TI - Correction: A new parrot taxon from the Yucatan Peninsula, Mexico-its position within genus Amazona based on morphology and molecular phylogeny. AB - [This corrects the article DOI: 10.7717/peerj.3475.]. PMID- 28904833 TI - Fluorination of vertically aligned carbon nanotubes: from CF4 plasma chemistry to surface functionalization. AB - The surface chemistry of plasma fluorinated vertically aligned carbon nanotubes (vCNT) is correlated to the CF4 plasma chemical composition. The results obtained via FTIR and mass spectrometry are combined with the XPS and Raman analysis of the sample surface showing the dependence on different plasma parameters (power, time and distance from the plasma region) on the resulting fluorination. Photoemission and absorption spectroscopies are used to investigate the evolution of the electronic properties as a function of the fluorine content at the vCNT surface. The samples suffer a limited ageing effect, with a small loss of fluorine functionalities after two weeks in ambient conditions. PMID- 28904834 TI - Methionine-mediated synthesis of magnetic nanoparticles and functionalization with gold quantum dots for theranostic applications. AB - Biocompatible superparamagnetic iron oxide nanoparticles (NPs) through smart chemical functionalization of their surface with fluorescent species, therapeutic proteins, antibiotics, and aptamers offer remarkable potential for diagnosis and therapy of disease sites at their initial stage of growth. Such NPs can be obtained by the creation of proper linkers between magnetic NP and fluorescent or drug probes. One of these linkers is gold, because it is chemically stable, nontoxic and capable to link various biomolecules. In this study, we present a way for a simple and reliable decoration the surface of magnetic NPs with gold quantum dots (QDs) containing more than 13.5% of Au+. Emphasis is put on the synthesis of magnetic NPs by co-precipitation using the amino acid methionine as NP growth-stabilizing agent capable to later reduce and attach gold species. The surface of these NPs can be further conjugated with targeting and chemotherapy agents, such as cancer stem cell-related antibodies and the anticancer drug doxorubicin, for early detection and improved treatment. In order to verify our findings, high-resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM), FTIR spectroscopy, inductively coupled plasma mass spectroscopy (ICP-MS), and X-ray photoelectron spectroscopy (XPS) of as-formed CoFe2O4 NPs before and after decoration with gold QDs were applied. PMID- 28904835 TI - Adsorption and diffusion characteristics of lithium on hydrogenated alpha- and beta-silicene. AB - Using first-principles density functional theory calculations, we investigate adsorption properties and the diffusion mechanism of a Li atom on hydrogenated single-layer alpha- and beta-silicene on a Ag(111) surface. It is found that a Li atom binds strongly on the surfaces of both alpha- and beta-silicene, and it forms an ionic bond through the transfer of charge from the adsorbed atom to the surface. The binding energies of a Li atom on these surfaces are very similar. However, the diffusion barrier of a Li atom on H-alpha-Si is much higher than that on H-beta-Si. The energy surface calculations show that a Li atom does not prefer to bind in the vicinity of the hydrogenated upper-Si atoms. Strong interaction between Li atoms and hydrogenated silicene phases and low diffusion barriers show that alpha- and beta-silicene are promising platforms for Li storage applications. PMID- 28904836 TI - Laser processing of thin-film multilayer structures: comparison between a 3D thermal model and experimental results. AB - In this research, a numerical model is introduced for simulation of laser processing of thin film multilayer structures, to predict the temperature and ablated area for a set of laser parameters including average power and repetition rate. Different thin-films on Si substrate were processed by nanosecond Nd:YAG laser pulses and the experimental and numerical results were compared to each other. The results show that applying a thin film on the surface can completely change the temperature field and vary the shape of the heat affected zone. The findings of this paper can have many potential applications including patterning the cell growth for biomedical applications and controlling the grain size in fabrication of polycrystalline silicon (poly-Si) thin-film transistors (TFTs). PMID- 28904837 TI - Nanotribological behavior of deep cryogenically treated martensitic stainless steel. AB - Cryogenic treatments are increasingly used to improve the wear resistance of various steel alloys by means of transformation of retained austenite, deformation of virgin martensite and carbide refinement. In this work the nanotribological behavior and mechanical properties at the nano-scale of cryogenically and conventionally treated AISI 420 martensitic stainless steel were evaluated. Conventionally treated specimens were subjected to quenching and annealing, while the deep cryogenically treated samples were quenched, soaked in liquid nitrogen for 2 h and annealed. The elastic-plastic parameters of the materials were assessed by nanoindentation tests under displacement control, while the friction behavior and wear rate were evaluated by a nanoscratch testing methodology that it is used for the first time in steels. It was found that cryogenic treatments increased both hardness and elastic limit of a low-carbon martensitic stainless steel, while its tribological performance was enhanced marginally. PMID- 28904838 TI - Synthesis and catalytic application of magnetic Co-Cu nanowires. AB - A rapid, template-free method was developed to prepare magnetic, bimetallic Co-Cu nanowires via liquid phase reduction and metal replacement under an external magnetic field. The characterization results confirmed that the as-prepared product was bimetallic Co-Cu nanowires with a desirable linear structure. Additionally, the magnetic hysteresis loop showed that the bimetallic Co-Cu nanowires were paramagnetic, which meant they could be easily separated from the reaction mixture. Furthermore, they were applied to the hydrolysis system of ammonia borane as a catalyst for the first time. More importantly, the catalysis results showed that the bimetallic nanowires possessed appealing catalytic performance. Therefore, a rapid and facile synthesis method is introduced which is capable of preparing bimetallic Co-Cu nanowires with great potential for industrial applications. PMID- 28904839 TI - Evaluation of preparation methods for suspended nano-objects on substrates for dimensional measurements by atomic force microscopy. AB - Dimensional measurements on nano-objects by atomic force microscopy (AFM) require samples of safely fixed and well individualized particles with a suitable surface specific particle number on flat and clean substrates. Several known and proven particle preparation methods, i.e., membrane filtration, drying, rinsing, dip coating as well as electrostatic and thermal precipitation, were performed by means of scanning electron microscopy to examine their suitability for preparing samples for dimensional AFM measurements. Different suspensions of nano-objects (with varying material, size and shape) stabilized in aqueous solutions were prepared therefore on different flat substrates. The drop-drying method was found to be the most suitable one for the analysed suspensions, because it does not require expensive dedicated equipment and led to a uniform local distribution of individualized nano-objects. Traceable AFM measurements based on Si and SiO2 coated substrates confirmed the suitability of this technique. PMID- 28904841 TI - Non-intuitive clustering of 9,10-phenanthrenequinone on Au(111). AB - The direct injection of a 9,10-phenanthrenequinone in tetrahydrofuran solution on a Au(111) substrate in high vacuum results in the formation of metastable clusters with a non-intuitive structure. Metastable, rectangular tetramers of this molecule form in which the net molecular dipoles all orient toward the center of the cluster. This structure does not allow for additional hydrogen bonding and thus the origin of its metastability is not clear. We compare this feature to other structures observed on this surface, as well as those formed during the deposition of 9-fluorenone, which does not exhibit this anomalous clustering behavior. PMID- 28904840 TI - (Metallo)porphyrins for potential materials science applications. AB - The bottom-up approach to replace existing devices by molecular-based systems is a subject that attracts permanently increasing interest. Molecular-based devices offer not only to miniaturize the device further, but also to benefit from advanced functionalities of deposited molecules. Furthermore, the molecules itself can be tailored to allow via their self-assembly the potential fabrication of devices with an application potential, which is still unforeseeable at this time. Herein, we review efforts to use discrete (metallo)porphyrins for the formation of (sub)monolayers by surface-confined polymerization, of monolayers formed by supramolecular recognition and of thin films formed by sublimation techniques. Selected physical properties of these systems are reported as well. The application potential of those ensembles of (metallo)porphyrins in materials science is discussed. PMID- 28904842 TI - alpha-Silicene as oxidation-resistant ultra-thin coating material. AB - By performing density functional theory (DFT)-based calculations, the performance of alpha-silicene as oxidation-resistant coating on Ag(111) surface is investigated. First of all, it is shown that the Ag(111) surface is quite reactive against O atoms and O2 molecules. It is known that when single-layer silicene is formed on the Ag(111) surface, the 3 * 3-reconstructed phase, alpha silicene, is the ground state. Our investigation reveals that as a coating layer, alpha-silicene (i) strongly absorbs single O atoms and (ii) absorbs O2 molecules by breaking the strong O-O bond. (iii) Even the hollow sites, which are found to be most favorable penetration path for oxygens, serves as high-energy oxidation barrier, and (iv) alpha-silicene becomes more protective and less permeable in the presence of absorbed O atom. It appears that single-layer silicene is a quite promising material for ultra-thin oxidation-protective coating applications. PMID- 28904843 TI - Synthesis and functionalization of NaGdF4:Yb,Er@NaGdF4 core-shell nanoparticles for possible application as multimodal contrast agents. AB - Upconverting nanoparticles (UCNPs) are promising, new imaging probes capable of serving as multimodal contrast agents. In this study, monodisperse and ultrasmall core and core-shell UCNPs were synthesized via a thermal decomposition method. Furthermore, it was shown that the epitaxial growth of a NaGdF4 optical inert layer covering the NaGdF4:Yb,Er core effectively minimizes surface quenching due to the spatial isolation of the core from the surroundings. The mean diameter of the synthesized core and core-shell nanoparticles was ~8 and ~16 nm, respectively. Hydrophobic UCNPs were converted into hydrophilic ones using a nonionic surfactant Tween 80. The successful coating of the UCNPs by Tween 80 has been confirmed by Fourier transform infrared (FTIR) spectroscopy. Scanning electron microscopy (SEM), powder X-ray diffraction (XRD), photoluminescence (PL) spectra and magnetic resonance (MR) T1 relaxation measurements were used to characterize the size, crystal structure, optical and magnetic properties of the core and core-shell nanoparticles. Moreover, Tween 80-coated core-shell nanoparticles presented enhanced optical and MR signal intensity, good colloidal stability, low cytotoxicity and nonspecific internalization into two different breast cancer cell lines, which indicates that these nanoparticles could be applied as an efficient, dual-modal contrast probe for in vivo bioimaging. PMID- 28904844 TI - The Story of Korean Health Insurance System. PMID- 28904845 TI - Biomarker for the Prediction of Major Adverse Cardiac Events in Patients with Non ST-Segment Elevation Myocardial Infarction. AB - N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-known biomarker for the diagnosis and prognosis of heart failure, and is directly associated with myocardial dysfunction. We evaluated the prognostic value of NT-proBNP for major adverse cardiac events (MACEs) among patients with non-ST-segment elevation myocardial infarction (NSTEMI) from the Korea Acute Myocardial Infarction Registry during their mid-term follow-up period. In this paper, we analyzed NT proBNP according to various MACE and level of NT-proBNP. We used multivariate logistic regression to determine the risk factors according to MACE type and NT proBNP levels, and to identify the cutoff value for each MACE by using the receiver operating characteristic (ROC) curve. NT-proBNP was a significant variable among cardiac deaths (p = 0.016), myocardial infarction (p = 0.000), and coronary artery bypass grafting (CABG) (p = 0.000) in patients with MACE compared with those without MACE. Two-vessel coronary artery disease (CAD) (p = 0.037) and the maximum creatinine kinase (max-CK) (p = 0.031) produced significant results in repeat percutaneous coronary intervention. The area under the ROC curve was found to be statistically significant for cardiac death and CABG. NT-proBNP is a useful predictor for 12-month MACEs among patients with NSTEMI and in those with heart failure. We propose that a new index incorporating NT-proBNP, max-CK, and CAD vessel will be useful as a prognostic indicator of MACEs in the future. PMID- 28904846 TI - Analyzing the Historical Development and Transition of the Korean Health Care System. AB - OBJECTIVES: Many economically advanced countries have attempted to minimize public expenditures and pursue privatization based on the principles of neo liberalism. However, Korea has moved contrary to this global trend. This study examines why and how the Korean health care system was formed, developed, and transformed into an integrated, single-insurer, National Health Insurance (NHI) system. METHODS: We describe the transition in the Korean health care system using an analytical framework that incorporates such critical variables as government economic development strategies and the relationships among social forces, state autonomy, and state power. This study focuses on how the relationships among social forces can change as a nation's economic development or governing strategy changes in response to changes in international circumstances such as globalization. RESULTS: The corporatist Social Health Insurance (SHI) system (multiple insurers) introduced in 1977 was transformed into the single-insurer NHI in July 2000. These changes were influenced externally by globalization and internally by political democratization, keeping Korea's private-dominant health care provision system unchanged over several decades. CONCLUSION: Major changes such as integration reform occurred, when high levels of state autonomy were ensured. The state's power (its policy capability), based on health care infrastructures, acts to limit the direction of any change in the health care system because it is very difficult to build the infrastructure for a health care system in a short timeframe. PMID- 28904847 TI - Correlation between Scapular Asymmetry and Differences in Left and Right Side Activity of Muscles Adjacent to the Scapula. AB - OBJECTIVES: The aim of this study was to analyze the correlation between scapular asymmetry in young female adults and differences in left and right side activity of muscles adjacent to the scapula. METHODS: This study included 60 female students from U university in Korea. In order to examine scapular asymmetry, the lateral scapular slide test (LSST) was used. The LSST was performed in 3 different postures (LSST-1, LSST-2, and LSST-3; i.e., 0 degrees , 45 degrees , and 90 degrees of upper limb abduction, respectively). Muscle activity was measured during external and internal rotation of the shoulder joints. Muscle activity was measured at the upper, middle, and lower trapezius, and the serratus anterior. RESULTS: In external shoulder rotation, there was a significant correlation (R = 0.450) between LSST-2 and the middle trapezius. In internal shoulder rotation, there was a significant correlation (R = 0.472) between LSST-2 and the upper trapezius, and between LSST-3 and the lower trapezius (R = 0.657); these results demonstrated a moderate positive linear correlation. CONCLUSION: There was a positive correlation between left and right scapular asymmetry and the difference in left and right muscle activity of the trapezius in female adults. Problems in the trapezius may lead to scapular asymmetry. PMID- 28904848 TI - Aflatoxin M1 Contamination Levels in Cheeses Sold in Isfahan Province, Iran. AB - OBJECTIVES: Aflatoxin M1 (AFM1)-contaminated dairy products pose serious human health risks, causing liver and renal failure if consumed. They are also related to decreased milk and egg production in infected animals. This study investigated the AFM1 contamination levels in cheeses sold in Isfahan province, Iran, by enzyme-linked immunosorbent assay (ELISA). METHODS: A total of 100 white cheese samples were randomly collected from supermarkets in Isfahan province and after extraction using dichloromethane were prepared for the ELISA. RESULTS: Of the 100 samples, 52 (52%) were contaminated by AFM1, at levels ranging from 50.2 to 424.4 ng/kg. The remaining 48% of the samples had undetectable AFM1 levels (< 50 ng/kg). Based on the standard limit set by the European Commission and Iran, 8% (8/100) of the AFM1-positive samples (with concentrations between 250.2 and 424.4 ng/kg) had levels higher than the permissible value of 250 ng/kg. CONCLUSION: Although the percentage of cheese samples in Isfahan province with AFM1 levels exceeding the national permissible limit was low, the examination of cheeses and the milk used for their production is nevertheless important for ensuring public health. Furthermore, optimum storage conditions of animal feed should be ensured, and livestock nutrition must be monitored for the presence of AFM1 and other aflatoxins. PMID- 28904849 TI - Influence of Socioeconomic Status, Comorbidity, and Disability on Late-stage Cancer Diagnosis. AB - OBJECTIVES: Understanding factors affecting advanced stage at diagnosis is vital to improve cancer outcomes and overall survival. We investigated the factors affecting later-stage cancer diagnosis. METHODS: Patients completed self-reported questionnaires. We collected cancer stage data from medical records review. Logistic regression analyses were performed to identify factors associated with later stage cancer at diagnosis by gender. RESULTS: In total, 1,870 cancer patients were included in the study; 55.8% were men, 31.1% had more than one comorbid condition, and 63.5% had disabilities. About half of the patients were smokers, and drank alcohol, and 58.0% were diagnosed at an advanced stage. By cancer type, lung and liver cancers (both genders), prostate (men), colorectal, cervical, and thyroid cancer (women) were more likely to be diagnosed at a later stage. After controlling for socioeconomic factors, comorbidity (odds ratio [OR], 1.48 in men) and disability (OR, 1.64 in men and 1.52 in women) remained significantly associated with late-stage diagnosis. CONCLUSION: In this nationwide study, using combined information from patients and medical records, we found that male patients with comorbidities or disabilities, and female patients with disabilities were more likely to have advanced stage cancer at diagnosis. Targeted approaches by cancer type and health conditions are recommended. PMID- 28904850 TI - Effects of Exercise on Cervical Angle and Respiratory Function in Smartphone Users. AB - OBJECTIVES: The aim of this study was to determine whether exercises can change the cervical angle and respiratory function in smartphone users. METHODS: Thirty healthy volunteers were recruited. The subjects were randomly divided into an exercise group and a control group. All participants used a smartphone for 1 hour while maintaining a sitting posture. Then, each group performed their assigned activity. The exercise group performed two types of exercises and the control group maintained routine activities for 20 minutes. To investigate the changes in cervical angle and respiratory function, we measured the craniovertebral angle by using a spirometer. RESULTS: Statistically significant differences were noted in the craniovertebral angle, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio, peak expiratory flow, maximal inspiratory pressure, and maximal expiratory pressure of the two groups (p < 0.05). CONCLUSION: Our findings showed that proper exercise could be a good method of improving the cervical angle and respiratory function in smartphone users. PMID- 28904851 TI - Body-related Perspectives and Weight Control Methods of Korean-Chinese Nursing School Students in Yanbian, China: A Pilot Study. AB - OBJECTIVES: This study aimed at identifying the current nutrition knowledge, body related perspectives, and weight control behaviors of Korean-Chinese college students. METHODS: We conducted a pilot study by employing a healthy weight education program targeting Korean-Chinese nursing school students at the Yanbian University of Science and Technology in Yanbian, China. RESULTS: This pilot study included 40 participants (38 women and 2 men; mean age, 20.5 years). The current weight status of the participants was as follows: 7.9% underweight, 78.9% normal weight, 7.9% overweight, and 5.3% obese. However, nearly two-thirds of the participants were dissatisfied with their current body size (43.6% a little dissatisfied; 20.5% very dissatisfied). Fifty percent of the participants perceived their current body size as being either slightly fat (35.0%) or very fat (15.0%). The following unhealthy weight control methods were commonly used among the 24 participants who practiced weight control: (1) laxatives or diuretics (91.7%), (2) saunas or spas (87.5%), and (3) a one-food diet (79.2%). In addition, the nutrition knowledge of the participants increased by 24 points from 117 points (pretest) to 141 points (posttest) through the healthy weight education program. CONCLUSION: The findings of this study indicate an urgent need to educate Korean-Chinese college students on healthy weight control methods and body-related perspectives. PMID- 28904852 TI - Seroprevalence of Brucellosis in Human Immunodeficiency Virus Infected Patients in Hamadan, Iran. AB - OBJECTIVES: Brucellosis is a systemic disease with a wide spectrum of clinical manifestations. This study aimed to determine the seroprevalence of brucellosis in human immunodeficiency virus (HIV) infected patients in Hamadan Province in the west of Iran. METHODS: A total of 157 HIV-infected patients were screened through standard serological tests, including Wright's test, Coombs' Wright test, and 2-mercaptoethanol Brucella agglutination test (2ME test), blood cultures in Castaneda media, and CD4 counting. Data were analyzed using Stata version 11. RESULTS: Wright and Coombs' Wright tests were carried out, and only 5 (3.2%) patients had positive serological results. However, all patients had negative 2ME results, and blood cultures were negative for Brucella spp. Moreover, patients with positive serology and a mean CD4 count of 355.8 +/- 203.11 cells/MUL had no clinical manifestations of brucellosis, and, and the other patients had a mean CD4 count of 335.55 +/- 261.71 cells/MUL. CONCLUSION: Results of this study showed that HIV infection is not a predisposing factor of acquiring brucellosis. PMID- 28904853 TI - Lyme Disease and YouTube TM: A Cross-Sectional Study of Video Contents. AB - OBJECTIVES: Lyme disease is the most common tick-borne disease. People seek health information on Lyme disease from YouTubeTM videos. In this study, we investigated if the contents of Lyme disease-related YouTubeTM videos varied by their sources. METHODS: Most viewed English YouTubeTM videos (n = 100) were identified and manually coded for contents and sources. RESULTS: Within the sample, 40 videos were consumer-generated, 31 were internet-based news, 16 were professional, and 13 were TV news. Compared with consumer-generated videos, TV news videos were more likely to mention celebrities (odds ratio [OR], 10.57; 95% confidence interval [CI], 2.13-52.58), prevention of Lyme disease through wearing protective clothing (OR, 5.63; 95% CI, 1.23-25.76), and spraying insecticides (OR, 7.71; 95% CI, 1.52-39.05). CONCLUSION: A majority of the most popular Lyme disease-related YouTube TM videos were not created by public health professionals. Responsible reporting and creative video-making facilitate Lyme disease education. Partnership with YouTubeTM celebrities to co-develop educational videos may be a future direction. PMID- 28904854 TI - Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/CKAMP44 through interactions with neuronal scaffold PICK1. AB - Synaptic alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors are essential mediators of neurotransmission in the central nervous system. Shisa9/cysteine-knot AMPAR modulating protein 44 (CKAMP44) is a transmembrane protein recently found to be present in AMPA receptor-associated protein complexes. Here, we show that the cytosolic tail of Shisa9/CKAMP44 interacts with multiple scaffold proteins that are important for regulating synaptic plasticity in central neurons. We focussed on the interaction with the scaffold protein PICK1, which facilitates the formation of a tripartite complex with the protein kinase C (PKC) and thereby regulates phosphorylation of Shisa9/CKAMP44 C-terminal residues. This work has implications for our understanding of how PICK1 modulates AMPAR-mediated transmission and plasticity and also highlights a novel function of PKC. PMID- 28904855 TI - Identification of genes associated with histologic tumor grade of esophageal squamous cell carcinoma. AB - The present study aimed to identify the genes associated with the histologic tumor grade of patients with esophageal squamous cell carcinoma (ESCC) and to provide valuable information for the identification of potential diagnostic biomarkers in ESCC. Tumor samples of ESCC patients retrieved from The Cancer Genome Atlas were divided into Grade 1 (well-differentiated; G1), Grade 2 (moderately-differentiated; G2) and Grade 3 (poorly-differentiated; G3) groups in accordance with the clinical record of the tumor grade of ESCC patients. The genes associated with tumor grade were identified. The signaling pathways of identified genes were enriched from the Kyoto Encyclopedia of Genes and Genomes (KEGG). The diagnostic value of candidate genes was assessed by receiver operating characteristic analysis. We used the GSE23400 dataset generated from the Gene Expression Omnibus to examine the expression levels of candidate genes in ESCC tissues compared to matched mucosa tissues. In total, 440 genes positively correlated with tumor grade and 882 genes negatively correlated with tumor grade were identified. There were 310 differentially expressed genes (DEGs) between G1 and G2, 184 DEGs between G2 and G3, and 710 DEGs between G1 and G3. There were 1322 genes associated with tumor grade that were significantly enriched in pathways in cancer and the phospholipase D signaling pathway. Cyclin dependent kinase inhibitor 1A, golgin A7 family member B and transforming growth factor B1-induced anti-apoptotic factor 1 (TIAF1) had potential diagnostic value for discriminating ESCC patients with G1 from those with G3. TIAF1 was significantly down-regulated in ESCC. The results of the present study comprise useful groundwork with respect to determining the tumorigenesis mechanism in ESCC and discovering potential diagnostic biomarkers for ESCC. PMID- 28904856 TI - MiR-101 inhibits ovarian carcinogenesis by repressing the expression of brain derived neurotrophic factor. AB - Ovarian cancer is one of the most lethal malignant gynecological tumors as a result of difficulties in early-stage detection and a lack of effective treatments for patients with advanced or recurrent cancer. In the present study, we aimed to explore whether some of the microRNA (miRNA) content of serum might be related to ovarian cancer, as well as the role of these miRNAs and their intercellular transport via exosomes in ovarian cancer. We first detected the expression of six candidate miRNAs in ovarian cancer tissues and adjacent nontumor ovarian samples from 36 patients and confirmed the altered expression of four miRNAs. The level of these six candidate miRNAs was also examined in exosomes from patient serum samples. Only the level of miR-101 was altered in both ovarian tissue samples and serum exosomes. After prediction using online bioinformatics tools and confirmation by dual-luciferase assay and immunoblotting, we identified that miR-101 can repress the expression of brain derived neurotrophic factor by targeting its 3'-UTR. Using Transwell assays, we examined the effect of miR-101 on migration and invasion capacity of ovarian cancer cells. The results indicated that the reduction of miR-101 is mostly related to significant enhanced ovarian cancer cell migration. Thus, the results of the present study indicate that miR-101 content in serum exosomes has potential as a marker for diagnosis of ovarian cancer and that miR-101 mimics are potential therapeutic drugs for the treatment of ovarian cancer. PMID- 28904857 TI - Dermatophagoides pteronyssinus lytFM encoding an NlpC/P60 endopeptidase is also present in mite-associated bacteria that express LytFM variants. AB - The bodies and faecal pellets of the house dust mite (HDM), Dermatophagoides pteronyssinus, are the source of many allergenic and nonallergenic proteins. One of these, the 14-kDa bacteriolytic enzyme LytFM, originally isolated from the spent HDM growth medium, may contribute to bacteriolytic activity previously detected by zymography at 14 kDa in the culture supernatants of some bacterial species isolated from surface-sterilised HDM. Based on previously reported findings of lateral gene transfer between microbes and their eukaryotic hosts, we investigated the presence of lytFM in the genomes of nine Gram-positive bacteria from surface-sterilised HDM, and the expression by these isolates of LytFM and its variants LytFM1/LytFM2. The lytFM gene was detected by PCR in the genomes of three of the isolates: Bacillus licheniformis strain 1, B. licheniformis strain 2 and Staphylococcus aureus. Expression of the variant LytFM1 was detected in culture supernatants of these bacteria by mass spectrometry (MS) and ELISA, and the bacterial LytFM proteins were shown by zymography to be able to hydrolyse peptidoglycan. Our previous reports of LytFM homologues in other mite species and their phylogenetic analysis had suggested that they originated from a common mite ancestor. The phylogenetic analysis reported herein and the detection of other D. pteronyssinus proteins by MS in the culture supernatants of the three isolates that secreted LytFM1 further support the hypothesis of lateral gene transfer to the bacterial endosymbionts from their HDM host. The complete sequence homology observed between the genes amplified from the microbes and those in their eukaryotic host indicated that the lateral gene transfer was an event that occurred recently. PMID- 28904858 TI - Maturation of phagosomes containing different erythrophagocytic particles in primary macrophages. AB - Erythrophagocytosis is a physiological process that aims to remove damaged red blood cells from the circulation in order to avoid hemolysis and uncontrolled liberation of iron. Many efforts have been made to understand heme trafficking inside macrophages, but little is known about the maturation of phagosomes containing different types of erythrophagocytic particles with different signals at their surfaces. Therefore, we performed a comparative study on the maturation of phagosomes containing three different models of red blood cells (RBC): aged/senescent, complement-opsonized, and IgG-opsonized. We also used two types of professional phagocytes: bone marrow-derived and peritoneal macrophages. By comparing markers from different stages of phagosomal maturation, we found that phagosomes carrying aged RBC reach lysosomes with a delay compared to those containing IgG- or complement-opsonized RBC, in both types of macrophages. These findings contribute to understanding the importance of the different signals at the RBC surface in phagolysosome biogenesis, as well as in the dynamics of RBC removal. PMID- 28904859 TI - Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway. AB - Dysregulation of sirtuin 6 (SIRT6) is actively involved in tumor progression. High levels of SIRT6 have been associated with hepatocellular carcinoma and non small cell lung cancer, and SIRT6 facilitates growth and metastasis of cancer cells. However, the clinical significance and biological function of SIRT6 are not known for osteosarcoma (OS). Here, we report that SIRT6 was notably overexpressed in OS tissues compared with non-cancerous specimens. The high level of SIRT6 was prominently correlated with malignant clinical parameters and poor prognosis of OS patients. SIRT6 was also up-regulated in OS cells. SIRT6 knockdown inhibited the invasion and migration of Saos-2 and U2OS cells in vitro, while SIRT6 restoration increased these cellular biological behaviors in MG-63 cells. Mechanistically, SIRT6 up-regulated expression of matrix metallopeptidase 9 (MMP9) in OS cells. MMP9 restoration partially abolished the effects of SIRT6 knockdown on OS cells, with increased cell migration and invasion. MMP9 knockdown reduced migration and invasion of SIRT6-overexpressing MG-63 cells. Furthermore, SIRT6 positively modulated the levels of phosphorylated extracellular signal regulated kinases 1 and 2 (ERK1/2). PD098059 and PD0325901, inhibitors of mitogen activated protein kinase kinase (MEK), blocked the regulatory effects of SIRT6 on p-ERK1/2 and MMP9 levels, suggesting that SIRT6 regulated MMP9 abundance probably through the MEK-ERK1/2 pathway. These results suggest that SIRT6 may act as a prognostic predictor and a drug target for OS patients. PMID- 28904860 TI - Regulation of Neisseria meningitidis cytochrome bc1 components by NrrF, a Fur controlled small noncoding RNA. AB - NrrF is a small regulatory RNA of the human pathogen Neisseria meningitidis. NrrF was previously shown to repress succinate dehydrogenase (sdhCDAB) under control of the ferric uptake regulator (Fur). Here, we provide evidence that cytochrome bc1 , encoded by the polycistronic mRNA petABC, is a NrrF target as well. We demonstrated differential expression of cytochrome bc1 comparing wild-type meningococci and meningococci expressing NrrF when sufficient iron is available. Using a gfp-reporter system monitoring translational control and target recognition of sRNA in Escherichia coli, we show that interaction between NrrF and the 5' untranslated region of the petABC mRNA results in its repression. The NrrF region essential for repression of petABC was identified by site-directed mutagenesis and is fully conserved among meningococci. Our results provide further insights into the mechanism by which Fur controls essential components of the N. meningitidis respiratory chain. Adaptation of cytochrome bc1 complex component levels upon iron limitation is post-transcriptionally regulated via the small regulatory RNA NrrF. PMID- 28904861 TI - A modified graft-versus-host-induced model for systemic sclerosis, with pulmonary fibrosis in Rag2-deficient mice. AB - Systemic sclerosis (SSc) is a connective tissue disease that results in fibrosis in multiple organs. Various animal models for this disease have been developed, both genetic and induced. One of the induced models, sclerodermatous graft-versus host disease (scl-GvHD), exhibits the main characteristics of SSc, but involves lethal gamma-irradiation of recipients. We sought to develop a modified scl-GvHD model. Spleen cells from B10.D2 donor mice were transplanted into immunodeficient Rag-2 recipients on the BALB/c genetic background. Tissue fibrosis was analyzed at 3 and 9 weeks after transplantation. In addition to serum levels of anti-Scl 70 autoantibody and cytokines, tissue inflammation, fibrosis, expression of collagen-I and alpha-smooth muscle actin (alpha-SMA), infiltration of leukocytes, mRNA expression of transforming growth factor (TGF)-beta, collagen-I, alpha-SMA, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6, the classical signal pathway of TGF-beta, Smad-3, and p-Smad-3 expression in tissue were analyzed. Skin thickening and increased collagen synthesis, as well as the manifestation of tissue fibrosis, could be detected in skin, kidney, and lung of modified scl-GvHD mouse model. Increased serum levels of anti-Scl-70 autoantibody, IL-10, and TGF beta could be detected. Increased CD4+ T cells and F4/80+ macrophage infiltration were found in skin, kidney, and lung. Gene expression of collagen-I, TGF-beta, alpha-SMA, TNF-alpha, and IL-6 was increased in tissue of the scl-GvHD model. Moreover, TGF-beta expression and Smad-3 phosphorylation were detected in skin, kidney, and lung of scl-GvHD mice. Our data show that spleen cells from B10.D2 donor mice transplanted into immunodeficient Rag-2 recipients could induce typical fibrosis not only of the skin and kidney but also of lung, which was missing from previous scl-GvHD models. Thus, the modified scl-GvHD model might be a promising model to explore the immunologic mechanisms of SSc and may be useful for investigation of new therapies for systemic sclerosis. PMID- 28904862 TI - t-Darpp is an elongated monomer that binds calcium and is phosphorylated by cyclin-dependent kinases 1 and 5. AB - t-Darpp (truncated isoform of dopamine- and cAMP-regulated phosphoprotein) is a protein encoded by the PPP1R1B gene and is expressed in breast, colon, esophageal, gastric, and prostate cancers, as well as in normal adult brain striatal cells. Overexpression of t-Darpp in cultured cells leads to increased protein kinase A activity and increased phosphorylation of AKT (protein kinase B). In HER2+ breast cancer cells, t-Darpp confers resistance to the chemotherapeutic agent trastuzumab. To shed light on t-Darpp function, we studied its secondary structure, oligomerization status, metal-binding properties, and phosphorylation by cyclin-dependent kinases 1 and 5. t-Darpp exhibits 12% alpha helix, 29% beta strand, 24% beta turn, and 35% random coil structures. It binds calcium, but not other metals commonly found in biological systems. The T39 site, critical for t-Darpp activation of the AKT signaling pathway, is a substrate for phosphorylation by cyclin-dependent kinase 1 and cyclin-dependent kinase 5. Gel filtration chromatography, sedimentation equilibrium analysis, blue native gel electrophoresis, and glutaraldehyde-mediated cross-linking experiments demonstrate that the majority of t-Darpp exists as a monomer, but forms low levels (< 3%) of hetero-oligomers with its longer isoform Darpp-32. t-Darpp has a large Stokes radius of 4.4 nm relative to its mass of 19 kDa, indicating that it has an elongated structure. PMID- 28904863 TI - Chimeric ZHHH neuroglobin acts as a cell membrane-penetrating inducer of neurite outgrowth. AB - Neuroglobin (Ngb) is a heme protein expressed in the vertebrate brain. We previously engineered a chimeric Ngb protein, in which module M1 of human Ngb is replaced by that of zebrafish Ngb, and showed that the chimeric ZHHH Ngb has a cell membrane-penetrating activity similar to that of zebrafish Ngb and also rescues cells from death caused by hypoxia/reoxygenation as does human Ngb. Recently, it was reported that overexpression of mammalian Ngb in neuronal cells induces neurite outgrowth. In this study, we performed neurite outgrowth assays of chimeric Ngb using rat pheochromocytoma PC12 cells. Addition of chimeric Ngb, but not human or zebrafish Ngb, exogenously to the cell medium induces neurite outgrowth. On the other hand, the K7A/K9Q chimeric Ngb double mutant, which cannot translocate into cells, did not induce neurite outgrowth, suggesting that the cell membrane-penetrating activity of the chimeric Ngb is crucial for its neurite outgrowth-promoting activity. We also prepared several site-directed chimeric Ngb mutants and demonstrated that residues crucial for neurite outgrowth inducing activity of the chimeric Ngb are not exactly the same as those for its neuroprotective activity. PMID- 28904864 TI - A G protein-coupled alpha7 nicotinic receptor regulates signaling and TNF-alpha release in microglia. AB - Acetylcholine activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) in microglia attenuates neuroinflammation and regulates TNF-alpha release. We used lipopolysaccharide to model inflammation in the microglial cell line EOC20 and examined signaling by the alpha7 nAChR. Co-immunoprecipitation experiments confirm that alpha7 nAChRs bind heterotrimeric G proteins in EOC20 cells. Interaction with Galphai mediates alpha7 nAChR signaling via enhanced intracellular calcium release and a decrease in cAMP, p38 phosphorylation, and TNF-alpha release. These alpha7 nAChR effects were blocked by the inhibition of Galphai signaling via pertussis toxin, PLC activity with U73122, and alpha7 nAChR channel activity with the selective antagonist alpha-bungarotoxin. Moreover, alpha7 nAChR signaling in EOC20 cells was significantly diminished by the expression of a dominant-negative alpha7 nAChR, alpha7345-8A, shown to be impaired in G protein binding. These findings indicate an essential role for G protein coupling in alpha7 nAChR function in microglia leading to the regulation of inflammation in the nervous system. PMID- 28904865 TI - Mouse glutamate carboxypeptidase II (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII. AB - Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA) or folate hydrolase, is a metallopeptidase expressed predominantly in the human brain and prostate. GCPII expression is considerably increased in prostate carcinoma, and the enzyme also participates in glutamate excitotoxicity in the brain. Therefore, GCPII represents an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are widely used. However, although mouse GCPII activity has been characterized, a detailed comparison of the enzymatic activity and tissue distribution of the mouse and human GCPII orthologs remains lacking. In this study, we prepared extracellular mouse GCPII and compared it with human GCPII. We found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein. Using a panel of GCPII inhibitors, we discovered that inhibition constants are generally similar for mouse and human GCPII. Furthermore, we observed highest expression of GCPII protein in the mouse kidney, brain, and salivary glands. Importantly, we did not detect GCPII in the mouse prostate. Our data suggest that the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse GCPII can approximate human GCPII in drug development and testing. On the other hand, significant differences in GCPII tissue expression must be taken into account when developing novel GCPII-based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism. PMID- 28904866 TI - IMM-H007, a new therapeutic candidate for nonalcoholic fatty liver disease, improves hepatic steatosis in hamsters fed a high-fat diet. AB - Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in humans, is characterized by the accumulation of triacylglycerols (TGs) in hepatocytes. We tested whether 2',3',5'-tri-acetyl-N6-(3-hydroxylaniline) adenosine (IMM-H007) can eliminate hepatic steatosis in hamsters fed a high-fat diet (HFD), as a model of NAFLD. Compared with HFD-only controls, IMM-H007 treatment significantly lowered serum levels of TG, total cholesterol, and free fatty acids (FFAs) in hamsters fed the HFD, with a prominent decrease in levels of serum transaminases and fasting insulin, without affecting fasting glucose levels. Moreover, 1H-MRI and histopathological analyses revealed that hepatic lipid accumulation and fibrosis were improved by IMM-H007 treatment. These changes were accompanied by improvement of insulin resistance and oxidative stress, and attenuation of inflammation. IMM-H007 reduced expression of proteins involved in uptake of hepatic fatty acids and lipogenesis, and increased very low density lipoprotein secretion and expression of proteins responsible for fatty acid oxidation and autophagy. In studies in vivo, IMM-H007 inhibited fatty acid import into hepatocytes and liver lipogenesis, and concomitantly stimulated fatty acid oxidation, autophagy, and export of hepatic lipids. These data suggest that IMM-H007 resolves hepatic steatosis in HFD-fed hamsters by the regulation of lipid metabolism. Thus, IMM-H007 has therapeutic potential for NAFLD. PMID- 28904867 TI - The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage-dependent inactivation. AB - Voltage-dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2-like 1 (PKD2L1) forms voltage-dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Here, we found that the mutation of an asparagine 533 residue (N533Q) in the outer pore loop region of PKD2L1 caused a marked increase in outward currents induced by depolarization. In addition, the tail current analysis demonstrated that the N533Q mutants are activated during depolarization but the subsequent inactivation does not occur. Interestingly, the N533Q mutants lacked the channel activation triggered by the removal of stimuli such as extracellular alkalization and heating. Our findings suggest that the N533 residue in the outer pore loop region of PKD2L1 has a key role in the voltage-dependent channel inactivation. PMID- 28904868 TI - High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway. AB - Low levels of plasma high-density lipoprotein (HDL) cholesterol are associated with an increased risk of heart failure, regardless of the presence or absence of coronary artery disease. However, the direct effects of HDL on failing myocardium have not been fully elucidated. We found that HDL treatment resulted in improved cell viability in H9c2 cardiomyocytes under oxidative stress. This cardioprotective effect of HDL was regulated via the phosphatidylinositol 3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. mTOR signaling promotes cell survival through the inactivation of the BCL2-associated agonist of cell death via phosphorylation of ribosomal protein S6 kinase. Modulation of cardiac PI3K/mTOR signaling by HDL could represent a novel therapeutic strategy for heart failure. PMID- 28904869 TI - High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells. AB - Aldosterone synthase is the key rate-limiting enzyme in adrenal aldosterone production, and induction of its gene (CYP11B2) results in the progression of hypertension. As hypertension is a frequent complication among patients with diabetes, we set out to elucidate the link between diabetes mellitus and hypertension. We examined the effects of high glucose on CYP11B2 expression and aldosterone production using human adrenal H295R cells and a stable H295R cell line expressing a CYP11B2 5'-flanking region/luciferase cDNA chimeric construct. d-glucose (d-glu), but not its enantiomer l-glucose, dose dependently induced CYP11B2 transcription and mRNA expression. A high concentration (450 mg.dL-1) of d-glu time dependently induced CYP11B2 transcription and mRNA expression. Moreover, high glucose stimulated secretion of aldosterone into the media. Transient transfection studies using deletion mutants/nerve growth factor-induced clone B (NGFIB) response element 1 (NBRE-1) point mutant of CYP11B2 5'-flanking region revealed that the NBRE-1 element, known to be activated by transcription factors NGFIB and NURR1, was responsible for the high glucose-mediated effect. High glucose also induced the mRNA expression of these transcription factors, especially that of NURR1, but NURR1 knockdown using its siRNA did not affect high glucose-induced CYP11B2 mRNA expression. Taken together, it is speculated that high glucose may induce CYP11B2 transcription via the NBRE-1 element in its 5' flanking region, resulting in the increase in aldosterone production although high glucose-induced NURR1 is not directly involved in the effect. Additionally, glucose metabolism and calcium channels were found to be involved in the high glucose effect. Our observations suggest one possible explanation for the high incidence of hypertension in patients with diabetes. PMID- 28904870 TI - Membrane dynamics of resting and internalin B-bound MET receptor tyrosine kinase studied by single-molecule tracking. AB - The human MET receptor tyrosine kinase contributes to vertebrate development and cell proliferation. As a proto-oncogene, it is a target in cancer therapies. MET is also relevant for bacterial infection by Listeria monocytogenes and is activated by the bacterial protein internalin B. The processes of ligand binding, receptor activation, and the diffusion behavior of MET within the plasma membrane as well as its interconnections with various cell components are not fully understood. We investigated the receptor diffusion dynamics using single-particle tracking and imaging fluorescence correlation spectroscopy and elucidated mobility states of resting and internalin B-bound MET. We show that internalin B bound MET exhibits lower diffusion coefficients and diffuses in a more confined area in the membrane. We report that the fraction of immobile receptors is larger for internalin B-bound receptors than for resting MET. Results of single-particle tracking in cells treated with various cytotoxins depleting cholesterol from the membrane and disrupting the actin cytoskeleton and microtubules suggest that cholesterol and actin influence MET diffusion dynamics, while microtubules do not have any effect. PMID- 28904871 TI - The potential renoprotection of xanthine oxidase inhibitors: Febuxostat versus allopurinol. PMID- 28904872 TI - Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. AB - Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO) deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb) levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA) therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis. PMID- 28904873 TI - A calpain inhibitor protects against fractalkine production in lipopolysaccharide treated endothelial cells. AB - BACKGROUND: Fractalkine (CX3CL1) is a chemokine with a unique CX3C motif and is produced by endothelial cells stimulated with lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and interferon-gamma. There have been several reports that the caspase/calpain system is activated in endotoxemia, which leads to cellular apoptosis and acute inflammatory processes. We aimed to determine the role of the caspase/calpain system in cell viability and regulation of fractalkine production in LPS-treated endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with 0.01-100 MUg/mL of LPS to determine cell viability. The changes of CX3CL1 expression were compared in control, LPS (1 MUg/mL)-, IL-1alpha (1 MUg/mL)-, and IL-1beta (1 MUg/mL) treated HUVECs. Cell viability and CX3CL1 production were compared with 50 MUM of inhibitors of caspase-1, caspase-3, caspase-9, and calpain in LPS-treated HUVECs. RESULTS: Cell viability was significantly decreased from 1 to 100 MUg/mL of LPS. Cell viability was significantly restored with inhibitors of caspase-1, caspase 3, caspase-9, and calpain in LPS-treated HUVECs. The expression of CX3CL1 was highest in IL-1beta-treated HUVECs. CX3CL1 production was highly inhibited with a calpain inhibitor and significantly decreased with the individual inhibitors of caspase-1, caspase-3, and caspase-9. CONCLUSION: The caspase/calpain system is an important modulator of cell viability and CX3CL1 production in LPS-treated endothelial cells. PMID- 28904874 TI - Red cell distribution width predicts incident dipstick albuminuria in Korean adults without chronic kidney disease. AB - BACKGROUND: Red cell distribution width (RDW) is an emerging marker of inflammation and a predictor of high cardiovascular morbidity and mortality as well as all-cause mortality. A previous cross-sectional study showed that RDW was associated with microalbuminuria, an indicator of target organ damage. However, the longitudinal association of RDW and development of albuminuria is not known. METHODS: We analyzed 83,040 participants without chronic kidney disease (CKD) at baseline who underwent two health check-ups at a 4-year interval during 2005 to 2014. Urine albumin was determined by single urine dipstick semi-quantitative analysis, and incident albuminuria was defined as >= 1+ dipstick albumin at the second check-up. We used logistic regression analysis to determine the relationship between RDW and incident albuminuria. RESULTS: Participants were divided into quartiles according to baseline RDW. After 4 years, 982 cases of incident albuminuria were observed. The cumulative incidences of albuminuria were 0.94, 1.05, 1.18, and 1.62% for the 1st through 4th quartiles of RDW, respectively. Multivariate logistic analysis showed that the odds ratios (95% confidence interval) for incident albuminuria compared to those in the 1st quartile were 1.11 (0.92-1.34), 1.26 (1.04-1.52), and 1.88 (1.58-2.24) for the 2nd, 3rd and 4th quartiles, respectively. CONCLUSION: RDW was associated with development of albuminuria in relatively healthy Korean adults without CKD. Further research is needed to verify the role of RDW in the development of albuminuria and renal injury. PMID- 28904875 TI - The influence of hypophosphatemia on outcomes of low- and high-intensity continuous renal replacement therapy in critically ill patients with acute kidney injury. AB - BACKGROUND: The purpose of this study was to assess the role of hypophosphatemia in major clinical outcomes of patients treated with low- or high-intensity continuous renal replacement therapy (CRRT). METHODS: We performed a retrospective analysis of data collected from 492 patients. We divided patients into two CRRT groups based on treatment intensity (greater than or equal to or less than 40 mL/kg/hour of effluent generation) and measured serum phosphate level daily during CRRT. RESULTS: We obtained a total of 1,440 phosphate measurements on days 0, 1, and 2 and identified 39 patients (7.9%), 74 patients (15.0%), and 114 patients (23.1%) with hypophosphatemia on each of these respective days. In patients treated with low-intensity CRRT, there were 23 episodes of hypophosphatemia/1,000 patient days, compared with 83 episodes/1,000 patient days in patients who received high-intensity CRRT (P < 0.01). Multiple Cox proportional hazards analysis showed that Acute Physiology and Chronic Health Evaluation (APACHE) III score, utilization of vasoactive drugs, and arterial pH on the second day of CRRT were significant predictors of mortality, while serum phosphate level was not a significant contributor to mortality. CONCLUSION: APACHE score, use of vasoactive drugs, and arterial pH on the second CRRT day were identified as significant predictors of mortality. Hypophosphatemia might not be a major risk factor of increased mortality in patients treated with CRRT. PMID- 28904876 TI - Heart rate is associated with mortality in patients undergoing continuous renal replacement therapy. AB - BACKGROUND: Heart rate (HR) is an essential vital sign based on the finding that HR beyond its normal range is associated with several conditions or diseases, including high mortality in several clinical settings. Nevertheless, the clinical implications of HR remain unresolved in patients undergoing continuous renal replacement therapy (CRRT). METHODS: This retrospective cohort study included 828 patients who underwent CRRT due to acute kidney injury between 2010 and 2014. HR and other baseline parameters at the time of CRRT initiation were retrieved. The odds ratio (OR) of 30-day mortality was calculated using a multivariate logistic model. RESULTS: CRRT significantly lowered the HR of patients such that the pre- and post-CRRT HRs (average 6 hours) were 107 beats/min and 103 beats/min, respectively (P < 0.001). When we explored the relationship with 30-day mortality, only HR at the time of CRRT initiation, but not pre- or post-CRRT HR, had a significant relationship with mortality outcome. Based on this result, we divided patients into quartiles of HR at the time of CRRT initiation. Mortality OR in the 4th quartile HR group was 2.6 (1.78-3.92) compared with the 1st quartile HR group. This relationship remained consistent despite adjusting for 28 baseline covariates: OR, 1.7 (1.09-2.76); P = 0.020. However, HR was not associated with the weaning rate from CRRT. CONCLUSION: High HR at the time of CRRT initiation is subsequently related with high mortality. These results can be a basis for a future predictive model of CRRT-related mortality. PMID- 28904877 TI - Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome. AB - BACKGROUND: Rituximab (RTX) can be used as a rescue therapy for steroid-dependent nephrotic syndrome (SDNS). However, the efficacy and safety of long-term, repeated use of RTX are not established. This study was conducted to assess the efficacy and safety of long-term, repeated RTX treatment in children. METHODS: Eighteen consecutive child patients with SDNS who were treated with three or more cycles of RTX for one year or longer were recruited, and their medical records were retrospectively reviewed. RESULTS: The patients were followed for 4.7 +/- 1.9 years and received 5.2 +/- 2.3 cycles of RTX over 2.8 +/- 1.1 years. Approximately 70% of the additional RTX cycles were administered due to recovery of B-cells without relapse. The relapse rate decreased from 3.4 +/- 2.0 per year initially to 0.4 +/- 0.8 per year at the third year after RTX treatment. Approximately 10% of the RTX infusions were accompanied by mild infusion reactions. Eight patients showed sustained remission without any oral medication after the last cycle of RTX, while 10 patients had one or more episodes of relapse after the last cycle of RTX. The relapse rate in the latter group decreased from 2.8 +/- 1.5 per year before RTX treatment to 1.3 +/- 0.8 per year after cessation of RTX treatment. No significant differences in clinical parameters were found between the two groups. CONCLUSION: This retrospective study showed that pre-emptive and long-term, repeated RTX treatment is relatively effective and safe in children with SDNS. However, well-designed prospective studies are needed to confirm these findings. PMID- 28904878 TI - The effects of different physical activities on atrial fibrillation in patients with hypertension and chronic kidney disease. AB - BACKGROUND: Atrial fibrillation (AF) is highly common, and is most frequently observed in individuals with hypertension and structural cardiac disease. Sympathetic hyperactivity plays a fundamental role in the progression, maintenance and aggravation of arrhythmia. Endurance exercise training clearly lowers sympathetic activity in sympathoexcitatory disease states, and is well tolerated by patients with chronic kidney disease (CKD). METHODS: We assessed 50 CKD patients with hypertension. Each patient provided a complete medical history and underwent a physical examination. We used an implantable cardiac monitor over a 3-year follow-up period to evaluate the effects of high-intensity interval training (HIIT) and moderate exercise (ModEx) physical activity protocols on AF occurrence, and determined the effectiveness of these protocols in improving renal function. Subjects were followed up every 6 months after the beginning of the intervention. RESULTS: During the 3-year follow-up, AF onset was higher in CKD patients who engaged in HIIT (72%) than in those who engaged in ModEx (24%) (hazard ratio, 3.847; 95% confidence interval, 1.694-8.740, P = 0.0013 by log rank test). Both groups exhibited significant intra-group changes in the mean systolic 24-hour ambulatory blood pressure measurements (ABPM) between baseline and 12, 24, and 36 months. There were also significant differences in the mean systolic 24-hour ABPM between the groups at the same time points. CONCLUSION: In CKD patients with hypertension, improvements in AF onset, renal function and some echocardiographic parameters were more evident in subjects who engaged in ModEx than in those who engaged in HIIT during 3 years of follow-up. PMID- 28904879 TI - Renoprotective effects of febuxostat compared with allopurinol in patients with hyperuricemia: A systematic review and meta-analysis. AB - BACKGROUND: Hyperuricemia is reported to be related to rapid progression of renal function in patients with chronic kidney disease (CKD). Allopurinol, a uric acid lowering agent, protects renal progression. However, it is not widely used in patients with CKD because of its serious adverse event. Febuxostat can be alternatively used for patients who are intolerable to allopurinol. We aimed to determine renoprotective effect and urate-lowering effect between the two drugs. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials to assess the effects of febuxostat compared to allopurinol in patients with hyperuricemia. MEDLINE, Embase, and Cochrane Library databases were searched to identify research publications. RESULTS: Four relevant publications were selected from among 3,815 studies. No significant differences were found in the changes in serum creatinine from baseline between the febuxostat and allopurinol groups. Changes in estimated glomerular filtration rate (eGFR) were observed between the two groups at 1 month (mean difference 1.65 mL/min/1.73 m2, 95% confidence interval [CI] 0.38, 2.91 mL/min/1.73 m2; heterogeneity chi2 = 1.25, I2 = 0%, P = 0.01); however, the changes in eGFR were not significantly different at 3 months. A significant difference did exist in the changes in albuminuria levels from baseline between the febuxostat and allopurinol groups (mean difference -80.47 mg/gCr, 95% CI -149.29, -11.64 mg/gCr; heterogeneity chi2 = 0.81, I2 = 0%, P = 0.02). A significant difference was also observed in the changes in serum uric acid from baseline between the febuxostat and allopurinol groups (mean difference -0.92 mg/dL, 95% CI -1.29, -0.56 mg/dL; heterogeneity chi2 = 6.24, I2 = 52%, P < 0.001). CONCLUSION: Febuxostat might be more renoprotective than allopurinol. PMID- 28904880 TI - Association of serum uric acid level with coronary artery stenosis severity in Korean end-stage renal disease patients. AB - BACKGROUND: Hyperuricemia is common in end-stage renal disease (ESRD) patients, and many previous studies have reported the associations between hyperuricemia and adverse cardiovascular outcomes, which are the major cause of death in such patients. We investigated the relationship between serum uric acid level and the severity of coronary stenosis in ESRD patients on maintenance hemodialysis (MHD). METHODS: Among 721 patients who started MHD treatment, 102 underwent coronary angiographic tests complaining of chest discomfort that was new at initiation of MHD. We collected data on uric acid level and coronary artery luminal diameter, defining luminal diameter narrowing of more than 50% in any major coronary artery as critical-stenosis. RESULTS: We detected critical coronary artery stenosis in 52 (57.8%) patients. The mean uric acid level was 6.6 +/- 2.2 mg/dL, and that was significantly higher in the critical-stenosis group (4.9 +/- 1.4 mg/dL vs. 7.8 +/ 2.0 mg/dL, P < 0.001). The only independent predictor of critical-stenosis in multivariate analysis was serum uric acid level (P < 0.001). CONCLUSION: High serum uric acid was associated with severe coronary artery stenosis in Korean ESRD patients. Hyperuricemia is a readily modifiable factor, and appropriately preventing it could provide significant benefits in ESRD patients. PMID- 28904881 TI - Numerical expression of volume status using the bioimpedance ratio in continuous ambulatory peritoneal dialysis patients: A pilot study. AB - BACKGROUND: Volume overload results in higher mortality rates in patients on continuous ambulatory peritoneal dialysis (CAPD). The ratio of bioimpedance (RBI) might be a helpful parameter in adjusting dry body weight in CAPD patients. This study examined whether it is possible to distinguish between non-hypervolemic status and hypervolemic status in CAPD patients by using only RBI. METHODS: RBI was calculated as follows: RBI = impedance at 50 kHz/impedance at 500 kHz. Based on the experts' judgements, a total of 64 CAPD patients were divided into two groups, a non-hypervolemic group and a hypervolemic group. The RBI was measured from right wrist to right ankle (rw-raRBI) by bioimpedance spectroscopy (BCM(r), Fresenius Medical Care) before and after the peritosol was emptied. Other RBIs were measured from the right side of the anterior superior iliac spine to the ipsilateral ankle (rasis-raRBI) to control for the electro-physiological effects of peritoneal dialysate. RESULTS: The mean rw-raRBI of non-hypervolemic patients was higher than that of hypervolemic patients in the presence (1.141 +/- 0.022 vs. 1.121 +/- 0.021, P < 0.001) of a peritosol. Likewise, the mean rasis-raRBI of non-hypervolemic patients was higher than that of hypervolemic patients (presence of peritosol: 1.136 +/- 0.026 vs. 1.109 +/- 0.022, P < 0.001; absence of peritosol: 1.131 +/- 0.022 vs. 1.107 +/- 0.022, P < 0.001). CONCLUSION: The volume status of CAPD patients was able to be simply expressed by RBI. Therefore, this study suggests that when patients cannot be analyzed using BCM, RBI could be an alternative. PMID- 28904882 TI - Staphylococcal infection-associated crescentic immunoglobulin A nephropathy. PMID- 28904883 TI - Spotlight on circulating tumour cells. PMID- 28904884 TI - Circulating tumor cells and CDX models as a tool for preclinical drug development. AB - Lung cancers are the main cause of cancer-related deaths worldwide. Efforts placed to improve the survival of lung cancer patients and untangle the complexity of this disease, have resulted in the generation of hundreds of lung cancer cell lines and several genetically engineered mouse models (GEMMs). Although these research tools have extended our knowledge of lung cancer, improvement in the clinical care of lung cancer patients have been limited overall, with measured optimism regarding initial responses to targeted therapies in stratified subgroups of patients. Patient-derived xenograft (PDX) models are beginning to assist 'personalized therapy' approaches particularly in non-small cell lung cancer (NSCLC) however biopsies of lung cancers to generate PDXs are not without challenges and risks to the patient. Liquid biopsies, on the other hand, are a rapid and non-invasive procedure allowing the collection of circulating tumor cells (CTCs) with a single 10 mL blood draw. These CTCs recapitulate the molecular heterogeneity of the corresponding tumors and, therefore, can be used as surrogates to study tumor biology and generate new patient-derived models. Here, we discuss the CTC-derived models that have been generated, most notably in small cell lung cancer (SCLC), highlighting challenges and opportunities related to these novel preclinical tools. PMID- 28904885 TI - The clinical utility of circulating tumour cells in patients with small cell lung cancer. AB - Small cell lung cancer (SCLC) accounts for 15% of lung cancer diagnosed worldwide. It is aggressive and characterised by early metastatic spread with rapid development of chemo resistance such that less than 5% of patients diagnosed survive 5 years. Surgery is rarely performed and failure to identify new effective treatments has been attributed in a large part to lack of good quality tumour biopsies available for translational research. Liquid biopsies provide a minimally invasive alternative to traditional tumour biopsy. Circulating tumour cells (CTCs) are abundant in SCLC and can be enriched and isolated from a venous blood sample. In recent years progress has been made into the molecular characterisation of CTCs and their use to form tumour xenografts in mice for preclinical studies. This review will discuss the current status of the clinical utility of CTCs in patients with SCLC, highlighting their potential application to treatment decision making, drug development in clinical trials and preclinical testing. PMID- 28904886 TI - Circulating tumor cell interactions with macrophages: implications for biology and treatment. AB - Cancer and metastasis are closely associated with inflammation. Macrophages are important effector cells in enhancing tumor proliferation, invasion and providing protection against the immune system. Despite advanced knowledge of tumor macrophage interactions, the role of macrophages in emergence and invasion of circulating tumor cells (CTCs) is not known. A series of six CTC cell lines have been derived from blood of patients with extensive disease small cell lung cancer (ED-SCLC) in our lab, most likely representing a homogenous cell population of the actual metastasis-initiating cells (MIC) of CTCs. SCLC has an unfavorable prognosis due to rapid dissemination and early chemoresistant relapses. SCLC CTCs recruit macrophages and elicit secretion of various cytokines and the six CTC lines express chitinase-3-like-1 (CHI3L1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) in abundance. CHI3L1 is cytokine/growth factor expressed in inflammation and cancer and found to be correlated to metastasis and a dismal prognosis. In conclusion, SCLC CTCs have acquired the essential means for aggressiveness and invasion in a tumor microenvironment specifically shaped by macrophages and inflammation. PMID- 28904887 TI - Biology and clinical significance of circulating tumor cell subpopulations in lung cancer. AB - By identifying and tracking genetic changes in primary tumors and metastases, patients can be stratified for the most efficient therapeutic regimen by screening for known biomarkers. However, retrieving tissues biopsies is not always feasible due to tumor location or risk to patient. Therefore, a liquid biopsies approach offers an appealing solution to an otherwise invasive procedure. The rapid growth of the liquid biopsy field has been aided by improvements in the sensitivity and specificity of enrichment assays for isolating circulating tumor cells (CTCs) from normal surrounding blood cells. Furthermore, the identification and molecular characterization of CTCs has been shown in numerous studies to be of diagnostic and prognostic relevance in breast, prostate and colon cancer patients. Despite these advancements, and the highly metastatic nature of lung cancer, it remains a challenge to detect CTCs in advanced non-small cell lung cancer (NSCLC). It may be that loss of epithelial features, in favor of a mesenchymal phenotype, and the highly heterogeneous nature of NSCLC CTCs contribute to their evasion from current detection methods. By identifying a broader spectrum of biomarkers that could better differentiate the various NSCLC CTCs subpopulations, it may be possible to not only improve detection rates but also to shed light on which CTC clones are likely to drive metastatic initiation. Here we review the biology of CTCs and describe a number of proteins and genetic targets which could potentially be utilized for the dissemination of heterogenic subpopulations of CTCs in NSCLC. PMID- 28904888 TI - Routine clinical use of circulating tumor cells for diagnosis of mutations and chromosomal rearrangements in non-small cell lung cancer-ready for prime-time? AB - In non-small cell lung cancer (NSCLC), diagnosis of predictive biomarkers for targeted therapies is currently done in small tumor biopsies. However, tumor biopsies can be invasive, in some cases associated with risk, and tissue adequacy, both in terms of quantity and quality is often insufficient. The development of efficient and non-invasive methods to identify genetic alterations is a key challenge which circulating tumor cells (CTCs) have the potential to be exploited for. CTCs are extremely rare and phenotypically diverse, two characteristics that impose technical challenges and impact the success of robust molecular analysis. Here we introduce the clinical needs in this disease that mainly consist of the diagnosis of epidermal growth factor receptor (EGFR) activating alterations and anaplastic lymphoma kinase (ALK) rearrangement. We present the proof-of-concept studies that explore the detection of these genetic alterations in CTCs from NSCLC patients. Finally, we discuss steps that are still required before CTCs are routinely used for diagnosis of EGFR-mutations and ALK rearrangements in this disease. PMID- 28904892 TI - Technique and complications from masters in andrological surgery. PMID- 28904890 TI - Biophysical technologies for understanding circulating tumor cell biology and metastasis. AB - An understanding of cancer evolution in lung cancer with its associated resistance to therapy can only be achieved with repeated sampling and analysis of the cancer. Given the high risks and costs associated with repeat physical biopsy, alternative technologies must be applied. Several modalities exist for analysis and re-analysis of cancer biology. Among them are the CellSearch platform, the CTC chip, and the high-definition CTC platform. While the former is primarily able to provide prognosticating information in the form of CTC enumeration, the latter two have the advantage of serving as a platform to study tumor biology. Techniques for analysis of single cell genomics, as well as protein expression on a single cell basis provide scientists with the capacity to understand cancer cell populations as a collection of individual cells, rather than as an average of all cells. A multimodal combination of circulating tumor DNAs (ctDNAs), CTCs, proteomics, and CTC-derived xenografts (CDXs) to create computational models useful in diagnosis, prognostication, and predictiveness to treatment is likely the future of tailoring individualized cancer care. PMID- 28904889 TI - Challenges and unanswered questions for the next decade of circulating tumour cell research in lung cancer. AB - Since blood borne circulating tumour cells (CTCs) initially shed from the primary tumour can seed and initiate metastasis at distant sites a better understanding of the biology of CTCs and their dissemination could provide valuable information that could guide therapeutic intervention and real time monitoring of disease progression. Although CTC enumeration has provided a reliable prognostic readout for a number of cancers, including lung cancer, the precise clinical utility of CTCs remains to be established. The rarity of CTCs together with the vanishingly small amounts of nucleic acids present in a single cell as well as cell to cell heterogeneity has stimulated the development of a wide range of powerful cellular and molecular methodologies applied to CTCs. These technical developments are now enabling researchers to focus on understanding the biology of CTCs and their clinical utility as a predictive and pharmacodynamics markers. This review summarises recent advances in the field of CTC research with focus on technical and biological challenges as well the progress made towards clinical utility of characterisation of CTCs with emphasis on studies in lung cancer. PMID- 28904893 TI - Surgical patient selection and counseling. AB - The objectives of patient selection and counseling are ultimately to enhance successful outcomes. However, the definition for success is often narrowly defined in published literature (ability to complete surgery, complications, satisfaction) and fails to account for patient desires and expectations, temporal changes, natural history of underlying diseases, or independent validation. Factors associated with satisfaction and dissatisfaction are often surgery specific, although correlation with pre-operative expectations, revisions, and complications are common with most procedures. The process of appropriate patient selection is determined by the integration of patient and surgeon factors, including psychological capacity to handle unsatisfactory results, baseline expectations, complexity of case, and surgeon volume and experience. Using this model, a high-risk scenario includes one in which a low-volume surgeon performs a complex case in a patient with limited psychological capacity and high expectations. In contrast, a high-volume surgeon performing a routine case in a male with low expectations and abundant psychiatric reserve is more likely to achieve a successful outcome. To further help identify patients who are at high risk for dissatisfaction, a previously published mnemonic is recommended: CURSED Patient (compulsive/obsessive, unrealistic, revision, surgeon shopping, entitled, denial, and psychiatric). Appropriate patient counseling includes setting appropriate expectations, reviewing the potential and anticipated risks of surgery, post-operative instruction to limit complications, and long-term follow up. As thorough counseling is often a time-consuming endeavor, busy practices may elect to utilize various resources including educational materials, advanced practice providers, or group visits, among others. The consequences for poor patient selection and counseling may range from poor surgical outcomes and patient dissatisfaction to lawsuits, loss of credibility, or even significant patient or personal harm. PMID- 28904891 TI - Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer. AB - Several different studies have addressed the role of the circulating tumor cells (CTC) in non-small-cell lung cancer (NSCLC). In particular, the potential of CTC analysis in the early diagnosis of NSCLC and in the prediction of the outcome of patients with early and advanced NSCLC have been explored. A major limit of these studies is that they used different techniques for CTC isolation and enumeration, they employed different thresholds to discriminate between high- and low-risk patients, and they enrolled heterogeneous and often small cohort of patients. Nevertheless, the results of many studies are concordant in indicating a correlation between high CTC count and poor prognosis in both early and advanced NSCLC. The reduction of CTC number following treatment might also represent an important indicator of sensitivity to therapy in patients with metastatic disease. Preliminary data also suggest the potential for CTC analysis in the early diagnosis of NSCLC in high-risk individuals. However, these findings need to be confirmed in large prospective trials in order to be transferred to the clinical practice. The molecular profiling of single CTC in NSCLC might provide important information on tumor biology and on the mechanisms involved in tumor dissemination and in acquired resistance to targeted therapies. In this respect, xenografts derived from CTC might represent a valuable tool to investigate these phenomena and to develop novel therapeutic strategies. PMID- 28904894 TI - The infrapubic surgical approach for inflatable penile prosthesis placement. AB - In this invited article, we briefly review the history of the penile prosthesis and the various surgical approaches that have been described. With intra operative photos and illustrations, we discuss Dr. Perito's infrapubic surgical approach. We also highlight the patient selection, post-operative care and complications. PMID- 28904895 TI - The penoscrotal surgical approach for inflatable penile prosthesis placement. AB - Optimizing outcomes with placement of inflatable penile prostheses (IPPs) can be challenging, especially in inexperienced hands. In this article, we outline Dr. Kohler's penoscrotal penile prosthesis surgical approach. We also highlight patient selection, post-operative care and complications. PMID- 28904896 TI - Peyronie's penile plication. AB - Penile plication has become the preferred surgical technique for Peyronie's disease (PD) as it can be performed efficiently, safely, with a high success rate, low morbidity and a low complication rate. Here in we describe two modern plication techniques in detail: the Kiels Knot plication and the minimally invasive penoscrotal plication. Benefits of the techniques include no palpable sutures for the Kiels Knot Plication and less surgical trauma for the penoscrotal plication. Plication has a low rate of failure. However, when it does occur it is usually secondary to under-correction. Failures typically present early postoperatively and a contributing factor to underestimating the deformity is a poor intraoperative artificial erection. Complex, severe, or multiplanar deformities will require more sophisticated intraoperative decision-making, but can be managed effectively with penile plication nonetheless. PMID- 28904897 TI - Peyronie's graft surgery-tips and tricks from the masters in andrologic surgery. AB - BACKGROUND: Grafting techniques in the surgical management of Peyronie's disease (PD) are challenging, especially in inexperienced hands. In order to improve surgical outcomes the urologist should follow a standard surgical approach, preferably of an established and reliable grafting technique. The aim of this study is to provide tips and tricks for graft surgery for PD. METHODS: This report offers a step-by-step tutorial for grafting techniques in PD, especially for the Sealing technique and the partial plaque excision and grafting (PEG) procedure. Two senior surgeons (GH, LAL) describe their surgical technique in detail, and provide important aspects and tips one has to be aware of when performing a grafting technique in patients with PD. Special attention is also paid to preoperative considerations and adequate patient counseling. Moreover, postoperative penile rehabilitation programs are discussed. RESULTS: Adequate preoperative counseling of patients is crucial, and should include possible adverse effects and negative outcomes, such as persistent or recurrent curvature, diminished sensation at the glans penis, diminished erectile function, or penile shortening. The correct indication for a grafting technique is imperative. There are many surgical details during grafting techniques, which have to be considered in order to achieve the best result possible. These include the correct preparation of the neurovascular bundle, the following partial plaque excision without damaging the underlying erectile tissue, and the sufficient closure of the resulting tunica albuginea defect. Defect closure can be done by grafts like pericardial graft (PEG procedure) or the collagen fleece (Sealing technique). Postoperatively, the patient should refrain from sexual activities for at least 6 weeks, and follow a penile rehabilitation program with Phoshodiesterase-Type-5 inhibitors, manual stretch, penile massage, and penile traction therapy. CONCLUSIONS: The present paper offers a step-by-step tutorial for grafting techniques in PD, especially for the Sealing technique and the PEG procedure, in order to help the reader to understand major steps during surgery and to avoid pitfalls. Careful patient selection, a reliable and established surgical technique and a postoperative rehabilitation program are main predictors for treatment success. In summary, the ultimate goal should be improved patient care, safety and satisfaction. PMID- 28904898 TI - Avoiding complications: surgery for ischemic priapism. AB - Ischemic, or low-flow, priapism is among the most common and challenging urologic emergencies. Management of recurrent or refractory ischemic priapism is even more challenging, with increasing levels of risk for both the patient and the urologist. The goal of this commentary is to condense a career of experience (TF Lue) in the management of ischemic priapism into a concise, practical clinical tool for the reader. We will describe our current algorithm for the treatment of ischemic priapism in addition to detailing how we arrived at these recommendations. We will also describe why we believe that the presented approach is the best available approach and why we have turned away from alternative procedures. PMID- 28904899 TI - Virtue Quadratic Male Sling for stress incontinence-surgical guide for placement and delayed revision. AB - The algorithm for surgical management of post prostatectomy incontinence classically includes male slings and artificial urinary sphincter (AUS) placement. The Virtue Quadratic Male Sling was designed to provide both urethral elevation and prepubic compression making it a viable option for a wider spectrum of incontinent men whose symptoms range from mild to severe. With a focus on two key steps of the surgery, (I) sling fixation (II) use of intraoperative retrograde leak point pressure (RLPP), this guide is intended to outline a safe and efficacious treatment for post-prostatectomy incontinence. Intriguingly, the sling can be revised in the event of refractory or worsening leakage, and does not preclude the placement of an AUS should it be needed. This paper describes a step by step approach to performing the procedure as well as expert tips to improve outcomes and avoid/manage complications that have been learned over the years. PMID- 28904900 TI - AdVance male sling. AB - The AdVance sling (American Medical Systems, Minnetonka, MN, United States of America) is a synthetic transobturator sling, which is a safe and effective minimally invasive treatment for mild to moderate stress urinary incontinence (SUI) in male patients. This article provides a step-by-step description of our technique for placement of the AdVance male sling, including details and nuances gained from surgical experience, advice for avoidance of complications and discussion on management of complications and sling failures. Patient selection is very important, including exclusion and preoperative treatment of urethral stenosis and bladder dysfunction. Previous pelvic radiation is a poor prognostic factor. In brief, the steps of sling placement are: (I) mobilization of the corpus spongiosum (CS); (II) marking and mobilization of the central tendon; (III) passage of the helical trocar needles exiting at the apex of the angle between the CS and inferior pubic ramus; (IV) fixation of the broad part of the sling body to the CS at the previous mark; (V) cystoscopy during sling tensioning; (VI) placement of a Foley urethral catheter; (VII) Subcutaneous tunnelling of the sling arms back toward the midline; (VIII) wound closure. The most common early postoperative complication is urinary retention but long-term retention is extremely rare. Management of sling failures include placement of an artificial urinary sphincter, repeat AdVance sling, urethral bulking agent or ProACT device. PMID- 28904901 TI - Artificial urinary sphincter. AB - Although currently still the gold standard treatment for post-prostatectomy urinary incontinence, the artificial urinary sphincter (AUS) (AMS800) is an invasive procedure with associated risks factors. In this paper, we aim to outline what the scientific literature and what we personally believe are the factors that are useful and/or necessary to mitigate these risks, including both patient factors and surgeon factors. We also review special populations, including transcorporal (TC) AUS approach, AUS with inflatable penile prosthesis, AUS after male urethral sling, AUS erosion management, and AUS after orthotopic urinary diversion. PMID- 28904902 TI - Technique considerations and complication management in transurethral resection of the prostate and photoselective vaporization of the prostate. AB - The prevalence of lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) increases with age. While a variety of treatments are available for these men, endoscopic treatments are generally preferred for men with small to moderate size glands. Novel treatment options are continually introduced into this large market. However, the practicing urologist should have a well tested surgical option in regular practice that is applicable to a wide range of patients. Herein we discuss two well recognized surgical options that can be used for the majority of men with LUTS due to BPH who have failed medical management. PMID- 28904903 TI - Vasectomy: tips and tricks. AB - According to data from the National Study of Family Growth, vasectomy is utilized by 6-13% of American couples for their form of contraception. Physician surveys have shown that over 500,000 men undergo vasectomies per year, and more than 75% of vasectomies are performed by urologists. This chapter provides a brief history of vasectomy, as well as recommendations for preoperative counseling, an overview of the modified no-scalpel vasectomy technique, and a brief description of the complications of vasectomy. PMID- 28904905 TI - The role of microsurgical varicocelectomy in treating male infertility. AB - Varicoceles are the most common cause of male infertility. They afflict 15-20% of the general male population and 40% of males with primary infertility. Although multiple treatment modalities exist, including radiographic embolization and laparoscopy, open subinguinal microsurgical varicocelectomy is currently the gold standard of treatment for this condition. In this article, we discuss the role of varicocelectomy in the treatment of the modern infertile male and present a practical, safe, and reproducible technique for the microsurgical approach. PMID- 28904906 TI - A step-by-step guide to office-based sperm retrieval for obstructive azoospermia. AB - A variety of surgical options exists for sperm retrieval in the setting of obstructive azoospermia (OA). With appropriate preparation, the majority of these techniques can safely be performed in the office with local anesthesia and with or without monitored anesthesia care (MAC). The available techniques include percutaneous options such as percutaneous epididymal sperm aspiration (PESA) and testicular sperm aspiration (TESA), as well as open techniques that include testicular sperm extraction (TESE) and microsurgical epididymal sperm aspiration (MESA). In addition to providing a step-by-step description of each available approach, we introduce and describe a new technique for sperm retrieval for OA called minimally invasive epididymal sperm aspiration (MIESA). The MIESA utilizes a tiny keyhole incision, and the epididymis is exposed without testicular delivery. Epididymal aspiration is performed in the style of MESA, except using loupe magnification rather than an operating microscope. MIESA is a safe, office based procedure in which millions of motile sperm can be retrieved for cryopreservation. While we prefer the MIESA technique for OA, there remain distinct advantages of each open and percutaneous approach. In the current era of assisted reproductive technology, sperm retrieval rates for OA should approach 100% regardless of the technique. This reference provides a roadmap for both advanced and novice male reproductive surgeons to guide them through every stage of sperm retrieval for OA, including preoperative evaluation, patient selection, procedural techniques, and complications. With the incredible advances in in vitro fertilization (IVF), combined with innovative surgical treatment for male factor infertility in recent years, OA is no longer a barrier for men to become biologic fathers. PMID- 28904904 TI - Scrotal reconstruction and testicular prosthetics. AB - Scrotal surgery encompasses a wide-variety of surgical techniques for an even wider variety of indications. In this manuscript, we review our indications, techniques, and pit-falls for various reconstructive scrotal surgeries as-well-as surgical tips for placement of testicular prostheses. Penoscrotal webbing (PSW) is an abnormal, often-problematic distal insertion of scrotal skin onto the ventral penile shaft. There are several effective and straightforward techniques used to revise this condition, which include simple scrotoplasty, single- or double-Z-plasty, or the VY-flap scrotoplasty. Reconstruction is also commonly indicated following scrotal skin loss caused by infection, trauma, lymphedema, hidradenitis, and cancer. Although initial management of these conditions often involves scrotal skin removal, repair of expansive scrotal skin loss can be technically difficult and can be accomplished by using one of several skin flaps or skin grafting. Split-thickness skin grafting of scrotal defects can be accomplished easily, and provides durable results. PMID- 28904907 TI - Microdissection testicular sperm extraction. AB - Microdissection testicular sperm extraction (microTESE) is considered the gold standard method for surgical sperm retrieval among patients with non-obstructive azoospermia (NOA). In this review, we will discuss the optimal evaluation of NOA patients and strategies to medically optimize NOA patients prior to microTESE. In addition, we will also discuss technical principles and pearls to maximize the chances of successful sperm retrieval, sperm retrieval rates (SRR) based upon testicular histology, predictors of successful sperm retrieval, gonadal recovery following microTESE, and potential complications. PMID- 28904908 TI - Vasectomy reversal: decision making and technical innovations. AB - Vasectomy is the method of contraception chosen by more than 500,000 American men annually, and by upwards of 8% of married couples worldwide. However, following the procedure, nearly 20% of men express the desire for children in the future, and approximately 2-6% of American men will ultimately undergo vasectomy reversal (VR). VR is a complex microsurgical procedure. Intraoperative decision-making, surgical technique, and postoperative management are each critical step in achieving high success rates. The aim of this article is to provide a detailed description of the operative and perioperative procedures employed by surgeons performing VRs. PMID- 28904909 TI - Office-based andrology and male infertility procedures-a cost-effective alternative. AB - BACKGROUND: From 2014-2016, our clinical practice progressively incorporated several male infertility and andrology procedures performed under local anesthesia, including circumcision, hydrocelectomy, malleable penile prostheses, orchiectomy, penile plication, spermatocelectomy, testicular prostheses, varicocelectomy, vasectomy reversal (VR), and testicular and microepididymal sperm aspiration (TESE/MESA). Given the observed outcomes and potential financial and logistical benefits of this approach for surgeons and patients, we sought to describe our initial experience. METHODS: A retrospective analysis was performed of all andrologic office-based (local anesthesia only) and select OR (general or monitored anesthesia care) procedures performed from 2014-2016. Financial and outcomes analyses were performed for infertility cases due to the homogeneity of payment modalities and number of cases available. Demographic, clinicopathologic, and procedural costs (direct and indirect) were reviewed and compared. RESULTS: A total of 32 VRs, 24 hydrocelectomies, 24 TESEs, 10 circumcisions, 9 MESA/TESEs, 4 spermatocelectomies, 3 orchiectomies (1 inguinal), 2 microTESEs, 2 testicular prostheses, 1 malleable penile prosthesis, 1 penile plication, and 1 varicocelectomy. Compared to the OR, male infertility procedures performed in the clinic with local anesthesia were performed for a fraction of the cost: MESA/TESE (78% reduction), TESE (89% reduction), and VR (62% reduction). All office-based procedures were completed successfully without significant modifications to technique. Outcomes were similar between the office and OR including operative time (VR: 181 vs. 190 min, P=0.34), rate of vasoepididymostomy (VE) (23% vs. 32%, P=0.56), total sperm counts (72.2 vs. 50.9 million, P=0.56), and successful sperm retrieval (MESA/TESE 100% vs. 100%, P=1.00; TESE 80% vs. 100%, P=0.36). To our knowledge, the current study also represents the first report of office-based VE under local anesthesia alone. For hydrocelectomy procedures, recurrence (4%) and hematoma (4%) rates were low (mean 4.2 months follow-up), although this likely relates to modifications with technique and not the anesthesia or operative setting. Overall, when given the choice, 86% of patients chose an office-based approach over the OR. CONCLUSIONS: Office-based andrology procedures using local anesthesia may be successfully performed without compromising surgical technique or outcomes. This approach significantly reduces costs for patients and the overall healthcare system and has become our treatment modality of choice. PMID- 28904911 TI - Insulin Resistance: Quest for Surrogate Markers. PMID- 28904910 TI - Complications: acknowledging, managing, and coping with human error. AB - Errors are inherent in medicine due to the imperfectness of human nature. Health care providers may have a difficult time accepting their fallibility, acknowledging mistakes, and disclosing errors. Fear of litigation, shame, blame, and concern about reputation are just some of the barriers preventing physicians from being more candid with their patients, despite the supporting body of evidence that patients cite poor communication and lack of transparency as primary drivers to file a lawsuit in the wake of a medical complication. Proper error disclosure includes a timely explanation of what happened, who was involved, why the error occurred, and how it will be prevented in the future. Medical mistakes afford the opportunity for individuals and institutions to be candid about their weaknesses while improving patient care processes. When a physician takes the Hippocratic Oath they take on a tremendous sense of responsibility for the care of their patients, and often bear the burden of their mistakes in isolation. Physicians may struggle with guilt, shame, and a crisis of confidence, which may thwart efforts to identify areas for improvement that can lead to meaningful change. Coping strategies for providers include discussing the event with others, seeking professional counseling, and implementing quality improvement projects. Physicians and health care organizations need to find adaptive ways to deal with complications that will benefit patients, providers, and their institutions. PMID- 28904912 TI - Assessment of Anxiety Level of Emergency Health-care Workers by Generalized Anxiety Disorder-7 Tool. AB - BACKGROUND: Dealing with emergency patients is considered to be a stressful situation to all health-care workers in the emergency department (ED). Prolonged stress predispose to physical and inconsequential psychiatric disturbances. Anxiety and depressive mode were found to be the most commonly experienced psychiatric manifestation among emergency health-care workers. The aim of this study is to screen and assess the severity of anxiety among health professionals working in ED. METHODS: Cross-sectional study design was used. Generalized anxiety disorder (GAD)-7 screening tool was used to assess for anxiety symptoms. GAD-7 is a validated self-report tool that comprises seven questions where each question is rated on a 3-point scale. Demographic data were collected from the study sample. The study sample consists of emergency physician, nurses, and other emergency medical services workers. Data analysis was performed using SAS version 9.2 software. Descriptive statistics, nonparametric comparison, and correlation were performed as part of data analysis. RESULTS: A total of 135 participants completed the questionnaire, of which, 66% of the participants were males. Occupational status of the respondents indicated that majority (35.6%) were physicians followed by 27.4% of emergency medical, and 27% of nurses. The results of this study indicated that 48% of the subjects were observed without an anxiety disorder. However, moderate to mild degrees of anxiety disorder was identified among 20.7% and 23.7% of the subjects, respectively. Severe anxiety disorder was found among 7.6% of the respondents. Emergency medical services workers were reported to have the highest GAD-7 score followed by physicians and nurses P = 0.039. Gender and older age group among health professionals were statistically significant correlated with higher GAD-7 score P = 0.028 and 0.048, respectively. There is no significant difference in GAD-7 score among health professional dealing with adult versus pediatrics patient. CONCLUSION: From this study, it was concluded that more than 52% of the health-care team members manifested with moderate to severe anxiety disorder that requires counseling and referral for support and treatment. Prolonged and unrecognized anxiety may predispose to major psychiatric morbidity, exhaustion, and resignations from the duties. Hospital administration needs to be aware of the level of anxiety and the most likely affected population to build preventive strategies. PMID- 28904913 TI - Inhibition by Benidipine of Contractility of Isolated Proximal and Distal Caprine Ureter. AB - CONTEXT: Benidipine is a calcium channel blocker that blocks all the major types (L, N, and T) of calcium channels. It has been shown to inhibit the contractility of many isolated smooth muscles but not isolated ureter. AIMS: This study evaluated the ability of benidipine to inhibit the spontaneous contractility of isolated proximal and distal caprine (goat) ureter. SETTINGS AND DESIGN: Spontaneous contractility of isolated goat ureter was recorded using a physiograph. MATERIALS AND METHODS: Benidipine at concentrations in the range of 1 nM to 10 MUM was analyzed for its inhibitory effects on the spontaneous contractility of the isolated proximal and distal caprine ureter. STATISTICAL ANALYSIS USED: Both parametric and nonparametric statistical tests were used. RESULTS: The EC50 of benidipine for inhibiting contractility in the distal ureter was found to be 54.68 nM. Benidipine was found to have a greater inhibitory effect on the distal ureter than on the proximal ureter. It was also found to inhibit amplitude of spontaneous ureteric contractility more readily than the frequency of spontaneous ureteric contractility. CONCLUSIONS: These results suggest that benidipine has differential inhibitory effects on the spontaneous contractility of the isolated ureter. Benidipine could be useful in the management of clinical conditions like ureteric colic due to its inhibitory effects on the contractility of the ureter. PMID- 28904914 TI - Novel Cardiovascular Risk Markers in Nigerian Cigarette Smokers. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. While the effect of cigarette smoking on conventional markers that account for <50% of CVD s has been well studied, there are only a few studies on the effect of cigarette smoking on novel cardiovascular (CV) risk markers. OBJECTIVE: To evaluate the effect of cigarette smoking on the novel CV markers such as homocysteine (HCY), lipoprotein (a) (Lp(a)), and C-reactive protein (CRP). MATERIALS AND METHODS: One hundred and forty smokers, 12 ex smokers, and 84 controls were recruited for the study. A structured questionnaire was used to obtain information on their clinical history, daily cigarette consumption, and duration of smoking. The smokers were further grouped according to the amount of cigarette consumption: light (<5 sticks/day), moderate (6-10 sticks/day), and heavy (>10 sticks/day) and duration of smoking: short (5-10 years), medium (11-20 years), and long (>20 years). HCY was determined by enzyme linked immunosorbent assay method, and Lp(a) and CRP were determined spectrophotometrically. RESULTS: HCY, Lp(a), and CRP were significantly elevated in smokers when compared with control (P < 0.05) and they correlated with daily cigarette consumption and duration of smoking. Ex-smokers also exhibited a significant increase in HCY, Lp(a), and CRP level (P < 0.05) when compared with the control, but were significantly lower than the current smokers. CONCLUSION: There is a linear relationship between the intensity and duration of cigarette smoking and serum levels of all three novel risk CV markers. These findings suggest that these markers may be an important mechanism by which smoking promotes atherosclerosis. PMID- 28904915 TI - Microbiological Surveillance of Operation Theatres: Five Year Retrospective Analysis from a Tertiary Care Hospital in North India. AB - INTRODUCTION: Microbiological contamination of air and environment in the operation theaters (OTs) are major risk factor for surgical site and other hospital-associated infections. OBJECTIVES: The aim was to identify bacterial colonization of surfaces and equipment and to determine the microbial contamination of air in the OTs of a tertiary care hospital. MATERIALS AND METHODS: Five years (January 2010-December 2014) retrospective analysis of the data obtained from routine microbiological surveillance of the five OTs of the hospital was done. Surface samples were taken with wet swabs from different sites and equipment. Bacterial species were isolated and identified by conventional methods. Air quality surveillance of OTs was done by settle plate method. RESULTS: A total of 4387 samples were collected from surfaces and articles of various OTs. Out of these only 195 (4.4%), samples showed bacterial growth and yielded 210 isolates. The predominant species isolated was Bacillus with 184 (87.6%) isolates followed by coagulase-negative Staphylococcus 17 (8.1%), Staphylococcus aureus 6 (2.9%), and Enteroccoccus spp. 3 (1.4%). Analysis of the OT air samples showed least colony forming unit (cfu) rate of air (27 cfu/m3) in ophthalmology OT and highest rate of 133 cfu/m3 in general surgery OT. CONCLUSION: The study shows that OTs of our hospital showed a very low bacterial contamination rate on surface swabbing and a cfu count per m3 of air well within permissible limits. PMID- 28904916 TI - Prevalence of Metabolic Syndrome in Psoriasis and Levels of Interleukin-6 and Tumor Necrosis Factor-alpha in Psoriasis Patients with Metabolic Syndrome: Indian Tertiary Care Hospital Study. AB - BACKGROUND: Psoriasis is a chronic inflammatory multisystem disease, found to be associated with metabolic syndrome (MS) and increased levels of cytokines. To evaluate the prevalence of MS in psoriasis and to determine the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in psoriasis patients with MS. METHODS: Observational study on 334 psoriasis patients and 230 controls. MS was diagnosed by the presence of three or more criteria of original, revised, and modified National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III). RESULTS: MS was significantly more common in psoriasis patients than in controls (multivariate odds ratio [95% confidence interval] of original NCEP ATP III = 5.73 [2.99-10.99], revised NCEP ATP III = 4.44 [2.43 8.10], and modified NCEP ATP III = 6.00 [3.43-10.52]). Higher prevalence of abdominal obesity (66.2% vs. 47%, P < 0.001), hypertriglyceridemia (40.4% vs. 29.6%, P = 0.009), systolic blood pressure (BP) >=130 mmHg (25.1% vs. 7.4%, P < 0.001), diastolic BP >=85 mmHg (30.2% vs. 12.2%, P < 0.001), and fasting plasma glucose >=100 mg/dl (17.4% vs. 9.1%, P = 0.005) among psoriasis patients as compared to controls. Mean (standard deviation) values of IL-6 and TNF-alpha were 76.7 (73.9) pg/ml and 234.3 (273.9) in subgroup of psoriasis patients with MS (n = 42), significantly higher than the normal population (P < 0.0001). CONCLUSION: MS is more common in psoriasis. IL-6 and TNF-alpha is significantly higher in psoriasis patients with MS, signifying their role in pathogenesis of psoriasis and MS. PMID- 28904917 TI - Evaluation of Leptin as a Marker of Insulin Resistance in Type 2 Diabetes Mellitus. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a leading cause of mortality and morbidity worldwide, whose incidence is rapidly increasing in India. T2DM is caused by varying degrees of insulin resistance (IR) and relative insulin deficiency. Leptin, an adipokine with the primary function of regulating energy balance, is found to mediate insulin secretion and sensitivity in peripheral tissues. Hence, we aimed to determine the role of leptin in the development of IR in newly diagnosed T2DM patients. AIM: This study aims to compare the leptin levels and homeostatic model assessment-IR (HOMA-IR) levels in the study population. MATERIAL AND METHODS: The study included a total of sixty patients newly diagnosed with T2DM. Their fasting blood samples were collected to estimate the glucose, insulin, and leptin levels. IR was calculated using HOMA-IR formula. Statistical analysis was done by Pearson's correlation, Spearman's correlation, and One-sample Wilcoxon Signed Rank test. RESULTS: Leptin and HOMA-IR levels were significantly high in T2DM patients (P < 0.001) when compared with reference values. Body mass index showed a significant positive correlations with insulin (r = 0.40, P < 0.01), HOMA-IR (r = 0.37, P < 0.01), and leptin levels (r = 0.90, P < 0.01). Leptin levels showed significant positive correlations with plasma insulin (r = 0.35, P < 0.01) and HOMA-IR levels (r = 0.31, P < 0.05). The correlation between leptin and HOMA-IR levels was more pronounced and significant among the obese T2DM subjects (r = 0.82, P = 0.01). CONCLUSION: Hyperleptinemia reflecting leptin resistance plays an important role in the development of IR in obeseT2DM patients, making leptin a possible biomarker for the same. PMID- 28904918 TI - Evaluation of Genetic Polymorphisms in Glutathione S-Transferase Theta1, Glutathione S-Transferase Mu1, and Glutathione S-Transferase Mu3 in Oral Leukoplakia and Oral Squamous Cell Carcinoma with Deleterious Habits using Polymerase Chain Reaction. AB - CONTEXT: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the world. As per previous studies, most patients who develop oral cancer are elderly males who are heavy users of tobacco and alcohol; however, the incidence is increasing in younger individuals and in those who neither smoke nor drink. Many of the genes that code for the detoxification enzymes are polymorphic with abnormal activity profiles. AIMS AND OBJECTIVES: The aim of this study was to evaluate the risk of development of oral leukoplakia (OLP) and OSCC in glutathione S-transferase polymorphisms genes in the east coast of Andhra Pradesh population with tobacco consumption habit and habit-free controls using polymerase chain reaction (PCR-restriction fragment length polymorphism). MATERIALS AND METHODS: This study included 15 patients each with histologically proven epithelial dysplasia and OSCC and compared with age- and gender-related controls with no tobacco habits in any form. A volume of 2 ml of blood sample was collected into presterilized vials containing ethylenediaminetetracetic acid from each individual under aseptic conditions. DNA extraction was done from whole blood, and PCR was performed. Statistical analysis was performed using Chi-square test and odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: The results are suggestive that glutathione S-transferase mu1 (GSTM1) null was associated with increased risk of OLP (OR = 5.5, 95% CI = 1.14-26.41, P = 0.021) and OSCC (OR = 11, 95% CI = 1.99-60.5, P = 0.021). Glutathione S-transferase theta1 (GSTT1) null genotype was associated with increased risk of OLP (OR = 2.154, 95% CI = 0.74-26.672, P > 0.99) and OSCC (OR = 2.154, 95% CI = 0.74-26.672, P > 0.99). The glutathione S-transferase mu3 (GSTM3) AB + BB genotypes appear to be risk factors for OSCC (OR = 1.31, 95% CI = 0.31-5.58, P = 0.7) although statistically insignificant. CONCLUSION: Hence to conclude, because of small sample size in the present study, statistically insignificant results were found and this study failed to observe the relationship between GSTM3 and GSTT1 polymorphism and risk of developing OSCC and positive relationship was observed with GSTM1 polymorphism and risk of developing OSCC. PMID- 28904919 TI - Pre- and Post-operative Comparative Analysis of Serum Lipid Profile in Patients with Cholelithiasis. AB - BACKGROUND: Gallstones have become a major health problem because of their silent manifestation and unclear pathogenesis. Although the association between the disturbed lipid metabolism and formation of gallstones has been elucidated in many studies, the effect of cholecystectomy on lipid profile has not been studied in detail. AIM: The aim of the present study was to study the effect of cholecystectomy on lipid levels in patients with gallstones. MATERIALS AND METHODS: The study was conducted on 50 patients with gallstones and 30 healthy volunteers for comparison of lipid levels. Subsequently, cholecystectomy was conducted on patients with gallstones and pre- and post-operative lipid levels were compared. RESULTS: There was a significant decrease in total cholesterol, and triglycerides levels and increase in high-density lipoprotein levels after 1 month of surgery, while low-density lipoprotein levels and very low-density lipoprotein were not statistically changed. CONCLUSION: Cholecystectomy can significantly improve lipid levels in patients with gallstones. PMID- 28904920 TI - Antimicrobial Susceptibility Pattern of Extended-spectrum Beta-lactamases Producing Organisms Isolated in a Tertiary Care Hospital, Bangladesh. AB - CONTEXT: Infection caused by extended-spectrum beta-lactamases (ESBL) producing organism is a major problem regarding antibiotic resistance. AIMS: The aim of this study was to find out the antibiogram of ESBL producing organisms isolated from various samples. SETTINGS AND DESIGN: This cross-sectional study was carried out in the Department of Microbiology of a Tertiary Care Hospital, Dhaka, Bangladesh from January to June 2014. SUBJECTS AND METHODS: One Hundred and seventy-nine ESBL producing Gram-negative organisms detected phenotypically by double-disc synergy test were enrolled in this study. Required data were collected from the records of the Microbiology laboratory. RESULTS: ESBL production was detected in 16.07% (179/1114) of isolated organism. Of Escherichia coli, 15.75% were ESBL producers; 14.01% Pseudomonas spp., 36.84% Proteus spp., 18.57% Klebsiella spp., and 21.05% of Acinetobacter spp., were ESBL producers. Maximum (43.58%) ESBL producers were isolated from surgery departments, and wound swabs yielded majority (53%) of them. About 13% ESBL producers were isolated in outdoor patients mostly from community-acquired infections. Most ESBL producers were resistant to commonly used antibiotics. Carbapenems especially imipenem was the most effective drug showing excellent sensitivity; colistin and piperacillin/tazobactam also had better sensitivity result. Most of the ESBL producers showed a good sensitivity to amikacin, but all of them were highly resistant to ciprofloxacin. CONCLUSIONS: ESBL production should be detected routinely in all Microbiology laboratories. Infection control, rational use of antibiotics must be done promptly to prevent the development and spread of ESBL producing organisms. PMID- 28904921 TI - Hashimoto's Encephalitis: Rare Manifestation of Hypothyroidism. AB - Hashimoto's encephalitis is a rare, heterogeneous and completely treatable form of neuroendocrine disorder manifesting with seizures, stroke-like episodes, encephalopathy, dementia and variable neuropsychiatric manifestations. It is generally associated with a background of Hashimoto's Thyroiditis, and the patient has high titers of antithyroid antibodies, especially antithyroid peroxidase antibodies. This entity responds dramatically to corticosteroids, hence should be always considered and excluded while treating a patient with encephalopathy in the background of a thyroid disease. PMID- 28904922 TI - Report of a Case and Review of Literature of Internal Hernia through Peritoneal Defect in Pouch of Douglas: A Rare Occurrence. AB - Intestinal obstruction attributable to internal hernia as a cause is a rare phenomenon with a reported incidence of 0.6%-5.8%. Internal hernias ensuing as a result of defect in the pouch of Douglas is extremely rare with only six such cases reported so far in the literature. We present a case of 74-year-old posthysterectomy status female who presented with features of intestinal obstruction. Intraoperatively, the site of obstruction was found to be a rent in the peritoneum of the pouch of Douglas through which a loop of ileum was found herniating. The viability of the bowel was confirmed, and the defect was closed. The postoperative course was uneventful. This report presents an extremely rare type of internal hernia caused by defect in the pouch of Douglas and review of the literature so far available. PMID- 28904923 TI - Congenital Cyst Adenoid Malformation Masquerading as Bronchial Asthma. AB - Congenital cyst adenoid malformation (CCAM) is a rare congenital malformation occurring in approximately 1-4 in 100,000 births. It is classified into five subtypes with type 1 CCAM is most common subtype. The diagnosis of CCAM is usually made in infancy, and it is rare in adolescents and adults. We report a 15 year-old female, who presented in pediatric outpatient department with a history of recurrent cough since infancy. On the basis of clinical examination, provisional diagnosis of asthma was considered and patient was started on inhaled corticosteroid and long-term beta2 agonist. Lung function of the patient revealed low forced expiratory volume-1 s but without bronchodilator reversibility. Therefore, alternative diagnosis was suspected, and the patient was further evaluated with X-ray chest and high resolution computed tomography thorax. Based on radiological findings, a final diagnosis of CCAM was established. The case was highly unusual due to its atypical and late age of presentation. Acquaintance about this condition benefit clinician in making differential diagnosis of recurrent cough. PMID- 28904924 TI - Rare Opportunistic Bread Mold Fungal Infection of Maxillary Sinus in a Diabetic Patient. AB - Mucormycosis is a rare potentially fatal opportunistic fungal infection that affects human beings. Normally, a healthy is immune to such infections but there are some risk factors which predispose a person to mucormycosis, of which malnutrition and diabetes mellitus are the most common risk factors. India is the most commonly affected country by mucormycosis because of high proportion people with low socioeconomic status and diabetes mellitus. In diabetes mellitus, mucormycosis is more aggressive and fatal due to an impaired host defense mechanism. In spite of being a rare and fatal fungal infection, early diagnosis and prompt multidisciplinary treatment comprising control of underlying predisposing factor, surgical management, and medical management can be helpful in such cases. PMID- 28904925 TI - A Rare Case of Transvesical Cesarean Section. AB - Cesarean section, also commonly known as C-section, is a surgical procedure in which incision is made through a mother's abdomen and uterus to deliver one or more babies. According to urgency, they are classified either as elective or emergency. According to technique, they have been classified as classical, lower uterine segment and cesarean hysterectomy. Intentional transvesical cesarean though not a routinely practiced technique is used for delivery in women born with imperforate anus, ectopic intravaginal urethra, vaginal and urethral strictures, and bladder adherent completely over the uterus. Since such cases are very rare, we are reporting one such case of transvesical cesarean section. PMID- 28904926 TI - Toxic Brain Injury with Nitrobenzene Poisoning. AB - Acute methemoglobinemia secondary to nitrobenzene ingestion is a rare but well known clinical entity. It is extremely important to identify such patients as rapid and effective management with methylene blue and other supportive measures will often save these lives. We present a rare and unfortunate case of a girl who developed acute toxic brain injury following nitrobenzene ingestion and succumbed. PMID- 28904927 TI - Cervical Lymph Nodes: Harbinger of Benign Inclusions As Well As Metastatic Deposits of Thyroid Malignancy. AB - Lymph nodes can be harbinger to benign epithelial inclusions as well as metastatic deposits. Cervical lymph nodes are home to benign epithelial inclusions from thyroid better known as lateral aberrant thyroid as well as inclusions from salivary gland due to the unique embryologic origins of nodes with these organs. We present a case of a young female suspected of thyroid malignancy who was intraoperative diagnosed by frozen sections with papillary carcinoma of the thyroid along with bilateral cervical nodes (Level I-V) positive for reactive lymphadenopathy with Level II node being positive to benign salivary gland inclusions and Level VI node being positive to metastatic deposits of papillary carcinoma of the thyroid. PMID- 28904928 TI - Prenatal Sonographic Diagnosis of Hypoplastic Left Heart Syndrome. AB - Hypoplastic left heart syndrome (HLHS) represents a variety of cardiac malformations that may result from errors in the early stages of cardiac development. HLHS includes a wide spectrum of cardiac malformations including hypoplasia of the left ventricle, ascending aorta, hypoplasia, or atresia of the aortic and mitral valves. Over the recent years, the improved resolution of advanced equipment with awareness and increased performance of second-trimester ultrasound examinations for the assessment of fetal anomalies have helped in understanding the spectrum and have expanded our knowledge of HLHS. They are one of the causes which constitute for neonatal morbidity and mortality and hence the rapid need for prenatal evaluation with ultrasound to detect cardiac anomalies. Prenatal recognition of disease also allows families to prepare for a child with a life-threatening defect by consultation with the multidisciplinary team that will care for their newborn and discussing the short- and long-term prognosis. PMID- 28904929 TI - Diagnosing Mucopolysaccharidosis type IV a by the fluorometric assay of N Acetylgalactosamine-6-sulfate sulfatase activity. AB - BACKGROUND: Mucopolysaccharidosis type IVA, also known as Morquio A or MPS IV A, is an autosomal recessive disease caused by the deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). The loss of GALNS activity leads to the impaired breakdown of glycosaminoglycans (GAGs) keratan sulfate and chondroitin-6-sulfate. The accumulation of GAGs results in multiple organ damage. The accurate and early diagnosis of this disorder helps enhance the effectiveness of the treatment. The present study uses a pre-designed protocol for testing GALNS activity in the leukocytes of Iranian patients with MPS IV A and their parents and compares it with healthy controls. METHODS: Patients with MPS IVA previously diagnosed through the measurement of enzyme activity or genetic analysis entered the study. Leukocytes were obtained from the heparinized blood of the participants. The GALNS activity was measured by a fluorometric method using 4-methylumbelliferyl-beta-D-galactoside-6-sulfate (4MU-G6S) as the substrate and proper buffer solutions and calibrators. RESULTS: The GALNS activity (nmol/17 h/mg protein) was reported as 0-7.4 in the MPSIV A patients, as 19.85-93.7 in their parents and as 38.4-164 in the healthy controls. Statistically significant differences were observed between the three groups in terms of enzyme activity. There were no significant differences in enzyme activity by age. The female subjects in both the patient and parents groups showed lower enzyme activity compared to the male subjects. CONCLUSION: The fluorometric method was validated for the measurement of GALNS activity in leukocyte samples and identifying Iranian patients with MPS IV A. PMID- 28904930 TI - Comment on "Prevalence of Occult Hepatitis B Virus Infection in Hemodialysis Patients in Isfahan, Iran". PMID- 28904931 TI - Isolation of Candida Species from Gastroesophageal Lesions among Pediatrics in Isfahan, Iran: Identification and Antifungal Susceptibility Testing of Clinical Isolates by E-test. AB - BACKGROUND: Candida species can become opportunistic pathogens causing local or systemic invasive infections. Gastroesophageal candidiasis may depend on the Candida colonization and local damage of the mucosal barrier. Risk factors are gastric acid suppression, diabetes mellitus, chronic debilitating states such as carcinomas, and the use of systemic antibiotics and corticosteroids. The aim of this study is collection and molecular identification of Candida species from gastroesophageal lesions among pediatrics in Isfahan, and determination of minimum inhibitory concentration (MIC) ranges for clinical isolates. MATERIALS AND METHODS: A total of 200 patients underwent endoscopy (130 specimens from gastritis and 70 samples from esophagitis) were included in this study between April 2015 and November 2015. All specimens were subcultured on sabouraud dextrose agar, and genomic DNA of all strains was extracted using boiling method. Polymerase chain reaction and DNA sequencing of the ITS1-5.8SrDNA-ITS2 region were used for the identification of all Candida strains. MIC ranges were determined for itraconazole (ITC), amphotericin B (AmB), and fluconazole (FLU) by E-test. RESULTS: Twenty of 200 suspected patients (10%) were positive by direct microscopy and culture. Candida albicans was the most common species (60%) followed by Candida glabrata (30%), Candida parapsilosis (5%), and Candida kefyr (5%). MIC ranges were determined for FLU (0.125-8 MUg/mL), ITC (0.008-0.75 MUg/mL), and AmB (0.008-0.75 MUg/mL), respectively. CONCLUSION: Every colonization of Candida species should be considered as a potentially factor of mucocutaneous candidiasis and should be treated with antifungal drugs. PMID- 28904932 TI - A Comparative Study on the Results of Estimating Children's Weights Based on Arm Circumference, Height, and Body Habitus against Estimated Weight Broselow on 2-24 Months Children in Isfahan. AB - BACKGROUND: Resuscitation of children in different treatment wards is a challenge. Given that the pediatric drug dosing is based on weight and weighing is not practical in emergency situations, it is critical to employ a fast, easy, and reliable technique. Hence, this study attempted to evaluate the real weight children against Broselow estimation. MATERIALS AND METHODS: This cross-sectional study involved 1500 children of 2-24 months referred to Isfahan urban and rural health centers in 2015. Children's estimated weights were measured based on the standard Broselow tape and real weights through a digital scale. The factors such as age, sex, height, arm circumference, head circumference, and living place of children were recorded. The collected data were analyzed through independent t test, ANOVA, and linear regression using SPSS (version 20). RESULTS: The weight difference of children through Broselow estimation was 0.019 kg, and the correlation coefficient was 0.893 (P > 0.05). The difference sorted by age ranges was significant only in >12 months (P < 0.05). It was estimated at error of 10% to be 68.9% correctly. The mean weight estimation error was significant sorted by weight, sex, habitus, and living place of children (P < 0.001). CONCLUSION: Although Broselow tape has been proved to be accurate it led to a significant error at different age ranges. Hence, the present study estimated the age, arm circumference, and height of Iranian children based on new formulas providing more successful tool through controlling the confounding factors in estimating the real weight. PMID- 28904933 TI - Electrospun Gelatin/poly(Glycerol Sebacate) Membrane with Controlled Release of Antibiotics for Wound Dressing. AB - BACKGROUND: The most important risk that threatens the skin wounds is infections. Therefore, fabrication of a membrane as a wound dressing with the ability of antibiotic delivery in a proper delivery rate is especially important. MATERIALS AND METHODS: Poly(glycerol sebacate) (PGS) was prepared from sebacic acid and glycerol with 1:1 ratio; then, it was added to gelatin in the 1:3 ratio and was dissolved in 80% (v/v) acetic acid, and finally, ciprofloxacin was added in 10% (w/v) of polymer solution. The gelatin/PGS membrane was fabricated using an electrospinning method. The membrane was cross-linked using ethyl-3-(3 dimethylaminopropyl) carbodiimide ethyl-3-(3-dimethylaminopropyl)carbodiim (EDC) and N-hydroxysuccinimide (NHS) in different time periods to achieve a proper drug release rate. Fourier-transform infrared (FTIR) spectroscopy was being used to manifest the peaks of polymers and drug in the membrane. Scanning electron microscopy (SEM) was used to evaluate the morphology, fibers diameter, pore size, and porosity before and after crosslinking process. Ultraviolet (UV)-visible spectrophotometry was used to show the ciprofloxacin release from the cross linked membrane. RESULTS: FTIR analysis showed the characteristic peaks of gelatin, PGS, and ciprofloxacin without any added peaks after the crosslinking process. SEM images revealed that nanofibers' size increased during the crosslinking process and porosity was higher than 80% before and after crosslinking process. UV-visible spectrophotometry showed the proper rate of ciprofloxacin release occurred from cross-linked membrane that remaining in EDC/NHS ethanol solution for 120 min. CONCLUSION: The obtained results suggest that this recently developed gelatin/PGS membrane with controlled release of ciprofloxacin could be a promising biodegradable membrane for wound dressing. PMID- 28904934 TI - Comparison of Complications of Arteriovenous Fistula with Permanent Catheter in Hemodialysis Patients: A Six-month Follow-up. AB - BACKGROUND: Arteriovenous fistula (AVF), permanent catheter (PC), and vascular graft are three vascular access types used for hemodialysis procedure. Due to insufficient reliable information on the comparison between AVF and PC, this study was conducted to compare AVF and PC regarding dialysis adequacy. MATERIALS AND METHODS: This prospective study was carried out from March, 2013 to September, 2013. In this study, 76 hemodialysis patients were enrolled and assigned to two unequal groups of AVF and PC. Before and after the dialysis session, blood samples were taken for laboratory examinations and measurement of urea reduction ratio (URR) and Kt/V. The patients were followed up for six months, and then laboratory examinations were repeated. RESULTS: Of the 76 hemodialysis patients, 30 had AVF and others PC. During the 6-month follow-up, 24 patients in PC group but only one patient in AVF group showed infection (P = 0.006), while in each group, three cases of thrombosis were seen (P = 0.58); however, catheter dysfunction was seen in 13 patients of PC group but no patients of AVF group (P = 0.004). There was no difference between the two groups in Kt/V and URR at the beginning of the study; however, after six months, Kt/V and URR were greater in AVF group (P < 0.05). CONCLUSIONS: In addition to some advantages of AVF over PC, such as lower rate of infection and thrombosis, we also found better dialysis adequacy in AVF group. We recommend that AVF be created in all of patients with chronic kidney disease who are candidates for hemodialysis. PMID- 28904935 TI - Evaluation of Dietary Intakes, Body Composition, and Cardiometabolic Parameters in Adolescent Team Sports Elite Athletes: A Cross-sectional Study. AB - BACKGROUND: Nutritional intake is an important issue in adolescent athletes. Proper athletes' performance is a multifactorial outcome of good training, body composition, and nutritional status. The aim of the present study was to assess nutritional status, body composition, and cardiometabolic factors in adolescent elite athlete's province of Isfahan, Iran. MATERIALS AND METHODS: In this cross sectional study, 100 adolescent elite athletes from volleyball, basketball, and soccer teams were selected for the study. Demographic, anthropometric, and cardiometabolic parameters were assessed. Nutritional intakes of participants were recorded using three 24-h recall questioners. RESULTS: Thirty-four female athletes and 66 male athletes participated in this study. Body mass index had not significantly different between the sexes. Energy, protein, carbohydrate, iron, and fat intakes were significantly higher in male athletes (P = 0.02), but calcium and folic acid intakes were not significantly different between the sexes, and Vitamin D intake was significantly higher in females (P = 0.01). Systolic and diastolic blood pressure was significantly higher in males (P = 0.04) and heart rate had not significantly different between the sexes (P = 0.09). Heart murmurs and heart sounds in the majority of participants were normal. CONCLUSION: All the evaluated anthropometric and cardiometabolic parameters were in normal range in the majority of participants. The results showed that dietary intake in these athletes is approximately normal but micronutrients intake status in these athletes needs to be investigated further and longer. PMID- 28904936 TI - Evaluation of Urokinase Plasminogen Activator Receptor, Soluble Urokinase Plasminogen Activator Receptor, and beta1 Integrin in Patients with Hodgkin's Lymphoma. AB - BACKGROUND: The objective of this study is to indicate the role of urokinase plasminogen activator receptor (uPAR), soluble uPAR (suPAR), and beta1 integrin in tumor growth and invasion of lymph nodes from Hodgkin's lymphoma (HL) patients. MATERIALS AND METHODS: In this study, 25 lymph nodes from HL patients were analyzed for the expression of beta1 integrin and uPAR on mononuclear cells using two-color flow cytometry and immunohistochemical analysis. Moreover, the levels of suPAR in the serum samples of HL patients were measured and compared with 32 healthy controls. RESULTS: Flowcytometry and immunohistochemical results indicated no significant association of uPAR expression with tumor size, different stages, or different histological subtypes of HL; however, an increased expression of beta1 integrin was detected in the advanced stages of HL. Higher expression of beta1 integrin was detected in nodular sclerosis compared to lymphocyte predominant. No significant difference was observed between the serum levels of suPAR in patients with different stages of HL and healthy controls. Moreover, the levels of suPAR were significantly higher in nodular sclerosis in comparison with other subtypes. CONCLUSIONS: This study showed that the levels of suPAR and beta1 integrin varied between different histological subtypes of HL. Although uPAR may play only a minor role in the growth and metastasis of lymphoma, beta1 integrin may be important in predicting prognosis and metastasis in HL. PMID- 28904937 TI - Effect of Magnesium Supplement on Pregnancy Outcomes: A Randomized Control Trial. AB - BACKGROUND: Magnesium (Mg) is an essential mineral required to regulate body temperature, nucleic acid, and protein synthesis with an important role in maintaining nerve and muscle cell electrical potentials. It may reduce fetal growth restriction and preeclampsia as well as increase birth weight. This study aimed to assess the effects of consuming Mg supplementation during pregnancy on pregnancy outcomes. MATERIALS AND METHODS: This is a randomized controlled trial with three sixty populated groups of pregnant women. Participants were randomized to treatment or control groups through random table numbers. Participants with Mg serum levels more than 1.9 mg/dl considered as control group A randomly. They just received one multimineral tablet once a day until the end of pregnancy participants with hypomagnesemia consider as Group B and C. Participants in Group B received one multimineral tablet daily until the end of pregnancy. Participants in Group C received 200 mg effervescent Mg tablet from Vitafit Company once daily for 1 month, and also they consumed one multimineral tablet from Alhavi Company, which contains 100 mg Mg, once a day until the end of pregnancy. Intrauterine growth retardation, preterm labor, maternal body mass index, neonatal weight, pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, cramps of the leg Apgar score were compared between three groups. RESULTS: In all pregnancy outcomes, Group C that received effervescent Mg tablet plus multimineral showed a better result than other groups, and frequency of complications of pregnancy was fewer than the other two groups and showed a significant difference. CONCLUSION: Mg supplement during pregnancy likely decrease probability occurrence of many complications of pregnancy. PMID- 28904938 TI - The Effects of Pentoxifylline on Serum Levels of Interleukin 10 and Interferon Gamma and Memory Function in Lipopolysaccharide-induced Inflammation in Rats. AB - BACKGROUND: Studies have shown that pentoxifylline (PTX) in addition to protective effects on blood vessels probably has positive influence against the brain inflammation. Therefore, the aim of this study was to evaluate the effects of PTX on serum levels of interleukin 10 (IL-10) and interferon gamma (IFN-gamma) and passive avoidance learning in lipopolysaccharide (LPS)-induced inflammation in rats. MATERIALS AND METHODS: Inflammation was induced by intraperitoneal (i.p.) injection of LPS (0.5 and 5 mg/kg) in male Wistar rats. After a week, PTX (25 mg/kg; i.p.) was injected for 14 days. Passive avoidance learning test was used for evaluation of learning and memory. Serum levels of cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: The behavioral results did not show any significant effect of LPS and PTX on learning and memory. Both doses of LPS (0.5 and 5 mg/kg) decreased IL-10 significantly (P < 0.05). PTX prevented this reduction just in the LPS 0.5 mg/kg + PTX 25 mg/kg group. Serum level of IFN-gamma was increased only in the LPS 0.5 mg/kg + PTX 25 mg/kg group comparing to the LPS 0.5 mg/kg group (P < 0.05). CONCLUSIONS: The results showed that LPS-induced inflammation decreased the serum levels of IL-10. PTX could prevent these decreases only in mild inflammation. Both PTX and LPS-induced inflammation had no significant effects on learning and memory; therefore, their effects on CNS require further study. PMID- 28904939 TI - Lung Cancer Prevalence in Iran by Histologic Subtypes. AB - BACKGROUND: Prevalence statistics are essential for cancer control in addition to incidence and mortality data. As we know, there is no published report regarding lung cancer (LC) prevalence in Iran. Herein, we provide model-based estimates of limited time LC prevalence in Iran, 2015. MATERIALS AND METHODS: Incidence numbers of LC were extracted from Iranian National Cancer Registry reports for 2003-2009. Trends were analyzed by joinpoint regression, assuming a logarithmic poisson model. Incidence numbers were projected up to 2015, using linear regression models which were trained by corrected annual percentage changes. A Monte Carlo-based model was generated, and absolute survival rates, number of incident cases, and incompleteness of Iranian cancer registry for LC were included into it. Limited-time prevalence (within 1, 2-3, and 4-5 years from diagnosis) and its respective 95% uncertainty level (UL) were estimated by age, gender, and histopathological type. RESULTS: Five-year prevalence was estimated to be 4.21 (95% UL: 3.37-5.38) per 100,000 adult person, with a male:female ratio of 2.01. Estimated number of patients within 1, 2-3, and 4-5 years from diagnosis were 1871 (1497-2392), 993 (770-1285), and 420 (322-550), respectively. Most prevalent form of LC were squamous cell carcinoma (802; 579-999) and adenocarcinoma (319; 230-389) in males and females, respectively. CONCLUSION: According to our results, the most plausible estimates of number of alive LC patients within initial treatment, clinical follow-up, and cure phases were 2392, 1285, and 550 cases in Iran in 2015. PMID- 28904940 TI - Association of Animal and Plant Proteins Intake with Hypertension in Iranian Adult Population: Isfahan Healthy Heart Program. AB - BACKGROUND: There is evidence regarding the relationship between dietary proteins intake and blood pressure (BP), but they had inconsistent results. Therefore, this study was designed to assess the association between different kinds of protein intake (animal and plant protein) and BP. MATERIALS AND METHODS: Data were collected from Isfahan Healthy Heart Program. We performed a cross-sectional study among 9660 randomly selected Iranian adults aged >=19-year-old that they were selected from three large Iranian regions in 2007. A simplified validated 48 item-food frequency questionnaire was used to assess dietary intake including all kinds of protein. Systolic and diastolic BPs were measured in duplicate by trained personnel using a standard protocol. Multivariable regressions were applied to assess the relationship between protein intake and BP levels and the presence of hypertension (HTN). RESULTS: More frequent consumption of animal, plant, and total protein intake were inversely associated with BP in a crude model (P < 0.001); however, after adjustment for potential confounders this relationship remained only for plant protein (P = 0.04). The risk of HTN occurrence decreased in the highest quintile of total and plant protein consumption by 19% (odds ratio [OR] = 0.81; confidence interval [CI]: [0.65 0.96]; P for trend = 0.004) and 18% (OR = 0.82; [CI: (0.67-0.94]; P for trend = 0.03), respectively. CONCLUSIONS: More frequent protein intake, especially plant protein consumption was inversely associated with BP and risk of HTN among Iranian adults. PMID- 28904941 TI - Is there any Relationship Between Bladder Trabeculation and Efficacy and Safety of Intravesical Botulinum Toxin A Injection in Refractory Idiopathic Overactive Bladder Women? AB - BACKGROUND: Intradetrusor injection of botulinum toxin A (BTX-A) might serve as a minimally invasive substitute in patients with refractory idiopathic overactive bladder (RIOAB). The aim of this study was to evaluate the clinical outcomes related to two different doses of abo-BTX-A (AboBTX-A) in patients with RIOAB. MATERIALS AND METHODS: This prospective clinical trial was performed on 55 women with RIOAB. After determination of trabeculation grade, 300 (no or mild) or 500 (moderate or severe) unit of AboBTX-A (Dysport) was intravesicaly injected. Before 1, 3, and 6 months after intervention, lower urinary tract symptoms during 24 h were recorded. RESULTS: Of the study population, 62% had severe bladder trabeculation. The mean duration of overactive bladder (OAB) was 1.76 versus 5.85 years, for no or mild versus severe trabeculation, respectively. After injections of 300- and 500-unit dosage, there were 19% and 26% early complications such as urinary retention. There was a statistically significant difference between the two groups in OAB score after 1 month (P < 0.001) and duration of OAB symptoms, over three follow-up times (P < 0.001). The mean preinjection OAB scores between patients with and without recurrence were statistically significant (29.36 vs. 25.07; P < 0.03). Urinary tract infection as a late complication was distinguished in four patients. CONCLUSION: In RIOAB, by adjusted dosage of AboBTX-A related to the grade of bladder trabeculation, in addition to maintain efficacy, consequent complications might not be affected by dosage and the drug dosage could be increased to nearly 60% with less concern associated to complication. PMID- 28904942 TI - A Simple but Accurate Method for Evaluating Drug-Resistance in Infectious HCVcc System. AB - Use of direct-acting antivirals sometimes causes viral drug resistance, resulting in inefficiency in treated patients in real-world practice. Therefore, how to rapidly and accurately evaluate drug resistance is an urgent problem to be solved for rational use and development of antivirals in the future. Here, we aim to develop a new method by which we can evaluate easily but effectively whether a drug will still be efficient in the future treatment in infectious hepatitis C virus cell culture system. HCV-infected Huh7.5 cells were treated with drugs and the culture supernatants were replaced with fresh culture media containing the same drugs at 24 hours. The supernatants were harvested at 48 hours and incubated with naive Huh7.5 cells. Intracellular HCV RNAs or proteins in the newly infected cells were extracted and analyzed at 48 hours or longer. Results showed that after being treated with telaprevir mutant viruses were easily detected which were resistant to telaprevir, while after being treated with sofosbuvir drug resistant viruses did not emerge. In conclusion, the new method is simple and quick but accurate to evaluate whether a drug will be still efficient in the forthcoming therapeutic regimen and whether drug resistance will occur after long term treatment with drugs. PMID- 28904943 TI - Exercise for Health and Disease: Time to Move Ahead. PMID- 28904944 TI - Antibacterial and Antibiotic-Modifying Activity of Methanol Extracts from Six Cameroonian Food Plants against Multidrug-Resistant Enteric Bacteria. AB - The present work was designed to investigate the antibacterial activities of methanol extracts from six Cameroonian edible plants and their synergistic effects with some commonly used antibiotics against multidrug-resistant (MDR) Gram-negative bacteria expressing active efflux pumps. The extracts were subjected to qualitative phytochemical screening and the microdilution broth method was used for antibacterial assays. The results of phytochemical tests indicate that all tested crude extracts contained polyphenols, flavonoids, triterpenes, and steroids. Extracts displayed selective antibacterial activities with the minimal inhibitory concentration (MIC) values ranging from 32 to 1024 MUg/mL. The lowest MIC value (32 MUg/mL) was recorded with Coula edulis extract against E. coli AG102 and K. pneumoniae K2 and with Mangifera indica bark extract against P. aeruginosa PA01 and Citrus sinensis extract against E. coli W3110 which also displayed the best MBC (256 MUg/mL) value against E. coli ATCC8739. In combination with antibiotics, extracts from M. indica leaves showed synergistic effects with 75% (6/8) of the tested antibiotics against more than 80% of the tested bacteria. The findings of the present work indicate that the tested plants may be used alone or in combination in the treatment of bacterial infections including the multidrug-resistant bacteria. PMID- 28904945 TI - Effectiveness of the Thermal Treatments Used for Curd Stretching in the Inactivation of Shiga Toxin-Producing O157 and O26 Escherichia coli. AB - The kneading treatment of the fresh curd in hot water is a critical control point in the manufacturing of mozzarella. Factors such as the ratio between hot water and curd mass, the rheological properties, and the mixing and kneading activity affect the processing time and the internal temperature of the curd. The aim of this study was to investigate the effect of thermal treatments on the fate of Shiga toxin-producing Escherichia coli (STEC). Nine curd samples (weight 160-270 g) were artificially contaminated with O157 or O26 STEC and stretched in hot water (90-95 degrees C) for 5-10 min. Depending on the heating process and spinning, different nonisothermal profiles were recorded. Observed reductions of O157 and O26 STEC varied between 1.01 and more than 5.38 log?MPN (Most Probable Number)/g at the end of the temperature treatments. Further, nonisothermal log linear tail models were developed to compare observed reductions for O157 and O26 VTEC under variable temperature conditions. Results obtained showed that the comparison of predictions provided by the dynamic model with observations described well the linear inactivation pattern since nonsignificant differences were denoted at all profiles tested. The dynamic model developed can be useful to evaluate the effectiveness of the thermal treatments used in the manufacturing of mozzarella in the inactivation of STEC. PMID- 28904946 TI - High-Density Lipoprotein Cholesterol, Blood Urea Nitrogen, and Serum Creatinine Can Predict Severe Acute Pancreatitis. AB - BACKGROUND AND AIMS: Early prediction of disease severity of acute pancreatitis (AP) would be helpful for triaging patients to the appropriate level of care and intervention. The aim of the study was to develop a model able to predict Severe Acute Pancreatitis (SAP). METHODS: A total of 647 patients with AP were enrolled. The demographic data, hematocrit, High-Density Lipoprotein Cholesterol (HDL-C) determinant at time of admission, Blood Urea Nitrogen (BUN), and serum creatinine (Scr) determinant at time of admission and 24 hrs after hospitalization were collected and analyzed statistically. RESULTS: Multivariate logistic regression indicated that HDL-C at admission and BUN and Scr at 24 hours (hrs) were independently associated with SAP. A logistic regression function (LR model) was developed to predict SAP as follows: -2.25-0.06 HDL-C (mg/dl) at admission + 0.06 BUN (mg/dl) at 24 hours + 0.66 Scr (mg/dl) at 24 hours. The optimism-corrected c index for LR model was 0.832 after bootstrap validation. The area under the receiver operating characteristic curve for LR model for the prediction of SAP was 0.84. CONCLUSIONS: The LR model consists of HDL-C at admission and BUN and Scr at 24 hours, representing an additional tool to stratify patients at risk of SAP. PMID- 28904947 TI - Sodium Hypochlorite Irrigation and Its Effect on Bond Strength to Dentin. AB - Effective shaping and cleaning of root canals are essential for the success of endodontic treatment. Due to the complex anatomy of root canal spaces, the use of various instrumentation techniques alone is not effective in producing bacteria free root canal spaces. Irrigation, disinfectants, rinses, and intervisit medications are used in conjunction with the mechanical instrumentation to ensure the success of endodontic treatment. Sodium hypochlorite (NaOCl), a halogenated compound, is routinely used to irrigate the root canal during endodontic treatments. NaOCl has been known for its antibacterial action, proteolytic and dissolution capacity, and debridement properties. NaOCl, however, can alter the composition of dentin and hence its interaction with the adhesive resins used to bond the restorative materials to treated dentin. This review therefore covers in depth the action of NaOCl on dentin-adhesive resin bond strength including both enhancement and reduction, then mechanisms proposed for such action, and finally how the adverse action of NaOCl on dentin can be reversed. PMID- 28904949 TI - Bioengineering Materials in Dental Application. PMID- 28904948 TI - Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy. AB - Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50-100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens. PMID- 28904950 TI - Quantitative Changes in Cerebral Perfusion during Urinary Urgency in Women with Overactive Bladder. AB - PURPOSE: To quantitatively measure changes in cerebral perfusion in select regions of interest in the brain during urinary urgency in women with overactive bladder (OAB) using arterial spin labeling (ASL). METHODS: Twelve women with OAB and 10 controls underwent bladder filling and rated urinary urgency (scale 0-10). ASL fMRI scans were performed (1) in the low urgency state after voiding and (2) high urgency state after drinking oral fluids. Absolute regional cerebral blood flow (rCBF) in select regions of interest was compared between the low and high urgency states. RESULTS: There were no significant differences in rCBF between the low and high urgency states in the control group. In the OAB group, rCBF (mean +/- SE, ml/100 g/min) increased by 10-14% from the low to the high urgency state in the right anterior cingulate cortex (ACC) (44.56 +/- 0.59 versus 49.52 +/- 1.49, p < 0.05), left ACC (49.29 +/- 0.85 versus 54.02 +/- 1.46, p < 0.05), and left insula (50.46 +/- 1.72 versus 54.99 +/- 1.09, p < 0.05). Whole-brain analysis identified additional areas of activation in the right insula, right dorsolateral prefrontal cortex, and pons/midbrain area. CONCLUSIONS: Urinary urgency is associated with quantitative increase in cerebral perfusion in regions of the brain associated with processing emotional response to discomfort. PMID- 28904952 TI - Internal Impingement of the Shoulder: A Risk of False Positive Test Outcomes in External Impingement Tests? AB - BACKGROUND: External impingement tests are considered as being particularly reliable for identifying subacromial and coracoid shoulder impingement mechanisms. The purpose of the present study was to evaluate if these tests are likely to provoke an internal shoulder impingement mechanism which, in cases of a pathologic condition, can lead to a positive test result. METHOD: In 37 subjects, the mechanical contact between the glenoid rim and the rotator cuff (RC) was measured quantitatively and qualitatively in external impingement test positions using an open MRI system. RESULTS: Mechanical contact of the supraspinatus with the posterosuperior glenoid was present in 30 subjects in the Neer test. In the Hawkins test, the subscapularis was in contact with the anterosuperior glenoid in 33 subjects and the supraspinatus in 18. In the horizontal impingement test, anterosuperior contact of the supraspinatus with the glenoid was identified in 35 subjects. CONCLUSION: The Neer, Hawkins, and horizontal impingement tests are likely to provoke the mechanism of an internal shoulder impingement. A posterosuperior internal impingement mechanism is being provoked predominately in the Neer test. The Hawkins test narrows the distance between the insertions of the subscapularis and supraspinatus and the anterosuperior labrum, which leads to an anterosuperior impingement mechanism. PMID- 28904951 TI - Diabetic Foot Ulcers and Epidermal Growth Factor: Revisiting the Local Delivery Route for a Successful Outcome. AB - Soon after epidermal growth factor (EGF) discovery, some in vivo models appeared demonstrating its property to enhance cutaneous wound healing. EGF was the first growth factor (GF) introduced in the clinical arena as a healing enhancer, exerting its mitogenic effects on epithelial, fibroblastoid, and endothelial cells via a tyrosine kinase membrane receptor. Compelling evidences from the 90s documented that, for EGF, locally prolonged bioavailability and hourly interaction with the receptor were necessary for a successful tissue response. Eventually, the enthusiasm on the clinical use of EGF to steer the healing process was wiped out as the topical route to deliver proteins started to be questioned. The simultaneous in vivo experiments, emphasizing the impact of the parenterally administered EGF on epithelial and nonepithelial organs in terms of mitogenesis and cytoprotection, rendered the theoretical fundamentals for the injectable use of EGF and shaped the hypothesis that locally infiltrating the diabetic ulcers would lead to an effective healing. Although the diabetic chronic wounds microenvironment is hostile for local GFs bioavailability, EGF local infiltration circumvented the limitations of its topical application, thus expanding its therapeutic prospect. Our clinical pharmacovigilance and basic studies attest the significance of the GF local infiltration for chronic wounds healing. PMID- 28904953 TI - Nonpaternity and Half-Siblingships as Objective Measures of Extramarital Sex: Mathematical Modeling and Simulations. AB - BACKGROUND: Understanding the epidemiology of HIV and other sexually transmitted infections (STIs) requires knowledge of sexual behavior, but self-reported behavior has limitations. We explored the reliability and validity of nonpaternity and half-siblings ratios as biomarkers of current and past extramarital sex. METHODS: An individual-based Monte Carlo simulation model was constructed to describe partnering and conception in human populations with a focus on Sub-Saharan Africa (SSA). The model was parameterized with representative biological, behavioral, and demographic data. RESULTS: Nonpaternity and half-siblings ratios were strongly correlated with extramarital sex, with Pearson correlation coefficients (PCC) of 0.79 (95% CI: 0.71-0.86) and 0.77 (0.68-0.84), respectively. Age-specific nonpaternity ratios correlated with past extramarital sex at time of conception for different scenarios: for example, PCC, after smoothing by moving averages, was 0.75 (0.52-0.89) in a scenario of steadily decreasing nonmarital sex and 0.39 (0.01-0.73) in a scenario of transient drops in nonmarital sex. Simulations assuming self-reported levels of extramarital sex from Kenya yielded nonpaternity levels lower than global nonpaternity data, suggesting sizable underreporting of extramarital sex. CONCLUSIONS: Nonpaternity and half-siblings ratios are useful objective measures of extramarital sex that avoid limitations in self-reported sexual behavior. PMID- 28904954 TI - Duodenum-Preserving Resection of the Pancreatic Head versus Pancreaticoduodenectomy for Treatment of Chronic Pancreatitis with Enlargement of the Pancreatic Head: Systematic Review and Meta-Analysis. AB - The results of this meta-analysis show that DPPHR should be established as first line treatment because of lower level of severe early postoperative complications, maintenance of endocrine pancreatic functions, shortening of postoperative hospitalization time, and increase of quality of life compared to pancreaticoduodenectomy. PMID- 28904955 TI - Dental Hygiene and Orthodontics: Effect of Ultrasonic Instrumentation on Bonding Efficacy of Different Lingual Orthodontic Brackets. AB - Dental hygienists are often faced with patients wearing lingual orthodontic therapy, as ultrasonic instrumentation (UI) is crucial for oral health. As the application of external forces can lead to premature bonding failure, the aim of this study was to evaluate the effect of UI on shear bond strength (SBS) and on adhesive remnant index (ARI) of different lingual orthodontic brackets. 200 bovine incisors were divided into 10 groups. Four different lingual (STB, Ormco; TTR, Rocky Mountain Orthodontics; Idea, Leone; 2D, Forestadent) and vestibular control (Victory, 3M) brackets were bonded. UI was performed in half of specimens, whereas the other half did not receive any treatment. All groups were tested with a universal testing machine. SBS and ARI values were recorded. Statistical analysis was performed (significance: P = 0.05). TTR, Idea, and 2D lingual brackets significantly lowered SBS after UI, whereas for other braces no effect was recorded. Appliances with lower mesh area significantly reduced their adhesion capacity after UI. Moreover groups subjected to UI showed higher ARI scores than controls. UI lowered SBS of lingual appliances of small dimensions so particular care should be posed avoiding prolonged instrumentation around bracket base during plaque removal. Moreover, UI influenced also ARI scores. PMID- 28904956 TI - Application of the Subtractive Genomics and Molecular Docking Analysis for the Identification of Novel Putative Drug Targets against Salmonella enterica subsp. enterica serovar Poona. AB - The emergence of novel pathogenic strains with increased antibacterial resistance patterns poses a significant threat to the management of infectious diseases. In this study, we aimed at utilizing the subtractive genomic approach to identify novel drug targets against Salmonella enterica subsp. enterica serovar Poona strain ATCC BAA-1673. We employed in silico bioinformatics tools to subtract the strain-specific paralogous and host-specific homologous sequences from the bacterial proteome. The sorted proteome was further refined to identify the essential genes in the pathogenic bacterium using the database of essential genes (DEG). We carried out metabolic pathway and subcellular location analysis of the essential proteins of the pathogen to elucidate the involvement of these proteins in important cellular processes. We found 52 unique essential proteins in the target proteome that could be utilized as novel targets to design newer drugs. Further, we investigated these proteins in the DrugBank databases and 11 of the unique essential proteins showed druggability according to the FDA approved drug bank databases with diverse broad-spectrum property. Molecular docking analyses of the novel druggable targets with the drugs were carried out by AutoDock Vina option based on scoring functions. The results showed promising candidates for novel drugs against Salmonella infections. PMID- 28904958 TI - Transcriptomic Analysis Reveals Genes Mediating Salt Tolerance through Calcineurin/CchA-Independent Signaling in Aspergillus nidulans. AB - Adaptation to changes in the environment is crucial for the viability of all organisms. Although the importance of calcineurin in the stress response has been highlighted in filamentous fungi, little is known about the involvement of ion responsive genes and pathways in conferring salt tolerance without calcium signaling. In this study, high-throughput RNA-seq was used to investigate salt stress-induced genes in the parent, DeltacnaB, and DeltacnaBDeltacchA strains of Aspergillus nidulans, which differ greatly in salt adaption. In total, 2,884 differentially expressed genes including 1,382 up- and 1,502 downregulated genes were identified. Secondary transporters, which were upregulated to a greater extent in DeltacnaBDeltacchA than in the parent or DeltacnaB strains, are likely to play important roles in response to salt stress. Furthermore, 36 genes were exclusively upregulated in the DeltacnaBDeltacchA under salt stress. Functional analysis of differentially expressed genes revealed that genes involved in transport, heat shock protein binding, and cell division processes were exclusively activated in DeltacnaBDeltacchA. Overall, our findings reveal that secondary transporters and stress-responsive genes may play crucial roles in salt tolerance to bypass the requirement for the CchA-calcineurin pathway, contributing to a deeper understanding of the mechanisms that influence fungal salt stress adaption in Aspergillus. PMID- 28904957 TI - Echocardiographic Techniques of Deformation Imaging in the Evaluation of Maternal Cardiovascular System in Patients with Complicated Pregnancies. AB - Cardiovascular diseases (CVD) represent the leading cause of maternal mortality and morbidity. Knowledge of CVD in women is constantly evolving and data are emerging that female-specific risk factors as complications of pregnancy are conditions associated with an increased risk for the long-term development of CVD. Echocardiography is a safe and effective imaging technique indicated in symptomatic or asymptomatic pregnant women with congenital heart diseases who require close monitoring of cardiac function. Deformation imaging is an echocardiographic technique used to assess myocardial function by measuring the actual deformation of the myocardium through the cardiac cycle. Speckle-tracking echocardiography (STE) is a two-dimensional (2D) technique which has been found to be more accurate than tissue Doppler to assess both left ventricular (LV) and right ventricular (RV) myocardial function. The use of 2D STE however might present some technical issues due to the tomographic nature of the technique and the motion in the three-dimensional space of the myocardial speckles. This has promoted the use of 3D STE to track the motion of the speckles in the 3D space. This review will focus on the clinical value of the new echocardiographic techniques of deformation imaging used to assess the maternal cardiovascular system in complicated pregnancies. PMID- 28904959 TI - A Novel Genetic Group of Bovine Hepacivirus in Archival Serum Samples from Brazilian Cattle. AB - Hepatitis C virus (HCV) (genus Hepacivirus; family Flaviviridae) is a major human pathogen causing persistent infection and hepatic injury. Recently, emerging HCV like viruses were described infecting wild animals, such as bats and rodents, and domestic animals, including dogs, horses, and cattle. Using degenerate primers for detecting bovine pestiviruses in a 1996 survey three bovine serum samples showed a low identity with the genus Pestivirus of the Flaviviridae family. A virus could not be isolated in cell culture. The description of bovine hepaciviruses (BovHepV) in 2015 allowed us to retrospectively identify the sequences as BovHepV, with a 88.9% nucleotide identity. In a reconstructed phylogenetic tree, the Brazilian BovHepV samples grouped within the bovine HCV like cluster in a separated terminal node that was more closely related to the putative bovine Hepacivirus common ancestor than to bovine hepaciviruses detected in Europe and Africa. PMID- 28904961 TI - Analysis of Epidemiology and Risk Factors of Atopic Dermatitis in Korean Children and Adolescents from the 2010 Korean National Health and Nutrition Examination Survey. AB - BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease, but only few studies involved samples of children and adolescents that are representative of the entire Korean population. This study aimed to estimate the prevalence and risk factors of AD among children and adolescents in Korea by using nationally representative data. METHODS: We used data from the fifth Korean National Health and Nutrition Examination Survey in 2010 and retrospectively evaluated 2,116 children and adolescents. Logistic regression analysis was performed to determine the relationship between AD and other variables, including IgE levels. RESULTS: The prevalence rate of AD in children and adolescents was 15.0%. In the multivariate analysis of ages from 1 to 18 years, age (adjusted odds ratio [aOR], 0.96; p < 0.01) was related to AD. From age of 12 to 18 years, smoking (aOR, 8.99; p < 0.01) and elevated total IgE serum level (aOR, 5.31; p < 0.01) were related to AD. CONCLUSION: Age, smoking, and elevated total IgE level were related to AD in the children and adolescents. Thus, an antismoking policy and public education are necessary for reducing the prevalence of allergic diseases. In addition, measurement of total IgE level and age may be helpful in the diagnosis of AD. PMID- 28904960 TI - Mystery of Retinal Vein Occlusion: Vasoactivity of the Vein and Possible Involvement of Endothelin-1. AB - Retinal vein occlusion (RVO) is a common vascular disease of retina; however, the pathomechanism leading to RVO is not yet clear. In general, increasing age, hypertension, arteriosclerosis, diabetes mellitus, dyslipidemia, cardiovascular disorder, and cerebral stroke are systemic risk factors of RVO. However, RVO often occur in the unilateral eye and sometimes develop in young subjects who have no arteriosclerosis. In addition, RVO show different variations on the degrees of severity; some RVO are resolved without any treatment and others develop vision-threatening complications such as macular edema, combined retinal artery occlusion, vitreous hemorrhage, and glaucoma. Clinical conditions leading to RVO are still open to question. In this review, we discuss how to treat RVO in practice by presenting some RVO cases. We also deliver possible pathomechanisms of RVO through our clinical experience and animal experiments. PMID- 28904962 TI - Self-Rated Health as a Predictor of Death after Two Years: The Importance of Physical and Mental Wellbeing Postintensive Care. AB - INTRODUCTION: The objective of this study is, among half-year intensive care survivors, to determine whether self-assessment of health can predict two-year mortality. METHODS: The study is a prospective cohort study based on the Procalcitonin and Survival Study trial. Half-year survivors from this 1200 patient multicenter intensive care trial were sent the SF-36 questionnaire. We used both a simple one-item question and multiple questions summarized as a Physical Component Summary (PCS) and a Mental Component Summary (MCS) score. The responders were followed for vital status 730 days after inclusion. Answers were dichotomized into a low-risk and a high-risk group and hazard ratios (HR) with 95% confidence interval (CI) were calculated by Cox proportional hazard analyses. CONCLUSION: We found that self-rated health measured by a single question was a strong independent predictor of two-year all-cause mortality (HR: 1.8; 95% CI: 1.1-3.0). The multi-item component scores of the SF-36 also predicted two-year mortality (PCS: HR: 2.9; 95% CI 1.7-5.0) (MCS: HR: 1.9; 95% CI 1.1-3.4). These results suggest that self-rated health questions could help in identifying patients at excess risk. Randomized controlled trials are needed to test whether our findings represent causality. PMID- 28904963 TI - Predictors of Good Long-Term Renal Outcomes in Lupus Nephritis: Results from a Single Lupus Cohort. AB - This study aims to elucidate the predictive capabilities of proteinuria, serum creatinine (Cr), and urine RBCs (uRBCs) with respect to long-term renal outcomes in lupus nephritis (LN) in patients followed in clinic. Methods. A retrospective analysis was performed on patients with LN. We evaluated the ability of proteinuria, serum Cr, and uRBCs at 12 months to predict good long-term renal outcomes defined as serum Cr <= 100 mmol/L and kidney transplant/dialysis-free at the 7th year. Receiver operator characteristic curves were generated for proteinuria, serum Cr, and uRBCs to study their ability to predict good long-term outcomes and to identify their best cut-off. Descriptive statistics studied the pattern of change of proteinuria and serum Cr. Results. Proteinuria of 0.6 g/d and Cr of 83 mmol/L performed independently moderately well in predicting good long-term renal outcomes while uRBC was less accurate. Combining serum Cr to proteinuria gave a small increase in positive predictive value with a trade-off in sensitivity. Proteinuria changed within the first year whereas serum Cr changed until the 7th year. Conclusions. Both proteinuria and Cr predict good long-term renal outcomes in LN. Proteinuria's ability to change faster at 12 months makes it a favorable endpoint for clinical trials and research studies. PMID- 28904964 TI - Plague: A Millenary Infectious Disease Reemerging in the XXI Century. AB - Plague, in the Middle Ages known as Black Death, continues to occur at permanent foci in many countries, in Africa, Asia, South America, and even the USA. During the last years outbreaks were reported from at least 3 geographical areas, in all cases after tens of years without reported cases. The recent human plague outbreaks in Libya and Algeria suggest that climatic and other environmental changes in Northern Africa may be favourable for Y. pestis epidemiologic cycle. If so, other Northern Africa countries with plague foci also may be at risk for outbreaks in the near future. It is important to remember that the danger of plague reoccurrence is not limited to the known natural foci, for example, those of Algeria, Angola, and Madagascar. In a general context, it is important that governments know the dangerous impact that this disease may have and that the health and medical community be familiar with the epidemiology, symptoms, treatment, and control of plague, so an appropriated and timely response can be delivered should the worst case happen. Plague can be used as a potential agent of bioterrorism. We have concluded that plague is without a doubt a reemerging infectious disease. PMID- 28904965 TI - Prevalence of Smear-Positive Tuberculosis among Patients Who Visited Saint Paul's Specialized Hospital in Addis Ababa, Ethiopia. AB - BACKGROUND: Tuberculosis (TB) continues to be a health problem in both developed and developing countries, including Ethiopia. OBJECTIVE: In this study, the prevalence of smear-positive tuberculosis among presumptive TB cases who visited the hospital was assessed. METHOD: Acid fast bacilli (AFB) test was performed on samples collected from 200 presumptive TB cases. Data were analyzed using appropriate statistical tools. RESULT: Among 200 presumptive TB cases, 10% (20 individuals) (60% were male and 40% were female) were found to be positive for the AFB. Of these AFB positive subjects, 11.2% and 6.3% were from urban and rural areas, respectively. Among 20 AFB positive cases, 45% (9), 45% (9), and 10% (2) were HIV positive, HIV negative, and with HIV status unknown, respectively. The highest AFB positive cases were found within age group between 25 and 44 years (70%) and followed by age above 40 years (30%). It was found out that 75% (15), 15% (3), 5% (1), and 5% (1) were unemployed, government employed, student, and nongovernment employed, accordingly. CONCLUSION: This study indicated higher level of AFB positive cases within age groups of 25-44 and 65-74 years and also exhibited higher prevalence of TB cases from urban areas. PMID- 28904967 TI - Foot Structure in Boys with Down Syndrome. AB - INTRODUCTION AND AIM: Down syndrome (DS) is associated with numerous developmental abnormalities, some of which cause dysfunctions of the posture and the locomotor system. The analysis of selected features of the foot structure in boys with DS versus their peers without developmental disorders is done. MATERIALS AND METHODS: The podoscopic examination was performed on 30 boys with DS aged 14-15 years. A control group consisted of 30 age- and gender-matched peers without DS. RESULTS: The feet of boys with DS are flatter compared to their healthy peers. The hallux valgus angle is not the most important feature differentiating the shape of the foot in the boys with DS and their healthy peers. In terms of the V toe setting, healthy boys had poorer results. CONCLUSIONS: Specialized therapeutic treatment in individuals with DS should involve exercises to increase the muscle strength around the foot joints, enhancing the stabilization in the joints and proprioception. Introducing orthotics and proper footwear is also important. It is also necessary to monitor the state of the foot in order to modify undertaken therapies. PMID- 28904966 TI - The Effect of Oral Dexmedetomidine Premedication on Preoperative Cooperation and Emergence Delirium in Children Undergoing Dental Procedures. AB - INTRODUCTION: The aim of this study was to detect the effect of 1 MUg/kg of oral dexmedetomidine (DEX) as premedication among children undergoing dental procedures. MATERIALS AND METHODS: The study involved 100 children between 2 and 6 years of age, ASA I, who underwent full-mouth dental rehabilitation. The DEX group (n = 50) received 1 MUg/kg DEX in apple juice, and the control group (n = 50) received only apple juice. The patients' scores on the Ramsay Sedation Scale (RSS), parental separation anxiety scale, mask acceptance scale, and pediatric anesthesia emergence delirium scale (PAEDS) and hemodynamic parameters were recorded. The data were analyzed using chi-square test, Fisher's exact test, Student's t-test, and analysis of variance in SPSS. RESULTS: RSS scores were significantly higher in the DEX group than group C at 15, 30, and 45 min (p < 0.05). More children (68% easy separation, 74% satisfactory mask acceptance) in the DEX group showed satisfactory ease of parental separation and mask acceptance behavior (p < 0.05). There was no significant difference in the PAEDS scores and mean hemodynamic parameters of both groups. CONCLUSIONS: Oral DEX administered at 1 MUg/kg provided satisfactory sedation levels, ease of parental separation, and mask acceptance in children but was not effective in preventing emergence delirium. The trial was registered (Protocol Registration Receipt NCT03174678) at clinicaltrials.gov. PMID- 28904968 TI - The Prevalence of Ocular Allergy and Comorbidities in Chinese School Children in Shanghai. AB - OBJECTIVE: To investigate the prevalence and features of ocular allergy (OA) and comorbidities among school children in Shanghai, China. METHODS: This was a population-based cross-sectional study. Each participant completed an ISAAC-based questionnaire. The prevalence of OA symptoms, allergic rhinitis (AR) asthma, atopic dermatitis (AD), and sensitization to mites, pollen, and food was analyzed. RESULTS: A total of 724 and 942 completed questionnaires from the 7-9 year-old (young group) and the 12-14-year-old (teen group) groups were analyzed, respectively. The overall prevalence of OA symptoms was 28%. However, more young students (10.6%) reported mild to severe daily life interference caused by OA than the teens (5.7%). The young group had higher prevalence of diagnosed allergic conjunctivitis (10.2%). The overall prevalence of AR symptom, diagnosed asthma, and diagnosed AD was 40.4%, 11.6%, and 16.7%, respectively. Young children had higher prevalence of diagnosed AR and AD than the teens. There were gender associated differences in the prevalence of AR and asthma among young children, but not among the teens. The comorbidities associated with OA was also analyzed. Sensitization to mites, food, and pollen was associated with higher prevalence of allergic conditions. CONCLUSIONS: OA together with other allergic conditions affected a significant number of children in Shanghai. PMID- 28904969 TI - Sociodemographic and Clinical Characteristics of Centenarians in Mexico City. AB - BACKGROUND: There is little evidence about the demography and health status of adults aged 100 years and over in Latin America and there are no studies in Mexico. OBJECTIVES: To describe the demographic characteristics and health status of centenarians residing in Mexico City. METHODS: This is a cross-sectional study using a population base of 393 community-dwelling centenarians in Mexico City. A comprehensive geriatric assessment was performed, including demographic information and health status. RESULTS: The mean age of centenarians was 101.82 +/- 2.02 years, of whom 44 (9.1%) were semisupercentenarians (105-109 years old) and 5 (0.2%) were supercentenarians (>=110 years old). The female/male ratio was 3.2 : 1. Twelve (4.5%) reside in nursing homes. Women versus men have unfavorable conditions given their criteria: being without a partner, dependence in 1 or more basic activities, dependence in 1 or more instrumental activities, hypertension, cancer, and Parkinson's disease. Nevertheless, as compared to other populations, Mexican centenarians report having good self-perception of health (78.9%), polypharmacy (17.8%), low rate of pain (11.4%), diabetes (4.8%), and dyslipidemia (1.8%). CONCLUSIONS: This is the first study in Latin America that describes the social and clinical characteristics of centenarians in Mexico City. This population has a high percentage of malnutrition and osteoarthrosis, a high self perception of health, low frequency of diabetes, dyslipidemia, cardiovascular disease, and a high frequency of "escapers" (24%). PMID- 28904970 TI - Responders to Platelet-Rich Plasma in Osteoarthritis: A Technical Analysis. AB - PURPOSE: To evaluate the similarities and differences between the variety of platelet-rich plasma (PRP) formulations, preparation, and uses to try to determine the best responses for the treatment of knee osteoarthritis. MATERIALS AND METHODS: A comparison of the outcomes of randomized controlled trials (RCTs) included in the 3 most recent and high-quality meta-analyses to classify the different studies in 2 groups (bad responders group (BRG) and very good responders group (VGRG)). RESULTS AND DISCUSSION: From the 19 RCTs analyzed, 7 trials were included in the VGRG and 4 in the BRG. In VGRG, 1 or 2 injections were performed in 4/7 trials, time between injections was 2 to 3 weeks in 4/5 studies with many injections, volume injected varied from 2.5 to 8 mL, and single spinning technique was used in 5/7 studies. PRP classification was Mishra 4B and PAWP2Bbeta in 5/7 studies. The use of PRP with leukocytes is only found in the BRG. CONCLUSION: There is a lack of standardization in PRP preparation technique for knee osteoarthritis. However it appears that the use of a single spinning technique, a platelet concentration lower than 5 times the baseline, and avoidance of leukocytes should be preferred. PMID- 28904971 TI - Cognitive or Cognitive-Motor Executive Function Tasks? Evaluating Verbal Fluency Measures in People with Parkinson's Disease. AB - INTRODUCTION: Executive function deficits are observed in people with Parkinson's disease (PD) from early stages and have great impact on daily living activities. Verbal fluency and oral diadochokinesia involve phonarticulatory coordination, response inhibition, and phonological processing and may also be affected in people with PD. This study aimed to describe the performance of PD patients and an age- and education-matched control group on executive function, verbal fluency, and oral diadochokinesia tests and to investigate possible relationships between them. METHODS: Forty people with PD and forty controls were evaluated with Trail Making Test (TMT, executive function) and phonemic/semantic verbal fluency and oral diadochokinesia (/pataka/) tests. Groups were compared by ANOVA and relationships were investigated by Pearson tests. RESULTS: People with PD showed longer times in parts A and B of TMT. They also said fewer words in phonemic/semantic verbal fluency tests and less syllables in the diadochokinesia test. Oral diadochokinesia strongly correlated to parts A and B of TMT and to phonemic verbal fluency. CONCLUSION: Oral diadochokinesia was correlated to executive function and verbal fluency. The cognitive-motor interaction in verbal fluency and oral diadochokinesia must be considered not to overestimate the cognitive or motor impairments in people with PD. PMID- 28904972 TI - Evaluation of the Bacterial Diversity in the Human Tongue Coating Based on Genus Specific Primers for 16S rRNA Sequencing. AB - The characteristics of tongue coating are very important symbols for disease diagnosis in traditional Chinese medicine (TCM) theory. As a habitat of oral microbiota, bacteria on the tongue dorsum have been proved to be the cause of many oral diseases. The high-throughput next-generation sequencing (NGS) platforms have been widely applied in the analysis of bacterial 16S rRNA gene. We developed a methodology based on genus-specific multiprimer amplification and ligation-based sequencing for microbiota analysis. In order to validate the efficiency of the approach, we thoroughly analyzed six tongue coating samples from lung cancer patients with different TCM types, and more than 600 genera of bacteria were detected by this platform. The results showed that ligation-based parallel sequencing combined with enzyme digestion and multiamplification could expand the effective length of sequencing reads and could be applied in the microbiota analysis. PMID- 28904974 TI - Microarray Analysis and Detection of MicroRNAs Associated with Chronic Thromboembolic Pulmonary Hypertension. AB - The aim of this study was to understand the importance of chronic thromboembolic pulmonary hypertension- (CTEPH-) associated microRNAs (miRNAs). miRNAs differentially expressed in CTEPH samples compared with control samples were identified, and the target genes were predicted. The target genes of the key differentially expressed miRNAs were analyzed, and functional enrichment analyses were carried out. Finally, the miRNAs were detected using RT-PCR. Among the downregulated miRNAs, MiR-3148 regulated the most target genes and was significantly enriched in pathways in cancer, glioma, and ErbB signaling pathway. Furthermore, the number of target genes coregulated by miR-3148 and other miRNAs was the most. AR (androgen receptor), a target gene of hsa-miR-3148, was enriched in pathways in cancer. PRKCA (Protein Kinase C Alpha), also a target gene of hsa miR-3148, was enriched in 15 of 16 KEGG pathways, such as pathways in cancer, glioma, and ErbB signaling pathway. In addition, the RT-PCR results showed that the expression of hsa-miR-3148 in CTEPH samples was significantly lower than that in control samples (P < 0.01). MiR-3148 may play an important role in the development of CTEPH. The key mechanisms for this miRNA may be hsa-miR-3148-AR pathways in cancer or hsa-miR-3148-PRKCA-pathways in cancer/glioma/ErbB signaling pathway. PMID- 28904975 TI - RAPD Profiling, DNA Fragmentation, and Histomorphometric Examination in Brains of Wistar Rats Exposed to Indoor 2.5 Ghz Wi-Fi Devices Radiation. AB - The advent of Wi-Fi connected high technology devices in executing day-to-day activities is fast evolving especially in developing countries of the world and hence the need to assess its safety among others. The present study was conducted to investigate the injurious effect of radiofrequency emissions from installed Wi Fi devices in brains of young male rats. Animals were divided into four equal groups; group 1 served as control while groups 2, 3, and 4 were exposed to 2.5 Ghz at intervals of 30, 45, and 60 consecutive days with free access to food and water ad libitum. Alterations in harvested brain tissues were confirmed by histopathological analyses which showed vascular congestion and DNA damage in the brain was assayed using agarose gel electrophoresis. Histomorphometry analyses of their brain tissues showed perivascular congestion and tissue damage as well. PMID- 28904973 TI - Effects of Bacillus Serine Proteases on the Bacterial Biofilms. AB - Serratia marcescens is an emerging opportunistic pathogen responsible for many hospital-acquired infections including catheter-associated bacteremia and urinary tract and respiratory tract infections. Biofilm formation is one of the mechanisms employed by S. marcescens to increase its virulence and pathogenicity. Here, we have investigated the main steps of the biofilm formation by S. marcescens SR 41-8000. It was found that the biofilm growth is stimulated by the nutrient-rich environment. The time-course experiments showed that S. marcescens cells adhere to the surface of the catheter and start to produce extracellular polymeric substances (EPS) within the first 2 days of growth. After 7 days, S. marcescens biofilms maturate and consist of bacterial cells embedded in a self produced matrix of hydrated EPS. In this study, the effect of Bacillus pumilus 3 19 proteolytic enzymes on the structure of 7-day-old S. marcescens biofilms was examined. Using quantitative methods and scanning electron microscopy for the detection of biofilm, we demonstrated a high efficacy of subtilisin-like protease and glutamyl endopeptidase in biofilm removal. Enzymatic treatment resulted in the degradation of the EPS components and significant eradication of the biofilms. PMID- 28904976 TI - Household Financial Burden and Poverty Impacts of Cancer Treatment in Vietnam. AB - PURPOSE: This paper aims to analyze the household financial burden and poverty impacts of cancer treatment in Vietnam. METHODS: Under the "ASEAN CosTs in ONcology" study design, three major specialized cancer hospitals were employed to assemble the Vietnamese data. Factors of socioeconomic, direct, and indirect costs of healthcare were collected prospectively through both individual interviews and hospital financial records. RESULTS: The rates of catastrophic expenditure based on the cut-off points of 20%, 30%, 40%, and 50% of household's income were 82.6%, 73.7%, 64.7%, and 56.9%, respectively. 37.4% of the households with patient were impoverished by the treatment costs for cancer. The statistically significant correlates of the impoverishment problem were higher among older patients (40-60 years: 1.77, 95% CI 1.14-2.73; above 60 years: 1.75, 95% CI 1.03-2.98); poorer patients (less than 100% national income: 29, 95% CI 18.6-45.24; less than 200% national income: 2.89, 95% CI 1.69-4.93); patients who underwent surgery alone (receiving nonsurgery treatment: 2.46, 95% CI 1.32-4.59; receiving multiple treatments: 2.4, 95% CI 1.38-4.17). CONCLUSIONS: Lots of households were pushed into poverty due to their expenditure on cancer care; more actions are urgently needed to improve financial protection to the vulnerable groups. PMID- 28904978 TI - Corrigendum to "Molecular Epidemiological Investigation of Porcine kobuvirus and Its Coinfection Rate with PEDV and SaV in Northwest China". AB - [This corrects the article DOI: 10.1155/2016/7590569.]. PMID- 28904977 TI - Misuse of Topical Corticosteroids for Cosmetic Purpose in Antananarivo, Madagascar. AB - This cross-sectional study was conducted in Antananarivo, Madagascar, from June to September 2012. We aim to evaluate the misuse of TC on the face for cosmetic purpose and the adverse effects due to its application. A questionnaire-based analysis was done among females who use topical corticosteroids on the face for cosmetic purpose. Of the 770 women questioned, 384 (49,8%) used topical corticosteroids for cosmetic purpose whose mean age was 38 years (range 16-73 years). Two hundred and sixty-one females (68%) used TC combined with handcrafted cosmetics, and 123 (32%) used TC alone. "Pandalao," which contains salicylic acid, peppermint oil, lanolin, powder of Juanes de Vigo (mercury powder), and Vaseline, is the most handcrafted cosmetic combined with TC in our study (used by 29,4% respondents). Only one (0,26%) had obtained the TC by physician's prescription, 234 (61%) from cosmetic retailers, 92 (23%) directly from local pharmacies, 49 (12%) from beauticians, and 15 (4%) from unspecified sources. Lightening of skin color was the main reason for using TC in 44,8% of respondents in the absence of any primary dermatosis. Pigmentation disorders (63,2%) and cutaneous atrophy (52,1%) were the most adverse effects noted. PMID- 28904979 TI - The Russians Are the Fastest in Marathon Cross-Country Skiing: The "Engadin Ski Marathon". AB - It is well known that athletes from a specific region or country are dominating certain sports disciplines such as marathon running or Ironman triathlon; however, little relevant information exists on cross-country skiing. Therefore, the aim of the present study was to investigate the aspect of region and nationality in one of the largest cross-country skiing marathons in Europe, the "Engadin Ski Marathon." All athletes (n = 197,125) who finished the "Engadin Ski Marathon" between 1998 and 2016 were considered. More than two-thirds of the finishers (72.5% in women and 69.6% in men) were Swiss skiers, followed by German, Italian, and French athletes in both sexes. Most of the Swiss finishers were from Canton of Zurich (20.5%), Grisons (19.2%), and Berne (10.3%). Regarding performance, the Russians were the fastest and the British the slowest. Considering local athletes, finishers from Canton of Uri and Glarus were the fastest and those from Canton of Geneva and Basel the slowest. Based on the findings of the present study, it was concluded that local athletes were not the fastest in the "Engadin Ski Marathon." Future studies need to investigate other cross-country skiing races in order to find the nationalities and regions of the fastest cross-country skiers. PMID- 28904980 TI - Enterovirus-Human Rhinovirus: A Rare Cause of Acute Respiratory Distress Syndrome. AB - A 22-year-old Asian woman presented with respiratory distress, cough, and wheezing for 1 week. Prior history included asthma and Turner syndrome. On presentation to the emergency department, the patient was hypotensive, tachycardic, tachypneic, with an oxyhemoglobin saturation in the mid 80% range while breathing ambient air. Chest radiograph revealed pulmonary vascular congestion and a left lower lobe infiltrate. Endotracheal intubation, mechanical ventilation, and vasopressors were initiated. Empiric therapy for community acquired pneumonia was administered utilizing broad-spectrum intravenous antibiotics. Routine sputum culture was negative for pathogens. Nasopharyngeal swab submitted for multiplex amplified nucleic acid testing yielded enterovirus human rhinovirus (EV-HRV). Thus, the diagnosis of EV-HRV pneumonia complicated by acute respiratory distress syndrome (ARDS) was established. Multiple attempts to wean from the ventilator were unsuccessful, and a tracheostomy was performed. This report highlights EV-HRV as a cause of severe ARDS and prolonged respiratory failure in adults. PMID- 28904981 TI - Median Arcuate Ligament Syndrome: It Is Not Always Gastritis. AB - Median arcuate ligament syndrome is a rare disorder that is clinically characterized by the triad of postprandial abdominal pain, weight loss, and often an abdominal bruit due to compression of the celiac artery by the median arcuate ligament. Given the nonspecific symptoms, this is a rare and difficult diagnosis to obtain. We present a patient with nonspecific abdominal pain in whom etiology was ultimately determined to be median arcuate ligament syndrome. PMID- 28904982 TI - Preseason Aerobic Fitness Predicts In-Season Injury and Illness in Female Youth Athletes. AB - BACKGROUND: Although preseason aerobic fitness has been suggested as a modifiable risk factor for injury in adult athletes, the relationship between aerobic fitness, injury, and illness in youth athletes is unknown. PURPOSE: To determine whether preseason aerobic fitness predicts in-season injury and illness risk in female adolescent soccer players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Fifty-four female adolescent soccer players underwent preseason evaluation to determine years of experience, body mass index (BMI), maximal aerobic capacity (VO2max), and time to exhaustion (Tmax) during cycle ergometer testing. All injuries and illnesses during the subsequent 20-week season were recorded. Variables were compared between individuals with and without a self-reported injury and individuals with and without a self-reported illness. Separate Poisson regression models were developed to predict number of injuries and illnesses for each individual by use of age, years of experience, BMI, VO2max, and Tmax. RESULTS: Twenty-eight injuries and 38 illnesses in 23 individuals were recorded during the season. Although not a statistically significant finding, individuals who reported an in-season injury had lower VO2max than those who did not (54.9 +/- 7.3 vs 58.3 +/- 8.5 mL/kg/min, P = .13). Individuals who reported an illness had significantly lower VO2max than those who did not (54.5 +/- 9.9 vs 58.8 +/- 6.2 mL/kg/min, P = .014). With the Poisson regression models, VO2max was a significant predictor of both injury (odds ratio [OR], 0.95; P = .046) and illness (OR, 0.94; P = .009), while no significant relationships were identified between injury or illness and age, years of experience, Tmax, or BMI (all P > .05). CONCLUSION: Among adolescent female soccer players, greater preseason aerobic fitness is associated with a reduced risk of in-season injury and illness. Off-season intervention to promote aerobic fitness may help reduce the risk of lost time during the season due to injury and illness. PMID- 28904983 TI - Structure-function relationships in the visual system in multiple sclerosis: an MEG and OCT study. AB - BACKGROUND: We conducted a multi-modal optical coherence tomography (OCT) and magnetoencephalography (MEG) study to test whether there is a relationship between retinal layer integrity and electrophysiological activity and connectivity (FC) in the visual network influenced by optic neuritis (ON) in patients with multiple sclerosis (MS). METHODS: One hundred and two MS patients were included in this MEG/OCT study. Retinal OCT data were collected from the optic discs, macular region, and segmented. Neuronal activity and FC in the visual cortex was estimated from source-reconstructed resting-state MEG data by computing relative power and the phase lag index (PLI). Generalized estimating equations (GEE) were used to account for intereye within-patient dependencies. RESULTS: There was a significant relationship for both relative power and FC in the visual cortex with retinal layer thicknesses. The findings were influenced by the presence of MSON, particularly for connectivity in the alpha bands and the outer macular layers. In the absence of MSON, this relationship was dominated by the lower frequency bands (theta, delta) and inner and outer retinal layers. CONCLUSION: These results suggest that visual cortex FC more than activity alters in the presence of MSON, which may guide the understanding of FC plasticity effects following MSON. PMID- 28904984 TI - Impact of diabetes in the Friedreich ataxia clinical outcome measures study. AB - OBJECTIVE: Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes. RESEARCH DESIGN AND METHODS: Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes. RESULTS: Mean age of participants was 30.1 years (SD 15.3, range: 7-82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: -0.56-0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals. CONCLUSIONS: DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function. PMID- 28904985 TI - Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study. AB - OBJECTIVE: To investigate the association between levodopa-induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease. METHODS: This study included 13 Parkinson's disease patients with peak-of-dose levodopa induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine single photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4 iodophenyl)nortropane single-photon emission computed tomography, to measure dopamine reuptake transporter density and 2-[18F]fluoro-2-deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed. RESULTS: Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side. INTERPRETATION: Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression. PMID- 28904986 TI - Sex matters: repetitive mild traumatic brain injury in adolescent rats. AB - OBJECTIVE: Whether sex differences contribute to the heterogeneity of mild traumatic brain injury (mTBI) and repeated mTBI (RmTBI) outcomes in adolescents is unknown. Therefore, this study examined changes in, and differences between, male and female rats following single mTBI and RmTBI. METHODS: Rats were given a single mTBI, RmTBI (i.e., 3x), or sham injuries. Injuries were administered using a lateral impact model that mimics forces common in human mTBI. After the final injury, rats underwent extensive behavioral testing to examine cognition, motor function, and anxiety- and depressive-like behavior. Postmortem analyses investigated gene expression and structural changes in the brain. RESULTS: Many of the outcomes exhibited a sex-dependent response to RmTBI. While all rats given RmTBI had deficits in balance, motor coordination, locomotion, and anxiety-like behavior, only male rats given RmTBI had short-term working memory deficits, whereas only females given RmTBI had increased depressive-like behavior. Volumetric and diffusion weighted MRI analyses found that while RmTBI-induced atrophy of the prefrontal cortex was greater in female rats, only the male rats exhibited worse white matter integrity in the corpus callosum following RmTBI. Sex-dependent changes in brain expression of mRNA for glial fibrillary acidic protein, myelin basic protein, and tau protein were also observed following injury. INTERPRETATION: These findings suggest that in adolescent mTBI, sex matters; and future studies incorporating both male and females are warranted to provide a greater understanding of injury prognosis and better inform clinical practice. PMID- 28904987 TI - Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy. AB - OBJECTIVE: To examine the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls. METHODS: In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. The lung segmentations were done by an automated pipeline based on a Holistically Nested Network model (HNN method). Lung areas, diaphragm, and chest wall motion were measured throughout the breathing cycle. RESULTS: The HNN method reliably identified the contours of the lung and the diaphragm in every frame of each dataset (~180 frames) within seconds. The lung areas at maximal inspiration and expiration were reduced in DMD patients relative to controls (P = 0.02 and <0.01, respectively). The change in the lung area between inspiration and expiration correlated with percent predicted forced vital capacity (FVC) in patients (rs = 0.75, P = 0.03) and was not significantly different between groups. The diaphragm position, length, contractility, and motion were not significantly different between groups. Chest wall motion was reduced in patients compared to controls (P < 0.01). INTERPRETATION: Cine breathing MRI allows independent and reliable assessment of the diaphragm and chest wall dynamics during the breathing cycle in DMD patients and controls. The MRI data indicate that ambulatory DMD patients breathe at lower lung volumes than controls when their FVC is in the normal range. The diaphragm moves normally, whereas chest wall motion is reduced in these boys with DMD. PMID- 28904988 TI - Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? AB - OBJECTIVE: Conventional magnetic resonance imaging (MRI) of the multiple sclerosis spinal cord is limited by low specificity regarding the underlying pathological processes, and new MRI metrics assessing microscopic damage are required. We aim to show for the first time that neurite orientation dispersion (i.e., variability in axon/dendrite orientations) is a new biomarker that uncovers previously undetected layers of complexity of multiple sclerosis spinal cord pathology. Also, we validate against histology a clinically viable MRI technique for dispersion measurement (neurite orientation dispersion and density imaging, NODDI), to demonstrate the strong potential of the new marker. METHODS: We related quantitative metrics from histology and MRI in four post mortem spinal cord specimens (two controls; two progressive multiple sclerosis cases). The samples were scanned at high field, obtaining maps of neurite density and orientation dispersion from NODDI and routine diffusion tensor imaging (DTI) indices. Histological procedures provided markers of astrocyte, microglia, myelin and neurofilament density, as well as neurite dispersion. RESULTS: We report from both NODDI and histology a trend toward lower neurite dispersion in demyelinated lesions, indicative of reduced neurite architecture complexity. Also, we provide unequivocal evidence that NODDI-derived dispersion matches its histological counterpart (P < 0.001), while DTI metrics are less specific and influenced by several biophysical substrates. INTERPRETATION: Neurite orientation dispersion detects a previously undescribed and potentially relevant layer of microstructural complexity of multiple sclerosis spinal cord pathology. Clinically feasible techniques such as NODDI may play a key role in clinical trial and practice settings, as they provide histologically meaningful dispersion indices. PMID- 28904989 TI - Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes. AB - Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma. PMID- 28904991 TI - Bioelectrospray Methodology for Dissection of the Host-pathogen Interaction in Human Tuberculosis. AB - Standard cell culture models have been used to investigate disease pathology and to test new therapies for over fifty years. However, these model systems have often failed to mimic the changes occurring within three-dimensional (3-D) space where pathology occurs in vivo. To truthfully represent this, an emerging paradigm in biology is the importance of modelling disease in a physiologically relevant 3-D environment. One of the approaches for 3-D cell culture is bioelectrospray technology. This technique uses an alginate-based 3-D environment as an inert backbone within which mammalian cells and extracellular matrix can be incorporated. These alginate-based matrices produce highly reproducible results and can be mixed with different extracellular matrix components. This protocol describes a 3-D system incorporating mycobacteria, primary human blood mononuclear cells and collagen-alginate matrix to dissect the host-pathogen interaction in tuberculosis. PMID- 28904990 TI - The Multiple Faces of Spinocerebellar Ataxia type 2. AB - Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin-2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin-2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin-2 plays a fundamental role in maintenance of neuronal homeostasis. PMID- 28904992 TI - Too Many Choices Confuse Patients With Dementia. AB - Choices are often difficult to make by patients with Alzheimer Dementia. They often become acutely confused when faced with too many options because they are not able to retain in their working memory enough information about the various individual choices available. In this case study, we describe how an essentially simple benign task (choosing a dress to wear) can rapidly escalate and result in a catastrophic outcome. We examine what went wrong in the patient/caregiver interaction and how that potentially catastrophic situation could have been avoided or defused. PMID- 28904993 TI - Abnormalities of signal transduction networks in chronic schizophrenia. AB - Schizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia. PMID- 28904994 TI - N-Acetylglucosamine Metabolism Promotes Survival of Candida albicans in the Phagosome. AB - Phagocytosis by innate immune cells is one of the most effective barriers against the multiplication and dissemination of microbes within the mammalian host. Candida albicans, a pathogenic yeast, has robust mechanisms that allow survival upon macrophage phagocytosis. C. albicans survives in part because it can utilize the alternative carbon sources available in the phagosome, including carboxylic acids and amino acids. Furthermore, metabolism of these compounds raises the pH of the extracellular environment, which combats the acidification and maturation of the phagolysosome. In this study, we demonstrate that metabolism by C. albicans of an additional carbon source, N-acetylglucosamine (GlcNAc), facilitates neutralization of the phagosome by a novel mechanism. Catabolism of GlcNAc raised the ambient pH through release of ammonia, which is distinct from growth on carboxylic acids but similar to growth on amino acids. However, the effect of GlcNAc metabolism on pH was genetically distinct from the neutralization induced by catabolism of amino acids, as mutation of STP2 or ATO5 did not impair the effects of GlcNAc. In contrast, mutants lacking the dedicated GlcNAc transporter gene NGT1 or the enzymes responsible for catabolism of GlcNAc were defective in altering the pH of the phagosome. This correlated with reduced survival following phagocytosis and decreased ability to damage macrophages. Thus, GlcNAc metabolism represents the third genetically independent mechanism that C. albicans utilizes to combat the rapid acidification of the phagolysosome, allowing for cells to escape and propagate infection. IMPORTANCECandida albicans is the most important medically relevant fungal pathogen, with disseminated candidiasis being the fourth most common hospital-associated bloodstream infection. Macrophages and neutrophils are innate immune cells that play a key role in host defense by phagocytosing and destroying C. albicans cells. To survive this attack by macrophages, C. albicans generates energy by utilizing alternative carbon sources that are available in the phagosome. Interestingly, metabolism of amino acids and carboxylic acids by C. albicans raises the pH of the phagosome and thereby blocks the acidification of the phagosome, which is needed to initiate antimicrobial attack. In this work, we demonstrate that metabolism of a third type of carbon source, the amino sugar GlcNAc, also induces pH neutralization and survival of C. albicans upon phagocytosis. This mechanism is genetically and physiologically distinct from the previously described mechanisms of pH neutralization, indicating that the robust metabolic plasticity of C. albicans ensures survival upon macrophage phagocytosis. PMID- 28904995 TI - Distribution of O-Acetylated Sialic Acids among Target Host Tissues for Influenza Virus. AB - Sialic acids (Sias) are important glycans displayed on the cells and tissues of many different animals and are frequent targets for binding and modification by pathogens, including influenza viruses. Influenza virus hemagglutinins bind Sias during the infection of their normal hosts, while the encoded neuraminidases and/or esterases remove or modify the Sia to allow virion release or to prevent rebinding. Sias naturally occur in a variety of modified forms, and modified Sias can alter influenza virus host tropisms through their altered interactions with the viral glycoproteins. However, the distribution of modified Sia forms and their effects on pathogen-host interactions are still poorly understood. Here we used probes developed from viral Sia-binding proteins to detect O-acetylated (4-O acetyl, 9-O-acetyl, and 7,9-O-acetyl) Sias displayed on the tissues of some natural or experimental hosts for influenza viruses. These modified Sias showed highly variable displays between the hosts and tissues examined. The 9-O-acetyl (and 7,9-) modified Sia forms were found on cells and tissues of many hosts, including mice, humans, ferrets, guinea pigs, pigs, horses, dogs, as well as in those of ducks and embryonated chicken egg tissues and membranes, although in variable amounts. The 4-O-acetyl Sias were found in the respiratory tissues of fewer animals, being primarily displayed in the horse and guinea pig, but were not detected in humans or pigs. The results suggest that these Sia variants may influence virus tropisms by altering and selecting their cell interactions. IMPORTANCE Sialic acids (Sias) are key glycans that control or modulate many normal cell and tissue functions while also interacting with a variety of pathogens, including many different viruses. Sias are naturally displayed in a variety of different forms, with modifications at several positions that can alter their functional interactions with pathogens. In addition, Sias are often modified or removed by enzymes such as host or pathogen esterases or sialidases (neuraminidases), and Sia modifications can alter those enzymatic activities to impact pathogen infections. Sia chemical diversity in different hosts and tissues likely alters the pathogen-host interactions and influences the outcome of infection. Here we explored the display of 4-O-acetyl, 9-O-acetyl, and 7,9-O acetyl modified Sia forms in some target tissues for influenza virus infection in mice, humans, birds, guinea pigs, ferrets, swine, horses, and dogs, which encompass many natural and laboratory hosts of those viruses. PMID- 28904996 TI - Environmental and Genetic Determinants of Biofilm Formation in Paracoccus denitrificans. AB - The genome of the denitrifying bacterium Paracoccus denitrificans predicts the expression of a small heme-containing nitric oxide (NO) binding protein, H-NOX. The genome organization and prior work in other bacteria suggest that H-NOX interacts with a diguanylate cyclase that cyclizes GTP to make cyclic di-GMP (cdGMP). Since cdGMP frequently regulates attached growth as a biofilm, we first established conditions for biofilm development by P. denitrificans. We found that adhesion to a polystyrene surface is strongly stimulated by the addition of 10 mM Ca2+ to rich media. The genome encodes at least 11 repeats-in-toxin family proteins that are predicted to be secreted by the type I secretion system (TISS). We deleted the genes encoding the TISS and found that the mutant is almost completely deficient for attached growth. Adjacent to the TISS genes there is a potential open reading frame encoding a 2,211-residue protein with 891 Asp-Ala repeats. This protein is also predicted to bind calcium and to be a TISS substrate, and a mutant specifically lacking this protein is deficient in biofilm formation. By analysis of mutants and promoter reporter fusions, we show that biofilm formation is stimulated by NO generated endogenously by the respiratory reduction of nitrite. A mutant lacking both predicted diguanylate cyclases encoded in the genome overproduces biofilm, implying that cdGMP is a negative regulator of attached growth. Our data are consistent with a model in which there are H-NOX-dependent and -independent pathways by which NO stimulates biofilm formation. IMPORTANCE The bacterium Paracoccus denitrificans is a model for the process of denitrification, by which nitrate is reduced to dinitrogen during anaerobic growth. Denitrification is important for soil fertility and greenhouse gas emission and in waste and water treatment processes. The ability of bacteria to grow as a biofilm attached to a solid surface is important in many different contexts. In this paper, we report that attached growth of P. denitrificans is stimulated by nitric oxide, an intermediate in the denitrification pathway. We also show that calcium ions stimulate attached growth, and we identify a large calcium binding protein that is required for growth on a polystyrene surface. We identify components of a signaling pathway through which nitric oxide may regulate biofilm formation. Our results point to an intimate link between metabolic processes and the ability of P. denitrificans to grow attached to a surface. PMID- 28904997 TI - Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice. AB - The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor beta (TGF-beta) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development. PMID- 28904998 TI - Parallel Evolution of Group B Streptococcus Hypervirulent Clonal Complex 17 Unveils New Pathoadaptive Mutations. AB - Group B Streptococcus (GBS) is a commensal of the gastrointestinal and genitourinary tracts, while a prevailing cause of neonatal disease worldwide. Of the various clonal complexes (CCs), CC17 is overrepresented in GBS-infected newborns for reasons that are still largely unknown. Here, we report a comprehensive genomic analysis of 626 CC17 isolates collected worldwide, identifying the genetic traits behind their successful adaptation to humans and the underlying differences between carriage and clinical strains. Comparative analysis with 923 GBS genomes belonging to CC1, CC19, and CC23 revealed that the evolution of CC17 is distinct from that of other human-adapted lineages and recurrently targets functions related to nucleotide and amino acid metabolism, cell adhesion, regulation, and immune evasion. We show that the most distinctive features of disease-specific CC17 isolates were frequent mutations in the virulence-associated CovS and Stk1 kinases, underscoring the crucial role of the entire CovRS regulatory pathway in modulating the pathogenicity of GBS. Importantly, parallel and convergent evolution of major components of the bacterial cell envelope, such as the capsule biosynthesis operon, the pilus, and Rib, reflects adaptation to host immune pressures and should be taken into account in the ongoing development of a GBS vaccine. The presence of recurrent targets of evolution not previously implicated in virulence also opens the way for uncovering new functions involved in host colonization and GBS pathogenesis. IMPORTANCE The incidence of group B Streptococcus (GBS) neonatal disease continues to be a significant cause of concern worldwide. Strains belonging to clonal complex 17 (CC17) are the most frequently responsible for GBS infections in neonates, especially among late-onset disease cases. Therefore, we undertook the largest genomic study of GBS CC17 strains to date to decipher the genetic bases of their remarkable colonization and infection ability. We show that crucial functions involved in different steps of the colonization or infection process of GBS are distinctly mutated during the adaptation of CC17 to the human host. In particular, our results implicate the CovRS two-component regulator of virulence in the differentiation between carriage- and disease-associated isolates. Not only does this work raise important implications for the ongoing development of a vaccine against GBS but might also drive the discovery of key functions for GBS adaptation and pathogenesis that have been overlooked until now. Author Video: An author video summary of this article is available. PMID- 28904999 TI - Linking Spatial Structure and Community-Level Biotic Interactions through Cooccurrence and Time Series Modeling of the Human Intestinal Microbiota. AB - The gastrointestinal (GI) microbiome is a densely populated ecosystem where dynamics are determined by interactions between microbial community members, as well as host factors. The spatial organization of this system is thought to be important in human health, yet this aspect of our resident microbiome is still poorly understood. In this study, we report significant spatial structure of the GI microbiota, and we identify general categories of spatial patterning in the distribution of microbial taxa along a healthy human GI tract. We further estimate the biotic interaction structure in the GI microbiota, both through time series and cooccurrence modeling of microbial community data derived from a large number of sequentially collected fecal samples. Comparison of these two approaches showed that species pairs involved in significant negative interactions had strong positive contemporaneous correlations and vice versa, while for species pairs without significant interactions, contemporaneous correlations were distributed around zero. We observed similar patterns when comparing these models to the spatial correlations between taxa identified in the adherent microbiota. This suggests that colocalization of microbial taxon pairs, and thus the spatial organization of the GI microbiota, is driven, at least in part, by direct or indirect biotic interactions. Thus, our study can provide a basis for an ecological interpretation of the biogeography of the human gut. IMPORTANCE The human gut microbiome is the subject of intense study due to its importance in health and disease. The majority of these studies have been based on the analysis of feces. However, little is known about how the microbial composition in fecal samples relates to the spatial distribution of microbial taxa along the gastrointestinal tract. By characterizing the microbial content both in intestinal tissue samples and in fecal samples obtained daily, we provide a conceptual framework for how the spatial structure relates to biotic interactions on the community level. We further describe general categories of spatial distribution patterns and identify taxa conforming to these categories. To our knowledge, this is the first study combining spatial and temporal analyses of the human gut microbiome. This type of analysis can be used for identifying candidate probiotics and designing strategies for clinical intervention. PMID- 28905002 TI - Health care expenditure associated with overweight/obesity: a study among urban married women in Delhi, India. AB - BACKGROUND: Obesity is a multifaceted problem with wide-reaching medical, social and economic consequences. While health consequences are much known, but due to paucity of data, economic consequences are less known in India. The prevalence for excessive weight particularly among women population has been increasing dramatically in India in the last decades. We examined the economic burden on individual and households due to overweight and obesity among women in the national capital territory of India, Delhi. We particularly examined the health expenditure pattern in absolute amount as well as a proportion to their household expenditure among women according to their level of body mass index (BMI). METHODS: A population based follow-up survey of 325 ever-married women aged 20-54 years residing in the national capital territory of Delhi in India, systematically selected from the second round of National Family Health Survey (NFHS-2, 1998-99) samples who were re-interviewed after four years in 2003. Women's expenditure on health has been seen as a gross and as a ratio of total household expenditure. Anthropometric measurements were obtained from women to compute their current body mass index. Multiple logistic regression analysis was used to estimate the odds ratios adjusting for various socio demographic confounders. RESULTS: A significantly (p<0.0001) higher monthly gross health expenditure as well as proportion of total household expenditure was found according to the women's level of BMI. Average monthly health expenditure was Rs. 132 among overweight women, Rs 143 among obese women which further increased to Rs. 224 among morbidly obese women compared to only Rs 68 among normal weight women. Almost, 15% overweight, 16% obese and 21% morbidly obese women (p<0.0001) had economic burden which accounts for more than 5% of their total household expenditure on their health compared to only 10% normal weight women. Significantly, obese and morbidly obese women were more than two times more likely to spend higher amount on their health (OR 2.29 95% CI: 1.07-4.90; p=0.033) than normal weight women. Also overweight women were significantly two times more likely to spend high proportion on their health with respect to total household expenditure (OR 2.11; 95% CI: 1.03-4.35; p=0.042) than normal weight women. CONCLUSIONS: There is substantial economic burden of obesity for individuals as well as for the households which calls for urgent intervention in the obesity awareness and health promotion among Indian women who faced the greatest burden of increasing body weight in the last decade. Prevention is obviously more cost effective than treatment, both in terms of healthcare and personal costs. Health care providers and policy makers need to critically understand the issue of obesity and develop effective policies and programs for its prevention among Indian women. PMID- 28905000 TI - Transcriptome Analysis of Polyhydroxybutyrate Cycle Mutants Reveals Discrete Loci Connecting Nitrogen Utilization and Carbon Storage in Sinorhizobium meliloti. AB - Polyhydroxybutyrate (PHB) and glycogen polymers are produced by bacteria as carbon storage compounds under unbalanced growth conditions. To gain insights into the transcriptional mechanisms controlling carbon storage in Sinorhizobium meliloti, we investigated the global transcriptomic response to the genetic disruption of key genes in PHB synthesis and degradation and in glycogen synthesis. Under both nitrogen-limited and balanced growth conditions, transcriptomic analysis was performed with genetic mutants deficient in PHB synthesis (phbA, phbB, phbAB, and phbC), PHB degradation (bdhA, phaZ, and acsA2), and glycogen synthesis (glgA1). Three distinct genomic regions of the pSymA megaplasmid exhibited altered expression in the wild type and the PHB cycle mutants that was not seen in the glycogen synthesis mutant. An Fnr family transcriptional motif was identified in the upstream regions of a cluster of genes showing similar transcriptional patterns across the mutants. This motif was found at the highest density in the genomic regions with the strongest transcriptional effect, and the presence of this motif upstream of genes in these regions was significantly correlated with decreased transcript abundance. Analysis of the genes in the pSymA regions revealed that they contain a genomic overrepresentation of Fnr family transcription factor-encoding genes. We hypothesize that these loci, containing mostly nitrogen utilization, denitrification, and nitrogen fixation genes, are regulated in response to the intracellular carbon/nitrogen balance. These results indicate a transcriptional regulatory association between intracellular carbon levels (mediated through the functionality of the PHB cycle) and the expression of nitrogen metabolism genes. IMPORTANCE The ability of bacteria to store carbon and energy as intracellular polymers uncouples cell growth and replication from nutrient uptake and provides flexibility in the use of resources as they are available to the cell. The impact of carbon storage on cellular metabolism would be reflected in global transcription patterns. By investigating the transcriptomic effects of genetically disrupting genes involved in the PHB carbon storage cycle, we revealed a relationship between intracellular carbon storage and nitrogen metabolism. This work demonstrates the utility of combining transcriptome sequencing with metabolic pathway mutations for identifying underlying gene regulatory mechanisms. PMID- 28905001 TI - Genome-Enabled Insights into the Ecophysiology of the Comammox Bacterium "Candidatus Nitrospira nitrosa". AB - The recently discovered comammox bacteria have the potential to completely oxidize ammonia to nitrate. These microorganisms are part of the Nitrospira genus and are present in a variety of environments, including biological nutrient removal (BNR) systems. However, the physiological traits within and between comammox and nitrite-oxidizing bacterium (NOB)-like Nitrospira species have not been analyzed in these ecosystems. In this study, we identified Nitrospira strains dominating the nitrifying community of a sequencing batch reactor (SBR) performing BNR under microaerobic conditions. We recovered metagenome-derived draft genomes from two Nitrospira strains: (i) Nitrospira sp. strain UW-LDO-01, a comammox-like organism classified as "Candidatus Nitrospira nitrosa," and (ii) Nitrospira sp. strain UW-LDO-02, a nitrite-oxidizing strain belonging to the Nitrospira defluvii species. A comparative genomic analysis of these strains with other Nitrospira-like genomes identified genomic differences in "Ca. Nitrospira nitrosa" mainly attributed to each strain's niche adaptation. Traits associated with energy metabolism also differentiate comammox from NOB-like genomes. We also identified several transcriptionally regulated adaptive traits, including stress tolerance, biofilm formation, and microaerobic metabolism, which might explain survival of Nitrospira under multiple environmental conditions. Overall, our analysis expanded our understanding of the genetic functional features of "Ca. Nitrospira nitrosa" and identified genomic traits that further illuminate the phylogenetic diversity and metabolic plasticity of the Nitrospira genus. IMPORTANCENitrospira-like bacteria are among the most diverse and widespread nitrifiers in natural ecosystems and the dominant nitrite oxidizers in wastewater treatment plants (WWTPs). The recent discovery of comammox-like Nitrospira strains, capable of complete oxidation of ammonia to nitrate, raises new questions about specific traits responsible for the functional versatility and adaptation of this genus to a variety of environments. The availability of new Nitrospira genome sequences from both nitrite-oxidizing and comammox bacteria offers a way to analyze traits in different Nitrospira functional groups. Our comparative genomics analysis provided new insights into the adaptation of Nitrospira strains to specific lifestyles and environmental niches. PMID- 28905003 TI - An immediate effect of PNF specific mobilization on the angle of trunk rotation and the Trunk-Pelvis-Hip Angle range of motion in adolescent girls with double idiopathic scoliosis-a pilot study. AB - BACKGROUND: Impairment of spine rotation is a key concept in several theories explaining the pathogenesis and progression of scoliosis. In previous studies, a more limited range of motion in scoliotic girls compared to their non-scoliotic peers was noted. The Trunk-Pelvis-Hip Angle measurement is a test used to assess the range of motion in the trunk-pelvis-hip complex in the transverse plane. The aim of this study was to assess an immediate effect of Proprioceptive Neuromuscular Facilitation specific mobilization (mPNF) on the angle of trunk rotation and Trunk-Pelvis-Hip Angle range of motion in adolescent girls with double scoliosis. METHODS: The study was conducted on 83 girls aged 10 to 17 years (mean 13.7 +/- 1.9) with double idiopathic scoliosis consisting of a right sided thoracic curve (mean 25.1 degrees +/- 13.9 degrees ) and a left-sided thoracolumbar or lumbar curve (mean 20.8 degrees +/- 11.4 degrees ). The angle of trunk rotation and Trunk-Pelvis-Hip Angle were measured at baseline and after PNF mobilization. Bilateral lower limb patterns of Proprioceptive Neuromuscular Facilitation were used in combination with the "contract-relax" technique and stimulation of asymmetrical breathing. In the statistical analysis, the SAS rel. 13.2 software was used. Preliminary statistical analysis was performed using descriptive statistics. According to Shapiro-Wilk criterion of normality, the Wilcoxon test was used to compare paired samples. Next, the data was analyzed using multivariate GLM models. RESULTS: In adolescent girls with double scoliosis, significant differences between the left and right side of the body concerning the Trunk-Pelvis-Hip Angle ranges were noted. A single, unilateral PNF mobilization significantly decreased the angle of trunk rotation in the thoracic (p < 0.001) and lumbar spine (p < 0.001). Unilateral PNF mobilization also increased the Trunk-Pelvis-Hip Angle ranges on the left (p < 0.001) and right (p < 0.001) side significantly. CONCLUSIONS: Unilateral PNF mobilization led to a decrease in the angle of trunk rotation, improvement in the range of motion, and the symmetry of mobility in the transverse plane in the trunk-pelvis-hip complex in adolescent girls with double idiopathic scoliosis. The effects should be treated only as immediate. Further studies are required to determine long-term effects of PNF mobilization on the spinal alignment. TRIAL REGISTRATION: ISRCTN11750900. PMID- 28905004 TI - Gastroenteritis Aggressive Versus Slow Treatment For Rehydration (GASTRO). A pilot rehydration study for severe dehydration: WHO plan C versus slower rehydration. AB - BACKGROUND: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children's responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes. Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate (WHO plan 'C' - 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae. Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. DISCUSSION: Results from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial. PMID- 28905005 TI - Management of gastric cancer in Indian population. AB - Adenocarcinoma stands the most common malignancies in the gastric carcinomas and holds a significant mortality and morbidity rates annually, due to the early vague symptoms among the population and hence the delayed presentation at advanced stages of cancer. In India the screening programs for gastric cancer has been a setback due to various logistics reasons and the data available from reporting is also not content. Our study is a review article featuring the management of gastric cancer in the Indian population. The lifestyle of India population is varied right from its southern region to its northern counterparts, which is due to its diversified culture within the country. Studies have concluded that the northern population tends to have a higher incidence comparatively and the various risk factors associated with the disease has been discussed. Management of the gastric cancer in India remains the same compared to the outside world, though the availability of endoscopic ultrasound and other technical advancements remain sparse in the field of diagnostics and staging of the disease. D2 gastrectomy remains the mainstay of surgery among the Indian population though significant number of patients are deemed inoperable on table. Neo adjuvant Chemotherapy, Radiotherapy and Targeted therapy is yet to be efficiently used across the country according to our study as there is lack of data in our registries. The incidence is decreasing in developing nations and more proximal cancers are reported. However, in India the major population-based cancer registries report an incidence decline only in Mumbai and Chennai. A shift from distal to proximal as the site of disease has not been reported from India. The contribution of the Indian scientific fraternity to the world medical literature for gastric cancer is sparse and it is clear that a lot more is to be done; the possible reason may be a busy clinical schedule or lack of initiatives. There is an urgent need for research in various aspects of gastric cancer from India including epidemiological and therapeutic areas. PMID- 28905006 TI - Overview of fluorescence imaging focusing on fusion-image for laparoscopic hepatectomy. PMID- 28905007 TI - Reconstruction after laparoscopic assisted distal gastrectomy: technical tips and pitfalls. AB - After the advent of the concept of laparoscopic assisted distal gastrectomy (LADG), the digestive reconstruction poses arguments among surgeons. There are three major different ways including Billroth I gastroduodenostomy, Billroth II gastrojejunostomy and Roux-en-Y gastrojejunostomy, and each of them has its own trick. In this article, the technical tips and pitfalls of each reconstruction will be discussed based on studies and author's experience. PMID- 28905008 TI - Probiotics as a preventive strategy for surgical infection in colorectal cancer patients: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Infection following abdominal surgery remains a major factor in morbidity among colorectal cancer (CRC) patients. Probiotic therapy has been suggested to improve the clinical and laboratory outcome of patients undergoing gastrointestinal surgery. The aim of this study was to investigate the efficacy of probiotic lactic acid bacteria in patients with CRC in the pre- and postoperative phases. METHODS: Systematic database searches identified 1,080 related articles. However, only seven articles were selected according to the eligibility criteria for qualitative and quantitative evaluation. RESULTS: Most of the reviewed articles presented satisfactory results related to the prevention of surgical inflammation in patients undergoing resection of CRC when using strains of Lactobacillus genus, predominantly. CONCLUSIONS: Probiotics are suggested to prevent surgical inflammation of CRC, at the same time that the combination of particular microorganisms administered is beneficial to the treatment and surgical recovery. PMID- 28905010 TI - Incomplete resection after macroscopic radical endoscopic resection of T1 colorectal cancer-should a paradigm-changing approach to address the risk be considered? PMID- 28905009 TI - Living donor liver transplantation for hepatocellular cancer: an (almost) exclusive Eastern procedure? AB - Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and it is linked with chronic liver disease. Liver transplantation (LT) is the best curative treatment modality, since it can cure simultaneously the underlying liver disease and HCC. Milan criteria (MC) are the benchmark for selecting patients with HCC for LT, achieving up to 91% 1-year survival post transplantation. However, when considering intention-to-treat (ITT) rates are substantially lower, mainly due dropout. Additionally, Milan criteria (MC) are too restrictive and more inclusive criteria have been reported with good outcomes. Mainly, in Eastern countries, deceased donors are scarce, therefore Asian centers have developed living-donor liver transplantation (LDLT) to a state of-art status. There are many eastern centers reporting huge numbers of LDLT with outstanding results. Regarding HCC patients, they have reported many criteria including more advanced tumors achieving reasonable outcomes. Western countries have well-established deceased-donor liver transplantation (DDLT) programs. However, organ shortage and restrictive criteria for listing patients with HCC endorses LDLT as a good option to offer curative treatment to more HCC patients. However, there are some controversial reports claiming higher rates of HCC recurrence after LDLT than DDLT. An extensive review included 30 studies with cohorts of HCC patients who underwent LDLT in both East and West countries. We reported also the results of our Institution, in Brazil, where it was performed the first LDLT. This review also addresses the eligibility criteria for transplanting patients with HCC developed in Western and Eastern countries. PMID- 28905011 TI - Acute portal vein thrombosis secondary to hyperhomocysteinemia with folic acid deficiency and methyl tetrahydrofolate reductase mutation: a case report and literature review. PMID- 28905012 TI - A rare case, diagnosed as calcified callosal lipoma, when the patient presented with acute stroke. PMID- 28905013 TI - Common rs5918 (PlA1/A2) polymorphism in the ITGB3 gene and risk of coronary artery disease. AB - INTRODUCTION: The T to C transition at nucleotide 1565 of the human glycoprotein IIIa (ITGB3) gene represents a genetic polymorphism (PlA1/A2) that can influence both platelet activation and aggregation and that has been associated with many types of disease. Here, we present a newly designed multiplex tetra-primer amplification refractory mutation system - polymerase chain reaction (T-ARMS-PCR) for genotyping a single nucleotide polymorphism (SNP) (dbSNP ID: rs5918) in the human ITGB3 gene. MATERIAL AND METHODS: We set up T-ARMS-PCR for the rs5918 SNP in a single-step PCR and the results were validated by the PCR-RFLP method in 132 coronary artery disease (CAD) patients and 122 unrelated healthy individuals. RESULTS: Full accordance was found for genotype determination by the PCR-RFLP method. The multiple logistic regression analysis showed a significant association of the rs5918 polymorphism and CAD according to dominant and recessive models (dominant model OR: 2.40, 95% CI: 1.33-4.35; p = 0.003, recessive model OR: 4.71, 95% CI: 1.32-16.80; p = 0.0067). CONCLUSIONS: Our T ARMS-PCR in comparison with RFLP and allele-specific PCR is more advantageous because this PCR method allows the evaluation of both the wild type and the mutant allele in the same tube. Our results suggest that the rs5918 (PlA1/A2) polymorphism in the ITGB3 gene may contribute to the susceptibility of sporadic Iranian coronary artery disease (CAD) patients. PMID- 28905014 TI - Levels of brain natriuretic peptide as a marker for the diagnosis and prognosis of acute ischemic stroke. AB - INTRODUCTION: The relationships between plasma levels of brain natriuretic peptide (BNP) and severity and location of stroke, prognosis, and infarct volume were investigated in acute ischemic stroke patients who presented within the first 24 hours (h) of stroke. MATERIAL AND METHODS: Brain natriuretic peptide levels were tested in 40 patients and 30 healthy controls. Infarct volume was automatically calculated by multi-slice computed tomography. Disease severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) at presentation, 24 h, 72 h and the 28th day. Progression was defined as an increase of more than two points in the NIHSS scores. RESULTS: The mean BNP levels were 284.16 +/-382.79 at presentation and 273.78 +/-451.91 at 72 h in the patient group, whereas the mean BNP level was 25.29 +/-13.47 in controls. There was a statistically significant difference between the two groups (p < 0.001). Differences in BNP levels among patient subgroups according to the TOAST and OCSP classifications were not statistically significant (p = 0.534, p = 0.943, respectively). There was no significant correlation between plasma BNP level and infarct volume or NIHSS scores (p = 0.5, p = 0.07). A positive correlation was found between BNP levels and the length of the hospitalization period (p = 0.03 and r = 0.33). There was no statistically significant relationship between elevated plasma BNP levels and progression of disease (p = 0.08). CONCLUSIONS: Plasma BNP levels were increased in the acute phase of stroke; therefore, BNP could be used as a biomarker for morbidity and mortality, even in patients without cardiac failure. PMID- 28905016 TI - Myocarditis suggesting acute myocardial ischemia, without occlusion of the coronary artery, in a patient with antiphospholipid syndrome and systemic vasculitis in the course of cold agglutinin disease. PMID- 28905015 TI - Usefulness of serum procalcitonin as a diagnostic biomarker of infection in children with chronic kidney disease. AB - INTRODUCTION: Serum procalcitonin (PCT) levels are known to be low in healthy individuals in healthy subjects but are increased in patients with a severe bacterial infection. It has not been extensively studied in children with chronic kidney disease (CKD), treated either with hemodialysis (HD) or with renal transplantation. MATERIAL AND METHODS: During a 6-month period, blood samples were taken from 102 (55 HD children and 47 renal transplant recipients) children with a strong clinical suspicion of infection. Procalcitonin levels were measured by ELISA. RESULTS: Thirty-four/102 cases had proven infections as defined previously. Children with proven infections had a significantly higher PCT (0.920 +/-0.24 ng/ml) than those without (0.456 +/-0.53 ng/ml), p = 0.04. The ideal cutoff value derived for serum PCT was 0.5 ng/ml. This threshold value established a sensitivity of 94.1% and a specificity of 87.9%. CONCLUSIONS: This study indicates that significantly increased PCT concentration is a promising predictor of systemic bacterial infection in children with CKD, with good sensitivity and specificity. This study proposes that serum PCT is a convenient index of infection in CKD children at a cutoff value of 0.5 ng/ml. PMID- 28905017 TI - Treat-to-target therapy does not prevent excessive progression of carotid intima media thickness during the first year of therapy in early rheumatoid arthritis. AB - INTRODUCTION: The aim of the study was to investigate the presence of subclinical atherosclerosis and predictors of change in carotid intima-media measures in early rheumatoid arthritis patients (eRA) as compared to chronic RA patients and patients without arthritis. MATERIAL AND METHODS: Fifty-five consecutive eRA patients were assessed at the time of diagnosis and after 1 year of therapy. Fifty-five sex- and age-matched chronic RA patients and 29 patients without inflammatory disease were used as controls. Carotid artery intima-media thickness (CIMT) and carotid plaques were measured at baseline and after follow-up. In eRA patients ultrasound assessment of hand joints was performed before and after treatment. Carotid artery intima-media thickness was assessed again after 2 years in 44 eRA patients. RESULTS: Carotid artery intima-media thickness progression after 1 year of therapy was higher in eRA patients compared to both control groups (p = 0.017) and correlated with symptoms duration (p = 0.017) and DMARD monotherapy (p = 0.015). Ultrasound progression of hand joint erosions was associated with longer symptoms duration (p = 0.006). After 2 years of observation CIMT progression was similar in all examined groups. CONCLUSIONS: We observed rapid CIMT progression during the first year of RA therapy. Longer symptoms duration and less aggressive therapy were associated with CIMT increase. PMID- 28905019 TI - A rare neurologic deficiency in HaNDL syndrome: cranial neuropathy. PMID- 28905018 TI - Correlation between leukocyte count and infarct size in ST segment elevation myocardial infarction. AB - INTRODUCTION: Regarding the inflammatory mechanisms involved in ischemic heart disease, currently the leukocyte count is the subject of studies related to its association with the prognosis and mortality of ST segment elevation myocardial infarction (STEMI). Our aim is correlate the leukocyte count rise with the size of STEMI, evaluated with the area under the curve (AUC) and the peak of necrosis markers release. MATERIAL AND METHODS: This study is a sub-analysis of the TETHYS trial, a clinical trial that evaluated the effects of methotrexate in STEMI. We evaluated the correlation between quantitative variables with Pearson's correlation, and the variables that did not follow a normal distribution were subjected to logarithmic transformation to base 10. The value of p < 0.05 indicated statistical significance. RESULTS: Males accounted for 73% of the participants, who had an average age of 59 years. A total of 58% were hypertensive and 53% smokers. The leukocyte count at hospital admission was significantly correlated with the AUC creatine kinase (CK) (r = 0.256, p = 0.021), troponin AUC (r = 0.247, p = 0.026), peak CK (r = 0.270, p = 0.015) and troponin peak (r = 0.233, p = 0.037). The leukocyte count at 72 h was significantly correlated with CK AUC (r = 0.238, p = 0.032), AUC of MB portion of CK (r = 0.240, p = 0.031) and peak CK (r = 0.224, p = 0.045). CONCLUSIONS: White blood cell count correlates with STEMI size assessed by serial cardiac biomarker levels. PMID- 28905021 TI - The importance of clinical signs as well as radiological findings in the diagnosis of incomplete locked-in syndrome. PMID- 28905020 TI - Increased circulating soluble urokinase-type plasminogen activator receptor (suPAR) levels in patients with slow coronary flow. AB - INTRODUCTION: Slow coronary flow (SCF) is an angiographic phenomenon characterized by delayed opacification of epicardial coronary arteries without an obstructive coronary disease. Serum soluble urokinase-type plasminogen activator receptor (suPAR) levels seem closely related to atherosclerosis due to increased inflammation and prothrombotic state. We studied whether circulating suPAR is related to SCF. MATERIAL AND METHODS: The present study was cross-sectional and observational. It included 75 individuals who underwent coronary angiography with suspected CAD and had angiographically normal coronary arteries of varying coronary flow rates. The relationship between suPAR, C-reactive protein (CRP) and SCF was investigated. Forty patients with isolated SCF (mean age: 46.0 +/-4.14 years) and 35 age- and gender-matched control participants with normal coronary flow (NCF) and normal coronary arteries (NCA) (mean age: 46.0 +/-5.7 years) were included in the study. We used logistic regression analysis to determine the predictors of SCF. RESULTS: The clinical characteristics were not statistically significantly different between SCF and NCA groups. Serum suPAR level was significantly higher in the SCF group than the control group (2.5-5.4 ng/ml vs. 0.1-1.4 ng/ml; p < 0.001). Also the serum CRP level was higher in the CSF group than the control group (1.57 +/-0.43 mg/l vs. 0.53 +/-0.23 mg/l; p < 0.001). CONCLUSIONS: This study revealed significantly increased serum suPAR levels in patients with SCF. Although we cannot draw conclusions on the underlying pathological process of SCF, we believe that these findings may be pioneering for further studies investigating the specific roles of circulating suPAR in the SCF phenomenon in the coronary vasculature. PMID- 28905022 TI - Contrast-induced encephalopathy after coronary angioplasty and stent implantation. PMID- 28905023 TI - Subclavian artery dissection: a rare complication of transradial coronary angiography. PMID- 28905024 TI - Microvolt T-wave alternans in young myocardial infarction patients with preserved cardiac function treated with single-vessel primary percutaneous coronary intervention. AB - INTRODUCTION: Myocardial infarction continues to be the most important cause of morbidity and mortality, and recently this disease has begun to be seen commonly at young ages. In our study we aimed to assess microvolt T-wave alternans in young patients who had ST segment elevation myocardial infarction with preserved left ventricular function and who underwent single-vessel revascularization. MATERIAL AND METHODS: We enrolled 108 consecutive patients (age: 39.5 +/-4.1) with ST segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention and 43 patients (age: 38.5 +/-3.7) with normal coronary angiograms as a control group. The myocardial infarction patients were younger than 45 and had a preserved left ventricular ejection fraction. They were divided into three groups according to the culprit artery. The microvolt T-wave alternans (MTWA) values were calculated an average of 12 months after the primary percutaneous coronary intervention using the modified moving average method. RESULTS: The MTWA positivity was significantly higher in the STEMI group compared to the controls (p < 0.001). It was also significantly higher in STEMI patients with left anterior descending artery lesions compared to patients with circumflex artery and right coronary artery lesions (p = 0.013). Moreover, the culprit artery was independent predictor of MTWA positivity (p = 0.043). CONCLUSIONS: In STEMI patients of a young age, MTWA positivity was higher than in healthy individuals, especially when the responsible vessel fed a wider region. PMID- 28905025 TI - Internal carotid artery occlusion should not exclude surgery. PMID- 28905026 TI - Estimating fat mass in heart failure patients. AB - INTRODUCTION: Body composition (BC) assessments in heart failure (HF) patients are mainly based on body weight, body mass index and waist-to-hip ratio. The present study compares BC assessments by basic anthropometry, dual energy X-ray absorptiometry (DXA), bioelectrical impedance spectroscopy (BIS), and air displacement plethysmography (ADP) for the estimation of fat (FM) and fat-free mass (FFM) in a HF population. MATERIAL AND METHODS: In this single-centre, observational pilot study we enrolled 52 patients with HF (33 HF with reduced ejection fraction (HFrEF), 19 HF with preserved ejection fraction (HFpEF); mean age was 67.7 +/-9.9 years, 41 male) and 20 healthy controls. DXA was used as a reference standard for the measurement of FM and FFM. RESULTS: In the HF population, linear regression for DXA-FM and waist-to-hip ratio (r = -0.05, 95% CI: (-0.32)-0.23), body mass index (r = 0.47, 95% CI: 0.23-0.669), and body density (r = -0.87, 95% CI: (-0.93)-(-0.87)) was obtained. In HF, Lin's concordance correlation coefficient of DXA-FM (%) with ADP-FM (%) was 0.76 (95% CI: 0.64-0.85) and DXA-FFM [kg] with DXA-ADP [kg] was 0.93 (95% CI: 0.88-0.96). DXA-FM (%) for BIS-FM (%) was 0.69 (95% CI: 0.54-0.80) and 0.73 (95% CI: 0.60 0.82) for DXA-FFM [kg] and BIS-FFM [kg]. CONCLUSIONS: Body density is a useful surrogate for FM. ADP was found suitable for estimating FM (%) and FFM [kg] in HF patients. BIS showed acceptable results for the estimation of FM (%) in HFrEF and for FFM [kg] in HFpEF patients. We encourage selecting a suitable method for BC assessment according to the compartment of interest in the HF population. PMID- 28905027 TI - Metabolic syndrome severity score: range and associations with cardiovascular risk factors. AB - INTRODUCTION: Metabolic Syndrome Severity Score (MSSS) is a new clinical prediction rule (CPR) for diagnostic and therapeutic decisions and employs available components (sex, age, race, systolic blood pressure, waistline circumference, high-density lipoprotein, triglycerides and fasting blood glucose). The aim of our work was to perform cross-sectional pilot trial on middle-aged healthy volunteers and patients with metabolic syndrome (MetS) with and without type 2 diabetes mellitus (T2DM) for studying feasibility and implementation of MSSS and its associations with cardiovascular risk factors. MATERIAL AND METHODS: We approached 64 eligible participants from Bulgaria. The MSSS values, together with demographic, anthropometric, medical history, laboratory findings, CVD risk factors, QRISK2 score for 10-year cardiovascular risk and predicted heart age, were analysed. Descriptive statistics with tests for comparison (e.g., t-test, chi2) between groups as well as ANOVA and logistic regression were applied. RESULTS: We analysed data from 56 participants (aged 50.11 +/-3.43 years). The MSSS was higher in MetS patients (including 6 T2DM patients) than in controls (n = 29; 51.8%) presented as percentiles (69.97% and 34.41%, respectively) and z-scores (0.60 and -0.45, respectively) (p < 0.05). The logistic regression model of MSSS indicated a positive association with MetS/T2DM cases (correctness > 85%, p < 0.01). For further validation purposes, positive correlations of MSSS with CVD risk factor as diastolic blood pressure (Rho = 0.399; p < 0.003) and QRISK2 score (Rho = 0.524; p < 0.001) or predicted heart age (Rho = 0.368; p < 0.007) were also found. CONCLUSIONS: The pilot study of MSSS in Bulgaria indicated feasibility and consistency of its implementation among patients with metabolic syndrome and/or T2DM and healthy volunteers. PMID- 28905028 TI - Reduction of NAA/Cr ratio in a patient with reversible posterior leukoencephalopathy syndrome using MR spectroscopy. PMID- 28905029 TI - In-stent graft restenosis in the carotid artery. What is your opinion about this patient? PMID- 28905030 TI - Should all coronary artery perforations be treated immediately? PMID- 28905032 TI - Is there any association between vitamin D levels and isolated coronary artery ectasia? AB - INTRODUCTION: It has been postulated that low vitamin D levels are associated with coronary artery diseases. Coronary artery ectasia (CAE) is associated with atherosclerosis, congenital cardiac defects, immunological diseases and connective tissue diseases. In this study, we aimed to investigate whether there is an association between vitamin D and parathormone levels and isolated coronary artery ectasia and its extent. MATERIAL AND METHODS: The study included 93 participants: 47 patients (35 male, 12 female) with isolated CAE and 46 subjects (28 male, 18 female) with normal coronary arteries. Demographic characteristics of patients and controls were obtained from medical records, and Markis scores of patients were calculated. Serum vitamin D and parathormone levels were quantitatively measured by the paramagnetic particle chemiluminescence method. RESULTS: Serum vitamin D levels were found to be significantly lower in patients with isolated CAE than the control group (9.15 +/-4.4 ng/ml, 13.35 +/-5.9 ng/ml, p < 0.001). Parathormone levels were significantly higher in the CAE group than the control group (61.4 +/-31.6, 48.7 +/-25.5, p < 0.036). However, the study revealed no association between serum vitamin D levels and the extent of CAE according to the Markis classification (p = 0.23). CONCLUSIONS: This study revealed that lower vitamin D levels and higher parathormone levels were associated with isolated CAE, but there was no association between vitamin D levels and the extent of CAE. PMID- 28905031 TI - Update of treatment of heart failure with reduction of left ventricular ejection fraction. AB - Underlying and precipitating causes of heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) should be identified and treated when possible. Hypertension should be treated with diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. Diuretics are the first-line drugs in the treatment of patients with HFrEF and volume overload. Angiotensin-converting enzyme inhibitors and beta-blockers (carvedilol, sustained-release metoprolol succinate, or bisoprolol) should be used in treatment of HFrEF. Use an angiotensin II receptor blocker (ARB) (candesartan or valsartan) if intolerant to ACE inhibitors because of cough or angioneurotic edema. Sacubitril/valsartan may be used instead of an ACE inhibitor or ARB in patients with chronic symptomatic HFrEF class II or III to further reduce morbidity and mortality. Add an aldosterone antagonist (spironolactone or eplerenone) in selected patients with class II-IV HF who can be carefully monitored for renal function and potassium concentration. (Serum creatinine should be <= 2.5 mg/dl in men and <= 2.0 mg/dl in women. Serum potassium should be < 5.0 mEq/l). Add isosorbide dinitrate plus hydralazine in patients self-described as African Americans with class II-IV HF being treated with diuretics, ACE inhibitors, and beta-blockers. Ivabradine can be used in selected patients with HFrEF. PMID- 28905033 TI - Left ventricular steal syndrome caused by multiple plexiform coronary artery fistulae: case report, literature review and treatment. PMID- 28905034 TI - Assessment of subclinical cardiac damage in chronic plaque psoriasis patients: a case control study. AB - INTRODUCTION: Epidemiological studies have suggested that patients with psoriasis are at an increased risk of developing cardiovascular diseases. Chronic inflammation may play a role in the pathogenesis of atherosclerosis in psoriasis patients. Recent studies have evaluated the expression of plasma endocan and homocysteine levels. Endocan is a marker of vascular endothelial damage, and homocysteine plays a role in the development of atherosclerosis. Plasma endocan and homocysteine levels, as well as echocardiographic parameters, were evaluated in patients with psoriasis to assess cardiovascular disease risk. MATERIAL AND METHODS: This was a prospective cohort analysis of 40 patients who were diagnosed with psoriasis and 40 healthy controls matched to the patient group according to demographic and biochemical parameters. RESULTS: Serum endocan and homocysteine concentrations were significantly higher in the psoriasis group than the control group (p < 0.001). Serum endocan concentrations correlated positively with disease duration (p < 0.001; r = 0.725). The Tei index (myocardial performance) was elevated in psoriasis patients (p < 0.001). Additionally, the E/A (mitral valve early diastolic peak flow velocity/mitral valve late diastolic peak flow velocity) and E/Em (early diastolic myocardial velocity) ratios were reduced in psoriasis patients (p < 0.001). Parameters indicative of left ventricular asynchrony were elevated significantly in the psoriasis group versus the control group (p < 0.001). CONCLUSIONS: We observed a substantial increase in serum endocan and homocysteine concentrations, and significant differences in key parameters of cardiac function, in psoriasis patients relative to controls. These results are consistent with the hypothesis that subclinical cardiac damage is increased in patients with psoriasis and that psoriasis itself may be a cardiovascular risk factor. PMID- 28905035 TI - The correlation between plasma human neutrophil peptide 1-3 levels and severity of coronary artery disease. AB - INTRODUCTION: Inflammation plays a key role in atherosclerosis, and discovering new biomarkers of inflammation is becoming important in order to uncover the pathogenesis of atherosclerotic coronary artery disease (CAD). Recent studies have focused on polymorphonuclear neutrophils. It has been suggested that human neutrophil peptide 1-3 (HNP1-3) is proatherogenic. In this study, we aimed to investigate the associations between plasma HNP1-3 levels and the severity of atherosclerosis via a generally accepted scoring system. MATERIAL AND METHODS: This cross-sectional, observational study included 107 consecutive patients suffering from stable angina pectoris and undergoing coronary angiography (CAG). Patients were divided into two groups according to the Gensini scoring (GS) system evaluating disease severity. Group 1 was composed of mild CAD patients with GS < 20 and group 2 consisted of severe CAD patients with GS >= 20. Plasma HNP1-3 levels were assessed by the ELISA method. RESULTS: The mean HNP1-3 levels were found to be lower in group 1 than group 2 (134.7 ng/ml vs. 147.5 ng/ml). HNP1-3 levels were significantly higher in the severe CAD group than the mild CAD group according to GS (p < 0.001). The results of multivariate logistic regression analysis revealed that only age > 62 years and HNP1-3 > 134 ng/ml were independent predictors of the severity of CAD after adjusting for gender, smoking, hypertension, hyperlipidemia, diabetes, family history of CAD and white blood cell count. In predicting the severity of CAD, the sensitivity and specificity of HNP1-3 were 83.9% (p < 0.001) and 58.8% (p < 0.001), respectively. CONCLUSIONS: This study revealed that the plasma levels of HNP1-3 were significantly higher in severe CAD than mild CAD. PMID- 28905037 TI - Platelet mass index is increased in psoriasis. A possible link between psoriasis and atherosclerosis. AB - INTRODUCTION: Psoriasis, whose relation with atherosclerosis etc. has long been known, is a chronic inflammatory disease. Besides providing hemostasis, platelets play important roles in inflammatory reactions and immune responses and contribute to endothelial damage, thus leading to atherosclerotic plaque formation. Mean platelet volume (MPV) has been previously reported as a platelet activation marker. Platelet mass index (PMI) is also related to platelet functionality and is thought to be a useful parameter for plaque formation capacity of platelets. MATERIAL AND METHODS: Sex, age, age of onset, disease duration, family history, psoriasis area severity index, nail and joint involvement, platelet count, mean platelet volume, platelet mass index, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) of 320 patients with psoriasis and 200 healthy persons were evaluated. RESULTS: Mean platelet counts were 277.7 +/-73.374 and 265.06 +/-59.682 (p = 0.032); MPV values were 8.248 +/-1.150 and 7.442 +/-1.626 (p < 0.001); and PMI values were 2259 +/ 545.617 and 1964 +/-622.762 (p < 0.001) respectively in the psoriasis and control group. The MPV showed a significant but inverse correlation with hs-CRP (p = 0.047, r = -0.149), and no correlation with ESR (p > 0.05). Platelet count and PMI had a significant and positive correlation with ESR (p < 0.001, r = 0.404 and p < 0.001, r = 0.371), but had no correlation with hs-CRP (p > 0.05). CONCLUSIONS: Higher PMI and MPV values, which mean higher plaque formation capacity and more active platelets, in psoriasis may make psoriasis patients more sensitive to atherosclerotic plaque formation and complications. On the other hand, because of the positive PMI correlation with ESR (MPV had no correlation with ESR and had a negative correlation with CRP), PMI may be a better predictor of inflammation than MPV in psoriasis. PMID- 28905036 TI - Can thrombectomy and catheters used increase angiographically visible distal embolization in ST elevation myocardial infarction? AB - INTRODUCTION: Primary percutaneous coronary intervention (PPCI) is the preferred treatment of ST segment elevation myocardial infarction (STEMI). Manual thrombectomy catheters developed to prevent distant embolization are theoretically attractive; however, their clinical efficacy remains controversial. The effects of manual thrombectomy catheters on angiographically visible distal embolisation (AVDE) have not been studied so far. The aim of this study was to evaluate the effects of manual thrombectomy during PPCI on AVDE and to investigate whether there are differences in the incidence of AVDE according to the catheters used. MATERIAL AND METHODS: Six hundred thirty-six consecutive patients undergoing primary PCI were included in the study between January 2010 and December 2012. Patients were divided into two groups: the PCI only group (465 patients) and the PCI plus manual thrombectomy group (171 patients). RESULTS: Thrombus aspiration was associated with higher AVDE (13.55% vs. 26.9%, p = 0.0001), lower thrombolysis in myocardial infarction frame rate (2.49 +/-0.86 vs. 2.79 +/-0.57, p = 0.0001), lower myocardial blush grade (2.31 +/-0.87 vs. 2.47 +/ 0.7, p = 0.016), lower ejection fraction (EF) (49.9 +/-8.5 vs. 46.1 +/-9.6, p = 0.0001) and higher maximal troponin release (15.7 +/-16 vs. 9.4 +/-11, p = 0.0001). No difference was observed in terms of mortality between the groups in follow-up (5.2% vs. 9.03%, p = 0.12). Angiographically visible distal embolisation was observed more frequently with Invatec catheters (p = 0.0001). CONCLUSIONS: Angiographically visible distal embolisation during primary PCI occurs in a significant number of patients treated with manual thrombectomy. The results indicated that the incidence of AVDE may be different depending on the thrombectomy catheters used. PMID- 28905038 TI - The impact of clinical and angiographic factors on percutaneous coronary angioplasty outcomes in patients with acute ST-elevation myocardial infarction. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) outcomes are dependent on certain clinical and angiographic factors. The impact of modifiable cardiovascular disease (CVD) risk factors on PCI outcomes is still controversial. The aim of the study was to evaluate the impact of clinical and angiographic factors on PCI outcomes for patients with acute ST-elevation myocardial infarction (STEMI). MATERIAL AND METHODS: Age, gender, CVD risk factors, Killip class and culprit coronary artery (CA) localization, total CA occlusion, initial and post-procedural thrombolysis in myocardial infarction (TIMI) flow grade, and thrombus aspiration characteristics were assessed retrospectively in 188 consecutive patients with STEMI who underwent primary PCI. Spearman's rho test was performed to assess hospital stay correlations, and logistic regression was applied to identify predictors of distal embolization (DE), in-hospital worsening of heart failure (WHF), and in-hospital mortality rate. Local ethics committee approval was obtained for the study. RESULTS: DE occurred in 12 (6.4%) patients. In-hospital WHF was diagnosed in 16 (8.5%) patients. Twelve (6.4%) patients died in hospital. Age had a positive weak correlation with hospital stay and was an independent predictor of distal embolization, in-hospital worsening of heart failure, and in-hospital mortality rate. Killip class, left main CA stenosis (> 50.0%), and post-procedural TIMI flow grade 1-2 were other predictors of death in hospital. CONCLUSIONS: Age was an independent predictor of distal embolization, in-hospital worsening of heart failure, and in-hospital mortality. Other independent predictors of in-hospital mortality rate were Killip class, left main CA stenosis (> 50.0%), and post-procedural TIMI flow grade 1-2. The present analysis highlighted the "cholesterol paradox" with respect to in-hospital worsening of heart failure and mortality in hospital. PMID- 28905039 TI - Metabolic syndrome may be an important comorbidity in patients with seborrheic dermatitis. AB - INTRODUCTION: Seborrheic dermatitis is a chronic inflammatory skin disease. One of the components of metabolic syndrome is inflammation, and many inflammatory cytokines play a critical role in the disease. The aim of this study is to investigate metabolic syndrome and to evaluate the relationship between the parameters of the disease and disease severity in patients with seborrheic dermatitis. MATERIAL AND METHODS: Forty-seven patients with seborrheic dermatitis and 36 healthy controls were included in the study. The parameters of metabolic syndrome were recorded in both groups. In the patient group, disease severity was determined with the seborrheic dermatitis area and severity index (SDASI). All the venous blood samples were taken at 8 a.m. after 10 h of fasting. RESULTS: High-density lipoprotein (HDL) levels in the patient group were statistically significantly lower than in the controls. There was no significant difference between groups according to other parameters. In terms of history of metabolic disease in first degree relatives (diabetes mellitus, cardiovascular disease, and dyslipidaemia), 78.7% of those in the patient group (n = 37) and 55.6% of those in the control group (n = 20) had a history of metabolic disease in their families, and the difference between the patient and control groups was found to be statistically significant (p < 0.05). There was a significant correlation between disease severity and plasma HDL levels (p = 0.033, r = -0.312). CONCLUSIONS: The presence of seborrheic dermatitis may be a predictive factor for metabolic syndrome. PMID- 28905040 TI - Postrenal acute kidney injury and abdominal compartment syndrome associated with bladder pressure: type III rectus sheath hematoma. PMID- 28905041 TI - Presepsin (sCD14-ST): could it be a novel marker for the diagnosis of ST elevation myocardial infarction? AB - INTRODUCTION: Acute myocardial infarction (AMI) could be considered to be a state of inflammation. Many inflammatory markers have been evaluated in the AMI setting so far. Presepsin (PSP) is a novel biomarker for diagnosis and prognosis of systemic inflammation that has not been studied in the AMI setting to date. In this study, we aimed to examine serum PSP levels in patients with acute ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS: Forty-eight patients with STEMI and fifty healthy controls without coronary artery disease, verified by coronary angiography, were included in the study. Together with routine laboratory tests needed for STEMI, plasma concentrations of PSP were measured in peripheral venous blood samples of the participants. RESULTS: Plasma PSP and troponin levels were significantly higher in patients with STEMI than controls (1988.89 +/-3101.55 vs. 914.22 +/-911.35 pg/ml, p = 0.001 and 3.46 +/ 3.39 vs. 0.08 +/-0.43 ng/ml, p = 0.001, respectively). The cut-off value for PSP of 447 pg/ml was found to detect STEMI with 87.5% sensitivity, 44% specificity, 60% positive predictive value and 78.5% negative predictive value. CONCLUSIONS: In this study, PSP levels were found to be significantly elevated in patients with STEMI together with high-sensitivity troponins. The PSP may be a new marker for AMI detection. Large scale studies are needed to reveal the importance of PSP in the diagnosis and prognosis of AMI. PMID- 28905042 TI - Social, demographic and clinical characteristics of patients suffering from peripheral vascular disease treated surgically compared to patients treated with endovascular angioplasty. AB - INTRODUCTION: Atherosclerosis is the most common cause of chronic lower limb ischaemia. Many factors that have a crucial influence on the development of the disease, its course and prognosis have been identified. The risk factors seem to be subject to interventions due to their susceptibility to changes. It is important to increase the engagement of doctors and nurses performing the screening oriented on risk factors, medical consultation regarding giving up smoking, changing the diet and undertaking physical activity. Therefore, knowledge of the patients' health situation allows introduction of optimal treatment in this group of patients. MATERIAL AND METHODS: The study group consisted of 119 patients with peripheral artery atherosclerosis, who underwent surgical and endovascular repair. The diagnostic survey method was used in this study. The socio-demographic and clinical data were collected using an originally developed questionnaire. The statistical analysis was performed using the data analysis software system Statistica, version 10.0, by StatSoft Inc. (2011) and an Excel spreadsheet. The statistical significance was set at p < 0.05 for all calculations. RESULTS: There were statistically significant differences between the analysed groups with regard to severity of ischaemia (p = 0.0001), intermittent claudication (p = 0.0001), rest pain (p = 0.0001), ulceration (p = 0.0031), smoking (p = 0.0075) and comorbidities (percutaneous coronary interventions p = 0.0299; ischaemic stroke p = 0.0235). CONCLUSIONS: There are significantly more patients with more advanced disease and ex-smokers in the surgically treated group. There are significantly more patients with a history of ischaemic stroke, surgical coronary interventions and current smokers in the endovascular group. PMID- 28905043 TI - Vascular parkinsonism and vascular dementia are associated with an increased risk of vascular events or death. AB - INTRODUCTION: The natural course of vascular parkinsonism (VaP) and dementia (VaD) due to cerebral small vessel disease (SVD) is not well known. The aim of this single-center study was to evaluate the long-term risk of vascular events, death and dependency in patients with VaP or VaD and to compare it with patients without cerebrovascular disease but with high atherothrombotic risk. MATERIAL AND METHODS: Seventy-eight consecutive, functionally independent patients with MRI features of SVD and with recently diagnosed VaD (n = 50) and VaP (n = 28) and 55 controls (control group - CG) with high 10-year risk of total cardiovascular disease (SCORE >= 5%) were prospectively recruited and followed for 24 months. RESULTS: Patients with SVD had lower prevalence of coronary artery disease compared with the CG (20.5% vs. 40%; p = 0.02) but similar prevalence of other atherothrombotic risk factors including mean age (73.7 +/-7.3 vs. 72 +/-5.9 years, p = 0.09). All outcomes were worse in SVD patients than controls. Thirty one percent of SVD patients (34% of VaD vs. 25% of VaP, p = 0.45) experienced vascular events or died compared to 6% of controls (p < 0.01). After adjustments for potential confounders (age, sex, vascular risk factors), patients with VaP (HR = 7.5; 95% CI: 1.6-33; p < 0.01) and VaD (HR = 8.7; 95% CI: 2.1-35; p < 0.01) had higher risk of vascular events or death and death or dependency (respectively; HR = 3.9; 95% CI: 0.83-18.8; p = 0.07 and HR = 4.7, 95% CI: 1.1 19.7; p = 0.03). CONCLUSIONS: Patients with VaP or VaD due to SVD had significantly higher risk of vascular events, death and dependency compared to controls with high cardiovascular risk and without cerebrovascular disease. PMID- 28905044 TI - Is there a relationship between blood lipids and lumbar disc herniation in young Turkish adults? AB - INTRODUCTION: Atherosclerosis might diminish the nutrient supply to intervertebral discs (IVD), leading to disc herniation. Therefore, there is interest in determining the possible association between the blood lipid profile and lumbar disc herniation (LDH). We aimed to evaluate the association between blood lipids and LDH in a homogeneous group of patients, controlling for age- and sex-specific effects. MATERIAL AND METHODS: This is a case-control study which consisted of 100 individuals (mean age: 41.25 +/-9.09; 50 men and 50 women), classified into two groups, as follows. Group I (G-I) consisted of 50 patients who underwent surgery for symptomatic LDH, while group II (G-II) consisted of 50 patients with nonspecific complaints of a headache, but with no previous history of back and/or leg pain, recruited among patients admitted to the outpatient clinic at the time of the study, and whose age and sex were matched to the study group. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose, and hemoglobin A1c levels were measured. The TC/HDL-C ratio was calculated. Blood pressure, waist circumference, body mass index, and the history of smoking were included in the analysis. RESULTS: The mean values of the TC, TG, LDL-C, HDL-C levels and TC/HDL-C ratio were 198.38, 132.76, 131.9, 40.38 mg/dl and 5.09, respectively. No statistically significant relationship between the blood lipid profile and LDH was identified in this population. CONCLUSIONS: Blood lipid levels in this young adult Turkish population did not predict LDH, and may not be a leading cause of IVD ischemia and IVD degeneration. PMID- 28905045 TI - Left atrial appendage occlusion in a patient with hereditary hemorrhagic telangiectasia and atrial fibrillation - a therapeutic option worth considering. PMID- 28905046 TI - Residents' Attitude, Knowledge, and Perceived Preparedness Toward Caring for Patients from Diverse Sociocultural Backgrounds. AB - Purpose: Training residents to deliver care to increasingly diverse patients in the United States is an important strategy to help alleviate racial and ethnic disparities in health outcomes. Cross-cultural care training of residents continues to present challenges. This study sought to explore the associations among residents' cross-cultural attitudes, preparedness, and knowledge about disparities to better elucidate possible training needs. Methods: This cross sectional study used web-based questionnaires from 2013 to 2014. Eighty-four internal medicine residency programs with 954 residents across the United States participated. The main outcome was perceived preparedness to care for sociocultural diverse patients. Key Results: Regression analysis showed attitude toward cross-cultural care (beta coefficient [beta]=0.57, 95% confidence interval [CI]: 0.49-0.64, p<0.001) and report of serving a large number of racial/ethnic minorities (beta=0.90, 95% CI: 0.56-1.24, p<0.001), and low-socioeconomic status patients (beta=0.74, 95% CI: 0.37-1.10, p<0.001) were positively associated with preparedness. Knowledge of disparities was poor and did not differ significantly across postgraduate year (PGY)-1, PGY-2, and PGY-3 residents (mean scores: 56%, 58%, and 55%, respectively; p=0.08). Conclusion: Residents' knowledge of health and healthcare disparities is poor and does not improve during training. Residents' preparedness to provide cross-cultural care is directly associated with their attitude toward cross-cultural care and their level of exposure to patients from diverse sociocultural backgrounds. Future studies should examine the role of residents' cross-cultural care-related attitudes on their ability to care for diverse patients. PMID- 28905048 TI - Social Determinants of Health, Violent Radicalization, and Terrorism: A Public Health Perspective. AB - Background: Terrorism-related deaths are at an all-time high as there were 32,685 and 29,376 terrorism-related deaths in 2014 and 2015, respectively. Terrorism is defined as the use of violence and intimidation in the pursuit of political aims. Terrorism is detrimental for mental health, premature mortality, and economic losses and undermines the central tenets of public health to improve the health and well-being of populations. Despite the impact terrorism has on avoidable morbidity and mortality, population health research largely overlooks social determinants of terrorism and risk factors that contribute to terrorist activities. Methods: Drawing from what is known about commonly studied social determinants of health topics, including the relationships between structural and interpersonal discrimination, social cohesion, and gang violence and health, we present a public health framework, rooted in the social determinants of health, for identifying potential factors influencing terrorism and violent radicalization. Results: Social determinants of health provide unique insight into how interpersonal and structural factors can influence risk for violent radicalization and terrorist activity. Each of the topics we review provides an entry point for existing public health and behavioral science knowledge to be used in preventing and understanding violent radicalization and terrorism. For example, anti-Muslim sentiment has promoted discrimination against Muslims, while also serving to marginalize and stigmatize Muslim communities. These conditions limit the social resources, like social cohesion, that Muslims have access to and make political violence more appealing to some. Conclusions: Public health can contribute much to the ongoing debate around terrorism. The field must take a more prevention-focused approach to the problem of terrorism. Failure to do so only perpetuates approaches that have not been successful. PMID- 28905047 TI - Use of Community Health Workers and Patient Navigators to Improve Cancer Outcomes Among Patients Served by Federally Qualified Health Centers: A Systematic Literature Review. AB - Introduction: In the United States, disparities in cancer screening, morbidity, and mortality are well documented, and often are related to race/ethnicity and socioeconomic indicators including income, education, and healthcare access. Public health approaches that address social determinants of health have the greatest potential public health benefit, and can positively impact health disparities. As public health interventions, community health workers (CHWs), and patient navigators (PNs) work to address disparities and improve cancer outcomes through education, connecting patients to and navigating them through the healthcare system, supporting patient adherence to screening and diagnostic services, and providing social support and linkages to financial and community resources. Clinical settings, such as federally qualified health centers (FQHCs) are mandated to provide care to medically underserved communities, and thus are also valuable in the effort to address health disparities. We conducted a systematic literature review to identify studies of cancer-related CHW/PN interventions in FQHCs, and to describe the components and characteristics of those interventions in order to guide future intervention development and evaluation. Method: We searched five databases for peer-reviewed CHW/PN intervention studies conducted in partnership with FQHCs with a focus on cancer, carried out in the United States, and published in English between January 1990 and December 2013. Results: We identified 24 articles, all reporting positive outcomes of CHW/PNs interventions in FQHCs. CHW/PN interventions most commonly promoted breast, cervical, or colorectal cancer screening and/or referral for diagnostic resolution. Studies were supported largely through federal funding. Partnerships with academic institutions and community-based organizations provided support and helped develop capacity among FQHC clinic leadership and community members. Discussion: Both the FQHC system and CHW/PNs were borne from the need to address persistent, complex health disparities among medically underserved communities. Our findings support the effectiveness of CHW/PN programs to improve completion and timeliness of breast, cervical, and colorectal cancer screening in FQHCs, and highlight intervention components useful to design and sustainability. PMID- 28905049 TI - A tandem annulation with a [1,3]-hydride transfer as the key step leading to isochromans. AB - An unprecedented method that enables the direct coupling of an alpha-C-H bond in alcohols with 2-arylacetaldehydes through a [1,3]-hydride transfer ([1,3]-HT) of oxocarbenium ions catalyzed by a Lewis acid has been developed. The redox neutral preparation of the isochroman derivatives proceeds via a tandem condensation/[1,3]-HT/Friedel-Crafts sequence with moderate to good yields. Deuterium-labeling studies provide mechanistic insights and reveal that the redox functionalization proceeds via a [1,3]-HT. PMID- 28905050 TI - Identification of inhibitors targeting Mycobacterium tuberculosis cell wall biosynthesis via dynamic combinatorial chemistry. AB - In this study, we report a dynamic combinatorial approach along with highly efficient in situ screening to identify inhibitors of UDP-galactopyranose mutase (UGM), an essential enzyme involved in mycobacterial cell wall biosynthesis. These two technologies converged to the identification of a new UGM inhibitor chemotype. Importantly, the best molecule not only displayed high affinity for the target enzyme but also exhibited in vitro growth inhibition against whole Mycobacterium tuberculosis cells. The strategy described here provides an avenue to explore a novel inhibitor class for UGMs and paves the way for further pharmacological studies on tuberculosis treatment. PMID- 28905051 TI - Scaling behavior of oxide-based electrothermal threshold switching devices. AB - Materials exhibiting insulator to metal transition (IMT) and transition metal oxides showing threshold switching behavior are considered as promising candidates for selector devices for crossbar non-volatile memory application. In this study, we use an electrothermal model to simulate the behavior of nanoscale selectors based on several different functional oxides (TaOx, VO2 and NbO2). We extract the device characteristics, such as threshold voltage (VTH), leakage current, device temperature in the ON state, and the size of the conductive filament as a function of selector diameter and functional layer thickness. In addition, we benchmark these devices in a 1 selector/1 resistor (1S1R) cell with a generic phase change-like memory element. These findings provide an insight into how device performance changes with scaling and help with material selection and design of selectors. PMID- 28905053 TI - Hetero-metallic, functionalizable polyoxomolybdate clusters via a "top-down" synthetic method. AB - Two bi-metallic, organophosphonate-stabilised sandwich-type polyoxomolybdate clusters, [Mo6Cu4O16(OH)2(C4H9PO3)4(C5H5N)2 (CH3O)4(H2O)]2- and [Mo7Cu7O19(OH)(CH3O)7(C4H9PO3)6(C5H5N)2]2-, are reported. These compounds are accessed via the "top-down" in situ disassembly of the [Mo6O19]2- Lindqvist species into reactive oligomers, followed by subsequent reassembly with polynuclear CuII assemblies to form the reported compounds. PMID- 28905054 TI - NaH promoted [4+3] annulation of crotonate-derived sulfur ylides with thioaurones: synthesis of 2,5-dihydrobenzo[4,5]thieno[3,2-b]oxepines. AB - The [4+3] annulation reaction of crotonate-derived sulfur ylides with thioaurones has, for the first time, been reported using NaH as the base. A diverse array of 2,5-dihydrobenzo[4,5]thieno[3,2-b]oxepines is obtained in good to excellent yields. The proposed mechanism is investigated and supported by DFT calculations. PMID- 28905052 TI - Cyclic peptide production using a macrocyclase with enhanced substrate promiscuity and relaxed recognition determinants. AB - Macrocyclic peptides have promising therapeutic potential but the scaling up of their chemical synthesis is challenging. The cyanobactin macrocyclase PatGmac is an efficient tool for production but is limited to substrates containing 6-11 amino acids and at least one thiazoline or proline. Here we report a new cyanobactin macrocyclase that can cyclize longer peptide substrates and those not containing proline/thiazoline and thus allows exploring a wider chemical diversity. PMID- 28905055 TI - The C-terminal cytidine deaminase domain of APOBEC3G itself undergoes intersegmental transfer for a target search, as revealed by real-time NMR monitoring. AB - APOBEC3G (A3G), an anti-human immunodeficiency virus 1 factor, deaminates cytidines. We examined deamination of two cytidines located separately on substrate ssDNA by the C-terminal domain (CTD) of A3G using real-time NMR monitoring. The deamination preference between the two cytidines was lost when either the substrate or non-substrate ssDNA concentration increased. When the non substrate ssDNA concentration increased, the deamination activity first increased, but then decreased. This indicates that even a single domain, A3G-CTD, undergoes intersegmental transfer for a target search. PMID- 28905056 TI - Surface alteration of calcite: interpreting macroscopic observations by means of AFM. AB - Wettability has been recognized to play a fundamental role in the efficacy of water flooding processes of carbonate oil and gas reservoirs. However, the theoretical mechanism governing this process is still not entirely understood. This can be partly attributed to the absence of ad hoc tools and standardized sample-preparation methodologies for comprehensive transient characterization of the mineral surface. Here, we use atomic force microscopy (AFM) to investigate the effect of different calcite sample-preparation methodologies in estimating the macroscopic water static contact angle (SCA). Single crystal calcite surfaces are aged in deionized (DI) water baths, for different exposure times, and dried by different techniques, to reveal SCA discrepancies. Trends and observations are explained with the use of time-dependent adhesion maps of the surface obtained by bimodal AFM. In this context, the AFM interpretation of macroscopic observations provides a means to single out the different factors influencing wettability, thus allowing for a more standardized description of the processes responsible for the modification of the affinity between the mineral rock and injected water. PMID- 28905057 TI - A water-mediated and substrate-assisted aminoacylation mechanism in the discriminating aminoacyl-tRNA synthetase GlnRS and non-discriminating GluRS. AB - Glutaminyl-tRNA synthetase (GlnRS) catalyzes the aminoacylation of glutamine to the corresponding tRNAGln. However, most bacteria and all archaea lack GlnRS and thus an indirect noncanonical aminoacylation is required. With the assistance of a non-discriminating version of Glutamyl-tRNA synthetases (ND-GluRS) the tRNAGln is misaminoacylated by glutamate. In this study, we have computationally investigated the aminoacylation mechanism in GlnRS and ND-GluRS employing Molecular Dynamics (MD) simulations, Quantum Mechanics (QM) cluster and Quantum Mechanics/Molecular Mechanics (QM/MM) calculations. Our investigations demonstrated the feasibility of a water-mediated, substrate-assisted catalysis pathway with rate limiting steps occurring at energy barriers of 25.0 and 25.4 kcal mol-1 for GlnRS and ND-GluRS, respectively. A conserved lysine residue participates in a second proton transfer to facilitate the departure of the adenosine monophosphate (AMP) group. Thermodynamically stable (-29.9 and -9.3 kcal mol-1 for GlnRS and ND-GluRS) product complexes are obtained only when the AMP group is neutral. PMID- 28905058 TI - A transition-metal-free fast track to flavones and 3-arylcoumarins. AB - A highly regioselective and transition-metal free one-pot arylation of chromenones with arylboronic acids has been achieved employing K2S2O8. The procedure consists of a sequence of some reactions including an arylation/decarboxylation cascade and proceeds well in aqueous media to afford biologically interesting flavones and 3-arylcoumarins. This method exhibited excellent selectivity and functional group tolerance under mild conditions. The reaction also showed perfect efficacy for the preparation of styryl coumarins. PMID- 28905059 TI - Fe2O3, a cost effective and environmentally friendly catalyst for the generation of NH3 - a future fuel - using a new Al2O3-looping based technology. AB - Fe2O3 is found to be a cost-effective and environmentally friendly catalyst for chemical looping generation of NH3 - a future fuel. The optimal Fe2O3 loading on nitrogen carriers, AIN, is 5 wt%. Fe2O3 can reduce the activation energy of the N desorption step of AIN by 100 kJ mol-1 or ~30%. PMID- 28905060 TI - An engineering approach to synthesis of gold and silver nanoparticles by controlling hydrodynamics and mixing based on a coaxial flow reactor. AB - In this work we present a detailed study of flow technology approaches that could open up new possibilities for nanoparticle synthesis. The synthesis of gold and silver nanoparticles (NPs) in a flow device based on a coaxial flow reactor (CFR) was investigated. The CFR comprised of an outer glass tube of 2 mm inner diameter (I.D.) and an inner glass tube whose I.D. varied between 0.142 and 0.798 mm. A split and recombine (SAR) mixer and coiled flow inverter (CFI) were further employed to alter the mixing conditions after the CFR. The 'Turkevich' method was used to synthesize gold NPs, with a CFR followed by a CFI. This assembly allows control over nucleation and growth through variation of residence time. Increasing the total flow rate from 0.25 ml min-1 to 3 ml min-1 resulted initially in a constant Au NP size, and beyond 1 ml min-1 to a size increase of Au NPs from 17.9 +/- 2.1 nm to 23.9 +/- 4.7 nm. The temperature was varied between 60-100 degrees C and a minimum Au NP size of 17.9 +/- 2.1 nm was observed at 80 degrees C. Silver NPs were synthesized in a CFR followed by a SAR mixer, using sodium borohydride to reduce silver nitrate in the presence of trisodium citrate. The SAR mixer provided an enhancement of the well-controlled laminar mixing in the CFR. Increasing silver nitrate concentration resulted in a decrease in Ag NP size from 5.5 +/- 2.4 nm to 3.4 +/- 1.4 nm. Different hydrodynamic conditions were studied in the CFR operated in isolation for silver NP synthesis. Increasing the Reynolds number from 132 to 530 in the inner tube created a vortex flow resulting in Ag NPs in the size range between 5.9 +/- 1.5 nm to 7.7 +/- 3.4 nm. Decreasing the inner tube I.D. from 0.798 mm to 0.142 mm resulted in a decrease in Ag NP size from 10.5 +/- 4.0 nm to 4.7 +/- 1.4 nm. Thus, changing the thickness of the inner stream enabled control over size of the Ag NPs. PMID- 28905061 TI - An anionic Na(i)-organic framework platform: separation of organic dyes and post modification for highly sensitive detection of picric acid. AB - A cage-based anionic Na(i)-organic framework with a unique Na9 cluster-based secondary building unit and a cage-in-cage structure was constructed. The selective separation of dyes with different charges and sizes was investigated. Furthermore, the Rh6G@MOF composite could be applied as a recyclable fluorescent sensor for detecting picric acid (PA) with high sensitivity and selectivity. PMID- 28905062 TI - Selective synthesis of tetrahydroimidazo[1,2-a]pyridine and pyrrolidine derivatives via a one-pot two-step reaction. AB - In the presence of triethylamine, the addition reaction of substituted alpha amino acid alkyl esters including ethyl hyperphenylalaninate, phenylalaninate, isoleucinate, and alaninate with dialkyl but-2-ynedioate afforded active beta enamino esters, which in turn reacted with aromatic aldehydes and malononitrile to give tetrahydroimidazo[1,2-a]pyridine derivatives in moderate yields. Under similar reaction conditions, the reaction of ethyl glycinate with dialkyl but-2 ynedioate resulted in a 1,3-dipolar azomethine ylide, which reacted further with in situ-generated arylidene malononitrile, alkyl cyanoacetate, and cyanoacetamide to give polysubstituted pyrrolidine derivatives in good yields. PMID- 28905063 TI - Palladium-catalyzed oxidative coupling of arylboronic acid with isocyanide to form aromatic carboxylic acids. AB - A valuable palladium-catalyzed oxidative coupling of aryl- and alkenyl borides with isocyanide for the synthesis of corresponding carboxylic acids has been developed. With wide substrate scopes and good functional group tolerance, this reaction offers corresponding carboxylic acids in moderate to excellent yields. PMID- 28905064 TI - Mechanochemical synthesis of high coercivity Nd2(Fe,Co)14B magnetic particles. AB - With increasing demand for magnets in energy conversion systems, the quest for the development and understanding of novel processing routes to produce permanent magnets has become urgent. We report a novel mechanochemical process for the synthesis of Nd2(Fe,Co)14B magnetic particles with a high coercivity of 12.4 kOe. This process involves the reduction of neodymium oxide, iron oxide, cobalt oxide and boron anhydride in the presence of a calcium reducing agent and a CaO diluent. The formation mechanism of Nd2(Fe,Co)14B changed with increasing CaO content, and the average crystal size of the Nd2(Fe,Co)14B particles also increased, resulting in an increase in the coercivity values. The reaction mechanism during milling was revealed through a study of the phase transformations as a function of milling time. It was found that unlike self propagating reactions, this reduction reaction during milling requires continuous input of mechanical energy to reach a steady state. PMID- 28905065 TI - Be positive: optimizing pramlintide from microcanonical analysis of amylin isoforms. AB - Amylin, or human islet amyloid polypeptide (hIAPP), is a 37-residue hormone synergistic to insulin and co-secreted with it by beta-cells in the pancreas. The deposition of its cytotoxic amyloid fibrils is strongly related to the progression of Type II diabetes (T2D) and islet graft failures. Notably, isoforms from some mammalian species, such as rats (rIAPP) and porcine (pIAPP), present a few key mutations preventing aggregation. This has lead to biotechnological development of drugs for adjunct therapies of T2D, such as pramlintide, a variant of hIAPP inspired by rIAPP whose proline substitutions have beta-strand fibril breaking properties. Ideally, such a drug should be formulated with insulin and co-administered, but this has been prevented by a poor solubility profile at the appropriate pH. Hopefully, this could be improved with appropriate point mutations, increasing the molecular net charge. Despite experimental progress, preliminary screening during rational drug design can greatly benefit from thermodynamic insight derived from molecular simulations. So we introduce microcanonical thermostatistics analysis of multicanonical (MUCA) simulations of wild-type amylin isoforms as a systematic assessment of protein thermostability. As a consequence of this comprehensive investigation, the most suitable single point mutations able to optimize pramlintide are located among the wild-type amylin isoforms. In particular, we find that aggregation inhibition and increased solubility are inherited by pramlintide through further S20R substitution typical of pIAPP. Thus, we provide a consistent thermostatistical methodology to aid the design of improved adjunct therapies for T2D according to current clinical knowledge. PMID- 28905066 TI - FeCl3/ZnI2-Catalyzed regioselective synthesis of angularly fused furans. AB - The FeCl3/ZnI2-catalyzed synthesis of angularly fused furans by intermolecular coupling between enols and alkynes has been developed in ambient air. The methodology is successfully applicable to 4-hydroxycoumarin, 4-hydroxyquinolinone and alpha-tetralone affording regioselective 2-aryl furans in good yields. The control experiments suggest the possibility of a radical reaction mechanism. PMID- 28905067 TI - Non-noble metal plasmonic photocatalysis in semimetal bismuth films for photocatalytic NO oxidation. AB - Recently, non-noble metals with plasmonic properties have attracted great attention due to their potential applications in photocatalytic solar-energy conversion. However, in contrast to the well-studied plasmonic noble metals (mainly Au and Ag), which have distinct absorption peaks, the understanding of light absorption and the photocatalytic reaction mechanism of non-noble metals is far less. In this study, semimetal bismuth films are deposited on fluorine-doped tin oxide substrates by a dc magnetron sputtering method. Both theoretical calculation and UV-vis absorption spectra confirm that the field enhancement and location of plasmonic resonance peaks are strongly correlated with the size of Bi particles. Through tuning the sputtering power, for the first time, four distinct absorption peaks are observed over isolated Bi particles. Moreover, it is found that the energy barrier for the conversion of NO into NO2 over Bi is even lower than that with Au nanoclusters. Thus, Bi films are highly active for photocatalytic oxidation of NO. Moreover, the low NO2 desorption energy over Bi indicates that Bi films can be the main active sites during the reaction process and that they possess good stability. PMID- 28905068 TI - Mild synthesis of monodisperse tin nanocrystals and tin chalcogenide hollow nanostructures. AB - We report a mild synthetic method to access Sn nanocrystals with tunable diameter and narrow size distribution (6-8%). The self-templated formation of various types of Sn chalcogenide hollow nanostructures including oxides, sulfides, selenides, and tellurides is also demonstrated for the first time. The use of air stable tungsten hexacarbonyl that produces carbon monoxide at elevated temperature to reduce the SnCl2 precursor and coordinate the nanoparticle surface is thought to play an essential role in this method. This synthesis method is likely to be extended to other metal systems and could find potential applications including battery anodes and catalysts. PMID- 28905069 TI - Hollow Co2P nanoflowers assembled from nanorods for ultralong cycle-life supercapacitors. AB - Hollow Co2P nanoflowers (Co2P HNFs) were successfully prepared via a one-step, template-free method. Microstructure analysis reveals that Co2P HNFs are assembled from nanorods and possess abundant mesopores and an amorphous carbon shell. Density functional theory calculations and electrochemical measurements demonstrate the high electrical conductivity of Co2P. Benefiting from the unique nanostructures, when employed as an electrode material for supercapacitors, Co2P HNFs exhibit a high specific capacitance, an outstanding rate capability, and an ultralong cycling stability. Furthermore, the constructed Co2P HNF//AC ASC exhibits a high energy density of 30.5 W h kg-1 at a power density of 850 W kg-1, along with a superior cycling performance (108.0% specific capacitance retained after 10 000 cycles at 5 A g-1). These impressive results make Co2P HNFs a promising candidate for supercapacitor applications. PMID- 28905070 TI - Sodium-cationized carbohydrate gas-phase fragmentation chemistry: influence of glycosidic linkage position. AB - We investigate the gas-phase structures and fragmentation chemistry of two isomeric sodium-cationized carbohydrates using combined tandem mass spectrometry, hydrogen/deuterium exchange experiments, and computational methods. Our model systems are the glucose-based disaccharide analytes cellobiose (beta-d glucopyranosyl-(1 -> 4)-d-glucose) and gentiobiose (beta-d-glucopyranosyl-(1 -> 6)-d-glucose). These analytes show substantially different tandem mass spectra. We characterize the rate-determining barriers to both the glycosidic and structurally-informative cross-ring bond cleavages. Sodiated cellobiose produces abundant Y1 and B1 peaks. Our deuterium labelling and computational chemistry approach provides evidence for 1,6-anhydroglucose B1 ion structures rather than the 1,2-anhydroglucose and oxacarbenium ion structures proposed elsewhere. Unlike those earlier proposals, this finding is consistent with the experimentally observed Bn/Ym branching ratios. In contrast to cellobiose, sodiated gentiobiose primarily fragments by cross-ring cleavage to form various A2 ion types. Fragmentation is facilitated by ring-opening at the reducing end which enables losses of CnH2nOn oligomers. Deuterium labelling and theory enables rationalization of these processes. Theory and experiment also support the importance of consecutive fragmentation processes at higher collision energies. PMID- 28905071 TI - ? PMID- 28905072 TI - ? PMID- 28905073 TI - Erratum to: Stress and the nonsense-mediated RNA decay pathway. AB - The original version of this article unfortunately contained errors in the section entitled "NMD in stress responses in plants". PMID- 28905074 TI - Erratum to: Anatomical recommendations for safe botulinum toxin injection into temporalis muscle: a simplified reproducible approach. PMID- 28905076 TI - [Life after ARDS]. AB - Patients who survive acute respiratory distress syndrome (ARDS) often suffer from long-term physical and psychological sequelae. Lung function is commonly only mildly reduced, whereas general physical activity and walking distance are often compromised. Most markedly, these patients have a high incidence of depression, anxiety, and posttraumatic stress disorder. The rate of cognitive dysfunction is as high as 70-100% at the time of hospital discharge, and remains 46-80% and 20% one year and five years post discharge, respectively. The possibility of returning to work is markedly limited. Because of these outcomes, preventative strategies must be identified to reduce the high prevalence of physical and psychological morbidity. Prevention and treatment of delirium as well as early and consequent mobilization and intensive care unit diaries are potentially beneficial. PMID- 28905077 TI - [Stroke due to acute occlusion of the basilar artery : Diagnosis and treatment]. AB - Acute occlusion of the basilar artery is a rare and, if left untreated, severe neurovascular condition with a high mortality. The clinical presentation is often atypical and hence diagnosis may be delayed. Because of the devastating natural course, recanalization strategies were often more aggressive than in patients with occlusions in the anterior circulation. To date, there is no evidence-based therapy, and recent larger registry studies and meta-analyses do not show a clear superiority of endovascular approaches over systemic thrombolysis alone. The current review aims to provide an overview of the most critical aspects in clinical and radiological diagnosis and treatment of basilar artery thrombosis. PMID- 28905078 TI - [Task force for falsified medicines]. AB - In 2014, a large number of falsified medicines of Italian origin had come to light. Because of the extent of the falsification, the situation that most of these falsified medicines had been traced back to thefts in Italy by criminal networks, and the necessity of actions by national and local authorities, an intensified exchange of information was essential, in addition to a process of coordination. A task force for falsified medicines was established to optimize the flow of information among all parties involved and to coordinate the necessary measures.One result was the implementation of a procedure for optimizing the exchange of information and for harmonisation of required measures on falsified medicines. In particular, this procedure covers situations in which there is no clear legal responsibility, and is now considered as part of the work of the authorities. In addition, a database has been established in which all pharmaceutical wholesalers located in Germany with a valid wholesale license are publicly accessible. As a preventive measure, information about known thefts will be forwarded to parallel traders and their associations. This is to avoid these products coming onto the market in Germany. PMID- 28905079 TI - [Falsified medicines in parallel trade]. AB - The number of falsified medicines on the German market has distinctly increased over the past few years. In particular, stolen pharmaceutical products, a form of falsified medicines, have increasingly been introduced into the legal supply chain via parallel trading. The reasons why parallel trading serves as a gateway for falsified medicines are most likely the complex supply chains and routes of transport. It is hardly possible for national authorities to trace the history of a medicinal product that was bought and sold by several intermediaries in different EU member states. In addition, the heterogeneous outward appearance of imported and relabelled pharmaceutical products facilitates the introduction of illegal products onto the market. Official batch release at the Paul-Ehrlich Institut offers the possibility of checking some aspects that might provide an indication of a falsified medicine. In some circumstances, this may allow the identification of falsified medicines before they come onto the German market. However, this control is only possible for biomedicinal products that have not received a waiver regarding official batch release. For improved control of parallel trade, better networking among the EU member states would be beneficial. European-wide regulations, e. g., for disclosure of the complete supply chain, would help to minimise the risks of parallel trading and hinder the marketing of falsified medicines. PMID- 28905075 TI - Ouabain attenuates ovalbumin-induced airway inflammation. AB - PURPOSE: Ouabain, an Na+/K+-ATPase inhibitor hormone, presents immunomodulatory actions, including anti-inflammatory effect on acute inflammation models. METHODS: In the present study, the effect of ouabain in a model of allergic airway inflammation induced by ovalbumin (OVA) was assessed. RESULTS: Initially, it was observed that ouabain treatment inhibited cellular migration induced by OVA on bronchoalveolar lavage fluid (BALF), mostly granulocytes, without modulating macrophage migration. In addition, it was observed, by flow cytometry, that ouabain reduces CD3high lymphocytes cells on BALF. Furthermore, treatment with ouabain decreased IL-4 and IL-13 levels on BALF. Ouabain also promoted pulmonary histological alterations, including decreased cell migration into peribronchiolar and perivascular areas, and reduced mucus production in bronchioles regions observed through hematoxylin-eosin (HE) and by periodic acid Schiff stain, respectively. Allergic airway inflammation is characterized by high OVA-specific IgE serum titer. This parameter was also reduced by the treatment with ouabain. CONCLUSIONS: Therefore, our data demonstrate that ouabain negatively modulates allergic airway inflammation induced by OVA. PMID- 28905080 TI - [Treatment of retroperitoneal sarcoma in Germany : Results of a survey of the German Society of General and Visceral Surgery, the German Interdisciplinary Sarcoma Study Group and the advocacy group Das Lebenshaus]. AB - OBJECTIVE: Retroperitoneal sarcomas (RPSs) are rare cancers with some variability in clinical and histopathological presentation. In Germany, general treatment strategies of retroperitoneal sarcoma are unknown since centralized registries do not exist. The objective of this survey was to access the medical care of RPS patients in Germany. METHODS: In cooperation with the German Society of General and Visceral surgery, the German Interdisciplinary Sarcoma Study Group and the patient advocacy group Das Lebenshaus we designed an online survey assessing diagnostic and treatment strategies (e. g. performance of tumor biopsies, administration of multimodal therapies and surgical strategy). All departments for general and visceral surgery in Germany were addressed (n = 976). RESULTS: Responses were received from 191 of 976 departments. Only 11 surgical departments treat more than 10 RPS patients per year. A multidisciplinary sarcoma board exists in 19 hospitals. Staging is generally performed by cross-sectional imaging. In 54% of the departments pretreatment tumor biopsy is a standard procedure. Surgery is performed as compartment resection in 85% of the departments. A systematic lymph node dissection is done in 40%. Adjuvant radio- or chemotherapy is performed as a standard treatment in 27% and 22% departments, respectively. CONCLUSION: The survey demonstrates a large heterogeneity in RPS diagnostic and treatment strategies. Dedicated education programs and centralized treatment strategies are warranted to improve the standard of care. PMID- 28905081 TI - [Cardiorenal syndrome]. AB - Patients in the intensive care unit often suffer from cardiorenal syndrome, which can have an important influence on the patient's outcome. The heart and kidney influence each other via organ crosstalk. We screened and evaluated current publications on cardiorenal syndromes and their therapy. A key role in the management of cardiorenal syndromes is renal decongestion via loop diuretics. PMID- 28905082 TI - [Attenuated zoster vaccine is not recommended as a standard vaccine : Missed opportunity or logical implementation of the evidence-based approach of the Standing Committee on Vaccination]. PMID- 28905083 TI - Assessing exercises recommended for women at risk of pelvic floor disorders using multivariate statistical techniques. AB - INTRODUCTION AND HYPOTHESIS: There is a widely held, but untested, belief that certain exercises and activities generate intraabdominal pressure (IAP) that may compromise the function of the pelvic floor muscles. Women with, or at risk of, pelvic floor disorders are advised therefore to refrain from these exercises and activities in order to theoretically protect their pelvic floor. The aim of this study was to compare IAPs generated during exercises of different types that are recommended to women as pelvic floor "safe" with those generated during the corresponding conventional exercises that women are typically cautioned against. METHODS: This was a cross-sectional cohort study. All participants were guided by a trained exercise practitioner through a series of ten exercise pairs, one version recommended to women as pelvic floor "safe" and one conventional version which women are cautioned against. IAP components were extracted from the pressure traces from a wireless intravaginal pressure sensor and used in multivariate linear regression modelling, canonical discriminant analysis, and linear mixed modelling. RESULTS: A total of 53 participants were recruited. After adjusting for age, body mass index and parity, there was an exercise type-version effect (p < 0.01). After taking into account all pressure components of the IAP trace, there was a significant difference in IAP between the recommended and discouraged versions of the same exercise for five of the ten exercise types. Coughing and the Valsalva manoeuvre generated IAPs that were distinct from those generated by the exercises. CONCLUSIONS: No differences in IAPs were found between the recommended and discouraged versions of the same exercise for all exercise types. In particular, the IAPs generated during the two versions of ball rotations, lunges, core, push-ups and squats did not differ significantly. Performing the recommended pelvic floor "safe" version instead of the discouraged conventional version of these exercises may not necessarily protect the pelvic floor and vice versa. PMID- 28905084 TI - Plasmonic cell nanocoating: a new concept for rapid microbial screening. AB - Nanocoating of single microbial cells with gold nanostructures can confer optical, electrical, thermal, and mechanical properties to microorganisms, thus enabling new avenues for their control, study, application, and detection. Cell nanocoating is often performed using layer-by-layer (LbL) deposition. LbL is time consuming and relies on nonspecific electrostatic interactions, which limit potential applications for microbial diagnostics. Here, we show that, by taking advantage of surface molecules densely present in the microbial outer layers, cell nanocoating with gold nanoparticles can be achieved within seconds using surface molecules, including disulfide- bond-containing (Dsbc) proteins and chitin. A simple activation of these markers and their subsequent interaction with gold nanoparticles allow specific microbial screening and quantification of bacteria and fungi within 5 and 30 min, respectively. The use of plasmonics and fluorescence as transduction methods offers a limit of detection below 35 cfu mL 1 for E. coli bacteria and 1500 cfu mL-1 for M. circinelloides fungi using a hand held fluorescent reader. Graphical abstract A new concept for rapid microbial screening by targeting disulfide - bond-containing (Dsbc) proteins and chitin with reducing agents and gold nanoparticles. PMID- 28905085 TI - [Focal lesions in whole-body MRI in multiple myeloma : Quantification of tumor mass and correlation with disease-related parameters and prognosis]. AB - BACKGROUND AND OBJECTIVES: In this study, we evaluated methods of quantification of tumor mass in whole-body MRI (wb-MRI) in multiple myeloma and correlated these with disease-related parameters in serum and bone marrow. MATERIALS AND METHODS: We retrospectively evaluated wb-MRIs of 52 patients with focal infiltration pattern and a total of 700 focal lesions (subsequently called lesions). We determined the longest diameter (LD), the segmented volume (SV), and the morphology (spherical or non-spherical). We correlated total number/volume of the lesions with clinical parameters and prognosis and furthermore LD with SV. After that we analyzed the agreement of SV and estimated volume (EV) using the volume formula of a sphere based on LD. RESULTS: Results showed no significant correlations of total number/volume with prognosis or clinical parameters. The latter were situated predominantly in the normal range. Furthermore, 10% of lesions were spherical. SV and LD correlated significantly in single lesions and on patient level. SV was in lesions <6 cm3 systematically larger and in lesions >=6 cm3 smaller than EV. In 95%, we found in small lesions a deviation of EV versus SV from +0.9 cm3 to -4.6 cm3 and in large lesions from +160 cm3 to -111 cm3 (EV-SV). CONCLUSIONS: Quantification of tumor mass in the focal infiltration pattern is performed more accurately by volumetry than LD due to the predominant existence of non-spherical lesions. The patient cohort with clinical parameters predominantly in the normal range is distributed to ISS stage I and partly pretreated, a fact that makes interpretation of absent correlations more difficult. Consider also a variation in activitiy of lesions and a diffuse infiltration not detectable by MRI. PMID- 28905086 TI - Identification and characterization of a novel (-)-vibo-quercitol 1-dehydrogenase from Burkholderia terrae suitable for production of (-)-vibo-quercitol from 2 deoxy-scyllo-inosose. AB - (-)-vibo-Quercitol is a deoxyinositol (1L-1,2,4/3,5-cyclohexanepentol) that naturally occurs in oak species, honeydew honey, wines aged in oak barrels, and Gymnema sylvestre and is a potential intermediate for pharmaceuticals. We found that (-)-vibo-quercitol is stereoselectively synthesized from 2-deoxy-scyllo inosose by the reductive reaction of a novel (-)-vibo-quercitol 1-dehydrogenase found in the proteomes of Burkholderia, Pseudomonas, and Arthrobacter. Among them, Burkholderia terrae sp. AKC-020 (40-1) produced a (-)-vibo-quercitol 1 dehydrogenase appropriate for synthesizing (-)-vibo-quercitol with a high diastereomeric excess. The enzyme was strongly induced in Bu. terrae cells when quercitol or 2-deoxy-scyllo-inosose was used as carbon source in the culture medium. The enzyme is NAD(H)-dependent and shows highly specific activity for (-) vibo-quercitol and myo-inositol among the substrates tested. The enzyme gene (qudh) was obtained by PCR using degenerate primers based on the N-terminal and internal amino acid sequences of the purified enzyme, followed by thermal asymmetric interlaced PCR. The qudh gene showed homology with inositol 2 dehydrogenase (sharing 49.5% amino acid identity with IdhA from Sinorhizobium meliloti 1021). We successfully produced several recombinant (-)-vibo-quercitol 1 dehydrogenases and related enzymes identified by genome database mining using an Escherichia coli expression system. This revealed that scyllo-inositol dehydrogenase (IolX) in Bacillus subtilis can catalyze the reduction of 2-deoxy scyllo-inosose to yield scyllo-quercitol, a stereoisomer of (-)-vibo-quercitol. Thus, we successfully identified two enzymes to produce both stereoisomers of deoxyinositols that are rare in nature. PMID- 28905087 TI - A droplet-based microfluidic chip as a platform for leukemia cell lysate identification using surface-enhanced Raman scattering. AB - A new approach is presented for cell lysate identification which uses SERS-active silver nanoparticles and a droplet-based microfluidic chip. Eighty-nanoliter droplets are generated by injecting silver nanoparticles, KCl as aggregation agent, and cell lysate containing cell constituents, such as nucleic acids, carbohydrates, metabolites, and proteins into a continuous flow of mineral oil. This platform enables accurate mixing of small volumes inside the meandering channels of the quartz chip and allows acquisition of thousands of SERS spectra with 785 nm excitation at an integration time of 1 s. Preparation of three batches of three leukemia cell lines demonstrated the experimental reproducibility. The main advantage of a high number of reproducible spectra is to apply statistics for large sample populations with robust classification results. A support vector machine with leave-one-batch-out cross-validation classified SERS spectra with sensitivities, specificities, and accuracies better than 99% to differentiate Jurkat, THP-1, and MONO-MAC-6 leukemia cell lysates. This approach is compared with previous published reports about Raman spectroscopy for leukemia detection, and an outlook is given for transfer to single cells. A quartz chip was designed for SERS at 785 nm excitation. Principal component analysis of SERS spectra clearly separates cell lysates using variations in band intensity ratios. PMID- 28905089 TI - [Radiochemotherapy improves failure-free survival in stage III endometrial cancer : Final results of the PORTEC-3 trial]. PMID- 28905090 TI - Thermodynamics of enzyme-catalyzed esterifications: II. Levulinic acid esterification with short-chain alcohols. AB - Levulinic acid was esterified with methanol, ethanol, and 1-butanol with the final goal to predict the maximum yield of these equilibrium-limited reactions as function of medium composition. In a first step, standard reaction data (standard Gibbs energy of reaction Delta R g 0 ) were determined from experimental formation properties. Unexpectedly, these Delta R g 0 values strongly deviated from data obtained with classical group contribution methods that are typically used if experimental standard data is not available. In a second step, reaction equilibrium concentrations obtained from esterification catalyzed by Novozym 435 at 323.15 K were measured, and the corresponding activity coefficients of the reacting agents were predicted with perturbed-chain statistical associating fluid theory (PC-SAFT). The so-obtained thermodynamic activities were used to determine Delta R g 0 at 323.15 K. These results could be used to cross-validate Delta R g 0 from experimental formation data. In a third step, reaction-equilibrium experiments showed that equilibrium position of the reactions under consideration depends strongly on the concentration of water and on the ratio of levulinic acid: alcohol in the initial reaction mixtures. The maximum yield of the esters was calculated using Delta R g 0 data from this work and activity coefficients of the reacting agents predicted with PC-SAFT for varying feed composition of the reaction mixtures. The use of the new Delta R g 0 data combined with PC-SAFT allowed good agreement to the measured yields, while predictions based on Delta R g 0 values obtained with group contribution methods showed high deviations to experimental yields. PMID- 28905088 TI - New horizons in cardiac innervation imaging: introduction of novel 18F-labeled PET tracers. AB - Cardiac sympathetic nervous activity can be uniquely visualized by non-invasive radionuclide imaging techniques due to the fast growing and widespread application of nuclear cardiology in the last few years. The norepinephrine analogue 123I-meta-iodobenzylguanidine (123I-MIBG) is a single photon emission computed tomography (SPECT) tracer for the clinical implementation of sympathetic nervous imaging for both diagnosis and prognosis of heart failure. Meanwhile, positron emission tomography (PET) imaging has become increasingly attractive because of its higher spatial and temporal resolution compared to SPECT, which allows regional functional and dynamic kinetic analysis. Nevertheless, wider use of cardiac sympathetic nervous PET imaging is still limited mainly due to the demand of costly on-site cyclotrons, which are required for the production of conventional 11C-labeled (radiological half-life, 20 min) PET tracers. Most recently, more promising 18F-labeled (half-life, 110 min) PET radiopharmaceuticals targeting sympathetic nervous system have been introduced. These tracers optimize PET imaging and, by using delivery networks, cost less to produce. In this article, the latest advances of sympathetic nervous imaging using 18F-labeled radiotracers along with their possible applications are reviewed. PMID- 28905091 TI - Added value of dedicated axillary hybrid 18F-FDG PET/MRI for improved axillary nodal staging in clinically node-positive breast cancer patients: a feasibility study. AB - PURPOSE: To investigate the feasibility and potential added value of dedicated axillary 18F-FDG hybrid PET/MRI, compared to standard imaging modalities (i.e. ultrasound [US], MRI and PET/CT), for axillary nodal staging in clinically node positive breast cancer. METHODS: Twelve patients with clinically node-positive breast cancer underwent axillary US and dedicated axillary hybrid 18F-FDG PET/MRI. Nine of the 12 patients also underwent whole-body PET/CT. Maximum standardized uptake values (SUVmax) were measured for the primary breast tumor and the most FDG-avid axillary lymph node. A positive axillary lymph node on dedicated axillary hybrid PET/MRI was defined as a moderate to very intense FDG avid lymph node. The diagnostic performance of dedicated axillary hybrid PET/MRI was calculated by comparing quantitative and its qualitative measurements to results of axillary US, MRI and PET/CT. The number of suspicious axillary lymph nodes was subdivided as follows: N0 (0 nodes), N1 (1-3 nodes), N2 (4-9 nodes) and N3 (>= 10 nodes). RESULTS: According to dedicated axillary hybrid PET/MRI findings, seven patients were diagnosed with N1, four with N2 and one with N3. With regard to mean SUVmax, there was no significant difference in the primary tumor (9.0 [+/-5.0] vs. 8.6 [+/-5.7], p = 0.678) or the most FDG-avid axillary lymph node (7.8 [+/-5.3] vs. 7.7 [+/-4.3], p = 0.767) between dedicated axillary PET/MRI and PET/CT. Compared to standard imaging modalities, dedicated axillary hybrid PET/MRI resulted in changes in nodal status as follows: 40% compared to US, 75% compared to T2-weighted MRI, 40% compared to contrast-enhanced MRI, and 22% compared to PET/CT. CONCLUSIONS: Adding dedicated axillary 18F-FDG hybrid PET/MRI to diagnostic work-up may improve the diagnostic performance of axillary nodal staging in clinically node-positive breast cancer patients. PMID- 28905093 TI - How do we measure success and at the same time meet patient expectations? PMID- 28905092 TI - Drug-induced oral lichenoid reactions: a real clinical entity? A systematic review. AB - PURPOSE: Drug-induced oral lichenoid reactions (DIOLRs) have been extensively reported in the literature, but the validity of the causality relationship between any drug and the oral lichenoid lesions (OLLs) still remains questionable. We sought to determine whether this causality relationship really exists, whether a resolution of the oral lesions upon withdrawal occurs, and what the most common alleged offending medications are. METHODS: Nine electronic databases from January 1966 to December 2016 were systematically searched to identify all relevant studies selected with specific inclusion criteria (a clinical and histopathological diagnosis of DIOLRs, and clearly statement on the systemic offending medication). Searched terms included but not limited to oral lichen planus/oral lichenoid lesions/oral lichenoid reactions, the adverse effects of medication, and drug-induced. Statistical analyses conducted. RESULTS: The search retrieved a total of 817 articles, of which only 46 were included into a qualitative synthesis: 40 case reports/series and 6 studies. The causality assessment was done only in 14.8% of cases with the C-D-R protocol. The Naranjo algorithm was not reported in the majority of cases (98.2%). Culprit medication was withdrawn in 68.5% of the cases, obtaining a partial or complete resolution without treatment in 16.7% of cases and with treatment in 27.7% of cases. The median number of culprit medication(s) described was 1 with the most frequent ones being Methyldopa (20.37%), Interferon (IFN)-alpha (11.11%), and Imatinib and Infliximab (9.26%). CONCLUSION: This systematic review demonstrated that there is no strong scientific evidence to support the causal relationship between any drug and oral lichenoid lesions; therefore, in all reviewed cases, we must question whether the DIOLRs represent a real and separate clinical entity. Further and more thorough investigations using one of the available algorithms for adverse drug reaction are warranted. PMID- 28905094 TI - Recent advances on the difructose anhydride IV preparation from levan conversion. AB - Difructose anhydride IV (DFA IV) is a cyclic disaccharide consisting of two fructose residues, which is obtained from levan conversion with levan fructotransferase (LFTase) and rarely found in nature as a low-calorie sugar substitute. Some beneficial effects of DFA IV connected with its consumption have been described. The article reviews the properties and physiological functions of DFA IV, levan conversion, resources and properties of LFTase and the produced methods of DFA IV. LFTase as a relatively novel enzyme and its molecular evolution are discussed as well. The aim is to better understand a novel sugar substituting sweetener of DFA IV as a food additive. PMID- 28905095 TI - Growing Canopy on a College Campus: Understanding Urban Forest Change through Archival Records and Aerial Photography. AB - Many municipalities are setting ambitious tree canopy cover goals to increase the extent of their urban forests. A historical perspective on urban forest development can help cities strategize how to establish and achieve appropriate tree cover targets. To understand how long-term urban forest change occurs, we examined the history of trees on an urban college campus: the University of Pennsylvania in Philadelphia, PA. Using a mixed methods approach, including qualitative assessments of archival records (1870-2017), complemented by quantitative analysis of tree cover from aerial imagery (1970-2012), our analysis revealed drastic canopy cover increase in the late 20th and early 21st centuries along with the principle mechanisms of that change. We organized the historical narrative into periods reflecting campus planting actions and management approaches; these periods are also connected to broader urban greening and city planning movements, such as City Beautiful and urban sustainability. University faculty in botany, landscape architecture, and urban design contributed to the design of campus green spaces, developed comprehensive landscape plans, and advocated for campus trees. A 1977 Landscape Development Plan was particularly influential, setting forth design principles and planting recommendations that enabled the dramatic canopy cover gains we observed, and continue to guide landscape management today. Our results indicate that increasing urban tree cover requires generational time scales and systematic management coupled with a clear urban design vision and long-term commitments. With the campus as a microcosm of broader trends in urban forest development, we conclude with a discussion of implications for municipal tree cover planning. PMID- 28905096 TI - Comparison of suction blistering and tape stripping for analysis of epidermal genes, proteins and lipids. AB - Analysis of epidermal genes, proteins and lipids is important in the research and diagnosis of skin diseases. Although punch biopsy is the first-choice technique for the skin sampling, it is unnecessarily invasive for obtaining a sample just for the epidermal analysis. Here we compare two less invasive methods, suction blistering (SB) and tape stripping (TS), for the analysis of selected epidermal genes (quantitative real-time reverse transcription PCR, qRT-PCR), proteins (western blotting, WB), and lipids in ten healthy volunteers. TS provided significantly less material than SB and no viable epidermal layers could be obtained according to the reflectance confocal microscopy. Consistently, only the SC protein filaggrin and housekeeping GAPDH together with FLG and RPL13A mRNA were detected by TS. In the SB samples, WB and qRT-PCR could easily detect all the selected proteins (claudin-1, occludin, filaggrin, laminin and GAPDH) and genes (CLDN1, OCLN, FLG, LAMA3 and RPL13A), respectively. A single SB sample further provided enough of material for immunohistochemistry and lipid analyses, which was not feasible with the TS samples. Immunohistochemistry of the SB samples showed intact epidermal structure and a characteristic expression of claudin-1. Infrared spectroscopy showed well-ordered lipids with both orthorhombic and hexagonal packing and high-performance thin layer chromatography confirmed all lipid classes (including ceramide subclasses) in correct proportions. Taken together, SB represents a reliable sampling technique that can be utilized for multipurpose epidermal analyses in various studies. PMID- 28905097 TI - Color Doppler and spectral Doppler ultrasound detection of active sacroiliitis in spondyloarthritis compared to physical examination as gold standard. AB - Sacroiliac joint (SIJ) involvement is a distinctive feature of spondyloarthritis (SpA). The main objective of this study was to assess the validity of color Doppler ultrasound (CDUS) in SIJ. This was a cross-sectional, blinded, case control study of 108 cases divided into three groups: (a) 53 SpA patients with inflammatory back pain (IBP); (b) 28 SpA patients with no IBP; and (c) 27 healthy mechanical lumbar pain subjects. Physical examinations of the SIJs were assessed as positive or negative in each SIJ and were used as the gold standard. SIJs were examined with CDUS and spectral Doppler, and the SIJs were assessed as positive when both color Doppler and the resistance index (RI) were less than the cut-off point within the SIJs area. A total of 108 cases (53 female; mean age 36 +/- 10 years old) were studied. The physical examination of the SIJs was positive in 38 patients (59 SIJs). Ultrasound detected Doppler signal within the SIJs in 37 cases (58 SIJs): 33 of them had symptomatic SpA (52 SIJs), 3 of them had asymptomatic SpA (5 SIJs), and 1 was a healthy control (1 SIJ). The accuracy of CDUS, when compared to physical SIJ examination, at the patient level in the overall group had a sensitivity of 70.3%, a specificity of 85.7%, a positive likelihood ratio of 4.9, and a negative likelihood ratio of 0.36. For the spectral Doppler RI, with an optimal cut-off point <=0.75, the sensitivity was 76.2%, and the specificity was 77.8%. CDUS of SIJs seems to be a feasible and valid method for detecting active inflammation in patients with SpA. PMID- 28905098 TI - Application of an Original Wildfire Smoke Health Cost Benefits Transfer Protocol to the Western US, 2005-2015. AB - Recent growth in the frequency and severity of US wildfires has led to more wildfire smoke and increased public exposure to harmful air pollutants. Populations exposed to wildfire smoke experience a variety of negative health impacts, imposing economic costs on society. However, few estimates of smoke health costs exist and none for the entire Western US, in particular, which experiences some of the largest and most intense wildfires in the US. The lack of cost estimates is troublesome because smoke health impacts are an important consideration of the overall costs of wildfire. To address this gap, this study provides the first time series estimates of PM2.5 smoke costs across mortality and several morbidity measures for the Western US over 2005-2015. This time period includes smoke from several megafires and includes years of record breaking acres burned. Smoke costs are estimated using a benefits transfer protocol developed for contexts when original health data are not available. The novelty of our protocol is that it synthesizes the literature on choices faced by researchers when conducting a smoke cost benefit transfer. On average, wildfire smoke in the Western US creates $165 million in annual morbidity and mortality health costs. PMID- 28905099 TI - Port Implantation in Patients with Severe Thrombocytopenia is Safe with Interventional Radiology. AB - PURPOSE: Platelet counts <50/nl are often considered a contraindication for surgical and interventional radiology procedures. Yet, there are patients requiring totally implantable venous access ports (TIVAP) in whom normalization of the coagulation state is not feasible. This retrospective study evaluates the safety of interventional radiological TIVAP implantation in patients with severe thrombocytopenia. MATERIALS AND METHODS: From 12/2010 to 12/2014, a total 1200 consecutive radiological TIVAP implantations were performed and retrospectively analyzed. Among those 181 patients had platelet counts (PC) below the reference value of 150-350 thrombocytes/nl: 55 patients with mild (PC: 100-150/nl), 58 patients with moderate (PC: 50-100/nl) and 68 patients with severe thrombocytopenia (PC <50/nl). All patients diagnosed with severe thrombocytopenia received platelet concentrates before or during the procedure according to a fixed preparation protocol. All patients were assessed at least 2 weeks before and up to 12 months after intervention. Outcome parameters were recorded with a particular focus on bleeding complications. Data were statistically analyzed with a p value <0.05 considered statistically significant. RESULTS: The technical success rate for TIVAP implantation was 100%. Patients were followed for a mean of 833 indwelling catheter days in patients with thrombocytopenia (total: 150.923 days) and for 936 indwelling catheter days in patients with normal platelet counts (total: 953.760 days). No significant differences in complication rates between patients with normal platelet counts and patients with mild to severe thrombocytopenia under platelet substitution were found (p > 0.05), especially no bleeding complications occurred during acute, early or late phase. CONCLUSION: With individualized platelet substitution, patients with severe thrombocytopenia may receive radiological TIVAP implantation without an increased risk of bleeding complications. LEVEL OF EVIDENCE: IV. PMID- 28905100 TI - Frequency and influencing factors of cardiopulmonary resuscitation-related injuries during implementation of the American Heart Association 2010 Guidelines: a retrospective study based on autopsy and postmortem computed tomography. AB - AIM: To determine the frequency of cardiopulmonary resuscitation (CPR)-related injuries and factors involved in their occurrence, data based on forensic autopsy and postmortem computed tomography (PMCT) during implementation of the 2010 American Heart Association Guidelines for CPR were studied. METHODS: We retrospectively evaluated data on adult patients with non-traumatic deaths who had undergone manual CPR and autopsy from January 2012 to December 2014. CPR related injuries were analyzed on autopsy records and PMCT images and compared with results of previous studies. RESULTS: In total, 180 consecutive cases were analyzed. Rib fractures and sternal fractures were most frequent (overall frequency, 66.1 and 52.8%, respectively), followed by heart injuries (12.8%) and abdominal visceral injuries (2.2%). Urgently life-threatening injuries were rare (2.8%). Older age was an independent risk factor for rib fracture [adjusted odds ratio (AOR), 1.06; 95% confidence interval (CI), 1.04-1.08; p < 0.001], >= 3 rib fractures (AOR, 1.06; 95% CI, 1.02-1.09; p = 0.002), and sternal fracture (AOR, 1.03; 95% CI, 1.01-1.05; p < 0.001). Female sex was significantly associated with sternal fracture (AOR, 2.08; 95% CI, 1.02-4.25; p = 0.04). Chest compression only by laypersons was inversely associated with rib and sternal fractures. Body mass index and in-hospital cardiac arrest were not significantly associated with any complications. The frequency of thoracic skeletal injuries was similar to that in recent autopsy-based studies. CONCLUSIONS: Implementation of the 2010 Guidelines had little impact on the frequency of CPR-related thoracic skeletal injuries or urgently life-threatening complications. Older age was the only independent factor related to thoracic skeletal injuries. PMID- 28905101 TI - Transanal minimally invasive surgery for rectal polyps and selected malignant tumors: caution concerning intermediate-term functional results. AB - PURPOSE: Transanal minimally invasive surgery (TAMIS) is gaining worldwide popularity as an alternative for the transanal endoscopic microsurgery (TEMS) method for the local excision of rectal polyps and selected neoplasms. Data on patient reported outcomes regarding short-term follow-up are scarce; data on functional outcomes for long-term follow-up is non-existent. METHODS: We used the fecal incontinence severity index (FISI) to prospectively assess the fecal continence on the intermediate-term follow-up after TAMIS. The primary outcome measure is postoperative fecal continence. Secondary outcome measures are as follows: perioperative and intermediate-term morbidity. RESULTS: Forty-two patients (m = 21:f = 21), median age 68.5 (range 34-94) years, were included in the analysis. In four patients (9.5%), postoperative complications occurred. The median follow-up was 36 months (range 24-48). Preoperative mean FISI score was 8.3 points. One year after TAMIS, mean FISI score was 5.4 points (p = 0.501). After 3 years of follow-up, mean FISI score was 10.1 points (p = 0.01). Fecal continence improved in 11 patients (26%). Continence decreased in 20 patients (47.6%) (mean FISI score 15.2 points, [range 3-31]). CONCLUSIONS: This study found that the incidence of impaired fecal continence after TAMIS is substantial; however, the clinical significance of this deterioration seems minor. The present data is helpful in acquiring informed consent and emphasizes the need of proper patient information. Functional results seem to be comparable to results after TEMS. Furthermore, we confirmed TAMIS is safe and associated with low morbidity. PMID- 28905103 TI - Influence of the MIF polymorphism -173G > C on Turkish postmenopausal women with osteoporosis. AB - BACKGROUND: MIF, a proinflammatory cytokine, contributes to the pathogenesis of acute, chronic, and autoimmune inflammatory disorders and balances the suppressive effect of glucocorticoids on the immune system. There is an interaction between bone metabolism and the immune system via the production of cytokines. We aimed to analyze the relationship between the MIF gene -173G > C promoter polymorphism and osteoporosis. METHODS: In this case-control study performed in a university hospital, 286 samples (136 women with osteoporosis and 150 healthy age-matched controls) participated. The polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) assay was used to genotype the MIF gene polymorphism. The alleles and genotypes frequencies of patients and controls were compared using the chi2 test. RESULTS: The genotype frequencies of MIF gene -173G > C polymorphism showed statistically significant differences between patients and controls (p = 0.038). Also, the subjects carrying the variant C allele in the MIF -173 position were at significantly higher risk of osteoporosis than subjects carrying the wild-type G allele (p = 0.009, odds ratio 1.7, 95% confidence interval 1.1-2.6). CONCLUSION: Our study suggested a strong association between MIF gene -173G > C polymorphism and osteoporosis in a Turkish population. PMID- 28905104 TI - Analysis of advanced glycation end products (AGEs) in dentine: useful for age estimation? AB - Ageing of the human organism results in the accumulation of modified molecules. Some of these molecular changes may be used for age estimation, as already shown for aspartic acid racemization (AAR). Another example for an accumulation of damaged molecules is advanced glycation end products (AGEs). We examined, (1) if the correlation between the concentration of AGEs (pentosidine) in root dentine and age is close enough to be used as basis for age estimation, and (2) if the combined analysis of AGEs and AAR in dentine may be a useful approach to rule out or to detect relevant effects of confounding factors in age estimation. We determined the pentosidine content of root dentine samples of 64 healthy teeth as well as in carious, "pink", diabetic and heated teeth, and in teeth after different storage times. In 23 teeth, the extent of aspartic acid racemization (AAR) was determined in parallel. We observed a close relationship between the concentration of pentosidine in dentine and chronological age (r = 0.94) in healthy teeth. The analysis of pentosidine in dentine can theoretically be used as a basis for age estimation in healthy teeth of non-diabetic individuals; diabetic individuals may exhibit very high pentosidine levels in dentine. This finding limits the application of this method, since information regarding the question if an unidentified person suffered from diabetes mellitus or not are missing in most cases. Moreover, the method is not suitable to identify or rule out the influence of confounding factors in age estimation based on AAR, since both methods are sensible to the most relevant confounding factors (caries, heat). PMID- 28905102 TI - Digestive system in psoriasis: an update. AB - Psoriasis is a chronic inflammatory immune-mediated disorder associated and often coexisting with many other immune-related clinical conditions including those affecting the gastrointestinal tract. Data obtained from the reviewed literature suggest an association between psoriasis and pathologies of the oral cavity, both psoriasis-specific lesions, as well as non-specific, such as geographic tongue or fissured tongue. These findings show the importance of thorough examination of oral mucosa in psoriatic patients. Inflammatory bowel diseases (IBD) are also linked with psoriasis. Crohn's disease and ulcerative colitis share a common genetic background, inflammatory pathways and have an evident iatrogenic anti-TNF treatment link, necessitating dermatological or gastroenterological care in patients with IBD or psoriasis, respectively, as well as treatment adjusted to manifestations. The presence of celiac disease-specific antibodies in psoriatic patients and their correlation with the severity of the disease show the association between these disorders. The linking pathogenesis comprises vitamin D deficiency, immune pathway, genetic background and increase in the intestinal permeability, which suggests a potential benefit from gluten-free diet among psoriatic patients. The link between psoriasis and non-alcoholic fatty liver disease implies screening patients for components of metabolic syndrome and lifestyle changes necessity. Some studies indicate increased prevalence of cancer in patients with psoriasis, probably due to negative influence of skin lesion impact on lifestyle rather than the role of psoriasis in carcinogenesis. However, there are no sufficient data to exclude such an oncogenic hit, which is yet to be confirmed. Therefore, all psoriasis-associated comorbidities establish the importance of a multidisciplinary approach in the treatment of these patients. PMID- 28905106 TI - Recombinant Mouse Osteocalcin Secreted by Lactococcus lactis Promotes Glucagon Like Peptide-1 Induction in STC-1 Cells. AB - An osteoblastic protein, osteocalcin (OC), exists in vivo in two forms: carboxylated OC, and uncarboxylated or low-carboxylated OC (ucOC). ucOC acts as a hormone to regulate carbon and energy metabolism. Recent studies demonstrated that ucOC exerts insulinotropic effects, mainly through the glucagon-like peptide 1 (GLP-1) pathway. GLP-1 is an insulinotropic hormone secreted by enteroendocrine L cells in the small intestine. Thus, efficient delivery of ucOC to the small intestine may be a new therapeutic option for metabolic diseases such as diabetes and obesity. Here, we genetically engineered a lactic acid bacterium, Lactococcus lactis, to produce recombinant mouse ucOC. Western blotting showed that the engineered strain (designated NZ-OC) produces and secretes the designed peptide (rOC) in the presence of nisin, an inducer of the recombinant gene. Highly purified rOC was obtained from the culture supernatants of NZ-OC using immobilized metal affinity chromatography. An in vitro assay showed that purified rOC promotes GLP-1 secretion in a mouse intestinal neuroendocrine cell line, STC 1, in a dose-dependent manner. These results clearly demonstrate that NZ-OC secretes rOC, and that rOC can promote GLP-1 secretion by STC-1 cells. Genetically modified lactic acid bacteria (gmLAB) have been proposed over the last two decades as an effective and low-cost mucosal delivery vehicle for biomedical proteins. NZ-OC may be an attractive tool for the delivery of rOC to trigger GLP-1 secretion in the small intestine to treat diabetes and obesity. PMID- 28905107 TI - Effect of changes of femoral offset on abductor and joint reaction forces in total hip arthroplasty. AB - BACKGROUND: Anatomical reconstruction in total hip arthroplasty (THA) allows for physiological muscle function, good functional outcome and implant longevity. Quantitative data on the effect of a loss or gain of femoral offset (FO) are scarce. The aim of this study was to quantitatively describe the effect of FO changes on abductor moment arms, muscle and joint reactions forces. METHODS: THA was virtually performed on 3D models built from preoperative CT scans of 15 patients undergoing THA. Virtual THA was performed with a perfectly anatomical reconstruction, a loss of 20% of FO (-FO), and a gain of 20% of FO (+FO). These models were combined with a generic musculoskeletal model (OpenSim) to predict moment arms, muscle and joint reaction forces during normal gait cycles. RESULTS: In average, with -FO reconstructions, muscle moment arms decreased, while muscle and hip forces increased significantly (p < 0.001). We observed the opposite with +FO reconstructions. Gluteus medius was more affected than gluteus minimus. -FO had more effect than +FO. A change of 20% of FO induced an average change 8% of abductor moment arms, 16% of their forces, and 6% of the joint reaction force. CONCLUSIONS: To our knowledge, this is the first report providing quantitative data on the effect of FO changes on muscle and joint forces during normal gait. A decrease of FO necessitates an increase of abductor muscle force to maintain normal gait, which in turn increases the joint reaction force. This effect underscores the importance of an accurate reconstruction of the femoral offset. PMID- 28905105 TI - Diagnostic and Prognostic Role of 18-FDG PET/CT in the Management of Resectable Biliary Tract Cancer. AB - OBJECTIVES: Role of 18-FDG PET/CT had been well established in other more prevalent malignancies such as colorectal and lung cancer; however, this is not as well defined in cholangiocarcinoma. Literature focusing on the prognostic values of preoperative PET/CT for resectable cholangiocarcinoma is scarce. METHOD: This is a retrospective cohort of 66 consecutive patients who had received curative resection for cholangiocarcinoma from 2010 to 2015. All patients had preoperative 18-FDG PET/CT performed. Accuracy of metastatic lymph node detection of PET/CT and the prognostic value of maximum standard uptake value (SUV-max) was explored. RESULTS: There were 38 male and 28 female recruited, and the median age was 66. Intrahepatic cholangiocarcinoma (ICC) constituted the majority (59.1%) of the cases, followed by hilar cholangiocarcinoma (22.8%), gallbladder cancer (13.6%) and common bile duct cancer (4.5%). The 3-year disease-free survival (DFS) and overall survival (OS) of the whole population were 27.1 and 39.2%, respectively. The median follow-up duration was 27 months. The accuracy of PET/CT in metastatic lymph node detection was 72.7% (P = 0.005, 95% CI 0.583-0.871) and 81.8% (P = 0.011, 95% CI 0.635 0.990) in whole population and ICC subgroup analysis, respectively. SUV-max was shown by multivariate analysis to be an independent factor for DFS (P = 0.007 OR 1.16, 95% CI 1.04-1.29) and OS (P = 0.012 OR 1.145, 95% CI 1.030-1.273) after resection. SUV-max of 8 was shown to be a discriminant cut-off for poor oncological outcomes in patients with early cholangiocarcinoma (TNM stage I or II) after curative resection (3-year DFS: 21.2 vs. 63.2%, P = 0.004, and 3-year OS: 29 vs. 74% P = 0.048, respectively). CONCLUSION: PET/CT is a reliable imaging modality for metastatic lymph node detection in cholangiocarcinoma. Tumour SUV max is an independent factor for oncological outcomes in patients with resectable disease. For patients who have TNM stage I or II cholangiocarcinoma, tumour SUV max over 8 is associated with significantly inferior disease-free and overall survival even after curative resection. PMID- 28905108 TI - A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002). AB - PURPOSE: A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC. METHODS: This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL). RESULTS: From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL. CONCLUSIONS: S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib. CLINICAL TRIAL REGISTRATION NO: UMIN000005308. PMID- 28905109 TI - White matter microstructure of attentional networks predicts attention and consciousness functional interactions. AB - Attention is considered as one of the pre-requisites of conscious perception. Phasic alerting and exogenous orienting improve conscious perception of near threshold information through segregated brain networks. Using a multimodal neuroimaging approach, combining data from functional MRI (fMRI) and diffusion weighted imaging (DWI), we investigated the influence of white matter properties of the ventral branch of superior longitudinal fasciculus (SLF III) in functional interactions between attentional systems and conscious perception. Results revealed that (1) reduced integrity of the left hemisphere SLF III was predictive of the neural interactions observed between exogenous orienting and conscious perception, and (2) increased integrity of the left hemisphere SLF III was predictive of the neural interactions observed between phasic alerting and conscious perception. Our results combining fMRI and DWI data demonstrate that structural properties of the white matter organization determine attentional modulations over conscious perception. PMID- 28905110 TI - [Indications and technique for transconjunctival optic nerve sheath fenestration : Video article]. AB - BACKGROUND: Placement of a ventricular shunt is the primary surgical procedure for lowering intracranial pressure in pseudotumor cerebri syndrome; however, if ophthalmological symptoms prevail over neurological symptoms or if there are no neurological symptoms at all, optic nerve sheath fenestration may be a valuable option for relief of pressure on the retrobulbar optic nerve when papilledema caused by pseudotumor cerebri syndrome threatens vision despite previous conservative measures. METHODS: This review covers the indications, technique and results of optic nerve sheath fenestration compared to competing procedures based on a systematic literature search, analysis of own cases and a documentation of the surgical technique. SURGICAL TECHNIQUE: After performing a medial transconjunctival orbitotomy the medial rectus muscle tendon is temporarily detached and the eye abducted by traction sutures. Using confocal illumination under a surgical microscope, the optic nerve can be visualized using orbital spatulas and the sheath can be punctured with a microscalpel. A video of this operation is available online. CONCLUSION: Transconjunctival optic nerve sheath fenestration is a relatively safe method to reduce the rate of visual loss in pseudotumor cerebri syndrome. In selected cases it can be a useful alternative to ventriculoperitoneal/atrial shunts or venous stents. PMID- 28905112 TI - Extracorporeal membrane oxygenation in spina bifida and (H1N1)-induced acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is characterized as an acute hypoxemic and/or hypercapnic respiratory failure seen in critically ill patients and is still, although decreased over the past few years, associated with high mortality. Furthermore, ARDS may be a life-threatening complication of H1N1 pneumonia. We report on a 45-year-old spina bifida patient with confirmed H1N1 influenza virus infection causing acute respiratory failure, who was successfully weaned from 42-day veno-venous extracorporeal membrane oxygenation (vv-ECMO) treatment with an excellent outcome. Due to the physical constitution of spina bifida patients, we experienced challenges concerning cannula positioning and mechanical ventilation settings during weaning. PMID- 28905111 TI - Maternal depressive symptoms in childhood and risky behaviours in early adolescence. AB - Longitudinal patterns of maternal depressive symptoms have yet to be linked to risky behaviours, such as substance use or violence, in early adolescence, when such behaviours may be particularly detrimental. This study was carried out to do this. Using data from the UK's Millennium Cohort Study, it modelled the effect of trajectories of maternal depressive symptoms at child ages 3, 5, 7 and 11 years on antisocial behaviour and delinquency at age 11 years (N = 12,494). It also explored their role in predicting moral judgement and attitudes to alcohol at age 11, important predictors of delinquent or antisocial behaviour and alcohol use, respectively. Latent class analysis showed four longitudinal types of maternal depressive symptoms (chronically high, consistently low, moderate-accelerating and moderate-decelerating). Maternal symptom typology predicted antisocial behaviour in males and attitudes to alcohol in females, even after adjusting for youth's age and pubertal status and after correcting for confounding. Specifically, compared to males growing up with never-depressed mothers, those exposed to chronically high or accelerating maternal depressive symptoms were more likely to report engaging in loud and rowdy behaviour, alcohol use and bullying. Females exposed to chronically high maternal depressive symptoms were more likely than those growing up with never-depressed mothers to support the view that alcohol use is harmless. While causal conclusions cannot be drawn, these findings suggest that preventing or treating maternal depressive symptoms in childhood may be a useful approach to reducing future externalising and health risk behaviours in offspring. PMID- 28905113 TI - Influence of increased heart rate and aortic pressure on resting indices of functional coronary stenosis severity. AB - : Baseline assessment of functional stenosis severity has been proposed as a practical alternative to hyperemic indices. However, intact autoregulation mechanisms may affect intracoronary hemodynamics. The aim of this study was to investigate the effect of changes in aortic pressure (Pa) and heart rate (HR) on baseline coronary hemodynamics and functional stenosis assessment. In 15 patients (55 +/- 3% diameter stenosis) Pa, intracoronary pressure (Pd) and flow velocity were obtained at control, and during atrial pacing at 120 bpm, increased Pa (+30 mmHg) with intravenous phenylephrine (PE), and elevated Pa while pacing at sinus heart rate (PE + sHR). We derived rate pressure product (RPP = systolic Pa * HR), baseline microvascular resistance (BMR = Pd/velocity), and stenosis resistance [BSR = (Pa - Pd)/velocity] as well as whole-cycle Pd/Pa. Tachycardia (120 +/- 1 bpm) raised RPP by 74% vs. CONTROL: Accordingly, BMR decreased by 27% (p < 0.01) and velocity increased by 36% (p < 0.05), while Pd/Pa decreased by 0.05 +/- 0.02 (p < 0.05) and BSR remained similar to control. Raising Pa to 121 +/- 3 mmHg (PE) with concomitant reflex bradycardia increased BMR by 26% (p < 0.001) at essentially unchanged RPP and velocity. Consequently, BSR and Pd/Pa were only marginally affected. During PE + sHR, velocity increased by 21% (p < 0.01) attributable to a 46% higher RPP (p < 0.001). However, BMR, BSR, and Pd/Pa remained statistically unaffected. Nonetheless, the interventions tended to increase functional stenosis severity, causing Pd/Pa and BSR of borderline lesions to cross the diagnostic threshold. In conclusion, coronary microvascular adaptation to physiological conditions affecting metabolic demand at rest influences intracoronary hemodynamics, which may lead to altered basal stenosis indices used for clinical decision-making. PMID- 28905114 TI - Long-term outcomes of microvascular decompression and Gamma Knife surgery for trigeminal neuralgia: a retrospective comparison study. AB - BACKGROUND: There is still no clear guideline for surgical treatment for patients with medically refractory trigeminal neuralgia (TN). When it comes to which surgical treatment to choose, microvascular decompression (MVD) or Gamma Knife surgery (GKS), we should know the long-term outcome of each treatment. METHODS: We analyzed 179 patients undergoing MVD and 52 patients undergoing GKS followed for 1 year or longer. We evaluated the patient's neurological status including pain relief, complications and recurrence. Results were assessed with Barrow Neurological Institute (BNI) pain intensity and facial numbness scores. Overall outcomes were compared between the two groups based on pain relief and complications. RESULTS: BNI pain intensity and facial numbness scores at the final visit were significantly lower in the MVD group than in the GKS group (P < 0.001, P = 0.04, respectively). Overall outcomes were superior following MVD than following GKS (P < 0.001). Following whichever treatment, there were initially high rates of pain-free status "without medication": 96.6% in the MVD group and 96.2% in the GKS group. However, 6.1% in the MVD group and 51.9% in the GKS group fell into a "with medication" state within median periods of 1.83 and 3.92 years, respectively (P < 0.001). Kaplan-Meier analysis revealed that pain recurred more often and later in the GKS group than in the MVD group (P < 0.001). CONCLUSIONS: Considering the long-term outcomes, MVD should be chosen as the initial surgical treatment for patients with medically refractory TN. PMID- 28905115 TI - Clinical application of SNP array analysis in fetuses with ventricular septal defects and normal karyotypes. AB - PURPOSE: The present study aims to evaluate the utility of high-resolution single nucleotide polymorphism (SNP) arrays in fetuses with ventricular septal defects (VSDs) with or without other structural anomalies but with normal karyotypes and to investigate the outcomes of cases of prenatal VSDs via clinical follow-up. METHODS: We analyzed 144 fetuses with VSDs and normal karyotypes using Affymetrix CytoScan HD arrays and the analyses were carried out a year after birth. RESULTS: Clinically significant CNVs were detected in 12 fetuses (8.3%). The most common pathogenic CNV was a 22q11.2 deletion with a detection rate of 2.8% (4/144). Well known microdeletion or microduplication syndromes, including Smith-Magenis, Miller-Dieker, 9q subtelomeric deletion, 1p36 microdeletion, 1q21.1 microduplication, and terminal 4q deletion syndrome, were identified in six cases. Three regions of chromosomal imbalance were also identified: microduplication at 12q24.32q24.33, microdeletion at 16p13.13p13.12 and microdeletion at Xp21.1. The genes TBX1, SKI, GJA5, EHMT1, NOTCH1 were identified as established genes and LZTR1, PRDM26, YWHAE, FAT1, AKAP10, ERCC4, and ULK1 were identified as potential candidate genes of fetal VSDs. There was no significant difference in pathogenic CNVs between isolated VSDs and VSDs with additional structural abnormalities. Ninety-five (74.8%) pregnant women with fetuses with benign CNVs chose to continue the pregnancy and had a favorable prognosis, while nine (75%) pregnant women with fetuses with pathogenic CNVs chose to terminate the pregnancy. CONCLUSIONS: High-resolution SNP arrays are valuable tools for identifying submicroscopic chromosomal abnormalities in the prenatal diagnosis of VSDs. An excellent outcome can be expected for VSD fetuses that are negative for chromosomal anomalies and other severe anatomic abnormalities. PMID- 28905116 TI - [Teledermoscopy by mobile phones : Reliable help in the diagnosis of skin lesions?] AB - BACKGROUND: Teledermoscopy is a promising modern technique to complement or to substitute dermatologic examination. OBJECTIVE: In this pilot study, we compared the outcomes of teledermoscopic consultations with clinical examinations and histologic results. METHODS: Conventional and dermatoscopic photos of single lesions were taken in 26 patients using a mobile phone and an attached handyscope optical system. Five resident physicians performed a clinical examination including dermoscopy while the teledermatologic and teledermoscopic photos were assessed by an experienced dermatologist. Examination results were compared regarding diagnosis, differential diagnoses, recommended further management, as well as subjective and objective accuracy of diagnosis. In addition, 23% of the lesions were excised and histologically examined. RESULTS: The most frequent diagnosis was "nevus cell nevus", followed by "subungual hematoma" and "basal cell carcinoma". The concordance of diagnoses was 92.3%; the concordance of recommended further management was 76.9%. Of the 6 histologically proven diagnoses, 66.7% were given the same diagnosis by teledermatoscopy and conventional clinical assessment. Concerning accuracy of diagnosis, teledermoscopy showed no disadvantage. CONCLUSIONS: Teledermatologic photos of single lesions combined with teledermatoscopic photos can be reliably and safely assessed. Especially when access to dermatologic examination is difficult, mobile teledermoscopy is a good and reliable alternative. PMID- 28905117 TI - Mechanical characteristics of the maxillary sinus Schneiderian membrane ex vivo. AB - OBJECTIVES: It has been speculated that certain Schneiderian membrane thickness (SMT) might be more prone to perforation. This investigation was aimed at studying the mechanical characteristics of the Schneiderian membrane under one- and two-dimensional tests and their correlation to the histological SMT in human samples. MATERIAL AND METHODS: Sixteen Schneiderian membranes were collected from 11 cadaver heads treated with Thiel's embalming method. The samples were processed and analyzed clinically and histologically. One-dimensional maximum elongation until perforation and two-dimensional resistance to ball penetration were performed after the biopsy. Data was analyzed by using the Wilcoxon rank test and the Spearman's rank correlation. RESULTS: The histological SMT was 1.36 +/- 0.42 mm, whereas the clinical thickness was 0.27 +/- 0.21 mm, yielding statistical significance (p = 0.000). The resistance under ball penetration was 0.59 +/- 0.43 N and the mean maximum elongation in the one-dimension test 11.19 +/- 7.14 mm. Expressed in percentage, the mean stretch was 241.36 +/- 227.97% (range 31.5 up to 947%). A weak positive correlation was found between the ball penetration test and the SMT (r = 0.10, p = 0.711), while a weak negative correlation was found between stretching test and the SMT (r = -0.021, p = 0.94). CONCLUSIONS: Mechanical tests seem to indicate that SMT might not significantly predispose to Schneiderian membrane perforation. Hence, other anatomical and operator's factors should be considered of surpassing importance. CLINICAL RELEVANCE: Thinner SM might be more prone to perforation when detaching it from the maxillary sinus antrum; however, a thick membrane is not prevented to tear, as their resistance under elastic forces is not higher than thinner ones. PMID- 28905118 TI - Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression. AB - The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect. The minimal effective dose was 10 MUg each. The effect was dependent on CD8 T cells. Intratumoral administration resulted in superior local and distant tumor control compared to systemic routes, supporting the in situ vaccine concept. In a single tumor A20 model, injection close to the tDLN resulted in similar efficacy as intratumoral and significantly better than targeting a non-tDLN, supporting the role of the tDLN as a viable immunotherapy target in addition to the tumor itself. Distribution studies confirmed expected concentration of antibodies in tumor and tDLN, in keeping with the anti-tumor results. Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration. PMID- 28905120 TI - Animal and human bite injuries: a 5-year retrospective study in a large urban public hospital in Venezuela. AB - INTRODUCTION: Animal bite injuries to the head and neck regions are an important public health problem. Most of these bites are from dogs. A 10-year retrospective study was undertaken to determine the prevalence of animal and human bites. MATERIALS AND METHODS: This retrospective study was done from January 2011 to December 2016 and included 387 patients with a mean age of 21.51 years. Data collection included age, sex, days of hospitalization, lesion type, and clinical management. RESULTS: Majority of patients were in age group of 21-29 years, followed by 31-55 years. Out of the total 281 patients, 42 patients (51.60%) were males and 34 patients (48.40%) were females. Mean hospital stay was 7.2 days with a minimum of 5 days and a maximum of 12 days. Surgical management included cleansing and primary closure of the wound. CONCLUSIONS: We concluded that the use of empiric antibiotic prophylaxis is essential for management of facial animal bite, and the antibiotic of first choice is amoxicillin-clavulanic acid. The aim of immediate surgical repair (< 6 h) is to avoid infections. The persistence of dog bite is public health problem in Venezuela. PMID- 28905119 TI - Jasmonic acid-induced tolerance to root-knot nematodes in tomato plants through altered photosynthetic and antioxidative defense mechanisms. AB - Plant parasitic nematodes cause severe damage to cultivated crops globally. Management of nematode population is a major concern as chemicals used as nematicides have negative impact on the environment. Natural plant products can be safely used for the control of nematodes. Among various plant metabolites, plant hormones play an essential role in developmental and physiological processes and also assist the plants to encounter stressful conditions. Keeping this in mind, the present study was designed to evaluate the effect of jasmonic acid (JA) on the growth, pigments, polyphenols, antioxidants, osmolytes, and organic acids under nematode infection in tomato seedlings. It was observed that nematode inoculation reduced the growth of seedlings. Treatment with JA improved root growth (32.79%), total chlorophylls (71.51%), xanthophylls (94.63%), anthocyanins (37.5%), and flavonoids content (21.11%) when compared to inoculated seedlings alone. The JA application enhanced the total antioxidant capacity (lipid- and water-soluble antioxidants) by 38.23 and 34.37%, respectively, in comparison to infected seedlings. Confocal studies revealed that there was higher accumulation of glutathione in hormone-treated seedlings under nematode infection. Treatment with JA increased total polyphenols content (74.56%) in comparison to nematode-infested seedlings. JA-treated seedlings also enhanced osmolyte and organic acid contents under nematode stress. Overall, treatment with JA improved growth, enhanced pigment levels, modulated antioxidant content, and enhanced osmolyte and organic acid content in nematode-infected seedlings. PMID- 28905121 TI - A probabilistic atlas of fiber crossings for variability reduction of anisotropy measures. AB - Diffusion imaging enables assessment of human brain white matter (WM) in vivo. WM microstructural integrity is routinely quantified via fractional anisotropy (FA). However, FA is also influenced by the number of differentially oriented fiber populations per voxel. To date, the precise statistical relationship between FA and fiber populations has not been characterized, complicating microstructural integrity assessment. Here, we used 630 state-of-the-art diffusion datasets from the Human Connectome Project, which allowed us to infer the number of fiber populations per voxel in a model-free fashion. Beyond the known impact on mean FA, variance of anisotropy distributions was drastically impacted, not only for FA, but also the more recent anisotropy indices generalized FA and multidimensional anisotropy. To ameliorate this bias, we introduce a probabilistic WM atlas delineating the number of distinctly oriented fiber populations per voxel. Our atlas shows that the majority of WM voxels features two differentially directed fiber populations (44.7%) rather than unidirectional fibers (32.9%) and identified WM regions with high numbers of crossing fibers, referred to as crossing pockets. Compartmentalizing anisotropy drastically reduced variance in group comparisons ranging from the whole brain to a few voxels in a single slice. In summary, we demonstrate a systematic effect of intra voxel diffusion inhomogeneity on anisotropy. Moreover, we introduce a potential solution: The provided probabilistic WM atlas can easily be used with any given diffusion dataset to enhance the statistical robustness of anisotropy measures and increase their neurobiological utility. PMID- 28905122 TI - Static and free-vibration analyses of dental prosthesis and atherosclerotic human artery by refined finite element models. AB - Static and modal responses of representative biomechanical structures are investigated in this paper by employing higher-order theories of structures and finite element approximations. Refined models are implemented in the domain of the Carrera unified formulation (CUF), according to which low- to high-order kinematics can be postulated as arbitrary and, eventually, hierarchical expansions of the generalized displacement unknowns. By using CUF along with the principle of virtual work, the governing equations are expressed in terms of fundamental nuclei of finite element arrays. The fundamental nuclei are invariant of the theory approximation order and can be opportunely employed to implement variable kinematics theories of bio-structures. In this work, static and free vibration analyses of an atherosclerotic plaque of a human artery and a dental prosthesis are discussed. The results from the proposed methodologies highlight a number of advantages of CUF models with respect to already established theories and commercial software tools. Namely, (i) CUF models can represent correctly the higher-order phenomena related to complex stress/strain field distributions and coupled mode shapes; (ii) bio-structures can be modeled in a component-wise sense by only employing the physical boundaries of the problem domain and without making any geometrical simplification. This latter aspect, in particular, can be currently accomplished only by using three-dimensional analysis, which may be computationally unbearable as complex bio-systems are considered. PMID- 28905123 TI - No difference between manual and different power toothbrushes with and without specific instructions in young, oral healthy adults-results of a randomized clinical trial. AB - BACKGROUND: The aim of this randomized clinical study was to detect the effect of an instruction within a group using oscillating-rotating (OR), sonic-active (SA), or manual toothbrushes (MTB) in young, oral healthy adults. METHODS: One hundred fifty participants were randomly assigned into six groups (n = 25): with (OR-I, SA-I, MTB-I) and without instruction (OR-NI, SA-NI, MTB-NI). Participants in I subgroups received one standardized instruction of the toothbrush system. At baseline (t0), after 2 (t1), 4 (t2), and 12 weeks (t3), plaque indices including modified Quigley-Hein Index (QHI) and Marginal Plaque Index (MPI) as well as inflammation indices including Papilla Bleeding Index (PBI) and Gingival Index (GI) were assessed. Kruskal-Wallis test, Friedman test, and chi-square or Fisher's exact test (p < 0.05) were used for statistical analysis. RESULTS: One hundred thirty-one participants completed the follow-up and were analyzed: OR-I = 21, OR-NI = 22, SA-I = 22, SA-NI = 22, MTB-I = 22, and MTB-NI = 22. Within groups between t0 and t3, OR and SA systems showed a significant plaque reduction, irrespective of instruction (p i < 0.05). In MTB-I and in SA-NI subgroups, a reduction of GI was detected, while an improvement in PBI within SA-I was found (p i < 0.05). Thereby, after 12 weeks, gingival inflammation and plaque indices were comparable between all subgroups (p i > 0.05). Irrespective of the toothbrush system used, only QHI was positively influenced by instruction (p < 0.01). CONCLUSION: The used toothbrush as well as the presence or absence of a single brush-specific instruction has no influence on plaque removal and reduction of gingival inflammation in young, oral healthy adults in an observation period of 12 weeks. CLINICAL RELEVANCE: A single instruction might bring no benefit in this patient group, independently of the used toothbrush system. PMID- 28905124 TI - Arthritic psoriasis during natalizumab treatment: a case report and review of the literature. PMID- 28905125 TI - Biometeorological forecasts for health surveillance and prevention of meteor tropic effects. AB - An early method of biometeorological forecasts was developed for Cuba during the late 90s. It was based on the relationship between the daily occurrence of massive health crisis and the magnitude of the 24-h differences of partial density of oxygen in the air (PODA index). Ten years later, applying new technological facilities, a new model was developed in order to offer operational biometeorological forecast to Cuban health institutions. After a satisfactory validation process, the official bioforecast service to health institutions in Villa Clara province began on February of 2012. The effectiveness had different success levels: for the bronchial asthma crisis (94%), in the hypertensive crisis (88%), with the cerebrovascular illnesses (85%), as well as migraines (82%) and in case of cardiovascular diseases (75%) were acceptable. Since 2008, the application of the model was extended to other regions of the world, including some national applications. Furthermore, it allowed the beginning of regional monitoring of meteor-tropic effects, following the occurrence and movement of areas with higher weather contrasts, defined according to the normalized scale of PODA index. The paper describes the main regional results already available, with emphasis in the observed meteor-tropic effects increasing in all regions during recent years. It coincides with the general increase of energy imbalance in the whole climate system. Finally, the paper describes the current development of new global biometeorological forecast services. PMID- 28905126 TI - Neuroanatomical correlates of haptic object processing: combined evidence from tractography and functional neuroimaging. AB - Touch delivers a wealth of information already from birth, helping infants to acquire knowledge about a variety of important object properties using their hands. Despite the fact that we are touch experts as much as we are visual experts, surprisingly, little is known how our perceptual ability in touch is linked to either functional or structural aspects of the brain. The present study, therefore, investigates and identifies neuroanatomical correlates of haptic perceptual performance using a novel, multi-modal approach. For this, participants' performance in a difficult shape categorization task was first measured in the haptic domain. Using a multi-modal functional magnetic resonance imaging and diffusion-weighted magnetic resonance imaging analysis pipeline, functionally defined and anatomically constrained white-matter pathways were extracted and their microstructural characteristics correlated with individual variability in haptic categorization performance. Controlling for the effects of age, total intracranial volume and head movements in the regression model, haptic performance was found to correlate significantly with higher axial diffusivity in functionally defined superior longitudinal fasciculus (fSLF) linking frontal and parietal areas. These results were further localized in specific sub-parts of fSLF. Using additional data from a second group of participants, who first learned the categories in the visual domain and then transferred to the haptic domain, haptic performance correlates were obtained in the functionally defined inferior longitudinal fasciculus. Our results implicate SLF linking frontal and parietal areas as an important white-matter track in processing touch-specific information during object processing, whereas ILF relays visually learned information during haptic processing. Taken together, the present results chart for the first time potential neuroanatomical correlates and interactions of touch related object processing. PMID- 28905127 TI - ADHD is associated with migraine: a systematic review and meta-analysis. AB - An association between primary headaches and attention-deficit/hyperactivity disorder (ADHD) has long been suggested. Moreover, headache is regarded as a common side effect of stimulants, the most effective treatment for ADHD. So far, no systematic review has evaluated the potential association between ADHD and headache. We performed a systematic review of the literature and a meta-analysis of all reported studies on ADHD and primary headaches. Our analysis showed a positive association between ADHD and migraine (OR 1.322, 95% CI 1.018-1717, p value 0.036), but not with tension-type headache. There is a significant association between migraine and ADHD. The mechanisms underlying this association remain to be elucidated, warranting further studies. PMID- 28905128 TI - Women's Subjective Experiences of Living with Vulvodynia: A Systematic Review and Meta-Ethnography. AB - Vulvodynia, the experience of an idiopathic pain in the form of burning, soreness, or throbbing in the vulval area, affects around 4-16% of the population. The current review used systematic search strategies and meta ethnography as a means of identifying, analyzing, and synthesizing the existing literature pertaining to women's subjective experiences of living with vulvodynia. Four key concepts were identified: (1) Social Constructions: Sex, Women, and Femininity: Women experienced negative consequences of social narratives around womanhood, sexuality, and femininity, including the prioritization of penetrative sex, the belief that it is the role of women to provide sex for men, and media portrayals of sex as easy and natural. (2) Seeking Help: Women experienced the healthcare system as dismissive, sometimes being prescribed treatments that exacerbated the experience of pain. (3) Psychological and Relational Impact of Vulvodynia: Women experienced feeling shame and guilt, which in turn led to the experience of psychological distress, low mood, anxiety, and low self-esteem. Moreover, women reported feeling silenced which in turn affected their heterosexual relationships and their peer relationships by feeling social isolated. (4) A Way Forward: Women found changing narratives, as well as group and individual multidisciplinary approaches, helpful in managing vulvodynia. The findings of the review conclude that interventions at the individual level, as well as interventions aimed at equipping women to challenge social narratives, may be helpful for the psychological well-being of women with vulvodynia. PMID- 28905129 TI - Trauma exposure and post-traumatic stress disorder in a cohort of pregnant Peruvian women. AB - Women have a higher prevalence of post-traumatic stress disorder (PTSD) than men, with a peak during the reproductive years. PTSD during pregnancy adversely impacts maternal and infant health outcomes. The objectives of this study were to estimate the prevalence of antepartum PTSD symptoms in a population of pregnant Peruvian women and to examine the impact of number of traumatic events and type of trauma experienced. The Traumatic Events Questionnaire was used to collect data about traumatic exposures. The Post-traumatic Stress Disorder Checklist Civilian Version (PCL-C) was used to assess PTSD. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). Three thousand three hundred seventy-two pregnant women were interviewed. Of the 2920 who reported experiencing one or more traumatic events, 41.8% met criteria for PTSD (PCL-C score >= 26). A quarter of participants had experienced four or more traumas, and 60.5% of those women had PTSD. Interpersonal trauma was most strongly associated with PTSD (aOR, 3.20; 95% CI, 2.74-3.74), followed by unspeakable trauma (aOR, 2.87; 95% CI, 2.35-3.50), and structural trauma (aOR, 1.39; 95% CI, 1.15-1.67). These findings indicate the high prevalence of PTSD during pregnancy in the Peruvian population, which is relevant to other countries suffering from terrorism, war, or high rates of violence. This underscores the importance of screening for PTSD in pregnancy. PMID- 28905130 TI - Clinico-serologic features of statin-induced necrotising autoimmune myopathy in a single-centre cohort. AB - Statin-induced necrotising autoimmune myopathy (NAM) is a rare but disabling complication of statin therapy. Data regarding treatment and outcomes in these patients is sparse. We retrospectively identified those patients with a diagnosis of statin-induced NAM who were managed in a single-tertiary referral centre from January 2014 to January 2017. Data regarding clinical features, serology, antibody status and functional outcome was collected. We identified 16 patients diagnosed with statin-induced NAM. Truncal weakness was present in 9/16 patients, of which one patient presented with camptocormia. Following treatment, the mean improvement in the 8-point manual muscle test (MMT8) score was 11 points (range 1 25). Antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were detected in 8/14 patients tested. Of patients who were HMGCR positive, 7/8 had significant truncal weakness, compared with 1/6 who were anti-HMGCR negative. In 4/7 patients who had anti-HMGCR retested following treatment, these antibodies subsequently became undetectable. The disappearance of anti-HMGCR was accompanied by sustained clinical improvement in all four patients. The mean Karnofsky Performance Status (KPS) prior to diagnosis was 89/100, and at latest follow-up had fallen to 68/100. We report a novel association of anti-HMGCR antibodies with truncal weakness in patients with statin-induced NAM. Functional impairments persist despite normalisation of muscle strength. Anti-HMGCR antibodies may disappear with treatment, paralleled by clinical remission of disease. Further prospective clinical trials are needed to determine optimal management strategies for statin-induced NAM. PMID- 28905132 TI - Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture using Genomics and Epidemiology (PAGE) consortium. AB - AIMS/HYPOTHESIS: Elevated levels of fasting glucose and fasting insulin in non diabetic individuals are markers of dysregulation of glucose metabolism and are strong risk factors for type 2 diabetes. Genome-wide association studies have discovered over 50 SNPs associated with these traits. Most of these loci were discovered in European populations and have not been tested in a well-powered multi-ethnic study. We hypothesised that a large, ancestrally diverse, fine mapping genetic study of glycaemic traits would identify novel and population specific associations that were previously undetectable by European-centric studies. METHODS: A multiethnic study of up to 26,760 unrelated individuals without diabetes, of predominantly Hispanic/Latino and African ancestries, were genotyped using the Metabochip. Transethnic meta-analysis of racial/ethnic specific linear regression analyses were performed for fasting glucose and fasting insulin. We attempted to replicate 39 fasting glucose and 17 fasting insulin loci. Genetic fine-mapping was performed through sequential conditional analyses in 15 regions that included both the initially reported SNP association(s) and denser coverage of SNP markers. In addition, Metabochip-wide analyses were performed to discover novel fasting glucose and fasting insulin loci. The most significant SNP associations were further examined using bioinformatic functional annotation. RESULTS: Previously reported SNP associations were significantly replicated (p <= 0.05) in 31/39 fasting glucose loci and 14/17 fasting insulin loci. Eleven glycaemic trait loci were refined to a smaller list of potentially causal variants through transethnic meta-analysis. Stepwise conditional analysis identified two loci with independent secondary signals (G6PC2-rs477224 and GCK-rs2908290), which had not previously been reported. Population-specific conditional analyses identified an independent signal in G6PC2 tagged by the rare variant rs77719485 in African ancestry. Further Metabochip-wide analysis uncovered one novel fasting insulin locus at SLC17A2-rs75862513. CONCLUSIONS/INTERPRETATION: These findings suggest that while glycaemic trait loci often have generalisable effects across the studied populations, transethnic genetic studies help to prioritise likely functional SNPs, identify novel associations that may be population-specific and in turn have the potential to influence screening efforts or therapeutic discoveries. DATA AVAILABILITY: The summary statistics from each of the ancestry-specific and transethnic (combined ancestry) results can be found under the PAGE study on dbGaP here: https://www.ncbi.nlm.nih.gov/projects/gap/cgi bin/study.cgi?study_id=phs000356.v1.p1. PMID- 28905133 TI - RABBIT risk score and ICU admission due to infection in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) patients are at increased risk of infection. Aim of the present study was to investigate whether RA patients admitted to an intensive care unit (ICU) due to infection have higher Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk scores compared to control RA patients. Seventy four RA patients (32.4% male) admitted to an ICU due to infection (from January 2002 to December 2013) and 74 frequency-matched control RA patients (16.2% male) were included in this cross-sectional study. There was strong evidence for a higher RABBIT risk score in ICU patients (median 2.0; IQR 1.3-3.2) as compared to controls (1.3; IQR 0.8-2.0; p < 0.0001). Traditional disease-modifying anti rheumatic drugs (DMARDs) (82.4 vs 64.9%; p = 0.015) and biological DMARDs (28.4 vs 14.9%; p = 0.012) were more frequently given to RA patients without ICU admission. Glucocorticoid users were more frequently found in the ICU group (51.4 vs 31.1%; p = 0.012). In a multivariable analysis tDMARD use was associated with lower (OR 0.38; 95% CI 0.15-0.93; p = 0.034) and glucocorticoid use with borderline higher odds of ICU admission (OR 2.05; 95% CI 0.92-4.58; p = 0.078). Chronic obstructive pulmonary disease (OR 2.89; 95% CI 1.10-7.54; p = 0.03), chronic kidney disease (OR 16.08; 95% CI 2.00-129.48; p = 0.009), and age category (OR 2.67; 95% CI 1.46-4.87; p = 0.001) were strongly associated with ICU admission. There was a strong trend towards higher odds of ICU admission with increasing RABBIT risk score. Use of tDMARDs was associated with lower odds of ICU admission. In an adjusted analysis, bDMARDs were not associated with ICU admission. COPD, CKD, and age were strong risk factors for ICU admission. PMID- 28905131 TI - Exploring evidence of positive selection signatures in cattle breeds selected for different traits. AB - Since domestication, the genome landscape of cattle has been changing due to natural and artificial selection forces resulting in several general and specialized cattle breeds of the world. Identifying genomic regions affected due to these forces in livestock gives an insight into the history of selection for economically important traits and genetic adaptation to specific environments of the populations under consideration. This study explores the genes/genomic regions under selection in relation to the phenotypes of Holstein, Hanwoo, and N'Dama cattle breeds using Tajima's D, XP-CLR, and XP-EHH population statistical methods. The whole genomes of 10 Holstein (South Korea), 11 Hanwoo (South Korea), and 10 N'Dama (West Africa-Guinea) cattle breeds re-sequenced to ~11x coverage and retained 37 million SNPs were used for the study. Selection signature analysis revealed 441, 512, and 461 genes under selection from Holstein, Hanwoo, and N'Dama cattle breeds, respectively. Among all these, seven genes including ARFGAP3, SNORA70, and other RNA genes were common between the breeds. From each of the gene lists, significant functional annotation cluster terms including milk protein and thyroid hormone signaling pathway (Holstein), histone acetyltransferase activity (Hanwoo), and renin secretion (N'Dama) were enriched. Genes that are related to the phenotypes of the respective breeds were also identified. Moreover, significant breed-specific missense variants were identified in CSN3, PAPPA2 (Holstein), C1orf116 (Hanwoo), and COMMD1 (N'Dama) genes. The genes identified from this study provide an insight into the biological mechanisms and pathways that are important in cattle breeds selected for different traits of economic significance. PMID- 28905134 TI - Postmortem MR diffusion-weighted imaging of the liver: time-behavior of the hepatic apparent diffusion coefficient in the early death interval. AB - OBJECTIVE: The objective of this study is to assess postmortem changes of the hepatic apparent diffusion coefficient (ADC) at multiple time points in the time interval of 16 hours postmortem in comparison to in vivo controls and to literature data. MATERIAL AND METHODS: Hepatic diffusion-weighted imaging (DWI) was repeatedly performed at 1.5 Tesla (b values 50, 400, and 800 s/mm2) in 2 hourly steps within 16 hours postmortem in 19 cases (male to female 13:6, mean age 68.5 +/- 12.2 years) and 5 in vivo controls. The core body temperature was measured rectally prior to every scan. Mean ADC values were calculated from regions of interest (ROIs) and compared to in vivo healthy controls and to literature data of normal liver parenchyma. Spearman rank correlation and Levenberg-Marquardt algorithm were used to assess a relationship between postmortem core body temperature and ADC values. RESULTS: Mean hepatic ADC values were significantly lower in postmortem cases than in in vivo controls (52.0 +/- 15.0 . 10-5 mm2/s vs. 111.0 +/- 15.7 . 10-5 mm2/s, p < 0.0001). The ex vivo liver ADC correlated inversely to calculated liver temperature (-3.5 +/- 0.8) . 10-5 mm2/s/ degrees C, r = -0.44, p < 0.0001. At low calculated liver temperature (< 30 degrees C), the ADC described an average increase of (22 +/- 10) . 10-5 mm2/s/ degrees C. CONCLUSION: Hepatic ADC values show a characteristic change in the immediate 16 hours postmortem, which is influenced by the postmortem liver temperature change. With the knowledge of characteristic postmortem liver changes, diffusion-weighted imaging could be added to conventional postmortem MRI for virtual autopsy. PMID- 28905135 TI - A case of reversible anti-NMDA-receptor encephalitis: neuropsychological and neuroradiological features. AB - Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune encephalitis mainly affecting young women. We report a case of a mild paraneoplastic anti-NMDAR encephalitis in a 31-year-old female with an ovarian immature teratoma. The patient exhibited a severe short-term episodic memory impairment and psychiatric symptoms. A detailed diagnostic work-up including complete clinical and laboratory examinations, neuropsychological assessments, and neuroradiological investigations has been done at the onset and during follow up. The amnestic syndrome and MRI medial-temporal abnormalities reversed after medical and surgical treatment. The present report indicates that the disease can be rapidly reversible if promptly diagnosed and treated. While the disease has already been described elsewhere, the course of neurospychological deficits in adults is not as much known. Usually, when the diagnosis of anti-NMDAR encephalitis is made, the severity of the disease makes the assessment of the neuropsycological profile particulary challenging. The present report is of interest because it describes the complete neuropsychological profile of a mild form of anti-NMDAR encephalitis. PMID- 28905136 TI - Highly sensitive detection of ESR1 mutations in cell-free DNA from patients with metastatic breast cancer using molecular barcode sequencing. AB - PURPOSE: We aimed to develop a highly sensitive method to detect ESR1 mutations in cell-free DNA (cfDNA) using next-generation sequencing with molecular barcode (MB-NGS) targeting the hotspot segment (c.1600-1713). METHODS: The sensitivity of MB-NGS was tested using serially diluted ESR1 mutant DNA and then cfDNA samples from 34 patients with metastatic breast cancer were analyzed with MB-NGS. The results of MB-NGS were validated in comparison with conventional NGS and droplet digital PCR (ddPCR). RESULTS: MB-NGS showed a higher sensitivity (0.1%) than NGS without barcode (1%) by reducing background errors. Of the cfDNA samples from 34 patients with metastatic breast cancer, NGS without barcode revealed seven mutations in six patients (17.6%) and MB-NGS revealed six additional mutations including three mutations not reported in the COSMIC database of breast cancer, resulting in total 13 ESR1 mutations in ten patients (29.4%). Regarding the three hotspot mutations, all the patients with mutations detected by MB-NGS had identical mutations detected by droplet digital PCR (ddPCR), and mutant allele frequency correlated very well between both (r = 0.850, p < 0.01). Moreover, all the patients without these mutations by MB-NGS were found to have no mutations by ddPCR. CONCLUSION: In conclusion, MB-NGS could successfully detect ESR1 mutations in cfDNA with a higher sensitivity of 0.1% than conventional NGS and was considered as clinically useful as ddPCR. PMID- 28905137 TI - The quality assessment of clinical practice guidelines for intracranial aneurysms: a systematic appraisal. AB - Intracranial aneurysms are common in adults. The relevant guidelines for patients with intracranial aneurysms aim to standardize the clinical practice and decision making for these patients. However, their management is controversial, and the quality of the guidelines has not been assessed. We aim to evaluate the quality of the guidelines for intracranial aneurysms as well as to compare and analyze the recommendations between different guidelines. Systematic searches were conducted to identify the guidelines for intracranial aneurysms from general electronic and guideline databases. Two independent reviewers identified the guidelines and extracted the data, and four reviewers independently evaluated the eligible guidelines through the AGREE II tool. Agreement among reviewers was measured using the intraclass correlation coefficient. A total of 12 guidelines, which were published from 1997 to 2016, were included. The agreement among reviewers was high (intraclass correlation coefficient, 0.85 (95% CI: 0.8-0.89)). The mean scores of six domains ranged from 16.5 to 57.5% (scope and purpose 57.5% (39-68%); stakeholder 30.8% (19-46%); rigor 31.9% (19-52%); clarity 57.2% (42 79%); applicability 24.9% (16-42%); and editorial independence: 16.5% (0-58%)). Furthermore, 202 recommendations related to intracranial aneurysms were collected from the included guidelines. Of these, 143 reported the quality of evidence and/or strength, and 119 reported both the quality of evidence and the strength. Of the 119 recommendations, there were six class A and 20 class B recommendations based on level III evidence. There were 12 recommendations in which the contents were similar between different guidelines and two recommendations with the opposite contents. The AGREE II scores of the guidelines for intracranial aneurysms were relatively low. The majority of recommendations were rated as classes A and B and based on levels II and III evidence. Approximately a fifth of strong recommendations was based on a low quality of evidence without interpretation or explanation. PMID- 28905138 TI - The Effectiveness of a Knowledge Translation Cognitive-Educational Intervention for Family Members of Persons Coping with Severe Mental Illness. AB - Keshet, a course for family members of persons' coping with mental illness, was developed to enhance positive family cognitive communication skills. Improving communication with the use of mediation techniques, primarily used by therapists, creates a learning environment viewed as a strategy of Knowledge Translation. To examine the effectiveness of Keshet in improving attitudes, problem solving, communication skills and attenuation of burden a quasi-experimental research design was applied with study and control condition. The same group of participants (N = 38) completed questionnaires at different stages: 3 months prior to course, initiation and completion. Following participation, significant changes were observed in attitudes regarding knowledge of how to cope and interact with family member. A correlation was found between improved knowledge and decline in burden. Implementing interventions which provide caregivers with professional "know-how" leads to lessened burden, thus contributing to maintaining well-being of family caregiver population. PMID- 28905139 TI - Fine-tuning indications for laparoscopic ventral mesh rectopexy. PMID- 28905140 TI - Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease. AB - BACKGROUND: Maple syrup urine disease (MSUD) is a rare disease that requires a protein-restricted diet for successful management. Little is known, however, about the psychosocial outcome of MSUD patients. This study investigates the relationship between metabolic and clinical parameters and psychosocial outcomes in a cohort of patients with neonatal-onset MSUD. METHODS: Data on academic achievement, psychological care, family involvement, and biochemical parameters were collected from the medical records of neonatal MSUD patients treated at Necker Hospital (Paris) between 1964 and 2013. RESULTS: Thirty-five MSUD patients with a mean age of 16.3 (2.1-49.0) years participated. Metabolic decompensations (plasma leucine >380 MUmol/L) were more frequent during the first year of life and after 15 years, mainly due to infection and dietary noncompliance, respectively. Leucine levels increased significantly in adulthood: 61.5% of adults were independent and achieved adequate social and professional integration; 56% needed occasional or sustained psychological or psychiatric care (8/19, with externalizing, mood, emotional, and anxiety disorders being the most common). Patients needing psychiatric care were significantly older [mean and standard deviation (SD) 22.6 (7.7) years] than patients needing only psychological follow-up [mean (SD) 14.3 (8.9) years]. Patients with psychological follow-up experienced the highest lifetime number of decompensations; 45% of families had difficulty coping with the chronic disease. Parental involvement was negatively associated with the number of lifetime decompensations. CONCLUSION: Adults had increased levels of plasma leucine, consistent with greater chronic toxicity. Psychological care was associated with age and number of decompensations. In addition, parental involvement appeared to be crucial in the management of MSUD patients. PMID- 28905141 TI - Insights into the simultaneous utilization of glucose and glycerol by Streptomyces albulus M-Z18 for high epsilon-poly-L-lysine productivity. AB - The simultaneous consumption of glucose and glycerol led to remarkably higher productivity of both biomass and epsilon-poly-L-lysine (epsilon-PL), which was of great significance in industrial microbial fermentation. To further understand the superior fermentation performances, transcriptional analysis and exogenous substrates addition were carried out to study the simultaneous utilization of glucose and glycerol by Streptomyces albulus M-Z18. Transcriptome analysis revealed that there was no mutual transcriptional suppression between the utilization of glucose and glycerol, which was quite different from typical "glucose effect". In addition, microorganisms cultivated with single glycerol showed significant demand for ribose-5-phosphate, which resulted in potential demand for glucose and xylitol. The above demand could be relieved by glucose (in the mixed carbon source) or xylitol addition, leading to improvement of biomass production. It indicated that glucose in the mixed carbon source was more important for biomass production. Besides, transcriptional analysis and exogenous citrate addition proved that single carbon sources could not afford enough carbon skeletons for Embden Meyerhof pathway (EMP) while a glucose-glycerol combination could provided sufficient carbon skeletons to saturate the metabolic capability of EMP, which contributed to the replenishment of precursors and energy consumed in epsilon-PL production. This study offered insight into the simultaneous consumption of glucose and glycerol in the epsilon-PL batch fermentation, which deepened our comprehension on the high epsilon-PL productivity in the mixed carbon source. PMID- 28905142 TI - N-Terminal seven-amino-acid extension simultaneously improves the pH stability, optimal temperature, thermostability and catalytic efficiency of chitosanase CsnA. AB - OBJECTIVE: To determine the effects of the extra N-terminal seven-amino-acid sequence on the function of chitosanase CsnA. RESULTS: Sequence and structure analysis indicated that the mature CsnA contains a seven-amino-acid extension in a disordered form at the N-terminus. To determine the function of this sequence, both mature CsnA and its N-terminus-truncated mutant, CsnADeltaN, were expressed in Escherichia coli and characterized. Compared with CsnADeltaN, CsnA exhibited a 15 degrees C higher temperature optimum, enhanced pH stability, thermostability and catalytic efficiency. The underlying mechanisms responsible for these changes were analyzed by circular dichroism (CD) spectroscopy. CD analysis revealed that the deletion of the N-terminal sequence resulted in a decrease in the Tm of 4.3 degrees C and this sequence altered the secondary structure of the enzyme. CONCLUSIONS: The N-terminal sequence is essential for the stability and activity of chitosanase CsnA. PMID- 28905143 TI - The value of quantitative shear wave elastography in differentiating the cervical lymph nodes in patients with thyroid nodules. AB - PURPOSE: This study aimed at evaluating the diagnostic performance of quantitative shear wave elastography (SWE) in differentiating metastatic cervical lymph nodes from benign nodes in patients with thyroid nodules. METHODS: One hundred and forty-one cervical lymph nodes from 39 patients with thyroid nodules that were diagnosed as papillary thyroid cancer had been imaged with SWE. The shear elasticity modulus, which indicates the stiffness of the lymph nodes, was measured in terms of maximum shear elasticity modulus (maxSM), minimum shear elasticity modulus (minSM), mean shear elasticity modulus (meanSM), and standard deviation (SD) of the shear elasticity modulus. RESULTS: All the patients underwent thyroid surgery, 50 of the suspicious lymph nodes were resected, and 91 lymph nodes were followed up for 6 months. The maxSM value, minSM value, meanSM value, and SD value of the metastatic lymph nodes were significantly higher than those of the benign nodes. The area under the curve of the maxSM value, minSM value, meanSM value, and SD value were 0.918, 0.606, 0.865, and 0.915, respectively. CONCLUSIONS: SWE can differentiate metastasis from benign cervical lymph nodes in patients with thyroid nodules, and the maxSM, meanSM, and SD may be valuable quantitative indicators for characterizing cervical lymph nodes. PMID- 28905145 TI - Brainstem herniation into the internal acoustic canal secondary to hydrocephalus in context of spontaneous cerebrospinal fluid otorrhea: report of a novel entity. AB - INTRODUCTION AND CLINICAL PRESENTATION: The authors report a case of a 5-year-old boy presenting with vision loss, right-sided hearing loss, and facial paralysis secondary to hydrocephalus causing brainstem herniation into the internal auditory canal (IAC) following cerebrospinal fluid (CSF) otorrhea. MANAGEMENT AND OUTCOME: After placement of a ventriculo-peritoneal shunt (VP shunt), the vision and facial palsy improved whilst hearing loss persisted. Imaging demonstrated partial reduction of the herniated brainstem and resolution of hydrocephalus. To our knowledge, this is the first case reported of brainstem herniation into the internal auditory canal. PMID- 28905144 TI - Knee osteoarthritis and associated cardio-metabolic clusters in a tertiary hospital in Nigeria. AB - Osteoarthritis (OA) of the knee is the most common type of arthritis all over the world. Obesity is the strongest modifiable risk factor and causes OA through a combination metabolic factors and mechanical loading. This study aimed to determine the frequency of metabolic syndrome (Mets) among patients with knee OA and its relationship with pain and functional status. This was a descriptive hospital-based cross-sectional study involving patients with knee OA. Pain was measured using a 0-10 numeric rating visual analog scale (VAS). Functional status was assessed using Steinbrocker's functional classification. Metabolic syndrome was diagnosed using the International Diabetic Federation criteria. Radiographs of both knees were taken and graded using Kellgren and Lawrence scale. Relationship of pain and functional status with obesity and Mets was assessed using Pearson's correlation. A p value of < 0.05 was considered significant. Two hundred and forty-four patients with knee OA comprising 63 (25.8%) males and 181 (74.2%) females were recruited. The median age was 50 years (range 18-73 years). Mets was diagnosed in 146 (59.8%). Obesity, diabetes, and hypertension were present in 154 (63.1%), 40 (16%), and 144 (59%) patients, respectively. Severe pain at first visit was present in 216 (88.5%) patients of which 128 (52.4%) had Mets compared to 85 (36.1%) without Mets (chi 2 = 2.40, p = 0.361). Two hundred and four (83.6%) had Steinbrocker's functional classes II and III. Waist circumference was higher in patients with Mets (p = 0.025) but age (p = 0.092), BMI (p = 0.831), VAS (p = 0.361), and functional class (p = 0.401) were similar in those with and without Mets. Body mass index showed significant association with severity of pain (p = 0.017) but not with functional class (p = 0.138). Kellgren and Lawrence radiographic grades III and IV were documented in 288 (48.5%) and 136 (27.2%) knees, respectively. A higher BMI correlated with more severe radiographic grading for the right (p = 0.043) and left (p < 0.001) knees, respectively. Mets is prevalent (59.8%) among Nigerians with knee OA, and those with Mets have higher waist circumference. Significant association was observed between BMI with pain and Kellgren-Lawrence (KL) grade. Mets was not associated with pain, function, or KL grade. PMID- 28905146 TI - Long-Range Temporal Correlations Reflect Treatment Response in the Electroencephalogram of Patients with Infantile Spasms. AB - Infantile spasms syndrome is an epileptic encephalopathy in which prompt diagnosis and treatment initiation are critical to therapeutic response. Diagnosis of the disease heavily depends on the identification of characteristic electroencephalographic (EEG) patterns, including hypsarrhythmia. However, visual assessment of the presence and characteristics of hypsarrhythmia is challenging because multiple variants of the pattern exist, leading to poor inter-rater reliability. We investigated whether a quantitative measurement of the control of neural synchrony in the EEGs of infantile spasms patients could be used to reliably distinguish the presence of hypsarrhythmia and indicate successful treatment outcomes. We used autocorrelation and Detrended Fluctuation Analysis (DFA) to measure the strength of long-range temporal correlations in 21 infantile spasms patients before and after treatment and 21 control subjects. The strength of long-range temporal correlations was significantly lower in patients with hypsarrhythmia than control patients, indicating decreased control of neural synchrony. There was no difference between patients without hypsarrhythmia and control patients. Further, the presence of hypsarrhythmia could be classified based on the DFA exponent and intercept with 92% accuracy using a support vector machine. Successful treatment was marked by a larger increase in the DFA exponent compared to those in which spasms persisted. These results suggest that the strength of long-range temporal correlations is a marker of pathological cortical activity that correlates with treatment response. Combined with current clinical measures, this quantitative tool has the potential to aid objective identification of hypsarrhythmia and assessment of treatment efficacy to inform clinical decision-making. PMID- 28905147 TI - Evaluation and control of miRNA-like off-target repression for RNA interference. AB - RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago-miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity. PMID- 28905148 TI - Building a PGC-LC-MS N-glycan retention library and elution mapping resource. AB - Porous graphitised carbon-liquid chromatography (PGC-LC) has been proven to be a powerful technique for the analysis and characterisation of complex mixtures of isomeric and isobaric glycan structures. Here we evaluate the elution behaviour of N-glycans on PGC-LC and thereby provide the potential of using chromatographic separation properties, together with mass spectrometry (MS) fragmentation, to determine glycan structure assignments more easily. We used previously reported N glycan structures released from the purified glycoproteins Immunoglobulin G (IgG), Immunoglobulin A (IgA), lactoferrin, alpha1-acid glycoprotein, Ribonuclease B (RNase B), fetuin and ovalbumin to profile their behaviour on capillary PGC-LC-MS. Over 100 glycan structures were determined by MS/MS, and together with targeted exoglycosidase digestions, created a N-glycan PGC retention library covering a full spectrum of biologically significant N-glycans from pauci mannose to sialylated tetra-antennary classes. The resultant PGC retention library ( http://www.glycostore.org/showPgc ) incorporates retention times and supporting fragmentation spectra including exoglycosidase digestion products, and provides detailed knowledge on the elution properties of N-glycans by PGC-LC. Consequently, this platform should serve as a valuable resource for facilitating the detailed analysis of the glycosylation of both purified recombinant, and complex mixtures of, glycoproteins using established workflows. PMID- 28905150 TI - Silver doped hydroxyapatite coatings by sacrificial anode deposition under magnetic field. AB - Uniform distribution of silver (Ag) in the hydroxyapatite (HA) coated Ti surface has been a concern for which an attempt has been made to dope Ag in HA coating with and without magnetic field. Cathodic deposition technique was employed to coat Ag incorporated hydroxyapatite coating using a sacrificial silver anode method by using NdFeB bar magnets producing 12 Tesla magnetic field. While uniform deposition of Ag was observed in the coatings under magnetic field, dense coating was evident in the coating without magnetic field conditions. Uniformly distributed Ag incorporated HA in the present study has potential to fight microorganism while providing osseoconduction properties of the composite coating. PMID- 28905151 TI - The role of the neural niche in brain metastasis. AB - Cancers with neurologic metastasis are a burdensome affliction. As primary cancer care improves, the incidence of metastatic cancer increases as a result of prolonged survival time. Because of this, advances in the understanding of the mechanisms of metastasis are important for the development of continuing management strategies. Knowing how metastatic tumor cells engage, survive, and proliferate in the central nervous system (CNS) is an important first step in developing treatment paradigms. The neural niche is the soil of the CNS that accommodates tumor cells, is a microenvironment of cell signaling that exists between the tumor cell and the native neural cellular network. Elements of the neural niche have been identified as acquaintances for metastatic tumor growth. As more is known about the neural niche, treatment strategies can be developed to target these networks of metastatic tumor progression. PMID- 28905149 TI - Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis. AB - Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway. PMID- 28905153 TI - Land use change and its driving forces toward mutual conversion in Zhangjiakou City, a farming-pastoral ecotone in Northern China. AB - Land use/cover change (LUCC), a local environmental issue of global importance, and its driving forces have been crucial issues in geography and environmental research. Previous studies primarily focused on major driving factors in various land use types, with few explorations of differences between driving forces of mutual land use type conversions, especially in fragile eco-environments. In this study, Zhangjiakou City, in a farming-pastoral ecotone in Northern China, was taken as an example to analyze land use change between 1989 and 2015, and explore the driving forces of mutual land use type conversions using canonical correlation analysis. Satellite images and government statistics, including social-economic and natural data, were used as sources. Arable land, forestland, and grassland formed the main land use structure. From 1989 to 2015 forestland, orchard land, and construction land significantly increased, while arable land, grassland, unused land, and water areas decreased. Conversions from grassland to forestland; from arable land to orchard land, forestland and construction land; and from unused land to grassland and forestland were the primary land use changes. Among these, the conversion from grassland to forestland had the highest ranking. Average annual precipitation and per capita net income of rural residents positively affected the conversion of arable land to forestland and unused land to grassland. GDP, total population, and urbanization rate contributed most significantly to converting arable land to construction land; total retail sales of social consumer goods, average annual temperature, and GDP had important positive influences in converting arable land to orchard land. PMID- 28905154 TI - Affordable self-regulating irrigation device for microsurgery using readily available malleable wire and a Silastic tube: a technical note. AB - BACKGROUND: A relevant irrigating and flushing maneuver during cerebral microsurgical procedures allows for a neat and optimal operative field. However, when operating on the deep region of the brain, a delicately created slim surgical corridor could unintentionally hinder the assisting surgeon from properly performing this routine maneuver. METHOD: To address this problem, the authors devised a useful and convenient irrigation system that can be used during cerebral microsurgery. RESULTS: This system only necessitates a readily available silastic feeding tube and a malleable wire. The advantages of our devised system include the convenience of free molding, good endurance of the molded contour, and easy control over the amount of irrigation. CONCLUSIONS: In this report, the authors demonstrated technical tips for using this newly devised system. PMID- 28905152 TI - A Controlled Trial to Reduce the Risk of Human Nipah Virus Exposure in Bangladesh. AB - Human Nipah virus (NiV) infection, often fatal in Bangladesh, is primarily transmitted by drinking raw date palm sap contaminated by Pteropus bats. We assessed the impact of a behavior change communication intervention on reducing consumption of potentially NiV-contaminated raw sap. During the 2012-2014 sap harvesting seasons, we implemented interventions in two areas and compared results with a control area. In one area, we disseminated a "do not drink raw sap" message and, in the other area, encouraged only drinking sap if it had been protected from bat contamination by a barrier ("only safe sap"). Post intervention, 40% more respondents in both intervention areas reported knowing about a disease contracted through raw sap consumption compared with control. Reported raw sap consumption decreased in all areas. The reductions in the intervention areas were not significantly greater compared to the control. Respondents directly exposed to the "only safe sap" message were more likely to report consuming raw sap from a protected source than those with no exposure (25 vs. 15%, OR 2.0, 95% CI 1.5-2.6, P < 0.001). While the intervention increased knowledge in both intervention areas, the "only safe sap" intervention reduced exposure to potentially NiV-contaminated sap and should be considered for future dissemination. PMID- 28905155 TI - Association of TLR4 gene polymorphisms with childhood Henoch-Schonlein purpura in a Chinese population. AB - Recent studies demonstrated that aberrant activation of Toll-like receptor (TLR) 4 was involved in the pathogenesis of Henoch-Schonlein purpura (HSP). In this study, we evaluated the association between TLR4 gene polymorphisms and the risk of childhood HSP in a Chinese population. A total of 175 HSP patients and 186 controls were recruited in this case-control study. Three single-nucleotide polymorphisms of the TLR4 gene (rs1927914, rs10759932 and rs1927907) were genotyped using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and Sequenom MassARRAY system. Our results revealed that a significantly reduced risk for HSP was associated with the G allele (OR = 0.71; p = 0.023) and G/G genotype (OR = 0.49; p = 0.021) of rs1927914. We also showed that rs1927914 variant decreased the risk of HSP in recessive inheritance model (OR = 0.55; p = 0.035, G/G vs A/A + A/G). In addition, we observed that a significantly decreased frequency of the haplotype GTC (rs1927914-rs10759932-rs1927907) in HSP patients compared with controls (OR = 0.56; p = 0.028). Our data suggested that TLR 4 rs1927914 polymorphism was associated with the decreased susceptibility to HSP in the Chinese children. PMID- 28905156 TI - Cultural Factors relevant to Korean Americans in Health Research: A Systematic Review. AB - To eliminate health disparities in the United States, identifying cultural contexts salient to the target populations in an intervention study is critical; however, little research has been conducted on the identification of cultural contexts among Korean Americans who have significant risk factors for chronic diseases. This systematic review identifies critical cultural contexts central to the literature discussed in health research on Korean Americans. We examined 14 research reports of 801 potentially eligible articles published between 2000 and 2016 and analyzed their contribution to cultural contexts among Korean Americans based on the PEN-3 model. This review highlights how cultural contexts impact health and health behaviors of Korean Americans, and may contribute to health disparities in the United States. The key cultural contexts highlighted in this review include social support/social network, family, gender role expectations, and a holistic view of health and illness. These cultural contexts should be incorporated in designing culturally relevant, effective, and sustainable health interventions for Korean Americans, which will contribute to eliminating health disparities for this ethnic group who experience great obstacles to healthcare access and healthy behaviors. PMID- 28905157 TI - Landscape genetics in the subterranean rodent Ctenomys "chasiquensis" associated with highly disturbed habitats from the southeastern Pampas region, Argentina. AB - Studies of genetic differentiation in fragmented environments help us to identify those landscape features that most affect gene flow and dispersal patterns. Particularly, the assessment of the relative significance of intrinsic biological and environmental factors affecting the genetic structure of populations becomes crucial. In this work, we assess the current dispersal patterns and population structure of Ctenomys "chasiquensis", a vulnerable and endemic subterranean rodent distributed on a small area in Central Argentina, using 9 polymorphic microsatellite loci. We use landscape genetics approaches to assess the relationship between genetic connectivity among populations and environmental attributes. Our analyses show that populations of C. "chasiquensis" are moderately to highly structured at a regional level. This pattern is most likely the outcome of substantial gene flow on the more homogeneous sand dune habitat of the Northwest of its distributional range, in conjunction with an important degree of isolation of eastern and southwestern populations, where the optimal habitat is surrounded by a highly fragmented landscape. Landscape genetics analysis suggests that habitat quality and longitude were the environmental factors most strongly associated with genetic differentiation/uniqueness of populations. In conclusion, our results indicate an important genetic structure in this species, even at a small spatial scale, suggesting that contemporary habitat fragmentation increases population differentiation. PMID- 28905158 TI - Referrals to Mental Health Services: Exploring the Referral Process in Genetic Counseling. AB - Genetic counselors (GCs) are trained to identify and attend to distress; however, GCs may have patients with distress better managed by mental health professionals (MHPs). To understand the GCs' role in mental health care, we explored patient cues prompting GCs to refer to MHPs and where GCs thought their expertise in managing patient distress ended. We recruited GCs who have referred a patient for mental health services within the last year to participate in an interview study. A twelve-question interview guide explored GC demographics, reasons for referrals to MHPs, the obstacles to referrals, and perceived differences in counseling competencies between GCs and MHPs. Twenty-eight semi-structured interviews were conducted, recorded, and transcribed verbatim. Transcripts were analyzed using an inductive approach, consisting of reading a subset of transcripts and assigning codes to meaningful segments of text. Common reasons for referral included the GC's perception of the patient having limited social support, or when the patient indicated significant anxiety related to their at-risk status or recent diagnosis. GCs felt they referred when they were limited by time and training to provide adequate psychosocial services. The participants in this study acknowledged that their scope of practice is limited to short-term, client centered counseling. Our findings are a first step in helping increase GCs' awareness of factors that contribute to the referral process to MHPs. PMID- 28905159 TI - Are there two different binding sites for ATP on the myosin head, or only one that switches between two conformers? PMID- 28905160 TI - School Age Outcomes of Children Diagnosed Early and Later with Autism Spectrum Disorder. AB - Early diagnosis of Autism Spectrum Disorder is considered best practice, increasing access to early intervention. Yet, many children are diagnosed after 3 years. The current study investigated the school age outcomes of children who received an early and later diagnosis of ASD. The cognitive and behavioural outcomes of children diagnosed early (n = 48), were compared to children diagnosed after 3-years (n = 37). Children diagnosed early accessed more intervention, demonstrated better verbal and overall cognition at school age, were more likely to attend mainstream school and required less ongoing support than children diagnosed later. Behavioural differences were not found between groups. Earlier diagnosis is important and is likely to promote more positive outcomes at school age due to increased opportunity for EI. PMID- 28905161 TI - Retrospective observation on trabeculectomy of primary congenital glaucoma by applying biological amniotic membranes soaked with 5-fluorouracil. AB - PURPOSE: To report our experience on treatment of primary congenital glaucoma with trabeculectomy in combination with biological amniotic membranes soaked with 5-fluorouracil. METHODS: This is a retrospective study. Thirty primary congenital glaucoma (PCG) patients (41 eyes) were treated with trabeculectomy in combination with biological amniotic membranes soaked with 5-fluorouracil before operation and followed up for 2.75 +/- 1.35 years in average ranging from 1.2 to 5.3 years (Group A). In addition, 22 PCG patients (32 eyes) treated with mitomycin C trabeculectomy were selected as control and followed up for 2.3 +/- 1.25 years in average ranging from 1.4 to 5.1 years (Group B). RESULTS: Patients in Group A were 4.74 +/- 2.13 years old. After treatment, their mean intraocular pressure decreased from preoperative 38.8 +/- 11.3-17.6 +/- 8.2 mmHg at 12 months of postoperation (P = 0.0000). At 12 months of follow-up, the intraocular pressure was less than 13 mmHg in 8 eyes (19.5%), between 17 and 13 mmHg in 15 eyes (36.6%), between 21 and 17 mmHg in 12 eyes (29.3%) and more than 21 mmHg in 6 eyes (14.6%). The overall success rate was 85.4%, and total complication rate was 17.1%. By comparison, the overall success rate and total complication rate were 87.5 and 34.4%, respectively, at 12 months of follow-up for patients in Group B. Although the overall success rate was not significantly different between Groups A and B (P = 0.1203) at the end of follow-up, the total complication rate was significantly decreased in Group A (P = 0.0419). CONCLUSION: Application of trabeculectomy in combination with biological amniotic membranes soaked with 5 fluorouracil can be an effective surgical treatment method for primary congenital glaucoma patients. PMID- 28905162 TI - Quality of prescribing in community-dwelling elderly patients in France: an observational study in community pharmacies. AB - Background In order to ensure safer prescriptions in the elderly, lists of potentially inappropriate medications (PIMs) and guidelines have been introduced. Whereas the effectiveness of these measures has been well studied in hospitals, data are sparse for the community-dwelling patients. Objective To assess the quality of prescriptions among community-dwelling elderly patients, and potential associations between prescription patterns, patient characteristics and medication adherence. Setting Community pharmacies in France. Method We conducted a prospective observational study between January and June 2013. Patients aged 75 and over coming to the community pharmacy with a prescription from a general practitioner were invited to participate to the study. The compliance of the prescription was assessed with regards to Beers Criteria and French Health Authority guidelines (FHA) for prescription in the elderly, the degree of adherence was assessed with the Girerd score. Main outcome measure Percentage of prescriptions compliant with Beers Criteria and FHA guidelines. Results Among the 1206 prescriptions analysed, 67.49% (n = 814) contained a PIM. Only 12.77% (n = 154) complied with mandatory requirements of the FHA. Prescriptions were ordered by therapeutic field in 51.24% (n = 618) of cases. Dosing regimen was incomplete in 57.21% (n = 690) of prescriptions. Only 29.19% (n = 352) of patients reported no difficulty with regard to adherence (Girerd score = 0). The use of International Non-proprietary Name was associated with an increased risk of nonadherence (adjusted OR = 1.59 [95% CI = 1.13-2.23] and 1.68 [95% CI = 1.12 2.49] respectively). Patient satisfaction with formulation was associated with a lower risk of non-adherence (adjusted OR = 0.63 [95% CI = 0.45-0.90]). Conclusion A substantial proportion of patients are exposed to PIMs and prescriptions that do not comply with the FHA Guidelines. This issue, as well as identified risk factors for non-adherence, should be taken into consideration by general practitioners and community pharmacists when prescribing/dispensing medications to the elderly. PMID- 28905163 TI - Data Sharing Mandates, Developmental Science, and Responsibly Supporting Authors. AB - Data sharing has come of age. Long expected as a professional courtesy but rarely honored, data sharing is now highlighted in codes of ethics, supported by research communities, required by leading funding organizations, and variously encouraged and mandated by journals and even publishers. These developments reveal how sharing generates many benefits, all of which go to the integrity of the scientific process. Yet, sharing remains a complex phenomenon. This Editorial explains the journal's response to the publisher's mandate to establish an appropriate data sharing policy for the Journal of Youth and Adolescence. It describes the need to balance the benefits of sharing with its costs for authors publishing in multidisciplinary, developmental science journals like this one. For this journal and at this time, that balance leads us to err on the side of caution, which means supporting those who created their data and not coercing public sharing as a condition for publishing. This approach recognizes authors' reliance on a wide variety of data, the needs of differentially situated authors, the requirements of robust peer review, and the potential harms that can come from editors' unilateral sharing mandates. PMID- 28905164 TI - Sauna bathing reduces the risk of respiratory diseases: a long-term prospective cohort study. AB - Sauna bathing has been linked with numerous health benefits. Sauna bathing may reduce the risk of respiratory diseases; however, no prospective evidence exists to support this hypothesis. We aimed to assess the association of frequency of sauna bathing with risk of respiratory diseases (defined as chronic obstructive pulmonary disease, asthma, or pneumonia). Baseline sauna bathing habits were assessed in a prospective cohort of 1935 Caucasian men aged 42-61 years. During a median follow-up of 25.6 years, 379 hospital diagnosed incident cases of respiratory diseases were recorded. In adjustment for several major risk factors for respiratory conditions and other potential confounders, the hazard ratios (HRs) 95% confidence intervals (CIs) of respiratory diseases were 0.73 (0.58 0.92) and 0.59 (0.37-0.94) for participants who had 2-3 and >=4 sauna sessions per week respectively compared with participants who had <=1 sauna session per week. The multivariate adjusted HR (95% CI) for pneumonia was 0.72 (0.57-0.90) and 0.63 (0.39-1.00) for participants who had 2-3 and >=4 sauna sessions per week respectively. Frequent sauna baths may be associated with a reduced risk of acute and chronic respiratory conditions in a middle-aged male Caucasian population. PMID- 28905165 TI - Interpersonal Relationships as Protective and Risk Factors for Psychopathy: A Follow-up Study in Adolescent Offenders. AB - Friendships and romantic relationships may function as protective and risk factors for psychopathic traits. To better understand potential causal associations, we investigated whether within-individual changes in relationship characteristics were related to changes in psychopathic traits over time. Data were derived from ten repeated measurements of the Pathways to Desistance longitudinal study of 1354 offending adolescents (14.3% female; 40.1% Black). Analyses were adjusted for age, gender, ethnicity, self-reported offending and living facilities. Relationships of high quality were associated with lower psychopathic traits, whereas antisocial behavior and antisocial influence in relationships were related to higher psychopathic traits. Within-individual analysis indicated that time-invariant individual characteristics did not confound these associations. The findings suggest that the quality and antisocial activities of interpersonal relationships can affect positively or negatively on the levels of psychopathy. PMID- 28905166 TI - Efficacy of a Self-Help Treatment for At-Risk and Pathological Gamblers. AB - Available evidence suggests that self-help treatments may reduce problem gambling severity but inconsistencies of results across clinical trials leave the extent of their benefits unclear. Moreover, no self-help treatment has yet been validated within a French Canadian setting. The current study therefore assesses the efficacy of a French language self-help treatment including three motivational telephone interviews spread over an 11-week period and a cognitive behavioral self-help workbook. At-risk and pathological gamblers were randomly assigned to the treatment group (n = 31) or the waiting list (n = 31). Relative to the waiting list, the treatment group showed a statistically significant reduction in the number of DSM-5 gambling disorder criteria met, gambling habits, and gambling consequences at Week 11. Perceived self-efficacy and life satisfaction also significantly improved after 11 weeks for the treatment group, but not for the waiting list group. At Week 11, 13% of participants had dropped out of the study. All significant changes reported for the treatment group were maintained throughout 1, 6 and 12-month follow-ups. Results support the efficacy of the self-help treatment to reduce problem gambling severity, gambling behaviour and to improve overall functioning among a sample of French Canadian problem gamblers over short, medium and long term. Findings from this study lend support to the appropriateness of self-help treatments for problem gamblers and help clarify inconsistencies found in the literature. The low dropout rate is discussed with respect to the advantages of the self-help format. Clinical and methodological implications of the results are put forth. PMID- 28905167 TI - Molecular diversity and phylogeny of indigenous Rhizobium leguminosarum strains associated with Trifolium repens plants in Romania. AB - The symbiotic nitrogen fixing legumes play an essential role in sustainable agriculture. White clover (Trifolium repens L.) is one of the most valuable perennial legumes in pastures and meadows of temperate regions. Despite its great agriculture and economic importance, there is no detailed available information on phylogenetic assignation and characterization of rhizobia associated with native white clover plants in South-Eastern Europe. In the present work, the diversity of indigenous white clover rhizobia originating in 11 different natural ecosystems in North-Eastern Romania were assessed by a polyphasic approach. Initial grouping showed that, 73 rhizobial isolates, representing seven distinct phenons were distributed into 12 genotypes, indicating a wide phenotypic and genotypic diversity among the isolates. To clarify their phylogeny, 44 representative strains were used in sequence analysis of 16S rRNA gene and IGS fragments, three housekeeping genes (atpD, glnII and recA) and two symbiosis related genes (nodA and nifH). Multilocus sequence analysis (MLSA) phylogeny based on concatenated housekeeping genes delineated the clover isolates into five putative genospecies. Despite their diverse chromosomal backgrounds, test strains shared highly similar symbiotic genes closely related to Rhizobium leguminosarum biovar trifolii. Phylogenies inferred from housekeeping genes were incongruent with those of symbiotic genes, probably due to occurrence of lateral transfer events among native strains. This is the first polyphasic taxonomic study to report on the MLSA-based phylogenetic diversity of indigenous rhizobia nodulating white clover plants grown in various soil types in South-Eastern Europe. Our results provide valuable taxonomic data on native clover rhizobia and may increase the pool of genetic material to be used as biofertilizers. PMID- 28905169 TI - The Interrelation of Prayer and Worship Service Attendance in Moderating the Negative Impact of Life Event Stressors on Mental Well-Being. AB - The interrelation of worship service attendance and private prayer in moderating the negative impact of life event stressors on mental well-being is examined using hierarchical multiple regressions on a national sample of 2601 Americans. A theoretical model is proposed in which stressful life events are made less distressing under conditions in which exposure to pro-social content at worship services is internalized through frequent private prayer. Interactive models controlling for a block of potential confounds are run to confirm that the stress moderating effects of worship service attendance are noted only when attendance is complemented by relatively frequent engagement in private prayer. PMID- 28905168 TI - The usefulness of testosterone administration in identifying false-positive elevation of serum human chorionic gonadotropin in patients with germ cell tumor. AB - OBJECTIVE: The pituitary production of human chorionic gonadotropin (hCG) can cause false-positive results during or after germ cell tumor (GCT) treatment. Because hypogonadism leads to pituitary hCG production, testosterone administration test (TAT) has been recommended for pituitary hCG diagnosis. However, little is known about its efficacy for the discrimination of pituitary hCG as detected by currently used hCG assays in treatment of GCT. We conducted a retrospective multicenter study to determine the usefulness of TAT. MATERIALS AND METHODS: The study included 60 patients who underwent TAT for the discrimination of pituitary hCG. In principle, serum hCG levels were measured 1 week after testosterone enanthate administration (250 mg). When the serum hCG levels decreased below the normal upper range, the results of TAT were determined positive. In this case, the elevated hCG was considered to be derived from pituitary and not from GCT. RESULTS: Serum hCG levels were normalized after TAT in 36 of 60 patients (60%). Before TAT, the hCG levels were below 1.0 IU/L in 13 patients (36%), 1.0-1.9 IU/L in 11 (31%), 2.0-2.9 IU/L in 7 (19%), and >3.0 IU/L in 5 (14%) of TAT-positive patients. Of them, 28 (78%) patients were successfully managed without further treatment with chemotherapy after TAT. Pituitary hCG was associated with higher levels of LH and not necessarily associated with low levels of testosterone. CONCLUSION: Determining the TAT status of patients was effective in discriminating pituitary hCG production. PMID- 28905170 TI - [Follow-up ultrasound of head and neck cancer]. AB - In Germany high-resolution sonography using the color duplex mode in addition to computed tomography (CT) is a well-established and proven method in the context of restaging after primary therapy of head and neck squamous cell cancer (HNSCC). There are no international evidence-based restaging guidelines. Decisions concerning neck dissection (ND) after primary radiochemotherapy (RCT) are often individually derived in the respective tumor conferences and are therefore subject to variance. Compared to the UK or USA, in Germany there is a high level of expertise in the use of ultrasound in combination with CT for the routine restaging of HNSCC after RCT. Using high-resolution sonography (B-mode and color duplex) morphological changes in neck lymph nodes can be clearly detected. Another important aspect in the field of sonographic follow-up is the accurate and standardized documentation of findings and control of dynamic changes during follow-up. In summary, clinical presentation and sonography enable therapeutic decisions and treatment from one source. PMID- 28905171 TI - Pharmacist intervention acceptance for the reduction of potentially inappropriate drug prescribing in acute psychiatry. AB - Background Prescribing for the elderly is challenging. A previous observational study conducted in our geriatric psychiatry admission unit (GPAU) using STOPP/START criteria showed a high number of potentially inappropriate drug prescriptions (PIDPs). A clinical pharmacist was added to our GPAU as a strategy to reduce PIDPs. Objective The objective of the present study was to assess the impact of a clinical pharmacist on PIDPs by measuring acceptance rates of pharmacist interventions (PhIs). Setting This study was conducted at the GPAU of Lausanne University Hospital. Method The clinical pharmacist attended four GPAU meetings weekly. Complete medication reviews were performed daily. The clinical pharmacist conducted standard analyses based on clinical judgment and STOPP/START criteria assessment. A PhI was generated when a PIDP was detected. When a PhI was accepted, the PIDP was considered as eliminated. Acceptance rate of PhI was calculated (number of PhI accepted/total number of PhI). Main outcome measure PhIs acceptance rates. Results In a cohort of 102 patients seen between July 2013 and February 2014, a total of 697 PhIs (average 6.8/patient) were made based on standard evaluation (n = 479) and STOPP/START criteria (n = 243). The global acceptance rate was 68% (standard, 78%; STOPP/START, 47%). Conclusion Good PhIs acceptance rates demonstrated that a clinical pharmacist can reduce PIDPs in a GPAU. PhIs based on standard evaluation had a higher acceptance than those based on STOPP/START criteria, probably because they are better adapted to individual patients. However, these two evaluation approaches can be used in a complementary manner. PMID- 28905172 TI - N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy. AB - BACKGROUND: Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear. METHODS: In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard of-care enoxaparin (40 mg once daily for 10 +/- 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization. RESULTS: In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47-8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03-7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36-6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35-9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30). CONCLUSIONS: Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement. PMID- 28905173 TI - Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model. AB - PURPOSE: Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice. METHODS: Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF + EVG solution) or as drug loaded NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non compartmental analysis was performed using WinNonlin. RESULTS: SubQ administration of TAF + EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0-72h) of TFV and EVG was 14.1 +/- 2.0, 7.2 +/- 1.8 MUg * hr./mL from drugs in solution (free) and the AUC(0-14day) for the same drugs was 23.1 +/- 4.4, 39.7 +/- 6.7 MUg * hr./mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. CONCLUSION: This study documents that a TAF + EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis. PMID- 28905174 TI - Mathematical Development and Computational Analysis of Harmonic Phase-Magnetic Resonance Imaging (HARP-MRI) Based on Bloch Nuclear Magnetic Resonance (NMR) Diffusion Model for Myocardial Motion. AB - Harmonic Phase-Magnetic Resonance Imaging (HARP-MRI) is a tagged image analysis method that can measure myocardial motion and strain in near real-time and is considered a potential candidate to make magnetic resonance tagging clinically viable. However, analytical expressions of radially tagged transverse magnetization in polar coordinates (which is required to appropriately describe the shape of the heart) have not been explored because the physics required to directly connect myocardial deformation of tagged Nuclear Magnetic Resonance (NMR) transverse magnetization in polar geometry and the appropriate harmonic phase parameters are not yet available. The analytical solution of Bloch NMR diffusion equation in spherical geometry with appropriate spherical wave tagging function is important for proper analysis and monitoring of heart systolic and diastolic deformation with relevant boundary conditions. In this study, we applied Harmonic Phase MRI method to compute the difference between tagged and untagged NMR transverse magnetization based on the Bloch NMR diffusion equation and obtained radial wave tagging function for analysis of myocardial motion. The analytical solution of the Bloch NMR equations and the computational simulation of myocardial motion as developed in this study are intended to significantly improve healthcare for accurate diagnosis, prognosis and treatment of cardiovascular related deceases at the lowest cost because MRI scan is still one of the most expensive anywhere. The analysis is fundamental and significant because all Magnetic Resonance Imaging techniques are based on the Bloch NMR flow equations. PMID- 28905175 TI - The promotion of hair regrowth by topical application of a Perilla frutescens extract through increased cell viability and antagonism of testosterone and dihydrotestosterone. AB - This study investigated the potential hair regrowth effects associated with a plant extract of Perilla frutescens, which was selected due to its putative hair regrowth activity. Extracts were prepared from dried P. frutescens suspended in distilled water, where the resultant aqueous suspension was fractionated sequentially using hexane, ethyl acetate, n-butanol, and distilled water. We observed that the n-butanol fraction resulted in the highest hair regrowth activity. The n-butanol soluble fraction of P. frutescens extract (BFPE) was further separated using AB-8 macroporous resin and silica gel chromatography to obtain rosmarinic acid (RA), which demonstrated effective hair growth regeneration potential. BFPE also showed in vivo anti-androgenic activity following the use of a hair growth assay in testosterone-sensitive male C57Bl/6NCrSlc mice. Furthermore, the effects of cell viability promotion were investigated following an in vitro analysis in primary hair follicle fibroblast cells (PHFCs) treated with RA. The results suggested that RA was the active compound in P. frutescens that triggers hair growth, and RA could be a potential therapeutic agent for the promotion of hair growth and prevention of androgenetic alopecia (AGA). PMID- 28905176 TI - The impact of a family history of prostate cancer on the prognosis and features of the disease in Korea: results from a cross-sectional longitudinal pilot study. AB - PURPOSE: Reports on the impact of a family history of prostate cancer among Asians are scarce. We evaluated whether a positive prostate cancer family history is associated with the prognosis and features of the disease. METHODS: From January 2006 to December 2015, patients who received treatment for pathologically diagnosed prostate cancer were enrolled. Information on family history was obtained via self-administered questionnaires between January 2015 and December 2016. The overall survival rate for all patients and the rate of biochemical failure after radical prostatectomy were assessed according to the presence of family history. RESULTS: Of 1266 patients (median age, 68.1 years; median prostate-specific antigen, 8.73 ng/mL; median follow-up, 40.0 months), 47 (3.8%) were identified as having a family history. Men with a family history had a younger age, higher proportion of cases diagnosed before 55 years of age, and lower stage than those without a family history. Family history was not a potential risk factor for overall survival. In an analysis of patients who underwent radical prostatectomy (median prostate-specific antigen, 7.40 ng/mL; median follow-up, 40.5 months), no differences in pathologic characteristics were found between patients with (n = 39, 93.5%) and without (n = 567, 6.4%) a family history. Family history was not predictive of biochemical failure. CONCLUSIONS: A family history of prostate cancer seemed to have no effect on prognosis and disease aggressiveness. However, this study proposed a rationale for performing earlier prostate-specific antigen testing in men with a family history of prostate cancer. PMID- 28905177 TI - Readability assessment of online patient education materials provided by the European Association of Urology. AB - PURPOSE: To assess the readability of the web-based patient education material provided by the European Association of Urology. MATERIALS AND METHODS: English patient education materials (PEM) as available in May 2017 were obtained from the EAU website. Each topic was analyzed separately using six well-established readability assessment tools, including Flesch-Kincaid Grade Level (FKGL), SMOG Grade Level (SMOG), Coleman-Liau Index (CLI), Gunning Fog Index (GFI), Flesch Reading Ease Formula (FRE) and Fry Readability Graph (FRG). RESULTS: A total of 17 main topics were identified of which separate basic and in-depth information is provided for 14 topics. Calculation of grade levels (FKGL, SMOG, CLI, GFI) showed readability scores of 7th-13th grade for basic information, 8th-15th grade for in-depth information and 7th-15th grade for single PEM. Median FRE score was 54 points (range 45-65) for basic information and 56 points (41-64) for in-depth information. The FRG as a graphical assessment revealed only 13 valid results with an approximate 8th-17th grade level. CONCLUSION: The EAU provides carefully worked out PEM for 17 urological topics. Although improved readability compared to similar analyses was found, a simplification of certain chapters might be helpful to facilitate better patient understanding. PMID- 28905178 TI - Single versus dual anti-platelet therapy post transcatheter aortic valve implantation: a meta-analysis of randomized controlled trials. AB - The purpose of this systematic review and meta-analysis was to assess the 30-days safety (bleeding and vascular events) and efficacy (reduction in major stroke, myocardial infarction and mortality) of single anti-platelet (SAPT) versus dual anti-platelet (DAPT) after transcatheter aortic valve implantation (TAVI). We used a meta-analytic method with Mantel-Haenszel methods to calculate the odds ratio (OR) and 95% confidence interval (CI). Only randomized clinical trials that compared 30-days safety and efficacy based on Valve Academic Research Consortium criteria were included. Studies that included patients on anticoagulants were excluded. Our analysis included three studies with a total of 421 patients (210 SAPT and 211 DAPT). Life-threatening and major bleeding as well as major vascular complications was similar between SAPT and DAPT. Similarly, major stroke, myocardial infarction and mortality was also comparable between the two groups. The combined outcomes of 30-day mortality, life-threatening and major bleeding showed tendency toward lower event rates in SAPT compared to DAPT (9.5 vs. 15.6%, OR 0.57; 95% CI 0.31-1.03, p = 0.06). In conclusion, SAPT provided similar safety without adding incremental efficacy compared to DAPT but showed tendency of lower combined endpoints of 30-day mortality, life-threatening and major bleeding. PMID- 28905180 TI - [Visual performance of animals and humans in comparison]. PMID- 28905179 TI - Overtreatment and Deintensification of Diabetic Therapy among Medicare Beneficiaries. AB - BACKGROUND: Deintensification of diabetic therapy is often clinically appropriate for older adults, because the benefit of aggressive diabetes treatment declines with age, while the risks increase. OBJECTIVE: We examined rates of overtreatment and deintensification of therapy for older adults with diabetes, and whether these rates differed by medical, demographic, and socioeconomic characteristics. DESIGN, SUBJECTS, AND MAIN MEASURES: We analyzed Medicare claims data from 10 states, linked to outpatient laboratory values to identify patients potentially overtreated for diabetes (HbA1c < 6.5% with fills for any diabetes medications beyond metformin, 1/1/2011-6/30/2011). We examined characteristics associated with deintensification for potentially overtreated diabetic patients. We used multinomial logistic regression to examine whether patient characteristics associated with overtreatment of diabetes differed from those associated with undertreatment (i.e. HbA1c > 9.0%). KEY RESULTS: Of 78,792 Medicare recipients with diabetes, 8560 (10.9%) were potentially overtreated. Overtreatment of diabetes was more common among those who were over 75 years of age and enrolled in Medicaid (p < 0.001), and was less common among Hispanics (p = 0.009). Therapy was deintensified for 14% of overtreated diabetics. Appropriate deintensification of diabetic therapy was more common for patients with six or more chronic conditions, more outpatient visits, or living in urban areas; deintensification was less common for those over age 75. Only 6.9% of Medicare recipients with diabetes were potentially undertreated. Variables associated with overtreatment of diabetes differed from those associated with undertreatment. CONCLUSIONS: Medicare recipients are more frequently overtreated than undertreated for diabetes. Medicare recipients who are overtreated for diabetes rarely have their regimens deintensified. PMID- 28905181 TI - Attenuated audiovisual integration in middle-aged adults in a discrimination task. AB - Numerous studies have focused on the diversity of audiovisual integration between younger and older adults. However, consecutive trends in audiovisual integration throughout life are still unclear. In the present study, to clarify audiovisual integration characteristics in middle-aged adults, we instructed younger and middle-aged adults to conduct an auditory/visual stimuli discrimination experiment. Randomized streams of unimodal auditory (A), unimodal visual (V) or audiovisual stimuli were presented on the left or right hemispace of the central fixation point, and subjects were instructed to respond to the target stimuli rapidly and accurately. Our results demonstrated that the responses of middle aged adults to all unimodal and bimodal stimuli were significantly slower than those of younger adults (p < 0.05). Audiovisual integration was markedly delayed (onset time 360 ms) and weaker (peak 3.97%) in middle-aged adults than in younger adults (onset time 260 ms, peak 11.86%). The results suggested that audiovisual integration was attenuated in middle-aged adults and further confirmed age related decline in information processing. PMID- 28905182 TI - Effects of cyproterone acetate and vertically transmitted microsporidia parasite on Gammarus pulex sperm production. AB - Endocrine disruption compounds (EDCs) and parasitism can both interfere with the reproduction process of organisms. The amphipod Gammarus pulex is the host of the vertically transmitted microsporidia Dictyocoela duebenum, and this work was devoted to the investigation of the effect of an exposure to the anti-androgen compound, cyproterone acetate (CPA), and/or of the presence of D. duebenum on the spermatozoa production and length. Significant reduction of the spermatozoa production was observed when G. pulex males were uninfected and exposed to CPA. There also appeared a lower number of spermatozoa when D. duebenum infects G. pulex, whatever the exposure condition. Moreover, we highlighted that CPA has no effect on spermatozoa production when males are infected by D. duebenum, and no treatment has impacted the spermatozoa length. Our results suggest CPA and D. duebenum could impact the endocrine system of G. pulex and especially processes close to the spermatozoa production (e.g., androgenic gland, androgen gland hormone released, gonad-inhibiting hormone synthesized by X-organ). However, as no mechanism of action was highlighted, further testing need to be performed to improve the understanding of their impacts. Finally, results confirm that vertically transmitted microsporidia could be a confounding factor in the endocrine disruption assessments in Gammaridae. PMID- 28905183 TI - Effects of quebracho tannin extract on intake, digestibility, rumen fermentation, and methane production in crossbred heifers fed low-quality tropical grass. AB - The aim of this work was to evaluate the effect of quebracho tannins extract (QTE) on feed intake, dry matter (DM) digestibility, and methane (CH4) emissions in cattle fed low-quality Pennisetum purpureum grass. Five heifers (Bos taurus * Bos indicus) with an average live weight (LW) of 295 +/- 19 kg were allotted to five treatments (0, 1, 2, 3, and 4% QTE/kg DM) in a 5 * 5 Latin square design. Intake, digestibility, and total methane emissions (L/day) were recorded for periods of 23 h when cattle were housed in open-circuit respiration chambers. Dry matter intake (DMI), organic matter intake (OMI), dry matter digestibility (DMD), and organic matter digestibility (OMD) were different between treatments with 0 and 4% of QTE/kg DM (P < 0.05). Total volatile fatty acid and the molar proportion of acetate in the rumen was not affected (P < 0.05); however, the molar proportion of propionate increased linearly (P < 0.01) for treatments with 3 and 4% QTE. Total CH4 production decreased linearly (P < 0.01) as QTE increased in the diet, particularly with 3 and 4% concentration. When expressed as DMI and OMI by CH4, production (L/kg) was different between treatments with 0 vs 3 and 4% QTE (P < 0.05). It is concluded that the addition of QTE at 2 or 3% of dry matter ration can decrease methane production up to 29 and 41%, respectively, without significantly compromising feed intake and nutrients digestibility. PMID- 28905184 TI - Energy transfer and kinetics in mechanochemistry. AB - Mechanochemistry (MC) exerts extraordinary degradation and decomposition effects on many chlorinated, brominated, and even fluorinated persistent organic pollutants (POPs). However, its application is still limited by inadequate study of its reaction kinetic aspects. In the present work, the ball motion and energy transfer in planetary ball mill are investigated in some detail. Almost all milling parameters are summarised in a single factor-total effective impact energy. Furthermore, the MC kinetic between calcium oxide/Al and hexachlorobenzene is well established and modelled. The results indicate that total effective impact energy and reagent ratio are the two factors sufficient for describing the MC degradation degree of POPs. The reaction rate constant only depends on the chemical properties of reactants, so it could be used as an important index to appraise the quality of MC additives. This model successfully predicts the reaction rate for different operating conditions, indicating that it could be suitably applied for conducting MC reactions in other reactors. PMID- 28905185 TI - Hepatotoxicity of monoterpenes and sesquiterpenes. AB - Public interest in natural therapies has increased significantly over past decades. Herbs and herbal products are extensively consumed worldwide and they are generally considered as safe. However, this may not always be true as many cases of herb-induced liver injury are reported every year. The liver is a frequent target tissue of toxicity from all classes of toxicants as liver structure and function predispose it to high sensitivity to xenobiotics. The present review is focused on the hepatotoxic properties of monoterpenes and sesquiterpenes, plant secondary metabolites that represent the major components of essential oils wildly used in folk medicines, pharmaceutical industry and cosmetics. Most of these terpenes easily enter the human body by oral absorption, penetration through the skin, or inhalation leading to measurable blood concentrations. Several studies showed that some monoterpenes (e.g., pulegone, menthofuran, camphor, and limonene) and sesquiterpenes (e.g., zederone, germacrone) exhibited liver toxicity, which is mainly based on reactive metabolites formation, increased concentration of reactive oxygen species and impaired antioxidant defense. There is a high probability that many other terpenes, without sufficiently known metabolism and effects in human liver, could also exert hepatotoxicity. Especially terpenes, that are important components of essential oils with proved hepatotoxicity, should deserve more attention. Intensive research in terpenes metabolism and toxicity represent the only way to reduce the risk of liver injury induced by essential oils and other terpenes containing products. PMID- 28905186 TI - Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes. AB - Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel alpha subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a beta1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the beta3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five alpha subunits with beta1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with beta1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 MUmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with beta1 was lowered from 8.4 to 4.5 MUmol/L by coexpression with beta3. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various alpha subunits. Moreover, the beta3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants. PMID- 28905187 TI - Altered B Cell Homeostasis in Patients with Major Depressive Disorder and Normalization of CD5 Surface Expression on Regulatory B Cells in Treatment Responders. AB - Pro-inflammatory activity and cell-mediated immune responses have been widely observed in patients with major depressive disorder (MDD). Besides their well known function as antibody-producers, B cells play a key role in inflammatory responses by secreting pro- and anti-inflammatory factors. However, homeostasis of specific B cell subsets has not been comprehensively investigated in MDD. In this study, we characterized circulating B cells of distinct developmental steps including transitional, naive-mature, antigen-experienced switched, and non switched memory cells, plasmablasts and regulatory B cells by multi-parameter flow cytometry. In a 6-weeks follow-up, circulating B cells were monitored in a small group of therapy responders and non-responders. Frequencies of naive lgD+CD27- B cells, but not lgD+CD27+ memory B cells, were reduced in severely depressed patients as compared to healthy donors (HD) or mildly to moderately depressed patients. Specifically, B cells with immune-regulatory capacities such as CD1d+CD5+ B cells and CD24+CD38hi transitional B cells were reduced in MDD. Also Bm1-Bm5 classification in MDD revealed reduced Bm2' cells comprising germinal center founder cells as well as transitional B cells. We further found that reduced CD5 surface expression on transitional B cells was associated with severe depression and normalized exclusively in clinical responders. This study demonstrates a compromised peripheral B cell compartment in MDD with a reduction in B cells exhibiting a regulatory phenotype. Recovery of CD5 surface expression on transitional B cells in clinical response, a molecule involved in activation and down-regulation of B cell responses, further points towards a B cell dependent process in the pathogenesis of MDD. PMID- 28905188 TI - Novel inhibitors of lysine (K)-specific Demethylase 4A with anticancer activity. AB - Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56 MUM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure-activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions. PMID- 28905189 TI - Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. AB - This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m2) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43-1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade >= 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade >=3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150. PMID- 28905190 TI - Primary synovial sarcoma of the left heart with large amount of necrotic tissue. AB - We present a case of primary synovial sarcoma arising from the left heart, an extremely rare occurrence, with a large amount of necrotic tissue, which suggested a poor prognosis. After incomplete tumor resection, chemotherapy and radiation therapy were performed; however, PET/CT findings at 26 months after the operation revealed local recurrence. Although we performed two additional operations following chemotherapy, the patient died from local recurrence at 36 months after the initial operation. In this case of synovial sarcoma arising from the left heart, even though aggressive multimodality therapy was performed, the prognosis was still poor. PMID- 28905191 TI - Introduction to special section on digital technology and cancer survivorship. PMID- 28905192 TI - SGLT2 inhibitors and cancer: why further evidence is required. PMID- 28905193 TI - Siglec-8 as mast cell selective target: developing paradigms amidst inconvenient truths. AB - Due to the limited efficacy of current drugs in treating systemic mast cell activation disease, there is an urgent need for more effective drugs selectively acting at mast cells. In the past, a large number of compounds have been claimed to be effective and mast cell selective on the basis of cell culture experiments and studies on blood leukocytes which could not be verified in organ and animal studies. Nevertheless, over time in review papers about potential mast cell targets mast cell selectivity of these targets has been no longer challenged. A recent example for such developing paradigms amidst inconvenient truths is the hype on the purported selective expression of the putative adhesion molecule sialic acid binding Ig-like lectin 8 (Siglec-8) in mast cells and eosinophils, although current data from different publically available databases/sources clearly demonstrate a widespread expression of Siglec-8 in the cells of most tissues. Two suggestions are presented: (1) In the specific case of Siglec-8, the limited mast cell selectivity should be kept in mind in the development and surveillance of Siglec-8-based mast cell- and eosinophil-targeted therapeutic strategies because of potential severe adverse effects in the Siglec-8-positive tissues. (2) In general, readers should always challenge reports about the selective expression of potential targets for drugs in a few cell types of the organism, even if they are published in highly renown journals. PMID- 28905194 TI - Is there an association between pemphigus and hepatitis viruses? A population based large-scale study. AB - The association between pemphigus and hepatitis viruses has not been investigated sufficiently and remains unclear. Our objective was to assess the association between pemphigus and chronic hepatitis B (HBV) and hepatitis C (HCV) infections using a large-scale real-life computerized database. This study was conducted as a cross-sectional study utilizing the database of Clalit Health Services. The proportion of chronic HBV and HCV infections was compared between patients diagnosed with pemphigus and age-, sex-, and ethnicity-matched controls. Univariate analysis was performed using chi-square and Student's t test, and multivariate analysis was performed using a logistic regression model. A total of 1985 pemphigus patients and 9874 controls were enrolled in the study. The prevalence of HBV chronic infection in patients with pemphigus was significantly higher than in control subjects (1.2 vs. 0.6%, respectively, p = 0.008). The prevalence rate of HCV carrier state was comparable between pemphigus patients and control subjects (1.1 vs. 1.0, respectively, p = 0.732). A multivariate analysis revealed a significant association between pemphigus and HBV with a multivariate odds ratio (OR) of 1.9 [95% confidence interval (CI), 1.2-3.90], whereas no association between pemphigus and HCV was identified (OR 1.1, 95% CI, 0.7-1.7). In conclusion, patients with pemphigus have a greater proportion of chronic HBV but not HCV infection relative to matched controls. PMID- 28905195 TI - Experimental evidences for miR-30b as a negative regulator of FOXO3 upregulated by kynurenine. AB - Molecular constituents regulated by the microenvironment components profoundly influence the propensity of cancer metastasis, a key event of estimating therapeutic actions of anticancer drugs. On one hand, kynurenine (Kyn), one of the microenvironment components, plays key roles in the metastasis of cancer cells in vivo; on the other hand, forkhead box O3 (FOXO3) can serve as a therapeutic target of various anticancer drugs. However, the effect of Kyn on FOXO3 is still not clear. The current study demonstrated that the selected dose of Kyn significantly upregulated the FOXO3 protein rather than FOXO3 messenger RNA (mRNA) in the lung cancer 95D cells. However, only 50 MUM Kyn markedly reduced miR-30b expression at the same time. Furthermore, the direct interaction between FOXO3 mRNA and miR-30b was also confirmed by dual-luciferase assay system. More importantly, miR-30b-induced suppression of FOXO3 protein was significantly attenuated on Kyn treatment, which demonstrated that Kyn-mediated increase of FOXO3 depended at least partly on miR-30b. In addition, Kyn-mediated upregulation of migration, a method of measuring cancer metastasis, was markedly decreased on miR-30b treatment, in vitro, which was altered in some degree via regulating FOXO3. These results suggest that miR-30b plays important roles in Kyn induced increase of FOXO3 expression. PMID- 28905196 TI - Mechanical evaluation of cerebral aneurysm clip scissoring phenomenon: comparison of titanium alloy and cobalt alloy. AB - Cerebral aneurysm clip blades crossing during surgery is well known as scissoring. Scissoring might cause rupture of the aneurysm due to laceration of its neck. Although aneurysm clip scissoring is well known, there have been few reports describing the details of this phenomenon. Quasi-scissoring phenomenon was introduced mechanically by rotating the clip head attached to a silicone sheet. The anti-scissoring torque during the twist of the blades was measured by changing the depth and the opening width. The closing force was also evaluated. Sugita straight clips of titanium alloy and cobalt alloy were used in the present study. In both materials, the anti-scissoring torque and the closing force were bigger 3 mm in thickness than 1 mm. The initial closing forces and the anti scissoring torque values at each rotation angles were increased in proportion to depth. Closing forces of titanium alloy clip were slightly higher than those of cobalt alloy clip. By contrast, anti-scissoring torque values of cobalt alloy clip were bigger than those of titanium alloy clip in all conditions. In condition of 3 mm in thickness and 3 mm in depth, anti-scissoring torque vales of titanium alloy clip decreased suddenly when an angle surpassed 70 degrees. Aneurysm clip scissoring phenomenon tends to occur when clipping the aneurysm neck only with blade tips. Based on the results of this experiment, titanium alloy clip is more prone to scissoring than cobalt alloy clip under the condition that the wide blade separation distance and the shallow blade length. PMID- 28905197 TI - Systemic glyceryl trinitrate reduces anal sphincter tone: is there a therapeutic indication? AB - BACKGROUND: Nitric oxide (NO) has diverse roles as a biological messenger. [1] Topically applied nitrate donors cause relaxation of the internal anal sphincter (IAS) and facilitate healing of anal fissures [2,3]. Systemic nitrates are commonly used for the treatment of ischaemic heart disease, yet the effects of systemically administered nitrates on the smooth muscle of the IAS are unknown. AIM: Our aim was to test the hypothesis that systemically administered nitrates at a normal dose, cause inhibition of anal sphincter activity. METHODS: With fully informed consent, anal manometry was performed on nine volunteers. Maximum and mean anal resting pressure (representing the IAS), maximum squeeze pressure (representing the external anal sphincter), heart rate and blood pressure were measured, before and after administration of a normal 400 MUg dose of sublingual glyceryl trinitrate spray. RESULTS: Data are expressed as mean (+/- standard error of the mean (SEM)). In four females and five males ranging from 19 to 50 years of age, administration of GTN resulted in a significant reduction in systolic blood pressure from 138 +/- 5 to 127 +/- 4 mmHg, P < 0.01. Mean resting pressure, over 5 min, was significantly reduced from 70 +/- 10 to 62 +/- 10 mmHg P < 0.05. The maximum resting pressure was also significantly reduced from 109 +/ 12 to 86 +/- 10 mmHg P = 0.04. Maximum squeeze pressure, heart rate and diastolic blood pressure were not significantly reduced. CONCLUSION: Systemic nitrates significantly inhibit internal anal sphincter function. PMID- 28905198 TI - Time for crowd knowledge-based approach in SBRT planning. PMID- 28905199 TI - Early prenatal diagnosis of a lumbo-costo-vertebral syndrome. AB - Lumbo-costo-vertebral syndrome (LCVS) is a rare type of lumbar hernia with associated abnormalities of the vertebral bodies, ribs, and trunk muscles. Only a few cases have been reported in the literature, all of which were diagnosed after birth. We present a case of LCVS diagnosed early in the second trimester of pregnancy using two- and three-dimensional ultrasound. In our case, the associated anomalies were: multiple costovertebral anomalies, lumbar hernia, anal imperforation, left hand supernumerary digit, and clubfoot. PMID- 28905200 TI - Development of a Stable Lung Microbiome in Healthy Neonatal Mice. AB - The lower respiratory tract has been previously considered sterile in a healthy state, but advances in culture-independent techniques for microbial identification and characterization have revealed that the lung harbors a diverse microbiome. Although research on the lung microbiome is increasing and important questions were already addressed, longitudinal studies aiming to describe developmental stages of the microbial communities from the early neonatal period to adulthood are lacking. Thus, little is known about the early-life development of the lung microbiome and the impact of external factors during these stages. In this study, we applied a barcoding approach based on high-throughput sequencing of 16S ribosomal RNA gene amplicon libraries to determine age-dependent differences in the bacterial fraction of the murine lung microbiome and to assess potential influences of differing "environmental microbiomes" (simulated by the application of used litter material to the cages). We could clearly show that the diversity of the bacterial community harbored in the murine lung increases with age. Interestingly, bacteria belonging to the genera Delftia and Rhodococcus formed an age-independent core microbiome. The addition of the used litter material influenced the lung microbiota of young mice but did not significantly alter the community composition of adult animals. Our findings elucidate the dynamic nature of the early-life lung microbiota and its stabilization with age. Further, this study indicates that even slight environmental changes modulate the bacterial community composition of the lung microbiome in early life, whereas the lung microbes of adults demonstrate higher resilience towards environmental variations. PMID- 28905201 TI - Assessment of intratumor heterogeneity in mesenchymal uterine tumor by an 18F-FDG PET/CT texture analysis. AB - OBJECTIVE: The aim of this study was to retrospectively evaluate the clinical significance of 18F-FDG PET/CT textural features for discriminating uterine sarcoma from leiomyoma. METHODS: Fifty-five patients with suspected uterine sarcoma based on ultrasound and MRI findings who underwent pretreatment 18F-FDG PET/CT were included. Fifteen patients were histopathologically proven to have uterine sarcoma, 14 patients by surgical operation and one by biopsy, and 40 patients were diagnosed with leiomyoma by surgical operation or in a follow-up for at least 2 years. A texture analysis was performed on PET/CT images from which second- and higher order textural features were extracted in addition to standardized uptake values (SUVs) and other first-order features. The accuracy of PET features for differentiating between uterine sarcoma and leiomyoma was evaluated using a receiver-operating-characteristic (ROC) analysis. RESULTS: The intratumor distribution of 18F-FDG was more heterogeneous in uterine sarcoma than in leiomyoma. Entropy, correlation, and uniformity calculated from normalized gray-level co-occurrence matrices and SUV standard deviation derived from histogram statistics showed greater area under the ROC curves (AUCs) than did maximum SUV for differentiating between sarcoma and leiomyoma. Entropy, as a single feature, yielded the greatest AUC of 0.974 and the optimal cut-off value of 2.85 for entropy provided 93% sensitivity, 90% specificity, and 92% accuracy. When combining conventional features with textural ones, maximum SUV (cutoff: 6.0) combined with entropy (2.85) and correlation (0.73) provided the best diagnostic performance (100% sensitivity, 94% specificity, and 95% accuracy). CONCLUSIONS: In combination with the conventional histogram statistics and/or volumetric parameters, 18F-FDG PET/CT textural features reflecting intratumor metabolic heterogeneity are useful for differentiating between uterine sarcoma and leiomyoma. PMID- 28905202 TI - Drug interactions in users of tablet vs. oral liquid levothyroxine formulations: a real-world evidence study in primary care. AB - PURPOSE: Several medications may interact with levothyroxine (LT4) intestinal absorption or metabolism, thus reducing its bioavailability. We investigated the variability of thyroid stimulating hormone (TSH) levels and prescribed daily dosages (PDDs) of LT4 before and during potential drug-drug interactions (DDIs) in users of tablets vs. oral liquid LT4 formulations. METHODS: By using the Italian general practice Health Search Database (HSD), we retrospectively selected adult patients with at least one LT4 prescription from 2012 to 2015 and at least 1 year of clinical history recorded. The incident prescription of interacting medications (e.g., proton pump inhibitors, calcium or iron salts) was the index date. Analysis was carried out using a self-controlled study design. RESULTS: Overall, 3965 users of LT4 formed the study cohort (84.1% women, mean age 56 +/- 16.5 years). TSH variability on the entry date was greater among liquid LT4 users than in those prescribed with tablets as shown by the difference between 75th and 25th centile, which were 3.01 and 3.8, respectively. The incidence rate ratio (IRR) for TSH variability did not differ between groups, before and during exposure to DDIs. In contrast, PDDs less likely increased during the exposure to DDI with oral liquid LT4 compared with tablets (IRR = 0.84; 95% CI: 0.77-0.92), especially in patients with post-surgical hypothyroidism (IRR = 0.75; 95% CI: 0.64-0.85). CONCLUSIONS: In clinical practice, the use of oral liquid LT4 is not associated with increased PDDs, compared with tablets formulation, during exposure to DDIs. These results support the need for individualizing LT4 formulation to prescribe, especially in patients with various comorbidities and complex therapeutic regimens. PMID- 28905205 TI - Body farms. PMID- 28905203 TI - Adaptive resolution simulations of biomolecular systems. AB - In this review article, we discuss and analyze some recently developed hybrid atomistic-mesoscopic solvent models for multiscale biomolecular simulations. We focus on the biomolecular applications of the adaptive resolution scheme (AdResS), which allows solvent molecules to change their resolution back and forth between atomistic and coarse-grained representations according to their positions in the system. First, we discuss coupling of atomistic and coarse grained models of salt solution using a 1-to-1 molecular mapping-i.e., one coarse grained bead represents one water molecule-for development of a multiscale salt solution model. In order to make use of coarse-grained molecular models that are compatible with the MARTINI force field, one has to resort to a supramolecular mapping, in particular to a 4-to-1 mapping, where four water molecules are represented with one coarse-grained bead. To this end, bundled atomistic water models are employed, i.e., the relative movement of water molecules that are mapped to the same coarse-grained bead is restricted by employing harmonic springs. Supramolecular coupling has recently also been extended to polarizable coarse-grained water models with explicit charges. Since these coarse-grained models consist of several interaction sites, orientational degrees of freedom of the atomistic and coarse-grained representations are coupled via a harmonic energy penalty term. The latter aligns the dipole moments of both representations. The reviewed multiscale solvent models are ready to be used in biomolecular simulations, as illustrated in a few examples. PMID- 28905204 TI - Racial (vs. self) affirmation as a protective mechanism against the effects of racial exclusion on negative affect and substance use vulnerability among black young adults. AB - Affirming one's racial identity may help protect against the harmful effects of racial exclusion on substance use cognitions. This study examined whether racial versus self-affirmation (vs. no affirmation) buffers against the effects of racial exclusion on substance use willingness and substance use word associations in Black young adults. It also examined anger as a potential mediator of these effects. After being included, or racially excluded by White peers, participants were assigned to a writing task: self-affirmation, racial-affirmation, or describing their sleep routine (neutral). Racial exclusion predicted greater perceived discrimination and anger. Excluded participants who engaged in racial affirmation reported reduced perceived discrimination, anger, and fewer substance use cognitions compared to the neutral writing group. This relation between racial-affirmation and lower substance use willingness was mediated by reduced perceived discrimination and anger. Findings suggest racial-affirmation is protective against racial exclusion and, more generally, that ethnic based approaches to minority substance use prevention may have particular potential. PMID- 28905206 TI - Improved diagnosis of the number of stenosed coronary artery vessels by segmentation with scatter and photo-peak window data for attenuation correction in myocardial perfusion SPECT. AB - BACKGROUND: Attenuation correction using segmentation of scatter and photo-peak window data (SSPAC) enables an evaluation of the attenuation map in a patient specific manner without additional radiation exposure. We compared the accuracy of SSPAC and non-corrected myocardial perfusion scintigraphy methods for diagnosing the number of stenosed coronary artery vessels. METHODS AND RESULTS: We retrospectively reviewed the data from 183 consecutive patients who underwent 99mTc-tetrofosmin stress/rest SPECT examination and a coronary angiography within 3 months. The MPS images were reconstructed with and without SSPAC attenuation correction. We examined the accuracy of the quantitative interpretation using summed differential score in the detection of coronary artery disease (CAD). The attenuation maps were successfully determined in 179 of 183 patients (98%). In terms of the vessel-based diagnostic ability, sensitivity, specificity, positive predictive and negative predictive values of the SSPAC and non-correction methods for diagnosing CAD in individual coronary territories were 77%*, 89%, 74%*, and 90%* vs 51%, 87%, 62%, and 82%, respectively (*P < .05). In 35 patients with multi-vessel CAD, those values were 78%*, 81%, 93%, and 55%* vs 49%, 81%, 89%, and 34%, respectively (*P < .05; AUC: 0.82 vs 0.62, P < .05). CONCLUSION: SSPAC corrected SPECT myocardial perfusion images exhibit improved accuracy in the detection of the number of stenosed coronary artery vessels, even in patients with multi-vessel CAD. PMID- 28905207 TI - Role of vasopressin V1a receptor in ?9-tetrahydrocannabinol-induced cataleptic immobilization in mice. AB - RATIONALE: Cannabis is a widely used illicit substance. ?9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to cause catalepsy in rodents. Recent studies have shown that vasopressin V1a and V1b receptors are widely distributed in the central nervous system and are capable of influencing a wide variety of brain functions such as social behavior, emotionality, and learning and memory. OBJECTIVES: The present study was designed to examine the possible involvement of V1a and V1b receptors in THC-induced catalepsy-like immobilization. METHODS: The induction of catalepsy following treatment with THC (10 mg/kg, i.p.) or haloperidol (1 mg/kg, i.p.) was evaluated in wild-type (WT), V1a receptor knockout (V1aRKO), and V1b receptor knockout (V1bRKO) mice. The effect of treatment with the selective 5-hydroxytryptamine1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.) on THC-induced catalepsy was also evaluated in V1aRKO mice. Moreover, the effects of the V1a receptor antagonist VMAX-357 and the V1b receptor antagonist ORG-52186 on THC-induced catalepsy were evaluated in ddY mice. RESULTS: THC and haloperidol markedly caused catalepsy in V1bRKO mice as well as in WT mice. However, V1aRKO mice exhibited a reduction in catalepsy induced by THC but not by haloperidol. WAY100635 dramatically enhanced THC induced catalepsy in V1aRKO mice. Although VMAX-357 (10 mg/kg, p.o.) but not ORG 52186 significantly attenuated THC-induced catalepsy, it had no significant effect on the enhancement of THC-induced catalepsy by WAY100635 in ddY mice. CONCLUSIONS: These findings suggest that V1a receptor regulates THC-induced catalepsy-like immobilization. PMID- 28905208 TI - Current Total Knee Designs: Does Baseplate Roughness or Locking Mechanism Design Affect Polyethylene Backside Wear? AB - BACKGROUND: Tibial baseplate roughness and polyethylene-insert micromotion resulting from locking-mechanism loosening can lead to polyethylene backside wear in TKAs. However, many retrieval studies examining these variables have evaluated only older TKA implant designs. QUESTIONS: We used implant-retrieval analysis to examine if there were differences in: (1) backside damage scores, (2) backside damage modes, and (3) backside linear wear rates in five TKA implant designs owing to differing baseplate surface roughness and locking mechanisms. Additionally, we examined if (4) patient demographics influence backside damage and wear. METHODS: Five TKA implant models (four modern and one historical design) were selected with different tibial baseplate and/or locking mechanism designs. Six tibial inserts retrieved at the time of revision from each TKA model were matched for time in vivo, age of the patient at TKA revision, BMI, sex, revision number, and revision reason. Each insert backside was analyzed for: (1) visual total damage score and (2) individual visual damage modes, both by two observers and with an intraclass correlation coefficient of 0.66 (95% CI, 0.39 0.92), and (3) linear wear rate measured by micro-CT. Median primary outcomes were compared among the five designs. For our given sample size among five groups we could detect with 80% power a 10-point difference in damage score and an 0.11 mm per year difference in wear rate. RESULTS: The polished tibial design with a partial peripheral capture locking mechanism and anterior constraint showed a lower total damage score compared with the nonpolished tibial design with only a complete peripheral-rim locking mechanism (median, 12.5; range, 9.5-18.0; 95% CI, 9.58-16.42 versus median, 22.3; range, 15.5-27.0; 95% CI, 17.5-26.5; p = 0.019). The polished baseplate with a tongue-in-groove locking mechanism showed more abrasions than the nonpolished baseplate with a peripheral-rim capture and antirotational island (median, 7.25; range, 0.5-8.0; 95% CI, 2.67-8.99 versus median, 0.75; range, 0-1.5; 95% CI, 0.20-1.47; p = 0.016)). Dimpling was a unique wear mode to the nonpolished baseplates with the peripheral-rim capture and antirotational island (median, 5.5; range, 2.0-9.0; 95% CI, 2.96-8.38) and the peripheral-rim capture alone (median, 9.0; range, 6.0-10.0; 95% CI, 7.29-10.38). Overall, the linear wear rate for polished designs was lower than for nonpolished designs (0.0102 +/- 0.0044 mm/year versus 0.0224 +/- 0.0119 mm/year; p < 0.001). Two of the polished baseplate designs, the partial peripheral capture with anterior constraint (median, 0.083 mm/year; range, 0.0037-0.0111 mm/year; 95% CI, 0.0050-0.0107 mm versus median, 0.0245 mm/year; range, 0.014-0.046 mm/year; 95% CI, 0.0130-0.0414 mm; p = 0.008) and the tongue-in-groove locking mechanism (median, 0.0085 mm/year; range, 0.005-0.015 mm/year; 95% CI, 0.0045-0.0138 mm; p = 0.032) showed lower polyethylene linear wear rates compared with the nonpolished baseplate design with only a peripheral-rim capture. CONCLUSIONS: Total damage scores and linear wear rates were highest involving the nonpolished design with only a peripheral rim capture. There were no differences among the other TKA designs regarding damage and wear, but this finding should be considered in the setting of a relatively small sample size. CLINICAL RELEVANCE: Our study showed that in the complex interplay between baseplate surface finish and locking mechanism design, a polished baseplate with a robust locking mechanism had the lowest backside damage and linear wear. However, improvements in locking mechanism design in nonpolished baseplates potentially may offset some advantages of a polished baseplate. Further retrieval analyses need to be done to confirm such findings, especially analyzing current crosslinked polyethylene. Additionally, we need mid- and long-term studies comparing TKA revisions attributable to wear and osteolysis among implants before understanding if such design differences are clinically relevant. PMID- 28905209 TI - Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls. AB - PURPOSE: The fusion gene BCR-ABL has an important role to the progression of chronic myeloid leukemia (CML) and several signaling pathways have been characterized as responsible for the terminal blastic phase (BP). However, the initial phase, the chronic phase (CP), is long lasting and there is much yet to be understood about the critical role of BCR-ABL in this phase. This study aims to evaluate transcriptional deregulation in CD34+ hematopoietic cells (CD34+ cells) from patients with untreated newly diagnosed CML compared with CD34+HC from healthy controls. METHODS: Gene expression profiling in CML-CD34 cells and CD34 cells from healthy controls were used for this purpose with emphasis on five main pathways important for enhanced proliferation/survival, enhanced self renewal and block of myeloid differentiation. RESULTS: We found 835 genes with changed expression levels (fold change >= +/-2) in CML-CD34 cells compared with CD34 cells. These include genes belonging to PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways. Four of these pathways converge to MYC activation. We also identified five transcripts upregulated in CD34-CML patients named OSBPL9, MEK2, p90RSK, TCF4 and FZD7 that can be potential biomarkers in CD34-CML CP. CONCLUSION: We show several mRNAs up- or downregulated in CD34-CML during the chronic phase. PMID- 28905210 TI - Impact of pharmacological spasm provocation test in patients with a history of syncope. AB - Coronary artery spasm is involved in the pathogenesis of various cardiac disorders. We investigated patients with a history of syncope who underwent elective coronary angiography. We retrospectively analyzed 5781 consecutive patients who had diagnostic or follow-up angiography during a 26-year period. During this period, we found 95 patients with a history of syncope before elective coronary angiography. Pharmacological spasm provocation testing was performed in 64 patients with a history of syncope (<1 year). Positive pharmacological response was observed in 48 patients, while the remaining 16 patients had negative tests. Positive spasm was defined as a transient >=90% narrowing with ischemic electrocardiographic changes. Among the 64 patients, definite coronary spastic angina (CSA) was found in 35 patients (54.7%) and suspected CSA was found in 13 patients (20.3%). Among the 35 patients with definite CSA, 22 patients (62.9%) had chest symptoms before syncope, but 13 (37.1%) had no chest symptom before syncope. No difference in clinical characteristics was observed between the two groups. Focal spasm during pharmacological spasm provocation tests was significantly higher in patients with chest symptoms than in those without chest symptoms before syncope (54.3 vs. 12.0%, p < 0.002). CSA was observed in 75.0% of patients with a history of syncope (<1 year). Thirteen patients with definite CSA had neither chest pain nor chest pressure before syncope. We should therefore investigate coronary artery spasm as a potential etiology in patients with a history of syncope. PMID- 28905211 TI - Three nights leg thermal therapy could improve sleep quality in patients with chronic heart failure. AB - Sleep quality is often impaired in patients with chronic heart failure (HF), which may worsen their quality of life and even prognosis. Leg thermal therapy (LTT), topical leg warming, has been shown to improve endothelial function, oxidative stress, and cardiac function in patients with HF. However, its short term influence to sleep quality has not been evaluated in HF patients. Eighteen of 23 patients with stable HF received LTT (15 min of warming at 45 degrees C and 30 min of insulation) at bedtime for 3 consecutive nights and 5 patients served as control. Subjective sleep quality was evaluated by St. Mary's Hospital Sleep Questionnaire, Oguri-Shirakawa-Azumi Sleep Inventory, and Epworth sleepiness scale, and also objectively evaluated by polysomnography. LTT significantly improved subjective sleep quality indicated by depth of sleep (p < 0.01), sleep duration (p < 0.05), number of awaking (p < 0.01), nap duration (p < 0.01), sleep quality (p < 0.05), and sleep satisfaction (p < 0.05). It was also objectively affirmed by a slight but significant decrease of sleep stage N1 (p < 0.01), and increase in sleep stage N2 (p < 0.05). No significant changes occurred in the controls. Hence, the short-term LTT could improve subjective and objective sleep quality in patients with HF. LTT can be a complimentary therapy to improve sleep quality in these patients. PMID- 28905212 TI - Hub-and-spoke stroke network in the Veneto region: a retrospective study investigating the effectiveness of the stroke pathway and trends over time. AB - After recognizing the pivotal role played by stroke unit (SU) admission in reducing mortality and dependency in stroke patients, the need to organize and monitor stroke networks has become an increasingly essential aspect of stroke care. We conducted a retrospective study of stroke patients admitted to hospitals in the Veneto region from 2007 to 2015 in order to evaluate the effectiveness of the stroke pathway and trends over time. Between 2007 and 2015, 61,062 stroke patients were discharged from Veneto hospitals: they were more frequently female, females were older than males, and had higher intrahospital mortality and a lower probability of undergoing systemic thrombolysis. Patients admitted to facilities with a level 2 SU were twice as likely to undergo thrombolytic treatment compared to those admitted to facilities with a level 1 and had a lower intrahospital mortality rate. During the collection period, thrombolytic treatments increased in both level 1 and 2 SUs, as did the number of patients admitted to neurology wards and to facilities with an SU. Our study confirmed that thrombolytic treatment and admission to a facility with an SU are important determinants in improving stroke patient outcome. The increase in the proportion of both SU admissions and thrombolytic treatments demonstrates the effectiveness of the regional hub-and-spoke organization model, suggesting that implementation of highly specialized facilities is an efficient strategy in improving stroke care. The role of the observed sex bias in stroke treatment and outcome needs to be explored. PMID- 28905213 TI - Questions about lower inner zone tumors in early-stage breast cancer. PMID- 28905214 TI - miR-217-5p induces apoptosis by directly targeting PRKCI, BAG3, ITGAV and MAPK1 in colorectal cancer cells. AB - Apoptosis is a genetically directed process of programmed cell death. A variety of microRNAs (miRNAs), endogenous single-stranded non-coding RNAs of about 22 nucleotides in length have been shown to be involved in the regulation of the intrinsic or extrinsic apoptotic pathways. There is increasing evidence that the aberrant expression of miRNAs plays a causal role in the development of diseases such as cancer. This makes miRNAs promising candidate molecules as therapeutic targets or agents. MicroRNA (miR)-217-5p has been implicated in carcinogenesis of various cancer entities, including colorectal cancer. Here, we analyzed the pro apoptotic potential of miR-217-5p in a variety of colorecatal cancer cell lines showing that miR-217-5p mimic transfection led to the induction of apoptosis causing the breakdown of mitochondrial membrane potential, externalization of phosphatidylserine, activation of caspases and fragmentation of DNA. Furthermore, elevated miR-217-5p levels downregulated mRNA and protein expression of atypical protein kinase c iota type I (PRKCI), BAG family molecular chaperone regulator 3 (BAG3), integrin subunit alpha v (ITGAV) and mitogen-activated protein kinase 1 (MAPK1). A direct miR-217-5p mediated regulation to those targets was shown by repressed luciferase activity of reporter constructs containing the miR-217-5p binding sites in the 3' untranslated region. Taken together, our observations have uncovered the apoptosis-inducing potential of miR-217-5p through its regulation of multiple target genes involved in the ERK-MAPK signaling pathway by regulation of PRKCI, BAG3, ITGAV and MAPK1. PMID- 28905215 TI - GmMYB58 and GmMYB205 are seed-specific activators for isoflavonoid biosynthesis in Glycine max. AB - KEY MESSAGE: GmMYB58 and GmMYB205 are key positive regulators that are involved in isoflavonoid biosynthesis in seeds of Glycine max, and they activate the expression of several structural genes in the isoflavonoid pathway. MYB transcription factors (TFs) are major regulators involved in flavonoid/isoflavonoid biosynthesis in many plant species. However, functions of most MYB TFs remain unknown in flavonoid/isoflavonoid pathway in Glycine max. In this study, we identified 321 MYB TFs by genome-wide searching, and further isolated and functionally characterized two MYB TFs, GmMYB58 and GmMYB205. The deduced GmMYB58 and GmMYB205 proteins contain highly conserved R2R3 repeat domain at the N-terminal region that is the signature motif of R2R3-type MYB TFs. GmMYB58 and GmMYB205 were highly expressed in early seed development stages than in the other tested organs. GmMYB58 and GmMYB205 GFP fusion proteins were found to be localized in the nucleus when they were transiently expressed in Arabidopsis thaliana mesophyll protoplast. Both GmMYB58 and GmMYB205 can activate the promoter activities of GmCHS, GmIFS2, and GmHID in the transient trans activation assays, and the activation of GmHID by both GmMYB58 and GmMYB205 was further confirmed by yeast one-hybrid assay. In addition, over-expression of GmMYB58 and GmMYB205 resulted in significant increases in expression levels of several pathway genes in soybean hairy roots, in particular, IFS2 by more than fivefolds in GmMYB205-over-expressing lines. Moreover, isoflavonoid contents were remarkably enhanced in the GmMYB58 and GmMYB205 over-expressing hairy roots than in the control. Our results suggest that GmMYB58 and GmMYB205 are seed-specific TFs, and they can enhance isoflavonoid biosynthesis mainly through the regulation of GmIFS2 and GmHID in G. max. PMID- 28905216 TI - Slowly progressing varicella zoster brainstem encephalitis complicating Ramsay Hunt syndrome in an immunocompetent patient: case report and review of the literature. AB - A 56-year-old immunocompetent male developed brainstem encephalitis complicating Ramsay Hunt syndrome. The disease had a slowly progressing course of months after the triggering infection, much longer than previously reported. Furthermore, magnetic resonance imaging, physical-chemical, and cell count analyses on cerebrospinal fluid were normal, whereas polymerase chain reaction for varicella zoster virus DNA was positive. The simultaneous negativity of both imaging and basic CSF exams is very rare, although possible event which confirms the irreplaceable role of viral screening on CSF. A systematic review of similar reports with highlights on the unusual aspects of our case is also presented. PMID- 28905217 TI - Early life arsenic exposure, infant and child growth, and morbidity: a systematic review. AB - Epidemiological studies have suggested a negative association between early life arsenic exposure and fetal size at birth, and subsequently with child morbidity and growth. However, our understanding of the relationship between arsenic exposure and morbidity and growth is limited. This paper aims to systematically review original human studies with an analytical epidemiological study design that have assessed arsenic exposure in fetal life or early childhood and evaluated the association with one or several of the following outcomes: fetal growth, birth weight or other birth anthropometry, infant and child growth, infectious disease morbidity in infancy and early childhood. A literature search was conducted in PubMed, TOXLINE, Web of Science, SciFinder and Scopus databases filtered for human studies. Based on the predefined eligibility criteria, two authors independently evaluated the studies. A total of 707 studies with morbidity outcomes were identified, of which six studies were eligible and included in this review. For the growth outcomes, a total of 2959 studies were found and nine fulfilled the criteria and were included in the review. A majority of the papers (10/15) emanated from Bangladesh, three from the USA, one from Romania and one from Canada. All included studies on arsenic exposure and morbidity showed an increased risk of respiratory tract infections and diarrhea. The findings in the studies of arsenic exposure and fetal, infant, and child growth were heterogeneous. Arsenic exposure was not associated with fetal growth. There was limited evidence of negative associations between arsenic exposures and birth weight and growth during early childhood. More studies from arsenic affected low- and middle-income countries are needed to support the generalizability of study findings. PMID- 28905218 TI - Health risk assessment of an abandoned herbicide factory site for transportation use in Dalian, China. AB - An abandoned herbicide factory site was used as an example of how planning should be considered for development of the site for transportation use in Dalian, China. Exposure pathways and parameters for three types of transportation use (land for a traffic hub, land for an urban road, and land for a subway) were developed. Twenty-five sampling sites were selected and 38 soil samples were collected in March 2015. Hexachlorobenzene and benzo(a)pyrene which were extracted by Soxhlet extraction and detected by gas chromatography mass spectrometry were the most significant pollutants detected. The maximum concentration of the two pollutants in the surface layer (0-0.5 m) were 0.57 and 3.10 mg/kg, and in the bottom layer (1.0 m) were 2.57 and 3.72 mg/kg, respectively. In this study, risk assessment results based on the established exposure scenario and parameters showed that there was a significant difference in traffic hub land use under specific exposure pathway and common insensitive land use exposure pathways (direct ingestion of soil, dermal contact with soil, and inhalation of soil-derived dust). Commonly considered hexachlorobenzene and benzo(a)pyrene carcinogenic risk values exceeded the maximum acceptable level (10 6) and were found to be 23.9-fold and 189-fold higher than the carcinogenic risk values, respectively. Parameter sensitivity analysis data showed that for transportation use, the two parameters "EFOa" and "OSIRa" were the most significant factors associated with variation of the carcinogenic risk value. For traffic hub land use, urban road land use, and subway land use, the main exposure pathways were through "inhalation of soil vapors outdoors (from surface soil)," "direct ingestion of soil," and "inhalation of soil vapors indoors (from bottom soil)," which contributed 84.75, 73.00, and 100.00% to the total risk value, respectively. PMID- 28905219 TI - Letter to the Editor: Presentation of extrapontine myelinolysis associated with hypernatremia in an infant: a case report. PMID- 28905220 TI - Haplotype Study in SCA10 Families Provides Further Evidence for a Common Ancestral Origin of the Mutation. AB - Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas. However, the ancestral origin of SCA10 mutation remains under speculation. Samples of SCA10 patients from two Latin American countries were analysed, being 16 families from Brazil (29 patients) and 21 families from Peru (27 patients) as well as 49 healthy individuals from Indigenous Quechua population and 51 healthy Brazilian individuals. Four polymorphic markers spanning a region of 5.2 cM harbouring the ATTCT expansion were used to define the haplotypes, which were genotyped by different approaches. Our data have shown that 19-CGGC-14 shared haplotype was found in 47% of Brazilian and in 63% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57%), but they are statistically different from Brazilian controls (12%) (p < 0.001). The most frequent expanded haplotype in Quechuas, 19-15-CGGC-14-10, is found in 50% of Brazilian and in 65% of Peruvian patients with SCA10. These findings bring valuable evidence that ATTCT expansion may have arisen in a Native American chromosome. PMID- 28905221 TI - Comparison between percutaneous and open reduction for treating paediatric talar neck fractures. AB - BACKGROUND: The purpose of the study was to introduce percutaneous reduction and fixation of paediatric talar neck fractures. The study also included a comparison between the technique and the conventional open surgery. METHODS: From October 2003 to May 2013, 23 children (group A) with closed two-part talar neck fractures were treated with percutaneous reduction. For comparison, another group of 26 children (group B) were treated with the conventional open surgery. A p value < 0.05 was considered statistically significant. RESULTS: In group A, bone healing was achieved in all cases at a mean of eight weeks. At the mean follow-up of 27 months, mean plantar flexion and dorsiflexion reached 96% of the opposite, normal, side. There were 20 excellent and three good results. In group B, bone healing occurred in 21 of 26 cases at a mean of 11 weeks. Nonunion was noted in five patients, among whom three were combined with avascular necrosis of the talar body. Mean follow-up was 29 months; mean plantar flexion and dorsiflexion reached 94% of the opposite normal side. There were 13 excellent, six good, two fair and five unsatisfactorily results. There were significant differences in the time to bone healing and in ankle-joint motion and function (p < 0.05). CONCLUSIONS: Percutaneous reduction is a successful technique for paediatric talar neck fractures. Compared with conventional open surgery, the mini-invasive procedure may produce rapid bone healing and better functional results. LEVEL OF EVIDENCE: Therapeutic study, Level Ia (perspective study). PMID- 28905222 TI - A Single-Center Retrospective Cohort Analysis of Maternal and Infant Outcomes in HIV-Infected Mothers Treated with Integrase Inhibitors During Pregnancy. AB - INTRODUCTION: Integrase strand transfer inhibitors (INSTI) are currently being investigated for the treatment of HIV in pregnancy. The purpose of this study is to evaluate the differences in maternal and infant outcomes in HIV-positive mothers treated with INSTI-containing antiretroviral therapy (ART) during pregnancy compared to protease inhibitor (PI)-containing ART. METHODS: A retrospective, cohort study of INSTI- and PI-based ART used in pregnancy between 2007 and 2015 was performed. The primary objective was to evaluate the differences in viral load (VL) suppression prior to delivery. Secondary endpoints included time to and duration of VL suppression and safety parameters in both mothers and infants. For the primary analysis, the two arms were matched 1:2 INSTI to PI based on the presence or absence of viremia at the time of pregnancy determination. Additional analysis was performed on the entire matched and unmatched dataset. RESULTS: Twenty-one patients were matched (7 INSTI and 14 PI). There were no significant differences between groups with respect to the proportion of patients with VL suppression prior to delivery (71.4% INSTI vs. 92.9% PI, p = 0.247), and there were no significant differences in any of the secondary endpoints. Patients with documented adherence issues were statistically more likely to not be virologically suppressed prior to delivery (p = 0.002). CONCLUSION: No differences in efficacy or safety were found between patients treated with INSTIs compared to PIs. This study supports the further investigation of the use of INSTIs during pregnancy to reduce HIV transmission. PMID- 28905223 TI - Phenotypic spectrum of POLG1 mutations. PMID- 28905224 TI - The outcome and risk factors for recurrence and extended hospitalization of secondary spontaneous pneumothorax. AB - PURPOSE: Secondary spontaneous pneumothorax (SSP) is difficult to treat by itself and due to its association with serious underlying diseases. It has a high rate of recurrence and often requires extended hospitalization. Therefore, we evaluated the outcome and risk factors associated with recurrence and extended hospitalization. METHODS: We retrospectively examined 61 patients with SSP, and evaluated the patients' characteristics, underlying diseases, introduction of home oxygen therapy, Brinkman index, and X-ray imaging findings to determine the risk factors for recurrence and extended hospitalization. RESULTS: There were 28 patients (46.0%) with chronic obstructive pulmonary disease, 8 (13.1%) with interstitial pneumonia, 16 (26.2%) with massive emphysema, and 9 (14.8%) with other diseases. Adhesion and mediastinal shift visualized by X-ray imaging were observed in 37 (37.9%) and 25 patients (40.1%), respectively. Recurrence occurred in 25 patients (40.9%) and the average hospitalization duration was 14.5 days (+/ 11.2). A multivariate analysis showed that adhesion on X-ray imaging was a significant risk factor for recurrence (odds ratio 4.90, 95% confidence interval 1.38-21.44) and mediastinal shift on X-ray imaging was a significant risk factor for extended hospitalization (odds ratio 6.05, 95% confidence interval 1.44 31.06). CONCLUSIONS: Findings from X-ray imaging, and not underlying diseases, are risk factors for recurrence and extended hospitalization. PMID- 28905225 TI - The feasibility and short-term clinical outcomes of single-incision laparoscopic surgery for patients with complex Crohn's disease. AB - PURPOSE: Single-incision laparoscopic surgery (SILS) offers excellent cosmetic results compared with conventional multi-port laparoscopic surgery. Recently, this technique has been applied to Crohn's disease (CD) with primary ileocolic strictures; however, the application of a laparoscopic approach for complex CD, which involves abscess formation, fistula formation, and recurrent CD, is controversial. The aim of this study was to investigate the safety and feasibility of SILS for patients with complex disease and to compare its clinical results in patients with complex disease vs. those with simple stricture disease. METHODS: Fifty patients who underwent SILS for CD were divided into two groups: those with complex disease (complex group, n = 25), and those with simple strictures (simple group, n = 25). The preoperative data and clinical outcomes were analyzed and compared between the groups. RESULTS: The operative time, blood loss and length of laparotomy incision were not significantly different between the groups. Although the rate of conversion and need for an additional port tended to be higher in the complex group, the rate of postoperative complications and length of hospital stay did not differ significantly between the groups. CONCLUSION: SILS may be feasible for carefully selected patients with complex CD. PMID- 28905226 TI - Identification and Characterization of Phospholipids with Very Long Chain Fatty Acids in Brewer's Yeast. AB - Yeast lipids and fatty acids (FA) were analyzed in Saccharomyces pastorianus from seven breweries and in the dietary yeast supplement Pangamin. GC-MS identified more than 30 FA, half of which were very-long chain fatty acids (VLCFA) with hydrocarbon chain lengths of >=22 C atoms. Positional isomers omega-9 and omega-7 were identified in FA with C18-C28 even-numbered alkyl chains. The most abundant omega-7 isomer was cis-vaccenic acid. The structure of monounsaturated FA was proved by dimethyl disulfide adducts (position of double bonds and cis geometric configuration) and by GC-MS of pyridyl carbinol esters. Ultra-high performance liquid chromatography-tandem mass spectrometry with negative electrospray ionization identified the phospholipids phosphatidylethanolamine, phosphatidylinositol and phosphatidylcholine, with more than 150 molecular species. Wild-type unmutated brewer's yeast strains conventionally used for the manufacture of food supplements were found to contain VLCFA. PMID- 28905227 TI - Genomics for all in the 21st century? AB - As the field of genomics enters the second decade after the completion of the International Human Genome Project, human genomics research is still far from reflective of the ancestral diversity found in global populations. This special issue of the Journal of Community Genetics brings together a global perspective on the need for researchers and health care professionals to support achievable milestones that will enhance global ancestral diversity in genomic research for the 21st century, and integrate the resulting knowledge into health care that benefits everyone. As the publications in this special issue illustrate, this will require focused community engagement, including often overlooked isolated populations, as well as meaningful integration of genomics and health services across the global landscape. With the advancement of sequencing technology and reduction in the cost, the time has come to address critical barriers. PMID- 28905228 TI - Genetic susceptibility in childhood acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future. PMID- 28905229 TI - Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes. AB - AIMS/HYPOTHESIS: Better understanding of type 2 diabetes and its prevention is a pressing need. Changes in human plasma N-glycome are associated with many diseases and represent promising diagnostic and prognostic biomarkers. Variations in glucose metabolism directly affect glycosylation through the hexosamine pathway but studies of plasma glycome in type 2 diabetes are scarce. The aim of this study was to determine whether plasma protein N-glycome is changed in individuals who are at greater risk of developing type 2 diabetes. METHODS: Using a chromatographic approach, we analysed N-linked glycans from plasma proteins in two populations comprising individuals with registered hyperglycaemia during critical illness (increased risk for development of type 2 diabetes) and individuals who stayed normoglycaemic during the same condition: AcuteInflammation (59 cases vs 49 controls) and AcuteInflammation Replication (52 cases vs 14 controls) populations. N-glycome was also studied in individuals from FinRisk (37 incident cases of type 2 diabetes collected at baseline vs 37 controls), Orkney Complex Disease Study (ORCADES; 94 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 658 controls) and Southall and Brent Revisited (SABRE) cohort studies (307 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 307 controls). RESULTS: Individuals with increased risk for diabetes type 2 development (AcuteInflammation and AcuteInflammation Replication populations), incident cases of type 2 diabetes collected at baseline (FinRisk population) and individuals with elevated HbA1c (ORCADES and SABRE populations) all presented with increased branching, galactosylation and sialylation of plasma protein N glycans and these changes were of similar magnitude. CONCLUSIONS/INTERPRETATION: Increased complexity of plasma N-glycan structures is associated with higher risk of developing type 2 diabetes and poorer regulation of blood glucose levels. Although further research is needed, this finding could offer a potential new approach for improvement in prevention of diabetes and its complications. PMID- 28905230 TI - Molecular detection of Anaplasma platys, Anaplasma phagocytophilum and Wolbachia sp. but not Ehrlichia canis in Croatian dogs. AB - The bacteria Anaplasma platys, Anaplasma phagocytophilum and Ehrlichia canis are tick-borne agents that cause canine vector-borne disease. The prevalence of these pathogens in South Eastern Europe is unknown with the exception of an isolated case of A. platys detected in a dog imported into Germany from Croatia. To gain a better insight into their presence and prevalence, PCR-based screening for these bacterial pathogens was performed on domesticated dogs from different regions of Croatia. Blood samples from 1080 apparently healthy dogs from coastal and continental parts of Croatia as well as tissue samples collected from 63 deceased dogs with a history of anaemia and thrombocytopenia were collected for molecular screening by an Anaplasmataceae-specific 16S rRNA conventional PCR. Positive samples were confirmed using a second Anaplasmataceae-specific PCR assay with the PCR product sequenced for the purpose of bacterial species identification. All sequenced isolates were georeferenced and a kernel intensity estimator was used to identify clusters of greater case intensity. 42/1080 (3.8%; CI 2.7-5.0) of the healthy dogs were PCR positive for bacteria in the Anaplasmataceae. Sequencing of the 16S rRNA gene amplified from these positive samples revealed the presence of A. platys in 2.5% (CI 1.6-3.4%, 27 dogs), A. phagocytophilum in 0.3% (CI 0-0.6%, 3 dogs) and a Wolbachia endosymbiont in 1.1% (CI 0.4-1.6%, 12 dogs) of dogs screened in this study. Necropsied dogs were free from infection. Notably, no evidence of E. canis infection was found in any animal. This survey represents a rare molecular study of Anaplasmataceae in dogs in South Eastern Europe, confirming the presence of A. platys and A. phagocytophilum but not E. canis. The absence of E. canis was surprising given it has been described in all other Mediterranean countries surveyed and raises questions over the regional vector capacity of the Rhipicephalus sanguineus tick. PMID- 28905231 TI - Sleep-disordered breathing and the risk of cognitive decline: a meta-analysis of 19,940 participants. AB - Sleep-disordered breathing (SDB) is related to the incidence of cognitive decline. However, results of cohort studies were inconsistent. We performed a meta-analysis of cohort studies to evaluate the sequential association between SDB and cognitive decline. Cohort studies were identified by the searching of PubMed and Embase databases. A random effect model was applied to combine the results. Nineteen thousand nine hundred forty participants from six cohort studies were included. Participants with SDB at baseline had significantly higher risk of cognitive decline, as indicated by a combined outcome of mild cognitive impairment (MCI) or dementia (RR = 1.69, p < 0.001; I 2 = 60%). The association between SDB and the subsequent risk of cognitive decline remains in older people (RR = 1.70, p < 0.001; I 2 = 66%). Results of subgroup analyses indicated consistent results regardless of whether SDB was confirmed by PSG or whether the apolipoprotein E4 allele was adjusted. However, participants with SDB at baseline were with higher risk for developing MCI (RR = 2.44, p < 0.001) than dementia (RR = 1.61, p < 0.001; p for subgroup difference = 0.04). Moreover, SDB was associated with a significantly higher risk of cognitive decline in female participants (RR = 2.06, p < 0.001), but not in the males (RR = 1.18, p = 0.19; p for subgroup difference = 0.03). SDB may be an independent risk factor for the developing of cognitive decline, and gender difference may exist regarding this association. PMID- 28905232 TI - Production of D-alanine from DL-alanine using immobilized cells of Bacillus subtilis HLZ-68. AB - Immobilized cells of Bacillus subtilis HLZ-68 were used to produce D-alanine from DL-alanine by asymmetric degradation. Different compounds such as polyvinyl alcohol and calcium alginate were employed for immobilizing the B. subtilis HLZ 68 cells, and the results showed that cells immobilized using a mixture of these two compounds presented higher L-alanine degradation activity, when compared with free cells. Subsequently, the effects of different concentrations of polyvinyl alcohol and calcium alginate on L-alanine consumption were examined. Maximum L alanine degradation was exhibited by cells immobilized with 8% (w/v) polyvinyl alcohol and 2% (w/v) calcium alginate. Addition of 400 g of DL-alanine (200 g at the beginning of the reaction and 200 g after 30 h of incubation) into the reaction solution at 30 degrees C, pH 6.0, aeration of 1.0 vvm, and agitation of 400 rpm resulted in complete L-alanine degradation within 60 h, leaving 185 g of D-alanine in the reaction solution. The immobilized cells were applied for more than 15 cycles of degradation and a maximum utilization rate was achieved at the third cycle. D-alanine was easily extracted from the reaction solution using cation-exchange resin, and the chemical and optical purity of the extracted D alanine was 99.1 and 99.6%, respectively. PMID- 28905234 TI - Endoscopic treatment of middle fossa arachnoid cysts. AB - BACKGROUND: Endoscopic treatment of middle fossa arachnoid cysts is an alternative option to microsurgical fenestration and shunting procedures. The procedure is minimally invasive and obviates the morbidity of craniotomy and shunting. METHODS: Operative charts and videos of patients undergoing endoscopic fenestration of middle fossa arachnoid cysts were retrieved from the senior author's database of endoscopic procedures and reviewed. Description of the surgical techniques was then formulated. CONCLUSIONS: Endoscopic fenestration of middle fossa arachnoid cysts entails communicating the cyst cavity to the basal cisterns via multiple fenestrations that should be made as large as possible with care to avoid injury of the juxtaposed neurovascular structures. PMID- 28905233 TI - Gated thoracic magnetic resonance angiography at 3T: noncontrast versus blood pool contrast. AB - Both noncontrast and contrast-enhanced approaches to gated thoracic magnetic resonance angiography (MRA) for aortic root evaluation have been reported at 3T. We compare qualitative and quantitative image quality measures for the two approaches, and assess the reproducibility of standard aortic measurements. Respiratory and cardiac gated MRA of the chest was performed at 3T in 45 patients: 23 after administration of iron-based blood pool contrast, and 22 without contrast. Image quality was assessed with a 5-point Likert scale, vessel lumen-to-muscle contrast ratios, and vessel wall sharpness. Two reviewers measured the ascending aorta diameter and valve annulus area. Interrater agreement was assessed using Bland-Altman plots and coefficient of variation (CV). Qualitative image quality was better with blood pool contrast in all principal vessels of the chest (mean Likert of 4.20 +/- 0.79 vs. 2.60 +/- 0.77, p < 0.001). Quantitative assessment was also improved with higher contrast ratios in all vessels (5.26 +/- 3.3 vs. 1.90 +/- 0.53, p < 0.001), and greater sharpness of the aortic annulus and ascending aorta (0.70 +/- 0.16 vs. 0.56 +/- 0.14 mm-1, p < 0.001, and 0.87 +/- 0.16 vs. 0.62 +/- 0.16 mm-1, p = 0.008, respectively). Reproducibility of measurement was marginally better for the ascending aorta diameter (CV of 2.80 vs. 3.23%), but substantially increased for the aortic valve annulus area with blood pool contrast (CV of 4.93 vs. 7.32%). The use of a blood pool contrast agent for gated thoracic MRA improves image quality compared to a noncontrast technique, and provides more reproducible measurements of the aortic valve annulus area. PMID- 28905235 TI - Two New Species of Xenotarsonemus (Acari: Tarsonemidae) from the Atlantic Forest, Brazil. AB - Two new species, Xenotarsonemus quiriri n. sp. and Xenotarsonemus scorpius n. sp., are described and illustrated in this paper based on specimens collected on Myrtaceae plants in Atlantic Forest areas of the states of Bahia and Santa Catarina, Brazil. A key to identification of Xenotarsonemus species reported from Brazil is provided. PMID- 28905236 TI - Diagnosis of coronary artery disease using an efficient hash table based closed frequent itemsets mining. AB - This paper proposes an efficient hash table based closed frequent itemsets (HCFI) mining algorithm to envisage coronary artery disease early. HCFI algorithm generates closed frequent itemsets efficiently by performing intersection operation on transaction id's of itemset without considering the name of item/itemset. The employed hash table reduces search efficiency to O(1) or constant time. HCFI algorithm is applied on the UCI (University of California, Irvine) Cleveland dataset, a biological database of cardiovascular disease to generate closed frequent itemsets on the dataset. The findings of HCFI algorithm are (1) it determines a set of distinguished features to differentiate a 'healthy' and a 'sick' class. The features such as heart status being normal, oldpeak being less than or equal to 1.2, slope being up, number of vessels colored being zero, absence of exercise-induced angina, maximum heart rate achieved between 151 and 180 are referred as 'healthy' class. The features like chest pain are being asymptomatic, heart-status being reversible defect, slope being flat, and presence of exercise-induced-angina and serum cholesterol being greater than 240 indicate a presumption of heart disease to both genders. (2) It predicts that females have less chance of coronary heart disease than males. This algorithm is also compared with two other state-of-the-art-algorithms 'NAFCP' (N list based algorithm for mining frequent closed patterns) and 'PredictiveApriori' to show the effectiveness of the proposed algorithm. PMID- 28905237 TI - 1H, 13C and 15N assignments of the C-terminal intrinsically disordered cytosolic fragment of the receptor tyrosine kinase ErbB2. AB - ErbB2 (or HER2) is a receptor tyrosine kinase that is involved in signaling pathways controlling cell division, motility and apoptosis. Though important in development and cell growth homeostasis, this protein, when overexpressed, participates in triggering aggressive HER2+ breast cancers. It is composed of an extracellular part and a transmembrane domain, both important for activation by dimerization, and a cytosolic tyrosine kinase, which activates its intrinsically disordered C-terminal end (CtErbB2). Little is known about this C-terminal part of 268 residues, despite its crucial role in interacting with adaptor proteins involved in signaling. Understanding its structural and dynamic characteristics could eventually lead to the design of new interaction inhibitors, and treatments complementary to those already targeting other parts of ErbB2. Here we report backbone and side-chain assignment of CtErbB2, which, together with structural predictions, confirms its intrinsically disordered nature. PMID- 28905238 TI - Methological quality of systematic reviews and meta-analyses on acupuncture for stroke: A review of review. AB - OBJECTIVE: To assess the methodological quality of systematic reviews and meta analyses regarding acupuncture intervention for stroke and the primary studies within them. METHODS: Two researchers searched PubMed, Cumulative index to Nursing and Allied Health Literature, Embase, ISI Web of Knowledge, Cochrane, Allied and Complementary Medicine, Ovid Medline, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang and Traditional Chinese Medical Database to identify systematic reviews and meta-analyses about acupuncture for stroke published from the inception to December 2016. Review characteristics and the criteria for assessing the primary studies within reviews were extracted. The methodological quality of the reviews was assessed using adapted Oxman and Guyatt Scale. The methodological quality of primary studies was also assessed. RESULTS: Thirty-two eligible reviews were identified, 15 in English and 17 in Chinese. The English reviews were scored higher than the Chinese reviews (P=0.025), especially in criteria for avoiding bias and the scope of search. All reviews used the quality criteria to evaluate the methodological quality of primary studies, but some criteria were not comprehensive. The primary studies, in particular the Chinese reviews, had problems with randomization, allocation concealment, blinding, dropouts and withdrawals, intent-to-treat analysis and adverse events. CONCLUSIONS: Important methodological flaws were found in Chinese systematic reviews and primary studies. It was necessary to improve the methodological quality and reporting quality of both the systematic reviews published in China and primary studies on acupuncture for stroke. PMID- 28905239 TI - Expression and distribution of three transient receptor potential vanilloid(TRPV) channel proteins in human odontoblast-like cells. AB - Odontoblasts have been suggested to contribute to nociceptive sensation in the tooth via expression of the transient receptor potential (TRP) channels. The TRP channels as a family of nonselective cation permeable channels play an important role in sensory transduction of human. In this study, we examined the expression of transient receptor potential vanilloid-1 (TRPV1), transient receptor potential vanilloid-2 (TRPV2) and transient receptor potential vanilloid-3 (TRPV3) channels in native human odontoblasts (HODs) and long-term cultured human dental pulp cells with odontoblast phenotyoe (LHOPs) obtained from healthy wisdom teeth with the use of immunohistochemistry (IHC), immunofluorescence (IF), quantitative real time polymerase chain reaction (qRT-PCR),western blotting (WB) and immunoelectron microscopy (IEM) assay. LHOPs samples were made into ultrathin sections, mounted on nickel grids, floated of three TRPV antibodies conjugated with 10 nm colloidal gold particles and observed under IEM at 60,000 magnifications. The relative intracellular distributions of these three channels were analyzed quantitatively on IEM images using a robust sampling, stereological estimation and statistical evaluation method. The results of IHC and IF convinced that TRPV1, TRPV2 and TRPV3 channels were expressed in native HODs and (LHOPs). The result of qRT-PCR and WB confirmed that the gene and protein expression of TRPV1, TRPV2, and TRPV3 channels and TRPV1 mRNA are more abundantly expressed than TRPV2 and TRPV3 in HODs (P < 0.05). Quantitative analysis of IEM images showed that the relative intracellular distributions of these three channels are similar, and TRPV1, TRPV2 and TRPV3 proteins were preferential labeled in human odontoblast processes, mitochondria, and endoplasmic reticulum. Thus, HODs could play an important role in mediating pulp thermo-sensation due to the expression of these three TRPV channels. The difference of relative intracellular distributions of three channels suggests that special structures such as processes may have an important role to sensing of the outer stimuli first. PMID- 28905240 TI - Different training programs decrease blood pressure during submaximal exercise. AB - OBJECTIVE: Our purpose was to study the effects of aerobic, resistance, and mixed (aerobic and resistance) training programs on blood pressure, both at rest and during submaximal exercise in healthy people. METHODS: We randomized 39 physically active, healthy participants into aerobic, resistance, and mixed (aerobic and resistance) exercise groups, and a control group. The exercise groups trained for 60 min three times/week for 6 weeks, and a submaximal cycle ergometer test was performed before and after training, and 3 weeks after detraining. Continuous blood pressure was determined before and during the test. RESULTS: At the submaximal test, both systolic and diastolic blood pressures decreased significantly (p < 0.05) after detraining in the exercise groups. However, between pre-training and detraining, we found significant reductions at rest only in the mixed exercise group (p < 0.05). CONCLUSION: Although all exercise had similar effects on blood pressure during submaximal exercise, the mixed aerobic and resistance exercise may be optimal for blood pressure reduction, by the addition of diverse physiological pathways. PMID- 28905241 TI - Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization. AB - Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products. PMID- 28905242 TI - Poly-N-Acetyl Glucosamine (sNAG) Enhances Early Rotator Cuff Tendon Healing in a Rat Model. AB - Rotator cuff injuries frequently require surgical repairs which have a high failure rate. Biological augmentation has been utilized in an attempt to improve tendon repair. Poly-N-acetyl glucosamine (sNAG) polymer containing nanofibers has been shown to increase the rate for healing of venous leg ulcers. The purpose of this study was to investigate the healing and analgesic properties of sNAG in a rat rotator cuff injury and repair model. 144 adult male Sprague-Dawley rats underwent a transection and repair of their left supraspinatus tendons. Half of the animals received a sNAG membrane on the tendon-to-bone insertion site. Animals were further subdivided, receiving 1 or 3 days of analgesics. Animals were sacrificed 2, 4, or 8 weeks post-injury. Animals sacrificed at 4 and 8 weeks underwent longitudinal in vivo ambulatory assessment. Histological properties were assessed at 2, 4, and 8 weeks, and mechanical properties at 4 and 8 weeks. In the presence of analgesics, tendons receiving the sNAG polymer had significantly increased max load and max stress at 4 weeks, but not at 8 weeks. Ambulatory improvements were observed at 14 days in stride length and speed. Therefore, sNAG improves tendon-to-bone healing in a rat rotator cuff detachment and repair model. PMID- 28905243 TI - 3D endothelial cell spheroid/human vitreous humor assay for the characterization of anti-angiogenic inhibitors for the treatment of proliferative diabetic retinopathy. AB - Proliferative diabetic retinopathy (PDR) represents a main cause of acquired blindness. Despite the recognition of the key role exerted by vascular endothelial growth factor (VEGF) in the pathogenesis of PDR, limitations to anti VEGF therapies do exist. Thus, rapid and cost-effective angiogenesis assays are crucial for the screening of anti-angiogenic drug candidates for PDR therapy. In this context, evaluation of the angiogenic potential of PDR vitreous fluid may represent a valuable tool for preclinical assessment of angiostatic molecules. Here, vitreous fluid obtained from PDR patients after pars plana vitrectomy was used as a pro-angiogenic stimulus in a 3D endothelial cell spheroid/human vitreous assay. The results show that PDR vitreous is able to stimulate the sprouting of fibrin-embedded HUVEC spheroids in a time- and dose-dependent manner. A remarkable variability was observed among 40 individual vitreous fluid samples in terms of sprouting-inducing activity that was related, at least in part, to defined clinical features of the PDR patient. This activity was hampered by various extracellular and intracellular signaling pathway inhibitors, including the VEGF antagonist ranibizumab. When tested on 20 individual vitreous fluid samples, the inhibitory activity of ranibizumab ranged between 0 and 100% of the activity measured in the absence of the drug, reflecting a variable contribution of angiogenic mediators distinct from VEGF. In conclusion, the 3D endothelial cell spheroid/human vitreous assay represents a rapid and cost effective experimental procedure suitable for the evaluation of the anti angiogenic activity of novel extracellular and intracellular drug candidates, with possible implications for the therapy of PDR. PMID- 28905244 TI - Bioresorbable vascular scaffold implantation to bail out nail gun injury in ST segment myocardial infarction. PMID- 28905245 TI - Identification of Polymorphic Forms of Active Pharmaceutical Ingredient in Low Concentration Dry Powder Formulations by Synchrotron X-Ray Powder Diffraction. AB - BACKGROUND: The identification of different (pseudo) polymorphs of an active pharmaceutical ingredient in dry powder formulations is of importance during development and entire product lifecycle, e.g., quality control. Whereas determination of polymorphic differences of pure substances is rather easy, in dry powder formulations, it is generally difficult and the difficulties increase particularly, if the substance of interest is present only in low concentrations in the formulation. Such a formulation is Spiriva(r) inhalation powder (Boehringer Ingelheim), which contains only 0.4 w/w% of the active pharmaceutical ingredient tiotropium bromide monohydrate in a matrix of alpha-lactose monohydrate as excipient. METHODS: In this study, identification of 0.4 w/w% tiotropium bromide in the dry powder formulation was examined by X-ray powder diffraction (XRPD) using a synchrotron radiation source and the results were compared with the conventional laboratory XRPD measurements. RESULTS: The detection limit of tiotropium bromide by the laboratory XRPD was around 2-5 w/w%, and hence, detection of 0.4 w/w% tiotropium bromide was impossible. The synchrotron XRPD was capable to detect significantly lower level of tiotropium bromide by at least an order of magnitude. CONCLUSION: Four different polymorphic forms of tiotropium bromide present at 0.4 w/w% concentration in lactose powder blends were unambiguously identified by the synchrotron XRPD method. PMID- 28905246 TI - [Immunizing is not only a children's matter! : Why vaccinations are also important for adults]. AB - Vaccinations belong to the ten most effective public health achievements worldwide. While immunization programms for children are installed in Europe, vaccinations for adults are not established. However, adult vaccination is extremely meaningful: increasing age means a higher susceptibility to infectious diseases, health problems and multimorbidity will increase. The burden of vaccine preventable diseases is still high in Europe. Due to immunosenescence (older) adults are less protected against pathogens, antibody titers after vaccinations are lower and immunity lasts shorter. There is striking lack of data of adult vaccination rates and an international consensus regarding adult vaccination recommendations or guidelines are not available in Europe. In only six countries a comprehensive document describing recommended vaccinations for adults is available, among them Austria. The awareness of the importance of adult vaccination over the whole lifetime is not present to the necessary extent in Europe and has to be promoted. PMID- 28905247 TI - Risky Sex in High-Risk Adolescents: Associations with Alcohol Use, Marijuana Use, and Co-Occurring Use. AB - Risky sexual behavior and substance use appear to be interconnected behaviors among adolescents, but data are scarce regarding the extent to which sexual risk behavior is associated with high levels of marijuana and alcohol use, both separately and in combination. 301 adolescents were recruited from a short-term detention facility, and substance use and risky sexual behavior were assessed. We found that adolescents who frequently used marijuana, but not alcohol, reported significantly less risky sex as well as greater intentions to use condoms than either adolescents who frequently used alcohol, but not marijuana, or adolescents who frequently used both substances. Substance use status as a predictor of future risky sexual behavior followed a similar pattern. When designing interventions to reduce substance use in the context of risky sex, it might be especially effective to target efforts toward reducing harm associated with alcohol use, either alone or in combination with marijuana use. PMID- 28905248 TI - Sexual Function and Breast-Specific Sensuality Remain Important After Breast Cancer Surgery. PMID- 28905249 TI - Difficulties in establishing the source of infection in recurrent neonatal group B streptococcal disease. PMID- 28905250 TI - Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer. AB - PURPOSE: The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. METHODS: We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. RESULTS: Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30-3.14, P = 0.025). CONCLUSIONS: TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes. PMID- 28905251 TI - Comparing the face inversion effect in crows and humans. AB - Humans show impaired recognition of faces that are presented upside down, a phenomenon termed face inversion effect, which is thought to reflect the special relevance of faces for humans. Here, we investigated whether a phylogenetically distantly related avian species, the carrion crow, with similar socio-cognitive abilities to human and non-human primates, exhibits a face inversion effect. In a delayed matching-to-sample task, two crows had to differentiate profiles of crow faces as well as matched controls, presented both upright and inverted. Because crows can discriminate humans based on their faces, we also assessed the face inversion effect using human faces. Both crows performed better with crow faces than with human faces and performed worse when responding to inverted pictures in general compared to upright pictures. However, neither of the crows showed a face inversion effect. For comparative reasons, the tests were repeated with human subjects. As expected, humans showed a face-specific inversion effect. Therefore, we did not find any evidence that crows-like humans-process faces as a special visual stimulus. Instead, individual recognition in crows may be based on cues other than a conspecific's facial profile, such as their body, or on processing of local features rather than holistic processing. PMID- 28905252 TI - Human and equipment resources for difficult airway management, airway education programs, and capnometry use in Japanese emergency departments: a nationwide cross-sectional study. AB - BACKGROUND: Although human and equipment resources, proper training, and the verification of endotracheal intubation are vital elements of difficult airway management (DAM), their availability in Japanese emergency departments (EDs) has not been determined. How ED type and patient volume affect DAM preparation is also unclear. We conducted the present survey to address this knowledge gaps. METHODS: This nationwide cross-sectional study was conducted from April to September 2016. All EDs received a mailed questionnaire regarding their DAM resources, airway training methods, and capnometry use for tube placement. Outcome measures were the availability of: (1) 24-h in-house back-up; (2) key DAM resources, including a supraglottic airway device (SGA), a dedicated DAM cart, surgical airway devices, and neuromuscular blocking agents; (3) anesthesiology rotation as part of an airway training program; and (4) the routine use of capnometry to verify tube placement. EDs were classified as academic, tertiary, high-volume (upper quartile of annual ambulance visits), and urban. RESULTS: Of the 530 EDs, 324 (61.1%) returned completed questionnaires. The availability of in-house back-up coverage, surgical airway devices, and neuromuscular blocking agents was 69.4, 95.7, and 68.5%, respectively. SGAs and dedicated DAM carts were present in 51.5 and 49.7% of the EDs. The rates of routine capnometry use (47.8%) and the availability of an anesthesiology rotation (38.6%) were low. The availability of 24-h back-up coverage was significantly higher in academic EDs and tertiary EDs in both the crude and adjusted analysis. Similarly, neuromuscular blocking agents were more likely to be present in academic EDs, high-volume EDs, and tertiary EDs; and the rate of routine use of capnometry was significantly higher in tertiary EDs in both the crude and adjusted analysis. CONCLUSIONS: In Japanese EDs, the rates of both the availability of SGAs and DAM carts and the use of routine capnometry to confirm tube placement were approximately 50%. These data demonstrate the lack of standard operating procedures for rescue ventilation and post-intubation care. Academic, tertiary, and high-volume EDs were likely to be well prepared for DAM. PMID- 28905253 TI - Co-transformation mediated stacking of blast resistance genes Pi54 and Pi54rh in rice provides broad spectrum resistance against Magnaporthe oryzae. AB - KEY MESSAGE: This is the first report of stacking two major blast resistance genes in blast susceptible rice variety using co-transformation method to widen the resistance spectrum against different isolates of Magnaporthe oryzae. Single resistance (R-) gene mediated approach for the management of rice blast disease has met with frequent breakdown in resistance response. Besides providing the durable resistance, gene pyramiding or stacking also imparts broad spectrum resistance against plant pathogens, including rice blast. In the present study, we stacked two R-genes; Pi54 and Pi54rh having broad spectrum resistance against multiple isolates of Magnaporthe oryzae (M. oryzae). Both Pi54 and Pi54rh expressed under independent promoters were transferred into the blast susceptible japonica rice Taipei 309 (TP309) using particle gun bombardment method. Functional complementation analysis of stacked transgenic rice lines showed higher level of resistance to a set of highly virulent M. oryzae isolates collected from different rice growing regions. qRT-PCR analysis has shown M. oryzae induced expression of both the R-genes in stacked transgenic lines. The present study also demonstrated the effectiveness of the strategy for rapid single step gene stacking using co-transformation approach to engineer durable resistance against rice blast disease and also this is the first report in which two blast R-genes are stacked together using co-transformation approach. The two gene-stacked transgenic line developed in this study can be used further to understand the molecular aspects of defense-related pathways vis-a-vis single R gene containing transgenic lines. PMID- 28905254 TI - Use of eculizumab in a systemic lupus erythemathosus patient presenting thrombotic microangiopathy and heterozygous deletion in CFHR1-CFHR3. A case report and systematic review. AB - The association of thrombotic microangiopathy (TMA) with systemic lupus erythematosus (SLE) has been described in 0.5 to 10% of cases, and patients present worse outcome. TMA is described as the association of microangiopathic hemolytic anemia, thrombocytopenia, and an organ injury, frequently the kidney. This study describes a successful case of use of eculizumab in a patient with SLE and TMA refractory to standard therapy, and provides a literature review. Case description and search in PubMed and MEDLINE using systemic lupus erythemathous and/or antiphospholipid syndrome (APS) and eculizumab retrieved 15 case reports. Eighteen-year-old female presented acute renal failure and TMA and was diagnosed with SLE. Steroids and IV cyclophosphamide were started together with plasma exchange. After 55 days, she still persisted with microangiopathic anemia, thrombocytopenia, and anuria, and eculizumab was introduced. She had rapid improvement in hematological parameters, and dialysis was discontinued 25 days after the first dose. Genetic analysis showed large heterozygous deletion encompassing the entire CFHR1 and CFHR3, a finding previously associated with patients presenting atypical hemolytic-uremic syndrome (aHUS). Twenty patients who received eculizumab with SLE and/or APS have been published to date: 11 were female and mean age at presentation was 31 years. Seven out of the 20 patients presented only SLE, 5 patients only APS and 8 patients both SLE and APS. Eighteen patients underwent plasma exchange, with a mean of 20 (4-120) sessions per patient. Thirteen patients received rituximab. Hematological response was evident in 100% and kidney recovery in 85% of patients. The terminal complement blockade with eculizumab is an optional treatment for patients with SLE and/or APS presenting TMA and refractory to current immunosuppression therapies. Genetic testing may help recognize patients with aHUS and SLE/APS and therefore help to determine length of treatment with eculizumab. PMID- 28905256 TI - Erratum to: Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status. AB - In the initial online publication, the values in the last two rows in Table 1 were in the wrong rows. The original article has been corrected. PMID- 28905255 TI - Benefit-Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis. AB - Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine 1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1 phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis. PMID- 28905257 TI - Complete genome analysis of a novel umbravirus-polerovirus combination isolated from Ixeridium dentatum. AB - Two novel viruses, isolated in Bonghwa, Republic of Korea, from an Ixeridium dentatum plant with yellowing mottle symptoms, have been provisionally named Ixeridium yellow mottle-associated virus 1 (IxYMaV-1) and Ixeridium yellow mottle associated virus 2 (IxYMaV-2). IxYMaV-1 has a genome of 6,017 nucleotides sharing a 56.4% sequence identity with that of cucurbit aphid-borne yellows virus (genus Polerovirus). The IxYMaV-2 genome of 4,196 nucleotides has a sequence identity of less than 48.3% with e other species classified within the genus Umbravirus. Genome properties and phylogenetic analysis suggested that IxYMaV-1 and -2 are representative isolates of new species classifiable within the genus Polerovirus and Umbravirus, respectively. PMID- 28905258 TI - Is Biomedical Research Protected from Predatory Reviewers? AB - Authors endure considerable hardship carrying out biomedical research, from generating ideas to completing their manuscripts and submitting their findings and data (as is increasingly required) to a journal. When researchers submit to journals, they entrust their findings and ideas to editors and peer reviewers who are expected to respect the confidentiality of peer review. Inherent trust in peer review is built on the ethical conduct of authors, editors and reviewers, and on the respect of this confidentiality. If such confidentiality is breached by unethical reviewers who might steal or plagiarize the authors' ideas, researchers will lose trust in peer review and may resist submitting their findings to that journal. Science loses as a result, scientific and medical advances slow down, knowledge may become scarce, and it is unlikely that increasing bias in the literature will be detected or eliminated. In such a climate, society will ultimately be deprived from scientific and medical advances. Despite a rise in documented cases of abused peer review, there is still a relative lack of qualitative and quantitative studies on reviewer-related misconduct, most likely because evidence is difficult to come by. Our paper presents an assessment of editors' and reviewers' responsibilities in preserving the confidentiality of manuscripts during the peer review process, in response to a 2016 case of intellectual property theft by a reviewer. Our main objectives are to propose additional measures that would offer protection of authors' intellectual ideas from predatory reviewers, and increase researchers' awareness of the responsible reviewing of journal articles and reporting of biomedical research. PMID- 28905259 TI - Unintended Pregnancy, Induced Abortion, and Mental Health. AB - PURPOSE OF REVIEW: The early medical literature on mental health outcomes following abortion is fraught with methodological flaws that can improperly influence clinical practice. Our goal is to review the current medical literature on depression and other mental health outcomes for women obtaining abortions. RECENT FINDINGS: The Turnaway Study prospectively enrolled 956 women seeking abortion in the USA and followed their mental health outcomes for 5 years. The control group was comprised of women denied abortions based on gestational age limits, thereby circumventing the major methodological flaw that had plagued earlier studies on the topic. Rates of depression are not significantly different between women obtaining abortion and those denied abortion. Rates of anxiety are initially higher in women denied abortion care. Counseling on decision-making for women with unintended pregnancies should reflect these findings. PMID- 28905260 TI - Reply to: Walley KC, Appleton PT, Rodriguez EK (2017): Comparison of outcomes of operative versus non-operative treatment of acetabular fractures in the elderly and severely comorbid patient, Eur J Orthop Surg Traumatol 27(5):689-694. PMID- 28905261 TI - International society for gastrointestinal hereditary tumours-InSiGHT. PMID- 28905262 TI - Non-sterile fermentations for the economical biochemical conversion of renewable feedstocks. AB - Heavy reliance on petroleum-based products drives continuous exploitation of fossil fuels, and results in serious environmental and climate problems. To address such an issue, there is a shift from petroleum sources to renewable ones. Biochemical conversion via fermentation is a primary platform for converting renewable sources to biofuels and bulk chemicals. In order to provide cost competitive alternatives, it is imperative to develop efficient, cost-saving, and robust fermentation processes. Non-sterile fermentation offers several benefits compared to sterile fermentation, including elimination of sterility, reduced maintenance requirements, relatively simple bioreactor design, and simplified operation. Thus, cost effectiveness of non-sterile fermentation makes it a practical platform for low cost, large volume production of biofuels and bulk chemicals. Many approaches have been developed to conduct non-sterile fermentation without sacrificing the yields and productivities of fermentation products. This review focuses on the strategies for conducting non-sterile fermentation. The challenges facing non-sterile fermentation are also discussed. PMID- 28905263 TI - The Cricotopus (Oliveiriella) (Diptera: Chironomidae) of the High Altitude Andean Streams, with Description of a New Species, C. (O.) rieradevallae. AB - The genus Oliveiriella (Chironomidae, Orthocladiinae) was erected by Wiedenbrug & Fittkau (1997). The adults have characteristic black spots on their wings and other characteristics similar to the genus Cricotopus. Pupal skins are very characteristic with strong short spines in the anal lobe instead of setae, while larvae are distinguishable by the long anal papillae and the intense blue color of their body. However, Andersen et al (2013) consider Oliveiriella as a subgenera of Cricotopus. In this paper, using the sequences of the cox1 gene, we conclude that Oliveiriella should be considered a subgenus within Cricotopus, confirming its status in Andersen et al (2013). Furthermore, we describe Cricotopus (Oliveiriella) rieradevallae Prat & Paggi sp. n. from the Saltana river (Ecuador). The adult males, females, and preimaginal stages of the two species of subgenus Oliveiriella known from South America Cricotopus (O.) almeidai n. comb. from Peru, Brazil, and Argentina and Cricotopus (O.) sanjavieri n. comb. from Argentina are compared with those of Cricotopus (O.) rieradevallae sp. n. from Ecuador. The differences allow the distinction of the three species. The cox1 gene reveals that at least three different undescribed species of the same subgenus are present in the high-altitude tropical Andes. The morphology of the available pupae and pupal exuviae reveals the presence of several morphotypes that are candidates to be described as new species. A key used to distinguish these pupal morphotypes is provided, including the three described species. Additionally, the distribution of the subgenus is discussed. PMID- 28905264 TI - Evolution of bovine brucellosis in Colombia over a 7-year period (2006-2012). AB - Bovine brucellosis is endemic in Colombia, and is a mandatory notifiable disease, subjected to a control program based on four surveillance procedures: passive surveillance, test-and-remove, certification of disease-free farms, and animal movements. The objective of this study is to estimate the evolution of bovine brucellosis in Colombia over a 7-year period (2006-2012) using data from the official control program. A total of 58 epidemiologic variables were analyzed for each year at the department level. Univariate descriptive analysis and principal components analysis (PCA) were performed to ascertain the behavior of the variables. These programs covered 3% of the census in 2006, increasing to 15% in 2012. The percentage of positive farms averaged 22% in 2006 and 23% in 2012. The highest proportion of positive farms was in the Orinoquia region (24.6 to 49.6%); the lowest was in the Amazon region, (17.9 to 32.7%). The percentage of positive animals presented certain differences between years but without any clear trend (4.7% in 2006 and 4.6% in 2012), indicating that the brucellosis control program had a low impact in Colombia in these years. The results for each surveillance procedure were 6.8% for passive surveillance, 5.9% for test-and-remove, and 4.4% both in disease-free farms and in animal movement tests. The results obtained by PCA led to finding three different clusters: geographic areas with low bovine production and low bovine brucellosis surveillance, areas with medium bovine production and medium surveillance for bovine brucellosis, and areas with a predominant bovine production, applying sanitary measures to control bovine brucellosis. PMID- 28905265 TI - Occurrence and effect of trematode metacercariae in two endangered killifishes from Greece. AB - We report digeneans (Diplostomidae, Crassiphialinae) in the endangered freshwater fishes Valencia letourneuxi and Valencia robertae, endemics of Western Greece. Digenean metacercariae occurred in two forms in the abdominal cavity, excysted and encysted, the latter attached to the gonads, liver and alimentary tract. Parasites were, using morphological and molecular techniques, identified as two representatives of Crassiphialinae, specifically part of the Posthodiplostomum Ornithodiplostomum clade. The spatial, seasonal, and age class variation in parasite prevalence was examined. Autumn parasite prevalence varied between the six populations sampled (18.2 to 100%). Seasonal prevalence at the two sites sampled quadannually peaked in autumn and reached its lowest value in spring; prevalence increased with size to 100% in young adult fish. We did not find a correlation between prevalence and host sex. Overall parasites' weight averaged 0.64% of the host's, while parasite weight increased with host weight. A comparison of relative condition and hepatosomatic and gonadosomatic indices of infected and metacercariae-free specimens showed that infection did not have a significant effect on host body condition and reproduction. Regarding the parasite's life cycle, planorbid gastropods are proposed as potential first intermediate hosts in view of the host's diet and occurrence data of molluscs in the ecosystem. This is the first record of a diplostomid digenean in valenciid fishes and of representatives of the Posthodiplostomum-Ornithodiplostomum clade in a native Greek freshwater fish. Our findings are discussed in conjunction to fish conservation interventions, since parasites may contribute to the decline of endangered species. PMID- 28905266 TI - Septin structure and filament assembly. AB - Septins are able to polymerize into long apolar filaments and have long been considered to be a component of the cytoskeleton alongside intermediate filaments (which are also apolar in nature), microtubules and actin filaments (which are not). Their central guanosine triphosphate (GTP)-binding domain, which is essential for stabilizing the filament itself, is flanked by N- and C-terminal domains for which no direct structural information is yet available. In most cases, physiological filaments are built from a number of different septin monomers, and in the case of mammalian septins this is most commonly either three or four. Comprehending the structural basis for the spontaneous assembly of such filaments requires a deeper understanding of the interfaces between individual GTP-binding domains than is currently available. Nevertheless, in this review we will summarize the considerable progress which has been made over the course of the last 10 years. We will provide a brief description of each structure determined to date and comment on how it has added to the body of knowledge which is rapidly growing. Rather than simply repeat data which have already been described in the literature, as far as is possible we will try to take advantage of the full set of information now available (mostly derived from human septins) and draw the reader's attention to some of the details of the structures themselves and the filaments they form which have not be commented on previously. An additional aim is to clarify some misconceptions. PMID- 28905267 TI - The Zappel-Philipp a historical example of ADHD Clinics. AB - In his book "Die Geschichte von dem Zappel-Philipp," the German psychiatrist Heinrich Hoffmann (1809-1894) offers a clinical vignette which raises the question of the description of a disobedient child or presenting hyperactivity symptoms. This article describes the historical context and the biographical aspects related to this interesting approach to describing a psychiatric syndrome to children and adults. It also underlines the importance of a global approach of ADHD that considers the familial environment and situational context of symptoms. PMID- 28905268 TI - Fluid- and Biomechanical Analysis of Ascending Thoracic Aorta Aneurysm with Concomitant Aortic Insufficiency. AB - We present a comprehensive and original framework for the biomechanical analysis of patients affected by ascending thoracic aorta aneurysm and aortic insufficiency. Our aim is to obtain crucial indications about the role played by deranged hemodynamics on the ATAAs risk of rupture. Computational fluid dynamics analysis was performed using patient-specific geometries and boundary conditions derived from 4D MRI. Blood flow helicity and wall shear stress descriptors were assessed. A bulge inflation test was carried out in vitro on the 4 ATAAs after surgical repair. The healthy volunteers showed no eccentric blood flow, a mean TAWSS of 1.5 +/- 0.3 Pa and mean OSI of 0.325 +/- 0.025. In 3 aneurismal patients, jet flow impingement on the aortic wall resulted in large TAWSS values and low OSI which were amplified by the AI degree. However, the tissue strength did not appear to be significantly reduced. The fourth patient, which showed the lowest TAWSS due to the absence of jet flow, had the smallest strength in vitro. Interestingly this patient presented a bovine arch abnormality. Jet flow impingement with high WSS values is frequent in ATAAs and our methodology seems to be appropriate for determining whether it may increase the risk of rupture or not. PMID- 28905269 TI - Differences in Neural Response to Romantic Stimuli in Monogamous and Non Monogamous Men. AB - In non-human animal research, studies comparing socially monogamous and promiscuous species of voles (Microtus) have identified some key neural differences related to monogamy and non-monogamy. Specifically, densities of the vasopressin V1a receptor and dopamine D2 receptors in subcortical reward-related and limbic areas of the brain have been linked to monogamous behavior in prairie voles (Microtus ochrogaster). Similar brain areas have been shown to be correlated with feelings of romantic love in monogamously pair-bonded humans. Humans vary in the degree to which they engage in (non-)monogamous behaviors. The present study examined the differences in neural activation in response to sexual and romantic stimuli in monogamous (n = 10) and non-monogamous (n = 10) men. Results indicated that monogamous men showed more reward-related neural activity when viewing romantic pictures compared to non-monogamous men. Areas with increased activation for monogamous men were all in the right hemisphere and included the thalamus, accumbens, striatum, pallidum, insula, and orbitofrontal cortex. There were no significant differences between groups in activation to sexual stimuli. These results demonstrate that the neural processing of romantic images is different for monogamous and non-monogamous men. There is some overlap in the neural areas showing increased activation in monogamous men in the present study and the neural areas that show differences in the vole models of monogamy and affiliation. Future research will be needed to clarify whether similar factors are contributing to the neural differences seen in monogamous and non monogamous humans and voles. PMID- 28905270 TI - Activities of Lysosomal Enzymes in Alloxan-Induced Diabetes in the Mouse. AB - The study investigated a panel of lysosomal enzymes in the liver and kidney tissues in alloxan-induced diabetes in the mouse. The mice were divided into six experimental groups receiving 10% alloxan at a dose of 50 and 75 mg/kg over a period of four, eight, and twelve days; each group was compared with controls receiving 0.9% NaCl. The findings were that diabetes induced by both doses of alloxan was accompanied by significant increases in the lysosomal activities of acid phosphatase and the glycosidases investigated: beta-glucuronidase, beta galactosidase, beta-glucosidase, and N-acetyl-hexosaminidase. The lysosomal enzyme activity in both liver and kidney cells peaked 12 days after onset of diabetes for most enzymes, at the time when hyperglycemia and hyperinsulinemia already started abating after their peak at 8 days into the course of diabetes. The enzyme activity was in most cases higher with the higher dose of alloxan and thus higher level of glycemia. Lysosomal enzymes degrade glycoconjugates, the molecules that are present in the basement membrane of endothelial cells where they contribute to capillary wall stability. Thus, enhanced activity of these enzymes could presage the progression of diabetic microangiopathy, atherosclerosis, and the development of microvascular complications. PMID- 28905271 TI - Pharmacokinetics of a New Oral Vitamin D Receptor Activator (2-Methylene-19-Nor (20S)-1alpha,25-Dihydroxyvitamin D3) in Patients with Chronic Kidney Disease and Secondary Hyperparathyroidism on Hemodialysis. AB - BACKGROUND: 2-Methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (DP001 or 2MD) is a novel, potent 1alpha-hydroxylated vitamin D analog that binds to the vitamin D receptor and suppresses parathyroid hormone synthesis and secretion with potential for an improved safety profile compared to existing active vitamin D analogs. The purpose of this study was to evaluate the pharmacokinetics of DP001 given orally after hemodialysis. METHODS: DP001 (550 ng) was given orally to 11 hemodialysis patients with secondary hyperparathyroidism after each dialysis session (3 times/week) for 4 weeks. Pharmacokinetic analyses were performed after the first and final dose. RESULTS: After the first and final dose, the half-life of DP001 was similar (55.8 +/- 13.0 and 50.8 +/- 8.2 h, respectively). At 4 weeks, the time to maximum plasma concentration was 4.0 +/- 0.8 h, with a concentration maximum of 3.4 +/- 0.3 pg/mL. The area under the curve (0 to infinity) after the final dose was 204.3 +/- 23.9 pg h/mL, and apparent volume of distribution was 2.03 +/- 0.22 L/kg. At week 4, mean intact parathyroid hormone was suppressed 33% from the baseline (pre-dose) value (313 +/- 52 vs 462 +/- 39 pg/mL, respectively). No clinically significant changes from baseline values were found for vital signs, electrocardiogram measurements, or other laboratory parameters, including serum calcium and phosphorus. CONCLUSIONS: In hemodialysis patients, DP001 has a longer half-life than existing vitamin D therapies and enables control of parathyroid hormone when administered every 2-3 days on the day of dialysis. It is effective at a lower concentration maximum and area under the curve than other clinically available vitamin D compounds. DP001 may represent a therapeutic improvement over existing compounds due to rapid and extensive distribution to its target and its long half-life enabling sustained parathyroid hormone suppression. These studies support further evaluation of DP001 in longer-term treatment of secondary hyperparathyroidism. PMID- 28905272 TI - What is a good doctor? AB - Changes in medical curricula have led to a shift of focus in medical education. The goal was to implement a more practical approach to teaching and thereby create better doctors. However, the question of what makes a good doctor is not easy to answer. This article gives an overview on the literature about this topic. A systematized review and narrative synthesis were conducted including 20 articles about the features of good doctors. Qualitative and quantitative studies as well as questionnaires were included. These studies reported research involving students, doctors, patients, and nurses. The resulting characteristics of good doctors fell into six categories: (1) General interpersonal qualities, (2) Communication and patient involvement, (3) Medical competence, (4) Ethics, (5) Medical management, (6) Teaching, research, and continuous education. The different stakeholders showed different ideas of the concept of a good doctor. Interestingly, patients had a stronger focus on communication skills, whereas doctors put more emphasis on medical skills. Balancing this discrepancy will be a challenge for future medical education. PMID- 28905274 TI - Erratum to: HIV Prevention Among Transgender Populations: Knowledge Gaps and Evidence for Action. PMID- 28905275 TI - Human Development and Pastoral Care in a Postmodern Age: Donald Capps, Erik H. Erikson, and Beyond. AB - This article discusses Donald Capps's use of Erik H. Erikson's life-cycle theory as the basic psychological framework for his theory of pastoral care. Capps was attracted to Erikson's existential-psychological model, his hermeneutic approach, and his religious sensitivity. Capps's thought develops from first exploring biblical foundations for using Eriksonian theory for pastoral care to gradually embracing certain postmodern features. The article concludes with reflections on the usefulness of Erikson's life-cycle theory and Capps's work for contemporary pastoral care. PMID- 28905273 TI - Early to Long-Term Alterations of CNS Barriers After Traumatic Brain Injury: Considerations for Drug Development. AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability, particularly amongst the young and the elderly. The functions of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are strongly impaired after TBI, thus affecting brain homeostasis. Following the primary mechanical injury that characterizes TBI, a secondary injury develops over time, including events such as edema formation, oxidative stress, neuroinflammation, and alterations in paracelullar and transcellular transport. To date, most therapeutic interventions for TBI have aimed at direct neuroprotection during the acute phase and have not been successful. Targeting the barriers of the central nervous system (CNS) could be a wider therapeutic approach, given that restoration of brain homeostasis would benefit all brain cells, including neurons. Importantly, BBB disregulation has been observed even years after TBI, concomitantly with neurological and psychosocial sequelae; however, treatments targeting the post-acute phase are scarce. Here, we review the mechanisms of primary and secondary injury of CNS barriers, the accumulating evidence showing long-term damage to these structures and some of the therapies that have targeted these mechanisms. Finally, we discuss how the injury characteristics (hemorrhagic vs non-hemorrhagic, involvement of head rotation, gray vs white matter), the sex, and the age of the patient need to be carefully considered to improve clinical trial design and outcome interpretation, and to improve future drug development. PMID- 28905276 TI - Causal explanation improves judgment under uncertainty, but rarely in a Bayesian way. AB - Three studies reexamined the claim that clarifying the causal origin of key statistics can increase normative performance on Bayesian problems involving judgment under uncertainty. Experiments 1 and 2 found that causal explanation did not increase the rate of normative solutions. However, certain types of causal explanation did lead to a reduction in the magnitude of errors in probability estimation. This effect was most pronounced when problem statistics were expressed in percentage formats. Experiment 3 used process-tracing methods to examine the impact of causal explanation of false positives on solution strategies. Changes in probability estimation following causal explanation were the result of a mixture of individual reasoning strategies, including non Bayesian mechanisms, such as increased attention to explained statistics and approximations of subcomponents of Bayes' rule. The results show that although causal explanation of statistics can affect the way that a problem is mentally represented, this does not necessarily lead to an increased rate of normative responding. PMID- 28905277 TI - On-site phytoremediation applicability assessment in Alur Ilmu, Universiti Kebangsaan Malaysia based on spatial and pollution removal analyses. AB - The present paper aims to assess the phytoremediation performance based on pollution removal efficiency of the highly polluted region of Alur Ilmu urban river for its applicability of on-site treatment. Thirteen stations along Alur Ilmu were selected to produce thematic maps through spatial distribution analysis based on six water quality parameters of Malaysia's Water Quality Index (WQI) for dry and raining seasons. The maps generated were used to identify the highly polluted region for phytoremediation applicability assessment. Four free-floating plants were tested in treating water samples from the highly polluted region under three different conditions, namely controlled, aerated and normal treatments. The selected free-floating plants were water hyacinth (Eichhornia crassipes), water lettuce (Pistia stratiotes), rose water lettuce (Pistia sp.) and pennywort (Centella asiatica). The results showed that Alur Ilmu was more polluted during dry season compared to raining season based on the water quality analysis. During dry season, four parameters were marked as polluted along Alur Ilmu, namely dissolve oxygen (DO), 4.72 mg/L (class III); ammoniacal nitrogen (NH3-N), 0.85 mg/L (class IV); total suspended solid (TSS), 402 mg/L (class V) and biological oxygen demand (BOD), 3.89 mg/L (class III), whereas, two parameters were classed as polluted during raining season, namely total suspended solid (TSS), 571 mg/L (class V) and biological oxygen demand (BOD), 4.01 mg/L (class III). The thematic maps generated from spatial distribution analysis using Kriging gridding method showed that the highly polluted region was recorded at station AL 5. Hence, water samples were taken from this station for pollution removal analysis. All the free-floating plants were able to reduce TSS and COD in less than 14 days. However, water hyacinth showed the least detrimental effect from the phytoremediation process compared to other free-floating plants, thus made it a suitable free-floating plants to be used for on-site treatment. PMID- 28905278 TI - Hierarchical Heterostructure of ZnO@TiO2 Hollow Spheres for Highly Efficient Photocatalytic Hydrogen Evolution. AB - The rational design and preparation of hierarchical nanoarchitectures are critical for enhanced photocatalytic hydrogen evolution reaction (HER). Herein, well-integrated hollow ZnO@TiO2 heterojunctions were obtained by a simple hydrothermal method. This unique hierarchical heterostructure not only caused multiple reflections which enhances the light absorption but also improved the lifetime and transfer of photogenerated charge carriers due to the potential difference generated on the ZnO-TiO2 interface. As a result, compared to bare ZnO and TiO2, the ZnO@TiO2 composite photocatalyst exhibited higher hydrogen production rated up to 0.152 mmol h-1 g-1 under simulated solar light. In addition, highly repeated photostability was also observed on the ZnO@TiO2 composite photocatalyst even after a continuous test for 30 h. It is expected that this low-cost, nontoxic, and readily available ZnO@TiO2 catalyst could exhibit promising potential in photocatalytic H2 to meet the future fuel needs. PMID- 28905279 TI - Capturing Budget Impact Considerations Within Economic Evaluations: A Systematic Review of Economic Evaluations of Rotavirus Vaccine in Low- and Middle-Income Countries and a Proposed Assessment Framework. AB - BACKGROUND: In low- and middle-income countries, budget impact is an important criterion for funding new interventions, particularly for large public health investments such as new vaccines. However, budget impact analyses remain less frequently conducted and less well researched than cost-effectiveness analyses. OBJECTIVE: The objective of this study was to fill the gap in research on budget impact analyses by assessing (1) the quality of stand-alone budget impact analyses, and (2) the feasibility of extending cost-effectiveness analyses to capture budget impact. METHODS: We developed a budget impact analysis checklist and scoring system for budget impact analyses, which we then adapted for cost effectiveness analyses, based on current International Society for Pharmacoeconomics and Outcomes Research Task Force recommendations. We applied both budget impact analysis and cost-effectiveness analysis checklists and scoring systems to examine the extent to which existing economic evaluations provide sufficient evidence about budget impact to enable decision making. We used rotavirus vaccination as an illustrative case in which low- and middle income countries uptake has been limited despite demonstrated cost effectiveness. A systematic literature review was conducted to identify economic evaluations of rotavirus vaccine in low- and middle-income countries published between January 2000 and February 2017. We critically appraised the quality of budget impact analyses, and assessed the extension of cost-effectiveness analyses to provide useful budget impact information. RESULTS: Six budget impact analyses and 60 cost effectiveness analyses were identified. Budget impact analyses adhered to most International Society for Pharmacoeconomics and Outcomes Research recommendations, with key exceptions being provision of undiscounted financial streams for each budget period and model validation. Most cost-effectiveness analyses could not be extended to provide useful budget impact information; cost effectiveness analyses also rarely presented undiscounted annual costs, or estimated financial streams during the first years of programme scale-up. CONCLUSIONS: Cost-effectiveness analyses vastly outnumber budget impact analyses of rotavirus vaccination, despite both being critical for policy decision making. Straightforward changes to the presentation of cost-effectiveness analyses results could facilitate their adaptation into budget impact analyses. PMID- 28905280 TI - Enzymatic synthesis of fucose-containing galacto-oligosaccharides using beta galactosidase and identification of novel disaccharide structures. AB - Fucosylated oligosaccharides have an important role in maintaining a healthy immune system and homeostatic gut microflora. This study employed a commercial beta-galactosidase in the production of fucose-containing galacto oligosaccharides (fGOS) from lactose and fucose. The production was optimized using experiment design and optimal conditions for a batch production in 3-liter scale. The reaction product was analyzed and the produced galactose-fucose disaccharides were purified. The structures of these disaccharides were determined using NMR and it was verified that one major product with the structure Galbeta1-3Fuc and two minor products with the structures Galbeta1-4Fuc and Galbeta1-2Fuc were formed. Additionally, the product composition was defined in more detail using several different analytical methods. It was concluded that the final product contained 42% total monosaccharides, 40% disaccharides and 18% of larger oligosaccharides. 290 MUmol of fGOS was produced per gram of reaction mixture and 37% of the added fucose was bound to fGOS. The fraction of fGOS from total oligosaccharides was determined as 44%. This fGOS product could be used as a new putative route to deliver fucose to the intestine. PMID- 28905281 TI - Enhanced degradation of acid red 1 dye using a coupled system of zero valent iron nanoparticles and sonolysis. AB - The heterogeneous catalytic degradation of a model azo dye, acid red 1 (AR1), initiated by zero valent iron nanoparticles (ZVINP), and its synergic effect with ultrasound (US) have been investigated in the present study. The treatment of AR1 using ZVINP at pH 3 showed maximum efficiency in terms of colour removal (53.0%) and mineralization (48.5% TOC reduction) after 25 min of reaction. However, the coupling of this system with US showed an enhanced efficiency against the decolourization and mineralization of AR1. More than 95% colour removal was achieved within 5 min in the case of US/ZVINP system. Around 55% TOC reduction suggests the conversion of the parent molecules in to aromatic transformed products, and it is further supported by LC-Q-TOF analysis. The remarkably higher efficiency in the coupled system is attributed to the synergic effect of ZVINPs and ultrasound. The highest degradation rates observed at highly acidic (pH 3) and alkaline pH (pH 9) suggests that different mechanisms are operating at both pH. The products identified gave some insight into the mechanism. The ZVINPs prepared in the present study was easily recoverable (and reusable) and hence may be considered as an effective replacement for the conventional Fenton's reagent. PMID- 28905282 TI - Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications. AB - Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov , 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials. PMID- 28905283 TI - Chrysotile effects on the expression of anti-oncogene P53 and P16 and oncogene C jun and C-fos in Wistar rats' lung tissues. AB - Chrysotile is the most widely used form of asbestos worldwide. China is the world's largest consumer and second largest producer of chrysotile. The carcinogenicity of chrysotile has been extensively documented, and accumulative evidence has shown that chrysotile is capable of causing lung cancer and other forms of cancer. However, molecular mechanisms underlying the tumorigenic effects of chrysotile remained poorly understood. To explore the carcinogenicity of chrysotile, Wistar rats were administered by intratracheal instillation (by an artificial route of administration) for 0, 0.5, 2, or 8 mg/ml of natural chrysotile (from Mangnai, Qinghai, China) dissolved in saline, repeated once a month for 6 months (a repeated high-dose exposure which may have little bearing on the effects following human exposure). The lung tissues were analyzed for viscera coefficients and histopathological alterations. Expression of P53, P16, C JUN, and C-FOS was measured by western blotting and qRT-PCR. Our results found that chrysotile exposure leads the body weight to grow slowly and lung viscera coefficients to increase in a dose-dependent manner. General sample showed white nodules, punctiform asbestos spots, and irregular atrophy; moreover, HE staining revealed inflammatory infiltration, damage of alveolar structures, agglomerations, and pulmonary fibrosis. In addition, chrysotile can induce inactivation of the anti-oncogene P53 and P16 and activation of the proto oncogenes C-JUN and C-FOS both in the messenger RNA and protein level. In conclusion, chrysotile induced an imbalanced expression of cancer-related genes in rats' lung tissue. These results contribute to our understanding of the carcinogenic mechanism of chrysotile. PMID- 28905284 TI - Effect of cadmium bioavailability in food on its compartmentalisation in carabids. AB - Metals assimilated by organisms are sequestered in various compartments and some forms are more stable than others. Sequestration mechanisms used by invertebrates to detoxify metals and prevent interaction with important biomolecules include metal binding to proteins and other ligands, and storage in inorganic granules. The rate and extent at which metal concentrations in different compartments respond to metal concentrations in food and food characteristics has not received much attention, despite being of great relevance. We performed an experiment on the carabid beetle Pterostichus oblongopunctatus exposed to Cd via food made of ground mealworm (Tenebrio molitor) larvae, either reared on Cd contaminated medium or artificially spiked after grinding with CdCl2 solution. Thus, in both cases we used the same type of food, differing only in the soluble Cd pool available to the predators, represented by P. oblongopunctatus. Subcellular compartmentalisation of Cd into organelles, heat-sensitive and heat-stable proteins (the first supernatant, S1 fraction), cellular debris (the second supernatant, S2 fraction) and metal-rich granules (G fraction) was checked a few times during the contamination (90 d) and decontamination (24 d) phases in a toxicokinetic experiment by using different centrifugation steps. The results showed no effect of the type of food (naturally, Cd-N, vs. artificially contaminated with Cd, Cd-A) on Cd sequestration kinetics in P. oblongopunctatus, but the amount of Cd sequestered in the S1 and G fractions were in general higher in the Cd-A than the Cd-N treatment, indicating that Cd transfer in the food web depends on the speciation of the metal in the food. The proportional distribution of Cd over different fractions was, however, similar in beetles fed both food types. Most of the accumulated Cd in the beetles existed as fraction S1 (ca. 35%), which is important for the transfer of metals to higher trophic levels in a food web. PMID- 28905285 TI - Effect of bacteriocin and exopolysaccharides isolated from probiotic on P. aeruginosa PAO1 biofilm. AB - Microorganisms develop biofilms on indwelling medical devices and are associated with biofilm-related infections, resulting in substantial morbidity and mortality. Therefore, to prevent and control biofilm-associated infections, the present study was designed to assess the anti-biofilm potential of postbiotics derived from probiotic organisms against most prevalent biofilm-forming Pseudomonas aeruginosa PAO1. Eighty lactic acid bacteria isolated from eight neonatal fecal samples possessed antibacterial activity against P. aeruginosa PAO1. Among these, only four lactic acid bacteria produced both bacteriocin and exopolysaccharides but only one isolate was found to maximally attenuate the P. aeruginosa PAO1 biofilm. More specifically, the phenotypic and probiotic characterization showed that the isolated lactic acid bacteria were gram positive, non-motile, and catalase and oxidase negative; tolerated acidic and alkaline pH; has bile salt concentration; showed 53% hydrophobicity; and was found to be non-hemolytic. Phylogenetically, the organism was found to be probiotic Lactobacillus fermentum with accession no. KT998657. Interestingly, pre coating of a microtiter plate either with bacteriocin or with exopolysaccharides as well as their combination significantly (p < 0.05) reduced the number of viable cells forming biofilms to 41.7% compared with simultaneous coating of postbiotics that had 72.4% biofilm-forming viable cells as observed by flow cytometry and confocal laser scanning microscopy. Therefore, it can be anticipated that postbiotics as the natural biointerventions can be employed as the prophylactic agents for medical devices used to treat gastrointestinal and urinary tract infections. PMID- 28905286 TI - Role of phase separation on the biological performance of 45S5 Bioglass(r). AB - We analyzed the biological performance of spinodally and droplet-type phase separated 45S5 Bioglass(r) generated by quenching the melt from different equilibrium temperatures. MC3T3-E1 pre-osteoblast cells attached more efficiently to 45S5 Bioglass(r) with spinodal than to the one with droplet morphology, providing the first demonstration of the role of micro-/nano-scale on the bioactivity of Bioglass(r). Upon exposure to biological solutions, phosphate buffered saline (PBS) and cell culture medium (alpha-MEM), a layer of hydroxyapatite (HA) formed on both glass morphologies. Although both Bioglass(r) varieties were incubated under identical conditions, and physico-chemical characteristics of the HA layers were similar, the adsorption magnitude of a model protein, bovine serum albumin (BSA, an abundant blood serum component) and its beta-sheet/beta-turn ratio and alpha-helix content were significantly higher on spinodal than droplet type Bioglass(r). These results indicate that: (i) a protein layer quickly adsorbs on the surface of 45S5 Bioglass(r) varieties (with or without HA layer), (ii) the amount and the conformation of adsorbed proteins are guided by the glass micro-/nano-structure, and (iii) cell attachment and proliferation are influenced by the concentration and the conformation of attached proteins with a significantly better cell adhesion to spinodal type 45S5 Bioglass(r) substrate. Taken together, our results indicate that the biological performance of 45S5 Bioglass(r) can be improved further with a relatively simple, inexpensive fabrication procedure that provides a superior glass micro-/nano structure. A simple modification to the fabrication procedure of classic 45S5 Bioglass(r) generates spinodal (A(a)) and droplet (A(b)) varieties and has a significant impact on protein adsorption (B) and cell adhesion (C). PMID- 28905287 TI - Transoral robotic surgery for the base of tongue squamous cell carcinoma: a preliminary comparison between da Vinci Xi and Si. AB - Considering the emerging advantages related to da Vinci Xi robotic platform, the aim of this study is to compare for the first time the operative outcomes of this tool to the previous da Vinci Si during transoral robotic surgery (TORS), both performed for squamous cell carcinomas (SCC) of the base of tongue (BOT). Intra- and peri-operative outcomes of eight patients with early stage (T1-T2) of the BOT carcinoma and undergoing TORS by means of the da Vinci Xi robotic platform (Xi TORS) are compared with the da Vinci Si group ones (Si-TORS). With respect to Si TORS group, Xi-TORS group demonstrated a significantly shorter overall operative time, console time, and intraoperative blood loss, as well as peri-operative pain intensity and length of mean hospital stays and nasogastric tube positioning. Considering recent advantages offered by surgical robotic techniques, the da Vinci Xi Surgical System preliminary outcomes could suggest its possible future routine implementation in BOT squamous cell carcinoma procedures. PMID- 28905288 TI - On (scientific) integrity: conceptual clarification. AB - The notion of "integrity" is currently quite common and broadly recognized as complex, mostly due to its recurring and diverse application in various distinct domains such as the physical, psychic or moral, the personal or professional, that of the human being or of the totality of beings. Nevertheless, its adjectivation imprints a specific meaning, as happens in the case of "scientific integrity". This concept has been defined mostly by via negativa, by pointing out what goes against integrity, that is, through the identification of its infringements, which has also not facilitated the elaboration of an overarching and consensual code of scientific integrity. In this context, it is deemed necessary to clarify the notion of "integrity", first etymologically, recovering the original meaning of the term, and then in a specifically conceptual way, through the identification of the various meanings with which the term can be legitimately used, particularly in the domain of scientific research and innovation. These two steps are fundamental and indispensable for a forthcoming attempt at systematizing the requirements of "scientific integrity". PMID- 28905289 TI - Lymph node-positive prostate cancer after robotic prostatectomy and extended pelvic lymphadenectomy. AB - Optimal management of node-positive prostate cancer patients after prostatectomy remains a challenge. We evaluated clinically localized patients who demonstrated node positivity and identified predictors for secondary treatment. From 2010 to 2015, clinically localized prostate cancer patients who underwent robot prostatectomy with extended lymphadenectomy and node-positive disease on pathologic analysis were identified. Clinical N1, M1 or salvage cases were excluded. Patients were stratified based on secondary treatments. Kaplan-Meier method was used to determine the time to biochemical and metastatic recurrence. Multivariate logistic regression was used to identify predictors for additional treatment. 145 patients (45 no additional therapy, 47 adjuvant, 53 salvage) had a median follow-up of 31.2 months. Salvage patients had higher median pre-operative prostate-specific antigen (10.8 vs. 9.7 vs. 8.2, p = 0.1), higher percentage of pathologic Gleason >=8 (50.9 vs. 38.3% and 22.2%, p < 0.01), and higher median positive nodes (3 vs. 1 and 1, p < 0.0001) compared to adjuvant and no treatment groups, respectively. Pathologic Gleason >=8 (OR = 3.5, p = 0.007) and positive nodes >=2 (OR = 3.3, p = 0.006) were associated with additional therapy. In the no treatment group, two-year estimated BCRFS was 74.3%. Two-year metastatic recurrence-free rates for no treatment, adjuvant and salvage groups were 100, 87.5, and 80.9%, respectively (p = 0.01). Observation is a viable alternative for low metastatic burden patients. In the largest series of node-positive patients from robotic prostatectomy and extended lymphadenectomy, those with pathologic Gleason >=8 and positive lymph nodes >=2 were more likely to receive additional treatment. PMID- 28905290 TI - Erratum to: Phenotyping Cellular Viability by Functional Analysis of Ion Channels: GlyR-Targeted Screening in NT2-N Cells. PMID- 28905291 TI - Morphology effect of nano-hydroxyapatite as a drug carrier of methotrexate. AB - In this study, morphology effect of nano-hydroxyapatite as a drug carrier was investigated for the first time. Hydroxyapatite/methotrexate (HAp/MTX) hybrids with different morphologies were successfully prepared in situ using polyethylene glycol (PEG) as a template. SEM, TEM, XRD and FTIR results confirmed that the hybrids of different morphologies (laminated, rod-like and spherical) with similar phase composition and functional groups were obtained by changing the preparation parameters. UV-Vis spectroscopy was used to identify the drug loading capacity and drug release mechanism of the three hybrids with different morphologies. It is concluded that the laminated hybrid exhibits a higher drug loading capacity compared to the other two hybrids, and all the three hybrids showed a sustained slow release which were fitted well by Bhaskar equation. Additionally, the result of in vitro bioassay test confirms that the inhibition efficacy of the three hybrids showed a positive correlation to the drug loading capacity. PMID- 28905293 TI - Kenneth B Jones Jr. MD FACS FASMBS. PMID- 28905292 TI - Effects of Laparoscopic Roux-en-Y Gastric Bypass for Type 2 Diabetes Mellitus: Comparison of BMI > 30 and < 30 kg/m2. AB - BACKGROUND: Recently, many studies focused on type 2 diabetes mellitus (T2DM) patients with body mass index (BMI) < 30 kg/m2 and suggested that those patients might benefit from Roux-en-Y gastric bypass (RYGB). However, evidence on its effectiveness to improve T2DM patients with BMI < 30 kg/m2 is still lacking. The aim of this study is to explore whether T2DM patients with BMI < 30 kg/m2 get similar surgical effect from RYGB compared with those patients with BMI > 30 kg/m2. METHODOLOGY: Seventy patients with uncontrolled T2DM underwent laparoscopic RYGB from May 2010 to December 2015 in the GI Department of Daping Hospital. Weight, BMI, waist circumference, glucose, and lipid metabolic parameters were collected and evaluated at baseline and 1, 3, 6, 12, and 24 months postsurgery. Patients with BMI < 30 kg/m2 were compared with those with BMI > 30 kg/m2. RESULTS: Among the 70 patients, 47 (67.1%) BMI < 30 kg/m2, and 23 (32.9%) BMI > 30 kg/m2. Patients with BMI < 30 kg/m2 are significantly older; they are female predominant and have longer duration of diabetes. The complete remission of T2DM was 28.2% of the BMI < 30 kg/m2 group and 57.9% of the BMI > 30 kg/m2 group (p = 0.029). There was no significant difference in the change of glucose and lipid metabolic parameters of both groups. FPG, 2hPG, and HbA1c% levels were significantly improved after 1 month (p < 0.05), and then remained essentially stable from the sixth month in both groups. CONCLUSIONS: The 2-year study has shown that RYGB is a safe and effective procedure in treating T2DM with BMI < 30 kg/m2, although the complete remission of T2DM in the BMI < 30 kg/m2 group is lower than the BMI > 30 kg/m2 group. PMID- 28905294 TI - High Patient Satisfaction with Daylight-Activated Methyl Aminolevulinate Cream in the Treatment of Multiple Actinic Keratoses: Results of an Observational Study in Australia. AB - INTRODUCTION: Actinic keratoses (AK) are treated to reduce the risk of progression to squamous cell carcinoma and for symptomatic and cosmetic benefits. The objective of this observational study was to generate real-life data on the use of daylight photodynamic therapy with methyl aminolevulinate cream (MAL DL PDT) in treating mild to moderate facial/scalp AK. METHODS: A multicenter, prospective, observational study was conducted in Australia in patients receiving a single treatment of MAL DL-PDT for mild to moderate AK. Efficacy was assessed 3 months after treatment by investigator-assessed improvement and patient- and physician-completed satisfaction questionnaires. Adverse events were recorded throughout the study. RESULTS: Overall, 81 patients were enrolled of mean age 62.7 years, mostly men (76.5%) with skin phototype I (64.2%) or II (35.8%) and a long history of AK (mean duration 16.8 years). Most had multiple lesions (82.7% had >10 lesions) of predominantly grade I (75.3%). At 3 months after treatment, almost half the patients (46.8%) required no further treatment. The proportions of patients and physicians satisfied to very satisfied with the MAL DL-PDT treatment were 79.7% and 83.3%, respectively. After receiving the treatment, 74.1% of patients indicated via the questionnaire that they were not bothered at all by the pain. Related AEs were reported in 48.1% of patients, mainly mild erythema (44.4%). CONCLUSIONS: In clinical practice in Australia, the use of MAL DL-PDT in treating multiple mild to moderate non-hyperkeratotic AK of the face and/or scalp results in high levels of patient and physician satisfaction reflecting the good efficacy and tolerability of this almost painless, convenient procedure. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02674048. FUNDING: Galderma R&D. PMID- 28905295 TI - Between-breed variations in resistance/resilience to gastrointestinal nematodes among indigenous goat breeds in Uganda. AB - Gastrointestinal nematodes (GINs), Haemonchus contortus, are a major health problem in goat production. Resistance to H. contortus, the most prevalent GIN in Uganda, was studied among three indigenous goat breeds to assess their differences. Twelve male goats of each breed approximately 7 months old of small East African (SEA), Mubende, and Kigezi goats from smallholder farmers in Arua, Mubende, and Kabale were assembled for the study. At the station, they were dewormed with a combination therapy of the broad-spectrum dewormers closantel and albendazole to free the goats of gastrointestinal parasites. During experimentation, the goats were kept indoors and ad libitum fed on clean banana peels and napier grass. On attainment of zero-worm-egg status, the goats were artificially infected with 18,000 third-stage (L3) larvae of H. contortus prepared according to Baermann's procedure. Data were collected on fecal egg count (FEC), packed cell volume (PCV), and body weight (BW) on a 2-week basis until 12 weeks post infection and carcass weight and total worm count (WC) in the abomasum at termination of the experiment. The data on FEC, PCV, and BW were subjected to repeated-measure analysis of variance and the others by one-way analysis of variance. FEC between breeds was only significantly different at 12 weeks post infection (p = 0.04). Generally, higher FEC was recorded in Kigezi compared to SEA and Mubende goats. Carcass weight was significantly different among breeds (p < 0.05), with Mubende having the highest carcass weight, followed by Kigezi and SEA. PCV and daily weight gains were significantly different between breeds (p < 0.05). WC was not significantly different between the breeds. FEC and PCV were weakly significant at later stages of the experiment with higher parasite burden suggesting potential variation in resistance to H. contortus. These differences could be exploited in designing breeding programs with disease resistance in indigenous goat breeds. PMID- 28905296 TI - Potentially Preventable Medical Hospitalizations and Emergency Department Visits by the Behavioral Health Population. AB - This study investigated geographic variation in potentially preventable medical outcomes that might be used to monitor access to high-quality medical care in the behavioral health population. Analyzing public and non-public data sources from California on adults admitted between 2009 and 2011 to all non-federal licensed medical inpatient (N = 6,603,146) or emergency department units (N = 21,011,958) revealed that 33.6% of nearly 1 million potentially preventable hospitalizations and 9.8% of 1.5 million potentially preventable emergency department visits were made by people with mental or substance use disorder diagnoses. Across California counties or county groups (N = 36), a higher preventable hospitalization rate in the behavioral health population was associated with higher poverty, higher primary care safety net utilization, and fewer mental health providers. Although further validation is required, rates of potentially preventable encounters, particularly hospitalizations, may be useful measures of access to high-quality care in the behavioral health population. PMID- 28905297 TI - Hydraulic performance and fouling characteristics of a membrane sequencing batch reactor (MSBR) for landfill leachate treatment under various operating conditions. AB - This study investigates the hydraulic performance and the fouling characteristics of a bench-scale membrane sequencing batch reactor (MSBR), treating mature landfill leachate under various time-based operating conditions. The MSBR system operated initially under a high-flux condition (Period 1) which resulted in a rapid trans-membrane pressure (TMP) rise due to intense fouling. Following the characterization of Period 1 as super-critical, the system was subsequently operated under a near-critical condition (Period 2). The overall filtration resistance analysis showed that cake layer formation was the dominant fouling mechanism during Period 1, contributing to 85.5% of the total resistance. However, regarding the MSBR operation during Period 2, adsorption was found to also be a dominant fouling mechanism (Days 1 to 47), contributing to 29.1% of the total resistance. Additionally, the irregular total resistance variation, which was observed during the subsequent operation (Days 48 to 75), and the respective filtration resistance analysis suggested also the formation of an initial sludge cake layer on the membrane surface, contributing to the 47.7% of the total resistance. PMID- 28905298 TI - Would environmental pollution affect home prices? An empirical study based on China's key cities. AB - With the development of China's economy, the problem of environmental pollution has become increasingly more serious, affecting the sustained and healthy development of Chinese cities and the willingness of residents to invest in fixed assets. In this paper, a panel data set of 70 of China's key cities from 2003 to 2014 is used to study the effect of environmental pollution on home prices in China's key cities. In addition to the static panel data regression model, this paper uses the generalized method of moments (GMM) to control for the potential endogeneity and introduce the dynamics. To ensure the robustness of the research results, this paper uses four typical pollutants: per capita volume of SO2 emissions, industrial soot (dust) emissions, industrial wastewater discharge, and industrial chemical oxygen demand discharge. The analysis shows that environmental pollution does have a negative impact on home prices, and the magnitude of this effect is dependent on the level of economic development. When GDP per capita increases, the size of the negative impact on home prices tends to reduce. Industrial soot (dust) has the greatest impact, and the impact of industrial wastewater is relatively small. It is also found that some other social and economic factors, including greening, public transport, citizen income, fiscal situation, loans, FDI, and population density, have positive effects on home prices, but the effect of employment on home prices is relatively weak. PMID- 28905299 TI - Use of Antihypertensive Drugs and Risk of Malignant Melanoma: A Meta-analysis of Observational Studies. AB - INTRODUCTION: Several antihypertensive drugs are photosensitizing and may promote the development of malignant melanoma (MM), but evidence remains inconsistent. We sought to quantify the association between use of antihypertensive drugs and MM risk. METHODS: We systematically searched PubMed, Embase, and CENTRAL from inception to August 17, 2017 to identify observational studies that reported the MM risk associated with the use of antihypertensive drugs. A random-effects meta analysis was used to estimate the odds ratio (OR) with 95% confidence interval (CI). RESULTS: Overall, we included eight observational studies (two cohort studies and six case-control studies). Compared with non-use, use of diuretics (OR 1.10; 95% CI 1.03-1.17) or beta-adrenergic blocking agents (OR 1.19; 95% CI 1.04-1.37) was significantly associated with increased risk of MM. The use of angiotensin-converting enzyme inhibitors (OR 1.08; 95% CI 0.95-1.23), angiotensin II receptor blockers (OR 1.12; 95% CI 0.95-1.31), and calcium channel blockers (OR 1.12; 95% CI 0.72-1.74) was not significantly associated with increased risk of MM. CONCLUSIONS: Current evidence from observational studies suggests that use of diuretics or beta-adrenergic blocking agents may be associated with increased risk of MM. Further large well-conducted prospective studies are required to confirm our findings. PMID- 28905301 TI - ArtiFacts: Ivory Hemiarthroplasty: The Forgotten Concept Lives On. PMID- 28905300 TI - P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis. AB - Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban. A model of subfailure overstretch injury in rat aorta (RA) was used to demonstrate impaired vasomotor function, increased extracellular ATP (eATP) release, and increased apoptosis following pathological vascular injury. The subfailure overstretch injury was associated with activation of p38 MAPK stress pathway and decreases in the phosphorylation of the anti apoptotic protein Niban. Treatment of RA after overstretch injury with antagonists to purinergic P2X7 receptor (P2X7R) antagonists or P2X7R/pannexin (PanX1) complex, but not PanX1 alone, restored vasomotor function. Inhibitors to P2X7R and PanX1 reduced stretch-induced eATP release. P2X7R/PanX1 antagonism led to decrease in p38 MAPK phosphorylation, restoration of Niban phosphorylation and increases in the phosphorylation of the anti-apoptotic protein Akt in RA and reduced TNFalpha-stimulated caspase 3/7 activity in cultured rat vascular smooth muscle cells. In conclusion, inhibition of P2X7R after overstretch injury restored vasomotor function and inhibited apoptosis. Treatment with P2X7R/PanX1 complex inhibitors after harvest and preparation injury of blood vessels used for bypass conduits may prevent the subsequent response to injury that lead to apoptosis and represents a novel therapeutic approach to prevent graft failure. PMID- 28905303 TI - Measuring what matters to the patient: health related quality of life after aortic valve and thoracic aortic surgery. AB - With improved outcomes following cardiac surgery, health related quality of life (HRQoL) gains increasing importance for the better judgement of choosing the preferred treatment strategy in the individual patient. The physician perception of patient preferences can differ considerably from actual patient preferences, underlining the importance of gathering evidence of actual patient preferences before and quality of life after cardiac surgery. The objective of the current review is to provide an overview of current insights into the quality of life measurements after aortic valve and thoracic aortic surgery and to provide starting points for the application of HRQoL measurements toward the future. The amount and level of evidence on HRQoL outcomes after aortic valve and thoracic aortic surgery seems to be insufficient. Little has been investigated about the natural course of HRQoL after cardiac surgery, HRQoL outcomes between different surgical strategies, HRQoL outcomes between surgical patients and the general population, the different factors influencing HRQoL after cardiac surgery, and the effect of HRQoL on healthcare costs. More prospective studies should be performed, taking into account the knowledge gaps that need to be filled. Computerized adaptive testing methods through open source programs can be implemented to keep the burden to the patient as low as possible and catalyze the use of these tools. Our cardiovascular surgery community has the responsibility to deliberate how it can proceed to effectively fill in these knowledge gaps, and use this newfound knowledge to improve shared treatment decision making, patient outcomes, and ultimately optimize health care efficiency. PMID- 28905302 TI - Non-health Care Facility Medication Errors Associated with Hormones and Hormone Antagonists in the United States. AB - INTRODUCTION: Hormones and hormone antagonists are frequently associated with medication errors and may result in important adverse outcomes. The purpose of this study is to investigate non-health care facility (non-HCF) medication errors associated with hormones and hormone antagonists in the United States (US). METHODS: A retrospective analysis of National Poison Data System data was conducted to identify characteristics and trends of unintentional non-HCF therapeutic errors involving hormones and hormone antagonists among individuals of all ages from 2000 to 2012. RESULTS: From 2000 to 2012, US poison control centers received 169,695 calls regarding unintentional non-HCF therapeutic errors associated with hormone therapies, averaging 13,053 medication error calls annually. The rate of reported errors increased significantly by 162.6% (p < 0.001), from 2.24 per 100,000 US residents in 2000 to 5.89 per 100,000 in 2012. Two thirds of the errors (65.2%) occurred among females. The medications most commonly associated with errors were thyroid preparations (23.2%), corticosteroids (21.9%), and insulin (20.0%). All nine deaths and 93.2% of major effects were attributed to hypoglycemic agents. Sulfonylureas alone accounted 43.9% of major effects. The number and rate of therapeutic errors increased significantly for all medication categories except estrogen and thiazolidinediones. Most errors were managed at the site of exposure (82.9%) and did not result in serious medical outcomes (95.6%). CONCLUSIONS: This study provides an overview of non-HCF medication errors associated with hormones and hormone antagonists in the US. While most errors did not result in adverse outcomes, their increasing frequency places a greater burden on the health care system. PMID- 28905305 TI - A Systematic Review of Promising Strategies of Faith-Based Cancer Education and Lifestyle Interventions Among Racial/Ethnic Minority Groups. AB - Church-based interventions have been used to reach racial/ethnic minorities. In order to develop effective programs, we conducted a comprehensive systematic review of faith-based cancer prevention studies (2005~2016) to examine characteristics and promising strategies. Combination terms "church or faith based or religion," "intervention or program," and "cancer education or lifestyle" were used in searching the five major databases: CINAHL; ERIC; Health Technology Assessments; MEDLINE; and PsycInfo. A total of 20 studies met study criteria. CDC's Community Guide was used to analyze and review group interventions. Analyses were organized by two racial groups: African American (AA) and Latino/Hispanic American groups. Results showed most studies reviewed focused on breast cancer alone or in combination with other cancers. Studies of Latino/Hispanic groups targeted more on uninsured, Medicare, or Medicaid individuals, whereas AA studies generally did not include specific insurance criteria. The sample sizes of the AA studies were generally larger. The majority of these studies reviewed used pre-post, posttest only with control group, or quasi-experience designs. The Health Belief Model was the most commonly used theory in both groups. Community-based participatory research and empowerment/ecological frameworks were also used frequently in the Latino/Hispanic studies. Small media and group education were the top two most popular intervention strategies in both groups. Although one-on-one strategy was used in some Latino studies, neither group used reducing client out-of-pocket costs strategy. Client reminders could also be used more in both groups as well. Current review showed church-based cancer education programs were effective in changing knowledge, but not always screening utilization. Results show faith based cancer educational interventions are promising. To maximize intervention impact, future studies might consider using stronger study designs, incorporating a variety of proven effective strategies, including those frequently used evidence-based strategies, as well as exploring promising strategies among specific target groups. PMID- 28905304 TI - Robotically assisted thymectomy: a review of the literature. AB - The aim of this literature review is to see where the robotic thymectomy stands nowadays. A thorough search of the PubMed revealed eighty-two related articles which reviewed comprehensively. The zero intraoperative mortality, the minimal intraoperative morbidity, as well as the recorded recurrence rate of 0-11.1% and complete stable remission rate of 0-40% suggests that the robotic-assisted thymectomy is a feasible, safe and an upcoming procedure. However, the lack of prospective randomized controlled trials prevents this technique to become the standard approach for the nonce. PMID- 28905306 TI - Erratum to: An Update on Implants for Minimally Invasive Glaucoma Surgery (MIGS). PMID- 28905307 TI - Pathology of idiopathic non-cirrhotic portal hypertension. PMID- 28905309 TI - Blame-a novel by Tony Holtzman. AB - After writing many scientific articles at the interface of genetics and society, Neil A (Tony) Holtzman published a novel in Autumn 2016: Blame. This book review summarizes several of the story lines, some of which are related to the Inclusion of Diverse Populations in Genomics Research and Health Services, the topic of a special issue of the Journal of Community Genetics. PMID- 28905308 TI - An Automated Multidose Synthesis of the Potentiometric PET Probe 4 [18F]Fluorobenzyl-Triphenylphosphonium ([18F]FBnTP). AB - PURPOSE: The aim of this study was the automated synthesis of the mitochondrial membrane potential sensor 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) on a commercially available synthesizer in activity yields (AY) that allow for imaging of multiple patients. PROCEDURES: A three-pot, four-step synthesis was implemented on the ELIXYS FLEX/CHEM radiosynthesizer (Sofie Biosciences) and optimized for radiochemical yield (RCY), radiochemical purity (RCP) as well as chemical purity during several production runs (n = 24). The compound was purified by solid-phase extraction (SPE) with a Sep-Pak Plus Accell CM cartridge, thereby avoiding HPLC purification. RESULTS: Under optimized conditions, AY of 1.4-2.2 GBq of [18F]FBnTP were obtained from 9.4 to 12.0 GBq [18F]fluoride in 90 92 min (RCY = 28.6 +/- 5.1 % with n = 3). Molar activities ranged from 80 to 99 GBq/MUmol at the end of synthesis. RCP of final formulations was > 99 % at the end of synthesis and > 95 % after 8 h. With starting activities of 23.2-33.0 GBq, RCY decreased to 16.1 +/- 0.4 % (n = 3). The main cause of the decline in RCY when high amounts of [18F]fluoride are used is radiolytic decomposition of [18F]FBnTP during SPE purification. CONCLUSIONS: In initial attempts, the probe was synthesized with RCY < 0.6 % when starting activities up to 44.6 GBq were used. Rapid radiolysis of the intermediate 4-[18F]fluorobenzaldehyde and the final product [18F]FBnTP during purification was identified as the main cause for low yields in high-activity runs. Radiolytic decomposition was hindered by the addition of radical scavengers during synthesis, purification, and formulation, thereby improving AY and RCP. The formulated probe in injectable form was synthesized without the use of HPLC and passed all applicable quality control tests. PMID- 28905310 TI - Erratum. PMID- 28905311 TI - [Abdominal pain in children: Rational diagnostics in the outpatient department]. PMID- 28905312 TI - [Cubital tunnel syndrome]. PMID- 28905313 TI - [Diagnosis and therapy of insomnia and basic aspects of other sleep disorders]. PMID- 28905314 TI - [Pharmacotherapy in chronic Heart Failure]. PMID- 28905315 TI - Preliminary Studies of Acute Cadmium Administration Effects on the Calcium Activated Potassium (SKCa and BKCa) Channels and Na+/K+-ATPase Activity in Isolated Aortic Rings of Rats. AB - Cadmium is an environmental pollutant closely linked with cardiovascular diseases that seems to involve endothelium dysfunction and reduced nitric oxide (NO) bioavailability. Knowing that NO causes dilatation through the activation of potassium channels and Na+/K+-ATPase, we aimed to determine whether acute cadmium administration (10 MUM) alters the participation of K+ channels, voltage activated calcium channel, and Na+/K+-ATPase activity in vascular function of isolated aortic rings of rats. Cadmium did not modify the acetylcholine-induced relaxation. After L-NAME addition, the relaxation induced by acetylcholine was abolished in presence or absence of cadmium, suggesting that acutely, this metal did not change NO release. However, tetraethylammonium (a nonselective K+ channels blocker) reduced acetylcholine-induced relaxation but this effect was lower in the preparations with cadmium, suggesting a decrease of K+ channels function in acetylcholine response after cadmium incubation. Apamin (a selective blocker of small Ca2+-activated K+ channels-SKCa), iberiotoxin (a selective blocker of large-conductance Ca2+-activated K+ channels-BKCa), and verapamil (a blocker of calcium channel) reduced the endothelium-dependent relaxation only in the absence of cadmium. Finally, cadmium decreases Na+/K+-ATPase activity. Our results provide evidence that the cadmium acute incubation unaffected the calcium activated potassium channels (SKCa and BKCa) and voltage-calcium channels on the acetylcholine vasodilatation. In addition, acute cadmium incubation seems to reduce the Na+/K+-ATPase activity. PMID- 28905317 TI - Healthcare Resource Utilization and Costs Associated with Ketosis Events in Pediatric and Adult Patients with Type 1 Diabetes Mellitus in the UK. AB - INTRODUCTION: Ketosis is a metabolic state associated with insulin deficiency. Untreated, it develops into diabetic ketoacidosis, a significant contributor to mortality and morbidity in people with type 1 diabetes mellitus (T1DM). Little is understood about how patients utilize healthcare resources during ketosis events. This study aimed to identify and quantify healthcare resource utilization and provide estimates of associated costs of ketosis events in T1DM, treated unaided or with healthcare professional (HCP) assistance in the UK. METHODS: Qualitative interviews with adult patients, pediatric carers, and HCPs identified resources used by patients/carers during ketosis events. An online quantitative survey was then used to quantify patients/carers resource use during their/their child's most recent ketosis event, and HCPs estimated patient resource uptake to corroborate the findings. Associated costs estimated from UK data sources were applied to the survey results to calculate the cost of ketosis events in adults and children. RESULTS: Quantitative survey responses from 93 adults, 76 carers, and 52 HCPs were analyzed. Patients and carers monitored ketosis during and following the event with ketone strips and additional glucose strips, and administered treatment comprising insulin and pump set changes where appropriate. Additionally, patients/carers accessed phone services and many received follow-up medical appointments. In total, 70% (n = 65) of adult and 66% (n = 50) of pediatric ketosis events were managed at home, for which resource use costs per event were L23.87 and L38.00 respectively. Remaining events were treated in NHS facilities costing L217.57 per adult and L352.92 per child. Weighted averages identified that ketosis events cost L81.98 per adult and L142.97 per child. Indirect costs from work productivity loss increase these figures to L225.11 per adult and L256.88 per child. CONCLUSIONS: Healthcare resource use for ketosis events is high in adults and children with T1DM and imposes an underappreciated economic burden for the NHS. FUNDING: Novo Nordisk A/S. PMID- 28905316 TI - Socially Housed Female Macaques: a Translational Model for the Interaction of Chronic Stress and Estrogen in Aging. AB - PURPOSE OF REVIEW: Estrogen's role in cognitive aging remains unclear. Despite evidence implicating stress in pathological aging, the interaction of stress with estrogen on cognition in older women has received little attention, and few animal models exist with which to examine this interaction. RECENT FINDINGS: We present evidence that aging socially subordinate female macaques that experience chronic psychosocial stress constitute a suitable model to investigate this. First, we review studies showing that estrogen modulates cognition in animal models, as well as studies demonstrating that estrogen's action on certain types of cognition is impaired by stress. Next, we discuss data showing that middle aged socially subordinate female macaques exhibit distinct stress-induced phenotypes, and review our investigations indicating that estrogen modulates behavior and physiology differently in subordinate female monkeys. We conclude that socially housed female macaques represent a translational animal model for investigating the interplay of chronic stress and estrogen on cognitive aging in women. PMID- 28905318 TI - The effects of climate, catchment land use and local factors on the abundance and community structure of sediment ammonia-oxidizing microorganisms in Yangtze lakes. AB - Ammonia-oxidizing archaea (AOA) and bacteria (AOB) play important roles in regulating the nitrification process in lake ecosystems. However, the relative effects of climate, catchment land use and local conditions on the sediment ammonia-oxidizing communities in lakes remain unclear. In this study, the diversity and abundance of AOA and AOB communities were investigated in ten Yangtze lakes by polymerase chain reaction (PCR), clone library and quantitative PCR techniques. The results showed that the abundances of both AOA and AOB in bare sediments were considerably but not significantly higher than those in vegetated sediments. Interestingly, AOB communities were more sensitive to changes in local environmental factors and vegetation characteristics than were AOA communities. Amongst climate and land use variables, mean annual precipitation, percentage of agriculture and percentage of vegetation were the key determinants of AOB abundance and diversity. Additionally, total organic carbon and chlorophyll-a concentrations in lake water were significantly related to AOB abundance and diversity. The results of the ordination analysis indicated that 81.2 and 84.3% of the cumulative variance for the species composition of AOA and AOB communities could be explained by the climate, land use and local factors. The climate and local environments played important roles in shaping AOA communities, whereas catchment agriculture and water chlorophyll-a concentration were key influencing factors of AOB communities. Our findings suggest that the composition and structure of sediment ammonia-oxidizing communities in Yangtze lakes are strongly influenced by different spatial scale factors. PMID- 28905319 TI - PI3K inhibition protects mice from NAFLD by down-regulating CMKLR1 and NLRP3 in Kupffer cells. AB - Inflammation induced by high-fat diet (HFD) is of critical importance in the development of hepatic steatosis. The role of chemerin in the progress of nonalcoholic fatty liver disease (NAFLD) remains controversial. Here, we have evaluated the effects and mechanism of chemerin on insulin sensitivity and inflammation. An inhibitor (wortmannin) and agonist (insulin-like growth factor 1 (IGF-1) of phosphatidyl inositol 3-kinase (PI3K) were applied to Kupffer cells (KCs) after treatment with a concentration gradient of chemerin in vitro. Mice were subjected to both HFD and intra-peritoneal injections of wortmannin and IGF 1 for 12 weeks. Levels of cytokines were evaluated by enzyme-linked immunosorbent assays and the mRNA and protein levels in the KCs were tested by quantitative real-time polymerase chain reaction and western blotting, respectively. Our data suggested that levels of interleukin 1beta (IL-1beta) and IL-18 in the KCs and mice treated with wortmannin were significantly lower than that of IGF-1. Consistently, the expression of chemokine-like receptor 1 (CMKLR1) and nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) was significantly lower in the KCs and mice treated with wortmannin than those treated with IGF-1. Consistently, liver function, insulin resistance, and hepatic steatosis were much more severe in mice treated with IGF-1 than those treated with wortmannin. In conclusions, PI3K inhibition attenuates hepatic steatosis and KC-mediated inflammation via down-regulation of CMKLR1 and NLRP3 in HFD mice. PMID- 28905320 TI - Genetic algorithm with a crossover elitist preservation mechanism for protein ligand docking. AB - Protein-ligand docking plays an important role in computer-aided pharmaceutical development. Protein-ligand docking can be defined as a search algorithm with a scoring function, whose aim is to determine the conformation of the ligand and the receptor with the lowest energy. Hence, to improve an efficient algorithm has become a very significant challenge. In this paper, a novel search algorithm based on crossover elitist preservation mechanism (CEP) for solving protein ligand docking problems is proposed. The proposed algorithm, namely genetic algorithm with crossover elitist preservation (CEPGA), employ the CEP to keep the elite individuals of the last generation and make the crossover more efficient and robust. The performance of CEPGA is tested on sixteen molecular docking complexes from RCSB protein data bank. In comparison with GA, LGA and SODOCK in the aspects of lowest energy and highest accuracy, the results of which indicate that the CEPGA is a reliable and successful method for protein-ligand docking problems. PMID- 28905321 TI - Network Analysis of MPO and Other Relevant Proteins Involved in Diabetic Foot Ulcer and Other Diabetic Complications. AB - Network analysis and visualization of genes are very important to understand large complex biological data in a better manner. Large data on genes and proteins in the biological systems are analyzed on the occurrence, interactions, co-expression, and co-regulations of various genes. Here we have visualized the genes involved in type 1 diabetes (T1D), type 2 diabetes (T2D), and foot ulcer condition to put light on the corrective measures to the problem of impaired healing. The goal of this study was to identify the important genes involved in the pathogenesis of diabetes complications and foot ulcer and its association with the free radical-producing enzyme, the myeloperoxidase (MPO). In this study, we have used bioinformatics tools for the analysis of 24 genes that play a major role in diabetes mellitus and its complications, especially diabetic foot ulcer to reveal the relation between the genes and proteins involved in these disease conditions. We could conclude from the network model that MPO is related to foot ulcer and involved in pathogenesis of various co-associated diseases, such as oxidative stress, inflammation, peripheral vascular disease, and other related diabetes complications. PMID- 28905322 TI - Differences in immune response to anesthetics used for day surgery versus hospitalization surgery for breast cancer patients. AB - BACKGROUND: Surgery/anesthetic technique-stimulated immunosuppression may be associated with outcome for cancer patients. Here, the immune responses of patients undergoing day surgery versus hospitalization surgery for breast cancer were compared in a prospective study. METHODS: Between February 2012 and August 2014, 21 breast cancer patients underwent day surgery and 16 breast cancer patients underwent hospitalization surgery. The former group received lidocaine/propofol/pethidine, while propofol/systemic opioid- and sevoflurane/propofol/systemic opioid-based anesthesia were administered to the latter group. Surgical stress response was evaluated based on time of operation and amount of bleeding during operation. Immune function was assessed based on natural killer (NK) cell activity, CD4/8 T cell ratio, and cytokine levels of IL 6 and IL-10 that were detected before surgery, after surgery, and on the first postoperative day. RESULTS: Operation time did not differ between the two groups. Blood loss was significantly less for the hospitalization surgery group. No change in NK cell activity was observed for either group, although the CD4/8 T cell ratio increased transiently following day surgery. Levels of IL-6 increased significantly in both groups following surgery, and these levels tended to be higher in the hospitalization surgery group. One patient who underwent hospitalization surgery had higher levels of IL-10. CONCLUSIONS: There were few differences in immune response between the two groups, potentially since a majority of the hospitalization surgery patients received propofol-based anesthesia. We hypothesize that the use of volatile anesthetic/opioid analgesia in hospitalization surgery has a greater influence on immune function in breast cancer patients than local anesthetic/propofol-based anesthesia in day surgery. PMID- 28905324 TI - The Diatraea Complex (Lepidoptera: Crambidae) in Colombia's Cauca River Valley: Making a Case for the Geographically Localized Approach. AB - The sugarcane stem borers Diatraea saccharalis (Fabricius) and D. indigenella Dyar & Heinrich are common pests of sugarcane crops in Colombia's Cauca river valley (CRV). In 2012, however, D. tabernella Dyar was recorded for the first time in northern CRV and just 1 year later, D. busckella Dyar & Heinrich was detected, also for the first time, in central CRV. The Diatraea outbreak in the CRV was studied, its distribution and population in the region was analyzed, and levels of larval parasitism were observed. During the study of the outbreak, Diatraea species in the CRV were characterized based on the morphology of larval, pupal, and adult stages. Keys to the identification of Diatraea in the CRV based on male genitalia and pupa are provided. Pupal cephalic horns and lateral lobes were discovered as new, reliable characteristics to separate the species at the pupal stage. We suggest biological control program modifications to decrease economic impact and studies at geographically localized levels to better understand the dynamics between the pest species and their parasitoids. PMID- 28905323 TI - Phase I study of panobinostat and 5-azacitidine in Japanese patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. AB - The current therapy for high-risk myelodysplastic syndrome (MDS) involves repeated cycles of the DNA demethylating agent 5-azacitidine (5-Aza), but combination treatments have been proposed to improve patient outcomes. We performed a phase Ib study to investigate the safety and tolerability of 5-Aza (75 mg/m2) combined with the histone deacetylase inhibitor panobinostat (PAN) in adult Japanese patients with MDS or chronic myelomonocytic leukemia (CMML). Eleven patients were enrolled; five received 20 mg PAN + 5-Aza and six received 30 mg PAN + 5-Aza. All patients in the 20 mg PAN cohort had MDS, while two in the 30 mg PAN cohort had MDS and three had CMML. All patients experienced >=1 adverse event (AE) related to the study treatment, and five discontinued the study treatment because of AEs. One patient in each group exhibited dose-limiting toxicities: lung infection (PAN 20 mg + 5-Aza) and cellulitis (PAN 30 mg + 5 Aza). PAN exposure increased with ascending doses, and combination therapy did not affect PAN plasma trough concentrations. In summary, 20 or 30 mg PAN combined with 5-Aza was safe and tolerable in adult Japanese patients with CMML or MDS. Study registration ClinicalTrials.gov Identifier: NCT01613976. PMID- 28905325 TI - Managing Alcohol Use Disorder in Primary Health Care. AB - PURPOSE OF REVIEW: The aim of this study is to summarise the current literature on both the impact and the implementation of primary health care-based screening and advice programmes to reduce heavy drinking, as an evidence-based component of managing alcohol use disorder in primary health care. RECENT FINDINGS: Systematic reviews of reviews find conclusive evidence for the impact of primary health care delivered screening and brief advice programmes in reducing heavy drinking. The content, length of advice and which profession delivers the advice seems less important than the actual encounter between provider and patient. Despite the global burden of disease due to heavy drinking and the evidence that this can be reduced by screening and brief advice programmes delivered in primary health care, such programmes remain poorly implemented. Were such programmes widely implemented, there would be substantial health and productivity gains. Systematic reviews and international studies indicate that improved implementation requires tailoring of training and programme content to match the needs of providers, training and ongoing support and embedding of programmes within local community support, championed by local leaders. The next stage of implementation and scale up of evidence-based screening and brief advice programmes should take place embedded within supportive local community action, with appropriate research to demonstrate impact. PMID- 28905326 TI - Circadian Rhythms, Sleep, and Cognitive Skills: Evidence From an Unsleeping Giant. AB - This study analyzes the effects of sleep duration on cognitive skills and depression symptoms of older workers in urban China. Cognitive skills and mental health have been associated with sleep duration and are known to be strongly related to economic behavior and performance. However, causal evidence is lacking, and little is known about sleep deprivation in developing countries. We exploit the relationship between circadian rhythms and bedtime to identify the effects of sleep using sunset time as an instrument. Using the Chinese Health and Retirement Longitudinal Study, we show that a later sunset time significantly reduces sleep duration and that sleep duration increases cognitive skills and eases depression symptoms of workers aged 45 years and older. The results are driven by employed individuals living in urban areas, who are more likely to be constrained by rigid work schedules. We find no evidence of significant effects on the self-employed, non-employed, or farmers. PMID- 28905327 TI - Development of a Mini-Freeze Dryer for Material-Sparing Laboratory Processing with Representative Product Temperature History. AB - The goal of the work described in this publication was to evaluate a new, small, material-sparing freeze dryer, denoted as the "mini-freeze dryer or mini-FD", capable of reproducing the product temperature history of larger freeze dryers, thereby facilitating scale-up. The mini-FD wall temperatures can be controlled to mimic loading procedures and dryer process characteristics of larger dryers. The mini-FD is equipped with a tunable diode laser absorption spectroscopy (TDLAS) water vapor mass flow monitor and with other advanced process analytical technology (PAT) sensors. Drying experiments were performed to demonstrate scalability to larger freeze dryers, including the determination of vial heat transfer coefficients, K v . Product temperature histories during K v runs were evaluated and compared with those obtained with a commercial laboratory-scale freeze dryer (LyoStar II) for sucrose and mannitol product formulations. When the mini-FD wall temperature was set at the LyoStar II band temperature (- 20 degrees C) to mimic lab dryer edge vials, edge vial drying in the mini-FD possessed an average K v within 5% of those obtained during drying in the LyoStar II. When the wall temperature of the mini-FD was set equal to the central vial product temperature, edge vials behaved as center vials, possessing a K v value within 5% of those measured in the LyoStar II. During both K v runs and complete product freeze drying runs, the temperature-time profiles for the average edge vials and central vial in the mini-FD agreed well with the average edge and average central vials of the LyoStar II. PMID- 28905329 TI - Kant's 'formula of humanity' and assisted reproductive technology: a case for duties to future children. AB - The paper asks the question whether Kant's ethical theory can be applied to issues in assisted reproductive technology (ART). It argues against three objections to applying Kant's ethics to ART: (i) the non-identity objection, (ii) the gen-ethics objection, and (iii) the care-ethics objection. After showing that neither of the three objections is sufficiently persuasive the paper proposes a reading of Kant's 'formula of humanity,' and especially its negative clause (i.e., the 'merely as means' clause), that can be of some guidance in ART. The paper conclude that although Kant's 'formula of humanity' cannot be used as a simple litmus test for determining whether an ART practice is morally permissible or not, it nonetheless can supply us with some guidance in our moral deliberation. PMID- 28905330 TI - Complete chloroplast genome sequences of two endangered Phoebe (Lauraceae) species. AB - BACKGROUND: Phoebe (Lauraceae) comprises of evergreen trees or shrubs with approximately 100 species, distributed in tropical and subtropical Asia and Neotropical America. A total of 34 species and three varieties occur in China. Despite of economic and ecological value, only limited genomic resources are available for this genus. RESULTS: We sequenced the two complete chloroplast (cp) genomes of Phoebe chekiangensis and P. bournei using Illumina sequencing technology via a combined strategy of de novo and reference-guided assembly. We also performed comparative analyses with the cp genomes of P. sheareri and P. sheareri var. oineiensis previously reported. The chloroplast genomes of P. chekiangensis and P. bournei identically contain 112 genes consisting of 78 protein coding genes, 30 tRNA genes, and 4 rRNA genes, with the size of 152,849 and 152,853 bp, respectively. From the two chloroplast genomes, 131 SSRs were identified and 12 different SSRs located in five protein coding genes. The analysis showed the extremely conserved structure of chloroplast genomes with surprisingly little variations at the LSC/IR and SSC/IR boundaries. Moreover, the mean nucleotide diversity was found to be 0.162% for 77 regions, suggesting an extraordinarily low level of sequence divergence. Four highest divergent regions (trnH-psbA, rps14-trnT, petA-psbJ, ccsA-ndhD) with the percentage of nucleotide diversity higher than 0.50% were identified, which had potential use for species identification and phylogenetic studies. CONCLUSION: This study will facilitate our understanding of population genetics, phylogenetic relationship and plant evolution of Phoebe species. PMID- 28905328 TI - Lessons learned from protein aggregation: toward technological and biomedical applications. AB - The close relationship between protein aggregation and neurodegenerative diseases has been the driving force behind the renewed interest in a field where biophysics, neurobiology and nanotechnology converge in the study of the aggregate state. On one hand, knowledge of the molecular principles that govern the processes of protein aggregation has a direct impact on the design of new drugs for high-incidence pathologies that currently can only be treated palliatively. On the other hand, exploiting the benefits of protein aggregation in the design of new nanomaterials could have a strong impact on biotechnology. Here we review the contributions of our research group on novel neuroprotective strategies developed using a purely biophysical approach. First, we examine how doxycycline, a well-known and innocuous antibiotic, can reshape alpha-synuclein oligomers into non-toxic high-molecular-weight species with decreased ability to destabilize biological membranes, affect cell viability and form additional toxic species. This mechanism can be exploited to diminish the toxicity of alpha synuclein oligomers in Parkinson's disease. Second, we discuss a novel function in proteostasis for extracellular glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in combination with a specific glycosaminoglycan (GAG) present in the extracellular matrix. GAPDH, by changing its quaternary structure from a tetramer to protofibrillar assembly, can kidnap toxic species of alpha-synuclein, and thereby interfere with the spreading of the disease. Finally, we review a brighter side of protein aggregation, that of exploiting the physicochemical advantages of amyloid aggregates as nanomaterials. For this, we designed a new generation of insoluble biocatalysts based on the binding of photo-immobilized enzymes onto hybrid protein:GAG amyloid nanofibrils. These new nanomaterials can be easily functionalized by attaching different enzymes through dityrosine covalent bonds. PMID- 28905332 TI - Study on the removal and transport and migration mechanism for As with activated sludge system. AB - In this paper, the removal of As and the transport and migration of As at the process of activated sludge system was studied. The results showed that the activated sludge system has high removal efficiency for As, and the removal efficiency could be nearly 100%. The initial concentration of As has effect on the removal efficiency, and within the experimental scope, the increase of initial concentration of As improved the removal efficiency for As. The distribution of As in the surface and internal in activated sludge indicates that in the process of activated sludge, the As was first transferred from water to the surface of solid and was adsorbed by the surface and then transport to the interior of microbes and take part in some metabolisms of the microorganisms. The adsorption of As by activated sludge conforms to Freundlich adsorption isotherm, and the removal of As in activated sludge system follows to the pseudo second order reaction kinetics. PMID- 28905333 TI - Osteoblastoma of the hamate bone - a case report. PMID- 28905331 TI - Antibiotic Distribution into Cerebrospinal Fluid: Can Dosing Safely Account for Drug and Disease Factors in the Treatment of Ventriculostomy-Associated Infections? AB - Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the cerebrospinal fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into cerebrospinal fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of cerebrospinal fluid penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness; drug factors include physiochemical properties, degree of plasma-protein binding, and affinity to active transporter proteins present in the blood cerebrospinal fluid barrier. The relationship between cerebrospinal fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic/pharmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing related dilemmas when treating patients with these challenging infections. PMID- 28905334 TI - Endoscopic submucosal dissection for a heterotopic gland in the transverse colon. PMID- 28905335 TI - Rescue antegrade diathermic dilation of hyperplastic tissue at partially covered metallic stent after EUS-guided hepaticogastrostomy. PMID- 28905336 TI - Endoscopic ultrasonography-guided photodynamic therapy for recurrent intraductal papillary mucinous neoplasm of the pancreas. PMID- 28905337 TI - Cholangioscopy-assisted guidewire placement in post-liver transplant anastomotic biliary stricture: efficient and potentially also cost-effective. PMID- 28905338 TI - Endoscopic ultrasound-guided choledochoduodenostomy with novel use of contrast enhanced harmonic imaging. PMID- 28905339 TI - Novel management of a necrotic pancreatic fluid collection with staged cystgastrostomy followed by cystgastrojejunostomy: the Lizzie Grace maneuver. PMID- 28905341 TI - Use of a Powered Stapling System for Minimally Invasive Lung Volume Reduction Surgery: Results of a Prospective Double-Blind Single-Center Randomized Trial. PMID- 28905340 TI - German Heart Surgery Report 2016: The Annual Updated Registry of the German Society for Thoracic and Cardiovascular Surgery. AB - Based on a long-standing voluntary registry founded by the German Society forThoracic and Cardiovascular Surgery (GSTCVS), well-defined data of all cardiac,thoracic, and vascular surgery procedures performed in 78 German heart surgerydepartments during the year 2016 are analyzed. In 2016, a total of 103,128 heartsurgery procedures (implantable defibrillator, pacemaker, and extracardiac proceduresexcluded) were submitted to the registry. Approximately 15.7% of the patients were atleast 80 years of age, resulting in an increase of 0.9% compared with the data of 2015.For 37,614 isolated coronary artery bypass grafting procedures (relationship on-/off-pump4.4:1), an unadjusted in-hospital mortality of 2.9% was observed. Concerning the33,451 isolated heart valve procedures (including 11,701 catheter-based procedures),the unadjusted in-hospital mortality was 4.3%.This annual updated registry of the GSTCVS represents voluntary public reporting byaccumulating actual information for nearly all heart surgical procedures in Germany,describes advancements in heart medicine, and is a basis for internal and externalquality assurances for all participants. In addition, the registry demonstrates that theprovision of cardiac surgery in Germany is appropriate and patients are treatednationwide at all times. PMID- 28905342 TI - Quality of Life after Free Fibula Flap Reconstruction of Segmental Mandibular Defects. AB - BACKGROUND: Free fibula flap (FFF) is considered gold standard in the reconstruction of mandibular defects. Despite the frequent use, patients' quality of life (QoL) after reconstruction has been sparsely investigated. This study aims to evaluate QoL and outcomes in patients who have undergone FFF reconstruction of segmental mandibular defects. METHODS: A retrospective cohort study of consecutive patients (n = 73) operated at a single center during the years 2000 to 2014 was performed. Charts were reviewed and all living patients (n = 41) were invited to fill out three quality of life questionnaires (QLQ): SF-36, EORTC QLQ-C30, and QLQ-H&N35. Factors associated with poor outcome were derived from regression models and the results of the QLQs were compared with Swedish reference populations. Subgroup analysis was performed for two groups depending on reconstructive indication: cancer and osteoradionecrosis (ORN). RESULTS: The response rate of the QLQs was 93%. General QoL did not differ from reference populations, but the study group had significantly larger proportions of poor functioning patients in three domains in EORTC QLQ-C30: global health status, role functioning, and social functioning. Patients also reported a high incidence of poor functioning/high symptom burden in EORTC QLQ-H&N35, with a significantly higher frequency in the ORN group compared with the cancer group for the domains "swallowing" and "social eating." The overall flap success rate was 92% and complication rate was 48%. Previous surgery had a significant association with reoperation due to bleeding, and longer duration of surgery was significantly associated with local infection. CONCLUSION: When evaluated with validated QLQs, most patients experienced persistent functional loss in one or several domains, but still perceived a general QoL that is close to that of reference populations. Patients having ORN as the indication for surgery, as compared with cancer, reported a higher frequency of poor functioning patients in disease-specific QoL domains. PMID- 28905343 TI - Multidetector Computed Tomography (CT) Analysis of 168 Cases in Diabetic Patients with Total Superficial Femoral Artery Occlusion: Is It Safe to Use an Anterolateral Thigh Flap without CT Angiography in Diabetic Patients? AB - BACKGROUND: The superficial femoral artery (SFA) is the most common site of lower extremity atherosclerosis, and collateral vessels from the deep femoral artery (DFA) play an important compensatory role between the iliofemoral segment and the popliteal artery. We examined SFA occlusion and collateral vessel developments in patients with diabetes mellitus using computed tomography (CT) angiography. We also compared the collateral systems from the DFA and the descending branch of the lateral circumflex femoral artery (dbLCFA) in the case of SFA occlusion. METHODS: We retrospectively reviewed 1,316 sets of CT angiographic data collected from 673 patients with diabetes between 2008 and 2010. The degree of stenosis in each segment of the proximal and distal SFA and the number and size of collateral vessels originating from the DFA and dbLCFA were measured using established scoring systems. In cases where the SFA was occluded, the numbers of collateral vessels originating from the DFA and the dbLCFA vessel were compared. RESULTS: The mean occlusion rate of the SFA was 15.6%. We noted that collateral vessels from DFA and dbLCFA were the main circulatory route in cases of occlusions of the SFA. More collateral vessels developed from the DFA than from the dbLCFA. Overall, 0.6% of the patients had only collateral systems from the dbLCFA. CONCLUSION: When planning to use anterolateral thigh free flaps in diabetic patients with suspected SFA total occlusion, thorough investigations of the peripheral vessels are essential. PMID- 28905344 TI - Application of Tissue Expansion with Perforator Flaps for Reconstruction of Challenging Skin Lesions. AB - BACKGROUND: One set of perforators can supply its own perforasome as well as the adjacent perforasome. The process of tissue expansion can mimic the effect of surgical delay to include more perforasomes into the perforator flap. By combining the perforasome theory with the technique of tissue expansion, large and various expanded perforator flaps can be achieved. METHODS: From July 2007 to July 2014, we performed eight different types of expanded perforator flaps in a total of 83 cases: 41 supraclavicular artery perforator flaps, 11 superficial cervical artery perforator flaps, 15 lateral thoracic perforator flaps, 6 internal mammary artery perforator flaps, 6 thoracoabdominal perforator flaps, 2 facial artery perforator flaps, 1 posterior interosseous perforator flap, and 1 ulnar collateral artery perforator flap. During the follow-up period, the survival rate, color, texture, and retraction of the flaps were assessed. RESULTS: The dimensions of the flaps ranged from 8 * 6 to 25 * 25 cm. Minor flap necrosis occurred in 20.5% of the cases, and severe flap necrosis developed in 2.4% of the cases. The donor sites were closed primarily in all but three cases. During the follow-up period (average, 13 months; range, 8-18 months), no flap contracture was observed with a good color and texture match. CONCLUSION: By combining the concept of perforasome with the technique of tissue expansion, flaps with large dimensions and reliable blood supply can be achieved, allowing a more flexible design to reconstruct various and challenging skin lesions. PMID- 28905345 TI - Same-day Routine Chest-X Ray After Thoracic Surgery is Not Necessary! AB - INTRODUCTION: Performing a routine postoperative chest X-ray (CXR) after general thoracic surgery is daily practice in many thoracic surgery departments. The quality, frequency of pathological findings and the clinical consequences have not been well evaluated. Furthermore, exposure to ionising radiation should be restricted to a minimum and therefore routine practice can be questioned. METHODS: As a hospital standard, each patient was given a routine CXR after opening of the pleura and inserting a chest tube. From October 2015 to March 2016, each postoperative patient with a routine CXR was included in a prospective database, including film quality, pathological findings, clinical and laboratory results and cardiorespiratory monitoring, as well as clinical consequences. RESULTS: 546 patients were included. Risk factors for postoperative complications were obesity in 50 patients (9.2%), emphysema in 127 patients (23.3%), coagulopathy in 34 patients (6.2%), longer operation time (more than two hours) in 242 patients (44.3%) and previous lung irradiation in 29 (5.3%) of patients. Major lung resections were performed in 191 patients (35.9%). 263 (48.2%) patients had procedures with minimally invasive access. The quality of the X-ray film was insufficient in 8.2% of patients. 90 (16.5%) of CXRs were found to show pathological findings, with a trend for more pathological findings after open surgery (55/283; 19.4%) compared to minimally invasive surgery (35/263; 13.3%) (p = 0.064). 11 (2.0%) patients needed a surgical or clinical intervention during postoperative observation; this corresponds to 12.2% of patients with a pathological finding on CXR. Nine of these 11 patients were clinically symptomatic and only two (0.37%) patients were asymptomatic with a relevant pneumothorax. CONCLUSIONS: Our study cannot support routine postoperative CXR after general thoracic procedures and we believe that restriction to clinically symptomatic cases should be a safe option. PMID- 28905346 TI - [Creating Enthusiasm for Surgery - Perceptions of the Impact of Undergraduate Practical Education (Clerkship) for Occupational Choices]. AB - Background/Aim Surgical and other disciplines have been noticing difficulties in recruiting junior staff for several years. In response to a decrease in interest within study courses, surgical associations recommend better supervision during undergraduate practical education as "clerkships" in order to increase the attractiveness of surgery. This clerkship has an initiation function, as students for the first time - albeit marginally - can act as physicians. The aim of this study was to investigate the impact of clerkships on the disciplinary orientations and preferences of undergraduates' perceptions of specialist training. Methods Medical students of the Otto-von-Guericke University Medical School at Magdeburg were interviewed at 4 different time points in their clinical training (n = 373). The questionnaire included different dimensions on i) their choice of the subjects of clerkships and ii) on their clerkship experiences. Questions were subdivided into 5 basic topics, including 5 options to answer according to "Likert's scale" ranging from 1 to 5 ("completely true" to "does not apply at all"). Data were statistically analysed. Results Clerkships are an important component of medical studies. Undergraduate medical students deliberately use clerkships to get to know and to discriminate between medical disciplines they consider as possible choices for later specialisation. Their own assessment as well as reported experiences of specific clinics, departments or supervisors influence decision-making with regard to medical disciplines and locations/institutions for clerkships. The contents of the clerkships is expected to be closely related to the medical curricula. Students expect a detailed insight and practical, cross-departmental, interdisciplinary integration and collaboration in the medical discipline selected for clerkship. Clerkship experience in surgery affects the students' preference for surgical disciplines. They are a relevant predictor. Conclusion High-quality teaching - an important part of practical undergraduate training (clerkship) is effective in fostering a subsequent surgical orientation. Preference for surgical specialisation can be strengthened during medical studies by preparing seminars and extended practical experiences during clerkship. PMID- 28905347 TI - [Mixed epithelial and stromal tumour of the kidney: a case report]. AB - Mixed epithelial and stromal tumours of the kidney are rare. Histologically, they are characterised by a complex of epithelium and stroma with cystic and solid areas. They usually occur in perimenopausal women receiving hormone replacement with oestrogen. Typical symptoms are haematuria, flank pain and a palpable mass, with more and more authors reporting incidentally diagnosed tumours. This also applies to our case report. We are reporting the first published case in Germany: a 60-year-old female with a mixed epithelial and stromal tumour of the right kidney. The tumour was removed through complete nephrectomy. PMID- 28905348 TI - [A rare complication of transrectal electrostimulation for sperm retrieval]. AB - In men who wish to have children after a spinal cord injury, assisted ejaculation is frequently needed for sperm retrieval. Transrectal electrostimulation (TES) is often used for this purpose. Typical side effects of TES are autonomic dysreflexia or pain. In a 33-year old man with complete tetraplegia below C6 since 2004, TES caused massive leg spasticity, leading to transcervical fracture of the femoral neck. This previously unreported complication of TES demonstrates that, in men with long-term chronic tetraplegia, spasticity and osteoporosis, TES in anesthesia should be taken into consideration. PMID- 28905349 TI - Managing and Supporting Surgery in Patients with Bleeding Disorders. PMID- 28905350 TI - Vitamin K-Dependent Protein S: Beyond the Protein C Pathway. AB - Protein S is a vitamin K-dependent plasma glycoprotein circulating in plasma at a concentration of around 350 nM. Approximately 60% of protein S in human plasma is bound to the complement regulatory protein C4b-binding protein (C4BP) in a high affinity, high-molecular-weight complex. Protein S in plasma has multiple anticoagulant properties and heterozygous protein S deficiency is associated with increased risk of venous thrombosis. Homozygous deficiency in man and mice is associated with severe thrombosis in fetal life, defects in the vascular system development, and not compatible with life. Protein S has additional functions beyond being an anticoagulant. It affects the complement regulatory properties of C4BP, and moreover, protein S interacts with tyrosine kinase receptors of the TAM family, which comprises Tyro3, Axl, and Mer. The TAM receptor interaction is important for the ability of protein S to stimulate phagocytosis of apoptotic cells. This review will discuss the multiple functions of protein S, describing its role as cofactor to activated protein C with a subsequent focus on the other functions of protein S. PMID- 28905351 TI - The Tissue Factor Pathway and Wound Healing. AB - The role of tissue factor (TF) as the major initiator of hemostatic blood coagulation is well recognized. The ability to form an adequate hemostatic clot is essential to the normal healing of an injury by staunching bleeding, stabilizing the injured tissue, and serving as a scaffold for repair processes. Also, some molecules produced during hemostasis, particularly thrombin, have cytokine and growth factor-like activities that contribute to inflammation and repair. However, TF itself has activities as a regulator of cellular processes via direct signaling, as well as by facilitating activation of proteolytically activated receptors by activated factors VII and X. The importance of hemostasis in the host response to injury makes it very difficult to separate the hemostatic from nonhemostatic effects of TF on wound healing. The literature in this area remains sparse but suggests that TF influences the course and tempo of healing by cell signaling events that impact inflammation, epithelialization, and angiogenesis. PMID- 28905352 TI - Factor IX Gene (F9) Genotyping Trends and Spectrum of Mutations Identified: A Reference Laboratory Experience. AB - In hemophilia B (HB), factor IX gene (F9) genotyping is used for molecular confirmation of affected individuals, for carrier testing, to facilitate the identification of those at risk for anaphylaxis/inhibitors (associated with large deletions), and to assist in assigning disease severity. Owing to test costs, optimal test utilization involves pre/post-test counseling and appropriate patient and test selection (e.g., mutation screening [F9MS] vs. known mutation [F9KM] testing). This article aims to review the trends and outcomes of F9 genotyping orders and describe the spectrum of variants identified in a sample of individuals in our reference laboratory. We performed a retrospective review of consecutive orders submitted to the Special Coagulation DNA Diagnostic Laboratory, Mayo Clinic, between 2012 and 2015. A total of 133 orders (38%) were identified for men: 118 (88%) were F9MS and 15 (12%) were F9KM. Thirteen orders (10%) were cancelled. A total of 209 orders were identified for women: 178 (85%) were F9MS and 31 (15%) were F9KM. Thirty-seven orders (18%) were cancelled and 30% of the tests performed yielded negative results. A total of 164 samples (47%) were received without clinical information. Seventeen previously unreported variants were identified. F9 genotyping provides useful information for HB management; however, 18% of our orders were cancelled and almost half were received without relevant clinical information, thus reaffirming the need for ongoing scrutiny of submitted orders. Optimal patient and test selection is important as is the accurate interpretation of variants identified. Most of the pathogenic variants identified were point mutations, with very few large deletions, consistent with the literature. PMID- 28905353 TI - Platelet RNA in Cancer Diagnostics. AB - Platelets are involved in several steps of cancer metastasis. During this process, platelets are exposed to the tumor and its environment, thereby exchanging biomolecules with the tumor cells and resulting in tumor-mediated "education" of the platelets and a change in their RNA profile. Analysis of platelet RNA profiles or direct measurement of tumor-derived biomarkers within platelets can provide information on ongoing cancer-related processes in the individual (e.g., whether the patient has cancer, the tumor type, and possibly identify oncogenic alterations driving the disease for treatment selection). The close interaction with the disease process and the ability to respond to systemic alterations make platelets an interesting biosource for implementation in precision medicine. PMID- 28905354 TI - Standardizing the Response to Category II Tracings during Induction with Oxytocin: A Cost-Effectiveness Analysis. PMID- 28905355 TI - Revealing hidden talents: The development, use, and benefit of VESPARCH. AB - BACKGROUND: School attainment tests and Cognitive Abilities Tests are used in the United Kingdom to set targets for educational outcome. Whilst these are good predictors, they depend not only on basic ability but also on learnt knowledge and skills, such as reading. METHOD AND AIMS: VESPARCH is an online group test of verbal and spatial reasoning, which we propose gives a measure that more closely approximates to basic ability - fluid intelligence. The verbal test contains highly familiar words, does not require the child to read them, is untimed, and provides detailed feedback on five practice questions for each part of the test. The tests - one suitable and standardized for children aged 7-9 years and one for children aged 10-12 years - have good test-retest reliability and validity and conform to the Rasch model. Comparison of VESPARCH scores with school attainment measures allows identification of those students who are underachieving academically relative to their potential. The matched nature of the verbal and spatial tests allows reasoning ability in the two domains to be compared; those with much higher spatial scores might be expected to do well in STEM subjects. CONCLUSION: VESPARCH can be used alongside current school tests to ensure targeted teaching and encouragement for every child. PMID- 28905356 TI - Impact of shoulder dystocia, stratified by type of manoeuvre, on severe neonatal outcome and maternal morbidity. AB - BACKGROUND: Shoulder dystocia is an uncommon and unpredictable obstetric emergency. It is associated with significant neonatal, maternal and medico-legal consequences. AIM: To ascertain the impact shoulder dystocia has on severe neonatal and maternal outcomes specific to the type of manoeuvre. MATERIALS AND METHODS: This was a retrospective study of 48 021 term singleton vaginal deliveries the Mater Mothers' Hospital in Brisbane between 2007 and 2015. Maternal and neonatal outcomes were compared between deliveries complicated by shoulder dystocia and those uncomplicated. RESULTS: Deliveries complicated by shoulder dystocia are associated with low Apgar scores (<=3) at five minutes (odds ratio (OR) 5.25, 95% CI 3.23-8.56, P < 0.001), acidosis (OR 3.10, 95% CI 2.76-3.50, P < 0.001), postpartum haemorrhage (OR 2.28, 95% CI 1.90-2.75, P < 0.001) and perineal trauma (OR 1.92, 95% CI 1.54-2.39, P < 0.001). Compared to McRoberts' manoeuvre and suprapubic pressure alone, the odds of serious neonatal outcome are increased with internal rotational manoeuvres (OR 3.82, 95% CI 2.54 5.74, P < 0.001) and delivery of the posterior arm (OR 4.49, 95% CI 3.54-5.69, P < 0.001). The OR of maternal injury is 2.07 (95% CI 1.77-2.45, P < 0.001), 2.26 (95% CI 1.21-4.21, P < 0.001) and 2.29 (95% CI 1.58-3.32, P < 0.001) with McRoberts'/suprapubic pressure, internal rotation and posterior arm delivery, respectively. Brachial plexus injuries and fractures complicate 1.4 and 0.9% of deliveries, with the risk of injury increasing when greater than one manoeuvre is required. CONCLUSION: The risk of neonatal and maternal trauma is strongly associated with the number and types of manoeuvres. Given the associated implications, adequate antenatal counselling, simulation training and enhanced labour surveillance are essential. PMID- 28905357 TI - Interval between IVF stimulation cycle and frozen embryo transfer: Is there a benefit to a delay between cycles? AB - BACKGROUND: There is currently limited evidence available regarding ideal timing for frozen embryo transfer (FET). Demonstrating that delaying FETs has few clinical benefits would allow patients to proceed with FET at their earliest convenience. AIMS: To examine whether the time interval between stimulation cycle and subsequent FET affects pregnancy and live birth rates. MATERIALS AND METHODS: This retrospective cohort study, based in a multi-site private in vitro fertilisation (IVF) clinic categorised women into two groups: those having FET cycles administered within 25-35 days or 50-70 days of IVF stimulation cycle and embryo freeze. Outcomes measured were clinical pregnancy and live birth rates. RESULTS: When comparing the patients who have had a 25-35 days gap between embryo freeze and FET, to the matched patients who had a 50-70 days gap, the statistically significant results showed an adjusted odds ratio for live birth of 1.31 (1.02-1.67). The adjusted odds ratio for clinical pregnancy in matched case : control analysis was not statistically significant at 1.22 (0.97-1.53). CONCLUSION: A gap of 25-35 days between embryo freeze and FET was associated with improved live birth rates compared to a gap of 50-70 days. PMID- 28905358 TI - Prognosis Communication in Late-Life Disability: A Mixed Methods Study. AB - IMPORTANCE: Long-term prognosis informs clinical and personal decisions for older adults with late-life disability. However, many clinicians worry that telling patients their prognosis may cause harm. OBJECTIVE: To explore the safety of and reactions to prognosis communication in late-life disability. DESIGN: Participants estimated their own life expectancy and were then presented their calculated life expectancy using a validated prognostic index. We used a semi structured interview guide to ask for their reactions. Qualitative data were analyzed using constant comparative analysis. Potential psychological and behavioral outcomes in response to receiving one's calculated prognosis were recorded and re-assessed 2-4 weeks later. SETTING: Community-dwelling older adults age 70+ residing in the San Francisco Bay Area. PARTICIPANTS: Thirty five older adults with a median age of 80 requiring assistance with >=1 Activity of Daily Living. RESULTS: Self-estimates of life expectancy were similar to calculated results for 16 participants. 15 estimated their life expectancy to be longer than their calculated life expectancy by >2 years, while 4 shorter by >2 years. An overarching theme of, "fitting life expectancy into one's narrative" emerged from qualitative analysis. Discussing life expectancy led participants to express how they could alter their life expectancy (subtheme "locus of control"), how they saw their present health (subtheme "perceived health"), and their hopes and fears for the remaining years of their lives (subtheme "outlook on remaining years"). Feelings of anxiety and sadness in reaction to receiving calculated prognosis were rare. CONCLUSIONS AND RELEVANCE: About half of the disabled older adults' self-estimates of prognosis were similar to calculated estimates. Evidence of sadness or anxiety was rare. These data suggest that in most cases, clinicians may offer to discuss prognosis. PMID- 28905360 TI - Distress levels in pregnant and matched non-pregnant women. AB - This study examined self-rated symptoms of distress (Depression Anxiety and Stress Scale-DASS-21 and Perceived Stress Scale-PSS-4) among 93 pregnant women and a comparison group of 93 non-pregnant women matched on age and educational attainment. There were no significant differences between the groups, either on mean levels of distress or on proportions above a clinical cut-off point. Overall, 22%, 31% and 16% of pregnant women reported experiencing at least moderate levels of depression, anxiety and stress, respectively. Implications for conceptualising distress in pregnancy and identifying and providing support for the substantial minority who are distressed are discussed. PMID- 28905359 TI - Guideline-Recommended Medications and Physical Function in Older Adults with Multiple Chronic Conditions. AB - BACKGROUND/OBJECTIVES: The benefit or harm of a single medication recommended for one specific condition can be difficult to determine in individuals with multiple chronic conditions and polypharmacy. There is limited information on the associations between guideline-recommended medications and physical function in older adults with multiple chronic conditions. The objective of this study was to estimate the beneficial or harmful associations between guideline-recommended medications and decline in physical function in older adults with multiple chronic conditions. DESIGN: Prospective observational cohort. SETTING: National. PARTICIPANTS: Community-dwelling adults aged 65 and older from the Medicare Current Beneficiary Survey study (N = 3,273). Participants with atrial fibrillation, coronary artery disease, depression, diabetes mellitus, or heart failure were included. MEASUREMENTS: Self-reported decline in physical function; guideline-recommended medications; polypharmacy (taking <7 vs >=7 concomitant medications); chronic conditions; and sociodemographic, behavioral, and health risk factors. RESULTS: The risk of decline in function in the overall sample was highest in participants with heart failure (35.4%, 95% confidence interval (CI) = 26.3-44.5) and lowest for those with atrial fibrillation (20.6%, 95% CI = 14.9 26.2). In the overall sample, none of the six guideline-recommended medications was associated with decline in physical function across the five study conditions, although in the group with low polypharmacy exposure, there was lower risk of decline in those with heart failure taking renin angiotensin system blockers (hazard ratio (HR) = 0.40, 95% CI = 0.16-0.99) and greater risk of decline in physical function for participants with diabetes mellitus taking statins (HR = 2.27, 95% CI = 1.39-3.69). CONCLUSIONS: In older adults with multiple chronic conditions, guideline-recommended medications for atrial fibrillation, coronary artery disease, depression, diabetes mellitus, and heart failure were largely not associated with self-reported decline in physical function, although there were associations for some medications in those with less polypharmacy. PMID- 28905361 TI - Association between oral health and upper respiratory tract infection among children. AB - BACKGROUND: The oral cavity is a potential reservoir for respiratory pathogens. This longitudinal study investigated the association between upper respiratory tract infection (URI) and oral health among children. METHODS: A total of 288 children aged 4 years were recruited. Their dental caries and oral hygiene status were clinically determined, using the dmft (decayed, missing and filled teeth) index and the Silness-Loe plaque index. Questionnaires were completed by parents to collect information on the child's socio-demographic background and URI episodes and symptoms in the following 12 months. Standard or zero-inflated negative binomial regressions were used to analyse the association between URI and both oral health indicators (dmft and plaque score). RESULTS: Some 138 (47.9%) children had URI in 12 months, including 63 (21.9%) and 75 (26.0%) children with 1-2 episodes and >=3 episodes, respectively. The reported URI episodes fell into two peaks, coinciding with the two influenza peaks in Hong Kong. Significantly a higher dmft was found among children without URI compared with children who had >=3 URI episodes (1.32 vs. 0.49; P = 0.043). The number of URI episodes was inversely associated with dmft (IRR = 0.851; 95% CI: 0.766 0.945; P = 0.003). There was no significant association between the plaque score and URI (P > 0.05). CONCLUSIONS: The children's caries experience was associated with reduced episodes of URI. Whether this inverse association is attributed to the immune response induced by dental caries is yet to be investigated. PMID- 28905362 TI - Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults. AB - BACKGROUND: Neuropathic pain, which is due to nerve disease or damage, represents a significant burden on people and society. It can be particularly unpleasant and achieving adequate symptom control can be difficult. Non-pharmacological methods of treatment are often employed by people with neuropathic pain and may include transcutaneous electrical nerve stimulation (TENS). This review supersedes one Cochrane Review 'Transcutaneous electrical nerve stimulation (TENS) for chronic pain' (Nnoaham 2014) and one withdrawn protocol 'Transcutaneous electrical nerve stimulation (TENS) for neuropathic pain in adults' (Claydon 2014). This review replaces the original protocol for neuropathic pain that was withdrawn. OBJECTIVES: To determine the analgesic effectiveness of TENS versus placebo (sham) TENS, TENS versus usual care, TENS versus no treatment and TENS in addition to usual care versus usual care alone in the management of neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, AMED, CINAHL, Web of Science, PEDro, LILACS (up to September 2016) and various clinical trials registries. We also searched bibliographies of included studies for further relevant studies. SELECTION CRITERIA: We included randomised controlled trials where TENS was evaluated in the treatment of central or peripheral neuropathic pain. We included studies if they investigated the following: TENS versus placebo (sham) TENS, TENS versus usual care, TENS versus no treatment and TENS in addition to usual care versus usual care alone in the management of neuropathic pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all database search results and identified papers requiring full-text assessment. Subsequently, two review authors independently applied inclusion/exclusion criteria to these studies. The same review authors then independently extracted data, assessed for risk of bias using the Cochrane standard tool and rated the quality of evidence using GRADE. MAIN RESULTS: We included 15 studies with 724 participants. We found a range of treatment protocols in terms of duration of care, TENS application times and intensity of application. Briefly, duration of care ranged from four days through to three months. Similarly, we found variation of TENS application times; from 15 minutes up to hourly sessions applied four times daily. We typically found intensity of TENS set to comfortable perceptible tingling with very few studies titrating the dose to maintain this perception. Of the comparisons, we had planned to explore, we were only able to undertake a quantitative synthesis for TENS versus sham TENS. Insufficient data and large diversity in the control conditions prevented us from undertaking a quantitative synthesis for the remaining comparisons.For TENS compared to sham TENS, five studies were suitable for pooled analysis. We described the remainder of the studies in narrative form. Overall, we judged 11 studies at high risk of bias, and four at unclear risk. Due to the small number of eligible studies, the high levels of risk of bias across the studies and small sample sizes, we rated the quality of the evidence as very low for the pooled analysis and very low individual GRADE rating of outcomes from single studies. For the individual studies discussed in narrative form, the methodological limitations, quality of reporting and heterogeneous nature of interventions compared did not allow for reliable overall estimates of the effect of TENS.Five studies (across various neuropathic conditions) were suitable for pooled analysis of TENS versus sham TENS investigating change in pain intensity using a visual analogue scale. We found a mean postintervention difference in effect size favouring TENS of -1.58 (95% confidence interval (CI) -2.08 to -1.09, P < 0.00001, n = 207, six comparisons from five studies) (very low quality evidence). There was no significant heterogeneity in this analysis. While this exceeded our prespecified minimally important difference for pain outcomes, we assessed the quality of evidence as very low meaning we have very little confidence in this effect estimate and the true effect is likely to be substantially different from that reported in this review. Only one study of these five investigated health related quality of life as an outcome meaning we were unable to report on this outcome in this comparison. Similarly, we were unable to report on global impression of change or changes in analgesic use in this pooled analysis.Ten small studies compared TENS to some form of usual care. However, there was great diversity in what constituted usual care, precluding pooling of data. Most of these studies found either no difference in pain outcomes between TENS versus other active treatments or favoured the comparator intervention (very low quality evidence). We were unable to report on other primary and secondary outcomes in these single trials (health-related quality of life, global impression of change and changes in analgesic use).Of the 15 included studies, three reported adverse events which were minor and limited to 'skin irritation' at or around the site of electrode placement (very low quality evidence). Three studies reported no adverse events while the remainder did not report any detail with regard adverse events. AUTHORS' CONCLUSIONS: In this review, we reported on the comparison between TENS and sham TENS. The quality of the evidence was very low meaning we were unable to confidently state whether TENS is effective for pain control in people with neuropathic pain. The very low quality of evidence means we have very limited confidence in the effect estimate reported; the true effect is likely to be substantially different. We make recommendations with respect to future TENS study designs which may meaningfully reduce the uncertainty relating to the effectiveness of this treatment modality. PMID- 28905363 TI - How Children Construct Views of Themselves: A Social-Developmental Perspective. AB - As they grow up, children construct views of themselves and their place in the world, known as their self-concept. This topic has often been addressed by social psychologists (studying how the self-concept is influenced by social contexts) and developmental psychologists (studying how the self-concept changes over time). Yet, relatively little is known about the origins of the self-concept. This article calls for research that bridges social and developmental psychology to illuminate this important issue. Adopting such a social-developmental approach, the current special section shows that children construct their self concept based on the social relationships they have, the feedback they receive, the social comparisons they make, and the cultural values they endorse. These findings underline the deeply social nature of self-development. PMID- 28905364 TI - A clinical risk score for pulmonary artery thrombosis during acute chest syndrome in adult patients with sickle cell disease. AB - Pulmonary artery thrombosis (PAT) is involved in lung vascular dysfunction during acute chest syndrome (ACS) complicating sickle cell disease (SCD). No clinical score is available to identify patients eligible for multi-detector computed tomography (MDCT) angiography during ACS. This retrospective study aimed to develop a risk score for PAT during ACS (PAT-ACS risk score). Patients with SCD were investigated by MDCT during ACS. A logistic regression was performed to determine independent risks factors for PAT and to build the PAT-ACS risk score. A total of 43 episodes (11.9%) of PAT were diagnosed in 361 episodes of ACS. Multivariate analysis identified four risk factors, which were included in the PAT-ACS risk score: a baseline haemoglobin >82 g/l, the lack of a triggering factor for ACS, a platelet count >440 * 109 /l and a PaCO2 <38 mmHg at ACS diagnosis. The area under the receiver operating characteristic curve for the PAT ACS risk score was 0.74 (95% confidence interval [CI] 0.69-0.79) and differed from that of the revised Geneva score (0.63 (95% CI 0.58-0.69); P = 0.04). The negative predictive value of a PAT-ACS risk score >=2 was 94%. In conclusion, we propose a simple clinical risk score to identify SCD patients at high risk of PAT during ACS. PMID- 28905365 TI - Iron storage in liver, bone marrow and splenic Gaucheroma reflects residual disease in type 1 Gaucher disease patients on treatment. AB - Gaucher disease (GD) is a lysosomal storage disorder characterized by the storage of glycosphingolipids in macrophages. Despite effective therapy, residual disease is present in varying degrees and may be associated with late complications, such as persistent bone or liver disease and increased cancer risk. Gaucher macrophages are capable of storing iron and locations of residual disease may thus be detectable with iron imaging. Forty type 1 GD (GD1) patients and 40 matched healthy controls were examined using a whole-body magnetic resonance imaging protocol consisting of standard sequences, allowing analysis of iron content per organ, expressed as R2* (Hz). Median R2* values were significantly elevated in GD1 patients as compared to healthy controls in liver [41 Hz (range 29-165) vs. 38 Hz (range 28-53), P < 0.01], femoral bone marrow [54 Hz (range 37 129) vs. 49 Hz (range 39-69), P = 0.036] and vertebral bone marrow (118 Hz (range 82-210) vs. 105 Hz (range 76-149), P < 0.01). In the spleen, primarily focal Gaucher lesions known as Gaucheroma were found to have increased R2* values. R2* values of liver, spleen and vertebral bone marrow strongly correlated with serum ferritin levels. GD1 patients with persistent hyperferritinaemia demonstrate increased iron levels in liver and bone marrow, which may carry a risk for liver fibrosis and cancer. PMID- 28905366 TI - The unregulated use of melanotan-II is of public health interest to Australian dermatologists. PMID- 28905368 TI - Interim FDG-PET has no value in selecting patients who require treatment modification in both early- and advanced-stage Hodgkin lymphoma. PMID- 28905367 TI - Nursing Care Disparities in Neonatal Intensive Care Units. AB - OBJECTIVES: To describe the variation across neonatal intensive care units (NICUs) in missed nursing care in disproportionately black and non-black-serving hospitals. To analyze the nursing factors associated with missing nursing care. DATA SOURCES/STUDY SETTING: Survey of random samples of licensed nurses in four large U.S. states. STUDY DESIGN: This was a retrospective, secondary analysis of 1,037 staff nurses in 134 NICUs classified into three groups based on their percent of infants of black race. Measures included the average patient load, individual nurses' patient loads, professional nursing characteristics, nurse work environment, and nursing care missed on the last shift. DATA COLLECTION: Survey data from a Multi-State Nursing Care and Patient Safety Study were analyzed (39 percent response rate). PRINCIPAL FINDINGS: The patient-to-nurse ratio was significantly higher in high-black hospitals. Nurses in high-black NICUs missed nearly 50 percent more nursing care than in low-black NICUs. Lower nurse staffing (an additional patient per nurse) significantly increased the odds of missed care, while better practice environments decreased the odds. CONCLUSIONS: Nurses in high-black NICUs face inadequate staffing. They are more likely to miss required nursing care. Improving staffing and workloads may improve the quality of care for the infants born in high-black hospitals. PMID- 28905369 TI - TSGA10 is a novel candidate gene associated with acephalic spermatozoa. AB - Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells. Subsequent whole-exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein. TSGA10 is a testis-specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient. One cycle of in vitro fertilization-assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality. Therefore, we speculate that the presence of rare sequence variants within TSGA10 may be associated with acephalic spermatozoa in humans. PMID- 28905370 TI - Neuromodulation and Devices in Trigeminal Neuralgia. AB - PREMISE: Trigeminal neuralgia is a severe facial pain disorder that has been studied for decades. Classical trigeminal neuralgia (CTN) is either idiopathic or caused by neurovascular compression. The related painful trigeminal neuropathies are often secondary to other causes, such as multiple sclerosis or trauma. PROBLEM: Therapies for trigeminal neuralgia and neuropathy have often been pharmacologic or surgical. Pharmacologic therapies are not effective in some cases and often cause side effects, some substantial. Surgery can have comorbidity (such as anesthesia dolorosa, or painful differentiation of the affected nerve distribution) and also is not always effective. There is a desire, as in all chronic conditions, to find effective treatments with minimal morbidity and side effects. POTENTIAL SOLUTIONS: We review several devices including neuromodulation, ranging in invasiveness, for treatment of trigeminal neuralgia and neuropathy. We review existing data on sphenopalatine ganglion blocks, transcranial magnetic stimulation, transcortical direct stimulation, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, and transcutaneous electrical stimulation for CTN and pain trigeminal neuropathies. We also offer hope for further research in this area with the goal of discovering a device that can provide treatment for many with few side effects and minimal morbidity. PMID- 28905371 TI - The Origins of Children's Growth and Fixed Mindsets: New Research and a New Proposal. AB - Children's mindsets about intelligence (as a quality they can grow vs. a trait they cannot change) robustly influence their motivation and achievement. How do adults foster "growth mindsets" in children? One might assume that adults act in ways that communicate their own mindsets to children. However, new research shows that many parents and teachers with growth mindsets are not passing them on. This article presents a new perspective on why this is the case, and reviews research on adult practices that do instill growth mindsets, concluding that a sustained focus on the process of learning is critical. After discussing key implications and promising future directions, we consider the topic in the context of important societal issues, like high-stakes testing. PMID- 28905372 TI - Therapeutic outcomes using subcutaneous low dose alemtuzumab for acquired bone marrow failure conditions. PMID- 28905373 TI - Interactions between range-expanding tropical fishes and the northern Gulf of Mexico red snapper Lutjanus campechanus. AB - Experimental investigation of the intensity of potential competitive interactions among increasingly abundant tropically-associated grey Lutjanus griseus and lane snapper Lutjanus synagris and resident northern Gulf of Mexico (nGOM) red snapper Lutjanus campechanus was undertaken in large outdoor mesocosms. In pair-wise interaction trials, compared with L. synagris, L. campechanus demonstrated significantly increased roving behaviour and predatory activity. While no significant difference in these activities was observed between L. campechanus and L. griseus, when all three snappers (Lutjanidae) were grouped together L. campechanus swimming activity significantly decreased in the presence of both tropically-associated species. Overall, L. campechanus were more active and aggressive predators and appear to be competitively resistant to L. griseus and L. synagris. As lower latitude species have continued to become increasingly prevalent in nGOM habitats and regional warming continues to affect resident reef associated fishes, these findings contribute to the assessment of the effects of warming-related species shifts upon nGOM fishes and document current partial resilience of L. campechanus to climate-related expansions of tropical confamilials. PMID- 28905374 TI - Heat and moisture exchangers versus heated humidifiers for mechanically ventilated adults and children. AB - BACKGROUND: Invasive ventilation is used to assist or replace breathing when a person is unable to breathe adequately on their own. Because the upper airway is bypassed during mechanical ventilation, the respiratory system is no longer able to warm and moisten inhaled gases, potentially causing additional breathing problems in people who already require assisted breathing. To prevent these problems, gases are artificially warmed and humidified. There are two main forms of humidification, heat and moisture exchangers (HME) or heated humidifiers (HH). Both are associated with potential benefits and advantages but it is unclear whether HME or HH are more effective in preventing some of the negative outcomes associated with mechanical ventilation. This review was originally published in 2010 and updated in 2017. OBJECTIVES: To assess whether heat and moisture exchangers or heated humidifiers are more effective in preventing complications in people receiving invasive mechanical ventilation and to identify whether the age group of participants, length of humidification, type of HME, and ventilation delivered through a tracheostomy had an effect on these findings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL up to May 2017 to identify randomized controlled trials (RCTs) and reference lists of included studies and relevant reviews. There were no language limitations. SELECTION CRITERIA: We included RCTs comparing HMEs to HHs in adults and children receiving invasive ventilation. We included randomized cross-over studies. DATA COLLECTION AND ANALYSIS: We assessed the quality of each study and extracted the relevant data. Where possible, we analysed data through meta analysis. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (95% CI). For continuous outcomes, we calculated the mean difference (MD) and 95% CI or standardized mean difference (SMD) and 95% CI for parallel studies. For cross-over trials, we calculated the MD and 95% CI using correlation estimates to correct for paired analyses. We aimed to conduct subgroup analyses based on the age group of participants, how long they received humidification, type of HME and whether ventilation was delivered through a tracheostomy. We also conducted sensitivity analysis to identify whether the quality of trials had an effect on meta-analytic findings. MAIN RESULTS: We included 34 trials with 2848 participants; 26 studies were parallel-group design (2725 participants) and eight used a cross-over design (123 participants). Only three included studies reported data for infants or children. Two further studies (76 participants) are awaiting classification.There was no overall statistical difference in artificial airway occlusion (RR 1.59, 95% CI 0.60 to 4.19; participants = 2171; studies = 15; I2 = 54%), mortality (RR 1.03, 95% CI 0.89 to 1.20; participants = 1951; studies = 12; I2 = 0%) or pneumonia (RR 0.93, 95% CI 0.73 to 1.19; participants = 2251; studies = 13; I2 = 27%). There was some evidence that hydrophobic HMEs may reduce the risk of pneumonia compared to HHs (RR 0.48, 95% CI 0.28 to 0.82; participants = 469; studies = 3; I2 = 0%)..The overall GRADE quality of evidence was low. Although the overall methodological risk of bias was generally unclear for selection and detection bias and low risk for follow-up, the selection of study participants who were considered suitable for HME and in some studies removing participants from the HME group made the findings of this review difficult to generalize. AUTHORS' CONCLUSIONS: The available evidence suggests no difference between HMEs and HHs on the primary outcomes of airway blockages, pneumonia and mortality. However, the overall low quality of this evidence makes it difficult to be confident about these findings. Further research is needed to compare HMEs to HHs, particularly in paediatric and neonatal populations, but research is also needed to more effectively compare different types of HME to each other as well as different types of HH. PMID- 28905375 TI - Elemental turnover rates and trophic discrimination in juvenile Lebranche mullet Mugil liza under experimental conditions. AB - The aim of this study was to determine the isotopic-turnover rate (RIT ) and trophic-discrimination factor (FTD ) in muscle tissues of Lebranche mullet Mugil liza fed an experimental diet (delta13 C = -27.10/00; delta15 N = 1.00/00). Juvenile M. liza exhibited a relatively fast RIT , with a half-life (t50 ) of only 16 and 14 days for delta13 C and delta15 N respectively and a nearly complete isotopic turnover (t95 ) of 68 and 60 days for delta13 C and delta15 N. PMID- 28905376 TI - HIV and Headache: A Cross-Sectional Study. AB - INTRODUCTION: The head and neck are the second most common locations for pain among HIV-positive individuals. Most studies were conducted among HIV patients at an advanced stage of the disease. METHODS: This was a cross-sectional study. Patients with HIV and CD4+ T lymphocyte counts >500 were included. Semi structured interview, the Headache Impact Test (HIT-6), and the Hospital Anxiety and Depression Scale were used. RESULTS: Of the 119 cases included, 63% were men. The mean age was 35.5 +/- 10.4 years. Among the patients, 103 (87%) had headaches, 53 (45%) had migraines, 50 (42%) had tension-type headaches, and 53 (45%) had substantial and severe impact of headaches. Eleven patients had headaches that started after they had been diagnosed with HIV. These patients had more migraines (72% vs 43%; P < 0.05), greater intensity (8 +/- 2 vs 6 +/- 2; P < 0.01), and impact (HIT-6: 60 +/- 11 vs 51 +/- 12; P = 0.02) of headaches compared to others HIV patients. There were no correlations between CD4 counts and the intensity, frequency, or impact of headaches. CONCLUSIONS: HIV-positive patients had a high frequency of headaches, which had a great impact on patients' lives. The pattern most often found was migraine. There was no correlation between CD4 counts and the severity of headaches. PMID- 28905377 TI - Implementation challenges and outcomes of a randomized controlled pilot study of a group prenatal care model in Malawi and Tanzania. AB - OBJECTIVE: To identify implementation challenges associated with conducting a randomized controlled trial (RCT) of group prenatal care (PNC) and report outcomes of the pilot. METHODS: A multi-site randomized pilot was conducted in Malawi and Tanzania between July 31, 2014, and June 30, 2015. Women aged at least 16 years with a pregnancy of 20-24 weeks were randomly assigned using sealed envelopes (1:1) to individual or group PNC. Structured interviews were conducted at baseline, in the third trimester and 6-8 weeks after delivery. The primary outcomes were attendance at four PNC visits and attendance at the 6-week postnatal visit. RESULTS: The pilot showed that an RCT with individual randomization can be conducted in these two low-resource settings. Significantly more women in group PNC than in individual PNC completed at least four PNC visits (96/102 [94.1%] vs 53/91 [58.2%]) and attended the postnatal visit (76/102 [74.5%] vs 45/90 [50.0%]; both P<0.001). CONCLUSION: Group PNC was feasible and associated with an increase in healthcare utilization and improved outcomes in Malawi and Tanzania. Lessons learned should be considered when designing large RCTs to determine efficacy. ClinicalTrials.gov: NCT02999334. PMID- 28905378 TI - Do Reduced Hospital Mortality Rates Lead to Increased Utilization of Inpatient Emergency Care? A Population-Based Cohort Study. AB - OBJECTIVES: To measure the impact of the improvement in hospital survival rates on patients' subsequent utilization of unplanned (emergency) admissions. DATA SOURCES/STUDY SETTING: Unplanned admissions occurring in all acute hospitals of the National Health Service in England between 2000 and 2009, including 286,027 hip fractures, 375,880 AMI, 387,761 strokes, and 9,966,246 any cause admissions. STUDY DESIGN: Population-based retrospective cohort study. Unplanned admissions experienced by patients within 28 days, 1 year, and 2 years of discharge from the index admission are modeled as a function of hospital risk-adjusted survival rates using patient-level probit and negative binomial models. Identification is also supported by an instrumental variable approach and placebo test. PRINCIPAL FINDINGS: The improvement in hospital survival rates that occurred between 2000 and 2009 explains 37.3 percent of the total increment in unplanned admissions observed over the same period. One extra patient surviving increases the expected number of subsequent admissions occurring within 1 year from discharge by 1.9 admissions for every 100 index admissions (0.019 per admission, 95% CI, 0.016 0.022). Similar results in hip fracture (0.006[0.004-0.007]), AMI (0.006[0.04 0.007]), and stroke (0.004(0.003-0.005)). CONCLUSIONS: The success of hospitals in improving survival from unplanned admissions can be an important contributory factor to the increase in subsequent admissions. PMID- 28905379 TI - A new species of Pomatoschistus (Teleostei, Gobiidae): the Mediterranean's smallest marine fish. AB - The new sand goby species Pomatoschistus nanus (Teleostei: Gobiidae) is described from the northern coast of the Levantine Sea (eastern Mediterranean Sea) based on both morphological and DNA barcoding data. The new species is the smallest fish in the Mediterranean Sea and may be distinguished from congeners by the following features: predorsal area, first dorsal-fin base and breast naked; delta-pore missing; anterior point of the suborbital row b not reaching level of posterior point of suborbital row d; slightly emarginated caudal fin and nape coloration pattern. DNA barcode data clearly discriminate Pomatoschistus spp. in the neighbour-joining tree with an average of 17.7% interspecific K2P distance. The most closely related taxon to P. nanus sp. nov. is Pomatoschistus bathi and the most distantly related is Pomatoschistus tortonesei with 11.9 and 21.9% K2P distances respectively. Morphometric and genetic data are also provided for Pomatoschistus bathi. PMID- 28905380 TI - Enhancing blood donor skin disinfection using natural oils. AB - BACKGROUND: Effective donor skin disinfection is essential in preventing bacterial contamination of blood components with skin flora bacteria like Staphylococcus epidermidis. Cell aggregates of S. epidermidis (biofilms) are found on the skin and are resistant to the commonly used donor skin disinfectants chlorhexidine-gluconate and isopropyl alcohol. It has been demonstrated that essential oils synergistically enhance the antibacterial activity of chlorhexidine-gluconate. The objective of this study was to test plant-extracted essential oils in combination with chlorhexidine-gluconate or chlorhexidine gluconate plus isopropyl alcohol for their ability to eliminate S. epidermidis biofilms. STUDY DESIGN AND METHODS: The composition of oils extracted from Artemisia herba-alba, Lavandula multifida, Origanum marjoram, Rosmarinus officinalis, and Thymus capitatus was analyzed using gas chromatography-mass spectrometry. A rabbit model was used to assess skin irritation caused by the oils. In addition, the anti-biofilm activity of the oils used alone or in combination with chlorhexidine-gluconate or chlorhexidine-gluconate plus isopropyl alcohol was tested against S. epidermidis biofilms. RESULTS: Essential oil concentrations 10%, 20%, and 30% were chosen for anti-biofilm assays, because skin irritation was observed at concentrations greater than 30%. All oils except for O. marjoram had anti-biofilm activity at these three concentrations. L. multifida synergistically enhanced the anti-biofilm activity of chlorhexidine gluconate and resulted in the highest anti-biofilm activity observed when combined with chlorhexidine-gluconate plus isopropyl alcohol. Gas chromatography mass spectrometry revealed that the main component contributing to the activity of L. multifida oil was a natural terpene alcohol called linalool. CONCLUSION: The anti-biofilm activity of chlorhexidine-gluconate plus isopropyl alcohol can be greatly enhanced by L. multifida oil or linalool. Therefore, these components could potentially be used to improve blood donor skin disinfection. PMID- 28905381 TI - False-positive pregnancy test after transfusion of solvent/detergent-treated plasma. AB - BACKGROUND: The transmission of pathogens, antibodies, and proteins is a possible consequence of blood product transfusion. A female patient had an unexpected positive serum beta-human chorionic gonadotropin result, indicative of pregnancy, after she had received a transfusion with 1 unit of platelet concentrate, 4 units of red blood cells, and 4 units of pooled solvent/detergent-treated plasma (Octaplas). STUDY DESIGN AND METHODS: To investigate the possibility of passive transfusion of beta-human chorionic gonadotropin from the plasma transfusion, one additional unit from the same batch was thawed and analyzed. To validate the beta human chorionic gonadotropin assay for use in solvent/detergent-treated plasma and to investigate any interference in the assay, dilution experiments were performed using the implicated plasma batch diluted with male and non-pregnant female sera. Also, plasma from a known pregnant woman was diluted with Octaplas (tested negative for beta-human chorionic gonadotropin) and with a male serum to validate the assay for use in solvent/detergent-treated plasma. RESULTS: The implicated solvent/detergent-treated plasma had a mean beta-human chorionic gonadotropin level of 91.5 mIU/mL. Results from the dilution experiments revealed an excellent correlation (r > 0.99) between beta-human chorionic gonadotropin measurement in solvent/detergent-treated plasma and male serum and no over or under recovery of the expected results. Further measurements of beta-human chorionic gonadotropin levels in the female recipient revealed an estimated half life of 6 hours. CONCLUSION: This case demonstrates the importance of considering the possibility of passive transmission of analytes to a patient from the transfusion of blood products. Furthermore, the measurement of beta-human chorionic gonadotropin is valid in solvent/detergent-treated plasma using a Roche Cobas analyzer. PMID- 28905382 TI - A new sexually dichromatic miniature Hyphessobrycon (Teleostei: Characiformes: Characidae) from the Rio Formiga, upper Rio Juruena basin, Mato Grosso, Brazil, with a review of sexual dichromatism in Characiformes. AB - Hyphessobrycon myrmex sp. nov., is described from the Rio Formiga, upper Rio Juruena, upper Rio Tapajos basin, Mato Grosso, Brazil. The new species can be distinguished from congeners by having the lower half of the body deeply pigmented with dark chromatophores, chromatophores concentrated above the anal fin and forming a broad, diffuse, dark midlateral stripe and by having a dense concentration of dark chromatophores along unbranched dorsal-fin rays and distal portions of the two or three subsequent branched rays. In life, H. myrmex exhibits a conspicuous sexual dichromatism, with adult males red to orange and females and immatures pale yellow. A list containing 108 sexually dichromatic taxa in six families of Characiformes is provided and the distribution of this poorly known type of dimorphism across the Characiformes is discussed. PMID- 28905383 TI - Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl- channel function and trafficking. AB - KEY POINTS: Characterisation of most mutations found in CLCN2 in patients with CC2L leukodystrophy show that they cause a reduction in function of the chloride channel ClC-2. GlialCAM, a regulatory subunit of ClC-2 in glial cells and involved in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), increases the activity of a ClC-2 mutant by affecting ClC-2 gating and by stabilising the mutant at the plasma membrane. The stabilisation of ClC-2 at the plasma membrane by GlialCAM depends on its localisation at cell-cell junctions. The membrane protein MLC1, which is defective in MLC, also contributes to the stabilisation of ClC-2 at the plasma membrane, providing further support for the view that GlialCAM, MLC1 and ClC-2 form a protein complex in glial cells. ABSTRACT: Mutations in CLCN2 have been recently identified in patients suffering from a type of leukoencephalopathy involving intramyelinic oedema. Here, we characterised most of these mutations that reduce the function of the chloride channel ClC-2 and impair its plasma membrane (PM) expression. Detailed biochemical and electrophysiological analyses of the Ala500Val mutation revealed that defective gating and increased cellular and PM turnover contributed to defective A500V-ClC-2 functional expression. Co expression of the adhesion molecule GlialCAM, which forms a tertiary complex with ClC-2 and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1), rescued the functional expression of the mutant by modifying its gating properties. GlialCAM also restored the PM levels of the channel by impeding its turnover at the PM. This rescue required ClC-2 localisation to cell-cell junctions, since a GlialCAM mutant with compromised junctional localisation failed to rescue the impaired stability of mutant ClC-2 at the PM. Wild-type, but not mutant, ClC-2 was also stabilised by MLC1 overexpression. We suggest that leukodystrophy-causing CLCN2 mutations reduce the functional expression of ClC-2, which is partly counteracted by GlialCAM/MLC1-mediated increase in the gating and stability of the channel. PMID- 28905384 TI - Heteromeric alpha/beta glycine receptors regulate excitability in parvalbumin expressing dorsal horn neurons through phasic and tonic glycinergic inhibition. AB - KEY POINTS: Spinal parvalbumin-expressing interneurons have been identified as a critical source of inhibition to regulate sensory thresholds by gating mechanical inputs in the dorsal horn. This study assessed the inhibitory regulation of the parvalbumin-expressing interneurons, showing that synaptic and tonic glycinergic currents dominate, blocking neuronal or glial glycine transporters enhances tonic glycinergic currents, and these manipulations reduce excitability. Synaptically released glycine also enhanced tonic glycinergic currents and resulted in decreased parvalbumin-expressing interneuron excitability. Analysis of the glycine receptor properties mediating inhibition of parvalbumin neurons, as well as single channel recordings, indicates that heteromeric alpha/beta subunit containing receptors underlie both synaptic and tonic glycinergic currents. Our findings indicate that glycinergic inhibition provides critical control of excitability in parvalbumin-expressing interneurons in the dorsal horn and represents a pharmacological target to manipulate spinal sensory processing. ABSTRACT: The dorsal horn (DH) of the spinal cord is an important site for modality-specific processing of sensory information and is essential for contextually relevant sensory experience. Parvalbumin-expressing inhibitory interneurons (PV+ INs) have functional properties and connectivity that enables them to segregate tactile and nociceptive information. Here we examine inhibitory drive to PV+ INs using targeted patch-clamp recording in spinal cord slices from adult transgenic mice that express enhanced green fluorescent protein in PV+ INs. Analysis of inhibitory synaptic currents showed glycinergic transmission is the dominant form of phasic inhibition to PV+ INs. In addition, PV+ INs expressed robust glycine-mediated tonic currents; however, we found no evidence for tonic GABAergic currents. Manipulation of extracellular glycine by blocking either, or both, the glial and neuronal glycine transporters markedly decreased PV+ IN excitability, as assessed by action potential discharge. This decreased excitability was replicated when tonic glycinergic currents were increased by electrically activating glycinergic synapses. Finally, we show that both phasic and tonic forms of glycinergic inhibition are mediated by heteromeric alpha/beta glycine receptors. This differs from GABAA receptors in the dorsal horn, where different receptor stoichiometries underlie phasic and tonic inhibition. Together these data suggest both phasic and tonic glycinergic inhibition regulate the output of PV+ INs and contribute to the processing and segregation of tactile and nociceptive information. The shared stoichiometry for phasic and tonic glycine receptors suggests pharmacology is unlikely to be able to selectively target each form of inhibition in PV+ INs. PMID- 28905385 TI - Synthetic breast phantoms from patient based eigenbreasts. AB - PURPOSE: The limited number of 3D patient-based breast phantoms available could be augmented by synthetic breast phantoms in order to facilitate virtual clinical trials (VCTs) using model observers for breast imaging optimization and evaluation. METHODS: These synthetic breast phantoms were developed using Principal Component Analysis (PCA) to reduce the number of dimensions needed to describe a training set of images. PCA decomposed a training set of M breast CT volumes (with millions of voxels each) into an M-1-dimensional space of eigenvectors, which we call eigenbreasts. Each of the training breast phantoms was compactly represented by the mean image plus a weighted sum of eigenbreasts. The distribution of weights observed from training was then sampled to create new synthesized breast phantoms. RESULTS: The resulting synthesized breast phantoms demonstrated a high degree of realism, as supported by an observer study. Two out of three experienced physicist observers were unable to distinguish between the synthesized breast phantoms and the patient-based phantoms. The fibroglandular density and noise power law exponent of the synthesized breast phantoms agreed well with the training data. CONCLUSIONS: Our method extends our series of digital breast phantoms based on breast CT data, providing the capability to generate new, statistically varying ensembles consisting of tens of thousands of virtual subjects. This work represents an important step toward conducting future virtual trials for task-based assessment of breast imaging, where it is vital to have a large ensemble of realistic phantoms for statistical power as well as clinical relevance. PMID- 28905386 TI - Squalus bassi sp. nov., a new long-snouted spurdog (Chondrichthyes: Squaliformes: Squalidae) from the Agulhas Bank. AB - The long-snouted African spurdog Squalus bassi sp. nov. is described based on material collected from the outer shelf and upper continental slope off South Africa and Mozambique. Squalus bassi shares with S. mitsukurii, S. montalbani, S. chloroculus, S. grahami, S. griffini, S. edmundsi, S. quasimodo and S. lobularis a large snout with prenarial length greater than distance between nostrils and upper labial furrows, dermal denticles tricuspidate and rhomboid and elevated number of vertebrae. Squalus bassi can be distinguished from all its congeners by a combination of body and fin colouration, external morphometrics, vertebral counts and shape of dermal denticles. Similar long-snouted congeners from the Indo-Pacific region, including S. montalbani, S. edmundsi and S. lalannei are compared in detail with the new species. This new species has been misidentified as the Japanese S. mitsukurii and the Mediterranean S. blainvillei due to the lack of comparative morphological analyses. The validity of the nominal species S. mitsukurii in the south-eastern Atlantic Ocean and western Indian Ocean is also clarified herein, indicating it has a more restricted geographical distribution in the North Pacific Ocean. PMID- 28905387 TI - Management of Leigh syndrome: Current status and new insights. AB - Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in pre-clinical studies. In this review, we summarize the genetic basis of LS, current treatment, pre-clinical studies in animal models and the management of other mitochondrial diseases. Future therapeutical strategies and challenges are also discussed. PMID- 28905388 TI - Alcohol and Road Traffic Injuries in Latin America and the Caribbean: A Case Crossover Study. AB - BACKGROUND: This study reports dose-response estimates for the odds ratio (OR) and population attributable risk of acute alcohol use and road traffic injury (RTI). METHODS: Data were analyzed on 1,119 RTI patients arriving at 16 emergency departments (EDs) in Argentina, Brazil, Costa Rica, Dominican Republic, Guatemala, Guyana, Mexico, Nicaragua, Panama, and Trinidad and Tobago. Case crossover analysis, pair-matching the number of standard drinks consumed within the 6 hours prior to the RTI with 2 control periods (prior d/wk), was performed using fractional polynomial analysis for dose-response. RESULTS: About 1 in 6 RTI patients in EDs were positive for self-reported alcohol 6 hours prior to the injury (country range 8.6 to 24.1%). The likelihood of an RTI with any drinking prior (compared to not drinking) was 5 times higher (country range OR 2.50 to 15.00) and the more a person drinks the higher the risk. Every drink (12.8 g alcohol) increased the risk of an RTI by 13%, even 1 to 2 drinks were associated with a sizable increase in risk of an RTI and a dose-response was found. Differences in ORs for drivers (OR = 3.51; 95% CI = 2.25 to 5.45), passengers (OR = 8.12; 95% CI = 4.22 to 15.61), and pedestrians (OR = 6.30; 95% CI = 3.14 to 12.64) and attributable fractions were noted. Acute use of alcohol was attributable to 14% of all RTIs, varying from 7% for females to 19% for being injured as a passenger. CONCLUSIONS: The finding that the presence of alcohol increases risk among drivers and nondrivers alike may further help to urge interventions targeting passengers and pedestrians. Routine screening and brief interventions in all health services could also have a beneficial impact in decreasing rates of RTIs. Higher priority should be given to alcohol as a risk factor for RTIs, particularly in Latin America and the Caribbean. PMID- 28905389 TI - The first reported case of concurrent trimethoprim-sulfamethoxazole-induced immune hemolytic anemia and thrombocytopenia. AB - BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) and drug-induced immune thrombocytopenia (DIIT) are rare but dangerous complications of pharmacotherapy that may be underrecognized in hematopoietic stem cell transplant (HSCT) patients due to overlap of signs and symptoms with those of more common disease processes. CASE REPORT: A 61-year-old woman with NK-cell deficiency and GATA-2-associated myelodysplastic syndrome, status post-recent allogeneic HSCT (Day +58), presented with 3 days of acute-onset severe back pain, muscle cramps, and increasingly dark urine. She was found to be anemic, thrombocytopenic, and in acute renal failure. On admission, the direct antiglobulin test was positive for complement (C3) only. After careful review of her medication list, the possibility of DIIHA was raised. She had started taking trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jiroveci pneumonia prophylaxis 24 days prior on a weekend dose schedule. Serologic tests on peripheral blood samples were performed using standard methods. Drug studies were performed at an immunohematology reference laboratory. RESULTS: The patient's serum showed hemolysis of donor red blood cells in the presence of TMP-SMX and also TMP-SMX-induced platelet antibodies. The patient was treated with transfusions, hemodialysis, and immunosuppressive agents. Her clinical condition improved and she was discharged after 8 days in stable condition. CONCLUSION: This case describes the first reported concurrent DIIHA and DIIT due to TMP-SMX-induced antibodies in an HSCT patient. DIIHA and DIIT can present a diagnostic challenge in the setting of intermittent medication dosing. PMID- 28905390 TI - Validation of the Gatortail method for accurate sizing of pulmonary vessels from 3D medical images. AB - PURPOSE: Detailed characterization of changes in vessel size is crucial for the diagnosis and management of a variety of vascular diseases. Because clinical measurement of vessel size is typically dependent on the radiologist's subjective interpretation of the vessel borders, it is often prone to high inter- and intra user variability. Automatic methods of vessel sizing have been developed for two dimensional images but a fully three-dimensional (3D) method suitable for vessel sizing from volumetric X-ray computed tomography (CT) or magnetic resonance imaging has heretofore not been demonstrated and validated robustly. METHODS: In this paper, we refined and objectively validated Gatortail, a method that creates a mathematical geometric 3D model of each branch in a vascular tree, simulates the appearance of the virtual vascular tree in a 3D CT image, and uses the similarity of the simulated image to a patient's CT scan to drive the optimization of the model parameters, including vessel size, to match that of the patient. The method was validated with a 2-dimensional virtual tree structure under deformation, and with a realistic 3D-printed vascular phantom in which the diameter of 64 branches were manually measured 3 times each. The phantom was then scanned on a conventional clinical CT imaging system and the images processed with the in-house software to automatically segment and mathematically model the vascular tree, label each branch, and perform the Gatortail optimization of branch size and trajectory. Previously proposed methods of vessel sizing using matched Gaussian filters and tubularity metrics were also tested. The Gatortail method was then demonstrated on the pulmonary arterial tree segmented from a human volunteer's CT scan. RESULTS: The standard deviation of the difference between the manually measured and Gatortail-based radii in the 3D physical phantom was 0.074 mm (0.087 in-plane pixel units for image voxels of dimension 0.85 * 0.85 * 1.0 mm) over the 64 branches, representing vessel diameters ranging from 1.2 to 7 mm. The linear regression fit gave a slope of 1.056 and an R2 value of 0.989. These three metrics reflect superior agreement of the radii estimates relative to previously published results over all sizes tested. Sizing via matched Gaussian filters resulted in size underestimates of >33% over all three test vessels, while the tubularity-metric matching exhibited a sizing uncertainty of >50%. In the human chest CT data set, the vessel voxel intensity profiles with and without branch model optimization showed excellent agreement and improvement in the objective measure of image similarity. CONCLUSIONS: Gatortail has been demonstrated to be an automated, objective, accurate and robust method for sizing of vessels in 3D non-invasively from chest CT scans. We anticipate that Gatortail, an image-based approach to automatically compute estimates of blood vessel radii and trajectories from 3D medical images, will facilitate future quantitative evaluation of vascular response to disease and environmental insult and improve understanding of the biological mechanisms underlying vascular disease processes. PMID- 28905391 TI - Vox Sanguinis International Forum on provision of granulocytes for transfusion and their clinical use: summary. PMID- 28905392 TI - Cryopreserved platelets demonstrate reduced activation responses and impaired signaling after agonist stimulation. AB - BACKGROUND: Room temperature-stored (20-24 degrees C) platelets (PLTs) have a shelf life of 5 days, making it logistically challenging to supply remote medical centers with PLT products. Cryopreservation of PLTs in dimethyl sulfoxide (DMSO) and storage at -80 degrees C enables an extended shelf life up to 2 years. Although cryopreserved PLTs have been widely characterized under resting conditions, their ability to undergo agonist-induced activation is yet to be fully explored. STUDY DESIGN AND METHODS: Buffy coat PLTs were cryopreserved at 80 degrees C with 5% to 6% DMSO and sampled before freezing and after thawing. PLTs were analyzed under resting conditions and after agonist stimulation with adenosine diphosphate, collagen, or thrombin receptor-activating peptide-6. The expression of activation markers, microparticle formation, and calcium mobilization were analyzed by flow cytometry. Soluble PLT proteins present in the PLT supernatant were examined by enzyme-linked immunosorbent assay. Protein phosphorylation was investigated with Western blotting. RESULTS: After cryopreservation, PLTs displayed increased surface activation markers and higher basal calcium levels. Cryopreserved PLTs demonstrated diminished aggregation responses. Additionally, cryopreserved PLTs showed a limited ability to become activated (as measured by CD62P and phosphatidylserine exposure and cytokine release) after agonist stimulation. A reduction in the abundance and phosphorylation of key signaling proteins (Akt, Src, Lyn, ERK, and p38) was seen in cryopreserved PLTs. CONCLUSIONS: Cryopreservation of PLTs induces dramatic changes to the basal PLT phenotype and renders them largely nonresponsive to agonist stimulation, likely due to the alterations in signal transduction. Therefore, further efforts are required to understand how cryopreserved PLTs achieve their hemostatic effect once transfused. PMID- 28905393 TI - PET motion correction in context of integrated PET/MR: Current techniques, limitations, and future projections. AB - Patient motion is an important consideration in modern PET image reconstruction. Advances in PET technology mean motion has an increasingly important influence on resulting image quality. Motion-induced artifacts can have adverse effects on clinical outcomes, including missed diagnoses and oversized radiotherapy treatment volumes. This review aims to summarize the wide variety of motion correction techniques available in PET and combined PET/CT and PET/MR, with a focus on the latter. A general framework for the motion correction of PET images is presented, consisting of acquisition, modeling, and correction stages. Methods for measuring, modeling, and correcting motion and associated artifacts, both in literature and commercially available, are presented, and their relative merits are contrasted. Identified limitations of current methods include modeling of aperiodic and/or unpredictable motion, attaining adequate temporal resolution for motion correction in dynamic kinetic modeling acquisitions, and maintaining availability of the MR in PET/MR scans for diagnostic acquisitions. Finally, avenues for future investigation are discussed, with a focus on improvements that could improve PET image quality, and that are practical in the clinical environment. PMID- 28905394 TI - Neutron damage induced in cardiovascular implantable electronic devices from a clinical 18 MV photon beam: A Monte Carlo study. AB - PURPOSE: The purpose of this study was to quantify the relative neutron damage induced in CIEDs from clinical 18 MV photon beams for varying field sizes, depths, and off axis distances. METHODS AND MATERIALS: Damage was assessed using silicon damage response functions and ICRP neutron dose conversion factors in MCNPX. Particular attention was devoted to the modelling of the Varian 2100C/D linear accelerator to ensure accurate contamination neutron spectra. Neutron dose, fluence and relative damage to CIEDs was calculated. RESULTS: CIED damage from neutrons is related to the neutron dose rather than the neutron fluence. As field size increases, the region of high damage probability extends to a greater distance beyond the edge of the field than with smaller fields. At a distance greater than 50 cm or from the central axis or a depth deeper than 10 cm, the probability of damage is less than 10% of the central axis damage probability for all field sizes. CONCLUSIONS: Clinically, increasing the depth or the distance from the central axis to the CIED will reduce the probability of damage from neutrons. Care must be taken when treating large fields as the overall probability of damage increase as does the distance the higher probability of damage extends beyond the field edge. PMID- 28905395 TI - St. Louis encephalitis virus possibly transmitted through blood transfusion Arizona, 2015. AB - BACKGROUND: St. Louis encephalitis virus is a mosquito-borne flavivirus that infrequently causes epidemic central nervous system infections. In the United States, blood donors are not screened for St. Louis encephalitis virus infection, and transmission through blood transfusion has not been reported. During September 2015, St. Louis encephalitis virus infection was confirmed in an Arizona kidney transplant recipient. An investigation was initiated to determine the infection source. STUDY DESIGN AND METHODS: The patient was interviewed, and medical records were reviewed. To determine the likelihood of mosquito-borne infection, mosquito surveillance data collected at patient and blood donor residences in timeframes consistent with their possible exposure periods were reviewed. To investigate other routes of exposure, organ and blood donor and recipient specimens were obtained and tested for evidence of St. Louis encephalitis virus infection. RESULTS: The patient presented with symptoms of central nervous system infection. Recent St. Louis encephalitis virus infection was serologically confirmed. The organ donor and three other organ recipients showed no laboratory or clinical evidence of St. Louis encephalitis virus infection. Among four donors of blood products received by the patient via transfusion, one donor had a serologically confirmed, recent St. Louis encephalitis virus infection. Exposure to an infected mosquito was unlikely based on the patient's minimal outdoor exposure. In addition, no St. Louis encephalitis virus-infected mosquito pools were identified around the patient's residence. CONCLUSION: This investigation provides evidence of the first reported possible case of St. Louis encephalitis virus transmission through blood product transfusion. Health care providers and public health professionals should maintain heightened awareness for St. Louis encephalitis virus transmission through blood transfusion in settings where outbreaks are identified. PMID- 28905396 TI - Vox Sanguinis International Forum on provision of granulocytes for transfusion and their clinical use. PMID- 28905397 TI - Alcohol Advertising in Magazines and Underage Readership: Are Underage Youth Disproportionately Exposed? AB - BACKGROUND: The question of whether underage youth are disproportionately exposed to alcohol advertising lies at the heart of the public health debate about whether restrictions on alcohol advertising are warranted. The aim of this study was to determine whether alcohol brands popular among underage (ages 12 to 20 years) drinkers ("underage brands") are more likely than others ("other brands") to advertise in magazines with high underage readerships. METHODS: We analyze the advertising of 680 alcohol brands in 49 magazines between 2006 and 2011. Using a random effects probit model, we examine the relationship between a magazine's underage readership and the probability of an underage or other brand advertising in a magazine, controlling for young adult (ages 21 to 29 years) and total readerships, advertising costs and expenditures, and readership demographics. RESULTS: We find that underage brands are more likely than other brands to advertise in magazines with a higher percentage of underage readers. Holding all other variables constant at their sample means, the probability of an "other" brand advertising in a magazine remains essentially constant over the range of underage readership from 0.010 (95% confidence interval [CI], 0.007 to 0.013) at 5% to 0.012 (95% CI, 0.008 to 0.016) at 35%. In contrast, the probability of an underage brand advertising nearly quadruples, ranging from 0.025 (95% CI, 0.015 to 0.035) to 0.096 (95% CI, 0.057 to 0.135), where underage brands are 7.90 (95% CI, 3.89 to 11.90) times more likely than other brands to advertise. CONCLUSIONS: Alcohol brands popular among underage drinkers are more likely than other brands to advertise in magazines with high underage readerships, resulting in the disproportionate exposure of underage youth. Current voluntary advertising industry guidelines are not adequate to protect underage youth from high and disproportionate exposure to alcohol advertising in magazines. To limit advertising exposure among underage youth, policy makers may want to consider regulation of alcohol advertising in magazines. PMID- 28905398 TI - Mitigation of acidified salmon rivers - effects of liming on young brown trout Salmo trutta. AB - In southern Norway, 22 acidified rivers supporting anadromous salmonids were mitigated with lime to improve water quality and restore fish populations. In 13 of these rivers, effects on Salmo trutta and Salmo salar densities were monitored over 10-12 years, grouped into age 0 and age >= 1 year fish. These rivers had a mean annual discharge of between 4.9 and 85.5 m3 s-1 , and six of them were regulated for hydro-power production. Salmo salar were lost in six of these rivers prior to liming, and highly reduced in the remaining seven rivers. Post liming, S. salar became re-established in all six rivers with lost populations, and recovered in the seven other rivers. Salmo trutta occurred in all 13 study rivers prior to liming. Despite the improved water quality, both age 0 and age >= 1 year S. trutta densities decreased as S. salar density increased, with an average reduction of >50% after 10 years of liming. For age 0 year S. trutta this effect was less strong in rivers where S. salar were present prior to liming. In contrast, densities of S. trutta increased in unlimed streams above the anadromous stretches in two of the rivers following improved water quality due to natural recovery. Density increases of both age 0 and age >= 1 year S. salar showed a positive effect of river discharge. The results suggest that the decline in S. trutta density after liming is related to interspecific resource competition due to the recovery of S. salar. Thus, improved water quality through liming may not only sustain susceptible species, but can have a negative effect on species that are more tolerant prior to the treatment, such as S. trutta. PMID- 28905399 TI - Microdosimetric measurements of a clinical proton beam with micrometer-sized solid-state detector. AB - PURPOSE: Microdosimetry is a vital tool for assessing the microscopic patterns of energy deposition by radiation, which ultimately govern biological effect. Solid state, silicon-on-insulator microdosimeters offer an approach for making microdosimetric measurements with high spatial resolution (on the order of tens of micrometers). These high-resolution, solid-state microdosimeters may therefore play a useful role in characterizing proton radiotherapy fields, particularly for making highly resolved measurements within the Bragg peak region. In this work, we obtain microdosimetric measurements with a solid-state microdosimeter (MicroPlus probe) in a clinical, spot-scanning proton beam of small spot size. METHODS: The MicroPlus probe had a 3D single sensitive volume on top of silicon oxide. The sensitive volume had an active cross-sectional area of 250 MUm * 10 MUm and thickness of 10 MUm. The proton facility was a synchrotron-based, spot scanning system with small spot size (sigma ~ 2 mm). We performed measurements with the clinical beam current (~1 nA) and had no detected pulse pile-up. Measurements were made in a water-equivalent phantom in water-equivalent depth (WED) increments of 0.25 mm or 1.0 mm along pristine Bragg peaks of energies 71.3 MeV and 159.9 MeV, respectively. For each depth, we measured lineal energy distributions and then calculated the dose-weighted mean lineal energy, y-D. The measurements were repeated for two field sizes: 4 * 4 cm2 and 20 * 20 cm2 . RESULTS: For both 71.3 MeV and 159.9 MeV and for both field sizes, y-D increased with depth toward the distal edge of the Bragg peak, a result consistent with Monte Carlo calculations and measurements performed elsewhere. For the 71.3 MeV, 4 * 4 cm2 beam (range at 80% distal falloff, R80 = 3.99 cm), we measured y D=1.96+/-0.08 keV/MUm at WED = 2 cm, and y-D=10.6+/-0.32 keV/MUm at WED = 3.95 cm. For the 71.3 MeV, 20 * 20 cm2 beam, we measured y-D=2.46+/-0.12 keV/MUm at WED = 2.6 cm, and y-D=11.0+/-0.24 keV/MUm at WED = 3 cm. For the 159.9 MeV, 4 * 4 cm2 beam (R80 = 17.7 cm), y-D=2.24+/-0.15 keV/MUm at WED = 5 cm, and y-D=8.99+/ 0.71 keV/MUm at WED = 17.6 cm. For the 159.9 MeV, 20 * 20 cm2 beam, y-D=2.56+/ 0.10 keV/MUm at WED = 5 cm, and y-D=9.24+/-0.73 keV/MUm at WED = 17.6 cm. CONCLUSIONS: We performed microdosimetric measurements with a novel solid-state, silicon-on-insulator microdosimeter in a clinical spot-scanning proton beam of small spot size and unmodified beam current. For all of the proton field sizes and energies considered, the measurements of y-D were in agreement with expected trends. Furthermore, we obtained measurements with a spatial resolution of 10 MUm in the beam direction. This spatial resolution greatly exceeded that possible with a conventional gaseous tissue-equivalent proportional counter and allowed us to perform a high-resolution investigation within the Bragg peak region. The MicroPlus probe is therefore suitable for applications in proton radiotherapy. PMID- 28905400 TI - Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is a highly prevalent neoplasia that is strongly influenced by the endocrine system. Somatostatin (SST) and its five receptors (sst1-5 encoded by SSTR1-5 genes) comprise a pleiotropic system present in most endocrine-related cancers, some of which are successfully treated with SST analogs. Interestingly, it has been reported that SSTR1 is overexpressed in PCa, but its regulation, functional role, and clinical implications are still poorly known. METHODS: PCa specimens (n = 52) from biopsies and control prostates from cystoprostatectomies (n = 12), as well as in silico databases were used to evaluate SSTR1 and miRNAs expression. In vitro studies in 22Rv1 PCa cells were implemented to explore the regulation of SSTR1/sst1 by different miRNAs, and to evaluate the consequences of SSTR1/sst1 overexpression, silencing and/or activation [with the specific BIM-23926 sst1 agonist (IPSEN)] on cell proliferation, migration, signaling-pathways, and androgen-signaling. RESULTS: We found that SSTR1 is overexpressed in multiple cohorts of PCa samples, as compared with normal prostate tissues, wherein it correlates with androgen receptor (AR) expression, and appears to be associated with aggressiveness (metastasis). Furthermore, our data revealed that SSTR1/sst1 expression might be regulated by specific miRNAs in PCa, including miR-24, which is downregulated in PCa samples and correlates inversely with SSTR1 expression. In vitro studies indicated that treatment with the BIM-23926 sst1 agonist, as well as SSTR1 overexpression, decreased, whereas SSTR1 silencing increased, cell-proliferation in 22Rv1 cells, likely through the regulation of PI3K/AKT-CCND3 signaling-pathway. Importantly, sst1 action was also able to modulate androgen/AR activity, and reduced PSA secretion from PCa cell lines. CONCLUSIONS: Altogether, our results indicate that SSTR1 is overexpressed in PCa, where it can exert a relevant pathophysiological role by decreasing cell-proliferation and PSA secretion. Therefore, sst1, possibly in combination with miR-24, could be used as a novel tool to explore therapeutic targets in PCa. PMID- 28905401 TI - Mycothiol acetyltransferase (Rv0819) of Mycobacterium tuberculosis is a potential biomarker for direct diagnosis of tuberculosis using patient serum specimens. AB - : Mycobacterium tuberculosis infection constitutes a global threat that results in significant morbidity and mortality worldwide. Efficient and early diagnosis of tuberculosis (TB) is of paramount importance for successful treatment. The aim of the current study is to investigate the mycobacterial mycothiol acetyltransferase Rv0819 as a potential novel biomarker for the diagnosis of active TB infection. The gene encoding Rv0819 was cloned and successfully expressed in Escherichia coli. The recombinant Rv0819 was purified using metal affinity chromatography and was used to raise murine polyclonal antibodies against Rv0819. The raised antibodies were employed for direct detection of Rv0819 in patient serum samples using dot blot assay and competitive enzyme linked immunosorbent assay (ELISA). Serum samples were obtained from 68 confirmed new TB patients and 35 healthy volunteers as negative controls. The dot blot assay showed sensitivity of 64.7% and specificity of 100%, whereas the competitive ELISA assay showed lower sensitivity (54.4%) and specificity (88.57%). The overall sensitivity of the combined results of the two tests was found to be 89.7%. Overall, the mycobacterial Rv0819 is a potential TB serum biomarker that can be exploited, in combination with other TB biomarkers, for efficient and reliable diagnosis of active TB infection. SIGNIFICANCE AND IMPACT OF THE STUDY: The early and accurate diagnosis of tuberculosis infection is of paramount importance for initiating treatment and avoiding clinical complications. Most current diagnostic tests have poor sensitivity and/or specificity and in many cases they are too expensive for routine diagnostic testing in resource-limited settings. In the current study, we examined a novel mycobacterial serum biomarker, namely mycothiol acetyltransferase Rv0819. The antigen was detectable in serum specimens of a significant number of tuberculosis patients. This article proves the importance of Rv0819 and paves the way towards its future use as a useful diagnostic marker for tuberculosis infection. PMID- 28905402 TI - Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate-based cholera toxin inhibitors. AB - Developing tools for the study of protein carbohydrate interactions is an important goal in glycobiology. Cholera toxin inhibition is an interesting target in this context, as its inhibition may help to fight against cholera. For the study of novel ligands an affinity capillary electrophoresis (ACE) method was optimized and applied. The method uses unlabeled cholera toxin B-subunit (CTB) and unlabeled carbohydrate ligands based on ganglioside GM1-oligosaccharides (GM1os). In an optimized method at pH 4, adsorption of the protein to the capillary walls was prevented by a polybrene-dextran sulfate-polybrene coating. Different concentrations of the ligands were added to the BGE. CTB binding was observed by a mobility shift that could be used for dissociation constant (Kd ) determination. The Kd values of two GM1 derivatives differed by close to an order of magnitude (600 +/- 20 nM and 90 +/- 50 nM) which was in good agreement with the differences in their reported nanomolar IC50 values of an ELISA-type assay. Moreover, the selectivity of GM1os towards CTB was demonstrated using Influenza hemagglutinin (H5) as a binding competitor. The developed method can be an important platform for preclinical development of drugs targeting pathogen induced secretory diarrhea. PMID- 28905403 TI - Infectious disease prediction with kernel conditional density estimation. AB - Creating statistical models that generate accurate predictions of infectious disease incidence is a challenging problem whose solution could benefit public health decision makers. We develop a new approach to this problem using kernel conditional density estimation (KCDE) and copulas. We obtain predictive distributions for incidence in individual weeks using KCDE and tie those distributions together into joint distributions using copulas. This strategy enables us to create predictions for the timing of and incidence in the peak week of the season. Our implementation of KCDE incorporates 2 novel kernel components: a periodic component that captures seasonality in disease incidence and a component that allows for a full parameterization of the bandwidth matrix with discrete variables. We demonstrate via simulation that a fully parameterized bandwidth matrix can be beneficial for estimating conditional densities. We apply the method to predicting dengue fever and influenza and compare to a seasonal autoregressive integrated moving average model and HHH4, a previously published extension to the generalized linear model framework developed for infectious disease incidence. The KCDE outperforms the baseline methods for predictions of dengue incidence in individual weeks. The KCDE also offers more consistent performance than the baseline models for predictions of incidence in the peak week and is comparable to the baseline models on the other prediction targets. Using the periodic kernel function led to better predictions of incidence. Our approach and extensions of it could yield improved predictions for public health decision makers, particularly in diseases with heterogeneous seasonal dynamics such as dengue fever. PMID- 28905404 TI - Current practice of allergy diagnosis and the potential impact of regulation in Europe. AB - In the European Union (EU), the regulatory framework regarding diagnostic allergen extracts is currently in the process of being implemented at the national level. Due to these regulations, the initial and periodic renewal expenses for the registration of diagnostic allergen extracts may render extract production unprofitable. Consequently, many extracts may be at risk of removal from the market. The current survey, which was conducted by a task force of the European Academy of Allergy and Clinical Immunology, aimed to assess the current practice of allergy diagnosis in Europe. This survey revealed that skin tests continue to be the main diagnostic procedure and are used as the first option in almost two-third of all types of allergic diseases and in 90% of individuals suffering from respiratory allergies. Therefore, there is a need to ensure the availability of high-quality allergen extracts to maintain the common diagnostic procedures used by EU professionals. To reach this goal, it is necessary to align efforts and establish active partnerships between manufacturers, relevant scientific societies, consumer organizations and authorities to maintain the availability of these diagnostic tools. PMID- 28905405 TI - Bioassay, determination and separation of enantiomers of atenolol by direct and indirect approaches using liquid chromatography: A review. AB - Atenolol, a beta-adrenergic receptor antagonist, is a chiral compound used for the treatment of cardiovascular diseases and to treat hypertension, coronary heart disease, arrhythmias, sinus tachycardia and myocardial infarction, where it acts preferentially upon the beta-adrenergic receptors in the heart. It is marketed as a racemate, but only the (S)-enantiomer of (RS)-atenolol is responsible for the beta-adrenoceptor blocking activity. Different chromatographic methods have been applied for the separation and determination of enantiomers. In this article a review is presented on liquid chromatographic methods for enantioseparation of (RS)-atenolol by both direct and indirect approaches involving practical applications of several chiral stationary phases, chiral derivatization reagents and ligand exchange and impregnation methods. These include methods using both HPLC and TLC for separation, determination and bioassay of enantiomers of atenolol. In addition, some aspects of enantioseparation under achiral phases of liquid chromatography have been briefly mentioned as applicable to (RS)-atenolol. This review provides current available enantioseparation choices not only for (RS)-atenolol but also for other applicable racemic drugs. PMID- 28905406 TI - Thiamine content of F-75 therapeutic milk for complicated severe acute malnutrition: time for a change? AB - Since community-based management of severe acute malnutrition has become the standard of care, the clinical profile of severe acutely malnourished patients admitted to hospitals or inpatient therapeutic feeding centers has changed significantly. These patients are usually very ill and often present with several comorbidities, such as shock, sepsis, and pneumonia. Complicated severe acute malnutrition patients are at risk of thiamine insufficiency, and critically ill patients have higher thiamine requirements. The thiamine content of F-75, the therapeutic milk formula used in the early stabilization phase of refeeding in patients with severe acute malnutrition, seems insufficient. Here, we discuss the need and rationale for a substantial increase in the thiamine content of F-75. PMID- 28905407 TI - Ethics of frailty: Some thoughts on equality and autonomy. PMID- 28905408 TI - Resting-state functional connectivity in the rat cervical spinal cord at 9.4 T. AB - PURPOSE: Numerous studies have adopted resting-state functional MRI methods to infer functional connectivity between cortical regions, but very few have translated them to the spinal cord, despite its critical role in the central nervous system. Resting-state functional connectivity between gray matter horns of the spinal cord has previously been shown to be detectable in humans and nonhuman primates, but it has not been reported previously in rodents. METHODS: Resting-state functional MRI of the cervical spinal cord of live anesthetized rats was performed at 9.4 T. The quality of the functional images acquired was assessed, and quantitative analyses of functional connectivity in C4-C7 of the spinal cord were derived. RESULTS: Robust gray matter horn-to-horn connectivity patterns were found that were statistically significant when compared with adjacent control regions. Specifically, dorsal-dorsal and ventral-ventral connectivity measurements were most prominent, while ipsilateral dorsal-ventral connectivity was also observed but to a lesser extent. Quantitative evaluation of reproducibility also revealed moderate robustness in the bilateral sensory and motor networks that was weaker in the dorsal-ventral connections. CONCLUSIONS: This study reports the first evidence of resting-state functional circuits within gray matter in the rat spinal cord, and verifies their detectability using resting-state functional MRI at 9.4 T. Magn Reson Med 79:2773-2783, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905409 TI - Generalized survival models for correlated time-to-event data. AB - Our aim is to develop a rich and coherent framework for modeling correlated time to-event data, including (1) survival regression models with different links and (2) flexible modeling for time-dependent and nonlinear effects with rich postestimation. We extend the class of generalized survival models, which expresses a transformed survival in terms of a linear predictor, by incorporating a shared frailty or random effects for correlated survival data. The proposed approach can include parametric or penalized smooth functions for time, time dependent effects, nonlinear effects, and their interactions. The maximum (penalized) marginal likelihood method is used to estimate the regression coefficients and the variance for the frailty or random effects. The optimal smoothing parameters for the penalized marginal likelihood estimation can be automatically selected by a likelihood-based cross-validation criterion. For models with normal random effects, Gauss-Hermite quadrature can be used to obtain the cluster-level marginal likelihoods. The Akaike Information Criterion can be used to compare models and select the link function. We have implemented these methods in the R package rstpm2. Simulating for both small and larger clusters, we find that this approach performs well. Through 2 applications, we demonstrate (1) a comparison of proportional hazards and proportional odds models with random effects for clustered survival data and (2) the estimation of time-varying effects on the log-time scale, age-varying effects for a specific treatment, and two-dimensional splines for time and age. PMID- 28905410 TI - Simultaneous determination of boscalid and fludioxonil in grape and soil under field conditions by gas chromatography/tandem triple quadrupole mass spectrometry. AB - A gas chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine boscalid and fludioxonil in grape and soil samples. These samples were extracted with 10 mL of acetonitrile and purified using a mixed primary secondary amine/octadecylsilane sorbent. The method showed good linearity (R2 > 0.99) in the calibration range 0.005-2 MUg/mL for both pesticides. The limits of detection and quantification for the two analytes in grape and soil were 0.006 and 0.02 mg/kg, respectively. Fungicide recoveries in grape and soil were 81.18-92.11% for boscalid and 82.73-97.67% for fludioxonil with relative standard deviations of 1.31-10.31%. The established method was successfully applied to the residual analysis of boscalid and fludioxonil in real grape and soil samples. The terminal residue concentrations of boscalid and fludioxonil in grape samples collected from Anhui and Guizhou were <5 mg/kg (the maximum residue limit set by China) 7 days after the last application and 1 mg/kg (the maximum residue limit set by USA) 14 days after the last application. These results could provide guidance for the proper and safe use of boscalid and fludioxonil in grape and help the Chinese government to establish an MRL for fludioxonil in grape. PMID- 28905411 TI - Joint arterial input function and tracer kinetic parameter estimation from undersampled dynamic contrast-enhanced MRI using a model consistency constraint. AB - PURPOSE: To develop and evaluate a model-based reconstruction framework for joint arterial input function (AIF) and kinetic parameter estimation from undersampled brain tumor dynamic contrast-enhanced MRI (DCE-MRI) data. METHODS: The proposed method poses the tracer-kinetic (TK) model as a model consistency constraint, enabling the flexible inclusion of different TK models and TK solvers, and the joint estimation of the AIF. The proposed method is evaluated using an anatomic realistic digital reference object (DRO), and nine retrospectively down-sampled brain tumor DCE-MRI datasets. We also demonstrate application to 30-fold prospectively undersampled brain tumor DCE-MRI. RESULTS: In DRO studies with up to 60-fold undersampling, the proposed method provided TK maps with low error that were comparable to fully sampled data and were demonstrated to be compatible with a third-party TK solver. In retrospective undersampling studies, this method provided patient-specific AIF with normalized root mean-squared-error (normalized by the 90th percentile value) less than 8% at up to 100-fold undersampling. In the 30-fold undersampled prospective study, the proposed method provided high resolution whole-brain TK maps and patient-specific AIF. CONCLUSION: The proposed model-based DCE-MRI reconstruction enables the use of different TK solvers with a model consistency constraint and enables joint estimation of patient-specific AIF. TK maps and patient-specific AIF with high fidelity can be reconstructed at up to 100-fold undersampling in k,t-space. Magn Reson Med 79:2804-2815, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905412 TI - Long-term treatment costs for aggressive periodontitis in a German population. AB - AIM: This study assessed the long-term annual costs for treating aggressive periodontitis (AgP) patients. METHODS: A cohort of compliant AgP patients was retrospectively evaluated. Costs for active periodontal therapy (APT, including scaling and root planing, open flap debridement, root resections, but not pocket elimination or regenerative surgery) and supportive periodontal therapy (SPT, including also costs for restorative, endodontic, prosthetic and surgical treatments) were estimated from a mixed payer perspective in Germany. The impact of tooth- and patient-level factors on annual costs was assessed using mixed modelling. RESULTS: A total of 52 patients (mean [SD] age: 35.2/6.8 years), with 26.5 (4.0) teeth (38% with bone loss >50%) were treated. Mean follow-up (retention) time was 16.9 (5.4) years. Total treatment costs per patient and per tooth were 6,998 (3,807) and 267 (148) Euro, respectively. Approximately 87% of the costs were generated during SPT, 13% during APT. Annual patient- and tooth level costs were 536 (209) and 20.1 (65.0) Euro, respectively. Annual tooth-level costs were significantly increased in patients aged 34 years or older, male patients, former or current smokers, teeth with furcation involvement degree II/III, and bone loss 50%-70%. CONCLUSIONS: Annual treatment costs for treating AgP patients were similar to those found for chronic periodontitis patients. Certain parameters might predict costs. PMID- 28905413 TI - Simultaneous acquisition sequence for improved hepatic pharmacokinetics quantification accuracy (SAHA) for dynamic contrast-enhanced MRI of liver. AB - PURPOSE: To propose a simultaneous acquisition sequence for improved hepatic pharmacokinetics quantification accuracy (SAHA) method for liver dynamic contrast enhanced MRI. METHODS: The proposed SAHA simultaneously acquired high temporal resolution 2D images for vascular input function extraction using Cartesian sampling and 3D large-coverage high spatial-resolution liver dynamic contrast enhanced images using golden angle stack-of-stars acquisition in an interleaved way. Simulations were conducted to investigate the accuracy of SAHA in pharmacokinetic analysis. A healthy volunteer and three patients with cirrhosis or hepatocellular carcinoma were included in the study to investigate the feasibility of SAHA in vivo. RESULTS: Simulation studies showed that SAHA can provide closer results to the true values and lower root mean square error of estimated pharmacokinetic parameters in all of the tested scenarios. The in vivo scans of subjects provided fair image quality of both 2D images for arterial input function and portal venous input function and 3D whole liver images. The in vivo fitting results showed that the perfusion parameters of healthy liver were significantly different from those of cirrhotic liver and HCC. CONCLUSIONS: The proposed SAHA can provide improved accuracy in pharmacokinetic modeling and is feasible in human liver dynamic contrast-enhanced MRI, suggesting that SAHA is a potential tool for liver dynamic contrast-enhanced MRI. Magn Reson Med 79:2629 2641, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905414 TI - High spatio-temporal resolution in functional MRI with 3D echo planar imaging using cylindrical excitation and a CAIPIRINHA undersampling pattern. AB - PURPOSE: The combination of 3D echo planar imaging (3D-EPI) with a 2D-CAIPIRINHA undersampling scheme provides high flexibility in the optimization for spatial or temporal resolution. This flexibility can be increased further with the addition of a cylindrical excitation pulse, which exclusively excites the brain regions of interest. Here, 3D-EPI was combined with a 2D radiofrequency pulse to reduce the brain area from which signal is generated, and hence, allowing either reduction of the field of view or reduction of parallel imaging noise amplification. METHODS: 3D-EPI with cylindrical excitation and 4 * 3-fold undersampling in a 2D CAIPIRINHA sampling scheme was used to generate functional MRI (fMRI) data with either 2-mm or 0.9-mm in-plane resolution and 1.1-s temporal resolution over a 5 cm diameter cylinder placed over both temporal lobes for an auditory fMRI experiment. RESULTS: Significant increases in image signal-to-noise ratio (SNR) and temporal SNR (tSNR) were found for both 2-mm isotropic data and the high resolution protocol when using the cylindrical excitation pulse. Both protocols yielded highly significant blood oxygenation level-dependent responses for the presentation of natural sounds. CONCLUSION: The higher tSNR of the cylindrical excitation 3D-EPI data makes this sequence an ideal choice for high spatiotemporal resolution fMRI acquisitions. Magn Reson Med 79:2589-2596, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905415 TI - Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up-regulation of IRF1. AB - BACKGROUND: Neuroendocrine-differentiated prostate cancer (NEPCa) is refractory to androgen deprivation therapy and shows a poor prognosis. The underlying mechanisms responsible for neuroendocrine differentiation (NED) are yet to be clarified. In this study, we investigated the role of mammalian target of rapamycin (mTOR) in NEPCa. METHODS: We utilized a gain-of-function analysis by establishing a human PCa LNCaP stable line that expresses hyperactive mTOR (LNCaP mTOR). Then, we employed a comprehensive mass spectrometric analysis to identify a key transcription factor in LNCaP-mTOR, followed by a loss-of-function analysis using CRISPR/Cas system. RESULTS: The activation of mTOR induced NED. We observed significant cell growth arrest in NED of LNCaP-mTOR, which accompanied increased expression of p21WAF1/CIP1 . A comprehensive mass spectrometric analysis identified interferon regulatory factor 1 (IRF1) as a key transcription factor in growth arrest of LNCaP-mTOR. The disruption of IRF1 gene in LNCaP-mTOR reversed cell growth arrest along with the suppression of its target p21WAF1/CIP1 . These results indicate that the growth arrest in NED is at least in part dependent on IRF1 through the induction of p21WAF1/CIP1 . CONCLUSIONS: We identified active mTOR as a novel inducer of NED, and elucidated a mechanism underlying the malignant transformation of NEPCa by recapitulating NED in vitro. PMID- 28905416 TI - SAR and scan-time optimized 3D whole-brain double inversion recovery imaging at 7T. AB - PURPOSE: The aim of this project was to implement an ultra-high field (UHF) optimized double inversion recovery (DIR) sequence for gray matter (GM) imaging, enabling whole brain coverage in short acquisition times ( ~5 min, image resolution 1 mm3 ). METHODS: A 3D variable flip angle DIR turbo spin echo (TSE) sequence was optimized for UHF application. We implemented an improved, fast, and specific absorption rate (SAR) efficient TSE imaging module, utilizing improved reordering. The DIR preparation was tailored to UHF application. Additionally, fat artifacts were minimized by employing water excitation instead of fat saturation. RESULTS: GM images, covering the whole brain, were acquired in 7 min scan time at 1 mm isotropic resolution. SAR issues were overcome by using a dedicated flip angle calculation considering SAR and SNR efficiency. Furthermore, UHF related artifacts were minimized. CONCLUSION: The suggested sequence is suitable to generate GM images with whole-brain coverage at UHF. Due to the short total acquisition times and overall robustness, this approach can potentially enable DIR application in a routine setting and enhance lesion detection in neurological diseases. Magn Reson Med 79:2620-2628, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905417 TI - Investigating the structural dynamics of the PIEZO1 channel activation and inactivation by coarse-grained modeling. AB - The PIEZO channels, a family of mechanosensitive channels in vertebrates, feature a fast activation by mechanical stimuli (eg, membrane tension) followed by a slower inactivation. Although a medium-resolution structure of the trimeric form of PIEZO1 was solved by cryo-electron microscopy (cryo-EM), key structural changes responsible for the channel activation and inactivation are still unknown. Toward decrypting the structural mechanism of the PIEZO1 activation and inactivation, we performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (ie, normal mode analysis, flexibility and hotspot analysis, correlation analysis, and cryo-EM-based hybrid modeling and flexible fitting). We identified four key motional modes that may drive the tension-induced activation and inactivation, with fast and slow relaxation time, respectively. These modes allosterically couple the lateral and vertical motions of the peripheral domains to the opening and closing of the intra-cellular vestibule, enabling external mechanical forces to trigger, and regulate the activation/inactivation transitions. We also calculated domain specific flexibility profiles, and predicted hotspot residues at key domain domain interfaces and hinges. Our results offer unprecedented structural and dynamic information, which is consistent with the literature on mutational and functional studies of the PIEZO channels, and will guide future studies of this important family of mechanosensitive channels. PMID- 28905418 TI - Misunderstanding the preorganization concept can lead to confusions about the origin of enzyme catalysis. AB - Understanding the origin of the catalytic power of enzymes has both conceptual and practical importance. One of the most important finding from computational studies of enzyme catalysis is that a major part of the catalytic power is due to the preorganization of the enzyme active site. Unfortunately, misunderstanding of the nontrivial preorganization idea lead some to assume that it does not consider the effect of the protein residues. This major confusion reflects a misunderstanding of the statement that the interaction energy of the enzyme group and the transition state (TS) is similar to the corresponding interaction between the water molecules (in the reference system) and the TS, and that the catalysis is due to the reorganization free energy of the water molecules. Obviously, this finding does not mean that we do not consider the enzyme groups. Another problem is the idea that catalysis is due to substrate preorganization. This more traditional idea is based in some cases on inconsistent interpretation of the action of model compounds, which unfortunately, do not reflect the actual situation in the enzyme active site. The present article addresses the above problems, clarifying first the enzyme polar preorganization idea and the current misunderstandings. Next we take a specific model compound that was used to promote the substrate preorganization proposal and establish its irrelevance to enzyme catalysis. Overall, we show that the origin of the catalytic power of enzymes cannot be assessed uniquely without computer simulations, since at present this is the only way of relating structure and energetics. PMID- 28905419 TI - Fast 3D rosette spectroscopic imaging of neocortical abnormalities at 3 T: Assessment of spectral quality. AB - PURPOSE: To use a fast 3D rosette spectroscopic imaging acquisition to quantitatively evaluate how spectral quality influences detection of the endogenous variation of gray and white matter metabolite differences in controls, and demonstrate how rosette spectroscopic imaging can detect metabolic dysfunction in patients with neocortical abnormalities. METHODS: Data were acquired on a 3T MR scanner and 32-channel head coil, with rosette spectroscopic imaging covering a 4-cm slab of fronto-parietal-temporal lobes. The influence of acquisition parameters and filtering on spectral quality and sensitivity to tissue composition was assessed by LCModel analysis, the Cramer-Rao lower bound, and the standard errors from regression analyses. The optimized protocol was used to generate normative white and gray matter regressions and evaluate three patients with neocortical abnormalities. RESULTS: As a measure of the sensitivity to detect abnormalities, the standard errors of regression for Cr/NAA and Ch/NAA were significantly correlated with the Cramer-Rao lower bound values (R = 0.89 and 0.92, respectively, both with P < 0.001). The rosette acquisition with a duration of 9.6 min, produces a mean Cramer-Rao lower bound (%) over the entire slab of 4.6 +/- 2.6 and 5.8 +/- 2.3 for NAA and Cr, respectively. This enables a Cr/NAA standard error of 0.08 (i.e., detection sensitivity of 25% for a 50/50 mixed gray and white matter voxel). In healthy controls, the regression of Cr/NAA versus fraction gray matter in the cingulate differs from frontal and parietal regions. CONCLUSIONS: Fast rosette spectroscopic imaging acquisitions with regression analyses are able to identify metabolic differences across 4-cm slabs of the brain centrally and over the cortical periphery with high efficiency, generating results that are consistent with clinical findings. Magn Reson Med 79:2470-2480, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905420 TI - The HIV-1 p66 homodimeric RT exhibits different conformations in the binding competent and -incompetent NNRTI site. AB - Non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase (RT), NNRTIs, which bind to the p66/p51 heterodimeric RT, also interact with the p66/p66 homodimer, whose structure is unknown. 19 F nuclear magnetic resonance of a single 4-trifluoromethylphenylalanine (tfmF) residue, incorporated into the NNRTI binding pocket of the p66/p66 homodimer at position 181, was used to investigate NNRTI binding. In the NNRTI-bound homodimer complex, two different 19 F signals are observed, with the resonance frequencies matching those of the NNRTI-bound p66/p51 heterodimer spectra, in which the individual p66 subunit or p51-subunit were labeled with tfmF at positions 181. These data suggest that the NNRTI-bound p66/p66 homodimer conformation, particularly around residue 181, is very similar to that in the p66/p51 heterodimer, explaining why NNRTI binding to p66/p66 enhances dimer formation. PMID- 28905421 TI - Exercise to preserve beta-cell function in recent-onset Type 1 diabetes mellitus (EXTOD) - a randomized controlled pilot trial. AB - AIM: Residual beta-cell function is present at the time of diagnosis with Type 1 diabetes. Preserving this beta-cell function reduces complications. We hypothesized that exercise preserves beta-cell function in Type 1 diabetes and undertook a pilot trial to address the key uncertainties in designing a definitive trial to test this hypothesis. METHODS: A randomized controlled pilot trial in adults aged 16-60 years diagnosed with Type 1 diabetes within the previous 3 months was undertaken. Participants were assigned to control (usual care) or intervention (exercise consultation every month), in a 1 : 1 ratio for 12 months. The primary outcomes were recruitment rate, drop out, exercise adherence [weeks with >= 150 min of self-reported moderate to vigorous physical activity (MVPA)], and exercise uptake in the control group. The secondary outcomes were differences in insulin sensitivity and rate of loss of beta-cell function between intervention and control at 6 and 12 months. RESULTS: Of 507 individuals who were approached, 58 (28 control, 30 intervention) entered the study and 41 completed it. Participants were largely white European males, BMI 24.8 +/- 3.8 kg/m2 , HbA1c 75 +/- 25 mmol/mol (9 +/- 2%). Mean level of objectively measured MVPA increased in the intervention group (mean 243 to 273 min/week) and 61% of intervention participants reached the target of >= 150 min/week of self-reported MVPA on at least 42 weeks of the year. Physical activity levels fell slightly in the control group (mean 277 to 235 min of MVPA/week). There was exploratory evidence that intervention group became more insulin sensitive and required less insulin. However, the rate of loss of beta cell function appeared similar between the groups, although the change in insulin sensitivity may have affected this. CONCLUSION: We show that it is possible to recruit and randomize people with newly diagnosed Type 1 diabetes to a trial of an exercise intervention, and increase and maintain their exercise levels for 12 months. Future trials need to incorporate measures of greater adherence to exercise training targets, and include more appropriate measures of beta-cell function. (Clinical Trials Registry No; ISRCTN91388505). PMID- 28905422 TI - The Role of Primary Care for the Oral Health of Rural and Urban Older Adults. AB - CONTEXT: Rural populations often have restricted access to dental care and poor oral health. These problems may disproportionately affect older blacks in rural areas. Little is known about how access to primary health care may improve the oral health of rural seniors. PURPOSE: This study examines whether the relationship between having a usual source of health care and oral health varies for white and black older adults in rural and urban areas in the United States. METHODS: We draw on cross-sectional data of adults (50 years+) from the nationally representative Health and Retirement Study (n = 15,473). Multivariate logistic regression examined the role of a usual source of health care in conditioning racial differences in complete tooth loss and a dental visit in the past 2 years. A usual source of health care is a place, not including an emergency room, where a person goes when he or she is sick or needs health advice. FINDINGS: In rural areas, blacks had high rates of tooth loss (28%) and low rates of dental visits (34%). Having a usual source of health care was associated with higher odds of a dental visit for all adults. In rural areas, the association between a usual source of health care and tooth loss varied by race (P < .001); blacks had more tooth loss than whites even with a usual source of health care. CONCLUSIONS: Access to primary health care was associated with improved oral health outcomes, but it did not close the gap between whites and blacks in rural areas. PMID- 28905423 TI - WHO standards for biotherapeutics, including biosimilars: an example of the evaluation of complex biological products. AB - The most advanced regulatory processes for complex biological products have been put in place in many countries to provide appropriate regulatory oversight of biotherapeutic products in general, and similar biotherapeutics in particular. This process is still ongoing and requires regular updates to national regulatory requirements in line with scientific developments and up-to-date standards. For this purpose, strong knowledge of and expertise in evaluating biotherapeutics in general and similar biotherapeutic products, also called biosimilars, in particular is essential. Here, we discuss the World Health Organization's international standard-setting role in the regulatory evaluation of recombinant DNA-derived biotherapeutic products, including biosimilars, and provide examples that may serve as models for moving forward with nonbiological complex medicinal products. A number of scientific challenges and regulatory considerations imposed by the advent of biosimilars are described, together with the lessons learned, to stimulate future discussions on this topic. In addition, the experiences of facilitating the implementation of guiding principles for evaluation of similar biotherapeutic products into regulatory and manufacturers' practices in various countries over the past 10 years are briefly explained, with the aim of promoting further developments and regulatory convergence of complex biological and nonbiological products. PMID- 28905424 TI - Editorial Comment to Intermittent everolimus administration for renal angiomyolipoma associated with tuberous sclerosis complex. PMID- 28905425 TI - Modeling CAPRI targets 110-120 by template-based and free docking using contact potential and combined scoring function. AB - The paper presents analysis of our template-based and free docking predictions in the joint CASP12/CAPRI37 round. A new scoring function for template-based docking was developed, benchmarked on the Dockground resource, and applied to the targets. The results showed that the function successfully discriminates the incorrect docking predictions. In correctly predicted targets, the scoring function was complemented by other considerations, such as consistency of the oligomeric states among templates, similarity of the biological functions, biological interface relevance, etc. The scoring function still does not distinguish well biological from crystal packing interfaces, and needs further development for the docking of bundles of alpha-helices. In the case of the trimeric targets, sequence-based methods did not find common templates, despite similarity of the structures, suggesting complementary use of structure- and sequence-based alignments in comparative docking. The results showed that if a good docking template is found, an accurate model of the interface can be built even from largely inaccurate models of individual subunits. Free docking however is very sensitive to the quality of the individual models. However, our newly developed contact potential detected approximate locations of the binding sites. PMID- 28905426 TI - Optically controlled on-coil amplifier with RF monitoring feedback. AB - PURPOSE: To develop a new optically controlled on-coil amplifier that facilitates safe use of multi-channel radiofrequency (RF) transmission in MRI by real-time monitoring of signal phase and amplitude. METHODS: Monitoring was carried out with a 4-channel prototype system by sensing, down sampling, digitizing, and optically transmitting the RF transmit signal to a remote PC to control the amplifiers. Performance was evaluated with benchtop and 7 T MRI experiments. RESULTS: Monitored amplitude and phase were stable across repetitions and had standard deviations of 0.061 MUT and 0.0073 rad, respectively. The feedback system allowed inter-channel phase and B1 amplitude to be adjusted within two iterations. MRI experiments demonstrated the feasibility of this approach to perform safe and accurate multi-channel RF transmission and monitoring at high field. CONCLUSION: We demonstrated a 4-channel transceiver system based on optically controlled on-coil amplifiers with RF signal monitoring and feedback control. The approach allows the safe and precise control of RF transmission fields, required to achieve uniform excitation at high field. Magn Reson Med 79:2833-2841, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905427 TI - Anion induced conformational preference of Calpha NN motif residues in functional proteins. AB - Among different ligand binding motifs, anion binding Calpha NN motif consisting of peptide backbone atoms of three consecutive residues are observed to be important for recognition of free anions, like sulphate or biphosphate and participate in different key functions. Here we study the interaction of sulphate and biphosphate with Calpha NN motif present in different proteins. Instead of total protein, a peptide fragment has been studied keeping Calpha NN motif flanked in between other residues. We use classical force field based molecular dynamics simulations to understand the stability of this motif. Our data indicate fluctuations in conformational preferences of the motif residues in absence of the anion. The anion gives stability to one of these conformations. However, the anion induced conformational preferences are highly sequence dependent and specific to the type of anion. In particular, the polar residues are more favourable compared to the other residues for recognising the anion. PMID- 28905429 TI - Intermittent everolimus administration for renal angiomyolipoma associated with tuberous sclerosis complex. AB - OBJECTIVES: To evaluate the effects and utility of intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. METHODS: We investigated a total of 26 patients with tuberous sclerosis complex who had angiomyolipoma >=4 cm in diameter. For each patient, we analyzed the reduction in the size of the angiomyolipoma, the change in size after everolimus withdrawal, the size reduction rate on everolimus readministration and adverse events caused by everolimus. The volume of angiomyolipoma was measured using abdominal computed tomography or magnetic resonance imaging. Adverse events were evaluated according to CTCAE v4.0-JCOG. RESULTS: The average size reduction rate of angiomyolipoma in the initial treatment with everolimus was 67%. Eight patients (31%) did not have enlarged angiomyolipoma after everolimus withdrawal. The other 18 patients (69%) restarted everolimus treatment because of enlargement of the angiomyolipoma. The average size reduction rate of angiomyolipoma in the everolimus retreatment group was 61%, which was equivalent to the rate for the initial treatment. There were fewer adverse events during everolimus retreatment than in the initial treatment. CONCLUSIONS: This is the first report regarding intermittent everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex. This treatment is effective for tumor control and adverse event management. This beneficial treatment option for patients can minimize the drug dosage and the occurrence of adverse events. PMID- 28905428 TI - Cost-effective screening of DNMT3A coding sequence identifies somatic mutation in pediatric T-cell acute lymphoblastic leukemia. AB - BACKGROUND AND OBJECTIVES: In pediatric T-cell acute lymphoblastic leukemia (T ALL), risk assignment schemes preclude reliable prediction of outcome, and thus, new prognostic factors are needed. Mutations in DNMT3A are candidate prognostic and classification markers in adults with acute myeloid leukemia (AML) and T-ALL and thus were considered as candidates prognostic markers in pediatric T-ALL. PATIENTS AND METHODS: DNMT3A mutational status was investigated in 74 pediatric T ALL samples collected at diagnosis. We applied high-resolution melt (HRM) analysis and Sanger sequencing to study the hotspot position (R882) within catalytic MTase domain and exons coding for other functional domains of the protein, known to be mutated in the wide spectrum of hematological malignancies. RESULTS: We demonstrate a low frequency of mutations in DNMT3A coding sequence in pediatric T-ALL (1.4%, n = 1/74). We identified missense mutation, p.Ala644Thr, which has not been described previously in pediatric T-ALL, but is recurrent in adults with T-ALL and AML. CONCLUSIONS: Low frequency of DNMT3A mutations in pediatric T-ALL is in striking contrast to adult T-ALL and renders the necessity for the search of other candidate prognostic markers. Combined Sanger sequencing HRM approach offers a cost-effective option for genotyping DNMT3A coding sequence, with potential clinical application in other hematological malignancies. PMID- 28905430 TI - Archaea S-layer nanotube from a "black smoker" in complex with cyclo-octasulfur (S8 ) rings. AB - Elemental sulfur exists primarily as an S80 ring and serves as terminal electron acceptor for a variety of sulfur-fermenting bacteria. Hyperthermophilic archaea from black smoker vents are an exciting research tool to advance our knowledge of sulfur respiration under extreme conditions. Here, we use a hybrid method approach to demonstrate that the proteinaceous cavities of the S-layer nanotube of the hyperthermophilic archaeon Staphylothermus marinus act as a storage reservoir for cyclo-octasulfur S8. Fully atomistic molecular dynamics (MD) simulations were performed and the method of multiconfigurational thermodynamic integration was employed to compute the absolute free energy for transferring a ring of elemental sulfur S8 from an aqueous bath into the largest hydrophobic cavity of a fragment of archaeal tetrabrachion. Comparisons with earlier MD studies of the free energy of hydration as a function of water occupancy in the same cavity of archaeal tetrabrachion show that the sulfur ring is energetically favored over water. PMID- 28905431 TI - Including health promotion and illness prevention in medical education: a progress report. AB - CONTEXT: In 1988, the World Federation of Medical Education called for reform in medical education, publishing 12 recommendations. The sixth recommendation of this Edinburgh Declaration was to 'complement instruction about the management of patients with increased emphasis on promotion of health and prevention of disease'. Thirty years on, this paper reports an exploration of what has changed since then. METHODS: Several search strategies were used, including websites of medical standards organisations, and formal searches of PubMed and Google Scholar using key words such as 'medical education standards', 'health promotion', 'illness prevention', 'effectiveness' and 'assessment'. As these searches produced more descriptive than evidence-based papers, the exploration widened to follow evolving discussions about changing emphases in medical education relevant to public health. RESULTS: Health promotion and illness prevention are in the undergraduate medical education standards of the more influential regulators. There is little evidence of the impact of this inclusion on graduate outcomes and later medical practice, although 'differently educated' doctors may have contributed to the success of broader public health strategies achieved through reorganisation of health care, media campaigns and legislation changes. There is greater success in postgraduate specialty training of general practitioners and public health doctors. The discussion about public health interventions and the roles of doctors has moved on to topics such as patient safety, the health of doctors, global health and planetary health. CONCLUSIONS: The inclusion of health promotion and illness prevention strategies in undergraduate curricula varied considerably, but was strongest in programmes claiming social accountability and responding to medical education standards of the more influential regulators. However, the contribution of medical education to improvements in health care and the health of populations is difficult to measure. It may be timely to revisit the purpose and practicality of broadening the scope of undergraduate medical curricula in public health medicine. PMID- 28905432 TI - "Taking the Bull by the Horns": Four Principles to Align Public Health, Primary Care, and Community Efforts to Improve Rural Cancer Control. PMID- 28905433 TI - Integrating Oral Health Into Rural Primary Care-the What and the Why. PMID- 28905434 TI - Decline of insulin therapy and delays in insulin initiation in people with uncontrolled diabetes mellitus. AB - AIMS: To design and validate a natural language processing algorithm to identify insulin therapy decline from the text of physician notes, and to determine the prevalence of insulin therapy decline and its impact on insulin initiation. METHODS: We designed the algorithm using the publicly available natural language processing platform Canary. We evaluated the accuracy of the algorithm on 1501 randomly selected primary care physicians' notes from the electronic medical record system of a large academic medical centre. Using the validated language model, we then studied the prevalence of insulin therapy decline between 2000 and 2014. RESULTS: The algorithm identified documentation of insulin therapy decline with a sensitivity of 100% (95% CI 82.4-100), a positive predictive value of 95% (95% CI 74.4-99.9), and a specificity of 99.9% (95% CI 99.6-100.0). We identified 3295 insulin-naive adults with Type 2 diabetes who were recommended insulin therapy; 984 of them (29.9%) initially declined insulin. People with HbA1c >= 75 mmol/mol (9.0%) were more likely [766/2239 (34.2%)] to have declined insulin than people with HbA1c 53-63 mmol/mol (7.0-7.9%) and 64-74 mmol/mol (8.0-8.9%; P < 0.0001). Among the people who initially declined but ultimately started insulin [374/984 (38.0%)], mean time to insulin initiation was 790 days. CONCLUSIONS: Insulin therapy decline is common, potentially leading to progression of hyperglycaemia and a delay in achievement of glycaemic control. Further investigation is needed to determine the reasons, risk factors and long-term outcomes of this important clinical phenomenon. PMID- 28905435 TI - Isatin-induced increase in the affinity of human ferrochelatase and adrenodoxin reductase interaction. AB - Isatin (indol-2,3-dione) is an endogenous non-peptide regulator exhibiting a wide range of biological and pharmacological activities, which are poorly characterized in terms of their molecular mechanisms. Identification of many isatin-binding proteins in the mammalian brain and liver suggests that isatin may influence their functions. We have hypothesized that besides direct action on particular protein targets, isatin can act as a regulator of protein-protein interactions (PPIs). In this surface plasmon resonance-based biosensor study we have found that physiologically relevant concentrations of isatin (25-100 MUM) increase affinity of interactions between human recombinant ferrochelatase (FECH) and NADPH-dependent adrenodoxin reductase (ADR). In the presence of increasing concentrations of isatin the Kd values demonstrated a significant (up to 6-fold) decrease. It is especially important that the interaction of isatin with each individual protein (FECH, ADR) was basically negligible and therefore could not contribute to the observed effect. This effect was specific only for the FECH/ADR complex formation and was not observed for other protein complexes studied: FECH/cytochrome b5(CYB5A) and FECH/SMAD4. PMID- 28905436 TI - Dentition of the apron ray Discopyge tschudii (Elasmobranchii: Narcinidae). AB - The present study provides quantitative and qualitative analyses of the dentition of Discopyge tschudii. Overall, 193 individuals (99 males and 94 females) of D. tschudii were collected on scientific trawl surveys conducted by the National Institute for Fisheries Research and Development (INIDEP) and commercial vessels in Argentina. Discopyge tschudii has rhombic-shaped teeth, arranged in a semipavement-like dentition; each tooth has an erect cusp slightly inclined posteriorly and holaulachorized root. Mature males have greater tooth lengths than females and immature specimens. Discopyge tschudii exhibits dignathic homodonty and gradient monognathic heterodonty where teeth of the commissural row are shorter than those of the symphyseal and internal rows. PMID- 28905437 TI - The Use of Traditional Herbal Medicines Amongst South Asian Diasporic Communities in the UK. AB - Migrant South Asian communities in the UK have brought with them their own traditional forms of medicine, yet little is known about their current use of herbal medicines (HMs) in the UK. The aim of the study was to explore the origins, use and transmission of knowledge of traditional HMs used by diasporic South Asian communities in the UK. A researcher-administered questionnaire was used for data collection (n = 192). An opportunity sampling technique was used to recruit participants across several locations in Birmingham and Leicester. Two thirds of participants (n = 126) stated they used HMs to maintain their health and to treat various health conditions such as digestive problems, skin conditions and diabetes. Almost 2000 actively used HMs were documented including 123 plant species that were identified. Participants imported HMs from abroad as well as sourcing them locally and even growing some of their own plants. Up to 82% (n = 87) of participants who took prescription medicines did not tell their healthcare professionals about any HMs they consumed; this raises concerns about people's knowledge of herb-drug interactions, compliance and effect on prescribed medicine regimens. Similar studies to explore the use of HMs by other ethnic groups are imperative to help optimise pharmaceutical care of patients. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28905438 TI - Research to support optimization of prescription drug monitoring programs. AB - PURPOSE: Research is needed to evaluate the impact of prescription drug monitoring programs (PDMPs). This paper describes research priorities for PDMPs that were initially discussed at a 2015 meeting of PDMP administrators, researchers, public health officials, and other stakeholders. METHODS: Meeting participants defined the current landscape of PDMP research and identified research gaps. Research priorities were grouped by theme. RESULTS: Prescription drug monitoring program research priorities were identified for 3 key areas: individual patient health outcomes, prescriber use and decision making, and population-level outcomes. Research areas for individual patient outcomes include examining drug-use thresholds that best predict risk for overdose or substance use disorder and unintended consequences of PDMP use. Proposed research on prescriber PDMP use include evaluating how enhancements to the content and format of PDMP reports informs clinical decision making and optimal clinician actions in response to a concerning PDMP report. Finally, research topics related to population-level outcomes include measuring the impact of PDMP policies on the incidence of substance misuse and harms and assessing the return on investment for these databases. CONCLUSIONS: The clinical, public health, and economic impacts of PDMPs must be evaluated, using both quantitative and qualitative methods. In addition to assessing patient outcomes, qualitative research should examine how clinicians use and interpret PDMP information. Research should also examine the impact of PDMP features and policies on prescriber utilization. Comparative analyses across states with differing PDMP policies should be conducted to inform best practices. PMID- 28905439 TI - Testing the performance of a prototype lateral flow device using bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in high-risk patients. AB - The diagnosis of invasive pulmonary aspergillosis (IPA) increasingly relies on non-culture-based biomarkers in bronchoalveolar lavage (BAL) fluid. The Aspergillus lateral flow device (LFD) is a rapid immunoassay that uses a novel Aspergillus monoclonal antibody to gain specificity. The objective of the study is to compare specificity and sensitivity of the prototype LFD and the galactomannan (GM) enzyme immunoassay in BAL fluid in high-risk patients. A total of 114 BAL samples from 106 patients at high risk for IPA were studied: 8 patients had proven/probable IPA, 16 had possible IPA and 82 did not have IPA. In patients with proven/probable IPA, specificity of LFD was 94% and GM was 89%; sensitivity of LFD was 38% and GM was 75%. Negative predictive value (NPV) for LFD was 94% and for GM was 98%; positive predictive value (PPV) was 38% for both tests. The use of anti-mould prophylaxis did not affect specificity but resulted in decreased NPV of both LFD and GM. Union and intersection analysis showed no improvement in the performance by using both tests. Among patients at risk for IPA, the diagnostic performance of LFD and GM in BAL fluid appears comparable; specificity is high, but sensitivity of both LFD and GM is poor. PMID- 28905440 TI - Child fosterage and sex-biased nutritional outcomes among Namibian pastoralists. AB - OBJECTIVES: Across cultures, fosterage has been shown to impact child health. Contextual factors, such as the reason for fosterage and the relationship between foster parent and child, are known to magnify variance in nutritional outcomes for foster children. Another important, but less studied, factor is the role of gender. Sex-biases in physiology and cultural norms are both known to affect child nutrition, and we posit these effects might be magnified in the presence of fosterage. In this study, we investigate how sex interacts with fosterage to affect nutritional outcomes among Namibian pastoralists. METHODS: Anthropometrics for children and adults were collected using standard procedures, and linear models were used to predict the effects of age, sex, and fosterage on height, weight, and body mass index Z-scores. Semi-structured interviews with adults provided context for understanding sex specific reasons for fosterage and biases in investment. RESULTS: Boys in this population have lower nutritional scores than girls, and fostered boys have lower weight and BMI Z-scores than nonfostered boys. Fostered girls have lower height Z-scores and are more likely to be stunted and underweight than nonfostered girls. These effects extend into adulthood, with fostered women being shorter than their nonfostered counterparts. CONCLUSIONS: Sex plays a role in the nutritional impact of fosterage among Himba children. These differences could be related to differential child labor demands, investment patterns, and the divergent reasons girls and boys are placed into fosterage. Future studies should consider how fosterage can magnify existing biases, like sex, when studying its impact on child health. PMID- 28905441 TI - The vasopressin system: new insights for patients with kidney diseases: Epidemiological evidence and therapeutic perspectives. AB - People with chronic kidney disease (CKD) are at risk of severe outcomes, such as end-stage renal disease or cardiovascular disease, and CKD is a globally increasing health burden with a high personal and economic cost. Despite major progresses in prevention and therapeutics in last decades, research is still needed to reverse this epidemic trend. The regulation of water balance and the state of activation of the vasopressin system have emerged as factors tightly associated with kidney health, in the general population but also in specific conditions; among them, various stages of CKD, diabetes and autosomal dominant polycystic kidney disease (ADPKD). Basic science findings and also epidemiological evidence have justified important efforts towards interventional studies supporting causality, and opening therapeutic avenues. On the basis of recent clinical data, the blockade of V2 vasopressin receptors using tolvaptan in patients with rapidly progressing ADPKD has been granted in several countries, and a long-term randomized trial evaluating the effect of an increase in water intake in patients with CKD is on-going. PMID- 28905443 TI - On the Mechanism of Connecting Deltahedral Zintl Clusters via Conjugated Buta-1,3 dien-1,4-diyl Functionalities: Synthesis and Structure of [Ge9 -CH=CH-CH=CH-Ge9 ]6. AB - We report on the synthesis and structure, as well as on the mechanism of formation of the [Ge9 -CH=CH-CH=CH-Ge9 ]6- unit. As shown by in situ NMR spectroscopy (1 H, COSY, HSQC, HMBC), both (1Z,3Z)- and (1E,3Z)-[Ge9 -CH=CH-CH=CH Ge9 ]6- are formed during the reaction of a mixture of 1,4 bis(trimethylsilyl)butadiyne and A4 Ge9 (A=K, Rb) with ethylenediamine. However, upon layering of the obtained solution with 222-crypt/toluene (222 crypt=4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8.8.8]hexacosan) only the (1Z,3Z)-isomer crystallizes as {[A(222-crypt)]6 [(1Z,3Z)-(Ge9 -CH=CH-CH=CH-Ge9 )]}(tol)2 (en)2 (A=K, Rb) salts. Single crystals of these salts were characterized by X-ray structure analysis and Raman spectroscopy, indicating the presence of three superimposed conformers of (1Z,3Z)-[Ge9 -CH=CH-CH=CH-Ge9 ]6- , which show different orientations of the cluster units with respect to the planar (1Z,3Z)-buta-1,3-dien-1,4-diyl linker unit. PMID- 28905444 TI - Response to hepatitis B vaccination in patients with liver cirrhosis. AB - Hepatitis B vaccination is strongly recommended for all infants and children but also for adults who are at risk of HBV infection. Attempts to immunize patients with liver cirrhosis have been proven relatively ineffective, and several strategies have already been used to improve the immune response in this group. The primary aim of this review is to examine, discuss, and summarize the immunogenicity of hepatitis B vaccination in patients with liver cirrhosis. MEDLINE search identified 11 studies (n = 961). The dose of the vaccine and the schedule of the vaccination varied. The response rates to the HBV vaccination ranged from 16% to 87% among patients with cirrhosis regardless of the number and vaccine dose. In particular, patients who received the standard dose of vaccination achieved seroprotection rates ranged from 16% to 79% (mean response rate 38%) and those who received a double dose achieved relatively better seroprotection rates (range: 26%-87%; mean response rate 53%). The overall mean response rate to the HBV vaccination was 47%. In conclusion, cirrhotic patients achieve lower seroprotection rates after the completion of HBV vaccination series. Several strategies have tried to improve the immunogenicity; however, there is a great need for additional studies to further explore (1) the immune response in relation to poor vaccination responsiveness confounding factors, (2) novel strategies to improve immunogenicity, and (3) the immune mechanism underlying the differences in response rates to HBV vaccination. PMID- 28905445 TI - The meaning of play for children and young people with physical disabilities: A systematic thematic synthesis. AB - BACKGROUND: Children and young people with physical disabilities are often reported to play less than their typically developing peers. Few studies explore the meaning of play from the child's perspective; this study carried out a thematic synthesis of the findings of qualitative studies about the meaning of play following the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. METHODS: A search of CINAHL, AHMED, PsycINFO, MEDLINE, EMBASE, and ERIC was undertaken between September 2015 and March 2016. Qualitative studies exploring the meaning of play from the perspective of 0- to 18-year-olds with physical disabilities impacting function were included. Quality appraisal and thematic synthesis were undertaken in order to develop analytical themes. RESULTS: Thirteen studies met the inclusion criteria in part addressing the meaning of play for children and young people with physical disabilities. Synthesis of the findings identified 5 analytical themes: Play can feel both positive and negative; play can draw attention towards or away from my disability; play is a social interaction; I participate differently to my peers, and needing help feels normal. CONCLUSIONS: The themes highlight the potential for play experiences of individuals with physical disabilities being overlooked by parents and professionals; further research is needed to explore play experience from these individual's perspective. PMID- 28905442 TI - Fell-Muir Lecture: Fibrillin microfibrils: structural tensometers of elastic tissues? AB - Fibrillin microfibrils are indispensable structural elements of connective tissues in multicellular organisms from early metazoans to humans. They have an extensible periodic beaded organization, and support dynamic tissues such as ciliary zonules that suspend the lens. In tissues that express elastin, including blood vessels, skin and lungs, microfibrils support elastin deposition and shape the functional architecture of elastic fibres. The vital contribution of microfibrils to tissue form and function is underscored by the heritable fibrillinopathies, especially Marfan syndrome with severe elastic, ocular and skeletal tissue defects. Research since the early 1990s has advanced our knowledge of biology of microfibrils, yet understanding of their mechanical and homeostatic contributions to tissues remains far from complete. This review is a personal reflection on key insights, and puts forward the conceptual hypothesis that microfibrils are structural 'tensometers' that direct cells to monitor and respond to altered tissue mechanics. PMID- 28905446 TI - Impact of five-tiered Gleason grade groups on prognostic prediction in clinical stage T3 prostate cancer undergoing high-dose-rate brachytherapy. AB - BACKGROUND: We evaluated a five-tiered Gleason grade groups arising from the 2014 International Society of Urological Pathology consensus conference on prognostic prediction in clinical stage T3a (extracapsular invasion) and T3b (seminal vesicle involvement) prostate cancer undergoing high-dose-rate brachytherapy (HDR BT). METHODS: From November 2003 to December 2012, 283 patients with stage T3 prostate cancer received HDR-BT and external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT). Of these, 203 (72%) and 80 (28%) patients had stage T3a and T3b disease, respectively. The mean dose to 90% of the planning target volume was 7.5 Gy/fraction of HDR-BT. After five fractions, EBRT with 10 fractions of 3 Gy was administered. All patients first underwent >=6 months of neoadjuvant ADT, and adjuvant ADT continued for 36 months. Median follow-up was 74 months from the start of radiotherapy. RESULTS: The 10-year biochemical recurrence (BCR) -free rate for stage T3a and T3b disease was 79% and 64%, respectively (P = 0.0083). The 10-year cancer-specific survival (CSS) rate for stage T3a and T3b was 96% and 91%, respectively (P = 0.0305). Although grade groups >=4 were independent predictors for BCR in cT3a patients (P = 0.0270), they failed to significantly predict prostate cancer-specific mortality (PCSM) among cT3a patients. Among cT3b patients, grade group 5 was a significant predictor of both BCR (P = 0.0017) and PCSM (P = 0.0233). Among stage T3a patients, no significant difference existed in 10-year CSS between grade groups 5 and 4 (94% vs 97%, P = 0.3960). In contrast, grade group 5 had a significantly worse outcome in 10-year CSS than grade group 4 among stage T3b patients (74% vs 100%, P = 0.0350). CONCLUSIONS: Stage T3a patients with grade groups 4/5 and stage T3b with grade group 4 had fairly low PCSM risk. Approximately one of four patients among stage T3b patients with grade group 5 showed PCSM after combined HDR-BT and EBRT with long-term ADT. Stage T3b patients with grade group 5 may have a greater risk for PCSM. PMID- 28905447 TI - Assessment of the quality of neonatal care in the Solomon Islands. AB - AIM: To identify strengths and obstacles for improving the quality of newborn care in the Solomon Islands. Improving the quality of newborn care is a priority in the Sustainable Development Goals and the Action Plan for Healthy Newborns in the Western Pacific. The neonatal mortality rate in the Solomon Islands, a lower middle-income country, has improved slower than overall child mortality. In 2013, neonatal mortality (13.2/1000) constituted 44% of under-5 deaths (30.1/1000). METHODS: A cross-sectional study of newborn care in five provincial hospitals using a World Health Organization assessment tool for hospital quality of care. Twelve months of neonatal records of the National Referral Hospital (NRH) labour ward and nursery were audited. RESULTS: Essential medications and basic equipment were generally available. Challenges included workforce shortages and lack of expertise, high costs, organisation and maintenance of equipment, infection control and high rates of stillbirth. Over 12 months at the NRH labour ward, there were 5412 live births, 65 (1.2%) 'fresh' stillbirths and 96 (1.8%) 'macerated' stillbirths. Over the same period, there were an associated 779 nursery admissions, and the main causes of mortality were complications of prematurity, birth asphyxia, congenital abnormalities and sepsis. Total neonatal mortality at NRH was 16 per 1000 live births, and 77% of deaths occurred in the first 3 days of life. CONCLUSIONS: Infrastructure limitations, technical maintenance and equipment organisation were obstacles to newborn care. Greater health-care worker knowledge and skills for early essential newborn care, infection control and management of newborn complications is needed. PMID- 28905448 TI - Myeloid Zinc Finger 1 and GA Binding Protein Co-Operate with Sox2 in Regulating the Expression of Yes-Associated Protein 1 in Cancer Cells. AB - The transcription factor (TF) yes-associated protein 1 (YAP1) is a major effector of the tumor suppressive Hippo signaling pathway and is also necessary to maintain pluripotency in embryonic stem cells. Elevated levels of YAP1 expression antagonize the tumor suppressive effects of the Hippo pathway that normally represses YAP1 function. High YAP1 expression is observed in several types of human cancers and is particularly prominent in cancer stem cells (CSCs). The stem cell TF Sox2, which marks and maintains CSCs in osteosarcomas (OSs), promotes YAP1 expression by binding to an intronic enhancer element and YAP1 expression is also crucial for the maintainance of OS stem cells. To further understand the regulation of YAP1 expression in OSs, we subjected the YAP1 intronic enhancer to scanning mutagenesis to identify all DNA cis-elements critical for enhancer function. Through this approach, we identified two novel TFs, GA binding protein (GABP) and myeloid zinc finger 1 (MZF1), which are essential for basal YAP1 transcription. These factors are highly expressed in OSs and bind to distinct sites in the YAP1 enhancer. Depletion of either factor leads to drastically reduced YAP1 expression and thus a reversal of stem cell properties. We also found that YAP1 can regulate the expression of Sox2 by binding to two distinct DNA binding sites upstream and downstream of the Sox2 gene. Thus, Sox2 and YAP1 reinforce each others expression to maintain stemness and tumorigenicity in OSs, but the activity of MZF1 and GABP is essential for YAP1 transcription. Stem Cells 2017;35:2340-2350. PMID- 28905449 TI - Lull pgm system: A suitable technique to improve the regenerative potential of autologous fat grafting. AB - Autologous fat grafting and methods of purification of harvested tissue have become one of the most current themes in regenerative medicine. The aim of this study was to evaluate the in vitro regenerative potential of abdomen lipoaspirates subjected to a combined washing-decantation purifying procedure, the Lull pgm System (Lull). Blood cells and stromal-vascular fraction (SVF) cells contained in the aspirates were investigated and compared with those obtained through more conventional fat-processing methods, that is, the decantation and Coleman's centrifugation techniques. The lowest number of erythrocytes, which are proinflammatory cells, was observed in the Lull samples, corresponding to about 50% of those isolated by decantation and centrifugation. The highest amount of SVF cells were isolated from the Lull samples whose number of colony forming units, representative of the amount of adipose-derived stem cells (ADSCs), was about fourfold and sixfold higher than in the decantation and centrifugation samples, respectively. Adipocyte and osteoblast commitment of SVF cells obtained from all the three procedures also confirmed that the subpopulation of ADSCs was actively represented in the processed aspirates. Moreover, the growth rate of the SVF cells was more accentuated in the samples obtained from decantation and Lull than centrifugation. In conclusion, Lull seems to be the best processing technique for adipose tissue graft with respect to decantation and centrifugation, because it clears more efficiently the fat from proinflammatory blood cells and provides the greatest number of proliferating SFV cells and ADSCs. PMID- 28905450 TI - Nrf2 transfection enhances the efficacy of human amniotic mesenchymal stem cells to repair lung injury induced by lipopolysaccharide. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinical emergencies with no effective pharmaceutical treatment. This study aims to determine the protective effects of Nrf2-transfected human amniotic mesenchymal stem cells (hAMSCs) against lipopolysaccharide (LPS)-induced lung injury in mice. hAMSCs stably transfected with Nrf2 or green fluorescent protein control were transplanted into male C57BL/6 mice via the tail vein 4 h after intratracheal instillation of LPS. At 3, 7, and 14 days after cell transplantation, total lung injury score (the Smith score) was determined by hematoxylin and eosin staining. Lung fibrosis was assessed by Masson's trichrome staining. Alveolar epithelial apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The plasma levels of interleukin (IL)-1beta, IL-6, and IL-10 were determined by enzyme-linked immunosorbent assays (ELISA). The homing and differentiation of hAMSCs into type II alveolar epithelial (AT II) cells were examined by immunofluorescent staining and/or western blot analysis. Nrf2, mRNA, and protein expression in lungs were examined by qRT-PCR and western blot analysis, and DNA-binding activity of Nrf2 was detected by ELISA. We found that, compared with control hAMSCs, treatment with Nrf2-overexpressing hAMSCs led to further reduced lung injury, lung fibrosis, and inflammation in LPS-challenged mice. Nrf2-overexpressing hAMSCs also exhibited increased cell retention in the lung, more efficient differentiation into AT II cells, and more prominent effects on the increased mRNA and protein expression as well as DNA-binding activity of Nrf2 than control. These results support Nrf2-overexpressing hAMSCs as a potential cell-based therapy for clinical ALI/ARDS. PMID- 28905452 TI - Influence of scanning rate on quality of AFM image: Study of surface statistical metrics. AB - The purpose of this work is to study the dependence of AFM-data reliability on scanning rate. The three-dimensional (3D) surface topography of the samples with different micro-motifs is investigated. The analysis of surface metrics for estimation of artifacts from inappropriate scanning rate is presented. Fractal analysis was done by cube counting method and evaluation of statistical metrics was carrying out on the basis of AFM-data. Combination of quantitate parameters is also presented in graphs for every measurement. The results indicate that the sensitivity to scanning rate growths with fractal dimension of the sample. This approach allows describing the distortion of the images against scanning rate and could be applied for dependences on the other measurement parameters. The article explains the relevance and comparison of fractal and statistical surface parameters for characterization of data distortion caused by inappropriate choice of scanning rate. PMID- 28905451 TI - Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development. AB - A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. Podocytes derived from human pluripotent stem cells (hPSC-podocytes) have recently been generated in nephron-like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC-podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC-podocytes in vitro progressively establish junction-rich basal membranes (nephrin+ podocin+ ZO-1+ ) and microvillus-rich apical membranes (podocalyxin+ ), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin-knockout hPSCs and derived podocytes, generated using CRISPR/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC-podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration. Stem Cells 2017;35:2366-2378. PMID- 28905453 TI - Sexual steroids in serum and prostatic tissue of human non-cancerous prostate (STERPROSER trial). AB - BACKGROUND: The specific involvement of the sex steroids in the growth of the prostatic tissue remains unclear. Sex steroid concentrations in plasma and in fresh surgical samples of benign central prostate were correlated to prostate volume. METHODS: Monocentric prospective study performed between September 2014 and January 2017. Age, obesity parameters, and both serum and intraprostatic concentrations of sex steroids were collected complying with the latest Endocrine Society guidelines and the steroids assessed by GC/MS. Statistical calculations were adjusted for age and body mass index (BMI). RESULTS: Thirty-two patients, equally divided between normal- and high-volume prostate groups, were included in the analysis. High-volume prostate patients were older, heavier and had higher BMI. Comparison adjusted for age and BMI showed higher DHT concentrations in high volume prostate. Both normal- and high-volume prostate tissues concentrate sex steroids in a similar way. Comparison of enzymatic activity surrogate marker ratios within tissue highlighted similar TT/E1 and TT/E2 ratios, and higher DHT/E1 ratio and lower DHT/PSA ratio in the high-volume prostates. CONCLUSIONS: STERPROSER trial provides evidence for higher DHT concentration in highvolume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase. PMID- 28905455 TI - Corrigendum. PMID- 28905456 TI - Corrigendum. PMID- 28905454 TI - Management considerations in the failing renal allograft. AB - Patients with a failed or failing renal transplant are increasing in number. Graft failure resulting in dialysis re-initiation is not uncommon, yet there are limited data to guide management of these patients. Physician practices vary regarding timing of dialysis initiation and the timing and extent of immunosuppression withdrawal. The risks of immunosuppression withdrawal need to be carefully balanced against the benefits of continuing low-dose therapy. The latter helps minimize the risk of sensitisation and has been proposed to possibly slow the loss of residual renal function; however, the use of common immunosuppressive agents may contribute to cardiovascular disease, malignancy, and infection, the major causes of death following the loss of a renal transplant. The evolving area of personalised transplant immunosuppression may offer future tools for monitoring and managing patients during and after transplant failure. This article aims to discuss some of the important issues that arise when managing these patients. PMID- 28905457 TI - Asthma management: A new phenotype-based approach using presence of eosinophilia and allergy. PMID- 28905458 TI - Phosphorylation of ETS-1 is a critical event in DNA polymerase iota-induced invasion and metastasis of esophageal squamous cell carcinoma. AB - An aberrantly elevated expression of DNA polymerase iota (Pol iota) is significantly associated with poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), yet the mechanisms behind this phenomenon remain obscure. Based on the RNA-Seq transcriptome and real-time PCR analysis, we identified ETS 1 as a candidate gene involved in Pol iota-mediated progression of ESCC. Wound healing and transwell assay indicated that downregulation of ETS-1 attenuates Pol iota-mediated invasiveness of ESCC. Signaling pathway analysis showed that Pol iota enhances ETS-1 phosphorylation at threonine-38 through the Erk signaling pathway in ESCC cells. Kaplan-Meier analysis, based on 93 clinical tissue samples, revealed that ETS-1 phosphorylation at threonine-38 is associated with poor prognosis of ESCC patients. The present study thus demonstrates that phosphorylation of ETS-1 is a critical event in the Pol iota-induced invasion and metastasis of ESCC. PMID- 28905460 TI - Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate. AB - A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N methyliminodiacetic acid) boronates. This reaction exhibits excellent functional group tolerance and is applicable to various acyl MIDA boronates and potassium acyltrifluroborates (KATs) which could not be synthesized by previous methods. In addition, alpha-amino acylborons, which would be essential for peptide ligations, were prepared for the first time. The acylboron of l-alanine was obtained in high enantiopurity and found to be configurationally stable. Oligopeptide synthesis between the alpha-amino KATs and amino acid in dilute aqueous media was studied. PMID- 28905459 TI - Rescue therapy within the UK Cystic Fibrosis Registry: An exploration of predictors of intravenous antibiotic use amongst adults with CF. AB - BACKGROUND AND OBJECTIVE: Intravenous (i.v.) antibiotics are needed for rescue when preventative therapy fails to achieve stability among adults with cystic fibrosis (CF). Understanding the distribution of i.v. days can provide insight into the care that adults with CF need. We aim to determine the baseline characteristics that are associated with higher i.v. use, in particular to test the hypothesis that prior-year i.v. use is associated with future-year i.v. use. METHODS: This is a cross-sectional analysis of the 2013-2014 UK CF registry data. Stepwise logistic regression was performed using current-year i.v. days as the dependent variable, and demographic variables including prior-year i.v. days as the covariates. Based on these results, study sample was divided into clinically meaningful subgroups using analysis similar to tree-based method. RESULTS: Data were available for 4269 adults in 2013 and 4644 adults in 2014. Prior-year i.v. use was the strongest predictor for current-year i.v. use followed by forced expiratory volume in 1 s (FEV1 ). Adults with high prior-year i.v. use (>14 days) continued to require high levels of i.v., regardless of FEV1 . Those with high prior-year i.v. use and FEV1 >=70% had higher current-year i.v. days compared to adults with low prior-year i.v. use and FEV1 <40% (28 days, interquartile range (IQR): 11-41 days vs 14 days, IQR: 0-28 days; Mann-Whitney P-value <0.001 in 2013). CONCLUSION: CF people with prior high levels of rescue often continue to need high levels of rescue even if they have good FEV1 . The reasons for this require further investigations. PMID- 28905461 TI - Assessment of ecosystem resilience to hydroclimatic disturbances in India. AB - Recent studies have shown an increasing trend in hydroclimatic disturbances like droughts, which are anticipated to become more frequent and intense under global warming and climate change. Droughts adversely affect the vegetation growth and crop yield, which enhances the risks to food security for a country like India with over 1.2 billion people to feed. Here, we compared the response of terrestrial net primary productivity (NPP) to hydroclimatic disturbances in India at different scales (i.e., at river basins, land covers, and climate types) to examine the ecosystems' resilience to such adverse conditions. The ecosystem water use efficiency (WUEe : NPP/Evapotranspiration) is an effective indicator of ecosystem productivity, linking carbon (C) and water cycles. We found a significant difference (p < .05) in WUEe across India at different scales. The ecosystem resilience analysis indicated that most of the river basins were not resilient enough to hydroclimatic disturbances. Drastic reduction in WUEe under dry conditions was observed for some basins, which highlighted the cross-biome incapability to withstand such conditions. The ecosystem resilience at land cover and climate type scale did not completely relate to the basin-scale ecosystem resilience, which indicated that ecosystem resilience at basin scale is controlled by some other ecohydrological processes. Our results facilitate the identification of the most sensitive regions in the country for ecosystem management and climate policy making, and highlight the need for taking sufficient adaptation measures to ensure sustainability of ecosystems. PMID- 28905462 TI - Referrals to dietitians/nutritionists: A cross-sectional analysis of Australian GP registrars' clinical practice. AB - AIM: The present study aimed to describe referral patterns of general practitioner (GP) registrars to dietitians/nutritionists. There is a paucity of research regarding GP referral patterns to dietitians/nutritionists. Limited data show increasing referrals from established GPs to dietitians/nutritionists. There are no data on GP registrar (trainee) referrals. METHODS: This was a cross sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study. ReCEnT is an ongoing, multicentre, prospective cohort study of registrars, which documents 60 consecutive consultations of each registrar in each of the three six-month GP training terms. The outcome factor in this analysis was a problem/diagnosis resulting in dietitian/nutritionist referral (2010-2015). Independent variables were related to registrar, patient, practice and consultation. RESULTS: A total of 1124 registrars contributed data from 145 708 consultations. Of 227 190 problems/diagnoses, 587 (0.26% (confidence interval: 0.23-0.29)) resulted in dietitian/nutritionist referral. The most common problems/diagnoses referred related to overweight/obesity (27.1%) and type 2 diabetes (21.1%). Of referrals to a dietitian/nutritionist, 60.8% were for a chronic disease, and 38.8% were related to a Chronic Disease Management plan. Dietitian/nutritionist referral was significantly associated with a number of independent variables reflecting continuity of care, patient complexity, chronic disease, health equity and registrar engagement. CONCLUSIONS: Established patients with chronic disease and complex care needs are more likely than other patients to be referred by registrars to dietitians/nutritionists. Nutrition behaviours are a major risk factor in chronic disease, and we have found evidence for dietitian/nutritionist referrals representing one facet of engagement by registrars with patients' complex care needs. PMID- 28905463 TI - Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey. AB - Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60-75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu-Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed. PMID- 28905465 TI - Inclusion of sepsis and hypoxaemia in mortality prediction of hospitalized patients with community-acquired pneumonia. PMID- 28905464 TI - Urinary desmosine is associated with emphysema severity and frequent exacerbation in patients with COPD. AB - BACKGROUND AND OBJECTIVE: Matrix degradation is a key feature of chronic obstructive pulmonary disease (COPD). Desmosine and isodesmosine (desmosines) are excreted in urine following matrix degradation. The main purpose of this study was to investigate the association between computed tomography (CT) emphysema indices and urinary desmosines in patients with COPD. METHODS: A total of 152 subjects were selected from the Korean Obstructive Lung Disease cohort. Their urine samples were assayed for desmosines using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The cohort was divided into emphysema-dominant (n = 80) and non-emphysema dominant- (n = 72) groups according to the CT emphysema index. RESULTS: The level of urinary desmosines was significantly higher in the emphysema-dominant group. Significant differences were also observed between the two groups for body mass index and lung function. Multivariate analysis indicated that a high level of urinary desmosines was a significant independent predictor of emphysema (relative risk: 2.6; 95% CI: 1.11 6.09; P = 0.028). The percentage of frequent exacerbators was significantly higher in the high urinary desmosine group in the first year of follow-up (P = 0.041). The mean number of exacerbations was higher in the high urinary desmosine group, although this difference was not statistically significant (P = 0.067). The changes in emphysema index did not differ between the two urinary desmosine groups over 3 years of follow-up. CONCLUSION: This study indicates that the level of urinary desmosines measured by LC-MS/MS methods is associated with the CT emphysema index. Urinary desmosine can be a useful predictor in identifying frequent exacerbators. PMID- 28905466 TI - Adherence to PI-based 2nd-line regimens in Cambodia is not simply a question of individual behaviour: the ANRS 12276 2PICAM study. AB - OBJECTIVES: To investigate whether adherence to antiretroviral treatment (ART) can be explained not only by individual factors but also by health care facilities' characteristics, among a sample of people living with HIV (PLWH) treated with PI-based regimens in Cambodia. METHODS: The ANRS 12276 2PICAM cross sectional survey was conducted between February 2013 and April 2014 among PLWH followed up in 13 health care facilities. The 1316 patients in this analysis corresponded to 90% of the total number of adult patients treated with 2nd-line PI-based regimens in Cambodia in the study period. A variable indicating whether patients were non-adherent (=1) or completely adherent (=0) was constructed. Health care facilities and individual characteristics were included in a two level logistic model to investigate their influence on patients' adherence to ART. RESULTS: A total of 17% of participants did not adhere to ART. Patients in health care facilities outside the capital Phnom Penh were six times more likely to be non-adherent than those treated in health care facilities in the capital (OR: 6.15, 95% CI [1.47, 25.79]). Providing psychosocial care (provided by psychologist counsellors and/or full-time coaches) was found to be a structural facilitator of adherence, as the probability of non-adherence fell by 38.5% per each additional psychological worker present in health care facilities (OR: 0.62, 95% CI [0.43, 0.89]). Financial constraints were the main individual factor preventing adherence. CONCLUSIONS: Our results suggest that inefficiencies in health care delivery are detrimental to PLWH health and to the exceptional progress currently being made by Cambodia in response to HIV. Policy makers should focus on increasing the number of psychosocial workers, especially in areas outside the capital. PMID- 28905467 TI - Modeling of protein complexes in CAPRI Round 37 using template-based approach combined with model selection. AB - We participated in Round 37 of the Critical Assessment of PRediction of Interactions (CAPRI), held jointly with the 12th edition of the Critical Assessment of protein Structure Prediction (CASP12), having two major objectives. First, we intended to test the utility of our PPI3D web server in finding and selecting templates for comparative modeling of structures of protein complexes. Our second aim was to evaluate the ability of our model accuracy estimation method VoroMQA to score and rank structural models for protein-protein interactions. Using sequence search in PPI3D and HHpred servers we identified multimeric templates for 7 of 11 CAPRI targets, and models of at least acceptable quality were constructed for 6 of them. The clustering and visual analysis features implemented in the PPI3D software were instrumental in detecting alternative protein-protein interaction interfaces among the identified templates. When a single binding mode was observed for homologous proteins, the structural modeling of the protein complex was fairly straightforward, whereas choosing the correct interaction template from several alternatives turned out to be a difficult task requiring manual intervention. The combination of full structure and interaction interface VoroMQA scores effectively ranked structural models of protein complexes and selected models of better quality from the CAPRI Scoring sets. The overall results show possible uses of PPI3D and VoroMQA in structural modeling of protein-protein interactions and suggest ways for further improvements of both methods. PMID- 28905468 TI - Preventive Dental Checkups and Their Association With Access to Usual Source of Care Among Rural and Urban Adult Residents. AB - PURPOSE: This study aimed to assess the relationship between rural or urban residence and having a usual source of care (USC), and the utilization of preventive dental checkups among adults. METHODS: Cross-sectional analysis was conducted using data from the Medical Expenditure Panel Survey 2012. We performed a logit regression on the relationship between rural and urban residence, having a USC, and having at least 1 dental checkup in the past year, adjusting for sociodemographic characteristics and health status. FINDINGS: After controlling for covariates, rural adult residents had significantly lower odds of having at least 1 dental checkup per year compared to their urban counterparts (odds ratio [OR] = 0.73, 95% confidence interval [CI]: 0.62-0.86, P < .001). Additionally, individuals with a USC had higher odds of having at least 1 dental checkup per year (OR = 1.76, 95% CI: 1.59-1.95, P < .001). Among both rural and urban residents, having a USC was significantly associated with an 11% (95% CI = 9% 13%) increase in the probability of having a preventive dental checkup within a year. CONCLUSIONS: Individuals with a USC were more likely to obtain a preventive dental visit, with similar effects in rural and urban settings. We attributed the lower odds of having a checkup in rural regions to the lower density of oral health care providers in these areas. Integration of rural oral health care into primary care may help mitigate the challenges due to a shortage of oral health care providers in rural areas. PMID- 28905469 TI - Institutional review boards' attitudes towards remuneration in paediatric research: Ethical considerations. AB - Remuneration in paediatric research poses an ethical dilemma. Too large a sum might cause parents to enrol their children in research projects with no benefit for the child, whereas too modest a sum might hamper recruitment. The institutional review boards have the responsibility to only approve remuneration in paediatric trials with ethically sound research plans. However, little is known about which factors influence institutional review boards' evaluation of remuneration in paediatric research. PMID- 28905470 TI - Outcomes of Berlin Heart EXCOR(r) pediatric ventricular assist device support in patients with restrictive and hypertrophic cardiomyopathy. AB - The outcomes of pediatric ventricular assist device support in patients with diastolic heart failure have not been well described. This study reviews the North American experience with Berlin Heart EXCOR(r) ventricular assist device implants in children with such physiology. The Berlin Heart clinical database was reviewed. Patients with primary diastolic dysfunction are included in this study. Twenty pediatric patients with restrictive cardiomyopathy (n = 13), hypertrophic cardiomyopathy (n = 3), or congenital heart disease with restrictive physiology (n = 4) who were supported with EXCOR(r) were identified. Of these, nine (45%) were successfully bridged to transplant, one (5%) weaned from support, and 10 (50%) died after support was withdrawn. Of patients under age 3 years (n = 13), 38.5% survived, whereas those aged 3 or older (n = 7) had 71.4% survival (P = .35). Biventricular assist device (BiVAD) patients experienced a 27.3% survival, vs 77.8% for patients with left ventricular assist device only (P = .07). Primary causes of death included stroke, infection, acidosis, multisystem organ failure, and bleeding. Pediatric patients with diastolic heart failure comprise a high risk population for mechanical circulatory support. However, half of patients with this physiology have been successfully supported to explant with EXCOR(r) . The trends toward higher mortality for younger patients and those receiving BiVAD support warrant consideration. PMID- 28905471 TI - Novel assessment tool to detect breathing pattern disorder in patients with refractory asthma. AB - BACKGROUND AND OBJECTIVE: Breathing pattern disorder (BPD) can co-exist with and mimic asthma, acting to amplify symptoms and confound assessment of disease control, resulting in inappropriate treatment escalation. The aim of this research was to report the utility of a novel breathing pattern assessment tool (BPAT) to detect BPD in treatment-refractory asthma. METHODS: As a component of a multidisciplinary assessment, adult patients referred with treatment-refractory asthma underwent respiratory physiotherapy assessment to diagnose BPD. Based on this assessment, patients were classified as having asthma, asthma + BPD or BPD alone. BPAT data were collected in addition to questionnaire data (Asthma Quality of Life Questionnaire (AQLQ) and Nijmegen Questionnaire (NQ)), pulmonary function and an assessment of exercise capacity. RESULTS: Data were retrospectively analysed for 150 (female; 69%) patients, mean (SD) age of 43 (14) years; characterized as asthma-only (n = 54, 36%), asthma + BPD (n = 63, 42%) and BPD only (n = 33, 22%). Of the total population, 113 (76%) had an NQ score >=23, but of these only 68% had physiotherapy evidence of BPD. Exercise capacity and AQLQ were lower in the asthma + BPD group than in the asthma-only group (P < 0.05), whilst lung function was similar between groups. Sensitivity analysis indicated that a BPAT score of >=4 corresponded to a sensitivity of 0.92 and a specificity of 0.75 for diagnosis of BPD in this cohort. CONCLUSION: Breathing pattern irregularities are highly prevalent in individuals referred with treatment refractory asthma and can be characterized using the BPAT. Further work is needed to determine inter-observer and within-subject variability and ensure the BPAT is a robust clinical tool. Watch the video abstract. PMID- 28905472 TI - Design paper: Japan Endoscopy Database (JED): A prospective, large database project related to gastroenterological endoscopy in Japan. AB - The advent of electronic medical records brought image filing systems to many hospitals, as well as electronic endoscopic medical records. However, data integration among multiple different vendors has not yet been accomplished. We start the Japan Endoscopic Database (JED) Project endorsed by Japan Gastroenterological Endoscopy Society (JGES) from January 2015. The purposes of this project are as follows: (i) developing the world's largest endoscopic database generated from daily use of the reporting system; (ii) capturing the actual performance of endoscopic practice in Japan; and (iii) standardizing the terminology and fundamental items for registry of clinical studies. Moreover, the JED project has the potential to automatically collect data about adverse events, competency and evaluation of residents, and actual numbers of procedures on a nationwide scale, certification for the specialty board system, and so on. We believe that this design paper will be helpful not only for future nationwide research but also for international research (UMIN000016093). PMID- 28905473 TI - Does multigenerational exposure to hormetic concentrations of imidacloprid precondition aphids for increased insecticide tolerance? AB - BACKGROUND: Hormetic preconditioning, whereby exposure to mild stress primes an organism to better tolerate subsequent stress, is well documented. It is unknown if exposure to hormetic concentrations of insecticide can trans-generationally prime insects to better tolerate insecticide exposure, or whether exposure to hormetic concentrations of insecticide can induce mutations in genes responsible for insecticide resistance. Using the aphid Myzus persicae (Sulzer) and the insecticide imidacloprid as a model, we examined if exposure to mildly toxic and hormetic concentrations of imidacloprid reduced aphid susceptibility to insecticides across four generations, and whether such exposures induced mutations in the imidacloprid binding site in post-synaptic nicotinic acetylcholine receptors. RESULTS: Chronic, multigenerational exposure of aphids to hormetic concentrations of imidacloprid primed offspring to better survive exposure to certain concentrations of imidacloprid, but not exposure to spirotetramat, an insecticide with a different mode of action. Exposure to hormetic and mildly toxic concentrations of imidacloprid did not result in mutations in any of the examined nicotinic acetylcholine receptor subunits. CONCLUSION: Our findings demonstrate that exposure to hormetic concentrations of insecticide can prime insects to better withstand subsequent chemical stress, but this is dependent upon the insecticide exposure scenario, and may be subtle over generations. (c) 2017 Society of Chemical Industry. PMID- 28905474 TI - Steer-PROP: a GRASE-PROPELLER sequence with interecho steering gradient pulses. AB - PURPOSE: This study demonstrates a novel PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) pulse sequence, termed Steer-PROP, based on gradient and spin echo (GRASE), to reduce the imaging times and address phase errors inherent to GRASE. The study also illustrates the feasibility of using Steer-PROP as an alternative to single-shot echo planar imaging (SS-EPI) to produce distortion-free diffusion images in all imaging planes. METHODS: Steer-PROP uses a series of blip gradient pulses to produce N (N = 3-5) adjacent k-space blades in each repetition time, where N is the number of gradient echoes in a GRASE sequence. This sampling strategy enables a phase correction algorithm to systematically address the GRASE phase errors as well as the motion-induced phase inconsistency. Steer-PROP was evaluated on phantoms and healthy human subjects at both 1.5T and 3.0T for T2 - and diffusion-weighted imaging. RESULTS: Steer-PROP produced similar image quality as conventional PROPELLER based on fast spin echo (FSE), while taking only a fraction (e.g., 1/3) of the scan time. The robustness against motion in Steer-PROP was comparable to that of FSE-based PROPELLER. Using Steer-PROP, high quality and distortion-free diffusion images were obtained from human subjects in all imaging planes, demonstrating a considerable advantage over SS-EPI. CONCLUSION: The proposed Steer-PROP sequence can substantially reduce the scan times compared with FSE based PROPELLER while achieving adequate image quality. The novel k-space sampling strategy in Steer-PROP not only enables an integrated phase correction method that addresses various sources of phase errors, but also minimizes the echo spacing compared with alternative sampling strategies. Steer-PROP can also be a viable alternative to SS-EPI to decrease image distortion in all imaging planes. Magn Reson Med 79:2533-2541, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905475 TI - Evaluation of volumetric dimensional changes in posterior extraction sites with and without ARP using a novel imaging device. AB - BACKGROUND: Alveolar ridge volume loss may be minimized when postextraction sockets are filled by bone substitutes. PURPOSE: The aim of the study was to measure the effect of alveolar ridge preservation (ARP) in maintaining the external contour of the ridge after fresh socket grafting with or without particulate anorganic bovine bone mineral (BBM) and resorbable barrier covering. MATERIALS AND METHODS: In the present controlled study, patients subjected to single-tooth extraction were allocated to 2 groups: postextraction sockets grafted with bovine bone mineral (bbm), and naturally healing sockets (nat). Before and at 5 months following tooth extraction, plaster cast contours of the sockets were acquired by means of an optical scanner; the 2 contours of each patient underwent voxelization and fusion using a matrix elaborator. Outcome variables at 5 months (volumetric, surface, and linear changes) were measured in digital fused plaster casts with a dental scan software analyzing a volume of interest ranging from residual papilla to 10 mm toward the apical point. Intra- and inter-group pair-wise variables' comparisons were conducted. Level of significance was set at 0.05. RESULTS: Twenty-four sites were enrolled: 12 ARP and 12 naturally healed. Five-month percentage of volume loss of the bbm-group (21.7% +/- 7.4%) was significantly lower (Ps < .0003) than that of the naturally healing group (38.8% +/- 7.9%). When tooth position was investigated, volume loss in percentage registered a significantly better (P values <= .0485) behavior in molars (DeltaV% = -19.1% +/- 6.5% and DeltaV% = -35.6% +/- 7.6%, respectively, for bbm and nat) than that in premolars (DeltaV% = -26.9% +/- 7.2% and DeltaV% = 45.1% +/- 4.2%, respectively, for bbm and nat), in both the preserved and naturally healing groups. CONCLUSION: The dimensional loss in postextraction sockets grafted with anorganic bovine bone substitute and covered by a resorbable collagen barrier was lower than that of the naturally healing sites. However, ridge preservation was able to maintain almost 80% of the pristine bone. PMID- 28905476 TI - Increased frequency of CD45 negative T cells (T zone cells) in older Golden retriever dogs. AB - T zone lymphoma (TZL) is characterized by the clonal expansion of T cells lacking expression of the pan-leukocyte antigen CD45 (TZ cells). A strong breed predisposition is observed in Golden retrievers. This study aimed to confirm aberrant CD45 mRNA expression and determine if Golden retrievers without clinical lymphoma have an increased frequency of circulating TZ cells. Gene expression analysis on confirmed TZL cases showed a significant decrease in CD45 expression compared to normal dogs. Peripheral blood samples from senior dogs, 242 Golden retrievers and 42 non-Golden retrievers, without evidence of lymphoproliferative disease were assessed for the presence of TZ cells by flow cytometry. Thirty-one percent of Golden retrievers had TZ cells compared to 14% of non-Golden retrievers. Thirty-four percent of Golden retrievers with TZ cells had a clonal T cell receptor gamma (TRG) gene rearrangement. Interestingly, 20% of Golden retrievers without TZ cells also had a clonal TRG rearrangement. Golden retrievers may have an increased risk of TZL due to an increased frequency of TZ cells. PMID- 28905477 TI - A HD-ZIP III gene, PtrHB4, is required for interfascicular cambium development in Populus. AB - Wood production is dependent on the activity of the vascular cambium, which develops from the fascicular and interfascicular cambia. However, little is known about the mechanisms controlling how the vascular cambium is developed in woody species. Here, we show that PtrHB4, belonging to the Populus HD-ZIP III family, plays a critical role in the process of vascular cambium development. PtrHB4 was specifically expressed in shoot tip and stem vascular tissue at an early developmental stage. Repression of PtrHB4 caused defects in the development of the secondary vascular system due to failures in interfascicular cambium formation. By contrast, overexpression of PtrHB4 induced cambium activity and xylem differentiation during secondary vascular development. Transcriptional analysis of PtrHB4 repressed plants indicated that auxin response and cell proliferation were affected in the formation of the interfascicular cambium. Taken together, these results suggest that PtrHB4 is required for interfascicular cambium formation to develop the vascular cambium in woody species. PMID- 28905479 TI - Abstracts of the Irish Society of Urology Annual Meeting, 15-16 September 2017, Kingsley Hotel, Cork, Ireland. PMID- 28905480 TI - Biogas. AB - Biogas production represents a fascinating process for the recovery of nutrients and renewable energy from various organic waste streams. The process is of interest for the production of value-added chemicals by mixed cultures and can also be applied in combined bioenergy production systems. Strategies and opportunities for optimization of biogas quality and quantity are presented. PMID- 28905478 TI - Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. AB - AIMS: To investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy. METHODS: Participants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels >=1.8 mmol/L (>=70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double-blind treatment. Alirocumab-treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were >=1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments. RESULTS: Alirocumab reduced LDL cholesterol from baseline to week 24 by a mean +/- standard error of 49.0% +/- 2.7% and 47.8% +/- 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non-HDL cholesterol (P < .0001), apolipoprotein B (P < .0001) and lipoprotein (a) (P <= .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations (P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment-emergent adverse events were observed in 64.5% of alirocumab- vs 64.1% of placebo-treated individuals (overall population). CONCLUSIONS: Alirocumab produced significant LDL cholesterol reductions in participants with insulin-treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778). PMID- 28905481 TI - Reducing copper use in the environment: the use of larixol and larixyl acetate to treat downy mildew caused by Plasmopara viticola in viticulture. AB - BACKGROUND: Plant extracts might provide sustainable alternatives to copper fungicides, which are still widely used despite their unfavourable ecotoxicological profile. Larch bark extract and its constituents, larixyl acetate and larixol, have been shown to be effective against grapevine downy mildew (Plasmopara viticola) under semi-controlled conditions. The aim of this study was to reduce the gap between innovation and the registration of a marketable product, namely to develop scalable extraction processes and to evaluate and optimise the performance of larch extracts under different conditions. RESULTS: Toxicologically and technically acceptable solvents like ethanol were used to extract the active compounds larixyl acetate and larixol from bark in sufficient amounts and their combined concentration could be increased by up to 39% by purification steps. The combined concentration of larixyl acetate and larixol from larch turpentine could be increased by up to 66%. The Minimal Inhibitory Concentration (MIC100 ) against P. viticola in vitro (6-23 ug mL-1 ) and the Effective Concentration (EC50 ) in planta under semi controlled conditions (0.2-0.4 mg mL-1 ) were promising compared with other plant extracts. In vineyards, efficacies of larch extracts reached up to 68% in a stand alone strategy and 84% in low-copper strategies. CONCLUSION: Larch extracts represent valid candidates for copper reduction in organic vineyards, and their development into a sustainable plant protection product might be feasible. (c) 2017 Society of Chemical Industry. PMID- 28905482 TI - Energy drink consumption among New Zealand adolescents: Associations with mental health, health risk behaviours and body size. AB - AIM: With the increase in popularity of energy drinks come multiple concerns about the associated health indicators of young people. The current study aims to describe the frequency of consumption of energy drinks in a nationally representative sample of adolescents and to explore the relationship between energy drink consumption and health risk behaviours, body size and mental health. METHODS: Data were collected as part of Youth'12, a nationally representative survey of high school students in New Zealand (2012). In total, 8500 students answered a comprehensive questionnaire about their health and well-being, including multiple measures of mental well-being, and were weighed and measured for height. RESULTS: More than one-third (35%) of young people consumed energy drinks in the past week, and 12% consumed energy drinks four or more times in the past week. Energy drink consumption was significantly associated with greater depressive symptoms, greater emotional difficulties and lower general subjective well-being. Frequent energy drink consumption was also associated with binge drinking, smoking, engagement in unsafe sex, violent behaviours, risky motor vehicle use and disordered eating behaviours. There was no association between consumption of energy drinks and student body size. CONCLUSIONS: Consumption of energy drinks is associated with a range of health risk behaviours for young people. Strategies to limit consumption of energy drinks by young people are warranted. PMID- 28905483 TI - Lung cancer in young women in southern Sweden: A descriptive study. AB - INTRODUCTION: Lung cancer, a common malignancy and cause of cancer-related deaths, is strongly linked to several environmental exposures, and thus primarily affects the elderly. Formerly a man's disease, its incidence is rising among women, and lung cancer is now more common in women than men in Sweden. Women are particularly over-represented among young patients. While overall cancer mortality in Europe is decreasing, female lung cancer mortality is increasing. OBJECTIVES: We describe the epidemiological presentation of lung cancer in young Swedish women, aiming to pinpoint its risk factors for young women. METHODS: 1159 women with newly diagnosed lung cancer in southern Sweden 1997-2015 answered questionnaires on their lifestyles and personal and family medical histories. We identified those below age 50. RESULTS: 70 (6.0%) of 1159 women were below age 50. Most (n = 49, 70.0%) were aged 45-50; eight (11.4%) were below age 40. The most common lung cancer subtype was adenocarcinoma (n = 33, 47.1%). 12.9% (n = 9) had carcinoid tumors. Most women reported both first- and second-hand tobacco smoke exposure (n = 54, 77.1%); 2.9% (n = 2) reported neither. 17.1% (n = 12) were never-smokers. 34.3% (n = 24) reported frequent X-ray radiation exposure. 78.6% reported at least one near relative with cancer. 25.7% reported relatives with lung cancer. CONCLUSIONS: Lung cancer remains rare in young women, and tobacco smoke exposure is the single greatest risk factor, even for never smokers. Thus, avoiding tobacco smoke exposure remains the most important preventive measure against lung cancer for young women in Sweden and elsewhere. PMID- 28905484 TI - Occult Hepatitis B Virus Infection With Increased Virus DNA Levels in a Chronic Hemodialysis Patient. PMID- 28905485 TI - Public expenditure costs of carers leaving employment in England, 2015/2016. AB - In the context of global population ageing, the reconciliation of employment and unpaid caring is becoming an important social issue. The estimation of the public expenditure costs of carers leaving employment is a valuable measure that is of considerable interest to policy makers. In 2012, the Personal Social Services Research Unit estimated that the public expenditure costs of unpaid carers leaving employment in England were approximately L1.3 billion a year, based on the costs of Carer's Allowance and lost tax revenues on forgone incomes. However, this figure was known to be an underestimate partly because it did not include other key benefits that carers who have given up work to care may receive. This paper presents a new estimate of the public expenditure costs of carers leaving employment. Key sources of information are the 2009/2010 Survey of Carers in Households, 2011 Census and 2015/2016 costs data. As well as Carer's Allowance, the estimate also now includes the costs of other benefits that carers leaving work may receive, namely, Income Support and Housing Benefit. The results show that the estimated numbers of carers who have left employment because of caring have increased from approximately 315,000 to 345,000. Due mainly to the inclusion of a wider range of benefits, the public expenditure costs of carers leaving employment in England are now estimated at L2.9 billion a year. The new estimate comprises L1.7 billion in social security benefits paid to people who have left their jobs because of unpaid caring, plus another L1.2 billion in taxes forgone on this group's lost earnings. The paper concludes that, if there was greater public investment in social care, such as "replacement care" to support carers in employment, and fewer carers then left employment, public spending on benefits would be lower and revenues from taxation would be higher. PMID- 28905487 TI - Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development. AB - GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABAA receptors (GABAA Rs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABAA Rs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABAA R are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABAA R function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABAA R subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABAA R-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABAA R interaction early in life may contribute to psychiatric conditions later in life. PMID- 28905486 TI - Peri-operative allogeneic blood transfusion does not adversely affect oncological outcomes after radical cystectomy for urinary bladder cancer: a propensity score weighted European multicentre study. AB - OBJECTIVES: To evaluate the effect of peri-operative blood transfusion (PBT) on recurrence-free survival, overall survival, cancer-specific mortality and other cause mortality in patients undergoing radical cystectomy (RC), using a contemporary European multicentre cohort. PATIENTS AND METHODS: The Prospective Multicentre Radical Cystectomy Series (PROMETRICS) includes data on 679 patients who underwent RC at 18 European tertiary care centres in 2011. The association between PBT and oncological survival outcomes was assessed using Kaplan-Meier, Cox regression and competing-risks analyses. Imbalances in clinicopathological features between patients receiving PBT vs those not receiving PBT were mitigated using conventional multivariable adjusting as well as inverse probability of treatment weighting (IPTW). RESULTS: Overall, 611 patients had complete information on PBT, and 315 (51.6%) received PBT. The two groups (PBT vs no PBT) differed significantly with respect to most clinicopathological features, including peri-operative blood loss: median (interquartile range [IQR]) 1000 (600 1500) mL vs 500 (400-800) mL (P < 0.001). Independent predictors of receipt of PBT in multivariable logistic regression analysis were female gender (odds ratio [OR] 5.05, 95% confidence interval [CI] 2.62-9.71; P < 0.001), body mass index (OR 0.91, 95% CI 0.87-0.95; P < 0.001), type of urinary diversion (OR 0.38, 95% CI 0.18-0.82; P = 0.013), blood loss (OR 1.32, 95% CI 1.23-1.40; P < 0.001), neoadjuvant chemotherapy (OR 2.62, 95% CI 1.37-5.00; P = 0.004), and >=pT3 tumours (OR 1.59, 95% CI 1.02-2.48; P = 0.041). In 531 patients with complete data on survival outcomes, unweighted and unadjusted survival analyses showed worse overall survival, cancer-specific mortality and other-cause mortality rates for patients receiving PBT(P < 0.001, P = 0.017 and P = 0.001, respectively). After IPTW adjustment, those differences no longer held true. PBT was not associated with recurrence-free survival (hazard ratio [HR] 0.92, 95% CI 0.53 1.58; P = 0.8), overall survival (HR 1.06, 95% CI 0.55-2.05; P = 0.9), cancer specific mortality (sub-HR 1.09, 95% CI 0.62-1.92; P = 0.8) and other-cause mortality (sub-HR 1.00, 95% CI 0.26-3.85; P > 0.9) in IPTW-adjusted Cox regression and competing-risks analyses. The same held true in conventional multivariable Cox and competing-risks analyses, where PBT could not be confirmed as a predictor of any given endpoint (all P values >0.05). CONCLUSION: The present results did not show an adverse effect of PBT on oncological outcomes after adjusting for baseline differences in patient characteristics. PMID- 28905488 TI - Genetically engineering better fungal biopesticides. AB - Microbial insect pathogens offer an alternative means of pest control with the potential to wean us off our heavy reliance on chemical pesticides. Insect pathogenic fungi play an important natural role in controlling disease vectors and agricultural pests. Most commercial products employ Ascomycetes in the genera Metarhizium and Beauveria. However, their utilization has been limited by inconsistent field results as a consequence of sensitivity to abiotic stresses and naturally low virulence. Other naturally occurring biocontrol agents also face these hurdles to successful application, but the availability of complete genomes and recombinant DNA technologies have facilitated design of multiple fungal pathogens with enhanced virulence and stress resistance. Many natural and synthetic genes have been inserted into entomopathogen genomes. Some of the biggest gains in virulence have been obtained using genes encoding neurotoxic peptides, peptides that manipulate host physiology and proteases and chitinases that degrade the insect cuticle. Prokaryotes, particularly extremophiles, are useful sources of genes for improving entomopathogen resistance to ultraviolet (UV) radiation. These biological insecticides are environmentally friendly and cost-effective insect pest control options. (c) 2017 Society of Chemical Industry. PMID- 28905489 TI - Consensus and controversies regarding the treatment of rhabdomyosarcoma. AB - Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients. PMID- 28905490 TI - Intrinsic Broadband White-Light Emission from Ultrastable, Cationic Lead Halide Layered Materials. AB - We report a family of cationic lead halide layered materials, formulated as [Pb2 X2 ]2+ [- O2 C(CH)2 CO2- ] (X=F, Cl, Br), exhibiting pronounced broadband white light emission in bulk form. These well-defined PbX-based structures achieve an external quantum efficiency as high as 11.8 %, which is comparable to the highest reported value (ca.9 %) for broadband phosphors based on layered organolead halide perovskites. More importantly, our cationic materials are ultrastable lead halide materials, which overcome the air/moisture-sensitivity problems of lead perovskites. In contrast to the perovskites and other bulk emitters, the white light emission intensity of our materials remains undiminished after continuous UV irradiation for 30 days under atmospheric conditions (ca.60 % relative humidity). Our mechanistic studies confirm that the broadband emission is ascribed to short-range electron-phonon coupling in the strongly deformable lattice and generated self-trapped carriers. PMID- 28905491 TI - Expressions of p53 and PUMA in fibroblasts of systemic sclerosis patients are normal at transcription level. AB - BACKGROUND: Systemic sclerosis (SSc) fibroblasts show resistance apoptosis mechanisms, which enhances the fibrosis stage of the disease. Impaired function of p53 upregulated modulator of apoptosis (PUMA) has been related to deficits in p53-dependant apoptosis pathway. This study aimed to evaluate the transcriptional levels of p53 and PUMA mRNAs in fibroblasts from SSc patients and compare it with healthy individuals. METHODS: In this case-control study, skin biopsy samples were obtained from 19 patients with diffuse cutaneous SSc (DcSSc) and 16 healthy controls. Afterward, dermal fibroblasts were isolated and cultured. After extraction of total RNA from cultured fibroblasts, complementary DNA (cDNA) was synthesized. mRNA quantification was carried out using real-time PCR, SYBR Green PCR master mix, and specific primers for p53 and PUMA. RESULTS: No significant alteration was observed in mRNA expression levels of p53 and PUMA (P = .99 and .23, respectively) in fibroblasts from SSc patients compared with controls. CONCLUSIONS: Apoptosis pathways are impaired in fibroblasts from patients with SSc, leading to chronic fibrosis. Nonetheless, PUMA/p53 pathway may not be involved in dysfunction of apoptosis mechanisms in fibroblasts of patients with SSc. PMID- 28905493 TI - Current status of robotic surgery in urology. AB - As a result of ergonomics, optimal magnification of the operative field, surgeon dexterity, and precision of surgical manipulation, robotic technology has been shown to overcome many difficulties associated with pure laparoscopy. With the recent expansion of robot-assisted surgery in the field of urology and following the success of robot-assisted prostatectomy and robot-assisted partial nephrectomy, robot-assisted surgery is being applied to treat many other genitourinary diseases, such as bladder cancer and ureteropelvic junction obstruction. The aim of the present review is to discuss the role of robotic surgery in urology and summarize recent developments in the field of urologic robotic surgery. PMID- 28905494 TI - Atopic Dermatitis, The Skin-Disease. PMID- 28905495 TI - Topical skin care - a domain for allergy prevention. PMID- 28905496 TI - Microbial biotechnologies for potable water production. PMID- 28905497 TI - Alveolar soft part sarcoma: A case report with emphasis on some unusual cytological features. AB - Alveolar soft part sarcoma is a very rare, slow growing highly angiogenic tumor with poor prognosis. Most common site in children and infants is head and neck region and in adults it most commonly occurs in extremities especially thigh. In our case study, an 8 years old female patient presented with a gradually progressive left shoulder lump. FNAC from the lesion showed cellular smears with polyhedral and spindly cells showing abundant finely vacuolated cytoplasm, nuclear pleomorphism, intranuclear pseudoinclusions, and few bare nuclei. Perivascular arrangement of cells was peculiar in addition to the presence of intracytoplasmic metachromatic PAS positive diastase resistant granules. A presumptive diagnosis of alveolar soft part sarcoma with differentials of granular cell tumor and PEComa was considered and the lesion was excised. Although the histopathological features were not characteristic (ie, showing mainly solid pattern without classic alveolar pattern), immunohistochemistry were diagnostic (negative for S 100, Desmin, Cytokeratin, EMA, and moderate to strong nuclear positivity for TFE3). Thus, the diagnosis of alveolar soft part sarcoma was established. This case is being presented for its rarity and unique cytological and histopathological features. PMID- 28905499 TI - Metabolic diseases: Breakthrough discoveries in diabetes and obesity. PMID- 28905498 TI - Effect of bimagrumab on thigh muscle volume and composition in men with casting induced atrophy. AB - BACKGROUND: Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization. METHODS: In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. RESULTS: Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. CONCLUSIONS: A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast. PMID- 28905501 TI - Outbreak of tularaemia connected to a contaminated well in the Vastra Gotaland region in Sweden. AB - Tularaemia, is a zoonotic disease caused by the bacterium Francisella tularensis. This disease has been reported in Sweden since 1931 and its wide distribution in the country poses a challenge for understanding the transmission, ecology and epidemiology of the disease. In Sweden, the disease is usually transmitted by mosquitoes, but in this study we could show that consumption of well water was epidemiologically linked to the outbreak, by isolating F. tularensis from the water. In this article, we describe an outbreak of tularaemia in the region of Vastra Gotaland in the southwest of Sweden in spring of 2013. PMID- 28905500 TI - Salidroside suppressing LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo. AB - The purpose of the present study was to investigate the effect of salidroside (Sal) on myocardial injury in lipopolysaccharide (LPS)-induced endotoxemic in vitro and in vivo. SD rats were randomly divided into five groups: control group, LPS group (15 mg/kg), LPS plus dexamethasone (2 mg/kg), LPS plus Sal groups with different Sal doses (20, 40 mg/kg). Hemodynamic measurement and haematoxylin and eosin staining were performed. Serum levels of creatine kinase (CK), lactate dehydrogenase, the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), glutathione, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) were measured after the rats were killed. iNOS, COX-2, NF-kappaB and PI3K/Akt/mTOR pathway proteins were detected by Western blot. In vitro, we evaluated the protective effect of Sal on rat embryonic heart-derived myogenic cell line H9c2 induced by LPS. Reactive oxygen species (ROS) in H9c2 cells was measured by flow cytometry, and the activities of the antioxidant enzymes CAT, SOD, GSH-px, glutathione-S-transferase, TNF-alpha, IL-6 and IL-1beta in cellular supernatant were measured. PI3K/Akt/mTOR signalling was examined by Western blot. As a result, Sal significantly attenuated the above indices. In addition, Sal exerts pronounced cardioprotective effect in rats subjected to LPS possibly through inhibiting the iNOS, COX-2, NF-kappaB and PI3K/Akt/mTOR pathway in vivo. Furthermore, the pharmacological effect of Sal associated with the ROS-mediated PI3K/Akt/mTOR pathway was proved by the use of ROS scavenger, N-acetyl-l cysteine, in LPS-stimulated H9C2 cells. Our results indicated that Sal could be a potential therapeutic agent for the treatment of cardiovascular disease. PMID- 28905502 TI - Prevalence trends of selected major birth defects: A multi-state population-based retrospective study, United States, 1999 to 2007. AB - BACKGROUND: We evaluated selected birth defects over a 9-year period to assess prevalence trends by selected maternal and infant factors. METHODS: Data were pooled from 11 population-based birth defects surveillance programs in the United States for children born between 1999 and 2007. Overall prevalence, as well as 3 year interval prevalence, was calculated for 26 specific birth defects, stratified by maternal age, maternal race/ethnicity, and infant sex. Average annual percent change (AAPC) was calculated for each birth defect. Poisson regression was used to determine change in AAPC, and joinpoint regression to identify breakpoints and changes in slope for prevalence of each defect over time. RESULTS: Between 1999 and 2001 and 2005 and 2007, four birth defects increased by 10% or more: coarctation of the aorta (17%), gastroschisis (83%), omphalocele (11%), and Down syndrome (10%). Among mothers <20 years of age, the gastroschisis AAPC increased 10.1% overall and, cross-classified by maternal race/ethnicity, the AAPC for mothers <20 years increased 9.2%, 25.7%, and 7.7% among non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic mothers, respectively. A small increase in Down syndrome (AAPC 4.4%) was found for NHB mothers >=35 years. CONCLUSION: No significant trends in prevalence were identified for most birth defects. Gastroschisis prevalence increased significantly among NHW and NHB mothers <20 years of age, with the greatest increases in NHB mothers. Prevalence of Down syndrome among NHB mothers >=35 years also increased slightly. Stratified results may suggest avenues of research in birth defect etiology and in evaluating prevention efforts. Birth Defects Research 109:1442-1450, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28905503 TI - The complex interplay between systolic and diastolic function at rest and during exercise in heart failure: the case of cardiac amyloidosis. PMID- 28905504 TI - Is essential tremor a single entity? AB - Essential tremor (ET) is a frequent movement disorder. The new tremor classification has subdivided ET into the classical form with bilateral action tremor of the hands with or without involvement of further tremor locations and without any other explaining signs or symptoms for the tremor and into 'ET plus' which comes additionally with further neurological signs of unknown origin. This will provide a better foundation for subclassifying the condition. The immediate cause of ET is a preformed oscillating network within the central nervous system as revealed with electrophysiological methods. The reason why this network is getting into the tremor mode is unclear. Pathology has so far not convincingly proved neurodegeneration for the condition but possibly adaptive changes of the brain particularly in the cerebellum are likely. Genetics have not yet provided insight into the molecular causes of the condition but several genetic diseases presenting with an ET syndrome have been uncovered. Treatment options cover medication (propranolol, primidone, topiramate) and surgical interventions with deep brain stimulation, gamma-knife surgery and the recently introduced magnetic resonance imaging guided focused ultrasound lesioning. Further progress is awaited from the better integration of large prospective cohort assessment and basic science studies on the possible etiologies. In particular, aging-related tremor may explain a large number of the patients seen in clinical practice. Currently ET is considered a clinically relatively uniform condition with presumably various underlying etiologies. PMID- 28905506 TI - Nutritive value and fermentation quality of palisadegrass and stylo mixed silages. AB - The nutritive value and fermentation quality of palisadegrass (Brachiaria brizantha cv. Xaraes) and stylo (Stylosanthes capitata * S. macrocephala cv. Campo Grande) mixed silages were evaluated. The experiment was analyzed in a factorial scheme (5 * 2) in a completely randomized design using increasing levels of stylo (0, 25, 50, 75 and 100% on a fresh matter basis) on palisadegrass silages, with and without microbial inoculants (MI). With the increased ratio of stylo in mixed silages, dry matter (DM), crude protein (CP), acid detergent fiber (ADF), and lignin content increased in silages. The presence of MI promoted lower DM content, and higher neutral detergent fiber corrected for ash and protein, ADF and lignin content. The acid detergent insoluble nitrogen content and the lactic acid bacteria populations were not affected by treatments. The in vitroDM digestibility was affected by the interaction of levels of the stylo and MI. The pH, NH3 -N/total nitrogen and butyric acid concentrations decreased with increasing levels of stylo. Better nutritive value and quality of fermentation was found in the silage containing higher proportions of this stylo mixed with palisadegrass. The microbial inoculant evaluated did not alter the nutritive value or quality of the fermentation of the silages in this experiment. PMID- 28905507 TI - September 2017 at a glance: epidemiology, prognosis, Mediterranean diet and different viewpoints on aspirin. PMID- 28905505 TI - Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. AB - Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC 6.1.1.2). Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability. Respiratory chain enzymes were usually normal in muscle and fibroblasts, while a severe combined respiratory chain deficiency was found in the liver of a severely affected individual. Exome sequencing revealed rare biallelic variants in WARS2 in all affected individuals. An increase of uncharged mitochondrial tRNATrp and a decrease of mtTrpRS protein content were found in fibroblasts of affected individuals. We hereby define the clinical, neuroradiological, and metabolic phenotype of WARS2 defects. This confidently implicates that mutations in WARS2 cause mitochondrial disease with a broad spectrum of clinical presentation. PMID- 28905508 TI - Tandem thiotepa with autologous hematopoietic cell rescue in patients with recurrent, refractory, or poor prognosis solid tumor malignancies. AB - BACKGROUND: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE: Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS: Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS: Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT. PMID- 28905510 TI - Corrigendum. PMID- 28905509 TI - De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus. AB - Although rare, 3p microdeletion cases have been well described in the clinical literature. The clinical phenotype includes; intellectual disability (ID), growth retardation, facial dysmorphism, and cardiac malformations. Advances in chromosome microarray (CMA) testing narrowed the 3p25 critical region to a 124 kb region, and recent Whole Exome Sequencing (WES) studies have suggested that the SETD5 gene contributes significantly to the 3p25 phenotype. Loss-of-Function (LoF) variants in SETD5 are now considered a likely cause of ID. We report here a patient with a frameshift LoF variant in exon 12 of SETD5. This patient has features overlapping with other patients described with LoF SETD5 variants to include; similar facial morphology, feeding difficulties, ID, behavioral abnormalities and leg length discrepancy. In addition, he presents with an aberrant blind ending bronchus. This report adds to publications describing intragenic mutations in SETD5 and supports the assertion that de novo LoF mutations in SETD5 present with an overlapping but distinct phenotype in comparison with 3p25 microdeletion syndromes. PMID- 28905511 TI - TALEN-mediated targeted mutagenesis of more than 100 COMT copies/alleles in highly polyploid sugarcane improves saccharification efficiency without compromising biomass yield. AB - Sugarcane is the world's most efficient feedstock for commercial production of bioethanol due to its superior biomass production and accumulation of sucrose in stems. Integrating first- and second-generation ethanol conversion processes will enhance the biofuel yield per unit area by utilizing both sucrose and cell wall bound sugars for fermentation. RNAi suppression of the lignin biosynthetic gene caffeic acid O-methyltransferase (COMT) has been demonstrated to improve bioethanol production from lignocellulosic biomass. Genome editing has been used in a number of crops for creation of loss of function phenotypes but is very challenging in sugarcane due to its highly polyploid genome. In this study, a conserved region of COMT was targeted with a single-transcription activator-like effector nuclease (TALEN) pair for multi-allelic mutagenesis to modify lignin biosynthesis in sugarcane. Field-grown TALEN-mediated COMT mutants showed up to 19.7% lignin reduction and significantly decreased syringyl to guaiacyl (S/G) ratio resulting in an up to 43.8% improved saccharification efficiency. Biomass production of COMT mutant lines with superior saccharification efficiency did not differ significantly from the original cultivar under replicated field conditions. Sanger sequencing of cloned COMT amplicons (1351-1657 bp) revealed co editing of 107 of the 109 unique COMT copies/alleles in vegetative progeny of line CB6 using a single TALEN pair. Line CB6 combined altered cell wall composition and drastically improved saccharification efficiency with good agronomic performance. These findings confirm the feasibility of co-mutagenesis of a very large number of target alleles/copies for improvement in crops with complex genomes. PMID- 28905512 TI - Comparison of molecular interactions of Ag2 Te and CdTe quantum dots with human serum albumin by spectroscopic approaches. AB - Ag2 Te quantum dots (QDs) have attracted great attention in biological applications due to their superior photoluminescence qualities and good biocompatibility, but their potential biotoxicity at a molecular biology level has been rarely discussed. In order to better understand the basic behavior of Ag2 Te QDs in biological systems and compare their biotoxicity to cadmium containing QDs, a series of spectroscopic measurements was applied to reveal the molecular interactions of Ag2 Te QDs and CdTe QDs with human serum albumin (HSA). Ag2 Te QDs and CdTe QDs statically quenched the intrinsic fluorescence of HSA by electrostatic interactions, but Ag2 Te QDs exhibited weaker quenching ability and weaker binding ability compared with CdTe QDs. Electrostatic interactions were the main binding forces and Sudlow's site I was the primary binding site during these binding interactions. Furthermore, micro-environmental and conformational variations of HSA were induced by their binding interactions with two QDs. Ag2 Te QDs caused less secondary structural and conformational change in HSA, illustrating the lower potential biotoxicity risk of Ag2 Te QDs. Our results systematically indicated the molecular binding mechanism of Ag2 Te QDs with HSA, which provided important information for possible toxicity risk of these cadmium free QDs to human health. PMID- 28905513 TI - Large cell neuroendocrine carcinoma of the maxillary sinus on fine needle aspiration cytology: Report of a rare case with a focus on pitfalls in diagnosis. AB - Head and neck large cell neuroendocrine carcinoma (LCNEC) is a rare high-grade malignant tumor with neuroendocrine differentiation. We report a case of LCNEC causing difficulty in cytological diagnosis. A 60-year-old man with right-sided face pain presented with a swelling at the right cheek, and he complained of right nasal obstruction and lacrimation. Preoperative fine-needle aspiration cytology (FNAC) showed high cellularity, with a moderate number of clusters of tumor cells on an abundant necrotic background. The clusters were arranged in sheet structures with palisading, and were cohesive with overlapping. The tumor cells had comparatively abundant cytoplasm, with conspicuous large, irregular nucleoli with a fine granular chromatin pattern. Mitotic figures were observed easily. On immunocytochemistry using LBC smear, tumor cells were negative for p40. High-grade carcinoma other than non-keratinizing squamous cell carcinoma was suggested from these findings on FNAC. The pretreatment histological biopsy sample revealed tumor cells with solid growth pattern, necrotic materials and large polygonal cells with abundant cytoplasm, fine granular chromatin, and conspicuous nucleoli. Head and neck LCNEC with abundant cytoplasm, fine granular chromatin patterns, prominent nucleoli, and necrotic background were very characteristic of LCNEC. If considered carefully, these findings can enable us to exclude the majority of non-keratinizing squamous cell carcinomas, and FNAC using ancillary technique can be very useful for proper diagnosis. PMID- 28905514 TI - Dosimetric characterization of GMS BT-125-1 125 I radioactive seed with Monte Carlo simulations and experimental measurement. AB - PURPOSE: To investigate the dosimetric characteristics of the new GMS BT-125-1 125 I radioactive seed, including dose rate constant, radial dose functions, and anisotropy functions. METHODS: Dosimetric parameters of GMS BT-125-1 125 I seed including dose rate constant, radial dose functions, and anisotropy functions were calculated using the Monte Carlo code of MCNP5, and measured with thermoluminescent dosimeters (TLDs). The results were compared with those of PharmaSeed BT-125-1, PharmaSeed BT-125-2 125 I, and model 6711 125 I seeds. RESULTS: The dose rate constant of GMS BT-125-1 125 I seed was 0.959 cGy.h-1.U-1, with the difference of 0.94%, 0.83%, and 0.73% compared with the PharmaSeed BT 125-1 125 I seed, PharmaSeed BT-125-2 125 I seed, and Model 6711 125 I seed, respectively. For radial dose function, the differences between the Monte Carlo and the experimental g(r) results were mostly within 10%. Monte Carlo results of g(r) for GMS BT-125-1 125 I seed were found in agreement (within 3.3%) with corresponding results for the PharmaSeed BT-125-2 125 I seed. The largest differences were 8.1% and 6.2% compared with PharmaSeed BT-125-1 125 I seed and model 6711 125 I seed, respectively. For anisotropy function, the difference between GMS BT-125-1 125 I seed and PharmaSeed BT-125-2 125 I seed was typically <10%. CONCLUSIONS: The measured dose rate constant, radial dose functions, and two-dimensional anisotropy functions for the GMS BT-125-1 125 I seed showed good agreement with the Monte Carlo results. The dose rate constant of the GMS BT-125 1 125 I seed is similar to that of the PharmaSeed BT-125-1 125 I seed, the PharmaSeed BT-125-2 125 I seed, and the model 6711 125 I seed. For radial dose functions and two-dimensional anisotropy functions, the GMS BT-125-1 125 I seed is similar to the PharmaSeed BT-125-2 125 I seed but different from the PharmaSeed BT-125-1 125 I seed and the model 6711 125 I seed. PMID- 28905516 TI - Simple method for RF pulse measurement using gradient reversal. AB - PURPOSE: To develop and evaluate a simple method for measuring the envelope of small-tip radiofrequency (RF) excitation waveforms in MRI, without extra hardware or synchronization. THEORY AND METHODS: Gradient reversal approach to evaluate RF (GRATER) involves RF excitation with a constant gradient and reversal of that gradient during signal reception to acquire the time-reversed version of an RF envelope. An outer-volume suppression prepulse is used optionally to preselect a uniform volume. GRATER was evaluated in phantom and in vivo experiments. It was compared with the programmed waveform and the traditional pick-up coil method. RESULTS: In uniform phantom experiments, pick-up coil, GRATER, and outer-volume suppression + GRATER matched the programmed waveforms to less than 2.1%, less than 6.1%, and less than 2.4% normalized root mean square error, respectively, for real RF pulses with flip angle less than or equal to 30 degrees , time bandwidth product 2 to 8, and two to five excitation bands. For flip angles greater than 30 degrees , GRATER measurement error increased as predicted by Bloch simulation. Fat-water phantom and in vivo experiments with outer-volume suppression + GRATER demonstrated less than 6.4% normalized root mean square error. CONCLUSIONS: The GRATER sequence measures small-tip RF envelopes without extra hardware or synchronization in just over two times the RF duration. The sequence may be useful in prescan calibration and for measurement and precompensation of RF amplifier nonlinearity. Magn Reson Med 79:2642-2651, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28905515 TI - CRISPR/Cas9-mediated efficient targeted mutagenesis in grape in the first generation. AB - The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is a powerful tool for editing plant genomes. Efficient genome editing of grape (Vitis vinifera) suspension cells using the type II CRISPR/Cas9 system has been demonstrated; however, it has not been established whether this system can be applied to get biallelic mutations in the first generation of grape. In this current study, we designed four guide RNAs for the VvWRKY52 transcription factor gene for using with the CRISPR/Cas9 system, and obtained transgenic plants via Agrobacterium-mediated transformation, using somatic embryos of the Thompson Seedless cultivar. Analysis of the first generation transgenic plants verified 22 mutant plants of the 72 T-DNA-inserted plants. Of these, 15 lines carried biallelic mutations and seven were heterozygous. A range of RNA-guided editing events, including large deletions, were found in the mutant plants, while smaller deletions comprised the majority of the detected mutations. Sequencing of potential off-target sites for all four targets revealed no off-target events. In addition, knockout of VvWRKY52 in grape increased the resistance to Botrytis cinerea. We conclude that the CRISPR/Cas9 system allows precise genome editing in the first generation of grape and represents a useful tool for gene functional analysis and grape molecular breeding. PMID- 28905517 TI - The prognostic significance of tricuspid valve regurgitation in pulmonary arterial hypertension. AB - INTRODUCTION: Tricuspid valve regurgitation (TR) is a frequent finding in patients with pulmonary arterial hypertension (PAH). However, its prognostic significance and relation to PAH, while suspected, are poorly understood. We assessed 727 consecutive patients with newly diagnosed PAH who underwent transthoracic echocardiographic evaluation of tricuspid valve function. OBJECTIVES: The study objective was to determine the association of TR presence and severity with patient characteristics, pulmonary artery hemodynamics and outcome. METHODS: Consecutive patients with newly diagnosed PAH (N = 727 with group 1 pulmonary hypertension) underwent transthoracic echocardiographic evaluation of tricuspid valve function at diagnosis. The primary study end point was all-cause mortality or lung transplantation. RESULTS: In this population, 702 patients (96.5%) had TR; in 165 patients (23%), TR was severe. Compared with those with no or mild TR by echocardiography criteria, patients with severe TR had shorter mean (SD) 6-minute walk distances (285 [125] m vs 360 [121] m; P = .02) and higher levels of B-type natriuretic peptide (695 [672] pg/dL vs 328 [300] pg/dL; P < .05). Severe TR was associated with greater right atrial dilatation (91% vs 47%; P = .004) and right ventricular (RV) dilatation (92% vs 51%; P = .008), greater right atrial pressure (mean [SD] 15 [7] mm Hg vs 10 [6] mm Hg; P < .001) and lower cardiac index (mean [SD], 2.2 [0.7] L/min/m2 vs 2.8 [0.9] L/min/m2; P < .001). Severe TR was strongly predictive of greater 5-year mortality risk after adjustment for age, sex, functional class, 6-minute walk distance, diffusing capacity, RV size and pulmonary vascular resistance index (adjusted hazard ratio, 1.83; 95% CI, 1.38-2.41; P < .001). CONCLUSIONS: Severe TR was a significant predictor of long-term mortality rate in PAH, and TR severity correlated with PAH severity. PMID- 28905519 TI - The cost of sarcopenia. PMID- 28905518 TI - Production of a novel medium chain length poly(3-hydroxyalkanoate) using unprocessed biodiesel waste and its evaluation as a tissue engineering scaffold. AB - This study demonstrated the utilization of unprocessed biodiesel waste as a carbon feedstock for Pseudomonas mendocinaCH50, for the production of PHAs. A PHA yield of 39.5% CDM was obtained using 5% (v/v) biodiesel waste substrate. Chemical analysis confirmed that the polymer produced was poly(3-hydroxyhexanoate co-3-hydroxyoctanoate-co-3-hydroxydecanoate-co-3-hydroxydodecanoate) or P(3HHx 3HO-3HD-3HDD). P(3HHx-3HO-3HD-3HDD) was further characterized and evaluated for its use as a tissue engineering scaffold (TES). This study demonstrated that P(3HHx-3HO-3HD-3HDD) was biocompatible with the C2C12 (myoblast) cell line. In fact, the % cell proliferation of C2C12 on the P(3HHx-3HO-3HD-3HDD) scaffold was 72% higher than the standard tissue culture plastic confirming that this novel PHA was indeed a promising new material for soft tissue engineering. PMID- 28905520 TI - Vaginal Enterobius vermicularis diagnosed on liquid-based cytology during Papanicolaou test cervical cancer screening: A report of two cases and a review of the literature. AB - Enterobiasis is one of the most common human parasitic infections. It is considered an intestinal parasite, but cases of extra-intestinal affections exist, notably infections of the female genital tract. Enterobius vermicularis (EV) eggs (or ova) have been found in the cervical smears of two patients in our institute during the last 16 years. No gynaecological or gastrointestinal symptoms were reported, and there was no known intestinal infection in these two cases. A review of the available literature revealed rare cases of vaginal enterobiasis, with a wide range of clinical presentations, many patients being asymptomatic. The diagnosis may sometimes be difficult, mainly because of the lack of clinical suspicion. However, cytological identification of EV in cervico vaginal smears is important, especially when considering the risk of ascending infections of the genital tract associated with severe complications. PMID- 28905521 TI - Covalently Assembled Monolayers of Homo- and Heteroleptic FeII -Terpyridyl Complexes on SiOx and ITO-Coated Glass Substrates: An Experimental and Theoretical Study. AB - Well-defined FeII -terpyridyl monolayers were fabricated on SiOx and conductive ITO-coated glass substrates through covalent-bond formation between the metallo organic complexes and a preassembled coupling layer. Three different homo- and heteroleptic complexes with terminal pyridyl, amine, and phenyl groups were tested. All the films were found to be densely packed and homogeneous, and consist of molecules standing upright. They exhibited high thermal (up to ~220 degrees C) and temporal (up to 5 h at 100 degrees C) stability. The UV/Vis spectra of the monolayers showed pronounced metal-to-ligand charge-transfer bands with a significant redshift compared with the solution spectra of the metallo ligands with a pendant pyridyl group quaternized with the coupling layer, whereas the shift was significantly smaller when the coupling layer was bonded to the primary amine (-NH2 ) group of the complex. Cyclic voltammograms of the monolayers showed reversible, one-electron redox behavior and suggested strong electronic coupling between the confined molecules and the underlying substrate. Analysis of the electrochemistry data allowed us to estimate the charge-transfer rate constant between the metal center and the substrate. Additionally, detailed quantum-chemical calculations were performed to support and rationalize the experimentally observed photophysical properties of the FeII -terpyridyl complexes both in the solution state and when bound to a SiOx -based substrate. PMID- 28905522 TI - Inclusion of sepsis and hypoxaemia in mortality prediction of hospitalized patients with community-acquired pneumonia - Reply. PMID- 28905523 TI - Abstractband anlasslich des 27. Deutschen Hautkrebskongresses (ADO-Jahrestagung) 21. bis 23. September 2017 in Mainz. PMID- 28905524 TI - First experience in colorectal surgery with a new robotic platform with haptic feedback. AB - : The use of robotic techniques is increasing in colorectal surgery. Recently, the SenhanceTM surgical robotic system was introduced as a novel robotic platform designed to overcome some of the limits of standard laparoscopy. This study describes the initial, single center experience, evaluating feasibility and safety of the new robotic system in performing colorectal surgical procedures. METHODS: From June 2015 to November 2016, perioperative data of the first 45 patients who underwent robotic colorectal surgery with the SenhanceTM surgical robotic system were collected and analyzed. Indications for surgery included inflammatory bowel disease, colorectal cancer, endoscopically unresectable adenomas and complicated diverticular disease. RESULTS: The median age was 57 years (18-92) and the median BMI was 24 Kg/m2 (16-30). Surgical indications were colorectal cancer (66%), complicated inflammatory bowel disease (18%), diverticular disease (11%) and endoscopically unresectable adenoma (4.4%). The median operative time was 256 minutes; the median docking time 10.7 min (range 2 25). There were 3 conversions to standard laparoscopy, and none to laparotomy. All patients operated on for malignancy (28 adenocarcinoma, 2 neuroendocrine tumors) underwent an appropriate oncological procedure. The median time to discharge was 5 days (range 3-19). The incidence of post-operative complications was 35.5% (Clavien-Dindo I/II-14 patients, III-2 patients). One patient was readmitted in the postoperative period. No patient required reoperation. CONCLUSION: The results of this audit suggest that adoption of The SenhanceTM surgical robotic system in colorectal surgery is feasible and safe. More clinical data are needed to determine whether this approach can offer any other benefits over other minimally invasive surgical techniques. This article is protected by copyright. All rights reserved. PMID- 28905525 TI - New insights into the mechanism of action of pyrazolo[1,2 a]benzo[1,2,3,4]tetrazin-3-one derivatives endowed with anticancer potential. AB - Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine 3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, in silico studies have been achieved to better understand the chemical space of the interactions. Interestingly some meaningful structural features, useful for further developments, were found. The 8,9-di-Cl substituted derivative revealed as the most effective in the intercalative process, as well as on the inhibition of catalytic activity of topoisomerase II. Predicted ADME studies confirm that PBTs are promising as potential drug candidates. PMID- 28905526 TI - Transmission and immunopathology of the avian influenza virus A/Anhui/1/2013 (H7N9) human isolate in three commonly commercialized avian species. AB - H7N9 virus infection is a global concern, given that it can cause severe infection and mortality in humans. However, the understanding of H7N9 epidemiology, animal reservoir species and zoonotic risk remains limited. This work evaluates the pathogenicity, transmissibility and local innate immune response of three avian species harbouring different respiratory distribution of alpha2,6 and alpha2,3 SA receptors. Muscovy ducks, European quails and SPF chickens were intranasally inoculated with 105 embryo infectious dose (EID)50 of the human H7N9 (A/Anhui/1/2013) influenza isolate. None of the avian species showed clinical signs or macroscopic lesions, and only mild microscopic lesions were observed in the upper respiratory tract of quail and chickens. Quail presented more severe histopathologic lesions and avian influenza virus (AIV) positivity by immunohistochemistry (IHC), which correlated with higher IL-6 responses. In contrast, Muscovy ducks were resistant to disease and presented higher IFNalpha and TLR7 response. In all species, viral shedding was higher in the respiratory than in the digestive tract. Higher viral shedding was observed in quail, followed by chicken and ducks, which presented similar viral titres. Efficient transmission was observed in all contact quail and half of the Muscovy ducks, while no transmission was observed between chicken. All avian species showed viral shedding in drinking water throughout infection. PMID- 28905527 TI - Small Airway Disease in Patients with Chronic Obstructive Pulmonary Disease. AB - Small airway disease (SAD) has been recognized for many years as a central feature of chronic obstructive pulmonary disease (COPD). Histopathology studies have shown that the narrowing and destruction of small airways in COPD combined with inflammatory cell infiltration in the submucosa increases the severity of the disease. SAD is present in the early stages of COPD and becomes more widespread over time as the disease progresses to more severe COPD. The development of inhalers containing extra-fine particles allows the small airways to be pharmacologically targeted. Recent clinical trials have shown the efficacy of extra-fine triple therapy that targets the small airways in patients with COPD. This article reviews the importance and treatment of SAD in COPD. PMID- 28905528 TI - Humidifier Disinfectant-Associated Lung Injury: Six Years after the Tragic Event. AB - In 2011, a cluster of peripartum patients were admitted to the intensive care unit of a tertiary hospital in Seoul with signs and symptoms of severe respiratory distress of unknown etiology. Subsequent epidemiological and animal studies suggested that humidifier disinfectant (HD) might represent the source of this pathology. Epidemiological studies, animal studies, and dose-response analysis demonstrated a strong association between HD use and lung injuries. The diagnostic criteria for HD-associated lung injury (HDALI) was defined on the basis of the clinical, pathological, and radiological attributes of the patients. The clinical spectrum of HDALI appears to range from asymptomatic to full-blown acute respiratory failure, and some patients have required actual lung transplantation for survival. The overall mortality of the exposed population was not significant, although peripartum patients and children who were admitted to the intensive care unit did show high mortality rates. Persistent clinical findings such as diffuse ill-defined centrilobular nodules and restrictive lung dysfunction were observed in some of the survivors. The findings of this review emphasize the importance of assessment of the level of toxicity of chemical inhalants utilized in a home setting, as well as the need to identify and monitor afflicted individuals after inhalational injury. PMID- 28905529 TI - WHO Treatment Guidelines for Drug-Resistant Tuberculosis, 2016 Update: Applicability in South Korea. AB - Despite progress made in tuberculosis control worldwide, the disease burden and treatment outcome of multidrug-resistant tuberculosis (MDR-TB) patients have remained virtually unchanged. In 2016, the World Health Organization released new guidelines for the management of MDR-TB. The guidelines are intended to improve detection rate and treatment outcome for MDR-TB through novel, rapid molecular testing and shorter treatment regimens. Key changes include the introduction of a new, shorter MDR-TB treatment regimen, a new classification of medicines and updated recommendations for the conventional MDR-TB regimen. This paper will review these key changes and discuss the potential issues with regard to the implementation of these guidelines in South Korea. PMID- 28905530 TI - Nonspecific Bronchoprovocation Test. AB - Bronchial asthma is a disease characterized by the condition of airway hyper responsiveness, which serves to produce narrowing of the airway secondary to airway inflammation and/or various spasm-inducing stimulus. Nonspecific bronchoprovocation testing is an important method implemented for the purpose of diagnosing asthma; this test measures the actual degree of airway hyper responsiveness and utilizes direct and indirect bronchoprovocation testing. Direct bronchoprovocation testing using methacholine or histamine may have superior sensitivity as these substances directly stimulate the airway smooth muscle cells. On the other hand, this method also engenders the specific disadvantage of relatively low specificity. Indirect bronchoprovocation testing using mannitol, exercise, hypertonic saline, adenosine and hyperventilation serves to produce reactions in the airway smooth muscle cells by liberating mediators with stimulation of airway inflammatory cells. Therefore, this method has the advantage of high specificity and also demonstrates relatively low sensitivity. Direct and indirect testing both call for very precise descriptions of very specific measurement conditions. In addition, it has become evident that challenge testing utilizing each of the various bronchoconstrictor stimuli requires distinct and specific protocols. It is therefore important that the clinician understand the mechanism by which the most commonly used bronchoprovocation testing works. It is important that the clinician understand the mechanism of action in the testing, whether direct stimuli (methacholine) or indirect stimuli (mannitol, exercise) is implemented, when the testing is performed and the results interpreted. PMID- 28905531 TI - Elucidation of Bacterial Pneumonia-Causing Pathogens in Patients with Respiratory Viral Infection. AB - BACKGROUND: Bacterial pneumonia occurring after respiratory viral infection is common. However, the predominant bacterial species causing pneumonia secondary to respiratory viral infections other than influenza remain unknown. The purpose of this study was to know whether the pathogens causing post-viral bacterial pneumonia vary according to the type of respiratory virus. METHODS: Study subjects were 5,298 patients, who underwent multiplex real-time polymerase chain reaction for simultaneous detection of respiratory viruses, among who visited the emergency department or outpatient clinic with respiratory symptoms at Ulsan University Hospital between April 2013 and March 2016. The patients' medical records were retrospectively reviewed. RESULTS: A total of 251 clinically significant bacteria were identified in 233 patients with post-viral bacterial pneumonia. Mycoplasma pneumoniae was the most frequent bacterium in patients aged <16 years, regardless of the preceding virus type (p=0.630). In patients aged >=16 years, the isolated bacteria varied according to the preceding virus type. The major results were as follows (p<0.001): pneumonia in patients with influenza virus (type A/B), rhinovirus, and human metapneumovirus infections was caused by similar bacteria, and the findings indicated that Staphylococcus aureus pneumonia was very common in these patients. In contrast, coronavirus, parainfluenza virus, and respiratory syncytial virus infections were associated with pneumonia caused by gram-negative bacteria. CONCLUSION: The pathogens causing post-viral bacterial pneumonia vary according to the type of preceding respiratory virus. This information could help in selecting empirical antibiotics in patients with post viral pneumonia. PMID- 28905532 TI - Incidence and Risk Factors of Pneumonia in Hospitalized Patients with Seasonal Influenza A or B. AB - BACKGROUND: Most patients with influenza recover spontaneously or following treatment with an anti-viral agent, but some patients experience pneumonia requiring hospitalization. We conducted a retrospective review to determine the incidence and risk factors of pneumonia in hospitalized patients with influenza A or B. METHODS: A total of 213 patients aged 18 years or older and hospitalized with influenza between January 2012 and January 2015 were included in this study. A reverse-transcriptase polymerase chain reaction assay was used to detect the influenza A or B virus in the patients' sputum samples. We collected demographic and laboratory data, combined coexisting diseases, and radiologic findings. RESULTS: The incidence of pneumonia was higher in patients in the influenza A group compared to those in the influenza B group (68.6% vs. 56.9%), but this difference was not statistically significant. The presence of underlying respiratory disease was significantly associated with pneumonia in the influenza A group (adjusted odds ratio [OR], 3.975; 95% confidence interval [CI], 1.312 12.043; p=0.015). In the influenza B group, the white blood cell count (adjusted OR, 1.413; 95% CI, 1.053-1.896; p=0.021), platelet count (adjusted OR, 0.988; 95% CI, 0.978-0.999; p=0.027), and existence of an underlying medical disease (adjusted OR, 15.858; 95% CI, 1.757-143.088; p=0.014) were all significantly associated with pneumonia in multivariate analyses. CONCLUSION: The incidence of pneumonia was 65.7% in hospitalized patients with influenza A or B. The risk factors of pneumonia differed in hospitalized patients with influenza A or B. PMID- 28905533 TI - Short-term Evaluation of a Comprehensive Education Program Including Inhaler Training and Disease Management on Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Proper education regarding inhaler usage and optimal management of chronic obstructive pulmonary disease (COPD) is essential for effectively treating patients with COPD. This study was conducted to evaluate the effects of a comprehensive education program including inhaler training and COPD management. METHODS: We enlisted 127 patients with COPD on an outpatient basis at 43 private clinics in Korea. The patients were educated on inhaler usage and disease management for three visits across 2 weeks. Physicians and patients were administered a COPD assessment test (CAT) and questionnaires about the correct usage of inhalers and management of COPD before commencement of this program and after their third visit. RESULTS: The outcomes of 127 COPD patients were analyzed. CAT scores (19.6+/-12.5 vs. 15.1+/-12.3) improved significantly after this program (p<0.05). Patients with improved CAT scores of 4 points or more had a better understanding of COPD management and the correct technique for using inhalers than those who did not have improved CAT scores (p<0.05). CONCLUSION: A comprehensive education program including inhaler training and COPD management at a primary care setting improved CAT scores and led to patients' better understanding of COPD management. PMID- 28905534 TI - Larger Testicular Volume Is Independently Associated with Favorable Indices of Lung Function. AB - BACKGROUND: Men with chronic obstructive pulmonary disease, have reduced endogenous testosterone levels, but the relationship between pulmonary function and endogenous testosterone levels, is inconsistent. Testicular volume is a known indicator of endogenous testosterone levels, male fertility, and male potency. In the present study, the authors investigated the relationship, between testicular volume and lung function. METHODS: One hundred and eighty-one South Korean men age 40-70, hospitalized for urological surgery, were retrospectively enrolled, irrespective of the presence of respiratory disease. Study subjects underwent pulmonary function testing, prior to procedures, and testicular volumes were measured by orchidometry. Testosterone levels of patients in blood samples collected between 7 AM and 11 AM, were measured by a direct chemiluminescent immunoassay. RESULTS: The 181 study subjects were divided into two groups, by testicular volume (>=35 mL vs. <35 mL), the larger testes group, had better lung functions (forced vital capacity [FVC]: 3.87+/-0.65 L vs. 3.66+/-0.65 L, p=0.037; forced expiratory volume in 1 second [FEV1]: 2.92+/-0.57 L vs. 2.65+/-0.61 L, p=0.002; FVC % predicted: 98.2+/-15.2% vs. 93.8+/-13.1%, p=0.040; FEV1 % predicted: 105.4+/-19.5% vs. 95.9+/-21.2%, p=0.002). In addition, the proportion of patients with a FEV1/FVC of <70%, was lower in the larger testes group. Univariate analysis conducted using linear regression models, revealed that testicular volume was correlated with FVC (r=0.162, p=0.029), FEV1 (r=0.218, p=0.003), FEV1/FVC (r=0.149, p=0.046), and FEV1 % predicted (r=0.178, p=0.017), and multivariate analysis using linear regression models, revealed that testicular volume was a significant predictive factor for FEV1 % predicted (beta=0.159, p=0.041). CONCLUSION: Larger testicular volume was independently associated, with favorable indices of lung function. These results suggest that androgens, may contribute to better lung function. PMID- 28905535 TI - Are There Any Additional Benefits to Performing Positron Emission Tomography/Computed Tomography Scans and Brain Magnetic Resonance Imaging on Patients with Ground-Glass Nodules Prior to Surgery? AB - BACKGROUND: A ground-glass nodule (GGN) represents early-stage lung adenocarcinoma. However, there is still no consensus for preoperative staging of GGNs. Therefore, we evaluated the need for the routine use of positron emission tomography/computed tomography (PET)/computed tomography (CT) scans and brain magnetic resonance imaging (MRI) during staging. METHODS: A retrospective analysis was undertaken in 72 patients with 74 GGNs of less than 3 cm in diameter, which were confirmed via surgery as malignancy, at the Samsung Medical Center between May 2010 and December 2011. RESULTS: The median age of the patients was 59 years. The median GGN diameter was 18 mm. Pure and part-solid GGNs were identified in 35 (47.3%) and 39 (52.7%) cases, respectively. No mediastinal or distant metastasis was observed in these patients. In preoperative staging, all of the 74 GGNs were categorized as stage IA via chest CT scans. Additional PET/CT scans and brain MRIs classified 71 GGNs as stage IA, one as stage IIIA, and two as stage IV. However, surgery and additional diagnostic work ups for abnormal findings from PET/CT scans classified 70 GGNs as stage IA, three as stage IB, and one as stage IIA. The chest CT scans did not differ from the combined modality of PET/CT scans and brain MRIs for the determination of the overall stage (94.6% vs. 90.5%; kappa value, 0.712). CONCLUSION: PET/CT scans in combination with brain MRIs have no additional benefit for the staging of patients with GGN lung adenocarcinoma before surgery. PMID- 28905536 TI - A Rare Case of Tracheobronchitis Alternariosis in a Renal Transplant Recipient. PMID- 28905538 TI - Staging Work-up for Early Lung Cancer: The More the Better? PMID- 28905537 TI - The Relationship between Airway Inflammation and Exacerbation in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with abnormal inflammatory response and airflow limitation. Acute exacerbation involves increased inflammatory burden leading to worsening respiratory symptoms, including dyspnea and sputum production. Some COPD patients have frequent exacerbations (two or more exacerbations per year). A substantial proportion of COPD patients may remain stable without exacerbation. Bacterial and viral infections are the most common causative factors that breach airway stability and lead to exacerbation. The increasing prevalence of exacerbation is associated with deteriorating lung function, hospitalization, and risk of death. In this review, we summarize the mechanisms of airway inflammation in COPD and discuss how bacterial or viral infection, temperature, air pollution, eosinophilic inflammation, and concomitant chronic diseases increase airway inflammation and the risk of exacerbation. PMID- 28905539 TI - New Treatment Modalities for Geographic Atrophy. AB - Age-related macular degeneration (AMD) is a significant cause of global visual morbidity and is projected to affect 288 million people by the year 2040. The advent of treatment with anti-vascular endothelial growth factor (anti-VEGF) drugs has revolutionized the treatment of neovascular AMD (nAMD) but there have been no similar breakthroughs for the treatment of geographic atrophy (GA) to retard its progression. The advancements in imaging and new understanding of disease mechanisms, based on molecular and genetic models, have paved the way for the development of novel experimental treatment options for GA that aim to cater to a thus far largely unmet need. This review paper focuses on the recent clinical trials of new treatment options for slowing GA progression rates with emphasis on the agents that are currently undergoing, or have already undergone, significant clinical trial testing. Several new groups of drugs, including those targeting the complement cascade and agents considered as neuroprotective, have shown some promising results and could potentially pave the way forward in the treatment of this devastating disease. PMID- 28905540 TI - Nanosecond Laser Cataract Surgery in LOCS III Grade 4 and 5: A Case Series. AB - PURPOSE: A major obstacle to the widespread implementation of nanosecond laser cataract removal has been its limited efficacy in cases when the cataract is harder than Lens Opacities Classification System III (LOCS III ) grade 3. The latest technological modifications seem to have overcome this obstacle. DESIGN: A case series. METHODS: This study presents a case series of 17 consecutive patients with a cataract classified as harder than LOCS III grade 3 who underwent nanolaser cataract surgery. The basic surgical procedure included administration of topical or local anesthesia, capsulorhexis, hydrodissection, cataract removal with a nanosecond laser, cortical cleanup, intraocular lens implantation, and clear corneal incision closure with physiological solution. RESULTS: The nanosecond laser system effectively removed the cataract in all patients. This result was statistically significant (P < 0.000001) compared with an expected conversion rate to ultrasound phacoemulsification of 100%. CONCLUSIONS: Harder cataracts should no longer be considered a limitation for the use of nanosecond laser in cataract surgery. PMID- 28905541 TI - The Role of New Imaging Methods in Managing Age-Related Macular Degeneration. AB - The use of imaging for age-related macular degeneration (AMD) depends on how it benefits clinical management and on reimbursement. The latter should relate to the former. This review assesses how different forms of AMD can be imaged and what information this provides. For nonneovascular AMD high-resolution optical coherence tomography (OCT), autofluorescence, and near infrared imaging can identify the type of drusen, such as reticular pseudodrusen, which influences prognosis, and the amount of atrophy, for which phase 3 trials are underway. Clarifying the correct diagnosis for late-onset Stargardt and macular telangiectasia, if treatment becomes available, will be especially important. Choroidal thickness can be measured and changes with anti-vascular endothelial growth factor treatment, but how this influences management is less clear. The finding of a thick choroid may alter the diagnosis to pachychoroid neovasculopathy, which may have a different treatment response. Peripheral retinal changes are commonly found on ultrawide-field imaging but their importance is not yet determined. The mainstay of imaging is OCT, which can detect neovascular AMD by detecting thickening and be used for follow-up, as the presence or absence of thickening is the main determinant of treatment. Higher resolution systems and now OCT angiography are able to distinguish neovascular type, especially type 2 choroidal neovascularization but also polypoidal choroidal vasculopathy and retinal angiomatous proliferation. Fundus fluorescein and indocyanine green angiographies still have a role, although that partly depends on whether photodynamic therapy is being considered. Automated image analysis and machine learning will be increasingly important in supporting clinician decisions. PMID- 28905542 TI - ? PMID- 28905543 TI - [How to start an antihypertensive treatment: from evidence to personalized choice]. AB - Considering the high prevalence of hypertension among general population, the general practitioner is frequently challenged to start an antihypertensive therapy, which aims to lower blood pressure and to reduce the cardiovascular risk. At the initial stage, several critical questions must be asked : " Is a pharmacological treatment necessary ? ", " Which are the target blood pressures ? " and " Which antihypertensive drug should be chosen to start therapy ? "The aim of this article is to give general practicioners some practical tools to guide them in the initial management of hypertensive patients. PMID- 28905544 TI - [Text messaging and self-care support of hypertensive patients : first achievements]. AB - Text messaging applied to self-care support of hypertensive patients is a new e health tool available via mobile phones and computers. First validated programs are just emerging. Without being a panacea intended to replace the doctors by machines they could be provide a significant reinforcement of the patient's empowerment for self-monitoring. It is now time to begin their evaluation in real life and in primary care setting. PMID- 28905545 TI - [Practical reading grids to better understand our hypertensive patients]. AB - Hypertension is well identified as the main factor of mortality, cardiovascular disease and renal damage worldwide. However, only half of hypertensive patients are diagnosed as hypertensive, and only a quarter of hypertensive patients has blood pressure values normalized by the medical treatment. The aim of this article is to propose a practical reading grid in order to get a better understanding of our patients, in the GP's office, and a comprehensive approach of problematics encountered by the patient with its own perception, to identify barriers, tools and patients' available ressources. PMID- 28905546 TI - [Hypertension in people of African descent]. AB - Hypertension in people of African descent presents an increased prevalence, an earlier and more severe target organ damage and is harder to control compared to other ethnicities. Preeclampsia and gestational hypertension are more frequent in black women. The physiological phenomenon of night time blood pressure dipping is often blunted. The low renin hypertension phenotype seems to be caused by an increase in sodium retention at renal level. The treatment of choice is calcium channel blockers and thiazide diuretics along with a renin-angiotensin aldosterone blocker for kidney protection. Addition of spironolactone or amiloride is advised for resistant hypertension. A diet poor in sodium and rich in potassium is recommended. PMID- 28905548 TI - ? PMID- 28905549 TI - ? PMID- 28905547 TI - [Fibromuscular dysplasia and hypertension : beyond renal arteries]. AB - Fibromuscular dysplasia (FMD) is a disease associated with abnormalities of the arterial wall of medium-sized arteries. These abnormalities can lead to stenosis or less frequently to dissections or aneurysms. FMD is probably more frequent than initially thought. Nowadays, it is often a chance finding during a radiologic exam. In symptomatic cases, poor organ perfusion due to stenosis, dissection or aneurysm rupture may lead to the diagnosis. The aim of this non systematic review illustrated with a clinical case is to present our current knowledge of FMD and to highlight the necessity of a standardized and multidisciplinary work-up to improve management of affected patients and understanding of the disease. PMID- 28905550 TI - ? PMID- 28905551 TI - ? PMID- 28905552 TI - ? PMID- 28905553 TI - ? PMID- 28905554 TI - ? PMID- 28905555 TI - [Pesudostellariae Radix industry status and development countermeasures]. AB - In recent years, with increasing role in traditional Chinese medicine industry of many provinces in china, Pseudostellariae Radix is one of the rapid development traditional Chinese medicine. Based on references and on-site investigation of main producing area, we clear the process of change from the small of the Panax ginseng to the Pseudostellariae Radix in aspects of history, and the change of producing area from Shandong, Jiangsu provinces to Fujian, Anhui and Guizhou provinces. And we clear how the Pseudostellariae Radix become a commonly used Chinese medicinal herbs from a small variety based on the market supply and demand and price changes, and it has gradually become a hot topic of the research. This paper summarized the status quo and the existing problems in the Pseudostellariae Radix industry. On this basis, we put forward countermeasures and suggestions for the development of the Pseudostellariae Radix industry. PMID- 28905556 TI - [Breeding and extension of Pseudostellaria heterophylla new variety "Shitai No.1" in Guizhou province]. AB - Based on collections and researches of Pesudostellaria heterophylla germplasm resources from different areas of China, by using Shibing SB-4 provenance as materials, the new variety "Shitai No.1" was bred by mass selection, small plot variety comparative test, regional variety comparative test and field trial planting. Compared with "Qian taizishen No.1" and P. heterophylla land races. The disease and lodging resistance, root yield, polysaccharide content and the first grade rate of "Shitai No.1" have obvious advantages. In addition, it is relatively stable of yield in "Shitai No.1" in different places. It is demonstrated that "Shitai No.1" is a fine variety that adapt to the producing areas of P. heterophylla in Guizhou province, it is worthy to be promoted. PMID- 28905557 TI - [Research on quality regionalization of cultivated Pseudostellaria heterophylla based on climate factors]. AB - Maxent model was applied in the study to filtering the climate factors layer by layer. Polysaccharides and pseudostellarin B the two internal quality evaluation index were combined to analyse the interlinkages between climate factors and chemical constituents in order to search for the critical climate factors of Pseudostellaria heterophylla. Then based on the key climate factors to explicit the quality spatial distribution of P. heterophylla. The results showed that polysaccharides and climatic factors had no significant correlation, suggesting that the indicator was not climate-driven metabolites. Pseudostellarin B could construct regression model with the precipitation. And quality regionalization results showed that pseudostellarin B content presented firstly increased and then decreased trend from southeast to northwest, which was the consistent change with precipitation. It clearly proposed that precipitation was the key climate factor, which affected the accumulation of cyclopeptide compound for Pseudostellariae Radix. PMID- 28905558 TI - [Quality evaluation and growing regionalization of Pseudostellaria heterophylla in Guizhou]. AB - This paper is aimed to study the potential ecological suitability regionalization of Pseudostellaria heterophylla for selecting GAP planting base location and designing rational production layout. The ecological factors and contribution rate were determined by using maximum entropy (Maxent) model. Then, the information entropy theory was used to determine the relative importance of each environmental factor, and thus to determine the most limiting habitat criteria. Finally, the probable spatial distribution of P. heterophylla was determined based on GIS spatial analysis of habitat conditions. Meanwhile, the optimal index range of ecological factors was quantified. The moderately and highly suitable habitats were mainly located in Shibing, Huangping, Cengong, the middle and east of Kaili, the south of Yuqing, the west of Tongren. The percentage of moderately and highly suitable habitats for P. heterophylla in the study area was 3.64%, and its area was 6 405.39 km2. The results also showed that seven dominant ecological factors controlled the distribution of P. heterophylla. These factors included agrotype, the warmest rain, aspect, slope, the warmest and highest temperature, contents of soil organic carbon, and the driest month precipitation. The habitat suitability assessment model based on GIS and Maxent model theory could accurately evaluate the habitat suitability distribution of P. heterophylla in Guizhou. In addition, we recommended Cengong and Zhenyuan county in Guizhou province as the worthy developing potential planting areas. PMID- 28905559 TI - [Cloning and bioinformatics analysis of abscisic acid 8'-hydroxylase from Pseudostellariae Radix]. AB - Abscisic acid 8'-hydroxylase was one of key enzymes genes in the metabolism of abscisic acid (ABA). Seven menbers of abscisic acid 8'-hydroxylase were identified from Pseudostellaria heterophylla transcriptome sequencing results by using sequence homology. The expression profiles of these genes were analyzed by transcriptome data. The coding sequence of ABA8ox1 was cloned and analyzed by informational technology. The full-length cDNA of ABA8ox1 was 1 401 bp,with 480 encoded amino acids. The predicated isoelectric point (pI) and relative molecular mass (MW) were 8.55 and 53 kDa,respectively. Transmembrane structure analysis showed that there were 21 amino acids in-side and 445 amino acids out-side. High level of transcripts can detect in bark of root and fibrous root. Multi-alignment and phylogenetic analysis both show that ABA8ox1 had a high similarity with the CYP707As from other plants,especially with AtCYP707A1 and AtCYP707A3 in Arabidopsis thaliana. These results lay a foundation for molecular mechanism of tuberous root expanding and response to adversity stress. PMID- 28905560 TI - [Cloning and expression analysis of four carotenoid cleavage dioxygenases genes from Pseudostellaria heterophylla]. AB - To investigate the molecular mechanism of quality formation of Pseudostellaria heterophylla, the carotenoid cleavage dioxygenases (CCDs) genes were cloned from the transcriptome database of P. heterophylla, and analyzed them with bioinformatics analysis and expression analysis. The sequence length of four new gene were 1 617, 1 461, 1 746, 1 875 bp, and subsequently, named as PhCCD1,PhNCED2,PhNCED3 and PhCCD4 according to its genetic relationship with Arabidopsis thaliana. The sequence analysis showed that four new gene were all containing REP65 domains and binding sites of ferrous ion, such as histidine, glutamates and aspartates. Analysis phylogeny showed that PhNCED2 and PhNCED3 were the cluster of NCEDs, PhCCD1 and PhCCD4 were the cluster of CCDs. In addition, PhCCD1 and AtCDD1 of Arabidopsis thaliana, PhCCD4 and AtCCD4 of A. thaliana,PhNCED2, PhNCED3 and AtNCED3 of A. thaliana have high similarities. Analysis of real-time fluorescence quantitative showed that PhNCED2 and PhNCED3 were expressed mainly in underground part, the expression quantity of PhNCED2 reached the highest in fibrous root, PhNCED3 keeps higher in phloem and xylem, it may be the key enzymes of ABA biosynthesis genes. Moreover,PhCCD1 and PhCCD4 were expressed mainly in aerial part,the expression quantity of PhCCD1 reached the highest in leaf,PhCCD4 keeps higher in stem and leaf.It may be involved in the biosynthesis of carotenoids for P. heterophylla. The study obtained CDDs gene of P. heterophylla for the first time,this would lay the foundation of developing the response mechanism of P. heterophylla about external stress further,and then exploring the biological approach of quality formation in P. heterophylla. PMID- 28905561 TI - [Pathogen identification, regularity of development and control measures of diseases on Atractylodes lancea]. AB - Based on current progress and field investigations,this review summarized the symptoms,epidemiology and control methods of 11 diseases on Atractylodes lancea, including the most severely harmed root diseases such as root rot and southern blight, as well as the sclerotinia rot that was newly happened. This review aims to demonstrate the progress of studies on diseases of A. lancea, providing guidance for field production. Sclerotonia disease and leaf spot disease are new diseases,suggesting the awareness of this disease on plant quarantine. PMID- 28905562 TI - [Pathomechanisms of podocyte injury in diabetic nephropathy and interventional effects of Chinese herbal medicine]. AB - Podocyte injury is closely related to proteinuria in the progress of diabetic nephropathy(DN). The pathological characters of podocyte injury mainly refer to the change of podocyte form and function, including foot process effacement, reduction of podocyte number and density, podocyte apoptosis, podocyte epithelial mesenchymal transdifferentiation(EMT)and podocyte hypertrophy. These pathological damages are controlled by multiple signaling pathways in the kidney, such as mammalian target of rapamycin(mTOR)/autophagy pathway, transforming growth factor(TGF)-beta1 pathway and Notch pathway. For podocyte injuries induced by high glucose or in murine models of DN, some Chinese herbal medicine(CHM)extracts, such as multiglycoside of Tripterygium wilfordii(GTW), triptolide(TP), astragaloside IV(AS-IV), astragalus polysaccharide(APS)and Panax notoginseng saponins(PNS), have the protective effects in vivo or in vitro. The preliminary studies in China showed that GTW improves podocyte injury in the DN model rats probably through regulating the activity of mTORC1 signaling pathway in the kidney. Therefore, it is the developmental direction for the further study to clarify the interventional effects of CHM based on podocyte injury-related signaling pathway in DN. PMID- 28905563 TI - [Research progress on pharmacological effects and their differences among the flowers, stems and leaves of Lonicera japonica]. AB - It's a common phenomenon that two kinds or more than two kinds of herbs belong to different parts of the same plant. Lonicera Japonica Flos, Lonicera Japonica Caulis and Lonicera Japonica Folium are the typical representative of this phenomenon. They belong to different parts of the Lonicera japonica Thunb. This paper reviewed the research progress on pharmacological effects and their differences among them. It was found that the research mainly concentrated on Lonicera Japonica Flos, and the others were ignored. However, some pharmacological effects in leaves are stronger than that of flowers and stems, such as antibacterial, anti-bird flu and antioxidant activity.Lonicera Japonica Flos is mainly used for the treatment of respiratory tract virus infection while Lonicera Japonica Caulis is mainly used for the treatment of hepatitis virus infection, respectively. Finally, main problems and suggestions on pharmacological effects among them were also discussed. PMID- 28905564 TI - [Research progress on meridian-guiding theory of traditional Chinese medicine]. AB - Ancient materia medica and medical formularies were consulted to illustrate the development history of meridian-guiding theory of traditional Chinese medicine (TCM). The influences of various meridian-guiding drugs (Achyranthis Bidentatae Radix, borneol, Bupleuri Radix, Platycodon Radix) on the pharmacokinetic and pharmacodynamic characteristics of other drugs were summarized. Meridian-guiding drugs can promote the absorption and targeted distribution of other drugs and enhance the efficacy of injured tissues. The possible mechanisms of meridian guiding are related with changing the component of cell membrane, inhibiting the efflux of P-gp, opening physiological barriers, modulating the levels of biochemicals, promoting microcirculation and adjusting the pH of targeted tissues. The chemical components of meridian-guiding drugs are the substance basis of meridian-guiding. The aim of exploring meridian-guiding chemicals is to find a natural targeted delivery system. At the present time, some progress has been made in the research on meridian-guiding field. However, further studies are required for the meridian-guiding theory of TCM. PMID- 28905565 TI - [Monitoring method for macroporous resin column chromatography process of salvianolic acids based on near infrared spectroscopy]. AB - To study and establish a monitoring method for macroporous resin column chromatography process of salvianolic acids by using near infrared spectroscopy (NIR) as a process analytical technology (PAT).The multivariate statistical process control (MSPC) model was developed based on 7 normal operation batches, and 2 test batches (including one normal operation batch and one abnormal operation batch) were used to verify the monitoring performance of this model. The results showed that MSPC model had a good monitoring ability for the column chromatography process. Meanwhile, NIR quantitative calibration model was established for three key quality indexes (rosmarinic acid, lithospermic acid and salvianolic acid B) by using partial least squares (PLS) algorithm. The verification results demonstrated that this model had satisfactory prediction performance. The combined application of the above two models could effectively achieve real-time monitoring for macroporous resin column chromatography process of salvianolic acids, and can be used to conduct on-line analysis of key quality indexes. This established process monitoring method could provide reference for the development of process analytical technology for traditional Chinese medicines manufacturing. PMID- 28905566 TI - [Optimize preparation parameters of colon-specific pellets of Angelica Sinensis Radix supercritical fluid extraction with response surface analysis methodology]. AB - To prepare pellets of supercritical fluid extraction (SFE) of Angelica Sinensis Radix by using the ionic crosslinking method, and the drug loading and encapsulation efficiency were used as the index to investigate the multiple factors which may impact the drug loading and encapsulation efficiency. Box Behnken design and response surface analysis method were then taken to optimize the prescription of pellets and study the coating technology. Through the study on the release of pellets in vitro, an optimal coating technology and prescription of colon-specific pellets of Angelica Sinensis Radix SFE were selected and their colon targeting was evaluated. The optimal preparation parameters of pellets were determined as follows: 3% pectin; 4?1 for pectin/lecithin; 4?5 for pectin/SFE of Angelica Sinensis Radix; 4% zinc acetate solution as crosslinking agent, blending temperature 35 C, crosslinking temperature 35 C, crosslinking time 30 min; coating technology: coating material Eudragit FS 30D, 1.5% triethyl citrate and polyoxyethylene sorbitan monooleate(tween-80), 1.2% monostearin and 15% coating weight gained. The colon specific pellets of Angelica Sinensis Radix SFE prepared with optimized conditions were almost not released in simulated gastric fluid in 2 h, released less than 20% in simulated intestine fluid in 4 h, and released more than 90% in simulated colon fluid in 6 h, indicating that the colon-specific pellets of Angelica Sinensis Radix SFE had an excellent colon targeting property. PMID- 28905567 TI - [Application of high performance liquid-ion trap mass spectrometry in analyzing saponins in sodium aescinate]. AB - Sodium aescinate, which is produced from saponins of Chinese Buckeye Seed, is a prescription drug for treatment of brain edema and all kinds of swellings caused by surgery. In this article, high-performance liquid chromatography/ion trap (HPLC-IT) mass spectrometry was applied to study the characteristic ions of ten reference substances, namely escin Ia, escin Ib, isoescin Ia, isoescin Ib, aesculiside A, aesculiside B, aesculuside A, escin IVc, escinIIa and escin V, which were isolated from aescinate. Furthermore, 19 saponin compounds were predicted in sodium aescinate, besides the above mentioned reference substances. The study showed that sapogenins in sodium aescinate had two structural types, namely protoaescigenin and barringenol C, and the substituent acetyl, tigloyl or angeloyl was usually located at C-21, C-22 or C-28 position. Among these predicted saponins, their sugar chains were all located at C-3 position consisting of glucose and glucuronide. This study provides experimental data for chemical constituents in sodium aescinate and scientific basis for quality and safety evaluation. PMID- 28905568 TI - [Chemical constituents of ethyl acetate fraction from seed melon (Citrulluslanatus ssp. vulgaris var. megalaspermus)]. AB - In this paper, the chemical composition of ethyl acetate parts of seed melon were studied by using ethanol re-flux method, extraction method, and isolated by column chromatography oversilica gel and Sephadex LH-20 and HPLC. The structures of the separated compounds were identified by physical-chemical methods and spectral data such as MS, 1H-NMR, 13C-NMR, etc. 12 compounds were got from the plant including one new compound, 4-hydroxymet-hyl-2-methoxyphenyl 1-O-beta-D-[6' O-(4"-hydroxybenzoyl)-glucopyranoside] (1) and 11 known compounds, uracil (2), thymine (3), 2'-deoxyuridine (4), 7,8-dimethylalloxazine (5), indole-3-carboxylic acid (6), beta-adenosine (7), 4-hydroxybenzoic acid (8), p-coumaric acid (9), cucumegastigmanesI (10), 3'-methoxyl-quercetin-7-O-beta-D-glucopyranoside (11) and 3,3'-dimethyloxy-4,4'-dihydroxy-9,9'-monoepoxy lignan (12). PMID- 28905569 TI - [Chemical constituents from Barringtonia racemosa]. AB - To investigate the chemical constituents from Barringtonia racemosa, twelve compounds were isolated by chromatography methods and identified as 3beta-p-E coumaroymaslinic acid (1), cis-careaborin (2), careaborin (3), maslinic acid (4), 2alpha, 3beta, 19alpha-trihydroxyolean-12-ene-24, 28-dioic acid (5), 3beta-p-Z coumaroylcorosolic acid (6), corosolic acid (7), 1alpha, 2alpha, 3beta, 19alpha tetrahydroxyurs-12-en-28-oic acid (8), 19alpha-hydroxyl ursolic acid (9), 3alpha, 19alpha-dihydroxyurs-12-en-24, 28-dioic acid (10), tormentic acid (11), 3-hydroxy 7, 22-dien-ergosterol(12) by the NMR and MS data analysis. Among them, compounds 1-4,7-12 were obtained from the genus Barringtonia for the first time. All the compounds didn't show nocytotoxic activity against MCF-7 and A549 cell lines (IC50>50 mg*L-1). PMID- 28905570 TI - [Cerebrosides isolated from Arisaema flavum]. AB - Silica gel, Sephadex LH-20, and reverse phase (C-18) column chromatography were used for the research of chemical constituents occurred in Arisaema flavum(Forsk.) Schott. The structures were elucidated by comparison physico chemical properties and NMR spectroscopic data with those of known compounds. Seventeen cerebrosides were identified as 1-O-beta-D-glucopyranosyl-(2S, 3R, 4E, 8E)-2-[(2'(R)-acetoxyoctadecanoyl)amido]-4, 8-octadecadiene-1, 3-diol (1), 2'-O acetylsoyacerebroside I (2), 1-O-(beta-D-glucopyranosyl)-(2S, 3R, 4E, 13Z)-2 [(2'R)-2-hydroxytetradecanoylamino]-1, 3-dihydroxy-4, 13-docosadiene (3), (2S, 3R, 4E, 8E)1-(beta-D-glucopyranosyl)-3-hydroxy-2-[(R)-2' hydroxyhexadecanoyl]amino-9-methyl-4, 8-heptadecadiene (4), (2S, 3R, 4E, 8E)1 (beta-D-glucopyranosyl)-3-hydroxy-2-[(R)-2'-hydroxyhexadecanoyl]amino-9-methyl-4, 8-octadecadiene (5), (2S, 3R, 4E, 8E)1-(beta-D-glucopyranosyl)-3-hydroxy-2-[(R) 2'-hydroxypalmitoyl]amino-9-methyl-4, 8-octadecadiene (6), (2S, 3R, 4E, 8E)1 (beta-D-glucopyranosyl)-3-hydroxy-2-[(R)-2'-hydroxyoctadecanoyl]amino-9-methyl-4, 8-octadecadiene (7), 1-O-(beta-D-glucopyranosyl)-(2S, 3R, 4E, 8E)-2-[(R)-2' hydroxytetradecanoylamino]-4, 8-octadecadiene-1, 3-diol (8), 1-O-(beta-D glucopyranosyl)-(2S, 3R, 4E, 8E)-2-[(R)-2'-hydroxypentadecanoylamino]-4, 8 octadecadiene-1, 3-diol (9), 1-O-(beta-D-glucopyranosyl)-(2S, 3R, 4E, 8E)-2-[(R) 2'-hydroxyhexadecanoylamino]-4, 8-octadecadiene-1, 3-diol (10), 1-O-(beta-D glucopyranosyl)-(2S, 3R, 4E, 8Z)-2-[(R)-2'-hydroxyhexadecanoylamino]-4, 8 octadecadiene-1, 3-diol (11), 1-O-(beta-D-glucopyranosyl)-(2S, 3R, 4E, 8E)-2-[(R) 2'-hydroxyoctadecanoylamino]-1, 3-hydroxy-4, 8-octadecadiene (12), 1-O-(beta-D glucopyranosyl)-(2S, 3R, 4E)-2-[(R)-2'-hydroxytetracosanoylamino]-1, 3-hydroxy-4 hexadecane (13), 1-O-(beta-D-glucopyranosyl)-(2S, 3R, 4R, 8Z)-2N-[(2'R)-2' hydroxytetracosanoyl]-8-(Z)-octadecene-1, 3, 4-triol (14), 1-O-(beta-D glucopyranosyl)-(2S, 3S, 4E, 8E)-2N-[(2'R)-2'-hydroxyhexadecanoyl]-4-(E), 8-(Z) octadecadiene-1, 3-diol (15), typhoniside A (16), and 1-O-beta-D-glucopyranosyl (2S, 3R, 8E)-2-[(2'R)-2-hydroxypalmitoylamino]-8-octadecene-1, 3-diol (17). Compounds 1 and 2 were isolated from the plant for the first time, while the remained compounds were isolated from the genus Arisaema for the first time. PMID- 28905571 TI - [Screening of active fractions with antithrombotic effect from Caragana jubata]. AB - The antithrombotic effect of Caragana jubata (Pall.)Poir.ethanolic extract (TE)was evaluated by inferior vena cava thrombosis in rats and acute pulmonary thrombosis in mice. To search for the bioactive fractions of TE, comparison on acute pulmonary thrombosis was made between the two main fractions of TE (TE-1 and TE-2). Besides, pharmacological effects of TE, TE-1 and TE-2 on bleeding time and clotting time were also studied. Reference substances combined with UPLC/DAD q-TOF-MS were applied to identify the main six compounds and other chemical constituents of the TE. The results showed that TE could significantly reduce the rat thrombosis weight in all doses (P<0.01) and improve the protective rate to mice in medium and high doses (P<0.05). TE-2 showed a stronger effect on protecting the mice from paralysis or death and prolonging the bleeding time and clotting time than TE-1. Chemical constituents in TE mainly include isoflavones, pterocarpans and stilbenoids. Constituents in TE-2 were mainly isoflavones and pterocarpans, while those in TE-1 were mainly stilbenoids, which could be inferred that all of these three kinds of constituents may be responsible for the antithrombotic effects of Caragana jubata. PMID- 28905572 TI - [Separation and identification of specific components and quality standard of stem of Dendrobium officinale]. AB - The violanthin, a specific component, was separated and identified from the stems of Dendrobium officinale by chromatographic technique and spectroscopic method for the first time. The microscopic characteristics of D. officinale powder were examined under a microscopy and described. Thin layer chromatography (TLC) method was used for qualitative analysis of the violanthin from D. officinale stems with a mixture of ethyl acetate, butanone, formic acid and water (4?3?1?1) as the developing solvent on high performance silica gel precoated plate (SGF254) and using aluminium trichloride as a chromagenic agent. The results showed significant characteristics of violanthin from D. officinale stems on TLC, with certain specificity, and could be used to distinguish it from other easily confusing processed medicinal stems of D. devonianum, D. gratiosissimum and D. aphyllum. The content of naringenin, an active ingredient in D. officinale stems was determined by HPLC analysis on a Bischoff Chromatography HIPAK NC-04 ODS AB column (4.4 mm*250 mm, 5 mm) with acetonitrile-0.1% phosphoric acid solution as the mobile phase for gradient elution. The wavelength was set at 226 nm and column temperature was 25 C. The HPLC method showed good linearity within the range of 3.90-250.00 g*mL-1 (r = 0.999 9) for naringenin. The average recovery of naringenin was 99.20% with 0.17% of RSD. The mass fraction of 20 batches of D. officinale stems was between 0.190 and 0.498 mg*g-1. The established qualitative and quantitative method was simple and rapid with good repeatability and accuracy, providing experimental basis for improving the quality standard of D. officinale, with a very important significance to ensure its quality and clinical effect. PMID- 28905573 TI - [Studies of pattern recognition of fingerprint profile of cattle bile powder and determination of multi-component in it]. AB - An HPLC-ELSD method with good specificity and good accuracy was used for the studies of fingerprint and quantification of multi-components for cattle bile powder. The chromatographic analysis was carried out on a Phenomenex Gemini C18 column (4.6 mm*250 mm, 5 MUm) with a column temperature of 40 C and a liquid flow rate of 1.0 mL*min-1 using 10 mmol ammonium acetate solution and acetonitrile as the mobile phase with a linear gradient. An ELSD was used with a nitrogen flow rate of 2.8 L*h-1, at a drift tube temperature of 110 C. The average contents of glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid were (25.2+/-17.0)%, (4.1+/-3.4)%, (24.5+/-20.0)% and (5.2+/-3.8)% respectively, and the total content of the four bile acids was (59.0+/-26.0)%. Beyond that, the preprocessing and pattern recognition analysis of the chromatographic fingerprints of samples were applied with chemometric method. The results of this chemometric analysis indicated that the samples from market and self-made samples were different signally, and four regions were noteworthy due to their great impact with poor chromatographic signal. All in one, because this HPLC-ELSD method was simple and accurate, it was suitable for the quality assessment and quality control of cattle bile powder and could be the technological base for its standard perfection. PMID- 28905574 TI - [Quantitative analysis of nucleosides in four Cordyceps genus by HPLC]. AB - To compare the main nucleosides in Cordyceps genus herbs (C. sinensis, C. millitaris, Hirsutella sinensis and C. sobolifera), an HPLC method for simultaneous determination of uridine, inosine, guanosine, adenosine and cordycepine in Cordyceps genus herbs was developed. The sample was extracted with 0.5% phosphoric acid solution to prepare test solution. The separation was performed on a Zorbax SB-Aq (4.6 mm*150 mm, 5 MUm) column with gradient elution by 0.04 mol*L-1 potassium dihydrogen phosphate solution and acetonitrile, column temperature 30 C,flow rate 0.8 mL*min-1,and detection wavelength 260 nm. The content of nucleosides in four Cordyceps genus herbs was evaluated by fingerprint analysis and hierarchical cluster analysis (HCA). The calibration curves of five nucleosides showed good linear regression (r>0.99) and the average recoveries were between 95.0% and 105.0%. The contents of the five nucleosides in the four Cordyceps genus herbs were different and could be obviously distinguished by HCA. The fingerprint analysis result showed that the similarity between C. sinensis and the others was less than 0.9. The method was accurate and reliable, which can be used for quality control of Cordyceps genus herbs. PMID- 28905575 TI - [Association between chemical composition of essential oil with penetration enhancement effect and drug properties of traditional Chinese medicine]. AB - The results of previous studies showed potential correlations between the penetration enhancement effect of essential oils and the drug properties of traditional Chinese medicine based on the data mining method. As chemical composition is the material basis of drug properties of traditional Chinese medicine, this article further analyzed the correlation between the chemical composition of essential oils and the drug properties. Firstly, essential oils were extracted by steam distillation, and then physicochemical parameters of essential oils, such as relative density and refractive index, were measured. The chemical components of 20 essential oils were analyzed by GC-MS, and divided into 12 categories according to skeleton features and functional groups. Finally, Logistic regression analysis was applied to reveal the correlations. The results proved that five flavors, four tastes and channel tropisms showed the correlation with chemical composition of essential oils (P<0.05). In conclusion, there were obvious correlations and regularity between the drug properties of traditional Chinese medicine and the chemical composition of essential oils. PMID- 28905576 TI - [Inhibitory effects of acteoside on LPS-induced inflammatory response on BV-2 microglial cells]. AB - To investigate the inhibitory effects of acteoside (ACT) on BV-2 microglial cells and the potential mechanism,LPS was used to treat BV-2 cells with or without ACT (12.5,25,50 MUmol*L -1). Then, the expressions of inflammatory factors (NO,TNF alpha,IL-6) and inflammation related proteins (iNOS,COX-2,p-IKKbeta,IKKbeta,p IkappaB,IkappaB) were detected. In addition,the nuclear translocation of NF kappaB was explored. The results showed that ACT could significantly suppress the inflammatory response against LPS stimulation by decreasing the expressions of NO,IL-6,TNF-alpha,iNOS,COX-2 and the phosphorylations of IKKbeta and IkappaB. Moreover,the nuclear translocation of NF-kappaB p65 was inhibited by ACT. Taken together, ACT could significantly inhibit the inflammatory response of BV-2 microglial cells which were induced by LPS via inhibition of NF-kappaB signaling pathway. PMID- 28905577 TI - [Screen potential CYP450 2E1 inhibitors from Chinese herbal medicine based on support vector regression and molecular docking method]. AB - Inhibition of cytochrome P450 (CYP450) enzymes is the most common reasons for drug interactions, so the study on early prediction of CYPs inhibitors can help to decrease the incidence of adverse reactions caused by drug interactions.CYP450 2E1(CYP2E1), as a key role in drug metabolism process, has broad spectrum of drug metabolism substrate. In this study, 32 CYP2E1 inhibitors were collected for the construction of support vector regression (SVR) model. The test set data were used to verify CYP2E1 quantitative models and obtain the optimal prediction model of CYP2E1 inhibitor. Meanwhile, one molecular docking program, CDOCKER, was utilized to analyze the interaction pattern between positive compounds and active pocket to establish the optimal screening model of CYP2E1 inhibitors.SVR model and molecular docking prediction model were combined to screen traditional Chinese medicine database (TCMD), which could improve the calculation efficiency and prediction accuracy. 6 376 traditional Chinese medicine (TCM) compounds predicted by SVR model were obtained, and in further verification by using molecular docking model, 247 TCM compounds with potential inhibitory activities against CYP2E1 were finally retained. Some of them have been verified by experiments. The results demonstrated that this study could provide guidance for the virtual screening of CYP450 inhibitors and the prediction of CYPs-mediated DDIs, and also provide references for clinical rational drug use. PMID- 28905578 TI - [Effect of allicin on myocardial fibrosis after myocardial infarction in rats and its relationship with TGFbeta/Smads signal transduction]. AB - Allicin is the internationally accepted active substance of garlic, and has cardiovascular protective effect. This research was designed to investigate the effect of allicin on myocardial fibrosis after myocardial infarction and explore the relationship between the effect and TGFbeta1/Smads signaling pathway. The rat myocardial infarction model were made by ligating the left anterior desending coronary artery. The drugs were administered intraperitoneally 24 h after the operation. After 21 days, the rats were sacrificed and myocardial collagen fibres were observed by Masson staining. The protein expression of I, III collagen and TGFbeta1, Smad3, Smad7 in the myocardium was measured by the immunohistochemistry. The results showed that myocardial fibrosis was serious and the expression of I, III collagen was increased in model group. After treatment with allicin, the myocardial fibrosis could be relieved markedly, and the expression of collagen was down-regulated. Meanwhile, TGFbeta1 and Smad3 in heart tissue could be down-regulated and Smad7 could be up-regulated in allicin groups. So allicin may exhibit anti-myocardial fibrosis effect on rats, and the mechanism of this is related to TGFbeta/Smads signal transduction. PMID- 28905579 TI - [Screening of anti-aging active ingredients and mechanism analysis based on molecular docking technology]. AB - Dampness evil is the source of all diseases, which is easy to cause disease and promote aging, while aging could also promote the occurence and development of diseases. In this paper, the relationship between the dampness evil and aging would be discussed, to find the anti-aging active ingredients in traditional Chinese medicine (TCM), and analyze the anti-aging mechanism of dampness eliminating drug. Molecular docking technology was used, with aging-related mammalian target of rapamycin as the docking receptors, and chemical components of Fuling, Sangzhi, Mugua, Yiyiren and Houpo as the docking molecules, to preliminarily screen the anti-aging active ingredients in dampness eliminating drug. Through the comparison with active drugs already on the market (temsirolimus and everolimus), 12 kinds of potential anti-aging active ingredients were found, but their drug gability still needs further study. The docking results showed that various components in the dampness eliminating drug can play anti-aging activities by acting on mammalian target of rapamycin. This result provides a new thought and direction for the method of delaying aging by eliminating dampness. PMID- 28905580 TI - [In vivo intestinal absorption characteristics of phloridzin in rats]. AB - To study the in vivo intestinal absorption kinetics of phloridzin in rats. The absorption of phloridzin in the small intestines and colon of rats was investigated using an in vivo single-pass perfusion method and the drug concentration was measured by HPLC. The effects on intestinal absorption of different drug concentration and P-glycoprotein (P-gp) inhibitor were conducted. The results showed that the phloridzin could be absorbed in whole intestine, but more fully in the jejunum and colon segment,poorly absorbed in the duodenum and ileum. The absorption rate constant (Ka) and the apparent absorption coefficient(Papp)of phloridzin decreased following the sequence of jejunum> colon > duodenum > ileum. Absorption parameters of phloridzin had no significant difference at different concentration (5.14, 10.28, 20.56 mg*L-1) . The saturate phenomena was not observed under the test range of drug concentration, and the absorption mechanism may be the passive diffusion transport.There had a significant difference in Ka and Papp values between P-gp inhibitor and no P-gp inhibitor groups. Phloridzin may be the substrate of P-gp. PMID- 28905581 TI - [Absorption and metabolism of icariin in different osteoporosis rat models]. AB - To compare the intestinal absorption and metabolism of icariin in different osteoporosis rat models. Ovariectomy and intragastric administration of cyclophosphamide were used to establish two kinds of rat osteoporosis models. Then the rat intestinal perfusion was conducted, and HPLC was used to measure and calculate the permeability coefficients of icariin in different intestines and production amount of metabolites. Western blot was used to detect LPH enzyme expression in two models. Experimental results showed that both ovariectomy and intragastric administration of cyclophosphamide 4.5 mg*kg-1 could reduce rat bone density and successfully construct the rat osteoporosis models. The apparent permeability coefficient Papp of 20 MUmol icariin in duodenum, jejunum, ileum, colon was 5.695, 5.224, 1.492, 0.520 respectively in sham operation group; 3.876, 3.608, 0.863, and 0.291 in ovariectomized group; 4.945, 3.601, 1.990, 1.042 in normal saline group; 3.301, 2.108, 1.209, 1.233 in cyclophosphamide-induced osteoporosis model group. In addition, the protein expression levels of LPH enzyme in two model groups were lower than those in normal group. The absorption and metabolism of icariin in two kinds of osteoporosis models was lower than that in sham operation group and normal saline group; the reduction of expression level of LPH enzymes in rat intestine of different osteoporosis models was one of the reasons for leading to the reduced intestinal absorption and metabolism of icariin. PMID- 28905582 TI - [In vitro recovery rate of bullatine A microdialysis probe]. AB - To establish UPLC-MS/MS method for determination of the recovery rate of bullatine A microdialysis probe. The concentration difference method(incremental method, decrement method) was used to measure in vitro recoveries, and the effects of perfusate pH value, flow rate, concentration, and temperature on the recovery rate were investigated to explore the feasibility of microdialysis for the pharmacokinetic study of bullatine A. The method of UPLC-MS/MS showed good linear relationship within the required range; the specificity, recovery rate and precision of chromatography met the requirements of microdialysis samples. There was no significant difference in the measured recovery rate between incremental method and decrement method. Under the same conditions, in vitro recovery rate of the probe was decreased with the increase of flow rate, and was significantly increased with the increase of temperature, but was independent of bullatine A concentrations around the probe. The results showed that, microdialysis technology can be used for the pharmacokinetic study of bullatine A, and retrodialysis method (decrement method) can be used for the determination of the in vivo recovery rate of bullatine A microdialysis. PMID- 28905583 TI - [Pharmacokinetics and tissue distribution of alpha-hederin sodium salt in rats]. AB - To study the pharmacokinetics and tissue distribution characteristics of alpha hederin sodium salt in rats. 100 mg*kg-1 alpha-hederin sodium salt was given to the rats by intragastric administration, and LC-MS/MS method was used to determine its concentration at different time in plasma and tissues. Plasma and tissue samples were treated with methanol protein deposition method. Main pharmacokinetic parameters were as follows: tmax (0.97+/-1.23) h, Cmax (222.53+/ 57.28) MUg*L-1, AUC0-t (1 262+/-788.9) h*MUg*L-1, T1/2 (17.94+/-9.50) h. alpha hederin can be detected in heart, liver, spleen, lung, kidney, brain, muscle and adipose. The results showed that alpha-hederin sodium salt was absorbed fast and eliminated slowly in rats after oral administration. It was widely distributed in body tissues and livers kept the highest concentrations among various tissues at different time, so it can be speculated that alpha-hederin may have certain targeting property on livers. PMID- 28905584 TI - [Analysis on composition principles of prescriptions for nausea by using traditional Chinese medicine inheritance support system]. AB - Nausea is special in the symptoms, and is different from hiccups and vomiting. The main symptom is that the patients throw up the indigested food from the stomach regularly--if the patients have a dinner, they will throw out it in the next morning, or if the patients have a breakfast, they will throw out it at night. Nausea is common in clinic, and different physicians may use different treatment methods for it. This disease also cannot be treated efficiently and may happen repeatedly with the western medicine. In this study, the composition principles of prescriptions in past traditional Chinese medicine for nausea were analyzed and summarized by using traditional Chinese medicine inheritance support system(V2.5), hoping to provide guidance for clinical drug use and summarize the basic rules for treatment of nausea.The prescriptions for nausea in "the prescription of traditional Chinese medicine dictionary" were selected, and the information was entered into the traditional Chinese medicine inheritance support system(TCMISS) to build a database. Data mining methods such as frequency statistics, association rules, complex system entropy clustering were used to analyze and summarize the composition principles of these prescriptions. The herb frequencies of the prescriptions were finally determined; herbs with higher use frequencies were obtained; and the association rules between herbs were found. 19 commonly used herb pairs, 10 core combinations and 10 newly developed prescriptions were found. The basic pathogenesis of nausea in traditional Chinese medicine is the weakness and coldness of spleen and stomach, and the Qi adverseness of stomach. Generations of physicians' main therapeutic method for nausea is mainly to warm the middle and invigorate the spleen, lower Qi and regulate stomach. The commonly used herbs for nausea are ginger, ginseng, large head attractylodes, tuckahoe, licorice, and appropriately supplemented with the herbs of eliminating dampness and eliminating phlegm, and regulating Qi-flowing for harmonizing stomach. In addition, it shall be treated according to the different accompanying syndromes such as phlegm, blood stasis, and yin deficiency. PMID- 28905585 TI - [Analysis of clinical medication rules in 48 398 patients with limb fractures based on hospital information system]. AB - To explore the clinical medication rules in the patients with limb fractures, and provide guidance for clinical practice. Data of 48 398 patients with limb fractures from 2001 to 2011 was extracted from the hospital information system(HIS) established by the institute of basic research in clinical medicine, China academy of Chinese medical sciences. The gender and age distribution of patients and clinical medication characteristics were described. Apriori algorithm was adopted to analyze the common drug combinations of Chinese medicine(CM) and western medicine(WM). The study results showed that the ratio of included males and females was 1.83?1. There was a high peak of incidence for the patients from 18 to 44 years. Apriori algorithm showed that the usage of WM was more frequent than that of CM. The most commonly used CM was Lugua polypeptide and sodium aescinate injection. Blood-activating and stasis-resolving medicines, as well as tendons and bones-strengthening medicines were the commonly used CM types. In addition, WM antibiotics plus blood-activating and stasis-resolving CM, or antibiotics plus tendons and bones-strengthening CM was the most commonly used drug combination. Based on the analysis of available data, the prevalence of limb fracture was higher in men than in women; more in young and middle-aged patients; the common drug combination was antibiotics plus blood-activating and stasis resolving CM, or antibiotics plus tendons and bones-strengthening CM. More prospective and high-quality clinical trials are necessary to evaluate the effect of CM or integrative medicine treatment for limb fracture in the future research. PMID- 28905586 TI - [Development of rapid setting-drying device for herbarium specimens and its application in survey of Chinese materia medica resources in Anhui]. AB - Herbarium specimens are the basis for the plant classification and indispensable media in teaching, scientific research and resources investigation. They have also played an important role in identifying and producing traditional Chinese medicine. High-quality herbarium specimens shall meet high requirements for integrity, smoothness, color and fabricating efficiency. Therefore, we designed a rapid setting and drying device for herbarium specimens, which could make the herbarium specimens smooth, colorful and not easy to mildew. In this paper, we pointed out the deficiency of traditional methods in making herbarium specimens, and introduced the structure and working principle of the device. Besides, we also discussed the effect of the device in setting and drying herbarium specimens and its application in the fourth national survey of the Chinese material medica resources (CMMR) in Anhui province. As a result, the device provides new ideas for producing herbarium specimens, with a reasonable design, good uniformity, high efficiency, safety and portability, and so is worthy of promotion and application in the national survey of CMMR. PMID- 28905587 TI - [Development ideas of fine pharmaceutical materials of traditional Chinese medicine preparations based on active cluster theory]. AB - The pharmaceutical materials are divided into coarse and fine types in the development of traditional Chinese medicine preparations. Fine materials with clear composition, stable content and high quality control conform to the international development trend of traditional Chinese medicine preparations. In this paper, the status of fine materials was analyzed, and the development ideas were tentatively put forward. On the one hand, the study on simple methods and efficient equipment shall be strengthened for the simultaneous separation of multiple components of traditional Chinese medicine; on the other hand, the knowledge for traditional Chinese medicine shall be broadened to further develop the scientific compatibility of monomers under the guidance of the theory of traditional Chinese medicine. PMID- 28905588 TI - [Comparison of sulfur fumigation processing and direct hot air heating technology on puerarin contents and efficacy of Puerariae Thomsonii Radix]. AB - In order to compare the effect of sulfur fumigation processing and direct hot air heating technology on puerarin contents and efficacy of Puerariae Thomsonii Radix, the fresh roots of Pueraria thomsonii were cut into small pieces and prepared into direct sunshine drying samples, direct hot air drying samples, and sulfur fumigation-hot air drying samples. Moisture contents of the samples were then determined. The puerarin contents of different samples were compared by HPLC method. Moreover, the models of drunkenness mice were established, and then with superoxide dismutase (SOD) content as the index, aqueous decoction extracts of Puerariae Thomsonii Radix samples with sulfur fumigation processing and non sulfur fumigation processing methods were administrated by ig; the effects of sulfur fumigation on contents of SOD in mice liver and serum were determined, and the sulfur fumigation samples and non-sulfur fumigation samples were investigated for moth and mildew under different packaging and storage conditions. Results showed that the sulfur fumigation samples significantly changed the puerarin content from Puerariae Thomsonii Radix. The content of puerarin was decreased gradually when increasing the times of sulfur fumigation and amount of sulfur. SOD content in drunken mice liver and serum was significantly decreased when increasing the times of sulfur fumigation, showing significant difference with both direct sunshine drying group and direct hot air drying group. Moth and mildew were not found in the sulfur fumigation samples and direct hot air drying samples whose moisture contents were lower than the limit in Pharmacopoeia. Research showed that sulfur fumigation can significantly reduce the content of main active ingredients and reduce the efficacy of Puerariae Thomsonii Radix, indicating that the quality of Puerariae Thomsonii Radix was significantly decreased after sulfur fumigation. However, the contents of the main active ingredients, efficacy and storage results of the direct hot air drying samples were similar to those in direct sunshine drying samples, so the hot air drying process was a nice drying technology which could be promoted for use. PMID- 28905589 TI - [Effects of Atractylodis Macrocephale Rhizoma processed by different methods on salivary amylase and D-xylose excretion rate in rats]. AB - To observe the effects of Atractylodis Macrocephale Rhizoma processed by different methods (sulfur-fumigation, different temperatures baking and microwave sterilization) on salivary amylase and D-xylose excretion rate in spleen deficiency rats. The rats were divided into blank control group, rhubarb-induced spleen deficiency model control group, and Atractylodis Macrocephale Rhizoma experimental groups processed with different methods. Amylase colorimetric method was used to determine the activities of salivary amylase and D-xylose excretion rate was measured with O-benzylamine method. Then the correlation of salivary amylase activity and D-xylose excretion rate in urinary was analyzed. As compared with blank control group, Atractylodis Macrocephale Rhizoma baked at 100,110 C can increase the unit content of rat salivary amylase and D-xylose excretion rate, with a significant difference (P<0.05). As compared with the model group, Atractylodis Macrocephale Rhizoma baked at 70 C and Atractylodis Macrocephale Rhizoma with microwave treatment had stronger effects than the others, with statistically significant differences (P<0.01). Atractylodis Macrocephale Rhizoma could improve D-xylose absorption function and salivary amylase activity in spleen deficiency rats. In addition, D-xylose excretion rate in urine was positively correlated with salivary amylase activity. Atractylodis Macrocephale Rhizoma processed with different temperatures baking and microwave sterilization had little impact on salivary amylase activity and D-xylose excretion rate in urine of spleen deficiency rats, while sulfur fumigation had great effects on the above two indexes. PMID- 28905590 TI - [Select alternative technology to sulfur fumigation for Astragali Radix based on multi-index method]. AB - Sulfur fumigation method is often used in the habitat processing of Astragali Radix in order to make it mothproof, mildewproof and easy to dry; however, this method has great influence on the inherent quality of Astragali Radix. Therefore, it is urgent to develop the alternative technology to sulfur fumigation. In the present paper, appearance characteristics, content of active ingredients, containing water, extracting content and microbial content in Astragali Radix were taken as the indexes to compare the quality of Astragali Radix processed with 9 kinds of processing methods (traditional processing method, sulfur fumigation and 7 kinds of alternative processing technologies). Combined hot air microwave technology was finally determined as an alternative technology to sulfur fumigation. PMID- 28905591 TI - [Effects of different drying methods on quality of Gastrodiae Rhizoma]. AB - Different drying methods, including drying in the sun, sulphur fumigation, hot air drying, microwave drying, infrared drying and various coupling techniques,were used to dry fresh Gastrodiae Rhizoma. Characteristics, extracts and the contents of active components of all samples were compared to investigate the effects of different drying methods on quality of Gastrodiae Rhizoma. The results showed that the characteristics of the samples would be better with use of sulphur fumigation, hot air drying, and hot air-microwave drying. Different drying methods had little effects on extracts. Among them, the extract content was higher after hot air drying. The stilbene glycosides would transformation and the contents of Gastrodiae Rhizoma polysaccharides would decline with use of sulphur fumigation, microwave drying and infrared drying. In the comprehensive analysis of characteristics, content of active components, production cost and other factors, hot air drying or hot air-microwave drying was recommended as the first choice. PMID- 28905592 TI - [Research progress on antioxidation effect of traditional Chinese medicine polysaccharides and sports for diabetes prevention and treatment]. AB - Researchers found that oxidative stress was closely related to the development of diabetes, and hyperglycemia was a main cause for oxidative stress. Many researchers have proved that oxidative stress, present in diabetes, can aggravate diabetes. Now, traditional Chinese medicines have certain treatment and relief effects for oxidative stress in diabetes, but there are no scientific and systematic conclusions on the efficacy of different Chinese medicines for diabetes and complications. Tomakea scientific and systematic review on the recent years' researches on antioxidation effects of traditional Chinese medication polysaccharides for diabetes, analyze the antioxidation effects of sports in treatment of diabetes, and provide the reference and basis for medications and sports in diabetic patients, as well as prevention and treatments of diabetes and complications from aspects of "internal nursing and external workouts". Databases of CNKI and PubMed were retrieved with key words of "diabetes, oxidative stress, antioxidant, traditional Chinese medication, polysaccharide, sports" in both Chinese and English from Jan 2000 to Apr 2016.Finally 118 papers were included in for analysis and review. Polysaccharides of traditional Chinese medications as well as sports have antioxidation effects for diabetes and its complications, and the combination of these two would produce huge significance for relieving oxidative stress in diabetes, as well as for the prevention and treatment of diabetes and its complications. We need further researches on the levels of oxidative stress markers, doses of Chinese medicines, and the time of taking medications. PMID- 28905593 TI - [Progress of antibacterial activity and antibacterial mechanism of isoquinoline alkaloids]. AB - This paper reviewed the antibacterial activity and structure-activity relationship of isoquinoline alkaloids, such as protoberberine, protopine, benzophenanthridine, aporphine, double benzyl isoquinoline, etc. The antibacterial mechanism of alkaloids were illustrated from cell wall and membrane damage, membrane permeability changes, related enzymes and efflux pump inhibition, influence of bacterial DNA and related protein synthesis and so on. In addition, this paper summarized the structure-activity relationship of isoquinoline alkaloids. In order to improve the screening efficiency of drug targets, the complementary effect of biological information science and combinatorial chemistry should be developed abundantly in the development of natural product. This paper will provide a theoretical reference for the research and development of new antibacterial agent. PMID- 28905594 TI - [Study on difference of functional components content of different Rheum tanguticum variation type]. AB - Rheum tanguticum from the same area was divided into 8 types of variation according to the plant morphology, content differences of free anthraquinones, combined anthraquinones, double anthrone were studied. The results showed that the functional components of different variation types were significantly different. The average content of free anthraquinone combined anthraquinone was 2.10-6.71 and 15.43-22.04 mg*g-1, respectively. The average content of sennoside A plus sennoside B was 32.88-42.36 mg*g-1. There were significant differences among the difference of 10 kinds of active components, except for sennoside B and physcion glycoside. Interred with the content and proportion of functional components, type B and type E might be potential special medicinal germplasm for diarrhea attack product, type G and type H might be a potential special medicinal germplasm for clearing heat and detoxifing, type C and type F might be potential special medicinal germplasm for activating blood circulation to dissipate blood stasis, type A and type D might be potential special medicinal germplasm with anastaltic funtion. The conclusion laid the foundation for the directional cultivation of fine varieties of special purpose of rhubarb. PMID- 28905595 TI - [Cloning, subcellular lacalization and expression analysis of chloroplast targeted Obg gene in Cyathula officinalis]. AB - According to ObgC gene sequences from Cyathula officinalis genomic data, the specific primers were designed, and a full-length CoObgC cDNA (2 226 bp) was obtained by polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE) methord. Sequence alignment showed that CoObgC gene contained a 1 818 bp open reading frame (ORF) encoding 605 amino acids. Sequence analysis predicted that molecular weight of CoObgC protein was about 66.39 kDa, the academic isoelectric point was 5.35, and the protein was stable protein. Then multiple sequence alignment was applied to construct phylogenetic tree. The real-time fluorescence quantification PCR (RT-qPCR) demonstrated that a high expression level in leaf, followed by root and flower, the low transcription was in stem. The recombinant vector pCABIA2300-CoObgC was constructed and introduced into tobacco epidermal cells by agrobacterium-mediated transformation, green fluorescence was tested and targeted to chloroplast under a laser scanning confocal microscope. These findings will be helpful to lay a foundation for studying the structure and function of CoObgC gene, and elucidating C. officinalis molecular biology experiment. PMID- 28905596 TI - [Preliminary studies on critical control point of traceability system in wolfberry]. AB - As a traditional Chinese medicine, wolfberry (Lycium barbarum) has a long cultivation history and a good industrial development foundation. With the development of wolfberry production, the expansion of cultivation area and the increased attention of governments and consumers on food safety, the quality and safety requirement of wolfberry is higher demanded. The quality tracing and traceability system of production entire processes is the important technology tools to protect the wolfberry safety, and to maintain sustained and healthy development of the wolfberry industry. Thus, this article analyzed the wolfberry quality management from the actual situation, the safety hazard sources were discussed according to the HACCP (hazard analysis and critical control point) and GAP (good agricultural practice for Chinese crude drugs), and to provide a reference for the traceability system of wolfberry. PMID- 28905597 TI - [Effects of fluridone, gibberellin acid and germination temperature on dormancy breaking for Epimedium wushanense]. AB - We introduced Epimedium wushanense seed which has been stratified for 90 days at 10/20 C as experimental materials, with which we studied the effects of fluridone, gibberellin acid and temperature on E. wushanense germination. The results were suggested as shown below. 1Temperature, fluridone and gibberellin acid can both solely or jointly affect germination energy, germination rate significantly. Among those factors, fluridone affect germination rate and germination energy the most, followed by gibberellin acid and temperature. The highest germination rate under 4 C and 10/20 C stratification are 79.3%, 72.0% respectively, which resulted from treatment of F10GA300 and F20GA200 respectively. The highest germination energy under 4 C and 10/20 C stratification are 52.7%, 52.0%, respectively, which both resulted from F20GA200. 2Compared with 4 C germination, seed could not germinate at 10/20 C germination. Nontheless, application of fluridone can lead E. wushanense seeds to germinating.3The effects of gibberellin acid and interaction between gibberellin acid and fluridone significantly affect seed rotten rate during germination. In addition, soaking is another remarkable factor which increased seed rotten rate. As a result, it is feasible to promote E. wushanense dormancy releasing with gibberellin acid and fluridone associating with a proper germination temperature. Further, it is necessary taking actions to avoid seed rotten rate for saving E. wushanense nurseries'cost. PMID- 28905598 TI - [Synergistic effect of Epimedii Folium fried with suet oil for warming kidney and enhancing yang in dosage form of self-assembled micelles]. AB - The fried method with suet oil, which can strengthen the effect of Epimedii Folium in warming kidney and enhancing yang, has been widely used in the processing of Epimedii Folium in traditional Chinese medicine. In this paper, we adopted hydrocortisone-induced kidney-yang deficiency rat models, and took physical signs, serum testosterone, corticosterone levels and histopathological examination of rats as indictors to systematically study the synergistic effect of suet oil in warming kidney and enhancing yang of fried Epimedii Folium in the dosage form of self-assembled micelles. Drugs were given orally, and compared with model group, indicating normal physical signs and biochemical indicators, and significant alleviation in disorder of hypothalamic-pituitary-adrenal-thymus (HPAT) axis suppression. All these experimental results indicated that both Epimedium flavonoids and its self-assembled micelles, especially the processed self-assembled micelles of Epimedii Folium, showed the significant effects in warming kidney and enhancing yang, which might be correlated with the regulation of the disorder of HPAT axis suppression and the improvement of major pathological conditions of testicular gonadal tissues. This discovery can further reveal the synergistic effect and mechanism of processing material suet oil on Epimedii Folium. PMID- 28905599 TI - [Differences in effective mechanisms of Coptidis Rhizoma and bile processed Coptidis Rhizoma on heat syndrome based on urinary metabonomics]. AB - A urinary metabonomics method based on ultra-performance liquid chromatography coupled with LTQ-Orbitrap-mass spectrometry (UPLC/LTQ-Orbitrap-MS) was developed to study the difference of action mechanism of Coptidis Rhizoma (CR) and bile processed CR on the heat syndromein rats, and reveal the scientificity of CR processing method. The heat syndrome rat models were established by intragastric administration of water decoction of Aconiti Lateralis Radix Preparata, Zingiberis Rhizoma and Cinnamomi Cortex for 15 days combined with subcutaneous injection of dry yeast suspension. After administration for 15 days, the urine of rats in each group was collected at 0-6 h after modeling, 6-12 h after modeling and 12-24 h after modeling; principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used for data treatment. Good separation was observed between the normal groups and model group at 0-6 h and 6 12 h, but overlapped at 12-24 h with no separation trend. Obvious separation was achieved in urine samples between CR group, BCR group and model groups at 0-6 h, close to the normal group. Separation trend occurred between CR group and BCR group at 0-6 h and 6-12 h. Thirty potential biomarkers related with heat syndrome were identified by PLS-DA approach. The results showed that the overall therapeutic effect of CR for heat syndrome had been changed after being processed with pig bile. Bile processed CR has the characteristics of multiple targets, rapid onset and strong effects, mainly playing a role of antipyretic effect through regulating cholinergic neurotransmitter, amino acid metabolism and purine metabolism. PMID- 28905600 TI - [GC-MS combined with AMDIS and Kovats retention index to investigate dynamic change rules of volatile components from Atractylodis Macrocephalae Rhizoma with different stir-baking degrees]. AB - To investigate the dynamic change rules of volatile components from Atractylodis Macrocephalae Rhizoma with different stir-baking degrees (from slight stir baking, stir-baking to yellow, stir-baking to brown, to stir-baking to scorch). In the present experiment, the Atractylodis Macrocephalae Rhizoma samples with different stir-baking degrees were collected at different processing time points. The contents of volatile oil in various samples were determined by steam distillation method, and the volatile compounds were extracted by using static headspace sampling method. Gas chromatography-mass spectrography (GC-MS) and automated mass spectral deconrolution and identification system (AMDIS) were combined with Kovats retention index to analyze the chemical constituents of the volatile compounds. The results showed that with the deepening of the stir-baking degree, the content of volatile oil was decreased step by step in 4 phases, and both the compositions and contents of volatile components from Atractylodis Macrocephalae Rhizoma showed significant changes. The results showed that the dynamic change rules of volatile components from Atractylodis Macrocephalae Rhizoma in the process of stir-baking were closely related to the processing degree; in addition, Atractylodis Macrocephalae Rhizoma and honey bran had adsorption on each other. These results can provide a scientific basis for elucidating the stir-baking (with bran) mechanism of Atractylodis Macrocephalae Rhizoma. PMID- 28905601 TI - [A new furan-2-carboxylic acid from stem bark of Cassia alata]. AB - A new furan-2-carboxylic acid, 5-[3-(hydroxymethyl)-4,5-dimethoxyphenyl]-3 methylfuran-2-carboxylic acid(1),has been isolated from the bark of Cassia alata by using various chromatographic techniques. It displayed cytotoxicity against NB4, A549, SHSY5Y, PC3 and MCF7 cell lines with IC50 values of 2.5, 1.2, 2.2, 3.6 and 1.9 MUmol*L-1, respectively. PMID- 28905602 TI - [Sesquiterpenoids from rhizome of Homalomena occulta]. AB - Twelve compounds were isolated from alcohol extracts of the rhizome of Homalomena occulta by using various chromatographic techniques including column chromatography onsilica gel and C18 reverse-phase silica gel, and semi preparative HPLC. Their structures were identified by physico-chemical properties and spectroscopic data analysis as 3alpha, 7alpha-dihydroxy-cadin-4-ene (1), 3 oxofabiaimbricatan (2), 3beta, 4alpha-dihydroxy-7-epi-eudesm-11(13)-ene (3), integrifonol A(4), 1beta, 6beta-dihydroxy-7-epi-eudesm-11(13)-ene (5), 4beta, 7beta, 11-enantioeudesmantriol (6), epi-guaidiol (7), oplopanone(8), (-)-1beta, 4beta, 6alpha-trihydroxy-eudesmane (9),2alpha-hydroxyhomalomenol(10), (-)-T muurolol (11) and hamalomenol A(12). Compounds 1-7 were obtained from the genus Homalomena for the first time and 11-12 were firstly reported from the species. Additionally, compounds 3, 5 and 8 displayed inhibitory effects against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse macrophage RAW264.7 cells with IC50 values of 6.51, 3.25, 7.78 MUmol*L-1, respectively. PMID- 28905603 TI - [Exploration on feasibility of introducing bioassay method into quality evaluation of Chinese herbal medicines by studying on the correlation between antioxidant activity of Prunella vulgaris and its total phenolic acids content for example]. AB - This paper aims to investigate the correlation between the antioxidant activity of Prunella vulgaris and its total phenolic acids content by measuring the antioxidant activity of different sources and different organs of P. vulgaris and the total contents of protocatechuic acid, protocatechuic aldehyde, caffeic acid, salviaflaside and rosmarinic acid in these samples. Using the 50% methanol extract of P. vulgaris samples as the research object, DPPH method and HPLC method were used respectively to determine the antioxidant activities and the total contents of the above-mentioned five analytes in P. vulgaris samples. 0.5 mL of 50% methanol extract of P. vulgaris reacts with 0.1 mmol*L-1 DPPH ethanol solution for 60 min, then the absorbance of the reaction solution was measured at 517 nm, scavenging rate and IC50 values were calculated by the absorbance and the sample concentration for evaluating the antioxidant activity. HPLC analysis was made on a C18 Epic column, with acetonitrile-0.1% formic acid aqueous solution as mobile phase (gradient elution), and the detection wavelength was set at 280 nm. The correlation between the antioxidant capacity of different habitats and different organs of P. vulgaris and the total contents of five kinds of phenolic acids was analyzed by partial least squares method. The reaction dose-response range of 50% methanol extract of P. vulgaris with 0.1 mmol*L-1 DPPH ethanol solution was 0.300-1.65 g*L-1. When the quantities of potocatechuic acid, protocatechuic aldehyde, caffeic acid, salviaflaside and rosmarinic acid were respectively in 0.007 84-0.980, 0.011 5-1.44, 0.008 64-1.08, 0.080 0-1.00 and 0.079 8-0.998 MUg range, their quantities were in good linear relationship with the corresponding peak areas. The average recovery of 5 components were 97.76%, 96.88%, 100.3%, 102.1%, 104.5%, with RSD of 1.8%, 1.6%, 1.7%, 1.6% and 1.7%, respectively. In a certain range of crude drug quantity, the antioxidant activity of each organ of P. vulgaris and total phenolic acids content inside has a good linear correlation. Therefore, in certain quality range of crude drug, DPPH bioassay combined with HPLC content determination can be used for the quality control of P. vulgaris, as is a new method for the quality control of P. vulgaris. PMID- 28905604 TI - [Study on characteristic spectrum of ingredients from different species Cordyceps and its anti-fibrotic activity on human embryonic fibroblasts]. AB - In this study, 10 samples of parasites, cursive, and the whole from six different species of Cordyceps were determined and compared by HPLC and LC-MS methods. Uridine, adenosine, and cordycepin were selected as the main evaluation index. The anti-fibrotic activity of different species Cordyceps extracts was observed using in vitro TGF-beta1-induced ECM accumulation in human embryonic fibroblasts CCC-ESF-1. The results demonstrated that the number of atoms and hyphae ingredients of different species showed little difference, however, the content distribution of each component has obvious significance. The in vitro anti fibrotic activities of different species were as follow: Cordyceps flower > Cicada Cordyceps (Cicada flower)> Silkworm Cordyceps> Tussah Cordyceps>natural Cordyceps. Our preliminary data could serve as reference for the discovery of artificial alternatives of natural Cordyceps. PMID- 28905605 TI - [Density functional theory investigation on antioxidation activity of four flavonoids from Rhododendri Daurici Folium]. AB - Four main flavonoids of the Chinese medicine Rhododendri Daurici Folium were studied using the density functional theory (DFT) B3LYP method with 6-311 + + G (d, p) basis set.Their activities were analyzed based on molecular structure, bond dissociation energy (BDE) and the energy gap between HOMO and LUMO. As a result, the antioxidant ability order of the four flavonoids compounds is farrerol7 d; 4.2%(95%CI 0.027 to 0.059) and 8.4% (95%CI 0.059 to 0.113) respectively in single use and combined medication. Three most frequent types of adverse reaction symptoms reported were in skin and mucosa, digestive system, and body temperature center, with an incidence of 4% (95%CI 0.03 to 0.04), 3% (95%CI 0.02 to 0.03), and 1% (95%CI 0.00 to 0.01), respectively. The systemic evaluation demonstrated that the occurrence of adverse reaction of Shuanghuanglian injection was related to age, menstruum, duration of medication and combined medication. Incidence of adverse reactions differed considerably among different damage types. From the study demonstrated above, this paper concludes that we should follow the principles of evidence based medication of traditional Chinese medicine; use Shuanghuanglian injection singly instead of combination with other drugs in clinical use; use Shuanghuanglian injection strictly in accordance to instructions, especially for children and the elderly, whose weight should be calculated and considered in medication; intensively monitor the drug adverse reaction after use; assess the risks of adverse effects for long-term usage, and take corresponding safety measures to ensure safety. PMID- 28905615 TI - [Adverse reactions and countermeasures of drugs for children in China]. AB - In recent years, the clinical medication safety for children has gained wide public concern. Because of the growth and development characteristics of the children and drug usage conditions for children, the adverse reactions of drugs in clinic are more common in children than those in adults. In this paper, the common adverse drug reactions and their causes would be briefly introduced, and some suggestions would be put forward on how to reduce the incidence of adverse drug reactions. PMID- 28905616 TI - Head Positioning in Acute Stroke. PMID- 28905617 TI - Head Positioning in Acute Stroke. PMID- 28905618 TI - Functionalization of Reduced Graphene Oxide via Thiol-Maleimide "Click" Chemistry: Facile Fabrication of Targeted Drug Delivery Vehicles. AB - Materials based on reduced graphene oxide (rGO) have shown to be amenable to noncovalent functionalization through hydrophobic interactions. The scaffold, however, does not provide sufficient covalent linkage given the low number of reactive carboxyl and alcohol groups typically available on the rGO. The integration of clickable groups, particularly the ones that can undergo efficient conjugation without any metal catalyst, would allow facile functionalization of these materials. This study reports on the noncovalent association of a maleimide containing catechol (dopa-MAL) surface anchor onto the rGO. Thiol-maleimide chemistry allows thereafter the facile attachment of thiol-containing molecules under ambient metal-free conditions. Although the attachment of glutathione and 6 (ferrocenyl)hexanethiol was used as model thiols, the attachment of a cancer cell targeting cyclic peptide, c(RGDfC), opened the possibility of using the dopa-MAL modified rGO as a targeted drug delivery system for doxorubicin (DOX). Although free DOX showed to be more effective at killing the human cervical cancer cells (HeLa) over human breast adenocarcinoma cancer cells (MDA-MB-231), the DOX-loaded rGO/dopa-MAL-c (RGDfC) nanostructure showed an opposite effect being notably more effective at targeting and killing the MDA-MB-231 cells. The effect is enhanced upon laser irradiation for 10 min at 2 W cm-2. The facile fabrication and functionalization to readily obtain a functional material in a modular fashion make this clickable-rGO construct an attractive platform for various applications. PMID- 28905619 TI - Determination of Trace Perfluoroalkyl Carboxylic Acids in Edible Crop Matrices: Matrix Effect and Method Development. AB - A robust method was developed for simultaneous determination of nine trace perfluoroalkyl carboxylic acids (PFCAs) in various edible crop matrices including cereal (grain), root vegetable (carrot), leafy vegetable (lettuce), and melon vegetable (pumpkin) using ultrasonic extraction followed by solid-phase extraction cleanup and high liquid chromatography-tandem mass spectrometry (HPLC MS/MS). The varieties of extractants and cleanup cartridges, the usage of Supelclean graphitized carbon, and the matrix effect and its potential influencing factors were estimated to gain an optimal extraction procedure. The developed method presented high sensitivity and accuracy with the method detection limits and the recoveries at four fortification levels in various matrices ranging from 0.017 to 0.180 ng/g (dry weight) and from 70% to 114%, respectively. The successful application of the developed method to determine PFCAs in various crops sampled from several farms demonstrated its practicability for regular monitoring of PFCAs in real crops. PMID- 28905620 TI - Hierarchically Structured Graphene Coupled Microporous Organic Polymers for Superior CO2 Capture. AB - Hierarchically porous materials containing interconnected macro-/meso-/micropores are promising candidates for energy storage, catalysis, and gas separation. Here, we present an effective approach for synthesizing three-dimensional (3D) sulfonated graphene coupled microporous organic polymers (SG-MOPs). The resulting SG-MOPs possess uniform macropores with an average size of ca. 350 nm, abundant mesopores, and micropores with an average size of ca. 0.6 nm. The SG-supported adsorbents exhibit a high nitrogen content (more than 38.1 wt %), high adsorption capacity (up to 3.37 mmol CO2 g-1), high CO2/N2 selectivity from 42 to 51, moderate heat of adsorption, as well as good stability because of the hierarchical porous structure and excellent thermal conductivity of the SG scaffold. Thus, these nitrogen-enriched adsorbents allow the overall CO2 capture process to be promising and sustainable. PMID- 28905621 TI - Optimizing Nonlinear Optical Visibility of Two-Dimensional Materials. AB - Two-dimensional (2D) materials have attracted broad research interests across various nonlinear optical (NLO) studies, including nonlinear photoluminescence (NPL), second harmonic generation (SHG), transient absorption (TA), and so forth. These studies have unveiled important features and information of 2D materials, such as in grain boundaries, defects, and crystal orientations. However, as most research studies focused on the intrinsic NLO processes, little attention has been paid to the substrates underneath. Here, we discovered that the NLO signal depends significantly on the thickness of SiO2 in SiO2/Si substrates. A 40-fold enhancement of the NPL signal of graphene was observed when the SiO2 thickness was varied from 270 to 125 nm under 800 nm excitation. We systematically studied the NPL intensity of graphene on three different SiO2 thicknesses within a pump wavelength range of 800-1100 nm. The results agreed with a numerical model based on back reflection and interference. Furthermore, we have extended our measurements to include TA and SHG of graphene and MoS2, confirming that SiO2 thickness has similar effects on all of the three major types of NLO signals. Our results will serve as an important guidance for choosing the optimum substrates to conduct NLO research studies on 2D materials. PMID- 28905622 TI - Proton Diffusion through Bilayer Pores. AB - The transport of protons through channels in complex environments is important in biology and materials science. In this work, we use multistate empirical valence bond simulations to study proton transport within a well-defined bilayer pore in a lamellar Lbeta phase lyotropic liquid crystal (LLC). The LLC is formed from the self-assembly of dicarboxylate gemini surfactants in water, and a bilayer spanning pore of radius of approximately 3-5 A results from the uneven partitioning of surfactants between the two leaflets of the lamella. Local proton diffusion within the pore is significantly faster than diffusion at the bilayer surface, which is due to the greater hydrophobicity of the surfactant/water interface within the pore. Proton diffusion proceeds by surface transport along exposed hydrophobic pockets at the surfactant/water interface and depends on the continuity of hydronium-water hydrogen bond networks. At the bilayer surface, there is a reduced fraction of the "Zundel" intermediates that are central to the Grotthuss transport mechanism, whereas the fraction of these species within the bilayer pore is similar to that in bulk water. Our results demonstrate that the chemical nature of the confining interface, in addition to confinement length scale, is an important determiner of local proton transport in nanoconfined aqueous environments. PMID- 28905623 TI - Electropumping of Water Through Human Aquaporin 4 by Circularly Polarized Electric Fields: Dramatic Enhancement and Control Revealed by Non-Equilibrium Molecular Dynamics. AB - An extensive suite of nonequilibrium molecular-dynamics (NEMD) simulations have been performed for ~60 ns of human aquaporin 4 in externally applied circularly polarized (CP) electric fields, applied axially along channels. These external fields were 0.05 V/A in intensity and 100 GHz in frequency. This has the effect of "electro-pumping" the water through the pores as prototypical biochannels, from conversion of molecules' spin angular momentum to linear momentum in the asymmetric heterogeneous-frictional environment of the pores, thus inducing overall net flow. Water's osmotic permeability was enhanced very substantially (doubled) vis-a-vis the zero-field case. This raises the tantalizing possibility of CP-field-mediated control of water permeability in aquaporins, or other biological (or biomimetic) channels as a potential viable and competitive water treatment technology. PMID- 28905624 TI - Zinc Bioavailability from Phytate-Rich Foods and Zinc Supplements. Modeling the Effects of Food Components with Oxygen, Nitrogen, and Sulfur Donor Ligands. AB - Aqueous solubility of zinc phytate (Ksp = (2.6 +/- 0.2) * 10-47 mol7/L7), essential for zinc bioavailability from plant foods, was found to decrease with increasing temperature corresponding to DeltaHdis of -301 +/- 22 kJ/mol and DeltaSdis of -1901 +/- 72 J/(mol K). Binding of zinc to phytate was found to be exothermic for the stronger binding site and endothermic for the weaker binding site. The solubility of the slightly soluble zinc citrate and insoluble zinc phytate was found to be considerably enhanced by the food components with oxygen donor, nitrogen donor, and sulfur donor ligands. The driving force for the enhanced solubility is mainly due to the complex formation between zinc and the investigated food components rather than ligand exchange and ternary complex formation as revealed by quantum mechanical calculations and isothermal titration calorimetry. Histidine and citrate are promising ligands for improving zinc absorption from phytate-rich foods. PMID- 28905625 TI - Oral Ingestion and Intraventricular Injection of Curcumin Attenuates the Effort Related Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Motivational Symptoms of Depression. AB - Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of tetrabenazine were reversed by oral ingestion of curcumin (80.0 160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0-8.0 MUg). Curcumin attenuates the effort-related effects of tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms. PMID- 28905626 TI - DNA-Assisted Dispersion of Carbon Nanotubes and Comparison with Other Dispersing Agents. AB - Separation and sorting of pristine carbon nanotubes (CNTs) from bundle geometry is a very challenging task due to the insoluble and nondispersive nature of CNTs in aqueous medium. Recently, many studies have been performed to address this problem using various organic and inorganic solutions, surfactant molecules, and biomolecules as dispersing agents. Recent experimental studies have reported the DNA to be highly efficient in dispersing CNTs from bundle geometry. However, there is no microscopic study and also quantitative estimation of the dispersion efficiency of the DNA. Using all-atom molecular dynamics simulation, we study the structure and stability of single-stranded DNA (ssDNA)-single-walled carbon nanotube (SWNT) (6,5) complex. To quantify the dispersion efficiency of various DNA sequences, we perform potential of mean forces (PMF) calculation between two bare SWNTs as well ssDNA-wrapped CNTs for different base sequences. From the PMF calculation, we find the PMF between two bare (6,5) SWNTs to be approximately -29 kcal/mol. For the ssDNA-wrapped SWNTs, the PMF reduces significantly and becomes repulsive. In the presence of ssDNA of different polynucleotide bases (A, T, G, and C), we present a microscopic picture of the ssDNA-SWNT (6,5) complex and also a quantitative estimate of the interaction strength between nanotubes from PMF calculation. From PMF, we show the sequence of dispersion efficiency for four different nucleic bases to be T > A > C > G. We have also presented a comparison of the dispersion efficiencies of ssDNA, flavin mononucleotide surfactant, and poly(amidoamine) (PAMAM) dendrimer by comparing their respective PMF values. PMID- 28905627 TI - An Aminocatalyzed Michael Addition/Iron-Mediated Decarboxylative Cyclization Sequence for the Preparation of 2,3,4,6-Tetrasubstituted Pyridines: Scope and Mechanistic Insights. AB - A novel, scalable strategy for the preparation of 2,3,4,6-tetrasubstituted pyridines is described. This protocol has two steps: an aminocatalyzed addition of ketones to alkylidene isoxazol-5-ones, followed by an iron-mediated decarboxylative cyclization event. Mechanistic insights for both steps are provided based on HRMS-ESI(+) studies. PMID- 28905628 TI - Impact of Interfaces and Laser Repetition Rate on Photocarrier Dynamics in Lead Halide Perovskites. AB - We studied charge carrier recombination in methylammonium lead iodide (MAPbI3) perovskite and the impact of interfaces on the charge carrier lifetime using time resolved photoluminescence. Pristine films and those covered with organic electron and hole transport materials (ETM and HTM) were investigated at various laser repetition rates ranging from 10 kHz to 10 MHz in order to separate the bulk and interface-affected recombination. We revealed two different components in the PL decay. The fast component (shorter than 300 ns) is assigned to interfacial processes and the slow one to bulk recombination. A high repetition pulse train was shown to shorten PL decay in pristine perovskite while significantly prolonging the photocarrier lifetime in MAPbI3 covered by TMs. This effect can be qualitatively explained with a kinetic model taking interface traps into account. We demonstrate a significant influence of the excitation repetition rate on photocarrier lifetime, which should be considered when studying charge carrier dynamics in perovskites. PMID- 28905629 TI - Nanoparticle and Ionic Zn Promote Nutrient Loading of Sorghum Grain under Low NPK Fertilization. AB - This study evaluated the effects of ZnO nanoparticles (NP) or Zn salt amendment on sorghum yield, macronutrient use efficiency, and grain Zn-enrichment. Amendments were through soil and foliar pathways, under "low" and "high" levels of nitrogen, phosphorus, and potassium (NPK). In soil and foliar amendments, grain yield was significantly (p <= 0.05) increased by both Zn types, albeit insignificantly with soil-applied Zn at low NPK. Across NPK levels and Zn exposure pathways, both Zn types increased N and K accumulation relative to control plants. Compared to N and K, both Zn types had a mixed effect on P accumulation, depending on NPK level and Zn exposure pathway, and permitted greater soil P retention. Both Zn types significantly (p <= 0.05) increased grain Zn content, irrespective of exposure pathway. These findings suggest a nanoenabled strategy for enhancing crop productivity, grain nutritional quality, and N use efficiency based on Zn micronutrient amendments, with potential implications for improved human and environmental health. PMID- 28905630 TI - Catalytic One-Pot Synthesis of Trisubstituted Allenes from Terminal Alkynes and Ketones. AB - An efficient one-pot synthesis of trisubstituted allenes from readily available terminal alkynes and ketones is realized. A wide range of trisubstituted allenes may be synthesized efficiently via this method. Preliminary mechanistic studies revealed that CuI and Ti(OEt)4 are in charge of the formation of propargylic amine, while ZnBr2 is responsible for the transformation from propargylic amine to allene. PMID- 28905631 TI - MS/MS-Free Protein Identification in Complex Mixtures Using Multiple Enzymes with Complementary Specificity. AB - In this work, we present the results of evaluation of a workflow that employs a multienzyme digestion strategy for MS1-based protein identification in "shotgun" proteomic applications. In the proposed strategy, several cleavage reagents of different specificity were used for parallel digestion of the protein sample followed by MS1 and retention time (RT) based search. Proof of principle for the proposed strategy was performed using experimental data obtained for the annotated 48-protein standard. By using the developed approach, up to 90% of proteins from the standard were unambiguously identified. The approach was further applied to HeLa proteome data. For the sample of this complexity, the proposed MS1-only strategy determined correctly up to 34% of all proteins identified using standard MS/MS-based database search. It was also found that the results of MS1-only search were independent of the chromatographic gradient time in a wide range of gradients from 15-120 min. Potentially, rapid MS1-only proteome characterization can be an alternative or complementary to the MS/MS based "shotgun" analyses in the studies, in which the experimental time is more important than the depth of the proteome coverage. PMID- 28905632 TI - A caution for suicide prevention focused on help-seeking in young people. PMID- 28905633 TI - Effect of particle size distribution of maize and soybean meal on the precaecal amino acid digestibility in broiler chickens. AB - 1. Herein, it was investigated whether different particle size distributions of feed ingredients achieved by grinding through a 2- or 3-mm grid would have an effect on precaecal (pc) amino acid (AA) digestibility. Maize and soybean meal were used as the test ingredients. 2. Maize and soybean meal was ground with grid sizes of 2 or 3 mm. Nine diets were prepared. The basal diet contained 500 g/kg of maize starch. The other experimental diets contained maize or soybean meal samples at concentrations of 250 and 500, and 150 and 300 g/kg, respectively, instead of maize starch. Each diet was tested using 6 replicate groups of 10 birds each. The regression approach was applied to calculate the pc AA digestibility of the test ingredients. 3. The reduction of the grid size from 3 to 2 mm reduced the average particle size of both maize and soybean meal, mainly by reducing the proportion of coarse particles. Reducing the grid size significantly (P < 0.050) increased the pc digestibility of all AA in the soybean meal. In maize, reducing the grid size decreased the pc digestibility of all AA numerically, but not significantly (P > 0.050). The mean numerical differences in pc AA digestibility between the grid sizes were 0.045 and 0.055 in maize and soybean meal, respectively. 4. Future studies investigating the pc AA digestibility should specify the particle size distribution and should investigate the test ingredients ground similarly for practical applications. PMID- 28905635 TI - Developing a Health Care System for Children in Foster Care. AB - In 2012, the Comprehensive Health Evaluations for Cincinnati's Kids (CHECK) Center was launched at Cincinnati Children's Hospital Medical Center to provide health care for over 1,000 children placed into foster care each year in the Cincinnati community. This consultation model clinical program was developed because children in foster care have been difficult to manage in the traditional health care setting due to unmet health needs, missing medical records, cumbersome state mandates, and transient and impoverished social settings. This case study describes the history and creation of the CHECK Center, demonstrating the development of a successful foster care health delivery system that is inclusive of all community partners, tailored for the needs and resources of the community, and able to adapt and respond to new information and changing systems. PMID- 28905634 TI - Fourier Transform Infrared (FT-IR) and Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) Imaging of Cerebral Ischemia: Combined Analysis of Rat Brain Thin Cuts Toward Improved Tissue Classification. AB - Microspectroscopic techniques are widely used to complement histological studies. Due to recent developments in the field of chemical imaging, combined chemical analysis has become attractive. This technique facilitates a deepened analysis compared to single techniques or side-by-side analysis. In this study, rat brains harvested one week after induction of photothrombotic stroke were investigated. Adjacent thin cuts from rats' brains were imaged using Fourier transform infrared (FT-IR) microspectroscopy and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The LA-ICP-MS data were normalized using an internal standard (a thin gold layer). The acquired hyperspectral data cubes were fused and subjected to multivariate analysis. Brain regions affected by stroke as well as unaffected gray and white matter were identified and classified using a model based on either partial least squares discriminant analysis (PLS-DA) or random decision forest (RDF) algorithms. The RDF algorithm demonstrated the best results for classification. Improved classification was observed in the case of fused data in comparison to individual data sets (either FT-IR or LA-ICP-MS). Variable importance analysis demonstrated that both molecular and elemental content contribute to the improved RDF classification. Univariate spectral analysis identified biochemical properties of the assigned tissue types. Classification of multisensor hyperspectral data sets using an RDF algorithm allows access to a novel and in-depth understanding of biochemical processes and solid chemical allocation of different brain regions. PMID- 28905636 TI - The Role of Leisure Activities in the Relationship Between Marital Transition in Later Midlife and Psychological Well-Being Trajectories. AB - This study examined the levels and rates of changes in psychological well-being for middle-aged adults of different statuses or marital transitions. The moderating effects of different leisure activities were also tested. Longitudinal data on 1,270 persons aged 50 to 65 years at baseline from the Taiwan longitudinal study on aging were analyzed. Adults who were stably unmarried or unpartnered reported worse mental health at baseline, but their psychological well-being improved over time. The trajectory of depressive symptoms fluctuated markedly in adults who became widowed during our observation period. Engagement in physical, cognitive, or social activities was significantly associated with participants' psychological well-being. Participation in religious activities was significantly associated with life satisfaction and decreased depressive symptoms for those undergoing bereavement. Findings from this study suggest that social and physical activities, among the four selected leisure activities, have the greatest association between decreasing depressive symptoms and increasing life satisfaction, respectively. Religious activities, in particular, may improve psychological well-being in bereaved middle-aged and older adults. PMID- 28905637 TI - Recent Changes in End-of-Life Decisions for Newborns in a Korean Hospital. AB - INTRODUCTION: Despite recent advances in neonatal intensive care in Korea, few studies exist on the end-of-life decisions in newborns. In this study, we sought to examine the status of end-of-life decisions in neonates, changes over time, and affecting factors. METHODS: This is a retrospective study of neonates who died between 2001 and 2015 in the neonatal intensive care unit of Dong-A University Hospital in Busan. The types of end-of-life decisions were divided into active resuscitation, withholding treatment, and withdrawing treatment. The study period was divided into 3 time frames using 5-year intervals to investigate changes over time. To identify the associated factors, we analyzed the demographic and clinical characteristics of the neonates and their parents using the chi2 test and independent t test. RESULTS: Of the neonatal deaths included in the analysis (n = 222), active resuscitation, withholding treatment, and withdrawing treatment groups accounted for 73.4%, 25.2%, and 1.4% of cases, respectively. When comparing changes over time, between period 1 (2001-2005), 2 (2006-2010), and 3 (2011-2015), the proportion of active resuscitation decreased significantly, from 80.9% to 60.8%, while that of nonactive resuscitation increased significantly from 19.1% to 39.2%. The factors associated with end-of life decisions were the clinical condition of the neonate at the time of death, rather than general characteristics or socioeconomic factors. CONCLUSIONS: In Korea, changes in the decisions on end-of-life care in neonates are shifting from active resuscitation to nonactive resuscitation based on clinical conditions. PMID- 28905638 TI - Higher Risk of Bleeding in Asians Presenting With ST-Segment Elevation Myocardial Infarction: Analysis of the National Inpatient Sample Database. AB - Bleeding is a major complication in patients presenting with ST-segment elevation myocardial infarction (STEMI). Several studies suggested that Asians are more susceptible to bleeding when treated with antiplatelets, anticoagulants, and thrombolytic agents. In our study, we aimed to investigate the association between Asian ethnicity and bleeding events in patients who presented with STEMI. We analyzed the Nationwide Inpatient Sample database from 2002 to 2013 and identified patients hospitalized with a primary diagnosis of STEMI. We compared clinical outcomes between patients of Asian and white ethnicity. Primary outcome was inhospital major bleeding defined as a composite of intracranial hemorrhage and blood transfusions for bleeding events. After exclusions, an estimated 1 695 680 white and 46 563 Asian patients with STEMI were included in the analysis. Asian patients had a higher incidence of inhospital major bleeding (3.6% vs 2.2%, P < .001) without a significant difference in inhospital mortality (9.3% vs 8.7%, P = .06). Asian ethnicity was an independent predictor for major bleeding (estimated odds ratio: 1.32; 95% confidence interval: 1.16-1.51; P < .001). This increased risk of bleeding would warrant further investigation of optimal treatment strategies tailored for patients with STEMI of Asian ethnicity. PMID- 28905639 TI - Clinical Manifestations of Kawasaki Disease Shock Syndrome. AB - A case-control study was performed to ascertain clinical features of children who had been diagnosed as Kawasaki disease shock syndrome (KDSS), a severe condition related to Kawasaki disease (KD). Hospitalized patients were selected in Nanjing Children's Hospital. Demographic characteristics, clinical presentation, laboratory data, cardiovascular findings, and therapies were analyzed. Compared with the control group, KDSS patients were older and had more serious skin rash. The proportions of leukocytosis, neutrophilia, and hypoalbuminemia was higher, as was the level of while blood cell count, C-reactive protein, brain natriuretic peptide, and ferroprotein. KDSS patients had higher incidence of arrhythmias and more severe coronary artery involvement. All case patients received aspirin, glucocorticoid, and intravenous immunoglobulin, 33.3% required albumin, and 90.4% needed vasoactive infusions. In conclusion, KDSS patients may have more serious inflammatory responses in the acute phase. Short-term use of glucocorticoid may be important in inhibiting the inflammatory response. Albumin and vasoactive drugs are useful to rescue shock. PMID- 28905640 TI - Neurobiological mechanisms of exercise and psychotherapy in depression: The SPeED study-Rationale, design, and methodological issues. AB - BACKGROUND/AIMS: Even though cognitive behavioral therapy has become a relatively effective treatment for major depressive disorder and cognitive behavioral therapy-related changes of dysfunctional neural activations were shown in recent studies, remission rates still remain at an insufficient level. Therefore, the implementation of effective augmentation strategies is needed. In recent meta analyses, exercise therapy (especially endurance exercise) was reported to be an effective intervention in major depressive disorder. Despite these findings, underlying mechanisms of the antidepressant effect of exercise especially in combination with cognitive behavioral therapy have rarely been studied to date and an investigation of its neural underpinnings is lacking. A better understanding of the psychological and neural mechanisms of exercise and cognitive behavioral therapy would be important for developing optimal treatment strategies in depression. The SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients) is a randomized controlled trial to investigate underlying physiological, neurobiological, and psychological mechanisms of the augmentation of cognitive behavioral therapy with endurance exercise. It is investigated if a preceding endurance exercise program will enhance the effect of a subsequent cognitive behavioral therapy. METHODS: This study will include 105 patients diagnosed with a mild or moderate depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). The participants are randomized into one of three groups: a high-intensive or a low-intensive endurance exercise group or a waiting list control group. After the exercise program/waiting period, all patients receive an outpatient cognitive behavioral therapy treatment according to a standardized therapy manual. At four measurement points, major depressive disorder symptoms (Beck Depression Inventory, Hamilton Rating Scale for Depression), (neuro)biological measures (neural activations during working memory, monetary incentive delay task, and emotion regulation, as well as cortisol levels and brain-derived neurotrophic factor), neuropsychological test performance, and questionnaires (psychological needs, self-efficacy, and quality of life) are assessed. RESULTS: In this article, we report the design of the SPeED study and refer to important methodological issues such as including both high- and low-intensity endurance exercise groups to allow the investigation of dose-response effects and physiological components of the therapy effects. CONCLUSION: The main aims of this research project are to study effects of endurance exercise and cognitive behavioral therapy on depressive symptoms and to investigate underlying physiological and neurobiological mechanisms of these effects. Results may provide important implications for the development of effective treatment strategies in major depressive disorder, specifically concerning the augmentation of cognitive behavioral therapy by endurance exercise. PMID- 28905641 TI - ?????? ??? ??? ???? ???? ? ??? ??? ?? ? ???? PMID- 28905642 TI - Socioeconomic Moderators of the Relationship Between Different Quitting Motives and Smoking Cessation in Hong Kong Men. AB - To facilitate effective tobacco control, it is important to identify the socioeconomic strata in which different quitting motives are more strongly associated with cessation. This study aims to examine such a moderating role of socioeconomic background. A total of 2022 past or current daily smoking men from the Hong Kong Thematic Household Survey 2010 who had attempted for cessation were analyzed. Binary socioeconomic indicators, quitting motives, and 1-year abstinence were entered in an exploratory backward-stepwise log-linear model, followed by a binary logistic regression to estimate the probability of one-year abstinence in each socioeconomic stratum. Results suggest that the association between cessation and health motives is stronger in less educated men ( P = .004) and nonmarried men ( P = .003). The estimated probability of cessation ranges from 0.02 (95% CI = 0.00-0.06) to 0.96 (95% CI = 0.89-1.00). Accordingly, policy makers should educate less-educated men and nonmarried men about the adverse health impacts of tobacco use. PMID- 28905643 TI - Hematemesis in a 5-Month-Old Girl: A Tale of Double Whammy. PMID- 28905644 TI - Utilizing two-tiered screening for early detection of autism spectrum disorder. AB - Despite advances in autism screening practices, challenges persist, including barriers to implementing universal screening in primary care and difficulty accessing services. The high false positive rate of Level 1 screening methods presents especially daunting difficulties because it increases the need for comprehensive autism evaluations. This study explored whether two-tiered screening-combining Level 1 (Modified Checklist for Autism in Toddlers, Revised with Follow-Up) and Level 2 (Screening Tool for Autism in Toddlers and Young Children) measures-improves the early detection of autism. This study examined a sample of 109 toddlers who screened positive on Level 1 screening and completed a Level 2 screening measure prior to a diagnostic evaluation. Results indicated that two-tiered screening reduced the false positive rate using published Screening Tool for Autism in Toddlers and Young Children cutoffs compared to Level 1 screening alone, although at a cost to sensitivity. However, alternative Screening Tool for Autism in Toddlers and Young Children scoring in the two tiered screening improved both positive predictive value and sensitivity. Exploratory analyses were conducted, including comparison of autism symptoms and clinical profiles across screening subsamples. Recommendations regarding clinical implications of two-tiered screening and future areas of research are presented. PMID- 28905645 TI - 'I'd rather you didn't come': The impact of stigma on exercising with epilepsy. AB - Epilepsy is a common but hidden disorder, leading to stigma in everyday life. Despite stigma being widely researched, little is known about the impact of stigma for people with epilepsy within a sports and exercise setting. Using constructionist grounded theory, we explored the barriers and adaptations to exercise for people with epilepsy. Three focus groups (2-3 participants per group) and three semi-structured interviews were conducted (11 participants in total). Stigma negatively impacted joining team sports, running groups, and disclosure to others. The effect of stigma was reduced by educating others about epilepsy, thus creating more awareness and understanding. PMID- 28905646 TI - Side-Effects of Convulsive Seizures and Anti-Seizure Therapy on Bone in a Rat Model of Epilepsy. AB - The severe sole effects of seizures on the cortical part of bone were reported in our previous study. However, the side effects of anti-epileptic drug therapy on bones has not been differentiated from the effects of the convulsive seizures, yet. This study provides the first report on differentiation of the effects of seizures and carbamazepine (a widely used antiepileptic drug) therapy on bones; 50 mg/kg/day drug was given to genetically induced absence epileptic rats for five weeks. Distinct bone regions including cortical, trabecular, and growth plate in each of tibia, femur, and spine tissues were studied using Fourier transform infrared (FT-IR) imaging and Vickers microhardness test. Blood levels of vitamin D and bone turnover biomarkers were also measured. According to the FT IR imaging results, both seizure and carbamazepine-treated groups, more dominantly the drug-treated group, had lower mineral content with altered collagen crosslinks and higher crystallinity, implying reduced bone strength. Lower microhardness values also supported lower mechanical strength in bones. The most affected bone tissue and region from seizures and treatment was found as the spine and cortical, respectively. While there was a reduction in vitamin D and calcium levels in both seizure and carbamazepin-treated groups, significantly elevated PTH and bone turnover biomarkers were only seen in the drug-treated group. PMID- 28905647 TI - The challenge pathway: A mixed methods evaluation of an innovative care model for the palliative and end-of-life care of people with dementia (Innovative practice). AB - An innovative service for the palliative and end-of-life care of people with dementia was introduced at a UK hospice. This evaluation involved analysis of audit data, semi-structured interviews with project staff (n=3) and surveys of family carers (n=15) and professionals (n=20). The service has increased access to palliative, end-of-life care and other services. Improvements were reported in the knowledge, confidence and care skills of family carers and professionals. Carers felt better supported and it was perceived that the service enabled more patients to be cared for at home or in their usual place of care. PMID- 28905648 TI - Personhood, dementia policy and the Irish National Dementia Strategy. AB - Personhood and its realisation in person-centred care is part of the narrative, if not always the reality, of care for people with dementia. This paper examines how personhood is conceptualised and actualised in Ireland through a content analysis of organisational and individual submissions from stakeholders in the development of the Irish National Dementia Strategy, followed by an examination of the Strategy itself. The organisational submissions are further categorised into dementia care models. A structural analysis of the Strategy examines its principles, actions and outcomes in relation to personhood. Of the 72 organisational and individual submissions received in the formulation of the Strategy, 61% contained references to personhood and its synonyms. Of the 35 organisational submissions, 40% fit a biomedical model, 31% a social model and 29% a biopsychosocial model. The Strategy contains one direct reference to personhood and 33 to personhood synonyms. Half of these references were contained within its key principles and objectives; none were associated with priority actions or outcomes. While stakeholders value personhood and the Strategy identifies personhood as an overarching principle, clearer direction on how personhood and person-centred care can be supported in practice and through regulation is necessary in Ireland. The challenge, therefore, is to provide the information, knowledge, incentives and resources for personhood to take hold in dementia care in Ireland. PMID- 28905649 TI - Participatory arts programs in residential dementia care: Playing with language differences. AB - This article examines connections between language, identity, and cultural difference in the context of participatory arts in residential dementia care. Specifically, it looks at how language differences become instruments for the language play that characterizes the participatory arts programs, TimeSlips and the Alzheimer's Poetry Project. These are two approaches that are predominantly spoken-word driven. Although people living with dementia experience cognitive decline that affects language, they are linguistic agents capable of participating in ongoing negotiation processes of connection, belonging, and in- and exclusion through language use. The analysis of two ethnographic vignettes, based on extensive fieldwork in the closed wards of two Dutch nursing homes, illustrates how TimeSlips and the Alzheimer's Poetry Project support them in this agency. The theoretical framework of the analysis consists of literature on the linguistic agency of people living with dementia, the notions of the homo ludens (or man the player) and ludic language, as well as linguistic strategies of belonging in relation to place. PMID- 28905650 TI - A Contextual Behavior Science Framework for Understanding How Behavioral Flexibility Relates to Anxiety. AB - There is a growing literature focusing on the emerging idea that behavioral flexibility, rather than particular emotion regulation strategies per se, provides greater promise in predicting and influencing anxiety-related psychopathology. Yet this line of research and theoretical analysis appear to be plagued by its own challenges. For example, middle-level constructs, such as behavioral flexibility, are difficult to define, difficult to measure, and difficult to interpret in relation to clinical interventions. A key point that some researchers have made is that previous studies examining flexible use of emotion regulation strategies (or, more broadly, coping) have failed due to a lack of focus on context. That is, examining strategies in isolation of the context in which they are used provides limited information on the suitability, rigid adherence, or effectiveness of a given strategy in that situation. Several of these researchers have proposed the development of new models to define and measure various types of behavioral flexibility. We would like to suggest that an explanation of the phenomenon already exists and that we can go back to our behavioral roots to understand this phenomenon rather than focusing on defining and capturing a new process. Indeed, thorough contextual behavioral analyses already yield a useful account of what has been observed. We will articulate a model explaining behavioral flexibility using a functional, contextual framework, with anxiety-related disorders as an example. PMID- 28905651 TI - Interdisciplinary Management of Pediatric Obesity: Lessons Learned in the Midsouth. AB - The Healthy Lifestyle Clinic (HLC) is an interdisciplinary weight management clinic conceived to address alarming rates of pediatric obesity and related comorbidities in the midsouth region of the United States. The clinical cohort presented is a subset of the 609 patients evaluated during the first 2 years of the HLC and comprises 380 patients with a minimum of 6 months of follow-up. The primarily non-Hispanic black (67.1%) cohort presented with severe obesity ( MzBMI = 2.52 +/- 0.41) and particularly high rates of insulin resistance, among other comorbidities. This article offers insight into the challenges of intervening with a cohort of youth and their families, many with limited resources to support intensive behavioral and lifestyle changes. Our experiences implementing a weight management clinic with a diverse clinical cohort provide guidance for emerging programs and impetus to investigate environmental and cultural factors that contribute to high attrition in the treatment of pediatric obesity. PMID- 28905652 TI - Determination of Rare Earth Elements in Geological Samples Using Laser-Induced Breakdown Spectroscopy (LIBS). AB - Laser-induced breakdown spectroscopy (LIBS) was used to detect rare earth elements (REEs) in natural geological samples. Low and high intensity emission lines of Ce, La, Nd, Y, Pr, Sm, Eu, Gd, and Dy were identified in the spectra recorded from the samples to claim the presence of these REEs. Multivariate analysis was executed by developing partial least squares regression (PLS-R) models for the quantification of Ce, La, and Nd. Analysis of unknown samples indicated that the prediction results of these samples were found comparable to those obtained by inductively coupled plasma mass spectrometry analysis. Data support that LIBS has potential to quantify REEs in geological minerals/ores. PMID- 28905653 TI - Induction of cellular and molecular Immunomodulatory pathways by vitamin E and vitamin C. AB - INTRODUCTION: Vitamins E and C are well known small molecules that have been used to maintain health for decades. Recent studies of the cellular and molecular pathways leading to immunomodulation by these molecules have been of interest, as have their anti-oxidant properties and signal transduction pathways for curing or improving infectious diseases and cancer. Areas covered: Herein, the authors provide a definition and the structural classification of vitamins E and C and how these molecules influence cellular function. The studies include in vitro, ex vivo and in vivo studies in animal models as well as clinical trials. The authors give particular focus to the scientifically factual and putative roles of these molecules in innate and adaptive immunomodulation and prevention or cure of diseases. Expert opinion: The antioxidant properties of vitamins E and C are well studied. However, whether there is a link between their antioxidant and immunomodulation properties is unclear. In addition, there is a strong, albeit putative, prevailing notion that vitamin C can prevent or cure infectious diseases or cancer. Presently, while there is proven evidence that vitamin E possesses immunomodulatory properties that may play a positive role in disease outcomes, this evidence is less available for vitamin C. PMID- 28905654 TI - Opsoclonus-myoclonus syndrome following long-term use of cyclosporine. AB - BACKGROUND: Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS). CASE DETAILS: A 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably. CONCLUSION: This is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity. PMID- 28905655 TI - Inverted Takotsubo syndrome in Androctonus australis scorpion envenomation. AB - CONTEXT: The nature of scorpion-related cardiomyopathy is still a matter of debate where specific toxin-induced cardiomyopathy, ischemic, or catecholaminergic cardiomyopathy is advocated as well. We report two cases of Takotsubo syndrome following envenomation by Androctonus australis, bringing new evidence for the fundamental role of catecholamines in the pathogenesis of this cardiomyopathy. Case 1: A woman aged 36 presented with pulmonary edema and shock following scorpion envenomation. Echocardiography-Doppler showed a LVEF at 30%. Cardiac magnetic resonance (CMR) imaging showed a basal ballooning of the left and right ventricles suggestive of an inverted biventricular Takotsubo syndrome. A second CMR performed after recovery was normal. Case 2: A woman aged 45 was admitted for pulmonary edema and shock consecutive to scorpion envenomation. Echocardiography showed a LVEF at 35%. CMR showed a basal ballooning. The patient was discharged four days following admission with a normal LV function on repeat echocardiography examination. CONCLUSIONS: Cardiomyopathy in these cases, following scorpion envenomation by Androctonus australis, fulfills the criteria of Takotsubo syndrome. These observations contribute to our understanding of the mechanism, prognosis, and treatment of scorpion-related cardiomyopathy. PMID- 28905656 TI - Comparison of low dose and standard dose abdominal CT scan in body stuffers. AB - PURPOSE: Detection of body stuffers is challenging in emergency departments. Because of the small size of baggies, plain radiograph is of little value in most suspects. On the other hand, abdomen CT scan is burdened by high cost and radiation dose. This study was performed to compare the image quality, radiation dose and accuracy of low-dose CT scan in comparison with standard dose. MATERIAL AND METHODS: In this prospective study, suspected body stuffers who were referred to the radiology department underwent two different protocols of abdominal non contrast CT scan simultaneously: low-dose (with equivalent dose to conventional abdominal x-ray) and standard dose. Standard dose CT scan was considered as the reference. Low-dose CT scans were evaluated for detection of baggies by two radiologists blinded to the result of standard dose CT. Image quality, noise, dose-length product (DLP) and effective dose (ED) compared between two groups. RESULTS: The study consisted of 40 patients (33.38 +/- 7.4 years). Standard dose CT evaluation was positive in 22 patients (55%). In comparison with standard dose CT scan, low-dose group had a sensitivity of 86%, specificity of 100%, PPV and NPV of 100% and 86%. The accuracy of low-dose CT scan for detection of baggies larger than 1 cm was 100%. However, from the 3 cases that could not be detected with low dose protocol, one had CT features suspected for baggies rupture which was intubated and later deceased. Noise average of low-dose protocol, was approximately 7 times greater than standard dose group, while DLP and ED were 9.7 times less. CONCLUSION: Low dose CT scan appears to be an appropriate screening method for body stuffers, especially when the baggies are larger than one centimeter. However, in the presence of severe clinical symptoms, a standard dose CT scan will be more helpful due to better image quality especially in suspected ruptured baggies. PMID- 28905657 TI - Selecting a Risk-Based SQC Procedure for a HbA1c Total QC Plan. AB - BACKGROUND: Recent US practice guidelines and laboratory regulations for quality control (QC) emphasize the development of QC plans and the application of risk management principles. The US Clinical Laboratory Improvement Amendments (CLIA) now includes an option to comply with QC regulations by developing an individualized QC plan (IQCP) based on a risk assessment of the total testing process. The Clinical and Laboratory Standards Institute (CLSI) has provided new practice guidelines for application of risk management to QC plans and statistical QC (SQC). METHODS: We describe an alternative approach for developing a total QC plan (TQCP) that includes a risk-based SQC procedure. CLIA compliance is maintained by analyzing at least 2 levels of controls per day. A Sigma-Metric SQC Run Size nomogram provides a graphical tool to simplify the selection of risk based SQC procedures. APPLICATIONS: Current HbA1c method performance, as demonstrated by published method validation studies, is estimated to be 4-Sigma quality at best. Optimal SQC strategies require more QC than the CLIA minimum requirement of 2 levels per day. More complex control algorithms, more control measurements, and a bracketed mode of operation are needed to assure the intended quality of results. CONCLUSIONS: A total QC plan with a risk-based SQC procedure provides a simpler alternative to an individualized QC plan. A Sigma-Metric SQC Run Size nomogram provides a practical tool for selecting appropriate control rules, numbers of control measurements, and run size (or frequency of SQC). Applications demonstrate the need for continued improvement of analytical performance of HbA1c laboratory methods. PMID- 28905658 TI - Decision Support for Diabetes in Scotland: Implementation and Evaluation of a Clinical Decision Support System. AB - BACKGROUND: Automated clinical decision support systems (CDSS) are associated with improvements in health care delivery to those with long-term conditions, including diabetes. A CDSS was introduced to two Scottish regions (combined diabetes population ~30 000) via a national diabetes electronic health record. This study aims to describe users' reactions to the CDSS and to quantify impact on clinical processes and outcomes over two improvement cycles: December 2013 to February 2014 and August 2014 to November 2014. METHODS: Feedback was sought via patient questionnaires, health care professional (HCP) focus groups, and questionnaires. Multivariable regression was used to analyze HCP SCI-Diabetes usage (with respect to CDSS message presence/absence) and case-control comparison of clinical processes/outcomes. Cases were patients whose HCP received a CDSS messages during the study period. Closely matched controls were selected from regions outside the study, following similar clinical practice (without CDSS). Clinical process measures were screening rates for diabetes-related complications. Clinical outcomes included HbA1c at 1 year. RESULTS: The CDSS had no adverse impact on consultations. HCPs were generally positive toward CDSS and used it within normal clinical workflow. CDSS messages were generated for 5692 cases, matched to 10 667 controls. Following clinic, the probability of patients being appropriately screened for complications more than doubled for most measures. Mean HbA1c improved in cases and controls but more so in cases (-2.3 mmol/mol [-0.2%] versus -1.1 [-0.1%], P = .003). DISCUSSION AND CONCLUSIONS: The CDSS was well received; associated with improved efficiencies in working practices; and large improvements in guideline adherence. These evidence-based, early interventions can significantly reduce costly and devastating complications. PMID- 28905659 TI - Comparative Handling Analysis of Different Insulin Pump Systems. AB - Insulin pumps are used by many patients with diabetes to manage their diabetes therapy. Adequate handling of the systems is important to avoid errors. In this study, one aspect of device handling-the number of steps required to operate the system-was evaluated for different insulin pump systems. Specific tasks that are usually performed by insulin pump users were simulated and all necessary actions were documented. Differences between the required numbers of steps strongly depended on the specific task. So did the level of guidance for these tasks provided by the systems. Results of this study provide an overview of this particular aspect of insulin pump handling rather than a general advice. PMID- 28905660 TI - Analysis of "Seven Year Surveillance of the Clinical Performance of a Blood Glucose Test-Strip Product". AB - The article titled "Seven Year Surveillance of the Clinical Performance of a Blood Glucose Test-Strip Product" by Setford and coworkers in this issue of Journal of Diabetes Science and Technology is an impressive study showing that over 7 years in three clinics, using multiple reagent lots, a total of 73 600 samples met the ISO 15197 2015 standard with no results in the D or E zones of a Parkes glucose meter error grid. Three requirements are suggested for a clinically acceptable glucose meter. The authors provide strong evidence for meeting two requirements but fail to provide summarized data about the number of nonnumeric results. Finally, the authors overstate some results, called "spin" by some which is not necessary. The superb results should stand on their own. PMID- 28905661 TI - Genetic parameters for the prediction of abdominal fat traits using blood biochemical indicators in broilers. AB - 1. Excessive deposition of body fat, especially abdominal fat, is detrimental in chickens and the prevention of excessive fat accumulation is an important problem. The aim of this study was to identify blood biochemical indicators that could be used as criteria to select lean Yellow-feathered chicken lines. 2. Levels of blood biochemical indicators in the fed and fasted states and the abdominal fat traits were measured in 332 Guangxi Yellow chickens. In the fed state, the genetic correlations (rg) of triglycerides and very low density lipoprotein levels were positive for the abdominal fat traits (0.47 <= rg <= 0.67), whereas total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) showed higher negative correlations with abdominal fat traits (-0.59 <= rg <= -0.33). Heritabilities of these blood biochemical parameters were high, varying from 0.26 to 0.60. 3. In the fasted state, HDL-C:LDL-C level was positively correlated with abdominal fat traits (0.35 <= rg <= 0.38), but triglycerides, total cholesterol, HDL-C, LDL-C, total protein, albumin, aspartate transaminase, uric acid and creatinine levels were negatively correlated with abdominal fat traits (-0.79 <= rg <= -0.35). The heritabilities of these 10 blood biochemical parameters were high (0.22 <= h2 <= 0.59). 4. In the fed state, optimal multiple regression models were constructed to predict abdominal fat traits by using triglycerides and LDL-C. In the fasted state, triglycerides, total cholesterol, HDL-C, LDL-C, total protein, albumin and uric acid could be used to predict abdominal fat content. 5. It was concluded that these models in both nutritional states could be used to predict abdominal fat content in Guangxi Yellow broiler chickens. PMID- 28905662 TI - Self-Reported Height and Weight in Oceanian School-Going Adolescents and Factors Associated With Errors. AB - We examined the accuracy of self-reported weight and height in New Caledonian school-going adolescents. Self-reported and measured height and weight data were collected from 665 adolescents of New Caledonia and were then compared. Multivariable logistic regressions identified the factors associated with inaccurate self-reports. Sensitivity and specificity of self-reported body mass index values to detect overweight or obesity were evaluated. Self-reported weight was significantly lower than measured weight (boys, -3.56 kg; girls, -3.13 kg). Similar results were found for height (boys, -2.51 cm; girls, -3.23 cm). Multiple regression analyses indicated that the difference between self-reported and measured height was significantly associated with ethnicity and pubertal status. Inaccurate self-reported weight was associated with socioeconomic status, place of residence, body-size perception and weight status. Screening accuracy of self reported body mass index was low, particularly in the Melanesian subgroup. These findings should be considered when overweight is estimated in the Melanesian adolescent population at individual scale. PMID- 28905663 TI - Epidemiology and clinics of mushroom poisoning in Northern Italy: A 21-year retrospective analysis. AB - BACKGROUND: Limited information exists about epidemiology and management of mushroom poisoning. We analyzed and described epidemiology, clinical presentation, and clinical course of mushroom-poisoned patients admitted to emergency departments (EDs) of the Province of Parma, Italy. METHODS: Data from the database of mycological service were matched with clinical information retrieved from hospitals' database, from January 1, 1996 to December 31, 2016. RESULTS: Mycologist consultation was obtained in 379/443 identified mushroom poisonings. A remarkable seasonality was found, with significant peak in autumn. Thanks to the collaboration, the implicated species could be identified in 397 cases (89.6%); 108 cases (24.4%) were due to edible mushrooms, Boletus edulis being the most represented (63 cases). Overall, 408 (92%) cases presented with gastrointestinal toxicity. Twenty cases of amatoxin poisoning were recorded (11 Amanita phalloides and 9 Lepiota brunneoincarnata). One liver transplantation was needed. We observed 13 cases of cholinergic toxicity and 2 cases of hallucinogenic toxicity. Finally, 46 cases were due to "mixed" toxicities, and a total of 69 needed hospitalization. CONCLUSIONS: Early identification and management of potentially life-threatening cases is challenging in the ED, so that a mycologist service on call is highly advisable, especially during periods characterized by the highest incidence of poisoning. PMID- 28905664 TI - Assessment of the neutralizing potency of antisera raised against native and gamma-irradiated Naja nigricollis (black-necked spitting cobra) venom in rabbits, concerning its cardiotoxic effect. AB - The present study was designed to prepare a specific safe antiserum for Naja nigricollis using gamma-irradiated (1.5KGy and3KGy) venoms. Rabbits were used for active immunization using irradiated venoms (1.5 and 3 kGy) as a toxoid, mice were used for determination of LD50 post immunization and the rats were used for neutralization of the cardiotoxic effect of venom. Results of the immunodiffusion test indicated that the sera of rabbits raised against non-irradiated, 1.5- and 3 kGy gamma-irradiated venom, had the same results of precipitin bands. A significant inhibition of phospholipase A2 activities was obtained when neutralized with native, gamma-irradiated (1.5KGy and3KGy) venoms. On the other hand, preincubation of the venom 1/2 LD50 (0.154 mg/kg i.p.) with each antiserum (non-irradiated or irradiated venom) at 37 degrees C for 1 h in a ratio (1:4) produced a significant reduction in the values of creatine kinase and creatine kinase isoenzyme-MB. However, significant elevation in aspartate aminotransferase level and no change in lactate dehydrogenase level were observed. So the results of this study indicated that the irradiated venom treatment reduces the cardiotoxic effect of venom in immunized immunization animals for preparing vaccines. PMID- 28905665 TI - Does the DEKA Arm substitute for or supplement conventional prostheses. AB - BACKGROUND: Research on home use of advanced upper limb prostheses is needed. OBJECTIVES: To describe and compare DEKA Arm usage patterns during the last 4 weeks of a home trial for participants with a personal prosthesis and those without. To compare usage patterns during home trial to those of the personal prosthesis prior to home trial. To evaluate user activity preferences for the DEKA Arm and personal prosthesis after a trial of home use. STUDY DESIGN: Quasi experimental, time-series design. METHODS: Data from 17 participants were analyzed. At baseline, prosthesis users reported days and hours they wore and used personal device(s). Home trial diaries documented days and hours of wear and use for the DEKA Arm and personal device(s), if applicable. Questionnaires asked prosthesis users to list activities they could do with the DEKA Arm but not with their current prosthesis and vice versa and activities they preferred doing with either devices. RESULTS: The DEKA Arm was worn 81% and used 73% of functioning days, averaging 4.2 h worn and 2.4 h used on days worn. During home trial, prosthesis users used personal devices and any prosthesis for fewer hours/day than at baseline. CONCLUSION: The DEKA supplemented but did not substitute for the personal prosthesis. Clinical relevance Findings strongly suggest that given the limitations of the DEKA Arm and conventional prosthesis, persons with upper limb amputation would be best served and would be able to perform the widest range of activities if they had several types of devices. PMID- 28905666 TI - Second Opinion Expert Pathology Review in Bladder Cancer: Implications for Patient Care. AB - OBJECTIVES: To review bladder specimens referred to our facility for secondary review to determine the frequency and degree of changes in pathological diagnoses, which could affect patient care. METHODS: A retrospective review of 246 bladder specimens sent to our pathology department for second opinion pathological review was performed. All consultation specimens were reviewed by a single genitourinary (GU)-subspecialized surgical pathologist. Any changes in the pathological grade, stage, or histological tumor type were noted as well as patient demographic data. Statistical analysis was performed to determine the frequency and type of discrepancies in diagnoses and determine any associations with patient demographic parameters. RESULTS: Secondary pathology consultation of 246 bladder specimens from 233 patients were reviewed and compared with the primary diagnosis. The diagnosis was altered in 91/246 cases (37.0%). The number of cases reviewed per patient and specimen type was not associated with a change in diagnosis ( P = .19; P = .1). Of the cases with a change in diagnosis, 8 (8.8%) changed malignancy status, 46 (50.5%) changed stage, 16 (17.6%) changed tumor type (ie, change from urothelial carcinoma to prostate adenocarcinoma), 16 (17.6%) changed histological variant subtype, and 14 (15.4%) changed grade. There was no association noted between age, gender, or race and changes in diagnosis ( P = .53; P = .41; P = .70). CONCLUSIONS: Secondary pathology review with a GU subspecialized surgical pathologist can change the stage, grade, or histological subtype on bladder biopsy and tumor resection specimens in more than one-third of cases. Age and gender were not associated with the frequency of change in diagnosis on consultation review. PMID- 28905667 TI - Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats. AB - Objectives The objectives were to evaluate the pharmacokinetics (PK) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PD) of SC dolasetron in healthy cats. Methods Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69-316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3-0.5 h), half-life 3.3 h (2.9-7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138-454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4-117 ng/ml), Tmax 0.5 h (0.5-1.0 h), half-life 3.8 h (2.9-5.3 h) and AUClast 437 h/ng/ml (221.5-621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious. PMID- 28905668 TI - The impact of Agent Orange exposure on prognosis and management in patients with chronic lymphocytic leukemia: a National Veteran Affairs Tumor Registry Study. AB - Exposure to Agent Orange (AO) has been associated with the development of chronic lymphocytic leukemia (CLL). We performed a retrospective study of 2052 Vietnam veterans identified in the National VA Tumor Registry to assess the impact of AO exposure on CLL prognosis, treatment and survival. Prognostic factors did not differ based on exposure. Veterans exposed to AO were diagnosed younger (63.2 vs. 70.5 years, p < .0001) and had longer overall survival (median not reached vs. 91 months, p < .001). This prolonged survival was in the subgroups of patients aged 60-69 years (p< .0001) and those with 11q deletion (p < .0001). Those exposed to AO were more likely to be treated with fludarabine, chlorambucil and rituximab (38 vs. 21%, p < .001) and bendamustine plus rituximab (25 vs. 18%, p = 0.039) as first line therapy. Exposure to AO was not associated with either poor prognostic factors or shortened overall survival in our large veteran population with CLL. PMID- 28905669 TI - Correction Notice. AB - Agee, M. D., & Gates, Z. (2014). The Impact of an Insurance Administration-Free Primary Care Office on Hospital Admissions: A Community-Level Comparison With Traditional Fee-for-Service Family Practice Groups. Journal of Primary Care & Community Health, 5, 202-207. doi: 10.1177/2150131914522123 The following Conflict of Interest statement was originally omitted and will be added to the article: Author Zane Gates's affiliation, UPMC Altoona, is the parent organization of Partnering for Health Services. Additionally, author Zane Gates has an ownership interest in the Empower3 Center for Health, a direct-pay primary care clinic using a subscription coverage model, that additionally provides insurance counseling and prescription programs. PMID- 28905670 TI - A model to facilitate implementation of the International Classification of Functioning, Disability and Health into prosthetics and orthotics. AB - BACKGROUND: The International Classification of Functioning, Disability and Health is a classification of human functioning and disability and is based on a biopsychosocial model of health. As such, International Classification of Functioning, Disability and Health seems suitable as a basis for constructing models defining the clinical P&O process. The aim was to use International Classification of Functioning, Disability and Health to facilitate development of such a model. Proposed model: A model, the Prosthetic and Orthotic Process (POP) model, is proposed. The Prosthetic and Orthotic Process model is based on the concepts of the International Classification of Functioning, Disability and Health and comprises four steps in a cycle: (1) Assessment, including the medical history and physical examination of the patient. (2) Goals, specified on four levels including those related to participation, activity, body functions and structures and technical requirements of the device. (3) Intervention, in which the appropriate course of action is determined based on the specified goal and evidence-based practice. (4) Evaluation of outcomes, where the outcomes are assessed and compared to the corresponding goals. After the evaluation of goal fulfilment, the first cycle in the process is complete, and a broad evaluation is now made including overriding questions about the patient's satisfaction with the outcomes and the process. This evaluation will determine if the process should be ended or if another cycle in the process should be initiated. CONCLUSION: The Prosthetic and Orthotic Process model can provide a common understanding of the P&O process. Concepts of International Classification of Functioning, Disability and Health have been incorporated into the model to facilitate communication with other rehabilitation professionals and encourage a holistic and patient-centred approach in clinical practice. Clinical relevance The Prosthetic and Orthotic Process model can support the implementation of International Classification of Functioning, Disability and Health in P&O practice, thereby providing a common understanding of the P&O process and a common language to facilitate communication with other rehabilitation professionals. PMID- 28905672 TI - The influence of ketogenic therapy on the 5 R's of radiobiology. AB - PURPOSE: Radiotherapy (RT) is a mainstay in the treatment of solid tumors and works by inducing free radical stress in tumor cells, leading to loss of reproductive integrity. The optimal treatment strategy has to consider damage to both tumor and normal cells and is determined by five factors known as the 5 R's of radiobiology: Reoxygenation, DNA repair, radiosensitivity, redistribution in the cell cycle and repopulation. The aim of this review is (i) to present evidence that these 5 R's are strongly influenced by cellular and whole-body metabolism that in turn can be modified through ketogenic therapy in form of ketogenic diets and short-term fasting and (ii) to stimulate new research into this field including some research questions deserving further study. CONCLUSIONS: Preclinical and some preliminary clinical data support the hypothesis that ketogenic therapy could be utilized as a complementary treatment in order to improve the outcome after RT, both in terms of higher tumor control and in terms of lower normal tissue complication probability. The first effect relates to the metabolic shift from glycolysis toward mitochondrial metabolism that selectively increases ROS production and impairs ATP production in tumor cells. The second effect is based on the differential stress resistance phenomenon, which is achieved when glucose and growth factors are reduced and ketone bodies are elevated, reprogramming normal but not tumor cells from proliferation toward maintenance and stress resistance. Underlying both effects are metabolic differences between normal and tumor cells that ketogenic therapy seeks to exploit. Specifically, the recently discovered role of the ketone body beta-hydroxybutyrate as an endogenous class-I histone deacetylase inhibitor suggests a dual role as a radioprotector of normal cells and a radiosensitzer of tumor cells that opens up exciting possibilities to employ ketogenic therapy as a cost-effective adjunct to radiotherapy against cancer. PMID- 28905673 TI - The Practice of Research Ethics in Lebanon and Qatar: Perspectives of Researchers on Informed Consent. AB - Informed consent requirements for conducting research with human participants are set by institutional review boards (IRBs) following established guidelines. Despite this, researchers continue to face challenges in seeking and obtaining informed consent. This study discusses researchers' views of such problems in Lebanon and Qatar, which vary in research regulation. We conducted in-depth interviews with 52 academic researchers from various fields of research in both countries and analyzed them using thematic analysis. Important disjunctions emerged between IRB requirements and actual practice. Variations in obtaining informed consent were affected by the research context, type of research, and the prevalent cultural norms and values. Regulatory systems and guidelines for informed consent do not necessarily ensure ethical research conduct. Implications for improvement are presented. PMID- 28905671 TI - Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease. AB - INTRODUCTION: Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas covered: This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert commentary: Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets. PMID- 28905674 TI - Angioleiomyoma of Uterus: A Clinicopathologic Study of 6 Cases. AB - BACKGROUND AND OBJECTIVES: Angioleiomyoma is a benign perivascular neoplasm commonly involving subcutaneous tissue of extremities, head, and trunk region. They rarely involve the female genital tract. This study analyses clinicopathological features of 6 cases of uterine angioleiomyoma. METHODS: Routine sections of 6 cases were reviewed and immunohistochemical markers namely muscle-specific actin, h-caldesmon, desmin, CD10, WT-1, HMB-45, and melan-A were done. RESULTS: Of the 6 cases, 4 cases had tumor involving the corpus and 2 cases had tumor in the cervix. Grossly, all tumors had a whorled and congested cut surface. Microscopic examination of all the cases revealed circumscribed neoplasms composed of interlacing fascicles of benign perivascular smooth muscle cells with evenly distributed slit-like blood vessels (solid variant) along with vessels exhibiting thick muscular walls with swirling pattern (venous variant). In only 2 cases many dilated vessels were seen (cavernous variant). Immunohistochemically, all cases were positive for muscle-specific actin, h caldesmon, and desmin. All cases were negative for CD10 and WT-1 ruling out endometrial stromal tumor and were negative for HMB-45 and melan-A ruling out perivascular epithelioid cell tumor (both endometrial stromal tumor and perivascular epithelioid cell tumor have prominent vessels but have different histomorphology). In all cases, surgical excision was curative and there were no intraoperative or postoperative complications. Follow-up of all the cases has been unremarkable. CONCLUSION: As the World Health Organization has not included angioleiomyoma in the classification of mesenchymal tumors of uterine corpus and cervix, we recommend that it should be included in the classification. PMID- 28905675 TI - An exploratory study of Behavioural Specialist experiences of involving service users in the development of their positive behavioural support plans. AB - : There is limited research that explores the experiences of how behavioural specialists actively involve people with a learning disability and challenging behaviour in the development of their positive behavioural support (PBS) plan. Accordingly, this exploratory research study aimed to explore this little understood area of practice. METHODS: The study included semi-structured interviews comprised of nine Behavioural Specialists in three focus groups across two health boards. A descriptive thematic analysis study. FINDINGS: Three major themes and 11 minor themes were identified illustrating how people with learning disabilities and behaviours that challenge were involved in developing their PBS plan. Significantly, the themes illustrated the complexity of truly involving service users in the process. CONCLUSION: Inclusion of people with a learning disability and behaviours that challenge in their PBS plan poses significant challenges. Person-centred care struggles to be truly embedded in the PBS model. PMID- 28905676 TI - Nurses', nursing students', and nursing instructors' perceptions of professional values: A comparative study. AB - BACKGROUND: In order to prove their commitment to the nursing profession, nurses need to base their professional activities on certain acknowledged values. Although a large number of studies have addressed professional values in nursing, only a few studies are available on the identification and comparison of nurses', nursing students', and nursing instructors' understanding of such values. OBJECTIVE: The study aims to compare nurses', nursing students', and nursing instructors' perception of nursing professional values. RESEARCH DESIGN: In this descriptive-comparative study, data were collected using Weis and Schank's Nurses' Professional Values Scale-Revised. The data were analyzed using the SPSS statistical software (v 22). Participants and research context: A total of 299 nurses, 341 nursing students, and 100 nursing instructors from multisite, 20 different wards from 3 university hospitals and associated nursing schools located in the cities of Shiraz, Fasa, and Jahrom in Fars province, participated in 2016. Ethical considerations: The Institutional Review Board of the researchers' primary university has verified that the study complies with research ethics. FINDINGS: The total mean scores of the nurses', nursing students', and nursing instructors' perception were found to be 4.23 (0.44), 3.92 (0.50), and 4.34 (0.35), respectively, in the domain of justice-this domain was the subjects' top priority-and 3.40 (0.56), 3.29 (0.49), and 3.55 (0.36), respectively, in the domain of activism-this domain was attached the least importance by the subjects. There were significant differences across the three groups' perception in all of the dimensions of professional values ( p < 0.001). DISCUSSION: The three study groups' overall mean scores fall within the range of relatively important or important. Several studies show the same results, but there are still controversies in this regard. CONCLUSION: There is need for plans to increase nurses' awareness of certain professional duties and improve their professional performance in all areas alongside their care duties. PMID- 28905677 TI - Ethical tensions: A qualitative systematic review of new graduate perceptions. AB - BACKGROUND: New graduate transition into the workforce is challenging and can involve managing ethical tensions. Ethical tensions cause new graduates to doubt their capabilities due to their lack of experience. To support new graduates, we need to know what these ethical tensions are. OBJECTIVES: To explore the ethical tensions perceived to occur in practice for new graduate health professionals. RESEARCH DESIGN: This qualitative systematic review involved a search of five databases (Medline, EMBASE, AMED, CINAHL and Scopus) which resulted in the retrieval of 3554 papers. After the two-phased screening process, eight studies were identified that met the inclusion criteria and had rich data on the review question. Articles were read several times, critically appraised and analysed through thematic analysis. Ethical considerations: No ethical approval was required for the systematic review. The review was conducted following well established reporting guidelines enabling transparency and rigour. FINDINGS: Studies originated from Australia, United States, Iran and China. One study included speech pathologists and seven were with nurses. Four themes included the following: (1) enduring an unknown workplace culture that generates uncertainty without support for new graduates; (2) being vulnerable because of distress from bullying, exclusion and being a scapegoat; (3) constraining systems and institutional restrictions that cause dilemmas; and (4) experiencing disillusionment from lost ideals about ethical practice. DISCUSSION: This review has brought to light the vulnerability of new graduates to negative workplace culture and collegial incivility. In addition, new graduates are subjected to ethical tensions created by institutional constraints which can create dilemmas and uncertainties through practice that does not align with what they anticipated. CONCLUSION: Understanding ethical tensions experienced by new graduates enables provision of informed support. There needs to be considerable cultural change for orientation and socialisation of new graduates to enable them to learn and manage ethical tensions. PMID- 28905678 TI - Negative emotional appraisal selectively disrupts retrieval of expected outcome values required for goal-directed instrumental choice. AB - Stress induction reduces people's ability to modify their instrumental choices following changes in the value of outcomes, but the mechanisms underpinning this effect have not been specified because previous studies have lacked crucial control conditions. To address this, the current study had participants learn two instrumental responses for food and water, respectively, before water was devalued by specific satiety. Choice between these two responses was then measured in extinction, reacquisition and Pavlovian to instrumental transfer (PIT) tests. Concurrently during these tests, a negative emotional appraisal group evaluated aversive images (stress induction), whereas a control group evaluated neutral images, at the same time as choosing between the two instrumental responses. Negative emotional appraisal abolished the impact of water devaluation on instrumental choice in the extinction test, but did not affect instrumental choice in the reacquisition or PIT tests. These findings suggest that negative emotional appraisal selectively impaired participants' ability to retrieve the expected value of outcomes required to make goal-directed instrumental choices in the extinction test, and that this effect was not due to task disengagement, nullification of the devaluation treatment or impaired knowledge of response-outcome relationships. PMID- 28905679 TI - The effect of liner design and materials selection on prosthesis interface heat dissipation. AB - BACKGROUND AND AIM: Thermal discomfort often affects prosthesis wearers and could be addressed by increasing liner thermal conductivity. This note explores a liner made from thermally conductive silicone and two additional alternative liner designs. TECHNIQUE: Thermally conductive silicone was used to create a conductive liner and a hybrid liner. Additionally, one with open elements was made. These were compared with a plain silicone liner and a no liner scenario. Scaled down liner prototypes were used due to the high-cost of the thermally conductive silicone. Temperature decay profiles were collected by attaching thermistors to a heated liner phantom and used to evaluate scenarios. DISCUSSION: No scenario performed much better than the plain silicone liner. Implementation of passive solutions may be easier, but alternative liner materials are unlikely to affect dissipation enough to address thermal discomfort. Based on this work, future research efforts may be better spent developing active thermal discomfort solutions. Clinical relevance Thermal discomfort can increase the probability of skin damage, reduce prosthesis satisfaction and, ultimately, the quality of life. The prosthesis-wearing experience could be improved if thermal discomfort can be addressed by technological improvements. PMID- 28905680 TI - Roma Never Die Alone. AB - A common characteristic of Roma as a cultural group is that they do not allow their elderly to die alone. Nevertheless, rooted in a mainstream cultural perspective of health provision services, public institutions usually do not allow Roma people to be with their loved ones in their last moments. Following the communicative methodology, we conducted a communicative case study on the death of the most relevant female Roma leader in Catalonia. She was accompanied by more than two hundred family members and friends in her room and corridor at an important hospital in Barcelona. We performed our research in the 2 years following her death to obtain the reflections of the Roma members involved. These reflections revealed the egalitarian dialogue forged between these Roma members and the hospital personnel, which enabled the former to embrace their culture and support their loved ones before death. Because this dialogue was possible and fruitful, the acknowledgment of cultural diversity and the improvement of the quality of services offered to Roma might also be possible in other health institutions. PMID- 28905681 TI - Re "Choosing between bad, worse and worst". PMID- 28905682 TI - Management of Post-Traumatic Phlegmasia Cerulea Dolens via Right-to-Left Femoral Vein to Femoral Vein Bypass (Palma Procedure). AB - Phlegmasia cerulea dolens (PCD) is a rare condition resulting from venous occlusion that impairs arterial flow. We report a rare case of post-traumatic PCD after ligation of the iliac vein with successful treatment by right-to-left femoral vein to femoral vein bypass using left great saphenous vein (Palma procedure). The clinical presentation, diagnostic process, and approach to management along with a literature review on the operative management of PCD are presented in this case report. PMID- 28905683 TI - A modified walk-in system versus scheduled appointments in a secondary-care prosthetic and orthotic clinic. AB - BACKGROUND: Waiting is common in health care, delays intervention, and has negative effects on satisfaction with services. OBJECTIVES: To evaluate effects of a modified walk-in system, where patients were invited consecutively from the waiting list to attend the clinic on a walk-in basis, on waiting times, services, and work environment. STUDY DESIGN: Parallel-group trial. METHODS: In all, 1286 consecutive patients in need of shoe insoles were randomized to waiting lists for modified walk-in ( n = 655) or a scheduled appointment ( n = 631). Seven staff members also participated. RESULTS: The median indirect waiting time to first appointment was 40 days shorter for modified walk-in (135 days) than for scheduled appointment (175 days; p < 0.001); 17% of those randomized to modified walk-in did not attend the clinic compared to 6% for scheduled appointment ( p < 0.001). Mean direct waiting time in the waiting room was 9.9 min longer for modified walk-in than for scheduled appointment ( p < 0.001). Patients attending modified walk-in or a scheduled appointment reported similar levels of satisfaction with services. Staff reported more support from co-workers with modified walk-in than with scheduled appointment ( p = 0.041). CONCLUSION: The modified walk-in can reduce indirect waiting times without any substantial worsening of direct waiting times, service quality, or work environment. Studies are needed to investigate why many patients drop out from modified walk-in. Clinical relevance A modified walk-in system can cut the queues and create more timely interventions by reducing indirect waiting times. This system can therefore be recommended in secondary-care prosthetic and orthotic clinics to reduce patients' suffering from their health condition. PMID- 28905684 TI - Distinctive role of income in the all-cause mortality among working age migrants and the settled population in Finland: A follow-up study from 2001 to 2014. AB - BACKGROUND: Although income level may play a significant part in mortality among migrants, previous research has not focused on the relationship between income, migration and mortality risk. The aim of this register study was to compare all cause mortality by income level between different migrant groups and the majority settled population of Finland. METHODS: A random sample was drawn of 1,058,391 working age people (age range 18-64 years; 50.4% men) living in Finland in 2000 and linked to mortality data from 2001 to 2014. The data were obtained from Statistics Finland. Cox proportional hazards models were used to investigate the association between region of origin and all-cause mortality in low- and high income groups. RESULTS: The risk for all-cause mortality was significantly lower among migrants than among the settled majority population (hazards ratio (HR) 0.57; 95% confidence interval (CI) 0.53-0.62). After adjustment for age, sex, marital status, employment status and personal income, the risk of mortality was significantly reduced for low-income migrants compared with the settled majority population with a low income level (HR 0.46; 95% CI 0.42-0.50) and for high income migrants compared with the high-income settled majority (HR 0.81; 95% CI 0.69-0.95). Results comparing individual high-income migrant groups and the settled population were not significant. Low-income migrants from Africa, the Middle East and Asia had the lowest mortality risk of any migrant group studied (HR 0.32; 95% CI 0.27-0.39). CONCLUSIONS: Particularly low-income migrants seem to display a survival advantage compared with the corresponding income group in the settled majority population. Downward social mobility, differences in health related lifestyles and the healthy migrant effect may explain this phenomenon. PMID- 28905685 TI - Helping coaches apply the principles of representative learning design: validation of a tennis specific practice assessment tool. AB - Representative Learning Design (RLD) is a framework for assessing the degree to which experimental or practice tasks simulate key aspects of specific performance environments (i.e. competition). The key premise being that when practice replicates the performance environment, skills are more likely to transfer. In applied situations, however, there is currently no simple or quick method for coaches to assess the key concepts of RLD (e.g. during on-court tasks). The aim of this study was to develop a tool for coaches to efficiently assess practice task design in tennis. A consensus-based tool was developed using a 4-round Delphi process with 10 academic and 13 tennis-coaching experts. Expert consensus was reached for the inclusion of seven items, each consisting of two sub questions related to (i) the task goal and (ii) the relevance of the task to competition performance. The Representative Practice Assessment Tool (RPAT) is proposed for use in assessing and enhancing practice task designs in tennis to increase the functional coupling between information and movement, and to maximise the potential for skill transfer to competition contexts. PMID- 28905686 TI - Long-term results of early myoelectric prosthesis fittings: A prospective case control study. AB - BACKGROUND: Different recommendations exist regarding what age is best for first time fitting of myoelectric hand prostheses in children. OBJECTIVES: To compare prosthetic skill, prosthetic use and risk for rejection over time between children fitted with myoelectric hand prostheses before or after 21/2 years of age. STUDY DESIGN: Prospective case-control design. METHODS: The cases were nine children fitted with myoelectric hand prostheses before the age of 21/2 years, whereas the controls were 27 children who were fitted with myoelectric hand prostheses after the age of 21/2 years. The Skills Index Ranking Scale was used to classify prosthetic skill, and prosthetic use was categorised based on wearing time and pattern. Independent samples tests were used to compare data between groups. To estimate and compare the risk of prosthesis rejection between groups and over time, survival analysis was used. RESULTS: Cases showed prosthetic skill early, but controls had caught up by the age of 31/2 years. Cases had a significant ( p = 0.046) decrease in prosthetic use at the age of 9 years. In the long term, cases had a higher percentage of prosthesis rejection. CONCLUSIONS: Considering young children's development of prosthetic skill and prosthetic use over time, this study shows no additional advantages from fitting a myoelectric hand prosthesis before 21/2 years of age. Clinical relevance Children may be fitted with myoelectric hand prostheses to assist in daily tasks and to prevent future over-use problems. Most children fitted with myoelectric hand prostheses before 4 years of age become regular users. No advantages of fitting myoelectric hand prostheses before 21/2 years of age were observed. PMID- 28905687 TI - Victimisation and life satisfaction of gay and bisexual individuals in 44 European countries: the moderating role of country-level and person-level attitudes towards homosexuality. AB - We examined the link between victimisation and life satisfaction for 85,301 gay and bisexual individuals across 44 European countries. We expected this negative link to be stronger when the internalised homonegativity of the victim was high (e.g. because the victim is more vulnerable) and weaker when victimisation occurs in countries that express intolerance towards homosexuality (e.g. because in such contexts victims expect victimisation more and they attribute it to their external environment). Additionally, we expected internalised homonegativity to relate negatively to life satisfaction. Multilevel analyses revealed that victimisation (i.e. verbal insults, threats of violence, minor or major physical assaults) and internalised homonegativity were negatively related to life satisfaction. Furthermore, as we expected, the negative link between victimisation and life satisfaction was stronger when high internalised homonegativity was reported (and the interaction effect occurred for verbal insults and major assaults as outcome variables), while it was weaker when there was low national tolerance of homosexuality (and the interaction effect occurred for verbal insults and for minor assaults). Future research and social policy should consider how the consequences of victimisation are dependent on personal as well as national attitudes towards homosexuality. PMID- 28905689 TI - IgG4-Related Cholangiopathy and Its Mimickers: A Case Report and Review Highlighting the Importance of Early Diagnosis. AB - Immunoglobulin (Ig) G4 (IgG4)-related disease is a recently described clinical entity that can involve multiple organs. It is an autoimmune disorder characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. A key distinguishing factor is its dramatic response to steroid therapy. Although best described in cases of autoimmune pancreatitis, IgG4-related disease has also been implicated in patients with cholangitis and is now commonly referred to as IgG4-related cholangiopathy. It is characterized by elevated serum IgG4 levels, an IgG4-positive plasma cell infiltration with storiform fibrosis/obliterative phlebitis of the bile duct wall, and a response to steroids. It is crucial to differentiate IgG4-related cholangiopathy from its mimickers, such as primary biliary cholangitis, secondary biliary cholangitis, primary sclerosing cholangitis, secondary sclerosing cholangitis, and cholangiocarcinoma, because treatment modalities and outcomes of IgG4-related cholangiopathy differ significantly from these disorders. Here, we present an interesting case of IgG4-related cholangiopathy, discuss clinical and pathological features crucial to its early diagnosis, and compare and contrast this condition with its potentially confounding mimickers. PMID- 28905688 TI - eHealth and behavioral weight loss interventions for female cancer survivors: A review. AB - Cancer survivors are at increased risk of chronic disease and diminished quality of life. The presence of overweight and obesity can exacerbate these health risks. Fortunately, even small weight losses have been found to produce clinically meaningful health outcomes. However, effective obesity treatment is difficult to access, and recently, efforts have been made to disseminate interventions using eHealth or distantly delivered technology. This review aims to focus on the efficacy and limitations of these technologies for female cancer survivors. Suggestions are also provided to encourage further meaningful work in this area. PMID- 28905690 TI - The acromiohumeral centre edge angle: A new radiographic measurement and its association with rotator cuff pathology. AB - BACKGROUND: Various radiographic measurements that describe humeral head coverage by the acromion and the effect on rotator cuff pathology have been reported. This study aimed to describe and validate a new radiographic measurement, the acromiohumeral centre edge angle (ACEA). METHODS: We compared the ACEA on computed tomography (CT) and plain X-ray to determine whether X-ray is accurate for measuring this angle. We then compared the results from this control population with 107 patients with acute rotator cuff tears. We compared functional outcomes in rotator cuff tear patients to determine whether the ACEA has any effect on outcome after surgery. An intra- and inter-observer variability analysis was performed and we compared the ACEA to the acromial index (AI) on rotation X-rays. RESULTS: The ACEA was comparable on CT and plain X-ray and was most accurate when true anteroposterior glenohumeral X-rays were used (15.94 degrees vs. 15.87 degrees on CT, p = 0.476). The ACEA showed high intra- and inter-observer reproducibility and was unchanged on internal and external rotation X-rays (20.48 vs. 20.47, p = 0.842), whereas the AI was significantly different (0.74 vs. 0.70, p < 0.001). The ACEA was significantly higher in our rotator cuff tear patients than the control population (23.9 degrees vs. 16.6 degrees , p < 0.001), although a higher ACEA was not associated with poorer outcomes. CONCLUSION: The ACEA is a valid measurement for describing humeral head coverage by the acromion and can be accurately measured on plain radiographs with good reproducibility. It is unaffected by shoulder rotation and was significantly higher in patients with acute rotator cuff tears. PMID- 28905691 TI - From Family Violence Exposure to Violent Offending: Examining Effects of Race and Mental Health in a Moderated Mediation Model Among Confined Male Juveniles. AB - Depression, substance use, and impulsivity have been linked to family violence exposure and to the development of violent offending during adolescence. Additionally, the indirect effects associated with these factors may not generalize across different racial/ethnic adolescent populations. The present study tested whether race/ethnicity moderated the mediated relationship between family violence exposure and violent offending, with depression, substance use, and impulsivity as mediators. A sample of 1,359 male adolescents was obtained from a juvenile correctional program. Between-racial/ethnic group comparisons were generally consistent with previous findings. The overall moderated mediation model was significant in predicting violence for both racial/ethnic groups. Different factors influenced violent offending among African Americans and European Americans in the tested model. Furthermore, race/ethnicity moderated the relationship between family violence exposure and impulsivity and substance use. Implications and future directions resolving issues are discussed concerning whether race/ethnicity should be included as a moderator in models of violence. PMID- 28905692 TI - The emerging challenge of optimal blood pressure management and hypertensive syndromes in pregnant women with sickle cell disease: a review. AB - INTRODUCTION: Sickle cell disease (SCD) is one of the most common hemoglobinopathy, affecting a considerable proportion of black populations of African origin, Middle East and in the Indian sub-continent. Women with SCD are more likely to experience adverse pregnancy and delivery outcomes. Hypertensive diseases in pregnancy such as preeclampsia and eclampsia are more common in women with sickle cell disease. Areas covered: This review examined the influence of hypertension and SCD in pregnancy, and provides the preliminary evidence that the traditional systolic and diastolic blood pressure thresholds for hypertensive disorders such as pre-eclampsia and eclampsia may require reassessment in pregnant women with SCD. The causes of maternal and perinatal morbidity and mortality, hypertensive complications of pregnancy in women with and without sickle cell disease were reviewed. A MEDLINE database search using medical subject headings (MeSH) and keywords for articles regarding sickle cell disease, pregnancy and hypertension was performed. Expert commentary: Pregnancy in women with sickle cell disease is associated with high maternal and perinatal morbidity and mortality. Using the existing thresholds for diagnosis and treatment for hypertensive disease in pregnancy without adjustment to accommodate for the lower systolic and diastolic blood pressure in those with sickle cell disease may worsen an already poor maternal and perinatal outcome in this population. PMID- 28905693 TI - SGEM Hot Off the Press: Management of bronchiolitis in community hospitals. PMID- 28905694 TI - Sphingomonas carri sp. nov., isolated from a car air-conditioning system. AB - A Gram-stain-negative, yellow-pigmented bacterial strain, designated PR0302T, was isolated from a car evaporator core collected in Korea. The cells were strictly aerobic, non-spore-forming and rod-shaped. The strain grew at 15-37 degrees C (optimum, 25 degrees C), at pH 6.0-8.0 (optimum, 7.0) and in the presence of 0-1 % (w/v) NaCl. Phylogenetically, the strain was closely related to members of the genus Sphingomonas(97.04-91.22 % 16S rRNA gene sequence similarities) and showed the highest sequence similarity of 97.04 % to Sphingomonas kyeonggiensis THG DT81T. It contained C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C14 : 0 2-OH as the predominant fatty acids and Q-10 as the major ubiquinone. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and sphingoglycolipid. The major polyamine was sym-homospermidine. The serine palmitoyl transferase gene (spt) was detected and sphingolipid synthesis was confirmed. The mean DNA G+C content of the strain was 67.8+/-0.5 mol%. DNA-DNA relatedness between strain PR0302T and closely related type strains of Sphingomonas species was less than 30 %. The low levels of DNA-DNA relatedness identified strain PR0302T as a member of a novel species in the genus Sphingomonas. Based on phenotypic, genotypic and chemotaxonomic data, strain PR0302T represents a novel species in the genus Sphingomonas, for which the name Sphingomonas carri sp. nov. is proposed. The type strain is PR0302T (=KACC 18487T=NBRC 111532T). PMID- 28905695 TI - Description of Anaerotignum aminivorans gen. nov., sp. nov., a strictly anaerobic, amino-acid-decomposing bacterium isolated from a methanogenic reactor, and reclassification of Clostridium propionicum, Clostridium neopropionicum and Clostridium lactatifermentans as species of the genus Anaerotignum. AB - A strictly anaerobic bacterial strain (SH021T) was isolated from a methanogenic reactor. Cells were Gram-stain-positive, motile, straight or slightly curved rods. The optimum temperature for growth was 35 degrees C, and the optimum pH was 6.1-7.7. The strain was asaccharolytic and utilized amino acids as growth substrates. The strain produced acetate and propionate from l-alanine and l serine, and propionate and butyrate from l-threonine. Branched-chain amino acids (l-isoleucine, l-leucine and l-valine) were utilized weakly, and isovalerate or isobutyrate was produced. Strain SH021T utilized pyruvate and lactate, and converted them to acetate and propionate. The genomic DNA G+C content was 38.2 mol%. Compounds related to iso-C15 : 0 were detected as major components in the cellular fatty acids analysis. The diagnostic diamino acid of the cell-wall peptidoglycan was meso-diaminopimelic acid. On the basis of 16S rRNA gene sequences, the most closely related known species were Clostridium propionicum, Clostridium neopropionicum and Clostridium lactatifermentans in cluster XIVb of the class Clostridia. Based on the phylogenetic and phenotypic data, Anaerotignum aminivorans gen. nov., sp. nov. is proposed to accommodate strain SH021T (=JCM 31556T=DSM 103575T). For the three related species of the genus Clostridium, Anaerotignum propionicum comb. nov. (type strain DSM 1682T=JCM 1430T=ATCC 25522T=CCUG 9280T=NCIMB 10656T=VPI 5303T), Anaerotignum neopropionicum comb. nov. (type strain X4T=DSM 3847T=KCTC 15564T) and Anaerotignum lactatifermentans comb. nov. (type strain G17T=DSM 14214T=LMG 20954T) are proposed with emended descriptions of these species. PMID- 28905696 TI - Paralkalibacillus indicireducens gen., nov., sp. nov., an indigo-reducing obligate alkaliphile isolated from indigo fermentation liquor used for dyeing. AB - Obligately alkaliphilic, indigo-reducing strains, designated Bps-1T, Bps-2 and Bps-3, were isolated from an indigo fermentation liquor used for dyeing, which was produced from sukumo (composted Polygonum indigo leaves) obtained from a craft centre in Data City, Hokkaido, Japan, by using medium containing cellulase treated sukumo. The 16S rRNA gene sequence phylogeny suggested that Bps-1T has a distinctive position among the alkaliphilic species of the genus Bacillus, with its closest neighbours being Bacillus pseudofirmus DSM 8715T, Bacillus lindianensis DSM 26864T and Bacillus alcalophilus DSM 485T (96.1, 95.8 and 95.5 % 16S rRNA gene sequence similarities, respectively). The 16S rRNA sequence of strain Bps-1T was identical to those of strains Bps-2 and Bps-3. Cells of the novel isolate were Gram-stain-positive and were facultatively anaerobic straight rods that were motile by means of a pair of flagella (subpolar and centre sides). Spherical endospores were formed in the terminal position. Strain Bps-1T grew between 18 and 40 degrees C with optimum growth at 33 degrees C. The isolate grew in the pH range 8-11, with optimum growth at pH 9-10. The isoprenoid quinone detected was menaquinone-7 (MK-7), and the DNA G+C content was 40.3 %. The whole cell fatty acid profile (>10 %) mainly consisted of anteiso-C15 : 0, iso-C15 : 0 and C16 : 0. On the basis of the phenotypic, chemotaxonomic and phylogenetic data, the isolates represent a novel species of a novel genus, for which the name Paralkalibacillus indicireducens gen. nov., sp. nov. is proposed. The type strain of this species is Bps-1T (JCM 31808T=NCIMB 15080T), with strains Bps-2 and Bps-3 representing additional strains of the species. PMID- 28905697 TI - Luteolibacter gellanilyticus sp. nov., a gellan-gum-degrading bacterium of the phylum Verrucomicrobia isolated from miniaturized diffusion chambers. AB - A novel chemo-organoheterotrophic bacterium, strain CB-286403T, was isolated from a Mediterranean forest soil, collected at Sierra de Tejeda, Almijara and Alhama Natural Park, Spain, by using the Diffusion Sandwich System, a device with 384 miniature diffusion chambers. The 16S rRNA gene sequence analyses identified the isolate as a member of the genus Luteolibacter where the type strains Luteolibacterpohnpeiensis A4T-83T (GenBank acc. no. AB331895), Luteolibacteryonseiensis EBTL01T (JQ319003), Luteolibacterluojiensis DR4-30T (JN630810) and Luteolibacteralgae A5J-41-2T (AB331893) were the closest relatives with similarities of 97.0, 96.3, 96.3 and 94.5 %, respectively. The novel isolate was characterized as a Gram-stain-negative, non-motile, short-rod-shaped bacterium. The strain showed a positive response for catalase and cytochrome-c oxidase, divided by binary fission and/or budding, and exhibited an aerobic metabolism. Strain CB-286403T showed a mesophilic and neutrophilic growth range and showed a nutritional preference for simple sugars and complex protein substrates. Major fatty acids included iso-C14 : 0, C16 : 0, C16 : 1omega7c/iso C15 : 0 2-OH and anteiso-C15 : 0. The predominant respiratory quinone was MK-9. Polar lipids comprised major amounts of phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol and minor amounts of three unidentified lipids, a glycolipid, a phospholipid and a phosphoglycolipid. Based on a polyphasic taxonomic characterization, strain CB-286403T represents a novel species of the genus Luteolibacter, for which the name Luteolibacter gellanilyticus sp. nov. is proposed. The type strain is CB-286403T (=DSM 28998T=CECT 8659T). PMID- 28905698 TI - Microbulbifer aggregans sp. nov., isolated from estuarine sediment from a mangrove forest. AB - A novel, rod-shaped, Gram-stain-negative, halophilic and non-motile bacterium, designated CCB-MM1T, was isolated from a sample of estuarine sediment collected from Matang Mangrove Forest, Malaysia. The cells possessed a rod-coccus cell cycle in association with growth phase and formed aggregates. Strain CCB-MM1T was both catalase and oxidase positive, and able to degrade starch. Optimum growth occurred at 30 degrees C and pH 7.0 in the presence of 2-3 % (w/v) NaCl. The 16S rRNA gene sequence of strain CCB-MM1T showed 98.12, 97.46 and 97.33 % sequence similarity with Microbulbifer rhizosphaerae Cs16bT, Microbulbifer maritimus TF 17T and Microbulbifergwangyangensis GY2T respectively. Strain CCB-MM1T and M. rhizosphaerae Cs16bT formed a cluster in the phylogenetic tree. The major cellular fatty acids were iso-C17 : 1 omega9c and iso-C15 : 0, and the total polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphoaminolipid, two unidentified lipids, an unidentified glycolipid and an unidentified aminolipid. The major respiratory quinone was ubiquinone Q-8 and the genomic DNA G+C content of the strain was 58.9 mol%. On the basis of the phylogenetic, phenotypic and genotypic data presented here, strain CCB-MM1T represents a novel species of the genus Microbulbifer, for which the name Microbulbiferaggregans sp. nov. is proposed. The type strain is CCB-MM1T (=LMG 29920T=JCM 31875T). PMID- 28905699 TI - Sphingomonas jeddahensis sp. nov., isolated from Saudi Arabian desert soil. AB - A novel Sphingomonas strain was isolated from a sample of desert soil collected near Jeddah in Saudi Arabia. A polyphasic approach was performed to characterize this strain, initially designated as G39T. Cells of strain G39T are motile, Gram negative, catalase- and oxidase-positive. The strain is able to grow aerobically at 20-35 degrees C, pH 6.5-8 and tolerates up to 4 % (w/v) NaCl. Based on 16S rRNA gene sequence similarity, the closest relative type strains of G39T are Sphingomonas mucosissima DSM 17494T (98.6 %), S. dokdonensis DSM 21029T (98.4 %) and S. hankookensis DSM 23329T (97.4 %). Furthermore, the average nucleotide identities between the draft genome sequence of strain G39T and the genome sequences of all other available and related Sphingomonas species are significantly below the threshold of 94 %. The G+C content of the draft genome (3.12 Mbp) is 65.84 %. The prevalent (>5 %) cellular fatty acids of G39T were C18 : 1omega7c, C16 : 1omega7c and/or C16 : 1omega6c, C14 : 0 2-OH and C16 : 0. The only detectable respiratory quinone was ubiquinone-10 and the polar lipids profile is composed of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid, as well as unidentified lipids, phospholipids and glycolipids. The results of the conducted polyphasic approach confirmed that this isolate represents a novel species of the genus Sphingomonas, for which the name Sphingomonas jeddahensis sp. nov. is proposed. The type strain of this species is G39T (=DSM 103790T=LMG 29955T). PMID- 28905700 TI - Roseomonas aerofrigidensis sp. nov., isolated from an air conditioner. AB - A Gram-stain-negative, strictly aerobic bacterium, designated HC1T, was isolated from an air conditioner in South Korea. Cells were orange, non-motile cocci with oxidase- and catalase-positive activities and did not contain bacteriochlorophyll a. Growth of strain HC1T was observed at 10-45 degrees C (optimum, 30 degrees C), pH 4.5-9.5 (optimum, pH 7.0) and 0-3 % (w/v) NaCl (optimum, 0 %). Strain HC1T contained summed feature 8 (comprising C18 : 1omega7c/C18 : 1omega6c), C16 : 0 and cyclo-C19 : 0omega8c as the major fatty acids and ubiquinone-10 as the sole isoprenoid quinone. Phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and an unknown aminolipid were detected as the major polar lipids. The major carotenoid was hydroxyspirilloxanthin. The G+C content of the genomic DNA was 70.1 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, showed that strain HC1T formed a phylogenetic lineage within the genus Roseomonas. Strain HC1T was most closely related to the type strains of Roseomonas oryzae, Roseomonas rubra, Roseomonas aestuarii and Roseomonas rhizosphaerae with 98.1, 97.9, 97.6 and 96.8 % 16S rRNA gene sequence similarities, respectively, but the DNA-DNA relatedness values between strain HC1T and closely related type strains were less than 70 %. Based on phenotypic, chemotaxonomic and molecular properties, strain HC1T represents a novel species of the genus Roseomonas, for which the name Roseomonas aerofrigidensis sp. nov. is proposed. The type strain is HC1T (=KACC 19097T=JCM 31878T). PMID- 28905701 TI - Outcomes of patients with severe influenza infection admitted to intensive care units: a retrospective study in a medical centre. AB - PURPOSE: This study assessed clinical manifestations and prognostic factors of critically ill patients with severe influenza admitted to the intensive care unit (ICU) in Taiwan's recent outbreak. METHODOLOGY: Patients admitted to ICU for severe influenza between January 1, 2015, and March 31, 2016, were identified and their medical records were retrospectively reviewed. The primary endpoints were outcomes and predictors of in-hospital mortality. RESULTS: There were 125 patients with an average Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 20.8. Hypertension (62.4 %) and diabetes mellitus (40.8 %) were the two most common underlying diseases. Ninety-eight (78.4 %) patients had at least one organ failure: the lungs were the most common (71.2 %), followed by the heart (53.6 %). Two of the most common symptoms of patients at ICU admission were fever (68.0 %) and cough (78.4 %). Thirty-three patients (26.4 %) died; most (40.9 %) were middle-aged (50-65 years old). A Cox regression analysis showed that multiple organ failure (MOF) [hazard ratio (HR)=3.618; 95 % CI=1.058-13.662] was significantly associated with higher risk of death. In contrast, a fluid negative balance within 7 days of admission (HR=0.362; 95 % CI=0.140-0.934) was significantly associated with a lower risk of death. CONCLUSION: The mortality rate of severe influenza patients admitted to the ICU was high, especially in middle-aged adults. The risk of mortality was associated with >=2 organ failures. A negative fluid balance predicts survival. PMID- 28905702 TI - Alteromonas pelagimontana sp. nov., a marine exopolysaccharide-producing bacterium isolated from the Southwest Indian Ridge. AB - A novel exopolysaccharide-producing strain, designated as 5.12T, was isolated from a sediment sample from the Southwest Indian Ridge, Indian Ocean. The strain was Gram-stain-negative, motile, strictly aerobic, and oxidase- and catalase positive. It grew optimally at 35 degrees C, at pH 6.0 and in the presence of 3.5 % (w/v) NaCl. Its major isoprenoid quinone was ubiquinone-8 (Q-8) and summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), C16 : 0 and C18 : 1omega7c were the major cellular fatty acids. The DNA G+C content was 46.1 mol%. 16S rRNA gene sequence analysis suggested that strain 5.12T is a member of the genus Alteromonas. Strain 5.12T exhibited close 16S rRNA gene sequence similarity to Alteromonas lipolytica JW12T (96.1 %), Alteromonas hispanica F-32T (95.9 %), Alteromonas confluentis DSSK2-12T (95.9 %), Alteromonas litorea TF-22T (95.6 %) and Alteromonas mediterranea DET (95.5 %). Strain 5.12T contained phosphatidylethanolamine and phosphatidylglycerol as the major polar lipids. Owing to significant differences in the 16S rRNA gene sequences, as well as the phenotypic and chemotaxonomic characteristics, the novel isolate described here merits classification as a representative of a novel species of the genus Alteromonas, for which the name Alteromonas pelagimontana sp. nov. is proposed. The type strain of this species is 5.12T (LMG 29661T= MCC 3250T). PMID- 28905703 TI - Saliphagus infecundisoli gen. nov., sp. nov., an extremely halophilic archaeon isolated from a saline soil. AB - Two extremely halophilic archaea, strains YIM 93745T and YIM 93707, were isolated from a saline soil sample collected from Loulan, China. Cells of the two strains were coccus, non-motile and Gram-stain negative. The strains were aerobic and grew at 25-50 degrees C (optimum, 37 degrees C), in the presence of 5-35 % (w/v) NaCl (optimum, 20 %), 0.01-0.1 M Mg2+ (optimum, 0.03 M) and pH 6.0-8.5 (optimum, 7.0-7.5). Cells lysed in distilled water and with 0-5 % NaCl. Major polar lipids were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate, sulfated mannosyl glycosyl diether and two unidentified glycolipids. Phylogenetic analysis based on the 16S rRNA sequence revealed that the two strains were most closely related to Halovivax cerinus IC35T (95.1 and 95.2 % sequence similarities, respectively). The two strains, however, shared highest rpoB' gene sequence identities with Natrinema pellirubrum JCM 10476T (87.8 and 87.7 % respectively). Phylogenetic trees based on 16S rRNA and rpoB' gene sequences demonstrated a robust clade of the two strains with members of related genera of the family Natrialbaceae. The DNA G+C contents of the two strains were 64.6 and 64.4 mol%, respectively. DNA-DNA relatedness values between them were 95+/-2 %. Phenotypic, chemotaxonomic characteristics and phylogenetic properties suggested that the two strains YIM 93745T and YIM 93707 represent a novel species in a new genus within the family Natrialbaceae, for which the name Saliphagus infecundisoli gen. nov., sp. nov. is proposed. The type strain is YIM 93745T (=KCTC 4228T=CGMCC 1.15824T). PMID- 28905704 TI - Nesterenkonia pannonica sp. nov., a novel alkaliphilic and moderately halophilic actinobacterium. AB - An alkaliphilic and moderately halophilic bacterial strain characterized by optimal growth at pH 9.0-10.0 and with 5-7 % (w/v) NaCl, designated BV-35T, was isolated from water of a soda pan located in Kiskunsag National Park, Hungary. Cells of the orange-pigmented colony were Gram-stain-positive, non-motile and non endospore-forming coccoid rods. The isolate was strictly aerobic, catalase positive and oxidase-negative. Strain BV-35T displayed a peptidoglycan similar to type A4alpha, l-Lys-l-Glu (A11.54 according to www.peptidoglycan-types.info) but containing additionally 4-aminobutyric acid. Menaquinone-7 (MK-7) was the predominant isoprenoid quinone, and anteiso-C15 : 0 and anteiso-C17 : 0 were its major cellular fatty acids. The DNA G+C content of strain BV-35T was 65.4 mol%. Based on 16S rRNA gene sequence similarities, the novel isolate showed the closest relationship to Nesterenkonia populi GP 10-3T (97.9 %). The DNA-DNA relatedness between BV-35T and N. populi was 46.7 %. The distinguishing phenotypic and genetic results of this polyphasic study revealed that strain BV 35T represents a novel member of the genus Nesterenkonia, for which the name Nesterenkonia pannonica sp. nov. is proposed. The type strain is BV-35T (=DSM 29786T=NCAIM B 02606T). PMID- 28905705 TI - Mucilaginibacter terrae sp. nov., isolated from Antarctic soil. AB - A bacterial strain designated CCM 8645T was isolated from a soil sample collected nearby a mummified seal carcass in the northern part of James Ross Island, Antarctica. The cells were short rods, Gram-stain-negative, non-motile, catalase and oxidase positive, and produced a red-pink pigment on R2A agar. A polyphasic taxonomic approach based on 16S rRNA gene sequencing, extensive biotyping using conventional tests and commercial identification kits and chemotaxonomic analyses were applied to clarify its taxonomic position. Phylogenetic analysis based on the 16S rRNA gene placed strain CCM 8645T in the genus Mucilaginibacter with the closest relative being Mucilaginibacter daejeonensis Jip 10T, exhibiting 96.5 % 16S rRNA pairwise similarity which was clearly below the 97 % threshold value recommended for species demarcation. The major components in fatty acid profiles were Summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), C15 : 0 iso and C17 : 0 iso 3OH. The cellular quinone content was exclusively menaquinone MK-7. The major polyamine was sym-homospermidine and predominant polar lipids were phosphatidylethanolamine and phosphatidylserine. Based on presented results, we propose a novel species for which the name Mucilaginibacter terrae sp. nov. is suggested, with the type strain CCM 8645T (=LMG 29437T). PMID- 28905706 TI - Classification of Actinoplanes sp. ATCC 33076, an actinomycete that produces the glycolipodepsipeptide antibiotic ramoplanin, as Actinoplanes ramoplaninifer sp. nov. AB - Strain ATCC 33076, which produces the antibiotic ramoplanin, was isolated from a soil sample collected in India, and it was classified as a member of the genus Actinoplanes on the basis of morphology and cell-wall composition. A phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain forms a distinct clade within the genus Actinoplanes, and it is most closely related to Actinoplanes deccanensis IFO 13994T (98.71 % similarity) and Actinoplanes atraurantiacus Y16T (98.33 %). The strain forms an extensively branched substrate mycelium; the sporangia are formed very scantily and are globose with irregular surface. Spores are oval and motile. The cell wall contains meso-diaminopimelic acid and the diagnostic sugars are xylose and arabinose. The predominant menaquinone is MK-9(H6), with minor amounts of MK-9(H4) and MK-9(H2). Mycolic acids are absent. The diagnostic phospholipids are phosphatidylethanolamine, hydroxyphosphatidylethanolamine and phosphatidylglycerol. The major cellular fatty acids are anteiso-C17 : 0 and iso-C16 : 0, followed by iso-C15 : 0 and moderate amounts of anteiso-C15 : 0, iso-C17 : 0 and C18 : 1omega9c. The genomic DNA G+C content is 71.4 mol%. Significant differences in the morphological, chemotaxonomic and biochemical data, together with DNA-DNA relatedness between strain ATCC 33076 and closely related type strains, clearly demonstrated that strain ATCC 33076 represents a novel species of the genus Actinoplanes, for which the name Actinoplanes ramoplaninifer sp. nov. is proposed. The type strain is ATCC 33076T (=DSM 105064T=NRRL B-65484T). PMID- 28905707 TI - 'Candidatus Phytoplasma wodyetiae', a new taxon associated with yellow decline disease of foxtail palm (Wodyetia bifurcata) in Malaysia. AB - Landscape-grown foxtail palm (Wodyetia bifurcata A. K. Irvine) trees displaying symptoms of severe foliar chlorosis, stunting, general decline and mortality reminiscent of coconut yellow decline disease were observed in Bangi, Malaysia, during 2012. DNA samples from foliage tissues of 15 symptomatic palms were analysed by employing a nested PCR assay primed by phytoplasma universal ribosomal RNA operon primer pairs, P1/P7 followed by R16F2n/R2. The assay yielded amplicons of a single band of 1.25 kb from DNA samples of 11 symptomatic palms. Results from cloning and sequence analysis of the PCR-amplified 16S rRNA gene segments revealed that, in three palms, three mutually distinct phytoplasmas comprising strains related to 'Candidatus Phytoplasma asteris' and 'Candidatus Phytoplasma cynodontis', as well as a novel phytoplasma, were present as triple infections. The 16S rRNA gene sequence derived from the novel phytoplasma shared less than 96 % nucleotide sequence identity with that of each previously describedspecies of the provisional genus 'Ca. Phytoplasma', justifying its recognition as the reference strain of a new taxon, 'Candidatus Phytoplasma wodyetiae'. Virtual RFLP profiles of the R16F2n/R2 portion of the 16S rRNA gene and the pattern similarity coefficient value (0.74) supported the delineation of 'Ca. Phytoplasma wodyetiae' as the sole representative subgroup A member of a new phytoplasma ribosomal group, 16SrXXXVI. PMID- 28905708 TI - Williamwhitmania taraxaci gen. nov., sp. nov., a proteolytic anaerobe with a novel type of cytology from Lake Untersee in Antarctica, description of Williamwhitmaniaceae fam. nov., and emendation of the order Bacteroidales Krieg 2012. AB - The proteolytic bacterium strain A7P-90mT was isolated from Lake Untersee, Antarctica. The anoxic water was collected from a perennially sealed (~100 millennia) glacial ice lake. Gram-stain-negative cells were 0.18-0.3*8.0-25.0 um in size, straight, slender rods with unusual gliding motility by external, not previously reported, organelles named here as antiae. At the end of stationary phase of growth, spheroplasts were terminally formed and the cells resembled dandelions. After death, cells were helical. The isolate was an athalassic, strictly anaerobic and catalase-negative proteolytic chemoorganotroph. It was moderately psychrophilic with a temperature range for growth of 3-26 degrees C and an optimum at 22-23 degrees C. The pH range for growth was 5.5-7.8 with an optimum at 6.9. Major cellular fatty acids were branched pentadecanoic and tridecanoic acids, and saturated tetradecanoic acids. The quinone system comprised menaquinone MK-7. The strain was sensitive to all checked antibiotics and ascorbic acid. The G+C content of the genomic DNA was 42.6 mol%. Based on average nucleotide identity, average amino acid identity and phylogenetic analyses, the novel isolate was placed within a unique phylogenetic cluster distant from all eight families in the order Bacteroidales and formed a novel family with the proposed name Williamwhitmaniaceae fam. nov. The description of the order Bacteroidales was emended accordingly. The name Williamwhitmania taraxaci gen. nov., sp. nov. is proposed for the new genus and novel species with the type strain A7P-90mT (=DSM 100563T=JCM 30888T). The complete draft genome sequence was deposited at the Joint Genomes Institute (JGI) under number IMG OID 2654588148 and in SRA listed as SRP088197. PMID- 28905709 TI - Antimicrobial Stewardship in Laboratory Animal Facilities. AB - Bacterial resistance to antimicrobial drugs has become a global health crisis. Physicians and veterinarians are embracing the concept of 'antimicrobial stewardship' (AMS) to preserve the efficacy of antibiotics for future generations. Antimicrobials are used in laboratory animals to treat clinical disease, to protect populations that may be vulnerable to infection, and in research projects including studies of the microbiome and to influence expression in genetically engineered animals. This overview provides a critical look at the use of antimicrobials in contemporary vivaria, with special attention to rodents because they are the most commonly used species in research and because antimicrobial use in rodents is not straightforward. Improvements in antibiotic use are encouraged with the goal of decreasing bacterial resistance while continuing to provide quality clinical care and research support. Suggestions are framed by using the 5 Rs: Reduce, Refine, Replace, and Review antimicrobial use in the vivarium, and take Responsibility for the judicious use of antibiotics in research animals. PMID- 28905710 TI - Cleavage Speed and Blastomere Number in DBA/2J Compared with C57BL/6J Mouse Embryos. AB - DBA/2J mice are among the oldest and most important inbred strains still used in many research fields. However, this strain has reproductive problems, which may consume considerable time and effort during experiments requiring a large population. Because the quality of DBA/2J embryos has not yet been described in detail, we compared DBA/2J mice with the reproductively efficient C57BL/6J strain. Compared with C57BL/6J embryos, DBA/2J embryos had a slower cleavage speed (mean +/- 1 SD; first cleavage: C57BL/6J, 16.87 +/- 1.32 ; DBA/2J, 19.64 +/ 0.96 h; P < 0.01; second cleavage: C57BL/6J, 41.12 +/- 2.02 h; DBA/2J, 46.20 +/- 2.68 h, P < 0.01) and lower cell counts at the morula and blastocyst stages (morula stage: C57BL/6J, 15 +/- 3 cells per embryo; DBA/2J, 9 +/- 5 cells per embryo; P < 0.05; blastocyst stage: C57BL/6J, 52 +/- 6 cells per embryo; DBA/2J, 35 +/- 14 cells per embryo; P < 0.05). In addition, the results of reciprocal in vitro fertilization and male-female reciprocal crosses revealed that these phenotypes were not affected by the sperm genome and were recessively inherited. These findings likely will facilitate the production of DBA/2J mice and genetically modified mice with their background. Our results also suggest that, due to their slow cleavage speed, DBA/2J mice can serve as a new model for human infertility. PMID- 28905711 TI - Automated Tracking of Motion and Body Weight for Objective Monitoring of Rats in Colony Housing. AB - Living together in large social communities within an enriched environment stimulates self-motivated activity in rats. We developed a modular housing system in which a single unit can accommodate as many as 48 rats and contains multiple functional areas. This rat colony cage further allowed us to remotely measure body weight and to continuously measure movement, including jumping and stair walking between areas. Compared with pair-housed, age-, strain-, and weight matched rats in conventional cages, the colony-housed rats exhibited higher body mass indices, had more exploratory behavior, and were more cooperative during handling. Continuous activity tracking revealed that the amount of spontaneous locomotion, such as jumping between levels and running through the staircase, fell after surgery, blood sampling, injections, and behavioral tests to a similar extent regardless of the specific intervention. Data from the automated system allowed us to identify individual rats with significant differences (>2 SD) from other cohoused rats; these rats showed potential health problems, as verified using conventional health scoring. Thus, our rat colony cage permits social interaction and provides a variety of functional areas, thereby perhaps improving animal wellbeing. Furthermore, automated online tracking enabled continuous quantification of spontaneous motion, potentially providing objective measures of animal behavior in various disease models and reducing the need for experimental manipulation. Finally, health monitoring of individual rats was facilitated in an objective manner. PMID- 28905712 TI - Evaluation of Traditional and Contemporary Methods for Detecting Syphacia obvelata and Aspiculuris tetraptera in Laboratory Mice. AB - There is no consensus regarding the best practice for detecting murine pinworm infections. Initially, we evaluated 7 fecal concentration methods by using feces containing Aspiculuris tetraptera (AT) eggs (n = 20 samples per method). Sodium nitrate flotation, sodium nitrate centrifugation, Sheather sugar centrifugation, and zinc sulfate centrifugation detected eggs in 100% of samples; zinc sulfate flotation and water sedimentation detected eggs in 90%. All had better detection rates than Sheather sugar flotation (50%). To determine optimal detection methods, Swiss Webster mice were exposed to Syphacia obvelata (SO; n = 60) or AT (n = 60). We compared the following methods at days 0, 30, and 90, beginning 21 or 28 d after SO and AT exposure, respectively: fecal concentration (AT only), anal tape test (SO only), direct examination of intestinal contents (cecum and colon), Swiss roll histology (cecum and colon), and PCR analysis (pooled fur swab and feces). Detection rates for SO-exposed mice were: PCR analysis, 45%; Swiss roll histology, 30%; intestinal content exam, 27%; and tape test, 27%. The SO detection rate for PCR analysis was significantly greater than that for the tape test. Detection rates for AT-exposed mice were: intestinal content exam, 53%; PCR analysis, 33%; fecal flotation, 22%; and Swiss roll histology, 17%. The AT detection rate of PCR analysis combined with intestinal content examination was greater than for PCR analysis only and the AT detection rate of intestinal content examination was greater than for Swiss roll histology. Combining PCR analysis with intestinal content examination detected 100% of infected animals. No single test detected all positive animals. We recommend combining PCR analysis with intestinal content examination for optimal pinworm detection. PMID- 28905713 TI - Interspecies Variation in the Susceptibility of a Wild-Derived Colony of Mice to Pinworms (Aspiculuris tetraptera). AB - Pinworms are common parasites in wild and laboratory rodents. Despite their relative nonpathogenicity in immunocompetent models, pinworm infections add an unwanted variable and may confound some types of research. For this reason, health monitoring programs and biosecurity measures aim to minimize the spread of pinworm infections into colonies free from the organisms. Wild-derived and laboratory strains of mice have shown varied susceptibility to infection with Aspiculuris tetraptera, the most commonly found murine pinworm. In particular, susceptibility is increased in wild-derived mice, young animals, and males. Routine surveillance at our institution revealed pinworm infection (A. tetraptera only) within a colony of multiple, wild-derived species of Mus, although only specific species showed positive results during initial sampling. To assess whether species-associated differences in susceptibility were present, we analyzed fecal egg counts of A. tetraptera in every cage of the colony. Our results revealed significant differences in susceptibility between various species and subspecies of Mus. Egg counts were significantly higher in Mus spicilegus than Mus m. domesticus (WSB/EiJ) and Mus macedonicus. Mus spretus had higher egg counts than M. m. domesticus (WSB/EiJ), M. m. musculus (PWK/PhJ), and M. macedonicus. Egg counts did not differ in regard to age, sex, or number of mice per cage. As wild-derived mouse models continue to compliment research largely based on laboratory strains, it will be important to understand host parasite interactions and their effects on research, particularly studies evaluating immune responses, behavior, growth, and other physiologic parameters. PMID- 28905714 TI - Cross-Foster Rederivation Compared with Antibiotic Administration in the Drinking Water to Eradicate Bordetella pseudohinzii. AB - Bordetella pseudohinzii is a microbial agent of potential importance in mice and has confounded pulmonary research at our institution. The purpose of this study was to evaluate cross-foster rederivation and antibiotic administration in the drinking water as methods to eradicate B. pseudohinzii. To evaluate the efficacy of cross-foster rederivation, 29 litters representing 16 strains of mice were cross-fostered from cages positive for B. pseudohinzii to B. pseudohinzii negative Crl:CD1-Elite surrogate dams. To evaluate antibiotic administration, sulfamethoxazole and trimethoprim (TMS; 0.66 and 0.13 mg/mL, respectively) and tetracycline (4.5 mg/mL) were administered in the drinking water. We assessed 3 antibiotic treatment groups with 12 B. pseudohinzii-positive cages per group (6 cages of CD1 and 6 cages of C57BL/6 mice): TMS for 4 wk, TMS for 6 wk, and tetracycline for 6 wk. Of the 29 litters that underwent cross-foster rederivation, 24 were negative for B. pseudohinzii. Five of the 12 cages treated with TMS for 4 wk and 1 of the 12 cages treated with TMS for 6 wk were negative for B. pseudohinzii at 2 wk after treatment. Three of the 12 cages treated with tetracycline were negative for B. pseudohinzii at 2 wk after treatment. Pearson chi2 analysis revealed significant association between the method of eradication (cross-foster rederivation compared with antibiotic administration) and B. pseudohinzii infection, and an odds-ratio estimate from a logistic regression demonstrated that cross-foster rederivation was more successful. Whereas antibiotic administration in the drinking water failed to eradicate B. pseudohinzii, cross-foster rederivation was successful and has been used to establish a B. pseudohinzii-negative barrier. PMID- 28905715 TI - Pilot Study to Assess the Efficacy of Ivermectin and Fenbendazole for Treating Captive-Born Olive Baboons (Papio anubis) Coinfected with Strongyloides fulleborni and Trichuris trichiura. AB - In this study, we evaluated the efficacy of combined treatment with ivermectin and fenbendazole (IVM-FBZ) for treating captive olive baboons (Papio anubis) infected with Strongyloides fulleborni and Trichuris trichiura, 2 common nematode parasites of these NHP. Infected baboons were treated for a total of 9 wk with ivermectin (400 MUg/kg IM twice weekly) and fenbendazole (50 mg/kg PO once daily for 3 d; 3 rounds of treatment, 21 d apart). Five baboons naturally infected with both S. fulleborni and T. trichiura (n = 4) or S. fulleborni alone (n = 1) received the combination therapy; an additional baboon infected with both parasites served as a nontreated control. The efficacy of IVM-FBZ was measured as the reduction in fecal egg counts of S. fulleborni and T. trichiura as determined by quantitative fecal flotation examination after treatment of baboons with IVM FBZ. All baboons treated with IVM-FBZ stopped shedding S. fulleborni and T. trichiura eggs by 8 d after treatment and remained negative for at least 161 d. The nontreated control baboon shed S. fulleborni and T. trichiura eggs throughout the study period. Our results indicate that the IVM-FBZ regimen was efficacious for treating olive baboons infected with S. fulleborni and T. trichiura. PMID- 28905716 TI - Lack of Trypanosoma cruzi Infection in Urban Roof Rats (Rattus rattus) at a Texas Facility Housing Naturally Infected Nonhuman Primates. AB - The protozoan parasite Trypanosoma cruzi causes Chagas disease, uses kissing bugs as a vector, and is maintained in nature by a variety of wildlife reservoirs. Many natural cases of Chagas disease have been reported in NHP at facilities across the southern United States, where infected vectors and wildlife occur. Infection of NHP with T. cruzi can diminish their value as research models and lead to health problems and death. Identifying the modes of transmission and role of wildlife reservoirs in these facilities is therefore critical to guide interventions to reduce transmission. Here we investigated the role of roof rats (Rattus rattus), the most abundant nuisance species at a primate facility in San Antonio, in the maintenance and transmission of T. cruzi. The hearts and blood from the carcasses of the 145 rats collected underwent 2 independent PCR assays for detection of T. cruzi and other trypanosomes. The 145 hearts and 61 blood samples were all negative for T. cruzi. This population sample of 145 subjects would allow the detection of disease prevalence of 0.020 with a confidence level of 95%. The limited active vector surveillance efforts by our team combined with passive surveillance by facility personnel yielded no kissing bugs during the study period. Our results suggest that roof rats are unlikely to be important local reservoirs of T. cruzi at this facility. Further investigation of transmission dynamics across multiple years and more comprehensive vector surveillance is warranted. PMID- 28905717 TI - Use of Liposomal Bupivacaine for Postoperative Analgesia in an Incisional Pain Model in Rats (Rattus norvegicus). AB - The local anesthetic bupivacaine is valuable for perioperative analgesia, but its use in the postoperative period is limited by its short duration of action. Here, we evaluated the application of a slow-release liposomal formulation of bupivacaine for postoperative analgesia. The aim was to assess whether liposomal bupivacaine effectively attenuates postoperative mechanical and thermal hypersensitivity in a rat model of incisional pain. Rats (n = 36) were randomly assigned to 1 of 5 treatment groups: saline, 1 mL/kg SC every 12 h for 2 d; buprenorphine HCl, 0.05 mg/kg SC every 12 h for 2 d (Bup HCl); 0.5% bupivacaine, 2 mg/kg SC local infiltration once (Bupi); liposomal bupivacaine, 1 mg/kg SC local infiltration once (Exp1); and liposomal bupivacaine, 6 mg/kg SC local infiltration once (Exp6). Mechanical and thermal hypersensitivity were evaluated daily on days -1, 0, 1, 2, 3, and 4. The saline group exhibited both hypersensitivities through all 4 evaluated postoperative days. Bup HCl attenuated mechanical hypersensitivity for 2 d and thermal hypersensitivity for 1 d. Bupi attenuated only thermal hypersensitivity for 4 d. Rats in the Exp1 group showed attenuation of both mechanical and thermal hypersensitivity for 4 d, and those in the Exp6 group had attenuation of mechanical hypersensitivity on day 0 and thermal hypersensitivity for 4 d. These data suggest that a single local infiltration of liposomal bupivacaine at a dose of 1 mg/kg SC effectively attenuates postoperative mechanical and thermal hypersensitivity for 4 d in a rat model of incisional pain. PMID- 28905718 TI - Physiologic, Behavioral, and Histologic Responses to Various Euthanasia Methods in C57BL/6NTac Male Mice. AB - Rodent euthanasia using exposure to increasing concentrations of CO2 has come under scrutiny due to concerns of potential pain during the euthanasia process. Alternatives to CO2, such as isoflurane and barbiturates, have been proposed as more humane methods of euthanasia. In this study, we examined 3 commonly used euthanasia methods in mice: intraperitoneal injection of pentobarbital-phenytoin solution, CO2 inhalation, and isoflurane anesthesia followed by CO2 inhalation. We hypothesized that pentobarbital-phenytoin euthanasia would cause fewer alterations in cardiovascular response, result in less behavioral evidence of pain or stress, and produce lower elevations in ACTH than would the isoflurane and CO2 methods, which we hypothesized would not differ in regard to these parameters. ACTH data suggested that pentobarbital-phenytoin euthanasia may be less stressful to mice than are isoflurane and CO2 euthanasia. Cardiovascular, behavioral, and activity data did not consistently or significantly support isoflurane or pentobarbital-phenytoin euthanasia as less stressful methods than CO2. Euthanasia with CO2 was the fastest method of the 3 techniques. Therefore, we conclude that using CO2 with or without isoflurane is an acceptable euthanasia method. Pathologic alterations in the lungs were most severe with CO2 euthanasia, and alternative euthanasia techniques likely are better suited for studies that rely on analysis of the lungs. PMID- 28905719 TI - Consequences of Oral Gavage during Gestation and Lactation on Rat Dams and the Neurodevelopment and Behavior of Their Offspring. AB - Oral gavage is a popular route of drug administration during preclinical testing. Despite the growing body of information regarding the effects of oral gavage and the stress associated with this technique, the consequences of such exposure during pregnancy or lactation have rarely been investigated. Therefore, we sought to determine the consequences of oral gavage exposure during pregnancy and lactation on the neurodevelopment and behavior of rat offspring. Pregnant Sprague Dawley dams underwent either no treatment or oral gavage of distilled water once daily from gestational day 7 until postnatal day 21. Oral gavage treatment had no significant effect on maternal parameters, including bodyweight gain, duration of gestation, litter size, and incidence of neonatal death. Compared with their counterparts from untreated dams, male and female progeny of gavaged dams had longer body lengths on PND 7 and 14 but reduced forelimb grip performance on PND 14 and 17. Therefore, the use of oral gavage during pregnancy and lactation in rats can have opposite effects on the somatic and behavioral development of the offspring. These factors should be considered when using oral gavage as a route of administration during pregnancy. In addition, the inclusion of no-treatment controls is important because they may reveal various restraint-associated effects. PMID- 28905720 TI - Evaluation of Infrared Thermometry in Cynomolgus Macaques (Macaca fascicularis). AB - Recording an accurate body temperature is important to assess an animal's health status. We compared temperature data from sedated cynomolgus macaques (Macaca fascicularis) to evaluate differences between rectal, infrared (inguinal and chest), and implanted telemetry techniques with the objective of demonstrating the diagnostic equivalence of the infrared device with other approaches. Infrared thermometer readings are instantaneous and require no contact with the animal. Body temperature data were obtained from 205 (137 male, 68 female) cynomolgus macaques under ketamine (10 mg/kg IM) sedation over a 3-mo period during scheduled physical examinations. Infrared measurements were taken 5 cm from the chest and inguinal areas. We evaluated 10 (9 functional devices) sedated cynomolgus macaques (5 male, 5 female) implanted with telemetry units in a muscular pouch between the internal and external abdominal oblique muscles. We determined that the mean body temperature acquired by using telemetry did not differ from either the mean of inguinal and chest infrared measurements but did differ from the mean of temperature obtained rectally. In addition, the mean rectal temperature differed from the mean of the inguinal reading but not the mean of the chest temperature. The results confirm our hypothesis that the infrared thermometer can be used to replace standard rectal thermometry. PMID- 28905722 TI - Calculation of Glucose Dose for Intraperitoneal Glucose Tolerance Tests in Lean and Obese Mice. AB - Glucose tolerance tests are used frequently in nonclinical research with laboratory animals, for example during characterization of obese phenotypes. Despite published standard operating procedures for glucose tolerance tests in rodents, how glucose doses should be calculated when obese and lean animals are compared is not well documented. Typically the glucose dose is calculated as 2 g/kg body weight, regardless of body composition. With this approach, obese mice receive larger glucose doses than do lean animals, potentially leading to overestimation of glucose intolerance in obese animals. In this study, we performed intraperitoneal glucose tolerance tests in mice with diet-induced obesity and their lean controls, with glucose doses based on either the total body weight or the lean body mass of the animals. To determine glucose tolerance, we determined the blood glucose AUC during the glucose tolerance test. We found that the blood glucose AUC was increased significantly in obese mice compared with lean mice by 75% on average when glucose was dosed according to the lean body mass and by 87% when the glucose dose was calculated according to total body weight. Therefore, mice with diet-induced obesity were approximately equally glucose intolerant between the 2 dose-calculation protocols. However, we recommend calculating the glucose dose according to the lean body mass of the mice, because doing so eliminates the concern regarding overdosing of obese animals. PMID- 28905721 TI - Using a Cageside Device for Testing Glycosylated Hemoglobin in Cynomolgus Macaques (Macaca fascicularis). AB - Nonhuman primates naturally develop type 2 diabetes mellitus and exhibit clinical features that are similar to those observed in humans, including obesity, insulin resistance, dyslipidemia, and pancreatic pathology. The glycosylated hemoglobin (HbA1C) test is the primary test used for diabetes management in humans because it reflects the average blood glucose levels over the previous 3 mo. The HbA1C results are a better predictor of potential risk of complications than are single or episodic measures of glucose levels. HbA1C levels have proven useful for the diagnosis and monitoring of blood glucose levels in NHP, but for testing by a commercial laboratory, the test requires a vial of whole blood, results are not available for several days, and the test is expensive. The cageside device requires a single drop of blood, it displays the HbA1C percentage in 5 min, and the cost per sample is less than for sending it to a commercial lab. We therefore assessed the correlation between a cageside test using a handheld unit and the commercial lab test for measuring HbA1C in cynomolgus macaques. From both normal and confirmed diabetic animals, 4 mL blood was collected from a peripheral vessel and sent to a commercial lab for HbA1C testing. At the same time, a drop of capillary blood was collected and tested immediately in the HbA1C cageside test. A comparison of the results revealed significant correlation between the cageside and commercial lab tests. Therefore, we feel that the HbA1C test using handheld device may help to rule out nondiabetics and indicate which animals require additional testing. PMID- 28905723 TI - Breeding and Rearing Naked Mole-Rats (Heterocephalus glaber) under Laboratory Conditions. AB - The unique biologic characteristics of naked mole-rats (NMR, Heterocephalus glaber) include longevity, cancer resistance, hypoxia tolerance, and pain insensitivity, making NMR an attractive model for biomedical research on aging, cancer, and neurobiology. However, breeding and rearing NMR in captivity is challenging. Here, we report a method for breeding NMR by using a closed-colony mating system. We selected sexually mature male and female NMR from different natal colonies and mated them 1:1. The 5 original colonies had an annual parity of 3.20 +/- 0.84 (mean +/- 1 SD), with 38.80 +/- 9.50 pups born, 33.80 +/- 8.32 pups weaned, and a survival rate of 87.19% +/- 6.09% after weaning. The average annual parity of 22 N1 pairs (established from the progeny of the 5 original pairs) was 3.09 +/- 0.81, with 34.86 +/- 10.66 total pups born during the year, 30.14 +/- 10.23 pups weaned, and a survival rate after weaning of 85.51% +/- 6.60%. The average annual parity of 29 N2 pairs (that is, offspring of N1 pairs) was 3.04 +/- 0.87, with 33.69 +/- 11.42 pups born, 28.17 +/- 10.43 pups weaned, and a survival rate after weaning of 83.66% +/- 10.75%. None of these measures differed among the 3 generations, with average reproductive success exceeding 70% for each. In addition, the reproduction and growth of the N1 and N2 generations was similar to the original colonies. Our breeding method remarkably increases the production of NMR, thus representing a great potential to promote experimental NMR research and its applications. PMID- 28905724 TI - Position Statement: "Functionally Appropriate Nonhuman Primate Environments" as an Alternative to the Term "Ethologically Appropriate Environments". AB - The American Society of Primatologists (ASP), the Association of Primate Veterinarians (APV), and the American College of Laboratory Animal Medicine (ACLAM) have come together to develop this position statement in which the term "functionally appropriate nonhuman primate environments" is proposed as a better descriptor and as an alternative to the previously used term, "ethologically appropriate environments" to describe environments that are suitable for nonhuman primates involved in biomedical research. In 2015, the United States Department of Agriculture requested comments on a petition which called for amending the Animal Welfare Act so that all research primates would be housed in "ethologically appropriate physical and social environments." We are critical of this term because: (1) it does not provide clarification beyond that in current regulatory language; (2) it does not provide for balance between animal welfare goals and the reasons why the primates are housed in captivity; (3) it discounts the adaptability that is inherent in the behavior of primates; (4) it conveys that duplication of features of the natural environment are required for suitable holding environments; (5) objective studies reveal that environments that appear to be more ethologically appropriate do not necessarily better meet the needs of animals; and (6) using the term "ethology" is inherently confusing. We propose that the term "functionally appropriate nonhuman primate environments" be used instead, as it emphasizes how environments work for nonhuman primates, it better describes current activities underway to improve nonhuman primate welfare, and the balance that is achieved between meeting the needs of the animals and the requirements of the research in which they are involved. PMID- 28905725 TI - Ethics Students Go to the Jail. AB - This article describes an educational initiative in which clinical ethics students, who were either in a bioethics master's degree program or in the fourth year of medical school, spent two days observing health care in an urban jail. Students submitted reflections about their experience, in which they drew attention to concerns about privacy, physical restriction, due care, drug addiction, mistrust, and the conflicting expectations that arise when incarcerated people become patients. The rotation was of great value to the students both because it exposed them to many of the ethical issues that arise in a correctional setting and because it deepened their understanding of various ethical concerns that are pervasive in health care. PMID- 28905726 TI - Compassionate Release Policy Reform: Physicians as Advocates for Human Dignity. AB - A rapidly aging correctional population has led to an increasing number of patients with serious progressive and terminal illnesses in correctional settings. "Compassionate release" describes a range of policies offering early release or parole to incarcerated patients with serious or debilitating illnesses. However, in many states that have compassionate release policies, few patients are actually granted release. We describe how the continued incarceration of patients with serious or debilitating illness can constitute a violation of human dignity if appropriate palliative care is unavailable. We argue that, given the importance in medical ethics of upholding dignity, physicians should advocate for the appropriate application and use of compassionate release. We describe several opportunities for physicians to take leadership on this issue. PMID- 28905728 TI - What Are Physicians' Responsibilities to Patients Whose Health Conditions Can Influence Their Legal Proceedings? AB - Correctional populations are disproportionately affected by conditions that affect cognition, such as psychiatric illness and head trauma. Honoring bioethical principles in the care of such patients can be particularly difficult in the correctional setting. However, the approach should not change markedly because a patient is incarcerated. That is, the same standards of respecting patient autonomy and confidentiality should be maintained, and the fact that correctional populations are already marginalized makes it all the more important for clinicians to honor these principles. Physicians should act in the best interest of their patients; in jails this might include disclosing information to and consulting with a patient's legal defense. However, this step should only be taken with a patient's consent or, in cases in which the patient does not have decision-making capacity, when it seems consistent with a patient's wishes. PMID- 28905727 TI - "Teach-to-Goal" to Better Assess Informed Consent Comprehension among Incarcerated Clinical Research Participants. AB - Correctional health research requires important safeguards to ensure that research participation is ethically conducted. In addition to having disproportionately low educational attainment and low literacy, incarcerated people suffer from health-related conditions that can affect cognition (e.g., traumatic brain injury, substance use disorders, mental illness). Yet modified informed consent processes that assess participants' comprehension of the risks and benefits of participation are not required by relevant federal guidelines. A push to assess comprehension of informed consent documents is particularly timely given an increase in demand for correctional health research in the context of criminal justice reform. We argue that comprehension assessments can identify persons who should be excluded from research and help those who will ultimately participate in studies better understand the risks and benefits of their participation. PMID- 28905729 TI - How to Talk with Patients about Incarceration and Health. AB - The United States has the highest incarceration rate of any nation in the world more than 700 people per 100,000. For this reason alone, clinicians practicing in the US should be aware of the numerous ways in which incarceration adversely affects the health of individuals, their families, and communities. While we clinicians are taught how to discuss ways that culture, religion, or sexuality can affect health outcomes, we are not instructed on how to talk about incarceration history with patients when it might be affecting their health, as highlighted in the case scenario. Here I present a "structural vulnerability" screen, a theoretical approach that clinics or individuals can take to better understand how structures of power (i.e., mass incarceration) directly and indirectly affect our patients. I also offer practical tips on how to talk to patients about incarceration history and why it matters for good health. PMID- 28905730 TI - How Should a Health Care Professional Respond to an Incarcerated Patient's Request for a Particular Treatment? AB - Incarceration complicates the ethical provision of clinical care through reduction in access to treatment modalities and institutional cultures that value order over autonomy. Correctional care clinicians should expand their guiding principles to consider autonomy and health justice for their patients, which in turn should prompt development of processes and care plans that are patient centered and account for the inherent restrictions of the setting. PMID- 28905731 TI - What Does Health Justice Look Like for People Returning from Incarceration? AB - Access to health care is a constitutional right in the United States correctional system, and many incarcerated adults are newly diagnosed with chronic diseases in prison. Despite this right, the quality of correctional health care is variable, largely unmeasured and unregulated, and characterized by patients' widespread distrust of a health system that is intimately tied to a punitive criminal justice system. Upon release, discontinuity of care is the norm, and when continuity is established, it is often hindered by distrust, discrimination, poor communication, and racism in the health system. In this paper, we will propose best practices in transitioning from correctional- to community-based health care and argue that achieving health equity for people with criminal justice involvement in the United States is not possible without ethical provision of health care. PMID- 28905732 TI - Medicine and Mass Incarceration: Education and Advocacy in the New York City Jail System. AB - The United States incarcerates more people than any other country in the world. The scale of mass incarceration ensures that almost all practicing physicians will treat formerly incarcerated patients. Yet the majority of physicians receive little training on this topic. In this paper, we will outline the need for expanded education on the interface between incarceration and health, describe initiatives taking place within the New York City jail system and nationally, and describe future directions for curriculum development. We conclude by highlighting the important role health care workers can play in transforming our criminal justice system and ending mass incarceration. PMID- 28905733 TI - Why It's Inappropriate Not to Treat Incarcerated Patients with Opioid Agonist Therapy. AB - Due to the criminalization of drug use and addiction, opioid use disorder is overrepresented in incarcerated populations. Decades of evidence supports opioid agonist therapy as a highly effective treatment that improves clinical outcomes and reduces illicit opioid use, overdose death, and cost. Opioid agonist therapy has been both studied within correctional facilities and initiated prerelease. It has been found to be beneficial, yet few incarcerated persons receive this evidence-based treatment. In addition to not offering treatment initiation for those who need it, most correctional facilities forcibly withdraw stable patients from opioid agonist therapy upon their entry into the criminal justice system. This approach limits their access to evidence-based health care and results in negative outcomes for individuals, communities, and society. PMID- 28905734 TI - Swift and Certain, Proportionate and Consistent: Key Values of Urine Drug Test Consequences for Probationers. AB - Traditionally, urine drug testing (UDT) in the correctional population (both prison and community corrections) has been infrequent, is scheduled, and has a high possibility of delayed results. Of practical relevance is that scheduled testing is ineffective for identifying drug misuse. Of ethical relevance is that consequences of positive scheduled tests can be unpredictable-in the form of overly severe punishment or a lack of treatment options-and that the scheduled testing paradigm is a poor way to change behaviors. More innovative programs now use a UDT paradigm with more frequent, random testing providing rapid results and certain, swift consequences and addiction treatment when warranted or requested. Studies have shown these new programs-the foundation of which is frequent, random UDTs-to significantly reduce drug use, criminal recidivism, and incarceration. PMID- 28905735 TI - Surgery in Shackles: What Are Surgeons' Obligations to Incarcerated Patients in the Operating Room? AB - Incarcerated patients frequently require surgery outside of the correctional setting, where they can be shackled to the operating table in the presence of armed corrections officers who observe them throughout the procedure. In this circumstance, privacy protection-central to the patient-physician relationship and the need to control the incarcerated patient for the safety of health care workers, corrections officers, and society must be balanced. Surgeons recognize the heightened need for gaining a patient's trust within the context of an operation. For an anesthetized patient, undergoing an operation while shackled and observed by persons in positions of power is a violation of patient privacy that can lead to increased feelings of vulnerability, mistrust of health care professionals, and reduced therapeutic potential of a procedure. PMID- 28905736 TI - Hydrochlorothiazide. PMID- 28905738 TI - Extraskeletal osteochondroma within the iliopsoas muscle: case report. AB - Osteochondromas, occurring usually in the metaphyses of long bones, are among the most frequent benign musculoskeletal neoplasms and both their sporadic and hereditary variants have been studied extensively. Extraskeletal osteochondromas, however, are much less common. They have been shown to arise near joints or synovial spaces of feet, hands, or bursae. Herein, we present a very rare case of an extraskeletal osteochondroma within the iliopsoas muscle. PMID- 28905737 TI - Giant cell tumor of bone revisited. AB - Giant cell tumor (GCT) of bone is a locally aggressive benign neoplasm that is associated with a large biological spectrum ranging from latent benign to highly recurrent and occasionally metastatic malignant bone tumor. It accounts for 4-10% of all bone tumors and typically affects the meta-epiphyseal region of long bones of young adults. The most common site involved is the distal femur, followed by the distal radius, sacrum, and proximal humerus. Clinical symptoms are nonspecific and may include local pain, swelling, and limited range of motion of the adjacent joint. Radiographs and contrast-enhanced magnetic resonance imaging (MRI) are the imaging modalities of choice for diagnosis. Surgical treatment with curettage is the optimal treatment for local tumor control. A favorable clinical outcome is expected when the tumor is excised to tumor-free margins, however, for periarticular lesions this is usually accompanied with a suboptimal functional outcome. Local adjuvants have been used for improved curettage, in addition to systematic agents such as denosumab, bisphosphonates, or interferon alpha. This article aims to discuss the clinicopathological features, diagnosis, and treatments for GCT of bone. PMID- 28905740 TI - Department of Error. PMID- 28905739 TI - Of pigs and people-WHO prepares to battle cysticercosis. PMID- 28905741 TI - Department of Error. PMID- 28905742 TI - Department of Error. PMID- 28905743 TI - Department of Error. PMID- 28905744 TI - August 16-22, 2014. PMID- 28905745 TI - Re: Rates of Prostate Surgery and Acute Urinary Retention for Benign Prostatic Hyperplasia in Men Treated with Dutasteride or Finasteride. PMID- 28905746 TI - Re: A Possible Relationship between Serum Sex Hormones and Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms in Men Who Underwent Transurethral Prostate Resection. PMID- 28905747 TI - Re: Analysis of Risk Factors Leading to Postoperative Urethral Stricture and Bladder Neck Contracture following Transurethral Resection of Prostate. PMID- 28905748 TI - Re: Do no Harm, Except to Ourselves? A Survey of Symptoms and Injuries in Oncologic Surgeons and Pilot Study of an Intraoperative Ergonomic Intervention. PMID- 28905749 TI - Re: Ultrasound-Assisted Prompted Voiding for Management of Urinary Incontinence of Nursing Home Residents: Efficacy and Feasibility. PMID- 28905750 TI - Re: Understanding Help-Seeking in Older People with Urinary Incontinence: An Interview Study. PMID- 28905751 TI - Re: Which Better Predicts Mortality among Older Men, a Prostate Cancer (PCa) Diagnosis or Vulnerability on the Vulnerable Elders Survey (VES-13)? A Retrospective Cohort Study. PMID- 28905752 TI - Re: Comorbidity and Age Cannot Explain Variation in Life Expectancy Associated with Treatment of Non-Metastatic Prostate Cancer. PMID- 28905753 TI - Re: Current Impact of Age and Comorbidity Assessment on Prostate Cancer Treatment Choice and Over/Undertreatment Risk. PMID- 28905754 TI - Re: Antibacterial Susceptibilities of Escherichia coli from Community-Acquired Urinary Tract Infections in the Faroe Islands, Associations with Antibacterial Sales, and Comparison with Iceland and Denmark. PMID- 28905755 TI - Re: Incidental Findings in Abdominal Dual-Energy Computed Tomography: Correlation between True Noncontrast and Virtual Noncontrast Images Considering Renal and Liver Cysts and Adrenal Masses. PMID- 28905756 TI - Re: Variation in the Use of Open Pyeloplasty, Minimally Invasive Pyeloplasty, and Endopyelotomy for the Treatment of Ureteropelvic Junction Obstruction in Adults. PMID- 28905757 TI - Re: Development and Characterization of a Stable Adhesive Bond between a Poly(dimethylsiloxane) Catheter Material and a Bacterial Biofilm Resistant Acrylate Polymer Coating. PMID- 28905758 TI - Re: Testosterone Treatment and Coronary Artery Plaque Volume in Older Men with Low Testosterone. PMID- 28905759 TI - Re: Statin, Testosterone and Phosphodiesterase 5-Inhibitor Treatments and Age Related Mortality in Diabetes. PMID- 28905760 TI - Re: High Prevalence of Low Serum Biologically Active Testosterone in Older Male Veterans. PMID- 28905761 TI - Re: Effects of Bariatric Surgery on Female Pelvic Floor Disorders. PMID- 28905762 TI - Re: Six out of Ten Women with Recurrent Urinary Tract Infections Complain of Distressful Sexual Dysfunction-A Case-Control Study. PMID- 28905763 TI - Re: Is Advanced Paternal Age a Health Risk for the Offspring? PMID- 28905764 TI - Re: Age-Related Alterations in the Genetics and Genomics of the Male Germ Line. PMID- 28905765 TI - Re: Behavioral, Cognitive, and Motor Performance and Physical Development of Five Year-Old Children Who Were Born after Intracytoplasmic Sperm Injection with the Use of Testicular Sperm. PMID- 28905766 TI - Re: Semen Quality of Young Adult ICSI Offspring: The First Results. PMID- 28905767 TI - Re: Applying Data Mining Techniques for Increasing Implantation Rate by Selecting Best Sperms for Intra-Cytoplasmic Sperm Injection Treatment. PMID- 28905768 TI - Re: Paratesticular Rhabdomyosarcoma: Importance of Initial Therapy. PMID- 28905769 TI - Re: Topical Dihydrotestosterone to Treat Micropenis Secondary to Partial Androgen Insensitivity Syndrome (PAIS) before, during, and after Puberty-A Case Series. PMID- 28905770 TI - Re: A Comparison between Tourniquet Application and Epinephrine Injection for Hemostasis during Hypospadias Surgery: The Effect on Bleeding and Postoperative Outcome. PMID- 28905771 TI - Re: Pediatric Inguinal and Scrotal Surgery-Practice Patterns in U.S. Academic Centers. PMID- 28905772 TI - Re: Sharp Decline in Prostate Cancer Treatment among Men in the General Population, but Not among Diagnosed Men. PMID- 28905773 TI - Re: Continuous Normothermic Ex Vivo Kidney Perfusion is Superior to Brief Normothermic Perfusion following Static Cold Storage in Donation after Circulatory Death Pig Kidney Transplantation. PMID- 28905774 TI - Re: Better Defining the Spectrum of Adult Hypospadias: Examining the Effect of Childhood Surgery on Adult Presentation. PMID- 28905775 TI - Re: Incidence of Urethral Stricture in Patients with Spinal Cord Injury Treated with Clean Intermittent Self-Catheterization. PMID- 28905776 TI - Re: Improving Outcomes of Bulbomembranous Urethroplasty for Radiation-Induced Urethral Strictures in Post-UroLume Era. PMID- 28905777 TI - Re: Primary SWL is an Efficient and Cost-Effective Treatment for Lower Pole Renal Stones between 10 and 20 mm in Size: A Large Single Center Study. PMID- 28905778 TI - Re: A Multi-Institutional Study of Struvite Stones: Patterns of Infection and Colonization. PMID- 28905779 TI - Re: Use of the Moses Technology to Improve Holmium Laser Lithotripsy Outcomes: A Preclinical Study. PMID- 28905780 TI - Re: Development of Endoscopic Diagnosis and Treatment for Chronic Unilateral Hematuria: 35 Years Experience. PMID- 28905782 TI - Re: Effects of Immunonutrition for Cystectomy on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial. PMID- 28905781 TI - Re: Effectiveness of Adjuvant Chemotherapy after Radical Nephroureterectomy for Locally Advanced and/or Positive Regional Lymph Node Upper Tract Urothelial Carcinoma. PMID- 28905783 TI - Re: Detrusor Muscle in TUR-Derived Bladder Tumor Specimens: Can we Actually Improve the Surgical Quality? PMID- 28905784 TI - Re: Active Surveillance in Younger Men with Prostate Cancer. PMID- 28905785 TI - Re: Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. PMID- 28905787 TI - Re: Association between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes after 3 Years. PMID- 28905786 TI - Re: Association between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes after 3 Years. PMID- 28905788 TI - Re: Presence of Invasive Cribriform or Intraductal Growth at Biopsy Outperforms Percentage Grade 4 in Predicting Outcome of Gleason Score 3+4=7 Prostate Cancer. PMID- 28905789 TI - Re: Inactivation of the PBRM1 Tumor Suppressor Gene Amplifies the HIF-Response in VHL-/- Clear Cell Renal Carcinoma. PMID- 28905790 TI - Re: Genetic Determinants of Cisplatin Resistance in Patients with Advanced Germ Cell Tumors. PMID- 28905791 TI - Re: Antagonists of Growth Hormone-Releasing Hormone Inhibit Proliferation Induced by Inflammation in Prostatic Epithelial Cells. PMID- 28905792 TI - Re: Genome-Wide Association Study of Prostate-Specific Antigen Levels Identifies Novel Loci Independent of Prostate Cancer. PMID- 28905793 TI - Re: Reduction of Urgency Severity is the Most Important Factor in the Subjective Therapeutic Outcome of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder. PMID- 28905794 TI - Re: Brain Activity on fMRI Associated with Urinary Bladder Filling in Patients with a Complete Spinal Cord Injury. PMID- 28905795 TI - Re: Continuous Urethral Pressure Measurements; Measurement Techniques; Pressure Variations; Clinical Interpretations; and Clinical Relevance. A Systematic Literature Analysis. PMID- 28905796 TI - Re: The Relationship between Anxiety and Overactive Bladder or Urinary Incontinence Symptoms in the Clinical Population. PMID- 28905797 TI - Re: Sacral Neuromodulation in Urological Practice. PMID- 28905798 TI - Re: Long-Term Efficacy of Holmium Laser Enucleation of the Prostate in Patients with Detrusor Underactivity or Acontractility. PMID- 28905799 TI - Improvement of psoriasiform eruptions after resection of breast cancer. PMID- 28905800 TI - Analysis of factors affecting the quality of life of those suffering from Crohn's disease. AB - INTRODUCTION: Crohn's disease is an inflammatory bowel disease of unknown etiology. Its chronic nature, as well as symptoms of intestinal and overall significantly impedes the daily functioning of patients. Alternately occurring periods of exacerbation and remission are the cause of reduced quality of life of patients. Understanding the factors that caused the decrease in the quality of life, it allows us to understand the behavior and the situation of the patient and the ability to cope with stress caused by the disease. AIM OF THE STUDY: The aim of the study was to analyze the factors affecting the quality of life of people with Crohn's disease. MATERIAL AND METHODS: The study group consisted of 50 people diagnosed with Crohn's disease. Respondents were treated at the Department of General Surgery and Colorectal Medical University of Lodz and Gastroenterological Clinic at the University Clinical Hospital No. 1 in Lodz. Quality of Life Survey was carried out by a diagnostic survey using a research tool SF-36v2 and surveys of its own design. RESULTS: Analysis of the results demonstrated that the quality of life of patients with Crohn's disease was reduced, especially during exacerbations. Evaluation of the quality of life of respondents in physical terms was slightly higher than in the mental aspect. Higher education subjects and the lack of need for surgical treatment significantly improves the quality of life. CONCLUSIONS: The occurrence of chronic disease reduces the quality of life of respondents. Elderly patients are better able to adapt to the difficult situation caused by the disease. The quality of life of women and men is at a similar level and patients in remission of the disease have a better quality of life of patients during exacerbations. PMID- 28905801 TI - The Impact of Obesity on the Perioperative, Clinicopathologic, and Oncologic Outcomes of Robot Assisted Total Mesorectal Excision for Rectal Cancer. AB - PURPOSE: To analyze the feasibility and outcomes of robotic rectal cancer surgery in obese patients. METHODS: From 2005 to 2012, 101 consecutive rectal cancers operated robotically were enrolled in a prospective database. Patients were stratified into obese (BMI >= 30 kg/m2) and non-obese (BMI < 30 kg/m2) groups. Operative, perioperative parameters, and pathologic outcomes were compared. Data were analyzed using SPSS 22.0, while statistical significance was defined as a p value <= .05. RESULTS: There were 33 obese patients (mean BMI 33.8 kg/m2). Patients were comparable regarding gender, T stage, and type of operation. Operative time and blood loss were higher in the obese group; only operative time was statistically significant. The conversion rate, length of stay, and anastomotic leak rates were similar. Circumferential margin positivity and lymph node yield were comparable. Disease free and overall survivals at 3 years were 75.8% versus 80.9% and 84.8% versus 92.6%, respectively for obese and non-obese subgroups. CONCLUSIONS: Robotic surgery for curative treatment of rectal cancer in the obese is safe and feasible. BMI does not influence conversion rates, length of stay, postoperative complications, and quality of the specimen or survival when the robotic platform is used. PMID- 28905802 TI - Coccygodynia - pathogenesis, diagnostics and therapy. Review of the writing. AB - Coccygodynia is a problem with a small percentage (1%) of the population suffering from musculoskeletal disorders. This pain is often associated with trauma, falling on the tailbone, long cycling, or by women after childbirth. The reason for the described problem can be the actual morphological changes. Idiopathic coccygodynia causes therapeutic difficulties to specialists of many fields. Unsatisfactory treatment, including coccygectomy tends to seek new solutions. They belong to them techniques exploited in the manual therapy which in their spectrum hold: direct techniques - per rectum as well as indirect techniques taking into account distant structures of the motor organ, remaining in dense interactions with the coccygeal part. Idiopathic coccygodynia is a result perhaps from exaggerated tension the muscle of the levator ani, coccygeus and gluteus maximus as well as from irritating soft tissue structures surrounding the coccyx: of sacrococcygeum, sacrospinale, and sacrotuberale ligament. Unfortunately we can't see them in objective examinations so as: the RTG, MR or TK, therefore constitute the both diagnostic and therapeutic problem. For describing the problem a writing of the object was used both from the field of the surgery and of manual therapy. Detailed and multifaceted knowledge about causes of the described problem allows more accurately to categorize the patient to the appropriate group and helps to select the best procedure of treatment. PMID- 28905803 TI - Diagnosis and treatment of gastroesophageal reflux disease complicated by Barrett's esophagus. AB - : The aim of the study was to evaluate the effectiveness of a diagnostic and therapeutic algorithm for gastroesophageal reflux disease complicated by Barrett's esophagus in 46 patients. MATERIALS AND METHODS: A diagnostic and therapeutic algorithm for complicated GERD was developed. To describe the changes in the esophagus with reflux esophagitis, the Los Angeles classification was used. Intestinal metaplasia of the epithelium in the lower third of the esophagus was assessed using videoendoscopy, chromoscopy, and biopsy. Quality of life was assessed with the Gastro-Intestinal Quality of Life Index. The used methods were modeling, clinical, analytical, comparative, standardized, and questionnaire based. Results and their discussion. Among the complications of GERD, Barrett's esophagus was diagnosed in 9 (19.6 %), peptic ulcer in the esophagus in 10 (21.7 %), peptic stricture of the esophagus in 4 (8.7 %), esophageal-gastric bleeding in 23 (50.0 %), including Malory-Weiss syndrome in 18, and erosive ulcerous bleeding in 5 people. Hiatal hernia was diagnosed in 171 (87.7 %) patients (sliding in 157 (91.8%), paraesophageal hernia in 2 (1.2%), and mixed hernia in 12 (7.0%) cases). One hundred ninety-five patients underwent laparoscopic surgery. Nissen fundoplication was conducted in 176 (90.2%) patients, Toupet fundoplication in 14 (7.2%), and Dor fundoplication in 5 (2.6%). It was established that the use of the diagnostic and treatment algorithm promoted systematization and objectification of changes in complicated GERD, contributed to early diagnosis, helped in choosing treatment, and improved quality of life. CONCLUSIONS: Argon coagulation and use of PPIs for 8-12 weeks before surgery led to the regeneration of the mucous membrane in the esophagus. The developed diagnostic and therapeutic algorithm facilitated systematization and objectification of changes in complicated GERD, contributed to early diagnosis, helped in choosing treatment, and improved quality of life. PMID- 28905804 TI - Large pancreatic pseudocyst penetrating into posterior mediastinum. AB - We report a rare case of a large mediastinal pancreatic pseudocyst compressing the left atrium and the esophagus and causing dyspnea, palpitations, and emesis. Chest radiograph was non-diagnostic, esophagogastroduodenoscopy showed diffuse extrinsic compression of the distal esophagus and gastric corpus, but a definitive diagnosis was confirmed by computed tomography. We decided to perform surgery due to the recurrence of the pancreatic pseudocyst, a history of unsuccessful radiologically guided external drainage a few years earlier, and a very large diameter of the pseudocyst causing acute cardio-pulmonary distress syndrome. PMID- 28905805 TI - A novel model of acellular dermal matrix plug for anal fistula treatment. Report of a case and surgical consideration based on first utility in Poland. AB - Anal fistula (AF) is a pathological connection between anus and skin in its surroundings. The main reason for the formation of anal fistula is a bacterial infection of the glands within the anal crypts. One of the modern techniques for the treatment of fistulas that do not interfere with the sphincters consists in implantation of a plug made from collagen material. We are presenting the first Polish experience with a new model of biomaterial plug for the treatment of anal fistula. We also point out key elements of the procedure (both preoperative and intraoperative) associated with this method. In the authors' opinion, the method is simple, safe and reproducible. Innovative shape of the plug minimizes the risk of its migration and rotation. It also perfectly blends with and adapts to the course and shape of the fistula canal, allowing it to become incorporated and overgrown with tissue in the fistula canal. The relatively short operation time, minor postoperative pain and faster convalescence are with no doubt additional advantages of the method. Long-term observation involving more patients is essential for evaluation of the efficacy of the treatment of fistulas with the new type of plug. PMID- 28905806 TI - Oesophageal perforation - therapeutic and diagnostics challenge. Retrospective, single-center case report analysis (2009-2015). AB - BACKGROUND: Esophageal perforation is a life-threatening condition of a complex etiology. No clear guidelines are available regarding the management of this condition. In this study, we review publications related to esophageal perforation, and analyze patients treated for this condition at our Department of Thoracic, General and Oncological Surgery. OBJECTIVE: The objective of the study was to retrospectively assess and analyze management methods for esophageal perforations of different etiologies. All patients were treated in the Department of Thoracic, General and Oncological Surgery in years 2009-2015. Patients with perforations resulting from post-operational leaks within surgical anastomoses were excluded from the study. Material, methods, results: The analysis involved a total of 16 cases of esophageal ruptures. All cases were treated in years 2009 2015. Patients with perforations resulting from postoperative leaks within surgical anastomoses following elective surgeries for either oncological or non oncological causes were excluded. The most common reason for esophageal rupture was iatrogenic injury (7 cases, 44%). Other causes included Boerhaave syndrome (5 cases, 31.2%), blunt trauma (2 cases, 12.5%), abscess perforation (1 case, 6.2%), and ulcer perforation (1 case, 6.2%). Ten patients underwent surgery, and the rest underwent esophageal prosthesis placement, of whom 2 cases required drainage of the mediastinum and pleural cavity. The mortality rate in the study group was 9/16 cases (56.2%). CONCLUSIONS: Esophageal perforation poses a significant interdisciplinary challenge regarding diagnostic workup, selection of treatment methods, and management of potential postoperative complications. This retrospective study was conducted in a single center. Although the analyzed period was long, we found only 16 cases. In spite of a variety of etiologies present, we found several statistically significant results of potential clinical value. 1. Most perforations that are not diagnosed within 48 hours affected the lower part of the esophagus and presented with unclear symptoms and imaging findings 2. Delaying diagnosis and treatment beyond 24 hours was associated with a higher mortality rate. PMID- 28905807 TI - Buttressing hepaticojejunostomy's with hepatic round ligament flap may be beneficial. AB - BACKGROUND: Bile leaks and anastomotic strictures are important complications of hepaticojejunostomy (HJ). Evidence suggests that the use of hepatic round ligament (HRL) to buttress HJ may be beneficial. This study evaluates the feasibility of this approach. METHODS: HJs performed over 2 years (Jun 2014- May 2016), with HRL reinforcement, were analyzed. Operative outcomes measured included technical difficulty, blood loss, time necessary for flap harvest, and reinforcement of HJ. The postoperative outcomes measured were the presence of bile leak and anastomotic stricture. RESULTS: Forty-one patients (27 M: 14 F), aged 2-79 years, median age of61 years, underwent HJ with HRL buttress; 27 for periampullary/ head of the pancreas carcinoma; 4 for choledochal cysts; 4 for chronic pancreatitis; 3 for gallbladder carcinoma; 3 for benign biliary stricture. The time for harvesting HRL flaps and buttressing HJ was <10 minutes. No blood was lost during harvesting the flaps. One patient (2.5 %) had grade A leak following radical cholecystectomy, and structures were not observed during a median follow-up of 18 months (6 months to 2years). CONCLUSION: HRL-based buttressing of HJ can reduce the bile leak and/or stricture rate. PMID- 28905808 TI - Patient with metastatic breast cancer presenting as acute cholecystitis with one year survival on hormonotherapy. AB - Breast cancer has high metastatic potential with distant metastases involving mainly lungs, liver and bones. Less frequently it gives distant spread to other organs. Herein we would like to present a very rare case of an acute cholecystitis which turned out to be a metastatic breast cancer in previously healthy woman. A female patient, 64-years old, presented to the emergency department with symptoms of biliary colic and acute abdomen. During the emergency cholecystectomy, we diagnosed the gallbladder empyema with thickened wall. There were also multiple metastatic nodules in the peritoneal cavity and an excessive amount of free fluid. The emergency physicians diagnosing female patient with the acute abdominal symptoms and a breast cancer history might suspect malignant spread into abdominal organs including gallbladder. On the other hand, acute cholecystitis symptoms might be the first symptoms of metastatic process in the gallbladder from the unknown primary source, which may be breast. PMID- 28905809 TI - The acceptance of illness in lung cancer patients before and after surgical treatment. AB - : Lung cancer is the most common malignant tumor in the world, as well as one of the cancers with the most fatal prognosis. The acceptance of the disease is the most important element of the adaptive process. The better the illness acceptance, the lower the stress level and the higher the self-esteem, which facilitates the adaptation to the health status. AIM: The aim of this study was to assess the acceptance of the disease in patients before and after lung cancer surgery. MATERIALS AND METHODS: The study was conducted in 2016 at the Center of Oncology in Bydgoszcz and the Kuyavian and Pomeranian Pulmonology Center in Bydgoszcz. The study involved 87 patients who were assessed both before and after lung cancer surgery. The original questionnaire, as well as the Acceptance of Illness Scale, were used. RESULTS: Men accounted for 75% of the probands, 65% of the study population were 50-69 years old. The highest number of patients - 25 (28.7%) had a 5-pack-year history, and the lowest amount of patients - 8 (9.2%) had a 2.5-pack-year history. The level of acceptance of illness before and after surgery differed in 58 persons. In 29, the level of acceptance remained the same, in 45, the level of acceptance decreased, and in 13 - it increased. Before surgery, the mean acceptance of illness score was 26.2 points, and after surgery 20.89 points. The patients both after and before surgery had acceptance of illness scores regardless of their gender, age, education, place of residence or occupational activity. CONCLUSIONS: In more than a half of the patients, the acceptance of illness decreases after surgery and is at an average level. Male patients, patients aged 50-69 years, with primary, middle or vocational education, employed persons show a significantly worse illness acceptance, regardless of their place of residence, and occupational activity do not influence the acceptance of the disease. PMID- 28905810 TI - Design and application of cationic amphiphilic beta-cyclodextrin derivatives as gene delivery vectors. AB - The nano self-assembly profiles of amphiphilic gene delivery vectors could improve the density of local cationic head groups to promote their DNA condensation capability and enhance the interaction between cell membrane and hydrophobic tails, thus increasing cellular uptake and gene transfection. In this paper, two series of cationic amphiphilic beta-cyclodextrin (beta-CD) derivatives were designed and synthesized by using 6-mono-OTs-beta-CD (1) as the precursor to construct amphiphilic gene vectors with different building blocks in a selective and controlled manner. The effect of different type and degree of cationic head groups on transfection and the endocytic mechanism of beta-CD derivatives/DNA nanocomplexes were also investigated. The results demonstrated that the designed beta-cyclodextrin derivatives were able to compact DNA to form stable nanocomplexes and exhibited low cytotoxicity. Among them, PEI-1 with PEI head group showed enhanced transfection activity, significantly higher than commercially available agent PEI25000 especially in the presence of serum, showing potential application prospects in clinical trials. Moreover, the endocytic uptake mechanism involved in the gene transfection of PEI-1 was mainly through caveolae-mediated endocytosis, which could avoid the lysosomal degradation of loaded gene, and had great importance for improving gene transfection activity. PMID- 28905811 TI - First-principles study of Enhanced Magnetic Anisotropies in Transition-Metal Atoms Doped WS2 Monolayer. AB - Considerable progress in contemporary spintronics has been made in recent years for developing nanoscale data memory and quantum information processing. It is, however, still a great challenge to achieve the ultimate limit of storage bit. Two-dimensional materials, fortunately, provide an alternative solution to design materials with the expected miniaturizing scale, the chemical stability as well as the giant magnetic anisotropy energy. By performing first-principles calculations, we have examined two possible doping sites on WS2 monolayer using three kind of transition metal (TM) atoms (Mn, Fe and Co). It is found that the TM atoms prefer to stay on the W atom site. Additionally, different from the case of Mn, doping Co and Fe atoms on the W vacancy can achieve perpendicular magnetic anisotropy with much larger magnitude, which provides a bright prospect for generating the atomic-scale magnets of storage devices. PMID- 28905812 TI - Carbon fiber on polyimide ultra-microelectrodes. AB - OBJECTIVE: Most preparations for making neural recordings degrade over time and eventually fail due to insertion trauma and reactive tissue response. The magnitudes of these responses are thought to be related to the electrode size (specifically, the cross-sectional area), the relative stiffness of the electrode, and the degree of tissue tolerance for the material. Flexible carbon fiber ultra-microelectrodes have a much smaller cross-section than traditional electrodes and low tissue reactivity, and thus may enable improved longevity of neural recordings in the central and peripheral nervous systems. Only two carbon fiber array designs have been described previously, each with limited channel densities due to limitations of the fabrication processes or interconnect strategies. Here, we describe a method for assembling carbon fiber electrodes on a flexible polyimide substrate that is expected to facilitate the construction of high-density recording and stimulating arrays. APPROACH: Individual carbon fibers were aligned using an alignment tool that was 3D-printed with sub-micron resolution using direct laser writing. Indium deposition on the carbon fibers, followed by low-temperature microsoldering, provided a robust and reliable method of electrical connection to the polyimide interconnect. MAIN RESULTS: Spontaneous multiunit activity and stimulation-evoked compound responses with SNR >10 and >120, respectively, were recorded from a small (125 um) peripheral nerve. We also improved the typically poor charge injection capacity of small diameter carbon fibers by electrodepositing 100 nm-thick iridium oxide films, making the carbon fiber arrays usable for electrical stimulation as well as recording. SIGNIFICANCE: Our innovations in fabrication technique pave the way for further miniaturization of carbon fiber ultra-microelectrode arrays. We believe these advances to be key steps to enable a shift from labor intensive, manual assembly to a more automated manufacturing process. PMID- 28905813 TI - Effect of hydrostatic pressure on the superconducting properties of quasi-one dimensional superconductor K2Cr3As3. AB - K2Cr3As3 is a newly discovered quasi-one-dimensional superconductor with a Tc = 6.1 K and an upper critical field MU0Hc2(0) ~ 40 T three times larger than the Pauli paramagnetic limit MU0Hp that is suggestive of a spin-triplet Cooper pairing. In this paper, we have investigated the effects of hydrostatic pressure on its Tc and MU0Hc2 by measuring the ac magnetic susceptibility chi(T) under magnetic fields at various hydrostatic pressures up to 7.5 GPa. The major findings include: (1) Tc is suppressed gradually to below 2 K at 7.5 GPa; (2) the estimated MU0Hc2(0) decreases dramatically to below MU0Hp above ~2 GPa and becomes slight lower than the orbital limiting field MU0Hc2orb(0) estimated from the initial slope of upper critical field via MU0Hc2orb(0) = -0.73TcdHc2/dTc|Tc in the clean limit; (3) the estimated Maki parameter alpha = ?2Hc2orb(0)/Hp drops from 4 at ambient pressure to well below 1 at P >2 GPa, suggesting the crossover from Pauli paramagnetic limiting to orbital limiting in the pair breaking process upon increasing pressure. These observations suggested that the application of hydrostatic pressure could drive K2Cr3As3 away from the ferromagnetic instability and lead to a breakdown of the spin-triplet pairing channel. We have also made a side-by-side comparison and discussed the distinct effects of chemical and physical pressures on the superconducting properties of K2Cr3As3. PMID- 28905814 TI - New electrical impedance methods for the in situ measurement of the complex permittivity of anisotropic biological tissues. AB - The capability of measuring the complex permittivity of tissues has the potential to provide valuable new insights to inform medical assessment and diagnosis. However, existing electrical impedance approaches have practical limitations when aiming to measure tissues' anisotropy with accuracy. Here we present new methods that overcome the limitations of previous approaches by modeling the anisotropy in both the resistivity and reactivity of tissues measured in three or more different directions. These new methods are validated with numerical simulations and in situ experiments on healthy ovine skeletal muscle. The obtained data between 3 kHz and 1 MHz are also made publicly available in the supplementary information. PMID- 28905815 TI - PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China. AB - Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level >=50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN >=17 weeks had a longer response time to chemotherapy compared to TTN <17 weeks (42.83 vs 21.50 weeks, P < 0.001). The time to PSA progression in patients with TTN >=17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was <17 weeks. We found several factors to be associated with OS, including TTN (hazard ratio [HR]: 3.937, 95% confidence interval [CI]: 1.502-10.309, P = 0.005), PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [<0 response] compared to Class 2 [0-50% response], HR: 3.978, 95% CI: 1.278-12.387, P = 0.017). In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission. PMID- 28905816 TI - How good a surgeon are you? - Standardized formative assessment of surgical competence for ophthalmology residents in training. PMID- 28905817 TI - Practice patterns in pediatric cataract management: Time for real world data. PMID- 28905818 TI - Retinopathy of Prematurity: An emerging and evolving challenge. PMID- 28905819 TI - Plication: How apt in application? PMID- 28905820 TI - Recent advances in corneal collagen cross-linking. AB - Corneal collagen cross-linking has become the preferred modality of treatment for corneal ectasia since its inception in late 1990s. Numerous studies have demonstrated the safety and efficacy of the conventional protocol. Our understanding of the cross-linking process is ever evolving, with its wide implications in the form of accelerated and pulsed protocols. Newer advancements in technology include various riboflavin formulations and the ability to deliver higher fluence protocols with customised irradiation patterns. A greater degree of customisation is likely the path forward, which will aim at achieving refractive improvements along with disease stability. The use of cross-linking for myopic correction is another avenue under exploration. Combination of half fluence cross-linking with refractive correction for high errors to prevent post LASIK regression is gaining interest. This review aims to highlight the various advancements in the cross-linking technology and its clinical applications. PMID- 28905821 TI - Update on conjunctival pathology. AB - Conjunctival biopsies constitute a fairly large number of cases in a typical busy ophthalmic pathology practice. They range from a single biopsy through multiple mapping biopsies to assess the extent of a particular pathological process. Like most anatomical sites, the conjunctiva is subject to a very wide range of pathological processes. This article will cover key, commonly encountered nonneoplastic and neoplastic entities. Where relevant, sections will include recommendations on how best to submit specimens to the ophthalmic pathology laboratory and the relevance of up-to-date molecular techniques. PMID- 28905822 TI - Higher-order aberration 4 years after corneal collagen cross-linking. AB - PURPOSE: Corneal collagen cross-linking (CXL) is a treatment strategy used in keratoconic eyes. Evaluation of long-term changes of higher-order aberrations (HOAs) after CXL is useful in understanding the efficacy of this procedure in improving optical, refractive, and visual acuity. This study aims to investigate the long-term effect of CXL on ocular HOA in patients with progressive keratoconus (KC). METHODS: Using an OPD-Scan II aberrometer, ocular HOAs measurements of 56 eyes of 56 patients that underwent CXL was evaluated at the baseline, 1, 2, and 4 years after the procedure. All OPD-Scan measurements were decomposed into Zernike coefficients from 3rd to 6th order. RESULTS: The results revealed that except for a few parameters, most of the aberration parameters continuously decreased during the study. In the 4-year postoperative period, a statistically significant improvement in all HOA parameters except 5th order Zernike polynomials (Z51, Z5-1, Z53, Z5-3, Z55, and Z5-5) was observed. All the values significantly decreased compared to the preoperative measurements (P < 0.05). The mean +/- standard deviation (SD) root mean square of the 3rd, 4th, and the 5th order as well as coma, coma like, and total HOA parameters were significantly decreased compared to both preoperative and previous visits (P < 0.001). There were significant correlations between preoperative measurements of HOAs parameters with best-corrected visual acuity (BCVA) including Z31, Z3-1, Z40, Z51, and Z42. Moreover, all the HOAs parameters in 4 years after the CXL were significantly correlated with BCVA (P < 0.05). CONCLUSION: CXL is effective in improving HOA parameters in eyes with progressive KC during a long-term follow up. PMID- 28905823 TI - Refractive outcomes of intraoperative wavefront aberrometry versus optical biometry alone for intraocular lens power calculation. AB - PURPOSE: To compare the outcomes of intraoperative wavefront aberrometry versus optical biometry alone for intraocular lens (IOL) power calculation in eyes undergoing cataract surgery with monofocal IOL implantation. METHODS: Preoperative data were obtained with the IOLMaster. Intraoperative aphakic measurements and IOL power calculations were obtained in some patients with the optiwave refractive analysis (ORA) system. Analysis was performed to determine the accuracy of monofocal IOL power prediction and postoperative manifest refraction at 1 month of the ORA versus IOLMaster. RESULTS: Two hundred and ninety-five eyes reviewed, 61 had only preoperative IOLMaster measurements and 234 had both IOLMaster and ORA measurements. Of these 234 eyes, 6 were excluded, 107 had the same recommended IOL power by ORA and IOLMaster. Sixty-four percent of these eyes were within +/-0.5D. 95 eyes had IOL power implantation based on ORA instead of IOLMaster. Seventy percent of these eyes were within +/-0.5D of target refraction. 26 eyes had IOL power chosen based on IOLMaster predictions instead of ORA. Sixty-five percent were within +/-0.5D. In the group with IOLMaster without ORA measurements, 80% of eyes were within +/-0.5D of target refraction. The absolute error was statistically smaller in those eyes where the ORA and IOLMaster recommended the same IOL power based on preoperative target refraction compared to instances in which IOL selection was based on ORA or IOLMaster alone. Neither prediction errors were statistically different between the ORA and IOLMaster alone. CONCLUSION: Intraoperative wavefront aberrometry with the ORA system provides postoperative refractive results comparable to conventional biometry with the IOLMaster for monofocal IOL selection. PMID- 28905824 TI - Management of cataracts and ectopia lentis in children: Practice patterns of pediatric ophthalmologists in India. AB - PURPOSE: To analyze the current practice patterns of Indian pediatric ophthalmologists in the management of lens anomalies. This study was conducted in a tertiary eye care hospital and involved an online questionnaire survey for practicing pediatric ophthalmologists in India. METHODS: A questionnaire was devised by the authors, which included the various options available for the management of lens anomalies in children. The questionnaire was sent to each of them using an online portal. Commercial software (Stata ver. 13.1; StataCorp, College Station, TX, USA) was used for statistical analysis. RESULTS: In unilateral cataracts in children aged <6 months, 85.42% of surgeons did not prefer to insert an intraocular lens (IOL). In the age group of 6-12 months, almost half of them preferred to insert an IOL. In the age group of 12-24 months and> 24 months, 92.63% and 88.54%, respectively, preferred to insert an IOL. In bilateral cataracts, in children aged <6 months, 91.84% of surgeons did not prefer to insert an IOL, whereas in the age group of 6-12 months, 69.39% did not prefer to insert an IOL. In the age group of 12-24 months and> 24 months, 80.61% and 90.82%, respectively, preferred to insert an IOL. Seventy-four percent of surgeons preferred to use a single-piece hydrophobic acrylic IOL. CONCLUSION: The management of lens anomalies by pediatric ophthalmologists in India varies with laterality and appears to be comparable to that followed worldwide. PMID- 28905825 TI - Intraocular pressure and its correlation with midnight plasma cortisol level in Cushing's disease and other endogenous Cushing's syndrome. AB - PURPOSE: The purpose of this study is to measure intraocular pressure (IOP) and evaluate the correlation between IOP and midnight plasma cortisol (MPC) level in patients with Cushing's disease (CD) and other endogenous Cushing's syndrome (ECS). METHODS: This is a cross-sectional study from a single center including newly diagnosed patients with CD or ECS. All patients underwent detailed ophthalmological evaluation. IOP was measured by Goldmann applanation tonometry in the morning and evening on two consecutive days. MPC value was obtained for each patient. The data were compared using paired and unpaired t-test, Mann Whitney U-test, and Spearman's rank correlation coefficient. RESULTS: Among 32 patients, 22 were CD (68.75%) and 10 patients were other ECS (31.25%). A total of 25 patients (78.12%) in our study group had normal IOP (<22 mmHg), and seven patients (21.88%) had increased IOP (>=22 mmHg). The percentage of patients with normal IOP was found to be significantly higher compared to percentage of patients with high IOP (P = 0.001) using one-sample Chi-square test. Mean MPC value was 468.6 +/- 388.3 nmol/L in patients having IOP >=22 mmHg and 658.5 +/- 584 nmol/L in those with IOP <22 mmHg from both CD and ECS groups, but the difference was not statistically significant. No correlation was found between IOP and MPC (Spearman's rank correlation rho = -0.16 [P = 0.38]). CONCLUSION: In CD and ECS patients, IOP elevation is an uncommon feature, and high IOP in either group does not correlate with MPC level. PMID- 28905826 TI - Risk factors in patients with macular telangiectasia 2A in an Asian population: A case-control study. AB - PURPOSE: The aim of this study was to evaluate risk factors in patients with macular telangiectasia (MacTel) 2A in an Asian population. This was a hospital based case-control study. METHODS: We reviewed the case records of patients in our hospital, diagnosed as MacTel 2A over a 3-year period from April 2011 to March 2014. Controls were selected from patients seen in the hospital at the same time for visual defects after matching for age and sex. A multivariate logistic regression model was constructed using the variables that showed a statistically significant association (P < 0.05) with MacTel 2A in the univariate analysis. RESULTS: The mean age of the patients with MacTel 2A was 58.63 years. A majority (76; 73.8%) of the patients were female. Of the patients with MacTel 2A, 61 (59.2%) patients had diabetes mellitus, and 50 (48.5%) revealed hypertension. Multivariate logistic regression analysis revealed the presence of diabetes mellitus to be the risk factor with the highest odds ratio (OR) of 5.7 followed by hypertension with an OR of 2.6. Binary logistic regression showed hypermetropia to have a greater risk factor compared to emmetropia, OR 2.64. CONCLUSION: Our case-control study revealed that MacTel 2A is significantly associated with systemic diseases. Diabetes mellitus was found to have the strongest association with MacTel 2A, showing a high OR of 5.7. Systemic hypertension followed by an OR of 2.6. Compared to emmetropia, hypermetropia was significantly associated with MacTel 2A. There could be a genetic link between the two. Determining risk factors draws us close to the goal of identifying the etiopathogenesis of MacTel 2A. PMID- 28905827 TI - Refractive and ocular biometric profile of children with a history of laser treatment for retinopathy of prematurity. AB - PURPOSE: Indian children belong to a diverse socioeconomic strata with retinopathy of prematurity (ROP) developing in mature, higher birth weight babies as well. The purpose of our study is to analyze the long-term status of refractive errors and its relationship with ocular biometry in children with ROP who were laser treated at a tertiary center in North India. METHODS: Cross sectional study. Children (<16 years) enrolled from January 2014 to December 2014 with a history of laser treatment for ROP and examined for refractive and biometric status. RESULTS: Thirty-six children presenting to us at the mean age of 7.37 +/- 3.07 years (6-15 years) were included. Mean spherical equivalent (SE) was -4.05 D +/- 5.10. 75% were myopic, with high astigmatism in 31%. Higher lens thickness (P = 0.03) and higher SE (P = 0.002) at 1 year postnatal age were predictors of larger SE. 79.4% achieved a favorable functional outcome (visual acuity >=20/40). 5.88% achieved unsatisfactory outcome (<20/200) despite having a favorable structural outcome. CONCLUSION: There are a substantial number of children who develop myopia and high astigmatism while undergoing laser treatment for ROP. We found myopia in our cohort to be lenticular and greater axial length contributing to the development of high myopia. An initial large refractive error predicts the future development of myopia in these children. Nearly 6% of patients with good structural outcome have unexplained subnormal vision. Our threshold for prescribing glasses in these children should be low. PMID- 28905828 TI - Influence of laser versus lens-sparing vitrectomy on myopia in children with retinopathy of prematurity. AB - PURPOSE: The purpose of this study is to compare the refractive error outcomes in the eyes of premature babies with retinopathy of prematurity (ROP) who underwent laser plus lens-sparing vitrectomy (LSV) in one eye and laser alone in the fellow eye. METHODS: This is a retrospective study. Fourteen babies with Stage 4A of ROP or worse who underwent laser plus LSV in one eye (Group 1) and laser alone in the fellow eye (Group 2) were followed at 2 months, 6 months, 1 year, one and a half year, and 2 years. The main outcome variable studied was cycloplegic refraction at the baseline and follow-up visits. The change in spherical and cylindrical power at each visit was compared in Groups 1 and 2. The changes in spherical equivalent in subgroups were analyzed. RESULTS: Mean gestational age at birth was 29.43 +/- 2.10 weeks (range 26-32 weeks). Mean chronological age at the time of surgery was 4.11 +/- 3.00 months (range 2-10 months). Mean postmenstrual age was 45.86 +/- 12.13 weeks (range 39-75 weeks). Mean birth weight was 1340.71 +/- 361.59 g (range 860-1980 g). All the babies in both groups had progressive myopia till 2 years follow-up; laser group had less myopia than LSV group till 1 year, thereafter, there was no difference in median till 2-year follow-up. The mean +/- standard deviation of spherical equivalent in LSV versus laser group was: -4.36 +/- 5.52 versus -3.21 +/- 4.59 at 2 months; -5.09 +/- 5.82 versus -4.04 +/- 4.68 at 6 months; -7.14 +/- 5.36 versus -5.36 +/- 5.09 at 1 year; and -7.47 +/- 1.38 versus -6.41 +/- 1.91 at 2 years. Spherical equivalent difference across the visits did not differ significantly between Groups 1 and Group 2 in children whose birth weight was <1500 g (P = 0.247) and those who had more than 1500 g (P = 0.748), in those with gestational age between 20 and 30 weeks (P = 0.215) compared to those> 30 weeks (P = 0.602). CONCLUSION: No difference in the progression of myopia was noted in eyes that underwent additional LSV following laser photocoagulation in one eye and laser alone in the fellow eye. PMID- 28905829 TI - Variation in the vitreoretinal configuration of Stage 4 retinopathy of prematurity in photocoagulated and treatment naive eyes undergoing vitrectomy. AB - PURPOSE: We sought to document the difference in the vitreoretinal configuration of Stage 4 retinopathy of prematurity (ROP) in photocoagulated and treatment naive eyes undergoing vitrectomy and to correlate it with surgical complexity. METHODS: Consecutive eyes posted for vitrectomy with Stage 4 ROP were documented preoperatively using a RetCam for the presence of peripheral traction (PT), presence of central traction just outside the arcades, and presence of traction extending to the lens. A note was made of the following intraoperative events: lensectomy, intraoperative bleeding, and iatrogenic breaks. Wilcoxon rank-sum test was used for analysis. RESULTS: From a total of 46 eyes, 16 and 30 eyes were from the treated and treatment naive group, respectively. More eyes in the treated group had central (P < 0.0001) and lenticular traction (P = 0.022). More eyes in the untreated group had PT (P < 0.0001). A significant number of eyes without photocoagulation needed lensectomy (P = 0.042), and no difference in intraoperative bleeding (P = 0.94) was demonstrable. Iatrogenic retinotomy occurred in three eyes, all naive. Notably, age at surgery was more in the untreated group (P = 0.00008). CONCLUSION: Vasoproliferative activity in all retinopathies occurs at the junction of the ischemic and nonischemic retina. In the natural course of ROP, this takes place peripherally, at the ridge. In photocoagulated eyes, this junction is displaced posteriorly due to peripheral ablation. Treated eyes manifested with posterior proliferative changes and were more amenable to lens-sparing vitrectomy. Naive eyes were older when they underwent surgery to relieve PT with greater chances of lensectomy and iatrogenic breaks. PMID- 28905830 TI - Plication as an alternative to resection in horizontal strabismus: A randomized clinical trial. AB - PURPOSE: Resections and plications tighten recti although the latter are less traumatic, potentially reversible, quicker, and vascularity preserving. To compare inflammation, scarring, and alignment in horizontal strabismus, operated uniocularly by either resections or plications (with recessions): recession and resection (R&R) or recession and plication (R&P) groups. This was a prospective, patient and assessor blind, randomized trial. METHODS: All consenting strabismus patients qualifying for the first-time uniocular horizontal rectus surgeries underwent detailed ocular examination and were randomized into standard R&R or R&P groups. For the latter, we folded the tendon-muscle strap the desired amount using 6-0 polyglactin, suturing it to its insertion, entailing no disinsertion. We compared the groups for inflammatory grades (individually for congestion, chemosis, discharge, foreign-body sensation, and drop intolerance and aggregated to a total inflammatory score (TIS), scar visibility (SV) at 1 m, and successful alignment (<=10 prism diopter of orthotropia). We used Mann-Whitney and Fisher's exact tests, with significance at P <= 0.05. RESULTS: We randomized 40 patients: 22 to R&R and 18 to R&P. The groups were comparable in age, strabismus onset and duration, and strabismus amount. The inflammatory scores, both individual and TIS, were comparable at all time-points: all P > 0.05. SV proportions were not significantly different: 16/22 in R&R versus 9/18 in R&P; P = 0.19. There were no significant differences in success rates: 14/22 versus 10/18, P = 0.74. CONCLUSION: Our study shows that plication is similarly effective as resection, when combined with recession in horizontal strabismus, and should be resorted to more frequently. PMID- 28905831 TI - Primary prevention of ocular injury in agricultural workers with safety eyewear. AB - PURPOSE: The purpose of this study was to determine the effectiveness of preventing eye injury with the use of safety eyewear in agriculture workers. METHODS: A sample group of 575 agricultural workers (Group A) engaged in harvesting paddy were provided with goggles with side covers. Following harvesting, a questionnaire-based survey was carried out to determine the frequency of their eye injuries. Workers with goggles were asked about the duration for which they used the goggles and also list barriers or difficulties with the same. The frequency of eye injuries in this group was compared with another group of agriculture workers (Group B) who did not use any safety eyewear. RESULTS: The frequency of eye injuries in Group A was 4 (0.7%) and Group B was 61 (11.3%) which was highly significant (P = 0.0001). The relative risk calculated was 0.06 (95% confidence interval: 0.02-0.2). Agricultural workers in Group A had 94% less risk of ocular trauma compared to those in Group B. Injuries in both groups were caused by parts of the paddy plant. A significant number (76.2%) of workers used the goggles all or most of the time during work. Impaired vision when wearing goggles was the most frequent barrier reported by the workers. Other barriers were discomfort, shyness, forgetfulness, apathy, slowing of work pace, awkward appearance, and breakages. CONCLUSION: Safety eyewear conferred significant protection against work-related eye injuries in agriculture. Although safety eyewear was widely adopted by the workers, barriers reported by them will need to be addressed to make such programs more effective. PMID- 28905832 TI - Multimodal imaging in dominant cystoid macular dystrophy. PMID- 28905833 TI - Unusual case of vitiligo reversal in Vogt-Koyanagi-Harada syndrome. PMID- 28905834 TI - Microsporidial infection masquerading as graft rejection post-Descemet's stripping automated endothelial keratoplasty. AB - A 51-year-old immunocompetent male with a history of Fuchs' endothelial dystrophy and immature cataract who underwent Descemet's stripping automated endothelial keratoplasty with intraocular lens implantation in both eyes presented with redness and defective vision of 1-day duration in his left eye. Slit lamp examination revealed coarse superficial punctate lesions with graft edema. He was diagnosed with acute graft rejection and treated with topical steroids. Two days later, symptoms worsened in his left eye with the involvement of his right eye showing a similar clinical picture. An infectious etiology was suspected and in vivo confocal microscopy ordered, which revealed hyperreflective dots, highly suggestive of microsporidial spores. The patient was prescribed topical fluconazole 0.3% in both eyes. This unique presentation of bilateral graft edema following microsporidial keratoconjunctivitis in postgraft patients requires a high index of suspicion as it can be easily be mistaken for and mismanaged as acute graft rejection. PMID- 28905835 TI - Corneal ulcer due to a rare coelomycetes fungus Chaetomium strumarium: Case report and global review of Chaetomium keratomycosis. AB - We present a rare case of corneal ulcer caused by a species of a coelomycetes fungus, Chaetomium strumarium. This fungal genus is a rare causative agent of keratomycosis, with only a handful of cases reported. The clinical presentation, investigative techniques, and preliminary management of our patient are reported. The cases reported in global literature are also summarized in a tabular form in the discussion. PMID- 28905836 TI - Rare ocular manifestations in keratosis follicularis (Darier-White disease). AB - Keratosis follicularis (Darier's disease) is a rare (1 in 30,000-100,000) genetic autosomal-dominant predominantly dermatological disorder characterized by hyperkeratosis and acantholysis due to a defective calcium transport in the cells. Ocular findings, if present, are very rare in this condition. Here, we are reporting a case of keratosis follicularis (Darier's disease) with ocular manifestations that have not been reported so far to the best of our knowledge. PMID- 28905837 TI - En face optical coherence tomography findings in a case of Alport syndrome. AB - Alport syndrome is a rare hereditary disease that is associated with retinal abnormalities such as dot-and-fleck retinopathy and temporal macular thinning. The main pathophysiological process of Alport syndrome is loss of the collagen network in the basement membrane. However, the alterations in each retinal layer have not been fully evaluated. In the case presented here, we evaluated the retina of a patient with Alport syndrome using en face optical coherence tomography (OCT). The findings suggested that the primary alterations occur in the internal limiting membrane and the retinal pigment epithelium basement membrane which is a part of the Bruch's membrane. The adjacent retinal layers are damaged subsequently. In conclusion, en face OCT could be useful in evaluating retinal abnormalities and understanding their underlying pathophysiology in Alport syndrome. PMID- 28905838 TI - Retinal meteor. AB - We describe a case of a 65-year old man diagnosed with retinal vasoproliferative tumour secondary to posterior uveitis. The fluorescein angiography shows an interesting meteor-like leak emanating from the tumour and rising towards the superior retina in the later frames of the angiogram. Pictorially, we call it the "Retinal Meteor" and also describe the possible mechanism for this pattern of leakage. PMID- 28905839 TI - Postvitrectomy macular hole undergoing delayed closure after 28 months. AB - Case report of a 70-year-old male who developed full thickness macular hole (MH) following vitrectomy for vitreomacular traction syndrome. The further intervention was deferred due to the unwillingness of the patient for the second surgery. Periodic follow up of the patient, revealed improvement in visual acuity with the closure of the MH after 28 months. PMID- 28905840 TI - Giant eyelid eccrine hidrocystoma-induced progressive ptosis in childhood. AB - An upper lid eccrine hidrocystoma presenting as early childhood progressive ptosis is very rare. We present a 9-year-old female child with droopy right upper lid since birth and progressive increase in symptoms. She had right upper lid ptosis (marginal reflex distance 1 of -1 mm) with fair levator function (8 mm) and abnormal cystic change on the conjunctival side. Computerized tomography imaging delineated the well-defined cystic lesion with homogeneous cavity with no contrast enhancement. Following the cyst excision, a giant eccrine hidrocystoma measuring 25 mm * 15 mm was removed, the largest reported in pediatric eyes. The case demonstrates the possibility of giant lid eccrine hidrocystomas presenting as progressive ptosis at a pediatric age and the need for early surgical intervention to prevent amblyopia. PMID- 28905841 TI - Lacrimal gland myxoma. AB - Myxomas are rare neoplasms of mesenchymal origin. Cases of conjunctival, corneal, and orbital myxomas have been reported in the literature; however, to the best of our knowledge, there is no report of a lacrimal gland myxoma. We report a case of an orbital myxoma involving the lacrimal gland and its management. PMID- 28905842 TI - Malignant perivascular epithelioid cell tumor of the orbit: Report of a case and review of literature. AB - Perivascular epithelioid cell tumor (PEComa) is a rare neoplasm considered to arise from myomelanocytic cell lineage. The uterus is reportedly the most common site to be involved. Orbital PEComa is extremely rare with only two cases reported till date. A 5-year-old male presented with a right medial orbital mass for the last 6 months. The patient was diagnosed with alveolar soft part sarcoma elsewhere. Magnetic resonance imaging features were suggestive of lymphangioma with bleeding. The excision biopsy revealed multiple tumor cells comprising epithelioid cells with clear cytoplasm, along with nuclear atypia and mitosis. Immunohistochemistry was positive for HMB-45, smooth muscle actin, vimentin, and CD-34. It was negative for cytokeratin, S-100, and synaptophysin, which clinched the diagnosis of malignant orbital PEComa. Neoadjuvant chemotherapy was administered. There was no recurrence at 24 months of follow-up. At present, there is no consensus on management protocol for malignant PEComa. Complete surgical excision with chemotherapy appears to offer the best prognosis. PMID- 28905843 TI - Orbital dermatofibrosarcoma protuberans with frontal and ethmoid sinus involvement: A case report and brief review of literature. AB - Dermatofibrosarcoma protuberans is a soft tissue sarcoma that is dermal in origin. The incidence is <0.1% of all malignancies and 1% of soft tissue sarcoma. Most commonly, it involves trunk (62%) followed by extremities (25%) and head and neck (13%). It is a slow growing tumor with locally aggressive behavior. Here, a 50-year-old female diagnosed with orbital dermatofibrosarcoma developed extra axial component in right frontal region even on chemotherapy. Hence, the bad prognostic factors are yet to be established in dermatofibrosarcoma protuberans. PMID- 28905844 TI - Metastatic renal cell carcinoma presenting as one-and-a-half syndrome. AB - We report a case of 43-year-old male, presented with sudden onset binocular diplopia on lateral gazes. Ocular examination showed features of ipsilateral one and-a-half syndrome. Comprehensive systemic work in conjunction with magnetic resonance imaging of the brain illustrated irregular mixed solid and cystic lesions in the brainstem, possibly indicative of brain metastases. Further imaging revealed hidden renal cell carcinoma as a primary neoplasm, which led to secondary manifestations. PMID- 28905845 TI - Use of modified international council of ophthalmology- ophthalmology surgical competency assessment rubric (ICO- OSCAR) for phacoemulsification- wet lab training in residency program. PMID- 28905846 TI - Comment: Allergen-specific exposure associated with high immunoglobulin E and eye rubbing predisposes to progression of keratoconus. PMID- 28905847 TI - Reply: Allergen-specific exposure associated with high immunoglobulin E and eye rubbing predisposes to progression of keratoconus. PMID- 28905848 TI - Comment: Intra-arterial chemotherapy for retinoblastoma. PMID- 28905849 TI - Reply: Intra-arterial chemotherapy for retinoblastoma: 2-year results from tertiary eye-care center in India. PMID- 28905850 TI - Erratum: A cross-sectional study to compare intraocular pressure measurement by sequential use of Goldman applanation tonometry, dynamic contour tonometry, ocular response analyzer, and Corvis ST. AB - [This corrects the article DOI: 10.4103/0301-4738.171956.]. PMID- 28905853 TI - Bone: Targeting old cells to protect old bones. PMID- 28905851 TI - Increased double product on Monday morning during work. AB - It has been reported that cardiovascular events often occur on Monday morning, especially in the young working population. Because hypertension is a major cardiovascular risk, we examined whether blood pressure was elevated on Monday, especially in the morning during work. However, there were no weekly rhythms in blood pressure itself. Instead, we found significant interactions between the double product (systolic blood pressure * heart rate) and weekly (high on Monday) and circadian (high in the morning) rhythms. Further studies are required to determine whether Monday morning preference in cardiovascular events is caused by increased double product. PMID- 28905854 TI - Pain: Caution needed in use of gabapentinoids for LBP. PMID- 28905852 TI - Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity? AB - A loss of humoral tolerance is a hallmark of many autoimmune diseases and the detection of self-reactive antibodies (autoantibodies) of the immunoglobulin G (IgG) isotype is widely used as a biomarker and diagnostic tool. However, autoantibodies might also be present in individuals without autoimmune disease, thus limiting their usefulness as a sole indicator of disease development. Moreover, while clear evidence exists of the pathogenic effects of autoantibodies in mouse model systems, the contribution of autoantibodies to the pathology of many autoimmune diseases has yet to be established. In this Review, the authors discuss the changes in total serum IgG and autoantibody glycosylation that occur during autoimmune disease and how these changes might help to predict disease development in the future. Furthermore, current knowledge of the signals regulating antibody glycosylation and how individual antibody glycoforms could be used to optimize current treatment approaches will be discussed. PMID- 28905857 TI - Risk factors: Oral contraceptive use linked to lower risk of RA. PMID- 28905856 TI - Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. AB - Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3) ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation. PMID- 28905858 TI - Infection: Infection risk after switching biologics. PMID- 28905855 TI - New insights into the epigenetics of inflammatory rheumatic diseases. AB - Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies. PMID- 28905859 TI - Clinical trials: Intravenous golimumab effective for PsA. PMID- 28905860 TI - Rheumatoid arthritis: Reducing the risk of herpes zoster. PMID- 28905862 TI - Vascular disease: Benefits of population screening for vascular risk. PMID- 28905863 TI - Antithrombotic therapy: COMPASS points to low-dose rivaroxaban and aspirin for secondary prevention. PMID- 28905864 TI - Antithrombotic therapy: Dual therapy after PCI in AF. PMID- 28905865 TI - Prevention: The healthy diet - fruits, vegetables, legumes, and fats. PMID- 28905861 TI - Giant cell arteritis and polymyalgia rheumatica: current challenges and opportunities. AB - The fields of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) have advanced rapidly, resulting in a new understanding of these diseases. Fast-track strategies and improved awareness programmes that prevent irreversible sight loss through early diagnosis and treatment are a notable advance. Ultrasonography and other imaging techniques have been introduced into routine clinical practice and there have been promising reports on the efficacy of biologic agents, particularly IL-6 antagonists such as tocilizumab, in treating these conditions. Along with these developments, which should improve outcomes in patients with GCA and PMR, new questions and unmet needs have emerged; future research should address which pathogenetic mechanisms contribute to the different phases and clinical phenotypes of GCA, what role imaging has in the early diagnosis and monitoring of GCA and PMR, and in which patients and phases of these diseases novel biologic drugs should be used. This article discusses the implications of recent developments in our understanding of GCA and PMR, as well as the unmet needs concerning epidemiology, pathogenesis, imaging and treatment of these diseases. PMID- 28905866 TI - Anticoagulation therapy: Bivalirudin not superior to heparin in PCI. PMID- 28905867 TI - Coronary artery disease: Coronary artery calcium testing. PMID- 28905868 TI - Lipids: Very low achieved LDL-cholesterol levels improve cardiovascular outcomes. PMID- 28905869 TI - Acute coronary syndromes: Supplemental oxygen in myocardial infarction. PMID- 28905870 TI - Inflammation: Targeting inflammatory pathways to treat atherosclerosis and cancer. PMID- 28905871 TI - Hypertension: Proof of concept for renal denervation. PMID- 28905872 TI - Hypertension: Ibuprofen increases blood pressure in patients with arthritis. PMID- 28905874 TI - Ovarian Hormones and Transdermal Nicotine Administration Independently and Synergistically Suppress Tobacco Withdrawal Symptoms and Smoking Reinstatement in the Human Laboratory. AB - Modeling intra-individual fluctuations in estradiol and progesterone may provide unique insight into the effects of ovarian hormones on the etiology and treatment of nicotine dependence. This randomized placebo-controlled laboratory study tested the independent and interactive effects of intra-individual ovarian hormone variation and nicotine on suppression of tobacco withdrawal symptoms and smoking behavior. Female smokers randomized to 21 mg nicotine (TNP; n=37) or placebo (PBO; n=43) transdermal patch following overnight abstinence completed three sessions occurring during hormonally distinct menstrual cycle phases. At each session, participants provided saliva for hormone assays and completed repeated self-report measures (ie, tobacco withdrawal symptoms, smoking urge, and negative affect (NA)) followed by an analog smoking reinstatement task for which participants could earn money to delay smoking and subsequently purchase cigarettes to smoke. Higher (vs lower) progesterone levels were associated with greater reductions in NA. Higher (vs lower) progesterone levels and progesterone to estradiol ratios were associated with reducing smoking urges over time to a greater extent with TNP compared to PBO. There was an interaction between Patch and estradiol on NA. With TNP, higher-than-usual estradiol was associated with greater decreases in NA. However with PBO, lower-than-usual estradiol was associated with greater decreases in NA. These results suggest that the effects of TNP on mood- and smoking-related outcomes may vary depending on the ovarian hormone levels. PMID- 28905873 TI - Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. AB - Dysregulation of the endogenous lipid mediators endocannabinoids and their G protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Delta9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies. PMID- 28905875 TI - Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions. AB - The importance of dopamine (DA) neurotransmission is emphasized by its direct implication in several neurological and psychiatric disorders. The DA transporter (DAT), target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of DA in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal. There is strong evidence suggesting that DAT interacting proteins may have a role in its function and regulation. Performing a two-hybrid screening, we identified snapin, a SNARE-associated protein implicated in synaptic transmission, as a new binding partner of the carboxyl terminal of DAT. Our data show that snapin is a direct partner and regulator of DAT. First, we determined the domains required for this interaction in both proteins and characterized the DAT-snapin interface by generating a 3D model. Using different approaches, we demonstrated that (i) snapin is expressed in vivo in dopaminergic neurons along with DAT; (ii) both proteins colocalize in cultured cells and brain and, (iii) DAT and snapin are present in the same protein complex. Moreover, by functional studies we showed that snapin produces a significant decrease in DAT uptake activity. Finally, snapin downregulation in mice produces an increase in DAT levels and transport activity, hence increasing DA concentration and locomotor response to amphetamine. In conclusion, snapin/DAT interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA transmission modulation. PMID- 28905876 TI - Lysenko and Russian genetics: an alternative view. PMID- 28905877 TI - Population-specific genetic variation in large sequencing data sets: why more data is still better. AB - We have generated a next-generation whole-exome sequencing data set of 2628 participants of the population-based Rotterdam Study cohort, comprising 669 737 single-nucleotide variants and 24 019 short insertions and deletions. Because of broad and deep longitudinal phenotyping of the Rotterdam Study, this data set permits extensive interpretation of genetic variants on a range of clinically relevant outcomes, and is accessible as a control data set. We show that next generation sequencing data sets yield a large degree of population-specific variants, which are not captured by other available large sequencing efforts, being ExAC, ESP, 1000G, UK10K, GoNL and DECODE. PMID- 28905879 TI - Lysenko and Russian genetics: Reply to Wang &Liu. PMID- 28905878 TI - Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer. AB - Interpretation of variants of unknown significance (VUS) is a major challenge for laboratories performing molecular diagnosis of hereditary breast and ovarian cancer (HBOC), especially considering that many genes are now known to be involved in this syndrome. One important way these VUS can have a functional impact is through their effects on RNA splicing. Here we present a custom RNA-Seq assay plus bioinformatics and biostatistics pipeline to analyse specifically alternative and abnormal splicing junctions in 11 targeted HBOC genes. Our pipeline identified 14 new alternative splices in BRCA1 and BRCA2 in addition to detecting the majority of known alternative spliced transcripts therein. We provide here the first global splicing pattern analysis for the other nine genes, which will enable a comprehensive interpretation of splicing defects caused by VUS in HBOC. Previously known splicing alterations were consistently detected, occasionally with a more complex splicing pattern than expected. We also found that splicing in the 11 genes is similar in blood and breast tissue, supporting the utility and simplicity of blood splicing assays. Our pipeline is ready to be integrated into standard molecular diagnosis for HBOC, but it could equally be adapted for an integrative analysis of any multigene disorder. PMID- 28905880 TI - Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. AB - Pelizaeus-Merzbacher disease (PMD) is a rare Mendelian disorder characterised by central nervous system hypomyelination. PMD typically manifests in infancy or early childhood and is caused by mutations in proteolipid protein-1 (PLP1). However, variants in several other genes including gap junction protein gamma 2 (GJC2) can also cause a similar phenotype and are referred to PMD-like disease (PMLD). Whole-exome sequencing in two siblings presenting with clinical symptoms of PMD revealed a homozygous variant in the arginyl-tRNA synthetase (RARS) gene: NM_002887.3: c.[5A>G] p.(Asp2Gly). Subsequent screening of a PMD cohort without a genetic diagnosis identified an unrelated individual with novel compound heterozygous variants including a missense variant c.[1367C>T] p.(Ser456Leu) and a de novo deletion c.[1846_1847delTA] p.(Tyr616Leufs*6). Protein levels of RARS and the multi-tRNA synthetase complex into which it assembles were found to be significantly reduced by 80 and 90% by western blotting and Blue native-PAGE respectively using patient fibroblast extracts. As RARS is involved in protein synthesis whereby it attaches arginine to its cognate tRNA, patient cells were studied to determine their ability to proliferate with limiting amounts of this essential amino acid. Patient fibroblasts cultured in medium with limited arginine at 30 degrees C and 40 degrees C, showed a significant decrease in fibroblast proliferation (P<0.001) compared to control cells, suggestive of inefficiency of protein synthesis in the patient cells. Our functional studies provide further evidence that RARS is a PMD-causing gene. PMID- 28905881 TI - Identification of ASAH1 as a susceptibility gene for familial keloids. AB - Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing. PMID- 28905882 TI - Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia. AB - Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Delta) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Delta promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Delta)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia. PMID- 28905884 TI - Clinical Utility Gene Card for hereditary angioedema with normal C1 inhibitor (HAEnC1). PMID- 28905883 TI - Acceptable applications of preimplantation genetic diagnosis (PGD) among Israeli PGD users. AB - The use of PGD technology to select against genetic disorders and traits is increasing. Although PGD may eliminate some of the obstacles related to conservative options of prenatal diagnosis, it can raise personal, social and moral questions. Ethical issues concerning the justified uses of PGD are a subject of ongoing debate among medical and bioethical communities. Although attitudes toward the acceptable uses of PGD were evaluated among population groups worldwide, bioethics councils were criticized for ignoring public perspectives. In the last decade PGD has been widely used in Israel. The ethical guidelines were created solely by medical-bioethics experts and, some felt, totally isolated from public opinions. Semi-structured in-depth interviews of 37 users (carriers of autosomal recessive, dominant and X-linked disorders, and HLA matching) were performed. The interviews explored attitudes toward ethical and sociological aspects of PGD. The overall results of this study show highly favorable attitudes of Israeli PGD users toward medical applications. Furthermore, our subjects demonstrate a more permissive stand toward the controversial application of social sex selection albeit with strong objection to esthetic means of selection. PGD users are coping with both genetic disease and load of the PGD procedure. Taking into consideration their opinion is important since it reflects the gains and burdens of these procedures alongside the demand for future optional services. Their attitudes should play an important role in the professional discussion concerning the justified uses of PGD and should significantly influence the design of policy making in this field. PMID- 28905885 TI - Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene. AB - Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes. In anticipation of future studies in FVIII-deficient dogs, we investigated the efficacy of FIV-delivered canine FVIII (cFVIII). Codon-optimization of the cFVIII sequence increased activity and decreased blood loss as compared to the native sequence. Further, we compared a standard B-domain deleted FVIII cDNA to a cDNA including 256 amino acids of the B-domain with 11 potential asparagine-linked oligosaccharide linkages. Restoring a partial B-domain resulted in modest reduction of endoplasmic reticulum (ER) stress markers. Importantly, our optimized vectors achieved wild-type levels of phenotypic correction with minimal inhibitor formation. These studies provide insights into optimal design of a therapeutically relevant gene therapy vector for a devastating bleeding disorder. PMID- 28905886 TI - Time-series oligonucleotide count to assign antiviral siRNAs with long utility fit in the big data era. AB - Oligonucleotides are key elements of nucleic acid therapeutics such as small interfering RNAs (siRNAs). Influenza and Ebolaviruses are zoonotic RNA viruses mutating very rapidly, and their sequence changes must be characterized intensively to design therapeutic oligonucleotides with long utility. Focusing on a total of 182 experimentally validated siRNAs for influenza A, B and Ebolaviruses compiled by the siRNA database, we conducted time-series analyses of occurrences of siRNA targets in these viral genomes. Reflecting their high mutation rates, occurrences of target oligonucleotides evidently fluctuate in viral populations and often disappear. Time-series analysis of the one-base changed sequences derived from each original target identified the oligonucleotide that shows a compensatory increase and will potentially become the 'awaiting-type oligonucleotide'; the combined use of this oligonucleotide with the original can provide therapeutics with long utility. This strategy is also useful for assigning diagnostic reverse transcription-PCR primers with long utility. PMID- 28905888 TI - Corrigendum: Sub-ice-shelf sediments record history of twentieth-century retreat of Pine Island Glacier. AB - This corrects the article DOI: 10.1038/nature20136. PMID- 28905887 TI - An efficient, non-viral dendritic vector for gene delivery in tissue engineering. AB - Recent developments within the field of tissue engineering (TE) have shown that biomaterial scaffold systems can be augmented via the incorporation of gene therapeutics. The objective of this study was to assess the potential of the activated polyamidoamine dendrimer (dPAMAM) transfection reagent (SuperfectTM) as a gene delivery system to mesenchymal stem cells (MSCs) in both monolayer and 3D culture on collagen based scaffolds. dPAMAM-pDNA polyplexes at a mass ratio (M:R) 10:1 (dPAMAM : pDNA) (1 ug pDNA) were capable of facilitating prolonged reporter gene expression in monolayer MSCs which was superior to that facilitated using polyethylenimine (PEI)-pDNA polyplexes (2 ug pDNA). When dPAMAM-pDNA polyplexes (1 ug pDNA) were soak loaded onto a collagen-chondroitin sulphate (CS) scaffold prolonged transgene expression was facilitated which was higher than that obtained for a PEI-pDNA polyplex (2 ug pDNA) loaded scaffold. Transgene expression was dependent on the composite nature of the collagen scaffold with varying expression profiles obtained from a suite of collagen constructs including a collagen alone, collagen-CS, collagen-hydroxyapatite, collagen nanohydroxyapatite and collagen-hyaluronic acid scaffold. Therefore, the dPAMAM vector described herein represents a biocompatible, effective gene delivery vector for TE applications which, via matching with a particular composite scaffold type, can be tailored for regeneration of various tissue defects. PMID- 28905890 TI - Correction. PMID- 28905889 TI - Real-space imaging of non-collinear antiferromagnetic order with a single-spin magnetometer. AB - Although ferromagnets have many applications, their large magnetization and the resulting energy cost for switching magnetic moments bring into question their suitability for reliable low-power spintronic devices. Non-collinear antiferromagnetic systems do not suffer from this problem, and often have extra functionalities: non-collinear spin order may break space-inversion symmetry and thus allow electric-field control of magnetism, or may produce emergent spin orbit effects that enable efficient spin-charge interconversion. To harness these traits for next-generation spintronics, the nanoscale control and imaging capabilities that are now routine for ferromagnets must be developed for antiferromagnetic systems. Here, using a non-invasive, scanning single-spin magnetometer based on a nitrogen-vacancy defect in diamond, we demonstrate real space visualization of non-collinear antiferromagnetic order in a magnetic thin film at room temperature. We image the spin cycloid of a multiferroic bismuth ferrite (BiFeO3) thin film and extract a period of about 70 nanometres, consistent with values determined by macroscopic diffraction. In addition, we take advantage of the magnetoelectric coupling present in BiFeO3 to manipulate the cycloid propagation direction by an electric field. Besides highlighting the potential of nitrogen-vacancy magnetometry for imaging complex antiferromagnetic orders at the nanoscale, these results demonstrate how BiFeO3 can be used in the design of reconfigurable nanoscale spin textures. PMID- 28905891 TI - Post-quantum cryptography. AB - Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence. PMID- 28905892 TI - Materials science: Nanomagnets boost thermoelectric output. PMID- 28905893 TI - Units: Don't tamper with SI-unit consistency. PMID- 28905895 TI - Superparamagnetic enhancement of thermoelectric performance. AB - The ability to control chemical and physical structuring at the nanometre scale is important for developing high-performance thermoelectric materials. Progress in this area has been achieved mainly by enhancing phonon scattering and consequently decreasing the thermal conductivity of the lattice through the design of either interface structures at nanometre or mesoscopic length scales or multiscale hierarchical architectures. A nanostructuring approach that enables electron transport as well as phonon transport to be manipulated could potentially lead to further enhancements in thermoelectric performance. Here we show that by embedding nanoparticles of a soft magnetic material in a thermoelectric matrix we achieve dual control of phonon- and electron-transport properties. The properties of the nanoparticles-in particular, their superparamagnetic behaviour (in which the nanoparticles can be magnetized similarly to a paramagnet under an external magnetic field)-lead to three kinds of thermoelectromagnetic effect: charge transfer from the magnetic inclusions to the matrix; multiple scattering of electrons by superparamagnetic fluctuations; and enhanced phonon scattering as a result of both the magnetic fluctuations and the nanostructures themselves. We show that together these effects can effectively manipulate electron and phonon transport at nanometre and mesoscopic length scales and thereby improve the thermoelectric performance of the resulting nanocomposites. PMID- 28905896 TI - Detection of titanium oxide in the atmosphere of a hot Jupiter. AB - As an exoplanet transits its host star, some of the light from the star is absorbed by the atoms and molecules in the planet's atmosphere, causing the planet to seem bigger; plotting the planet's observed size as a function of the wavelength of the light produces a transmission spectrum. Measuring the tiny variations in the transmission spectrum, together with atmospheric modelling, then gives clues to the properties of the exoplanet's atmosphere. Chemical species composed of light elements-such as hydrogen, oxygen, carbon, sodium and potassium-have in this way been detected in the atmospheres of several hot giant exoplanets, but molecules composed of heavier elements have thus far proved elusive. Nonetheless, it has been predicted that metal oxides such as titanium oxide (TiO) and vanadium oxide occur in the observable regions of the very hottest exoplanetary atmospheres, causing thermal inversions on the dayside. Here we report the detection of TiO in the atmosphere of the hot-Jupiter planet WASP 19b. Our combined spectrum, with its wide spectral coverage, reveals the presence of TiO (to a confidence level of 7.7sigma), a strongly scattering haze (7.4sigma) and sodium (3.4sigma), and confirms the presence of water (7.9sigma) in the atmosphere. PMID- 28905897 TI - Impact of a global temperature rise of 1.5 degrees Celsius on Asia's glaciers. AB - Glaciers in the high mountains of Asia (HMA) make a substantial contribution to the water supply of millions of people, and they are retreating and losing mass as a result of anthropogenic climate change at similar rates to those seen elsewhere. In the Paris Agreement of 2015, 195 nations agreed on the aspiration to limit the level of global temperature rise to 1.5 degrees Celsius ( degrees C) above pre-industrial levels. However, it is not known what an increase of 1.5 degrees C would mean for the glaciers in HMA. Here we show that a global temperature rise of 1.5 degrees C will lead to a warming of 2.1 +/- 0.1 degrees C in HMA, and that 64 +/- 7 per cent of the present-day ice mass stored in the HMA glaciers will remain by the end of the century. The 1.5 degrees C goal is extremely ambitious and is projected by only a small number of climate models of the conservative IPCC's Representative Concentration Pathway (RCP)2.6 ensemble. Projections for RCP4.5, RCP6.0 and RCP8.5 reveal that much of the glacier ice is likely to disappear, with projected mass losses of 49 +/- 7 per cent, 51 +/- 6 per cent and 64 +/- 5 per cent, respectively, by the end of the century; these projections have potentially serious consequences for regional water management and mountain communities. PMID- 28905898 TI - Protein maps chart the causes of disease. PMID- 28905899 TI - Detecting recovery of the stratospheric ozone layer. AB - As a result of the 1987 Montreal Protocol and its amendments, the atmospheric loading of anthropogenic ozone-depleting substances is decreasing. Accordingly, the stratospheric ozone layer is expected to recover. However, short data records and atmospheric variability confound the search for early signs of recovery, and climate change is masking ozone recovery from ozone-depleting substances in some regions and will increasingly affect the extent of recovery. Here we discuss the nature and timescales of ozone recovery, and explore the extent to which it can be currently detected in different atmospheric regions. PMID- 28905900 TI - Statues: learn from mistakes. PMID- 28905901 TI - Optical physics: A laser model for cosmology. PMID- 28905902 TI - Roads towards fault-tolerant universal quantum computation. AB - A practical quantum computer must not merely store information, but also process it. To prevent errors introduced by noise from multiplying and spreading, a fault tolerant computational architecture is required. Current experiments are taking the first steps toward noise-resilient logical qubits. But to convert these quantum devices from memories to processors, it is necessary to specify how a universal set of gates is performed on them. The leading proposals for doing so, such as magic-state distillation and colour-code techniques, have high resource demands. Alternative schemes, such as those that use high-dimensional quantum codes in a modular architecture, have potential benefits, but need to be explored further. PMID- 28905903 TI - Climate science: The future of Asia's glaciers. PMID- 28905906 TI - Programming languages and compiler design for realistic quantum hardware. AB - Quantum computing sits at an important inflection point. For years, high-level algorithms for quantum computers have shown considerable promise, and recent advances in quantum device fabrication offer hope of utility. A gap still exists, however, between the hardware size and reliability requirements of quantum computing algorithms and the physical machines foreseen within the next ten years. To bridge this gap, quantum computers require appropriate software to translate and optimize applications (toolflows) and abstraction layers. Given the stringent resource constraints in quantum computing, information passed between layers of software and implementations will differ markedly from in classical computing. Quantum toolflows must expose more physical details between layers, so the challenge is to find abstractions that expose key details while hiding enough complexity. PMID- 28905907 TI - Statues: a mother of gynaecology. PMID- 28905909 TI - Quantum software. PMID- 28905910 TI - Microbiology: A fight for scraps of ammonia. PMID- 28905912 TI - Quantum computational supremacy. AB - The field of quantum algorithms aims to find ways to speed up the solution of computational problems by using a quantum computer. A key milestone in this field will be when a universal quantum computer performs a computational task that is beyond the capability of any classical computer, an event known as quantum supremacy. This would be easier to achieve experimentally than full-scale quantum computing, but involves new theoretical challenges. Here we present the leading proposals to achieve quantum supremacy, and discuss how we can reliably compare the power of a classical computer to the power of a quantum computer. PMID- 28905914 TI - Erratum: A novel mechanism for mechanosensory-based rheotaxis in larval zebrafish. AB - This corrects the article DOI: 10.1038/nature23014. PMID- 28905915 TI - Statues: for those deserving respect. PMID- 28905911 TI - The 4D nucleome project. AB - The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells. PMID- 28905916 TI - Hardware-efficient variational quantum eigensolver for small molecules and quantum magnets. AB - Quantum computers can be used to address electronic-structure problems and problems in materials science and condensed matter physics that can be formulated as interacting fermionic problems, problems which stretch the limits of existing high-performance computers. Finding exact solutions to such problems numerically has a computational cost that scales exponentially with the size of the system, and Monte Carlo methods are unsuitable owing to the fermionic sign problem. These limitations of classical computational methods have made solving even few-atom electronic-structure problems interesting for implementation using medium-sized quantum computers. Yet experimental implementations have so far been restricted to molecules involving only hydrogen and helium. Here we demonstrate the experimental optimization of Hamiltonian problems with up to six qubits and more than one hundred Pauli terms, determining the ground-state energy for molecules of increasing size, up to BeH2. We achieve this result by using a variational quantum eigenvalue solver (eigensolver) with efficiently prepared trial states that are tailored specifically to the interactions that are available in our quantum processor, combined with a compact encoding of fermionic Hamiltonians and a robust stochastic optimization routine. We demonstrate the flexibility of our approach by applying it to a problem of quantum magnetism, an antiferromagnetic Heisenberg model in an external magnetic field. In all cases, we find agreement between our experiments and numerical simulations using a model of the device with noise. Our results help to elucidate the requirements for scaling the method to larger systems and for bridging the gap between key problems in high performance computing and their implementation on quantum hardware. PMID- 28905918 TI - Palaeontology: Plenty of fish in the tree. PMID- 28905917 TI - Quantum machine learning. AB - Fuelled by increasing computer power and algorithmic advances, machine learning techniques have become powerful tools for finding patterns in data. Quantum systems produce atypical patterns that classical systems are thought not to produce efficiently, so it is reasonable to postulate that quantum computers may outperform classical computers on machine learning tasks. The field of quantum machine learning explores how to devise and implement quantum software that could enable machine learning that is faster than that of classical computers. Recent work has produced quantum algorithms that could act as the building blocks of machine learning programs, but the hardware and software challenges are still considerable. PMID- 28905920 TI - Support Ismail Serageldin. PMID- 28905919 TI - Erratum: T cells from patients with Parkinson's disease recognize alpha-synuclein peptides. AB - This corrects the article DOI: 10.1038/nature22815. PMID- 28905922 TI - Correction. PMID- 28905921 TI - South Korean researchers lobby government to lift human-embryo restrictions. PMID- 28905923 TI - Geneticists pan paper that claims to predict a person's face from their DNA. PMID- 28905924 TI - Hurricane havoc, deep-ocean floats and Mexico's fatal quake. PMID- 28905925 TI - Faculty promotion must assess reproducibility. PMID- 28905926 TI - Pregnant mice illuminate risk factors that could lead to autism. PMID- 28905927 TI - UK gender-equality scheme spreads across the world. PMID- 28905928 TI - Giraffes could have evolved long necks to keep cool. PMID- 28905929 TI - First quantum computers need smart software. PMID- 28905930 TI - The new economy of excrement. PMID- 28905931 TI - Jordan seeks to become an oasis of water-saving technology. PMID- 28905932 TI - Insurance companies should collect a carbon levy. PMID- 28905933 TI - Researchers riled by lack of detail in Brexit science plans. PMID- 28905934 TI - Conversion and pharmacokinetics profiles of a novel pro-drug of 3-n butylphthalide, potassium 2-(1-hydroxypentyl)-benzoate, in rats and dogs. AB - Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a novel pro-drug of 3-n butylphthalide (dl-NBP) that is used to treat ischemic stroke. Currently, dl-PHPB is in phase II-III clinical trials in China. In this study, we investigated the conversion and pharmacokinetics profiles of dl-PHPB in vitro and in vivo. The conversion of dl-PHPB to dl-NBP was pH- and calcium-dependent, and paraoxonase was identified as a major enzyme for the conversion in rat plasma. The pharmacokinetics, tissue distribution and excretion of dl-PHPB were studied and compared with equal-molar doses of dl-NBP in rats and dogs. The in vivo studies showed that dl-PHPB could be quickly and completely converted to dl-NBP. The plasma concentration-time course of converted dl-NBP after intravenous dl-PHPB administration was nearly the same as that after equal-molar dl-NBP. The Cmax and AUC of dl-NBP after oral dl-PHPB administration in rats and dogs were higher by 60% and 170%, respectively, than those after oral dl-NBP administration. Analysis of the tissue distribution of dl-PHPB revealed that converted dl-NBP was primarily distributed in fat, the brain and the stomach. In the brain, the levels of dl-NBP were relatively higher after dl-PHPB treatment by orally than after treatment with equal-molar dl-NBP. Approximately 3%-4% of dl-NBP was excreted within 72 h after dosing with dl-PHPB or dl-NBP, but no dl-PHPB was detected in urine or feces excrements. Our results demonstrate that the conversion of dl-PHPB is fast after oral or intravenous administration. Furthermore, the bioavailability of dl-PHPB was obviously better than that of dl-NBP. PMID- 28905935 TI - Age-related differences in interferon regulatory factor-4 and -5 signaling in ischemic brains of mice. AB - Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-alpha, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-beta, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses. PMID- 28905936 TI - Combing oncolytic adenovirus expressing Beclin-1 with chemotherapy agent doxorubicin synergistically enhances cytotoxicity in human CML cells in vitro. AB - Cancer virotherapy provides a new strategy to treat cancer that can directly kill cancer cells by oncolysis. Insertion of therapeutic genes into the genome of a modified adenovirus, thereby creating a so-called gene-virotherapy that shares the advantages of gene therapy and virotherapy. In this study we investigated whether a strategy that combines the oncolytic effects of an adenoviral vector with the simultaneous expression of the autophagy gene Beclin-1 offered a therapeutic advantage for chronic myeloid leukemia (CML) cells with resistance to chemotherapy and evaluated the synergistic effects of SG511-BECN and doxorubicin (Dox) in human CML cells in vitro. Oncolytic virus SG511-BECN was constructed through introducing the Beclin-1 gene into the oncolytic adenoviral backbone. SG511-BECN displayed significantly improved antileukemia activity on multidrug resistant CML cell line K562/A02, which was mediated via induction of autophagic cell death. Furthermore, Dox could synergize with SG511-BECN to kill the CML cells by improving the infectious efficiency of the oncolytic adenovirus without causing significant damage to normal human mononuclear cells. The results demonstrate that targeting the autophagic cell death pathway and combination of a chemotherapy agent with oncolytic adenovirus may be a novel strategy for the treatment of leukemia with chemotherapy resistance. PMID- 28905937 TI - SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models. AB - Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases. In 3 representative human cancer cell lines with different mechanisms of FGFR activation tested, SOMCL-085 (20-500 nmol/L) dose-dependently inhibited FGFR1-3 phosphorylation and the phosphorylation of their key downstream effectors PLCgamma and Erk. In 7 FGFR aberrant human cancer cell lines, regardless of the mechanistic complexity of FGFR over-activation, SOMCL-085 potently inhibited FGFR-driven cell proliferation by arresting cells at the G1/S phase. In the FGFR1-amplified lung cancer cell line H1581 xenograft mice and FGFR2-amplified gastric cancer cell line SNU16 xenograft mice, oral administration of SOMCL-085 (25, 50 mg.kg-1.d-1) for 21 days substantially suppressed tumor growth without affecting their body-weight. These results suggest that SOMCL-085 is a potent multi-target FGFR inhibitor that inhibits the FGFR-dependent neoplastic phenotypes of human cancer cells in vitro and in vivo. PMID- 28905938 TI - Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response. AB - Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury in vitro and in vivo. TP (5-50000 nmol/L) dose dependently decreased the viability of TM4 Sertoli cells with an IC50 value of 669.5-269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO 1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg.kg-1.d-1, for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation. PMID- 28905940 TI - Bivalirudin for patients with STEMI at high risk of bleeding undergoing PPCI. PMID- 28905939 TI - Curcumin administration suppresses collagen synthesis in the hearts of rats with experimental diabetes. AB - Cardiac fibrosis is considered the initial change of diabetic cardiomyopathy (DCM). We have shown that curcumin alleviates collagen deposition in DCM, but the mechanism remains unknown. In this study we sought to investigate the effects of curcumin on cardiac fibrosis in vivo and in vitro and to elucidate the underlying mechanisms. Experimental diabetes was induced in rats by injection of low-dose streptozotocin (STZ) combined with high energy diet. The rats were orally treated with curcumin (300 mg.kg-1.d-1) for 16 weeks. Curcumin administration significantly suppressed the deposition of type I and type III collagens in the heart tissues of diabetic rats, accompanied by markedly reduced TGF-beta1 production, suppressed TbetaR II levels and Smad2/3 phosphorylation, and increased Smad7 expression. Similar effects were observed in human cardiac fibroblasts exposed to high glucose (HG, 30 mmol/L) or exogenous TGF-beta1 (5 ng/mL). Furthermore, TGF-beta1 or HG treatment significantly increased the phosphorylation levels of AMPK and p38 MAPK in the fibroblasts. Application of curcumin (25 MUmol/L) inhibited TGF-beta1- or HG-induced AMPK/p38 MAPK activation and suppressed collagen synthesis in the fibroblasts. These effects were similar to those of the AMPK inhibitor compound C (10 MUmol/L) but opposite to the effects of the AMPK activator metformin (2 mmol/L) in the fibroblasts. Our results demonstrate that curcumin suppresses diabetes-associated collagen synthesis in rat myocardium not only by inhibiting TGF-beta1 production and canonical Smad signaling but also by blocking the non-canonical AMPK/p38 MAPK pathway. PMID- 28905941 TI - A quantitative point-of-care test for periodontal and dental peri-implant diseases. PMID- 28905942 TI - Authors' reply: Predictive diagnostic tests in periodontal diseases. PMID- 28905944 TI - Snakebite envenoming. AB - Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions. PMID- 28905945 TI - The effect of Sn doping on thermoelectric performance of n-type half-Heusler NbCoSb. AB - Herein, Sn was successfully doped into the Sb site of n-type NbCoSb half-Heusler compounds to tune the carrier concentration, and a maximum ZT value of ~0.56 was obtained at 973 K for NbCoSb1-xSnx with x = 0.2, an increase of ~40% as compared to that of NbCoSb. This enhancement is mainly attributed to the reduced carrier concentration by Sn doping, leading to a doubled Seebeck coefficient at 300 K. More importantly, the total thermal conductivity was reduced with Sn doping, and the reduction was mainly due to the lowered electron thermal conductivity. The decreased electron thermal conductivity resulted from the reduced carrier concentration and the consequent enhanced carrier degeneracy, contributing to a reduced Lorenz constant. A quantitative description of the electron transport characteristics was performed under a single parabolic band model supposing that the acoustic phonon scattering was dominant in the carrier transport. A high density of the state effective mass, m* ~ 10 me, and relatively high deformation potential Edef = 21 eV were found for the solid solutions. PMID- 28905947 TI - Ab initio molecular dynamics of thiophene: the interplay of internal conversion and intersystem crossing. AB - The fast and slow components of the relaxation of photoexcited thiophene have been investigated by means of SHARC (surface hopping including arbitrary couplings) molecular dynamics based on multiconfiguration electronic structure calculations. Triplet states are included to ascertain their role in the relaxation process. After thiophene is excited to the S1 state, ultrafast dynamics (taufast = 96 fs) initiates a ring opening due to cleavage of a carbon sulfur bond and simultaneous ring puckering. This time constant is in agreement with previous experimental and theoretical studies. The subsequent dynamics of the open-ring structures is characterized by the interplay of internal conversion and intersystem crossing. For the open-ring structures, the S0, S1, T1 and T2 states are nearly degenerate and the spin-orbit couplings are large. The underlying potential energy surface is flat and long-lived open-ring structures in the singlet as well as in the triplet states are formed. Both the participation of triplet states and the shape of the energy surface explain the experimentally observed slow ring closure in the ground state. PMID- 28905946 TI - Sequential molecule-triggered-release system based on acetylated amylose helix aggregates. AB - We developed a novel sequential molecule-triggered-release system based on acetylated amylose helix aggregates with a proper degree of substitution, in which a loaded molecule can be trigger-released by trigger molecules in sequence. The system is sensitive and capable of time-controllable triggered release. The mechanism involves the sequential pushing of wrapped molecules with low binding free energy out of the helix cavity by a triggered molecule with a high binding free energy. PMID- 28905948 TI - Bistriazole-p-benzoquinone and its alkali salts: electrochemical behaviour in aqueous alkaline solutions. AB - Quinones are well known as redox-active compounds. In this work bistriazole-p benzoquinone was prepared and its electrochemical behaviour in aqueous alkaline solutions was studied by cyclic voltammetry. Two successive one-electron reduction steps were observed - the first step was reversible and the second quasireversible. Based on the nature of the alkali cation, the potential of the cathodic peak minimum and the anodic peak maximum was shifted towards positive direction as follows Li+ > Na+ > K+. In order to know more about the chemical structure of the alkali salts, the lithium, sodium and potassium salts of bistriazole-p-benzoquinone were crystallized and their structure could be revealed by single crystal X-ray analysis. Additionally, the thermal stability of the compounds was investigated by thermogravimetric analysis and variable temperature X-ray powder diffraction analysis. PMID- 28905949 TI - Electronic and molecular structure relations in diiron compounds mimicking the [FeFe]-hydrogenase active site studied by X-ray spectroscopy and quantum chemistry. AB - Synthetic diiron compounds of the general formula Fe2(MU-S2R)(CO)n(L)6-n (R = alkyl or aromatic groups; L = CN- or phosphines) are versatile models for the active-site cofactor of hydrogen turnover in [FeFe]-hydrogenases. A series of 18 diiron compounds, containing mostly a dithiolate bridge and terminal ligands of increasing complexity, was characterized by X-ray absorption and emission spectroscopy in combination with density functional theory. Fe K-edge absorption and Kbeta main-line emission spectra revealed the varying geometry and the low spin state of the Fe(i) centers. Good agreement between experimental and calculated core-to-valence-excitation absorption and radiative valence-to-core decay emission spectra revealed correlations between spectroscopic and structural features and provided access to the electronic configuration. Four main effects on the diiron core were identified, which were preferentially related to variation either of the dithiolate or of the terminal ligands. Alteration of the dithiolate bridge affected mainly the Fe-Fe bond strength, while more potent donor substitution and ligand field asymmetrization changed the metal charge and valence level localization. In contrast, cyanide ligation altered all relevant properties and, in particular, the frontier molecular orbital energies of the diiron core. Mutual benchmarking of experimental and theoretical parameters provides guidelines to verify the electronic properties of related diiron compounds. PMID- 28905950 TI - A DFT study on the aldol condensation reaction on MgO in the process of ethanol to 1,3-butadiene: understanding the structure-activity relationship. AB - Using periodic density functional theory calculations, the aldol condensation of acetaldehyde to 3-hydroxybutanal over dehydroxylated MgO surfaces with and without structure defects was investigated. Compared with the C-C coupling step, the enolization step via proton transfer of the alpha-hydrogen of acetaldehyde to the MgO surface or the proton back-transfer step to form the desired 3 hydroxybutanal has a higher energy barrier, indicating that the proton transfer process is the key step for the aldol condensation on MgO. To highlight the effect of water, we also calculated the proton transfer steps in the presence of water and studied the reaction pathways over the partially hydroxylated MgO surface. The results show that water can participate in the proton back-transfer step by donating a proton to the alkoxide anion to form the 3-hydroxybutanal, thus reducing the activation energy; the surface OH groups induce a lowering of the activation energy barriers for the overall reaction. The results of the electronic structure analysis indicate that a strong Lewis acid-weak/medium base pair may have the best performance for aldol condensation, such as Mg3C-O4C-D produced by divacancy defects and Mg4C-O2CH produced by the dissociative adsorption of water. A strong Lewis acid generated by low-coordinated Mg2+ can adsorb and stabilize the acetaldehyde molecule near the catalyst surface which is beneficial for the abstraction of an alpha-proton from an acetaldehyde molecule, and a medium or weak Bronsted base is favorable for the proton back-transfer step. PMID- 28905951 TI - Order-disorder phase transition in an anhydrous pyrazole-based proton conductor: the enhancement of electrical transport properties. AB - The crystal structure of 1H-pyrazol-2-ium hydrogen oxalate has been studied at 100 K. It consists of two-dimensional layers built with one-dimensional chains that contain pyrazolium and oxalate acids bonded by N-HO and O-HO hydrogen bonds. According to the X-ray data and the Quantum Theory of Atoms in Molecules, it was shown that weak and moderate hydrogen bonds are present in the crystal at room temperature. The thermal stability was studied with the DSC, TGA, and DTG methods: three endothermic peaks are observed at 384, 420, and 469 K. Conductivity measurements have been performed in the temperature range from 300 to 433 K. At 383 K the pyrazole-oxalic acid framework loses its rigidity and the crystal undergoes an ordered-disordered phase transition. At this temperature, the value of the activation energy of proton conductivity changes from 1.14 to 2.31 eV. The proton conduction pathways and the transport mechanism have been studied with theoretical methods. PMID- 28905953 TI - Protective effect of Potentilla anserina polysaccharide on cadmium-induced nephrotoxicity in vitro and in vivo. AB - The aim of this research was to investigate the antioxidant and anti-apoptotic activities of Potentilla anserina polysaccharide (PAP) on kidney damage induced by cadmium (Cd) in vitro and in vivo. PAP has been suggested to have anti oxidation, anti-apoptosis, immunoregulation, antimicrobial, antitussive, and expectorant abilities. In this study, PAP was extracted and the major components of PAP were analyzed. It was shown that PAP pretreatment remarkably improved redox homeostasis, both in human embryonic kidney 293 (HEK293) cells and in BALB/c mice. Administration of PAP attenuated the mitochondrial dysfunction, degeneration, and fibrosis of kidney induced by Cd. Furthermore, PAP exhibited anti-apoptotic activity, which involved regulating both the mitochondria-mediated intrinsic apoptotic pathway and the death receptor-initiated extrinsic pathway. These results suggest that PAP is a potential therapeutic agent for Cd-induced nephrotoxicity. PMID- 28905952 TI - Detection of membrane-bound and soluble antigens by magnetic levitation. AB - Magnetic levitation is a technique for measuring the density and the magnetic properties of objects suspended in a paramagnetic field. We describe a novel magnetic levitation-based method that can specifically detect cell membrane-bound and soluble antigens by measurable changes in levitation height that result from the formation of antibody-coated bead and antigen complex. We demonstrate our method's ability to sensitively detect an array of membrane-bound and soluble antigens found in blood, including T-cell antigen CD3, eosinophil antigen Siglec 8, red blood cell antigens CD35 and RhD, red blood cell-bound Epstein-Barr viral particles, and soluble IL-6, and validate the results by flow cytometry and immunofluorescence microscopy performed in parallel. Additionally, employing an inexpensive, single lens, manual focus, wifi-enabled camera, we extend the portability of our method for its potential use as a point-of-care diagnostic assay. PMID- 28905954 TI - Nanoelectromagnetic of the N-doped single wall carbon nanotube in the extremely high frequency band. AB - Materials offering excellent mechanical flexibility, high electrical conductivity and electromagnetic interference (EMI) attenuation with minimal thickness are in high demand, particularly if they can be easily processed into films. Carbon nanotube films deposited on a PDMS substrate combine these requirements. In this work, the potential of single wall carbon nanotubes (SWCNT) deposited on flexible polydimethylsiloxane (PDMS) polymer substrates for EMI attenuation is demonstrated. A 6-micrometer-thick SWCNT film exhibits EMI shielding effectiveness of 24.5 decibels in the extreme high frequency band (EHF), reaching 40 decibels when the SWCNTs are N-doped, which is one of the highest specific EMI attenuation performances optimized with film thickness realized to date. This performance stems from the good electrical conductivity of N-SWCNT films (150 Siemens per centimeter) and possible internal multireflections within the SWCNTs network. The excellent mechanical flexibility and easy coating processing enable them to sheathe complex shaped surfaces while providing high electromagnetic interference attenuation efficiency. PMID- 28905955 TI - A low-cost, large field-of-view scanning ion conductance microscope for studying nanoparticle-cell membrane interactions. AB - Nanoparticles have the potential to become versatile tools in the medical and life sciences. One potential application is delivering drugs or other compounds to the cell cytoplasm, which requires the nanoparticles to bind to or cross the cell membrane. However, there are only a few tools available which allow studying the interaction of nanoparticles and the cell membrane of living cells in a physiological environment. Currently, the tool which least biases living cells is Scanning Ion Conductance Microscopy (SICM). Specialized SICMs allow imaging at high resolution, however, they are cost intensive, particularly when providing a large field-of-view. In contrast, less cost intensive SICMs which provide a large field-of-view do not allow imaging at high resolutions. We have developed a SICM setup consisting of a compact three-axis piezo system and an additional fast shear-force piezo actor. This combination allows imaging fields-of-view of up to 80 MUm * 80 MUm, recording sections of living cells with a temporal resolution in the range of minutes as well as imaging with a spatial resolution of below 70 nm. Using our SICM we found that the cell membrane of HeLa cells treated with carboxylated latex nanoparticles was significantly more convoluted compared to control cells. The SICM setup we introduce here combines high resolution imaging with a large field-of-view at low costs. Our setup only requires a mounting adapter to extend existing inverted light microscopes, thus it could be a valuable and cost effective tool for researchers in all fields of the medical and life sciences performing investigations at the nanometer scale. PMID- 28905957 TI - Correction: A dual-ion electrochemistry deionization system based on AgCl Na0.44MnO2 electrodes. AB - Correction for 'A dual-ion electrochemistry deionization system based on AgCl Na0.44MnO2 electrodes' by Fuming Chen et al., Nanoscale, 2017, 9, 10101-10108. PMID- 28905956 TI - Poly-cytosine-mediated nanotags for SERS detection of Hg2. AB - Highly sensitive and selective detection of heavy metal ions, such as Hg2+, is of great importance because the contamination of heavy metal ions has been a serious threat to human health. Herein, we have developed poly-cytosine (polyC)-mediated surface-enhanced Raman scattering (SERS) nanotags as a sensor system for rapid, selective, and sensitive detection of Hg2+ based on thymidine-Hg2+-thymidine (T Hg2+-T) coordination and polyC-mediated Raman activity. The SERS nanotags exploit the mismatched T-T base pairs to capture Hg2+ form T-Hg2+-T bridges, which induce the aggregation of nanotags giving rise to the drastic amplification in the SERS signals. Moreover, this polyC not only provides the anchoring function to induce the formation of intrinsic silver-cytosine coordination but also engineers the Raman-activity of SERS nanotags by mediating its length. As a result, the polyC mediated SERS nanotags show an excellent response for Hg2+ in the concentration range from 0.1 to 1000 nM and good selectivity over other metal ions. Given its simple principle and easy operation, the polyC-mediated SERS nanotags, therefore, could serve as a promising sensor for practical use. PMID- 28905960 TI - Correction: A study of pH-dependence of shrink and stretch of tetrahedral DNA nanostructures. AB - Correction for 'A study of pH-dependence of shrink and stretch of tetrahedral DNA nanostructures' by Ping Wang et al., Nanoscale, 2015, 7, 6467-6470. PMID- 28905961 TI - Correction: Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on beta-glucocerebrosidase activity. AB - Correction for 'Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on beta-glucocerebrosidase activity' by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681-3705. PMID- 28905962 TI - The dendritic effect and magnetic permeability in dendron coated nickel and manganese zinc ferrite nanoparticles. AB - The collective magnetic properties of nanoparticle (NP) solid films are greatly affected by inter-particle dipole-dipole interactions and therefore the proximity of the neighboring particles. In this study, a series of dendritic ligands (generations 0 to 3, G0-G3) have been designed and used to cover the surface of magnetic NPs to control the spacings between the NP components in single lattices. The dendrons of different generations introduced here were based on the 2,2-bis(hydroxymethyl)propionic acid (Bis-MPA) scaffold and equipped with an appropriate surface binding group at one end and several fatty acid segments at the other extremity. The surface of the NPs was then modified by partial ligand exchange between the primary stabilizing surfactants and the new dendritic wedges. It was shown that this strategy permitted very precise tuning of inter particle spacings in the range of 2.9-5.0 nm. As expected, the increase in the inter-particle spacings reduced the dipole-dipole interactions between magnetic NPs and therefore allowed changes in their magnetic permeability. The dendron size and inter-particle distance dependence was studied to reveal the dendritic effect and identify the optimal geometry and generation. PMID- 28905964 TI - Development and applications of a near-infrared dye-benzylguanine conjugate to specifically label SNAP-tagged proteins. AB - Near-infrared (NIR) fluorescent probes are advantageous over visible ones, for they can avoid the interference from the short-wavelength background emission in biological systems. However, there are a very limited number of NIR probes that can specifically label target proteins in living cells. In this work, a series of long-wavelength dyes (N-NIR, S-NIR, and K-NIR) analogous to the novel Changsha NIR family are synthesized conveniently through a new approach that is different from the previously reported one. These three dyes have similar conjugation structures but exhibit tunable photophysical properties. N-NIR and S-NIR have large extinction coefficients over 100 000, and high fluorescence quantum yields. Although NIR absorption and emission of K-NIR are inferior to the former two, it emits in a much longer wavelength region. And all the three dyes can easily pass through the cell membranes to obtain the high-resolution NIR fluorescence images. Furthermore, N-NIR is chosen as the NIR fluorophore to develop a protein-labeling reagent PYBG-D, since it demonstrates the highest fluorescence quantum yield of up to 0.4 (in methanol). PYBG-D is efficiently synthesized through Sonogashira coupling between bromo-substituted N-NIR and alkyne-substituted benzylguanine (PYBG). The conjugate PYBG-D proves to be a specific and efficient label for O6 alkylguanine-DNA alkyltransferase (SNAP-tag) that fused to target proteins in living cells, which contributes to high resolution NIR fluorescence images under a laser confocal microscope. PMID- 28905963 TI - Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments. AB - Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc., 2013, 135(8), 2907]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti cancer drug camptothecin [Kang et al., Macromolecules, 2016, 49(3), 994]. We found that the pi-pi stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 MUm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications. PMID- 28905966 TI - Computational insights into active site shaping for substrate specificity and reaction regioselectivity in the EXTL2 retaining glycosyltransferase. AB - Glycosyltransferases are enzymes that catalyze a monosaccharide transfer reaction from a donor to an acceptor substrate with the synthesis of a new glycosidic bond. They are highly substrate specific and regioselective, even though the acceptor substrate often presents multiple reactive groups. Currently, many efforts are dedicated to the development of biocatalysts for glycan synthesis and, therefore, a better understanding of how natural enzymes achieve this goal can be of valuable help. To gain a deeper insight into the catalytic strategies used by retaining glycosyltransferases, the wild type EXTL2 (CAZy family GT64) and four mutant forms (at positions 293 and 246) were studied using QM(DFT)/MM calculations and molecular dynamics simulations. Existing hypotheses on the roles of Arg293, an enigmatic residue in the CAZy family GT64 that seemed to contradict a mechanism through an oxocarbenium intermediate, and of Asp246 have been tested. We also provide a molecular interpretation for the results of site-directed mutagenesis experiments. Moreover, we have investigated why an Asp, and not a Glu like in the family GT6, is found on the beta-face of the transferred GlcNAc. It is predicted that an Asp246Glu mutant of EXTL2 would be unable to catalyze the alpha-1,4 transfer. The results herein presented clarify the roles that Arg293, Asp246 and Leu213 have at different stages of the catalytic process (for binding but also for efficient chemical reaction). Altogether, we provide a molecular view that connects the identity and conformation of these residues to the substrate specificity and regioselectivity of the enzyme, illustrating a delicate interplay between all these aspects. PMID- 28905969 TI - Highly stretchable hydrogels from complex coacervation of natural polyelectrolytes. AB - The controlled complex coacervation of oppositely charged hyaluronic acid (Mw ~ 800-1000 kg mol-1) and chitosan (Mw ~ 160 kg mol-1, degree of acetylation = 15%) led to hydrogels with controllable properties in terms of elasticity and strength. In this work, we performed desalting by dialysis of high ionic strength solutions of mixed polyelectrolytes and showed that the control of the pH during the polyelectrolyte assembly greatly impacts the mechanical properties of the hydrogel. First, for pHs from 5.5 to 7.5, a slight coacervation was observed due to low chitosan protonation and poor polyelectrolyte associations. Then, for pHs from 3.0 to 5.5, coacervation and syneresis led to free-standing and easy to handle hydrogels. Finally, for pHs from 2.0 to 3.0 (close to the pKa of the hyaluronic acid), we observed the unusual stretchability of these hydrogels that could arise from the pre-folding of hyaluronic acid chains while physical crosslinking was achieved by hyaluronic acid/chitosan polyelectrolyte complexation. PMID- 28905970 TI - On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives. AB - In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors. PMID- 28905971 TI - Structural behavior of competitive temperature and pH-responsive tethered polymer layers. AB - Herein, we develop a molecular theory to examine a class of pH and temperature responsive tethered polymer layers. The response of pH depends on intramolecular charge repulsion of weakly acidic monomers and the response of temperature depends on hydrogen bonding between polymer monomers and water molecules akin to the behavior of water-soluble polymers such as PEG (poly-ethylene glycol) or NIPAAm (n-isopropylacrylamide). We investigate the changes in structural behavior that result for various end-tethered copolymers: pH/T responsive monomers alone, in alternating sequence with hydrophobic monomers, and as 50/50 diblocks with hydrophobic monomers. We find that the sequence and location of hydrophobic units play a critical role in the thermodynamic stability and structural behavior of these responsive polymer layers. Additionally, the polymers exhibit tunable collapse when varying the surface coverage, location and sequence of hydrophobic units as a function of temperature and pH. As far as we know, our results present the first molecularly detailed theory for end-tethered polymers that are both pH and temperature-responsive via hydrogen bonding. We propose that this work holds predictive power for the guided design of future biomaterials. PMID- 28905972 TI - Red-emissive triplex-forming PNA probes carrying cyanine base surrogates for fluorescence sensing of double-stranded RNA. AB - Red-emissive fluorescent probes have been developed by integration of quinoline blue or thiazole red as the base surrogate into triplex-forming PNAs, allowing selective sensing of a sequence of double-stranded RNA. PMID- 28905973 TI - Copper-catalyzed oxidative cross-coupling of alpha-aminocarbonyl compounds with primary amines toward 2-oxo-acetamidines. AB - A general and mild method for the construction of a carbon-nitrogen bond via copper-catalyzed oxidative cross-coupling of amines with alpha-aminocarbonyl compounds was achieved. Amines, either aliphatic primary amines, aromatic primary amines or secondary amines can be used as the starting materials. When R2 was different from R3, two isomers would be observed. Therefore, this reaction system has a broad substrate scope and provides a facile pathway for the synthesis of 2 oxo-acetamidines. PMID- 28905974 TI - Synthesis of functionalized indolizines via gold(i)-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes. AB - A gold-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes has been developed. This method provides a concise and straightforward route to functionalized indolizines through the construction of the pyridine ring of indolizines and also allows elaboration of its pyrrole moiety with or without functional groups. In addition, a wide variety of functional groups, such as aryl, alkenyl, alkynyl, pyridyl or thienyl groups, can be easily incorporated into the pyridine unit of the indolizine products under mild conditions. The utility of the indolizine products was demonstrated by their efficient transformations into various C3-functionalized indolizine derivatives. PMID- 28905975 TI - Visible light-induced C3-sulfonamidation of imidazopyridines with sulfamides. AB - A visible light-induced regioselective sulfonamidation of imidazo[1,2-a]pyridines was developed using sulfamides as the nitrogen sources and aqueous NaClO solution as the oxidant under mild conditions. With the imidazo[1,2-a]pyridines bearing various substituents, the reaction proceeded smoothly to furnish the C3 sulfonamidation products in moderate to good yields. The method was also suitable for the sulfonamidation of some other imidazoheterocycles. PMID- 28905976 TI - Cutaneous alternariosis in an immunocompromised dog successfully treated with cold plasma and cessation of immunosuppressive medication. AB - A cutaneous infection with Alternaria spp. was diagnosed in a 2-year-old male intact Irish setter dog, presenting with multifocal papules, plaques and ulcerations involving all four distal limbs, shoulder blades, scrotum, pinnae and nasal mucous membranes. The dog had been treated for inflammatory bowel disease and lymphangiectasia with immunosuppressive doses of cyclosporine and prednisolone for approximately 3 months. The diagnosis was based on clinical signs, the demonstration of fungal elements within skin biopsies, deep fungal culture and fungal PCR from a formalin-fixed tissue specimen. Complete clinical remission was achieved by tapering and cessation of the immunosuppressive medication, treatment with cold atmospheric-pressure plasma (CAPP) and topical enilconazole within 8 weeks. PMID- 28905977 TI - [Incidence and mortality of common neonatal diseases in the foal during the first 10 days post natum in a veterinary hospital]. AB - OBJECTIVE: The aim of this study was to present the incidence and lethality of diseases in foals during the first 10 days following birth by analyzing patient data. MATERIAL AND METHODS: Over a period of 6 years, patient data from 393 foals, that had been presented within the first 10 days after birth in a hospital, were evaluated. The number of diseases, the sex of the affected foals and the lethality were documented. RESULTS: A total of 28 diseases were diagnosed, with systemic inflammatory response syndrome (SIRS), meconium impaction and bronchopneumonia being the most frequent diagnoses. The mortality rate for SIRS was 41.8%, for meconium impaction 29.7% and for bronchopneumonia 37.9%. The mean time of death for patients with SIRS was 4.2 +/- 2.9 days, for patients with meconium impaction 4.6 +/- 3.2 days and for foals suffering from bronchopneumonia 5.2 +/- 3.5 days post partum. CONCLUSION AND CLINICAL RELEVANCE: Based on the data collection, the frequency and thus the importance of individual disease patterns can be deduced. The information on lethality helps to make predictions for the prognosis of the most common neonatal foal diseases based on first diagnosis. PMID- 28905979 TI - [Cyanosis in a calf with a double outlet right ventricle]. AB - A 4-day-old female Holstein Friesian calf was presented for evaluation of cyanosis and dyspnea. On auscultation, severe bronchovesicular sounds and a systolic heart murmur of grade IV/VI above the tricuspid valve were found. On echocardiography, a marked dextroposition of the aorta (> 50% originating from the right ventricle), leading to both great arteries arising from the right ventricle - a so-called double-outlet right ventricle - was detected. Two ventricular septal defects were present, one in the perimembranous, subpulmonary region, the other non-committed in the muscular region. The subpulmonary ventricular septal defect was responsible for the shunting of unoxygenated blood into the aorta. Additionally, an aneurysma-like atrial septal defect (type secundum) and a large patent ductus arteriosus were visualized. The main pulmonary artery was severely enlarged without the presence of a stenotic defect. The findings could be verified by angiography. Additionally, a diffuse hypoplastic ascending aorta was visualized. Necropsy confirmed the echocardiographic and angiographic findings. PMID- 28905978 TI - Redesign of computerized decision support to improve antimicrobial prescribing. A controlled before-and-after study. AB - OBJECTIVE: To determine the impact of the introduction of new pre-written orders for antimicrobials in a computerized provider order entry (CPOE) system on 1) accuracy of documented indications for antimicrobials in the CPOE system, 2) appropriateness of antimicrobial prescribing, and 3) compliance with the hospital's antimicrobial policy. Prescriber opinions of the new decision support were also explored to determine why the redesign was effective or ineffective in altering prescribing practices. METHODS: The study comprised two parts: a controlled pre-post study and qualitative interviews. The intervention involved the redesign of pre-written orders for half the antimicrobials so that approved indications were incorporated into pre-written orders. 555 antimicrobials prescribed before (September - October, 2013) and 534 antimicrobials prescribed after (March - April, 2015) the intervention on all general wards of a hospital were audited by study pharmacists. Eleven prescribers participated in semi structured interviews. RESULTS: Redesign of computerized decision support did not result in more appropriate or compliant antimicrobial prescribing, nor did it improve accuracy of indication documentation in the CPOE system (Intervention antimicrobials: appropriateness 49% vs. 50%; compliance 44% vs. 42%; accuracy 58% vs. 38%; all p>0.05). Via our interviews with prescribers we identified five main reasons for this, primarily that indications entered into the CPOE system were not monitored or followed-up, and that the antimicrobial approval process did not align well with prescriber workflow. CONCLUSION: Redesign of pre-written orders to incorporate appropriate indications did not improve antimicrobial prescribing. Workarounds are likely when compliance with hospital policy creates additional work for prescribers or when system usability is poor. Implementation of IT, in the absence of support or follow-up, is unlikely to achieve all anticipated benefits. PMID- 28905980 TI - Response to Lapkoff and Sittig. Who Watches the Watchers: Working Towards Safety for Clinical Decision Support Knowledge Resources. PMID- 28905981 TI - [Heterogeneity of canine immune responses to Borrelia burgdorferi in a line immunoassay comprising recombinant VlsE and C6 peptide]. AB - OBJECTIVE: The study aimed to investigate the distribution of specific immune responses (IgG) to Borrelia burgdorferi using a line immunoassay with recombinant VlsE (variable major protein-like sequence, expressed) protein and synthetic C peptide among other antigens. We compared the immune responses to VlsE protein and C6 peptide, because both antigens have been considered specific for a Borrelia infection. MATERIALS AND METHODS: A total of 1355 blood samples from dogs suspected of Borrelia infection were analysed. The line immunoassay employed nine antigens. RESULTS: A total of 64.4% of all samples tested negative, 16.4% were positive for an infection and 17.4% were positive for vaccination. Band patterns specific for both infection and vaccination were observed in 1.2% of the dogs. The bands that most frequently tested positive were p100 (24.3%), p31/OspA (18.5%), C6 (16.3%) and VlsE (13.9%). A total of 236 dogs (17.4% of the population) had antibodies to VlsE and/or C6 peptide. In 73.3% of these dogs, results for VlsE and C6 peptide were consistent, whereas this was not the case for 26.7% of these animals. CONCLUSION AND CLINICAL RELEVANCE: Testing using a line immunoassay allows for qualitative analyses of different immune responses to various antigens used as probes. In our study, > 26% of the dogs displayed discrepant results with regard to VlsE and C6, the two antigens considered specific for Borrelia burgdorferi infection. To confirm or rule out infection, the results of several band patterns, thought to be specific for infection, need to be taken into consideration. PMID- 28905982 TI - Vector-borne diseases in cats in Germany. AB - Vector-borne diseases (VBDs) are caused by a wide range of pathogens, which are transmitted by a variety of vectors, such as ticks and fleas. As a result of climate changes, more vector-borne diseases are becoming endemic in Germany, not only in dogs, but also in cats. For some of the pathogens prevalence data still need to be investigated in Germany. However, natural infections with Bartonella, Anaplasma, haemotropic Mycoplasma and Borrelia species have already been described in German cats. Clinical relevance of these pathogens is not fully understood, and it is still unknown, why most infected cats stay asymptomatic and which predisposing factors contribute to the development of clinical signs in cats. Moreover, there is a risk of zoonotic transmission for some of the pathogens, e. g., for some Bartonella spp. infections that are associated with cat scratch disease in humans. Due to the increasing number of VBDs in cats in Germany, preventive measures, such as the use of acaricides and insecticides, should be performed on a regular base in order to reduce the risk of these infections. PMID- 28905983 TI - [Occurrence of Ehrlichia canis in dogs living in Germany and comparison of direct and indirect diagnostic methods]. AB - OBJECTIVE: To study the occurrence of Ehrlichia (E.) canis in dogs living in Germany and evaluate the possibilities and limits of direct and indirect diagnostic methods. MATERIAL AND METHODS: The first part of the study was a retrospective analysis of routine samples, which had been examined for E. canis antibodies using an indirect immunofluorescence antibody test (IFAT). The examination was part of a laboratory profile for the detection of travel-related diseases (travel disease profile) or was performed on an individual basis. In the second part, samples which were examined within a travel disease profile, including E. canis antibodies, were further evaluated for E. canis DNA by a polymerase chain reaction (PCR). Medical histories were obtained of E. canis positive dogs (animals which were positive in IFAT and/or PCR) and for a part of the negative animals. RESULTS: For 2015, 11.8% of 12220 samples had antibodies for E. canis. Dogs, which were examined with a travel disease profile, displayed antibodies in 5.6% cases of 1172 animals (investigation period February to March 2016). Of the E. canis-positive dogs (n = 67), 91% were positive with only the IFAT, 7.5% with the IFAT and PCR and 1.5% were only positive by PCR. Anamnesis showed that particularly imported dogs without symptoms were controlled for travel diseases during their first year in Germany. CONCLUSION AND CLINICAL RELEVANCE: Although endemic E. canis infections play a minor role in Germany, infections with this pathogen are still of importance in this country, particularly because of the import of dogs. Therefore, a medical history helps in early ehrlichiosis diagnosis and to start an adequate treatment. Pathogen detection in imported E. canis-seropositive dogs, which often did not display clinical symptoms in this study, was frequently negative in blood samples by PCR. The diagnostic method should be chosen depending on the disease phase and the underlying question (symptoms or preventive screening). PMID- 28905984 TI - Fetal Intra-abdominal Umbilical Vein Aneurysm. AB - Importance: Fetal umbilical vein aneurysm is an uncommon anomaly that accounts for approximately 4% of umbilical cord abnormalities. The rate of intrauterine fetal death is reported to be approximately 4% to 5%, higher than the background rate of 0.7% that is generally reported during pregnancy. Objective: The aim of this study was to review the pathophysiology, diagnosis, and clinical management of fetal umbilical vein aneurysm. Evidence Acquisition: Advances in high resolution ultrasound combined with color Doppler and 3-dimensional rendering have contributed to an increased understanding of the fetal venous circulation in recent years. Results: When the diagnosis of umbilical vein aneurysm is made, the patient should undergo a detailed ultrasound evaluation of the fetal anatomy, including fetal echocardiography, to exclude associated anomalies. Amniocentesis should be offered when other anomalies are found. Patients should be informed about the potential for an unfavorable outcome of pregnancy and should undergo close ultrasound surveillance to assess the size of the aneurysm, as well as any evidence of thrombosis or signs of hydrops. Conclusions: The main prognostic feature associated with a poor outcome of umbilical vein aneurysm seems to be the presence of other anomalies. Early diagnosis is associated with a somewhat worse prognosis, and most fetal deaths have been observed between 27 and 30 weeks of gestation. In the third trimester, it is reasonable to perform serial ultrasound examinations to assess fetal growth, the size of the aneurysm, and the blood flow pattern within the aneurysm. PMID- 28905985 TI - It Is Time for Routine Screening for Perinatal Mood and Anxiety Disorders in Obstetrics and Gynecology Settings. AB - Importance: Women are 2 to 3 times more likely than men to experience depression in their lifetime, and the greatest risk occurs during the reproductive years. As an obstetrics and gynecology physician or provider, you will likely encounter women who are at risk of development or relapse of a mental disorder during this vulnerable time. Objective: The aim of this review is to examine theory and research on mood and anxiety disorders during the perinatal period with an emphasis on screening recommendations. Evidence Acquisition: A PubMed and PsycINFO search for English-language publications about perinatal mood and anxiety disorders and screening was performed and included studies on subtopics. Results: The literature reviewed suggests that perinatal mood and anxiety symptoms are prevalent and have significant consequences, and best practices for early detection are through routine depression and anxiety screening in the obstetrics setting. This includes overcoming barriers to care and use of liaison services to potentially reduce risk. Conclusions and Relevance: High-quality prenatal care systems should develop the capacity for depression and anxiety risk assessment and treatment. Providers should routinely screen using validated screening tools, provide maternal mental health education, and be aware of the various medical, psychological, and complementary approaches for treating mood and anxiety disorders, to best guide and refer patients. The use of this practice will increase the quality of life in pregnant women with depression and anxiety and may help to reduce the likelihood of adverse birth outcomes, postpartum mental health problems, and adverse effects on offspring. PMID- 28905986 TI - Gearing up for the Pearl Anniversary: AGNP Set to Hold its 30th Meeting in Munich October 4-6, 2017. Overview and Abstracts PMID- 28905988 TI - Lack of Bioequivalence Among Low-dose, Enteric-coated Aspirin Preparations. AB - Low-dose aspirin (75 mg or 81 mg) is considered to be the lowest effective dose for cardiovascular protection; however, the use of enteric preparations has created a source of variability in bioavailability. As part of regulatory requirements, we carried out bioequivalence tests for two 75 mg enteric-coated aspirin preparations (Caprin and Protek) using Nu-Seals 75 mg aspirin as the comparator. The primary endpoint was serum thromboxane levels after 14 days of treatment. Protek failed to meet bioequivalence, as it was significantly less effective than Nu-Seals. In contrast, Caprin was not bioequivalent with Nu-Seals but as it was more effective it was granted approval. However, 75 mg plain aspirin was found to be more effective than Nu-Seals at inhibiting serum thromboxane production. Thus, there is significant variation in the ability of low-dose aspirin preparations to inhibit serum thromboxane production. PMID- 28905987 TI - Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer. AB - Small cell lung cancer (SCLC) has an extremely poor prognosis and methods of improving chemotherapeutic intervention are much sought after. A promising approach lies in inhibiting the tumour-associated enzyme, carbonic anhydrase IX (CA IX), which supports tumour cell survival. The aim of this study was to assess the potential of CA IX inhibition using 4-(3'-(3",5"-dimethylphenyl)ureido)phenyl sulfamate (S4), for the treatment of human SCLC alone and in combination with cisplatin chemotherapy. Treating SCLC cell lines (DMS 79 and COR-L24) with 100 uM S4 reduced viability in vitro and enhanced cell death when combined with 7 uM cisplatin, most prominently under hypoxic conditions (0.1% O2 ). When either cell line was grown as a xenograft tumour in nude mice, intraperitoneal injection of 50 mg/kg S4 alone and in combination with 3 mg/kg cisplatin led to significantly reduced tumour growth. Combination therapy was superior to single agents and response was greatly accentuated when administering repeated doses of cisplatin in DMS 79 tumours. The mechanism of therapeutic response was investigated in vitro, where S4 treatment increased apoptosis under hypoxic conditions in both DMS 79 and COR-L24 cells. DMS 79 tumours receiving S4 in vivo also displayed increased apoptosis and necrosis. Combining S4 with cisplatin reduced both the area of hypoxia and CA IX-positive cells within tumours and increased necrosis, suggesting hypoxia-specific targeting. This study presents a novel, targeted approach to improving current SCLC therapy via inhibition of CA IX, which enhances apoptosis and significantly inhibits xenograft tumour growth when administered alone and in combination with cisplatin chemotherapy. PMID- 28905989 TI - Assessment of futility in out-of-hospital cardiac arrest. AB - BACKGROUND: Our aim was to evaluate the impact of futile resuscitation attempts to the outcome calculations of attempted resuscitation in out-of-hospital cardiac arrest (OHCA). Defined as partial resuscitations, we focused on a subgroup of patients in whom cardiopulmonary resuscitation (CPR) was initiated, but further efforts were soon abandoned due to evidence of futility. METHODS: We conducted this study using the Utstein template during a 12-month study period. We compared the event characteristics between full and partial resuscitation attempts and determined the incidence, survival and neurological outcome. RESULTS: Emergency Medical Services (EMS) attended a total of 314 OHCA cases. In 34 cases, resuscitation was not attempted due to futility. Seventy-four cases were partial resuscitation attempts where resuscitation was soon discontinued due to dismal prognostic factors. Partial attempts were associated with an unwitnessed OHCA, prolonged downtime, end-stage malignant disease, multiple trauma, asystole or pulseless electrical activity as the initial rhythm, and a first responding unit being the first unit on the scene (P < 0.05, respectively). The calculation of survival to hospital discharge rate was 14% and increased 5% when partial resuscitation attempts were excluded from the analysis. Seventy-four percentage had a Cerebral Performance Category 1-2 at hospital discharge. Shockable initial rhythm, public location and bystander CPR had a positive impact on survival. CONCLUSIONS: Resuscitative efforts were considered futile in 11% of cases and resuscitation was discontinued due to evidence of futility in additional 24% cases based on additional information. Terminating resuscitation should be identified as a separate subgroup of OHCA cases to better reflect the outcome. PMID- 28905990 TI - The mTOR kinase inhibitor everolimus synergistically enhances the anti-tumor effect of the Bruton's tyrosine kinase (BTK) inhibitor PLS-123 on Mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment. Here, we have developed a novel irreversible BTK inhibitor, PLS-123, that has more potent and selective anti-tumor activity than ibrutinib in vitro and in vivo. Using in vitro screening, we discovered that the combination of PLS-123 and the mammalian target of rapamycin (mTOR) inhibitor everolimus exert synergistic activity in attenuating proliferation and motility of MCL cell lines. Simultaneous inhibition of BTK and mTOR resulted in marked induction of apoptosis and cell cycle arrest in the G1 phase, which were accompanied by upregulation of pro-apoptotic proteins (cleaved Caspase-3, cleaved PARP and Bax), repression of anti-apoptotic proteins (Mcl-1, Bcl-xl and XIAP), and downregulation of regulators of the G1/S phase transition (CDK2, CDK4, CDK6 and Cyclin D1). Gene expression profile analysis revealed simultaneous treatment with these agents led to inhibition of the JAK2/STAT3, AKT/mTOR signaling pathways and SGK1 expression. Finally, the anti-tumor and pro-apoptotic activities of combination strategy have also been demonstrated using xenograft mice models. Taken together, simultaneous suppression of BTK and mTOR may be indicated as a potential therapeutic modality for the treatment of MCL. PMID- 28905992 TI - The vertebrate heart: an evolutionary perspective. AB - Convergence is the tendency of independent species to evolve similarly when subjected to the same environmental conditions. The primitive blueprint for the circulatory system emerged around 700-600 Mya and exhibits diverse physiological adaptations across the radiations of vertebrates (Subphylum Vertebrata, Phylum Chordata). It has evolved from the early chordate circulatory system with a single layered tube in the tunicate (Subphylum Urchordata) or an amphioxus (Subphylum Cephalochordata), to a vertebrate circulatory system with a two chambered heart made up of one atrium and one ventricle in gnathostome fish (Infraphylum Gnathostomata), to a system with a three-chambered heart made up of two atria which maybe partially divided or completely separated in amphibian tetrapods (Class Amphibia). Subsequent tetrapods, including crocodiles and alligators (Order Crocodylia, Subclass Crocodylomorpha, Class Reptilia), birds (Subclass Aves, Class Reptilia) and mammals (Class Mammalia) evolved a four chambered heart. The structure and function of the circulatory system of each individual holds a vital role which benefits each species specifically. The special characteristics of the four-chamber mammalian heart are highlighted by the peculiar structure of the myocardial muscle. PMID- 28905991 TI - Target of rapamycin signaling orchestrates growth-defense trade-offs in plants. AB - Plant defense to microbial pathogens is often accompanied by significant growth inhibition. How plants merge immune system function with normal growth and development is still poorly understood. Here, we investigated the role of target of rapamycin (TOR), an evolutionary conserved serine/threonine kinase, in the plant defense response. We used rice as a model system and applied a combination of chemical, genetic, genomic and cell-based analyses. We demonstrate that ectopic expression of TOR and Raptor (regulatory-associated protein of mTOR), a protein previously demonstrated to interact with TOR in Arabidopsis, positively regulates growth and development in rice. Transcriptome analysis of rice cells treated with the TOR-specific inhibitor rapamycin revealed that TOR not only dictates transcriptional reprogramming of extensive gene sets involved in central and secondary metabolism, cell cycle and transcription, but also suppresses many defense-related genes. TOR overexpression lines displayed increased susceptibility to both bacterial and fungal pathogens, whereas plants with reduced TOR signaling displayed enhanced resistance. Finally, we found that TOR antagonizes the action of the classic defense hormones salicylic acid and jasmonic acid. Together, these results indicate that TOR acts as a molecular switch for the activation of cell proliferation and plant growth at the expense of cellular immunity. PMID- 28905994 TI - MicroRNA-324-5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling. AB - Chromosome 17p deletions are present in 10% of patients with newly diagnosed multiple myeloma (MM), and are associated with inferior prognosis. miR-324-5p is located on chromosome 17p, and shows diverse functions in different types of cancers. However, its role in MM is largely unknown. Here we found the expression of miR-324-5p was decreased in MM, especially in del(17p) MM. In contrast, the expression of hedgehog (Hh) signaling components was elevated, indicating a correlation between miR-324-5p and Hh signaling in MM. Hh signaling is important for the pathogenesis of MM and maintenance of MM stem cell compartment. Indeed, overexpression of miR-324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. Moreover, miR-324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Consistent results were obtained in vivo. Finally, miR-324-5p overcame the protective effect of bone marrow stromal cells on MM cells. Taken together, our data demonstrate that miR-324-5p is essential for MM pathogenesis and downregulation of miR-324-5p is a novel mechanism of Hh signaling activation in MM. Therefore, targeting miR-324-5p provides a potential therapeutic strategy for MM. PMID- 28905993 TI - Overexpression of F-box only protein 31 predicts poor prognosis and deregulates p38alpha- and JNK-mediated apoptosis in esophageal squamous cell carcinoma. AB - F-box only protein 31 (FBXO31), a subunit of the Skp1-Cul1-F box ubiquitin ligase, plays a crucial role in DNA damage response and tumorigenesis. Yet its expression and function vary in different types of human cancer. The expression of FBXO31 in esophageal squamous cell carcinoma (ESCC) and its association with clinicopathological features is not well studied. The underlying mechanism by which deregulated FBXO31 contributes to ESCC tumorigenesis is largely unknown. By immunohistochemical analysis of a tissue microarray containing 85 cases of ESCC and matched adjacent noncancerous tissue and an additional 10 cases of ESCC tissue samples, we found that FBXO31 was overexpressed in ESCC, and that its expression was significantly correlated with histological grade (p = 0.04) and clinical stage (p = 0.022). Higher expression of FBXO31 was associated with poor prognosis in univariate (p = 0.013) and multivariate (p = 0.014) analyses. We found that FBXO31 functioned as an antiapoptotic molecule in ESCC cells exposed to different types of genotoxic stress. Knockdown of FBXO31 inhibited serum starved cell viability and decreased tumorigenicity of ESCC cells. In addition, the antiapoptotic effects of FBXO31 were associated with deactivation of stress induced MAPK p38alpha and JNK. Furthermore, in vitro and in vivo data showed that silencing of FBXO31-sensitized ESCC cells and tumors to cisplatin treatment. Taken together, in addition to revealing that FBXO31 is an independent prognostic marker for ESCC, our findings substantiate a novel regulatory role of FBXO31 in tumorigenesis and drug resistance of ESCC. PMID- 28905995 TI - Leptomeningeal collateral status predicts outcome after middle cerebral artery occlusion. AB - OBJECTIVES: Perfusion through leptomeningeal collateral vessels is a likely pivotal factor in the outcome of stroke patients. We aimed to investigate the effect of collateral status on outcome in a cohort of unselected, consecutive stroke patients with middle cerebral artery occlusion undergoing reperfusion therapy. MATERIALS AND METHODS: This retrospectively planned analysis was passed on prospectively collected data from 187 consecutive patients with middle cerebral artery occlusion admitted within 4.5 hours to one center and treated with intravenous thrombolysis alone (N = 126), mechanical thrombectomy alone (N = 5), or both (N = 56) from May 2009 to April 2014. Non-contrast CT (NCCT) and computed tomography angiography (CTA) were provided on admission and NCCT repeated at 24 hours. Collateral status was assessed based on the initial CTA. Hemorrhagic transformation was evaluated on the 24-hour NCCT and according to European Cooperative Acute Stroke Study (ECASS) criteria. Modified Rankin Scale score was assessed at 90 days, and mortality at 1 year. RESULTS: At 90 days, median (IQR) modified Rankin Scale score in patients with poor collateral status was 4 (3-6) compared to 2 (1-4) in patients with good collateral status (P < .0001). Patients with poor collateral status were less likely to achieve a good 90-day outcome (modified Rankin Scale score 0-2) (Adjusted odds ratio 0.27, 95% CI: 0.09-0.86). During the first year, 40.9% of patients with poor collateral status died vs 18.2% of the remaining population (P = .001). CONCLUSIONS: Leptomeningeal collateral status predicts functional outcome, mortality, and hemorrhagic transformation following middle cerebral artery occlusion. PMID- 28905996 TI - Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity. AB - The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell neurite complexes, Meissner-like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20+ , chromogranin A+ and synaptophisin+ ) Merkel cells. Most of them were in close contact with Piezo2- nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2+ , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans. PMID- 28905997 TI - Children with neurodevelopmental disorders and disabilities: a population-based study of healthcare service utilization using administrative data. AB - AIM: The aim of this study was to identify children with neurodevelopmental disorders and disabilities (NDD/D) and compare their healthcare service utilization to children without NDD/D using provincial linked administrative data. METHOD: The sample included children aged 6 to 10 years (n=183 041), who were registered with the British Columbia Medical Services Plan. Diagnostic information was used for the identification and classification of NDD/D in six functional domains. Healthcare service utilization included outcomes based on physician claims, prescription medication use, and hospitalization. RESULTS: Overall, 8.3% of children were identified with NDD/D. Children with NDD/D had higher healthcare service utilization rates than those without NDD/D. Effect sizes were: very large for the number of days a prescription medication was dispensed; large for the number of prescriptions; medium for the number of physician visits, different specialists visited, number of different prescription medications, and ever hospitalized; and small for the number of laboratory visits, X-ray visits, and number of days hospitalized. INTERPRETATION: The findings have policy implications for service and resource planning. Given the high use of psychostimulants, specialized services for both NDD/D and psychiatric conditions may be the most needed services for children with NDD/D. Future studies may examine patterns of physician behaviours and costs attributable to healthcare service utilization for children with NDD/D. WHAT THIS PAPER ADDS: Children with neurodevelopmental disorders and disabilities (NDD/D) have higher healthcare service utilization than those without. Based on provincial population based linked administrative health data, a sizeable number of children are living with NDD/D. Given the high use of psychostimulants, specialized services for children with both NDD/D and psychiatric conditions may be the most needed services for children with NDD/D. PMID- 28905998 TI - Mast cells and sphingosine-1-phosphate underlie prelesional remodeling in a mouse model of eczema. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic skin inflammation that affects children and adults worldwide, but its pathogenesis remains ill-understood. METHODS: We show that a single application of OVA to mouse skin initiates remodeling and cellular infiltration of the hypodermis measured by a newly developed computer-aided method. RESULTS: Importantly, we demonstrate that skin mast cell (MC) activation and local sphingosine-1-phosphate (S1P) are significantly augmented after OVA treatment in mice. Deficiency in sphingosine kinase (SphK)1, the S1P-producing enzyme, or in MC, remarkably mitigates all signs of OVA-mediated remodeling and MC activation. Furthermore, skin S1P levels remain unchanged in MC-deficient mice exposed to OVA. LPS-free OVA does not recapitulate any of the precursor signs of AD, supporting a triggering contribution of LPS in AD that, per se, suffice to activate local MC and elevate skin S1P. CONCLUSION: We describe MC and S1P as novel pathogenic effectors that initiate remodeling in AD prior to any skin lesions and reveal the significance of LPS in OVA used in most studies, thus mimicking natural antigen (Ag) exposure. PMID- 28905999 TI - Validation of patient-reported global severity of atopic dermatitis in adults. AB - BACKGROUND: Atopic dermatitis (AD) is associated with a heterogeneous presentation and clinical course. There is a lack of simple and validated severity assessments that are feasible for clinical practice and epidemiological research. OBJECTIVES: We sought to validate patient-reported global AD severity in adults. METHODS: We performed a prospective dermatology practice-based study using questionnaires and evaluation by a dermatologist (n = 265). RESULTS: At baseline and follow-up, patient-reported global AD severity significantly correlated with oSCORAD (Spearman rho = 0.56 and 0.49), SCORAD (0.64 and 0.56), EASI (0.56 and 0.50), BSA (0.52 and 0.45), NRS-itch (0.60 and 0.53), POEM (0.50 and 0.48), and DLQI (0.50 and 0.49) (P < .0001 for all). Patient-reported moderate and severe AD vs mild AD were associated with significantly higher oSCORAD, SCORAD, EASI, BSA, NRS-itch, POEM, and DLQI (P < .0001 for all). There was moderate concordance between patient-reported AD severity (mild, moderate, and severe) and previously developed severity strata for oSCORAD (kappa = 0.39), SCORAD (kappa = 0.47), EASI (kappa = 0.37), NRS-itch (kappa = 0.49), POEM (kappa = 0.37), and DLQI (kappa = 0.40). Among patients with severe disease at baseline, those who reported mild or moderate disease on follow-up had significantly greater absolute reductions of oSCORAD (-23.4/-9.7/-1.8), SCORAD (-33.0/-13.2/ 2.3), EASI (-17.1/-9.8/-3.2), BSA (-46%/-15%/-4%), NRS-itch (-5/-2/0), POEM (-5/ 2/0), and DLQI (-8/-6/-1) than those who continued to report severe disease (Kruskal-Wallis, P <= .0003 for all). CONCLUSIONS: Patient-reported AD severity appears to be sufficiently valid for assessing AD severity in the clinical and epidemiological setting. PMID- 28906000 TI - A phosphoarray platform is capable of personalizing kinase inhibitor therapy in head and neck cancers. AB - Tyrosine kinase inhibitors are effective treatments for cancers. Knowing the specific kinase mutants that drive the underlying cancers predict therapeutic response to these inhibitors. Thus, the current protocol for personalized cancer therapy involves genotyping tumors in search of various driver mutations and subsequently individualizing the tyrosine kinase inhibitor to the patients whose tumors express the corresponding driver mutant. While this approach works when known driver mutations are found, its limitation is the dependence on driver mutations as predictors for response. To complement the genotype approach, we hypothesize that a phosphoarray platform is equally capable of personalizing kinase inhibitor therapy. We selected head and neck squamous cell carcinoma as the cancer model to test our hypothesis. Using the receptor tyrosine kinase phosphoarray, we identified the phosphorylation profiles of 49 different tyrosine kinase receptors in five different head and neck cancer cell lines. Based on these results, we tested the cell line response to the corresponding kinase inhibitor therapy. We found that this phosphoarray accurately informed the kinase inhibitor response profile of the cell lines. Next, we determined the phosphorylation profiles of 39 head and neck cancer patient derived xenografts. We found that absent phosphorylated EGFR signal predicted primary resistance to cetuximab treatment in the xenografts without phosphorylated ErbB2. Meanwhile, absent ErbB2 signaling in the xenografts with phosphorylated EGFR is associated with a higher likelihood of response to cetuximab. In summary, the phosphoarray technology has the potential to become a new diagnostic platform for personalized cancer therapy. PMID- 28906001 TI - Overcoming interference of plasma phospholipids using HybridSPE for the determination of trimetazidine by UPLC-MS/MS. AB - An improved, precise and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the quantification of trimetazidine, using trimetazidine-d8 as the internal standard (IS). Interference owing to plasma phospholipids during sample preparation was overcome using a hybrid solid-phase extraction-phospholipid ultra cartridge. The mean extraction recovery of trimetazidine (98.66%) and trimetazidine-d8 (97.63%) from spiked plasma was consistent and reproducible. Chromatographic analysis was performed on a UPLC Ethylene Bridged Hybrid (BEH) C18 (50 * 2.1 mm, 1.7 MUm) column with isocratic elution using acetonitrile-5 mm ammonium formate, pH 3.5 (40:60, v/v) as the mobile phase. The parent -> product ion transitions for trimetazidine (m/z 267.1 -> 181.1) and trimetazidine-d8 (m/z 275.2 -> 181.1) were monitored on a triple quadrupole mass spectrometer with electrospray ionization functioning in the positive multiple reaction monitoring mode. The linearity of the method was established in the concentration range of 0.05-100 ng/mL for trimetazidine. The intra-batch and inter-batch accuracy and precision (CV) were 97.3-103.1 and 1.7-5.3%, respectively. Qualitative and quantitative assessment of matrix effect showed no interference of endogenous/exogenous components. The developed method was used to measure plasma trimetazidine concentration for a bioequivalence study with 12 healthy subjects. PMID- 28906002 TI - Anti-inflammatory activities and glycerophospholipids metabolism in KLA stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum. AB - Alpinia officinarum is used for its anti-inflammatory activity historically in China. Diarylheptanoids isolated from A. officinarum play important biological roles in the prevention and treatment of inflammatory disorders. Seven diarylheptanoids (1-7) were isolated from A. officinarum. The cell viabilities and anti-inflammatory activities of diarylheptanoids were evaluated by MTT assay and tumor necrosis factor-alpha production in Kdo2-lipid A-stimulated RAW 264.7 cells in vitro. The relationships between their anti-inflammatories and structure activities are discussed. The results indicated that compounds 1 and 3-7 had significant anti-inflammatory activities. The relationships between inflammation and phospholipids metabolism were elucidated by multivariate data analysis. Twenty-two potential biomarkers were identified in inflammatory group vs. blank group, and 11 potential biomarkers were identified for inflammatory group vs. drug-treatment groups. Ten common phospholipids were characterized. On the basis of a previous study in our laboratory, we found that phosphatidylethanolamine (18:0/18:1) might be the important glycerophospholipid biomarker in inflammation. In this study, we firstly combined anti-inflammatory activities and glycerophospholipids changes of traditional Chinese medicine. This work suggests that the anti-inflammatory activities of diarylheptanoids might be significantly related to glycerophospholipids and could provide a useful database for investigating the anti-inflammatory effects of traditional Chinese medicine. PMID- 28906003 TI - Inclusion of MERS-spike protein ELISA in algorithm to determine serologic evidence of MERS-CoV infection. AB - The Centers for Disease Control and Prevention (CDC) algorithm for detecting presence of serum antibodies against Middle East Respiratory Syndrome coronavirus (MERS-CoV) in subjects with potential infections with the virus has included screening by indirect ELISA against recombinant nucleocapsid (N) protein and confirmation by immunofluorescent staining of infected monolayers and/or microneutralization titration. Other international groups include indirect ELISA assays using the spike (S) protein, as part of their serological determinations. In the current study, we describe development and validation of an indirect MERS CoV S ELISA to be used as part of our serological determination for evidence of previous exposure to the virus. PMID- 28906004 TI - Acute myeloid leukaemia (FAB AML-M4Eo) with cryptic insertion of cbfb resulting in cbfb-Myh11 fusion. AB - Inv(16)(p13q22) and t(16;16)(p13;q22) are cytogenetic hallmarks of acute myelomonoblastic leukaemia, most of them associated with abnormal bone marrow eosinophils [acute myeloid leukaemia French-American-British classification M4 with eosinophilia (FAB AML-M4Eo)] and a relatively favourable clinical course. They generate a 5'CBFB-3'MYH11 fusion gene. However, in a few cases, although RT PCR identified a CBFB-MYH11 transcript, normal karyotype and/or fluorescent in situ hybridization (FISH) analyses using commercially available probes are found. We identified a 32-year-old woman with AML-M4Eo and normal karyotype and FISH results. Using two libraries of Bacterial Artificial Chromosome clones on 16p13 and 16q22, FISH analyses identified an insertion of 16q22 material in band 16p13, generating a CBFB-MYH11 type A transcript. Although very rare, insertions should be searched for in patients with discordant cytological and cytogenetic features because of the therapeutic consequences. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28906005 TI - Group A rotaviruses circulating prior to a national immunization programme in Nigeria: Clinical manifestations, high G12P[8] frequency, intra-genotypic divergence of VP4 and VP7. AB - Nigeria having approximately 50 000 Rotavirus A (RVA) deaths annually is yet to introduce RVA vaccine into routine national immunization; therefore surveillance of RVA strains circulating before vaccine introduction is essential in evaluating impact of the intervention. Stool samples and sociodemographic data of diarrhoeic children, <5 years were collected between August 2012 and December 2013. While a high prevalence of RVA infection (47.6%; 49/103) was observed by quantitative reverse transcription real time PCR, only 25% (26/103) had high RVA genome concentrations and were antigen positive. G and P types were obtained for 31 and 37 samples respectively. G12P[8] strains were predominant (30.6%; 16/31); Other genotypes found included G9, G3, G2 and P[4], P[6], P[8]. A G12 + G2/P[8] + P[6] mixed infection was detected. The P[8] genotype showed divergence with strains distributed in lineage III and IV. Compared to the vaccines, changes in antigenic sites of VP8* and VP7 were found. The finding of the G2P[6] genotype combination and emergence of G12 strains support observations in most of the recent RVA studies from Africa. P[6] is common in many African countries, in contrast to countries in Europe and the Americas. In conclusion, this study shows the circulation of other RVA genotypes compared to the common RVA genotypes in Nigeria. PCR results should be interpreted with caution to avoid significant bias from samples with low RVA genome concentrations. These findings provide important information on the detection and molecular epidemiology of RVA prior to vaccination and contribute as a baseline for future evaluations after possible vaccine introduction. PMID- 28906006 TI - Prevalence of anal, oral, penile and urethral Human Papillomavirus in HIV infected and HIV uninfected men who have sex with men. AB - Aims of the study were to evaluate Human Papillomavirus (HPV) and type-specific prevalence in four anatomical sites in HIV infected men who have sex with men (MSM) compared with HIV uninfected MSM. Participants were recruited among the attendees of Infectious Diseases Clinics in Central Italy. A trained medical practitioner collected by interview sociodemographic data and information on medical history, sexual behavior, and drug use. Swabs from anal canal, oral cavity, urethral mucosa, and coronal sulcus were tested for HPV DNA and genotyping. Ninety MSM were enrolled, 45 subjects within each group. Overall, 48.9% MSM were HPV positive and prevalence was higher in HIV infected men (60.0% vs 37.8%, P = 0.035). HPV at multiple anatomic sites occurred in 59.1% MSM, with 34.1% and 22.7% at two and three sites, respectively. Prevalence of anal, coronal sulcus, oral, and urethral HPV was 96.3%, 37%, 21.6%, and 18.5% in HIV infected MSM, and 70.6%, 70.6%, 29.4%, and 23.5% among HIV uninfected. A similar proportion of HIV infected and uninfected MSM (59.2% and 58.8%) carried at least one high-risk genotype. Prevalence of types covered by nonavalent vaccine was 77.8% in HIV infected compared with 82.3% in HIV uninfected MSM. HPV 58 and 16 were mostly detected in HIV positive (43.7% and 31.2%) and negative MSM (50.0% and 40.0%). HPV detection rate underlined the high vulnerability of MSM to acquire multisite infections, characterized by various genotype combinations. Since nonavalent vaccine could have prevented 80% of HPV infections, study findings support the implementation of vaccination programs among MSM. PMID- 28906007 TI - Intergrated metabonomic study of the effects of Guizhi Fuling capsule intervention on primary dysmenorrheal using RP-UPLC-MS complementary with HILIC UPLC-MS technique. AB - Guizhi Fuling capsule (GFC), developed from the traditional Chinese prescription of Guizhi Fuling Wan, has been commonly used for the treatment of primary dysmenorrhea (PD). However, the intervention effective mechanism in vivo has not been well elucidated. In this study, an integrated plasma metabonomic strategy based on RP-UPLC-MS coupled with HILIC-UPLC-MS technique has been developed to investigate the global therapeutic effects and intervention mechanisms of GFC on dysmenorrhea rats induced by oxytocin. The 20 potential biomarkers were identified and primarily related to sphingolipid metabolism, steroid hormone biosynthesis, glycerophospholipid metabolism, amino acid metabolism, lipid metabolism and energy metabolism. The results showed that the GFC has therapeutic effects on rats with dysmenorrhea via the regulation of multiple metabolic pathways. Some new potential biomarkers associated with primary dysmenorrhea such as phenylalanine, tryptophan, taurine, carnitine, betaine, creatine and creatinine have been discovered in this study for the first time. This study provides a metabonomic platform based on RP-UPLC-MS complementary to HILIC-UPLC MS technique to investigate both nonpolar and polar compounds, so as to get a more comprehensive metabolite information to yield insight into the pathophysiology of PD and assessing the efficacy of GFC on PD rats. PMID- 28906008 TI - Role of macrophage migration inhibitory factor (MIF) in the effects of oxidative stress on human retinal pigment epithelial cells. AB - Proliferative vitreoretinopathy (PVR) is the major cause of treatment failure in individuals who undergo surgery for retinal detachment. The epithelial mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells contributes to the pathogenesis of PVR. Oxidative stress is thought to play a role in the progression of retinal diseases including PVR. We have now examined the effects of oxidative stress on the EMT and related processes in the human RPE cell line. We found that H2 O2 induced the contraction of RPE cells in a three dimensional collagen gel. Analysis of a cytokine array revealed that H2 O2 specifically increased the release of macrophage migration inhibitory factor (MIF) from RPE cells. Reverse transcription-polymerase chain reaction and immunoblot analyses showed that H2 O2 increased the expression of MIF in RPE cells. Immunoblot and immunofluorescence analyses revealed that H2 O2 upregulated the expression of alpha-SMA and vimentin and downregulated that of ZO-1 and N cadherin. Consistent with these observations, the transepithelial electrical resistance of cell was reduced by exposure to H2 O2 . The effects of oxidative stress on EMT-related and junctional protein expression as well as on transepithelial electrical resistance were inhibited by antibodies to MIF, but they were not mimicked by treatment with recombinant MIF. Finally, analysis with a profiling array for mitogen-activated protein kinase signalling revealed that H2 O2 specifically induced the phosphorylation of p38 mitogen-activated protein kinase. Our results thus suggest that MIF may play a role in induction of the EMT and related processes by oxidative stress in RPE cells and that it might thereby contribute to the pathogenesis of PVR. Proliferative vitreoretinopathy is a major complication of rhegmatogenous retinal detachment, and both oxidative stress and induction of the EMT in RPE cells are thought to contribute to the pathogenesis of this condition. We have now examined the effects of oxidative stress on the EMT and related processes in the human RPE cell line ARPE19. Our results thus implicate MIF in induction of the EMT and related processes by oxidative stress in RPE cells and the regulated expression of EMT markers. They further suggest that MIF may play an important role in the pathogenesis of PVR. PMID- 28906009 TI - Does Lesion Size Affect the Value of Shear Wave Elastography for Differentiating Between Benign and Malignant Thyroid Nodules? AB - OBJECTIVES: We aimed to investigate the diagnostic performance of shear wave elastography (SWE) combined with conventional ultrasonography (US) for differentiating between benign and malignant thyroid nodules of different sizes. METHODS: A total of 445 thyroid nodules from 445 patients were divided into 3 groups based on diameter (group 1, <= 10 mm; group 2, 10-20 mm; and group 3, > 20 mm). The mean elasticity index of the whole lesion was automatically calculated, and the threshold for differentiation between benign and malignant nodules was constructed by a receiver operating characteristic curve analysis. Diagnostic performances of conventional US and SWE were compared by using pathologic results as reference standards. RESULTS: The mean elasticity was significantly higher in malignant versus benign nodules for all size groups. The differences in mean elasticity in the size groups were not statistically significant for malignant or benign nodules. The specificity of US combined with SWE for group 1 was significantly higher than that for groups 2 and 3 (77.8% versus 62.9% and 53.3%; P < .05), and compared with group 1, the sensitivity was significantly higher for groups 2 and 3 (92.4% and 94.3% versus 80.7%; P < .05). When SWE was added, the specificity increased and the sensitivity and diagnostic accuracy decreased for group 1, and the sensitivity increased and the specificity decreased for groups 2 and 3; however, the differences were not significant. CONCLUSIONS: Combined with SWE, US yielded higher specificity for nodules of 10 mm and smaller and higher sensitivity for nodules larger than 10 mm. PMID- 28906010 TI - Serial changes in liver stiffness and controlled attenuation parameter following direct-acting antiviral therapy against hepatitis C virus genotype 1b. AB - Little information is available on the impact of direct-acting antiviral (DAA) therapy on changes in liver fibrosis and steatosis. Liver stiffness (LS) and controlled attenuation parameter (CAP) values were evaluated using transient elastography. The study subjects were 214 elderly patients infected with HCV genotype 1b who received 24-week daclatasvir and asunaprevir dual therapy. All patients of this retrospective study had no hepatocellular carcinoma before and during DAA therapy. LS and CAP were assessed before treatment (baseline), at end of treatment (EOT), and at 24, 48, 72 weeks (W) after EOT. The rate of sustained viral response (SVR) by daclatasvir and asunaprevir therapy was 91%. LS values for the entire group correlated with Fib-4 index at baseline (r = 0.565, P < 0.001). LS in both chronic hepatitis group (Fib-4 index <3.25) and cirrhosis group (Fib-4 index >=3.25) decreased significantly at each time point compared with baseline (P < 0.001). Especially, a larger decrease in LS from baseline to EOT was seen in the cirrhosis group than chronic hepatitis group (P < 0.001). LS was also significantly lower in the SVR group at EOT, 24W, 48W, 72W compared with baseline (P < 0.001). Even in the non-SVR group, LS tended to be lower at EOT (P = 0.039), 24W (P = 0.009), 48W (P = 0.475), 72W (P = 0.033) compared with baseline. CAP increased significantly following the treatment from baseline to 48W post-EOT (P = 0.018). Our results showed significant improvement in LS in response to daclatasvir and asunaprevir dual therapy. In the other hand, there was a tendency that CAP increased from baseline. PMID- 28906012 TI - PacBio metabarcoding of Fungi and other eukaryotes: errors, biases and perspectives. AB - Second-generation, high-throughput sequencing methods have greatly improved our understanding of the ecology of soil microorganisms, yet the short barcodes (< 500 bp) provide limited taxonomic and phylogenetic information for species discrimination and taxonomic assignment. Here, we utilized the third-generation Pacific Biosciences (PacBio) RSII and Sequel instruments to evaluate the suitability of full-length internal transcribed spacer (ITS) barcodes and longer rRNA gene amplicons for metabarcoding Fungi, Oomycetes and other eukaryotes in soil samples. Metabarcoding revealed multiple errors and biases: Taq polymerase substitution errors and mis-incorporating indels in sequencing homopolymers constitute major errors; sequence length biases occur during PCR, library preparation, loading to the sequencing instrument and quality filtering; primer template mismatches bias the taxonomic profile when using regular and highly degenerate primers. The RSII and Sequel platforms enable the sequencing of amplicons up to 3000 bp, but the sequence quality remains slightly inferior to Illumina sequencing especially in longer amplicons. The full ITS barcode and flanking rRNA small subunit gene greatly improve taxonomic identification at the species and phylum levels, respectively. We conclude that PacBio sequencing provides a viable alternative for metabarcoding of organisms that are of relatively low diversity, require > 500-bp barcode for reliable identification or when phylogenetic approaches are intended. PMID- 28906011 TI - The Allergic Rhinitis and its Impact on Asthma (ARIA) score of allergic rhinitis using mobile technology correlates with quality of life: The MASK study. AB - Mobile technology has been used to appraise allergic rhinitis control, but more data are needed. To better assess the importance of mobile technologies in rhinitis control, the ARIA (Allergic Rhinitis and its Impact on Asthma) score ranging from 0 to 4 of the Allergy Diary was compared with EQ-5D (EuroQuol) and WPAI-AS (Work Productivity and Activity Impairment in allergy) in 1288 users in 18 countries. This study showed that quality-of-life data (EQ-5D visual analogue scale and WPA-IS Question 9) are similar in users without rhinitis and in those with mild rhinitis (scores 0-2). Users with a score of 3 or 4 had a significant impairment in quality-of-life questionnaires. PMID- 28906013 TI - Novel Insights into the Inhibitory Effect and Mechanism of Proanthocyanidins from Pyracantha fortuneana Fruit on alpha-Glucosidase. AB - : Proanthocyanidins were extracted from Pyracantha fortuneana fruit (PFF), and their structures were investigated through 13 C nuclear magnetic resonance (13 C NMR), high performance liquid chromatography (HPLC) and high resolution mass spectrometry (HRMS). The results showed that these compounds were predominantly constituted of procyanidin with A-type and B-type linkage and coexistence of procyanidins glucoside. Spectroscopy methods were used to analyze the inhibitory activity of proanthocyanidins on alpha-glucosidase. The results demonstrated that these compounds exhibited excellent inhibitory effect on alpha-glucosidase with the IC50 value of 0.15 +/- 0.01 MUg/mL, and they reversibly inhibited alpha glucosidase in a non-competitive type. The fluorescence quenching analysis revealed that proanthocyanidins statically quenched the fluorescence spectra by forming an inhibitor-alpha-glucosidase complex. Molecular docking results further indicated that the driving powers of the interaction between proanthocyanidins and alpha-glucosidase were hydrogen bonds and hydrophobic force. The main inhibitory mechanism of proanthocyanidins on alpha-glucosidase may be due to the insertion of proanthocyanidins into the pocket of the enzyme altering the catalytic configuration of the active site in a manner, thus reducing substrate binding affinity. The findings of this work provided a new perspective that proanthocyanidins from PFF with a possibility to be used as novel natural anti diabetic agents in functional food industries. PRACTICAL APPLICATION: In this study, Pyracantha fortuneana fruit proanthocyanidins with a yield of 3.05% were identified for the first time as predominantly constituted of procyanidin with A type and B-type linkage and coexistence of procyanidins glucoside. Proanthocyanidins from P. fortuneana fruit had higher anti-alpha-glucosidase activity value compared with positive control acarbose, which indicated that P. fortuneana fruit proanthocyanidins with a possibility to be used as novel natural antidiabetic agents in functional food industries. PMID- 28906014 TI - Development and initial validation of a novel smoothed-particle hydrodynamics based simulation model of trabecular bone penetration by metallic implants. AB - A novel computational model of implant migration in trabecular bone was developed using smoothed-particle hydrodynamics (SPH), and an initial validation was performed via correlation with experimental data. Six fresh-frozen human cadaveric specimens measuring 10 * 10 * 20 mm were extracted from the proximal femurs of female donors (mean age of 82 years, range 75-90, BV/TV ratios between 17.88% and 30.49%). These specimens were then penetrated under axial loading to a depth of 10 mm with 5 mm diameter cylindrical indenters bearing either flat or sharp/conical tip designs similar to blunt and self-tapping cancellous screws, assigned in a random manner. SPH models were constructed based on microCT scans (17.33 um) of the cadaveric specimens. Two initial specimens were used for calibration of material model parameters. The remaining four specimens were then simulated in silico using identical material model parameters. Peak forces varied between 92.0 and 365.0 N in the experiments, and 115.5-352.2 N in the SPH simulations. The concordance correlation coefficient between experimental and simulated pairs was 0.888, with a 95%CI of 0.8832-0.8926, a Pearson rho (precision) value of 0.9396, and a bias correction factor Cb (accuracy) value of 0.945. Patterns of bone compaction were qualitatively similar; both experimental and simulated flat-tipped indenters produced dense regions of compacted material adjacent to the advancing face of the indenter, while sharp-tipped indenters deposited compacted material along their peripheries. Simulations based on SPH can produce accurate predictions of trabecular bone penetration that are useful for characterizing implant performance under high-strain loading conditions. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1114-1123, 2018. PMID- 28906015 TI - Influence of coexistent Hashimoto's thyroiditis on the extent of cervical lymph node dissection and prognosis in papillary thyroid carcinoma. AB - OBJECTIVE: Previous studies did not focus on the differences in the extent of cervical lymph node (LN) dissection according to coexistent Hashimoto's thyroiditis (HT) in patients with papillary thyroid carcinoma (PTC) and its clinical impact. We aimed to determine whether extensive cervical LN dissection is responsible for favourable clinical outcomes in PTC patients with HT and whether the coexistence of HT itself has an independent protective effect regardless of LN status. DESIGN: Retrospective cohort study. PATIENTS: 1369 patients with PTC who underwent total thyroidectomy with central compartment neck dissection. MEASUREMENTS: Metastatic LN ratio, defined as number of metastatic LNs divided by number of removed LNs, was used to evaluate the extent of LN dissection as well as the status of LN metastasis. Disease-free survival and dynamic risk stratification were compared for clinical outcomes. RESULTS: Presence of HT did not lower the risk of cervical LN metastasis (61.6% in patients with HT vs 65.1% in patients without HT, P = .292). Patients with HT had significantly larger numbers of removed LNs than patients without HT (11 vs 8, respectively, P < .001). Accordingly, metastatic LN ratio was smaller in patients with HT (P = .002), which was independently associated with structural persistent/recurrent disease (hazard ratio [HR] 2.33, 95% confidence interval [CI] 1.30-4.16, P = .004). HT itself was negatively associated with structural persistent/recurrent disease after adjustment for other clinicopathological factors (HR 0.39, 95% CI 0.18-0.87, P = .020). CONCLUSIONS: Coexistence of HT itself is an independent factor associated with favourable outcome in PTC patients, regardless of the extent of LN dissection. PMID- 28906016 TI - CXCL10 is upregulated in synovium and cartilage following articular fracture. AB - The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with post-traumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) versus 3 days post fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1alpha-stimulated total MMP activity (p = 0.09) and S-GAG (p = 0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1220-1227, 2018. PMID- 28906017 TI - Assessing recovery of in vitro steroid production in male rainbow darter (Etheostoma caeruleum) in response to municipal wastewater treatment plant infrastructure changes. AB - The present study examined in vitro 11-ketotestosterone and testosterone production by the testes of rainbow darter (Etheostoma caeruleum) collected from selected reference sites and downstream of 2 municipal wastewater treatment plants (MWWTPs; Waterloo and Kitchener) on the central Grand River (Ontario, Canada), over a 6-yr period (2011-2016). The main objective was to investigate if infrastructure upgrades at the Kitchener MWWTP in 2012 resulted in a recovery of this response in the post-upgrade period (2013-2016). Two supporting studies showed that the fall season is appropriate for measuring in vitro sex steroid production because it provides stable detection of steroid patterns, and that the sample handling practiced in the present study did not introduce a bias. Infrastructure upgrades of the Kitchener MWWTP resulted in significant reductions in ammonia and estrogenicity. After the upgrades, 11-ketotestosterone production by MWWTP-exposed fish increased in 2013 and it continued to recover throughout the study period of 2014 through 2016, returning to levels measured in reference fish. Testosterone production was less sensitive and it lacked consistency. The Waterloo MWWTP underwent some minor upgrades but the level of ammonia and estrogenicity remained variable over time. The production of 11-ketotestosterone and testosterone in rainbow darter below the Waterloo MWWTP was variable and without a clear recovery pattern over the course of the present study. The results of the present study demonstrated that measuring production of sex steroids (especially 11-ketotestosterone) over multiple years can be relevant for assessing responses in fish to environmental changes such as those resulting from major infrastructure upgrades. Environ Toxicol Chem 2018;37:501-514. (c) 2017 SETAC. PMID- 28906018 TI - Normal hematology and serum chemistry of northern fur seals (Callorhinus ursinus) in captivity. AB - Northern fur seals (Callorhinus ursinus) are endemic to the North Pacific Ocean. They were hunted for their fur and became endangered in the late 1800s, but their populations recovered following the introduction of protection laws. Recently, populations have been decreasing again, although the reasons are unclear. For individuals that are bred and reared in captivity as part of ex situ conservation projects, details of blood characteristics are essential to ensure good health. However, the normal ranges of hematology and serum chemistry of captive northern fur seals have not been defined. This study determined the normal ranges of hematology and serum chemistry of captive fur seals. Blood samples were collected every month for 2 years from four captive northern fur seals in Japan (three born in an aquarium and one kept in the same aquarium following rescue). Fifteen blood characteristics and 29 serum chemistry properties were compared with those previously reported for wild northern fur seals in the USA. Several parameters were not within the normal ranges reported previously in wild northern fur seals. In particular, levels of alkaline phosphatase was outside of the normal ranges previously reported. The hematological and serum chemistry ranges in this study can help provide a guideline for understanding the health of northern fur seals in captivity. PMID- 28906019 TI - Response Letter to 'Optimising physiology for adolescents with dysautonomia'. PMID- 28906020 TI - Diagnostic impact of anterior segment angiography of limbal stem cell insufficiency in PAX6-related aniridia. AB - PAX6 is a master gene of ocular development and postnatal ocular equilibrium. Congenital aniridia is the hallmark of PAX6 gene haploinsufficiency (Chr. 11 p. 13), but PAX6-associated aniridia is a profound, progressive pan-ocular developmental disorder often leading to blindness. There is congenital visual impairment with advancing loss of vision mainly due to secondary glaucoma and to corneal blindness caused by limbal stem cell insufficiency (LSCI). LSCI leads to ARK (aniridia-related keratopathy), which typically develops in four stages. Incipient LSCI with vessels starting to grow into the cornea can be imaged by fluorescein anterior segment angiography, which enables fine vessels to be more easily detected than by routine slit lamp examination, especially in patients with nystagmus. Thus, clinical stage 1 ARK is often diagnosed at stage 2 by angiography. Corneal neovascularizations often start at the 12 and 6 positions and subsequently progress circumferentially, not at the 3 and 9 positions as previously believed. Anterior segment angiography can provide an easily standardizable tool for monitoring progress, treatment-induced regress or stabilization of ARK. Especially in children, angiography could be used to monitor new treatment regimens for reducing LSCI. Angiography could enable treatment to begin earlier to preserve corneal hemostasis. In addition, the fact that vascularization often starts at the subpalpebral 6 and 12 positions as opposed to the 3 and 9 positions raises more questions concerning factors that promote LSCI and related corneal injuries. Clin. Anat. 31:392-397, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 28906021 TI - Primary hyperparathyroidism: Dynamic postoperative metabolic changes. AB - OBJECTIVE: Little is known about the natural changes in parathyroid function after successful parathyroid surgery for primary hyperparathyroidism. The association of intact parathyroid hormone (iPTH) and calcium (Ca) with "temporary hypoparathyroidism" and "hungry bone syndrome" (HBS) was evaluated. DESIGN: Potential risk factors for temporary hypoparathyroidism and HBS were evaluated by taking blood samples before surgery, intra-operatively, at postoperative day (POD) 1, at POD 5 to 7, in postoperative week (POW) 8 and in postoperative month (POM) 6. PATIENTS: Of 425 patients, 43 (10.1%) had temporary hypoparathyroidism and 36 (8.5%) had HBS. MEASUREMENTS: The discriminative ability of iPTH and Ca on POD 1 for temporary hypoparathyroidism and HBS. RESULTS: Intact parathyroid hormone (IPTH) on POD 1 showed the highest discriminative ability for temporary hypoparathyroidism (C-index = 0.952), but not for HBS. IPTH was helpful in diagnosing HBS between POD 5 and 7 (C-index = 0.708). Extending the model by including Ca resulted in little improvement of the discriminative ability for temporary hypoparathyroidism (C-index = 0.964) and a decreased discriminative ability for HBS (C-index = 0.705). Normal parathyroid metabolism was documented in 139 (32.7%) patients on POD 1 and in 423 (99.5%) 6 months postoperatively, while 2 (0.5%) patients had persistent hyperparathyroidism, one diagnosed between POD 5 and 7 and another at POW 8. No patients suffered from permanent hypoparathyroidism. CONCLUSIONS: The necessity for Ca and vitamin D3 substitution cannot be predicted with certainty before POD 5 to 7 without serial laboratory measurements. Based on the results, a routine 8-week course of Ca and vitamin D3 treatment seems reasonable and its necessity should be evaluated in a follow-up study. PMID- 28906022 TI - Identification and characterization of a brilliant yellow pigment produced by Bordetella pertussis. AB - Culture supernatants of Bordetella pertussis are a brilliant yellow; however, the structure and biological role of the responsible pigment have not been investigated. In this study, a brilliant yellow-colored fraction was extracted from culture supernatants of B. pertussis and analyzed by HPLC. UV-visible spectral analysis and mass spectrometry identified the brilliant yellow pigment as riboflavin. Riboflavin production was high in lag and early log phases and riboflavin was found to enhance growth of B. pertussis in low-density cultures. Riboflavin production is not regulated by the BvgAS system. In addition, it was found that other Bordetella species, such as B. parapertussis, B. holmesii and B. bronchiseptica, also release riboflavin into their culture supernatants. This is the first report that B. pertussis secrets riboflavin to the extracellular space and that riboflavin may promote its growth. The mechanism may be associated with pathogenesis of B. pertussis. PMID- 28906023 TI - Immunophenotypic and molecular comparison between allogeneic and autologous graft vs-host disease of the skin: A retrospective study using immunohistochemical and proteomics methods. PMID- 28906024 TI - Father group leaders' experiences of creating an arena for father support - A qualitative study. AB - BACKGROUND: Parental classes consisting of only fathers, hereafter referred to as father groups, have existed in Sweden since the mid-1990s. OBJECTIVE: To describe the father group leaders' perspectives on and experiences of father groups. METHOD: A qualitative study was conducted using content analysis. Eleven individual interviews with father group leaders were conducted. An interview guide was used. SETTINGS AND PARTICIPANTS: The study was set in different parts of Sweden. The participants were eleven men who are father group leaders. They were recruited using the snowball method. FINDINGS: The father group leaders described how participants often have high education levels and orderly social circumstances. The leaders described that the groups increased the fathers' reflection about parenthood, which could benefit the whole family in both the short and long term. The father group leaders reported that some of the topics in the sessions directly influenced fathers to discuss issues regarding equality and their co-parenting relationship. They also argued that participating in father groups might help convince fathers to take more parental leave and build stronger relationships with their partner and child. PMID- 28906025 TI - Vitamin D in the Parkinson Associated Risk Syndrome (PARS) study. AB - BACKGROUND: Lower vitamin D levels have been associated with manifest Parkinson's disease, prompting the hypothesis that vitamin D insufficiency or deficiency may increase risk for PD. OBJECTIVES: To evaluate vitamin D levels in a population at risk for developing PD. METHODS: Plasma vitamin D levels were measured in the Parkinson Associated Risk Syndrome Study, a cohort of asymptomatic individuals, some of whom are at high risk for PD. Vitamin D levels were compared between subjects at high risk for PD (hyposmia and dopamine transporter scan deficit) versus all others and examined for correlations with dopaminergic system integrity. RESULTS: Mean vitamin D levels did not differ between groups, with a level of 27.8 ng/mL (standard deviation = 12.0) in the high-risk group versus 24.7 ng/mL (standard deviation = 9.0) in all others (P = 0.09). Vitamin D levels did not associate with putaminal dopamine transporter uptake. CONCLUSIONS: Our data from the asymptomatic Parkinson Associated Risk Syndrome cohort do not support the hypothesis that chronic vitamin D insufficiency threatens dopaminergic system integrity, contributing to PD pathogenesis. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28906026 TI - Total synthesis and biological evaluation of spirotryprostatin A analogs. AB - Based on the spirotryprostatin A structure, a series of compounds belonging to spiro-indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all-carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven-step reaction sequence with 18 28% overall yield from commercially available materials, and a highly enantioselective 1,3-dipolar cycloaddition, N-acylation of the resulting stereochemically complex spiro[pyrrolidin-3,3'-oxindole]s core with Fmoc-L-pro-Cl and spontaneous ring closure upon N-deprotection were obtained. The synthesized compounds 13a-e and 15a-e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram-positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis. Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure-activity relationship is also discussed. PMID- 28906028 TI - Graft outcomes following diagnosis of post-transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study. AB - Data related to graft outcomes following post-transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3 years after diagnosis of PTLD, with a loss of follow-up after 2 years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED-PTLD-2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet-PHL C1. In four patients, donor-specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7 years, respectively. One patient developed chronic antibody-mediated rejection (cAMR) 12 years after diagnosis, losing the graft 1 year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4 years. Range-based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3 years after diagnosis of PTLD (P = 0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B-cell-depleting therapy of PTLD with rituximab. PMID- 28906027 TI - SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. AB - Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na+ -permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na+ -permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na+ -permeable channels that are newly upregulated. Here, using co-immunoprecipitation and Forster resonance energy transfer, we report that AQP4 physically co-assembles with the sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) monovalent cation channel to form a novel heteromultimeric water/ion channel complex. In vitro cell-swelling studies using calcein fluorescence imaging of COS-7 cells expressing various combinations of AQP4, SUR1, and TRPM4 showed that the full tripartite complex, comprised of SUR1 TRPM4-AQP4, was required for fast, high-capacity transmembrane water transport that drives cell swelling, with these findings corroborated in cultured primary astrocytes. In a murine model of brain edema involving cold-injury to the cerebellum, we found that astrocytes newly upregulate SUR1-TRPM4, that AQP4 co associates with SUR1-TRPM4, and that genetic inactivation of the solute pore of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1-TRPM4-AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4-mediated pathological conditions. PMID- 28906030 TI - Pathological and immunoblot analysis of phosphorylated TDP-43 in sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration. AB - Transactivation response DNA-binding protein 43 kDa (TDP-43) is a key protein of sporadic amyotrophic lateral sclerosis (ALS), and phosphorylated form of TDP-43 (p-TDP-43) is a major pathological protein that accumulates in sporadic ALS. p TDP-43 is found not only in primary motor neurons, but often propagates to non motor systems as well. However, pallido-nigro-luysian (PNL) degeneration (PNLD) is rarely associated with ALS. We describe here a 68-year-old ALS patient presenting severe PNLD. He had difficulty walking due to poor movement of his right leg, and was diagnosed as having Parkinson's disease because of akinesia. About 2 years after onset, weakness of his left hand and leg led to a diagnosis of ALS. Tube feeding and non-invasive positive-pressure ventilation were initiated. He died of respiratory failure at the age of 71. There was no family history of either neurological disorders or dementia. Neuropathological examination revealed severe loss of neurons and gliosis in the PNL system in addition to the upper and lower motor neuron system. p-TDP-43 pathology was widespread in the PNL and motor neuron systems and also in the amygdala and hippocampus where no significant gliosis or neuronal loss was detected. Synuclein pathology was not observed in the investigated areas. Immunoblot analysis of p TDP-43 C-terminal fragments showed a type B band pattern consistent with sporadic ALS. This is the first case of ALS with PNLD, in which p-TDP-43 distribution was widespread in the hippocampal formation (Nishihira type 2 and Brettschneider stage 4), and the type B immunoblot pattern was confirmed. Our case indicated that the PNL system can be involved in the disease process in sporadic ALS cases, although rarely. We also reviewed previous autopsy cases of ALS with PNLD to clarify the clinicopathological features. PMID- 28906029 TI - IL-6 production by monocytes is associated with graft function decline in patients with borderline changes suspicious for acute T-cell-mediated rejection: a pilot study. AB - Although borderline changes (BL) suspicious for acute T-cell-mediated rejection represent a diagnostic category, its clinical relevance is questioned leading to heterogeneous therapeutic management. We hypothesized that measuring IL-6 secretion by peripheral blood mononuclear cells identifies patients with ongoing graft damage. We examined the association between secreted IL-6 and the change in estimated glomerular filtration rate at 6 months after the biopsy (DeltaeGFR). We then conducted phenotypic and functional studies on patient and mouse innate immune cells in the blood and the kidney. In a training set, DeltaeGFR was strongly associated with IL-6 levels, showing a clinically meaningful decline of 4.6 +/- 1.5 ml/min per increase in log10 IL-6 (P = 0.001). These results were consistent after adjustment and were reproduced in a validation cohort. Phenotyping of peripheral blood cells revealed that the main source of IL-6 was CD14+ CD16- CCR2+ HLA-DR+ CD86+ CD11c+ inflammatory monocytes. There was a significant correlation between IL-6 secretion and interstitial dendritic cell density in the biopsy. Finally, characterization of mouse kidney dendritic cells revealed that they share features with macrophages and function as effector cells secreting IL-6. In conclusion, measuring IL-6 secreted by peripheral blood cells can be useful in the management of patients with BL in the absence of a concurrent inflammatory condition. PMID- 28906031 TI - Design optimization for clinical trials in early-stage manifest Huntington's disease. AB - OBJECTIVES: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. METHODS: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. RESULTS: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. DISCUSSION: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28906032 TI - From Anilines to Quinolines: Iodide- and Silver-Mediated Aerobic Double C-H Oxidative Annulation-Aromatization. AB - Quinoline synthesis from easily accessible raw materials such as anilines is a valuable and meaningful task. Herein, we communicate an iodide- and silver mediated C-H/C-H oxidative annulation-aromatization between anilines and allyl alcohols. This protocol provides a direct route to the synthesis of quinoline derivatives from inexpensive commodities. Various kinds of anilines, even heterocyclic anilines, were shown to be workable substrates, generating the corresponding multi-substituted quinolines in good yields. PMID- 28906033 TI - Collagen peptides modulate the metabolism of extracellular matrix by human dermal fibroblasts derived from sun-protected and sun-exposed body sites. AB - Clinical data published in recent years have demonstrated positive effects of collagen hydrolysate (CH) on skin aging clinical signs. CH use as food supplement has a long history; however, few studies have addressed the underlying purpose of CH on the cellular and molecular biology of skin cells that could elucidate clinical improvement findings. Wide diversity of characteristics has been reported for dermal fibroblasts derived from different body sites and it is unknown whether collagen peptides could modulate differently cells from chronological aged and photoaged skin areas. This study investigated the influence of CH on the extracellular matrix metabolism and proliferation of human dermal fibroblasts (HDFs) derived from chronological aged (sun-protected) and photoaged (sun-exposed) body sites. CH treatment did not affect cellular proliferation of either cell cultures, but notably modulated cell metabolism in monolayer model, increasing the content of dermal matrix precursor and main protein, procollagen I and collagen I, respectively. These effects were confirmed in the human dermal equivalent model. The increase in collagen content in the cultures was attributed to stimulation of biosynthesis and decreased collagen I metabolism through inhibition of metalloproteinase activity (MMP) 1 and 2. Modulation of CH in dermal metabolism did not differ between cells derived from sun-protected and sun-exposed areas, although lower concentrations of CH seemed to be enough to stimulate sun-exposed-derived HDFs, suggesting more pronounced effect in these cells. This study contributes to understanding the biological effects of CH on skin cells and viability of its use as a functional ingredient in food supplements. PMID- 28906034 TI - Small airway disease: A different phenotype of early stage COPD associated with biomass smoke exposure. AB - BACKGROUND AND OBJECTIVE: Chronic exposure to biomass smoke (BS) can significantly compromise pulmonary function and lead to chronic obstructive pulmonary disease (COPD). To determine whether BS exposure induces a unique phenotype of COPD from an early stage, with different physiopathological features compared with COPD associated with smoking (cigarette-smoke (CS) COPD), we assessed the physiopathology of early COPD associated with BS exposure (BS COPD) by incorporating spirometry, high-resolution computed tomography (HRCT) imaging, bronchoscopy and pathological examinations. METHODS: In this cross-sectional study, we recruited 29 patients with BS COPD, 31 patients with CS COPD and 22 healthy controls, including 12 BS-exposed subjects who did not smoke and 10 healthy smokers without BS exposure. Spirometry, HRCT scans, bronchoscopy and bronchial mucosa biopsies were performed to assess lung function, emphysema and air trapping, as well as the pathological characteristics and levels of inflammatory cells in bronchoalveolar lavage fluid (BALF). RESULTS: Among COPD patients with mild-to-moderate airflow limitation, BS exposure caused greater small airway dysfunction in BS COPD patients, although these patients had less emphysema and air trapping, as detected by HRCT (P < 0.05). We also observed significantly thicker basement membranes and greater endobronchial pigmentation in BS COPD than in CS COPD (P < 0.05). Moreover, patients with BS COPD exhibited greater macrophage and lymphocyte infiltration but reduced neutrophil infiltration in their BALF (P < 0.05). CONCLUSION: We used both radiology and pathology to document a distinct COPD phenotype associated with BS exposure. This is characterized by small airway disease. PMID- 28906035 TI - Magnetic Control of MOF Crystal Orientation and Alignment. AB - Most metal-organic frameworks (MOFs) possess anisotropic properties, the full exploitation of which necessitates a general strategy for the controllable orientation of such MOF crystals. Current methods largely rely upon layer-by layer MOF epitaxy or tuning of MOF crystal growth on appropriate substrates, yielding MOFs with fixed crystal orientations. Here, the dynamic magnetic alignment of different MOF crystals (NH2 -MIL-53(Al) and NU-1000) is shown. The MOFs were magnetized by electrostatic adsorption of iron oxide nanoparticles, dispersed in curable polymer resins (Formlabs 1+ clear resin/ Sylgard 184), magnetically oriented, and fixed by resin curing. The importance of crystal orientation on MOF functionality was demonstrated whereby magnetically aligned NU 1000/Sylgard 184 composite was excited with linearly polarized 405 nm light, affording an anisotropic fluorescence response dependent on the polarization angle of the excitation beam relative to NU-1000 crystal orientation. PMID- 28906036 TI - Phosphorus and Fluorine Co-Doping Induced Enhancement of Oxygen Evolution Reaction in Bimetallic Nitride Nanorods Arrays: Ionic Liquid-Driven and Mechanism Clarification. AB - Electrocatalytic splitting of water is becoming increasingly crucial for renewable energy and device technologies. As one of the most important half reactions for water splitting reactions, the oxygen evolution reaction (OER) is a kinetically sluggish process that will greatly affect the energy conversion efficiency. Therefore, exploring a highly efficient and durable catalyst to boost the OER is of great urgency. In this work, we develop a facile strategy for the synthesis of well-defined phosphorus and fluorine co-doped Ni1.5 Co1.5 N hybrid nanorods (HNs) by using ionic liquids (ILs; 1-butyl-3-methylimidazolium hexafluorophosphate). In comparison to the IrO2 catalyst, the as-obtained PF/Ni1.5 Co1.5 N HNs manifests a low overpotential of 280 mV at 10 mA cm-2 , Tafel slope of 66.1 mV dec-1 , and excellent durability in 1.0 m KOH solution. Furthermore, the iR-corrected electrochemical results indicate it could achieve a current density of 100 mA cm-2 at an overpotential of 350 mV. The combination of cobalt and nickel elements, 1D mesoporous nanostructure, heteroatom incorporation, and ionic liquid-assisted nitridation, which result in faster charge transfer capability and more active surface sites, can facilitate the release of oxygen bubbles from the catalyst surface. Our findings confirm that surface heteroatom doping in bimetallic nitrides could serve as a new class of OER catalyst with excellent catalytic activity. PMID- 28906037 TI - Patterns of Smoking and Unhealthy Alcohol Use Following Sexual Trauma Among U.S. Service Members. AB - In the first known longitudinal study of the topic, we examined whether experiencing sexual assault or sexual harassment while in the military was associated with increased risk for subsequent unhealthy alcohol use and smoking among U.S. service members in the Millennium Cohort Study (2001-2012). Adjusted complementary log-log models were fit to estimate the relative risk of (a) smoking relapse among former smokers (men: n = 4,610; women: n = 1,453); (b) initiation of unhealthy alcohol use (problem drinking and/or drinking over recommended limits) among those with no known history of unhealthy alcohol use (men: n = 8,459; women: n = 4,816); and (c) relapse among those previously reporting unhealthy alcohol use (men: n = 3,487; women: n = 1,318). Men who reported experiencing sexual assault while in the military had sixfold higher risk for smoking relapse: relative risk (RR) = 6.62; 95% confidence interval (CI) [2.34, 18.73], than men who did not. Women who reported experiencing sexual assault while in the military had almost twice the risk for alcohol relapse: RR = 1.73; 95% CI [1.06, 2.83]. There were no other significant associations. These findings suggest that men and women may respond differently following sexual trauma, and support future concerted policy efforts by military leadership to prevent, detect, and intervene on sexual assault. PMID- 28906038 TI - beta-carotene suppresses Porphyromonas gingivalis lipopolysaccharide-mediated cytokine production in THP-1 monocytes cultured with high glucose condition. AB - Periodontitis is associated with development of diabetes mellitus. Although lipopolysaccharide (LPS) of Porphyromonas gingivalis (Pg), a major pathogen of periodontitis, may lead the progression of diabetes complications, the precise mechanisms are unclear. We, therefore, investigated the effects of beta-carotene on production of Pg LPS-induced inflammatory cytokines in human monocytes cultured high glucose (HG) condition. THP-1 cells were cultured under 5.5 mM or 25 mM glucose conditions, and cells were stimulated with Pg LPS. To investigate the productivity of TNF-alpha, IL-6, and MCP-1, cell supernatants were collected for ELISA. To examine the effects of NF-kB signals on cytokine production, Bay11 7082 was used. HG enhanced Pg LPS-induced production of TNF-alpha, IL-6, and MCP 1 via NF-kB signals in THP-1. beta-carotene suppressed the enhancement of the Pg LPS-induced cytokine production in THP-1 via NF-kappaB inactivation. Our results suggest that beta-carotene might be a potential anti-inflammatory nutrient for circulating Pg LPS-mediated cytokine production in diabetic patients with periodontitis. PMID- 28906041 TI - Total Synthesis of Skyllamycins A-C. AB - The skyllamycins are a family of highly functionalized non-ribosomal cyclic depsipeptide natural products which contain the extremely rare alpha-OH-glycine functionality. Herein the first total synthesis of skyllamycins A-C is reported, together with the biofilm inhibitory activity of the natural products. Linear peptide precursors for each natural product were prepared through an efficient solid-phase route incorporating a number of synthetic modified amino acids. A novel macrocyclization step between a C-terminal amide and an N-terminal glyoxylamide moiety served as a key transformation to install the unique alpha-OH glycine unit and generate the natural products in the final step of the synthesis. PMID- 28906040 TI - A blinded, randomized clinical trial evaluating the efficacy and safety of lokivetmab compared to ciclosporin in client-owned dogs with atopic dermatitis. AB - BACKGROUND: Lokivetmab is an injectable anti-canine-IL-31 monoclonal antibody to treat clinical manifestations of atopic dermatitis (AD) in dogs. HYPOTHESIS/OBJECTIVES: To characterize the efficacy and safety of lokivetmab, and to demonstrate its noninferiority to ciclosporin under field conditions. ANIMALS: Dogs with chronic AD (n = 274) were enrolled from 40 practices in Belgium, The Netherlands, France and Germany. METHODS: Animals were randomized (1:1) to oral ciclosporin (5 mg/kg/once daily) or monthly injectable lokivetmab (1-3.3 mg/kg) for three months. Eighty one animals that successfully completed the comparative phase were enrolled in a continuation phase receiving lokivetmab for an additional six months. Owners assessed pruritus on a Visual Analog Scale, skin lesions were assessed by veterinary investigators with a Canine AD Extent and Severity Index (CADESI-03) scale. RESULTS: Lokivetmab was noninferior to ciclosporin for pruritus reduction on Day 28 (51.90% versus 43.72%). For Day 28 CADESI-03 percentage reduction, noninferiority of lokivetmab (54.17) versus ciclosporin (56.86%) was not achieved. At none of the time points were mean CADESI-03 scores significantly different between groups. Continued efficacy towards pruritus and lesions was demonstrated in the continuation phase where 76.3% of animals (n = 45) were assessed as 'normal' for pruritus at study end. No abnormal health events associated with lokivetmab were observed during the initial three month phase (142 dogs) or during the subsequent six month phase (81 dogs). CONCLUSIONS AND CLINICAL IMPORTANCE: Lokivetmab at a minimum monthly dose of 1 mg/kg provided quick onset (within one day) of a lasting effect in reducing pruritus and skin lesions with a good safety profile. PMID- 28906039 TI - Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes. AB - Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain. PMID- 28906042 TI - Vascular configurations of anastomotic basket of conus medullaris in human spinal cord. AB - The arterial basket of the conus medullaris is one of several anastomoses between the anterior and posterior spinal arteries. The anatomy of this structure has attracted little attention. This work sought to investigate its configuration in human spinal cords. Spinal cords from male and female cadavers (n = 32) were injected with colored latex through the intercostal, lumbar, medial sacral and the posterior trunks of the hypogastric arteries. After injection, specimens preserving the dural sac were obtained and fixed in formaldehyde solution. Finally, the spinal arteries were microdissected. In 18.75% of the specimens, the anterior spinal artery divided symmetrically and formed anastomoses with the posterior spinal arteries. In 81.25%, the branching pattern observed was asymmetrical. In 21.87% there were differences in the diameter of the anastomotic arteries, and 40.63% originated at different levels along the craniocaudal axis. Interestingly, 12.5% of the specimens presented an intraparenchymatous anastomosis that has not been described previously. True unilateral anastomosis was only observed in 6.25% of the spinal cords. The most frequent configuration of the anastomotic basket of the conus medullaris is a bilateral asymmetric anastomosis. The asymmetry of the branches could be caused by differences in their diameters or in their origins along the craniocaudal axis. Symmetrical patterns are less frequent, and unilateral anastomoses are rare. In reality, some cases of apparently unilateral anastomosis present an intramedullary course of the anastomotic artery. Clin. Anat. 31:441-448, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28906043 TI - Diluted sodium hypochlorite (bleach) in dogs: antiseptic efficacy, local tolerability and in vitro effect on skin barrier function and inflammation. AB - BACKGROUND: Diluted sodium hypochlorite represents an inexpensive and widely available topical antiseptic, but there are no tolerability and efficacy data in veterinary dermatology. OBJECTIVES: To determine the in vivo antibacterial effect and tolerability of topical diluted bleach application and to assess its in vitro effect on skin barrier lipids and anti-inflammatory properties on keratinocytes. METHODS: Topical hypochlorite at 0.05% and tap water were applied to both sides of the thorax of four healthy dogs. The anti-inflammatory effect on canine keratinocytes was determined by real-time polymerase chain reaction; skin barrier integrity was assessed by evaluating stratum corneum lipid changes in canine stratified epidermal constructs. RESULTS: The cell viability of primary keratinocytes treated with water and diluted hypochlorite at 0.005 and 0.01%, reduced the percentage of viable cells by 10%. The exposure of primary keratinocytes to 0.005% diluted hypochlorite significantly reduced the induction of inflammatory genes chemokine ligand-2 (CCL2; P = 0.015) and thymus and activation-regulated chemokine (TARC/CCL17, P = 0.032). There were no changes in skin lipid ceramide and nonceramide fractions in stratified epidermal constructs cultured for 17 days with 0.05% hypochlorite. Topical hypochlorite at 0.05% and tap water were well-tolerated without signs of skin irritation. Although a marked reduction in bacterial counts was seen within 20 min of diluted bleach application compared to the tap water control, this was only marginally significant (P = 0.06). CONCLUSIONS AND CLINICAL IMPORTANCE: The results indicate that a topical diluted bleach solution, at either 0.05 or 0.005% hypochlorite concentrations, is a well-tolerated antiseptic that also exhibits anti inflammatory properties. PMID- 28906044 TI - Specific IgE to peanut 2S albumin Ara h 7 has a discriminative ability comparable to Ara h 2 and 6. AB - BACKGROUND: Little is known on the clinical relevance of peanut 2S albumin Ara h 7. OBJECTIVE: To investigate the discriminative ability of Ara h 7 in peanut allergy and assess the role of cross-reactivity between Ara h 2, 6 and Ara h 7 isoforms. METHODS: Sensitization to recombinant peanut storage proteins Ara h 1, 2, 3, 6, and 7 was assessed using a line blot in sera from 40 peanut-tolerant and 40 peanut-allergic patients, based on food challenge outcome. A dose-dependent ELISA inhibition experiment was performed with recombinant Ara h 2, 6 and Ara h 7 isoforms. RESULTS: For Ara h 7.0201, an area under the ROC curve was found of 0.83, comparable to Ara h 2 (AUC 0.81) and Ara h 6 (AUC 0.85). Ara h 7 intensity values strongly correlated with those from Ara h 2 and 6 (rs = 0.81). Of all patients sensitized to 2S albumins Ara h 2, 6, or 7, the majority was co sensitized to all three (n = 24, 68%), although mono-sensitization to either 2S albumin was also observed in selected patients (Ara h 2: n = 6, 17%; Ara h 6: n = 2, 6%; Ara h 7: n = 2, 6%). Binding to Ara h 7.0101 could be strongly inhibited by Ara h 7.0201, but not the other way around. CONCLUSIONS AND CLINICAL RELEVANCE: Specific IgE against Ara h 7.0201 has a predictive ability for peanut allergy similar to Ara h 2 and 6 and possesses unique IgE epitopes as well as epitopes shared between the other Ara h 7 isoform and Ara h 2 and 6. While co sensitization to all three 2S albumins is most common, mono-sensitization to either Ara h 2, 6, or 7 occurs in selected patients, leading to a risk of misdiagnosis when testing for a single 2S albumin. PMID- 28906045 TI - Actinorhodin is a redox-active antibiotic with a complex mode of action against Gram-positive cells. AB - Actinorhodin is a blue-pigmented, redox-active secondary metabolite that is produced by the bacterium Streptomyces coelicolor. Although actinorhodin has been used as a model compound for studying secondary metabolism, its biological activity is not well understood. Indeed, redox-active antibiotics in general have not been widely investigated at the mechanistic level. In this work, we have conducted a comprehensive chemical genetic investigation of actinorhodin's antibacterial effect on target organisms. We find that actinorhodin is a potent, bacteriostatic, pH-responsive antibiotic. Cells activate at least three stress responses in the presence of actinorhodin, including those responsible for managing oxidative damage, protein damage and selected forms of DNA damage. We find that mutations in the Staphylococcus aureus walRKHI operon can confer low level resistance to actinorhodin, indicating possible targeting of the cell envelope. Our study indicates a complex mechanism of action, involving multiple molecular targets, that is distinct from other antibiotics. PMID- 28906046 TI - The unique N-terminal zinc finger of synaptotagmin-like protein 4 reveals FYVE structure. AB - Synaptotagmin-like protein 4 (Slp4), expressed in human platelets, is associated with dense granule release. Slp4 is comprised of the N-terminal zinc finger, Slp homology domain, and C2 domains. We synthesized a compact construct (the Slp4N peptide) corresponding to the Slp4 N-terminal zinc finger. Herein, we have determined the solution structure of the Slp4N peptide by nuclear magnetic resonance (NMR). Furthermore, experimental, chemical modification of Cys residues revealed that the Slp4N peptide binds two zinc atoms to mediate proper folding. NMR data showed that eight Cys residues coordinate zinc atoms in a cross-brace fashion. The Simple Modular Architecture Research Tool database predicted the structure of Slp4N as a RING finger. However, the actual structure of the Slp4N peptide adopts a unique C4 C4 -type FYVE fold and is distinct from a RING fold. To create an artificial RING finger (ARF) with specific ubiquitin-conjugating enzyme (E2)-binding capability, cross-brace structures with eight zinc-ligating residues are needed as the scaffold. The cross-brace structure of the Slp4N peptide could be utilized as the scaffold for the design of ARFs. PMID- 28906047 TI - A systematic review to explore influences on parental attitudes towards antibiotic prescribing in children. AB - AIMS AND OBJECTIVES: To understand the factors influencing parental attitudes towards antibiotic prescribing. BACKGROUND: Overuse of antibiotics and inappropriate prescribing has resulted in rapid development of antimicrobial resistance (AMR) and is a significant global threat to patient safety. In primary care settings, substantial numbers of antibiotics are prescribed for young children, despite viral nature of illness for which antibiotics are ineffective. Parents play a vital role in decision-making regarding accessing healthcare services and requesting treatment for their children. DESIGN: A systematic review was conducted in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (Moher et al., Systematic Reviews, 4, 2015, p. 1). METHODS: The CINAHL, MEDLINE, PsycINFO, The Cochrane Library, BRITISH NURSING INDEX, EMBASE and PUBMED databases were searched for primary research published between 2006-2016. All types of primary research were searched and screened against inclusion criteria. The Critical Appraisal Skills Programme tool was used to appraise identified publications. Quantitative data were summarised descriptively, and qualitative data were thematically analysed. RESULTS: A total of 515 publications were initially screened, and 55 full-text articles were eligibility assessed. Twenty papers met inclusion criteria. Four main themes were identified: the quality of relationships with healthcare providers, dealing with conflicting messages, rationalising antibiotic use and parental practices informed by past experience. CONCLUSIONS: Parents wanted reassurance and advice regarding children's illnesses, had poor antibiotic knowledge and were influenced by personal past experiences. More accessible education, including simple information leaflets, is required. Further research on the influence of culture, ethnicity and socio-economic factors would be beneficial. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals must provide adequate time for reassurance and explanations of decision-making. Easy-to-read information regarding appropriate antibiotic usage should be easily accessible for parents. PMID- 28906048 TI - Synthesis of RNA Containing 5-Hydroxymethyl-, 5-Formyl-, and 5-Carboxycytidine. AB - 5-Hydroxymethyl-, 5-formyl-, and 5-carboxy-2'-deoxycytidine are new epigenetic bases (hmdC, fdC, cadC) that were recently discovered in the DNA of higher eukaryotes. The same bases (5-hydroxymethyl-, 5-formyl-, and 5-carboxycytidine; hmC, fC, and caC) have now also been detected in mammalian RNA with a high abundance in mRNA. While DNA phosphoramidites (PAs) that allow the synthesis of xdC-containing oligonucleotides for deeper biological studies are available, the corresponding silyl-protected RNA PAs for fC and caC have not yet been disclosed. Here, we report novel RNA PAs for hmC, fC, and caC that can be used in routine RNA synthesis. The new building blocks are compatible with the canonical PAs and also with themselves, which enables even the synthesis of RNA strands containing all three of these bases. The study will pave the way for detailed physical, biochemical, and biological studies to unravel the function of these non canonical modifications in RNA. PMID- 28906049 TI - Alitretinoin treatment of lichen amyloidosis. AB - Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49-year-old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6-month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis. PMID- 28906050 TI - Labral calcification in end-stage osteoarthritis of the hip correlates with pain and clinical function. AB - : The acetabular labrum of the hip (ALH) is recognized as a clinically important structure, but knowledge about the pathophysiology of this fibrocartilage is scarce. In this prospective study we determined the prevalence of ALH calcification in patients with end-stage osteoarthritis (OA) and analyzed the relationship of cartilage calcification (CC) with hip pain and clinical function. Cohort of 80 patients (70.2 +/- 7.6years) with primary OA scheduled for total hip replacement. Harris Hip Score (HHS) was recorded preoperatively. Total ALH and femoral head (FH) were sampled intraoperatively. CC of the ALH and FH was analyzed by high-resolution digital contact radiography. Histological degeneration of the ALH (Krenn-Score) and FH (OARSI-Score) was determined. Multivariate linear regression model and partial correlation analyses were performed. The prevalence of cartilage calcification both in the ALH and FH was 100%, while the amount of CC in the ALH was 1.55 times higher than in the FH (p < 0.001). There was a significant inverse regression between the amount of calcification of both the ALH and the FH and preoperative HHS (betaALH = -2.1, p = 0.04), (betaFH = -2.9, p = 0.005), but pain was influenced only by ALH calcification (betaALH = -2.7, p = 0.008). Age-adjusted, there was a significant correlation between cartilage calcification and histological degeneration (ALH:rs = 0.53, p < 0.001/FH: rs = 0.30, p = 0.007). Fibrocartilage and articular cartilage calcification are inseparable pathological findings in end-stage osteoarthritis of the hip. Fibrocartilage calcification is associated with poor and painful hip function. CLINICAL SIGNIFICANCE: ALH fibrocartilage appears to be particularly prone to calcification, which may explain higher pain levels in individuals with a high degree of ALH calcification independent of age and histological degeneration. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1248-1255, 2018. PMID- 28906051 TI - Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study. AB - Secukinumab (anti-IL17A) is effective as treatment for moderate to severe plaque psoriasis, but real-life data on effectiveness and safety lack. We aimed to present real-life data of all Danish patients treated with secukinumab (n = 69). At baseline, before initiation of treatment with secukinumab 300 mg (47.8%) or off-label treatment with secukinumab 150 mg (52.2%), the median PASI score was 7.1. A total of 66.7% (34/51) and 52.9% (27/51) of patients still on secukinumab at week 12 achieved a PASI (Psoriasis Area and Severity Index)-50 and PASI-75 of 66.7% and 52.9%, respectively. A total of 83.0% (44/53) and 60.4% (32/53) of the patients had a PASI-score < 5 and PASI-score < 2, respectively, after 12 weeks on treatment with secukinumab. A third of the patients had secukinumab discontinued due to limited clinical improvement or adverse events (n = 23) within a median of 92 days (interquartile range 51-212 days). Notably, the majority of the patients may represent a particularly difficult-to-treat group of patients, as 92.8% had been refractory to other biologic treatment. A total of 26.1% (n = 18) experienced adverse events. Secukinumab appears to be an effective treatment option with a favorable side effect profile in patients with plaque psoriasis who are refractory to or have side effects of traditional biologic drugs. PMID- 28906053 TI - The effects of menstrual cycle phase on the incidence of plateau at VO2max and associated cardiorespiratory dynamics. AB - The purpose of this study was to examine the effect of menstrual cycle phase on maximal oxygen uptake (VO2max) and associated cardiodynamic responses. A total of 16 active females volunteered of which n = 10 formed the non-oral contraceptive pill group (n-OCP), displaying a regular menstrual cycle of 28.4 +/- 2.2 days (age 20.6 +/- 1.6 years, height 169.9 +/- 6.4 cm, mass 68.7 +/- 7.9 kg) and n = 6 formed the oral contraceptive pill group (OCP) (monophasic pill) (age 21.7 years +/- 2.16, height 168.1 cm +/- 6.8 cm, mass 61.6 +/- 6.8 kg). Each completed four incremental exercise tests for determination of VO2max, cardiac output, stroke volume and heart rate. Each test was completed according to the phases of the menstrual cycle as determined through salivary analysis of 17-beta oestrodiol and progesterone. Non-significant differences were observed for VO2max across phases and between groups (P>0.05) with additional non-significant differences for Qmax, HRmax and SVmax between groups. For ? VO2 during the final 60 s of the VO2max trial, significant differences were observed between OCP and n-OCP (P<0.05) with OCP showing zero VO2 plateaus in three pseudo-phases. Significant difference observed for a-vO2dif n-OCP between premenstruation and menstruation at 30-100% VO2max (P<0.05). Data suggest that the VO2 -plateau is effected by monophasic oral contraceptive pill, furthermore these data imply that VO2max test outcome is independent of menstrual cycle phase but caution should be applied when evaluating maximal oxygen uptake in females who are administered a monophasic oral contraceptive pill. PMID- 28906052 TI - Forest biomass, productivity and carbon cycling along a rainfall gradient in West Africa. AB - Net Primary Productivity (NPP) is one of the most important parameters in describing the functioning of any ecosystem and yet it arguably remains a poorly quantified and understood component of carbon cycling in tropical forests, especially outside of the Americas. We provide the first comprehensive analysis of NPP and its carbon allocation to woody, canopy and root growth components at contrasting lowland West African forests spanning a rainfall gradient. Using a standardized methodology to study evergreen (EF), semi-deciduous (SDF), dry forests (DF) and woody savanna (WS), we find that (i) climate is more closely related with above and belowground C stocks than with NPP (ii) total NPP is highest in the SDF site, then the EF followed by the DF and WS and that (iii) different forest types have distinct carbon allocation patterns whereby SDF allocate in excess of 50% to canopy production and the DF and WS sites allocate 40%-50% to woody production. Furthermore, we find that (iv) compared with canopy and root growth rates the woody growth rate of these forests is a poor proxy for their overall productivity and that (v) residence time is the primary driver in the productivity-allocation-turnover chain for the observed spatial differences in woody, leaf and root biomass across the rainfall gradient. Through a systematic assessment of forest productivity we demonstrate the importance of directly measuring the main components of above and belowground NPP and encourage the establishment of more permanent carbon intensive monitoring plots across the tropics. PMID- 28906054 TI - Neuropathological comorbidity associated with argyrophilic grain disease. AB - Argyrophilic grain disease (AGD) is a common four-repeat tauopathy in elderly people. While dementia is a major clinical picture of AGD, recent studies support the possibility that AGD may be a pathological base in some patients with mild cognitive impairment, late-onset psychosis, bipolar disorder and depression. AGD often coexists with various other degenerative changes. The frequency of AGD in progressive supranuclear palsy (PSP) cases was reported to range from 18.8% to 80%. The frequency of AGD in corticobasal degeneration (CBD) cases tends to be higher than that in PSP cases, ranging from 41.2% to 100%. Conversely, in our previous study of the frequencies of mild PSP and CBD pathologies in AGD cases, five of 20 AGD cases (25%) had a few Gallyas-positive tufted astrocytes, six cases (30%) had a few granular/fuzzy astrocytes, and one case (5.0%) had a few Gallyas-positive astrocytic plaques in the putamen, caudate nucleus and/or superior frontal gyrus. Both Gallyas-positive tufted astrocytes and Gallyas negative tau-positive granular/fuzzy astrocytes preferentially developed in the putamen, caudate nucleus and superior frontal cortex in AGD cases, being consistent with the predilection sites of Gallyas-positive tufted astrocytes in PSP cases. Further, in AGD cases, the quantities of Gallyas-positive tufted astrocytes, overall tau-positive astrocytes, and tau-positive neurons in the subcortical nuclei and superior frontal cortex were significantly correlated with Saito AGD stage, respectively. The frequency of AGD in AD cases was reported to reach up to 25% when using four-repeat tau immunohistochemistry. Pretangles are essential pathologies in AGD; however, the Braak stage of three-repeat tau positive NFTs, which may indicate mild AD pathology or primary age-related tauopathy, was not correlated with Saito AGD stage. Clinicians should be aware of the possibility that coexisting AGD may impact clinical and radiological features in cases of other degenerative diseases. PMID- 28906056 TI - Perioperative management of haemophilia A using recombinant factor VIII Fc fusion protein in a patient undergoing endoscopic nasal pituitary adenomectomy for a growth hormone-producing pituitary adenoma. PMID- 28906055 TI - The role of genomic location and flanking 3'UTR in the generation of functional levels of variant surface glycoprotein in Trypanosoma brucei. AB - Trypanosoma brucei faces relentless immune attack in the mammalian bloodstream, where it is protected by an essential coat of Variant Surface Glycoprotein (VSG) comprising ~10% total protein. The active VSG gene is in a Pol I-transcribed telomeric expression site (ES). We investigated factors mediating these extremely high levels of VSG expression by inserting ectopic VSG117 into VSG221 expressing T. brucei. Mutational analysis of the ectopic VSG 3'UTR demonstrated the essentiality of a conserved 16-mer for mRNA stability. Expressing ectopic VSG117 from different genomic locations showed that functional VSG levels could be produced from a gene 60 kb upstream of its normal telomeric location. High, but very heterogeneous levels of VSG117 were obtained from the Pol I-transcribed rDNA. Blocking VSG synthesis normally triggers a precise precytokinesis cell cycle checkpoint. VSG117 expression from the rDNA was not adequate for functional complementation, and the stalled cells arrested prior to cytokinesis. However, VSG levels were not consistently low enough to trigger a characteristic 'VSG synthesis block' cell-cycle checkpoint, as some cells reinitiated S phase. This demonstrates the essentiality of a Pol I-transcribed ES, as well as conserved VSG 3'UTR 16-mer sequences for the generation of functional levels of VSG expression in bloodstream form T. brucei. PMID- 28906057 TI - A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug-Resistant Staphylococcus aureus. AB - The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. We utilized a high-throughput screen against the ClpXP complex and identified a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversification, with only minor changes tolerated. Subsequent analysis of the most active compound revealed strong attenuation of S. aureus toxin production, which was quantified with a customized MS-based assay platform. Transcriptome and whole-proteome studies further confirmed the global reduction of virulence and revealed characteristic signatures of protein expression in the compound-treated cells. Although these partially matched the pattern of ClpX knockout cells, further depletion of toxins was observed, leading to the intriguing perspective that additional virulence pathways may be directly or indirectly addressed by the small molecule. PMID- 28906058 TI - Stabilization of Low-Valent Iron(I) in a High-Valent Vanadium(V) Oxide Cluster. AB - Low-valent iron centers are critical intermediates in chemical and bio-chemical processes. Herein, we show the first example of a low-valent FeI center stabilized in a high-valent polyoxometalate framework. Electrochemical studies show that the FeIII -functionalized molecular vanadium(V) oxide (DMA)[FeIII ClVV12 O32 Cl]3- (DMA=dimethylammonium) features two well-defined, reversible, iron-based electrochemical reductions which cleanly yield the FeI species (DMA)[FeI ClVV12 O32 Cl]5- . Experimental and theoretical studies including electron paramagnetic resonance spectroscopy and density functional theory computations verify the formation of the FeI species. The study presents the first example for the seemingly paradoxical embedding of low-valent metal species in high-valent metal oxide anions and opens new avenues for reductive electron transfer catalysis by polyoxometalates. PMID- 28906059 TI - Benefits and Limitations of DNA Barcoding and Metabarcoding in Herbal Product Authentication. AB - INTRODUCTION: Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono-substance medicines. Current quality and authentication assessment methods rely mainly on morphology and analytical phytochemistry-based methods detailed in pharmacopoeias. Herbal products however are often highly processed with numerous ingredients, and even if these analytical methods are accurate for quality control of specific lead or marker compounds, they are of limited suitability for the authentication of biological ingredients. OBJECTIVE: To review the benefits and limitations of DNA barcoding and metabarcoding in complementing current herbal product authentication. METHOD: Recent literature relating to DNA based authentication of medicinal plants, herbal medicines and products are summarised to provide a basic understanding of how DNA barcoding and metabarcoding can be applied to this field. RESULTS: Different methods of quality control and authentication have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. CONCLUSIONS: DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. Standardisation of protocols for DNA barcoding and DNA sequence-based identification are necessary before DNA-based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures. (c) 2017 The Authors. Phytochemical Analysis Published by John Wiley & Sons Ltd. PMID- 28906061 TI - Electrostatic interactions drive native-like aggregation of human alanine:glyoxylate aminostransferase. AB - Protein aggregate formation is the basis of several misfolding diseases, including those displaying loss-of-function pathogenesis. Although aggregation is often attributed to the population of intermediates exposing hydrophobic surfaces, the contribution of electrostatic forces has recently gained attention. Here, we combined computational and in vitro studies to investigate the aggregation process of human peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme involved in glyoxylate detoxification. We demonstrated that AGT is susceptible to electrostatic aggregation due to its peculiar surface charge anisotropy and that PLP binding counteracts the self-association process. The two polymorphic mutations P11L and I340M exert opposite effects. The P11L substitution enhances the aggregation tendency, probably by increasing surface charge anisotropy, while I340M plays a stabilizing role. In light of these results, we examined the effects of the most common missense mutations leading to primary hyperoxaluria type I (PH1), a rare genetic disorder associated with abnormal calcium oxalate precipitation in the urinary tract. All of them endow AGT with a strong electrostatic aggregation propensity. Moreover, we predicted that pathogenic mutations of surface residues could alter charge distribution, thus inducing aggregation under physiological conditions. A global model describing the AGT aggregation process is provided. Overall, the results indicate that the contribution of electrostatic interactions in determining the fate of proteins and the effect of amino acid substitutions should not be underestimated and provide the basis for the development of new therapeutic strategies for PH1 aimed at increasing AGT stability. PMID- 28906060 TI - Novel coordination of lipopolysaccharide modifications in Vibrio cholerae promotes CAMP resistance. AB - In the environment and during infection, the human intestinal pathogen Vibrio cholerae must overcome noxious compounds that damage the bacterial outer membrane. The El Tor and classical biotypes of O1 V. cholerae show striking differences in their resistance to membrane disrupting cationic antimicrobial peptides (CAMPs), such as polymyxins. The classical biotype is susceptible to CAMPs, but current pandemic El Tor biotype isolates gain CAMP resistance by altering the net charge of their cell surface through glycine modification of lipid A. Here we report a second lipid A modification mechanism that only functions in the V. cholerae El Tor biotype. We identify a functional EptA ortholog responsible for the transfer of the amino-residue phosphoethanolamine (pEtN) to the lipid A of V. cholerae El Tor that is not functional in the classical biotype. We previously reported that mildly acidic growth conditions (pH 5.8) downregulate expression of genes encoding the glycine modification machinery. In this report, growth at pH 5.8 increases expression of eptA with concomitant pEtN modification suggesting coordinated regulation of these LPS modification systems. Similarly, efficient pEtN lipid A substitution is seen in the absence of lipid A glycinylation. We further demonstrate EptA orthologs from non-cholerae Vibrio species are functional. PMID- 28906062 TI - Gemcitabine, Pyrrologemcitabine, and 2'-Fluoro-2'-Deoxycytidines: Synthesis, Physical Properties, and Impact of Sugar Fluorination on Silver Ion Mediated Base Pairing. AB - The stability of silver-mediated "dC-dC" base pairs relies not only on the structure of the nucleobase, but is also sensitive to structural modification of the sugar moiety. 2'-Fluorinated 2'-deoxycytidines with fluorine atoms in the arabino (up) and ribo (down) configuration as well as with geminal fluorine substitution (anticancer drug gemcitabine) and the novel fluorescent phenylpyrrolo-gemcitabine (ph PyrGem) have been synthesized. All the nucleosides display the recognition face of naturally occurring 2'-deoxycytidine. The nucleosides were converted into phosphoramidites and incorporated into 12-mer oligonucleotides by solid-phase synthesis. The addition of silver ions to DNA duplexes with a fluorine-modified "dC-dC" pair near the central position led to significant duplex stabilization. The increase in stability was higher for duplexes with fluorinated sugar residues than for those with an unchanged 2' deoxyribose moiety. Similar observations were made for "dC-dT" pairs and to a minor extent for "dC-dA" pairs. The increase in silver ion mediated base-pair stability was reversed by annulation of a pyrrole ring to the cytosine moiety, as shown for 2'-fluorinated ph PyrGem in comparison with phenylpyrrolo-dC (ph PyrdC). This phenomenon results from stereoelectronic effects induced by fluoro substitution, which are transmitted from the sugar moiety to the silver ion mediated base pairs. The extent of the effect depends on the number of fluorine substituents, their configuration, and the structure of the nucleobase. PMID- 28906064 TI - Reactive oxygen species generated in chloroplasts contribute to tobacco leaf infection by the necrotrophic fungus Botrytis cinerea. AB - Reactive oxygen species (ROS) play fundamental roles in plant responses to pathogen infection, including modulation of cell death processes and defense related gene expression. Cell death triggered as part of the hypersensitive response enhances resistance to biotrophic pathogens, but favors the virulence of necrotrophs. Even though the involvement of ROS in the orchestration of defense responses is well established, the relative contribution of specific subcellular ROS sources to plant resistance against microorganisms with different pathogenesis strategies is not completely known. The aim of this work was to investigate the role of chloroplastic ROS in plant defense against a typical necrotrophic fungus, Botrytis cinerea. For this purpose, we used transgenic Nicotiana tabacum (tobacco) lines expressing a plastid-targeted cyanobacterial flavodoxin (pfld lines), which accumulate lower chloroplastic ROS in response to different stresses. Tissue damage and fungal growth were significantly reduced in infected leaves of pfld plants, as compared with infected wild-type (WT) counterparts. ROS build-up triggered by Botrytis infection and associated with chloroplasts was significantly decreased (70-80%) in pfld leaves relative to the wild type. Phytoalexin accumulation and expression of pathogenesis-related genes were induced to a lower degree in pfld plants than in WT siblings. The impact of fungal infection on photosynthetic activity was also lower in pfld leaves. The results indicate that chloroplast-generated ROS play a major role in lesion development during Botrytis infection. This work demonstrates that the modulation of chloroplastic ROS levels by the expression of a heterologous antioxidant protein can provide a significant degree of protection against a canonical necrotrophic fungus. PMID- 28906065 TI - Colloidal Synthesis and Photophysics of M3 Sb2 I9 (M=Cs and Rb) Nanocrystals: Lead-Free Perovskites. AB - Herein we report the colloidal synthesis of Cs3 Sb2 I9 and Rb3 Sb2 I9 perovskite nanocrystals, and explore their potential for optoelectronic applications. Different morphologies, such as nanoplatelets and nanorods of Cs3 Sb2 I9 , and spherical Rb3 Sb2 I9 nanocrystals were prepared. All these samples show band-edge emissions in the yellow-red region. Exciton many-body interactions studied by femtosecond transient absorption spectroscopy of Cs3 Sb2 I9 nanorods reveals characteristic second-derivative-type spectral features, suggesting red-shifted excitons by as much as 79 meV. A high absorption cross-section of ca. 10-15 cm2 was estimated. The results suggest that colloidal Cs3 Sb2 I9 and Rb3 Sb2 I9 nanocrystals are potential candidates for optical and optoelectronic applications in the visible region, though a better control of defect chemistry is required for efficient applications. PMID- 28906063 TI - Models of convergent extension during morphogenesis. AB - Convergent extension (CE) is a fundamental and conserved collective cell movement that forms elongated tissues during embryonic development. Thus far, studies have demonstrated two different mechanistic models of collective cell movements during CE. The first, termed the crawling mode, was discovered in the process of notochord formation in Xenopus laevis embryos, and has been the established model of CE for decades. The second model, known as the contraction mode, was originally reported in studies of germband extension in Drosophila melanogaster embryos and was recently demonstrated to be a conserved mechanism of CE among tissues and stages of development across species. This review summarizes the two modes of CE by focusing on the differences in cytoskeletal behaviors and relative expression of cell adhesion molecules. The upstream molecules regulating these machineries are also discussed. There are abundant studies of notochord formation in X. laevis embryos, as this was one of the pioneering model systems in this field. Therefore, the present review discusses these findings as an approach to the fundamental biological question of collective cell regulation. WIREs Dev Biol 2018, 7:e293. doi: 10.1002/wdev.293 This article is categorized under: Early Embryonic Development > Gastrulation and Neurulation Comparative Development and Evolution > Model Systems. PMID- 28906066 TI - Nitrogen-Doped Carbon Activated in Situ by Embedded Nickel through the Mott Schottky Effect for the Oxygen Reduction Reaction. AB - The development of low-cost non-precious-metal electrocatalysts with high activity and stability in the oxygen reduction reaction (ORR) remains a great challenge. Heteroatom-doped carbon materials are receiving increased attention in research as effective catalysts. However, the uncontrolled doping of heteroatoms into a carbon matrix tends to inhibit the activity of a catalyst. Here, the in situ activation of a uniquely structured nitrogen-doped carbon/Ni composite catalyst for the ORR is demonstrated. This well-designed catalyst is composed of a nitrogen-doped carbon shell and embedded metallic nickel. The embedded Ni nanoparticles, dispersed on stable alumina with a high specific surface area for protecting them from agglomeration and in an unambiguous composite structure, are electron-donating and are shielded by the nitrogen-doped carbon from oxidation/dissolution in harsh environments. The electronic structure of the nitrogen-doped carbon shell is modulated by the transfer of electrons at the interface of nitrogen-doped carbon-Ni heterojunctions owing to the Mott-Schottky effect. The electrochemically active surface area result implies that the active sites do not relate to Ni directly and the enhanced catalytic activity mainly arises from the modulation of nitrogen-doped carbon by nickel. XPS and theoretical calculations suggest that the donated electrons are transferred to pyridinic N primarily, which ought to enhance the catalytic activity intrinsically. Benefiting from these transferred electrons, the half-wave potential of the nitrogen-doped carbon/Ni composite catalyst is 94 mV positively shifted compared to the Ni-free sample. PMID- 28906067 TI - Ruminal phytate degradation of maize grain and rapeseed meal in vitro and as affected by phytate content in donor animal diets and inorganic phosphorus in the buffer. AB - The ruminal disappearance of phytate phosphorus (InsP6 -P) from maize grain and rapeseed meal (RSM) was determined in two in vitro studies. In experiment 1, two diets differing in phosphorus (P) and InsP6 -P concentration were fed to the donor animals of rumen fluid (diet HP: 0.49% P in dry matter, diet LP: 0.29% P). Maize grain and RSM were incubated in a rumen fluid/saliva mixture for 3, 6, 12 and 24 h. In experiment 2, a diet similar to diet HP was fed, and the rumen fluid was mixed with artificial saliva containing 120 mg inorganic P/l (Pi) or no inorganic P (P0). Maize grain and RSM were incubated with either buffer for 3, 6, 12 and 24 h. Total P (tP) and InsP6 concentration were analysed in the fermenter fluids and feed residues. The disappearance of InsP6 -P from maize was completed after 12 h of incubation in both experiments. From RSM, 93% (diet LP) and 99% (diet HP) of the InsP6 -P in experiment 1 and 80% (Pi) and 89% (P0) in experiment 2 had disappeared after 24 h of incubation. InsP6 -P disappearance was higher when diet HP was fed (maize: 3 and 6 h; RSM: 6 and 24 h of incubation) and when rumen fluid was mixed with buffer P0 (maize: 6 h; RSM: 12 and 24 h of incubation). InsP6 -P concentration in the fermenter fluids was higher for maize, but no accumulation of InsP6 -P occurred, indicating a prompt degradation of soluble InsP6 . These results confirmed the capability of rumen micro-organisms to efficiently degrade InsP6 . However, differences between the feedstuffs and diet composition as well as the presence of inorganic P in the in vitro system influenced the degradation process. Further studies are required to understand how these factors affect InsP6 degradation and their respective relevance in vivo. PMID- 28906068 TI - Human mating strategies: from past causes to present consequences. AB - In both humans and nonhuman animals, mating strategies represent a set of evolutionary adaptations aimed at promoting individual fitness by means of reproduction with the best possible partners. Given this critical role, mating strategies influence numerous aspects of human life. In particular, between-sex divergence in the intensity of intrasexual competition could account for robust cross-cultural sex differences in psychology and behavior (e.g., personality, psychiatric disorders, social behavior, violence). Several other factors (including individual differences, relationship type and environment) affect-in an evolutionarily consistent manner-variation in mating strategy that individuals pursue (as one example, awareness of one's own attractiveness impinges on mating standards). Here we provide an overview of relevant theoretical frameworks and empirical evidence on variation in mating strategies. Given its multifaceted nature and intense research interest over several decades, this is a challenging task, and we highlight areas where further investigation is warranted in order to achieve a clearer picture and resolve apparent inconsistencies. However, we suggest that addressing outstanding questions using a variety of different methodological approaches, a deeper understanding of the cognitive representations involved in mating strategies is within reach. WIREs Cogn Sci 2018, 9:e1456. doi: 10.1002/wcs.1456 This article is categorized under: Cognitive Biology > Evolutionary Roots of Cognition Neuroscience > Behavior Neuroscience > Cognition. PMID- 28906069 TI - Distribution of Amyloid-Like and Oligomeric Species from Protein Aggregation Kinetics. AB - Amyloid fibrils and soluble oligomers are two types of protein aggregates associated with neurodegeneration. Classic therapeutic strategies try to prevent the nucleation and spread of amyloid fibrils, whilst diffusible oligomers have emerged as promising drug targets affecting downstream pathogenic processes. We developed a generic protein aggregation model and validate it against measured compositions of fibrillar and non-fibrillar assemblies of ataxin-3, a protein implicated in Machado-Joseph disease. The derived analytic rate-law equations can be used to 1) identify the presence of parallel aggregation pathways and 2) estimate the critical sizes of amyloid fibrils. The discretized population balance supporting our model is the first to quantitatively fit time-resolved measurements of size and composition of both amyloid-like and oligomeric species. The new theoretical framework can be used to screen a new class of drugs specifically targeting toxic oligomers. PMID- 28906070 TI - Ring Expansion, Photoisomerization, and Retrocyclization of 1,4,2-Diazaboroles. AB - Diverse skeletal transformations of 1,4,2-diazaboroles through ring expansion, photoisomerization, and retrocyclization led to the isolation of various B,N dihydroindole (compounds 3 and 6), 1,3-azaborolidin-2-imine (compound 7), and 1,4,2-diazaborol-3-imine derivatives (compound 11). PMID- 28906071 TI - Construction of Quaternary Stereogenic Centers in the Total Synthesis of Natural Products. AB - Total syntheses of the tetracyclic terpene waihoensene and the densely functionalized tetracyclic compound ryanodol have recently been reported. Both approaches constitute examples of the efficient and innovative construction of multiple quaternary centers. PMID- 28906072 TI - "It just made me feel so desolate": Patients' narratives of weight gain following laparoscopic insertion of a gastric band. AB - AIMS AND OBJECTIVES: To describe the experiences of patients who have failed to maintain weight loss following the insertion of a laparoscopic adjustable gastric band (LAGB) for the treatment of morbid obesity. BACKGROUND: Obesity is a global health problem resulting in physical, psychological and economic problems and presenting challenges for health services. Surgical intervention is an increasingly common approach to treatment; however, some patients do not sustain their weight loss following bariatric surgery and little is known about people's longer-term experiences following LAGB insertion. DESIGN: A narrative-based qualitative interview study. METHODS: A purposive sample of ten participants who had undergone LAGB insertion for morbid obesity was recruited. Semistructured interviews were conducted in 2014. Thematic analysis identified codes and emerging themes common to the participants' experiences. FINDINGS: Three major themes emerged: living with the side effects, regret and lack of support. These reflect the difficulties participants experienced and provide new insights on why weight loss is not sustained after 2 years following surgery. CONCLUSION: Participants reported that the surgery had a detrimental effect on their lives and some regretted having the band inserted. These findings identify areas of care that need to be addressed if patients undergoing LAGB are to experience its potential benefits and indicate that further research is needed into the long term effects of gastric band insertion. Patients need to be better informed about the consequences of bariatric surgery if it is to have a lasting impact on their weight reduction. RELEVANCE TO CLINICAL PRACTICE: Patients require comprehensive information and support before and after LAGB insertion to develop strategies which will help them lose weight and sustain it over the longer term. Clinicians need to be sensitive to patients' needs when weight loss plateaus or weight is regained and intensify support during these periods. PMID- 28906073 TI - Salvage radiotherapy for regional lymph node oligo-recurrence after radical surgery of non-small cell lung cancer. AB - BACKGROUND: Currently, evidence-based guidelines for salvage therapy to treat mediastinal lymph node (LN) oligo-recurrence in post-resection non-small cell lung cancer (NSCLC) are limited. In patients previously treated by surgery without irradiation, radiotherapy (RT) might be safely utilized. We evaluate the clinical outcomes of salvage RT for patients with LN oligo-recurrence that developed after radical surgery for NSCLC. METHODS: Thirty-one patients with stage I-IIIA NSCLC who developed regional LN oligo-recurrence between 2008 and 2013 were reviewed. The median time from surgery to recurrence was 12 months. Fifteen patients (48.4%) had single LN recurrence. All patients were irradiated by 3-dimensional conformal RT at the recurrent LN area with daily fractions of 2 3 Gy, with a median dose of 66 Gy (range 51-66). Sixteen patients also received chemotherapy. RESULTS: After salvage RT, 16 patients achieved a complete response, nine a partial response, and six had stable disease. The median follow up was 14 months (range 3-76). One and two-year in-field control rates were 88.4% and 75.8%, respectively. One and two-year progression-free survival rates were 73.1% and 50.9%, respectively. Progression sites were predominantly distant. Ten of the 31 patients (32.3%) met the revised Response Evaluation Criteria for Solid Tumors for a complete response by the final follow-up. Recurrent LN size (<3 vs. >=3 cm) was a significant prognostic factor for progression-free survival (P = 0.013). CONCLUSION: Salvage RT for patients with regional LN oligo-recurrence after radical surgery was an effective treatment option with an acceptable level of toxicity. PMID- 28906074 TI - Fully Automated Quantum-Chemistry-Based Computation of Spin-Spin-Coupled Nuclear Magnetic Resonance Spectra. AB - We present a composite procedure for the quantum-chemical computation of spin spin-coupled 1 H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight-binding method GFN-xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR-specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin-spin couplings are computed at state-of-the-art DFT levels with continuum solvation. A few (in)organic and transition-metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100-150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules. PMID- 28906076 TI - Stimulus-sensitive myoclonus with trigeminal neuralgia. PMID- 28906077 TI - Thalamotomy for paroxysmal kinesigenic dyskinesias in a multiplex family. PMID- 28906078 TI - Response to Dr Voring et al. PMID- 28906079 TI - Comment on 'Efficacy and feasibility of antidepressants for the prevention of migraine in adults: a meta-analysis'. PMID- 28906080 TI - Persistence and adherence with mirabegron vs antimuscarinics in overactive bladder: Retrospective analysis of a UK General Practice prescription database. AB - INTRODUCTION AND OBJECTIVES: Persistence with antimuscarinic (AM) drugs prescribed for overactive bladder (OAB) is poor. This study aimed to compare persistence and adherence with the beta-3-adrenoceptor agonist mirabegron (MIR) vs AMs over 12 months. PATIENTS AND METHODS: This retrospective cohort analysis included patients aged >=18 years who were prescribed MIR, or any AM. A 12-month look-back was used to assess inclusion eligibility. The primary end-point was persistence, defined as time to first discontinuation of index drug, during 1 year follow-up. The secondary end-point was adherence, estimated by medication possession ratio (MPR). RESULTS: Inclusion criteria were met by 6189 patients. Those prescribed AMs were mostly treatment-naive (range 72.9%-95.3%) vs 54.4% of MIR patients. There was greater persistence with MIR vs AM. The median number of days on therapy with MIR was 101, vs 27-56 for AMs. Patients receiving AMs were significantly more likely to discontinue than those receiving MIR (hazard ratio [HR] range 1.24-2.05, P < .01 for each AM vs MIR. In treatment-naive patients, HRs ranged from 1.25 (solifenacin, P = .012) to 2.07 (oxybutynin IR, P < .001). In treatment-experienced patients, they ranged from 1.10 (fesoterodine, P = NS) to 2.12 (oxybutynin IR, P < .001). Adherence was greater with MIR (mean MPR 48.4%) than with AMs (range 27.6%-40.4%, P < .001). Treatment-experienced patients were significantly less likely to discontinue treatment (HR 0.87, P = .006). DISCUSSION AND CONCLUSION: MIR was associated with a significantly longer time to discontinuation, greater persistence and better adherence than AMs. However, there was a steep decline in persistence with all drugs after 1 month. This is unlikely to be wholly explained by anticholinergic adverse events, as it was also seen with MIR. The lower proportion of MIR patients who were treatment naive reflects current prescribing guidelines whereby MIR is prescribed after an initial generic AM trial. The study was limited by the small number of MIR patients. Study identifier: ISN 178-MA-3059. PMID- 28906082 TI - Public money spent in pursuit of public money: Does it add up? PMID- 28906083 TI - Are in-house diagnostic MR physicists necessary for clinical implementation of MRI guided radiotherapy? PMID- 28906084 TI - Updates on the Epidemiology of Age-Related Macular Degeneration. AB - This meta-analysis reports on current estimates of the prevalence of age-related macular degeneration (AMD) based on a review of recent meta-analyses and literature research. Within an age of 45-85 years, global prevalences of any AMD, early AMD, and late AMD were 8.7% [95% credible interval (CrI), 4.3-17.4], 8.0% (95% CrI, 4.0-15.5), and 0.4% (95% CrI, 0.2-0.8). Early AMD was more common in individuals of European ancestry (11.2%) than in Asians (6.8%), whereas prevalence of late AMD did not differ significantly. AMD of any type was less common in individuals of African ancestry. The number of individuals with AMD was estimated to be 196 million (95% CrI, 140-261) in 2020 and 288 million (95% CrI, 205-399) in 2040. The worldwide number of persons blind (presenting visual acuity < 3/60) or with moderate to severe vision impairment (MSVI; presenting visual acuity < 6/18 to 3/60 inclusive) due to macular disease in 2010 was 2.1 million [95% uncertainty interval (UI), 1.9-2.7] individuals out of 32.4 million individuals blind and 6.0 million (95% UI, 5.2-8.1) persons out of 191 million people with MSVI. Age-standardized prevalence of macular diseases as cause of blindness in adults aged 50+ years worldwide decreased from 0.2% (95% UI, 0.2 0.2) in 1990 to 0.1% (95% UI, 0.1-0.2) in 2010; as cause for MSVI, it remained mostly unchanged (1990: 0.4%; 95% UI, 0.3-0.5; 2010: 0.4%; 95% UI, 0.4-0.6), with no significant sex difference. In 2015, AMD was the fourth most common cause of blindness globally (in approximately 5.8% of blind individuals) and third most common cause for MSVI (3.9%). These data show the globally increasing importance of AMD. PMID- 28906085 TI - Quality of life of psoriasis patients measured by the PSOdisk: a new visual method for assessing the impact of the disease. AB - BACKGROUND: Psoriasis is an inflammatory disease with a chronic course; often it is associated with various serious comorbidity and a compromised quality of life. Psoriasis patients experience a low self-esteem, feelings of shame and frustration, they report a seriously compromised social and sentimental sphere, difficulties at work and in daily activities, coming in most serious cases to suicidal ideation. METHODS: Our job is to experiment the introduction of the innovative PSOdisk tool to quantify the impact of psoriasis on quality of life, comparing it with PASI Index. We presented the empirical analysis, gathered through a sample of 24 patients, followed for 6 months of therapy with biologics. Patients were encountered three times, at a distance of three months each, during which we calculated a PASI score and we administered the PSOdisk. RESULTS: Through various statistical analyses we have identified a relationship between PSOdisk value and other parameters such as patient age and particular locations of psoriasis. Specifically we systematically observed that patients aged less than 50 years reported a more compromised quality of life (QoL) when compared to older patients with the same clinical severity. At the same time patients with hands or genitals involvement show higher values associated with the PSOdisk compared with patients without such anatomical deficiency. CONCLUSIONS: PSOdisk instrument proved to be effective and optimal for widespread distribution in the outpatient activity. It also encourages dialogue between doctor and patient; it increases compliance of the latter with regard to the therapy and a desirable improvement in outcomes. A systematic assessment of the impact of psoriasis on patients' QoL is fundamental and must complement the objective assessment in clinical practice. PMID- 28906086 TI - New formulation for topical treatment of onychomycoses. AB - BACKGROUND: In order to treat onychomycosis, topical and systemic medications are available. The choice of a systemic or topic treatment depends on numerous factors, such as patient's age, the presence of comorbidity, responsible fungal species, the clinical form of onychomycosis, its location (fingernails or toenails), the number of nails affected and the percentage of the nail plate infected. As for topical medications, given that nail plate has an insufficiently permeable structure, it is necessary to use appropriate formulae that create in the surface of the nail plate a film able, in turn, to function both as an active ingredient's deposit and moisturising agent in nail's superficial layers in order to facilitate the spread of the active ingredient. In this manuscript, we wanted to evaluate the effectiveness and tolerability rate of a new topical formulation (Miconal Nails(r), Morgan srl, Vicenza, Italy) composed of hydrogenated castor oil, hydroxyethyl cellulose, and other ingredients (urea, climbazole, piroctone olamine, undecylenic acid). METHODS: We selected 25 patients of both sexes whose median age was between 20 and 70 years, and were affected by onychomycosis in a single toe. Their onychomycosis was a distolateral subungual type (with a <50% invasion of nail plate and sparing of lunula) and white superficial. The treatment was evaluated with the following possible outcomes: complete healing, improvement, stationarity, worsening. RESULTS: Patients were 11 female subjects and 14 male subjects, whose median age was 45. A complete healing was achieved in 15 patients. In 3 cases the clinical presentation appeared unchanged with a persistence of mycological evidence. The response to the treatment was assessed as improvement in 7 patients. CONCLUSIONS: In our experience, this new product is an effective weapon that enhances the therapeutic selection of topical formulae for treating onychomycosis. If used alone in the cases that meet inclusion criteria for topical treatment, it allowed us to achieve a complete healing just with a 5-month treatment in 60% of cases, data that reached 76% on the follow-up visit. PMID- 28906087 TI - Phototherapy for vitiligo, what's new? AB - Vitiligo is a disorder characterized by the development of depigmented macules and patches. Existing treatments include topical and systemic immunosuppressants, topical vitamin D analogues in monotherapy or in association with phototherapy, phototherapy and surgical techniques, which together may serve to halt disease progression, stabilize depigmented lesions, and encourage repigmentation. Narrow band UVB (NB-UVB 310-315 nm) radiation is now considered as the "gold standard" for the treatment of diffuse vitiligo. This article provides a brief overview of the different phototherapy based treatments in vitiligo. PMID- 28906088 TI - Bullous cutaneous larva migrans: case series and review of atypical clinical presentations. AB - Hookworm-related cutaneous larva migrans (HRCLM) is caused by the penetration and migration in the epidermis of larvae of Ancylostoma braziliense and Ancylostoma caninum. It is characterized by slightly raised and erythematous tracks, located especially on the feet. These tracks may be single or multiple, serpiginous or linear, ramified and intertwined, accompanied by pruritus. Atypical clinical presentations of HRCLM are currently more frequent than in the past. We present six patients with bullous HRCLM and discuss the possible pathogenetic factors. Furthermore, we present a review of atypical clinical presentations of HRCLM. From 1998 to 2013 we observed approximately 180 patients with HRCLM. In all patients race, nationality, sex, age, country of infestation, location of the disease, clinical picture, laboratory and instrumental examinations and therapy were collected. In six patients (4 males and 2 females), we made a diagnosis, based on the history and clinical picture, of bullous HRCLM. The infestation was characterized by single or multiple blisters, round or oval in shape, of different size, with a clear serous fluid. Some tracks were also visible. All patients complained of pruritus. General physical examination and laboratory and instrumental examinations were normal or negative. Cytological examinations of the blisters showed the presence of lymphocytes and neutrophils, with numerous eosinophils. All patients were successfully treated with oral albendazole. Blisters appear because of the release by the larvae of lytic enzymes (metalloproteases and hyaluronidases). Furthermore, blisters might be the final clinical result of a delayed hypersensitivity reaction due to the release by larvae of unknown antigens. Finally, only in some patients, bullous HRCLM might represent an acute irritant/allergic contact dermatitis caused by topical drugs applied on the lesions. This hypothesis has been excluded in our patients because no topical treatment was made before our observation. PMID- 28906089 TI - Alopecia as unique clue to syphilis in a patient. AB - Alopecia is an uncommon manifestation of syphilis, simulating other common forms of hair-loss, but representing a crucial complaint for the patient, who might by converse have not noticed other signs and symptoms of the disease. Esthetic issues undervaluation might prolong illness, and postpone appropriate treatment. A 42-year-old patient, HIV negative, presented with a 2-month history of progressive generalized thinning of the hairs and small non-scarring irregular alopecia patches of the parietal-occipital areas of the scalp. The patient was under sertraline hydrochloride therapy for a recent diagnosis of bipolar disorder, and expressed the concern that the drug was causing the hair-loss. Accurate anamnesis and visiting of the patients revealed asymptomatic pale pink speckles of the trunk and limbs, and a bilateral psoriasis-like palmo-plantar hyperkeratosis, suggestive of secondary syphilis, further confirmed by serology. Specific antibiotic treatment healed all skin and scalp manifestations, but also the moodiness disorders, which allowed complete psychiatric drug dismissing. Skilled expertise and careful patient's examination are the clue to recognize minimal signs of serious systemic disease, such as syphilis, considered disappeared for decades. The risk of minimizing esthetic complaints, such as hair loss can deceive a not trained eye, or escape in busy daily practice. Physicians should maintain a high level of clinical suspicion to contain the disease burden, especially among heterosexual apparently not at risk patients. PMID- 28906090 TI - Multiple keratoacanthoma centrifugum marginatum associated with juvenile idiopathic arthritis and persistent corneal epithelial defect: an unusual case. AB - We report here a case of a child with multiple keratoacanthoma centrifugum marginatum in association with corneal epithelial defect and juvenile arthritis. Keratoacanthoma is a skin tumor and the patient presented with an uncommon type of it. PMID- 28906091 TI - Acquired disseminated superficial porokeratosis in a patient affected by chronic lymphocitic leukemia. PMID- 28906092 TI - Prevalence of actinic keratosis in a French cohort of elderly people: the PROOF study. PMID- 28906093 TI - Cutaneous extramedullary hematopoiesis. PMID- 28906094 TI - Retinitis pigmentosa: an unusual ocular manifestation in a patient with neurofibromatosis type 1. PMID- 28906095 TI - Can taurine energy drink worsen psoriasis? PMID- 28906096 TI - Becker's nevus in neurofibromatosis type 1: a single center experience in Italy. PMID- 28906097 TI - Hypertrophic perianal Herpes simplex in renal transplant recipient. PMID- 28906098 TI - Anemic nevus is a new diagnostic criterion for neurofibromatosis type 1. PMID- 28906099 TI - One-Dimensional Hydroxyapatite Nanostructures with Tunable Length for Efficient Stem Cell Differentiation Regulation. AB - It is well-accepted that most osteogenic differentiation processes do need growth factors assistance to improve efficiency. As a material cue, hydroxyapatite (HAp) can promote osteogenic differentiation of stem cells only in a way. Up to now, rare work related to the relationship between HAp nanostructures and stem cells in osteogenic differentiation process without the assistance of growth factors has been reported. In this study, one-dimensional (1D) HAp nanostructures with tunable length were synthesized by an oleic acid assisted solvothermal method by adjusting the alcohol/water ratio (eta). The morphology of 1D HAp nanostructures can be changed from long nanowires into nanorods with the eta value change. Different substrates constructed by 1D HAp nanostructures were prepared to investigate the effect of morphology of nanostructured HAp on stem cell fate without any growth factors or differentiation induce media. Human adipose-derived stem cells (hADSCs), a kind of promising stem cell for autologous stem cell tissue engineering, were used as the stem cell model. The experiments prove that HAp morphology can determine the performance of hADSCs cultured on different substrates. Substrate constructed by HAp nanorods (100 nm) is of little benefit to osteogenic differentiations. Substrate constructed on HAp long nanowires (50 MUm) causes growth and spread inhibition of hADSCs, which even causes most cells death after 7 days of culture. However, substrate constructed by HAp short nanowires (5 MUm) can destine the hADSCs differentiation to osteoblasts efficiently in normal medium (after 3 weeks) without any growth factors. It is surprise that hADSCs have changed to polyhedral morphology and exhibited the tendency to osteogenic differentiation after only 24 h culture. Hydroxyapatite nanostructures mediated stem cell osteogenic differentiation excluding growth factors provides a powerful cue to design biomaterials with special nanostructures, and helps to elucidate the interaction of stem cell and biomaterials nanostructures. The results from this study are promising for application in bone tissue engineering. PMID- 28906100 TI - Exploration of the Electrical Conductivity of Double-Network Silver Nanowires/Polyimide Porous Low-Density Compressible Sponges. AB - Stress-responsive, highly flexible, and breathable nanocomposite sponges show an electrical conductivity from 1.7 to 166.6 S/cm depending on the applied stress. Key for the responsive electrical conductivity of the sponges is the change of percolation of the silver nanowires. These sponges made of short electrospun fibers and silver nanowires could be applied without any amplifier for the operation of automobile bulbs and as an efficient Joule heater. The time required for electric heating (current on) and cooling is very short. Interestingly, the maximum temperature reached by electric heating depends on the compression status. The higher the compression status, the lower is the maximum temperature, which is in accordance with the understanding of Joule heaters. It is noteworthy that these sponges are thermally, chemically, and mechanically very stable. These conductive sponges will open a new area for novel conductive devices with relevance for real-world applications. PMID- 28906101 TI - Sulfur in Hyper-cross-linked Porous Polymer as Cathode in Lithium-Sulfur Batteries with Enhanced Electrochemical Properties. AB - Sulfur was impregnated into hyper-cross-linked porous polymer (HCP) with a high specific area and unique porous structure. Compared to its inorganic or carbon counterparts, the HCP has a relatively high specific surface area of 1980 m2 g-1 with a total pore volume of 2.61 cm3 g-1, resulting in sulfur content in HCP/S of as high as 80 wt %. As a benefit of the unique HCP structure, the HCP/S composite exhibits a high initial discharge specific capacity (1333 mA h g-1 at 0.2 C), high-rate property, and good cycling stability (658 mA h g-1 after 120 cycles at 0.5 C and 604 mA h g-1 after 80 cycles at 1 C). Furthermore, the capacity of cells loses less than 1% after the first 20 charge/discharge cycles, while the HCP/S cathode can be cycled with an excellent Coulombic efficiency of above 94% after 120 cycles. Compared with pristine sulfur, the superior electrochemical performance of HCP/S composite is related to the cross-linked porous framework. Such structure could provide short ionic/electronic conduction pathways and suppress the polysulfide shuttle during the discharge process. PMID- 28906102 TI - Porous Coconut Shell Carbon Offering High Retention and Deep Lithiation of Sulfur for Lithium-Sulfur Batteries. AB - Retaining soluble polysulfides in the sulfur cathodes and allowing for deep redox are essential to develop high-performance lithium-sulfur batteries. The versatile textures and physicochemical characteristics of abundant biomass offer a great opportunity to prepare biochar materials that can enhance the performance of Li-S batteries in sustainable mode. Here, we exploit micro-/mesoporous coconut shell carbon (CSC) with high specific surface areas as a sulfur host for Li-S batteries. The sulfur-infiltrated CSC materials show superior discharge-charge capacity, cycling stability, and high rate capability. High discharge capacities of 1599 and 1500 mA h g-1 were achieved at current rates of 0.5 and 2.0 C, respectively. A high reversible capacity of 517 mA h g-1 was retained at 2.0 C even after 400 cycles. The results demonstrate a high retention and a deep lithiation of the CSC-confined sulfur. The success of this strategy provides insights into seeking high-performance biochar materials for Li-S batteries from abundant bioresources. PMID- 28906103 TI - Resolving the Atomistic Modes of Anle138b Inhibitory Action on Peptide Oligomer Formation. AB - The diphenyl-pyrazole compound anle138b is a known inhibitor of oligomeric aggregate formation in vitro and in vivo. Therefore, anle138b is considered a promising drug candidate to beneficially interfere with neurodegenerative processes causing devastating pathologies in humans. The atomistic details of the aggregation inhibition mechanism, however, are to date unknown since the ensemble of small nonfibrillar aggregates is structurally heterogeneous and inaccessible to direct structural characterization. Here, we set out to elucidate anle138b's mode of action using all-atom molecular dynamics simulations on the multi microsecond time scale. By comparing simulations of dimeric to tetrameric aggregates from fragments of four amyloidogenic proteins (Abeta, hTau40, hIAPP, and Sup35N) in the presence and absence of anle138b, we show that the compound reduces the overall number of intermolecular hydrogen bonds, disfavors the sampling of the aggregated state, and remodels the conformational distributions within the small oligomeric peptide aggregates. Most notably, anle138b preferentially interacts with the disordered structure ensemble via its pyrazole moiety, thereby effectively blocking interpeptide main chain interactions and impeding the spontaneous formation of ordered beta-sheet structures, in particular those with out-of-register antiparallel beta-strands. The structurally very similar compound anle234b was previously identified as inactive by in vitro experiments. Here, we show that anle234b has no significant effect on the aggregation process in terms of reducing the beta-structure content. Moreover, we demonstrate that the hydrogen bonding capabilities are autoinhibited due to steric effects imposed by the molecular geometry of anle234b and thereby indirectly confirm the proposed inhibitory mechanism of anle138b. We anticipate that the prominent binding of anle138b to partially disordered and dynamical aggregate structures is a generic basis for anle138b's ability to suppress toxic oligomer formation in a wide range of amyloidogenic peptides and proteins. PMID- 28906104 TI - Synthesis and Electrochemical Performance of SnOx Quantum Dots@ UiO-66 Hybrid for Lithium Ion Battery Applications. AB - A novel method that combines the dehydration of inorganic clusters in metal organic frameworks (MOFs) with nonaqueous sol-gel chemistry and pyrolysis processes is developed to synthesize SnOx quantum dots@Zr-MOFs (UIO-66) composites. The size of as-prepared SnOx nanoparticles is approximately 4 nm. Moreover, SnOx nanoparticles are uniformly anchored on the surface of the Zr MOFs, which serves as a matrix to alleviate the agglomeration of SnOx grains. This structure provides an accessible surrounding space to accommodate the volume change of SnOx during the charge/discharge process. Cyclic voltammetry and galvanostatic charge/discharge were employed to examine the electrochemical properties of the ultrafine SnOx@Zr-MOF (UIO-66) material. Benefiting from the advantages of the smaller size of SnOx nanoparticles and the synergistic effect between SnOx nanoparticles and the Zr-MOFs, the SnOx@Zr-MOF composite exhibits enhanced electrochemical performance when compared to that of its SnOx bulk counterpart. Specifically, the discharge-specific capacity of the SnOx@Zr-MOF electrode can still remain at 994 mA h g-1 at 50 mA g-1 after 100 cycles. The columbic efficiencies can reach 99%. PMID- 28906105 TI - Enantioselective Phytotoxicity of Dichlorprop to Arabidopsis thaliana: The Effect of Cytochrome P450 Enzymes and the Role of Fe. AB - The ecotoxicology effects of chiral herbicides have long been recognized and have drawn increasing attention. The toxic mechanisms of herbicides in plants are involved in production of reactive oxygen species (ROS) and cause damage to target enzymes, but the relationship between these two factors in the enantioselectivity of chiral herbicides has rarely been investigated. Furthermore, even though cytochromes P450 enzymes (CYP450s) have been related to the phytotoxicity of herbicides, their roles in the enantioselectivity of chiral herbicides have yet to be explored. To solve this puzzle, the CYP450s suicide inhibitor 1-aminobenzotriazole (ABT) was added to an exposure system made from dichlorprop (DCPP) enantiomers in the model plant Arabidopsis thaliana. The results indicated that different phytotoxicities of DCPP enantiomers by causing oxidative stress and acetyl-CoA carboxylase (ACCase) damage were observed in the presence and the absence of ABT. The addition of ABT decreased the toxicity of (R)-DCPP but was not significantly affected that of (S)-DCPP, resulting in smaller differences between enantiomers. Furthermore, profound differences were also observed in Fe uptake and distribution, exhibiting different distribution patterns in A. thaliana leaves exposed to DCPP and ABT, which helped bridge the relationship between ROS production and target enzyme ACCase damage through the function of CYP450s. These results offer an opportunity for a more-comprehensive understanding of chiral herbicide action mechanism and provide basic evidence for risk assessments of chiral herbicides in the environment. PMID- 28906106 TI - Cobalt-Catalyzed and Lewis Acid-Assisted Nitrile Hydrogenation to Primary Amines: A Combined Effort. AB - The selective hydrogenation of nitriles to primary amines using a bench-stable cobalt precatalyst under 4 atm of H2 is reported herein. The catalyst precursor was reduced in situ using NaHBEt3, and the resulting Lewis acid formed, BEt3, was found to be integral to the observed catalysis. Mechanistic insights gleaned from para-hydrogen induced polarization (PHIP) transfer NMR studies revealed that the pairwise hydrogenation of nitriles proceeded through a Co(I/III) redox process. PMID- 28906107 TI - Concepts and Methods of Solid-State NMR Spectroscopy Applied to Biomembranes. AB - Concepts of solid-state NMR spectroscopy and applications to fluid membranes are reviewed in this paper. Membrane lipids with 2H-labeled acyl chains or polar head groups are studied using 2H NMR to yield knowledge of their atomistic structures in relation to equilibrium properties. This review demonstrates the principles and applications of solid-state NMR by unifying dipolar and quadrupolar interactions and highlights the unique features offered by solid-state 2H NMR with experimental illustrations. For randomly oriented multilamellar lipids or aligned membranes, solid-state 2H NMR enables direct measurement of residual quadrupolar couplings (RQCs) due to individual C-2H-labeled segments. The distribution of RQC values gives nearly complete profiles of the segmental order parameters SCD(i) as a function of acyl segment position (i). Alternatively, one can measure residual dipolar couplings (RDCs) for natural abundance lipid samples to obtain segmental SCH order parameters. A theoretical mean-torque model provides acyl-packing profiles representing the cumulative chain extension along the normal to the aqueous interface. Equilibrium structural properties of fluid bilayers and various thermodynamic quantities can then be calculated, which describe the interactions with cholesterol, detergents, peptides, and integral membrane proteins and formation of lipid rafts. One can also obtain direct information for membrane-bound peptides or proteins by measuring RDCs using magic angle spinning (MAS) in combination with dipolar recoupling methods. Solid-state NMR methods have been extensively applied to characterize model membranes and membrane-bound peptides and proteins, giving unique information on their conformations, orientations, and interactions in the natural liquid-crystalline state. PMID- 28906109 TI - Aqueous Reaction of Alcohols, Organohalides, and Odorless Sodium Thiosulfate under Transition-Metal-Free Conditions: Synthesis of Unsymmetrical Aryl Sulfides via Dual C-S Bond Formation. AB - A transition-metal-free process for the synthesis of unsymmetrical aryl sulfides via dual C-S bond formation by a one-pot three-component reaction of alcohols, organohalides, and odorless sodium thiosulfate in water has been developed. In addition, the aryl sulfides could also be prepared by the reaction of the corresponding alcohols and Bunte salts under the identical conditions. This protocol provides a green and efficient manner for the construction of various unsymmetrical aryl sulfides. PMID- 28906108 TI - A Diaminopropane-Appended Metal-Organic Framework Enabling Efficient CO2 Capture from Coal Flue Gas via a Mixed Adsorption Mechanism. AB - A new diamine-functionalized metal-organic framework comprised of 2,2-dimethyl 1,3-diaminopropane (dmpn) appended to the Mg2+ sites lining the channels of Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) is characterized for the removal of CO2 from the flue gas emissions of coal-fired power plants. Unique to members of this promising class of adsorbents, dmpn-Mg2(dobpdc) displays facile step-shaped adsorption of CO2 from coal flue gas at 40 degrees C and near complete CO2 desorption upon heating to 100 degrees C, enabling a high CO2 working capacity (2.42 mmol/g, 9.1 wt %) with a modest 60 degrees C temperature swing. Evaluation of the thermodynamic parameters of adsorption for dmpn-Mg2(dobpdc) suggests that the narrow temperature swing of its CO2 adsorption steps is due to the high magnitude of its differential enthalpy of adsorption (Deltahads = -73 +/- 1 kJ/mol), with a larger than expected entropic penalty for CO2 adsorption (Deltasads = -204 +/- 4 J/mol.K) positioning the step in the optimal range for carbon capture from coal flue gas. In addition, thermogravimetric analysis and breakthrough experiments indicate that, in contrast to many adsorbents, dmpn-Mg2(dobpdc) captures CO2 effectively in the presence of water and can be subjected to 1000 humid adsorption/desorption cycles with minimal degradation. Solid-state 13C NMR spectra and single-crystal X-ray diffraction structures of the Zn analogue reveal that this material adsorbs CO2 via formation of both ammonium carbamates and carbamic acid pairs, the latter of which are crystallographically verified for the first time in a porous material. Taken together, these properties render dmpn-Mg2(dobpdc) one of the most promising adsorbents for carbon capture applications. PMID- 28906110 TI - Anti-inflammatory Effect of Essential Oil from Citrus aurantium L. var. amara Engl. AB - Essential oil has been popularly used as an alternative for the treatment of inflammation. The bioactivities of essential oil from blossoms of Citrus aurantium L. var. amara Engl (CAVAO) showed greater anti-inflammation potential than that of antioxidant, anticancer, and 3T3-L1 proliferation inhibition. CAVAO (250 MUg/mL) significantly inhibited production of nitric oxide (NO) (99.54 +/- 2.81%), interleukin-6 (IL-6) (98.11 +/- 1.62%), tumor necrosis factor-alpha (TNF alpha) (41.84 +/- 1.52%), and interleukin-1beta (IL-1beta) (56.09 +/- 2.21%) as well as their gene expression level. CAVAO also markedly decreased the expression levels of cyclooxygenase-2 (COX-2) gene and protein. Furthermore, CAVAO inhibited nuclear factor-kappaB (NF-kappaB) activation, which was justified by the inhibitory effect on NF-kappaB nuclear translocation, IkappaBalpha phosphorylation and degradation, and phosphorylation-dependent IkappaB kinase activation in RAW264.7 cells stimulated with lipopolysaccharides. CAVAO also suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38, indicating that mitogen-activated protein kinase (MAPK) signaling pathways were also blocked. The major constituents of CAVAO were characterized as linalool (64.6 +/- 0.04%), alpha-terpineol (7.61 +/- 0.03%), (R)-limonene (6.15 +/- 0.04%), and linalyl acetate (5.02 +/- 0.03%), which might be responsible for its observed anti-inflammation activity. It is concluded that CAVAO has great potential to be developed into a functional food for the treatment of inflammatory-associated diseases. PMID- 28906112 TI - Copper(I)-Catalyzed Ligand-Promoted Multicomponent Reactions of Isocyanides, Selenium, Amines, and Iodoarenes: Access to Highly Functionalized Carbamimidoselenoates. AB - A new and facile approach toward highly functionalized carbamimidoseleknoates was developed through the copper(I)-catalyzed ligand-promoted four-component reaction of isocyanides, selenium, amines, and aryl iodides. The reaction constructed a range of organoselenium compounds containing an isoselenourea skeleton with potential bioactivity directly from selenium powder. The simplicity of method and broad diversity of substrates also highlight this work. PMID- 28906113 TI - Photoinduced Electron Transfer Coupled to Donor Deprotonation and Acceptor Protonation in a Molecular Triad Mimicking Photosystem II. AB - The first artificial donor-sensitizer-acceptor compound in which photoinduced long-range electron transfer is coupled to donor deprotonation and acceptor protonation is reported. The long-lived photoproduct stores energy in the form of a radical pair state in which the charges of the donor and the acceptor remain unchanged, much in contrast to previously investigated systems that exhibit charge-separated states comprised of electron-hole pairs. This finding is relevant for light-driven accumulation of redox equivalents, because it exemplifies how the buildup of charge can be avoided yet light energy can be stored. Proton-coupled electron transfer (PCET) reactions at a phenol donor and a monoquat acceptor triggered by excitation of a Ru(II) sensitizer enable this form of photochemical energy storage. Our triad emulates photosystem II more closely than previously investigated systems, because tyrosine Z is oxidized and deprotonated, whereas plastoquinone B is reduced and protonated. PMID- 28906114 TI - doGlycans-Tools for Preparing Carbohydrate Structures for Atomistic Simulations of Glycoproteins, Glycolipids, and Carbohydrate Polymers for GROMACS. AB - Carbohydrates constitute a structurally and functionally diverse group of biological molecules and macromolecules. In cells they are involved in, e.g., energy storage, signaling, and cell-cell recognition. All of these phenomena take place in atomistic scales, thus atomistic simulation would be the method of choice to explore how carbohydrates function. However, the progress in the field is limited by the lack of appropriate tools for preparing carbohydrate structures and related topology files for the simulation models. Here we present tools that fill this gap. Applications where the tools discussed in this paper are particularly useful include, among others, the preparation of structures for glycolipids, nanocellulose, and glycans linked to glycoproteins. The molecular structures and simulation files generated by the tools are compatible with GROMACS. PMID- 28906115 TI - Use of the Antimicrobial Peptide Sublancin with Combined Antibacterial and Immunomodulatory Activities To Protect against Methicillin-Resistant Staphylococcus aureus Infection in Mice. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is the major pathogen causing serious hospital infections worldwide. With the emergence and rapid spread of drug-resistant bacteria, there is extraordinary interest in antimicrobial peptides (AMPs) as promising candidates for the treatment of antibiotic-resistant bacterial infections. Sublancin, a glycosylated AMP produced by Bacillus subtilis 168, has been reported to possess protective activity against bacterial infection. This study was performed to evaluate the efficacy of sublancin in the prevention of MRSA ATCC43300 intraperitoneal infection in mice. We determined that sublancin had a minimal inhibitory concentration of 15 MUM against MRSA ATCC43300. The antimicrobial action of sublancin involved the destruction of the bacterial cell wall. Dosing of mice with sublancin greatly alleviated (p < 0.05) the bacterial burden caused by MRSA intraperitoneal infection and considerably reduced the mortality and weight loss (19.2 +/- 0.62 g vs 20.6 +/- 0.63 g for MRSA vs 2.0 mg/kg sublancin, respectively, on day 3) of MRSA-challenged mice (p < 0.05). Sublancin was further found to balance the immune response during infection and relieve intestinal inflammation through inhibition of NF-kappaB activation (p < 0.01). With their combined antibacterial and immunomodulatory activities, sublancin may have potent therapeutic potential for drug-resistant infections and sepsis. PMID- 28906116 TI - PhID: An Open-Access Integrated Pharmacology Interactions Database for Drugs, Targets, Diseases, Genes, Side-Effects, and Pathways. AB - The current network pharmacology study encountered a bottleneck with a lot of public data scattered in different databases. There is a lack of an open-access and consolidated platform that integrates this information for systemic research. To address this issue, we have developed PhID, an integrated pharmacology database which integrates >400 000 pharmacology elements (drug, target, disease, gene, side-effect, and pathway) and >200 000 element interactions in branches of public databases. PhID has three major applications: (1) assisting scientists searching through the overwhelming amount of pharmacology element interaction data by names, public IDs, molecule structures, or molecular substructures; (2) helping visualizing pharmacology elements and their interactions with a web-based network graph; and (3) providing prediction of drug-target interactions through two modules: PreDPI-ki and FIM, by which users can predict drug-target interactions of PhID entities or some drug-target pairs of their own interest. To get a systems-level understanding of drug action and disease complexity, PhID as a network pharmacology tool was established from the perspective of data layer, visualization layer, and prediction model layer to present information untapped by current databases. PMID- 28906111 TI - Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary alpha-(1'-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators. AB - Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor development but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling and proteolysis targeting chimeras. We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, alpha-(1'-fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids. These are obtained by the capture of suitably protected amino acid enolates with beta,beta difluorovinyl phenyl sulfone, a new (1'-fluoro)vinyl cation equivalent, and an electrophile that previously eluded synthesis, capture and characterization. A significant variety of biologically relevant AA side chains are tolerated including those for alanine, valine, leucine, methionine, lysine, phenylalanine, tyrosine, and tryptophan. Following addition/elimination, the resulting transoid alpha-(1'-fluoro)-beta-(phenylsulfonyl)vinyl AA-esters undergo smooth sulfone stannane interchange to stereoselectively give the corresponding transoid alpha (1'-fluoro)-beta-(tributylstannyl)vinyl AA-esters. Protodestannylation and global deprotection then yield these sterically encumbered and densely functionalized quaternary amino acids. The alpha-(1'-fluoro)vinyl trigger, a potential allene generating functionality originally proposed by Abeles, is now available in a quaternary AA context for the first time. In an initial test of this new inhibitor class, alpha-(1'-fluoro)vinyllysine is seen to act as a time-dependent, irreversible inactivator of lysine decarboxylase from Hafnia alvei. The enantiomers of the inhibitor could be resolved, and each is seen to give time dependent inactivation with this enzyme. Kitz-Wilson analysis reveals similar inactivation parameters for the two antipodes, L-alpha-(1'-fluoro)vinyllysine (Ki = 630 +/- 20 MUM; t1/2 = 2.8 min) and D-alpha-(1'-fluoro)vinyllysine (Ki = 470 +/ 30 MUM; t1/2 = 3.6 min). The stage is now set for exploration of the efficacy of this trigger in other PLP-enzyme active sites. PMID- 28906117 TI - Conformational Entropy as Collective Variable for Proteins. AB - Many enhanced sampling methods rely on the identification of appropriate collective variables. For proteins, even small ones, finding appropriate descriptors has proven challenging. Here we suggest that the NMR S2 order parameter can be used to this effect. We trace the validity of this statement to the suggested relation between S2 and conformational entropy. Using the S2 order parameter and a surrogate for the protein enthalpy in conjunction with metadynamics or variationally enhanced sampling, we are able to reversibly fold and unfold a small protein and draw its free energy at a fraction of the time that is needed in unbiased simulations. We also use S2 in combination with the free energy flooding method to compute the unfolding rate of this peptide. We repeat this calculation at different temperatures to obtain the unfolding activation energy. PMID- 28906118 TI - Pauli Repulsion Versus van der Waals: Interaction of Indenocorannulene with a Cu(111) Surface. AB - Modification of metal electrode surfaces with functional organic molecules is an important step toward organic electronics. The interaction of the buckybowl indenocorannulene with a Cu(111) surface and the two-dimensional self-assembly on the same surface was studied by means of scanning tunneling microscopy and dispersion-enabled density functional theory. Based on the conjecture of maximizing van der Waals interaction with the surface one would expect the indeno group to be aligned parallel to the surface. Theoretical investigations predict a nonparallel arrangement with the benzo ring of the indeno group located higher above the surface than the bowl rim connected to the indeno group. This adsorbate geometry is due to strong electronic interaction between molecule and surface, including substantial Pauli repulsion. The long-range ordered monolayer shows differences for two molecules of the unit cell in scanning tunneling microscopy contrast, suggesting either different polar alignments, and therefore a different tilt of the indeno group, or occupation of different adsorption sites. PMID- 28906119 TI - High Quality Factor Graphene-Based Two-Dimensional Heterostructure Mechanical Resonator. AB - Ultralight mechanical resonators based on low-dimensional materials are well suited as exceptional transducers of minuscule forces or mass changes. However, the low dimensionality also provides a challenge to minimize resistive losses and heating. Here, we report on a novel approach that aims to combine different two dimensional (2D) materials to tackle this challenge. We fabricated a heterostructure mechanical resonator consisting of few layers of niobium diselenide (NbSe2) encapsulated by two graphene sheets. The hybrid membrane shows high quality factors up to 245,000 at low temperatures, comparable to the best few-layer graphene mechanical resonators. In contrast to few-layer graphene resonators, the device shows reduced electrical losses attributed to the lower resistivity of the NbSe2 layer. The peculiar low-temperature dependence of the intrinsic quality factor points to dissipation over two-level systems which in turn relax over the electronic system. Our high sensitivity readout is enabled by coupling the membrane to a superconducting cavity which allows for the integration of the hybrid mechanical resonator as a sensitive and low loss transducer in future quantum circuits. PMID- 28906120 TI - Diastereodivergent and Enantioselective Access to Spiroepoxides via Organocatalytic Epoxidation of Unsaturated Pyrazolones. AB - Readily available chiral amine-thioureas are effective catalysts for the first diastereo- and enantioselective epoxidation of unsaturated pyrazolones. The trans or cis-spiroepoxides are preferentially obtained in good yield and high to excellent enantioselectivity using an appropriate organocatalyst and tert-butyl hydroperoxide as the oxidant. The epoxidation appears applicable to highly challenging beta,beta'-substituted unsaturated pyrazolones, giving access to spiroepoxides bearing two vicinal quaternary stereocenters. The reaction represents a unique example of Weitz-Scheffer epoxidation, where the catalyst controlled ring-closure step is usefully exploited to prepare both enantioenriched diastereomeric epoxides. PMID- 28906121 TI - N-Heterocyclic Carbene Catalyzed Stereoselective Glycosylation of 2 Nitrogalactals. AB - An efficient N-heterocyclic carbene catalyzed glycosylation of 2-nitrogalactals with alcohols and phenol has been developed for the first time. A wide variety of 1,2-cis-2-nitroglycosides can be obtained with good to excellent yields and high to excellent alpha-selectivities. PMID- 28906122 TI - Tip-triggered Thermal Cascade Manipulation of Magic Number Gold-Fullerene Clusters in the Scanning Tunnelling Microscope. AB - We demonstrate cascade manipulation between magic number gold-fullerene hybrid clusters by channelling thermal energy into a specific reaction pathway with a trigger from the tip of a scanning tunnelling microscope (STM). The (C60)m-Aun clusters, formed via self-assembly on the Au(111) surface, consist of n Au atoms and m C60 molecules; the three smallest stable clusters are (C60)7-Au19, (C60)10 Au35, and (C60)12-Au49. The manipulation cascade was initiated by driving the STM tip into the cluster followed by tip retraction. Temporary, partial fragmentation of the cluster was followed by reorganization. Self-selection of the correct numbers of Au atoms and C60 molecules led to the formation of the next magic number cluster. This cascade manipulation is efficient and facile with an extremely high selectivity. It offers a way to perform on-surface tailoring of atomic and molecular clusters by harnessing thermal energy, which is known as the principal enemy of the quest to achieve ultimate structural control with the STM. PMID- 28906123 TI - Manganese-Catalyzed Directed Methylation of C(sp2)-H Bonds at 25 degrees C with High Catalytic Turnover. AB - We report here a manganese-catalyzed C-H methylation reaction of considerable substrate scope, using MeMgBr, a catalytic amount of MnCl2.2LiCl, and an organic dihalide oxidant. The reaction features ambient temperature, low catalyst loading, typically 1%, high catalytic turnover reaching 5.9 * 103, and no need for an extraneous ligand and illustrates a unique catalytic use of simple manganese salts for C-H activation, which so far has relied on catalysis by manganese carbonyls. PMID- 28906124 TI - Temperature-Dependent Electron-Electron Interaction in Graphene on SrTiO3. AB - The electron band structure of graphene on SrTiO3 substrate has been investigated as a function of temperature. The high-resolution angle-resolved photoemission study reveals that the spectral width at Fermi energy and the Fermi velocity of graphene on SrTiO3 are comparable to those of graphene on a BN substrate. Near the charge neutrality, the energy-momentum dispersion of graphene exhibits a strong deviation from the well-known linearity, which is magnified as temperature decreases. Such modification resembles the characteristics of enhanced electron electron interaction. Our results not only suggest that SrTiO3 can be a plausible candidate as a substrate material for applications in graphene-based electronics but also provide a possible route toward the realization of a new type of strongly correlated electron phases in the prototypical two-dimensional system via the manipulation of temperature and a proper choice of dielectric substrates. PMID- 28906125 TI - Imaging of rare appendicular non-acral soft-tissue chondromas in adults with histopathologic correlation. AB - Background Soft-tissue chondroma (STC) is a rare benign soft tissue tumor that arises primarily in acral extra-skeletal locations. Occasionally, STCs may arise in more proximal non-acral locations, accompanied by non-classic features that label them as indeterminate lesions and pose diagnostic challenge for both radiologists and pathologists alike. Purpose To explicate the potential of diagnostic imaging in the identification and characterization of appendicular non acral STCs with emphasis on their morphologic magnetic resonance imaging (MRI) enhancement. Material and Methods Our clinical database records were searched for patients with histologically proven primary soft-tissue chondroid lesions over a five-year period. Two musculoskeletal (MSK) trained radiologists evaluated the imaging studies and an MSK pathologist revised the pathological findings. Results The study included six cases of appendicular non-acral STCs (mean age = 40.5 years). The mean size of the tumors was 5.6 cm, with four localized to the knee region, one in the thigh, and one in the sternoclavicular region. All cases showed high signal intensity matrix with low-signal intensity septa on T2 weighted MRI and post-contrast marginal/septal enhancement. The lesions were lobulated and lacked host tissue reaction except for one showing subjacent mild soft-tissue edema. Histologically, the cases lacked overt features of malignancy although one was originally misdiagnosed as chondrosarcoma. Conclusion Non-acral STCs are benign cartilaginous tumors that may pose a diagnostic challenge, both radiologically and pathologically. Collaborative imaging and pathologic workup is needed for better characterization of non-aggression of these lesions, and to avoid diagnostic pitfalls and unnecessary radical resections. PMID- 28906126 TI - Isolated cortical vasogenic edema and hyperintense vessel signs may be early features of reversible cerebral vasoconstriction syndrome: Case reports. AB - Background The temporal and anatomical features of vasoconstriction in patients with reversible cerebral vasoconstriction syndrome within hours after symptom onset, in the hyperacute phase, are unclear. Case result Herein we report the cases of two patients with acute severe headache who were diagnosed with reversible cerebral vasoconstriction syndrome. Magnetic resonance imaging within hours after symptom onset revealed multiple areas of isolated cortical vasogenic edema and hyperintense vessel signs of the distal cerebral arteries. Follow-up imaging performed four days later in both cases showed diffuse segmental arterial vasoconstriction in the proximal regions of the cerebral arteries. Both patients received antivasoconstrictive therapy shortly after admission, and neither had neurological sequelae at discharge. The magnetic resonance imaging findings improved gradually within three months after symptom onset. Conclusion Isolated cortical vasogenic edema and hyperintense vessel signs, when observed within hours from sudden severe headache onset, may be useful early markers of reversible cerebral vasoconstriction syndrome. PMID- 28906127 TI - Cluster headache - clinical pattern and a new severity scale in a Swedish cohort. AB - Background The aim of this study was to investigate clinical features of a cluster headache cohort in Sweden and to construct and test a new scale for grading severity. Methods Subjects were identified by screening medical records for the ICD 10 code G44.0, that is, cluster headache. Five hundred participating research subjects filled in a questionnaire including personal, demographic and medical aspects. We constructed a novel scale for grading cluster headache in this cohort: The Cluster Headache Severity Scale, which included number of attacks per day, attack and period duration. The lowest total score was three and the highest 12, and we used the Cluster Headache Severity Scale to grade subjects suffering from cluster headache. We further implemented the scale by defining a cluster headache maximum severity subgroup with a high Cluster Headache Severity Scale score >= 9. Results A majority (66.7%) of the patients reported that attacks appear at certain time intervals. In addition, cluster headache patients who were current tobacco users or had a history of tobacco consumption had a later age of disease onset (31.7 years) compared to non-tobacco users (28.5 years). The Cluster Headache Severity Scale score was higher in the patient group reporting sporadic or no alcohol intake than in the groups reporting an alcohol consumption of three to four standard units per week or more. Maximum severity cluster headache patients were characterised by higher age at disease onset, greater use of prophylactic medication, reduced hours of sleep, and lower alcohol consumption compared to the non-cluster headache maximum severity group. Conclusion There was a wide variation of severity grade among cluster headache patients, with a very marked impact on daily living for the most profoundly affected. PMID- 28906129 TI - Perceptions of U.S. Veterans Affairs and community healthcare providers regarding cross-system care for heart failure. AB - OBJECTIVES: This study explores perceptions of US Veterans Affairs (VA) and non VA healthcare providers caring for Veterans with heart failure (HF) regarding Veteran knowledge and motivations for dual use, provider roles in recommending and coordinating dual use, systems barriers and facilitators, and suggestions for improving cross-system care. METHODS: Twenty VA and 11 non-VA providers participated in semi-structured interviews, which were analyzed using parallel qualitative content and discourse analysis. RESULTS: VA and non-VA providers described variable HF knowledge and self-management among Veterans, and both groups described the need for improved education addressing medication adherence, self-care, and management of acute symptoms. Both groups described highly limited roles for providers in shaping choices surrounding dual use. VA and non-VA providers had significantly different perceptions regarding the availability, quality, and effectiveness of VA HF services. Multiple non-VA providers expressed frustration with and difficulty in contacting VA providers, accessing records, and making referrals into the VA system. Suggestions for improved care focused on patient education and care coordination. DISCUSSION: Dual healthcare system use for Veterans is increasingly common. Similarities and contrasts in perceptions of VA and non-VA providers are instructive and should be incorporated into future policy and program initiatives. PMID- 28906128 TI - Effect of Preoperative Fatty Degeneration of the Rotator Cuff Muscles on the Clinical Outcome of Patients With Intact Tendons After Arthroscopic Rotator Cuff Repair of Large/Massive Cuff Tears. AB - BACKGROUND: Fatty degeneration of the rotator cuff muscles is associated not only with postoperative retear but also with postoperative muscle weakness; therefore, fatty changes in the muscles may affect the clinical outcome even in patients with these tears who have intact tendons after arthroscopic rotator cuff repair (ARCR). PURPOSE: To evaluate the effect of fatty infiltration on the clinical outcome in patients with intact tendons after arthroscopic repair of large/massive cuff tears. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: One hundred fifty-five consecutive patients with large/massive rotator cuff tears underwent ARCR. Of these, 55 patients (mean +/- SD age, 64.4 +/- 9.1 years) in whom intact tendons after surgery were confirmed with magnetic resonance imaging at final follow-up (mean +/- SD, 2.5 +/- 1.4 years) were included in this study. Depending on their University of California Los Angeles (UCLA) score at the final follow-up, they were assigned to either the unsatisfactory group (score <=27; n = 12) or the satisfactory group (score >27; n = 43). Various clinical parameters affecting the clinical outcome were examined through univariate and multivariate analyses. RESULTS: The UCLA score of all patients significantly improved from 18.1 +/- 4.4 points preoperatively to 29.8 +/- 4.5 points postoperatively ( P < .0001). The mean preoperative UCLA scores were not significantly different between the satisfactory and unsatisfactory groups ( P = .39). Multivariate analysis showed that the preoperative Goutallier stages of the infraspinatus (odds ratio [OR], 8.87; 95% confidence interval [CI], 1.51-52.0; P = .016) and/or subscapularis (OR, 7.53; 95% CI, 1.58-35.9; P = .011) were significantly associated with outcome. Receiver operating characteristic curve analysis revealed a cutoff value of Goutallier stage 1 in both muscles, with area under the curve values of 0.79 (sensitivity 91% and specificity 51%) and 0.84 (sensitivity 100% and specificity 54%) in the infraspinatus and subscapularis, respectively. CONCLUSION: Preoperative fatty degeneration of the infraspinatus and/or subscapularis with Goutallier stage 2 or higher was significantly associated with worse outcome in patients with large/massive tears who had intact tendons after ARCR. PMID- 28906130 TI - Human Movement Responses to the Rorschach and Mirroring Activity: An fMRI Study. AB - It has been suggested that the Rorschach human movement (M) response could be associated with an embodied simulation mechanism mediated by the mirror neuron system (MNS). To date, evidence for this hypothesis comes from two electroencephalogram studies and one repetitive transcranial magnetic stimulation study. To provide additional data on this topic, the Rorschach was administered during fMRI to a sample of 26 healthy adult volunteers. Activity in MNS-related brain areas temporally associated with M responses was compared with such activity for other, non-M Rorschach responses. Data analyses focused on MNS regions of interest identified by Neurosynth, a web-based platform for large scale, automated meta-analysis of fMRI data. Consistent with the hypothesis that M responses involve embodied simulation and MNS activity, univariate region of interest analyses showed that production of M responses associated with significantly greater activity in MNS-related brain areas when compared with non M Rorschach responses. This finding is consistent with the traditional interpretation of the M code. PMID- 28906131 TI - Effects of immunomodulators on the response induced by vaccines against autoimmune diseases. AB - A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity. Another type of vaccines is the DNA vaccines, where cells transiently express the self-antigen encoded by DNA, which induces a Th2 immunity. Actually, DNA vaccines can benefit from the presence of an adjuvant that elicits a systemic sole Th2 immunity to enhance the initially weak immune response characteristic of these vaccines. While in the tolerogenic vaccines, cytokines are the endogenous immunomodulators, in the immunogenic vaccines, the adjuvants are exogenous agents that elicit Th2 immunity with a production of anti-inflammatory cytokines and antibodies against the self antigen. Because the commonly used Th2 adjuvant alum, fails to induce an effective immunity in the elderly population, it is unlikely that it would be widely used. Another Th2 adjuvant, the oil/water emulsions mixed with the antigen, while effective in vaccines against infectious agents, due to potential aldehydes in their formulation may be not suitable for autoimmune vaccines. A unique compound is glatiramer, which seems to be both a random polypeptide antigen and an immune modulator that biases the response to Th2 immunity. Its mechanism of action seems to implicate binding to MHC-II, which alters the outcome of T-cell signaling, leading to anergy. Glatiramer, while effective in the treatment of multiple sclerosis has not shown efficacy in other autoimmune diseases. An important new group of promising sole Th2 adjuvants are the fucosylated glycans, which by binding to DC-SIGN bias dendritic cells to Th2 immunity while inhibiting Th1/Th7 immunities. These glycans are similar to those produced by parasitic helminths to prevent inflammatory responses by mammalian hosts. A novel group of sole Th2 adjuvants are some plant-derived fucosylated triterpene glycosides, which share the immune modulatory properties from the fucosylated glycans. These glycosides have also an aldehyde group that delivers an alternative co-stimulatory signal to T-cells, averting the anergy associated with aging due to the loss of the CD28 receptor on T-cells. Hence, the development of vaccines to treat and/or prevent autoimmune conditions and some proteopathies, will significantly benefit from the availability of new sole Th2 adjuvants that while inducing an anti-inflammatory immunity, they do not abrogate pro-inflammatory Th1/Th17 immunities. PMID- 28906132 TI - Effects of different dietary sources and levels of selenium supplements on growth performance, antioxidant status and immune parameters in Ross 308 broiler chickens. AB - 1. Although different impacts of various sources of selenium (Se) on chicken performance have been largely studied, there is a lack of comparative experiments studying the effects of these sources on the immune system and antioxidant indices of broiler tissues. The aim of this study was to examine the effects of various sources and levels of dietary Se supplements on performance, antioxidant status and immune parameters in Ross 308 broiler chickens. 2. A total of 1200 1-d old male broilers (Ross * Ross 308) were divided into 8 treatments with 6 replicate pens and 25 birds per pen. This experiment was conducted as a completely randomised design with a 4 * 2 factorial arrangement. Main factors included Se sources as sodium selenite (SS), Se-enriched yeast (SY), DL selenomethionine (SM) and nano-selenium (NS) and levels at 0.1 or 0.4 mg/kg Se. 3. Dietary supplementation of organic Se sources significantly improved average daily gain (ADG), gain: feed ratio and European production efficiency factor (P < 0.05) compared to birds fed on diets supplemented with inorganic source. In addition, ADG was increased in response to increased level of supplemental Se. Based on contrast comparison, there were significant differences in these parameters between organic versus inorganic sources of Se. However, there was no difference between contrast comparisons of NS versus SM and SY. 4. Total anti sheep red blood cell (SRBC) and Immunoglobulin G (IgG) titres and hypersensitivity were enhanced by increasing supplemental concentration of Se and using organic sources of Se rather than SS (P < 0.05). 5. Oxidation resistance assessment of tissues demonstrated that supplementation of organic sources of Se and increase in supplemental concentration of Se ameliorated glutathione peroxidase activity, total antioxidant capacity and malondialdehyde formation (P < 0.05). Mostly, there were significant differences between organic versus inorganic sources of Se in oxidation resistance. 6. Overall, dietary supplementation of 0.4 mg/kg Se from an organic source resulted in better production performance and immune system response. Moreover, minimum formation of malondialdehyde in broiler tissue was observed in birds fed on diets supplemented with SM at 0.4 mg/kg. 7. It can be concluded that SM is more effective than other sources of Se in reducing lipid oxidation. PMID- 28906133 TI - An Online Calculator to Estimate the Impact of Changes in Breastfeeding Rates on Population Health and Costs. AB - OBJECTIVE: We sought to determine the impact of changes in breastfeeding rates on population health. MATERIALS AND METHODS: We used a Monte Carlo simulation model to estimate the population-level changes in disease burden associated with marginal changes in rates of any breastfeeding at each month from birth to 12 months of life, and in rates of exclusive breastfeeding from birth to 6 months of life. We used these marginal estimates to construct an interactive online calculator (available at www.usbreastfeeding.org/saving-calc ). The Institutional Review Board of the Cambridge Health Alliance exempted the study. RESULTS: Using our interactive online calculator, we found that a 5% point increase in breastfeeding rates was associated with statistically significant differences in child infectious morbidity for the U.S. population, including otitis media (101,952 cases, 95% confidence interval [CI] 77,929-131,894 cases) and gastrointestinal infection (236,073 cases, 95% CI 190,643-290,278 cases). Associated medical cost differences were $31,784,763 (95% CI $24,295,235 $41,119,548) for otitis media and $12,588,848 ($10,166,203-$15,479,352) for gastrointestinal infection. The state-level impact of attaining Healthy People 2020 goals varied by population size and current breastfeeding rates. CONCLUSION: Modest increases in breastfeeding rates substantially impact healthcare costs in the first year of life. PMID- 28906134 TI - Direct axillary artery cannulation in cardiac surgery: clinical outcomes. AB - Objective Axillary artery cannulation is still regarded with distrust by surgeons because the artery is supposed to be fragile, difficult to access, and its cannulation is often considered time-consuming. This study was carried out to assess our results in a series of patients, using a simplified surgical approach to axillary artery cannulation. Methods Data were collected retrospectively from our prospective database. All patients operated on in our department between January 2004 and October 2016 and scheduled for various cardiac procedures with direct axillary artery cannulation were included in this study. In this twelve year period, 246 patients had direct axillary artery cannulation during a cardiac surgical procedure. The mean age was 67.3 +/- 14.7 years. The artery was approached at the level of the deltopectoral groove and cannulated by the direct Seldinger technique. Results The main indications for axillary artery cannulation were: right minithoracotomy aortic valve replacement ( n = 93), aortic dissection ( n = 57), extracorporeal life support ( n = 36), transarterial valve replacement ( n = 27), ascending aortic aneurysm ( n = 16), and others ( n = 17). The cannulation was right-sided in 90.6% of patients. Axillary cannulation-related morbidity was 6.1%. Axillary cannulation-related mortality was 0.8% (2 patients). Conclusions The axillary artery is a reliable site for rapid cannulation, carrying a low risk of morbidity and mortality. Our findings show that this artery is solid and can be very useful in everyday cardiac surgical practice. PMID- 28906135 TI - Cement fragment from hip arthroplasty causing deep femoral artery pseudoaneurysm. AB - An 81-year-old woman who had undergone total hip arthroplasty 12 years earlier presented with a painful spontaneous hematoma in the proximal left thigh. A left hip radiograph showed a displaced cement fragment from the acetabular component of the hip prosthesis. Computed tomography confirmed an extruded cement fragment causing a large pseudoaneurysm of the deep femoral artery. The patient underwent successful percutaneous embolization of the pseudoaneurysm with coils. PMID- 28906136 TI - Redo quadruple-valve repair after Ross procedure: a viable option? AB - Quadruple-valve repair or replacement is associated with significant morbidity and mortality because the clinical situation of severe disease of all 4 valves implies incipient myocardial damage. We report a case of redo quadruple-valve repair in a patient with rheumatic heart disease who had undergone the Ross procedure 14 years earlier. He presented with heart failure. Cardiac evaluation revealed severe disease of all 4 valves, necessitating surgery. Because he was in advanced heart failure and all 4 valves were suitable for repair, a quadruple valve repair was performed. PMID- 28906137 TI - Treatment of Achromobacter Ventilator-Associated Pneumonia in Critically Ill Trauma Patients. AB - BACKGROUND: Achromobacter sp are nonfermenting Gram-negative bacilli (NFGNB) that rarely cause severe infections, including ventilator-associated pneumonia (VAP). Data on the treatment of Achromobacter pneumonia are very limited, and the organism has been associated with a high mortality rate. Thus, more data are needed on treating this organism. OBJECTIVE: To evaluate the treatment of Achromobacter VAP in critically ill trauma patients. METHODS: This retrospective, observational study evaluated critically ill trauma patients who developed Achromobacter VAP. A previously published pathway for the diagnosis and management of VAP was used according to routine patient care. This included the use of quantitative bronchoscopic bronchoalveolar lavage cultures to definitively diagnose VAP. RESULTS: A total of 37 episodes of Achromobacter VAP occurred in 34 trauma intensive care unit patients over a 15-year period. The most commonly used definitive antibiotics were imipenem/cilastatin, cefepime, or trimethoprim/sulfamethoxazole. The primary outcome of clinical success was achieved in 32 of 37 episodes (87%). This is similar to previous studies of other NFGNB VAP (eg, Pseudomonas, Acinetobacter) from the study center. Microbiological success was seen in 21 of 28 episodes (75%), and VAP-related mortality was 9% (3 of 34 patients). CONCLUSIONS: Achromobacter is a rare but potentially serious cause of VAP in critically ill patients. In this study, there was an acceptable success rate compared with other causes of NFGNB VAP in this patient population. PMID- 28906138 TI - In vivo effect of antibacterial and fluoride-releasing adhesives on enamel demineralization around brackets: A micro-CT study. AB - OBJECTIVES: The aim of this in vivo study was to investigate the preventive effect of two different adhesives on enamel demineralization and compare these adhesives with a conventional one. MATERIALS AND METHODS: Fifteen patients requiring the extraction of their first four premolars for orthodontic treatment were included in the study. One premolar was randomly selected, and an antibacterial monomer-containing and fluoride-releasing adhesive (Clearfil Protect Bond, Kuraray Medical, Okayama, Japan) was used for orthodontic bracket bonding. Another premolar was randomly selected, and a fluoride-releasing and recharging orthodontic adhesive (Opal Seal, Ultradent Products, South Jordan, Utah) was used. One premolar was assigned as a control, and a conventional adhesive (Transbond XT, 3M Unitek, Monrovia, Calif) was used. The teeth were extracted after 8 weeks, and the demineralization areas of the 45 extracted teeth were analyzed using microcomputed tomography with software. RESULTS: There was no significant difference between the white spot lesion (WSL) rates of the adhesives (P > .05). The volumes of the WSLs varied from 0 to 0.019349 mm3. Although Opal Seal showed the smallest lesion volumes, there was no significant difference in volumetric measurements of the lesions among the groups (P > .05). CONCLUSIONS: The findings indicated no significant differences between the preventive effects of the adhesives used in this in vivo study over 8 weeks. PMID- 28906139 TI - Evaluation of maxillary central incisors on the noncleft and cleft sides in patients with unilateral cleft lip and palate-Part 1: Relationship between root length and orthodontic tooth movement. AB - OBJECTIVES: To measure the root lengths of maxillary central incisors (U1) and evaluate the relationship among U1 root length, tooth movement, and type of treatment appliance in patients with unilateral cleft lip and palate over a long term follow-up period. MATERIALS AND METHODS: Occlusal radiographs of 30 patients with unilateral cleft lip and palate, acquired less than 6 months before secondary alveolar bone grafting (SBG, T1) and after edgewise treatment (T2), were measured for U1 root length (R1 and R2, root lengths at T1 and T2, respectively). Frontal and lateral cephalometric radiographs acquired at eruption of U1 (T0), T1, and T2 were evaluated to determine the inclination and position of U1. RESULTS: The average values of R1 and R2 on the cleft side were significantly lower than those on the noncleft side. Frontal cephalometric analysis revealed that the horizontal distance of the root apex from the median vertical line at T0 on the cleft side was significantly smaller than that on the noncleft side and was correlated with short U1 root length on the cleft side. On the other hand, R1 in patients treated with maxillary protraction appliances between T0 and T1 was significantly shorter than that in patients without maxillary protraction appliances. However, none of the changes in cephalometric measurements were correlated with root length. CONCLUSIONS: In patients with unilateral cleft lip and palate, the short root length of cleft-adjacent central incisors might be associated with the horizontal position of the root apex. In addition, orthodontic treatment with a maxillary protraction appliance before secondary alveolar bone grafting might be associated with short U1 root length. PMID- 28906140 TI - Evaluation of maxillary central incisors on the noncleft and cleft sides in patients with unilateral cleft lip and palate-Part 2: Relationship between root resorption, horizontal tooth movement, and quantity of grafted autogenous bone. AB - OBJECTIVE: To evaluate the relationship between external apical root resorption (EARR) of the maxillary central incisors (U1), horizontal orthodontic tooth movement, and quantity of grafted bone in subjects with unilateral cleft lip and palate (UCLP) over an average duration of 8 years. MATERIALS AND METHODS: Thirty subjects with UCLP were evaluated for EARR of U1 after edgewise treatment (T2). The teeth were classified as having no EARR, moderate EARR (combined into "no/moderate" EARR), or severe EARR. Frontal cephalometric radiographs acquired at eruption of U1 (T0), less than 6 months before secondary alveolar bone grafting (T1), and T2 were evaluated to determine the horizontal inclination (U1 axis angle) and distance of the root apex from the median line (U1-root-VL distance). On the cleft side, the quantities of grafted bone at less than 12 months postsecondary bone grafting and at T2 were evaluated using the alveolar bone graft (ABG) scale. RESULTS: Cleft-adjacent teeth exhibited more severe EARR than did teeth on the noncleft side. The cleft side exhibited greater changes in U1-axis angle and U1-root-VL distance between T0 and T2 than did the noncleft side. On the cleft side, the ABG score at T2 in the severe EARR group was significantly lower than that in the no/moderate EARR group. These measurements were correlated with EARR grade. CONCLUSIONS: Cleft-adjacent U1 exhibited more severe EARR than did the U1 on the noncleft side, which might be associated with orthodontic treatment-induced changes in horizontal inclination and root apex movement. On the cleft side, severity of EARR may be correlated with the success of ABG. PMID- 28906141 TI - A new dihydrochalcone glycoside from the stems of Homalium stenophyllum. AB - A new dihydrochalcone glycoside, phloretin-4-O-beta-D-glucopyranoside (1), together with seven known flavonoids (2-8), were isolated from the stems of Homalium stenophyllum. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. The known compounds (2-8) were isolated from the genus Homalium for the first time. All compounds were evaluated for their antibacterial activities against six pathogenic bacteria in vitro. PMID- 28906142 TI - Educational Quality of YouTube Videos in Thumb Exercises for Carpometacarpal Osteoarthritis: A Search on Current Practice. AB - BACKGROUND: Conservative treatments are commonly performed therapeutic interventions for the management of carpometacarpal (CMC) joint osteoarthritis (OA). Physical and occupational therapies are starting to use video-based online content as both a patient teaching tool and a source for treatment techniques. YouTube is a popular video-sharing website that can be accessed easily. The purpose of this study was to analyze the quality of content and potential sources of bias in videos available on YouTube pertaining to thumb exercises for CMC OA. METHODS: The YouTube video database was systematically searched using the search term thumb osteoarthritis and exercises from its inception to March 10, 2017. Authors independently selected videos, conducted quality assessment, and extracted results. RESULTS: A total of 832 videos were found using the keywords. Of these, 10 videos clearly demonstrated therapeutic exercise for the management of CMC OA. In addition, the top-ranked video found by performing a search of "views" was a video with more than 121 863 views uploaded in 2015 that lasted 12.33 minutes and scored only 2 points on the Global Score for Educational Value rating scale. CONCLUSIONS: Most of the videos viewed that described conservative interventions for CMC OA management have a low level of evidence to support their use. Although patients and novice hand therapists are using YouTube and other online resources, videos that are produced by expert hand therapists are scarce. PMID- 28906143 TI - Composition of essential oils from four Apiaceae and Asteraceae species growing in Uzbekistan. AB - The chemical composition of essential oils isolated from the aerial parts of Heracleum lehmannianum, Prangos pabularia, Pseudohandelia umbellifera and Pulicaria salviifolia, all of them growing in Uzbekistan, were determined by GC MS analysis. The main components of the oil from H. lehmannianum were alpha phellandrene (10.5%), 1-butanol (9.0%), delta-cadinene (6.2%), alpha-cadinol (5.7%), tau-muurolol (3.1%), 4-terpineol (2.4%) and alpha-muurolene (2.6%), while cis-allo-ocimene (17.6%), delta-3-carene (14.2%), limonene (7.6%), 2,4,6 trimethylbenzaldehyde (6.8%), alpha-terpinolene (6.1%), beta-ocimene (4.3%), alpha-ocimene (4.2%), alpha-phellandrene (4.2%) were the major oil components in P. pabularia, and borneol (4.4%), t-cadinol (4.1%), alpha-humulene oxide (4.0%), caryophyllene oxide (3.6%), bornyl chloride (3.1%), beta-pinene (2.9%) in P. umbellifera. The essential oil of P. salviifolia had a much more complex composition which was dominated by 4-terpineol (13.4%), alpha-cadinol (5.7%), 6 epi-shyobunol (5.2%), gamma-terpinene (5.0%), delta-cadinene (4.4%), alpha terpinene (3.5%). PMID- 28906144 TI - Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability. AB - Multicomponent formulations have attracted increasing attention because of their favourable patient compliance and greater therapeutic effect. The aim of this study was to develop a multicomponent nanosuspension formulation of bufadienolides, the antitumor components of a traditional Chinese medicine, toad venom, using a wet-milling technique to improve its dissolution behaviour. Croscarmellose sodium (CCS) and sodium lauryl sulfate (SLS) were chosen as the combined stabilizers of the nanosuspension. A Taguchi orthogonal array design was used for this study to optimize the formulation and process parameters. The optimized nanosuspension was characterized by its particle size distribution, zeta potential, morphology, crystallinity, molecular interactions, stability and dissolution. The results showed that the nanosuspension was a homogeneous amorphous system with average particle sizes of <100 nm and significantly improved dissolution behaviour. It was also physically stable for at least 2 months; steric and kinetic stabilization were its main stability mechanisms. These findings suggested that the use of wet milling to fabricate nanosuspensions is a promising method for achieving the fast and synchronized dissolution of multicomponent formulations, presumably increasing the bioavailability of poorly water-soluble drugs. PMID- 28906145 TI - Protective effect of rutin against brain injury induced by acrylamide or gamma radiation: role of PI3K/AKT/GSK-3beta/NRF-2 signalling pathway. AB - This study was designed to evaluate the effect of rutin on PI3K/AKT-signalling in case of acrylamide or gamma-radiation-induced neurotoxicity. To induce brain damage, animals were received acrylamide (25 mg/kg b.wt./orally/day) or 5 Gy of gamma-radiation exposure accompanied with an administration of rutin (200 mg/kg b.wt./orally/day). Our data revealed that, compared to acrylamide or gamma radiation, rutin activated PI3K/AKT/GSK-3beta/NRF-2-pathway through increased protein levels of p-PI3K, p-AKT and p-GSK-3beta and up-regulated the expression of NRF-2. This was achieved by modulating MDA, GST, IL-1beta, IL-6 and reduced the interference of ROS with IGF-1 and NGF stimulating the PI3K/AKT-signaling. Furthermore, histopathological examinations of brain tissues showed that rutin has modulated tissue architecture after acrylamide or gamma-radiation induced tissue damage. It could be concluded that rutin provides protection effect against acrylamide or gamma-radiation-induced neurotoxicity via activation of the PI3K/AKT/GSK-3beta/NRF-2-pathway by altering the phosphorylation state through its ability to scavenge free radicals generation, modulating gene expression and its anti-inflammatory effects. PMID- 28906146 TI - New cerebroside and chondrocyte proliferation activity of Caryota mitis L. AB - Caryota mitis L., a flowering plant, belongs to the family Arecaceae. In Vietnam, its fruits were used to treat joint pain. The present study was designed to investigate the phytochemicals and chondrocyte proliferation activity of C. mitis L. fruits on young human chondrocyte. The results showed that all of extracts (crude extract as well as n-hexane, chloroform, ethyl acetate and methanol fractions) were stimulated the growth of chondrocyte at 0.1 MUg/mL; 0.01 MUg/mL concentrations, of which the n-hexane and methanol fractions significantly increased the proliferation of chondrocyte by 30.75 and 24.42% at concentrations of 0.01 MUg/mL, respectively. Repeated chromatography of the methanol fraction on silica gel, Sephadex LH-20 and ODS columns afforded a new cerebroside and eight known ones. Their structures were elucidated by analysis of spectral data and in comparison with the published reports. PMID- 28906147 TI - Carbon monoxide poisoning from waterpipe smoking: a retrospective cohort study. AB - OBJECTIVE: Waterpipe smoking may increasingly account for unintentional carbon monoxide poisoning, a serious health hazard with high morbidity and mortality. We aimed at identifying waterpipe smoking as a cause for carbon monoxide poisoning in a large critical care database of a specialty care referral center. METHODS: This retrospective cohort study included patients with a history of exposure to waterpipe smoking and carbon monoxide blood gas levels >10% or presence of clinical symptoms compatible with CO poisoning admitted between January 2013 and December 2016. Patients' initial symptoms and carbon monoxide blood levels were retrieved from records and neurologic status was assessed before and after hyperbaric oxygen treatment. RESULTS: Sixty-one subjects with carbon monoxide poisoning were included [41 males, 20 females; mean age 23 (SD +/- 6) years; range 13-45] with an initial mean carboxyhemoglobin of 26.93% (SD +/- 9.72). Most common symptoms included syncope, dizziness, headache, and nausea; 75% had temporary syncope. Symptoms were not closely associated with blood COHb levels. CONCLUSION: CO poisoning after waterpipe smoking may present in young adults with a wide variability of symptoms from none to unconsciousness. Therefore diagnosis should be suspected even in the absence of symptoms. PMID- 28906148 TI - Hip and knee arthroplasty are common among patients with transthyretin cardiac amyloidosis, occurring years before cardiac amyloid diagnosis: can we identify affected patients earlier? AB - Transthyretin cardiac amyloidosis (ATTR-CA) causes a restrictive cardiomyopathy in older adults, often diagnosed at advanced stages when emerging therapies in late phase clinical trials may not have clinical benefit. This investigation aimed to detect clinical entities that may provide more advanced warning of ATTR CA. Since ATTR preferentially deposits in ligaments, tendons, and articular cartilage, we hypothesized that ATTR-CA patients have a greater prevalence of total hip (THA) and knee (TKA) arthroplasties compared with the general population, and that arthroplasty occurs significantly before ATTR-CA diagnosis. Three-hundred and thirteen patients with cardiac amyloidosis (172 with ATTR-CA, 141 with light-chain) from our institutional database were analyzed and compared to published data in over 300 million patients. Overall, 23.3% of patients with ATTR-CA and 9.2% of patients with light-chain cardiac amyloidosis (AL-CA) underwent lower extremity arthroplasty. Compared to the general population, both THA and TKA were significantly more common among patients with ATTR-CA (THA: RR 5.61, 95% CI 2.25-4.64; TKA: RR 3.32, 95% CI 2.25-4.64) but not those with AL-CA (THA: RR 1.87, 95% CI 0.85-4.08; TKA: RR 1.42, 95% CI 0.73-2.84). On an average, arthroplasty occurred 7.2 years before ATTR-CA diagnosis. PMID- 28906149 TI - A rare cause of sciatica discovered during digital rectal examination: case report of an intrapelvic sciatic notch schwannoma. AB - Intrapelvic sciatic nerve schwannomas are rare causes for non-discogenic sciatica. We describe a 44-year-old female who had a palpable mass on digital rectal examination that exhibited a positive Tinel's sign. The schwannoma was excised by a posterior transgluteal approach. Patients with negative spinal imaging should undergo pelvic scanning to rule out these tumors. PMID- 28906150 TI - Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy. AB - OBJECTIVES: Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTRwt)). Clinically disease progression from time of diagnosis to death is usually quoted as 5- to 15-years. In prior studies, significant progression of cardiac parameters in patients with moderate to severe cardiomyopathy has been noted within a 12-month time span. METHODS: The present study was designed to prospectively monitor changes in cardiac parameters, both structural and functional, in patients with ATTR cardiomyopathy while treated with a TTR specific antisense oligonucleotide (ASO; IONIS-TTRPx) designed to lower blood levels of the amyloid fibril precursor protein. To date 22 patients have been admitted to the study, 15 have completed 12 months on the drug and are the subject of this report. RESULTS: Eight patients with hereditary ATTR amyloidosis and 7 patients with wild-type ATTR amyloidosis with moderate to severely advanced restrictive cardiomyopathy showed stabilization of disease as measured by left ventricular wall thickness, left ventricular mass (LVM), 6-min walk test (6MWT), and echocardiographic global systolic strain. IONIS-TTRPx was well tolerated by all 15 subjects and showed a good safety profile. CONCLUSIONS: ASO treatment of patients with moderate to advanced ATTR cardiomyopathy shows indication of stabilization of disease progression and may therefore contribute to enhanced life expectancy. PMID- 28906151 TI - Photopolymerization-based synthesis of iron oxide nanoparticle embedded PNIPAM nanogels for biomedical applications. AB - Conventional therapeutic techniques treat patients by delivering biotherapeutics to the entire body. With targeted delivery, biotherapeutics are transported to the afflicted tissue reducing exposure to healthy tissue. Targeted delivery devices are minimally composed of a stimuli responsive polymer allowing triggered release and magnetic nanoparticles enabling targeting as well as alternating magnetic field (AMF) heating. Although more traditional methods, like emulsion polymerization, have been used to realize such devices, the synthesis is problematic. For example, surfactants preventing agglomeration must be removed from the product increasing time and cost. Ultraviolet (UV) photopolymerization is more efficient and ensures safety by using biocompatible substances. Reactants selected for nanogel fabrication were N-isopropylacrylamide (monomer), methylene bis-acrylamide (crosslinker), and Irgacure 2959 (photoinitiator). The 10 nm superparamagnetic nanoparticles for encapsulation were composed of iron oxide. Herein, a low-cost, scalable, and rapid, custom-built UV photoreactor with in situ, spectroscopic monitoring system is used to observe synthesis. This method also allows in situ encapsulation of the magnetic nanoparticles simplifying the process. Nanogel characterization, performed by transmission electron microscopy, reveals size-tunable nanogel spheres between 40 and 800 nm in diameter. Samples of nanogels encapsulating magnetic nanoparticles were subjected to an AMF and temperature increase was observed indicating triggered release is possible. Results presented here will have a wide range of applications in medical sciences like oncology, gene delivery, cardiology, and endocrinology. PMID- 28906152 TI - Relapse outcomes, safety, and treatment patterns in patients diagnosed with relapsing-remitting multiple sclerosis and initiated on subcutaneous interferon beta-1a or dimethyl fumarate: a real-world study. AB - OBJECTIVE: To estimate real-world treatment patterns, safety, and relapse outcomes of subcutaneous (sc) interferon (IFN) beta-1a (Rebif) vs dimethyl fumarate (DMF; Tecfidera), to treat relapsing-remitting multiple sclerosis (RRMS). METHODS: A US retrospective chart review of 450 randomly selected adults newly diagnosed with RRMS who received sc IFN beta-1a (n = 143) or DMF (n = 307) was conducted. Patients were either (a) treatment-naive, initiating first-line treatment with sc IFN beta-1a or DMF, or (b) previously treated, switching to sc IFN beta-1a or DMF. Two years' follow-up data were captured. Patient characteristics, persistence, and adverse events between treatment groups were compared using t-tests or Chi-square tests. Kaplan-Meier curves with log-rank tests and Cox proportional hazards models were used to compare time to, and risk of non-persistence. Annualized Relapse Rates (ARR) were calculated using a robust variance Poisson model adjusting for covariates. Propensity scores were used to address possible selection bias. RESULTS: One hundred and twelve patients became non-persistent, most commonly due to an adverse event (n = 37). No difference was observed in time to overall non-persistence between sc IFN beta-1a and DMF patients. Among treatment-naive patients, those receiving DMF had 2.4-times the risk (HR = 2.439, 95% CI = 1.007-5.917, p = .0483) of experiencing a discontinuation than patients receiving sc IFN beta-1a. Non-persistent patients receiving DMF had 2.3-times the risk (HR = 2.311, 95% CI = 1.350-3.958, p = .0023) of experiencing an adverse event at a given time point than patients prescribed sc IFN beta-1a. No differences in relapse risk or ARR between sc IFN beta-1a- and DMF-treated patients were observed. CONCLUSIONS: sc IFN beta-1a treated patients had comparable persistence and relapse outcomes, and better safety outcomes vs DMF-treated patients across 2 years. PMID- 28906153 TI - Investigational drugs in phase II clinical trials for the treatment of neuroblastoma. AB - INTRODUCTION: Neuroblastoma (NB) is an embryonal tumor originating from undifferentiated neural crest cell, highly heterogeneous ranging from spontaneous regression to progression despite multimodal treatments. Approximately, 20% of patients are refractory to frontline therapy and 50% will relapse/progress after an initial response. The overall five year survival for high-risk neuroblastoma ranges from 35-45%. Despite enhanced understanding of NB biology and the addition of myeloablative chemotherapy, isotretinoin and immunotherapy, survival for high risk NB remains less than 50%. Areas covered: This review summarizes and gives a critical overview of phase II trials investigating therapies for relapsed refractory and high risk neuroblastoma. Expert opinion: Several novel molecules have been developed and are currently under investigation for the treatment of NB. The trend of novel targeted agents is one towards individualized, tailored therapy, based on the molecular and biological differences that characterize tumors that seem similar based solely on histological analysis. The task of developing new molecules is particularly difficult for NB, given the recurrent development of new patterns of drug resistance. However, even if current research is focused towards identifying the best treatments for each children and young adult with a NB defined disease, a deeper knowledge of the molecular biology and genetics is needed. PMID- 28906154 TI - Moving toward consensus on diagnosis and management of severe asthma in adults. AB - Asthma is a considerable health problem with an increasing global prevalence. The burden of severe asthma is expected to notably increase in the following years. Some misleading concepts that sometimes appear in the literature can drive the physician responsible for a patient's management to make incorrect decisions. Furthermore, some of the concepts that appear in the literature and in the guidelines may not be clear to understand, follow or adapt to regional and local realities. This could again drive the physicians responsible for a patient's management to make incorrect clinical judgments. In this article, we review the definition, prevalence and immunopathology of severe asthma, describe the asthma phenotypes, clinical features and comorbidities, the diagnosis of severe asthma and personalized asthma treatment. At the end, we offer a treatment approach based on literature publications, personalized medicine and marketed biologic treatment options. PMID- 28906155 TI - The role of tapentadol as a strong opioid in cancer pain management: a systematic and critical review. AB - AIM: The aim of this review was to assess the role of tapentadol given at medium high doses in opioid-tolerant patients for cancer pain management in place of step-3 analgesics. METHODS AND RESULTS: A systematic literature search was performed out of which six studies and one secondary analysis provided data regarding tapentadol used as a step-3 analgesic for this review. Tapentadol, when used at >=60 mg of oral morphine equivalents in opioid-tolerant patients with cancer pain, or passing from step-2 doses to >=60 mg of oral morphine equivalents, was well tolerated and effective and could be considered as a flexible drug to be used for the management of moderate-to-severe cancer pain. The limited occurrence of gastrointestinal adverse effects may be a great advantage in the context of a disease like cancer, where multiple causes contribute to nausea, vomiting, or constipation; however, studies of tapentadol given at doses equivalent to step-3 level have some weaknesses, as data from prospective observational studies are poorly generalizable due to a small number of participants, controlled studies do not clearly show a superiority of tapentadol with respect to other opioids, and the sample size is often small. CONCLUSIONS: More studies are necessary to confirm the role of tapentadol in cancer patients requiring strong opioids for their pain. PMID- 28906156 TI - Canadian Consumer Food Safety Practices and Knowledge: Foodbook Study. AB - Understanding consumers' food safety practices and knowledge supports food safety education for the prevention of foodborne illness. The objective of this study was to describe Canadian consumer food safety practices and knowledge. This study identifies demographic groups for targeted food safety education messaging and establishes a baseline measurement to assess the effectiveness of food safety interventions over time. Questions regarding consumer food safety practices and knowledge were included in a population-based telephone survey, Foodbook, conducted from November 2014 to March 2015. The results were analyzed nationally by age group and by gender. The results showed that approximately 90% of Canadians reported taking the recommended cleaning and separating precautions when handling raw meat to prevent foodborne illness. Only 29% of respondents reported using a food thermometer when cooking any meat, and even fewer (12%) reported using a food thermometer for small cuts of meat such as chicken pieces. The majority (>80%) of Canadians were aware of the foodborne illness risks related to chicken and hamburger, but fewer (<40%) were aware of the risks related to frozen chicken nuggets, alfalfa sprouts, soft unpasteurized cheese, and unpasteurized juices. Generally, men were less likely to follow cooking instructions on packaging and took fewer steps to prevent cross-contamination than women. The youngest (18 to 29 years) age group was less likely to take steps to avoid cross-contamination and was less aware of the risks associated with eating an undercooked hamburger. The oldest (60+ years) respondents were less likely to be aware of the risks associated with raw eggs, alfalfa sprouts, and unpasteurized juice than the middle (30 to 59 years) age group. As a priority, food safety education in Canada should focus on increasing people's awareness of high-risk foods, specifically foods for which the awareness of risk found in this study was low; targeting messaging to demographic groups as appropriate; and promoting the use of food thermometers when cooking meat and poultry. PMID- 28906157 TI - Economic Factors Impacting Food Allergen Management: Perspectives from the Food Industry. AB - Food allergies affect up to 8% of children in the United States and may occasionally lead to severe life-threatening reactions. Because there is currently no cure for food allergies, strict avoidance of the allergen-containing foods is the only means of preventing an allergic reaction. Consumers rely on food manufacturers to reliably track and declare the presence of food allergens in products. Over the past 10 to 20 years, the food industry has increasingly adopted allergen control approaches in its processing facilities. However, the major industry costs related to food allergen management have not been fully described. The objective of this study was to characterize the factors that contribute to the economic impact of food allergen control practices on the food industry. A focus group (n = 100) was conducted with food industry professionals to identify key areas of cost for food allergen management. A survey based on the domains identified was then developed and disseminated to a convenience sample (n = 50) of quality control food industry specialists with knowledge of their company's food allergen management practices. Nearly all companies (92%) produced food products containing one or more of the top eight allergenic foods recognized by the U.S. Food and Drug Administration or sesame seeds. Cleaning procedures, employee training, and the potential for a recall due to allergen cross-contact were most frequently rated as the important factors in food allergen management. Recalls due to food allergen cross-contact, cleaning procedures, equipment and premises design, and employee training were ranked as the greatest allergen management expenses. Although 96% of companies had a food allergen control plan in place, nearly half (42%) had at least one food allergen-related recall within the past 5 years. The industry appears to endorse a willingness to unify precautionary allergen labeling to communicate a clear message more effectively to consumers. PMID- 28906158 TI - Prevalence of Putative Virulence Genes in Campylobacter and Arcobacter Species Isolated from Poultry and Poultry By-Products in Tunisia. AB - Campylobacter and Arcobacter spp. are common causes of gastroenteritis in humans; these infections are commonly due to undercooked poultry. However, their virulence mechanism is still poorly understood. The aim of this study was to evaluate the presence of genotypic virulence markers in Campylobacter and Arcobacter species using PCR. The prevalence of virulence and cytolethal distending toxin (CDT) genes was estimated in 71 Campylobacteraceae isolates. PCR was used to detect the presence of virulence genes (iam, cadF, virB1, flaA, cdtA, cdtB, and cdtC) using specific primers for a total of 45 Campylobacter isolates, including 37 C. jejuni and 8 C. coli. All the Campylobacter isolates were positive for the cadF gene. The plasmid gene virB11 was not detected in any strain. The invasion associated marker was not detected in C. jejuni. Lower detection rates were observed for flaA, cdtA, cdtB, and cdtC. The presence of nine putative Arcobacter virulence genes (cadF, ciaB, cj1349, mviN, pldA, tlyA, irgA, hecA, and hecB) was checked in a set of 22 Arcobacter butzleri and 4 Arcobacter cryaerophilus isolates. The pldA and mviN genes were predominant (88.64%). Lower detection rates were observed for tlyA (84.76%), ciaB (84.61%), cadF and cj1349 (76.92%), IrgA and hecA (61.53%), and hecB (57.69%). The findings revealed that a majority of the Campylobacteraceae strains have these putative virulence genes that may lead to pathogenic effects in humans. PMID- 28906159 TI - Advances in nano-delivery systems for doxorubicin: an updated insight. AB - Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet(r)) and pegylated liposomal (Doxil(r)) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems. PMID- 28906160 TI - Tone production and perception and intelligibility of produced speech in Mandarin speaking cochlear implanted children. AB - OBJECTIVE: This study explored tone production, tone perception and intelligibility of produced speech in Mandarin-speaking prelingually deaf children with at least 5 years of cochlear implant (CI) experience. Another focus was on the predictive value of tone perception and tone production as they relate to speech intelligibility. DESIGN: Cross-sectional research. STUDY SAMPLE: Thirty three prelingually deafened children aged over eight years with over five years of experience with CI underwent tests for tone perception, tone production, and the Speech Intelligibility Rating (SIR). A Pearson correlation and a stepwise regression analysis were used to estimate the correlations among tone perception, tone production, and SIR scores. RESULTS: The mean scores for tone perception, tone production, and SIR were 76.88%, 90.08%, and 4.08, respectively. Moderately positive Pearson correlations were found between tone perception and production, tone production and SIR, and tone perception and SIR (p < 0.01, p < 0.01 and p < 0.01, respectively). In the stepwise regression analysis, tone production, as the major predictor, accounted for 29% of the variations in the SIR (p < 0.01). CONCLUSIONS: Mandarin-speaking cochlear-implanted children with sufficient duration of CI use produce intelligent speech. Speech intelligibility can be predicted by tone production performance. PMID- 28906162 TI - Effects of tinnitus treatments on sleep disorders in patients with tinnitus. AB - OBJECTIVE: To assess the effects of tinnitus treatments on sleep disorders in patients with tinnitus. DESIGN: Subjects completed the Pittsburg Sleep Quality Index (PSQI), Tinnitus Handicap Inventory (THI), Self-rating Depression Scale (SDS), and State Trait Anxiety Inventory (STAI). The questionnaire results and the patients' sex, age, time since the onset of tinnitus, and mean hearing level were examined, and differences between a sleep disorder group and a normal sleep group were examined. Patients completed the questionnaires again after initiating tinnitus treatments (counselling and use of sound generators), and the change in questionnaire scores at follow-up was evaluated. STUDY SAMPLE: Patients (N = 100) with tinnitus who visited Keio University Hospital and started treatment without medication between 2005 and 2008. RESULTS: Sixty-six percent of the patients had sleep disorders. Compared with patients without sleep disorders, patients with sleep disorders had significantly higher SDS and STAI scores at the first visit. The mean PSQI scores showed significant improvement at follow-up. CONCLUSIONS: Sleep disorders in patients with tinnitus improved after tinnitus treatments. Complex interactions between depressive symptoms and anxiety may occur in these patients. The improvement in sleep disorders at follow-up was correlated with improvements in tinnitus severity and state anxiety. PMID- 28906161 TI - Heat stress modulated gastrointestinal barrier dysfunction: role of tight junctions and heat shock proteins. AB - Increased environmental temperature exerts a visible impact on an individual's physiology. At the onset of heat stress, there is an increase in core body temperature which triggers peripheral vasodilation and sweating in an effort to dissipate the elevated body heat. The increase in peripheral circulation however reduces blood flow to the internal organs which are thus adversely affected. In particular, the gastrointestinal (GI) tract gets adversely affected during hyperthermia resulting in loosening of the tight junctions (TJs) that finally leads to higher intestinal permeability. At the cellular level, elevated levels of heat shock proteins (HSPs) induced in response to heat stress mediated cytoprotection by maintaining proper protein folding, releasing survival signals and preserving cytoskeleton integrity. Recent studies have indicated that HSPs play a crucial role in maintaining the localization of TJ proteins. Dietary supplements have also shown to have a positive effect on the maintenance of intestinal TJs. Therefore, it becomes imperative to understand the cellular, molecular and physiological alterations in response to heat stress in GI tract. In the present report, the effect of thermal stress on GI tract has been summarized. Specific role of HSPs along with mitogen activated protein (MAP) kinase signaling pathway in response to hyperthermia has also been discussed. PMID- 28906163 TI - Colorectal cancer death after adenoma removal in Scandinavia. AB - OBJECTIVES: Improved understanding of the subsequent risk death from colorectal cancer (CRC) among individuals who had adenomas removed is needed. We aimed to quantify this risk using prospectively collected data from population-based cohorts. MATERIALS AND METHODS: Using Norwegian and Swedish registries, a cohort of 90,864 individuals with colorectal adenomas removed between 1980 and 2013 was identified. Surveillance was only recommended for high-risk adenomas. The validity of the registry data did not allow classification into low- and high risk adenomas. Virtually complete follow-up was achieved through linkage to nationwide registers. We calculated incidence-based standardised mortality ratios (SMRs) with 95% confidence intervals (CI). RESULTS: The median follow-up was 7.2 years; 48,058 individuals were followed for more than 10 years. We observed 819 deaths (0.9%) from CRC and expected 731 CRC deaths (0.8%), corresponding to an absolute excess risk of 88 cases (0.1%) and a relative risk of 12% (SMR 1.12; 95%CI 1.05-1.20). The relative risk of CRC death following adenoma removal was slightly higher in Sweden (SMR 1.22; 95%CI 1.11-1.34) than in Norway (SMR 1.03; 95%CI 0.93-1.14), and higher in women (SMR 1.24; 95%CI 1.12-1.36) than in men (SMR 1.02; 95%CI 0.93-1.13). Among individuals with more than 10 years of follow up, the estimates were similar to the overall cohort, absolute excess risk 0.1% (SMR 1.15; 95%CI 1.06-1.24). CONCLUSION: The excess risk of CRC death following adenoma removal is small. Optimal surveillance recommendations should be tested in randomised trials. PMID- 28906164 TI - Comparative pharmacokinetics study of anastrozole after single administration and combination with celecoxib. AB - 1. There are numerous investigations demonstrating that the cyclooxygenase-2 (COX 2) inhibitors might enhance the efficiency of anastrozole in breast cancer. Hence, this study was conducted to investigate the comparative pharmacokinetics of anastrozole after single administration and combination with celecoxib. 2. A simple protein precipitation procedure was adopted for the sample preparation with satisfactory extraction recovery for both anastrozole and the internal standard, and then anastrozole was separated and analysed on an ACQUITY BEH UPLC C18 column (50 * 2.0 mm, 1.7 MUm, Waters) within 2 min. The calibration curves showed good linarites (r = 0.994). Intra- and inter-day precision were within 4.93 and 13.83%, respectively. The mean extraction recoveries across QC levels were within 91.4%, and the matrix effects were within 94.5%. 3. Results showed that the method was reliable to determine anastrozole in rat plasma. Compared with rats in single administration group, no significant difference was found in the combination group. It is workable to use celecoxib combined with anastrozole in clinical therapy. PMID- 28906165 TI - Radiologically isolated syndrome should be treated with disease-modifying therapy - Yes. PMID- 28906166 TI - Radiologically isolated syndrome should be treated with disease-modifying therapy - Commentary. PMID- 28906167 TI - "It's Totally Destroyed Our Life": Exploring the Pathways and Mechanisms Between Precarious Employment and Health and Well-being Among Immigrant Men and Women in Toronto. AB - Precarious employment is rapidly growing, but qualitative data on pathways to and mechanisms for health and well-being is lacking. This article describes the cumulative and intersecting micro-level pathways and mechanisms between precarious employment and health among immigrant men and women in Toronto. It draws on semi-structured interviews conducted in 2014 with 15 women and 12 men from 11 countries of origin. The article describes how precarious employment, conceptualized by workers as encompassing powerlessness, economic insecurity, work for multiple employers, nonstandard and unpredictable schedules, hazardous working conditions, and lack of benefits and protections, negatively impacts workers' physical and mental health as well as that of their spouses or partners and children. It documents pathways to health and well-being, including stress, material and social deprivation, and exposure to hazards, as well as commuting difficulties and childcare challenges. Throughout, gender and migration are shown to influence experiences of work and health. The findings draw attention to dimensions of precarity and pathways to health that are not always highlighted in research and discourse on precarious employment and provide valuable insights into the vicious circle of precarious employment and health. PMID- 28906168 TI - The Affordable Care Act: How Nixon's Health Reform Proposal Became Democrats' Albatross. AB - President Obama's signature health care reform, the Affordable Care Act (ACA), was passed in 2010 and fully implemented in 2014. Two years later, Republicans' attacks on the ACA as a failed reform helped fuel their recent electoral victory. The legislation significantly expanded insurance coverage. But it was built on, and fortified, private health insurance firms, and it accelerated the corporate takeover of hospitals and physicians' practices. This obeisance to corporate interests precluded making coverage universal or care affordable. As a result, the reform failed to address the grave health care problems faced by most working and middle-class Americans and left many of them feeling betrayed by Democrats who oversold the ACA's benefits. PMID- 28906169 TI - Radiologically isolated syndrome should be treated with disease-modifying therapy - No. PMID- 28906171 TI - Association of State-Level Restrictions in Nurse Practitioner Scope of Practice With the Quality of Primary Care Provided to Medicare Beneficiaries. AB - CONTEXT: State scope of practice (SoP) laws impose significant restrictions on the services that a nurse practitioner (NP) may provide in some states, yet evidence about SoP limitations on the quality of primary care is very limited. METHOD: This study uses six different classifications of state regulations and bivariate and multivariate analyses to compare beneficiaries attributed to primary care nurse practitioners and primary care physicians in 2013 testing two hypotheses: (1) chronic disease management, cancer screening, preventable hospitalizations, and adverse outcomes of care provided by primary care nurse practitioners are better in reduced and restricted practice states compared to states without restrictions and (2) by decreasing access to care, SoP restrictions negatively affect the quality of primary care. FINDINGS: Results show a lack of consistent association between quality of primary care provided by NPs and state SoP restrictions. CONCLUSION: State regulations restricting NP SoP do not improve the quality of care. PMID- 28906170 TI - Developmental graphemic buffer dysgraphia in English: A single case study. AB - A single case study is reported of a 10-year-old, English-speaking boy, L.S., who presented with spelling errors similar to those described in acquired graphemic buffer dysgraphia (GBD). We used this case to evaluate the appropriateness of applying adult cognitive models to the investigation of developmental cognitive disorders. The dual-route model of spelling guided this investigation. L.S. primarily made "letter errors" (deletions, additions, substitutions, transpositions, or a combination of these errors) on words and nonwords and in all input (aural and visual) and output modalities (writing, typing, oral spelling); there was also some evidence of a length effect and U-shaped serial position curve. An effect of lexical variables on spelling performance was also found. We conclude that the most parsimonious account is an impairment at the level of the graphemic buffer and without systematic cognitive neuropsychological investigation, the nature of L.S.'s spelling difficulty would likely have been missed. PMID- 28906172 TI - From Misperception to Social Connection: Correlates and Consequences of Overestimating Others' Social Connectedness. AB - Two studies document the existence and correlates of a widespread social belief, wherein individuals who have recently moved to a new social environment see their peers as more socially connected than they themselves are. In Study 1, the prevalence of this belief was documented in a large sample of first-year students ( N = 1,099). In Study 2, the prevalence of this social belief was replicated in a targeted sample of university students ( N = 389). Study 2 also documented both positive and negative implications of this belief. Specifically, at any given time, students who believed that their peers were more socially connected reported lower well-being and belonging. Over time, however, the belief that one's peers are moderately more socially connected than oneself was associated with more friendship formation. PMID- 28906173 TI - Diagnosing prosopagnosia in East Asian individuals: Norms for the Cambridge Face Memory Test-Chinese. AB - The Cambridge Face Memory Test (CFMT) is widely accepted as providing a valid and reliable tool in diagnosing prosopagnosia (inability to recognize people's faces). Previously, large-sample norms have been available only for Caucasian face versions, suitable for diagnosis in Caucasian observers. These are invalid for observers of different races due to potentially severe other-race effects. Here, we provide large-sample norms (N = 306) for East Asian observers on an Asian-face version (CFMT-Chinese). We also demonstrate methodological suitability of the CFMT-Chinese for prosopagnosia diagnosis (high internal reliability, approximately normal distribution, norm-score range sufficiently far above chance). Additional findings were a female advantage on mean performance, plus a difference between participants living in the East (China) or the West (international students, second-generation children of immigrants), which we suggest might reflect personality differences associated with willingness to emigrate. Finally, we demonstrate suitability of the CFMT-Chinese for individual differences studies that use correlations within the normal range. PMID- 28906174 TI - A patent review of oxytocin receptor antagonists 2013-2017. PMID- 28906175 TI - Iatrogenic patient injuries in otology during a 10-year period: review of national patient insurance charts. AB - OBJECTIVE: To assess patient injury characteristics and contributing factors in otology. METHODS: Data on the accepted patient-injury claims involving otorhinolaryngology (ORL), closed between 2001 and 2011, from the Finnish Patient Insurance Centre registry was retrieved. We included all injuries concerning otology, with evaluation and classification of their causes and types. RESULTS: During the 10-year study period, a total of 44 claims were accepted as compensated patient injuries in otology. From a total of 233 patient injuries in all ORL, this amounted to 19%. In outpatient care, occurred 12 (27%) injuries and in surgical procedures 32 (73%). Five (11%) patients were children. Errors in surgical technique were identified as the primary cause of the injury in 22 (69%) operation-related cases. Failure to remove all auricular tampons or packing in postoperative control was a contributing factor in 4 (13%) injuries, a facial nerve was damaged in 9 (28%) operations, and in 12 (38%) patients, the injury resulted in severe hearing loss or deafness. Six patients (21%) needed one or more re-operations related to the injury, of which two were due to an incomplete primary operation. CONCLUSION: Typical compensated patient injuries in operative otology resulted from common complications of common operations in high volume centres. PMID- 28906176 TI - Developmental dysgraphia: An overview and framework for research. AB - Developmental deficits in the acquisition of writing skills (developmental dysgraphias) are common and have significant consequences, yet these deficits have received relatively little attention from researchers. We offer a framework for studying developmental dysgraphias (including both spelling and handwriting deficits), arguing that research should be grounded in theories describing normal cognitive writing mechanisms and the acquisition of these mechanisms. We survey the current state of knowledge concerning developmental dysgraphia, discussing potential proximal and distal causes. One conclusion emerging from this discussion is that developmental writing deficits are diverse in their manifestations and causes. We suggest an agenda for research on developmental dysgraphia, and suggest that pursuing this agenda may contribute not only to a better understanding of developmental writing impairment, but also to a better understanding of normal writing mechanisms and their acquisition. Finally, we provide a brief introduction to the subsequent articles in this special issue on developmental dysgraphia. PMID- 28906177 TI - Brachyspira hyodysenteriae detection in the large intestine of slaughtered pigs. AB - Detection of subclinical Brachyspira hyodysenteriae infection in pig herds using feces is challenging. However, the ability to detect the pathogen in intestinal samples of slaughtered pigs has not been investigated, to our knowledge. Therefore, we determined the detection of B. hyodysenteriae in the colon, cecum, and rectum from slaughtered pigs. We analyzed the correlation between detection rates and intestinal lesions, ingesta or fecal consistency, and time from sample collection until processing. A total of 400 ingesta-mucosal (colon, cecum) and 200 fecal (rectum) samples from 200 pigs originating from 20 different herds were bacteriologically examined using selective culture followed by Brachyspira spp. identification by PCR and matrix-assisted laser desorption/ionization time-of flight mass spectrometry. Ingesta or fecal consistency and intestinal lesions were scored. Brachyspira hyodysenteriae was detected in 23 samples from 16 intestines originating from 7 herds. Brachyspira spp. were detected in 96 samples. More intestinal (16) than fecal (7) samples tested positive for B. hyodysenteriae. For Brachyspira spp., this difference was significant (69 vs. 27; p < 0.01). In particular, colon samples tested positive ( n = 42, p = 0.06). Most (91%) of the intestines showed no lesions typical for clinical B. hyodysenteriae infection, and median ingesta or fecal consistency was "soft and formed," indicating subclinical infection, colonization, or absence of infection. Ingesta from slaughtered pigs, in particular from the colon and sites with lesions, is useful material for detection of B. hyodysenteriae. PMID- 28906178 TI - Comparison of whole genome sequencing to restriction endonuclease analysis and gel diffusion precipitin-based serotyping of Pasteurella multocida. AB - The gel diffusion precipitin test (GDPT) and restriction endonuclease analysis (REA) have commonly been used in the serotyping and genotyping of Pasteurella multocida. Whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) analysis has become the gold standard for other organisms, offering higher resolution than previously available methods. We compared WGS to REA and GDPT on 163 isolates of P. multocida to determine if WGS produced more precise results. The isolates used represented the 16 reference serovars, isolates with REA profiles matching an attenuated fowl cholera vaccine strain, and isolates from 10 different animal species. Isolates originated from across the United States and from Chile. Identical REA profiles clustered together in the phylogenetic tree. REA profiles that differed by only a few bands had fewer SNP differences than REA profiles with more differences, as expected. The GDPT results were diverse but it was common to see a single serovar show up repeatedly within clusters. Several errors were found when examining the REA profiles. WGS was able to confirm these errors and compensate for the subjectivity in analysis of REA. Also, results of WGS and SNP analysis correlated more closely with the epidemiologic data than GDPT. In silico results were also compared to a lipopolysaccharide rapid multiplex PCR test. From the data produced in our study, WGS and SNP analysis was superior to REA and GDPT and highlighted some of the issues with the older tests. PMID- 28906179 TI - Multi-locus sequence types of Mycoplasma bovis isolated from Ontario, Canada in the past three decades have a temporal distribution. AB - A total of 217 Mycoplasma bovis isolates cultured from clinical cases in Ontario, Canada, over the past 30 y were selected to be characterized by a multi-locus sequence typing (MLST) method. Eleven housekeeping genes were evaluated for suitability for MLST; 2 loci that had been used in prior MLST schemes, dnaN and metS, along with hsp70 were chosen for further sequence analysis. The remaining loci- adk, efp, gmk, gyrB, polC, rpoB, tpiA, and uvrC genes-were not used because they had little to no sequence variation. The sequence data from the chosen loci ( dnaN, hsp70, metS) generated 28 sequence types (STs), with the 3 loci having 15, 5, and 7 alleles, respectively. These molecular typing results revealed that the STs had a temporal distribution; over the course of 3 decades, some STs disappeared and new STs appeared. Recent isolates had a greater variety of STs, which may indicate that new strains are emerging more rapidly now than in the past. PMID- 28906180 TI - Amplification of Mycoplasma haemofelis DNA by a PCR for point-of-care use. AB - We compared a qualitative in-clinic (IC)-PCR for the detection of Mycoplasma haemofelis DNA with the results of a commercial qualitative laboratory-based, conventional (c)PCR. In order to determine the specificity of both tests, Bartonella spp. samples were included. Forty-three previously tested blood samples with known PCR results for hemoplasmas and Bartonella spp. were selected. The samples were split between 2 laboratories. At the first laboratory, DNA was purified and run on 2 cPCR assays for the detection of hemoplasmas and Bartonella spp. At the second laboratory, DNA was purified using 2 purification protocols and both run in the IC-PCR assay. The cPCR results confirmed that 18 samples were positive for M. haemofelis, 5 for ' Candidatus M. haemominutum', 8 for Bartonella henselae, 2 for Bartonella clarridgeiae, and 10 were negative for both genera. No mixed infections were observed. The IC-PCR assay for the detection of M. haemofelis had a sensitivity of 94.4% and specificity of 96%, when using the same DNA purification method as the first laboratory. Using the second purification method, the sensitivity of the IC-PCR assay was 77.8% and specificity was 96%. Bartonella species were not detected by the IC-PCR M. haemofelis assay. The IC PCR assay decreased the amount of time to final result compared to a cPCR assay. PMID- 28906181 TI - A decade of using small-to-medium throughput allele discrimination assay to determine prion protein gene ( Prnp) genotypes in sheep in Slovenia. AB - Sheep with valine (V) at codon 136 and glutamine (Q) at codon 171 of the prion protein gene ( Prnp) are highly susceptible to classical scrapie, whereas phenylalanine (F) at codon 141 and histidine (H) at codon 154 play a major role in the susceptibility to atypical scrapie. A TaqMan real-time PCR assay was developed to determine Prnp alleles at codons 136, 141, 154, and 171 and used in classical scrapie eradication and breeding programs adopted in Slovenia. The frequency of the most resistant genotypes ARR/ARR and ARR/ARQ increased significantly in tested animals ( n = 35,138) from 6.7 and 27.1% of the tested sheep in 2006 to 12.1 and 32.4%, respectively, in 2015. Frequencies of more susceptible genotypes ARQ/ARQ and ARQ/VRQ decreased significantly from 36.4 and 3.5% in 2006 to 31.1 and 1.8%, respectively, in 2015. The most susceptible genotype VRQ/VRQ was detected in <0.5% of tested sheep. Frequencies of alleles AFRQ and AHQ affecting the susceptibility to atypical scrapie did not change significantly. The developed assay was suitable for genotyping on a small-to medium throughput scale and was successfully used in classical scrapie eradication, as well as for the selection of classical scrapie-resistant sheep within breeding programs in Slovenia. PMID- 28906183 TI - Odontomas in two long-finned ocellaris clownfish ( Amphiprion ocellaris). AB - Two adult long-finned ocellaris clownfish ( Amphiprion ocellaris) from 2 different aquaculture facilities were examined at the University of Florida, Tropical Aquaculture Laboratory for oral masses. Incisional biopsies were obtained from the masses under anesthesia, and histologic examination revealed both to be odontomas. Most benign odontomas are classified as hamartomas (disorganized proliferations of tissues found normally at the site of origin). Odontomas have previously been reported in wild teleost fish in association with viral infections and pollution. PMID- 28906182 TI - Multi-locus sequence typing of Streptococcus equi subspecies zooepidemicus strains isolated from cats. AB - Streptococcus equi subspecies zooepidemicus ( S. zooepidemicus) causes outbreaks of fatal respiratory disease in dog shelters and fatal respiratory and neurologic disease in cat shelters. We conducted multi-locus sequence typing analysis on S. zooepidemicus isolates from 5 Canadian and 3 Israeli cats with severe respiratory and neurologic disease, plus 1 isolate from a clinically normal shelter cat. Our aim was to determine if feline outbreaks are clonal and whether there is commonality between feline and canine strains. ST363 was identified as the causative strain of a Canadian outbreak of S. zooepidemicus-linked disease, and is a double-locus variant of ST173, which was isolated from one of the Israeli cats. ST363 was also isolated from the clinically normal cat, indicative of the potential for enzootic infection in shelters. Strains within the ST173 clonal complex were responsible for 2 large canine outbreaks in the United States and the United Kingdom, as well as the death of 1 cat in the United States outbreak. ST215 was isolated from 2 cats in the Israeli outbreak, and is unrelated to the ST173 complex. We conclude that S. zooepidemicus outbreaks in cat shelters are clonal and that strains within the ST173 clonal complex are pathogenic for both dogs and cats. PMID- 28906184 TI - Teetering on the Edge of Rejection. PMID- 28906186 TI - Midwest Nursing Research Society News. PMID- 28906185 TI - Effects of Abbreviated Progressive Muscle Relaxation on Stress in Jordanian Nursing Students. PMID- 28906187 TI - Assessing Dysphagia in Older Adults. PMID- 28906188 TI - Analysis of the Omaha System Prototype Icons for Health Literacy: A Global Survey. PMID- 28906189 TI - The Rehabilitation Continuum from Hospital to Cardiac Rehabilitation: A Study of 147,000 Medicare Beneficiaries. PMID- 28906190 TI - Exploring factors associated with pressure ulcers in long-term care facilities using decision tree analysis: Use of the Health Insurance Review and Assessment Service National Inpatient Sample. PMID- 28906191 TI - Implementation of a Mentor Led Physical Activity Program among Disadvantaged Youth. PMID- 28906192 TI - Preoperative Risks for Subsyndromal Delirium in Older Adults following Orthopedic Surgery. PMID- 28906193 TI - Translation and Psychometric Properties of a Chinese Version of the Dutch Eating Behavior Questionnaire for Children in Taiwanese Preadolescents. PMID- 28906195 TI - Impact of Leg Elevation and Compression Bandaging on Skin Microcirculation in Healthy Adults. PMID- 28906194 TI - Physical and Psychological Effects of Qigong Exercise in Community-Dwelling Older Adults: An Exploratory Study. PMID- 28906196 TI - Photovoice: Primary Care Redesign Guided by Nursing Research. PMID- 28906197 TI - Teaching to the Affective Domain: An end-of-life Simulation. PMID- 28906198 TI - Supplemental Oxygen Quality Improvement Process. PMID- 28906199 TI - Improving intimate partner violence detection in the primary care setting: review of the literature. PMID- 28906200 TI - Using Personal ResilienceTM Techniques to Reduce Anxiety in University Students. PMID- 28906201 TI - Coercive Control and Suicide Risk: What is Known? PMID- 28906202 TI - Predictors of Maternal Vaccination in the United States: An Integrative Review of Literature. PMID- 28906203 TI - The relation between total cerebral small vessel disease burden and gait impairment in patients with minor stroke. AB - Background and aims Individual MRI markers of cerebral small vessel disease are associated with gait impairment. The impact of total cerebral small vessel disease-related brain damage, expressed by a cerebral small vessel disease MRI burden score, on mobility after stroke, has not been considered, although this score gives a better representation of the overall effect of cerebral small vessel disease on the brain. We determined if the total cerebral small vessel disease burden is associated with gait impairment three years after minor stroke. Methods In total, 200 patients with minor lacunar or non-lacunar stroke (NIHSS <= 7) underwent a brain MRI at presentation. Presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces were summed in a total cerebral small vessel disease MRI burden score (range 0-4). Gait disturbances, measured by timed-up-and-go test and self-reported stroke impact scale mobility domain were assessed three years after stroke. We tested associations adjusted for key variables by linear regression analysis. Results Total cerebral small vessel disease burden was not associated with gait impairment after minor stroke in all patients, nor in lacunar stroke patients ( n = 87). In non-lacunar stroke patients ( n = 113), total cerebral small vessel disease burden was associated with lower stroke impact scale mobility domain scores, independent of age, vascular risk factors, and stroke severity (unstandardized B -4.61; 95% CI -8.42; -0.79, p < 0.05). Conclusion Patients with non-lacunar stroke and a higher total cerebral small vessel disease burden have more subjective mobility impairment three years after stroke. The total cerebral small vessel disease MRI burden score is a possible marker to identify patients at risk for subjective gait impairment. These findings should be confirmed in larger studies. PMID- 28906204 TI - Context is everything: From cardiovascular disease to cerebral microbleeds. AB - Increasingly, our approach to cerebrovascular disease has become blurred by evidence published in literature often without careful consideration of what this evidence implies for specific patients at hand. In this essay, we analyze key contextual issues in cerebrovascular small vessel disease, in an attempt to highlight the symbolic gap that exists between research and clinical practice, a recurring theme in medicine. We highlight the importance of considering context when using data from epidemiologic, neuroimaging, and biomarker studies in determining relevance to the patient at hand. We argue, that while biomarkers and neuroimaging may eventually serve to help to identify individuals with specific cerebrovascular diseases, we must always continue to understand patients in a specific clinical context. These reflections are particularly relevant when considering cerebral microbleeds-a key marker of cerebrovascular small vessel disease whose detection often raises thorny clinical dilemmas. PMID- 28906205 TI - Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination. AB - Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI 1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015 001953-33). PMID- 28906206 TI - Anatomical characteristics of the styloid process in internal carotid artery dissection: Case-control study. AB - Introduction Pathophysiology of cervical artery dissection is complex and poorly understood. In addition to well-known causative and predisposing factors, including major trauma and monogenic connective tissue disorders, morphological characteristics of the styloid process have been recently recognized as a possible risk factor for cervical internal carotid artery dissection. Aims To study the association of the anatomical characteristics of styloid process with internal carotid artery dissection. Methods Retrospective, multicenter, case control study of patients with internal carotid artery dissection and age- and sex-matched controls. Consecutive patients with internal carotid artery dissection and controls with ischemic stroke or transient ischemic attack of any etiology excluding internal carotid artery dissection, who had performed computed tomography angiography, diagnosed between January 2010 and September 2016. Two independent observers measured styloid process length and styloid process distance to internal carotid artery. Results Sixty-two patients with internal carotid artery dissection and 70 controls were included. Interobserver agreement was good for styloid process length and styloid process-internal carotid artery distance (interclass correlation coefficient = 0.89 and 0.76, respectively). Styloid process ipsilateral to dissection was longer than left and right styloid process in controls (35.8 +/- 14.4 mm versus 30.4 +/- 8.9 mm and 30.3 +/- 8.2 mm, p = 0.011 and p = 0.008, respectively). Styloid process-internal carotid artery distance ipsilateral to dissection was shorter than left and right distance in controls (6.3 +/- 1.9 mm versus 7.2 +/- 2.1 mm and 7.0 +/- 2.3 mm, p = 0.003 and p = 0.026, respectively). Internal carotid artery dissection was associated with styloid process length (odds ratio = 1.04 mm-1, 95% confidence interval = 1.01 1.08, p = 0.015) and styloid process-internal carotid artery distance (OR = 0.77 mm-1, 95% confidence interval = 0.64-0.92, p = 0.004). Conclusion Longer styloid process and shorter distance between styloid process and cervical internal carotid artery are associated with cervical internal carotid artery dissection. PMID- 28906207 TI - High absolute basophil count is a powerful independent predictor of inferior overall survival in patients with primary myelofibrosis. AB - OBJECTIVES: To investigate the clinical and prognostic significance of absolute basophil count (ABC) in patients with primary myelofibrosis (PMF). METHODS: We retrospectively investigated 58 patients with PMF treated in our institution in the period from 2006 to 2017. ABC was obtained in addition to other hematological and clinical parameters. Patients were separated into high and low ABC groups using the Receiver operating characteristic curve analysis. RESULTS: ABC was higher in PMF patients than in healthy controls (P < 0.001). Patients with high ABC had higher white blood cells (P < 0.001), higher red cell distribution width (P = 0.035), higher lactate dehydrogenase (P < 0.001), more frequently had circulatory blasts (P < 0.001), constitutional symptoms (P = 0.030) and massive splenomegaly (P = 0.014). ABC was also positively correlated with absolute monocyte count (AMC) (P < 0.001) and other components of differential blood count. There was no difference in ABC regarding driver mutations or degree of bone marrow fibrosis. Univariately, high ABC was significantly associated with inferior overall survival (hazard ratio (HR) 4.79, P < 0.001). This effect remained statistically significant (HR 4.27, P = 0.009) in a multivariate Cox regression model adjusted for age, gender, Dynamic International Prognostic Scoring System (HR 2.6, P = 0.001) and AMC (HR 8.45, P = 0.002). DISCUSSION: High ABC reflects higher disease activity and stronger proliferative potential of disease. ABC and AMC independently predict survival and therefore seem to reflect different underlying pathophysiologic processes. Hence, both have a potential for improvement of current prognostic scores. CONCLUSION: Basophils represent a part of malignant clone in PMF and are associated with unfavorable disease features and poor prognosis which is independent of currently established prognostic scoring system and monocytosis. PMID- 28906208 TI - Pattern-recognition receptors: signaling pathways and dysregulation in canine chronic enteropathies-brief review. AB - Pattern-recognition receptors (PRRs) are expressed by innate immune cells and recognize pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular pattern (DAMP) molecules. With a large potential for synergism or convergence between their signaling pathways, PRRs orchestrate a complex interplay of cellular mediators and transcription factors, and thus play a central role in homeostasis and host defense. Aberrant activation of PRR signaling, mutations of the receptors and/or their downstream signaling molecules, and/or DAMP/PAMP complex-mediated receptor signaling can potentially lead to chronic auto-inflammatory diseases or development of cancer. PRR signaling pathways appear to also present an interesting new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets. Evidence for a dysregulation of the PRR toll-like receptor (TLR)2, TLR4, TLR5, and TLR9, nucleotide-binding oligomerization domain-containing protein (NOD)2, and the receptor of advanced glycation end products (RAGE) exists in dogs with chronic enteropathies. We describe the TLR, NOD2, and RAGE signaling pathways and evaluate the current veterinary literature-in comparison to human medicine-to determine the role of TLRs, NOD2, and RAGE in canine chronic enteropathies. PMID- 28906231 TI - Health and Healthcare in Canada 150 Years After Confederation and Beyond. PMID- 28906230 TI - Novel insights into bat influenza A viruses. AB - In 2012 and 2013, influenza virus genome sequences of two new influenza A virus (IAV) subtypes were discovered in bat specimens, but further characterization was largely impeded by the lack of infectious virus. With the identification of highly susceptible cell lines, reconstitution of infectious bat IAV by reverse genetics recently succeeded and allowed a first insight into the life cycle of these viruses. Although there is a certain degree of functional compatibility between bat and conventional influenza A virus proteins, there are striking differences, including receptor usage, polarity of infection and reassortment potential. PMID- 28906232 TI - The Pharmaceutical Industry and the Canadian Government: Folie a Deux. AB - The interest of the pharmaceutical industry is in achieving a profit for its shareholders while the interest of the Canadian government should be in protecting public health. However, over the course of the past few decades the actions of the Canadian government have been tilted in favour of industry in two areas. The first is in the relationship between industry and Health Canada and is manifested in the regulation of clinical trials, the drug approval system, drug safety and promotion. The second is in economic policy as it applies to policies about patent protection, the price of medications and measures taken to incentivize research and development. The problems in the relationship are structural and will only be solved through systemic changes. PMID- 28906233 TI - Marijuana Use and Perceptions of Risk and Harm: A Survey among Canadians in 2016. AB - OBJECTIVES: To describe marijuana use by Canadians and their perceptions of risk and harm. DESIGN: A cross-sectional, structured, online and telephone survey. PARTICIPANTS: A nationally representative sample of Canadians. METHODS: This survey used random probability sampling and targeted respondents based on age, sex, region and their expected response rate. RESULTS: Of the 20% of respondents reporting marijuana use in the past 12 months, they were more likely to be younger and male. The most common form of use was smoking, 79%. When asked about harmfulness, 42% and 41% responded that they considered marijuana more harmful than helpful to mental health and to physical health, respectively. When asked about driving under the influence, 71% responded that it was the same as alcohol. CONCLUSION: This research is important for health providers and policy makers seeking to maximize public health through clinical and legislative reform of non medical use of marijuana. PMID- 28906234 TI - An Integrated Needs-Based Approach to Health Service and Health Workforce Planning: Applications for Pandemic Influenza. AB - Healthcare systems must be responsive to the healthcare needs of the populations they serve. However, typically neither health services nor health workforce planning account for populations' needs for care, resulting in substantial and unnecessary unmet needs. These are further exacerbated during unexpected surges in need, such as pandemics or natural disasters. To illustrate the potential of improved methods to help planning for these types of events, we applied an integrated, needs-based approach to health service and workforce planning in the context of a potential influenza pandemic at the provincial level in Canada. This application provides evidence on the province's capacity to respond to surges in need for healthcare and identifies specific services which may be in short supply in such scenarios. This type of approach can be implemented by planners to address a variety of health issues in different contexts. PMID- 28906235 TI - Is Canadian Healthcare Affordable? A Comparative Analysis of the Canadian Healthcare System from 2004 to 2014. AB - OBJECTIVE: To compare cost-related non-adherence (CRNA), serious problems paying medical bills and average annual out-of-pocket cost over time in five countries. METHODS: Repeated cross-sectional analysis of the Commonwealth Fund International Health Policy survey from 2004 to 2014. Responses were compared between Canada, the UK, Australia, New Zealand and the US. RESULTS: Compared to the UK, respondents in Canada, Australia and New Zealand were two to three times and respondents in the US were eight times more likely to experience CRNA; these odds remained stable over time. From 2004 to 2014, Canadian respondents paid US $852 1,767 out-of-pocket for care. The US reported the largest risks of serious problems paying for care (13-18.5%), highest out-of-pocket costs (US $2,060 3,319) and greatest rise in expenditures. INTERPRETATION: Over the 10-year period, financial barriers to care were identified in Canada and internationally. Such persistent challenges are of great concern to countries striving for equitable access to healthcare. PMID- 28906238 TI - Safe Stimulus Intensities for VEMP Testing. PMID- 28906236 TI - Ranked Performance of Canada's Health System on the International Stage: A Scoping Review. AB - INTRODUCTION: Since the release of the World Health Report in 2000, health system performance ranking studies have garnered significant health policy attention. However, this literature has produced variable results. The objective of this study was to synthesize the research and analyze the ranked performance of Canada's health system on the international stage. METHOD: We conducted a scoping review exploring Canada's place in ranked health system performance among its peer Organisation for Economic Co-operation and Development countries. Arksey and O'Malley's five-stage scoping review framework was adopted, yielding 48 academic and grey literature articles. A literature extraction tool was developed to gather information on themes that emerged from the literature. SYNTHESIS: Although various methodologies were used to rank health system performance internationally, results generally suggested that Canada has been a middle-of-the pack performer in overall health system performance for the last 15 years. Canada's overall rankings were 7/191, 11/24, 10/11, 10/17, "Promising" and "B" grade across different studies. According to past literature, Canada performed well in areas of efficiency, productivity, attaining health system goals, years of life lived with disability and stroke mortality. By contrast, Canada performed poorly in areas related to disability-adjusted life expectancy, potential years of life lost, obesity in adults and children, diabetes, female lung cancer and infant mortality. CONCLUSION: As countries introduce health system reforms aimed at improving the health of populations, international comparisons are useful to inform cross-country learning in health and social policy. While ranking systems do have shortcomings, they can serve to shine a spotlight on Canada's health system strengths and weaknesses to better inform the health policy agenda. PMID- 28906237 TI - Exploring Context and the Factors Shaping Team-Based Primary Healthcare Policies in Three Canadian Provinces: A Comparative Analysis. AB - This paper discusses findings from a high-level scan of the contextual factors and actors that influenced policies on team-based primary healthcare in three Canadian provinces: British Columbia, Alberta and Saskatchewan. The team searched diverse sources (e.g., news reports, press releases, discussion papers) for contextual information relevant to primary healthcare teams. We also conducted qualitative interviews with key health system informants from the three provinces. Data from documents and interviews were analyzed qualitatively using thematic analysis. We then wrote narrative summaries highlighting pivotal policy and local system events and the influence of actors and context. Our overall findings highlight the value of reviewing the context, relationships and power dynamics, which come together and create "policy windows" at different points in time. We observed physician-centric policy processes with some recent moves to rebalance power and be inclusive of other actors and perspectives. The context review also highlighted the significant influence of changes in political leadership and prioritization in driving policies on team-based care. While this existed in different degrees in the three provinces, the push and pull of political and professional power dynamics shaped Canadian provincial policies governing team-based care. If we are to move team-based primary healthcare forward in Canada, the provinces need to review the external factors and the complex set of relationships and trade-offs that underscore the policy process. PMID- 28906239 TI - Auditory Processing Testing: In the Booth versus Outside the Booth. AB - BACKGROUND: Many audiologists believe that auditory processing testing must be carried out in a soundproof booth. This expectation is especially a problem in places such as elementary schools. Research comparing pure-tone thresholds obtained in sound booths compared to quiet test environments outside of these booths does not support that belief. Auditory processing testing is generally carried out at above threshold levels, and therefore may be even less likely to require a soundproof booth. The present study was carried out to compare test results in soundproof booths versus quiet rooms. PURPOSE: The purpose of this study was to determine whether auditory processing tests can be administered in a quiet test room rather than in the soundproof test suite. The outcomes would identify that audiologists can provide auditory processing testing for children under various test conditions including quiet rooms at their school. RESEARCH DESIGN: A battery of auditory processing tests was administered at a test level equivalent to 50 dB HL through headphones. The same equipment was used for testing in both locations. STUDY SAMPLE: Twenty participants identified with normal hearing were included in this study, ten having no auditory processing concerns and ten exhibiting auditory processing problems. All participants underwent a battery of tests, both inside the test booth and outside the booth in a quiet room. Order of testing (inside versus outside) was counterbalanced. DATA COLLECTION AND ANALYSIS: Participants were first determined to have normal hearing thresholds for tones and speech. Auditory processing tests were recorded and presented from an HP EliteBook laptop computer with noise-canceling headphones attached to a y-cord that not only presented the test stimuli to the participants but also allowed monitor headphones to be worn by the evaluator. The same equipment was used inside as well as outside the booth. RESULTS: No differences were found for each auditory processing measure as a function of the test setting or the order in which testing was done, that is, in the booth or in the room. CONCLUSIONS: Results from the present study indicate that one can obtain the same results on auditory processing tests, regardless of whether testing is completed in a soundproof booth or in a quiet test environment. Therefore, audiologists should not be required to test for auditory processing in a soundproof booth. This study shows that audiologists can conduct testing in a quiet room so long as the background noise is sufficiently controlled. PMID- 28906240 TI - Listening Effort Measured in Adults with Normal Hearing and Cochlear Implants. AB - BACKGROUND: Studies have examined listening effort in individuals with hearing loss to determine the extent of the impairment. Regarding cochlear implants (CIs), results suggest that listening effort is improved using bilateral CIs compared to unilateral CIs. Few studies have investigated listening effort and outcomes related to the hybrid CI. PURPOSE: Here, we compared listening effort across three CI groups, and to a normal-hearing control group. The impact of listener traits, that is, age, age at onset of hearing loss, duration of CI use, and working memory capacity, were examined relative to listening effort. RESEARCH DESIGN: The participants completed a dual-task paradigm with a primary task identifying sentences in noise and a secondary task measuring reaction time on a Stroop test. Performance was assessed for all participant groups at different signal-to-noise ratios (SNRs), ranging in 2-dB steps from 0 to +10 dB relative to an individual's SNR-50, at which the speech recognition performance is 50% correct. Participants completed three questions on listening effort, the Spatial Hearing Questionnaire, and a reading span test. STUDY SAMPLE: All 46 participants were adults. The four participant groups included (1) 12 individuals with normal hearing, (2) 10 with unilateral CIs, (3) 12 with bilateral CIs, and (4) 12 with a hybrid short-electrode CI and bilateral residual hearing. DATA COLLECTION AND ANALYSIS: Results from the dual-task experiment were compared using a mixed 4 (hearing group) by 6 (SNR condition) analysis of variance (ANOVA). Questionnaire results were compared using one-way ANOVAs, and correlations between listener traits and the objective and subjective measures were compared using Pearson correlation coefficients. RESULTS: Significant differences were found in speech perception among the normal-hearing and the unilateral and the bilateral CI groups. There was no difference in primary task performance among the hybrid CI and the normal-hearing groups. Across the six SNR conditions, listening effort improved to a greater degree for the normal-hearing group compared to the CI groups. However, there was no significant difference in listening effort between the CI groups. The subjective measures revealed significant differences between the normal-hearing and CI groups, but no difference among the three CI groups. Across all groups, age was significantly correlated with listening effort. We found no relationship between listening effort and the age at the onset of hearing loss, age at implantation, the duration of CI use, and working memory capacity for these participants. CONCLUSIONS: Listening effort was reduced to a greater degree for the normal-hearing group compared to the CI users. There was no significant difference in listening effort among the CI groups. For the CI users in this study, age was a significant factor with regard to listening effort, whereas other variables such as the duration of CI use and the age at the onset of hearing loss were not significantly related to listening effort. PMID- 28906241 TI - Tracking of Noise Tolerance to Measure Hearing Aid Benefit. AB - BACKGROUND: The benefits offered by noise reduction (NR) features on a hearing aid had been studied traditionally using test conditions that set the hearing aids into a stable state of performance. While adequate, this approach does not allow the differentiation of two NR algorithms that differ in their timing characteristics (i.e., activation and stabilization time). PURPOSE: The current study investigated a new method of measuring noise tolerance (Tracking of Noise Tolerance [TNT]) as a means to differentiate hearing aid technologies. The study determined the within-session and between-session reliability of the procedure. The benefits provided by various hearing aid conditions (aided, two NR algorithms, and a directional microphone algorithm) were measured using this procedure. Performance on normal-hearing listeners was also measured for referencing. RESEARCH DESIGN: A single-blinded, repeated-measures design was used. STUDY SAMPLE: Thirteen experienced hearing aid wearers with a bilaterally symmetrical (<=10 dB) mild-to-moderate sensorineural hearing loss participated in the study. In addition, seven normal-hearing listeners were tested in the unaided condition. DATA COLLECTION AND ANALYSIS: Participants tracked the noise level that met the criterion of tolerable noise level (TNL) in the presence of an 85 dB SPL continuous discourse passage. The test conditions included an unaided condition and an aided condition with combinations of NR and microphone modes within the UNIQUE hearing aid (omnidirectional microphone, no NR; omnidirectional microphone, NR; directional microphone, no NR; and directional microphone, NR) and the DREAM hearing aid (omnidirectional microphone, no NR; omnidirectional microphone, NR). Each tracking trial lasted 2 min for each hearing aid condition. Normal-hearing listeners tracked in the unaided condition only. Nine of the 13 hearing-impaired listeners returned after 3 mo for retesting in the unaided and aided conditions with the UNIQUE hearing aid. The individual TNL was estimated for each participant for all test conditions. The TNT index was calculated as the difference between 85 dB SPL and the TNL. RESULTS: The TNT index varied from 2.2 dB in the omnidirectional microphone, no NR condition to -4.4 dB in the directional microphone, NR on condition. Normal-hearing listeners reported a TNT index of -5.7 dB using this procedure. The averaged improvement in TNT offered by the NR algorithm on the UNIQUE varied from 2.1 dB when used with a directional microphone to 3.0 dB when used with the omnidirectional microphone. The time course of the NR algorithm was different between the UNIQUE and the DREAM hearing aids, with the UNIQUE reaching a stable TNL sooner than the DREAM. The averaged improvement in TNT index from the UNIQUE directional microphone was 3.6 dB when NR was activated and 4.4 dB when NR was deactivated. Together, directional microphone and NR resulted in a total TNT improvement of 6.5 dB. The test-retest reliability of the procedure was high, with an intrasession 95% confidence interval (CI) of 2.2 dB and an intersession 95% CI of 4.2 dB. CONCLUSIONS: The effect of the NR and directional microphone algorithms was measured to be 2-3 and 3.6-4.4 dB, respectively, using the TNT procedure. Because of its tracking property and reliability, this procedure may hold promise in differentiating among some hearing aid features that also differ in their time course of action. PMID- 28906242 TI - Safe Use of Acoustic Vestibular-Evoked Myogenic Potential Stimuli: Protocol and Patient-Specific Considerations. AB - BACKGROUND: Vestibular-evoked myogenic potentials (VEMPs) are commonly used clinical assessments for patients with complaints of dizziness. However, relatively high air-conducted stimuli are required to elicit the VEMP, and ultimately may compromise safe noise exposure limits. Recently, research has reported the potential for noise-induced hearing loss (NIHL) from VEMP stimulus exposure through studies of reduced otoacoustic emission levels after VEMP testing, as well as a recent case study showing permanent sensorineural hearing loss associated with VEMP exposure. PURPOSE: The purpose of this report is to review the potential for hazardous noise exposure from VEMP stimuli and to suggest clinical parameters for safe VEMP testing. RESEARCH DESIGN: Literature review with presentation of clinical guidelines and a clinical tool for estimating noise exposure. RESULTS: The literature surrounding VEMP stimulus induced hearing loss is reviewed, including several cases of overexposure. The article then presents a clinical calculation tool for the estimation of a patient's safe noise exposure from VEMP stimuli, considering stimulus parameters, and includes a discussion of how varying stimulus parameters affect a patient's noise exposure. Finally, recommendations are provided for recognizing and managing specific patient populations who may be at higher risk for NIHL from VEMP stimulus exposure. A sample protocol is provided that allows for safe noise exposure. CONCLUSIONS: VEMP stimuli have the potential to cause NIHL due to high sound exposure levels. However, with proper safety protocols in place, clinicians may reduce or eliminate this risk to their patients. Use of the tools provided, including the noise exposure calculation tool and sample protocols, may help clinicians to understand and ensure safe use of VEMP stimuli. PMID- 28906243 TI - Pediatric Hearing Aid Management: Challenges among Hispanic Families. AB - BACKGROUND: Hearing aid fitting in infancy has become more common in the United States as a result of earlier identification of hearing loss. Consistency of hearing aid use is an area of concern for young children, as well as other hearing aid management challenges parents encounter that may contribute to less than-optimal speech and language outcomes. Research that describes parent hearing aid management experiences of Spanish-speaking Hispanic families, or the extent of their needs, is not available. To effectively support parent learning, in a culturally sensitive manner, providers may benefit from having a better understanding of the needs and challenges Hispanic families experience with hearing aid management. PURPOSE: The purpose of the current study was to describe challenges with hearing aid management and use for children from birth to 5 yr of age, as reported by Spanish-speaking parents in the United States, and factors that may influence hearing aid use. RESEARCH DESIGN: This study used a cross sectional survey design. STUDY SAMPLE: Forty-two Spanish-speaking parents of children up to 5 yr of age who had been fitted with hearing aids. DATA COLLECTION AND ANALYSIS: Responses were obtained from surveys mailed to parents through early intervention programs and audiology clinics. Descriptive statistics were used to describe frequencies and variance in responses. RESULTS: Forty-seven percent of the parents reported the need for help from an interpreter during audiology appointments. Even though parents received information and were taught skills by their audiologist, many wanted to receive more information. For example, 59% wanted to know how to meet other parents of children who have hearing loss, although 88% had previously received this information; 56% wanted to know how to do basic hearing aid maintenance, although 71% had previously received instruction. The two most frequently reported hearing aid use challenges were fear of losing the hearing aids, and not seeing benefit from the hearing aids. Hearing aid use during all waking hours was reported by more parents (66%) when their child had a good day than when their child had a bad day (37%); during the previous two weeks, 35% of the parents indicated their child had all good days. CONCLUSIONS: Hispanic parents wanted more comprehensive information, concrete resources, and emotional support from the audiologist to overcome hearing aid management challenges. Understanding parents' perspectives, experiences, and challenges is critical for audiologists to provide appropriate support in a culturally sensitive manner and to effectively address families' needs. PMID- 28906244 TI - Hearing Aid Use and Mild Hearing Impairment: Learnings from Big Data. AB - BACKGROUND: Previous research, mostly reliant on self-reports, has indicated that hearing aid (HA) use is related to the degree of hearing impairment (HI). No large-scale investigation of the relationship between data-logged HA use and HI has been conducted to date. PURPOSE: This study aimed to investigate if objective measures of overall daily HA use and HA use in various listening environments are different for adults with mild HI compared to adults with moderate HI. RESEARCH DESIGN: This retrospective study used data extracted from a database of fitting appointments from an international group of HA providers. Only data from the participants' most recent fitting appointment were included in the final dataset. STUDY SAMPLE: A total of 8,489 bilateral HA fittings of adults over the age of 18 yr, conducted between January 2013 and June 2014, were included. Participants were subsequently allocated to HI groups, based on British Society of Audiology and American Speech-Language-Hearing Association audiometric descriptors. DATA COLLECTION AND ANALYSIS: Fitting data from participating HA providers were regularly transferred to a central server. The data, with all personal information except age and gender removed, contained participants' four-frequency average (at 500, 1000, 2000, and 4000 Hz) as well as information on HA characteristics and usage. Following data cleaning, bivariate and post hoc statistical analyses were conducted. RESULTS: The total sample of adults' average daily HA use was 8.52 hr (interquartile range [IQR] = 5.49-11.77) in the left ear and 8.51 hr (IQR = 5.49-11.72) in the right ear. With a few exceptions, there were no statistical differences between hours of HA use for participants with mild HI compared to those with moderate impairment. Across all mild and moderate HI groups, the most common overall HA usage was between 8 and 12 hr per day. Other factors such as age, gender, and HA style also showed no relationship to hours of use. HAs were used, on average, for 7 hr (IQR = 4.27-9.96) per day in quiet and 1 hr (IQR = 0.33-1.41) per day in noisy listening situations. CONCLUSIONS: Clinical populations with mild HI use HAs as frequently as those with a moderate HI. These findings support the recommendation of HAs for adults with milder degrees of HI. PMID- 28906245 TI - Potential Audiological and MRI Markers of Tinnitus. AB - BACKGROUND: Subjective tinnitus, or ringing sensation in the ear, is a common disorder with no accepted objective diagnostic markers. PURPOSE: The purpose of this study was to identify possible objective markers of tinnitus by combining audiological and imaging-based techniques. RESEARCH DESIGN: Case-control studies. STUDY SAMPLE: Twenty adults drawn from our audiology clinic served as participants. The tinnitus group consisted of ten participants with chronic bilateral constant tinnitus, and the control group consisted of ten participants with no history of tinnitus. Each participant with tinnitus was closely matched with a control participant on the basis of age, gender, and hearing thresholds. DATA COLLECTION AND ANALYSES: Data acquisition focused on systematic administration and evaluation of various audiological tests, including auditory evoked potentials (AEP) and otoacoustic emissions, and magnetic resonance imaging (MRI) tests. A total of 14 objective test measures (predictors) obtained from audiological and MRI tests were subjected to statistical analyses to identify the best predictors of tinnitus group membership. The least absolute shrinkage and selection operator technique for feature extraction, supplemented by the leave one-out cross-validation technique, were used to extract the best predictors. This approach provided a conservative model that was highly regularized with its error within 1 standard error of the minimum. RESULTS: The model selected increased frontal cortex (FC) functional MRI activity to pure tones matching their respective tinnitus pitch, and augmented AEP wave N1 amplitude growth in the tinnitus group as the top two predictors of tinnitus group membership. These findings suggest that the amplified responses to acoustic signals and hyperactivity in attention regions of the brain may be a result of overattention among individuals that experience chronic tinnitus. CONCLUSIONS: These results suggest that increased functional MRI activity in the FC to sounds and augmented N1 amplitude growth may potentially be the objective diagnostic indicators of tinnitus. However, due to the small sample size and lack of subgroups within the tinnitus population in this study, more research is needed before generalizing these findings. PMID- 28906246 TI - The Relationship between Central Auditory Processing, Language, and Cognition in Children Being Evaluated for Central Auditory Processing Disorder. AB - BACKGROUND: Pediatric central auditory processing disorder (CAPD) is frequently comorbid with other childhood disorders. However, few studies have examined the relationship between commonly used CAPD, language, and cognition tests within the same sample. PURPOSE: The present study examined the relationship between diagnostic CAPD tests and "gold standard" measures of language and cognitive ability, the Clinical Evaluation of Language Fundamentals (CELF) and the Wechsler Intelligence Scale for Children (WISC). RESEARCH DESIGN: A retrospective study. STUDY SAMPLE: Twenty-seven patients referred for CAPD testing who scored average or better on the CELF and low average or better on the WISC were initially included. Seven children who scored below the CELF and/or WISC inclusion criteria were then added to the dataset for a second analysis, yielding a sample size of 34. DATA COLLECTION AND ANALYSIS: Participants were administered a CAPD battery that included at least the following three CAPD tests: Frequency Patterns (FP), Dichotic Digits (DD), and Competing Sentences (CS). In addition, they were administered the CELF and WISC. Relationships between scores on CAPD, language (CELF), and cognition (WISC) tests were examined using correlation analysis. RESULTS: DD and FP showed significant correlations with Full Scale Intelligence Quotient, and the DD left ear and the DD interaural difference measures both showed significant correlations with working memory. However, ~80% or more of the variance in these CAPD tests was unexplained by language and cognition measures. Language and cognition measures were more strongly correlated with each other than were the CAPD tests with any CELF or WISC scale. Additional correlations with the CAPD tests were revealed when patients who scored in the mild-moderate deficit range on the CELF and/or in the borderline low intellectual functioning range on the WISC were included in the analysis. CONCLUSIONS: While both the DD and FP tests showed significant correlations with one or more cognition measures, the majority of the variance in these CAPD measures went unexplained by cognition. Unlike DD and FP, the CS test was not correlated with cognition. Additionally, language measures were not significantly correlated with any of the CAPD tests. Our findings emphasize that the outcomes and interpretation of results vary as a function of the subject inclusion criteria that are applied for the CELF and WISC. Including participants with poorer cognition and/or language scores increased the number of significant correlations observed. For this reason, it is important that studies investigating the relationship between CAPD and other domains or disorders report the specific inclusion criteria used for all tests. PMID- 28906248 TI - Transcription of a 5' extended mRNA isoform directs dynamic chromatin changes and interference of a downstream promoter. AB - Cell differentiation programs require dynamic regulation of gene expression. During meiotic prophase in Saccharomyces cerevisiae, expression of the kinetochore complex subunit Ndc80 is downregulated by a 5' extended long undecoded NDC80 transcript isoform. Here we demonstrate a transcriptional interference mechanism that is responsible for inhibiting expression of the coding NDC80 mRNA isoform. Transcription from a distal NDC80 promoter directs Set1-dependent histone H3K4 dimethylation and Set2-dependent H3K36 trimethylation to establish a repressive chromatin state in the downstream canonical NDC80 promoter. As a consequence, NDC80 expression is repressed during meiotic prophase. The transcriptional mechanism described here is rapidly reversible, adaptable to fine-tune gene expression, and relies on Set2 and the Set3 histone deacetylase complex. Thus, expression of a 5' extended mRNA isoform causes transcriptional interference at the downstream promoter. We demonstrate that this is an effective mechanism to promote dynamic changes in gene expression during cell differentiation. PMID- 28906250 TI - The AAA protein Msp1 mediates clearance of excess tail-anchored proteins from the peroxisomal membrane. AB - Msp1 is a conserved AAA ATPase in budding yeast localized to mitochondria where it prevents accumulation of mistargeted tail-anchored (TA) proteins, including the peroxisomal TA protein Pex15. Msp1 also resides on peroxisomes but it remains unknown how native TA proteins on mitochondria and peroxisomes evade Msp1 surveillance. We used live-cell quantitative cell microscopy tools and drug inducible gene expression to dissect Msp1 function. We found that a small fraction of peroxisomal Pex15, exaggerated by overexpression, is turned over by Msp1. Kinetic measurements guided by theoretical modeling revealed that Pex15 molecules at mitochondria display age-independent Msp1 sensitivity. By contrast, Pex15 molecules at peroxisomes are rapidly converted from an initial Msp1 sensitive to an Msp1-resistant state. Lastly, we show that Pex15 interacts with the peroxisomal membrane protein Pex3, which shields Pex15 from Msp1-dependent turnover. In sum, our work argues that Msp1 selects its substrates on the basis of their solitary membrane existence. PMID- 28906249 TI - Kinetochore inactivation by expression of a repressive mRNA. AB - Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis. Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes. How the meiotic gene expression program temporally restricts kinetochore function is unknown. We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80. Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression. Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5' leader. Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis. This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression. PMID- 28906251 TI - Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells. AB - Centrioles are composed of long-lived microtubules arranged in nine triplets. However, the contribution of triplet microtubules to mammalian centriole formation and stability is unknown. Little is known of the mechanism of triplet microtubule formation, but experiments in unicellular eukaryotes indicate that delta-tubulin and epsilon-tubulin, two less-studied tubulin family members, are required. Here, we report that centrioles in delta-tubulin and epsilon-tubulin null mutant human cells lack triplet microtubules and fail to undergo centriole maturation. These aberrant centrioles are formed de novo each cell cycle, but are unstable and do not persist to the next cell cycle, leading to a futile cycle of centriole formation and disintegration. Disintegration can be suppressed by paclitaxel treatment. Delta-tubulin and epsilon-tubulin physically interact, indicating that these tubulins act together to maintain triplet microtubules and that these are necessary for inheritance of centrioles from one cell cycle to the next. PMID- 28906253 TI - Latest Insights on Food Protein-Induced Enterocolitis Syndrome: An Emerging Medical Condition. AB - Food protein-induced enterocolitis syndrome (FPIES) is a type of non-IgE-mediated gastrointestinal food hypersensitivity characterized by profuse vomiting that is frequently associated with pallor or/and lethargy and appears within 1 to 3 hours after ingestion of the offending food. A less frequent chronic form of FPIES is characterized by protracted vomiting, diarrhea, or both accompanied by poor growth. Although FPIES is considered a rare allergic disorder, increasing reports in recent years point to a real increase in incidence, or at least an increased awareness of this condition by pediatricians. The foods most frequently implicated are cow's milk, soy formula, grains, and fish, depending on the geographic area. Diagnosis is based on clinical manifestations and requires a high index of suspicion, since we still lack a diagnostic laboratory tool. Early recognition of FPIES and removal of the offending food are mandatory. International consensus guidelines on diagnosis and management have been published. Prognosis is usually good, with most children tolerating foods before 6 years of age. PMID- 28906252 TI - The Work Productivity and Activity Impairment Allergic Specific (WPAI-AS) Questionnaire Using Mobile Technology: The MASK Study. PMID- 28906254 TI - A synoptic review of Caryophyllaeus Gmelin, 1790 (Cestoda: Caryophyllidea), parasites of cyprinid fishes. AB - Tapeworms of the genus Caryophyllaeus Gmelin, 1790 (Caryophyllidea: Caryophyllaeidae), common parasites of cyprinid fishes, are reviewed and taxonomic status of 42 nominal taxa that have been placed in the genus during its long history is clarified. The following seven species occurring in the Palaearctic Region are recognised as valid: C. laticeps (Pallas, 1781), C. auriculatus (Kulakovskaya, 1961), C. balticus (Szidat, 1941) comb. n. (syn. Khawia baltica Szidat, 1941), C. brachycollis Janiszewska, 1953, C. fimbriceps Annenkova-Chlopina, 1919, C. syrdarjensis Skrjabin, 1913, and newly described Caryophyllaeus chondrostomi sp. n. (= C. laticeps morphotype 4 of Bazsalovicsova et al., 2014) from common nase, Chondrostoma nasus (Linnaeus), found in Austria and Slovakia. The new species differs by the paramuscular or cortical position of preovarian vitelline follicles, a large, robust body (up to 64 mm long), conspicuously long vas deferens, flabellate scolex with small wrinkles on the anterior margin, and anteriormost testes located in a relatively short distance from the anterior extremity. Caryophyllaeus kashmirenses Mehra, 1930 and Caryophyllaeus prussicus (Szidat, 1937) comb. n. are considered to be species inquirendae, C. truncatus von Siebold in Baird, 1853 and C. tuba von Siebold in Baird, 1853 are nomina nuda. Data on the morphology, host spectra, distribution and known life-cycles of valid species are provided. Phylogenetic interrelations of four species of the genus including its type species and newly described C. chondrostomi were assessed based on an analysis of sequences of lsrDNA and cox1. A key to identification of all valid species of Caryophyllaeus is also provided. PMID- 28906255 TI - Echinococcus multilocularis vesicular fluid inhibits activation and proliferation of natural killer cells. AB - Alveolar echinococcosis is a severe chronic helminthic disease that mimics slow growing liver cancer. The immune evasion strategy of Echinococcus multilocularis Leuckart, 1863 remains poorly understood. The aim of this study was to investigate in vitro the impact of E. multilocularis vesicular fluid (Em-VF) on peripheral blood mononuclear cells (PBMC) and on natural killer (NK) cells. PBMC and NK cells were exposed to Em-VF (1 ug/ml) during six days. The effect of Em-VF was assessed on CD69, viability and proliferation, and on and transforming growth factor beta (TGF-beta), interferon gamma (IFN-gamma), interleukin 17 (IL-17) and interleukin 10, using flow cytometry and ELISA, respectively. Exposure to Em-VF had no bearing on PBMC's viability, proliferation and expression of CD69. In contrast, higher levels of IL-17 at day three and of TGF-beta at day six were observed in PBMC supernatant after exposure to Em-VF (p < 0.05, Wilcoxon signed rank test). Exposure to Em-VF induced a significant decrease of CD69 expression of NK cells at day three and a significant decrease of proliferation of NK cells at day six (p < 0.05, Wilcoxon signed-rank test). In contrast, NK cells viability and levels of cytokines did not vary significantly over Em-VF stimulation. Exposure to Em-VF had a significant bearing on activation and proliferation of NK cells. NK cells may play an important role in the immune response of the host against E. multilocularis. PMID- 28906256 TI - Variability of species of Babesia Starcovici, 1893 in three sympatric ticks (Ixodes ricinus, Dermacentor reticulatus and Haemaphysalis concinna) at the edge of Pannonia in the Czech Republic and Slovakia. AB - The distribution, variability and host specificity of species of Babesia Starcovici, 1893 were studied in questing ticks collected on the northwestern edge of the Pannonian Basin in the south-easternmost part of the Czech Republic and in western Slovakia. The area is characterised by relatively natural floodplain habitats and the sympatric occurrence of three tick species possessing wide host spectra, namely Ixodes ricinus (Linnaeus), Dermacentor reticulatus (Fabricius) and Haemaphysalis concinna Koch. Analysis was carried out on 1,408 I. ricinus, 2,999 D. reticulatus and 150 H. concinna altogether, collected from 59 localities. We documented the presence of Babesia spp. not only in I. ricinus but also in H. concinna in the Czech Republic. Two isolates from I. ricinus were classified as B. venatorum Herwaldt, Caccio, Gherlinzoni, Aspock, Slemenda, Piccaluga, Martinelli, Edelhofer, Hollenstein, Poletti, Pampiglione, Loschenberger, Tura et Pieniazek, 2003 (formerly determined as Babesia sp. EU1), which is a zoonotic parasite and can cause human babesiosis. The rest of our amplicons were very similar to B. canis (Piana et Galli-Valerio, 1895), which is usually transmitted by D. reticulatus. Despite the huge amount of examined samples, all D. reticulatus ticks were Babesia-free. Due to this finding, we did not consider our obtained isolates to be B. canis, but other closely related species possessing a similar sequence of the studied portion of 18S rDNA. Although this genetic marker is most frequently used in PCR-based diagnostic methods of babesias, its low variability compromises its reliability in studies based only on this marker. PMID- 28906258 TI - Early tumor shrinkage indicates a favorable response to bevacizumab-based first line chemotherapy for metastatic colorectal cancer. AB - A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R=0.429), whereas EETS and DPR were less correlated with OS (R=0.0682, 0.186). EETS was well correlated with DPR (R=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy. PMID- 28906257 TI - Double printing of hyaluronic acid/poly(glycidol) hybrid hydrogels with poly(epsilon-caprolactone) for MSC chondrogenesis. AB - This study investigates the use of allyl-functionalized poly(glycidol)s (P(AGE-co G)) as a cytocompatible cross-linker for thiol-functionalized hyaluronic acid (HA SH) and the optimization of this hybrid hydrogel as bioink for 3D bioprinting. The chemical cross-linking of gels with 10 wt.% overall polymer concentration was achieved by a UV-induced radical thiol-ene coupling between the thiol and allyl groups. The addition of unmodified high molecular weight HA (1.36 MDa) enabled the rheology to be tuned for extrusion-based bioprinting. The incorporation of additional HA resulted in hydrogels with a lower Young's modulus and a higher swelling ratio, especially in the first 24 h, but a comparable equilibrium swelling for all gels after 24 h. Embedding of human and equine mesenchymal stem cells (MSCs) in the gels and subsequent in vitro culture showed promising chondrogenic differentiation after 21 d for cells from both origins. Moreover, cells could be printed with these gels, and embedded hMSCs showed good cell survival for at least 21 d in culture. To achieve mechanically stable and robust constructs for the envisioned application in articular cartilage, the formulations were adjusted for double printing with thermoplastic poly(epsilon caprolactone) (PCL). PMID- 28906259 TI - Radiation and Immunotherapy in High-grade Gliomas: Where Do We Stand? AB - High-grade glioma is the most common primary brain tumor, with glioblastoma multiforme (GBM) accounting for 52% of all brain tumors. The current standard of care (SOC) of GBM involves surgery followed by adjuvant fractionated radiotherapy and chemotherapy. However, little progress has been made in extending overall survival, progression-free survival, and quality of life. Attempts to characterize and customize treatment of GBM have led to mitigating the deleterious effects of radiotherapy using hypofractionated radiotherapy, as well as various immunotherapies as a promising strategy for the incurable disease. A combination of radiotherapy and immunotherapy may prove to be even more effective than either alone, and preclinical evidence suggests that hypofractionated radiotherapy can actually prime the immune system to make immunotherapy more effective. This review addresses the complications of the current radiotherapy regimen, various methods of immunotherapy, and preclinical and clinical data from combined radioimmunotherapy trials. PMID- 28906260 TI - Effectiveness of a post-emergency department discharge multidisciplinary bundle in reducing acute hospital admissions for the elderly. AB - OBJECTIVE: We evaluated the effectiveness of the Subacute Ambulatory care for the Functionally challenged and Elderly (SAFE) programme, a post-emergency department (ED) discharge intervention for elderly and functionally challenged patients, in reducing acute hospital admissions. METHODS: This study was a 32-month retrospective quasi-experimental study comparing patients with at least one of six diagnostic classifications who underwent SAFE intervention with those who were eligible but declined and received usual ED care (control). The primary outcomes were rates of first acute hospital admission at 30 and 60 days post-ED discharge. Secondary outcomes were 20-day withdrawal rate and 60-day mortality. The difference in primary outcome between the two groups was compared using a Cox proportional hazards model. We reported adjusted hazard ratios (HRs) with their 95% confidence intervals (CIs) adjusting for predefined factors of age, sex, triage risk assessment tool scores and baseline ED utilization and acute hospital admission rates in the past year. RESULTS: There were 438 and 209 patients in the intervention and control groups, respectively. The intervention group had reduced risk of first acute hospital admission at 30 days (10 vs. 27%, HR=0.34, 95% CI: 0.22-0.52) and 60 days (18 vs. 33%, HR=0.48, 95% CI: 0.34-0.69) compared with the control. The 20-day withdrawal rate was 3.2%. Both groups did not differ in 60 day mortality rates. CONCLUSION: The SAFE programme was effective in reducing first acute hospital admissions in selected elderly and functionally challenged patients after ED discharge at 30 and 60 days compared with usual ED discharge care. PMID- 28906261 TI - The Disability Impact and Associated Cost per Disability in Women Who Underwent Surgical Revision of Transvaginal Mesh Kits for Prolapse Repair. AB - OBJECTIVES: The aim of this study was to investigate disability impact in patients and cost to the families of patients who have had complications of transvaginal prolapse mesh kits and underwent surgical revision. METHODS: Patients who developed complications of transvaginal mesh kits for prolapse and who had undergone vaginal prolapse mesh surgical revision/removal in 2009 to 2014 at a single institution were identified by Current Procedural Terminology codes. The group was invited to complete a phone survey pertaining to the initial vaginal mesh used for prolapse surgery utilizing Sheehan Disability Scale (scale 0-10) and Years of life Lived with Disability (YLDs) questionnaires. The data collected were used to estimate the disability and cost analysis. We used our data to estimate the economic and quality-of-life impact of vaginal mesh complications on patients in the United States RESULTS: Sixty-two patients (62/198 [31.2%]) were consented to participate and completed the questionnaires by phone. Extremely disabled patients were 18 (29%) of 62 of whole cases, and 5 (8%) of 62 reported that they had no disability after vaginal mesh surgery. The median for overall disability score after vaginal mesh procedure was 8 (which reflects marked disability on a scale of 0-10). The majority of patients missed a median of 12 months of their school or work because of their mesh complications. Thirty-seven (59.6%) of 62 did not improve after mesh removal. Twenty-one (33.9%) of 62 stated that their family income dropped because of productivity loss related to mesh complications. The mean time between vaginal mesh surgery and mesh removal procedure was 4.7 years. Sheehan Disability Scale scores are significantly correlated with YLDs outcomes. Patients' overall disability score showed a significant correlation with YLDs scores (P < 0.0001). CONCLUSIONS: Vaginal mesh for prolapse reduction complications had a sustained disability impact that continued despite mesh removal. Likewise, the complications were associated with increased economic burden on the families of the effected individuals and a drop in the family income in more than one third of the families. PMID- 28906262 TI - Characteristics of Interim Deans at U.S. Medical Schools: Implications for Institutions and Individuals. AB - PURPOSE: To provide a baseline, descriptive understanding of individuals serving as interim deans at U.S. medical schools. Over the past quarter century, roughly 9% to 16% of all medical school deans were serving as interim leaders. This research reviews demographic characteristics, how long they served, and the impact of having served on one's likelihood of serving as a permanent dean. METHOD: The Association of American Medical Colleges' Council of Deans national database was the data source for this study. The authors reviewed counts and information by year for academic years 1989-1990 through 2014-2015 to yield a snapshot of interim dean counts. The authors analyzed data by demographic characteristics-namely, sex, race/ethnicity, degree, specialty, and years of service-and compared data with those of permanent deans. Descriptive statistics are presented. RESULTS: Overall, between 14 and 27 individuals served as interim deans during each academic year in this study (9%-16% of all unique individuals with a dean or interim dean appointment). Of all individuals serving as interim deans in this time frame, 88% were men (228/259) and 86% were white (222/259). The average time in the interim dean role was roughly 13 months, and a high percentage went on to serve as permanent deans (ranging from 15% to 63%). CONCLUSIONS: The results of this study add detail to the collective understanding of these leaders in medical schools. The authors discuss how individuals and institutions can facilitate success and preparedness for an interim dean appointment. PMID- 28906263 TI - Governing Academic Medical Center Systems: Evaluating and Choosing Among Alternative Governance Approaches. AB - The ability of academic medical centers (AMCs) to fulfill their triple mission of patient care, medical education, and research is increasingly being threatened by rising financial pressures and resource constraints. Many AMCs are, therefore, looking to expand into academic medical systems, increasing their scale through consolidation or affiliation with other health care systems. As clinical operations grow, though, the need for effective governance becomes even more critical to ensure that the business of patient care does not compromise the rest of the triple mission. Multi-AMC systems, a model in which multiple AMCs are governed by a single body, pose a particular challenge in balancing unity with the needs of component AMCs, and therefore offer lessons for designing AMC governance approaches. This article describes the development and application of a set of criteria to evaluate governance options for one multi-AMC system-the University of California (UC) and its five AMCs. Based on a literature review and key informant interviews, the authors identified criteria for evaluating governance approaches (structures and processes), assessed current governance approaches using the criteria, identified alternative governance options, and assessed each option using the identified criteria. The assessment aided UC in streamlining governance operations to enhance their ability to respond efficiently to change and to act collectively. Although designed for UC and a multi-AMC model, the criteria may provide a systematic way for any AMC to assess the strengths and weaknesses of its governance approaches. PMID- 28906264 TI - Governance of Academic Medical Centers Is Indeed a Complex and Unique Operation. AB - As academic medical centers (AMCs) have extended their operations into their communities, partnered with new organizations, and developed new modes of operation to achieve their missions, new governance approaches are required. Chari and colleagues, in this issue of Academic Medicine, describe the development and application of criteria to evaluate governance options for the University of California (UC), which has a number of public AMCs, almost all of which are components of individual UC universities. Although many of these criteria may also be applicable to smaller AMCs, a more individual approach to governance is required-that is, one must step back and first ask about the organization, structure, and goals of the entities to be governed. The major nonfederal and nonspecialty teaching hospitals in the United States are about evenly split between those that are university owned or controlled and those having an independent relationship with their associated medical school. However, the challenges, obstacles, and desired end points are similar. The development of a successful governance structure will require identifying and appreciating many factors. PMID- 28906265 TI - A Retrospective Analysis of the Clinical Effectiveness of Supraclavicular, Ultrasound-guided Brachiocephalic Vein Cannulations in Preterm Infants. AB - BACKGROUND: The aim of this retrospective analysis was to evaluate the clinical effectiveness of the supraclavicular ultrasound-guided cannulation of the brachiocephalic vein in preterm infants. METHODS: The ultrasound probe was placed in the supraclavicular region so as to obtain the optimum sonographic long-axis view of the brachiocephalic vein. By using a strict in-plane approach the brachiocephalic vein was cannulated by advancing a 22- or 24-gauge iv cannula from lateral to medial under the long axis of the ultrasound probe under real time ultrasound guidance into the vein. RESULTS: One hundred and forty-two cannulations in infants weighing between 0.59 and 2.5 kg (median: 2.1; CI: 2.0 to 2.2) were included. Ultimate success rate was 94% (134 of 142). One cannulation attempt was required in 100 (70%) patients, two attempts in 21 (15%), and three attempts in 13 (9%). The smaller the weight of the infant the more attempts were needed. More attempts also were needed for the right brachiocephalic vein, which was primarily targeted in 75 (53%) neonates. One (1%) inadvertent arterial puncture was noted. CONCLUSIONS: This supraclavicular, in-plane, real-time, ultrasound-guided cannulation of the brachiocephalic vein seems to be a convenient and effective method to insert central venous catheters in preterm infants. PMID- 28906267 TI - Evidence-Based Guidelines for Interface Design for Data Entry in Electronic Health Records. AB - Electronic health records use a variety of data entry methods that are often customized to clinician needs. Data entry interfaces must be appropriately designed to maximize benefits and minimize unintended consequences. There was relatively little evidence in the literature to guide the selection of specific data entry methods according to the type of data documented. This literature review summarizes existing data entry design recommendations to guide data entry interface design. Structured data entry uses predefined charting elements to limit acceptable data entry to standard coded data and improve completeness and data reuse at the expense of correctness. Unstructured data entry methods use natural language and improve correctness, at the expense of completeness and data reusability. Semistructured data entry uses a combination of these data entry methods to complement the strengths and minimize the weaknesses of each method. Documentation quality is influenced by the method of data entry. It is important to choose data entry methods based on the type of data to be documented. This literature review summarizes data entry design guidelines to inform clinical practice and future research. PMID- 28906266 TI - Impact of Public Reporting of 30-day Mortality on Timing of Death after Coronary Artery Bypass Graft Surgery. AB - BACKGROUND: Recent reports have raised concerns that public reporting of 30-day mortality after cardiac surgery may delay decisions to withdraw life-sustaining therapies for some patients. The authors sought to examine whether timing of mortality after coronary artery bypass graft surgery significantly increases after day 30 in Massachusetts, a state that reports 30-day mortality. The authors used New York as a comparator state, which reports combined 30-day and all in hospital mortality, irrespective of time since surgery. METHODS: The authors conducted a retrospective cohort study of patients who underwent coronary artery bypass graft surgery in hospitals in Massachusetts and New York between 2008 and 2013. The authors calculated the empiric daily hazard of in-hospital death without censoring on hospital discharge, and they used joinpoint regression to identify significant changes in the daily hazard over time. RESULTS: In Massachusetts and New York, 24,864 and 63,323 patients underwent coronary artery bypass graft surgery, respectively. In-hospital mortality was low, with 524 deaths (2.1%) in Massachusetts and 1,398 (2.2%) in New York. Joinpoint regression did not identify a change in the daily hazard of in-hospital death at day 30 or 31 in either state; significant joinpoints were identified on day 10 (95% CI, 7 to 15) for Massachusetts and days 2 (95% CI, 2 to 3) and 12 (95% CI, 8 to 15) for New York. CONCLUSIONS: In Massachusetts, a state with a long history of publicly reporting cardiac surgery outcomes at day 30, the authors found no evidence of increased mortality occurring immediately after day 30 for patients who underwent coronary artery bypass graft surgery. These findings suggest that delays in withdrawal of life-sustaining therapy do not routinely occur as an unintended consequence of this type of public reporting. PMID- 28906268 TI - New PET markers for the diagnosis of dementia. AB - PURPOSE OF REVIEW: To present the new PET markers that could become in the coming years, relevant to advanced clinical approaches to dementia diagnosis, drug trials, and treatment strategies and discuss their advantages and limitations. RECENT FINDINGS: The most advanced new PET tracers are the markers of the amyloid plaques, the tau compounds and the tracers of the translocator protein as markers of neuroinflammation. The main advantages but also the weaknesses of each of these markers are discussed. The main pitfall remains the heterogeneity of the available results that cast doubt to a rapid introduction of these new ligands in clinical practice. SUMMARY: With the advent of biomarkers in clinical management and findings of molecular neuroimaging studies in the evaluation of patients with suspected dementia, the impact of functional neuroimaging has increased considerably these last years and has been integrated into many clinical guidelines in the field of dementia. In addition to conventional single PET brain perfusion and dopaminergic neurotransmission, 18F-fluorodeoxyglucose (18F-FDG) PET is used in advanced diagnosis procedures. Furthermore, new tracers are being developed to quantify key neuropathological features in the brain tissue as highly specific diagnosis is crucial to comply with the global medical and public health objectives in this domain. A strategic road map for further developments, adapted from the approach to cancer biomarkers, should be proposed so as to optimize the rationale of the PET-based molecular diagnosis of Alzheimer's disease and related disorders. PMID- 28906269 TI - Improving diagnosis and management of primary brain tumors. PMID- 28906270 TI - Microbiota and neurodegenerative diseases. AB - PURPOSE OF REVIEW: Despite the extensive research carried out in the past decades, the current pathophysiological notions of neurodegenerative disease as well as effective treatments to reduce their progression are largely unknown. Alterations of the human microbiota, the plethora of different microscopic organisms that our body hosts, have been linked to neurodegenerative disease risk, onset and progression. This review summarizes the current knowledge on the possible role of microbiota in neurodegenerative disorders and briefly discusses strategies to restore microbiota homeostasis. RECENT FINDINGS: Preclinical evidences and human cross-sectional studies posit the gut microbiota as a key actor in the Parkinson's disease onset and progression, reporting the presence of a specific gut microbiota profile in association with the modulation of disease and symptoms. Gut microbiota alterations have been correlated with brain disease and peripheral inflammation also in Alzheimer's patients. SUMMARY: The interaction between the microbiota and the host is promising to answer clinical questions that have so far escaped clarification with the current pathophysiological notions of health and disease. However, human longitudinal studies starting in the earlier disease phases are needed to understand the causative relation between microbiota and the hallmarks of these neurodegenerative disorders and to develop innovative treatments aimed at preventing or slowing brain damages. PMID- 28906271 TI - Neurosensory Disturbance of the Inferior Alveolar Nerve After 3025 Implant Placements. AB - PURPOSE: The aim of this retrospective study was to evaluate the incidence of inferior alveolar nerve (IAN) lesion and duration of sensitivity disturbances after the insertion of dental implants. METHODS: One thousand sixty-five patients (mean age: 58.9 years) enrolled between February 2004 and July 2015 with partial or full mandibular edentulism were selected to receive dental implants for oral rehabilitation. A total of 3025 implants were placed. After surgical procedures, controls were scheduled at suture removal, that is, 10 days after surgery, and repeated at intervals of 1, 3, and 6 months, and comprised patient interview, clinical examination, and sensitivity tests. RESULTS: Only 23 (2.2%) of the 1065 patients presented sensitivity disturbances 1 month after implant insertion, and only 2 (0.19%) after 6 months, though a complete recovery was observed in these patients within 13 months. CONCLUSIONS: Considering the debilitating effects resulting from IAN lesion and the complexity of the therapeutic diagnostic protocols, all patients undergoing oral rehabilitation through dental implants should be evaluated with CBCT imaging. PMID- 28906272 TI - Transforming the Role of the Nurse Manager: A Call to Action. PMID- 28906273 TI - Utilization and Outcomes of Temporary Mechanical Circulatory Support for Graft Dysfunction After Heart Transplantation. AB - Graft dysfunction is the main cause of early mortality after heart transplantation. In cases of severe graft dysfunction, temporary mechanical circulatory support (TMCS) may be necessary. The aim of this systematic review was to examine the utilization and outcomes of TMCS in patients with graft dysfunction after heart transplantation. Electronic search was performed to identify all studies in the English literature assessing the use of TMCS for graft dysfunction. All identified articles were systematically assessed for inclusion and exclusion criteria. Of the 5,462 studies identified, 41 studies were included. Among the 11,555 patients undergoing heart transplantation, 695 (6.0%) required TMCS with patients most often supported using venoarterial extracorporeal membrane oxygenation (79.4%) followed by right ventricular assist devices (11.1%), biventricular assist devices (BiVADs) (7.5%), and left ventricular assist devices (LVADs) (2.0%). Patients supported by LVADs were more likely to be supported longer (p = 0.003), have a higher death by cardiac event (p = 0.013) and retransplantation rate (p = 0.015). In contrast, patients supported with BiVAD and LVAD were more likely to be weaned off support (p = 0.020). Overall, no significant difference was found in pooled 30 day survival (p = 0.31), survival to discharge (p = 0.19), and overall survival (p = 0.51) between the subgroups. Temporary mechanical circulatory support is an effective modality to support patients with graft dysfunction after heart transplantation. Further studies are needed to establish the optimal threshold and strategy for TMCS and to augment cardiac recovery and long-term survival. PMID- 28906274 TI - Flexible Bronchoscope Use by Pulmonologists in Collaboration With Gastroenterologists for Placement of Percutaneous Endoscopic Gastrostomy Via Transnasal Route in Patients With Head and Neck Cancer: A 10-Year Experience in a Single Cancer Institution. AB - This study was conducted with the aim of evaluating a 10-year experience in the Pulmonology Department of a cancer center for percutaneous endoscopic gastrostomy through transnasal route (TN-PEG) in patients with head and neck cancer whose oral access is precluded. This study was a retrospective analysis of 40 consecutive head and neck cancer patients referred for PEG placement, between 2005 and 2014, using a transnasal route because of the impossibility of intubation through the oral cavity. Demographics, outcome of TN-PEG procedure, indications for bronchoscopic approach (prophylactic/palliative), clinical need for bronchoscopy (trismus, oropharyngeal obstruction), location of cancer, complications, and overall survival were reviewed. In 40 TN-PEG procedures, executed by 1 of 3 pulmonologists, 39 were successfully placed and there were no immediate complications. All except 1 complication were minor, but no surgery or PEG removal was required. There was a rapid learning curve among all operators. A combined TN-PEG placement by a gastroenterologist and a pulmonologist is a safe and useful option for these patients; the learning curve for successfully performing the procedure was short. PMID- 28906275 TI - VV-ECMO-Assisted High-Risk Endobronchial Stenting as Rescue for Asphyxiating Mediastinal Mass. AB - The use of venovenous extracorporeal membrane oxygenation (VV-ECMO) has traditionally been limited to a narrow set of clinical circumstances, such as acute hypoxic respiratory failure, submassive pulmonary embolism, and cardiopulmonary collapse. Within the pediatric population, there have been cases of VV-ECMO in the context of extrinsic airway compression by a mediastinal mass, typically in the setting of either a lymphoma or germ cell tumors. However, the use of VV-ECMO for adults with extrinsic airway compression is comparatively limited. More specifically, VV-ECMO has been used as a bridge for tracheal reconstruction in both children and adults. Although, it has not been used in adults in the context of palliative endobronchial stent placement. We present a case of a 49-year-old woman with refractory multiple myeloma and extramedullary plasmacytoma presenting with acute hypoxic respiratory failure from extrinsic airway compression by a mediastinal plasmacytoma. We were able to use VV-ECMO to assist with endobronchial stent placement, followed by radiation therapy, and ultimately hospital discharge. In this article, we also review the literature surrounding VV-ECMO for extrinsic airway compression. PMID- 28906276 TI - Towards standardized definitions for monitoring the continuum of HIV care in Europe. PMID- 28906278 TI - Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy. AB - : Hepatitis B virus (HBV) reactivation has been documented in association with multiple immunotherapy regimens . These reactivations can be life-threatening and result in fulminant hepatic failure. There are currently no reports of HBV reactivation on nivolumab treatment. This is a case of a patient with known HIV infection and previous HBV workup that revealed him to be anti-hepatitis B core antibody positive, hepatitis B surface antigen negative, and HBV DNA negative. He experienced a HBV reactivation while on therapy with nivolumab for stage IIIa poorly differentiated carcinoma of the lung, which was a recurrence from a prior surgically resected stage Ia well differentiated adenocarcinoma of the lung. He is a long-term nonprogressor in regards to his HIV and had previously had a negative HBV DNA level and had declined antiretroviral therapy until just prior to starting nivolumab. This case is also of interest as antiprogrammed death-1 receptors are involved in CD4-related HIV control , and the effects of nivolumab in a patient who was an HIV long-term nonprogressor are unknown. There was concern that he would develop increased HIV viremia and CD4-related immune dysfunction without antiretroviral therapy, and thus, he agreed to treatment prior to starting antineoplastic immunotherapy. PMID- 28906277 TI - Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals. AB - BACKGROUND: HIV-infection is associated with dramatic changes in the intestinal mucosa. The impact of other viral pathogens is unclear. METHODS: One hundred and eight (108) biopsies from left and right colon (n = 79) and terminal ileum (n = 29) were collected from 19 HIV-infected and 22 HIV-uninfected participants. Levels of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured by droplet digital PCR. Mucosal gene expression was measured via multiplex-assay. Microbiome analysis was performed using bacterial 16S-rDNA-pyrosequencing. The effect of CMV and EBV replication on the microbiome composition and mRNA expression of selected cytokines (IL-6, IFN-gamma, IL-1beta, CCL2, IL-8, and IFN beta1) was evaluated. RESULTS: Overall, CMV and EBV were detected in at least one intestinal site in 60.5 and 78.9% of participants, respectively. HIV-infected individuals demonstrated less detectable CMV (P = 0.04); CMV was more frequently detected in terminal ileum than colon (P = 0.04). Detectable EBV was more frequent among HIV-infected (P = 0.05) without differences by intestinal site. The number of operational taxonomic units did not differ by CMV or EBV detection status. Among HIV-infected participants, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (P = 0.03). Presence of CMV was associated with upregulated expression of all selected cytokines in the ileum (all P = 0.02) and higher expression of IL-8 and IFN-beta1 in the colon (all P < 0.05) of HIV-uninfected participants, but not among HIV-infected. EBV had no effect on cytokine expression or microbiome composition whatsoever. CONCLUSION: These results illustrate a complex interplay among HIV-infection, intestinal CMV replication, and mucosal gut environment, and highlight a possible modulatory effect of CMV on the microbial and immune homeostasis. PMID- 28906280 TI - Both coinfections of Penicillium marneffei and Cryptococcus neoformans in AIDS patient: a report of rare case. PMID- 28906279 TI - The value of point-of-care CD4+ and laboratory viral load in tailoring antiretroviral therapy monitoring strategies to resource limitations. AB - OBJECTIVE: To examine the clinical and economic value of point-of-care CD4 (POC CD4) or viral load monitoring compared with current practices in Mozambique, a country representative of the diverse resource limitations encountered by HIV treatment programs in sub-Saharan Africa. DESIGN/METHODS: We use the Cost Effectiveness of Preventing AIDS Complications-International model to examine the clinical impact, cost (2014 US$), and incremental cost-effectiveness ratio [$/year of life saved (YLS)] of ART monitoring strategies in Mozambique. We compare: monitoring for clinical disease progression [clinical ART monitoring strategy (CLIN)] vs. annual POC-CD4 in rural settings without laboratory services and biannual laboratory CD4 (LAB-CD4), biannual POC-CD4, and annual viral load in urban settings with laboratory services. We examine the impact of a range of values in sensitivity analyses, using Mozambique's 2014 per capita gross domestic product ($620) as a benchmark cost-effectiveness threshold. RESULTS: In rural settings, annual POC-CD4 compared to CLIN improves life expectancy by 2.8 years, reduces time on failed ART by 0.6 years, and yields an incremental cost effectiveness ratio of $480/YLS. In urban settings, biannual POC-CD4 is more expensive and less effective than viral load. Compared to biannual LAB-CD4, viral load improves life expectancy by 0.6 years, reduces time on failed ART by 1.0 year, and is cost-effective ($440/YLS). CONCLUSION: In rural settings, annual POC CD4 improves clinical outcomes and is cost-effective compared to CLIN. In urban settings, viral load has the greatest clinical benefit and is cost-effective compared to biannual POC-CD4 or LAB-CD4. Tailoring ART monitoring strategies to specific settings with different available resources can improve clinical outcomes while remaining economically efficient. PMID- 28906282 TI - Dolutegravir and metformin: a case of hyperlactatemia. PMID- 28906281 TI - Autoimmune hepatitis and HIV infection: two case reports and review of the literature. PMID- 28906283 TI - Preexposure prophylaxis: a cautionary tale. PMID- 28906284 TI - Effect of Transfusion on Mortality and Other Adverse Events Among Critically Ill Septic Patients: An Observational Study Using a Marginal Structural Cox Model. AB - OBJECTIVES: RBC transfusion is often required in patients with sepsis. However, adverse events have been associated with RBC transfusion, raising safety concerns. A randomized controlled trial validated the 7 g/dL threshold, but previously transfused patients were excluded. Cohort studies led to conflicting results and did not handle time-dependent covariates and history of treatment. Additional data are thus warranted to guide patient's management. DESIGN: To estimate the effect of one or more RBC within 1 day on three major outcomes (mortality, ICU-acquired infections, and severe hypoxemia) at day 30, we used marginal structural models. A trajectory modeling, based on hematocrit evolution pattern, allowed identification of subgroups. Secondary analyses were performed into each of them. SETTING: A prospective French multicenter database. PATIENTS: Patients with sepsis at admission. Patients with hemorrhagic shock at admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall, in our cohort of 6,016 patients, RBC transfusion was not associated with death (hazard ratio, 1.07; 95% CI, 0.88-1.30; p = 0.52). However, RBC transfusion was associated with increased occurrence of ICU-acquired infections (hazard ratio, 2.77; 95% CI, 2.33-3.28; p < 0.01) and of severe hypoxemia (hazard ratio, 1.29; 95% CI, 1.14-1.47; p < 0.01). A protective effect from death by the transfusion was found in the subgroup with the lowest hematocrit level (26 [interquartile range, 24-28]) (hazard ratio, 0.72; 95% CI, 0.55-0.95; p = 0.02). CONCLUSIONS: RBC transfusion did not affect overall mortality in critically ill patients with sepsis. Increased occurrence rate of ICU-acquired infection and severe hypoxemia are expected outcomes from RBC transfusion that need to be weighted with its benefits in selected patients. PMID- 28906285 TI - Impact of Missing Physiologic Data on Performance of the Simplified Acute Physiology Score 3 Risk-Prediction Model. AB - OBJECTIVES: The Simplified Acute Physiology 3 outcome prediction model has a narrow time window for recording physiologic measurements. Our objective was to examine the prevalence and impact of missing physiologic data on the Simplified Acute Physiology 3 model's performance. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Sixty-three ICUs in the Swedish Intensive Care Registry. PATIENTS: Patients admitted during 2011-2014 (n = 107,310). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Model performance was analyzed using the area under the receiver operating curve, scaled Brier's score, and standardized mortality rate. We used a recalibrated Simplified Acute Physiology 3 model and examined model performance in the original dataset and in a dataset of complete records where missing data were generated (simulated dataset). One or more data were missing in 40.9% of the admissions, more common in survivors and low-risk admissions than in nonsurvivors and high-risk admissions. Discrimination did not decrease with one to two missing variables, but accuracy was highest with no missing data. Calibration was best in the original dataset with a mix of full records and records with some missing values (area under the receiver operating curve was 0.85, scaled Brier 27%, and standardized mortality rate 0.99). With zero, one, and two data missing, the scaled Brier was 31%, 26%, and 21%; area under the receiver operating curve was 0.84, 0.87, and 0.89; and standardized mortality rate was 0.92, 1.05 and 1.10, respectively. Datasets where the missing data were simulated for oxygenation or oxygenation and hydrogen ion concentration together performed worse than datasets with these data originally missing. CONCLUSIONS: There is a coupling between missing physiologic data, admission type, low risk, and survival. Increased loss of physiologic data reduced model performance and will deflate mortality risk, resulting in falsely high standardized mortality rates. PMID- 28906286 TI - Serial Daily Organ Failure Assessment Beyond ICU Day 5 Does Not Independently Add Precision to ICU Risk-of-Death Prediction. AB - OBJECTIVES: To identify circumstances in which repeated measures of organ failure would improve mortality prediction in ICU patients. DESIGN: Retrospective cohort study, with external validation in a deidentified ICU database. SETTING: Eleven ICUs in three university hospitals within an academic healthcare system in 2014. PATIENTS: Adults (18 yr old or older) who satisfied the following criteria: 1) two of four systemic inflammatory response syndrome criteria plus an ordered blood culture, all within 24 hours of hospital admission; and 2) ICU admission for at least 2 calendar days, within 72 hours of emergency department presentation. INTERVENTION: NoneMEASUREMENTS AND MAIN RESULTS:: Data were collected until death, ICU discharge, or the seventh ICU day, whichever came first. The highest Sequential Organ Failure Assessment score from the ICU admission day (ICU day 1) was included in a multivariable model controlling for other covariates. The worst Sequential Organ Failure Assessment scores from the first 7 days after ICU admission were incrementally added and retained if they obtained statistical significance (p < 0.05). The cohort was divided into seven subcohorts to facilitate statistical comparison using the integrated discriminatory index. Of the 1,290 derivation cohort patients, 83 patients (6.4%) died in the ICU, compared with 949 of the 8,441 patients (11.2%) in the validation cohort. Incremental addition of Sequential Organ Failure Assessment data up to ICU day 5 improved the integrated discriminatory index in the validation cohort. Adding ICU day 6 or 7 Sequential Organ Failure Assessment data did not further improve model performance. CONCLUSIONS: Serial organ failure data improve prediction of ICU mortality, but a point exists after which further data no longer improve ICU mortality prediction of early sepsis. PMID- 28906287 TI - Racial Disparities in Sepsis-Related In-Hospital Mortality: Using a Broad Case Capture Method and Multivariate Controls for Clinical and Hospital Variables, 2004-2013. AB - OBJECTIVES: As sepsis hospitalizations have increased, in-hospital sepsis deaths have declined. However, reported rates may remain higher among racial/ethnic minorities. Most previous studies have adjusted primarily for age and sex. The effect of other patient and hospital characteristics on disparities in sepsis mortality is not yet well-known. Furthermore, coding practices in claims data may influence findings. The objective of this study was to use a broad method of capturing sepsis cases to estimate 2004-2013 trends in risk-adjusted in-hospital sepsis mortality rates by race/ethnicity to inform efforts to reduce disparities in sepsis deaths. DESIGN: Retrospective, repeated cross-sectional study. SETTING: Acute care hospitals in the Healthcare Cost and Utilization Project State Inpatient Databases for 18 states with consistent race/ethnicity reporting. PATIENTS: Patients diagnosed with septicemia, sepsis, organ dysfunction plus infection, severe sepsis, or septic shock. MEASUREMENTS AND MAIN RESULTS: In hospital sepsis mortality rates adjusted for patient and hospital factors by race/ethnicity were calculated. From 2004 to 2013, sepsis hospitalizations for all racial/ethnic groups increased, and mortality rates decreased by 5-7% annually. Mortality rates adjusted for patient characteristics were higher for all minority groups than for white patients. After adjusting for hospital characteristics, sepsis mortality rates in 2013 were similar for white (92.0 per 1,000 sepsis hospitalizations), black (94.0), and Hispanic (93.5) patients but remained elevated for Asian/Pacific Islander (106.4) and "other" (104.7; p < 0.001) racial/ethnic patients. CONCLUSIONS: Our results indicate that hospital characteristics contribute to higher rates of sepsis mortality for blacks and Hispanics. These findings underscore the importance of ensuring that improved sepsis identification and management is implemented across all hospitals, especially those serving diverse populations. PMID- 28906288 TI - IBD LIVE Series-Case 8: Treatment Options for Refractory Esophageal Crohn's Disease and Hidradenitis Suppurativa. PMID- 28906289 TI - Update on the Therapeutic Efficacy of Tregs in IBD: Thumbs up or Thumbs down? AB - Crohn's disease and ulcerative colitis, the 2 major forms of inflammatory bowel disease (IBD) in humans, arise in genetically predisposed individuals because of an abnormal immune response direct against constituents of the gut flora. Defects in counter-regulatory mechanisms are supposed to amplify and maintain the IBD associated mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory pathways in the gut could contribute to halt the IBD-associated tissue-damaging immune response. Various suppressive T cell (Tregs) subsets have been characterized phenotypically and functionally and over the last decade, there has been enormous effort for optimizing the procedures for the in vitro expansion/generation of these cells for therapeutic purposes. Here we review the mechanisms of action and functional relevance of Tregs in the maintenance of gut inflammation and analyze the available data about the use of these cells in the treatment of IBD patients. PMID- 28906290 TI - Safety Considerations with the Use of Corticosteroids and Biologic Therapies in Mild-to-Moderate Ulcerative Colitis. AB - BACKGROUND: The risk of corticosteroid-associated adverse events can limit the use of systemic corticosteroids. Oral, topically acting, second-generation corticosteroids that deliver drug to the site of inflammation, and biologic therapies, are effective treatment alternatives. The aim of this review was to evaluate the safety and tolerability of topically acting corticosteroids and biologic therapies versus oral systemic corticosteroids for ulcerative colitis (UC). METHODS: The PubMed database was searched for clinical and observational trials, systematic reviews, and case reports/series published between January 1950 and September 30, 2016. Search terms used included "corticosteroids," "beclomethasone dipropionate," "budesonide," "infliximab," "adalimumab," "golimumab," and "vedolizumab" in combination with "ulcerative colitis" or "inflammatory bowel disease." RESULTS: A total of 582 studies were identified from PubMed searches. Only 1 direct comparative trial for oral topically acting corticosteroids and systemic corticosteroids was available, and no comparative trials versus biologic therapies were identified. In patients with mild-to moderate UC, short-term (4-8 wk) oral beclomethasone dipropionate or oral budesonide multimatrix system demonstrated safety profiles comparable with placebo with few corticosteroid-related adverse events reported. Based on long term data in patients with moderate-to-severe UC, biologics have a generally tolerable adverse event profile, although infections, infusion reactions, and autoimmune disorders were frequently reported. CONCLUSIONS: Second-generation corticosteroids, beclomethasone dipropionate and budesonide multimatrix system, exhibited a favorable safety profile in patients with mild-to-moderate UC. For biologics, which are only indicated in moderate-to-severe UC, additional studies are needed to further ascertain the benefit to risk profile of these agents in patients with mild-to-moderate disease (see Video Abstract, Supplemental Digital Content, http://links.lww.com/IBD/B653). PMID- 28906291 TI - Systematic Review and Meta-analysis: Fecal Microbiota Transplantation for Treatment of Active Ulcerative Colitis. AB - BACKGROUND: Changes in the colonic microbiota may play a role in the pathogenesis of ulcerative colitis (UC) and restoration of healthy gut microbiota may ameliorate disease. A systematic review and meta-analysis was conducted to assess fecal microbiota transplantation (FMT) as a treatment for active UC. METHODS: A literature search was conducted to identify high-quality studies of FMT as a treatment for patients with UC. The primary outcome was combined clinical remission and endoscopic remission or response. Secondary outcomes included clinical remission, endoscopic remission, and serious adverse events. Odds ratios with 95% confidence intervals (CIs) are reported. RESULTS: Overall, 4 studies with 277 participants were eligible for inclusion. Among 4 randomized controlled trials, FMT was associated with higher combined clinical and endoscopic remission compared with placebo (risk ratio UC not in remission was 0.80; 95% CI: 0.71 0.89) with a number needed to treat of 5 (95% CI: 4-10). There was no statistically significant increase in serious adverse events with FMT compared with controls (risk ratio adverse event was 1.4; 95% CI: 0.55-3.58). CONCLUSIONS: Among randomized controlled trials, short-term use of FMT shows promise as a treatment to induce remission in active UC based on the efficacy and safety observed. However, there remain many unanswered questions that require further research before FMT can be considered for use in clinical practice. PMID- 28906292 TI - SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCepsilon-dependent Pathway. AB - BACKGROUND: The integrity of the gut barrier in patients with inflammatory bowel disease is known to be impaired but the exact mechanisms remain mostly unknown. SHANK3 mutations are associated with autism, and patients with autism are known to have higher proportions of inflammatory bowel disease. Here, we explore the role of SHANK3 in inflammatory bowel disease, both in vivo and in vitro. METHODS: Dextran sulfate sodium colitis was induced in SHANK3 knockout mice. Transepithelial electrical resistance, paracellular permeability, and Salmonella invasion assays were used to evaluate epithelial barrier function, in vitro and in vivo. Expression of tight junction proteins, protein kinases, and MAP kinase phosphorylation changes were analyzed by immunoblotting after overexpression or knockdown of SHANK3 expression. SHANK3 expression in intestinal tissue from patients with Crohn's disease was analyzed by quantitative polymerase chain reaction and immunohistochemistry. RESULTS: SHANK3 knockout mice were more susceptible to dextran sulfate sodium. SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion. Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1. Regulation of ZO-1 expression by SHANK3 seems to be mediated through a PKCepsilon-dependent pathway. SHANK3 expression correlated with ZO-1 and PKCepsilon in colonic tissue of patients with Crohn's disease. CONCLUSIONS: The expression level of SHANK3 affects ZO-1 expression and the barrier function in intestinal epithelial cells. This may provide novel insights in Crohn's disease pathogenesis and treatment. PMID- 28906293 TI - Frequency and Variables Associated with Fasting Orders in Inpatients with Ulcerative Colitis: The Audit of Diet Orders-Ulcerative Colitis (ADORE-UC) Study. AB - INTRODUCTION: Current clinical practice guidelines suggest that patients with ulcerative colitis (UC) hospitalized because of a disease flare should be offered a normal diet, unless such a diet is not tolerated. Studies of hospitalized patients have demonstrated iatrogenic malnutrition from unjustified or inappropriate nil per os (NPO) or clear liquid diet (CLD) orders. In this study, we aim to characterize the burden of this problem in hospitalized patients with UC. METHODS: We conducted a retrospective cohort study of all patients with UC admitted to the gastroenterology service or the general internal medicine service at a tertiary, academic hospital between January 2009 and December 2014, with a length of stay between 2 and 30 days. The frequency and duration of bowel rest and CLD orders was recorded, and the number of meals missed because of these orders was assessed. NPO or CLD diet orders were considered justified if the patient had intractable nausea or vomiting, pancreatitis, bowel obstruction, toxic megacolon or were awaiting endoscopy, or if alternative enteral nutrition was provided. Clinical and demographic factors associated with unjustified underfeeding were identified. RESULTS: A total of 187 admissions among 158 patients with UC were identified during the study period and included in the final analysis. Most admissions were to the gastroenterology service (148/187, 79.1%). The mean age at admission was 35.0 years (SD = 15), and 83/158 (52.5%) were female. The median length of stay was 8 days (interquartile range = 4-12). Registered dietician consultation was obtained in only 32 admissions (17.1%), and admission weight was recorded in only 68 (36.4%) admissions. A total of 252 NPO or CLD dietary orders were encountered in 142 admissions (75.9%). Of those, 112 orders were unjustified (44%). On average, patients with unjustified NPO or CLD orders spent 3 days on an NPO or CLD diet, which corresponded to a mean of 10 missed meals. Characteristics associated with unnecessary fasting included female gender, less frequent endoscopic disease staging, less frequent escalation of therapy to prednisone and/or biologics, and admission to a non-gastroenterology service. CONCLUSIONS: There is a high burden of unjustified underfeeding among hospitalized patients with UC, particularly in patients admitted without evidence of objective disease flare. This may lead to nutritional compromise in an at-risk population, and further studies are needed to assess the nutritional impact of unjustified bowel rest on patients with UC. Our findings also suggest that targeted quality improvement interventions are needed to decrease the frequency of inappropriate bowel rest among hospitalized patients with UC. PMID- 28906294 TI - Fecal Calprotectin in Pregnancy. PMID- 28906295 TI - Caution When Assessing Immunity to Varicella Through Antibody Testing in Patients with Inflammatory Bowel Disease. PMID- 28906296 TI - Quality of Sex Life in Patients with Inflammatory Bowel Disease: The Gastroenterologists' Perspective. PMID- 28906297 TI - Evidence-Based Medicine in Plastic Surgery: Are We There Yet? AB - BACKGROUND: The practice of evidence-based medicine in plastic surgery is no longer a trend but a reality, with a growing number of studies published in recent years using evidence-based medicine as an assessment tool. OBJECTIVE: The aim of this study was to verify whether the number of citations to articles with a high level of evidence is greater than articles with low level of evidence. METHODS: A search was conducted in the 4 main international journals of plastic surgery. All original articles published in 2011 were analyzed, selected, and classified based on the study design. The articles were then divided into 2 groups: group 1, high level of evidence; and group 2, low level of evidence. Next, Scopus was searched for the number of citations of each article in the 2 subsequent years. The proportion of the number of citations received by articles in groups 1 and 2 was statistically compared. RESULTS: The articles with the highest level of evidence were the most cited among original articles, with 48.6% of them being cited more than 10 times over 2 years, whereas only 18.4% of articles in group 2 were cited with the same frequency. The mean number of citations was 12.6 citations per article in group 1 and 6.56 citations in group 2, with a significant difference between groups (P < 0.0001). CONCLUSIONS: The articles with a higher level of evidence are, on average, cited more often than those with low levels of evidence in the leading journals of plastic surgery. PMID- 28906298 TI - A Simple Flap Design for the Salvage of Immediate Implant-Based Breast Reconstruction. AB - BACKGROUND: Breast reconstruction with implants is a real challenge in patients with large breast volume. Skin-reducing inverted-T mastectomy is the best solution for these patients. Delayed wound healing or necrosis at the T-junction area can be seen in this procedure, although it may also lead to severe conditions such as the exposure and loss of implant. In this article, the use of local pedicled flap for the management of these situations was discussed. METHODS: Between April 2010 and July 2015, 54 patients underwent breast reconstruction by inverted-T skin-reducing mastectomy and immediate implant-based breast reconstruction at our clinic. During the postoperative follow-up period, necrosis at the T-junction area was observed in 8 patients. All the patients received proper wound care, and the necrosis was surgically debrided. The defect was closed with Limberg-like rectangular flap. RESULTS: The mean age was 45.2 (range, 33-54) years. The mean body mass index was 25.57 +/- 6.53 (range, 21.2 35.2) kg/m. The mean follow-up was 10.9 (range, 4-19) months. Two patients had implant exposure at the defect site after the debridement. There was no implant loss in any of the patients. CONCLUSIONS: The Limberg-like rectangular flap can be used as a salvage option in complicated skin-reducing mastectomies and can be considered as a safe and effective method because of its easy-to-use nature, low cost, and no need for microsurgery experience. PMID- 28906299 TI - Integrated Plastic Surgery Residency Applicant Trends and Comparison With Other Surgical Specialties. AB - BACKGROUND: There has been a relatively rapid increase in the number and size of "integrated" residency programs in plastic surgery (PS) over the past decade. The objective of this study is to evaluate trends of US senior applicants of PS compared with other surgical specialties from 2007 to 2016. METHODS: Data were obtained from "NRMP: Main Residency Match" and from "NRMP: Charting Outcomes in the Match." Frequencies, percentages, and proportions were calculated for categorical variables. Odds ratios with 95% confidence interval were calculated to evaluate the relationship of Alpha Omega Alpha membership and match success. RESULTS: The overall National Resident Matching Program match rate ranged from 93.1% to 95.1%, but rates were lower for surgical specialties, ranging from 74.7% to 86.6% in 2016. From 2008 to 2016, PS had a relatively high growth rate in the number of positions (65.2%) from 2008 to 2016. Matched PS and Otolaryngology applicants routinely had the highest mean United States Medical Licensing Examination Step 1 and Step 2 Clinical Knowledge scores. Alpha Omega Alpha membership has a significant impact on successfully matching into a surgical specialty (P < 0.1). Matched applicants of surgical subspecialties (PS, Otolaryngology, orthopedics, and neurosurgery) had similar mean number of research, work, and volunteer experiences. However, PS and neurosurgery matched applicants had notably higher mean research productivity. CONCLUSIONS: The rapid increase in the number of positions in PS residency training has not resulted in a decrease in caliber of matched applicants, even though match rates have dramatically increased. Currently, PS continues to attract and successfully match highly qualified applicants, but other surgical specialties have increasingly similar board scores and mean number of extracurricular experiences. PMID- 28906300 TI - Isolated Dorsoradial Capsular Tear of the Thumb Metacarpophalangeal Joint: Missed Diagnosis and the Management of Delayed Presentation. AB - Isolated dorsoradial capsule injuries of the thumb metacarpophalangeal joint are different from those associated with collateral ligament disruption. Early suspicion of this rare injury is important because, if overlooked, ulnarward subluxation of extensor pollicis longus tendon can develop. Functionally, active thumb extension becomes impaired, and over the long term, a thumb Boutonniere's deformity becomes established. Joint hypermobility/instability may predispose to this injury. The 2 cases presented illustrate this through anatomic differences. At the time of acute injury, 3 presenting clinical features should raise suspicion of dorsoradial capsular rupture: a history of isolated hyperflexion injury to the thumb, stable collateral ligaments on examination, and x-ray evidence of palmar subluxation of the proximal phalanx on the metacarpal. Ulnarward subluxation of the extensor pollicis longus is a delayed sign. Diagnostic imaging, beyond x-ray studies, may not be helpful in defining the injury. Early exploration and repair of this injury give the best long-term outcome. Postrepair, metacarpophalangeal joint range of motion may not be fully restored, but stability and a preinjury level of hand function can usually be reestablished. PMID- 28906301 TI - A Comparative Study of Lateral Extension Versus Conventional Deltopectoral Flap in Head and Neck Reconstruction After Surgical Extirpation of Tumor. AB - BACKGROUND: We investigated outcomes for nondelayed conventional deltopectoral (CDP) flaps and lateral extension deltopectoral (LEDP) flaps. MATERIAL AND METHODS: Fifteen CDP flaps and 17 LEDP flaps were raised in 32 patients. All flaps were nondelayed. The flaps were folded only in the LEDP flap group. Six of 17 LEDP flaps were folded to become bilayered flaps to repair full thickness defects. Flap success rates and complication rates were compared between the CDP flap and LEDP flap groups. RESULTS: Success rates were 93.33% in the CDP flap group and 94.12% in the LEDP flap group. Overall complication rates of the transferred flaps were 6.67% and 11.76% for CDP and LEDP flaps, respectively. Flap failure rates were 6.67% and 5.88% with CDP flaps and LEDP flaps, respectively. CONCLUSIONS: Although the CDP flap is the "aged workhorse" in contemporary head and neck reconstructions, it was shown to be a beneficial regional flap with a dependable pedicle and easy technique. The LEDP flap is of value particularly when used to treat full thickness defects of the head and neck or in cases when higher reach is required. PMID- 28906302 TI - Chemotherapy Extravasation Management: 21-Year Experience. AB - Chemotherapy extravasation may result in serious damage to patients, with irreversible local injures and disability. Evidence-based standardization on extravasation management is lacking and many institutions do not practice adequate procedures to prevent the severer damages. Our aim was to explore the prevention and treatment of extravasation injuries, proposing a standard therapeutic protocol together with a review of the literature. From January 1994 to December 2015, 545 cases were reviewed (age range, 5-87 years; 282 men and 263 women). Our therapeutic protocol consisted of local infiltration of saline solution and topical occlusive applications of corticosteroids. The infiltrations were administrated 3 to 6 times a week depending on damage severity. Our protocol allowed us to prevent ulceration in 373 cases. Only 27 patients required surgery (escarectomy, skin graft, regional, and free flap). Numerous treatments have been proposed in literature. The antidotes have been discussed controversially and are not considered standard methods for treatment, especially when polychemotherapy is administrated and the identification of the responsible drug is not possible. We proposed the use of saline solution injection to dilute rapidly the drug, thus reducing its local toxic effects. This method is easy to use and always reproducible even when the drug is not known or when it is administrated in combination with other drugs. It is possible to perform it in ambulatory regimen, and, overall, it represents a standard method. PMID- 28906303 TI - Relationship of low doses of alcohol voluntarily consumed during adolescence and early adulthood with subsequent behavioral flexibility. AB - Previous alcohol use is associated with impaired decision-making and impulsivity in humans, but the relationship between alcohol use and decision making/impulsivity is unclear. In two experiments, we determined whether chronic intermittent access to alcohol during adolescence and early adulthood would alter or be correlated with performance in a go/no-go reversal task, a devaluation task, or operant extinction. Rats received 6 weeks of chronic intermittent access to 20% alcohol or water from postnatal day 26 to 66 and then behavioral testing was initiated 1.5-2.5 weeks later. We found no evidence that voluntary alcohol consumption altered behavior in either task. However, we found that rats that consumed more alcohol made fewer commission errors in reversal learning compared with rats that drank less. There was no relationship between alcohol consumption and reversal learning omission errors. Alcohol consumption was not correlated with the magnitude of the devaluation effect, but rats that consumed more alcohol showed faster extinction during the devaluation test. Our results suggest that the relationships between behavioral flexibility and alcohol consumption may represent individual differences. Future work will determine the neurobiological and genetic bases of these behavioral differences. PMID- 28906304 TI - Comparison of Expert Opinion, Majority Rule, and a Clinical Prediction Rule to Estimate Distal Radius Malalignment. AB - OBJECTIVES: To investigate the ability of individual surgeons [expert opinion (EO)] to predict distal radius fracture (DRF) healing above a threshold malalignment compared with the majority prediction of the group of surgeons ["majority rule," (MR)] and a statistically derived clinical prediction formula [Edinburgh wrist calculator (EWC)]. DESIGN: Comparative diagnostic study from prospectively collected data of consecutive patients. SETTING: Two academic level 1 and 1 academic level 2 trauma centers. PATIENTS/PARTICIPANTS: Eighteen surgeons assessed probability of healing above a threshold malalignment (often referred to as fracture "instability") for 71 fractures based on radiographs taken initially and after closed reduction and cast application. The probability of losing alignment according to the EWC was dichotomized (likely to lose alignment >=0.5 vs. unlikely <0.5). MAIN OUTCOME MEASURES: Accuracy parameters of prediction of EO, MR, and EWC. RESULTS: EWC and MR demonstrated higher accuracy (0.77 and 0.75, respectively) and sensitivity (0.95 and 0.79, respectively) compared with EO (accuracy, 0.66 and sensitivity, 0.58) for predicting healing above the threshold malalignment. Reliability was higher for MR (kappa 0.88) than for EWC (kappa 0.63) or EO (kappa coefficient 0.44). The negative predictive value of the EWC for healing above a threshold of malalignment was excellent (0.97). CONCLUSIONS: Surgeon opinion is not reliable or accurate for predicting loss of alignment of a DRF above a threshold malalignment after closed reduction and immobilization. Dichotomized EWC may be a useful tool in predicting loss of alignment (instability) of a DRF. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28906305 TI - Risk of Knee Sepsis After Treatment of Open Tibia Fractures: A Multicenter Comparison of Suprapatellar and Infrapatellar Approaches. AB - OBJECTIVES: The suprapatellar approach for medullary nailing of the tibia is increasing. This requires intra-articular passage of instruments, which theoretically places the knee at risk of postoperative sepsis in the setting of open fracture. We hypothesized that the risk of knee sepsis is similar after suprapatellar or infrapatellar nailing of open tibia fractures. DESIGN: Retrospective, multicenter. SETTING: Three urban level 1 trauma centers. PATIENTS: All patients treated with medullary nailing for open diaphyseal tibia fractures (OTA 42) from 2009 to 2015. Patients younger than 18 years of age and with less than 12 weeks of follow-up were excluded. We identified 289 fractures in 282 patients. INTERVENTION: Suprapatellar (SP) or infrapatellar (IP) medullary nailing of open tibia fractures. MAIN OUTCOME MEASUREMENT: Occurrence of ipsilateral knee sepsis, defined as presence of a positive culture from knee aspiration or arthrotomy. Deep infection requiring operative debridement, superficial infection requiring antibiotic therapy alone, and all-cause reoperation were also recorded. RESULTS: IP nailing was used for 142 fractures. There were 20 infections (14.1%), of which 14 (9.8%) were deep. Fourteen tibias (9.8%) required reoperation for noninfectious reasons for 28 total reoperations (19.7%). SP nailing was used in 147 fractures. There were 24 infections (16.2%), of which 16 (10.8%) were deep. Fourteen additional tibias (9.5%) required reoperation for noninfectious reasons for a total of 30 reoperations (20.4%). There were no differences in the rates of infection, deep infection, or reoperation between groups. There were 2 cases of knee sepsis after SP nailing (1.4%) but zero cases after IP nailing (P = 0.5). CONCLUSIONS: There was no significant difference in the rate of knee sepsis with SP or IP approaches. The risk of knee sepsis after SP nailing of open fractures is low, but present. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28906306 TI - Predicting Early Mortality After Hip Fracture Surgery: The Hip Fracture Estimator of Mortality Amsterdam. AB - OBJECTIVES: Early mortality after hip fracture surgery is high and preoperative risk assessment for the individual patient is challenging. A risk model could identify patients in need of more intensive perioperative care, provide insight in the prognosis, and allow for risk adjustment in audits. This study aimed to develop and validate a risk prediction model for 30-day mortality after hip fracture surgery: the Hip fracture Estimator of Mortality Amsterdam (HEMA). METHODS: Data on 1050 consecutive patients undergoing hip fracture surgery between 2004 and 2010 were retrospectively collected and randomly split into a development cohort (746 patients) and validation cohort (304 patients). Logistic regression analysis was performed in the development cohort to determine risk factors for the HEMA. Discrimination and calibration were assessed in both cohorts using the area under the receiver operating characteristic curve (AUC), the Hosmer-Lemeshow goodness-of-fit test, and by stratification into low-, medium and high-risk groups. RESULTS: Nine predictors for 30-day mortality were identified and used in the final model: age >=85 years, in-hospital fracture, signs of malnutrition, myocardial infarction, congestive heart failure, current pneumonia, renal failure, malignancy, and serum urea >9 mmol/L. The HEMA showed good discrimination in the development cohort (AUC = 0.81) and the validation cohort (AUC = 0.79). The Hosmer-Lemeshow test indicated no lack of fit in either cohort (P > 0.05). CONCLUSIONS: The HEMA is based on preoperative variables and can be used to predict the risk of 30-day mortality after hip fracture surgery for the individual patient. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28906307 TI - Lateral Compression-I Pelvic Ring Injury: Not Benign to the Developing Fetus. AB - OBJECTIVE: To determine whether certain patterns of pelvic ring injury are associated with more frequent intrauterine fetal demise (IUFD). DESIGN: Retrospective review. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Of 44 pregnant patients with pelvic and/or acetabular fractures, 40 had complete records that allowed determination of fetal viability. chi2 tests were used for categorical variables (Fisher exact tests when expected cell counts were fewer than 5), and t tests were used for continuous variables. MAIN OUTCOME MEASUREMENTS: Fetal or maternal death. RESULTS: Sixteen patients had isolated acetabular fractures, 25 had isolated pelvic ring injuries, and 3 had acetabular fractures with concomitant pelvic ring injuries. Maternal and fetal mortality were 2% and 40%, respectively. No patients with isolated acetabular fractures experienced IUFD, compared with 68% (15/22) of those with isolated pelvic ring injuries (P < 0.0001). Eight (53%) of 15 IUFDs were associated with lateral compression (LC)-I pelvic ring injuries (Orthopaedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen 61-B2). Of the 13 LC-I pelvic ring injuries, 8 (62%) resulted in IUFD. Pelvic ring stability, Young Burgess classification, and operative treatment were not associated with IUFD. Maternal Glasgow Coma Scale (average 13.2) and Injury Severity Score (average 18.2) at admission were predictive of IUFD. CONCLUSIONS: The most frequent pelvic fractures in gravid trauma patients are LC-I. Although the rate of maternal mortality was low, the risk of IUFD was quite high (40%). LC-I pelvic ring injuries often had catastrophic outcomes, with IUFD in 62% of cases. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28906308 TI - Is Contralateral Templating Reliable for Establishing Rotational Alignment During Intramedullary Stabilization of Femoral Shaft Fractures? A Study of Individual Bilateral Differences in Femoral Version. AB - OBJECTIVES: To determine native individual bilateral differences (IBDs) in femoral version in a diverse population. METHODS: Computed tomography scans with complete imaging of uninjured bilateral femora were used to determine femoral version and IBDs in version. Age, sex, and ethnicity of each subject were also collected. Femoral version and IBDs in version were correlated with demographic variables using univariate and multivariate regression models. RESULTS: One hundred sixty-four subjects were included in the study. The average femoral version was 9.4 degrees (+/-9.4 degrees). The mean IBD in femoral version was 5.4 degrees (+/-4.4 degrees, P < 0.001). A total of 17.7% of subjects had a difference in version >=10 degrees, and 4.3% had a difference in version >=15 degrees. A femur with anteversion >=20 degrees or retroversion was associated with a greater mean difference in version from the contralateral side compared with those with midrange anteversion. CONCLUSIONS: Bilateral differences in femoral version are common and can result in a difference from native anatomy that may be clinically significant if only the contralateral limb is used to establish rotational alignment during intramedullary stabilization of diaphyseal femur fractures. This is also an important consideration when considering malrotation of femur fractures because most studies define malrotation as a greater than 10-15-degree difference compared with the contralateral side. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28906309 TI - Cancer Stem Cell-Related Marker NANOG Expression in Ovarian Serous Tumors: A Clinicopathological Study of 159 Cases. AB - OBJECTIVE: The objectives of this study were to assess cancer stem cell-related marker NANOG expression in ovarian serous tumors and to evaluate its prognostic significance in relation to ovarian serous carcinoma. METHODS: NANOG protein expression was immunohistochemically evaluated in the ovarian tissue microarrays of 20 patients with benign ovarian serous tumors, 30 patients with borderline ovarian serous tumors, and 109 patients with ovarian serous carcinomas, from which 106 were of high-grade and 3 of low-grade morphology Immunohistochemical reaction was scored according to signal intensity and the percentage of positive cells in tumor samples. Pursuant to our summation of signal intensity and positive cell occurrence, we divided our samples into 4 groups: NANOG-negative, NANOG-slightly positive, NANOG-moderately positive, and NANOG-strongly positive group. Complete clinical data were obtained for the ovarian serous carcinoma group, and correlation between clinical data and NANOG expression was analyzed. RESULTS: A specific brown nuclear, or cytoplasmic reaction, was considered a positive NANOG staining. In terms of the ovarian serous carcinoma group, 69.7% were NANOG positive, 22.9% slightly positive, 22.9% moderately positive, and 23.9% strongly positive. All NANOG-positive cases were of high-grade morphology. Benign and borderline tumors and low-grade serous carcinomas were NANOG negative. There was no significant correlation between NANOG expression and clinical parameters in terms of the ovarian serous carcinoma group. CONCLUSIONS: Positive NANOG expression is significantly associated with high-grade ovarian serous carcinoma and is absent in benign, borderline, and low-grade serous lesions. In our study, there was no correlation between NANOG expression and clinical parameters, including its use in the prognosis of ovarian serous carcinoma. PMID- 28906310 TI - Endometrial Stromal Sarcoma of the Uterus: Magnetic Resonance Imaging Findings Including Apparent Diffusion Coefficient Value and Its Correlation With Ki-67 Expression. AB - OBJECTIVE: This study aimed to investigate the conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) features of endometrial stromal sarcoma (ESS) including a preliminary investigation of the correlation between the apparent diffusion coefficient (ADC) value and Ki-67 expression. METHODS: The clinical and MRI data of 15 patients with ESS confirmed by surgery and pathology were analyzed retrospectively. The conventional MR morphological features, signal intensity on DWI, ADC value (n = 14), and clinicopathological marker Ki-67 (n = 13) were evaluated. RESULTS: Of 15 patients with ESS, 13 tumors were low-grade ESS (LGESS), and the remaining 2 were high-grade ESS (HGESS); 9 tumors were located in the myometrium, 5 were located in the endometrium and/or cervical canal, and 1 was located in extrauterine. Thirteen (87%) of 15 tumors showed a homo- or heterogeneous isointensity on T1-weighted imaging and a heterogeneous hyperintensity on T2-weighted imaging. The hypointense bands were observed in 11 tumors (73%) on T2-weighted imaging. The degenerations (cystic/necrosis/hemorrhage) were observed in 7 LGESS tumors and 2 HGESS tumors. The DWI hyperintensity was observed in 13 tumors (93%) and isointensity in remaining 1. The mean ADC value of the solid components in 14 ESSs was (1.05 +/- 0.20) * 10mm/s. The contrast-enhanced MRI showed an obvious enhancement in 14 tumors (93%) (heterogeneous in 7 LGESSs and 2 HGESSs; homogeneous in 5 LGESSs). The ADC value was inversely correlated with the Ki-67 expression (r = -0.613, P = 0.026). CONCLUSIONS: Patients with ESS showed some characteristics on conventional MRI and DWI, and there was an inverse correlation between the ADC value and Ki-67 expression. PMID- 28906311 TI - Genetic Predisposition to Cervical Cancer and the Association With XRCC1 and TGFB1 Polymorphisms. AB - OBJECTIVE: Cervical carcinoma (CC), a multifactorial cancer, is assumed to have a host genetic predisposition component that modulates its susceptibility in various populations. We investigated the association between CC risk in Saudi women and 6 single-nucleotide polymorphisms (SNPs) in hypothesis-driven candidate genes. METHODS: A total of 545 females were included, comprising 232 CC patients and 313 age-/sex-matched control subjects. Six SNPs (CDKN1A C31A, ATM G1853A, HDM2 T309G, TGFB1 T10C, XRCC1 G399A, and XRCC3 C241T) were genotyped by direct sequencing. RESULTS: Of the 6 SNPs studied, TGFB1 T10C (odds ratio, 0.74; 95% confidence interval, 0.57-0.94) and XRCC1 G399A (odds ratio, 1.45; 95% confidence interval, 1.11-1.90) displayed different frequencies in cancer patients and control subjects and showed statistically significant association in univariate (P = 0.017, P = 0.005, respectively) analysis. The Cochran-Armitage trend test had confirmed the results (P = 0.027 and P = 0.006, respectively), indicating an ordering in the effect of the risk alleles in CC patients. The 2 SNPs, TGFB1 T10C and XRCC1 G399A, showed also degrees of deviation from Hardy-Weinberg equilibrium in cancer patients (P = 0.001 and P = 0.083, respectively) but not in the control subjects. Furthermore, correction for multiple testing using multivariate logistic regression to assess the joint effect of all SNPs has sustained significant statistical association (P = 0.025 and P = 0.009, respectively). CONCLUSIONS: TGFB1 T10C and XRCC1 G399A SNPs were associated with CC risk in univariate and multivariate analysis and displayed allele-dosage effects and coselection in cancer patients. Patients harboring the majority allele TGFB1 T10 (Leu) or the variant allele XRCC1 399A (Gln) have approximately 1.5-fold increased risk to develop CC. Host SNPs genotyping may provide relevant biomarkers for CC risk assessment in personalized preventive medicine. PMID- 28906312 TI - Redesigning Oncology Care Delivery: Early Wins, Lessons Learned, and a Roadmap. PMID- 28906313 TI - Two Innovative Cancer Care Programs Have Potential to Reduce Utilization and Spending. AB - BACKGROUND: Cancer patients often present to the emergency department (ED) and hospital for symptom management, but many of these visits are avoidable and costly. OBJECTIVE: We assessed the impact of 2 Health Care Innovation Awards that used an oncology medical home model [Community Oncology Medical Home (COME HOME)] or patient navigation model [Patient Care Connect Program (PCCP)] on utilization and spending. METHODS: Participants in COME HOME and PCCP models were matched to similar comparators using propensity scores. We analyzed utilization and spending outcomes using Medicare fee-for-service claims with unadjusted and adjusted difference-in-differences models. RESULTS: In the adjusted models, both COME HOME and PCCP were associated with fewer ED visits than a comparison group (15 and 22 per 1000 patients/quarter, respectively; P<0.01). In addition, COME HOME had lower spending ($675 per patient/quarter; P<0.01), and PCCP had fewer hospitalizations (11 per 1000 patients/quarter; P<0.05), relative to the comparison group. Among patients undergoing chemotherapy, fewer COME HOME and PCCP patients had ED visits (18 and 28 per 1000 patients/quarter, respectively; P<0.01) and fewer PCCP patients had hospitalizations (13 per 1000 patients/quarter; P<0.05), than comparison patients. CONCLUSIONS: The oncology medical home and patient navigator programs both showed reductions in spending or utilization. Adoption of such programs holds promise for improving cancer care. PMID- 28906314 TI - Quality of Care in the United States Territories, 1999-2012. AB - BACKGROUND: Millions of Americans live in the US territories, but health outcomes and payments among Medicare beneficiaries in these territories are not well characterized. METHODS: Among Fee-for-Service Medicare beneficiaries aged 65 years and older hospitalized between 1999 and 2012 for acute myocardial infarction (AMI), heart failure (HF), and pneumonia, we compared hospitalization rates, patient outcomes, and inpatient payments in the territories and states. RESULTS: Over 14 years, there were 4,350,813 unique beneficiaries in the territories and 402,902,615 in the states. Hospitalization rates for AMI, HF, and pneumonia declined overall and did not differ significantly. However, 30-day mortality rates were higher in the territories for all 3 conditions: in the most recent time period (2008-2012), the adjusted odds of 30-day mortality were 1.34 [95% confidence interval (CI), 1.21-1.48], 1.24 (95% CI, 1.12-1.37), and 1.85 (95% CI, 1.71-2.00) for AMI, HF, and pneumonia, respectively; adjusted odds of 1 year mortality were also higher. In the most recent study period, inflation adjusted Medicare in-patient payments, in 2012 dollars, were lower in the territories than the states, at $9234 less (61% lower than states), $4479 less (50% lower), and $4403 less (39% lower) for AMI, HF, and pneumonia hospitalizations, respectively (P<0.001 for all). CONCLUSIONS AND RELEVANCE: Among Medicare Fee-for-Service beneficiaries, in 2008-2012 mortality rates were higher, or not significantly different, and hospital reimbursements were lower for patients hospitalized with AMI, HF, and pneumonia in the territories. Improvement of health care and policies in the territories is critical to ensure health equity for all Americans. PMID- 28906315 TI - Development of the Aim to Decrease Anxiety and Pain Treatment for Pediatric Functional Abdominal Pain Disorders. AB - OBJECTIVES: To evaluate the feasibility and acceptability of the Aim to Decrease Anxiety and Pain Treatment (ADAPT), a brief, on-line and in-person behavioral intervention targeting pain and anxiety in youth with functional abdominal pain disorders (FAPDs). METHODS: Patients were recruited from several outpatient pediatric gastroenterology clinics. Nine participants (ages 9-13) completed the full protocol. Thematic analysis of detailed qualitative feedback was obtained via semistructured patient and caregiver interviews after treatment was conducted. Feasibility and preliminary outcomes were examined using nonparametric tests. RESULTS: Preliminary results indicate that the ADAPT treatment is feasible, acceptable, and potentially effective for youth with FAPD. Treatment completers reported that they enjoyed the program and used the skills to manage their pain and worry. Results also indicated that the majority of participants experienced a reduction in anxiety and several reported reductions in pain and functional disability levels. CONCLUSIONS: Findings from this study suggest that targeting both pain and anxiety may positively impact outcomes in youth with FAPD. The ADAPT intervention has the potential to provide a cost effective and practical application of cognitive behavioral therapy using an innovative combination of in-person and technology-based platforms. Overall, the ADAPT intervention is a promising and innovative intervention to improve the outcomes of youth with FAPD. PMID- 28906316 TI - Secondary Loss of Response to Infliximab in Pediatric Crohn Disease: Does It Matter How and When We Start? AB - OBJECTIVES: A significant proportion of children with Crohn disease develop a secondary loss of response (LOR) to infliximab. Our aim was to study the impact of initial treatment strategies on secondary LOR. METHODS: We reviewed the medical records of children with Crohn disease who received scheduled maintenance infliximab therapy for at least 12 months. We compared children who developed LOR with those who did not; with regards to their clinical and laboratory parameters, disease phenotype, and treatment strategy before developing LOR. RESULTS: A total of 73 children (median age at diagnosis 11 (2-16) years, 41 boys) who had received a median duration of 33 (13-110) months of infliximab therapy were included in the final analysis. LOR was seen in 25(34.2%). Demographic variables, disease phenotype (age, disease location, and behavior), inflammatory parameters, and pediatric Crohn disease activity index at induction with infliximab were similar between both groups. Children with LOR had a significantly greater number of flares of the disease when compared to those who did not have LOR (4 [1-8] vs 2 [1-5] P = 0.03). The choice of the concomitant immunomodulator-methotrexate (11/29 [37.9%]) versus azathioprine (11/36 [30.5%]) (P = 0.6) did not affect LOR rates. The median time-lag between diagnosis and induction with infliximab was significantly longer in children with LOR as compared to those who did not have an LOR (28 [4-90] months vs 12.5 [1-121] months, P = 0.004). CONCLUSION: Early use of infliximab in pediatric Crohn disease is associated with a decrease in secondary LOR. The type of concomitant immunomodulator used does not make a difference to LOR rates. PMID- 28906317 TI - Polyethylene Glycol 3350 With Electrolytes Versus Polyethylene Glycol 4000 for Constipation: A Randomized, Controlled Trial. AB - OBJECTIVE: The long-term efficacy and safety of polyethylene glycol (PEG) in constipated children are unknown, and a head-to-head comparison of the different PEG formulations is lacking. We aimed to investigate noninferiority of PEG3350 with electrolytes (PEG3350 + E) compared to PEG4000 without electrolytes (PEG4000). METHODS: In this double-blind trial, children aged 0.5 to 16 years with constipation, defined as a defecation frequency of <3 times per week, were randomized to receive either PEG3350 + E or PEG4000. Primary outcomes were change in total sum score (TSS) at week 52 compared to baseline, and dose range determination. TSS was the sum of the severity of 5 constipation symptoms rated on a 4-point scale (0-3). Noninferiority margin was a difference in TSS of <=1.5 based on a 95%-confidence interval [CI]. Treatment success was defined as a defecation frequency of >=3 per week with <1 episode of fecal incontinence. RESULTS: Ninety-seven subjects were included, of whom 82 completed the study. Mean reduction in TSS was -3.81 (95% CI: -4.96 to -2.65) and -3.74 (95%CI: -5.08 to -2.40), for PEG3350 + E and PEG4000, respectively. Noninferiority criteria were not met (maximum difference between groups: -1.81 to 1.68). Daily sachet use was: 0 to 2 years: 0.4 to 2.3 and 0.9 to 2.1; 2 to 4 years: 0.1 to 3.5 and 1.2 to 3.2; 4 to 8 years: 1.1 to 2.8 and 0.7 to 3.8; 8 to 16 years 0.6 to 3.7 and 1.0 to 3.7, in PEG3350 + E and PEG4000, respectively. Treatment success after 52 weeks was achieved in 50% and 45% of children, respectively (P = 0.69). Rates of adverse events were similar between groups, and no drug-related serious adverse events occurred. CONCLUSIONS: Noninferiority regarding long-term constipation related symptoms of PEG3350 + E compared to PEG4000 was not demonstrated. However, analysis of secondary outcomes suggests similar efficacy and safety of these agents. PMID- 28906318 TI - Nutritional State and Feeding Behaviors of Children With Eosinophilic Esophagitis and Gastroesophageal Reflux Disease. AB - OBJECTIVE: As both gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) are associated with malnutrition and feeding dysfunction, this study compares growth, nutrition, and feeding behaviors in children with GERD and EoE. METHODS: Subjects ages 1 to 7 years with GERD or EoE were enrolled in a prospective study. Assessments included length/height, weight, 3-day food diary, serum biomarkers of nutrition, and the Behavioral Pediatric Feeding Assessment Scale. RESULTS: Mean weight-for-length z scores in GERD and EoE children were 0.93 and -1.14 (p = NS) and mean body mass index z scores were 0.29 and -0.13 (P = NS). Vitamin D intake was below the daily recommended intake in GERD subjects. EoE subjects' intake was below daily recommended intake of Vitamin D and calcium. GERD and EoE groups both had normal intake of calories, carbohydrates, proteins, fats, and iron, and normal serum ferritin (25 vs 34 ng/mL), prealbumin (21 vs 20 mg/dL), parathyroid hormone (42 vs 37 pg/mL), and Vitamin D (both 30 ng/mL). Behavioral Pediatric Feeding Assessment Scale problem and frequency scores were similar in GERD and EoE subjects but were higher than those of a historical cohort of healthy controls (Hedges' g of 0.95 and 1.1, respectively). EoE subjects on food allergen restriction diets had significantly less feeding dysfunction than those on regular diets. CONCLUSIONS: As a selected group of children with uncomplicated GERD or EoE were without nutritional deficiencies but had maladaptive feeding, providing anticipatory guidance to minimize mealtime challenges, monitoring for improvement, or referring to a feeding therapist, may be beneficial. A trial of food allergen restriction may provide additional benefit for those with EoE. PMID- 28906319 TI - Enteroaggregative E. coli Subclinical Infection and co-Infections and Impaired Child Growth in the MAL-ED Cohort Study. AB - OBJECTIVE: We evaluated the impact of subclinical enteroaggregative Escherichia coli (EAEC) infection alone and in combination with other pathogens in the first six months of life on child growth. METHODS: Non-diarrheal samples from 1,684 children across eight Multisite Birth Cohort Study, Malnutrition and Enteric Diseases (MAL-ED) sites in Asia, Africa, and Latin America were tested monthly; over 90% of children were followed-up twice weekly for the first six months of life. RESULTS: Children with subclinical EAEC infection did not show altered growth between enrollment and six months. Conversely, EAEC co-infection with any other pathogen was negatively associated with delta weight-for-length (WLZ) (p < 0.05) and weight-for-age (WAZ) (p > 0.05) z-scores between 0 and 6 months. The presence of two or more pathogens without EAEC was not significantly associated with delta WLZ and WAZ. The most frequent EAEC co-infections included Campylobacter spp. heat-labile toxin-producing enterotoxigenic E. coli, Cryptosporidium spp., and atypical enteropathogenic E. coli. Myeloperoxidase levels were increased with EAEC co-infection (p < 0.05). EAEC pathogen co detection was associated with lower neopterin levels compared to those of no pathogen control children (p < 0.05). Mothers of children with EAEC co-infections had lower levels of education, poorer hygiene and sanitation, lower socioeconomic status, and lower breastfeeding rates compared to mothers of children in whom no pathogen was detected (p < 0.05). CONCLUSIONS: These data emphasize the public health importance of subclinical EAEC infection in early infancy in association with other pathogens and the need for improved maternal and child care, hygiene, sanitation, and socioeconomic factors. PMID- 28906320 TI - Changes in Proteases, Antiproteases, and Bioactive Proteins From Mother's Breast Milk to the Premature Infant Stomach. AB - OBJECTIVE: Our previous studies suggested that human milk proteases begin to hydrolyze proteins in the mammary gland and continue within the term infant' stomach. No research has measured milk protease and pepsin activity in the gastric aspirates of preterm infants after human milk feeding. This study investigated how the concentrations of human milk proteases and protease inhibitors changed in the premature infant stomach. METHODS: Human milk and infant gastric samples were collected from 18 preterm-delivering mother-infant pairs (24-32 week gestational age). Paired human milk and gastric samples were collected across postnatal age (2-47 days). Protease concentrations were determined by spectrophotometric or fluorometric assays, and the concentrations of protease inhibitors and bioactive proteins were determined by enzyme-linked immunosorbent assay. Paired t tests were applied to compare enzymes, antiproteases, and bioactive proteins between human milk and gastric samples. RESULTS: Our study reveals that although human milk proteases, including carboxypeptidase B2, kallikrein, plasmin, cathepsin D, elastase, thrombin, and cytosol aminopeptidase, are present in the preterm infant stomach, only plasmin and cathepsin D can actively hydrolyze proteins at gastric pH. Enzyme-linked immunosorbent assay and peptidomic evidence suggest that all milk antiproteases as well as lactoferrin and immunoglobulin A are partially digested in the preterm stomach. CONCLUSIONS: Most human milk proteases are active in milk but not at preterm infant gastric pH. Only cathepsin D and plasmin have potential to continue degrading milk proteins within the preterm infant stomach. PMID- 28906321 TI - Variceal Hemorrhage and Adverse Liver Outcomes in Patients With Cystic Fibrosis Cirrhosis. AB - OBJECTIVES: Cirrhosis occurs in 5% to 10% of cystic fibrosis (CF) patients, often accompanied by portal hypertension. We analyzed 3 adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver-related death (LD), and risk factors for these in CF Foundation Patient Registry subjects with reported cirrhosis. METHODS: We determined 10-year incidence rates for VB, LT, LD, and all cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression. RESULTS: From 2003 to 2012, 943 participants (41% females, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had previous pseudomonas. Seventy-three subjects had reported VB: 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. Ten-year cumulative VB, LT, and LD rates were 6.6% (95% confidence interval [CI]: 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (hazard ratio [HR] 1.10, 95% CI: 0.59, 2.08). CF-related diabetes (HR: 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk, whereas only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver. CONCLUSIONS: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report. PMID- 28906322 TI - The Effect of Ophthalmic Artery Chemosurgery on Immune Function in Retinoblastoma Patients: A Single Institution Retrospective Analysis. AB - BACKGROUND: Ophthalmic artery chemosurgery (OAC) is associated with grade 3 and 4 neutropenia, however the effect on T-cell number and function is unknown. The purpose of this retrospective review was to confirm that patients treated with OAC do not develop immunosuppression warranting Pneumocystis pneumonia prophylaxis. PROCEDURE: IRB approval was obtained for a single center retrospective review of immune function tests in retinoblastoma patients who received OAC. RESULTS: Twenty-three patients received >=3 cycles of OAC and had immune function testing (absolute CD4 count) performed at a median of 34 days postcompletion of therapy (range, 15 to 63 d). Only 1 patient had a low absolute CD4 count of 189 cells/MUL (normal, 359 to 1570 cells/MUL) 2 and a half months after IV carboplatin and 28 days after their third dose of OAC. This patient was found to have coexisting hypogammaglobulinemia. Repeat immune function testing normalized through continued OAC treatment. CONCLUSIONS: Clinically significant immune suppression appears rare following OAC alone, but patients previously treated with IV chemotherapy may be immunosuppressed and may benefit from pneumocystis pneumonia prophylaxis until the CD4 count recovers. PMID- 28906323 TI - Novel Method Enabling the Use of Cryopreserved Primary Acute Myeloid Leukemia Cells in Functional Drug Screens. AB - The ability to assess antileukemic drug activity on primary patient samples is a powerful tool in determining potential drug targets and selection of therapeutic agents with biological and functional rationale. We previously established small molecule inhibitor screens for use on freshly isolated leukemia cells for this purpose. Here we describe a method that produces functional small molecule inhibitor screening results using cryopreserved primary acute myeloid leukemia cells. This method was established to take advantage of biorepositories containing archival material, such as those established by the Children's Oncology Group, and to enable validation of potential pathway dependencies uncovered by genomic analysis. Various conditions used to thaw and culture cryopreserved specimens were assessed for effect on viability, differentiation, and the ability to recapitulate sensitivity results obtained on fresh samples. The most reproducible results were obtained by quick-thawing and culturing samples in cytokine rich media before performing drug screens. Our data suggest that cytokine-enriched media aids in maintaining the viability and numbers required to perform functional analysis on cryopreserved leukemia cells. This method can aid in producing informative data on therapeutic targeting and precision medicine efforts in leukemia by making use of biorepositories and bio banks. PMID- 28906324 TI - Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm: A Systematic Literature Review. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive hematologic malignancy characterized by frequent skin involvement that most commonly affects older patients. BPDCN is known to have a poor prognosis. Our objective was to assess if outcome and disease prognosis were independently influenced by age when evaluated with clinical presentation, sex, and treatment regimens. We conducted a systematic review to identify BPDCN cases, to compare pediatric BPDCN cases with adult cases. A total of 125 publications were identified detailing 356 cases. Including 1 pediatric case from our institution, 74 were children, and 283 were adults aged 19 or over. Age was shown to be an independent prognostic factor predictive of more favorable outcomes across measures including initial response to therapy, likelihood of relapse, and overall survival at follow-up. The distribution of affected organs at diagnosis was similar across children and adults and type of clinical presentation did not disproportionately influence 1 age group's prognosis over the other. Acute lymphoblastic leukemia-type chemotherapy regimens were shown to be superior to other chemotherapy regimens (acute myeloid leukemia, lymphoma, acute lymphoblastic leukemia/lymphoma, other, or none) in inducing complete remission. Allogeneic stem cell transplantation was shown to increase mean survival time. Future research may be directed toward elucidating the further morphologic, cytogenetic, and cytochemical differences between younger and older BPDCN patients. PMID- 28906325 TI - Antidepressant combination versus antidepressants plus second-generation antipsychotic augmentation in treatment-resistant unipolar depression. AB - Patients with treatment-resistant unipolar depression (TRD) are treated with antidepressant combinations (ADs) or with second-generation antipsychotics plus AD (SGA+AD) augmentation; however, the clinical characteristics, the factors associated independently with response to SGA+AD, and the outcome trajectories have not yet been characterized. We performed a naturalistic study on the latest stable trial (medication unchanged for about 3 months) in 86 TRD patients with resistance to at least two ADs trials, who received ADs (n=36) or SGA+AD (n=50) treatments. Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D17), and other scales were administered before (T0) and after the latest 3-month stable trial (T3). Compared to ADs, the SGA+AD group showed increased percentage of depression with psychotic features, comorbidity for personality disorders and substance use disorders (SUD), higher number of failed ADs pharmacotherapies and depressive symptoms at T0 on all scales (P<0.001). Compared to T0, both treatments significantly decreased depressive symptoms on MADRS and HAM-D17 at T3 (P<0.001); however, the SGA+AD augmentation produced a greater decline in mean score. Logistic regression analysis indicated that psychotic features, personality disorders, and SUD were independently associated with SGA+AD treatment. Given the greater improvement in depression following SGA+AD augmentation, SGA augmentation should be indicated as a first line treatment in severe TRD with psychotic features, SUD, and personality disorders. PMID- 28906326 TI - Tissue Engineering Strategies for Auricular Reconstruction. AB - Simulating natural characteristics and aesthetics in reconstructed ears has provided a complex 3-dimensional puzzle for those treating patients with microtia. Costochondral grafts remain the gold standard for autologous reconstruction. However, other options such as Medpor and prosthetics are indicated depending on patient circumstances and personal choice. Research into tissue engineering offers an alternative method to a traditional surgical approach that may reduce donor-site morbidity. However, tissue engineering for microtia reconstruction brings new challenges such as cell sourcing, promotion of chondrogenesis, scaffold vascularization, and prevention of scaffold contraction. Advancements in 3D printing, nanofiber utilization, stem cell technologies, and decellularization techniques have played significant roles in overcoming these challenges. These recent advancements and reports of a successful clinical-scale study in an immunocompetent animal suggest a promising outlook for future clinical application of tissue engineering for auricular reconstruction. PMID- 28906327 TI - Role of Negative Orbit Vector in Orbital Blow-Out Fractures. AB - BACKGROUND: Negative orbit vector is defined as the most anterior globe portion protrudes past the malar eminence. The aim of the study was to evaluate the relationship between negative orbit vector and blow-out fracture location analyzing the distance between the anterior corneal surface and orbital bone with facial soft tissue in medial and orbital floor blow out fractures using orbital computed tomography (CT). METHODS: Seventy-seven patients diagnosed with blow-out fractures involving the medial or orbital floor were included. Distances from the anterior cornea to lower lid fat, inferior orbital wall, inferior orbital rim, and anterior cheek mass were measured using orbital CT scans. The proportion of negative orbit vector and measured distanced were compared between medial wall fracture and orbital floor fracture. Medical records including age, sex, concomitant ophthalmic diagnosis, and nature of injury were retrospectively reviewed. RESULTS: Forty-three eyes from 43 patients diagnosed with medial wall fracture and 34 eyes from 34 patients diagnosed with orbital floor fracture were included. There was no significant difference in the distance from the anterior cornea to lower lid fat (P = 0.574), inferior orbital wall (P = 0.494), or orbital rim (P = 0.685). The distance from anterior cornea to anterior cheek mass was significantly different in medial wall fracture (-0.19 +/- 3.49 mm) compared with orbital floor fracture (-1.69 +/- 3.70 mm), P = 0.05. Negative orbit vector was significantly higher in orbital floor fracture patients (24 among 34 patients, 70.6%) compared with those with medial wall fractures (19 among 43 patients, 44.2%) (P = 0.04). CONCLUSIONS: Patients presenting with a negative orbit vector relationship when the most anterior portion of globe protruded past the anterior cheek mass and malar eminence were more likely to develop orbital floor fracture than medial wall fracture. PMID- 28906328 TI - The Americleft Project: A Modification of Asher-McDade Method for Rating Nasolabial Esthetics in Patients With Unilateral Cleft Lip and Palate Using Q sort. AB - The purpose of this study was to investigate ways to improve rater reliability and satisfaction in nasolabial esthetic evaluations of patients with complete unilateral cleft lip and palate (UCLP), by modifying the Asher-McDade method with use of Q-sort methodology. Blinded ratings of cropped photographs of one hundred forty-nine 5- to 7-year-old consecutively treated patients with complete UCLP from 4 different centers were used in a rating of frontal and profile nasolabial esthetic outcomes by 6 judges involved in the Americleft Project's intercenter outcome comparisons. Four judges rated in previous studies using the original Asher-McDade approach. For the Q-sort modification, rather than projection of images, each judge had cards with frontal and profile photographs of each patient and rated them on a scale of 1 to 5 for vermillion border, nasolabial frontal, and profile, using the Q-sort method with placement of cards into categories 1 to 5. Inter- and intrarater reliabilities were calculated using the Weighted Kappa (95% confidence interval). For 4 raters, the reliabilities were compared with those in previous studies. There was no significant improvement in inter-rater reliabilities using the new method. Intrarater reliability consistently improved. All raters preferred the Q-sort method with rating cards rather than a PowerPoint of photos, which improved internal consistency in rating compared to previous studies using the original Asher-McDade method. All raters preferred this method because of the ability to continuously compare photos and adjust relative ratings between patients. PMID- 28906330 TI - Does Fat Grafting Influence Postoperative Edema in Orthognathic Surgery? AB - PURPOSE: Autologous fat grafting is a useful adjunctive procedure to orthognathic surgery and may also confer anti-inflammatory properties. The purpose of this study is to answer the clinical question: among patients undergoing orthognathic operations, what are the effects of fat grafting on facial edema (magnitude, duration, and rate of decrease)? METHODS: A retrospective cohort study was performed. Three-dimensional photos (Canfield, Fairfield, NJ) from preoperative and a series of postprocedure time-points were analyzed. The data set was divided into a fat-grafted cohort and a non-fat-grafted cohort and later analyzed using paired and unpaired t tests and linear regressions to determine significant correlations. RESULTS: One hundred sixteen pre- and postoperative three dimensional photo data sets were included. The sample included 29 subjects. The facial volume was analyzed both overall and comparing each subgroup (orthognathic vs. orthognathic + fat grafting group). Postoperative facial volume increase averaged 23.7% for the entire cohort (FG and nFG). By week 12, the swelling decreased about 62% from baseline. In all patients, there was a statistically significant decrease in facial volume with time. In the fat-grafted group, despite adding volume, the facial volume was equal to the non-fat-grafted group at week 1, yet the rate of decrease was faster through week 12. CONCLUSION: The majority of postoperative facial edema decreases by 12 weeks following orthognathic surgery. In this cohort of patients, despite the addition of volume, concurrent fat grafting lessened postoperative edema, and led to a greater magnitude and speed of resolution. PMID- 28906331 TI - Mandibular Surgical Navigation: An Innovative Guiding Method. AB - Mandibular osteotomies are usually required to treat craniomaxillofacial disorders. Losses of mandibular continuity result in esthetic and functional deficiency. During the past 30 years, the spread of the computer-assisted surgery techniques, rapid prototyping, and surgical navigation technique has improved the reliability and the outcomes of mandibular resections and reconstructions, by providing realtime feedback to surgeon. Recent studies reported the feasibility and the precision of surgical navigation applied to mandibular surgical resection and reconstruction with fibula flap but none of them describes a method to navigate the jaw allowing its full motility during the operation. To our knowledge, this is the first-time description of such a kind of method to navigate the jaw positioning the dynamic reference frame directly on the mandibular branch to maintain the full mobility of the mandible. The method described in our series has allowed an accurate surgical navigation of the jaw without the need of intermaxillary fixation. This technique could greatly facilitate resection and reconstructive surgical procedures of the jaw while ensuring precision and accuracy. The encouraging results obtained in the present report suggest to further investigate the possibilities of this technique to better define the method and its indications. PMID- 28906332 TI - A Novel Dissector and Needle Holder Within One Tool. PMID- 28906333 TI - Partial Scalp and Auricula Avulsion in a Child. PMID- 28906334 TI - Tear Trough Deformity: Study of Filling Procedures for Its Correction. AB - The aim of this work is to discuss the anatomy of the tear trough region with relative danger areas, and to describe 2 different options to correct this deformity.The tear trough is a concave deformity of the orbital fat that is noticeable as a result of inherited anatomic differences and aging. However, the periorbital region is a complex area with its own septa and ligaments, fat compartments, muscles, vascularization, and lymphatic drainage and presents anatomic characteristics that must be taken into account in order to achieve good results and avoid complications.The use of hyaluronic acid gel or autologous fat for soft tissue correction is a good option.A total of 96 patients with periorbital hollowing were divided into 2 groups; each group received a different treatment, from December of 2013 to December of 2015, with hyaluronic- or lipo filling. PMID- 28906335 TI - Stagnant Water Is Bound to Corrupt. PMID- 28906336 TI - Interobserver Consistency of Drug-Induced Sleep Endoscopy in Diagnosing Obstructive Sleep Apnea Using a VOTE Classification System. AB - OBJECTIVES: To explore the interobserver consistency of drug-induced sleep endoscopy (DISE) for patients with obstructive sleep apnea syndrome (OSAS) and review the current literature. METHODS: In total, 55 patients with an apnea hypopnea index >5, as determined by on overnight sleep study, were included in this study, 45 males and 10 females, with an average age of 46.87 +/- 10.06 years old (range, 19-71). For all OSAS patients, DISE was performed by the same surgeon, which was recorded digitally. The video recordings of DISE were evaluated independently by 3 experienced surgeons who were asked to note his or her decisions as the pattern, site, and degree of upper airway collapse using a VOTE (velum, oropharynx lateral wall, tongue base, and the epiglottis) classification system. RESULTS: Interobserver consistency in the diagnosis of velum-related obstruction in anteroposterior, lateral, and concentric configurations ranged from poor to good. Only significant interobserver consistency among observers A and B was obtained in the diagnosis of oropharynx related obstruction in the lateral configuration (concordance 60.0%, kappa: 0.365, P < 0.05). Interobserver consistency in the diagnosis of the tongue related collapse in an anteroposterior configuration, the epiglottis-related collapse in an anteroposterior and lateral configuration ranged from fair to moderate (all kappa values >0.20, all P values < 0.05). CONCLUSION: Our data suggested that the interobserver consistency of DISE ranged from poor to good. Therefore, further studies with larger numbers of patients are needed to standardize DISE procedures, training, and interpretation. PMID- 28906337 TI - A Three-Dimensional Study of Midfacial Changes Following Le Fort II Distraction With Zygomatic Repositioning in Syndromic Patients. AB - Le Fort II distraction with zygomatic repositioning introduced the ability to restore central midfacial height and convexity independent of changes in orbital morphology. This study analyzes midfacial and orbital morphology before and after Le Fort II distraction with zygomatic repositioning.All patients who underwent Le Fort II Distraction with zygomatic repositioning between 2013 and 2015 were included. Two- and 3-dimensional measurements were made using 3dMD Vultus software to assess canthal tilt, nasolabial angle, ratio of midfacial to lower facial height, and absolute change in nasal length. Presence of an open bite and Angle classification were assessed before and after surgery.Four patients underwent segmental midface advancement using Le Fort II distraction with zygomatic repositioning. Associated diagnoses included Apert syndrome, Goldenhar syndrome, and achondroplasia. Changes in facial dimensions included: 3.19 degrees improvement in canthal tilt (range -4.7 degrees to 8.4 degrees ), 9 degrees change in nasolabial angle (range -1.0 degrees to 19 degrees ), and 0.69 cm increase in absolute nasal length (range 0.2-0.94 cm). Mean ratio of midfacial to lower facial height was 0.79 preoperatively and 0.89 postoperatively. Preoperatively, all patients demonstrated Angle class III with 3 of 4 patients demonstrating anterior open bite. All achieved closure of open bite and demonstrated class I or II occlusion. No complications were observed.Le Fort II distraction with zygomatic repositioning resulted in normalization of midfacial soft tissue landmarks. This form of advancement demonstrates the ability to selectively improve midfacial height and canthal tilt while restoring normal occlusion. PMID- 28906338 TI - A Pharmacokinetics, Efficacy, and Safety Study of Gadoterate Meglumine in Pediatric Subjects Aged Younger Than 2 Years. AB - OBJECTIVES: The primary objective of this study was to investigate the pharmacokinetic profile of gadoterate meglumine in pediatric patients younger than 2 years; the secondary objectives were to document its efficacy and safety. MATERIAL AND METHODS: This was a Phase IV open-label, prospective study conducted in 9 centers (4 countries). Forty-five patients younger than 2 years with normal estimated glomerular filtration rate and scheduled to undergo routine gadolinium enhanced magnetic resonance imaging (MRI) of any organ were included and received a single intravenous injection of gadoterate meglumine (0.1 mmol/kg). To perform the population pharmacokinetics analysis, 3 blood samples per subject were drawn during 3 time windows at time points allocated by randomization. RESULTS: Gadoterate meglumine concentrations were best fitted using a 2-compartmental model with linear elimination from central compartment. The median total clearance adjusted to body weight was estimated at 0.06 L/h per kg and increased with estimated glomerular filtration rate according to a power model. The median volume of distribution at steady state (Vss) adjusted to body weight was estimated at 0.047 L/kg. Estimated median terminal half-life (t1/2beta) was 1.35 h, and the median systemic exposure (area under the curve) was 1591 MUmol h/L. Efficacy was assessed by comparing precontrast +postcontrast images to precontrast images in a subset of 28 subjects who underwent an MRI examination of brain, spine, and associated tissues. A total of 28 lesions were identified and analyzed in 15 subjects with precontrast images versus 30 lesions in 16 subjects with precontrast + postcontrast images. Lesion visualization was improved with a mean (SD) increase in scores at subject level of 0.7 (1.0) for lesion border delineation, 0.9 (1.6) for internal morphology, and 3.1 (3.2) for contrast enhancement. Twenty-six adverse events occurred postinjection in 13 subjects (28.9%), including 3 serious reported in 1 subject (2.2%). One subject (2.2%) experienced 1 rash of moderate intensity considered as related to gadoterate meglumine. CONCLUSIONS: The pharmacokinetic profile of gadoterate meglumine after a single intravenous injection of 0.1 mmol/kg was appropriately described in newborns and infants younger than 2 years, for whom no dose adjustment is required. The improved efficacy of gadoterate meglumine for contrast-enhanced MRI examination of brain, spine, and associated tissues, as well as its good safety profile, was also demonstrated in this population. PMID- 28906339 TI - Multiparametric Magnetic Resonance Imaging of Prostate Cancer Bone Disease: Correlation With Bone Biopsy Histological and Molecular Features. AB - OBJECTIVES: The aim of this study was to correlate magnetic resonance imaging (MRI) of castration-resistant prostate cancer (CRPC) bone metastases with histological and molecular features of bone metastases. MATERIALS AND METHODS: Forty-three bone marrow biopsies from 33 metastatic CRPC (mCRPC) patients with multiparametric MRI and documented bone metastases were evaluated. A second cohort included 10 CRPC patients with no bone metastases. Associations of apparent diffusion coefficient (ADC), normalized b900 diffusion-weighted imaging (nDWI) signal, and signal-weighted fat fraction (swFF) with bone marrow biopsy histological parameters were evaluated using Mann-Whitney U test and Spearman correlations. Univariate and multivariate logistic regression models were analyzed. RESULTS: Median ADC and nDWI signal was significantly higher, and median swFF was significantly lower, in bone metastases than nonmetastatic bone (P < 0.001). In the metastatic cohort, 31 (72.1%) of 43 biopsies had detectable cancer cells. Median ADC and swFF were significantly lower and median nDWI signal was significantly higher in biopsies with tumor cells versus nondetectable tumor cells (898 * 10 mm/s vs 1617 * 10 mm/s; 11.5% vs 62%; 5.3 vs 2.3, respectively; P < 0.001). Tumor cellularity inversely correlated with ADC and swFF, and positively correlated with nDWI signal (P < 0.001). In serial biopsies, taken before and after treatment, changes in multiparametric MRI parameters paralleled histological changes. CONCLUSIONS: Multiparametric MRI provides valuable information about mCRPC bone metastases. These data further clinically qualify DWI as a response biomarker in mCRPC. PMID- 28906340 TI - Contemporary approach to joint hypermobility and related disorders. AB - PURPOSE OF REVIEW: Joint hypermobility is a common, although largely ignored physical sign. Joint hypermobility is often asymptomatic but may be a feature of an underlying genetic disorder with systemic manifestations. The present article presents a comprehensive approach to considering joint hypermobility and clinically related issues in children and adults. RECENT FINDINGS: Ehlers-Danlos syndrome (EDS) is an umbrella term for various Mendelian connective tissue disorders sharing joint hypermobility, skin hyperextensibility, and tissue fragility. Hypermobile EDS is the default diagnosis in many individuals and still lacks of any confirmatory test. There is also a continuous spectrum of phenotypes between asymptomatic, nonsyndromic joint hypermobility, and hypermobile EDS. In 2017, a new international classification of EDSs, joint hypermobility, and related disorders was published. EDSs are now classified in 13 different variants because of mutations in 19 genes. The gap between joint hypermobility and hypermobile EDS is filled by the descriptive diagnosis of 'hypermobility spectrum disorders'. Alongside the new criteria recommendations for the assessment and management of selected issues related to joint hypermobility such as fatigue and physical therapy have also been published by expert panels. SUMMARY: Asymptomatic, nonsyndromic joint hypermobility, hypermobility spectrum disorders and EDS (particularly, the hypermobile type) are the most common phenotypes in children and adults with joint hypermobility. Their prompt recognition is crucial to the appropriate application of evidence-based management and the reduction in burden of ill health. PMID- 28906341 TI - The neurophysiology of paediatric movement disorders. AB - PURPOSE OF REVIEW: To demonstrate how neurophysiological tools have advanced our understanding of the pathophysiology of paediatric movement disorders, and of neuroplasticity in the developing brain. RECENT FINDINGS: Delineation of corticospinal tract connectivity using transcranial magnetic stimulation (TMS) is being investigated as a potential biomarker for response to therapy. TMS measures of cortical excitability and neuroplasticity are also being used to investigate the effects of therapy, demonstrating neuroplastic changes that relate to functional improvements. Analyses of evoked potentials and event-related changes in the electroencephalogaphy spectral activity provide growing evidence for the important role of aberrant sensory processing in the pathophysiology of many different movement disorders. Neurophysiological findings demonstrate that children with clinically similar phenotypes may have differing underlying pathophysiology, which in turn may explain differential response to therapy. Neurophysiological parameters can act as biomarkers, providing a means to stratify individuals, and are well suited to provide biofeedback. They therefore have enormous potential to facilitate improvements to therapy. SUMMARY: Although currently a small field, the role of neurophysiology in paediatric movement disorders is poised to expand, both fuelled by and contributing to the rapidly growing fields of neuro-rehabilitation and neuromodulation and the move towards a more individualized therapeutic approach. PMID- 28906342 TI - Deep brain stimulation for monogenic dystonia. AB - PURPOSE OF REVIEW: Deep brain stimulation (DBS) has recently emerged as an important management option in children with medically refractory dystonia. DBS is most commonly used, best studied, and thought to be most efficacious for a select group of childhood or adolescent onset monogenic dystonias (designated with a standard 'DYT' prefix). We review how to clinically recognize these types of dystonia and the relative efficacy of DBS for key monogenic dystonias. RECENT FINDINGS: Though used for dystonia in adults for several years, DBS has only lately been used in children. Recent evidence shows that patients with shorter duration of dystonia often experience greater benefit following DBS. This suggests that early recognition of the appropriate dystonic phenotypes and consideration of DBS in these patients may improve the management of dystonia. SUMMARY: DBS should be considered early in patients who have medically refractory dystonia, especially for the monogenic dystonias that have a high response rate to DBS. It is important to differentiate between these monogenic dystonias and dystonias of other causes to properly prognosticate for these patients and to determine whether DBS is an appropriate management option. PMID- 28906343 TI - Movement disorders: an update. PMID- 28906344 TI - Value of the visual and semiquantitative analysis of carbon-11-methionine PET/CT in brain tumors' recurrence versus post-therapeutic changes. AB - To compare the visual and semiquantitative analysis of carbon-11-methionine (C MET) PET/computed tomography (CT) images in patients with primary brain tumors and suspected recurrence, persistence, or necrotic post-therapeutic changes. A total of 41 consecutive C-MET-PET/CT scans on 35 (21 men, mean age 44.1+/-16.6 years) patients were requested for MRI suspicion of recurrent or persistent primary tumor after therapy. The C-MET PET/CT were obtained 20 min after an intravenous injection of 555-740 MBq (15-20 mCi) of C-MET. Both visual and semiquantitative evaluations were performed comparing C-MET uptake between suspicious areas and different lesion/normal-to-background ratios. The final diagnosis was established by histological examination in 12 cases and clinical and MRI follow-up in 29 cases. Visual analyses were positive in 27 (63.4%) and negative in 14 (36.6%) of the C-MET PET/CT. The sensitivity was 83.9%, specificity was 90.0%, positive predictive value was 96.3%, negative predictive value was 64.3% and accuracy was 71.4%. For the semiquantitative analysis, all the lesion/normal-to-background ratios could differentiate between tumor and nontumor (P<0.001), the lesion/contralateral parenchyma (L/CP) maximum standardized uptake value (SUVmax) being the index with the highest area under de curve (0.938). Applying an L/CP SUVmax index of 1.21, the sensitivity was 89.3%, specificity was 90.0%, positive predictive value was 96.1%, negative predictive value was 75%, and accuracy was 82.9%. C-MET-PET/CT was a useful technique to differentiate post-therapeutic changes from tumor presence in treated patients with brain neoplasm in whom cerebral MRI is nonconclusive, showing a high diagnostic performance. Our results showed only slight differences between visual analysis methods and the L/CP SUVmax ratio, the best of the semiquantitative methods. PMID- 28906345 TI - Folic acid exerts antidepressant effects by upregulating brain-derived neurotrophic factor and glutamate receptor 1 expression in brain. AB - Folic acid is a vitamin with a variety of pharmacological effects. The present study aims to explore the beneficial effects of folic acid on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including open-field test, tail suspension test, and forced swimming test were used to evaluate the antidepressant effects of folic acid. Then the changes of brain 5 hydroxytryptamine (5-HT) concentration, brain-derived neurotrophic factor (BDNF), glutamate receptor 1 (GluR1) expression levels, and synaptic organization were assessed to explore the antidepressant mechanisms of folic acid. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, BDNF, and GluR1 expression in the hippocampus and association cortex. In conclusion, the results showed that folic acid significantly improved depression-like behaviors in CUMS-induced rats, and its antidepressant effects might be related to the increase of brain 5-HT concentration, BDNF and GluR1 expression, and repair of synaptic organization in the brain. PMID- 28906346 TI - Time course of changes in corticospinal excitability after short-term forearm/hand immobilization. AB - The short-term joint immobilization induces a decrease of corticospinal excitability; however, detailed time course of the immobilization-induced central nervous system changes and their extent have not yet been clarified. To evaluate the time course of changes in corticospinal excitability during forearm/hand immobilization for 24 h and investigate the effect on muscle strength, adhesive casting tape was used to immobilize the nondominant forearm/hand. The amplitude of the motor-evoked potential of the flexor pollicis brevis muscle induced by transcranial magnetic stimulation was measured during immobilization and after cast removal. The muscle strength was evaluated after the termination of immobilization. The resting motor-evoked potential recorded from flexor pollicis brevis muscle showed a significant decrease 3 h after initiation of immobilization and gradually declined further until the end of immobilization. It then increased over 2 h after cast removal, but was still significantly below baseline. However, no significant difference from baseline was observed at 3 h. Both pinch power and integrated electromyogram were significantly reduced by immobilization, and then gradually returned to baseline after the cast was removed. These results indicate that short-term forearm/hand immobilization rapidly reduces corticospinal excitability, and this change is rapidly reversed after resumption of movement. PMID- 28906347 TI - Exercise-induced Bronchoconstriction with Firefighting Contained Breathing Apparatus. AB - PURPOSE: Protective self-contained breathing apparatus (SCBA) used for firefighting delivers decompressed (cold) dehumidified air that may enhance the severity of exercise-induced bronchoconstriction (EIB) in those susceptible. We investigated the effect of SCBA during exercise on airway caliber in people with asthma and healthy controls. METHODS: Two exercise challenges (EC) designed to elicit EIB were performed on separate days within 1 wk. The initial challenge was breathing room air (ECRA) with workload titrated to elicit >60% estimated maximum voluntary ventilation. The exercise intensity was repeated for the second challenge using SCBA (ECSCBA). Forced expiratory volume in 1 s (FEV1) was measured before and up to 20 min after exercise. Bronchial hyperresponsivenss (BHR) to the hyperosmolar mannitol test was measured in the subjects with asthma. RESULTS: Twenty subjects with current asthma (mean [SD]: age 27 [6] yr) and 10 healthy controls (31 [5] yr, P = 0.1) were studied. The percent fall in FEV1 after ECSCBA was greater in the mannitol-positive asthma subjects (14.4% [15.1%]) compared with mannitol-negative asthmatic subjects (1.6% [1.7%]; P = 0.02) and controls (2.3% [2.3%]; P = 0.04). The FEV1 response was not different between ECRA and ECSCBA (0.49% [5.57%]; P = 0.6). No BHR to mannitol (n = 7) was highly sensitive for identifying a negative response to ECSCBA (negative predictive value 100%). CONCLUSIONS: The SCBA does not increase the propensity or severity for EIB in subjects with BHR. Those subjects with asthma but no BHR to inhaled mannitol did not exhibit EIB. The BHR to a hyperosmolar stimulus maybe considered a useful screening tool for potential recruits with a history of asthma. PMID- 28906348 TI - Effect of Anodal Transcranial Direct Current Stimulation of the Motor Cortex on Elbow Flexor Muscle Strength in the Very Old. AB - BACKGROUND AND PURPOSE: Muscle weakness predisposes older adults to a fourfold increase in functional limitations and has previously been associated with reduced motor cortex excitability in aging adults. The purpose of this study was to determine whether a single session of anodal transcranial direct current stimulation (tDCS) of the motor cortex would increase elbow flexion muscle strength and electromyographic (EMG) amplitude in very old individuals. METHODS: Eleven very old individuals-85.8 (4.3) years-performed 3 maximal isometric elbow flexion contractions before and after 20 minutes of sham or anodal tDCS on different days. Order of stimulation was randomized, and the study participants and investigators were blinded to condition. In addition, voluntary activation capacity of the elbow flexors was determined by comparing voluntary and electrically evoked forces. RESULTS: Anodal tDCS did not alter muscle strength or EMG activity in comparison to sham stimulation. Elbow flexion voluntary activation capacity was very high among the study participants: 99.3% (1.8%). CONCLUSION: Contrary to our hypothesis, we observed no effect of anodal tDCS and no impairment in elbow flexor voluntary activation capacity in the very old. Whether anodal tDCS would exert a positive effect and support our initial hypothesis in another muscle group that does exhibit impairments in voluntary activation in older adults is a question that is still to be addressed. PMID- 28906349 TI - Intestinal obstruction due to kaposiform hemangioendothelioma in a 1-month-old infant: A case report. AB - RATIONALE: Kaposiform hemangioendothelioma (KHE) is an aggressive vascular tumor, mainly occurring in infants and young children and previously reported cases were mainly cutaneous or visceral form. Intestinal kaposiform hemangioma was first reported in 2012. Intestinal type KHE showed better prognosis if the lesion was limited in the gastrointestinal tract and coagulopathy was not accompanied. Since the number of reported cases is small, further study for treatment options and prognosis need to be done. PATIENT CONCERNS: We described the case of a 1-month old female who had abdominal distention and bilious vomiting. DIAGNOSES: She was suspected as intestinal obstruction after diagnostic work up. INTERVENTIONS: Surgical exploration was performed and jejunal obstruction with a mass was identified. Small bowel segmental resection and anastomosis was performed. OUTCOMES: The patient discharged with symptom free. Through the pathological examination, the mass was identified as intestinal type KHE. LESSONS: Intestinal KHE can cause bowel obstruction and be managed successfully with complete surgical resection. More cases should be reported and further evaluation for treatment options and prognosis evaluation is necessary. PMID- 28906350 TI - The hundred most-cited publications in microbiota of diabetes research: A bibliometric analysis. AB - BACKGROUND: Bibliometric analysis is an approach to evaluate the circumstances and trends in specific research field over time and to provide inspiration in future research and policy. Researches have a tremendous increase focus on the role of the microbiota in the development of diabetes in recent years; however, there is no published literature conducting a bibliometric analysis to explore the tendency. The aim of this study was to provide a detailed evaluation of the hundred most cited articles in microbiota of diabetes research. METHODS: The database of the Web of Science was utilized for identification of articles. The top 100 were selected for further analysis of authorship, number of citations, article type, source journal, geographic origin, and interactions. RESULTS: The articles selected were published from 2007 to 2015. The total citations ranged from 1289 to 35, citation density ranged from 163.75 to 6.5. The article type included basic science (n = 32), review (n = 29), expert opinion (n = 19), cross sectional study (n = 12), RCT (n = 3), and others (n = 5). The study content included pathogenesis (n = 58), risk factor (n = 11), modifying of intestinal microbiota (n = 10), prebiotic treatment (n = 8), antibiotic treatment (n = 4), diet control (n = 4), and others (n = 5). The 100 most cited articles were published in 59 journals. Among them, Diabetes (n = 7), Diabetologia (n = 7), and Plos one (n = 7) published the most T100 articles. In total, 24 countries and 174 scientific research institutions participated in those researches. USA (n = 32) and Belgium (n = 22) were the leading countries in this field, followed by France (n = 18) and Finland (n = 16). Patrice D. Cani contributed the most top cited articles (n = 15). CONCLUSION: This bibliometric study is likely to include a list of intellectual milestones focused on microbiota of diabetes research in the past decade, which provides insights into the circumstances and trends in preventing and treating diabetes from a new perspective. PMID- 28906351 TI - Prevalence, evolution, and related risk factors of kidney disease among Spanish HIV-infected individuals. AB - Prevalence of kidney disease (KD) is increasing among human immunodeficiency virus (HIV)-infected population. Different factors have been related, varying on different published series.The objectives were to study prevalence of KD in those patients, its evolution, and associated risk factors.An observational cohort study of 1596 HIV-positive patients with cross-sectional data collection in 2008 and 2010 was conducted. We obtained clinical and laboratory markers, and registered previous or current treatment with tenofovir (TDF) and indinavir (IDV). The sample was divided according to estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) equation. Group 1: eGFR <=60 mL/min/1.73 m; group 2: eGFR >60 mL/min/1.73 m.Among the patients, 76.4% were men, mean age (SD) 45 +/- 9 years, time since diagnose of HIV 14 +/- 7 years, and 47.2% of the patients received previous treatment with TDF and 39.1% with IDV. In 2008, eGFR <=60: 4.9% (91.4% of them in chronic kidney disease [CKD] stage 3, eGFR 59-30 mL/min); this group was older, presented higher fibrinogen levels, and more patients were treated previously with TDF and IDV. In 2010, eGFR <=60: 3.9% (87.1% stage 3 CKD). The 2.4% of cohort showed renal improvement and 1.3% decline of renal function over time. The absence of hypertension and treatment with TDF were associated with improvement in eGFR. Increased age, elevated fibrinogen, decreased albumin, diabetes mellitus, hyperTG, and worse virological control were risk factors for renal impairment.The HIV-positive patients in our area have a CKD prevalence of 4% to 5% (90% stage 3 CKD) associated with ageing, inflammation, worse immune control of HIV, TDF treatment, and metabolic syndrome. PMID- 28906352 TI - Clinical and angiographic outcomes following endovascular treatment of very small (3 mm or smaller) intracranial aneurysm: A single-center experience. AB - Treatments for very small (3 mm or smaller) intracranial aneurysms (VSAs) remain controversial. The aim of this study was to evaluate the efficacy of endovascular treatment for VSAs and to evaluate clinical risk factors associated with complications.This retrospective study enrolled 82 VSA patients who underwent coil embolization in our institution. Angiographic outcomes were assessed according to the Meyers classification. The clinical results were evaluated using the modified Rankin scale (mRS) immediately after coiling, at discharge, and during follow-up. A Mann-Whitney U test was performed for non-normally distributed continuous variables. A Pearson chi test or Fisher's exact test was performed for categorical variables.Among 82 aneurysms, 54 were treated with stent-assisted coiling (SAC) embolization. Thromboembolic complications were seen in 2 patients (2.4%). Intraoperative rupture occurred in 4 patients (4.9%). Other adverse events occurred in 2 patients (2.4%). Two patients (2.4%) had permanent disabling neurologic deficit (mRS 3-6) because of complications. The overall mortality rate was 1.2%. Adverse events were correlated with the location of aneurysms (P = .02), Fisher grade (P = .01), and treatment experience (P = .03). Patients with middle cerebral artery (MCA) bifurcation and anterior communicating artery (ACoA) aneurysms were more likely to experience a higher incidence of complication. Thirty-five patients underwent angiographic follow-up. The complete occlusion rate improved from an immediate 37.8% to 80.0% at follow-up.In the short term, coiling is a safe and effective approach for the treatment of VSAs. SAC may be associated with a high rate of further occlusion during short-term follow-up. Endovascular treatment of VSAs at middle cerebral artery bifurcation or anterior communicating artery is associated with a higher incidence of complications. PMID- 28906353 TI - Immunomodulatory treatments for persistent and chronic immune thrombocytopenic purpura: A PRISMA-compliant systematic review and meta-analysis of 28 studies. AB - BACKGROUND: Corticosteroid sparing is required in 15% to 40% of adults with persistent or chronic primary immune thrombocytopenic purpura (ITP). Herein, the efficacy of immunomodulatory drugs (dapsone, interferon alpha, danazol, and hydroxychloroquine as second-third-line therapies in ITP is investigated. METHODS: MEDLINE was searched for studies that included patients with persistent or chronic primary ITP and published before the end of December 2014. Two investigators independently extracted data regarding study design, patient characteristics, dosage schedule, time to response, and occurrence of adverse events. The pooled overall response rate (ORR; platelet count >30 * 10 L) and the complete response rate (CRR; platelet count >100 * 10 L) were evaluated to determine drug efficacy by calculating weighted mean proportion using a fixed or random-effects model according to heterogeneity (I > 50%). The study was performed following the MOOSE and PRISMA guidelines. RESULTS: A total of 28 studies (415 patients) were included (dapsone: k = 7 studies, n = 80; danazol: k = 12, n = 224; interferon alpha: k = 8, n = 83; hydroxychloroquine: k = 1, n = 28). The mean patient age was 50 years (female sex 70%, splenectomy 47%). The ORR and CRR were 55% (95% CI: 44%-66%, I = 0%) and 21% (95% CI: 13%-31%, I = 0%), respectively, for dapsone; 42% (95% CI: 22%-65%, I = 63%) and 18% (95% CI: 10% 29%, I = 9%), respectively, for interferon alpha; and 58% (95% CI: 42%-72%, I = 67%) and 29% (95% CI: 19%-42%, I = 63%), respectively, for danazol. The ORR was 50% (95% CI: 32%-67%) for hydroxychloroquine (data not available for CRR). Meta regression analysis found a correlation between the ORR for interferon alpha and the splenectomized status of the patient (P = .02) and between the CRR for danazol and disease duration (P < .001). In total, 73%, 51%, 30%, and 0% of patients who received danazol, dapsone, interferon alpha, and hydroxychloroquine experienced side effects, respectively. CONCLUSION: The ORR was equivalent for hydroxychloroquine, danazol, and dapsone in ITP. Regarding their low CRR, patients at high risk of infection or at low risk of bleeding should benefit from these treatments. Thanks to their best efficacy and safety profiles, dapsone and hydroxychloroquine in patients with antinuclear antibodies should be preferred over danazol and interferon alpha. PMID- 28906354 TI - The influence of renal dialysis and hip fracture sites on the 10-year mortality of elderly hip fracture patients: A nationwide population-based observational study. AB - Hip fractures in older people requiring dialysis are associated with high mortality. Our study primarily aimed to evaluate the specific burden of dialysis on the mortality rate following hip fracture. The secondary aim was to clarify the effect of the fracture site on mortality. A retrospective cohort study was conducted using Taiwan's National Health Insurance Research Database to analyze nationwide health data regarding dialysis and non-dialysis patients >=65 years who sustained a first fragility-related hip fracture during the period from 2001 to 2005. Each dialysis hip fracture patient was age- and sex-matched to 5 non dialysis hip fracture patients to construct the matched cohort. Survival status of patients was followed-up until death or the end of 2011. Survival analyses using multivariate Cox proportional hazards models and the Kaplan-Meier estimator were performed to compare between-group survival and impact of hip fracture sites on mortality. A total of 61,346 hip fracture patients were included nationwide. Among them, 997 dialysis hip fracture patients were identified and matched to 4985 non-dialysis hip fracture patients. Mortality events were 155, 188, 464, and 103 in the dialysis group, and 314, 382, 1505, and 284 in the non-dialysis group, with adjusted hazard ratios (associated 95% confidence intervals) of 2.58 (2.13 3.13), 2.95 (2.48-3.51), 2.84 (2.55-3.15), and 2.39 (1.94-2.93) at 0 to 3 months, 3 months to 1 year, 1 to 6 years, and 6 to 10 years after the fracture, respectively. In the non-dialysis group, survival was consistently better for patients who sustained femoral neck fractures compared to trochanteric fractures (0-10 years' log-rank test, P < .001). In the dialysis group, survival of patients with femoral neck fractures was better than that of patients with trochanteric fractures only within the first 6 years post-fracture (0-6 years' log-rank, P < .001). Dialysis was a significant risk factor of mortality in geriatric hip fracture patients. Survival outcome was better for non-dialysis patients with femoral neck fractures compared to those with trochanteric fractures throughout 10 years. However, the survival advantage of femoral neck fractures was limited to the first 6 years postinjury among dialysis patients. PMID- 28906355 TI - Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early-intermediate stage hepatocellular carcinoma: A post hoc analysis of the START trial. AB - BACKGROUND/OBJECTIVE: The survival benefit of treatment for unresectable hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE) combined with sorafenib remains uncertain. We compared the survival of patients treated with TACE and sorafenib with that of patients treated with TACE alone. METHODS: This was a post hoc analysis of the Study in Asia of the Combination of TACE with Sorafenib in Patients with HCC (START) trial. All patients who received TACE and interrupted dosing of sorafenib for early or intermediate-stage HCC in Taiwan from 2009 to 2010 were recruited into the TACE and sorafenib group. They were randomly matched 1:1 by age, sex, Child-Pugh score, tumor size, tumor number, and tumor stage with patients from Taichung Veterans General Hospital in Taiwan who received TACE alone and who fulfilled the selection criteria of the START trial during the same time period (control group). Patient survival [cumulative incidence and hazard ratio (HR)] of the 2 groups were analyzed and compared. RESULTS: The baseline characteristics of the 36 patients in each group were similar. Tumor response rates were significantly better in the TACE and sorafenib group (P < .04). Overall survival of the TACE and sorafenib group was also significantly better than that of the control (TACE alone) group over the 2 years [78%, 95% confidence interval (95% CI) 64-91 vs 49, 95% CI 32-66; P = .012]. In the multivariate regression analysis, TACE and sorafenib was found to be independently associated with a decreased risk of mortality (HR 0.33, 95% CI 0.12-0.89; P = .015). Multivariate stratified analyses verified this association in each patient subgroup (all HR < 1.0). CONCLUSION: With a high patient tolerance to an interrupted sorafenib dosing schedule, the combination of TACE with sorafenib was associated with improved overall survival in early-intermediate stage HCC when compared with treatment with TACE alone. PMID- 28906356 TI - Shared polymorphisms and modifiable behavior factors for myocardial infarction and high cholesterol in a retrospective population study. AB - Genetic and environmental (behavior, clinical, and demographic) factors are associated with increased risks of both myocardial infarction (MI) and high cholesterol (HC). It is known that HC is major risk factor that may cause MI. However, whether there are common single nucleotide polymorphism (SNPs) associated with both MI and HC is not firmly established, and whether there are modulate and modified effects (interactions of genetic and known environmental factors) on either HC or MI, and whether these joint effects improve the predictions of MI, is understudied.The purpose of this study is to identify novel shared SNPs and modifiable environmental factors on MI and HC. We assess whether SNPs from a metabolic pathway related to MI may relate to HC; whether there are moderate effects among SNPs, lifestyle (smoke and drinking), HC, and MI after controlling other factors [gender, body mass index (BMI), and hypertension (HTN)]; and evaluate prediction power of the joint and modulate genetic and environmental factors influencing the MI and HC.This is a retrospective study with residents of Erie and Niagara counties in New York with a history of MI or with no history of MI. The data set includes environmental variables (demographic, clinical, lifestyle). Thirty-one tagSNPs from a metabolic pathway related to MI are genotyped. Generalized linear models (GLMs) with imputation based analysis are conducted for examining the common effects of tagSNPs and environmental exposures and their interactions on having a history of HC or MI.MI, BMI, and HTN are significant risk factors for HC. HC shows the strongest effect on risk of MI in addition to HTN; gender and smoking status while drinking status shows protective effect on MI. rs16944 (gene IL-1beta) and rs17222772 (gene ALOX) increase the risks of HC, while rs17231896 (gene CETP) has protective effects on HC either with or without the clinical, behavioral, demographic factors with different effect sizes that may indicate the existence of moderate or modifiable effects. Further analysis with the inclusions of gene-gene and gene environmental interactions shows interactions between rs17231896 (CETP) and rs17222772 (ALOX); rs17231896 (CETP) and gender. rs17237890 (CETP) and rs2070744 (NOS3) are found to be significantly associated with risks of MI adjusted by both SNPs and environmental factors. After multiple testing adjustments, these effects diminished as expected. In addition, an interaction between drinking and smoking status is significant. Overall, the prediction power in successfully classifying MI status is increased to 80% with inclusions of all significant tagSNPs and environmental factors and their interactions compared with environmental factors only (72%).Having a history of either HC or MI has significant effects on each other in both directions, in addition to HTN and gender. Genes/SNPs identified from this analysis that are associated with HC may be potentially linked to MI, which could be further examined and validated through haplotype-pairs analysis with appropriate population stratification corrections, and function/pathway regulation analysis to eliminate the limitations of the current analysis. PMID- 28906357 TI - ERCP-related complication is not the only cause of GI bleeding in post-liver transplantation patients: A case report. AB - RATIONALE: Endoscopic retrograde cholangiopancreatography (ERCP) is the treatment of choice for biliary complications in liver transplantation (LT) recipients as it is both diagnostic and therapeutic. The specific risks following ERCP among LT recipients have not been well studied. PATIENT CONCERNS: A 56-year-old man with a history of orthotopic LT underwent endoscopic retrograde cholangiopancreatography (ERCP) as a treatment of biliary strictures, whereby a plastic stent was implanted. Thirteen days after ERCP the patient developed multiple episodes of hematemesis. DIAGNOSIS: Digital subtraction angiography (DSA) of the hepatic artery and superior mesenteric artery showed a hepatic pseudoaneurysm (PA) in the left hepatic artery. The final diagnosis was bleeding from the PA. INTERVENTION: Interventional embolization of the branch with PA was performed to stop the bleeding. OUTCOME: The patient remained free of GI bleeding for 25 days after interventional embolization, but he developed another bout of bleeding and unfortunately passed away. LESSONS: ERCP-related complication is not the only cause of post-ERCP bleeding, and that other primary causes should also be ruled out. PMID- 28906358 TI - Efficacy evaluation of low-dose aspirin in IVF/ICSI patients evidence from 13 RCTs: A systematic review and meta-analysis. AB - BACKGROUND: We conducted a systematic review and meta-analysis of existing literature to evaluate the different outcomes of low-dose aspirin on patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), including clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate, fertilization rate, number of oocytes retrieved, and so forth. METHODS: Electronic databases including PubMed, MEDLINE, and Embase were searched between 1997 and March 2016 to identity eligible studies. The following comparisons between treatment groups were included: aspirin versus placebo; aspirin versus control group; aspirin versus aspirin + prednisolone + control. RESULTS: Thirteen randomized controlled trials which included 3104 participants were selected. There were no significant differences in implantation rate (RR = 1.15; 95% CI = 0.78-1.70), live birth rate (RR = 1.06; 95% CI = 0.93-1.21), miscarriage rate (RR = 1.28; 95% CI = 0.93-1.77), fertilization rate (RR = 0.91; 95% CI = 0.75-1.11), and endometrial thickness (WMD = 0.15; 95% CI = -0.38-0.67). But the research showed that aspirin treatment may improve the clinical pregnancy rate (RR = 1.16; 95% CI = 1.04-1.28) compared to placebo or no treatment, and reduce the number of oocytes retrieved (WMD = -0.68; 95% CI = -0.91-0.46). CONCLUSIONS: Our findings suggest that low-dose aspirin may improve the pregnancy rate in IVF/ICSI, with the recommended clinical use dose of 100 mg/day. Considering the limitation of included studies, further well-designed large scaled RCTs are necessary to clarify whether aspirin may improve assisted reproduction outcomes in IVF/ICSI patients. PMID- 28906359 TI - Relationship between sleep duration and Framingham cardiovascular risk score and prevalence of cardiovascular disease in Koreans. AB - Studies have shown sleep duration to be related to the prevalence of metabolic syndrome and hypertension. However, whether sleep duration is associated with cardiovascular disease (CVD) risk and the prevalence of CVD irrespective of conventional CV-risk factor, such as diabetes mellitus, obesity, and metabolic syndrome, has not been well established for the Korean population.A total of 23,878 individuals aged 18 years or older from the 2007-2010 Korean National Health and Nutrition Examination Survey were analyzed. We evaluated the relationship between sleep duration and CV-event risk using the Framingham Cardiovascular Risk Score (FRS; >=10% or >=20%) and the prevalence of CVD.After adjusting for traditional risk factors of CVD, a short sleep duration (<=5 hours) yielded odds ratios (OR) of 1.344 (95% confidence interval [CI] 1.200-1.505) for intermediate to high risk and 1.357 (95% CI, 1.140-1.614) for high risk. A long sleep duration (>=9 hours) was also associated with both intermediate to high (OR 1.142, 95% CI 1.011-1.322) and high cardiovascular FRS (OR 1.276, 95% CI 1.118 1.457).Both short and long sleep durations were related with high CVD risk, irrespective of established CVD risk, and a short sleep duration was associated with a higher prevalence of CVD than an optimal or long sleep duration. PMID- 28906360 TI - Plastic wound protectors decreased surgical site infections following laparoscopic-assisted colectomy for colorectal cancer: A retrospective cohort study. AB - Laparoscopic surgery is widespread and safe for the management of patients with colorectal cancer (CRC). Although the use of standard surgical techniques can prevent perioperative wound infections, surgical site infections (SSIs) remain an unresolved complication in laparoscopic-assisted colectomy. The present study investigated the ability of plastic wound protectors applied to the extraction incision during the externalized portion of the procedure to reduce the rate of infection in laparoscopic-assisted colectomy. We completed a retrospective review of the medical records of patients who underwent nonemergent laparoscopic assisted between January 2015 and June 2016. Outcomes for patients with and without the use of a wound protector were compared. A total of 109 patients were included in this study. There was 1 patient in the wound protector group (n = 57) and 7 in the nonwound protector group (n = 52) who developed a wound infection at the colon extraction site (P = .02). Furthermore, the average postoperative hospital stay in the wound protector group was shorter compared to the nonwound protector group (7.47 +/- 0.24 vs 8.73 +/- 0.54 days, P = .03). In conclusion, this study indicates that the use of a plastic wound protector during laparoscope assisted colectomy does reduce postoperative wound infection rates, and the wound protectors are beneficial for specimen extraction and digestive tract reconstruction. PMID- 28906361 TI - Is there an extraclinical value of automated breast volume scanner compared with hand-held ultrasound?: A pilot study. AB - The aim of this study was to investigate the extraclinical value of automated breast volume scanning (ABVS) in the diagnosis of breast tumor compare to hand handle ultrasound (HHUS).One hundred twenty-four patients with breast tumor were performed HHUS and ABVS before operation. The research focused on whether there were newly found tumors or new findings on the coronal planes by using ABVS compared with HHUS. Then, the classification adjustments of breast imaging reporting and data system (BI-RADS) were made according to new findings on the coronal planes by using ABVS.There are totally 166 breast tumors found in 124 patients by HHUS, while 8 more were observed by ABVS, 4 of which were malignant and the rest were benign. The sensitivity and specificity of ABVS coronal plane findings were 37.0% and 92.5%, respectively. The area under receiver operating characteristic curve was 0.89 before the corrected classification versus 0.93 after the corrected classification, there were no significant differences (P > .05).There was no significant extraclinical value in differentiating diagnosis of malignant tumors and benign breast tumors by ABVS comparing to HHUS. However, those minimal lesions missed diagnosis could be found by ABVS with continuously automatic scanning. PMID- 28906362 TI - Are we ever too old?: Characteristics and outcome of octogenarians admitted to a medical intensive care unit. AB - The aging population increases the demand of intensive care unit (ICU) treatments. However, the availability of ICU beds is limited. Thus, ICU admission of octogenarians is considered controversial. The population above 80 years is a very heterogeneous group though, and age alone might not be the best predictor. Aim of this study was to analyze resource consumption and outcome of octogenarians admitted to a medical ICU to identify reliable survival predictors in a senescent society.This retrospective observational study analyzes 930 octogenarians and 5732 younger patients admitted to a medical ICU. Admission diagnosis, APACHE II and SAPS II scores, use of ICU resources, and mortality were recorded. Long-term mortality was analyzed using Kaplan-Meier survival curves and multivariate cox regression analysis.Patients >=80 years old had higher SAPS II (43 vs 38, P < .001) and APACHE II (23 vs 21, P = .001) scores. Consumption of ICU resources by octogenarians was lower in terms of length of stay, mechanical ventilation, and renal replacement therapy. Among octogenarians, ICU survivors got less mechanical ventilation or renal replacement therapy than nonsurvivors. Intra-ICU mortality in the very old was higher (19% vs 12%, P < .001) and long term survival was lower (HR 1.76, P < .001). Multivariate cox regression analysis of octogenarians revealed that admission diagnosis of myocardial infarction (HR 1.713, P = .023), age (1.08, P = .002), and SAPS II score (HR 1.02, 95%, P = .01) were independent risk factors, whereas admission diagnoses monitoring post coronary intervention (HR .253, P = .002) and cardiac arrhythmia (HR .534, P = .032) had a substantially reduced mortality risk.Octogenarians show a higher intra-ICU and long-term mortality than younger patients. Still, they show a considerable life expectancy after ICU admission even though they get less invasive care than younger patients. Furthermore, some admission diagnoses like myocardial infarction, cardiac arrhythmia and monitoring post cardiac intervention are much stronger predictors for long-term survival than age or SAPS II score in the very old. PMID- 28906363 TI - Predictors of noninstitutionalized survival 1 year after hip fracture: A prospective observational study to develop the Marburg Rehabilitation Tool for Hip fractures (MaRTHi). AB - Hip fractures are frequent fractures in geriatric patients. These fractures have great socioeconomic implications because of the significantly higher risk of mortality and institutionalization. The aim of this study was to develop a prognostic tool to predict survival without institutionalization within 1 year after hip fracture.A total of 402 hip fracture patients aged >60 years (84% community-dwelling) were included in a prospective observational cohort study. Multiple regression analyses determined independent predictors for noninstitutionalized 1-year survival. Finally, the Marburg Rehabilitation Tool for Hip fractures (MaRTHi) was developed based on these independent predictors.Of the 312 patients who were followed up for 1 year, 168 (54%) survived noninstitutionalized, 104 (33%) died, and 40 (13%) lived in nursing homes. Independent predictors for patients' noninstitutionalized survival included the American Society of Anesthesiologists (ASA) score [ASA 1 or 2: odds ratio (OR) = 7.828; 95% confidence interval (CI) = 2.496-24.555 and ASA 3: OR = 8.098; 95% CI = 2.982-21.993 compared with ASA 4 or 5], the Mini Mental State Examination upon admission to the hospital (OR = 7.365; 95% CI = 2.967-18.282 for 27-30 compared with 0-10), patients' age (OR = 2.814; 95% CI = 1.386-5.712 for 75-89 y and OR = 2.520; 95% CI = 0.984-6.453 for 90-99 y compared with 60-74 ys), and prefracture EQ-5D (OR = 2.163; 95% CI = 1.119-4.179 for EQ-5D >0.80 compared with <0.60). The area under the receiver-operating characteristic curve was 0.756 (95% CI = 0.703 0.809), and the sensitivity analysis yielded a MaRTHi score that ranged from 0 to 12 points.The MaRTHi score is the first instrument to predict noninstitutionalized survival with only 4 variables. In addition to 3 well-known factors influencing outcome (age, comorbidities, and cognitive ability), prefracture health-related quality of life was identified as an independent predictor of noninstitutionalized survival. Further studies must be conducted to validate the MaRTHi score and define cutoff scores. Health-related quality of life seems to be an important patient-reported outcome measurement and may play a role in determining patient prognosis. PMID- 28906364 TI - Altered default mode network configuration in posttraumatic stress disorder after earthquake: A resting-stage functional magnetic resonance imaging study. AB - The neural substrates of posttraumatic stress disorder (PTSD) are still not fully elucidated. Hence, this study is to explore topological alterations of the default mode network (DMN) in victims with PTSD after a magnitude of 8.0 earthquake using resting-state functional magnetic resonance imaging (rs fMRI).This study was approved by the local ethical review board, and all participants signed written informed consent. Sixty-two PTSD victims from the 2008 Sichuan earthquake and 62 matched exposed controls underwent rs-fMRI. PTSD was diagnosed by Clinician-Administered PTSD Scale, and underwent PTSD Checklist Civilian Version for symptom scoring. The DMN was analyzed by using graph theoretical approaches. Further, Pearson correlation analysis was performed to correlate neuroimaging metrics to neuropsychological scores in victims with PTSD.Victims with PTSD showed decreased DMN functional connectivity strength between the right superior frontal gyrus and left inferior parietal lobule (IPL), and showed increased functional connectivity between the right IPL and precuneus or left posterior cingulate cortex. It was also found that victims with PTSD exhibited decreased nodal efficiency in right superior frontal gyrus and precuneus, and increased nodal efficiency in right hippocampus/parahippocampus. Apart from that, PTSD showed higher nodal degree in bilateral hippocampus/parahippocampus. In addition, the functional connectivity strength between the right IPL and precuneus correlated negatively to the avoid scores (r = -0.26, P = .04).This study implicates alteration of topological features on the DMN in PTSD victims after major earthquake, and provides new insights into DMN malfunction in PTSD based on graph theory. PMID- 28906365 TI - The antibiotic susceptibility patterns of uropathogens among children with urinary tract infection in Shiraz. AB - Urinary tract infection (UTI) is one of the most common bacterial infections in pediatrics. Delay in diagnosis and treatment can cause significant morbidity. The physicians knowledge regarding the symptoms, microorganisms that caused UTI, and effective antibiotics in a geographical area can help them to select the appropriate antibiotics. This study was performed to determine the prevalence of bacteria that cause UTI and their susceptibility to common antibiotics as well as the common symptoms and associated factors in children of Shiraz, Southern Iran.This cross sectional study was performed among 202 children with UTI, aged 2 months to 18 years old, between August and November 2014 in pediatric medical centers of Shiraz University of Medical Sciences. Urine samples were collected using urinary catheter or suprapubic in children < 2 years and mid-stream in children over 2 years, respectively. The type of micro-organisms causing UTI was determined and evaluation of antibiotic susceptibility for each organism was assayed by the Kirby Bauer method using antibiogram test. Patient's information was collected through checking the medical documents and interview with parents.Our results showed that the frequency of UTI was significantly higher in girls (70.3%) than in boys. The most commonly discovered pathogens were Escherichia coli (E coli) (51.5%), followed by Klebsiella spp. (16.8%), and Enterococcus spp. (9.9%). Overall susceptibility test showed the highest resistance to ampicillin (81.2%) and cotrimoxazole (79.2%), and the highest sensitivity to imipenem (90.1%) and Gentamicin (65.3%). Gram negative and positive bacteria showed the highest antibiotic resistance to amoxicillin (83.8%) and clindamycin (100%), respectively. In addition, production of extended spectrum beta lactamase (ESBL) was 69.2% and 30.8% in E coli and Kelebsiella respectively.The efficacy of third generation of the cephalosporins was reduced because of the high rate of production of ESBL and drug resistance. These results inform the physician as to which antibiotics are appropriate to prescribe for the patient, as well as urine culture reports and following the patient's clinical response so that high antimicrobial resistance is not developed at the community level. PMID- 28906366 TI - Risk factors for lymph node metastasis of early gastric cancers in patients younger than 40. AB - This research aims to explore the potential risk factors of lymph node metastasis (LNM) for early gastric cancers in young patients.We retrospectively collected data from 4287 patients who underwent gastrectomy from January 2005 to December 2015 at Linyi People's Hospital. Of these, we enrolled 397 eligible consecutive patients who had early gastric cancer, then divided them into 2 groups according to age (<=40 years and >40 years). The association between the clinicopathological factors and LNM was analyzed by univariate and multivariate analysis.Compared to older patients (>40 years), younger patients (<=40 years) with early gastric cancer had more diffuse and mixed types (51.1% and 37.8% vs 40% and 8.3%, respectively), less proximal gastric cancer (0% vs 33.8%, P < .01) and higher LNM (33.3% vs 13%, P < .01). Univariate analysis showed tumor invasion depth (P < .01), lymphovascular invasion (P < .01), and E-cadherin expression (P = .024) were associated with LNM in the younger cohort. Multivariate analysis revealed that lymphovascular invasion (OR = 17.740, 95% CI: 1.458-215.843) was an independent risk factor for LNM (P = .024). Further analysis showed 3 patients who were within expanded endoscopic resection indications were positive for LNM.Given the high risk of lymph node involvement in young patients with early gastric cancer, both endoscopic and surgical resection procedures should be performed with caution, and active postoperative surveillance is warranted. PMID- 28906367 TI - Predicting the mortality in geriatric patients with dengue fever. AB - Geriatric patients have high mortality for dengue fever (DF); however, there is no adequate method to predict mortality in geriatric patients. Therefore, we conducted this study to develop a tool in an attempt to address this issue.We conducted a retrospective case-control study in a tertiary medical center during the DF outbreak in Taiwan in 2015. All the geriatric patients (aged >=65 years) who visited the study hospital between September 1, 2015, and December 31, 2015, were recruited into this study. Variables included demographic data, vital signs, symptoms and signs, comorbidities, living status, laboratory data, and 30-day mortality. We investigated independent mortality predictors by univariate analysis and multivariate logistic regression analysis and then combined these predictors to predict the mortality.A total of 627 geriatric DF patients were recruited, with a mortality rate of 4.3% (27 deaths and 600 survivals). The following 4 independent mortality predictors were identified: severe coma [Glasgow Coma Scale: <=8; adjusted odds ratio (AOR): 11.36; 95% confidence interval (CI): 1.89-68.19], bedridden (AOR: 10.46; 95% CI: 1.58-69.16), severe hepatitis (aspartate aminotransferase >1000 U/L; AOR: 96.08; 95% CI: 14.11 654.40), and renal failure (serum creatinine >2 mg/dL; AOR: 6.03; 95% CI: 1.50 24.24). When we combined the predictors, we found that the sensitivity, specificity, positive predictive value, and negative predictive value for patients with 1 or more predictors were 70.37%, 88.17%, 21.11%, and 98.51%, respectively. For patients with 2 or more predictors, the respective values were 33.33%, 99.44%, 57.14%, and 98.51%.We developed a new method to help decision making. Among geriatric patients with none of the predictors, the survival rate was 98.51%, and among those with 2 or more predictors, the mortality rate was 57.14%. This method is simple and useful, especially in an outbreak. PMID- 28906368 TI - Traumatic fractures as a result of falls in children and adolescents: A retrospective observational study. AB - The aim of this study is to investigate the incidence and pattern of traumatic fractures (TFs) as a result of falls in a population of children and adolescents (<=18 years old) in China.This was a cross-sectional study. We retrospectively reviewed 1412 patients who were children and adolescents with TFs as a result of falls admitted to our university-affiliated hospitals in China from 2001 to 2010. Etiologies included high fall (height >=2) and low fall (height <2 m). The incidence and pattern were summarized with respect to different age groups, year of admission, etiologies, genders, and the neurological function.This study enrolled 1054 males (74.6%) and 358 females (25.4%) aged 10.8 +/- 4.7 years. The etiologies were low fall (1059, 75.0%) and high fall (353, 25.0%). There were 2073 fractures in total and 92 patients (6.5%) presented with multiple fractures. The most common fracture sites were upper extremity fractures in 814 patients (57.6%) and lower extremity fractures in 383 patients (27.1%), followed by craniofacial fractures in 233 patients (16.5%). A total of 231 (16.4%) patients suffered a nerve injury. The frequencies of early and late complications/associated injuries were 19.5% (n = 275) and 9.2% (n = 130). The frequencies of emergency admission, nerve injury, spinal fracture, lower extremity fractures, craniofacial fracture, sternum and rib fracture, and early complications/ASOIs were significantly larger in high fall than low fall (all P <.001, respectively). The frequencies of medical insurance rate (P = .042) and upper extremity fractures (P <.001) were significantly larger in low fall than high fall. The frequencies of spinal fracture (P = .039), lower extremity fractures (P = .048), and craniofacial fracture (P = .041) were significantly larger in female than the male patients. The frequency of upper extremity fractures (P <.001) and the mean age (P <.001) was significantly larger in male than female patients. The frequencies of emergency admission, high fall, spinal fracture, and craniofacial fracture were significantly larger in patients with nerve injury than other patients without nerve injury (all P <.001, respectively).Low falls and upper extremity fractures were the most common etiologies and sites, respectively. High fall, spinal fracture and craniofacial fracture were risk factors for nerve injury. Therefore, we should focus on patients who were caused by high fall and presented with spinal and craniofacial fracture to determine the presence of a nerve injury so that we can provide early, timely diagnosis and targeted treatment to children. PMID- 28906369 TI - The efficacy of tranexamic acid in reducing blood loss in total shoulder arthroplasty: A meta-analysis. AB - BACKGROUND: The purpose of this meta-analysis is to compare the efficacy of tranexamic acid (TXA) versus placebo after a total shoulder arthroplasty (TSA). METHODS: In April 2017, a systematic computer-based search was conducted in the databases of PubMed, Embase, Web of Science, Cochrane Library, and Google. Studies comparing TXA versus placebo in reducing blood loss after TSA were included. The endpoints were the need for transfusion, blood loss in drainage, hemoglobin drop, and total blood loss. Stata 12.0 software was used for the meta analysis. RESULTS: Six studies involving a total of 637 patients met the inclusion criteria. The meta-analysis revealed that, compared with control groups, treatment with TXA could decrease the need for transfusion (P < .00001), blood loss in drainage (P = .000), hemoglobin drop (P = .001), and total blood loss (P = .000). CONCLUSION: TXA can decrease the need for transfusion as well as total blood loss in TSA patients. There was a negative correlation between the TXA dose and the need for transfusion and blood loss in drainage. Because the administration route and the dose of TXA were different, more studies are needed in order to identify the optimal dose and route. PMID- 28906370 TI - The association of hypernatremia and hypertonic saline irrigation in hepatic hydatid cysts: A case report and retrospective study. AB - RATIONALE: Hypernatremia is a rare but fatal complication of hypertonic saline (HS) irrigation in hepatic hydatid disease. It needs careful monitoring and treatment. PATIENT CONCERNS: A 28-year-old woman with hepatic hydatid cysts who received operation treatment developed electrolyte disturbances. We also conducted a retrospective study about influence of HS application on electrolytes in patients with hepatic hydatid disease receiving surgery. DIAGNOSES: Hypernatremia, developed after HS irrigation. INTERVENTIONS: Normal saline, 5% dextrose and other supportive treatment were administered. In the retrospective study, a comparison of electrolyte and glucose fluctuation was made among different HS application groups. OUTCOMES: The patient developed hypernatremia after irrigation with HS and died from severe complications. Although some cases of complications are found, no significant relationship between HS irrigation and hypernatremia was reported according to the retrospective study. LESSONS: Hypernatremia after HS irrigation remains rare but might cause severe complications. Monitoring and appropriate treatment are needed to improve prognosis. PMID- 28906371 TI - Survival prediction model for postoperative hepatocellular carcinoma patients. AB - This study is to establish a predictive index (PI) model of 5-year survival rate for patients with hepatocellular carcinoma (HCC) after radical resection and to evaluate its prediction sensitivity, specificity, and accuracy.Patients underwent HCC surgical resection were enrolled and randomly divided into prediction model group (101 patients) and model evaluation group (100 patients). Cox regression model was used for univariate and multivariate survival analysis. A PI model was established based on multivariate analysis and receiver operating characteristic (ROC) curve was drawn accordingly. The area under ROC (AUROC) and PI cutoff value was identified.Multiple Cox regression analysis of prediction model group showed that neutrophil to lymphocyte ratio, histological grade, microvascular invasion, positive resection margin, number of tumor, and postoperative transcatheter arterial chemoembolization treatment were the independent predictors for the 5 year survival rate for HCC patients. The model was PI = 0.377 * NLR + 0.554 * HG + 0.927 * PRM + 0.778 * MVI + 0.740 * NT - 0.831 * transcatheter arterial chemoembolization (TACE). In the prediction model group, AUROC was 0.832 and the PI cutoff value was 3.38. The sensitivity, specificity, and accuracy were 78.0%, 80%, and 79.2%, respectively. In model evaluation group, AUROC was 0.822, and the PI cutoff value was well corresponded to the prediction model group with sensitivity, specificity, and accuracy of 85.0%, 83.3%, and 84.0%, respectively.The PI model can quantify the mortality risk of hepatitis B related HCC with high sensitivity, specificity, and accuracy. PMID- 28906372 TI - Efficacy and safety of laparoscopic bile duct exploration versus endoscopic sphincterotomy for concomitant gallstones and common bile duct stones: A meta analysis of randomized controlled trials. AB - BACKGROUND: The purpose of this study was to compare the efficacy and safety of laparoscopic cholecystectomy (LC) plus laparoscopic common bile duct (CBD) stones exploration (LCBDE) with LC plus endoscopic sphincterotomy (EST) in the treatment of patients with gallstones and CBD stones. METHODS: The authors searched PubMed, Web of Science, and Embase to identify relevant studies. Risk ratios (RRs) were pooled to compare stone clear, retained stone, conversion to other procedures, and complications. Weighted mean differences (WMDs) were pooled to compare operative time, and length of hospital stay. A fixed-effects model or random effects model was used to pool the estimates, according to the heterogeneity among the included studies. RESULTS: A total of 11 randomized controlled trials (RCTs) involving 1663 patients were included in this meta-analysis. The pooled estimate suggested that LC-LCBDE had comparable effects with LC-EST in terms of CBD stone clear rate (RR = 1.02, 95% CI: 0.95, 1.09; P = .583), retained stones rate (RR = 1.27, 95% CI: 0.51, 3.19; P = .607), and length of hospital stay (WMD = -0.96 days, 95% CI: -2.20, 0.28). In addition, LC-LCBDE was associated with significantly higher conversion rate (RR = 1.59, 95% CI: 1.08, 2.35; P = .019) and less operative time (WMD = -11.55 minutes, 95% CI: -16.68, -6.42; P < .001) than LC-EST. The incidence of complications was not significant difference between the 2 surgical approaches (RR = 1.07, 95% CI: 0.86, 1.34; P = .550). CONCLUSION: Based on the current evidence, both LC-LCBDE and LC-EST were highly effective in detecting and removing CBD stones and were equivalent in complications. However, our results might be biased by the limitations. Large scale well-designed RCTs are needed to confirm our findings. PMID- 28906373 TI - Predictive value of insufficient contrast medium filling in pulmonary veins in patients with acute pulmonary embolism. AB - This study is to investigate the predictive value of insufficient contrast medium filling (ICMF) in patients with acute pulmonary embolism (PE).A total of 108 PE patients were enrolled and divided into group A and group B according to the presence of ICMF. PE index and ventricul araxial lengths were measured. Heart cavity volumes were examined and right ventricle (RV) to left ventricle (LV) diameter ratio (RV/LV(d)) and volume ratio (RV/LV(V)) and right atrium (RA) to left atrium (LA) volume ratio (RA/LA(V)) were calculated and compared. Group A was further divided into A1 and A2 based upon the pulmonary vein filling degree and each index was compared.There were no significant differences between group A and B in general condition. PE index of group A was higher than that of group B. LA and LV in group A were smaller than that of group B, whereas RA in group A was larger than that of group B. RV/LV(d), RV/LV(V), and RA/LA(V) in group A were significantly larger than that of group B. Embolism index of group A2 was higher than that of groupA1, but without statistical significant difference. LA in group A2 was smaller than that of group A1, whereas RA, RV/LV(d), and RV/LV(V) were larger than that of group A1, all with significant differences.PE increased with serious ICMF in pulmonary veins could be used as an indicator for risk stratification in patients with acute PE. PMID- 28906374 TI - A single nucleotide polymorphism in codon F31I and V57I of the AURKA gene in invasive ductal breast carcinoma in Middle East. AB - Although few studies have suggested a carcinogenic role for polymorphism of F31I and V57I codons of AURKA gene in invasive ductal carcinoma, contradictory results from different populations mandates regional investigations. We aimed to determine polymorphisms of F31I and V57I codons of AURKA gene and their association with cancer prognosis in patients compared with controls in an eastern population of Iran.A case-control study was conducted on specimens from 100 patients and 100 age- and gender-matched controls. DNA was extracted and the codons F31I and V57I were amplified. The different genotypes were analyzed by PCR RFLP and electrophoresis.In codon F31I, the frequency of Phe/Ile was 70% and 82% in patients and healthy controls respectively, whereas (Ile/Ile) was 30% in patients and 18% in healthy (P = .047). Analyzing V57I genotypes showed a higher homozygote Val/Val genotype in patients compared with controls (76% vs 68%), whereas the frequency of heterozygous Val/Ile genotype was lower in patients (17%) than controls (30%), yielding a marginal association between breast cancer and Val/Val genotype (P = .048). No association was observed between SNPs of either F31I or V57I genotypes and histological grades. However, there was a significant association between tumor stages and F31I genotype (P for trend = .003).This is the first report of F31I and V57I polymorphisms in AURKA gene in breast cancer in Iran. Determination of allelic polymorphism of those codons will help to understand background genetic predisposition and could have prognostic value in management of breast cancer in the target population. PMID- 28906375 TI - Correlations between clinical characteristics and neuroimaging in Chinese patients with subtypes of frontotemporal lobe degeneration. AB - The aim of the study was to obtain an overview of the clinical and neuroimaging features of Chinese patients with subtypes of frontotemporal lobe degeneration (FTLD).We evaluated the demographic features, clinical presentation, and lobe atrophy depicted by magnetic resonance imaging (MRI) in 133 patients with FTLD. Two positron emission tomography (PET) scans were performed at baseline: [C]Pittsburgh compound B PET to assess amyloid-beta plaque load and [F]fluorodeoxyglucose (FDG) PET to assess glucose metabolism.The behavioral variant of FTD (bvFTD) was the most common subtype (67.7%) of FTLD. The percentages of progressive nonfluent aphasia (PNFA) and semantic dementia (SD) were similar. Cerebral lobe atrophy was seen in 87.7% of the cases. The Activities of Daily Living scale, Mini-Mental State Examination, and Montreal Cognitive Assessment scores were significantly correlated with the degree of overall atrophy. The severity of abnormal behavior was correlated with right anterior and right posterior temporal atrophy scores. The overall atrophy scores and atrophy score in the left temporal region were related to cognitive outcomes and Activities of Daily Living scores. Most of the bvFTD patients presented symmetric/asymmetric hypometabolism in the bilateral temporal cortex, frontal cortex, anterior cingulate cortex, insula, and caudate nucleus. All the PNFA patients presented left dominant hypometabolism in the frontal cortex. All the SD patients presented left dominant hypometabolism in the anterior temporal cortex.FTLD is not rare in cognitive clinics, and the ratios of subtypes in Chinese patients are similar to other ethnic groups. Overall atrophy scores, determined by MRI, were related to the severity of cognitive dysfunction and deficits in Activities of Daily Living. Patterns of hypometabolism, determined by [F]FDG PET, were more specific to subtypes of FTLD and may help provide differential diagnoses of variants of FTLD. PMID- 28906376 TI - Nucleotide variants of the NAT2 and EGF61 genes in patients in Northern China with nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common orofacial congenital anomaly. The objective of the present study was to analyze the association of single nucleotide polymorphisms (SNPs) in the NAT2 and EGF61genes with NSCL/P in a Chinese population. METHODS: The frequencies of NAT2 (rs1799929)and EGF61 (rs4444903) gene variations were examined in a group of 285 NSCL/P patients and in 315 controls. Peripheral venous blood samples were collected for DNA extraction. Genotyping of the 2 SNPs was carried out using a mini sequencing (SNaPshot) method. Data were analyzed using the chi-square test. RESULTS: We found a significant association between the EGF61 (rs4444903) and NSCL/P (P = .01) genes.Conversely, NAT2 (rs1799929) was not significantly different between the cases and the control group.The genotype frequencies of rs4444903GA showed a significant difference compared with GG genotype as a reference (odds ratio = 0.59; 95% confidence interval: 0.42-0.84, P = .01). CONCLUSION: Our study showed that the EGF61 rs4444903GA genotype had a decreased risk of NSCL/P. Our data provides further evidence regarding the role of EGF61 variations in the development of NSCL/P in families of the studied populations. PMID- 28906377 TI - Reflux episodes and esophageal impedance levels in patients with typical and atypical symptoms of gastroesophageal reflux disease. AB - To determine the relationship between baseline impedance levels and gastroesophageal reflux, we retrospectively enrolled 110 patients (54 men and 56 female; mean age, 51 +/- 14 years) with suspected gastroesophageal reflux disease (GERD) who underwent 24-h multichannel intraluminal impedance and pH monitoring. Patients were stratified according to symptom (typical or atypical) and reflux types (acid reflux, nonacid reflux [NAR], or no abnormal reflux). Mean nocturnal baseline impedance (MNBI) were measured 3 cm (distal esophagus) and 17 cm (proximal esophagus) above the lower esophageal sphincter. Median distal esophageal MNBI was lower in the acid reflux group (1244 Omega; 647-1969 Omega) than in the NAR (2586 Omega; 1368-3666 Omega) or no abnormal reflux groups (3082 Omega; 2495-4472 Omega; all P < .05). Distal MNBI were negatively correlated with DeMeester score and acid exposure time. Atypical symptoms were more frequently associated with NAR than typical symptoms (P < .01). Among patients with positive symptom-association probability (SAP) for NAR, median proximal MNBI tended to be lower in patients with typical symptoms (median, 3013 Omega; IQR, 2535-3410 Omega) than in those with atypical symptoms (median, 3386 Omega; IQR, 3044-3730 Omega, P = .05). Thus, atypical GERD symptoms were more likely to be associated with NAR. The mucosal integrity of the proximal esophagus might be relatively impaired in GERD patients with typical symptoms for NAR. PMID- 28906378 TI - The need for psycho-oncological support for melanoma patients: Central role of patients' self-evaluation. AB - Despite an increasing number of promising treatment options, only a limited number of studies concerning melanoma patients' psycho-oncological distress have been carried out. However, multiple screening tools are in use to assess the need for psycho-oncological support. This study aimed first to identify parameters in melanoma patients that are associated with a higher risk for being psycho oncologically distressed and second to compare patients' self-evaluation concerning the need for psycho-oncological support with the results of established screening tools.We performed a cross-sectional study including 254 melanoma patients from the Center for Dermatooncology at the University of Tuebingen. The study was performed between June 2010 and February 2013. Several screening instruments were included: the Distress Thermometer (DT), Hospital Anxiety and Depression Scale and the patients' subjective evaluation concerning psycho-oncological support. Binary logistic regression was performed to identify factors that indicate the need for psycho-oncological support.Patients' subjective evaluation concerning the need for psycho-oncological support, female gender, and psychotherapeutic or psychiatric treatment at present or in the past had the highest impact on values above threshold in the DT. The odds ratio of patients' self-evaluation (9.89) was even higher than somatic factors like female gender (1.85), duration of illness (0.99), or increasing age (0.97). Patients' self-evaluation concerning the need for psycho-oncological support indicated a moderate correlation with the results of the screening tools included.In addition to the results obtained by screening tools like the DT, we could demonstrate that patients' self-evaluation is an important instrument to identify patients who need psycho-oncological support. PMID- 28906379 TI - Accessory ovarian steroid cell tumor producing testosterone and cortisol: A case report. AB - RATIONALE: An accessory ovary is a rare structure containing normal ovarian tissue, which has a direct or ligamentous connection with a normal and eutopic ovary. PATIENT CONCERNS: In the study, we reported a 46-year-old woman presented with secondary amenorrhea and virilization symptoms for 1 year. DIAGNOSES: Endocrine evaluation revealed slightly elevated serum cortisol, extremely elevated 24-hour urinary-free cortisol and serum testosterone. Clinical assessment exhibited a large solid mass with heterogeneous enhancement in the left adnexauteri compounded with hypercortisolism and hyperandrogenemia. An accessory ovarian tumor attached to the infundibulum of the left fallopian tube was found, and a separate normal ovary was present on the same side. INTERVENTIONS: The patient underwent a left adnexectomy. OUTCOMES: During surgery, a 12 cm * 8 cm, gray-red, and well-circumscribed solid mass was be identified. The tumor had ligamentous attachment with the infundibulum of left fallopian tube. The sectioned surface was gray-brown, lobulated and did not exhibit either significant necrosis or hemorrhage. Pathological findings demonstrated that tumor cells had small round nuclei, mild atypia, no mitosis were arranged in a diffuse pattern of columns or nests separated by a rich vascular network and no crystals of Reinke were found. It was diagnosis ovarian steroid cell tumor (NOS) without malignant behavior by immunohistochemical staining. The patient was finally diagnosed as accessory ovarian steroid. The patient was discharged from the hospital on the seventeenth day after surgery. During postoperative follow-up, the first postoperative menstrual flow recovered and blood pressure regained 1 month after surgery. Furthermore, her Cushing syndrome regressed and hirsutism disappeared completely 4 months after surgery cell tumor. LESSONS: It is vitally important to establish a final diagnosis according to the clinical manifestations and laboratory values in addition to imaging studies and laparoscopic examination of a rare coexistence of hyperandrogenemia and Cushing syndrome based on the accessory ovarian pathology. PMID- 28906380 TI - SYNTAX score based on coronary computed tomography angiography may have a prognostic value in patients with complex coronary artery disease: An observational study from a retrospective cohort. AB - The SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) score is an invasive coronary angiography (ICA)-based score for quantifying the complexity of coronary artery disease (CAD). Although the SYNTAX score was originally developed based on ICA, recent publications have reported that coronary computed tomography angiography (CCTA) is a feasible modality for the estimation of the SYNTAX score.The aim of our study was to investigate the prognostic value of the SYNTAX score, based on CCTA for the prediction of major adverse cardiac and cerebrovascular events (MACCEs) in patients with complex CAD.The current study was approved by the institutional review board of our institution, and informed consent was waived for this retrospective cohort study. We included 251 patients (173 men, mean age 66.0 +/- 9.29 years) who had complex CAD [3-vessel disease or left main (LM) disease] on CCTA. SYNTAX score was obtained on the basis of CCTA. Follow-up clinical outcome data regarding composite MACCEs were also obtained. Cox proportional hazards models were developed to predict the risk of MACCEs based on clinical variables, treatment, and computed tomography (CT)-SYNTAX scores.During the median follow-up period of 1517 days, there were 48 MACCEs. Univariate Cox hazards models demonstrated that MACCEs were associated with advanced age, low body mass index (BMI), and dyslipidemia (P < .2). In patients with LM disease, MACCEs were associated with a higher SYNTAX score. In patients with CT-SYNTAX score >=23, patients who underwent coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention had significantly lower hazard ratios than patients who were treated with medication alone. In multivariate Cox hazards model, advanced age, low BMI, and higher SYNTAX score showed an increased hazard ratio for MACCE, while treatment with CABG showed a lower hazard ratio (P < .2).On the basis of our results, CT-SYNTAX score can be a useful method for noninvasively predicting MACCEs in patients with complex CAD, especially in patients with LM disease. PMID- 28906381 TI - Comparison of secondary cytoreductive surgery plus chemotherapy with chemotherapy alone for recurrent epithelial ovarian, tubal, or peritoneal carcinoma: A propensity score-matched analysis of 112 consecutive patients. AB - To compare secondary cytoreductive surgery (SCS) plus chemotherapy with chemotherapy alone in Japanese patients with recurrent epithelial ovarian, tubal, or peritoneal cancer (ROC).From our institutional database, we identified 112 patients who underwent therapy for ROC between 2005 and 2013. Of the 112 patients, 77 received salvage chemotherapy alone (CT group) and 35 received SCS plus chemotherapy (SCS group). To reduce the impact of treatment selection bias on treatment outcomes, propensity score-matching analysis was used.In the entire cohort, prognostic features were poorer in the CT group than in the SCS group. The platinum-free interval was significantly lower (15.35 months vs 30.77 months), cancer antigen 125 (CA125) level was significantly higher (247.38 IU/mL vs 83.17 IU/mL), and number of solitary recurrence sites was significantly lower in the CT group than in the SCS group. The matched cohort consisted of 29 CT and 29 SCS patients with a median follow-up period of 24 and 58 months, respectively. In the matched cohort, progression-free survival (PFS) was longer in the SCS group than in the CT group (P = .02); however, overall survival did not differ (P = .23).SCS might be associated with improved PFS in ROC patients. SCS is beneficial in appropriately selected ROC patients. PMID- 28906382 TI - The efficacy of gabapentin in reducing pain intensity and postoperative nausea and vomiting following laparoscopic cholecystectomy: A meta-analysis. AB - BACKGROUND: It is unknown whether gabapentin is effective in reducing acute pain following laparoscopic cholecystectomy. The purpose of the current meta-analysis was to evaluate the efficacy of gabapentin in reducing pain intensity and postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy. METHODS: All randomized controlled trials (RCTs) evaluating the efficacy of gabapentin in reducing pain intensity and PONV after laparoscopic cholecystectomy were searched on the following databases: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Google database, the Chinese Wanfang database, and the China National Knowledge Infrastructure (CNKI). The most recent literature search was conducted on March 21, 2017. Outcomes including visual analog scale (VAS) at 12 and 24 hours, total morphine consumption, and the occurrence of PONV. Continuous outcomes were expressed as the weighted mean difference (WMD) and 95% confidence interval (CI), and the one discontinuous outcome was expressed as risk ratio (RR) and 95% CI. Stata 12.0 software was used for meta-analysis. RESULTS: A total of 9 studies involving 966 patients were identified. In total, there were 484 gabapentin subjects and 482 controls. Compared with the control group, gabapentin was associated with lower VAS at 12 hours (WMD = -10.18, 95% CI: -17.36 to -2.80, P = .007) and 24 hours (WMD = 6.33, 95% CI: -8.41 to -4.25, P = .000), which was equivalent on a 110-point VAS scale to 10.18 points at 12 hours and 6.33 points at 24 hours. Compared with the control group, gabapentin was associated with less total morphine consumption by approximately 110.83 mg (WMD = -110.83, 95% CI: -183.25 to -38.42, P = .003). In addition, the occurrence of nausea and vomiting in gabapentin was decreased (25.2% vs 47.6, RR = 0.53, 95% CI: 0.44-0.63, P = .000). CONCLUSION: Gabapentin was efficacious in reducing postoperative pain, total morphine consumption, and morphine-related complications following laparoscopic cholecystectomy. In addition, there was a negative correlation between the gabapentin dosage and the occurrence of nausea and vomiting. The number of included studies is limited, and more studies are needed to verify the effects of gabapentin in laparoscopic cholecystectomy patients. PMID- 28906383 TI - Comparing minimally invasive transforaminal lumbar interbody fusion and posterior lumbar interbody fusion for spondylolisthesis: A STROBE-compliant observational study. AB - Although spondylolisthesis was traditionally treated with posterior lumbar interbody fusion (PLIF), minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) was recently proposed as an alternative treatment for spondylolisthesis. However, no studies have focused on the comparison of these 2 techniques' outcome on spondylolisthesis.The operative reports and perioperative data of patients who underwent single-level primary open PLIF (n = 29) and MIS TLIF (n = 26) for I/II spondylolisthesis were retrospectively evaluated. Patients' demographics, operative blood loss, hospital length of stay, creatine kinase (CK) level, radiographic fusion, complications, and patient-reported outcomes were evaluated. Radiographic fusion was assessed using the Bridwell grading criteria. Preoperative and postoperative patient-reported outcomes included the visual analog scale (VAS) and Oswestry Disability Index (ODI).Average follow-up was 28 +/- 3.6 months (range 24-32 months). Bed rest time, hospital stay, estimated blood loss, and operative time in the MIS-TLIF group were significantly lower than those in the PLIF group (P < .05). The 3 month postoperative ODI and VAS in the MIS-TLIF group were significantly better than the PLIF group (P < .05). However, at the time of the last follow-up, both groups had similar ODI scores and complication, slip reduction, and spinal fusion rates (P > .05).Compared with PLIF, MIS-TLIF for grade I/II spondylolisthesis can achieve similar reduction and fusion results with better short-term quality of life, shorter hospital stays, less estimated blood loss, and shorter operative times. PMID- 28906384 TI - The safety and efficacy of oral anticoagulants with dual versus single antiplatelet therapy in patients after percutaneous coronary intervention: A meta analysis. AB - BACKGROUND: A growing number of patients require oral anticoagulant (OAC) after undergoing percutaneous coronary intervention (PCI) with stent implantation due to the development of atrial fibrillation, but the optimal antithrombotic regimen remains controversial in these patients. METHODS: We systematically searched PUBMED, EMBASE, and CENTRAL from inception until September 2016 for randomized controlled trials or cohort studies that evaluated the comparative effects of TT versus DT. Relative risks (RRs) with 95% confidence intervals (95% CIs) were pooled by a random-effects model or a fixed-effects model. RESULTS: Twelve studies with a total of 30,823 patients were included in this analysis, including 6134 in the TT group and 24,689 in the DT group. No significant differences were found between the TT group and the DT group regarding major adverse cardiovascular events (MACE) (RR = 0.82, 95% CI: 0.58-1.17; I = 87.3%), stroke (RR = 1.08, 95% CI: 0.56-2.07; I = 65.5%), all-cause mortality (RR = 0.90, 95% CI: 0.54-1.51; I = 79.1%), or stent thrombosis (RR = 0.71, 95% CI: 0.41-1.24; I = 12.7%), and lower rates were observed for myocardial infarction (RR = 0.59, 95% CI: 0.50-0.70; I = 31.1%) and major bleeding with TT (RR = 0.86, 95% CI: 0.74 0.99; I = 24.3%). Meanwhile, we also found that compared with TT, OAC with clopidogrel treatment shows equal efficacy and safety outcomes. CONCLUSION: In patients on OAC undergoing PCI with stent implantation, compared with DT, TT shows equal effectiveness in terms of MACE, stroke, all-cause mortality, and stent thrombosis and lower risks of myocardial infarction and major bleeding. However, similar efficacy and safety outcomes were observed between the TT group and the OAC along with clopidogrel group. PMID- 28906386 TI - Development and validation of a prediction score system in lupus nephritis. AB - The risk assessment for developing end-stage renal disease (ESRD) remains unclear in patients with lupus nephritis (LN). The purpose of this study was to develop and validate a prediction rule for estimating the individual risk of ESRD in patients with LN using clinical and pathological data.A total of 599 patients with LN diagnosed by renal biopsy between June 2009 and June 2014 in West China Hospital of Sichuan University were retrospectively followed. Patients were randomly divided into derivation cohort (n = 379) and validation cohort (n = 220). The SLEDAI score was used to evaluate the clinical disease activity. Pathological lesions according to the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) systems were meticulously evaluated. The risk factors for developing ESRD were evaluated using a Cox proportional hazard model with a stepwise backward elimination method.In the derivation cohort, 100 patients (26.5%) developed ESRD during the average 46.0 +/- 21.1 months' follow up. The final prediction model included cellular crescents, active index >20, glomerular sclerosis, fibrous crescents, interstitial fibrosis, chronic index >5, nephrotic syndrome, and eGFR <45 mL/min as independent risk factors for developing ESRD. To create a prediction rule, the score for each variable was weighted by the regression coefficients calculated using the relevant Cox model. The prediction rule was validated in the validation cohort. During the follow-up period, 45 patients (21.5%) in validation cohort progressed to ESRD.This study developed and validated a new prediction rule using clinical measures and pathological changes for developing ESRD in patients with LN. PMID- 28906385 TI - Percutaneous intratumoral injection of gemcitabine plus cisplatin mixed with fibrin glue for advanced pancreatic carcinoma: Case Report. AB - RATIONALE: The aim of this study was to determine the effectiveness of intratumoral injection of chemotherapeutics in improving the quality of life and survival of patients with pancreatic carcinoma. PATIENT CONCERNS: We present a case series of 5 patients with unresectable pancreatic adenocarcinoma. DIAGNOSES: Patients diagnosed with unresectable poorly differentiated pancreatic ductal adenocarcinoma by intraoperative frozen biopsyor percutaneous biopsy. INTERVENTIONS: Five patients with unresectable pancreatic adenocarcinoma received a computed tomography-guided percutaneous intratumoral injection of gemcitabine plus cisplatin mixed with fibrin glue. OUTCOMES: Mean overall survival was 16.2 +/- 3.7 months. Local control rates were 100% and 80% at postoperative 3 and 6 months, respectively. Mean Visual Analogue Scale pain score decreased from 7.2 +/ .84 preoperatively to 2 +/- 1.22 at postoperative 4 weeks. There were no complications associated with the procedure. LESSONS: Percutaneous intratumoral injection of gemcitabine plus cisplatin mixed with fibrin glue for advanced pancreatic may be safe and effective. PMID- 28906387 TI - A nearly full-recovery from AVM hemorrhagic stroke 17 years after insult using a new integrated neurodevelopmental approach: A case report. AB - RATIONAL: With the prevalence of stroke increasing in the USA and the world along with increased survival and longevity due to medical advancements, it has become increasingly necessary to look at the chronic phase of stroke recovery. Previous paradigms of stroke treatment have proven ineffective when looking at 10, 15, or 20 years of survival post insult. PATIENT CONCERNS: The patient, being a young man just out of high school, was concerned with his overall morbidity. He was highly concerned with the quality of life he could expect as a stroke survivor with a life expectancy of 60 years or more. DIAGNOSES: C was diagnosed with a hemorrhagic AVM stroke that impacted several regions of the brain, particularly the right occipital and temporal lobes as well as bilateral motor control. C experienced severe hpertonicity of the musculature and significant vertigo. INTERVENTIONS: This study investigated a novel approach to chronic-phase stroke rehabilitation using traditional child motor-learning techniques, play, and proprioceptive-building activities in addition to current stroke rehabilitation techniques. During an initial six-month period, followed by a three-year period, the participant used motor-developmental learning activities as well as traditional strength, gait, and balance training. During the initial phase of treatment, clinically-significant improvements were recorded along with self reported lifestyle enhancements. These gains continued throughout the three-and-a half year process. OUTCOMES: C regained the ability to free-walk in small bouts and went from the use of a walker to canes. He regained use of his hands and removed a large partion of his vertigo. Of specific interest was the participant's ability to progress from using a walker to driving, returning to school, and starting a family. LESSONS: This study lays the groundwork for future studies into this type of therapeutic approach as well as highlighting the ability of chronic-phase stroke patients to recover well into the second decade post stroke. After the initial six month period, as gains were being observed, a more formal measurement process was begun for a second six-month period. Initial measurements of progress were taken every six weeks using the Fugl-Meyer test, the Berg Balance Test, the Barthel Index, and the Stroke Specific Quality Of Life scale. Results showed clinically significant improvements in all areas of recovery. PMID- 28906389 TI - Risk factor analysis for nonocclusive mesenteric ischemia following cardiac surgery: A case-control study. AB - Although rare, postcardiac surgery nonocclusive mesenteric ischemia (NOMI) is a life-threatening condition. Identifying the risk factors for NOMI during immediate postoperative period may help early detection and intervention, which leads to improved clinical outcomes. The objective of this study was to identify the clinical features and risk factors of NOMI for prognosis identification after cardiac surgery, focusing on immediate postoperative parameters.Among 9445 patients who underwent cardiac surgery over a span of 9 years, 40 NOMI cases (0.4%) requiring surgical interventions were reviewed. Suspected NOMI was diagnosed by sigmoidoscopy or computed tomography. To identify the risk factors, a control group (case: control = 1:3 ratio) was randomly selected and compared using logistic regression models.NOMI was diagnosed after a mean of 8.1 +/- 9.6 days following cardiac surgery. Age (odds ratio: 1.16, 95% confidence interval: 1.08-1.25, P < .001), total vasoactive-inotropic score (VIS), and the maximal lactate level at postoperative day 0 (1.003, [1.001-1.005], P = .012), (1.23, [1.04-1.44], P = .011) were shown as risk factors. NOMI cases showed persistent hyperlactatemia without washout during the first 48 hours (P = .04). Thirty-four cases underwent exploratory laparotomy within a median of 10 (2-356) hours after the diagnosis, but only 17 patients (42.5%) survived. Compared with survivors, nonsurvivors showed higher total VIS at diagnosis, higher lactate levels during the first 24 hours postoperatively, and more frequently required extensive bowel resection (P < .05).Old age, postoperative high-dose vasoactive-inotropic use, and persistent high lactate level during the first 24 hours postsurgery were identified as risk factors for NOMI. Lactic acidosis and necrotic-bowel extent at surgical exploration were associated with poor survival. PMID- 28906388 TI - Retrospective cause analysis of troponin I elevation in non-CAD patients: Special emphasis on sepsis. AB - BACKGROUND: Troponin I is one of the most commonly tested biochemical markers in the emergency room (ER) and in the hospital setting. Besides coronary artery disease (CAD), demand ischemia with underlying tachycardia, anemia, hypertensive emergency, congestive heart failure, kidney disease, sepsis, and pulmonary embolism have also been reported to cause troponin I elevations. Few reports have excluded patients with CAD, and no study has summarized the proportion of these factors relative to an increased troponin I level. METHODS: The aim of this retrospective study was to investigate the level of contribution of causative factors in troponin I elevation. Charts of patients tested for troponin I during an ER visit or during hospitalization were collected. Patients with known CAD, abnormal stress tests, cardiac catheterizations, or discharge without an adequate cardiac evaluation were excluded. Logistic regression was used to identify predictors of elevated troponin I levels. RESULTS: A total of 586 patients were investigated in this study. Age, hemoglobin (Hb), heart rate (HR), glomerularfiltration rate, atrial fibrillation, congestive heart failure (CHF), and sepsis were significant predictors of elevated troponin I by analysis in univariate logistic regression (all P < .001). In multivariate logistic regression, sepsis, CHF, age, Hb, and HR were independent predictors of troponin I (all P < .01). A simple clinical scoring system was generated with 1 score on patients with age >= 60, Hb < 10 g/dL, and HR >= 100 beats per minute (bpm). The prevalence of elevated troponin I was 4%, 16%, 38%, and 50% for patients with scores of 0, 1, 2, and 3, respectively. In patients without sepsis and CHF, the chances of elevated troponin I were 2%, 11%, 28%, and 43%. CONCLUSIONS: Sepsis was found to be the strongest independent cause of elevated troponin I levels in non-CAD patients. The scoring system composed of age, hemoglobin (Hb), and heart rate (HR) can assist clinical evaluation of elevated troponin I test in non-CAD patients. PMID- 28906390 TI - Empathy and burnout of emergency professionals of a health region: A cross sectional study. AB - The objective of this study is to assess the association between levels of empathy and burnout of emergency professionals in all the assistance levels.A cross-sectional observational study was conducted in the health region of Lleida and the Pyrenees with 100 professionals from the field of Urgency. Participation reached 40.8%. Empathy and burnout were measured using the Spanish versions of the Jefferson Scale of Physician Empathy (JSPE) and Maslach Burnout Inventory (MBI) respectively. The total MBI score and its 3 dimensions (emotional exhaustion, depersonalization, and personal accomplishment) were analyzed. The JSPE and MBI scores were categorized into tertiles that were identified as "low," "moderate," and "high" levels.The median (interquartile range) was 112 (102-123) and 37 (27-53.5) for the JSPE and MBI scores respectively. Professionals with high burnout (MBI>=47) showed the lowest levels of empathy, that is, JSPE score of 105 (98-114); those with moderate burnout (31<=MBI < 47) had a JSPE score of 114 (104.5-120.5); and those with low burnout (MBI < 31) had a JSPE score of 120.5 (105.8-127.2). In addition, the highest levels of empathy were associated with the lowest levels of burnout, especially in depersonalization, and to a lesser extent in personal accomplishment. There were no differences in empathy and burnout for any of the other study variables.Our findings suggest that the empathy of emergency professionals is associated with burnout. Hence, reducing professional burnout could help keep emergency professionals' empathy levels high, which in turn would ensure a better quality of care. Nevertheless, it would be necessary to carry out prospective studies to describe the profiles of burnout and empathy as well as their association and evolution. PMID- 28906391 TI - A meta-analysis of the preoperative use of gabapentinoids for the treatment of acute postoperative pain following spinal surgery. AB - BACKGROUND: Gabapentinoid drugs, which include gabapentin and pregabalin, play an established role in the management of neuropathic pain. However, whether preoperative administration of gabapentinoids has a beneficial role in controlling acute pain after spinal surgery is unknown. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the efficacy and safety of the preoperative use of gabapentinoids (gabapentin and pregabalin) for the treatment of acute postoperative pain following spinal surgery. METHODS: In March 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, Cochrane Library, and Google databases. RCTs comparing gabapentinoids (gabapentin and pregabalin) with placebo in patients undergoing spine surgery were retrieved. The primary endpoint was the visual analogue scale (VAS) score with rest or mobilization at 6, 12, 24, and 48 hours and cumulative morphine consumption at 24 and 48 hours. The secondary outcomes were complications of nausea, vomiting, sedation, dizziness, headache, urine retention, pruritus, and visual disturbances. After tests for publication bias and heterogeneity among studies were performed, data were aggregated for random effects models when necessary. RESULTS: Sixteen clinical studies (gabapentin group n = 8 and pregabalin group n = 8) were ultimately included in the meta analysis. Gabapentinoids were associated with reduced pain scores at 6, 12, 24, and 48 hours. Similarly, gabapentinoids were associated with a reduction in cumulative morphine consumption at 24 and 48 hours. Furthermore, gabapentinoids can significantly reduce the occurrence of nausea, vomiting, and pruritus. There were no significant differences in the occurrence of sedation, dizziness, headache, visual disturbances, somnolence, or urine retention. CONCLUSIONS: Preoperative use of gabapentinoids was able to reduce postoperative pain, total morphine consumption, and morphine-related complications following spine surgery. Further studies should determine the optimal dose and whether pregabalin is superior to gabapentin in controlling acute pain after spine surgery. PMID- 28906392 TI - Comparison of fertility-sparing treatments in patients with early endometrial cancer and atypical complex hyperplasia: A meta-analysis and systematic review. AB - BACKGROUND: There are some fertility-sparing treatments in patients with early endometrial cancer (EEC) or atypical complex hyperplasia (ACH), and the objective is to compare them by evaluating the oncologic and reproductive outcomes. METHODS: We searched the published literature using Medline, Cochrane, EMBASE, and Google Scholar databases up to January 3, 2017, with various combinations of keywords fertility-sparing treatments, progesterone, progestin, intrauterine devices, early endometrial cancer, and atypical complex hyperplasia. The primary endpoint is the complete response (CR) rate, and the secondary endpoints are the partial response (PR) rate, relapse rate (RR), pregnancy rate, and live birth rate. RESULTS: Twenty-eight studies containing 1038 women with EEC or ACH were included for review and meta-analysis. The results demonstrated that women with EEC or ACH managed with progestin had a pooled CR rate of 71% (95% confidence interval [CI]: 63-77%). The pooled pregnancy outcomes showed that 34% of women taking progestin treatment for EEC or ACH became pregnant (95% CI: 30-38%); however, only 20% of them delivered live newborns. The pooled CR rate for women using intrauterine device (IUD) was 76% (95% CI: 67-83%), and pooled RR was 9% (95% CI: 5-17%). The pregnancy rate for women whom underwent IUD was 18% (95% CI: 7-37%), and 14% of them delivered live newborns. In patients using progestin plus IUD, the pooled CR rate was 87% (95% CI: 75-93%); among those patients, 40% became pregnant (95% CI: 20-63%), and 35% delivered live newborns. There is no publication bias for the CR rate. CONCLUSION: For patients with EEC and ACH, treatments with progestin, with or without IUD, or IUD alone can reach good CR rate; however, the pregnancy outcomes might be worse in patients treated with IUD alone. Further randomized-controlled studies are warranted to find out a better solution. PMID- 28906393 TI - Transcutaneous electrical nerve stimulation for postoperative pain control after total knee arthroplasty: A meta-analysis of randomized controlled trials. AB - BACKGROUND: This meta-analysis aimed to evaluate the efficiency and safety of transcutaneous electrical nerve stimulation (TENS) for pain control after total knee arthroplasty. METHODS: A systematic search was performed in Medline (1966 to June 2017), PubMed (1966 to June 2017), Embase (1980 to June 2017), ScienceDirect (1985 to June 2017), and the Cochrane Library. Only randomized controlled trial (RCT) was included. The fixed/random effect model was used according to the heterogeneity tested by I statistic. Meta-analysis was performed using Stata 11.0 software. RESULTS: Five RCTs including 472 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of visual analogue scale score at 12 hours (average: 3.58 vs 4.34, SMD = -0.260, 95% CI: -0.442 to -0.078, P = .005), 24 hours (average: 3.18 vs 3.52, SMD = -0.244, 95% CI: -0.426 to -0.063, P = .008), and 48 hours (average: 2.70 vs 2.96, SMD = -0.214, 95% CI: -0.395 to -0.033, P = .021) after total knee arthroplasty. Significant differences were found regarding opioid consumption at 12 hours (average: 14.44 vs 18.54, SMD = -0.503, 95% CI: -0.687 to -0.319, P = .000), 24 hours (average: 16.10 vs 18.40, SMD = -0.262, 95% CI: 0.443 to -0.080, P = .005), and 48 hours (average: 12.92 vs 15.12, SMD = -0.183, 95% CI: -0.364 to -0.002, P = .048). CONCLUSION: TENS could significantly reduce pain and opioid consumption after total knee arthroplasty. In addition, there were fewer adverse effects in the TENS groups. Higher quality RCTs are required for further research. PMID- 28906394 TI - Growth discordance of monoamniotic twin because of difference of cords diameter in forked umbilical cord: Case report. AB - A case of monochorionic-monoamniotic (MCMA) twin pregnancy with growth discordance because of difference of cord diameter in forked umbilical cord is reported.MCMA twins were diagnosed at 12 weeks of gestation and twin growth discordance was considered during the follow-up twice-weekly visits to the ultrasound and prenatal care units. The pregnancy was terminated at 34 weeks. Two live female babies weighing 2510 g and 1940 g were delivered. Examination of placenta and umbilical cords after birth showed that the 2 cords merged into a conjoint cord 1 cm from insertion to the placenta (forked umbilical cord). Placental color injection showed that the 2 fetuses shared the same placenta area. The diameters of the 2 cords were significantly different (1.5 vs 0.8 cm). This caused an unequal distribution of blood and nutrients, which is the real reason of twin growth discordance in this case.This case reveals that the diameter discordance of cords can be an important factor for twin growth discordance. Few relevant cases have previously been reported. Cords diameter measurement is suggested for ultrasound surveillance of twin growth discordance. PMID- 28906395 TI - Prognostic impact of surgical margin in patients with hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND: Surgical margin is an important prognostic factor in hepatectomy for patients with hepatocellular carcinoma (HCC). But the extent of surgical margins is still controversial. Our study was designed to systematically evaluate the prognosis of different width of resection margin. METHODS: We conducted comprehensive searches of electronic databases including PubMed, MEDLINE, EMBASE, Cochrane, and the ISI Web of Science for relevant studies. A meta-analysis was performed by RevMan 5.3 software. RESULTS: A total of 7 studies comprising 1932 patients were included. The patients with wider surgical margin were significantly higher than those with narrow surgical margin on 3-year overall survival (odds ratio [OR]: 1.58, 95% confidence interval (95% CI): 1.21-2.06, P = .0008), 5-year overall survival (OR: 1.76, 95% CI: 1.20-2.59, P = .004), 1-year disease-free survival (DFS)/recurrence-free survival (RFS) (OR: 1.43, 95% CI: 1.12-1.82, P = .005), 3-year DFS/RFS (OR: 1.66, 95% CI: 1.35-2.03, P < .00001), and 5-year DFS/RFS (OR: 1.69, 95% CI: 1.37-2.08, P < .00001). There was no significant difference in the 1-year overall survival rate for the 2 groups (OR: 1.24, 95% CI: 0.89-1.72, P = .20). CONCLUSION: In comparison with the narrow surgical margin group (<1 cm), the wide surgical margin (>=1 cm) can significantly improve the prognosis in patients with HCC. PMID- 28906396 TI - Chondrosarcoma of the patella: A case report. AB - RATIONALE: Chondrosarcoma, characterized by the production of cartilage matrix, is a common bone tumor, accounting for 20% to 27% of all malignant bone tumors. It often occurs in the cartilage of the pelvis, femur, tibia, and humerus. However, chondrosarcoma of the patella is extremely rare. PATIENT CONCERNS: The present study describes a case of chondrosarcoma affecting the right patella in a 68-year-old woman. The chief complaints were painful swelling and limitation of motion of the right knee for about half a year. The pain was a kind of dull ache. The skin around the right knee was red and hot. Moreover, she had a claudication gait due to the symptoms. DIAGNOSES: Irregular lytic lesions with ill-defined margins in the patella were determined through computed tomography and magnetic resonance imaging. The diagnosis of primary grade II chondrosarcoma was finally confirmed on the basis of postoperative pathological examination. INTERVENTIONS: The patient underwent an open surgery named extensive resection of patellar tumor to remove the tumor tissue completely. OUTCOMES: The patient was discharged without any complications 1 week after the surgery. At the 3-month follow-up, the patient was completely free from pain during daily activities, and normal range of motion of the right knee was achieved. Her gait was normal. There was no evidence of recurrence. LESSONS: We believe that an extensive resection is suitable for treating chondrosarcoma to avoid as far as possible local recurrence. An awareness of the potential for chondrosarcoma to present in the patella is crucial for both orthopedic surgeons and radiologists when confronted with similar cases. Besides, as reports of chondrosarcoma of the patella are rare, this study adds a better understanding of this rare condition to the medical literature. PMID- 28906397 TI - Clinical and microbiological characteristics of pyogenic liver abscess in a tertiary hospital in East China. AB - Pyogenic liver abscess (PLA) is a potentially life-threatening disease affecting many parts of the world, especially Asia. In this study, we explored the clinical and microbiological characteristics of PLA in Chinese patients.A 5-year (2010 2014) retrospective review of medical records on all PLA patients who were admitted to a tertiary teaching hospital was performed.Among 217 PLA cases who were confirmed cultural positive, Klebsiella pneumonia (K pneumonia) was the most common pathogen (n = 165, 76.0%), followed by Escherichia coli (n = 21, 9.7%). Notably, there is a higher incidence of diabetes mellitus in patients with K pneumoniae-induced PLA (KP-PLA) than that with non-K pneumoniae-induced PLA (non KP-PLA)(43.0% vs 21.2%, P = .005). However, it was less prevalent for concomitant hepatobiliary disease (20.0% vs 34.6%, P = .039) and history of intraabdominal trauma or surgery (13.3% vs 38.5%, P < .001) in patients with KP-PLA. Although K pneumoniae are sensitive to most common antibiotics (antibiotic resistance rates below 10%), some strains (1.2%) developed resistant to carbapenem. These results confirmed K pneumoniae as the predominant pathogen of PLA in the area in which the study was conducted. More attention should be directed toward monitoring the emergence of carbapenem-resistant K pneumoniae.KP-PLA is frequently diagnosed in patients with metabolic diseases accompanied by serious consequences, and it is therefore prudent to see that they receive sensitivity-directed antibiotic therapy. PMID- 28906398 TI - Abdominal fat distribution measured using computed tomography is associated with an increased risk of colorectal adenoma in men. AB - A few studies have shown inconsistent results regarding the association between the visceral fat proportion and colorectal adenomas. We aimed to investigate the association between abdominal fat distribution measured by computed tomography (CT) and colon adenoma.A total of 336 participants underwent physical examination, blood tests, colonoscopy, and abdominal computed tomography at Chung Ang University Hospital. The associations between the obesity indicies (body mass index, visceral fat area (VFA), subcutaneous fat area (SFA), VFA-to-SFA ratio (VFA/SFA), and colorectal adenomas were evaluated.Of 309 subjects, 119 patients (38.5%) had colorectal adenoma. Mean age and fasting plasma glucose were higher in the patients with colorectal adenoma (P < .05, respectively). The mean VFA (153.3 cm vs 131.4 cm, P < .01) and VFA/SFA (1.07 vs 0.92, P < .05) were higher in the adenoma group than in the nonadenoma group. Males had higher mean VFA and VFA/SFA (P < .001). The mean VFA, SFA, and VFA/SFA were not associated with the location, size, number, and advancement of colorectal adenoma. In multivariate analysis, colorectal adenoma was significantly associated with VFA rather than VFA/SFA. In addition, colorectal adenoma was significantly associated with VFA rather than VFA/SFA in the men. The VFA, SFA, and VFA/SFA were not associated with colorectal adenoma in the women.The VFA measured by using a CT scan was positively associated with the presence of colorectal adenoma, especially in men. Furthermore, average risk men with large visceral fat volume should be examined carefully in screening colonoscopy. PMID- 28906399 TI - Characteristics of infection and its impact on short-term outcome in patients with acute-on-chronic liver failure. AB - Bacterial infections are an important cause of mortality in liver failure. However, the type of infection, predictors of infection, and their impact on outcomes in patients with acute-on-chronic liver failure (ACLF) are limited.A total of 389 patients with ACLF were admitted in this retrospective, corhort study. Once admitted, clinical data including first infection site, type (community-acquired, healthcare-associated, or nosocomial), and second infection occurrence during hospitalization were collected. The outcome was mortality within 90 days. Multivariable logistic regression models were preformed to predict second infection development and 90-day mortality. Survival probability curves were calculated by the Kaplan-Meier method.Among 389 patients, 316 (81.2%) patients had infection. The 90-day mortality of patients with and without infection was 52.2% and 16.4%, respectively (P <.001). The most common first infection was healthcare associated (51.3%), followed by nosocomial (30.1%) and community-acquired infections (18.7%). Respiratory tract infection, spontaneous bacterial peritonitis, and urinary tract infection were most prevalent. Gram positive organism was more frequently seen than gram-negative organisms. Of note, fungi accounted for 15.9% of the total infection cases. During hospitalization, 26.6% patients developed second infections. The 90-day mortality of patients developed or did not develop a second infection were 67.9% and 46.6%, respectively (P <.001). Independent predictors of 90-day mortality in infected patients with ACLF were age, white blood cell (WBC) count, model for end-stage liver disease (MELD) score, hepatic encephalopathy (HE), and second infection.Infections (regardless of first or second infection) can increase the 90-day mortality significantly in patients with ACLF. And age, WBC count, MELD score, HE, and the presence of second infection are independent risk factors affecting 90-day mortality in patients with ACLF showing infection. PMID- 28906400 TI - The atherogenic index of plasma is a strong and independent predictor for coronary artery disease in the Chinese Han population. AB - Dyslipidemia is one of the most important factors for coronary artery disease (CAD). The atherogenic index of plasma (AIP), a new comprehensive lipid index, might be a strong marker for predicting the risk of CAD.A hospital-based case control study including 2936 CAD patients and 2451 controls was conducted in a Chinese population. Traditional lipid parameters were detected, and nontraditional lipid comprehensive indexes were calculated.Compared with controls, CAD patients had higher levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). By contrast, the level of high-density lipoprotein cholesterol (HDL-C) was lower in CAD patients. The values of nontraditional lipid profiles, including non-HDL-C, TC/HDL-C, LDL-C/HDL C, non-HDL-C/HDL-C (atherogenic index, AI), TC*TG*LDL/HDL-C (lipoprotein combine index, LCI), and lg (TG/HDL-C) (AIP), were all significantly higher in the cases than in the controls. The results of Pearson correlation analyses indicated that AIP was positively and significantly correlated with TC (r = 0.125, P < .001), TG (r = 0.810, P < .001), LDL-C (r = 0.035, P < .001), non-HDL-C (r = 0.322, P < .001), TC/HDL-C (r = 0.669, P < .001), LDL-C/HDL-C (r = 0.447, P < .001), AI (r = 0.669, P < .001), and LCI (r = 0.688, P < .001) and was negatively correlated with age (r = -0.122, P < .001) and HDL-C (r = -0.632, P < .001). In the univariate logistic regression analysis, AIP was the lipid parameter that was most strongly associated with CAD, with an unadjusted odds ratio of 1.782 (95% confidence interval: 1.490-2.131, P < .001), for an increase of 1-SD. Multivariate logistic regression analyses revealed that AIP was an independent risk factor for CAD.AIP might be a strong and independent predictor for CAD in the Chinese Han population. PMID- 28906402 TI - Barriers and facilitators to participation in clinical trial among lymphoma patients from Sun Yat-sen University Cancer Center in China: An observation study. AB - Recruitment rate of clinical trials in cancer patients is pretty low in China. Little is known about factors influencing trial recruitment in Chinese cancer patients. The aim of present study is to evaluate the barriers and facilitators to participation in clinical trials among lymphoma patients in China.From December 2014 to August 2015, the survey was carried out in the Department of Medical Oncology in Sun Yat-sen University Cancer Center. A self-made questionnaire was used among lymphoma patients (N = 331) to evaluate their attitude toward clinical trials. The questionnaire included 2 parts: patients' basic information and whether they were willing to participate in future clinical trials and their reasons.There were 53.5% patients willing to participate in clinical trials. The most common reasons were thirst for new treatments, trust on hospital and doctors, the idea that clinical trials may be more effective than conventional therapy, and to get more management and monitoring. The following patients are more likely to participate in clinical trials: patients who have children (P = .019) or spouse (P = .037), cannot afford treatment cost (P = .019), have tumor relapse (P = .045), and cared about the medical development (P = .032). Patients who have little knowledge of clinical trials are less likely to participate in clinical trials (P = .047).Popularization of knowledge about clinical trial is helpful to improve clinical trial participation in Chinese lymphoma patients. PMID- 28906401 TI - Transabdominal ultrasonography of the pancreas is superior to that of the liver for detection of ectopic fat deposits resulting from metabolic syndrome. AB - The aim of our study was to investigate the rate of nonalcoholic fatty pancreas disease (NAFPD) in the south China province of Fujian and its relationship to nonalcoholic fatty liver disease (NAFLD) and metabolic parameters.NAFPD is frequently identified on transabdominal ultrasound examination. The incidence of NAFPD varies from 16% to 69.7% depending on the country.A total of 256 subjects were recruited. Each was assessed by abdominal sonography to diagnose NAFLD and NAFPD. The ages, sexes, heights, weights, blood pressure, and detection of peripheral blood biochemical indices (cholesterol, triglycerides, high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL], and glucose) were recorded. The relationships among metabolic parameters and NAFPD or NAFLD were evaluated, and the positive rates of NAFLD and NAFPD in the general population were compared.The age, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), cholesterol, triglycerides, HDL, LDL, and glucose were significantly associated with NAFPD and NAFLD but the positive rate of NAFPD was significantly higher than that of NAFLD. The BMI, age, and NAFLD were the independent risk factors of NAFPD. The sex distribution, weight, SBP, DBP, BMI, LDL, HDL, triglycerides, glucose, cholesterol, NAFPD, and NAFLD were different significantly between metabolic syndrome and normal subjects.NAFPD and NAFLD can reflect the body metabolism, but NAFPD has a higher detection rate. PMID- 28906403 TI - The role of serum angiopoietin-2 levels in progression and prognosis of lung cancer: A meta-analysis. AB - BACKGROUND: Angiogenesis is an essential process in the development and progression of malignant tumors including lung cancer, in which angiopoietin-2 (Ang-2) plays an important role. The objective of this study was to assess the prognostic value of serum Ang-2 levels in patients with lung cancer. METHODS: A comprehensive systematic electronic search was performed in the Pubmed, Embase, Web of Science, china national knowledge infrastructure, and VIP databases update to October, 2016 (qikan.cqvip.com). Literatures examining the relevance of serum Ang-2 levels to progression and prognosis of lung cancer were eligible for our study. Standardized mean differences (SMD) with 95% confidence interval (95% CI) and a P value were applied to compare continuous variables, and hazard ratio (HR) with 95% CI as well as P value were applied for prognostic role. RESULTS: Twenty studies with 1911 patients met the eligibility criteria. Among them, 7 studies with 575 patients with lung cancer assessed the association between expression of serum Ang-2 and prognosis. According to our results, higher levels of serum Ang-2 were associated with the later stage of tumor. Serum Ang-2 levels were significantly lower in stage I than in stage II (SMD: -0.51; 95% CI: -0.75 to 0.27; P < .001), in stage II than in stage III (SMD: -0.52; 95% CI: -0.80 to 0.24; P < .001), in stage III than in stage IV (SMD: -0.58; 95% CI: -0.93 to 0.23; P = .001). In addition, serum Ang-2 levels were higher in patients with lymph node metastasis (SMD: 1.06; 95% CI, 0.57-1.56; P < .001). Meanwhile, patients with lung cancer with higher levels of serum Ang-2 were associated with a significant poorer prognosis when compared to those with lower serum Ang-2 levels (HR: 1.64; 95% CI: 1.20-2.25; P = .002), and this role was further detected when stratified by ethnicity and histological type. CONCLUSIONS: This systematic review and meta-analysis suggested that serum Ang-2 levels might be a potential predictor for staging, and were associated with prognosis of lung cancer. PMID- 28906404 TI - Ticagrelor-induced life-threatening bleeding via the cyclosporine-mediated drug interaction: A case report. AB - RATIONALE: Ticagrelor has become one of the first-line antiplatelet agents in acute coronary syndrome (ACS) patients recommend by the guideline due to its more potent and predictable antiplatelet effect. However, bleeding is still a severe drug adverse reaction of ticagrelor therapy. We report a first case on ticagrelor induced life-threatening bleeding via the cyclosporine-mediated drug interaction. PATIENT CONCERNS: A 58-year-old Chinese male who received cyclosporine 200 mg daily 5 years after renal transplantation. Ticagrelor was added for treating ACS. Unfortunately, gum bleeding and life-threatening bloody stool appeared 8 days later, accompanied with the sudden drop of blood pressure. INTERVENTIONS: Ticagrelor was replaced with clopidogrel. Intravenous injection of proton pump inhibitor and agkistrodon snake venom hemocoagulase were used to stop the bleeding. Meanwhile, packed red blood cells and plasma were continuously transfused to maintain adequate blood volume. OUTCOMES: The patient's bloody stool was well controlled after treatment. LESSONS: The present case demonstrates that a potential drug-drug interaction (DDI) may lead to a life-threatening drug adverse reaction especially in special subjects. Therefore, regarding DDI, optimizing antiplatelet treatment should be considered for the efficacy and safety of P2Y12 receptor antagonist in this fragile population. PMID- 28906405 TI - Repetitive optimizing left ventricular pacing configurations with quadripolar leads improves response to cardiac resynchronization therapy: A single-center randomized clinical trial. AB - BACKGROUND: This study aimed to investigate whether repetitive optimizing left ventricular pacing configurations (LVPCs) with quadripolar leads (QUAD) can improve response to cardiac resynchronization therapy (CRT). METHODS: Fifty-two eligible patients were enrolled and 1:1 randomized to either the quadripolar LV leads (QUAD) group or the conventional bipolar leads (CONV) group. In the QUAD group, optimization of LVPC was performed for all patients before discharge and for nonresponders at 3 months follow-up. Clinical evaluations and transthoracic echocardiograms were performed before, 3, and 6 months after CRT implantation. RESULTS: At 3 months follow-up, 16 of 25 (64%) patients in the CONV group (1 patient was lost to follow-up) and 18 of 26 (69%) patients in the QUAD group were classified as responders. After optimizing the LVPCs in 3-month nonresponders in the QUAD group, 21 of 26 (80.8%) patients in the QUAD group were classified as responders at 6 months as compared with 17 of 25 (68%) patients in the CONV group. Left ventricular end-systolic volume (LVESV) reduction, left ventricular ejection fraction (LVEF) increase, and New York Heart Association (NYHA) functional class reduction at 6 months were significantly greater in the QUAD group than in the CONV group (LVESV: -26.9 +/- 13.8 vs -17.2 +/- 13.3%; P = .013; LVEF: +12.7 +/- 8.0 vs +7.8 +/- 6.3 percentage points; P = .017; NYHA: -1.27 +/- 0.67 vs -0.72 +/- 0.54 functional classes; P = .002). CONCLUSIONS: Compared with conventional bipolar leads, CRT using quadripolar leads with repetitive optimized LVPCs resulted in an additional increase in LVEF and reduction in LVESV and NYHA functional class at 6-month follow-up. PMID- 28906406 TI - Parathyroid hormone in relation to various vitamin D metabolites in adult females. AB - Vitamin D binding protein (DBP) and albumin are the important determinants of circulatory 25(OH)D in adults. Physiological function of vitamin D is particularly regulated by DBPs. Serum parathyroid hormone (PTH) is considered as the biological activity reader of circulating 25(OH)D. We therefore examined the relationships between serum total, free, and bioavailable 25(OH)D versus PTH in apparently healthy Saudi female adults.A total of 350 apparently healthy Saudi female adults ([Mean +/- standard deviation] age [years] 52.9 +/- 9.2; body mass index [kg/m] 32.9 +/- 5.4) were included in this observational study. Anthropometrics was measured as well as fasting glucose, lipid profile, calcium and phosphorous using routine methods. Serum 25(OH)D was measured using an electrochemiluminescence immunoassay. Serum DBP was determined by ELISA. Free and bioavailable 25(OH)D were calculated by comparing concentrations of total 25(OH)D, DBP, and albumin.Data revealed that circulating total 25(OH)D had weak but significant inverse association with DBP (R = -0.24; P < .01), and strong inverse associations with free 25(OH)D (R = -0.87; P < .001), albumin-bound 25(OH)D (R = -0.88; P < .001), and bioavailable 25(OH)D (R = -0.89; p < 0.001). None of the vitamin D metabolites, including 25(OH)D, correlated with serum PTH.Various metabolites of 25(OH)D are not correlated with serum PTH in Saudi adult females. Bioavailable, albumin-bound and free 25(OH)D cannot be surrogate measures for vitamin D status, at least in this population. PMID- 28906407 TI - Gelatinases and physical exercise: A systematic review of evidence from human studies. AB - BACKGROUND: Matrix metalloproteinases (MMPs), particularly gelatinase A (MMP-2) and gelatinase B (MMP-9), as well as their tissue inhibitors (TIMP-1 and TIMP-2), are involved in the development of skeletal muscle tissue, in the repair process after muscle injury and in the adaptive modifications induced by physical exercise in skeletal muscle. This paper aims at reviewing results from human studies that investigated the role of gelatinases and their inhibitors in skeletal muscle response to acute physical exercise or training. METHODS: Electronic databases PubMed/MEDLINE, Scopus and Web of Science were searched for papers published between January 2000 and February 2017. The papers were eligible when reporting human studies in which MMP-2 and/or MMP-9 and/or the inhibitors TIMP-1/TIMP-2 were evaluated, in blood or muscular tissue, before and after acute physical exercise or before and after a period of structured physical training. We included studies on healthy subjects and patients with chronic metabolic diseases (obesity, diabetes mellitus, metabolic syndrome-MS) or asymptomatic coronary artery disease. We excluded studies on patients with neurological, rheumatologic or neoplastic diseases. RESULTS: Studies conducted on muscle biopsies showed an early stimulation of MMP-9 gene transcription as a result of acute exercise, whereas MMP-2 and TIMP transcription resulted from regular repetition of exercise over time. Studies on serum or plasma level of gelatinases and their inhibitors showed an early release of MMP-9 after acute exercise of sufficient intensity, while data on MMP-2 and TIMP were more contrasting. Most of the studies dealing with the effect of training indicated a trend toward reduction in blood gelatinase levels, once again more clear for MMP-9. This result was related to an anti-inflammatory effect of regular exercise and was more evident when training consisted of aerobic activities. This study has limitations: as the initial selection was done through titles and abstracts, incomplete retrieval cannot be excluded, as well as we cannot exclude bias due to selective reporting within studies. CONCLUSION: A better knowledge of the molecular events activated by different types of acute exercise and regular training could be of great relevance in order to maximize the benefits of physical activity in healthy subjects and patients. PMID- 28906408 TI - Eosinophilic gastroenteritis presenting as upper gastrointestinal hematoma and ulcers after endoscopic biopsy: A case report and literature review. AB - RATIONALE: Eosinphilic gastroenteritis (EG) is a gastrointestinal disorder characterized by eosinophilic infiltration with various manifestations. The diagnosis is usually confirmed by an endoscopic biopsy, which is considered a safe and routine procedure for the majority. PATIENT CONCERNS: We report a 54 year-old male who was presented with intermittent periumbilical pain and melena, and only revealed verrucous gastritis by endoscopy. DIAGNOSES: The patient's condition worsened two days after the endoscopic biopsy, and another endoscopy found hematoma and ulcers in upper gastrointestinal tract. He was diagnosed with EG by the pathological analysis of biopsy specimen. INTERVENTIONS: Oral methylprednisolone and Montelukast were prescribed. OUTCOMES: The patient got remission after initiation of the treatment. LESSONS: This case highlights an extremely rare but potentially severe complication of endoscopic biopsies in patients with EG. Physicians should be cautious with hematoma or ulceration, and consider it in such patients who undergo this procedure. PMID- 28906409 TI - The study on the core personality trait words of Chinese medical university students based on social network analysis. AB - The medical university students in China whose school work is relatively heavy and educational system is long are a special professional group. Many students have psychological problems more or less. So, to understand their personality characteristics will provide a scientific basis for the intervention of psychological health.We selected top 30 personality trait words according to the order of frequency. Additionally, some methods such as social network analysis (SNA) and visualization technology of mapping knowledge domain were used in this study.Among these core personality trait words Family conscious had the 3 highest centralities and possessed the largest core status and influence. From the analysis of core-peripheral structure, we can see polarized core-perpheral structure was quite obvious. From the analysis of K-plex, there were in total 588 "K-2"K-plexs. From the analysis of Principal Components, we selected the 11 principal components.This study of personality not only can prevent disease, but also provide a scientific basis for students' psychological healthy education. In addition, we have adopted SNA to pay more attention to the relationship between personality trait words and the connection among personality dimensions. This study may provide the new ideas and methods for the research of personality structure. PMID- 28906410 TI - Augmented reality navigation in open surgery for hilar cholangiocarcinoma resection with hemihepatectomy using video-based in situ three-dimensional anatomical modeling: A case report. AB - RATIONALE: Patients who undergo hilar cholangiocarcinoma (HCAC) resection with concomitant hepatectomy have a high risk of postoperative morbidity and mortality due to surgical trauma to the hepatic and biliary vasculature. PATIENT CONCERNS: A 58-year-old Chinese man with yellowing skin and sclera, abdominal distension, pruritus, and anorexia for approximately 3 weeks. DIAGNOSES: Magnetic resonance cholangiopancreatography and enhanced computed tomography (CT) scanning revealed a mass over the biliary tree at the porta hepatis, which diagnosed to be s a hilar cholangiocarcinoma. INTERVENTION: Three-dimensional (3D) images of the patient's hepatic and biliary structures were reconstructed preoperatively from CT data, and the 3D images were used for preoperative planning and augmented reality (AR)-assisted intraoperative navigation during open HCAC resection with hemihepatectomy. A 3D-printed model of the patient's biliary structures was also used intraoperatively as a visual reference. OUTCOMES: No serious postoperative complications occurred, and the patient was tumor-free at the 9-month follow-up examination based on CT results. LESSONS: AR-assisted preoperative planning and intraoperative navigation might be beneficial in other patients with HCAC patients to reduce postoperative complications and ensure disease-free survival. In our postoperative analysis, we also found that, when the3D images were superimposed 3D-printed model using a see-through integral video graphy display device, our senses of depth perception and motion parallax were improved, compared with that which we had experienced intraoperatively using the videobased AR display system. PMID- 28906411 TI - Prognostic value of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of positron emission tomography/computed tomography in patients with nasopharyngeal carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: The maximal standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of positron emission tomography/computed tomography (PET/CT) in patients with nasopharyngeal carcinoma (NPC) perform as new prognostic factors, but the outcomes of the published articles were inconclusive. In this meta-analysis, we evaluated the prognostic value of SUVmax, MTV, and TLG of PET/CT in patients with NPC. METHODS: Relevant English articles were searched in PubMed and EMBASE. The data of patients and the survival outcomes were extracted. Pooled hazard ratios (HRs) were accounted to assess the prognostic value of the SUVmax, MTV, and TLG. RESULTS: This meta-analysis combined 10 primary studies including 941 patients with NPC. The combined HRs (95% confidence interval [CI] of higher SUVmax, higher MTV, and higher TLG for event-free survival were 2.33 (95% CI, 1.39-3.91, P = .001), 2.51 (95% CI, 1.61 3.91, P < .0001), and 2.74 (95% CI, 1.91-3.93, P < .00001), respectively. Regarding overall survival, the combined HRs were 2.50 (95%CI, 1.65-3.78, P < .0001) with higher SUVmax, 3.30 (95% CI, 1.92-5.69, P < .0001) with higher MTV and 3.18 (95% CI, 1.70-5.96, P = .0003) with higher TLG. CONCLUSION: SUVmax, MTV, and TLG were significant prognostic predictors in patients with NPC. And the results suggested that higher SUVmax, MTV, and TLG were associated with worse prognosis. PMID- 28906412 TI - Laparoscopic Nissen (total) versus anterior 180 degrees fundoplication for gastro-esophageal reflux disease: A meta-analysis and systematic review. AB - BACKGROUND: Laparoscopic Nissen fundoplication (LNF) has been the gold standard for the surgical management of Gastro-esophageal reflux disease (GERD). Laparoscopic anterior 180 degrees fundoplication (180 degrees LAF) is reported to reduce the incidence of postoperative complications while obtaining similar control of reflux. The present meta-analysis was conducted to confirm the value of the 2 techniques. METHODS: PubMed, Medline, Embase, Cochrane Library, Springerlink, and China National Knowledge Infrastructure Platform databases were searched for randomized controlled trials (RCTs) comparing LNF and 180 degrees LAF. Data regarding the benefits and adverse results of 2 techniques were extracted and compared using a meta-analysis. RESULTS: Six eligible RCTs comparing LNF (n = 266) and 180 degrees LAF (n = 265) were identified. There were no significant differences between LNF and 180 degrees LAF with regard to operating time, perioperative complications, length of hospital stay, patient satisfaction, willingness to undergo surgery again, quality of life, postoperative heartburn, proton pump inhibitor (PPI) use, postoperative DeMeester scores, postoperative lower esophageal sphincter (LES) pressure, postoperative gas-bloating, unable to belch, diarrhea, or overall reoperation. LNF was associated with a higher prevalence of postoperative dysphagia compared with 180 degrees LAF, while 180 degrees LAF was followed by more reoperation for recurrent reflux symptoms. CONCLUSION: LNF and 180 degrees LAF are equally effective in controlling reflux symptoms and obtain a comparable prevalence of patient satisfaction. 180 degrees LAF can reduce the incidence of postoperative dysphagia while this is offset by a higher risk of reoperation for recurrent symptoms. The risk of recurrent symptoms should need to be balanced against the risk of dysphagia when surgeons choose surgical procedures for each individual with GERD. PMID- 28906413 TI - Differences in clinical features observed between childhood-onset versus adult onset systemic lupus erythematosus: A systematic review and meta-analysis. AB - BACKGROUND: Systemic lupus erythematosus (SLE) affects people in childhood (childhood onset) or in adulthood (adult onset). Observational studies that have previously compared childhood-onset versus adult-onset SLE were often restricted to 1 ethnic group, or to a particular area, with a small sample size of patients. We aimed to systematically compare childhood-onset versus adult-onset SLE through a meta-analysis. METHODS: Electronic databases were searched for relevant publications comparing childhood-onset with adult-onset SLE. Adverse clinical features were considered as the endpoints. The Newcastle Ottawa Scale (NOS) was used to assess the methodological quality of the studies and RevMan software (version 5.3) was used to carry out this analysis whereby risk ratios (RRs) and 95% confidence intervals (95% CIs) were used as the statistical parameters. RESULTS: A total number of 10,261 participants (1560 participants with childhood onset SLE and 8701 participants with adult-onset SLE) were enrolled. Results of this analysis showed that compared with childhood-onset SLE, pulmonary involvement was significantly higher with adult-onset SLE (RR: 1.51, 95% CI: 1.18 1.93; P = .001), whereas renal involvement was significantly higher with childhood-onset SLE (RR: 0.65, 95% CI: 0.55-0.77; P = .00001). Raynaud phenomenon and photosensitivity were significantly higher in adult-onset SLE (RR: 1.29, 95% CI: 1.04-1.60; P = .02) and (RR: 1.08, 95% CI: 1.01-1.17; P = .03), respectively. Malar rash significantly favored adult-onset SLE (RR: 0.84, 95% CI: 0.75-0.94; P = .002). Childhood-onset SLE was associated with significantly higher hemolytic anemia, thrombocytopenia, leukocytopenia, and lymphopenia. Seizure and ocular manifestations were significantly higher with childhood-onset SLE (RR: 0.57, 95% CI: 0.47-0.70; P = .00001) and (RR: 0.34, 95% CI: 0.21-0.55; P = .00001), respectively, whereas pleuritis was significantly higher with adult-onset SLE (RR: 1.45, 95% CI: 1.17-1.79; P = .0008). Vasculitis and fever were significantly higher with childhood-onset SLE (RR: 0.51, 95% CI: 0.36-0.74; P = .0004) and (RR: 0.78, 95% CI: 0.68-0.89; P = .0002) respectively. CONCLUSION: Significant differences were observed between childhood-onset versus adult-onset SLE, showing the former to be more aggressive. PMID- 28906414 TI - The effect of lidocaine jelly on a taper-shaped cuff of an endotracheal tube on the postoperative sore throat: a prospective randomized study: A CONSORT compliant article. AB - BACKGROUND: Postoperative sore throat (POST) following general anesthesia with endotracheal intubation is a common complication. We hypothesized that lidocaine jelly applied to the tapered cuff of the endotracheal tube (ETT) might decrease the incidence of POST most commonly arising from endotracheal intubation. METHODS: A total of 208 patients under general anesthesia were randomly assigned into 1 of 2 groups. In the lidocaine group (n = 104), the distal part of ETTs with tapered-shaped cuff was lubricated with lidocaine jelly. In the control group (n = 104), the distal part of ETTs with tapered-shaped cuff was lubricated with normal saline. The incidence of POST, hoarseness, and cough in the postanesthesia patients was compared. RESULTS: The overall incidence of POST was higher in the lidocaine group than in the normal saline group [60 (58%) vs 40 (39%), P = .006]. The incidence of POST at 1 hour postoperatively was higher in the lidocaine group than in the normal saline group [53 (51%) vs 32 (31%), P = .003]. The overall incidence of hoarseness for 24 hours postoperatively was comparable (P = .487). The overall incidence of cough for 24 hours postoperatively is higher in the lidocaine group (P = .045). CONCLUSION: The lidocaine jelly applied at the distal part of ETT with tapered-shaped cuff increased the overall incidence of POST in patients undergoing general anesthesia. PMID- 28906416 TI - In favor of followership. PMID- 28906415 TI - Teaching Culturally Competent Veteran Nursing Care in Prelicensure Programs. AB - With the publication of Healthy People 2020, health disparities have been redefined to expand concepts beyond traditional racial and ethnic minorities and include a broader range of populations. Veterans, with their unique experiences and values, comprise a distinct culture with health risks and potential disparities. Although accrediting agencies require programs of nursing to teach culturally competent care, it is unknown whether nurse faculty recognize veterans as having a culture distinct from the rest of the population. Recognizing veterans as possessing a distinct culture is a first step in the provision of culturally competent care. PMID- 28906417 TI - Ripple effect: Shared governance and nurse engagement. PMID- 28906418 TI - Detection Rate, Anatomic Sites, and Pathologic Types of Colorectal Cancer During Colonoscopy Procedures. AB - PURPOSE: This study aims to help physicians obtain the detection rate and colonoscopic information of colorectal cancer (CRC) among patients in a city in China. METHODS: A total of 15,189 participants who underwent total colonoscopy between January 2000 and December 2015 were studied. A total of 1022 CRCs were diagnosed. We analyzed the detection rate, anatomic sites, and pathologic types among different sex, age, and decade groups. Moreover, we investigated the corresponding relationships between the anatomic sites and the pathologic types. RESULTS: Colonoscopic examinations revealed that the risk for CRC between men and women showed no significant difference (6.97% vs. 6.42%). The detection rate of CRC significantly increased with age (2.08% vs. 5.95% vs. 15.09%). The proportion of poorly differentiated adenocarcinoma among the youth group was significantly higher than that in the other age groups (25.0% vs. 11.54% vs. 8.33%). However, the numbers of cases with well-differentiated and moderately differentiated adenocarcinoma observed in the old-aged group were higher than other age groups. This finding demonstrated that the differentiation degree of adenocarcinoma increased with the age. Neuroendocrine tumor was mainly located in the rectum (95.0%), and appeared more frequently among the youth group (7.5% vs. 1.48% vs. 1.06%). CONCLUSIONS: We found the detection rate of CRC varied in terms of sex and decade. The CRC cases in the youth group exhibited a high malignant degree. The most common anatomic site was rectum, so we should focus more on digital rectal examination. PMID- 28906420 TI - Outcomes of Consistent Conservative Management for Acute Cholecystitis Followed by Delayed Cholecystectomy. AB - OBJECTIVE: This study's objective was to assess outcomes of a totally conservative strategy for acute cholecystitis (AC) followed by delayed elective cholecystectomy. PATIENTS AND METHODS: Consecutive patients who underwent cholecystectomy for AC were divided into the Emergent and Elective cholecystectomy groups. Patients in the elective cholecystectomy group were divided into early, medium, and late groups according to time from symptoms onset. RESULTS: The success rate for conservative management reached 97.2%. Increased blood loss and a higher conversion rate were significantly associated with the emergent group. Patients in the late group had significantly lower operative time and tended to have lower blood loss and less frequent conversion to open surgery than those in the early and medium groups. CONCLUSIONS: Most AC cases could be managed conservatively, and elective cholecystectomy was performed safely regardless of the time. Elective cholecystectomy carried out in late phase was likely to be associated with decreased surgical difficulty. PMID- 28906419 TI - Outcome Analyses of 15,189 Screenings Via Colonoscopy. AB - PURPOSE: This study investigated the detection rates of common colorectal diseases during colonoscopy procedures to provide reference for clinical diagnoses in China. METHODS: A total of 15,189 participants, who underwent total colonoscopy, were studied. We analyzed the detection rates of common colorectal diseases in different sex, age, and decade groups. RESULTS: The most common indication for colonoscopy is abdominal pain followed by change in bowel habits. Among the 15,189 participants, 5658 cases (37.25%) were normal. The most common positive finding was colorectal polyp (27.32%) followed by nonspecific colitis (12.06%), colorectal cancer (CRC) (7.71%), and ulcerative colitis (4.64%). The frequencies of polyp (31.56% vs. 21.99%; P=0.000) and CRC (8.28% vs. 7.00%; P=0.004) were higher in males than in females. By contrast, ischemic colitis (0.08% vs. 0.31%; P=0.001) and melanosis coli (1.15% vs. 1.87%; P=0.000) were more seen in females than in males. In addition, the detection rates for CRC (2.42% vs. 7.18% vs. 16.67%; P=0.000), colorectal polyp (17.65% vs. 32.27% vs. 34.73%; P=0.000), ischemic colitis (0.09% vs. 0.19% vs. 0.32%; P=0.033), and melanosis coli (0.71% vs. 1.09% vs. 3.21%; P=0.000) increased with age. CONCLUSIONS: The frequent positive findings were colorectal polyp, nonspecific colitis, and CRC. Patients showing alarming symptoms definitely require colonoscopy. The detection rates for colorectal polyp and melanosis coli were significantly higher in the later decade, so we should focus on these deseases. PMID- 28906421 TI - The Relationship Between Remoteness and Outcomes in Critically Ill Children. AB - OBJECTIVE: A significant number of children live in remote geographic areas without direct access to tertiary care PICU. Our objective was to explore the relationship between remoteness and outcomes of critically ill children in Canada. DESIGN: Retrospective cohort study of patients admitted to the PICU from February 1, 2015, to January 31, 2016. SETTING: Pediatric tertiary care PICU in Canada. PATIENTS: All children admitted to PICU during the study period. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS:: Four hundred fifty-five unique PICU admissions were included. One hundred sixty-nine patients were transported from another center of whom 28 lived in remote areas. For transported patients, remoteness (hazard ratio, 2.76, p < 0.001; hazard ratio, 2.22, p = 0.006), admission Pediatric Risk of Mortality (hazard ratio, 1.11; p = 0.001; hazard ratio, 1.05, p = 0.016), and transport by a noncritical care trained team (hazard ratio, 0.61, p = 0.021; hazard ratio, 0.66, p = 0.045) were associated with increased PICU and hospital lengths of stay, respectively. PICU mortality increased with duration of transport (odds ratio, 1.46; 95% CI, 1.09-1.97; p = 0.012). The odds of a remote-area patient being refused admission during the winter were significantly higher (odds ratio, 8.2; 95% CI, 3.0-22.3; p < 0.001) than a patient not requiring transport. Admission Pediatric Risk of Mortality score (4, interquartile range, 1-8 vs 2, interquartile range, 0-5; p = 0.001) and mortality rate (7.1%, 12/169 vs 0%, 0/286; p < 0.001) were significantly higher for transported than for nontransported patients. CONCLUSIONS: Remoteness was associated with increased PICU and hospital length of stay, and duration of transport was associated with higher admission Pediatric Risk of Mortality (PRISM) scores and mortality rates. Patients requiring transport had a significantly higher PICU mortality rate than those presenting directly to a tertiary care center. Further studies are needed to explore potential policy and healthcare resource implications of these findings. PMID- 28906422 TI - Increased Risk of Acute Kidney Injury in Critically Ill Children Treated With Vancomycin and Piperacillin/Tazobactam. AB - OBJECTIVES: Compare the rates of acute kidney injury in critically ill children treated with vancomycin and piperacillin-tazobactam versus vancomycin and ceftriaxone. DESIGN: Retrospective cohort study. SETTING: A large tertiary care children's hospital in an urban setting. PATIENTS: Children greater than or equal to 2 months old admitted to the PICU who received greater than or equal to 48 consecutive hours of vancomycin and piperacillin-tazobactam or vancomycin and ceftriaxone. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined as a minimum 50% increase in serum creatinine, adjusted for total fluid balance, from baseline over a 48-hour period. Bivariate analysis compared treatment groups and acute kidney injury groups. A multivariable logistic regression model was fit for acute kidney injury including covariable analysis. The study included 93 children. There were no differences between treatment groups in terms of age, severity of illness, baseline renal function, vancomycin dosing, or vancomycin trough concentrations. Children who received vancomycin and piperacillin-tazobactam had a higher cumulative frequency of acute kidney injury than those who received vancomycin and ceftriaxone 915/58 [25.9%] vs 3/35 [8.6%]; p = 0.041). After controlling for vancomycin trough concentration, age, concurrent nephrotoxin exposure, and use of vasopressors, exposure to piperacillin-tazobactam significantly increased the risk of acute kidney injury (adjusted odds ratio, 4.55; 95% CI [1.11-18.7]; p = 0.035) compared with ceftriaxone. Use of vasopressors (adjusted odds ratio, 3.73 [95% CI, 1.14 12.3]) and a vancomycin trough greater than or equal to 15 mg/dL (adjusted odds ratio, 4.12 [95% CI, 1.12-15.2)] was also associated with acute kidney injury. Length of stay was longer in children with acute kidney injury (median, 18.0 days; interquartile range, 7.76-29.7) compared with those without acute kidney injury (median, 6.21 days; interquartile range, 2.92-15.6; p = 0.017). CONCLUSIONS: In critically ill children, acute kidney injury occurred more in patients treated with vancomycin and piperacillin-tazobactam versus vancomycin plus ceftriaxone. After controlling for covariates, exposure to piperacillin tazobactam was associated with an increased odds of acute kidney injury development. PMID- 28906423 TI - Empowering Parents of Australian Infants and Children in Hospital: Translation, Cultural Adaptation, and Validation of the EMpowerment of PArents in The Intensive Care-30-AUS Questionnaire. AB - OBJECTIVES: To translate, culturally adapt, and psychometrically test the EMpowerment of PArents in The Intensive Care-30 questionnaire in Australian pediatric critical care, neonatal, and pediatric ward settings. DESIGN: Cross sectional, descriptive, multicenter study conducted in two phases; 1) translation and cultural adaptation and 2) validation of the EMpowerment of PArents in The Intensive Care-30 questionnaire. SETTINGS: Two Western Australian sites, the PICU and two pediatric wards of a children's hospital and the neonatal unit of a women's and newborn hospital. PARTICIPANTS: Parents whose baby or child was admitted to the participating wards or units with a length of hospital stay greater than 24 hours. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Phase 1: A structured 10-step translation process adhered to international principles of good practice for translation and cultural adaptation of patient-reported outcomes. Thirty parents participated in cognitive debriefing. Phase 2: A total of 328 parents responded to the EMpowerment of PArents in The Intensive Care-30 AUS questionnaire. Reliability was sufficient (Cronbach alpha at domain level 0.70 -0.82, for each clinical area 0.56-0.86). Congruent validity was adequate between the domains and three general satisfaction items (rs 0.38-0.69). Nondifferential validity showed no significant effect size between three patient or parent demographic characteristics and the domains (Cohen's d < 0.36). Between the different clinical areas, significant differences in responses were found in all domains. CONCLUSIONS: The translated and culturally adapted EMpowerment of PArents in The Intensive Care-30-AUS is a reliable and valid questionnaire to measure parent-reported outcomes in pediatric critical care, pediatric ward, and neonatal hospital settings. Using this questionnaire can provide a framework for a standardized quality improvement approach and identification of best practices across specialties, hospital services and for benchmarking similar health services worldwide. PMID- 28906424 TI - Accurate Identification of Colonoscopy Quality and Polyp Findings Using Natural Language Processing. AB - OBJECTIVES: The aim of this study was to test the ability of a commercially available natural language processing (NLP) tool to accurately extract examination quality-related and large polyp information from colonoscopy reports with varying report formats. BACKGROUND: Colonoscopy quality reporting often requires manual data abstraction. NLP is another option for extracting information; however, limited data exist on its ability to accurately extract examination quality and polyp findings from unstructured text in colonoscopy reports with different reporting formats. STUDY DESIGN: NLP strategies were developed using 500 colonoscopy reports from Kaiser Permanente Northern California and then tested using 300 separate colonoscopy reports that underwent manual chart review. Using findings from manual review as the reference standard, we evaluated the NLP tool's sensitivity, specificity, positive predictive value (PPV), and accuracy for identifying colonoscopy examination indication, cecal intubation, bowel preparation adequacy, and polyps >=10 mm. RESULTS: The NLP tool was highly accurate in identifying examination quality-related variables from colonoscopy reports. Compared with manual review, sensitivity for screening indication was 100% (95% confidence interval: 95.3%-100%), PPV was 90.6% (82.3% 95.8%), and accuracy was 98.2% (97.0%-99.4%). For cecal intubation, sensitivity was 99.6% (98.0%-100%), PPV was 100% (98.5%-100%), and accuracy was 99.8% (99.5% 100%). For bowel preparation adequacy, sensitivity was 100% (98.5%-100%), PPV was 100% (98.5%-100%), and accuracy was 100% (100%-100%). For polyp(s) >=10 mm, sensitivity was 90.5% (69.6%-98.8%), PPV was 100% (82.4%-100%), and accuracy was 95.2% (88.8%-100%). CONCLUSION: NLP yielded a high degree of accuracy for identifying examination quality-related and large polyp information from diverse types of colonoscopy reports. PMID- 28906425 TI - Impact of Changeover to Newer Endoscopic Systems on Quality and Efficiency of Screening and Surveillance Colonoscopy: Equipment or Endoscopist. AB - GOALS: The goal of this study is to assess whether changeover to newer endoscopic systems impacts quality or efficiency, and quantify the relation between increased withdrawal time and detection rates of sessile serrated polyps (SSPDR) and adenomas (ADR) in real-world practice. STUDY: Beginning 2 months after new endoscopic systems were implemented at 2 endoscopy units, we included all outpatients undergoing screening/surveillance colonoscopy for 4 months. Outpatients during the same 4-month period 1 year earlier comprised the control group. Quality endpoints included ADR, advanced ADR, SSPDR, polyp detection rate (PDR), and withdrawal time. The efficiency endpoint was procedure time. Statistical adjustment for potential confounding factors was performed with multivariable analysis. RESULTS: Significant increases occurred in postchangeover (N=1122) versus prechangeover (N=1131) procedure time (difference=2.6 minutes; 1.6 to 3.6) and withdrawal time (difference=1.6 minutes; 0.8 to 2.5). Significant increases also occurred in ADR [435 (39%) vs. 380 (34%)], advanced ADR [82 (7%) vs. 50 (4%)], and PDR [664 (59%) vs. 611 (54%)], but these differences lost significance when withdrawal time was added to the multivariable model. For every minute increase in withdrawal time a significant increase was seen in ADR (OR=1.09; 1.08 to 1.11), advanced ADR (OR=1.10; 1.08 to 1.13), SSPDR (OR=1.07; 1.06 to 1.09), and PDR (OR=1.16; 1.14 to 1.18). CONCLUSIONS: After changeover to newer endoscopy systems withdrawal times lengthened, resulting in increased procedure time, ADR, and advanced ADR. Regardless of endoscopic system, lengthening withdrawal time increased SSPDR, ADR, and advanced ADR: odds of detection increased 7% to 10% with every additional minute of withdrawal time. Greater attention to withdrawal time and endoscopist examination may be more productive than upgrading endoscopic systems. PMID- 28906426 TI - MELD Stratified Outcomes Among Recipients With Diabetes or Hypertension: Simultaneous Liver Kidney Versus Liver Alone. AB - BACKGROUND AND AIM: Data are scanty on allocating simultaneous liver kidney (SLK) based on model for end-stage disease (MELD) score. Diabetes mellitus (DM) and hypertension (HTN) are frequent in cirrhosis patients. We analyzed transplant recipients with DM and/or HTN to compare MELD-based outcomes of SLK to liver transplantation alone (LTA). MATERIALS AND METHODS: Of 13,584 first deceased donor liver transplantation among patients with DM and/or HTN (1530 or 11.2% SLK), MELD score predicted SLK [1.02 (1.01-1.03)]. SLK was beneficial for 5-year patient survival at MELD score >=43 (78.6% vs. 62.6%, P=0.017), but not at MELD score <29 (74.8% vs. 76.2%, P=0.63). Among 11,405 recipients (976 SLK) at MELD score <29, SLK (n=816) was beneficial compared with 706 LTA [75% vs. 64%, P<0.001; 0.71 (0.55-0.91)] at serum creatinine (SC) >=2 but not at SC<2 [73% vs. 76%, P=0.32; 0.85 (0.60-1.2)]. Among patients with MELD score 29 to 42, SLK (n=484) and LTA (n=1403) had similar survival [69% vs. 69%, P=0.58; 0.9 (0.7 1.5)]. Among patients with MELD score >=43, SLK (n=70) was associated with 35% improved patient survival at 5 years compared with 222 LTA [0.65 (0.46-0.93)]. CONCLUSIONS: Among patients with DM and/or HTN, SLK is useful at: (a) MELD score <29 and SC>=2 and (b) MELD score >=43. Prospective studies are needed to confirm these findings as basis to optimize use of SLK. PMID- 28906428 TI - Spatial Scale Gap Filling Using an Unmanned Aerial System: A Statistical Downscaling Method for Applications in Precision Agriculture. AB - Applications of satellite-borne observations in precision agriculture (PA) are often limited due to the coarse spatial resolution of satellite imagery. This paper uses high-resolution airborne observations to increase the spatial resolution of satellite data for related applications in PA. A new variational downscaling scheme is presented that uses coincident aerial imagery products from "AggieAir", an unmanned aerial system, to increase the spatial resolution of Landsat satellite data. This approach is primarily tested for downscaling individual band Landsat images that can be used to derive normalized difference vegetation index (NDVI) and surface soil moisture (SSM). Quantitative and qualitative results demonstrate promising capabilities of the downscaling approach enabling effective increase of the spatial resolution of Landsat imageries by orders of 2 to 4. Specifically, the downscaling scheme retrieved the missing high-resolution feature of the imageries and reduced the root mean squared error by 15, 11, and 10 percent in visual, near infrared, and thermal infrared bands, respectively. This metric is reduced by 9% in the derived NDVI and remains negligibly for the soil moisture products. PMID- 28906427 TI - Biological Pathways Involved in Tumor Angiogenesis and Bevacizumab Based Anti Angiogenic Therapy with Special References to Ovarian Cancer. AB - The creation of new blood vessels from existing ones, which is a mechanism called "angiogenesis", is essential in cancer to supply cancerous growth. Moreover, the development and the progression of the tumor and its metastases are the result of an efficient vascular response. Cancer cells release and activate different angiogenic growth factors and their receptors in the tumor microenvironment to promote the angiogenic process. The most important pro-angiogenic factor is the "Vascular Endothelial Growth Factor" (VEGF) because of its mitogen activity on vascular endothelium. Bevacizumab is a monoclonal antibody that obstructs the binding of circulating vascular endothelial growth factor to its receptors and has been approved for the treatment of primary and recurrent ovarian cancer but also for many other solid tumors. PMID- 28906429 TI - Comment on: Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring. Int. J. Environ. Res. Public Health 2017, 14, 27. AB - There are considerable inconsistencies in the results of Haraux et al. [1].[...]. PMID- 28906431 TI - An Optical-Fiber-Based Airborne Particle Sensor. AB - A new optical-fiber-based airborne particle counter is reported. Unlike traditional light-scatter-based techniques, the particle is detected through the drop in optical fiber coupling efficiency as the particle disrupts the electromagnetic mode of the optical beam. The system is simple, substantially smaller than traditional systems, and does not require high power laser input. This makes it attractive for wearable air quality monitors where size is a premium. There is close agreement between theoretical model and experimental results for solid and liquid particles in the 1 to 10 um range. PMID- 28906430 TI - Identification of a Novel Inhibitor against Middle East Respiratory Syndrome Coronavirus. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated in 2012, and circulated worldwide with high mortality. The continual outbreaks of MERS-CoV highlight the importance of developing antiviral therapeutics. Here, we rationally designed a novel fusion inhibitor named MERS-five-helix bundle (MERS 5HB) derived from the six-helix bundle (MERS-6HB) which was formed by the process of membrane fusion. MERS-5HB consists of three copies of heptad repeat 1 (HR1) and two copies of heptad repeat 2 (HR2) while MERS-6HB includes three copies each of HR1 and HR2. As it lacks one HR2, MERS-5HB was expected to interact with viral HR2 to interrupt the fusion step. What we found was that MERS-5HB could bind to HR2P, a peptide derived from HR2, with a strong affinity value (KD) of up to 0.24 nM. Subsequent assays indicated that MERS-5HB could inhibit pseudotyped MERS-CoV entry effectively with 50% inhibitory concentration (IC50) of about 1 MUM. In addition, MERS-5HB significantly inhibited spike (S) glycoprotein-mediated syncytial formation in a dose-dependent manner. Further biophysical characterization showed that MERS-5HB was a thermo-stable alpha-helical secondary structure. The inhibitory potency of MERS-5HB may provide an attractive basis for identification of a novel inhibitor against MERS-CoV, as a potential antiviral agent. PMID- 28906432 TI - Total Power Radiometer for Medical Sensor Applications Using Matched and Mismatched Noise Sources. AB - This paper presents a simple total power radiometer to noninvasively measure the temperature of the human body. The proposed 3-GHz radiometer consists of an antenna collecting the noise power generated by a target, a low-noise and high gain receiver amplifying the noise power, and a detector converting the noise power to voltage. A single-pole-triple-throw (SP3T) switch is placed between the antenna and the receiver, while a personal computer is used to control the SP3T switch, collect and process the data such as detector output voltages and physical temperatures of the reference noise sources and the target. The fabricated radiometer shows a good performance agreement with a thermometer in the temperature measurement of water from 25.0 to 43.1 degrees C. For the accurate prediction of the target temperature, the radiometer is calibrated adaptively to the environment and radiometer variations. For this purpose, two reference noise sources (hot and cold) are proposed using matched and mismatched resistors at room temperature. These resistor-based noise sources offer a reliable performance without complex temperature control systems. Furthermore, they can be easily calibrated in real time by periodically measuring the physical temperatures of the resistors. In addition, the logarithmic detector with wide dynamic range is adopted and logarithmically-fitted based on the measurement results instead of linear approximation, which reduces the error caused by the limited dynamic range of resistor-based noise sources. In order to further increase the accuracy, the performance imbalances between ports in the SP3T switch are also taken into account by employing offsets in the radiometer output voltages. PMID- 28906433 TI - Effect of Environmental Factors on Intra-Specific Inhibitory Activity of Carnobacterium maltaromaticum. AB - Carnobacterium maltaromaticum is frequently associated with foods having extended shelf-life due to its inhibitory activity to other bacteria. The quantification of such inhibition interactions affected by various environmental factors is limited. This study investigated the effect of environmental factors relevant to vacuum-packaged beef on inhibition between two model isolates of C. maltaromaticum, D0h and D8c, specifically D8c sensitivity to D0h inhibition and D0h inhibitor production. The effects of temperature (-1, 7, 15, 25 degrees C), atmosphere (aerobic and anaerobic), pH (5.5, 6, 6.5), lactic acid (0, 25, 50 mM) and glucose (0, 0.56, 5.55 mM) on D8c sensitivity (diameter of an inhibition zone) were measured. The effects of pH, glucose, lactic acid and atmosphere on D0h inhibitor production were measured at 25 degrees C. Sensitivity of D8c was the highest at 15 degrees C, under aerobic atmosphere, at higher concentrations of undissociated lactic acid and glucose, and at pH 5.5 (p < 0.001). pH significantly affected D0h inhibitor production (p < 0.001), which was the highest at pH 6.5. The effect of lactic acid depended upon pH level; at relatively low pH (5.5), lactic acid decreased the production rate (arbitrary inhibition unit (AU)/mL/h). This study provides a quantitative description of intra-species interactions, studied in in vitro environments that are relevant to vacuum-packaged beef. PMID- 28906434 TI - Surface Profiling and Core Evaluation of Aluminum Honeycomb Sandwich Aircraft Panels Using Multi-Frequency Eddy Current Testing. AB - Surface damage on honeycomb aircraft panels is often measured manually, and is therefore subject to variation based on inspection personnel. Eddy current testing (ECT) is sensitive to variations in probe-to-specimen spacing, or lift off, and is thus promising for high-resolution profiling of surface damage on aluminum panels. Lower frequency testing also allows inspection through the face sheet, an advantage over optical 3D scanning methods. This paper presents results from the ECT inspection of surface damage on an approximately flat aluminum honeycomb aircraft panel, and compares the measurements to those taken using optical 3D scanning technology. An ECT C-Scan of the dented panel surface was obtained by attaching the probe to a robotic scanning apparatus. Data was taken simultaneously at four frequencies of 25, 100, 400 and 1600 kHz. A reference surface was then defined that approximated the original, undamaged panel surface, which also compensated for the effects of specimen tilt and thermal drift within the ECT instrument. Data was converted to lift-off using height calibration curves developed for each probe frequency. A damage region of 22,550 mm2 area with dents ranging in depth from 0.13-1.01 mm was analyzed. The method was accurate at 1600 kHz to within 0.05 mm (2sigma) when compared with 231 measurements taken via optical 3D scanning. Testing at 25 kHz revealed a 3.2 mm cell size within the honeycomb core, which was confirmed via destructive evaluation. As a result, ECT demonstrates potential for implementation as a method for rapid in-field aircraft panel surface damage assessment. PMID- 28906435 TI - Mitochondrial Biogenesis in Response to Chromium (VI) Toxicity in Human Liver Cells. AB - Hexavalent chromium (Cr(VI)) is a ubiquitous environmental pollutant, which poses a threat to human public health. Recent studies have shown that mitochondrial biogenesis can be activated by inflammatory and oxidative stress. However, whether mitochondrial biogenesis is involved in Cr(VI)-induced hepatotoxicity is unclear. Here, we demonstrated the induction of inflammatory response and oxidative stress, as indicated by upregulation of inflammatory factors and reactive oxygen species (ROS). Subsequently, we demonstrated that mitochondrial biogenesis, comprising the mitochondrial DNA copy number and mitochondrial mass, was significantly increased in HepG2 cells exposed to low concentrations of Cr(VI). Expression of genes related to mitochondrial function complex I and complex V was upregulated at low concentrations of Cr(VI). mRNA levels of antioxidant enzymes, including superoxide dismutase 1 and 2 (SOD1 and SOD2, respectively), kech like ECH associate protein 1 (KEAP1) and nuclear respiratory factor 2 (NRF-2), were also upregulated. Consistent with the above results, mRNA and protein levels of key transcriptional regulators of mitochondrial biogenesis such as the peroxisome-proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), NRF-1 and mitochondrial transcription factor A (TFAM) were increased by low concentrations of Cr(VI) in HepG2 cells. Moreover, we found that PGC-1alpha and NRF-1 tended to translocate into the nucleus. The expression of genes potentially involved in mitochondrial biogenesis pathways, including mRNA level of silent information regulator-1 (SIRT1), forkhead box class-O (FOXO1), threonine kinase 1 (AKT1), and cAMP response element-binding protein (CREB1), was also upregulated. In contrast, mitochondrial biogenesis was inhibited and the expression of its regulatory factors and antioxidants was downregulated at high and cytotoxic concentrations of Cr(VI) in HepG2 cells. It is believed that pretreatment with alpha-tocopherol could be acting against the mitochondrial biogenesis imbalance induced by Cr(VI). In conclusion, our study suggests that the homeostasis of mitochondrial biogenesis may be an important cellular compensatory mechanism against Cr(VI)-induced toxicity and a promising detoxification target. PMID- 28906436 TI - Development and Evaluation of a Manganese and Iron Food Frequency Questionnaire for Pediatrics. AB - Manganese (Mn) is an essential nutrient, but overexposure can lead to neurotoxicity. Given the essentiality of Mn in the diet, particularly during children's growth and development, it is imperative to quantify dietary Mn intake in populations that may be exposed to industrial sources of Mn. Dietary absorption of Mn is inversely associated with iron (Fe) stores, yet there is currently no food frequency questionnaire (FFQ) to assess dietary Mn and Fe intake. The study objective was to develop and evaluate the validity of a FFQ to measure dietary Mn and Fe intake in pediatrics by comparing the estimated intakes of Mn and Fe with biomarkers: Mn in blood and hair and Fe in serum. This study utilized a subset of the Communities Actively Researching Exposure Study (CARES) population residing in Guernsey County, Ohio. Dietary Mn was not correlated with either blood or hair Mn; however, dietary Mn and serum ferritin were significantly correlated, with a correlation coefficient of 0.51, p < 0.01. Moreover, dietary Fe and serum ferritin were also significantly correlated, with a correlation coefficient of 0.51, p < 0.01. This FFQ is a valid measurement tool for Fe intake as measured by serum ferritin; however, Mn intake did not correlate with either blood or hair Mn. PMID- 28906437 TI - Developing Fine-Grained Actigraphies for Rheumatoid Arthritis Patients from a Single Accelerometer Using Machine Learning. AB - In addition to routine clinical examination, unobtrusive and physical monitoring of Rheumatoid Arthritis (RA) patients provides an important source of information to enable understanding the impact of the disease on quality of life. Besides an increase in sedentary behaviour, pain in RA can negatively impact simple physical activities such as getting out of bed and standing up from a chair. The objective of this work is to develop a method that can generate fine-grained actigraphies to capture the impact of the disease on the daily activities of patients. A processing methodology is presented to automatically tag activity accelerometer data from a cohort of moderate-to-severe RA patients. A study of procesing methods based on machine learning and deep learning is provided. Thirty subjects, 10 RA patients and 20 healthy control subjects, were recruited in the study. A single tri-axial accelerometer was attached to the position of the fifth lumbar vertebra (L5) of each subject with a tag prediction granularity of 3 s. The proposed method is capable of handling unbalanced datasets from tagged data while accounting for long-duration activities such as sitting and lying, as well as short transitions such as sit-to-stand or lying-to-sit. The methodology also includes a novel mechanism for automatically applying a threshold to predictions by their confidence levels, in addition to a logical filter to correct for infeasible sequences of activities. Performance tests showed that the method was able to achieve around 95% accuracy and 81% F-score. The produced actigraphies can be helpful to generate objective RA disease-specific markers of patient mobility in-between clinical site visits. PMID- 28906439 TI - PSDAAP: Provably Secure Data Authenticated Aggregation Protocols Using Identity Based Multi-Signature in Marine WSNs. AB - Data authenticated aggregation is always a significant issue for wireless sensor networks (WSNs). The marine sensors are deployed far away from the security monitoring. Secure data aggregation for marine WSNs has emerged and attracted the interest of researchers and engineers. A multi-signature enables the data aggregation through one signature to authenticate various signers on the acknowledgement of a message, which is quite fit for data authenticated aggregation marine WSNs. However, most of the previous multi-signature schemes rely on the technique of bilinear pairing involving heavy computational overhead or the management of certificates, which cannot be afforded by the marine wireless sensors. Combined with the concept of identity-based cryptography, a few pairing-free identity-based multi-signature (IBMS) schemes have been designed on the basis of the integer factorization problem. In this paper, we propose two efficient IBMS schemes that can be used to construct provably secure data authenticated aggregation protocols under the cubic residue assumption, which is equal to integer factorization. We also employ two different methods to calculate a cubic root for the cubic residue number during the signer's private key extraction. The algorithms are quite efficient compared to the previous work, especially for the algorithms of the multi-signature generation and its verification. PMID- 28906438 TI - Acetylcholinesterase and Nicotinic Acetylcholine Receptors in Schistosomes and Other Parasitic Helminths. AB - Schistosomiasis, which is caused by helminth trematode blood flukes of the genus Schistosoma, is a serious health and economic problem in tropical areas, and the second most prevalent parasitic disease after malaria. Currently, there is no effective vaccine available and treatment is entirely dependent on a single drug, praziquantel (PZQ), raising a significant potential public health threat due to the emergence of PZQ drug resistance. It is thus urgent and necessary to explore novel therapeutic targets for the treatment of schistosomiasis. Previous studies demonstrated that acetylcholinesterase (AChE) and nicotinic acetylcholine receptors (nAChRs) play important roles in the schistosome nervous system and ion channels, both of which are targeted by a number of currently approved and marketed anthelminthic drugs. To improve understanding of the functions of the cholinergic system in schistosomes, this article reviews previous studies on AChE and nAChRs in schistosomes and other helminths and discusses their potential as suitable targets for vaccine development and drug design against schistosomiasis. PMID- 28906440 TI - Native and Heated Hydrolysates of Milk Proteins and Their Capacity to Inhibit Lipid Peroxidation in the Zebrafish Larvae Model. AB - Casein and whey proteins with and without heat treatment were obtained of whole milk and four commercial milks in Ecuador, and were hydrolyzed. Then, their capacity to inhibit the lipid peroxidation using the TBARS method was evaluated at concentrations of 0.02, 0.04, 0.2, and, 0.4 mg/mL. Native and heated hydrolysates of milk proteins present high inhibitions of lipid peroxidation with a dose dependent effect both in vivo and in vitro tests. Casein and whey proteins obtained from whole milk were the ones with the highest anti-oxidant activity in vitro and in vivo test. Native casein hydrolysate at 0.4 mg/mL present a value of 55.55% of inhibition of lipid peroxidation and heated casein hydrolysate at 0.4 mg/mL presents a value of 58.00% of inhibition of lipid peroxidation. Native whey protein at 0.4 mg/mL present a value of 34.84% of inhibition of lipid peroxidation, and heated whey protein at 0.4 mg/mL presents a value of 40.86% of inhibition of lipid peroxidation. Native and heated casein hydrolysates were more active than native and heated whey protein hydrolysates. Heat treatments have an effect of increasing the in vitro inhibition of lipid peroxidation of hydrolysates of milk protein. Casein and whey hydrolysates were able to inhibiting lipid peroxidation in the zebrafish larvae model. Native casein hydrolysate obtained of whole milk presents 48.35% of inhibition TBARS in vivo, this activity was higher in heated casein hydrolysate obtained of whole milk with a value of 56.28% of inhibition TBARS in vivo. Native whey protein hydrolysate obtained of whole milk presents 35.30% of inhibition TBARS, and heated whey protein hydrolysate obtained of whole milk was higher, with a value of 43.60% of inhibition TBARS in vivo. PMID- 28906441 TI - Bonding Behavior of Deformed Steel Rebars in Sustainable Concrete Containing both Fine and Coarse Recycled Aggregates. AB - In order to assess the bond behavior of deformed steel rebars in recycled aggregate concrete (RAC) incorporating both fine and coarse recycled aggregate, pull-out tests were carried out in this study on 16-mm diameter deformed steel rebars embedded concentrically in RAC. The concrete was designed using equivalently mixed proportions of both recycled coarse aggregate and recycled fine aggregate. The tests employed five types of recycled aggregate replacement combinations and three types of rebar placement orientation (i.e., vertical bars and two-tiered and three-tiered horizontal bars). Based on the pull-out test results, the maximum bond strength tended to decrease and the slip at the maximum bond strength increased as the average water absorption of the aggregate increased, irrespective of the rebar orientation or placement location within the concrete member. The pull-out test results for the horizontal steel rebars embedded in RAC indicate that the casting position effect could be determined from the mid-depth of the concrete member, irrespective of the member's height. The normalized bond versus slip relationship between the deformed rebar and the RAC could be predicted using an empirical model based on regression analysis of the experimental data. PMID- 28906442 TI - The Role of Ion Exchange Membranes in Membrane Capacitive Deionisation. AB - Ion-exchange membranes (IEMs) are unique in combining the electrochemical properties of ion exchange resins and the permeability of a membrane. They are being used widely to treat industrial effluents, and in seawater and brackish water desalination. Membrane Capacitive Deionisation (MCDI) is an emerging, energy efficient technology for brackish water desalination in which these ion exchange membranes act as selective gates allowing the transport of counter-ions toward carbon electrodes. This article provides a summary of recent developments in the preparation, characterization, and performance of ion exchange membranes in the MCDI field. In some parts of this review, the most relevant literature in the area of electrodialysis (ED) is also discussed to better elucidate the role of the ion exchange membranes. We conclude that more work is required to better define the desalination performance of the proposed novel materials and cell designs for MCDI in treating a wide range of feed waters. The extent of fouling, the development of cleaning strategies, and further techno-economic studies, will add value to this emerging technique. PMID- 28906443 TI - Cytotoxic Polyketides with an Oxygen-Bridged Cyclooctadiene Core Skeleton from the Mangrove Endophytic Fungus Phomosis sp. A818. AB - Plant endophytic microorganisms represent a largely untapped resource for new bioactive natural products. Eight polyketide natural products were isolated from a mangrove endophytic fungus Phomosis sp. A818. The structural elucidation of these compounds revealed that they share a distinct feature in their chemical structures, an oxygen-bridged cyclooctadiene core skeleton. The study on their structure-activity relationship showed that the alpha,beta-unsaturated delta lactone moiety, as exemplified in compounds 1 and 2, was critical to the cytotoxic activity of these compounds. In addition, compound 4 might be a potential agonist of AMPK (5'-adenosine monophosphate-activated protein kinase). PMID- 28906445 TI - Shape Memory Polyurethane Materials Containing Ferromagnetic Iron Oxide and Graphene Nanoplatelets. AB - Intelligent materials, such as memory shape polymers, have attracted considerable attention due to wide range of possible applications. Currently, intensive research is underway, in matters of obtaining memory shape materials that can be actuated via inductive methods, for example with help of magnetic field. In this work, an attempt was made to develop a new polymer composite-polyurethane modified with graphene nanoplates and ferromagnetic iron oxides-with improved mechanical properties and introduced magnetic and memory shape properties. Based on the conducted literature review, gathered data were compared to the results of similar materials. Obtained materials were tested for their thermal, rheological, mechanical and shape memory properties. Structure of both fillers and composites were also analyzed using various spectroscopic methods. The addition of fillers to the polyurethane matrix improved the mechanical and shape memory properties, without having a noticeable impact on thermal properties. As it was expected, the high content of fillers caused a significant change in viscosity of filled prepolymers (during the synthesis stage). Each of the studied composites showed better mechanical properties than the unmodified polyurethanes. The addition of magnetic particles introduced additional properties to the composite, which could significantly expand the functionality of the materials developed in this work. PMID- 28906444 TI - Short-Term Intake of a Fructose-, Fat- and Cholesterol-Rich Diet Causes Hepatic Steatosis in Mice: Effect of Antibiotic Treatment. AB - Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet +/- AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function. PMID- 28906446 TI - A Novel Low-Power-Consumption All-Fiber-Optic Anemometer with Simple System Design. AB - A compact and low-power consuming fiber-optic anemometer based on single-walled carbon nanotubes (SWCNTs) coated tilted fiber Bragg grating (TFBG) is presented. TFBG as a near infrared in-fiber sensing element is able to excite a number of cladding modes and radiation modes in the fiber and effectively couple light in the core to interact with the fiber surrounding mediums. It is an ideal in-fiber device used in a fiber hot-wire anemometer (HWA) as both coupling and sensing elements to simplify the sensing head structure. The fabricated TFBG was immobilized with an SWCNT film on the fiber surface. SWCNTs, a kind of innovative nanomaterial, were utilized as light-heat conversion medium instead of traditional metallic materials, due to its excellent infrared light absorption ability and competitive thermal conductivity. When the SWCNT film strongly absorbs the light in the fiber, the sensor head can be heated and form a "hot wire". As the sensor is put into wind field, the wind will take away the heat on the sensor resulting in a temperature variation that is then accurately measured by the TFBG. Benefited from the high coupling and absorption efficiency, the heating and sensing light source was shared with only one broadband light source (BBS) without any extra pumping laser complicating the system. This not only significantly reduces power consumption, but also simplifies the whole sensing system with lower cost. In experiments, the key parameters of the sensor, such as the film thickness and the inherent angle of the TFBG, were fully investigated. It was demonstrated that, under a very low BBS input power of 9.87 mW, a 0.100 nm wavelength response can still be detected as the wind speed changed from 0 to 2 m/s. In addition, the sensitivity was found to be -0.0346 nm/(m/s) under the wind speed of 1 m/s. The proposed simple and low-power-consumption wind speed sensing system exhibits promising potential for future long-term remote monitoring and on chip sensing in practical applications. PMID- 28906447 TI - Material Viscoelasticity-Induced Drift of Micro-Accelerometers. AB - Polymer-based materials are commonly used as an adhesion layer for bonding die chip and substrate in micro-system packaging. Their properties exhibit significant impact on the stability and reliability of micro-devices. The viscoelasticity, one of most important attributes of adhesive materials, is investigated for the first time in this paper to evaluate the long-term drift of micro-accelerometers. The accelerometer was modeled by a finite element (FE) method to emulate the structure deformation and stress development induced by change of adhesive property. Furthermore, the viscoelastic property of the adhesive was obtained by a series of stress-relaxation experiments using dynamic mechanical analysis (DMA). The DMA curve was imported into the FE model to predict the drift of micro-accelerometers over time and temperature. The prediction results verified by experiments showed that the accelerometer experienced output drift due to the development of packaging stress induced by both the thermal mismatch and viscoelastic behaviors of the adhesive. The accelerometers stored at room temperature displayed a continuous drift of zero offset and sensitivity because of the material viscoelasticity. Moreover, the drift level of accelerometers experiencing high temperature load was relatively higher than those of lower temperature in the same period. PMID- 28906448 TI - Valorization of By-Products from Commercial Fish Species: Extraction and Chemical Properties of Skin Gelatins. AB - Fish skins constitute an important fraction of the enormous amount of wastes produced by the fish processing industry, part of which may be valorized through the extraction of gelatins. This research exploited the extraction and characterization of gelatins from the skin of three seawater fish species, namely yellowfin tuna (Thunnus albacares), blue shark (Prionace glauca), and greenland halibut (Reinhardtius hippoglossoides). Characterization included chemical composition, rheology, structure, texture, and molecular weight, whereas extraction studies intended to reduce costly steps during extraction process (reagents concentration, water consumption, and time of processing), while maintaining extraction efficiency. Chemical and physical characterization of the obtained gelatins revealed that the species from which the gelatin was extracted, as well as the heat treatment used, were key parameters in order to obtain a final product with specific properties. Therefore, the extraction conditions selected during gelatin production will drive its utilization into markets with well-defined specifications, where the necessity of unique products is being claimed. Such achievements are of utmost importance to the food industry, by paving the way to the introduction in the market of gelatins with distinct rheological and textural properties, which enables them to enlarge their range of applications. PMID- 28906449 TI - Facile Preparation of a Robust and Durable Superhydrophobic Coating Using Biodegradable Lignin-Coated Cellulose Nanocrystal Particles. AB - It is a challenge for a superhydrophobic coating to overcome the poor robustness and the rough surface structure that is usually built using inorganic particles that are difficult to degrade. In this study, a robust superhydrophobic coating is facilely prepared by using commercial biodegradable lignin-coated cellulose nanocrystal (L-CNC) particles after hydrophobic modification to build rough surface structures, and by choosing two different adhesives (double-sided tape and quick-setting epoxy) to support adhesion between the L-CNC particles and the substrates. In addition to excellent self-cleaning and water repellence properties, the resulting coatings show outstanding mechanical strength and durability against sandpaper abrasion, finger-wipe, knife-scratch, water jet, UV radiation, high temperature, and acidic and alkali solutions, possessing a wide application prospect. PMID- 28906450 TI - Obstacle Recognition Based on Machine Learning for On-Chip LiDAR Sensors in a Cyber-Physical System. AB - Collision avoidance is an important feature in advanced driver-assistance systems, aimed at providing correct, timely and reliable warnings before an imminent collision (with objects, vehicles, pedestrians, etc.). The obstacle recognition library is designed and implemented to address the design and evaluation of obstacle detection in a transportation cyber-physical system. The library is integrated into a co-simulation framework that is supported on the interaction between SCANeR software and Matlab/Simulink. From the best of the authors' knowledge, two main contributions are reported in this paper. Firstly, the modelling and simulation of virtual on-chip light detection and ranging sensors in a cyber-physical system, for traffic scenarios, is presented. The cyber-physical system is designed and implemented in SCANeR. Secondly, three specific artificial intelligence-based methods for obstacle recognition libraries are also designed and applied using a sensory information database provided by SCANeR. The computational library has three methods for obstacle detection: a multi-layer perceptron neural network, a self-organization map and a support vector machine. Finally, a comparison among these methods under different weather conditions is presented, with very promising results in terms of accuracy. The best results are achieved using the multi-layer perceptron in sunny and foggy conditions, the support vector machine in rainy conditions and the self-organized map in snowy conditions. PMID- 28906451 TI - Radish (Raphanus sativus) and Diabetes. AB - For more than three decades, various in vitro and in vivo studies have linked radishes with diabetes, though this link has not been discussed. This review systematically addresses and summarizes the effect of radishes on diabetes. We searched the Web of Science, PubMed, and EMBASE databases for English language articles from June 1987 through May 2017 using the key words "radish" and "diabetes," and the references from particular reports were also considered if relevant. In summary, radish has been identified as having antidiabetic effects, making it favorable for those with diabetic conditions. This may be due to its ability to enhance the antioxidant defense mechanism and reduce the accumulation of free radicals, affect hormonal-induced glucose hemostasis, promote glucose uptake and energy metabolism, and reduce glucose absorption in the intestine. However, this summary requires further confirmation in research in vivo studies and clinical trials. PMID- 28906452 TI - An Embedded Multi-Agent Systems Based Industrial Wireless Sensor Network. AB - With the emergence of cyber-physical systems, there has been a growing interest in network-connected devices. One of the key requirements of a cyber-physical device is the ability to sense its environment. Wireless sensor networks are a widely-accepted solution for this requirement. In this study, an embedded multi agent systems-managed wireless sensor network is presented. A novel architecture is proposed, along with a novel wireless sensor network architecture. Active and passive wireless sensor node types are defined, along with their communication protocols, and two application-specific examples are presented. A series of three experiments is conducted to evaluate the performance of the agent-embedded wireless sensor network. PMID- 28906454 TI - Multiple Fatigue Failure Behaviors and Long-Life Prediction Approach of Carburized Cr-Ni Steel with Variable Stress Ratio. AB - Axial loading tests with stress ratios R of -1, 0 and 0.3 were performed to examine the fatigue failure behavior of a carburized Cr-Ni steel in the long-life regime from 104 to 108 cycles. Results show that this steel represents continuously descending S-N characteristics with interior inclusion-induced failure under R = -1, whereas it shows duplex S-N characteristics with surface defect-induced failure and interior inclusion-induced failure under R = 0 and 0.3. The increasing tension eliminates the effect of compressive residual stress and promotes crack initiation from the surface or interior defects in the carburized layer. The FGA (fine granular area) formation greatly depends on the number of loading cycles, but can be inhibited by decreasing the compressive stress. Based on the evaluation of the stress intensity factor at the crack tip, the surface and interior failures in the short life regime can be characterized by the crack growth process, while the interior failure with the FGA in the long life regime can be characterized by the crack initiation process. In view of the good agreement between predicted and experimental results, the proposed approach can be well utilized to predict fatigue lives associated with interior inclusion FGA-fisheye induced failure, interior inclusion-fisheye induced failure, and surface defect induced failure. PMID- 28906453 TI - Vitamin D Supplementation and Non-Alcoholic Fatty Liver Disease: Present and Future. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease throughout the Western world and is recognized as the main cause of cryptogenic cirrhosis; however, the identification of an effective therapy for NAFLD is still a major challenge. Vitamin D deficiency is a wide-spread condition which reaches epidemic proportions in industrialized countries, mainly in relation to current lifestyle and limited dietary sources. Epidemiological studies point towards an association between hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH), independently of confounders such as obesity and insulin resistance. Furthermore, several pieces of experimental data have shown the anti-fibrotic, anti-inflammatory and insulin-sensitizing properties exerted by vitamin D on hepatic cells. However, results from trials evaluating the effects of oral vitamin D supplementation on liver damage in NAFLD and NASH are controversial. The aim of this review is to give an overview of the evidence currently available from clinical trials and to discuss possible shortcomings and new strategies to be considered in future investigations. PMID- 28906455 TI - Deep Circular RNA Sequencing Provides Insights into the Mechanism Underlying Grass Carp Reovirus Infection. AB - Grass carp hemorrhagic disease, caused by the grass carp reovirus (GCRV), is a major disease that hampers the development of grass carp aquaculture in China. The mechanism underlying GCRV infection is still largely unknown. Circular RNAs (circRNAs) are important regulators involved in various biological processes. In the present study, grass carp were infected with GCRV, and spleen samples were collected at 0 (control), 1, 3, 5, and 7 days post-infection (dpi). Samples were used to construct and sequence circRNA libraries, and a total of 5052 circRNAs were identified before and after GCRV infection, of which 41 exhibited differential expression compared with controls. Many parental genes of the differentially expressed circRNAs are involved in metal ion binding, protein ubiquitination, enzyme activity, and nucleotide binding. Moreover, 72 binding miRNAs were predicted from the differentially expressed circRNAs, of which eight targeted genes were predicted to be involved in immune responses, blood coagulation, hemostasis, and complement and coagulation cascades. Upregulation of these genes may lead to endothelial and blood cell damage and hemorrhagic symptoms. Our results indicate that an mRNA-miRNA-circRNA network may be present in grass carp infected with GCRV, providing new insight into the mechanism underlying grass carp reovirus infection. PMID- 28906456 TI - Effects of beta-Glucans Ingestion on Alveolar Bone Loss, Intestinal Morphology, Systemic Inflammatory Profile, and Pancreatic beta-Cell Function in Rats with Periodontitis and Diabetes. AB - This study aimed to evaluate the effects of beta-glucan ingestion (Saccharomyces cerevisiae) on the plasmatic levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10), alveolar bone loss, and pancreatic beta-cell function (HOMA-BF) in diabetic rats with periodontal disease (PD). Besides, intestinal morphology was determined by the villus/crypt ratio. A total of 48 Wistar rats weighing 203 +/- 18 g were used. Diabetes was induced by the intraperitoneal injection of streptozotocin (80 mg/kg) and periodontal inflammation, by ligature. The design was completely randomized in a factorial scheme 2 * 2 * 2 (diabetic or not, with or without periodontitis, and ingesting beta-glucan or not). The animals received beta-glucan by gavage for 28 days. Alveolar bone loss was determined by scanning electron microscopy (distance between the cementoenamel junction and alveolar bone crest) and histometric analysis (bone area between tooth roots). beta-glucan reduced plasmatic levels of TNF-alpha in diabetic animals with PD and of IL-10 in animals with PD (p < 0.05). beta-glucan reduced bone loss in animals with PD (p < 0.05). In diabetic animals, beta-glucan improved beta-cell function (p < 0.05). Diabetic animals had a higher villus/crypt ratio (p < 0.05). In conclusion, beta-glucan ingestion reduced the systemic inflammatory profile, prevented alveolar bone loss, and improved beta cell function in diabetic animals with PD. PMID- 28906457 TI - Antibacterial Properties of Flavonoids from Kino of the Eucalypt Tree, Corymbia torelliana. AB - Traditional medicine and ecological cues can both help to reveal bioactive natural compounds. Indigenous Australians have long used kino from trunks of the eucalypt tree, Corymbia citriodora, in traditional medicine. A closely related eucalypt, C. torelliana, produces a fruit resin with antimicrobial properties that is highly attractive to stingless bees. We tested the antimicrobial activity of extracts from kino of C. citriodora, C. torelliana * C. citriodora, and C. torelliana against three Gram-negative and two Gram-positive bacteria and the unicellular fungus, Candida albicans. All extracts were active against all microbes, with the highest activity observed against P. aeruginosa. We tested the activity of seven flavonoids from the kino of C. torelliana against P. aeruginosa and S. aureus. All flavonoids were active against P. aeruginosa, and one compound, (+)-(2S)-4',5,7-trihydroxy-6-methylflavanone, was active against S. aureus. Another compound, 4',5,7-trihydroxy-6,8-dimethylflavanone, greatly increased biofilm formation by both P. aeruginosa and S. aureus. The presence or absence of methyl groups at positions 6 and 8 in the flavonoid A ring determined their anti-Staphylococcus and biofilm-stimulating activity. One of the most abundant and active compounds, 3,4',5,7-tetrahydroxyflavanone, was tested further against P. aeruginosa and was found to be bacteriostatic at its minimum inhibitory concentration of 200 ug/mL. This flavanonol reduced adhesion of P. aeruginosa cells while inducing no cytotoxic effects in Vero cells. This study demonstrated the antimicrobial properties of flavonoids in eucalypt kino and highlighted that traditional medicinal knowledge and ecological cues can reveal valuable natural compounds. PMID- 28906458 TI - Combination of Hypertension Along with a High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-kappaB, MAPK, and Nrf2 Pathways. AB - Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. An increased activation of proinflammatory signaling (transforming growth factor-beta1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH. PMID- 28906459 TI - Hospital Costs of Foreign Non-Resident Patients: A Comparative Analysis in Catalonia, Spain. AB - Although patient mobility has increased over the world, in Europe there is a lack of empirical studies. The aim of the study was to compare foreign non-resident patients versus domestic patients for the particular Catalan case, focusing on patient characteristics, hospitalisation costs and differences in costs depending on the typology of the hospital they are treated. We used data from the 2012 Minimum Basic Data Set-Acute Care hospitals (CMBD-HA) in Catalonia. We matched two case-control groups: first, foreign non-resident patients versus domestic patients and, second, foreign non-resident patients treated by Regional Public Hospitals versus other type of hospitals. Hospitalisation costs were modelled using a GLM Gamma with a log-link. Our results show that foreign non-resident patients were significantly less costly than domestic patients (12% cheaper). Our findings also suggested differences in the characteristics of foreign non resident patients using Regional Public Hospitals or other kinds of hospitals although we did not observe significant differences in the healthcare costs. Nevertheless, women, 15-24 and 35-44 years old patients and the days of stay were less costly in Regional Public Hospitals. In general, acute hospitalizations of foreign non-resident patients while they are on holiday cost substantially less than domestic patients. The typology of hospital is not found to be a relevant factor influencing costs. PMID- 28906460 TI - A Critical Assessment of the Therapeutic Potential of Resveratrol Supplements for Treating Mitochondrial Disorders. AB - In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation (OXPHOS). Impaired OXPHOS activity leads to a heterogeneous group of inherited diseases for which therapeutic options today remain very limited. Potential innovative strategies aim to ameliorate mitochondrial function by increasing the total mitochondrial load of tissues and/or to scavenge the excess of reactive oxygen species generated by OXPHOS malfunctioning. In this respect, resveratrol, a compound that conveniently combines mitogenetic with antioxidant activities and, as a bonus, possesses anti-apoptotic properties, has come forward as a promising nutraceutical. We review the scientific evidence gathered so far through experiments in both in vitro and in vivo systems, evaluating the therapeutic effect that resveratrol is expected to generate in mitochondrial patients. The obtained results are encouraging, but clearly show that achieving normalization of OXPHOS function with this strategy alone could prove to be an unattainable goal. PMID- 28906461 TI - alpha-Conotoxin Decontamination Protocol Evaluation: What Works and What Doesn't. AB - Nine publically available biosafety protocols for safely handling conotoxin peptides were tested to evaluate their decontamination efficacy. Circular dichroism (CD) spectroscopy and mass spectrometry (MS) were used to assess the effect of each chemical treatment on the secondary and primary structure of alpha CTx MII (L10V, E11A). Of the nine decontamination methods tested, treatment with 1% (m/v) solution of the enzymatic detergent ContrexTM EZ resulted in a 76.8% decrease in alpha-helical content as assessed by the mean residue ellipticity at 222 nm, and partial peptide digestion was demonstrated using high performance liquid chromatography mass spectrometry (HPLC-MS). Additionally, treatment with 6% sodium hypochlorite (m/v) resulted in 80.5% decrease in alpha-helical content and complete digestion of the peptide. The ContrexTM EZ treatment was repeated with three additional alpha-conotoxins (alpha-CTxs), alpha-CTxs LvIA, ImI and PeIA, which verified the decontamination method was reasonably robust. These results support the use of either 1% ContrexTM EZ solution or 6% sodium hypochlorite in biosafety protocols for the decontamination of alpha-CTxs in research laboratories. PMID- 28906462 TI - Time-Resolved Diffuse Optical Spectroscopy and Imaging Using Solid-State Detectors: Characteristics, Present Status, and Research Challenges. AB - Diffuse optical spectroscopy (DOS) and diffuse optical imaging (DOI) are emerging non-invasive imaging modalities that have wide spread potential applications in many fields, particularly for structural and functional imaging in medicine. In this article, we review time-resolved diffuse optical imaging (TR-DOI) systems using solid-state detectors with a special focus on Single-Photon Avalanche Diodes (SPADs) and Silicon Photomultipliers (SiPMs). These TR-DOI systems can be categorized into two types based on the operation mode of the detector (free running or time-gated). For the TR-DOI prototypes, the physical concepts, main components, figures-of-merit of detectors, and evaluation parameters are described. The performance of TR-DOI prototypes is evaluated according to the parameters used in common protocols to test DOI systems particularly basic instrumental performance (BIP). In addition, the potential features of SPADs and SiPMs to improve TR-DOI systems and expand their applications in the foreseeable future are discussed. Lastly, research challenges and future developments for TR DOI are discussed for each component in the prototype separately and also for the entire system. PMID- 28906463 TI - Inhibition of Adherence of Mycobacterium avium to Plumbing Surface Biofilms of Methylobacterium spp. AB - Both Mycobacterium spp. and Methylobacterium spp. are opportunistic premise plumbing pathogens that are found on pipe surfaces in households. However, examination of data published in prior microbiological surveys indicates that Methylobacterium spp. and Mycobacterium spp. tend not to coexist in the same household plumbing biofilms. That evidence led us to test the hypothesis that Methylobacterium spp. in biofilms could inhibit the adherence of Mycobacterium avium. Measurements of adherence of M. avium cells to stainless steel coupons using both culture and PCR-based methods showed that the presence of Methylobacterium spp. biofilms substantially reduced M. avium adherence and vice versa. That inhibition of M. avium adherence was not reduced by UV-irradiation, cyanide/azide exposure, or autoclaving of the Methylobacterium spp. biofilms. Further, there was no evidence of the production of anti-mycobacterial compounds by biofilm-grown Methylobacterium spp. cells. The results add to understanding of the role of microbial interactions in biofilms as a driving force in the proliferation or inhibition of opportunistic pathogens in premise plumbing, and provide a potential new avenue by which M. avium exposures may be reduced for at risk individuals. PMID- 28906464 TI - Enhanced Plasmonic Wavelength Selective Infrared Emission Combined with Microheater. AB - The indirect wavelength selective thermal emitter that we have proposed is constructed using a new microheater, demonstrating the enhancement of the emission peak generated by the surface plasmon polariton. The thermal isolation is improved using a 2 MUm-thick Si membrane having 3.6 and 5.4 mm outer diameter. The emission at around the wavelength of the absorption band of CO2 gas is enhanced. The absorption signal increases, confirming the suitability for gas sensing. Against input power, the intensity at the peak wavelength shows a steeper increasing ratio than the background intensity. The microheater with higher thermal isolation gives larger peak intensity and its increasing ratio against the input power. PMID- 28906465 TI - Low-Temperature Self-Healing of a Microcapsule-Type Protective Coating. AB - Low-temperature self-healing capabilities are essential for self-healing materials exposed to cold environments. Although low-temperature self-healing concepts have been proposed, there has been no report of a microcapsule-type low temperature self-healing system wherein the healing ability was demonstrated at low temperature. In this work, low-temperature self-healing of a microcapsule type protective coating was demonstrated. This system employed silanol-terminated polydimethylsiloxane (STP) as a healing agent and dibutyltin dilaurate (DD) as a catalyst. STP underwent a condensation reaction at -20 degrees C in the presence of DD to give a viscoelastic product. The reaction behavior of STP and the viscoelasticity of the reaction product were investigated. STP and DD were separately microencapsulated by in situ polymerization and interfacial polymerization methods, respectively. The STP- and DD-loaded microcapsules were mixed into a commercial enamel paint, and the resulting formulation was applied to glass slides, steel panels, and mortars to prepare self-healing coatings. When the self-healing coatings were damaged at a low temperature (-20 degrees C), STP and DD were released from broken microcapsules and filled the damaged area. This process was effectively visualized using a fluorescent dye. The self-healing coatings were scratched and subjected to corrosion tests, electrochemical tests, and saline solution permeability tests. The temperature of the self-healing coatings was maintained at -20 degrees C before and after scratching and during the tests. We successfully demonstrated that the STP/DD-based coating system has good low-temperature self-healing capability. PMID- 28906467 TI - Underlying Physics of Conductive Polymer Composites and Force Sensing Resistors (FSRs) under Static Loading Conditions. AB - Conductive polymer composites are manufactured by randomly dispersing conductive particles along an insulating polymer matrix. Several authors have attempted to model the piezoresistive response of conductive polymer composites. However, all the proposed models rely upon experimental measurements of the electrical resistance at rest state. Similarly, the models available in literature assume a voltage-independent resistance and a stress-independent area for tunneling conduction. With the aim of developing and validating a more comprehensive model, a test bench capable of exerting controlled forces has been developed. Commercially available sensors-which are manufactured from conductive polymer composites-have been tested at different voltages and stresses, and a model has been derived on the basis of equations for the quantum tunneling conduction through thin insulating film layers. The resistance contribution from the contact resistance has been included in the model together with the resistance contribution from the conductive particles. The proposed model embraces a voltage dependent behavior for the composite resistance, and a stress-dependent behavior for the tunneling conduction area. The proposed model is capable of predicting sensor current based upon information from the sourcing voltage and the applied stress. This study uses a physical (non-phenomenological) approach for all the phenomena discussed here. PMID- 28906466 TI - Therapeutic Effect of Exogenous Truncated IK Protein in Inflammatory Arthritis. AB - Inhibitor K562 (IK) protein was first isolated from the culture medium of K562, a leukemia cell line. It is known to be an inhibitory regulator of interferon-gamma induced major histocompatibility complex class (MHC) II expression. Previously, we found that transgenic (Tg) mice constitutively expressing truncated IK (tIK) showed reduced numbers of pathogenic Th1 and Th17 cells, which are known to be involved in the development of rheumatoid arthritis (RA). Here, we investigated whether exogenous tIK protein has a therapeutic effect in arthritis in disease models and analyzed its mechanism. Exogenous tIK protein was produced in an insect expression system and applied to the collagen antibody-induced arthritis (CAIA) mouse disease model. Injection of tIK protein alleviated the symptoms of arthritis in the CAIA model and reduced Th1 and Th17 cell populations. In addition, treatment of cultured T cells with tIK protein induced expression of A20, a negative regulator of nuclear factor-kappaB (NFkappaB)-induced inflammation, and reduced expression of several transcription factors related to T cell activation. We conclude that exogenous tIK protein has the potential to act as a new therapeutic agent for RA patients, because it has a different mode of action to biopharmaceutical agents, such as tumor necrosis factor antagonists, that are currently used to treat RA. PMID- 28906468 TI - Understanding of MYB Transcription Factors Involved in Glucosinolate Biosynthesis in Brassicaceae. AB - Glucosinolates (GSLs) are widely known secondary metabolites that have anticarcinogenic and antioxidative activities in humans and defense roles in plants of the Brassicaceae family. Some R2R3-type MYB (myeloblastosis) transcription factors (TFs) control GSL biosynthesis in Arabidopsis. However, studies on the MYB TFs involved in GSL biosynthesis in Brassica species are limited because of the complexity of the genome, which includes an increased number of paralog genes as a result of genome duplication. The recent completion of the genome sequencing of the Brassica species permits the identification of MYB TFs involved in GSL biosynthesis by comparative genome analysis with A. thaliana. In this review, we describe various findings on the regulation of GSL biosynthesis in Brassicaceae. Furthermore, we identify 63 orthologous copies corresponding to five MYB TFs from Arabidopsis, except MYB76 in Brassica species. Fifty-five MYB TFs from the Brassica species possess a conserved amino acid sequence in their R2R3 MYB DNA-binding domain, and share close evolutionary relationships. Our analysis will provide useful information on the 55 MYB TFs involved in the regulation of GSL biosynthesis in Brassica species, which have a polyploid genome. PMID- 28906469 TI - Silicon Integrated Dual-Mode Interferometer with Differential Outputs. AB - The dual-mode interferometer (DMI) is an attractive alternative to Mach-Zehnder interferometers for sensor purposes, achieving sensitivities to refractive index changes close to state-of-the-art. Modern designs on silicon-on-insulator (SOI) platforms offer thermally stable and compact devices with insertion losses of less than 1 dB and high extinction ratios. Compact arrays of multiple DMIs in parallel are easy to fabricate due to the simple structure of the DMI. In this work, the principle of operation of an integrated DMI with differential outputs is presented which allows the unambiguous phase shift detection with a single wavelength measurement, rather than using a wavelength sweep and evaluating the optical output power spectrum. Fluctuating optical input power or varying attenuation due to different analyte concentrations can be compensated by observing the sum of the optical powers at the differential outputs. DMIs with two differential single-mode outputs are fabricated in a 250 nm SOI platform, and corresponding measurements are shown to explain the principle of operation in detail. A comparison of DMIs with the conventional Mach-Zehnder interferometer using the same technology concludes this work. PMID- 28906470 TI - The Role of Controlled Surface Topography and Chemistry on Mouse Embryonic Stem Cell Attachment, Growth and Self-Renewal. AB - The success of stem cell therapies relies heavily on our ability to control their fate in vitro during expansion to ensure an appropriate supply. The biophysical properties of the cell culture environment have been recognised as a potent stimuli influencing cellular behaviour. In this work we used advanced plasma based techniques to generate model culture substrates with controlled nanotopographical features of 16 nm, 38 nm and 68 nm in magnitude, and three differently tailored surface chemical functionalities. The effect of these two surface properties on the adhesion, spreading, and self-renewal of mouse embryonic stem cells (mESCs) were assessed. The results demonstrated that physical and chemical cues influenced the behaviour of these stem cells in in vitro culture in different ways. The size of the nanotopographical features impacted on the cell adhesion, spreading and proliferation, while the chemistry influenced the cell self-renewal and differentiation. PMID- 28906471 TI - Largest Magnetic Moments in the Half-Heusler Alloys XCrZ (X = Li, K, Rb, Cs; Z = S, Se, Te): A First-Principles Study. AB - A recent theoretical work indicates that intermetallic materials LiMnZ (Z = N, P) with a half-Heusler structure exhibit half-metallic (HM) behaviors at their strained lattice constants, and the magnetic moments of these alloys are expected to reach as high as 5 MUB per formula unit. (Damewood et al. Phys. Rev. B2015, 91, 064409). This work inspired us to find new Heusler-based half-metals with the largest magnetic moment. With the help of the first-principles calculation, we reveal that XCrZ (X = K, Rb, Cs; Z = S, Se, Te) alloys show a robust, half metallic nature with a large magnetic moment of 5 MUB at their equilibrium and strained lattice constants in their most stable phases, while the excellent HM nature of LiCrZ (Z = S, Se, Te) alloys can be observed in one of their metastable phases. Moreover, the effects of uniform strain in LiCrZ (Z = S, Se, Te) alloys in type II arrangement have also been discussed. PMID- 28906472 TI - Therapeutic Effect of Cilostazol Ophthalmic Nanodispersions on Retinal Dysfunction in Streptozotocin-Induced Diabetic Rats. AB - We previously prepared ophthalmic formulations containing cilostazol (CLZ) nanoparticles by bead mill methods (CLZnano), and found that instillation of CLZnano into rat eyes supplies CLZ into the retina. In this study, we investigated changes in the electroretinograms (ERG) of streptozotocin-induced diabetic rats (STZ rats), a model of diabetes mellitus. In addition, we demonstrated that dispersions containing CLZ nanoparticles attenuate changes in the ERG of STZ rats. The instillation of CLZnano had no effect on body weight or plasma glucose and insulin levels. Furthermore, no corneal toxicity was observed in the in vivo study using STZ rats. The a-wave and b-wave levels in addition to oscillatory potentials (OP) amplitude decreased in STZ rats two weeks after the injection of streptozotocin, with the instillation of CLZnano attenuating these decreases. In addition, the level of vascular endothelial growth factor (VEGF) in the retinas of STZ rats was 9.26-fold higher than in in normal rats, with this increase also prevented by the instillation of CLZnano Thus, we have found that a wave and b-wave levels in addition to OP amplitude are decreased in rats following the injection of excessive streptozotocin. Furthermore, the retinal disorders associated with diabetes mellitus are attenuated by the instillation of CLZnano. These findings provide significant information that can be used to design further studies aimed at developing anti-diabetic retinopathy drugs. PMID- 28906473 TI - Engineered Disease Resistance in Cotton Using RNA-Interference to Knock down Cotton leaf curl Kokhran virus-Burewala and Cotton leaf curl Multan betasatellite Expression. AB - Cotton leaf curl virus disease (CLCuD) is caused by a suite of whitefly transmitted begomovirus species and strains, resulting in extensive losses annually in India and Pakistan. RNA-interference (RNAi) is a proven technology used for knockdown of gene expression in higher organisms and viruses. In this study, a small interfering RNA (siRNA) construct was designed to target the AC1 gene of Cotton leaf curl Kokhran virus-Burewala (CLCuKoV-Bu) and the betaC1 gene and satellite conserved region of the Cotton leaf curl Multan betasatellite (CLCuMB). The AC1 gene and CLCuMB coding and non-coding regions function in replication initiation and suppression of the plant host defense pathway, respectively. The construct, Vbeta, was transformed into cotton plants using the Agrobacterium-mediated embryo shoot apex cut method. Results from fluorescence in situ hybridization and karyotyping assays indicated that six of the 11 T1 plants harbored a single copy of the Vbeta transgene. Transgenic cotton plants and non transgenic (susceptible) test plants included as the positive control were challenge-inoculated using the viruliferous whitefly vector to transmit the CLCuKoV-Bu/CLCuMB complex. Among the test plants, plant Vbeta-6 was asymptomatic, had the lowest amount of detectable virus, and harbored a single copy of the transgene on chromosome six. Absence of characteristic leaf curl symptom development in transgenic Vbeta-6 cotton plants, and significantly reduced begomoviral-betasatellite accumulation based on real-time polymerase chain reaction, indicated the successful knockdown of CLCuKoV-Bu and CLCuMB expression, resulting in leaf curl resistant plants. PMID- 28906474 TI - Non-Clinical Studies for Evaluation of 8-C-Rhamnosyl Apigenin Purified from Peperomia obtusifolia against Acute Edema. AB - Compound 8-C-rhamnosyl apigenin (8CR) induced a moderate reduction in the enzymatic activity of secretory phospholipase A2 (sPLA2) from Crotalus durissus terrificus and cytosolic phospholipase A2 (cPLA2), but the compound also significantly inhibited the enzymatic activity of the enzyme cyclooxygenase. In vitro assays showed that the compound induced a slight change in the secondary structure of sPLA2 from Crotalus durissus terrificus snake venom. In vivo assays were divided into two steps. In the first step, the 8CR compound was administered by intraperitoneal injections 30 min prior to administration of sPLA2. In this condition, 8CR inhibited edema and myonecrosis induced by the sPLA2 activity of Crotalus durissus terrificus in a dose-dependent manner by decreasing interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2), and lipid peroxidation. This has been demonstrated by monitoring the levels of malondialdehyde (MDA) in rat paws after the course of edema induced by sPLA2. These results, for the first time, show that sPLA2 of Crotalus durissus terrificus venom induces massive muscle damage, as well as significant edema by mobilization of cyclooxygenase enzymes. Additionally, its pharmacological activity involves increased lipid peroxidation as well as TNF-alpha and IL-1beta production. Previous administration by the peritoneal route has shown that dose dependent 8CR significantly decreases the enzymatic activity of cyclooxygenase enzymes. This resulted in a decrease of the amount of bioactive lipids involved in inflammation; it also promoted a significant cellular protection against lipid peroxidation. In vivo experiments performed with 8CR at a concentration adjusted to 200 MUg (8 mg/kg) of intraperitoneal injection 15 min after sPLA2 injection significantly reduced sPLA2 edema and the myotoxic effect induced by sPLA2 through the decrease in the enzymatic activity of cPLA2, cyclooxygenase, and a massive reduction of lipid peroxidation. These results clearly show that 8CR is a potent anti-inflammatory that inhibits cyclooxygenase-2 (COX-2), and it may modulate the enzymatic activity of sPLA2 and cPLA2. In addition, it was shown that Crotalus durissus terrificus sPLA2 increases cell oxidative stress during edema and myonecrosis, and the antioxidant properties of the polyphenolic compound may be significant in mitigating the pharmacological effect induced by sPLA2 and other snake venom toxins. PMID- 28906475 TI - Can We Predict the Efficacy of Anti-TNF-alpha Agents? AB - The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-alpha, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-alpha therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated. PMID- 28906476 TI - Ultra-Sensitive NT-proBNP Quantification for Early Detection of Risk Factors Leading to Heart Failure. AB - Cardiovascular diseases such as acute myocardial infarction and heart failure accounted for the death of 17.5 million people (31% of all global deaths) in 2015. Monitoring the level of circulating N-terminal proBNP (NT-proBNP) is crucial for the detection of people at risk of heart failure. In this article, we describe a novel ultra-sensitive NT-proBNP test (us-NT-proBNP) that allows the quantification of circulating NT-proBNP in 30 min at 25 degrees C in the linear detection range of 7.0-600 pg/mL. It is a first report on the application of a fluorescence bead labeled detection antibody, DNA-guided detection method, and glass fiber membrane platform for the quantification of NT-proBNP in clinical samples. Limit of blank, limit of detection, and limit of quantification were 2.0 pg/mL, 3.7 pg/mL, and 7 pg/mL, respectively. The coefficient of variation was found to be less than 10% in the entire detection range of 7-600 pg/mL. The test demonstrated specificity for NT-proBNP without interferences from bilirubin, intra-lipid, biotin, and hemoglobin. The serial dilution test for plasma samples containing various NT-proBNP levels showed the linear decrement in concentration with the regression coefficient of 0.980-0.998. These results indicate that us-NT proBNP test does not suffer from the interference of the plasma components for the measurement of NT-proBNP in clinical samples. PMID- 28906477 TI - MicroRNA Signaling in Embryo Development. AB - Expression of microRNAs (miRNAs) is essential for embryonic development and serves important roles in gametogenesis. miRNAs are secreted into the extracellular environment by the embryo during the preimplantation stage of development. Several cell types secrete miRNAs into biological fluids in the extracellular environment. These fluid-derived miRNAs have been shown to circulate the body. Stable transport is dependent on proper packaging of the miRNAs into extracellular vesicles (EVs), including exosomes. These vesicles, which also contain RNA, DNA and proteins, are on the forefront of research on cell-to-cell communication. Interestingly, EVs have been identified in many reproductive fluids, such as uterine fluid, where their miRNA content is proposed to serve as a mechanism of crosstalk between the mother and conceptus. Here, we review the role of miRNAs in molecular signaling and discuss their transport during early embryo development and implantation. PMID- 28906478 TI - Complementary RNA-Sequencing Based Transcriptomics and iTRAQ Proteomics Reveal the Mechanism of the Alleviation of Quinclorac Stress by Salicylic Acid in Oryza sativa ssp. japonica. AB - To uncover the alleviation mechanism of quinclorac stress by salicylic acid (SA), leaf samples of Oryza sativa ssp. Japonica under quinclorac stress with and without SA pre-treatment were analyzed for transcriptional and proteomic profiling to determine the differentially expressed genes (DEGs) and proteins (DEPs), respectively. Results showed that quinclorac stress altered the expression of 2207 DEGs (1427 up-regulated, 780 down-regulated) and 147 DEPs (98 down-regulated, 49 up-regulated). These genes and proteins were enriched in glutathione (GSH) metabolism, porphyrin and chlorophyll metabolism, the biosynthesis of secondary metabolites, glyoxylate and dicarboxylate metabolism, and so on. It also influenced apetala2- ethylene-responsive element binding protein (AP2-EREBP) family, myeloblastosis (MYB) family and WRKY family transcription factors. After SA pre-treatment, 697 genes and 124 proteins were differentially expressed. Pathway analysis showed similar enrichments in GSH, glyoxylate and dicarboxylate metabolism. Transcription factors were distributed in basic helix-loop-helix (bHLH), MYB, Tify and WRKY families. Quantitative real time PCR results revealed that quinclorac stress induced the expression of glutathion reductase (GR) genes (OsGR2, OsGR3), which was further pronounced by SA pre-treatment. Quinclorac stress further mediated the accumulation of acetaldehyde in rice, while SA enhanced the expression of OsALDH2B5 and OsALDH7 to accelerate the metabolism of herbicide quinclorac for the protection of rice. Correlation analysis between transcriptome and proteomics demonstrated that, under quinclorac stress, correlated proteins/genes were mainly involved in the inhibition of intermediate steps in the biosynthesis of chlorophyll. Other interesting proteins/genes and pathways regulated by herbicide quinclorac and modulated by SA pre-treatment were also discussed, based on the transcriptome and proteomics results. PMID- 28906480 TI - Disaster Governance for Community Resilience in Coastal Towns: Chilean Case Studies. AB - This study aimed to further our understanding of a characteristic of Community Resilience known as Disaster Governance. Three attributes of Disaster Governance redundancy, diversity, and overlap-were studied in four coastal towns in southern Chile that are at risk of tsunamis. Overall, we explored how different spatial structures of human settlements influence Disaster Governance. Using the Projective Mapping Technique, the distribution of emergency institutions (N = 32) and uses given to specific sites (e.g., for refuge, sanitary purposes and medical attention) were mapped. Content and GIS analyses (Directional Distribution and Kernel Density Index) were used to explore the dispersion and concentration of institutions and uses in each town. Disaster Governance was found to be highly influenced by decisions taken during regional, urban, and emergency planning. Governance is better in towns of higher order in the communal hierarchical structure. Most of the emergency institutions were found to be located in central and urban areas, which, in turn, assures more redundancy, overlap, and diversity in governance in the event of a tsunami. Lack of flexibility of emergency plans also limits governance in rural and indigenous areas. While the spatial relationships found in this study indicate that urban sectors have better Disaster Governance than rural and indigenous sectors, the influence of resource availability after tsunamis, the role and responsibility of different levels of governments, and the politics of disaster also play an important role in Disaster Governance for determining Community Resilience. These findings shed light on emergency planning and aspects of the Disaster Management cycle. PMID- 28906479 TI - Characterization of vB_SauM-fRuSau02, a Twort-Like Bacteriophage Isolated from a Therapeutic Phage Cocktail. AB - Staphylococcus aureus is a commensal and pathogenic bacterium that causes infections in humans and animals. It is a major cause of nosocomial infections worldwide. Due to increasing prevalence of multidrug resistance, alternative methods to eradicate the pathogen are necessary. In this respect, polyvalent staphylococcal myoviruses have been demonstrated to be excellent candidates for phage therapy. Here we present the characterization of the bacteriophage vB_SauM fRuSau02 (fRuSau02) that was isolated from a commercial Staphylococcus bacteriophage cocktail produced by Microgen (Moscow, Russia). The genomic analysis revealed that fRuSau02 is very closely related to the phage MSA6, and possesses a large genome (148,464 bp), with typical modular organization and a low G+C (30.22%) content. It can therefore be classified as a new virus among the genus Twortlikevirus. The genome contains 236 predicted genes, 4 of which were interrupted by insertion sequences. Altogether, 78 different structural and virion-associated proteins were identified from purified phage particles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The host range of fRuSau02 was tested with 135 strains, including 51 and 54 Staphylococcus aureus isolates from humans and pigs, respectively, and 30 coagulase-negative Staphylococcus strains of human origin. All clinical S. aureus strains were at least moderately sensitive to the phage, while only 39% of the pig strains were infected. Also, some strains of Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus and Staphylococcus pseudointer were sensitive. We conclude that fRuSau02, a phage therapy agent in Russia, can serve as an alternative to antibiotic therapy against S. aureus. PMID- 28906482 TI - Real-life experience with bortezomib-based regimens in elderly patients with newly diagnosed multiple myeloma and comorbidities: a Polish retrospective multicenter study. AB - INTRODUCTION Bortezomib was the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Currently, VMP (bortezomib, melphalan, prednisone) is one of the standard regimens recommended as the first-line therapy for patients with MM ineligible for high-dose chemotherapy (HDT) with autologous stem-cell transplantation (auto-SCT). OBJECTIVES Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. PATIENTS AND METHODS We retrospectively analyzed the data on the efficacy and safety of bortezomib-based regimens in 154 patients with newly diagnosed MM ineligible for HDT with auto-SCT (median age, 73 years; range, 39-89 years) with particular attention to the effect of age, performance status, and concomitant diseases. RESULTS Patients aged 75 years or older constituted 53.2% of the study cohort. Performance status was impaired in 34.4% of the patients, according to the Eastern Cooperative Oncology Group scale. Comorbidities were reported in 83.8% of the patients (mainly arterial hypertension and atherosclerotic vascular disease). A total of 798 courses of bortezomib-based regimens (mainly VMP, 86%) were administered. The overall response rate was 81.7%, including 12.7% for complete response and 29.6% for very good partial response. The median progression-free survival (PFS) and event-free survival were 17.3 and 7.1 months, respectively. The impaired performance status and age of 75 or older were negative predictors of PFS. The most common severe adverse events were neuropathy (19.4%), infections (19.2%), and neutropenia (14.9%). CONCLUSIONS Bortezomib-based regimens are effective and well tolerated in the first-line therapy of elderly patients with MM and comorbidities, with advanced disease, and light chain MM. A more detailed assessment of patients' frailty is needed to increase the efficacy of treatment. PMID- 28906483 TI - Possible undertreatment of women with Crohn disease in Poland. A subgroup analysis from a prospective multicenter study of patients on anti-tumor necrosis factor therapy. AB - INTRODUCTION In Poland, anti-tumor necrosis factor (TNF) therapy for Crohn disease (CD) is reimbursed in inflammatory disease (CD activity index [CDAI] >300 points) or perianal disease, in cases where conventional treatment has failed. OBJECTIVES We assessed patients receiving TNF inhibitors to establish how limited access to the therapy influences the selection of the population for treatment. PATIENTS AND METHODS Consecutive adult patients with CD starting infliximab or adalimumab in the years 2014 to 2015 were included in the study. Age at symptom onset and diagnosis of CD, disease location and behavior, previous treatment, CDAI, and body mass index (BMI) were evaluated. Subsequently, the age and sex of all patients with CD on anti-TNF therapy reimbursed by the Polish National Health Fund were analyzed. RESULTS Among 256 patients, there were 113 women (44.1%) and 143 men (55.9%). The median time from diagnosis to enrollment was longer in women than in men (9 years vs 5.5 years; P = 0.02), and the proportion of women receiving TNF inhibitors for 5 years or less since diagnosis was lower than that of men (42.5% vs 57.7%; P = 0.017). Disease locations, behavior, and CDAI were similar between the groups, while the median BMI was lower in women than in men (20.6 kg/m2 vs 22.6 kg/m2; P = 0.01). In Poland in general, in the years 2010 to 2015, TNF inhibitors for CD were taken by fewer women than men (2208 vs 4789; 46%; 95% confidence interval, 45-48). The median age of treated women was 29 years and that of men-27 years (P <0.001). CONCLUSIONS Compared with their male counterparts, women with CD receive TNF inhibitors less frequently, at an older age, and following a longer disease duration. It is unknown whether this is a regional or more widespread phenomenon. PMID- 28906481 TI - Insights into the Diagnostic Potential of Extracellular Vesicles and Their miRNA Signature from Liquid Biopsy as Early Biomarkers of Diabetic Micro/Macrovascular Complications. AB - Extracellular vesicles (EVs) represent a heterogeneous population of small vesicles, consisting of a phospholipidic bilayer surrounding a soluble interior cargo. Almost all cell types release EVs, thus they are naturally present in all body fluids. Among the several potential applications, EVs could be used as drug delivery vehicles in disease treatment, in immune therapy because of their immunomodulatory properties and in regenerative medicine. In addition to general markers, EVs are characterized by the presence of specific biomarkers (proteins and miRNAs) that allow the identification of their cell or tissue origin. For these features, they represent a potential powerful diagnostic tool to monitor state and progression of specific diseases. A large body of studies supports the idea that endothelial derived (EMPs) together with platelet-derived microparticles (PMPs) are deeply involved in the pathogenesis of diseases characterized by micro- and macrovascular damages, including diabetes. Existing literature suggests that the detection of circulating EMPs and PMPs and their specific miRNA profile may represent a very useful non-invasive signature to achieve information on the onset of peculiar disease manifestations. In this review, we discuss the possible utility of EVs in the early diagnosis of diabetes associated microvascular complications, specifically related to kidney. PMID- 28906484 TI - Whole- person care: a hope for modern medicine? PMID- 28906485 TI - Weight status, cardiorespiratory fitness and high blood pressure relationship among 5-12-year-old Chinese primary school children. AB - Cardiorespiratory fitness (CRF) and adiposity contribute to high blood pressure (HBP) in adults and children. However, their relative importance as risk factors is unknown. We examined the relationships between weight status, CRF and HBP among Chinese primary school children. A cross-sectional study was conducted with 4926 school children aged 5-12 years. CRF was estimated from a modified Cooper test, body mass index z-scores and weight categories were calculated from objective height and weight measurements and BP was measured using an electronic sphygmomanometer. HBP was defined as >95th percentile based on reference cutoffs for Chinese boys and girls. Generalised Linear Mixed models, adjusting for age, pubertal status and height, were developed for boys and girls to explore the independent and combined associations between fitness, weight status and HBP. Seven hundred and fifty-two (15.3%) children had HBP, with a higher prevalence in obese (40.5% and 45.9% in boys and girls, respectively) and overweight (27.6% and 30.2% in boys and girls, respectively) compared with non-overweight (9.0% and 13.8% in boys and girls, respectively) children. HBP prevalence was lower in boys with higher CRF (odds ratio (OR) for the highest vs lowest CRF quartile in boys 0.64; 95% confidence interval (CI) 0.46-0.89). This association was not seen in girls. With weight status and CRF in the same model, weight status, but not CRF, remained significantly associated with HBP (obesity in boys: OR 4.19; 95% CI 2.63 6.67; in girls: OR 2.49; 95% CI 1.19-5.19). The interaction effect for CRF and weight status was non-significant. Overweight/obesity was significantly associated with HBP among children. There was no evidence of modification of this relationship by CRF. PMID- 28906487 TI - Identification of 11(13)-dehydroivaxillin as a potent therapeutic agent against non-Hodgkin's lymphoma. AB - Despite great advancements in the treatment of non-Hodgkin lymphoma (NHL), sensitivity of different subtypes to therapy varies. Targeting the aberrant activation NF-kappaB signaling pathways in lymphoid malignancies is a promising strategy. Here, we report that 11(13)-dehydroivaxillin (DHI), a natural compound isolated from the Carpesium genus, induces growth inhibition and apoptosis of NHL cells. Multiple signaling cascades are influenced by DHI in NHL cells. PI3K/AKT and ERK are activated or inhibited in a cell type dependent manner, whereas NF kappaB signaling pathway was inhibited in all the NHL cells tested. Applying the cellular thermal shift assay, we further demonstrated that DHI directly interacts with IKKalpha/IKKbeta in NHL cells. Interestingly, DHI treatment also reduced the IKKalpha/IKKbeta protein level in NHL cells. Consistent with this finding, knockdown of IKKalpha/IKKbeta inhibits cell proliferation and enhances DHI induced proliferation inhibition. Overexpression of p65, p52 or RelB partially reverses DHI-induced cell growth inhibition. Furthermore, DHI treatment significantly inhibits the growth of NHL cell xenografts. In conclusion, we demonstrate that DHI exerts anti-NHL effect in vitro and in vivo, through a cumulative effect on NF-kappaB and other pathways. DHI may serve as a promising lead compound for the therapy of NHL. PMID- 28906486 TI - Small-molecule RL71-triggered excessive autophagic cell death as a potential therapeutic strategy in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71 induced TNBC cell death. RL71 augmented the release of Ca2+ from the endoplasmic reticulum (ER) into the cytosol by inhibiting SERCA2 activity. The disruption of calcium homeostasis induced ER stress, leading to apoptosis. More importantly, the elevated intracellular calcium signals induced autophagy through the activation of the CaMKK-AMPK-mTOR pathway and mitochondrial damage. In two TNBC xenograft mouse models, RL71 also displayed strong efficacy including the inhibition of tumor growth, the reduction of metastasis, as well as the prolongation of survival time. These findings suggest SERCA2 as a previous unknown target candidate for TNBC treatment and support the idea that autophagy inducers could be useful as new therapeutics in TNBC treatment. PMID- 28906488 TI - Novel chimeric transcript RRM2-c2orf48 promotes metastasis in nasopharyngeal carcinoma. AB - Recently, chimeric transcripts have been found to be associated with the pathogenesis and poor prognosis of malignant tumors. Through our preliminary experiment, a novel chimeric transcript called chimeric transcript RRM2-c2orf48 was detected in C666-1, a classical cell line of human nasopharyngeal carcinoma (NPC). Therefore, the objective of this study was to demonstrate the existence and expression of novel chimeric transcript RRM2-c2orf48 and to explore the main functions and mechanisms of RRM2-c2orf48 in NPC. In this study, the expression of RRM2-c2orf48 was evaluated in NPC cells and specimens. Effects of RRM2-c2orf48 on migration and invasive capacities were detected in vivo and vitro. Moreover, ways in which RRM2-c2orf48 increases the invasive capacities of NPC were explored. As a result, the presence of novel chimeric transcript RRM2-c2orf48 was confirmed in C666-1 by RT-PCR and sequencing, and it was a read-through between RRM2 and c2orf48 through the transcription of interchromosome. Higher expressions of novel RRM2-c2orf48 were detected in NPC cell lines and NPC tissue specimens relative to the controls and its expression was be statistically relevant to TNM staging. High level of RRM2-c2orf48 could increase the migration and invasive capacities of NPC cells, potentially as a result of NPC cell epithelial-mesenchymal transition. RRM2-c2orf48 could also enhance resistance of chemotherapy. In vivo, RRM2-c2orf48 could enhance lung and lymph node metastasis in nude mice. These results demonstrate that high levels of RRM2-c2orf48 expression may be a useful predictor of NPC patients of metastatic potency, presenting potential implications for NPC diagnosis and therapy. PMID- 28906489 TI - Disrupting CCT-beta : beta-tubulin selectively kills CCT-beta overexpressed cancer cells through MAPKs activation. AB - We have previously demonstrated the ability of I-Trp to disrupt the protein protein interaction of beta-tubulin with chaperonin-containing TCP-1beta (CCT beta). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-beta overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-beta overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-MUM EC50, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-beta : beta tubulin complex disruption. We thus establish an effective strategy to treat CCT beta overexpressed cancers by disrupting the CCT-beta : beta-tubulin complex. PMID- 28906491 TI - Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer. AB - This corrects the article DOI: 10.1038/cddis.2017.100. PMID- 28906490 TI - POPX2 phosphatase regulates apoptosis through the TAK1-IKK-NF-kappaB pathway. AB - Chemoresistance is one of the leading causes that contributes to tumor relapse and poor patient outcome after several rounds of drug therapy. The causes of chemoresistance are multi-factorial. Ultimately, it is the balance of pro- and anti-apoptotic activities in the cells. We have previously reported links between POPX2 serine/threonine phosphatase with cell motility and invasiveness of breast cancer cells. Here, we show that POPX2 plays a role in the regulation of apoptosis. The effect of POPX2 on apoptosis centers on the inactivation of TGF beta activated kinase (TAK1). TAK1 is essential for several important biological functions including innate immunity, development and cell survival. We find that POPX2 interacts directly with TAK1 and is able to dephosphorylate TAK1. Cells with lower levels of POPX2 exhibit higher TAK1 activity in response to etoposide (VP-16) treatment. This subsequently leads to increased translocation of NF kappaB from the cytosol to the nucleus. Consequently, NF-kappaB-mediated transcription of anti-apoptotic proteins is upregulated to promote cell survival. On the other hand, cells with higher levels of POPX2 are more vulnerable to apoptosis induced by etoposide. Our data demonstrate that POPX2 is a negative regulator of TAK1 signaling pathway and modulates apoptosis through the regulation of TAK1 activity. As inhibition of TAK1 has been proposed to reduce chemoresistance and increase sensitivity to chemotherapy in certain types of cancer, modulation of POPX2 levels may provide an additional avenue and consideration in fine-tuning therapeutic response. PMID- 28906492 TI - NDRG1 inhibition sensitizes osteosarcoma cells to combretastatin A-4 through targeting autophagy. AB - Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome-lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors. PMID- 28906493 TI - Rapid curation of gene disruption collections using Knockout Sudoku. AB - Knockout Sudoku is a method for the construction of whole-genome knockout collections for a wide range of microorganisms with as little as 3 weeks of dedicated labor and at a cost of ~$10,000 for a collection for a single organism. The method uses manual 4D combinatorial pooling, next-generation sequencing, and a Bayesian inference algorithm to rapidly process and then accurately annotate the extremely large progenitor transposon insertion mutant collections needed to achieve saturating coverage of complex microbial genomes. This method is ~100* faster and 30* lower in cost than the next comparable method (In-seq) for annotating transposon mutant collections by combinatorial pooling and next generation sequencing. This method facilitates the rapid, algorithmically guided condensation and curation of the progenitor collection into a high-quality, nonredundant collection that is suitable for rapid genetic screening and gene discovery. PMID- 28906494 TI - Lab-scale production of anhydrous diazomethane using membrane separation technology. AB - Diazomethane is among the most versatile and useful reagents for introducing methyl or methylene groups in organic synthesis. However, because of its explosive nature, its generation and purification by distillation are accompanied by a certain safety risk. This protocol describes how to construct a configurationally simple tube-in-flask reactor for the in situ on-demand generation of anhydrous diazomethane using membrane separation technology and thus avoiding distillation methods. The described reactor can be prepared from commercially available parts within ~1 h. In this system, solutions of Diazald and aqueous potassium hydroxide are continuously pumped into a spiral of membrane tubing, and diazomethane is generated upon mixing of the two streams. Pure diazomethane gas diffuses out of the reaction mixture through the membrane tubing (made of gas-permeable Teflon AF-2400). As the membrane tubing is immersed in a flask filled with the substrate solution, diazomethane is instantly consumed, which minimizes the risk of diazomethane accumulation. For this protocol, the reaction of diazomethane with benzoic acid on a 5-mmol scale has been selected as a model reaction and is described in detail. Methyl benzoate was isolated in an 88-90% yield (597-611 mg) within ~3 h. PMID- 28906495 TI - Effects of a transition home program on preterm infant emergency room visits within 90 days of discharge. AB - OBJECTIVE: To evaluate effects of a transition home program (THP) and risk factors on emergency room (ER) use within 90 days of discharge for preterm (PT) infants <37 weeks gestation. STUDY DESIGN: This is a prospective 3-year cohort study of 804 mothers and 954 PT infants. Mothers received enhanced neonatal intensive care unit transition support services until 90 days postdischarge. Regression models were run to identify the effects of THP implementation year and risk factors on ER visits. RESULTS: Of the 954 infants, 181 (19%) had ER visits and 83/181 (46%) had an admission. In regression analysis, THP year 3 vs year 1 and human milk at discharge were associated with decreased risk of ER visits, whereas increased odds was associated with non-English speaking, maternal mental health disorders and bronchopulmonary dysplasia. CONCLUSION: Enhanced THP services were associated with a 33% decreased risk of all ER visits by year 3. Social and environmental risk factors contribute to preventable ER visits. PMID- 28906496 TI - Urinary NT-proBNP levels and echocardiographic parameters for patent ductus arteriosus. AB - OBJECTIVE: Patent ductus arteriosus (PDA) is common in preterm infants and is associated with significant morbidities. B type natriuretic peptide (BNP) is synthesized in the ventricles secondary to volume overload and excreted as urinary N-terminal pro-brain natriuretic peptide (NT-proBNP). STUDY DESIGN: We report an observational prospective study of 64 preterm infants with birth weight ?1000 g. Echocardiographic parameters were obtained from clinical echocardiograms performed in the first week of life. Urinary NT-proBNP/creatinine ratios (pg mg 1) were measured on the same day of the echocardiograms. RESULTS: Infants with medium to large PDA (n=39) had significantly higher NT-proBNP/creatinine levels compared with infants with small PDA (n=10) (median (IQ range): 2333 (792-6166) vs 714 (271-1632) pg mg-1, P=0.01) and compared with infants with no PDA (n=15) (2333 (792-6166) vs 390 (134-1085) pg mg-1, P=0.0003). Urinary NT proBNP/creatinine ratios were significantly lower post treatment if PDA closed (n=17), P=0.001 or if PDA became smaller after treatment (n=9), P=0.004. Urinary NT-proBNP/creatinine levels correlated with ductal diameter (P?0.0001), but not with LA/Ao ratio (P=0.69) or blood flow velocity through the ductus (P=0.06). CONCLUSION: Our findings indicate that there is a positive correlation between ductal diameter and urinary NT-proBNP in preterm infants. PMID- 28906499 TI - [Incomplete POEMS syndrome with multicentric Castleman's disease]. AB - Castleman's disease (CD) is an atypical lymphoproliferative disorder of unknown cause, characterized by non-clonal nodal hyperplastic growth. Two forms of clinical presentation are currently recognized, one localized and the other multicentric, and four histopathologic variants. It is characterized by generalized lymphadenopathy, hepatosplenomegaly, fever and night sweats. CD may present severe pancytopenia, multi-organ failure, lymphoma evolution and it can sometimes be associated with paraneoplastic syndromes such as POEMS syndrome. Associations of these two entities have been widely described in the current literature, although its less common association with amyloidosis is described as isolated clinical cases. We report a case with this triple association: EC, POEMS and amyloidosis. PMID- 28906497 TI - Different formulas, different thresholds and different performance-the prediction of macrosomia by ultrasound. AB - OBJECTIVE: The sonographic prediction of fetal macrosomia affects obstetrical decision regarding the timing and mode of delivery. We aimed to compare the accuracy of various formulas for prediction of macrosomia at different thresholds. STUDY DESIGN: This was a retrospective cohort study of singleton gestations at term, with fetal biometrical measurements taken up to 7 days prior to delivery (2007 to 2014). Sonographic estimated fetal weight was calculated using 20 previously published formulas. Macrosomia prediction was evaluated for every formula utilizing: (1) measures of accuracy (sensitivity, specificity and so on); (2) comparison of the systematic and random errors (SE and RE), and the proportion of estimates within 10% of actual birth weight for macrosomic and non macrosomic neonates. Performance measurements were evaluated for different macrosomia thresholds: 4000, 4250 and 4500 g. Best performing formula for every threshold was defined as the one with the lowest Euclidean distance (=SQRT(SE2+RE2)). RESULTS: Out of 7977 women who met the inclusion criteria, 754 (9.4%) delivered a neonate weighing ?4000 g, 266 (3.3%) delivered a neonate weighing?4250 g and 75 (0.9%) delivered a neonate weighing?4500 g. Considerable variability was noted between the accuracy parameters of the different formulas, with Woo's formula integrating Abdominal circumference (AC) and femur length (FL) as the most sensitive formula with the highest negative predictive value for all thresholds and Woo's formula using AC, FL and biparietal diameter (BPD) as the most specific for all thresholds. The same formula also demonstrated the best overall accuracy. Regardless of threshold chosen, 80% or more of formulas demonstrated negative systematic error, meaning lower EFW than actual birthweight. As for the Euclidean distance, Hadlock's formula (AC, FL and BPD) ranked the highest for the 4000 and 4250 g thresholds, whereas Shepard's formula (AC and BPD) ranked the highest for the 4500 g threshold. CONCLUSION: Considerable variability exist between formulas for prediction of neonatal macrosomia. Formulas by Hadlock's and Shepard's utilizing AC, BPD+/-FL were most accurate for macrosomia prediction at 4000, 4250 and 4500 g thresholds, respectively. PMID- 28906501 TI - Impact of Cleaning Procedures on Adhesion of Living Cells to Three Abutment Materials. AB - PURPOSE: To test the adhesion properties of live gingival fibroblasts to three different implant abutment materials after five different cleaning procedures. MATERIALS AND METHODS: Highly polished discs of lithium disilicate (LS), zirconium dioxide (Zr), and titanium alloy (Ti) were fabricated. The specimens were cleaned by one of five different methods: steam (S), argon plasma (AP), ultrasound and disinfection (UD), ultrasound and sterilization in an autoclave (UA), or photofunctionalization with high-intensity ultraviolet light (PF). Cell detachment force (adhesion) was measured by single-cell force spectroscopy, which is a method to quantify cell adhesion at the single cell level. Data were statistically analyzed using parametric tests (analysis of variance [ANOVA], t tests). RESULTS: Cell detachment forces in the low nN regime were recorded in all experiments. Significant differences in cell adhesion on the different materials were found as a function of the cleaning method (P <= .0001). For LS abutments, no significant differences between the cleaning methods could be found (P > .05). For Zr specimens, the AP method showed the highest cell detachment forces, followed by UD, PF, S, and UA (S/UD, S/UA, S/PF, AP/UD, and UD/PF were not significantly different from each other). For Ti abutments, UD showed the highest cell detachment forces, followed by S, AP, and UA/PF (S/UD, S/UA, S/PF, AP/U, and UA/PF were not significantly different from each other). CONCLUSION: All cleaning methods provided comparable cell detachment forces for LS abutments. AP/PF or ultrasonic cleaning were the most suitable methods for strong cell adhesion on Zr. UD provided the best cell adhesion for Ti. PMID- 28906500 TI - Fracture of Reduced-Diameter Zirconia Dental Implants Following Repeated Insertion. AB - PURPOSE: Achievement of high insertion torque values indicating good primary stability is a goal during dental implant placement. The objective of this study was to evaluate whether or not two-piece implants made from zirconia ceramic may be damaged as a result of torque application. MATERIALS AND METHODS: A total of 10 two-piece zirconia implants were repeatedly inserted into polyurethane foam material with increasing density and decreasing osteotomy size. The insertion torque applied was measured, and implants were checked for fractures by applying the fluorescent penetrant method. Weibull probability of failure was calculated based on the recorded insertion torque values. RESULTS: Catastrophic failures could be seen in five of the implants from two different batches at insertion torques ranging from 46.0 to 70.5 Ncm, while the remaining implants (all belonging to one batch) survived. Weibull probability of failure seems to be low at the manufacturer-recommended maximum insertion torque of 35 Ncm. Chipping fractures at the thread tips as well as tool marks were the only otherwise observed irregularities. CONCLUSION: While high insertion torques may be desirable for immediate loading protocols, zirconia implants may fracture when manufacturer-recommended insertion torques are exceeded. Evaluating bone quality prior to implant insertion may be useful. PMID- 28906502 TI - Opinions Regarding Reuse or Replacement of Implant Prosthesis Retaining Screws: A Systematic Review. AB - PURPOSE: To identify whether reuse or replacement is better for managing loose screws. MATERIALS AND METHODS: An electronic search was performed utilizing PubMed, and a further manual search of the reference lists of relevant reviews and articles was conducted. Selected inclusion and exclusion criteria were used to limit the search. RESULTS: The electronic and manual search provided 243 titles and abstracts. Full-text analysis was performed for 98 articles, resulting in a total of 15 articles that qualified for inclusion in this study. All the included articles reported that loose screws were reused and retightened or were replaced by new screws. The time of screw loosening ranged from 1 month to 3 years after delivery. Available details of numbers and frequency of screw loosening permitted only limited analysis from very few articles. A total of 44 loose screws reported in two articles did not loosen again after retightening once. CONCLUSION: From the very limited available literature, it appears that retightening an occlusal screw or abutment screw is an acceptable procedure, as the evidence shows that retightened screws seem to remain tight. Replacement of screws as a routine procedure cannot be recommended. Routine assessment of screw tightness is recommended to minimize additional and more severe complications. PMID- 28906503 TI - Release of Irretrievable Abutment Healing Caps Using Cooling: Proof of Concept and Clinical Recommendations. AB - PURPOSE: To study the relation between irretrievable abutment healing caps (AHCs), temperature, and the torque required to remove the AHCs from implants. MATERIALS AND METHODS: Twenty implants, 13 mm long and 4.2 mm in diameter, were inserted into four acrylic boxes and covered with acrylic resin. An AHC was screwed into each implant, using a 30 N/cm torque. The acrylic blocks were placed in a 37 degrees C water bath, and subsequently, a block was removed from the bath, the AHCs were cooled, and the torque needed to release each AHC from the implant was measured using a torque wrench. The cooling methods applied were contact with an ice cube for 10 or 25 seconds or spraying of endodontic refrigerant spray for 3 seconds. The control abutments were similarly tested, but without prior cooling. RESULTS: The application of ice cubes for 10 seconds reduced the mean releasing torque from 29.60 +/- 1.22 N/cm to 28.55 +/- 1.96 N/cm (P = .01). Cooling the AHCs with ice cubes for 25 seconds reduced the mean required releasing torque from 29.6 N/cm to 27.85 +/- 1.22 N/cm (P < .001). Cooling the same abutments using endodontic refrigerant spray for 3 seconds reduced the mean releasing torque to 27.74 +/- 2.13 N/cm (P < .001). CONCLUSION: Within the limitations of this study, it is possible to conclude that cooling the AHC reduces the torque required for its release from the implant. This finding may also be relevant to the removal of prosthetic abutments with irretrievable screws. PMID- 28906504 TI - Association Between Clinical and Microbiologic Cluster Profiles and Peri implantitis. AB - PURPOSE: The correlation between associated local factors and peri-implantitis remains unknown. The aim of this study was to investigate the association between the clinical and microbiologic profiles and peri-implantitis to eventually categorize different groups of this disease. MATERIALS AND METHODS: Subjects with at least one implant presenting signs of peri-implantitis were selected. The clinical, radiographic, occlusal, and microbiologic profiles of these infected implants were collected. Cases were classified into five peri-implantitis groups according to potential disease-triggering factors: surgically, prosthetically, biomechanically, purely plaque-associated, and a combination of them. Generalized estimating equations models were used to study differences among the potential risk factors. Cluster analyses were applied to investigate the correlation between clinical and microbiologic profiles and diseased implant samples. RESULTS: Overall, 110 diseased and 121 healthy implants were included. The biomechanically associated group showed higher levels of microbiologic contamination inside the connection; however, the plaque-associated group had a higher level of microbial variety in the peri-implant sulcus. Cluster analyses demonstrated a significant ability to predict the associated factor of peri implantitis. Moreover, radiographic marginal bone loss and implant width demonstrated the largest influence on the model. CONCLUSION: While peri implantitis represents a plaque-induced inflammatory condition, certain local factors might be associated with this biologic complication, as they imply plaque retention. Therefore, disease classification could be further implemented with the associated surgical, prosthetic, and biomechanical factors to better target the etiology. PMID- 28906505 TI - Outcomes Assessment of Treating Completely Edentulous Patients with a Fixed Implant-Supported Profile Prosthesis Utilizing a Graftless Approach. Part 2: Patient-Related Outcomes. AB - PURPOSE: To assess outcomes of treating completely edentulous patients with a fixed implant-supported profile prosthesis, utilizing a graftless approach, for the maxilla and for the mandible, with an emphasis on patient-related outcomes, specifically maximum occlusal force, patient satisfaction, and impact on quality of life. MATERIALS AND METHODS: This was a cross-sectional study with the following inclusion criteria: completely edentulous patients rehabilitated with a fixed implant-supported profile denture, utilizing a graftless approach. Patients fulfilling the inclusion criteria were asked to participate in the study during their follow-up visits; hence, a consecutive sampling strategy was used. To measure maximum occlusal force, a digital occlusal force gauge was used. Subjects were asked to answer a paper survey distributed in the clinic. The survey contained general demographic questions, visual analog scale (VAS) categories, and Oral Health Impact Profile-14 (OHIP-14). RESULTS: The mean VAS score was 8.9 out of a possible 10. The mean OHIP-14 score was 7.5 out of a possible 56. The mean maximum occlusal force recorded in the anterior region was 108 Ncm. The mean maximum occlusal force recorded in the posterior region was 205 Ncm. CONCLUSION: Results indicated that patients treated with a graftless approach reported high satisfaction and impact on quality of life. Regarding maximum occlusal force values, significant differences between men and women were reported. The impact on quality of life seemed to improve when patients presented completely edentulous at the time of treatment as opposed to terminal dentition. Finally, significant positive correlations were detected between satisfaction and impact on quality of life, impact on quality of life and posterior maximum occlusal force, anterior and posterior maximum occlusal force, and complications and anterior maximum occlusal force. PMID- 28906506 TI - Stability of Grafted Implant Placement Sites After Sinus Floor Elevation Using a Layering Technique: 10-Year Clinical and Radiographic Results. AB - PURPOSE: To evaluate long-term survival rates and radiographic stability of sinus floor elevations carried out using a two-layer grafting technique. MATERIALS AND METHODS: Records were analyzed for patients treated with sinus floor elevations using a modified technique. Phycogenic hydroxyapatite (Algipore, Dentsply Sirona Implants) and autogenous bone particles harvested from intraoral sites were grafted in two distinct layers after elevation of the sinus mucosae. In this approach, the basal part of the sinus floor is grafted with autogenous bone, while the cranial part is grafted with the phycogenic hydroxyapatite. In some cases, implants were placed simultaneously, such that the entire surface of each implant was covered by autogenous bone particles. A titanium membrane was used to close the sinus window, and the implants were loaded 3 months later. In two-stage approaches, the implants were inserted 3 to 4 months after the grafting and loaded after 3 additional months. Panoramic radiographs were taken after the grafting procedure, after implant insertion, after the prosthetic restoration, and then annually for 10 years. These radiographs were used to measure the height between the implant shoulders and the top of the graft. RESULTS: Of the 214 sinus floor elevations performed on 129 patients using the bilayering technique, 198 procedures in 118 patients were included in the study (136 one-stage and 62 two stage). Membrane perforations during surgery occurred in 17.9% of the procedures and were sutured and sealed with fibrin glue. A total of 487 implants were placed in the grafted areas. No severe postoperative complications occurred, but three implants were lost throughout the 10-year follow-up period. A small decrease of vertical height was observed between the grafting surgery and the stage-two surgery (mean: 1.8 mm). After that, no bone height was lost over the 10 years. CONCLUSION: The layer grafting technique in combination with sinus floor elevation resulted in radiographically stable vertical bone height for 10 years. This technique enabled early placement and loading of implants in the grafted areas. The survival rate obtained with this procedure is similar to that expected for implants placed in nongrafted areas. PMID- 28906507 TI - Influence of the Diameter of Dental Implants Replacing Single Molars: 3- to 6 Year Follow-Up. AB - PURPOSE: The aim of this study was to evaluate the influence of the implant diameter on marginal bone remodeling around dental implants replacing single molars after a follow-up period of 3 to 6 years. MATERIALS AND METHODS: Patients who received dental implants with an external hexagon platform in healed sites to support a single metal-ceramic crown in the molar region were recalled to the office. The implantation sites and implant length information were recorded, and the implants were divided according to the implant diameter: regular (RP) or wide (WP). Each implant was assessed by digital periapical radiography, using a sensor holder for the paralleling technique. The marginal bone remodeling was determined as the distance from the implant platform to the first bone-to-implant contact, and the known implant length was used to calibrate the images in the computer software. The follow-up measurements were compared with those obtained from the radiograph taken at the time of prosthetic loading to determine the late bone remodeling. The independent t test was used to compare data. RESULTS: A total of 67 implants from 46 patients were evaluated with a mean follow-up period of 4.5 +/- 1.0 years. The RP group comprised 36 implants from 29 patients (mean age: 58.3 +/- 10.6 years), while 31 implants from 17 patients (mean age: 56.9 +/- 11.5 years) were included in the WP group. The RP group presented lower survival rates (86.1%) than the WP group (100.0%). Similar marginal bone loss (P < .05) was identified for the RP and WP groups (1.35 +/- 0.96 mm and 1.06 +/- 0.70 mm, respectively). CONCLUSION: Although wide-diameter implants exhibited lower incidence failures, the bone levels were similar after the prosthetic loading around regular- and wide-diameter implants supporting single molar crowns. PMID- 28906508 TI - A Prospective Case-Control Clinical Study of Titanium-Zirconium Alloy Implants with a Hydrophilic Surface in Patients with Type 2 Diabetes Mellitus. AB - PURPOSE: To evaluate prospectively the behavior of narrow-diameter (3.3-mm) titanium-zirconium alloy implants with a hydrophilic surface (Straumann Roxolid SLActive) in patients with type 2 diabetes mellitus in single-unit restorations, compared with a healthy control group (assessed using the glycosylated hemoglobin HbA1c test). MATERIALS AND METHODS: The patients evaluated in this study required single-unit implant treatment; 15 patients had type 2 diabetes mellitus, and 14 patients were healthy (control group [CG]). Marginal bone level (MBL) change around the implants was evaluated using conventional, sequential periapical digital radiographs. Patient HbA1c was assessed in each check-up. Normality test (Kolmogorov-Smirnov), univariate and multivariate logistic regression, analysis of variance (ANOVA), and Mann-Whitney U test were used for statistical analysis. RESULTS: No differences in MBL change and implant survival and success rates were found between the diabetes mellitus group (DMG) versus the control group, either during the initial recording (DMG, 0.99 +/- 0.56 vs CG, 0.68 +/- 0.54; P > .05) or 6 months after restoration (DMG, 1.28 +/- 0.38 vs CG, 1.11 +/- 0.59; P > .05). No significant correlation between HbA1c levels and MBL change was detected in these patients (P > .05). CONCLUSION: Patients with glycemic control exhibit similar outcomes to healthy individuals with regard to the investigated parameters. In light of these findings, the titanium-zirconium alloy small diameter implants can be used in the anterior region of the mouth in type 2 diabetic patients. PMID- 28906509 TI - Association of Systemic Conditions with Dental Implant Failures in 6,384 Patients During a 31-Year Follow-up Period. AB - PURPOSE: Outcome research has become an increasingly important form of clinical evidence for making health care decisions, including oral health considerations in the field of dentistry. In oral reconstruction involving dental implants, the risk of implant failure may be influenced by a patient's underlying medical condition. To identify associations, implant failure and systemic conditions or diseases were studied in a consecutive series of patients who received dental implants from October 1, 1983, to December 31, 2014, in the Department of Dental Specialties at Mayo Clinic in Rochester, Minnesota. MATERIALS AND METHODS: Data were abstracted from a prospective clinical database and electronic health records for patients' demographic, implant-specific, and medical profiles to determine time to first implant failure. Survival free of implant failure at the patient level was estimated by using the Kaplan-Meier method. Associations of demographic and systemic characteristics with implant failure were evaluated by using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals. RESULTS: The patient cohort consisted of 6,358 patients with a median age of 53 years at placement of the first implant. A total of 713 patients experienced implant failure at a median of 0.6 years. Among the 5,645 patients who did not experience implant failure, the median duration of follow-up was 5.8 years. More than 20 systemic diseases or conditions were identified for assessment, of which 15 comprised more than 50 patients and five comprised more than 500 patients. All associations were adjusted for age, sex, and era of implant, given the strong influence of these features on implant failure. After adjustment, no systemic disease or condition was shown to increase the risk for implant failure in the population and setting studied. CONCLUSION: Patients considering oral reconstruction involving implants in the medical setting studied do not appear to risk implant loss because of systemic conditions or diseases. PMID- 28906510 TI - Retrospective Analysis on Survival Rate, Template-Related Complications, and Prevalence of Peri-implantitis of 694 Anodized Implants Placed Using Computer Guided Surgery: Results Between 1 and 10 Years of Follow-Up. AB - PURPOSE: To report survival rate, early surgical template-related complications, and prevalence of peri-implantitis of dental implants placed in private practices using computer-guided, template-assisted surgery and followed between 1 and 10 years. MATERIALS AND METHODS: The present retrospective multicenter study evaluated data collected from fully or partially edentulous patients, with anodized-surface implants placed using computer-guided, template-assisted surgery between January 2006 and December 2015. The outcome measures were implant cumulative survival rate (CSR), early surgical complications involving the surgical template, and prevalence of peri-implantitis. RESULTS: A total of 694 implants were placed in 141 patients. Ten patients (7.1%) with 48 implants (6.9%) dropped out during the study period. One hundred seventeen patients, who received 121 surgical and prosthetic procedures, were treated according to a double-scan protocol, while the remaining 24 patients were treated by using the integrated treatment workflow. Most of the implants were immediately loaded (528 implants, 76.1%; 112 patients, 79.4%). Overall, 107 complete full-arch restorations (supported by four to eight implants each) were delivered in 103 patients (73%) with 595 implants (85.7%), while 13 single and 30 partial restorations (two to five implants each) were delivered in 38 patients (27%) with 99 implants (14.3%). Patients were followed for up to 10 years (mean: 58.2 months, range: 12 to 120 months). Implant- and patient-level CSR (Kaplan-Meier estimation) at the 10-year follow-up was 97.4% (95% CI: 1.0309 to 0.9161) and 92.1% (95% CI: 1.1575 to 0.6836), respectively. All failed implants were lost before definitive prosthesis delivery (early failure). Ten (7.1%) minor template-related complications were experienced and resolved chairside. Over the entire follow-up period, four patients (2.8%) with 12 implants (1.7%) showed signs of peri-implantitis at the 1 (four implants), 2- (four implants), and 4-year (four implants) visits. CONCLUSION: High long-term survival rates and low complications and prevalence of peri-implantitis were observed for a large cohort of anodized-surface implants placed in private practices. Further studies are needed to confirm these preliminary results. PMID- 28906511 TI - Association of Cytokine Gene Polymorphism with Peri-implantitis Risk. AB - PURPOSE: To investigate whether polymorphisms of cluster of differentiation 14 (CD14), tumor necrosis factor alpha (TNFalpha), interleukin (IL)6, IL10, and IL1ra genes are associated with the risk of peri-implantitis susceptibility in patients with dental implants in the Serbian population. MATERIALS AND METHODS: Isolated DNA from the blood was used for IL10-1082, TNFalpha-308, IL6-174, CD14 159, and interleukin 1 receptor antagonist (IL1ra) genotyping using polymerase chain reaction (PCR)-based methodology. Clinical parameters included: peri implant pocket depth (PPD), Plaque Index (PI), Gingival Index (GI), bleeding on probing (BOP), and radiologic bone loss. RESULTS: The study included 98 patients with dental implants in function for at least 1 year, divided into peri implantitis (34) and healthy peri-implant tissue (64) groups. The percentage distribution of smokers was significantly different between patients who developed peri-implantitis and patients with healthy peri-implant tissue (71% vs 42%, respectively) and associated with increased peri-implantitis risk (OR: 3.289, 95% CI: 1.352 to 8.001; P = .007). A positive history of periodontitis was more frequent in the peri-implantitis group (62%) than in the healthy peri implant tissue (20%) group and associated with increased peri-implantitis risk (OR: 6.337, 95% CI: 2.522 to 15.927; P = .0001). Frequencies of CD14-159, TNFalpha-308, IL10-1082, and IL6-174 genotypes were significantly different between patients with and without peri-implantitis. However, logistic regression revealed only TNFalpha-308 polymorphic GA/AA genotypes (OR: 8.890, 95% CI: 2.15 to 36.7; P = .003) and smoking (OR: 6.2, 95% CI: 1.44 to 26.7; P = .014) as independent factors associated with increased peri-implantitis risk, while CD14 159 polymorphic CT/TT genotypes were associated with decreased risk for peri implantitis (OR: 0.059, 95% CI: 0.009 to 0.355; P = .002). CONCLUSION: The findings suggest that smoking and the presence of TNFalpha-308 GA/AA genotypes may increase the risk for peri-implantitis, while CD14-159 polymorphic CT/TT genotypes decrease the risk. The results also indicate significant association of CD14-159, TNFalpha-308, and IL6-174 genotypes and clinical parameters in the Serbian population. However, future studies in larger patient groups are necessary to confirm these observations. PMID- 28906512 TI - Three series of heterometallic NiII-LnIII Schiff base complexes: synthesis, crystal structures and magnetic characterization. AB - Three series of NiII-LnIII complexes were synthesized with the general formulae [(MU3-CO3)2{Ni(HL)(CH3-CH2OH)Ln(CH3COO)}2].2CH3CH2OH (1-6) (Ln = Tb (1), Dy (2), Ho (3), Er (4), Tm (5), Yb (6); H3L = N,N'-bis(3-methoxysalicylidene)-1,3-diamino 2-prop-anol), [Ni(HL)Ln(dbm)3].CH3OH2.2CH2Cl2 (7-10) (Ln = Tb (7), Eu (8), Gd (9), Ho (10); Hdbm = 1,3-diphenyl-1,3-propanedione) and [Ni(HL)(H2O)(tfa)Ln(hfac)2] (11-15) (Ln = Tb (11), Dy (12), Eu (13), Gd (14), Ho (15); Hhfac = 1,1,1,5,5,5-hexafluoropentane-2,4-dione, tfa- = trifluoroacetate) using compartmental Schiff base ligands in conjunction with auxiliary ligands. For the NiLn series, the tetranuclear structure could be considered as two NiII LnIII dinuclear subunits bridged by two carbonates derived from atmospheric carbon dioxide. The LnIII ions of complexes 1-6 were octa-coordinated with distorted triangular dodecahedral geometry, while the LnIII ions of the dinuclear complexes 7-15 were nona-coordinated with distorted muffin geometry. The magnetic properties of the three series complexes were studied using dc and ac magnetic measurements. For the NiII-GdIII complexes, the dc magnetic susceptibility measurements suggested the existence of the anticipated ferromagnetic interaction between NiII and GdIII ions. The fitting of the chiMT vs. T data processed by PHI software provided the parameters g = 2.08 (J = +0.87 cm-1) for 9 and g = 2.02 (J = +1.83 cm-1) for 14. The interaction exchange was magneto-structurally correlated to the Ni-O-Gd angle (alpha) and Ni(MU-O)Gd dihedral angle (beta). With an applied dc field, complexes 1 (Tb), 2 (Dy), 7 (Tb) and 12 (Dy) exhibited single magnetic relaxation with SMM parameters of Ueff/k = 13.60 K, 11.52 K, 7.69 K and 5.14 K, respectively. Analysis of the Cole-Cole plots for complexes 2 and 7 suggested that a single relaxation process was mainly involved in the relaxation process, with alpha values in the range of 0.37-0.17 and 0.14-0.11, respectively. PMID- 28906513 TI - Valence directed binding mode of [2 * 2] iron grids of an unsymmetrical picolinic hydrazone based ligand. AB - A new unsymmetrical ditopic ligand H2L was used to synthesize two [2 * 2] grid type tetranuclear trivalent and mixed-valent Fe, FeFe complexes, respectively. Both complexes [Fe(L')4] (1) and [FeFe(L)4](BF4)2.2CH3CN (2) have been X-ray structurally characterized. The magnetic properties of complexes 1 and 2 show dominant antiferromagnetic coupling. Mossbauer studies were carried out to confirm the electronic states of the iron centres. The structural properties of the two complexes are diverse though they have been synthesized from the same ligand but under different conditions. In 1, all the Fe(iii) metal centres are coordinated by two pairs of parallel but oppositely aligned ligand strands arranged in a 'head-to-tail' fashion, whereas in 2, Fe(ii) and Fe(iii) metal centres are coordinated by two pairs of parallel aligned ligand strands arranged in a 'head-to-head' fashion. PMID- 28906514 TI - Anionic cyclometallated Pt(ii) square-planar complexes: new sets of highly luminescent compounds. AB - Two series of novel NBu4+ salts of anionic cyclometallated Pt(ii) complexes were synthesized and fully characterized. These highly luminescent compounds (NBu4[(C^N)Pt(O^N)] and NBu4[(C^N)Pt(O^O)]) are incorporated as testing examples of cyclometallating ligands 2-phenylpyridine (PhPy), 2-(2,4-difluorophenyl) pyridine (F2PhPy) and 2-thienylpyridine (ThPy), and a benzo[h]quinoline (Bzq) fragment. All complexes display a square-planar coordination sphere, wherein the "(C^N)Pt" fragment is completed either by an O^N orotate (Ort) or an O^O tetrabromocatecholate (Cat) ligand. The HOMO and LUMO levels of all complexes were estimated by cyclic voltammetry and a comprehensive electrochemical and photophysical study was performed. The new complexes are emissive in solution at 298 K and the NBu4[(ThPy)Pt(Ort)] complex displays good photosensitizing properties (Phi = 28% in deaerated solution vs. Phi = 1.4% in the presence of O2). Both series of NBu4[(C^N)Pt(Ort)] and NBu4[(C^N)Pt(Cat)] complexes are highly luminescent in the solid state (emission quantum yields from 10 to 85%). Remarkably, the square-planar Pt(ii) anionic complexes showed an important increase in luminescence quantum yields on changing from the dilute solution to the solid state (the most significant from 0.13% to 85% for the NBu4[(PhPy)Pt(Ort)] complex, an ideal candidate as an active species for LEECs). PMID- 28906515 TI - Study of the presence of spherical deformations on the Al top electrode due to electroforming in rewritable organic resistive memories. AB - Physical deformations are observed at the top electrodes during the electroforming process in Al/PEDOT:PSS + nitrogen doped multiwalled carbon nanotube (N-MWCNTs)/Al rewritable resistive memory devices. These physical deformations arise from electrochemical reactions, i.e., a reduction reaction in the native Al oxide layer, which are similar to those reported in TiO2-based resistive memory devices. These memory devices are electroformed at the ON state using an ~-2 V pulse or at the OFF state using an ~3 V pulse. These processes are current-controlled; a minimum compliance current is necessary to obtain the electroforming of the device, generally between 5 to 10 mA. SEM and AFM micrographs show the presence of spherical deformations at the top electrode due to O2 gas formation generated by the reduction in the native AlOx layer during the electroformation, with a diameter of ~7 micrometres for positive voltage or a smaller diameter of ~3 micrometres for negative voltage. After top-electrode delamination, circular craters are found in the active layer in the vicinity of the N-MWCNTs, which only occurs when a negative voltage is used in the electroformation, indicating that film damage is induced by oxygen bubbles created at the bottom electrode/polymeric film interface. PMID- 28906516 TI - A highly fluorinated lithium iron phosphate with interpenetrating lattices: electrochemistry and ionic conductivity. AB - Li5Fe2PO4F8, a new member of the family of alkali transition metal fluorophosphates, has been synthesized and characterized using single-crystal X ray diffraction, 57Fe Mossbauer spectroscopy and magnetic susceptibility measurements. The existence of an infinite {-[PO4(FeF4)2]-}infinity tetrahedral network in an inter-penetrated diamond lattice, along with the presence of seven unique Li sites, presents interesting structural features of this structure-type for energy storage applications. The initial results of (de)lithiation reveal that a relatively low fraction of theoretical capacity may be utilized reversibly (0.2 Li+ ion per formula unit), possibly due to the lack of available free volume for Li+ insertion. The high Li content and the existence of large channels in all 3-dimensions of space also offer opportunities to study this material as a candidate for solid-state electrolytes. The results from electro-impedance measurements reveal the reasonable activation energy of Li diffusion (0.70 eV), which is also supported by theoretical calculations. PMID- 28906520 TI - Strontium-coordination polymers based on tetrafluorophthalic and phthalic acids: mechanochemical synthesis, ab initio structures determination, and spectroscopic characterization. AB - Two strontium-based dicarboxylate systems [Sr(oBDC-F4)(H2O)2] (1) and [{Sr(oBDC)(H2O)2}.H2O] (2) were synthesized mechanochemically via milling of Sr(OH)2.8H2O with tetrafluorophthalic acid (H2oBDC-F4) or phthalic acid (H2oBDC), respectively. The new structures were determined ab initio from the powder X-ray diffraction (PXRD) data. Both compounds 1 and 2 crystallize in the monoclinic space group P21/c as two-dimensional coordination polymers (2D-CPs). The determined structures were validated by extended X-ray absorption (EXAFS) data. Compounds 1 and 2 show different thermal stabilities. The fluorinated CP 1 is decomposed at 300 degrees C while the nonfluorinated CP 2 transforms into a new phase after thermal treatment at 400 degrees C. The two hydrated CPs exhibit small surface areas which increase after the thermal post-treatment for 1 but remains unchanged for the dehydrated sample of 2. Dynamic vapor sorption (DVS) experiments indicate that both the dehydrated and hydrated samples of 2 depict no significant differences in their adsorption isotherms. The DVS of water indicates that the phase transition after thermal post-treatment of 2 is irreversible. PMID- 28906521 TI - Inter-cluster distance dependence of electrical properties in single crystals of a mixed-valence polyoxometalate. AB - The electrical conductivity of mixed-valence [MoMoO54(SO3)2]6- tetraalkylammonium salts was investigated through dependence on the inter-cluster distance that is controlled by tetraethylammonium, tetrapropylammonium, and tetrabutylammonium cations. The crystallographic analysis of single crystals revealed that the inter cluster distances are dependent on the chain length of the alkyl groups on the counter cations. In addition, the electrical conductivities of the single crystals were found to be dependent on both temperature and chain length. Mixed valence polyoxometalate (POM) clusters are considered to be a molecular particle of Mo bronze by which highly ordered networks will be developed using single crystals, where POMs are rather small and have a well-organized structure compared to colloidal nanostructures. PMID- 28906522 TI - Correlation between electronic structure, transport and electrochemical properties of a LiNi1-y-zCoyMnzO2 cathode material. AB - Herein, the correlation between electronic structure, transport and electrochemical properties of layered LixNi1-y-zCoyMnzO2 cathode material is revealed. Comprehensive experimental studies of physicochemical properties of LixNi1-y-zCoyMnzO2 cathode material (XRD, electrical conductivity, thermoelectric power) are supported by electronic structure calculations performed using the Korringa-Kohn-Rostoker method with the coherent potential approximation (KKR-CPA) to account for the chemical disorder. It is found that even small O defects (~1%) could significantly modify electronic density of states DOS characteristics via the formation of extra broad peaks inside the former band gap leading to its substantial narrowing. The calculated DOS values and their changes near EF tend to support experimental findings with irregular changes in the sign of thermoelectric power as well as the behavior of electrical conductivity curves as a function of Li content. Furthermore, the variations of the electromotive force of the Li/Li+/LixNi1-y-zCoyMnzO2 cell (for 0 < x < 1) remains in a quite good agreement with the relative variation of EF on DOS calculated from the KKR-CPA method. PMID- 28906523 TI - Low-temperature-flux syntheses of ultraviolet-transparent borophosphates Na4MB2P3O13 (M = Rb, Cs) exhibiting a second-harmonic generation response. AB - The first non-centrosymmetric mixed-alkali-metal borophosphates, Na4MB2P3O13 (M = Rb 1, Cs 2), were obtained using a low-temperature flux method. Single-crystal X ray diffraction studies of 1 and 2 reveal that the two compounds are isostructural, both crystallizing in the orthorhombic space group Pna21; their structures consist of novel 1D borophosphate chains constructed from B2P3O14 fundamental building units, assembled into a 3D framework by alkali metal cations. Second-harmonic generation (SHG) measurements show that 1 and 2 are type I phase-matchable, with SHG responses ca. 0.35 and 0.42 times that of KH2PO4, respectively. The cut-off edges of 1 and 2 are ca. 276 and 267 nm, respectively, which suggests that they are potential ultraviolet nonlinear optical materials. Density functional theory calculations were employed to shed light on the band structure and density of states as well as the electron density distribution. PMID- 28906524 TI - Spiers Memorial Lecture. Surface-enhanced Raman spectroscopy: from single particle/molecule spectroscopy to angstrom-scale spatial resolution and femtosecond time resolution. AB - Four decades on, surface-enhanced Raman spectroscopy (SERS) continues to be a vibrant field of research that is growing (approximately) exponentially in scope and applicability while pushing at the ultimate limits of sensitivity, spatial resolution, and time resolution. This introductory paper discusses some aspects related to all four of the themes for this Faraday Discussion. First, the wavelength-scanned SERS excitation spectroscopy (WS-SERES) of single nanosphere oligomers (viz., dimers, trimers, etc.), the distance dependence of SERS, the magnitude of the chemical enhancement mechanism, and the progress toward developing surface-enhanced femtosecond stimulated Raman spectroscopy (SE-FSRS) are discussed. Second, our efforts to develop a continuous, minimally invasive, in vivo glucose sensor based on SERS are highlighted. Third, some aspects of our recent work in single molecule SERS and the translation of that effort to angstrom-scale spatial resolution in ultrahigh vacuum tip-enhanced Raman spectroscopy (UHV-TERS) and single molecule electrochemistry using electrochemical (EC)-TERS will be presented. Finally, we provide an overview of analytical SERS with our viewpoints on SERS substrates, approaches to address the analyte generality problem (i.e. target molecules that do not spontaneously adsorb and/or have Raman cross sections <10-29 cm2 sr-1), SERS for catalysis, and deep UV-SERS. PMID- 28906526 TI - A series of Mg-Zn heterometallic coordination polymers: synthesis, characterization, and fluorescence sensing for Fe3+, CS2, and nitroaromatic compounds. AB - Herein, the solvothermal preparations, crystal structures, and fluorescence properties of three Mg-Zn heterometallic coordination polymers (CPs), i.e. [Mg2Zn2(OH)2(1,4-NDC)3(H2O)2].6H2O (1), [Mg1.13Zn1.87(1,4-NDC)3(dppe)(CH3OH)] (2), and [Mg1.17Zn1.83(1,4-NDC)3(py)2].1.5py (3), based on the mixed ligands of 1,4-naphthalene dicarboxylic acid (1,4-H2NDC) and N-containing ligands of 1,3 di(4-pyridyl)propane (dppe) or pyridine (py) are presented. In the title compounds, Zn and Mg are statistically distributed, as confirmed by single crystal analysis, and the ratios of Zn and Mg have been identified by inductively coupled plasma (ICP) measurements. In compound 1, the metal ions are tetra- or hexa-coordinated by the oxygen atoms of the carboxylate and MU3-OH group to form a one-dimensional (1D) ribbon, and these 1D ribbons are further bridged by 1,4 NDC linkers to grow into a 3D framework with 1D channels along the b axis. In compounds 2 and 3, the metal ions also adopt tetra- or hexa-coordination modes and are inter-bridged by carboxylate oxygen atoms to form a tri-nuclear secondary building unit (SBU). Due to the introduction of N-containing ligands acting as terminal molecules, these SBUs are linked by 1,4-NDC ligands to form a 2D network. Photoluminescence (PL) studies indicated that the title compounds showed strong blue emissions. Significantly, compound 1 demonstrated sensitive fluorescence sensing for Fe3+, carbon disulfide (CS2), and nitroaromatic compounds at low concentrations. The fluorescence sensing properties of compound 2 were also comparatively investigated in detail. PMID- 28906525 TI - Stereolithographic printing of ionically-crosslinked alginate hydrogels for degradable biomaterials and microfluidics. AB - 3D printed biomaterials with spatial and temporal functionality could enable interfacial manipulation of fluid flows and motile cells. However, such dynamic biomaterials are challenging to implement since they must be responsive to multiple, biocompatible stimuli. Here, we show stereolithographic printing of hydrogels using noncovalent (ionic) crosslinking, which enables reversible patterning with controlled degradation. We demonstrate this approach using sodium alginate, photoacid generators and various combinations of divalent cation salts, which can be used to tune the hydrogel degradation kinetics, pattern fidelity, and mechanical properties. This approach is first utilized to template perfusable microfluidic channels within a second encapsulating hydrogel for T-junction and gradient devices. The presence and degradation of printed alginate microstructures were further verified to have minimal toxicity on epithelial cells. Degradable alginate barriers were used to direct collective cell migration from different initial geometries, revealing differences in front speed and leader cell formation. Overall, this demonstration of light-based 3D printing using non-covalent crosslinking may enable adaptive and stimuli-responsive biomaterials, which could be utilized for bio-inspired sensing, actuation, drug delivery, and tissue engineering. PMID- 28906527 TI - Mango-bagasse functional-confectionery: vehicle for enhancing bioaccessibility and permeability of phenolic compounds. AB - Functional confectionery can be exploited as a vehicle for the protection of phenolic compounds (PCs) and for enhancing absorption during the gastrointestinal (GI) process. In this study, a confection containing 20% of mango bagasse (MB), gelatin and pectin was formulated. The PC profile, antioxidant capacity, in vitro bioaccessibility and apparent permeability (Papp) during mouth-stomach-intestine digestion (15, 30, 60, 120 min) and in vitro colonic fermentation (6, 12, 24 h) were evaluated for MB and the mango bagasse confection (MBC). HPLC-DAD analysis showed that mangiferin (830.69 MUg g-1) was the most abundant compound in MBC. Total PCs (4.14 mg g-1), quercetin (244.83 MUg g-1), and gallic acid (GA) (285.43 MUg g-1) were highly bioaccessible mainly at the intestine at 60-120 min of digestion. GA was the most bioaccessible compound. Total flavonoids (TFs) and condensed tannins (CTs) had the maximum bioaccessibility in the mouth and stomach, respectively. For the permeability studies, PCs showed efflux rather than uptake in the intestine. Those compounds that exhibited intestinal absorption were mangiferin > GA > total PCs > TFs, whereas quercetin and CT absorption was negligible. The antioxidant capacity remained unchanged along the GI, mangiferin and quercetin being the most likely compounds to exert this activity. Overall results indicate that MBC has higher bioaccessibility, absorption and antioxidant capacity than MB, suggesting an effective protective role of gelatin and pectin, giving insight into the potential of MBC as a functional food. PMID- 28906528 TI - Real-time activity assays of beta-lactamases in living bacterial cells: application to the inhibition of antibiotic-resistant E. coli strains. AB - The emergence of antibiotic resistance caused by beta-lactamases, including serine beta-lactamases (SbetaLs) and metallo-beta-lactamases (MbetaLs), is a global public health threat. L1, a B3 subclass MbetaL, hydrolyzes almost all of known beta-lactam antibiotics. We report a simple and straightforward UV-Vis approach for real-time activity assays of beta-lactamases inside living bacterial cells, and this method has been exemplified by choosing antibiotics, L1 enzyme, Escherichia coli expressing L1 (L1 E. coli), Escherichia coli expressing extended spectrum beta-lactamases (ESBL-E. coli), clinical bacterial strains, and reported MbetaL and SbetaL inhibitors. The cell-based studies demonstrated that cefazolin was hydrolyzed by L1 E. coli and clinical strains, and confirmed the hydrolysis to be inhibited by two known L1 inhibitors EDTA and azolylthioacetamide (ATAA), with an IC50 value of 1.6 and 18.9 MUM, respectively. Also, it has been confirmed that the breakdown of cefazolin caused by ESBL-E. coli was inhibited by clavulanic acid, the first SbetaL inhibitor approved by FDA. The data gained through this approach are closely related to the biological function of the target enzyme in its physiological environment. The UV-Vis method proposed here can be applied to target-based whole-cell screening to search for potent beta lactamase inhibitors, and to assays of reactions in complex biological systems, for instance in medical assays. PMID- 28906529 TI - The effect of iloprost and sildenafil, alone and in combination, on myocardial ischaemia and nitric oxide and irisin levels. AB - AIM: Insufficient oxygen supply to organs and tissues due to reduced arterial or venous blood flow results in ischaemia, during which, although ATP production stops, AMP and adenosine continue to be produced from ATP. The fate of irisin, which causes the production of heat instead of ATP during ischaemia, is unknown. Iloprost and sildenafil are two pharmaceutical agents that mediate the resumption of reperfusion (blood supply) via vasodilatation during ischaemic conditions. Our study aimed to explore the effects of iloprost and sildenafil on irisin levels in the heart, liver and kidney tissues and whether these pharmaceutical agents had any impact on serum irisin and nitric oxide levels in rats with induced experimental myocardial ischaemia. METHODS: The study included adult male Sprague Dawley rats aged 10 months and weighing between 250 and 280 g. The animals were randomly allocated to eight groups, with five rats in each group. The groups were: sham (control), iloprost (ILO), sildenafil (SIL), ILO + SIL, myocardial ischaemia (MI), MI + ILO, MI + SIL and MI + ILO + SIL. The treatment protocols were implemented before inducing ischaemia, which was done by occluding the left coronary artery with a plastic ligature for 30 minutes. Following the reperfusion procedure, all rats were sacrificed after 24 hours, and their heart, liver and kidney tissues and blood samples were collected for analyses. An immunohistochemical method was used to measure the change in irisin levels, the ELISA method to quantify blood irisin levels, and Griess' assay to determine nitric oxide (NO) levels in the serum and tissue. Myocardial ischaemia was confirmed based on the results of Masson's trichrome staining, as well as levels of troponin and creatine kinase MB. RESULTS: Irisin levels in biological tissue and serum dropped statistically significantly in the ischaemic group (MI), but were restored with ILO and SIL administration. Individual SIL administration was more potently restorative than individual ILO administration or the combined administration of the two agents. NO level, on the other hand, showed the opposite tendency, reaching the highest level in the MI group, and falling with the use of pharmaceutical agents. CONCLUSIONS: Individual or combined administration of ILO and SIL reduced myocardial ischaemia and NO levels, and increased irisin levels. Elevated levels of irisin obtained by drug administration could possibly contribute to accelerated wound recovery by local heat production. Sildenafil was more effective than iloprost in eliminating ischaemia and may be the first choice in offsetting the effects of ischaemia in the future. PMID- 28906530 TI - The effect of lifestyle interventions on maternal body composition during pregnancy in developing countries: a systematic review. AB - Optimal maternal body composition during pregnancy is a public health priority due to its implications on maternal health and infant development. We therefore aimed to conduct a systematic review of randomised, controlled trials, and case control and cohort studies using lifestyle interventions to improve body composition in developing countries. Of the 1 708 articles that were searched, seven studies, representing three countries (Brazil, Iran and Argentina), were included in the review. Two articles suggested that intervention with physical activity during pregnancy may significantly reduce maternal weight gain, and five studies were scored as being of poor quality. This systematic review highlights the lack of research within developing countries on lifestyle interventions for the management of excessive weight gain during pregnancy. Similar reviews from developed countries demonstrate the efficacy of such interventions, which should be confirmed using well-designed studies with appropriate intervention methods in resource-limited environments. PMID- 28906531 TI - Red cell distribution width is correlated with extensive coronary artery disease in patients with diabetes mellitus. AB - INTRODUCTION: Previous studies have predicted an independent relationship between red cell distribution width (RDW) and the risk of death and cardiovascular events in patients with coronary artery disease (CAD). The aim of this study was to investigate the relationship between RDW and extensiveness of CAD in patients with diabetes mellitus (DM). METHODS: Two hundred and thirty-three diabetic patients who underwent coronary angiographies at our centre in 2010 were included in the study. All of the angiograms were re-evaluated and Gensini scores were calculated. Triple-vessel disease was diagnosed in the presence of stenosis > 50% in all three coronary artery systems. RESULT: RDW was significantly higher in diabetic CAD patients (p < 0.001). Patients with CAD who had a RDW value above the cut-off point also had higher Gensini scores, higher percentages of obstructive CAD and triple-vessel disease (p <= 0.001 for all). According to the cut-off values calculated using ROC analysis, RDW > 13.25% had a high diagnostic accuracy for predicting CAD. RDW was also positively correlated with Gensini score, obstructive CAD and triple-vessel disease (r < 0.468 and p < 0.001 for all). CONCLUSION: RDW values were found to be increased in the diabetic CAD population. Higher RDW values were related to more extensive and complex coronary lesions in patients with DM. PMID- 28906533 TI - Cardiac diastolic function after recovery from pre-eclampsia. AB - BACKGROUND: Pre-eclampsia is associated with significant changes to the cardiovascular system during pregnancy. Eccentric and concentric remodelling of the left ventricle occurs, resulting in impaired contractility and diastolic dysfunction. It is unclear whether these structural and functional changes resolve completely after delivery. AIMS: The objective of the study was to determine cardiac diastolic function at delivery and one year post-partum in women with severe pre-eclampsia, and to determine possible future cardiovascular risk. METHODS: This was a descriptive study performed at Steve Biko Academic Hospital, a tertiary referral hospital in Pretoria, South Africa. Ninety-six women with severe preeclampsia and 45 normotensive women with uncomplicated pregnancies were recruited during the delivery admission. Seventy-four (77.1%) women in the pre-eclamptic group were classified as a maternal near miss. Transthoracic Doppler echocardiography was performed at delivery and one year post-partum. RESULTS: At one year post-partum, women with pre-eclampsia had a higher diastolic blood pressure (p = 0.001) and body mass index (p = 0.02) than women in the normotensive control group. Women with early onset pre-eclampsia requiring delivery prior to 34 weeks' gestation had an increased risk of diastolic dysfunction at one year post-partum (RR 3.41, 95% CI: 1.11-10.5, p = 0.04) and this was irrespective of whether the patient had chronic hypertension or not. CONCLUSION: Women who develop early-onset pre-eclampsia requiring delivery before 34 weeks are at a significant risk of developing cardiac diastolic dysfunction one year after delivery compared to normotensive women with a history of a low-risk pregnancy. PMID- 28906534 TI - Management of a complicated redo giant dissecting aortic aneurysm. AB - Giant aortic aneurysm is defined as an aneurysm of the aorta of greater than 10 cm in diameter. This rare condition is associated with a high risk of morbidity and mortality and it may lead to fatal complications such as rupture and/or dissection if not managed with proper surgical planning and expertise. Other than atherosclerosis, the main causes of giant ascending aortic aneurysms include Marfan and Ehlers-Danhlos syndromes. Herein we report on a young male patient who had had an aortic valve replacement five years earlier due to a bicuspid aortic valve leading to aortic failure, accompanied by aortic coarctation. He had an aneurysmal expansion rate of 1.81 cm/year to reach a final aneurysmal diameter of 13.25 cm, which, to our knowledge, represents the largest size ever reported in the literature for such lesions, and in which the redo and aneurysmal wall were adjacent to the sternal margins. PMID- 28906532 TI - The aetiology of cardiovascular disease: a role for mitochondrial DNA? AB - Cardiovascular disease (CVD) is a world-wide cause of mortality in humans and its incidence is on the rise in Africa. In this review, we discuss the putative role of mitochondrial dysfunction in the aetiology of CVD and consequently identify mitochondrial DNA (mtDNA) variation as a viable genetic risk factor to be considered. We then describe the contribution and pitfalls of several current approaches used when investigating mtDNA in relation to complex disease. We also propose an alternative approach, the adjusted mutational load hypothesis, which would have greater statistical power with cohorts of moderate size, and is less likely to be affected by population stratification. We therefore address some of the shortcomings of the current haplogroup association approach. Finally, we discuss the unique challenges faced by studies done on African populations, and recommend the most viable methods to use when investigating mtDNA variation in CVD and other common complex disease. PMID- 28906535 TI - From the Editor's Desk. PMID- 28906536 TI - Endomyocardial fibrosis in Sudan: clinical and echocardiographic features. AB - OBJECTIVE: Endomyocardial fibrosis (EMF) is a rare disease and is often an underdiagnosed and forgotten cardiomyopathy. The objective of this study was to document the current frequency of EMF in Sudan by defining and selecting cases from patients attending the echocardiography laboratory. Additionally we aimed to create an EMF registry for Sudan. METHODS: The study started in January 2007 and is on-going. All the patients attending our echocardiography clinics in four different hospitals in Khartoum, Sudan, were included. Transthoracic echocardiography was used as the main diagnostic and selection tool. The diagnosis of EMF was based on predefined criteria and definitions, and was further supported by additional clinical, ECG, laboratory and chest X-ray findings. RESULTS: Out of 4 332 cases studied, 23 (0.5%) were found to have features of EMF. Females constituted 52% and the age range was 24 to 67 years. All patients presented with dyspnoea grades III-IV. Advanced heart failure with gross fluid overload was seen in 54% of cases and ascites was seen in 30%. EMF was biventricular in 53%, left ventricular in 29% and right ventricular in 18% of cases. Apical and ventricular wall fibrosis was found in all cases, followed by atrial enlargement, atrioventricular valve incompetence, ventricular cavity obliteration, restrictive flow pattern and pericardial effusion. Additional echocardiographic features are defined and discussed. CONCLUSION: Although a rare disease, cases of EMF can be identified in Sudan if a high index of suspicion is observed. New echocardiographic features of ventricular wall layering, endocardial fibrous shelf and endomyocardiopericarial fibrosis were identified and are discussed. PMID- 28906537 TI - The changing spectrum of rheumatic mitral regurgitation in Soweto, South Africa. AB - OBJECTIVES: To determine the clinical and echocardiographic characteristics of contemporary patients with rheumatic mitral regurgitation (MR) at Chris Hani Baragwanath Academic Hospital. METHODS: This prospective, cross-sectional study included 84 patients with isolated moderate or severe rheumatic MR who underwent clinical and echocardiographic assessment. RESULTS: Mean age of the patients was 44 +/- 15.3 years (84% females). Acute rheumatic fever was rare. Hypertension and HIV were present in 52 and 26%, respectively. Echocardiography showed leaflet thickening and calcification, restricted motion and subvalvular disease in 41, 25 and 34%, respectively. Carpentier IIIa leaflet dysfunction occurred in 80% of patients and leaflet prolapse was seen in only 20%. These findings contrast with the previous literature, where patients were younger, they had rheumatic carditis and there were no co-morbidities. Leaflets were pliable, isolated leaflet prolapse was common and commissural fusion was absent. CONCLUSION: Contemporary patients with rheumatic MR were older, fewer had rheumatic fever and there were more co-morbidities. Echocardiographic features had evolved to greater leaflet thickening, calcification and reduced motion with minimal prolapse. These findings may have important implications for surgical management of this disease. PMID- 28906538 TI - Nuclear cardiology practices and radiation exposure in Africa: results from the IAEA Nuclear Cardiology Protocols Study (INCAPS). AB - OBJECTIVE: While nuclear myocardial perfusion imaging (MPI) offers many benefits to patients with known or suspected cardiovascular disease, concerns exist regarding radiation-associated health effects. Little is known regarding MPI practice in Africa. We sought to characterise radiation doses and the use of MPI best practices that could minimise radiation in African nuclear cardiology laboratories, and compare these to practice worldwide. METHODS: Demographics and clinical characteristics were collected for a consecutive sample of 348 patients from 12 laboratories in six African countries over a one-week period from March to April 2013. Radiation effective dose (ED) was estimated for each patient. A quality index (QI) enumerating adherence to eight best practices, identified a priori by an IAEA expert panel, was calculated for each laboratory. We compared these metrics with those from 7 563 patients from 296 laboratories outside Africa. RESULTS: Median (interquartile range) patient ED in Africa was similar to that of the rest of the world [9.1 (5.1-15.6) vs 10.3 mSv (6.8-12.6), p = 0.14], although a larger proportion of African patients received a low ED, <= 9 mSv targeted in societal recommendations (49.7 vs 38.2%, p < 0.001). Bestpractice adherence was higher among African laboratories (QI score: 6.3 +/- 1.2 vs 5.4 +/- 1.3, p = 0.013). However, median ED varied significantly among African laboratories (range: 2.0-16.3 mSv; p < 0.0001) and QI range was 4-8. CONCLUSION: Patient radiation dose from MPI in Africa was similar to that in the rest of the world, and adherence to best practices was relatively high in African laboratories. Nevertheless there remain opportunities to further reduce radiation exposure to African patients from MPI. PMID- 28906539 TI - A programme to increase appropriate usage of benzathine penicillin for management of streptococcal pharyngitis and rheumatic heart disease in Zambia. AB - Rheumatic heart disease is highly prevalent and associated with substantial morbidity and mortality in many resource-poor areas of the world, including sub Saharan Africa. Primary and secondary prophylaxis with penicillin has been shown to significantly improve outcomes and is recognised to be the standard of care, with intra-muscular benzathine penicillin G recommended as the preferred agent by many technical experts. However, ensuring compliance with therapy has proven to be challenging. As part of a public-private partnership initiative in Zambia, we conducted an educational and access-to-medicine programme aimed at increasing appropriate use of benzathine penicillin for the prevention and management of rheumatic heart disease, according to national guidelines. The programme was informed early on by identification of potential barriers to the administration of injectable penicillin, which included concern by health workers about allergic events. We describe this programme and report initial signs of success, as indicated by increased use of benzathine penicillin. We propose that a similar approach may have benefits in rheumatic heart disease programmes in other endemic regions. PMID- 28906540 TI - Reviewing the causes of electrocardiographic pauses. AB - The electrocardiographic term 'pause' refers to the prolonged R-R interval that represents the interruption in ventricular depolarisation. This article presents a case of sinus node dysfunction and provides a diagnostic approach to pauses on the ECG. PMID- 28906541 TI - Roadmap to achieve 25% hypertension control in Africa by 2025. AB - BACKGROUND AND AIM: The Pan-African Society of Cardiology (PASCAR) has identified hypertension as the highest area of priority for action to reduce heart disease and stroke on the continent. The aim of this PASCAR roadmap on hypertension was to develop practical guidance on how to implement strategies that translate existing knowledge into effective action and improve detection, treatment and control of hypertension and cardiovascular health in sub-Saharan Africa (SSA) by the year 2025. METHODS: Development of this roadmap started with the creation of a consortium of experts with leadership skills in hypertension. In 2014, experts in different fields, including physicians and non-physicians, were invited to join. Via faceto-face meetings and teleconferences, the consortium made a situation analysis, set a goal, identified roadblocks and solutions to the management of hypertension and customised the World Heart Federation roadmap to Africa. RESULTS: Hypertension is a major crisis on the continent but very few randomised, controlled trials have been conducted on its management. Also, only 25.8% of the countries have developed or adopted guidelines for the management of hypertension. Other major roadblocks are either government and health-system related or healthcare professional or patient related. The PASCAR hypertension task force identified a 10-point action plan to be implemented by African ministries of health to achieve 25% control of hypertension in Africa by 2025. CONCLUSIONS: Hypertension affects millions of people in SSA and if left untreated, is a major cause of heart disease and stroke. Very few SSA countries have a clear hypertension policy. This PASCAR roadmap identifies practical and effective solutions that would improve detection, treatment and control of hypertension on the continent and could be implemented as is or adapted to specific national settings. PMID- 28906542 TI - Illuminating the pathway for the next generation of cardiovascular medicine practitioners and researchers: Highlights of the Joint PASCAR-SCC clinical symposium on hypertension and heart failure, Cameroon. AB - The Pan-African Society of Cardiology roadmap aims to achieve a 25% control of hypertension by the year 2025. Whether this is attainable or not depends largely on the capacity of healthcare providers and policy makers to address the rising prevalence of hypertension and its complications, including heart failure. Task sharing is fundamental in optimising hypertension control. The Clinical Research Education, Networking and Consultancy (CRENC) engaged with the Pan-African Society of Cardiology (PASCAR) and the Cameroon Cardiac Society (SCC) in a joint hypertension and heart failure symposium at the Douala General Hospital in 2016. The primary aims were to foster clinical research in cardiovascular medicine by raising awareness on cardiovascular diseases, to provide evidence-based training of an international standard, to encourage the conduction and dissemination of high-quality research, and to build programmes for continuing medical education. The secondary aim was to potentiate the 2nd Douala Research and Scientific Days. The symposium, which featured didactic lectures interspaced with oral/poster abstract presentations and a clinical visit, culminated in the launching of the book Heart of Africa, and the Young Investigator award. It is hoped that these served to capacitate existing cardiovascular structures, breed the next generation of cardiovascular physicians and researchers, and imprint a trail of clinical research excellence to be emulated in Cameroon and beyond. PMID- 28906543 TI - The role of atrial fibrillation in patients with an embolic stroke of unknown source (ESUS). PMID- 28906544 TI - Hypoglycemic Effect of Chinese Yam (Dioscorea opposita rhizoma) Polysaccharide in Different Structure and Molecular Weight. AB - : Three new Chinese yam polysaccharides (namely HSY, huaishanyao in Chinese) were isolated using the methods of boiled water extraction and stepwise ethanolic precipitation, combined with the tangential flow ultrafiltration membrane system. Their molecular weights were determined by high performance gel permeation chromatography. Three type yam polysaccharides in different molecular weight were isolated: HSY-I (>50 kDa), HSY-II (10 to 50 kDa), HSY-III (<10 kDa). The monosaccharide and glycosidic bond links composition were analyzed with GC and Smith degradation. The structure characteristics were further discussed combined with infrared spectrophotometry. Dexamethasone-induced insulin resistance glucose/lipid metabolism diabetic mice model was established to evaluate the hypoglycemic effect of different concentration of HSY and different molecular weights polysaccharide HSY-I, HSY-II, and HSY-III. The results indicated that the HSY polysaccharide mixture, HSY-I and HSY-II had hypoglycemic effect. PRACTICAL APPLICATION: Three polysaccharides from Chinese yam tuber were isolated in this study. Their structures were characterized and hypoglycemic effects were evaluated. The result clearly identified the benefits of this plant as a healthy functional food. PMID- 28906545 TI - Adipose tissue content of saturated fatty acids and atrial fibrillation: A case cohort study. AB - OBJECTIVES: The aim of this study was to investigate the association between adipose tissue content of total saturated fatty acids including myristic (C14:0), palmitic (C16:0) and stearic (C18:0) acid, as a measure of exposure to saturated fatty acids and the risk of incident atrial fibrillation. MATERIALS AND METHODS: A total of 57 053 Danish men and women aged 50-64 years participating in the Diet, Cancer and Health cohort had an adipose tissue biopsy taken at baseline, and this was analysed for saturated fatty acids content by gas chromatography. Follow-up was registry based and in this case-cohort study we used all cases and a randomly drawn subcohort of 3500 participants representative for the entire cohort. RESULTS: Data were analysed using weighted Cox proportional hazards regression. During a median follow-up of 14.6 years, a total of 4722 cases of incident atrial fibrillation were diagnosed. For both men and women, no association between adipose tissue content of total saturated fatty acids and the risk of atrial fibrillation could be demonstrated. CONCLUSION: We did not find an association between adipose tissue content of total saturated fatty acids and the risk of incident atrial fibrillation. PMID- 28906546 TI - Chronic urticaria and irritable bowel syndrome: a cross-sectional study of 11 271 patients. PMID- 28906547 TI - Reflexive convention: civil partnership, marriage and family. AB - Drawing on an analysis of qualitative interview data from a study of formalized same-sex relationships (civil partnerships) this paper examines the enduring significance of marriage and family as social institutions. In doing so, it intervenes in current debates in the sociology of family and personal life about how such institutions are undermined by reflexivity or bolstered by convention. Against the backdrop of dominating sociological frames for understanding the links between the changing nature of marriage and family and same-sex relationship recognition, the paper analyses the diverse and overlapping ways (including the simple, relational, strategic, ambivalent and critical ways) in which same-sex partners reflexively constructed and engaged with marriage and family conventions. My analysis suggests that instead of viewing reflexivity and convention as mutually undermining, as some sociologists of family and personal life do, it is insightful to explore how diverse forms of reflexivity and convention interact in everyday life to reconfigure the social institutions of marriage and family, but do not undermine them as such. I argue the case for recognizing the ways in which 'reflexive convention', or reflexive investment in convention, contributes to the continuing significance of marriage and family as social institutions. PMID- 28906549 TI - Developing a protocol to identify and prioritize research questions for psoriasis: a James Lind Alliance Priority Setting Partnership. AB - BACKGROUND: Psoriasis affects over two million people in the U.K. It has a significant psychological and social impact on individuals and an associated high economic cost to the U.K. National Health Service. There are many unanswered questions about psoriasis. OBJECTIVES: To develop a protocol in order to work with patients, families, carers and healthcare professionals to identify psoriasis uncertainties; to agree by consensus a top-10 list of psoriasis uncertainties; and to disseminate prioritized unanswered questions to researchers and funders so as to promote work that will focus on answering the uncertainties considered most important by stakeholders. METHODS: A Psoriasis Priority Setting Partnership has been established to gather psoriasis uncertainties following the transparent methodology advocated by the James Lind Alliance. A steering group composed of stakeholders has disseminated an initial survey to patients, families, carers and healthcare professionals to collect information on important psoriasis questions. After removing duplications, uncertainties will be collated and checked against existing evidence to determine whether any have already been resolved. 'True uncertainties' will be circulated to stakeholders in a second survey where they will be ranked by importance. At a final workshop, information will be distilled to generate a top-10 list of uncertainties. RESULTS: By following the protocol outlined in this paper a prioritized list of uncertainties will be identified that will be used to inform the psoriasis research agenda. CONCLUSIONS: Research targeted to address priorities identified by a range of stakeholders is imperative. This project will inform policy makers and research funding bodies about what really matters to these groups. PMID- 28906550 TI - Efficacy and safety of autologous haematopoietic stem cell transplantation in systemic sclerosis: a systematic review of the literature. AB - We aimed to assess the efficacy of autologous haematopoietic stem cell transplantation (HSCT) for skin sclerosis (SSc) and lung function in SSc. We performed a systematic literature review in the PubMed and Scopus databases from the earliest records to March 2016. We assessed study quality using the Cochrane tool for randomized studies, the Newcastle-Ottawa Scale for controlled cohort studies and an 18-item quality-appraisal checklist for case series. The primary outcome was the improvement of skin thickening using the modified Rodnan Skin Score (mRSS). The secondary outcome was efficacy on lung function, using diffusing capacity of the lungs for carbon monoxide and forced vital capacity (FVC). The safety of the procedure was evaluated. The literature search identified 431 citations. There were 38 studies involving a total of 344 patients who fulfilled our inclusion criteria. No meta-analysis was performed due to a high heterogeneity. There was a significant improvement in mRSS in the majority of the reports (P < 0.05), and the results were sustained for up to 8 years after autologous HSCT. The randomized studies and the four cohort studies each showed a slight but statistically significant improvement in FVC at 1 or 2 years. The treatment-related mortality calculated by pooling patients of 35 studies (336 patients with a follow-up up to 146 months) was 8.3% after autologous HSCT and 1% in cyclophosphamide-treated groups. Despite heterogeneity among the studies, we determined that autologous HSCT significantly improved cutaneous fibrosis and slightly improved FVC. Safety of autologous HSCT is acceptable given the severity of the disease. This systematic review was registered on PROSPERO, number CRD42016027951. PMID- 28906548 TI - Activation of G protein-coupled oestrogen receptor 1 at the onset of reperfusion protects the myocardium against ischemia/reperfusion injury by reducing mitochondrial dysfunction and mitophagy. AB - BACKGROUND AND PURPOSE: Recent evidence indicates that GPER (G protein-coupled oestrogen receptor 1) mediates acute pre-ischaemic oestrogen-induced protection of the myocardium from ischaemia/reperfusion injury via a signalling cascade that includes PKC translocation, ERK1/2/ GSK-3beta phosphorylation and inhibition of the mitochondrial permeability transition pore (mPTP) opening. Here, we investigated the impact and mechanism involved in post-ischaemic GPER activation in ischaemia/reperfusion injury. We determined whether GPER activation at the onset of reperfusion confers cardioprotective effects by protecting against mitochondrial impairment and mitophagy. EXPERIMENTAL APPROACH: In vivo rat hearts were subjected to ischaemia followed by reperfusion with oestrogen (17beta oestradiol, E2), E2 + G15, a GPER antagonist, or vehicle. Myocardial infarct size, the threshold for the opening of mPTP, mitophagy, mitochondrial membrane potential, ROS production, proteins ubiquitinated including cyclophilin D, and phosphorylation levels of ERK and GSK-3beta were measured. RESULTS: We found that post-ischaemic E2 administration to both male and female ovariectomized-rats reduced myocardial infarct size. Post-ischaemic E2 administration preserved mitochondrial structural integrity and this was associated with a decrease in ROS production and increased mitochondrial membrane potential, as well as an increase in the mitochondrial Ca2+ load required to induce mPTP opening via activation of the MEK/ERK/GSK-3beta axis. Moreover, E2 reduced mitophagy via the PINK1/Parkin pathway involving LC3I, LC3II and p62 proteins. All these post-ischaemic effects of E2 were abolished by G15 suggesting a GPER-dependent mechanism. CONCLUSION: These results indicate that post-ischaemic GPER activation induces cardioprotective effects against ischaemia/reperfusion injury in males and females by protecting mitochondrial structural integrity and function and reducing mitophagy. PMID- 28906551 TI - Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. PMID- 28906552 TI - Disappearance of epidermal transglutaminase and IgA deposits from the papillary dermis of patients with dermatitis herpetiformis after a long-term gluten-free diet. PMID- 28906553 TI - Novel CLDN1 mutation in ichthyosis-hypotrichosis-sclerosing cholangitis syndrome without signs of liver disease. PMID- 28906554 TI - Changes in phytochemical composition, bioactivity and in vitro digestibility of guayusa leaves (Ilex guayusa Loes.) in different ripening stages. AB - BACKGROUND: Guayusa (Ilex guayusa Loes.) leaves, native of the Ecuadorian Amazon, are popularly used for preparing teas. This study aimed to assess the influence of leaf age on the phenolic compounds and carotenoids and the bioactivity and digestibility (in vitro) of aqueous and hydroalcoholic leaf extracts. RESULTS: In total, 14 phenolic compounds were identified and quantified. Chlorogenic acid and quercetin-3-O-hexose were the main representatives of the hydroxycinnamic acids and flavonols respectively. Seven carotenoids were quantified, lutein being the main compound. Ripening affected phenolic content significantly, but there was no significant difference in carotenoid content. Antioxidant capacity, measured by the DPPH* method, was also significantly affected by leaf age. The measurement of in vitro digestibility showed a decrease in phenolic content (59%) as well as antioxidant capacity, measured by the ABTS*+ method, in comparison with initial conditions of the guayusa infusion. Antibacterial and anti-inflammatory activities were assayed with young leaves owing to their higher phenolic contents. Guayusa did not show any antibacterial activity against Escherichia coli ATCC 25922 or Staphylococcus aureus ATCC 25923. Finally, the hydroalcoholic and aqueous extracts exhibited high in vitro anti-inflammatory activity (>65%). CONCLUSION: Young guayusa leaves have potential applications as a functional ingredient in food and pharmaceutical industries. (c) 2017 Society of Chemical Industry. PMID- 28906555 TI - Application of power ultrasound on the convective drying of fruits and vegetables: effects on quality. AB - Drying gives rise to products with a long shelf life by reducing the water activity to a level that is sufficiently low to inhibit the growth of microorganisms, enzymatic reactions and other deteriorative reactions. Despite the benefits of this operation, the quality of heat sensitive products is diminished when high temperatures are used. The use of low drying temperatures reduces the heat damage but, because of a longer drying time, oxidation reactions occur and a reduction of the quality is also observed. Thus, drying is a method that lends itself to being intensified. For this reason, alternative techniques are being studied. Power ultrasound is considered as an emerging and promising technology in the food industry. The potential of this technology relies on its ability to accelerate the mass transfer processes in solid-liquid and solid-gas systems. Intensification of the drying process with power ultrasound can be achieved by modifying the product behavior during drying, using pre-treatments such as soaking in a liquid medium assisted acoustically or, during the drying process itself, by applying power ultrasound in the gaseous medium. This review summarises the effects of the application of the power ultrasound on the quality of different dried products, such as fruits and vegetables, when the acoustic energy is intended to intensify the drying process, either when the application is performed before pretreatment or during the drying process. (c) 2017 Society of Chemical Industry. PMID- 28906556 TI - Physico-chemical and sensory characteristics of young dairy bull beef derived from two breed types across five production systems employing two first season feeding regimes. AB - BACKGROUND: The present study aimed to assess the physico-chemical and sensory characteristics of Longissimus thoracis muscle from young dairy bulls: Holstein Friesian (HF) and Jersey * Holstein-Friesian (JEX). Bulls slaughtered at 15 months of age differed with respect to the finishing system, whereas 19-month-old bulls differed in energy consumption during a second grazing season and finishing period. All bulls were offered different diets during the first grazing season. RESULTS: Insoluble and total collagen contents increased with slaughter age, whereas collagen solubility and hue angle reduced with age. Bulls fed a higher concentrate finishing diet held a longer beef flavour. Intramuscular fat (IMF) content and beef flavour score were enhanced by higher concentrate intake during the second season and finishing period. Beef from a higher forage diet displayed a more intense red colour and higher thawing loss. There was limited effect of silage finishing or first and second grazing season on quality traits. Beef from JEX breed had a higher IMF content, higher flavour, juiciness and texture-related scores while lower moisture content compared to HF beef. CONCLUSION: The eating quality of beef from young dairy bulls was generally good. Slaughter age and the energy level of diet had obvious effects on quality characteristics. Cross breeding Jersey with the HF breed can improve the beef quality of young dairy bulls. (c) 2017 Society of Chemical Industry. PMID- 28906557 TI - The unusual S locus of Leavenworthia is composed of two sets of paralogous loci. AB - The Leavenworthia self-incompatibility locus (S locus) consists of paralogs (Lal2, SCRL) of the canonical Brassicaceae S locus genes (SRK, SCR), and is situated in a genomic position that differs from the ancestral one in the Brassicaceae. Unexpectedly, in a small number of Leavenworthia alabamica plants examined, sequences closely resembling exon 1 of SRK have been found, but the function of these has remained unclear. BAC cloning and expression analyses were employed to characterize these SRK-like sequences. An SRK-positive Bacterial Artificial Chromosome clone was found to contain complete SRK and SCR sequences located close by one another in the derived genomic position of the Leavenworthia S locus, and in place of the more typical Lal2 and SCRL sequences. These sequences are expressed in stigmas and anthers, respectively, and crossing data show that the SRK/SCR haplotype is functional in self-incompatibility. Population surveys indicate that < 5% of Leavenworthia S loci possess such alleles. An ancestral translocation or recombination event involving SRK/SCR and Lal2/SCRL likely occurred, together with neofunctionalization of Lal2/SCRL, and both haplotype groups now function as Leavenworthia S locus alleles. These findings suggest that S locus alleles can have distinctly different evolutionary origins. PMID- 28906558 TI - Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P-glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers. AB - Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated. PMID- 28906559 TI - Characterization of microRNAs from Arabidopsis galls highlights a role for miR159 in the plant response to the root-knot nematode Meloidogyne incognita. AB - Root knot nematodes (RKN) are root parasites that induce the genetic reprogramming of vascular cells into giant feeding cells and the development of root galls. MicroRNAs (miRNAs) regulate gene expression during development and plant responses to various stresses. Disruption of post-transcriptional gene silencing in Arabidopsis ago1 or ago2 mutants decrease the infection rate of RKN suggesting a role for this mechanism in the plant-nematode interaction. By sequencing small RNAs from uninfected Arabidopsis roots and from galls 7 and 14 d post infection with Meloidogyne incognita, we identified 24 miRNAs differentially expressed in gall as putative regulators of gall development. Moreover, strong activity within galls was detected for five miRNA promoters. Analyses of nematode development in an Arabidopsis miR159abc mutant had a lower susceptibility to RKN, suggesting a role for the miR159 family in the plant response to M. incognita. Localization of mature miR159 within the giant and surrounding cells suggested a role in giant cell and gall. Finally, overexpression of miR159 in galls at 14 d post inoculation was associated with the repression of the miR159 target MYB33 which expression is restricted to the early stages of infection. Overall, these results implicate the miR159 in plant responses to RKN. PMID- 28906560 TI - Left atrial appendage ablation using cryoballoon. PMID- 28906561 TI - Bioequivalence of Intravenous and Oral Rolapitant: Results From a Randomized, Open-Label Pivotal Study. AB - Rolapitant, a selective and long-acting neurokinin-1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open-label phase 1 study, healthy volunteers were administered rolapitant as a 180-mg oral dose or a 30 minute 166.5-mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least-squares means (GLSMs) for the area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ) and AUC from time 0 extrapolated to infinity (AUC0-infinity ) for rolapitant were within 0.80-1.25. Mean rolapitant systemic exposure and half-lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80-1.25 range for AUC0-t (0.94-1.09) and AUC0-infinity (0.93 1.10). The incidence of treatment-emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5-mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180-mg oral dose and was well tolerated. PMID- 28906562 TI - Dose-dependent interactions between two loci trigger altered shoot growth in BG-5 * Krotzenburg-0 (Kro-0) hybrids of Arabidopsis thaliana. AB - Hybrids occasionally exhibit genetic interactions resulting in reduced fitness in comparison to their parents. Studies of Arabidopsis thaliana have highlighted the role of immune conflicts, but less is known about the role of other factors in hybrid incompatibility in plants. Here, we present a new hybrid incompatibility phenomenon in this species. We have characterized a new case of F1 hybrid incompatibility from a cross between the A. thaliana accessions Krotzenburg-0 (Kro-0) and BG-5, by conducting transcript, metabolite and hormone analyses, and identified the causal loci through genetic mapping. The F1 hybrids showed arrested growth of the main stem, altered shoot architecture, and altered concentrations of hormones in comparison to parents. The F1 phenotype could be rescued in a developmental-stage-dependent manner by shifting to a higher growth temperature. These F1 phenotypes were linked to two loci, one on chromosome 2 and one on chromosome 3. The F2 generation segregated plants with more severe phenotypes which were linked to the same loci as those in the F1 . This study provides novel insights into how previously unknown mechanisms controlling shoot branching and stem growth can result in hybrid incompatibility. PMID- 28906563 TI - Cryoballoon-based isolation of left atrial appendage: Is it reasonable? PMID- 28906564 TI - Use of monolithic supports for high-throughput protein and peptide separation in proteomics. AB - The exclusive properties of monolithic supports enable fast mass transfer, high porosity, low back pressure, easy preparation process and miniaturisation, and the availability of different chemistries make them particularly suitable materials for high-throughput (HTP) protein and peptide separation. In this review recent advances in monolith-based chromatographic supports for HTP screening of protein and peptide samples are presented and their application in HTP sample preparation (separation, enrichment, depletion, proteolytic digestion) for HTP proteomics is discussed. Development and applications of different monolithic capillary columns in HTP MS-based bottom-up and top-down proteomics are overviewed. By discussing the chromatographic conditions and the mass spectrometric data acquisition conditions an attempt is made to present currently demonstrated capacities of monolithic capillary columns for HTP identification and quantification of proteins and peptides from complex biological samples by MS based proteomics. Some recent advances in basic monolith technology of importance for proteomics are also discussed. PMID- 28906565 TI - Correction of antebrachial angulation-rotation deformities in dogs with oblique plane inclined osteotomies. AB - OBJECTIVE: To describe oblique plane inclined osteotomies and report preliminary data on outcomes in dogs treated for antebrachial angulation-rotation deformities. STUDY DESIGN: Retrospective clinical study. ANIMALS: Six antebrachii from 5 dogs. METHODS: Records of dogs with antebrachial angulation-rotation deformities treated with oblique plane inclined osteotomies were reviewed. Postoperative frontal, sagittal, and transverse plane alignments were assessed subjectively, and alignment in the frontal and sagittal planes was quantified on radiographs. Outcomes were classified based on owner's and veterinarian's evaluation as full, acceptable, and unacceptable function. Complications were classified as minor, major, or catastrophic. RESULTS: Limb alignment was subjectively considered excellent in 1 case, good in 3 cases, and fair in 2 cases. Osseous union was achieved in all cases (mean 10.5 weeks; range, 6-13 weeks). Outcomes were assessed by the veterinarian as return to full function in 5 cases and acceptable function in 1 case at the final in-hospital follow-up (mean 44 weeks; range, 6-124 weeks). All owners classified their dogs as returning to full function at the final phone/email interview (mean 107 weeks; range, 72-153 weeks). Implants were removed due to infection or irritation in 3/6 limbs, while the other 3 limbs had minor dermatitis secondary to postoperative external coaptation. No catastrophic complications occurred. CONCLUSION: Oblique plane inclined osteotomies led to a successful outcome in all 6 limbs, but the technique can be challenging and does not always lead to optimal alignment. Future refinement of this technique could focus on the development of patient specific osteotomy guides to improve accuracy and precision. PMID- 28906566 TI - Minimally invasive small intestinal exploration and targeted abdominal organ biopsy with a wound retraction device in 42 cats (2005-2015). AB - OBJECTIVE: To describe the surgical technique and evaluate short-term outcome after minimally invasive small intestinal exploration and targeted organ biopsy with a wound retractor device (WRD) in cats. STUDY DESIGN: Multi-institutional retrospective study. ANIMALS: Forty-two cats. METHODS: A wound retractor was inserted into the abdomen on the ventral midline through a 2-4 cm incision at the level of the umbilicus. Short segments (6-10 cm long) of intestinal tract were sequentially exteriorized and explored through the WRD. Full thickness, small intestinal biopsies were obtained extracorporeally via the WRD. A commercially available single-port device was inserted through the WRD for laparoscopic exploration of the abdomen. RESULTS: The majority of the small intestine could be exteriorized and explored through the WRD. In all cases, full thickness biopsies of the small intestine of diagnostic quality were obtained. The most common histological findings were inflammatory bowel disease (n = 16), intestinal lymphoma (n = 14), and eosinophilic enteritis (n = 7). Two cases required conversion to a traditional open laparotomy due to abdominal pathology diagnosed after placement of the WRD (abdominal adhesions and need for a splenectomy). Postoperative complications occurred in 4 of 39 cats (10.3%), leading to 2 deaths after discharge from the hospital. CONCLUSIONS AND CLINICAL RELEVANCE: MISIETB with a WRD alone or combined with laparoscopy is a safe technique for small intestinal exploration and targeted abdominal organ biopsy in cats. Single-port laparoscopy can effectively be performed through the WRD for complete abdominal exploration and biopsy of abdominal organs. PMID- 28906567 TI - Self-Calibrating Wave-Encoded Variable-Density Single-Shot Fast Spin Echo Imaging. AB - BACKGROUND: It is highly desirable in clinical abdominal MR scans to accelerate single-shot fast spin echo (SSFSE) imaging and reduce blurring due to T2 decay and partial-Fourier acquisition. PURPOSE: To develop and investigate the clinical feasibility of wave-encoded variable-density SSFSE imaging for improved image quality and scan time reduction. STUDY TYPE: Prospective controlled clinical trial. SUBJECTS: With Institutional Review Board approval and informed consent, the proposed method was assessed on 20 consecutive adult patients (10 male, 10 female, range, 24-84 years). FIELD STRENGTH/SEQUENCE: A wave-encoded variable density SSFSE sequence was developed for clinical 3.0T abdominal scans to enable high acceleration (3.5*) with full-Fourier acquisitions by: 1) introducing wave encoding with self-refocusing gradient waveforms to improve acquisition efficiency; 2) developing self-calibrated estimation of wave-encoding point spread function and coil sensitivity to improve motion robustness; and 3) incorporating a parallel imaging and compressed sensing reconstruction to reconstruct highly accelerated datasets. ASSESSMENT: Image quality was compared pairwise with standard Cartesian acquisition independently and blindly by two radiologists on a scale from -2 to 2 for noise, contrast, confidence, sharpness, and artifacts. The average ratio of scan time between these two approaches was also compared. STATISTICAL TESTS: A Wilcoxon signed-rank tests with a P value under 0.05 considered statistically significant. RESULTS: Wave-encoded variable density SSFSE significantly reduced the perceived noise level and improved the sharpness of the abdominal wall and the kidneys compared with standard acquisition (mean scores 0.8, 1.2, and 0.8, respectively, P < 0.003). No significant difference was observed in relation to other features (P = 0.11). An average of 21% decrease in scan time was achieved using the proposed method. DATA CONCLUSION: Wave-encoded variable-density sampling SSFSE achieves improved image quality with clinically relevant echo time and reduced scan time, thus providing a fast and robust approach for clinical SSFSE imaging. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2018;47:954-966. PMID- 28906568 TI - Diode laser to treat small oral vascular malformations: A prospective case series study. AB - OBJECTIVE: The current work examined a consecutive series of patients presenting vascular malformations (VMs) and venous lakes (VLs) of the lip and oral mucosa who were treated with transmucosal diode laser applications and assessed over a 1 year period. STUDY DESIGN AND METHODS: Fifty-nine patients (31 males and 28 females) presenting low-flow VMs or VLs of the oral cavity were treated transmucosally using a diode laser (with an 830 nm operating wavelength and 1.6 W output power) with a 320 um diameter flexible fiber. All the lesions were assessed 7 days, 30 days, and 1 year after the laser treatment, and the lesion reduction percentage was scored on a one to five scale. The patients were also asked to assess their pain perception daily during the 7 days following the treatment using a visual analog scale (VAS). RESULTS: There were no procedure related intra- or post-operative complications; only modest pain intensity was reported. Thirty days after the treatment, lesion reduction was described as excellent or good in 52 cases; it was fair or poor in 7. Six patients (F:M ratio 2:4) required a second diode laser application. At the 1 year follow-up, volume reduction was complete in 48 out of 59 patients; there were five recurrences (F:M ratio 3:2). No relevant gender-related differences were noted. CONCLUSION: The use of diode laser application to treat small oral VMs and VLs was associated to shorter operating times and fewer postoperative complications with respect to the scapel surgery approach. More than one session may nevertheless be required if the anomaly is larger than 10 mm. Lasers Surg. Med. 50:111-116, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28906569 TI - Prevalence and socio-demographic predictors of food insecurity among regional and remote Western Australian children. AB - OBJECTIVE: Inequities can negatively impact the health outcomes of children. The aims of this study were to: i) ascertain the prevalence of food insecurity (FI) among regional and remote Western Australian (WA) children; and ii) determine which socio-demographic factors predicted child FI. METHODS: Caregiver-child dyads (n=219) completed cross-sectional surveys. Descriptive statistics and logistic regression analyses were conducted using IBM SPSS version 23. RESULTS: Overall, 20.1% of children were classified as FI. Children whose family received government financial assistance were more likely to be FI (OR 2.60; CI 1.15, 5.91; p=0.022), as were children living in a Medium disadvantage area (OR 2.60; CI 1.18, 5.72; p=0.017), compared to High or Low SEIFA ratings. CONCLUSIONS: Study findings are suggestive of the impact low income has on capacity to be food secure. The higher FI prevalence among children from families receiving financial assistance and living in medium disadvantage areas indicates more support for these families is required. Recommendations include: ensuring government plans and policies adequately support disadvantaged families; increasing employment opportunities; establishing evidence on the causes and the potential impact of FI on children's health. Implications for public health: One in five children were FI, demonstrating that FI is an issue in Western Australia. PMID- 28906570 TI - Probing Novel Microstructural Evolution Mechanisms in Aluminum Alloys Using 4D Nanoscale Characterization. AB - Dispersions of nanoscale precipitates in metallic alloys have been known to play a key role in strengthening, by increasing their strain hardenability and providing resistance to deformation. Although these phenomena have been extensively investigated in the last century, the traditional approaches employed in the past have not rendered an authoritative microstructural understanding in such materials. The effect of the precipitates' inherent complex morphology and their 3D spatial distribution on evolution and deformation behavior have often been precluded. This study reports, for the first time, implementation of synchrotron-based hard X-ray nanotomography in Al-Cu alloys to measure kinetics of different nanoscale phases in 3D, and reveals insights behind some of the observed novel phase transformation reactions. The experimental results of the present study reconcile with coarsening models from the Lifshitz-Slyozov-Wagner theory to an unprecedented extent, thereby establishing a new paradigm for thermodynamic analysis of precipitate assemblies. Finally, this study sheds light on the possibilities for establishing new theories for dislocation-particle interactions, based on the limitations of using the Orowan equation in estimating precipitation strengthening. PMID- 28906571 TI - Photodynamic therapy for glioblastoma: A preliminary approach for practical application of light propagation models. AB - PURPOSE: Photodynamic therapy (PDT) is a promising treatment modality to be added in the management of glioblastoma multiforme (GBM). Light distribution modeling is required for planning and optimizing PDT. Several models have been developed to predict the light propagation inside biological tissues. In the present study, two analytical methods of light propagation emitted from a cylindrical fiber source were evaluated: a discrete and a continuous method. METHODS: The two analytical approaches were compared according to their fluence rate results. Several cylindrical diffuse lengths were evaluated, and the relative deviation in the fluence rates was estimated. Moreover, a sensitivity analysis was conducted to compute the variance of each analytical model. RESULTS: The discrete method provided fluence rate estimations closer to the Monte-Carlo simulations than the continuous method. The sensitivity study results did not reveal significant differences between the variance of the two analytical models. CONCLUSIONS: Although the discrete model provides relevant light distribution, the heterogeneity of GBM tissues was not considered. With the improvement in parallel computing that drastically decreased the computing time, replacing the analytical model by a Monte-Carlo GPU-accelerated code appeared relevant to the GBM case. Nonetheless, the analytical modeling may still function in the optimization algorithms, which might be used in the Photodynamic treatment planning system. Lasers Surg. Med. 50:523-534, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28906572 TI - Culex torrentium mosquitoes from Germany are negative for Wolbachia. AB - Wolbachia (Rickettsiales: Anaplasmataceae) infects a wide range of arthropods, including several mosquito species. The bacterium is known to induce a plethora of phenotypes in its host, examples being the reproductive phenotype cytoplasmic incompatibility or resistance against infection with arboviruses. The latter is especially relevant when assessing the vector competence of mosquito species for emerging arboviruses. Thus, knowledge of Wolbachia infection status is important for the assessment of vector competence. To facilitate Wolbachia screening in mosquito populations, a quantitative polymerase chain reaction (qPCR) assay was developed to enable high-throughput analysis of mosquito samples. Using this assay, the Wolbachia infection status of the two most common Culex mosquito species in Germany, Culex pipiens biotype pipiens Linnaeus (Diptera: Culicidae) and Culex torrentium Martini (Diptera: Culicidae), was assessed. About 93% of all tested C. pipiens biotype pipiens individuals were positive for Wolbachia, whereas none of the C. torrentium samples was found to be infected. Furthermore, other applications of the qPCR assay were explored by assessing a potential link between the levels of Wolbachia and West Nile virus (WNV) infections in German C. pipiens biotype pipiens mosquitoes. No relationship was found between the two variables, indicating that a Wolbachia-induced antiviral phenotype in this mosquito population is not exclusively attributable to the general level of bacterial infection. PMID- 28906573 TI - Bis-Copper(II)/pi-Radical Multi-Heterospin System with Non-innocent Doubly N Confused Dioxohexaphyrin(1.1.1.1.1.0) Ligand. AB - A contracted doubly N-confused dioxohexaphyrin(1.1.1.1.1.0) complex consisting of two paramagnetic copper metals and open-shell pi-radical ligand was synthesized as a new multi-heterospin motif. X-ray spectroscopy supported the divalent character of the inner copper centers, and electron paramagnetic resonance and magnetometric studies suggested the presence of unpaired d electrons strongly antiferromagnetically coupled with pi-radicals delocalized on the macrocycle. The 25 pi non-innocent dioxohexaphyrin ligand allowed the facile interconversion between antiaromatic 24 pi and aromatic 26 pi species, respectively, upon redox reactions. PMID- 28906574 TI - Efficacy and safety of a novel picosecond laser using combination of 1 064 and 595 nm on patients with melasma: A prospective, randomized, multicenter, split face, 2% hydroquinone cream-controlled clinical trial. AB - BACKGROUND AND OBJECTIVES: Melasma is a common acquired, chronic hypermelanosis and still remains a therapeutic challenge. The low-fluence 1 064 nm Q-switched Nd:YAG laser is the most widely used for the treatment of moderate to severe melasma in Asia. Recently, the picosecond laser has been introduced for various pigmentary disorders such as melasma. We evaluated the efficacy and safety of a picosecond laser with dual-wavelengths (1 064 and 595 nm) and topical 2% hydroquinone (HQ) combination therapy on patients with melasma, and compared results with those obtained with 2% HQ alone. STUDY DESIGN/MATERIALS AND METHODS: This was a prospective, randomized, split-face, controlled trial comparing two treatments with combined 7 week 2% HQ (daily) and 5 week picosecond laser (weekly) versus 7 week 2% HQ. The primary efficacy variable was the change rate of the relative lightness values (RL*I) at week 7 from baseline. RL*I at a follow up visit, modified melasma severity score (mMASI), and satisfaction were assessed. RESULTS: Picosecond laser and 2% HQ had superior efficacy to 2% HQ alone: 30/39 (76.92%) subjects on combination treatment achieved >=51% improvement of RL*I versus 1/39 (2.56%) subjects on 2% HQ. The mMASI, RL*I, and satisfaction on the laser-treated side at week 7 supported these results. Aside from RL*I, no difference between the laser-treated versus control side was found after follow-up. No serious adverse events were reported. CONCLUSION: A 750 picosecond laser using 1 064 and 595 nm was effective and safe for the treatment of Korean melasma patients. The picosecond laser with dual-wavelength used in this study can reduce the photothermal effect generated during the removal of pigment and total duration of the procedure, and can be expected to reduce the occurrence of adverse events. Lasers Surg. Med. 49:899-907, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28906575 TI - Prevalence, correlates and impact of pain and cramps in anti-MAG neuropathy: a multicentre European study. AB - BACKGROUND AND PURPOSE: The frequency of pain and cramps is uncertain in anti myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown. METHODS: A cross sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy. RESULTS: Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P < 0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P = 0.006) and 10-m timed walk (P = 0.019). An independent association was ascertained with I-RODS (P = 0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P = 0.004). Cramp severity correlated with ONLS (P = 0.04) and I-RODS (P = 0.028) and inversely with level of physiotherapy input (P = 0.009). Cramp frequency was associated with tremor score (P = 0.004) and multiple SF-36 HR-QoL subsections. CONCLUSIONS: Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research. PMID- 28906576 TI - Families living with parental mental illness and their experiences of family interventions. AB - : WHAT IS KNOWN ON THE SUBJECT?: Coping with parental mental illness in families can be challenging for both children and parents. Providing evidence-based family interventions to families where a parent has a mental illness can enhance the relationships in the family. Although psychiatric research has shown that evidence-based family interventions may improve the communication and understanding of parental mental illness, there is a lack in this area of research from an everyday clinical context. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: Our study reinforces the fact that parents with mental illnesses are searching for support from psychiatric services in order to talk to their children about their illness. The finding that under-age children comply when they are told by their parents to join an intervention in psychiatric services supporting the family is something not observed earlier in research. This study once more illuminates the fact that partners of a person with parental mental illness are seldom, in an obvious way, included in family support interventions. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Psychiatric services, and especially mental health nurses, have an important task in providing families with parental mental illness with support concerning communication with their children and in including the "healthy" partner in family support interventions. ABSTRACT: Introduction Although research has shown that evidence-based family interventions in research settings improve the communication and understanding of parental mental illness, there is a lack of knowledge about interventions in an everyday clinical context. Aim This study explores how families with parental mental illness experience family interventions in a natural clinical context in psychiatric services. Method Five families with children aged 10-12 were recruited from psychiatric services in southern Sweden and interviewed in a manner inspired by naturalistic inquiry and content analysis. Both family and individual interviews were performed. Results In striving to lead an ordinary life while coping with the parental mental illness, these families sought the support of the psychiatric services, especially in order to inform their children about the mental illness. Despite different family interventions, the family members felt supported and reported that the number of conflicts in the family had decreased. The parents were appreciative of help with child-rearing questions, and the children experienced a calmer family atmosphere. However, the partner of the person with mental illness experienced being left without support. Implications for practice Our study shows that psychiatric services, and especially mental health nurses, are in a position to more regularly offer family interventions in supporting the children and the healthy partners. PMID- 28906577 TI - Laparoscopic ileocolic iterative resection with fluorescence-guided lymphatic mapping - a video vignette. PMID- 28906579 TI - Promoting openness and transparency in mental health nursing science. PMID- 28906578 TI - Ultra-early hematoma growth in antithrombotic pretreated patients with intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Patients with acute intracerebral hemorrhage (ICH) pretreated with antithrombotic drugs may have increased early hematoma growth, which would increase mortality risk. The effect of antiplatelet (AP) and vitamin K antagonist (VKA) pretreatment on ultra-early hematoma growth (uHG) and its relationship with mortality in patients with acute supratentorial ICH was analyzed. METHODS: This is an observational retrospective study of a prospective register of 197 ICH patients with first computed tomography (CT) scan taken <6 h from ICH symptom onset. ICH volume was calculated by the ABC/2 formula and uHG by the baseline ICH volume/onset-to-CT time (ml/h) formula. The uHG analysis took into account the patient's pretreatment (none, AP or VKA) and the relationship between uHG and very-early (first 24 h) and 3-month mortality. RESULTS: In the pretreatment group, 50 (25.4%) patients were treated with AP and 37 (18.8%) with VKA. The median (interquartile range 25-75) uHG was 19.7 ml/h (2.9-44.8) for AP pretreated patients, 16.2 ml/h (5.1-42.5) for VKA pretreated patients and 8.4 ml/h (2.4-21.8) for non-pretreated patients, P = 0.019. The uHG was higher in patients with very-early [42.1 ml/h (20.1-79.6)] and total 3-month mortality [28.0 ml/h (15.8-52.5)] compared with survivors [3.9 ml/h (1.5-10.4)], P < 0.0001. Adjusted by ICH severity and previous functional status, uHG was an independent factor related to very-early (P = 0.028) and total 3-month mortality (P = 0.014). CONCLUSIONS: Patients pretreated with antithrombotics have much higher uHG, which would explain the increased mortality in these patients compared to untreated patients. PMID- 28906580 TI - Comparison of one commercial and two in-house TaqMan multiplex real-time PCR assays for detection of enteropathogenic, enterotoxigenic and enteroaggregative Escherichia coli. AB - OBJECTIVE: Enteropathogenic, enterotoxigenic and enteroaggregative Escherichia coli (EPEC, ETEC, EAEC) are among the most frequent causes of diarrhoea during travel or on military deployments. Cost-efficient and reliable real-time multiplex PCR (mPCR) assays are desirable for surveillance or point prevalence studies in remote and resource-limited tropical settings. We compared one commercial PCR kit and two in-house assays without using a gold standard to estimate sensitivity and specificity of each assay. METHODS: Residual materials from nucleic acid extractions of stool samples from two groups with presumably different prevalences and increased likelihood of being infected or colonised by diarrhoeagenic E. coli were included in the assessment. One group comprised samples from returnees from tropical deployments, the second group was of migrants and study participants from high-endemicity settings. Each sample was assessed with all of the PCR assays. Cycle threshold (Ct) values were descriptively compared. RESULTS: The calculated sensitivities for the commercial test vs. the in-house tests were for EPEC 0.84 vs. 0.89 and 0.96, for ETEC 0.83 vs. 0.76 and 0.61, and for EAEC 0.69 vs. 0.54 and 0.69. False positive results were rare - specificity was 0.94 and 0.97 for two EPEC tests and 1.0 for all other tests. Most positive samples had late Ct values corresponding to low quantities of pathogens. Discordant test results were associated with late Ct values. CONCLUSIONS: As commercial and in-house assays showed comparable results, in-house tests can be assumed to be safe while affording considerable savings, making them a valuable alternative for surveillance testing in resource-limited tropical areas. PMID- 28906581 TI - Is there a benefit of mechanical thrombectomy in patients with large stroke (DWI ASPECTS <= 5)? AB - BACKGROUND AND PURPOSE: Whether to withhold mechanical thrombectomy when the diffusion-weighted imaging (DWI) lesion exceeds a given volume is undetermined. Our aim was to identify markers that will help to select patients with large DWI lesions [DWI-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) <= 5] that may benefit from thrombectomy. METHODS: From May 2010 to November 2016, 82 acute ischaemic stroke patients with DWI-ASPECTS <=5 (43 men, 64.6 +/- 14.4 years, National Institutes of Health Stroke Scale 18.4 +/- 5.4) treated with state-of-the-art mechanical thrombectomy were studied. Thrombectomy alone was performed in 28 (34%) and bridging therapy in 54 (66%) patients. Recanalization was defined as a thrombolysis in cerebral infarction score 2B-3 and significant hemorrhagic transformation as parenchymal haematoma type 2 (European Cooperative Acute Stroke Study 3 classification). Pretreatment variables were compared between patients with a good (modified Rankin Scale 0-2) and a poor (modified Rankin Scale 3-6) neurological outcome at 3 months. RESULTS: Overall, 28 patients (34%) achieved good neurological outcome at 3 months. Recanalizers were significantly more likely to achieve good outcome (61% vs. 7.3%, P < 0.0001), had lower mortality (24% vs. 49%, P = 0.03) and similar rates of parenchymal haematoma type 2 (9.8% vs. 7.3%, P = 1) compared to non-recanalizers. Regression modelling identified DWI-ASPECTS >2 [odds ratio (OR) 6.93; 95% confidence interval (CI) 1.05-45.76, P = 0.04), glycaemia <=6.8 mmol/l (OR 4.05; 95% CI 1.09 15.0, P = 0.03) and thrombolysis (OR 3.67; 95% CI 1.04-12.9, P = 0.04) as independent predictors of good neurological outcome. CONCLUSIONS: In patients with DWI-ASPECTS <=5, two-thirds of patients experienced good neurological outcome when recanalized by state-of-the-art thrombectomy, whilst only one in 14 non-recanalizers achieved similar outcomes. Pretreatment markers of good neurological outcomes were DWI-ASPECTS >2, intravenous thrombolysis and glycaemia <=6.8 mmol/l. PMID- 28906582 TI - Mammalian MSC from selected species: Features and applications. AB - Mesenchymal stromal/stem cells (MSC) are promising candidates for cellular therapy of different diseases in humans and in animals. Following the guidelines of the International Society for Cell Therapy, human MSC may be identified by expression of a specific panel of cell surface markers (CD105+, CD73+, CD90+, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-). In addition, multiple differentiation potential into at least the osteogenic, adipogenic, and chondrogenic lineage is a main criterion for MSC definition. Human MSC and MSC of a variety of mammals isolated from different tissues meet these criteria. In addition to the abovementioned, they express many more cell surface markers. Yet, these are not uniquely expressed by MSC. The gross phenotypic appearance like marker expression and differentiation potential is similar albeit not identical for MSC from different tissues and species. Similarly, MSC may feature different biological characteristics depending on the tissue source and the isolation and culture procedures. Their versatile biological qualities comprising immunomodulatory, anti-inflammatory, and proregenerative capacities rely largely on the migratory and secretory capabilities of MSC. They are attracted to sites of tissue lesion and secrete factors to promote self-repair of the injured tissue. This is a big perspective for clinical MSC applications in both veterinary and human medicine. Phase I/II clinical trials have been initiated to assess safety and feasibility of MSC therapies in acute and chronic disease settings. Yet, since the mode of MSC action in a specific disease environment is still unknown at large, it is mandatory to unravel the response of MSC from a given source onto a specific disease environment in suitable animal models prior to clinical applications. (c) 2017 International Society for Advancement of Cytometry. PMID- 28906583 TI - Reduced-port robotic total mesorectal resection for rectal cancer using the robotic single-site platform - a video vignette. PMID- 28906584 TI - Erythematous livid, discolorated plaques on both lower legs. PMID- 28906585 TI - Improved Thermal Stability of Lithium-Rich Layered Oxide by Fluorine Doping. AB - The thermal stability of lithium-rich layered oxide with the composition Li(Li1/6 Ni1/6 Co1/6 Mn1/2 )O2-x Fx (x=0.00 and 0.05) is evaluated for use as a cathode material in lithium-ion batteries. Thermogravimetric analysis, evolved gas analysis, and differential scanning calorimetry show that, upon fluorine doping, degradation of the lithium-rich layered oxides commences at higher temperatures and the exothermic reaction is suppressed. Hot box tests also reveal that the prismatic cell with the fluorine-doped powder does not explode, whereas that with the undoped one explodes at about 135 degrees C with a sudden temperature increase. XRD analysis indicates that fluorine doping imparts the lithium-rich layered oxide with better thermal stability by mitigating oxygen release at elevated temperatures that cause an exothermic reaction with the electrolyte. The origin of the reduced oxygen release from the fluorinated lithium-rich layered oxide is also discussed. PMID- 28906587 TI - Vascularized thumb metacarpal periosteal pedicled flap for scaphoid nonunion: An anatomical study and pediatric case report. AB - PURPOSE: Through an anatomical review, the primary aim of this study was to delineate the dorsal thumb metacarpal (TM) periosteal branches of the radial artery (RA). In addition, we report here the clinical utility of a vascularized TM periosteal pedicled flap (VTMPF), supplied by the first dorsal metacarpal artery (FDMA), in a complex case of scaphoid nonunion. METHODS: Ten latex-colored upper limbs from fresh human cadavers were used. Branches of the RA were dissected under 3x loupe magnification, noting the periosteal branches arising from the FDMA. The VTMPF was measured for both length (cm) and width (cm). RESULTS: The FDMA provided a mean 12 periosteal branches (range 9 to 15), with a mean distance between branches of 0.5 cm (range 0.2-1.1), allowing for the design of a VTMPF which measured a mean 4 cm in length and 1.2 cm in width. We used a VTMPF to treat recalcitrant scaphoid nonunion, with a volar defect of 0.7 cm, in a 16-year-old boy. No bone graft was used. The patient experienced no postoperative complications. Successful consolidation was achieved three months after surgery, confirming the flap's survival. At 14-months of postoperative follow-up, the patient's VAS pain rating was 0 out of 100, and his DASH questionnaire score was 5. The patient had painless range that was 95% that of the contralateral limb. The patient's pinch and grip strengths were 6.5 kg and 28 kg, respectively (95% of unaffected side). CONCLUSIONS: VTMPF may be considered a valuable and reliable surgical option for scaphoid nonunion in complex clinical scenarios. PMID- 28906586 TI - Equivalent linear change in cognition between individuals with bipolar disorder and healthy controls over 5 years. AB - OBJECTIVES: Cognitive dysfunction is a key feature of bipolar disorder (BD). However, not much is known about its temporal stability, as some studies have demonstrated a neurodegenerative model in BD while others have shown no change in cognitive functioning over time. Building upon our prior work, which examined the natural course of executive functioning, the current study aimed to investigate the natural course of memory, emotion processing, and fine motor dexterity over a 5-year period in BD and healthy control (HC) samples. METHODS: Using a 5-year longitudinal cohort, 90 individuals with BD and 17 HCs were administered a battery of neuropsychological tests at study baseline and at 1 and 5 years after study entry that captured four areas of cognitive performance: visual memory, auditory memory, emotion processing, and fine motor dexterity. RESULTS: Latent growth curve modeling showed no group differences in the slopes of any of the cognitive factors between the BD and HC groups. Age at baseline was negatively associated with visual memory, emotion processing, and fine motor dexterity. Education level was positively associated with auditory and visual memory and fine motor. Female gender was negatively associated with emotion processing. CONCLUSIONS: Extending our prior work on longitudinal evaluation of executive functioning, individuals with BD show similar linear change in other areas of cognitive functioning including memory, emotion processing, and fine motor dexterity as compared to unaffected HCs. Age, education, and gender may have some differential effects on cognitive changes. PMID- 28906588 TI - Surface glycan pattern of canine, equine, and ovine bone marrow-derived mesenchymal stem cells. AB - The use of bone marrow-derived mesenchymal stem cells (MSCs) for clinical and experimental studies is increasing, but full characterization of MSCs in veterinary species is hindered by the variability in species-specific cell surface marker expression and antibody cross reactivity. Recent studies demonstrated that the glycans in the glycocalyx of MSCs are promising candidates as cell biomarkers. In the present study, we analyzed the glycocalyx of canine MSCs (cMSCs), ovine MSCs (oMSCs), and equine MSCs (eMSCs) using a cell microarray procedure in which MSCs were spotted on microarray slides and incubated with a panel of 14 biotinylated lectins and Cy3-conjugated streptavidin. The signal intensity was then detected using a microarray scanner. The lectin-binding signals indicated that the MSC surface of the investigated species contained both N- and O-linked glycan types, with N-glycosylation predominating over O glycosylation and fucosylation being more abundant than sialylation. Relative quantification revealed an interspecific difference between these glycans. In addition, cMSCs expressed more alpha2,3-linked sialic acid (MAL II), terminal lactosamine (RCA120 ), and alpha1,6 and alpha1,3 fucosylated oligosaccharides (PSA, LTA); oMSCs exhibited more T antigen (Jacalin), GalNAcalpha1,3(LFucalpha1,2)Galbeta1,3/4GlcNAcbeta1 (DBA), chitotriose (succinylated WGA), and alpha1,2-linked fucose (UEA I); and eMSCs showed a higher density of alpha2,6 sialic acids (SNA) and high mannose N-glycans (Con A). Using cell microarray methodology, we have for the first time demonstrated differences in the glycosylation profiles of cMSC, oMSC, and eMSC surfaces. These results could be valuable as resources and references for MSC differentiation and molecular remodeling in clinical cell-based therapy and tissue engineering studies. (c) 2017 International Society for Advancement of Cytometry. PMID- 28906589 TI - Neoadjuvant therapy of bevacizumab in combination with oxaliplatin and capecitabine (XELOX) for patients with metastatic colorectal cancer with unresectable liver metastases: a phase II, open-label, single-arm, noncomparative trial. AB - AIM: This phase II, open-label study evaluated the efficacy and safety of neoadjuvant therapy with bevacizumab plus XELOX (capecitabine and oxaliplatin) for untreated metastatic colorectal cancer with unresectable liver metastases and assessed conversion of unresectable to resectable metastases after neoadjuvant treatment. METHODS: Patients received bevacizumab 5 mg/kg and oxaliplatin 85 mg/m2 on day 1, and capecitabine 1000 mg/m2 twice daily on days 1-5 followed by 2 days of rest in a 14-day cycle for 12 cycles; bevacizumab was excluded in cycles 6 and 7. Patients were later divided into resected and unresected groups, depending upon whether they underwent curative resection after chemotherapy. Efficacy and safety were evaluated. RESULTS: Of 45 patients enrolled, 17.8% completed the study. The resection rate of liver metastases after neoadjuvant therapy was 42.2%. The median time to disease progression was 10.1 and 8.7 months in the resected and unresected groups, respectively (P = 0.1341). Response rate was significantly higher in the resected (47.4%) versus the unresected group (34.6%; P = 0.0010), and seven patients achieved complete response (resected group). Overall, 94.3% of adverse events were of mild or moderate severity, and grade >=3 adverse events occurred in 4.3% and 7.3% of patients in the resected and unresected groups, respectively. The most common adverse events in both groups were palmar-plantar erythrodysesthesia syndrome, decreased appetite, thrombocytopenia, peripheral neuropathy, fatigue, diarrhea, vomiting, proteinuria and nausea. CONCLUSION: Neoadjuvant therapy with bevacizumab plus XELOX was well tolerated and effective in previously untreated metastatic colorectal cancer patients with initially unresectable liver metastases. PMID- 28906591 TI - Scalp necrosis of the forehead and temple region. PMID- 28906590 TI - FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas. AB - BACKGROUND: Although FGF19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma (LSCC) and FGF19 amplification as a potential therapeutic target for LSCC are not well understood. METHODS: Fluorescence in situ hybridization analysis and quantitative real-time PCR was used to detect FGF19 genetic amplification and FGF19 messenger RNA expression in LSCC tumor and paired adjacent samples. Small interfering RNA and short hairpin RNA were used to knockdown FGF19 in vitro and in vivo. RESULTS: FGF19 amplification was identified in a subset of LSCC patients (37.5%, 15/40), and upregulation of FGF19 expression was found in 60% (24/40) of tumor tissues compared to adjacent non-tumorous tissues. Correlation analysis with clinicopathologic parameters showed that FGF19 upregulation was significantly associated with heavy smoking. Small interfering RNA knockdown of FGF19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF19 gene, but these effects was not observed in non amplified LSCC cells. Interfering FGF19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF19 in tumor cells. CONCLUSION: Our results suggested that FGF19 signaling activation is required for cell growth and survival of FGF19 amplified LSCC cells, both in vitro and in vivo. Intervention of FGF19 activation could be a potential therapeutic strategy for LSCC patients with FGF19 amplification. PMID- 28906592 TI - Influence of bronchial diameter change on the airflow dynamics based on a pressure-controlled ventilation system. AB - Bronchial diameter is a key parameter that affects the respiratory treatment of mechanically ventilated patients. In this paper, to reveal the influence of bronchial diameter on the airflow dynamics of pressure-controlled mechanically ventilated patients, a new respiratory system model is presented that combines multigeneration airways with lungs. Furthermore, experiments and simulation studies to verify the model are performed. Finally, through the simulation study, it can be determined that in airway generations 2 to 7, when the diameter is reduced to half of the original value, the maximum air pressure (maximum air pressure in lungs) decreases by nearly 16%, the maximum flow decreases by nearly 30%, and the total airway pressure loss (sum of each generation pressure drop) is more than 5 times the original value. Moreover, in airway generations 8 to 16, with increasing diameter, the maximum air pressure, maximum flow, and total airway pressure loss remain almost constant. When the diameter is reduced to half of the original value, the maximum air pressure decreases by 3%, the maximum flow decreases by nearly 5%, and the total airway pressure loss increases by 200%. The study creates a foundation for improvement in respiratory disease diagnosis and treatment. PMID- 28906593 TI - Analysis of NFU-1 metallocofactor binding-site substitutions-impacts on iron sulfur cluster coordination and protein structure and function. AB - Iron-sulfur (Fe/S) clusters are ancient prosthetic groups found in numerous metalloproteins and are conserved across all kingdoms of life due to their diverse, yet essential functional roles. Genetic mutations to a specific subset of mitochondrial Fe/S cluster delivery proteins are broadly categorized as disease-related under multiple mitochondrial dysfunction syndrome (MMDS), with symptoms indicative of a general failure of the metabolic system. Multiple mitochondrial dysfunction syndrome 1 (MMDS1) arises as a result of the missense mutation in NFU1, an Fe/S cluster scaffold protein, which substitutes a glycine near the Fe/S cluster-binding pocket to a cysteine (p.Gly208Cys). This substitution has been shown to promote protein dimerization such that cluster delivery to NFU1 is blocked, preventing downstream cluster trafficking. However, the possibility of this additional cysteine, located adjacent to the cluster binding site, serving as an Fe/S cluster ligand has not yet been explored. To fully understand the consequences of this Gly208Cys replacement, complementary substitutions at the Fe/S cluster-binding pocket for native and Gly208Cys NFU1 were made, along with six other variants. Herein, we report the results of an investigation on the effect of these substitutions on both cluster coordination and NFU1 structure and function. The data suggest that the G208C substitution does not contribute to cluster binding. Rather, replacement of the glycine at position 208 changes the oligomerization state as a result of global structural alterations that result in the downstream effects manifest as MMDS1, but does not perturb the coordination chemistry of the Fe-S cluster. PMID- 28906596 TI - Web alert: Microbial enhancement of plant growth: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28906595 TI - Superiority of occipital donor sites for split-thickness skin grafting in dermatosurgery: Results of a prospective randomized controlled study. AB - BACKGROUND: Split-thickness skin grafts are commonly used in dermatosurgery. For occipital donor sites, retrospective studies have shown good results with respect to graft take and healing rates. Nevertheless, the majority of grafts in dermatosurgery are harvested from the thigh. To date, there has been no prospective randomized controlled study comparing occipital versus femoral donor sites. PATIENTS AND METHODS: Following micrographically controlled R0 tumor resection, 108 patients were randomized prior to undergoing split-thickness skin grafting (donor site: occiput vs. thigh). Follow-up examinations were carried out on day 3, 5, 7, and 14, as well as one month and three months after surgery. Documented data included graft take rates, re-epithelialization rates at the donor site, pain, cosmetic outcome, Vancouver Scar Scale (VSS), and complications. RESULTS: Occipital donor sites showed significantly faster reepithelization, less pain, fewer complications, a better cosmetic outcome, and better results on the VSS. With regard to graft take rates, grafts harvested from the occiput were significantly superior on days 3 and 5. CONCLUSIONS: This is the first randomized controlled trial showing a significant superiority of occipital compared to femoral donor sites regarding re-epithelialization, pain, cosmetic outcome and the Vancouver Scar Scale. PMID- 28906594 TI - Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 (MMDS1): impact of a disease-causing Gly189Arg substitution on NFU1. AB - Iron-sulfur (Fe/S) cluster-containing proteins constitute one of the largest protein classes, with highly varied function. Consequently, the biosynthesis of Fe/S clusters is evolutionarily conserved and mutations in intermediate Fe/S cluster scaffold proteins can cause disease, including multiple mitochondrial dysfunctions syndrome (MMDS). Herein, we have characterized the impact of defects occurring in the MMDS1 disease state that result from a point mutation (p.Gly189Arg) near the active site of NFU1, an Fe/S scaffold protein. In vitro investigation into the structure-function relationship of the Gly189Arg derivative, along with two other variants, reveals that substitution at position 189 triggers structural changes that increase flexibility, decrease stability, and alter the monomer-dimer equilibrium toward monomer, thereby impairing the ability of the Gly189X derivatives to receive an Fe/S cluster from physiologically relevant sources. PMID- 28906597 TI - More than Graphene. PMID- 28906598 TI - Is the supply of continuing education in the anatomical sciences keeping up with the demand? Results of a national survey. AB - Continuing education (CE) is an essential element in the life-long learning of health care providers and educators. Despite the importance of the anatomical sciences in the training and practice of clinicians, no studies have examined the need/state of anatomy-related CE nationally. This study assessed the current landscape of CE in the anatomical sciences to contextualize preferences for CE, identify factors that influence the perceived need for CE, and examine the association between supply and demand. Surveys were distributed to educators in the anatomical sciences, practicing physical therapists (PTs), and anatomy training programs across the United States. Twenty-five percent (9 of 36) of training programs surveyed offered CE, certificates, or summer series programs related to anatomy. The majority of PTs (92%) and anatomy educators (81%) felt they had a potential or actual need for anatomy related CE with the most popular formats being online videos/learning modules and intensive, hands-on workshops. The most commonly perceived barriers to participating in CE for both groups were program location, cost, and duration, while educators also perceived time of year as a significant factor. Logistic regression analyses revealed that no investigated factor influenced the need or desire for PTs to engage in anatomy related CE (P <= 0.124), while teaching experience and the highest level of learner taught significantly influenced the perceived need among anatomy educators (P < 0.001). Overall, quantitative and qualitative analyses revealed a robust need for CE that strategically integrates anatomy with areas of clinical practice and education. Anat Sci Educ 11: 225-235. (c) 2017 American Association of Anatomists. PMID- 28906599 TI - Dual-extrusion 3D printing of anatomical models for education. AB - Two material 3D printing is becoming increasingly popular, inexpensive and accessible. In this paper, freely available printable files and dual extrusion fused deposition modelling were combined to create a number of functional anatomical models. To represent muscle and bone FilaFlex3D flexible filament and polylactic acid (PLA) filament were extruded respectively via a single 0.4 mm nozzle using a Big Builder printer. For each filament, cubes (5 mm3 ) were printed and analyzed for X, Y, and Z accuracy. The PLA printed cubes resulted in errors averaging just 1.2% across all directions but for FilaFlex3D printed cubes the errors were statistically significantly greater (average of 3.2%). As an exemplar, a focus was placed on the muscles, bones and cartilage of upper airway and neck. The resulting single prints combined flexible and hard structures. A single print model of the vocal cords was constructed which permitted movement of the arytenoids on the cricoid cartilage and served to illustrate the action of intrinsic laryngeal muscles. As University libraries become increasingly engaged in offering inexpensive 3D printing services it may soon become common place for both student and educator to access websites, download free models or 3D body parts and only pay the costs of print consumables. Novel models can be manufactured as dissectible, functional multi-layered units and offer rich possibilities for sectional and/or reduced anatomy. This approach can liberate the anatomist from constraints of inflexible hard models or plastinated specimens and engage in the design of class specific models of the future. Anat Sci Educ 11: 65-72. (c) 2017 American Association of Anatomists. PMID- 28906600 TI - Bright Light Therapy for Negative Symptoms. PMID- 28906601 TI - Graves' Disease and Psychosis in a Young Woman: Pathophysiologic Considerations. PMID- 28906602 TI - Addressing Diagnosis and Treatment Gaps in Adults With Attention Deficit/Hyperactivity Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) was originally defined in children but is now recognized to persist into adulthood for some patients. Despite this recognition, adult ADHD remains underdiagnosed. This narrative review describes the negative impact of ADHD across multiple functional domains, diagnostic guidelines for adult ADHD and its clinical features, the importance of screening tools and clinical interviews to help evaluate adults for ADHD, and adult ADHD treatment options. Diagnostic guidelines for ADHD now incorporate adult-specific symptoms and behavioral manifestations, which may aid in diagnosing adult ADHD. However, diagnosis of ADHD is complicated by symptom overlap between ADHD and psychiatric disorders that might be comorbid with ADHD. Screening tools, such as the Adult ADHD Self-Report Screening Scale for DSM-5, can identify adults requiring evaluation for ADHD. However, clinical interviews and longitudinal family histories provide critical information that diagnoses ADHD and differentiates ADHD from psychiatric comorbidities. Various pharmacologic and nonpharmacologic treatments are available for adults diagnosed with ADHD. First-line pharmacologic treatment of ADHD usually consists of treatment with a psychostimulant, and a variety of short-acting and long-acting formulations are available for use in adults. When developing a treatment plan for adults with ADHD, it is important to recognize that the demands of adult life, both at work and at home, necessitate symptom control throughout the entire day and into the evening and indicate that a long-acting medication formulation is often preferable. Furthermore, there are important safety concerns, including the potential for drug dependence and serious cardiovascular events, which must be considered before prescribing stimulants.. PMID- 28906603 TI - Auditory Hallucinations or Tinnitus? A Case of Framing Effects and a High Jugular Bulb. PMID- 28906604 TI - A Multisymptomatic Child With Bipolar Disorder: How to Track and Sequence Treatment. AB - Treatment sequences for the multisymptomatic child with bipolar disorder are not adequately described or based on a systematic clinical trial database, and systems for longitudinal tracking of symptoms are rarely utilized. We present a patient whose symptoms of depression, anxiety, attention-deficit/hyperactivity disorder, oppositional behavior, and mania are rated by a parent and plotted on a weekly basis in the Child Network under a Johns Hopkins Institutional Review Board-approved protocol. This 9-year-old girl remained inadequately responsive to lithium or risperidone. We describe a range of other treatment options and a possible sequence for their introduction. We encourage the use of systematic longitudinal ratings to help better visualize course of symptom fluctuations and response of the child to treatment. Given the highly fluctuating course of many symptoms in very young children as illustrated here, prospective monitoring appears essential. The current case also highlights the great unmet need for comparative effectiveness data in children less than 10 years of age to better guide clinical therapeutics. PMID- 28906605 TI - The State of Sleep Medicine Education in North American Psychiatry Residency Training Programs in 2013: Chief Resident's Perspective. AB - Objective: To assess the current state of sleep medicine educational resources and training offered by North American psychiatry residency programs. Methods: In June 2013, a 9-item peer-reviewed Sleep Medicine Training Survey was administered to 39 chief residents of psychiatry residency training programs during a meeting in New York. Results: Thirty-four percent of the participating programs offered an elective rotation in sleep medicine. A variety of innovative approaches for teaching sleep medicine were noted. The majority of the chief residents felt comfortable screening patients for obstructive sleep apnea (72%), half felt comfortable screening for restless legs syndrome (53%), and fewer than half were comfortable screening for other sleep disorders (47%). Conclusions: This is the first report in the last decade to provide any analysis of current sleep medicine training in North American psychiatry residency training programs. These data indicate that sleep medicine education in psychiatry residency programs is possibly in decline. PMID- 28906607 TI - Two Causes for Macrocytic Anaemia in One Patient: Clinico-Pathological Conference. PMID- 28906606 TI - Direct Measurement of Noise Levels in a Large Hospital. PMID- 28906609 TI - Cancer in Africa. PMID- 28906608 TI - Unorthodoxy in Medicine and Religion. PMID- 28906610 TI - Editorial. PMID- 28906611 TI - Congenital Ano-Rectal Anomalies. PMID- 28906612 TI - Juvenile Delinquency: A Family Practitioner's Problem? PMID- 28906613 TI - Experience with Abdominal Aortic Aneurysims. PMID- 28906615 TI - Child Health Group. PMID- 28906614 TI - Subacute Hepatitis in a Patient Treated with Parstelin: Clinical-Pathological Conference. PMID- 28906616 TI - Cataract. PMID- 28906617 TI - The Doctor in the Law Courts. PMID- 28906618 TI - Paroxysmal Nocturnal Haemoglobinuria: Clinical-Pathological Conference. PMID- 28906619 TI - How to Win a "House Job". PMID- 28906620 TI - South West Surgeons. PMID- 28906621 TI - Last Conscious Thoughts. PMID- 28906622 TI - Medicine in North America. PMID- 28906623 TI - Classification of Juvenile Delinquents. PMID- 28906624 TI - Haematuria and Office Urology. PMID- 28906625 TI - Correspondence. PMID- 28906626 TI - A Foetus with Down's Syndrome. PMID- 28906627 TI - Wessex Rahere Club. PMID- 28906628 TI - NSPCC: An Urgent Appeal. PMID- 28906629 TI - Translocation Mongolism Arising de Novo? PMID- 28906630 TI - Conference Report: Sixth International Congress of Gerontology. PMID- 28906631 TI - Editorial: Caving Hazards. PMID- 28906633 TI - Brook's Family Herbal. PMID- 28906632 TI - Corrigenda. AB - [This corrects the article on p. 39 in vol. 81.]. PMID- 28906634 TI - Viruses and Cancer. PMID- 28906635 TI - The Evolution of Liver Surgery. PMID- 28906636 TI - Advances in the Management of Rh Haemolytic Disease. PMID- 28906638 TI - William Budd. PMID- 28906637 TI - The Nature and the Mode of Propagation of Phthisis. PMID- 28906639 TI - Correspondence. PMID- 28906640 TI - Newly Appointed Consultants. PMID- 28906641 TI - Recently Appointed Consultants. PMID- 28906642 TI - Correspondence. PMID- 28906643 TI - Problems of Anticoagulant Control-II, Which Test? PMID- 28906644 TI - Compression Plating for Non-Union of the Tibia. PMID- 28906645 TI - Erratum: Vipers and Viper Bites in the West Country. AB - [This corrects the article on p. 3 in vol. 85.]. PMID- 28906646 TI - This Week in Parliament: From Our Parliamentary Correspondent, Thursday, 27th June 2070. PMID- 28906647 TI - Editorial: Changes in the Journal. PMID- 28906648 TI - Southmead Orchestral Society. PMID- 28906649 TI - Ave Atque Vale: Some Reflections by the Retiring Hon. Treasurer, Bristol Medico Chirurgical Society. PMID- 28906650 TI - Newly-Appointed Consultants. PMID- 28906652 TI - Editorial. PMID- 28906653 TI - The Centenary Dinner. PMID- 28906654 TI - Rectal Cancer-Report of Symposium: Report on a Symposium at the Edward Jenner Centre, November 1984. PMID- 28906655 TI - From Our Correspondents. PMID- 28906656 TI - From Our Correspondents. PMID- 28906657 TI - Editorial. PMID- 28906658 TI - From Our Foreign Correspondent. PMID- 28906659 TI - Bristol Final FRCS Course. PMID- 28906660 TI - Pseudo-Malignancy: A Defensible Neologism? PMID- 28906662 TI - Editorial. PMID- 28906661 TI - The Fleece Medical Society. PMID- 28906663 TI - From Our Correspondents. PMID- 28906664 TI - Surgery of the Circulation: Long Fox Memorial Lecture, 11th November 1981, at the University of Bristol. PMID- 28906665 TI - Some Famous Bristol Doctors. PMID- 28906666 TI - The Treatment of Pancreatitis. PMID- 28906668 TI - From Our Correspondents. PMID- 28906669 TI - Editorial. PMID- 28906667 TI - Familial Mental Handicap. PMID- 28906670 TI - Liver and Pancreas Transplantation: Report on the Marjorie Budd Lecture by Professor R. Y. Calne. PMID- 28906671 TI - From Our Foreign Correspondent. PMID- 28906672 TI - From Our Correspondents. PMID- 28906674 TI - From Our 'Foreign' Correspondent. PMID- 28906673 TI - Emerods. PMID- 28906675 TI - From Our Correspondents. PMID- 28906676 TI - From Our Foreign Correspondent. PMID- 28906677 TI - Programmes of Societies. PMID- 28906678 TI - From Our Correspondents. PMID- 28906679 TI - Editorial. PMID- 28906680 TI - From Our Correspondents. PMID- 28906681 TI - From Our Foreign Correspondents. PMID- 28906682 TI - Letter to the Editor. PMID- 28906683 TI - From Our Correspondents. PMID- 28906684 TI - Bristol Medico-Chirurgical Society Summer Meeting: Held at the Jenner Museum, the Chantry, Berkeley, Gloucestershire Wednesday, 8th May 1985. PMID- 28906685 TI - From Our Foreign Correspondent. PMID- 28906686 TI - Letter to the Editor. PMID- 28906687 TI - Editorial. PMID- 28906688 TI - Exhibition of Art and Craft Work by Bristol Doctors. PMID- 28906689 TI - From Our Correspondents. PMID- 28906690 TI - Editorial. PMID- 28906692 TI - Cossham Medical Society 1982-83. PMID- 28906691 TI - Centenary Dinner for the Bristol Medico-Chirurgical Journal. PMID- 28906693 TI - Editorial. PMID- 28906694 TI - From Our Correspondents. PMID- 28906696 TI - From Our Correspondents. PMID- 28906695 TI - Correspondence. PMID- 28906697 TI - Opening of the Monica Britton Exhibition Hall. PMID- 28906698 TI - Editorial: February 1986. PMID- 28906699 TI - Starting to Sail. PMID- 28906701 TI - From Our Foreign Correspondent. PMID- 28906700 TI - Letter to the Editor. PMID- 28906702 TI - A Memorable Membership Moment. PMID- 28906703 TI - From Our Correspondents. PMID- 28906704 TI - Should Every Cow Carry a Government Health Warning? PMID- 28906705 TI - Woodcarving. PMID- 28906707 TI - Redevelopment of Frenchay Hospital. PMID- 28906706 TI - Bogus Allergy Treatment. PMID- 28906708 TI - Changing Face of Ham Green Hospital. PMID- 28906709 TI - From Our Foreign Correspondents. PMID- 28906710 TI - From Our Correspondents. PMID- 28906711 TI - From Our Correspondents. PMID- 28906712 TI - Letters to the Editor. PMID- 28906713 TI - Letters to the Editor. PMID- 28906714 TI - Splendid but Hopeless. PMID- 28906715 TI - Children of the Future Age. PMID- 28906717 TI - Heart and Lung Transplantation: Present and Future. PMID- 28906718 TI - Expanding Horizons of Diagnostic Imaging. PMID- 28906716 TI - The Vaccine Control of Virus-Induced Cancers. PMID- 28906720 TI - From Our Correspondents. PMID- 28906719 TI - Eating Tomorrow. PMID- 28906721 TI - Molecular Medicine. PMID- 28906722 TI - Bone Marrow Transplantation. PMID- 28906723 TI - Primary Care in the Future. PMID- 28906725 TI - An Evening with Iris Murdoch: Meeting of the Bristol Medico-Chirurgical Society on March 12th, 1986. PMID- 28906724 TI - The Green Paper. An Hypothesis to Explain the Delay in Its Appearance. PMID- 28906727 TI - From Our Correspondents. PMID- 28906726 TI - Letter to the Editor. PMID- 28906728 TI - On a Bicycle Made for Two. PMID- 28906729 TI - A Case of Dysphagia. PMID- 28906730 TI - Marjorie Budd Lecture, Abdominal Aortic Aneurysms, Trials and Tribulations, Sir Geoffrey Slaney. PMID- 28906731 TI - Letters to the Editor. PMID- 28906732 TI - General Practice and Hospital Medicine-A New Relationship. PMID- 28906734 TI - From Our Correspondents. PMID- 28906733 TI - A National Doctor Morbidity Survey. PMID- 28906736 TI - Wishful Thinking. PMID- 28906735 TI - Toboggan or Not Toboggan. PMID- 28906737 TI - Letters to the Editor. PMID- 28906738 TI - Letters to the Editor. PMID- 28906739 TI - A Predictive Index for Postoperative Deep Vein Thrombosis in Thoracic Surgery Patients. AB - In a single-centre prospective trial 200 consecutive patients undergoing thoracic surgery were randomised to receive one of two prophylactic regimes against deep vein thrombosis (DVT). These were 5000 units of subcutaneous heparin twice a day, alone or combined with the wearing of graded compression stockings. The diagnosis of DVT was made clinically and with 131I labelled fibrinogen. Six DVTs developed in the stocking group and 11 in the non-stocking group. The results suggest that the use of stockings reduces the incidence of DVT when added to herparin but the difference is not statistically significant. To obtain a predictive index for the development of DVT, discriminant analysis was applied to the control and stocking groups separately and combined. Five simple clinical variables gave a true positive prediction rate, for the combined group, of 94% and a false positive prediction rate of 26%. PMID- 28906741 TI - Technical Data from Philips. PMID- 28906740 TI - Technical Data from Agfa. PMID- 28906742 TI - Towards a West of England Medical Journal. PMID- 28906743 TI - The Journal. PMID- 28906744 TI - The White Paper and the New NHS. PMID- 28906745 TI - From Our Correspondents. PMID- 28906746 TI - Academic Practice or Primitive Physic. PMID- 28906747 TI - On Gardening. PMID- 28906748 TI - Abdominal Symptoms in General Practice, a Case Control Study. AB - A survey was carried out of three hundred general practice patients who were questioned about recurrent abdominal pain or discomfort and other related symptoms. Patients who responded positively to the questionnaire fell into three main groups. Twenty two patients (7%) were found to have previously diagnosed irritable bowel syndrome. A further twenty patients (7%) had similar symptoms but had not sought medical help for them. Finally there were twenty eight (9%) patients with abdominal pain due to miscellaneous organic diseases. Age-sex matched controls were selected from the two hundred and thirty patients who responded negatively to assess the rate of consultation and the rate of prescribing benzodiazepines and antidepressants. PMID- 28906749 TI - The Dangers of Cassava (Tapioca) Consumption. AB - Cassava (Tapioca) is a worldwide staple food consumed by over 800 million people. It contains cyanide which may lead to acute toxicity or chronically may be an aetiological factor in tropical nutritional amblyopia, tropical neuropathy, endemic goitre, cretinism and tropical diabetes. It may also have carcinogenic potential. However, despite nutritional limitations it has many advantages as a crop to the subsistence farmer and would be difficult to replace. PMID- 28906750 TI - From Our Correspondents. PMID- 28906751 TI - Oesophageal Pain and Catecholamine Mediated Ecg Changes Mimicking Myocardial Ischaemia. AB - It is known that oesophageal pain can imitate angina and also that non specific ECG changes, probably catecholamine mediated, can be similar to those due to true myocardial ischaemia. Both of these can therefore pose a problem for the diagnosis of angina pain due to cardiac ischaemia. We report a patient who had both of these conditions simultaneously, pain on exertion appearing as angina but due to oesophagitis, and "ischaemic" ECG changes due to catecholamines-a double mimic of myocardial ischaemia. PMID- 28906752 TI - Gastric Carcinoid Presenting with Haematemesis. PMID- 28906753 TI - Putting the Boot in. PMID- 28906755 TI - From Our Foreign Correspondent. PMID- 28906754 TI - Phenytoin (Epanutin) Associated Hodgkin's Disease. AB - We report a case of phenytoin-associated Hodgkin's disease of lymphocyte predominance subtype, which developed after two years of phenytoin (Epanutin) treatment. Four other English cases of phenytoin-associated lmphoid malignancy are also reviewed. PMID- 28906756 TI - From Our Foreign Correspondent: Bus 237 to Pokhara. PMID- 28906757 TI - Letter to the Editor. PMID- 28906758 TI - Distraction, Displacement and Alarm. PMID- 28906759 TI - Poet's Corner. PMID- 28906760 TI - Glass Paperweights. PMID- 28906761 TI - From Our Correspondents. PMID- 28906763 TI - Editorial. PMID- 28906762 TI - Axillary Aneurysm Presenting as a Brachial Plexus Palsy. PMID- 28906764 TI - The AIDS Epidemic and Its Control. PMID- 28906765 TI - The Origin of AIDS. PMID- 28906766 TI - Correspondence. PMID- 28906767 TI - Correspondence. PMID- 28906769 TI - From Our Correspondents. PMID- 28906768 TI - Adverse Reactions to Sulphasalazine. PMID- 28906770 TI - Ten Years on. PMID- 28906771 TI - Erratum: Oesophageal Pain Mimicking Cardiac Ischaemia. AB - [This corrects the article on p. 41 in vol. 102.]. PMID- 28906772 TI - From Our Foreign Correspondents. PMID- 28906774 TI - From Our Correspondents. PMID- 28906773 TI - Pediculus Humanus Capitis in an Immuno Compromised Patient. PMID- 28906775 TI - To Be or Not to Be? PMID- 28906776 TI - Letter from Dr. John Seale in Reply to Brown et al. PMID- 28906777 TI - Screening for Allergy. PMID- 28906778 TI - The Volvo 740 Turbo Estate. PMID- 28906779 TI - G.P. and Hospital Medicine. PMID- 28906781 TI - Editor's Note. PMID- 28906780 TI - From Our Correspondents. PMID- 28906783 TI - An Evening with Beau Nash and Juliana Popjoy. PMID- 28906782 TI - Bristol Medico-Chirurgical Journal "The Medical Journal of the South West". PMID- 28906784 TI - MRI in Oncology. PMID- 28906786 TI - Stress and Coping in Paediatric Oncology. PMID- 28906785 TI - Staff Hazards in Handling Chemotherapy. PMID- 28906787 TI - Prediction of Psychosocial Sequelae in Families of Leukaemic Children. PMID- 28906788 TI - The Importance of Commmunication with the Primary Care Team. PMID- 28906789 TI - Growth and Growth Hormone Secretion Following Cranial and Craniospinal Irradiation in Children with Malignant Disease. PMID- 28906790 TI - Current Prognosis for Childhood Cancer in the South West Region. PMID- 28906791 TI - Medulloblastoma in the South West. PMID- 28906792 TI - Management of Pulmonary Metastases in Osteogenic Sarcoma. AB - Twenty-three patients presented with isolated pulmonary metastases from osteogenic sarcoma following primary treatment by amputation or limb salvage, combined with chemotherapy. The metastases were treated by conservative surgical excision, combined with chemotherapy; surgicl excision was repeated for recurrent pulmonary metastases provided there were none elsewhere. Six patients are alive and disease free following their initial surgery. Of the remaining 17, 10 had recurrence confined to the lungs, and seven developed extra pulmonary metastases. The ten with isolated pulmonary metastases all had further thoracotomies but eventually seven died, as did all those with extra pulmonary metastases. There were in all 45 operations, with one hospital death and one serious complication. Actuarial survival at 1,3,5 and 7 years was 87, 45, 39 and 31% respectively. In the ten patients who had recurrence of isolated pulmonary metastases, survival at 1 and 3 years was 70 and 34%. PMID- 28906793 TI - Caring for the Dying Child and Family. PMID- 28906794 TI - Carboplatinum. PMID- 28906795 TI - Foreword: Paediatric Oncology in Bristol. PMID- 28906796 TI - Cellular Biology of Teratoma. PMID- 28906797 TI - Children's Understanding of Their Illness. PMID- 28906798 TI - Some Educational Implications of Childhood Cancer. PMID- 28906799 TI - Epirubicin. PMID- 28906800 TI - Molecular Biology of Wilm's Tumour. PMID- 28906801 TI - Ifosfamide +/-VP16 in Childhood' Malignancy: A Phase II (toxicity) Study. PMID- 28906802 TI - Control of Bacteraemia from Indwelling Central Venous Catheters. PMID- 28906803 TI - Causes of Death in a Paediatric Oncology Unit. PMID- 28906804 TI - Primary Hodgkin's Disease of the Rectum: Seven-Year Cure after Surgical Excision. PMID- 28906805 TI - An Atypical Case of Spontaneous Rupture of the Oesophagus. AB - A case of spontaneous rupture of the oesophagus is described in which the presentation is unusual. The rarity of the condition is emphasized. The diagnosis and treatment are briefly considered and the difficulties in diagnosis stressed. The similarities and differences between this condition and the Mallory-Weiss syndrome are discussed. PMID- 28906806 TI - New Voices for Old: Restoration of Effective Speech after Laryngectomy by the Pulmonary Air Shunt-Vocal Fistula Principle. PMID- 28906807 TI - Tumour-To-Tumour Metastasis. PMID- 28906809 TI - The Malcolm Campbell Memorial Meeting. PMID- 28906808 TI - Paralysis of Down-Gaze. PMID- 28906810 TI - The Burden Heritage. PMID- 28906811 TI - Imitation. PMID- 28906812 TI - Dermatological Do-It-Yourself: How to Nail Your Neighbour's Wife to the Bedroom Floor. PMID- 28906813 TI - Editorial. PMID- 28906814 TI - Editorial: Sponsorship for Survival. PMID- 28906816 TI - Cossham Medical Society. PMID- 28906815 TI - Editorial: Progress Report. PMID- 28906817 TI - British Medical Association, Bristol Division. PMID- 28906818 TI - Editorial. PMID- 28906819 TI - From Our Correspondents. PMID- 28906821 TI - Editorial. PMID- 28906820 TI - Letters to the Editor. PMID- 28906823 TI - Editorial. PMID- 28906822 TI - Editorial. PMID- 28906825 TI - Mechanical Restraint in the Management or Treatment of the Insane. PMID- 28906824 TI - Intemperance and Dipsomania as Related to Insanity. PMID- 28906826 TI - Natural History of Crime: Address of Professor Moriz Benedikt, Delivered at the Meeting of the Juridical Society of Vienna, December 28, 1875. PMID- 28906827 TI - Diseases of the Nervous System. No. II. PMID- 28906828 TI - Second-Sight, or Deuteroscopia. PMID- 28906829 TI - Pathology and Treatment of Cerebral Disease. No. II. PMID- 28906831 TI - Case of Homicidal Insanity. PMID- 28906830 TI - Clinical and Physiological Researches on the Nervous System. PMID- 28906832 TI - Physical Culture, and Its Influence on the Body. PMID- 28906833 TI - Professor Tyndall and His Opponents. PMID- 28906834 TI - Contributions to the Physical Psychology of Criminals: An Address Delivered in the Vienna Section of the Medical Association in Lower Austria, November 10, 1875. PMID- 28906836 TI - Psychological Retrospect and Medico-Legal Cases. PMID- 28906835 TI - Remarks on the Lunacy Acts (Scotland). PMID- 28906837 TI - Quis Custodiet Custodes? PMID- 28906838 TI - General Paralysis in Combination with Other Diseases of the Brain. PMID- 28906839 TI - Skae's Classification of Mental Diseases. PMID- 28906840 TI - Psychological Retrospect and Medico-Legal Cases. PMID- 28906841 TI - The Psychological Aspect of the Bravo Case. PMID- 28906842 TI - Nightmare and Dreaming. PMID- 28906843 TI - The Physical Signs of Reasoning Madness: ("Folie Raisonnante"). PMID- 28906844 TI - Condition of Lunacy in England and Wales. PMID- 28906845 TI - Idiots, Imbeciles, and Harmless Lunatics. PMID- 28906846 TI - Problems for Pathologists. PMID- 28906847 TI - The Localisation of the Functions of the Brain. PMID- 28906848 TI - Pathology and Treatment of Cerebral Disease. No. III. PMID- 28906849 TI - The Psychology of General Paralysis of the Insane. PMID- 28906850 TI - A Note on Spectral Illusions, &c. PMID- 28906851 TI - Mind. PMID- 28906853 TI - Psychological Retrospect and Medico-Legal Trials. PMID- 28906852 TI - On the Artificial Feeding of the Insane. PMID- 28906854 TI - Treatment of Melancholia. PMID- 28906855 TI - Opiophagism, or Psychology of Opium-Eating. PMID- 28906856 TI - Visit to St. Clement's Asylum, Venice. PMID- 28906858 TI - Religious Insanity Metaphysically Considered: Being an Address Delivered by the Editor before the Medical Society of London, January 25, 1875. PMID- 28906857 TI - Materialism. PMID- 28906860 TI - Will and Volition. PMID- 28906859 TI - The Delusions of the Insane. PMID- 28906861 TI - Dipsomania. PMID- 28906862 TI - Hallucination of Satanic Possession Induced by a Vesical Calculus. PMID- 28906863 TI - Reminiscences of Lunacy Practice. PMID- 28906865 TI - Lunacy in Scotland. PMID- 28906864 TI - Notes on Asylum Surgery. PMID- 28906866 TI - State Medicine and Its Relations to Insanity and Public Charity. PMID- 28906868 TI - Condition of Lunacy in England. PMID- 28906867 TI - Pathology and Treatment of Cerebral Diseases. PMID- 28906869 TI - Lunacy in the Commonwealth of Massachusetts. PMID- 28906870 TI - Lunacy in Ireland. PMID- 28906871 TI - Psychological Retrospect and Medico-Legal Trials. PMID- 28906872 TI - Morbid Appetites of the Insane. PMID- 28906873 TI - Diseases of the Nervous System. PMID- 28906875 TI - Hereditary Disease. PMID- 28906874 TI - Arachnoid Cysts. PMID- 28906876 TI - Lunacy in Scotland: Twenty-Fourth Annual Report of the Commissioners in Lunacy for Scotland. PMID- 28906877 TI - Comments on Contemporary Journals. PMID- 28906878 TI - Lunacy in England: Thirty-Sixth Report of the Commissioners in Lunacy. PMID- 28906879 TI - Suicide. No. 2. PMID- 28906880 TI - Another Failure of the Lunacy Law Reformers. PMID- 28906881 TI - The Genesis of Ideas in the Blind Deaf Mute. PMID- 28906882 TI - General Paralysis. PMID- 28906883 TI - Note on the Essential Psychic Signs of General Functional Neuratrophia or Neurasthenia. PMID- 28906884 TI - Mimosis Inquieta. PMID- 28906885 TI - Darwin. PMID- 28906886 TI - The Origin and Growth of Dreaming. PMID- 28906888 TI - Lunacy in Scotland. PMID- 28906887 TI - Legal Medicine in France. PMID- 28906889 TI - On Albuminuria during Paralytic Insanity. PMID- 28906891 TI - Thomas Carlyle Viewed Psychologically. PMID- 28906890 TI - Visual Disturbances Experienced. PMID- 28906893 TI - Codification of the Common Law as to Insanity. PMID- 28906892 TI - A Psychological Study of Shakespeare. PMID- 28906895 TI - Lord Beaconsfield Viewed Psychologically. PMID- 28906894 TI - Materialism at the International Medical Congress. PMID- 28906896 TI - Lunacy in England. (England's Irren-Wesen.): The Address Read at the Opening of Section VIII. Mental Diseases of the International Medical Congress. PMID- 28906898 TI - The Psychological Aspect of the Guiteau Case. PMID- 28906897 TI - Mania Errabunda. PMID- 28906899 TI - Comments on Contemporary Journals. PMID- 28906900 TI - Lunacy in England and Wales. PMID- 28906901 TI - Was Guiteau Insane? PMID- 28906903 TI - Suicide. No. 1. PMID- 28906902 TI - Moral (Affective) Insanity : A Plea for Its Retention in Medical Nomenclature. PMID- 28906904 TI - Mad Actors. No. 1. PMID- 28906905 TI - Early Education and Spiritualism. PMID- 28906906 TI - The Plea of Insanity in the Case of Lefroy. PMID- 28906907 TI - The Causes of Insanity. PMID- 28906908 TI - Opium-Eating Teetotallers. PMID- 28906910 TI - Lunacy Law Reform. PMID- 28906909 TI - Prophylaxis of Insanity. PMID- 28906911 TI - Transference of Special Sense. PMID- 28906912 TI - Epitomised Translations. PMID- 28906913 TI - Psychology in Our Poets. PMID- 28906914 TI - On the Treatment of Blindness and Deafness Resulting from Cerebro-Spinal Meningitis, by the Constant Current of Electricity. PMID- 28906915 TI - Psychological Retrospect. PMID- 28906916 TI - The Mental Development of the Infant of To-Day. PMID- 28906917 TI - The Asylums of Europe. PMID- 28906918 TI - Medical Proprietors of Private Asylums. PMID- 28906919 TI - Private Asylums. PMID- 28906921 TI - Psychological Peculiarity. PMID- 28906920 TI - Psychological Retrospect. PMID- 28906922 TI - Notes on the Psychological Pathology of the Brain. PMID- 28906923 TI - Charles Lever. PMID- 28906924 TI - Microcephalism. PMID- 28906925 TI - The Lunacy Laws. PMID- 28906926 TI - Lunacy in England. PMID- 28906927 TI - The British Association for the Advancement of Science. PMID- 28906928 TI - Education of Girls, Connected with Growth and Physical Development. PMID- 28906929 TI - Lunacy in Scotland. PMID- 28906930 TI - Lunacy in America. PMID- 28906931 TI - Mental Responsibility and the Diagnosis of Insanity in Criminal Cases. PMID- 28906932 TI - Pathology and Treatment of Cerebral Disease: No. V. PMID- 28906933 TI - Mind and Living Particles. PMID- 28906934 TI - Mad Poets. No. 2. PMID- 28906935 TI - What Can Be Done with Criminal Lunatics? PMID- 28906936 TI - Idiocy. PMID- 28906937 TI - Psychology of Hamlet. PMID- 28906938 TI - The Physiology of Nightmare. PMID- 28906939 TI - Constance Kent and the Road Murder. PMID- 28906940 TI - Notes on the Localisation of Diseases of the Brain. PMID- 28906941 TI - Psychological Annotations. PMID- 28906942 TI - Sensori-Motor Affections. PMID- 28906944 TI - Psychological Retrospect. PMID- 28906943 TI - State Medicine in Its Relations to Intemperance. PMID- 28906945 TI - Lunacy in Scotland. PMID- 28906946 TI - Materialistic Physiology. PMID- 28906947 TI - Epidemic Paralysis: Translated from the Annales Medico-Psychologiques, September 1876. PMID- 28906948 TI - A Visit to Cairo Asylum. PMID- 28906949 TI - The Physiologist as a Preacher. PMID- 28906950 TI - Classification of Mental Diseases. PMID- 28906951 TI - Coloured Light in the Treatment of the Insane. PMID- 28906952 TI - Religio Psycho-Medici. PMID- 28906954 TI - Military Lunatics. PMID- 28906953 TI - Diseases of the Nervous System: No III. - Insanity. PMID- 28906955 TI - Lunacy in Ireland. PMID- 28906956 TI - Cases of Heart Disease with Melancholia. PMID- 28906957 TI - General Paralysis. PMID- 28906958 TI - Laws of Hereditary Descent. PMID- 28906959 TI - Notes on a Visit to the Asylum of St. Anne, at Paris. PMID- 28906961 TI - Lunacy in England. PMID- 28906960 TI - Insanity in the Middle States of America. PMID- 28906962 TI - Lunacy in Scotland. PMID- 28906963 TI - States of Unconsciousness: Irresistible Impulses-Epilepsy-Treadaway. PMID- 28906964 TI - Religio Psycho-Medici. Part II. PMID- 28906965 TI - On "Agoraphobia." PMID- 28906966 TI - On Statistical Tables of the Causes of Insanity. PMID- 28906968 TI - A Death Blow to Spiritualism. PMID- 28906967 TI - Sensational Science. PMID- 28906970 TI - The Dillwyn Committee. PMID- 28906969 TI - Effects of Alcohol on the Offspring. PMID- 28906971 TI - Pathology and Treatment of Cerebral Disease: No. IV. PMID- 28906972 TI - Diseases of the Nervous System: No. IV.-Mania. PMID- 28906974 TI - Commission of Lunacy on the Rev. W. Basset. PMID- 28906973 TI - The Curability of Insanity: Psychological Shadows. PMID- 28906975 TI - On General Paresis. PMID- 28906976 TI - Psychology in Its Relation to Medicine. PMID- 28906977 TI - Translations from French Journals. PMID- 28906978 TI - Mad Artists. PMID- 28906979 TI - Discussion on Private Lunatic Asylums. PMID- 28906980 TI - The Collapse of Scientific Atheism. PMID- 28906981 TI - Is "Palaeolithic Man" a Reality of the past or a Myth of the Present? No. 2. PMID- 28906982 TI - Suicide in Its Social Relations. PMID- 28906983 TI - Lunacy in England. PMID- 28906984 TI - The Case of the Rev. Mr. Dodwell. PMID- 28906985 TI - A Case of Moral Insanity. PMID- 28906986 TI - Mad Poets. No. 1. PMID- 28906987 TI - Lunacy in Scotland. PMID- 28906988 TI - Felo-de-se. PMID- 28906989 TI - Prevention of Disease, Insanity, Crime and Pauperism. PMID- 28906990 TI - A Last Word for Constance Kent. PMID- 28906991 TI - Lunacy in Scotland: The Twenty-Second Annual Report of the Commissioners in Lunacy for Scotland. PMID- 28906992 TI - Lunacy in England. PMID- 28906993 TI - Electrisation of the Membranes of the Brain. PMID- 28906994 TI - The British Association Picnic at Swansea. PMID- 28906995 TI - Epidemical Contagion in Spiritualism. PMID- 28906996 TI - The Study of Medical Psychology-Circles of Mental Disorders-Modern Nervous Diseases-Education in Relation to Mental Diseases. PMID- 28906997 TI - Asylum Supervision. PMID- 28906998 TI - Dr. Bucknill and Private Asylums. PMID- 28906999 TI - The Centralisation of Energy. PMID- 28907000 TI - Psychological Aspect of the Laros Case, on the Trial of Allen C. Laros, at Easton, Pennsylvania, U.S.A., for the Murder of His Father, Martin Laros, by Poison, the Defence Being Based upon the Allegation of Epileptic Insanity. PMID- 28907001 TI - Lunacy in New South Wales. PMID- 28907002 TI - Fasting and Feeding: A Detailed Account of Recorded Instances of Unusual Abstinence from Food, and of Cases Illustrating Inordinate Appetite. PMID- 28907004 TI - Nuggets, Gold and Other Dust from Various Diggings. PMID- 28907003 TI - The Brain in Health and Disease. PMID- 28907005 TI - Report of the Lunacy Committee. PMID- 28907006 TI - Case of Opium Habit and Chloral Habit Combined. PMID- 28907007 TI - Modern Pseudo-Philosophy. PMID- 28907008 TI - Athetosis. PMID- 28907009 TI - Is "Palaeolithic Man" a Reality of the past or a Myth of the Present? PMID- 28907010 TI - Diseases of the Nervous System. No. V: Partial Insanity. PMID- 28907011 TI - Catalepsy Consequent upon an Attack of Acute Mania-Recovery. PMID- 28907012 TI - The St. Clement's Asylum at Venice. PMID- 28907014 TI - Psychological Retrospect. PMID- 28907013 TI - Analysis of the Evidence of the Dillwyn Committee. PMID- 28907016 TI - Insanity in Massachusetts. PMID- 28907015 TI - Mental Disorders. PMID- 28907017 TI - French Psychological Literature. PMID- 28907018 TI - The Asylum Journal. PMID- 28907019 TI - British Asylums for the Insane. PMID- 28907021 TI - Cerebral Pathology. PMID- 28907020 TI - The Histology of the Blood in the Insane. PMID- 28907022 TI - American Institutions for the Insane. PMID- 28907023 TI - On Seclusion in the Treatment of the Insane. PMID- 28907024 TI - On Epilepsy. PMID- 28907025 TI - On the Causes and Morbid Anatomy of Mental Diseases. PMID- 28907026 TI - Hospitals for the Intemperate. PMID- 28907027 TI - Suggestions for a New Psychological Terminology. PMID- 28907029 TI - On Medico-Legal Evidence in Cases of Insanity: Conclusion. PMID- 28907028 TI - On the Connexion Between Morbid Physical and Religious Phenomena: No. II. of a Series. PMID- 28907030 TI - On Pledges Exacted from the Insane. PMID- 28907031 TI - To the Editor of the Journal of Psychological Medicine. PMID- 28907032 TI - Heigham Hall Lunatic Asylum, Norwich. PMID- 28907033 TI - Psychology of Descartes. PMID- 28907034 TI - On the Treatment of Puerperal Mania. PMID- 28907035 TI - Critical Remarks on the "Plea of Insanity," &c. PMID- 28907037 TI - Oinomania; or, the Mental Pathology of Intemperance. PMID- 28907036 TI - The Materialism of Insanity. PMID- 28907038 TI - On Epilepsy. PMID- 28907040 TI - A Visit to the American State School for Idiots: From the New York Tribune. PMID- 28907041 TI - Medico-Legal Jurisprudence.-Important Trial: High Court of Justiciary, Edinburgh. PMID- 28907039 TI - On the Causes and Morbid Anatomy of Mental Diseases. PMID- 28907042 TI - The Responsibility of the Insane. PMID- 28907043 TI - Origin of Insanity. PMID- 28907044 TI - On the Condition of Lunatics and Idiots in Ireland. PMID- 28907045 TI - An Analysis of Guislain's Work on Insanity. PMID- 28907046 TI - Critical Remarks on the "Plea of Insanity". PMID- 28907047 TI - On the Connexion Between Morbid Physical and Religious Phenomena: No. 3 of a Series. PMID- 28907048 TI - On the Uses and Influence of Mental Philosophy. PMID- 28907049 TI - Autobiography of the Insane. PMID- 28907050 TI - The Brain in Relation to the Mind. PMID- 28907051 TI - American Institutions for the Insane. PMID- 28907052 TI - Psychology of Berkeley. PMID- 28907053 TI - Does Any Analogy Exist Between Insanity and Demoniacal Possession? PMID- 28907054 TI - Great Will Case: Dyce Sombre v. Troup. PMID- 28907055 TI - American Psychological Literature. PMID- 28907056 TI - Suggestions in Reference to the Study of the Philosophy of the Human Mind. PMID- 28907057 TI - Remarks on the Religious Persuasion, Degree of Education, and Employments of Persons Affected with Insanity. PMID- 28907058 TI - On the Connexion Between Morbid Physical and Religious Phenomena: No. 4 of a Series. PMID- 28907059 TI - Case of a Gentleman Who Was Born Deaf and Dumb, and Subsequently Became Insane. PMID- 28907060 TI - Retrospect of the Autopsies Performed in the Vienna Lunatic Asylum of the Patients Who Died in 1853. PMID- 28907061 TI - William Tuke, the Founder of the York Retreat. PMID- 28907062 TI - Insanity and Demoniacal Possession. PMID- 28907063 TI - Cerebral Pathology Based upon the Examination of 411 Cases. Specific Gravity of the Brain in Cases of Insanity. PMID- 28907064 TI - Private Lunatic Asylums in Ireland. PMID- 28907065 TI - Researches into the Functions of the Brain. PMID- 28907066 TI - Opening of an Institution for the Treatment of Idiocy in Edinburgh. PMID- 28907068 TI - Influence of Ether and Chloroform on the Mind. PMID- 28907067 TI - On the Policy of Maintaining the Limits at Present Imposed by Law on the Criminal Responsibility of Madmen. PMID- 28907069 TI - State of Lunatic Asylums and the Insane in Ireland. PMID- 28907070 TI - American Institutions for the Insane. PMID- 28907071 TI - On the Causes and Treatment of Insanity. PMID- 28907072 TI - Religious Consolation to the Insane. PMID- 28907073 TI - Claim of Priority in the Reformation of the Treatment of the Insane. PMID- 28907075 TI - Psychological Quarterly Retrospect. PMID- 28907074 TI - On the Mind. PMID- 28907077 TI - Literary Fools.-Guillaume Postel, Christopher Smart, and Others. PMID- 28907076 TI - On the Moral Therapeutics of London. PMID- 28907078 TI - Judicial Psychology in France. PMID- 28907079 TI - On General Paralysis. PMID- 28907081 TI - The Method and Statistics of Suicide. PMID- 28907080 TI - Proposed Amendment of the Law of Lunacy. PMID- 28907082 TI - Murderous Assault on the Visiting Physician in the Maryboro' Lunatic Asylum. PMID- 28907083 TI - On the Artificial Production of Stupidity in Schools. PMID- 28907084 TI - Statistics of Insanity. PMID- 28907085 TI - Dante: A Psychological Study. PMID- 28907086 TI - Pauper Lunacy. PMID- 28907087 TI - Medico-Legal Trial: Disputed Will.-Plea of Unsound Mind. Court of Probate, Westminster, May 5th. (Before Sir C. Cresswell, the Judge Ordinary, and a Special Jury.) Terrington v. Terrington and Johnson. PMID- 28907088 TI - Psychological Quarterly Retrospect. PMID- 28907089 TI - The Case of Mr. Ruck. PMID- 28907090 TI - Sir William Hamilton's Lectures on Metaphysics. PMID- 28907091 TI - Proposed Legislation in Lunacy. PMID- 28907092 TI - Principles of Early Mental Education. PMID- 28907093 TI - Sussex Lunatic Asylum: How the Inmates Will Be Lodged, Fed, Clothed, Employed, and Amused. PMID- 28907095 TI - The Law of Lunacy and the Condition of the Insane in Scotland. PMID- 28907094 TI - Errata. AB - [This corrects the article on p. 277 in vol. 12.][This corrects the article on p. 299 in vol. 12.]. PMID- 28907096 TI - On Puerperal Insanity. PMID- 28907097 TI - Psychological Quarterly Retrospect. PMID- 28907098 TI - On Convulsion. PMID- 28907099 TI - Literary Fools.-Bluet D'Arberes. PMID- 28907100 TI - On the State and Condition of Lunacy in Ireland. PMID- 28907101 TI - Psychology of Kant. PMID- 28907102 TI - The Statistics of Justice. PMID- 28907103 TI - Don Quixote: A Psychological Study. PMID- 28907104 TI - Plea of Insanity-Trial for Murder. PMID- 28907105 TI - On the Insanity of Children. PMID- 28907106 TI - On the Obscure Mental Disorders of Criminals. PMID- 28907107 TI - The Select Committee on Lunatics. PMID- 28907108 TI - The AEsthetics of Suicide. PMID- 28907109 TI - Psychological Quarterly Retrospect. PMID- 28907110 TI - Law and Lunacy: Notes of Recent Cases. PMID- 28907111 TI - Medico-Legal Trial.-Unlawful Detention in a Lunatic Asylum: Court of Queen's Bench, Westminster, June 21st. (Sitting at Nisi Prius, before Mr. Justice Hill and Special Juries.) Ruck v. Stilwell and Another. PMID- 28907112 TI - On Inflammatory Affections of the Brain. PMID- 28907113 TI - Transitory Homicidal Mania: Where Does Reason End or Mania Begin? PMID- 28907114 TI - The Psychology of Kant. PMID- 28907115 TI - State of Lunacy in England. PMID- 28907116 TI - The Asylums of Italy, France, and Germany. PMID- 28907117 TI - Hysteria in Connexion with the Belfast Revival. PMID- 28907118 TI - On the Distribution of Suicides in England and Wales: With a Map. PMID- 28907120 TI - On Suicide. PMID- 28907119 TI - Tendency of Misdirected Education and the Unbalanced Mind to Produce Insanity. PMID- 28907121 TI - A Singular Case of Insanity. PMID- 28907122 TI - On the Paralysis of the Insane. PMID- 28907123 TI - On the Causes of Idiocy. PMID- 28907125 TI - An Autobiographical Sketch of a Drunkard. PMID- 28907124 TI - Psychology of Kant. PMID- 28907126 TI - On a Particular Class of Dreams Induced by Food. PMID- 28907127 TI - The Present State of Lunacy in England and Wales. PMID- 28907128 TI - On the Psychological Basis of the Language of Orators, Poets, and Philosophers. PMID- 28907129 TI - Medico-Legal Trial-Plea, "Lunacy". PMID- 28907130 TI - Lunacy Legislation. PMID- 28907131 TI - Foreign Psychological Literature. PMID- 28907132 TI - On the Moral Pathology of London. PMID- 28907134 TI - On Insanity and Lunatic Asylums in Norway. PMID- 28907133 TI - The Asylums of Italy, Germany, and France, &c. PMID- 28907135 TI - On Dipsomania. PMID- 28907137 TI - Physiological Psychology: No. V. PMID- 28907136 TI - Mind and Body. PMID- 28907139 TI - Charlotte Bronte-A Psychological Study. PMID- 28907138 TI - The Legal Doctrine of Responsibility in Cases of Insanity, Connected with Alleged Criminal Acts. PMID- 28907140 TI - On Civilization. PMID- 28907141 TI - Congratulatory Address to Samuel Gaskell, Esq.: And One of Her Majesty's Commissioners in Lunacy, Etc. Etc. PMID- 28907142 TI - Correspondence from Paris. PMID- 28907143 TI - Address to Our Readers. PMID- 28907144 TI - Bentley's Miscellany and Mad Doctors. PMID- 28907145 TI - Analysis of Crime: Being an Attempt to Distinguish Its Chief Causes, in Answer to the Statistical Deductions of M. Guerry, and the Rev. Whitworth Russell; the Former Finding That Popular Education Did Not Prevent Crime-The Latter That It Was a Cause of Crime. PMID- 28907146 TI - Insanity from Chloroform. PMID- 28907148 TI - Somerset County Lunatic Asylum. PMID- 28907147 TI - Insanity of Advanced Life. PMID- 28907149 TI - Moral State of Society. PMID- 28907150 TI - The Editor's Portfolio. PMID- 28907152 TI - Annals of Medico-Psychology. PMID- 28907151 TI - The Treatment of Insanity, Ancient and Modern. PMID- 28907153 TI - Lectures on the Pathological Appearances in the Bodies of the Insane. No. I: Delivered at the Middlesex County Lunatic Asylum. PMID- 28907154 TI - The Human Mind, Considered in Some of Its Medical Aspects. PMID- 28907155 TI - Supposed Demoniacal Possession: To the Editor of the "Journal of Psychological Medicine". PMID- 28907156 TI - The Passions. PMID- 28907157 TI - The Anatomy of the Human Brain. PMID- 28907159 TI - Religious Insanity. PMID- 28907158 TI - Mr. Dyce Sombre on the English Law of Lunacy. PMID- 28907160 TI - Case of Pyromania. PMID- 28907161 TI - The French Law of Lunacy. PMID- 28907162 TI - Dr. Davey's Mental Pathology. PMID- 28907163 TI - Causes, Cure, and Prevention of Idiocy. PMID- 28907165 TI - Confessions of a Patient after Recovering from an Attack of Lunacy. PMID- 28907164 TI - Lectures on the Pathological Appearances Observed in the Bodies of the Insane. No. II. PMID- 28907166 TI - Colney Hatch Asylum. PMID- 28907167 TI - The Physiology of the Human Brain. PMID- 28907168 TI - The Pennsylvania Hospital for the Insane. PMID- 28907169 TI - The Morbid Anatomy of the Coverings of the Brain. PMID- 28907170 TI - Dr. Ogilvie's Course of Lectures on Medical Psychology. PMID- 28907171 TI - On Taedium Vitae. PMID- 28907172 TI - Notes of a Recent Visit to Several Provincial Asylums for the Insane in France. PMID- 28907173 TI - Earl's-Court House, Old Brompton, near London. Mrs. Bradbury's Establishment for the Care and Recovery of Ladies Labouring under Nervous Affection. PMID- 28907174 TI - Periodicals in Exchange. PMID- 28907175 TI - Testimonial to Dr. Conolly. PMID- 28907176 TI - English County Lunatic Asylums. PMID- 28907177 TI - The Ohio Lunatic Asylum. PMID- 28907178 TI - The State Lunatic Asylum, New York. (With an Engraving.). PMID- 28907179 TI - Mixed Insanity-Reason and Madness. PMID- 28907180 TI - The Trial of Robert Pate, or the Plea of Lunacy. PMID- 28907181 TI - Trial of Robert Pate for the Outrage upon Her Majesty. PMID- 28907183 TI - The History and Present State of Lunatic Asylums-Public and Private. PMID- 28907182 TI - The Pathology of Insanity: A Lecture, Delivered May 25th, 1850, in the Middlesex County Asylum, Hanwell. PMID- 28907185 TI - The Sedative Treatment of Insanity. PMID- 28907184 TI - Lord Brougham on Partial Insanity. PMID- 28907186 TI - The Plea of Insanity. PMID- 28907187 TI - Selections. PMID- 28907189 TI - The Connexion between Physiology, Psychology, Natural Theology, and Other Sciences. PMID- 28907188 TI - Letters from Paris. PMID- 28907191 TI - Supposed Demoniacal Possession. PMID- 28907190 TI - Transient Insanity. PMID- 28907192 TI - Case of Double Consciousness Connected with Hysteria. PMID- 28907194 TI - Commissions in Lunacy: Court of Chancery, Westminster, April 25. In Re Anstie (Lunacy). PMID- 28907193 TI - Juvenile Delinquency and Degeneration in the Upper Classes of Society. PMID- 28907195 TI - Miscellaneous. PMID- 28907196 TI - Letters from Paris. PMID- 28907198 TI - Impulsive Insanity.-The French Vampire. PMID- 28907197 TI - Miscellaneous. PMID- 28907199 TI - Judicial Insanity-Trial of Nottidge v. Ripley. PMID- 28907200 TI - Monograph II. On Softening of the Brain, Arising from Anxiety and Undue Mental Exercise, and Resulting in Impairment of Mind. PMID- 28907201 TI - Madness, as Treated by Shakspere: A Psychological Essay. PMID- 28907202 TI - Psychological Fragments. PMID- 28907203 TI - Works and Memoirs on General Psychology. PMID- 28907204 TI - To Our Readers. PMID- 28907205 TI - Selections. PMID- 28907206 TI - Chemical Investigations on the Blood in the Neuroses: A Memoir Presented to the Academy of Sciences at Paris, on the 29th of November, 1847. PMID- 28907207 TI - Dr. Winslow on the Effect of Solitary Confinement on the Mind. PMID- 28907208 TI - Medical Intelligence and News. PMID- 28907209 TI - The Manchester Royal Lunatic Hospital. PMID- 28907210 TI - On the Religious Instruction of the Insane. PMID- 28907211 TI - Statistics of Insanity. PMID- 28907213 TI - Professor Valentin's Physiology. PMID- 28907212 TI - No.I. The Psychological Vocation of the Physician. PMID- 28907214 TI - The Pilgrimage of Thought. PMID- 28907215 TI - On the Hygeine of Crime. PMID- 28907216 TI - Logic and Psychology. PMID- 28907217 TI - General Paralysis of the Insane. PMID- 28907218 TI - Elements of Psychological Medicine. PMID- 28907219 TI - Modern Demonology and Divination. PMID- 28907220 TI - Upon the Morbid Desire to Kill. PMID- 28907221 TI - Dr. Charlesworth and Mr. Gardiner Hill; or the Non-Restraint System of Treatment in Lunacy. PMID- 28907222 TI - Psychological Inquiries. PMID- 28907223 TI - On Non-Mechanical Restraint in the Treatment of the Insane. PMID- 28907224 TI - Recent Trials in Lunacy. PMID- 28907225 TI - Symptomatology of Insanity. PMID- 28907226 TI - On the Classification of Mental Diseases. PMID- 28907227 TI - The Correlation of Psychology and Physiology. PMID- 28907228 TI - On the Connexion between Morbid Physical and Religious Phenomena. PMID- 28907229 TI - Artistic Anatomy. PMID- 28907230 TI - On the Causes and Morbid Anatomy of Mental Diseases. PMID- 28907231 TI - Institutions for the Insane in Prussia, Austria, and Germany. PMID- 28907232 TI - Spiritual Pathology; or, the Autobiography of the Insane. PMID- 28907233 TI - The Psychology of Monomaniacal Societies and Literature. PMID- 28907234 TI - No. III. On Medico-Legal Evidence in Cases of Insanity: Delivered before the Medical Society of London. PMID- 28907235 TI - On Paralysis and Diseases of the Brain. PMID- 28907236 TI - On Criminal Lunacy. PMID- 28907237 TI - An Analysis of Guislain's Work on Insanity. PMID- 28907238 TI - Medical Jurisprudence of Insanity. PMID- 28907241 TI - On the Construction of Hospitals for the Insane. PMID- 28907240 TI - Psychology of Locke. PMID- 28907239 TI - The Asylums of Holland: Their past and Present Condition. PMID- 28907243 TI - State of Lunacy in Paris. PMID- 28907242 TI - Pathology of Insanity: To the Editor of the Psychological Journal. PMID- 28907244 TI - A Subject for Psychological Adjudication. PMID- 28907245 TI - On the Organization of Hospitals for the Insane. PMID- 28907247 TI - The Plea of Insanity in Criminal Cases. PMID- 28907246 TI - American Asylums for the Insane. PMID- 28907248 TI - St. Luke's Hospital. PMID- 28907249 TI - On a Substance Presenting the Chemical Reaction of Cellulose, Found in the Brain and Spinal Cord of Man. PMID- 28907250 TI - On the Weight and Specific Gravity of the Brain in Insanity. PMID- 28907252 TI - On Some of the Latent Causes of Insanity. PMID- 28907251 TI - The Psychology of Opium Eating. PMID- 28907253 TI - Mental Dynamics in Relation to the Science of Medicine. PMID- 28907254 TI - An Analysis of Guislain's Work on Insanity. PMID- 28907255 TI - No. II. On the Medical Treatment of Insanity: Delivered before the Medical Society of London, April 7, 1852. PMID- 28907256 TI - Liability of a Lunatic's Estate for Necessaries Supplied to the Lunatic: Seaton v. Adcock. PMID- 28907257 TI - A Psychological Problem. (?). PMID- 28907258 TI - German Psychological Literature. PMID- 28907259 TI - Remarks upon the Morbid Anatomy of the Brain in Insanity. PMID- 28907260 TI - Philosophy of Spirits. PMID- 28907261 TI - Extraordinary Will Case, Involving the Question of Mental Capacity: Dryden v. Fryer.-The Will of the Late Sir Gregory Page Turner. Court of Queen's Bench. Sittings at Nisi Prius at Westminster. Before Lord Campbell and a Special Jury. PMID- 28907262 TI - The Last Sentiments of Suicides. PMID- 28907263 TI - The Closing Scene. PMID- 28907264 TI - The Mental Aspect of Epidemics. PMID- 28907265 TI - Bethlem Hospital. PMID- 28907266 TI - Medical Jurisprudence of Insanity. PMID- 28907267 TI - An Appeal from Bethlehem. PMID- 28907268 TI - The Chancellor of the Exchequer and County and Private Lunatic Asylums. PMID- 28907269 TI - Insanity from Solitary and Separate Confinement. Also, Mortality in Lunatic Asylums. PMID- 28907270 TI - On the Premonitory Symptoms of Cerebral Disease. PMID- 28907271 TI - On Nervous Diseases. PMID- 28907272 TI - Evidence of a Lunatic Taken in a Case of Manslaughter in a Lunatic Asylum. PMID- 28907274 TI - Syphiliphobia. PMID- 28907273 TI - Modern Scepticism. PMID- 28907275 TI - Statistics of Suicide in France: From 1835 to 1846, Inclusive. PMID- 28907276 TI - The Last Sentiments of Suicides: II. Bad Sentiments. PMID- 28907277 TI - On the Mental Manifestations and Impulses of the Insane. PMID- 28907278 TI - Selections. PMID- 28907279 TI - On the Inadmissibility of the Evidence of a Lunatic in a Court of Justice. PMID- 28907280 TI - Notes of a Recent Visit to Some of the American Asylums. PMID- 28907281 TI - Modern Metaphysics. PMID- 28907282 TI - Influence of Mental Emotion in the Production of Disease of the Heart. PMID- 28907283 TI - The Nature and Treatment of Insanity. PMID- 28907285 TI - On Idiotic Crania, Idiocy, and Cretinism. PMID- 28907284 TI - Remarks upon the Morbid Anatomy of the Brain in Insanity. PMID- 28907286 TI - The Process of Thought; or, Electro-Biology. PMID- 28907287 TI - Instinct and Reason; or, the Intellectual Difference between Man and Animals. PMID- 28907289 TI - The Association of Medical Officers of Hospitals for the Insane. PMID- 28907288 TI - On Improving the Condition of the Insane: Public Asylums for the Middle Classes. PMID- 28907290 TI - The Last Sentiments of Suicides: III. Mixed Sentiments. PMID- 28907291 TI - Lunatic Asylums in Ireland. PMID- 28907292 TI - Criminal Lunatics. PMID- 28907293 TI - British Lunatic Asylums. PMID- 28907294 TI - The Theory of Reasoning. PMID- 28907295 TI - The Maniac's Wail. PMID- 28907296 TI - Chancery Lunatics. PMID- 28907297 TI - Medical Evidence in Cases of Insanity. PMID- 28907298 TI - The Murderer's Confession. PMID- 28907299 TI - Sleep, Dreaming, and Insanity. PMID- 28907300 TI - Theory of Insanity. PMID- 28907301 TI - On the Education of Idiots. PMID- 28907302 TI - Lunatic Asylums in Ireland. PMID- 28907303 TI - State of Lunacy in England. PMID- 28907304 TI - Woman in Her Psychological Relations. PMID- 28907305 TI - The Great Exhibition of 1851. PMID- 28907306 TI - Commissions in Lunacy. PMID- 28907307 TI - Mental Dietetics:-The Effects of Stimulants, Solid and Fluid, on the Mind. PMID- 28907308 TI - Case of Mr. Dyce Sombre. (Morning Chronicle.). PMID- 28907310 TI - Description of a New Window for the Use of Asylums. PMID- 28907309 TI - The Census of 1851, in Relation to Public and Private Lunatic Asylums. PMID- 28907311 TI - On the Psychical Progress of Nations. PMID- 28907313 TI - Report of the Board of Visitors of the Boston Lunatic Asylum, in the Matter of the Superintendent of That Institution: Boston, 1849. PMID- 28907312 TI - Notes of a Recent Visit to Several Provincial Asylums for the Insane in France. PMID- 28907314 TI - On Somnambulism. PMID- 28907315 TI - The War. PMID- 28907316 TI - Autobiography of the Insane. PMID- 28907317 TI - On Some Unrecognised Forms of Mental Disorder. PMID- 28907318 TI - Notes of a Visit to the Public Lunatic Asylums of Scotland. PMID- 28907319 TI - Foreign Psychological Literature. PMID- 28907320 TI - On the Connexion between Morbid Physical and Religious Phenomena. PMID- 28907321 TI - Judicial Department. PMID- 28907322 TI - A Psychological Quarterly Retrospect. PMID- 28907323 TI - Foreign Psychological Literature. PMID- 28907324 TI - New Scotch Lunacy Law. PMID- 28907325 TI - Annual Meeting of the Association of Medical Officers of Asylums and Hospitals for the Insane. PMID- 28907326 TI - Sardinian Law of Lunacy. PMID- 28907327 TI - The Present State of Lunacy in England and Wales. PMID- 28907328 TI - Proposed Scheme to Establish a Society for the Protection and Cure of Invalids in Belgium. PMID- 28907329 TI - Philosophical Progress. PMID- 28907330 TI - Psychology of Wolf. PMID- 28907331 TI - State of Lunacy in Ireland. PMID- 28907332 TI - On the Compensatory Relations between the Faculties of Order and Memory. PMID- 28907333 TI - On Moral Liberty. PMID- 28907334 TI - Inspectors of Lunacy for Scotland. PMID- 28907335 TI - The Mission of the Psychologist. PMID- 28907337 TI - The Asylums of Italy, Germany, and France: Notes of a Visit Made in the Year 1855. PMID- 28907336 TI - On the Insanity of Early Life. PMID- 28907338 TI - Judicial Department. PMID- 28907339 TI - William Dove. PMID- 28907340 TI - On the Physiological and Psychological Phenomena of Dreams and Apparitions. PMID- 28907341 TI - Woman in Her Social Relations, past and Present. PMID- 28907342 TI - The Statistics of Insanity, and Idiocy and Cretinism.-Reports of the International Statistical Congress: To the Editor of the Journal of Psychological Medicine. PMID- 28907344 TI - Leaves from the Diary of a Patient Confined in Hanwell Asylum. PMID- 28907343 TI - On the Connexion between Morbid Physical and Moral Phenomena. PMID- 28907345 TI - The District Hospitals for the Insane in Ireland.-Superannuations. PMID- 28907346 TI - Triune Man.-The Inaugural Discourse Delivered at the Opening of the Last Session of the London Hospital Medical College. PMID- 28907348 TI - Psychological Quarterly Retrospect. PMID- 28907347 TI - Psychology of Malebranche. PMID- 28907350 TI - Mental Labour; Its Effects on the Blood. PMID- 28907349 TI - On Monomania. PMID- 28907351 TI - On the Use of Chloroform in the Treatment of Puerperal Insanity. PMID- 28907352 TI - Professor Ferrier's New Scottish Philosophy. PMID- 28907353 TI - The Case of Mr. Millar: From the "Bucks Advertiser and Aylesbury News" of Oct. 18, 1856. PMID- 28907354 TI - Autobiography of the Insane. PMID- 28907355 TI - Notes on Belgian Lunatic Asylums, Including the Insane Colony of Gheel. PMID- 28907356 TI - Philosophical Medicine. PMID- 28907357 TI - Physiological Psychology: No. III. PMID- 28907358 TI - Prolonged Shower-Baths in the Treatment of the Insane. PMID- 28907359 TI - The Insanity of King George III. PMID- 28907360 TI - Contributions to the Chemistry and Histology of the Urine in the Insane. PMID- 28907362 TI - On the Physiological and Psychological Phenomena of Dreams and Apparitions. PMID- 28907361 TI - Physiological Psychology: No. II. PMID- 28907363 TI - Psychology of Leibnitz. PMID- 28907364 TI - Lunatic Asylums in Ireland. PMID- 28907366 TI - The Peace. PMID- 28907365 TI - Foreign Psychological Literature. PMID- 28907367 TI - Notes of a Visit to the Public Lunatic Asylums of Scotland. PMID- 28907368 TI - William Palmer. PMID- 28907369 TI - The "Private Lunacy Committee" and the Commissioners in Lunacy. PMID- 28907370 TI - On the Connexion between Morbid Physical and Religious Phenomena. PMID- 28907371 TI - On Marriages of Consanguinity. PMID- 28907372 TI - Psychology of Spinoza. PMID- 28907374 TI - Psychological Intelligence. PMID- 28907373 TI - Pathology of Insanity: Based on the Post-Mortem Examinations in Bethlehem Hospital. PMID- 28907376 TI - On the Degeneracy of the Human Race. PMID- 28907375 TI - Reports of American Institutions for the Insane : From the American Journal of Medical Science. PMID- 28907377 TI - Insanity among the Convicts at Pentonville, Milbank, and Dartmoor Prisons. PMID- 28907378 TI - Notes on Belgian Lunatic Asylums, Including the Insane Colony of Gheel. PMID- 28907379 TI - Hereditary Influence, Animal and Human : From the "Westminster Review". PMID- 28907380 TI - Capital Punishment for Murder Scripturally Considered. PMID- 28907381 TI - On Civilization and Insanity. PMID- 28907382 TI - On the Physiological and Psychological Phenomena of Dreams and Apparitions. PMID- 28907383 TI - Physiological Psychology: No. IV. PMID- 28907384 TI - Education of Idiots. PMID- 28907385 TI - On Some Unrecognised Forms of Mental Disorder. PMID- 28907386 TI - Medical Jurisprudence of Insanity: Part I.-On Lucid Intervals. PMID- 28907388 TI - On Moral and Criminal Epidemics. PMID- 28907387 TI - Psychological Quarterly Retrospect. PMID- 28907390 TI - The Parish of St. Pancras and Its Lunatic Poor. PMID- 28907389 TI - Notes of a Visit to the Public Lunatic Asylums of Scotland. PMID- 28907392 TI - Physiological Psychology. PMID- 28907391 TI - Autobiography of the Insane. PMID- 28907393 TI - Foreign Psychological Literature. PMID- 28907394 TI - Ethnological Psychology. PMID- 28907396 TI - Spencer's Psychology. PMID- 28907395 TI - On Criminal Responsibility. PMID- 28907397 TI - State of Lunacy in England. PMID- 28907398 TI - Statistics of Insanity. PMID- 28907399 TI - State of Lunacy in Scotland. PMID- 28907400 TI - Popular Psychological Literature. PMID- 28907401 TI - The Demon of Socrates. PMID- 28907402 TI - Neglected Brain Disease-Suicide. PMID- 28907403 TI - On the Increase of Insanity. PMID- 28907405 TI - Phantasmata. PMID- 28907404 TI - The Asylums of Italy, Germany, and France: Notes of a Visit Made in the Year 1855. PMID- 28907406 TI - On the Treatment of Insanity in Julius Hospital, Wurzburg: Under the Management of Der Herr Hofrath Dr. von Marcus, Senior Physician of Julius Hospital, Ritter des verdienst Orders der Bayrischen Krone, &c. &c. PMID- 28907407 TI - The Condition of the Insane. PMID- 28907408 TI - Dr. E. Brown-Sequard on the Physiology and Pathology of the Nervous System. PMID- 28907409 TI - The Indian Rebellion in Its Moral and Psychological Aspects. PMID- 28907410 TI - Intemperance Considered as a Form of Mental Disorder. PMID- 28907411 TI - Psychological Quarterly Retrospect. PMID- 28907412 TI - The Asylums of Italy, Germany, and France: Notes of a Visit Made in the Year 1855. PMID- 28907413 TI - Homicide in Insanity. PMID- 28907414 TI - Body v. Mind. PMID- 28907415 TI - The Juridical Society, and the Criminal Responsibility of the Insane. PMID- 28907417 TI - The State of Lunacy in Ireland. PMID- 28907416 TI - Pathology of Insanity: Based on the Post-Mortem Examinations in Bethlehem Hospital. PMID- 28907418 TI - The Commissioners in Lunacy and the Poor-Law Board. PMID- 28907419 TI - William Cullen: A Psychological Study. PMID- 28907420 TI - On Lesions of the Cutaneous Sensibility among the Insane. PMID- 28907421 TI - Instrumental Music in the Asylum of Quatre-Mares. PMID- 28907422 TI - Psychological Quarterly Retrospect. PMID- 28907423 TI - Paradoxical Psychology. PMID- 28907424 TI - Medico-Legal Trial: Disputed Will-Plea of Mental Incapacity Skipper and Skipper v. Bodkin and Others. PMID- 28907426 TI - Hysteria in Connexion with Religious Revivals. PMID- 28907425 TI - Statistics. PMID- 28907427 TI - The Parliamentary Inquiry and Popular Notions Concerning the Treatment of Lunatics. PMID- 28907428 TI - On Epilepsy. PMID- 28907429 TI - Dr. B. A. Morel on Mental Disorders. PMID- 28907430 TI - Foreign Psychological Literature. PMID- 28907431 TI - Bain's Psychology. PMID- 28907432 TI - Modern Magicians and Mediomaniacs. PMID- 28907434 TI - Psychological Quarterly Retrospect. PMID- 28907433 TI - The Platonic Dialogues. PMID- 28907435 TI - The Asylums of Spain. PMID- 28907436 TI - The Mental Philosophy of Fichte the Younger. PMID- 28907437 TI - On Habits of Intoxication as Causing a Type of Disease. PMID- 28907438 TI - Nervousness. PMID- 28907440 TI - Medico-Legal Trial: Disputed Will.-Plea of Unsound Mind. Court of Probate, May 18. Before Sir C. Cresswell and a Special Jury. Williams v. Evans. PMID- 28907439 TI - Pinel: A Biographical Study. PMID- 28907441 TI - Psychological Quarterly Retrospect. PMID- 28907442 TI - Notes on the Asylums of Italy, France, and Germany. PMID- 28907443 TI - The Independence of the Soul: Proved by a Contemplation of Man in His Various Periods of Development. PMID- 28907445 TI - The State of Lunacy in Scotland. PMID- 28907444 TI - On the Reform of Lunatic Asylums. PMID- 28907446 TI - Popular Physiology.-The Nervous System. PMID- 28907447 TI - Dr. Laycock on Mind and Brain. PMID- 28907448 TI - Foreign Psychological Literature. PMID- 28907449 TI - The Census of 1861 and Lunacy. PMID- 28907451 TI - The State of Lunacy in England. PMID- 28907450 TI - A Medical Psychologist of the Seventeenth Century. PMID- 28907452 TI - Foreign Psychological Literature. PMID- 28907453 TI - The Parliamentary Inquiry Concerning Lunatics. PMID- 28907454 TI - Prize Essay on Cretinism. PMID- 28907455 TI - Psychological Quarterly Retrospect. PMID- 28907456 TI - Gheel.-Letter from Dr. Willers Jessen: To the Editor of the Journal of Psychological Medicine. PMID- 28907458 TI - Braidism. PMID- 28907457 TI - Statistics of Insanity in the United States. PMID- 28907459 TI - The Status of Crime in 1859. PMID- 28907460 TI - Recent Legislation on Criminal Lunatics. PMID- 28907461 TI - The Modern Drama: A Contribution to Mental Dietetics. PMID- 28907463 TI - Modern Developments of the Marvellous. PMID- 28907462 TI - On the Unity of the Human Species: Considered with Relation to the Amelioration of Races by Education and Intermarriage. PMID- 28907464 TI - Extracts and Varieties. PMID- 28907465 TI - Malformation of the Brain. PMID- 28907466 TI - On the Psychological Effects of Certain Medicinal Agents. PMID- 28907467 TI - Reports and Statistics of the German Hospitals for the Insane. PMID- 28907468 TI - Homicidal Insanity. PMID- 28907469 TI - Commission of Lunacy on Two Sisters: Miss Maria Collings and Miss Amelia Maria Hortensia Collings, on 20th December, 1847, at the Roebuck Tavern, Chiswick, before Francis Barlow, Esq. Master in Lunacy. PMID- 28907471 TI - Notes on Feigned Insanity. PMID- 28907470 TI - Puerperal Insanity. PMID- 28907472 TI - Suicide-Life Assurance: To the Editor of the Journal of Psychological Medicine. PMID- 28907474 TI - On Hereditary Insanity. PMID- 28907473 TI - Case of Mania in a Child Six Years Old. PMID- 28907475 TI - Sir G. Stephen on the Plea of Monomania. PMID- 28907477 TI - Chelmsford-Charge of Murder-Acquittal on the Ground of Puerperal Insanity. PMID- 28907476 TI - Dr. Baillarger on the Pellagra. PMID- 28907479 TI - The Influence of the Penitentiary System. PMID- 28907478 TI - Demande en Interdiction. PMID- 28907480 TI - A Will Contested on the Plea of the Insanity of the Testator. PMID- 28907481 TI - Dr. Cattell on Insanity. PMID- 28907483 TI - Correspondence from Paris. PMID- 28907482 TI - M. A. Brierre de Boismont on the Employment of Baths in Mania. PMID- 28907485 TI - Arson-Mental Alienation. PMID- 28907484 TI - Dr. Michea on the Blood in the Neuroses: A Memoir Presented to the Academy of Sciences, at Paris, 29th Novermber, 1847. PMID- 28907487 TI - Commission of Lunacy on Miss Amelia Maria Hortensia Collings: On Friday, the 4th of February, 1848, at the Roebuck Tavern, Chiswick, before Francis Barlow, Esq., Master in Lunacy, and a Special Jury. PMID- 28907486 TI - Maidstone-Acquittal of the Charge of Murder on the Ground of Insanity. PMID- 28907488 TI - Dr. C. L. Robertson on the Treatment of Insanity Resulting from Injury to the Head. PMID- 28907489 TI - On the Psychological Education of Medical Men. PMID- 28907490 TI - On the State of Lunatic Asylums in Ireland. PMID- 28907491 TI - Dr. Sigmond on the Treatment of Idiots. PMID- 28907492 TI - Mr. Charles Pearson on the Treatment of Criminal Lunatics. PMID- 28907493 TI - Translations. PMID- 28907495 TI - Medical Intelligence. PMID- 28907494 TI - Mr. Dendy on the Treatment of the Dying. PMID- 28907497 TI - Trial of Ovenston; with Remarks. PMID- 28907496 TI - Commission in Lunacy: Henry Keith Stewart, Esq. PMID- 28907498 TI - Advertisement. PMID- 28907499 TI - Dr. Stubb's Visit to the Parisian Lunatic Asylums. PMID- 28907500 TI - Dr. Reid on Puerperal Insanity. PMID- 28907502 TI - Correspondence from Paris. PMID- 28907501 TI - Monograph I. On the Cerebral Diseases of Children, with Regard to Their Early Manifestations and Treatment. PMID- 28907503 TI - Treatment of Idiots. PMID- 28907504 TI - Translations. PMID- 28907506 TI - On Impulsive Insanity. PMID- 28907505 TI - Dr. Sigmond on Hallucinations. PMID- 28907507 TI - Cour D'Appel at Paris: President, M. le Premier President Seguier. July 31. PMID- 28907508 TI - A Case of Monomania: With Remarks. PMID- 28907510 TI - Derby County Asylum, Mickleover. PMID- 28907509 TI - Dr. Waller on Compression of the Carotids. PMID- 28907511 TI - Mind and the Emotions. PMID- 28907512 TI - Treatment of Criminal Lunatics;-The Case of Captain Johnston. PMID- 28907513 TI - Bethlem Hospital in 1852. PMID- 28907515 TI - Lunatic Asylums of Ireland. PMID- 28907514 TI - The Commissioners in Lunacy's Report on Bethlem Hospital: To the Right Hon. Sir George Grey, Bart., &c. PMID- 28907517 TI - British Institutions for the Insane. PMID- 28907516 TI - On the Epidemic Mental Diseases of Children. PMID- 28907518 TI - An Analysis of Guislain's Work on Insanity: Third Lecture. Of the Elements Which Must Enter into the Definition of Mental Diseases. PMID- 28907519 TI - Importance of Early Detecting the Existence of Insanity. PMID- 28907520 TI - Hanwell Asylum. PMID- 28907522 TI - The Statistics of Mental Diseases in Denmark. PMID- 28907521 TI - Habit-Physiologically Considered: A Lecture Delivered May 9th, 1853, at the Bristol Literary and Philosophical Institution, by John Addington Symonds, M.D., Consulting Physician to the Bristol General Hospital, etc., etc. PMID- 28907523 TI - Chancery Lunatics. PMID- 28907524 TI - The Association of Medical Officers of Asylums and Hospitals for the Insane. PMID- 28907525 TI - Derby County Asylum. PMID- 28907526 TI - Our Pauper Lunatic Asylums. PMID- 28907527 TI - The New Lunacy Act for the "Regulation of the Care and Treatment of Lunatics": 16 and 17 Vict., Cap. 96. PMID- 28907528 TI - On the Reading, Recreation, and Amusements of the Insane. PMID- 28907529 TI - Mental Dynamics, in Relation to the Science of Medicine. PMID- 28907530 TI - Lunacy and Lunatic Asylums of Ireland. PMID- 28907531 TI - Moral Sanitary Economy. PMID- 28907533 TI - American Hospitals for the Insane. PMID- 28907532 TI - On the Proposed Abolition of Private Asylums. PMID- 28907534 TI - Haydon;-A Psychological Study. PMID- 28907535 TI - State of Lunacy in England. PMID- 28907536 TI - The Decline of Life in Health and Disease. PMID- 28907537 TI - The Report of Bethlehem Hospital. PMID- 28907539 TI - Table-Turning and Spirit-Rapping. PMID- 28907538 TI - On the Pathology of Insanity: To the Editor of the Journal of Psychological Medicine. PMID- 28907540 TI - The Proximate Cause of Insanity. PMID- 28907541 TI - British Asylums for the Insane. PMID- 28907542 TI - Legal Cases in Lunacy: And in Chancery, Involving Questions of Insanity, Argued before the Lord Chancellor, the Lords Justices of the Court of Appeal, and the Full Court of Appeal in Chancery. PMID- 28907543 TI - On a Method of Administering, by Means of a New Contrivance, Nourishment to Insane Persons Who Refuse Food. PMID- 28907544 TI - Brief Notice of a Case of Moral Insanity, Unaccompanied by Any Obvious Symptoms of Intellectual Aberration. PMID- 28907545 TI - Psychotherapeia, or the Remedial Influence of Mind. PMID- 28907546 TI - Belfast Lunatic Asylum and the Chaplaincy Question. PMID- 28907547 TI - The Influence of Civilization upon the Development of Insanity: A Fragment. PMID- 28907548 TI - An Analysis of Guislain's Work on Insanity : No. I. PMID- 28907549 TI - Crime and Punishment. PMID- 28907550 TI - Contemplated Alterations in the Law of Lunacy. PMID- 28907551 TI - Suggestions with Reference to Cases of Incurable Lunacy: From Appendix to Report of Commissioners on the Law of Divorce. PMID- 28907552 TI - Mental Dynamics, in Relation to the Science of Medicine. PMID- 28907553 TI - On the Extent of the Surface of the Brain, and Its Relations to the Development of the Intellect. PMID- 28907554 TI - Legal Cases in Lunacy. PMID- 28907555 TI - American Institutions for the Insane. PMID- 28907557 TI - German Psychology. PMID- 28907556 TI - Mental Dynamics, in Relation to the Science of Medicine. PMID- 28907558 TI - Descartes. PMID- 28907559 TI - Mortality and Insanity in Separate Plan Prisons in England and America. PMID- 28907560 TI - The Law of Lunacy in France. PMID- 28907561 TI - Bethlem Hospital. PMID- 28907563 TI - Crime and Its Punishment in the United States. PMID- 28907562 TI - On the Organization of Asylums for the Insane. PMID- 28907564 TI - Education of Criminal Children. PMID- 28907565 TI - Statistics of Crime, and the Moral and Mental Condition of Prisoners. PMID- 28907566 TI - Homicidal Monomania. PMID- 28907567 TI - Additional Notes on Provincial Asylums for the Insane in France; with a Brief Report of the Institution at Illnau, in the Grand Duchy of Baden. PMID- 28907568 TI - Bethlem Hospital. PMID- 28907569 TI - Colney-Hatch Lunatic Asylum. PMID- 28907571 TI - A Singular Case of Monomania. PMID- 28907570 TI - State of Lunacy in England. PMID- 28907572 TI - The Overworked Mind. PMID- 28907573 TI - Magic, Witchcraft, and Animal Magnetism. PMID- 28907574 TI - Mortality and Insanity in Separate Plan Prisons in England and America. PMID- 28907575 TI - Dr. Williams on Insanity. PMID- 28907576 TI - Description of a New Bed and Bedstead for the Use of Insane and Other Patients. PMID- 28907577 TI - Private and Public Asylums. PMID- 28907578 TI - The Election of Medical Superintendent of Bethlem Hospital. PMID- 28907579 TI - Mrs. C. Cumming. PMID- 28907580 TI - On Mental Physiology. PMID- 28907581 TI - Baron Alderson's "Charge" against Private Lunatic Asylums. PMID- 28907582 TI - Mental Dynamics, in Relation to the Science of Medicine. PMID- 28907583 TI - Private Asylums. PMID- 28907585 TI - History of Mental Philosophy. PMID- 28907584 TI - On the Physiology and Pathology of the Brain. PMID- 28907586 TI - The Wear and Tear of Literary Life; or, the Last Days of Robert Southey. PMID- 28907587 TI - Additional Notes on Provincial Asylums for the Insane in France; with a Brief Notice of the Institution at Illnau, in the Grand Duchy of Baden. PMID- 28907588 TI - The Pathology of Sleep. PMID- 28907590 TI - On the Structure and Functions of Nervous Tissue. PMID- 28907589 TI - On the Prevention of Crime. PMID- 28907591 TI - German Psychological Literature. PMID- 28907592 TI - The Plea of Insanity in Criminal Cases. PMID- 28907594 TI - Medical Evidence for Mrs. Cumming. PMID- 28907593 TI - The Report of Dr. Monro and Sir Alexander Morison to the Lord Chancellor. PMID- 28907596 TI - Opening Speech of Mr. James. PMID- 28907595 TI - The Report of Dr. Forbes Winslow to the Right Hon. The Lords Justices of the Court of Appeal. PMID- 28907598 TI - Nervous Influence. PMID- 28907597 TI - Opening Speech of Sir F. Thesiger. PMID- 28907599 TI - General Evidence in Support of the Commission. PMID- 28907600 TI - The Psychology of Epochs. PMID- 28907602 TI - Crime, Education, and Insanity. PMID- 28907601 TI - Additional Notes on Provincial Asylums for the Insane in France; with a Brief Report of the Institution at Illnau, in the Grand Duchy of Baden. PMID- 28907603 TI - List of Counsel and Witnesses. PMID- 28907604 TI - Medical Evidence in Support of the Commission. PMID- 28907605 TI - Third Examination of Mrs. Cumming by the Commissioner. January 23rd. PMID- 28907606 TI - First Examination of Mrs. Cumming by the Commissioner. January 13th, 1852. PMID- 28907607 TI - Second Examination of Mrs. Cumming. On the 9th Day-January 16th. PMID- 28907608 TI - General Evidence on Behalf of Mrs. Cumming. PMID- 28907609 TI - The Commissioner's Summing-Up, and the Verdict. PMID- 28907610 TI - The Case of Mrs. Catherine Cumming. PMID- 28907611 TI - Subsequent Proceedings before the Lord Chancellor and the Lords Justices of Appeal. PMID- 28907612 TI - The Charge of Mr. Commissioner Barlow. PMID- 28907613 TI - On the Unconscious Life of the Soul. PMID- 28907614 TI - On the Nature of Volition: Part II. PMID- 28907615 TI - On Cooling of the Body after Death. PMID- 28907616 TI - Dangerous Classes. PMID- 28907617 TI - Literary Retrospect. PMID- 28907618 TI - Morell's Inductive Mental Philosophy. PMID- 28907619 TI - On Morbid Impulse. PMID- 28907620 TI - Gossip. PMID- 28907621 TI - On a New Theory of Vision. PMID- 28907622 TI - The Sickness and Mortality of the Federal Volunteers. PMID- 28907623 TI - Free Trade in Medicine. PMID- 28907625 TI - Gratuitous Medical Services. PMID- 28907624 TI - Medical Certificates in Lunacy. PMID- 28907627 TI - The State of Lunacy in Scotland. PMID- 28907626 TI - Mania Ephemera. PMID- 28907628 TI - On Mental and Physical Life in Relation to Time: Part II. PMID- 28907629 TI - Observations on Some of the Operations of the Human Understanding. PMID- 28907630 TI - On "Spiritualism" as a Cause of Insanity. PMID- 28907632 TI - The Discovery and Discoverer of Etherization. PMID- 28907631 TI - Ghosts, Patent and Prescriptive. PMID- 28907633 TI - Sensation Novels. PMID- 28907634 TI - Gossip. PMID- 28907635 TI - Comparative Medicine. PMID- 28907636 TI - Literary Retrospect. PMID- 28907637 TI - Physiognomy of the Insane. PMID- 28907638 TI - On the Law of Certainty. PMID- 28907639 TI - On a Peculiar Form of Mental Alienation, Caused by the Political and Social Disturbances in France, during 1848. PMID- 28907640 TI - Scutari-March, 1863. PMID- 28907641 TI - On Partial Responsibility in Lunacy and Nervous Disorders. PMID- 28907642 TI - The Dublin School of Surgery. PMID- 28907643 TI - The Times on the Insanity of George III. PMID- 28907645 TI - Literary Retrospect. PMID- 28907644 TI - The British Medical Association. PMID- 28907646 TI - The State of Lunacy in England. PMID- 28907647 TI - The State of Lunacy in Ireland. PMID- 28907648 TI - Libertinage. PMID- 28907649 TI - Gossip. PMID- 28907650 TI - Murchison on Fever. PMID- 28907651 TI - On the Legal Responsibility of Pregnant Women. PMID- 28907652 TI - Baits for Suicide.-"Lady Audley's Secret" and "Aurora Floyd". PMID- 28907653 TI - The Sanitary State of the Army in India. PMID- 28907655 TI - Medico-Legal Trials in Lunacy: The Bridport Murder. PMID- 28907654 TI - On the Diagnosis and Treatment of Morbid Impulse. PMID- 28907657 TI - Erratum: Addendum to the New Theory of Vision. AB - [This corrects the article on p. 92 in vol. 3.]. PMID- 28907656 TI - The Influence of Material Objects upon the Mind. PMID- 28907658 TI - Lunacy on the Stock Exchange. PMID- 28907659 TI - Hypochondriasis. PMID- 28907660 TI - A Rare Case of Mania. PMID- 28907661 TI - The Cotton Famine. PMID- 28907662 TI - American Asylums for the Insane. PMID- 28907663 TI - Sanitary Instruction for the Masses. PMID- 28907664 TI - Autobiography of the Insane. PMID- 28907666 TI - St. Thomas's and Bethlem Hospitals. PMID- 28907665 TI - On Mental and Physical Life in Relation to Time. PMID- 28907667 TI - The Insane in France. PMID- 28907668 TI - Phrenology and Character. PMID- 28907670 TI - The Medical Evidence of Crime. PMID- 28907669 TI - The Diet of the Insane. PMID- 28907672 TI - Medical Gossip. PMID- 28907671 TI - On the Nature of Volition: Part III. PMID- 28907673 TI - On Hallucinations in Insanity. PMID- 28907674 TI - The Health of the Royal Navy. PMID- 28907675 TI - The International Exhibition. PMID- 28907676 TI - Pathological Description of Continued, Remittent, and Intermittent Drunkenness. PMID- 28907677 TI - Romantic Psychology: A Strange Story and Elsie Venner. PMID- 28907678 TI - Counter Practice. PMID- 28907679 TI - Colonisation of Lunatics by the Legislature. PMID- 28907680 TI - Quarterly Retrospect. PMID- 28907682 TI - The Debateable Land in Psychology. PMID- 28907681 TI - Literary Gossip and Record: The Antiquity of Plague. PMID- 28907684 TI - The State of Lunacy in Ireland. PMID- 28907683 TI - The Windham Case. PMID- 28907685 TI - Micropsychology. PMID- 28907686 TI - On Hallucinations in Their Relation to Medical Jurisprudence. PMID- 28907687 TI - The Medical Council. PMID- 28907688 TI - The Street Folk. PMID- 28907689 TI - Medical Gossip. PMID- 28907691 TI - The Report of the Social Science Association Committee on Quarantine. PMID- 28907690 TI - A Recent Visit to Gheel. PMID- 28907693 TI - Literary Gossip and Record. PMID- 28907692 TI - Quarterly Retrospect. PMID- 28907694 TI - The New Educational Minute. PMID- 28907695 TI - Periodicity. PMID- 28907697 TI - Dream-Thought and Dream-Life. PMID- 28907696 TI - On Instinct and Reason; or, the Intellectual Difference between Man and Animals. PMID- 28907698 TI - Quarterly Retrospect. PMID- 28907699 TI - The Province of Psychology. PMID- 28907701 TI - Literary Gossip and Record. PMID- 28907700 TI - The Unity of the Human Species. PMID- 28907702 TI - Earl Stanhope's Account of the Mental Malady of George III. PMID- 28907703 TI - The Legal Doctrine of "Fact" in Lunacy, and the Case of George Clark. PMID- 28907705 TI - Slow and Secret Poisoning. PMID- 28907704 TI - Erratum: Note on Quarantine. AB - [This corrects the article on p. 86 in vol. 2.]. PMID- 28907706 TI - The Health of the Army, Prospective and Retrospective. PMID- 28907707 TI - On Hallucinations in Insanity. PMID- 28907709 TI - Parochial Lunacy Reform in Scotland. PMID- 28907708 TI - Medical Gossip. PMID- 28907710 TI - The "AEsthetics of Suicide." PMID- 28907711 TI - On Mental Suggestion, Association, and Reproduction. PMID- 28907712 TI - The Sanitary Condition of the United States Volunteers. PMID- 28907714 TI - Noxious Vapours. PMID- 28907713 TI - On the Nature of Volition, Psychologically and Physiologically Considered: Part I. PMID- 28907715 TI - Literary Gossip and Record. PMID- 28907716 TI - Medical Gossip. PMID- 28907717 TI - The Outbreak of Smallpox among Sheep in Wiltshire. PMID- 28907718 TI - English Suicide-Fields, and the Restraint of Suicide. PMID- 28907720 TI - The State of Lunacy in Great Britain. PMID- 28907719 TI - Proposed Reforms in the French Metropolitan Asylums. PMID- 28907722 TI - Anthropophagy. PMID- 28907721 TI - Quarterly Retrospect. PMID- 28907723 TI - On the Moral Phenomena of Insanity and Eccentricity. PMID- 28907724 TI - Cellular Pathology. PMID- 28907725 TI - Professional Tricksters. PMID- 28907726 TI - Cottage Asylums. PMID- 28907727 TI - Quarterly Retrospect. PMID- 28907728 TI - Quarantine and the Spread of Epidemic Diseases. PMID- 28907729 TI - Special Hospitals. PMID- 28907730 TI - Literary Gossip and Record. PMID- 28907731 TI - Medical Gossip. PMID- 28907732 TI - Physiology and Legislation. PMID- 28907733 TI - Modern Surgery. PMID- 28907734 TI - Honoraria. PMID- 28907735 TI - Metanoia:-A Plea for the Insane. PMID- 28907736 TI - The Deformed and Their Mental Characteristics. PMID- 28907737 TI - The "Art of Rising" in Physic. PMID- 28907738 TI - The Classic Land of Suicide. PMID- 28907739 TI - On the Structure of the Inductive Syllogism and Its Correlation to the Deductive. PMID- 28907741 TI - Reason, Genius, and Madness. PMID- 28907740 TI - Miscellanea Medica. PMID- 28907743 TI - Medical Gossip. PMID- 28907742 TI - Medico-Legal Studies on the Perversion of the Moral and Affective Faculties in the Precursory Period of General Paralysis. PMID- 28907744 TI - Maternal Love in Nature. PMID- 28907746 TI - The Wear and Tear of Medical Life. PMID- 28907745 TI - Quarterly Retrospect. PMID- 28907747 TI - Criminal Lunatics. PMID- 28907748 TI - On the Exposition of the Principles and Details of the Syllogism. PMID- 28907749 TI - Specialists and Specialities. PMID- 28907750 TI - Medical Evidence:-The Colney Hatch Case. PMID- 28907751 TI - Medical Observation.-Diphtheria. PMID- 28907752 TI - The Marvellous. PMID- 28907753 TI - On "Non-Restraint," in the Treatment of the Insane, and the Increase of Lunatics. PMID- 28907754 TI - Female Physicians. PMID- 28907755 TI - The Case of the Egyptian Frigate at Liverpool, with Remarks on the Causation of Fevers, &c. PMID- 28907756 TI - On Hallucinations in Their Relation to Medical Jurisprudence. PMID- 28907757 TI - The Study of Medicine. PMID- 28907758 TI - Unrecognised Insanity. PMID- 28907759 TI - Literary Gossip and Record. PMID- 28907760 TI - Medical Students:-A New Generation. PMID- 28907762 TI - Swedenborg's Dreams. PMID- 28907761 TI - Quarterly Retrospect. PMID- 28907763 TI - Medical Gossip. PMID- 28907764 TI - On the Educational Treatment of Cretinism. PMID- 28907765 TI - The State of Lunacy in England. PMID- 28907766 TI - Orientalism. PMID- 28907767 TI - The AEsthetics of Suicide. PMID- 28907768 TI - The Medical Profession of Scotland, and the Lunacy Act of That Kingdom. PMID- 28907769 TI - Who Is a Doctor? PMID- 28907770 TI - The Amenities of Statistics. PMID- 28907771 TI - The Great Arcanum:-The Turkish Bath. PMID- 28907772 TI - Miscellanea Medica. PMID- 28907774 TI - The Vacation. PMID- 28907773 TI - The State of Lunacy in Scotland. PMID- 28907775 TI - On the Distinction between Analytical and Synthetical Judgments. PMID- 28907776 TI - Cottage Asylums:-A Sequel. PMID- 28907777 TI - The Gheel Question. PMID- 28907778 TI - Literary Gossip and Record. PMID- 28907779 TI - Three Thousand a Year:-A Soliloquy. PMID- 28907781 TI - The Road Murder Psychologically Considered. PMID- 28907780 TI - Quarterly Retrospect. PMID- 28907782 TI - Medical Gossip. PMID- 28907783 TI - Eunuchs Do Not Take the Gout. PMID- 28907784 TI - Visiting Professors. PMID- 28907785 TI - Modern Trends in Public Health. PMID- 28907786 TI - Student Apprenticeship to General Practitioners. PMID- 28907787 TI - Domenique Jean Larrey, 1766-1842. PMID- 28907788 TI - Visit to Iraq and Turkey. PMID- 28907789 TI - News from Societies. PMID- 28907790 TI - Islet Cell Tumour of the Pancreas: Clinical Pathological Conference. PMID- 28907791 TI - News from Societies. PMID- 28907792 TI - Medicine at Home and Abroad. PMID- 28907793 TI - Foreword. PMID- 28907794 TI - Marasmus. PMID- 28907795 TI - Underwater Breathing. PMID- 28907796 TI - The Elderly Chronic Sick. PMID- 28907797 TI - Colonial Medical Research. PMID- 28907798 TI - Mongolism, Hypertrophic Pyloric Stenosis Treated with "Skopyl" and Death from Miliary Tuberculosis and Meningitis. PMID- 28907799 TI - Changes in the Editorial Committee. PMID- 28907800 TI - Damned Drugs (Part I): The Presidential Address, Given at the Royal Fort, Bristol, on 8th October, 1952 at the Opening of the Seventy-Fourth Session of the Bristol Medico-Chirurgical Society. PMID- 28907802 TI - Respirator Research at Ham Green Hospital. PMID- 28907801 TI - A Radiologist Visits Africa. PMID- 28907803 TI - The Tropics on Our Doorstep. PMID- 28907804 TI - Practical Points in the Home Treatment of Tuberculosis. PMID- 28907805 TI - A Morbid View of the over-65's. PMID- 28907807 TI - Maternal Death Due to Rheumatic Heart Disease: Clinical Pathological Conference. PMID- 28907806 TI - Vital Statistics of the South-West in 1954. PMID- 28907808 TI - Perspective in Paediatrics. PMID- 28907810 TI - Statutory or Voluntary. PMID- 28907809 TI - The Position of Nursing in Hospitals in Bristol. PMID- 28907811 TI - The New Outlook in Oto-Laryngology. PMID- 28907812 TI - News from Societies. PMID- 28907813 TI - Paediatric Comment. PMID- 28907814 TI - Annotations. PMID- 28907815 TI - Colloid Cyst of 3rd Ventricle : Clinico-Pathological Conference. PMID- 28907816 TI - General Practice. PMID- 28907817 TI - Some New Methods of Radiotherapy. PMID- 28907818 TI - Cat-Scratch Disease. PMID- 28907819 TI - News from Societies. PMID- 28907820 TI - Memorial to the Late Dr. Norman Lloyd Price. PMID- 28907821 TI - Damned Drugs (Part II): Inaugural Presidential Address: Given at the Royal Fort, Bristol, on 8th October, 1952. PMID- 28907822 TI - Domestic Deaths from Electrocution. PMID- 28907823 TI - Medical Worthies of the West Country. PMID- 28907824 TI - The Growth of Human Tumours in Laboratory Animals: A New Approach to the Assay of Anti-Carcinogens. PMID- 28907825 TI - Space Medicine. PMID- 28907826 TI - Generalized Osteitis Fibrosa with Parathyroid Adenoma: Clinical Pathological Conference. PMID- 28907828 TI - News from Societies. PMID- 28907827 TI - Hypercalcaemia with Hypocalcuria, an Unusual Case of Primary Hyperparathyroidism. PMID- 28907829 TI - College of General Practitioners: South Western Regional Faculty. PMID- 28907830 TI - Phaeochromocytoma of Adrenal Gland with Paroxysmal Hypertension. PMID- 28907831 TI - Correspondence. PMID- 28907832 TI - Miss Nott of St. Brenda's. PMID- 28907833 TI - Herpes Zoster Generalisatus. PMID- 28907834 TI - Observations on Blindness: The Presidential Address, Delivered on Wednesday, 14th October, 1953, at the Opening of the Seventy-Fifth Session of the British Medico Chirurgical Society. PMID- 28907835 TI - Neurosurgical Unit, Frenchay. PMID- 28907836 TI - Diffuse Angiomatosis of the Small Intestine Causing Melaena. PMID- 28907837 TI - Casualty Officers. PMID- 28907838 TI - Herpes Zoster Encephalitis: In Association with the Ramsay Hunt Syndrome. PMID- 28907839 TI - Mortimer House, Clifton. PMID- 28907840 TI - Home Care of the Diabetic. PMID- 28907841 TI - That Backbone: The Presidential Address, Delivered on Wednesday, 13th October, 1954, at the Seventy-Sixth Session of the Bristol Medico-Chirurgical Society. PMID- 28907843 TI - News from Societies. PMID- 28907842 TI - The Changing Pattern of Pulmonary Tuberculosis. PMID- 28907844 TI - Haemorrhage from a Cavernous Haemangioma of the Cord Clinically Resembling an Ascending Myelitis: A Clinical Pathological Conference of the University of Bristol Medical School. PMID- 28907846 TI - Annotations. PMID- 28907845 TI - Child Life in past Times. PMID- 28907848 TI - Dr. Robert Hughes Parry. PMID- 28907847 TI - The General and the Special in Medical Practice. PMID- 28907849 TI - Telling the Public about Medicine. PMID- 28907851 TI - Caleb Parry of Bath: The Bi-Centenary of a Great West Country Physician. PMID- 28907850 TI - Congenital Bladder-Neck Obstruction. PMID- 28907852 TI - Primary Myelosclerosis with Leuco-Erythroblastic Anaemia: Clinical Pathological Conference. PMID- 28907854 TI - News from Societies. PMID- 28907853 TI - Cancer of the Uterus. PMID- 28907855 TI - Casualty Departments. PMID- 28907856 TI - What the G.P. Wants from a Casualty Department. PMID- 28907857 TI - Cousin Marriage: Forty-Second Long Fox Memorial Lecture Delivered on 20th October, 1953. PMID- 28907858 TI - Meningitis. PMID- 28907859 TI - Case Report-Jaundice with Hepatic Failure: A Case Illustrating Diagnostic Problems: A Clinico-Pathological Conference of the University of Bristol Medical School. PMID- 28907860 TI - Editorial. PMID- 28907861 TI - Meningitis in Childhood: Purulent and Tuberculous Infections. PMID- 28907862 TI - Disgraceful "Ladies". PMID- 28907864 TI - Diabetes Mellitus with Renal Papillary Necrosis: Clinical Pathological Conference. PMID- 28907863 TI - The Use and Misuse of Sedatives and Hypnotic Drugs. PMID- 28907865 TI - The Public Analyst and the New Food and Drugs Act (1955). PMID- 28907866 TI - A Doctor's Visit to U.S.S.R. PMID- 28907867 TI - Perinatal Mortality. PMID- 28907868 TI - Modern Developments in Peripheral Vascular Surgery. PMID- 28907869 TI - The Investigation of Persistent Diarrhoea. PMID- 28907870 TI - An Exhibition of Important Anatomical Books. PMID- 28907872 TI - News from Societies. PMID- 28907871 TI - Hereditary Telangiectasia: Hodgkin's Disease: Clinical Pathological Conference. PMID- 28907873 TI - Editorial. PMID- 28907874 TI - Hospital Cross-Infection. PMID- 28907875 TI - Memingococcal Septicaemia with Bilateral Adrenal Haemorrhage (Waterhouse Friderichsen Syndrome): Clinical Pathological Conference. PMID- 28907876 TI - On Growing Old. PMID- 28907878 TI - Some Notes of a Medical Visitor to the British West Indies. PMID- 28907877 TI - The Port Health Service. PMID- 28907879 TI - From Blue to Pink. PMID- 28907880 TI - The Symptoms and Treatment of Acute Follicular Tonsillitis. PMID- 28907881 TI - Astrocytoma Treated by Radiotherapy: Death from Acute Leukaemia: Clinical Pathological Conference. PMID- 28907882 TI - Correspondence. PMID- 28907883 TI - Some Thoughts of Medical Education: Presidential Address Delivered to the Bristol Medico-Chirurgical Society 9th October, 1957. PMID- 28907884 TI - Foreword. PMID- 28907886 TI - The Medical Library of the University of Bristol. PMID- 28907885 TI - Kyphoscoliosis with Pulmonary Hypertension: Clinical Pathological Conference. PMID- 28907888 TI - Medical Education. PMID- 28907887 TI - Carcinoma of the Thyroid: A Review of 100 Cases. PMID- 28907889 TI - Erratum: Apology. AB - [This corrects the article on p. 22 in vol. 73.]. PMID- 28907890 TI - Accidental Poisoning with the Antihistamine Drug "Histantin": Clinical Pathological Conference. PMID- 28907891 TI - Pain Related to the Teeth and Jaws. PMID- 28907892 TI - Diseases in Search of Viruses. PMID- 28907894 TI - The Prevention of Acute Rheumatism. PMID- 28907893 TI - Supportive Treatment of Acute Cor Pulmonale Due to Massive Pulmonary Embolism. PMID- 28907895 TI - A Tour of the South-Western Pacific. PMID- 28907897 TI - Sarcoidosis Treated with Cortisone: Clinical Pathological Conference. PMID- 28907896 TI - Bristol and Bordeaux. PMID- 28907898 TI - Head Injuries. PMID- 28907899 TI - Child Art. PMID- 28907900 TI - Acute Necrosis of the Liver in Pregnancy: Clinical Pathological Conference. PMID- 28907902 TI - Clinical Pathology and General Practice. PMID- 28907901 TI - Towards Better Health at Work. PMID- 28907903 TI - News from Societies. PMID- 28907904 TI - News from Societies. PMID- 28907905 TI - Cardiac Ischaemia. PMID- 28907906 TI - Post-Partum Necrosis of the Pituitary: Clinical Pathological Conference. PMID- 28907907 TI - A Pathologist's Survey of Superficial Tumors Removed in a Casualty Department. PMID- 28907908 TI - Baby Farming in England. PMID- 28907910 TI - Ignaz Philipp Semmelweis and His Times. PMID- 28907909 TI - The Use of an Animal Lung as Oxygenator in a Heart-Lung Machine. PMID- 28907911 TI - Renal Complications of Diabetes Mellitus: A Clinical Pathological Conference of the University of Bristol Medical School (P.M. 6169). PMID- 28907913 TI - Aplastic Anaemia with Post-Transfusional Haemosiderosis: Clinical Pathological Conference. PMID- 28907912 TI - Domestic Hazards with Neurological Significance. PMID- 28907914 TI - Transporting Severely Paralysed Patients. PMID- 28907915 TI - Squint. PMID- 28907916 TI - A Review of Acute Intestinal Obstruction. PMID- 28907917 TI - Unusual Type of Bacterial Endocarditis in a Case of Myocardial Infarction: Clinico-Pathological Conference. PMID- 28907918 TI - News from the Societies. PMID- 28907919 TI - A Case of Unilateral Involuntary Movements Treated with Procaine Amide. PMID- 28907920 TI - Some Lesser-Known Activities of the General Medical Council. PMID- 28907921 TI - Reflections on the Indications for Prostatectomy. PMID- 28907922 TI - A Coagulation Defect in Amyloidosis. PMID- 28907924 TI - News from Societies. PMID- 28907923 TI - Lung Cancer-A Symposium. PMID- 28907925 TI - Alveolar Cell Carcinoma of Lung: Clinical Pathological Conference. PMID- 28907926 TI - Decay of the Teeth. PMID- 28907927 TI - The Evolution of Paediatrics. PMID- 28907928 TI - A Case of Meningeal Carcinomatis: Clinical Pathological Conference. PMID- 28907929 TI - Clinical Genetics and the Practitioner. PMID- 28907930 TI - Pain. PMID- 28907931 TI - News from Societies. PMID- 28907932 TI - Diseases Due to Medical Treatment. PMID- 28907933 TI - Chronic Osteomyelitis with Maturation Arrest of Granulocytes: Clinical Pathological Conference. PMID- 28907934 TI - Restorative Resection of the Rectum-Its History and Present Status. PMID- 28907935 TI - Research on Rheumatic Diseases. PMID- 28907936 TI - The Geriatric Service. PMID- 28907937 TI - Fungus Infections of the Skin in Bristol and the West Country. PMID- 28907938 TI - News from the Societies. PMID- 28907939 TI - Ankylosing Spondylitis with Mitral Stenosis: Clinico-Pathological Conference. PMID- 28907940 TI - The University and the Medical School. PMID- 28907942 TI - Management of Sepsis. PMID- 28907941 TI - X-Rays in Everyday Life: Long Fox Memorial Lecture-13th October 1959. PMID- 28907943 TI - Nephrotic Syndrome with Steatorrhoea: Clinical Pathological Conference. PMID- 28907944 TI - Mountains. PMID- 28907945 TI - Clonorchiasis: Clinical Pathological Conference. PMID- 28907946 TI - The Unstable Cervical Disc. PMID- 28907947 TI - The Skeleton in the Pit. PMID- 28907948 TI - Cave Rescue: Edward Long Fox Memorial Lecture 1960. PMID- 28907949 TI - Subarachnoid Haemorrhage: Early Assessment in a General Hospital. PMID- 28907950 TI - Acute Encephalitis: Clinico-Pathological Conference. PMID- 28907952 TI - The Elimination of Piltdown Man. PMID- 28907951 TI - Programmes of Medical Societies. PMID- 28907953 TI - Recent Work on the Demyelinating Diseases. PMID- 28907954 TI - Prolonged Coma in Barbiturate Poisoning. PMID- 28907955 TI - Recent Developments in Cardiac Surgery. PMID- 28907956 TI - Herpes Zoster with Chicken-Pox and Lymphosarcoma: Clinical Pathological Conference. PMID- 28907957 TI - Open Cardiac Surgery during Profound Hypothermia: A Report of an Early Operation in Bristol. PMID- 28907958 TI - Malignant Ependymoma Masquerading as Tuberculous Meningitis: Clinico-Pathological Conference. PMID- 28907959 TI - The Fascial Flap Operation for Inguinal Hernia. PMID- 28907960 TI - Tranquillizers. PMID- 28907961 TI - Disease of Major Cerebral Vessels. PMID- 28907962 TI - News from the Societies. PMID- 28907963 TI - What 'Little Hans' Started. PMID- 28907964 TI - Soothing Sounds for Crying Babies. PMID- 28907965 TI - Schooling the Disturbed Child. PMID- 28907966 TI - Through the Office Door. PMID- 28907967 TI - Do We Need Psychiatric Hospitals? PMID- 28907969 TI - Foster Care. PMID- 28907968 TI - Scene 2-Take 2: Abandoned & Forgotten. PMID- 28907971 TI - Child Guidance: Ideology and Institution or Ideal? PMID- 28907972 TI - School in the Round. PMID- 28907970 TI - Work and the ESN School-Leaver. PMID- 28907975 TI - General Secretary's Letter. PMID- 28907974 TI - Scene 1-News. PMID- 28907973 TI - The Visit. PMID- 28907976 TI - The Quality of Communication. PMID- 28907977 TI - The Clinics: Recommendations and Reality. PMID- 28907978 TI - Living with the Normal. PMID- 28907979 TI - All I Remember. PMID- 28907980 TI - Family of the Handicapped. PMID- 28907981 TI - Scene 2. PMID- 28907983 TI - Don't Shoot the Relative. PMID- 28907982 TI - The Lower Depths. PMID- 28907984 TI - Say 'Hello' to Christine. PMID- 28907985 TI - Coloured Family + White World = Stress. PMID- 28907986 TI - Scene 1. PMID- 28907987 TI - Parents on a Limb. PMID- 28907988 TI - Marriage at Risk. PMID- 28907989 TI - What's Best for Grandma? PMID- 28907990 TI - Phenylketonuria. PMID- 28907991 TI - Give Us a Chance, Matron. PMID- 28907992 TI - What Is a Psychopath? PMID- 28907993 TI - Money for Good Behaviour. PMID- 28907994 TI - Design for Play. PMID- 28907995 TI - Scene 2-Take 1: South Ockendon. PMID- 28907996 TI - The Twisted Nerve. PMID- 28907997 TI - New Cogs for Old. PMID- 28907998 TI - Scene 1-News. PMID- 28907999 TI - The Usurped Personality. PMID- 28908000 TI - A Position of Choice. PMID- 28908001 TI - Editorial: Ely-Shuffling the Money Around. PMID- 28908002 TI - Impressions of Hospitals. PMID- 28908003 TI - Unwillingly to the Scrap Heap. PMID- 28908004 TI - Back on the Market. PMID- 28908005 TI - Put Away. PMID- 28908006 TI - Clergy and Community Care. PMID- 28908007 TI - A Better Frame of Mind. PMID- 28908008 TI - Platform-Open Door Dilemma. PMID- 28908009 TI - Learning Not to Bet. PMID- 28908010 TI - New Scope for Industrial Therapy. PMID- 28908011 TI - A Place in the Family. PMID- 28908012 TI - Secret Ceremony. PMID- 28908013 TI - A Very Vulnerable Child. PMID- 28908014 TI - Student Casualties. PMID- 28908015 TI - Taking the Final Risk. PMID- 28908016 TI - The Scene. PMID- 28908017 TI - The Gamblers. PMID- 28908018 TI - Not so Idyllic. PMID- 28908020 TI - The Mental Health Service in 1954. PMID- 28908019 TI - Brotherhood of Self-Criticism. PMID- 28908021 TI - Notes and News. PMID- 28908022 TI - The Psychological Aspects of Backwardness. PMID- 28908024 TI - Inside Mental Hospitals. PMID- 28908023 TI - Starting School. PMID- 28908025 TI - Treatment by Self Expression. PMID- 28908027 TI - Treatment by Self-Expression. PMID- 28908026 TI - An Investigation into the Cinematograph and Deterioration in Behaviour. PMID- 28908029 TI - Sterilisation of Mental Defectives. PMID- 28908028 TI - Bibliotherapy. PMID- 28908031 TI - Notes and News. PMID- 28908030 TI - Group Therapy with Mental Defectives. PMID- 28908032 TI - Development of a Geriatric Club Attached to a Mental Hospital. PMID- 28908033 TI - The Maladjusted Child and Child Guidance Clinics. PMID- 28908034 TI - Psycho-Therapy in a Child Guidance Clinic. PMID- 28908035 TI - Istanbul, August 1955: Eighth Annual Meeting of the World Federation for Mental Health. PMID- 28908036 TI - Friends of Mental Deficiency Hospitals. PMID- 28908037 TI - Harmful Certification? PMID- 28908038 TI - An Investigation into the Cinematograph and Deterioration in Behaviour. PMID- 28908039 TI - Propaganda: Its Psychological Aspect. PMID- 28908040 TI - Sterilisation of Mental Defectives. PMID- 28908042 TI - Eviction and the Children. PMID- 28908041 TI - A Rehabilitation Programme for Certified Mental Defectives. PMID- 28908043 TI - The Toronto Conference. PMID- 28908044 TI - The Mental Hospital and the Alcoholic. PMID- 28908045 TI - Erratum. AB - [This corrects the article on p. 98 in vol. 13.]. PMID- 28908046 TI - Menopause: Normal or Abnormal. PMID- 28908047 TI - Letter to the Editor. PMID- 28908048 TI - An Experiment in Psychiatric Follow-Up: Three Year Report from the York Clinic, Guy's Hospital, London. PMID- 28908049 TI - The Roots of Crime. PMID- 28908050 TI - Treatment of Alcoholics. PMID- 28908051 TI - An Investigation into the Cinematograph and Deterioration in Behaviour. PMID- 28908052 TI - Mind and Body. PMID- 28908053 TI - Mental Health in 1953. PMID- 28908054 TI - The Patron Saint of the Insane. PMID- 28908056 TI - A New Era. PMID- 28908055 TI - A New Advance in Mental Deficiency Nursing. PMID- 28908058 TI - The Mental Health Service in 1957: Some Facts and Figures. PMID- 28908057 TI - Approaching a Marriage Bureau. PMID- 28908059 TI - Effect of Children's Television on Behaviour. PMID- 28908060 TI - Letters to the Editor. PMID- 28908061 TI - Adler and His Psychology: Seen through His Early Memories. PMID- 28908062 TI - Religion and Medicine. PMID- 28908063 TI - The Hospitals as Part of the Mental Health Service. PMID- 28908064 TI - The Role of the Clinical Psychologist in a Mental Deficiency Hospital. PMID- 28908065 TI - The Mental Health Service in 1955. PMID- 28908066 TI - Enuresis-A Major Social Problem. PMID- 28908067 TI - Training of Mental Welfare Officers. PMID- 28908068 TI - An Inquiry into Health Visiting. PMID- 28908069 TI - The Mental Deficiency Services Today and Tomorrow. PMID- 28908070 TI - Psychological Aspects of Self-Government in the Residential Treatment of the Delinquent Child and Adolescent. PMID- 28908071 TI - The Day to Day Management of the Mentally Handicapped Child in Its Own Home. PMID- 28908072 TI - Marriage and Divorce. PMID- 28908073 TI - Erratum: The Moon Is Full. AB - [This corrects the article on p. 36 in vol. 17.]. PMID- 28908074 TI - The Mental Health Services in 1956. PMID- 28908075 TI - Voluntary Patients in Mental Deficiency Hospitals. PMID- 28908076 TI - Psychological Methods in Psychiatric Diagnosis: The Clinical Study of Cognitive Functioning. PMID- 28908077 TI - The Effect of Children's Television on Behaviour. PMID- 28908078 TI - Letters to the Editor. PMID- 28908079 TI - Suicide: Threatened and Attempted. PMID- 28908080 TI - Neglected Fathers. PMID- 28908081 TI - Letters to the Editor. PMID- 28908083 TI - The Worthing Experiment. PMID- 28908082 TI - Letters to the Editor. PMID- 28908084 TI - Psychological Methods in Psychiatric Diagnosis: The Clinical Use of Projective Techniques. PMID- 28908085 TI - Religion and Healing. PMID- 28908086 TI - Letter to the Editor. PMID- 28908088 TI - Debate in the House of Lords. PMID- 28908087 TI - Mental Disorder in the Defective under Community Care. PMID- 28908089 TI - The Wolfenden Report. PMID- 28908091 TI - A Musical Experiment with Maladjusted Children. PMID- 28908090 TI - Music in the Treatment of Mental Illness. PMID- 28908092 TI - In Copenhagen: Some Points from Addresses Given during Meetings of the World Federation and the European League for Mental Hygiene, August 1957. PMID- 28908093 TI - Letter to Editor. PMID- 28908094 TI - On Having a Baby. PMID- 28908095 TI - Montessori in Britain: Fiftieth Anniversary of Dr. Montessori's First School. PMID- 28908096 TI - Music in the Training of Mental Defectives. PMID- 28908097 TI - The Royal Commission on Law Relating to Mental Illness and Mental Deficiency. Some Points from Its Report. PMID- 28908098 TI - Correspondence. PMID- 28908099 TI - The Ideas of the Television Public about Mental Illness. PMID- 28908100 TI - The Draw a Person Test in Mental Defectives. PMID- 28908101 TI - The Hospitals as Part of the Mental Health Service. PMID- 28908102 TI - Courage and Vision. PMID- 28908103 TI - Adoption: A Study of the Problems Involved in Child Guidance Cases, from the View Point of a Psychiatric Social Worker. PMID- 28908104 TI - Criminal Responsibility. PMID- 28908106 TI - Some Psychological and Spiritual Aspects of Acute Anterior Poliomyelitis. PMID- 28908105 TI - Children in Hospitals. PMID- 28908107 TI - Half-Way Houses. PMID- 28908108 TI - Case History of a Mental Defective. PMID- 28908109 TI - Memorandum on Young M.D. Children. PMID- 28908110 TI - Race and Prejudice. PMID- 28908111 TI - "Rationalization" and Mental Hygiene. PMID- 28908113 TI - Scandinavians in Britain. PMID- 28908112 TI - Community Participation in the Mental Hospital : An Account of the Work of a Voluntary Auxiliary Committee in a Mental Hospital. PMID- 28908114 TI - Mental Deficiency in 1949. PMID- 28908115 TI - Diversional Educational Activities in a Mental Hospital. PMID- 28908116 TI - National Association of Authorised Officers. PMID- 28908118 TI - Letters to the Editor. PMID- 28908117 TI - Maternal Care and Mental Health. PMID- 28908119 TI - Factory Doctors and Mental Hygiene. PMID- 28908121 TI - Methods of Dealing with Young M.D. Children. PMID- 28908120 TI - The Problem Epileptic. PMID- 28908122 TI - Diversional Educational Activities in a Mental Hospital. PMID- 28908123 TI - Correspondence. PMID- 28908124 TI - Preventive Psychiatry in Industry. PMID- 28908125 TI - The Nursing of the Deteriorated Patient. PMID- 28908126 TI - European Committee for Mental Hygiene. Seventh Conference. PMID- 28908128 TI - The Mentally Defective Child at Home. PMID- 28908127 TI - Building a University Psychological Service: The First Three Years. PMID- 28908129 TI - Emotional Dangers to Children in Hospitals. PMID- 28908131 TI - The Communication of Ideas. PMID- 28908130 TI - Practical Aspects of Alcoholism. PMID- 28908132 TI - Film Review. PMID- 28908133 TI - The Work of a Family Casework Agency. PMID- 28908134 TI - Children without Genealogy-A Problem of Adoption. PMID- 28908135 TI - World Federation for Mental Health, Brussels, 1952. PMID- 28908136 TI - The Education and Training of Mental Defectives at Darenth. PMID- 28908138 TI - The Mental Health Services in 1951: Recent Statistics. PMID- 28908137 TI - Intelligence and Modern Social Trends. PMID- 28908140 TI - Social Workers in Contact. PMID- 28908139 TI - Psychiatry and the Community, II: An Experiment in Mental Health Education. PMID- 28908141 TI - Popular Psychology. PMID- 28908143 TI - Mental Deficiency as a Basic Discipline in the Training of a Psychiatrist. PMID- 28908142 TI - Psychiatry and the Community. Part I: An Experiment in Mental Health Education. PMID- 28908144 TI - Problems of Families with Epileptic Children. PMID- 28908145 TI - Vacation Students in a Mental Hospital. PMID- 28908146 TI - Letters to the Editor. PMID- 28908147 TI - Reform of the Law. PMID- 28908148 TI - Psychiatric Social Work in a Mental Hospital. PMID- 28908149 TI - Movement and Rhythm in Remedial Education. PMID- 28908151 TI - The Art of Being a Father. PMID- 28908150 TI - A System of Daily Licence in a Colony for Mental Defectives. PMID- 28908153 TI - The Church and Mental Health. PMID- 28908152 TI - Fathercraft. PMID- 28908154 TI - The Work of a Mental Deficiency Colony. PMID- 28908155 TI - Mental Health and Ill-Health: Relief of Strain and Stress Conditions. PMID- 28908157 TI - Questionnaire on "Mental Health": Note by the Editor. PMID- 28908156 TI - Music and Mental Health. PMID- 28908158 TI - Mental Health Services, 1952. PMID- 28908159 TI - Friendship and Mental Health. PMID- 28908160 TI - "Mental Deficiency": A Misnomer? PMID- 28908162 TI - The Probation Officer. PMID- 28908161 TI - Letters to the Editor. PMID- 28908163 TI - Individual Movement Therapy. PMID- 28908164 TI - The Speed of Living. PMID- 28908165 TI - Psychiatric Social Workers. PMID- 28908166 TI - Letters to the Editor. PMID- 28908167 TI - Their Own Orchestra. PMID- 28908168 TI - Correspondence. PMID- 28908170 TI - Mental Deficiency in 1947. PMID- 28908169 TI - Psychology and "Outworn Theology": To the Editor of Mental Health. PMID- 28908171 TI - Film Reviews. PMID- 28908172 TI - Maintenance of Mental Health.: 2. The First Five Years. PMID- 28908173 TI - The Personal Touch. PMID- 28908174 TI - The Effect of Rhythm and Functional Music on Mental Defectives. PMID- 28908175 TI - Training and Scope of Psychiatric Social Workers in Relation to Adults. PMID- 28908176 TI - Not like Other Children. PMID- 28908178 TI - Went the Day Well? PMID- 28908177 TI - Film Reviews. PMID- 28908179 TI - The International Congress on Mental Health: London, August 11th to 21st, 1948. PMID- 28908180 TI - Film Reviews. PMID- 28908181 TI - The Place of the Family. PMID- 28908182 TI - Erratum: The Mental Health Aspect of Public Health. AB - [This corrects the article on p. 24 in vol. 9.]. PMID- 28908183 TI - The Second World Mental Health Assembly. PMID- 28908184 TI - Maintenance of Mental Health.: 3. Going to School-The Second Five Years. PMID- 28908185 TI - The Re-Adjustment of the Hospital In-Patient. How the Nurse Can Help. PMID- 28908186 TI - Occupational and Physio-Therapy as Adjuncts to Child Guidance: A Suggestion for Designers of Child Guidance Clinics. PMID- 28908188 TI - The Prison Service in 1948. PMID- 28908187 TI - The Effect of Imprisonment on Mental Health. PMID- 28908189 TI - S.E.P.E.G. PMID- 28908191 TI - After-Care or Treatment? PMID- 28908190 TI - Regional Community Care. I. PMID- 28908193 TI - Film Review. PMID- 28908192 TI - The Handicap of High Intelligence. PMID- 28908194 TI - Training and Scope of the Psychiatric Social Worker in Relation to Adults. II. PMID- 28908196 TI - Editorial. PMID- 28908195 TI - Convalescence for the Elderly Patient. PMID- 28908197 TI - Mentally Defective Children with Additional Handicaps. PMID- 28908198 TI - The Place of the Mentally Handicapped Child in Society. PMID- 28908199 TI - The Child's Need for Identification. PMID- 28908200 TI - Backwardness in Speech Development. PMID- 28908201 TI - The Fourth Member of the Child Guidance Team. PMID- 28908203 TI - Editorial. PMID- 28908202 TI - The Progress of Mental Hospitals. II. PMID- 28908204 TI - Film Reviews. PMID- 28908205 TI - Northern Ireland's Mental Health Act. PMID- 28908206 TI - Inside the Mental Hospital. PMID- 28908207 TI - Film Review. PMID- 28908208 TI - Diversional and Educational Activities in a Mental Hospital: An Experiment. 1948 1950. PMID- 28908209 TI - The Re-Socialization of the Psychiatric Case. PMID- 28908210 TI - Erratum: An Apology. AB - [This corrects the article on p. 66 in vol. 10.][This corrects the article on p. 67 in vol. 10.]. PMID- 28908211 TI - Mental Hygiene Clinics in the United States. PMID- 28908212 TI - Maintenance of Mental Health.: 5. Adolescence. PMID- 28908213 TI - Lord Memorial Prize Essay: What Satisfaction Would Mental Nurses Gain from Exercising to the Full Their Personal Talents and Professional Skills? PMID- 28908215 TI - The National Assistance Board in Action. PMID- 28908214 TI - Occupational Therapy. PMID- 28908217 TI - Editorial. PMID- 28908216 TI - The Progress of Mental Hospitals. I. PMID- 28908218 TI - Juvenile Delinquency: Memorandum Issued by the Royal Medico Psychological Association. PMID- 28908220 TI - World Federation for Mental Health: Impressions of the Third Annual Meeting. PMID- 28908219 TI - A Colony for Maladjusted Children. PMID- 28908221 TI - Return from Holiday. PMID- 28908222 TI - Home Conditions and Employment of Mental Defectives. PMID- 28908224 TI - Social Workers in Paris, July 1950. PMID- 28908223 TI - The Psychiatrist's Dilemma. PMID- 28908225 TI - An Association of Patients. PMID- 28908227 TI - Portrait of Jane. PMID- 28908226 TI - Supplement: Report of Eighth Inter-Clinic Child Guidance Conference, December, 1949. PMID- 28908228 TI - Institutions for Defectives. PMID- 28908229 TI - Film Reviews. PMID- 28908230 TI - The Social Adaptation of Institution Children. PMID- 28908231 TI - Mental Hygiene as an Academic Discipline at the University of Basle. PMID- 28908232 TI - Morale and Mental Health in Modern Society. PMID- 28908233 TI - W.H.O. And Mental Health. PMID- 28908234 TI - An Educational Centre for Mentally Handicapped Children. PMID- 28908235 TI - Film Reviews. PMID- 28908236 TI - The Church and Mental Health. PMID- 28908237 TI - Mental Health and Education. PMID- 28908238 TI - The Mental Health Services in 1948. PMID- 28908239 TI - Maintenance of Mental Health.: 4. The School Years. PMID- 28908240 TI - The Colony and the Young High-Grade Mental Defective. PMID- 28908242 TI - Bread and Circuses. PMID- 28908241 TI - British National Conference on Social Work: Harrogate, April 1950. PMID- 28908243 TI - Erratum: Maternity in Great Britain. AB - [This corrects the article on p. 83 in vol. 8.]. PMID- 28908244 TI - The End of an Experiment in Community Care. PMID- 28908246 TI - Prevention and Early Treatment. PMID- 28908245 TI - "The Snake Pit": Featuring Olivia de Havilland and Leo Genn. PMID- 28908247 TI - Regional Community Care. II. PMID- 28908248 TI - The Mental Health Programme of the United States. PMID- 28908249 TI - General Secretary's Letter. PMID- 28908250 TI - Parliament, Press, Radio and Television. PMID- 28908251 TI - On Bringing up Other People's Children. PMID- 28908252 TI - The Elderly: "Living and Partly Living". PMID- 28908253 TI - Homes for Old People. PMID- 28908254 TI - Special Difficulties of Mental Welfare Officers with the Aged. PMID- 28908255 TI - Living with Leisure. PMID- 28908256 TI - Introducing N.A.M.H. Homes, Hostels & Schools 2: "Parnham". PMID- 28908258 TI - Discussion Points. PMID- 28908257 TI - Meet the Local Associations: 4. Somerset Association. PMID- 28908259 TI - Parliament, Press, Radio and Television. PMID- 28908260 TI - Local Associations at Work. PMID- 28908261 TI - General Secretary's Letter. PMID- 28908262 TI - Psychiatric Halfway Hostels. PMID- 28908263 TI - No Uniform. PMID- 28908264 TI - Our Responsibility? PMID- 28908265 TI - Causes for Depression. PMID- 28908266 TI - The Bournemouth Samaritans. PMID- 28908267 TI - Depression, Suicide and Loneliness. PMID- 28908268 TI - Training the Subnormal. PMID- 28908269 TI - Patient Help. PMID- 28908270 TI - The Camberwell Samaritans. PMID- 28908271 TI - How "The Samaritans" Combat Suicide. PMID- 28908273 TI - Parliament, Press, Radio and TV. PMID- 28908272 TI - Dangerous Drugs. PMID- 28908274 TI - The New Look. PMID- 28908275 TI - Letters to the Editor. PMID- 28908277 TI - Psychiatric Halfway Hostels in England: I. PMID- 28908276 TI - You-And the New Look. PMID- 28908278 TI - President Kennedy Calls for a Frontal Attack on Mental Retardation. PMID- 28908279 TI - Subnormality Services in the Hospital Plan. PMID- 28908280 TI - The 18th Inter-Clinic Conference. PMID- 28908281 TI - Letters to the Editor. PMID- 28908282 TI - Letters to the Editor. PMID- 28908283 TI - Explanation of Criminality. PMID- 28908285 TI - Letters to the Editor. PMID- 28908284 TI - Tape Recording in Social Rehabilitation. PMID- 28908286 TI - The Rees-Thomas Donation. PMID- 28908288 TI - Meet the Local Associations: 1: Cambridgeshire. PMID- 28908287 TI - An Author's Comment. PMID- 28908290 TI - General Secretary's Letter. PMID- 28908289 TI - Women in Prison. PMID- 28908291 TI - Press, Radio and Television. PMID- 28908292 TI - Loneliness. PMID- 28908293 TI - Filling the Gaps. PMID- 28908295 TI - Meet the Local Associations: 3. Halifax and Its Social Club. PMID- 28908294 TI - Introducing N.A.M.H. Homes and Hostels 1: 'Fairhaven' and 'Fairlop'. PMID- 28908296 TI - Porritt Committee Report Published. PMID- 28908297 TI - A Psychiatric Community Centre. PMID- 28908299 TI - Correction. AB - [This corrects the article on p. 134 in vol. 21.]. PMID- 28908298 TI - Noise and Mental Health. PMID- 28908301 TI - The Association's A.G.M. Discusses the Scott Report. PMID- 28908300 TI - An N.A.M.H. Conference Debates the E.S.N. School-Leaver and His Problems. PMID- 28908302 TI - The Contribution of the D.R.O. PMID- 28908303 TI - The N.A.M.H. Writes to the Ministry on Mental Health Review Tribunals. PMID- 28908304 TI - Symptom and Handicap. PMID- 28908306 TI - General Secretary's Letter. PMID- 28908305 TI - Letters to the Editor. PMID- 28908307 TI - Violence and the Mental Health Services-Conference Report. PMID- 28908308 TI - Parliament, Press, Radio and TV. PMID- 28908309 TI - Aggression-Good or Bad? PMID- 28908311 TI - General Secretary's Letter. PMID- 28908310 TI - Dance as a Therapy for the Mentally Ill. PMID- 28908312 TI - What Is "Community Care"? PMID- 28908313 TI - Psychiatric Services in the Hospital Plan. PMID- 28908315 TI - The Gaps. PMID- 28908314 TI - National Assistance for Mentally Handicapped Persons. PMID- 28908316 TI - Child Guidance in the Community. PMID- 28908317 TI - Rees-Thomas Donation. PMID- 28908318 TI - The Reactions of Parents of Handicapped Babies. PMID- 28908319 TI - "New Look" and Loneliness. PMID- 28908320 TI - The Future of the Child Guidance Services. PMID- 28908322 TI - Meet the Local Associations: Friern Barnet. PMID- 28908321 TI - The Consequences of Separation. PMID- 28908323 TI - Parliament, Press, Radio and TV. PMID- 28908324 TI - Some Needs of the Paediatrician. PMID- 28908325 TI - Correction. AB - [This corrects the article on p. 73 in vol. 21.]. PMID- 28908326 TI - Child Psychiatrist and Paediatrician. PMID- 28908327 TI - Psychiatric Halfway Hostels in England: II. PMID- 28908328 TI - Psychotic Children. PMID- 28908329 TI - The Child Guidance Clinic and Other Agencies. PMID- 28908330 TI - General Secretary's Letter. PMID- 28908331 TI - Diary. PMID- 28908332 TI - Old People-Must We Shut Them Away? PMID- 28908333 TI - Schizophrenia from the inside. PMID- 28908335 TI - Where Private Enterprise Can Help. PMID- 28908334 TI - Mental Health Scene. PMID- 28908336 TI - My Baby Led Me to a Psychiatrist. PMID- 28908337 TI - The Heart of the Matter. PMID- 28908338 TI - When Thinking Replaces Fear. PMID- 28908339 TI - There Is No Dividing Line. PMID- 28908340 TI - Cruelty in the Old People's Ward. PMID- 28908342 TI - Parents Want to Know. PMID- 28908341 TI - Correction. AB - [This corrects the article on p. 12 in vol. 25.]. PMID- 28908343 TI - A Better Deal for Subnormals. PMID- 28908344 TI - The Problem of Schizophrenia and Social Class. PMID- 28908345 TI - Cruel Practice. PMID- 28908346 TI - No Joke. PMID- 28908347 TI - The Nature of Aggression. PMID- 28908349 TI - Message from the Minister. PMID- 28908348 TI - Councillor's Case Book. PMID- 28908350 TI - Goodies and Baddies. PMID- 28908351 TI - Destiny of Insignificance. PMID- 28908352 TI - Crime and Mental Subnormality. PMID- 28908354 TI - How to Diminish Intolerance. PMID- 28908353 TI - One Day in the Life of Group No. 3. PMID- 28908355 TI - Mental Health Scene. PMID- 28908356 TI - How Trivial Is Trivial. PMID- 28908357 TI - Subnormality Hostel. PMID- 28908358 TI - A Factory in the Hospital. PMID- 28908360 TI - Childless Marriage as a Basis for Adoption. PMID- 28908359 TI - Moors' Murders Publicity. PMID- 28908361 TI - A Place for the Volunteer: Northern Local Associations Annual Conference. PMID- 28908362 TI - Are Approved Schools the Answer? PMID- 28908363 TI - Hazards of Separation. PMID- 28908364 TI - Changes in Visiting. PMID- 28908365 TI - Children of a Broken Marriage. PMID- 28908366 TI - A Question of Feeding. PMID- 28908367 TI - Adoption Procedures Dissected. PMID- 28908368 TI - Film: Who's Afraid of Virginia Woolf? PMID- 28908369 TI - Face to Face with Stress. PMID- 28908370 TI - Patients' Opinion Poll. PMID- 28908371 TI - A Home of Their Own. PMID- 28908372 TI - I Said Goodbye to My Baby. PMID- 28908373 TI - Mental Hospital Overcrowding: Formula for Change. PMID- 28908374 TI - Adjusting to Separation. PMID- 28908375 TI - The Bereaved Child. PMID- 28908376 TI - Mental Health Scene. PMID- 28908377 TI - Prison or Psychiatric Hospital? PMID- 28908378 TI - Drugs and the Young Law Breaker. PMID- 28908379 TI - How Is Addiction Spreading? PMID- 28908380 TI - Congratulations. PMID- 28908381 TI - They Said He Would Never Read. PMID- 28908383 TI - First Step to Independence. PMID- 28908382 TI - Who Is Vulnerable? PMID- 28908384 TI - Diary. PMID- 28908385 TI - Mission to the Misfit. PMID- 28908387 TI - People in Search of Dreams. PMID- 28908386 TI - Film: A Case Not Suitable for Treatment. PMID- 28908389 TI - Dangers of the 'Hard' Line. PMID- 28908388 TI - Disabled and the Employment Tax. PMID- 28908390 TI - Problems and Pseudo-Problems. PMID- 28908391 TI - The Course of Depression. PMID- 28908392 TI - Keeping Youth off the 'Failure' List. PMID- 28908393 TI - Blueprint for the Self-Help Group. PMID- 28908394 TI - Slimming Hazard. PMID- 28908396 TI - Destructive Report. PMID- 28908395 TI - Determination Needed. PMID- 28908397 TI - A Loser All the Way. PMID- 28908398 TI - Rebels without a Cause. PMID- 28908399 TI - America's New Psychiatric Frontier. PMID- 28908400 TI - Mental Health Scene. PMID- 28908401 TI - The Fountain Hospital. PMID- 28908402 TI - Community Care and the Question of Training. PMID- 28908403 TI - The Mental Health Act, 1959. PMID- 28908404 TI - The Mental Health Service in 1958: Some Facts and Figures. PMID- 28908405 TI - The Next Steps. PMID- 28908406 TI - Mental Health Work in Nottingham: An Exercise in Co-Operation. PMID- 28908407 TI - A New Look at Mental Health. PMID- 28908409 TI - Parliament, Press and Broadcasting. PMID- 28908408 TI - A Social Club for Mental Defectives. PMID- 28908410 TI - Some Aspects of Placing Detectives in Work. PMID- 28908412 TI - Full Employment. PMID- 28908411 TI - The Psychological Significance of Work. PMID- 28908413 TI - Psycho-Pathology in Industrial Life. PMID- 28908414 TI - Parliament, Press and Broadcasting. PMID- 28908416 TI - The Social Workers' Viewpoint. PMID- 28908415 TI - The Place of the Mental Deficiency Hospital in a Community Care Programme. PMID- 28908417 TI - The Mental Health Bill and the Psychopath. PMID- 28908418 TI - Parliament, Press and Broadcasting. PMID- 28908419 TI - The Public and the Mental Health Bill. PMID- 28908420 TI - Thinking Internationally. PMID- 28908421 TI - Mental Health-Or Mental Illness? PMID- 28908423 TI - Changes in the Journal. PMID- 28908422 TI - Effect of Children's Television on Behaviour. PMID- 28908425 TI - Lessons of the War for Psychiatry. PMID- 28908424 TI - The New Bill and the Mental Deficiency Services. PMID- 28908426 TI - The "New Look" in the Care of the Mentally Ill. PMID- 28908427 TI - Parliament, Press and Broadcasting. PMID- 28908428 TI - The Local Authorities' Part. PMID- 28908429 TI - Fairhaven: A Hostel for Educationally Sub-Normal School Leavers. PMID- 28908430 TI - Implementing the Mental Health Act: Local Authority Schemes. PMID- 28908431 TI - Preventive Medicine for Older People. PMID- 28908432 TI - Local Authorities and the Mental Health Act. PMID- 28908434 TI - Everybody's Business. PMID- 28908433 TI - Training for Social Workers. PMID- 28908436 TI - Mental Health Guides for the General Practitioner. PMID- 28908435 TI - Parliament, Press and Broadcasting. PMID- 28908437 TI - The Future of Psychiatry in General Practice. PMID- 28908438 TI - Postgraduate Education in Psychiatry for the General Practitioner. PMID- 28908439 TI - Psychiatric Skills in General Practice. PMID- 28908441 TI - Psychiatry and the General Practitioner. PMID- 28908440 TI - A First Visit to Nigeria. PMID- 28908443 TI - A Visit to the U.S.S.R. and Poland (Part II). PMID- 28908442 TI - Keeping in Touch with New Developments. PMID- 28908445 TI - Social Clubs for the Mentally Disordered. PMID- 28908444 TI - Parliament, Press and Broadcasting. PMID- 28908446 TI - Psychiatric Illness in General Practice: The Urgency of the Problem. PMID- 28908447 TI - Child Victims of Sexual Assault. PMID- 28908448 TI - Reflections after 30 Years of Psychiatric Nursing. PMID- 28908449 TI - Mental Subnormality-Whose Baby? PMID- 28908450 TI - A Psychiatric Out-Patient Nursing Service. PMID- 28908451 TI - Mental Nurses: What Is Their Future? PMID- 28908452 TI - The Future of Psychiatric Hospitals. PMID- 28908453 TI - A Sequel to the Lords' Debate. PMID- 28908454 TI - Parliament, Press and Broadcasting. PMID- 28908455 TI - Alcoholism. PMID- 28908456 TI - Parliament, Press and Broadcasting. PMID- 28908458 TI - What Is A.A.?: Alcoholics Anonymous. PMID- 28908457 TI - The Alcoholic and Society. PMID- 28908459 TI - Principles of Clinical Policy in the Setting up of In-Patient Units for Treatment of Alcoholism. PMID- 28908461 TI - Corporal Punishment. PMID- 28908460 TI - Recent Progress in Yugoslavia in the Treatment and Prevention of Alcoholism. PMID- 28908462 TI - Parliament, Press and Broadcasting. PMID- 28908463 TI - An Introduction to Psychiatry for Probation Officers. PMID- 28908465 TI - The Mental Health Service in 1959. PMID- 28908464 TI - Training in Child Guidance. PMID- 28908466 TI - A Challenge to Social Work Education. PMID- 28908467 TI - Correspondence. PMID- 28908468 TI - The Probation Officer's Needs. PMID- 28908469 TI - The Training of General Practitioners in Psychiatry. PMID- 28908471 TI - Still the Cinderella. PMID- 28908470 TI - The General Nurse's Training and Psychiatry. PMID- 28908472 TI - The Parental Role in the Care and Training of Mental Defectives. PMID- 28908473 TI - Truancy-Or School Phobia? PMID- 28908474 TI - Terrible God. PMID- 28908475 TI - Liverpool Police Liaison Scheme. PMID- 28908476 TI - Erratum: An Apology. AB - [This corrects the article on p. 122 in vol. 18.]. PMID- 28908477 TI - Mind and Spirit. PMID- 28908478 TI - Co-Operation between the Churches and Medicine. PMID- 28908479 TI - Messages from Church Leaders. PMID- 28908480 TI - Religion and the Mentally Sick: Some Fundamental Issues. PMID- 28908482 TI - Some Moral Issues of Mental Health Training in Professional Education. PMID- 28908481 TI - Religion and Psychiatry. PMID- 28908484 TI - Mental Health in 1958. PMID- 28908483 TI - Mental Illness in Cross-Cultural Perspective. PMID- 28908485 TI - Industrial Mental Health in Britain. PMID- 28908486 TI - Parliament, Press and Broadcasting. PMID- 28908487 TI - Mental Health and the Child. PMID- 28908488 TI - World Mental Health Year. PMID- 28908489 TI - Parliament, Press and Broadcasting. PMID- 28908490 TI - A Visit to U.S.S.R. and Poland, Part I. PMID- 28908491 TI - The Case against Termination on Psychiatric Grounds. PMID- 28908492 TI - Legal Aspects of Abortion. PMID- 28908494 TI - Abortion Law in Other Countries. PMID- 28908493 TI - The Case for Reform. PMID- 28908495 TI - Legal Abortion? PMID- 28908496 TI - General Secretary's Letter. PMID- 28908497 TI - Teenagers in Their First Jobs. PMID- 28908498 TI - The Adolescent at School. PMID- 28908499 TI - Parliament, Press, Radio and TV. PMID- 28908500 TI - Teenagers Who Leave Home. PMID- 28908501 TI - Bradford and District Local Association. PMID- 28908502 TI - The Space between. PMID- 28908503 TI - Duncroft Approved School. PMID- 28908504 TI - Learning to Be a Student. PMID- 28908505 TI - Gangs and Groups. PMID- 28908506 TI - Music in Psychiatry. PMID- 28908507 TI - New Social Workers Group. PMID- 28908508 TI - Children's Bill. PMID- 28908509 TI - Creative Therapy. PMID- 28908511 TI - Some Films on Art and Metal Illness. PMID- 28908510 TI - Art and Therapy. PMID- 28908513 TI - The Ten-Year Plan. PMID- 28908512 TI - The History of Dance Therapy in England. PMID- 28908514 TI - Art and Mental Health. PMID- 28908515 TI - Living with Leisure. PMID- 28908516 TI - Meet Portsmouth and District Association for Mental Health. PMID- 28908518 TI - Deputy General Secretary's Letter. PMID- 28908517 TI - Creative Therapy and Creative Drama. PMID- 28908519 TI - Parliament, Press, Radio and TV. PMID- 28908520 TI - Clinical Problems in Children of Primary School Age. PMID- 28908521 TI - Music in Psychiatric and Social Rehabilitation. PMID- 28908523 TI - NAMH Annual Conference, 1963, Debates: Community Care-The Distant Goal. PMID- 28908522 TI - Depression. PMID- 28908524 TI - The Responsibility of the Psychiatrist. PMID- 28908525 TI - In-Patient Treatment: Should It Become a Last Resort? PMID- 28908526 TI - 1959 Act and Admissions to a Mental Hospital. PMID- 28908527 TI - Mental Health in Northern Ireland-Laws Ancient and Modern. PMID- 28908528 TI - Meet the Local Associations: 5, Wirral. PMID- 28908529 TI - Care or Interference? PMID- 28908530 TI - Birmingham Confers on Psychotic Children. PMID- 28908531 TI - Preventive Care. PMID- 28908533 TI - Psychopathic Disorder. PMID- 28908532 TI - The Citizen's Responsibility. PMID- 28908535 TI - General Secretary's Letter. PMID- 28908534 TI - Parliament, Press, Radio and Television. PMID- 28908537 TI - Backward Children in Sweden. PMID- 28908536 TI - Community Centres. PMID- 28908538 TI - Communities and Social Change. PMID- 28908540 TI - Editorial. PMID- 28908539 TI - Some Social Problems of New Towns. PMID- 28908541 TI - Parliament, Press, Radio and TV. PMID- 28908542 TI - General Secretary's Letter. PMID- 28908543 TI - Psychiatric Problems in New Communities. PMID- 28908544 TI - Meet Harlow Local Association. PMID- 28908546 TI - NAMH Annual Conference 1964 Investigates the Whole Truth about Care of the Mentally Disordered. PMID- 28908545 TI - Occupational Therapy, Taxi-Drivers and Columbine. PMID- 28908547 TI - A Place to Play. PMID- 28908548 TI - Making a Home for the Mentally Disordered. PMID- 28908549 TI - Nature of Art Therapy. PMID- 28908550 TI - Mental Health in Industry. PMID- 28908551 TI - Towards Community Care in the Mental Health Services? PMID- 28908552 TI - Correction. AB - [This corrects the article on p. 26 in vol. 22.]. PMID- 28908553 TI - Hospital or Home? PMID- 28908554 TI - Need for Community Care. PMID- 28908555 TI - Meet Devon and Exeter Association. PMID- 28908556 TI - Some Films on Rehabilitation. PMID- 28908557 TI - Return to Work. PMID- 28908558 TI - Parliament, Press, Radio and TV. PMID- 28908559 TI - Swalcliffe Park School. PMID- 28908560 TI - Rehabilitation of a Problem Family. PMID- 28908562 TI - General Secretary's Letter. PMID- 28908561 TI - Principles of the Rehabilitation of Those Suffering from Neurosis. PMID- 28908563 TI - Executive Stress. PMID- 28908564 TI - Local Associations and Rehabilitation. PMID- 28908565 TI - The Fear of Leisure. PMID- 28908566 TI - Adaptive Automation and Mental Processes. PMID- 28908567 TI - Letters to the Editor. PMID- 28908568 TI - Prevention or Treatment? PMID- 28908569 TI - Meet Blackpool and Fylde. PMID- 28908571 TI - Letters to the Editor. PMID- 28908570 TI - Parliament, Press, Radio and TV. PMID- 28908572 TI - General Secretary's Letter. PMID- 28908573 TI - An Employer's View of Automation. PMID- 28908575 TI - Mental Health in Industry. PMID- 28908574 TI - Salary Success Story. PMID- 28908576 TI - Guilt and Insanity. PMID- 28908577 TI - The Uses of Leisure. PMID- 28908578 TI - Automation, Leisure and the Unions. PMID- 28908579 TI - Gambling and Mental Health. PMID- 28908581 TI - Lords' Debate Problem of Leisure. PMID- 28908580 TI - Automation's Effects upon Those of below Average Intelligence. PMID- 28908582 TI - Pastures New. PMID- 28908583 TI - Copenhagen Congress on the Scientific Study of Mental Retardation. PMID- 28908584 TI - Introducing the Slough Play-Group for Mentally Handicapped Children. PMID- 28908586 TI - General Secretary's Letter. PMID- 28908585 TI - Preparation for Work. PMID- 28908588 TI - A Working Community for Mentally Handicapped Adults. PMID- 28908587 TI - P. E. P. Report. PMID- 28908589 TI - Two Diagnostic Clinics for Retarded Children. PMID- 28908590 TI - A Danish Training Programme for Personnel of Hospitals for Mentally Subnormal. PMID- 28908591 TI - Meet Staffordshire Association for Mental Welfare. PMID- 28908593 TI - Parliament, Press, Radio and TV. PMID- 28908592 TI - Progress and Planning. PMID- 28908594 TI - Specialists in Human Relations. PMID- 28908595 TI - Research into Research. PMID- 28908597 TI - Teaching and Learning Mental Health. PMID- 28908596 TI - How to Be Psychoanalysed. PMID- 28908598 TI - Social Attitudes and Mental Disorder. PMID- 28908599 TI - Caring in the Community. PMID- 28908600 TI - Introducing the Minister of Health. PMID- 28908602 TI - N.A.M.H. A.G.M.-1965: From a Correspondent. PMID- 28908601 TI - The Anatomy of the Sick Joke. PMID- 28908603 TI - General Secretary's Letter. PMID- 28908604 TI - Dementia in the Elderly-A Community Problem. PMID- 28908605 TI - Some Books of 1964. PMID- 28908606 TI - An Acid-Reaction or Society in the Test-Tube. PMID- 28908607 TI - Press, Radio and TV. PMID- 28908608 TI - Hospitals and People. PMID- 28908609 TI - Givers and Not Getters. PMID- 28908610 TI - Some Characteristics of Mental Illness in North-East Scotland. PMID- 28908611 TI - Anglesey Mental Health Survey. PMID- 28908613 TI - 2nd NAMH Conference on Preventive Aspects of the Education Service in the Mental Health Field. PMID- 28908612 TI - Meet Manchester, Salford and District Association. PMID- 28908614 TI - Correction. AB - [This corrects the article on p. 43 in vol. 23.]. PMID- 28908615 TI - When I Was a Patient. PMID- 28908616 TI - Plans for the Journal. PMID- 28908617 TI - Psychiatric Teaching Films. PMID- 28908618 TI - Art as Communication. PMID- 28908619 TI - Erratum: Printing Error. AB - [This corrects the article on p. 78 in vol. 23.]. PMID- 28908620 TI - General Secretary's Letter. PMID- 28908621 TI - Epidemiology of Mental Subnormality. PMID- 28908623 TI - Parliament, Press, Radio and TV. PMID- 28908622 TI - Adolescence: 20th Child Guidance Inter-Clinic Conference. PMID- 28908624 TI - Home-Making Group. PMID- 28908626 TI - Parliament, Press, Radio and TV. PMID- 28908625 TI - Planned Programme. PMID- 28908628 TI - Meet Ealing District Local Association. PMID- 28908627 TI - What Is Therapy? PMID- 28908629 TI - Problems of Middle Age in Industry. PMID- 28908631 TI - Report of N.A.M.H. 1963 A.G.M.: Mental Health Services in the Local Authority Ten Year Plan. PMID- 28908630 TI - Middle Age and Family-Focussed Women. PMID- 28908632 TI - Occupational Therapy for the Middle-Aged Patient. PMID- 28908633 TI - Using Mental Health Films in Educational Programmes. PMID- 28908634 TI - Over-Simplification. PMID- 28908635 TI - Postal Publicity for Mental Health. PMID- 28908636 TI - The Contribution of the Untrained Social Worker. PMID- 28908637 TI - Psychiatric Problems in Children. PMID- 28908639 TI - Stepping Happily Aside. PMID- 28908638 TI - Poetry Readings. PMID- 28908640 TI - General Secretary's Letter. PMID- 28908641 TI - The Middle Period of Life. PMID- 28908642 TI - In the Swim. PMID- 28908643 TI - A Cry from Kenya. PMID- 28908644 TI - Human Problems of Student Nurses. PMID- 28908646 TI - Parliament, Press, Radio and TV. PMID- 28908645 TI - Community Care in the Mental Health Services. PMID- 28908648 TI - Research and Enquiry. PMID- 28908647 TI - A New Crusade for Widows. PMID- 28908650 TI - The Price of Mental Health. PMID- 28908649 TI - N.A.M.H. Annual Conference Weighs the Price of Mental Health. PMID- 28908651 TI - A Relatives' Meeting. PMID- 28908653 TI - Living Longer! Living Happier? PMID- 28908652 TI - Mental Subnormality and Industrial Work. PMID- 28908655 TI - Film-Making Conference. PMID- 28908654 TI - If I Could Alter One Thing... PMID- 28908656 TI - Play in Hospital. PMID- 28908657 TI - School in a Children's Psychiatric Unit. PMID- 28908658 TI - The Avondale Project: Youth Counselling in an Educational Setting. PMID- 28908660 TI - Two Special Surveys. PMID- 28908659 TI - Student Mental Health. PMID- 28908661 TI - Young People's Consultation Centre. PMID- 28908663 TI - Infanticide. PMID- 28908662 TI - Tutorial Responsibility. PMID- 28908665 TI - Research and Enquiry: Research Supported by the Mental Health Research Fund: 1954 1964. PMID- 28908664 TI - Subnormality Hostels: Two Different Functions. PMID- 28908666 TI - Personal Viewpoint: A Patient's View of Psychotherapy. PMID- 28908667 TI - Postscript on Coralie. PMID- 28908668 TI - Parliament, Press, Radio and TV. PMID- 28908669 TI - 21st Child Guidance Inter-Clinic Conference. PMID- 28908670 TI - Mental Health in Education. PMID- 28908671 TI - Teaching for the National Childbirth Trust. PMID- 28908672 TI - Boarding-Out Elderly Psychiatric Patients. PMID- 28908673 TI - A Fatherless Family. PMID- 28908674 TI - Their Lot. PMID- 28908675 TI - Beneath the Skin. PMID- 28908676 TI - Reynolds House: A Hostel for Maladjusted School-Leavers. PMID- 28908677 TI - Research and Enquiry. PMID- 28908678 TI - A Year's Recreation at South Ockendon Hospital. PMID- 28908679 TI - Artificial Insemination-The Social Implications. PMID- 28908680 TI - Parliament, Press, Radio and T.V. PMID- 28908681 TI - Local Associations and International Cooperation Year. PMID- 28908682 TI - London Looks at Mental Health. PMID- 28908683 TI - The Doctor and the Mother Instinct. PMID- 28908684 TI - Beyond the Fringe. PMID- 28908686 TI - 25 and Under-Opportunities for Service. PMID- 28908687 TI - Film-Making Conference at Keele. PMID- 28908688 TI - Radio, TV and Press. PMID- 28908689 TI - Research on Children in Substitute Care. PMID- 28908690 TI - Personal Viewpoint: The Forgotten Ones. PMID- 28908691 TI - The Immorality of Marriage. PMID- 28908692 TI - Psychosomatic Medicine. PMID- 28908694 TI - 40 Years Ago. PMID- 28908693 TI - Research and Enquiry: More Light on Our Psychiatric Hospitals. PMID- 28908695 TI - Continuity of Treatment: Hospital and Home. PMID- 28908697 TI - Our Future Mental Health. PMID- 28908696 TI - A Doctor Comments on the Mother. PMID- 28908698 TI - A New Town in the North. PMID- 28908699 TI - U.S.S.R. and Mental Disease. PMID- 28908700 TI - Hospital Sector. PMID- 28908701 TI - Research and Enquiry: Development of the African Child. PMID- 28908702 TI - Social and Mental Health Contrasts in California and Wales. PMID- 28908703 TI - Mental Disease on the Wane. PMID- 28908704 TI - Mental Nursing in British Columbia. PMID- 28908705 TI - Culture and Madness. PMID- 28908707 TI - Parliament, Press, Radio and TV. PMID- 28908706 TI - A Psychiatric Social Worker Abroad. PMID- 28908708 TI - Glimpses of Child Care and Psychiatric Services in Hungary. PMID- 28908710 TI - Personal Viewpoint: A Mother Writes about Enuresis the Following Feature Is Reprinted from the March 1965 Edition of Nova. PMID- 28908709 TI - A Ward Adoption Scheme. PMID- 28908711 TI - Facilitating International Communication in Mental Health. PMID- 28908712 TI - The Law and the Mentally Abnormal Offender. PMID- 28908713 TI - Subnormality Hostels. PMID- 28908714 TI - Delinquents and Their Parents. PMID- 28908716 TI - Why Not? PMID- 28908717 TI - Parliament, Press, Radio and TV. PMID- 28908715 TI - Detention Centres-The First Phase. PMID- 28908718 TI - Ex-Prisoners Find a Home. PMID- 28908719 TI - Psychiatry and Criminology. PMID- 28908721 TI - Age and Crime. PMID- 28908722 TI - 40 Years Ago. PMID- 28908723 TI - Research and Enquiry: Physical Disability and Crime. PMID- 28908724 TI - Government Plans for Young Offenders. PMID- 28908725 TI - Personal Viewpoint: The Experience of Electro-Convulsive Therapy. PMID- 28908726 TI - Criminal Responsibility. PMID- 28908727 TI - When Health Is a Handicap. AB - A study of the difficulties that can arise in a family with a mentally handicapped child and brothers or sisters who are normal. PMID- 28908728 TI - A Guide to Good Practice. AB - The full text of the report of a working party set up in an attempt to formulate standards of practice in the care of difficult patients. PMID- 28908729 TI - The Mind Manifesto. AB - The Mind Campaign, launched on February 16th 1971, is based on the Mind Manifesto printed here to express the philosophy behind the campaign. PMID- 28908730 TI - Parliament. PMID- 28908731 TI - Only Connect. AB - A very individual and personal manifesto by one of London's leading directors of experimental theatre. PMID- 28908732 TI - Living in the Twilight. AB - The crippling effects on children of growing up and going to school in educational priority areas. PMID- 28908733 TI - Reflections. AB - Poems written while suffering from mental illness. PMID- 28908734 TI - Right of Appeal. AB - A new book on Mental Health Review Tribunals puts the present system and procedure on trial. PMID- 28908735 TI - On Incontinence. AB - Practical advice on incontinence both for the patient and those who care for him. PMID- 28908736 TI - Scan. PMID- 28908737 TI - At Risk in the East End. AB - An examination of a report published by the Psychiatric Rehabilitation Association. PMID- 28908738 TI - News Review. PMID- 28908739 TI - The Classroom at Large. AB - An educationalist argues for the need for a place to be found for voluntary service within the school curriculum. PMID- 28908740 TI - Ennals Errant. PMID- 28908741 TI - Scan. PMID- 28908743 TI - Ideals and Charm at Omi-Gakuen. AB - Impressions of a visit to a home for mentally handicapped children in Japan. PMID- 28908742 TI - God Psychiatry Versus Good Psychiatry. AB - Since psychiatry often requires an intimate, informal dialogue between patient and doctor, can psychiatrists afford to retain the remote, omnipotent image which they have inherited? PMID- 28908744 TI - From Where I Sit: Editorial Comment. PMID- 28908745 TI - Images of Insanity. AB - An examination of the way the cinema has dealt with mental illness and the introspective fascination with which it has mirrored the spirit of experimentation and fragmentation of the last decade. PMID- 28908746 TI - Management with Two-Way Stretch. AB - A formula for new-style management in hospitals for the mentally handicapped which is needed to liberate the staff before they can get on with the job of liberating the patients. PMID- 28908747 TI - Plea to West on Soviet 'Mad-House' Jails. PMID- 28908748 TI - One at Night. AB - Review of a play centring on the proceedings of a mental health review tribunal. PMID- 28908749 TI - Bursting Point and beyond. AB - The world's population crisis has become a very fashionable topic yet everyone remains in the dark about the way overcrowding will modify and radically change our way of life. Preparatory research is needed now. PMID- 28908750 TI - The O'Hagan Column. PMID- 28908751 TI - The Act-4 Years after. AB - The MP who did most to put the Abortion Act on to the statute book assesses the way it has been used and abused and whether it needs to be amended. PMID- 28908753 TI - News Review. PMID- 28908752 TI - The Generation War-Game. AB - With no wide agreement about beliefs and standards of behaviour being set, and with the mass media in constant pursuit, young people are often thought to be more vulnerable today than in the past. A book with this theme is assessed by an eminent teacher. PMID- 28908754 TI - Your Life on Their Tapes. AB - Can 'they'-government agencies and big business-discover too much about the individual too easily? One implication of the growth of data banks could be discrimination and monitoring on an Orwellian scale. PMID- 28908755 TI - After the Break-Up. AB - How much help do people need after a divorce? Plenty of advice is available on how to save a marriage but what about the problems of restructuring life if it cannot be saved - a Divorce Counselling Service may be needed. PMID- 28908756 TI - The House That Wills' Built. AB - A discussion of the contribution made by David Wills to the residential care of young people prompted by his book on the Reynolds House experiment. PMID- 28908757 TI - Caring for Deprived Children. PMID- 28908759 TI - New Medical Group on Adoption. PMID- 28908758 TI - Meet Bournemouth Association for Mental Health. PMID- 28908760 TI - Parliament, Press, Radio and TV. PMID- 28908761 TI - The Family in the Welfare State: Extracts from Presidential Address to N.A.P.O. PMID- 28908762 TI - Two Editors. PMID- 28908763 TI - General Secretary's Letter. PMID- 28908764 TI - The Family of Today. PMID- 28908766 TI - Taking Care. PMID- 28908765 TI - The Parent-Child Relationship in the Treatment of Elderly Psychiatric Patients. PMID- 28908767 TI - Club in the Crypt. PMID- 28908768 TI - The Case for Voluntary Help. PMID- 28908769 TI - Boarders, Not Patients. PMID- 28908770 TI - Young Minds at Risk. PMID- 28908771 TI - Bright but Maladjusted. PMID- 28908772 TI - Psychiatry on a Sunday. PMID- 28908774 TI - Scientology in the House. PMID- 28908773 TI - A 'Long Vac' in Community Service. PMID- 28908776 TI - The Adolescent Treatment Gap. PMID- 28908775 TI - SET and the Handicapped. PMID- 28908777 TI - What Price Vocation? PMID- 28908778 TI - In Two Worlds: Immigrant School-Leavers. PMID- 28908779 TI - On the outside Looking in. PMID- 28908780 TI - From Prurience to Maturity. PMID- 28908781 TI - Sixpence to Gawp. PMID- 28908782 TI - Class, Language and Learning. PMID- 28908783 TI - Diary. PMID- 28908784 TI - In Two Minds. PMID- 28908785 TI - Mental Health Scene. PMID- 28908786 TI - Breaking down the Barrier. PMID- 28908787 TI - Mental Deficiency and Divorce. PMID- 28908788 TI - The Monks and the Psychiatrist. PMID- 28908789 TI - The Sellout to Swinging Youth. PMID- 28908790 TI - Diary. PMID- 28908791 TI - Treatment by Revulsion. PMID- 28908792 TI - Are We Ignoring the Real Needs of the Young? PMID- 28908793 TI - Looking at Psychoanalysis. PMID- 28908794 TI - No Place for the Teenager. PMID- 28908795 TI - Personal Guidance for Schoolchildren. PMID- 28908796 TI - When the Mentally Handicapped Paint. PMID- 28908797 TI - Five Months with the Process. PMID- 28908798 TI - Bellow: A New Dimension in Literature. PMID- 28908799 TI - Successful Hostel Scheme. PMID- 28908800 TI - Mental Health Scene. PMID- 28908801 TI - Approved School Helped Me. PMID- 28908803 TI - The Uses and Abuses of Corporal Punishment. PMID- 28908802 TI - The Process. PMID- 28908804 TI - Birth of 'A Child Possessed'. PMID- 28908805 TI - School for the Disappointed. PMID- 28908806 TI - Neurotics Not Anonymous. PMID- 28908807 TI - Disorders of Attention. PMID- 28908808 TI - Student Wastage. PMID- 28908810 TI - Seventh International Congress: Keys to Progress. PMID- 28908809 TI - Chaplains in Hospitals. PMID- 28908811 TI - Scale of Subnormality. PMID- 28908813 TI - Scene 1. PMID- 28908812 TI - Stress and Higher Education Breakdown. PMID- 28908814 TI - The Shabby Brown Suede. PMID- 28908815 TI - Belmont Adolescent Unit. PMID- 28908816 TI - I Gave Up-Why Carla Markham Got off the Couch. PMID- 28908817 TI - Apathy or Activity? PMID- 28908818 TI - Scene 2. PMID- 28908819 TI - Warneford 'College'. PMID- 28908820 TI - Children in Need. PMID- 28908821 TI - Scene 2. PMID- 28908822 TI - Phobias. PMID- 28908823 TI - Parliament. PMID- 28908824 TI - Fear and Personality. PMID- 28908826 TI - Scene 1. PMID- 28908825 TI - An Open-Eyed Look at Sleep. PMID- 28908827 TI - Croydon Pioneers. PMID- 28908829 TI - Design for Play. PMID- 28908828 TI - Swimming up a Sewer: A Hard Look at 'Last Exit'. PMID- 28908830 TI - Childhood Fears. PMID- 28908831 TI - The Gold Watch Syndrome. PMID- 28908832 TI - The Fear of Humiliation. PMID- 28908834 TI - How to Use the Hospitals. PMID- 28908833 TI - Mental Health USA. PMID- 28908836 TI - Who's in the Waiting Room? PMID- 28908835 TI - How Many Psychiatrists? PMID- 28908837 TI - The Whole Child. PMID- 28908839 TI - Psychiatric Bridges. PMID- 28908838 TI - The State of the Nation. PMID- 28908840 TI - In Cold Blood. PMID- 28908841 TI - An American Eye View. PMID- 28908842 TI - On the Receiving End 1 2. PMID- 28908843 TI - Through the Net. PMID- 28908844 TI - Parliament. PMID- 28908845 TI - Scene 2. PMID- 28908846 TI - Conspiracy of Ignorance. PMID- 28908847 TI - Scene 1. PMID- 28908848 TI - Public Parts. AB - Review of 'Oh! Calcutta!' PMID- 28908849 TI - Origins of Apathy. AB - A new book, reporting on a research programme, sheds more light on the vexed question of the adverse effects on schizophrenics of a prolonged stay in hospital. PMID- 28908850 TI - Homes Fit for the Handicapped. AB - Detailed criticism of a book on the design of buildings for handicapped children which, if it becomes a reference book, could perpetuate some unfortunate misconceptions. PMID- 28908851 TI - A Chance to Adjust. AB - When a mother learns her baby is mentally handicapped the news comes as a knock out blow. She, and her family, need time to digest the shock; they also need sympathy and practical help which is not as readily available as it should be. PMID- 28908852 TI - Keeping Watch over the Old. AB - Caring for old people within the community is largely a question of meeting trouble half-way-dealing with problems and ailments while they are minor so as to avoid the major crisis of hospitalisation and the end of treasured independence. PMID- 28908853 TI - Imprisoned in Suspicion. AB - Paranoia is a self-inflicted mental torture of which the sufferer himself is unaware. A paranoiac is perpetually guarded and suspicious, convinced that he is being persecuted by all who inhabit his deluded world. PMID- 28908854 TI - Bronco Bullfrog. AB - Review of a film which shows all too clearly how the already under-priveleged can be heavily penalised by an environment from which only the prosperous can escape. PMID- 28908855 TI - In Society's Gutter. AB - Who are the vagrants that we try our best to avoid in the city streets? How have they reached such a state of hopelessness and destitution? Do we care anyway? PMID- 28908856 TI - Scan. PMID- 28908857 TI - A Code of Practice. AB - Psychiatric nurses have been 'put through the mill' of bad publicity in the last couple of years. Some guidelines for the profession are being worked out at the moment but how helpful can they be and in what spirit will they be received? PMID- 28908858 TI - Parliament. PMID- 28908859 TI - News Review. PMID- 28908860 TI - News Review. PMID- 28908861 TI - Slimming Sickness. AB - Anorexia nervosa, a rare illness which occurs predominantly among adolescent girls, usually begins with dieting which gradually gets out of hand. PMID- 28908862 TI - It Will Happen to You. AB - Everyone experiences bereavement but few give prior thought to it. Knowing something about the possible reactions and repercussions of bereavement is the best preparation for it. PMID- 28908863 TI - Outposts of Old-Style Management. AB - Despite their size and complexity, mental hospitals have been scarcely touched by the management methods revolution of the last decade. The factors which complicate the use of new techniques in hospital management are not insurmountable. PMID- 28908864 TI - Voices for the Silent Minority. AB - How do you comply with a patient's wishes when he can't express them? The protection of the rights of people in hospital who are inarticulate is in the hands of the nurses. PMID- 28908865 TI - The Classless Turmoil. AB - The mother of a schizophrenic son demolishes the assumption, apparently made by medical and social workers, that the intelligent, middle-class family is able to cope better than most with a disturbed family member. PMID- 28908866 TI - Stumbling-Blocks of Reform. AB - An assessment of the Children and Young Persons Act and the difficulties which stand in the way of its full implementation. PMID- 28908867 TI - Early Warning System at Work. AB - Since we spend so much of our time at work it is there that the first warning signs of impending mental illness are likely to appear. So, ideally, the factory floor and the office should become the 'front line' of positive mental health. PMID- 28908868 TI - Tall in the Saddle. AB - Pony riding can give a new dimension to the life of a handicapped child. PMID- 28908869 TI - Two Cheers for Psychiatry. AB - Critics within psychiatry suggest that too many people are being classified as 'ill' and in need of treatment. Are psychiatrists casting their nets too wide and is society too psychiatry conscious? PMID- 28908870 TI - The Feelings inside. AB - A personal impression of anorexia nervosa. PMID- 28908871 TI - Control and Trust. PMID- 28908872 TI - Diary. PMID- 28908873 TI - Scene 2. PMID- 28908874 TI - Scene 1. PMID- 28908875 TI - Life and the Handicapped Child. PMID- 28908876 TI - Please Don't Bring Your Lips so Close. PMID- 28908877 TI - Freudian Nostalgia. PMID- 28908878 TI - Almost a Home. PMID- 28908879 TI - Long, Hot Years to Come. PMID- 28908880 TI - The Young and Their Marriages. PMID- 28908881 TI - Poor Cow. PMID- 28908883 TI - Help with Dignity. PMID- 28908882 TI - When Motherhood Doesn't Come Naturally. PMID- 28908885 TI - Psychosomatics. PMID- 28908884 TI - Psychiatrist in the Old People's Ward. PMID- 28908886 TI - The Subnormal: Train or Teach? PMID- 28908887 TI - Coping with Incontinence. PMID- 28908888 TI - Warrendale. PMID- 28908889 TI - Parnham-A Pioneer Venture. PMID- 28908890 TI - "We Rob Banks". PMID- 28908891 TI - The Betrayed Generation. PMID- 28908892 TI - Vicious Circles of Care. PMID- 28908893 TI - Blueprint for Voluntary Action. PMID- 28908895 TI - Mental Health Scene. PMID- 28908894 TI - The Work of a Residential Child Psychiatry Unit. PMID- 28908896 TI - The Electronic Whipping Boy. PMID- 28908897 TI - Diary. PMID- 28908898 TI - What's Funny about Handicap? PMID- 28908899 TI - Open Door Controversy. PMID- 28908900 TI - The Mind of a Child Murderer. PMID- 28908901 TI - The Undergrowth of Literature. PMID- 28908902 TI - A Hospital Reality. PMID- 28908903 TI - The Volunteers' Advocate. PMID- 28908904 TI - Laying the Blame. PMID- 28908905 TI - In a Strange Land. PMID- 28908906 TI - When You're Drunk: ...It Don't Count. PMID- 28908907 TI - Tolerating Stress. PMID- 28908908 TI - Forgotten Teenagers. PMID- 28908909 TI - Limitations of Restraint. PMID- 28908910 TI - An Unfortunate Blow. PMID- 28908911 TI - Electrical Treatment: ... A Balanced View. PMID- 28908912 TI - Sympathy or Brass Tacks. PMID- 28908913 TI - A Management Ideal. PMID- 28908914 TI - A Way of Caring. PMID- 28908916 TI - The Scene. PMID- 28908915 TI - Diagnosis for a King. PMID- 28908917 TI - The Shattered Image. PMID- 28908918 TI - Origins of Psychology. PMID- 28908919 TI - An End to Hanging. PMID- 28908920 TI - The German Psychological Machine and the Need to Combat It. PMID- 28908921 TI - Agricultural Hostels for Defectives. PMID- 28908922 TI - Social Work in Medicine. PMID- 28908923 TI - Discipline and Obedience. PMID- 28908924 TI - Paying Lip Service to Change. PMID- 28908925 TI - Death-The Doctor's Dilemma. PMID- 28908926 TI - A High and Hostile Utopia. PMID- 28908927 TI - Neurotics Anonymous. PMID- 28908928 TI - The Vatican Versus Freud. PMID- 28908930 TI - Mental Health Scene. PMID- 28908929 TI - Alice in the Space Age. PMID- 28908931 TI - Disturbing Conscience into Action. PMID- 28908932 TI - Mental Illness and the Public: Old Fears, Old Ideas. PMID- 28908933 TI - Old Habits Dying Easy. PMID- 28908934 TI - Scenes in Search of a Film. PMID- 28908935 TI - Changing Opinion-Optimism for the Future. PMID- 28908936 TI - Vietnam! Vietnam! PMID- 28908937 TI - Adapting to Survive. PMID- 28908938 TI - Thinking in the Deep End. PMID- 28908939 TI - Adapting to Teach Adaptability. PMID- 28908940 TI - One Old Lady. PMID- 28908941 TI - 'O' Levels by Post. PMID- 28908943 TI - In Place of Boredom: Photo Feature. PMID- 28908942 TI - Family Crisis. PMID- 28908944 TI - Extending the Umbrella. PMID- 28908946 TI - Gandhi's Truth. PMID- 28908945 TI - Expecting the Worst. PMID- 28908947 TI - Room to Relax. PMID- 28908948 TI - Words under Sentence. PMID- 28908949 TI - The Right to Earn a Living. PMID- 28908951 TI - The Scene. PMID- 28908950 TI - Vacant Seat on the 7.57. PMID- 28908952 TI - When Love Is Lacking. PMID- 28908953 TI - Refugee Children in England. PMID- 28908954 TI - Group Teaching in Wartime: An Educational Opportunity. PMID- 28908956 TI - Behaviour in Relation to War Conditions: A Preliminary Enquiry. PMID- 28908955 TI - Mental Nursing as a Career. PMID- 28908957 TI - Electroencephalography in Relation to Behaviour Problems. PMID- 28908958 TI - The Trend of Scientific Thought. PMID- 28908959 TI - A Special School Evacuation Unit: Some Observations on Its Value. PMID- 28908961 TI - Emergency Hostels for Difficult Children. PMID- 28908960 TI - A Mental Deficiency Institution in Wartime. PMID- 28908962 TI - Strategic Planning for Mental Health. PMID- 28908963 TI - Arithmetic without Fear. PMID- 28908964 TI - The Modern Mental Hospital: How the Mental Nurse Can Play a Part in Educating Public Opinion. PMID- 28908965 TI - The Children's Magistrate and the Child Guidance Clinic. PMID- 28908966 TI - The Provisional National Council for Mental Health. PMID- 28908967 TI - Observations on the Relationship between Child and Adult Neurosis. PMID- 28908968 TI - Post-War Reform in Mental Nursing. PMID- 28908969 TI - Child Guidance, the Clinic and the School. PMID- 28908970 TI - Matrix Tests. PMID- 28908971 TI - Some Psychological Difficulties of Evacuation. PMID- 28908972 TI - Foreword. PMID- 28908974 TI - Special Evacuation Difficulties of the Residential School Child. PMID- 28908973 TI - The Bedwetting Problem. PMID- 28908975 TI - Emergency Gardening. PMID- 28908976 TI - Military Service for Mental Defectives. PMID- 28908977 TI - Backwardness in Rural Areas. PMID- 28908979 TI - The Problem of Illiteracy. PMID- 28908978 TI - A New Form of Group Psychotherapy. PMID- 28908980 TI - The Problem Child in the Hostel. PMID- 28908981 TI - Hostels for Children in Need of Psychiatric Attention. PMID- 28908982 TI - Special Schools and the Education Act. PMID- 28908983 TI - The Mental Hygiene Movement. PMID- 28908984 TI - Special Schools and the Education Bill. PMID- 28908985 TI - The Training of Teachers and Youth Leaders. PMID- 28908986 TI - The Therapy of Play. PMID- 28908987 TI - A Psychologist Looks at Educational Reconstruction. PMID- 28908988 TI - Some Observations on the Effect of Evacuation upon Mentally Defective Children. PMID- 28908989 TI - Juvenile Delinquency and the War: A Critical Survey of Current Comments. PMID- 28908990 TI - Mental Health in Post-War Reconstruction. PMID- 28908991 TI - Observed Effects of Wartime Conditions on Children. PMID- 28908992 TI - The Need for a Positive Philosophy of Life. PMID- 28908993 TI - Play Therapy. PMID- 28908994 TI - Mobile Child Guidance Teams in the Liberated Countries of Europe. PMID- 28908995 TI - Children in Need of Homes: Some Suggestions by Two Psychiatric Social Workers. PMID- 28908996 TI - Psychiatry in the National Health Service of the Future. PMID- 28908997 TI - Lord Memorial Prize Essay: The Nurse's Part in Helping the Newly Admitted Patient to Settle down. PMID- 28908999 TI - A Study of the General Development of the Preschool Child by Means of Record Forms. PMID- 28908998 TI - Mental Health Work for Air Raid Victims. PMID- 28909000 TI - How Can the Nurse Help the Refractory Patient? PMID- 28909001 TI - Child Guidance Service in Wartime. PMID- 28909003 TI - Intelligence and Fertility. PMID- 28909002 TI - Fortitude in War. PMID- 28909005 TI - A Psychologist's Contribution to Air Raid Problems. PMID- 28909004 TI - Some Wartime Problems of Mental Health. PMID- 28909007 TI - Editorial. PMID- 28909006 TI - Occupational Therapy in Wartime. PMID- 28909008 TI - National Association for Mental Health, Current Educational Activities. PMID- 28909009 TI - The Contribution of Alfred Adler to Mental Health. PMID- 28909010 TI - Residential Schools for Epileptic Children in England. PMID- 28909011 TI - ... And Nobody Cares for Me! PMID- 28909012 TI - Certified. PMID- 28909013 TI - The International Congress on Mental Health: London, 11th to 21st August, 1948. PMID- 28909014 TI - Juvenile Delinquency. PMID- 28909015 TI - Child Guidance. PMID- 28909016 TI - Film Reviews. PMID- 28909018 TI - Mine Own Executioner. PMID- 28909017 TI - How Can the Mental Nurse Contribute to the Recovery of the Depressed Patient? PMID- 28909019 TI - National Health Service Act, 1946: Local Authorities' Schemes for a Mental Health Service. PMID- 28909020 TI - Editorial. PMID- 28909022 TI - Forthcoming Activities of the Provisional National Council for Mental Health. PMID- 28909021 TI - Forty Years in an Institution. PMID- 28909024 TI - Mental Deficiency in Northern Ireland. PMID- 28909023 TI - Social Work in a Military Hospital. PMID- 28909025 TI - Editorial. PMID- 28909026 TI - What Are the Essential Personal Qualities Required for Success in Mental Nursing? PMID- 28909027 TI - The Mental Health Service in England and Wales : 1939 to 1945. PMID- 28909028 TI - Scottish Lunacy and Mental Deficiency Laws. PMID- 28909029 TI - National Association for Mental Health. Forthcoming Activities. PMID- 28909030 TI - Forthcoming Activities. PMID- 28909031 TI - The Value of Conferences. PMID- 28909032 TI - Film Reviews. PMID- 28909033 TI - International Congress on Mental Health. PMID- 28909034 TI - Notes on Recent Legislation. PMID- 28909035 TI - A Mental Health Exhibition. PMID- 28909036 TI - Editorial. PMID- 28909037 TI - Film Reviews. PMID- 28909038 TI - International Congress on Mental Health: London, August 11th to 21st, 1948. PMID- 28909039 TI - Corrective Teaching for Defects of Speech in Backward and Mentally Defective Children. PMID- 28909040 TI - Mental Inefficiency and Crime: Report of the Prison Commissioners. PMID- 28909041 TI - The Value of Social Service in the Out-Patient Treatment of Mental Disorder. PMID- 28909042 TI - The Essential Unity of the Mental Problem. PMID- 28909043 TI - The Child Guidance Council and the Commonwealth Fund. PMID- 28909044 TI - The Question of Sterilization in Denmark. PMID- 28909045 TI - The International Society for "Logopaedia". PMID- 28909046 TI - The Sterilization of Mental Defectives. PMID- 28909047 TI - Performance Tests with Defectives. PMID- 28909048 TI - The Diagnosis of Adolescent Mental Conditions, with Special Reference to Delinquents. PMID- 28909049 TI - A Letter from America. PMID- 28909050 TI - Work among the Mentally Defective in Switzerland. PMID- 28909051 TI - Some Thoughts on Juvenile Delinquency. PMID- 28909052 TI - The Lost Rhythm: A Few Notes on the Marjorie Gullan Method of Rhythmic Movement to Spoken Poetry. PMID- 28909053 TI - Notes on the Investigation and Treatment of "Difficult" Children in the United States of America. PMID- 28909054 TI - Architecture and the Care of the Mentally Deficient. PMID- 28909055 TI - Mental Welfare and the Endocrine Organs. PMID- 28909056 TI - Some Reflections on the Report of the Royal Commission on Lunacy and Mental Disorder. PMID- 28909057 TI - Combined Defect. PMID- 28909058 TI - Intelligence Tests at the Royal Eastern Counties' Institution. PMID- 28909059 TI - Christmas Days. PMID- 28909060 TI - At What Age Does Intelligence Cease to Develop? and Intelligence in Relation to Different Social Classes. PMID- 28909061 TI - Review of the Year 1925-26. PMID- 28909062 TI - The Evidence of the C.A.M.W. before the Royal Commission on Lunacy and Mental Disorders. PMID- 28909063 TI - Correspondence. PMID- 28909064 TI - The British Medical Association and the Prevention of Mental Deficiency. PMID- 28909065 TI - Some Observations on the Mental Changes Occurring in Encephalitis Lethargica. PMID- 28909066 TI - State Institutions for Violent and Dangerous Defectives. PMID- 28909068 TI - Education of Children of Combined Defect. PMID- 28909067 TI - The Montessori Method and the Education of the High Grade Moron. PMID- 28909069 TI - The Munich Psychiatric Clinic and the Present Movement for the Foundation of Similar Institutions in England. PMID- 28909071 TI - Erratum: A Correction. AB - [This corrects the article on p. 93 in vol. 7.]. PMID- 28909070 TI - The Education and Care of the Mentally Defective Child in Renfrewshire. PMID- 28909072 TI - Combined Defect. PMID- 28909073 TI - A Modified Dalton Plan in a Special School. PMID- 28909074 TI - Fifteen Years' Experience with Defectives on Livo. PMID- 28909075 TI - Diphtheria in an Institution: An Account of the Application of the Schick Test at the Royal Eastern Counties Institution. PMID- 28909076 TI - Dulness in Rural Children. PMID- 28909077 TI - The Border Line Feeble-Minded Child: How Can He Be Catered for in the School System? PMID- 28909079 TI - Some Lesser Known Views of Mental Deficiency. PMID- 28909078 TI - Some Aspects of Stammering. PMID- 28909080 TI - An Experiment in Boarding out. PMID- 28909082 TI - Report of the Departmental Committee on Sterilisation. PMID- 28909081 TI - Report of Departmental Committee on Sterilisation. PMID- 28909083 TI - Impressions of Mental Deficiency Work in England. PMID- 28909084 TI - The Sex Incidence of Mental Deficiency (Amentia), with a Consideration of Mental Variation in the Sexes. PMID- 28909085 TI - Emotional Factors in the Diagnosis and Treatment of Mental Defect. PMID- 28909086 TI - Some Observations on the Treatment of Delinquents. PMID- 28909087 TI - Gardening and the Feeble-Minded. PMID- 28909088 TI - Birmingham Child Guidance Clinic. A Review of Two Years' Work. PMID- 28909089 TI - Voluntary Sterilisation: An Account of a Discussion Held by the Public Health Congress Council in Conjunction with the Joint Committee on Sterilisation. PMID- 28909090 TI - Departmental Report on Sterilisation. PMID- 28909091 TI - The Work of an Approved School. PMID- 28909092 TI - Social Work in Mental Hospitals and Out-Patient Clinics. PMID- 28909093 TI - Occupation Therapy. PMID- 28909094 TI - Another Year's Work: Report of the Board of Control, 1934. PMID- 28909095 TI - Some Aspects of Character Defect. PMID- 28909096 TI - Guardianship: A Lighter Aspect. PMID- 28909097 TI - Co-Operation in Mental Health Administration. PMID- 28909098 TI - Q Camps. PMID- 28909099 TI - Recent Educational Experiments. I. PMID- 28909100 TI - Special Schools: An International Pronouncement. PMID- 28909101 TI - A Friend of Defective Children. PMID- 28909102 TI - National Special Schools Union: Edinburgh Conference, June, 1935. PMID- 28909104 TI - Beyond Hospital Gates. PMID- 28909103 TI - Joint Committee on Voluntary Sterilisation. PMID- 28909105 TI - An Experiment in Listening. PMID- 28909106 TI - The Home Teaching of Defectives. PMID- 28909107 TI - Play Therapy. PMID- 28909108 TI - Correspondence. PMID- 28909110 TI - Mental Welfare Activities in New Zealand. PMID- 28909109 TI - "Nerves" as a Handicap to Efficiency. PMID- 28909112 TI - News of the Voluntary Associations. PMID- 28909111 TI - Testing the Development of Young Children. PMID- 28909113 TI - Prisons and the Mentally Defective. PMID- 28909114 TI - The Personnel of a Psychiatric Clinic. PMID- 28909115 TI - The Treatment of Insanity. PMID- 28909116 TI - Mental Nursing: Some Present Day Difficulties. PMID- 28909117 TI - Occupational Therapy. PMID- 28909118 TI - Special Education for Retarded Children. PMID- 28909120 TI - New Zealand News: Communicated. PMID- 28909119 TI - Miss Evelyn Fox, C.B.E.: A Tribute. PMID- 28909121 TI - Modern Educational Experiments III: Experimental Schools. PMID- 28909122 TI - Denmark's Care of Mental Defectives. PMID- 28909123 TI - Religion and Psychotherapy. PMID- 28909124 TI - The Therapeutic Value in Mental Illness of Physical Fitness through Exercise. PMID- 28909125 TI - Modern Educational Experiments, II: Visiting Teachers for Retarded Children. PMID- 28909126 TI - The Need for Community Care of Epileptics. PMID- 28909127 TI - Backward Children in the Junior School. PMID- 28909128 TI - Joint Register of Foster-Homes and Schools for Nervous, Difficult and Retarded Children. PMID- 28909129 TI - Dulcimer Playing for Defectives. PMID- 28909130 TI - Observations on the Training of Idiots and Low-Grade Imbeciles. PMID- 28909131 TI - Modern Educational Experiments, VI: The Use of Films in the Education of Backward Boys. PMID- 28909132 TI - Modern Mental Treatment in an "Asylum". PMID- 28909133 TI - The Children's Branch of the Home Office. PMID- 28909134 TI - Towards a Unified Mental Health Service. PMID- 28909135 TI - Evacuation and Mental Health Problems. PMID- 28909136 TI - The Voluntary Mental Health Services: Report of the Feversham Committee. PMID- 28909137 TI - Mental Health Emergency Committee. PMID- 28909138 TI - Eurhythmics in the Special School. PMID- 28909139 TI - Creative Music in the Progressive Education Programme for the Exceptional Child. PMID- 28909140 TI - Holiday Homes for Mental Patients. PMID- 28909141 TI - Mental Observation Wards in London. PMID- 28909142 TI - The Physical Education of Mentally Deficient Children. PMID- 28909144 TI - The Board of Education & Backward Children. PMID- 28909143 TI - Educational Provision for Retarded Children. PMID- 28909145 TI - The Treatment of Speech Defects in Elementary Schools. PMID- 28909147 TI - Mental Deficiency Administration, 1937. PMID- 28909146 TI - "Well Done, Considering..." PMID- 28909148 TI - Some Experiences of an Educational Psychologist. PMID- 28909149 TI - The Relative Functions of the Occupation Centre and the Mental Deficiency Colony in the Training of Defectives. PMID- 28909150 TI - Mental Health Work in Germany: Contributed. PMID- 28909152 TI - A Social Problem Group? PMID- 28909151 TI - Denmark's Care of Mental Defectives. PMID- 28909154 TI - Modern Educational Experiments, IV: Classes for Retarded Children in Elementary Schools. PMID- 28909153 TI - Care Committees in M.D. Schools. PMID- 28909156 TI - The Physical Education of Backward Children. PMID- 28909155 TI - Modern Educational Experiments, V: "Opportunity" Pupils in a Senior Boys' School. PMID- 28909157 TI - A Talk on Epilepsy. PMID- 28909158 TI - Some Psychological Problems in "Institutionalising" Defectives. PMID- 28909160 TI - A Judgment Test for Measuring Intelligence. PMID- 28909159 TI - Psychiatric Work in a Mental Hospital. PMID- 28909162 TI - Report on the Psychological Treatment of Crime. PMID- 28909161 TI - Recent Penal Legislation in Relation to Mental Health Problems. PMID- 28909163 TI - About Institutions and Epilepsy. PMID- 28909165 TI - The Primary School and Wood Reports. PMID- 28909164 TI - Some Impressions of Mental Deficiency Work in the United States. PMID- 28909167 TI - Some Physical Aspects of Mental Deficiency: Article 3. PMID- 28909166 TI - Speech Training for Backward and Defective Children: Article III Nasal Speech. PMID- 28909168 TI - The Making of Stories. PMID- 28909169 TI - Vocational Testing in Relation to Professor Spearman's Theories. PMID- 28909170 TI - The Use and Abuse of Mental Tests. PMID- 28909171 TI - Maladjustment and Readjustment. PMID- 28909172 TI - Mental Defect. The Point of View of an Individualist. PMID- 28909173 TI - Primary and Secondary Amentia. PMID- 28909174 TI - A New Experiment. PMID- 28909175 TI - Research Work at Birmingham into the Use of Psychological Tests in Vocational Guidance. PMID- 28909176 TI - The Reading Difficulties Shown by Types of Retarded Children. PMID- 28909178 TI - Mental Defectiveness: As Defined in the Mental Deficiency Act, 1927. PMID- 28909177 TI - Following-Up the Special School Child. PMID- 28909179 TI - Combined Open Air Schools for Mentally Defective and Other Handicapped Children. PMID- 28909180 TI - The Investigation and Diagnosis of Behaviour Disorders in Children. PMID- 28909181 TI - Libraries in Mental Hospitals. PMID- 28909183 TI - A Typical Holiday Fortnight for Mental Defectives. PMID- 28909182 TI - Defects of Speech among School Children. PMID- 28909184 TI - The Royal Medico-Psychological Association: Contributed. PMID- 28909185 TI - Mental Deficiency and Venereal Disease. PMID- 28909186 TI - Mental Health Workers-An Appreciation. PMID- 28909187 TI - Moral Deficiency and the Persistent Offender. PMID- 28909188 TI - The Difficult Child in Industry. PMID- 28909189 TI - Speech Training for Defective Children: Article Two. PMID- 28909191 TI - Mental Deficiency in Vienna and Berlin. PMID- 28909190 TI - Vocational Guidance. PMID- 28909192 TI - Child Guidance and Juvenile Delinquency. PMID- 28909194 TI - Special Class Handwork in a London School. PMID- 28909193 TI - The Rome State School and Its Colony System. PMID- 28909195 TI - The Sterilization of Mental Defectives. PMID- 28909196 TI - Visiting in Mental Hospitals. PMID- 28909197 TI - The Sterilization of Mental Defectives. PMID- 28909198 TI - Impressions. PMID- 28909199 TI - Social Work in Out-Patient Clinics. PMID- 28909200 TI - Training for Occupational Therapy. PMID- 28909201 TI - Mental after Care. PMID- 28909202 TI - Occupational Therapy as a Profession. PMID- 28909203 TI - The C.A.M.W. Guardianship Scheme. PMID- 28909204 TI - Cheaper Institutional Care. PMID- 28909205 TI - A Visit to Gheel Colony, Belgium. PMID- 28909206 TI - Living Institution Life. PMID- 28909207 TI - Habit Formation. PMID- 28909208 TI - The Education of Children Suffering from Defects of Speech. PMID- 28909209 TI - The Eugenics Society's Draft Sterilization Bill. PMID- 28909211 TI - The Report of the Joint Committee on Mental Deficiency. PMID- 28909210 TI - Mental Deficiency under the Local Government Bill, 1928. PMID- 28909212 TI - Child Guidance. PMID- 28909214 TI - The Development of Social Work in Edinburgh. PMID- 28909213 TI - Resolution Passed by the Executive Council and Letter to the "Times": Incorporated. PMID- 28909215 TI - Merely Dull or Backward. PMID- 28909216 TI - The British Medical Association Report on Mental Deficiency. PMID- 28909217 TI - Occupational Therapy in Mental Hospitals. PMID- 28909218 TI - The Teaching of Art to Children of Limited Intelligence: A Few Hints to Teachers. PMID- 28909219 TI - Guiding in a Welsh Workhouse. PMID- 28909220 TI - Sterilization of Mental Defectives. PMID- 28909221 TI - Speech Training for Backward and for Defective Children. PMID- 28909222 TI - Syphilis and Birth Difficulties in "Combined Defect." PMID- 28909223 TI - A Note on the Sterilisation of Mental Defectives. PMID- 28909224 TI - Aphasia in Children. PMID- 28909225 TI - The Mental Treatment Bill. PMID- 28909227 TI - A Psychiatrist's Week in Paris. PMID- 28909226 TI - Speech Training and the Teacher. PMID- 28909228 TI - Mental Deficiency as a Community Problem. PMID- 28909229 TI - Community Schemes for the Social Control of Mental Defectives. PMID- 28909230 TI - The Hostel Method for Feeble-Minded Young Men and Women. PMID- 28909231 TI - Hostel for Girls at Bath. PMID- 28909232 TI - Mental Deficiency and the Local Government Bill. PMID- 28909233 TI - Report of the Joint Committee on Mental Deficiency: Questions and Answers in the House. PMID- 28909234 TI - The Organisation of Classes for Retarded Children. PMID- 28909235 TI - Experiments in the Education and Training of Retarded Children: With Special Reference to Some of the Recommendations of the Joint Committee. PMID- 28909236 TI - An Experiment in the Education of Retarded Children in a Rural County. PMID- 28909237 TI - The Report of the Special Investigation Carried out on Behalf of the Joint Committee. PMID- 28909238 TI - A Case of Pathological Day Dreaming. PMID- 28909240 TI - News and Comment. PMID- 28909239 TI - The Witmer Formboard and Cylinders as Tests for Children Two to Six Years of Age. PMID- 28909241 TI - News and Comment. PMID- 28909242 TI - Obadiah, a Child with a Numerical Obsession. PMID- 28909243 TI - Effects of Smoking on Mental and Motor Efficiency. PMID- 28909244 TI - A Study of 100 Retarded Fourth Grade Pupils Tested by the Binet Scale. PMID- 28909246 TI - Clinic Reports. PMID- 28909245 TI - Preliminary Impressions of the Stanford Revision of the Binet-Simon Scale. PMID- 28909247 TI - News and Comment. PMID- 28909248 TI - A Report on the Standardization of the Witmer Cylinder Test. PMID- 28909249 TI - Errors in Scoring Binet Tests. PMID- 28909251 TI - Clinic Reports. PMID- 28909250 TI - The Peg Formboards. PMID- 28909253 TI - A Clinical Survey of a First Grade. PMID- 28909252 TI - News and Comment. PMID- 28909254 TI - Diagnostic Problems in Educational Guidance at the Observation School, University of Pennsylvania. PMID- 28909256 TI - Clinical Psychology and Diagnostic Education. PMID- 28909255 TI - A Case of Special Difficulty with Reading. PMID- 28909257 TI - Four Cases of Diagnostic Teaching. PMID- 28909258 TI - Failures Due to Language Deficiency. PMID- 28909259 TI - Five Cases in Vocational Guidance. PMID- 28909260 TI - A Day in Court-Problems in Correctional Guidance. PMID- 28909262 TI - An Analysis of the Proficiency and Competency of a Fourth Grade Class. PMID- 28909261 TI - Some Problems at the Work Age Level. PMID- 28909263 TI - Diagnostic Teaching: A Case of Deficient Energy. PMID- 28909264 TI - A Demonstration Clinic. PMID- 28909265 TI - The Classification of Criminals. PMID- 28909266 TI - The Present Status of the Subnormal Class. PMID- 28909267 TI - Shell-Shock. PMID- 28909268 TI - The Training of Very Bright Children. PMID- 28909269 TI - The Meaning of a Binet Score. PMID- 28909270 TI - Diagnostic Teaching: A Question of Imagery. PMID- 28909271 TI - Intelligence and Efficiency Tests Distinguished. PMID- 28909272 TI - Debit or Credit. PMID- 28909273 TI - The Analytical Diagnosis. PMID- 28909274 TI - Effects of Smoking on Mental and Motor Efficiency (Conclusion). PMID- 28909276 TI - Dick-A Case of Atavism: A Clinical Lecture Reported by the Recorder of the Psychological Clinic. PMID- 28909275 TI - The Educability Level: The Determination of Competency to Do the Work of the First School Year. PMID- 28909277 TI - Canton Kallikaks. PMID- 28909278 TI - The Children of a Jewish Orphanage: A Preliminary Report of a Psychological Survey. PMID- 28909279 TI - Memory Span Tests. PMID- 28909280 TI - Sometime Later: A Follow-Up of Two Clinic Cases. PMID- 28909281 TI - A Comparison of Test Ratings and College Grades. PMID- 28909282 TI - Diagnostic Teaching: A Case of Infantile Stammer Resulting in Apparent Imbecility. PMID- 28909283 TI - Diagnostic Teaching: The Grading and Analytic Diagnosis of a Feebleminded Boy. PMID- 28909285 TI - News and Comment. PMID- 28909284 TI - Diagnostic Teaching: A Case of Mental Deficiency and Doubtful Social Competency. PMID- 28909286 TI - The Henderson Family: The Social Level of a Group Determined by the Clinical Field Service. PMID- 28909288 TI - A Student's Report of a Clinical Examination. PMID- 28909287 TI - Diagnostic Teaching: A Case of Deficient Retentiveness. PMID- 28909289 TI - Performance and Success: An Outline of Psychology for Diagnostic Testing and Teaching. PMID- 28909290 TI - Efficiency and Other Factors of Success. PMID- 28909291 TI - The Problem of Educability. PMID- 28909292 TI - Irregularity on a Binet Examination as a Measure of Its Reliability. PMID- 28909294 TI - Mental and Moral Deficiency in a High-School Girl. PMID- 28909293 TI - A Case of Loss of Psycho-Motor Control, Suspected of Malingering. PMID- 28909295 TI - Intelligence Tests Versus Teacher's Estimate. PMID- 28909296 TI - The Feminine Absolute. PMID- 28909297 TI - The Educability Level of Five-Year-Old Children. PMID- 28909298 TI - The Attempt to Teach: A Diagnostic Method Illustrated by the Clinic Teaching of Typical Cases. PMID- 28909299 TI - Don: A Curable Case of Arrested Development Due to a Fear Psychosis the Result of Shock in a Three-Year-Old Infant. PMID- 28909300 TI - Grace. PMID- 28909301 TI - A Comparison of Two Cases. PMID- 28909302 TI - Spoken Language an Essential Tool. PMID- 28909303 TI - The Continuation Girl. PMID- 28909304 TI - Speed and Accuracy of the Feebleminded on Performance Tests. PMID- 28909305 TI - Psychomotor Activity and Feeblemindedness. PMID- 28909306 TI - News and Comment. PMID- 28909307 TI - A Case Study of Dextral Training of a Left-Handed Boy. PMID- 28909308 TI - A Clinical Study of a Severe Case of Reading Disability in a Left-Handed Child. PMID- 28909309 TI - The Significance of Vocabulary in the Interview. PMID- 28909310 TI - Measuring General Intelligence by Interview. PMID- 28909311 TI - Teaching Student Assistants to Use Objective Aids in Their Interviews with Younger Students. PMID- 28909312 TI - Objective Methods in the Personal Interview in Vocational Guidance. PMID- 28909314 TI - Three Behavior Problems. PMID- 28909313 TI - Normal but Undomesticated. PMID- 28909316 TI - A Case of Inefficiency Due to Physical Handicaps. PMID- 28909315 TI - Psychonomic Personeering. PMID- 28909317 TI - Sibship: Intelligence and Behavior. PMID- 28909318 TI - A Case of Reading Disability Due to Deficient Visual Imagery. PMID- 28909320 TI - The Status of Tests for the Measurement of Clerical Aptitude. PMID- 28909319 TI - A Study of Causes of Left-Hand Writing Preferences of Some Right-Handed Children. PMID- 28909321 TI - The Significance of Test Results in Predicting Efficiency in Garment Machine Operating. PMID- 28909323 TI - The Use of Tests in the Selection of Pupils for Rapid Advancement. PMID- 28909322 TI - The Differentiation of Vocational Aptitudes. PMID- 28909324 TI - Intelligence of Unmarried Mothers, II. PMID- 28909326 TI - News and Comment. PMID- 28909325 TI - The Psychological Manifestations of Post-Choreic Conditions as Shown in Five Case Studies. PMID- 28909327 TI - Case Studies: Two Cases of Probable Post-Encephalitis. PMID- 28909328 TI - The Training of Mental Hygienists. PMID- 28909329 TI - The Correlation of the Reverse Audito-Vocal Digit Memory Span with the General Intelligence and Other Mental Abilities of 308 Prisoners. PMID- 28909330 TI - Eugene, a Brilliant Boy Who Failed in School. PMID- 28909331 TI - Procedure for Scoring an Interest Test. PMID- 28909332 TI - Investigation of Vocational Interests among Workers. PMID- 28909333 TI - The Psychological Examination of Interests for Guidance. PMID- 28909334 TI - An Information Test of Interests. PMID- 28909335 TI - The Interest Inventory in College Vocational Guidance. PMID- 28909336 TI - The Respiratory Significance of Blood Counts. PMID- 28909338 TI - News and Comment. PMID- 28909337 TI - Foreign Born Parentage and Social Maladjustment. PMID- 28909339 TI - A Case of Intellectual Superiority with Personality Handicaps and General Maladjustment. PMID- 28909340 TI - What Do Children Come to the Psychological Clinic for? PMID- 28909341 TI - Variability of I.Q.s for Psychopaths Compared with Normal Children. PMID- 28909342 TI - Three Case Studies in the Diagnostic Education of Children with Speech Defects. PMID- 28909344 TI - A Study of the Reading Attainment of Children in Ungraded Classes. PMID- 28909343 TI - Small Head Size Associated with Mental Defect. PMID- 28909345 TI - The Clinical Examination and Diagnostic Teaching of Cases at the Psychological Clinic of the University of Pennsylvania. PMID- 28909346 TI - The Personnel of a Children's Home, a Cumulative Psychological Study (Part II). PMID- 28909347 TI - Social Psychiatric Treatment of a Post-Encephalitic Boy of Twelve Years. PMID- 28909348 TI - The Performance Level of Children in the Sixth Grade in Two Philadelphia Public Schools. PMID- 28909349 TI - Clinical Problems in the Vocational Guidance of the Mentally Deficient. PMID- 28909350 TI - The Vocational Adjustment of Mental Defectives. PMID- 28909351 TI - An Investigation of the Adjustment of the Feebleminded in the Community. PMID- 28909352 TI - Jean Marc Gaspard Itard. PMID- 28909353 TI - The Personnel of a Children's Home, a Cumulative Psychological Study (Part I). PMID- 28909354 TI - A Study of Test Results at the Third and Fifth Grade Levels. PMID- 28909355 TI - The Psychological Study of Blind Children. PMID- 28909356 TI - Case Studies in Diagnostic Education. PMID- 28909357 TI - The Remedial Treatment of a Case of Defective Speech Due to Deafness. PMID- 28909358 TI - Restlessness in a Delinquent Group. PMID- 28909359 TI - Three Case Studies in Diagnostic Education. PMID- 28909360 TI - A Psychological Analysis of Three Delusional States: The Belief in the Control of Thought from Without, in the Unreality of the External World, and in the Unreality of the Self. PMID- 28909361 TI - News and Comment. PMID- 28909362 TI - A Clinical Examination Blank for Backward Children in the Public Schools. PMID- 28909363 TI - The Retardation of the Pupils of Five City School Systems. PMID- 28909364 TI - A Clinical Examination Blank for Backward Children in the Public Schools: III. PMID- 28909365 TI - News and Comment. PMID- 28909366 TI - News and Comment. PMID- 28909367 TI - The Fifteen Months' Training of a Feeble-Minded Child. PMID- 28909369 TI - News and Comment. PMID- 28909368 TI - Public Day Schools for Backward Children. PMID- 28909370 TI - Clinical Studies of Retarded Children. PMID- 28909371 TI - The Influence of Physiological Age upon Scholarship. PMID- 28909372 TI - The Need for Special Classes in the Public Schools. PMID- 28909374 TI - News and Comment. PMID- 28909373 TI - A Case of Chronic Bad Spelling-Amnesia Visualis Verbalis, Due to Arrest of Post Natal Development. PMID- 28909376 TI - News and Comment. PMID- 28909375 TI - A Method for Determining the Extent and Causes of Retardation in a City School System. PMID- 28909377 TI - An Infantile Stammer (Baby Talk) in a Boy of Twelve Years. PMID- 28909378 TI - University Courses in Psychology. PMID- 28909379 TI - A Juvenile Delinquent. PMID- 28909380 TI - Clinical Psychology. PMID- 28909381 TI - The Relation of Physical to Mental Defect in School Children. PMID- 28909382 TI - A Clinical Examination Blank for Backward Children in the Public Schools: II. PMID- 28909383 TI - News and Comment. PMID- 28909385 TI - Retardation through Neglect in Children of the Rich. PMID- 28909384 TI - The Vision of the Pupils of an Elementary School Tested by the Alphabet and Illiterate Cards. PMID- 28909386 TI - News and Comment. PMID- 28909387 TI - News and Comment. PMID- 28909388 TI - The Hospital School. PMID- 28909389 TI - The Mental Condition of Juvenile Delinquents. PMID- 28909390 TI - Summer Camps. PMID- 28909392 TI - News and Comment. PMID- 28909391 TI - Sixty-Two Days' Training of a Backward Boy: II. PMID- 28909394 TI - What Do Histories of Cases of Insanity Teach Us Concerning Preventive Mental Hygiene during the Years of School Life? PMID- 28909393 TI - News and Comment. PMID- 28909395 TI - Provision for Exceptional Children in the Public Schools. PMID- 28909396 TI - The Need of Improved Records of the Physical Condition of School Children. PMID- 28909398 TI - Retardation and Elimination in the Schools of Mauch Chunk Township. PMID- 28909397 TI - The Prevalence of Visual and Aural Defects among the Public School Children of St. Louis County, MO. PMID- 28909399 TI - News and Comment. PMID- 28909400 TI - News and Comment. PMID- 28909401 TI - Retrospect and Prospect: An Editorial. PMID- 28909402 TI - Sixty-Two Days' Training of a Backward Boy. PMID- 28909403 TI - News and Comment. PMID- 28909405 TI - Some Factors Affecting Grade Distribution. PMID- 28909404 TI - The Training of a Backward Boy. PMID- 28909406 TI - Penny Luncheons. PMID- 28909408 TI - Intelligent Imitation and Curiosity in a Monkey. PMID- 28909407 TI - The Dental Disabilities of School Children. PMID- 28909409 TI - News and Comment. PMID- 28909410 TI - Promotion, Retardation, and Elimination. PMID- 28909411 TI - News and Comment. PMID- 28909412 TI - The Effect of School Room Temperature on the Work of Pupils. PMID- 28909413 TI - Our Schoolhouses. PMID- 28909414 TI - A Simple and Practical Test of Hearing. PMID- 28909415 TI - Irregular Attendance in the Primary Grades. PMID- 28909416 TI - The Reading Free Dental Dispensary. PMID- 28909417 TI - News and Comment. PMID- 28909418 TI - The Restoration of Children of the Slums. PMID- 28909420 TI - News and Comment. PMID- 28909419 TI - Promotion, Retardation, and Elimination, II. PMID- 28909421 TI - Some Further Considerations upon the Retardation of the Pupils of Five City School Systems. PMID- 28909423 TI - News and Comment. PMID- 28909422 TI - Mentally Defective Children in the Public Schools. PMID- 28909425 TI - Mental Healing and the Emmanuel Movement. PMID- 28909424 TI - Some Uses of Statistics in the Supervision of Schools. PMID- 28909426 TI - An Examination of the Eyes, Ears, and Throats of Children in the Public Schools of Jefferson City, MO. PMID- 28909427 TI - News and Comment. PMID- 28909428 TI - A Concrete Example of the Value of Individual Teaching. PMID- 28909429 TI - Mental Healing and the Emmanuel Movement. PMID- 28909430 TI - Gymnastics as a Factor in the Treatment of Mental Retardation. PMID- 28909431 TI - News and Comment. PMID- 28909432 TI - The Playground as a Factor in School Hygiene. PMID- 28909433 TI - Irregular Attendance-A Cause of Retardation. PMID- 28909434 TI - A Lesson from Medical Inspection of Schools. PMID- 28909435 TI - Report of a Year's Work on Defectives in a Public School. PMID- 28909436 TI - The Money Cost of the Repeater. PMID- 28909437 TI - News and Comment. PMID- 28909439 TI - Orthogenics in the Public Schools: An Editorial. PMID- 28909438 TI - A Cincinnati Special Class. PMID- 28909440 TI - Medical Inspection in the Saint Paul Schools. PMID- 28909441 TI - The Effect of Physical Defects on School Progress. PMID- 28909442 TI - A Plea for the Systematic Annual and Universal Examination of School Children's Eyes and Ears. PMID- 28909443 TI - Starvation and Mental Development. PMID- 28909444 TI - The Physical Condition of the School Children of the School of Observation, University of Pennsylvania. PMID- 28909445 TI - Conservation of Health in the School Room. PMID- 28909446 TI - Progress and Retardation of a Baltimore Class. PMID- 28909448 TI - News and Comment. PMID- 28909447 TI - A Class of Backward and Defective Children. PMID- 28909449 TI - News and Comment. PMID- 28909450 TI - The Treatment and Cure of a Case of Mental and Moral Deficiency. PMID- 28909452 TI - News and Comment. PMID- 28909451 TI - Classification and Education of Afflicted Children. PMID- 28909453 TI - Size of Classes and School Progress. PMID- 28909454 TI - A Monkey with a Mind. PMID- 28909455 TI - Association Tests in Practical Work for the Insane. PMID- 28909456 TI - News and Comment. PMID- 28909457 TI - Elimination of Pupils from School: A Review of Recent Investigations. PMID- 28909458 TI - News and Comment. PMID- 28909459 TI - Retardation in Salt Lake City. PMID- 28909460 TI - Difficulties in the Interpretation of Mental Tests-Types and Examples. PMID- 28909461 TI - Bringing Children up to Grade. PMID- 28909462 TI - The Social Aspect of an Experiment with Retarded Children. PMID- 28909463 TI - An Organized Mental Survey in Philadelphia Special Classes. PMID- 28909464 TI - News and Comment. PMID- 28909466 TI - News and Comment. PMID- 28909465 TI - A Study of the Fernald Form-Board. PMID- 28909468 TI - On the Relation of Intelligence to Efficiency. PMID- 28909467 TI - A Study of the Comparative Retardation of Negro and White Pupils in a Philadelphia Public School. PMID- 28909469 TI - News and Comment. PMID- 28909470 TI - Vocational Guidance in the High School. PMID- 28909471 TI - Difficulties in the Interpretation of Mental Tests-Types and Examples. PMID- 28909472 TI - The Practical Application of Psychology in Social Service Work. PMID- 28909473 TI - Classification of Fifty Backward and Feebleminded Children. PMID- 28909474 TI - How Can Parents Understand Their Children? PMID- 28909475 TI - News and Comment. PMID- 28909477 TI - News and Comment. PMID- 28909476 TI - The Speech of a Left-Handed Child. PMID- 28909478 TI - The Public Schools and the Abnormal Child. PMID- 28909479 TI - The Form Board Ability of Young Deaf and Hearing Children. PMID- 28909480 TI - A Possible Restoration Case. PMID- 28909481 TI - The Social Treatment of Unmarried Mothers. PMID- 28909482 TI - Reproduction of Short Prose Passages: A Study of Two Binet Tests. PMID- 28909483 TI - News and Comment. PMID- 28909484 TI - Effect of Adolescent Instability on Conduct. PMID- 28909485 TI - Clinical Psychology and the Rural Schools. PMID- 28909486 TI - The Binet-Simon Tests in Relation to the Factors of Experience and Maturity. PMID- 28909488 TI - News and Comment. PMID- 28909487 TI - Obstructed Breathing and Memory. PMID- 28909489 TI - Improvement of Dental Hygiene in the High School, with Relation to Efficiency. PMID- 28909490 TI - Six Weeks with a Supposedly Hopeless Case. PMID- 28909491 TI - A Study of Delinquent Girls. PMID- 28909493 TI - News and Comment. PMID- 28909492 TI - Speech Defects in Young Children. PMID- 28909494 TI - The Hygiene of Eugenic Generation. PMID- 28909495 TI - News and Comment. PMID- 28909496 TI - The Artistic Value of the Montessori Geometrical Insets. PMID- 28909497 TI - Incorrigibility Due to Mismanagement and Misunderstanding. PMID- 28909498 TI - The Montessori Method. PMID- 28909499 TI - The Factor of Experience in Intelligence Testing. PMID- 28909500 TI - A Group of Children as Clinical Problems. PMID- 28909502 TI - Moral Imbecility from a Respectable Family. PMID- 28909501 TI - Open Window Classes. PMID- 28909504 TI - News and Comment. PMID- 28909503 TI - News and Comment. PMID- 28909505 TI - Need for Correlation of Binet-Simon Tests with Other Tests of Doing. PMID- 28909507 TI - News and Comment. PMID- 28909506 TI - Clinical Records. PMID- 28909508 TI - Retardation as Indicated by One Hundred City School Reports. PMID- 28909509 TI - Class Size and School Progress. PMID- 28909510 TI - A Study of the School Inquiry Report on Ungraded Classes. PMID- 28909511 TI - The Psychology of It. PMID- 28909512 TI - A Study of the School Inquiry Report on Ungraded Classes. PMID- 28909513 TI - The Problem of Life from a Girl's Point of View. PMID- 28909514 TI - News and Comment. PMID- 28909515 TI - The Further History of Some Troublesome Boys. PMID- 28909516 TI - The Hygiene of Eugenic Generation. PMID- 28909517 TI - News and Comment. PMID- 28909518 TI - A Study of Defective Pupils in the Public Schools of Tacoma, Wash. PMID- 28909519 TI - News and Comment. PMID- 28909520 TI - The Binet Tests Applied to Colored Children. PMID- 28909521 TI - Experience and the Binet-Simon Tests. PMID- 28909522 TI - The Significance of the Binet Mental Ages. PMID- 28909524 TI - A Study of the School Inquiry Report on Ungraded Classes. PMID- 28909523 TI - A Study in the Borderland of Morality. PMID- 28909526 TI - News and Comment. PMID- 28909525 TI - The Exceptional Child in School. PMID- 28909527 TI - The Significance, Limitations and Possibilities of Psycho-Biochemistry Findings. PMID- 28909528 TI - News and Comment. PMID- 28909529 TI - A Study of Probable Causal Factors of Masturbation in a Girl of Six Years. PMID- 28909530 TI - Shall We Continue to Train Clinical Psychologists for Second-String Jobs? PMID- 28909531 TI - Talented Imbeciles. PMID- 28909532 TI - Problems in Child Placing. PMID- 28909534 TI - News and Comment. PMID- 28909533 TI - Clinical Field Work in Social Service as Presented in the Psychological Clinic at the University of Pennsylvania by E. B. Twitmyer, Ph.D. PMID- 28909535 TI - A Case of Lack of Speech Due to Negativism. PMID- 28909536 TI - News and Comment. PMID- 28909537 TI - Cultivating a Wild Rose. PMID- 28909538 TI - Two Cases of Retardation Due to Educational Deprivation. PMID- 28909539 TI - Triplets. PMID- 28909540 TI - A Comparison of the P.C. and I.Q. PMID- 28909541 TI - The Nature of G as Seen by the Clinical Psychologist. PMID- 28909543 TI - Studies in Diagnostic Education: James: Mentally Deficient and Socially Retarded. PMID- 28909542 TI - Studies in Diagnostic Education: A Case of Intermittent Imbecility. PMID- 28909544 TI - Psychological Classification Versus Clinical Diagnosis. PMID- 28909545 TI - The Variability of I.Q.'S for Psychopaths Retested within Fifteen Days. PMID- 28909547 TI - Clinic Reports. PMID- 28909546 TI - A Case Study from the Vocational Guidance Clinic. PMID- 28909548 TI - Studies in Diagnostic Education: The Educational Treatment of an Intellectually Superior Boy. PMID- 28909549 TI - Studies in Diagnostic Education: A Case of Non-Conformability. PMID- 28909550 TI - The Function of the Psycho-Biochemistry Laboratory. PMID- 28909551 TI - Intelligence of Unmarried Mothers. PMID- 28909553 TI - Studies in Diagnostic Teaching: Ruth. PMID- 28909552 TI - Stanford-Binet "Indicators" of Mechanical Ability. PMID- 28909554 TI - Validating the Clinical Method in Vocational Guidance: A Preliminary Report. PMID- 28909555 TI - The Constancy of the Intelligence Quotient of Mental Defectives. PMID- 28909556 TI - Rich Man, Poor Man, Beggar Man, Thief?: An Experiment in Social Adjustment. PMID- 28909557 TI - Studies in Diagnostic Teaching: Louis. PMID- 28909558 TI - Jack Q.-A Clinic Study. PMID- 28909559 TI - Educational Guidance Leading to a Better Social Adjustment. PMID- 28909560 TI - The Play Hour. PMID- 28909561 TI - Studies in Diagnostic Teaching: Bobby. PMID- 28909562 TI - Studies in Diagnostic Teaching: Albert. PMID- 28909563 TI - Psychological Clinics in Connecticut. PMID- 28909564 TI - The Correspondence of School Achievement and Industrial Efficiency with Mental Age as Obtained by the Stanford-Binet. PMID- 28909566 TI - Account of a Fainting Epidemic in a High School. PMID- 28909565 TI - Studies in Diagnostic Teaching: Mary. PMID- 28909567 TI - Follow-Up Investigation of Five Hundred Children Who Previously Attended Classes for the Physically Handicapped. PMID- 28909568 TI - The Accuracy of the Abbreviated Stanford-Binet Intelligence Scale. PMID- 28909569 TI - An Analysis of the Binet Test of Naming Words. PMID- 28909570 TI - Some Performance Test Norms for Children. PMID- 28909571 TI - Testing the Ocular Dominance of Infants. PMID- 28909572 TI - The Relation of Continuous Association Scores to Mental Age of Adults. PMID- 28909573 TI - The Incidence of Feeblemindedness among Cases Examined in the Psychological Clinic of the University of Pennsylvania. PMID- 28909574 TI - An Analytical and Comparative Study of the Binet-Simon Test Responses of 1,306 Philadelphia School Children with an Attempt to Evaluate and Grade the Separate Tests. PMID- 28909576 TI - The Relation between Intelligence and Age of Walking in Normal and Feebleminded Children. PMID- 28909575 TI - Some Immigration Methods and Results in Deviates. PMID- 28909577 TI - The Field of Psychodietetics. PMID- 28909579 TI - The Determination of Laterality. PMID- 28909578 TI - A Comparison of Orthogenic Backward Children and Regular Grade Children at the Six Year Performance Level. PMID- 28909580 TI - Informational Content of Children in the First Four Grades. PMID- 28909582 TI - Notes and Comment. PMID- 28909581 TI - A Clinical Demonstration of Superior Children. PMID- 28909583 TI - Almost Feebleminded. PMID- 28909584 TI - A Study of Behavior Problems. PMID- 28909585 TI - Certain Phases in the Psychology of Psychologists. PMID- 28909586 TI - The Selection of Candidates for Trade School from a Group of Subnormal Italian Girls. PMID- 28909587 TI - Associative Tendencies in Psychoneurotics. PMID- 28909588 TI - Another Attempt at Measures of Extraversion-Introversion. PMID- 28909589 TI - Statistical Results of an Eight Year Testing Program of a Psychological Clinic in a Charity Hospital. PMID- 28909590 TI - The Reaction of Native White Convicts to the Bernreuter Personality Inventory. PMID- 28909591 TI - The Only Child of Age Five. PMID- 28909592 TI - Further Data on the Stanford-Binet VIII- and IX-Year Tests. PMID- 28909594 TI - A Comparative Study of Three Vocational Interest Tests. PMID- 28909593 TI - Mental Ability and Its Relation to Physical Health and Social Economic Status. PMID- 28909595 TI - Concerning the Dynamics of Crime. PMID- 28909596 TI - A Statistical Study of the Responses of a Group of Normal Children to the Individual Tests in the Stanford-Revision of the Binet-Simon Scale. PMID- 28909597 TI - A Review of the Description and Measurement of Qualifications for Dentistry and Dental Training. PMID- 28909598 TI - School Maladjustments of Some Mentally Superior Patients in a Psychiatric Clinic. PMID- 28909600 TI - Part I: A Psychonomic Contribution to Analytical Technique. PMID- 28909599 TI - The Relationship of Psychological Tests in the First Grade to School Progress: A Follow-Up Study. PMID- 28909601 TI - The Public School and the Problem Child. PMID- 28909603 TI - Concerning School Psychologists. PMID- 28909602 TI - Delinquency and Primogeniture. PMID- 28909604 TI - The Superiority Measures of the Performance of Fourth Grade Children: An Analysis of the Witmer Clinical Standards. PMID- 28909605 TI - Part II: Certain Analytical Discriminations. PMID- 28909606 TI - A Study of Criminal Conversations. PMID- 28909607 TI - Chapter I. Classification of Clinics and Tabulation of Data. PMID- 28909608 TI - Chapter II. Summarized Facts Concerning Each Clinic. PMID- 28909609 TI - Part I: The Definition of Clinical Psychology and Standards of Training for Clinical Psychologists. PMID- 28909610 TI - Report of Committee of Clinical Section of American Psychological Association. PMID- 28909611 TI - Index of Clinics. PMID- 28909612 TI - Chapter II. Summarized Facts Concerning Each Clinic: New York State-West Virginia. PMID- 28909613 TI - Enrolment by Grades in Fourteen School Systems of Central Illinois. PMID- 28909614 TI - News and Comment. PMID- 28909615 TI - How Detroit Cares for Her Backward Children. PMID- 28909616 TI - A Survey of Mentally Defective Children in the Schools of San Luis Obispo, California. PMID- 28909617 TI - A Case from the Indiana University Clinic. PMID- 28909618 TI - Retardation in the Elementary Schools of Philadelphia. PMID- 28909619 TI - Treatment of Stuttering, Stammering, and Lisping in a New York City School. PMID- 28909620 TI - News and Comment. PMID- 28909621 TI - Seven Years with Unusually Gifted Pupils. PMID- 28909622 TI - Some Results of Standard Tests. PMID- 28909624 TI - News and Comment. PMID- 28909623 TI - Some Studies on So-Called "Abnormally Intelligent" Pupils. PMID- 28909625 TI - Aspects of Infant and Child Orthogenesis. PMID- 28909626 TI - Are the Elementary Schools Getting a Square Deal? PMID- 28909627 TI - An Experiment in Concentration. PMID- 28909628 TI - The Borderland between Feeblemindedness and Insanity. PMID- 28909630 TI - News and Comment. PMID- 28909629 TI - Retardation in Nebraska. PMID- 28909632 TI - How a Psychological Clinic Can Help a Special Class. PMID- 28909631 TI - The Binet Tests Applied to Delinquent Girls. PMID- 28909633 TI - News and Comment. PMID- 28909635 TI - News and Comment. PMID- 28909634 TI - Accuracy of Pupil Reporting. PMID- 28909636 TI - A Second Study of Mental Fatigue in Relation to the Daily School Program. PMID- 28909637 TI - Vocational Training as a Preventive of Crime. PMID- 28909638 TI - Politics, Efficiency, and Retardation. PMID- 28909639 TI - Mental and Physical Examination of School Children in Rural Districts. PMID- 28909640 TI - News and Comment. PMID- 28909641 TI - Bibliography of Social Service. PMID- 28909642 TI - Individual Differences in School Children. PMID- 28909643 TI - Causes of Non-Promotion. PMID- 28909644 TI - Constructive Morals and School Life. PMID- 28909646 TI - News and Comment. PMID- 28909645 TI - Curriculum Making. PMID- 28909647 TI - Progress of Repeaters of the Class of 1912 of the Public Schools of Washington, D. C. PMID- 28909649 TI - The School Feeding Movement. PMID- 28909648 TI - Effects of Coffee-Drinking upon Children. PMID- 28909650 TI - Administration of School Luncheons. PMID- 28909652 TI - News and Comment. PMID- 28909651 TI - The Training of the School Dietitian. PMID- 28909653 TI - Retardation in the Elementary Schools of Philadelphia. PMID- 28909654 TI - Dr. Dawson's Inductive Study of School Children. PMID- 28909655 TI - Elimination and Vocational Training. PMID- 28909657 TI - News and Comment. PMID- 28909656 TI - Athletics and the Boy. PMID- 28909658 TI - Retardation in Nebraska. PMID- 28909659 TI - Age and Progress in a New York City School. PMID- 28909660 TI - Language Development in 285 Idiots and Imbeciles. PMID- 28909661 TI - Shall Elective Courses Be Established in the Seventh and Eighth Grades of the Elementary School? PMID- 28909662 TI - News and Comment. PMID- 28909663 TI - Physiological Age and School Standing. PMID- 28909664 TI - Binet-Simon Tests of a Thirty-Nine Months Old Child. PMID- 28909665 TI - The Scope of Education as a University Department. PMID- 28909666 TI - News and Comment. PMID- 28909668 TI - News and Comment. PMID- 28909667 TI - A Third Study of Mental Fatigue in Relation to the Daily School Program. PMID- 28909669 TI - Some Reconstructive Movements within the Kindergarten. PMID- 28909671 TI - Syllabus Making. PMID- 28909670 TI - Re-Averments Respecting Psycho-Clinical Norms and Scales of Development. PMID- 28909672 TI - Retarded Sixth Grade Pupils. PMID- 28909673 TI - What Is Sanity? PMID- 28909674 TI - Measuring Efficiency of Instruction. PMID- 28909675 TI - News and Comment. PMID- 28909677 TI - The Physical Status of the Special Class for Bright Children at the University of Pennsylvania, Summer Session of 1912. PMID- 28909676 TI - A Little More "Truth about Tobacco". PMID- 28909678 TI - News and Comment. PMID- 28909679 TI - Whistling at Work-A Crime? PMID- 28909680 TI - Elimination from a Different Angle. PMID- 28909682 TI - News and Comment. PMID- 28909681 TI - The Vitality of Teaching. PMID- 28909683 TI - Clinical Psychology Adversely Criticized. PMID- 28909684 TI - Children with Mental Defects Distinguished from Mentally Defective Children. PMID- 28909685 TI - Some Thinking Processes of Grade Children. PMID- 28909686 TI - The Effect of Self-Interest on Scores Made on the Allport Test for Measuring Ascendance-Submission. PMID- 28909687 TI - Notes: An Apparent Epidemic of Left-Handedness. PMID- 28909688 TI - Intelligence Test Ratings and Trainability of Nurses. PMID- 28909689 TI - A Clinical Study of Twenty-Six Pairs of Twins. PMID- 28909691 TI - Psychological Tests in the First Grade. PMID- 28909690 TI - The Relation of General Intelligence, Motor Adaptability, and Motor Learning to Success in Dental Technical Courses. PMID- 28909692 TI - Vocational Guidance toward the Higher Professions with Special Reference to Its Psychological Bases. PMID- 28909693 TI - A Reorientation in Psychotherapy. PMID- 28909694 TI - Predicting Musical Progress-A Technique for Guidance. PMID- 28909695 TI - The Mental Hygiene Problems of School Attendants. PMID- 28909697 TI - Auditory Perceptibility: Acuity and Dominance. PMID- 28909696 TI - Education of Parents and Intelligence of Children. PMID- 28909698 TI - Is There a Relation between Kleptomania and Female Periodicity in Neurotic Individuals? PMID- 28909699 TI - The Influence of Distraction upon Mental Test Performance. PMID- 28909700 TI - The Effect of Verbal Suggestion on Output and Variability of Muscular Work. PMID- 28909701 TI - Some Behavior Changes in a Juvenile Paretic. PMID- 28909703 TI - News and Comment. PMID- 28909702 TI - The Practical in Educational Research. PMID- 28909704 TI - The Outlook for James: A Clinic Teacher's Report. PMID- 28909705 TI - Reproduction of Prose Passages. PMID- 28909707 TI - The Significance of the Binet-Simon Tests. PMID- 28909706 TI - A Survey of Medical Inspection in the City Schools of California. PMID- 28909708 TI - News and Comment. PMID- 28909709 TI - Physical and Mental Factors Involved in the Formboard Test. PMID- 28909710 TI - News and Comment. PMID- 28909711 TI - Point Scale Ratings of Ninety-Three Dependent Children. PMID- 28909712 TI - Clinic Reports: Three Cases. PMID- 28909713 TI - Tom the Enigma-A Clinic Teacher's Report. PMID- 28909715 TI - News and Comment. PMID- 28909714 TI - Two Feebleminded Maidens-A Clinical Lecture. PMID- 28909716 TI - Correlation of the Witmer Formboard and Cylinder Test. PMID- 28909717 TI - The Witmer Formboard. PMID- 28909718 TI - News and Comment. PMID- 28909720 TI - Billy. PMID- 28909719 TI - Results of Examination of 91 Girls at a State Institution. PMID- 28909721 TI - A Vocabulary Study of Children in a Foreign Industrial Community. PMID- 28909722 TI - Psychological Concomitants of High Alveolar Carbon Dioxide: A Psychobiochemical Study of the Etiology of Stammering. PMID- 28909723 TI - A Formboard Demonstration. PMID- 28909724 TI - A Discussion of the Index of Formboard Ability. PMID- 28909725 TI - News and Comment. PMID- 28909726 TI - Transient Delusions Due to Syphilis. PMID- 28909728 TI - News and Comment. PMID- 28909727 TI - Congenital Aphasia and Feeblemindedness-A Clinical Diagnosis. PMID- 28909729 TI - "Construction Test A" of the Healy-Fernald Series. PMID- 28909731 TI - Retarded Children Not Defectives. PMID- 28909730 TI - Standard Tests and Scales of Measurements. PMID- 28909732 TI - Weights and School Progress. PMID- 28909734 TI - News and Comment. PMID- 28909733 TI - Experimenting with Children under the Gary Plan in New York City. PMID- 28909735 TI - An Experimental Study of the Suggestibility of Twelve and Fifteen-Year-Old Boys. PMID- 28909736 TI - The Use of Methods and Devices. PMID- 28909737 TI - Retarded School Children in Madison, Wisconsin. PMID- 28909739 TI - Clinic Reports. PMID- 28909738 TI - A Fettered Mind. PMID- 28909740 TI - News and Comment. PMID- 28909741 TI - A Report on the Examination of One Hundred 6B Children in Philadelphia Schools. PMID- 28909742 TI - An Analytic Study of One Class in High School. PMID- 28909743 TI - The Relation of Enuresis to Intelligence, to Conduct and Personality Problems, and to Other Factors. PMID- 28909744 TI - A Problem in Social Adjustment: A Statistical Study of the Mentality and Personality Types of More Than Thirteen Thousand Consecutive Cases, Examined at the Neuro-Psychiatric Clinic of the Municipal Court of Philadelphia. PMID- 28909745 TI - A Case of Congenital Word-Blindness. PMID- 28909746 TI - The Ten Year Level of Competency. PMID- 28909748 TI - Tommy: Preliminary Report on a Superior Child. PMID- 28909747 TI - A Pre-School Character Rating Chart. PMID- 28909749 TI - Lester: A Study in Diagnostic Teaching. PMID- 28909751 TI - A Comparative Study of Audito-Vocal Digit Spans. PMID- 28909750 TI - The Study of a Special Class Center. PMID- 28909752 TI - Buster. PMID- 28909753 TI - Orthogenic Cases XVI-George: Mentally Restored to Normal but Intellectually Deficient. PMID- 28909754 TI - Tests of the Stanford Revision of the Binet-Simon Scale Most Frequently Failed by Children in Orthogenic Backward Classes. PMID- 28909755 TI - The Effect of Verbal Suggestion upon Perseverance. PMID- 28909756 TI - Studies in Diagnostic Teaching: Martin. PMID- 28909757 TI - Studies in Diagnostic Teaching: William. PMID- 28909758 TI - Studies in Diagnostic Teaching: John. PMID- 28909759 TI - Studies in Diagnostic Teaching: Lillian. PMID- 28909760 TI - Studies in Diagnostic Teaching: Parker. PMID- 28909761 TI - Orthogenic Cases-XVII-Jack: Feeble-Minded or Normal. PMID- 28909762 TI - A Study of Five Problem Cases. PMID- 28909764 TI - Methods and Results of Teaching a Case of Congenital Word-Blindness. PMID- 28909763 TI - Gordon-A Clinic Picture. PMID- 28909765 TI - Recording Emotional Qualities. PMID- 28909767 TI - News and Comment. PMID- 28909766 TI - Diagnostic Education-An Education for the Fortunate Few. PMID- 28909768 TI - Clinic Reports. PMID- 28909769 TI - The Individual Tests in the Binet-Simon Scale. PMID- 28909770 TI - The Educability of a Two Year Old. PMID- 28909772 TI - News and Comment. PMID- 28909771 TI - Tests and Norms for Vocational Guidance at the Fifteen Year Old Level: A Comparative Study of the Proficiency of Six Hundred Children. PMID- 28909773 TI - The Feebleminded in the State of Missouri. PMID- 28909774 TI - A Picture Arrangement Test: Contributed from the Bureau of Juvenile Research, Columbus, Ohio. PMID- 28909775 TI - Clinic Reports. PMID- 28909776 TI - News and Comment. PMID- 28909777 TI - A Study of the Interplay of Personality. PMID- 28909778 TI - Clinic Reports. PMID- 28909779 TI - Children Tested by the Point Scale and the Performance Scale. PMID- 28909780 TI - The Progress of Pupils in an Ungraded Class. PMID- 28909781 TI - Clinic Reports. PMID- 28909782 TI - A Retarded Pupil Restored to Grade. PMID- 28909784 TI - News and Comment. PMID- 28909783 TI - The Senile Mind. PMID- 28909785 TI - The Mentality of Some Freaks of Nature. PMID- 28909786 TI - A Study of the Interplay of Personality. PMID- 28909787 TI - Clinic Reports. PMID- 28909788 TI - Wasted Effort. PMID- 28909790 TI - Clinic Reports. PMID- 28909789 TI - A Brief Binet-Simon Scale. PMID- 28909792 TI - News and Comment. PMID- 28909791 TI - A Case of Educational Retardation. PMID- 28909793 TI - A Study of the Interplay of Personality. PMID- 28909794 TI - The Phenomenon of Scattering in the Binet-Simon Scale. PMID- 28909795 TI - The Superficial Idiot-A Type. PMID- 28909796 TI - News and Comment. PMID- 28909797 TI - Clinic Reports. PMID- 28909798 TI - A Pseudo-Talent for Words: The Teacher's Report to Dr. Witmer. PMID- 28909799 TI - Mother's Son. PMID- 28909800 TI - Clinic Reports. PMID- 28909802 TI - News and Comment. PMID- 28909801 TI - Clinical Studies of Failures with the Witmer Formboard. PMID- 28909803 TI - A Brief Binet-Simon Scale. PMID- 28909804 TI - Miss Inconsistency: A Study of an Atypical Child Who Is in No Sense Feebleminded. PMID- 28909806 TI - The Analytical Diagnosis. PMID- 28909805 TI - The Increase of the Intelligence Quotient through Training. PMID- 28909807 TI - Clinical Reports. PMID- 28909808 TI - Diagnostic Teaching: Albert-A Lazy Boy. PMID- 28909809 TI - Children Applying for Working Certificates: An Aspect of Vocational Guidance. PMID- 28909810 TI - Eighteen Children from an Orthogenic Backward Class. PMID- 28909811 TI - An Analytical Study of the Intelligence of a Group of Adolescent Delinquent Girls. PMID- 28909812 TI - The Americanization of Tony. PMID- 28909813 TI - Sergeant X-A Study in Vocational Guidance. PMID- 28909814 TI - Jimmie, the Italian Boy. PMID- 28909815 TI - Joseph. PMID- 28909816 TI - George. PMID- 28909817 TI - An Ancient Score Card. PMID- 28909818 TI - The Competency of Fifty College Students: A Diagnostic Study. PMID- 28909819 TI - Freddie-A Problem in Diagnostic Education. PMID- 28909820 TI - The Importance of a Complete Social History in Clinical Examination. PMID- 28909821 TI - Was He Bad?: The Record of a Small Boy. PMID- 28909822 TI - The Coaching Class-Its Aims and Accomplishments. PMID- 28909823 TI - Diagnostic Teaching: Earl. PMID- 28909824 TI - Sebastian: The Effect of Increased Physical Fitness on Mental Test Results. PMID- 28909825 TI - The Problem of the Special Class. PMID- 28909826 TI - A "Slow Normal" Developing a "Failure Morale". PMID- 28909827 TI - A Social and Psychological Study of a Mountain Community. PMID- 28909829 TI - Diagnostic Teaching: William. PMID- 28909828 TI - Bright Children: Mental and Physical Correlations. PMID- 28909830 TI - Statistical and Non-Statistical Interpretation of Test Results. PMID- 28909831 TI - Intelligence-A Definition. PMID- 28909832 TI - Trainability and Emotional Reaction in the Human Infant. PMID- 28909833 TI - Clinical Reports. PMID- 28909834 TI - Job Specifications and Diagnostic Tests of Job Competency Designed for the Auditing Division of a Street Railway Company: A Psychological Study in Industrial Guidance. PMID- 28909835 TI - Slot Maze A. PMID- 28909837 TI - Educational Aspects of Christian Science. PMID- 28909836 TI - Birth Rate and Native Intelligence. PMID- 28909839 TI - News and Comment. PMID- 28909838 TI - Classification of Clinic Cases. PMID- 28909840 TI - A Practical Guide for the Administration of the Binet-Simon Scale for Measuring Intelligence. PMID- 28909841 TI - A Study of the Binet Definition Tests. PMID- 28909843 TI - News and Comment. PMID- 28909842 TI - The Binet-Simon Scale for Measuring Intelligence : Impressions Gained by Its Application upon Four Hundred Non-Selected Children. PMID- 28909844 TI - Courses in Psychology at the Summer School of the University of Pennsylvania. PMID- 28909845 TI - Boys' Backs. PMID- 28909846 TI - A New Method for Determining Rate of Progress in a Small School System. PMID- 28909848 TI - News and Comment. PMID- 28909847 TI - School Clinics for Free Medical and Dental Treatment. PMID- 28909849 TI - A New Method for Determining Rate of Progress in a Small School System. PMID- 28909850 TI - A Year's Work in a "Superior" Class. PMID- 28909851 TI - News and Comment. PMID- 28909852 TI - The Binet-Simon Scale and the Psychologist. PMID- 28909853 TI - Elimination and Retention of Pupils. PMID- 28909854 TI - News and Comment. PMID- 28909855 TI - Retardation Statistics from the Smaller Minnesota Towns. PMID- 28909856 TI - Problems of the Social Worker. PMID- 28909857 TI - A Moral Imbecile or a Bad Boy: Which? PMID- 28909859 TI - News and Comment. PMID- 28909858 TI - Medical and Dental Inspection in the Cleveland Schools. PMID- 28909860 TI - Health and Development Supervision of the Public Schools of California. PMID- 28909861 TI - News and Comment. PMID- 28909862 TI - Our Responsibility for Retardation. PMID- 28909863 TI - The Boy and the Cigarette. PMID- 28909864 TI - Retardation and Elimination in Graded and Rural Schools. PMID- 28909865 TI - The Nervous Disorders of School Children. PMID- 28909866 TI - Physiological Age as a Basis for the Classification of Pupils Entering High Schools-Relation of Pubescence to Height. PMID- 28909867 TI - A Further Study of Retardation in Illinois. PMID- 28909868 TI - News and Comment. PMID- 28909870 TI - The Irrepressible Ego. PMID- 28909869 TI - A Simple System for Discovering Some Factors Influencing Non-Promotion. PMID- 28909872 TI - The Nurse as a Municipal Officer. PMID- 28909871 TI - News and Comment. PMID- 28909873 TI - Moral Aberration Due to Physical Irritants. PMID- 28909875 TI - News and Comment. PMID- 28909874 TI - An Educational Experiment with Troublesome Adolescent Boys. PMID- 28909876 TI - Retardation in the Schools of Stockton, California. A Study of 300 Pedagogical Life Histories. PMID- 28909877 TI - Retardation in the Schools of Palo Alto, California. A Study of Pedagogical Life Histories. PMID- 28909878 TI - The Renaissance of Bob. PMID- 28909879 TI - News and Comment. PMID- 28909880 TI - Criminals in the Making. PMID- 28909882 TI - News and Comment. PMID- 28909881 TI - The Fundamental Expression of Retardation. PMID- 28909883 TI - Age per Grade of Truant and Difficult School Boys. PMID- 28909884 TI - The Boy in the Private School. PMID- 28909885 TI - News and Comment. PMID- 28909886 TI - The Training of a Case of Infantile Stammer. PMID- 28909887 TI - What Is Meant by Retardation? PMID- 28909888 TI - The Bright Child. PMID- 28909889 TI - A First Lesson in Thrift. PMID- 28909890 TI - Can Impacted Teeth Cause Moral Delinquency? PMID- 28909891 TI - News and Comment. PMID- 28909892 TI - What Can and Do School Reports Show? PMID- 28909893 TI - An Experimental-Critical Study of the Problem of Grading and Promotion. PMID- 28909895 TI - News and Comment. PMID- 28909894 TI - Medical Inspection of Schools in California. PMID- 28909896 TI - News and Comment. PMID- 28909897 TI - An Experimental-Critical Study of the Problem of Grading and Promotion. PMID- 28909898 TI - A Score of Difficult Boys. PMID- 28909899 TI - The Binet-Simon Measuring Scale for Intelligence: Some Criticisms and Suggestions. PMID- 28909900 TI - A Speech Defect Case Treated at Columbia University. PMID- 28909901 TI - Congenital Aphasia. PMID- 28909902 TI - Some Memory Span Test Problems, an Analytical Study at the College-Adult Level. PMID- 28909903 TI - Correlation of the Auditory Digit Memory Span with General Intelligence. PMID- 28909904 TI - Tests and Norms at the Six Year Old Performance Level. PMID- 28909905 TI - Reginald. PMID- 28909906 TI - James: A Study of a Post-Encephalitic Child. PMID- 28909907 TI - The Superior Child: A Series of Case Studies. PMID- 28909908 TI - The Relation of Mental to Physical Growth. PMID- 28909909 TI - What Are Little Boys Made of? PMID- 28909910 TI - The Spotless Child. PMID- 28909911 TI - A Comparative Study of 100 Italian Children at the Six Year Level. PMID- 28909912 TI - The Application of the Hutt Color Cube Test to a Group of Subnormal Mentality. PMID- 28909913 TI - The Reliability and Validity of the Wallin Peg Boards. PMID- 28909914 TI - The Printing Trade in Philadelphia. PMID- 28909915 TI - Vocational Guidance and Job Analysis, the Psychological Viewpoint. PMID- 28909916 TI - The Textile Industry in Philadelphia. PMID- 28909918 TI - The Interrogation Mark. PMID- 28909917 TI - Twenty-Four Cases of Acute Epidemic Encephalitis. PMID- 28909919 TI - Another Mary. PMID- 28909920 TI - One Hundred Non-Conformed Boys. PMID- 28909921 TI - The Relation of Psychology to Social Service. PMID- 28909922 TI - A Comparison of the Detroit First Grade Tests Given in Italian and English. PMID- 28909923 TI - The Diagnostic Value of the Audito-Vocal Digit Memory Span. PMID- 28909924 TI - Mental Changes after Removing Tonsils and Adenoids. PMID- 28909925 TI - The Witmer Formboard-First Trial Records. PMID- 28909927 TI - A Note on the Digit Test. PMID- 28909926 TI - The Superior Child: A Series of Case Studies. PMID- 28909928 TI - Grouping by Abilities. PMID- 28909929 TI - Standardization of a Color Cube Test. PMID- 28909930 TI - The Etiology of Mongolism. PMID- 28909931 TI - Design Blocks-A Description of a Simple Clinical Test. PMID- 28909932 TI - Theory of Constancy of Intelligence. PMID- 28909933 TI - Relationship between Suggestibility and Intelligence in Delinquents. PMID- 28909934 TI - Notwithstanding a High I.Q. PMID- 28909935 TI - Mental Tests for Pre-School Children. PMID- 28909936 TI - Study of Relative Values of Audito-Vocal Forward and Reverse Spans. PMID- 28909937 TI - Diagnostic Teaching: Albert. PMID- 28909938 TI - Diagnostic Teaching: Maurice. PMID- 28909939 TI - Patsy. PMID- 28909940 TI - Diagnostic Teaching: Gladys. PMID- 28909941 TI - Allison-And His Parents. PMID- 28909942 TI - A Small Group of Irish-American Children. PMID- 28909943 TI - A Thousand Children Who Do Not Conform to School Routine. PMID- 28909945 TI - The School Psychologist. PMID- 28909944 TI - The Superior Child: Beginning a Series of Case Studies. PMID- 28909946 TI - An Analytical Study of One Hundred Twenty Superior Children. PMID- 28909948 TI - Some Rambling Experiences in the Training of Low-Grade Defectives. PMID- 28909947 TI - Psychological Diagnosis and the Psychonomic Orientation of Analytic Science: An Epitome. PMID- 28909949 TI - The Definition and Diagnosis of Mental Deficiency. Part I. PMID- 28909950 TI - Correspondence. PMID- 28909951 TI - Correspondence. PMID- 28909952 TI - Errata. AB - [This corrects the article on p. 49 in vol. 1.]. PMID- 28909953 TI - The Lilian Greg Occupation Centre for Defective Children. PMID- 28909954 TI - Correspondence. PMID- 28909956 TI - Notes and News. PMID- 28909955 TI - The Definition and Diagnosis of Mental Deficiency. Part II. PMID- 28909957 TI - Extra-Institutional Care of Mental Defectives in New York State, U.S.A. PMID- 28909958 TI - Eurhythmics in the Special School. PMID- 28909959 TI - Scheme for the Interchange of British and American Teachers. PMID- 28909960 TI - The Certification of Children of School Age. PMID- 28909961 TI - Post Graduate Course on Mental Deficiency. PMID- 28909962 TI - Notes about Institutions for Defectives. PMID- 28909963 TI - The Physical Education of the Mentally Defective Child. PMID- 28909964 TI - The Special School in Norway and Work Connected with It. PMID- 28909965 TI - A Method of Personality Diagnosis and Evaluation with Provision for Social Service Propaganda. PMID- 28909967 TI - Treasury Restrictions on Local Authorities: Campaign of Protest. PMID- 28909966 TI - The Need for the Early Diagnosis and Treatment of Potential Delinquency in Cases of Mental Disorder and Defect. PMID- 28909968 TI - The Mentally Unstable Child and Its Needs. PMID- 28909969 TI - Notes and News. PMID- 28909970 TI - The Fountain Mental Hospital as a Pioneer in Its Relation to the Working of the Mental Deficiency Act, 1913. PMID- 28909971 TI - Natural Inheritance and Social Policy. PMID- 28909972 TI - A New Graded Scheme of Needlecraft for M.D. Institutions. PMID- 28909973 TI - Classes for Dull and Backward Children. PMID- 28909974 TI - Notes and News. PMID- 28909975 TI - The Neurotic School Child. PMID- 28909976 TI - Notes and News. PMID- 28909977 TI - Lunacy Law and Institutional and Home Treatment of the Insane: Being the Final of a Course of Lectures on Psychiatry for Local Secretaries of Mental Welfare Associations Delivered at Horton Mental Hospital, Epsom. PMID- 28909978 TI - Mental Defectives under the Poor Law: How the Problem Is Dealt with at Ipswich by Co-Operation with Other Bodies. PMID- 28909980 TI - Moral Defectives. PMID- 28909979 TI - The Memory of the Feeble-Minded. PMID- 28909981 TI - Foreword. PMID- 28909983 TI - Correspondence. PMID- 28909982 TI - Correspondence. PMID- 28909985 TI - Editorial. PMID- 28909984 TI - Individual Studies, Their Educational Significance. PMID- 28909986 TI - The Work of Local Voluntary Associations and Possible Future Developments. PMID- 28909987 TI - Vocational Tests for Mental Defectives. PMID- 28909988 TI - Correspondence. PMID- 28909989 TI - Law Report. PMID- 28909990 TI - The "Jean Jacques Rousseau" Institute and the Training of Teachers of Sub-Normal Children. PMID- 28909991 TI - Editorial. PMID- 28909992 TI - Reports of Local Voluntary Associations. PMID- 28909993 TI - Legal Notes. PMID- 28909994 TI - The Biological Factor in Criminal Conduct. PMID- 28909995 TI - Correspondence. PMID- 28909997 TI - Legal Notes. PMID- 28909996 TI - Notes and News. PMID- 28909999 TI - Glimpses of Canada and the United States. PMID- 28909998 TI - The Younger Generation and the "Almosts". PMID- 28910000 TI - On the Rate of Progress of the Mentally Defective. PMID- 28910001 TI - Occupation Centres-The Present Position. PMID- 28910002 TI - A Note on the Size-Weight Illusion. PMID- 28910003 TI - Some Aspects of the Epileptic Problem. PMID- 28910005 TI - How the Mental Deficiency Act Is Working: The Ninth Annual Report of the Board of Control Has Just Been Issued. PMID- 28910004 TI - The Mentally Defective and the Community. PMID- 28910006 TI - Report on the Committee on Insanity and Crime. PMID- 28910007 TI - The Training and Qualifications of Nurses and Attendants in Certified Institutions. PMID- 28910008 TI - The Educational Significance of Certain Specific Mental Defects. PMID- 28910009 TI - The Manor Institution. Epsom, Some Comments on Its First Two Years. PMID- 28910010 TI - The Training of Attendants in Certified Institutions. PMID- 28910011 TI - Mental Deficiency and Venereal Disease. PMID- 28910013 TI - Country Holidays for Mentally Deficient Children. Some Recent Developments. PMID- 28910012 TI - Recent Trends in the Control of Mental Deficiency in the United States. PMID- 28910014 TI - The Mentally Defective and the Poor Law: Report of the C.A.M.W. Conference at Wembley. PMID- 28910015 TI - The Board of Education's Circular on Mentally Defective Children. PMID- 28910016 TI - Some Modifications in the Teaching of the Three R's to M.D. Children. PMID- 28910018 TI - The Changing Face of Bristol Medicine: A Symposium Organised by the Bristol Medico-Chirurgical Society. PMID- 28910017 TI - Screening for Disease: Possibilities and Problems Southmead Foundation Lecture Delivered at Southmead Hospital Bristol November 1990. PMID- 28910019 TI - Four Hunterian Lectures and Bristol-1990. PMID- 28910020 TI - Junior Doctors' Hours. PMID- 28910022 TI - After the Operation. PMID- 28910021 TI - What's New from the British Journal of Surgery. PMID- 28910023 TI - Editorial. PMID- 28910024 TI - What Is This Life If Full of Care. PMID- 28910025 TI - The Place for Paediatricians: Based on the "Victor Neale Memorial Lecture" Given at the Meeting of the S.W. Paediatric Club, April 1991. AB - Professor Victor Neale was a leading paediatrician and respected teacher at a time when the specialty was growing rapidly and employing new professional skills, knowledge and attitudes. The benefits of these developments might be more fully realized by the establishment of a college of Paediatricians. But the consequential loss of affinity with the general medicine of adults and the Royal Colleges of Physicians could weaken the power of the medical profession to maintain the highest standards of medical practice. PMID- 28910026 TI - An Old Concept Achieved. PMID- 28910028 TI - How to Deal with the Telephone Sales Menace. PMID- 28910027 TI - Report on the VIII World Congress of Physchiatry, Athens: October 1989. PMID- 28910029 TI - The New Journal, Hopes and Aims for the Future. PMID- 28910030 TI - Traveller's Tale from You Nice States. PMID- 28910031 TI - First Bristol Radiology Course, November 1989. PMID- 28910033 TI - Editorial: Urology Mini Symposium. PMID- 28910032 TI - Give Us Back Our 11 Days. PMID- 28910035 TI - Launch of the 'New Journal'. PMID- 28910034 TI - Editorial-The Last Post. PMID- 28910036 TI - Aversion Therapy for the Football Hooligan. PMID- 28910037 TI - Dartmoor: A Place to Explore. PMID- 28910038 TI - A West Country Composer. PMID- 28910040 TI - A New Approach to Medical Records. PMID- 28910039 TI - Get-Up-And-Go Hospitals and Hotels. PMID- 28910041 TI - A Pathological Rose by Any Other Name. PMID- 28910042 TI - Albanian Treatment for Ribbentrop's Chauffeur. PMID- 28910043 TI - Oman, What a Challenge! PMID- 28910044 TI - All Quiet on the Far Western Front. PMID- 28910045 TI - Exhibition to Celebrate 5 Years of the Bristol University Chair of Orthopoedics. PMID- 28910046 TI - Franglais a la mode moderne. PMID- 28910047 TI - Joint Meeting of the South West Radiologists Association and the Societe d'Electro-Radiologie Medicale de l'Quest, St Malo, June 1990. PMID- 28910048 TI - How Basic Can You Get? PMID- 28910049 TI - New Senior Lecturer in Transplantation at Southmead. PMID- 28910050 TI - Erratum: Arthroscopic Management for Tibial Plateau Fractures. AB - [This corrects the article on p. 128 in vol. 105.]. PMID- 28910051 TI - The Bristol Medico-Historical Society. PMID- 28910052 TI - Vale Atque Salve. PMID- 28910053 TI - The Nuffield Sponsorship Ends. PMID- 28910054 TI - Notes from Cornwall. PMID- 28910055 TI - A Lousy Story. PMID- 28910056 TI - References for Medical Posts-How Best to Utilise Them. PMID- 28910057 TI - Bedding out. PMID- 28910058 TI - Royal College of Surgeons Council Visit to Bristol. PMID- 28910059 TI - Unauthorized Version. PMID- 28910061 TI - Physicians for Human Rights (UK). PMID- 28910060 TI - Professional Society. PMID- 28910062 TI - Which Journal? PMID- 28910064 TI - Cooking the Books. PMID- 28910063 TI - Why I like Chest Physicians. PMID- 28910068 TI - Iodine-Mediated Etching of Triangular Gold Nanoplates for Colorimetric Sensing of Copper Ion and Aptasensing of Chloramphenicol. AB - A colorimetric method for fast, simple, and selective detection of Cu2+ was developed using I--mediated etching of triangular gold nanoplates (AuNPLs). The method was based on our finding that Cu2+ efficiently promoted this etching in the presence of SCN-. The etching process was accompanied by a dramatic color change from blue to red, allowing for visual and spectroscopic detection of Cu2+ with detection limits of 10 and 1 MUM, respectively. When molecular recognition by a DNA aptamer was incorporated into this method, visual detection of chloramphenicol was also achieved with a detection limit of 5 MUM. PMID- 28910069 TI - 2D Hybrid Nanomaterials for Selective Detection of NO2 and SO2 Using "Light On and Off" Strategy. AB - In order to distinguish NO2 and SO2 gas with one sensor, we designed a paper chip assembled with a 2D g-C3N4/rGO stacking hybrid fabricated via a layer-by-layer self-assembly approach. The g-C3N4/rGO hybrid exhibited a remarkable photoelectric property due to the construction of a van der Waals heterostructure. For the first time, we have been able to selectively detect NO2 and SO2 gas using a "light on and off" strategy. Under the "light off" condition, the g-C3N4/rGO sensor exhibited a p-type semiconducting behavior with a low detection limit of 100 ppb of NO2, but with no response toward SO2. In contrast, the sensor showed n-type semiconducting behavior which could detect SO2 at concentration as low as 2 ppm under UV light irradiation. The effective electron transfer among the 2D structure of g-C3N4 and rGO nanosheets as well as highly porous structures could play an important role in gas sensing. The different sensing mechanisms at "light on and off" circumstances were also investigated in detail. PMID- 28910070 TI - Ultrafast and Efficient Extraction of Uranium from Seawater Using an Amidoxime Appended Metal-Organic Framework. AB - Enrichment of uranyl from seawater is crucial for the sustainable development of nuclear energy, but current uranium extraction technology suffers from multiple drawbacks of low sorption efficiency, slow uptake kinetics, or poor extraction selectivity. Herein, we prepared the first example of amidoxime appended metal organic framework UiO-66-AO by a postsynthetic modification method for rapid and efficient extraction of uranium from seawater. UiO-66-AO can remove 94.8% of uranyl ion from Bohai seawater within 120 min and 99% of uranyl ion from Bohai seawater containing extra 500 ppb uranium within 10 min. The uranyl sorption capacity in a real seawater sample was determined to be 2.68 mg/g. In addition, the recyclability of the UiO-66-AO framework was demonstrated for at least three adsorption/desorption cycles. The origin for the superior sorption capability was further probed by extended X-ray absorption fine structure (EXAFS) analysis on the uranium-sorbed sample, suggesting multiple amidoxime ligands are able to chelate uranyl(VI) ions, forming a hexagonal bipyramid coordination geometry. PMID- 28910071 TI - Simple InCl3 Doped PEDOT:PSS and UV-Ozone Treatment Strategy: External Quantum Efficiency up to 21% for Solution-Processed Organic Light-Emitting Devices with a Thermally Activated Delayed Fluorescence Emitter. AB - A low-cost and easy-process scheme for solution-processed organic light-emitting devices (OLEDs) was provided to overcome the flaws of poly(styrene sulfonic acid) doped poly(3,4-ethylenedioxythiphene) (PEDOT:PSS) together with the indium tin oxide anode. The modified PEDOT:PSS with higher work function (5.66 eV) and more efficient hole injecting ability was obtained by simply mixing the aqueous PEDOT:PSS with InCl3 and then consecutive ultraviolet-ozone treatment. The simply structured and solution-processed OLEDs with our modified PEDOT:PSS achieved a very high external quantum efficiency of 21.0% using a classic thermally activated delayed fluorescence emitter, 2,4,5,6-tetrakis(carbazol-9-yl)-1,3 dicyanobenzene. The origin of this great promotion was explored through photoelectron spectroscopy, Fourier transform infrared reflection spectroscopy, and atomic force microscopy, from which we inferred that InCl3 itself, the losing of insulting PSS outer shell, and transformation to quinoid structure of PEDOT chains accounted for this improvement. Our modification method of PEDOT:PSS is beneficial for promoting solution-processed organic semiconducting devices. PMID- 28910072 TI - Mapping the Binding Site for Escitalopram and Paroxetine in the Human Serotonin Transporter Using Genetically Encoded Photo-Cross-Linkers. AB - In spite of the important role of the human serotonin transporter (hSERT) in depression treatment, the molecular details of how antidepressant drugs bind are still not completely understood, in particular those related to potential high- and low-affinity binding sites in hSERT. Here, we utilize amber codon suppression in hSERT to encode the photo-cross-linking unnatural amino acid p-azido-l phenylalanine into the suggested high- and low-affinity binding sites. We then employ UV-induced cross-linking with azF to map the binding site of escitalopram and paroxetine, two prototypical selective serotonin reuptake inhibitors (SSRIs). We find that the two antidepressant drugs exclusively cross-link to azF incorporated at the high-affinity binding site of hSERT, while cross-linking is not observed at the low-affinity binding site. Combined with previous homology models and recent structural data on hSERT, our results provide important information to understand the molecular details of these clinical relevant binding sites. PMID- 28910073 TI - Solution-Processed Lithium-Doped ZnO Electron Transport Layer for Efficient Triple Cation (Rb, MA, FA) Perovskite Solar Cells. AB - The current work reports the lithium (Li) doping of a low-temperature processed zinc oxide (ZnO) electron transport layer (ETL) for highly efficient, triple cation-based MA0.57FA0.38Rb0.05PbI3 (MA: methylammonium, FA: formamidinium, Rb: rubidium) perovskite solar cells (PSCs). Lithium intercalation in the host ZnO lattice structure is dominated by interstitial doping phenomena, which passivates the intrinsic defects in ZnO film. In addition, interstitial Li doping also downshifts the Fermi energy position of Li-doped ETL by 30 meV, which contributes to the reduction of the electron injection barrier from the photoactive perovskite layer. Compared to the pristine ZnO, the power conversion efficiency (PCE) of the PSCs incorporating lithium-doped ZnO (Li-doped) is raised from 14.07 to 16.14%. The superior performance is attributed to the reduced current leakage, enhanced charge extraction characteristics, and mitigated trap-assisted recombination phenomena in Li-doped devices, thoroughly investigated by means of electrochemical impedance spectroscopy (EIS) analysis. Li-doped PSCs also exhibit lower photocurrent hysteresis than ZnO devices, which is investigated with regard to the electrode polarization phenomena of the fabricated devices. PMID- 28910074 TI - Highly Luminescent Phase-Stable CsPbI3 Perovskite Quantum Dots Achieving Near 100% Absolute Photoluminescence Quantum Yield. AB - Perovskite quantum dots (QDs) as a new type of colloidal nanocrystals have gained significant attention for both fundamental research and commercial applications owing to their appealing optoelectronic properties and excellent chemical processability. For their wide range of potential applications, synthesizing colloidal QDs with high crystal quality is of crucial importance. However, like most common QD systems such as CdSe and PbS, those reported perovskite QDs still suffer from a certain density of trapping defects, giving rise to detrimental nonradiative recombination centers and thus quenching luminescence. In this paper, we show that a high room-temperature photoluminescence quantum yield of up to 100% can be obtained in CsPbI3 perovskite QDs, signifying the achievement of almost complete elimination of the trapping defects. This is realized with our improved synthetic protocol that involves introducing organolead compound trioctylphosphine-PbI2 (TOP-PbI2) as the reactive precursor, which also leads to a significantly improved stability for the resulting CsPbI3 QD solutions. Ultrafast kinetic analysis with time-resolved transient absorption spectroscopy evidence the negligible electron or hole-trapping pathways in our QDs, which explains such a high quantum efficiency. We expect the successful synthesis of the "ideal" perovskite QDs will exert profound influence on their applications to both QD-based light-harvesting and -emitting devices. PMID- 28910075 TI - Mechanochemical Synthesis of PEDOT:PSS Hydrogels for Aqueous Formulation of Li Ion Battery Electrodes. AB - Water-soluble binders can enable greener and cost-effective Li-ion battery manufacturing by eliminating the standard fluorine-based formulations and associated organic solvents. The issue with water-based dispersions, however, remains the difficulty in stabilizing them, requiring additional processing complexity. Herein, we show that mechanochemical conversion of a regular poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) water-based dispersion produces a hydrogel that meets all the requirements as binder for lithium-ion battery electrode manufacture. We particularly highlight the suitable slurry rheology, improved adhesion, intrinsic electrical conductivity, large potential stability window and limited corrosion of metal current collectors and active electrode materials, compared to standard binder or regular PEDOT:PSS solution based processing. When incorporating the active materials, conductive carbon and additives with PEDOT:PSS, the mechanochemical processing induces simultaneous binder gelation and fine mixing of the components. The formed slurries are stable, show no phase segregation when stored for months, and produce highly uniform thin (25 MUm) to very thick (500 MUm) films in a single coating step, with no material segregation even upon slow drying. In conjunction with PEDOT:PSS hydrogels, technologically relevant materials including silicon, tin, and graphite negative electrodes as well as LiCoO2, LiMn2O4, LiFePO4, and carbon sulfur positive electrodes show superior cycling stability and power-rate performances compared to standard binder formulation, while significantly simplifying the aqueous-based electrode assembly. PMID- 28910076 TI - Gold-Decorated Porous Silicon Nanopillars for Targeted Hyperthermal Treatment of Bacterial Infections. AB - In order to address the issue of pathogenic bacterial colonization of diabetic wounds, a more direct and robust approach is required, which relies on a physical form of bacterial destruction in addition to the conventional biochemical approach (i.e., antibiotics). Targeted bacterial destruction through the use of photothermally active nanomaterials has recently come into the spotlight as a viable approach to solving the rising problem of antibiotic resistant microorganisms. Materials with high absorption coefficients in the near-infrared (NIR) region of the electromagnetic spectrum show promise as alternative antibacterial therapeutic agents, since they preclude the development of bacterial resistance and can be activated on demand. Here were report on a novel approach for the fabrication of gold nanoparticle decorated porous silicon nanopillars with tunable geometry that demonstrate excellent photothermal conversion properties when irradiated with a 808 nm laser. These photothermal antibacterial properties are demonstrated in vitro against the Gram-positive bacteria Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). Results show a reduction in bacterial viability of up to 99% after 10 min of laser irradiation. We also show an increase in antibacterial performance after modifying the nanopillars with S. aureus targeting antibodies causing up to a 10 fold increase in bactericidal efficiency compared to E. coli. In contrast, the nanomaterial resulted in minimal disruption of metabolic processes in human foreskin fibroblasts (HFF) after an equivalent period of irradiation. PMID- 28910077 TI - And There Was Light: Prospects for the Creation of Micro- and Nanostructures through Maskless Photolithography. AB - In photolithographic processes, the light inducing the photochemical reactions is confined to a small volume, which enables direct writing of micro- and nanoscale features onto solid surfaces without the need of a predefined photomask. The direct writing process can be used to generate topographic patterns through photopolymerization or photo-cross-linking or can be employed to use light to generate chemical patterns on the surface with high spatial control, which would make such processes attractive for bioapplications. The prospects of maskless photolithography technologies with a focus on two-photon lithography and scanning probe-based photochemical processes based on scanning near-field optical microscopy or beam pen lithography are discussed. PMID- 28910078 TI - BiFACIAL ( Biomimetic Freestanding Anisotropic Catechol- Interfaces with Asymmetrically Layered) Films as Versatile Extracellular Matrix Substitutes. AB - Biological naive extracellular matrices (ECMs) exhibit anisotropic functions in their physical, chemical, and morphological properties. Representative examples include anisotropic skin layers or blood vessels simultaneously facing multiphasic environments. Here, anisotropically multifunctional structures called BiFACIAL ( biomimetic freestanding anisotropic catechol- interfaces with asymmetrically layered) films were developed simply by contacting two polysaccharide solutions of heparin-catechol (Hep-C) and chitosan-catechol (Chi C). Such anisotropic characters were due to controlling catechol cross-linking by alkaline pH, resulting in a trimodular structure: a rigid yet porous Hep-C exterior, nonporous interfacial zone, and soft/highly porous Chi-C interior. The anisotropic features of each layer, including the porosity, rigidity, rheology, composition, and ionic strength, caused the BiFACIAL films to show spontaneously biased stimuli responses and differential behaviors against biological substances (e.g., blood plasma). The films could be created in situ in live animals and imitated the structural/functional aspects of the representative anisotropic tissues (e.g., skin and blood vessels), providing valuable ECM-like platforms for the creation of favorable environments or for tissue regeneration or disease treatment by effectively manipulating cellular behaviors. PMID- 28910079 TI - Silver-Loaded Aluminosilicate Aerogels As Iodine Sorbents. AB - In this paper, aluminosilicate aerogels were used as scaffolds for silver nanoparticles to capture I2(g). The starting materials for these scaffolds included Na-Al-Si-O and Al-Si-O aerogels, both synthesized from metal alkoxides. The Ag0 particles were added by soaking the aerogels in aqueous AgNO3 solutions followed by drying and Ag+ reduction under H2/Ar to form Ag0 crystallites within the aerogel matrix. In some cases, aerogels were thiolated with 3 (mercaptopropyl)trimethoxysilane as an alternative method for binding Ag+. During the Ag+-impregnation steps, for the Na-Al-Si-O aerogels, Na was replaced with Ag, and for the Al-Si-O aerogels, Si was replaced with Ag. The Ag-loading of thiolated versus nonthiolated Na-Al-Si-O aerogels was comparable at ~35 atomic %, whereas the Ag-loading in unthiolated Al-Si-O aerogels was significantly lower at ~7 atomic % after identical treatment. Iodine loadings in both thiolated and unthiolated Ag0-functionalized Na-Al-Si-O aerogels were >0.5 mI ms-1 (denoting the mass of iodine captured per starting mass of the sorbent) showing almost complete utilization of the Ag through chemisorption to form AgI. Iodine loading in the thiolated and Ag0-functionalized Al-Si-O aerogel was 0.31 mI ms-1. The control of Ag uptake over solution residence time and [Ag] demonstrates the ability to customize the Ag-loading in the base sorbent to regulate the loading capacity of iodine. PMID- 28910080 TI - Cell-Surface Interactions on Arginine-Rich Cell-Penetrating Peptides Allow for Multiplex Modes of Internalization. AB - One of the recent hot topics in peptide-related chemical biology research is the potential of cell-penetrating peptides (CPPs). Owing to their ability to deliver exogenous molecules into cells easily and effectively, their flexible design that allows transporters to comprise various chemical structures and functions, and their potential in chemical and cell biology studies and clinical applications, CPPs have been attracting enormous interest among researchers in related fields. Consequently, publications on CPPs have increased significantly. Although there are many types of CPPs with different physicochemical properties and applications, arginine-rich CPPs, which include the human immunodeficiency virus type 1 (HIV-1) TAT peptide and oligoarginines, are among the most extensively employed and studied. Previous studies demonstrated the importance of the guanidino group in arginine, which confers flexibility in transporter design. Therefore, in addition to peptides, various transporters rich in guanidino groups, which do not necessarily share specific chemical and three-dimensional structures, have been developed. Typically, cell-penetrating transporters have 6 12 guanidino groups. Since the pKa of the guanidino group in arginine is approximately 12.5, these molecules are highly basic and hydrophilic. Our group is interested in why these cationic molecules can penetrate cells. Understanding their mechanism of action should lead to the rational design of intracellular delivery systems that have high efficacy. Additionally, novel cellular uptake mechanisms may be elucidated during the course of these studies. Therefore, our group is trying to understand the basic aspects underlying the ability of these peptides to penetrate cells. Regarding the delivery of biopharmaceuticals including proteins and nucleic acids, achieving efficient and effective delivery to target organs and cells is one of the biggest challenges. Furthermore, when the target sites of these drug molecules are within cells, effective cell penetration becomes another obstacle. Cells are surrounded by a membrane that separates the inside of the cell from its outside. This barrier function is critical for keeping cellular contents inside cells, and without this, cells cannot function. Therefore, understanding the mechanism of action of CPPs is necessary to overcome these obstacles and will allow us not only to improve CPP mediated delivery but also to create other types of intracellular delivery systems. In this Account, we summarize the current knowledge on the mechanisms of internalization of arginine-rich CPPs, from the viewpoints of both direct cell membrane penetration (i.e., physicochemical aspects) and endocytic uptake (i.e., physiological aspects), and discuss the implications of this knowledge. We also discussed loosening of lipid packing as a factor to promote direct cell-membrane penetration. PMID- 28910081 TI - Vanadium As a Potential Membrane Material for Carbon Capture: Effects of Minor Flue Gas Species. AB - Vanadium and its surface oxides were studied as a potential nitrogen-selective membrane material for indirect carbon capture from coal or natural gas power plants. The effects of minor flue gas components (SO2, NO, NO2, H2O, and O2) on vanadium at 500-600 degrees C were investigated by thermochemical exposure in combination with X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and in situ X-ray diffraction (XRD). The results showed that SO2, NO, and NO2 are unlikely to have adsorbed on the surface vanadium oxides at 600 degrees C after exposure for up to 10 h, although NO and NO2 may have exhibited oxidizing effects (e.g., exposure to 250 ppmv NO/N2 resulted in an 2.4 times increase in surface V2O5 compared to exposure to just N2). We hypothesize that decomposition of surface vanadium oxides and diffusion of surface oxygen into the metal bulk are both important mechanisms affecting the composition and morphology of the vanadium membrane. The results and hypothesis suggest that the carbon capture performance of the vanadium membrane can potentially be strengthened by material and process improvements such as alloying, operating temperature reduction, and flue gas treatment. PMID- 28910082 TI - Macromolecular Profiling of Organelles in Normal Diploid and Cancer Cells. AB - To advance an understanding of cellular regulation and function it is crucial to identify molecular contents in cellular organelles, which accommodate specific biochemical processes. Toward achievement of this goal, we applied micro-Raman Biomolecular Component Analysis assay for molecular profiling of major organelles in live cells. We used this assay for comparative analysis of proteins 3D conformation and quantification of proteins, RNA, and lipids concentrations in nucleoli, endoplasmic reticulum, and mitochondria of WI 38 diploid lung fibroblasts and HeLa cancer cells. Obtained data show substantial differences in the concentrations and conformations of proteins in the studied organelles. Moreover, differences in the intraorganellar concentrations of RNA and lipids between these cell lines were found. We report the biological significance of obtained macromolecular profiles and advocate for micro-Raman BCA assay as a valuable proteomics tool. PMID- 28910084 TI - Changes in Flame Retardant and Legacy Contaminant Concentrations in Indoor Air during Building Construction, Furnishing, and Use. AB - A newly constructed university building was selected for targeted assessment of changes in the levels of flame retardants and legacy contaminants during the installation of building equipment, furniture, electronics, and first year of building use. Indoor air samples were collected during several periods of intensive equipment installation to determine a relationship between newly introduced equipment and changes in the concentrations and profiles of contaminants in indoor air. Samples were analyzed for polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDDs), and new types of flame retardants: brominated (BFRs) and organophosphate esters (OPEs). Additionally, typical outdoor contaminants such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were also analyzed for comparison. From the set of 90 compounds analyzed here, hexabromobenzene (HBB) and tris(2 chloroisopropyl)phosphate (TCIPP) showed a significant concentration increase in indoor air concentrations during computer installation and operation, suggesting emission by operating computers, while an order of magnitude concentration increase in tris(1,3-dichloro-2-propyl)phosphate (TDCIPP) and tri-m-cresyl phosphate (TMTP) was observed after the furniture and carpet was introduced to the computer room, suggesting furniture or carpet as a source. However, the majority of compounds had no systematic change in concentrations during equipment installation, indicating that no sources of target compounds were introduced or, that source introduction was not reflected in indoor air concentrations. Generally, low levels of legacy flame retardants compared to their novel alternatives were observed. PMID- 28910083 TI - Inhibiting Mercury Re-emission and Enhancing Magnesia Recovery by Cobalt-Loaded Carbon Nanotubes in a Novel Magnesia Desulfurization Process. AB - Mercury re-emission, because of the reduction of Hg2+ to form Hg0 by sulfite, has become a great concern in the desulfurization process. Lowering the concentrations of Hg2+ and sulfite in the desulfurization slurry can retard the Hg0 formation and, thus, mitigate mercury re-emission. To that end, cobalt-based carbon nanotubes (Co-CNTs) were developed for the simultaneous Hg2+ removal and sulfite oxidation in this work. Furthermore, the thermodynamics and kinetics of the Hg2+ adsorption and effect of Hg2+ adsorption on catalytic activity of Co CNTs were investigated. Experimental results revealed that the Co-CNTs not only accelerated sulfite oxidation to enable the recovery of desulfurization by products but also acted as an effective adsorbent of Hg2+ removal. The Hg2+ adsorption rate mainly depended on the structure of the adsorption material regardless of the cobalt loading and morphological distribution. The catalytic activity of the Co-CNTs for sulfite oxidation was not significantly affected due to the Hg2+ adsorption. Additionally, the isothermal adsorption behavior was well fitted to the Langmuir model with an adsorption capacity of 166.7 mg/g. The mercury mass balance analysis revealed that the Hg0 re-emission was decreased by 156% by adding 2.0 g/L of Co-CNTs. These results can be used as a reference for the simultaneous removal of multiple pollutants in the wet-desulfurization process. PMID- 28910085 TI - Cholesterol Changes the Mechanisms of Abeta Peptide Binding to the DMPC Bilayer. AB - Using isobaric-isothermal all-atom replica-exchange molecular dynamics (REMD) simulations, we investigated the equilibrium binding of Abeta10-40 monomers to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer containing cholesterol. Our previous REMD simulations, which studied binding of the same peptide to the cholesterol-free DMPC bilayer, served as a control, against which we measured the impact of cholesterol. Our findings are as follows. First, addition of cholesterol to the DMPC bilayer partially expels the Abeta peptide from the hydrophobic core and promotes its binding to bilayer polar headgroups. Using thermodynamic and energetics analyses, we argued that Abeta partial expulsion is not related to cholesterol-induced changes in lateral pressure within the bilayer but is caused by binding energetics, which favors Abeta binding to the surface of the densely packed cholesterol-rich bilayer. Second, cholesterol has a protective effect on the DMPC bilayer structure against perturbations caused by Abeta binding. More specifically, cholesterol reduces bilayer thinning and overall depletion of bilayer density beneath the Abeta binding footprint. Third, we found that the Abeta peptide contains a single cholesterol binding site, which involves hydrophobic C-terminal amino acids (Ile31-Val36), Phe19, and Phe20 from the central hydrophobic cluster, and cationic Lys28 from the turn region. This binding site accounts for about 76% of all Abeta-cholesterol interactions. Because cholesterol binding site in the Abeta10-40 peptide does not contain the GXXXG motif featured in cholesterol interactions with the transmembrane domain C99 of the beta-amyloid precursor protein, we argued that the binding mechanisms for Abeta and C99 are distinct reflecting their different conformations and positions in the lipid bilayer. Fourth, cholesterol sharply reduces the helical propensity in the bound Abeta peptide. As a result, cholesterol largely eliminates the emergence of helical structure observed upon Abeta transition from a water environment to the cholesterol-free DMPC bilayer. We explain this effect by the formation of hydrogen bonds between cholesterol and the Abeta backbone, which prevent helix formation. Taken together, we expect that our simulations will advance understanding of a molecular-level mechanism behind the role of cholesterol in Alzheimer's disease. PMID- 28910086 TI - Intercluster Redox Coupling Influences Protonation at the H-cluster in [FeFe] Hydrogenases. AB - [FeFe] hydrogenases catalyze proton reduction and hydrogen oxidation displaying high rates at low overpotential. Their active site is a complex cofactor consisting of a unique [2Fe] subcluster ([2Fe]H) covalently bound to a canonical [4Fe-4S] cluster ([4Fe-4S]H). The [FeFe] hydrogenase from Desulfovibrio desulfuricans is exceptionally active and bidirectional. This enzyme features two accessory [4Fe-4S]F clusters for exchanging electrons with the protein surface. A thorough understanding of the mechanism of this efficient enzyme will facilitate the development of synthetic molecular catalysts for hydrogen conversion. Here, it is demonstrated that the accessory clusters influence the catalytic properties of the enzyme through a strong redox interaction between the proximal [4Fe-4S]F cluster and the [4Fe-4S]H subcluster of the H-cluster. This interaction enhances proton-coupled electronic rearrangement within the H-cluster increasing the apparent pKa of its one electron reduced state. This may help to sustain H2 production at high pH values. These results may apply to all [FeFe] hydrogenases containing accessory clusters. PMID- 28910087 TI - Analysis of Costs and Time Frame for Reducing CO2 Emissions by 70% in the U.S. Auto and Energy Sectors by 2050. AB - Using a least-cost optimization framework, it is shown that unless emissions reductions beyond those already in place begin at the latest by 2025 (+/-2 years) for the U.S. automotive sector, and by 2026 (-3 years) for the U.S. electric sector, 2050 targets to achieve necessary within-sector preventative CO2 emissions reductions of 70% or more relative to 2010 will be infeasible. The analysis finds no evidence to justify delaying climate action in the name of reducing technological costs. Even without considering social and environmental damage costs, delaying aggressive climate action does not reduce CO2 abatement costs even under the most optimistic trajectories for improvements in fuel efficiencies, demand, and technology costs in the U.S. auto and electric sectors. In fact, the abatement cost for both sectors is found to increase sharply with every year of delay beyond 2020. When further considering reasonable limits to technology turnover, retirements, and new capacity additions, these costs would be higher, and the feasible time frame for initiating successful climate action on the 70% by 2050 target would be shorter, perhaps having passed already. The analysis also reveals that optimistic business-as-usual scenarios in the U.S. will, conservatively, release 79-108 billion metric tons of CO2. This could represent up to 13% of humanity's remaining carbon budget through 2050. PMID- 28910088 TI - Balancing Excellent Performance and High Thermal Stability in a Dinitropyrazole Fused 1,2,3,4-Tetrazine. AB - The key to successfully designing high-performance and insensitive energetic compounds for practical applications is through adjusting the molecular organization including both fuel and oxidizer. Now a superior hydrogen-free 5/6/5 fused ring energetic material, 1,2,9,10-tetranitrodipyrazolo[1,5-d:5',1' f][1,2,3,4]tetrazine (6) obtained from 4,4',5,5'-tetranitro-2H,2'H-3,3' bipyrazole (4) by N-amination and N-azo coupling reactions is described. The structures of 5 and 6 were confirmed by single crystal X-ray diffraction measurements. Compound 6 has a remarkable room temperature experimental density of 1.955 g cm-3 and shows excellent detonation performance. In addition, it has a high decomposition temperature of 233 degrees C. These fascinating properties, which are comparable to those of CL-20, make it very attractive in high performance applications. PMID- 28910089 TI - Reduction of Human Norovirus GI, GII, and Surrogates by Peracetic Acid and Monochloramine in Municipal Secondary Wastewater Effluent. AB - The objective of this study was to characterize human norovirus (hNoV) GI and GII reductions during disinfection by peracetic acid (PAA) and monochloramine in secondary wastewater (WW) and phosphate buffer (PB) as assessed by reverse transcription-qPCR (RT-qPCR). Infectivity and RT-qPCR reductions are also presented for surrogate viruses murine norovirus (MNV) and bacteriophage MS2 under identical experimental conditions to aid in interpretation of hNoV molecular data. In WW, RT-qPCR reductions were less than 0.5 log10 for all viruses at concentration-time (CT) values up to 450 mg-min/L except for hNoV GI, where 1 log10 reduction was observed at CT values of less than 50 mg-min/L for monochloramine and 200 mg-min/L for PAA. In PB, hNoV GI and MNV exhibited comparable resistance to PAA and monochloramine with CT values for 2 log10 RT qPCR reduction between 300 and 360 mg-min/L. Less than 1 log10 reduction was observed for MS2 and hNoV GII in PB at CT values for both disinfectants up to 450 mg-min/L. Our results indicate that hNoVs exhibit genogroup dependent resistance and that disinfection practices targeting hNoV GII will result in equivalent or greater reductions for hNoV GI. These data provide valuable comparisons between hNoV and surrogate molecular signals that can begin the process of informing regulators and engineers on WW treatment plant design and operational practices necessary to inactivate hNoVs. PMID- 28910090 TI - Improved Accuracy for Constant pH-REMD Simulations through Modification of Carboxylate Effective Radii. AB - The accuracy of computational models for simulating biomolecules under specific solution pH conditions is critical for properly representing the effect of pH in biological processes. Constant pH (CpH) simulations involving implicit solvent using the AMBER software often incorrectly estimate pKa values of aspartate and glutamate residues due to large effective radii stemming from the presence of dummy protons. These inaccuracies stem from problems in the sampled ensembles of titratable residues that can influence other observable pH-dependent behavior, such as conformational change. We investigate new radii assignments for atoms in titratable residues with carboxylate groups to mitigate the systematic overestimation in the current method. We find that decreased carboxylate radii correspond with increased agreement with experimentally derived pKa values for residues in hen egg-white lysozyme and Delta+PHS variants of staphylococcal nuclease (SNase) and improved conformation state sampling compared to experimentally described expectations of native-like structure. Our CpH simulations suggest that decreasing the effective radii of these carboxylate groups is essential for eliminating a significant source of systematic error that hurts the accuracy of both conformational and protonation state sampling with implicit solvent. PMID- 28910091 TI - Bioassay-Guided Isolation of Antioxidant and Cytoprotective Constituents from a Maqui Berry (Aristotelia chilensis) Dietary Supplement Ingredient As Markers for Qualitative and Quantitative Analysis. AB - Bioassay-guided phytochemical investigation of a commercially available maqui berry (Aristotelia chilensis) extract used in botanical dietary supplement products led to the isolation of 16 compounds, including one phenolic molecule, 1, discovered for the first time from a natural source, along with several known compounds, 2-16, including three substances not reported previously in A. chilensis, 2, 14, and 15. Each isolate was characterized by detailed analysis of NMR spectroscopic and HRESIMS data and tested for their in vitro hydroxyl radical scavenging and quinone-reductase inducing biological activities. A sensitive and accurate LC-DAD-MS method for the quantitative determination of the occurrence of six bioactive compounds, 6, 7, 10-12, and 14, was developed and validated using maqui berry isolates purified in the course of this study as authentic standards. The method presented can be utilized for dereplication efforts in future natural product research projects or to evaluate chemical markers for quality assurance and batch-to-batch standardization of this botanical dietary supplement component. PMID- 28910093 TI - Uptake of Gaseous Alkylamides by Suspended Sulfuric Acid Particles: Formation of Ammonium/Aminium Salts. AB - Amides represent an important class of nitrogen-containing compounds in the atmosphere that can in theory interact with atmospheric acidic particles and contribute to secondary aerosol formation. In this study, uptake coefficients (gamma) of six alkylamides (C1 to C3) by suspended sulfuric acid particles were measured using an aerosol flow tube coupled to a high resolution time-of-flight chemical ionization mass spectrometer (HRToF-CIMS). At 293 K and < 3% relative humidity (RH), the measured uptake coefficients for six alkylamides were in the range of (4.8-23) * 10-2. A negative dependence upon RH was observed for both N methylformamide and N,N-dimethylformamide, likely due to decreased mass accommodation coefficients (alpha) at lower acidities. A negative temperature dependence was observed for N,N-dimethylformamide under < 3% RH, also consistent with the mass accommodation-controlled uptake processes. Chemical analysis of reacted sulfuric acid particles indicates that alkylamides hydrolyzed in the presence of water molecules to form ammonium or aminium. Our results suggest that multiphase uptake of amides will contribute to growth of atmospheric acidic particles and alter their chemical composition. PMID- 28910094 TI - Hemicellulosic Polysaccharides Mimics: Synthesis of Tailored Bottlebrush-Like Xyloglucan Oligosaccharide Glycopolymers as Binders of Nanocrystalline Cellulose. AB - We report in this contribution that while low molecular weight hemicellulosic building blocks are known not to interact with cellulosic materials, their multivalent presentation on a polymeric scaffold significantly enhanced the binding interactions that are remarkably in the same range as those usually observed for lectin-carbohydrate interactions. We developed a poly(propargyl methacrylate) scaffold on which we conjugated, by "post-click" reaction, a variety of azide reducing-end functionalized xyloglucan oligosaccharides with controlled enzymatic-mediated rate of degalactosylation. Bottlebrush-like xyloglucan oligosaccharide glycopolymers (poly(XGOn)) were obtained and their self-assemblies in aqueous solution were investigated using dynamic light scattering (DLS). We demonstrated that increasing the extent of degalactosylation promoted self-association of poly(XGOn), which we attribute to the appearance of hydrophobic domains. A sharp thermoresponsiveness, which corresponds to a decrease in aggregate size with increasing temperature, was observed when the extent of degalactosylation was 30% or greater. Importantly, isothermal titration calorimetry (ITC) and polarized/depolarized DLS revealed that poly(XGOn) exhibit a significant capacity to interact with nanocrystalline cellulose (NCC) surfaces particularly for the nondegalactosylated form, emphasizing the important role of galactosyl residues in the binding mechanism and in the 3-dimensional structures of glycopolymers. PMID- 28910092 TI - Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis. AB - Whereas numerous asymmetric methods for formation of quaternary carbon stereocenters in cyclic systems have been documented, the construction of acyclic quaternary carbon stereocenters with control of absolute stereochemistry remains a formidable challenge. This Review summarizes enantioselective methods for the construction of acyclic quaternary carbon stereocenters from achiral or chiral racemic reactants via transition metal catalysis. PMID- 28910095 TI - Signature of Metallic Behavior in the Metal-Organic Frameworks M3(hexaiminobenzene)2 (M = Ni, Cu). AB - The two-dimensionally connected metal-organic frameworks (MOFs) Ni3(HIB)2 and Cu3(HIB)2 (HIB = hexaiminobenzene) are bulk electrical conductors and exhibit ultraviolet-photoelectron spectroscopy (UPS) signatures expected of metallic solids. Electronic band structure calculations confirm that in both materials the Fermi energy lies in a partially filled delocalized band. Together with additional structural characterization and microscopy data, these results represent the first report of metallic behavior and permanent porosity coexisting within a metal-organic framework. PMID- 28910096 TI - Finite Size Effects in Submonolayer Catalysts Investigated by CO Electrosorption on PtsML/Pd(100). AB - A combination of scanning tunneling microscopy, subtractively normalized interfacial Fourier transform infrared spectroscopy (SNIFTIRS), and density functional theory (DFT) is used to quantify the local strain in 2D Pt clusters on the 100 facet of Pd and its effect on CO chemisorption. Good agreement between SNIFTIRS experiments and DFT simulations provide strong evidence that, in the absence of coherent strain between Pt and Pd, finite size effects introduce local compressive strain, which alters the chemisorption properties of the surface. Though this effect has been widely neglected in prior studies, our results suggest that accurate control over cluster sizes in submonolayer catalyst systems can be an effective approach to fine-tune their catalytic properties. PMID- 28910097 TI - Visible-Light-Promoted C-S Cross-Coupling via Intermolecular Charge Transfer. AB - Disclosed is a mild, scalable, visible-light-promoted cross-coupling reaction between thiols and aryl halides for the construction of C-S bonds in the absence of both transition metal and photoredox catalysts. The scope of aryl halides and thiol partners includes over 60 examples and therefore provides an entry point into various aryl thioether building blocks of pharmaceutical interest. Furthermore, to demonstrate its utility, this C-S coupling protocol was applied in drug synthesis and late-stage modifications of active pharmaceutical ingredients. UV-vis spectroscopy and time-dependent density functional theory calculations suggest that visible-light-promoted intermolecular charge transfer within the thiolate-aryl halide electron donor-acceptor complex permits the reactivity in the absence of catalyst. PMID- 28910098 TI - Fast and Simple Protocols for Mass Spectrometry-Based Proteomics of Small Fresh Frozen Uterine Tissue Sections. AB - Human tissues are an important link between organ-specific spatial molecular information, patient pathology, and patient treatment options. However, patient tissues are uniquely obtained by time and location, and limited in their availability and size. Currently, little knowledge exists about appropriate and simplified protocols for routine MS-based analysis of the various types and sizes of tissues. Following standard procedures used in pathology, we selected small fresh frozen uterine tissue samples to investigate how the tissue preparation protocol affected the subsequent proteomics analysis. First, we observed that protein extraction with 0.1% SDS followed by extraction with a 30% ACN/urea resulted in a decrease in the number of identified proteins, when compared to extraction with 30% ACN/urea only. The decrease in the number of proteins was approximately 55% and 20%, for 10 and 16 MUm thick tissue, respectively. Interestingly, the relative abundance of the proteins shared between the two methods was higher when SDS/ACN/urea was used, compared to the 30% ACN/urea extraction, indicating the role of SDS to be beneficial for protein solubility. Second, the influence of tissue thickness was investigated by comparing the results obtained for 10, 16, and 20 MUm thick (1 mm2) tissue using urea/30% ACN. We observed an increase in the number of identified proteins and corresponding quantity with an increase in the tissue thickness. Finally, by analyzing very small amounts of tissues (~0.2 mm2) of 10, 16, and 20 MUm thickness, we observed that the increase in tissue thickness resulted in a higher number of protein identifications and corresponding quantitative values. PMID- 28910099 TI - Classical Force Fields Tailored for QM Applications: Is It Really a Feasible Strategy? AB - Classical molecular dynamics is more and more often coupled to quantum mechanical based techniques as a statistical tool to sample configurations of molecular systems embedded in complex environments. Nonetheless, the classical potentials describing the molecular systems are seldom parametrized to reproduce electronic processes, such as electronic excitations, which are instead very sensitive to the underlining description of the molecular structure. Here, we analyze the challenging case of the peridinin molecule, a natural apocarotenoid responsible for the light-harvesting process in the PCP antenna protein of dinoflagellates. Ground-state structural and vibrational properties, as well as electronic transitions of the pigment are studied by means of quantum-mechanical static and dynamic calculations. Thereafter, classical molecular dynamics simulations are performed with a number of different force-fields, ranging from a popular, general purpose one to refined potentials of increasing level of complexity. From the comparison of classical results with their quantum mechanical counterparts, it appears that, while very poor results are obtained from standard transferrable force-fields, specifically tuned potentials are able to correctly characterize most of the structural and vibrational features of the pigment. Nonetheless, only an advanced parametrization technique is able to give a semiquantitative description of the coupling between vibrations and electronic excitations, thus suggesting that the use of classical MD in combination of QM calculations for the study of photoinduced processes, albeit possible, should be considered with care. PMID- 28910100 TI - Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug Design. AB - Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology (LOGSY titration) that allows the determination of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addition of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodology and in contrast to conventional ligand-based methods is the independence of the molecular weight of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain containing protein 4, a prominent cancer target in pharmaceutical industry. PMID- 28910101 TI - Anisotropic Fluctuations in the Ribosome Determine tRNA Kinetics. AB - The ribosome is a large ribonucleoprotein complex that is responsible for the production of proteins in all organisms. Accommodation is the process by which an incoming aminoacyl-tRNA (aa-tRNA) molecule binds the ribosomal A site, and its kinetics has been implicated in the accuracy of tRNA selection. In addition to rearrangements in the aa-tRNA molecule, the L11 stalk can undergo large-scale anisotropic motions during translation. To explore the potential impact of this protruding region on the rate of aa-tRNA accommodation, we used molecular dynamics simulations with a simplified model to evaluate the free energy as a function of aa-tRNA position. Specifically, these calculations describe the transition between A/T and elbow-accommodated (EA) configurations (~20 A displacement). We find that the free-energy barrier associated with elbow accommodation is proportional to the degree of mobility exhibited by the L11 stalk. That is, when L11 is more rigid, the free-energy barrier height is decreased. This effect arises from the ability of L11 to confine, and thereby destabilize, the A/T ensemble. In addition, when elongation factor Tu (EF-Tu) is present, the A/T ensemble is further destabilized in an L11-dependent manner. These results provide a framework that suggests how next-generation experiments may precisely control the dynamics of the ribosome. PMID- 28910102 TI - Effects of Charge State, Charge Distribution, and Structure on the Ion Mobility of Protein Ions in Helium Gas: Results from Trajectory Method Calculations. AB - Collision cross section (Omega) values of gas-phase ions of proteins and protein complexes are used to probe the structures of the corresponding species in solution. Ions of many proteins exhibit increasing Omega-values with increasing charge state but most Omega-values calculated for protein ions have used simple collision models that do not explicitly account for charge. Here we use a combination of ion mobility mass spectrometry experiments with helium gas and trajectory method calculations to characterize the extents to which increases in experimental Omega-values with increasing charge state may be attributed to increased momentum transfer concomitant with enhanced long-range interactions between the protein ion and helium atoms. Ubiquitin and C-to-N terminally linked diubiquitin ions generated from different solution conditions exhibit more than a 2-fold increase in Omega with increasing charge state. For native and energy relaxed models of the proteins and most methods for distributing charge, Omega values calculated using the trajectory method increase by less than 1% over the range of charge states observed from typical solution conditions used for native mass spectrometry. However, the calculated Omega-values increase by 10% to 15% over the full range of charge states observed from all solution conditions. Therefore, contributions from enhanced ion-induced dipole interactions with increasing charge state are significant but without additional structural changes can account for only a fraction of the increase in Omega observed experimentally. On the basis of these results, we suggest guidelines for calculating Omega-values in the context of applications in biophysics and structural biology. PMID- 28910103 TI - Difluorocarbene for Dehydroxytrifluoromethylthiolation of Alcohols. AB - Dehydroxytrifluoromethylthiolation of alcohols with a Ph3P+CF2CO2-/S8/F- system is described. Difluorocarbene generated from Ph3P+CF2CO2- would readily combine with elemental sulfur to furnish S?CF2. S?CF2 can be considered as a bifunctional intermediate, activating alcohol and providing scaffold for CF3S- formation, thus allowing for the convenient dehydroxytrifluoromethylthiolation of alcohols. PMID- 28910104 TI - Reaction of Silyllithium, alpha-Keto N-tert-Butanesulfinyl Imidates and Aldehydes for Asymmetric Synthesis of alpha-Substituted beta-(Silyloxy)-alpha-hydroxy Acid Derivatives. AB - A single-flask reaction of silyllithium, alpha-keto N-tert-butanesulfinyl imidates and aldehydes has been developed for the diastereoselective synthesis of alpha,beta-dihydroxy acid derivatives. In this reaction, the nucleophilic addition of silyllithium to chiral alpha-keto imidates followed by silyl migration forms chiral aza-enolates, which react diastereoselectively with aldehydes. Subsequent [1,4]-O -> O silyl migration affords alpha-substituted beta (silyoxy)-alpha-hydroxy imidates. PMID- 28910105 TI - Modeling Oil Shale Pyrolysis: High-Temperature Unimolecular Decomposition Pathways for Thiophene. AB - The thermal decomposition mechanism of thiophene has been investigated both experimentally and theoretically. Thermal decomposition experiments were done using a 1 mm * 3 cm pulsed silicon carbide microtubular reactor, C4H4S + Delta -> Products. Unlike previous studies these experiments were able to identify the initial thiophene decomposition products. Thiophene was entrained in either Ar, Ne, or He carrier gas, passed through a heated (300-1700 K) SiC microtubular reactor (roughly <=100 MUs residence time), and exited into a vacuum chamber. The resultant molecular beam was probed by photoionization mass spectroscopy and IR spectroscopy. The pyrolysis mechanisms of thiophene were also investigated with the CBS-QB3 method using UB3LYP/6-311++G(2d,p) optimized geometries. In particular, these electronic structure methods were used to explore pathways for the formation of elemental sulfur as well as for the formation of H2S and 1,3 butadiyne. Thiophene was found to undergo unimolecular decomposition by five pathways: C4H4S -> (1) S?C?CH2 + HCCH, (2) CS + HCCCH3, (3) HCS + HCCCH2, (4) H2S + HCC-CCH, and (5) S + HCC-CH?CH2. The experimental and theoretical findings are in excellent agreement. PMID- 28910108 TI - Hydration Friction in Nanoconfinement: From Bulk via Interfacial to Dry Friction. AB - The viscous properties of nanoscopically confined water are important when hydrated surfaces in close contact are sheared against each other. Numerous experiments have probed the friction between atomically flat hydrated surfaces in the subnanometer separation regime and suggested an increased water viscosity, but the value of the effective viscosity of ultraconfined water, the mechanism of hydration layer friction, and the crossover to the dry friction limit are unclear. We study the shear friction between polar surfaces by extensive nonequilibrium molecular dynamics simulations in the linear-response regime at low shearing velocity, which is the relevant regime for typical biological applications. With decreasing water film thickness we find three consecutive friction regimes: For thick films friction is governed by bulk water viscosity. At separations of about a nanometer the highly viscous interfacial water layers dominate and increase the surface friction, while at the transition to the dry friction limit interfacial slip sets in. Based on our simulation results, we construct a confinement-dependent friction model which accounts for the additive friction contributions from bulklike water, interfacial water layers, and interfacial slip and which is valid for arbitrary water film thickness. PMID- 28910106 TI - Stereoselective and Regioselective Synthesis of Heterocycles via Copper-Catalyzed Additions of Amine Derivatives and Alcohols to Alkenes. AB - This Perspective describes the development of a family of copper(II)-catalyzed alkene difunctionalization reactions that enable stereoselective addition of amine derivatives and alcohols onto pendant unactivated alkenes to provide a range of valuable saturated nitrogen and oxygen heterocycles. 2-Vinylanilines and related substrates undergo alternative oxidative amination or allylic amination pathways, and these reactions will also be discussed. The involvement of both polar and radical steps in the reaction mechanisms have been implicated. Major product formation is a function of the lowest energy pathway, which in turn is a function of structural aspects of the various reaction components. PMID- 28910107 TI - Perturbation of the F19-L34 Contact in Amyloid beta (1-40) Fibrils Induces Only Local Structural Changes but Abolishes Cytotoxicity. AB - We explored structural details of fibrils formed by a mutated amyloid beta (Abeta(1-40)) peptide carrying a Phe19 to Lys19 mutation, which was shown to completely abolish the toxicity of the molecule. Computer models suggest that the positively charged Lys19 side chain is expelled from the hydrophobic fibril interior upon fibrillation. This can be accommodated by either a 180 degrees flip of the entire lower beta-strand (model M1) or local perturbations of the secondary structure in the direct vicinity of the mutated site (model M2). This is accompanied by the formation of a new salt bridge between Glu22 and Lys28 in model M1. Experimentally, a novel contact between Phe20 and Leu34 as well as the significant structural perturbation of residues 20-23 could be confirmed. However, the mutated fibrils do not show the formation of any salt bridges. This demonstrates that although morphologically very robust, local perturbations of the Abeta(1-40) sequence lead to moderate structural alterations with tremendous impact on the physiological importance of these aggregates, which may suggest alternative strategies for the development of a remedy against Alzheimer's disease. PMID- 28910109 TI - Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions. AB - Experimental and theoretical studies on ion-lipid interactions predict that binding of calcium ions to cell membranes leads to macroscopic mechanical effects and membrane remodeling. Herein, we provide experimental evidence that a point source of Ca2+ acting upon a negatively charged membrane generates spontaneous curvature and triggers the formation of tubular protrusions that point away from the ion source. This behavior is rationalized by strong binding of the divalent cations to the surface of the charged bilayer, which effectively neutralizes the surface charge density of outer leaflet of the bilayer. The mismatch in the surface charge density of the two leaflets leads to nonzero spontaneous curvature. We probe this mismatch through the use of molecular dynamics simulations and validate that calcium ion binding to a lipid membrane is sufficient to generate inward spontaneous curvature, bending the membrane. Additionally, we demonstrate that the formed tubular protrusions can be translated along the vesicle surface in a controlled manner by repositioning the site of localized Ca2+ exposure. The findings demonstrate lipid membrane remodeling in response to local chemical gradients and offer potential insights into the cell membrane behavior under conditions of varying calcium ion concentrations. PMID- 28910110 TI - Enhancing Organic Semiconductor-Surface Plasmon Polariton Coupling with Molecular Orientation. AB - Due to strong electric field enhancements, surface plasmon polaritons (SPPs) are capable of drastically increasing light-molecule coupling in organic optoelectronic devices. The electric field enhancement, however, is anisotropic, offering maximal functional benefits if molecules are oriented perpendicular to the interface. To provide a clear demonstration of this orientation dependence, we study SPP dispersion and SPP-mediated photoluminescence at a model Au/small molecule interface where identical molecules can be deposited with two very different molecular backbone orientations depending on processing conditions. First, we demonstrate that thin films of p-SIDT(FBTTh2)2 can be deposited with either all "in-plane" (parallel to substrate) or a 50/50 mix of in-plane/"out-of plane" (perpendicular to substrate) optical transition dipoles by the absence or presence, respectively, of diiodooctane during spin-coating. In contrast to typical orientation control observed in organic thin films, for this particular molecule, this corresponds to films with conjugated backbones purely in-plane, or with a 50/50 mix of in-plane/out-of-plane backbones. Then, using momentum resolved reflectometry and momentum-resolved photoluminescence, we study and quantify changes in SPP dispersion and photoluminescence intensity arising solely from changes in molecular orientation. We demonstrate increased SPP momentum and a 2-fold enhancement in photoluminescence for systems with out-of-plane oriented transition dipoles. These results agree well with theory and have direct implications for the design and analysis of organic optoelectronic devices. PMID- 28910111 TI - Chemical versus Electrochemical Electrolyte Oxidation on NMC111, NMC622, NMC811, LNMO, and Conductive Carbon. AB - We compare the stability of alkyl carbonate electrolyte on NMC111, -622, and 811, LNMO, and conductive carbon electrodes. We prove that CO2 and CO evolution onset potentials depend on the electrode material and increase in the order NMC811 < NMC111 ~ NMC622 < conductive carbon ~ LNMO, which we rationalize by two fundamentally different oxidation mechanisms, the chemical and the electrochemical electrolyte oxidation. Additionally, in contrast to the widespread understanding that transition metals in cathode active materials catalyze the electrolyte oxidation, we will prove that such a catalytic effect on the electrochemical electrolyte oxidation does not exist. PMID- 28910113 TI - Tandem Synthesis of Pyrrolo[2,3-b]quinolones via Cadogen-Type Reaction. AB - A tandem [3 + 2] cycloaddition/reductive cyclization of nitrochalcones with activated methylene isocyanides for the efficient synthesis of pyrrolo[2,3 b]quinolones is reported. In this reaction, the in situ generated dihydropyrroline acts as the internal reductant to convert the nitro into an electrophilic nitroso group, which undergoes subsequent C-N bond formation. Transition-metal-free, simple experimental procedure and ready accessibility of starting materials characterize the present transformation. PMID- 28910112 TI - Modular Approach to pseudo-Neoclerodanes as Designer kappa-Opioid Ligands. AB - Informed by previous semisynthetic work on salvinorin A, a modular total synthesis has been developed capable of producing novel compounds targeting the kappa-opioid receptor. The strategy has permitted the deliberate simplification and introduction of functionality about the target molecule to provide access to molecular features on salvinorin A otherwise unattainable by semisynthesis. Using this approach, a potent pseudo-neoclerodane kappa-opioid receptor ligand (2) has been realized. PMID- 28910114 TI - Double-Diels-Alder Approach to Maoecrystal V. Unexpected C-C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core. AB - Synthetic studies toward maoecrystal V are reported. An oxidative dearomatization/Diels-Alder cascade to assemble the natural product carbocyclic core in one step is proposed. A facile electrocyclization is shown to suppress the intramolecular allene Diels-Alder pathway. This obstacle is alleviated via a stepwise approach with an allene equivalent to access the key cyclopentadiene fused [2.2.2]-bicyclic core. Upon treatment with Lewis acid, the proposed intramolecular hetero-Diels-Alder reaction is cleanly and unexpectedly diverted either via C-C bond-forming fragmentation to the spiro-indene product (when R = OMe) or via elimination (when R = H). PMID- 28910115 TI - Bulky Dehydroamino Acids Enhance Proteolytic Stability and Folding in beta Hairpin Peptides. AB - The bulky dehydroamino acids dehydrovaline (DeltaVal) and dehydroethylnorvaline (DeltaEnv) can be inserted into the turn regions of beta-hairpin peptides without altering their secondary structures. These residues increase proteolytic stability, with DeltaVal at the (i + 1) position having the most substantial impact. Additionally, a bulky dehydroamino acid can be paired with a d-amino acid (i.e., d-Pro) to synergistically enhance resistance to proteolysis. A link between proteolytic stability and peptide structure is established by the finding that a stabilized DeltaVal-containing beta-hairpin is more highly folded than its Asn-containing congener. PMID- 28910116 TI - Hard X-ray-Induced Valence Tautomeric Interconversion in Cobalt-o-Dioxolene Complexes. AB - Valence tautomeric interconversion (VTI) is a reversible process occurring in metal complexes in which an intramolecular metal-ligand electron transfer is accompanied by a change of metal ion spin state, creating two switchable electronic states (redox isomers). Herein, we describe the low-temperature, 30 100 K, single-crystal study of the [Co(diox)2(4-CN-py)2].benzene complex (1) (diox = 3,5-di-t-butylsemiquinonate (SQ*-) and/or 3,5-di-t-butylcatecholate (Cat2 ) radical; 4-CN-py = 4-cyano-pyridine) using hard synchrotron X-ray radiation with different intensities. We demonstrate for the first time that hard X-rays can induce VTI, and that the interconversion molar fraction is dependent on both intensity and exposure time. This in turn shows that X-rays, as a probe, might be altering the very nature of many structures under investigation at low temperatures, and consequently their properties. Our findings add new perspectives to VTI studies and might be of significant interest to the entire community investigating photoresponsive complexes. PMID- 28910117 TI - Light-Directed Patchy Particle Fabrication and Assembly from Isotropic Silver Nanoparticles. AB - We demonstrate the creation of anisotropic patchy silver nanospheroids (AgNSs) using linearly polarized UV light and a photo-uncaging o-nitrobenzyl-based ligand, which anchors to the AgNSs by two gold-sulfur bonds. Exposure to a 1 J/cm2 dose of UV light induces a photo-uncaging reaction in the ligand that reveals a primary amine on the surface. By using linearly polarized UV light, we meter the exposure dose such that only the poles of the nanoparticle receive a full dose, limiting the photo-uncaging reaction primarily to the particle's plasmonic hot spots. We reveal this anisotropy by preferentially adhering negatively charged gold nanospheres (AuNSs) to the AgNSs' poles by using the electrostatic attraction between them and the positively charged primary amines generated by photo-uncaging. When the assembly is performed onto silver particles that are immobilized on a substrate, it results in nanoscale structures with a strong tendency to align with the polarization of the exposing light. This manifests in polarimetric spectroscopy as a linear dichroism aligned with the polarization direction. PMID- 28910118 TI - Cascade Radical Reaction of N-Sulfonyl-2-allylanilines with [60]Fullerene: Synthesis and Functionalization of (2-Indolinyl)methylated Hydrofullerenes. AB - The copper-promoted cascade radical reaction of N-sulfonyl-2-allylanilines with [60]fullerene has been developed to efficiently provide novel and scarce (2 indolinyl)methylated hydrofullerenes, featuring a broad substrate scope and excellent functional group tolerance. A plausible reaction mechanism for the formation of (2-indolinyl)methylated hydrofullerenes is proposed on the basis of the experimental results. In addition, further transformation into other carbocyclic derivatives of [60]fullerene as well as their applications in organic photovoltaic devices of the obtained products has also been explored. PMID- 28910119 TI - NbCl5/Zn/PCy3-System-Catalyzed Intramolecular [2 + 2 + 2] Cycloadditions of Diynes and Alkenes To Form Bicyclic Cyclohexadienes. AB - A NbCl5, Zn, and PCy3 catalytic system that generated low-valent Nb species is used for the synthesis of bicyclic cyclohexadienes from diynes and simple alkenes. A phosphine ligand is important for stabilizing low-valent Nb in the cycloaddition. The bicyclic cyclohexadiene skeleton is important in transition metal-catalyzed intramolecular cycloadditions. PMID- 28910120 TI - A Universal Pattern in the Percolation and Dissipation of Protein Structural Perturbations. AB - Understanding the extent to which information is transmitted through the intramolecular interaction network of proteins upon a perturbation, that is, an allosteric effect, has long remained an unsolved problem. Through an analysis of high-resolution NMR data from the literature on 28 different proteins and 49 structural perturbations, we show that the extent of induced structural changes through mutations and molecular events including protein-protein, protein peptide, protein-ligand binding, and post-translational modifications exhibit a near-universal exponential functional form. The extent of percolation into the protein structures can be up to 20-25 A despite no apparent change in the 3D structures. These observations are also consistent with theoretical expectations, elementary graph theoretic analysis of protein structures, detailed molecular dynamics simulations, and experimental double-mutant cycles. Our analysis highlights that most molecular events would contribute to allosteric effects independent of protein structure, topology, or identity and provides a simple avenue to test and potentially model their effects. PMID- 28910121 TI - The impact of uncertain threat on affective bias: Individual differences in response to ambiguity. AB - Individuals who operate under highly stressful conditions (e.g., military personnel and first responders) are often faced with the challenge of quickly interpreting ambiguous information in uncertain and threatening environments. When faced with ambiguity, it is likely adaptive to view potentially dangerous stimuli as threatening until contextual information proves otherwise. One laboratory-based paradigm that can be used to simulate uncertain threat is known as threat of shock (TOS), in which participants are told that they might receive mild but unpredictable electric shocks while performing an unrelated task. The uncertainty associated with this potential threat induces a state of emotional arousal that is not overwhelmingly stressful, but has widespread-both adaptive and maladaptive-effects on cognitive and affective function. For example, TOS is thought to enhance aversive processing and abolish positivity bias. Importantly, in certain situations (e.g., when walking home alone at night), this anxiety can promote an adaptive state of heightened vigilance and defense mobilization. In the present study, we used TOS to examine the effects of uncertain threat on valence bias, or the tendency to interpret ambiguous social cues as positive or negative. As predicted, we found that heightened emotional arousal elicited by TOS was associated with an increased tendency to interpret ambiguous cues negatively. Such negative interpretations are likely adaptive in situations in which threat detection is critical for survival and should override an individual's tendency to interpret ambiguity positively in safe contexts. (PsycINFO Database Record PMID- 28910122 TI - Race and recession: Effects of economic scarcity on racial discrimination. AB - When the economy declines, existing racial disparities typically expand, suggesting that economic scarcity may promote racial discrimination. To understand this pattern, we examined the effect of perceived scarcity on resource allocations to Black and White American recipients, and tested whether this effect depends on a decision maker's motivation to respond without prejudice. We proposed that scarcity would lead to increased discrimination among those with relatively low internal motivation but not those high in internal motivation. Indeed, we found that when resources were framed as scarce (vs. abundant or a control condition), low-motivation participants allocated less to Black than White recipients, whereas high-motivation participants allocated more to Black than White recipients (Studies 1 and 2). This pattern was strongest when decisions could be made deliberatively (Study 3), and anti-Black allocation bias emerged even in a non-zero-sum context (Studies 4 and 5), suggesting a strategic bias directed against Black recipients rather than in favor of White recipients. These findings indicate that the psychological perception of scarcity can produce racial bias in the distribution of economic resources, depending on the motivations of the decision maker-an effect that may contribute to the increase in racial disparities observed during economic stress. (PsycINFO Database Record PMID- 28910123 TI - Consumer factors predicting level of treatment response to illness management and recovery. AB - OBJECTIVE: This study aims to identify consumer-level predictors of level of treatment response to illness management and recovery (IMR) to target the appropriate consumers and aid psychiatric rehabilitation settings in developing intervention adaptations. METHOD: Secondary analyses from a multisite study of IMR were conducted. Self-report data from consumer participants of the parent study (n = 236) were analyzed for the current study. Consumers completed prepost surveys assessing illness management, coping, goal-related hope, social support, medication adherence, and working alliance. Correlations and multiple regression analyses were run to identify self-report variables that predicted level of treatment response to IMR. RESULTS: Analyses revealed that goal-related hope significantly predicted level of improved illness self-management, F(1, 164) = 10.93, p < .001, R2 = .248, R2 change = .05. Additionally, we found that higher levels of maladaptive coping at baseline were predictive of higher levels of adaptive coping at follow-up, F(2, 180) = 5.29, p < .02, R2 = .38, R2 change = .02. Evidence did not support additional predictors. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Previously, consumer-level predictors of level of treatment response have not been explored for IMR. Although 2 significant predictors were identified, study findings suggest more work is needed. Future research is needed to identify additional consumer-level factors predictive of IMR treatment response in order to identify who would benefit most from this treatment program. (PsycINFO Database Record PMID- 28910124 TI - Paid sick leave and psychological distress: An analysis of U.S. workers. AB - Paid sick leave is increasingly identified as a social justice issue having important implications for health and wellness; however, little is known about its relationship to mental health. Data from the 2015 cross section of the National Health Interview Survey (NHIS; 2015) were used to examine the relationship between paid sick leave and psychological distress during the last 30 days among N = 17,897 working United States adults. The 6-item Kessler Psychological Distress Scale (K6), a valid and reliable instrument for assessing psychological distress in population based samples, was used to measure the outcome variable of interest. The K6 score was computed from 6 questions and was regressed on paid sick leave status, after controlling for variables known to be related to psychological distress. Results indicated that workers who lack paid sick leave benefits report a statistically significant higher level of psychological distress, and are 1.45 times more likely to report their distress symptoms interfere a lot with their life or activities compared with workers with paid sick leave. This research adds to a body of work analyzing institutional structures and social determinants of health. Findings support the potential value of paid sick leave as an intervention to promote behavioral health. (PsycINFO Database Record PMID- 28910125 TI - Threat of shock and aversive inhibition: Induced anxiety modulates Pavlovian instrumental interactions. AB - Anxiety can be an adaptive response to potentially threatening situations. However, if experienced in inappropriate contexts, it can also lead to pathological and maladaptive anxiety disorders. Experimentally, anxiety can be induced in healthy individuals using the threat of shock (ToS) paradigm. Accumulating work with this paradigm suggests that anxiety promotes harm-avoidant mechanisms through enhanced inhibitory control. However, the specific cognitive mechanisms underlying anxiety-linked inhibitory control are unclear. Critically, behavioral inhibition can arise from at least 2 interacting valuation systems: instrumental (a goal-directed system) and Pavlovian (a "hardwired" reflexive system). The present study (N = 62) replicated a study showing improved response inhibition under ToS in healthy participants, and additionally examined the impact of ToS on aversive and appetitive Pavlovian-instrumental interactions in a reinforced go/no-go task. When Pavlovian and instrumental systems were in conflict, ToS increased inhibition to aversive events, while leaving appetitive interactions unperturbed. We argue that anxiety promotes avoidant behavior in potentially harmful situations by potentiating aversive Pavlovian reactions (i.e., promoting avoidance in the face of threats). Critically, such a mechanism would drive adaptive harm-avoidant behavior in threatening situations where Pavlovian and instrumental processes are aligned, but at the same time, result in maladaptive behaviors when misaligned and where instrumental control would be advantageous. This has important implications for our understanding of the mechanisms that underlie pathological anxiety. (PsycINFO Database Record PMID- 28910127 TI - Visual shape perception as Bayesian inference of 3D object-centered shape representations. AB - Despite decades of research, little is known about how people visually perceive object shape. We hypothesize that a promising approach to shape perception is provided by a "visual perception as Bayesian inference" framework which augments an emphasis on visual representation with an emphasis on the idea that shape perception is a form of statistical inference. Our hypothesis claims that shape perception of unfamiliar objects can be characterized as statistical inference of 3D shape in an object-centered coordinate system. We describe a computational model based on our theoretical framework, and provide evidence for the model along two lines. First, we show that, counterintuitively, the model accounts for viewpoint-dependency of object recognition, traditionally regarded as evidence against people's use of 3D object-centered shape representations. Second, we report the results of an experiment using a shape similarity task, and present an extensive evaluation of existing models' abilities to account for the experimental data. We find that our shape inference model captures subjects' behaviors better than competing models. Taken as a whole, our experimental and computational results illustrate the promise of our approach and suggest that people's shape representations of unfamiliar objects are probabilistic, 3D, and object-centered. (PsycINFO Database Record PMID- 28910126 TI - Negative emotional content disrupts the coherence of episodic memories. AB - Events are thought to be stored in episodic memory as coherent representations, in which the constituent elements are bound together so that a cue can trigger reexperience of all elements via pattern completion. Negative emotional content can strongly influence memory, but opposing theories predict strengthening or weakening of memory coherence. Across a series of experiments, participants imagined a number of person-location-object events with half of the events including a negative element (e.g., an injured person), and memory was tested across all within event associations. We show that the presence of a negative element reduces memory for associations between event elements, including between neutral elements encoded after a negative element. The presence of a negative element reduces the coherence with which a multimodal event is remembered. Our results, supported by a computational model, suggest that coherent retrieval from neutral events is supported by pattern completion, but that negative content weakens associative encoding which impairs this process. Our findings have important implications for understanding the way traumatic events are encoded and support therapeutic strategies aimed at restoring associations between negative content and its surrounding context. (PsycINFO Database Record PMID- 28910129 TI - How is the serial order of a visual sequence represented? Insights from transposition latencies. AB - A central goal of research on short-term memory (STM) over the past 2 decades has been to identify the mechanisms that underpin the representation of serial order, and to establish whether these mechanisms are the same across different modalities and domains (e.g., verbal, visual, spatial). A fruitful approach to addressing this question has involved comparing the transposition error latency predictions of models built from different candidate mechanisms for representing serial order. Experiments involving the output-timed serial recall of sequences of verbal (Farrell & Lewandowsky, 2004) and spatial (Hurlstone & Hitch, 2015) items have revealed an error latency profile consistent with the prediction of a competitive queuing mechanism within which serial order is represented via a primacy gradient of activations over items, associations between items and position markers, with suppression of items following recall. In this paper, we extend this chronometric analysis of recall errors to the serial recall of sequences of visual, nonspatial, items and find across 3 experiments an error latency profile broadly consistent with the prediction of the same representational mechanism. The findings suggest that common mechanisms and principles contribute to the representation of serial order across the verbal, visual, and spatial STM domains. The implications of these findings for theories of short-term and working memory are considered. (PsycINFO Database Record PMID- 28910128 TI - Future so bright? Delay discounting and consideration of future consequences predict academic performance among college drinkers. AB - College student drinking is a major public health concern and can result in a range of negative consequences, from acute health risks to decreased academic performance and drop out. Harm reduction interventions have been developed to reduce problems associated with drinking but there is a need to identify specific risk/protective factors related to academic performance among college drinkers. Behavioral economics suggests that chronic alcohol misuse reflects a dysregulated behavioral process or reinforcer pathology-alcohol is overvalued and the value of prosocial rewards are sharply discounted due, in part, to their delay. This study examined delay discounting, consideration of future consequences (CFC) and protective behavioral strategies (PBS) as predictors of academic success (grade point average; GPA) and engagement (time devoted to academic activities) among 393 college drinkers (61% female). In multivariate models, PBS were associated with greater academic engagement, but were not with academic success. Lower discounting of delayed rewards and greater CFC were associated with both academic success and engagement among drinkers. Previous research suggests that future time orientation is malleable, and the current results provide support for efforts to enhance future time orientation as part of alcohol harm-reduction approaches. (PsycINFO Database Record PMID- 28910130 TI - And still WE rise: Parent-child relationships, resilience, and school readiness in low-income urban Black families. AB - The Family Stress Model acknowledges forms of resilience in the face of hardship; however, few studies have emerged on the potentially positive role of familial relationships in the academic, psychological, and prosocial success of impoverished Black children. The current study evaluates how parent-child relationship conflict and financial stress are associated with children's school readiness (i.e., academic, psychosocial, and socioemotional indicators). Latent profile analyses, incorporating financial stress, general stress, and parent child relationship variables were used to test whether varying family stress profiles differentially predicted children's school readiness in Black families with children entering kindergarten (N = 292). Findings revealed 4 latent classifications with profiles of low, moderate, moderate/high, and high/moderate stress and conflict variables, respectively. Whereas the low-profile was associated with the most desirable school readiness indicators overall, children in the high/moderate-profile were rated as significantly more psychosocially and socioemotionally prepared for school than their moderate/high-profile counterparts. Families with less conflictual parent-child relationships had more optimal school readiness relative to families with higher conflict and less financial strain. The findings of the current study have the potential to contribute to theories of poverty and parent-child relationships, as well as guide therapeutic services focused on family relationships through school- and community-related programs for impoverished urban Black youth and their families. (PsycINFO Database Record PMID- 28910131 TI - Lung Tissue Injury as an Atypical Response to Nivolumab in Non-Small Cell Lung Cancer. PMID- 28910132 TI - Modified African Ngoma Healing Ceremony for Stress Reduction: A Pilot Study. AB - OBJECTIVE: Indigenous people's ceremonies using rhythm and dance have been used for countless generations throughout the world for healing, conflict resolution, social bonding, and spiritual experience. A previous study reported that a ceremony based on the Central African ngoma tradition was favorably received by a group of Americans. The present trial compared the effects of the modified ngoma ceremony (Ngoma) with those of mindfulness-based stress reduction (MBSR) in a randomized pilot study. METHODS: Twenty-one women were randomized to either Ngoma or MBSR. Both groups had sessions on a weekly basis for 8 weeks and completed questionnaires at baseline, week 8, and 1 month after the intervention. Participants completed questionnaires, which included self-report of depressive and anxiety symptoms, health status (e.g., quality of life and functioning), social bonding, and perception of the credibility of the two interventions. RESULTS: Both groups showed improvements in depression, anxiety, emotional well being, and social functioning as measured by respective scales. Social bonding also increased in both groups during the study and may be a mechanism for both interventions. Participants found both interventions credible. CONCLUSIONS: In this pilot study, Ngoma showed significant and durable beneficial effects comparable to MBSR. The effects of Ngoma and other indigenous rhythm-dance ceremonies on distress and health status in western culture should be investigated in larger clinical studies. PMID- 28910133 TI - A Comparison of 2-Year Outcomes in Patients Undergoing Tibiofemoral or Patellofemoral Matrix-Induced Autologous Chondrocyte Implantation. AB - BACKGROUND: Matrix-induced autologous chondrocyte implantation (MACI) has demonstrated encouraging clinical results in the treatment of knee chondral defects. However, earlier studies suggested that chondrocyte implantation in the patellofemoral (PF) joint was less effective than in the tibiofemoral (TF) joint. PURPOSE: To compare the radiological and clinical outcomes of those undergoing MACI to either the femoral condyles or PF joint. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 194 patients were included in this analysis, including 127 undergoing MACI to the medial (n = 94) and lateral (n = 33) femoral condyle, as well as 67 to the patella (n = 35) or trochlea (n = 32). All patients were evaluated clinically (Knee injury and Osteoarthritis Outcome Score [KOOS], visual analog scale, Short Form-36) before surgery and at 3, 12, and 24 months after surgery, while magnetic resonance imaging (MRI) was undertaken at 3, 12, and 24 months, with the MOCART (magnetic resonance observation of cartilage repair tissue) scoring system employed to evaluate the quality and quantity of repair tissue, as well as an MRI composite score. Patient satisfaction was evaluated. RESULTS: No significant group differences ( P > .05) were seen in demographics, defect size, prior injury, or surgical history, while the majority of clinical scores were similar preoperatively. All clinical scores significantly improved over time ( P < .05), with a significant group effect observed for KOOS activities of daily living ( P = .008), quality of life ( P = .008), and sport ( P = .017), reflecting better postoperative scores in the TF group. While the PF group had significantly lower values at baseline for the KOOS activities of daily living and quality of life subscales, it actually displayed a similar net improvement over time compared with the TF group. At 24 months, 93.7% (n = 119) and 91.0% (n = 61) of patients were satisfied with the ability of MACI to relieve their knee pain, 74.0% (n = 94) and 65.7% (n = 44) with their ability to participate in sport, and 90.5% (n = 115) and 83.6% (n = 56) satisfied overall, in the TF and PF groups, respectively. MRI evaluation via the MOCART score revealed a significant time effect ( P < .05) for the MRI composite score and graft infill over the 24-month period. While subchondral lamina scored significantly better ( P = .002) in the TF group, subchondral bone scored significantly worse ( P < .001). At 24 months, the overall MRI composite score was classified as good/excellent in 98 TF patients (77%) and 54 PF patients (81%). CONCLUSION: MACI in the PF joint with concurrent correction of PF maltracking if required leads to similar clinical and radiological outcomes compared with MACI on the femoral condyles. PMID- 28910135 TI - Imaging of Vanadium in Microfossils: A New Potential Biosignature. AB - The inability to unambiguously distinguish the biogenicity of microfossil-like structures in the ancient rock record is a fundamental predicament facing Archean paleobiologists and astrobiologists. Therefore, novel methods for discriminating biological from nonbiological chemistries of microfossil-like structures are of the utmost importance in the search for evidence of early life on Earth. This, too, is important for the search for life on Mars by in situ analyses via rovers or sample return missions for future analysis here on Earth. Here, we report the application of synchrotron X-ray fluorescence imaging of vanadium, within thermally altered organic-walled microfossils of bona fide biological origin. From our data, we demonstrate that vanadium is present within microfossils of undisputable biological origin. It is well known in the organic geochemistry literature that elements such as vanadium are enriched and contained within crude oils, asphalts, and black shales that have been formed by diagenesis of biological organic material. It has been demonstrated that the origin of vanadium is due to the diagenetic alteration of precursor chlorophyll and heme porphyrin pigment compounds from living organisms. We propose that, taken together, microfossil-like morphology, carbonaceous composition, and the presence of vanadium could be used in tandem as a biosignature to ascertain the biogenicity of putative microfossil-like structures. Key Words: Microfossils-Synchrotron micro-X-ray fluorescence-Vanadium-Tetrapyrrole-Biosignature. Astrobiology 17, 1069-1076. PMID- 28910137 TI - The Role of S1PR3 in Protection from Bacterial Sepsis. PMID- 28910134 TI - Eosinophilic and Noneosinophilic Asthma. PMID- 28910136 TI - NRP1 Accelerates Odontoblast Differentiation of Dental Pulp Stem Cells Through Classical Wnt/beta-Catenin Signaling. AB - Neuropilin-1 (NRP1) is one of the members of neuropilin family. It can combine with disparate ligands involved in regulating cell proliferation, apoptosis, and differentiation. The binding of NRP1 to Sema3A stimulates osteoblast differentiation through the classical Wnt/beta-catenin pathway. However, the functions of NRP1 in dental pulp stem cells (DPSCs) are not clear. The aim of our study was to investigate how NRP1 controlled odontoblast differentiation in DPSCs and clarified the underlying mechanisms. NRP1 expression was increased in time dependent manner along with cell odontoblast differentiation. Overexpression of NRP1 upregulated dentin matrix protein-1, dentin sialophosphoprotein, alkaline phosphatase protein level, and mineralization in DPSCs, while knockdown of NRP1 induced the opposite effects. SiNRP1 similar to DKK1 availably blocked classical Wnt/beta-catenin signaling and odontoblast differentiation. In summary, NRP1, as a promoter of odontoblast differentiation, regulates DPSCs via the classical Wnt/beta-catenin pathway. PMID- 28910138 TI - HSP90 Inhibition and Cellular Stress Elicits Phenotypic Plasticity in Hematopoietic Differentiation. AB - Cancer cells exist in a state of Darwinian selection using mechanisms that produce changes in gene expression through genetic and epigenetic alteration to facilitate their survival. Cellular plasticity, or the ability to alter cellular phenotype, can assist in survival of premalignant cells as they progress to full malignancy by providing another mechanism of adaptation. The connection between cellular stress and the progression of cancer has been established, although the details of the mechanisms have yet to be fully elucidated. The molecular chaperone HSP90 is often upregulated in cancers as they progress, presumably to allow cancer cells to deal with misfolded proteins and cellular stress associated with transformation. The objective of this work is to test the hypothesis that inhibition of HSP90 results in increased cell plasticity in mammalian systems that can confer a greater adaptability to selective pressures. The approach used is a murine in vitro model system of hematopoietic differentiation that utilizes a murine hematopoietic stem cell line, erythroid myeloid lymphoid (EML) clone 1, during their maturation from stem cells to granulocytic progenitors. During the differentiation protocol, 80%-90% of the cells die when placed in medium where the major growth factor is granulocyte-macrophage-colony stimulating factor. Using this selection point model, EML cells exhibit increases in cellular plasticity when they are better able to adapt to this medium and survive. Increases in cellular plasticity were found to occur upon exposure to geldanamycin to inhibit HSP90, when subjected to various forms of cellular stress, or inhibition of histone acetylation. Furthermore, we provide evidence that the cellular plasticity associated with inhibition of HSP90 in this model involves epigenetic mechanisms and is dependent upon high levels of stem cell factor signaling. This work provides evidence for a role of HSP90 and cellular stress in inducing phenotypic plasticity in mammalian systems that has new implications for cellular stress in progression and evolution of cancer. PMID- 28910139 TI - Quality of Life in Children and Youth with Obsessive-Compulsive Disorder. AB - OBJECTIVE: The study examined clinical correlates of quality of life (QoL), impact of treatment on QoL, and predictors of QoL change among children with obsessive-compulsive disorder (OCD). METHODS: One hundred forty-two children with primary OCD who were enrolled as part of a larger clinical trial participated. Children were administered a structured diagnostic interview, as well as clinician-administered measures of OCD and depression symptom severity. Children and parents completed reports of QoL, as well as measures of impairment and internalizing and externalizing symptoms. Youth received 10 sessions of family based cognitive-behavioral therapy (CBT). RESULTS: At baseline, QoL was inversely related to obsessive-compulsive symptom severity, impairment, externalizing and internalizing symptoms, and severity of depression symptoms according to children and parents. After CBT, QoL improved according to parent ratings, but not child ratings. None of the predictors examined were associated with changes in QoL scores over time. Impairment, and externalizing and internalizing symptoms predicted QoL after accounting for OCD symptom severity. After accounting for OCD symptoms, externalizing symptoms inversely predicted changes in QoL. CONCLUSION: These data suggest that QoL is related to more severe clinical presentation and improves with evidence-based treatment, but QoL improvements may be inversely related to externalizing symptomology. PMID- 28910140 TI - Impact of Clinical Salmonellosis in Veal Calves on the Recovery of Salmonella in Lymph Nodes at Harvest. AB - The objective of this study was to determine the prevalence, serotypes, antimicrobial resistance phenotypes, and pulsed-field gel electrophoresis (PFGE) patterns of Salmonella recovered in feces and mesenteric and prefemoral lymph nodes (LNs) from cohorts of calves with and without a confirmed outbreak of salmonellosis. In a prospective cohort study, 160 calves from four farms without a reported outbreak (nonoutbreak farms) were sampled at farm and harvest. In addition, harvest samples from 80 calves of two farms with a confirmed outbreak (outbreak farms) were collected. A culture protocol for Salmonella isolation was applied for all samples and recovered isolates were further characterized by serotyping, antimicrobial susceptibility testing, and PFGE. Among nonoutbreak farms, Salmonella was recovered from 0% (0/160) farm fecal samples, 3.7% (6/160) harvest fecal swabs, 21.9% (35/160) mesenteric LNs, and 0.6% (1/160) prefemoral LNs. Serotypes identified in nonoutbreak herds included Salmonella Typhimurium, Cerro, Hartford, and Newport. Most isolates (64.3%, 27/42) exhibited a unique multidrug-resistant (MDR) phenotype, including resistance to extended-spectrum cephalosporins. Salmonella prevalence in harvest fecal samples and prefemoral LNs among calves from outbreak farms was numerically higher, but not significantly different than those without an outbreak. Serotypes recovered from outbreak farms included Salmonella Heidelberg and Typhimurium, and the monophasic Salmonella Typhimurium strains 4,5,12:i:- and 4,12:i:-, which have been also reported as highly pathogenic in humans. All isolates (33/33) exhibited an MDR phenotype. Salmonella strains recovered from ill calves in two outbreaks had indistinguishable PFGE patterns, suggesting between-farm transmission. In addition, the genotype of Salmonella Heidelberg causing an outbreak among calves was recovered from three prefemoral LNs of surviving members of the cohort at harvest. Implementation of preharvest biosecurity measures (limited personnel and visitor traffic, vehicle, footwear, and utensils disinfection) should be highly recommended to decrease the prevalence of Salmonella on farms and safeguard the food safety. PMID- 28910141 TI - Rapid Screening of Natural Plant Extracts with Calcium Diacetate for Differential Effects Against Foodborne Pathogens and a Probiotic Bacterium. AB - This study focused on advancing a rapid turbidimetric bioassay to screen antimicrobials using specific cocktails of targeted foodborne bacterial pathogens. Specifically, to show the relevance of this rapid screening tool, the antimicrobial potential of generally recognized as safe calcium diacetate (DAX) and blends with cranberry (NC) and oregano (OX) natural extracts was evaluated. Furthermore, the same extracts were evaluated against beneficial lactic acid bacteria. The targeted foodborne pathogens evaluated were Escherichia coli O157:H7, Salmonella spp., Listeria monocytogenes, and Staphylococcus aureus using optimized initial cocktails (~108 colony-forming unit/mL) containing strains isolated from human food outbreaks. Of all extracts evaluated, 0.51% (w/v) DAX in ethanol was the most effective against all four pathogens. However, DAX when reduced to 0.26% and with added blends from ethanol extractions consisting of DAX:OX (3:1), slightly outperformed or was equal to same levels of DAX alone. Subculture of wells in which no growth occurred after 1 week indicated that all water and ethanol extracts were bacteriostatic against the pathogens tested. All the targeted antimicrobials had no effect on the probiotic organism Lactobacillus plantarum. The use of such rapid screening methods combined with the use of multistrain cocktails of targeted foodborne pathogens from outbreaks will allow rapid large-scale screening of antimicrobials and enable further detailed studies in targeted model food systems. PMID- 28910142 TI - Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma. AB - RATIONALE: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. METHODS: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2 day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. RESULTS: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. CONCLUSIONS: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma. PMID- 28910143 TI - The Lost City Hydrothermal Field: A Spectroscopic and Astrobiological Analogue for Nili Fossae, Mars. AB - Low-temperature serpentinization is a critical process with respect to Earth's habitability and the Solar System. Exothermic serpentinization reactions commonly produce hydrogen as a direct by-product and typically produce short-chained organic compounds indirectly. Here, we present the spectral and mineralogical variability in rocks from the serpentine-driven Lost City Hydrothermal Field on Earth and the olivine-rich region of Nili Fossae on Mars. Near- and thermal infrared spectral measurements were made from a suite of Lost City rocks at wavelengths similar to those for instruments collecting measurements of the martian surface. Results from Lost City show a spectrally distinguishable suite of Mg-rich serpentine, Ca carbonates, talc, and amphibole minerals. Aggregated detections of low-grade metamorphic minerals in rocks from Nili Fossae were mapped and yielded a previously undetected serpentine exposure in the region. Direct comparison of the two spectral suites indicates similar mineralogy at both Lost City and in the Noachian (4-3.7 Ga) bedrock of Nili Fossae, Mars. Based on mapping of these spectral phases, the implied mineralogical suite appears to be extensive across the region. These results suggest that serpentinization was once an active process, indicating that water and energy sources were available, as well as a means for prebiotic chemistry during a time period when life was first emerging on Earth. Although the mineralogical assemblages identified on Mars are unlikely to be directly analogous to rocks that underlie the Lost City Hydrothermal Field, related geochemical processes (and associated sources of biologically accessible energy) were once present in the subsurface, making Nili Fossae a compelling candidate for a once-habitable environment on Mars. Key Words: Mars-Habitability-Serpentinization-Analogue. Astrobiology 17, 1138-1160. PMID- 28910144 TI - ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension. AB - RATIONALE: Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis. OBJECTIVES: We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling. METHODS: A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models. MEASUREMENTS AND MAIN RESULTS: Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS 444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH. CONCLUSIONS: ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis. PMID- 28910145 TI - The Clinical Pharmacokinetics of Amphetamines Utilized in the Treatment of Attention-Deficit/Hyperactivity Disorder. AB - Amphetamine (AMP), an indirectly acting psychostimulant approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults, is among the most long-standing therapeutic agents in all of clinical psychopharmacology. This review focuses on AMP absorption, metabolism, and elimination brought to bear on comparative pharmacokinetics in its various formulations. A comprehensive search of the published literature was conducted using MEDLINE (PubMed) and Google Scholar databases through April 2017 to retrieve all pertinent in vitro and human studies for review and synthesis. Additionally, Food and Drug Administration (FDA) databases were accessed for otherwise unavailable data when possible. Initially available as racemic (dl) AMP, this drug was later supplanted by enantiopure (d)-AMPH or enantioenriched (75:25 dl)-AMP formulations; although racemic AMP returned as an approved drug to treat ADHD in 2014. Presently, there are several immediate-release (IR) formulations available, including d-AMP, dl-AMP, and mixed amphetamine salts, which are neither racemic nor the pure d-enantiomer (i.e., a 3:1 mixture of d-AMP and l-AMP). Furthermore, new modified-release AMP formulations, including an oral suspension and an orally disintegrating tablet, are now available. A lysine bonded prodrug form of d-AMP also serves as a treatment option. Oral AMP is rapidly absorbed, with high absolute bioavailability, followed by extensive metabolism involving multiple enzymes. Some metabolic pathways exhibit stereoselective biotransformations favoring the l-isomer substrate. Drug exposure exhibits dose-proportional pharmacokinetics. Body weight is a fundamental determinant of differences in observed AMP plasma concentrations. IR formulations typically provide a Tmax from 2 to 3 hours. In replicated studies, children exhibit a shorter plasma T1/2 (~7 hours) relative to adults (~10 to 12 hours). There are few documented pharmacokinetic drug interactions of clinical significance beyond influences of drug-induced alteration of urinary pH. The array of AMP formulations addressed in this review offer flexibility in dosing, drug onset, and offset to assist in individualized pharmacotherapy of ADHD. PMID- 28910146 TI - Management of Acute Respiratory Distress Syndrome and Refractory Hypoxemia. A Multicenter Observational Study. AB - RATIONALE: Clinicians' current practice patterns in the management of acute respiratory distress syndrome (ARDS) and refractory hypoxemia are not well described. OBJECTIVES: To describe mechanical ventilation strategies and treatment adjuncts for adults with ARDS, including refractory hypoxemia. METHODS: This was a prospective cohort study (March 2014-February 2015) of mechanically ventilated adults with moderate-to-severe ARDS requiring an FiO2 of 0.50 or greater in 24 intensive care units. RESULTS: We enrolled 664 patients: 222 (33%) with moderate and 442 (67%) with severe ARDS. On Study Day 1, mean Vt was 7.5 (SD = 2.1) ml/kg predicted body weight (n = 625); 80% (n = 501) received Vt greater than 6 ml/kg. Mean positive end-expiratory pressure (PEEP) was 10.5 (3.7) cm H2O (n = 653); 568 patients (87%) received PEEP less than 15 cm H2O. Treatment adjuncts were common (n = 440, 66%): neuromuscular blockers (n = 276, 42%), pulmonary vasodilators (n = 118, 18%), prone positioning (n = 67, 10%), extracorporeal life support (n = 29, 4%), and high-frequency oscillatory ventilation (n = 29, 4%). Refractory hypoxemia, defined as PaO2 less than 60 mm Hg on FiO2 of 1.0, occurred in 138 (21%) patients. At onset of refractory hypoxemia, mean Vt was 7.1 (SD = 2.0) ml/kg (n = 124); 95 patients (77%) received Vt greater than 6 ml/kg. Mean PEEP was 12.1 (SD = 4.4) cm H2O (n = 133); 99 patients (74%) received PEEP less than 15 cm H2O. Among patients with refractory hypoxemia, 91% received treatment adjuncts (126/138), with increased use of neuromuscular blockers (n = 87, 63%), pulmonary vasodilators (n = 57, 41%), and prone positioning (n = 32, 23%). CONCLUSIONS: Patients with moderate-to-severe ARDS receive treatment adjuncts frequently, especially with refractory hypoxemia. Paradoxically, therapies with less evidence supporting their use (e.g., pulmonary vasodilators) were over-used, whereas those with more evidence (e.g., prone positioning, neuromuscular blockade) were under-used. Patients received higher Vts and lower PEEP than would be suggested by the evidence. PMID- 28910147 TI - Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization. PMID- 28910148 TI - Bulk Scale Formulation of Therapeutic Doses of Clinical Grade Ready-to-Use 177Lu DOTA-TATE: The Intricate Radiochemistry Aspects. AB - INTRODUCTION: 177Lu-DOTA-TATE is a clinically useful and promising therapeutic radiopharmaceutical for peptide receptor radionuclide therapy of neuroendocrine tumors (NETs) overexpressing somatostatin receptors. Currently, the radiopharmaceutical is prepared in-house at nuclear medicine centers, thereby restricting its use to limited centers only. In this article, the authors describe systematic studies toward bulk scale formulation of "ready-to-use" 177Lu DOTA-TATE using medium specific activity 177Lu (740-1110 GBq/mg) at a centralized radiopharmacy facility. METHODS: In an optimized protocol, 177Lu-DOTA-TATE synthesis was carried out by direct heating of 177LuCl3 (Sp. act. 740-1110 GBq/mg) with DOTA-TATE peptide (1.5-3.0 equivalents) in ammonium acetate buffer (0.2 M) containing 2,5-dihydroxy benzoic acid (gentisic acid). Thereafter, the crude labeled product was purified using a Sep-Pak(r) C18 column and diluted with acetate buffer-gentisic acid (1.5% w/v) solution to final radioactive concentration of 740 MBq/mL. This was further sterilized and dispensed as 7.4 GBq patient dose/vial with 2 days postformulation calibration. RESULTS: A peptide/metal ratio of 1.5-3.0 is essential for complexation wherein radiolabeling yields >90% are obtained minimizing free 177Lu waste. For formulation of 7.4 GBq patient dose (2 days postproduction), even specific activity of about 555 GBq/mg was found to be adequate for the radiometal. The ready-to-use 740 MBq/mL 177Lu-DOTA-TATE formulation with gentisic acid (1.5% w/v) is observed to be safe for human use for more than 1 week (radiochemical purity >98%) from the day of production when stored at -70 degrees C. However, the target specificity may get affected beyond 2 days as the total peptide content for 7.4 GBq dose may exceed the critical peptide limit of 300 MUg. Patient treatment carried with several batches of present formulation in diseased NET patients exhibited desired distribution at the tumor and its metastatic site. CONCLUSIONS: A ready-to-use formulation of 177Lu-DOTA-TATE was successfully prepared and optimized for regular bulk scale production and supply to distant nuclear medicine centers. PMID- 28910149 TI - Dual Targeting of Epidermal Growth Factor Receptor and HER3 by MEHD7945A as Monotherapy or in Combination with Cisplatin Partially Overcomes Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cell Lines. AB - Aberrant signaling of the epidermal growth factor receptor (EGFR) plays a crucial role in the tumorigenesis of many cancer types, including head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. After initial promising results of EGFR-targeted therapies such as cetuximab, the problem of therapeutic resistance is emerging and new treatment options are necessary. In contrast to first-generation EGFR inhibitors, MEHD7945A (duligotuzumab) is a monoclonal antibody with dual EGFR/HER3 specificity. Consequently, treatment with MEHD7945A may result in a more pronounced therapeutic benefit. In this study, sensitivity to MEHD7945A as a single agent and in combination with cisplatin was investigated in cetuximab-sensitive and -resistant HNSCC cell lines under normal and reduced oxygen conditions. The results demonstrated that sensitivity to MEHD7945A was cell line dependent and influenced by oxygen concentration. An additive, but not synergistic, interaction between MEHD7945A and cisplatin was observed. In conclusion, MEHD7945A has the potential to partially overcome cetuximab resistance. Nevertheless, further research is warranted to determine additional resistance mechanisms to cetuximab treatment besides HER3 signaling. Unraveling these mechanisms will ultimately lead to the development of new therapeutic strategies to improve the response to EGFR blockage. PMID- 28910152 TI - Why Should We Care About Health Equity? PMID- 28910150 TI - Phase I/II Trial of Anticarcinoembryonic Antigen Radioimmunotherapy, Gemcitabine, and Hepatic Arterial Infusion of Fluorodeoxyuridine Postresection of Liver Metastasis for Colorectal Carcinoma. AB - OBJECTIVES: Report the feasibility, toxicities, and long-term results of a Phase I/II trial of 90Y-labeled anticarcinoembryonic antigen (anti-CEA) (cT84.66) radioimmunotherapy (RIT), gemcitabine, and hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUdR) after maximal hepatic resection of metastatic colorectal cancer to the liver. METHODS: Patients with metastatic colorectal cancer to the liver postresection or ablation to minimum disease were eligible. Each cohort received HAI of FUdR for 14 days on a dose escalation schedule. The maximum HAI FUdR dose level planned was 0.2 mg/kg/day, which is the standard dose for HAI FUdR alone. On day 9, 90Y-cT84.66 anti-CEA at 16.6 mCi/m2 as an i.v. bolus infusion and on days 9-11 i.v. gemcitabine at 105 mg/m2 were given. Patients could receive up to three cycles every 6 weeks of protocol therapy. Four additional cycles of HAI FUdR were allowed after RIT. RESULTS: Sixteen patients were treated on this study. A maximum tolerated dose of 0.20 mg/kg/day of HAI FUdR combined with RIT at 16.6 mCi/m2 and gemcitabine at 105 mg/m2 was achieved with only 1 patient experiencing grade 3 reversible toxicity (mucositis). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. With a median follow-up of 41.8 months (18.7-114.6), median progression free survival was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months. CONCLUSION: This study demonstrates the safety, feasibility, and potential utility of HAI FUdR, RIT, and systemic gemcitabine. The trimodality approach does not have higher hematologic toxicities than seen in prior RIT-alone studies. Future efforts evaluating RIT in colorectal cancer should integrate RIT with systemic and regional therapies in the minimal tumor burden setting. PMID- 28910151 TI - Synthesis, Positron Emission Tomography Imaging, and Therapy of Diabody Targeted Drug Lipid Nanoparticles in a Prostate Cancer Murine Model. AB - The blood clearance of chemotherapeutic drugs such as doxorubicin (Dox) can be extended by incorporation into lipid nanoparticles (LNPs) and further improved by tumor targeting with antibody fragments. We used positron emission tomography (PET) imaging in a murine prostate cancer model to evaluate tumor targeting of LNPs incorporating Dox and antiprostate-specific membrane antigen (PSMA) diabodies. Dox-LNPs were generated by mixing or covalent attachment to water soluble distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG)2000. Cu-64 PET imaging was performed with DOTA-conjugated Dox, PEG-LNP, or an anti PSMA site-specific cysteine-diabody. Since the mixture Dox+PEG-LNP was unstable in serum, further studies utilized Dox covalently bound to LNP +/- covalently bound DOTA-cys-diabody (cys-DB)-LNP. Blood clearance of covalent Dox-PEG-LNP was slower than Dox alone or Dox+PEG-LNP. PET imaging of 64Cu-DOTA-Dox-PEG-LNP reached a maximum of 10% ID/g in tumors compared with 3% ID/g of 64Cu-DOTA-Dox, due to the prolonged blood clearance. Mixing 64Cu-DOTA-cys-DB-PEG-LNP with covalent Dox-PEG-LNP gave LNPs containing both drug and tumor targeting cys-DB. The mixed LNPs exhibited increased tumor uptake (15% ID/g) versus untargeted 64Cu DOTA-Dox-PEG-LNPs (10% ID/g) demonstrating feasibility of the approach. Based on these results, a therapy study with mixed LNPs containing cys-DB-LNP and either Dox-LNP or the antitubulin drug auristatin-LNP showed significant reduction of tumor growth with the auristatin-diabody-LNP mixture, but not the Dox-diabody-LNP mixture. PMID- 28910153 TI - The longitudinal effects of grandchild care on depressive symptoms and physical health of grandmothers in South Korea: a latent growth approach. AB - OBJECTIVES: This study examined longitudinal effects of grandmothers' patterns in caring for their grandchildren, and observed the influence of these patterns on grandmothers' depressive symptoms and self-rated health status, using latent growth curve models. METHOD: Four waves of the large-scale Korean Longitudinal Study of Aging data were used for this study. The total sample consisted of 1,948 female participants, who have at least one grandchild, and who were age 50-74 in 2006. The study employed the multiple-group latent growth curve using Mplus to analyze if patterns of grandchild care predicted developmental trajectories of depressive symptoms and self-rated health over time. RESULTS: Grandmothers who stopped raising grandchildren reported more depressive symptoms over time than did grandmothers who never raised grandchildren. However, this pattern was not found in the group with income more than 60 percent of the median income in Korea, but this pattern was found in the group with income below 60 percent of the median. CONCLUSION: Findings from the latent growth curve modeling indicate how caring for grandchildren affected grandmothers' depressive symptoms and self rated health status from a longitudinal perspective. Implications for future research and policies on grandchild care are discussed. PMID- 28910154 TI - Activation of Veratridine Sensitive Sodium Channels, But not Electrical Field Stimulation, Dilates Porcine Retinal Arterioles with Preserved Perivascular Tissue. AB - PURPOSE: Disturbances in retinal blood flow are a prominent feature of vision threatening retinal diseases. The regulation of tone in retinal resistance vessels involves the perivascular retinal tissue, but it is unknown to what extent neurons or glial cells contribute to the effect. Therefore, the purpose of the present study was to study the contribution of neurons in the perivascular retina to vascular tone during activation of voltage-gated sodium channels with veratridine and electrical field stimulation (EFS). METHODS: Porcine retinal arterioles with and without perivascular tissue were mounted in an isometric myograph system for studying the effects of the voltage-gated sodium channel opener veratridine and EFS on retinal vascular tone. RESULTS: Veratridine induced concentration-dependent relaxation of retinal arterioles which was more pronounced in arterioles with preserved perivascular retinal tissue than in isolated vessels. In the presence of this tissue, veratridine-induced relaxation was inhibited by the voltage-gated sodium channel blocker tetrodotoxin and the nitric oxide synthase inhibitor, Nomega-Nitro-L-arginine methyl ester (L-NAME), but was unaffected by the inhibition of the cyclo-oxygenase inbitior ibuprofen and by blocking of adenosine receptors with 8-(p-Sulfophenyl)theophylline hydrate (8-PSPT). Electrical field stimulation induced no changes in retinal vascular tone. CONCLUSIONS: Sodium channels of neuronal origin are likely to be involved in the regulation of retinal vascular tone. The lack of effect of EFS on retinal vascular tone may be due to the lack of autonomic nerves in the retina. PMID- 28910155 TI - Identification of the Molecular Mechanism of Trimethoprim Resistance in Listeria monocytogenes. AB - Trimethoprim with sulfamethoxazole is a therapeutic agent combination used to treat infections caused by the facultative intracellular foodborne pathogen Listeria monocytogenes. The aim of this study was to assess the frequency of resistance of L. monocytogenes arising due to exposure to trimethoprim and subsequently investigate the molecular mechanisms of resistance. After exposure of a culture of L. monocytogenes ATCC 13932 to trimethoprim at 10-fold the minimal inhibitory concentration spontaneous resistant mutants were recovered, giving a frequency of resistance development of 6.85 +/- 0.92 * 10-8. The isolates exhibited a 32-64-fold decrease in susceptibility compared with the parental strain. These results indicate the capacity of L. monocytogenes to develop low-level resistance toward trimethoprim after exposure to the drug. The trimethoprim resistance genes (dhfr) and their promoter regions from all trimethoprim-resistant isolates were amplified and sequenced, leading to the identification of four single amino acid substitutions (Met20-Val, Pro21-Leu, Thr46-Asn, Val95-Leu) and two double substitutions (Met20-Ile+Thr46-Asn and Thr46 Asn+Leu85-Phe) in DHFR. Of the identified mutations, the Thr46-Asn substitution has not been previously reported as the mechanism of resistance to trimethoprim in other bacteria; thus this substitution seems to be unique to L. monocytogenes. The expression of the mutated L. monocytogenes dhfr genes in Escherichia coli led to decreased susceptibility of the heterological host, therefore proving that the identified point mutations in dhfr serve as the molecular mechanism of acquired resistance of L. monocytogenes to trimethoprim. PMID- 28910156 TI - Antiproliferative Effects of Bacillus coagulans Unique IS2 in Colon Cancer Cells. AB - In the present study, the in vitro anticancer (antiproliferative) effects of Bacillus coagulans Unique IS2 were evaluated on human colon cancer (COLO 205), cervical cancer (HeLa), and chronic myeloid leukemia (K562) cell lines with a human embryonic kidney cell line (HEK 293T) as noncancerous control cells. The Cytotoxicity assay (MTT) clearly demonstrated a 22%, 31.7%, and 19.5% decrease in cell proliferation of COLO 205, HeLa, and K562 cells, respectively, when compared to the noncancerous HEK 293T cells. Normal phase-contrast microscopic images clearly suggested that the mechanism of cell death is by apoptosis. To further confirm the induction of apoptosis by Unique IS2, the sub-G0-G1 peak of the cell cycle was quantified using a flow cytometer and the data indicated 40% of the apoptotic cells in Unique IS2-treated COLO cells when compared with their untreated control cells. The Western blot analysis showed an increase in pro apoptotic protein BAX, decrease in antiapoptotic protein, Bcl2, decrease in mitochondrial membrane potential, increase in cytochrome c release, increase in Caspase 3 activity, and cleavage of poly(ADP-ribose) polymerase. The present study suggests that the heat-killed culture supernatant of B. coagulans can be more effective in inducing apoptosis of colon cancer cells and that can be considered for adjuvant therapy in the treatment of colon carcinoma. PMID- 28910157 TI - Photochemical Cross-Linking for Penetrating Corneal Wound Closure in Enucleated Porcine Eyes. AB - PURPOSE: To compare the efficacy of photochemical-induced tissue cross-linking (PCL), utilizing Rose Bengal (RB) and 532 nm green light irradiation (RB-PCL), with standard sutures for closure of penetrating corneal incision in porcine cadaver eyes. METHODS: A full-thickness penetrating incision, 3 mm in length parallel to the limbus and perpendicular to the corneal surface, was made in the enucleated porcine cornea. Photochemical cross-linking was performed with tropical RB application and irradiation of 532 nm green light (0.6 W/cm2) for 200, 250, and 300 seconds at laser fluences of 120, 150, and 180 J/cm2, respectively, which was compared with the standard 10-0 nylon suture group. Following treatment, intraocular pressure to the point where wound leakage occurred (IOPL) was measured. Corneal central thickness and surface temperature before and after PCL treatment were recorded. Optical coherence tomography (OCT) and scanning electron microscopy (SEM) were utilized to evaluate wound closure. RESULTS: The mean corneal central thickness was increased from 812.0 +/- 47.0 to 838.0 +/- 45.6 um after the incision as a result of cornea aqueous humor infiltration. RB penetrated approximately 140 MUm into the porcine corneal stroma. The mean IOPL for untreated blank group after incision was 4.27 +/- 0.36 mmHg. Increased laser fluences produced increased IOPL of 27.02 +/- 3.01 (PCL120), 31.60 +/- 3.67 (PCL150) and 36.73 +/- 3.25 mmHg (PCL180), which were statistically different from the control intact group. The mean IOPL in the sutured cornea was 57.30 +/- 4.59 mmHg. The average surface temperature difference before and after PCL treatment was 2.03 +/- 0.45-2.47 +/- 0.79 degrees C. OCT demonstrated not only complete but also improved closure in comparison with disorganized collagen fibers after conventional suturing, which is further confirmed by SEM. CONCLUSIONS: Complete and clinically relevant seal of full thickness porcine corneal incision was achieved using PCL method ex vivo, which provides potential application of this technique in ocular wound closure. PMID- 28910158 TI - Interaction Between Rare Variants in NOTCH1 and Betel Quid Chewing in Oral Squamous Cell Carcinoma. AB - BACKGROUND: In this study, we investigated rare variants of the NOTCH1 gene located near somatic mutations as surrogate markers, as well as the relationship of these rare variants with betel quid (BQ) chewing and the occurrence of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: A total of 410 patients diagnosed with OSCC and 282 unrelated, healthy subjects without cancer were recruited from two medical centers in Taiwan. Odds ratios (OR) and 95% confidence intervals (CI) were assessed by logistic regression. The Cox proportional hazard model was used to assess the interaction between rare NOTCH1 variants and BQ chewing in OSCC. RESULTS: The genetic variant rs139994842 in exon15 of NOTCH1 was significantly associated with an increased risk of OSCC (OR = 2.88 95% CI: 1.07 7.79), and the association between rs202133782 in exon13 of NOTCH1 with OSCC was borderline significant (p = 0.0627). Moreover, a combination of four rare variants was significantly associated with OSCC (p = 0.012). Patients who carried these NOTCH1 variants were at a higher risk of recurrence (OR = 18.95; 95% CI, 1.01-326.74; p = 0.0428). Furthermore, of the mean 24-year BQ exposure period, the OSCC incidence rate was significantly higher in OSCC patients who chewed BQ and had a NOTCH1 variant (p < 0.0001). CONCLUSION: This information is applicable to prevention; the surveillance of patients at risk; and for early detection to reduce morbidity and mortality from OSCC. PMID- 28910159 TI - Glaucoma Diagnostic Ability of the Optical Coherence Tomography Angiography Vessel Density Parameters. AB - PURPOSE: To investigate the glaucoma diagnostic abilities of vessel density parameters as determined by optical coherence tomography (OCT) angiography in different stages of glaucoma. MATERIALS AND METHODS: A total of 113 healthy eyes and 140 glaucomatous eyes were enrolled. Diagnostic abilities of the OCT vessel density parameters in the optic nerve head (ONH), peripapillary, and macular regions were evaluated by calculating the area under the receiver operation characteristic curves (AUCs). AUCs of the peripapillary vessel density parameters and circumpapillary retinal nerve fiber layer (RNFL) thickness were compared. RESULTS: OCT angiography vessel densities in the ONH, peripapillary, and macular regions in the glaucomatous eyes were significantly lower than those in the healthy eyes (P < 0.05). Among the vessel density parameters, the average peripapillary vessel density showed higher AUC than the ONH and macular region (AUCs: 0.807, 0.566, and 0.651, respectively) for glaucoma detection. The peripapillary vessel density parameters showed similar AUCs with the corresponding sectoral RNFL thickness (P > 0.05). However, in the early stage of glaucoma, the AUCs of the inferotemporal and temporal peripapillary vessel densities were significantly lower than that of the RNFL thickness (P < 0.05). CONCLUSIONS: The glaucomatous eyes showed decreased vessel density as determined by OCT angiography. Although the peripapillary vessel density parameters showed similar glaucoma diagnostic ability with circumpapillary RNFL thickness, in the early stage, the vessel density parameters showed limited clinical value. PMID- 28910160 TI - A Novel Approach to the Differentiation of Intrabulbar Tumors in Color Doppler Imaging. AB - AIM OF THE STUDY: The similarity of many benign intrabulbar lesions to a malignant tumor requires detailed differential diagnostics. However, none of the known methods can be used as the only one to determine the type of lesions. The aim of this study was to determine color Doppler imaging (CDI) markers characteristic of choroidal melanoma and metastatic intrabulbar tumors, increasing the diagnostic value and giving a new insight into the use of this method. MATERIALS AND METHODS: CDI was performed in 44 patients with malignant tumors and in 49 patients with benign tumors. Patients with malignant tumors were divided into melanomas (n = 28) and metastatic tumors (n = 16). Univariate analysis with the logistic regression method and multivariate stepwise logistic regression analysis to create models testing tumor malignancy and differentiating melanoma from metastatic lesions were used. Model sensitivity and specificity were evaluated by the receiver-operating characteristic curve. A K-fold validation was performed. RESULTS: Arterial blood flow, regular tumor surface, and tumor location in peripheral choroid were found significant for tumor malignancy. Mixed blood flow increased the accuracy of the test (p > 0.05). Model sensitivity and specificity were 83.7% and 75.7%. A regular tumor surface and hypoechoic or isoechoic tumor mass differentiated melanoma and metastatic masses in the regression model, with a sensitivity of 85.2% and a specificity of 75.0%. The area under curve (AUC) for both the models was 0.851 SE (standard error) 0.041 and 0.853 SE 0.063, respectively. AUC in five-fold cross-validation was 0.80 SE 0.0477 and 0.743 SE 0.094, respectively. CONCLUSIONS: Arterial or mixed blood flow, regular tumor surface, and tumor location in peripheral choroid may be characteristic of malignant tumors. Regular tumor surface and echogenicity of tumor mass could differentiate melanoma from metastatic tumor. PMID- 28910161 TI - Long-Term Surgical Outcomes of Early Surgery for Intermittent Exotropia in Children Less than 4 Years of Age. AB - PURPOSE: To investigate the long-term outcomes of intermittent exotropia surgery for children less than 4 years of age. MATERIALS AND METHODS: Consecutive patients who underwent surgery for intermittent exotropia and had follow-up durations longer than 2 years were recruited. The patients were classified according to age at surgery-the patients of group 1 had undergone surgery before 4 years of age and those of group 2 at or after 4 years of age. Motor success was defined by exodeviation < 10 prism diopters (PD) and esodeviation < 5 PD at distance at 2 years postoperatively. Stereoacuity was considered as success at a value <= 60 arc seconds. The motor and sensory success rates as well as the surgical complications were compared. RESULTS: Of the 73 patients, 36 were allocated to group 1 and 37 to group 2. At 2 years after surgery, 13 of the 36 (36.1%) patients in group 1 and 12 of the 37 (32.4%) in group 2 had achieved successful alignment; 32 (88.9%) patients in group 1 and 35 (94.6%) in group 2 achieved normal stereoacuity. No significant differences in the motor or sensory success rates were observed between the two groups (p = 0.46 and 0.32, respectively). CONCLUSIONS: The surgical success rates for intermittent exotropia were comparable between the patients operated upon before 4 years of age and those operated upon after 4 years of age. The incidence of postsurgical complications was low and not significantly different between the two study groups. PMID- 28910163 TI - Anterior Lens Capsule and Iris Thicknesses in Pseudoexfoliation Syndrome. AB - PURPOSE: The aim of this study was to evaluate anatomic properties of the lens capsule and iris by anterior segment optical coherence tomography (AS-OCT) in patients with pseudoexfoliation (PEX). METHODS: This prospective study included 62 eyes of 62 patients with PEX syndrome and 43 eyes of 43 age- and gender matched controls. All subjects underwent full ophthalmologic examinations including AS-OCT. Pupillary diameter, midperipheral stromal iris thickness, central and temporal lens capsule thicknesses, and peripheral pseudoexfoliation material thickness on the anterior lens capsule surface were measured and recorded. RESULTS: Mean age was 66.8 +/- 9.3 years in the PEX group and 65.5 +/- 8.9 years in the control group (p = 0.44). The PEX group consisted of 62 patients: 38 men (61.3%) and 24 women (38.7%); the control group included 43 subjects: 25 men (58.1%) and 18 women (41.9%). Pupillary diameter after pharmacologic mydriasis was 21% smaller in the PEX group than controls. Mean midperipheral iris thickness was 36 +/- 7.2 MUm (7.8%) thinner in the PEX group than that of control group (p = 0.047). The central anterior capsule was a mean of 3.40 +/- 0.51 MUm (18%) thicker in the PEX group compared to the control group (p = 0.0001). The temporal anterior lens capsule was a mean of 0.17 +/- 0.15 MUm thicker in the PEX group compared to the control group (p = 0.81). CONCLUSIONS: With high-resolution OCT imaging, it has become possible to evaluate the anterior lens capsule without histologic examination and demonstrate that it is thicker than normal in PEX patients. PMID- 28910162 TI - Patient Engagement Is Related to Impairment Reduction During Digital Game-Based Therapy in Stroke. AB - OBJECTIVE: Upper limb impairment in the chronic phase of stroke recovery is persistent, disabling, and difficult to treat. The objectives of this study were to determine whether therapeutic enjoyment is related to clinical improvement after upper limb rehabilitation and to assess the feasibility of a therapy gaming system. MATERIALS AND METHODS: Ten chronic stroke survivors with persistent upper limb impairment were enrolled in the study. Upper limb impairment was evaluated by using the Fugl-Meyer Assessment of Upper Extremity Function (FMA-UE). The Physical Activity Enjoyment Scale (PACES) assessed the level of therapy enjoyment, and the System Usability Scale (SUS) measured the ease of operation of the game. Upper limb therapy involved 30 minutes of novel digital gaming therapy, three times per week, for 6 weeks. RESULTS: The average improvement in the FMA-UE after the digital gaming therapy was 2.8 (+/-2.1) points. Participants scored the digital gaming system as having good usability (SUS: 72 +/- 7.9), and the physical activity as enjoyable (PACES: 65.8 +/- 10.6). There was a strong positive correlation between improvement in the FMA-UE score and the PACES (Spearman's Rho = 0.84; P < 0.002). CONCLUSION: This pilot study demonstrates the feasibility and potential for improvements in upper limb motor function by using digital gaming in the chronic stroke patient population. The positive correlation found between therapy enjoyment and clinical gains highlights the importance of engagement in therapy to optimize outcomes in chronic stroke survivors. PMID- 28910164 TI - Botryoid odontogenic cyst. Exploration of proliferative activity, apoptosis and expression of TP53 and BCL2 compared to the histologically identical lateral periodontal and gingival cysts. AB - The botryoid odontogenic cyst (BOC) is a rare, locally more aggressive variant of the usually indolent lateral periodontal cyst (LPC) and gingival cyst (GC). A recent case of BOC provided an opportunity for an exploratory study on the causes of its more aggressive behavior. The limited objective was to see if the BOC was sufficiently different from the other cysts to warrant an investment in a large study. Sections of neutral buffered formalin fixed, paraffin-embedded tissues from the BOC and archival specimens of four GCs, four LPCs and three odontogenic keratocysts (OKCs) were stained using immunohistochemistry for Ki-67, a marker of proliferating cells, caspase-3, a marker of cells undergoing apoptosis, tumor suppressor p53, and the apoptosis inhibitor BCL2. The mean labeling index (LI) of immunoreactive cyst epithelial cells was computed for each antibody and type of cyst. Compared to the LPCs and GCs, the BOC exhibited a moderately larger Ki 67/caspase-3 LI difference, which indicates that the BOC had a net higher rate of growth. We found a much higher level of LI, therefore likely dysregulation of p53. We also found a much higher LI of BCL2. The LIs of p53 and BCL2 in the BOC were similar to and more than twice that of the OKCs, respectively. Although meaningful statistical analysis was precluded by our use of only one case of BOC and a small number of the other cysts, the high p53 and very high BCL2 labeling indices of the BOC offer a potential explanation for its reportedly more aggressive behavior that clearly is worthy of further investigation. PMID- 28910165 TI - Peripapillary Choroidal Thickness and Retinal Nerve Fiber Layer in Untreated Patients with Obstructive Sleep Apnea-Hypopnea Syndrome: A Case-Control Study. AB - PURPOSE: To evaluate peripapillary choroidal thickness (PPCT), central macular choroidal thickness (CMCT), and retinal nerve fiber layer (RNFL) thickness in untreated patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: This prospective, randomized, and comparative study was conducted in a university ophthalmology clinic. 106 eyes of 106 patients with OSAHS and 44 eyes of 44 healthy individuals were evaluated in this study. Only right eyes were evaluated. The patients with OSAHS were divided into three groups as mild (group 1), moderate (group 2), and severe (group 3) according to apnea-hypopnea index. The PPCT, CMCT, and RNFL measurements were performed by using spectral domain optical coherence tomography with enhanced depth imaging technique. The main parameters assessed were PPCT-Temporal, PPCT-Superior, PPCT-Nasal, PPCT-Inferior quadrants, CMCT, and RNFL thicknesses. RESULTS: The PPCT of all quadrants was significantly thicker in the control group compared with the moderate and severe subgroups of OSAHS (p < 0.05). The PPCT-Superior and PPCT-Temporal were significantly thinner in the mild subgroup compared with the control group (p = 0.003 and p = 0.028, respectively). There was no difference between the control and mild groups regarding the RNFL thicknesses except nasal RNFL and inferotemporal RNFL which are thinner in the mild group. The RNFL thicknesses of all quadrants were significantly thicker in the control group compared with moderate and severe subgroups (p < 0.05). The CMCT was significantly thicker in the control group compared with all subgroups of OSAHS (p < 0.05). CONCLUSIONS: In OSAHS patients, PPCT, CMCT, and RNFL were significantly thinner compared with the control group. These results may explain why OSAHS patients are prone to normotensive glaucoma. PMID- 28910166 TI - Prevalence, Antimicrobial Resistance, and Relatedness of Salmonella Isolated from Chickens and Pigs on Farms, Abattoirs, and Markets in Sichuan Province, China. AB - This study aims at investigating the distribution, antimicrobial resistance, and genetic relationship of Salmonella isolated from 18 farms, their downstream abattoirs, and markets of chickens and pigs in Sichuan province, China. A total of 193 Salmonella isolates were identified from 693 samples with an isolation rate of 26.27% (88/335) in chickens and 29.33% (105/358) in pigs. Salmonella was isolated more frequently in abattoirs and markets than from farms. Serotypes were determined according to the White-Kauffmann-Le Minor scheme and 16 different serotypes were identified, with Derby being the most common, followed by Typhimurium and Meleagridis. Antimicrobial resistance phenotypes and genotypes were studied by using the disk diffusion method and polymerase chain reaction (PCR) amplification, respectively. Overall, 44.04% (n = 85) of all isolates were multidrug resistant (MDR) and resistance to nalidixic acid (51.30%) was the most frequently observed. blaCTX-M-55 was the most prevalent extended-spectrum beta lactamases gene, and polymyxin resistance gene mcr-1 was present in strains with various serotypes. Multilocus sequence typing indicated that sequence type (ST) had a close relationship with serotype, and 34.20% of all strains were ST40, which was the most prevalent. The unweighted pair group method with arithmetic means (UPGMA) dendrogram of pulsed-field gel electrophoresis showed that Salmonella isolates belonging to the same serovar from different parts of the production chain were highly genetic related, indicating that Salmonella as well as resistance genes could potentially be transmitted from farms to markets. Our study highlights the fact that Salmonella isolates from chicken and pig production chain were frequently exhibiting MDR profiles, and the dissemination of MDR Salmonella from farm to market could pose significant threats to food safety and public health. PMID- 28910167 TI - Expression of Antimicrobial Peptides by Uveal and Cutaneous Melanoma Cells and Investigation of Their Role in Tumor Cell Migration and Vasculogenic Mimicry. AB - AIMS: Antimicrobial peptides (AMPs) have been implicated in the pathogenesis of several cancers, although there is also evidence suggesting potential for novel, AMP-based antitumor therapies. Discerning potential roles of AMPs in tumor pathogenesis may provide valuable insight into the mechanisms of novel AMP-based antitumor therapy. METHODS: mRNA expression of the AMPs alpha defensin (HNP-1); cathelicidin (LL-37); and beta defensins (hBD-1, hBD-2, hBD-3, hBD-4) in human uveal and cutaneous melanoma cell lines, primary human uveal melanocytes, and primary human uveal melanoma cells was determined by reverse transcriptase polymerase chain reaction. An in vitro scratch assay and custom Matlab analysis were used to determine the AMP effects on melanoma cell migration. Last, the effect of specific AMPs on vasculogenic mimicry was determined by three dimensional (3D) culture and light and fluorescence microscopy. RESULTS: Low-to moderate AMP transcript levels were detected, and these varied across the cells tested. Overall, LL-37 expression was increased while hBD-4 was decreased in most melanoma cell lines, compared to primary cultured uveal melanocytes. There was no observable influence of HNP-1 and LL-37 on tumor cell migration. Additionally, aggressive cutaneous melanoma cells grown in 3D cultures exhibited vasculogenic mimicry, although AMP exposure did not alter this process. CONCLUSIONS: Collectively, our data show that although AMP mRNA expression is variable between uveal and cutaneous melanoma cells, these peptides have little influence on major characteristics that contribute to tumor aggressiveness and progression. PMID- 28910168 TI - Reduced Central Retinal Artery Blood Flow Is Related to Impaired Central Visual Function in Retinitis Pigmentosa Patients. AB - PURPOSE: We evaluated the test-retest repeatability of blood flow velocities in the retrobulbar central retinal artery (CRA) and explored whether reduced blood flow is related to the degree of visual function loss in retinitis pigmentosa (RP) patients with wide range of disease severity. MATERIALS AND METHODS: We measured CRA peak systolic velocity (PSV) and end diastolic velocity (EDV) to calculate mean flow velocity (MFV) in 18 RP patients using color Doppler imaging with spectral flow Doppler (GE Logiq7 ultrasound) twice in each eye at each of two visits within a month. At each of these two visits, we measured ETDRS visual acuity (VA), quick Contrast Sensitivity Function (qCSF), Goldmann visual fields (GVF), 10-2 Humphrey visual fields (HVF), and dark-adaptation at 5 degrees from fixation with the AdaptDx; multifocal electroretinography (mfERG) was obtained at a single visit. RESULTS: Mean coefficients of variation for PSV, EDV and MFV were 16.1-19.2% for within-visit measurements and 20.1-22.4% for between-visit measures. Across patients, greater visual function loss assessed with VA (p = 0.04), extinguished versus measurable amplitude in ring 1 for mfERG (p = 0.001), and cone-only versus rod function with the AdaptDx (p = 0.002) were statistically significantly correlated with reduced MFV in the CRA when included a multilevel multivariate regression model along with the qCSF and HVF results, which all together accounted for 47% of the total variance in MFV. GVF log retinal areas (V4e and III4e; p = 0.30 and p = 0.95, respectively) and measurable far peripheral vision during GVF testing (p = 0.66) were not significantly related to MFV. CONCLUSIONS: MFV in the CRA decreased with impaired central vision due to loss of both rod and cone function, had good test-retest repeatability, and may serve as a biomarker outcome to determine the potential physiological basis for improvements in RP clinical trials of therapies with indirect effects on blood flow to the retina. PMID- 28910170 TI - The protective effect of vitamin D against carbon tetrachloride damage to the rat liver. AB - We investigated the protective effect of vitamin D against liver damage caused by carbon tetrachloride (CCl4). Twenty-four male rats were divided into four equal groups: G1, untreated controls; G2, administered CCl4; G3, administered both CCl4 and vitamin D for 10 weeks; G4, administered CCl4 for 10 weeks and vitamin D for 12 weeks. At the end of experiment, intracardiac blood samples were taken and liver samples were removed. Hepatic damage due to CCl4 was assessed using biochemistry and histopathology. Glutathione (GSH) levels decreased, while malondialdehyde (MDA) levels increased in liver tissues of G2. Alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl-transaminase (GGT) levels increased, while albumin (ALB) levels decreased. Hepatocyte degeneration, lobular disorder, sinusoid dilation, focal necrotic areas, hyperemia, and glycogen loss were observed. Hepatic fibrosis was observed around portal areas and central veins. Bridging fibrous septa were formed between portal veins. By immunohistochemistry, both matrix metalloproteinase-9 (MMP-9) and desmin reactivity were increased. All aspects of liver damage were at least partially prevented in rats treated with vitamin D. Vitamin D appears to act as an antioxidant and anti-fibrotic to protect the rat liver against damage. PMID- 28910169 TI - Perceptions of Equid Well Being Well-Being in South Dakota. AB - In South Dakota, the status of equid well being is relatively unknown. This study sought to (a) gain understanding about the current perceptions of nonhuman animal well being in South Dakota, with an emphasis on horses and other equids; (b) determine the level of care equids are reportedly receiving and the perceived challenges to equine well being in South Dakota, and (c) determine if people from diverse geographical locations (east or west of the Missouri River) have similar views on the well being of equids in South Dakota. Respondents indicated the current level of equid well being in South Dakota is sufficient, but there is room for improvement. Current challenges for the equid population of South Dakota were the high annual cost of horse care, poor horsemanship, dental problems, and whether caregivers understand basic equine care. Several significant associations arose between where a respondent lives (Western or Eastern South Dakota) and their level of agreement with various statements. The results provide a benchmark to gauge well being and help give direction for future educational needs that can continue to improve equid care. PMID- 28910171 TI - Immunohistochemical localization of TLR2 and CD14 in gingival tissue of healthy individuals and patients with chronic periodontitis. AB - We used immunohistochemistry to quantify and compare the expression of Toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) in gingival tissues of both healthy individuals and patients with chronic periodontitis. We also correlated the expression of TLR2 and CD14 with the histological grades of chronic periodontitis. We examined 30 gingival specimens from chronic periodontitis patients and 10 from healthy individuals. Tissues from both groups were immunostained with antibodies against TLR2 and CD14. TLR2 and CD14 were expressed by endothelial cells, fibroblasts, lymphocytes and plasma cells. The immunohistochemical expression of TLR2 and CD14 was significantly greater in inflammatory cells of the chronic periodontitis group than in healthy individuals. Expression of these molecules was greater in the inflammatory cells of connective tissue adjacent to pocket epithelium in both groups. The expression of TLR2 and CD14 was greatest in the periodontitis group that was classified as severe grade, followed by moderate and mild grades, which suggests a role of TLR2 and CD14 in the pathogenesis of chronic periodontitis. The positive correlation of TLR2 and CD14 expression levels with the severity grades of chronic periodontitis suggests that they are correlated also with disease severity; therefore, they may be useful for predicting disease progression. Our findings are consistent with the possibility that CD14 acts as a co-receptor for TLR2. PMID- 28910172 TI - Quirks of dye nomenclature. 9. Fluorescein. AB - Adolf Baeyer announced the discovery of fluorescein in 1871 and named it after its most striking property, i.e., fluorescence. I describe here the synthesis of fluorescein. There are seven molecular species in both the solid state or in solution. I also summarize some of the diverse applications of the dye, both medical and nonmedical, which depend mostly on the facile detection of fluorescein at low concentration. Both animal and human toxicity are examined. PMID- 28910174 TI - Family and Peer-Group Substance Abuse as a Risk-Factor for Opioid Misuse Behaviors for a Young Adult with Cancer-Related Pain-A Case Study. AB - The purpose of this report is to illustrate the importance of assessing for family, peer, and personal substance abuse risk factors in the case of a young adult with cancer-related pain and behaviors potentially indicative of opioid misuse (OM). A thorough clinical interview and an OM screening measure revealed important information about the patient's family and social environment. Based on this information, the treatment team acted quickly to prevent additional aberrant opioid-associated behaviors (AOBs). Despite these efforts, additional AOBs occurred; however, the case highlights the importance of family and social environments for adolescents and young adults with cancer-related pain. PMID- 28910173 TI - Alcohol Use Severity Among Adult Hispanic Immigrants: Examining the Roles of Family Cohesion, Social Support, and Gender. AB - BACKGROUND: This study examined (a) the direct association of family cohesion on alcohol use severity among adult Hispanic immigrants; (b) the indirect association of family cohesion on alcohol use severity via social support; and (c) if gender moderates the direct and indirect associations between family cohesion and alcohol use severity. METHOD: Mediation and moderation analyses were conducted on a cross-sectional sample of 411 (men = 222, women = 189) participants from Miami-Dade, Florida. RESULTS: Findings indicate that higher family cohesion was directly associated with higher social support and lower alcohol use severity. Higher social support was also directly associated with lower alcohol use severity. Additionally, family cohesion had an indirect association with alcohol use severity via social support. Moderation analyses indicated that gender moderated the direct association between family cohesion and alcohol use severity, but did not moderate the indirect association. CONCLUSIONS: Some potential clinical implications may be that strengthening family cohesion may enhance levels of social support, and in turn, lower alcohol use severity among adult Hispanic immigrants. Furthermore, strengthening family cohesion may be especially beneficial to men in efforts to lower levels of alcohol use severity. PMID- 28910175 TI - Neurotrophic Keratopathy: Therapeutic Approach Using a Novel Matrix Regenerating Agent. AB - PURPOSE: To evaluate the efficacy and tolerance of a new matrix-regenerating agent (RGTA), Cacicol(r), a polymer that mimics heparan sulfates bound to extracellular matrix proteins, avoiding its proteolysis, to treat neurotrophic keratopathy (NK). METHODS: Uncontrolled prospective clinical study performed between January 2014 and May 2016. Twenty-five patients (25 eyes) with corneal neurotrophic ulcers, nonresponsive to at least 2 weeks of conservative therapy, were treated with Cacicol, instilled once/twice a week. During follow-up, slit lamp examination, anterior segment photography, fluorescein-dye testing, and best corrected visual acuity were analyzed. Ulcer evolution was evaluated using image analysis software (ImageJ(r)) and healing defined as decrease of the corneal ulcer area. An independent observer measured ulcer area. RESULTS: All patients had complete corneal healing within an average of 4.13 +/- 2.32 weeks. Mean ulcer area decreased significantly (P = 0.001) from 16.51% +/- 18.56% (1st day) to 8.68% +/- 11.25% at the 7th day and to 4.73% +/- 10.75% at the 14th day. Compared with day 1, mean ulcer area decreased 60.24% after 7 days (P = 0.001), 54.92% after 14 days (P = 0.059), and 83.00% after 21 days (P = 0.003). Two cases of recurrence (8.0%) were registered. No systemic or local side effects were noticed. CONCLUSIONS: The new regenerating agent, Cacicol, represents an effective and safe therapy to treat NK. PMID- 28910176 TI - Alcohol Use and Psychosocial Stressors in the Norwegian Workforce. AB - BACKGROUND: Although alcohol use can have detrimental effects for employees, little is known about the prevalence, distribution, and correlates in the Norwegian workforce. AIMS: To determine the overall and the work-related prevalence of weekly alcohol use, and to establish associations between psychosocial work stressors and alcohol use among Norwegian employees. METHODS: Data were from a 2015 national probability sample of 1,608 Norwegian employees (response rate 32%). Job demands, lack of job control, role expectations, workplace bullying, and leadership were examined as correlates of several dimensions of alcohol use. RESULTS: Average weekly alcohol consumption was 4.28 units (SD = 7.91). Male workers reported significantly higher consumption than female workers. Also, 2.6% of male and 2.0% of female workers reported problematic alcohol use. Only 0.1% of workers reported weekly alcohol use before the workday, 0.4% reported weekly use during the workday, 20.1% reported weekly use after ending the work day, and 80% reported use during weekends/days off. Alcohol intake increased with age, but was not related to marital status, educational level, work schedule, or leadership position. Problematic alcohol use was related to job demands and workplace bullying. Alcohol use after work was positively related to lack of job control and role ambiguity and negatively related to bullying. Conclusions/importance: Weekly alcohol use before and during the workday is not prevalent among Norwegian workers. Interventions to reduce job demands and workplace bullying may reduce problematic alcohol intake, whereas increasing job control and reducing role ambiguity may reduce after work use. PMID- 28910177 TI - Development and Validation of a Brief Measure of Eating Compulsivity (MEC). AB - Food addiction is increasingly being recognised as a contributory factor in overweight and obesity. Management of eating compulsivity, a key component of food addiction, may assist greatly in the successful treatment of obesity. Measurement of food addiction and its core characteristic of eating compulsivity is fundamental to increasing understandings of the concept of food addiction, its prevalence among people with and without obesity and its utility within a treatment context. The current study describes the development and initial validation of a brief measure of eating compulsivity that can be used within clinical and research settings to establish a person's level of eating compulsivity. Sixty five participants with a BMI >=30 (mean BMI 38.1) were recruited from a general population sample within Christchurch, New Zealand. Participants completed the test version of the Measure of Eating Compulsivity (MEC) and the Yale Food Addiction Scale (YFAS) as well as providing self-reported measures of height and weight. The 10-item MEC was developed. This measure was shown to have excellent internal consistency (Cronbach's alpha =.946), based on a single factor accounting for 67.4% of the variance and excellent test-retest reliability (r =.923). MEC10 score was strongly predictive of being categorised as having food addiction based on the YFAS, although not associated with BMI. This brief tool is likely to have high utility in clinical and research settings and requires further validation with a range of populations including those with and without obesity, binge eating disorder and other eating disorders. PMID- 28910178 TI - Interpersonal and Intrapersonal Differences among Adolescent Nonsmokers, Ex Smokers, and Smokers. AB - BACKGROUND: A large body of research has traced tobacco dependence among adolescents to a series of intrapersonal and interpersonal factors. However, there are remaining questions regarding the differences on these factors related to tobacco use. OBJECTIVES: We sought to investigate intrapersonal and interpersonal differences among adolescent nonsmokers, ex-smokers, and smokers. METHODS: We used data from a 3-year project designed to investigate and address tobacco dependence among 1071 students (Mage = 15.76, SD = 1.52; girls = 51.54%) who were recruited from 11 high schools. Participants, filling out a survey, provided information on tobacco use (nonsmoker, ex-smoker, and smoker), tobacco related experiences (smoking-related risk perception, parental smoking, number of friends who smoke, resisting peer pressure to smoke), cognitive variables (metacognitive skills), and personality traits (disinhibition and impulsivity). RESULTS: Results from a discriminant function analysis showed that smokers and ex smokers reported more disinhibition, impulsivity, number of friends who smoke and less self-control under peer pressure to smoke compared to nonsmokers. Ex-smokers reported less metacognitive processes, more smoking-related risk perception and were less likely to have parents who smoke. Conclusions/Importance: Interventions and campaigns aimed to persuade adolescents to stop smoking should work to develop adaptive metacognitive skills and an accurate risk perception of tobacco use. PMID- 28910179 TI - Phenotypic differences between familial versus non-familial Juvenile onset open angle glaucoma patients. AB - AIM: To evaluate phenotypic differences among familial and non-familial JOAG patients. METHODS: First degree relatives of unrelated JOAG patients were screened for glaucoma and ocular hypertension. JOAG probands were grouped as familial or non-familial and phenotypic differences in terms of age of onset, gender, baseline untreated IOP, presence angle dysgenesis, and refractive error was compared between the two groups. RESULTS: Out of 368 unrelated JOAG patients, 134 in whom all first degree relatives had been examined were included in the study. The non-familial JOAG (n = 96) had similar age of onset as familial JOAG (n = 38); (p = 0.076) but had greater male preponderance (p = 0.046), and had the higher baseline IOP (p = 0.044) compared to familial JOAG. However, on adjustment using the Bonferroni correction, the observed differences were not found to be significant. Both groups had similar proportion of patients with angle dysgenesis (p = 0.46) and high myopia (p = 0.72). CONCLUSIONS: Non-familial JOAG were not found to be phenotypically different from the familial JOAG patients in this cohort. PMID- 28910181 TI - Mother's Milk: In Sickness and In Health? PMID- 28910180 TI - Nrf2-Mediated HO-1 Induction and Antineuroinflammatory Activities of Halleridone. AB - Nuclear factor E2-related factor 2 (Nrf2) is the master regulator of antioxidant enzymes and is known to act on the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) signaling pathway. Few studies have examined the bioactivity of halleridone. Herein, we investigated whether halleridone, which was isolated from the stems of the plant Cornus walteri, could regulate Nrf2 mediated heme oxygenase (HO)-1 expression and prevent intramicroglial inflammation induced by amyloid beta (Abeta)1-42 overexpression. Biochemical and molecular experiments, such as real-time polymerase chain reaction, Western blot analysis, immunocytochemistry, immunofluorescence, and luciferase reporter gene assays, were performed. The results demonstrated that halleridone promoted the upregulation of Nrf2 expression and its translocation to the nucleus, thereby activating antioxidant response element gene transcription and HO-1 expression in murine hippocampal HT22 cells. Additionally, halleridone removed intramicroglial Abeta1-42 and suppressed the production of inflammatory mediators such as interleukin (IL)-1beta, IL-6, prostaglandin E2, and nitric oxide (NO) induced by artificially overexpressed Abeta1-42 and decreased pNF-kappaB accumulation in the nucleus and the expression of inducible NO synthase and cyclooxygenase II in BV-2 cells. In conclusion, halleridone activated Nrf2-mediated HO-1 expression and inhibited Abeta1-42-overexpressed microglial BV-2 cell activation. These observations suggest that halleridone may have therapeutic potential for targeting neurodegeneration through neuroinflammation. PMID- 28910182 TI - Consumers' Perceptions of Edible Marijuana Products for Recreational Use: Likes, Dislikes, and Reasons for Use. AB - BACKGROUND: Edible marijuana products have become extremely popular in states that have legalized marijuana for recreational use. OBJECTIVES: The goal of this research was to provide a better understanding of consumer perceptions of edible marijuana products, including why they prefer edibles relative to other forms of marijuana (e.g., smoking) and their concerns regarding the consumption of edibles. METHODS: We conducted eight focus groups (four groups in Denver, Colorado, and four groups in Seattle, Washington) in February 2016 with 62 adult consumers of edibles. Focus group transcripts were coded in QSR NVivo 10.0 qualitative analysis software, and coding reports identified trends across participants. RESULTS: Most participants preferred edibles to smoking marijuana because there is no smell from smoke and no secondhand smoke. Other reasons participants like edibles included convenience, discreetness, longer-lasting highs, less intense highs, and edibles' ability to aid in relaxation and reduce anxiety more so than smoking marijuana. Concerns and dislikes about edibles included delayed effects, unexpected highs, the unpredictability of the high, and inconsistency of distribution of marijuana in the product. No participants in either location mentioned harmful health effects from consuming edibles as a concern. Conclusions/Importance: The present study was qualitative in nature and provides a good starting point for further research to quantify through surveys how consumers understand and use edibles. Such information will help guide policy makers and regulators as they establish regulations for edibles. Also, such research can help inform educational campaigns on proper use of edibles for recreational purposes. PMID- 28910183 TI - The Effects of Barrier Agents in Postoperative Pelvic Adhesion Formation: A Comparative Study of a Temperature-Sensitive Poloxamer-Based Solution/Gel and a Hyaluronic Acid-Based Solution in a Rat Uterine Horn Model. AB - OBJECTIVE: The aim is to evaluate the efficacy of poloxamer/alginate/CaCl2 mixture (PACM) solution/gel and hyaluronic acid/carboxymethylcellulose (HA-CMC) solution for reducing pelvic adhesion in a rat uterine horn model. STUDY DESIGN: A total of 48 females, Sprague Dawley rats, were divided into three groups according to the applied materials. A uterine horn adhesion model was created. The control group (group CO; n = 16) received no special materials except saline infusion. The experimental groups were treated with 1.0 mL HA-CMC solution (group HA-CMC; n = 16) or 1.0 mL PACM solution/gel (group PACM; n = 16). Adhesion scores were evaluated with macroscopic, microscopic, and immunohistochemistry grading 14 days postoperatively. RESULTS: Macroscopic adhesion scores, including extent, severity, and total scores in group HA-CMC and group PACM, were significantly lower than those in group CO (P < .001). Among these three categories of scoring, group PACM had a significantly lower score than did group HA-CMC in adhesion severity (P = .025). In the microscopic adhesion score analysis, the fibrosis scores in group HA-CMC and group PACM were also significantly lower than that of group CO. In group PACM, the fibrosis score was significantly lower than that of group HA-CMC. There were no statistical differences across all three groups in the microscopic inflammation and immunohistochemistry staining. CONCLUSION: Both HA-CMC solution and PACM solution/gel effectively reduced adhesion formation. PACM solution/gel was superior to HA-CMC solution in preventing pelvic adhesion, especially in adhesion severity and microscopic fibrosis. PMID- 28910184 TI - The Impact of Alexithymia on Desire for Alcohol during a Social Stress Test. AB - BACKGROUND: Alexithymia is a personality construct comprising difficulty in identifying and describing emotions and externally oriented thinking. Its role in heavy and problematic alcohol consumption is well documented, together with its relationship with social stress. However, little research has examined whether social stress has any effect on desire for alcohol among alexithymic individuals. OBJECTIVES: In this experimental study, we explored the relationship between alexithymia and desire for alcohol in response to an experimental social stressor. METHODS: One hundred and thirty eight social drinkers completed the Toronto Alexithymia Scale, self-report measures of alcohol consumption and a stress-inducing task. Desire for alcohol was measured at three time points: baseline, stressor and recovery. RESULTS: Correlation analysis demonstrated that alexithymia was associated with significantly higher rates of alcohol consumption and higher levels of desire for alcohol. Mixed measures ANOVA demonstrated a significant main effect of alexithymia and a significant group by time effect of alexithymia on desire for alcohol. Conclusions/Importance: The findings demonstrate increased desire for alcohol before, during and after a social stressor among alexithymic participants. These findings offer an insight into the relationship between alexithymia, social stress and alcohol consumption. PMID- 28910185 TI - Examining the Effects of Art Therapy on Reoccurring Tobacco Use in a Taiwanese Youth Population: A Mixed-Method Study. AB - BACKGROUND: Cigarette smoking is a primary risk factor affecting mental and physical health worldwide. Many chronic diseases are closely related to smoking. Adolescents in Taiwan are increasingly using tobacco, especially in rural areas. OBJECTIVES: This research project used a mixed-method study to examine the effects of art therapy on smoking cessation in rural Taiwanese youth smokers. METHODS: Participants from years 10-11, were drawn from three senior high schools in Taiwan. The experimental group participated in a six-week smoking cessation intervention using art therapy. The comparison group participated in typical courses on smoking cessation. Quantitative measures included need for smoking, nicotine dependence, self-esteem, self-efficacy, and smoking cessation status. Qualitative analysis was based on phenomenology. RESULTS: A total of 66 students (n = 40 experimental group; n = 26 comparison group) were the subjects of quantitative analysis. No differences were noted in baseline characteristics of groups. Generalized estimating equation analyses suggested significant between group differences in change from pre- to follow-up test scores in the "social domain" (B = -5.12, p < 0.05). Qualitative data (n = 17 experimental group; n = 10 control group) suggested three domains: effects of art therapy on smoking prevention, benefits of art therapy on other outcome measures, and comparison between art therapy and traditional smoking cessation programs. Conclusions/importance: The findings of this study can potentially contribute significantly to existing knowledge regarding the perceptions of art therapy on reoccurring tobacco use in Taiwanese youth. PMID- 28910186 TI - Applying the Problem Behavior Theory to Adolescent Drug Use Among a Cross Sectional Sample of Boys Participating in a Community-Based Youth Organization. AB - BACKGROUND: Drug use remains an important public health concern in the United States, and understanding drug use among young adolescents is vital towards improving the health of the population. OBJECTIVE: This study applied the Problem Behavior Theory (PBT) to lifetime drug use among a cross-sectional sample of Boy Scouts (N = 770). The PBT provides a conceptual framework for identifying risk and protective factors for adolescent problem behaviors, including drug use. METHODS: Scouts reported their drug use and socio-demographics, and were assessed on several risk and protective factors. For analyses, sociodemographic and risk and protective factors were selected according to the framework provided by PBT, and use of each drug was regressed logistically on these selected factors. Final logistic models were assessed for goodness of fit and discriminatory power. RESULTS: The PBT demonstrated discriminatory power for all drugs (Tjur's R2 values >=.29), but fell sharply for illicit drug use (Tjur's R2 =.20). There were no consistent correlates of drug use. Conclusions/Importance: The PBT had less explanatory power for illicit drug use compared to tobacco, alcohol, and marijuana, which suggests different risk and protective factors were associated with illicit drug use. PMID- 28910187 TI - Sternal Route More Effective than Tibial Route for Intraosseous Amiodarone Administration in a Swine Model of Ventricular Fibrillation. AB - OBJECTIVE: The pharmacokinetics of IO administered lipid soluble amiodarone during ventricular fibrillation (VF) with ongoing CPR are unknown. This study measured mean plasma concentration over 5 minutes, maximum plasma concentration (Cmax), and time to maximum concentration (Tmax) of amiodarone administered by the sternal IO (SIO), tibial IO (TIO), and IV routes in a swine model of VF with ongoing CPR. METHODS: Twenty-one Yorkshire-cross swine were randomly assigned to three groups: SIO, TIO, and IV. Ventricular fibrillation was induced under general anesthesia. After 4 minutes in VF, 300 mg amiodarone was administered as indicated by group assignment. Serial blood specimens collected at 30, 60, 90, 120, 150, 180, 240, and 300 seconds were analyzed using high performance liquid chromatography with tandem mass spectrometry. RESULTS: The mean plasma concentration of IV amiodarone over 5 minutes was significantly higher than the TIO group at 60 seconds (P = 0.02) and 90 seconds (P = 0.017) post-injection. No significant differences in Cmax between the groups were found (P <0.05). The Tmax of amiodarone was significantly shorter in the SIO (99 secs) and IV (86 secs) groups compared to the TIO group (215 secs); P = 0.002 and P = 0.002, respectively. CONCLUSIONS: The SIO and IV routes of amiodarone administration were comparable. The TIO group took nearly three times longer to reach Tmax than the SIO and IV groups, likely indicating depot of lipid-soluble amiodarone in adipose-rich tibial yellow bone marrow. The SIO route was more effective than the TIO route for amiodarone delivery in a swine model of VF with ongoing CPR. Further investigations are necessary to determine if the kinetic differences found between the SIO and TIO routes in this study affect survival of VF in humans. PMID- 28910188 TI - Sedative and Analgesic Drugs Online: A Content Analysis of the Supply and Demand Information Available in Thailand. AB - BACKGROUND: Evidence from other countries has suggested that many controlled drugs are also offered online, even though it is illegal to sell these drugs without a license. OBJECTIVES: To evaluate the current contents related to the supply and demand of sedatives and analgesic drugs available online in Thailand, with a particular focus on Facebook. METHODS: A team of reviewers manually searched for data by entering keywords related to analgesic drugs and sedatives. The contents of the website were screened for supply and demand-related information. FINDINGS: A total of 5,352 websites were found publicly available. The number of websites and Facebook pages containing the information potentially related to the supply and demand of analgesic drugs and sedatives was limited. Nine websites sold sedatives, and six websites sold analgesics directly. Fourteen Facebook pages were found, including 7 sedative pages and 7 analgesic pages. Within one year, the three remaining active pages multiplied in the number of followers by three- to nine-fold. The most popular Facebook page had over 2,900 followers. CONCLUSIONS: Both the internet and social media contain sites and pages where sedatives and analgesics are illegally advertised. These websites are searchable through common search engines. Although the number of websites is limited, the number of followers on these Facebook pages does suggest a growing number of people who are interested in such pages. Our study emphasized the importance of monitoring and developing potential plans relative to the online marketing of prescription drugs in Thailand. PMID- 28910189 TI - Associations among Omega-3 Fatty Acid Status, Anxiety, and Mental Toughness in Female Collegiate Athletes. AB - OBJECTIVE: Poor omega-3 fatty acid status has been linked to anxiety in the general population, but scarce data are available describing omega-3 fatty acid levels in athletes and their associations with anxiety and mental toughness. METHODS: Whole blood samples were obtained from 54 female collegiate athletes and analyzed for fatty acids as a part of this cross-sectional observational study. Participants also completed a food frequency questionnaire on the intake of omega 3 fatty acids, as well as the Beck Anxiety Inventory (BAI), Sport Anxiety Scale (SAS)-2, and Mental Toughness Scale (MTS). Measures were collected during the athletes' off-season. Spearman's rho coefficients were used to examine the associations between fatty acid levels and psychological scores. RESULTS: Blood levels of the HS-Omega-3 Index(r) (rho = -0.32, p = 0.02), eicosapentaenoic acid (rho = -0.40, p = 0.003), and docosapentaenoic acid (rho = -0.33, p = 0.02) were negatively correlated with BAI scores. Likewise, dietary intakes of eicosapentaenoic acid (rho = -0.38, p = 0.007) and docosahexaenoic acid (rho = 0.35, p = 0.02) were negatively correlated with BAI scores. Blood docosapentaenoic acid was positively correlated with MTS (rho = 0.27, p = 0.049). None of the dietary or blood fatty acids were significantly correlated with SAS-2 scores. CONCLUSIONS: Both blood and dietary omega-3 fatty acid levels are associated with general but not sport-specific anxiety in female collegiate athletes during an off-season period. Randomized trials should be conducted to evaluate the effects of omega-3 fatty acid supplementation on anxiety and mental toughness in athletes. PMID- 28910190 TI - Waist-to-Height Ratio as a Predictor of C-Reactive Protein Levels. AB - BACKGROUND: C-reactive protein is an acute-phase protein that has been found in association with adiposity and cardiovascular disease risk. In this paper, the objective was to assess the relationship of C-reactive protein to four anthropometric measurements: body mass index, waist-to-height ratio, C index, and waist circumference. METHODS: A cross-sectional random sample of the Study of Cardiovascular Risk in Adolescents (Portuguese acronym "ERICA") was included in the study. The analysis was adjusted for the complex sampling design. Poisson regression models with robust variance were used to estimate a multivariate adjusted prevalence rate ratio expressing the relationship of each anthropometric measure to C-reactive protein. We evaluated adolescents aged 12 to 17 years participating in the capital of Porto Alegre, Brazil. RESULTS: In all, 778 adolescents were included (60% female, 58% aged 15-17 years). Waist-to-height ratio was found to be the strongest adiposity marker associated with C-reactive protein even after adjusting for age, sex, smoking, physical activity, and insulin resistance (prevalence rate ratio = 7.09; 95% confidence interval, 5.01 9.18; p < 0.001). CONCLUSIONS: Waist-to-height ratio is a strong predictor of C reactive protein in adolescents in Porto Alegre, Brazil. PMID- 28910192 TI - Subjective Life Expectancy Among College Students. AB - Establishing healthy habits in college is important for long-term health. Despite existing health promotion efforts, many college students fail to meet recommendations for behaviors such as healthy eating and exercise, which may be due to low perceived risk for health problems. The goals of this study were to examine: (1) the accuracy of life expectancy predictions, (2) potential individual differences in accuracy (i.e., gender and conscientiousness), and (3) potential change in accuracy after inducing awareness of current health behaviors. College students from a small northeastern university completed an electronic survey, including demographics, initial predictions of their life expectancy, and their recent health behaviors. At the end of the survey, participants were asked to predict their life expectancy a second time. Their health data were then submitted to a validated online algorithm to generate calculated life expectancy. Participants significantly overestimated their initial life expectancy, and neither gender nor conscientiousness was related to the accuracy of these predictions. Further, subjective life expectancy decreased from initial to final predictions. These findings suggest that life expectancy perceptions present a unique-and potentially modifiable-psychological process that could influence college students' self-care. PMID- 28910191 TI - Lysophosphatidic Acid is a Biomarker for Peritoneal Carcinomatosis of Gastric Cancer and Correlates with Poor Prognosis. AB - BACKGROUND: Peritoneal carcinomatosis (PC) is an important cause of morbidity and mortality among patients with gastric cancer. Thus, it is important to identify an ideal biomarker for PC. METHODS: Plasma and ascites samples were collected from gastric cancer patients with PC and a control group. Lysophosphatidic acid (LPA) levels were tested and analyzed. RESULTS: The plasma LPA levels of gastric cancer patients with PC were significantly higher than those in gastric cancer patients after radical resection (p = 0.046) and healthy volunteers (p < 0.001). Besides, plasma LPA levels were statistically lower after chemotherapy in gastric cancer patients with PC (p = 0.028). Furthermore, the ascites LPA levels were significantly higher in gastric cancer patients with peritoneal carcinomatosis than those in liver cirrhosis patients (p < 0.001). Moreover, ascites LPA levels were statistically lower after intraperitoneal chemotherapy injection than before (p < 0.001). In addition, the plasma LPA levels were significantly associated with serum CA125 levels (p = 0.032) and TNM stage in gastric cancer patients (p = 0.009). Individuals with plasma LPA levels >20,000 ng/mL had significantly worse overall survival (OS) than those with plasma LPA levels <20,000 ng/mL group (p = 0.006). In addition the group with ascites LPA levels >24,000 ng/mL showed significantly worse progression-free survival (PFS) and OS (p < 0.001 in PFS and OS). CONCLUSIONS: This study demonstrated that LPA levels in plasma and ascites may be useful diagnostic biomarkers for PC of gastric cancer and that higher levels are associated with poor prognosis. PMID- 28910193 TI - Lifestyle Markers Predict Cognitive Function. AB - OBJECTIVE: Rates of mild cognitive impairment and Alzheimer's disease are increasing rapidly. None of the current treatment regimens for Alzheimer's disease are effective in arresting progression. Lifestyle choices may prevent cognitive decline. This study aims to clarify which factors best predict cognitive function. METHODS: This was a prospective cross-sectional analysis of 799 men and women undergoing health and cognitive testing every 1 to 3 years at an outpatient center. This study utilizes data collected from the first patient visit. Participant ages were 18 to 88 (mean = 50.7) years and the sample was 26.6% female and 73.4% male. OUTCOME MEASURES: Measurements were made of body composition, fasting laboratory and anthropometric measures, strength and aerobic fitness, nutrient and dietary intake, and carotid intimal media thickness (IMT). Each participant was tested with a computerized neurocognitive test battery. Cognitive outcomes were assessed in bivariate analyses using t-tests and correlation coefficients and in multivariable analysis (controlling for age) using multiple linear regression. RESULTS: The initial bivariate analyses showed better Neurocognitive Index (NCI) scores with lower age, greater fitness scores (push-up strength, VO2max, and exercise duration during treadmill testing), and lower fasting glucose levels. Better cognitive flexibility scores were also noted with younger age, lower systolic blood pressure, lower body fat, lower carotid IMT scores, greater fitness, and higher alcohol intake. After controlling for age, factors that remained associated with better NCI scores include no tobacco use, lower fasting glucose levels, and better fitness (aerobic and strength). Higher cognitive flexibility scores remained associated with greater aerobic and strength fitness, lower body fat, and higher intake of alcohol. CONCLUSIONS: Modifiable biomarkers that impact cognitive performance favorably include greater aerobic fitness and strength, lower blood sugar levels, greater alcohol intake, lower body fat, and avoidance of tobacco. Further studies are warranted to study whether modifying these lifestyle factors improves cognitive function and slows cognitive decline. PMID- 28910194 TI - Chikungunya Virus-Induced Arthritis: Role of Host and Viral Factors in the Pathogenesis. AB - Chikungunya virus (CHIKV), a member of Alphavirus genus, is responsible for chikungunya fever (CHIKF), which is characterized by the presence of fever, rash, myalgia, and arthralgia. Reemergence of CHIKV has become a significant public health concern in Asian and African countries and is newly emerging in the Middle East, Pacific, American, and European countries. Cytokines, innate (monocytes, natural killer cells) and adaptive immune response (role of B cells and T cells i.e. CD4+ and CD8+), and/or viral factors contribute to CHIKV-induced arthritis. Vector factors such as vector competence (that includes extrinsic and intrinsic factors) and effect of genome mutations on viral replication and fitness in mosquitoes are responsible for the spread of virus, although they are not directly responsible for CHIKV-induced arthritis. CHIKV-induced arthritis mimics arthritis by involving joints and a common pattern of leukocyte infiltrate, cytokine production, and complement activation. Successful establishment of CHIKV infection and induction of arthritis depends on its ability to manipulate host cellular processes or host factors. CHIKV-induced joint damage is due to host inflammatory response mediated by macrophages, T cells, and antibodies, as well as the possible persistence of the virus in hidden sites. This review provides insight into mechanisms of CHIKV-induced arthritis. Understanding the pathogenesis of CHIKV-induced arthritis will help in developing novel strategies to predict and prevent the disease in virus-infected subjects and combat the disease, thereby decreasing the worldwide burden of the disease. PMID- 28910195 TI - Elevated Neutrophil-to-Lymphocyte Ratio in Metabolic Syndrome Is Associated with Increased Risk of Colorectal Adenoma. AB - BACKGROUND: Metabolic syndrome (MetS) is an important cardiovascular risk factor for insulin resistance and has been linked to colorectal adenoma via inflammation. The neutrophil-to-lymphocyte ratio (NLR) has been suggested as an important inflammatory marker. We initiated this investigation to determine the relationship between colorectal adenoma and NLR in patients with MetS. METHODS: We examined participants who visited the Health Promotion Center at Kosin University Gospel Hospital, Busan, Korea. Subjects who underwent both colonoscopy and liver ultrasonography were included. Colorectal adenoma was defined as the presence of a colon polyp with a histologically adenomatous component. MetS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III definition for South Asians. Anthropometric measurements and biochemical tests of liver and metabolic function were assessed. RESULTS: A total of 1007 subjects were included in the study sample. Their mean age was 48.3 +/- 9.7 years and 262 (26.0%) subjects had MetS, while 439 (43.6%) subjects had pathologically proven colorectal adenoma. Subjects with MetS were older, more likely to be male, and had significantly higher prevalences of colorectal adenoma (49.2% vs. 41.6%, P = 0.032), nonalcoholic fatty liver disease (62.8% vs. 19.5%, P < 0.001), and higher NLR (2.0 +/- 0.9 vs. 1.7 +/- 0.7, P < 0.001) compared to those without MetS. High NLR (>=2.0) was an independent factor affecting the prevalence of colorectal adenoma [odds ratio (OR) 1.38, confidence interval (95% CI) 1.02-1.88, P = 0.040], especially in subjects with MetS (OR 1.91, 95% CI 1.12 3.28, P = 0.018). CONCLUSION: High NLR was associated with increased colorectal adenomatous polyps, particularly in subjects with MetS. Screening colonoscopies for the prevention of colorectal adenoma may be warranted for patients with high NLR and MetS. PMID- 28910196 TI - Effect of Alpinia galanga on Mental Alertness and Sustained Attention With or Without Caffeine: A Randomized Placebo-Controlled Study. AB - OBJECTIVE: Although Alpinia galanga has been reported to improve cognitive performance in animals, it has not been thoroughly studied for its potential psychostimulant effect in humans. A randomized, double-dummy, double-blind, placebo-controlled cross-over study was conducted to determine the effect of A galanga on mental alertness and sustained attention in comparison with caffeine and placebo in participants with a habitual caffeine intake. METHODS: Fifty-nine participants (18-40 years and body mass index of >=18.5 and <25.00 kg/m2) with moderate caffeine consumption were enrolled. The participants had a Generalized Anxiety Disorder-7 score <=7, Patient Health Questionnaire-9 score <=14 and a Jin Fan's Attention Network Test alertness score of 50 +/- 20 ms. The interventional product (placebo, A galanga proprietary extract [E-AG-01], caffeine, and a combination of E-AG-01 with caffeine) was administered to the participants, followed by sequential administration of the remaining interventions on the consecutive study visits; the effects on mental alertness, sustained attention, and sleep architecture, along with safety and tolerability, were analyzed by validated methods. RESULTS: In the E-AG-01 group, the alertness score was increased by 11.65 +/- 23.94, 12.50 +/- 19.73, and 12.62 +/- 0.68 ms from baseline at 1, 3 (p = 0.042), and 5 hours, respectively, indicating its efficacy to enhance mental alertness and the increase in alertness score as compared to placebo. In the composite group (E-AG-01 with caffeine), mean response time was significantly reduced, by 15.55 ms (p = 0.026) at 3 hours. CONCLUSIONS: A galanga (E-AG-01) induces a beneficial effect in mental alertness and the combination of A galanga with caffeine impedes the caffeine crash and improves sustained attention at 3 hours. Thus, these stimulant effects might yield a new usage for A galanga as a key ingredient in energy drinks or similar products. PMID- 28910197 TI - Optimal reference genes for RT-qPCR normalization in the newborn. AB - It is difficult to identify reliable reference genes for transcriptomic analyses in biofluids such as saliva. This situation is particularly relevant for the newborn population, where rapid development is associated with dynamic changes in gene expression. Real-time gene expression monitoring holds great promise for elucidating disrupted pathways that result in morbidities unique to this population, such as retinopathy of prematurity, but its impact depends on identifying stable and consistently expressed genes across a wide range of gestational ages. We extracted total RNA from 400 neonatal saliva samples (postconceptional ages: 32 5/7 to 48 2/7 weeks), converted it to cDNA, and pre amplified and analyzed it by qPCR for three commonly used reference genes, ACTB, GAPDH, and YWHAZ. Relative quantification was determined using the Delta Ct method. Data were analyzed as a whole and also stratified by age and sex. Descriptive statistics and homogeneity of variance were performed to identify optimal reference genes. Data analyzed from all ages and both sexes showed significant expression variation for ACTB, while GAPDH and YWHAZ showed greater stability. Male infants exhibited increased expression variation compared to females for ACTB, but neither GAPDH nor YWHAZ showed significant variance for either sex. We suggest that ACTB is an unreliable reference gene for the newborn population. Males showed significantly more variation in ACTB expression compared to females, which suggests a sex-specific developmental role for this biomarker. By contrast, GAPDH and YWHAZ were less variable and therefore preferable for use in neonates. Our findings may improve the use of reference genes for the RT-qPCR platform in the newborn over a wide range of gestational ages, thereby minimizing the likelihood of erroneous interpretation of gene expression during rapid growth, development, and differentiation. PMID- 28910198 TI - Re: "Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Susceptiblity to Dengue Virus Infection in a Mexican Population" by Sanchez-Leyva et al. (Viral Immunol 2017;30:615-621). PMID- 28910199 TI - Fixed or Random? A Resolution Through Model Averaging: Reply to Carlsson, Schimmack, Williams, and Burkner (2017). PMID- 28910201 TI - Reentry High Altitude Pulmonary Edema in the Himalayas. AB - Baniya, Santosh, Christopher Holden, and Buddha Basnyat. Reentry high altitude pulmonary edema in the Himalayas. High Alt Med Biol. 18:425-427, 2017.-Reentry high altitude pulmonary edema (HAPE), a subset of HAPE, is a well recognized, life-threatening illness documented almost exclusively in the North and South Americans, who live at high altitude (>2500 m) and return to their homes after a brief sojourn of days to months at lower altitude. This phenomenon has not been reported in Sherpas or other people of Tibetan origin in Nepal or India. And it has rarely been reported from Tibet. In this study we document a case of reentry HAPE in Manang region (3500 m) of Nepal in a 7-year-old Nepali boy of Tibetan ancestry who fell ill when he ascended to his village (Manang, 3500 m) from Besisahar (760 m) in 1 day in a motor vehicle after spending the winter (December to March) at Besisahar with his family. With more motorable road access to high altitude settlements in the Himalayas, reentry HAPE may need to be strongly considered by healthcare professionals in local residents of high altitude; otherwise life-threatening complications may ensue as in our case report. PMID- 28910200 TI - Comparison of Two beta-Alanine Dosing Protocols on Muscle Carnosine Elevations. AB - OBJECTIVE: beta-alanine (BA) is a nonproteogenic amino acid that combines with histidine to form carnosine. The amount taken orally in individual doses, however, is limited due to symptoms of paresthesia that are associated with higher doses. The use of a sustained-release formulation has been reported to reduce the symptoms of paresthesia, suggesting that a greater daily dose may be possible. The purpose of the present study was to determine whether increasing the daily dose of BA can result in a similar increase in muscle carnosine in a reduced time. METHODS: Eighteen men and twelve women were randomized into either a placebo (PLC), 6-g BA (6G), or 12-g BA (12G) groups. PLC and 6G were supplemented for 4 weeks, while 12G was supplemented for 2 weeks. A resting blood draw and muscle biopsy were obtained prior to (PRE) and following (POST) supplementation. Plasma and muscle metabolites were measured by high-performance liquid chromatography. The loss in peak torque (DeltaPT) was calculated from maximal isometric contractions before and after 250 isokinetic kicks at 180 degrees .sec-1 PRE and POST. RESULTS: Both 12G (p = 0.026) and 6G (p = 0.004) increased muscle carnosine compared to PLC. Plasma histidine was decreased from PRE to POST in 12G compared to PLC (p = 0.002) and 6G (p = 0.001), but no group x time interaction (p = 0.662) was observed for muscle histidine. No differences were observed for any hematological measure (e.g., complete blood counts) or in symptoms of paresthesia among the groups. Although no interaction was noted in DeltaPT, a trend (p = 0.073) was observed. CONCLUSION: Results of this investigation indicate that a BA supplementation protocol of 12 g/d-1, using a sustained-release formulation, can accelerate the increase in carnosine content in skeletal muscle while attenuating paresthesia. PMID- 28910202 TI - Bayes Factors From Pooled Data Are No Substitute for Bayesian Meta-Analysis: Commentary on Scheibehenne, Jamil, and Wagenmakers (2016). PMID- 28910203 TI - The T-Box Transcription Factor TBX2 Regulates Cell Proliferation in the Retinal Pigment Epithelium. AB - PURPOSE: Vertebrate eye development and function critically depend on the regulation of proliferation of retinal pigment epithelium (RPE) cells. Hence, a thorough analysis of the molecular parameters controlling RPE cell proliferation is crucial for our understanding of the physiology of this cell type both in health and in disease. The T-box transcription factor TBX2 is an important cell cycle regulator in development and oncogenesis, but its specific role in RPE cell proliferation is far from clear. The purpose of the present study is to investigate whether TBX2 plays any role in regulating RPE cell proliferation. MATERIALS AND METHODS: The expression of TBX2 in RPE cells was analyzed in wildtype mice and ARPE-19 cells by co-staining for RPE-specific markers and cell proliferation. In vitro, the role of TBX2 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels. RESULTS: Here, we find that TBX2 is expressed in RPE cells both in vivo and in vitro. Specific knockdown of TBX2 in the human RPE cell line ARPE-19 leads to an accumulation of cells at G1. This cell cycle arrest is accompanied by changes in the levels of known cell cycle regulators and, in particular, by an increase in the levels of the tumor suppressor gene CCAAT/enhancer-binding protein delta (CEBPD). In fact, simultaneous knockdown of both TBX2 and CEBPD interferes with the reduction in cell proliferation brought about by TBX2 reduction alone. CONCLUSIONS: Our results provide novel insights into the regulatory mechanisms of cell proliferation in the RPE and may contribute to our understanding of normal RPE maintenance and its pathology in degenerative and proliferative disorders of the eye. PMID- 28910204 TI - Chemotherapy-induced neutropenia and the prognosis of colorectal cancer: a meta analysis of cohort studies. AB - INTRODUCTION: Recently, there has been a controversial discussion about the prognostic value of chemotherapy-induced neutropenia (CIN) in colorectal cancer patients. Thus, a meta-analysis was conducted to determine the relationship between CIN and the prognosis of colorectal cancer patients. METHODS: We searched the PubMed, EMBASE, and Cochrane library databases to identify studies evaluating the association between CIN and colorectal cancer prognosis. Pooled random/fixed effect models were used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association. RESULTS: Eight studies were selected for the meta-analysis, for a total of 2,745 patients. There was significant improved survival among colorectal cancer patients with CIN (HR = 0.62, 95% CI = 0.47-0.76). However, significant heterogeneity was found (p = 0.000, Iota2 = 75.0%). Through subgroup analysis, we could greatly eliminate the heterogeneity and found that neutropenia was associated with better survival in stage IV colorectal cancer patients, no matter the HR calculated by overall survival (OS) or progression-free survival (PFS). Meanwhile, the prognostic value of neutropenia in stage II/III colorectal cancer can be found when the HR is calculated by disease-free survival (DFS). Additionally, we observed significant differences after stratification according to various tumor stages, endpoints, and the use of G-CSF. CONCLUSIONS: Our results which, based on a cohort study, indicate that CIN is associated with improved survival in patients with colorectal cancer. However, further randomized controlled trials are warranted. PMID- 28910205 TI - Gender Differences in the Relationship between Sex Hormone Deficiency and Soft Drusen. AB - PURPOSE: To investigate the association between sex hormone deficiency and soft drusen in women and men. MATERIALS AND METHODS: We retrospectively reviewed the medical records and fundus photographs of subjects who underwent a health screening for additional examination of climacterium and age-related changes including sex hormone status. In women, sex hormone deficiency was defined as cessation of menstruation that had lasted for at least 12 months and follicular stimulating hormone (FSH) levels >= 25 mIU/mL; in men, it was defined as testosterone levels <= 3.5 ng/mL. The subjects were divided into two groups-the soft drusen and control groups-based on the presence of soft drusen in the fundus photographs. The total drusen area was measured using ImageJTM software. RESULTS: Of total 2036 subjects, 638 (271 women; 367 men) were included. Two hundred thirteen subjects (33.4%) had soft drusen (97/271 women, 116/367 men). In women, sex hormone deficiency was more common in the soft drusen group than in the control group (P < 0.001); this was not the case in men. Multivariate logistic regression analysis revealed that sex hormone deficiency was an independent risk factor for soft drusen in women (P < 0.001; odds ratio [OR] = 3.494), as was age (P < 0.001; OR = 1.092). A long post-menopausal period was a risk factor for large soft drusen (>= 125 MUm). (P < 0.001; OR = 1.220). Age was significantly associated with total drusen area in both women (P = 0.022; beta = 0.406) and men (P = 0.015; beta = 0.246). CONCLUSIONS: Sex hormone deficiency and its duration were significantly associated with the development and progression of soft drusen in women but not in men. It may be necessary to assess and manage the sex hormone deficiency in women with age-related macular degeneration. PMID- 28910206 TI - A framework for polyvictimization in later life. AB - This article provides a context and overview for what is known about polyvictimization in later life. Drawing from previous literature, the article includes a definition of the phenomenon, as well as theoretical constructs by which it may be understood. We place other forms of polyvictimization within the context of elder abuse, recognize frameworks for conceptualizing polyvictimization in later life, and distinguish between polyvictimization at younger ages and polyvictimization in later life. The paper concludes with implications of the framework for research, practice, and policy. PMID- 28910207 TI - Challenges of Using Probabilistic Linkage Methodology to Characterize Post Cardiac Arrest Care in Michigan. AB - BACKGROUND: To improve survival of patients resuscitated from out of hospital cardiac arrest (OCHA), data is needed to assess and improve inpatient post resuscitation care. Our objective was to apply probabilistic linkage methodology to link EMS and inpatient databases and evaluate whether it may be used to describe post-arrest care in Michigan. METHODS: We performed a retrospective study to describe post-cardiac arrest care in adult OHCA patients who were transported to Michigan hospitals from July 1, 2010, to June 30, 2013. Using probabilistic linkage methodology we linked two databases, the Michigan EMS Information System (MI_EMSIS) and the Michigan Inpatient Database (MIDB), which describes inpatient care and outcome of all admissions. Rates of case incidence and survival were compared to published literature. We compared the linked dataset to existing cardiac arrest databases from three counties to evaluate the quality of this linkage. RESULTS: Multiple iterations of match strategies were used to create a linked EMS-inpatient dataset. There were 12,838 MI_EMSIS cardiac arrest records of which 1,977 were matched with MIDB records, identifying them as surviving to hospital admission. Of these 590 (30.0%) survived to hospital discharge. The annual survival incidence/100,000 population to admission was 6.93/100,000 and survival incidence to discharge was 2.1/100,000. The matched dataset was compared to county databases identified a limited sensitivity [48.2%, 95% CI 42.1%-55.3%)] and positive predictive value [64.4%, 95% CI 56.8%-71.3%)]. CONCLUSION: Use of the MI_EMSISEMS database and the Michigan Inpatient database was feasible and produced rates of cardiac arrest admission and survival rates similar to published literature. This process yielded a limited match compared to existing county cardiac arrest databases. We conclude that such a linked dataset is useful for descriptive purposes but not as a population based dataset to evaluate statewide post-cardiac arrest care. PMID- 28910208 TI - Immunohistochemical and immunocytochemical findings associated with Marek's disease virus in naturally infected laying hens. AB - We compared immunohistochemical (IHC) staining of tissue sections of liver, kidney, spleen, lung, proventriculus, sciatic nerve, bursa of Fabricius, brain, heart, intestine and skin; immunocytochemical (ICC) staining of peripheral blood samples and touch preparations of liver, spleen and kidney of laying hens naturally infected with Marek's disease (MD) virus. We used one hundred and fifty 5-17-week-old commercial hens. IHC and ICC staining were performed using polymer based techniques. IHC staining exhibited mostly free immunopositive reactions in tumor cells and in the cytoplasm of the parenchymal cells of liver, kidney, spleen and bursa of Fabricius. In the sciatic nerve, severe reactions were observed in the cytoplasm of plasma and MD cells in the lymphoproliferative areas. Pronounced staining was found in the lymphoid cells in the medulla of intrafollicular regions in the bursa of Fabricius. Although immunostaining was observed in the liver and spleen touch preparations, there was no staining in the kidneys and peripheral blood cell samples. The presence of virus in the tissue and peripheral blood samples and in touch preparations was compared immunohistochemically and immunocytochemically. IHC and ICC techniques were helpful for diagnosis of MD. Peripheral blood samples are inappropriate for field conditions and natural infections. PMID- 28910210 TI - Gender Differences in Nonprescribed Psychostimulant Use in Young Adults. AB - BACKGROUND: In order to better understand the recent rise in nonprescribed use of psychostimulants on college campuses, motives, outcomes, and acceptability of nonprescribed psychostimulants have been evaluated. Despite knowledge that students use nonprescribed medical stimulants for improved academic performance and recreational use, gender differences in these motives have not been examined, despite the fact that the social construction of gender may well affect motives for use. OBJECTIVES: The goal of the present study was to examine gender differences in motives, outcomes, and acceptability of nonprescribed psychostimulant use. METHODS: 2716 undergraduates (1448 male) between the ages of 17 and 57 years (M = 19.43 years, SD = 1.7 years) completed an online survey examining subjective motives of nonprescribed psychostimulant use, as well as behaviors after use and moral views of nonprescribed use. RESULTS: Consistent with hypotheses and known gender differences in social motivation, results suggested that while females are more likely to use nonprescribed psychostimulants for reasons related to schoolwork, males are typically more likely to use psychostimulants for reasons related to partying and socializing. Additional gender differences were that males are more likely to take part in other risky behaviors after use of psychostimulants, as well as view nonprescribed use as more moral and less physically dangerous than females. Conclusions/Importance: This work suggests that there are striking gender differences in motivation and outcomes of use of nonprescribed psychostimulants, which may have implications for personalized approaches for prevention of nonprescribed psychostimulant use on campuses based on gender. PMID- 28910209 TI - Effects of Treatment Type on Alcohol Consumption Partially Mediated by Alcoholics Anonymous Attendance. AB - BACKGROUND: As insurance coverage, funding sources and venues for drug and alcohol treatment evolve in the United States, it is important to assess how the type of treatment received may impact long-term outcomes. The current study aims were to examine effects of treatment type on alcohol consumption in the year after treatment intake and to test mediators of effects of treatment type on later alcohol use. METHODS: Longitudinal data from clients in inpatient and outpatient alcohol treatment programs in California (n = 560) were used in ordinary least squares path analysis adjusting for respondent characteristics typically associated with both treatment completion and alcohol use. The primary outcome was amount of alcohol consumed in the 12 months after treatment entry; hypothesized mediators were treatment duration and participation in Alcoholics Anonymous (AA). RESULTS: Despite higher baseline problem severity and a shorter treatment duration, inpatient clients consumed less alcohol after treatment than outpatient clients (B [95% CI] = -0.95 [-1.67, -0.23]). AA involvement was a significant mediator of the relationship between treatment type and alcohol consumption, with inpatient clients being more involved in AA and also drinking less after treatment than outpatient clients; the bias-corrected bootstrap 95% confidence interval for the indirect effect (B = -0.20) was entirely below zero ( 0.43 to -0.05). CONCLUSIONS: Outpatient clients may benefit from customized posttreatment recommendations to identify additional resources to assist in the recovery process during the first year after treatment. PMID- 28910212 TI - Feasibility of Paramedic Performed Prehospital Lung Ultrasound in Medical Patients with Respiratory Distress. AB - OBJECTIVE: Prehospital ultrasound is not yet widely implemented. Most studies report on convenience samples and trauma patients, often by prehospital physicians or critical care clinicians. We assessed the feasibility of paramedic performed prehospital lung ultrasound in medical patients with respiratory distress. METHODS: Paramedics at 2 ambulance stations in the city of Pittsburgh, Pennsylvania, USA underwent a 2-hour training session in prehospital lung ultrasound using the SonoSite iViz, a handheld ultrasound device. Emergency medical services (EMS) command center (EMS-CC) physicians were instructed in the interpretation of lung ultrasound images. Paramedics enrolled patients presenting with signs and symptoms of respiratory distress over a 3-month period. The ultrasound exam included anterior and lateral views from both sides of the chest. Images were transmitted wirelessly using a mobile hotspot device and uploaded into an online image archiving system. Images were interpreted remotely by the EMS-CC physicians, and 2 expert sonographers provided an overread. We assessed agreement between EMS-CC physicians and experts, as well as between chart-review derived ED diagnosis and both EMS-CC physician and expert interpretation. We defined four a priori hypotheses that would need to be met for the intervention to be considered "feasible." RESULTS: A total of 34 of 78 (43.6%) eligible patients had an ultrasound exam completed. Image transmission was successful in 25 (73.5%) of cases where ultrasound was performed. The primary reason for not enrolling an otherwise eligible patient was equipment failure (25.0%), followed by patient acuity and patient refusal (18.2% each). A total of 20 (58.8%) completed scans were deemed uninterpretable upon expert review. Agreement between EMS physicians and experts was poor. Agreement between EMS-CC physicians and ED diagnosis, as well as between experts and ED diagnosis, was fair. The predetermined thresholds for feasibility were not met. CONCLUSIONS: Paramedic performed prehospital lung ultrasound for patients with respiratory distress and remote interpretation by EMS physicians did not meet the predetermined thresholds to be considered "feasible" in a real-world environment with currently available technologies. This study identified important barriers to the implementation of prehospital lung ultrasound, which should be addressed in future studies. PMID- 28910211 TI - Establishment of CMab-43, a Sensitive and Specific Anti-CD133 Monoclonal Antibody, for Immunohistochemistry. AB - CD133, also known as prominin-1, was first described as a cell surface marker on early progenitor and hematopoietic stem cells. It is a five-domain transmembrane protein composed of an N-terminal extracellular tail, two small cytoplasmic loops, two large extracellular loops containing seven potential glycosylation sites, and a short C-terminal intracellular tail. CD133 has been used as a marker to identify cancer stem cells derived from primary solid tumors and as a prognostic marker of gliomas. Herein, we developed novel anti-CD133 monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. We expressed the full length of CD133 in LN229 glioblastoma cells, immunized mice with LN229/CD133 cells, and performed the first screening using flow cytometry. After limiting dilution, we established 100 anti-CD133 mAbs, reacting with LN229/CD133 cells but not with LN229 cells. Subsequently, we performed the second and third screening with Western blot and immunohistochemical analyses, respectively. Among 100 mAbs, 11 strongly reacted with CD133 in Western blot analysis. One of 11 clones, CMab-43 (IgG2a, kappa), showed a sensitive and specific reaction against colon cancer cells, warranting the use of CMab-43 in detecting CD133 in pathological analyses of CD133 expressing cancers. PMID- 28910214 TI - Outcome Trajectories and Prognostic Factors for Suicide and Self-Harm Behaviors in Patients With Borderline Personality Disorder Following One Year of Outpatient Psychotherapy. AB - This study examined suicide and self-harm trajectories in 180 individuals with BPD receiving dialectical behavior therapy or general psychiatric management in a randomized controlled trial. Suicide and self-harm behaviors were assessed at baseline, every four months throughout treatment, and every 6 months over 2 years of follow-up. Latent class growth mixture modeling identified suicide and self harm trajectories. Multinomial logistic regression analyses examined baseline patient characteristics. Three latent subgroups were identified. The largest responded rapidly to treatment and sustained a favorable response post-discharge. The second progressed slowly during treatment but achieved and maintained a favorable response. A third subgroup showed a rapid favorable response during treatment, however symptoms returned to near baseline levels post-discharge. This third subgroup had higher baseline depression, emergency department visits, and unemployment. BPD patients with high baseline health care utilization, depression, and unemployment may benefit from modifications to treatment specifically targeting these issues. PMID- 28910215 TI - Substance Misuse Is Associated With Increased Psychiatric Severity Among Treatment-Seeking Individuals With Borderline Personality Disorder. AB - Despite high prevalence rates of concurrent borderline personality disorder (BPD) and substance use disorders (SUDs), little is known about the impact of substance misuse on the presentation of BPD. Sixty-five individuals with BPD were assessed at intake and at 3- and 6-month follow-up. Assessment included validated instruments such as the Addiction Severity Index and the Revised Symptom Checklist (SCL-90-R). Over half (58.5%) of individuals entering treatment were currently misusing substances. Substance misuse was associated with more legal and employment problems, greater mood disturbance, impulsivity, and psychiatric severity, including almost all SCL-90-R subscales. For the majority of patients (58%), there was little change in substance misuse post-treatment. The high prevalence of substance misuse and its association with psychiatric severity among individuals with BPD suggest that substance misuse should be a targeted behavior during treatment, and further specialized interventions are needed for individuals with comorbid BPD and SUD. PMID- 28910216 TI - Psychopathy in the Medical Emergency Department. AB - Psychopathy is a personality disorder representing an admixture of a fearless and dominant temperament with an impulsive and antisocial orientation. A sample of 1,026 participants in the waiting room of the medical emergency department of a city hospital exhibited levels of fearless dominance similar to university undergraduates and federal inmates; their levels of impulsive antisociality fell between those of federal and state inmates. Both psychopathy factors were correlated with male gender, younger age, and more frequent average alcohol consumption. Fearless dominance was associated with agentic success (e.g., being employed, higher household income), fewer psychological problems, and less use of psychotropic medications, including anxiolytics. Impulsive antisociality was negatively related to both agentic and communal (e.g., ever being married) success and positively correlated with substance use and self-reported bipolar, ADHD, and psychotic psychiatric conditions. Further, only impulsive antisociality was associated with presenting to the emergency department for physical injury or psychological disturbance. PMID- 28910217 TI - Substance and Evaluation in Personality Disorder Diagnoses. AB - Like person judgments in everyday life, diagnoses of personality disorders (PDs) reflect at least two influences: first, the actual characteristics of the target person (substance), and second, the more positive or negative view that the perceiver has of the target person (evaluation). In this article, we present a systematic account of substance and evaluation in PD diagnoses, using a modified version of Brunswik's (1956) lens model. An empirical study shows that the items of the alternative DSM-5 model for personality disorders (AMPD) are in fact saturated with evaluation, that this evaluation is largely the same as "social desirability," and that the two mandatory components of the AMPD (criterion A and B) are not easily distinguishable from one another in that regard. We provide concrete recommendations as to how the conceptual clarity of PD diagnostics may be improved, by distinguishing people's personality dispositions from their (likely) long-term consequences. PMID- 28910213 TI - The Challenge of Transforming the Diagnostic System of Personality Disorders. AB - While the DSM-5 alternative model of personality disorder (PD) diagnosis allows the field to systematically compare categorical and dimensional classifications, the ICD-11 proposal suggests a radical change by restricting the classification of PDs to one category, deleting all specific types, basing clinical service provision exclusively upon a severity dimension, and restricting trait domains to secondary qualifiers without defining cutoff points. This article reflects broad international agreement about the state of PD diagnosis. It is argued that diagnosis according to the ICD-11 proposal is based on broad, potentially stigmatizing descriptions of impaired functioning and ignores much of the impressive body of research and treatment guidelines that have advanced the care of adults and adolescents with borderline and other PDs. Before radically changing classification, which highly impacts the provision of health care, head to-head field trials coupled with the views of patients as well as thorough debate among scientists are urgently needed. PMID- 28910218 TI - The Weight Game: Fighting Childhood Obesity with Childhood Video Technology. PMID- 28910219 TI - With a Worthless Services Hammer, Everything Looks Like a Nail: Litigating Quality of Care Under the False Claims Act. PMID- 28910220 TI - Founders Series Interview with Dr. Cyril Wecht. PMID- 28910221 TI - Net Neutrality and a Fast Lane for Health. PMID- 28910223 TI - Pigments and Vaccines: Evaluating the Constitutionality of Targeting Melanin Groups for Mandatory Vaccination. PMID- 28910222 TI - Restricted Access: State Medicaid Coverage of Sofosbuvir Hepatitis C Treatment. AB - Chronic hepatitis C (HCV) infection can persist for decades without symptoms. Many Americans are unaware of their infection status and are not receiving necessary care and treatment. This places them at greater risk for severe, even fatal, complications from the disease and increases the likelihood that they will transmit the virus to others. In late 2013, the Food and Drug Administration approved a direct acting antiviral drug called sofosbuvir to treat chronic HCV infection. Sofosbuvir is a highly effective, but very expensive, curative treatment for HCV. Unfortunately, the high price of sofosbuvir has led payers, including Medicaid, to restrict patient access. Looking at the sheer cost of the HCV crisis facing the United States, particularly among minority communities, it is a critical time to invest in prevention, screening, and treatment. These pharmaceutical treatments have the potential to cure HCV, eliminate the virus, and mitigate future health care expenses. This article argues that restricting access to this pharmaceutical treatment may be a discriminatory practice under both Medicaid law and the Affordable Care Act (ACA). In addition to potential legal challenges, there are strong economic and public health imperatives to removing barriers to HCV treatment. PMID- 28910224 TI - An Ethical Analysis of Euthanasia and Physician-Assisted Suicide: Rejecting Euthanasia and Accepting Physician Assisted Suicide with Palliative Care. PMID- 28910225 TI - Direct Primary Care Business of Insurance and State Law Considerations. PMID- 28910226 TI - The Bacterial Renaissance: A Supply-Side Answer to the Icarus Paradox of Antibiotic Usage Undermining Its Own Usefulness. PMID- 28910227 TI - Swipe Right for Health Care: How the State May Decide the Future of the mHealth App Industry in the Wake of FDA Uncertainty. PMID- 28910228 TI - Addressing Inadequate Federal Legislation Concerning Viral Disasters: A Hard Look at the Emergency Treatment and Active Labor Act. PMID- 28910229 TI - Special Delivery: Pushing for Pregnant Workers Fairness Rights. PMID- 28910230 TI - Educational Attainment and Personality Are Genetically Intertwined. AB - Heritable variance in psychological traits may reflect genetic and biological processes that are not necessarily specific to these particular traits but pertain to a broader range of phenotypes. We tested the possibility that the personality domains of the five-factor model and their 30 facets, as rated by people themselves and their knowledgeable informants, reflect polygenic influences that have been previously associated with educational attainment. In a sample of more than 3,000 adult Estonians, education polygenic scores (EPSs), which are interpretable as estimates of molecular-genetic propensity for education, were correlated with various personality traits, particularly from the neuroticism and openness domains. The correlations of personality traits with phenotypic educational attainment closely mirrored their correlations with EPS. Moreover, EPS predicted an aggregate personality trait tailored to capture the maximum amount of variance in educational attainment almost as strongly as it predicted the attainment itself. We discuss possible interpretations and implications of these findings. PMID- 28910231 TI - Professionals' Attitude Toward Reporting Child Sexual Abuse in Saudi Arabia. AB - Child sexual abuse (CSA) requires specialized knowledge and training that includes forensic interview skills. The aim of this study was to determine variations in professionals' attitudes toward CSA by measuring three aspects of forensic attitudes (sensitivity, specificity, and skepticism) and evaluating disagreements concerning the assessment of CSA cases in Saudi Arabia. A cross sectional, web-based study, in which the Child Forensic Attitude Scale was used to measure professionals' attitudes, was conducted. Professionals who dealt with suspected cases of CSA as part of their jobs or were in professions that necessitated involvement with such cases, were selected as participants. Of 327 participants, 53% were aged <=40 years, and 54% were men. In addition, 24% were doctors/nurses, 20% were therapists/psychiatrists, 24% were social workers, 17% were educators, 9% were law enforcement professionals, and 5% were medical examiners. Attitude subscale scores differed significantly according to participants' sex, specialty, and training. Women, healthcare professionals, and those who had participated in more than five training courses were more concerned about the underreporting of abuse (high sensitivity) relative to other professionals. In comparison, men, medical examiners, law enforcement officers, and undertrained professionals tended to underreport suspected sexual abuse cases (high specificity). High specificity in attitudes toward suspected cases of CSA could affect professionals' judgment and contribute to low reporting rates. Certain strategies, including increasing self-awareness of personal bias, specific CSA recognition courses, and team approaches to case assessment and management, should be implemented to control the influence of subjective factors. PMID- 28910232 TI - Characterizing Blunt Use Among Twitter Users: Racial/Ethnic Differences in Use Patterns and Characteristics. AB - BACKGROUND: Young adult Twitter users are exposed to and often participate in tweets that promote risky behaviors, such as blunt use. Blunts are hollowed out cigars or cigarillos that are filled with marijuana. OBJECTIVES: The current study was designed to determine the use patterns and characteristics of African American, Hispanic and White young adult Twitter users who reported past month blunt use. METHODS: Young adults (N = 753, 74% male) who reported past month blunt use were recruited via Twitter to participate in a brief anonymous online survey about their blunt use. RESULTS: Findings revealed that African American young adults initiated blunt smoking at an earlier age (14.8 years), reported more days of blunt smoking in the past month (23.2 days) and smoked more blunts in the past month (27.2 blunts) than their Hispanic (16.5 years, 19.7 days, and 15.4 blunts) and White (18.1 years, 15.8 days, and 22.2 blunts) counterparts, p <.01. African American young adults were more likely than their White counterparts to report physical craving as an obstacle to quitting blunt smoking. Several racial/ethnic differences were also found on attitudes about blunt use and reasons for initiating and continuing to smoke blunts. CONCLUSIONS: Findings suggest that blunt use patterns and attitudes about blunt use vary by race/ethnicity. Understanding racial/ethnic differences in blunt use patterns and characteristics offers opportunities to tailor future interventions and enhance outcomes among African American, Hispanic and White young adults. PMID- 28910233 TI - Effects of Supplementation with Beef or Whey Protein Versus Carbohydrate in Master Triathletes. AB - OBJECTIVE: The present study compares the effect of ingesting hydrolyzed beef protein, whey protein, and carbohydrate on performance, body composition (via plethysmography), muscular thickness, and blood indices of health, including ferritin concentrations, following a 10-week intervention program. METHODS: After being randomly assigned to one of the following groups-beef, whey, or carbohydrate-24 master-age (35-60 years old) male triathletes (n = 8 per treatment) ingested 20 g of supplement mixed with plain water once a day (immediately after training or before breakfast). All measurements were performed pre- and postinterventions. RESULTS: Only beef significantly reduced body mass (p = 0.021) along with a trend to preserve or increase thigh muscle mass (34.1 +/- 6.1 vs 35.5 +/- 7.4 mm). Both whey (38.4 +/- 3.8 vs 36.9 +/- 2.8 mm) and carbohydrate (36.0 +/- 4.8 vs 34.1 +/- 4.4 mm) interventions demonstrated a significantly (p < 0.05) decreased vastus medialis thickness Additionally, the beef condition produced a significant (p < 0.05) increase in ferritin concentrations (117 +/- 78.3 vs 150.5 +/- 82.8 ng/mL). No such changes were observed for the whey (149.1 +/- 92.1 vs 138.5 +/- 77.7 ng/mL) and carbohydrate (149.0 +/- 41.3 vs 150.0 +/- 48.1 ng/mL) groups. Furthermore, ferritin changes in the beef group were higher than the modification observed in whey (p < 0.001) and carbohydrate (p = 0.025) groups. No differences were found between whey and carbohydrate conditions (p = 0.223). No further changes were observed. CONCLUSION: Ingesting a hydrolyzed beef protein beverage after workout or before breakfast (nontraining days) can be effective in preserving thigh muscle mass and in improving iron status in male master-age triathletes. PMID- 28910234 TI - Relative Effects of Forward and Backward Planning on Goal Pursuit. AB - Considerable research has shown that planning plays an important role in goal pursuit. But how does the way people plan affect goal pursuit? Research on this question is scarce. In the current research, we examined how planning the steps required for goal attainment in chronological order (i.e., forward planning) and reverse chronological order (i.e., backward planning) influences individuals' motivation for and perceptions of goal pursuit. Compared with forward planning, backward planning not only led to greater motivation, higher goal expectancy, and less time pressure but also resulted in better goal-relevant performance. We further demonstrated that this motivational effect occurred because backward planning allowed people to think of tasks required to reach their goals more clearly, especially when goals were complex to plan. These findings suggest that the way people plan matters just as much as whether or not they plan. PMID- 28910236 TI - Quantitative Responses of Adult Zebrafish to Changes in Ambient Illumination. AB - The use of zebrafish models to study central nervous system aging and late-onset neurological diseases will be facilitated by assays allowing rapid evaluation of neurological phenotypes in adult zebrafish. We analyzed groups of 12 adult zebrafish swimming simultaneously in single-animal arenas, and quantified their responses to changes in ambient illumination. Under these conditions, stereotypical locomotor patterns were observed and readily quantified using open source software. Continuous, low-velocity movements were observed during 10-min periods of darkness, whereas intermittent high-velocity movements occurred in bright light. At 80%-90% of abrupt light-to-dark or dark-to-light transitions, adult zebrafish produced a synchronous short-latency (20-22 ms) turn, followed by a propulsive movement with a high transient maximum velocity (400-500 mm/s). Between 5 and 35 months of age, latency increased by ~10%, and peak velocity decreased by ~30%, suggesting that the response declines in aged adults. Light transition responses can be measured rapidly and automatically in multiple adult zebrafish simultaneously, providing a convenient quantitative method for evaluating sensorimotor function in adult zebrafish models of neurological disease. PMID- 28910238 TI - Telemanagement of Heart Failure Patients Across the Post-Acute Care Continuum. AB - BACKGROUND: Heart failure (HF) is a chronic condition causing nearly 1 million hospital admissions annually in the United States with 25% of patients rehospitalized within 30 days. INTRODUCTION: The purpose of this study was to investigate whether telemanagement of HF patients throughout the post-acute continuum of care would reduce rehospitalization rates and improve patient self care knowledge and satisfaction. MATERIALS AND METHODS: HF patients discharged to a skilled nursing facility (SNF) received telemanagement by HF clinicians with opportunity for continuation at home with assistance of home healthcare (HHC) nurses. Wireless sensors worn at SNF and home captured continuous health information visible to HF clinicians on secure cloud database. Point-of-care devices were available at SNF. Patients had scheduled and as-needed video visits with audio and auscultation capacity with HF clinician. HF education was provided by SNF and HHC nursing. Patients were compared with historical control group receiving standard care at same SNF. RESULTS: Patients receiving telemanagement had 29% lower rehospitalization rates (17% vs. 24%), despite higher predicted rehospitalization risk. Median age was 81. Seven of eight patients who were rehospitalized in the telemanagement group had advanced HF symptoms (New York Heart Association Class IV). Five patients in telemanagement group were receiving continuous inotrope infusions. Patients reported good satisfaction and self-care knowledge. DISCUSSION: Reduction of rehospitalization rates was clinically significant in population of advanced age and HF symptoms. Technology enhanced communication content and timeliness across the post-acute care continuum. CONCLUSION: Post-acute telemanagement may reduce rehospitalization rates even in high-risk, older HF populations. PMID- 28910239 TI - Social Epidemiology in HIV/AIDS: What Else Should We Consider to Prevent the HIV/AIDS Progression? AB - More than 35 years after the description of the first cases of a new immunodeficiency syndrome that was named AIDS, health care providers hardly have a global perspective of those factors that coexist with this syndrome and also contribute to immunosupression and progression of disease. This report presents some of these factors (drug use, nutrition, psychological conditions, socioeconomic factors) to propose some areas of research and intervention strategies that could prevent the progression of HIV/AIDS. PMID- 28910240 TI - Special section on dental public health: A collaboration between the Canadian Journal of Public Health and the Canadian Association of Public Health Dentistry. PMID- 28910241 TI - Indigenous oral health inequity: An Indigenous provider perspective. PMID- 28910242 TI - How does the social "get under the gums"? The role of socio-economic position in the oral-systemic health link. AB - OBJECTIVES: To evaluate the extent of association between systemic inflammation and periodontal disease in American adults, and to assess whether socio-economic position mediated this relationship. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES IV) (2001-2010). Systemic inflammation was defined by individual and aggregate (cumulative inflammatory load) biomarkers (C-reactive protein, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio). Loss of attachment and bleeding on probing were used to define periodontal disease. Poverty:income ratio and education were indicators of socio-economic position. Covariates included age, sex, ethnicity, smoking, alcohol, and attendance for dental treatment. Univariate and multivariable logistic regressions were constructed to assess the relationships of interest. RESULTS: In a total of 2296 respondents, biomarkers of systemic inflammation and cumulative inflammatory load were significantly associated with periodontal disease after adjusting for age, sex, and behavioural factors. Socio economic position attenuated the association between markers of systemic inflammation and periodontal disease in the fully adjusted model. CONCLUSION: Socio-economic position partly explains how systemic inflammation and periodontal disease are coupled, and may thus have a significant role in the mechanisms linking oral and non-oral health conditions. It is of critical importance that the social and living conditions are taken into account when considering prevention and treatment strategies for inflammatory diseases, given what appears to be their impactful effect on disease processes. PMID- 28910243 TI - Fluoride exposure and reported learning disability diagnosis among Canadian children: Implications for community water fluoridation. AB - OBJECTIVES: Recent studies have connected increased fluoride exposure with increased risk of neurodevelopmental-related outcomes, such as ADHD (attention deficit hyperactivity disorder) and lower IQ in children. Our primary objective was to examine the association between fluoride exposure and reported diagnosis of a learning disability among a population-based sample of Canadian children aged 3-12 years. METHODS: We analyzed data from Cycles 2 and 3 of the Canadian Health Measures Survey. Four measures of fluoride exposure were available: 1) urinary fluoride (MUmol/L), 2) creatinine-adjusted urinary fluoride (MUmol/mmol), 3) specific gravity-adjusted urinary fluoride (MUmol/L), and 4) fluoride concentration of tap water (mg/L) (Cycle 3 only). Diagnosis of a learning disability (yes/no) was based on parental- or self-report. Associations were examined using logistic regression (where possible), unadjusted and adjusted for covariates. RESULTS: When Cycles 2 and 3 were examined separately, reported learning disability diagnosis was not significantly associated with any measure of fluoride exposure in unadjusted or adjusted models. When Cycles 2 and 3 were combined, a small but statistically significant effect was observed such that children with higher urinary fluoride had higher odds of having a reported learning disability in the adjusted model (p = 0.03). However, the association was not observed in models that used creatinine-adjusted urinary fluoride and specific gravity-adjusted urinary fluoride, which are believed to be more accurate measures due to their correction for urinary dilution. CONCLUSION: Overall, there did not appear to be a robust association between fluoride exposure and parental- or self-reported diagnosis of a learning disability among Canadian children. PMID- 28910244 TI - Inequalities in oral health: Understanding the contributions of education and income. AB - OBJECTIVE: To quantify the extent to which income and education explain gradients in oral health outcomes. METHODS: Using data from the Canadian Community Health Survey (CCHS 2003), binary logistic regression models were constructed to examine the relationship between income and education on self-reported oral health (SROH) and chewing difficulties (CD) while controlling for age, sex, ethnicity, employment status and dental insurance coverage. The relative index of inequality (RII) was utilized to quantify the extent to which income and education explain gradients in poor SROH and CD. RESULTS: Income and education gradients were present for SROH and CD. From fully adjusted models, income inequalities were greater for CD (RIIinc = 2.85) than for SROH (RIIinc = 2.75), with no substantial difference in education inequalities between the two. Income explained 37.4% and 42.4% of the education gradient in SROH and CD respectively, whereas education explained 45.2% and 6.1% of income gradients in SROH and CD respectively. Education appears to play a larger role than income when explaining inequalities in SROH; however, it is the opposite for CD. CONCLUSION: In this sample of the Canadian adult population, income explained over one third of the education gradient in SROH and CDs, whereas the contribution of education to income gradients varied by choice of self-reported outcome. Results call for stakeholders to improve affordability of dental care in order to reduce inequalities in the Canadian population. PMID- 28910245 TI - Trends in emergency department visits for non-traumatic dental conditions in Ontario from 2006 to 2014. AB - OBJECTIVE: In Canada, non-traumatic dental conditions (NTDCs) presenting in emergency departments (EDs) are dealt with by non-dental professionals who are generally not equipped to deal with such emergencies, resulting in an inefficient usage of heath care resources. This study aimed to assess the burden of ED visits for NTDCs in Ontario by observing trends from 2006 to 2014. METHODS: Aggregate data for Ontario were obtained from the Canadian Institute for Health Information's National Ambulatory Care Reporting System. Data were examined for the whole of Ontario and stratified by 14 Local Health Integration Networks. Descriptive analysis was conducted for both number of people and number of visits, stratified by sex and age groups (0-5, 6-18, 19-64, and 65+ years). Numbers were also examined by neighbourhood stratifications, including urban/rural, income quintile and immigrant tercile. RESULTS: Over the study period, an upward trend of visiting EDs for NTDCs was observed. Approximately 403 628 people in Ontario made 482 565 visits over the period of nine years. On average, 341 per 100 000 people, per year, visited. Young children, people living in neighbourhoods with lower income and higher immigrant concentration, and people living in the rural regions, visited EDs more for NTDCs during 2006-2014. CONCLUSION: The upward and inequitable trends of utilization of EDs for NTDCs reinforce recognition of the important need for both universal and targeted approaches for primary prevention of dental conditions. To enhance equitable access to dental care, policy advocacy is required for publicly funding essential and emergency dental services for all. PMID- 28910246 TI - Waiting room time: An opportunity for parental oral health education. AB - OBJECTIVES: The UBC Children's Dental Program (CDP) has provided free dental treatments to underserved low-income children, but its preventive component needs to be enhanced. The study aims were: 1) to develop a "waiting-room based" dental education program engaging caregivers of these children, and 2) to assess the program's feasibility, acceptability and effectiveness. METHODS: In preparation, a situational analysis (SA) included structured interviews with caregivers, and with various stakeholders (e.g., dental students, instructors, health authority) involved in the CDP program. Based on the SA, caregiver-centered education was designed using an interactive power point presentation; after the presentation, each caregiver set personalized goals for modifying his/her child's dental behaviours. Evaluation of the program was done with follow-up telephone calls; the program's effectiveness was assessed by comparing before/after proportions of caregivers brushing their child's teeth, children brushing teeth in the morning and evening, children eating sugar-containing snacks, and children drinking sugar containing drinks. RESULTS: The program proved to be easy to implement (feasible) and the recruitment rate was 99% (acceptable). The follow-up rate was 81%. The SA identified that the caregivers' knowledge about caries etiology and prevention was limited. All recruited caregivers completed the educational session and set goals for their family. The evaluation demonstrated an increase in caregiver reported short-term diet and oral self-care behaviours of their children. CONCLUSION: A dental education program engaging caregivers in the waiting room was a feasible, acceptable and promising strategy for improving short-term dental behaviours of children. PMID- 28910247 TI - Pediatric ambulatory care sensitive conditions: Birth cohorts and the socio economic gradient. AB - OBJECTIVES: This study examines the socio-economic gradient in utilization and the risk factors associated with hospitalization for four pediatric ambulatory care sensitive conditions (dental conditions, asthma, gastroenteritis, and bacterial pneumonia). Dental conditions, where much care is provided by dentists and insurance coverage varies among different population segments, present special issues. METHODS: A population registry, provider registry, physician ambulatory claims, and hospital discharge abstracts from 28 398 children born in 2003-2006 in urban centres in Manitoba, Canada were the main data sources. Physician visits and hospitalizations were compared across neighbourhood income groupings using rank correlations and logistic regressions. RESULTS: Very strong relationships between neighbourhood income and utilization were highlighted. Additional variables - family on income assistance, mother's age at first birth, breastfeeding - helped predict the probability of hospitalization. Despite the complete insurance coverage (including visits to dentists and physicians and for hospitalizations) provided, receiving income assistance was associated with higher probabilities of hospitalization. CONCLUSIONS: We found a socio-economic gradient in utilization for pediatric ambulatory care sensitive conditions, with higher rates of ambulatory visits and hospitalizations in the poorest neighbourhoods. Insurance coverage which varies between different segments of the population complicates matters. Providing funding for dental care for Manitobans on income assistance has not prevented physician visits or intensive treatment in high-cost facilities, specifically treatment under general anesthesia. When services from one type of provider (dentist) are not universally insured but those from another type (physician) are, using rates of hospitalization to indicate problems in the organization of care seems particularly difficult. PMID- 28910248 TI - Parents' online discussions about children's dental caries: A critical content analysis. AB - OBJECTIVES: Through an analysis of postings to an online parenting forum, we aimed to explore the many ways in which parents orient to (i.e., take up, challenge, re-articulate) information about child dental health in the context of their online interactions. Our analysis is anchored in Nettleton's theoretical work on dental authority and power, which we apply in a digital context. METHODS: We examined discussion threads from the public online forums on BabyCenter Canada. We identified relevant threads using the site search function and keywords related to dental health, with a focus on dental caries (tooth decay), related care behaviours (e.g., toothbrushing), and the controversial issue of fluoride. Following descriptive content coding, we applied a critical lens to unpack themes related to expert knowledge, gender and parenting online cultures. RESULTS: We analyzed 479 relevant threads. Our findings focus on two central themes: the tension between parents' views and those of dental health professionals; and, the gendered, cultural roles and expectations that position mothers as primarily responsible for the care of children's dental health. Though these themes are not new, our findings show that they persist in the digital context where social divisions (e.g., expert/non-expert) may be blurred. CONCLUSIONS: Our analysis of online discussions provides an opportunity to think critically about ways in which parents engage with public health, in digital contexts. Although some mothers express disconnect when communicating with dental professionals, they are very engaged and concerned with dental health issues for their children. A challenge for dental public health is to find ways to shift perspective towards recognizing that the target population is empowered and already engaged in discussions of research evidence and clinical encounters on their own terms, facilitated by an online context. PMID- 28910249 TI - Redirecting public oral health fluoride varnish intervention to low socio economic status children in Alberta. AB - SETTING: Dental decay is most prevalent among low socio-economic status (SES) groups where cost limits access to dental care. To address inequities in oral health outcomes, Alberta Health Services (AHS) Oral Health Action Plan encompasses a population health approach that redirects fluoride varnish (FV) applications to low SES children. Using low SES measures to establish the eligibility criteria is fundamental to the delivery of FV applications to the target population. INTERVENTION: A series of four FV applications over two years is directed to children age 12-35 months and two applications per year to children in Kindergarten and grades 1 and 2, using low SES measures for eligibility criteria. The provincial objective for children receiving the first FV application is 10%-20% of the population age. Additional objectives are set for rates of subsequent FV applications for each population group. OUTCOMES: From 2015 to 2016, the rate of first FV applications for eligible target populations is below the provincial objective for children age 12-35 months (5%) and within the objective for children in Kindergarten and grades 1 and 2 (16%). Rates of subsequent FV applications in the school setting are being met. IMPLICATIONS: Encompassing a population health approach to deliver standardized fluoride varnish applications to low SES children better targets inequities in oral health outcomes in Alberta. Challenges of redirecting the FV intervention include creating the eligibility criteria and engaging the target population, particularly for the preschool population. Achieving population objectives are challenged by unequal distribution of resources across the province. PMID- 28910250 TI - The 1% of emergency room visits for non-traumatic dental conditions in British Columbia: Misconceptions about the numbers. AB - In Canada, about 1% of all emergency room (ER) visits in a given year are made by patients with a primary diagnosis of a non-traumatic, non-urgent and yet preventable condition, such as tooth decay. This percentage is typically dismissed as irrelevant. Using 2013-2014 British Columbia data on ER use from the Canadian Institute for Health Information, however, we argue that the 1% figure (and its associated cost) has to be considered beyond its percentage value. In 2013-2014 alone, 12 357 non-traumatic dental visits were made to ERs in BC representing 1% of the total number of ER visits at a cost of $154.8 million to the taxpayers (across Canada, all visits to ER cost $1.8 billion/year). But the vast majority of these dental visits are discharged while the oral problem likely persists, hence taxpayer dollars are wasted. The belief that these dental-related ER visits are insignificant within the total cost for the health care system is misleading: treatment is not given, the problem is not resolved, and yet there is a high cost to taxpayers and to the society at large. Public health resources should be reallocated. PMID- 28910251 TI - Therapeutic use of cannabis: Prevalence and characteristics among adults in Ontario, Canada. AB - OBJECTIVE: To investigate the prevalence of therapeutic cannabis use within a general population sample of adults and to describe various characteristics associated with use. METHODS: Data were derived from the 2013 and 2014 CAMH Monitor Survey of adults in Ontario, Canada. This repeated cross-sectional survey employed a regionally stratified design and utilized computer-assisted telephone interviewing. Analyses were based on 401 respondents who reported using cannabis. RESULTS: The data indicated that 28.8% of those who used cannabis in the past year self-reported using cannabis for therapeutic purposes. Of therapeutic users, 15.2% reported having medical approval to use cannabis for therapeutic purposes. Cannabis use for therapeutic purposes was associated with more frequent use of cannabis, a moderate to high risk of problematic cannabis use, and a greater likelihood of using prescription opioids for medical purposes. There was little difference in cannabis use for therapeutic purposes according to sex, age, and marital status after adjusting for opioid use and problematic cannabis use. CONCLUSION: Findings suggest some potential negative consequences of cannabis use for therapeutic purposes; however, further research is needed to better understand the range and patterns of use and their corresponding vulnerabilities. PMID- 28910252 TI - Lifetime excess cancer risk due to carcinogens in food and beverages: Urban versus rural differences in Canada. AB - OBJECTIVES: To explore differences in urban versus rural lifetime excess risk of cancer from five specific contaminants found in food and beverages. METHODS: Probable contaminant intake is estimated using Monte Carlo simulations of contaminant concentrations in combination with dietary patterns. Contaminant concentrations for arsenic, benzene, lead, polychlorinated biphenyls (PCBs) and tetrachloroethylene (PERC) were derived from government dietary studies. The dietary patterns of 34 944 Canadians from 10 provinces were available from Health Canada's Canadian Community Health Survey, Cycle 2.2, Nutrition (2004). Associated lifetime excess cancer risk (LECR) was subsequently calculated from the results of the simulations. RESULTS: In the calculation of LECR from food and beverages for the five selected substances, two (lead and PERC) were shown to have excess risk below 10 per million; whereas for the remaining three (arsenic, benzene and PCBs), it was shown that at least 50% of the population were above 10 per million excess cancers. Arsenic residues, ingested via rice and rice cereal, registered the greatest disparity between urban and rural intake, with LECR per million levels well above 1000 per million at the upper bound. The majority of PCBs ingestion comes from meat, with values slightly higher for urban populations and LECR per million estimates between 50 and 400. Drinking water is the primary contributor of benzene intake in both urban and rural populations, with LECR per million estimates of 35 extra cancers in the top 1% of sampled population. CONCLUSION: Overall, there are few disparities between urban and rural lifetime excess cancer risk from contaminants found in food and beverages. Estimates could be improved with more complete Canadian dietary intake and concentration data in support of detailed exposure assessments in estimating LECR. PMID- 28910253 TI - Characterizing non-monosexual women at risk for poor mental health outcomes: A mixed methods study. AB - OBJECTIVES: Non-monosexual women - those who report attraction to or sexual relationships with individuals of more than one gender - have elevated risk for poor mental health outcomes. We aimed to examine which elements of non-monosexual experience are associated with this elevated risk. METHODS: We conducted a sequential exploratory mixed methods analysis of qualitative interview and survey data from 39 non-monosexual women recruited consecutively through prenatal care providers. Qualitative analyses identified distinguishing features, and quantitative analyses tested associations between these features and mental health symptoms. RESULTS: Nine qualitative themes were identified to describe distinguishing features of non-monosexual women. Of these, current and past five years partner gender, lack of LGBTQ community connection, and low centrality of sexual minority identity were associated with anxiety symptoms. Latent class analysis revealed significantly higher levels of anxiety symptoms among non monosexual women partnered with men relative to those partnered with women. CONCLUSION: Sexual minority women who partner with men may be particularly at risk for poor mental health. Considering this group's invisibility in public health research and practice, interventions are needed to address this disparity. PMID- 28910254 TI - Organizational level indicators to address health equity work in local public health agencies: A scoping review. AB - OBJECTIVE: To determine what organizational level indicators exist that could be used by local Ontario public health agencies to monitor and guide their progress in addressing health equity. METHOD: This scoping review employed Arksey and O'Malley's (2005) six-stage framework. Multiple online databases and grey literature sources were searched using a comprehensive strategy. Studies were included if they described or used indicators to assess an organization's health equity activity. Abstracted indicator descriptions were classified using the roles for public health action identified by the Canadian National Collaborating Centre for Determinants of Health (NCCDH). Health equity experts participated in a consultation phase to examine items extracted from the literature. SYNTHESIS: Eighteen peer-reviewed studies and 30 grey literature reports were included. Abstracted indicators were considered for 1) relevance for organizational assessment, 2) ability to highlight equity-seeking populations, and 3) potential feasibility for application. Twenty-eight items formed the basis for consultation with 13 selected health equity experts. Items considered for retention were all noted to require significant clarification, definition and development. Those eliminated were often redundant or not an organizational level indicator. CONCLUSION: Few evidence-based, validated indicators to monitor and guide progress to address health inequities at the level of the local public health organization were identified. There is a need for continued development of identified indicator items, including careful operationalization of concepts and establishing clear definitions for key terms. PMID- 28910255 TI - Better Strength, Better Balance! Partnering to deliver a fall prevention program for older adults. AB - SETTING: Falls incur significant health and economic costs, particularly among older adults. Physical activity has been found to be the single most important fall prevention behaviour an older adult can do. This manuscript describes Ottawa Public Health's (OPH) experience implementing the Better Strength, Better Balance! (BSBB) program, a fall prevention exercise program for older adults, through an innovative partnership with the local Recreation, Cultural & Facility Services (RCFS) Department. BSBB aims to reach 1300 community-dwelling adults (aged 65 years and older) per year through approximately 86-130 exercise programs. Designed as a universal program, BSBB addresses participation barriers such as transportation, cost and location. BSBB was enabled with funding from the Champlain Local Health Integration Network, and coincided with the implementation of an Older Adult Plan for the City of Ottawa. INTERVENTION: BSBB is a beginner level, fall prevention exercise and education program that takes place twice a week, over 12 weeks. Certified RCFS instructors delivered the exercise components of the program and OPH staff incorporated fall prevention messaging and conducted the evaluation. OUTCOMES: The formative evaluation indicated that participants experienced improved strength and balance, decreased fear of falling and the intent to adopt new fall prevention behaviours following the program. The partnership between OPH and RCFS allowed both partners to leverage their unique and mutual strengths to continually improve the program. IMPLICATIONS: Improving access to strength and balance programming is an important public health strategy to reduce falls. The recreation sector is an ideal partner to help public health in this pursuit. PMID- 28910256 TI - An introduction to the healthy corner store intervention model in Canada. AB - SETTING: The majority of Canadians' food acquisition occurs in retail stores. Retail science has become increasingly sophisticated in demonstrating how consumer environments influence population-level diet quality and health status. The retail food environment literature is new but growing rapidly in Canada, and there is a relative paucity of evidence from intervention research implemented in Canada. INTERVENTION: The healthy corner store model is a comprehensive complex population health intervention in small retail stores, intended to transform an existing business model to a health-promoting one through intersectoral collaboration. Healthy corner store interventions typically involve conversions of existing stores with the participation of health, community, and business sector partners, addressing business fundamentals, merchandising, and consumer demand. OUTCOMES: This article introduces pioneering experiences with the healthy corner store intervention in Canada. First, we offer a brief overview of the state of evidence within and outside Canada. Second, we discuss three urban and one rural healthy corner store initiatives, led through partnerships among community food security organizations, public health units, academics, and business partners, in Manitoba, Ontario, and Newfoundland and Labrador. Third, we synthesize the promising practices from these local examples, including aspects of both intervention science (e.g., refinements in measuring the food environment) and community-based practice (e.g., dealing with unhealthy food items and economic impact for the retailer). IMPLICATIONS: This article will synthesize practical experiences with healthy corner stores in Canada. It offers a baseline assessment of promising aspects of this intervention for health and health equity, and identifies opportunities to strengthen both science and practice in this area of retail food environment work. PMID- 28910257 TI - Between a rock and a hard place: Prescription opioid restrictions in the time of fentanyl and other street drug adulterants. AB - Non-medical prescription opioid use (NMPOU) has increased alarmingly across Canada and resulted in strict prescribing restrictions on opioids. Despite a clear need to reduce opioid prescriptions in response to this crisis, few other policies have been implemented and this singular focus is incongruent with the known characteristics of substance use disorders, negative effects of supply reduction policies, and realities of pain management. Given the recent rise of fentanyl and other dangerous adulterants in street drugs, this commentary argues that a comprehensive response to NMPOU that includes improvements to addiction management and harm-reduction services is urgently needed. PMID- 28910258 TI - Recommendations: Will the Tobacco and Vaping Products Act go far enough? AB - E-cigarette use among adolescents and young adults in Canada is increasing. Potvin's (2016) editorial outlined the need for more evidence on e-cigarettes as a gateway to combustible cigarettes and their toxicity. Since then, new evidence has emerged supporting the gateway effect and establishing toxicity. Health Canada has reviewed the evidence and recently opted to regulate e-cigarettes, including prohibiting brick-and-mortar retail access for youth under 18 years of age. However, many online e-cigarette retailers exist, which increases adolescents' access to e-cigarettes and currently unregulated nicotine-containing refills. Recent evidence on the toxicity of particular compounds in e-cigarette refills has demonstrated how these compounds may be amplified by certain types of e-cigarette devices. The toxicity of e-cigarettes is not only of concern to the user but potentially a concern to the public as well. The message that e cigarettes have a benign effect on users and the public needs to change and should be reflected in Health Canada's future regulations concerning the Tobacco and Vaping Products Act. PMID- 28910259 TI - Estimation of smoking prevalence in Canada: Implications of survey characteristics in the CCHS and CTUMS/CTADS. AB - One of the main enterprises associated with tobacco control is surveillance, that is, to measure and follow over time the extent of smoking among the Canadian population. While surveillance systems have been in place for more than 50 years, knowing the exact prevalence of smoking in Canada continues to be a complex matter and understanding its estimation requires a critical appreciation of our national surveys' idiosyncrasies. This commentary describes the two Statistics Canada surveys that are most commonly used to examine smoking prevalence in this country: the Canadian Community Health Survey (CCHS) and the Canadian Tobacco, Alcohol and Drugs Survey (CTADS). It compares estimates of smoking prevalence obtained from each source and examines potential reasons for their noticeable discrepancies. Canadian researchers interested in smoking prevalence should be aware of current and future limitations, and should discuss and analyze these accordingly. PMID- 28910260 TI - Shining new light on newborn screening of cystic fibrosis in the province of Quebec. AB - Newborn screening of cystic fibrosis, a severe genetic disease with high treatment burden, is offered in all of North America with the exception of the province of Quebec. This condition, when diagnosed on symptomatic presentation, is marked by chronic infections and progressive lung function decline leading to eventual respiratory failure. Patients continue to have a median age of survival notably below the Canadian average. Despite prevalence rates of cystic fibrosis almost three times the national average in certain regions of Quebec, the province still does not offer screening to its newborns. However, the results of newly published research comparing patients from Quebec with those of other provinces has shown that screening is associated with better nutritional status and overall growth, lower hospitalization rates as well as fewer episodes of infection, hence contributing to the prevention of lung damage in the long term. This research appears to confirm the benefits and pertinence of implementing a neonatal screening program for patients with cystic fibrosis in the province. PMID- 28910261 TI - Where is the outrage? The abandonment of long-established public health travel clinics in Saskatchewan. PMID- 28910263 TI - Enzymatic insights into an inherited genetic disorder. AB - Mutations in an enzyme involved in protein degradation affect a signaling pathway that stimulates the development of the digestive tract. PMID- 28910262 TI - Work minimization accounts for footfall phasing in slow quadrupedal gaits. AB - Quadrupeds, like most bipeds, tend to walk with an even left/right footfall timing. However, the phasing between hind and forelimbs shows considerable variation. Here, we account for this variation by modeling and explaining the influence of hind-fore limb phasing on mechanical work requirements. These mechanics account for the different strategies used by: (1) slow animals (a group including crocodile, tortoise, hippopotamus and some babies); (2) normal medium to large mammals; and (3) (with an appropriate minus sign) sloths undertaking suspended locomotion across a range of speeds. While the unusual hind-fore phasing of primates does not match global work minimizing predictions, it does approach an only slightly more costly local minimum. Phases predicted to be particularly costly have not been reported in nature. PMID- 28910264 TI - Estimation and comparison of the radiation effective dose during coronary computed tomography angiography examinations on single-source 64-MDCT and dual source 128-MDCT. AB - GOAL: To estimate and compare the radiation dose associated with coronary computed tomography angiography (CCTA) examinations on two multi-detector CT scanners (MDCT), 64-MDCT and 128-MDCT, in daily practice. METHODS: Scan parameters of 90 patients undergoing retrospective electrocardiographic gating spiral CCTA exam were recorded during a period on a single-source 64-MDCT and a dual-source 128-MDCT, and average scan parameters were derived that were used for dosimetry. The computed tomography dose index (CTDI) with a pencil ionisation chamber and polymethyl methacrylate body phantom with diameter of 32 cm was measured on both scanners. The dose-length product (DLP) was calculated and the DLP to effective dose conversion factor (for chest scan at 120 kV of 0.014 mSv mGy-1 cm-1) was used to estimate effective dose (ED). RESULTS: Patients' heart rate, scan length, pitch factor, CTDIv, DLP and ED for 128-MDCT were 64 (5) (beats min-1), 161 (10) (mm), 0.26, 47 (12) (mGy), 769 (212) (mGy cm) and 10.3 (3.1) (mSv), respectively [mean (one standard deviation)]. Patients' heart rate, scan length, pitch factor, CTDIv, DLP and ED for 64-MDCT were 60 (7) (beats min 1), 172 (14) (mm), 0.2, 60 (6) (mGy), 1068 (98) (mGy cm) and 14.9 (1.4) (mSv), respectively. CONCLUSION: Our results indicated that the CTDIv, DLP and the effective dose with 128-MDCT is significantly lower than with 64-MDCT (p < 0.05). As differences between the exposure parameter mAs on two CT scanners was not significant (p > 0.05) and the kV was constant for both scanners (120 kV), the differences resulted from a shorter scan length on the 128-MDCT and use of a higher pitch factor (0.26 and 0.2 in the 128-MDCT and 64-MDCT, respectively). Comparison with other published studies confirms the findings and indicates methods for reducing patient dose. PMID- 28910237 TI - Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. AB - BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .). PMID- 28910265 TI - Kiss and Tell: Limited Empirical Data on Oropharyngeal Neisseria gonorrhoeae Among Men Who Have Sex With Men and Implications for Modeling. PMID- 28910268 TI - Assessment of Hospital Emergency Department Response to Potentially Infectious Diseases Using Unannounced Mystery Patient Drills - New York City, 2016. AB - Recent outbreaks of infectious diseases have revealed significant health care system vulnerabilities and highlighted the importance of rapid recognition and isolation of patients with potentially severe infectious diseases. During December 2015-May 2016, a series of unannounced "mystery patient drills" was carried out to assess New York City Emergency Departments' (EDs) abilities to identify and respond to patients with communicable diseases of public health concern. Drill scenarios presented a patient reporting signs or symptoms and travel history consistent with possible measles or Middle East Respiratory Syndrome (MERS). Evaluators captured key infection control performance measures, including time to patient masking and isolation. Ninety-five drills (53 measles and 42 MERS) were conducted in 49 EDs with patients masked and isolated in 78% of drills. Median time from entry to masking was 1.5 minutes (range = 0-47 minutes) and from entry to isolation was 8.5 minutes (range = 1-57). Hospitals varied in their ability to identify potentially infectious patients and implement recommended infection control measures in a timely manner. Drill findings were used to inform hospital improvement planning to more rapidly and consistently identify and isolate patients with a potentially highly infectious disease. PMID- 28910266 TI - Therapeutic Effect and Mechanism of Action of Abnormal Savda Munziq in Development of Degenerative Atherosclerotic Aortic Valve Disease. AB - BACKGROUND The aim of this study was to investigate the therapeutic effect of abnormal Savda Munziq (ASMq) on the development of degenerative atherosclerotic aortic valve disease and its underlying mechanisms. MATERIAL AND METHODS We randomly divided 80 rabbits into 4 groups: a normal control group (group N, n=20); a high-fat diet group (group HC, n=20); a high-fat diet and Atorvastatin calcium intervention group (group AI, n=20); and a high-fat diet and ASMq intervention group (group MI, n=20). For evaluation of blood lipid profiles, blood samples were collected at week 0 and at the end of week 8. Aortic valve samples were taken at weeks 0, 2, 4, 6, and 8 for atomic force microscopy (AFM) examination of endothelial cell nanostructures, and at week 8 for pathological examinations. RESULTS Triglyceride (TG), cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein HDL levels of rabbits in group HC were significantly different from those in group N (P<0.01). TG, TC, LDL, and HDL values of rabbits in group MI were significantly different from rabbits in group HC (P<0.05). Pathological examination revealed that the aortic valves from rabbits in group MI were visibly clear, with strong endothelial cell continuity. No infiltration of macrophages or other inflammatory cells nor subendothelial calcium deposition was found when compared with rabbits in group HC. CONCLUSIONS ASMq therapy can delay the onset of degenerative calcific aortic valve disease, and its effects are similar to those of Atorvastatin. PMID- 28910270 TI - Updated Dosing Instructions for Immune Globulin (Human) GamaSTAN S/D for Hepatitis A Virus Prophylaxis. AB - GamaSTAN S/D (Grifols Therapeutics, Inc., Research Triangle Park, North Carolina) is a sterile, preservative-free solution of immune globulin (IG) for intramuscular administration and is used for prophylaxis against disease caused by infection with hepatitis A, measles, varicella, and rubella viruses (1). GamaSTAN S/D is the only IG product approved by the Food and Drug Administration for hepatitis A virus (HAV) prophylaxis. In July 2017, GamaSTAN S/D prescribing information was updated with changes to the dosing instructions for hepatitis A preexposure and postexposure prophylaxis indications. These changes were made because of concerns about decreased HAV immunoglobulin G antibody (anti-HAV IgG) potency, likely resulting from decreasing prevalence of previous HAV infection among plasma donors, leading to declining anti-HAV antibody levels in donor plasma (2). No changes in dosing instructions were made for measles, varicella, or rubella preexposure or postexposure prophylaxis. PMID- 28910267 TI - Surveillance for Certain Health Behaviors and Conditions Among States and Selected Local Areas - Behavioral Risk Factor Surveillance System, United States, 2013 and 2014. AB - PROBLEM: Chronic diseases and conditions (e.g., heart diseases, stroke, arthritis, and diabetes) are the leading causes of morbidity and mortality in the United States. These conditions are costly to the U.S. economy, yet they are often preventable or controllable. Behavioral risk factors (e.g., excessive alcohol consumption, tobacco use, poor diet, frequent mental distress, and insufficient sleep) are linked to the leading causes of morbidity and mortality. Adopting positive health behaviors (e.g., staying physically active, quitting tobacco use, obtaining routine physical checkups, and checking blood pressure and cholesterol levels) can reduce morbidity and mortality from chronic diseases and conditions. Monitoring the health risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services at multilevel public health points (states, territories, and metropolitan and micropolitan statistical areas [MMSA]) can provide important information for development and evaluation of health intervention programs. REPORTING PERIOD: 2013 and 2014. DESCRIPTION OF THE SYSTEM: The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing, state-based, random-digit-dialed telephone survey of noninstitutionalized adults aged >=18 years residing in the United States. BRFSS collects data on health risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services and practices related to the leading causes of death and disability in the United States and participating territories. This is the first BRFSS report to include age-adjusted prevalence estimates. For 2013 and 2014, these age-adjusted prevalence estimates are presented for all 50 states, the District of Columbia, the Commonwealth of Puerto Rico, Guam, and selected MMSA. RESULTS: Age-adjusted prevalence estimates of health status indicators, health care access and preventive practices, health risk behaviors, chronic diseases and conditions, and cardiovascular conditions vary by state, territory, and MMSA. Each set of proportions presented refers to the range of age-adjusted prevalence estimates of selected BRFSS measures as reported by survey respondents. The following are estimates for 2013. Adults reporting frequent mental distress: 7.7%-15.2% in states and territories and 6.3% 19.4% in MMSA. Adults with inadequate sleep: 27.6%-49.2% in states and territories and 26.5%-44.4% in MMSA. Adults aged 18-64 years having health care coverage: 66.9%-92.4% in states and territories and 60.5%-97.6% in MMSA. Adults identifying as current cigarette smokers: 10.1%-28.8% in states and territories and 6.1%-33.6% in MMSA. Adults reporting binge drinking during the past month: 10.5%-25.2% in states and territories and 7.2%-25.3% in MMSA. Adults with obesity: 21.0%-35.2% in states and territories and 12.1%-37.1% in MMSA. Adults aged >=45 years with some form of arthritis: 30.6%-51.0% in states and territories and 27.6%-52.4% in MMSA. Adults aged >=45 years who have had coronary heart disease: 7.4%-17.5% in states and territories and 6.2%-20.9% in MMSA. Adults aged >=45 years who have had a stroke: 3.1%-7.5% in states and territories and 2.3%-9.4% in MMSA. Adults with high blood pressure: 25.2%-40.1% in states and territories and 22.2%-42.2% in MMSA. Adults with high blood cholesterol: 28.8% 38.4% in states and territories and 26.3%-39.6% in MMSA. The following are estimates for 2014. Adults reporting frequent physical distress: 7.8%-16.0% in states and territories and 6.2%-18.5% in MMSA. Women aged 21-65 years who had a Papanicolaou test during the past 3 years: 67.7%-87.8% in states and territories and 68.0%-94.3% in MMSA. Adults aged 50-75 years who received colorectal cancer screening on the basis of the 2008 U.S. Preventive Services Task Force recommendation: 42.8%-76.7% in states and territories and 49.1%-79.6% in MMSA. Adults with inadequate sleep: 28.4%-48.6% in states and territories and 25.4% 45.3% in MMSA. Adults reporting binge drinking during the past month: 10.7%-25.1% in states and territories and 6.7%-26.3% in MMSA. Adults aged >=45 years who have had coronary heart disease: 8.0%-17.1% in states and territories and 7.6%-19.2% in MMSA. Adults aged >=45 years with some form of arthritis: 31.2%-54.7% in states and territories and 28.4%-54.7% in MMSA. Adults with obesity: 21.0%-35.9% in states and territories and 19.7%-42.5% in MMSA. INTERPRETATION: Prevalence of certain chronic diseases and conditions, health risk behaviors, and use of preventive health services varies among states, territories, and MMSA. The findings of this report highlight the need for continued monitoring of health status, health care access, health behaviors, and chronic diseases and conditions at state and local levels. PUBLIC HEALTH ACTION: State and local health departments and agencies can continue to use BRFSS data to identify populations at risk for certain unhealthy behaviors and chronic diseases and conditions. Data also can be used to design, monitor, and evaluate public health programs at state and local levels. PMID- 28910269 TI - Rates and Trends of Pediatric Acute Lymphoblastic Leukemia - United States, 2001 2014. AB - Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and adolescents in the United States, representing 20% of all cancers diagnosed in persons aged <20 years, or >3,000 new cases each year (1). Past studies reported increasing trends of ALL overall and among Hispanics, but these represented <=28% of the U.S. population and did not provide state-based estimates (1-3). To describe U.S. ALL incidence rates and trends among persons aged <20 years during 2001-2014, CDC analyzed rigorous data (based on established publication criteria) from the United States Cancer Statistics data set, which includes incidence data on approximately 15,000 new cases per year of all types of invasive cancer among children and adolescents aged <20 years (4). The data set represented 98% of the U.S. population during the study period. Overall incidence of pediatric ALL during 2001-2014 was 34.0 cases per 1 million persons and among all racial/ethnic groups was highest among Hispanics (42.9 per 1 million). Both overall and among Hispanics, pediatric ALL incidence increased during 2001-2008 and remained stable during 2008-2014. ALL incidence was higher in the West than in any other U.S. Census region. State-specific data indicated that the highest rates of pediatric ALL incidence were in California, New Mexico, and Vermont. These demographic and geographic ALL incidence data might better inform public health interventions targeting the following areas: exposures to recognized risk factors for leukemia; ALL treatment, including clinical trial enrollment; survivorship care planning; and studies designed to understand the factors affecting changes in pediatric cancer incidence. PMID- 28910272 TI - Announcement: Community Preventive Services Task Force Recommendation for Interventions Engaging Community Health Workers for Diabetes Management. PMID- 28910271 TI - Announcement: National Child Passenger Safety Week - September 17-23, 2017. PMID- 28910273 TI - QuickStats: Percentage of Women Who Missed Taking Oral Contraceptive Pills* Among Women Aged 15-44 Years Who Used Oral Contraceptive Pills and Had Sexual Intercourse, Overall and by Age and Number of Pills Missed - National Survey Of Family Growth, United States, 2013-2015?. PMID- 28910274 TI - Notes from the Field: Vibrio cholerae Serogroup O1, Serotype Inaba - Minnesota, August 2016. PMID- 28910275 TI - Occupational Animal Exposure Among Persons with Campylobacteriosis and Cryptosporidiosis - Nebraska, 2005-2015. AB - Campylobacter and Cryptosporidium are two common causes of gastroenteritis in the United States. National incidence rates measured for these pathogens in 2015 were 17.7 and 3.0 per 100,000 population, respectively; Nebraska was among the states with the highest incidence for both campylobacteriosis (26.6) and cryptosporidiosis (>=6.01) (1). Although campylobacteriosis and cryptosporidiosis are primarily transmitted via consumption of contaminated food or water, they can also be acquired through contact with live animals or animal products, including through occupational exposure (2). This exposure route is of particular interest in Nebraska, where animal agriculture and associated industries are an important part of the state's economy. To estimate the percentage of disease that might be related to occupational animal exposure in Nebraska, the Nebraska Department of Health and Human Services (NDHHS) and CDC reviewed deidentified investigation reports from 2005 to 2015 of cases of campylobacteriosis and cryptosporidiosis among Nebraska residents aged >=14 years. Case investigation notes were searched for evidence of occupational animal exposures, which were classified into discrete categories based on industry, animal/meat, and specific work activity/exposure. Occupational animal exposure was identified in 16.6% of 3,352 campylobacteriosis and 8.7% of 1,070 cryptosporidiosis cases, among which animal production (e.g., farming or ranching) was the most commonly mentioned industry type (68.2% and 78.5%, respectively), followed by employment in animal slaughter and processing facilities (16.3% and 5.4%, respectively). Among animal/meat occupational exposures, cattle/beef was most commonly mentioned, with exposure to feedlots (concentrated animal feeding operations in which animals are fed on stored feeds) reported in 29.9% of campylobacteriosis and 7.9% of cryptosporidiosis cases. Close contact with animals and manure in feedlots and other farm settings might place workers in these areas at increased risk for infection. It is important to educate workers with occupational animal exposure about the symptoms of enteric diseases and prevention measures. Targeting prevention strategies to high-risk workplaces and activities could help reduce disease. PMID- 28910276 TI - IGF2 stimulates fetal growth in a sex- and organ-dependent manner. AB - BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33+/-9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13+/-3%; P<0.05) and weight of fetal stomach (+42+/-10%; P<0.01), intestine (+26+/-5%; P<0.05), liver (+13+/-4%; P<0.05), and pancreas (+25+/-8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26+/-9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses. PMID- 28910277 TI - Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C. elegans oocyte meiosis. AB - In many species, oocyte meiosis is carried out in the absence of centrioles. As a result, microtubule organization, spindle assembly, and chromosome segregation proceed by unique mechanisms. Here, we report insights into the principles underlying this specialized form of cell division, through studies of C. elegans KLP-15 and KLP-16, two highly homologous members of the kinesin-14 family of minus-end-directed kinesins. These proteins localize to the acentriolar oocyte spindle and promote microtubule bundling during spindle assembly; following KLP 15/16 depletion, microtubule bundles form but then collapse into a disorganized array. Surprisingly, despite this defect we found that during anaphase, microtubules are able to reorganize into a bundled array that facilitates chromosome segregation. This phenotype therefore enabled us to identify factors promoting microtubule organization during anaphase, whose contributions are normally undetectable in wild-type worms; we found that SPD-1 (PRC1) bundles microtubules and KLP-18 (kinesin-12) likely sorts those bundles into a functional orientation capable of mediating chromosome segregation. Therefore, our studies have revealed an interplay between distinct mechanisms that together promote spindle formation and chromosome segregation in the absence of structural cues such as centrioles. PMID- 28910278 TI - Defective erythropoiesis caused by mutations of the thyroid hormone receptor alpha gene. AB - Patients with mutations of the THRA gene exhibit classical features of hypothyroidism, including erythroid disorders. We previously created a mutant mouse expressing a mutated TRalpha1 (denoted as PV; Thra1PV/+ mouse) that faithfully reproduces the classical hypothyroidism seen in patients. Using Thra1PV/+ mice, we explored how the TRalpha1PV mutant acted to cause abnormalities in erythropoiesis. Thra1PV/+ mice exhibited abnormal red blood cell indices similarly as reported for patients. The total bone marrow cells and erythrocytic progenitors were markedly reduced in the bone marrow of Thra1PV/+ mice. In vitro terminal differentiation assays showed a significant reduction of mature erythrocytes in Thra1PV/+ mice. In wild-type mice, the clonogenic potential of progenitors in the erythrocytic lineage was stimulated by thyroid hormone (T3), suggesting that T3 could directly accelerate the differentiation of progenitors to mature erythrocytes. Analysis of gene expression profiles showed that the key regulator of erythropoiesis, the Gata-1 gene, and its regulated genes, such as the Klf1, beta-globin, dematin genes, CAII, band3 and eALAS genes, involved in the maturation of erythrocytes, was decreased in the bone marrow cells of Thra1PV/+ mice. We further elucidated that the Gata-1 gene was a T3 directly regulated gene and that TRalpha1PV could impair erythropoiesis via repression of the Gata-1 gene and its regulated genes. These results provide new insights into how TRalpha1 mutants acted to cause erythroid abnormalities in patients with mutations of the THRA gene. Importantly, the Thra1PV/+ mouse could serve as a preclinical mouse model to identify novel molecular targets for treatment of erythroid disorders. PMID- 28910279 TI - Longitudinal multiparameter single-cell analysis of macaques immunized with pneumococcal protein-conjugated or unconjugated polysaccharide vaccines reveals distinct antigen specific memory B cell repertoires. AB - BACKGROUND: The efficacy of protein-conjugated pneumococcal polysaccharide vaccines has been well characterized for children. The level of protection conferred by unconjugated polysaccharide vaccines remains less clear, particularly for elderly individuals who have had prior antigenic experience through immunization with unconjugated polysaccharide vaccines or natural exposure to Streptococcus pneumoniae. METHODS: We compared the magnitude, diversity and genetic biases of antigen-specific memory B cells in two groups of adult cynomolgus macaques that were immunized with a 7-valent conjugated vaccine and boosted after five years with either a 13-valent pneumococcal polysaccharide conjugate vaccine (13vPnC) or a 23-valent unconjugated pneumococcal polysaccharide vaccine (23vPS) using microengraving (a single-cell analysis method) and single-cell RT-PCR. RESULTS: Seven days after boosting, the mean frequency of antigen-specific memory B cells was significantly increased in macaques vaccinated with 13vPnC compared to those receiving 23vPS. The 13vPnC vaccinated macaques also exhibited a more even distribution of antibody specificities to four polysaccharides in the vaccine (PS4, 6B, 14, 23F) that were examined. However, single-cell analysis of the antibody variable region sequences from antigen-specific B cells elicited by unconjugated and conjugated vaccines indicated that both the germline gene segments forming the heavy chains and the average lengths of the Complementary Determining Region 3 (CDR3) were similar. CONCLUSIONS: Our results confirm that distinctive differences can manifest between antigen-specific memory B cell repertoires in nonhuman primates immunized with conjugated and unconjugated pneumococcal polysaccharide vaccines. The study also supports the notion that the conjugated vaccines have a favorable profile in terms of both the frequency and breadth of the anamnestic response among antigen specific memory B cells. PMID- 28910280 TI - The eBioKit, a stand-alone educational platform for bioinformatics. AB - Bioinformatics skills have become essential for many research areas; however, the availability of qualified researchers is usually lower than the demand and training to increase the number of able bioinformaticians is an important task for the bioinformatics community. When conducting training or hands-on tutorials, the lack of control over the analysis tools and repositories often results in undesirable situations during training, as unavailable online tools or version conflicts may delay, complicate, or even prevent the successful completion of a training event. The eBioKit is a stand-alone educational platform that hosts numerous tools and databases for bioinformatics research and allows training to take place in a controlled environment. A key advantage of the eBioKit over other existing teaching solutions is that all the required software and databases are locally installed on the system, significantly reducing the dependence on the internet. Furthermore, the architecture of the eBioKit has demonstrated itself to be an excellent balance between portability and performance, not only making the eBioKit an exceptional educational tool but also providing small research groups with a platform to incorporate bioinformatics analysis in their research. As a result, the eBioKit has formed an integral part of training and research performed by a wide variety of universities and organizations such as the Pan African Bioinformatics Network (H3ABioNet) as part of the initiative Human Heredity and Health in Africa (H3Africa), the Southern Africa Network for Biosciences (SAnBio) initiative, the Biosciences eastern and central Africa (BecA) hub, and the International Glossina Genome Initiative. PMID- 28910281 TI - Global health policy and neglected tropical diseases: Then, now, and in the years to come. PMID- 28910282 TI - Characterization of intravascular cellular activation in relationship to subclinical atherosclerosis in postmenopausal women. AB - OBJECTIVE: Mechanisms and interactions among intravascular cells contributing to development of subclinical atherosclerosis are poorly understood. In women, both menopausal status and pregnancy history influence progression of atherosclerosis. This study examined activation and interactions among blood elements with subclinical atherosclerosis in menopausal women with known pregnancy histories. METHODS: Carotid intima-media thickness (CIMT), as a marker of subclinical atherosclerosis, was measured using B-mode ultrasound in age- and parity-matched women [40 with and 40 without a history of preeclampsia] 35 years after the index pregnancy. Interactions among intravascular cells (38 parameters) were measured by flow cytometry in venous blood. Data analysis was by principal component which retained 7 independent dimensions accounting for 63% of the variability among 38 parameters. RESULTS: CIMT was significantly greater in women with a history of preeclampsia (P = 0.004). Platelet aggregation and platelet interactions with granulocytes and monocytes positively associated with CIMT in postmenopausal women independent of their pregnancy history (rho = 0.258, P< 0.05). However, the association of the number of platelets, platelet activation and monocyte-platelet interactions with CIMT differed significantly depending upon pregnancy history (test for interaction, P<0.001). CONCLUSION: Interactions among actived intravascular cells and their association with subclinical atherosclerosis differ in women depending upon their pregnancy histories. PMID- 28910283 TI - Stochastic principles governing alternative splicing of RNA. AB - The dominance of the major transcript isoform relative to other isoforms from the same gene generated by alternative splicing (AS) is essential to the maintenance of normal cellular physiology. However, the underlying principles that determine such dominance remain unknown. Here, we analyzed the physical AS process and found that it can be modeled by a stochastic minimization process, which causes the scaled expression levels of all transcript isoforms to follow the same Weibull extreme value distribution. Surprisingly, we also found a simple equation to describe the median frequency of transcript isoforms of different dominance. This two-parameter Weibull model provides the statistical distribution of all isoforms of all transcribed genes, and reveals that previously unexplained observations concerning relative isoform expression derive from these principles. PMID- 28910285 TI - Correction: Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006379.]. PMID- 28910284 TI - Caretakers' perspectives of paediatric TB and implications for care-seeking behaviours in Southern Mozambique. AB - BACKGROUND: Tuberculosis (TB) remains an important public health concern, especially in poorly resourced settings. TB diagnosis is challenging, particularly for children, who are the most vulnerable to its' impacts. Lack of knowledge and awareness of the disease compromises prompt diagnosis and treatment compliance. OBJECTIVE: To gain insights regarding caretakers' knowledge of the aetiology and prevention of paediatric TB in southern Mozambique, to describe their care-seeking behaviours and to assess the acceptability of diagnostic procedures. METHODS: A total of 35 caretakers were interviewed, all of which had children with TB compatible symptoms. Eleven were caretakers of children diagnosed with TB at the health facility, 11 of children for whom TB was excluded as a diagnosis at the health facility and 13 of children with TB compatible symptoms identified in the community. The first two groups took part in a TB incidence study, while the third group did not. All underwent the same semi structured interviews, the results of which were analysed and compared using content analysis. RESULTS: Even when confronted with signs suggestive of TB, most caretakers never suspected it or misinterpreted the signs, even among caretakers with TB and TB contacts. There was limited knowledge of TB, except among those undergoing treatment. The transgression of social norms was often presented as an explanation for TB in parallel to medically sound causes. The use of traditional care for prevention is widespread, but it varied for treatment purposes. TB diagnostic procedures were considered painful but were unanimously tolerated. CONCLUSIONS AND SIGNIFICANCE: Misconceptions of paediatric TB, associated complex care-seeking itineraries and negative feelings of the diagnostic procedures may result in delays, low adherence and lost to follow-up, which needs to be addressed by adequately framed health promotion approaches. PMID- 28910286 TI - Potential DNA barcodes for Melilotus species based on five single loci and their combinations. AB - Melilotus, an annual or biennial herb, belongs to the tribe Trifolieae (Leguminosae) and consists of 19 species. As an important green manure crop, diverse Melilotus species have different values as feed and medicine. To identify different Melilotus species, we examined the efficiency of five candidate regions as barcodes, including the internal transcribed spacer (ITS) and two chloroplast loci, rbcL and matK, and two non-coding loci, trnH-psbA and trnL-F. In total, 198 individuals from 98 accessions representing 18 Melilotus species were sequenced for these five potential barcodes. Based on inter-specific divergence, we analysed sequences and confirmed that each candidate barcode was able to identify some of the 18 species. The resolution of a single barcode and its combinations ranged from 33.33% to 88.89%. Analysis of pairwise distances showed that matK+rbcL+trnL-F+trnH-psbA+ITS (MRTPI) had the greatest value and rbcL the least. Barcode gap values and similarity value analyses confirmed these trends. The results indicated that an ITS region, successfully identifying 13 of 18 species, was the most appropriate single barcode and that the combination of all five potential barcodes identified 16 of the 18 species. We conclude that MRTPI is the most effective tool for Melilotus species identification. Taking full advantage of the barcode system, a clear taxonomic relationship can be applied to identify Melilotus species and enhance their practical production. PMID- 28910287 TI - Generation of a serum free CHO DG44 cell line stably producing a broadly protective anti-influenza virus monoclonal antibody. AB - Because of the broad neutralization and in vivo protection across influenza A and influenza B virus strains, monoclonal antibody CR9114 is widely used in influenza virus research as a positive control in many experiments. To produce amounts sufficient for the demand requires regular transient transfections, resulting in varying yield as well as differing batch to batch quality. Here, we report the development of a serum-free CHO DG44 cell line, stably producing a CR9114-like antibody with a potential to become a useful influenza virus research tool. PMID- 28910288 TI - Genomics-enabled analysis of the emergent disease cotton bacterial blight. AB - Cotton bacterial blight (CBB), an important disease of (Gossypium hirsutum) in the early 20th century, had been controlled by resistant germplasm for over half a century. Recently, CBB re-emerged as an agronomic problem in the United States. Here, we report analysis of cotton variety planting statistics that indicate a steady increase in the percentage of susceptible cotton varieties grown each year since 2009. Phylogenetic analysis revealed that strains from the current outbreak cluster with race 18 Xanthomonas citri pv. malvacearum (Xcm) strains. Illumina based draft genomes were generated for thirteen Xcm isolates and analyzed along with 4 previously published Xcm genomes. These genomes encode 24 conserved and nine variable type three effectors. Strains in the race 18 clade contain 3 to 5 more effectors than other Xcm strains. SMRT sequencing of two geographically and temporally diverse strains of Xcm yielded circular chromosomes and accompanying plasmids. These genomes encode eight and thirteen distinct transcription activator-like effector genes. RNA-sequencing revealed 52 genes induced within two cotton cultivars by both tested Xcm strains. This gene list includes a homeologous pair of genes, with homology to the known susceptibility gene, MLO. In contrast, the two strains of Xcm induce different clade III SWEET sugar transporters. Subsequent genome wide analysis revealed patterns in the overall expression of homeologous gene pairs in cotton after inoculation by Xcm. These data reveal important insights into the Xcm-G. hirsutum disease complex and strategies for future development of resistant cultivars. PMID- 28910289 TI - How TAVI registries report clinical outcomes-A systematic review of endpoints based on VARC-2 definitions. AB - INTRODUCTION: Transcatheter aortic valve implantation (TAVI) has been demonstrated to be an alternative treatment for severe aortic stenosis in patients considered as high surgical risk. Since its first human implantation by Cribier et al., TAVI has been shown to increase survival rate and quality of life for high surgical risks patients. The objective of this study is to provide an overview of TAVI registries and the reporting clinical outcomes based on the VARC 2 definitions. In addition, the comparability and adherence of VARC-2 reporting within the identified TAVI registries was reviewed. MATERIALS AND METHODS: A systematic review of TAVI registries reporting VARC-2 definitions has been performed in line with PRISMA guidelines in PubMed, ScienceDirect, Scopus databases and EMBASE. Based on VARC-2, patients' characteristics and procedure characteristics, 30-day clinical outcomes, 1-year mortality and composited endpoints were extracted from each registry's publications. RESULTS: This review identified 466 studies that were potentially relevant, and 20 TAVI registries reported VARC-2 definitions involved in our present review. Of all 20 registries, an overall sample size of 12,583 patients was involved. The 30-day all-cause mortality ranged from 0 to 12.7%. From 20 registries, 14 registries reported the cardiovascular mortality at 30 days. 9 registries reported myocardial infarction (MI) rate based on VARC-2 definitions, and 7 registries reported peri-procedural MI rate (<72h). In our review, most of registries presented MI rates ranging from 0.5% to 2%. The majority of registries have reported complications such as bleeding, vascular complications and new pacemaker implantation. CONCLUSION: Since the introduction of VARC definitions from 2011, VARC and VARC-2 definitions are still not systematically used by all TAVI studies. These endpoint definitions warrant a concise and systemic analysis of outcome measures. Reporting TAVI outcome uniformly makes study result comparison feasible. This definitely will increase patient safety, additionally to provide sufficient evidence to support decision makers like regulatory bodies, HTA agencies, payers. PMID- 28910290 TI - Bird use of organic apple orchards: Frugivory, pest control and implications for production. AB - As the largest terrestrial biomes, crop and pasturelands can have very large positive or negative impacts on biodiversity and human well-being. Understanding how animals use and impact agroecosystems is important for making informed decisions that achieve conservation and production outcomes. Yet, few studies examine the tradeoffs associated with wildlife in agricultural systems. We examined bird use of organic apple orchards as well as how birds influence fruit production positively through control of an economically important insect pest (codling moth (Cydia pomonella)) and negatively through fruit damage. We conducted transect surveys, observed bird frugivory and assessed bird and insect damage with an exclosure experiment in small organic farms in western Colorado. We found that organic apple orchards in this region provide habitat for a large number of both human-adapted and human-sensitive species and that the species in orchards were relatively similar to adjacent hedgerow habitats. Habitat use did not vary as a function of orchard characteristics, and apple damage by both birds and C. pomonella was consistent within and across apple blocks that varied in size. A small subset of bird species was observed foraging on apples yet the effect of birds as agents of fruit damage appeared rather minor and birds did not reduce C. pomonella damage. Our results demonstrate that organic apple orchards have the potential to provide habitat for diverse bird communities, including species typically sensitive to human activities, with little apparent effect on production. PMID- 28910291 TI - Minimizing nocebo effects by conditioning with verbal suggestion: A randomized clinical trial in healthy humans. AB - Nocebo effects, i.e., adverse treatment effects which are induced by patients' expectations, are known to contribute to the experience of physical symptoms such as pain and itch. A better understanding of how to minimize nocebo responses might eventually contribute to enhanced treatment effects. However, little is known about how to reduce nocebo effects. In the current randomized controlled study, we tested whether nocebo effects can be minimized by positive expectation induction with respect to electrical and histaminic itch stimuli. First, negative expectations about electrical itch stimuli were induced by verbal suggestion and conditioning (part 1: induction of nocebo effect). Second, participants were randomized to either the experimental group or one of the control groups (part 2: reversing nocebo effect). In the experimental group, positive expectations were induced by conditioning with verbal suggestion. In the control groups either the negative expectation induction was continued or an extinction procedure was applied. Afterwards, a histamine application test was conducted. Positive expectation induction resulted in a significantly smaller nocebo effect in comparison with both control groups. Mean change itch NRS scores showed that the nocebo effect was even reversed, indicating a placebo effect. Comparable effects were also found for histamine application. This study is the first to demonstrate that nocebo effects can be minimized and even reversed by conditioning with verbal suggestion. The results of the current study indicate that learning via counterconditioning and verbal suggestion represents a promising strategy for diminishing nocebo responses. PMID- 28910292 TI - Host outdoor exposure variability affects the transmission and spread of Zika virus: Insights for epidemic control. AB - BACKGROUND: Zika virus transmission dynamics in urban environments follow a complex spatiotemporal pattern that appears unpredictable and barely related to high mosquito density areas. In this context, human activity patterns likely have a major role in Zika transmission dynamics. This paper examines the effect of host variability in the amount of time spent outdoors on Zika epidemiology in an urban environment. METHODOLOGY/PRINCIPAL FINDINGS: First, we performed a survey on time spent outdoors by residents of Miami-Dade County, Florida. Second, we analyzed both the survey and previously published national data on outdoors time in the U.S. to provide estimates of the distribution of the time spent outdoors. Third, we performed a computational modeling evaluation of Zika transmission dynamics, based on the time spent outdoors by each person. Our analysis reveals a strong heterogeneity of the host population in terms of time spent outdoors-data are well captured by skewed gamma distributions. Our model-based evaluation shows that in a heterogeneous population, Zika would cause a lower number of infections than in a more homogenous host population (up to 4-fold differences), but, at the same time, the epidemic would spread much faster. We estimated that in highly heterogeneous host populations the timing of the implementation of vector control measures is the major factor for limiting the number of Zika infections. CONCLUSIONS/SIGNIFICANCE: Our findings highlight the need of considering host variability in exposure time for managing mosquito-borne infections and call for the revision of the triggers for vector control strategies, which should integrate mosquito density data and human outdoor activity patterns in specific areas. PMID- 28910293 TI - Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation. AB - BACKGROUND: Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions. METHODS AND FINDINGS: We used Cooke's Classical Model to elicit and aggregate judgments of 73 international experts. Judgments were elicited from each expert individually and aggregated using both equal and performance weights. Performance weighted results are reported as they increased the informativeness of estimates, while retaining accuracy. We report measures of central tendency and uncertainty bounds on food source attribution estimate. For some pathogens we see relatively consistent food source attribution estimates across subregions of the world; for others there is substantial regional variation. For example, for non-typhoidal salmonellosis, pork was of minor importance compared to eggs and poultry meat in the American and African subregions, whereas in the European and Western Pacific subregions the importance of these three food sources were quite similar. Our regional results broadly agree with estimates from earlier European and North American food source attribution research. As in prior food source attribution research, we find relatively wide uncertainty bounds around our median estimates. CONCLUSIONS: We present the first worldwide estimates of the proportion of specific foodborne diseases attributable to specific food exposure routes. While we find substantial uncertainty around central tendency estimates, we believe these estimates provide the best currently available basis on which to link FBDs and specific foods in many parts of the world, providing guidance for policy actions to control FBDs. PMID- 28910294 TI - Auto-correlation in the motor/imaginary human EEG signals: A vision about the FDFA fluctuations. AB - In this paper we analyzed, by the FDFA root mean square fluctuation (rms) function, the motor/imaginary human activity produced by a 64-channel electroencephalography (EEG). We utilized the Physionet on-line databank, a publicly available database of human EEG signals, as a standardized reference database for this study. Herein, we report the use of detrended fluctuation analysis (DFA) method for EEG analysis. We show that the complex time series of the EEG exhibits characteristic fluctuations depending on the analyzed channel in the scalp-recorded EEG. In order to demonstrate the effectiveness of the proposed technique, we analyzed four distinct channels represented here by F332, F637 (frontal region of the head) and P349, P654 (parietal region of the head). We verified that the amplitude of the FDFA rms function is greater for the frontal channels than for the parietal. To tabulate this information in a better way, we define and calculate the difference between FDFA (in log scale) for the channels, thus defining a new path for analysis of EEG signals. Finally, related to the studied EEG signals, we obtain the auto-correlation exponent, alphaDFA by DFA method, that reveals self-affinity at specific time scale. Our results shows that this strategy can be applied to study the human brain activity in EEG processing. PMID- 28910295 TI - Identification of a mouse Lactobacillus johnsonii strain with deconjugase activity against the FXR antagonist T-beta-MCA. AB - Bile salt hydrolase (BSH) activity against the bile acid tauro-beta-muricholic acid (T-beta-MCA) was recently reported to mediate host bile acid, glucose, and lipid homeostasis via the farnesoid X receptor (FXR) signaling pathway. An earlier study correlated decreased Lactobacillus abundance in the cecum with increased concentrations of intestinal T-beta-MCA, an FXR antagonist. While several studies have characterized BSHs in lactobacilli, deconjugation of T-beta MCA remains poorly characterized among members of this genus, and therefore it was unclear what strain(s) were responsible for this activity. Here, a strain of L. johnsonii with robust BSH activity against T-beta-MCA in vitro was isolated from the cecum of a C57BL/6J mouse. A screening assay performed on a collection of 14 Lactobacillus strains from nine different species identified BSH substrate specificity for T-beta-MCA only in two of three L. johnsonii strains. Genomic analysis of the two strains with this BSH activity revealed the presence of three bsh genes that are homologous to bsh genes in the previously sequenced human associated strain L. johnsonii NCC533. Heterologous expression of several bsh genes in E. coli followed by enzymatic assays revealed broad differences in substrate specificity even among closely related bsh homologs, and suggests that the phylogeny of these enzymes does not closely correlate with substrate specificity. Predictive modeling allowed us to propose a potential mechanism driving differences in BSH activity for T-beta-MCA in these homologs. Our data suggests that L. johnsonii regulates T-beta-MCA levels in the mouse intestinal environment, and that this species may play a central role in FXR signaling in the mouse. PMID- 28910296 TI - The impact of the protein interactome on the syntenic structure of mammalian genomes. AB - Conserved synteny denotes evolutionary preserved gene order across species. It is not well understood to which degree functional relationships between genes are preserved in syntenic blocks. Here we investigate whether protein-coding genes conserved in mammalian syntenic blocks encode gene products that serve the common functional purpose of interacting at protein level, i.e. connectivity. High connectivity among protein-protein interactions (PPIs) was only moderately associated with conserved synteny on a genome-wide scale. However, we observed a smaller subset of 3.6% of all syntenic blocks with high-confidence PPIs that had significantly higher connectivity than expected by random. Additionally, syntenic blocks with high-confidence PPIs contained significantly more chromatin loops than the remaining blocks, indicating functional preservation among these syntenic blocks. Conserved synteny is typically defined by sequence similarity. In this study, we also examined whether a functional relationship, here PPI connectivity, can identify syntenic blocks independently of orthology. While orthology-based syntenic blocks with high-confident PPIs and the connectivity based syntenic blocks largely overlapped, the connectivity-based approach identified additional syntenic blocks that were not found by conventional sequence-based methods alone. Additionally, the connectivity-based approach enabled identification of potential orthologous genes between species. Our analyses demonstrate that subsets of syntenic blocks are associated with highly connected proteins, and that PPI connectivity can be used to detect conserved synteny even if sequence conservation drifts beyond what orthology algorithms normally can identify. PMID- 28910297 TI - Evaluation of auditory perception development in neonates by quantitative electroencephalography and auditory event-related potentials. AB - OBJECTIVE: The present study was performed to investigate neonatal auditory perception function by quantitative electroencephalography (QEEG) and auditory event-related potentials (aERPs) and identify the characteristics of auditory perception development in newborns. METHODS: Fifty-three normal full-term neonates were divided into three groups according their age in days. An auditory oddball paradigm was used. QEEG (resting state and task state) and aERPs were performed. EEG delta power in the resting and task states and at different ages was respectively analyzed. The N2 area and latency of aERPs at different ages were also compared. RESULTS: The four main findings of this study are as follows. First, the increase in the EEG delta power was significantly greater in the task than resting state in Group 3 at the Fz lead (t = -3.371, P = 0.004) and in Groups 2 and 3 at the Cz lead (Group 2: t = -3.149, P = 0.005; Group 3: t = 3.609, P = 0.002). Second, the delta power gradually increased from 1 to 10 days of age (Group 1), peaked at 11 to 20 days (Group 2), and gradually decreased from 21 to 28 days (Group 3). The data in the Fz lead during the task state and in the Cz lead during the resting and task states were statistically significant (F = 5.875, P = 0.005; F = 5.523, P = 0.007; and F = 5.402, P = 0.008, respectively). Third, the N2 area significantly increased with age by presentation of target stimuli (F = 5.26, P = 0.01). The N2 area increased most significantly from 21 to 28 days (Group 3). Finally, the N2 latency significantly decreased with age (Fz lead: F = 4.66, P = 0.023; Cz lead: F = 7.18, P = 0.005). The N2 latency decreased most significantly from 11 to 20 days of age (Group 2). CONCLUSION: Rapid cognitive development occurs during the neonatal period. In the first several days after birth, the EEG delta power and N2 area manifested the characteristic performance of identifying task information. QEEG and aERP measurement can be used as objective indices with which to evaluate auditory perception development in neonates. PMID- 28910298 TI - Adult hippocampal neurogenesis poststroke: More new granule cells but aberrant morphology and impaired spatial memory. AB - Stroke significantly stimulates neurogenesis in the adult dentate gyrus, though the functional role of this postlesional response is mostly unclear. Recent findings suggest that newborn neurons generated in the context of stroke may fail to correctly integrate into pre-existing networks. We hypothesized that increased neurogenesis in the dentate gyrus following stroke is associated with aberrant neurogenesis and impairment of hippocampus-dependent memory. To address these questions we used the middle cerebral artery occlusion model (MCAO) in mice. Animals were housed either under standard conditions or with free access to running wheels. Newborn granule cells were labelled with the thymidine analoque EdU and retroviral vectors. To assess memory performance, we employed a modified version of the Morris water maze (MWM) allowing differentiation between hippocampus dependent and independent learning strategies. Newborn neurons were morphologically analyzed using confocal microscopy and Neurolucida system at 7 weeks. We found that neurogenesis was significantly increased following MCAO. Animals with MCAO needed more time to localize the platform and employed less hippocampus-dependent search strategies in MWM versus controls. Confocal studies revealed an aberrant cell morphology with basal dendrites and an ectopic location (e.g. hilus) of new granule cells born in the ischemic brain. Running increased the number of new neurons but also enhanced aberrant neurogenesis. Running, did not improve the general performance in the MWM but slightly promoted the application of precise spatial search strategies. In conclusion, ischemic insults cause hippocampal-dependent memory deficits which are associated with aberrant neurogenesis in the dentate gyrus indicating ischemia-induced maladaptive plasticity in the hippocampus. PMID- 28910299 TI - Access to benznidazole for Chagas disease in the United States-Cautious optimism? AB - Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism. PMID- 28910300 TI - Acute and chronic effects of treatment with mesenchymal stromal cells on LPS induced pulmonary inflammation, emphysema and atherosclerosis development. AB - BACKGROUND: COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS)-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L) mice. METHODS: Hyperlipidemic E3L mice were intranasally instilled with 10 MUg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study) or in week 14, 16, 18 and 20 (chronic study). Inflammatory parameters were measured in bronchoalveolar lavage (BAL) and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study. RESULTS: In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment. CONCLUSION: These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study. PMID- 28910301 TI - Prevalence of overweight, obesity, abdominal obesity and obesity-related risk factors in southern China. AB - OBJECTIVES: The purpose of this study is to assess the prevalence of overweight/obesity, abdominal obesity and obesity-related risk factors in southern China. METHODS: A cross-sectional survey of 15,364 participants aged 15 years and older was conducted from November 2013 to August 2014 in Jiangxi Province, China, using questionnaire forms and physical measurements. The physical measurements included body height, weight, waist circumference (WC), body fat percentage (BFP) and visceral adipose index (VAI). Multivariate logistic regression analysis was performed to evaluate the risk factors for overweight/obesity and abdominal obesity. RESULTS: The prevalence of overweight was 25.8% (25.9% in males and 25.7% in females), while that of obesity was 7.9% (8.4% in males and 7.6% in females). The prevalence of abdominal obesity was 10.2% (8.6% in males and 11.3% in females). The prevalence of overweight/obesity was 37.1% in urban residents and 30.2% in rural residents, and this difference was significant (P < 0.001). Urban residents had a significantly higher prevalence of abdominal obesity than rural residents (11.6% vs 8.7%, P < 0.001). Among the participants with an underweight/normal body mass index (BMI), 1.3% still had abdominal obesity, 16.1% had a high BFP and 1.0% had a high VAI. Moreover, among obese participants, 9.7% had a low /normal WC, 0.8% had a normal BFP and 15.9% had a normal VAI. Meanwhile, the partial correlation analysis indicated that the correlation coefficients between VAI and BMI, VAI and WC, and BMI and WC were 0.700, 0.666, and 0.721, respectively. A multivariate logistic regression analysis indicated that being female and having a high BFP and a high VAI were significantly associated with an increased risk of overweight/obesity and abdominal obesity. In addition, living in an urban area and older age correlated with overweight/obesity. CONCLUSION: This study revealed that obesity and abdominal obesity, which differed by gender and age, are epidemic in southern China. Moreover, there was a very high, significant, positive correlation between WC, BMI and VAI. However, further studies are needed to explore which indicator of body fat could be used as the best marker to indirectly reflect cardiometabolic risk. PMID- 28910302 TI - A look back on how far to walk: Systematic review and meta-analysis of physical access to skilled care for childbirth in Sub-Saharan Africa. AB - OBJECTIVES: To (i) summarize the methods undertaken to measure physical accessibility as the spatial separation between women and health services, and (ii) establish the extent to which distance to skilled care for childbirth affects utilization in Sub-Saharan Africa. METHOD: We defined spatial separation as the distance/travel time between women and skilled care services. The use of skilled care at birth referred to either the location or attendant of childbirth. The main criterion for inclusion was any quantification of the relationship between spatial separation and use of skilled care at birth. The approaches undertaken to measure distance/travel time were summarized in a narrative format. We obtained pooled adjusted odds ratios (aOR) from studies that controlled for financial means, education and (perceived) need of care in a meta-analysis. RESULTS: 57 articles were included (40 studied distance and 25 travel time), in which distance/travel time were found predominately self-reported or estimated in a geographic information system based on geographic coordinates. Approaches of distance/travel time measurement were generally poorly detailed, especially for self-reported data. Crucial features such as start point of origin and the mode of transportation for travel time were most often unspecified. Meta-analysis showed that increased distance to maternity care had an inverse association with utilization (n = 10, pooled aOR = 0.90/1km, 95%CI = 0.85-0.94). Distance from a hospital for rural women showed an even more pronounced effect on utilization (n = 2, pooled aOR = 0.58/1km increase, 95%CI = 0.31,1.09). The effect of spatial separation appears to level off beyond critical point when utilization was generally low. CONCLUSION: Although the reporting and measurements of spatial separation in low-resource settings needs further development, we found evidence that a lack of geographic access impedes use. Utilization is conditioned on access, researchers and policy makers should therefore prioritize quality data for the evidence-base to ensure that women everywhere have the potential to access obstetric care. PMID- 28910303 TI - The influence of analgesic-based sedation protocols on delirium and outcomes in critically ill patients: A randomized controlled trial. AB - OBJECTIVE: To investigate the influence of analgesic-based midazolam sedation on delirium and outcomes in critically ill patients and to analyze the risk factors of delirium. DESIGN: Single center, prospective randomized controlled trial. SETTING: A surgical intensive care unit (ICU) in a tertiary care hospital in China. PATIENTS: Mechanically ventilated patients requiring sedation. MEASUREMENTS AND MAIN RESULTS: Patients admitted to the surgical intensive care unit who required sedation and were undergoing mechanical ventilation for longer than 24 hours were randomly divided into three groups: 1) the remifentanil group received remifentanil and midazolam, 2) the fentanyl group received fentanyl and midazolam, and 3) the control group received only midazolam. The analgesic effect, sedation depth, and presence of delirium were evaluated. To compare the effect of different therapies on the occurrence of delirium, days of mechanical ventilation, length of the ICU stay, and 28-day mortality were measured along with the risk factors for delirium. A total of 105 patients were enrolled, and 35 patients were included in each group. Compared to the control group, patients who received remifentanil and fentanyl required less midazolam each day (P = 0.038 and <0.001, respectively). Remifentanil has a significant effect on reducing the occurrence of delirium (P = 0.007). The logistic regression analysis of delirium demonstrated that remifentanil (OR 0.230, 95%Cl 0.074-0.711, P = 0.011) is independent protective factors for delirium, and high APACHE II score (OR 1.103, 95%Cl 1.007-1.208, P = 0.036) is the independent risk factor for delirium. CONCLUSION: Remifentanil and fentanyl can reduce the amount of midazolam required, and remifentanil could further reduce the occurrence of delirium. PMID- 28910304 TI - Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin. AB - Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics. PMID- 28910305 TI - Aspirin increases metabolism through germline signalling to extend the lifespan of Caenorhabditis elegans. AB - Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid beta oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF 16 to extend lifespan. PMID- 28910306 TI - A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions. AB - All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 * 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies. PMID- 28910307 TI - Dealing with AFLP genotyping errors to reveal genetic structure in Plukenetia volubilis (Euphorbiaceae) in the Peruvian Amazon. AB - An analysis of the population structure and genetic diversity for any organism often depends on one or more molecular marker techniques. Nonetheless, these techniques are not absolutely reliable because of various sources of errors arising during the genotyping process. Thus, a complex analysis of genotyping error was carried out with the AFLP method in 169 samples of the oil seed plant Plukenetia volubilis L. from small isolated subpopulations in the Peruvian Amazon. Samples were collected in nine localities from the region of San Martin. Analysis was done in eight datasets with a genotyping error from 0 to 5%. Using eleven primer combinations, 102 to 275 markers were obtained according to the dataset. It was found that it is only possible to obtain the most reliable and robust results through a multiple-level filtering process. Genotyping error and software set up influence both the estimation of population structure and genetic diversity, where in our case population number (K) varied between 2-9 depending on the dataset and statistical method used. Surprisingly, discrepancies in K number were caused more by statistical approaches than by genotyping errors themselves. However, for estimation of genetic diversity, the degree of genotyping error was critical because descriptive parameters (He, FST, PLP 5%) varied substantially (by at least 25%). Due to low gene flow, P. volubilis mostly consists of small isolated subpopulations (PhiPT = 0.252-0.323) with some degree of admixture given by socio-economic connectivity among the sites; a direct link between the genetic and geographic distances was not confirmed. The study illustrates the successful application of AFLP to infer genetic structure in non model plants. PMID- 28910308 TI - Pulmonary hypertension among 5 to 18 year old children with sickle cell anaemia in Nigeria. AB - BACKGROUND: Pulmonary hypertension (PHT) is a significant cause of mortality in patients with sickle cell disease (SCD). Few studies on PHT in SCD have been carried out in children. This study aimed to estimate the prevalence of PHT in children with sickle cell anaemia (SCA) and determine its clinical and laboratory correlates. METHODS: In this cross sectional study, evaluation involved obtaining bio-data, history and physical examination findings in 175 SCA subjects with haemoglobin genotype SS aged 5 to 18 years and 175 age and sex matched controls with haemoglobin genotype AA. PHT was determined using peak Tricuspid Regurgitant Velocity (TRV) obtained from echocardiography as a marker. Complete blood count (CBC), lactate dehydrogenase (LDH) assay, reticulocyte count, foetal haemoglobin (HbF) estimation as well as Human Immunodeficiency Virus (HIV) I and II, Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) screening were done for patients with SCA. RESULTS: The mean peak TRV of subjects with SCA and controls was 2.2 +/- 0.4 m/s and 1.9 +/- 0.3 m/s respectively and prevalence of PHT among children with SCA and controls was 22.9% and 2.3% respectively. PHT in SCA correlated negatively with body mass index, haematocrit and haemoglobin. CONCLUSION: This study affirms that PHT prevalence is high in children with SCA in Nigeria. Cardiovascular examination for signs of PHT is recommended for children with SCA and if required, further echocardiographic assessment from as early as five years. PMID- 28910309 TI - Pattern and severity of multimorbidity among patients attending primary care settings in Odisha, India. AB - Multimorbidity is increasingly the primary concern of healthcare systems globally with substantial implications for patient outcomes and resource cost. A critical knowledge gap exists as to the magnitude of multimorbidity in primary care practice in low and middle income countries with available information limited to prevalence. In India, primary care forms the bulk of the health care delivery being provided through both public (community health center) and private general practice setting. We undertook a study to identify multimorbidity patterns and relate these patterns to severity among primary care attendees in Odisha state of India. A total of 1649 patients attending 40 primary care facilities were interviewed using a structured multimorbidity assessment questionnaire. Multimorbidity patterns (dyad and triad) were identified for 21 chronic conditions, functional limitation was assessed as a proxy measure of severity and the mean severity score for each pattern, was determined after adjusting for age. The leading dyads in younger age group i.e. 18-29 years were acid peptic disease with arthritis/ chronic back ache/tuberculosis /chronic lung disease, while older age groups had more frequent combinations of hypertension + arthritis/ chronic lung disease/vision difficulty, and arthritis + chronic back ache. The triad of acid peptic disease + arthritis + chronic backache was common in men in all age groups. Tuberculosis and lung diseases were associated with significantly higher age-adjusted mean severity score (poorer functional ability). Among men, arthritis, chronic backache, chronic lung disease and vision impairment were observed to have highest severity) whereas women reported higher severity for combinations of hypertension, chronic back ache and arthritis. Given the paucity of studies on multimorbidity patterns in low and middle income countries, future studies should seek to assess the reproducibility of our findings in other populations and settings. Another task is the potential implications of different multimorbidity clusters for designing care protocols, as currently the protocols are disease specific, hardly taking comorbidity into account. PMID- 28910311 TI - Hearing impairment in premature newborns-Analysis based on the national hearing screening database in Poland. AB - OBJECTIVES: The incidence of sensorineural hearing loss is between 1 and 3 per 1000 in healthy neonates and 2-4 per 100 in high-risk infants. The national universal neonatal hearing screening carried out in Poland since 2002 enables selection of infants with suspicion and/or risk factors of hearing loss. In this study, we assessed the incidence and risk factors of hearing impairment in infants <=33 weeks' gestational age (wga). METHODS: We analyzed the database of the Polish Universal Newborns Hearing Screening Program from 2010 to 2013. The study group involved 11438 infants born before 33 wga, the control group-1487730 infants. Screening was performed by means of transient evoked otoacoustic emissions. The risk factors of hearing loss were recorded. Infants who failed the screening test and/or had risk factors were referred for further audiological evaluation. RESULTS: Hearing deficit was diagnosed in 11% of infants <=25 wga, 5% at 26-27 wga, 3.46% at 28 wga and 2-3% at 29-32 wga. In the control group the incidence of hearing deficit was 0.2% (2.87% with risk factors). The most important risk factors were craniofacial malformations, very low birth weight, low Apgar score and mechanical ventilation. Hearing screening was positive in 22.42% newborns <=28 wga and 10% at 29-32 wga and in the control group. CONCLUSIONS: Hearing impairment is a severe consequence of prematurity. Its prevalence is inversely related to the maturity of the baby. Premature infants have many concomitant risk factors which influence the occurrence of hearing deficit. PMID- 28910310 TI - Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice. AB - For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown. The aim of this study was to determine the effects of gugulipid on cholesterol homeostasis and development of mild and severe atherosclerosis in male mice. For this purpose, we evaluated the impact of gugulipid treatment on liver histology, plasma lipoprotein cholesterol, endothelial function, and development of atherosclerosis and/or ischemic heart disease in wild-type mice; apolipoprotein E knockout mice, a model of atherosclerosis without ischemic complications; and SR-B1 knockout and atherogenic-diet-fed apolipoprotein E hypomorphic (SR-BI KO/ApoER61h/h) mice, a model of lethal ischemic heart disease due to severe atherosclerosis. Gugulipid administration was associated with histological abnormalities in liver, increased alanine aminotransferase levels, lower hepatic SR-BI content, hypercholesterolemia due to increased HDL cholesterol levels, endothelial dysfunction, enhanced atherosclerosis, and accelerated death in animals with severe ischemic heart disease. In conclusion, our data show important adverse effects of gugulipid intake on HDL metabolism and atherosclerosis in male mice, suggesting potential and unknown deleterious effects on cardiovascular health in humans. In addition, these findings reemphasize the need for rigorous preclinical and clinical studies to provide guidance on the consumption of natural products and regulation of their use in the general population. PMID- 28910312 TI - IkappaK-16 decreases miRNA-155 expression and attenuates the human monocyte inflammatory response. AB - Excessive inflammatory responses in the surgical patient may result in cellular hypo-responsiveness, which is associated with an increased risk of secondary infection and death. microRNAs (miRNAs), such as miR-155, are powerful regulators of inflammatory signalling pathways including nuclear factor kappaB (NFkappaB). Our objective was to determine the effect of IkappaK-16, a selective blocker of inhibitor of kappa-B kinase (IkappaK), on miRNA expression and the monocyte inflammatory response. In a model of endotoxin tolerance using primary human monocytes, impaired monocytes had decreased p65 expression with suppressed TNF alpha and IL-10 production (P < 0.05). miR-155 and miR-138 levels were significantly upregulated at 17 h in the impaired monocyte (P < 0.05). Notably, IkappaK-16 decreased miR-155 expression with a corresponding dose-dependent decrease in TNF-alpha and IL-10 production (P < 0.05), and impaired monocyte function was associated with increased miR-155 and miR-138 expression. In the context of IkappaK-16 inhibition, miR-155 mimics increased TNF-alpha production, while miR-155 antagomirs decreased both TNF-alpha and IL-10 production. These data demonstrate that IkappaK-16 treatment attenuates the monocyte inflammatory response, which may occur through a miR-155-mediated mechanism, and that IkappaK 16 is a promising approach to limit the magnitude of an excessive innate inflammatory response to LPS. PMID- 28910313 TI - A detailed comparison of analysis processes for MCC-IMS data in disease classification-Automated methods can replace manual peak annotations. AB - MOTIVATION: Disease classification from molecular measurements typically requires an analysis pipeline from raw noisy measurements to final classification results. Multi capillary column-ion mobility spectrometry (MCC-IMS) is a promising technology for the detection of volatile organic compounds in the air of exhaled breath. From raw measurements, the peak regions representing the compounds have to be identified, quantified, and clustered across different experiments. Currently, several steps of this analysis process require manual intervention of human experts. Our goal is to identify a fully automatic pipeline that yields competitive disease classification results compared to an established but subjective and tedious semi-manual process. METHOD: We combine a large number of modern methods for peak detection, peak clustering, and multivariate classification into analysis pipelines for raw MCC-IMS data. We evaluate all combinations on three different real datasets in an unbiased cross-validation setting. We determine which specific algorithmic combinations lead to high AUC values in disease classifications across the different medical application scenarios. RESULTS: The best fully automated analysis process achieves even better classification results than the established manual process. The best algorithms for the three analysis steps are (i) SGLTR (Savitzky-Golay Laplace operator filter thresholding regions) and LM (Local Maxima) for automated peak identification, (ii) EM clustering (Expectation Maximization) and DBSCAN (Density Based Spatial Clustering of Applications with Noise) for the clustering step and (iii) RF (Random Forest) for multivariate classification. Thus, automated methods can replace the manual steps in the analysis process to enable an unbiased high throughput use of the technology. PMID- 28910314 TI - The variability of the steps preceding obstacle avoidance (approach phase) is dependent on the height of the obstacle in people with Parkinson's disease. AB - Gait variability may serve as a sensitive and clinically relevant parameter to quantify adjustments in walking and the changes with aging and neurological disease. Variability of steps preceding obstacle avoidance (approach phase) are important for efficiency in the task, especially in people with Parkinson's disease (PD). However, variability of gait during the approach phase to obstacle avoidance in people with PD has been rarely reported, particularly when ambulating obstacles of different heights. The aim of the present study was to investigate the effects of obstacle height on step-to-step variability (step-to step variability provides information on the variation between the "equivalent steps" for all trials, and walking variability (indicates the within-step variability of each, providing information about the modulations between the steps performed. of spatial-temporal parameters during the approach phase to obstacle avoidance in people with PD and neurologically healthy older people. Twenty-eight older people; 15 with PD and 13 neurologically healthy individuals (control group), participated in the study. Participants were instructed to walk at their preferred speed until the end of the pathway and to avoid the obstacle when it was present. Each subject performed 10 trials of the following tasks: unobstructed walking, low obstacle avoidance (3cm length, height equal ankle's height, 60 cm wide), intermediate obstacle (3cm length, low plus high obstacle height divided by 2, 60 cm wide) avoidance and high obstacle avoidance (3cm length, knee's height, 60 cm wide). The obstacle was positioned 4m from to the start position. The step-to-step and walking variability of the spatial-temporal parameters (acquiring with GAITRite(r)) of the four steps before obstacle avoidance were analyzed. MANOVAs were used to compare the data. PD group showed the characteristic gait deficits associated with PD. The obstacle increased the spatial-temporal variability (step-to-step and walking variability) during the approach phase to the obstacle. Specifically, both groups increased i) the step to- step variability of the step length during low obstacle avoidance when compared to the other conditions; ii) the variability during low obstacle avoidance in the last step before obstacle (n-1) compared to higher obstacle avoidance; iii) variability during higher obstacle avoidance in further steps (n 3 and n-4). In conclusion, the presence of the obstacle during walking increased the variability of spatial-temporal parameters in older people with PD and the control group during the steps preceding obstacle avoidance. In addition motor planning (and motor adaptations) was initiated much earlier in the approach phase for the higher obstacle conditions compared to the low obstacle condition. PMID- 28910315 TI - For how many days and what types of group activities should older Japanese adults be involved in to maintain health? A 4-year longitudinal study. AB - OBJECTIVE: Studies have suggested that frequent participation in social groups contributes to the well-being of older people. The primary aim of this study was to identify the number of days older adults should participate in the activities of social groups to maintain their health for 4 years. This study also aimed to examine whether the effective frequency differs by the type of social group activity. METHOD: We examined a prospective cohort of 1,320 community-dwelling older adults over 65 years of age, who responded to both a baseline and a follow up mail survey, in a suburban city of Tokyo, Japan. The dependent variable was the change in functional competence during 4 years. Logistic regression analyses were conducted to examine the effects of participation in the activities of the 5 most common social groups among older Japanese on maintaining functional competence. RESULTS: Nine hundred and ninety-four participants (76.5%) maintained their functional competence for 4 years. The results of the logistic regression analyses showed that participating in alumni groups less than once a month and being an inactive member were associated with higher odds of maintaining functional competence, after controlling for socioeconomic, demographic and baseline health status. Additionally, the odds of maintaining functional competence for 4 years increased upon participating in volunteer groups once a month or more. These results were also confirmed using logistic regression analysis, even after adjustment for the effects of participation in other social groups. DISCUSSION: The results indicated the effectiveness of volunteer activities that fulfill a social role in maintaining health. Therefore, older adults should be encouraged to participate in activities of volunteer groups at least once a month. Additionally, older adults can obtain positive health outcomes through less frequent participation in alumni groups, compared with the activities of volunteer groups. PMID- 28910316 TI - Sources of pain in laparoendoscopic gynecological surgeons: An analysis of ergonomic factors and proposal of an aid to improve comfort. AB - Minimally invasive surgery (MIS) offers cosmetic benefits to patients; however, surgeons often experience pain during MIS. We administered an ergonomic questionnaire to 176 Korean laparoscopic gynecological surgeons to determine potential sources of pain during surgery. Logistic regression analysis was used to identify factors that had a significant impact on gynecological surgeons' pain. Operating table height at the beginning of surgery and during the operation were significantly associated with neck and shoulder discomfort (P <0.001). The ability to control the operating table height was the single factor most significantly associated with neck (P <0.001) and shoulder discomfort (P <0.001). Discomfort of the hand/digits was significantly associated with the trocar site (P = 0.035). The type of electrocautery activation switch and foot pedal were significantly related to surgeons' foot and leg discomfort (P <0.001). In evaluating the co-occurrence of pain in 4 different sites (neck, shoulder, back, hand/digits), the neck and shoulder were determined to have the highest co occurrence of pain (Spearman's rho = 0.64, P <0.001). These results provide guidance for identifying ergonomic solutions to reduce gynecological laparoscopic surgeons' pain. Based on our results, we propose the use of an ergonomic surgical step stool to reduce physical pain related to performing laparoscopic operations. PMID- 28910317 TI - The influence of threatening visual warnings on tobacco packaging: Measuring the impact of threat level, image size, and type of pack through psychophysiological and self-report methods. AB - The first aim of this research was to assess the effectiveness, in terms of emotional and behavioral reactions, of moderately vs. highly TVWs (Threatening Visual Warnings) displayed on tobacco packs. Given the key role that emotional reactions play in explaining the effect of TVWs on behaviors, psychophysiological and self-report methods were used-for the first time in this context-to measure the emotions provoked by TVWs. The second aim of this research was to determine whether increasing the size of warnings, and their display on plain packaging (compared with branded packaging) would improve their effectiveness. A within subjects experiment was conducted. Three variables were manipulated: health warning threat level (high vs. moderate), image size (40% vs. 75%) and pack type (plain vs. branded). A convenience sample of 48 French daily smokers participated. They were exposed to eight different packs of cigarettes in a research lab at the University of Rennes. Smokers' emotions and behavioral intentions were recorded through self-reports. Emotions were also evaluated using psychophysiological measurements: electrodermal activity and facial electromyography. The results revealed that TVWs with a high threat level are the most effective in increasing negative emotions (fear, disgust, valence, arousal) and behavioral intentions conducive to public health (desire to quit, etc.). They also highlight the appeal of increasing the size of the warnings and displaying them on plain packs, because this influences emotions, which is the first step toward behavioral change. Increasing the threat level of TVWs from moderate to high seems beneficial for public health. Our results also confirm the relevance of recent governmental decisions to adopt plain packaging and larger TVWs (in the UK, France, Ireland, Canada, New Zealand, Hungary, etc.). PMID- 28910318 TI - Characterization of a novel panel of plasma microRNAs that discriminates between Mycobacterium tuberculosis infection and healthy individuals. AB - Cavities are important in clinical diagnosis of pulmonary tuberculosis (TB) infected by Mycobacterium tuberculosis. Although microRNAs (miRNAs) play a vital role in the regulation of inflammation, the relation between plasma miRNA and pulmonary tuberculosis with cavity remains unknown. In this study, plasma samples were derived from 89 cavitary pulmonary tuberculosis (CP-TB) patients, 89 non cavitary pulmonary tuberculosis (NCP-TB) patients and 95 healthy controls. Groups were matched for age and gender. In the screening phase, Illumina high-throughput sequencing technology was employed to analyze miRNA profiles in plasma samples pooled from CP-TB patients, NCP-TB patients and healthy controls. During the training and verification phases, quantitative RT-PCR (qRT-PCR) was conducted to verify the differential expression of selected miRNAs among groups. Illumina high throughput sequencing identified 29 differentially expressed plasma miRNAs in TB patients when compared to healthy controls. Furthermore, qRT-PCR analysis validated miR-769-5p, miR-320a and miR-22-3p as miRNAs that were differently present between TB patients and healthy controls. ROC curve analysis revealed that the potential of these 3 miRNAs to distinguish TB patients from healthy controls was high, with the area under the ROC curve (AUC) ranged from 0.692 to 0.970. Moreover, miR-320a levels were decreased in drug-resistant TB patients than pan-susceptible TB patients (AUC = 0.882). In conclusion, we identified miR 769-5p, miR-320a and miR-22-3p as potential blood-based biomarkers for TB. In addition, miR-320a may represent a biomarker for drug-resistant TB. PMID- 28910319 TI - Chronic social defeat induces long-term behavioral depression of aggressive motivation in an invertebrate model system. AB - Losing a fight against a conspecific male (social defeat) induces a period of suppressed aggressiveness and general behaviour, often with symptoms common to human psychiatric disorders. Agonistic experience is also discussed as a potential cause of consistent, behavioral differences between individuals (animal "personality"). In non-mammals, however, the impact of single agonistic encounters typically last only hours, but then again studies of repeated intermittent defeat (chronic social defeat) are seldom. We report the effect of chronic social defeat in adult male crickets (Gryllus bimaculatus), for which all known behavioral effects of defeat last only 3 h. Firstly, after 48 h social isolation, crickets that experienced 5 defeats at 24 h intervals against the same, weight-matched opponent exhibited suppressed aggressiveness lasting >24 h, which was still evident when the animals were matched against an unfamiliar opponent at the last trial. Secondly, this longer-term depression of aggression also occurred in 48 h isolated crickets that lost 6 fights at 1 h intervals against unfamiliar opponents at each trial. Thirdly, crickets isolated as larvae until adult maturity (>16 days) were significantly more aggressive, and less variable in their aggressiveness at their very first fight than 48 h isolates, and also significantly more resilient to the effects of chronic social defeat. We conclude that losing an aggressive encounter in crickets has a residual effect, lasting at least 24 h, that accumulates when repeated defeats are experienced, and leads to a prolonged depression of aggressive motivation in subordinates. Furthermore, our data indicate that social interactions between young adults and possibly larvae can have even longer, possibly lifelong influences on subsequent behavior. Social subjugation is thus likely to be a prime determinant of inter individual behavioral differences in crickets. Our work also opens new avenues for investigating proximate mechanisms underlying depression-like phenomena. PMID- 28910320 TI - Differential gene expression following TLR stimulation in rag1-/- mutant zebrafish tissues and morphological descriptions of lymphocyte-like cell populations. AB - In the absence of lymphocytes, rag1-/- mutant zebrafish develop protective immunity to bacteria. In mammals, induction of protection by innate immunity can be mediated by macrophages or natural killer (NK) cells. To elucidate potential responsive cell populations, we morphologically characterized lymphocyte-like cells (LLCs) from liver, spleen and kidney hematopoietic tissues. In fish, these cells include NK cells and Non-specific cytotoxic cells (NCCs). We also evaluated the transcriptional expression response of select genes that are important indicators of NK and macrophage activation after exposure to specific TLR ligands. The LLC cell populations could be discriminated by size and further discriminated by the presence of cytoplasmic granules. Expression levels of mx, tnfalpha, ifngamma, t-bet and nitr9 demonstrated dynamic changes in response to intra-coelomically administered beta glucan (a TLR2/6 ligand), Poly I:C (a TLR3 ligand) and resiquimod (R848) (a TLR7/8 ligand). Following TLR 2/6 stimulation, there was a greater than 100 fold increase in ifngamma in liver, kidney and spleen and moderate increases in tnfalpha in liver and kidney. TLR3 stimulation caused broad up regulation of mx, down-regulation of tnfalpha in kidney and spleen tissues and up regulation of nitr9 in the kidney. Following TLR 7/8 stimulation, there was a greater than 100 fold increase in ifngamma in liver and kidney and t-bet in liver. Our gene expression findings suggest that LLCs and macrophages are stimulated following beta glucan exposure. Poly I:C causes type I interferon response and mild induction of LLC in the kidney and R-848 exposure causes the strongest LLC stimulation. Overall, the strongest NK like gene expression occurred in the liver. These differential effects of TLR ligands in rag1-/- mutant zebrafish shows strong NK cell-like gene expression responses, especially in the liver, and provides tools to evaluate the basis for protective immunity mediated by the innate immune cells of fish. PMID- 28910322 TI - Social interactions promote adaptive resource defense in ants. AB - Social insects vigorously defend their nests against con- and heterospecific competitors. Collective defense is also seen at highly profitable food sources. Aggressive responses are elicited or promoted by several means of communication, e.g. alarm pheromones and other chemical markings. In this study, we demonstrate that the social environment and interactions among colony members (nestmates) modulates the propensity to engage in aggressive behavior and therefore plays an important role in allocating workers to a defense task. We kept Formica rufa workers in groups or isolated for different time spans and then tested their aggressiveness in one-on-one encounters with other ants. In groups of more than 20 workers that are freely interacting, individuals are aggressive in one-on-one encounters with non-nestmates, whereas aggressiveness of isolated workers decreases with increasing isolation time. We conclude that ants foraging collectively and interacting frequently, e.g. along foraging trails and at profitable food sources, remain in a social context and thereby maintain high aggressiveness against potential competitors. Our results suggest that the nestmate recognition system can be utilized at remote sites for an adaptive and flexible tuning of the response against competitors. PMID- 28910321 TI - Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts. AB - BACKGROUND: Lung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-beta), and are therefore crucial in lung tissue repair and remodeling. Abnormal repair and remodeling has been observed in lung diseases like COPD. As miRNA levels can be influenced by TGF-beta, we hypothesized that TGF-beta influences miRNA expression in lung fibroblasts, thereby affecting their function. MATERIALS AND METHODS: We investigated TGF-beta1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays. TGF-beta1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR. Ago2 immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-beta1-stimulated primary lung fibroblasts (n = 2). The genes affected by TGF-beta1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-beta1 stimulated fibroblasts. RESULTS: Twenty-nine miRNAs were significantly differentially expressed after TGF-beta1 stimulation (FDR<0.05). The TGF-beta1 induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05). We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF beta1-stimulated lung fibroblasts, respectively. The TGF-beta and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p. The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-beta1 stimulation. CONCLUSION: Two miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-beta1 in lung fibroblasts. The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-beta and/or Wnt pathways (NGF, DLD, HHEX) in TGF-beta1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function. PMID- 28910323 TI - Comparative proteomic analyses reveal the proteome response to short-term drought in Italian ryegrass (Lolium multiflorum). AB - Drought is a major abiotic stress that impairs growth and productivity of Italian ryegrass. Comparative analysis of drought responsive proteins will provide insight into molecular mechanism in Lolium multiflorum drought tolerance. Using the iTRAQ-based approach, proteomic changes in tolerant and susceptible lines were examined in response to drought condition. A total of 950 differentially accumulated proteins was found to be involved in carbohydrate metabolism, amino acid metabolism, biosynthesis of secondary metabolites, and signal transduction pathway, such as beta-D-xylosidase, beta-D-glucan glucohydrolase, glycerate dehydrogenase, Cobalamin-independent methionine synthase, glutamine synthetase 1a, Farnesyl pyrophosphate synthase, diacylglycerol, and inositol 1, 4, 5 trisphosphate, which might contributed to enhance drought tolerance or adaption in Lolium multiflorum. Interestingly, the two specific metabolic pathways, arachidonic acid and inositol phosphate metabolism including differentially accumulated proteins, were observed only in the tolerant lines. Cysteine protease cathepsin B, Cysteine proteinase, lipid transfer protein and Aquaporin were observed as drought-regulated proteins participating in hydrolysis and transmembrane transport. The activities of phospholipid hydroperoxide glutathione peroxidase, peroxiredoxin, dehydroascorbate reductase, peroxisomal ascorbate peroxidase and monodehydroascorbate reductase associated with alleviating the accumulation of reactive oxygen species in stress inducing environments. Our results showed that drought-responsive proteins were closely related to metabolic processes including signal transduction, antioxidant defenses, hydrolysis, and transmembrane transport. PMID- 28910324 TI - Effect of dialyzer membrane materials on survival in chronic hemodialysis patients: Results from the annual survey of the Japanese Nationwide Dialysis Registry. AB - BACKGROUND: Little information is available regarding which type of dialyzer membrane results in good prognosis in patients on chronic hemodialysis. Therefore, we conducted a cohort study from a nationwide registry of hemodialysis patients in Japan to establish the association between different dialyzer membranes and mortality rates. METHODS: We followed 142,412 patients on maintenance hemodialysis (female, 39.1%; mean age, 64.8 +/- 12.3 years; median dialysis duration, 7 [4-12] years) for a year from 2008 to 2009. We included patients treated with seven types of high-flux dialyzer membranes at baseline, including cellulose triacetate (CTA), ethylene vinyl alcohol (EVAL), polyacrylonitrile (PAN), polyester polymer alloy (PEPA), polyethersulfone (PES), polymethylmethacrylate (PMMA), and polysulfone (PS). Cox regression was used to estimate the association between baseline dialyzers and all-cause mortality as hazard ratios (HRs) and 95% confidence intervals for 1-year mortality adjusting for potential confounders, and propensity score matching analysis was performed. RESULTS: The distribution of patients treated with each membrane was as follows: PS (56.0%), CTA (17.3%), PES (12.0%), PEPA (7.5%), PMMA (4.9%), PAN (1.2%), and EVAL (1.1%). When data were adjusted using basic factors, with PS as a reference group, the mortality rate was significantly higher in all groups except for the PES group. When data were further adjusted for dialysis-related factors, HRs were significantly higher for the CTA, EVAL, and PEPA groups. When the data were further adjusted for nutrition-and inflammation-related factors, HRs were significantly lower for the PMMA and PES groups compared with the PS group. After propensity score matching, HRs were significantly lower for the PMMA group than for the PS group. CONCLUSION: The results suggest that the use of different membrane types may affect mortality in hemodialysis patients. However, further long-term prospective studies are needed to clarify these findings, including whether the use of the PMMA membrane can improve prognosis. PMID- 28910325 TI - Src- and Fyn-dependent apical membrane trafficking events control endothelial lumen formation during vascular tube morphogenesis. AB - Here we examine the question of how endothelial cells (ECs) develop their apical membrane surface domain during lumen and tube formation. We demonstrate marked apical membrane targeting of activated Src kinases to this apical domain during early and late stages of this process. Immunostaining for phosphotyrosine or phospho-Src reveals apical membrane staining in intracellular vacuoles initially. This is then followed by vacuole to vacuole fusion events to generate an apical luminal membrane, which is similarly decorated with activated phospho-Src kinases. Functional blockade of Src kinases completely blocks EC lumen and tube formation, whether this occurs during vasculogenic tube assembly or angiogenic sprouting events. Multiple Src kinases participate in this apical membrane formation process and siRNA suppression of Src, Fyn and Yes, but not Lyn, blocks EC lumen formation. We also demonstrate strong apical targeting of Src-GFP and Fyn-GFP fusion proteins and increasing their expression enhances lumen formation. Finally, we show that Src- and Fyn-associated vacuoles track and fuse along a subapically polarized microtubule cytoskeleton, which is highly acetylated. These vacuoles generate the apical luminal membrane in a stereotypically polarized, perinuclear position. Overall, our study identifies a critical role for Src kinases in creating and decorating the EC apical membrane surface during early and late stages of lumen and tube formation, a central event in the molecular control of vascular morphogenesis. PMID- 28910326 TI - Sex differences in the herding styles of working sheepdogs and their handlers. AB - Working sheepdog trials test the attributes of dogs as well as the dogmanship and stockmanship skills of handlers. They generally include standard elements such as outrun, lift, fetch, drive, shed, pen and single to test all facets of the work that dogs perform on a farm. While both male and female handlers participate, these trials are traditionally dominated by male handlers. Both male and female dogs compete on equal terms within the same events. Drawing data from files (n = 60) downloaded from YouTube, the current study explores whether behaviours of dogs and their handlers during sheepdog trials differ between handler gender and dog sex at different levels of competition. It compared the stalking, crouching, chasing and stationary behaviours of dogs in open (n = 28 dogs: 10 females, 18 males) and not-open trials (n = 32 dogs: 20 females, 12 males). The dogs in this study had male (n = 38) and female (n = 22) handlers, whose movement and use of vocal cues and arm elevations were also compared. However, the small sample size and limitations of these videos as a data source should be noted before the results are generalised to the broader field of working-dog behaviour. The results of an REstricted Maximum Likelihood test showed that male handlers spent, on average, significantly more time in the fetch and drive elements than female handlers, but this difference between sexes was present only in not-open events (mean time to Fetch, female handler = 44.07s, male handler = 124.00s, P<0.001, mean time to Drive, female handler = 95.8s, male handler = 152.4, P = 0.010). This may suggest that female handlers of less experienced dogs are better at the early training of these elements. The results showed that male dogs spent more time stationary than female dogs, but only in open competition (male dog predicted mean 6.17s, P = 0.014). Revealing differences between men/women, and between dogs/bitches in this context may identify pairings that complement each other and improve selection, training and handling of working dogs. It is also hoped that ultimately, it will lead to improved welfare for dogs and the livestock with which they interact. PMID- 28910327 TI - In-silico analysis of cis-acting regulatory elements of pathogenesis-related proteins of Arabidopsis thaliana and Oryza sativa. AB - Pathogenesis related (PR) proteins are low molecular weight family of proteins induced in plants under various biotic and abiotic stresses. They play an important role in plant-defense mechanism. PRs have wide range of functions, acting as hydrolases, peroxidases, chitinases, anti-fungal, protease inhibitors etc. In the present study, an attempt has been made to analyze promoter regions of PR1, PR2, PR5, PR9, PR10 and PR12 of Arabidopsis thaliana and Oryza sativa. Analysis of cis-element distribution revealed the functional multiplicity of PRs and provides insight into the gene regulation. CpG islands are observed only in rice PRs, which indicates that monocot genome contains more GC rich motifs than dicots. Tandem repeats were also observed in 5' UTR of PR genes. Thus, the present study provides an understanding of regulation of PR genes and their versatile roles in plants. PMID- 28910328 TI - Non-governmental organization facilitation of a community-based nutrition and health program: Effect on program exposure and associated infant feeding practices in rural India. AB - BACKGROUND: Integrated nutrition and health programs seek to reduce undernutrition by educating child caregivers about infant feeding and care. Data on the quality of program implementation and consequent effects on infant feeding practices are limited. This study evaluated the effectiveness of enhancing a nutrition and health program on breastfeeding and complementary-feeding practices in rural India. METHODS: Utilizing a quasi-experimental design, one of the implementing districts of a Cooperative for Assistance and Relief Everywhere (CARE) nutrition and health program was randomly selected for enhanced services and compared with a district receiving the Government of India's standard nutrition and health package alone. A cohort of 942 mother-child dyads was longitudinally followed from birth to 18 months. In both districts, the evaluation focused on responses to services delivered by community-based nutrition and health care providers [anganwadi workers (AWWs) and auxiliary nurse midwives (ANMs)]. FINDINGS: The CARE enhanced program district showed an improvement in program coverage indicators (e.g., contacts, advice) through outreach visits by both AWWs (28.8-59.8% vs. 0.7-12.4%; all p<0.05) and ANMs (8.6 46.2% vs. 6.1-44.2%; <0.05 for ages >=6 months). A significantly higher percentage of child caregivers reported being contacted by the AWWs in the CARE program district (20.5-45.6% vs. 0.3-21.6%; p<0.05 for all ages except at 6months). No differences in ANM household contacts were reported. Overall, coverage remained low in both areas. Less than a quarter of women received any infant feeding advice in the intervention district. Earlier and exclusive breastfeeding improved with increasing number or quality of visits by either level of health care provider (OR: 2.04-3.08, p = <0.001), after adjusting for potentially confounding factors. Socio-demographic indicators were the major determinants of exclusive breastfeeding up to 6 month and age-appropriate complementary-feeding practices thereafter in the program-enhanced but not comparison district. INTERPRETATION: An enhanced nutrition and health intervention package improved program exposure and associated breastfeeding but not complementary-feeding practices, compared to standard government package. TRIAL REGISTRATION: ClinicalTrials.gov NCT00198835. PMID- 28910329 TI - Classification and conservation priority of five Deccani sheep ecotypes of Maharashtra, India. AB - Characterization of Indian livestock breeds has mostly been limited to single breed/population focused on either physical description of traditionally recognized breeds/populations or to their genetic description. Usually, morphological and genetic characterization has taken place in isolation. A parallel morphological characterization of genetically identified breeds or genetic characterization of morphologically described breeds is mostly missing, and their conservation priorities have largely been based on solely considering degree of endangerment. This study uses parallel approach based on morphometric and genetic differentiation for classification of five sheep ecotypes of Maharashtra state, and sets their conservation priority using threat parameters, current utilities/merits and contribution to genetic diversity. A total of 1101 animals were described for 7 body measurements for morphometric characterization. From this sample set, 456 animals were genotyped for 25 microsatellite markers for genetic characterization. Conservation priorities were assessed combining genetic and non-genetic factors. All studied traits varied significantly among ecotypes (p<0.05). All morphometric traits exhibited substantial sexual dimorphism except ear length. Males were 42% heavier than females. Madgyal sheep were the largest amongst the five ecotypes. In the stepwise discriminant analysis, all measured traits were significant and were found to have potential discriminatory power. Tail length was the most discriminatory trait. The Mahalanobis distance of the morphological traits between Kolhapuri and Madgyal was maximum (12.07) while the least differentiation was observed between Madgyal and Solapuri (1.50). Discriminant analysis showed that 68.12% sheep were classified into their source population. The Sangamneri sheep showed least assignment error (22%) whilst Solapuri exhibited maximum error level (41%). A total of 407 alleles were observed, with an average of 16.28 alleles per locus. Sufficient levels of genetic diversity were observed in all the ecotypes with observed heterozygosity values exceeding 0.47 and gene diversity values exceeding 0.76. About 6% of the total genetic variation was explained by population differences (FST = 0.059). Pairwise FST values indicated least differentiation between Solapuri and Madgyal (0.025). In terms of genetic distances, Kolhapuri and Lonand were most closely related (Ds = 0.177). The most probable structure clustering of the five studied populations was at K = 5. The study showed a fair congruence between the dendrogram constructed on the basis of Mahalanobis distances and Nei's as well as Reynolds genetic distances. The findings gave highest conservation priority to Lonand and least to Solapuri ecotype. PMID- 28910330 TI - Quality of life measures predict cardiovascular health and physical performance in chronic renal failure patients. AB - BACKGROUND: Patients with advanced chronic kidney disease (CKD) experience complex functional and structural changes of the cardiopulmonary and musculoskeletal system. This results in reduced exercise tolerance, quality of life and ultimately premature death. We investigated the relationship between subjective measures of health related quality of life and objective, standardised functional measures for cardiovascular and pulmonary health. METHODS: Between April 2010 and January 2013, 143 CKD stage-5 or CKD5d patients (age 46.0+/-1.1y, 62.2% male), were recruited prospectively. A control group of 83 healthy individuals treated for essential hypertension (HTN; age 53.2+/-0.9y, 48.22% male) were recruited at random. All patients completed the SF-36 health survey questionnaire, echocardiography, vascular tonometry and cardiopulmonary exercise testing. RESULTS: Patients with CKD had significantly lower SF-36 scores than the HTN group; for physical component score (PCS; 45.0 vs 53.9, p<0.001) and mental component score (MCS; 46.9 vs. 54.9, p<0.001). CKD subjects had significantly poorer exercise tolerance and cardiorespiratory performance compared with HTN (maximal oxygen uptake; VO2peak 19.9 vs 25.0ml/kg/min, p<0.001). VO2peak was a significant independent predictor of PCS in both groups (CKD: b = 0.35, p = 0.02 vs HTN: b = 0.27, p = 0.001). No associations were noted between PCS scores and echocardiographic characteristics, vascular elasticity and cardiac biomarkers in either group. No associations were noted between MCS and any variable. The interaction effect of study group with VO2peak on PCS was not significant (DeltaB = 0.08; 95%CI -0.28-0.45, p = 0.7). However, overall for a given VO2peak, the measured PCS was much lower for patients with CKD than for HTN cohort, a likely consequence of systemic uremia effects. CONCLUSION: In CKD and HTN, objective physical performance has a significant effect on quality of life; particularly self-reported physical health and functioning. Therefore, these quality of life measures are indeed a good reflection of physical health correlating highly with objective physical performance measures. PMID- 28910331 TI - Reproducibility of frequency-dependent low frequency fluctuations in reaction time over time and across tasks. AB - OBJECTIVE: Increased levels of reaction time variability (RTV) are characteristics of sustained attention deficits. The clinical significance of RTV has been widely recognized. However, the reliability of RTV measurements has not been widely studied. The present study aimed to assess the test-retest reliability of RTV conventional measurements, e.g., the standard deviation (SD), the coefficient of variation (CV), and a new measurement called the amplitude of low frequency fluctuation (ALFF) of RT. In addition, we aimed to assess differences and similarities of these measurements between different tasks. METHOD: Thirty-seven healthy college students participated in 2 tasks, i.e., an Eriksen flanker task (EFT) and a simple reaction task (SRT), twice over a mean interval of 56 days. Conventional measurements of RTV including RT-SD and RT-CV were assessed first. Then the RT time series were converted into frequency domains, and RT-ALFF was further calculated for the whole frequency band (0.0023 0.167 Hz) and for a few sub-frequency bands including Slow-6 (<0.01 Hz), Slow-5 (0.01-0.027 Hz), Slow-4 (0.027-0.073 Hz), and Slow-3 (0.073-0.167 Hz). The test retest reliability of these measurements was evaluated through intra-class correlation (ICC) tests. Differences and correlations between each EFT and SRT measurement were further examined during both visits. RESULTS: 1) The RT-ALFF of the Slow-5/4/3 and conventional measurements of RT-SD and RT-CV showed moderate to high levels of test-retest reliability. EFT RT-ALFF patterns generated slightly higher ICC values than SRT values in higher frequency bands (Slow-3), but SRT RT-ALFF values showed slightly higher ICC values than EFT values in lower frequency bands (Slow-5 and Slow-4). 2) RT-ALFF magnitudes in each sub-frequency band were greater for the SRT than those for the EFT. 3) The RT-ALFF in the Slow 4 of the EFT was found to be correlated with the RT-ALFF in the Slow-5 of the SRT for both two visits, but no consistently significant correlation was found between the same frequency bands. CONCLUSIONS: These findings reveal good test retest reliability for conventional measurements and for the RT-ALFF of RTV. The RT-ALFF presented frequency-dependent similarities across tasks. All of our results reveal the presence of different frequency structures between the two tasks, and thus the frequency-dependent characteristics of different tasks deserve more attention in future studies. PMID- 28910332 TI - Concurrent treatment with simvastatin and NF-kappaB inhibitor in human castration resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-kappaB/LIN28/let-7 miRNA signaling pathway. AB - We examined the anti-cancer effects and molecular mechanism of simvastatin in human castration-resistant prostate cancer (CRPC) cells, particularly focused on LIN28B and its target molecule, let-7 microRNA (miRNA) among the various target genes of NF-kappaB. A human CRPC cell line (PC3) was used in the current study. Gene expression patterns were evaluated using real time-PCR and western blot analysis. CCK-8 assay was used for assessing cell viability and proliferation, and a clonogenic assay was adopted to evaluate clonal proliferative capabilities. Induction of apoptotic cell death was analyzed via flow cytometry. Small interfering RNA (siRNA) and short-hairpin RNA (shRNA) were used for manipulating the expression of genes of interest. PC3 showed relatively higher expression levels of LIN28B and lower expression levels of let-7 miRNAs. Simvastatin treatment significantly inhibited cell viability and clonal proliferation in a dose-dependent manner. Importantly, the downregulated let-7 miRNA family was restored after simvastatin treatment. We further observed that human CRPC cells transfected with LIN28B-siRNA or shRNA also showed upregulated let-7 miRNAs. Finally, dual treatment with simvastatin and an NF-kappaB inhibitor (CAPE) synergistically induced apoptotic cell death, along with reduction of LIN28B expression, and restoration of let-7 miRNAs levels. Our data illustrate that simvastatin remarkably inhibits the growth of human CRPC cells by suppressing NF kappaB and LIN28B and subsequently upregulating let-7 miRNAs. Moreover, concurrent treatment with simvastatin and an NF-kappaB inhibitor synergistically suppressed the growth of human CRPC cells, suggesting a novel therapeutic approach for human CRPC treatment. PMID- 28910333 TI - Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction. AB - BACKGROUND: Venous thromboembolic disease (VTD) is a public health problem. We recently reported that endothelial colony-forming cells (ECFCs) derived from endothelial cells (EC) (ECFC-ECs) from patients with VTD have a dysfunctional state. For this study, we proposed that a dysfunctional status of these cells generates a reduction of its proliferative ability, which is also associated with senescence and reactive oxygen species (ROS). METHODS AND RESULTS: Human mononuclear cells (MNCs) were obtained from peripheral blood from 40 healthy human volunteers (controls) and 50 patients with VTD matched by age (20-50 years) and sex to obtain ECFCs. We assayed their proliferative ability with plasma of patients and controls and supernatants of cultures from ECFC-ECs, senescence associated beta-galactosidase (SA-beta-gal), ROS, and expression of ephrin-B2/Eph B4 receptor. Compared with cells from controls, cells from VTD patients showed an 8-fold increase of ECFCs that emerged 1 week earlier, reduced proliferation at long term (39%) and, in passages 4 and 10, a highly senescent rate (30+/-1.05% vs. 91.3+/-15.07%, respectively) with an increase of ROS and impaired expression of ephrin-B2/Eph-4 genes. Proliferation potential of cells from VTD patients was reduced in endothelial medium [1.4+/-0.22 doubling population (DP)], control plasma (1.18+/-0.31 DP), or plasma from VTD patients (1.65+/-0.27 DP). CONCLUSIONS: As compared with controls, ECFC-ECs from individuals with VTD have higher oxidative stress, proliferation stress, cellular senescence, and low proliferative potential. These findings suggest that patients with a history of VTD are ECFC-ECs dysfunctional that could be associated to permanent risk for new thrombotic events. PMID- 28910334 TI - Academic career intentions in the life sciences: Can research self-efficacy beliefs explain low numbers of aspiring physician and female scientists? AB - A lack of physician scientists as well as a high female dropout rate from academic medicine and basic life sciences is a concern in many countries. The current study analyzes academic career intentions within a sample of recent doctoral graduates from medicine and basic life sciences (N = 1109), focusing on research self-efficacy beliefs as explanatory variable of gender and disciplinary differences. To ensure that differences in research self-efficacy could not be attributed solely to objective scientific performance, we controlled for number of publications and dissertation grade. The results of multivariate analyses pointed to a strong and significant association between research self-efficacy and academic career intentions (beta = 0.49, p<0.001). The lower academic career intentions of medical doctoral graduates were no longer significant when controlling for research self-efficacy. Within the field of medicine, female doctoral graduates expressed lower research self-efficacy beliefs and academic career intentions. When controlling for research self-efficacy, the correlation between gender and academic career intention was no longer significant. In contrast, no gender differences were found within the basic life sciences with respect to neither academic career intentions nor research self-efficacy. PMID- 28910335 TI - Medical leaders or masters?-A systematic review of medical leadership in hospital settings. AB - Medical leadership is increasingly considered as crucial for improving the quality of care and the sustainability of healthcare. However, conceptual clarity is lacking in the literature and in practice. Therefore, a systematic review of the scientific literature was conducted to reveal the different conceptualizations of medical leadership in terms of definitions, roles and activities, and personal-and context-specific features. Eight databases were systematically searched for eligible studies, including empirical studies published in peer-reviewed journals that included physicians carrying out a manager or leadership role in a hospital setting. Finally, 34 articles were included and their findings were synthesized and analyzed narratively. Medical leadership is conceptualized in literature either as physicians with formal managerial roles or physicians who act as informal 'leaders' in daily practices. In both forms, medical leaders must carry out general management and leadership activities and acts to balance between management and medicine, because these physicians must accomplish both organizational and medical staff objectives. To perform effectively, credibility among medical peers appeared to be the most important factor, followed by a scattered list of fields of knowledge, skills and attitudes. Competing logics, role ambiguity and a lack of time and support were perceived as barriers. However, the extent to which physicians must master all elicited features, remains ambiguous. Furthermore, the extent to which medical leadership entails a shift or a reallocation of tasks that are at the core of medical professional work remains unclear. Future studies should implement stronger research designs in which more theory is used to study the effect of medical leadership on professional work, medical staff governance, and subsequently, the quality and efficiency of care. PMID- 28910336 TI - Application of unsupervised analysis techniques to lung cancer patient data. AB - This study applies unsupervised machine learning techniques for classification and clustering to a collection of descriptive variables from 10,442 lung cancer patient records in the Surveillance, Epidemiology, and End Results (SEER) program database. The goal is to automatically classify lung cancer patients into groups based on clinically measurable disease-specific variables in order to estimate survival. Variables selected as inputs for machine learning include Number of Primaries, Age, Grade, Tumor Size, Stage, and TNM, which are numeric or can readily be converted to numeric type. Minimal up-front processing of the data enables exploring the out-of-the-box capabilities of established unsupervised learning techniques, with little human intervention through the entire process. The output of the techniques is used to predict survival time, with the efficacy of the prediction representing a proxy for the usefulness of the classification. A basic single variable linear regression against each unsupervised output is applied, and the associated Root Mean Squared Error (RMSE) value is calculated as a metric to compare between the outputs. The results show that self-ordering maps exhibit the best performance, while k-Means performs the best of the simpler classification techniques. Predicting against the full data set, it is found that their respective RMSE values (15.591 for self-ordering maps and 16.193 for k Means) are comparable to supervised regression techniques, such as Gradient Boosting Machine (RMSE of 15.048). We conclude that unsupervised data analysis techniques may be of use to classify patients by defining the classes as effective proxies for survival prediction. PMID- 28910338 TI - Rapid plasticity of visually evoked responses in rat monocular visual cortex. AB - Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs. PMID- 28910337 TI - Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression. AB - Electroconvulsive therapy (ECT) is an effective treatment for depression, but can have negative side effects including amnesia. The mechanisms of action underlying both the antidepressant and side effects of ECT are not well understood. An equivalent manipulation that is conducted in experimental animals is electroconvulsive seizure (ECS). Rodent studies have provided valuable insights into potential mechanisms underlying the antidepressant and side effects of ECT. However, relatively few studies have investigated the effects of ECS in animal models with a depression-relevant manipulation such as chronic stress. In the present study, mice were first exposed to chronic social stress (CSS) or a control procedure for 15 days followed by ECS or a sham procedure for 10 days. Behavioral effects were investigated using an auditory fear conditioning (learning) and expression (memory) test and a treadmill-running fatigue test. Thereafter, immunohistochemistry was conducted on brain material using the microglial marker Iba-1 and the cholinergic fibre marker ChAT. CSS did not increase fear learning and memory in the present experimental design; in both the control and CSS mice ECS reduced fear learning and fear memory expression. CSS induced the expected fatigue-like effect in the treadmill-running test; ECS induced increased fatigue in CSS and control mice. In CSS and control mice ECS induced inflammation in hippocampus in terms of increased expression of Iba-1 in radiatum of CA1 and CA3. CSS and ECS both reduced acetylcholine function in hippocampus as indicated by decreased expression of ChAT in several hippocampal sub-regions. Therefore, CSS increased fatigue and reduced hippocampal ChAT activity and, rather than reversing these effects, a repeated ECS regimen resulted in impaired fear learning-memory, increased fatigue, increased hippocampal Iba-1 expression, and decreased hippocampal ChAT expression. As such, the current model does not provide insights into the mechanism of ECT antidepressant function but does provide evidence for pathophysiological mechanisms that might contribute to important ECT side-effects. PMID- 28910339 TI - Genome-wide association mapping of resistance to Phytophthora sojae in a soybean [Glycine max (L.) Merr.] germplasm panel from maturity groups IV and V. AB - Phytophthora sojae, an oomycete pathogen of soybean, causes stem and root rot, resulting in annual economic loss up to $2 billion worldwide. Varieties with P. sojae resistance are environmental friendly to effectively reduce disease damages. In order to improve the resistance of P. sojae and broaden the genetic diversity in Southern soybean cultivars and germplasm in the U.S., we established a P. sojae resistance gene pool that has high genetic diversity, and explored genomic regions underlying the host resistance to P. sojae races 1, 3, 7, 17 and 25. A soybean germplasm panel from maturity groups (MGs) IV and V including 189 accessions originated from 10 countries were used in this study. The panel had a high genetic diversity compared to the 6,749 accessions from MGs IV and V in USDA Soybean Germplasm Collection. Based on disease evaluation dataset of these accessions inoculated with P. sojae races 1, 3, 7, 17 and 25, which are publically available, five accessions in this panel were resistant to all races. Genome-wide association analysis identified a total of 32 significant SNPs, which were clustered in resistance-associated genomic regions, among those, ss715619920 was only 3kb away from the gene Glyma.14g087500, a subtilisin protease. Gene expression analysis showed that the gene was down-regulated more than 4 fold (log2 fold > 2.2) in response to P. sojae infection. The identified molecular markers and genomic regions that are associated with the disease resistance in this gene pool will greatly assist the U.S. Southern soybean breeders in developing elite varieties with broad genetic background and P. sojae resistance. PMID- 28910340 TI - Successful 1:1 proportion ventilation with a unique device for independent lung ventilation using a double-lumen tube without complications in the supine and lateral decubitus positions. A pilot study. AB - INTRODUCTION: Adequate blood oxygenation and ventilation/perfusion matching should be main goal of anaesthetic and intensive care management. At present, one of the methods of improving gas exchange restricted by ventilation/perfusion mismatching is independent ventilation with two ventilators. Recently, however, a unique device has been developed, enabling ventilation of independent lungs in 1:1, 2:1, 3:1, and 5:1 proportions. The main goal of the study was to evaluate the device's utility, precision and impact on pulmonary mechanics. Secondly- to measure the gas distribution in supine and lateral decubitus position. MATERIALS AND METHODS: 69 patients who underwent elective thoracic surgery were eligible for the study. During general anaesthesia, after double lumen tube intubation, the aforementioned control system was placed between the anaesthetic machine and the patient. In the supine and lateral decubitus (left/right) positions, measurements of conventional and independent (1:1 proportion) ventilation were performed separately for each lung, including the following: tidal volume, peak pressure and dynamic compliance. RESULTS: Our results show that conventional ventilation using Robertshaw tube in the supine position directs 47% of the tidal volume to the left lung and 53% to the right lung. Furthermore, in the left lateral position, 44% is directed to the dependent lung and 56% to the non dependent lung. In the right lateral position, 49% is directed to the dependent lung and 51% to the non-dependent lung. The control system positively affected non-dependent and dependent lung ventilation by delivering equal tidal volumes into both lungs with no adverse effects, regardless of patient's position. CONCLUSIONS: We report that gas distribution is uneven during conventional ventilation using Robertshaw tube in the supine and lateral decubitus positions. However, this recently released control system enables precise and safe independent ventilation in the supine and the left and right lateral decubitus positions. PMID- 28910341 TI - Individual, household and contextual factors associated with skilled delivery care in Ethiopia: Evidence from Ethiopian demographic and health surveys. AB - Despite evidence that social contexts are key determinants of health, research into factors associated with maternal health service utilization in Ethiopia has often focused on individual and household factors. The downside is that this underestimates the importance of taking contextual factors into account when planning appropriate interventions in promoting safe motherhood in the country. The purpose of this study is to fill this knowledge gap drawing attention to the largely unexplored contextual factors affecting the uptake of skilled attendance at delivery in a nationally representative sample. Data for the study comes from two rounds of the Ethiopian Demographic and Health Surveys (EDHS) conducted in the year 2005 and 2011. Analysis was done using a two-level multivariable multilevel logistic regression model with data from 14, 242 women who had a live birth in the five years preceding the surveys clustered within 540 (in the year 2005) and 624 (in the year 2011) communities. The results of the study point to multiple levels of measured and unmeasured factors affecting the uptake of skilled delivery care in the country. At community level, place of residence, community level of female education and fertility significantly predict the uptake of skilled delivery care. At individual and household level, maternal age, birth order, maternal education, household wealth and access to media predict the uptake of such service. Thus, there is a need to consider community contexts in the design of maternal health programs and employ multi-sectorial approach to addressing barriers at different levels. For example, improving access and availability of skilled delivery care should eventually enhance the uptake of such services at community level in Ethiopia. At individual level, efforts to promote the uptake of such services should constitute targeted interventions paying special attention to the needs of the youth, the multiparous, the less educated and women in the poorest households. PMID- 28910342 TI - Home modification to reduce falls at a health district level: Modeling health gain, health inequalities and health costs. AB - BACKGROUND: There is some evidence that home safety assessment and modification (HSAM) is effective in reducing falls in older people. But there are various knowledge gaps, including around cost-effectiveness and also the impacts at a health district-level. METHODS AND FINDINGS: A previously established Markov macro-simulation model built for the whole New Zealand (NZ) population (Pega et al 2016, Injury Prevention) was enhanced and adapted to a health district level. This district was Counties Manukau District Health Board, which hosts 42,000 people aged 65+ years. A health system perspective was taken and a discount rate of 3% was used for both health gain and costs. Intervention effectiveness estimates came from a systematic review, and NZ-specific intervention costs were extracted from a randomized controlled trial. In the 65+ age-group in this health district, the HSAM program was estimated to achieve health gains of 2800 quality adjusted life-years (QALYs; 95% uncertainty interval [UI]: 547 to 5280). The net health system cost was estimated at NZ$8.44 million (95% UI: $663 to $14.3 million). The incremental cost-effectiveness ratio (ICER) was estimated at NZ$5480 suggesting HSAM is cost-effective (95%UI: cost saving to NZ$15,300 [equivalent to US$10,300]). Targeting HSAM only to people age 65+ or 75+ with previous injurious falls was estimated to be particularly cost-effective (ICERs: $700 and $832, respectively) with the latter intervention being cost-saving. There was no evidence for differential cost-effectiveness by sex or by ethnicity: Maori (Indigenous population) vs non-Maori. CONCLUSIONS: This modeling study suggests that a HSAM program could produce considerable health gain and be cost effective for older people at a health district level. Nevertheless, comparisons may be desirable with other falls prevention interventions such as group exercise programs, which also provide social contact and may prevent various chronic diseases. PMID- 28910344 TI - The rise of the middle author: Investigating collaboration and division of labor in biomedical research using partial alphabetical authorship. AB - Contemporary biomedical research is performed by increasingly large teams. Consequently, an increasingly large number of individuals are being listed as authors in the bylines, which complicates the proper attribution of credit and responsibility to individual authors. Typically, more importance is given to the first and last authors, while it is assumed that the others (the middle authors) have made smaller contributions. However, this may not properly reflect the actual division of labor because some authors other than the first and last may have made major contributions. In practice, research teams may differentiate the main contributors from the rest by using partial alphabetical authorship (i.e., by listing middle authors alphabetically, while maintaining a contribution-based order for more substantial contributions). In this paper, we use partial alphabetical authorship to divide the authors of all biomedical articles in the Web of Science published over the 1980-2015 period in three groups: primary authors, middle authors, and supervisory authors. We operationalize the concept of middle author as those who are listed in alphabetical order in the middle of an authors' list. Primary and supervisory authors are those listed before and after the alphabetical sequence, respectively. We show that alphabetical ordering of middle authors is frequent in biomedical research, and that the prevalence of this practice is positively correlated with the number of authors in the bylines. We also find that, for articles with 7 or more authors, the average proportion of primary, middle and supervisory authors is independent of the team size, more than half of the authors being middle authors. This suggests that growth in authors lists are not due to an increase in secondary contributions (or middle authors) but, rather, in equivalent increases of all types of roles and contributions (including many primary authors and many supervisory authors). Nevertheless, we show that the relative contribution of alphabetically ordered middle authors to the overall production of knowledge in the biomedical field has greatly increased over the last 35 years. PMID- 28910343 TI - Escherichia coli attachment to model particulates: The effects of bacterial cell characteristics and particulate properties. AB - E. coli bacteria move in streams freely in a planktonic state or attached to suspended particulates. Attachment is a dynamic process, and the fraction of attached microorganisms is thought to be affected by both bacterial characteristics and particulate properties. In this study, we investigated how the properties of cell surfaces and stream particulates influence attachment. Attachment assays were conducted for 77 E. coli strains and three model particulates (ferrihydrite, Ca-montmorillonite, or corn stover) under environmentally relevant conditions. Surface area, particle size distribution, and total carbon content were determined for each type of particulate. Among the three particulates, attachment fractions to corn stover were significantly larger than the attachments to 2-line ferrihydrite (p-value = 0.0036) and Ca montmorillonite (p-value = 0.022). Furthermore, attachment to Ca-montmorillonite and corn stover was successfully modeled by a Generalized Additive Model (GAM) using cell characteristics as predictor variables. The natural logarithm of the net charge on the bacterial surface had a significant, positive, and linear impact on the attachment of E. coli bacteria to Ca-montmorillonite (p-value = 0.013), but it did not significantly impact the attachment to corn stover (p value = 0.36). The large diversities in cell characteristics among 77 E. coli strains, particulate properties, and attachment fractions clearly demonstrated the inadequacy of using a static parameter or linear coefficient to predict the attachment behavior of E. coli in stream water quality models. PMID- 28910345 TI - Circulating mRNAs and miRNAs as candidate markers for the diagnosis and prognosis of prostate cancer. AB - Circulating nucleic acids are found in free form in body fluids and may serve as minimally invasive tools for cancer diagnosis and prognosis. Only a few studies have investigated the potential application of circulating mRNAs and microRNAs (miRNAs) in prostate cancer (PCa). The Cancer Genome Atlas (TCGA) database was used for an in silico analysis to identify circulating mRNA and miRNA as potential markers of PCa. A total of 2,267 genes and 49 miRNAs were differentially expressed between normal and tumor samples. The prediction analyses of target genes and integrative analysis of mRNA and miRNA expression revealed eleven genes and eight miRNAs which were validated by RT-qPCR in plasma samples from 102 untreated PCa patients and 50 cancer-free individuals. Two genes, OR51E2 and SIM2, and two miRNAs, miR-200c and miR-200b, showed significant association with PCa. Expression levels of these transcripts distinguished PCa patients from controls (67% sensitivity and 75% specificity). PCa patients and controls with prostate-specific antigen (PSA) <= 4.0 ng/mL were discriminated based on OR51E2 and SIM2 expression levels. The miR-200c expression showed association with Gleason score and miR-200b, with bone metastasis, bilateral tumor, and PSA > 10.0 ng/mL. The combination of circulating mRNA and miRNA was useful for the diagnosis and prognosis of PCa. PMID- 28910346 TI - The evolution of Lachancea thermotolerans is driven by geographical determination, anthropisation and flux between different ecosystems. AB - The yeast Lachancea thermotolerans (formerly Kluyveromyces thermotolerans) is a species with remarkable, yet underexplored, biotechnological potential. This ubiquist occupies a range of natural and anthropic habitats covering a wide geographic span. To gain an insight into L. thermotolerans population diversity and structure, 172 isolates sourced from diverse habitats worldwide were analysed using a set of 14 microsatellite markers. The resultant clustering revealed that the evolution of L. thermotolerans has been driven by the geography and ecological niche of the isolation sources. Isolates originating from anthropic environments, in particular grapes and wine, were genetically close, thus suggesting domestication events within the species. The observed clustering was further validated by several means including, population structure analysis, F statistics, Mantel's test and the analysis of molecular variance (AMOVA). Phenotypic performance of isolates was tested using several growth substrates and physicochemical conditions, providing added support for the clustering. Altogether, this study sheds light on the genotypic and phenotypic diversity of L. thermotolerans, contributing to a better understanding of the population structure, ecology and evolution of this non-Saccharomyces yeast. PMID- 28910347 TI - High HPgV replication is associated with improved surrogate markers of HIV progression. AB - BACKGROUND: Human Pegivirus (HPgV) may have a beneficial effect on HIV disease progression in co-infected patients; however, the virologic characteristics of this infection are not well defined. In this study, we determined HPgV viremia prevalence in Mexico and provide new insights to understand HPgV infection and HPgV/HIV co-infection. METHODS: We analyzed and quantified 7,890 serum samples for HPgV viremia by One-Step RT-Real-Time PCR, 6,484 from healthy blood donors and 1,406 from HIV-infected patients. Data on HIV progression were obtained from patients' records. HPgV genotyping was performed in 445 samples by nested PCR of the 5'URT region. Finite Mixture Models were used to identify clustering patterns of HPgV viremia in blood donors and co-infected antiretroviral (ART)-naive patients. RESULTS: HPgV was detected in 2.98% of blood donors and 33% of HIV patients, with a wide range of viral loads. The most prevalent genotypes were 3 (58.6%)and 2 (33.7%). HPgV viral loads from healthy blood donors and HPgV/HIV+ ART-naive co-infected patients were clustered into two component distributions, low and high, with a cut-off point of 5.07log10 and 5.06log10, respectively. High HPgV viremia was associated with improved surrogate markers of HIV infection, independent of the estimated duration of HIV infection or HIV treatment. CONCLUSIONS: HPgV prevalence in Mexico was similar to that reported for other countries. The prevalent genotypes could be related to Mexico's geographic location and ethnicity, since genotype 2 is frequent in the United States and Europe and genotype 3 in Asia and Amerindian populations. HPgV viral load demonstrated two patterns of replication, low and high. The more pronounced beneficial response observed in co-infected patients with high HPgV viremia may explain discrepancies found between other studies. Mechanisms explaining high and low HPgV replication should be explored to determine whether the persistently elevated replication depends on host or viral factors. PMID- 28910348 TI - The effect of corn trypsin inhibitor, anti-tissue factor pathway inhibitor antibodies and phospholipids on microvesicle-associated thrombin generation in patients with pancreatic cancer and healthy controls. AB - Circulating microvesicles (MVs) are suggested to be important contributors to cancer-associated thrombosis due to the presence of surface-bound procoagulant molecules like tissue factor (TF) and phosphatidylserine (PS). Pancreatic cancer is considered to be one of the most prothrombotic malignancies. The aim of this study was to describe the impact of analytical variables on MV-associated thrombin generation in patients with pancreatic cancer and in healthy controls. MVs were isolated from citrated plasma and added to pooled normal plasma (PNP). Thrombin generation was measured by the calibrated automated thrombogram. The impact of corn trypsin inhibitor (CTI), anti-tissue factor pathway inhibitor (TFPI) antibodies and phospholipids was described. Antibodies against TF were used to assess TF-dependency, and MV-bound PS activity was measured with the Zymuphen MP-activity kit. MVs from the pancreatic cancer patients displayed higher thrombin generation and higher PS-activity than MVs from the healthy control group, while TF-dependency was observed in only 1 out of 13 patient samples. Adequate thrombin generation-curves were only achieved when CTI was omitted and anti-TFPI antibodies were added to PNP prepared in low contact activating tubes. Addition of phospholipids reduced the significant differences between the two groups, and should be omitted. This modified thrombin generation assay could be useful for measurement of procoagulant circulating MVs, allowing the contribution from MVs affecting both the intrinsic and the extrinsic pathway to be measured. PMID- 28910349 TI - A semi-symmetric image encryption scheme based on the function projective synchronization of two hyperchaotic systems. AB - Both symmetric and asymmetric color image encryption have advantages and disadvantages. In order to combine their advantages and try to overcome their disadvantages, chaos synchronization is used to avoid the key transmission for the proposed semi-symmetric image encryption scheme. Our scheme is a hybrid chaotic encryption algorithm, and it consists of a scrambling stage and a diffusion stage. The control law and the update rule of function projective synchronization between the 3-cell quantum cellular neural networks (QCNN) response system and the 6th-order cellular neural network (CNN) drive system are formulated. Since the function projective synchronization is used to synchronize the response system and drive system, Alice and Bob got the key by two different chaotic systems independently and avoid the key transmission by some extra security links, which prevents security key leakage during the transmission. Both numerical simulations and security analyses such as information entropy analysis, differential attack are conducted to verify the feasibility, security, and efficiency of the proposed scheme. PMID- 28910352 TI - Deep learning approach to bacterial colony classification. AB - In microbiology it is diagnostically useful to recognize various genera and species of bacteria. It can be achieved using computer-aided methods, which make the recognition processes more automatic and thus significantly reduce the time necessary for the classification. Moreover, in case of diagnostic uncertainty (the misleading similarity in shape or structure of bacterial cells), such methods can minimize the risk of incorrect recognition. In this article, we apply the state of the art method for texture analysis to classify genera and species of bacteria. This method uses deep Convolutional Neural Networks to obtain image descriptors, which are then encoded and classified with Support Vector Machine or Random Forest. To evaluate this approach and to make it comparable with other approaches, we provide a new dataset of images. DIBaS dataset (Digital Image of Bacterial Species) contains 660 images with 33 different genera and species of bacteria. PMID- 28910350 TI - Phylogeographic, genomic, and meropenem susceptibility analysis of Burkholderia ubonensis. AB - The bacterium Burkholderia ubonensis is commonly co-isolated from environmental specimens harbouring the melioidosis pathogen, Burkholderia pseudomallei. B. ubonensis has been reported in northern Australia and Thailand but not North America, suggesting similar geographic distribution to B. pseudomallei. Unlike most other Burkholderia cepacia complex (Bcc) species, B. ubonensis is considered non-pathogenic, although its virulence potential has not been tested. Antibiotic resistance in B. ubonensis, particularly towards drugs used to treat the most severe B. pseudomallei infections, has also been poorly characterised. This study examined the population biology of B. ubonensis, and includes the first reported isolates from the Caribbean. Phylogenomic analysis of 264 B. ubonensis genomes identified distinct clades that corresponded with geographic origin, similar to B. pseudomallei. A small proportion (4%) of strains lacked the 920kb chromosome III replicon, with discordance of presence/absence amongst genetically highly related strains, demonstrating that the third chromosome of B. ubonensis, like other Bcc species, probably encodes for a nonessential pC3 megaplasmid. Multilocus sequence typing using the B. pseudomallei scheme revealed that one third of strains lack the "housekeeping" narK locus. In comparison, all strains could be genotyped using the Bcc scheme. Several strains possessed high-level meropenem resistance (>=32 MUg/mL), a concern due to potential transmission of this phenotype to B. pseudomallei. In silico analysis uncovered a high degree of heterogeneity among the lipopolysaccharide O-antigen cluster loci, with at least 35 different variants identified. Finally, we show that Asian B. ubonensis isolate RF23-BP41 is avirulent in the BALB/c mouse model via a subcutaneous route of infection. Our results provide several new insights into the biology of this understudied species. PMID- 28910351 TI - Lab meets real life: A laboratory assessment of spontaneous thought and its ecological validity. AB - People's minds frequently wander towards self-generated thoughts, which are unrelated to external stimuli or demands. These phenomena, referred to as "spontaneous thought" (ST) and "mind wandering" (MW), have previously been linked with both costs and benefits. Current assessments of ST and MW have predominantly been conducted in the laboratory, whereas studies on the ecological validity of such lab-related constructs and their interrelations are rare. The current study examined the stability of ST dimensions assessed in the lab and their predictive value with respect to MW, repetitive negative thought (uncontrollable rumination, RUM), and affect in daily life. Forty-three university students were assessed with the Amsterdam Resting State Questionnaire (2nd version) to assess ten ST dimensions during the resting state in two laboratory sessions, which were separated by five days of electronic ambulatory assessment (AA). During AA, individuals indicated the intensity of MW and RUM, as well as of positive and negative affect in daily life ten times a day. ST dimensions measured in the lab were moderately stable across one week. Five out of ten ST lab dimensions were predicted by mental health-related symptoms or by dispositional cognitive traits. Hierarchical linear models revealed that a number of ST lab dimensions predicted cognitive and affective states in daily life. Mediation analyses showed that RUM, but not MW per se, accounted for the relationship between specific ST lab dimensions and mood in daily life. By using a simple resting state task, we could demonstrate that a number of lab dimensions of spontaneous thought are moderately stable, are predicted by mental health symptoms and cognitive traits, and show plausible associations with categories of self-generated thought and mood in daily life. PMID- 28910353 TI - Reference equations for the six-minute walk distance in the healthy Chinese population aged 18-59 years. AB - BACKGROUND: The six-minute walk test (6MWT) is a safe, simple, inexpensive tool for evaluating the functional exercise capacity of patients with chronic respiratory disease. However, there is a lack of standard reference equations for the six-minute walk distance (6MWD) in the healthy Chinese population aged 18-59 years. AIMS: The purposes of the present study were as follows: 1) to measure the anthropometric data and walking distance of a sample of healthy Chinese Han people aged 18-59 years; 2) to construct reference equations for the 6MWD; 3) to compare the measured 6MWD with previously published equations. METHOD: The anthropometric data, demographic information, lung function, and walking distance of Chinese adults aged 18-59 years were prospectively measured using a standardized protocol. We obtained verbal consent from all the subjects before the test, and the study design was approved by the ethics committee of Wenzhou People's Hospital. The 6MWT was performed twice, and the longer distance was used for further analysis. RESULTS: A total of 643 subjects (319 females and 324 males) completed the 6MWT, and average walking distance was 601.6+/-55.51 m. The walking distance was compared between females and males (578+/-49.85 m vs. 623+/ 52.53 m; p < 0.0001) and between physically active subjects and sedentary subjects (609.3+/-56.17 m vs. 592+/-53.23 m; p < 0.0001). Pearson's correlation indicated that the 6MWD was significantly correlated with various demographic and the 6MWT variables, such as age, height, weight, body mass index (BMI), heart rate after the test and the difference in the heart rate before and after the test. Stepwise multiple regression analysis showed that age and height were independent predictors associated with the 6MWD. The reference equations from white, Canadian and Chilean populations tended to overestimate the walking distance in our subjects, while Brazilian and Arabian equations tended to underestimate the walking distance. There was no significant difference in the walking distance between Korean reference equations and the results of the current study. CONCLUSION: In summary, age and height were the most significant predictors of the 6MWD, and regression equations could explain approximately 34% and 28% of the distance variance in the female and male groups, respectively. PMID- 28910354 TI - Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. AB - A hallmark of acute hepatic injury is the recruitment of neutrophils, monocytes and lymphocytes, including natural killer (NK) or T cells, towards areas of inflammation. The recruitment of leukocytes from their reservoirs bone marrow or spleen into the liver is directed by chemokines such as CCL2 (for monocytes) and CCL5 (for lymphocytes). We herein elucidated the impact of chemokine receptor inhibition by the dual CCR2 and CCR5 inhibitor cenicriviroc (CVC) on the composition of myeloid and lymphoid immune cell populations in acute liver injury. CVC treatment effectively inhibited the migration of bone marrow monocytes and splenic lymphocytes (NK, CD4 T-cells) towards CCL2 or CCL5 in vitro. When liver injury was induced by an intraperitoneal injection of carbon tetrachloride (CCl4) in mice, followed by repetitive oral application of CVC, flow cytometric and unbiased t-SNE analysis of intrahepatic leukocytes demonstrated that dual CCR2/CCR5 inhibition in vivo significantly decreased numbers of monocyte derived macrophages in acutely injured livers. CVC also reduced numbers of Kupffer cells (KC) or monocyte derived macrophages with a KC like phenotype, respectively, after injury. In contrast to the inhibitory effects in vitro, CVC had no impact on the composition of hepatic lymphoid cell populations in vivo. Effective inhibition of monocyte recruitment was associated with reduced inflammatory macrophage markers and moderately ameliorated hepatic necroses at 36h after CCl4. In conclusion, dual CCR2/CCR5 inhibition primarily translates into reduced monocyte recruitment in acute liver injury in vivo, suggesting that this strategy will be effective in reducing inflammatory macrophages in conditions of liver disease. PMID- 28910355 TI - Effects of reduced nitrogen inputs on crop yield and nitrogen use efficiency in a long-term maize-soybean relay strip intercropping system. AB - The blind pursuit of high yields via increased fertilizer inputs increases the environmental costs. Relay intercropping has advantages for yield, but a strategy for N management is urgently required to decrease N inputs without yield loss in maize-soybean relay intercropping systems (IMS). Experiments were conducted with three levels of N and three planting patterns, and dry matter accumulation, nitrogen uptake, nitrogen use efficiency (NUE), competition ratio (CR), system productivity index (SPI), land equivalent ratio (LER), and crop root distribution were investigated. Our results showed that the CR of soybean was greater than 1, and that the change in root distribution in space and time resulted in an interspecific facilitation in IMS. The maximum yield of maize under monoculture maize (MM) occurred with conventional nitrogen (CN), whereas under IMS, the maximum yield occurred with reduced nitrogen (RN). The yield of monoculture soybean (MS) and of soybean in IMS both reached a maximum under RN. The LER of IMS varied from 1.85 to 2.36, and the SPI peaked under RN. Additionally, the NUE of IMS increased by 103.7% under RN compared with that under CN. In conclusion, the separation of the root ecological niche contributed to a positive interspecific facilitation, which increased the land productivity. Thus, maize soybean relay intercropping with reduced N input provides a very useful approach to increase land productivity and avert environmental pollution. PMID- 28910356 TI - Recent trends in 30-day mortality in patients with blunt splenic injury: A nationwide trauma database study in Japan. AB - BACKGROUND: Splenic injury frequently occurs after blunt abdominal trauma; however, limited epidemiological data regarding mortality are available. We aimed to investigate mortality rate trends after blunt splenic injury in Japan. METHODS: We retrospectively identified 1,721 adults with blunt splenic injury (American Association for the Surgery of Trauma splenic injury scale grades III V) from the 2004-2014 Japan Trauma Data Bank. We grouped the records of these patients into 3 time phases: phase I (2004-2008), phase II (2009-2012), and phase III (2013-2014). Over the 3 phases, we analysed 30-day mortality rates and investigated their association with the prevalence of certain initial interventions (Mantel-Haenszel trend test). We further performed multiple imputation and multivariable analyses for comparing the characteristics and outcomes of patients who underwent TAE or splenectomy/splenorrhaphy, adjusting for known potential confounders and for within-hospital clustering using generalised estimating equation. RESULTS: Over time, there was a significant decrease in 30-day mortality after splenic injury (p < 0.01). Logistic regression analysis revealed that mortality significantly decreased over time (from phase I to phase II, odds ratio: 0.39, 95% confidence interval: 0.22-0.67; from phase I to phase III, odds ratio: 0.34, 95% confidence interval: 0.19-0.62) for the overall cohort. While the 30-day mortality for splenectomy/splenorrhaphy diminished significantly over time (p = 0.01), there were no significant differences regarding mortality for non-operative management, with or without transcatheter arterial embolisation (p = 0.43, p = 0.29, respectively). CONCLUSIONS: In Japan, in-hospital 30-day mortality rates decreased significantly after splenic injury between 2004 and 2014, even after adjustment for within hospital clustering and other factors independently associated with mortality. Over time, mortality rates decreased significantly after splenectomy/splenorrhaphy, but not after non-operative management. This information is useful for clinicians when making decisions about treatments for patients with blunt splenic injury. PMID- 28910357 TI - The quality of invasive breast cancer care for low reimbursement rate patients: A retrospective study. AB - Though evidence-based treatments have been recommended for breast cancer, underuse of the treatments was still observed. To certain extent, patients' access to care, which can be enhanced by increasing the coverage of health insurance, could account for the current underuse in recommended care. This study aimed to examine the association between different proportions of reimbursement and quality of recommended breast cancer care, as well as length of hospital stay. In this retrospective study, 3669 patients diagnosed with invasive breast cancer between 1 June, 2011 and 30 June, 2013 were recruited. Seven quality indicators from preoperative diagnosis procedures to adjuvant therapy and one composite indicator were selected as dependent variables. Logistic regression and generalized linear models were used to explore the association between quality of care and length of hospital stay with different reimbursement rates. Compared with UEBMI (urban employment basic medical insurance), which represented high level reimbursement rate, patients with lower rates of reimbursement were less likely to receive core biopsy, HER-2 (human epidermal growth factor receptor-2) testing, BCS (breast conserving surgery), SLNB (sentinel lymph nodes biopsy), adjuvant therapy and hormonal treatment. No significant difference in preoperative length of hospital stay was observed among the three insurance schemes, however URBMI (urban resident basic medical insurance) insured patients stayed longer for total length of hospital stay. Significant disparities in utilization of evidence-based breast cancer care among patients with different proportions of reimbursement were observed. Patients with lower rate of reimbursement were less likely to receive recommended care. Our findings could provide important support for further healthcare reform and quality improvement in breast cancer care. PMID- 28910358 TI - E-inclusion: Beyond individual socio-demographic characteristics. AB - The changing demographic structure of the population, resulting in unparalleled growth of the elderly population, means that e-inclusion of this population group is considered to be a social and political priority in the context of the Information Society. Most research studies have only considered individual variables -such as age, gender, education, income and health- in the explanatory models of e-inclusion of senior citizens, while ignoring macro variables, such as the welfare systems and public policies in each country. Simultaneously, most studies focus on small-scale samples, lack international comparisons and do not consider the combined effect of several variables that influence Internet use. This study aims to analyse possible differences between two countries that have different welfare systems and public policies, after controlling for the effects of the individual variables that have been identified in the literature as relevant for Internet use. The study focuses on a sample of 8639 individuals, aged 50 years and over, residing in Portugal and Estonia, who participated in the SHARE project (Survey of Health, Ageing and Retirement in Europe). The results of the logistic regression analysis demonstrate that welfare systems and public policies have an impact on the likelihood of Internet use, thus reinforcing the importance of developing public policies to foster e-inclusion of senior citizens. PMID- 28910359 TI - Prevalence and determinants of oral infection by Human Papillomavirus in HIV infected and uninfected men who have sex with men. AB - BACKGROUND: Oral Human Papillomavirus (HPV) infection is rare in the general population but common in high-risk individuals. Recent data indicate that oral HPV is associated with the development of head and neck carcinomas. HPV16 infection, in particular, increases the risk of oropharyngeal cancer. METHODS: We evaluated oral HPV prevalence and determinants of infection in cancer-free HIV infected and uninfected men who have sex with men (MSM) recruited among attendees of an STI/HIV centre. Oral rinse and gargles were collected using a mouthwash and analyzed with the Linear Array HPV Genotyping Test. Socio-demographic and behavioral data were collected through face-to-face interviews. RESULTS: Overall, 170 MSM participated: 98 HIV-uninfected and 72 HIV-infected (91.7% under cART). Oral HPV was detected in 17.3% and 27.8% of the subjects, respectively (p = 0.13). Non-carcinogenic HPVs were significantly more common among HIV-infected MSM (18.1% vs. 5.1%, p = 0.01). Prevalence of the HPV types included in the quadrivalent HPV vaccine was similar (6.1% vs. 8.3% for the HIV-negative and positive MSM, respectively, p = 0.76). HPV16 was the most frequent type in HIV negative (5.1%), and HIV-positive individuals, in the latter group together with HPV18, 72 and 84 (4.2% each). Older age at first sex (AOR: 4.02, 95% CI: 1.17 13.86 for those older than 18 years of age at first intercourse, p = 0.027) and a higher lifetime number of receptive oral sex partners (AOR: 9.14, 95% CI: 2.49 33.62 for those with >50 compared to <=50 partners, p<0.001) were determinants of oral HPV among HIV-infected MSM. CONCLUSION: Oral HPV infection among MSM attending an urban STI center is very frequent compared to the general population. Sexual behavior appears to be the major determinant of infection among the HIV-infected individuals. PMID- 28910360 TI - Transgelin-2 is upregulated on activated B-cells and expressed in hyperplastic follicles in lupus erythematosus patients. AB - Transgelin-2 (TAGLN2) is an actin-binding protein that controls actin stability and promotes T cell activation. TAGLN2 is also expressed on B-cells but its function in B-cells is unknown. We found that TAGLN2-expressing B-cells were localized in the germinal center (GC) of secondary lymphoid tissues and TAGLN2 mRNA was significantly upregulated after IgM+IgG stimulation in primary human B cells, suggesting that TAGLN2 was upregulated upon B-cell activation. In support of this, lymph nodes (LNs) from patients with systemic lupus erythematosus (SLE), in which the intense GC activity have been recognized, showed increased TAGLN2 expression in B-cells compared to control LNs. Moreover, TAGLN2+B-cells were distributed widely not only in the GC but also in the perifollicular areas in SLE LNs. In contrast, CD19+ B-cells and CD19+CD27+ memory-B cells in peripheral blood of SLE patients showed no increase in TAGLN2 mRNA. Two-photon excitation microscopy of Raji cells demonstrated that TAGLN2 colocalized with F-actin and moved together to the periphery upon stimulation. TAGLN2-knockdown in Raji cells resulted in impaired phosphorylation of PLCgamma2 leading to inhibition of cell migration. Microarray analysis of TAGLN2-knockdown Raji cells showed decreased expression of the genes associated with immune function including CCR6 and as well as of those associated with regulation of the actin cytoskeleton including ABI2, compared to controls. These results suggest that TAGLN2 might regulate activation and migration of B-cells, in particular, the entry of activated B cells into the follicle. We also suggest that TAGLN2 could be used as a marker for activated B-cells. PMID- 28910361 TI - Fever as an initial manifestation of spondyloarthritis: A retrospective study. AB - OBJECTIVES: We aimed to evaluate a wide spectrum of clinical features of adult patients with spondyloarthritis (SpA) whose initial manifestation was fever, using the Assessment of SpondyloArthritis international Society (ASAS) classification criteria. METHODS: We retrospectively collected the electronic medical records of hospitalized SpA patients who initially presented to the Severance Hospital (Seoul, Korea) with fever from January 2010 to May 2016. As a control group, we also recruited one-hundred consecutive patients who were diagnosed with SpA in our outpatient clinic. Clinical features and laboratory findings were compared in two patient groups. RESULTS: There were 26 patients who had fever as initial presentation of SpA (reactive arthritis 50%, undifferentiated SpA 26.9%, ankylosing spondylitis 15.4%, enteropathic arthritis 3.8%, psoriatic arthritis 3.8%). Peripheral SpA was more common in febrile SpA patients than in control SpA patients (65.4% vs 24.0%, p<0.001). Febrile SpA patients were less frequently HLA-B27 positive than control SpA patients (52.2% vs 77.0%, p<0.05). At baseline, systemic inflammatory markers were significantly higher in the febrile SpA patients (white blood cell count, 11.57 vs 7.81 cells/MUL, p<0.001; erythrocyte sedimentation rate, 69.2 vs 41.0 mm/h, p<0.001; C reactive protein, 109.6 vs 15.3 mg/L, p<0.001). The proportion of patients treated with systemic steroids was significantly higher in febrile SpA patients (57.7% vs. 11.0%, p<0.001). The proportion of patients who visited rheumatology specialty was significantly lower in febrile SpA patients than in control SpA patients (7.7% vs 59.0%, p<0.001). CONCLUSION: Various subgroups of SpA can be presented with fever as an initial manifestation. Febrile SpA patients demonstrated higher systemic inflammation and a lower chance to visit rheumatology in early stage. When evaluating febrile patients with any clinical features of SpA, clinicians are advised to consider performing SpA-focused evaluation including HLA-B27 or a simple sacroiliac joint radiograph. PMID- 28910362 TI - Systematic review and meta-analysis of school-based obesity interventions in mainland China. AB - BACKGROUND: Numerous school-based interventions for childhood obesity have been emerging in mainland China in recent decades, but little is known about the effectiveness of such interventions. This study aims to assess the effectiveness of school-based interventions for childhood obesity conducted in mainland China. METHODS: A systematic search was undertaken in eight databases to identify both randomized and non-randomized controlled trials from January 1990 to December 2015 examining the effectiveness of school-based obesity interventions. A random effects meta-analysis was conducted assessing the impact of included interventions on (body mass index) BMI. The quality of each included studies were assessed using Effective Public Health Practice Project Quality Assessment Tool. A P value <0.05 (two-sided) was considered statistically significant. RESULT: Of the seventy-six included studies, we found physical activity and health education were the two most common components of interventions. More treatment studies were effective compared with prevention studies (85.0% vs. 58.3%). Comprehensive interventions involving physical activity and health education appeared more effective than the physical activity only interventions in both obesity treatment and prevention studies. The meta-analyses showed comprehensive interventions involving physical activity and health education had larger effect on the change of BMI than physical activity only interventions (treatment studies: -1.80 kg/m2 (95% CI: -2.15,-1.44) vs. -0.91 kg/m2 (95% CI: -1.15,-0.67); prevention studies: 0.19 kg/m2 (95% CI: -0.27, -0.11) vs. +0.05 kg/m2 (95% CI: -0.04, +0.15)). CONCLUSIONS: Comprehensive school-based interventions may assist in tackling the rising prevalence of childhood obesity in mainland China. PMID- 28910363 TI - Impaired bone formation in ovariectomized mice reduces implant integration as indicated by longitudinal in vivo micro-computed tomography. AB - Although osteoporotic bone, with low bone mass and deteriorated bone architecture, provides a less favorable mechanical environment than healthy bone for implant fixation, there is no general agreement on the impact of osteoporosis on peri-implant bone (re)modeling, which is ultimately responsible for the long term stability of the bone-implant system. Here, we inserted an implant in a mouse model mimicking estrogen deficiency-induced bone loss and we monitored with longitudinal in vivo micro-computed tomography the spatio-temporal changes in bone (re)modeling and architecture, considering the separate contributions of trabecular, endocortical and periosteal surfaces. Specifically, 12 week-old C57BL/6J mice underwent OVX/SHM surgery; 9 weeks after we inserted special metal ceramics implants into the 6th caudal vertebra and we measured bone response with in vivo micro-CT weekly for the following 6 weeks. Our results indicated that ovariectomized mice showed a reduced ability to increase the thickness of the cortical shell close to the implant because of impaired peri-implant bone formation, especially at the periosteal surface. Moreover, we observed that healthy mice had a significantly higher loss of trabecular bone far from the implant than estrogen depleted animals. Such behavior suggests that, in healthy mice, the substantial increase in peri-implant bone formation which rapidly thickened the cortex to secure the implant may raise bone resorption elsewhere and, specifically, in the trabecular network of the same bone but far from the implant. Considering the already deteriorated bone structure of estrogen depleted mice, further bone loss seemed to be hindered. The obtained knowledge on the dynamic response of diseased bone following implant insertion should provide useful guidelines to develop advanced treatments for osteoporotic fracture fixation based on local and selective manipulation of bone turnover in the peri implant region. PMID- 28910364 TI - Surge of immune cell formation at birth differs by mode of delivery and infant characteristics-A population-based cohort study. AB - BACKGROUND: Birth by cesarean section is associated with increased risks of immune disorders. We tested whether establishment of immune function at birth relates to mode of delivery, taking other maternal and infant characteristics into account. METHODS AND FINDINGS: Using a prospectively collected database, we retrieved information on maternal and infant characteristics of 6,014 singleton infants delivered from February to April 2014 in Stockholm, Sweden, with gestational age >=35 weeks, Apgar scores >=7, and without congenital malformations or any neonatal morbidity. We linked our data to blood levels of T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), determined as part of a neonatal screening program for immune deficiencies, and representing quantities of newly formed T- and B-lymphocytes. Multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for participants having TREC and KREC levels in the lowest quintile. Multivariate models were adjusted for postnatal age at blood sampling, and included perinatal (mode of delivery, infant sex, gestational age, and birth weight for gestational age), and maternal characteristics (age, parity, BMI, smoking, diabetes, and hypertensive disease). Low TREC was associated with cesarean section before labor (adjusted OR:1.32 [95% CI 1.08-1.62]), male infant sex (aOR:1.60 [1.41-1.83]), preterm birth at 35-36 weeks of gestation (aOR:1.89 [1.21-2.96]) and small for gestational age (aOR:1.67 [1.00-2.79]). Low KREC was associated with male sex (aOR:1.32 [1.15-1.50]), postterm birth at >=42 weeks (aOR:1.43 [1.13-1.82]) and small for gestational age (aOR:2.89 [1.78-4.69]). Maternal characteristics showed no consistent associations with neonatal levels of either TREC or KREC. CONCLUSION: Cesarean section before labor was associated with lower T-lymphocyte formation, irrespective of maternal characteristics, pregnancy, and neonatal risk factors. The significance of a reduced birth-related surge in lymphocyte formation for future immune function and health remains to be investigated. PMID- 28910365 TI - Acute effects of strength exercises and effects of regular strength training on cell free DNA concentrations in blood plasma. AB - Creatine kinase (CK) is a marker for muscle cell damage with limited potential as marker for training load in strength training. Recent exercise studies identified cell free DNA (cfDNA) as a marker for aseptic inflammation and cell damage. Here we overserved in a pilot study the acute effects during strength exercise and chronic effects of regular strength training on cfDNA concentrations over a period of four weeks in three training groups applying conservation training (CT) at 60% of the 1 repetition maximum, high intensity-low repetition training (HT) at 90% of the 1 repetition maximum and differential training (DT) at 60% of the 1 repetition maximum. EDTA-plasma samples were collected before every training session, and on the first and last training day repeatedly after every set of exercises. CfDNA increased significantly by 1.62-fold (mean (+/-SD) before first exercise: 8.31 (2.84) ng/ml, after last exercise 13.48 (4.12) ng/ml) across all groups within a single training session (p<0.001). The increase was 1.77-fold higher (mean (+/-SD) before first exercise: 12.23 (6.29) ng/ml, after last exercise 17.73 (11.24) ng/ml) in HT compared to CT (mean (+/-SD) before first exercise: 6.79 (1.28) ng/ml, after last exercise 10.05 (2.89) ng/ml) (p = 0.01). DNA size analysis suggested predominant release of short, mononucleosomal DNA fragments in the acute exercise setting, while we detected an increase of mostly longer, polynucleosomal cfDNA-fragments at rest before the training session only at day two with a subsequent return to baseline (p<0.001). In contrast, training procedures did not cause any alterations in CK. Our results suggest that during strength exercise short-fragmented cfDNA is released, reflecting a fast, aseptic inflammatory response, while elevation of longer fragments at baseline on day two seemed to reflect mild cellular damage due to a novel training regime. We critically discuss the implications of our findings for future evaluations of cfDNA as a marker for training load in strength training. PMID- 28910366 TI - Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. AB - Gulf War Illness (GWI) is a chronic multi-symptom illness not currently diagnosed by standard medical or laboratory test that affects 30% of veterans who served during the 1990-1991 Gulf War. The clinical presentation of GWI is comparable to that of patients with certain mitochondrial disorders-i.e., clinically heterogeneous multisystem symptoms. Therefore, we hypothesized that mitochondrial dysfunction may contribute to both the symptoms of GWI as well as its persistence over time. We recruited 21 cases of GWI (CDC and Kansas criteria) and 7 controls to participate in this study. Peripheral blood samples were obtained in all participants and a quantitative polymerase chain reaction (QPCR) based assay was performed to quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn) from peripheral blood mononuclear cells. Samples were also used to analyze nuclear DNA lesion frequency and enzyme activity for mitochondrial complexes I and IV. Both mtDNA lesion frequency (p = 0.015, d = 1.13) and mtDNAcn (p = 0.001; d = 1.69) were elevated in veterans with GWI relative to controls. Nuclear DNA lesion frequency was also elevated in veterans with GWI (p = 0.344; d = 1.41), but did not reach statistical significance. Complex I and IV activity (p > 0.05) were similar between groups and greater mtDNA lesion frequency was associated with reduced complex I (r2 = 0.35, p = 0.007) and IV (r2 = -0.28, p < 0.01) enzyme activity. In conclusion, veterans with GWI exhibit greater mtDNA damage which is consistent with mitochondrial dysfunction. PMID- 28910367 TI - A novel panel of alpha-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. AB - Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein alpha-synuclein leading to multiple outcomes, including dementia and Parkinsonism. Recent findings support the notion that across the spectrum of synucleinopathies there exist diverse but specific biochemical modifications and/or structural conformations of alpha-synuclein, which would give rise to protein strain specific prion-like intercellular transmission, a proposed model that could explain synucleinopathies disease progression. Herein, we characterized a panel of antibodies with epitopes within both the C- and N- termini of alpha-synuclein. A comprehensive analysis of human pathological tissue and mouse models of synucleinopathy with these antibodies support the notion that alpha-synuclein exists in distinct modified forms and/or structural variants. Furthermore, these well-characterized and specific tools allow the investigation of biochemical changes associated with alpha-synuclein inclusion formation. We have identified several antibodies of interest with diverse staining and epitope properties that will prove useful in future investigations of strain specific disease progression and the development of targeted immunotherapeutic approaches to synucleinopathies. PMID- 28910368 TI - Mercerized mesoporous date pit activated carbon-A novel adsorbent to sequester potentially toxic divalent heavy metals from water. AB - A substantive approach converting waste date pits to mercerized mesoporous date pit activated carbon (DPAC) and utilizing it in the removal of Cd(II), Cu(II), Pb(II), and Zn(II) was reported. In general, rapid heavy metals adsorption kinetics for Co range: 25-100 mg/L was observed, accomplishing 77-97% adsorption within 15 min, finally, attaining equilibrium in 360 min. Linear and non-linear isotherm studies revealed Langmuir model applicability for Cd(II) and Pb(II) adsorption, while Freundlich model was fitted to Zn(II) and Cu(II) adsorption. Maximum monolayer adsorption capacities (qm) for Cd(II), Pb(II), Cu(II), and Zn(II) obtained by non-linear isotherm model at 298 K were 212.1, 133.5, 194.4, and 111 mg/g, respectively. Kinetics modeling parameters showed the applicability of pseudo-second-order model. The activation energy (Ea) magnitude revealed physical nature of adsorption. Maximum elution of Cu(II) (81.6%), Zn(II) (70.1%), Pb(II) (96%), and Cd(II) (78.2%) were observed with 0.1 M HCl. Thermogravimetric analysis of DPAC showed a total weight loss (in two-stages) of 28.3%. Infra-red spectral analysis showed the presence of carboxyl and hydroxyl groups over DPAC surface. The peaks at 820, 825, 845 and 885 cm-1 attributed to Zn-O, Pb-O, Cd-O, and Cu-O appeared on heavy metals saturated DPAC, confirmed their binding on DPAC during the adsorption. PMID- 28910369 TI - Heightened circulating levels of antimicrobial peptides in tuberculosis-Diabetes co-morbidity and reversal upon treatment. AB - BACKGROUND: The association of antimicrobial peptides (AMPs) with tuberculosis diabetes comorbidity (PTB-DM) is not well understood. METHODS: To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin- 2 (HBD2), human neutrophil peptides 1-3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB). RESULTS: Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the levels of cathelicidin and/or HBD2 were significantly higher in PTB-DM or PTB individuals with bilateral and cavitary disease and also exhibited a significant positive relationship with bacterial burden. Cathelidin, HBD2 and HNP1-3 levels exhibited a positive relationship with HbA1c and/or fasting blood glucose levels. Finally, anti-tuberculosis therapy resulted in significantly diminished levels of cathelicidin, HBD2, granulysin and significantly enhanced levels of HNP1-3 and granulysin in PTB-DM and/or PTB individuals. CONCLUSION: Therefore, our data demonstrate that PTB-DM is associated with markedly enhanced levels of AMPs and diminished levels of granulysin. PMID- 28910370 TI - Intra and inter-session reliability of rapid Transcranial Magnetic Stimulation stimulus-response curves of tibialis anterior muscle in healthy older adults. AB - OBJECTIVE: The clinical use of Transcranial Magnetic Stimulation (TMS) as a technique to assess corticospinal excitability is limited by the time for data acquisition and the measurement variability. This study aimed at evaluating the reliability of Stimulus-Response (SR) curves acquired with a recently proposed rapid protocol on tibialis anterior muscle of healthy older adults. METHODS: Twenty-four neurologically-intact adults (age:55-75 years) were recruited for this test-retest study. During each session, six SR curves, 3 at rest and 3 during isometric muscle contractions at 5% of maximum voluntary contraction (MVC), were acquired. Motor Evoked Potentials (MEPs) were normalized to the maximum peripherally evoked response; the coil position and orientation were monitored with an optical tracking system. Intra- and inter-session reliability of motor threshold (MT), area under the curve (AURC), MEPmax, stimulation intensity at which the MEP is mid-way between MEPmax and MEPmin (I50), slope in I50, MEP latency, and silent period (SP) were assessed in terms of Standard Error of Measurement (SEM), relative SEM, Minimum Detectable Change (MDC), and Intraclass Correlation Coefficient (ICC). RESULTS: The relative SEM was <=10% for MT, I50, latency and SP both at rest and 5%MVC, while it ranged between 11% and 37% for AURC, MEPmax, and slope. MDC values were overall quite large; e.g., MT required a change of 12%MSO at rest and 10%MSO at 5%MVC to be considered a real change. Inter-sessions ICC were >0.6 for all measures but slope at rest and MEPmax and latency at 5%MVC. CONCLUSIONS: Measures derived from SR curves acquired in <4 minutes are affected by similar measurement errors to those found with long-lasting protocols, suggesting that the rapid method is at least as reliable as the traditional methods. As specifically designed to include older adults, this study provides normative data for future studies involving older neurological patients (e.g. stroke survivors). PMID- 28910371 TI - Surveillance of norovirus among children with diarrhea in four major hospitals in Bhutan: Replacement of GII.21 by GII.3 as a dominant genotype. AB - BACKGROUND: Diarrhea is a major cause of morbidity and mortality among Bhutanese children. The etiology of diarrhea is not well known due to the challenges of conducting routine surveillance with Bhutan's modest research facilities. Establishing an etiology is crucial toward generating evidence that will contribute to policy discussions on a diarrheal disease control program. Our previous study, during 2010-2012, revealed that norovirus (NoV) is an important cause of diarrhea among Bhutanese children, and that GII.21 was the major genotype circulating at that time. In other countries, GII.4 is the major genotype responsible for NoV infections. In this update report, we provide new prevalence data to describe the progression of the transformation and distribution of the NoV genotype among Bhutanese children. METHODS: From June 2013 through May 2014, diarrheal stool samples were collected at one national referral hospital in Thimphu, two regional referral hospitals in the eastern and central regions, and one general hospital in the western region of Bhutan. NoV was detected by reverse transcription-polymerase chain reaction (RT-PCR), by amplifying the capsid gene. The RT-PCR results were confirmed by nucleotide sequencing of the amplicons. RESULTS: The proportion of NoV-positive stool samples was 23.6% (147/623), of which 76.9% were NoV GII and the remainders were NoV GI. The median age of infected children was 15.5 months, with a fairly balanced female: male ratio. NoV GII was most prevalent in the colder months (late November-mid April) and NoV GI had the highest prevalence in the summer (mid April-late September). Nucleotide sequencing was successful in 99 samples of GII strains. The most common genotypes were GII.3 (42.6%), GII.4 Sydney 2012 (15.8%), and GII.4 unassigned (11.9%). No GII.21 was found in any child in the present study. Phylogenetic analysis showed that GII.3 strains in the present study belonged to an independent cluster in lineage B. These strains shared an ancestor with those from different countries and Bhutanese strains circulating during 2010. CONCLUSION: NoV remains an important cause of diarrhea among Bhutanese children. Genotype GII.3 from a single ancestor strain has spread, replacing the previously circulating GII.21. Current NoV genotypes are similar to the strains circulating worldwide but are primarily related to those in neighboring countries. NoV GII is prevalent during the cold season, while GI is prevalent during the summer. To develop a NoV infection control policy, further studies are needed. PMID- 28910372 TI - Correlation of serum cartilage oligomeric matrix protein (COMP) and interleukin 16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population. AB - OBJECTIVE: The aim of this study was to investigate the correlations between serum cartilage oligomeric matrix protein (COMP), interleukin-16 (IL-16) and different grades of knee osteoarthritis (KOA) in Malaysian subjects. METHODS: Ninety subjects were recruited comprising 30 with Kellgren-Lawrence (K-L) grade 2 KOA, 27 with K-L grade 3 KOA, 7 with grade 4 KOA, and 30 healthy controls. All subjects completed the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Serum COMP and IL-16 levels were measured using ELISA and their values log transformed to ensure a normal distribution. RESULTS: There was no significant differences in levels of log serum COMP and IL-16 between healthy controls and KOA patients. There were no significant differences in the log serum COMP and IL-16 levels within the different K-L grades in the KOA patients. In KOA patients, log serum IL-16 levels significantly correlated with the WOMAC score (p = 0.001) and its subscales, pain (p = 0.005), stiffness (p = 0.019) and physical function (p<0.0001). Serum IL-16 levels were significantly higher in Malaysian Indians compared to Malays and Chinese (p = 0.024). CONCLUSIONS: In this multi ethnic Malaysian population, there was no difference in serum COMP and IL-16 levels between healthy controls and patients with KOA, nor was there any difference in serum COMP or IL-16 levels across the various K-L grades of KOA. However, there were significant inter-racial differences in serum IL-16 levels. PMID- 28910373 TI - Lack of association of MRI determined subclinical cardiovascular disease with dizziness and vertigo in a cross-sectional population-based study. AB - OBJECTIVE: We investigated the association between subclinical cardiovascular diseases assessed by MRI examination and symptoms of dizziness and vertigo in participants of a population-based sample. METHODS: Data from 400 participants (169 women) aged from 39 to 73 of a cross-sectional MRI sub-study of the "Kooperative Gesundheitsforschung in der Region Augsburg" (KORA) FF4 study from the south of Germany was used. MRI determined subclinical cardiovascular diseases include left and right ventricular structure and function as well as the presence of carotid plaque and carotid wall thickness. Cerebrum diseases include white matter lesions (WML) and cerebral microbleeds (CMB). The main outcomes of dizziness and vertigo were assessed by standardized interview. Logistic regression models were applied and adjusted odds ratios (OR) with 95% confidence intervals (CI) were provided. RESULTS: Lifetime and 12-month prevalence of dizziness and vertigo were 30% (95%CI 26% to 35%) and 21% (95%CI 17% to 26%) respectively in this sample. On multivariable analysis, cardiac and carotid measurements were not associated with dizziness and vertigo excluding orthostatic vertigo (20%, 95CI 16% to 24%). Only in male participants, there was a significant association between WML and the presence of dizziness and vertigo (OR = 2.95, 95%CI 1.08 to 8.07). There was no significant association of CMB with dizziness and vertigo. However, CMB and WML were tending to associate with a higher risk of dizziness and vertigo in the whole sample (CMB: OR = 1.48, 95%CI 0.70; 3.15; WML: OR = 1.71, 95%CI 0.80 to 3.67;), in persons with prediabetes and diabetes (WML: OR = 2.71, 95%CI 0.89 to 8.23) and in men with normal glucose metabolism (CMB: OR = 2.60, 95%CI 0.56 to 12.0; WML: OR = 3.08, 95%CI 0.58 to 16.5). CONCLUSIONS: In this sample of participants without manifest cardiovascular diseases, subclinical left and right ventricular function and carotid structure were consistently not associated with dizziness and vertigo. Subclinical cerebrum measurements, however, tend to increase the risk for dizziness and vertigo, especially in men and in persons with prediabetes or diabetes. PMID- 28910374 TI - Expression of surfactant protein B is dependent on cell density in H441 lung epithelial cells. AB - BACKGROUND: Expression of surfactant protein (SP)-B, which assures the structural stability of the pulmonary surfactant film, is influenced by various stimuli, including glucocorticoids; however, the role that cell-cell contact plays in SP-B transcription remains unknown. The aim of the current study was to investigate the impact of cell-cell contact on SP-B mRNA and mature SP-B expression in the lung epithelial cell line H441. METHODS: Different quantities of H441 cells per growth area were either left untreated or incubated with dexamethasone. The expression of SP-B, SP-B transcription factors, and tight junction proteins were determined by qPCR and immunoblotting. The influence of cell density on SP-B mRNA stability was investigated using the transcription inhibitor actinomycin D. RESULTS: SP-B mRNA and mature SP-B expression levels were significantly elevated in untreated and dexamethasone-treated H441 cells with increasing cell density. High cell density as a sole stimulus was found to barely have an impact on SP-B transcription factor and tight junction mRNA levels, while its stimulatory ability on SP-B mRNA expression could be mimicked using SP-B-negative cells. SP-B mRNA stability was significantly increased in high-density cells, but not by dexamethasone alone. CONCLUSION: SP-B expression in H441 cells is dependent on cell-cell contact, which increases mRNA stability and thereby potentiates the glucocorticoid-mediated induction of transcription. Loss of cell integrity might contribute to reduced SP-B secretion in damaged lung cells via downregulation of SP-B transcription. Cell density-mediated effects should thus receive greater attention in future cell culture-based research. PMID- 28910375 TI - Application of droplet digital PCR for quantitative detection of Spiroplasma citri in comparison with real time PCR. AB - Droplet digital polymerase chain reaction (ddPCR) is a method for performing digital PCR that is based on water-oil emulsion droplet technology. It is a unique approach to measure the absolute copy number of nucleic acid targets without the need of external standards. This study evaluated the applicability of ddPCR as a quantitative detection tool for the Spiroplasma citri, causal agent of citrus stubborn disease (CSD) in citrus. Two sets of primers, SP1, based on the spiral in housekeeping gene, and a multicopy prophage gene, SpV1 ORF1, were used to evaluate ddPCR in comparison with real time (quantitative) PCR (qPCR) for S. citri detection in citrus tissues. Standard curve analyses on tenfold dilution series showed that both ddPCR and qPCR exhibited good linearity and efficiency. However, ddPCR had a tenfold greater sensitivity than qPCR and accurately quantified up to one copy of spiralin gene. Receiver operating characteristic analysis indicated that the ddPCR methodology was more robust for diagnosis of CSD and the area under the curve was significantly broader compared to qPCR. Field samples were used to validate ddPCR efficacy and demonstrated that it was equal or better than qPCR to detect S. citri infection in fruit columella due to a higher pathogen titer. The ddPCR assay detected both the S. citri spiralin and the SpV1 ORF1 targets quantitatively with high precision and accuracy compared to qPCR assay. The ddPCR was highly reproducible and repeatable for both the targets and showed higher resilience to PCR inhibitors in citrus tissue extract for the quantification of S. citri compare to qPCR. PMID- 28910377 TI - Parametric analysis of occupant ankle and tibia injuries in frontal impact. AB - OBJECTIVE: Non-fatal tibia and ankle injuries without proper protection from the restraint system has gotten wide attention from researchers. This study aimed to investigate occupant tibia and ankle injuries under realistic frontal impact environment that is rarely considered in previous experimental and simulant studies. METHODS: An integrated occupant-vehicle model was established by coupling an isolated car cab model and a hybrid occupant model with a biofidelic pelvis-lower limb model, while its loading conditions were extracted from the realistic full-frontal impact test. A parametric study was implemented concerning instrument panel (IP) design and pedal intrusion/rotation parameters. RESULTS: The significant influences of the IP angle, pedal intrusion and pedal rotation on tibia axial force, tibia bending moment and ankle dorsiflexion angle are noted. By coupling their effects, a new evaluation index named CAIEI (Combined Ankle Injury Evaluation Index) is established to evaluate ankle injury (including tibia fractures in ankle region) risk and severity in robustness. CONCLUSIONS: Overall results and analysis indicate that ankle dorsiflexion angle should be considered when judging the injury in lower limb under frontal impact. Meanwhile, the current index with coupling effects of tibia axial force, bending moment and ankle dorsiflexion angle is in a good correlation with the simulation injury outcomes. PMID- 28910376 TI - Long non-coding RNA SeT and miR-155 regulate the Tnfalpha gene allelic expression profile. AB - It is becoming increasingly appreciated that the non-coding genome may have a great impact on the regulation of chromatin structure and gene expression. The innate immune response can be mediated upon lipopolysaccharide stimulation of macrophages which leads to immediate transcriptional activation of early responsive genes including tumor necrosis factor alpha (Tnfalpha). The functional role of non-coding RNAs, such as lncRNAs and microRNAs, on the transcriptional activation of proinflammatory genes and the subsequent regulation of the innate immune response is still lacking mechanistic insights. In this study we wanted to unravel the functional role of the lncRNA SeT, which is encoded from the murine Tnfalpha gene locus, and miR-155 on the transcriptional regulation of the Tnfalpha gene. We utilized genetically modified mice harboring either a deletion of the SeT promoter elements or the mature miR-155 and studied the response of macrophages to lipopolysaccharide (LPS) stimulation. We found that decreased expression of the lncRNA SeT in murine primary macrophages resulted in increased mortality of mice challenged with LPS, which was corroborated by increased Tnfalpha steady state mRNA levels and a higher frequency of biallelically expressing macrophages. On the contrary, miR-155 deletion resulted in reduced Tnfalpha mRNA levels supported by a lower frequency of biallelically expressing macrophages upon stimulation with LPS. In both cases, in the absence of either lncRNA SeT or miR-155 we observed a deregulation of the Tnfalpha allele homologous pairing, previously shown to regulate the switch from mono- to bi allelic gene expression. Although lncRNA SeT was not found to be a direct target of miR-155 its stability was increased upon miR-155 deletion. This study suggests a role of the non-coding genome in mediating Tnfalpha mRNA dosage control based on the regulation of homologous pairing of gene alleles and their subsequent biallelic expression. PMID- 28910378 TI - Neuroinflammation, myelin and behavior: Temporal patterns following mild traumatic brain injury in mice. AB - Traumatic brain injury (TBI) results in white matter injury (WMI) that is associated with neurological deficits. Neuroinflammation originating from microglial activation may participate in WMI and associated disorders. To date, there is little information on the time courses of these events after mild TBI. Therefore we investigated (i) neuroinflammation, (ii) WMI and (iii) behavioral disorders between 6 hours and 3 months after mild TBI. For that purpose, we used experimental mild TBI in mice induced by a controlled cortical impact. (i) For neuroinflammation, IL-1b protein as well as microglial phenotypes, by gene expression for 12 microglial activation markers on isolated CD11b+ cells from brains, were studied after TBI. IL-1b protein was increased at 6 hours and 1 day. TBI induced a mixed population of microglial phenotypes with both pro inflammatory, anti-inflammatory and immunomodulatory markers from 6 hours to 3 days post-injury. At 7 days, microglial activation was completely resolved. (ii) Three myelin proteins were assessed after TBI on ipsi- and contralateral corpus callosum, as this structure is enriched in white matter. TBI led to an increase in 2',3'-cyclic-nucleotide 3'-phosphodiesterase, a marker of immature and mature oligodendrocyte, at 2 days post-injury; a bilateral demyelination, evaluated by myelin basic protein, from 7 days to 3 months post-injury; and an increase in myelin oligodendrocyte glycoprotein at 6 hours and 3 days post-injury. Transmission electron microscopy study revealed various myelin sheath abnormalities within the corpus callosum at 3 months post-TBI. (iii) TBI led to sensorimotor deficits at 3 days post-TBI, and late cognitive flexibility disorder evidenced by the reversal learning task of the Barnes maze 3 months after injury. These data give an overall invaluable overview of time course of neuroinflammation that could be involved in demyelination and late cognitive disorder over a time-scale of 3 months in a model of mild TBI. This model could help to validate a pharmacological strategy to prevent post-traumatic WMI and behavioral disorders following mild TBI. PMID- 28910379 TI - A one-year prospective study of colonization with antimicrobial-resistant organisms on admission to a Vietnamese intensive care unit. AB - There is a paucity of data regarding initial bacterial colonization on admission to Intensive Care Units (ICUs) in low and middle-income countries (LMICs). Patients admitted to ICUs in LMICs are at high-risk of subsequent infection with antimicrobial-resistant organisms (AROs). We conducted a prospective, observational study at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam from November 2014 to January 2016 to assess the colonization and antimicrobial susceptibility of Staphylococcus aureus, Escherichia coli, Klebsiella spp., Pseudomonas spp. and Acinetobacter spp. among adult patients within 48 hours of ICU admission. We found the admission colonization prevalence (with at least one of the identified organisms) was 93.7% (785/838) and that of AROs was 63.1% (529/838). The colonization frequency with AROs among patients admitted from the community was comparable to those transferred from other hospitals (62.2% vs 63.8%). Staphylococcus aureus was the most commonly isolated bacteria from nasal swabs (13.1%, 110/838) and the methicillin-resistant Staphylococcus aureus nasal colonization prevalence was 8.6% (72/838). We isolated Escherichia coli from rectal swabs from almost all enrolled patients (88.3%, 740/838) and 52.1% (437/838) of patients were colonized by extended spectrum beta-lactamase producing Escherichia coli. Notably, Klebsiella pneumoniae was the most frequently isolated bacteria from the tracheal swabs (11.8%, 18/153). Vietnamese ICU patients have a high rate of colonization with AROs and are thus at risk of subsequent infections with these organisms if good infection control practices are not in place. PMID- 28910380 TI - Validation of the diabetes screening tools proposed by the American Diabetes Association in an aging Chinese population. AB - AIM: Diabetes is a serious global health problem. A simple and effective screening tool should have substantial public health benefit. We investigated the performance of the latest American Diabetes Association diabetes screening methods in our aging Chinese population. METHODS: Subjects without diabetes who returned for the 4th Hong Kong Cardiovascular Risk Factors Prevalence Study in 2010-2012 were evaluated for the probability of having diabetes with reference to the age- and body mass index-based screening criteria (screening criteria) and the diabetes risk test (risk test), and the conclusion drawn was compared to their measured glycaemic status. Diabetes was defined by fasting glucose >= 7 mmol/L or 2-hour post oral glucose tolerance test glucose >= 11.1 mmol/L. RESULTS: 1415 subjects, aged 58.1+/-10.2, were evaluated. 95 (6.7%) had diabetes. The risk test showed good accuracy (area under the receiver operating curve 0.725) in screening for diabetes with an optimal cut-off score of five. Compared to the screening criteria, the risk test had significantly better specificity (0.57 vs. 0.41, p<0.001), positive predictive value (0.12 vs. 0.09, p<0.001) and positive diagnostic likelihood ratio (1.85 vs. 1.37, p<0.001). To diagnose one case of diabetes, fewer subjects (11 vs. 18) needed to be tested for blood glucose if the risk test was adopted. CONCLUSION: The risk test appears to be a more effective screening tool in our population. It is simple to use and can be adopted as a public health strategy for identifying people with undiagnosed diabetes for early intervention. PMID- 28910381 TI - Genetic characterization of blaNDM-harboring plasmids in carbapenem-resistant Escherichia coli from Myanmar. AB - The bacterial enzyme New Delhi metallo-beta-lactamase hydrolyzes almost all beta lactam antibiotics, including carbapenems, which are drugs of last resort for severe bacterial infections. The spread of carbapenem-resistant Enterobacteriaceae that carry the New Delhi metallo-beta-lactamase gene, blaNDM, poses a serious threat to public health. In this study, we genetically characterized eight carbapenem-resistant Escherichia coli isolates from a tertiary care hospital in Yangon, Myanmar. The eight isolates belonged to five multilocus-sequence types and harbored multiple antimicrobial-resistance genes, resulting in resistance against nearly all of the antimicrobial agents tested, except colistin and fosfomycin. Nine plasmids harboring blaNDM genes were identified from these isolates. Multiple blaNDM genes were found in the distinct Inc-replicon types of the following plasmids: an IncA/C2 plasmid harboring blaNDM 1 (n = 1), IncX3 plasmids harboring blaNDM-4 (n = 2) or blaNDM-7 (n = 1), IncFII plasmids harboring blaNDM-4 (n = 1) or blaNDM-5 (n = 3), and a multireplicon F plasmid harboring blaNDM-5 (n = 1). Comparative analysis highlighted the diversity of the blaNDM-harboring plasmids and their distinct characteristics, which depended on plasmid replicon types. The results indicate circulation of phylogenetically distinct strains of carbapenem-resistant E. coli with various plasmids harboring blaNDM genes in the hospital. PMID- 28910382 TI - Refining experimental dental implant testing in the Gottingen Minipig using 3D computed tomography-A morphometric study of the mandibular canal. AB - This study reports morphometric and age-related data of the mandibular canal and the alveolar ridge of the Gottingen Minipig to avoid complications during in vivo testing of endosseus dental implants and to compare these data with the human anatomy. Using 3D computed tomography, six parameters of the mandibular canal as well as the alveolar bone height and the alveolar ridge width were measured in Gottingen Minipigs aged 12, 17 and 21 months. Our null hypothesis assumes that the age and the body mass have an influence on the parameters measured. The study found that the volume, length and depth of the mandibular canal all increase with age. The width of the canal does not change significantly with age. The body mass does not have an influence on any of the measured parameters. The increase in canal volume appears to be due to loss of deep spongy bone in the posterior premolar and molar regions. This reduces the available space for dental implantations, negatively affecting implant stability and potentially the integrity of the inferior alveolar neurovascular bundle. Dynamic anatomical changes occur until 21 months. On ethical grounds, using minipigs younger than 21 months in experimental implant dentistry is inadvisable. Paradoxically the measurements of the 12 months old pigs indicate a closer alignment of their mandibular anatomy to that of humans suggesting that they may be better models for implant studies. Given the variability in mandibular canal dimensions in similar age cohorts, the use of imaging techniques is essential for the selection of individual minipigs for dental prosthetic interventions and thus higher success rates. PMID- 28910383 TI - Structural signatures of thermal adaptation of bacterial ribosomal RNA, transfer RNA, and messenger RNA. AB - Temperature adaptation of bacterial RNAs is a subject of both fundamental and practical interest because it will allow a better understanding of molecular mechanism of RNA folding with potential industrial application of functional thermophilic or psychrophilic RNAs. Here, we performed a comprehensive study of rRNA, tRNA, and mRNA of more than 200 bacterial species with optimal growth temperatures (OGT) ranging from 4 degrees C to 95 degrees C. We investigated temperature adaptation at primary, secondary and tertiary structure levels. We showed that unlike mRNA, tRNA and rRNA were optimized for their structures at compositional levels with significant tertiary structural features even for their corresponding randomly permutated sequences. tRNA and rRNA are more exposed to solvent but remain structured for hyperthermophiles with nearly OGT-independent fluctuation of solvent accessible surface area within a single RNA chain. mRNA in hyperthermophiles is essentially the same as random sequences without tertiary structures although many mRNA in mesophiles and psychrophiles have well-defined tertiary structures based on their low overall solvent exposure with clear separation of deeply buried from partly exposed bases as in tRNA and rRNA. These results provide new insight into temperature adaptation of different RNAs. PMID- 28910384 TI - Correction: Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006510.]. PMID- 28910385 TI - Improving the characterization of endothelial progenitor cell subsets by an optimized FACS protocol. AB - The characterization of circulating endothelial progenitor cells (EPCs) is fundamental to any study related to angiogenesis. Unfortunately, current literature lacks consistency in the definition of EPC subsets due to variations in isolation strategies and inconsistencies in the use of lineage markers. Here we address critical points in the identification of hematopoietic progenitor cells (HPCs), circulating endothelial cells (CECs), and culture-generated outgrowth endothelial cells (OECs) from blood samples of healthy adults (AB) and umbilical cord (UCB). Peripheral blood mononuclear cells (PBMCs) were enriched using a Ficoll-based gradient followed by an optimized staining and gating strategy to enrich for the target cells. Sorted EPC populations were subjected to RT-PCR for tracing the expression of markers beyond the limits of cell surface based immunophenotyping. Using CD34, CD133 and c-kit staining, combined with FSC and SSC, we succeeded in the accurate and reproducible identification of four HPC subgroups and found significant differences in the respective populations in AB vs. UCB. Co-expression analysis of endothelial markers on HPCs revealed a complex pattern characterized by various subpopulations. CECs were identified by using CD34, KDR, CD45, and additional endothelial markers, and were subdivided according to their apoptotic state and expression of c-kit. Comparison of UCB CECs vs. AB-CECs revealed significant differences in CD34 and KDR levels. OECs were grown from PBMC-fractions We found that viable c-kit+ CECs are a candidate circulating precursor for CECs. RT-PCR to angiogenic factors and receptors revealed that all EPC subsets expressed angiogenesis-related molecules. Taken together, the improvements in immunophenotyping and gating strategies resulted in accurate identification and comparison of better defined cell populations in a single procedure. PMID- 28910386 TI - DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers. AB - BACKGROUND: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. METHODS: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines. RESULTS: BRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion. CONCLUSIONS: Our results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models. PMID- 28910387 TI - Epstein Barr virus Latent Membrane Protein-1 enhances dendritic cell therapy lymph node migration, activation, and IL-12 secretion. AB - Dendritic cells (DC) are a promising cell type for cancer vaccines due to their high immunostimulatory capacity. However, improper maturation of DC prior to treatment may account for the limited efficacy of DC vaccine clinical trials. Latent Membrane Protein-1 (LMP1) of Epstein-Barr virus was examined for its ability to mature and activate DC as a gene-based molecular adjuvant for DC vaccines. DC were transduced with an adenovirus 5 vector (Ad5) expressing LMP1 under the control of a Tet-inducible promoter. Ad5-LMP1 was found to mature and activate both human and mouse DC. LMP1 enhanced in vitro migration of DC toward CCL19, as well as in vivo migration of DC to the inguinal lymph nodes of mice following intradermal injection. LMP1-transduced DC increased T cell proliferation in a Pmel-1 adoptive transfer model and enhanced survival in B16 F10 melanoma models. LMP1-DC also enhanced protection in a vaccinia-Gag viral challenge assay. LMP1 induced high levels of IL-12p70 secretion in mouse DC when compared to standard maturation protocols. Importantly, LMP1-transduced human DC retained the capacity to secrete IL-12p70 and TNF in response to DC restimulation. In contrast, DC matured with Monocyte Conditioned Media-Mimic cocktail (Mimic) were impaired in IL-12p70 secretion following restimulation. Overall, LMP1 matured and activated DC, induced migration to the lymph node, and generated high levels of IL-12p70 in a murine model. We propose LMP1 as a promising molecular adjuvant for DC vaccines. PMID- 28910388 TI - Structure of the human transcobalamin beta domain in four distinct states. AB - Vitamin B12 (cyanocobalamin, CNCbl) is an essential cofactor-precursor for two biochemical reactions in humans. When ingested, cobalamins (Cbl) are transported via a multistep transport system into the bloodstream, where the soluble protein transcobalamin (TC) binds Cbl and the complex is taken up into the cells via receptor mediated endocytosis. Crystal structures of TC in complex with CNCbl have been solved previously. However, the initial steps of holo-TC assembly have remained elusive. Here, we present four crystal structures of the beta domain of human TC (TC-beta) in different substrate-bound states. These include the apo and CNCbl-bound states, providing insight into the early steps of holo-TC assembly. We found that in vitro assembly of TC-alpha and TC-beta to a complex was Cbl dependent. We also determined the structure of TC-beta in complex with cobinamide (Cbi), an alternative substrate, shedding light on the specificity of TC. We finally determined the structure of TC-beta in complex with an inhibitory antivitamin B12 (anti-B12). We used this structure to model the binding of anti B12 into full-length holo-TC and could rule out that the inhibitory function of anti-B12 was based on an inability to form a functional complex with TC. PMID- 28910389 TI - Cross-species conservation of episome maintenance provides a basis for in vivo investigation of Kaposi's sarcoma herpesvirus LANA. AB - Many pathogens, including Kaposi's sarcoma herpesvirus (KSHV), lack tractable small animal models. KSHV persists as a multi-copy, nuclear episome in latently infected cells. KSHV latency-associated nuclear antigen (kLANA) binds viral terminal repeat (kTR) DNA to mediate episome persistence. Model pathogen murine gammaherpesvirus 68 (MHV68) mLANA acts analogously on mTR DNA. kLANA and mLANA differ substantially in size and kTR and mTR show little sequence conservation. Here, we find kLANA and mLANA act reciprocally to mediate episome persistence of TR DNA. Further, kLANA rescued mLANA deficient MHV68, enabling a chimeric virus to establish latent infection in vivo in germinal center B cells. The level of chimeric virus in vivo latency was moderately reduced compared to WT infection, but WT or chimeric MHV68 infected cells had similar viral genome copy numbers as assessed by immunofluorescence of LANA intranuclear dots or qPCR. Thus, despite more than 60 Ma of evolutionary divergence, mLANA and kLANA act reciprocally on TR DNA, and kLANA functionally substitutes for mLANA, allowing kLANA investigation in vivo. Analogous chimeras may allow in vivo investigation of genes of other human pathogens. PMID- 28910391 TI - Different rates of spontaneous mutation of chloroplastic and nuclear viroids as determined by high-fidelity ultra-deep sequencing. AB - Mutation rates vary by orders of magnitude across biological systems, being higher for simpler genomes. The simplest known genomes correspond to viroids, subviral plant replicons constituted by circular non-coding RNAs of few hundred bases. Previous work has revealed an extremely high mutation rate for chrysanthemum chlorotic mottle viroid, a chloroplast-replicating viroid. However, whether this is a general feature of viroids remains unclear. Here, we have used high-fidelity ultra-deep sequencing to determine the mutation rate in a common host (eggplant) of two viroids, each representative of one family: the chloroplastic eggplant latent viroid (ELVd, Avsunviroidae) and the nuclear potato spindle tuber viroid (PSTVd, Pospiviroidae). This revealed higher mutation frequencies in ELVd than in PSTVd, as well as marked differences in the types of mutations produced. Rates of spontaneous mutation, quantified in vivo using the lethal mutation method, ranged from 1/1000 to 1/800 for ELVd and from 1/7000 to 1/3800 for PSTVd depending on sequencing run. These results suggest that extremely high mutability is a common feature of chloroplastic viroids, whereas the mutation rates of PSTVd and potentially other nuclear viroids appear significantly lower and closer to those of some RNA viruses. PMID- 28910390 TI - Identify changes of brain regional homogeneity in early and later adult onset patients with first-episode depression using resting-state fMRI. AB - OBJECTIVE: Previous work exhibited different brain grey matter volume (GMV) changes between patients with early adult onset depression (EOD, age 18-29) and later adult onset depression (LOD, age 30-44) by using 30-year-old as the cut-off age. To identify whether regional homogeneity (ReHo) changes are also different between EOD and LOD by using same cut-off age, we used resting-state functional magnetic resonance imaging (fMRI) to detect the abnormal ReHo between patients with EOD and LOD in the present study. METHODS: Resting-state fMRI scans of 58 patients with EOD, 62 patients with LOD, 60 young healthy controls (HC), and 52 old HC were obtained. The ReHo approach was used to analyze the images. RESULTS: The ANOVA analysis revealed that the ReHo values in the frontoparietal, occipital, and cerebellar regions were significantly different among the four groups. Relative to patients with LOD, patients with EOD displayed significantly increased ReHo in the left precuneus, and decreased ReHo in the right fusiform. The ReHo values in the left precuneus and the right fusiform had no significant correlation with the score of the depression rating scale or illness duration in both patient subgroups. Compared to young HC, patients with EOD showed significantly increased ReHo in the right frontoparietal regions and the right calcarine. Furthermore, the increased ReHo in the right frontoparietal regions, right insula and left hippocampus, and decreased ReHo in the left inferior occipital gyrus, right middle occipital gyrus, left calcarine, and left supplementary motor area were observed in patients with LOD when compared to old HC. CONCLUSIONS: The ReHo of brain areas that were related to mood regulation was changed in the first-episode, drug-naive adult patients with MDD. Adult patients with EOD and LOD exhibited different ReHo abnormalities relative to each age matched comparison group, suggesting that depressed adult patients with different age-onset might have different pathological mechanism. PMID- 28910392 TI - Karyotype analysis and sex determination in Australian Brush-turkeys (Alectura lathami). AB - Sexual differentiation across taxa may be due to genetic sex determination (GSD) and/or temperature sex determination (TSD). In many mammals, males are heterogametic (XY); whereas females are homogametic (XX). In most birds, the opposite is the case with females being heterogametic (ZW) and males the homogametic sex (ZZ). Many reptile species lack sex chromosomes, and instead, sexual differentiation is influenced by temperature with specific temperatures promoting males or females varying across species possessing this form of sexual differentiation, although TSD has recently been shown to override GSD in Australian central beaded dragons (Pogona vitticeps). There has been speculation that Australian Brush-turkeys (Alectura lathami) exhibit TSD alone and/or in combination with GSD. Thus, we sought to determine if this species possesses sex chromosomes. Blood was collected from one sexually mature female and two sexually mature males residing at Sylvan Heights Bird Park (SHBP) and shipped for karyotype analysis. Karyotype analysis revealed that contrary to speculation, Australian Brush-turkeys possess the classic avian ZW/ZZ sex chromosomes. It remains a possibility that a biased primary sex ratio of Australian Brush-turkeys might be influenced by maternal condition prior to ovulation that result in her laying predominantly Z- or W-bearing eggs and/or sex-biased mortality due to higher sensitivity of one sex in environmental conditions. A better understanding of how maternal and extrinsic factors might differentially modulate ovulation of Z- or W-bearing eggs and hatching of developing chicks possessing ZW or ZZ sex chromosomes could be essential in conservation strategies used to save endangered members of Megapodiidae. PMID- 28910393 TI - Genetic and epigenetic engines of diversity in pathogenic microbes. PMID- 28910394 TI - Up-regulation of gap junction in peripheral blood T lymphocytes contributes to the inflammatory response in essential hypertension. AB - Inflammation has been shown to play an important role in the mechanisms involved in the pathogenesis of hypertension. Connexins (Cxs)-based gap junction channels (GJCs) or hemichannels (HCs) are involved in the maintenance of homeostasis in the immune system. However, the role of Cx43-based channels in T-lymphocytes in mediating the immune response in essential hypertension is not fully understand. The present study was designed to investigate the role of Cxs-based channels in T lymphocytes in the regulation of hypertension-mediated inflammation. The surface expressions of T lymphocyte subtypes, Cx40/Cx43, and inflammatory cytokines (IFN gamma (interferon-gamma) and TNF-alpha (tumor necrosis factor alpha)) in T cells, as well as gap junction communication of peripheral blood lymphocytes from essential hypertensive patients (EHs) and normotensive healthy subjects (NTs) were detected by flow cytometry. Expression levels and phosphorylation of Cx43 protein in peripheral blood lymphocytes of EHs and NTs were analyzed by Western blot. The proliferation rate of peripheral blood mononuclear cells (PBMCs) after treatment with a Cxs inhibitor was examined by a CCK-8 assay. The levels of inflammatory cytokines were detected using ELISA. Within the CD3+ T cell subsets, we found a significant trend toward an increase in the percentage of CD4+ T cells and CD4+/CD8+ ratio as well as in serum levels of IFN-gamma and TNF-alpha in the peripheral blood of EHs compared with those in NTs. Moreover, the peripheral blood lymphocytes of EH patients exhibited enhanced GJCs formation, increased Cx43 protein level and Cx43 phosphorylation at Ser368, and a significant increase in Cx40/Cx43 surface expressions levels in CD4+ or CD8+ T lymphocytes. Cx43-based channel inhibition by a mimetic peptide greatly reduced the exchange of dye between lymphocytes, proliferation of stimulated lymphocytes and the pro inflammatory cytokine levels of EHs and NTs. Our data suggest that Cx40/Cx43 based channels in lymphocytes may be involved in the regulation of T lymphocyte proliferation and the production of pro-inflammatory cytokines, which contribute to the hypertensive inflammatory response. PMID- 28910395 TI - Multilocus genotyping of Giardia duodenalis in captive non-human primates in Sichuan and Guizhou provinces, Southwestern China. AB - Giardia duodenalis is a common human and animal pathogen. It has been increasingly reported in wild and captive non-human primates (NHPs) in recent years. However, multilocus genotyping information for G. duodenalis infecting NHPs in southwestern China is limited. In the present study, the prevalence and multilocus genotypes (MLGs) of G. duodenalis in captive NHPs in southwestern China were determined. We examined 207 fecal samples from NHPs in Sichuan and Guizhou provinces, and 16 specimens were positive for G. duodenalis. The overall infection rate was 7.7%, and only assemblage B was identified. G. duodenalis was detect positive in northern white-cheeked gibbon (14/36, 38.9%), crab-eating macaque (1/60, 1.7%) and rhesus macaques (1/101, 0.9%). Multilocus sequence typing based on beta-giardin (bg), triose phosphate isomerase (tpi) and glutamate dehydrogenase (gdh) revealed nine different assemblage B MLGs (five known genotypes and four novel genotypes). Based on a phylogenetic analysis, one potentially zoonotic genotype of MLG SW7 was identified in a northern white cheeked gibbon. A high degree of genetic diversity within assemblage B was observed in captive northern white-cheeked gibbons in Southwestern China, including a potentially zoonotic genotype, MLG SW7. To the best of our knowledge, this is the first report using a MLGs approach to identify G. duodenalis in captive NHPs in Southwestern China. PMID- 28910397 TI - A three-dimensional strain measurement method in elastic transparent materials using tomographic particle image velocimetry. AB - BACKGROUND: The mechanical interaction between blood vessels and medical devices can induce strains in these vessels. Measuring and understanding these strains is necessary to identify the causes of vascular complications. This study develops a method to measure the three-dimensional (3D) distribution of strain using tomographic particle image velocimetry (Tomo-PIV) and compares the measurement accuracy with the gauge strain in tensile tests. METHODS AND FINDINGS: The test system for measuring 3D strain distribution consists of two cameras, a laser, a universal testing machine, an acrylic chamber with a glycerol water solution for adjusting the refractive index with the silicone, and dumbbell-shaped specimens mixed with fluorescent tracer particles. 3D images of the particles were reconstructed from 2D images using a multiplicative algebraic reconstruction technique (MART) and motion tracking enhancement. Distributions of the 3D displacements were calculated using a digital volume correlation. To evaluate the accuracy of the measurement method in terms of particle density and interrogation voxel size, the gauge strain and one of the two cameras for Tomo-PIV were used as a video-extensometer in the tensile test. The results show that the optimal particle density and interrogation voxel size are 0.014 particles per pixel and 40 * 40 * 40 voxels with a 75% overlap. The maximum measurement error was maintained at less than 2.5% in the 4-mm-wide region of the specimen. CONCLUSIONS: We successfully developed a method to experimentally measure 3D strain distribution in an elastic silicone material using Tomo-PIV and fluorescent particles. To the best of our knowledge, this is the first report that applies Tomo-PIV to investigate 3D strain measurements in elastic materials with large deformation and validates the measurement accuracy. PMID- 28910398 TI - Body composition and prediction equations using skinfold thickness for body fat percentage in Southern Brazilian adolescents. AB - OBJECTIVES: The purpose of this study was to: a) determine the nutritional status of Brazilian adolescents, and; b) present a skinfold thickness model (ST) to estimate body fat developed with Brazilian samples, using dual energy x-ray absorptiometry (DXA) as reference method. METHODS: The main study group was composed of 374 adolescents, and further 42 adolescents for the validation group. Weight, height, waist circumference measurements, and body mass index (BMI) were collected, as well as nine ST-biceps (BI), triceps (TR), chest (CH), axillary (AX) subscapularis (SB), abdominal (AB), suprailiac (SI), medial thigh (TH), calf (CF), and fat percentage (%BF) obtained by DXA. RESULTS: The prevalence of overweight in adolescents was 20.9%, and obesity 5.8%. Regression analysis through ordinary least square method (OLS) allowed obtainment of three equations with values of R2 = 0.935, 0.912 and 0.850, standard error estimated = 1.79, 1.78 and 1.87, and bias = 0.06, 0.20 and 0.05, respectively. CONCLUSION: the innovation of this study lies in presenting new regression equations for predicting body fat in Southern Brazilian adolescents based on a representative and heterogeneous sample from DXA. PMID- 28910396 TI - PI3K-C2alpha knockdown decreases autophagy and maturation of endocytic vesicles. AB - Phosphoinositide 3-kinase (PI3K) family members are involved in diverse cellular fates including cell growth, proliferation, and survival. While many molecular details are known about the Class I and III PI3Ks, less is known about the Class II PI3Ks. To explore the function of all eight PI3K isoforms in autophagy, we knock down each gene individually and measure autophagy. We find a significant decrease in autophagy following siRNA-mediated PIK3C2A (encoding the Class 2 PI3K, PI3K-C2alpha) knockdown. This defective autophagy is rescued by exogenous PI3K-C2alpha, but not kinase-dead PI3K-C2alpha. Using confocal microscopy, we probe for markers of endocytosis and autophagy, revealing that PI3K-C2alpha colocalizes with markers of endocytosis. Though endocytic uptake is intact, as demonstrated by transferrin labeling, PIK3C2A knockdown results in vesicle accumulation at the recycling endosome. We isolate distinct membrane sources and observe that PI3K-C2alpha interacts with markers of endocytosis and autophagy, notably ATG9. Knockdown of either PIK3C2A or ATG9A/B, but not PI3KC3, results in an accumulation of transferrin-positive clathrin coated vesicles and RAB11 positive vesicles at the recycling endosome. Taken together, these results support a role for PI3K-C2alpha in the proper maturation of endosomes, and suggest that PI3K-C2alpha may be a critical node connecting the endocytic and autophagic pathways. PMID- 28910399 TI - Cholesterol added prior to vitrification on the cryotolerance of immature and in vitro matured bovine oocytes. AB - This study examines whether incorporating cholesterol-loaded methyl-beta cyclodextrin (CLC) in the bovine oocyte plasma membrane improves oocyte tolerance to vitrification. In vitro matured oocytes were incubated with 2 mg/ml BODIPY labeled CLC for different time intervals in FCS or PVA supplemented medium or exposed to different CLC concentrations to examine the subcellular localization of cholesterol by confocal microscopy live-cell imaging. Subsequently, the effects of optimized CLC concentrations and incubation times prior to vitrification on early embryo development were assessed. Then, we evaluated the effects of pretreatment with 2 mg/ml CLC for 30 min before the vitrification of immature (GV) and in vitro matured (MII) oocytes on developmental competence and gene expression. Our results indicate a high plasma membrane labeling intensity after 30 min of incubation with 2 mg/ml CLC for 30 min, regardless of the holding medium used. When oocytes were incubated with 1 mg/ml, 2 mg/ml and 3 mg/ml of CLC, intense labeling was observed at the plasma membrane after 40, 30 and 20 min, respectively. CLC pre-treatment before the vitrification of bovine oocytes did not affect subsequent cleavage and embryo development rates irrespective of CLC concentrations, incubation times or meiotic stage. However, pretreatment seems to improve the quality of embryos derived from vitrified oocytes, mainly when oocytes were vitrified at the GV stage. PMID- 28910400 TI - Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection. AB - Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient's cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR 146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs), BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71 infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response. PMID- 28910401 TI - Strontium-doped hydroxyapatite polysaccharide materials effect on ectopic bone formation. AB - Previous studies performed using polysaccharide-based matrices supplemented with hydroxyapatite (HA) particles showed their ability to form in subcutaneous and intramuscular sites a mineralized and osteoid tissue. Our objectives are to optimize the HA content in the matrix and to test the combination of HA with strontium (Sr-HA) to increase the matrix bioactivity. First, non-doped Sr-HA powders were combined to the matrix at three different ratios and were implanted subcutaneously for 2 and 4 weeks. Interestingly, matrices showed radiolucent properties before implantation. Quantitative analysis of micro-CT data evidenced a significant increase of mineralized tissue formed ectopically with time of implantation and allowed us to select the best ratio of HA to polysaccharides of 30% (w/w). Then, two Sr-substitution of 8% and 50% were incorporated in the HA powders (8Sr-HA and 50Sr-HA). Both Sr-HA were chemically characterized and dispersed in matrices. In vitro studies performed with human mesenchymal stem cells (MSCs) demonstrated the absence of cytotoxicity of the Sr-doped matrices whatever the amount of incorporated Sr. They also supported osteoblastic differentiation and activated the expression of one late osteoblastic marker involved in the mineralization process i.e. osteopontin. In vivo, subcutaneous implantation of these Sr-doped matrices induced osteoid tissue and blood vessels formation. PMID- 28910402 TI - Nasopharyngeal bacterial load as a marker for rapid and easy diagnosis of invasive pneumococcal disease in children from Mozambique. AB - BACKGROUND: Current diagnostic methods for detection of Streptococcus pneumoniae in children with suspected invasive pneumococcal disease have limitations of accuracy, timeliness, and patient convenience. This study aimed to determine the performance of pneumococcal load quantified with a real-time polymerase-chain reaction in nasopharyngeal samples to diagnose invasive pneumococcal disease in children. METHODS: Matched case-control study of patients <5 years of age with invasive pneumococcal disease admitted to the Manhica District Hospital (Mozambique) and asymptomatic controls recruited in different periods between 2006 and 2014. Cases were confirmed by a positive bacterial culture for S. pneumoniae in blood or cerebrospinal fluid. Nasopharyngeal aspirates were collected from cases and controls and pneumococcal density was quantified by lytA real-time polymerase-chain reaction. RESULTS: Thirty cases (median age 12.8 months) and sixty controls (median age 11.7 months) were enrolled and 70% of them were male. Nasopharyngeal pneumococcal carriage was high in both groups: 28/30 (93.3%) for cases vs. 53/60 (88.3%) for controls (p = 0.71). Mean nasopharyngeal pneumococcal load was identified as a marker for invasive pneumococcal disease (7.0 log10 copies/mL in cases vs. 5.8 log10 copies/mL in controls, p<0.001) and showed good discriminatory power (AUC-ROC: 82.1%, 95% CI 72.5%-91.8%). A colonization density of 6.5 log10 copies/mL was determined as the optimal cut-off value to distinguish cases from controls (sensitivity 75.0%, specificity 73.6%). CONCLUSION: Use of non-invasive nasopharyngeal aspirates coupled with rapid and accurate quantification of pneumococcal load by real-time polymerase chain reaction has the potential to become a useful surrogate marker for early diagnosis of invasive pneumococcal disease in children. PMID- 28910404 TI - Accuracy of cited "facts" in medical research articles: A review of study methodology and recalculation of quotation error rate. AB - Previous reviews estimated that approximately 20 to 25% of assertions cited from original research articles, or "facts," are inaccurately quoted in the medical literature. These reviews noted that the original studies were dissimilar and only began to compare the methods of the original studies. The aim of this review is to examine the methods of the original studies and provide a more specific rate of incorrectly cited assertions, or quotation errors, in original research articles published in medical journals. Additionally, the estimate of quotation errors calculated here is based on the ratio of quotation errors to quotations examined (a percent) rather than the more prevalent and weighted metric of quotation errors to the references selected. Overall, this resulted in a lower estimate of the quotation error rate in original medical research articles. A total of 15 studies met the criteria for inclusion in the primary quantitative analysis. Quotation errors were divided into two categories: content ("factual") or source (improper indirect citation) errors. Content errors were further subdivided into major and minor errors depending on the degree that the assertion differed from the original source. The rate of quotation errors recalculated here is 14.5% (10.5% to 18.6% at a 95% confidence interval). These content errors are predominantly, 64.8% (56.1% to 73.5% at a 95% confidence interval), major errors or cited assertions in which the referenced source either fails to substantiate, is unrelated to, or contradicts the assertion. Minor errors, which are an oversimplification, overgeneralization, or trivial inaccuracies, are 35.2% (26.5% to 43.9% at a 95% confidence interval). Additionally, improper secondary (or indirect) citations, which are distinguished from calculations of quotation accuracy, occur at a rate of 10.4% (3.4% to 17.5% at a 95% confidence interval). PMID- 28910403 TI - Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells. AB - Sepsis is a systemic infection that enhances host vulnerability to secondary infections normally controlled by T cells. Using CLP sepsis model, we observed that sepsis induces apoptosis of circulating memory CD8 T-cells (TCIRCM) and diminishes their effector functions, leading to impaired CD8 T-cell mediated protection to systemic pathogen re-infection. In the context of localized re infections, tissue resident memory CD8 T-cells (TRM) provide robust protection in a variety of infectious models. TRM rapidly 'sense' infection in non-lymphoid tissues and 'alarm' the host by enhancing immune cell recruitment to the site of the infection to accelerate pathogen clearance. Here, we show that compared to pathogen-specific TCIRCM, sepsis does not invoke significant numerical decline of Vaccinia virus induced skin-TRM keeping their effector functions (e.g., Ag dependent IFN-gamma production) intact. IFN-gamma-mediated recruitment of immune cells to the site of localized infection was, however, reduced in CLP hosts despite TRM maintaining their 'sensing and alarming' functions. The capacity of memory CD8 T-cells in the septic environment to respond to inflammatory cues and arrive to the site of secondary infection/antigen exposure remained normal suggesting T-cell-extrinsic factors contributed to the observed lesion. Mechanistically, we showed that IFN-gamma produced rapidly during sepsis-induced cytokine storm leads to reduced IFN-gammaR1 expression on vascular endothelium. As a consequence, decreased expression of adhesion molecules and/or chemokines (VCAM1 and CXCL9) on skin endothelial cells in response to TRM-derived IFN-gamma was observed, leading to sub-optimal bystander-recruitment of effector cells and increased susceptibility to pathogen re-encounter. Importantly, as visualized by intravital 2-photon microscopy, exogenous administration of CXCL9/10 was sufficient to correct sepsis-induced impairments in recruitment of effector cells at the localized site of TRM antigen recognition. Thus, sepsis has the capacity to alter skin TRM anamnestic responses without directly impacting TRM number and/or function, an observation that helps to further define the immunoparalysis phase in sepsis survivors. PMID- 28910405 TI - Linking extreme interannual changes in prey availability to foraging behaviour and breeding investment in a marine predator, the macaroni penguin. AB - Understanding the mechanisms that link prey availability to predator behaviour and population change is central to projecting how a species may respond to future environmental pressures. We documented the behavioural responses and breeding investment of macaroni penguins Eudyptes chrysolophus across five breeding seasons where local prey density changed by five-fold; from very low to highly abundant. When prey availability was low, foraging trips were significantly longer and extended overnight. Birds also foraged farther from the colony, potentially in order to reach more distant foraging grounds and allow for increased search times. These extended foraging trips were also linked to a marked decrease in fledgling weights, most likely associated with reduced rates of provisioning. Furthermore, by comparing our results with previous work on this population, it appears that lowered first-year survival rates associated, at least partially, with fledging masses were also evident for this cohort. This study integrates a unique set of prey density, predator behaviour and predator breeding investment data to highlight a possible behavioural mechanism linking perturbations in prey availability to population demography. PMID- 28910406 TI - Cancer therapy in a microbial bottle: Uncorking the novel biology of the protozoan Toxoplasma gondii. PMID- 28910407 TI - The spectral features of EEG responses to transcranial magnetic stimulation of the primary motor cortex depend on the amplitude of the motor evoked potentials. AB - Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event related desynchronization (ERD-peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation. PMID- 28910408 TI - Effects of tumour necrosis factor alpha upon the metabolism of the endocannabinoid anandamide in prostate cancer cells. AB - Tumour necrosis factor alpha (TNFalpha) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase-2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. TNFalpha treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acyl phosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon gamma treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE2-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFalpha treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal endocannabinoid signalling system in prostate cancer. PMID- 28910409 TI - Risk of acute gastroenteritis associated with human bocavirus infection in children: A systematic review and meta-analysis. AB - Human bocaviruses (HBoVs), which were first identified in 2005 and are composed of genotypes 1-4, have been increasingly detected worldwide in pediatric patients with acute gastroenteritis. To investigate if HBoV infection is a risk factor of acute gastroenteritis in children younger than 5 years old, we searched PubMed, Embase (via Ovid), the Chinese Biomedical Literature Database (CBM), and the Cochrane Library for studies assessing the prevalence of HBoVs in individuals from Oct 25, 2005 to Oct 31, 2016. We included studies using PCR-based diagnostics for HBoVs from stool specimens of patients with or without acute gastroenteritis that carried out research for over 1 year on pediatric patients aged younger than 5 years old. The primary outcome was the HBoV prevalence among all cases with acute gastroenteritis. Pooled estimates of the HBoV prevalence were then generated by fitting linear mixed effect meta-regression models. Of the 36 studies included, the pooled HBoV prevalence in 20,591 patients with acute gastroenteritis was 6.90% (95% confidence interval (95% CI): 5.80-8.10%). In the ten studies with a control group, HBoVs were detected in 12.40% of the 3,620 cases with acute gastroenteritis and in 12.22% of the 2,030 control children (odds ratio (OR): 1.44; 95% CI: 0.95-2.19, p = 0.09 between case and control groups). HBoV1 and HBoV2 were detected in 3.49% and 8.59% of acute gastroenteritis cases, respectively, and in 2.22% and 5.09% of control children, respectively (OR: 1.40; 95% CI: 0.61-3.25; p = 0.43 and OR: 1.68; 95% CI: 1.21 2.32; p = 0.002, respectively). Current evidence suggests that the overall HBoV prevalence in children younger than 5 years old is not significantly different between groups with or without acute gastroenteritis. However, when HBoV1 was excluded, the HBoV2 prevalence was significantly different between these two groups, which may imply that HBoV2 is a risk factor of acute gastroenteritis in children younger than 5 years old. PMID- 28910410 TI - The function of Drosophila larval class IV dendritic arborization sensory neurons in the larval-pupal transition is separable from their function in mechanical nociception responses. AB - The sensory and physiological inputs which govern the larval-pupal transition in Drosophila, and the neuronal circuity that integrates them, are complex. Previous work from our laboratory identified a dosage-sensitive genetic interaction between the genes encoding the Rho-GEF Trio and the zinc-finger transcription factor Sequoia that interfered with the larval-pupal transition. Specifically, we reported heterozygous mutations in sequoia (seq) dominantly exacerbated the trio mutant phenotype, and this seq-enhanced trio mutant genotype blocked the transition of third instar larvae from foragers to wanderers, a requisite behavioral transition prior to pupation. In this work, we use the GAL4-UAS system to rescue this phenotype by tissue-specific trio expression. We find that expressing trio in the class IV dendritic arborization (da) sensory neurons rescues the larval-pupal transition, demonstrating the reliance of the larval pupal transition on the integrity of these sensory neurons. As nociceptive responses also rely on the functionality of the class IV da neurons, we test mechanical nociceptive responses in our mutant and rescued larvae and find that mechanical nociception is separable from the ability to undergo the larval-pupal transition. This demonstrates for the first time that the roles of the class IV da neurons in governing two critical larval behaviors, the larval-pupal transition and mechanical nociception, are functionally separable from each other. PMID- 28910411 TI - Molecular population genetics of the Polycomb genes in Drosophila subobscura. AB - Polycomb group (PcG) proteins are important regulatory factors that modulate the chromatin state. They form protein complexes that repress gene expression by the introduction of posttranslational histone modifications. The study of PcG proteins divergence in Drosophila revealed signals of coevolution among them and an acceleration of the nonsynonymous evolutionary rate in the lineage ancestral to the obscura group species, mainly in subunits of the Pcl-PRC2 complex. Herein, we have studied the nucleotide polymorphism of PcG genes in a natural population of D. subobscura to detect whether natural selection has also modulated the evolution of these important regulatory genes in a more recent time scale. Results show that most genes are under the action of purifying selection and present a level and pattern of polymorphism consistent with predictions of the neutral model, the exceptions being Su(z)12 and Pho. MK tests indicate an accumulation of adaptive changes in the SU(Z)12 protein during the divergence of D. subobscura and D. guanche. In contrast, the HKA test shows a deficit of polymorphism at Pho. The most likely explanation for this reduced variation is the location of this gene in the dot-like chromosome and would indicate that this chromosome also has null or very low recombination in D. subobscura, as reported in D. melanogaster. PMID- 28910412 TI - Transcriptional responses in the hepatopancreas of Eriocheir sinensis exposed to deltamethrin. AB - Deltamethrin is an important pesticide widely used against ectoparasites. Deltamethrin contamination has resulted in a threat to the healthy breeding of the Chinese mitten crab, Eriocheir sinensis. In this study, we investigated transcriptional responses in the hepatopancreas of E. sinensis exposed to deltamethrin. We obtained 99,087,448, 89,086,478, and 100,117,958 raw sequence reads from control 1, control 2, and control 3 groups, and 92,094,972, 92,883,894, and 92,500,828 raw sequence reads from test 1, test 2, and test 3 groups, respectively. After filtering and quality checking of the raw sequence reads, our analysis yielded 79,228,354, 72,336,470, 81,859,826, 77,649,400, 77,194,276, and 75,697,016 clean reads with a mean length of 150 bp from the control and test groups. After deltamethrin treatment, a total of 160 and 167 genes were significantly upregulated and downregulated, respectively. Gene ontology terms "biological process," "cellular component," and "molecular function" were enriched with respect to cell killing, cellular process, other organism part, cell part, binding, and catalytic. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes showed that the metabolic pathways were significantly enriched. We found that the CYP450 enzyme system, carboxylesterase, glutathione-S-transferase, and material (including carbohydrate, lipid, protein, and other substances) metabolism played important roles in the metabolism of deltamethrin in the hepatopancreas of E. sinensis. This study revealed differentially expressed genes related to insecticide metabolism and detoxification in E. sinensis for the first time and will help in understanding the toxicity and molecular metabolic mechanisms of deltamethrin in E. sinensis. PMID- 28910413 TI - The influence of the Japanese waving cat on the joint spatial compatibility effect: A replication and extension of Dolk, Hommel, Prinz, and Liepelt (2013). AB - In a joint go/no-go Simon task, each of two participants is to respond to one of two non-spatial stimulus features by means of a spatially lateralized response. Stimulus position varies horizontally and responses are faster and more accurate when response side and stimulus position match (compatible trial) than when they mismatch (incompatible trial), defining the social Simon effect or joint spatial compatibility effect. This effect was originally explained in terms of action/task co-representation, assuming that the co-actor's action is automatically co-represented. Recent research by Dolk, Hommel, Prinz, and Liepelt (2013) challenged this account by demonstrating joint spatial compatibility effects in a task-setting in which non-social objects like a Japanese waving cat were present, but no real co-actor. They postulated that every sufficiently salient object induces joint spatial compatibility effects. However, what makes an object sufficiently salient is so far not well defined. To scrutinize this open question, the current study manipulated auditory and/or visual attention attracting cues of a Japanese waving cat within an auditory (Experiment 1) and a visual joint go/no-go Simon task (Experiment 2). Results revealed that joint spatial compatibility effects only occurred in an auditory Simon task when the cat provided auditory cues while no joint spatial compatibility effects were found in a visual Simon task. This demonstrates that it is not the sufficiently salient object alone that leads to joint spatial compatibility effects but instead, a complex interaction between features of the object and the stimulus material of the joint go/no-go Simon task. PMID- 28910414 TI - Genome sequences and SNP analyses of Corynespora cassiicola from cotton and soybean in the southeastern United States reveal limited diversity. AB - Corynespora cassiicola attackes diverse agriculturally important plants, including soybean and cotton, in the US. It is a reemerge pathogen on cotton in southeastern US. Whole genome sequences of four cotton and one soybean isolate from Tennessee were used to develop single nucleotide polymorphism markers for cotton isolates. Cotton isolates had little diversity at the genome level and very little differentiation from the soybean isolate. Analysis of 75 isolates from cotton and soybean, using targeted-sequencing of 22 polymorphic SNP sites, revealed eight multi-locus genotypes and it appears a single clonal lineage predominates across the southeastern region. The cotton and soybean genome sequences were significantly different from the public reference genome derived from a rubber isolate and the utility of these novel resources will be discussed. PMID- 28910415 TI - Cystatin C, a potential marker for cerebral microvascular compliance, is associated with white-matter hyperintensities progression. AB - Cerebral white matter hyperintensities (WMHs) are central MRI markers of the brain aging process, but the mechanisms for its progression remain unclear. In this study, we aimed to determine whether the baseline serum cystatin C level represented one mechanism underlying WMH progression, and whether it was associated with the long-term progression of cerebral WMH volume in MRI. 166 consecutive individuals who were >=50 years of age and who underwent initial/follow-up MRI evaluations within an interval of 34-45 months were included. Serum cystatin C level, glomerular-filtration rate (GFR), and other laboratory parameters were measured at their initial evaluation and at the end of follow-up. Cerebrovascular risk factors, medications, and blood-pressure parameters were also reviewed. WMH progression rate was measured by subtracting WMH volume at baseline from that at the follow-up using volumetric analysis, divided by the MRI intervals. At baseline, WMH volume was 9.61+/-13.17 mL, mean GFR was 77.3+/-22.8 mL/min, and mean cystatin C level was 0.92+/-0.52 mg/L. After 37.9+/-3.4 months, the change in WMH volume was 3.64+/-6.85 mL, the progression rate of WMH volume was 1.18+/-2.28 mL/year, the mean DeltaGFR was 2.4+/-7.9 mL/min, and the mean Deltacystatin C was 0.03+/-0.34 mg/L. The progression rate of WMH volume was linearly associated with cystatin C level (B coefficient = 0.856; 95% confidence interval [CI] 0.174-1.538; P = 0.014), along with the baseline WMH volume (B = 0.039; 95% CI 0.019-0.059; P<0.001), after adjusting for the conventional vascular risk factors, laboratory parameters, medication profiles, and GFR. Especially, patients with a baseline level of cystatin C >=1.00 mg/L exhibited a much higher progression rate of WMH as compared with those with a baseline level of cystatin C <1.00 mg/L (1.60+/-1.91 mL/year vs. 0.82+/-1.63 mL/year, P = 0.010). We concluded that serum cystatin C level is independently associated with the long-term progression rate of the cerebral WMH volume. Therefore, serum cystatin C level might predict the progression of cerebral WMH. PMID- 28910416 TI - Lateralized behaviour as indicator of affective state in dairy cows. AB - In humans, there is evidence that sensory processing of novel or threatening stimuli is right hemisphere dominated, especially in people experiencing negative affective states. There is also evidence for similar lateralization in a number of non-human animal species. Here we investigate whether this is also the case in domestic cattle that may experience long-term negative states due to commonly occurring conditions such as lameness. Health and welfare implications associated with pain in lame cows are a major concern in dairy farming. Behavioural tests combining animal behaviour and cognition could make a meaningful contribution to our understanding of disease-related changes in sensory processing in animals, and consequently enhance their welfare. We presented 216 lactating Holstein Friesian cows with three different unfamiliar objects which were placed either bilaterally (e.g. two yellow party balloons, two black/white checkerboards) or hung centrally (a KongTM) within a familiar area. Cows were individually exposed to the objects on three consecutive days, and their viewing preference/eye use, exploration behaviour/nostril use, and stop position during approach was assessed. Mobility (lameness) was repeatedly scored during the testing period. Overall, a bias to view the right rather than the left object was found at initial presentation of the bilateral objects. More cows also explored the right object rather than the left object with their nose. There was a trend for cows appearing hesitant in approaching the objects by stopping at a distance to them, to then explore the left object rather than the right. In contrast, cows that approached the objects directly had a greater tendency to contact the right object. No significant preference in right or left eye/nostril use was found when cows explored the centrally-located object. We found no relationship between lameness and lateralized behaviour. Nevertheless, observed trends suggesting that lateralized behaviour in response to bilaterally located unfamiliar objects may reflect an immediate affective response are discussed. Further study is needed to understand the impact of long-term affective states on hemispheric dominance and lateralized behaviour. PMID- 28910417 TI - Differential cellular responses associated with oxidative stress and cell fate decision under nitrate and phosphate limitations in Thalassiosira pseudonana: Comparative proteomics. AB - Diatoms are important components of marine ecosystems and contribute greatly to the world's primary production. Despite their important roles in ecosystems, the molecular basis of how diatoms cope with oxidative stress caused by nutrient fluctuations remains largely unknown. Here, an isobaric tags for relative and absolute quantitation (iTRAQ) proteomic method was coupled with a series of physiological and biochemical techniques to explore oxidative stress- and cell fate decision-related cellular and metabolic responses of the diatom Thalassiosira pseudonana to nitrate (N) and inorganic phosphate (P) stresses. A total of 1151 proteins were detected; 122 and 56 were significantly differentially expressed from control under N- and P-limited conditions, respectively. In N-limited cells, responsive proteins were related to reactive oxygen species (ROS) accumulation, oxidative stress responses and cell death, corresponding to a significant decrease in photosynthetic efficiency, marked intracellular ROS accumulation, and caspase-mediated programmed cell death activation. None of these responses were identified in P-limited cells; however, a significant up-regulation of alkaline phosphatase proteins was observed, which could be the major contributor for P-limited cells to cope with ambient P deficiency. These findings demonstrate that fundamentally different metabolic responses and cellular regulations are employed by the diatom in response to different nutrient stresses and to keep the cells viable. PMID- 28910418 TI - The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch. AB - The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with S-substitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening. PMID- 28910421 TI - Correction: Adiponectin Signaling Regulates Lipid Production in Human Sebocytes. AB - [This corrects the article DOI: 10.1371/journal.pone.0169824.]. PMID- 28910420 TI - Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates. AB - Mammalian prion structures and replication mechanisms are poorly understood. Most synthetic recombinant prion protein (rPrP) amyloids prepared without cofactors are non-infectious or much less infectious than bona fide tissue-derived PrPSc. This effect has been associated with differences in folding of the aggregates, manifested in part by reduced solvent exclusion and protease-resistance in rPrP amyloids, especially within residues ~90-160. Substitution of 4 lysines within residues 101-110 of rPrP (central lysine cluster) with alanines (K4A) or asparagines (K4N) allows formation of aggregates with extended proteinase K (PK) resistant cores reminiscent of PrPSc, particularly when seeded with PrPSc. Here we have compared the infectivity of rPrP aggregates made with K4N, K4A or wild type (WT) rPrP, after seeding with scrapie brain homogenate (ScBH) or normal brain homogenate (NBH). None of these preparations caused clinical disease on first passage into rodents. However, the ScBH-seeded fibrils (only) led to a subclinical pathogenesis as indicated by increases in prion seeding activity, neuropathology, and abnormal PrP in the brain. Seeding activities usually accumulated to much higher levels in animals inoculated with ScBH-seeded fibrils made with the K4N, rather than WT, rPrP molecules. Brain homogenates from subclinical animals induced clinical disease on second passage into "hamsterized" Tg7 mice, with shorter incubation times in animals inoculated with ScBH-seeded K4N rPrP fibrils. On second passage from animals inoculated with ScBH-seeded WT fibrils, we detected an additional PK resistant PrP fragment that was similar to that of bona fide PrPSc. Together these data indicate that both the central lysine cluster and scrapie seeding of rPrP aggregates influence the induction of PrP misfolding, neuropathology and clinical manifestations upon passage in vivo. We confirm that some rPrP aggregates can initiate further aggregation without typical pathogenesis in vivo. We also provide evidence that there is little, if any, biohazard associated with routine RT-QuIC assays. PMID- 28910419 TI - IL-10-mediated signals act as a switch for lymphoproliferation in Human T-cell leukemia virus type-1 infection by activating the STAT3 and IRF4 pathways. AB - Human T-cell leukemia virus type-1 (HTLV-1) causes two distinct diseases, adult T cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since there are no disease-specific differences among HTLV 1 strains, the etiological mechanisms separating these respective lymphoproliferative and inflammatory diseases are not well understood. In this study, by using IL-2-dependent HTLV-1-infected T-cell lines (ILTs) established from patients with ATL and HAM/TSP, we demonstrate that the anti-inflammatory cytokine IL-10 and its downstream signals potentially act as a switch for proliferation in HTLV-1-infected cells. Among six ILTs used, ILTs derived from all three ATL patients grew much faster than those from three HAM/TSP patients. Although most of the ILTs tested produced IFN-gamma and IL-6, the production of IL-10 was preferentially observed in the rapid-growing ILTs. Interestingly, treatment with exogenous IL-10 markedly enhanced proliferation of the slow growing HAM/TSP-derived ILTs. The IL-10-mediated proliferation of these ILTs was associated with phosphorylation of STAT3 and induction of survivin and IRF4, all of which are characteristics of ATL cells. Knockdown of STAT3 reduced expression of IL-10, implying a positive-feedback regulation between STAT3 and IL-10. STAT3 knockdown also reduced survivin and IRF4 in the IL-10- producing or IL-10- treated ILTs. IRF4 knockdown further suppressed survivin expression and the cell growth in these ILTs. These findings indicate that the IL-10-mediated signals promote cell proliferation in HTLV-1-infected cells through the STAT3 and IRF4 pathways. Our results imply that, although HTLV-1 infection alone may not be sufficient for cell proliferation, IL-10 and its signaling pathways within the infected cell itself and/or its surrounding microenvironment may play a critical role in pushing HTLV-1-infected cells towards proliferation at the early stages of HTLV-1 leukemogenesis. This study provides useful information for understanding of disease mechanisms and disease-prophylactic strategies in HTLV-1 infection. PMID- 28910422 TI - A prolonged chronological lifespan is an unexpected benefit of the [PSI+] prion in yeast. AB - Self-replicating 'proteinaceous infectious particles' or prions are responsible for complex heritable traits in the yeast Saccharomyces cerevisiae. Our current understanding of the biology of yeast prions stems from studies mostly done in the context of actively dividing cells in optimal laboratory growth conditions. Evidence suggest that fungal prions exist in the wild where most cells are in a non-dividing quiescent state, because of imperfect growth conditions, scarcity of nutrients and competition. We know little about the faithful transmission of yeast prions in such conditions and their physiological consequences throughout the lifespan of yeast cells. We addressed this issue for the [PSI+] prion that results from the self-assembly of the translation release factor Sup35p into insoluble fibrillar aggregates. [PSI+] leads to increased nonsense suppression and confers phenotypic plasticity in response to environmental fluctuations. Here, we report that while [PSI+] had little to no effect on growth per se, it dramatically improved the survival of yeast cells in stationary phase. Remarkably, prolonged chronological lifespan persisted even after [PSI+] was cured from the cells, suggesting that prions may facilitate the acquisition of complex new traits. Such an important selective advantage may contribute to the evolutionary conservation of the prion-forming ability of Sup35p orthologues in distantly related yeast species. PMID- 28910424 TI - The Arc of Change in Optical Coherence Tomographic Angiography Technology: Progression Toward Greater Reliability. PMID- 28910425 TI - Reporting of Effect Size and Confidence Intervals in JAMA Otolaryngology-Head & Neck Surgery. AB - Importance: Effect sizes and confidence intervals (CIs) are critical for the interpretation of the results for any outcome of interest. Objective: To evaluate the frequency of reporting effect sizes and CIs in the results of analytical studies. Design, Setting, and Participants: Descriptive review of analytical studies published from January 2012 to December 2015 in JAMA Otolaryngology-Head & Neck Surgery. Methods: A random sample of 121 articles was reviewed in this study. Descriptive studies were excluded from the analysis. Seven independent reviewers participated in the evaluation of the articles, with 2 reviewers assigned per article. The review process was standardized for each article; the Methods and Results sections were reviewed for the outcomes of interest. Descriptive statistics for each outcome were calculated and reported accordingly. Main Outcomes and Measures: Primary outcomes of interest included the presence of effect size and associated CIs. Secondary outcomes of interest included a priori descriptions of statistical methodology, power analysis, and expectation of effect size. Results: There were 107 articles included for analysis. The majority of the articles were retrospective cohort studies (n = 36 [36%]) followed by cross-sectional studies (n = 18 [17%]). A total of 58 articles (55%) reported an effect size for an outcome of interest. The most common effect size used was difference of mean, followed by odds ratio and correlation coefficient, which were reported 17 (16%), 15 (13%), and 12 times (11%), respectively. Confidence intervals were associated with 29 of these effect sizes (27%), and 9 of these articles (8%) included interpretation of the CI. A description of the statistical methodology was provided in 97 articles (91%), while 5 (5%) provided an a priori power analysis and 8 (7%) provided a description of expected effect size finding. Conclusions and Relevance: Improving results reporting is necessary to enhance the reader's ability to interpret the results of any given study. This can only be achieved through increasing the reporting of effect sizes and CIs rather than relying on P values for both statistical significance and clinically meaningful results. PMID- 28910426 TI - Optical Coherence Tomography Angiography Features of Iris Racemose Hemangioma in 4 Cases. AB - Importance: Optical coherence tomography angiography (OCTA) allows visualization of iris racemose hemangioma course and its relation to the normal iris microvasculature. Objective: To describe OCTA features of iris racemose hemangioma. Design, Setting, and Participants: Descriptive, noncomparative case series at a tertiary referral center (Ocular Oncology Service of Wills Eye Hospital). Patients diagnosed with unilateral iris racemose hemangioma were included in the study. Main Outcomes and Measures: Features of iris racemose hemangioma on OCTA. Results: Four eyes of 4 patients with unilateral iris racemose hemangioma were included in the study. Mean patient age was 50 years, all patients were white, and Snellen visual acuity was 20/20 in each case. All eyes had sectoral iris racemose hemangioma without associated iris or ciliary body solid tumor on clinical examination and ultrasound biomicroscopy. By anterior segment OCT, the racemose hemangioma was partially visualized in all cases. By OCTA, the hemangioma was clearly visualized as a uniform large-caliber vascular tortuous loop with intense flow characteristics superimposed over small caliber radial iris vessels against a background of low-signal iris stroma. The vascular course on OCTA resembled a light bulb filament (filament sign), arising from the peripheral iris (base of light bulb) and forming a tortuous loop on reaching its peak (midfilament) near the pupil (n = 3) or midzonal iris (n = 1), before returning to the peripheral iris (base of light bulb). Intravenous fluorescein angiography performed in 1 eye depicted the iris hemangioma; however, small-caliber radial iris vessels were more distinct on OCTA than intravenous fluorescein angiography. Conclusions and Relevance: Optical coherence tomography angiography is a noninvasive vascular imaging modality that clearly depicts the looping course of iris racemose hemangioma. Optical coherence tomography angiography depicted fine details of radial iris vessels, not distinct on intravenous fluorescein angiography. PMID- 28910427 TI - Epidemiology of Conjunctivitis in US Emergency Departments. PMID- 28910428 TI - Retinal Indentation by a Dexamethasone Implant in a Gas-Filled Eye: Report of an Unusual Complication. PMID- 28910423 TI - Anesthetic effects and body weight changes associated with ketamine-xylazine lidocaine administered to CD-1 mice. AB - Anesthesia for mice is commonly performed through the injection of parenteral agents via the intraperitoneal (IP) route. Variability in anesthetic sensitivities has been noted in mice resulting in inconsistencies in anesthetic depth and/or mortality. Anesthetic protocols that improve consistency and safety are needed. The objectives of this study were to assess the effects of intraperitoneal (IP) ketamine (95 mg/kg) and xylazine (7 mg/kg) alone or combined with lidocaine at 4, 8, or 16 mg/kg on time to loss (LRR) and return (RRR) of righting reflex, duration of immobilization and loss of pedal withdrawal response (PWR), body weight and histopathology in CD-1 mice. In a prospective, randomized trial, 36 male CD-1 mice, 4-6 weeks of age were randomly assigned to 5 groups: saline (SA, n = 4); ketamine-xylazine (KX, n = 8); ketamine-xylazine-lidocaine 4 mg/kg (KXL4, n = 8); ketamine-xylazine-lidocaine 8 mg/kg (KXL8, n = 8); ketamine xylazine-lidocaine 16 mg/kg (KXL16, n = 8). Two mice in each group were euthanized at day 2 post-injection and the remaining mice were euthanized at day 11 post-injection. After IP injection, LRR and RRR, duration of immobilization and loss of PWR, body weight and histopathology were evaluated. LRR occurred sooner in mice receiving KXL16 compared with KX, with median (range) times of 78 (62-104) and 107 (91-298) seconds, respectively. Loss of PWR occurred in 1, 5, 4, 6 mice for groups KX, KXL4, KXL8, and KXL16 respectively. Median (range) duration of absent PWR was longer in mice receiving KXL16 at 13 (0-30) minutes, compared to KX at 0 (0-9) minutes. Duration of immobilization and RRR were not different between groups. Weight loss occurred 2 days following anesthesia but was not different between groups. Weight gain was significantly greater in all lidocaine groups 11 days post-injection compared to KX. No mortality or histopathologic abnormalities were observed in any group. Lidocaine administered with ketamine and xylazine shortens the onset of anesthesia in mice and improves anesthetic depth without prolonging recovery time. PMID- 28910429 TI - Evaluation and Management of Unilateral Congenital Ptosis in a Healthy Child. PMID- 28910430 TI - Work Progresses on Male Contraceptives, but Hurdles Remain. PMID- 28910433 TI - Error in Figure and Methods Section. PMID- 28910432 TI - Is There Merit for MET-Targeted Therapies in Gastroesophageal Cancer? PMID- 28910431 TI - HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia: Results From the Microtransplantation Interest Group. AB - Importance: The outcome of older patients with acute myeloid leukemia (AML) remains unsatisfactory. Recent studies have shown that HLA-mismatched microtransplant could improve outcomes in such patients. Objective: To evaluate outcomes in different age groups among older patients with newly diagnosed AML who receive HLA-mismatched microtransplant. Design, Setting, and Participants: This multicenter clinical study included 185 patients with de novo AML at 12 centers in China, the United States, and Spain in the Microtransplantation Interest Group. Patients were divided into the following 4 age groups: 60 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 85 years. The study period was May 1, 2006, to July 31, 2015. Exposures: Induction chemotherapy and postremission therapy with cytarabine hydrochloride with or without anthracycline, followed by highly HLA-mismatched related or fully mismatched unrelated donor cell infusion. No graft-vs-host disease prophylaxis was used. Main Outcomes and Measures: The primary end point of the study was to evaluate the complete remission rates, leukemia-free survival, and overall survival in different age groups. Additional end points of the study included hematopoietic recovery, graft-vs-host disease, relapse rate, nonrelapse mortality, and other treatment-related toxicities. Results: Among 185 patients, the median age was 67 years (range, 60-85 years), and 75 (40.5%) were female. The denominators in adjusted percentages in overall survival, leukemia-free survival, relapse, and nonrelapse mortality are not the sample proportions of observations. The overall complete remission rate was not significantly different among the 4 age groups (75.4% [52 of 69], 70.2% [33 of 47], 79.1% [34 of 43], and 73.1% [19 of 26). The 1-year overall survival rates were 87.7%, 85.8%, and 77.8% in the first 3 age groups, which were much higher than the rate in the fourth age group (51.7%) (P = .004, P = .008, and P = .04, respectively). The 2-year overall survival rates were 63.7% and 66.8% in the first 2 age groups, which were higher than the rates in the last 2 age groups (34.2% and 14.8%) (P = .02, P = .03, P < .001, and P < .001, respectively). The 1-year cumulative incidences of nonrelapse mortality were 10.2%, 0%, 3.4%, and 26.0% in the 4 age groups and 8.1% in all patients. The median times to neutrophil and platelet recovery were 12 days and 14 days after induction chemotherapy, respectively. Five patients had full or mixed donor engraftment, and 30.8% (8 of 26) of patients demonstrated donor microchimerism. Two patients (1.1%) developed severe acute graft-vs-host disease. Conclusions and Relevance: Microtransplant achieved a high complete remission rate in AML patients aged 60 to 85 years and higher 1-year overall survival in those aged 60 to 74 years. PMID- 28910434 TI - Anesthesia Exposure and Neurotoxicity in Children-Understanding the FDA Warning and Implications for the Otolaryngologist. PMID- 28910436 TI - Integrating Data Collection Into Office Work Flow and Electronic Health Records for Clinical Outcomes Research. AB - Meticulous collection of clinical outcomes metrics in patients undergoing elective surgery is important to ensure quality care; it is also increasing in importance as the Centers for Medicare & Medicaid Services moves to tie reimbursement to outcomes and insurance approval. This study assesses a systematic method for gathering preoperative and postoperative data on patients with nasal obstruction who undergo functional septorhinoplasty that was developed at the Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts. The electronic database was initiated in July 2013, patients continue to be actively enrolled, and follow-up data continue to be collected. This procedure represents a systematic method for the initial visit evaluation, collection of patient-reported outcome measures, documentation of surgical management, and follow-up of patients. For consistency and ease of data collection, as well as data interpretation, this method is integrated into a RedCap survey database and the institution's electronic health record system. During the 4 years that this process has been in place, outcomes data have been collected on more than 1000 patients at 7 time points to create an institutional database. This system allows the tracking of patients' outcomes data and the mining of the institutional database for future research. As Centers for Medicare & Medicaid Services moves from a volume-driven health care model to a value driven health care model, demonstration of measurable outcomes in patients undergoing elective surgery will be of paramount importance. PMID- 28910435 TI - Repeatability and Reproducibility of Superficial Macular Retinal Vessel Density Measurements Using Optical Coherence Tomography Angiography En Face Images. AB - Importance: The repeatability and reproducibility of quantitative metrics from optical coherence tomographic angiography (OCTA) must be assessed before these data can be confidently interpreted in clinical research and practice. Objective: To evaluate the repeatability and reproducibility of OCTA-derived retinal vascular quantitative metrics. Design, Setting and Participants: In this cross sectional study, 21 healthy volunteers (42 eyes) and 22 patients with retinal disease (22 eyes), including 14 with age-related macular degeneration, 3 with epiretinal membrane, 2 with diabetic retinopathy, 2 with myopic macular degeneration, and 1 with retinal vein occlusion, were enrolled. Participants were recruited from September 1 through November 31, 2016. Each eye underwent 3 repeated scans with 3 instruments for a total of 9 acquisitions. Eyes were randomly assigned to scanning with a 3 * 3-mm or 6 * 6-mm pattern. Eyes were excluded from subsequent analysis if any acquisition had a signal strength of less than 7. Repeatability (defined as the agreement in measurements within a device) and reproducibility (defined as the agreement between devices of the same type) were assessed by intraclass correlation coefficient (ICC) and coefficient of variation. Exposures: All eyes underwent scanning using 3 separate devices. Main Outcomes and Measures: Vessel length density (VLD) and perfusion density (PD) of the superficial retinal vasculature. Results: A total of 21 healthy volunteers (8 men and 13 women; mean [SD] age, 36 [6] years) and 22 patients with retinal disease (15 men and 7 women; mean [SD] age, 79 [9] years) underwent evaluation. Of these, 40 of 42 normal eyes and 15 of 22 eyes with retinal disease met signal strength criteria and were included in this analysis. The ICC among the 3 consecutive scans ranged from 0.82 to 0.98 for VLD and from 0.83 to 0.95 for PD. The coefficient of variation (CV) ranged from 2.2% to 5.9% for VLD and from 2.4% to 5.9% for PD. For reproducibility, the ICC ranged from 0.62 to 0.95 and the CV was less than 6% in all groups. The agreement was highest for the 3 * 3-mm pattern in the inner ring (ICC range, 0.92 [95% CI, 0.85-0.96] to 0.96 [95% CI, 0.93-0.98]) and 6 * 6-mm pattern in the outer ring (ICC range, 0.93 [95% CI, 0.86-0.97] to 0.96 [95% CI, 0.92-0.98]). Conclusions and Relevance: Vessel length density and PD of the superficial retinal vasculature can be obtained from OCTA images with high levels of repeatability and reproducibility but can vary with scan pattern and location. PMID- 28910437 TI - The Difficult Transition. PMID- 28910438 TI - Long-term Outcomes of Subtotal Septal Reconstruction in Rhinoplasty. AB - Importance: Significant nasal septal deviation may require complex reconstruction to achieve complete correction. Subtotal septal reconstruction is a method for addressing deviations in the L-strut. Objectives: To review the long-term outcomes of subtotal septal reconstruction and provide objective evidence of functional and aesthetic improvement. Design, Setting, and Participants: This medical record review obtained data on 144 patients who underwent subtotal septal reconstruction from September 1, 2008, to September 1, 2013. Data analysis was performed from September 1, 2013, to September 1, 2014. Main Outcomes and Measures: Functional outcomes were measured using the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, and objective aesthetic outcomes were measured using 3-dimensional (3-D) stereophotogrammetry. Follow-up times were classified as time point 1 (TP1; preoperative), time point 2 (TP2; early postoperative), and time point 3 (TP3; final postoperative). Results: Of the 144 patients who underwent subtotal septal reconstruction, 104 (72.2%) were female; the mean (SD) age was 37.3 (13.7) years; 57 underwent primary septorhinoplasty; and 87 (60.5%) underwent revision septorhinoplasty. The NOSE scores improved in all 5 categories of nasal obstruction, with mean (SD) survey completion at 270 (260.1) days. Aesthetic results were measured with 3-D imaging after a mean (SD) follow-up of 613.5 (434.4) days postoperatively. No statistically significant loss was found in mean (SD) nasal length over time (TP2 to TP 3, -0.16 [1.36] mm; 95% CI, -0.54 to 0.22 mm; P = .41) or between mean (SD) postoperative loss of projection (TP2 and TP3, -0.19 [0.92] mm, 95% CI, -0.45 to 0.07 mm; P = .17). An increase in mean (SD) rotation (nasolabial angle) generated with septorhinoplasty (4.24 degrees [11.08 degrees ]; 95% CI, 1.14 degrees -7.34 degrees ; P = .01) and a mean (SD) decrease in rotation detected during postoperative healing (-2.63 degrees [6.96 degrees ]; 95% CI, -4.63 degrees to -0.63 degrees ; P = .01) were found. Although measurement of symmetry was improved in the early postoperative period (TP1 to TP2, -0.16 [1.26] mm; 95% CI, -0.52 to 0.20 mm; P = .40), this finding did not become statistically significant until the final measurement (TP1 to TP3, -0.43 [1.07] mm; 95% CI, -0.73 to -0.13 mm; P = .007; TP2 to TP3, -0.28 [0.87] mm; 95% CI, -0.53 to -0.03 mm; P = .03). A mean (SD) decrease in columellar show was achieved with surgery (-0.66 [1.37] mm; 95% CI, -1.05 to -0.27 mm; P = .001). No statistically significant change was found in the alar-columellar association from TP2 to TP3 in this patient population, confirming no unwanted alar or columellar retraction over time (0.10 [0.61] mm; 95% CI, -0.07 to 0.27 mm; P = .25). A total of 114 patients (79.2%) required costal cartilage harvest for adequate reconstruction. Conclusions and Relevance: Subtotal septal reconstruction yields improved functional and aesthetic outcomes and has the potential to be a useful tool for the rhinoplasty surgeon in the treatment of severe septal deviation. Level of Evidence: 4. PMID- 28910440 TI - Harnessing the Power of Data in Facial Plastic and Reconstructive Surgery-From Refuse to Riches. PMID- 28910439 TI - Spectral-Domain Optical Coherence Tomographic Angiography in Children With Amblyopia. AB - Importance: Amblyopia is the most common cause of visual impairment in childhood, with a prevalence of 1% to 4% in children in the United States. To date, no studies using noninvasive optical coherence tomographic angiography (OCTA) have measured blood flow in the retinal capillary layers in children with amblyopia. Objective: To evaluate the retinal and microvascular features using OCTA in children (<18 years) with amblyopia. Design, Setting, and Participants: This observational case-control study enrolled patients from September 1, 2016, through May 31, 2017, and was conducted from September 1, 2016, through June 30, 2017, at the Stein Eye Institute at UCLA (University of California, Los Angeles). Participants included 59 children (<18 years) with amblyopia and without amblyopia examined at a pediatric ophthalmology clinic or referred to the clinic by coinvestigators. All patients underwent comprehensive ophthalmological examination, including visual acuity, refraction, and ocular motility tests; anterior and posterior segment examination; and OCTA. Main Outcomes and Measures: Reduced superficial and deep retinal capillary vessel density on OCTA. Results: Of the 63 eyes evaluated, 13 (21%) were amblyopic and 50 (79%) were control eyes. Of the 59 patients, the mean (SD) age of patients with amblyopia was 8.0 (4.0) years and 10.3 (3.3) years for the controls; 33 patients (56%) were female; and 5 of 13 (39%) and 27 of 46 (54%) patients in the amblyopic and control groups, respectively, were identified as white. The macular vessel density of the superficial capillary plexus was lower in the amblyopic group than in the control group in both 3 * 3-mm and 6 * 6-mm scans. After adjusting for age and refractive error, the mean (SD) difference in the superficial capillary plexus in the 6 * 6 mm scan was statistically significant (49.3% [4.1] vs 51.2% [2.9]; P = .02). Macular vessel density of the deep capillary plexus in the 6 * 6-mm scans was also considerably different between groups: mean (SD) vessel density of the deep retinal capillary plexus was 54.4% (4.7%) in the amblyopia group and 60.1% (3.3%) in the control group, with a difference of 5.7% (95% CI, 3.4%-8.1%; P = .002). Conclusions and Relevance: The study found that OCTA reveals subnormal superficial and deep retinal capillary density in the macula of patients with amblyopia. Further studies are needed to determine the clinical relevance of this finding. PMID- 28910441 TI - Faith Healer. PMID- 28910442 TI - Unilateral Laryngoscopic Findings Associated With Response to Gabapentin in Patients With Chronic Cough. AB - Importance: Chronic cough is a debilitating, often multifactorial problem. Vagal neuropathy has been proposed as a cause for a fraction of these cases. There are certain features that support the clinical diagnosis of vagal neuropathy. It is hypothesized that patients with neurogenic cough who have vocal fold motion asymmetry (VFMA) on laryngoscopy will be more likely to respond to gabapentin. Objective: To evaluate the association between the history, physical and videostroboscopic examinations, and clinical response to gabapentin. Design, Setting, and Participants: In a retrospective cohort study, patients with chronic cough visiting an academic tertiary laryngology clinic from January 1, 2013, to September 1, 2015, were identified through International Classification of Diseases, Ninth Revision. Of those who had a chronic cough (>8 weeks), 27 patients who received a prescription for gabapentin were included. Patients without videostroboscopy, who did not complete voice therapy, or those without a follow-up examination more than 1 month from the initial evaluation were excluded. Initial history, physical and videostroboscopic examinations, and follow-up evaluations, were performed in a multidisciplinary laryngology clinic including a speech-language pathologist. Documented VFMA by a multidisciplinary team was decided by consensus after review of videostroboscopy recording at the time of the visit. Main Outcomes and Measures: Response to gabapentin was defined by physician-documented subjective patient report of improvement in cough symptoms. Results: Follow-up data were available on 25 of the 27 patients (15 [60%] women; mean [SD] age, 57 [11.8] years). Therapy was initiated in patients with chronic cough with gabapentin, 100 mg twice daily, which was titrated to response or adverse effects. The maximum daily dose was 1800 mg. Partial or complete response to gabapentin was noted in 16 (64%) patients. Vocal fold motion asymmetry was noted in 20 (80%) patients. Fifteen of 16 (94%) responders had VFMA compared with 5 of 9 (56%) nonresponders. The difference in the frequency of VFMA between responders and nonresponders was 38% (95% CI, 18%-58%). Adverse effects limited the gabapentin dose in 4 of 9 (44%) nonresponders and 4 of 16 (25%) responders (odds ratio, 2.5; 95% CI, 0.42-13.6). Conclusions and Relevance: In patients with chronic cough suspected to be related to vagal neuropathy, the odds of response to gabapentin are higher with the presence of VFMA noted on videostroboscopy. PMID- 28910444 TI - Erratum. PMID- 28910443 TI - Spatiotemporally Controlled Ablation of Klf5 Results in Dysregulated Epithelial Homeostasis in Adult Mouse Corneas. AB - Purpose: Corneal epithelial (CE) homeostasis requires coordination between proliferation and differentiation. Here we examine the role of cell proliferation regulator Kruppel-like factor 5 (Klf5) in adult mouse CE homeostasis. Methods: Klf5 was ablated in a spatiotemporally restricted manner by inducing Cre expression in 8-week-old ternary transgenic Klf5LoxP/LoxP/Krt12rtTA/rtTA/Tet-O Cre (Klf5Delta/DeltaCE) mouse CE by administering doxycycline via chow. Normal chow-fed ternary transgenic siblings served as controls. The control and Klf5Delta/DeltaCE corneal (1) histology, (2) cell proliferation, and (3) Klf5 target gene expression were examined using (1) periodic acid Schiff reagent stained sections, (2) Ki67 expression, and (3) quantitative PCR and immunostaining, respectively. The effect of KLF4, KLF5, and OCT1 on gastrokine-1 (GKN1) promoter activity was determined by transient transfection in human skin keratinocyte NCTC-2544 cells. Results: Klf5 expression was decreased to 23% of the controls in Klf5Delta/DeltaCE corneas, which displayed increased fluorescein uptake, downregulation of tight junction proteins Tjp1 and Gkn1, desmosomal Dsg1a, and basement membrane Lama3 and Lamb1, suggesting defective permeability barrier. In transient transfection assays, KLF5 and OCT1 synergistically stimulated GKN1 promoter activity. Klf5Delta/DeltaCE CE displayed significantly fewer cell layers and Ki67+ proliferative cells coupled with significantly decreased cyclin-D1, and elevated phospho(Ser-10) p27/Kip1 expression. Expression of Krt12, E-cadherin, and beta-catenin remained unaltered in Klf5Delta/DeltaCE corneas. Conclusions: Klf5 contributes to adult mouse CE homeostasis by promoting (1) permeability barrier function through upregulation of Tjp1, Gkn1, Dsg1a, Lama3, and Lamb1, and (2) basal cell proliferation through upregulation of cyclin D1 and suppression of phospho(Ser-10) p27/Kip1, without significantly affecting the expression of epithelial markers Krt12, E-cadherin, and beta-catenin. PMID- 28910445 TI - Corneal Epithelium-Derived Neurotrophic Factors Promote Nerve Regeneration. AB - Purpose: To explore the neurotrophic factor expression in corneal epithelium and evaluate their effects on the trigeminal ganglion (TG) neurite outgrowth and corneal nerve regeneration in mice. Methods: The expression of neurotrophic factors was compared among the intact, regenerating, and regenerated mouse corneal epithelium. Mouse primary TG neurons were treated with the conditioned medium of mouse corneal epithelial cells. Nerve growth factor (NGF) neutralizing antibody and glial cell-derived neurotrophic factor (GDNF) neutralizing antibody were used to evaluate their roles in mouse corneal nerve regeneration and TG neurite outgrowth. The promoting effects of NGF and GDNF for the corneal nerve regeneration were further evaluated in the diabetic mice. Results: The expression of NGF and GDNF showed significant up-regulation in regenerating corneal epithelium and return to the preinjury levels in the regenerated epithelium, which was consistent with the progress of corneal subbasal nerve regeneration. The conditioned medium of corneal epithelial cells promoted the TG neurite outgrowth with extended branching and elongation. Furthermore, the blockage of either NGF or GDNF significantly impaired the promotion of the neurite outgrowth by the conditioned medium or the corneal nerve regeneration in normal mice. Moreover, the expression of NGF and GDNF was attenuated in the diabetic regenerating corneal epithelium as compared to that in normal mice, while exogenous NGF or GDNF supplement promoted the corneal epithelial and nerve regeneration in diabetic mice. Conclusions: Corneal epithelium expresses multiple neurotrophic factors, among which NGF and GDNF may play an important role in the corneal nerve regeneration. PMID- 28910446 TI - Retinal Astrocytes and GABAergic Wide-Field Amacrine Cells Express PDGFRalpha: Connection to Retinal Ganglion Cell Neuroprotection by PDGF-AA. AB - Purpose: Our previous experiments demonstrated that intravitreal injection of platelet-derived growth factor-AA (PDGF-AA) provides retinal ganglion cell (RGC) neuroprotection in a rodent model of glaucoma. Here we used PDGFRalpha-enhanced green fluorescent protein (EGFP) mice to identify retinal cells that may be essential for RGC protection by PDGF-AA. Methods: PDGFRalpha-EGFP mice expressing nuclear-targeted EGFP under the control of the PDGFRalpha promoter were used. Localization of PDGFRalpha in the neural retina was investigated by confocal imaging of EGFP fluorescence and immunofluorescent labeling with a panel of antibodies recognizing different retinal cell types. Primary cultures of mouse RGCs were produced by immunopanning. Neurobiotin injection of amacrine cells in a flat-mounted retina was used for the identification of EGFP-positive amacrine cells in the inner nuclear layer. Results: In the mouse neural retina, PDGFRalpha was preferentially localized in the ganglion cell and inner nuclear layers. Immunostaining of the retina demonstrated that astrocytes in the ganglion cell layer and a subpopulation of amacrine cells in the inner nuclear layer express PDGFRalpha, whereas RGCs (in vivo or in vitro) did not. PDGFRalpha-positive amacrine cells are likely to be Type 45 gamma-aminobutyric acidergic (GABAergic) wide-field amacrine cells. Conclusions: These data indicate that the neuroprotective effect of PDGF-AA in a rodent model of glaucoma could be mediated by astrocytes and/or a subpopulation of amacrine cells. We suggest that after intravitreal injection of PDGF-AA, these cells secrete factors protecting RGCs. PMID- 28910448 TI - Iridoschisis in Angle-Closure Glaucoma Associated With Alkali Burn. PMID- 28910449 TI - Carotid Artery Stenosis Causing Choroidal Infarction. PMID- 28910447 TI - Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors. AB - Purpose: The neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]). Methods: A whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice). Results: Orexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons. Conclusions: Our results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina. PMID- 28910450 TI - Neglected Intraocular Cysticercosis. PMID- 28910451 TI - Ptosis Masquerading as Progression of Severe Glaucoma. PMID- 28910454 TI - FDA Approval of Nonadjunctive Use of Continuous Glucose Monitors for Insulin Dosing: A Potentially Risky Decision. PMID- 28910455 TI - Development and Evaluation of Semiautomated Quantification of Lissamine Green Staining of the Bulbar Conjunctiva From Digital Images. AB - Importance: Lissamine green (LG) staining of the conjunctiva is a key biomarker in evaluating ocular surface disease. The disease currently is assessed using relatively coarse subjective scales. Objective assessment would standardize comparisons over time and between clinicians. Objective: To develop a semiautomated, quantitative system to assess lissamine green staining of the bulbar conjunctiva on digital images. Design, Setting, and Participants: Using a standard photography protocol, 35 digital images of the conjunctiva of 11 patients with a diagnosis of dry eye disease based on characteristic signs and symptoms were obtained after topical administration of preservative-free LG, 1%, solution. Images were scored independently by 2 masked ophthalmologists in an academic medical center using the van Bijsterveld and National Eye Institute (NEI) scales. The region of interest was identified by manually marking 7 anatomic landmarks on the images. An objective measure was developed by segmenting the images, forming a vector of key attributes, and then performing a random forest regression. Subjective scores were correlated with the output from a computer algorithm using a cross-validation technique. The ranking of images from least to most staining was compared between the algorithm and the ophthalmologists. The study was conducted from April 26, 2012, through June 2, 2016. Main Outcomes and Measures: Correlation and level of agreement among computerized algorithm scores, van Bijsterveld scale clinical scores, and NEI scale clinical scores. Results: The scores from the automated algorithm correlated well with the mean scores obtained from the gradings of 2 ophthalmologists for the 35 images using the van Bijsterveld scale (Spearman correlation coefficient, rs = 0.79), and moderately with the NEI scale (rs = 0.61) scores. For qualitative ranking of staining, the correlation between the automated algorithm and the 2 ophthalmologists was rs = 0.78 and rs = 0.83. Conclusions and Relevance: The algorithm performed well when evaluating LG staining of the conjunctiva, as evidenced by good correlation with subjective gradings using 2 different grading scales. Future longitudinal studies are needed to assess the responsiveness of the algorithm to change of conjunctival staining over time. PMID- 28910457 TI - Error in Figure. PMID- 28910460 TI - Sudden Flank Pain in a Patient Receiving Ibrutinib for Mantle Cell Lymphoma. PMID- 28910456 TI - Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma. AB - Importance: Malignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown. Objective: To investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors. Design, Setting, and Participants: We studied 88 consecutive patients (39 men, 49 women; median age 61, range 17-84 years) with peritoneal mesotheliomas diagnosed at a single institution between 2005 and 2015. We identified ALK-positive mesotheliomas by immunohistochemistry and confirmed ALK rearrangement by fluorescence in situ hybridization (FISH). In ALK-rearranged cases, we characterized the fusion partners using targeted next-generation sequencing of both tumor DNA and RNA. In select cases, we quantified asbestos fibers by combined scanning electron microscopy and x-ray spectroscopy. We also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma. Main Outcomes and Measures: Identification and characterization of novel ALK rearrangements and correlations with clinicopathologic characteristics. Results: Anaplastic lymphoma kinase was positive by immunohistochemistry in 11 (13%) peritoneal mesotheliomas (focal weak in 8, diffuse strong in 3). In focal weak ALK-positive cases, no ALK rearrangement was detected by FISH or next generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN, and TPM1. Patients with ALK-rearranged peritoneal mesotheliomas were women and younger than patients without ALK rearrangement (median age 36 vs 62; Mann-Whitney test, P = .02), but all other clinicopathologic characteristics (size of tumor nodules, histology, treatment, and survival) were not different. No asbestos fibers were detected in ALK-rearranged cases. Furthermore, loss of chromosomal region 9p or 22q or genetic alterations in BAP1, SETD2, or NF2 typically present in peritoneal mesothelioma were absent in the ALK-rearranged cases. All pleural mesotheliomas were ALK-negative by immunohistochemistry. Conclusions and Relevance: We identified unique ALK rearrangements in a subset of patients with peritoneal mesothelioma, each lacking asbestos fibers, therapeutic radiation, and cytogenetic and molecular alterations typically found in these tumors. Identification of clinically actionable ALK rearrangements may represent a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy. PMID- 28910461 TI - Exertional Heat Illness Resulting in Acute Liver Failure and Liver Transplantation. AB - Heat illness remains a large medical burden for militaries around the world. Mitigating the incidence as well as the complications of heat illness must remain on the forefront of operational planning when operating in hot environments. We report the case of a 27-year-old male U.S. Marine who sustained a heat-related illness resulting in fulminant liver failure and permanent disability. The patient was transferred from the field to a civilian hospital. On hospital day 5, liver failure was identified. The patient was transferred to a transplant center, where he successfully received a liver transplant. PMID- 28910462 TI - Prehospital Cricothyrotomy Kits Used in Combat. AB - BACKGROUND: Surgical cricothyrotomy remains the only definitive airway management modality for the tactical setting recommended by Tactical Combat Casualty Care guidelines. Some units have fielded commercial cricothyrotomy kits to assist Combat Medics with surgical cricothyrotomy. To our knowledge, no previous publications report data on the use of these kits in combat settings. This series reports the the use of two kits in four patients in the prehospital combat setting. METHODS: Using the Department of Defense Trauma Registry and the Prehospital Trauma Registry, we identified four cases of patients who underwent prehospital cricothyrotomy with the use of commercial kits. In the first two cases, a Medic successfully used a North American Rescue CricKit (NARCK) to obtain a surgical airway in a Servicemember with multiple amputations from an improvised explosive device explosion. In case 3, the Medic unsuccessfully used an H&H Medical kit to attempt placement of a surgical airway in a Servicemember shot in the head by small arms fire. A second attempt to place a surgical airway using a NARCK was successful. In case 4, a Soldier sustained a gunshot wound to the chest. A Medic described fluid in the airway precluding bag-valve-mask ventilation; the Medic attempted to place a surgical airway with the H&H kit without success. CONCLUSION: Four cases of prehospital surgical airway cannulation on the battlefield demonstrated three successful uses of prehospital cricothyrotomy kits. Further research should focus on determining which kits may be most useful in the combat setting. PMID- 28910463 TI - Use of Acetylsalicylic Acid in the Prehospital Setting for Suspected Acute Ischemic Stroke. AB - Acute ischemic stroke (AIS) treatment guidelines include various recommendations for treatment once the patient arrives at the hospital. Prehospital care recommendations, however, are limited to expeditious transport to a qualified hospital and supportive care. The literature has insufficiently considered prehospital antiplatelet therapy. An otherwise healthy 30-year-old black man presented with headache for about 3 hours, left-sided facial and upper extremity numbness, slurred speech, miosis, lacrimation, and general fatigue and malaise. The presentation occurred at a time and location where appropriate resources to manage potential AIS were limited. The patient received a thorough physical examination and electrocardiogram. Acetylsalicylic acid (ASA) 325mg was administered within 15 minutes of history and examination. A local host-nation ambulance arrived approximately 30 minutes after presentation. The patient's neurologic symptoms had abated by the time the ambulance arrived. The patient did not undergo magnetic resonance imaging (MRI) until 72 hours after being admitted, owing to lack of neurology staff over the weekend. The MRI showed evidence of a left-sided, posteriorinferior cerebellar artery stroke. The patient was then taken to a different hospital, where he received care for his acute stroke. The patient eventually was prescribed a statin, ASA, and an angiotensin-converting enzyme inhibitor. The patient has no lingering symptoms or neurologic deficits. PMID- 28910464 TI - Unwrapping a First Aid Tourniquet From Its Plastic Wrapper With and Without Gloves Worn: A Preliminary Study. AB - BACKGROUND: The purpose of this study was to gather data about unwrapping a packaged limb tourniquet from its plastic wrapper while wearing different types of gloves. Because already unwrapped tourniquets require no time to unwrap, unwrapping data may provide insights into the issue of having tourniquets unwrapped when stowed in a first aid kit of a Serviceperson at war. MATERIALS AND METHODS: In a laboratory setting, 36 tests of nine glove groups were performed in which four people, gloved and ungloved, unwrapped tourniquets. Other tourniquets were environmentally exposed for 3 months. RESULTS: All the users successfully unwrapped each tourniquet. Mean times to unwrap by glove group were not significantly different (p = .0961). When mean values of eight experimental groups were compared with that of one control group (i.e., bare hands), results showed no significant difference (p > .07). Mean time was least for bare hands (12 seconds) and most for cold gloves layered under mittens (22 seconds). Among the 36 pairwise comparisons of difference between glove group means, after adjustment for multiple comparisons, no comparison was noted to be statistically significant (p > .052, all 36 pairs). Glove thickness ranged from 0 mm for bare hands to 2.5 mm for cold gloves layered under mittens. By glove group, the thickness-time association was moderate, as tested by linear regression (R2 = 0.6096). The tourniquets exposed to the environment had evidence of rapid photodegradation due to direct exposure to sunlight. Such exposure also destroyed the wrappers. CONCLUSION: In a preliminary study, different gloves performed similarly when wearers unwrapped a tourniquet from its wrapper. The tourniquet wrappers gave no visible protection from sunlight, and environmental exposure destroyed the wrappers. PMID- 28910465 TI - Combat Trousers as Effective Improvised Pelvic Binders A Comparative Cadaveric Study. AB - BACKGROUND: Improvised explosive devices and landmines can cause pelvic fractures, which, in turn, can produce catastrophic hemorrhage. This cadaveric study compared the intrapelvic pressure changes that occurred with the application of an improvised pelvic binder adapted from the combat trousers worn by British military personnel with the commercially available trauma pelvic orthotic device (TPOD). METHODS: Six unembalmed cadavers (three male, three female) were used to simulate an unstable pelvic fracture with complete disruption of the posterior arch (AO/OTA 61-C1) by dividing the pelvic ring anteriorly and posteriorly. A 3-4cm manometric balloon filled with water was placed in the retropubic space and connected to a 50mL syringe and water manometer via a three-way tap. A baseline pressure of 8cm H2O (average central venous pressure) was set. The combat trouser binder (CTB) and TPOD were applied to each cadaver in a random sequence and the steady intrapelvic pressure changes were recorded. Statistical analysis was performed using the Wilcoxon rank-sum test and a paired t test depending on the normality of the data to determine impact on the intrapelvic pressure of each intervention compared with baseline. RESULTS: The median steady intrapelvic pressure achieved after application of the CTB was 16cm H2O and after application of the TPOD binder was 18cm H2O, both of which were significantly greater than the baseline pressure (rho < .01 and .036, respectively) but not significantly different from each other (rho > .05). CONCLUSION: Pelvic injuries are increasingly common in modern theaters of war. The CTB is a novel, rapidly deployable, yet effective, method of pelvic binding adapted from the clothes the casualty is already wearing. This technique may be used in austere environments to tamponade and control intrapelvic hemorrhage. PMID- 28910466 TI - Surgical Instrument Sets for Special Operations Expeditionary Surgical Teams. AB - BACKGROUND: The deployment of surgical assets has been driven by mission demands throughout years of military operations in Iraq and Afghanistan. The transition to the highly expeditious Golden Hour Offset Surgical Transport Team (GHOST- T) now offers highly mobile surgical assets in nontraditional operating rooms; the content of the surgical instrument sets has also transformed to accommodate this change. METHODS: The 102nd Forward Surgical Team (FST) was attached to Special Operations assigned to southern Afghanistan from June 2015 to March 2016. The focus was to decrease overall size and weight of FST instrument sets without decreasing surgical capability of the GHOST-T. Each instrument set was evaluated and modified to include essential instruments to perform damage control surgery. RESULTS: The overall number of main instrument sets was decreased from eight to four; simplified augmentation sets have been added, which expand the capabilities of any main set. The overall size was decreased by 40% and overall weight decreased by 58%. The cardiothoracic, thoracotomy, and emergency thoracotomy trays were condensed to thoracic set. The orthopedic and amputation sets were replaced with an augmentation set of a prepackaged orthopedic external fixator set). An augmentation set to the major or minor basic sets, specifically for vascular injuries, was created. CONCLUSION: Through the reorganization of conventional FST surgical instrument sets to maintain damage control capabilities and mobility, the 102nd GHOST-T reduced surgical equipment volume and weight, providing a lesson learned for future surgical teams operating in austere environments. PMID- 28910467 TI - The Golden Hour Offset Surgical Treatment Team Operational Concept: Experience of the 102nd Forward Surgical Team in Operation Freedom's Sentinel 2015-2016. AB - Theater Special Operations Force (SOF) medical planners have begun using Army Forward Surgical Teams (FSTs) to maintain a golden hour for U.S. SOF during Operation Freedom's Sentinel required adaptation in FST training, configuration, personnel, equipment, and employment to form Golden Hour Offset Surgical Treatment Teams (GHOST-Ts). This article describes one such FST's experience in Operation Freedom's Sentinel while deployed for 9 months in support of SOF in southern Afghanistan. PMID- 28910468 TI - Estimation of Dog-Bite Risk and Related Morbidity Among Personnel Working With Military Dogs. AB - BACKGROUND: Soldiers serving in the Israel Defense Force Military Working Dogs (MWD) Unit spend many hours taming dogs' special skills, taking them on combat missions, and performing various dogkeeping activities. During this intensive work with the aggressive military dogs, bites are common, and some of them result in permanent disability. However, this phenomenon has not been quantified or reported as an occupational hazard. METHODS: This was a retrospective cohort study based on self-administered questionnaires. Information was collected about soldiers' baseline demographics, duration of the experience of working with dogs, total number of bites they had, circumstances of bite events, and complications and medical treatment of each bite. Bite risk was quantified by incidence, mean time to first bite, and a Cox proportional hazards model. Rates of complications and the medical burden of bites were compared between combat soldiers and noncombat dogkeepers. Bite locations were presented graphically. RESULTS: Seventy eight soldiers participated and reported on 139 bites. Mean time of working with dogs was 16 months (standard deviation, +/-9.4 months). Overall bite incidence was 11 bites per 100 person-months; the mean time to first bite event was 6.3 months. The Cox proportional hazards model showed that none of baseline characteristics significantly increased bite hazard. About 90% of bites occurred during routine activities, and 3.3% occurred on combat missions. Only in 9% of bite events did soldiers observed the safety precautions code. Bite complications included fractures, need for intravenous antibiotic treatment and surgical repair, prominent scarring, diminished sensation, and stiffness of proximal joints. Bite complications were similar between combat soldiers and dogkeepers. Most bites (57%) were located on hands and arms. CONCLUSION: MWD bites are an occupational hazard resulting in significant medical burden. Hands and arms were most common bite locations. Observance of safety precautions may be the most appropriate first-line preventive intervention. Barrier protection of upper extremities may reduce bite severity and complication rates. PMID- 28910470 TI - A Comparison of Ventilation Rates Between a Standard Bag-Valve-Mask and a New Design in a Prehospital Setting During Training Simulations. AB - BACKGROUND: Excessive ventilation of sick and injured patients is associated with increased morbidity and mortality. Combat Medical Systems(r) (CMS) is developing a new bag-valve-mask (BVM) designed to limit ventilation rates. The purpose of this study was to compare ventilation rates between a standard BVM device and the CMS device. METHODS: This was a prospective, observational, semirandomized, crossover study using Army Medics. Data were collected during Brigade Combat Team Trauma Training classes at Camp Bullis, Texas. Subjects were observed during manikin simulation training in classroom and field environments, with total duration of manual ventilation and number of breaths given recorded for each device. Analysis was performed on overall ventilation rate in breaths per minute (BPM) and also by grouping the subjects by ventilation rates in low, correct, and high groups based on an ideal rate of 10-12 BPM. RESULTS: A total of 89 Medics were enrolled and completed the classroom portion of the study, with a subset of 36 evaluated in the field. A small but statistically significant difference in overall BPM between devices was seen in the classroom (rho < .001) but not in the field (rho > .05). The study device significantly decreased the incidence of high ventilation rates when compared by groups in both the classroom (rho < .001) and the field (rho = .044), but it also increased the rate of low ventilation rates. CONCLUSION: The study device effectively reduced rates of excessive ventilation in the classroom and the field. PMID- 28910469 TI - Prehospital Administration of Tranexamic Acid by Ground Forces in Afghanistan: The Prehospital Trauma Registry Experience. AB - BACKGROUND: Tranexamic acid (TXA) was shown to reduce overall mortality and death secondary to hemorrhage in a large prospective study. This intervention is time sensitive. As such, the Tactical Combat Casualty Care (TCCC) guidelines recommend use of this low-cost, safe intervention among patients with possible hemorrhagic shock, penetrating trauma to the thorax or trunk, or extremity amputation. OBJECTIVE: Prehospital administration of TXA by ground forces in the Afghanistan combat theater is described. METHODS: We obtained data from the Prehospital Trauma Registry. We searched for all patients with documented hypotension, amputation, or penetrating trauma to the torso. RESULTS: From January 2013 to September 2014, there were 272 patients who met inclusion criteria. Most injuries (97.8%; n = 266) were battle injuries. Of the 272 patients who met criteria to receive prehospital TXA, 51 (18.8%) received TXA, whereas the remaining 221 (81.2%) did not. Higher proportions of patients receiving TXA versus patients not receiving TXA received hemostatic dressings, pressure dressings, and tourniquet placement. Conversely, the proportion of patients receiving intravenous fluids was higher in the no-TXA group. CONCLUSION: Overall, proportions of eligible patients receiving TXA were low despite emphasis in the guidelines. The reasons for this low adherence to TCCC guidelines are likely multifactorial. Future research should seek to identify reasons TXA is not given when indicated and to develop training and technology to increase prehospital TXA administration. PMID- 28910471 TI - Evaluation of XSTAT(r) and QuickClot(r) Combat Gauze(r) in a Swine Model of Lethal Junctional Hemorrhage in Coagulopathic Swine. AB - BACKGROUND: Hemorrhage is associated with most potentially survivable deaths on the battlefield. Effective and field-tested products are lacking to treat junctional and noncompressible injuries. XSTAT(r) is a newly developed, U.S. Food and Drug Administration-approved product designed to treat junctional hemorrhage. The Committee on Tactical Combat Casualty Care has recently approved the product for use as part of its treatment guidelines, but data are lacking to assess its efficacy in different wounding patterns and physiologic states. METHODS: Dilutional coagulopathy was induced in 19 large (70-90kg), healthy, male swine by replacing 60% of each animal's estimated blood volume with room temperature Hextend (r). After dissection, isolation, and lidocaine incubation, uncontrolled hemorrhage was initiated by transection of both axillary artery and vein. Free bleeding was allowed to proceed for 30 seconds until intervention with either XSTAT or QuickClot(r) Combat Gauze(r) (CG) followed by standard backing. Primary outcomes were survival, hemostasis, and blood loss. RESULTS: XSTAT-treated animals achieved hemostasis in less time and remained hemostatic longer than those treated with CG. Less blood was lost during the first 10 minutes after injury in the XSTAT group than the CG group. However, no differences in survival were observed between XSTAT-treated and CG-treated groups. All animals died before the end of the observation period except one in the XSTAT-treated group. CONCLUSION: XSTAT performed better than CG in this model of junctional hemorrhage in coagulopathic animals. Continued testing and evaluation of XSTAT should be performed to optimize application and determine appropriate indications for use. PMID- 28910472 TI - A Descriptive Analysis of Occupational Fatalities Due to Felonious Assault Among U.S. Law Enforcement Officers During Tactical Incidents, 1996-2014. AB - INTRODUCTION: Little is known about occupational fatalities among tactical officers. A greater understanding of such injuries is needed to improve officer safety. The purpose of this study was to provide a descriptive analysis of line of-duty deaths secondary to felonious assault during tactical incidents. METHODS: Retrospective analysis was performed of open-source de-identified Federal Bureau of Investigation Uniform Crime Reporting Law Enforcement Officers Killed and Assaulted (LEOKA) data inclusive of the years 1996-2014. Officers were included if the fatal injury occurred during operations by a Special Weapons and Tactics (SWAT) team, fugitive task force, narcotics task force, or if the LEOKA narrative described the event as a tactical situation. RESULTS: Of 1,012 officer deaths during the study period, 57 (5.6%) involved tactical officers. On average (+/- standard deviation), victim officers were 37.3 +/- 7.8 years of age at the time of death, with 11.7 +/- 6.6 years of law enforcement experience. High-risk warrant service accounted for 63.2% of fatalities. A single officer was killed in 91.2% of incidents; 49.1% of cases involved injuries to other officers. The majority of officers (59.6%) killed were the first officer(s) to enter the scene. The most commonly identified cause of death was head trauma (n = 28). Chest trauma accounted for 14 deaths; 10 (71.4%) sustained an entry wound via the ballistic vest armhole. Where recorded, 52.0% of officers died within the first hour of injury. The provision or nature of buddy care, tactical emergency medical services (EMS) care, or conventional EMS care was rarely noted. CONCLUSION: Tactical officer deaths most commonly occur during high-risk warrant service, and most often involve the first officer(s) to enter a scene, suggesting an opportunity for improved operational tactics. The frequency of fatal axillary penetration suggests the opportunity for ballistic protection redesign. Information is lacking regarding on-scene care, limiting the ability to determine optimal medical procedures for downed officers during tactical operations. Nearly 50% of victim officers survived more than 1 hour from time of injury, suggesting opportunities to intervene and potentially affect outcomes. PMID- 28910473 TI - Optimization of Simulation and Moulage in Military-Related Medical Training. AB - Preparation of Special Operations Forces (SOF) Medics as first responders for the battle space and austere environments is critical to optimize survival and quality of life for our Operators who may sustain serious and complex wounding patterns and illnesses. In the absence of constant clinical exposure for these medics, it is necessary to maximize all available training opportunities. The incorporation of scenario-based training helps weave together teamwork and the ability to practice treatment protocols in a tactical, controlled training environment to reproduce, to some degree, the environment in and stressors under which care will need to be delivered. We reviewed the evolution of training scenarios within one Pararescue (PJ) team since 2008 and codified various tools used to simulate physical findings and drive medical exercises as part of scenario-based training. We also surveyed other SOF Medic training resources. PMID- 28910474 TI - Atropine Eye Drops: A Proposed Field Expedient Substitute in the Absence of Atropine Autoinjectors. AB - Nerve agents are a threat to military and civilian health. The antidote, atropine sulfate, is delivered by autoinjector, which is a limited resource. We propose the use of 1% atropine ophthalmic solution (supplied commercially in 5mL or 15 mL bottles) via oral, ocular, and intranasal administration as an expedient substitute in austere environments. PMID- 28910475 TI - Chest Seal Placement for Penetrating Chest Wounds by Prehospital Ground Forces in Afghanistan. AB - BACKGROUND: Thoracic trauma represents 5% of all battlefield injuries. Communicating pneumothoraces resulting in tension physiology remain an important etiology of prehospital mortality. In addressing penetrating chest trauma, current Tactical Combat Casualty Care (TCCC) guidelines advocate the immediate placement of a vented chest seal device. Although the Committee on TCCC (CoTCCC) has approved numerous chest seal devices for battlefield use, few data exist regarding their use in a combat zone setting. OBJECTIVE: To evaluate adherence to TCCC guidelines for chest seal placement among personnel deployed to Afghanistan. METHODS: We obtained data from the Prehospital Trauma Registry (PHTR). Joint Trauma System personnel linked patients to the Department of Defense Trauma Registry, when available, for outcome data upon reaching a fixed facility. RESULTS: In the PHTR, we identified 62 patients with documented gunshot wound (GSW) or puncture wound trauma to the chest. The majority (74.2%; n = 46) of these were due to GSW, with the remainder either explosive-based puncture wounds (22.6%; n = 14) or a combination of GSW and explosive (3.2%; n = 2). Of the 62 casualties with documented GSW or puncture wounds, 46 (74.2%) underwent chest seal placement. Higher proportions of patients with medical officers in their chain of care underwent chest seal placement than those that did not (63.0% versus 37.0%). The majority of chest seals placed were not vented. CONCLUSION: Of patients with a GSW or puncture wound to the chest, 74.2% underwent chest seal placement. Most of the chest seals placed were not vented in accordance with guidelines, despite the guideline update midway through the study period. These data suggest the need to improve predeployment training on TCCC guidelines and matching of the Army logistical supply chain to the devices recommended by the CoTCCC. PMID- 28910476 TI - No Ordinary Sleeper Cell: Managing the Varied Problems of Plasmodium vivax Malaria. AB - Plasmodium vivax malaria is an essential yet elusive target of tropical disease eradication efforts, and is the focus of this literature review. This review will reacquaint Special Operations Forces (SOF) Medics with the basic principles of malaria as context for understanding the several confounding issues particular to P. vivax infections. The review concludes with current malaria guidelines and malaria mitigation strategies. PMID- 28910477 TI - Humanitarian Struggle in Burma's Conflict Zones. AB - The Back Pack Health Worker Team (BPHWT), a community- based health organization, provides primary health care to ethnic people in conflict, remote, and internally displaced areas, in Burma (aka Myanmar), controlled by ethnic armed organizations fighting against the Burma government. Its services include both curative and preventative health care through a network of 1,425 health personnel including community health workers and village-embedded traditional birth attendants and village health workers. The BPHWT organizational and program model may prove useful to Special Operations medical actions in support of insurgent movements and conversely with a host nation's counterinsurgency strategies, which include the extension of its health services into areas that may be remote and/or inhabited by indigenous people and have insurgency potential. In the former respect, special attention is directed toward "humanitarian struggle" that uses health care as a weapon against the counterinsurgency strategies of a country's oppressive military. PMID- 28910478 TI - A Shift From Resilience to Human Performance Optimization in Special Operations Training: Advancements in Theory and Practice. AB - Within the Department of Defense over the past decade, a focus on enhancing Warfighter resilience and readiness has increased. For Special Operation Forces (SOF), who bear unique burdens for training and deployment, programs like the Preservation of the Force and Family have been created to help support SOF and their family members in sustaining capabilities and enhancing resilience in the face of prolonged warfare. In this review, we describe the shift in focus from resilience to human performance optimization (HPO) and the benefits of human performance initiatives that include holistic fitness. We then describe strategies for advancing the application of HPO for future initiatives through tailoring and cultural adaptation, as well as advancing methods for measurement. By striving toward specificity and precision performance, SOF human performance programs can impact individual and team capabilities to a greater extent than in the past, as well as maintaining the well-being of SOF and their families across their careers and beyond. PMID- 28910479 TI - Hepatitis E. PMID- 28910480 TI - Tools to Assess and Reduce Injury Risk (Part 1). AB - Many injuries are preventable. Useful tools are available that can aid in assessing injury risks and developing methods to reduce these risks. This is part 1 of a two-part article that will discuss these tools, which include the Haddon Matrix, the 10 Countermeasure Strategies, the Injury Control Process, and the Army Risk-Management Process. The Haddon Matrix is 3 (r) 3 table that, across the top (columns), provides an approach to conceptualizing injury prevention and control through modifications of the human, equipment, and environment; and, across rows, thinking about injury prevention and control before, during, and after the injury-producing event. The basic premise of the 10 Countermeasure Strategies is that injuries are largely due to energy exchanges between a person and the external environment in such a way that body cannot properly avoid or absorb the energy and anatomic structures are damaged. The Countermeasure Strategies are (1) eliminating the hazard altogether, (2) reducing the amount of the hazard, (3) preventing release of the hazard, (4) modifying the rate or spatial distribution of the hazard, (5) separating in space or time the hazard and the individual, (6) separating the individual from the hazard using a barrier, (7) modifying the basic qualities of the hazard, (8) strengthening the individual to make them more resistant to damage, (9) countering the damage done, and (10) stabilizing, healing, and rehabilitating the individual. Part 2 of this series will discuss the injury control process and the Army risk management process. PMID- 28910481 TI - Carfentanil: A New and Often Unrecognized Threat. AB - Law enforcement officers, whether working the streets or on narcotic detail, and even those who operate in strike teams, face a new danger from an old drug: carfentanil. Drug dealers seeking to increase profits cut this cheap synthetic drug into expensive heroin, providing an extreme high. As a potent synthetic opioid narcotic, it is finding its way to the streets of the United States and can pose a threat to life for law enforcement, first responders, and medical examiners. PMID- 28910482 TI - An Outbreak Investigation Report and Lessons Learned by Multinational Coalition Forces: October 2016, Baghdad, Iraq. AB - BACKGROUND: Public health personnel from the 28th Combat Support Hospital in Baghdad, Iraq, conducted an outbreak investigation in response to many local cases of gastrointestinal (GI) illness presenting to U.S. medical facilities. The investigation was conducted to identify the source of the illness, assess the extent of cases, and make recommendations to prevent similar outbreaks. METHODS AND MATERIALS: For this retrospective cohort study, medical records and patient outbreak questionnaires were reviewed. A patient case, relative to the outbreak, was defined as any person who had developed a GI illness and presented for medical evaluation to either sick call or an emergency service at a diplomatic or military medical facility in Baghdad from 30 September to 12 October 2016. RESULTS: A total of 123 people met the case definition. The most common presenting symptom was diarrhea (91% to 96% of cases). Other symptoms included abdominal cramps, fatigue, and headache. Most cases were military personnel (n =100). Salad was significantly associated with GI illness (70% of respondents). Five salad ingredients had significantly elevated levels of Escherichia coli. CONCLUSION: Mitigation strategies to reduce the probability of similar outbreaks include purchasing food solely from approved vendors or thoroughly cooking all foods, including fruits and vegetables. PMID- 28910483 TI - Traumatic Brain Injury Management in Prolonged Field Care. PMID- 28910485 TI - To Cut or Not to Cut: That Is an Ultrasound Question! PMID- 28910484 TI - Teleconsultation in Prolonged Field Care Position Paper. PMID- 28910486 TI - We Cannot Afford to Lose the Lessons We Have Learned: COL (Ret) Rob Lutz's Reflections on a 20-Year SOF Medical Career. PMID- 28910487 TI - Remote Dental Surgery as a Medical Civilian Assistance Program (MEDCAP): Helping Iraqi, Kurdish, and U.S. Forces Win Hearts and Minds in the Fight Against Daesh. AB - Dr Ferreira discusses the work of the Humanitarian Aid and Security Forces (HASF) in providing volunteer dental services to a local Christian militia in Mosul, Iraq. PMID- 28910488 TI - Tactical Combat Casualty Care Updates. PMID- 28910489 TI - Nucleoside/nucleotide reverse transcriptase inhibitors attenuate angiogenesis and lymphangiogenesis by impairing receptor tyrosine kinases signalling in endothelial cells. AB - BACKGROUND AND PURPOSE: Cardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV-positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis. EXPERIMENTAL APPROACH: The angiogenesis/lymphangiogenesis capability of endothelial cells (ECs) was evaluated using migration, proliferation and tube formation assays in vitro, and mouse ear and Matrigel plug assays in vivo. Expressions of signalling molecules and mitochondrial antioxidant catalases were determined using Western blotting. Receptor tyrosine kinase (RTK) internalization and endocytosis were examined using flow cytometry and confocal immunofluorescence microscopy respectively. Mitochondrial DNA copy number and ROS were determined using quantitative real-time PCR and MitoSOX staining respectively. KEY RESULTS: Pharmaceutical doses of NRTIs [azidothymidine (AZT), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC)] inhibited angiogenesis and lymphangiogenesis both in vivo and in vitro by affecting the proliferation and migration of ECs. Correspondingly, NRTIs selectively attenuated the activation and transduction of endothelial RTK signals, VEGFR2 and FGFR1 pathways, in vascular ECs and the VEGFR3 pathway in lymphatic ECs. Both TDF and 3TC restrained RTKs' endocytosis into early endosomes but not internalization, while AZT blocked the protein maturation of RTKs. Excessive ROS levels were detected in NRTI-treated ECs, and the MnSOD mimic MnTMPyP alleviated the angiogenic/lymphangiogenic defects induced by NRTIs. CONCLUSIONS AND IMPLICATIONS: NRTIs negatively regulate angiogenesis and lymphangiogenesis by inducing mitochondrial oxidative stress and subsequently impairing RTK signalling in ECs. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. PMID- 28910491 TI - A double EPSPS gene mutation endowing glyphosate resistance shows a remarkably high resistance cost. AB - A novel glyphosate resistance double point mutation (T102I/P106S, TIPS) in the 5 enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene has been recently identified for the first time only in the weed species Eleusine indica. Quantification of plant resistance cost associated with the TIPS and the often reported glyphosate resistance single P106S mutation was performed. A significant resistance cost (50% in seed number currency) associated with the homozygous TIPS but not the homozygous P106S EPSPS variant was identified in E. indica plants. The resistance cost associated with the TIPS mutation escalated to 85% in plants under resource competition with rice crops. The resistance cost was not detected in nonhomozygous TIPS plants denoting the recessive nature of the cost associated with the TIPS allele. An excess of 11-fold more shikimate and sixfold more quinate in the shikimate pathway was detected in TIPS plants in the absence of glyphosate treatment compared to wild type, whereas no changes in these compounds were observed in P106S plants when compared to wild type. TIPS plants show altered metabolite levels in several other metabolic pathways that may account for the expression of the observed resistance cost. PMID- 28910493 TI - Using interpersonal process recall to compare patients' accounts of resistance in two psychotherapies for generalized anxiety disorder. AB - In a trial examining whether cognitive-behavioral therapy (CBT) could be improved by integrating motivational interviewing (MI) to target resistance, MI-CBT outperformed CBT over 12-month follow-up (Westra, Constantino, & Antony, 2016). Given that effectively addressing resistance is both a theoretically and an empirically supported mechanism of MI's additive effect, we explored qualitatively patients' experience of resistance, possibly as a function of treatment. For 5 patients from each treatment who exhibited early in-session change ambivalence, and thus were at risk for later resistance, we conducted interpersonal process recall interviews after a session. Transcripts were analyzed with grounded theory and consensual qualitative research. A salient contrast in patient narratives was a sense of compliance engendered in standard CBT versus connection in MI-CBT. Yet both narratives supported the superordinate category of resistance as an interpersonal process triggered by patient perceptions of therapist beliefs and behaviors. Findings contribute to the conceptualization of resistance from patients' first-hand accounts. PMID- 28910490 TI - Regulation of Wnt/beta-catenin signalling by tankyrase-dependent poly(ADP ribosyl)ation and scaffolding. AB - : The Wnt/beta-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/beta-catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the beta-catenin destruction complex, and targets it for degradation, thereby fine-tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt-dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/beta catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re-tune Wnt/beta-catenin signalling in colorectal cancer cells. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 28910492 TI - p53-mediated regulation of bile acid disposition attenuates cholic acid-induced cholestasis in mice. AB - BACKGROUND AND PURPOSE: The tumour suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have demonstrated that it contributes to metabolic diseases. Here, we investigated the role of p53 in the regulation of bile acid disposition and cholestasis. EXPERIMENTAL APPROACH: The bile acid disposition-related gene expression profile affected by p53 activation was assessed in mouse primary hepatocytes with p53 depletion and in Trp53-null mice. Dual luciferase reporter assay was used to detect the transcriptional activities of target genes. Anticholestatic effects of p53 activator doxorubicin were investigated in a 0.5% cholic acid-fed mouse model of cholestasis. Changes in bile acids were evaluated using metabolomics analysis. KEY RESULTS: Doxorubicin-mediated p53 activation induced Cyp2b10, Sult2a1 and Abcc2/3/4 expression in mice in vitro and in vivo. ABCC3 and CYP2B6 (human orthologue of Cyp2b10) were identified as direct p53 target genes. Doxorubicin attenuated cholic acid-induced cholestasis in mice, as demonstrated by shrunken gall bladder, decreased serum total bile acid and total bilirubin levels and alkaline phosphatase activity. Targeted metabolomics analysis revealed that doxorubicin enhanced the excretion of bile acid metabolites from serum and liver to intestine and faeces. Up-regulation of Cyp2b10, Sult2a1 and Abcc2/3/4 expression was further confirmed in cholestatic mice. Cholic acid-induced cholestatic injury was aggravated in p53-deficient mice and levels of bile acid in intestine and faeces were decreased. CONCLUSIONS AND IMPLICATIONS: Our findings suggest a novel role of p53 in promoting bile acid disposition and alleviating cholestatic syndrome, which provides a potential therapeutic target for cholestasis. PMID- 28910494 TI - The relationship between emotional intelligence, previous caring experience and successful completion of a pre-registration nursing/midwifery degree. AB - AIM: To examine the relationship between baseline emotional intelligence and prior caring experience with completion of pre-registration nurse and midwifery education. BACKGROUND: Selection and retention of nursing students is a global challenge. Emotional intelligence is well-conceptualized, measurable and an intuitive prerequisite to nursing values and so might be a useful selection criterion. Previous caring experience may also be associated with successful completion of nurse training. DESIGN: Prospective longitudinal study. METHOD: Self-report trait and ability emotional intelligence scores were obtained from 876 student nurses from two Scottish Universities before they began training in 2013. Data on previous caring experience were recorded. Relationships between these metrics and successful completion of the course were calculated in SPSS version 23. RESULTS: Nurses completing their programme scored significantly higher on trait emotional intelligence than those that did not complete their programme. Nurses completing their programme also scored significantly higher on social connection scores than those that did not. There was no relationship between "ability" emotional intelligence and completion. Previous caring experience was not statistically significantly related to completion. CONCLUSION: Students with higher baseline trait emotional intelligence scores were statistically more likely to complete training than those with lower scores. This relationship also held using "Social connection" scores. At best, previous caring experience made no difference to students' chances of completing training. Caution is urged when interpreting these results because the headline findings mask considerable heterogeneity. Neither previous caring experience or global emotional intelligence measures should be used in isolation to recruit nurses. PMID- 28910495 TI - Nursing service innovation: A case study examining emergency nurse practitioner service sustainability. AB - AIM: This research aimed to explore factors that influence sustainability of health service innovation, specifically emergency nurse practitioner service. BACKGROUND: Planning for cost effective provision of healthcare services is a concern globally. Reform initiatives are implemented often incorporating expanding scope of practice for health professionals and innovative service delivery models. Introducing new models is costly in both human and financial resources and therefore understanding factors influencing sustainability is imperative to viable service provision. DESIGN: This research used case study methodology (Yin, ). METHODS: Data were collected during 2014 from emergency nurse practitioners, emergency department multidisciplinary team members and documents related to nurse practitioner services. Collection methods included telephone and semi-structured interviews, survey and document analysis. Pattern matching techniques were used to compare findings with study propositions. FINDINGS: In this study, emergency nurse practitioner services did not meet factors that support health service sustainability. Multidisciplinary team members were confident that emergency nurse practitioner services were safe and helped to meet population health needs. Organizational support for integration of nurse practitioner services was marginal and led to poor understanding of service capability and underuse. CONCLUSION: This research provides evidence informing sustainability of nursing service models but more importantly raises questions about this little explored field. The findings highlight poor organizational support, excessive restrictions and underuse of the service. This is in direct contrast to contemporary expanding practice reform initiatives. Organizational support for integration is imperative to future service sustainability. PMID- 28910496 TI - Using blogs to explore the lived-experience of life after stroke: "A journey of discovery I never wanted to take". AB - AIMS: To explore the lived-experiences of stroke survivors as expressed in blogs and to discover the role the blogs play in the writers' lives. BACKGROUND: Stroke can be a devastating, life changing event. Previous qualitative studies tend to examine one aspect of life after stroke. As stroke often has multiple effects, it is necessary to look widely at its lived-experience. New resources which can enable researchers to explore the lived-experience of stroke are blogs. DESIGN: Phenomenological exploration using an interpretive thematic analysis. METHODS: The Internet was searched for stroke survivors' blogs (January-March 2016) using pre-set criteria, seeking blogs with entries over an extended time (>1 year). Suitable blogs were identified and codes of meaning were identified and developed into categories, subthemes and themes. FINDINGS: Eight blogs were identified for analysis. Of the 40 categories, eight subthemes were assimilated; internal dialogue, emotions, transition, stroke effects, health care, "in the world", relationships, rehabilitation. Two main themes were identified related to perspectives of lived-experience; Internal relationship with "self" and External relationship with "the world". Participants expressed loss and initially strove to regain their "old" lives, their focus being recovery and independence. CONCLUSION: Stroke survivors must transition from their previous life to a new and initially unwelcome way of being. Rehabilitation should respect this process and support stroke survivors as they undertake this individual journey. PMID- 28910497 TI - Tuning Surface Structure of 3D Nanoporous Gold by Surfactant-Free Electrochemical Potential Cycling. AB - 3D dealloyed nanoporous metals have emerged as a new class of catalysts for various chemical and electrochemical reactions. Similar to other heterogeneous catalysts, the surface atomic structure of the nanoporous metal catalysts plays a crucial role in catalytic activity and selectivity. Through surfactant-assisted bottom-up synthesis, the surface-structure modification has been successfully realized in low-dimensional particulate catalysts. However, the surface modification by top-down dealloying has not been well explored for nanoporous metal catalysts. Here, a surfactant-free approach to tailor the surface structure of nanoporous gold by surface relaxation via electrochemical redox cycling is reported. By controlling the scan rates, nanoporous gold with abundant {111} facets or {100} facets can be designed and fabricated with dramatically improved electrocatalysis toward the ethanol oxidation reaction. PMID- 28910499 TI - Joint model selection of marginal mean regression and correlation structure for longitudinal data with missing outcome and covariates. AB - This work develops a joint model selection criterion for simultaneously selecting the marginal mean regression and the correlation/covariance structure in longitudinal data analysis where both the outcome and the covariate variables may be subject to general intermittent patterns of missingness under the missing at random mechanism. The new proposal, termed "joint longitudinal information criterion" (JLIC), is based on the expected quadratic error for assessing model adequacy, and the second-order weighted generalized estimating equation (WGEE) estimation for mean and covariance models. Simulation results reveal that JLIC outperforms existing methods performing model selection for the mean regression and the correlation structure in a two stage and hence separate manner. We apply the proposal to a longitudinal study to identify factors associated with life satisfaction in the elderly of Taiwan. PMID- 28910498 TI - PDE1A inhibition elicits cGMP-dependent relaxation of rat mesenteric arteries. AB - BACKGROUND AND PURPOSE: PDE1, a subfamily of cyclic nucleotide PDEs consisting of three isoforms, PDE1A, PDE1B and PDE1C, has been implicated in the regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896 and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone. EXPERIMENTAL APPROACH: In rat mesenteric arteries, expression and localization of Pde1 isoforms were determined by quantitative PCR and in situ hybridization, and physiological impact of PDE1 inhibition was evaluated by isometric tension recordings. KEY RESULTS: In rat mesenteric arteries, Pde1a mRNA expression was higher than Pde1b and Pde1c. In situ hybridization revealed localization of Pde1a to vascular smooth muscle cells (VSMCs) and only minor appearance of Pde1b and Pde1c. The potency of the PDE1 inhibitors at eliciting relaxation showed excellent correlation with their potency at inhibiting PDE1A. Thus, Lu AF58027 was the most potent at inhibiting PDE1A and was also the most potent at eliciting relaxation in mesenteric arteries. Inhibition of NOS with l-NAME, soluble GC with ODQ or PKG with Rp-8-Br PET-cGMP all attenuated the inhibitory effect of PDE1 on relaxation, whereas PKA inhibition with H89 had no effect. CONCLUSIONS AND IMPLICATIONS: Pde1a is the dominant PDE1 isoform present in VSMCs, and relaxation mediated by PDE1A inhibition is predominantly driven by enhanced cGMP signalling. These results imply that isoform-selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms. PMID- 28910500 TI - Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway. AB - BACKGROUND AND PURPOSE: An ever-growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single-drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. EXPERIMENTAL APPROACH: Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. KEY RESULTS: We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi-drug treatments with high efficacy and minimal off-target effects. CONCLUSION AND IMPLICATIONS: We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses. PMID- 28910502 TI - Using narrative inquiry to listen to the voices of adolescent mothers in relation to their use of social networking sites (SNS). AB - AIM: This article presents a discussion highlighting the relevance and strengths of using narrative inquiry to explore experiences of social networking site (SNS) use by adolescent mothers. BACKGROUND: Narrative inquiry as a method reveals truths about holistic human experience. Knowledge gleaned from personal narratives informs nursing knowledge and clinical practice. This approach gives voice to adolescent mothers in relation to their experiences with SNS as a means of providing social support. DESIGN: Discussion paper. DATA SOURCES: This paper draws and reflects on the author's experiences using narrative inquiry and is supported by literature and theory. The following databases were searched: CINAHL, Cochrane Library, Medline, Scopus, ERIC, ProQuest, PsychINFO, Web of Science and Health Collection (Informit). Key terms and Boolean search operators were used to broaden the search criteria. Search terms included: adolescent mother, teenage mother, "social networking sites", online, social media, Facebook, social support, social capital and information. Dates for the search were limited to January 1995-June 2017. IMPLICATIONS FOR PRACTICE/RESEARCH: Narrative research inherently values the individual "story" of experience. This approach facilitates rapport building and methodological flexibility with an often difficult to engage sample group, adolescents. CONCLUSION: Narrative inquiry reveals a deep level of insight into social networking site use by adolescent mothers. The flexibility afforded by use of a narrative approach allows for fluidity and reflexivity in the research process. PMID- 28910501 TI - Serum cystatin C level: An excellent predictor of mortality in patients with cirrhotic ascites. AB - BACKGROUND AND AIM: Although serum cystatin C level is considered a more accurate marker of renal function in patients with liver cirrhosis, its prognostic efficacy remains uncertain. This study aimed to evaluate the prognostic efficacy of serum cystatin C level in patients with cirrhotic ascites. METHODS: Patients with cirrhotic ascites from 15 hospitals were prospectively enrolled between September 2009 and March 2013. Cox regression analyses were performed to identify independent predictive factors of mortality and development of type 1 hepatorenal syndrome (HRS-1). RESULTS: In total, 350 patients were enrolled in this study. The mean age was 55.4 +/- 10.8 years, and 267 patients (76.3%) were men. The leading cause of liver cirrhosis was alcoholic liver disease (64.3%), followed by chronic viral hepatitis (29.7%). Serum creatinine and cystatin C levels were 0.9 +/- 0.4 mg/dL and 1.1 +/- 0.5 mg/L, respectively. Multivariate analyses revealed that international normalized ratio and serum bilirubin, sodium, and cystatin C levels were independent predictors of mortality and international normalized ratio and serum sodium and cystatin C levels were independent predictors of the development of HRS-1. Serum creatinine level was not significantly associated with mortality and development of HRS-1 on multivariate analysis. CONCLUSION: Serum cystatin C level was an independent predictor of mortality and development of HRS-1 in patients with cirrhotic ascites, while serum creatinine level was not. Predictive models based on serum cystatin C level instead of serum creatinine level would be more helpful in the assessment of the condition and prognosis of patients with cirrhotic ascites. PMID- 28910503 TI - Triplet Harvesting from Intramolecular Singlet Fission in Polytetracene. AB - Singlet fission (SF), a promising mechanism of multiple exciton generation, has only recently been engineered as a fast, efficient, intramolecular process (iSF). The challenge now lies in designing and optimizing iSF materials that can be practically applied in high-performance optoelectronic devices. However, most of the reported iSF systems, such as those based on donor-acceptor polymers or pentacene, have low triplet energies, which limits their applications. Tetracene based materials can overcome significant challenges, as the tetracene triplet state is practically useful, ~1.2 eV. Here, the synthesis and excited state dynamics of a conjugated tetracene homopolymer are studied. This polymer undergoes ultrafast iSF in solution, generating high-energy triplets on a sub picosecond time scale. Magnetic-field-dependent photocurrent measurements of polytetracene-based devices demonstrate the first example of iSF-generated triplet extraction in devices, exhibiting the potential of iSF materials for use in next-generation devices. PMID- 28910504 TI - Ca2+ Induced Crosslinking of AIE-Active Polyarylene Ether Nitrile into Fluorescent Polymeric Nanoparticles for Cellular Bioimaging. AB - Biocompatible fluorescent polymeric nanoparticles (FPNs) are promising luminescent probes in cellular bioimaging, while the fabrication of high-quantum yield FPN using nonconjugated heterochain polymers derived from step-growth polymerization is still in its infancy. Herein, the nonconjugated polyarylene ether nitrile (PEN) is endowed with aggregation-induced emission (AIE) feature by incorporation of an AIEgen named of 1,2-di(4-hydroxyphenyl)-1,2-diphenylethene into macromolecular backbone. Furthermore, the AIE-active PEN is crosslinked into water soluble fluorescent nanospheres showing good biocompatibility and strong emission ~480 nm with a quantum yield of 21% in the presence of Ca2+ , which allows the successful bioimaging of cancer cells. Due to the facile fabrication of FPNs and their effective bioimaging performance, the current work will open the way for the biomedical applications of various high performance polyarylene ethers. PMID- 28910505 TI - A Review on Organic-Inorganic Halide Perovskite Photodetectors: Device Engineering and Fundamental Physics. AB - The last eight years (2009-2017) have seen an explosive growth of interest in organic-inorganic halide perovskites in the research communities of photovoltaics and light-emitting diodes. In addition, recent advancements have demonstrated that this type of perovskite has a great potential in the technology of light signal detection with a comparable performance to commercially available crystalline Si and III-V photodetectors. The contemporary growth of state-of-the art multifunctional perovskites in the field of light-signal detection has benefited from its outstanding intrinsic optoelectronic properties, including photoinduced polarization, high drift mobilities, and effective charge collection, which are excellent for this application. Photoactive perovskite semiconductors combine effective light absorption, allowing detection of a wide range of electromagnetic waves from ultraviolet and visible, to the near-infrared region, with low-cost solution processability and good photon yield. This class of semiconductor might empower breakthrough photodetector technology in the field of imaging, optical communications, and biomedical sensing. Therefore, here, the focus is specifically on the critical understanding of materials synthesis, design, and engineering for the next-stage development of perovskite photodetectors and highlighting the current challenges in the field, which need to be further studied in the future. PMID- 28910506 TI - Tainted love: Gothic imaging of nurses in popular culture. AB - AIMS: To discuss representations of nursing in popular culture using the Contemporary Gothic theory. BACKGROUND: Nursing is stereotypically known as a caring profession. Caring in both the natural and professional perspectives is inextricably attached to love and love, we are told, is universal. In popular culture, however, there are numerous examples of nurses being portrayed in ways where love-its expression and its practice-has been transgressed or tainted. Exploring this dark side of nursing, even if fictitious, is significant because it illuminates social and cultural tensions. DESIGN: Discussion paper. DATA SOURCES: CINAHL, Scopus and Humanities International Databases were searched for terms related to nursing, love, abject and the gothic, published between 1990 2016. Four popular culture texts which ranged in genre and gothic elements were selected for analysis. IMPLICATIONS FOR NURSING: The types of transgressive love these nurses express to patients ranges from the obsessive and the pornographic, to the monstrous. We suggest this positioning illuminates a hidden reality that nursing work is at once intimate and personal but also hidden, profane, repellent, horrifying and feared. Nursing's allure for storytellers may rest in its association with the abject. How nurses find redemption, satisfaction and meaning in these locations is relevant for how we can imbue our lives and work with greater humanity. CONCLUSION: The Contemporary Gothic is a useful tool in exposing and exploring ambiguous, challenging and taboo aspects of nursing in society. Such and analysis helps to explain phenomena-including nursing itself which exists in the shadow of dominant and often stereotyped discourses. PMID- 28910507 TI - Intermolecular C-C Coupling between 1-Methyl-1,2,3-Triazole and 2,2'-Bipyridine or 1,10-Phenanthroline in MoII Complexes. AB - Unsupported 1-methyl-1,2,3-triazole has been coordinated to {Mo(eta3 methallyl)(CO)2 (N-N)} (N-N=2,2'-bipyridine, bipy; or 1,10-phenanthroline, phen) fragments, yielding cationic complexes that can be regarded as metalated triazolium salts. Their reactivity towards a strong base led to the deprotonation of the C5-H group of the triazole moiety, followed by an intermolecular nucleophilic attack to the ortho CH group of a bipy or phen ligand affording cyclic, bimetallic dearomatized C-C coupling products. The reaction of the neutral bipy derivative with an acid led to the formation of dihydropyridyl units by protonation of a CH group of the dearomatized rings, the dimeric nature of complexes being mantained upon protonation. PMID- 28910508 TI - Immobilizing Organic-Based Molecular Switches into Metal-Organic Frameworks: A Promising Strategy for Switching in Solid State. AB - Organic-based molecular switches (OMS) are essential components for the ultimate miniaturization of nanoscale electronics and devices. For practical applications, it is often necessary for OMS to be incorporated into functional solid-state materials. However, the switching characteristics of OMS in solution are usually not transferrable to the solid state, presumably because of spatial confinement or inefficient conversion in densely packed solid phase. A promising way to circumvent this issue is harboring the functional OMS within the robust and porous environment of metal-organic frameworks (MOFs) as their organic components. In this feature article, recent research progress of OMS-based MOFs is briefly summarized. The switching behaviors of OMS under different stimuli (e.g., light, redox, pH, etc.) in the MOF state are first introduced. After that, the technological applications of these OMS-based MOFs in different areas, including CO2 adsorption, gas separation, drug delivery, photodynamic therapy, and sensing, are outlined. Finally, perspectives and future challenges are discussed in the conclusion. PMID- 28910509 TI - The experience of palliative care service provision for people with non-malignant respiratory disease and their family carers: An all-Ireland qualitative study. AB - AIM: To explore specialist and generalist palliative care provision for people with non-malignant respiratory disease, in rural and urban areas in the North and Republic of Ireland. BACKGROUND: Globally, palliative care is recommended as an appropriate healthcare option for people with advanced non-malignant lung disease. Yet, there is limited evidence regarding the integration of palliative care for this client group. DESIGN: Qualitative study. METHODS: Convenience sample of 17 bereaved carers and 18 healthcare professionals recruited from two rural and two urban sites on the Island of Ireland. Data were collected throughout 2012 and 2013 through semi-structured interviews with carers of patients with Chronic Obstructive Pulmonary Disease (N = 12), interstitial lung disease (N = 4) or bronchiectasis (N = 1) who had died 3-18 months previously; and four focus groups with healthcare professionals. Data were analysed using a thematic analysis framework. RESULTS: Carers' interviews yielded three overarching themes: (1) lack of preparedness for death, due to ambiguity regarding disease trajectory; (2) lack of consistency in palliative care delivery, in relation with the receipt of generalist and specialist palliative care; and (3) role ambiguity, related to their caregiving role. Focus groups identified two overarching themes: (1) barriers to appropriate palliative care; and (2) the future direction of palliative care for patient with non-malignant respiratory disease. CONCLUSION: The uncertain disease trajectory was not only experienced by carers but also healthcare professionals. Although referral to specialist palliative care services was perceived as increasing, the availability and coordination of generalist and specialist palliative care services were fragmented and varied dependent on geographical location. PMID- 28910510 TI - Tuning of CO2 Reduction Selectivity on Metal Electrocatalysts. AB - Climate change, caused by heavy CO2 emissions, is driving new demands to alleviate the rising concentration of atmospheric CO2 levels. Enlightened by the photosynthesis of green plants, photo(electro)chemical catalysis of CO2 reduction, also known as artificial photosynthesis, is emerged as a promising candidate to address these demands and is widely investigated during the past decade. Among various artificial photosynthetic systems, solar-driven electrochemical CO2 reduction is widely recognized to possess high efficiencies and potentials for practical application. The efficient and selective electroreduction of CO2 is the key to the overall solar-to-chemical efficiency of artificial photosynthesis. Recent studies show that various metallic materials possess the capability to play as electrocatalysts for CO2 reduction. In order to achieve high selectivity for CO2 reduction products, various efforts are made including studies on electrolytes, crystal facets, oxide-derived catalysts, electronic and geometric structures, nanostructures, and mesoscale phenomena. In this Review, these methods for tuning the selectivity of CO2 electrochemical reduction of metallic catalysts are summarized. The challenges and perspectives in this field are also discussed. PMID- 28910511 TI - Kinetic-Controlled Formation of Bimetallic Metal-Organic Framework Hybrid Structures. AB - Heterometallic metal-organic frameworks (MOFs) are constructed from two or more kinds of metal ions, while still remaining their original topologies. Due to distinct reaction kinetics during MOF formation, partial distribution of different metals within a single MOF crystal can lead to sophisticated heterogeneous nanostructures. Here, this study reports an investigation of reaction kinetics for different metal ions in a bimetallic MOF system, the ZIF 8/67 (M(2-mIM)2 , M = Zn for ZIF-8, and Co for ZIF-67, 2-mIM = 2 methylimidazole), by in situ optical method. Distinct kinetics of the two metals forming single-component MOFs are revealed, and when both Co and Zn ions are present in the starting solution, homogeneous distributions of the two metals are only achieved at high Co/Zn ratio, while at low Co/Zn ratio concentration gradient from Co-rich cores to Zn-rich shells is observed. Further, by adding the two metals in sequence, more sophisticated structures are achieved. Specifically, when Co2+ is added first, ZIF-67@ZIF-8/67 core-shell nanocrystals are achieved with tunable core/shell thickness ratio depending on the time intervals; while when Zn2+ is added first, only agglomerates of irregular shape form due to the weak nucleation ability of Zn2+ . PMID- 28910513 TI - Quality of life outcomes following pediatric lung transplantation. AB - PURPOSE: Compared to other solid organs, survival after lung transplantation (LTx) is still poor. Discussions on survival benefits following LTx in children, however, have largely concentrated on medical outcome data. Little research describes quality of life (QoL) of pediatric LTx recipients, which is partly due to the small number of pediatric LTxs performed. Only two centers worldwide performed >10 pediatric LTxs in 2013, making data on QoL in this population difficult to obtain. The primary objective was to examine the impact of LTx on QoL of pediatric recipients. METHODS: LTx recipients aged 8-17 years and their parents were recruited from a Canadian pediatric transplant centre. Participants completed the PedsQL 4.0 Generic Core Scales, a validated health-related QoL patient-reported outcome measure for children and adolescents, pre-transplant and two times post-transplant. Pre-LTx QoL scores were compared with initial assessment scores post-LTx and changes in QoL over time were described. Correlations between self- and proxy-reports were also discussed. RESULTS: Ten pediatric LTx recipients (six male, mean age = 13.3 years) and their parents were enrolled. Assessments were completed pre-LTx (mean months = 4.8) and two times post-LTx (mean months 8.7 and 24.6, respectively). Pre- and post-transplant total scores differed significantly for both self- and proxy-report, which remained consistent at a second assessment post-transplant (P = 0.018 and 0.028, respectively). CONCLUSIONS: Findings highlight the importance of QoL outcomes when exploring LTx as a treatment option. Future research should explore long term QoL outcomes post-LTx and examine standardized integration of patient reported outcomes into clinical practice. PMID- 28910514 TI - Pharmacokinetics of single-dose ceftaroline fosamil in children with cystic fibrosis. AB - BACKGROUND: Single-dose pharmacokinetics (PK) and safety of ceftaroline fosamil with population pharmacokinetic/pharmacodynamic (PK/PD) modeling for staphylococcal pneumonia was performed in children with CF. METHODS: Subjects between 6 and 18 years old were evaluated in this phase 1, open-label, single dose, prospective study using 10 mg/kg (up to 600 mg). Non-compartmental analysis and population-based PK analyses with Monte Carlo simulation (for doses 8-20 mg/kg every 8 h, infused over 1-4 h) were conducted. RESULTS: A total of 20 subjects were enrolled. The median age and weight were 12 yr (range 6.3-17.4) and 38.7 kg (range 17.8-94.3), respectively. A 3-compartment linear model incorporating age and weight provided the best fit for the data. Comparing children 6 to <12 years to those 12 to <18 years, the mean posthoc Bayesian parameter estimates for total volume of distribution (VT ) were 0.32 +/- 0.05 L/kg versus 0.32 +/- 0.04 L/kg, P = 0.7; and total Clearance (CLT ), 0.50 +/- 0.10 L/h/kg versus 0.30 +/- 0.07 L/h/kg, P = 0.001. Using susceptibility data from pediatric MRSA lower respiratory tract isolates, 8 mg/kg (maximum of 1000 mg per dose) infused over 1 h every 8 h achieved free-drug plasma concentrations above the minimum inhibitory concentration for >=60% of the dosing interval in at least 95% of virtual subjects. CONCLUSIONS: Since children with CF have increased ceftaroline CL compared with published data from non-CF children; greater dosages may be required in children with CF to achieve adequate exposure in the treatment of MRSA pneumonia. Pharmacodynamic-based dosing predicts that dosing should also be based on the patient's MRSA MIC. PMID- 28910512 TI - Differences in staining intensities affect reported occurrences and concentrations of Giardia spp. in surface drinking water sources. AB - AIM: USEPA Method 1623, or its equivalent, is currently used to monitor for protozoan contamination of surface drinking water sources worldwide. At least three approved staining kits used for detecting Cryptosporidium and Giardia are commercially available. This study focuses on understanding the differences among staining kits used for Method 1623. METHODS AND RESULTS: Merifluor and EasyStain labelling kits were used to monitor Cryptosporidium oocyst and Giardia cyst densities in New York City's raw surface water sources. In the year following a change to the approved staining kits for use with Method 1623, an anomaly was noted in the occurrence of Giardia cysts in New York City's raw surface water. Specifically, Merifluor-stained samples had higher Giardia cyst densities as compared with those stained with EasyStain. Side by side comparison revealed significantly lower fluorescence intensities of Giardia muris as compared with Giardia duodenalis cysts when labelled with EasyStain. CONCLUSIONS: This study showed very poor fluorescence intensity signals by EasyStain on G. muris cysts resulting in lower cyst counts, while Merifluor, with its broader Giardia cyst staining specificity, resulted in higher cyst counts, when using Methods 1623. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that detected Giardia cyst concentrations are dependent on the staining kits used, which can result in a more or less conservative estimation of occurrences and densities of zoonotic Giardia cysts by detecting a broader range of Giardia species/Assemblages. PMID- 28910515 TI - Chiral Kagome Lattices from On-Surface Synthesized Molecules. AB - Kagome lattices have attracted much attention owing to their potential applications in spin-frustrated magnetism and host-guest chemistry. Examples toward the fabrication of 2D Kagome lattices reported previously have in common that the precursor molecules were typically deposited on the surface structurally intact with no chemical reactions accompanied. Herein, by using a combination of synchrotron radiation photoelectron spectroscopy (SRPES) and scanning tunneling microscopy (STM), we demonstrated the fabrication of two types of chiral Kagome lattices from on-surface synthesized organometallic compounds, which are known as intermediates of Glaser coupling on silver single crystal surfaces. These Kagome lattices are stabilized by the interplay of various intermolecular interactions, including Br???Br bonds, C-Br???pi bonds and pi-pi stacking. The chiral transference and host-guest supramolecular structure in the novel Kagome lattices were also studied. Our studies may pave a new way to engineer complex supramolecular networks through on-surface reactions. PMID- 28910516 TI - Controlling Differentiation of Stem Cells for Developing Personalized Organ-on Chip Platforms. AB - Organ-on-chip (OOC) platforms have attracted attentions of pharmaceutical companies as powerful tools for screening of existing drugs and development of new drug candidates. OOCs have primarily used human cell lines or primary cells to develop biomimetic tissue models. However, the ability of human stem cells in unlimited self-renewal and differentiation into multiple lineages has made them attractive for OOCs. The microfluidic technology has enabled precise control of stem cell differentiation using soluble factors, biophysical cues, and electromagnetic signals. This study discusses different tissue- and organ-on-chip platforms (i.e., skin, brain, blood-brain barrier, bone marrow, heart, liver, lung, tumor, and vascular), with an emphasis on the critical role of stem cells in the synthesis of complex tissues. This study further recaps the design, fabrication, high-throughput performance, and improved functionality of stem-cell based OOCs, technical challenges, obstacles against implementing their potential applications, and future perspectives related to different experimental platforms. PMID- 28910517 TI - Pediatric flexible and rigid bronchoscopy in European centers-Availability and current practice. AB - AIM: Eighteen years have passed since the last European survey concerning practices in pediatric bronchoscopy was conducted. Therefore, members of the European Respiratory Society (ERS) Pediatric Bronchology Group 7.7, initiated the "European Pediatric Bronchoscopy Survey 2015," which aimed to assess the current state of this evolving diagnostic and therapeutic procedure in the field of pediatric respiratory medicine. METHOD: A questionnaire was sent to national representatives of 44 European countries with the request to distribute it to all centers performing pediatric bronchoscopies. Questions concerned the following areas of interest: number of procedures, personnel and technical equipment, indications, complications, anesthesia, and diagnostic possibilities. RESULTS: In total, 198 European centers from 33 European countries participated in the survey. From 2012 to 2014 a total of 57 145 bronchoscopies were reported. Both flexible and rigid techniques were available at most of the centers. The most frequently mentioned indications were suspected aspiration, infection, radiographic abnormalities, airway obstruction, and cough. Hypoxemia, airway obstruction, and cough were the most common complications mentioned, followed by airway hemorrhage. Most centers were able to perform bronchoalveolar lavage (BAL) and endobronchial biopsies and some performed more special procedures, such as transbronchial biopsies. Interventions like balloon dilation, laser procedures, or stent placement were less common and rarely available. CONCLUSION: Compared to the 1997 survey, our results suggest that pediatric bronchoscopy has become more widely available and established in Europe. Different practices in individual countries suggest that more effort should be put on standardizing bronchoscopic procedures across Europe. PMID- 28910518 TI - Maybe this is just asthma. PMID- 28910519 TI - Trans-nasal flexible bronchoscopy in wheezing children: Diagnostic yield, impact on therapy, and prevalence of laryngeal cleft. AB - AIM: Persistent or recurrent wheezing is a common indication for flexible bronchoscopy, as anatomic and infectious or inflammatory changes are highly prevalent. We sought to evaluate the prevalence of anatomic, infectious, and inflammatory disease in a cohort of children undergoing flexible bronchoscopy for wheezing or poorly controlled asthma. METHODS: We retrospectively reviewed all children <18 years old who underwent flexible bronchoscopy at our center from October 29, 2012-December 31, 2016 for the primary or secondary indication of wheezing (persistent, frequently recurring, or atypical) or poorly controlled asthma. RESULTS: A total of 101 procedures were identified in 94 patients, aged 3 months to 18 years. Potential anatomic causes for wheezing identified in 45.7% of patients and inflammatory changes in 49.5% of procedures. This included the identification of a laryngeal cleft in 17% for which half required medical or surgical management. Tracheobronchomalacia was the most commonly identified anatomic lesion. Thirty children from this cohort had poorly controlled asthma. Among this subgroup, 54% had increased neutrophils on BAL and 30% had an anatomic contributor to wheezing, including one with a laryngeal cleft. Based on findings from flexible bronchoscopy, management changes made in 63.8% of patients. This included medication changes in 54 and surgical intervention in 9. DISCUSSION: We conclude that transnasal flexible bronchoscopy has high yield in children with recurrent, persistent, or atypical wheezing and those with poorly controlled asthma. Laryngeal cleft has a reasonably high prevalence that warrants specific evaluation in this population. PMID- 28910520 TI - Data that empower: The success and promise of CF patient registries. AB - In this article, we describe existing CF registries with a focus on US registry data collected through the CF Foundation Patient Registry (CFFPR) and the Epidemiologic Study of CF (ESCF); highlight what registries have taught us regarding epidemiology of CF; showcase the impact of registries on research and clinical care; and discuss future directions. This manuscript complements the plenary address given by Dr Wayne Morgan at the 2016 North American CF Conference by summarizing the key points from the presentation and providing additional detail and information. PMID- 28910521 TI - Response to the Editor: "Carbon dioxide washout time, HFNC vs. NCPAP: A bench study". PMID- 28910522 TI - Giant Pressure-Induced Enhancement of Seebeck Coefficient and Thermoelectric Efficiency in SnTe. AB - The thermoelectric properties of polycrystalline SnTe have been measured up to 4.5 GPa at 330 K. SnTe shows an enormous enhancement in Seebeck coefficient, greater than 200 % after 3 GPa, which correlates to a known pressure-induced structural phase transition that is observed through simultaneous in situ X-ray diffraction measurement. Electrical resistance and relative changes to the thermal conductivity were also measured, enabling the determination of relative changes in the dimensionless figure of merit (ZT), which increases dramatically after 3 GPa, reaching 350 % of the lowest pressure ZT value. The results demonstrate a fundamental relationship between structure and thermoelectric behaviours and suggest that pressure is an effective tool to control them. PMID- 28910524 TI - Cover Image, Volume 175C, Number 3, September 2017. AB - The cover image, by Gene S. Fisch, is based on the Introduction Introduction to Behavioral Phenotypes In Medical Genetics, DOI: 10.1002/ajmg.c.31573. PMID- 28910527 TI - Comparative Structural Characterization of Spiral Dextrin Inclusion Complexes with Vitamin E or Soy Isoflavone. AB - In this study, the preparation and structural properties of spiral dextrin (SD)/vitamin E and SD/soy isoflavone inclusion complexes were studied. SD was obtained from debranched normal maize starch using isoamylases. After fractionation using a novel method of gradient ethanol precipitation, SD was separated into different fractions, among which SD-40 was found to be the optimal host molecule to prepare SD inclusion complexes with vitamin E or soy isoflavone. X-ray diffraction (XRD) and 13C cross-polarization magic angle spinning nuclear magnetic resonance (NMR) suggested that the crystalline structures of SD 40/vitamin E and SD-40/soy isoflavone were V6II and V6III types, respectively. Small-angle X-ray scattering revealed that the SD-40/vitamin E inclusion complex formed a tighter and more compact crystallite than the SD-40/soy isoflavone inclusion complex. Furthermore, the connection structures of inclusion complexes were investigated by two-dimensional nuclear Overhauser effect spectroscopy NMR, indicating that part of vitamin E with an alkyl chain was encapsulated in the helix cavity of SD-40, whereas the aromatic ring B of the soy isoflavone molecule was complexed by the helix cavity and screw of SD. PMID- 28910528 TI - Statistical Mechanical Model for Adsorption Coupled with SAFT-VR Mie Equation of State. AB - We extend the SAFT-VR Mie equation of state to calculate adsorption isotherms by considering explicitly the residual energy due to the confinement effect. Assuming a square-well potential for the fluid-solid interactions, the structure imposed by the fluid-solid interface is calculated using two different approaches: an empirical expression proposed by Travalloni et al. ( Chem. Eng. Sci. 65 , 3088 - 3099 , 2010 ), and a new theoretical expression derived by applying the mean value theorem. Adopting the SAFT-VR Mie ( Lafitte et al. J. Chem. Phys. , 139 , 154504 , 2013 ) equation of state to describe the fluid-fluid interactions, and solving the phase equilibrium criteria, we calculate adsorption isotherms for light hydrocarbons adsorbed in a carbon molecular sieve and for carbon dioxide, nitrogen, and water adsorbed in a zeolite. Good results are obtained from the model using either approach. Nonetheless, the theoretical expression seems to correlate better the experimental data than the empirical one, possibly implying that a more reliable way to describe the structure ensures a better description of the thermodynamic behavior. PMID- 28910526 TI - Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies. AB - Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches. PMID- 28910529 TI - Metal-Ion Distribution and Oxygen Vacancies That Determine the Activity of Magnetically Recoverable Catalysts in Methanol Synthesis. AB - Here, we report on the development of novel Zn-, Zn-Cr-, and Zn-Cu-containing catalysts using magnetic silica (Fe3O4-SiO2) as the support. Transmission electron microscopy, powder X-ray diffraction, and X-ray photoelectron spectroscopy (XPS) showed that the iron oxide nanoparticles are located in mesoporous silica pores and the magnetite (spinel) structure remains virtually unchanged despite the incorporation of Zn and Cr. According to XPS data, the Zn and Cr species are intermixed within the magnetite structure. In the case of the Zn-Cu-containing catalysts, a separate Cu2O phase was also observed along with the spinel structure. The catalytic activity of these catalysts was tested in methanol synthesis from syngas (CO + H2). The catalytic experiments showed an improved catalytic performance of Zn- and Zn-Cr-containing magnetic silicas compared to that of the ZnO-SiO2 catalyst. The best catalytic activity was obtained for the Zn-Cr-containing magnetic catalyst prepared with 1 wt % Zn and Cr each. X-ray absorption spectroscopy demonstrated the presence of oxygen vacancies near Fe and Zn in Zn-containing, and even more in Zn-Cr-containing, magnetic silica (including oxygen vacancies near Cr ions), revealing a correlation between the catalytic properties and oxygen vacancies. The easy magnetic recovery, robust synthetic procedure, and high catalytic activity make these catalysts promising for practical applications. PMID- 28910530 TI - Efficient Implicit Solvation Method for Full Potential DFT. AB - With the advent of efficient electronic structure methods, effective continuum solvation methods have emerged as a way to, at least partially, include solvent effects into simulations without the need for expensive sampling over solvent degrees of freedom. The multipole moment expansion (MPE) model, while based on ideas initially put forward almost 100 years ago, has recently been updated for the needs of modern electronic structure calculations. Indeed, for an all electron code relying on localized basis sets and-more importantly-a multipole moment expansion of the electrostatic potential, the MPE method presents a particularly cheap way of solving the macroscopic Poisson equation to determine the electrostatic response of a medium surrounding a solute. In addition to our implementation of the MPE model in the FHI-aims electronic structure theory code [ Blum , V. ; Comput. Phys. Commun. 2009 , 180 , 2175 - 2196 , DOI: 10.1016/j.cpc.2009.06.022 ], we describe novel algorithms for determining equidistributed points on the solvation cavity-defined as a charge density isosurface-and the determination of cavity surface and volume from just this collection of points and their local density gradients. We demonstrate the efficacy of our model on an analytically solvable test case, against high accuracy finite-element calculations for a set of ~140000 2D test cases, and finally against experimental solvation free energies of a number of neutral and singly charged molecular test sets [ Andreussi , O. ; J. Chem. Phys. 2012 , 136 , 064102 , DOI: 10.1063/1.3676407 ; Marenich , A. V. ; Minnesota Solvation Database , Version 2012; University of Minnesota : Minneapolis, MN, USA , 2012 . ]. In all test cases we find that our MPE approach compares very well with given references at computational overheads < 20% and sometimes much smaller compared to a plain self-consistency cycle. PMID- 28910531 TI - Propane-Water Mixtures Confined within Cylindrical Silica Nanopores: Structural and Dynamical Properties Probed by Molecular Dynamics. AB - Despite the multiple length and time scales over which fluid-mineral interactions occur, interfacial phenomena control the exchange of matter and impact the nature of multiphase flow, as well as the reactivity of C-O-H fluids in geologic systems. In general, the properties of confined fluids, and their influence on porous geologic phenomena are much less well understood compared to those of bulk fluids. We used equilibrium molecular dynamics simulations to study fluid systems composed of propane and water, at different compositions, confined within cylindrical pores of diameter ~16 A carved out of amorphous silica. The simulations are conducted within a single cylindrical pore. In the simulated system all the dangling silicon and oxygen atoms were saturated with hydroxyl groups and hydrogen atoms, respectively, yielding a total surface density of 3.8 OH/nm2. Simulations were performed at 300 K, at different bulk propane pressures, and varying the composition of the system. The structure of the confined fluids was quantified in terms of the molecular distribution of the various molecules within the pore as well as their orientation. This allowed us to quantify the hydrogen bond network and to observe the segregation of propane near the pore center. Transport properties were quantified in terms of the mean square displacement in the direction parallel to the pore axis, which allows us to extract self-diffusion coefficients. The diffusivity of propane in the cylindrical pore was found to depend on pressure, as well as on the amount of water present. It was found that the propane self-diffusion coefficient decreases with increasing water loading because of the formation of water bridges across the silica pores, at sufficiently high water content, which hinder propane transport. The rotational diffusion, the lifespan of hydrogen bonds, and the residence time of water molecules at contact with the silica substrate were quantified from the simulated trajectories using the appropriate autocorrelation functions. The simulations contribute to a better understanding of the molecular phenomena relevant to the behavior of fluids in the subsurface. PMID- 28910532 TI - Roles of Wettability and Supercooling in the Spreading of Cyclopentane Hydrate over a Substrate. AB - We use transmission optical microscopy to observe cyclopentane hydrate growth in sub-mm, open glass capillaries, mimicking cylindrical pores. The capillary is initially loaded with water and the guest fluid (cyclopentane) and thus possesses three menisci, that between water and cyclopentane (CP) in the middle and two menisci with the vapors at the ends. At temperatures T below the equilibrium temperature Teq ~ 7 degrees C, the hydrate nucleates on the water-CP meniscus, rapidly coating it with an immobile, polycrystalline crust. Continued movement of the other two menisci provides insights into hydrate growth mechanisms, via the consumption and displacement of the fluids. On water-wet glass, the subsequent growth consists of a hydrate "halo" creeping with an underlying water layer on the glass on the CP side of the meniscus. Symmetrically, on CP-wet glass (silane treated), a halo and a CP layer grow on the water side of the interface. No halo is observed on intermediate wet glass. The halo consists of an array of large monocrystals, over a thick water layer at low supercooling (DeltaT = Teq - T below 5 K), and a finer, polycrystalline texture over a thinner water layer at higher DeltaT. Furthermore, the velocity varies as DeltaTalpha, with alpha ~ 2.7, making the early stages of growth very similar to gas hydrate crusts growing over water-guest interfaces. Beyond a length in the millimeter range, the halo and its water layer abruptly decelerate and thin down to submicron thickness. The halo passes through the meniscus with the vapor without slowing down or change of texture. A model of the mass balance of the fluids helps rationalize all of these observations. PMID- 28910533 TI - One-Pot MCR-Oxidation Approach toward Indole-Fused Heteroacenes. AB - A straightforward synthetic route toward indole-fused heteroacenes was developed. The strategy is composed of a one-pot process starting with a multicomponent reaction of cyclohexanone, primary amine and N-tosyl-3-nitroindole followed by an oxidation step. The one-pot approach was found to be general, affording both symmetric and nonsymmetric indolo[3,2-b]indoles in good yields. The strategy was also utilized for accessing 5-ring fused benzo[g]indolo[3,2-b]indole. We could extend the methodology for the synthesis of benzothieno[3,2-b]indoles starting from 3-nitrobenzothiophene. The importance of the developed method was exemplified by performing the reaction sequence on gram scale and also by the synthetic transformations of indolo[3,2-b]indoles. In addition, the change in photophysical properties with extension of conjugation of the synthesized heteroacenes was studied. PMID- 28910534 TI - Pressure Enhancement in Confined Fluids: Effect of Molecular Shape and Fluid-Wall Interactions. AB - Recently, several experimental and simulation studies have found that phenomena that normally occur at extremely high pressures in a bulk phase can occur in nanophases confined within porous materials at much lower bulk phase pressures, thus providing an alternative route to study high-pressure phenomena. In this work, we examine the effect on the tangential pressure of varying the molecular shape, strength of the fluid-wall interactions, and pore width, for carbon slit shaped pores. We find that, for multisite molecules, the presence of additional rotational degrees of freedom leads to unique changes in the shape of the tangential pressure profile, especially in larger pores. We show that, due to the direct relationship between the molecular density and the fluid-wall interactions, the latter have a large impact on the pressure tensor. The molecular shape and pore size have a notable impact on the layering of molecules in the pore, greatly influencing both the shape and scale of the tangential pressure profile. PMID- 28910535 TI - Emergence of a New Self-Replicator from a Dynamic Combinatorial Library Requires a Specific Pre-Existing Replicator. AB - Our knowledge regarding the early steps in the formation of evolvable life and what constitutes the minimal molecular basis of life remains far from complete. The recent emergence of systems chemistry reinvigorated the investigation of systems of self-replicating molecules to address these questions. Most of these studies focus on single replicators and the effects of replicators on the emergence of other replicators remains under-investigated. Here we show the cross catalyzed emergence of a novel self-replicator from a dynamic combinatorial library made from a threonine containing peptide building block, which, by itself, only forms trimers and tetramers that do not replicate. Upon seeding of this library with different replicators of different macrocycle size (hexamers and octamers), we observed the emergence of hexamer replicator consisting of six units of the threonine peptide only when it is seeded with an octamer replicator containing eight units of a serine building block. These results reveal for the first time how a new replicator can emerge in a process that relies critically on the assistance by another replicator through cross-catalysis and that replicator composition is history dependent. PMID- 28910536 TI - State-to-State Differential Cross Sections for Inelastic Collisions of NO Radicals with para-H2 and ortho-D2. AB - We present state-to-state differential cross sections for collisions of NO molecules (X2Pi1/2, j = 1/2f) with para-H2 and ortho-D2 molecules, at a collision energy of 510 and 450 cm-1, respectively. The angular scattering distributions for various final states of the NO radical are measured with high resolution using a crossed molecular beam apparatus that employs the combination of Stark deceleration and velocity map imaging. Rotational rainbows as well as diffraction oscillations are fully resolved in the scattering images. The observed angular scattering distributions are in excellent agreement with the cross sections obtained from quantum close-coupling scattering calculations based on recently computed NO-H2 potential energy surfaces, except for excitation of NO into the j = 7/2f channel. For this particular inelastic channel, a significant discrepancy with theory is observed, despite various additional measurements and calculations, at present, not understood. PMID- 28910537 TI - Analysis of mechanics of side impact test defined in UN/ECE Regulation 129. AB - OBJECTIVE: This article discusses differences between a side impact procedure described in United Nations/Economic Commission for Europe (UN/ECE) Regulation 129 and scenarios observed in real-world cases. METHODS: Numerical simulations of side impact tests utilizing different boundary conditions are used to compare the severity of the Regulation 129 test and the other tests with different kinematics of child restraint systems (CRSs). In the simulations, the authors use a validated finite element (FE) model of real-world CRSs together with a fully deformable numerical model of the Q3 anthropomorphic test device (ATD) by Humanetics Innovative Solution, Inc. RESULTS: The comparison of 5 selected cases is based on the head injury criterion (HIC) index. Numerical investigations reveal that the presence of oblique velocity components or the way in which the CRS is mounted to the test bench seat fixture is among the significant factors influencing ATD kinematics. The results of analyses show that the side impact test procedure is very sensitive to these parameters. A side impact setup defined in Regulation 129 may minimize the effects of the impact. CONCLUSIONS: It is demonstrated that an artificial anchorage in the Regulation 129 test does not account for a rotation of the CRS, which should appear in the case of a realistic anchorage. Therefore, the adopted procedure generates the smallest HIC value, which is at the level of the far-side impact scenario where there are no obstacles. It is also shown that the presence of nonlateral acceleration components challenges the quality of a CRS and its headrest much more than a pure lateral setup. PMID- 28910538 TI - Muscular contraction frequency does not affect plasma homocysteine concentration in response to energy expenditure- and intensity-matched acute exercise in sedentary males. AB - Acute exercise seems to increase total plasma homocysteine (tHcy); since this variable associated with cardiovascular risk, it is important to understand the determinants of its response to all types of exercise. The aim of this study was to examine the impact of cycling at 2 different rates of muscle contraction on the complete tHcy kinetics. Eight young sedentary males were required to complete 2 isocaloric (400 kcal) acute exercise trials at 50% peak oxygen uptake on separate occasions at 50 or 80 rpm. Blood samples were drawn at different points before (4 h before exercise and immediately before exercise), during (10, 20, 30, 45, and 60 min during exercise), and after exercise (immediately and 19 h after exercise). Dietary and lifestyle factors were controlled during the research. Maximum tHcy occurred during exercise for both conditions (50 rpm: 11.4 +/- 2.7 MUmol.L-1; 80 rpm: 10.8 +/- 3.2 MUmol.L-1). From this point onwards tHcy declined until the cessation of exercise and continued descending below pre-exercise values at 19 h postexercise (p < 0.05). No hyperhomocysteinemia were observed at any sampling point in both trials. In conclusion, the different muscular contraction frequency during exercise has no impact on tHcy during an acute bout of exercise in sedentary individuals, when at least 400 kcal are spent during exercise and the nutritional status for folate, B12, and B6 is adequate. This information is relevant to further inform healthy exercise prescription, not only in terms of duration and intensity of exercise, but also taking into account frequency of contraction. PMID- 28910539 TI - Actual versus preferred sleep times as a proxy of biological time for social jet lag. PMID- 28910541 TI - Seasonal variability of NT-proBNP in Swedish primary care patients. AB - The aim of this study was to determine if there is a seasonal variation in the widely used heart failure marker NT-proBNP. The study included all primary care requests for NT-proBNP in the county of Uppsala, Sweden, between January 2007 and December 2015. For seasonal variation, the NT-proBNP results for individual months were compared. The NT-proBNP values were highest in July to September, but there was also a minor peak in December-January. In conclusion, a seasonal periodicity for NT-proBNP was demonstrated in primary care patients. The data could be useful for practitioners for evaluation of NT-proBNP results and monitoring of patients with heart failure. PMID- 28910540 TI - Sleep quality, chronotype and metabolic syndrome components in bipolar disorders during the remission period: Results from the FACE-BD cohort. AB - Data on sleep or circadian abnormalities and metabolic disturbances in euthymic bipolar disorders are scarce and based on small sample sizes. The aim of this study was to explore the associations between sleep disturbances, chronotype and metabolic components in a large sample of euthymic patients with bipolar disorders (BD). From 2009 to 2015, 752 individuals with bipolar disorders from the FACE-BD cohort were included and assessed for sleep quality, chronotype and metabolic components. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was used to confirm the diagnosis of BD. Subjective sleep quality was measured with the Pittsburgh Sleep Quality Index and chronotype with the Composite Scale of Morningness. Sociodemographic and clinical characteristics, psychotropic treatment, psychiatric comorbidities and blood samples were collected. In our sample, 22.4% of individuals with BD presented with a metabolic syndrome, 53.7% had sleep disturbances, 25.4% were considered as having an evening chronotype and 12.6% as having a morning chronotype. Independently of potential confounders, euthymic patients with sleep disturbances had a higher abdominal circumference, and patients with evening chronotype had a significantly higher level of triglycerides. There was an association between evening chronotype and an increased atherogenic index of plasma (OR = 4.8, 95%CI = 1.6-14.7). Our findings contribute the scant literature on the relationship between sleep quality, chronotype and cardiometabolic components in euthymic individuals with BD and highlight the need to improve quality of sleep and patient education about healthier sleep-hygiene practices. PMID- 28910542 TI - Effect of monochromatic light on circadian rhythmic expression of clock genes and arylalkylamine N-acetyltransferase in chick retina. AB - Birds have more developed visual function. They not only have the ability to detect light and darkness but also have the color vision. Previous study showed that monochromatic light influenced avian physiological processes, which were controlled by clock genes. Therefore, bird's eye is a good model to studying the impact of color of light on circadian rhythms. Avian retina is one of the most important central oscillations. The study was designed to investigate the effect of color of light on the expression of clock genes and arylalkylamine N acetyltransferase (Aanat) mRNA expression in chick retina. A total of 240 post hatching day (P) 0 broiler chickens were exposed to blue (BL), green (GL), red (RL) and white light (WL) from a LED system under a light-dark cycle 12L:12D for 14 d. The results show that the significant daily variations existed in the gene expression of cBmal1, cBmal2, cCry1, cCry2, cPer2 and cPer3, but not for cClock under four light treatments. The genes cBmal1, cCry1, cPer2 and cPer3 presented circadian rhythmic expression under the various monochromatic lights. When compared with WL, GL elevated the expression of positive regulators of cellular clock (cBmal1, cBmal2 and cClock) and cAanat mRNA level, whereas RL increased the mRNA levels of negative regulators of cellular clock (cCry1, cCry2, cPer2 and cPer3) and decreased the cAanat mRNA expression in the retina. These results demonstrated that monochromatic light affect the periodic expression levels of the biological clock mRNA by positive and negative feedback loop interactions, GL activated the transcription of cAanat; while RL suppressed the transcription of cAanat. Thereby, color of light regulates ocular cAanat expression by affecting on expression of cellular clock regulators. PMID- 28910543 TI - Intra-individual variability in the sleep of senior and junior rugby league athletes during the competitive season. AB - This study examined the sleep intra-individual variability (IIV) of rugby league athletes across senior and junior levels during one week of the competitive season. Forty-five rugby league athletes across elite senior, sub-elite senior and elite junior levels each wore actigraphy monitors for seven days during the competitive season, and completed a subjective sleep diary each morning upon waking. Linear mixed models were used to assess differences in sleep measures between playing levels. Intra-individual standard deviations for each sleep measure were calculated for each athlete to determine their respective IIV, allowing differences in IIV between groups to be assessed. Elite junior athletes went to bed later (ES = 0.94 +/- 0.50, p < 0.05) and woke later than elite senior athletes (ES = 0.94 +/- 0.40, p < 0.05), while also displaying greater IIV when considering time in bed (ES = 1.14 +/- 0.60, p < 0.05) and sleep duration (ES = 1.53 +/- 0.64, p < 0.05) compared with elite senior athletes. Similarly, IIV was more pronounced in elite junior players for time in bed (ES = 0.88 +/- 0.60, p < 0.05) and sleep duration (ES = 1.03 +/- 0.64, p < 0.05) compared with sub-elite senior athletes. Despite this, elite junior athletes still obtained sufficient sleep duration, efficiency and quality. The outcomes of this investigation show a distinct difference in the habitual sleep-wake patterns of senior and junior rugby league athletes, and show how sleep IIV differs between playing levels in rugby league. PMID- 28910544 TI - Human microbiota in aging and infection: A review. AB - In most developed countries, ageing of the population started more than a century ago and it seems to be emerged in a wide range of developing countries as well. Moreover, research into ageing has moved forward in extremely rapidly rhythms nowadays, and the scientific area is of great interest, as implications for nearly all sectors of society, including work, social, economic features, in addition to nutrition and health issues which are involved. The fragile elder population is affected and experienced more frequently infections than the younger population. Infections in elderly patients are of major medical importance because of hormonal changes, increased production of pro-inflammatory cytokines and chemokines, abnormalities of the telomeres which could cause a dysfunction of the immune system called immunosenescence and malnutrition. PMID- 28910545 TI - Complementing the Social Jet Lag by considering pristine internal time. PMID- 28910546 TI - Could hop-derived bitter compounds improve glucose homeostasis by stimulating the secretion of GLP-1? AB - Hops (Humulus lupulus L.) is by far the greatest contributors to the bitter property of beer. Over the past years, a large body of evidence demonstrated the presence of taste receptors in different locations of the oral cavity. In addition to the taste buds of the tongue, cells expressing these receptors have been identified in olfactory bulbs, respiratory and gastrointestinal tract. In the gut, the attention was mainly directed to sweet Taste Receptor (T1R) and bitter Taste Receptor (T2R) receptors. In particular, T2R has shown to modulate secretion of different gut hormones, mainly Glucagon-like Peptide 1 (GLP-1), which are involved in the regulation of glucose homeostasis and the control of gut motility, thereby increasing the sense of satiety. Scientific interest in the activity of bitter taste receptors emerges because of their wide distribution in the human species and the large range of natural substances that interact with them. Beer, whose alcohol content is lower than in other common alcoholic beverages, contains a considerable amount of bitter compounds and current scientific evidence shows a direct effect of beer compounds on glucose homeostasis. The purpose of this paper is to review the available literature data in order to substantiate the novel hypothesis of a possible direct effect of hop derived bitter compounds on secretion of GLP-1, through the activation of T2R, with consequent improvement of glucose homeostasis. PMID- 28910547 TI - Diurnal opposite variation between angiotensinase activities in photo-neuro endocrine tissues of rats. AB - Central and peripheral renin-angiotensin systems (RASs) act in a coordinated manner for the physiologic functions regulated by neuroendocrine events. However, whereas the diurnal rhythm of peripheral circulatory and tissue RASs is well known, the circadian behaviour of their components in central photo-neuro endocrine structures, key elements for the control of circadian rhythms, has been barely studied. In the present study, we analysed the aspartyl- (AspAP) and glutamyl-aminopeptidase (GluAP) (aminopeptidase A) activities, the angiotensinases responsible for the metabolism of Ang I to Ang 2-10 and Ang II to Ang III, respectively, in the retina, anterior hypothalamus and pituitary at different light and dark time-points of a 12:12 h light:dark cycle (7-19 h light), using arylamide derivatives as substrates. The results demonstrated that while retina and pituitary exhibited their highest levels of AspAP activity in the light period and the lowest in the dark one, the contrary occurred in the hypothalamus - the lowest levels were observed in light conditions and the highest in darkness. The outcome for GluAP showed the highest levels in the light period and the lowest in the dark one in the three tissues analysed. In conclusion, changes in angiotensinase activities throughout the daytime may cause changes of their respective substrates and derived peptides and, consequently, in their functions. This observation may have implications for the treatment of hypertension. PMID- 28910548 TI - Time-of-day effects of exposure to solar radiation on thermoregulation during outdoor exercise in the heat. AB - High solar radiation has been recognised as a contributing factor to exertional heat-related illness in individuals exercising outdoors in the heat. Although solar radiation intensity has been known to have similar time-of-day variation as body temperature, the relationship between fluctuations in solar radiation associated with diurnal change in the angle of sunlight and thermoregulatory responses in individuals exercising outdoors in a hot environment remains largely unknown. The present study therefore investigated the time-of-day effects of variations in solar radiation associated with changing solar elevation angle on thermoregulatory responses during moderate-intensity outdoor exercise in the heat of summer. Eight healthy, high school baseball players, heat-acclimatised male volunteers completed a 3-h outdoor baseball trainings under the clear sky in the heat. The trainings were commenced at 0900 h in AM trial and at 1600 h in PM trial each on a separate day. Solar radiation and solar elevation angle during exercise continued to increase in AM (672-1107 W/m2 and 44-69 degrees ) and decrease in PM (717-0 W/m2 and 34-0 degrees ) and were higher on AM than on PM (both P < 0.001). Although ambient temperature (AM 32-36 degrees C, PM 36-30 degrees C) and wet-bulb globe temperature (AM 31-33 degrees C, PM 34-27 degrees C) also continued to increase in AM and decrease in PM, there were no differences between trials in these (both P > 0.05). Tympanic temperature measured by an infrared tympanic thermometer and mean skin temperature were higher in AM than PM at 120 and 180 min (P < 0.05). Skin temperature was higher in AM than PM at the upper arm and thigh at 120 min (P < 0.05) and at the calf at 120 and 180 min (both P < 0.05). Body heat gain from the sun was greater during exercise in AM than PM (P < 0.0001), at 0-60 min in PM than AM (P < 0.0001) and at 120-180 min in AM than PM (P < 0.0001). Dry heat loss during exercise was greater at 0-60 min (P < 0.0001), and lower at 60-120 min (P < 0.05) and 120-180 min (P < 0.0001) in AM than PM. Evaporative heat loss during exercise was greater in PM than AM at 120-180 min (P < 0.0001). Total (dry + evaporation) heat loss at the skin was greater during exercise in PM than AM (P < 0.0001), at 0-60 min in AM than PM (P < 0.0001) and at 60-120 and 120-180 min in PM than AM (P < 0.05 and 0.0001). Heart rate at 120-150 min was also higher in AM than PM (P < 0.05). Neither perceived thermal sensation nor rating of perceived exertion was different between trials (both P > 0.05). The current study demonstrates a greater thermoregulatory strain in the morning than in the afternoon resulting from a higher body temperature and heart rate in relation to an increase in environmental heat stress with rising solar radiation and solar elevation angle during moderate-intensity outdoor exercise in the heat. This response is associated with a lesser net heat loss at the skin and a greater body heat gain from the sun in the morning compared with the afternoon. PMID- 28910550 TI - Overview of craft brewing specificities and potentially associated microbiota. AB - The brewing process differs slightly in craft breweries as compared to industrial breweries, as there are fewer control points. This affects the microbiota of the final product. Beer contains several antimicrobial properties that protect it from pathogens, such as low pH, low oxygen and high carbon dioxide content, and the addition of hops. However, these hurdles have limited power controlling spoilage organisms. Contamination by these organisms can originate in the raw materials, persist in the environment, and be introduced by using flavoring ingredients later in the process. Spoilage is a prominent issue in brewing, and can cause quality degradation resulting in consumer rejection and product waste. For example, lactic acid bacteria are predominately associated with producing a ropy texture and haze, along with producing diacetyl which gives the beer butter flavor notes. Other microorganisms may not affect flavor or aroma, but can retard fermentation by consuming nutrients needed by fermentation yeast. Quality control in craft breweries today relies on culturing methods to detect specific spoilage organisms. Using media can be beneficial for detecting the most common beer spoilers, such as Lactobacillus and Pediococci. However, these methods are time consuming with long incubation periods. Molecular methods such as community profiling or high throughput sequencing are better used for identifying entire populations of beer. These methods allow for detection, differentiation, and identification of taxa. PMID- 28910549 TI - Upregulation of alpha-enolase protects cardiomyocytes from phenylephrine-induced hypertrophy. AB - Cardiac hypertrophy often refers to the abnormal growth of heart muscle through a variety of factors. The mechanisms of cardiomyocyte hypertrophy have been extensively investigated using neonatal rat cardiomyocytes treated with phenylephrine. alpha-Enolase is a glycolytic enzyme with "multifunctional jobs" beyond its catalytic activity. Its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the change of alpha-enolase during cardiac hypertrophy and explore its role in this pathological process. We revealed that mRNA and protein levels of alpha-enolase were significantly upregulated in hypertrophic rat heart induced by abdominal aortic constriction and in phenylephrine-treated neonatal rat cardiomyocytes. Furthermore, knockdown of alpha-enolase by RNA interference in cardiomyocytes mimicked the hypertrophic responses and aggravated phenylephrine-induced hypertrophy without reducing the total glycolytic activity of enolase. In addition, knockdown of alpha-enolase led to an increase of GATA4 expression in the normal and phenylephrine-treated cardiomyocytes. Our results suggest that the elevation of alpha-enolase during cardiac hypertrophy is compensatory. It exerts a catalytic independent role in protecting cardiomyocytes against pathological hypertrophy. PMID- 28910551 TI - Effects of differences in the availability of light upon the circadian rhythms of institutionalized elderly. AB - The aim of this study was to compare the availability of diurnal and nocturnal light in two residences for aged persons (R1 and R2, Palma de Mallorca, Illes Balears, Spain). We found that the R1 inmates were exposed to lower amounts of light during waking time and higher amounts during sleeping time. The main traits of the circadian rhythms and the quality of sleep in the inmates of the two residences were found to be positively related to the availability of light during waking time and negatively to the increased light exposure during bed time. In addition, the sleep of R1 inmates suffered higher disturbances as a consequence of the different policy for nocturnal diapers check and change. Altogether, these two factors may explain the differences observed in the two residences regarding the circadian rhythms, health status and quality of life. Two conclusions stem from these results: (1) the circadian rhythms of aged people are particularly sensitive to the contrast between diurnal and nocturnal light and (2) the nursing staff of institutions for aged people must receive specific formation on the best practices for maintaining the circadian health of aged people. PMID- 28910552 TI - The Use of Topical Corticosteroids for Treatment of Dry Eye Syndrome. AB - Dry eye disease (DED) is a multifactorial disease that results in symptoms of discomfort, visual disturbance, and damage to the ocular surface. Because chronic inflammation plays an important role in DED, treatment with topical corticosteroids has been demonstrated to ameliorate the signs and symptoms of the disease. Although these agents have proven short-term efficacy, their long-term use may cause intraocular pressure elevation and cataract progression. A carefully review of the different studies shows that differences between corticosteroids may exist regarding the incidence of side effects and evidence of efficacy in DED patients. PMID- 28910553 TI - Sympathetic Ophthalmia Following Accidental Burn with Hot Water Involving the Other Eye. PMID- 28910554 TI - Ocular Self-Microemulsifying Drug Delivery System of Prednisolone Improves Therapeutic Effectiveness in the Treatment of Experimental Uveitis. AB - PURPOSE: The purpose of this study was to investigate the self-microemulsifying drug delivery systems (SMEDDS) for ophthalmic delivery of Prednisolone (PDN) to treat uveitis. MATERIALS AND METHODS: The pseudo-ternary phase diagrams were developed, and various SMEDDS were prepared using Linoleic acid as oil, Cremophore RH 40 as a surfactant, and propylene glycol as a co-surfactant. Physicochemical parameters (globule size, zeta potential, viscosity, and pH) and in vitro release of SMEDDS were studied. The in vivo efficacy of prepared formulations and the marketed drug solution was studied by administering them topically to an endotoxin-induced uveitis rabbit model. RESULTS: All formulations displayed an average globule size less than 100 nm. The developed SMEDDS exhibited acceptable physicochemical behavior and displayed sustained drug release. In vivo studies in a rabbit eye showed a marked improvement in the anti inflammatory activity of developed formulation compared with a marketed formulation in a uveitis-induced rabbit eye model. CONCLUSIONS: The developed SMEDDS are a feasible option to conventional eye drops for its capability to improve bioavailability via its longer precorneal residence time and its capacity to sustain the release of the drug. PMID- 28910555 TI - Conjunctival Necrosis Masquerading as Necrotizing Scleritis. PMID- 28910557 TI - Vogt-Koyanagi-Harada Syndrome in a Group of Patients in Two Ophthalmology Referral Centers in Bogota, Colombia. AB - PURPOSE: To describe the clinical presentation of Vogt-Koyanagi-Harada (VKH) syndrome in a group of patients in Colombia. METHODS: Retrospective review of 2638 medical records of patients with uveitis in two centers during 17 years. RESULTS: A total of 25 patients with uveitis were diagnosed with VKH syndrome (0.95%), 23 patients were included in the data analysis (0.87%), 78.3% females, and mean age of diagnosis was 37 years (SD +/- 29). Main complaints: blurred vision (87%), headaches (47.8%), tinnitus (26.1%), and hearing impairments (21.7%). Ophthalmic findings: bilateral serous retinal detachment (73.9%) and non granulomatous uveitis (52.3%). Most of the patients were diagnosed with probable disease (56.5%). Mean duration of follow-up was 14 months; disease relapse was encountered in 26% of patients despite treatment. CONCLUSION: Patients in Colombia with VKH had clinical features similar to those reported in other Hispanic populations, except for the non-granulomatous uveitis. This disease may be considered as having variation of clinical manifestations across population groups. PMID- 28910556 TI - Probing the influence of SIBLING proteins on collagen-I fibrillogenesis and denaturation. AB - Bone tissue is comprised of collagen, non-collagenous proteins, and hydroxyapatite and the SIBLING (small integrin binding, N-linked glycoprotein) family of proteins is the primary group of non-collagenous proteins. By replicating the native interactions between collagen and the SIBLING proteins at the interface of an implant, it is believed that a bone scaffold will more easily integrate with the surrounding tissue. In this work, bone sialoprotein, osteopontin (OPN), dentin sialoprotein (DSP), dentin phosphoprotein (DPP), C terminal fragment of dentin matrix protein 1 (DMP1-C), and proteoglycan versions of DSP (DSP-PG) and DMP1 (DMP1-PG) were tested individually to determine their roles in collagen fibrillogenesis and the prevention of denaturation. It was shown that DSP and DPP slowed down fibrillogenesis, while other SIBLINGs had limited impact. In addition, the denaturation time was faster in the presence of DSP and OPN, indicating a negative impact. The role of calcium ions in these processes was also investigated. The presence of calcium ions sped up fibrillogenesis in all scenarios tested, but it had a negative impact by reducing the extent. Calcium also sped up the denaturation in most cases, with the exception of DMP1-C and DSP where the opposite was seen. Calcium had a similar effect on the proteoglycan variants in the fibrillogenesis process, but had no impact on the denaturation process in the presence of these two. It is believed that incorporating DMP1-C or DSP on the surface of a bone implant may improve the collagen interactions with the implant, thereby facilitating improved osteointegration. PMID- 28910558 TI - Horizontal Transfer of Tamoxifen Resistance in MCF-7 Cell Derivates: Proteome Study. AB - Using estrogen-dependent MCF-7 breast cancer cells and tamoxifen-resistant MCF 7/T subline we have shown that their co-cultivation lead to increase in tamoxifen resistance in the parent MCF-7 cells. The proteome analysis of MCF-7/T cells and new-generated resistant cells revealed 21 common proteins differently expressed in both the resistant cell lines, among them - 6 proteins were associated with the drug or hormonal resistance. Both resistant lines were characterized with suppression of estrogen receptor and activation of SNAIL1-signaling - mesenchymal pathway playing an important role in the down-regulation of estrogen receptor and maintaining of the estrogen-independent phenotype. PMID- 28910559 TI - The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005-2011. AB - OBJECTIVE: Evidence of safety issues associated with long-acting beta2-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. METHODS: A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. RESULTS: LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. CONCLUSION: The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities. PMID- 28910560 TI - Intravitreal Adalimumab for the Control of Breakthrough Intraocular Inflammation. AB - PURPOSE: Investigate the efficacy of intravitreal adalimumab in breakthrough panuveitis in patients on systemic adalimumab for more than 3 months. METHODS: Retrospective study of patients on systemic adalimumab with breakthrough panuveitis requiring intravitreal adalimumab therapy. RESULTS: Seven eyes of four patients with Adamantiades-Behcet disease panuveitis were included and all were maintained on systemic adalimumab for 7.3 months (range 3-11) with inflammation controlled for 4.1 months (range 2-10) before breakthrough uveitis. The total number of attacks was 13 over 24.5 months (range 12-30). Resolution of attack was defined as return to baseline visual acuity with resolution of inflammatory markers. Three attacks resolved after only one injection and 10 attacks required an average of 2.4 injections (range 2-3). No systemic or ocular complications were noted. CONCLUSIONS: Intravitreal adalimumab warrants further investigation as a potentially effective, practical and safe adjunctive therapy for the control of breakthrough inflammation in select patients maintained on systemic adalimumab. PMID- 28910561 TI - Assessment of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Patients with Dry Eye Disease. AB - PURPOSE: To evaluate the neutrophil-to-lymphocyte ratio (NLR) and platelet-to lymphocyte ratio (PLR) levels in patients with dry eye disease (DED). METHODS: The white blood cell, neutrophil, platelet, and lymphocyte counts were performed in 78 dry eye patients and 60 controls. The NLR was calculated by dividing neutrophil count by lymphocyte count and the PLR was calculated by dividing platelet count by lymphocyte count. RESULTS: The mean age was 53.4 +/- 3.8 years in the DED group and 52.7 +/- 3.4 years in the control group. The mean NLR was 2.6 +/- 1.2 and the mean PLR was 138.4 +/- 62.6 in the DED group and the mean NLR was 1.84 +/- 0.5 and the mean PLR was 118.5 +/- 64.7 in the control group. A significant difference was found in the NLR and PLR between the DED and the controls (p = 0.032 and p = 0.026, respectively). CONCLUSION: The NLR and PLR values were found higher in patients with dry eye than in healthy subjects. PMID- 28910562 TI - The Epidemiology of Trachoma in Mozambique: Results of 96 Population-Based Prevalence Surveys. AB - PURPOSE: Surveys are needed to guide trachoma control efforts in Mozambique, with WHO guidelines for intervention based on the prevalence of trachomatous inflammation-follicular (TF) in children aged 1-9 years and the prevalence of trichiasis in adults aged 15 years and above. We conducted surveys to complete the map of trachoma prevalence in Mozambique. METHODS: Between July 2012 and May 2015, we carried out cross-sectional surveys in 96 evaluation units (EUs) covering 137 districts. RESULTS: A total of 269,217 individuals were enumerated and 249,318 people were examined using the WHO simplified trachoma grading system. Overall, 102,641 children aged 1-9 years, and 122,689 individuals aged 15 years and above were examined. The prevalence of TF in children aged 1-9 years was >=10% in 12 EUs, composed of 20 districts, covering an estimated total population of 2,455,852. These districts require mass distribution of azithromycin for at least 3 years before re-survey. The TF prevalence in children was 5.0-9.9% in 17 EUs (28 districts, total population 3,753,039). 22 EUs (34 districts) had trichiasis prevalences >=0.2% in adults 15 years and above, and will require public health action to provide surgical services addressing the backlog of trichiasis. Younger age, more children resident in the household, and living in a household that had an unimproved latrine or no latrine facility, were independently associated with an increased odds of TF in children aged 1-9 years. CONCLUSIONS: Trachoma represents a significant public health problem in many areas of Mozambique. PMID- 28910563 TI - Safety and immunogenicity of the killed bivalent (O1 and O139) whole-cell cholera vaccine in the Philippines. AB - The killed bivalent (O1 and O139) whole cell oral cholera vaccine (OCV) (ShancholTM) was first licensed in India in 2009 and World Health Organization pre-qualified in 2011. We assessed the safety and immunogenicity of this OCV in the Philippines. This was a phase IV, single-arm, descriptive, open-label study. We recruited 336 participants from 2 centers: 112 participants in each age group (1-4, 5-14 and >= 15 years). Participants received 2 OCV doses 14 d apart. Safety was monitored throughout the trial. Blood samples were collected at baseline (pre vaccination) and 14 d after each dose. Serum vibriocidal antibody titers to V. cholerae O1 (El Tor Inaba and El Tor Ogawa) and O139 strains were assessed, with seroconversion defined as >= 4-fold increase from baseline in titers. No immediate unsolicited systemic adverse events/reactions were observed. Unsolicited systemic adverse events were mostly grade 1 intensity. One serious adverse event occurred after the first dose, but was unrelated to vaccination. High seroconversion rates (range 69-92%) were achieved against the O1 serotypes with a trend toward higher rates in the 1-4 y (86-92%) and 5-14 y (86-88%) age groups than the >= 15 y age group (69-83%). Lower seroconversion rates were achieved against the O139 serotype (35-70%), particularly in those aged >= 15 y (35-42%). The 2-dose regimen of the killed bivalent whole cell OCV was well tolerated in this study conducted in the Philippines, a cholera-endemic country. Robust immune responses were observed even after a single-dose. PMID- 28910564 TI - Nonspecificity in a nonimmune human scFv repertoire. AB - Efforts to develop effective antibody therapeutics are frequently hampered by issues such as aggregation and nonspecificity, often only detected in late stages of the development process. In this study, we used a high throughput cross reactivity assay to select nonspecific clones from a naive human repertoire scFv library displayed on the surface of yeast. Most antibody families were de enriched; however, the rarely expressed VH6 family was highly enriched among nonspecific clones, representing almost 90% of isolated clones. Mutational analysis of this family reveals a dominant role of CDRH2 in driving nonspecific binding. Homology modeling of a panel of VH6 antibodies shows a constrained beta sheet structure in CDRH2 that is not present in other families, potentially contributing to nonspecificity of the family. These findings confirm the common decision to exclude VH6 from synthetic antibody libraries, and support VH6 polyreactivity as a possible important role for the family in early ontogeny and cause for its overabundance in cases of some forms of autoimmunity. PMID- 28910565 TI - An In vivo study: Adjuvant activity of poly-n-vinyl-2-pyrrolidone-co-acrylic acid on immune responses against Melanoma synthetic peptide. AB - Peptides have been studied as an important class of components in medicine to control many major diseases with vaccination. Polymers as adjuvants are capable of enhancing the vaccine potential against various diseases by improving the delivery of antigens, and they reduce the booster doses of vaccines. In brief, polymers are promising candidates for peptide-based vaccine delivery platforms. The purpose of the present study was to create a possible alternative approach in the treatment of malignant melanoma and/or to prevent metastasis of melanoma. The study was designed as both an experimental and an in vivo study. We prepared a complex and covalent conjugate of MAGE-3 121-134 (L-L-K-Y-R-A-R-E-P-V-T-K-A-E) T cell epitope as a vaccine candidate for melanoma. These conjugates were able to generate an immune response in mice after a single immunization, without the help of any external adjuvant. The peptide-polymer complexes activated the immune system in the best way and formed the highest antigen specific immune response. These results indicate the adjuvant activity of Poly(N-vinyl-2- pyrrolidone-co acrylic acid) [P(VP-co-AA)] and the potential use of P(VP-coAA)-peptide based vaccine prototypes for future melanoma cancer vaccine formulations. PMID- 28910566 TI - Environmental biodegradation of halophenols by activated sludge from two different sewage treatment plants. AB - Halophenols make a group of aromatic compounds that are resistible to biodegradation by environmental microorganisms. In this study, the biodegradation of 4-bromo-, 4-chloro- and 4-fluorophenols was studied with two types of activated sludges (from a small rural plant and from a bigger municipal plant) as an inoculum. Because of their wide use, surfactants are present in the wastewater and inhibitors enhance the biodegradation of different pollutants; the influence of natural surfactants on halophenols' biodegradation was also tested. Both types of activated sludge contained bacterial strains which were active in the halophenols' biodegradation process. The coexistence of surfactants and halophenols in the wastewater does not prevent microorganisms from effective halophenols' biodegradation. Moreover, surfactants can enhance the effectiveness of halophenols' removal from the environment. Different cell surface modifications of two isolated bacterial strains were observed in the same system of halophenols with or without surfactants. Halophenols and surfactants may also induce changes in bacteria cell surface properties. PMID- 28910567 TI - G0S2 represses PI3K/mTOR signaling and increases sensitivity to PI3K/mTOR pathway inhibitors in breast cancer. AB - G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target implicated in cancer biology and therapy based on frequent methylation-mediated silencing in diverse solid tumors. We recently reported that low G0S2 expression in breast cancer, particularly estrogen receptor-positive (ER+) breast cancer, correlates with increased rates of recurrence, indicating that G0S2 plays a role in breast cancer progression. However, the function(s) and mechanism(s) of G0S2 tumor suppression remain unclear. In order to determine potential mechanisms of G0S2 anti-oncogenic activity, we performed genome-wide expression analysis that revealed an enrichment of gene signatures related to PI3K/mTOR pathway activation in G0S2 null cells as compared to G0S2 wild-type cells. G0S2 null cells also exhibited a dramatic decreased sensitivity to PI3K/mTOR pathway inhibitors. Conversely, restoring G0S2 expression in human ER+ breast cancer cells decreased basal mTOR signaling and sensitized the cells to pharmacologic mTOR pathway inhibitors. Notably, we provide evidence here that the increase in recurrence seen with low G0S2 expression is especially prominent in patients who have undergone antiestrogen therapy. Further, ER+ breast cancer cells with restored G0S2 expression had a relative increased sensitivity to tamoxifen. These findings reveal that in breast cancer G0S2 functions as a tumor suppressor in part by repressing PI3K/mTOR activity, and that G0S2 enhances therapeutic responses to PI3K/mTOR inhibitors. Recent studies implicate hyperactivation of PI3K/mTOR signaling as promoting resistance to antiestrogen therapies in ER+ breast cancer. Our data establishes G0S2 as opposing this form of antiestrogen resistance. This promotes further investigation of the role of G0S2 as an antineoplastic breast cancer target and a biomarker for recurrence and therapy response. PMID- 28910568 TI - Network of phosphatases and HDAC complexes at repressed chromatin. AB - Tight regulation of gene expression is achieved by a variety of protein complexes that selectively bind chromatin, modify it and change its transcription competency. Histone acetylases (HATs) and deacetylases (HDACs) play an important role in this process. They can generate transcriptionally active or inactive chromatin through the addition (HATs) or removal (HDACs) of acetyl groups on histones, respectively. Repo-Man is a Protein Phosphatase 1 targeting subunit that accumulates on chromosomes during mitotic exit and mediates the removal of mitotic histone H3 phosphorylations. It was shown recently that Repo-Man also regulates heterochromatin formation in interphase and that its depletion favours the switch between transcriptionally inactive and active chromatin, demonstrating that its role goes well beyond mitosis. Here, we provide the first link between a phosphatase and HDAC complexes. We show that genome-wide Repo-Man binding sites overlap with chromatin regions bound by members of the three HDAC complexes (Sin3a, NuRD and CoREST). We establish that members of the NuRD and Sin3a HDAC complexes interact with Repo-Man by mass spectrometry and that Repo-Man is in close proximity to SAP18 (Sin3a) in interphase as observed by the Proximity Ligation Assay. Altogether, these data suggest a mechanism by which Repo-Man/PP1 complex, via interactions with HDACs, could stabilise gene repression. PMID- 28910569 TI - Hierarchical recruitment of Polycomb complexes revisited. AB - Polycomb Group (PcG) proteins epigenetically repress key developmental genes and thereby control alternative cell fates. PcG proteins act as complexes that can modify histones and these histone modifications play a role in transmitting the "memory" of the repressed state as cells divide. Here we consider mainstream models that link histone modifications to hierarchical recruitment of PcG complexes and compare them to results of a direct test of interdependence between PcG complexes for recruitment to Drosophila genes. The direct test indicates that PcG complexes do not rely on histone modifications to recognize their target genes but use them to stabilize the interactions within large chromatin domains. It also shows that multiple strategies are used to coordinate the targeting of PcG complexes to different genes, which may make the repression of these genes more or less robust. PMID- 28910571 TI - Factors that influence tear meniscus area and conjunctivochalasis: The Singapore Indian eye study. AB - PURPOSE: Assessment of tear film and conjunctiva is critical to define presence and severity of ocular surface disease. We aimed to characterize tear meniscus area (TMA) and conjunctivochalasis by anterior segment optical coherence tomography (ASOCT) in population-based patients and identify potential factors associated with low TMA and severe conjunctivochalasis. METHODS: Study subjects were enrolled from The Singapore Indian Eye Study, a population-based study of Asian Indian in Singapore. Imaging with ASOCT was performed on three ocular regions (nasal, central and temporal). TMA was obtained by measuring the cross sectional area of the inferior tear meniscus. Severity of conjunctivochalasis was quantified by measuring the conjunctivochalasis ratio (CCR), the ratio of area of redundant conjunctiva to the TMA. Ocular symptoms and demographic factors were assessed by standardized questionnaires. RESULTS: A total of 403 participants (52.9% women) 40 years of age and older were included. TMA centrally was 2818 +/- 5308 pixel2. Female sex and the presence of meibomian gland dysfunction (MGD), but not older age, were associated with a lower TMA (p = 0.031, p = 0.031 and p = 0.956 respectively). In this population, 9.2% had severe conjunctivochalasis (CCR>0.7) whereas 39.0% had mild to no conjunctivochalasis (CCR<=0.3). Conjunctivochalasis was more severe in temporal, followed by nasal and central sections. Older age was associated with severe conjunctivochalasis (p < 0.001). CONCLUSION: MGD and female gender were associated with lower TMA, while older age was associated with increased severity of conjunctivochalasis. Objective measurement of TMA and CCR using ASOCT imaging may be useful in the assessment of tear volume and ocular surface tear function. PMID- 28910570 TI - Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype. AB - Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family ( n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations ( n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis. PMID- 28910572 TI - Silver nanoparticles toxicity against airborne strains of Staphylococcus spp. AB - The aim of this study was to explore the toxicity of silver nanoparticles (AgNPs) synthesized by chemical reduction method assessment with regard to airborne strains of Staphylococcus spp. The first step of the experiment was the preparation of silver nanoparticle suspension. The suspension was obtained by a fast and simple chemical method involving the reduction of silver ions through a reducing factor in the presence of the suitable stabilizer required to prevent the aggregation. In the second stage, varied instrumental techniques were used for the analysis and characterization of the obtained nanostructures. Third, the bacteria of the Staphylococcus genus were isolated from the air under stable conditions with 47 sports and recreational horses, relatively. Next, isolated strains were identified using biochemical and spectrophotometric methods. The final step was the evaluation of the Staphylococcus genus sensitivity to nanosilver using the disk diffusion test. It has been proven that prepared silver nanoparticles exhibit strong antibacterial properties. The minimum inhibitory concentration for tested isolates was 30 MUg/mL. It has been found that the sensitivity of Staphylococcus spp. isolated from six identified species differs considerably. The size distribution of bacterial growth inhibition zones indicates that resistance to various nanosilver concentrations is an individual strain feature, and has no connection with belonging to a specific species. PMID- 28910574 TI - O-GlcNAcylation of boundary element associated factor (BEAF 32) in Drosophila melanogaster correlates with active histone marks at the promoters of its target genes. AB - Boundary Element-Associated Factor 32 (BEAF 32) is a sequence specific DNA binding protein involved in functioning of chromatin domain boundaries in Drosophila. Several studies also show it to be involved in transcriptional regulation of a large number of genes, many of which are annotated to have cell cycle, development and differentiation related function. Since post-translational modifications (PTMs) of proteins add to their functional capacity, we investigated the PTMs on BEAF 32. The protein is known to be phosphorylated and O GlcNAcylated. We mapped O-GlcNAc site at T91 of BEAF 32 and showed that it is linked to the deposition of active histone (H3K4me3) marks at transcription start site (TSS) of associated genes. Its role as a boundary associated factor, however, does not depend on this modification. Our study shows that by virtue of O-GlcNAcylation, BEAF 32 is linked to epigenetic mechanisms that activate a subset of associated genes. PMID- 28910573 TI - An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function. AB - Tryptophanyl-tRNA synthetase (TrpRS) in vertebrates contains a N-terminal extension in front of the catalytic core. Proteolytic removal of the N-terminal 93 amino acids gives rise to T2-TrpRS, which has potent anti-angiogenic activity mediated through its extracellular interaction with VE-cadherin. Zinc has been shown to have anti-angiogenic effects and can bind to human TrpRS. However, the connection between zinc and the anti-angiogenic function of TrpRS has not been explored. Here we report that zinc binding can induce structural relaxation in human TrpRS to facilitate the proteolytic generation of a T2-TrpRS-like fragment. The zinc-binding site is likely to be contained within T2-TrpRS, and the zinc bound conformation of T2-TrpRS is mimicked by mutation H130R. We determined the crystal structure of H130R T2-TrpRS at 2.8 A resolution, which reveals drastically different conformation from that of wild-type (WT) T2-TrpRS. The conformational change creates larger binding surfaces for VE-cadherin as suggested by molecular dynamic simulations. Surface plasmon resonance analysis indicates more than 50-fold increase in binding affinity of H130R T2-TrpRS for VE cadherin, compared to WT T2-TrpRS. The enhanced interaction is also confirmed by a cell-based binding analysis. These results suggest that zinc plays an important role in activating TrpRS for angiogenesis regulation. PMID- 28910575 TI - Behaviour of biopolymeric substances in the activated sludge of an MBR system working with high hydraulic retention time. AB - This study was undertaken to analyse the activated sludge of a membrane bioreactor (MBR), the behaviour of extracellular polymeric substances (EPS) and soluble microbial products (SMP) as well as their biopolymers composition, in the activated sludge of a membrane bioreactor (MBR) and their influence on membrane fouling were analysed. For the experiment an experimental fullscale MBR working with real urban wastewater at high hydraulic retention time with a variable sludge-retention time (SRT) was used. The MBR system worked in denitrification/nitrification conformation at a constant flow rate (Q = 0.45 m3/h) with a recirculation flow rate of 4Q. The concentrations of SMP in the activated sludge were lower than the concentrations of EPS over the entire study, with humic substances being the main components of the two biopolymers. SMP and, more specifically, SMP carbohydrates, were the most influential biopolymers in membrane fouling, while for EPS and their components, no relation was found with fouling. The SRT and temperature were the operational variables that most influenced the SMP and EPS concentration, causing the increase of SRT and temperature a lower concentration in both biopolymers, although the effect was not the same for all the components, particularly for the EPS carbohydrates, which increased with longer SRTs. Both operational variables were also the ones most influential on the concentration of organic matter of the effluent, due to their effect on the SMP. The volatile suspended solid/total suspended solid (VSS/TSS) ratio in the activated sludge can be applied as a good indicator of the risk of membrane fouling by biopolymers in MBR systems. PMID- 28910576 TI - Impact of Staphylococcus aureus regulatory mutations that modulate biofilm formation in the USA300 strain LAC on virulence in a murine bacteremia model. AB - Staphylococcus aureus causes acute and chronic forms of infection, the latter often associated with formation of a biofilm. It has previously been demonstrated that mutation of atl, codY, rot, sarA, and sigB limits biofilm formation in the USA300 strain LAC while mutation of agr, fur, and mgrA has the opposite effect. Here we used a murine sepsis model to assess the impact of these same loci in acute infection. Mutation of agr, atl, and fur had no impact on virulence, while mutation of mgrA and rot increased virulence. In contrast, mutation of codY, sarA, and sigB significantly attenuated virulence. Mutation of sigB resulted in reduced accumulation of AgrA and SarA, while mutation of sarA resulted in reduced accumulation of AgrA, but this cannot account for the reduced virulence of sarA or sigB mutants because the isogenic agr mutant was not attenuated. Indeed, as assessed by accumulation of alpha toxin and protein A, all of the mutants we examined exhibited unique phenotypes by comparison to an agr mutant and to each other. Attenuation of the sarA, sigB and codY mutants was correlated with increased production of extracellular proteases and global changes in extracellular protein profiles. These results suggest that the inability to repress the production of extracellular proteases plays a key role in attenuating the virulence of S. aureus in acute as well as chronic, biofilm-associated infections, thus opening up the possibility that strategies aimed at the de repression of protease production could be used to broad therapeutic advantage. They also suggest that the impact of codY, sarA, and sigB on protease production occurs via an agr-independent mechanism. PMID- 28910578 TI - Subjective Well-Being in Older Chinese and Korean Immigrants in the United States: Effects of Self-Rated Health and Employment Status. AB - This study examined the effects of association between self-rated health and employment status on subjective well-being among older Chinese and Korean immigrants in the United States. Data were collected from 171 Chinese and 205 Korean older adult immigrants living in Los Angeles County. The primary variables included demographic data, subjective index of well-being, self-rated health, and employment status. Data support the association between self-rated health and subjective well-being for both groups. Employment, education, and age were associated with the level of subjective well-being only for older Korean immigrants. Similarities and differences were noted in these two Asian American subgroups. Findings suggest the need to develop health promotion services for both populations and employment opportunities targeted more so for Korean older immigrants to further support their subjective well-being. Results may have implications for other for older immigrants. PMID- 28910577 TI - Subnuclear distribution of proteins: Links with genome architecture. AB - Metazoan genomes have a hierarchal 3-dimensional (3D) organization scaling from nucleosomes, loops, topologically associating domains (TADs), compartments, to chromosome territories. The 3D organization of genome has been linked with development, differentiation and disease. However, the principles governing the 3D chromatin architecture are just beginning to get unraveled. The nucleus has very high concentration of proteins and these proteins are either diffusely distributed throughout the nucleus, or aggregated in the form of foci/bodies/clusters/speckles or in combination of both. Several evidences suggest that the distribution of proteins within the nuclear space is linked to the organization and function of genome. Here, we describe advances made in understanding the relationship between subnuclear distribution of proteins and genome architecture. PMID- 28910579 TI - Phosphorylation is required for the pathogen defense function of the Arabidopsis PEN3 ABC transporter. AB - The Arabidopsis PEN3 ABC transporter accumulates at sites of pathogen detection, where it is involved in defense against a number of pathogens. Perception of PAMPs by pattern recognition receptors initiates recruitment of PEN3 and also leads to PEN3 phosphorylation at multiple amino acid residues. Whether PAMP induced phosphorylation of PEN3 is important for its defense function or focal recruitment has not been addressed. In this study, we evaluated the role of PEN3 phosphorylation in modulating the localization and defense function of the transporter. We report that PEN3 phosphorylation is critical for its function in defense, but dispensable for recruitment to powdery mildew penetration sites. These results indicate that PAMP-induced phosphorylation is likely to regulate the transport activity of PEN3. PMID- 28910580 TI - Differential responses of cell wall bound phenolic compounds in sensitive and tolerant varieties of rice in response to salinity. AB - In plants, cell wall bound phenolics change in response to stress. The aim of the study was to investigate the effect of NaCl induced stress on wall bound phenolics in four rice varieties, of which two (Bhutnath, Nonabokra) were salt tolerant and two (MTU 7029, Sujala) were salt sensitive. After germination, seedlings were grown in hydroponic solution and subjected to salinity stress (25 mM, 50 mM, 100 mM and 150 mM NaCl) on day 12. Wall bound phenolic compounds were determined by GC-MS based metabolite analysis. Total seven wall bound phenols were identified from the leaf tissues and eight from the root tissues. Ferulic acid and 4-hydroxycinnamic acid were found in all the four varieties. After NaCl treatment, these two wall bound phenols increased in the leaves of tolerant varieties only. Significant inverse correlation between leaf length and leaf fresh weight with wall bound ferulic acid and 4-hydroxycinnamic acid in Nonabokra suggests the positive role of these wall bound phenolics in salt tolerance. PMID- 28910581 TI - Aminoacyl-tRNA quality control is required for efficient activation of the TOR pathway regulator Gln3p. AB - The aminoacylation status of the cellular tRNA pool regulates both general amino acid control (GAAC) and target of rapamycin (TOR) stress response pathways in yeast. Consequently, fidelity of translation at the level of aminoacyl-tRNA synthesis plays a central role in determining accuracy and sensitivity of stress responses. To investigate effects of translational quality control (QC) on cell physiology under stress conditions, phenotypic microarray analyses were used to identify changes in QC deficient cells. Nitrogen source growth assays showed QC deficient yeast grew differently compared to WT. The QC deficient strain was more tolerant to caffeine treatment than wild type through altered interactions with the TOR and GAAC pathways. Increased caffeine tolerance of the QC deficient strain was consistent with the observation that the activity of Gln3p, a transcription factor controlled by the TOR pathway, is decreased in the QC deficient strain compared to WT. GCN4 translation, which is typically repressed in the absence of nutritional stress, was enhanced in the QC deficient strain through TOR inhibition. QC did not impact cell cycle regulation; however, the chronological lifespan of QC deficient yeast strains decreased compared to wild type, likely due to translational errors and alteration of the TOR-associated regulon. These findings support the idea that changes in translational fidelity provide a mechanism of cellular adaptation by modulating TOR activity. This, in turn, supports a central role for aminoacyl-tRNA synthesis QC in the integrated stress response by maintaining the proper aa-tRNA pools necessary to coordinate the GAAC and TOR. PMID- 28910583 TI - Performance evaluation of startup for a yeast membrane bioreactor (MBRy) treating landfill leachate. AB - The startup process of a membrane bioreactor inoculated with yeast biomass (Saccharomyces cerevisiae) and used in the treatment of landfill leachate was evaluated. The yeast membrane bioreactor (MBRy) was inoculated with an exogenous inoculum, a granulated active dry commercial bakers' yeast. The MBRy was successfully started up with a progressive increase in the landfill leachate percentage in the MBRy feed and the use of Sabouraud Dextrose Broth. The membrane plays an important role in the startup phase because of its full biomass retention and removal of organic matter. MBRy is a suitable and promising process to treat recalcitrant landfill leachate. After the acclimation period, the COD and NH3 removal efficiency reached values of 72 +/- 3% and 39 +/- 2% respectively. MBRy shows a low membrane-fouling potential. The membrane fouling was influenced by soluble microbial products, extracellular polymeric substances, sludge particle size, and colloidal dissolved organic carbon. PMID- 28910582 TI - Model-based performance and energy analyses of reverse osmosis to reuse wastewater in a PVC production site. AB - A pilot-scale reverse osmosis (RO) followed behind a membrane bioreactor (MBR) was developed for the desalination to reuse wastewater in a PVC production site. The solution-diffusion-film model (SDFM) based on the solution-diffusion model (SDM) and the film theory was proposed to describe rejections of electrolyte mixtures in the MBR effluent which consists of dominant ions (Na+ and Cl-) and several trace ions (Ca2+, Mg2+, K+ and SO42-). The universal global optimisation method was used to estimate the ion permeability coefficients (B) and mass transfer coefficients (K) in SDFM. Then, the membrane performance was evaluated based on the estimated parameters which demonstrated that the theoretical simulations were in line with the experimental results for the dominant ions. Moreover, an energy analysis model with the consideration of limitation imposed by the thermodynamic restriction was proposed to analyse the specific energy consumption of the pilot-scale RO system in various scenarios. PMID- 28910584 TI - Problematic Gaming Behavior Among Finnish Junior High School Students: Relation to Socio-Demographics and Gaming Behavior Characteristics. AB - Multiplatform digital media use and gaming have been increased in recent years. The aim of this study was to examine associations between sociodemographics and digital gaming behavior characteristics (i.e., gaming time, medium, and genres) with problematic gaming behavior in adolescents. A convenience sample of Finnish junior high school students (n = 560; mean age 14 years, ranging from 12 to 16 years) participated in the cross-sectional survey, of which, 83% (n = 465) reported having played digital games regularly. Sociodemographic data, different forms of digital media use, gaming behavior characteristics and problematic gaming behavior was assessed. Study participants spent on average one hour per day playing digital games; casual games (23.9%), shooting games (19.8%), and sport games (12.9%), were the most popular games among participants. By using regression analysis, a blended family structure and gaming time related positively to problematic gaming behavior. Preferences for game genres such as solo, Massively Multiplayer Online Role-Playing and strategy-management games were also positively associated with problematic use of digital games. These findings provide knowledge that can be utilized in the prevention of the possible negative consequences of digital gaming. PMID- 28910585 TI - Analysis of glycols, glycol ethers, and other volatile organic compounds present in household water-based hand pump sprays. AB - The aim of this investigation is to clarify the types and concentrations of VOCs present in various commercial household water-based hand pump spray products used in Japan, and to estimate their average concentrations in indoor air when the spray product is used. We selected glycol and glycol ethers as the main target compounds, as these chemicals were detected at high frequencies and concentrations in a national survey of Japanese indoor air pollution. The extraction of these chemicals using graphite carbon cartridges was examined, with good recoveries and reproducibilities being obtained. Eighteen chemicals were analyzed in 54 commercial products and 8 chemicals were detected. More specifically, dipropylene glycol (DPG) was present in 44 samples (1.1 * 101-1.8 * 104 MUg/mL); propylene glycol (PG) was present in 22 samples (1.5 * 101-2.9 * 104 MUg/mL); diethylene glycol monoethyl ether (DGMEE) was found in 15 samples (trace amount-1.9 * 103 MUg/mL); diethylene glycol (DEG) was present in 9 samples (1.0 * 101-2.4 * 103 MUg/mL); 1,3-butandiol (13BG) was found in 5 samples (trace amount 7.4 * 103 MUg/mL); 2-ethyl-1-hexanol (2E1H) was detected in 5 samples (3.2 * 10-1 4.4 * 101 MUg/mL); diethylene glycol monobutyl ether (DGMBE) was present in 4 samples (2.1 * 101-7.1 * 101 MUg/mL); and 3-methoxy-3-methylbutanol (MMB) was found in 2 samples (2.4 * 101-4.7 * 102 MUg/mL). In addition, the average concentrations of these chemicals in indoor air were estimated using their maximum concentrations observed in the spray product. The estimated average concentrations of the chemicals in indoor air were determined to range between 1.0 * 10-2 and 1.0 mg/m3, with the exception of 2E1H and DGMBE. Furthermore, the estimated average concentrations of PG, 13BG, and DGMEE in indoor air were comparable to or higher than those reported in a national survey of Japanese indoor air pollution. It therefore appeared that household water-based hand pump sprays may contribute to the presence of these chemicals in indoor air. In contrast, estimated average concentrations of 2E1H in indoor air were low, its concentrations observed in a national survey of Japanese indoor air pollution are likely due to the use of plasticizers and paints. PMID- 28910586 TI - Global and regional cardiac function in lifelong endurance athletes with and without myocardial fibrosis. AB - The aim of the present study was to compare cardiac structure as well as global and regional cardiac function in athletes with and without myocardial fibrosis (MF). Cardiac magnetic resonance imaging with late gadolinium enhancement was used to detect MF and global cardiac structure in nine lifelong veteran endurance athletes (58 +/- 5 years, 43 +/- 5 years of training). Transthoracic echocardiography using tissue-Doppler and myocardial strain imaging assessed global and regional (18 segments) longitudinal left ventricular function. MF was present in four athletes (range 1-8 g) and not present in five athletes. MF was located near the insertion points of the right ventricular free wall on the left ventricle in three athletes and in the epicardial lateral wall in one athlete. Athletes with MF demonstrated a larger end diastolic volume (205 +/- 24 vs 173 +/ 18 ml) and posterior wall thickness (11 +/- 1 vs 9 +/- 1 mm) compared to those without MF. The presence of MF did not mediate global tissue velocities or global longitudinal strain and strain rate; however, regional analysis of longitudinal strain demonstrated reduced function in some fibrotic regions. Furthermore, base to apex gradient was affected in three out of four athletes with MF. Lifelong veteran endurance athletes with MF demonstrate larger cardiac dimensions and normal global cardiac function. Fibrotic areas may demonstrate some co-localised regional cardiac dysfunction, evidenced by an affected cardiac strain and base to apex gradient. These data emphasize the heterogeneous phenotype of MF in athletes. PMID- 28910587 TI - Trichosanthin attenuates vascular injury-induced neointimal hyperplasia following balloon catheter injury in rats. AB - Trichosanthin (TCS), isolated from the root tuber of Trichosantheskirilowii, a well-known traditional Chinese medicinal plant, belonging to the Cucurbitaceae family, was found to exhibit numerous biological and pharmacological activities including anti-inflammatory. However, the effects of TCS on arterial injury induced neointimal hyperplasia and inflammatory cell infiltration remains poorly understood. The aim of study was to examine the effectiveness of TCS on arterial injury-mediated inflammatory processes and underlying mechanisms. A balloon injured carotid artery induced injury in vivo in rats was established as a model of vascular injury. After 1 day TCS at 20, 40, or 80 mg/kg/day was administered intraperitoneally, daily for 14 days. Subsequently, the carotid artery was excised and taken for immunohistochemical staining. Data showed that TCS significantly dose-dependently reduced balloon injury-induced neointima formation in the carotid artery model rat, accompanied by markedly decreased positive expression percentage proliferating cell nuclear antigen (PCNA). In the in vitro study vascular smooth muscle cells (VSMC) were cultured, proliferation stimulated with platelet-derived growth factor-BB (PDGF-BB) (20 ng/ml) and TCS at 1, 2, or 4 MUM added. Data demonstrated that TCS inhibited proliferation and cell cycle progression of VSMC induced by PDGF-BB. Further, TCS significantly lowered mRNA expression of cyclinD1, cyclinE1, and c-fos, and protein expression levels of Akt1, Akt2, and mitogen-activated protein kinase MAPK (ERK1) signaling pathway mediated by PDGF-BB. These findings indicate that TCS inhibits vascular neointimal hyperplasia induced by vascular injury in rats by suppression of VSMC proliferation and migration, which may involve inhibition of Akt/MAPK/ERK signal pathway. PMID- 28910588 TI - Control Strategy in Movements with Transmission Delay. AB - The strategy used by participants was studied when making movements in a Fitts movement paradigm with transmission delay between control input and display output. Fitts' law in the modified form developed by E. R. Hoffmann (1992) gave an excellent description of the data. Movement time could also be expressed as a function of the total delay time (number of submovements * transmission delay) and Fitts' index of difficulty (ID). Two types of submovement were identified, being step and drag forms. The number of step submovements was the most important in determining movement time. These were related to a move-and-wait strategy used by participants. Number of submovements increased with the level of ID and transmission delay and was linearly related to the ID and product of ID by transmission delay. PMID- 28910589 TI - Persistent organic pollutants and related biological responses measured in coastal fish using chemical and biological screening methods. AB - The aim of this study was to investigate the spatial distribution, levels of dioxin-like compounds (DLC), and biological responses in two fish species. The viviparous eelpout (Zoarces viviparus) was collected from various locations in the Baltic Sea and in fjords of Kattegat and Skagerrak, while shorthorn sculpin (Myoxocephalus scorpius) was obtained at the polychlorinated biphenyl (PCB) polluted site in North West Greenland. Significant differences were detected both in contaminant levels and relative contributions from either polychlorinated dibenzodioxins (PCDD) or polychlorinated dibenzofurans (PCDF or furans) and mono ortho- and non-ortho (coplanar) polychlorinated biphenyls (dl-PCB). Fish from the eastern Baltic Sea generally displayed higher contributions from PCDD/F compared to dl-PCB, whereas dl-PCB were generally predominated in fish from Danish, Swedish, and German sites. Levels of dl-PCB in muscle tissues were above OSPAR environmental assessment criteria (EAC) for PCB118, indicating a potential risk of adverse biological effects in the ecosystem, whereas levels of the total WHO TEQs were below threshold for sea food suggesting limited risks for humans. No significant relationships between levels of DLC (expressed as WHO-TEQ), and biological responses such as the induction of CYP1A enzymatic activity and fry reproductive disorders were observed in eelpout. No marked relationship between WHO-TEQ and combined biological aryl hydrocarbon receptor-mediated transactivity (expressed as AhR-TEQ) was noted. However, there was a positive correlation between polycyclic aromatic hydrocarbon (PAH) metabolites and induction of CYP1A activity, suggesting that PAH exhibited greater potential than DLC to produce biological effects in eelpout from the Baltic Sea. PMID- 28910590 TI - Redox-mediator-free degradation of sulfathiazole and tetracycline using Phanerochaete chrysosporium. AB - The removal of two of the most commonly used antibiotics, tetracycline (TC) and sulfathiazole (STZ), using laccase-producing Phanerochaete chrysosporium was studied in liquid-phase batch experiments in the absence of any synthetic redox mediator. The removal of STZ and TC from single antibiotic spikes varied from 97.8% to 15.4% and 98.8% to 31%, respectively, with increasing initial doses of 10-250 mg L-1 within 14 days of incubation. The enzyme activity of P. chrysosporium was only minimally influenced by the concentrations of these antibiotics. The degradation of antibiotics initiated before an appreciable extracellular enzyme activity was noted in the fungal culture. The appearance of low-molecular weight molecular fragments from parent antibiotics in liquid chromatography-mass spectrometry confirmed the biodegradation process. PMID- 28910591 TI - The denial of the association between youth cannabis and opiate use: A "Split Brain Syndrome"? PMID- 28910592 TI - Optimization of process condition for the preparation of amine-impregnated activated carbon developed for CO2 capture and applied to methylene blue adsorption by response surface methodology. AB - The present research describes the optimal adsorption condition for methylene blue (MB). The adsorbent used here was monoethanol amine-impregnated activated carbon (MEA-AC) prepared from green coconut shell. Response surface methodology (RSM) is the multivariate statistical technique used for the optimization of the process variables. The central composite design is used to determine the effect of activation temperature, activation time and impregnation ratio on the MB removal. The percentage (%) MB adsorption by MEA-AC is evaluated as a response of the system. A quadratic model was developed for response. From the analysis of variance, the factor which was the most influential on the experimental design response has been identified. The optimum condition for the preparation of MEA-AC from green coconut shells is the temperature of activation 545.6 degrees C, activation time of 41.64 min and impregnation ratio of 0.33 to achieve the maximum removal efficiency of 98.21%. At the same optimum parameter, the % MB removal from the textile-effluent industry was examined and found to be 96.44%. PMID- 28910593 TI - Construction of a North American Cancer Survival Index to Measure Progress of Cancer Control Efforts. AB - INTRODUCTION: Population-based cancer survival data provide insight into the effectiveness of health care delivery. Comparing survival for all cancer sites combined is challenging, because the primary cancer site and age distribution of patients may differ among areas or change over time. Cancer survival indices (CSIs) are summary measures of survival for cancers of all sites combined and are used in England and Europe to monitor temporal trends and examine geographic differences in survival. We describe the construction of the North American Cancer Survival Index and demonstrate how it can be used to compare survival by geographic area and by race. METHODS: We used data from 36 US cancer registries to estimate relative survival ratios for people diagnosed with cancer from 2006 through 2012 to create the CSI: the weighted sum of age-standardized, site specific, relative survival ratios, with weights derived from the distribution of incident cases by sex and primary site from 2006 through 2008. The CSI was calculated for 32 registries for all races, 31 registries for whites, and 12 registries for blacks. RESULTS: The survival estimates standardized by age only versus age-, sex-, and site-standardized (CSI) were 64.1% (95% confidence interval [CI], 64.1%-64.2%) and 63.9% (95% CI, 63.8%-63.9%), respectively, for the United States for all races combined. The inter-registry ranges in unstandardized and CSI estimates decreased from 12.3% to 5.0% for whites, and from 5.4% to 3.9% for blacks. We found less inter-registry variation in CSI estimates than in unstandardized all-sites survival estimates, but disparities by race persisted. CONCLUSIONS: CSIs calculated for different jurisdictions or periods are directly comparable, because they are standardized by age, sex, and primary site. A national CSI could be used to measure temporal progress in meeting public health objectives, such as Healthy People 2030. PMID- 28910594 TI - Concordance Between Common Hypertension Control Algorithms in Electronic Medical Record Data. AB - Because quality improvement metrics and treatment guidelines are used to conduct research, evaluate care quality, and assess population health, they should, ideally, align. We used electronic medical record data to analyze variation between blood pressure control estimates calculated by using thresholds derived from National Quality Forum 0018 (NQF 0018) and Joint National Committee (JNC) treatment guidelines in a cohort of patients with hypertension. Percentage of patients with controlled blood pressure derived from each quality improvement or treatment guideline cutoff varied up to 16.1 percentage points. This variance demonstrates that discrepancies in blood pressure thresholds produce considerable variation in estimates; thus, treatment guidance and metrics should be selected carefully. PMID- 28910595 TI - A Method for Evaluating Physical Activity Programs in Schools. AB - Providing opportunities for students to be physically active during the school day leads to increased academic performance, better focus, and fewer behavioral problems. As schools begin to incorporate more physical activity programming into the school day, evaluators need methods to measure how much physical activity students are being offered through this programming. Because classroom-based physical activity is often offered in 3-minute to 5-minute bouts at various times of the day, depending on the teachers' time to incorporate it, it is a challenge to evaluate this activity. This article describes a method to estimate the number of physical activity minutes provided before, during, and after school. The web based tool can be used to gather data cost-effectively from a large number of schools. Strategies to increase teacher response rates and assess intensity of activity should be explored. PMID- 28910596 TI - Recombinant Viral Vaccines Expressing Merozoite Surface Protein-1 Induce Antibody and T Cell-Mediated Multistage Protection against Malaria. PMID- 28910597 TI - Predictors of change in social networks, support and satisfaction following a first episode psychosis: A cohort study. AB - BACKGROUND: Diminished social networks are common in psychosis but few studies have measured these comprehensively and prospectively to determine how networks and support evolve during the early phase. There is little information regarding perceived support in the early phase of illness. The aim of this study was to describe social support, networks and perceived satisfaction, explore the clinical correlates of these outcomes and examine whether phases of untreated psychosis are linked with social network variables to determine potential opportunities for intervention. METHODS: During the study period, we assessed 222 people with first-episode psychosis at entry into treatment using valid and reliable measures of diagnosis, positive and negative symptoms, periods of untreated psychosis and prodrome and premorbid adjustment. For follow-up we contacted participants to conduct a second assessment (n=158). There were 97 people who participated which represented 61% of those eligible. Social network and support information obtained at both time points included the number of friends, self-reported satisfaction with support and social network size and clinician's evaluation of the degree of support received through networks. Mixed effects modelling determined the contribution of potential explanatory variables to social support measured. RESULTS: A number of clinical variables were linked with social networks, support and perceived support and satisfaction. The size of networks did not change over time but those with no friends and duration of untreated psychosis was significantly longer for those with no friends at entry into treatment (n=129, Median=24.5mths, IQR=7.25-69.25; Mann-Whitney U=11.78, p=0.008). Social support at baseline and at one year was predicted by homelessness (t=-2.98, p=0.001, CI -4.74 to -1.21), duration of untreated psychosis (t=-0.86, p=0.031, CI -1.65 to -0.08) and premorbid adjustment (t= 2.26, p=0.017, CI -4.11 to -0.42). Social support improved over time but the duration of untreated psychosis was not linked with the rate of improvement in this outcome. CONCLUSIONS: Improved social support could indicate greater reliance on social support or becoming more adept at mobilising resources to meet social needs. Particularly vulnerable groups with very long duration of untreated psychosis confirm the need for earlier intervention or targeted social network interventions to preserve social connectedness. PMID- 28910598 TI - Why does happiness matter? Understanding the relation between positive emotion and health outcomes. PMID- 28910599 TI - A meta-analytic review on social relationships and suicidal ideation among older adults. AB - Social relationships play an important role in mental health as well as suicidal ideation in later life. In contrast with the other well-established risk factors, despite an increasing number of related studies, no meta-analyses focusing on social relationships and late-life suicidal ideation have been published. Synthesis of data across the studies using different measurements of social relationships would allow for comparison of the effects on late-life suicidal ideation that have not been studied before. Therefore, we conducted a meta analysis on the studies published between January 1, 2000 and November 31, 2016 extracted from 7 medical and social science databases. 31 studies with 83 estimates of Odds Ratios ("ORs") on the associations between social relationships and late-life suicidal ideation were identified to compute effect sizes using a random-effect model. Sensitivity analyses were also performed to evaluate their heterogeneity and bias. Moderator analyses were further conducted to determine moderating factors of the associations. Eventually, across the 31 studies (203,152 participants), the overall random effect size was OR = 1.57(95% CI [1.40, 1.76]), indicating a 57% likelihood increase of suicidal ideation for elderly participants with discordant social relationships. The functional measures (OR = 1.77; 95%CI [1.48, 2.10]) of social relationships, however, were more predictive than structural measures (OR = 1.37; 95%CI [1.25, 1.51]). Among all the measures of social relationships, elderly mistreatment (OR = 2.31; 95%CI [1.81, 2.94]) had the strongest effect size, followed by perceived loneliness (OR = 2.24; 95%CI [1.73, 2.90]) and poorly perceived social support (OR = 1.59; 95% CI [1.37, 1.83]). The associations between social relationships and late-life suicidal ideation were moderated by country income levels, social-cultural context, study types, and various measurements of social relationships. More importantly, our study is the first meta-analysis to provide significant evidence for improving social relationships, especially in perceived bonds, is a promising strategy in reducing late-life suicide risks. PMID- 28910600 TI - An acceptor analogue of beta-1,4-galactosyltransferase: Substrate, inhibitor, or both? AB - Many glycosyltransferase inhibitors in the literature are structurally derived from the donor or acceptor substrate of the respective enzyme. A representative example is 2-naphthyl beta-d-GlcNAc, a synthetic GlcNAc glycoside that has been reported as a galactosyltransferase inhibitor. This GlcNAc derivative is attractive as a chemical tool compound for biological and biochemical studies because of its reported potency as an inhibitor, and its short and straightforward synthesis from readily available starting materials. We report that in our hands, 2-naphthyl beta-d-GlcNAc behaved, unexpectedly, as an acceptor substrate of the inverting beta-1,4-galactosyltransferase (beta-1,4-GalT) from bovine milk. This substrate activity has not previously been described. We found that 2-naphthyl beta-d-GlcNAc can be an acceptor substrate both for recombinantly expressed beta-1,4-GalT, and for a commercial batch of the same enzyme, and both in the presence and absence of bovine serum albumin (BSA). As expected for a full acceptor substrate, this substrate activity was time- and concentration dependent. Additional experiments show that the observed inhibitor/substrate switch is facilitated by a phosphatase that is an essential component of our enzyme-coupled glycosyltransferase assay. These findings suggest that the behaviour of 2-naphthyl beta-d-GlcNAc and related acceptor-based glycosyltransferase inhibitors is strongly dependent on the individual assay conditions. Our results therefore have important implications for the use of 2 naphthyl beta-d-GlcNAc and related glycosides as tool compounds in glycobiology and glycobiochemistry. PMID- 28910601 TI - Identification of plasma biomarkers for distinguishing bipolar depression from major depressive disorder by iTRAQ-coupled LC-MS/MS and bioinformatics analysis. AB - It is important to differentiate between bipolar disorder (BD) and major depressive disorder (MDD) in the first depressive episode because of the potential treatment implications. Previous studies have mainly focused on the different clinical features or pathological biomarkers to distinguish these two diseases; however, a better understanding of the proteomics profiling of BD may help aid future therapeutic strategies. Here, we applied isobaric tags for relative and absolute quantification (iTRAQ) technology combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins between MDD and bipolar depression (BP). In total, 30 MDD, 30 BP and 30 healthy subjects were included. Proteins from depleted plasma samples were digested into peptides, individually labeled with iTRAQ reagents, combined and subjected to LC-MS/MS and further bioinformatics analyses. Our results showed that 9 proteins were significantly altered between MDD and BP. Briefly, B2RAN2, B4E1B2, APOA1, ENG, SBSN and QSOX2 were up-regulated, whereas ORM1, MRC2 and SLPI were down-regulated. Most identified proteins were related to the immune system. The bioinformatics analysis showed that B2RAN2 (highly similar to vanin-1) was involved in the significantly enriched KEGG pathways "pantothenate and CoA biosynthesis" (P=0.009). B2RAN2 and ENG may play important roles in depression. They may serve as candidate biomarkers for distinguishing MDD and BP. Further validation and investigation are required to illuminate the roles of B2RAN2 and ENG in MDD and BP. The current study provided a potential and novel biomarker panel that may, in turn, aid the diagnosis of BD. PMID- 28910602 TI - Hair cortisol concentration in preschoolers with attention-deficit/hyperactivity symptoms-Roles of gender and family adversity. AB - OBJECTIVE: Previous studies on the association between hypothalamic-pituitary adrenal axis (HPAA) activity and ADHD yielded inconsistent findings, particularly in younger children. This might be due to the heterogeneity of the disorder, making moderator effects of variables probable, which circumscribe more homogenous subgroups. There have been indications of moderator effects on this association by gender of child and exposure to family adversity. Moreover, difficulties in capturing long-term basal HPAA activity in younger children might have contributed to the inconsistencies. We therefore analyzed moderator effects of gender and family adversity while using the hair cortisol concentration (HCC) to assess integrated long-term HPAA. METHODS: The community-based sample consisted of 122 4-5-year-old preschoolers (71 screened positive for elevated ADHD symptoms). ADHD symptoms were measured by a clinical parent interview and parent and teacher questionnaires. HCC in the most proximal 3-cm scalp hair segment was analyzed using luminescence immunoassay. An extended family adversity index was used. RESULTS: Hierarchical linear regression analyses yielded an interaction effect (p<.05) between ADHD symptom groups and gender on HCC, indicating a low HCC in boys with elevated ADHD symptoms. Further exploratory analyses revealed that this interaction effect was most pronounced under the condition of family adversity. The results held after controlling for oppositional, anxiety, and depressive symptoms. CONCLUSION: Low HCC might indicate a specific pathogenic mechanism in boys with elevated ADHD symptoms. This mechanism might further involve an exposure to family adversity. However, the results need to be cross-validated before definitive conclusions can be drawn. PMID- 28910604 TI - Ovarioleukodystrophy in Chinese Han: A case report. PMID- 28910603 TI - Apolipoprotein A-IV constrains HPA and behavioral stress responsivity in a strain dependent manner. AB - There is a critical gap in our knowledge of the mechanisms that govern interactions between daily life experiences (e.g., stress) and metabolic diseases, despite evidence that stress can have profound effects on cardiometabolic health. Apolipoprotein A-IV (apoA-IV) is a protein found in chylomicrons (lipoprotein particles that transport lipids throughout the body) where it participates in lipid handling and the regulation of peripheral metabolism. Moreover, apoA-IV is expressed in brain regions that regulate energy balance including the arcuate nucleus. Given that both peripheral and central metabolic processes are important modulators of hypothalamic-pituitary adrenocortical (HPA) axis activity, the present work tests the hypothesis that apoA-IV activity affects stress responses. As emerging data suggests that apoA-IV actions can vary with background strain, we also explore the strain-dependence of apoA-IV stress regulation. These studies assess HPA axis, metabolic (hyperglycemia), and anxiety-related behavioral responses to psychogenic stress in control (wildtype) and apoA-IV-deficient (KO) mice on either the C57Bl/6J (C57) or 129*1/SvJ (129) background strain. The results indicate that apoA-IV KO increases post-stress corticosterone and anxiety-related behavior specifically in the 129 strain, and increases stress-induced hyperglycemia exclusively in the C57 strain. These data support the hypothesis that apoA-IV is a novel factor that limits stress reactivity in a manner that depends on genetic background. An improved understanding of the complex relationship among lipid homeostasis, stress sensitivity, and genetics is needed to optimize the development of personalized treatments for stress- and metabolism-related diseases. PMID- 28910605 TI - Risk factors for postoperative pneumonia after microsurgery for vestibular schwannoma. AB - OBJECTIVES: Postoperative complications occurred in about 30% patients after vestibular schwannoma (VS) microsurgical excision. Although many specific complications have been extensively studied, postoperative pneumonia (POP) has received little attention. This study was designed to identify the risk factors for POP after microsurgery for VS. PATIENTS AND METHODS: Patients undergoing VS microsurgical resection (n=244) between December 2014 and November 2016 at West China Hospital of Sichuan University were retrospectively assessed for POP. Univariate and multivariate analyses were performed to identify the risk factors for POP. RESULTS: POP (Clavien-Dindo grade II or higher) was diagnosed in 29 (11.9%) patients. Univariate analysis revealed that age (>=60years; p=0.013), diabetes mellitus (DM; p=0.040) and Koos grade IV (p=0.017) were significantly associated with POP. Multivariate analysis revealed that these factors were all independent risk factors for POP. Association between POP and prolonged postoperative hospitalization was also revealed. However, no risk factor associated with severity of POP was found in this study. CONCLUSION: Older age, DM and Koos grade IV were identified as independent risk factors for POP after microsurgery for VS Moreover, POP caused a prolonged hospital stay. PMID- 28910606 TI - Multivariate analysis as a key tool in chemotaxonomy of brinjal eggplant, African eggplants and wild related species. AB - The brinjal eggplant (Solanum melongena L.) is an important vegetable species worldwide, while African eggplants (S. aethiopicum L., S. macrocarpon L.) are indigenous vegetable species of local significance. Taxonomy of eggplants and their wild relatives is complicated and still unclear. Hence, the objective of the study was to clarify taxonomic position of cultivars and landraces of brinjal, its wild relatives and African eggplant species and their wild ancestors using chemotaxonomic markers and multivariate analysis techniques for data processing, with special attention paid to the recognition of markers characteristic for each group of the plants. The total of 34 accessions belonging to 9 species from genus Solanum L. were used in the study. Chemotaxonomic analysis was based on the profiles of cuticular n-alkanes and methylalkanes, obtained using gas chromatography-mass spectrometry and gas chromatography with flame ionization detector. Standard hierarchical cluster analysis (HCA) and principal component analysis (PCA) were used for the classification, while the latter and two-way HCA allowed to identify markers responsible for the clustering of the species. Cultivars, landraces and wild forms of S. melongena were practically identical in terms of their taxonomic position. The results confirmed high and statistically significant distinctiveness of all African eggplant species from the brinjal eggplant. The latter was characterized mostly by abundant long chain hydrocarbons in the range of 34-37 carbon atoms. The differences between both African eggplant species were, however, also statistically significant; S. aethiopicum displayed the highest contribution of 2 methylalkanes to the total cuticular hydrocarbons, while S. macrocarpon was characterized by elevated n-alkanes in the range of 25-32 carbon atoms. Wild ancestors of both African eggplant species were identical with their cultivated relatives. Concluding, high usefulness of the chemotaxonomic approach in classification of this important group of plants was confirmed. PMID- 28910607 TI - Molecular cloning and functional expression of Lewis type alpha1,3/alpha1,4 fucosyltransferase cDNAs from Mangifera indica L. AB - In higher plants, complex type N-glycans contain characteristic carbohydrate moieties that are not found in mammals. In particular, the attachment of the Lewis a (Lea) epitope is currently the only known outer chain elongation that is present in plant N-glycans. Such a modification is of great interest in terms of the biological function of complex type N-glycans in plant species. However, little is known regarding the exact molecular basis underlying their Lea expression. In the present study, we cloned two novel Lewis type fucosyltransferases (MiFUT13) from mango fruit, Mangifera indica L., heterologously expressed the proteins and structurally and functionally characterized them. Using an HPLC-based assay, we demonstrated that the recombinant MiFUT13 proteins mediate the alpha1,4-fucosylation of acceptor tetrasaccharides with a strict preference for type I-based structure to type II. The results and other findings suggest that MiFUT13s are involved in the biosynthesis of Lea containing glycoconjugates in mango fruits. PMID- 28910608 TI - Strengthening advocacy efforts with empirical evidence: A case example of the conduct, uptake and utilisation of research in drug policy decision-making in Vietnam. AB - During the last decade, international aid agencies and advocates have been working with Southeast Asian governments to move away from punitive responses towards people who use drugs to more public health, humane approaches. The lack of local scientific evidence about the effectiveness of different treatment approaches has made this advocacy work more challenging. This paper reflects on a generation of treatment research evidence and how it can assist advocacy efforts. The case example is the cost-effectiveness research, comparing centre-based compulsory treatment with community-based voluntary methadone maintenance treatment in Vietnam (2012-2015). Using our long-term and on-going connections with key Vietnamese decision-makers and government agencies, our collective experiences in drug policy advocacy and our unique insight into the working of government in Vietnam, we have used strategies to maximise opportunities for research to inform policy discussions. We have made an assessment here about the extent to which study findings have contributed to policy change in Vietnam and the challenges that impede progressive policy implementation. In doing this, we hope to make a contribution to the research evidence use literature. PMID- 28910609 TI - Categorical perception of facial expressions in individuals with non-clinical social anxiety. AB - BACKGROUND AND OBJECTIVES: According to the well-established categorical perception (CP) of facial expressions, we decode complicated expression signals into simplified categories to facilitate expression processing. Expression processing deficits have been widely described in social anxiety (SA), but it remains to be investigated whether CP of expressions are affected by SA. The present study examined whether individuals with SA had an interpretation bias when processing ambiguous expressions and whether the sensitivity of their CP was affected by their SA. METHODS: Sixty-four participants (high SA, 30; low SA, 34) were selected from 658 undergraduates using the Interaction Anxiousness Scale (IAS). With the CP paradigm, specifically with the analysis method of the logistic function model, we derived the categorical boundaries (reflecting interpretation bias) and slopes (reflecting sensitivity of CP) of both high- and low-SA groups while recognizing angry-fearful, happy-angry, and happy-fearful expression continua. RESULTS: Based on a comparison of the categorical boundaries and slopes between the high- and low-SA groups, the results showed that the categorical boundaries between the two groups were not different for any of the three continua, which means that the SA does not affect the interpretation bias for any of the three continua. The slopes for the high-SA group were flatter than those for the low-SA group for both the angry-fearful and happy-angry continua, indicating that the high-SA group is insensitive to the subtle changes that occur from angry to fearful faces and from happy to angry faces. LIMITATIONS: Since participants were selected from a sample of undergraduates based on their IAS scores, the results cannot be directly generalized to individuals with clinical SA disorder. CONCLUSIONS: The study indicates that SA does not affect interpretation biases in the processing of anger, fear, and happiness, but does modulate the sensitivity of individuals' CP when anger appears. High-SA individuals perceive angry expressions in a less categorical manner than the low SA group, but no such difference was found in the perception of happy or fearful expressions. PMID- 28910610 TI - Platelet transfusion refractoriness in patients with acute myeloid leukemia treated by intensive chemotherapy. AB - Platelet transfusion refractoriness (PTR) is a major adverse event in the management of acute myeloid leukemia (AML). In a series of 897 adult patients with AML receiving intensive chemotherapy, we identified 41 patients (4.8%) with PTR. PTR was more frequently observed in parous women, patients with extra medullary disease, a low white blood cell count, an infection, or hemophagocytic syndrome. Among the 31 patients with anti-human leucocyte antigen (HLA) antibodies, an HLA-matched donor was identified for 18 patients (58.1%). Median time between diagnosis of PTR and the first HLA-matched transfusion was 12.5days. HLA-matched transfusions induced a significant increment in platelet counts in 37% of cases. Thrombopoietin receptor agonists were given to 10 patients but did not shorten the duration of thrombocytopenia, reduce severe bleeding, or early death. Grade 3-4 bleeding events during induction, early death caused by bleeding, and death caused by bleeding at any time were significantly greater in patients that had platelet transfusion refractoriness (22% vs. 4.1%, P<0.0001; 12.2% vs. 1.4%, P=0.0006; and 24.4% vs. 5.3%, P<0.0001; respectively). PTR during chemotherapy for AML significantly increased the risk of early and late deaths caused by a severe bleeding event. Improved understanding of platelet destruction is needed to design mechanism-based therapeutic strategies. PMID- 28910611 TI - Revealing a Role for NMDA Receptors in Regulating STN Inputs following the Loss of Dopamine. AB - In this issue of Neuron, Chu et al. (2017) show that dopamine depletion using a 6 OHDA model causes a decrease in hyperdirect inputs from the motor cortex directly to the STN and that rescuing this loss alleviates Parkinsonian symptoms. PMID- 28910612 TI - Smells Familiar: Pheromone-Induced Neurotransmitter Switching Mediates Social Discrimination. AB - Social discrimination is regulated by a variety of sensory inputs. In this issue of Neuron, Dulcis et al. (2017) show that chemosensory-mediated kin preference in Xenopus is determined by changes in neurotransmitter composition, which are regulated by specific microRNAs. PMID- 28910613 TI - Resolving CNS mRNA Heterogeneity: Examining mRNA Alternative Polyadenylation at a Cell-Type-Specific Level. AB - Alternative polyadenylation often regulates mRNA isoform usage. In this issue of Neuron, Hwang et al. (2017) describe a powerful new cell-type-specific methodology, cTag-PAPERCLIP, which can be used to study alternative polyadenylation in the CNS. PMID- 28910614 TI - Movement Coding at the Mesoscale in Posterior Parietal Cortex. AB - Neural correlates of movement planning have been studied most commonly using signals isolated from single cells. However, in this issue of Neuron, Wilber et al. (2017) show that movement trajectories are encoded and replayed in the collective activity of thousands of cells at a time in the posterior parietal cortex. PMID- 28910615 TI - "Beginning with the Smallest Intake": Children's Brain Development and the Role of Neuroscience in Global Environmental Health. AB - Early exposure to environmental toxins like lead, air pollution, and arsenic can have long-lasting and irreversible consequences for children's neurodevelopment, especially in the developing world. Though the number of pollutants increases each year, some neuroscientists are forging partnerships to improve measurement, raise awareness, and promote global health. PMID- 28910617 TI - Whole-Cell Recording of Neuronal Membrane Potential during Behavior. AB - Neuronal membrane potential is of fundamental importance for the mechanistic understanding of brain function. This review discusses progress in whole-cell patch-clamp recordings for low-noise measurement of neuronal membrane potential in awake behaving animals. Whole-cell recordings can be combined with two-photon microscopy to target fluorescently labeled neurons, revealing cell-type-specific membrane potential dynamics of retrogradely or genetically labeled neurons. Dual whole-cell recordings reveal behavioral modulation of membrane potential synchrony and properties of synaptic transmission in vivo. Optogenetic manipulations are also readily integrated with whole-cell recordings, providing detailed information about the effect of specific perturbations on the membrane potential of diverse types of neurons. Exciting developments for future behavioral experiments include dendritic whole-cell recordings and imaging, and use of the whole-cell recording pipette for single-cell delivery of drugs and DNA, as well as RNA expression profiling. Whole-cell recordings therefore offer unique opportunities for investigating the neuronal circuits and synaptic mechanisms driving membrane potential dynamics during behavior. PMID- 28910618 TI - RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. AB - Several microsatellite-expansion diseases are characterized by the accumulation of RNA foci and RAN proteins, raising the possibility of a mechanistic connection. We explored this question using myotonic dystrophy type 2, a multisystemic disease thought to be primarily caused by RNA gain-of-function effects. We demonstrate that the DM2 CCTG?CAGG expansion expresses sense and antisense tetrapeptide poly-(LPAC) and poly-(QAGR) RAN proteins, respectively. In DM2 autopsy brains, LPAC is found in neurons, astrocytes, and glia in gray matter, and antisense QAGR proteins accumulate within white matter. LPAC and QAGR proteins are toxic to cells independent of RNA gain of function. RNA foci and nuclear sequestration of CCUG transcripts by MBNL1 is inversely correlated with LPAC expression. These data suggest a model that involves nuclear retention of expansion RNAs by RNA-binding proteins (RBPs) and an acute phase in which expansion RNAs exceed RBP sequestration capacity, are exported to the cytoplasm, and undergo RAN translation. VIDEO ABSTRACT. PMID- 28910616 TI - Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift. AB - Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with a considerable socioeconomic burden. Heterogeneity of pathoanatomical subtypes and diversity in the pathogenesis and extent of injury contribute to differences in the course and outcome of TBI. Following the primary injury, extensive and lasting damage is sustained through a complex cascade of events referred to as "secondary injury." Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. Because neuroinflammation can be detrimental or beneficial, before developing immunomodulatory therapies, it is necessary to better understand the timing and complexity of the immune responses that follow TBI. With a rapidly increasing body of literature, there is a need for a clear summary of TBI neuroimmunology. This review presents our current understanding of the immune response to TBI in a chronological and compartment-based manner, highlighting early changes in gene expression and initial signaling pathways that lead to activation of innate and adaptive immunity. Based on recent advances in our understanding of innate immune cell activation, we propose a new paradigm to study innate immune cells following TBI that moves away from the existing M1/M2 classification of activation states toward a stimulus- and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling. PMID- 28910619 TI - Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. AB - The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%-75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction. PMID- 28910621 TI - A Fully Automated Approach to Spike Sorting. AB - Understanding the detailed dynamics of neuronal networks will require the simultaneous measurement of spike trains from hundreds of neurons (or more). Currently, approaches to extracting spike times and labels from raw data are time consuming, lack standardization, and involve manual intervention, making it difficult to maintain data provenance and assess the quality of scientific results. Here, we describe an automated clustering approach and associated software package that addresses these problems and provides novel cluster quality metrics. We show that our approach has accuracy comparable to or exceeding that achieved using manual or semi-manual techniques with desktop central processing unit (CPU) runtimes faster than acquisition time for up to hundreds of electrodes. Moreover, a single choice of parameters in the algorithm is effective for a variety of electrode geometries and across multiple brain regions. This algorithm has the potential to enable reproducible and automated spike sorting of larger scale recordings than is currently possible. PMID- 28910622 TI - Dopamine Neurons Respond to Errors in the Prediction of Sensory Features of Expected Rewards. AB - Midbrain dopamine neurons have been proposed to signal prediction errors as defined in model-free reinforcement learning algorithms. While these algorithms have been extremely powerful in interpreting dopamine activity, these models do not register any error unless there is a difference between the value of what is predicted and what is received. Yet learning often occurs in response to changes in the unique features that characterize what is received, sometimes with no change in its value at all. Here, we show that classic error-signaling dopamine neurons also respond to changes in value-neutral sensory features of an expected reward. This suggests that dopamine neurons have access to a wider variety of information than contemplated by the models currently used to interpret their activity and that, while their firing may conform to predictions of these models in some cases, they are not restricted to signaling errors in the prediction of value. PMID- 28910620 TI - cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation. AB - Alternative polyadenylation (APA) is increasingly recognized to regulate gene expression across different cell types, but obtaining APA maps from individual cell types typically requires prior purification, a stressful procedure that can itself alter cellular states. Here, we describe a new platform, cTag-PAPERCLIP, that generates APA profiles from single cell populations in intact tissues; cTag PAPERCLIP requires no tissue dissociation and preserves transcripts in native states. Applying cTag-PAPERCLIP to profile four major cell types in the mouse brain revealed common APA preferences between excitatory and inhibitory neurons distinct from astrocytes and microglia, regulated in part by neuron-specific RNA binding proteins NOVA2 and PTBP2. We further identified a role of APA in switching Araf protein isoforms during microglia activation, impacting production of downstream inflammatory cytokines. Our results demonstrate the broad applicability of cTag-PAPERCLIP and a previously undiscovered role of APA in contributing to protein diversity between different cell types and cellular states within the brain. PMID- 28910624 TI - A Sensorimotor Circuit in Mouse Cortex for Visual Flow Predictions. AB - The cortex is organized as a hierarchical processing structure. Feedback from higher levels of the hierarchy, known as top-down signals, have been shown to be involved in attentional and contextual modulation of sensory responses. Here we argue that top-down input to the primary visual cortex (V1) from A24b and the adjacent secondary motor cortex (M2) signals a prediction of visual flow based on motor output. A24b/M2 sends a dense and topographically organized projection to V1 that targets most neurons in layer 2/3. By imaging the activity of A24b/M2 axons in V1 of mice learning to navigate a 2D virtual environment, we found that their activity was strongly correlated with locomotion and resulting visual flow feedback in an experience-dependent manner. When mice were trained to navigate a left-right inverted virtual environment, correlations of neural activity with behavior reversed to match visual flow. These findings are consistent with a predictive coding interpretation of visual processing. PMID- 28910623 TI - Laminar Organization of Encoding and Memory Reactivation in the Parietal Cortex. AB - Egocentric neural coding has been observed in parietal cortex (PC), but its topographical and laminar organization is not well characterized. We used multi site recording to look for evidence of local clustering and laminar consistency of linear and angular velocity encoding in multi-neuronal spiking activity (MUA) and in the high-frequency (300-900 Hz) component of the local field potential (HF LFP), believed to reflect local spiking activity. Rats were trained to run many trials on a large circular platform, either to LED-cued goal locations or as a spatial sequence from memory. Tuning to specific self-motion states was observed and exhibited distinct cortical depth-invariant coding properties. These patterns of collective local and laminar activation during behavior were reactivated in compressed form during post-experience sleep and temporally coupled to cortical delta waves and hippocampal sharp-wave ripples. Thus, PC neuron motion encoding is consistent across cortical laminae, and this consistency is maintained during memory reactivation. PMID- 28910625 TI - Role of soil-to-leaf tritium transfer in controlling leaf tritium dynamics: Comparison of experimental garden and tritium-transfer model results. AB - Environmental transfer models assume that organically-bound tritium (OBT) is formed directly from tissue-free water tritium (TFWT) in environmental compartments. Nevertheless, studies in the literature have shown that measured OBT/HTO ratios in environmental samples are variable and generally higher than expected. The importance of soil-to-leaf HTO transfer pathway in controlling the leaf tritium dynamics is not well understood. A model inter-comparison of two tritium transfer models (CTEM-CLASS-TT and SOLVEG-II) was carried out with measured environmental samples from an experimental garden plot set up next to a tritium-processing facility. The garden plot received one of three different irrigation treatments - no external irrigation, irrigation with low tritium water and irrigation with high tritium water. The contrast between the results obtained with the different irrigation treatments provided insights into the impact of soil-to-leaf HTO transfer on the leaf tritium dynamics. Concentrations of TFWT and OBT in the garden plots that were not irrigated or irrigated with low tritium water were variable, responding to the arrival of the HTO-plume from the tritium processing facility. In contrast, for the plants irrigated with high tritium water, the TFWT concentration remained elevated during the entire experimental period due to a continuous source of high HTO in the soil. Calculated concentrations of OBT in the leaves showed an initial increase followed by quasi equilibration with the TFWT concentration. In this quasi-equilibrium state, concentrations of OBT remained elevated and unchanged despite the arrivals of the plume. These results from the model inter-comparison demonstrate that soil-to leaf HTO transfer significantly affects tritium dynamics in leaves and thereby OBT/HTO ratio in the leaf regardless of the atmospheric HTO concentration, only if there is elevated HTO concentrations in the soil. The results of this work indicate that assessment models should be refined to consider the importance of soil-to-leaf HTO transfer to ensure that dose estimates are accurate and conservative. PMID- 28910626 TI - Long-term modelling of fly ash and radionuclide emissions as well as deposition fluxes due to the operation of large oil shale-fired power plants. AB - Two of the world's largest oil shale-fired power plants (PPs) in Estonia have been operational over 40 years, emitting various pollutants, such as fly ash, SOx, NOx, heavy metals, volatile organic compounds as well as radionuclides to the environment. The emissions from these PPs have varied significantly during this period, with the maximum during the 1970s and 1980s. The oil shale burned in the PPs contains naturally occurring radionuclides from the 238U and 232Th decay series as well as 40K. These radionuclides become enriched in fly ash fractions (up to 10 times), especially in the fine fly ash escaping the purification system. Using a validated Gaussian-plume model, atmospheric dispersion modelling was carried out to determine the quantity and a real magnitude of fly ash and radionuclide deposition fluxes during different decades. The maximum deposition fluxes of volatile radionuclides (210Pb and 210Po) were around 70 mBq m-2 d-1 nearby the PPs during 1970s and 1980s. Due to the reduction of burned oil shale and significant renovations done on the PPs, the deposition fluxes were reduced to 10 mBq m-2 d-1 in the 2000s and down to 1.5 mBq m-2 d-1 in 2015. The maximum deposition occurs within couple of kilometers of the PPs, but the impacted area extends to over 50 km from the sources. For many radionuclides, including 210Po, the PPs have been larger contributors of radionuclides to the environment via atmospheric pathway than natural sources. This is the first time that the emissions and deposition fluxes of radionuclides from the PPs have been quantified, providing the information about their radionuclide deposition load on the surrounding environment during various time periods. PMID- 28910627 TI - Dancing with the Stars: Phenolic Glycolipids Partners with Macrophages. AB - How Mycobacterium leprae infection causes demyelination to mediate leprosy pathogenesis has been a long-standing question. In a recent Cell paper, Madigan et al. (2017) use a zebrafish model of M. leprae infection to show that infected macrophages patrol axons to trigger mitochondrial damage and induce demyelination of nerve cells. PMID- 28910628 TI - Tooth Be Told, Genetics Influences Oral Microbiome. AB - The mix of bacteria that coat our teeth impact oral health, but it remains unclear what factors govern their composition. In this issue of Cell Host & Microbe, Gomez et al. (2017) examine the relationship between host genetics and the oral microbiome in the context of health and disease. PMID- 28910629 TI - Choline Theft-An Inside Job. AB - Choline is a crucial methyl donor necessary for epigenetic regulation. In this issue of Cell Host & Microbe, Romano et al. (2017) demonstrate that choline utilizing gut bacteria compete with their host for this essential resource, calling for a systematic consideration of gut microbial composition for personalized diet recommendations. PMID- 28910630 TI - Fragment and Conquer. AB - The replication vacuole of Legionella pneumophila makes contact with host mitochondria. In this issue of Cell Host & Microbe, Escoll et al. (2017) dissect the mechanisms of this interaction, the effect of the T4SS effector MitF on mitochondrial function, and the resultant metabolic reprogramming of infected cells to benefit the bacteria. PMID- 28910631 TI - Specialized Weaponry: How a Type III-A CRISPR-Cas System Excels at Combating Phages. AB - CRISPR-Cas-mediated defense against phage invaders usually requires recognition of short sequences, termed protospacer-adjacent motifs (PAMs), in phage DNA. In this issue of Cell Host & Microbe, Pyenson et al. (2017) show that the lack of a PAM requirement in some CRISPR-Cas systems prevents interference evasion and facilitates phage extinction. PMID- 28910632 TI - Drivers of Dengue Intrahost Evolution. AB - RNA viruses circulate as rapidly evolving swarms of related variants, and their evolutionary dynamics within hosts may be key to understanding virus emergence. In this issue of Cell Host & Microbe, Parameswaran et al. (2017) combine next generation sequencing and functional studies to characterize viral populations in acute dengue infections. PMID- 28910633 TI - Host Genetic Control of the Oral Microbiome in Health and Disease. AB - Host-associated microbial communities are influenced by both host genetics and environmental factors. However, factors controlling the human oral microbiome and their impact on disease remain to be investigated. To determine the combined and relative effects of host genotype and environment on oral microbiome composition and caries phenotypes, we profiled the supragingival plaque microbiome of 485 dizygotic and monozygotic twins aged 5-11. Oral microbiome similarity always increased with shared host genotype, regardless of caries state. Additionally, although most of the variation in the oral microbiome was determined by environmental factors, highly heritable oral taxa were identified. The most heritable oral bacteria were not associated with caries state, did not tend to co occur with other taxa, and decreased in abundance with age and sugar consumption frequency. Thus, while the human oral microbiome composition is influenced by host genetic background, potentially cariogenic taxa are likely not controlled by genetic factors. PMID- 28910634 TI - Collaboration between Distinct Rab Small GTPase Trafficking Circuits Mediates Bacterial Clearance from the Bladder Epithelium. AB - Rab small GTPases control membrane trafficking through effectors that recruit downstream mediators such as motor proteins. Subcellular trafficking typically involves multiple Rabs, with each specific step mediated by a distinct Rab protein. We describe a collaboration between two distinct Rab-protein orchestrated trafficking circuits in bladder epithelial cells (BECs) that expels intracellular uropathogenic Escherichia coli (UPEC) from their intracellular niche. RAB11a and RAB27b and their trafficking circuitry are simultaneously involved in UPEC expulsion. While RAB11a recruits its effector RAB11FIP3 and cytoskeletal motor Dynein, RAB27b mobilizes the effector MyRIP and motor Myosin VIIa to mediate bacterial expulsion. This collaboration is coordinated by deposition of the exocyst complex on bacteria-containing vesicles, an event triggered by the innate receptor Toll-like receptor 4. Both RAB11a and RAB27b are recruited and activated by the exocyst complex components SEC6/SEC15. Thus, the cell autonomous defense system can mobilize and coalesce multiple subcellular trafficking circuitries to combat infections. PMID- 28910635 TI - Gestational Stage and IFN-lambda Signaling Regulate ZIKV Infection In Utero. AB - Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-lambda signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN lambda2 reduced ZIKV infection. IFN-lambda treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage dependence of ZIKV pathogenesis and IFN-lambda-mediated immunity at the maternal-fetal interface. PMID- 28910636 TI - Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication. AB - Many viral RNAs are modified by methylation of the N6 position of adenosine (m6A). m6A is thought to regulate RNA splicing, stability, translation, and secondary structure. Influenza A virus (IAV) expresses m6A-modified RNAs, but the effects of m6A on this segmented RNA virus remain unclear. We demonstrate that global inhibition of m6A addition inhibits IAV gene expression and replication. In contrast, overexpression of the cellular m6A "reader" protein YTHDF2 increases IAV gene expression and replication. To address whether m6A residues modulate IAV RNA function in cis, we mapped m6A residues on the IAV plus (mRNA) and minus (vRNA) strands and used synonymous mutations to ablate m6A on both strands of the hemagglutinin (HA) segment. These mutations inhibited HA mRNA and protein expression while leaving other IAV mRNAs and proteins unaffected, and they also resulted in reduced IAV pathogenicity in mice. Thus, m6A residues in IAV transcripts enhance viral gene expression. PMID- 28910637 TI - Intrahost Selection Pressures Drive Rapid Dengue Virus Microevolution in Acute Human Infections. AB - Dengue, caused by four dengue virus serotypes (DENV-1 to DENV-4), is a highly prevalent mosquito-borne viral disease in humans. Yet, selection pressures driving DENV microevolution within human hosts (intrahost) remain unknown. We employed a whole-genome segmented amplification approach coupled with deep sequencing to profile DENV-3 intrahost diversity in peripheral blood mononuclear cell (PBMC) and plasma samples from 77 dengue patients. DENV-3 intrahost diversity appears to be driven by immune pressures as well as replicative success in PBMCs and potentially other replication sites. Hotspots for intrahost variation were detected in 59%-78% of patients in the viral Envelope and pre Membrane/Membrane proteins, which together form the virion surface. Dominant variants at the hotspots arose via convergent microevolution, appear to be immune escape variants, and were evolutionarily constrained at the macro level due to viral replication defects. Dengue is thus an example of an acute infection in which selection pressures within infected individuals drive rapid intrahost virus microevolution. PMID- 28910639 TI - RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. PMID- 28910638 TI - The Landscape of Type VI Secretion across Human Gut Microbiomes Reveals Its Role in Community Composition. AB - Although gut microbiome composition is well defined, the mechanisms underlying community assembly remain poorly understood. Bacteroidales possess three genetic architectures (GA1-3) of the type VI secretion system (T6SS), an effector delivery pathway that mediates interbacterial competition. Here we define the distribution and role of GA1-3 in the human gut using metagenomic analysis. We find that adult microbiomes harbor limited effector and cognate immunity genes, suggesting selection for compatibility at the species (GA1 and GA2) and strain (GA3) levels. Bacteroides fragilis GA3 is known to mediate potent inter-strain competition, and we observe GA3 enrichment among strains colonizing infant microbiomes, suggesting competition early in life. Additionally, GA3 is associated with increased Bacteroides abundance, indicating that this system confers an advantage in Bacteroides-rich ecosystems. Collectively, these analyses uncover the prevalence of T6SS-dependent competition and reveal its potential role in shaping human gut microbial composition. PMID- 28910640 TI - The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. PMID- 28910641 TI - Thoughts and sensations, twin galaxies of the inner space: The propensity to mind wander relates to spontaneous sensations arising on the hands. AB - Sensations and thoughts have been described as potentially related to self awareness. We therefore asked whether sensations that arise in the absence of external triggers, i.e., spontaneous sensations (SPS), which were shown to relate to interoception and perception of the self, vary as a function of the individual propensity to generate spontaneous thoughts, i.e., mind-wandering. The Mind Wandering Questionnaire (MWQ) was used as a specific tool to assess the frequency and propensity to mind-wander several weeks before completing an SPS task. Correlational analyses between the MWQ score and SPS showed that greater propensity to mind-wander coincided with widespread perception of SPS, while lesser propensity to mind-wander coincided with more spatially restricted perception of SPS. The results are interpreted in light of the role of spontaneous thoughts and sensations in self-awareness. The potential psychological processes and the way they might regulate the relation between mind wandering and the perception of SPS are discussed. PMID- 28910642 TI - Cytotoxic Cells Kill Intracellular Bacteria through Granulysin-Mediated Delivery of Granzymes. PMID- 28910643 TI - Induction of Pluripotency in Mouse Somatic Cells with Lineage Specifiers. PMID- 28910644 TI - Long term effects of cerium dioxide nanoparticles on the nitrogen removal, micro environment and community dynamics of a sequencing batch biofilm reactor. AB - The influences of cerium dioxide nanoparticles (CeO2 NPs) on nitrogen removal in biofilm were investigated. Prolonged exposure (75d) to 0.1mg/L CeO2 NPs caused no inhibitory effects on nitrogen removal, while continuous addition of 10mg/L CeO2 NPs decreased the treatment efficiency to 53%. With the progressive concentration of CeO2 NPs addition, the removal efficiency could nearly stabilize at 67% even with the continues spike of 10mg/L. The micro-profiles of dissolved oxygen, pH, and oxidation reduction potential suggested the developed protection mechanisms of microbes to progressive CeO2 NPs exposure led to the less influence of microenvironment, denitrification bacteria and enzyme activity than those with continuous ones. Furthermore, high throughput sequencing illustrated the drastic shifted communities with gradual CeO2 NPs spiking was responsible for the adaption and protective mechanisms. The present study demonstrated the acclimated microbial community was able to survive CeO2 NPs addition more readily than those non-acclimated. PMID- 28910645 TI - Performance and stability of sewage sludge digestion under CO2 enrichment: A pilot study. AB - Carbon dioxide (CO2) injection in anaerobic digestion has recently been proposed as an interesting possibility to boost methane (CH4) recovery from sludge and organic waste by converting a greenhouse gas into a renewable resource. This research assessed the effects of exogenous CO2 injection on performance and process stability of single-phase continuous anaerobic digesters. Two pilot scale reactors treating sewage sludge were operated for 130days. One reactor was periodically injected with CO2 while the other acted as control. Two injection frequencies and injection devices were tested. The results indicated that CO2 enrichment allowed an increase in CH4 production of ca. 12%, with a CH4 production rate of 371+/-100L/(kgVSfed.d) and a CH4 concentration of ca. 60% when dissolved CO2 levels inside the test reactor were increased up to 1.9-fold. Results also indicated an improvement in process resilience to temporary overloads and no impacts on stability parameters. PMID- 28910646 TI - Minimizing mixing intensity to improve the performance of rice straw anaerobic digestion via enhanced development of microbe-substrate aggregates. AB - The aim of this work was to study the effect of the differential development of microbe-substrate aggregates at different mixing intensities on the performance of anaerobic digestion of rice straw. Batch and semi-continuous reactors were operated for up to 50 and 300days, respectively, under different mixing intensities. In both batch and semi-continuous reactors, minimal mixing conditions exhibited maximum methane production and lignocellulose biodegradability, which both had strong correlations with the development of microbe-substrate aggregates. The results implied that the aggregated microorganisms on the particulate substrate played a key role in rice straw hydrolysis, determining the performance of anaerobic digestion. Increasing the mixing speed from 50 to 150rpm significantly reduced the methane production rate by disintegrating the microbe-substrate aggregates in the semi-continuous reactor. A temporary stress of high-speed mixing fundamentally affected the microbial communities, increasing the possibility of chronic reactor failure. PMID- 28910647 TI - Impact of a high ammonia-ammonium-pH system on methane-producing archaea and sulfate-reducing bacteria in mesophilic anaerobic digestion. AB - A novel strategy for acclimation to ammonia stress was implemented by stimulating a high ammonia-ammonium-pH environment in a high-solid anaerobic digestion (AD) system in this study. Three semi-continuously stirred anaerobic reactors performed well over the whole study period under mesophilic conditions, especially in experimental group (R-2) when accommodated from acclimation period which the maximum total ammonia nitrogen (TAN) and free ammonia nitrogen (FAN) increased to 4921 and 2996mg/L, respectively. Moreover, when it accommodated the high ammonia-ammonium-pH system, the daily biogas production and methane content were similar to those in R-1 (the blank control to R-2), but the hydrogen sulfide (H2S) content lower than the blank control. Moreover, mechanistic studies showed that high ammonia stress enhanced the activity of coenzyme F420. The results of real-time fluorescent quantitative polymerase chain reaction (PCR) showed that ammonia stress decreased the abundance of sulfate-reducing bacteria and increased the abundance of methane-producing archaea. PMID- 28910648 TI - Biochar for volatile organic compound (VOC) removal: Sorption performance and governing mechanisms. AB - Sorption is one of the most efficient and low cost strategies for volatile organic compound (VOC) removal, but VOC sorption by biochar has seen limited research. In this work, gas phase sorption experiments were conducted to determine the sorption potential and mechanisms of VOCs onto biochar. A total of 15 biochars produced from 5 common feedstocks at 300, 450, and 600 degrees C were evaluated as sorbents. Three common VOCs (acetone, cyclohexane, and toluene) were chosen as sorbates. The results showed that all the tested biochars had VOC sorption capacity in the range of 5.58-91.2mgg-1. The sorption capacities were mainly influenced by both the surface area of biochar and its noncarbonized organic matter content. The vapor sorption process was exothermic, and the removal of VOCs by the biochars decreased with increasing feedstock temperature. Both the physical adsorption and partition mechanisms played important roles in controlling the VOC removal by the biochars. Biochar maintained its VOC removal ability after five consecutive sorption-desorption cycles, which indicated good reusability. Findings of this work suggest that biochar is a promising alternative sorbent for gaseous VOC removal. PMID- 28910649 TI - Recovery of phosphorus and volatile fatty acids from wastewater and food waste with an iron-flocculation sequencing batch reactor and acidogenic co fermentation. AB - A sequencing batch reactor-based system was developed for enhanced phosphorus (P) removal and recovery from municipal wastewater. The system consists of an iron dosing SBR for P precipitation and a side-stream anaerobic reactor for sludge co fermentation with food waste. During co-fermentation, sludge and food waste undergo acidogenesis, releasing phosphates under acidic conditions and producing volatile fatty acids (VFAs) into the supernatant. A few types of typical food waste were investigated for their effectiveness in acidogenesis and related enzymatic activities. The results show that approximately 96.4% of total P in wastewater was retained in activated sludge. Food waste with a high starch content favoured acidogenic fermentation. Around 55.7% of P from wastewater was recovered as vivianite, and around 66% of food waste loading was converted into VFAs. The new integration formed an effective system for wastewater treatment, food waste processing and simultaneous recovery of P and VFAs. PMID- 28910650 TI - Cholinium amino acids-glycerol mixtures: New class of solvents for pretreating wheat straw to facilitate enzymatic hydrolysis. AB - New solvents for pretreating wheat straw, mixtures of cholinium amino acids ionic liquids ([Ch][AA] ILs) and glycerol, were developed. As a typical result, 50% cholinium alanine-glycerol is capable of removing 67.6% lignin while reserving 95.1% cellulose (90 degrees C, L/S mass ratio of 20:1, 6h) and the conversions of cellulose and xylan are 89.7% and 70.9%, respectively, which is comparable to the pretreatment capability of other solvents, while [Ch][AA]-glycerol mixtures have desirable advantages, e.g., biocompatibility, lower cost with adding glycerol than pure IL, much lower pretreatment temperature (typically <100 degrees C) than that by glycerol (typically >200 degrees C). Lignin removal and polysaccharide conversion are dependent on [Ch][AA] content and pH of pretreatment solvents. [Ch][AA] not only remove lignin in wheat straw effectively but also swell cellulose while not remarkably dissolve cellulose with high cellulose reservation, favoring the enzymatic hydrolysis. Such mixtures of ILs and co solvents are potential solvents for pretreating biomass. PMID- 28910651 TI - Inhibitory effects of acidic pH and confounding effects of moisture content on methane biofiltration. AB - This study focussed on evaluating the effect of hydrogen sulfide (H2S) on biological oxidation of waste methane (CH4) gas in compost biofilters, Batch experiments were conducted to determine the dependency of maximum methane oxidation rate (Vmax) on two main factors; pH and moisture content, as well as their interaction effects. The maximum Vmax was observed at a pH of 7.2 with decreasing Vmax values observed with decreasing pH, irrespective of moisture content. Flow-through columns operated at a pH of 4.5 oxidized CH4 at a flux rate of 53g/m2/d compared to 146g/m2/d in columns operated at neutral pH. No oxidation activity was observed for columns operated at pH 2.5, and DNA sequencing analysis of samples led to the conclusion that highly acidic conditions were responsible for inhibiting the ability of methanotrophs to oxidize CH4. Biofilter columns operated at pH 2.5 contained only 2% methanotrophs (type I) out of the total microbial population, compared to 55% in columns operated at pH 7.5. Overall, changes in the population of methanotrophs with acidification within the biofilters compromised its capacity to oxidize CH4 which demonstrated that a compost biofilter could not operate efficiently in the presence of high levels of H2S. PMID- 28910652 TI - Disintegration of Nannochloropsis sp. cells in an improved turbine bead mill. AB - The Nannochloropsis sp. cells in aqueous solution were disintegrated in an improved bead mill with turbine agitator. The disintegration rates of cell samples disrupted under various operating parameters (i.e., circumferential speed, bead size, disintegration time, and cell concentration) were analyzed. An experimental strategy to optimize the parameters affecting the cell disintegration process was proposed. The results show that Nannochloropsis sp. cells can be effectively disintegrated in the turbine stirred bead mill under the optimum condition (i.e., circumferential speed of 2.3m/s, concentration of 15vol.%, disintegration time of 40min and bead size of 0.3-0.4mm). The disintegration mechanism was discussed via the selection and breakage functions from population balance modelling. It is revealed that the impact and compression effects of stirring beads are more effective for the disruption of coarser fraction of cells, and the shear effect dominates the production of finer fractions of disintegrated cells. PMID- 28910653 TI - Biobased polyelectrolyte multilayer-coated hollow mesoporous silica as a green flame retardant for epoxy resin. AB - Here, we describe a multifunctional biobased polyelectrolyte multilayer-coated hollow mesoporous silica (HM-SiO2@CS@PCL) as a green flame retardant through layer-by-layer assembly using hollow mesoporous silica (HM-SiO2), chitosan (CS) and phosphorylated cellulose (PCL). The electrostatic interactions deposited the CS/PCL coating on the surface of HM-SiO2. Subsequently, this multifunctional flame retardant was used to enhance thermal properties and flame retardancy of epoxy resin. The addition of HM-SiO2@CS@PCL to the epoxy resin thermally destabilized the epoxy resin composite, but generated a higher char yield. Furthermore, HM-SiO2 played a critical role and generated synergies with CS and PCL to improve fire safety of the epoxy resin due to the multiple flame retardancy elements (P, N and Si). This multi-element, synergistic, flame retardant system resulted in a remarkable reduction (51%) of peak heat release rate and a considerable removal of flammable decomposed products. Additionally, the incorporation of HM-SiO2@CS@PCL can sustainably recycle the epoxy resin into high value-added hollow carbon spheres during combustion. Therefore, the HM SiO2@CS@PCL system provides a practical possibility for preparing recyclable polymer materials with multi-functions and high performances. PMID- 28910654 TI - Kinect-based assessment of lower limb kinematics and dynamic postural control during the star excursion balance test. AB - Assessments using dynamic postural control tests, like the Star Excursion Balance Test (SEBT), in combination with three-dimensional (3D) motion analysis can yield critical information regarding a subject's lower limb movement patterns. 3D analysis can provide a clear understanding of the mechanisms that lead to specific outcome measures on the SEBT. Currently, the only technology for 3D motion analysis during such tests is expensive marker-based motion analysis systems, which are impractical for use in clinical settings. In this study we validated the use of the Microsoft Kinect as a cost-effective and marker-less alternative to more complex and expensive gold-standard motion analysis systems. Ten healthy subjects performed the SEBT while their lower limb kinematics were measured concurrently using a traditional motion capture system and a single Kinect v2 sensor. Analyses revealed errors in lower limb kinematics of less than 5 degrees , except for the knee frontal-plane angle (5.7 degrees ) in the posterior-lateral direction. Ensemble curve analyses supported these findings, showing minimal between-system differences in all directions. Additionally, we found that the Kinect displayed excellent agreement (ICC3,k=0.99) and consistency (ICC2,k=0.99) when assessing reach distances in all directions. These results indicate that this low-cost and easy to implement technology may provide to clinicians a simple tool to simultaneously assess reach distances while developing a clearer understanding of the lower extremity movement patterns associated with SEBT performance in healthy and injured populations. PMID- 28910655 TI - Self-esteem recognition based on gait pattern using Kinect. AB - BACKGROUND: Self-esteem is an important aspect of individual's mental health. When subjects are not able to complete self-report questionnaire, behavioral assessment will be a good supplement. In this paper, we propose to use gait data collected by Kinect as an indicator to recognize self-esteem. METHODS: 178 graduate students without disabilities participate in our study. Firstly, all participants complete the 10-item Rosenberg Self-Esteem Scale (RSS) to acquire self-esteem score. After completing the RRS, each participant walks for two minutes naturally on a rectangular red carpet, and the gait data are recorded using Kinect sensor. After data preprocessing, we extract a few behavioral features to train predicting model by machine learning. Based on these features, we build predicting models to recognize self-esteem. RESULTS: For self-esteem prediction, the best correlation coefficient between predicted score and self report score is 0.45 (p<0.001). We divide the participants according to gender, and for males, the correlation coefficient is 0.43 (p<0.001), for females, it is 0.59 (p<0.001). CONCLUSION: Using gait data captured by Kinect sensor, we find that the gait pattern could be used to recognize self-esteem with a fairly good criterion validity. The gait predicting model can be taken as a good supplementary method to measure self-esteem. PMID- 28910656 TI - Test-retest reliability of a balance testing protocol with external perturbations in young healthy adults. AB - External perturbations are utilized to challenge balance and mimic realistic balance threats in patient populations. The reliability of such protocols has not been established. The purpose was to examine test-retest reliability of balance testing with external perturbations. Healthy adults (n=34; mean age 23 years) underwent balance testing over two visits. Participants completed ten balance conditions in which the following parameters were combined: perturbation or non perturbation, single or double leg, and eyes open or closed. Three trials were collected for each condition. Data were collected on a force plate and external perturbations were applied by translating the plate. Force plate center of pressure (CoP) data were summarized using 13 different CoP measures. Test-retest reliability was examined using intraclass correlation coefficients (ICC) and Bland-Altman plots. CoP measures of total speed and excursion in both anterior posterior and medial-lateral directions generally had acceptable ICC values for perturbation conditions (ICC=0.46 to 0.87); however, many other CoP measures (e.g. range, area of ellipse) had unacceptable test-retest reliability (ICC<0.70). Improved CoP measures were present on the second visit indicating a potential learning effect. Non-perturbation conditions generally produced more reliable CoP measures than perturbation conditions during double leg standing, but not single leg standing. Therefore, changes to balance testing protocols that include external perturbations should be made to improve test-retest reliability and diminish learning including more extensive participant training and increasing the number of trials. CoP measures that consider all data points (e.g. total speed) are more reliable than those that only consider a few data points. PMID- 28910657 TI - The use of real-time feedback to improve kinematic marker placement consistency among novice examiners. AB - Marker placement deviation has been shown to be the largest source of error in gait kinematic data, limiting the ability of clinicians and researchers to conduct between-day or between-center investigations. Prior marker-placement standardization methods are either impractical for a clinical setting or rely on expert marker placement. However, a recently developed, real-time feedback tool has been developed and shown to improve marker placement and downstream kinematic calculations. The purpose of this study was to determine whether this real-time marker-placement tool could improve the consistency of gait kinematic data collected by a group of novice examiners. Twelve novice examiners identified anatomical landmarks and placed retroreflective markers on a single subject. For each examiner, a running trial was analyzed separately using two static trials: (1) PRE and (2) POST implementation of the feedback tool. The protocol was repeated a second time, one week later. Between-examiner consistency was represented by the 95% confidence interval (CI) of the mean joint angles for the entire stride, and compared between the PRE and POST conditions. The POST feedback trials showed an average 27.45% reduction of the 95%CI range for eight out of nine joint angles on day one, and an average 24.73% for five out of nine joint angles on day two, compared to POST. The results indicate a real-time feedback tool improves the consistency in marker placement for novice users. PMID- 28910658 TI - Postural regulatory strategies during quiet sitting are affected in individuals with thoracic spinal cord injury. AB - Thoracic spinal cord injury (SCI) can have significant negative consequences, which can affect the ability to maintain unsupported sitting. The objectives of this study were to compare postural control of individuals with high- and low thoracic SCI to able-bodied people and evaluate the effects of upper-limb support on postural control during quiet sitting. Twenty-five individuals were recruited into: (a) high-thoracic SCI; (b) low-thoracic SCI; and (c) able-body subgroups. Participants were seated and asked to maintain a steady balance in the following postures: (1) both hands resting on thighs; (2) both arms crossed over the chest; and (3) both arms extended. Center of pressure (COP) fluctuations were evaluated to compare postural performance between groups and different postures. Results showed that individuals with high- and low-thoracic SCI swayed more compared to the able-bodied group regardless of upper-limb support. No differences between the two SCI groups were observed, but the neurological level of injury was correlated to postural performance implying that those with higher injuries swayed more and faster. Unsupported sitting was more unstable in comparison to supported sitting posture, especially in the anterior-posterior direction. The velocity of postural sway was not different between groups, but the results suggest that postural regulation had unique effect during different postures in different groups. These results imply reduced postural stability after thoracic SCI. Overall, the way individuals with high-thoracic SCI achieved stability was different from that of individuals with low-thoracic SCI, suggesting different postural regulation strategies. PMID- 28910659 TI - Effects of triphenyltin on reproduction in Japanese medaka (Oryzias latipes) across two generations. AB - Triphenyltin (TPT) is an organotin compound used in marine anti-fouling coatings to prevent the attachment and growth of marine organisms, and it has negative effects on aquatic organisms. TPT is still detected at low concentrations, although its use has been prohibited at least in the European Community and is restricted in Japan as well. Studies using Japanese medaka (Oryzias latipes) indicate that TPT has the potential to inhibit reproduction. Although TPT is detected in many aquatic ecosystems, the multi-generational impact of TPT remains unknown. We investigated the two-generational effects of TPT on Japanese medaka and examined the relationships of several such effects between the F0 and F1 generations. Suppression of fecundity was observed in both generations, and fertility and growth were inhibited in the F1 generation. Moreover, delayed hatching and lower hatchability were observed in F1 embryos. Importantly, the value of the lowest observed effect concentration (LOEC) for these influences in F1 was lower than that in F0: that is, the LOEC values of fecundity and mortality were 3.2MUg/L in the F0 generation and 1.0MUg/L in the F1 generation. Fertility was not affected by TPT in F0, whereas it was significantly suppressed in the 1.0MUg/L-exposure group of the F1 generation. Our results provide the first evidence of the effects of TPT on reproduction in a teleost fish across two generations, highlighting the concern that TPT could affect reproduction and mortality at decreasing concentrations in temporally overlapping generations. PMID- 28910660 TI - Toxic effects of Pb2+ entering sperm through Ca2+ channels in the freshwater crab Sinopotamon henanense. AB - Lead (Pb) is a heavy metal that can damage animal sperm. To study the effects of Pb on calcium homeostasis and calcium channel in the sperm of freshwater crab Sinopotamon henanense, the induction of acrosome reaction (AR) and acrosin activity were investigated when crabs were exposed to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8mg/L) for 3, 5 and 7 d separately. Fluorescent probe Fluo-3/AM was loaded into the sperm, and [Ca2+] in the sperm was measured by fluorescence microscopy and using microplate reader. The calmodulin (CaM) concentration was measured by ELISA method. Verapamil (VRP), a calcium channel blocker, was used to evaluate whether Pb can enter the sperm through calcium channels leading to sperm damage. After sperm were exposed at 50MUg/L VRP, 100MUg/L Pb, 50MUg/L VRP+100MUg/L Pb, 1000MUg/L Pb and 50MUg/L VRP+1000MUg/L Pb for 1h in vitro,sperm quality parameters (sperm survival and sperm DNA integrity) and levels of parameters indicating oxidative stress (protein carbonylation [PCO] and malondialdehyde [MDA]) were measured. Our data showed that Pb reduced the induction of acrosome reaction (AR), down-regulated the acrosin activity, decreased the intracellular concentration of Ca2+ and elevated CaM concentration. Compared to controls, Pb alone induced significant stress, as reflected by decreasing sperm survival and sperm DNA integrity, and increasing PCO and MDA contents. In the presence of VRP, 100MUg/L Pb-induced stresses were reduced, all the measured parameters in the sperm exposed at 100MUg/L Pb returned to control levels. Our results indicate that Pb enters the sperm of the crab S. henanense through calcium channels, the inhibition of which blocks Pb-induced stresses such as sperm quality decline and oxidative damage. PMID- 28910661 TI - Describing the holistic toxicokinetics of hepatotoxic Chinese herbal medicines by a novel integrated strategy: Dioscorea bulbifera rhizome as a case study. AB - It is vital to monitor the holistic toxicokinetics of toxic Chinese herbal medicines (CHMs) for safety. Although an integrated strategy based on the area under the curve (AUC) has been proposed to characterize the pharmacokinetic/toxicokinetic properties of CHMs, improvement is still needed. This study attempted to use 50% inhibitory concentration (IC50) as weighting coefficient to investigate holistic toxicokinetics of the major diosbulbins i.e. diosbulbin A (DA), diosbulbin B (DB), and diosbulbin C (DC) after oral administration of Dioscorea bulbifera rhizome (DBR) extract. Firstly, the cytotoxicities of the three diosbulbins on human hepatic L02 cells were evaluated and the IC50 values were calculated. Then, integrated toxicokinetics of multiple diosbulbins based on AUC and IC50 were determined. Finally, correlations between integrated plasma concentrations and hepatic injury biomarkers including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bile acid (TBA) were analyzed. As a result, integrated plasma concentrations were correlated well with TBA and the correlation between TBA and IC50-weighting integrated plasma concentrations was better than that of AUC weighting integrated plasma concentrations. In conclusion, the newly developed IC50-weighting method is expected to generate more reasonable integrated toxicokinetic parameters, which will help to guide the safe usage of DBR in clinical settings. PMID- 28910662 TI - Effect of a clinical skills refresher course on the clinical performance, anxiety and self-efficacy of the final year undergraduate nursing students. AB - Although the final year of nursing undergraduate programs that focus on clinical education are planned to prepare nursing students to better transition to the real world of health care service; evidence has shown that this program is not sufficient to reach this end goal. This controlled trial study was to investigate the effectiveness of a basic clinical skills refresher course for nursing students before entering the internship program. The sample consisted of 160 undergraduate nursing students assigned into two groups. The intervention was a three-day refresher course directed by nurse instructors for intervention group focused on 10 basic nursing procedures in the clinical skill lab. The control group did not receive any intervention. The students' anxiety, clinical self- efficacy and clinical skills practice were measured before and after intervention in both groups. The results indicated that the students who took part in the refresher course experienced lower anxiety levels, higher levels of clinical self efficacy, and have better clinical skills during their internships. The undergraduate nursing curriculum can be strengthened by the basic clinical skills refresher course. This refresher course can bridge the theory - practice gap and provide a better transition from the student to nurse role. PMID- 28910663 TI - Strategies for overcoming tropical disease by ruthenium complexes with purine analog: Application against Leishmania spp. and Trypanosoma cruzi. AB - Tropical diseases currently constitute a major health problem and thus a challenge in the field of drug discovery. The current treatments show serious disadvantages due to cost, toxicity, long therapy duration and resistance, and the use of metal complexes as chemotherapeutic agents against these ailments appears to be a very attractive alternative. Herein, we describe three newly synthesized ruthenium complexes with a bioactive molecule, the purine analogue 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp): cis,fac [RuCl2(dmso)3(tmtp)] (1), mer-[RuCl3(dmso)(H2O)(tmtp)].2H2O (2) and fac,cis [RuCl3(H2O)(tmtp)2] (3). Their structures were characterized using X-ray and spectroscopic methods (IR, NMR or EPR). The stability of the synthesized complexes 1-3 in various buffered solutions (pH=3-7.4) was monitored using conventional and stopped-flow techniques. The in vitro antiproliferative activity of all ruthenium complexes against promastigote forms of Leishmania spp. (L. infantum, L. braziliensis, and L. donovani) and epimastigote forms of Trypanosoma cruzi was investigated. Notably, the results showed that the activity of 1 against L. brasiliensis was more than three-fold higher than that of glucantime, and 1 showed no appreciable toxicity towards J774.2 macrophages. Additionally, 2 displayed even 141-fold lower toxicity against host cells than glucantime, demonstrating significantly higher selectivity than the reference drug. Therefore, 1 and 2 appear to be excellent candidates for further development as potential drugs for the effective treatment of leishmaniasis and Chagas disease. All novel complexes were also shown to be potent inhibitors of Fe-SOD in the studied species, while their effects on human CuZn-SOD were very low. PMID- 28910664 TI - The analysis of 132 novel psychoactive substances in human hair using a single step extraction by tandem LC/MS. AB - A rapid LC-MS/MS method for the targeted screening of 132 NPS in hair is described. Drugs include cathinones and synthetic cannabinoids, as well as amphetamine-type stimulants, piperazines and other hallucinogenic compounds. This method utilizes hair pulverization in acidified methanol followed by analysis using liquid chromatography coupled with tandem MS. The limit of detection varied from 0.001 to 0.1ng/mg hair among the various analytes. The method was validated in terms of sensitivity, selectivity, repeatability and stability. The limit of reporting was set at 0.1ng/mg of hair. The method was successfully applied to 23 medico-legal cases where NPS were detected in blood or where NPS use was suspected. The identified NPS included acetyl fentanyl, 25C-NBOMe, MDPV, PB-22 and AB-FUBINACA, allowing hair to be used where historical or retrospective information on use of NPS is sought. This technique has proven to be efficient for the one step extraction from hair of different classes of NPS in routine toxicological investigations; from unstable and volatile compounds, such as most of the cathinones, to hydrophobic compounds such as synthetic cannabinoids. PMID- 28910665 TI - Influence of the axial rotation angle on tool mark striations. AB - A tool's axial rotation influences the geometric properties of a tool mark. The larger the axial rotation angle, the larger the compression of structural details like striations. This complicates comparing tool marks at different axial rotations. Using chisels, tool marks were made from 0 degrees to 75 degrees axial rotation and compared using an automated approach Baiker et al. [10]. In addition, a 3D topographic surface of a chisel was obtained to generate virtual tool marks and to test whether the axial rotation angle of a mark could be predicted. After examination of the tool mark and chisel data-sets it was observed that marks lose information with increasing rotation due to the change in relative distance between geometrical details on the tool and the disappearance of smaller details. The similarity and repeatability were high for comparisons between marks with no difference in axial rotation, but decreasing with increased rotation angle from 0 degrees to 75 degrees . With an increasing difference in the rotation angles, the tool marks had to be corrected to account for the different compression factors between them. For compression up to 7.5%, this was obtained automatically by the tool mark alignment method. For larger compression, manually re-sizing the marks to the uncompressed widths at 0 degrees rotation before the alignment was found suitable for successfully comparing even large differences in axial rotation. The similarity and repeatability were decreasing however, with increasing degree of re-sizing. The quality was assessed by determining the similarity at different detail levels within a tool mark. With an axial rotation up to 75 degrees , tool marks were found to reliably represent structural details down to 100MUm. The similarity of structural details below 100MUm was dependent on the angle, with the highest similarity at small rotation angles and the lowest similarity at large rotation angles. Filtering to remove the details below 100MUm lead to consistently higher similarity between tool marks at all angles and allowed for a comparison of marks up to 75 degrees axial rotation. Finally, generated virtual tool mark profiles with an axial rotation were compared to experimental tool marks. The similarity between virtual and experimental tool marks remained high up to 60 degrees rotation after which it decreased due to the loss in quality in both marks. Predicting the rotation angle is possible under certain conditions up to 45 degrees rotation with an accuracy of 2.667+/-0.577 degrees rotation. PMID- 28910666 TI - Nonlinear elastic multi-path reciprocal method for damage localisation in composite materials. AB - Nonlinear ultrasonic techniques rely on the measurement of nonlinear elastic effects caused by the interaction of ultrasonic waves with the material damage, and have shown high sensitivity to detect micro-cracks and defects in the early stages. This paper presents a nonlinear ultrasonic technique, here named nonlinear elastic multi-path reciprocal method, for the identification and localisation of micro-damage in composite laminates. In the proposed methodology, a sparse array of surface bonded ultrasonic transducers is used to measure the second harmonic elastic response associated with the material flaw. A reciprocal relationship of nonlinear elastic parameters evaluated from multiple transmitter receiver pairs is then applied to locate the micro-damage. Experimental results on a damaged composite panel revealed that an accurate damage localisation was obtained using the normalised second order nonlinear parameter with a high signal to-noise-ratio (~11.2dB), whilst the use of bicoherence coefficient provided high localisation accuracy with a lower signal-to-noise-ratio (~1.8dB). The maximum error between the calculated and the real damage location was nearly 13mm. Unlike traditional linear ultrasonic techniques, the proposed nonlinear elastic multi path reciprocal method allows detecting material damage on composite materials without a priori knowledge of the ultrasonic wave velocity nor a baseline with the undamaged component. PMID- 28910667 TI - Properties of afterdischarges from electrical stimulation in patients with epilepsy. AB - OBJECTIVE: To investigate the properties of afterdischarges (ADs) from intracerebral electrical stimulation (ES) in patients with epilepsy who underwent stereotactic electroencephalography (SEEG) and determine the relationship between epileptogenic zone (EZ) or irritative zone (IZ) and ADs. METHODS: We retrospectively analyzed 10 patients with intractable epilepsy who underwent SEEG. ESs were delivered following the given parameters: bipolar, biphasic, 50Hz, 0.2ms pulse duration, 0.5-10mA. The properties of ADs were documented, including their incidence, location, threshold, morphology and evolution. RESULTS: A total of 213 ADs (5%) were elicited by 4701 trains of ES. Stimulation through contacts implanted in the hippocampus (59%) generally evoked more ADs than contacts elsewhere (19%). AD thresholds for hippocampal stimulation were significantly lower than those for stimulation in grey matter. Polyspikes (58%) were the most common AD morphology. Evolution occurred more commonly with sequential spikes (47%) than with other AD morphologies (14%). There was no significant correlation between the location of ADs and EZ. However, ADs were significantly more frequently localized to IZ than areas outside IZ (P<0.05). CONCLUSIONS: There seemed to be a lack of correlation between the location of ADs and EZ. However, ADs were more likely to be elicited in IZ. PMID- 28910668 TI - Specific contributions of basal ganglia and cerebellum to the neural tracking of rhythm. AB - How specific brain networks track rhythmic sensory input over time remains a challenge in neuroimaging work. Here we show that subcortical areas, namely the basal ganglia and the cerebellum, specifically contribute to the neural tracking of rhythm. We tested patients with focal lesions in either of these areas and healthy controls by means of electroencephalography (EEG) while they listened to rhythmic sequences known to induce selective neural tracking at a frequency corresponding to the most-often perceived pulse-like beat. Both patients and controls displayed neural responses to the rhythmic sequences. However, these response patterns were different across groups, with patients showing reduced tracking at beat frequency, especially for the more challenging rhythms. In the cerebellar patients, this effect was specific to the rhythm played at a fast tempo, which places high demands on the temporally precise encoding of events. In contrast, basal ganglia patients showed more heterogeneous responses at beat frequency specifically for the most complex rhythm, which requires more internal generation of the beat. These findings provide electrophysiological evidence that these subcortical structures selectively shape the neural representation of rhythm. Moreover, they suggest that the processing of rhythmic auditory input relies on an extended cortico-subcortico-cortical functional network providing specific timing and entrainment sensitivities. PMID- 28910669 TI - Peri-hand space representation in the absence of a hand - Evidence from congenital one-handers. PMID- 28910670 TI - Mental imagery of gravitational motion. AB - There is considerable evidence that gravitational acceleration is taken into account in the interaction with falling targets through an internal model of Earth gravity. Here we asked whether this internal model is accessed also when target motion is imagined rather than real. In the main experiments, naive participants grasped an imaginary ball, threw it against the ceiling, and caught it on rebound. In different blocks of trials, they had to imagine that the ball moved under terrestrial gravity (1g condition) or under microgravity (0g) as during a space flight. We measured the speed and timing of the throwing and catching actions, and plotted ball flight duration versus throwing speed. Best fitting duration-speed curves estimate the laws of ball motion implicit in the participant's performance. Surprisingly, we found duration-speed curves compatible with 0g for both the imaginary 0g condition and the imaginary 1g condition, despite the familiarity with Earth gravity effects and the added realism of performing the throwing and catching actions. In a control experiment, naive participants were asked to throw the imaginary ball vertically upwards at different heights, without hitting the ceiling, and to catch it on its way down. All participants overestimated ball flight durations relative to the durations predicted by the effects of Earth gravity. Overall, the results indicate that mental imagery of motion does not have access to the internal model of Earth gravity, but resorts to a simulation of visual motion. Because visual processing of accelerating/decelerating motion is poor, visual imagery of motion at constant speed or slowly varying speed appears to be the preferred mode to perform the tasks. PMID- 28910671 TI - Delayed effects of accelerated heavy ions on the induction of HPRT mutations in V79 hamster cells. AB - Fundamental research on the harmful effects of ionizing radiation on living cells continues to be of great interest. Recently, priority has been given to the study of high-charge and high-energy (HZE) ions that comprise a substantial part of the galactic cosmic ray (GCR) spectra that would be encountered during long-term space flights. Moreover, predictions of the delayed genetic effects of high linear energy transfer (LET) exposure is becoming more important as heavy ion therapy use is increasing. This work focuses mainly on the basic research on the delayed effects of HZE ions on V79 Chinese hamster cells, with emphasis on the induction of HPRT mutations after prolonged expression times (ET). The research was conducted under various irradiation conditions with accelerated ions 18O (E=35.2MeV/n), 20Ne (E=47.7MeV/n and 51.8MeV/n), and 11B (E=32.4MeV/n), with LET in the range from 49 to 149 keV/MUm and with 60Co gamma-rays. The HPRT mutant fractions (MF) were detected in irradiated cells in regular intervals during every cell culture recultivation (every 3days) up to approximately 40days (70-80 generations) after irradiation. The MF maximum was reached at different ET depending on ionizing radiation characteristics. The position of the maximum was shifting towards longer ET with increasing LET. We speculate that the delayed mutations are created de novo and that they are the manifestation of genomic instability. Although the exact mechanisms involved in genomic instability initiation are yet to be identified, we hypothesize that differences in induction of delayed mutations by radiations with various LET values are related to variations in energy deposition along the particle track. A dose dependence of mutation yield is discussed as well. PMID- 28910672 TI - Brief report: A network analysis of self-cutting risk among late adolescent girls exposed to dating violence. AB - Adolescent self-directed violence (SDV) is a major public health concern. Adolescent girls exposed to dating violence (DV) are a particularly vulnerable group. Numerous studies have examined the number and type of SDV risk factors, but few examined global patterns of relationships among them. Exploring global patterns of risk is crucial to developing targeted prevention efforts. In this study we applied a network model to identify risk patterns for a common form of SDV, self-cutting, among American adolescent girls (N = 109) with history of DV. Risk factor networks were compared among girls who did/did not endorse lifetime self-cutting. Girls with a history of self-cutting (19%) had a risk factor network characterized by a higher number of associations than girls who did not (test statistic = 0.142; 95% CI = 02-.03). For these girls, the experience of one risk factor is more likely to co-occur with multiple others, thereby potentially compounding effects and unwanted consequences. PMID- 28910673 TI - A randomized controlled evaluation of a secondary school mindfulness program for early adolescents: Do we have the recipe right yet? AB - OBJECTIVE: Mindfulness is being promoted in schools as a prevention program despite a current small evidence base. The aim of this research was to conduct a rigorous evaluation of the .b ("Dot be") mindfulness curriculum, with or without parental involvement, compared to a control condition. METHOD: In a randomized controlled design, students (Mage 13.44, SD 0.33; 45.4% female) across a broad range of socioeconomic indicators received the nine lesson curriculum delivered by an external facilitator with (N = 191) or without (N = 186) parental involvement, or were allocated to a usual curriculum control group (N = 178). Self-report outcome measures were anxiety, depression, weight/shape concerns, wellbeing and mindfulness. RESULTS: There were no differences in outcomes between any of the three groups at post-intervention, six or twelve month follow-up. Between-group effect sizes (Cohen's d) across the variables ranged from 0.002 to 0.37. A wide range of moderators were examined but none impacted outcome. CONCLUSIONS: Further research is required to identify the optimal age, content and length of mindfulness programs for adolescents in universal prevention settings. TRIAL REGISTRATION: ACTRN12615001052527. PMID- 28910674 TI - The inhibitory activity of HL-7 and HL-10 peptide from scorpion venom (Hemiscorpius lepturus) on angiotensin converting enzyme: Kinetic and docking study. AB - The hypertension is one of the highest risk factors for stroke, myocardial infarction, vascular disease and chronic kidney disease. Angiotensin converting enzyme (ACE) has an important role in the physiological regulation of cardiovascular system. ACE inhibition is a key purpose for hypertension treatment. In this study, two peptides named HL-7 with the sequence of YLYELAR (MW: 927.07Da) and HL-10 with the sequence of AFPYYGHHLG (MW: 1161.28Da) were identified from scorpion venom of H. lepturus. The inhibitory activity of HL-7 and HL-10 was examined on rabbit ACE. The inhibition mechanisms were assayed by kinetic and docking studies. The IC50 values for ACE inhibition of HL-7 and HL-10 were 9.37uM and 17.22uM, respectively. Lineweaver-Burk plots showed that two peptides inhibited rabbit ACE with competitive manner. The molecular docking conformed experimental results and showed that the two peptides interacted with N domain and C-domain active sites. Also, docking study revealed that the two peptides can form hydrogen and hydrophobic bonds at their binding sites. Both peptides had higher affinity to N-domain. Our results showed that HL-7 exhibited more strong interactions with amino acids at active site. It seems that HL-10 peptide could occupy more space, thereby inhibiting the substrate entrance to active site. PMID- 28910675 TI - Equine chorionic gonadotropin administration after insemination affects luteal function and pregnancy establishment in postpartum anestrous beef cows. AB - Two experiments were conducted with the aim of determining the effect of equine chorionic gonadotropin (eCG) administration on day 14 after insemination on ovarian response and pregnancy establishment in postpartum anestrous beef cows. In both experiments, cows were subjected to a progesterone- and estradiol-based treatment for fixed-time artificial insemination (FTAI) and were randomly allocated into 4 groups to receive or not receive eCG (400 IU) at the time of device removal and/or at 14 d after FTAI. In experiment 1, from day 14 to 22, daily ultrasonographic determinations were performed to monitor ovarian dynamics, and blood was collected to determine hormone concentrations in 60 cows. In experiment 2, confirmation of pregnancy was performed at 30 and 60 d after FTAI in 1,060 anestrous cows assigned to the same experimental design. Cows that received eCG on day 14 after FTAI showed increases in corpus luteum area (P < 0.01), follicle diameter (P < 0.05), serum progesterone concentrations (P < 0.01), and estradiol-17beta concentrations (P < 0.01), compared with cows that did not receive eCG on day 14. Pregnancy rate on day 30 was greater in those cows that received both eCG treatments (ie, at device removal and 14 d after insemination) than in those that did not receive eCG treatment (P < 0.05). In conclusion, eCG administered on day 14 after FTAI increases serum progesterone concentrations during the critical period of pregnancy in anestrous cows, and this second eCG treatment seems to have a positive effect on achieving pregnancy. PMID- 28910677 TI - The deepest personal truth - Why the ability to detect it is useful for nurses. PMID- 28910676 TI - Porous NH2-MIL-125 as an efficient nano-platform for drug delivery, imaging, and ROS therapy utilized Low-Intensity Visible light exposure system. AB - Metal-organic frameworks are a novel class of organic-inorganic hybrid polymer with potential applications in bioimaging, drug delivery, and ROS therapy. NH2 MIL-125, which is a titanium-based metal organic framework with a large surface area of 1540m2/g, was synthesized using a hydrothermal method. The material was characterized by powder X-ray diffreaction (PXRD), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM), and N2 isotherm analyses. The size of the polymer was reduced to the nanoscale using a high-frequency sonication process. PEGylation was carried out to improve the stability and bioavailability of the NMOF. The as-synthesized nano-NH2-MIL-125/PEG (NMOF/PEG) exhibited good biocompatibility over the (Cancer) MCF-7 and (Normal) COS-7 cell line. The interaction of NMOF/PEG with the breast cancer cell line (MCF-7) was examined by BIO-TEM analysis and laser confocal imaging. 2',7'-dichlorofluorescin diacetate (DCFDA) analysis confirmed that NMOF/PEG produced free radicals inside the cancer cell line (MCF-7) upon visible light irradiation. NMOF/PEG absorbed a large amount of DOX (20wt.% of DOX) and showed pH, and photosensitive release. This controlled drug delivery was attributed to the presence of NH2, Ti group in MOF and a hydroxyl group in PEG. This combination of chemo- and ROS-therapy showed excellent efficiency in killing cancer MCF-7 cells. PMID- 28910678 TI - Colorimetric aptasensor for the detection of Salmonella enterica serovar typhimurium using ZnFe2O4-reduced graphene oxide nanostructures as an effective peroxidase mimetics. AB - A new colorimetric aptasensor platform was fabricated to detect Salmonella enterica serovar typhimurium based on the peroxidase-like activity of ZnFe2O4 reduced graphene oxide (ZnFe2O4/rGO) nanostructures. The synthesized ZnFe2O4/rGO can catalytically oxidize 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 and generate a typical blue product, which was detected by micro-reader at 652nm. Therefore, ZnFe2O4/rGO was conjugated with aptamer to act as the signal probe. Biotin modified aptamer was immobilized onto the micro-plate to act as the capture probe. In the presence of target, a "sandwich-type" complex of aptamer (on micro-plate)-target-aptamer-ZnFe2O4/rGO complexes was formed through specific recognition of aptamers and corresponding target. The limit of detection was 11cfu/mL and the detection range was 11 to 1.10*105cfu/mL of S. typhimurium in buffer solution. Actual samples analysis indicated that this colorimetric aptasensor produced results consistent with plate-counting analysis. The developed method was simple and sensitive, which may pave the way for the detection of other pathogenic bacteria with suitable aptamers. PMID- 28910679 TI - The role of the B lymphocytes in endometriosis: A systematic review. AB - The physiopathology of endometriosis is not completely understood and its progression is associated with a local and systemic inflammatory reaction. It is important to clarify the potential role of the immune system to better understand its implication in the pathogenesis of endometriosis, which includes the study of the role of B cells and antibodies. The aim of this study was to review the literature about the role of B lymphocytes in endometriosis. A search for "endometriosis", "B cells" and "B lymphocytes" in databases resulted in 140 citations; after applying inclusion and exclusion criteria, a total of 22 studies were assessed. The analyzed samples in the studies varied and different markers and techniques were used by the authors to evaluate the direct or indirect role of B lymphocytes in endometriosis. Most studies demonstrated increased number and/or activation of B cells while seven studies found no difference and two studies showed decreased number of B cells. Increased B lymphocytes and excessive production of autoantibodies in endometriosis have been described in the literature, but their role in the development of the disease is not well understood. Moreover, the association of these factors with clinical symptoms, location and severity of the disease has not been investigated. Further studies are necessary to clarify the role of B cells in the development of endometriosis and propose new therapeutic strategies such as the use of drugs that target these cells. PMID- 28910680 TI - CT and MRI features of pseudoaneurysms of the mitral-aortic intervalvular fibrosa. AB - OBJECTIVE: To describe the CT and MR features of pseudoaneurysms of the mitral aortic intervalvular fibrosa (PMAIVF). MATERIALS AND METHODS: This retrospective study included 9 patients with a diagnosis of PMAIVF who had CT or MRI within 3months of echocardiography. Echocardiography images were reviewed by a cardiologist and CT and MRI images were reviewed by two experienced cardiothoracic radiologists. RESULTS: Recognizable imaging features of PMAIVFs were communication with the Left ventricular outflow tract, location between the anterior leaflet of the mitral valve and the aortic valve, systolic expansion and diastolic collapse. CONCLUSION: CT and MRI show characteristic appearances of PMAIVFs and are complementary to echocardiography. PMID- 28910681 TI - The imaging spectrum of posterior reversible encephalopathy syndrome: A pictorial review. AB - Posterior reversible encephalopathy syndrome (PRES) is characterized by the acute onset of neurologic symptoms (headache, altered mental status, visual changes, seizures) with accompanying vasogenic edema on brain imaging. Risk factors for PRES include infection, uremia, malignancy, autoimmune disorders, the peripartum state and hypertension. PRES is classically described as being posterior (i.e. parieto-occipital) but radiologic variants are increasingly recognized. This pictorial review demonstrates the heterogeneity of the different radiologic presentations of PRES in reference to lesion distribution, hemorrhage, diffusion restriction, contrast enhancement, and other associated findings. PMID- 28910682 TI - Overcoming the drawbacks of plastic strain estimation based on KAM. AB - Plastic strain estimation using electron backscatter diffraction (EBSD) based on kernel average misorientation (KAM) is affected by random orientation measurement error, EBSD step length, choice of kernel and average grain size. These sensitivities complicate reproducibility of results between labs, but it is shown in this work how these drawbacks can be overcome. The modifications to KAM were verified against a similar misorientation metric based on grain orientation spread (GOS), which does not show sensitivity to these factors. Both metrics were used in parallel to estimate the plastic strain distribution in Alloy 690 heat affected zones from component mockups, and showed the same results where the grain size was correctly compensated for. PMID- 28910683 TI - The coordination of shoulder girdle muscles during repetitive arm movements at either slow or fast pace among women with or without neck-shoulder pain. AB - PURPOSE: The aim of this study was to evaluate the coordination of the shoulder girdle muscles among subjects with or without neck-shoulder pain performing repetitive arm movement at either a slow or fast pace. METHODS: Thirty female adults were allocated to one of two groups-healthy controls or cases with neck shoulder pain. Surface electromyography (sEMG) signals from the clavicular, acromial, middle and lower trapezius portions and the serratus anterior muscles were recorded during a task performed for 20min at a slow pace and 20min at a fast pace. The root mean square (RMS), relative rest time (RRT) and normalised mutual information (NMI, an index of functional connectivity between two muscles in a pair) were computed. RESULTS: No significant differences on RMS, RRT and NMI were found between groups. For both groups, the fast movement pace resulted in increased levels of RMS, lower degrees of RRT and higher NMI compared to the slow pace. No interaction between group and movement pace was found. CONCLUSIONS: This study highlights the change in sEMG activity of muscles to meet the demands of performing a task at fast movement pace. The fast pace imposed a higher muscle demand evidenced by increased sEMG amplitude, low degree of muscle rest and increased functional connectivity for subjects in both the case and control groups. No indication of impaired sEMG activity was found in individuals with neck-shoulder pain. PMID- 28910684 TI - The effect of ambient light condition on road traffic collisions involving pedestrians on pedestrian crossings. AB - Previous research suggests darkness increases the risk of a collision involving a pedestrian and the severity of any injury suffered. Pedestrian crossings are intended to make it safer to cross the road, but it is not clear whether they are effective at doing this after-dark, compared with during daylight. Biannual clock changes resulting from transitions to and from daylight saving time were used to compare RTCs in the UK during daylight and darkness but at the same time of day, thus controlling for potential influences on RTC numbers not related to the ambient light condition. Odds ratios and regression discontinuity analysis suggested there was a significantly greater risk of a pedestrian RTC at a crossing after-dark than during daylight. Results also suggested the risk of an RTC after-dark was greater at a pedestrian crossing than at a location at least 50m away from a crossing. Whilst these results show the increased danger to pedestrians using a designated crossing after-dark, this increased risk is not due to a lack of lighting at these locations as 98% of RTCs at pedestrian crossings after-dark were lit by road lighting. This raises questions about the adequacy and effectiveness of the lighting used at pedestrian crossings. PMID- 28910685 TI - The deposition of colloidal particles from a sessile drop of a volatile suspension subject to particle adsorption and coagulation. AB - Electrical double layer and van der Waals (DLVO) forces are known to determine the morphology of the deposit of colloidal particles following the evaporation of the carrier liquid. It is assumed that the adsorption of particles to the solid substrate and their coagulation in the liquid are the mechanisms connecting DLVO forces to the morphology of the deposit. We use theory to test this assertion. We model the deposition of particles from a volatile drop while accounting for the contribution of adhesion and coagulation. The rate of both mechanisms is connected to DLVO forces via the interaction-force boundary layer and the Smoluchowski theorems, respectively. We present analytical solutions for the morphology of the deposit, accounting for particle adsorption and pair-limited coagulation, and a corresponding numerical analysis for the case where particle adhesion and coagulation are concurrent. We conclude that larger aggregates of particles are found near the edge of the drop at the expense of the smaller ones in the absence of adhesion. The adhesion of particles to the substrate smears the deposit, rendering large aggregates to appear near the center of the drop. The analysis is in agreement with a previous experiment when accounting for the corresponding DLVO forces. PMID- 28910686 TI - A simple and environment-friendly approach for synthesizing macroporous polymers from aqueous foams. AB - We propose a facile and environment-friendly approach for the preparation of macroporous polyacrylamide (PAM) via thermal-initiated polymerization of aqueous foams that are stabilized by surface-modified silica nanoparticles. Cetyltrimethylammonium bromide (CTAB) is used to delicately adjust the surface amphiphilicity of silica to stabilize aqueous foams. The air bubble size and size distribution is affected by the wettability of silica particles, solid content and air volume fraction in the foams. The morphology of macroporous polymers is observed by a scanning electron microscope (SEM). The pore and pore throat size can be tailored effectively by varying the silica content and air volume fraction. A high porosity of 83% is achieved when the air volume fraction of the aqueous foam is 65%. PAM hydrogels obtained via polymerizing aqueous foams show pronounced advantage over the ones prepared from oil-in-water (O/W) emulsions in wastewater treatment because of their unique pore structure. This strategy would also be extended to prepare other macroporous polymers with well-defined pore structures. PMID- 28910687 TI - Somatic mosaicism in a severe haemophilia B family detected by allele specific PCR: An alert to the genetic diagnostic laboratories. PMID- 28910688 TI - Aortic fibromuscular dysplasia complicated by dissection: a case report and review of literature. AB - Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized. PMID- 28910689 TI - Numerical simulation of endoscopic magnetoacoustic tomography with magnetic induction. AB - Endoscopic magnetoacoustic tomography with magnetic induction (EMAT-MI) provides an interventional tool to detect the electrical conductivity distribution of a tubular structure with high spatial resolution. In this work, a preliminary study on the numerical simulation of EMAT-MI images was conducted. The magnetic excitation, generation and propagation of magnetoacoustic (MA) waves in the multi layered wall tissues were modeled and numerically simulated. The cross-sectional distribution of the acoustic source and electrical conductivity was recovered from the acoustic pressure series based on time-reversal. The validity has been demonstrated on two computer-generated phantoms. Results suggested that the conductivity boundaries can be clearly distinguished in the images of acoustic source or conductivity distribution which are highly consistent with the numerical simulation. The resolution of the MA signals excited by the Lorentz force divergence is closely related to the pulse width of the excitation current. Sparse measuring locations and limited-view scanning may reduce the image quality although higher SNR of the MA signals leads to better image reconstruction. PMID- 28910690 TI - Smoking cessation for substance misusers: A systematic review of qualitative studies on participant and provider beliefs and perceptions. AB - INTRODUCTION: Smoking prevalence among those in substance misuse treatment remains much higher than the general population, despite evidence for effective cessation interventions that do not negatively impact substance misuse outcomes. This systematic review summarises qualitative data on barriers and facilitators to smoking cessation for people in substance misuse treatment, participants' and providers' perceptions about effects of smoking cessation on substance misuse treatment, timing of intervention delivery and aspects of interventions perceived to be effective. METHODS: Systematic review of qualitative studies and thematic synthesis of published qualitative data. RESULTS: 10939 records and 132 full texts were screened. 22 papers reporting on 21 studies were included. Key themes identified were: strong relationships between smoking and other substance misuse; environmental influences; motivation; mental health; aspects of interventions perceived to be effective/ineffective; barriers and facilitators to intervention implementation; smoking bans/restrictions; and relationships with professionals. Many service users were motivated toward smoking cessation but were not offered support. Some felt interventions should be delivered after substance misuse treatment, whilst others felt concurrent/dual interventions would be beneficial, due to strong associations between smoking and other substances. Treatment providers felt they lacked training and resources for supporting smoking cessation, and were concerned about impact on substance misuse outcomes. CONCLUSIONS: Many substance misusers who also smoke are motivated to quit but perceive a lack of support from professionals. Additional training and resources are required to enable professionals to provide the support needed. More research is required to develop enhanced packages of care for this deprived group of smokers. PMID- 28910691 TI - Phylogeny and taxonomy of new and re-examined strains of Tubulinea (Amoebozoa). AB - Morphological and molecular characterizations of three newly isolated tubulinean strains and re-examination of five strains formerly considered representatives of Saccamoeba and one strain formerly considered as Trichamoeba resulted in (a) the determination of strain BA02, isolated from a dripping rock ledge in Skansbukta (Billefjorden, Svalbard), as a new representative of Ptolemeba bulliensis Brown et al., 2014; (b) identification of strain ATCC(r) 50249TM, deposited in the American Type Culture Collection as Trichamoeba, as the same species (P. bulliensis); (c) characterization of the new strain POHL into the Saccamoeba clade as a member closely related to S. lacustris; and (d) changing the generic residence of three strains formerly considered as representatives of Saccamoeba (strain PV67 to the P. bulliensis clade, and W187G and DP7 into the sister group of Ptolemeba noxubium Brown et al., 2014) whereas two other strains (MSED6, NTSHR) retain their original Saccamoeba clade position. Within the individual clades, the ultrastructure (especially the inner architecture of mitochondria) is congruent and thus of superior taxonomic value to that of light microscopic (morphometric) features. PMID- 28910692 TI - Conceptual achievement of 1GBq activity in a Plasma Focus driven system. AB - This is an approach to evaluate the radioisotope production by means of typical dense plasma focus devices. The production rate of the appropriate positron emitters, F-18, N-13 and O-15 has been studied. The beam-target mechanism was simulated by GEANT4 Monte Carlo tool using QGSP_BIC and QGSP_INCLXX physic models as comparison. The results for positron emitters have been evaluated by reported experimental data and found conformity between simulations and experimental reports that leads to using this code as a reliable tool in optimizing the DPF driven systems for achieving to 1GBq activity of produced radioisotope. PMID- 28910693 TI - Combining child social skills training with a parent early intervention program for inhibited preschool children. AB - BACKGROUND: Previous studies have demonstrated the efficacy of early intervention for anxiety in preschoolers through parent-education. The current study evaluated a six-session early intervention program for preschoolers at high risk of anxiety disorders in which a standard educational program for parents was supplemented by direct training of social skills to the children. METHODS: Seventy-two children aged 3-5 years were selected based on high behavioural inhibition levels and concurrently having a parent with high emotional distress. Families were randomly assigned to either the intervention group, which consisted of six parent education group sessions and six child social skills training sessions, or waitlist. After six months, families on waitlist were offered treatment consisting of parent-education only. RESULTS: Relative to waitlist, children in the combined condition showed significantly fewer clinician-rated anxiety disorders and diagnostic severity and maternal (but not paternal) reported anxiety symptoms and life interference at six months. Mothers also reported less overprotection. These gains were maintained at 12-month follow-up. Parent only education following waitlist produced similar improvements among children. Quasi experimental comparison between combined and parent-only interventions indicated greater reductions from combined intervention according to clinician reports, but no significant differences on maternal reports. CONCLUSIONS: Results suggest that this brief early intervention program for preschoolers with both parent and child components significantly reduces risk and disorder in vulnerable children. The inclusion of a child component might have the potential to increase effects over parent-only intervention. However, future support for this conclusion through long-term, randomised controlled trials is needed. PMID- 28910694 TI - An epidemiologic perspective on the stem cell hypothesis in human carcinogenesis. AB - BACKGROUND: Tomasetti and Vogelstein have hypothesized that the patterns of cancer incidence in various cells and tissues are highly correlated with the estimated lifetime number of stem cell divisions. The authors reviewed the risks in tissues of 17 types of cancer from the United States and 69 additional countries. Positive correlations were observed consistently between the tissue - specific cancer incidence and the estimated lifetime number of stem cell divisions. The authors concluded that approximately two-thirds of global cancer incidence may be attributed to random DNA replication errors. METHODS: An epidemiologic perspective is presented that may serve as a counterpoint in interpreting organ-specific cancer risks. The unifying nature of the Tomasetti/Vogelstein hypothesis must be viewed in the context of diverse and contrasting global trends and patterns of types and "causes" of cancers that are closely linked with economic development and cultural lifestyle practices. The presentation is organized by reviewing the global burden of cancer; concepts of causal inferences and counterfactual assumptions; multifactorial causes of hepatocellular carcinoma and a hierarchy of causes that varies internationally; tobacco carcinogenesis and the multiplex associations with 19 cancer sites and tissues; profile in contrasts in transit through the small and large intestine. OBSERVATIONS AND CONCLUSIONS: It is readily recognized that DNA replication errors and number of stem cell divisions may vary in individuals and populations due to external environmental genotoxic chemicals and biologic agents, and internal hormonal and metabolic factors. There is a striking contrast in the risk of adenocarcinoma in the small intestine with that in the large intestine. Tomasetti and Vogelstein indicated that the cumulative number of divisions of stem cells over a lifetime in normal epithelial mucosal cells from colorectal cancer patients was 4 time greater than in the epithelial tissue from patients with adenocarcinoma of the small intestine. Their conclusion would suggest a "seed" and "soil" interaction rather than exclusively the independence of either component. Namely, that the contrasting physiological, biochemical, microbial and immunological features in the lumen and on the mucosal surface of the large intestine, in contrast to that in the small intestine, would foster molecular genetic and epigenetic events that are advantageous to neoplasia in the large intestine. PMID- 28910695 TI - MDS classification is improving in an era of the WHO 2016 criteria of MDS: A population-based analysis among 9159 MDS patients diagnosed in the Netherlands. AB - BACKGROUND: Morphologic and cytogenetic assessments are required to characterize diagnostic and prognostic features of myelodysplastic syndromes (MDS). We assessed whether these assessments were performed among newly diagnosed MDS patients in the Netherlands. METHODS: MDS cases were retrieved from the nationwide Netherlands Cancer Registry (N=9159; period 2001-2014) and the regional PHAROS MDS registry (N=676; period 2008-2011). RESULTS: The proportion of unclassified MDS decreased from 58% in 2001 to 13% in 2014. Data from the more detailed PHAROS registry revealed that the degree of bone marrow dysplasia was only reported in ~30% of all evaluable bone marrow aspirates. Further, the International Prognostic Scoring System was undetermined in 55% of patients, primarily owing to unperformed cytogenetics in 46% of patients. CONCLUSION: The classification of MDS is improving in the Netherlands. Nevertheless, particular diagnostic and prognostic procedures that are essential for the diagnosis and subsequent treatment decision-making of MDS were not fully utilized in particular patient subsets. PMID- 28910696 TI - Tissue microstructure estimation using a deep network inspired by a dictionary based framework. AB - Diffusion magnetic resonance imaging (dMRI) captures the anisotropic pattern of water displacement in the neuronal tissue and allows noninvasive investigation of the complex tissue microstructure. A number of biophysical models have been proposed to relate the tissue organization with the observed diffusion signals, so that the tissue microstructure can be inferred. The Neurite Orientation Dispersion and Density Imaging (NODDI) model has been a popular choice and has been widely used for many neuroscientific studies. It models the diffusion signal with three compartments that are characterized by distinct diffusion properties, and the parameters in the model describe tissue microstructure. In NODDI, these parameters are estimated in a maximum likelihood framework, where the nonlinear model fitting is computationally intensive. Therefore, efforts have been made to develop efficient and accurate algorithms for NODDI microstructure estimation, which is still an open problem. In this work, we propose a deep network based approach that performs end-to-end estimation of NODDI microstructure, which is named Microstructure Estimation using a Deep Network (MEDN). MEDN comprises two cascaded stages and is motivated by the AMICO algorithm, where the NODDI microstructure estimation is formulated in a dictionary-based framework. The first stage computes the coefficients of the dictionary. It resembles the solution to a sparse reconstruction problem, where the iterative process in conventional estimation approaches is unfolded and truncated, and the weights are learned instead of predetermined by the dictionary. In the second stage, microstructure properties are computed from the output of the first stage, which resembles the weighted sum of normalized dictionary coefficients in AMICO, and the weights are also learned. Because spatial consistency of diffusion signals can be used to reduce the effect of noise, we also propose MEDN+, which is an extended version of MEDN. MEDN+ allows incorporation of neighborhood information by inserting a stage with learned weights before the MEDN structure, where the diffusion signals in the neighborhood of a voxel are processed. The weights in MEDN or MEDN+ are jointly learned from training samples that are acquired with diffusion gradients densely sampling the q-space. We performed MEDN and MEDN+ on brain dMRI scans, where two shells each with 30 gradient directions were used, and measured their accuracy with respect to the gold standard. Results demonstrate that the proposed networks outperform the competing methods. PMID- 28910697 TI - In vitro assessment of neurotoxicity and neuroinflammation of homemade MWCNTs. AB - Multi walled carbon nanotubes (MWCNTs) activate pathways involved in cytotoxicity, genotoxicity and inflammation. Inhaled MWCNTs are translocated to extra pulmonary organs and their hydrophobicity allows them to cross the blood brain barrier (BBB). Further exposure of central nervous system (CNS) occurs via olfactory neurons. Using differentiated SH-SY5Y, we studied the neurotoxicity and neuroinflammation of pristine and functionalised MWCNTs. ROS overproduction was dose- and time-dependent (P<0.01) and was related to mitochondrial impairment, DNA damage and decreased viability (P<0.05). Transcript levels of TNFalpha, IL 1beta and IL-6 increased, as confirmed by an ELISA test. Raman spectra were acquired to assess MWCNT-cells interactions. The almost superimposable pro oxidant activity of both CNTs could be imputable to excessive lengths with regard to the pristine MWCNTs and to the eroded surface, causing increased reactivity, with regard to functionalised MWCNTs. Considering the ease with which lightweight MWCNTs aerosolize and the increased production, the results underlined the potential onset of neurodegenerative diseases, due to unintentional MWCNT exposure. PMID- 28910698 TI - Temperature, inocula and substrate: Contrasting electroactive consortia, diversity and performance in microbial fuel cells. AB - The factors that affect microbial community assembly and its effects on the performance of bioelectrochemical systems are poorly understood. Sixteen microbial fuel cell (MFC) reactors were set up to test the importance of inoculum, temperature and substrate: Arctic soil versus wastewater as inoculum; warm (26.5 degrees C) versus cold (7.5 degrees C) temperature; and acetate versus wastewater as substrate. Substrate was the dominant factor in determining performance and diversity: unexpectedly the simple electrogenic substrate delivered a higher diversity than a complex wastewater. Furthermore, in acetate fed reactors, diversity did not correlate with performance, yet in wastewater fed ones it did, with greater diversity sustaining higher power densities and coulombic efficiencies. Temperature had only a minor effect on power density, (Q10: 2 and 1.2 for acetate and wastewater respectively): this is surprising given the well-known temperature sensitivity of anaerobic bioreactors. Reactors were able to operate at low temperature with real wastewater without the need for specialised inocula; it is speculated that MFC biofilms may have a self-heating effect. Importantly, the warm acetate fed reactors in this study did not act as direct model for cold wastewater fed systems. Application of this technology will encompass use of real wastewater at ambient temperatures. PMID- 28910699 TI - Intraspecific variation and influence of diet on the venom chemical profile of the Ectatomma brunneum Smith (Formicidae) ant evaluated by photoacoustic spectroscopy. AB - Studies of venomous animals have shown that environmental and genetic factors contribute to determining the chemical composition of venom. It is well known that external effects cause differences in the toxicity, concentration, and prey specificity of venom. However, the influence of different factors on the chemical profile of Hymenoptera venom remains little explored. In view of this, the aim of this study was to evaluate intraspecific differences and the influence of diet on the chemical profile of Ectatomma brunneum venom using Fourier transform infrared photoacoustic spectroscopy. For the study of intraspecific variation of the venom, foragers were collected at locations with different environmental conditions, such as urban, intermediate, woodland and monoculture sites. To investigate the influence of diet on the venom, two colonies were sampled in the same area and were maintained in the laboratory under controlled diet conditions and at room temperature. The mid-infrared absorption spectra obtained were interpreted using discriminant function analysis. The results showed significant differences among the chemical profiles of the venoms of individuals from different environments and individuals exposed to a controlled diet in the laboratory, suggesting that venom composition was determined not only by genetic traits inherent to the species, but also by exogenous factors. PMID- 28910700 TI - Characterization of light-dependent hydrogen production by new green microalga Parachlorella kessleri in various conditions. AB - Nowadays, hydrogen (H2) production by green microalgae seems to be a very perspective, as stocks of water and solar energy are practically inexhaustible and renewable. The aim of this study was the optimization of conditions (organic carbon sources and lighting regime), which can provide light-dependent H2 production by green microalga Parachlorella kessleri RA-002 newly isolated in Armenia. The results indicated that carbon sources and lighting regimes affected H2 production. In the presence of used carbon sources H2 production was observed, but the highest yield of H2 was obtained in the presence of acetate. It was 2 fold higher than the H2 yield determined in the presence of glucose. The increase of H2 production might be connected with the stimulation of H2-producing enzyme - [Fe]-hydrogenase synthesis. The data obtained show that acetate can be used as an effective carbon source in H2 production. H2 production by microalga (in the presence of acetate and glucose) was enhanced by 1.5-2.5-fold in comparison with continuously illuminated algal cells, when P. kessleri was illuminated during 24h, and then was moved in the darkness. H2 yield increase is possible due to hydrogenase activation and the creation of anaerobic conditions. This study was significant to find out available effective substrates and optimal lighting regime to provide with light-dependent H2 production by microalgae. PMID- 28910701 TI - Biomechanical analysis of lumbar decompression surgery in relation to degenerative changes in the lumbar spine - Validated finite element analysis. AB - BACKGROUND: There are no studies about the biomechanical analysis of lumbar decompression surgery in relation to degenerative changes of the lumbar spine. Therefore, the purpose of this study was to compare, by using finite element (FE) analysis, the biomechanical changes of the lumbar spine in terms of annulus stress and nucleus pressure after two different kinds of lumbar decompression surgery in relation to disc degenerative changes. METHODS: The validated intact and degenerated FE models (L2-5) were used in this study. In these two models, two different decompression surgical scenarios at L3-4, including conventional laminectomy (ConLa) and the spinous process osteotomy (SpinO), were simulated. Therefore, a total of six models were simulated. Under preloading, 7.5 Nm moments of flexion, extension, lateral bending, and torsion were imposed. In each model, the maximal von Mises stress on the annulus fibrosus and nucleus pressure at the index segment (L3-4) and adjacent segments (L2-3 and L4-5) were analyzed. RESULTS: The ConLa model and disc degeneration model demonstrated a larger annulus stress at the decompression level (L3-4) under all four moments than were seen in the SpinO model and healthy disc model, respectively. Therefore, the ConLa model with moderate disc degeneration showed the highest annulus stress at the decompression level (L3-4). However, the percent change of annulus stress at L3-4 from the intact model to the matched decompression model was less in the moderate disc degeneration model than in the healthy disc model. CONCLUSIONS: Although the ConLa model with moderate disc degeneration showed the highest annulus stress, the degenerative models would be less influenced by the decompression technique. PMID- 28910702 TI - Respiratory ATP cost and benefit of arbuscular mycorrhizal symbiosis with Nicotiana tabacum at different growth stages and under salinity. AB - Growth and maintenance partly depend on both respiration and ATP production during oxidative phosphorylation in leaves. Under stress, ATP is needed to maintain the accumulated biomass. ATP production mostly proceeds from the cytochrome oxidase pathway (COP), while respiration via the alternative oxidase pathway (AOP) may decrease the production of ATP per oxygen consumed, especially under phosphorus (P) limitation and salinity conditions. Symbiosis with arbuscular mycorrhizal (AM) fungi is reputed by their positive effect on plant growth under stress at mature stages of colonization; however, fungal colonization may decrease plant growth at early stages. Thus, the present research is based on the hypothesis that AM fungus colonization will increase both foliar respiration and ATP production at mature stages of plant growth while decreasing them both at early stages. We used the oxygen-isotope-fractionation technique to study the in vivo respiratory activities and ATP production of the COP and AOP in AM and non-AM (NM) tobacco plants grown under P-limiting and saline conditions in sand at different growth stages (14, 28 and 49days). Our results suggest that AM symbiosis represents an ATP cost detrimental for shoot growth at early stages, whilst it represents a benefit on ATP allowing for faster rates of growth at mature stages, even under salinity conditions. PMID- 28910703 TI - Long-term manganese-toxicity-induced alterations of physiology and leaf protein profiles in two Citrus species differing in manganese-tolerance. AB - Manganese (Mn)-intolerant 'Sour pummelo' (Citrus grandis) and Mn-tolerant 'Xuegan' (Citrus sinensis) seedlings were irrigated for 17 weeks with 2 (control) or 600MUM (Mn-toxicity or -excess) MnSO4. C. sinensis had higher Mn-tolerance than C. grandis, as indicated by the higher photosynthesis rates in Mn-excess C. sinensis leaves. Under Mn-toxicity, Mn levels were similar between C. sinensis and C. grandis roots, but lower in C. sinensis leaves than in C. grandis leaves. This might be responsible for C. sinensis Mn-tolerance. Using two-dimensional electrophoresis, we identified more differentially abundant proteins (DAPs) in Mn excess C. grandis than in Mn-excess C. sinensis leaves, which agrees with the higher Mn levels in Mn-excess C. grandis leaves. DAPs were mainly related to carbohydrate and energy metabolism, stress response, and protein and amino acid metabolism. DAPs involved in the cytoskeleton and signal transduction were found only in Mn-excess C. grandis leaves. We isolated more photosynthesis-related proteins with decreased abundances in Mn-excess C. grandis leaves than in Mn excess C. sinensis leaves, which might account for the larger decrease in photosynthesis rates in C. grandis leaves. The abundances of proteins involved in reactive oxygen species (ROS) scavenging and photorespiration were increased in Mn-excess C. grandis leaves, while only proteins involved in ROS detoxification were increased in Mn-excess C. sinensis leaves. This agrees with the increased requirement for dissipating the excess absorbed light energy, which was higher in Mn-excess C. grandis leaves than Mn-excess C. sinensis leaves because Mn-toxicity inhibited photosynthesis to a greater degree in C. grandis leaves. PMID- 28910704 TI - Class advantages and disadvantages are not so Black and White: intersectionality impacts rank and selves. AB - At the intersection of race and class the consequences of being working-class or middle-class are not so Black and White. Rather, established and emerging research suggests that race/ethnicity and social class intersect to differentially afford benefits and burdens. For instance, racial/ethnic minorities often do not reap the social, psychological or economic benefits of higher social class; yet, in some key life domains (e.g. health and mortality) racial/ethnic minorities in the U.S. seem to be buffered from some burdens of lower social class. We integrate empirical evidence to suggest that such differential advantages and disadvantages along racial lines reflect that social class exists alongside, rather than separate from, race/ethnicity as two distinct yet intersecting sources of rank and in turn selves. PMID- 28910705 TI - Pharmacophore modeling, virtual screening and molecular docking of ATPase inhibitors of HSP70. AB - Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals. Consequently, the screened compounds were refined by rule of five, ADMET and molecular docking to retain the best competitive hits. Finally Phytochemical compounds Muricatetrocin B, Diacetylphiladelphicalactone C, Eleutheroside B and 5-(3-{[1 (benzylsulfonyl)piperidin-4-yl]amino}phenyl)- 4-bromo-3-(carboxymethoxy)thiophene 2-carboxylic acid were obtained as leads to inhibit the ATPase activity of HSP70 in our findings and thus can be proposed for further in vitro and in vivo evaluation. PMID- 28910706 TI - Pharmacokinetics and tissue distribution of five major triterpenoids after oral administration of Rhizoma Alismatis extract to rats using ultra high-performance liquid chromatography-tandem mass spectrometry. AB - Rhizoma Alismatis (RA) was wildly used for treatment of dysuria, pyelonephritis, hyperlipidemia, enteritis diarrhea, diabetes, inflammation, and cancer. Triterpenoids are the major active components of RA, and its extract is mainly composed of alisol A (ALA), alisol B (ALB), alisol C 23-acetate (ALC-23A), alisol A 24-acetate (ALA-24A), and alisol B 23-acetate (ALB-23A). In this study, a simple, reliable, and sensitive ultra high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) method was created and validated for the quantification of the five major triterpenoids in rat plasma and various tissues biosamples (including intestine, stomach, liver, kidney, fat, muscle, brain, heart, lung, spleen, and testes). The plasma and tissues biosamples were pretreated by direct precipitation deproteinization method with acetonitrile. 17alpha-Hydroxyprogesterone was used as internal standard (IS). The chromatography was performed on a Phenomenex C8 column (30*2.00mm, 1.8MUm) at room temperature with gradient elution. Compounds were quantified by selected multi-reactions monitoring (SRM) scanning with positive electric spray ionization mode. The linearity of detection for each triterpene was respectively from 1 to 1000ng/mL for ALC-23A and ALA, from 4 to 4000ng/mL for ALA-24A, from 10 to 10,000ng/mL for ALB, and from 2 to 2000ng/mL for ALB-23B (r>0.99) with low quantification limits of 1-10ng/mL for all analytes. All of the other validation parameters were also in an acceptable range. The validated UHPLC-MS/MS method subsequently applied for the pharmacokinetic and tissue distribution studies of RA extract. After orally given 100mg/kg of RA extract, ALA was the most exposed component, followed by ALB and ALA-24A. Whereas significant gender difference was observed for ALB, ALA, and ALA-24A between female and male rats. The AUC(0 infinity) of ALA, ALB, and ALA-24A in female rats were approximately 2-5 fold larger than that in male rats. These triterpenoids also displayed approximately 1.5-2 times longer half-life (t1/2) in female rats. Appearant Km, Vmax and Clint of ALA, ALB, and ALA-24A were calculated by substrate depletion approach, rat P450 CYP3A2 plays an important role in the metabolism of ALA, ALB, and ALA-24A, which is an important factor leading to the different exprosures of ALA, ALB, and ALA-24A between the male rats and the female rats. Furthermore, results from tissue distribution in male rats showed that the main tissue depots of five triterpenoids were the stomach/intestine, followed by the liver, brain, and fat. However, ALA was still measured in the kidney after a long elimination time. ALB and ALB-23B exhibited lower elimination rate in the testis. These results provide a fundamental support for further pharmacological development and clinical safety application of RA. PMID- 28910707 TI - Spectral phasor analysis reveals altered membrane order and function of root hair cells in Arabidopsis dry2/sqe1-5 drought hypersensitive mutant. AB - Biological membranes allow the regulation of numerous cellular processes, which are affected when unfavorable environmental factors are perceived. Lipids and proteins are the principal components of biological membranes. Each lipid has unique biophysical properties, and, therefore the lipid composition of the membrane is critical to maintaining the bilayer structure and functionality. Membrane composition and integrity are becoming the focus of studies aiming to understand how plants adapt to its environment. In this study, using a combination of di-4-ANEPPDHQ fluorescence and spectral phasor analysis, we report that the drought hypersensitive/squalene epoxidase (dry2/sqe1-5) mutant with reduced major sterols such as sitosterol and stigmasterol in roots presented higher membrane fluidity than the wild type. Moreover, analysis of endomembrane dynamics showed that vesicle formation was affected in dry2/sqe1-5. Further analysis of proteins associated with sterol rich micro domains showed that dry2/sqe1-5 presented micro domains function altered. PMID- 28910708 TI - Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia. AB - Recent imaging studies have suggested that accelerated aging occurs in schizophrenia. However, the exact cause of these findings is still unclear. In this study we measured telomere length, a marker for cell senescence, in gray and white matter brain tissue from the medial frontal gyrus (MFG) and superior temporal gyrus (STG) of 9 patients with schizophrenia and 11 controls. No alterations in telomere length were found in MFG gray and white matter and in STG gray matter. A significant reduction in telomere length was observed in STG white matter of patients with schizophrenia as compared to controls (fold change of 0.42, U = 5, P = 0.008). Our results support previous findings that telomere length in gray matter is not affected, whereas they suggest that increased cell senescence may affect white matter temporal brain tissue. PMID- 28910709 TI - Psychological reactions to the 2017 Manchester Arena bombing: A population based study. PMID- 28910710 TI - Outer nuclear membrane fusion of adjacent nuclei in varicella-zoster virus induced syncytia. AB - Syncytia formation has been considered important for cell-to-cell spread and pathogenesis of many viruses. As a syncytium forms, individual nuclei often congregate together, allowing close contact of nuclear membranes and possibly fusion to occur. However, there is currently no reported evidence of nuclear membrane fusion between adjacent nuclei in wild-type virus-induced syncytia. Varicella-zoster virus (VZV) is one typical syncytia-inducing virus that causes chickenpox and shingles in humans. Here, we report, for the first time, an interesting observation of apparent fusion of the outer nuclear membranes from juxtaposed nuclei that comprise VZV syncytia both in ARPE-19 human epithelial cells in vitro and in human skin xenografts in the SCID-hu mouse model in vivo. This work reveals a novel aspect of VZV-related cytopathic effect in the context of multinucleated syncytia. Additionally, the information provided by this study could be helpful for future studies on interactions of viruses with host cell nuclei. PMID- 28910712 TI - Raman analysis of cobalt blue pigment in blue and white porcelain: A reassessment. AB - Cobalt blue is a famous pigment in human history. In the past decade it is widely reported that the cobalt aluminate has been detected in ancient ceramics as blue colorant in glaze, yet the acquired Raman spectra are incredibly different from that of synthesised references, necessitating a reassessment of such contradictory scenario with more accurate analytic strategies. In this study, micro-Raman spectroscopy (MRS) and scanning electron microscopy (SEM) in association with energy dispersive spectrometry (EDS) were performed on under glaze cobalt pigments from one submerged blue and white porcelain shard dated from Wanli reign (1573-1620CE) of Ming dynasty (1365-1644CE) excavated at Nan'ao I shipwreck off the southern coast of China. The micro-structural inspection reveals that the pigment particles have characteristics of small account, tiny size, heterogeneously distribution, and more importantly, been completely enwrapped by well-developed anorthite crystals in the glaze, indicating that the signals recorded in previous publications are probably not from cobalt pigments themselves but from outside thickset anorthite shell. The further spectromicroscopic analyses confirm this presumption when the accurate spectra of cobalt aluminate pigment and surrounding anorthite were obtained separately with precise optical positioning. Accordingly, we reassess and clarify the previous Raman studies dedicated to cobalt blue pigment in ancient ceramics, e.g. cobalt blue in celadon glaze, and in turn demonstrate the superiority and necessity of coupling spectroscopic analysis with corresponding structure observation, especially in the characterization of pigments from complicated physico-chemical environment like antiquities. Thus, this study promotes a better understanding of Raman spectroscopy study of cobalt blue pigments in art and archaeology field. PMID- 28910711 TI - A novel micro-to-macro structural approach for mechanical characterization of adipose tissue extracellular matrix. AB - Mechanical characterization of adipose tissue micro-components is important for various biomedical applications such as tissue engineering and predicting adipose tissue response to forces involved in relevant medical intervention procedures (e.g. breast needle biopsy). For this characterization, we introduce a novel structural method for micromechanical modeling of the adipose tissue. The micromechanical model was developed using fluid-structure interaction (FSI) formulation. We utilized this model within an inverse problem framework to estimate the hyperelastic parameters of adipose tissue extracellular matrix (ECM). Using this framework, the ECM hyperelastic parameters were changed in the FSI model systematically using an optimization algorithm such that the mechanical response obtained from the FSI model matches the corresponding experimental response reported in previous studies. To account for adipocyte size variation, the hyperelastic parameters were determined for different adipocyte sizes in the FSI model. Results obtained in this investigation indicate that at various strains under quasi-static conditions, the stiffness of adipose tissue ECM is ~ (2-3) times higher than that of the adipose tissue. The results also indicate a very good fit between the FSI model responses and their experimental counterparts. This indicates the reliability of the proposed FSI model in capturing major elements of the adipose tissue micromechanics. As such, it is potentially useful in applications such as tissue engineering, estimating tissue deformation pertaining to medical intervention and cataloging the mechanical properties of adipose tissue under health and pathological conditions. It can also be utilized as a forward model for developing inversion algorithms designed to determine pathological adipose microstructural alterations. PMID- 28910713 TI - Beneficial effect of compost utilization on reducing greenhouse gas emissions in a rice cultivation system through the overall management chain. AB - Livestock manure application can stimulate greenhouse gas (GHG) emissions, especially methane (CH4) in rice paddy. The stabilized organic matter (OM) is recommended to suppress CH4 emission without counting the additional GHG emission during the composting process. To evaluate the effect of compost utilization on the net global warming potential (GWP) of a rice cropping system, the fluxes of GHGs from composting to land application were calculated by a life cycle assessment (LCA) method. The model framework was composed of GHG fluxes from industrial activities and biogenic GHG fluxes from the composting and rice cultivation processes. Fresh manure emitted 30MgCO2-eq.ha-1, 90% and 10% of which were contributed by CH4 and nitrous oxide (N2O) fluxes, respectively, during rice cultivation. Compost utilization decreased net GWP by 25% over that of the fresh manure during the whole process. The composting process increased the GWP of the industrial processes by 35%, but the 60% reduction in CH4 emissions from the rice paddy mainly influenced the reduction of GWP during the overall process. Therefore, compost application could be a good management strategy to reduce GHG emissions from rice paddy systems. PMID- 28910714 TI - Nitrogen discharge pathways in vegetable production as non-point sources of pollution and measures to control it. AB - Discharge of nitrogen (N) from fertilizers applied to vegetables is becoming a serious environmental problem. In a field experiment involving a celery-tomato fallow-lettuce rotation, leaching was the primary pathway of N loss (56.1+/-0.4% of the total), followed, in descending order, by runoff (11.7+/-0.3%), N2O emissions (1.6+/-0.1%), and volatilization of ammonia (0.5+/-0.1%). Decreasing the traditional dose of N by 40% in each growth season decreased N leaching by 22.3+/-4.5, 39.8+/-6.7, 40.3+/-2.9 and 27.4+/-3.6% in celery, tomato, fallow and lettuce seasons, respectively, without any yield loss, and modifying the rotation to include a leguminous crop reduced the N leaching by 72+/-2, 40+/-3, 24+/-2 and 13+/-1% in each season, respectively, without any economic impact. These measures decreased annual N leaching by 36+/-4%. A combination of the eco-ditches and wetland paddy fields adjacent to the vegetable plot led to annual N removal efficiency of 73+/-6% in runoff. PMID- 28910715 TI - Intercomparison of in situ CRDS and CEAS for measurements of atmospheric N2O5 in Beijing, China. AB - Dinitrogen pentoxide (N2O5) is one of the basic trace gases which plays a key role in nighttime atmosphere. An intercomparison and validation of different N2O5 measurement methods is important for determining the true accuracy of these methods. Cavity ring down spectroscopy (CRDS) and cavity enhanced absorption spectrometer (CEAS) were used to measure N2O5 at the campus of the University of Chinese Academy of Sciences (UCAS) from February 21, 2016 to March 4, 2016. The detection limits were 1.6ppt (1sigma) at 30s intervals for the CEAS instrument and 3.9ppt (1sigma) at 10s time resolution for the CRDS instrument respectively. In this study, a comparison of the 1min observations from the two instruments was presented. The two data sets showed a good agreement within their uncertainties, with an absolute shift of 15.6ppt, slope of 0.94 and a correlation coefficient R2=0.97. In general, the difference between the CRDS and CEAS instruments for N2O5 measurement can be explained by their combined measurement uncertainties. However, high relative humidity (>60%) and high PM2.5 concentration (>200MUg/m3) may contribute to the discrepancies. The excellent agreement between the measurement by the CRDS and CEAS instruments demonstrates the capability of the two instruments for accurately measuring N2O5 with high sensitivity. PMID- 28910716 TI - Understanding sustained use of ecological sanitation in rural Burkina Faso. AB - Access to safe sanitation services is fundamental for healthy and productive lives, but in rural Burkina Faso only around 7% of the population uses improved sanitation. Ecological sanitation (ecosan) systems that allow safe agricultural reuse of nutrients in human waste have been promoted in these areas, as a way to meet sanitation needs while contributing to food security. However, little is known about the success of these interventions in terms of both sustained use of the toilet and safe excreta reuse practices. We assessed the use of ecosan systems in 44 rural communities where such interventions had taken place. Structured interviews and observations conducted at 520 randomly selected concessions (residential properties), suggested a large-scale shift from open defecation to ecosan toilet use. However, only 58% of surveyed concessions reported ever emptying the ecosan toilet vault, which is required for optimal long-term functioning. Concessions that received ecosan training programmes with a greater emphasis on agricultural reuse were more strongly associated with toilet use and emptying than those that whose training focused more on sanitation access and health benefits. The findings suggest that the safe agricultural reuse of nutrients can provide a strong motivation for long-term adoption of improved sanitation among rural smallholders. PMID- 28910717 TI - Time- and age-related effects of experimentally simulated nitrogen deposition on the functioning of montane heathland ecosystems. AB - Ecosystems adapted to low nitrogen (N) conditions such as Calluna-heathlands are especially sensitive to enhanced atmospheric N deposition that affects many aspects of ecosystem functioning like nutrient cycling, soil properties and plant microbial-enzyme relationships. We investigated the effects of five levels of experimentally-simulated N deposition rates (i.e., N fertilization treatments: 0, 10, 20 and 50kgNha-1yr-1 for 3years, and 56kgNha-1yr-1 for 10years) on: plant, litter, microbial biomass and soil nutrient contents, soil extracellular enzymatic activities, and plant root ericoid mycorrhizal colonization. The study was conducted in marginal montane Calluna-heathlands at different developmental stages resulting from management (young/building-phase and mature-phase). Our findings revealed that many soil properties did not show a statistically significant response to the experimental addition of N, including: total N, organic carbon (C), C:N ratio, extractable N-NO3-, available phosphorus (P), urease and beta-glucosidase enzyme activities, and microbial biomass C and N. Our results also evidenced a considerable positive impact of chronic (10-year) high-N loading on soil extractable N-NH4+, acid phosphatase enzyme activity, Calluna root mycorrhizal colonization by ericoid fungi, Calluna shoot N and P contents, and litter N content and N:P ratio. The age of heathland vegetation influenced the effects of N addition on ericoid mycorrhizal colonization, resulting in higher colonized roots in young heathlands at the control, low and medium N-input rates; and in mature ones at the high and chronically high N rates. Also, young heathlands exhibited greater soil extractable N-NO3-, available P, microbial biomass N, Calluna shoot N and P contents, and litter N content, compared to mature ones. Our results highlighted that accounting for the N-input load and duration, as well as the developmental stage of the vegetation, is important for assessing the effects of added N, particularly at the heathlands' southern distribution limit. PMID- 28910718 TI - Water quality of surface runoff and lint yield in cotton under furrow irrigation in Northeast Arkansas. AB - Use of furrow irrigation in row crop production is a common practice through much of the Midsouth US and yet, nutrients can be transported off-site through surface runoff. A field study with cotton (Gossypium hirsutum, L.) was conducted to understand the impact of furrow tillage practices and nitrogen (N) fertilizer placement on characteristics of runoff water quality during the growing season. The experiment was designed as a randomized complete block design with conventional (CT) and conservation furrow tillage (FT) in combination with either urea (URN) broadcast or 32% urea ammonium nitrate (UAN) injected, each applied at 101kgNha-1. Concentrations of ammonium (NH4-N), nitrate (NO3-N), nitrite (NO2-N), and dissolved phosphorus (P) in irrigation runoff water and lint yields were measured in all treatments. The intensity and chemical form of nutrient losses were primarily controlled by water runoff volume and agronomic practice. Across tillage and fertilizer N treatments, median N concentrations in the runoff were <0.3mgNL-1, with NO3-N being relatively the highest among N forms. Concentrations of runoff dissolved P were <0.05mgPL-1 and were affected by volume of runoff water. Water pH, specific electrical conductivity, alkalinity and hardness were within levels that common to local irrigation water and less likely to impair pollution in waterways. Lint yields averaged 1111kgha-1 and were higher (P value=0.03) in FT compared to CT treatments. Runoff volumes across irrigation events were greater (P-value=0.02) in CT than FT treatments, which increased NO3 N mass loads in CT treatments (394gNO3-Nha-1season-1). Nitrate-N concentrations in CT treatments were still low and pose little threat to N contaminations in waterways. The findings support the adoption of conservation practices for furrow tillage and N fertilizer placement that can reduce nutrient runoff losses in furrow irrigation systems. PMID- 28910719 TI - Latitudinal variation in summer monsoon rainfall over Western Ghat of India and its association with global sea surface temperatures. AB - The Western Ghats (WG) of India are basically north-south oriented mountains having narrow zonal width with a steep rising western face. The summer monsoon winds during June to September passing over the Arabian Sea are obstructed by the WG and thus orographically uplift to produce moderate-to-heavy precipitation over the region. However, it is seen that characteristic features of rainfall distribution during the season vary from north to south. Also its correlation with all-India summer monsoon rainfall increases from south to north. In the present study, an attempt is also made to examine long-term as well as short-term trends and variability in summer monsoon rainfall over different subdivisions of WG using monthly rainfall data for the period 1871-2014. Konkan & Goa and Coastal Karnataka show increase in rainfall from 1871 to 2014 in all individual summer monsoon months. Short-term trend analysis based on 31-year sliding window indicates that the trends are not monotonous, but has epochal behavior. In recent epoch, magnitudes of negative trends are consistently decreasing and have changed its sign to positive during 1985-2014. It has been observed that Indian Ocean Dipole (IOD) plays a dominant positive role in rainfall over entire WG in all summer monsoon months, whereas role of Nino regions are asymmetric over WG rainfall. Indian summer monsoon is known for its negative relationship with Nino SST. Negative correlations are also seen for WG rainfall with Nino regions but only during onset and withdrawal phase. During peak monsoon months July and August subdivisions of WG mostly show positive correlation with Nino SST. PMID- 28910720 TI - Study of the influence of physical, chemical and biological conditions that influence the deterioration and protection of Underwater Cultural Heritage. AB - Two wrecks related to the Battle of Trafalgar (1805) were studied. Following the guidelines of the UNESCO-2001 Convention for the Protection of the Underwater Cultural Heritage, a holistic and interdisciplinary approach based on the development of four of the thirty-six Rules of this international agreement was applied. A non-destructive survey technique was developed to obtain information from the scattered cannons and anchors without altering their condition (Rule 4). The work performed provided information about the origin of both wrecks, the Fougueux and the Bucentaure, two ships of the line of the French Navy, and allowed to characterize the state of conservation at each site without jeopardizing their future conservation in the marine environment. In addition, measurements of the main physical, chemical and biological variables allowed correlating the conservation status at each site with the marine environmental conditions (Rule 15). Thus, in Fougueux shipwreck large iron objects are corroding at a higher rate (between 0.180 and 0.246mmpy) due to high sediment remobilization and transport induced by waves at this site, causing damage by direct mechanical effect on metallic material and by removing the layer of corrosion products developed on the artefacts. Meanwhile artillery on Bucentaure site, covered with thick layers of biological concretion, is well preserved, with lower corrosion rates (0.073 to 0.126mmpy), and archaeological information is guaranteed. Finally, the effectiveness of the cathodic protection as a temporary measure for in situ conservation (Rule 1) was evaluated on a cannon. The use of a sacrificial anode after 9months reduced the average corrosion rate (from 0.103 to 0.064mmpy) and the percent of corrosion rate in 37.9%. These results are very useful for developing a decision making system of the Site Management Program, based on predictive models of artefacts permanence and risk factors in the marine environment (Rule 25). PMID- 28910721 TI - An amino acid domino effect orchestrates ClpP's conformational states. AB - Maintaining the cellular protein homeostasis means managing life on the brink of death. This balance is largely based on precise fine-tuning of enzyme activities. For instance, the ClpP protease possesses several conformational switches which are fundamental to regulating its activity. Efforts have focused on revealing the structural basis of ClpP's conformational control. In the last decade, several amino acid clusters have been identified and functionally linked to specific activation states. Researchers have now begun to couple these hotspots to one another, uncovering a global network of residues that switch in response to internal and external stimuli. For these studies, they used small molecules to mimic intermolecular interactions and point-mutational studies to shortcut regulating amino acid circuits. PMID- 28910722 TI - Analysis of in-vivo articular cartilage contact surface of the knee during a step up motion. AB - BACKGROUND: Numerous studies have reported on the tibiofemoral articular cartilage contact kinematics, however, no data has been reported on the articular cartilage geometry at the contact area. This study investigated the in-vivo tibiofemoral articular cartilage contact biomechanics during a dynamic step-up motion. METHODS: Ten healthy subjects were imaged using a validated magnetic resonance and dual fluoroscopic imaging technique during a step-up motion. Three dimensional bone and cartilage models were constructed from the magnetic resonance images. The cartilage contact along the motion path was analyzed, including cartilage contact location and the cartilage surface geometry at the contact area. FINDINGS: The cartilage contact excursions were similar in anteroposterior and mediolateral directions in the medial and lateral compartments of the tibia plateau (P>0.05). Both medial and lateral compartments were under convex (femur) to convex (tibia) contact in the sagittal plane, and under convex (femur) to concave (tibia) contact in the coronal plane. The medial tibial articular contact radius was larger than the lateral side in the sagittal plane along the motion path (P<0.001). INTERPRETATIONS: These data revealed that both the medial and lateral compartments of the knee experienced convex (femur) to convex (tibia) contact in sagittal plane (or anteroposterior direction) during the dynamic step-up motion. These data could provide new insight into the in-vivo cartilage contact biomechanics research, and may provide guidelines for development of anatomical total knee arthroplasties that are aimed to reproduce normal knee joint kinematics. PMID- 28910723 TI - Sorption-desorption equilibrium and diffusion of tetracycline in poultry litter and municipal biosolids soil amendments. AB - Tetracycline (TET) is commonly used to treat bacterial diseases in humans and chickens (Gallus gallus domesticus), is largely excreted, and is found at elevated concentrations in treated sewage sludge (biosolids) and poultry litter (excrement plus bedding materials). Routine application of these nutrient-and carbon-enriched materials to soils improves fertility and other characteristics, but the presence of antibiotics (and other pharmaceuticals) in amendments raises questions about potential adverse effects on biota and development of antibiotic resistance in the environment. Hazard risks are largely dictated by sorption desorption and diffusion behavior in amendments, so these processes were evaluated from sorption-desorption equilibrium isotherm and diffusion cell experiments with four types amendments (biosolids, poultry manure, wood chip litter, and rice hull litter) at three temperatures (8 degrees C, 20 degrees C and 32 degrees C). Linear sorption-desorption equilibrium distribution constants (Kd) in native amendments ranged between 124-2418 L kg-1. TET sorption was significantly increased after treatment with alum, and there was a strong exponential relationship between Kd and the concentration of bound Al3+ in amendments (R2 = 0.94), which indicated that amendments contained functional groups capable of chelating Al3+ and forming metal bridges with TET. Effective diffusion coefficients of TET in amendments ranged between 0.1 and 5.2 * 10-6 cm2 s-1, which were positively related to temperature and inversely related to Kd by a multiple regression model (R2 = 0.86). Treatment of organic amendments with alum greatly increased Kd, would decrease Ds, and so would greatly reduce hazard risks of applying these organic amendments with this antibiotic to soils. PMID- 28910724 TI - Optical property of dissolved organic matters (DOMs) and its link to the presence of metal ions in surface freshwaters in China. AB - It is believed that dissolved organic matter (DOM) plays an important role in carrying metal ions through global cycle and distribution, while this point has not yet been elucidated clearly as DOM is extremely heterogeneous and site specific. In this study, optical properties of DOM in 53 surface freshwater sites all over China were recorded by UV-Vis absorbance spectroscopy in pH range 3-11. The subtle processes of protonation-deprotonation of DOM were quantified by tracking the changes of DOM spectra. The binding capacities of DOMs-binding sites and affinity constants-were interpreted by introducing a spectral parameter, differential log-transformed differential absorbance at 400 nm (DlnA400) in combination with Non-Ideal Competitive Adsorption (NICA) Model. It is found that the presence of dissolved Zn, Hg and Ni in the examined waters show strong correlation with total binding sites in DOMs. However, the presence of some other metals with high affinities to DOM, e.g. Cu, Fe and so on, have not demonstrated strong correlation with the total binding sites in DOMs. This indicates the presence of these metals may be seriously influenced by other factors besides DOM. This study demonstrates that the spectroscopic titration approach could potentially provide more structure-specific in situ information about DOM and help to understand the role of DOM in the speciation and bioavailability of toxic metal ions. PMID- 28910725 TI - Acute and subchronic toxicity of pyraclostrobin in zebrafish (Danio rerio). AB - The aim of the present study was to assess the toxic effects of pyraclostrobin on DNA damage and antioxidant enzymatic activities in the zebrafish (Danio rerio) liver. Based on the 96-h median lethal concentration (96 h LC50, 0.056 mg/L) of this chemical, fish were exposed to three doses (0.001, 0.01, and 0.02 mg/L) and sampled on days 7, 14, 21 and 28 after the initiation of a subchronic toxicity test. The levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), glutathione S-transferase (GST), reactive oxygen species (ROS) and DNA damage were determined. The amount of pyraclostrobin residue in the water was also measured. The concentrations in the three treatment groups varied no more than 5% during the exposure periods, indicating that pyraclostrobin is relatively stable during this time in an aquatic environment. ROS and MDA levels significantly changed in a dose dependent manner during the experiment. Enzymatic activities were inhibited to a certain extent. DNA damage was significantly enhanced. These results collectively indicate that pyraclostrobin induces oxidative stress and DNA damage in zebrafish. PMID- 28910726 TI - Knockdown of NADPH-cytochrome P450 reductase increases the susceptibility to carbaryl in the migratory locust, Locusta migratoria. AB - BACKGROUND: NADPH-cytochrome P450 reductase (CPR) plays important roles in cytochrome P450-mediated metabolism of endogenous and exogenous compounds, and participates in cytochrome P450-related detoxification of insecticides. However, the CPR from Locusta migratoria has not been well characterized and its function is still undescribed. RESULTS: The full-length of CPR gene from Locusta migratoria (LmCPR) was cloned by RT-PCR based on transcriptome information. The membrane anchor region, and 3 conserved domains (FMN binding domain, connecting domain, FAD/NADPH binding domain) were analyzed by bioinformatics analysis. Phylogenetic analysis showed that LmCPR was grouped in the Orthoptera branch and was more closely related to the CPRs from hemimetabolous insects. The LmCPR gene was ubiquitously expressed at all developmental stages and was the most abundant in the fourth-instar nymphs and the lowest in the egg stage. Tissue-specific expression analysis showed that LmCPR was higher expressed in ovary, hindgut, and integument. The CPR activity was relatively higher in Malpighian tubules and integument. Silencing of LmCPR obviously reduced the enzymatic activity of LmCPR, and enhanced the susceptibility of Locusta migratoria to carbaryl. CONCLUSION: These results suggest that LmCPR contributes to the susceptibility of L. migratoria to carbaryl and could be considered as a novel target for pest control. PMID- 28910728 TI - Hygroscopicity of internally mixed particles composed of (NH4)2SO4 and citric acid under pulsed RH change. AB - In this research, we applied a pulsed RH controlling system and a rapid scan vacuum FTIR spectrometer (PRHCS-RSVFTIR) to investigate hygroscopicity of internally mixed (NH4)2SO4(AS)/citric acid (CA) particles. The water content and efflorescence ratio of AS in the particles and ambient relative humidity (RH) as a function of time were obtained with a subsecond time resolution. The hygroscopic behavior of AS aerosols in two different RH control processes (equilibrium and RH pulsed processes) showed that AS droplets crystallize with RH ranging from 42% to 26.5%. It was found that the half-life time ratio between the water content in the CA particles and the gas phase under RH pulsed change was greater than one under low RH conditions (<40% RH), indicating the significant water transfer limitation due to the high viscosity of CA aerosols at low RH, especially at RH<20%. In addition, water diffusion constants between 10-12 m2 s-1 and 10-13 m2 s-1 in micron size CA aerosols were obtained in a sub-second and second timescale. The addition of AS enhanced the water transfer limitation in the mixed aerosols. The efflorescence relative humidity (ERH) of the mixed particles with AS/CA by molar ratio 3:1 was found between 22.7% and 5.9%, which was much lower than AS particles. No efflorescence process was observed for the 1:1 mixed particles, indicating that CA greatly suppressed nucleation of AS. Our results have shown that the PRHCS-RSVFTIR is effective to simulate hygroscopicity and water transport of aerosols under fast variations in RH in atmosphere. PMID- 28910727 TI - Gene-environment interaction: Does fluoride influence the reproductive hormones in male farmers modified by ERalpha gene polymorphisms? AB - The occurrence of endemic fluorosis is derived from high fluoride levels in drinking water and industrial fumes or dust. Reproductive disruption is also a major harm caused by fluoride exposure besides dental and skeletal lesions. However, few studies focus on the mechanism of fluoride exposure on male reproductive function, especially the possible interaction of fluoride exposure and gene polymorphism on male reproductive hormones. Therefore, we conducted a cross-sectional study in rural areas of Henan province in China to explore the interaction between the estrogen receptor alpha (ERalpha) gene and fluoride exposure on reproductive hormone levels in male farmers living in the endemic fluorosis villages. The results showed that fluoride exposure significantly increased the serum level of estradiol in the hypothalamic-pituitary-testicular (HPT) axis in male farmers. Moreover, the observations indicated that fluoride exposure and genetic markers had an interaction on serum concentration of follicle-stimulating hormone and estradiol, and the interaction among different loci of the ERalpha gene could impact the serum testosterone level. Findings in the present work suggest that chronic fluoride exposure in drinking water could modulate the levels of reproductive hormones in males living in endemic fluorosis areas, and the interaction between fluoride exposure and ERalpha polymorphisms might affect the serum levels of hormones in the HPT axis in male farmers. PMID- 28910729 TI - TiO2 particles in seafood and surimi products: Attention should be paid to their exposure and uptake through foods. AB - The sustainable development of nanotechnology requires a thorough understanding of the life cycle of synthesized nanomaterials, including environmental release, deposition, exposure, and potential health risks. Titanium dioxide (TiO2) materials containing nanosized TiO2 (nTiO2) are commonly used as food additives. Thus, dietary intake through foods is the most important route for the exposure of TiO2 materials. Given the toxic effects of nTiO2 on the gastrointestinal tract and other tissues, it is imperative to investigate their sources and concentrations in popular foods. Therefore, we conducted a survey on TiO2 particles in white-colored seafood and surimi products in Beijing. Our data indicated that the total Ti levels reached 6-12 MUg/g (dry weight) in some white colored seafood products, such as squid and cuttlefish, whereas relatively low concentrations were observed in jellyfish at approximately 1-3 MUg/g (dry weight). For the locally favorite surimi-based food products in the market, the Ti concentrations ranged from 2 to 81 MUg/g (dry weight). The exposure assessment showed that the average daily intake of TiO2 particles through foods varied from 0.02 to 3.09 MUg TiO2/kgbw/day, reflected by the Ti concentrations in this study, and that young people of age 20-30 showed the highest exposure level. Together, these results show relatively high concentrations of TiO2 particles in some seafood and surimi products available in the market, and our findings therefore call for attention on TiO2 particle exposure and uptake through daily foods. PMID- 28910730 TI - Pathogenic and likely pathogenic genetic alterations and polymorphisms in growth hormone gene (GH1) and growth hormone releasing hormone receptor gene (GHRHR) in a cohort of isolated growth hormone deficient (IGHD) children in Sri Lanka. AB - OBJECTIVE: Genetic alterations in GH1 and GHRHR genes are known to cause isolated growth hormone deficiency (IGHD). Of these, GHRHR codon 72 mutation has been reported to be highly prevalent in the Indian subcontinent, but among Sri Lankans its prevalence was low compared to reports from neighboring countries. The present study was therefore carried out to identify genetic alterations in the GH1 gene and rest of the GHRHR gene in a cohort of Sri Lankan IGHD patients who tested negative for GHRHR codon 72 mutation. METHODS: Fifty five IGHD children negative for codon 72 (GHRHR) mutation were screened for gross GH1 gene deletion by polymerase chain reaction (PCR) and restriction fragment length polymorphism technique. The coding, intronic and promoter regions of the GH1 gene were sequenced in children who were negative for GH1 deletion (N=53). In a subset (N=40), coding, flanking intronic and promoter regions of the GHRHR gene were screened by single strand conformation polymorphism/sequencing. Identified coding region and intronic variants were subjected to in silico analysis to ascertain pathogenicity. Family members available were screened for the significant variants observed in the index child. RESULTS: Gross GH1 gene deletions, 6.7kb and 7.0kb were observed in one child each. One novel and 24 reported single nucleotide variants (SNVs) were observed in the GH1 gene and its promoter. These included one reported pathogenic splice site mutation (c.172-2A>T) and one reported likely pathogenic missense mutation (c.406G>T). One large novel deletion of 5875 base pairs that included exon 1, one likely pathogenic novel SNV (c.211G>T) and 18 reported SNVs were observed in the GHRHR gene. Fourteen variants observed were of uncertain significance (8 in GH1 and 6 in GHRHR), twenty three variants were likely benign (11 in GH1 and 12 in GHRHR) and four variants were benign (4 in GH1 and none in GHRHR). CONCLUSION: In a cohort of IGHD children, six pathogenic or likely pathogenic genetic alterations of either GH1 gene or GHRHR gene were found. These affected a total of six children. Pathogenic status of four of these had been reported in the literature. Novel SNV in the GHRHR gene was predicted to be pathogenic through in silico analysis. The large novel deletion is likely to be pathogenic as it included exon 1 of GHRHR gene. Analysis of other genes will be needed to ascertain the genetic cause of IGHD in the remaining children. PMID- 28910731 TI - Triclosan removal from surface water by ozonation - Kinetics and by-products formation. AB - Removal of triclosan from surface water by ozonation was investigated. The results showed that complete elimination of triclosan from a surface water bearing 1-5 mg/L triclosan via continuous ozonation at 5 mg/L, require an ozonation time of 20-30 min depending on pH. Triclosan oxidation followed pseudo first order kinetics with an apparent reaction rate constant varying from 0.214 min-1 to 0.964 min-1 depending on pH, initial triclosan concentration and water composition. Although the effect of pH was complex due to possible existence of different moieties, higher TCS removal efficiencies were obvious at weak-base conditions. Experiments performed to identify degradation by-products showed the formation of four by-products, namely, 2,4-dichlorophenol, 4-chlorocatechol and two unidentified compounds. Additionally, 2,4-dichloroanisole was detected when a methyl moieties exist in water. By-products were found to be eliminated upon further ozonation. The required exposure time varied from 20 to 30 min depending on pH of water. The ozone demand exerted for the complete oxidation of triclosan and its by-products was calculated as 13.04 mg ozone per mg of triclosan. A triclosan degradation pathway, which was found to be highly pH dependent, was proposed. PMID- 28910732 TI - Degradation of toxic PAHs in water and soil using potassium zinc hexacyanoferrate nanocubes. AB - Polycyclic aromatic hydrocarbons (PAHs) the ubiquitous, persistent and carcinogenic environmental contaminants have raised concern worldwide. Recently, their removal methodologies are advanced after exploring nanomaterials. Therefore, degradation of selected toxic PAHs (3-5 rings) using potassium zinc hexacyanoferrate (KZnHCF) nanocubes was studied. Highly crystalline and sharp KZnHCF nanocubes (~100 nm) were obtained by green route using sapindus mukorossi. In both water and soil, anthracene and phenanthrene were degraded to maximum extent (80-93%), whereas, the degradation of fluorene, chrysene and benzo (a) pyrene were ~70-80%.Because of small size (lower molecular weight), large number of anthracene and phenanthrene molecules were adsorbed on catalyst as compared to other PAHs. Higher degradation of PAHs in water than in the soil is attributed to the easy absorption of PAHs on catalyst in water and slow diffusion of PAHs on organic content of soil. PAHs were degraded at the concentration of 50 mg/L, 25 mg catalyst dose, neutral pH and solar irradiation. Higher proficiency of the catalyst was revealed by degradation of PAHs into small and non-toxic by-products such as malealdehyde, 4-oxobut-2-enoic acid and o-xylene. Overall, the potential KZnHCF nanostructures open future scope for eradication of other pollutants from the environment. PMID- 28910733 TI - Survey of the effect of odour impact on communities. AB - In the context of environmental malodour, surveys are valuable as they allow for the relatively detailed analysis of multiple factors pertaining to odour perception and subsequent reaction. However, the causes for an individual to experience odour impact while a neighbour will not are still not understood. The goal of this current survey design was to consolidate varying research paths for surveys within the environmental odour research space. This survey investigated the area of effect for wastewater treatment plants by using stratified random sampling techniques that radiated from the industrial areas. Additionally, this survey provided a "non-alerted" response to environmental malodour that represents a step forward for ecological validity. We found a small number of items relating to odour annoyance and home ownership that can be used in order to predict odour impact for individual community members. However, we also did not find any relationship with odour impact and perceived control. This survey design and analysis reconciles the varied approaches towards community surveys administered in prior literature, as well as providing information to improve future community engagement policies. PMID- 28910734 TI - Single, simultaneous and consecutive biosorption of Cr(VI) and Orange II onto chemically modified masau stones. AB - Novel and low cost chemically modified masau stone (CMMS) was investigated for its biosorption of an anionic azo dye, Orange II (OII), and toxic hexavalent chromium (Cr(VI)) from aqueous systems: individually, simultaneously and consecutively. XPS and FTIR analyses indicated the introduction of quaternary Nitrogen to the CMMS surface after activation with epichlorohydrin (etherifying agent) and diethylenetriamine (crosslinking agent). The effects of pH, contact time and initial concentration (Co), and loading order on mechanisms of biosorption/reduction of OII and Cr(VI) onto CMMS were examined in detail. Several analytical techniques were employed to characterise the physio-chemical properties of the CMMS and determine the biosorption mechanisms. The pseudo second order and redox models were able to adequately predict the kinetics of biosorption. The Langmuir maximum OII biosorption capacity (qmax) was calculated as 136.8 mg/g for the dye onto the Cr(VI)-loaded CMMS consecutive system at Co = 100 mg/dm3. The qmax for the Cr(VI) system was found to be 87.32 mg/g at the same Co max. This reveals that the biosorption of OII and Cr(VI) mainly takes place via two different mechanisms i.e. hydrogen bonding and electrostatic attraction for the dye, and biosorption-coupled reduction for Cr(VI). PMID- 28910735 TI - Abatement of tetrafluoromethane by chemical absorption with molten aluminum. AB - Chemical absorption with molten aluminum to abate tetrafluoromethane (CF4) was investigated in this paper. The experiments were conducted at a series of different temperatures of 973 K, 1003 K, 1103 K, and 1188 K and the abatement rate of CF4 was calculated. It was found that CF4 can be adsorbed firstly and then react with molten aluminum automatically. The initial abatement rate of CF4 in molten aluminum was 3.10 * 10-2 mol.m-3.s-1 at 973 K, while it reached its maximum value of 1.08 * 10-1 mol.m-3.s-1 at the temperature of 1103 K. The highest abatement efficiency was 48.4%, reached at 1003 K. Higher temperatures up to 1188 K did not affect the abatement efficiency, however, they accelerated slightly the initial reaction rate. The products of the chemical absorption are white solid AlF3 and black graphite powder identified by XRD and SEM-EDS analysis. Due to density differences, solid AlF3 and graphite powder in the product tend to accumulate on the top of molten aluminum where they form two separate layers. This makes them recover more easily. The gas-liquid reaction process between CF4 and molten aluminum is accorded with the two-film theory model, diffusion process is considered to be the control step of the whole process. PMID- 28910736 TI - Soil microbial community responses to acid exposure and neutralization treatment. AB - Changes in microbial community induced by acid shock were studied in the context of potential release of acids to the environment due to chemical accidents. The responses of microbial communities in three different soils to the exposure to sulfuric or hydrofluoric acid and to the subsequent neutralization treatment were investigated as functions of acid concentration and exposure time by using 16S rRNA gene based pyrosequencing and DGGE (Denaturing Gradient Gel Electrophoresis). Measurements of soil pH and dissolved ion concentrations revealed that the added acids were neutralized to different degrees, depending on the mineral composition and soil texture. Hydrofluoric acid was more effectively neutralized by the soils, compared with sulfuric acid at the same normality. Gram negative beta-Proteobacteria were shown to be the most acid-sensitive bacterial strains, while spore-forming Gram-positive Bacilli were the most acid-tolerant. The results of this study suggest that the Gram-positive to Gram-negative bacterial ratio may serve as an effective bio-indicator in assessing the impact of the acid shock on the microbial community. Neutralization treatments helped recover the ratio closer to their original values. The findings of this study show that microbial community changes as well as geochemical changes such as pH and dissolved ion concentrations need to be considered in estimating the impact of an acid spill, in selecting an optimal remediation strategy, and in deciding when to end remedial actions at the acid spill impacted site. PMID- 28910737 TI - CHD2 mutations: Only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation. PMID- 28910738 TI - Burst suppression on EEG: Not always an ominous sign. PMID- 28910739 TI - Novel ruthenium azo-quinoline complexes with enhanced photonuclease activity in human cancer cells. AB - Coordinatively saturated ruthenium complexes with a variable net charge are currently under intense investigation for their anticancer potential. These complexes, possessing long wavelength metal-to-ligand charge transfer with DNA photonuclease activity, have shown promising cytotoxic profiles. Although most of the ruthenium complexes exhibit significant photochemotherapeutic activity, their poor entry into cells hinder their development as potential drug molecules. Here, we report the synthesis and characterization of four new ruthenium (II) azo-8 hydroxyquinoline complexes, their mode of in vitro DNA binding and antiproliferative properties against cultured human cancer cell lines. The activity of these compounds prior to photoirradiation is minimal. However, they could induce DNA photonuclease activity through the generation of reactive oxygen species upon exposure to light. The activities exhibited by these complexes were found to be more efficient (>5-fold) than cisplatin, emphasizing their therapeutic potential. Collectively, these results support the idea that ruthenium (II) azo-8-hydroxyquinoline complexes can serve as potential agents in photodynamic anticancer therapy. PMID- 28910740 TI - Generation of low-gamma oscillations in a GABAergic network model of the striatum. AB - Striatal oscillations in the low-gamma frequency range have been consistently recorded in a number of experimental studies. However, whether these rhythms are locally generated in the striatum circuit, which is mainly composed of GABAergic neurons, remains an open question. GABAergic medium spiny projection neurons represent the great majority of striatal neurons, but they fire at very low rates. GABAergic fast-spiking interneurons typically show firing rates that are approximately 10 times higher than those of principal neurons, but they are a very small minority of the total neuronal population. In this study, based on physiological constraints we developed a computational network model of these neurons and dissected the oscillations. Simulations showed that the population of medium spiny projection neurons, and not the GABAergic fast-spiking interneurons, determines the frequency range of the oscillations. D2-type dopamine receptor expressing neurons dominate the generation of low-gamma rhythms. Feedforward inputs from GABAergic fast-spiking interneurons promote the oscillations by strengthening the inhibitory interactions between medium spiny projection neurons. The promotion effect is independent of the degree of synchronization in the fast-spiking interneuron population but affected by the strength of their feedforward inputs to medium spiny projection neurons. Our results provide a theoretical explanation for how firing properties and connections of the three types of GABAergic neurons, which are susceptible to on-going behaviors, experience, and dopamine disruptions, sculpt striatal oscillations. PMID- 28910741 TI - Drug susceptibility testing in microaerophilic parasites: Cysteine strongly affects the effectivities of metronidazole and auranofin, a novel and promising antimicrobial. AB - The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen. However, drug susceptibility assays can be strongly affected by certain compounds in the growth media. In the case of microaerophilic parasites, cysteine which is added in large amounts as an antioxidant is an obvious candidate because it is highly reactive and known to modulate the toxicity of metronidazole in several microaerophilic parasites. In this study, it was attempted to reduce cysteine concentrations as far as possible without affecting parasite viability by performing drug susceptibility assays under strictly anaerobic conditions in an anaerobic cabinet. Indeed, T. vaginalis and E. histolytica could be grown without any cysteine added and the cysteine concentration necessary to maintain G. lamblia could be reduced to 20%. Susceptibilities to metronidazole were found to be clearly reduced in the presence of cysteine. With auranofin the protective effect of cysteine was extreme, providing protection to concentrations up to 100-fold higher as observed in the absence of cysteine. With three other drugs tested, albendazole, furazolidone and nitazoxanide, all in use against G. lamblia, the effect of cysteine was less pronounced. Oxygen was found to have a less marked impact on metronidazole and auranofin than cysteine but bovine bile which is standardly used in growth media for G. lamblia, displayed a marked synergistic effect with metronidazole. PMID- 28910742 TI - Nonsteroidal mycotoxin alternariol is a full androgen agonist in the yeast reporter androgen bioassay. AB - Alternariol (AOH) is a toxic metabolite of phytopathogenic fungi of the Alternaria spp. and important contaminant of agricultural commodities. According to the recent studies, AOH has a potential to modulate the endocrine system of humans and animals. In the view of these reports, our study addressed the effects of AOH on human estrogen receptor (hERalpha) and androgen receptor (hAR) signaling with the use of the yeast estrogen and androgen reporter bioassays. Our results show that, apart from a weak estrogenic response, AOH induces full androgenic response of the bioassay with the EC50 of 269.4MUM. The androgenic potency of AOH relative to testosterone (T) is 0.046%. Moreover, in the presence of T, AOH at 5MUM acts as a weak antiandrogen, whereas at higher concentrations AOH sum up with the androgenic activity of T in a dose-dependent manner, suggesting additive effect. To our knowledge it is the first report of the androgenic potency of natural, nonsteroidal substance and may have the impact on the direction of the further studies. Further research is warranted to clarify the role of AOH in disruption of AR signaling in humans and animals. PMID- 28910743 TI - Is SCENA a good approach for side-stream integrated treatment from an environmental and economic point of view? AB - The environmental and economic benefits and burdens of including the first Short Cut Enhanced Nutrient Abatement (SCENA) into a real municipal wastewater treatment plant were evaluated using life cycle assessment (LCA) and life cycle cost (LCC). The implications of accomplishing nitrogen (N) removal and phosphorus (P) recovery via nitrite in the side stream were assessed taking into account the actual effluent quality improvement, the changes in the electricity and chemical consumption, N2O, CO2 and CH4 emissions and the effects of land application of biosolids, among others. In addition, a case-specific estimation of the P availability when sludge is applied to land, therefore replacing conventional fertilizer, was performed. Furthermore, to account for the variability in input parameters, and to address the related uncertainties, Monte Carlo simulation was applied. The analysis revealed that SCENA in the side stream is an economic and environmentally friendly solution compared to the traditional plant layout with no side-stream treatment, thanks to the reduction of energy and chemical use for the removal of N and P, respectively. The uncertainty analysis proved the validity of the LCA results for global warming potential and impact categories related to the consumption of fossil-based electricity and chemicals, while robust conclusions could not be drawn on freshwater eutrophication and toxicity related impact categories. Furthermore, three optimization scenarios were also evaluated proving that the performance of the WWTP can be further improved by, for instance, substituting gravitational for mechanical thickening of the sludge or changing the operational strategy to the chemically enhanced primary treatment, although this second alternative will increase the operational cost by 5%. Finally, the outcomes show that shifting P removal from chemical precipitation in the main line to biologically enhanced uptake in the side stream is key to reducing chemicals use, thus the operational cost, and increasing the environmental benefit of synthetic fertilizers replacement. PMID- 28910745 TI - miR-200bc/429 cluster alleviates inflammation in IgA nephropathy by targeting TWEAK/Fn14. AB - Immunoglobulin A nephropathy (IgAN) is one of the most common glomerular diseases worldwide. Various studies have identified a host of microRNAs (miRNAs) abnormally expressed in IgAN and might affect the pathogenesis and progression of IgAN. However, miR-200bc/429 cluster in the pathopoiesis of IgAN remains poorly understood. For this study, we found that miR-200bc/429 cluster is downregulated in IgAN tissues and IgAN podocytes and HK2 cells compared with their matched controls respectively. In addition, overexpression of miR-200bc/429 cluster in IgAN podocytes and HK2 cells could attenuate the release of inflammatory cytokines MCP-1, IL-6 and RANTES. Moreover, the 3' untranslated region (UTR) of TNF-like weak inducer of apoptosis (TWEAK) was identified to be a direct target of miR-200bc/429 cluster. Furthermore, our results showed that miR-200bc/429 cluster can inhibit TWEAK mediated NF-kappaB pathway activation in IgAN. Overall, our findings revealed that miR-200bc/429 cluster alleviates inflammation in IgAN through TWEAK/Fn14 system and might serve as a biomarker as well as a promising therapeutic target for IgAN. PMID- 28910744 TI - Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways. AB - Advanced glycation end products (AGEs) are involved in osteopenia in people with diabetes and the elderly. Interleukin-6 (IL-6) and vascular endothelial growth factor-A (VEGF-A) are potent regulators of bone metabolism, and in bone tissue, osteocytes are an important source of these regulators. However, whether AGEs can directly regulate IL-6 and VEGF-A secretion by osteocytes is unknown. In this study, we evaluated the effect of AGEs on IL-6 and VEGF- A production as well as apoptosis in osteocyte-like MLO-Y4 cells. We also studied the involvement of receptor for advanced glycation end products (RAGE) and the role of extracellular signal-regulated kinases 1 and 2 (ERK1/2), P38 and signal transducer and activator of transcription 3 (STAT3) signalling pathways. We found that 100MUg/ml AGEs significantly induced apoptosis and up-regulated the expression of IL-6 and VEGF-A in MLO-Y4 cells. Additionally, AGEs significantly activated the ERK1/2, P38 and STAT3 signalling pathways. The ERK1/2 inhibitor U0126, the P38 inhibitor SB239063 and the STAT3 inhibitor S3I-201 all attenuated the effects of AGEs on MLO-Y4 cell apoptosis and IL-6 and VEGF-A secretion. Moreover, activation of the three signalling pathways was abolished by their respective inhibitors. Additionally, the AGEs-induced effects, including increased apoptosis, up regulated expression of IL-6 and VEGF-A and activation of the three signalling pathways, were all abolished by pre-treating the osteocytes with the RAGE antagonist FPS-ZM1. Together, these data convince us that AGEs can activate the ERK1/2, P38 and STAT3 signalling pathways via RAGE and that their activation involves the AGEs-induced up-regulation of IL-6 and VEGF-A production as well as apoptosis in osteocytes. These results highlight the role of osteocytes in the regulation of bone metabolism by AGEs. PMID- 28910746 TI - Transport of imidazolium-based ionic liquids with different anion/cation species in sand/soil columns. AB - Ionic liquids (ILs) have been widely used as environmentally friendly solvents to replace volatile organic solvents in the chemistry industries. They have a high water solubility and potential risk to organisms in the soil-water environment. At present, most studies focused on the batch sorption of ILs in soil and neglected the investigation of IL transports in soil, which results in a lack of understanding of the structure-dependent mobility of ILs in the environment. Laboratory-scale sand/soil column experiments were performed to study the transport of imidazolium-based ILs, such as [C4mim][OTF], [C4mim][TOS], [C4mim][MeSO3], [C4mim][BF4], [C2mim][BF4], and [C6mim][BF4] including different counteranions and alkyl chain lengths of IL cations. Batch experiments were also carried out to compare the difference of sorption distribution coefficient (Kd) between the batch and column experiments. A one-dimensional convective-dispersive model using CXTFIT code was created based on the measured breakthrough curves (BTCs) to estimate the column transport parameters. For the anion, [BF4-], the Kd of ILs in both batch and column experiments increased with increasing alkyl chain lengths of the IL cation. In batch tests, counteranions showed no influence on the Kd of [C4mim][OTF], [C4mim][TOS], [C4mim][MeSO3], [C4mim][BF4], [C2mim][BF4], and [C6mim][BF4]. However, in column tests, the BTCs of 1-butyl-3 methylimidazolium-based ILs were anion dependent as evidenced by the change of retardation factor (R) for different counteranions. Furthermore, the effects of transport distance (11cm, 15cm, 19cm, and 24cm) on the mobility of ILs were estimated. The longer distances signified an increase in the contact time and more binding sites for ILs and therefore, the smoother shapes of BTCs in column experiments. PMID- 28910747 TI - Transcriptome analysis of Rana chensinensis liver under trichlorfon stress. AB - Trichlorfon is a selective organophosphate insecticide that is widely applied in aquaculture and agriculture for control of various parasites. However, repeated and excess applications of trichlorfon often lead to water pollution and threaten non-targeted species. Our previous studies showed that trichlorfon could cause oxidative stress, lipid peroxidation and hepatic lesions in the liver of Rana chensinensis, but the related molecular mechanisms remain unclear. To explore the interference of trichlorfon in gene transcription, the differentially expressed genes in the liver of R. chensinensis exposed to trichlorfon were characterized using the RNA-seq platform. A search of all unigenes against non-redundant protein sequence (Nr), non-redundant nucleotide (Nt), Swiss-Prot, Kyoto Encyclopaedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases resulted in 22,888, 21,719, 20,934, 16,923, 7375 and 15,631 annotations, respectively, and provided a total of 27,781 annotated unigenes. Among the annotated unigenes, 16,923 were mapped to 257 signalling pathways. A set of 3329 differentially expressed unigenes was identified by comparison of the two groups in liver. Notably, relative expression of metabolism related genes, including both up- and down-regulated genes, were also validated by qPCR. The present study depicts the high degree of transcriptional complexity in R. chensinensis under trichlorfon stress and provides new insights into the molecular mechanisms of organophosphate insecticide toxicology. Some of these metabolism-responsive genes could be useful for understanding the toxicological mechanism of trichlorfon on non-target aquatic organisms and will contribute to the conservation of aquatic life. PMID- 28910748 TI - Local functional connectivity density is closely associated with the response of electroconvulsive therapy in major depressive disorder. AB - BACKGROUND: Electroconvulsive therapy (ECT) has been demonstrated to be an effective treatment of major depressive disorder (MDD). However, the neuroanatomical basis of response to ECT is still largely unknown. METHODS: In present study, we used functional connectivity density (FCD) and resting-state functional connectivity (RSFC) to identify the relationship between the changes of resting-state activities and ECT responses in 23 MDD patients before and after ECT. In addition, the identified neural indices as classification characteristics were entered into multivariate pattern analysis using linear support vector machine (SVM) to classify 23 MDD patients before ECT from 25 gender, age and years of education matched healthy controls. RESULTS: We found that the changes of local FCD (lFCD), not long-range FCD, of the left pre-/postcentral gyrus (Pre /postCG), left superior temporal gyrus (STG), and right STG were significantly correlated with the changes of Hamilton Rating Scale for Depression (HRSD) scores in MDD patients before and after ECT. The subsequent functional connectivity analysis revealed significantly decreased functional connectivity between right STG and right intraparietal sulcus (IPS) in MDD after ECT in spite of no correlation with HRSD scores. Finally, SVM-based classification achieved an accuracy of 72.92% with a sensitivity of 73.91% and a specificity of 72% by leave one-out cross-validation. CONCLUSIONS: Our findings indicated that Pre-/postCG and bilateral STG play an important role in response of ECT in MDD patients, and the lFCD in these areas may serve as a biomarker for predicting ECT response. PMID- 28910749 TI - Optimizing assessment of sexual arousal in postmenopausal women using erotic film clips. AB - OBJECTIVES: This study sought to assess sexual arousal in a subgroup of women by identifying erotic film clips that would be most mentally appealing and physically arousing to postmenopausal women. STUDY DESIGN: By measuring levels of mental appeal and self-reported physical arousal using a bidirectional scale, we aimed to elucidate the clips that would best be utilized for sexual health research in the postmenopausal or over 50-year-old subpopulation. RESULTS: Our results showed that postmenopausal women did not rate clips with older versus younger actors differently (p>0.05). The mean mental and mean physical scores were significantly correlated for both premenopausal subject ratings (r=0.69, p<0.001) and postmenopausal subject ratings (r=0.94, p<0.001). CONCLUSIONS: Thus postmenopausal women do not show a preference for the age of actors used in erotic film clips; this knowledge is relevant for design of future sexual function research. PMID- 28910750 TI - Analysis of methylation profiling data of hyperplasia and primary and metastatic endometrial cancers. AB - OBJECTIVE: Endometrial cancer is a prevalent cancer, and its metastasis causes low survival rate. This study aims to utilize DNA methylation data to investigate the mechanism of the development and metastasis of endometrial cancer. STUDY DESIGN: Methylation profiling data were down-loaded from Gene Expression Omnibus, including 8 hyperplasias, 33 primary and 53 metastatic endometrial cancers. COHCAP package and annotation files were utilized to identify differentially methylated genes (DMGs) and CpG islands between the three different endometrial diseases. STRING database and Cytoscape were used to analyze and visualize protein-protein interactions (PPIs) between DMGs. CytoNCA plugin was utilized to identify key nodes in PPI network. RESULTS: A total of 610, 1076, and 501 DMGs were identified between primary endometrial cancer and hyperplasia, metastatic endometrial cancer and hyperplasia, as well as metastatic and primary endometrial cancers, respectively. For the three DMG sets, 53 common hypermethylated DMGs (e.g. PAX6 and INSR) and 6 common hypomethylated DMGs (e.g. PRDM8, KLHL14, and DUSP6) were found. For primary-hyperplasia DMG set and metastasis-hyperplasia DMG set, 527 common DMGs were found. For these common DMGs, a PPI network involving 692 PPIs was constructed. For DMGs between metastatic and primary endometrial cancers, a PPI network involving 673 PPIs was established, with PAX6 and INSR in the top 20 DMGs in both networks. PRDM8, KLHL14, and DUSP6 had hypomethylated CpG islands. CONCLUSION: DMGs comparison, PPI network analysis, and analysis of differentially methylated CpG islands indicated that PAX6, INSR, PRDM8, KLHL14, and DUSP6 might participate in the development and metastasis of endometrial cancer. PMID- 28910751 TI - Chromatin reorganisation in Epstein-Barr virus-infected cells and its role in cancer development. AB - The oncogenic Epstein-Barr virus (EBV) growth transforms B cells and drives lymphoma and carcinoma development. The virus encodes four key transcription factors (EBNA2, EBNA3A, EBNA3B and EBNA3C) that hijack host cell factors to bind gene control elements and reprogramme infected B cells. These viral factors predominantly target long-range enhancers to alter the expression of host cell genes that control B cell growth and survival and facilitate virus persistence. Enhancer and super-enhancer binding by these EBNAs results in large-scale reorganisation of three-dimensional enhancer-promoter architecture to drive the overexpression of oncogenes, the silencing of tumour suppressors and the modulation of transcription, cell-cycle progression, migration and adhesion. PMID- 28910752 TI - Prevalence of metabolic syndrome among elderly Mexicans. AB - BACKGROUND: One of the most prevalent chronic diseases among elderly population is the Metabolic Syndrome (MetS). The aim of this study was to assess the prevalence of MetS and associated factors among Mexican elderly people. SUBJECTS: Cross-sectional survey carried out in Mexico (2007). A random sample (n=516) of the elderly population (>=65years; 277 female, 239 male) was interviewed. Anthropometric and analytical measurements, and a general questionnaire incorporating questions related to socio-demographic and life-style factors were used. MetS definition AHA/NHLBI/IDF was applied. RESULTS: The prevalence of MetS in the elderly (>=65years) was of 72.9% (75.7% men; 70.4% women). Participants with values above MetS cut-off points were 92.4% (hypertension), 77.8% (hypertriglyceridemia), 77.1% (low HDL-cholesterol), 71.1% (hyperglycaemia), and 65.4% (central obesity). People with MetS showed higher values of anthropometric and biochemical variables than those without MetS, except for the height, cholesterol and creatinine. Mid-high education level (9-12 years), no smokers and former smokers, and Central-Western inhabitants of Mexico were associated with MetS components. BMI status was the main determinant of MetS prevalence and MetS components. CONCLUSION: The reported prevalence of MetS among the elderly Mexican population was higher than those previously obtained in the geographical area, showing a major public health problem in Mexican elders. PMID- 28910753 TI - Fall prevalence, time trend and its related risk factors among elderly people in China. AB - OBJECTIVES: To study the fall prevalence, time trends and related risk factors among elderly people in the Chinese mainland from 2011 to 2013. METHODS: Our data were from China Health and Retirement Longitudinal Study in 2011 and 2013. The population sample included people aged 60 years and over. Whether the person had experienced fall accident in the last two years was used to measure fall incidence. The time trend and age groups were investigated through the chi-square test. The related risk factors were examined based on the binary logistic regression model. RESULTS: In 2011, 19.64% (95% CI, 18.66%, 20.67%) of elderly people experienced fall incidents and in 2013, 19.28% (95% CI, 18.46%, 20.13%) of elderly people experienced fall incidents. However, no significant difference was seen in the fall prevalence between 2011 and 2013. The fall prevalence among elderly people aged 66-70 declined significantly while that among people aged over 80 showed an increasing time trend. The fall prevalence was affected significantly by factors including age (66-70), gender, marital status, self rated health, quantity of chronic diseases, quantity of disability items, activities of daily living and physical functioning. CONCLUSIONS: It is revealed the fall prevalence showed no increment from 2011 to 2013 but at a high level. More efforts should be made to reduce the fall prevalence, and special attention should be paid to the elderly people aged over 80 and older. PMID- 28910754 TI - A Phase Variable Approach for IMU-Based Locomotion Activity Recognition. AB - OBJECTIVE: This paper describes a gait classification method that utilizes measured motion of the thigh segment provided by an inertial measurement unit. METHODS: The classification method employs a phase-variable description of gait, and identifies a given activity based on the expected curvature characteristics of that activity over a gait cycle. The classification method was tested in experiments conducted with seven healthy subjects performing three different locomotor activities: level ground walking, stair descent, and stair ascent. Classification accuracy of the phase variable classification method was assessed for classifying each activity, and transitions between activities, and compared to a linear discriminant analysis (LDA) classifier as a benchmark. RESULTS: For the subjects tested, the phase variable classification method outperformed LDA when using nonsubject-specific training data, while the LDA outperformed the phase variable approach when using subject-specific training. CONCLUSIONS: The proposed method may provide improved classification accuracy for gait classification applications trained with nonsubject-specific data. SIGNIFICANCE: This paper offers a new method of gait classification based on a phase variable description. The method is shown to provide improved classification accuracy relative to an LDA pattern recognition framework when trained with nonsubject specific data. PMID- 28910755 TI - SimiNet: A Novel Method for Quantifying Brain Network Similarity. AB - Quantifying the similarity between two networks is critical in many applications. A number of algorithms have been proposed to compute graph similarity, mainly based on the properties of nodes and edges. Interestingly, most of these algorithms ignore the physical location of the nodes, which is a key factor in the context of brain networks involving spatially defined functional areas. In this paper, we present a novel algorithm called "SimiNet" for measuring similarity between two graphs whose nodes are defined a priori within a 3D coordinate system. SimiNet provides a quantified index (ranging from 0 to 1) that accounts for node, edge and spatiality features. Complex graphs were simulated to evaluate the performance of SimiNet that is compared with eight state-of-art methods. Results show that SimiNet is able to detect weak spatial variations in compared graphs in addition to computing similarity using both nodes and edges. SimiNet was also applied to real brain networks obtained during a visual recognition task. The algorithm shows high performance to detect spatial variation of brain networks obtained during a naming task of two categories of visual stimuli: animals and tools. A perspective to this work is a better understanding of object categorization in the human brain. PMID- 28910756 TI - Coresets for Triangulation. AB - Multiple-view triangulation by $?ell _?infty$ minimisation has become established in computer vision. State-of-the-art $?ell _?infty$ triangulation algorithms exploit the quasiconvexity of the cost function to derive iterative update rules that deliver the global minimum. Such algorithms, however, can be computationally costly for large problem instances that contain many image measurements, e.g., from web-based photo sharing sites or long-term video recordings. In this paper, we prove that $?ell _?infty$ triangulation admits a coreset approximation scheme, which seeks small representative subsets of the input data called coresets. A coreset possesses the special property that the error of the $?ell _?infty$ solution on the coreset is within known bounds from the global minimum. We establish the necessary mathematical underpinnings of the coreset algorithm, specifically, by enacting the stopping criterion of the algorithm and proving that the resulting coreset gives the desired approximation accuracy. On large scale triangulation problems, our method provides theoretically sound approximate solutions. Iterated until convergence, our coreset algorithm is also guaranteed to reach the true optimum. On practical datasets, we show that our technique can in fact attain the global minimiser much faster than current methods. PMID- 28910757 TI - Learning Building Extraction in Aerial Scenes with Convolutional Networks. AB - Extracting buildings from aerial scene images is an important task with many applications. However, this task is highly difficult to automate due to extremely large variations of building appearances, and still heavily relies on manual work. To attack this problem, we design a deep convolutional network with a simple structure that integrates activation from multiple layers for pixel-wise prediction, and introduce the signed distance function of building boundaries to represent output, which has an enhanced representation power. To train the network, we leverage abundant building footprint data from geographic information systems (GIS) to generate large amounts of labeled data. The trained model achieves a superior performance on datasets that are significantly larger and more complex than those used in prior work, demonstrating that the proposed method provides a promising and scalable solution for automating this labor intensive task. PMID- 28910758 TI - Viewpoint-Consistent 3D Face Alignment. AB - Most approaches to face alignment treat the face as a 2D object, which fails to represent depth variation and is vulnerable to loss of shape consistency when the face rotates along a 3D axis. Because faces commonly rotate three dimensionally, 2D approaches are vulnerable to significant error. 3D morphable models, employed as a second step in 2D+3D approaches are robust to face rotation but are computationally too expensive for many applications, yet their ability to maintain viewpoint consistency is unknown. We present an alternative approach that estimates 3D face landmarks in a single face image. The method uses a regression forest-based algorithm that adds a third dimension to the common cascade pipeline. 3D face landmarks are estimated directly, which avoids fitting a 3D morphable model. The proposed method achieves viewpoint consistency in a computationally efficient manner that is robust to 3D face rotation. To train and test our approach, we introduce the Multi-PIE Viewpoint Consistent database. In empirical tests, the proposed method achieved simple yet effective head pose estimation and viewpoint consistency on multiple measures relative to alternative approaches. PMID- 28910759 TI - Multi-Rate Acquisition for Dead Time Reduction in Magnetic Resonance Receivers: Application to Imaging With Zero Echo Time. AB - For magnetic resonance imaging of tissues with very short transverse relaxation times, radio-frequency excitation must be immediately followed by data acquisition with fast spatial encoding. In zero-echo-time (ZTE) imaging, excitation is performed while the readout gradient is already on, causing data loss due to an initial dead time. One major dead time contribution is the settling time of the filters involved in signal down-conversion. In this paper, a multi-rate acquisition scheme is proposed to minimize dead time due to filtering. Short filters and high output bandwidth are used initially to minimize settling time. With increasing time since the signal onset, longer filters with better frequency selectivity enable stronger signal decimation. In this way, significant dead time reduction is accomplished at only a slight increase in the overall amount of output data. Multi-rate acquisition was implemented with a two-stage filter cascade in a digital receiver based on a field-programmable gate array. In ZTE imaging in a phantom and in vivo, dead time reduction by multi-rate acquisition is shown to improve image quality and expand the feasible bandwidth while increasing the amount of data collected by only a few percent. PMID- 28910760 TI - Structure Prediction for Gland Segmentation With Hand-Crafted and Deep Convolutional Features. AB - We present a novel method to segment instances of glandular structures from colon histopathology images. We use a structure learning approach which represents local spatial configurations of class labels, capturing structural information normally ignored by sliding-window methods. This allows us to reveal different spatial structures of pixel labels (e.g., locations between adjacent glands, or far from glands), and to identify correctly neighboring glandular structures as separate instances. Exemplars of label structures are obtained via clustering and used to train support vector machine classifiers. The label structures predicted are then combined and post-processed to obtain segmentation maps. We combine hand crafted, multi-scale image features with features computed by a deep convolutional network trained to map images to segmentation maps. We evaluate the proposed method on the public domain GlaS data set, which allows extensive comparisons with recent, alternative methods. Using the GlaS contest protocol, our method achieves the overall best performance. PMID- 28910761 TI - Phantomless Auto-Calibration and Online Calibration Assessment for a Tracked Freehand 2-D Ultrasound Probe. AB - This paper presents a method for automatically calibrating and assessing the calibration quality of an externally tracked 2-D ultrasound (US) probe by scanning arbitrary, natural tissues, as opposed a specialized calibration phantom as is the typical practice. A generative topic model quantifies the posterior probability of calibration parameters conditioned on local 2-D image features arising from a generic underlying substrate. Auto-calibration is achieved by identifying the maximum a-posteriori image-to-probe transform, and calibration quality is assessed online in terms of the posterior probability of the current image-to-probe transform. Both are closely linked to the 3-D point reconstruction error (PRE) in aligning feature observations arising from the same underlying physical structure in different US images. The method is of practical importance in that it operates simply by scanning arbitrary textured echogenic structures, e.g., in-vivo tissues in the context of the US-guided procedures, without requiring specialized calibration procedures or equipment. Observed data take the form of local scale-invariant features that can be extracted and fit to the model in near real-time. Experiments demonstrate the method on a public data set of in vivo human brain scans of 14 unique subjects acquired in the context of neurosurgery. Online calibration assessment can be performed at approximately 3 Hz for the US images of pixels. Auto-calibration achieves an internal mean PRE of 1.2 mm and a discrepancy of [2 mm, 6 mm] in comparison to the calibration via a standard phantom-based method. PMID- 28910762 TI - Deep Edge Guided Recurrent Residual Learning for Image Super-Resolution. AB - In this paper, we consider the image super-resolution (SR) problem. The main challenge of image SR is to recover high-frequency details of a low-resolution (LR) image that are important for human perception. To address this essentially ill-posed problem, we introduce a Deep Edge Guided REcurrent rEsidual (DEGREE) network to progressively recover the high-frequency details. Different from most of the existing methods that aim at predicting high-resolution (HR) images directly, the DEGREE investigates an alternative route to recover the difference between a pair of LR and HR images by recurrent residual learning. DEGREE further augments the SR process with edge-preserving capability, namely the LR image and its edge map can jointly infer the sharp edge details of the HR image during the recurrent recovery process. To speed up its training convergence rate, by-pass connections across the multiple layers of DEGREE are constructed. In addition, we offer an understanding on DEGREE from the view-point of sub-band frequency decomposition on image signal and experimentally demonstrate how the DEGREE can recover different frequency bands separately. Extensive experiments on three benchmark data sets clearly demonstrate the superiority of DEGREE over the well established baselines and DEGREE also provides new state-of-the-arts on these data sets. We also present addition experiments for JPEG artifacts reduction to demonstrate the good generality and flexibility of our proposed DEGREE network to handle other image processing tasks. PMID- 28910763 TI - Feature Augmentation for Learning Confidence Measure in Stereo Matching. AB - Confidence estimation is essential for refining stereo matching results through a post-processing step. This problem has recently been studied using a learning based approach, which demonstrates a substantial improvement on conventional simple non-learning based methods. However, the formulation of learning-based methods that individually estimates the confidence of each pixel disregards spatial coherency that might exist in the confidence map, thus providing a limited performance under challenging conditions. Our key observation is that the confidence features and resulting confidence maps are smoothly varying in the spatial domain, and highly correlated within the local regions of an image. We present a new approach that imposes spatial consistency on the confidence estimation. Specifically, a set of robust confidence features is extracted from each superpixel decomposed using the Gaussian mixture model, and then these features are concatenated with pixel-level confidence features. The features are then enhanced through adaptive filtering in the feature domain. In addition, the resulting confidence map, estimated using the confidence features with a random regression forest, is further improved through K-nearest neighbor based aggregation scheme on both pixel- and superpixel-level. To validate the proposed confidence estimation scheme, we employ cost modulation or ground control points based optimization in stereo matching. Experimental results demonstrate that the proposed method outperforms state-of-the-art approaches on various benchmarks including challenging outdoor scenes. PMID- 28910764 TI - Efficient Message Passing Methods With Fully Connected Models for Early Vision. AB - Fully connected Markov random fields and conditional random fields have recently been shown to be advantageous in many early vision tasks being formulated as multi-labeling problems, such as stereo matching and image segmentation. The maximum posterior marginal (MPM) inference method in solving fully connected models uses a hybrid framework of mean-field (MF) method and a filtering like approach, and yields excellent results. In this paper, we extend this framework in several aspects. First, we provide an alternative inference method employing fractional belief propagation based method instead of MF. Second, we reformulate the MPM problem into a maximum a posterior (MAP) problem and provide efficient algorithms for solving this. Third, we extend the fully connected model into a multi-resolution approach. Finally, we propose an integral image based approach which makes it possible for efficiently integrating the local linear regression technique into this framework. Comparisons are carried out among different algorithms and different formulations to find the best combination. We demonstrate that the use of our multi-resolution approach with MAP formulation substantially outperforms the ordinary MF-based inference scheme. PMID- 28910765 TI - Multiple Semantic Matching on Augmented $N$ -Partite Graph for Object Co Segmentation. AB - Recent methods for object co-segmentation focus on discovering single co occurring relation of candidate regions representing the foreground of multiple images. However, region extraction based only on low and middle level information often occupies a large area of background without the help of semantic context. In addition, seeking single matching solution very likely leads to discover local parts of common objects. To cope with these deficiencies, we present a new object co-segmentation framework, which takes advantages of semantic information and globally explores multiple co-occurring matching cliques based on an N-partite graph structure. To this end, we first propose to incorporate candidate generation with semantic context. Based on the regions extracted from semantic segmentation of each image, we design a merging mechanism to hierarchically generate candidates with high semantic responses. Second, all candidates are taken into consideration to globally formulate multiple maximum weighted matching cliques, which complement the discovery of part of the common objects induced by a single clique. To facilitate the discovery of multiple matching cliques, an N partite graph, which inherently excludes intralinks between candidates from the same image, is constructed to separate multiple cliques without additional constraints. Further, we augment the graph with an additional virtual node in each part to handle irrelevant matches when the similarity between the two candidates is too small. Finally, with the explored multiple cliques, we statistically compute pixel-wise co-occurrence map for each image. Experimental results on two benchmark data sets, i.e., iCoseg and MSRC data sets achieve desirable performance and demonstrate the effectiveness of our proposed framework. PMID- 28910766 TI - Light Field Compression With Disparity-Guided Sparse Coding Based on Structural Key Views. AB - Recent imaging technologies are rapidly evolving for sampling richer and more immersive representations of the 3D world. One of the emerging technologies is light field (LF) cameras based on micro-lens arrays. To record the directional information of the light rays, a much larger storage space and transmission bandwidth are required by an LF image as compared with a conventional 2D image of similar spatial dimension. Hence, the compression of LF data becomes a vital part of its application. In this paper, we propose an LF codec with disparity guided Sparse Coding over a learned perspective-shifted LF dictionary based on selected Structural Key Views (SC-SKV). The sparse coding is based on a limited number of optimally selected SKVs; yet the entire LF can be recovered from the coding coefficients. By keeping the approximation identical between encoder and decoder, only the residuals of the non-key views, disparity map, and the SKVs need to be compressed into the bit stream. An optimized SKV selection method is proposed such that most LF spatial information can be preserved. To achieve optimum dictionary efficiency, the LF is divided into several coding regions, over which the reconstruction works individually. Experiments and comparisons have been carried out over benchmark LF data set, which show that the proposed SC-SKV codec produces convincing compression results in terms of both rate-distortion performance and visual quality compared with Joint Exploration Model: with 37.9% BD-rate reduction and 1.17-dB BD-PSNR improvement achieved on average, especially with up to 6-dB improvement for low bit rate scenarios. PMID- 28910767 TI - Single Image De-Hazing Using Globally Guided Image Filtering. AB - Local edge-preserving smoothing techniques such as guided image filtering (GIF) and weighted guided image filtering (WGIF) could not preserve fine structure. In this paper, a new globally guided image filtering (G-GIF) is introduced to overcome the problem. The G-GIF is composed of a global structure transfer filter and a global edge-preserving smoothing filter. The proposed filter is applied to study single image haze removal. Experimental results show that fine structure of the dehazed image is indeed preserved better by the proposed G-GIF and the dehazed images by the proposed G-GIF are sharper than those dehazed images by the existing GIF. PMID- 28910768 TI - Example-Based Image Synthesis via Randomized Patch-Matching. AB - Image and texture synthesis is a challenging task that has long been drawing attention in the fields of image processing, graphics, and machine learning. This problem consists of modeling the desired type of images, either through training examples or via a parametric modeling, and then generating images that belong to the same statistical origin. This paper addresses the image synthesis task, focusing on two specific families of images-handwritten digits and face images. This paper offers two main contributions. First, we suggest a simple and intuitive algorithm capable of generating such images in a unified way. The proposed approach taken is pyramidal, consisting of upscaling and refining the estimated image several times. For each upscaling stage, the algorithm randomly draws small patches from a patch database and merges these to form a coherent and novel image with high visual quality. The second contribution is a general framework for the evaluation of the generation performance, which combines three aspects: the likelihood, the originality, and the spread of the synthesized images. We assess the proposed synthesis scheme and show that the results are similar in nature, and yet different from the ones found in the training set, suggesting that true synthesis effect has been obtained. PMID- 28910769 TI - Single-Image Shadow Removal Using 3D Intensity Surface Modeling. AB - Shadow removal from a single image is a challenging problem, whose solution is proposed in this paper using 3D intensity surface modeling. Due to the high-order textural content in the original images, a direct modeling of the intensity surface of shadow image is difficult. In this paper, image decomposition technology is used as an edge-preserving filter to remove the textural detail while keeping the local-smoothness pattern of image intensity surface. Using 3D modeling, a proper intensity surface of illumination in shadow region can be obtained based on that corresponding to the same texture in the non-shadow one. Thus, the intensity surface of shadow region can be compensated with a respective shadow-removal. Experimental results demonstrate the effectiveness of the proposed approach in the aspect of single-image shadow removal. In contrast to the alternative methods, it is not limited by additional assumptions or conditions; moreover, it can deal with the non-uniform and curved surface shadows, and is applicable to the shadow regions consisting of different types of textures. PMID- 28910770 TI - Global-Local Temporal Saliency Action Prediction. AB - Action prediction on a partially observed action sequence is a very challenging task. To address this challenge, we first design a global-local distance model, where a global-temporal distance compares subsequences as a whole and local temporal distance focuses on individual segment. Our distance model introduces temporal saliency for each segment to adapt its contribution. Finally, a global local temporal action prediction model is formulated in order to jointly learn and fuse these two types of distances. Such a prediction model is capable of recognizing action of: 1) an on-going sequence and 2) a sequence with arbitrarily frames missing between the beginning and end (known as gap-filling). Our proposed model is tested and compared with related action prediction models on BIT, UCF11, and HMDB data sets. The results demonstrated the effectiveness of our proposal. In particular, we showed the benefit of our proposed model on predicting unseen action types and the advantage on addressing the gapfilling problem as compared with recently developed action prediction models. PMID- 28910771 TI - A General Framework for Linear Distance Preserving Hashing. AB - Binary hashing approaches the approximate nearest neighbor search problem by transferring the data to Hamming space with explicit or implicit distance preserving constraint. With compact data representation, binary hashing identifies the approximate nearest neighbors via very efficient Hamming distance computation. In this paper, we propose a generic hashing framework with a new linear pairwise distance preserving objective and pointwise constraint. In our framework, the direct distance preserving objective aims to keep the linear relationship between the Euclidean distance and the Hamming distance of data points. On the other hand, to impose the pointwise constraint, we instantiate the framework from three different perspectives with pseudo-supervised, unsupervised, and supervised clues and obtain three different hashing methods. The first one is a pseudo-supervised hashing method, which adopts a certain existing unsupervised hashing method to generate binary codes as pseudo-supervised information. For the second one, we get an unsupervised hashing method by considering the quantization loss. The third one, as a supervised hashing method, learns the hash functions in a two-step paradigm. Furthermore, we improve the above-mentioned framework by constraining the global scope of the proposed linear distance preserving objective to a local range. We validate our framework on four large-scale benchmark data sets. The experiments demonstrate that our pseudo-supervised method achieves consistent improvement over the state-of-the-art unsupervised hashing methods, while our unsupervised and supervised methods achieve promising performance compared with the state-of-the-art algorithms. PMID- 28910772 TI - Semantic-Driven Generation of Hyperlapse from 360 Degree Video. AB - We present a system for converting a fully panoramic (360 degree) video into a normal field-of-view (NFOV) hyperlapse for an optimal viewing experience. Our system exploits visual saliency and semantics to non-uniformly sample in space and time for generating hyperlapses. In addition, users can optionally choose objects of interest for customizing the hyperlapses. We first stabilize an input 360 degree video by smoothing the rotation between adjacent frames and then compute regions of interest and saliency scores. An initial hyperlapse is generated by optimizing the saliency and motion smoothness followed by the saliency-aware frame selection. We further smooth the result using an efficient 2D video stabilization approach that adaptively selects the motion model to generate the final hyperlapse. We validate the design of our system by showing results for a variety of scenes and comparing against the state-of-the-art method through a large-scale user study. PMID- 28910773 TI - A Vector Field Design Approach to Animated Transitions. AB - Animated transitions can be effective in explaining and exploring a small number of visualizations where there are drastic changes in the scene over a short interval of time. This is especially true if data elements cannot be visually distinguished by other means. Current research in animated transitions has mainly focused on linear transitions (all elements follow straight line paths) or enhancing coordinated motion through bundling of linear trajectories. In this paper, we introduce animated transition design, a technique to build smooth, non linear transitions for clustered data with either minimal or no user involvement. The technique is flexible and simple to implement, and has the additional advantage that it explicitly enhances coordinated motion and can avoid crowding, which are both important factors to support object tracking in a scene. We investigate its usability, provide preliminary evidence for the effectiveness of this technique through metric evaluations and user study and discuss limitations and future directions. PMID- 28910774 TI - Influence of Hip Prosthesis Size and Its Coating Area on Bone Remodeling. AB - We developed a numerical model to describe the bone remodeling process in periprosthetic bone tissues and validated it by means of dual energy X-ray absorptiometry methods with different types of hip implants. In this paper, we applied the numerical model to investigate the influence of implant size and of the size of the porous coated area on bone remodeling in a periprosthetic human femur in an effort to define properties of implants, which would reduce bone remodeling after total hip arthroplasty. Two different sizes of a newly designed implant and three different coating area sizes were investigated in this paper. The results show that the smaller the implant, the less bone remodeling occurs. Reducing prosthesis size by 2mm from all sides has decreased bone remodeling by 14.4%. Extending the coating area on both, lateral and medial parts of the implant, has decreased bone remodeling in the lateral part of the femur and increased it in the medial part. In conclusion, depending on these results, the oversized hip replacement would cause more bone resorption in the femur. Concerning the coating area, the manufacturer must find a compromise between the small coating area with less bone remodeling in the medial part of the femur as well as less primary stability and the bigger coating area with less bone remodeling in the lateral part of the femur, but with higher bone remodeling in its medial part and more primary stability. PMID- 28910775 TI - Classification of Schizophrenia Based on Individual Hierarchical Brain Networks Constructed From Structural MRI Images. AB - With structural magnetic resonance imaging (MRI) images, conventional methods for the classification of schizophrenia (SCZ) and healthy control (HC) extract cortical thickness independently at different regions of interest (ROIs) without considering the correlation between these regions. In this paper, we proposed an improved method for the classification of SCZ and HC based on individual hierarchical brain networks constructed from structural MRI images. Our method involves constructing individual hierarchical networks where each node and each edge in these networks represents a ROI and the correlation between a pair of ROIs, respectively. We demonstrate that edge features make significant improvement in performance of SCZ/HC classification, when compared with only node features. Classification performance is further investigated by combining edge features with node features via a multiple kernel learning framework. The experimental results show that our proposed method achieves an accuracy of 88.72% and an area under the receiver operating characteristic (ROC) curve (AUC) of 0.9521 for SCZ/HC classification, which demonstrate that our proposed method is efficient and promising for clinical applications for the diagnosis of SCZ via structural MRI images. Therefore, this paper provides an alternative method for extracting high-order cortical thickness features from structural MRI images for classification of neurodegenerative diseases such as SCZ. PMID- 28910776 TI - FastEtch: A Fast Sketch-based Assembler for Genomes. AB - De novo genome assembly describes the process of reconstructing an unknown genome from a large collection of short (or long) reads sequenced from the genome. A single run of a Next-Generation Sequencing (NGS) technology can produce billions of short reads, making genome assembly computationally demanding (both in terms of memory and time). One of the major computational steps in modern day short read assemblers involves the construction and use of a string data structure called the de Bruijn graph. In fact, a majority of short read assemblers build the complete de Bruijn graph for the set of input reads, and subsequently traverse and prune low-quality edges, in order to generate genomic "contigs"-the output of assembly. These steps of graph construction and traversal, contribute to well over 90% of the runtime and memory. In this paper, we present a fast algorithm, FastEtch, that uses sketching to build an approximate version of the de Bruijn graph for the purpose of generating an assembly. The algorithm uses Count-Min sketch, which is a probabilistic data structure for streaming data sets. The result is an approximate de Bruijn graph that stores information pertaining only to a selected subset of nodes that are most likely to contribute to the contig generation step. In addition, edges are not stored; instead that fraction which contribute to our contig generation are detected on-the-fly. This approximate approach is intended to significantly improve performance (both execution time and memory footprint) whilst possibly compromising on the output assembly quality. We present two main versions of the assembler-one that generates an assembly, where each contig represents a contiguous genomic region from one strand of the DNA, and another that generates an assembly, where the contigs can straddle either of the two strands of the DNA. For further scalability, we have implemented a multi-threaded parallel code. Experimental results using our algorithm conducted on E. coli, Yeast, C. elegans and Human (Chr2 and Chr2+3) genomes show that our method yields one of the best time-memory quality tradeoffs, when compared against many state-of-the-art genome assemblers. PMID- 28910777 TI - Haptic Collision Detection on Disjoint Objects with Overlapping and Inclusive Bounding Volumes. AB - This paper presents a method to alleviate performance degradation issues of Haptic Collision Detection when the Bounding Volumes or Bounding Volume Hierarchies of multiple disjoint objects are overlapping or inclusive and force the Haptic Collision Detection methods into narrow phase collision detection with all involved objects. The proposed method aims to generate tighter, mutually exclusive Bounding Volumes at the pre-processing stage, and to quickly cull irrelevant nearby objects at the broad phase to ensure that the Haptic Collision Detection methods will not be overloaded with unnecessary narrow phase collision detection. The proposed method is based on a hybrid representation of Bounding Volume and Space Partitioning and is implemented as an algorithm that automatically generates these new Bounding Volumes for disjoint objects, with details and corner cases discussed. A series of experiments based on real-life Haptic Collision Detection applications has been conducted. The results are analyzed and compared with those from an existing Haptic Collision Detection algorithm. The outcome demonstrates the capability of the proposed method in maintaining a stable Haptic Collision Detection performance under various challenging situations. PMID- 28910778 TI - Self-Weighted Supervised Discriminative Feature Selection. AB - In this brief, a novel self-weighted orthogonal linear discriminant analysis (SOLDA) problem is proposed, and a self-weighted supervised discriminative feature selection (SSD-FS) method is derived by introducing sparsity-inducing regularization to the proposed SOLDA problem. By using the row-sparse projection, the proposed SSD-FS method is superior to multiple sparse feature selection approaches, which can overly suppress the nonzero rows such that the associated features are insufficient for selection. More specifically, the orthogonal constraint ensures the minimal number of selectable features for the proposed SSD FS method. In addition, the proposed feature selection method is able to harness the discriminant power such that the discriminative features are selected. Consequently, the effectiveness of the proposed SSD-FS method is validated theoretically and experimentally. PMID- 28910779 TI - Partial-Nodes-Based State Estimation for Complex Networks With Unbounded Distributed Delays. AB - In this brief, the new problem of partial-nodes-based (PNB) state estimation problem is investigated for a class of complex network with unbounded distributed delays and energy-bounded measurement noises. The main novelty lies in that the states of the complex network are estimated through measurement outputs of a fraction of the network nodes. Such fraction of the nodes is determined by either the practical availability or the computational necessity. The PNB state estimator is designed such that the error dynamics of the network state estimation is exponentially ultimately bounded in the presence of measurement errors. Sufficient conditions are established to ensure the existence of the PNB state estimators and then the explicit expression of the gain matrices of such estimators is characterized. When the network measurements are free of noises, the main results specialize to the case of exponential stability for error dynamics. Numerical examples are presented to verify the theoretical results. PMID- 28910780 TI - Finite-Time Synchronization of Discontinuous Neural Networks With Delays and Mismatched Parameters. AB - This paper investigates the problem of finite-time drive-response synchronization for a class of neural networks with discontinuous activations, time-varying discrete and infinite-time distributed delays, and mismatched parameters. In order to cope with the difficulties induced by discontinuous activations, time delays, as well as mismatched parameters simultaneously, new 1-norm-based analytical techniques are developed. Both state feedback and adaptive controllers with and without the sign function are designed. Based on differential inclusion theory and Lyapunov functional method, several sufficient conditions on the finite-time synchronization are obtained. Our results show that the controllers with a sign function can reduce the conservativeness of control gains and the controllers without a sign function can overcome the chattering phenomenon. Numerical examples are given to show the effectiveness of the theoretical analysis. PMID- 28910781 TI - Weighted Performance Metrics for Automatic Neonatal Seizure Detection Using Multiscored EEG Data. AB - In neonatal intensive care units, there is a need for around the clock monitoring of electroencephalogram (EEG), especially for recognizing seizures. An automated seizure detector with an acceptable performance can partly fill this need. In order to develop a detector, an extensive dataset labeled by experts is needed. However, accurately defining neonatal seizures on EEG is a challenge, especially when seizure discharges do not meet exact definitions of repetitiveness or evolution in amplitude and frequency. When several readers score seizures independently, disagreement can be high. Commonly used metrics such as good detection rate (GDR) and false alarm rate (FAR) derived from data scored by multiple raters have their limitations. Therefore, new metrics are needed to measure the performance with respect to the different labels. In this paper, instead of defining the labels by consensus or majority voting, popular metrics including GDR, FAR, positive predictive value, sensitivity, specificity, and selectivity are modified such that they can take different scores into account. To this end, 353 hours of EEG data containing seizures from 81 neonates were visually scored by a clinical neurophysiologist, and then processed by an automated seizure detector. The scored seizures were mixed with false detections of an automated seizure detector and were relabeled by three independent EEG readers. Then, all labels were used in the proposed performance metrics and the result was compared with the majority voting technique and showed higher accuracy and robustness for the proposed metrics. Results were confirmed using a bootstrapping test. PMID- 28910782 TI - Spectral Analysis of Epidemic Thresholds of Temporal Networks. AB - Many complex systems can be modeled as temporal networks with time-evolving connections. The influence of their characteristics on epidemic spreading is analyzed in a susceptible-infected-susceptible epidemic model illustrated by the discrete-time Markov chain approach. We develop the analytical epidemic thresholds in terms of the spectral radius of weighted adjacency matrix by averaging temporal networks, e.g., periodic, nonperiodic Markovian networks, and a special nonperiodic non-Markovian network (the link activation network) in time. We discuss the impacts of statistical characteristics, e.g., bursts and duration heterogeneity, as well as time-reversed characteristic on epidemic thresholds. We confirm the tightness of the proposed epidemic thresholds with numerical simulations on seven artificial and empirical temporal networks and show that the epidemic threshold of our theory is more precise than those of previous studies. PMID- 28910783 TI - Diverse Non-Negative Matrix Factorization for Multiview Data Representation. AB - Non-negative matrix factorization (NMF), a method for finding parts-based representation of non-negative data, has shown remarkable competitiveness in data analysis. Given that real-world datasets are often comprised of multiple features or views which describe data from various perspectives, it is important to exploit diversity from multiple views for comprehensive and accurate data representations. Moreover, real-world datasets often come with high-dimensional features, which demands the efficiency of low-dimensional representation learning approaches. To address these needs, we propose a diverse NMF (DiNMF) approach. It enhances the diversity, reduces the redundancy among multiview representations with a novel defined diversity term and enables the learning process in linear execution time. We further propose a locality preserved DiNMF (LP-DiNMF) for more accurate learning, which ensures diversity from multiple views while preserving the local geometry structure of data in each view. Efficient iterative updating algorithms are derived for both DiNMF and LP-DiNMF, along with proofs of convergence. Experiments on synthetic and real-world datasets have demonstrated the efficiency and accuracy of the proposed methods against the state-of-the-art approaches, proving the advantages of incorporating the proposed diversity term into NMF. PMID- 28910784 TI - Fetal Surgery for Myelomeningocele: A Systematic Review and Meta-Analysis of Outcomes in Fetoscopic versus Open Repair. AB - BACKGROUND/OBJECTIVES: The Management of Myelomeningocele (MMC) Study (MOMS) showed that prenatal repair of MMC resulted in improved neurological outcomes but was associated with high rates of obstetrical complications. This study compares outcomes of open and fetoscopic MMC repair. DATA SOURCES: PubMed and Embase studies reporting outcomes of fetal MMC repair published since the completion of the MOMS. RESULTS: We analyzed 11 studies and found no difference in mortality or the rate of shunt placement for hydrocephalus. Percutaneous fetoscopic repair was associated with higher rates of premature rupture of membranes (91 vs. 36%, p < 0.01) and preterm birth (96 vs. 81%, p = 0.04) compared to open repair, whereas fetoscopic repair via maternal laparotomy reduced preterm birth. The rate of dehiscence and leakage from the MMC repair site was higher after both types of fetoscopic surgery (30 vs. 7%, p < 0.01), while the rate of uterine dehiscence was higher after open repair (11 vs. 0%, p < 0.01). DISCUSSION: Fetoscopic repair is a promising alternative to open fetal MMC repair with a lower risk of uterine dehiscence; however, fetoscopic techniques should be optimized to overcome the high rate of dehiscence and leakage at the MMC repair site. A fetoscopic approach via maternal laparotomy reduces the risk of preterm birth. PMID- 28910785 TI - Oral Tolerization with Mycobacterial Heat Shock Protein 65 Reduces Chronic Experimental Atherosclerosis in Aged Mice. AB - BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the artery wall where both innate and adaptive immunity play important roles. Modulation of the immune response against the stress protein antigen, heat shock protein (HSP) 60, by administration of mycobacterial HSP65 (mbHSP65) orally and/or nasally shows promising therapeutic results in young animals in the sense of less severe experimental atherosclerosis; however, the case of aged animals with already established atherosclerosis has so far never been investigated. OBJECTIVE: To investigate if mbHSP65 immunization would further accelerate atherosclerotic progression in aged ApoE-/- mice (18 months old) with already long-established atherosclerosis and if these mice could be orally tolerized against mbHSP65. METHODS: Aged wild-type (WT) and ApoE-/- mice (65 weeks) were immunized and/or orally treated with mbHSP65 and then either kept on normal chow or changed to high-cholesterol diet (HCD). Atherosclerosis was assessed by en face analysis and the number of CD4+CD25+FoxP3+ T regulatory cells (Tregs) was assessed by flow cytometry in lymph node and spleen cells. Total cholesterol and triglyceride levels were determined. Soluble mammalian HSP60 and anti-mouse HSP60 (mHSP60) and anti-mbHSP65 antibodies were detected by enzyme-linked immunosorbent assay. RESULTS: As expected, aged WT mice had only minor lesions in the aorta, which did not change under HCD for 14 weeks. Aged ApoE-/- mice already had large complicated plaques, which increased in size under HCD. mbHSP65 immunization led to a significant aggravation of atherosclerosis in both WT and ApoE-/- mice irrespective of the nature of their diet. This increase was accompanied by increased titers of both anti-mHSP60 and anti-mbHSP65 antibodies in the circulation. The increased plaque formation could be significantly diminished with oral mbHSP65 tolerization. An increased number of Tregs and lower or unchanged levels of cholesterol and triglycerides were associated with the reduced size of aortal lesions. CONCLUSION: Oral tolerization against mbHSP65 could be used both to prevent and to treat chronic atherosclerosis in aged individuals. PMID- 28910786 TI - The Evolving Patterns of Uremia: Unmet Clinical Needs in Dialysis. AB - End-stage renal disease (ESRD) has become a challenging health problem worldwide. Currently, ESRD patients treated with hemodialysis mainly undergo low-flux hemodialysis, high-flux hemodialysis (HF-HD), or hemodiafiltration (HDF). The clearance of middle and large molecules is, however, quite insufficient as regards HF-HD, HDF, and on-line HDF. An unsatisfactory prognosis has led to improved dialysis technology and materials; both protein-leaking membranes and high cut-off membranes increase the clearance of uremic toxin, but in clinical application they may induce albumin loss. Novel membranes with similar clearance efficiency but little impact on albumin leakage are yet to be developed. To enhance the removal of uremic toxins and increase membrane permeability, a high retention onset (HRO) membrane with larger pore size and HRO, once defined as medium cut-off, has been developed in the past few years. Such a membrane enables leakage of larger size molecules including albumin. The dialysis using HRO membranes has recently been proposed as expanded hemodialysis (HDx). Theoretically, HDx could promote the removal of more toxin solutes retained in the blood of ESRD patients, and improve the outcomes of dialysis. However, randomized controlled trials are required to evaluate the long-term efficacy, safety, and side effects of HDx in the future. PMID- 28910787 TI - Middle-Molecule Uremic Toxins and Outcomes in Chronic Kidney Disease. AB - In patients with chronic kidney disease (CKD), uremic toxins constitute a specific nontraditional risk factor. Research in this field started in the early 1990s, and a growing body of preclinical and epidemiological evidence suggests that elevated levels of uremic toxins are associated with poor outcomes in a CKD setting. The present review focuses on a specific class of uremic toxins (the "middle molecules"), which includes well-known candidates like beta-2 microglobulin and fibroblast growth factor 23. Here, we summarize the epidemiological evidence linking the middle-molecule uremic toxin (and especially the larger ones) with hard clinical end points. Our findings highlight the urgent need for clinical trials of interventions designed to decrease levels of these middle molecules in CKD patients. PMID- 28910788 TI - Uremia Retention Molecules and Clinical Outcomes. AB - Chronic kidney disease is characterized by the accumulation of organic compounds in the bloodstream that may exert a variety of toxic effects in the body. These compounds, collectively known as uremic toxins, may be classified according to their physicochemical properties as free water-soluble low molecular weight molecules, middle molecules or protein-bound uremic toxins. Most of these retention molecules, due to either their size and/or binding to protein, constitute a complex therapeutic challenge to the nephrologist, particularly in end-stage renal disease, because of their limited removal by conventional dialysis therapies. Therefore, we review in this article the current clinical evidences that have supported the important role of uremic toxins in uremia by contributing to the adverse outcomes related to chronic kidney disease, such as increased mortality and cardiovascular events, as well as renal impairment progression that cannot be solely explained by traditional risk factors. These observations have ultimately contributed to testing new therapeutic targets, such as the gut, and the development of modern dialysis strategies to manage chronic kidney disease patients. PMID- 28910789 TI - End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes. AB - Despite marked improvements in renal replacement therapy during the last 30 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients is still unacceptably high and comparable to that of many malignancies. Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in ESRD patients. However, traditional risk factors can only partially explain the high premature cardiovascular burden in this population. Nontraditional risk factors, including persistent low-grade inflammation, are critical in the pathogenesis of atherosclerosis, vascular calcification, and other causes of CVD and may also contribute to protein-energy wasting and other complications in chronic kidney disease (CKD) patients. Inflammatory biomarkers, such as high sensitivity C-reactive protein and interleukin-6, independently predict mortality in these patients. The causes of inflammation in CKD are multifactorial and include imbalance between increased production (due to multiple sources of inflammatory stimuli such as oxidative stress, acidosis, volume overload, co morbidities, especially infections, genetic and epigenetic influences, and the dialysis procedure) and inadequate removal (due to decreased glomerular filtration rate or in ESRD patients, inadequate dialytic clearance) of pro inflammatory cytokines. Though there are currently no established guidelines for the treatment of low-grade inflammation in ESRD patients, several strategies have been proposed, such as lifestyle modifications, pharmacological treatment, and optimization of dialysis. Further studies on pathways involved in pathogenic processes of inflammation in ESRD, and long-term effects of anti-inflammatory interventions targeting production or removal of cytokines or both on premature CVD and clinical outcomes in this patient group are warranted. PMID- 28910790 TI - The Cardiovascular Burden in End-Stage Renal Disease. AB - It is well documented that chronic kidney disease patients have an extremely high risk of developing cardiovascular (CV) disease (CVD) compared to the general population. Declining renal function itself represents a continuum of CV risk, and in those individuals who survive to reach end-stage renal disease, the risk of suffering a cardiac event is uncomfortably and unacceptably high. Several pathophysiological pathways have been suggested to account for this, including endothelial dysfunction, dyslipidemia, inflammation, left ventricular hypertrophy, troponins, phosphate, vitamin D, fibroblast growth factor-23, and NT proBNP. All these conditions and biomarkers may have clear associations with current and subsequent CVD. PMID- 28910791 TI - Inflammation and Protein-Energy Wasting in the Uremic Milieu. AB - Inflammation is normally a protective and physiological response to harmful stimuli, but typically becomes an uncontrolled, maladaptive, and persistent process in patients with end-stage renal disease (ESRD). Through a deleterious cascade of poorly controlled reactions mediated by biologically active molecules (also called middle molecular weight uremia retention solutes), inflammation associates with a range of complications including cardiovascular disease and protein-energy wasting (PEW). Persistent inflammation, which is central to the conceptual etiological models of PEW and the malnutrition, inflammation, and atherosclerosis syndrome, induces and reignites processes leading to PEW in a number of ways including stimulation of both direct and indirect mechanisms of muscle proteolysis. Similar to other chronic diseases, inflammation in the uremic milieu is the consequence of multiple factors including comorbidities, such as infections. In addition, inflammation is further aggravated in ESRD by uremic immune dysfunction, inadequate renal removal of cytokines, and inflammatory responses to dialysis. It is plausible that only by disrupting this vicious circle(s) by acting on several levels of the inflammatory cascade rather than targeting single causes of inflammation will it be possible to improve the prognosis in ESRD patients. Accordingly, treatment of uremic inflammation and PEW require an integrated approach. In addition to lifestyle modifications, nutritional supplements, and drugs with anti-inflammatory potential, improved dialysis therapy using high retention onset membranes has emerged recently. This novel dialysis technique, also called expanded hemodialysis (HDx), may provide a more efficient removal of middle molecules involved in the cascade of inflammatory mediators with selectivity against albumin losses. Plausibly, the implementation of HDx, integrated with strategies blocking an excessive secretion of inflammatory mediators, may offer a new therapeutic approach to chronic inflammation and PEW in ESRD. PMID- 28910792 TI - Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease. AB - It has become apparent that inflammation and inflammatory reactions can evoke renal injury and promote chronic kidney disease (CKD) progression. Under physiological condition, intrarenal vascular distribution is heterogeneous, and medulla is hypoxic. To avoid energy deprivation in the low pO2 regions of the kidney, an array of hormones, autocoids, and vasoactive substances, including medullipin, prostaglandins, endothelins, nitric oxide, angiotensin II, kinins, and adenosine, tonically regulates the microvasculature to ensure a perfect match of the microcirculation (O2 supply) and renal tubules (O2 demand). Inflammation, systemic or intrarenal, not only can abolish the microvascular response to its regulators, but also induces an array of tubular toxins, including reactive oxygen species, leading to tubular injury, nephron dropout, and onset of CKD. Positive acid balance, electrolyte alterations, and intestinal dysbiosis can perpetuate CKD progression. Understanding the role of inflammation in the genesis and progression of CKD will foster the development of strategies to prevent and treat the underlying inflammation and improve CKD outcomes. PMID- 28910793 TI - Solute Transport in Hemodialysis: Advances and Limitations of Current Membrane Technology. AB - Extracorporeal therapy for end-stage renal disease is now provided to more than three million patients globally. Nearly all treatments are performed with filters containing hollow fiber membranes, removing solutes and water by diffusion, convection, and ultrafiltration. In this review, we will provide a detailed quantitative analysis of the transport processes involved in different hemodialysis (HD) therapies. We will also report some technical aspects of hollow fiber membranes and filters composed of them along with the mechanisms of solute and water removal for such devices. Diffusive mass transfer will be assessed according to the three major aspects of a hollow fiber filter (blood compartment, membrane, and dialysate compartment). With regard to convective transport, the importance of internal filtration as a solute removal mechanism in high-flux HD will be highlighted, along with the critical role that blood/membrane interactions assume in filtration-based therapies. PMID- 28910794 TI - Membrane Innovation in Dialysis. AB - Despite advances in renal replacement therapy, the adequate removal of uremic toxins over a broad molecular weight range remains one of the unmet needs in hemodialysis. Therefore, membrane innovation is currently directed towards enhanced removal of uremic toxins and increased membrane permeability. This chapter presents a variety of opportunities where innovation is brought into dialysis membranes. It covers the membrane formation from solution, describing different approaches to control the phase inversion process through additives that either swell in the polymer solution or influence the pore shrinkage during the membrane drying process. Additionally, large-scale manufacturing is described, and the influence of raw materials, spinning, and drying processes on membrane selectivity are presented. Finally, new characterization methods developed for the latest innovations around the application of membranes in dialysis are discussed, which allow the membrane performance for removal of a broad range of uremic toxins and the expected albumin loss in clinical use. PMID- 28910795 TI - Multidimensional Classification of Dialysis Membranes. AB - Hemodialysis is a process of mass separation by a semipermeable membrane, utilized to cleanse blood from waste products retained in case of kidney failure. Traditionally, dialysis membranes have been classified based on composition and hydraulic conductance, creating the net differentiation between cellulosic versus non-cellulosic on one hand and low-flux versus high-flux on the other. With the evolution of biomaterials and improved spinning technology, new membranes have been introduced in the market with specific characteristics and refined individual properties. Therefore, we should consider new parameters to classify dialysis membranes including polymer blending, surface functionalization, molecular weight cut-off (MWCO), hydrophilic/hydrophobic properties, thickness and architecture, adsorption capacity, and electric potential. All these parameters may be utilized to characterize a membrane alone or in combination. Recently, a new parameter has been identified as an important element to characterize a new class of membranes. Beyond the classic MWCO describing the molecular weight at which the sieving value in pure convection = 0.1, the molecular weight retention onset (MWRO) is a new parameter that defines membrane sieving properties. The retention onset value is the molecular weight at which the sieving value = 0.9. The relationship between MWCO and MWRO describes the steepness of the sieving curve and the membrane pore size distribution with important consequences on the final mass separation process and solute removal. PMID- 28910796 TI - Modeling of Internal Filtration in Theranova Hemodialyzers. AB - High retention onset (HRO) is the designation for a new class of hemodialysis membranes. A unique characteristic of this class is the highly selective and controlled porosity resulting in sieving properties that provide a clinically desirable balance between middle/large molecular weight solute removal and albumin loss. Another defining feature of this membrane class is the relatively small fiber diameter, which produces high convective volumes in the form of internal filtration. The aim of the present study was to estimate, by semi empirical methods, convective volumes for 2 new HRO dialyzers: Theranova 400 and Theranova 500 (Baxter International Inc., Deerfield, IL, USA). Axial blood and dialysate compartment pressure drop along with transmembrane pressure, measured in vitro with blood (Qb = 300 or 400 mL/min; Qd = 500 mL/min; net ultrafiltration rate = 0), served as input parameters for 3 different models: linear, geometric, and (non-linear) mathematical. Based on the most rigorous mathematical model, the estimated convective volumes were 1,661 mL/h (Qb = 300 mL/min) and 1,911 mL/h (Qb = 400 mL/min) for Theranova 400 and 1,864 mL/h (Qb = 300 mL/min) and 1,978 mL/h (Qb = 400 mL/min) for Theranova 500. These results suggest that the unique fiber characteristics of this new class of membranes provide substantial convective volumes without the need for exogenous substitution fluid. As such, HRO membranes are a major end-stage renal disease treatment advance in the quest to enhance the removal of larger-sized uremic toxins. PMID- 28910797 TI - The Rationale for Expanded Hemodialysis Therapy (HDx). AB - As dialysis membrane technologies have advanced, the ability to clear increasing numbers of uremic toxins has occurred. To date, however, the class of uremic toxins known as large middle-molecules has been classified as "difficult to remove." Expanded hemodialysis utilizes a new generation of high-retention-onset hemodialysis membranes; these membranes provide the ability to remove large middle-molecules effectively for the first time, without significant albumin loss. In this review, we evaluate the removal of large middle-molecules by the new high-retention-onset membranes, the clinical relevance of these molecules, and how expanded hemodialysis can be prescribed. PMID- 28910798 TI - Expanded Hemodialysis Therapy: Prescription and Delivery. AB - Expanded hemodialysis (HDx) therapy is a novel treatment concept in hemodialysis patients, using innovative membrane technology with a high retention onset for improved solute clearance in the upper middle molecular range. HDx therapy thereby resolves a key limitation of current hemodialysis techniques and targets an important pathophysiologic link to many of the sequelae of end-stage renal disease. The present chapter reviews the current evidence and discusses considerations for prescription and delivery of HDx therapy upon implementation in clinical practice. PMID- 28910799 TI - Effects of Hemodialysis Therapy Using Dialyzers with Medium Cut-Off Membranes on Middle Molecules. AB - The removal of larger middle molecules, such as free immunoglobulin light chains (FLC), is poor with most currently used dialysis technologies. While hemodiafiltration (HDF) provides enhanced clearance of middle molecules compared to high-flux hemodialysis (HD), this technique is currently not approved in some regions and, hence, not accessible for all patients. The retention of middle molecules is thought to be one factor, which contributes to excessive morbidity and mortality in HD patients. The development of medium cut-off (MCO) dialysis membranes is aimed at a more efficient clearance of larger uremic toxins while retaining albumin and may extend the benefit of enhanced solute removal to more patients. In 2 pilot studies, the removal of middle molecules using HD with an MCO dialyzer prototype was compared to (1) high-flux HD and (2) high-flux HD and HDF. The primary outcome was the overall clearance of lambda FLC, and the secondary outcome was the clearance of other middle molecules and safety. Pre-to post reduction ratios and instantaneous clearances during HD were also assessed. In both trials, the overall lambda FLC clearance with MCO HD was significantly larger than with high-flux HD and HDF. Accordingly, instantaneous clearances at 30 and 120 min showed significantly higher removal of lambda FLC compared to high flux HD and HDF. MCO HD provides a more efficient removal of larger middle molecules compared to high-flux HD and HDF. A potential drawback is slightly increased albumin loss, yet preliminary data suggest that this does not lead to permanently decreased albumin levels. Thus, MCO HD may present a promising approach to further improve middle molecule removal in maintenance dialysis patients and to extend its benefit to more patients. PMID- 28910800 TI - The Place of Large Pore Membranes in the Treatment Portfolio of Patients on Hemodialysis. AB - Cardiovascular disease is a major concern in patients with end-stage kidney disease (ESKD). Inflammation induced by retention of uremic toxins, of which a substantial fraction has a molecular weight in the middle molecular range, has been associated with increased cardiovascular risk. In an attempt to reduce inflammation and thus cardiovascular toxicity in patients with ESKD, hemodiafiltration (HDF) has been promoted to enhance the clearance of middle molecular weight substances during dialysis. However, HDF increases the technical complexity and costs, and requires ultrapure dialysis fluid. Also, HDF becomes less beneficial when it is not possible to achieve sufficient convective volume in all patients. Over the last years, membranes with larger pore sizes, such as medium cut-off and high cut-off, have been introduced. These membranes, applied in hemodialysis mode, appear to have removal rates of middle molecular weight molecules that are comparable to those achieved with HDF, and could thus obviate the need for HDF. However, ultrapure dialysis fluid might still be required if there is a risk of transmigration of contaminants from the dialysate side into the blood because of the increased pore size. This transmigration of pyrogens might upregulate the expression of cytokines and other pro-inflammatory factors, and thus completely neutralize the beneficial effects of higher clearance of middle molecules. This chapter will explore the existing evidence on permeability of membranes with large pores for bacterial degradation products, and based on this information we will try to define the position of these novel membranes among the spectrum of existing membranes. PMID- 28910801 TI - Large Middle Molecule and Albumin Removal: Why Should We Not Rest on Our Laurels? AB - Large middle molecules (LMM) are an important subclass of uremic toxins. Many of them have been linked with poor outcomes in hemodialysis (HD) patients. The onset of high-flux membranes and convective techniques allowed to dramatically improve their clearance but without a clear and undebatable reduction of mortality in HD patients. Despite the real effect on the removal of selected toxins, little is known about the influence of modern HD techniques on the global removal of uremic toxins. Mostly explained by a lack of knowledge and selective assays, LMM removal is not evaluated appropriately. The development of highly sensitive and widespread detection techniques such as mass spectrometry could increase our knowledge about the real state of their removal in HD. Nevertheless, these techniques remain cost effective and are difficult to handle. On the contrary, the improvement of LMM removal raises the question of a tolerable albumin removal. Indeed, increasing membrane permeability can significantly increase LMM removal accompanied by a higher albumin loss. However, in chronic kidney disease and particularly in HD patients, albumin can be modified, and it subsequently exerts detrimental effects. This could be avoided by the clearance of the modified forms in HD, but future efforts should be done to investigate the real impact of their removal. PMID- 28910802 TI - Effects of Expanded Hemodialysis Therapy on Clinical Outcomes. AB - The invention of dialysis has been a phenomenal advance in the treatment of kidney failure. The introduction of artificial kidneys in clinical care remains one of the most successful lifesaving interventions in modern medicine. Its glory, however, has been tempered by poor long-term outcomes and a negative qualitative impact on the lives of patients who suffer from an extremely complex, burdensome, and restricted life on dialysis. There remains a huge gap in patient well-being and outcomes between artificial kidney treatments and kidney transplantation. The inadequacy of dialysis, at least in part, is due to the chronic accumulation of organic retention solutes of middle and large molecules in chronic kidney disease, which are poorly removed by current dialytic treatment modalities. Incremental benefits observed through alternative strategies such as high volume hemodiafiltration, high frequency, and expanded hemodialysis (HD) schedules have had limited success, due to a host of organizational, complex technology need and human factor barriers. Expanded HD (HDx) therapy offers a novel blood purification technology, with the use of high retention onset (HRO) membranes designed to achieve a superior spectrum of solute waste removal in uremia. Limited studies have demonstrated the potential benefit of HRO membranes in reducing cardiovascular risk, vascular calcification, and inflammation commonly associated with the "residual uremic syndrome" and patient symptom burden. Robust and efficient clinical trials are now required to establish the rationale and impact of HDx therapy in driving improvements in both physician- and patient-directed clinical goals and outcomes in dialysis. PMID- 28910803 TI - Consanguinity Rates Predict Long Runs of Homozygosity in Jewish Populations. AB - OBJECTIVES: Recent studies have highlighted the potential of analyses of genomic sharing to produce insight into the demographic processes affecting human populations. We study runs of homozygosity (ROH) in 18 Jewish populations, examining these groups in relation to 123 non-Jewish populations sampled worldwide. METHODS: By sorting ROH into 3 length classes (short, intermediate, and long), we evaluate the impact of demographic processes on genomic patterns in Jewish populations. RESULTS: We find that the portion of the genome appearing in long ROH - the length class most directly related to recent consanguinity - closely accords with data gathered from interviews during the 1950s on frequencies of consanguineous unions in various Jewish groups. CONCLUSION: The high correlation between 1950s consanguinity levels and coverage by long ROH explains differences across populations in ROH patterns. The dissection of ROH into length classes and the comparison to consanguinity data assist in understanding a number of additional phenomena, including similarities of Jewish populations to Middle Eastern, European, and Central and South Asian non-Jewish populations in short ROH patterns, relative lengths of identity-by-descent tracts in different Jewish groups, and the "population isolate" status of the Ashkenazi Jews. PMID- 28910804 TI - EBUS-TBNA Can Distinguish Sarcoid-Like Side Effect of Nivolumab Treatment from Tumor Progression in Non-Small Cell Lung Cancer. AB - With the expansion of immunotherapy in the treatment of lung cancer, clinicians have to face new clinical pictures and adapt their practice. We report the case of a 69-year-old man diagnosed with non-small cell lung cancer using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and treated with nivolumab as second-line therapy. After 8 injections of nivolumab, a new CT and PET scan revealed massive growth and increase in metabolism of hilar and mediastinal lymph nodes, whereas the size and metabolism of the left upper lobe lesion were reduced. A new EBUS-TBNA was thus performed and showed an epithelioid cell reaction compatible with sarcoidosis in the 3 punctured lymph nodes (stations 4R, 11L, 7). In the absence of cancer evolution, nivolumab was continued, and the CT after the twelfth injection showed stability. PMID- 28910805 TI - Infection and Erosion Rates in Trials of a Cranially Implanted Neurostimulator Do Not Increase with Subsequent Neurostimulator Placements. AB - BACKGROUND/AIMS: The RNS(r) System utilizes a cranially implanted neurostimulator attached to leads placed at the seizure focus to provide brain responsive stimulation for the treatment of medically intractable partial onset epilepsy. Infection and erosion rates related to the cranial implant site were assessed overall and by neurostimulator procedure to determine whether rates increased with additional procedures. METHODS: Infection and erosion rates were calculated as (1) chance per neurostimulator procedure, (2) incidence per patient implant year, and (3) rates for initial and each subsequent neurostimulator implant (generalized estimating equation). RESULTS: In 256 patients followed for an average of 7 years, the infection rate was 3.7% per neurostimulator procedure (n = 31/840), and the rate of erosions was 0.8% per neurostimulator procedure (n = 7/840). Rates did not increase with subsequent neurostimulator procedures (p = 0.66, infection; p = 0.70, erosion). A prior infection or erosion at the implant site did not significantly increase the risk at a later procedure (p >= 0.05 for all combinations). CONCLUSION: These data indicate that the risk for infection compares favorably to other neurostimulation devices and suggest that rates of infection and erosion do not increase with subsequent neurostimulator replacements. PMID- 28910807 TI - Cerebral Infarct Topography and Early Outcome after Surgery for Symptomatic Carotid Stenosis: A Multicentre Study. AB - INTRODUCTION: Although carotid stenosis can cause both territorial and border zone (BZ) cerebral infarcts (CI), the influence of CI topography on postoperative complications after surgery remains unclear. We compared early outcomes after endarterectomy on the basis of CI location: territorial (T group) or BZ group. MATERIAL AND METHODS: During the period between 2009 and 2013, ischaemic stroke patients who had undergone surgery for symptomatic carotid stenosis were identified from prospective databases from 3 French centres. The outcome was the identification of a combined stroke/death rate 30 days after endarterectomy. RESULTS: Two hundred and eighty-nine patients were included, 216 (74.7%) in the T group and 73 (25.3%) in the BZ group. The mean degree of stenosis was comparable in the 2 groups (78 +/- 12% in the T group vs. 80 +/- 12% in the BZ group, p = 0.105), with, however, more sub-occlusions (stenosis >90%) in the BZ group (38.4 vs. 23.1%, p = 0.012). The mean time between the time CI developed and the time surgery was performed was 19.6 +/- 24.8 days, with a majority of patients being operated upon within 2 weeks following the formation of CI (66.7% in the T group vs. 60.3% in the BZ group, p = 0.322). The combined endpoint was significantly more frequent in the BZ group (9.6 vs. 1.9%, p = 0.003), with 4 ischaemic strokes and 3 deaths. In multivariate analysis, BZ CI was an independent predictor of postoperative stroke or death at 30 days (HR 4.91-95% CI [1.3-18.9], p = 0.020). CONCLUSION: BZ infarcts carry a greater risk of postoperative complications after carotid surgery, thus suggesting that topography of the CI should be considered in the decision-making process regarding surgery. PMID- 28910806 TI - Warfarin Use and Increased Mortality in End-Stage Renal Disease. AB - BACKGROUND: Controversy exists regarding the benefits and risks of warfarin therapy in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. In this study, we assessed mortality and cardiovascular outcomes associated with warfarin treatment in patients with stages 3-5 CKD and ESRD admitted to the University of California-Irvine Medical Center. METHODS: In a retrospective matched cohort study, we identified 59 adult patients with stages 3 6 CKD initiated on warfarin during the period 2011-2013, and 144 patients with stages 3-6 CKD who had indications for anticoagulation therapy but were not initiated on warfarin. All-cause mortality risk associated with warfarin treatment was estimated using Cox proportional hazard regression analysis, and the risk of significant bleeding and major adverse cardiovascular events were analyzed with Poisson regression analysis. Adjustment models were used to account for age, gender, diabetes mellitus, use of antiplatelet agents, and preexisting cardiovascular disease, and stratified by pre-dialysis CKD stages 3-5 vs. ESRD. FINDINGS: During 5.8 years of follow-up, unadjusted mortality risk was higher in CKD patients on warfarin therapy (hazard ratio [HR] 2.34 with 95% CI 1.25-4.39; p < 0.01). After multivariate adjustment and stratification by CKD stage, the mortality risk remained significant in ESRD patients receiving warfarin (HR 6.62 with 95% CI 2.56-17.16; p < 0.001). Furthermore, adjusted rates of significant bleeding (incident rate ratio, IRR 3.57 with 95% CI 1.51-8.45; p < 0.01) and myocardial infarction (IRR 4.20 with 95% CI 1.78-9.91; p < 0.01) were higher among warfarin users. No differences in rates of ischemic or hemorrhagic strokes were found between the 2 groups. CONCLUSIONS: Warfarin use was associated with several-fold higher risk of death, bleeding, and myocardial infarction in dialysis patients. If additional studies suggest similar associations, the use of warfarin in dialysis patients warrants immediate reconsideration. PMID- 28910809 TI - Ingeborg Syllm-Rapoport (1912-2017): An Exemplary Life for Children and Paediatrics. AB - Ingeborg Syllm-Rapoport, the first Chair in neonatology in Europe, passed away on March 23. Her biography illustrates how medical and scientific work has been influenced by social, ideological, and economic frames and boundaries in the 20th century. Regarded as a "Half-Jew" by the Nazi racist laws, she was denied her medical doctorate. She went to the USA, where she trained in paediatrics and met her husband, the biochemist Samuel Mitja Rapoport. During the "McCarthy Era" both were persecuted as communists. They returned to Europe and became two of the most influential figures at the Charite Hospital in East Berlin. She had to wait until 2015 to finally undergo the doctoral examination at the age of 102 years, making her the oldest person in history to receive a doctorate. We describe Syllm Rapoport's life and the challenges she had to face living in several countries under different political systems in the 20th century. PMID- 28910808 TI - Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency. AB - BACKGROUND/AIMS: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid stimulating hormone (TSH) test approach. CH-C must be distinguished from T4 binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency. METHODS: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency. RESULTS: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 ug/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 ug/mL, range 19.1 44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions. CONCLUSION: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C. PMID- 28910810 TI - Concurrent Infection with Plasmodium vivax and the Dengue and Chikungunya Viruses in a Paediatric Patient from New Delhi, India in 2016. AB - Dengue and chikungunya fevers are transmitted by the common mosquito vector Aedes and malaria by Anopheles. Concurrent infections are reported due to co circulation of these pathogens, especially in endemic regions. We report a rare case of triple infection with 3 arthropod-borne pathogens (Plasmodium vivax and the dengue and chikungunya viruses) in a 3-year-old child from New Delhi, India, in August 2016. The viruses were identified by RT-PCR and the parasite by microscopy and antigen detection. The dengue virus serotype 3 sequence was clustered in the genotype III by the phylogenetic analysis. Mixed infection with multiple pathogens is a challenge for accurate diagnosis due to the overlapping clinical symptoms. The accurate and timely diagnosis of multiple pathogens in such cases is important for rapid and effective patient management. PMID- 28910811 TI - Impact of Age and Aerobic Exercise Training on Conduit Artery Wall Thickness: Role of the Shear Pattern. AB - Hemodynamic shear stress is the frictional force of blood on the arterial wall. The shear pattern in the conduit artery affects the endothelium and may participate in the development and progression of atherosclerosis. We investigated the role of the shear pattern in age- and aerobic exercise-induced changes in conduit artery wall thickness via cross-sectional and interventional studies. In a cross-sectional study, we found that brachial shear rate patterns and brachial artery intima-media thickness (IMT) correlated with age. Additionally, brachial artery shear rate patterns were associated with brachial artery IMT in 102 middle-aged and older individuals. In an interventional study, 39 middle-aged and older subjects were divided into 2 groups: control and exercise. The exercise group completed 12 weeks of aerobic exercise training. Aerobic exercise training significantly increased the antegrade shear rate and decreased the retrograde shear rate and brachial artery IMT. Moreover, changes in the brachial artery antegrade shear rate and the retrograde shear rate correlated with the change in brachial artery IMT. The results of the present study indicate that changes in brachial artery shear rate patterns may contribute to age- and aerobic exercise training-induced changes in brachial artery wall thickness. PMID- 28910812 TI - What Can Be Expected from Prostate Cancer Biomarkers A Clinical Perspective. AB - Along with significant advances in prostate cancer biology research, we also observe the rapid development of modern diagnostic tests. New biomarkers are derived to detect disease while it is organ-confined to stratify the risk and to aid clinical decision-making. Majority of these tools have already been validated clinically, but only a few have received premarket clearance and administration approval. Superiority of novel tests is visible not only in improved detection accuracy but predominantly in the assessment of tumour aggressiveness and selection of patients eligible for conservative management. Two factors limiting the clinical implementation of validated biomarker candidates are costs and local availability. For these reasons, currently, their true clinical role starts after routine screening with prostate-specific antigen test. With this review of prostate cancer biomarkers, we attempted to draw general conclusions on clinical perspectives of these novel tools. PMID- 28910813 TI - The Neighborhood Built Environment and Cognitive Function of Older Persons: Results from the Singapore Longitudinal Ageing Study. AB - BACKGROUND: We investigated the association of subjective (perceived) and objective (geographical information system [GIS]-based) measures of the neighborhood built environment (BE) attributes with cognitive function among older persons, and the mediating effect of transportation physical activity (TPA) and leisure time (physical, social and productive) activities (LTA). METHOD: A cross-sectional study of 402 residents aged 55 years and above in the Singapore Longitudinal Ageing Study. Perceived neighborhood BE attributes (residential density, street connectivity, land use mix - diversity, land use mix - access, infrastructure for walking or cycling, aesthetics, traffic safety, and crime safety) and objective GIS measures of walkability and accessibility were related to participants' cognitive global and domain-specific performance measured by Repeatable Battery for the Assessment of Neurocognitive Status (RBANS). RESULTS: Controlling for age, sex, education, race, chronic medical illnesses, self-rated health, Geriatric Depression Scale depression score, POMA measures of balance and gait, and other BE attributes, the subjective measure of land use mix-diversity (standardized coefficient beta = 0.161, p = 0.008) and GIS measure of walkability (beta = 0.163, p = 0.002) were positively and significantly associated with RBANS global z-score, and immediate and delayed memory recall, visuospatial/ constructional ability and language, except attention. In hierarchical modeling, TPA and LTA attenuated the effect estimates, but the associations remained significant. CONCLUSION: BE features which increase opportunities and easy access to a diversity of destinations for services and facilities that promote physical, social and cognitively stimulating activities is associated with better cognitive functioning in older people. PMID- 28910814 TI - Feasibility and Effectiveness of Intervention Programmes Integrating Functional Exercise into Daily Life of Older Adults: A Systematic Review. AB - BACKGROUND: Traditionally, exercise programmes for improving functional performance and reducing falls are organised as structured sessions. An alternative approach of integrating functional exercises into everyday tasks has emerged in recent years. OBJECTIVES: Summarising the current evidence for the feasibility and effectiveness of interventions integrating functional exercise into daily life. METHODS: A systematic literature search was conducted including articles based on the following criteria: (1) individuals >=60 years; (2) intervention studies of randomised controlled trials (RCTs) and non-randomised studies (NRS); (3) using a lifestyle-integrated approach; (4) using functional exercises to improve strength, balance, or physical functioning; and (5) reporting outcomes on feasibility and/or effectiveness. Methodological quality of RCTs was evaluated using the PEDro scale. RESULTS: Of 4,415 articles identified from 6 databases, 14 (6 RCTs) met the inclusion criteria. RCT quality was moderate to good. Intervention concepts included (1) the Lifestyle-integrated Functional Exercise (LiFE) programme integrating exercises into everyday activities and (2) combined programmes using integrated and structured training. Three RCTs evaluated LiFE in community dwellers and reported significantly improved balance, strength, and functional performance compared with controls receiving either no intervention, or low-intensity exercise, or structured exercise. Two of these RCTs reported a significant reduction in fall rate compared with controls receiving either no intervention or low-intensity exercise. Three RCTs compared combined programmes with usual care in institutionalised settings and reported improvements for some (balance, functional performance), but not all (strength, falls) outcomes. NRS showed behavioural change related to LiFE and feasibility in more impaired populations. One NRS comparing a combined home-based programme to a gym-based programme reported greater sustainability of effects in the combined programme. CONCLUSIONS: This review provides evidence for the effectiveness of integrated training for improving motor performances in older adults. Single studies suggest advantages of integrated compared with structured training. Combined programmes are positively evaluated in institutionalised settings, while little evidence exists in other populations. In summary, the approach of integrating functional exercise into daily life represents a promising alternative or complement to structured exercise programmes. However, more RCTs are needed to evaluate this concept in different target populations and the potential for inducing behavioural change. PMID- 28910815 TI - The Outcome and Patterns of Traumatic Brain Injury in the Paediatric Population of a Developing Country Secondary to TV Trolley Tip-Over. AB - BACKGROUND: Television (TV) trolley tip-over incidences are common and can cause significant morbidity and mortality in children. This study was aimed at analyzing the pattern and outcomes of head injuries resulting from TV trolley tip over. METHOD: We conducted a medical chart review of children with TV trolley tip over head injuries from January 2009 to April 2016. We collected data on demographics, the mechanism of injury, clinical and radiological features of the injury, and outcomes. Outcomes were measured by means of the Glasgow Outcome Scale (GOS) at 6 months (except in 1 case). A descriptive analysis was carried out using SPSS v19. RESULT: Twenty-two children were included in the study (median age 23.5 months). Sixteen children were male. Most of the children (n = 16) were aged 12-35 months. The median Glasgow Coma Scale score on admission was 15. The median Rotterdam Score for the patients was 2.0. Common symptoms upon admission were vomiting, irritability, scalp laceration, and bruises. Median length of hospital stay was 3 days. Skull bone fractures were present in 12 children. Other CT findings included contusions, extradural and subdural haematomas, intraventricular haemorrhage, and pneumocranium. Surgical intervention was required in 4 cases. Although most of the patients made a good recovery (GOS = 5), 1 patient developed a mild disability and another died in hospital. CONCLUSION: TV trolley tip-over is most common in toddlers and can lead to significant head injury and mortality. This can be avoided by parental supervision and adjustments in the household. PMID- 28910816 TI - Mediastinal and Subcutaneous Chest Fat Are Differentially Associated with Emphysema Progression and Clinical Outcomes in Smokers. AB - BACKGROUND: Studies have demonstrated both positive and negative effects of obesity on clinical outcomes in chronic obstructive pulmonary disease (COPD). In other chronic diseases, fat location is differentially associated with disease outcomes; however, this relationship has not been well studied in COPD. OBJECTIVE: To determine if fat location explains the differential association of body mass index (BMI) with clinical outcome measures in smokers. METHODS: Baseline and 6-year chest computed tomography scans from 68 current and former smokers were used to quantify mediastinal and subcutaneous fat. The relationships of BMI, mediastinal fat, and subcutaneous fat with cross-sectional and 6-year changes in pulmonary function, incremental shuttle walk distance (ISWD), quantitative emphysema, and circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed using generalized linear models adjusted for clinically relevant covariates. RESULTS: Baseline subcutaneous fat was negatively associated with emphysema progression over 6 years (p < 0.01). BMI and mediastinal fat volume were inversely associated with baseline ISWD (p < 0.01 and p = 0.043, respectively) as well as 6-year change in ISWD (p = 0.020 and p = 0.028, respectively). IL-6 was directly associated with BMI and mediastinal fat (p < 0.01) and CRP was directly associated with BMI only (p = 0.033). CONCLUSIONS: Increased subcutaneous chest fat is associated with less emphysema progression over time in smokers, while increased mediastinal fat volume is associated with decreased walk distance and increased IL-6 levels. These findings suggest a complex interaction between fat, inflammation, and emphysema that should be considered when phenotyping patients with COPD and provide new evidence of an inverse association between emphysema progression and chest subcutaneous fat. PMID- 28910817 TI - The Lung in Dysregulated States of Humoral Immunity. AB - In common variable immunodeficiency, lung manifestations are related to different mechanisms: recurrent pneumonias due to encapsulated bacteria responsible for diffuse bronchiectasis, diffuse infiltrative pneumonia with various patterns, and lymphomas, mostly B cell extranodal non-Hodgkin type. The diagnosis relies on significant serum Ig deficiency and the exclusion of any primary or secondary cause. Histopathology may be needed. Immunoglobulin (IgG) replacement is crucial to prevent infections and bronchiectasis. IgG4-related respiratory disease, often associated with extrapulmonary localizations, presents with solitary nodules or masses, diffuse interstitial lung diseases, bronchiolitis, lymphadenopathy, and pleural or pericardial involvement. Diagnosis relies on international criteria including serum IgG4 dosage and significantly increased IgG4/IgG plasma cells ratio in pathologically suggestive biopsy. Respiratory amyloidosis presents with tracheobronchial, nodular, and cystic or diffuse interstitial lung infiltration. Usually of AL (amyloid light chain) subtype, it may be localized or systemic, primary or secondary to a lymphoproliferative process. Very rare other diseases due to nonamyloid IgG deposits are described. Among the various lung manifestations of dysregulated states of humoral immunity, this article covers only those associated with the common variable immunodeficiency, IgG4-related disease, amyloidosis, and pulmonary light-chain deposition disease. Autoimmune connective-vascular tissue diseases or lymphoproliferative disorders are addressed in other chapters of this issue. PMID- 28910818 TI - Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma. AB - OBJECTIVES: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. MATERIALS AND METHODS: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. RESULTS: Overexpression of PD L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. CONCLUSIONS: PD L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1. PMID- 28910819 TI - Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors. AB - BACKGROUND/AIMS: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. METHODS: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. RESULTS: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin 3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. CONCLUSION: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors. PMID- 28910820 TI - Prospective investigation of risk factors for prostate cancer in the UK Biobank cohort study. AB - BACKGROUND: Prostate cancer is the most common cancer in British men but its aetiology is not well understood. We aimed to identify risk factors for prostate cancer in British males. METHODS: We studied 219 335 men from the UK Biobank study who were free from cancer at baseline. Exposure data were collected at recruitment. Prostate cancer risk by the different exposures was estimated using multivariable-adjusted Cox proportional hazards models. RESULTS: In all, 4575 incident cases of prostate cancer occurred during 5.6 years of follow-up. Prostate cancer risk was positively associated with the following: black ethnicity (hazard ratio black vs white=2.61, 95% confidence interval=2.10-3.24); having ever had a prostate-specific antigen test (1.31, 1.23-1.40); being diagnosed with an enlarged prostate (1.54, 1.38-1.71); and having a family history of prostate cancer (1.94, 1.77-2.13). Conversely, Asian ethnicity (Asian vs white hazard ratio=0.62, 0.47-0.83), excess adiposity (body mass index (?35 vs <25 kg m-2=0.75, 0.64-0.88) and body fat (?30.1 vs <20.5%=0.81, 0.73-0.89)), cigarette smoking (current vs never smokers=0.85, 0.77-0.95), having diabetes (0.70, 0.62-0.80), and never having had children (0.89, 0.81-0.97) or sexual intercourse (0.53, 0.33-0.84) were related to a lower risk. CONCLUSIONS: In this new large British prospective study, we identified associations with already established, putative and possible novel risk factors for being diagnosed with prostate cancer. Future research will examine associations by tumour characteristics. PMID- 28910821 TI - Vascular disrupting agent in pancreatic and hepatic tumour allografts: observations of location-dependent efficacy by MRI, microangiography and histomorphology. AB - BACKGROUND: Tumours growing in organs of different vascular environment could exhibit diverse responses to vascular disrupting agent (VDA). This study was aimed to identify in vivo imaging biomarkers for evaluation of pancreatic and hepatic tumours and comparison of their responses to a VDA Combretastatin A4 Phosphate (CA4P) using multiparametric MRI. METHODS: Male WAG/Rij rats were used for orthotopic pancreatic head tumour and hepatic tumour implantation; tumour growth was monitored by 3D isotropic MRI using a 3.0-T clinic scanner. Therapeutic intervention using CA4P was investigated by in vivo quantitative MRI measurements including T2/T1 relaxation mapping, diffusion kurtosis imaging and dynamic contrast-enhancement (DCE) imaging. Animals were scarified 10 h after CA4P treatment for ex vivo validation using microangiography and histomorphology. RESULTS: State-of-the-art clinical MRI protocols were successfully adapted for imaging small animal tumour with high reliability. One hour after CA4P injection, marked vascular shutdown was detected with DCE MRI in both pancreatic and hepatic tumours. However, 10 h later, therapeutic necrosis was limited in pancreatic tumours compared with that in hepatic tumours (P<0.01). Heterogeneous therapeutic changes were depicted in tumour lesions using pixel-wise Tofts model, which was generated from dynamic T1 mapping. In addition, tumour responses including haemorrhage, oedema and necrosis were detected using quantitative T2/T1 relaxation maps and diffusion kurtosis images, and were validated using histomorphology. CONCLUSIONS: Using multiparametric imaging biomarkers, hepatic tumours were found to be significantly more responsive to CA4P than pancreatic tumours, which could be of reference for designing future clinical trials on this agent. PMID- 28910822 TI - A new molecular-based lymph node staging classification determines the prognosis of breast cancer patients. AB - BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can detect metastasis in a whole lymph node based on cytokeratin 19 mRNA copy number. This cohort study aimed to establish an OSNA based nodal staging (pN(mol)) classification for breast cancer. METHODS: The cohort consisted of 1039 breast cancer patients who underwent sentinel node (SN) biopsy using the OSNA assay. Cutoff value of the SN tumour burden stratifying distant disease-free survival (DDFS) was determined, and predictive factors for DDFS and breast cancer-specific survival (BCSS) were investigated. pN(mol) classification of the SN status was defined as: pN0(mol)(sn), SN negative; pN1mi(mol)(sn), SN positive and tumour burden = 40 mm). The endpoints were Forrest classification of the post-ESD ulcer on second-look endoscopy 2 days after the procedure and bleeding rates within 48 h and at 4 weeks. RESULTS: Forty four patients underwent gastric ESD and treatment with hemostatic powder. Among them, 33 patients (70.5%) underwent large resection (>= 40 mm) without antithrombotic therapy, and 13 patients (29.5%) received antithrombotic therapy. The mean resected specimen size was 55.3 +/- 13.9 mm. The proportion of high-risk delayed bleeding lesions (Forrest IIa) at second-look endoscopy was 4.5% (2/44). The overall bleeding rate was 9.1% (4/44). There was no early bleeding event. The median (interquartile range) timing of bleeding after the procedure was 12.5 (interquartile range 10.3-15.5) days. The bleeding rate in the large resection (>= 40 mm) group without antithrombotic therapy and the antithrombotic therapy group was 3.2% (1/33) and 23.1% (3/13), respectively. CONCLUSIONS: Hemostatic powder may be a promising new simple and effective method to prevent early post ESD bleeding in high-risk patients, especially for those with larger resection. (Clinical trial registration number: NCT02625792). PMID- 28910852 TI - Origin and Evolution of Aquitard Porewater in the Western Coastal Plain of Bohai Bay, China. AB - High-salinity paleowater from low-permeability aquitards in coastal areas can be a major threat to groundwater resources; however, such water has rarely been studied. The chemical and isotopic compositions of porewater extracted from a 200 m-thick Quaternary sedimentary sequence in the western coastal plain of Bohai Bay, China, were analyzed to investigate the salinity origin and chemical evolution of porewater in aquitards. Porewater samples derived at depths shallower than 32 m are characterized by Cl-Na type saline water (total dissolved solids [TDS], 10.9-84.3 g/L), whereas those at depths greater than 32 m comprise Cl.SO4 -Na type brackish water (TDS, 2.2-6.3 g/L). Saline porewater is interpreted as evaporated seawater prior to halite saturation, as evidenced by Cl Br relationships. Although substantial dilution of saline porewater with meteoric water is supported by a wider Cl- range and delta2 H-delta18 O covariance, the original marine waters were not completely flushed out. The deeper brackish porewater is determined to be a mixture of fresher porewater and brine groundwater and had a component of old brine of less than 10%, as indicated by a mixing model defined using delta2 H and Cl- tracers. Porewater delta2 H-delta18 O relationships and negative deuterium excess ranging from -25.90/00 to -2.90/00 indicate the existence of an arid climate since Late Pleistocene in Tianjin Plain. The aquitard porewaters were chemically modified through water-rock interactions due to the long residence time. PMID- 28910853 TI - Impacts of Streambed Heterogeneity and Anisotropy on Residence Time of Hyporheic Zone. AB - The hyporheic zone (HZ), which is the region beneath or alongside a streambed, plays an important role in the stream's ecology. The duration that a water molecule or a solute remains within the HZ, or residence time (RT), is one of the most common metrics used to evaluate the function of the HZ. The RT is greatly influenced by the streambed's hydraulic conductivity (K), which is intrinsically difficult to characterize due to its heterogeneity and anisotropy. Many laboratory and numerical studies of the HZ have simplified the streambed K to a constant, thus producing RT values that may differ from those gathered from the field. Some studies have considered the heterogeneity of the HZ, but very few have accounted for anisotropy or the natural K distributions typically found in real streambeds. This study developed numerical models in MODFLOW to examine the influence of heterogeneity and anisotropy, and that of the natural K distribution in a streambed, on the RT of the HZ. Heterogeneity and anisotropy were both found to shorten the mean and median RTs while increasing the range of the RTs. Moreover, heterogeneous K fields arranged in a more orderly pattern had longer RTs than those with random K distributions. These results could facilitate the design of streambed K values and distributions to achieve the desired RT during river restoration. They could also assist the translation of results from the more commonly considered homogeneous and/or isotropic conditions into heterogeneous and anisotropic field situations. PMID- 28910854 TI - Characterizing the Nano-Bio Interface Using Microscopic Techniques: Imaging the Cell System is Just as Important as Imaging the Nanoparticle System. AB - The rapid growth of nanotechnology and its industries has elevated the need to understand the risks associated with handling, using, and disposing of nanomaterials. These risks can be assessed through exposure measurement and hazard identification. One of the common challenges associated with quantifying nanomaterials in products, waste, humans, or the environment is the lack of tools available to measure concentration. The ability of refined tools and techniques to qualitatively detect nanoparticles in complex matrices has been demonstrated. For biological and ecological tests systems, dose can be represented as initial concentration in the applied matrix, concentration administered during the route of exposure, concentration at the target organ, and intake concentration at the cellular level. Each of these concentration measurements requires different sets of tools to perform accurate analyses. Advances in microscopy techniques provide new opportunities for reporting observations occurring at the interaction of a nanoparticle with a biomolecular entity of similar size within a biological test(s) system. This protocol outlines the steps to image nanomaterials within cell-based systems. (c) 2017 by John Wiley & Sons, Inc. PMID- 28910855 TI - Optimized PEI-based Transfection Method for Transient Transfection and Lentiviral Production. AB - Polyethyleneimine (PEI), a cationic polymer vehicle, forms a complex with DNA which then can carry anionic nucleic acids into eukaryotic cells. PEI-based transfection is widely used for transient transfection of plasmid DNA. The efficiency of PEI-based transfection is affected by numerous factors, including the way the PEI/DNA complex is prepared, the ratio of PEI to DNA, the concentration of DNA, the storage conditions of PEI solutions, and more. Considering the major influencing factors, PEI-based transfection has been optimized to improve its efficiency, reproducibility, and consistency. This protocol outlines the steps for ordinary transient transfection and lentiviral production using PEI. (c) 2017 by John Wiley & Sons, Inc. PMID- 28910856 TI - High-Throughput Screening of HECT E3 Ubiquitin Ligases Using UbFluor. AB - HECT E3 ubiquitin ligases are responsible for many human disease phenotypes and are promising drug targets; however, screening assays for HECT E3 inhibitors are inherently complex, requiring upstream E1 and E2 enzymes as well as ubiquitin, ATP, and detection reagents. Intermediate ubiquitin thioesters and a complex mixture of polyubiquitin products provide further opportunities for off-target inhibition and increase the complexity of the assay. UbFluor is a novel ubiquitin thioester that bypasses the E1 and E2 enzymes and undergoes direct transthiolation with HECT E3 ligases. The release of fluorophore upon transthiolation allows fluorescence polarization detection of HECT E3 activity. In the presence of inhibitors, HECT E3 activity is ablated, and thus no reaction and no change in FP are observed. This assay has been adapted for high-throughput screening of small molecules against HECT E3 ligases, and its utility has been proven in the discovery of HECT E3 ligase inhibitors. (c) 2017 by John Wiley & Sons, Inc. PMID- 28910857 TI - A Guide to Quantitative Biomarker Assay Development using Whispering Gallery Mode Biosensors. AB - Whispering gallery mode (WGM) sensors are a class of powerful analytical techniques defined by the measurement of changes in the local refractive index at or near the sensor surface. When functionalized with target-specific capture agents, analyte binding can be measured with very low limits of detection. There are many geometric manifestations of WGM sensors, with chip-integrated silicon photonic devices first commercialized because of the robust, wafer-scale device fabrication, facile optical interrogation, and amenability to the creation of multiplexed sensor arrays. Using these arrays, a number of biomolecular targets have been detected in both label-free and label-enhanced assay formats. For example, sub-picomolar detection limits for multiple cytokines were achieved using an enzymatically enhanced sandwich immunoassay that showed high analyte specificity suitable for detection in complex, clinical matrices. This protocol describes a generalizable approach for the development of quantitative, multiplexed immunoassays using silicon photonic microrings as an example WGM platform. (c) 2017 by John Wiley & Sons, Inc. PMID- 28910858 TI - Overview of Methods and Strategies for Conducting Virtual Small Molecule Screening. AB - Virtual screening (VS) in the context of drug discovery is the use of computational methods to discover novel ligands with a desired biological activity from within a larger collection of molecules. These techniques have been in use for many years, there is a wide range of methodologies available, and many successful applications have been reported in the literature. VS is often used as an alternative or a complement to High-throughput screening (HTS) or other methods to identify ligands for target validation or medicinal chemistry projects. This unit does not present an exhaustive review of available methods, or document specific instructions on use of individual software packages. Rather, a general overview of the methods available are presented and general strategies are described for VS based on accepted practices and the authors' experience as computational chemists in an industrial research laboratory. First, the most common methods available for VS are reviewed, categorized as either receptor- or ligand-based. Subsequently, strategic considerations are presented for choosing a VS method, or a combination of methods, as well as the necessary steps to prepare, run, and analyze a VS campaign. (c) 2017 by John Wiley & Sons, Inc. PMID- 28910859 TI - Investigation of the effects of storage and freezing on mixes of heavy-labeled metabolite and amino acid standards. AB - RATIONALE: High-throughput metabolomics has now made it possible for small/medium sized laboratories to analyze thousands of samples/year from the most diverse biological matrices including biofluids, cell and tissue extracts. In large-scale metabolomics studies, stable-isotope-labeled standards are increasingly used to normalize for matrix effects and control for technical reproducibility (e.g. extraction efficiency, chromatographic retention times and mass spectrometry signal stability). However, it is currently unknown how stable mixes of commercially available standards are following repeated freeze/thaw cycles or prolonged storage of aliquots. METHODS: Standard mixes for 13 C, 15 N or deuterated isotopologues of amino acids and key metabolites from the central carbon and nitrogen pathways (e.g. glycolysis, Krebs cycle, redox homeostasis, purines) were either repeatedly frozen/thawed for up to 10 cycles or diluted into aliquots prior to frozen storage for up to 42 days. Samples were characterized by ultra-high-pressure liquid chromatography/mass spectrometry to determine the stability of the aliquoted standards upon freezing/thawing or prolonged storage. RESULTS: Metabolite standards were stable over up to 10 freeze/thaw cycles, with the exception of adenosine and glutathione, showing technical variability across aliquots in a freeze/thaw-cycle-independent fashion. Storage for up to 42 days of mixes of commercially available standards did not significantly affect the stability of amino acid or metabolite standards for the first 2 weeks, while progressive degradation (statistically significant for fumarate) was observed after 3 weeks. CONCLUSIONS: Refrigerated or frozen preservation for at least 2 weeks of aliquoted heavy-labeled standard mixes for metabolomics analysis is a feasible and time-/resource-saving strategy for standard metabolomics laboratories. PMID- 28910860 TI - Isolation of Probiotic Piliated Lactobacillus rhamnosus Strains from Human Fecal Microbiota Using SpaA Antiserum-Based Colony Immunoblotting. AB - Piliated Lactobacillus rhamnosus (pLR) strains possess higher adherent capacity than non-piliated strains. The objective of this study was to isolate and characterize probiotic pLR strains in human fecal samples. To this end, mouse polyclonal antiserum (anti-SpaA) against the recombinant pilus protein (SpaA) of L. rhamnosus strain GG (LGG) was prepared and tested for its reactivity and specificity. With the anti-SpaA, a method combining the de Man, Rogosa, and Sharpe (MRS) agar plating separation and colony immunoblotting (CIB) was developed to isolate pLR from 124 human fecal samples. The genetic and phenotypic characteristics of the resultant pLR isolates were compared by randomly amplified polymorphic DNA (RAPD) fingerprinting, and examination of adhesion to Caco-2 cells, hydrophobicity, autoaggregation, and in vitro gastrointestinal tolerance. Anti-SpaA specifically reacted with three pLR strains of 25 test strains, as assessed by western blotting, immunofluorescence flow cytometry, and immunoelectron microscopy (IEM) assays. The optimized MRS agar separation plus anti-SpaA-based CIB procedure could quantitatively detect 2.5 * 103 CFU/ml of pLR colonies spiked in 106 CFU/ml of background bacteria. Eight pLR strains were identified in 124 human fecal samples, and were confirmed by 16S RNA gene sequencing and IEM identification. RAPD fingerprinting of the pLR strains revealed seven different patterns, of which only two isolates from infants showed the same RAPD profiles with LGG. Strain PLR06 was obtained with high adhesion and autoaggregation activities, hydrophobicity, and gastrointestinal tolerance. Anti SpaA-based CIB is a rapid and inexpensive method for the preliminary screening of novel adherent L. rhamnosus strains for commercial purposes. PMID- 28910861 TI - Antioxidative and Antiaging Activities and Component Analysis of Lespedeza cuneata G. Don Extracts Fermented with Lactobacillus pentosus. AB - Lespedeza cuneata G. Don is a traditional herb that has been associated with multiple biological activities. In this study, we investigated the antioxidative/antiaging activities and performed an active component analysis of the non-fermented and fermented (using Lactobacillus pentosus) extracts of Lespedeza cuneata G. Don. The antioxidative activities of the fermented extract were higher than those of non-fermented extracts. The elastase inhibitory activity, inhibitory effects on UV-induced MMP-1 expression, and ability to promote type I procollagen synthesis were investigated in Hs68 human fibroblasts cells. These tests also revealed that the fermented extract had increased antiaging activities compared with the non-fermented extract. A component analysis of the ethyl acetate fractions of non-fermented and fermented extracts was performed using TLC, HPLC, and LC/ESI-MS/MS to observe changes in the components before and after fermentation. Six components that were different before and after fermentation were investigated. It was thought that kaempferol and quercetin were converted from kaempferol glucosides and quercetin glucosides, respectively, via bioconversion with the fermentation strain. These results indicate that the fermented extract of L. cuneata G. Don has potential for use as a natural cosmetic material with antioxidative and antiaging effects. PMID- 28910863 TI - Acceleration of Aglycone Isoflavone and gamma-Aminobutyric Acid Production from Doenjang Using Whole-Cell Biocatalysis Accompanied by Protease Treatment. AB - Recently, soybean isoflavone aglycones (i.e., daidzein and genistein) and gamma aminobutyric acid (GABA) have begun to receive considerable consumer attention owing to their potential as nutraceuticals. To produce these ingredients, multiple microorganisms and their enzymes are commonly used for catalysis in the nutraceutical industry. In this work, we introduce a novel fermentation process that uses whole-cell biocatalysis to accelerate GABA and isoflavone aglycone production in doenjang (a traditional Korean soybean paste). Microbial enzymes transform soybean isoflavone glycosides (i.e., daidzin and genistin) and monosodium glutamate into soybean isoflavone aglycones and GABA. Lactobacillus brevis GABA 100 and Aspergillus oryzae KACC 40250 significantly reduced the production time with the aid of a protease. The resulting levels of GABA and daidzein were higher, and genistein production resembled the levels in traditional doenjang fermented for over a year. Concentrations of GABA, daidzein, and genistein were measured as 7,162, 60, and 59 MUg/g, respectively on the seventh day of fermentation. Our results demonstrate that the administration of whole-cell L. brevis GABA 100 and A. oryzae KACC 40250 paired with a protease treatment is an effective method to accelerate GABA, daidzein, and genistein production in doenjang. PMID- 28910862 TI - Effects of Newly Synthesized Recombinant Human Amyloid-beta Complexes and Poly Amyloid-beta Fibers on Cell Apoptosis and Cognitive Decline. AB - The main pathological hallmark of Alzheimer's disease is the deposition of amyloid-beta (Abeta) peptides in the brain. Abeta has been widely used to mimic several aspects of Alzheimer's disease. However, several characteristics of amyloid-induced Alzheimer's disease pathology are not well established, especially in mice. The present study aimed to develop a new Alzheimer's disease model by investigating how Abeta can be effectively aggregated using prokaryotes and eukaryotes. To express the Abeta42 complex in HEK293 cells, we cloned the Abeta42 region in a tandem repeat and incorporated the resulting construct into a eukaryotic expression vector. Following transfection into HEK293 cells via lipofection, cell viability assay and western blotting analysis revealed that exogenous Abeta42 can induce cell death and apoptosis. In addition, recombinant His-tagged Abeta42 was successfully expressed in Escherichia coli BL21 (DE3) and not only readily formed Abeta complexes, but also inhibited the proliferation of SH-SY5Y cells and E. coli. For in vivo testing, recombinant His-tagged Abeta42 solution (3 MUg/MUl in 1* PBS containing 1 mM Ni2+) was injected stereotaxically into the left and right lateral ventricles of the brains of C57BL/6J mice (n = 8). Control mice were injected with 1* PBS containing 1 mM Ni2+ following the same procedure. Ten days after the sample injection, the Morris water maze test confirmed that exogenous Abeta caused an increase in memory loss. These findings demonstrated that Ni2+ is capable of complexing the 50-kDa amyloid and that intracerebroventricular injection of Abeta42 can lead to cognitive impairment, thereby providing improved Alzheimer's disease models. PMID- 28910864 TI - Madurahydroxylactone, an Inhibitor of Staphylococcus aureus FtsZ from Nonomuraea sp. AN100570. AB - FtsZ, a bacterial cell-division protein, is an attractive antibacterial target. In the screening for an inhibitor of Staphylococcus aureus FtsZ, madurahydroxylactone (1) and its related derivatives 2-5 were isolated from Nonomuraea sp. AN100570. Compound 1 inhibited S. aureus FtsZ with an IC50 of 53.4 MUM and showed potent antibacterial activity against S. aureus and MRSA with an MIC of 1 MUg/ml, whereas 2-5 were weak or inactive. Importantly, 1 induced cell elongation in the cell division phenotype assay, whereas 2-5 did not. It indicates that 1 exhibits its potent antibacterial activity via inhibition of FtsZ, and the hydroxyl group and hydroxylactone ring of 1 are critical for the activity. Thus, madurahydroxylactone is a new type of inhibitor of FtsZ. PMID- 28910865 TI - A Novel Chemical Compound for Inhibition of SARS Coronavirus Helicase. AB - We have discovered a novel chemical compound, (E)-3-(furan-2-yl)-N-(4 sulfamoylphenyl) acrylamide, that suppresses the enzymatic activities of SARS coronavirus helicase. To determine the inhibitory effect, ATP hydrolysis and double-stranded DNA unwinding assays were performed in the presence of various concentrations of the compound. Through these assays, we obtained IC50 values of 2.09 +/- 0.30 uM (ATP hydrolysis) and 13.2 +/- 0.9 uM (DNA unwinding), respectively. Moreover, we found that the compound did not have any significant cytotoxicity when 40 uM of it was used. Our results showed that the compound might be useful to be developed as an inhibitor against SARS coronavirus. PMID- 28910866 TI - An Aptamer-Based Electrochemical Sensor That Can Distinguish Influenza Virus Subtype H1 from H5. AB - The surface protein hemagglutinin (HA) mediates the attachment of influenza virus to host cells containing sialic acid and thus facilitates viral infection. Therefore, HA is considered as a good target for the development of diagnostic tools for influenza virus. Previously, we reported the isolation of single stranded aptamers that can distinguish influenza subtype H1 from H5. In this study, we describe a method for the selective electrical detection of H1 using the isolated aptamer as a molecular probe. After immobilization of the aptamer on Si wafer, enzyme-linked immunosorbent assay (ELISA) and field emission scanning electron microscopy (FE-SEM) showed that the immobilized aptamer bound specifically to the H1 subtype but not to the H5 subtype. Assessment by cyclic voltammetry (CV) also demonstrated that the immobilized aptamer on the indium thin oxide-coated surface was specifically bound to the H1 subtype only, which was consistent with the ELISA and FE-SEM results. Further measurement of CV using various amounts of H1 subtype provided the detection limit of the immobilized aptamer, which showed that a nanomolar scale of target protein was sufficient to produce the signal. These results indicated that the selected aptamer can be an effective probe for distinguishing the subtypes of influenza viruses by monitoring current changes. PMID- 28910868 TI - [Comments on the TNM classification for the Vater ampullary cancer in the Cancer Staging Manual (eighth edition) of American Joint Committee on Cancer]. PMID- 28910867 TI - [Current status and prospect of artificial intelligence in pathology]. PMID- 28910869 TI - [Lymphomatoid papulosis: a clinicopathologic analysis and whole exome sequencing]. AB - Objective: To study the clinicopathologic characteristics and immunophenotype of lymphomatoid papulosis(LyP), followed by exon mutation analysis with focus on gene mutations involved in apoptosis pathway and other possible pathogenic genes. Methods: Clinical data analysis and immunohistochemical staining were carried out in 20 cases of LyP. Whole exome sequencing technology was employed in 2 cases of type C of LyP. Results: Of the 20 cases, there were 9 males and 11 females with a median age of 28.6 years. Nineteen patients presented with multiple papules and nodules, and one case presented with only one tumor nodule. Of the fifteen cases with available followed-up data, all were alive (20-155 months). Histologically, the tumors primarily involved the dermis and subcutaneous layer, in which 6 were type A, 3 were type B, 10 were type C and 1 was type D. Main infiltration patterns included wedge-shaped, band-like, sheets and large nodular. Immunohistochemistry showed that most cases expressed CD30 in the large tumor cells. Sixteen cases expressed CD3, 17 cases expressed CD4 and 8 cases expressed CD8. Sixteen cases expressed TIA1. Ten cases expressed GrB and 1 case expressed CD15. All but one case did not expressed CD20. All cases did not express ALK1.A total of 101 common non-synonymous mutations were detected in 2 cases of LyP type C by whole exome sequencing, including 87 missense mutations, 6 missense mutation/frame-shift deletions, 2 missense mutation/nonframe-shift deletions, 5 frame-shift deletions, 1 missense mutations/synonymous mutation. Syndecan 1(SDC1), COL4A1, Laminin-5 were involved in the extracellular matrix receptor pathway. Conclusions: Clinical presentations are crucial for the diagnosis of LyP. LyP has a favorable prognosis. SDC1, COL4A1 and Laminin-5 gene mutations may be associated with tumor recurrence or progression into a higher gradelymphoma. PMID- 28910870 TI - [Primary mediastinal large B-cell lymphoma: a clinicopathologic study of 27 cases]. AB - Objective: To study the clinicopathologic characteristics and diagnostic criteria of primary mediastinal B-cell lymphoma (PMBL), and to distinguish PMBL from classic Hodgkin lymphoma(CHL) and systemic diffuse large B-cell lymphoma(DLBCL). Methods: The clinical features, histologic findings, results of immunohistochemical study and prgnosis in 27 PMBL cases were analyzed, with review of literature. Results: The age of patients ranged from 19 to 82 years (median age 34 years). All cases were located in the mediastinum and frequently accompanied by superior vein cava syndrome. Histologically, the tumor cells were pleomorphic and diffusely distributed. Clear cytoplasm and spindle tumor cells were seen in some cases. Varying amount of sclerosing stroma with collagen deposition was seen.Immunohistochemical study showed that the tumor cells were positive for CD20(100%, 27/27), CD30 (64.0%, 16/25), CD23 (77.3%, 17/22) and p63 (16/19). Clonal B cell gene rearrangement was seen. Conclusions: PMBL is a subtype of diffuse large B-cell lymphoma with various histomorphology. Immunohistochemistry can help to confirm the diagnosis, and the prognosis is better than diffuse large B cell lymphoma, not otherwise specified. PMID- 28910871 TI - [Mucosa-associated lymphoid tissue lymphoma in children and adolescents: a clinicopathologic study of 5 cases]. AB - Objective: To investigate the pathological features and clinical manifestations of mucosa-associated lymphoid tissue (MALT) lymphoma in children and adolescents. Methods: Five cases of MALT lymphoma in children were investigated by morphology and immunophenotyping along with clinical follow-up. Results: Five cases of MALT lymphoma occurred in the antrum, orbit, parotid gland and nasopharynx. All patients had no B symptoms and only one patient showed a local mass with ulcer. One case presented with cervical lymph node enlargement, and 4 cases showed no evidence of lymphadenopathy.All cases had pathological features similar to those of adult MALT lymphoma, with proliferation of monocytoid B cells orcentralcyte like tumor cells, with plasma cell differentiation and lymphoid epithelial lesions.No specific immunophenotypic marker was found. Clonal Ig gene rearrangement was detected in two cases.One patient was treated with rituximab treatment, 1 patient was given anti-Helicobacter pylori therapy, and 2 patients had no additional treatment.The follow-up data showed that 4 patients survived without tumor recurrence. Conclusions: Similar to adult patients, MALT lymphoma in children and adolescents has similar pathological features with indolent clinical course and good prognosis. It is important to note that misdiagnosis and incorrect diagnosis mightoccur because of the young age of the patients. PMID- 28910872 TI - [Pathologic subtyping of primary lymphoma of breast and prognostic analysis]. AB - Objective: To investigate the pathological types and prognostic factors of primary lymphoma of breast (PLB). Methods: The clinical pathological data of 115 cases of PLB during October 2006 to October 2016 were retrospectively analyzed, and the basic clinical and pathological data, pathology types and the immunohistochemical slides by EliVision two-step method for staining were summarized. Results: Almost all the patients were women (113/115), and the median age was 52 years old (range: 27 to 81 years old). The main symptom was painless progressive mass in breast. Ten cases (8.7%) showed B symptoms. The masses were mainly confined to the unilateral breast (80.9%, 93/115), of which 22 cases showed axillary lymph nodes enlargement in the same side. The average diameter of masses was 3.0 cm (range from 0.5 to 9.0 cm). There is no differences between the sides (left or right). Pathologically, 106 cases (92.2%) were mature non Hodgkin's B-cell lymphomas, of which there were mainly diffuse large B cell lymphoma (DLBCL, 64.3%) and mucosa associated lymphoid tissue (MALT) extranodal marginal lymphoma (17.4%). Five cases (4.4%) were mature T/NK cell lymphomas, including extranodal nasal NK/T cell lymphoma (1.7%), peripheral T-cell lymphoma non-specific type (0.9%), subcutaneous panniculitis-like T cells lymphoma (0.9%) and undivided (0.9%). Four cases were lymphoblastic lymphoma. According to Ann Arbor staging criteria, 93 cases were stage IE (6 cases were stage IEB), 22 cases were stage IIE (4 cases were stage IIEB). Ninety-two cases were followed 1 to 122 months (median: 36 months). The five-year overall survival rate was 85.3%, and 13 patients dead. B symptom was one of the factors that affect the prognosis (P<0.05), but the pathological type has no relationship with the prognosis (P>0.05). Conclusions: PLB is relatively rare, the main clinical manifestation is painless mass, which is difficult to distinguish with breast carcinoma. The most common type is DLBCL, followed by MALT lymphoma, while T cell lymphoma is rarely seen. PLB is early stage tumor with good prognosis, while patients with B symptom turn out to suffer worse prognosis. PMID- 28910873 TI - [Differential expression and clinical significance of calretinin in total colonic aganglionosis]. AB - Objective: To evaluate the differential calretinin immunostaining in different segments of total colonic aganglionosis and its utility in the diagnosis. Methods: Nine specimens including ileum and colon segments were obtained from 9 patients with total colonic aganglionosis (TCA), from 2010 to 2016 year, in Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology. Another 9 ganglionic specimens including the same segments from patients with non-Hirschsprung disease (non-HD) patients were collected as control. All cases were immunostained with calretinin. The patterns of calretinin immunostaining were observed, and morphometric analysis of each sample was performed by image analysis program (Image-Pro-Plus). The mean absorbance was evaluated by calculating the areas of the lamina propria occupied by the positively stained area of the calretinin at high power field. Results: The same pattern of calretinin immunostaining was seen in ganglionic ileum and ganglionic colon segments, with staining seen in intrinsic nerves fibers (INF), and in granular aggregates in the lamina propria and muscularis mucosae. There was no significant difference in the numbers of calretinin-positive INF from the ganglionic segments. In contrast, the number of calretinin-positive INF and granular aggregates in aganglionic segments were significantly lower than those in the ganglionic group (P<0.01). In the ileum transitional zone, scattered calretinin staining was observed, and the amount of calretinin-positive INF was significantly lower than those in the proximal segment of ganlionic ileum (P<0.01). Conclusions: Since there is significant different expression of calretinin among the different segments from TCA, calretinin immunostaining has potential value in detecting TCA. It could be an important adjunctive method in detecting TCA in the future. PMID- 28910874 TI - [Expression of C3d in normal human liver tissues with non-immunologic osmostic mechanism]. AB - Objective: To observe the deposition of complement C3d at different development stages in human normal organs and tissues, and investigate the significance of its deposition. Methods: Using immunohistochemical methods, the deposition of C3d was detected at different development stages of 60 normal human organs and tissue specimens and double staining was performed in some specimens. Ninty-five cases of other organs or tissues were collected as control group. Results: In 50 of 60 livers, it was observed the deposition of C3d in Glisson's capsule and periportal sheath, with irregular linear network-like disposition surrounding the portal sheath. In different age groups, the expression of C3d was more beyond the 20 year-old group than 3 to 20 year-old group. There wasn't any expression of C3d under 3-year-old group. Under the immuning electron micrograph, C3d depositing at the Glisson's capsule was observed, without immuning compounding. Thirty in 40 spleens, deposition of C3d in capsules, arteries of lymphatic sheath, follicles in the spleen was observed. Conclusions: The deposition of C3d in Glisson's capsule, splenic trabeculae, fibrous sheath, endarterium of liver and spleen arterioles, within normal human tissues from patients elder than 3 years, are osmosis/immunogenic deposition. The deposition of C3d is a normal physiological phenomenon, and treatment of the deposition of C3d should be avoided, as it is an immune complex or immuning reaction phenomenon. PMID- 28910876 TI - [Clinicopathologic study of follicular lymphoma with features of Castleman's disease]. PMID- 28910875 TI - [Clinicopathologic and prognosis features of Claudin-low breast cancers]. AB - Objective: To investigate the clinicopathologic and prognostic features of Claudin-low breast cancers (CLBC). Methods: Tissue microarray sections were scored semiquantitatively for the immunohistochemical expression of claudin-1, 3, -4, -7 and -8 in 233 cases of invasive breast cancers collected from Qingdao Central Hospital from January 2010 to December 2011. Results: The expression rate of Claudin-3 (72/212, 33.9%) and -4 (56/212, 45.2%) was most similar, and Claudin 4 showed the highest expression. Twenty one cases (21/212, 9.0%) were diagnosed as CLBC, with triple-negative breast cancer (TNBC) accounted for the highest proportion (11/21, 52.4%). Among the CLBC cases, the invasive carcinoma no special type (66.7%, 14/21) and metaplastic carcinoma (14.3%, 3/21) were mostly seen, while metaplastic squamous carcinoma did not show Claudin-low pattern. Compared to the non CLBC in this cohort, CLBC had higher proportion of histologic grade 3 and tumors larger than 2 cm, and the proportions were slightly lower than TNBC. Patients with CLBC had lower 5 year disease-free(P>0.05) and overall survival rates(P=0.018). Conclusion: CLBC shows distinct clinicopathologic and prognostic features comparing to other subtypes, and is associated with poor prognosis. PMID- 28910877 TI - [Multiple cutaneous erythematous lesions]. PMID- 28910878 TI - [Thyroid-like follicular renal cell carcinoma with extramedullary hematopoiesis: report of a case]. PMID- 28910879 TI - [Composite CD20-positive T-cell lymphoma and peripheral T-cell lymphoma, NOS: report of a case]. PMID- 28910880 TI - [Pituicytoma: report of a case]. PMID- 28910881 TI - [Primary pulmonary alveolar rhabdomyosarcoma: report of a case]. PMID- 28910882 TI - [New applications of "old" antibodies in diagnostic pathology]. PMID- 28910883 TI - [Hereditary cancer syndromes in female reproductive system: an overview]. PMID- 28910884 TI - [Progress in molecular mechanism of Epstein-Barr virus driving cell cycle and promoting oncogenesis]. PMID- 28910885 TI - [New progression and challenges in transnasal endoscopic rhino-orbital related surgery]. PMID- 28910886 TI - [The interactive role of rhinology and ophthalmology in the development of transnasal endoscopic rhino-orbital related surgery]. PMID- 28910887 TI - [Clinical practice of transnasal endoscopic operation for retrobulbar lesions]. AB - Objective: To summarize the skill and experience of transnasal endoscopic operation for retrobulbar lesions. Methods: Seven patients aged from 25 to 67 years old diagnosed as retrobulbar lesions who underwent transnasal endoscopic operation in Department of Otorhinolaryngology Head and Neck Surgery, Xiangya Hospital between January 2013 and October 2016 were retrospectively analyzed. Two males and five females were included in this study. Five patients underwent transnasal endoscopic operation via media rectus-inferior rectus space, with the other 2 cases via media rectus-superior rectus space. Results: Total lesion removal was achieved in 6 of 7 patients, while 1 patient underwent subtotal removal of the lesion. The visual acuity and visual field improved in 3 cases. The pathological examination showed hemangioma(5 cases), bone cyst(1 case) and fibroma(1 case). All patients were followed up for 9 months to 4 years without complications such as eye movement disorder or blindness, except for 1 case with preoperatively proptosis occurred postoperatively transient diplopia. There was no recurrence in 6 patients with total lesion removal, and the patient underwent subtotal removal of fibroma did not undertake operation again. Conclusion: Transnasal endoscopic operation for retrobulbar lesions is a minimally invasive, safe and effective operatiiv method, which could be taken via different surgical approaches according to the size and location of the lesion. PMID- 28910888 TI - [Endoscopic salvage treatment for optic neuropathy caused by sinonasal fibro osseous lesions]. AB - Objective: To summarize the surgical techniques, benefits and limitations of transnasal endoscopic resection and optic nerve decompression for patients with optic neuropathy caused by fibro-osseous lesions. Methods: Eight patients with optic neuropathy caused by fibro-osseous lesions who accepted endoscopic surgery of either resection of the lesion or decompression of optic nerve in Otorhinolaryngology Hospital, First Affiliated Hospital of Sun Yat-sen University from 2007 to 2016 were retrospectively reviewed and followed until April, 2017. Analyses were performed on the pathology type, disease extent and disease duration, especially on the visual acuity and visual field changes before and after surgery. Results: Eight patients (5 male and 3 female) were included in this study, with a median age of 12 years old (8-19 years old). The median disease duration was 12 months (1-72 months). The visual acuity (VA) of five patients (40 cm/FC, 0.2, 0.1, 0.2, 10 cm/FC, respectively) improved after surgery (0.1, 0.3, 1.2, 0.1, 0.6, respectively), and one patient had no change of VA after the surgery. Two patients (0.02, hand movement, before surgery) became deprived of light perception (VA=0) immediately after surgery. One patient complicated with intra orbital hemorrhage because of anterior artery injury. No complications of cerebral spinal fluid leak, intra-ocular muscle injury, intra cranial hemorrhage or brain tissue injury occurred. Conclusion: For the treatment of optic neuropathy caused by fibro-osseous lesions, transnasal endoscopic surgery might have a good outcome. PMID- 28910889 TI - [Clinical features of traumatic optic neuropathy in 265 cases]. AB - Objective: To analyze the clinical features and the pathogenetic law of traumatic optic neuropathy through epidemiologic study. Methods: 265 cases (275 eyes) with TON treated in Department of Otorhinolaryngology Head and Neck Surgery, the Affiliated Hospital of Qingdao University from April 1999 to August 2015 were retrospectively analyzed. Multiple Logistic regression analyses were used to evaluate potential prognostic factors on visual acuity. Results: TON occured mostly in young (194/265, 73.21%) man (235/265, 88.68%), the majority of patients came from villages and towns (209/265, 78.87%). Traffic accident (197/265, 74.34%) remained the main etiology, with strike (36/265, 13.58%) and fall (17/265, 6.42%) as the common etiology. Most patients had head injuries. The effective rate of vision improvement was 53.45%(147/275). Multiple logistic regression analyses identified that initial visual acuity with light perception or better vision, optic canal fracture and orbital wall fracture were visual acuity key factors of TON (chi(2) value was 24.674, 19.755, 9.175, respectively, all P<0.01), initial visual acuity with light perception or better vision was the protective factor on visual acuity recovery (OR=5.008, P<0.001), the presence of optic canal fracture and orbital wall fracture were the risk factors on visual acuity recovery (OR value was 0.110, 0.329, respectively, all P<0.01). Conclusions: Ton occurs mostly in young man because of traffic accident. Visual impairment of TON is severe. The suitable preventive measures should be carried out according to its epidemiological features. PMID- 28910890 TI - [Clinical analysis of orbital complications due to rhinosinusitis in 28 cases]. AB - Objective: To investigate the clinical characteristics of orbital complications due to rhinosinusitis and to provide the basis for the diagnosis and treatment of this disease. Methods: Retrospectively analyzed the clinical data of 28 patients with orbital complications due to rhinosinusitis who were admitted into the Affiliated Hospital of Qingdao University, Department of Otorhinolaryngology from August 2009 to April 2017. In all 28 cases, there were 1 case with preseptal cellulites, 9 cases with orbital cellulites, 13 cases with subperiosteal orbital abscess and 5 cases with orbital abscess. Among all the patients, 9 were younger than 14. Two patients were in ages from 14 to 17 and 7 patients were at or above 18 years. Absolute medicine therapy was performed on 8 patients and combined therapy of operation and pharmacotherapy on 20 patients. Results: The patients were followed up for 2 to 19 months. Both the general symptoms and ocular symptoms disappeared and nasal ventilation function recovered well. Conclusions: The treatment for orbital complications of rhinosinusitis includes absolute medicine therapy and combined therapy of operation and pharmacotherapy. And the selection of treatment depends on disease stage. Timely diagnosis and reasonable treatment would be beneficial in the recovery of patients. PMID- 28910891 TI - [Clinical study of aged patients with secondary benign paroxysmal positional vertigo]. AB - Objective: To investigate the clinical features and evaluate the efficacy of manual reduction in treatment of age patients with secondary benign paroxysmal positional vertigo (s-BPPV). Methods: Thirty-two cases of aged patients ( the s BPPV group: including 19 cases of female and 13 males, age from 60 to 86 years old)with secondary benign paroxysmal positional vertigo from Jul. 2013 to Sep. 2015 in our hospital were retrospectively analyzed. The results were compared with 121 patients( the primary group: including 82 cases of female and 39males, aged from 60 to 86 years old)with aged primary benign paroxysmal positional vertigo(p -BPPV). All the patients were followed up for 12 months. Statistical data analysis was carried out with SPSS 19.0. Results: 20.92%(32/153)of all the observed elderly patients with BPPV was the aged s-BPPV. The sex ratio and onset age had no significant difference between the two groups(chi(2)=0.79, P>0.05; t=0.37, P>0.05). The rate of two or more semicircular canal involvement in the secondary group(21.88%) was higher than that in primary group(6.61%)(chi(2)=6.67, P<0.05). Bilateral semicircular canals were involved in 5 of the 32 cases in secondary group(15.63%) and 4 of the 121 cases in aged primary group(3.31%), The difference was significant(chi(2)=6.94, P<0.05). The effective rate after first manual reduction was 57.50%(23/40)in secondary group and 82.31%(107/130)in primary group, the difference was significant(chi(2)=10.46, P<0.05). The total effective rate were 87.50%(35/40) after more than once manual reduction in secondary group and 91.54%(119/130) in primary group, the difference was not significant(chi(2)= 0.59, P>0.05). The numbers of circulation of the first successful manual reduction management were (3.9+/-1.3)times in secondary group and (2.1+/-1.1)times in primary group, the difference was significant(t=3.15, P<0.05). The recurrence rate was 37.50%(15/40) in the secondary group and 16.15%(21/130)in primary group after during follow-up for 12 months, the difference was statistically significant(chi(2)=8.35, P<0.05). Conclusions: It's shown that the aged patients with secondary BPPV is not rare in clinical practice, sudden deafness and head trauma are frequent more than other reasons. The aged patients with secondary BPPV are prone to injury in multi-semicircular and bilateral canal compared with the primary BPPV. The effective rate after first manual reduction of secondary BPPV is lower than primary BPPV, it's needed more circulation of first success in manual reduction management. The total effective rates are not significant in two groups and recurrence rate is relatively high in secondary group. PMID- 28910892 TI - [Study on pharyngeal wall floppiness of patients with obstructive sleep apnea hypopnea syndrome attributable to non-structural factors]. AB - Objective: Acoustic pharyngealmetry technology is utilized to evaluate the change and clinical significance of obstructive sleep apnea-hypopnea syndrome (OSAHS) patients caused by non-upper airway structural factor and normal individuals' PWF(pharyngeal wall floppiness). Methods: Acoustic pharyngealmetry instrument of Ecconvision was utilized to examine 102 OSAHS patients and 50 normal individuals, separately recorded their volume of pharyngeal cavity in sit or supine position, calculated PWF in sit or supine position, and SPSS 12.0 of tware was used to analyze data. Results: PWF was 0.14+/-0.09 in sit position and PWF was 0.21+/ 0.10, (t=5.96, t=9.63, P<0.001)in supine position of OSAHS group, which were all significantly higher than those of control group. PWFs in supine position of OSAHS group and control group were evidently higher than PWF(t=-11.91, P<0.001; t=-2.32, P=0.025) in sit position. DeltaPWF(PWF_supine-PWF_sit)was 0.063+/-0.054 in OSAHS group which was significantly greater than in control(F=41.173, P<0.01). PWF in sit position and supine position were all positively related with age(r=0.714, r=0.735, P<0.001)while irrelevant with BMI(P>0.05). Conclusions: PWF can be utilized to be an index to reflect the physiological feature of upper airway. PWF can more precisely reflect upper airway collapsibility of OSAHS patients on the condition of PWF in supine position. Pharyngeal wall floppiness quantified as a high PWF index is a non-structure vital factor of OSAHS patients and plays a role of guiding us to make personal treatment plans for OSAHS patients. PMID- 28910893 TI - [Pediatric laryngeal clefts: an experience in the diagnosis and management of 13 cases]. AB - Objective: To investigate the diagnosis and management of laryngeal cleft. Method: The clinical data of 13 cases of laryngeal cleft treated between 2007 and 2015 was analyzed retrospectively. Results: The children with laryngeal cleft were classified according to the classification of Benjamin-Inglis, as type I(11 cases), typeII(1 case) and type III(1 case). All patients were confirmed by microlaryngobronchoscopy under general anaesthetic. Eleven typeI and 1 type II clefts were managed conservatively, with which all type I patients were successfully managed, while the type II patient was resolved by surgical endoscopy. The type III patient was treated by open repair but the results was poor. Conclusions: Patients who suffered with choking on feeding or recurrent aspiration pneumonia, especially coexisted with other congenital malformation, needed detailed evaluation for laryngeal cleft, although which was a rare congenital abnormality. Electronic laryngoscope could be the first step to screen the cleft, while microlaryngobronchoscopy is the gold standard for diagnosis of laryngeal cleft. The majority of children with lower type clefts can be managed conservatively. Surgical endoscopy has high success rate when strictly following the indication. Type III and IV clefts have high mortality for usually combining with severe complications and abnormalities. PMID- 28910894 TI - [Diagnostic values of BRAF(V600E) mutation analysis and Bethesda system for reporting thyroid cytopathology in thyroid nodules with TIRADS 4 and 5]. AB - Objective: To evaluate the diagnostic efficacies of BRAF(V600E) testing and Bethesda system for reporting thyroid cytopathology (BSRTC) in thyroid nodules with thyroid imaging reporting and data system (TIRADS) category 4 and 5. Methods: A total of 187 thyroid nodules in 187 patients underwent the examinations of ultrasound-guided fine needle aspiration cytology (FNAC) and BRAF(V600E) mutation were analyzed retrospectively. Receive operating characteristic (ROC) curve was used to investigate the diagnostic values of both methods and the clinical application of BRAF(V600E) combined with BSRTC was evaluated. SPSS17.0 software was used to analyze the data. Results: Among 187 thyroid nodules, 123 were malignant nodules confirmed with histopathological examination and 64 benign nodules determined by FNAC, histopathological examination, or long-term follow-up. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BRAF(V600E) test were better than those of BSRTC [69.1%, 98.4%, 98.8%, 62.4%(chi(2)=77.3, P=0.000) vs 62.6%, 93.8%, 95.1%, 56.6%(chi(2)=54.4, P=0.000)]. While the sensitivity, specificity, PPV and NPV of the combined test of BRAF(V600E) and BSRTC for diagnosis of malignant thyroid nodules were 87.8%, 92.2%, 95.6%, 79.7%(chi(2)=112.6, P=0.000), respectively. The area under the ROC curve for the combined test was higher than that for each of tests (0.900 vs 0.858 or 0.838). Conclusions: The combined test of BRAF(V600E) mutation and BSRTC has a higher diagnostic efficacy for malignant thyroid nodules compared with BRAF(V600E) mutation or BSRTC alone. PMID- 28910895 TI - [Correlation analysis of the Epstein-Barr virus recruited regulatory T cells in nasopharyngeal carcinoma of immune escape]. AB - Objective: To investigate the relation of Epstein-Barr virus (EBV)-induced immune escape to regulatory T cells(Treg) in nasopharyngeal carcinoma(NPC). Methods: We recruited 83 patients who were pathologically diagnozed as nasopharyngeal carcinoma and treated in Nanfang Hospital from January to September 2016. CD4(+) CD25(+) FOXP3(+) Treg in peripheral blood was examined by flow cytometry and the level of EBV DNA in the blood was detected by quantitative real-time polymerase chain reaction(qRT-PCR)in 83 patients and 51 healthy adults as control. The expression of FOXP3(+) Treg and EBER in NPC in 32 of 83 patients and in nasopharyngitis in 16 control patients were tested by immunohistochemistry(IHC) and in-situ hybridization(ISH). Results: The ratio of Treg in blood in patients with NPC(5.29+/-1.45)% was higher than that in control group (4.78+/-1.19) %, with a statistically significant difference(P=0.035). The ratio of Treg in blood in patients with positive EBV was higher than that in patients with negative EBV(P=0.013), and there was a positive correlation between EBV DNA copies and Treg ratio(r=0.335, P=0.002). The density of FOXP3(+) Treg in NPC was higher than that in nasopharyngitis(P=0.001). Positive correlation was found between the density of FOXP3(+) Treg and the stain intensity of EBER(r=0.496, P=0.004). Conclusion: The ratios of Treg in blood and tissue in NPC patients with positive EBV are significantly increased, indicating a role of Treg in EBV-induced immune escape in NPC. PMID- 28910896 TI - [Measurement of morphological parameters of internal acousticmeatus using thin section CT]. AB - Objective: This study aimed to measure the morphological parameters of the internal acoustic meatus(IAM) and its adjacent structures using temporal-bone thin-section CT(computed tomography). Methods: CT images were obtained from 50 Chinese adult patients (25 males and 25 females, 100 sides) which had no visible lesion in the petrous part of the temporal bone and inner ear, the morphological parameters of all inner ear parts were sectionally measured on the specified plane using SPSS 22.0 software for statistical analysis. Results: The integral morphological characteristics of the IAM were observed. These results revealed that anterior-posterior diameter of the internal acoustic poer(IAP)(CD) was (6.93+/-1.85)mm, the superior-inferior diameter of the IAP(EF) was (4.40+/ 0.86)mm, the length of the IAM(AB) was (9.30+/-1.60)mm, the superior-inferior diameter of the IAM(the intersection of inner 1/3 section and middle 1/3 section) was (4.13+/-0.83)mm, the superior-inferior diameter of the IAM(the intersection of middle 1/3 section and outer 1/3 section) was (4.61+/-1.02)mm, the anterior posterior diameter of the IAM(the intersection of inner 1/3 section and middle 1/3 section) was (6.62+/-1.92)mm, the anterior-posterior diameter of the IAM(the intersection of middle 1/3 section and outer 1/3 section) was (6.28+/-1.65)mm, the depth of transverse crest (superior wall) was (3.10+/-0.75)mm, the depth of transverse crest (interior wall)the was (1.46+/-0.59)mm, the distance from transverse crest vertex A to the superior wall of the IAM was (2.05+/-0.42)mm, the distance from transverse crest vertex A to the interior wall of the IAM was (2.93+/-0.41)mm, the thickness of the superior bone wall of the IAM (the intersection of inner 1/3 section and middle 1/3 section) was (4.45+/-1.34)mm, the thickness of the superior bone wall of the IAM (the intersection of middle 1/3 section and outer 1/3 section) was (4.32+/-1.12)mm, the thickness of the superior bone wall of the IAM (the intersection of outer 1/3 section and transverse crest vertex) was (4.37+/-1.28)mm, and the appearance ratio of the cells in the whole IAM superior wall was 32%.The whole IAM assumed the shape of short cylinder, inclining about 1 cm outward, with the upper-lower diameter and anterior-posterior diameter about 5 mm. Conclusion: It is necessary for carrying out preoperative the temporal-bone thin-section CT to obtain the morphological parameters of the IAM, determine its basic morphology, and provide references to avoid damaging the other important structures during IAM surgeries. PMID- 28910897 TI - [The application of microvascular anastomotic coupler in vascular anastomosis of free tissue flap for reconstruction of defect after head and neck cancer resection]. AB - Objective: To investigate the application and operation skills in vein anastomosis by microvascular anastomotic coupler (MAC) in reconstruction of defects after head and neck cancer resection. Methods: From August 2015 to July 2016, in Department of Head and Neck Surgery, Sichuan Cancer Hosipital, 17 cases underwent the reconstruction of defects after head and neck cancer resection with free tissue flaps, including forearm flaps in 11 casess, anterolateral flaps in 4 casess and fibula flaps in 2 casess. Totally 17 MAC were used, including 14 MAC for end-to-end anastomosis and 3 MAC for end-to-side anastomosis. SPSS 22.0 software was used to analyze the data. Results: Venous anastomoses in 17 free tissue flaps were successfully completed, with no anastomotic errhysis. All flaps survived well. The time required for vascular anastomoses with MAC varied 2-9 min, with average time of (4.2+/-2.3) min, which was significantly shorter than that with manually anastomosis (17.4 +/- 2.7) min (t=15.1, P<0.01). The followed up time ranged from 6 to 18 months. The flaps in recipient area healed well. The shape and function of recipient area were satisfying. Conclusions: Microvascular anastomotic coupler can be used for vessel anastomosis in free tissue flap for reconstruction of defect after head and neck cancer resection, which requires for less operation time and shows good results. PMID- 28910898 TI - [Eosinophilic otitis media: a case report]. PMID- 28910899 TI - [One case of foreign body in right bronchus taken out of left bronchus]. PMID- 28910900 TI - [The function of Kolliker's organ in mammalian cochlear]. AB - Kolliker's organ, which is a transient structure of cochlea during development, in late embryonic and early postnatal period, is one of the signs of cochlear immaturity.Kolliker's organ degradates after the sensory structures become sensitive to external sound. The putative role of Kolliker's organ is important for generating the intrinsic spontaneous activity whichpromotes the development and maturation of a fully functional auditory system. PMID- 28910902 TI - [To strengthen the standardization of noninvasive ventilation in obstructive sleep apnea]. PMID- 28910901 TI - [Clinical research on immune checkpoint and head and neck squamous cell carcinoma]. AB - T cell immune checkpoint pathways contribute to tumor immune escape. Many studies have shown that immune checkpoint is demonstrably correlated with tumor grade or prognosis in several types of malignancies and immune checkpoint has become a new biological index for tumor detection and prognosis. Immune checkpoint inhibitors have shown promising tumor outcomes in clinical trials for some advanced solid tumors and it will become a new target for cancer immunotherapy. In this review we will explore the correlation between expressions of immune checkpoint associated genes and proteins in immune microenviroment and prognosis of head and neck squamous cell carcinoma, and specifically will discuss how this pathway can be manipulated with immune therapeutic drugs. PMID- 28910903 TI - [Patient-ventilator synchrony in noninvasive positive pressure ventilation]. PMID- 28910904 TI - [Noninvasive ventilation in pediatric respiratory failure: use at the right time]. PMID- 28910905 TI - [Application of noninvasive ventilation in postoperative patients: indications and clinical strategies]. PMID- 28910906 TI - [Noninvasive ventilation in neuromuscular diseases: respiratory support and airway management]. PMID- 28910907 TI - [Clinical practices of noninvasive positive pressure ventilation in stable obesity-hypoventilation syndrome]. PMID- 28910909 TI - [The overseas guidelines and consensus for domiciliary noninvasive positive pressure ventilation for patients with sleep disordered breathing: a summary]. PMID- 28910908 TI - [To standardize the noninvasive positive pressure ventilation in obstructive sleep apnea]. PMID- 28910910 TI - [Respiratory function measurement and noninvasive ventilation therapy for neuromuscular diseases]. PMID- 28910911 TI - [Experience in exploring clinical indications of some special noninvasive ventilation modes]. PMID- 28910912 TI - [Percutaneous catheterization for extracorporeal membrane oxygenation: a retrospective case series]. AB - Objective: To review the experience of percutaneous catheterization for extracorporeal membrane oxygenation (ECMO) by respiratory intensivists at a single institution. Methods: A retrospective review of 87 patients undergoing percutaneous catheterization for ECMO in Department of Respiratory and Critical Care Medicine of Beijing Chaoyang Hospital from November 2009 to January 2017. Subject demographics, type of support, cannulation configuration, types of cannulas, use of imaging modalities, and complications were recorded and summarized. Results: The 87 patients consisted of 61 males and 26 females. The average age was (47+/-16)years (range 15-82 years ). Fifty-six patients were given ECMO therapy because of acute respiratory distress syndrome(ARDS), and 16 were treated as a bridge for lung transplantation and 15 for other causes. Eighty one cases were given VV-ECMO support, and 6 cases were given VA-ECMO support. The most commonly used cannulas were 15-17 F arterial cannulas and 21-23 F venous cannulas. Preinsertion ultrasound was performed in 62 patients (71%) . Bedside chest radiography was used to help adjust the position of the end of the cannula in 11 patients (13%). Percutaneous catheterization was successful in 85 cases (97%) , while it failed in 2 female patients due to thick subcutaneous fat layer, and open surgical approach was used. Percutaneous femoral artery collateral circulation was established by ourselves in 5 cases. One patient with femoral artery catheterization without collateral circulation had gangrene of limbs. The complications included 9 cases of catheter site hemorrhage, 4 catheter-related bloodstream infection and 1 pulmonary embolism during ECMO weaning. Conclusion: Percutaneous catheterization for ECMO can be performed with a high rate of success and a low rate of complications. PMID- 28910913 TI - [Effect of transcutaneous oximetry on prognosis of patients with severe acute respiratory failure receiving extracorporeal membrane oxygenation]. AB - Objective: To investigate the prognostic value of transcutaneous oximetry in patients with severe acute respiratory failure receiving extracorporeal membrane oxygenation(ECMO). Methods: Forty-nine patients diagnosed as severe acute respiratory failure receiving Venous-Venous(V-V)ECMO were enrolled from January 2013 to December 2015 in intensive care unit(ICU) of Wuxi People's Hospital Affiliated to Nanjing Medical University.The 10-min oxygen challenge test was performed using transcutaneous oximetry 6 h after the initiation of ECMO, and the 10-min oxygen challenge test value(OCT(10)) and oxygen challenge index(OCI) were calculated.The following data were collected: patients' baseline characteristics, results of arterial blood gas analysis, ventilator settings, APACHEII, SOFA and Murray lung injury score. Patients were stratified into the survival group and the death group based on their mortality status at 60 d after initiation of ECMO.Patients' characteristics and clinical data were analyzed with SPSS 22.0 software. Receiver operating characteristics (ROC) analysis for predicting 60 d mortality was carried out to find area under curve (AUC) and threshold levels of OCT(10) and OCI. Analysis of survival probability was carried out by Kaplan-Meier method and log-rank test. Multivariable logistic regression was used to identify factors associated with outcomes. Results: There were 25 patients in the survival group and 24 patients in the death group. The characteristics(i.e., age, sex, primary disease) and clinical data(i.e., results of arterial blood gas, ventilator settings) of the 2 groups were similar (P>0.05). The survival group had a significant higher OCT(10) and OCI [(77+/-11) mmHg(1 mmHg=0.133 kPa), 0.77+/-0.17] than the death group [(57+/-12) mmHg, 0.55+/-0.13, all P<0.05]. The AUC value of OCT(10) and OCI for predicting 60 d mortality were 0.87+/ 0.07(95%CI: 0.69-0.96, P<0.05) and 0.83+/-0.18(95%CI: 0.64-0.94, P<0.05) respectively, and the cutoff points for OCT(10) and OCI were 72.00 mmHg and 0.80. Kaplan-Meier survival analysis showed that a OCT(10)>=72 mmHg (81.3% vs 15.4%, chi(2)=7.04, P<0.01) and a OCI>=0.8(77.8% vs 21.7%, chi(2)=13.15, P<0.01) were related to better outcome. Multivariate logistic regression analysis showed that OCT(10)(OR=0.88, 95%CI: 0.80-0.96, P<0.01) and OCI (OR=0.01, 95%CI: 0.001-0.086, P<0.01) were both risk factors associated with 60 d mortality. Conclusion: The OCT(10) and OCI are predictive of mortality for patients with severe acute respiratory failure receiving ECMO support. PMID- 28910914 TI - [Changes to sleep patterns in young migrants at high altitude]. AB - Objective: To explore the relationship between the level of acclimatization and the changes to sleep architecture in migrants at high altitude. Methods: Nocturnal sleep recordings of 50 subjects aged between 18 and 25 years [mean age (20.9+/-2.0) years] were analyzed. Those young volunteers were divided into 3 700 m-3 m group(n=10, migrated to an altitude of 3 700 metres for 3 months), 3 700 m 1 y group(n=10, for 1 year) , 5 380 m-3 m group(n=8), 5 380 m-1 y group(n=9), and compared with a control group(n=13, at 1 400 m altitude). Results: When the migrants stayed at 5 380 m for 3 months or 1 year, the wake time increased significantly during sleep[(81.81+/-59.80)min vs(47.19+/-24.98) min, P=0.026; (77.94+/-25.64)min vs(47.19+/-24.98)min, P=0.040]. Concerning the percentage of total sleep time(TST) in each stage, participants in the 5 380 m-3 m group had a shift in sleep stage distribution with near absence of slow wave sleep(SWS) and a significant increase of N1 , but N2 and rapid eye movement(REM) did not differ. Interestingly, there were entirely concordant changes among the other 3 groups of results, decreased N2 and increased REM. Conclusions: The migrants' abilities to acclimatize themselves to plateau were varied according to the arrived altitude and the length of stay. The sleep of short- time migrants was characterized by increased N1 and decreased SWS, whereas that of well acclimatized migrants was characterized by less N2 and more REM. The efficient recovery in SWS may be an objective reference in high altitude acclimatization. PMID- 28910915 TI - [Assessment of sleep-disordered breathing using hypoxia index]. AB - Objective: To analyze the clinical significance of hypoxia index (HI) in assessing the severity of hypoxemia in obstructive sleep apnoea hypopnea syndrome(OSAHS). Methods: A total of 127 patients with a complaint of snoring visiting our hospital were recruited from February 2014 to January 2016. All patients received polysomnography (PSG) test. The PSG results were analyzed by a technician and the SpO(2) data were analyzed by a pre-designed computer software. The patients were grouped according to apnea hypopnea index (AHI) and lowest oxygen saturation (LSpO(2)) respectively. Receiver operating characteristic (ROC) curve was used to evaluate the best HI diagnostic value. Results: The HI (median) of the simple snoring, mild, moderate and severe OSAHS groups (according to AHI) were 0.027(0.004, 0.554), 0.281(0.045, 0.353), 0.429(0.099, 1.677), 21.714(2.737, 95.473), respectively. There were statistically significant correlation between HI and AHI, LSpO(2), >=3% oxygen desaturation index(ODI(3)), the correlation coefficient being 0.78, -0.92, 0.87(U value were 8.76, -10.34, 9.72, all P<0.01). Grouped according to LSpO(2), the HI was significantly different between groups (H value were 7.62-14.39, all P<0.05). Conclusion: If the HI diagnostic value was set reasonably, it might be used as an effective index for evaluating the severity of OSAHS. PMID- 28910916 TI - [Primary tracheal malignant glomus tumor with lung metastasis diagnosed by pathological analysis: a case report and literature review]. AB - Objective: To study the clinical manifestations, pathological features, diagnosis, differential diagnosis, treatment and prognosis of primary tracheobronchial or pulmonary malignant glomus tumor (MGT). Methods: A case of primary tracheal MGT with lung metastasis diagnosed by pathological analysis admitted to Affiliated Shantou Hospital of Sun Yat-sen University in May. 2015 was analyzed, and the related literatures were reviewed. We searched databases including PubMed, Embase, Ovid, Cochrane, Wanfang and Chinese National Knowledge infrastructure (CNKI), using the keyword "tracheal or bronchial or pulmonary malignant glomus tumor" from Jan. 1975 to Dec. 2016. Results: A 47 year-old male patient was admitted to the hospital because of cough, chest tightness and shortness of breath for 3 days. The chest CT showed a soft tissue mass with a diameter of 2.5 cm in the lower tracheal segment, and the lumen was narrowed. Meanwhile, multiple nodular opacities were shown in both lungs. The admission diagnosis was thyroid cancer with multiple metastases of lung. Electronic bronchoscopic airway tumor ablation and cryotherapy were performed, and then the biopsy of the tumor was conducted and the pathological study confirmed the diagnosis of primary tracheal MGT. After 1 month, the tracheal tumor recurred. Then, electronic bronchoscopic airway tumor ablation and cryotherapy were performed again. The patient declined further therapy such as radiotherapy or chemotherapy and died one month later. A total of 14 literatures including 15 cases were retrieved from databases. In addition of this case, a total of 16 cases were analyzed, including 9 males, 7 females. Age of onset ranged from 9 to 74 years, and the average age was 49 years. These patients' chest CT showed airway mass or lung space occupying lesions, and the clinical manifestations were nonspecific. Conclusions: Primary MGT in trachea, bronchus or lung is a rare disease, which is easy to be misdiagnosed or to miss diagnosis. The final diagnosis depends on pathological morphology, and the main treatment is lobectomy or tracheal segment resection surgery. Due to its high invasiveness, local recurrence and metastasis may occur easily. The primary MGT in trachea, bronchus or lung is of poor prognosis. PMID- 28910917 TI - [The Advances in vetilator induced diaphragm dysfunction]. PMID- 28910918 TI - [Advances in the role of interleukin-18 in acute respiratory distress syndrome]. PMID- 28910919 TI - [The value of serum VEGF-D concentration and TSC gene in diagnosis and treatment of lymphangioleiomyomatosis]. PMID- 28910920 TI - [High flow nasal cannula in obstructive sleep apnea hypopnea syndrome]. PMID- 28910921 TI - [Effectiveness of rapid hepatitis B vaccination with different vaccine dosages and types in adults]. AB - Objective: To evaluate the effectiveness of rapid hepatitis B vaccination with different vaccine dosages and types in adults. Methods: Adults who were aged >=20 years, negative in the detections of 5 HBV serum markers or only anti-HBc positive were selected from Chaoyang district of Beijing. They were divided into 4 community-based specific groups and given three doses of 10 MUg HepB-SCY vaccine, 20 MUg HepB-SCY vaccine, 20 MUg HepB-CHO vaccine and 10 MUg HepB-HPY vaccine respectively at month 0, 1, and 2. Their blood samples were collected within 1-2 months after completing the three dose vaccination to test anti-HBs level by using chemiluminesent microparticle immunoassay. A face to face questionnaire survey was conducted, and chi(2) test, Mantel- Haensel chi(2) test, Kruskal-Wallis rank test and multiple logistic regression analysis were performed. Results: A total of 1 772 participants completed vaccination and observation. Their average age was 48.5 years, and 62.75% of them were females. The anti-HBs positive rates in the groups of 10 MUg HepB-SCY, 20 MUg HepB-SCY, 20 MUg HepB-CHO and 10 MUg HepB-HPY vaccines were 79.49%, 84.34%, 82.50% and 74.15%, respectively (P=0.005), and the geometric mean titers (GMT) were39.53 mIU/ml, 62.37 mIU/ml, 48.18 mIU/ml and 33.64 mIU/ml respectively (P=0.025). The overall anti-HBs positive rate and GMT were 79.01% and 41.18 mIU/ml. The anti-HBs GMT of 4 groups declined with age. The differences in anti-HBs GMT among 4 groups minimized with age. The result of logistic modeling indicated that vaccine type and dosage, age and smoking were associated with anti-HBs statistically after controlling the variables of"only anti-HBc positive or not"and"history of hepatitis B vaccination". Conclusion: Hepatitis B vaccination at dosage of 20 MUg based on 0-1-2 month rapid schedule could achieved anti-HBs positive rates>80% in middle aged and old people, which can be used as supplement of 0-1-6 month routine schedule. PMID- 28910922 TI - [Comparison of antibody persistence after primary immunization with 5 MUg and 10 MUg recombinant hepatitis B vaccine among newborns with normal and high response: a five-year following-up]. AB - Objective: To compare the antibody persistence 5 years after primary immunization with 5 MUg and 10 MUg recombinant hepatitis B vaccine (HepB) among newborns with normal and high response. Methods: Newborns who completed three doses of 5 MUg HepB made by recombinant dexyribonucleic acid technique in Saccharomyces (HepB SC) or 10 MUg HepB made by recombinant dexyribonucleic acid technique in Hansenula polymorpha (HepB-HP) were recruited. Standardized questionnaire was used and blood samples were collected 1-6 months (T(0)) and five years (T(1)) after the third dose respectively. The titer of anti-HBs was detected by chemiluminescence microparticle imunoassay (CMIA). Those who achieved normal or high antibody response (anti-HBs titer >=100 mIU/ml) were included in the study and the positive rate (>=10 mIU/ml) and titer of anti-HBs at T(1) were compared between 5 MUg HepB group and 10 MUg HepB group. Multivariable analysis was conducted to identify the independent factors associated with the antibody persistence. Results: The positive rate of anti-HBs at T(1) was 49.92% (943/1 883) and 75.92% (1 135/1 495) respectively in 5 MUg HepB group and 10MUg HepB group, the difference was significant (chi(2)=237.75, P<0.001). The anti-HBs geometric mean concentrations at T(1) were 10.23 mIU/ml (95%CI: 9.38-11.16) and 28.91 mIU/ml (95%CI: 26.65-31.35) in the two groups respectively, the difference was also significant (F=280.36, P<0.001). Among those whose anti-HBs titer was<10 mIU/ml at T(1), the distributions of anti-HBs titer were significantly different between 5 MUg HepB group and 10 MUg HepB group (chi(2)=39.75, P<0.001). The multivariable analysis showed that dosage of HepB was independently associated with both positive rate and titer of anti-HBs at T(1) after excluding the other factors[P<0.001, OR=1.44 (95%CI: 1.20-1.73); P<0.001, beta=0.27 (95%CI: 0.14 0.40)]. Conclusion: Five year anti-HBs persistence after primary immunization with 10 MUg HepB might be better than that after primary immunization with 5 MUg HepB among infants who achieved normal or high anti-HBs response after primary HepB immunization. PMID- 28910923 TI - [A qualitative study on high risk behaviors and related factors of reported HIV/AIDS cases aged 60 years and above in some areas of Henan province]. AB - Objective: To understand the major high risk behaviors and related factors among reported HIV/AIDS cases aged >=60 years in some areas of Henan province. Methods: In Dengzhou, Xunxian county of Hebi and Xiangcheng county of Xuchang, where the reported number and proportion of HIV/AIDS cases aged >=60 years were high, a face to face interview was conducted among the cases aged >=60 years during July August in 2016. The information about the high risk behaviors before HIV infection confirmation were collected by using a semi-structured questionnaire. Results: A total of 33 HIV/AIDS cases aged >=60 years were interviewed, including 28 males and 5 females. Their average age was 67.4 years. The infection route was sexual contact. The main findings revealed that the main factor for HIV infection in elder males was commercial heterosexual behavior with local female sex workers. The condom use rate was low. The poor awareness of the knowledge about AIDS prevention could explain why the elderly could not recognize the risk of HIV infection. There were also homosexual and bisexual behaviors in elder male HIV/AIDS patients. Late detection of HIV transmission among couples was the main cause of HIV infection in elder women. Conclusions: The major epidemiological related factors for HIV infection in the elderly in some areas of Henan were unsafe sex behavior and the poor awareness of knowledge about AIDS prevention. A targeted strategy should be taken to control the spread of HIV in the elderly. PMID- 28910924 TI - [A survey of HIV, HBV and HCV infections in children aged 1-13 years in Yi ethnic area, Sichuan province]. AB - Objective: To investigate the prevalence of HIV, HBV and HCV infections in children aged 1-13 years in Yi ethnic area in Sichuan province. Methods: A cross sectional study was conducted in the form of field survey in four townships selected from Yi ethnic area of Sichuan during 2014-2015. Participants were children aged 1-13 years by sample size of 900 and were screened for HIV antibody, HBV surface antigen and HCV antibody, and laboratory comfirmation was conducted. The area, age, gender and ethnic group specific infection rates were compared by using Fisher's exact test, and multiple comparisons were corrected by using Bonferroni correction. Results: A total of 677 children aged 1-13 years were surveyed. The infection rates of HIV, HBV and HCV were 1.03% (7/677, 95%CI: 0.42%-1.12%), 6.65% (45/677, 95%CI: 4.89%-8.79%) and 0.15% (1/677, 95%CI: 0% 0.82%), respectively. The infection rates of HIV differed among townships (P=0.000), the infection rate was higher in township D than in township B, the difference was significant (P<0.001). The differences in HIV infection rate among different age, gender and ethnic groups were not significant. The differences in HBV and HCV infections were not significant among different townships, age, gender and ethnic groups. The difference in HBV viral load between age group 5-9 years and age groups 10-13 years was not significant (U=115.000, P=0.967). Conclusions: The burden of HIV and HBV infections in children aged 1-13 years was heavy in rural area of Yi ethnic area in Sichuan. Therefore, it is necessary to take effective measures to block the vertical transmission of HIV and HBV as well as to increase the coverage of HBV vaccination. PMID- 28910925 TI - [Effect of data missing on population based viral load survey in HIV infected men who have sex with men sampled in 16 large cities, China]. AB - Objective: To analyze the effect of missing data in population based viral load (PVL) survey in HIV infected men who have sex with men (MSM) sampled in 16 cities in China. Methods: The database of 3 virus load sampling survey conducted consecutively in HIV infected MSM population in 16 large cities (Beijing, Shanghai, Nanjing, Hangzhou, Wuhan, Chongqing, Kunming, Xi'an, Guangzhou, Shenzhen, Nanning, Urumuqi, Harbin, Changchun, Chengdu and Tianjin) during 2013 2015 was used. SPSS 17.0 software was used to describe distribution of the missing data and analyze associated factors. Results: A total of 12 150 HIV infected MSM were randomly selected for the surveys, in whom, 9 141 (75.2%) received virus load tests, while 3 009 (24.8%) received no virus load tests, whose virus load data missed. The virus load data missing rates in MSM with or without access to antiretroviral therapy (ART) were 11.5% (765/6 675) and 39.4% (2 060/5 223) respectively, and the virus load data missing rates were 21.9% (1 866/8 523) and 28.4% (959/3 374), respectively, in local residents and non-local residents (migrants). Conclusions: The analysis indicated that the data missing occurred in the virus load survey in HIV infected MSM population. ART status and census registering status were the main influencing factors. Data missing could influence the accurate evaluation of community viral load (CVL) and population viral load(PVL) levels in HIV infected MSM in China. PMID- 28910926 TI - [Survey on a public health emergency event caused by norovirus]. AB - Objective: To study the epidemiological characteristics of an outbreak caused by norovirus infection in a school in Haidian district, Beijing. Methods: Basic information of the school and data related to patients in the fields survey were collected and analyzed descriptively. Laboratory tests were performed to test the stool and anal swab specimens of both patients and cooks as well as the environmental specimens. Risk factors related to the incidence were analyzed through a case-control study. Results: A total number of 119 patients were identified in the school. Clinical symptoms were mild, mainly involving vomiting (94.1%, 112/119), abdominal pain (46.2%, 55/119), but no need of hospitalization. The average age of the student patients was 6.38, with minimum and maximum between 5 and 11. Patients were found in 22 classes, but mainly in grade 1 and class 7 where 35 patients were found (30.17%). A total of 134 specimens of rectal swabs and stool were collected, with 7 positive for norovirus and 6 for sappovirus. Salmonella, Shigella, lapactic Escherichia coli and Vibrio parahaemolyticus were not found in on dinner sets, residual foods, bottled water or in drinking fountains. Index on water hygiene was unsatisfactory in classrooms or dormitories where more cases were found. Accommodation, north-facing classrooms, abnormal water hygiene indexes were found related to the occurance of the disease (P<0.05). Conclusions: The outbreak was identified a gastroenteritis infection, caused by norovirus with symptoms as vomiting and abdominal pain. This event reached the reporting standards of public health emergencies-level IV. Discovery and isolation of the first case was not timely while transmission of the disease might be water-borne. Surveillance programs on symptoms, disinfection of vomit and stool in places like nurseries and schools should be strengthened to prevent the norovirus outbreak. PMID- 28910927 TI - [Pregnancy intention and pregnancy-related anxiety in the second and third trimester: a birth cohort study]. AB - Objective: To understand the association between pregnancy intention and pregnancy-related anxiety in the second and third trimester and its strength. Methods: A prospective cohort study was conducted in Ma'anshan, Anhui province. A total of 3 474 eligible pregnant women within 14 weeks of gestation were recruited. The information about their demographic characteristics were collected in early pregnancy. The completed questionnaire of pregnancy-related anxiety were asked to return in the second and third trimester. Logistic regression analysis was conducted to evaluate the association between pregnancy intention and pregnancy-related anxiety in the second and third trimester. Results: A total of 3 083 pregnant women were included in final analysis, The rate of unintentional pregnancy was 15.00% (n=461). The detection rates of pregnancy-related anxiety in the second and third trimester were 29.13% (n=898) and 30.36% (n=936). After controlling potential confounding factors, unintentional pregnancy increased the risk of pregnancy-related anxiety in the second trimester compared with intentional pregnancy (OR=1.85, 95%CI: 1.44-2.38); The risk of pregnancy-related anxiety also increased in the third trimester (OR=1.84, 95%CI: 1.44-2.35). Intentional pregnancy did not increase the risk of pregnancy-related anxiety in the second and third trimester. Conclusion: The study results suggests that unintentional pregnancy could increase the risk of pregnancy-related anxiety in the second and third trimester. PMID- 28910928 TI - [A twin study of genetic and environmental influences on relationship between attention deficit and anxiety/depression in children and adolescents]. AB - Objective: To understand the genetic and environmental influences on the relationship between attention deficit and anxiety/depression in children and adolescents. Methods: A total of 1 062 same-sex twins aged 6-18 years were included in this study. A parent-rated child behavior checklist (CBCL) was used in the assessment. Software Mx was used to fit the univariate model of structural equation. The relationship between attention deficit and anxiety/depression was analyzed through bivariate genetic modeling. Results: The genetic factor had influence on the relationship between attention deficit and anxiety/depression (r(g)=0.48). Shared and non-shared environmental correlation scores of attention deficit and anxiety/depression were 0.86 and 0.14 respectively. Conclusion: Common genetic and shared environmental influences can explain the relationship between attention deficit and anxiety/depression in children and adolescents. PMID- 28910929 TI - [Cross-sectional survey of autism spectrum disorders in children aged 0-6 years in Hainan province]. AB - Objective: To understand the prevalence of autism spectrum disorders (ASD) in children aged 0-6 years old and influencing factors in Hainan province. Methods: A total of 37 862 children aged 0-6 years were selected from 18 counties in Hainan province for a screening by using questionnaire of"warning signs in child development", then field diagnosis was made, and general descriptive statistic analysis was conducted. The prevalence of ASD and related factors were analyzed with chi(2) test and unconditional logistic regression model. Results: Among 37 862 children aged 0-6 years, 235 were diagnosed with ASD, the prevalence of ASD was 0.62% (0.99% in boys, 0.17% in girls), the differences was significant (chi(2)=101.91, P=0.000). The prevalence of ASD increased with age (chi(2)=288.62, P=0.000). The prevalence of ASD was significantly higher in urban area than in other areas (chi(2)=114.77, P=0.000). Factors such as full term pregnancy or not, neonatal asphyxia, father's characteristics, father's habit of chewing areca or smoking, mother's general mood, and mother's induced abortion history were the influencing factors for ASD. Conclusion: The prevalence of ASD in children aged 0-6 years was high in Hainan and was influenced by genetic factors, pregnancy and delivery process, parents unhealthy habit before and during pregnancy and other factors. PMID- 28910930 TI - [Emotional and behavioral problems associated with sleep problems in preschool aged children]. AB - Objective: To examine whether sleep problems are related to both emotional and behavioral problems in children aged 3-6 years. Methods: A large cross-sectional study was conducted in Anqing, Wuhu, Tongling and Yangzhou from March to June 2015. A total of 8 900 preschool aged children were included. Sleep problems were obtained by using adapted BISQ completed by the parents or the people who took care of children. Emotional and behavioral problems of the children were accessed by using Strengths and Difficulties Questionnaire (SDQ), and multivariate logistic regression model was used for statistical analyses. Results: The detected rates of emotional symptoms, conduct problems, hyperactivity problems, peer problems, total difficulties and prosocial behavior in preschool aged children were 9.0%, 13.9%, 18.9%, 25.5%, 13.6% and 16.2% respectively. All the detected rates were higher in boys than in girls except the higher rate of emotional symptoms. The proportions of children with high sleep quality, moderate sleep quality and poor or worse sleep quality were 3.9%, 52.9% and 43.2% respectively. After controlling the confounding factors of demographic variables, including gender, age, delivery mode, birth weight, birth height and patent's educational level, multinomial logistic regression analysis showed that the risk of emotional symptoms, conduct problems, hyperactivity problems, peer problems, total difficulties and prosocial behavior in children with longer sleep duration was lower than that in children with shorter sleep duration, the ORs were 0.86 (95%CI: 0.77-0.95), 0.85 (95%CI: 0.78-0.93), 0.85 (95%CI: 0.79-0.92), 0.87(95%CI: 0.81-0.93), 0.83 (95%CI: 0.76-0.91) and 0.82 (95%CI: 0.76-0.89) respectively. Compared with the children with good sleep quality, the risk of emotional symptoms, conduct problems, hyperactivity problems, peer problems, total difficulties and prosocial behavior were higher in children with poor or worse sleep quality, the ORs were 3.26 (95%CI: 2.40-4.42), 2.86 (95%CI: 2.16-3.78), 2.60 (95%CI: 2.00-3.38), 1.96 (95%CI: 1.52-2.54), 4.02 (95%CI: 3.06-5.27) and 2.56 (95%CI: 1.96-3.35) respectively. Conclusion: There was a negative impact of shorter sleep and poor or worse sleep on emotional and behavioral problems of preschool aged children. PMID- 28910931 TI - [Quality of network direct reporting of information about intervention service in population at high risk for HIV infection in China, 2013-2014]. AB - Objective: To analyze the problems in the network direct reporting of information about intervention service conducted in population at high risk for HIV infection in China during 2013-2014, and provide evidence for the improvement of the network direct reporting of the intervention information. Methods: The wrong records of the intervention service in population at high-risk were collected from national AIDS prevention and treatment information system. The wrong records, including those found at county (district) level and those found at state level, were analyzed with descriptive statistical method. Results: A total of 1 066 wrong records were found during 2013-2014, and average annual wrong record rate was <0.1%. Up to 71.3% (760/1 066) of wrong records occurred in the first half year. The wrong records in eastern, central and western areas accounted for 14.9% (159/1 066), 22.6% (241/1 066) and 62.5% (666/1 066) of the total respectively. More wrong records were found in the intervention information for men who have sex with men and injecting drug users than in those for female sex workers. Among the total wrong records, 86.4% (921/1 066) were found at county level and 13.6% (145/1 066) were found at state level. The wrong records were mainly"annual number of persons receiving the first HIV test"and"annual number of persons covered by intervention". Common causes of wrong records were underreporting and delay, staff fault, miscalculation and misunderstanding. Conclusion: In general, the wrong record rate in intervention information for population at high risk for HIV infection reported directly through network was low in China. It is necessary to strengthen the recording of the intervention service, the quality control of statistics and network direct reporting and staff training to improve the quality of reported data of intervention service. PMID- 28910932 TI - [Downscaling research of spatial distribution of incidence of hand foot and mouth disease based on area-to-area Poisson Kriging method]. AB - Objective: To understand the spatial distribution of incidence of hand foot and mouth disease (HFMD) at scale of township and provide evidence for the better prevention and control of HFMD and allocation of medical resources. Methods: The incidence data of HFMD in 108 counties (district) in Shandong province in 2010 were collected. Downscaling interpolation was conducted by using area-to-area Poisson Kriging method. The interpolation results were visualized by using geographic information system (GIS). The county (district) incidence was interpolated into township incidence to get the distribution of spatial distribution of incidence of township. Results: In the downscaling interpolation, the range of the fitting semi-variance equation was 20.38 km. Within the range, the incidence had correlation with each other. The fitting function of scatter diagram of estimated and actual incidence of HFMD at country level was y=1.053 1x, R(2)=0.99. The incidences at different scale were consistent. Conclusions: The incidence of HFMD had spatial autocorrelation within 20.38 km. When HFMD occurs in one place, it is necessary to strengthen the surveillance and allocation of medical resource in the surrounding area within 20.38 km. Area to area Poisson Kriging method based downscaling research can be used in spatial visualization of HFMD incidence. PMID- 28910933 TI - [Visual-spatial and temporal characteristics related to infectious Tuberculosis epidemics in Guangxi Zhuang Autonomous Region, 2012-2015]. AB - Objective: To study the spatial and temporal mode of infectious TB transmission in Guangxi Zhuang Autonomous Region (Guangxi). Methods: Data related to infectious TB case (Include smear and/or culture positive patients) in Guangxi were collected from the National Notifiable Disease Reported System (NNDRS) from 2010 to 2015. Spatial-temporal analysis and prediction were performed by SaTScan 7.0.2, GeoDa 1.8.12, R program v 3.3.1 and SPSS 19.0 software, using the time series model, Moran's I global and local spatial autocorrelation (Empirical Bayes adjustment). Kulldorff 's space-time scan statistics displayed by R software was used to identify the temporal and spatial trend of TB. Results: The total number of infectious TB cases, collected from NNDRS was 76 151, and showing a decreasing trend on annual incidence (value of Chi-square for Linear trend=3 464.53, P value=0.000). The forecast value of TB cases in 2016 was 7 764 (4 971-10 557), with peak in March, analyzed through the Winters'multiplicative model. The Moran's I global Statistics was greater than 0 (0.257-0.390). TB cluster seemed to have been existed for several years. The most significant hot spots seemed to be mainly located in the central and western parts of Guangxi, shown by local spatial autocorrelation statistics and the result from space-time scanning.Counties or districts that located in the east parts of Guangxi presented the low-low relation (significant cold spots). The situation of infectious TB seemed migratory. Conclusions: Our data showed an annual decreasing trend of incidence on infectious TB with temporal concentration in spring and summer. Main clusters (hot spots) were found to be located in the central and western parts of Guangxi. Hopefully, our findings can provide clues to uncover the real mode of TB transmission at the molecular-biological level. PMID- 28910934 TI - [Analysis on epidemiology and spatial-temporal clustering of human brucellosis in Fujian province, 2011-2016]. AB - Objective: To analyze the epidemiological characteristics and spatial distribution of human brucellosis in Fujian province during 2011-2016, and provide evidence for the prevention and control of the disease. Methods: The surveillance data of human brucellosis in Fujian during 2011-2016 was analyzed with software R 3.3.1, ArcGIS 10.3.1, GeoDa 1.8.8 and SaTScan 9.4.3. Results: During 2011-2016, a total of 319 human brucellosis cases were reported, the incidence increased year by year (F=11.838, P=0.026) with the annual incidence of 0.14/100 000. The male to female rate ratio of the incidence was 2.50 ? 1. Farmers and herdsmen accounted for 57.37%. The incidence was 0.40/100 000 in Zhangzhou and 0.32/100 000 in Nanping, which were higher than other areas. The number of affected counties (district) increased from 12 in 2011 to 28 in 2016, showing a significant increase (F=13.447, P=0.021). The Moran's I of brucellosis in Fujian between January 2011 and December 2016 was 0.045, indicating the presence of a high value or low value clustering areas. Local spatial autocorrelation analysis showed that, high-high clustering area (hot spots) were distributed in Zhangpu, Longhai, Longwen, etc, while high-low clustering areas were distributed in Nan'an and Jiaocheng, etc. Temporal scanning showed that there were three clustering areas in areas with high incidence, the most possible clustering, occurring during January 1, 2013- December 31,2015, covered 6 counties, including Yunxiao, Pinghe, Longhai, etc, and Zhangpu was the center, (RR=7.96, LLR=92.62, P<0.001). Conclusions: The epidemic of human brucellosis in Fujian is becoming serious, and has spread to general population and non-epidemic areas. It is necessary to strengthen the prevention and control of human brucellosis in areas at high risk. PMID- 28910935 TI - [Application of State Space model in the evaluation of the prevention and control for mumps]. AB - Objective: To analyze the epidemiological characteristics of mumps in 2012 and 2014, and to explore the preventive effect of the second dose of mumps-containing vaccine (MuCV) in mumps in Shandong province. Methods: On the basis of certain model assumptions, a Space State model was formulated. Iterated Filter was applied to the epidemic model to estimate the parameters. Results: The basic reproduction number (R(0)) for children in schools was 4.49 (95%CI: 4.30-4.67) and 2.50 (95%CI: 2.38-2.61) respectively for the year of 2012 and 2014. Conclusions: Space State model seems suitable for mumps prevalence description. The policy of 2-dose MuCV can effectively reduce the number of total patients. Children in schools are the key to reduce the mumps. PMID- 28910936 TI - [Current status and change trend of violence against children in China from 2006 to 2015, an analysis on data from National Injury Surveillance System]. AB - Objective: To understand the current status and change trend of violence against children in China and provide evidence for the risk factor and intervention priority identifications and intervention strategy development. Methods: The data of National Injury Surveillance System (NISS) from 2006 to 2015 were used to analyze the change in outpatient visit due to violence against children, injury cases'demographic characteristics, incidence of injury and clinical outcomes of injury cases. Results: A total of 44 319 injury cases caused by violence against children were reported through NISS during this period. The proportion of violence related child injury cases in total child injury cases decreased year by year. In child violence cases reported in 2015, boys accounted for 81.31%, the boy to girl ratio was 2.22?1. Violence related injuries caused by blunt strike accounted for 65.69%. The incidences of child violence were low in February and during July-August and 48.87% of violence related injuries occurred in schools and public places, bruise accounted for 63.52%. The main injured body part caused by child violence was head (51.18%), and most violence caused injuries (82.66%) were mild, while 83.21% of the injury cases went home after treatment. Conclusions: Violence against children should not be ignored. Male students of middle/high schools are at high risk. Schools are the places where violence against children is prone to occur. Health and safety education should be strengthened to prevent the occurrence of campus violence and improve the child's awareness of self-protection and reduce the incidence of serious violence. PMID- 28910937 TI - [Co-prevalence of chronic disease risk factors and influencing factors in floating population in China]. AB - Objective: To investigate the prevalence and co-prevalence of tobacco use, excessive alcohol use, insufficient intake of vegetable and fruit, physical inactivity, and overweight or obesity in floating population and influencing factors in China, 2012. Methods: Data from the 2012 China Chronic Disease Risk Factor Survey in Floating Population in China were used. In this survey, 48 704 people aged 18-59 years in floating population were selected through stratified multistage clustering sampling in 170 counties and districts from 31 province (autonomous regions and municipalities) and Xinjiang Production and Construction Corps. The gender specific prevalence and co-prevalence of five risk factors were estimated, and the rank sum test was used for result comparison. Results: Among the people surveyed, 27.4% had one risk factor, 37.1% had two risk factors, 28.5% had >=3 risk factors. The prevalence or co-prevalence of risk factors were positively correlated with age (P<0.05), income level (P<0.05) and migration time (P<0.05), and negatively correlated with educational level (P<0.05). People who were males, in Han ethnic group, engaged in construction and from other provinces were more likely to have more risk factors (P<0.05). Conclusion: The prevalence and co-prevalence of tobacco use, excessive alcohol use, insufficient intake of vegetable and fruit, physical inactivity and overweight or obesity were high in floating population in China, suggesting that it is necessary to strengthen the comprehensive behavior intervention in floating population. PMID- 28910938 TI - [Comparison of commercial HIV-1 viral load tests by using proficiency test results in China, 2013- 2015]. AB - Objective: To compare the bio-equivalence among commercial HIV-1 viral load tests, including EasyQ HIV-1 v2.0 (EasyQ) from bioMerieux NucliSens of France; VERSANT HIV-1 RNA 3.0 assay (bDNA) from Siemens Healthcare Diagnostics of USA; COBAS AmpliPrep/COBAS TaqMan HIV-1 test (Taqman) from Roche Molecular Diagnosis of USA; Abbott Real Time HIV-1 Kit (M2000) from Abbott Molecular of USA and two domestic HIV-1 viral load test kits (domestic kit) from DaAn Gene Company of Sun Yat-Sen University and Liaoning Bio-Pharmaceutical company of Northeast pharmaceutical group, by using proficiency test results in China from 2013 to 2015. Methods: A total of 2 954 proficiency test results, obtained from 22 positive samples of 6 proficiency tests in 155 laboratories conducted by China CDC were analyzed during 2013-2015. The results from each sample were first logarithmic transformed and then grouped according to the method used, the mean value of logarithmic results was calculated. Subsequently, 22 clusters of mean values were analyzed by Bland-Altman analysis for the consistency, and linear regression analysis for the interdependency. Results: The results indicated that, by taking Taqman as the reference, EasyQ, M2000, bDNA and domestic kit had good consistency (90%-100%) and interdependency. Conclusion: All the viral load tests were bio-equivalent. Moreover, according to the conversion formula derived from domestic proficiency test results, all the viral load results could be converted, which is critical for epidemiological analysis. PMID- 28910939 TI - [Genotyping and drug susceptibility of Mycobacterium tuberculosis isolated in Changping district in Beijing, 2011-2015]. AB - Objective: To understand the genotype distribution of Mycobacterium tuberculosis and the drug susceptibility of M. tuberculosis with different genotypes in Changping district of Beijing and evaluate the application of genotyping of M. tuberculosis in local tuberculosis (TB) prevention and control. Methods: A total of 1 099 M. tuberculosis strains isolated in Changping from 2011 to 2015 were used. Spoligotyping and 12-locus VNTR recommended by Gao were used for the genotyping of these isolates. In addition, the susceptibility of the M. tuberculosis isolates to rifampin (RFP), isoniazid (INH), ethambutol (EMB), streptomycin (SM), amikacin (AMK) and ofloxcin (OFX) were detected by using conventional drug susceptibility test. Results: From 2011 to 2015, the detection rate of OFX-resistance increased from 2.9% to 8.9% (P=0.01). Of all the M. tuberculosis isolates, 976 belonged to Beijing genotype (88.8%), and the other 123 belonged to non-Beijing genotype (11.2%). In addition, there were 189 ancient Beijing genotype isolates and 787 modern Beijing genotype isolates, respectively. The proportion of Beijing genotype strains showed no significant increase in the past five years (81.1% in 2011 vs. 82.0% in 2015). On the basis of VTNR genotyping, only 2 isolates belonged to one cluster (0.1%). In addition, the AMK resistant rate of Beijing genotype strains (1.7%) was significantly lower than that of non-Beijing genotype strains (4.9%, P=0.02). Compared with modern Beijing genotype strains, the SM resistant rate of ancient Beijing genotype strains was significantly higher (28.0% vs. 15.7%, P=0.01). Conclusions: In the past five years, the OFX- resistant rate of M.tuberculosis in Changping was in increase. There was no significant difference in the detection of Beijing genotype strains during this period. In addition, the low clustering rate indicated that the TB transmission rate was low in Changping. PMID- 28910940 TI - [Diagnostic value of p16/mcm2 dual staining in cervical intraepithelial neoplasia and its association with high-risk HPV infection]. AB - Objective: To study the expression of p16/mcm2 immunocytochemical dual staining in cervical lesions and its association with high-risk HPV infection, and discuss its clinical value in cervical cancer screening. Methods: From May to December 2015, a total of 1 127 women receiving cervical cancer screening, high-risk HPV (HR-HPV) test and liquid-based cytology test were included in the study. p16/mcm2 immunocytochemical dual staining was performed on residual cytology specimens and the results were compared with histopathology results. Results: p16/mcm2 had a higher expression risk in HPV16/18 group and other HR-HPV group compared with HPV negative group, with OR of 15.95 (95%CI: 9.59-26.51) and 10.53 (95%CI: 7.41 14.98), respectively. The positive rate of p16/mcm2 increased with cervical intraepithelial neoplasia (CIN) severity, and was higher in both CIN2 group and CIN3 group than in benign lesion group (P<0.05). The overall sensitivity of p16/mcm2 to detect CIN2+and CIN3+lesions were 86.1% and 92.0%, respectively, and the overall specificity were 46.1% and 44.4%, respectively. In group with cytologic diagnoses of atypical squamous cells (ASC) and low-grade squamous intraepithelial lesion (LSIL), the sensitivity to detect CIN2+and CIN3+lesions were 85.7% and 87.5%, respectively, and the specificity were 45.5% and 44.1%, respectively. Conclusions: p16/mcm2 dual staining has higher sensitivity than cytology test and better specificity than HPV test. It can identify high-grade cervical lesions and guide the classification of CIN. p16/mcm2 might be used as an innovative biomarker for cervical cancer screening. PMID- 28910941 TI - [Effects of Src on cervical cancer cells proliferation and apoptosis through ERK signal transduction pathway]. AB - Objective: To explore the effect of Src on cervical cancer cells through ERK signal transduction pathway. Methods: Experimental study was carried out in vitro. Cervical cancer cell lines Hela (HPV-positive) and C33A (HPV-negative) were treated with Src kinase inhibitor PP2. Then, the cell cycle and apoptosis of each group were evaluated by using flow cytometry (FCM). Western blotting and Real-time PCR were used to detect the levels of the expression of ERK 1/2, c-Fos and c-Jun mRNA and protein respectively. The database was established and analyzed with SPSS statistical software (version 20.0). Results: After down regulating Src, the cell proliferation was inhibited and cell apoptosis was induced. The proportions of G0/G1 stage of Hela and C33A cell in cell cycle increased while G2/M and S stages decreased. Meanwhile, the mRNA levels of ERK 1, ERK 2, c-Fos and c-Jun increased. And the expression levels of ERK 1/2, phosphorylated ERK 1/2 (p-ERK 1/2) and phosphorylated c-Fos (p-c-Fos) protein decreased, while c-Jun and phosphorylated c-Jun (p-c-Jun) protein expression increased. In addtion, the change level of Hela cell, p-ERK 1/2 and c-Fos protein were lower than that of C33A cell before and after the Src inhibition. Conclusions: Src, involved in regulating the expression of key factors of the ERK signal transduction pathway including p-ERK 1/2 and p-c-Fos, might be capable of promoting the proliferation of cervical cancer cells and inhibiting their apoptosis. The infection with HPV might have adjustable effect on this process. PMID- 28910942 TI - [Association between expression of plasma miRNA and the risk of childhood acute lymphocytic leukemia]. AB - Objective: To investigate the characteristics of distribution and expression profiles of plasma miRNA in childhood acute lymphocytic leukemia (cALL) patients; the association between cALL incidence risk and plasma miRNA levels; the feasibility of plasma miRNA serving as cALL diagnostic biomarker. Methods: A total of 111 pairs of newly diagnosed cALL patients and patients with fractures were collected from Shenzhen Children's Hospital, China, between January 2015 and November 2016. Age and sex of the cases and controls were 1? 1 matched and LNA(TM) miRNA microarray was performed using 4 pairs of cALL and controls selected from the sample population. The expression level of miRNA was validated by real time quantitative PCR. Conditional logistic regression analysis was applied to evaluate the association between miRNA expression levels and the incidence risk of cALL. The receiver operating characteristic curve (ROC) and reclassification analysis were conducted to assess the feasibility of miRNAs serving as biomarkers for cALL. Results: A total of 204 differentially expressed miRNA were screened out and let-7f-5p, miR-5100, miR-25-3p and miR-3654 were selected for validation identified according to the inclusion criteria. The expression levels of let-7f-5p, miR-5100 and miR-25-3p in the cALL patients were significantly lower than those of the controls (P<0.01). After adjusting for confounding factors, 3 miRNAs remained significantly associated with the risk of cALL (OR and 95%CI were 0.84 (0.76-0.92), 0.81 (0.73-0.90) and 0.81 (0.74-0.89), respectively. Results from both the ROC analysis and reclassification analysis showed that introduction of one or more miRNA to traditional risk factors improved the area under the curve (P<0.05) and provided additional values to diagnosis (P<0.01). Conclusion: The expression levels of let-7f-5p, miR-5100 and miR-25-3p were significantly associated with the incidence rate of cALL, and these miRNAs might serve as promising biomarkers for cALL. PMID- 28910943 TI - [Study on antibiotic resistance of Escherichia coli and Enterococcus colonized in intestine of neonates from neonatal intensive care unit]. AB - Objective: To understand the antibiotic resistance of bacteria colonized in intestine of the neonates from neonatal intensive care unit (NICU) and provide evidence to guide clinical antibiotic treatment. Methods: From May, 2014 to May, 2015, a total of 572 stool samples were collected from the neonates of NICU in our hospital. Escherichia coli and Enterococcus were detected with VITEK-2 system. Results: A total of 328 strains of E. coli and 243 strains of Enterococcus were isolated respectively in this study. The 199 strains of E. coli selected for drug susceptibility test showed lower resistant rate to imipenem, ertapenem, amikacin, nitrofurantoin, ranging from 0.50% to 3.52% and showed higher resistant rate to ampicillin, tetracycline, trimethoprim/sulfamethoxazole and cefazolin, ranging from 54.27% to 84.92%. No meropenem resistant strainsere were found. The percentage of ESBLs production strains was 45%. The multi drug resistance test showed that 34.6% of the strains were resistant to four antibiotics. Three strains were resistant to seven antibiotics. The 243 strains of Enterococcus showed lower resistant rate to quinupristin/dalfopristin, nitrofurantoin, streptomycin, ranging from 0.41% to 4.53% and showed higher resistant rate to ampicillin, benzylpenicillin, ciprofloxacin, tetracycline, gentamicin and erythromycin, ranging from 70.78% to 91.77%. No strains which were resistant to tigecycline, vancomycin, rina thiazole amine/ketone were found. The multi drug-resistance test showed that 86.5% of the strains were resistant to five antibiotics. Conclusions: According to the analysis of the 199 strains of E. coli and 243 strains of Enterococcus isolated from the neonates, we found that the resistance of intestinal bacteria in the neonates was very serious, showing multi drug resistance. It is necessary to use antibiotics according to the drug susceptibility test results in clinical treatment. PMID- 28910944 TI - [Association between periconceptional folic acid supplementation and small for gestational age birth based on pre-pregnancy body mass index]. AB - Objective: To investigate the association between periconceptional folic acid supplementation and small for gestational age (SGA) birth based on maternal pre pregnancy body mass index (BMI) and provide evidence for the development of comprehensive prevention programs on SGA birth. Methods: Between March, 2012 and September, 2016, a total of 8 523 pregnant women delivering in the First Affiliated Hospital of Shanxi Medical University were surveyed to collect the information about their demographic characteristics, folic acid supplementation before and during pregnancy and about their infants. Among their infants, 1 066 were small for gestational age (case group), 7 457 were appropriate for gestational age (AGA) (control group). Unconditional logistic regression model was used to evaluate the association between periconceptional folic acid supplementation and SGA birth in the context of different pre-pregnancy BMI. Results: The overall incidence of SGA birth was 12.51% (1 066/8 523). After adjusting the confounding factors, pre-pregnancy BMI<18.5 kg/m(2) was a risk factor for SGA birth (OR=1.22, 95%CI: 1.01-1.47), pre-pregnancy BMI>=24.0 kg/m(2) was associated with a reduced risk of SGA birth (OR=0.81, 95%CI:0.68-0.97). After adjusting confounding factors, periconceptional folic acid supplementation was a protective factor for SGA birth (OR=0.82, 95%CI: 0.68-0.98). After stratified by pre-pregnancy BMI, periconceptional folic acid supplementation was associated with the reduced risk of SGA birth in overweight group (24.0 kg/m(2)<=BMI<28.0 kg/m(2)) with OR of 0.55 (95%CI: 0.36-0.85). No significant association was observed in other groups. When examined by folic acid supplement type, periconceptional single folic acid supplementation (400 MUg per tablet) was a protective factor for SGA birth (OR=0.82, 95%CI: 0.69-0.99). After stratified by pre-pregnancy BMI, periconceptional single folic acid supplementation (400 MUg per tablet) was associated with the reduced risk of SGA birth in overweight groups (OR=0.56, 95%CI: 0.36-0.86). No association was observed between periconceptional folic acid containing multivitamin supplementation and SGA birth. Conclusions: Periconceptional folic acid supplementation (400 MUg) was associated with reduced risk of SGA birth in women with pre-pregnancy BMI>=24.0 kg/m(2) and<28.0 kg/m(2). No association between folic acid supplementation and SGA was observed in other groups. This study suggests that pre-pregnancy BMI might modify the influence of folic acid supplementation on the risk of SGA birth. PMID- 28910945 TI - [Nested case-control study on associated factors for anemia during pregnancy]. AB - Objective: To explore the related factors of anemia during pregnancy and provide scientific evidence for the primary prevention of anemia during pregnancy. Methods: The pregnant women (<=12 pregnant weeks) who received the first pregnancy care in a local medical institution in Hunan province from June 2013 to November 2014 were included in this cohort study, and for them anemia had been excluded by physical examination. Baseline survey and follow up till childbirth were conducted for them. A queue-based nested case-control study (1 ? 2) was conducted (380 pregnant women with anemia detected in this study as case group, 760 pregnant women without anemia randomly selected and matched by age, habitual residence during pregnancy as control group. And t test, chi(2) test and logistic regression analysis were conducted to identify related factors of anemia during pregnancy. Results: Multivariate logistic regression analysis indicated that low family annual income level (net income) (OR=2.08, 95%CI: 1.22-3.59), low educational level (OR=2.09, 95%CI: 1.22-3.59), pre-pregnancy perm/hair dye (OR=2.23, 95%CI: 1.63-3.05), early pregnancy vomiting (OR=2.51, 95%CI: 1.56-4.03) were the risk factors for anemia during pregnancy. Intake of vitamin and trace element supplements (OR=0.69, 95%CI: 0.50-0.94), frequent meat, fish, shrimp, egg intakes (OR=0.68, 95%CI: 0.49-0.92), frequent soy milk, milk intakes (OR=0.51, 95%CI: 0.27-0.95) were the protective factors for anemia during pregnancy. Conclusion: A number of factors, such as family annual income level, education level, poisonous and harmful material contact, pregnancy reaction, nutrition, are related to the incidence of anemia during pregnancy, it is necessary to take preventive measures to reduce the incidence of anemia during pregnancy. PMID- 28910946 TI - [Joint effect of smoking and diabetes on stroke]. AB - Objective: To explore the interaction of smoking and diabetes on stroke. Methods: In this case-control study, a face to face questionnaire survey was conducted. Logistic regression models were used to analyze the relationship between smoking or diabetes and stroke. The indicators of interaction were calculated according to the Bootstrap method in this study. Results: A total of 918 cases and 918 healthy controls, who participated in the chronic disease risk factor survey in Xuzhou in 2013, were included in this study. Logistic regression analysis found that cigarette smoking was associated with stroke (OR=1.63, 95%CI: 1.33-2.00), and diabetes was also associated with stroke (OR=2.75, 95%CI: 2.03-3.73) after adjusting confounders. Compared with those without diabetes and smoking habit, the odds ratio of stroke in those with diabetes and smoking habits was 8.94 (95%CI:3.77-21.19). Diabetes and smoking combined interaction index was 3.65 (95%CI: 1.68-7.94), the relative excess risk was 5.77 (95%CI: 0.49-11.04), the attributable proportion was 0.65 (95%CI: 0.42-0.87). Conclusion: The results suggest that there are additive interactions between smoking and diabetes on stroke. PMID- 28910947 TI - [Meta analysis on HBsAg-positive rate among general populations aged 1-59 years, 2007-2016, China]. AB - Objective: To perform a Meta-analysis on hepatitis B surface antigen (HBsAg) positive rates among general Chinese population aged 1-59 years. Methods: We systemically reviewed the related data (January 2007 to August 2016) published from Chinese National Knowledge Infrastructure (CNKI), VIP, and PubMed. We also assessed the HBsAg-positive rates among general Chinese populations aged 1-59 years, using a random effects regression model with the comprehensive Meta analysis software 2.2. Results: A total of 46 papers were finally included, with a total sample size of 625 053 individuals. Results from the Meta-analysis showed that the overall combined HBsAg-positive rate was 5.7% (95%CI: 4.8%-6.6%) among general Chinese populations aged 1-59 years. When comparing the HBsAg-positive rates in different regions, data showed that the HBsAg-positive rate of was higher in the mid-western areas (6.3%, 95%CI: 4.9%-8.0%) than in the eastern areas (5.5%, 95%CI: 4.4%-6.8%). Results showed that HBsAg-positive rates was higher in males (6.1%, 95%CI: 5.3%-7.0%) than in females (4.8%, 95%CI: 4.2% 5.5%). As for the HBsAg-positive rates in different time periods, data showed positive rate of 6.3% (95%CI: 5.5%-7.2%) in 2007-2009, 5.9% (95%CI: 4.4%-8.0%) in 2010-2012 and 3.5% (95%CI: 2.0%-6.1%) in 2013- 2016, respectively. Conclusion: The prevalence of hepatitis B virus infection was decreasing between 2007 and 2016 in China, making the country an intermediate endemic area on HBV. PMID- 28910948 TI - [Risk on bias assessment: (2) Revised Cochrane risk of bias tool for individually randomized, parallel group trials (RoB2.0)]. AB - This paper introduces the revised cochrane risk of bias tool for individually randomized, parallel group trials (RoB2.0), compates RoB2.0 and the previous version (RoB1.0). And illustrates the application of RoB2.0 for a published clinical trial. As a comprehensive tool, RoB2.0 provides more information on the risk of bias for evidence synthesis. RoB2.0 is still under development and it is suggested that the users should follow the updates of the developers in the future. PMID- 28910950 TI - [Liquid biopsy, coming to clinical practice]. PMID- 28910951 TI - [The detection of circulating tumor cell in patients with liver cancer]. PMID- 28910949 TI - [China Hainan Centenarian Cohort Study: study design and preliminary results]. AB - Objective: To investigate the health status, functional ability, mental psychology, health care and other longevity-related characteristics of individuals aged >=100 years as well as risk factors in Hainan province, China. Methods: China Hainan Centenarian Cohort Study (CHCCS) is a community-based, prospective cohort study to establish multi-dimensional database consisting of questionnaire findings, anthropometric parameters and biological specimens as well as imaging features. With the household registration information provided by the Department of Civil Affairs of Hainan province, a baseline survey was conducted in centenarians in 18 counties in Hainan with the oldest old in 5 counties as controls between 2014 and 2017. The survey included face to face interview, physical examination and biological specimen collection. After the baseline survey, the participants of CHCCS were followed up at an interval of 2 years to collect the information about their living status, disease status or major death causes. Results: According to the information provided by the Department of Civil Affairs of Hainan province in 2014, the survey found that 1 473 centenarians were still living. By December 2016, 1 002 of them had agreed to be surveyed. The average age of 722 centenarians with complete information in the baseline survey was (102.7+/-2.7) years, the majority of them were females (83.0%), widows (88.8%), in Han ethnic group (84.5%), lived with family members (87.8%), illiterates (89.7%) and farmers (81.0%). Conclusion: CHCCS has provided longevity-related information of the large longevity population and collected the valuable and rare biological specimens with great urgency to establish an interdisciplinary platform and base for longevity, senility and healthy aging research. PMID- 28910952 TI - [Establishment of cut-off value of serum pro-gastrin-releasing peptide for diagnosis of small cell lung cancer and evaluation on the clinical diagnosis efficiency]. AB - Objective: To determine critical reference value (cut-off value) of serum pro gastrin-releasing peptide (ProGRP) and neuron specific enolase(NSE) in the diagnosis of small cell lung cancer(SCLC). To evaluate the clinical significance of serum levels of ProGRP and NSE in diagnosis and differential diagnosis in SCLC. Methods: Three hundred and fifty-two SCLC patients, 163 non small cell lung cancer(NSCLC)patients , 193 benign pulmonary disease patients and 140 healthy people visiting in National Cancer Hospital were analyzed retrospectively from January 2014 to July 2017.The levels of serum ProGRP and NSE of people were determined using electrochemiluminescent immunoassay respectively . Reference value ranges of the makers were determined by using the method of ROC curves. Results: In NSCLC group, benign lung disease group, healthy control group and mixed group (NSCLC+ lung benign diseases+ healthy control group) as a reference, the cut-off values were 58.3, 62.3, 57.8, 61.3 ng/L. In the diagnosis and differential diagnosis of SCLC and NSCLC, benign lung diseases, healthy controls and mixed group, AUC of ProGRP was 0.940 (0.919-0.961), 0.941 (0.921-0.960), 0.959 (0.944-0.975), 0.946 (0.928-0.963) respectively. The sensitivities of ProGRP were 86.4%, 84.9%, 86.4% and 84.7% respectively. The specificities of ProGRP were 95.7%, 96.9%, 99.3%, 98% respectively. In all groups the Youden's index of ProGRP and NSE were 0.821 vs 0.612, 0.818 vs 0.674, 0.857 vs 0.810, 0.827 vs 0.674. In healthy controls, no statistically significant difference was found between ProGRP and NSE (P>0.05) in the diagnosis of AUC. However, in the remaining 3 groups, the ProGRP diagnosis of AUC was significantly greater than that of NSE (P<0.01). Compared with single marker detection, the sensitivity of combined detection of ProGRP and NSE in diagnosis of SCLC increased to 95.5%, 94%, 96.6% and 94% in each group. There was no significant difference between ProGRP and ProGRP+ NSE in the diagnosis of AUC when compared with the NSCLC group and the mixed group (P>0.05). However, when combined with a healthy control group and a benign lung disease group, the ProGRP+ NSE combination was the highest for AUC diagnosis, compared with ProGRP and NSE (P<0.01). In the SCLC ED group serum ProGRP and NSE levels[776.33(3 103.4)ng/L, 52.14(60.59)MUg/L]were higher than those in the SCLC LD group[295.59(799.65)ng/L, 23.36(22.97)MUg/L], respectively (all P<0.001). The serum ProGRP levels of N0, N1, N2 and N3 in TNM staging were 113.0(343.65), 167.04(724.56), 427.42(1 388.62), 735.99(1 709.95)ng/L respectively (all P<0.001). Serum ProGRP and NSE levels were not statistically different between the sex groups and the age groups (all P>0.05). Conclusion: To establish the cut-off value of serum ProGRP is helpful for the diagnosis and differential diagnosis of SCLC. PMID- 28910953 TI - [The expression and association of CD14(+) HLA-DR(Low/-) myeloid-derived suppressor cell-like cells and interleukin-1beta in ovarian cancer]. AB - Objective: To analyze the percentage of CD14(+) HLA-DR(Low/-) myeloid-derived suppressor cell-like cell subtypes(MDSCs) and interleukin-1beta(IL-1beta) concentration in peripheral blood and ascites of ovarian cancer patients, and to explore their association with clinicopathological characteristics. Methods: Blood samples of 31 patients and ascites of 5 patients in Qilu Hospital of Shandong University from January 2016 to December 2016 were collected. Blood samples of 20 healthy volunteers with matched age were collected as control. The percentages of CD14(+) HLA-DR(Low/-) cell subtypes in CD14(+) monocytes were collected by flow cytometry and their phenotypes were analyzed. qRT-PCR was used to analyze the expression of immunosuppression factors in this subtype. ELISA was used to analyze IL-1beta concentration in peripheral blood and ascites of ovarian cancer patients and healthy controls. The correlation between CD14(+) HLA-DR(Low/ ) cell percentage and IL-1beta concentration was explored. The association between CD14(+) HLA-DR(Low/-) cell percentage, IL-1beta concentration and clinicopathological characteristics were analyzed. Results: The percentage of CD14(+) HLA-DR(Low/-) cells in CD14(+) monocytes of peripheral blood of healthy controls was (2.30+/-0.49)%, and the percentage in ovarian cancer patients was (3.74+/-0.95)%, with statistical significance (t=6.96, P<0.01). This cell subset showed similar phenotypes and factor expression with monocytic MDSCs. The percentage of CD14(+) HLA-DR(Low/-) cells in peripheral blood ascites of ovarian cancer patients was (16.60+/-7.35)%, significantly higher than those in peripheral bloods (4.03+/-0.94)%(t=3.87, P<0.05). The concentration of IL-1beta in peripheral blood of healthy controls was[3.88(0.41, 7.07)]ng/L, and the concentration in ovarian cancer patients was (12.77+/-3.52) ng/L, with statistical significance (Z=-4.93, P<0.01). IL-1beta concentration in ascites of ovarian cancer patients was (62.17+/-23.05) ng/L, significantly higher than that in peripheral bloods (12.65+/-3.93) ng/L(t=5.20, P<0.01). IL-1beta concentration was correlated with CD14(+) HLA-DR(Low/-) cell percentage in ovarian cancer patients (R(2)=0.36 in peripheral blood, P<0.01; R(2)=0.68 in ascites, P<0.05), but not in healthy controls (R(2)=0.02, P>0.05). The percentage of CD14(+) HLA DR(Low/-) cells and IL-1beta concentration were associated with metastasis and FIGO stage of ovarian cancer. Conclusion: The elevated percentage of CD14(+) HLA DR(Low/-) cells and IL-1beta concentration might involve in the development of ovarian cancer. PMID- 28910954 TI - [The value of serum human tumor protein P53 in colorectal cancer combined diagnosis and postoperative monitoring]. AB - Objective: The aim of this paper is to investigate the application value of serum human tumor protein P53 (TP53) in the diagnosis and postoperative monitoring of colorectal cancer. Methods: One hundred and fifteen patients with colorectal cancer diagnosed without colorectal cancer and without surgery, radiotherapy and chemotherapy and total of 158 patients with colorectal benign disease and 182 healthy subjects were enrolled in this study. The levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) were detected by electrochemiluminescence assay. The expression of TP53 was analyzed by ELISA. Fourth-one patients with colorectal cancer were detected with one day before operation and the first seven days after operation. The expression of CEA, CA199 and TP53 was analyzed by ROC curve. The results were compared with those of CEA and CA199 diagnostic value. Results: The medians of the levels of TP53 in patients with colorectal cancer patients, colorectal benign, and healthy subjects are 316.0(24.6, 940.8 ) , 9.8(3.7, 30.1 ) and 1.9(1.4, 2.5 ) MUg/L (H=260.161, P<0.01), respectively. The level of TP53 in patients with colorectal cancer was significantly higher than that in colorectal benign and healthy subjects. The levels of serum TP53 in patients with colorectal cancer show great discrepancies in different TNM stages, different tumor location, depth of invasion and lymph node metastasis (P<0.05) , but no difference in sex, age, and tumor growth type. The levels of TP53 in the same patient is 711.5(354.9, 1 068.0) MUg/L in the first seven days after operation, significantly decreased when compared to it in the one day before the operation with the value of 952.6 (419.7, 1485.4) MUg/L (Z=-1.989, P<0.05). The difference was statistically significant, and CEA, CA199 were not statistically significant. And the sensitivity (79.1%) and specificity (81.8%) of TP 53 were significantly higher than those of CEA (39.1%, 70.3%) and CA199 (47.8%, 69.1%). If TP53 was combined with CEA and CA199, sensitivity (86.1%) and specificity (87.9%) can be significantly improved, in which the area of Receiver Operating Characteristic (ROC) curve was 0.924. Conclusions: Serum TP53 has a certain positive significance for the diagnosis, postoperative monitoring of colorectal cancer. Combined detection with CEA and CA199 can improve the sensitivity and specificity, implicating good clinical application value. PMID- 28910955 TI - [The localization diagnosis of patients with adrenocorticotropic hormone dependent Cushing's syndrome in adolescence]. AB - Objective: To elucidate the clinical characteristics and localization diagnosis of patients with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) in adolescence. Methods: The clinical data, laboratory examination and localization diagnosis from 35 patients aged less than 18 years old with adolescent CS who were treated at Peking Union Medical College Hospital between January 1990 and March 2012 were analyzed. Results: There were 29 cases of Cushing's disease (CD) and 6 cases of ectopic ACTH syndrome (EAS). Compared to patients with EAS, those with CD were older at diagnosis[(15.2+/-2.7) vs (12.8+/ 4.4) years], and had longer disease course[(1.9+/-1.5) vs (0.7+/-0.3) years]and higher serum potassium[(3.8+/-0.6) vs (2.5+/-0.7) mmol/L], however the plasma ACTH level[(15.4+/-14.9) vs (42.5+/-22.7) pmol/L]was lower (all P<0.05). If the cut-off of the ratio of 24-hour urine free cortisol (24 h UFC) after low-dose dexamethasone suppression test (LDDST) to before LDDST was 0.65, the sensibility to diagnose CD was 70.8%, and the specificity was 100%. If the cut-off of the 24 h UFC ratio after high-dose dexamethasone suppression test (HDDST) to before HDDST was 0.54, the sensibility to diagnose CD was 91.7%, and the specificity was 100%. If the cut-off of the plasma ACTH ratio of inferior petrosal vein[bilateral inferior petrosal sinus sampling (BIPSS)]to peripheral vein was 2, only 6 CD patients (6/8) met it. Conclusion: The study suggested that HDDST was more meaningful in the localization diagnosis of patients with ACTH-dependent CS in adolescence. PMID- 28910956 TI - [Modulation of umbilical cord blood mesenchymal stem cells on Treg cells in the patients with aplastic anemia]. AB - Objective: To research the modulation of Umbilical cord blood mesenchymal stem cells on the number and function of Treg cells in the patients with aplastic anemia, as well as the expression of LFA-1 on Treg cells. Methods: A total of 20 newly diagnosed NSAA patients were collected from May 2015 to Jun 2016 in Department of Hematopathy, General Hospital of Jinan Military, and 10 healthy volunteers were recruited as controls. Separation of the patients and controls with peripheral blood mononuclear cells were divided into two groups, including PBMCs culture alone, PBMCs co-culture with UC-MSCs, application of flow cytometry detect respectively the proportion of the Treg cells and the expression of LFA-1 on Treg cells under different culture conditions. The Treg cells and CD4(+) CD25( )T lymphocyte were separated by magnetic cell sorting (MACS) system, CFSE label CD4(+) CD25(-)T lymphocyte, comparing the inhibitive function of Treg cells on CD4(+) CD25(-)T lymphocyte with or without co-culture with UC-MSCs. Results: The intensity of fluorescence expression of LFA-1 on T lymphocyte in aplastic anemia increased obviously((71.4+/-10.1)vs(52.5+/-8.7) , P=0.002), but the LFA-1 expressed on Treg cells had no significant difference(P=0.199). After co-cultured with UC-MSCs, the proportion of LFA-1 on Treg cells in aplastic anemia reduced greatly ((20.96+/-1.76)% vs(44.26+/-1.19)%, P=0.012), at the same time, UC-MSCs increased the proportion of Treg cells obviously ((5.33+/-1.14)%vs(1.94+/-0.65)%, P=0.003), but the effect of Treg cells on the mean frquency of dividing CD4(+) CD25(-)T lymphocyte had no significant difference with or without co-culture with UC-MSCs(P=0.290). Conclusions: The intensity of fluorescence expression of LFA-1 on lymphocyte in aplastic anemia increases obviously, indicating the possible pathogenesis of AA. UC-MSCs inhibit the expression of LFA-1 on Treg cells and enhance the proportion of Treg cells, but UC-MSCs doesn't directly improve the immunosuppression of single Treg cells. PMID- 28910957 TI - [Effects of cell cycle regulatory genes on breast cancer neo-adjuvant chemotherapy by M-FISH]. AB - Objective: The dysregulation of cell cycle could influence cell proliferation, differentiation and response to medicine. The purpose of this study is to explore the correlation between cell cycle regulatory genes and breast cancer neo adjuvant chemotherapy (NAC) in patients with local advanced breast cancer, and thus to find some predictors of NAC to provide guidance for clinical treatment. Methods: Ninety five cases of local advanced breast cancer were collected, which were treated with NAC of TAC (Taxanes/Anthracycline/Cyclophosphamide) regimen. Multi-gene fluorescence in situ hybridization (M-FISH) was used to study the correlation between copy number variations of cell cycle regulatory genes (c-myc, Mdm2, CCND1, CHEK2, Rb1, p53, p16, p21) and clinical effect of NAC. Results: In the effective group, there were 18 cases of c-Myc amplification and 52 cases of no amplification. There were 11 cases of CCND1 amplification and 59 cases of no amplification; 12 cases of p53 deletion and 58 cases without deletion; 11 cases of p16 deletion and 59 cases without deletion. In the ineffective group, there were 12 cases of c-Myc amplification and 13 cases of no amplification; CCND1 amplification in 9 cases, no amplification in 16 cases; p53 deletion in 10 cases, no deletion in 15 cases; p16 deletion in 10 cases and no deletion in 15 cases. The copy number of the above four genes was statistically different between the two groups. C-Myc gene amplification (P=0.040), CCND1 gene amplification (P=0.033), p53 gene deletion (P=0.020) and p16 gene deletion (P=0.012) were significant correlation with poor effect of NAC. Among them, the effect of NAC in patients with two or more genes copy number variations of c-Myc, CCND1, p53, p16 were poorer than that in patients with one or not gene copy number variations (P=0.000). In addition, the copy number variations of CCND1 (P=0.049), c-Myc (P=0.049), and p16 (P=0.008) were correlated with neo-adjuvant chemotherapeutic effect respectively in Luminal breast cancer, Her-2 positive breast cancer, and triple-negative breast cancer. Conclusion: These results indicated that the copy number variations of c-Myc, CCND1, p53, and p16 in patients were significant correlation with poor effect of NAC. PMID- 28910958 TI - [Therapeutic effect of AngioJet mechanical thrombus aspiration system combined with catheter directed thrombolysis on acute deep vein thrombosis]. AB - Objective: To analyze the curative effect of AngioJet mechanical thrombus aspiration combined with catheter directed thrombolysis (CDT) on acute lower extremity deep vein thrombosis (LEDVT). Methods: The clinical data of 20 cases of acute LEDVT treated by AngioJet combined with CDT were analyzed. The inferior vena cava filter was implanted preoperatively, and then the thrombolysis was performed by using AngioJet. The thrombolytic catheter was placed for CDT treatment, and the thrombolysis was evaluated by review angiography. Results: All cases were successfully punctured and catheterized. The suction time was (235+/ 75) seconds. The usage of urokinase was (180+/-90)*10(4) U. The differences before and after thrombolysis of ipsilateral and contralateral thigh circumference were (8.3+/-1.5) cm and (2.5+/-1.0) cm, respectively. The differences before and after thrombolysis of the ipsilateral and contralateral calf circumference were (2.4+/-1.0)cm and (1.5+/-0.7) cm, respectively. All of which had statistical significant (P<0.01). Conclusion: AngioJet mechanical thrombus aspiration system is a novel and safe method for the treatment of acute LEDVT. When used in conjunction with CDT, its advantages was more significant. PMID- 28910959 TI - [Ischemia/reperfusion injury study in isolated mouse hearts using a pressure volume curve]. AB - Objective: To establish and assess the feasibility and sensitivity of left ventricular elasticity, compliance and stiffness for study of ischemia/reperfusion injury in an isolated mouse heart model utilizing the pressure-volume curve framework. Methods: An isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused Langendorff heart preparation was set up from 15 male C57/6BL mice aged 12-14 weeks. End-systolic pressure volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) were obtained by measuring left ventricular (LV) systolic pressure (LVSP) and diastolic pressure under different balloon volumes. End-systolic elasticity (E(es)), end-diastolic stiffness (S(ed)) and compliance (C(ed)) were calculated from the slope of ESPVR and EDPVR. Measurements of LVSP, developed pressure (LVDP), end of diastolic pressure (EDP), the rate of pressure development dp/dt(max) and dp/dt(min) were monitored during 30 min stabilization, 20 min global ischemia and 40 min reperfusion. The reliability and coefficient of variation (CV) of these parameters were compared with E(es) and C(ed). Results: During stabilization, the heart rate was (395+/-40) bpm, LVDP was (126+/-25) mmHg, + dp/dt(max) was (5 590+/-625) mmHg/s, -dp/dt(min) was (-4 128+/-625) mmHg/s, E(es) was 5.7+/-0.3, C(ed) was 0.7+/-0.2, S(ed) was 1.4+/-0.1. Ischemia/reperfusion injury resulted in significant decrease in contractile function parameters. The recovery level of LVSP, LVDP, dp/dt(max) and dp/dt(min) were (57+/-19)%, (23+/-6)%, (23+/-7)% and (21+/-5)% (all P<0.001), respectively. The EDP increased to (5.4+/-2.0) times than the baseline after ischemia/reperfusion injury. The E(es) and C(ed) was deceased to (42+/-2)% and (33+/-2)%, compared with baseline. The stiffness was increased up to (3.1+/-0.2) times higher than the baseline. The CV of E(es,)S(ed) and C(ed) were lower than LVSP, LVDP, EDP, dp/dt(max,)dp/dt(min,)while the reliability of E(es), S(ed) and C(ed) were higher than the classic contractile function parameters. Conclusion: Pressure-volume curves are feasible during ischemia/reperfusion injury in the isolated mouse heart model with acceptable reliability and sensitivity. PMID- 28910960 TI - [Effects of human mesenchymal stem cells on airway inflammation in allergic asthma mice and the underlying mechanism]. AB - Objectives: To investigate the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on airway inflammation in an ovalbumin (OVA) induced asthma mouse model and the underlying mechanism. Methods: Twenty-four BALB/c mice were randomly divided into four equal groups: normal control group, OVA-induced asthmatic model group, hUC-MSCs treated group (50 MUl of hUC-MSCs was transplanted into the trachea of asthmatic mice ) and hUC-MSCs control group (50 MUl of hUC-MSCs was transplanted into the trachea of control mice). Human umbilical cord mesenchymal stem cells from umbilical cord of healthy new born babies were used as the source of hUC-MSCs for this study. The asthmatic conditions of the airways and the lungs were assessed by examining: (1) histopathological changes of the airways and the lungs; (2) expression of cytokines IL-6 and TGF-beta mRNA by real-time PCR; (3) total leukocytes and mast cell count in bronchoalveolar lavage fluid (BALF) and number of IL-17-expressing CD4(+) cells (Th17 cells) in the lung tissue using flow cytometry. Results: Typical histopathological changes of asthma were confirmed in the asthmatic model group. These changes included intensive inflammatory cell infiltration around the airways and patchy airway occlusion by hyperviscous mucus. The number of total leukocytes and mast cells in BALF were significantly increased in the asthmatic mice when compared with the control group (P<0.05). Mice in the asthmatic model group had significantly higher percentage of Th17 cells in lung tissues when compared with the control group (2.90% vs 0.76%, P<0.05). In contrast, in the asthmatic mice treated with hUC-MSCs, the inflammatory cell infiltration was significantly reduced compared with asthmatic mice, as observed by significantly lower leukocytes and mast cells in BALF (P<0.05) and significant reduction in the percentage of Th17 cells in the lung of OVA-challenged mice following hUC-MSCs treatment (percentage of Th17 cells: 0.24% vs 2.90%, P<0.05). The expression of mRNA for IL-6 and TGF-beta was significantly suppressed in the hUC-MSCs treatment group (0.23 vs 2.30 and 0.56 vs 6.60, both P<0.01). No asthmatic pathological changes in both normal and hUC-MSCs control groups were observed. Conclusions: hUC-MSCs significantly inhibit the airway inflammation in OVA-induced asthmatic mice. This inhibition is associated with the suppression of Th17 cells and the down-regulation of inflammatory factors such as IL-6 and TGF-beta in the lungs. PMID- 28910961 TI - Paeonol alleviates interleukin-1beta-induced inflammatory responses in chondrocytes during osteoarthritis. AB - Interleukin-1beta (IL-1beta)-induced inflammatory responses in chondrocytes play an important role in the pathogenesis of osteoarthritis (OA). Searching medicines that affect IL-1beta-mediated chondrocytes function is critical in developing therapies for OA. Paeonol, as an important component in traditional Chinese medicine, has anti-inflammatory activity and can offer therapy for a multitude of inflammatory-related diseases. The purpose of this study was to investigate whether paeonol could alleviate the progression of OA through inhibition of IL 1beta-induced inflammatory responses in chondrocytes. The cell counting kit-8 assay, 5-ethynil-2'-deoxyuridine staining, hoechst 33258 staining and flow cytometric staining were used to observe the chondrocytes proliferation and apoptosis. Western blot and quantitative real-time PCR were applied to examine the expression of extracellular matrix and cartilage degrading enzymes. Reactive oxygen species (ROS) production was monitored by 2',7'-dichlorodihydrofluoresce in diacetate staining. Furthermore, paeonol was intra-articularly injected into joint capsule in destabilized medial meniscus (DMM)-induced OA rat model for 8 and 12 weeks. The results showed that paeonol could negatively affect IL-1beta mediate chondrocyte apoptosis and proliferation. Application of paeonol attenuated the secretion of cartilage extracellular matrix and cartilage degrading enzymes induced by IL-1beta in chondrocytes. Increasing of ROS production by IL-1beta was obviously alleviated by paeonol. Besides, paeonol alleviated DMM-induced articular cartilage degeneration in vivo. Taken together, we concluded that paeonol might be used as therapeutic agent for treating OA. PMID- 28910962 TI - Pharmaceuticals and other anthropogenic chemicals in atmospheric particulates and precipitation. AB - Air and precipitation samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS) for pharmaceuticals, personal care products, and other commercial chemicals within the St. Paul/Minneapolis metropolitan area of Minnesota, U.S. Of the 126 chemicals analyzed, 17 were detected at least once. Bisphenol A, N,N-diethyl-meta toluamide (DEET), and cocaine were the most frequently detected; their maximum concentrations in snow were 3.80, 9.49, and 0.171ng/L and in air were 0.137, 0.370, and 0.033ng/m3, respectively. DEET and cocaine were present in samples of rain up to 14.5 and 0.806ng/L, respectively. Four antibiotics - ofloxacin, ciprofloxacin, enrofloxacin, and sulfamethoxazole - were detected at concentrations up to 10.3ng/L in precipitation, while ofloxacin was the sole antibiotic detected in air at 0.013ng/m3. The X-ray contrast agent iopamidol and the non-steroidal anti-inflammatory drug naproxen were detected in snow up to 228ng/L and 3.74ng/L, respectively, while caffeine was detected only in air at 0.069 and 0.111ng/m3. Benzothiazole was present in rain up to 70ng/L, while derivatives of benzotriazole - 4-methylbenzotriazole, 5-methylbenzotriazole, and 5-chlorobenzotriazole - were detected at concentrations up to 1.5ng/L in rain and 3.4ng/L in snow. Nonylphenol and nonylphenol monoethoxylate were detected once in air at 0.165 and 0.032ng/m3, respectively. Although the sources of these chemicals to atmosphere are not known, fugacity analysis suggests that wastewater may be a source of nonylphenol, nonylphenol monoethoxylate, DEET, and caffeine to atmosphere. The land-spreading of biosolids is known to generate PM10 that could also account for the presence of these contaminants in air. Micro-pollutant detections in air and precipitation are similar to the profile of contaminants reported previously for surface water. This proof of concept study suggests that atmospheric transport of these chemicals may partially explain the ubiquity of these contaminants in the aquatic environment. PMID- 28910963 TI - Placental transfer of persistent organic pollutants and feasibility using the placenta as a non-invasive biomonitoring matrix. AB - The placenta is a crucial organ for the supply of oxygen and nutritional elements from mother to fetus. Several studies have reported evidence of the placental transfer of persistent organic pollutants (POPs). Despite the importance of prenatal exposure to POPs, the transport process of POPs via the human placenta is not well understood. To investigate the transport processes of these contaminants and to assess the feasibility of the placenta as a non-invasive biological matrix, we measured 19 polychlorinated biphenyls (PCBs), 18 organochlorine pesticides (OCPs), and 24 polybrominated diphenyl ethers (PBDEs) in placenta tissues. The total concentrations of PCBs, OCPs, and PBDEs in placental tissues ranged from 0.36 to 75.2 (median: 5.85) ng/g lipid wt, 1.37 to 250 (63.5) ng/g lipid wt, and 1.21 to 427 (11.7) ng/g lipid wt, respectively. The BDE 209 concentrations were higher than those reported in previous studies presumably because of the high consumption of deca-BDE technical mixtures in Korea. The concentrations of all of the POPs in placental tissues correlated significantly with each other, but BDE 209 concentration did not correlate with that of any other contaminants possibly because of different exposure sources and kinetics. Maternal age, body mass index, and parity were contributors to the accumulation of several POPs in the placenta. Partitioning ratios between maternal blood-placenta-cord blood showed that lower molecular-weight and hydrophobic POPs were preferentially transported from maternal blood to the placenta and that higher molecular-weight and hydrophobic contaminants tended to remain in placental tissues. Regression analysis showed significant relationships between the POP concentrations in multiple biological matrices such as maternal blood, placenta, cord blood, and meconium. These relationships suggest that the placenta can be used as a non-invasive matrix for biomonitoring prenatal exposure to several POPs. PMID- 28910964 TI - Improving the Quality of Clinical Neuropsychological Research: Mandatory Use of Reporting Guidelines. PMID- 28910965 TI - Actinobacteria phylogenomics, selective isolation from an iron oligotrophic environment and siderophore functional characterization, unveil new desferrioxamine traits. AB - Desferrioxamines are hydroxamate siderophores widely conserved in both aquatic and soil-dwelling Actinobacteria. While the genetic and enzymatic bases of siderophore biosynthesis and their transport in model families of this phylum are well understood, evolutionary studies are lacking. Here, we perform a comprehensive desferrioxamine-centric (des genes) phylogenomic analysis, which includes the genomes of six novel strains isolated from an iron and phosphorous depleted oasis in the Chihuahuan desert of Mexico. Our analyses reveal previously unnoticed desferrioxamine evolutionary patterns, involving both biosynthetic and transport genes, likely to be related to desferrioxamines chemical diversity. The identified patterns were used to postulate experimentally testable hypotheses after phenotypic characterization, including profiling of siderophores production and growth stimulation of co-cultures under iron deficiency. Based in our results, we propose a novel des gene, which we term desG, as responsible for incorporation of phenylacetyl moieties during biosynthesis of previously reported arylated desferrioxamines. Moreover, a genomic-based classification of the siderophore-binding proteins responsible for specific and generalist siderophore assimilation is postulated. This report provides a much-needed evolutionary framework, with specific insights supported by experimental data, to direct the future ecological and functional analysis of desferrioxamines in the environment. PMID- 28910966 TI - Pneumococcal 23B Molecular Subtype Identified Using Whole Genome Sequencing. AB - The polysaccharide capsule is a major virulence factor of Streptococcus pneumoniae and the target of all currently licensed pneumococcal vaccines. At present, there are 92 serologically distinct pneumococcal serotypes. Structural and antigenic variation of capsular types is the result of genetic variation within the capsular polysaccharide synthesis (CPS) locus; however, genetic variation may not always result in phenotypic differences which produce novel serotypes. With the introduction of high throughput whole genome sequencing, discovery of novel genotypic variants is not unexpected and this study describes a novel variant of the serotype 23B CPS operon. This novel variant was characterized as a novel genotypic subtype (23B1) with ~70% homology to the published 23B CPS sequence. High sequence variability was determined in eight cps genes involved in sugar biosynthesis. However, there was no distinction between the classic 23B serotype and 23B1 serologically or in terms of polysaccharide structure. Phylogenetic and eBURST analysis revealed a distinct lineage for 23B1 with multiple clones (UK, Thailand, and USA) that arose at different points during pneumococcal evolution. Analysis of the UK S. pneumoniae isolates (n = 121) revealed an upsurge of 23B1 ST2372 in 2011, after which this previously unseen ST increased to reach 50% proportion of the 23B sequenced isolates from 2013 and remained prevalent within our sequenced isolates from later years. Therefore, although the 23B1 variant appears to have no phenotypic impact and cannot be considered as novel serotype, it appears to have led to a genetic restructuring of the UK serotype 23B population. PMID- 28910968 TI - Efficiency of antibody therapy in demyelinating diseases. AB - Monoclonal antibody therapy is a new treatment strategy for many types of diseases including cancers and autoimmune diseases, realizing a high efficacy and tolerability. In multiple sclerosis (MS) and neuromyelitis optica (NMO) spectrum disorders, several monoclonal antibodies have been suggested to decrease the incidence of clinical relapse and the disease activity. In MS, anti-alpha4 integrin (natalizumab), anti-CD52 (alemtuzumab), anti-CD25 (daclizumab) and anti CD20 (ocrelizumab) have been shown to effectively reduce the relapses in randomized controlled trials and have been approved by the Food and Drug Administration. Specifically, ocrelizumab is the first drug that has shown significant suppression of brain volume loss and suppression of chronic disability progression. In NMO, though there have yet to be any approved monoclonal antibodies, rituximab, anti-complement C5 (eculizumab), anti-IL-6 receptor (tocilizumab), anti-CD19 (inebilizumab) and non-pathogenic anti aquaporin 4 (aquaporumab) have been suggested to be effective, and some of these are now under clinical trials. Aquaporumab is a non-pathogenic recombinant human monoclonal antibody that competitively inhibits the binding of the pathogenic auto-antibody against aquaporin 4 in NMO patients; thus, it is expected to be highly disease specific with less non-specific adverse events. Some of these monoclonal antibodies in MS and NMO are known to cause several notable adverse events. Natalizumab and rituximab increase the risk of progressive multifocal leukoencephalopathy. Eculizumab increases the risk of meningococcal infection. Tocilizumab is known to cause intestinal diverticulitis that can cause intestinal perforation. In this review, we summarize the characteristics of, evidence for and notable adverse events of each monoclonal antibody in MS and NMO. PMID- 28910967 TI - Identification and Characterization of Domesticated Bacterial Transposases. AB - Selfish genetic elements, such as insertion sequences and transposons are found in most genomes. Transposons are usually identifiable by their high copy number within genomes. In contrast, REP-associated tyrosine transposases (RAYTs), a recently described class of bacterial transposase, are typically present at just one copy per genome. This suggests that RAYTs no longer copy themselves and thus they no longer function as a typical transposase. Motivated by this possibility we interrogated thousands of fully sequenced bacterial genomes in order to determine patterns of RAYT diversity, their distribution across chromosomes and accessory elements, and rate of duplication. RAYTs encompass exceptional diversity and are divisible into at least five distinct groups. They possess features more similar to housekeeping genes than insertion sequences, are predominantly vertically transmitted and have persisted through evolutionary time to the point where they are now found in 24% of all species for which at least one fully sequenced genome is available. Overall, the genomic distribution of RAYTs suggests that they have been coopted by host genomes to perform a function that benefits the host cell. PMID- 28910969 TI - Polymorphisms of immunoglobulin receptors and the effects on clinical outcome in cancer immunotherapy and other immune diseases: a general review. AB - Receptors for the Fc domain of immunoglobulins [Fc receptors (FcRs)] are essential for the maintenance of antibody-mediated immune responses. FcRs consist of activating- and inhibitory-type receptors that regulate adequate thresholds for various immune cells. In particular, polymorphisms and/or gene copy-number variations of FcRs for IgG (FcgammaRs) are closely associated with the development of inflammatory disorders, including autoimmune diseases. Recent evidence has implicated polymorphisms of FcRs in the efficacy of monoclonal antibody (mAb)-mediated therapy. This review provides an overview of genetic variations in human FcgammaRs and the clinical contribution of FcgammaR polymorphisms in mAb treatments for cancer, autoimmune diseases and allergies. PMID- 28910971 TI - Alteration of SSAO interactome reveals weakened cell adhesion and motor function of adipocytes in T2D. PMID- 28910972 TI - Sas/PTP10D signaling drives tumor-suppressive cell competition. PMID- 28910970 TI - Antibody therapy for the management of severe asthma with eosinophilic inflammation. AB - One of the characteristic features of asthma is chronic airway inflammation typically with eosinophil infiltration. Most asthmatics can be treated successfully with conventional treatment appropriate for their severity, but in some severe cases, asthma cannot be well controlled even with thorough treatment and this condition is known as 'refractory asthma'. To overcome severe refractory asthma, a new therapeutic strategy with biologics has been developed based on the knowledge of molecular mechanisms of airway inflammation in asthma, induced by the condition of high Th2-type responses and activation of eosinophils as well as allergic reactions. Humanized anti-human IgE antibody (anti-IgE; omalizumab) was the first biological preparation approved for treating asthma. Based on clinical evidence, treatment with anti-IgE (anti-IgE therapy) has been accepted as a new therapeutic approach for severe allergic asthma in adults since 2009 and in children since 2012 and has been shown to have ~60% efficacy. More recently, a humanized anti-IL-5 antibody (anti-IL-5; mepolizumab) was launched in June 2016 and has attracted great interest due to its potential effects. Several clinical studies are also ongoing to evaluate the biological preparations targeting IL-5 receptor alpha (IL-5Ralpha), IL-4 receptor alpha (IL-4Ralpha), which is shared by IL-4 and IL-13, thymic stromal lymphopoietin (TSLP) and IL-33. The new strategy with biologics targeting eosinophilic airway inflammation might open a new array for us to overcome severe refractory asthma in the future. PMID- 28910973 TI - Lycorine inhibits the growth and metastasis of breast cancer through the blockage of STAT3 signaling pathway. AB - Signal transducer and activator of transcription 3 (STAT3) is involved in the growth and metastasis of breast cancer, and represents a potential target for developing new anti-tumor drugs. The purpose of this study is to investigate whether Lycorine, a pyrrolo[de]phenanthridine ring-type alkaloid extracted from Amaryllidaceae genera, could inhibit breast cancer by targeting STAT3 signaling pathway. The human breast cancer cell lines were incubated with various concentrations of Lycorine, and cell proliferation, colony formation, cell cycle distribution, apoptosis, migration and invasion were assayed by several in vitro approaches. Results showed that Lycorine significantly suppressed cell proliferation, colony formation, migration and invasion, as well as induced cell apoptosis, but showed no apparent impact on cell cycle. In addition, the effect of Lycorine on tumor growth and metastasis in nude mouse models was investigated, and results showed that Lycorine significantly inhibited tumor growth and metastasis in vivo. Mechanistically, Lycorine significantly inhibited STAT3 phosphorylation and transcriptional activity through upregulating SHP-1 expression. Lycorine also downregulated the expressions of STAT3 target genes, including Mcl-1, Bcl-xL, MMP-2, MMP-9, which are involved in apoptosis and invasion of breast cancer. Taken together, these findings suggest that Lycorine may be a promising candidate for the prevention and treatment of human breast cancer. PMID- 28910974 TI - Resveratrol suppresses P-selectin, PSGL-1, and VWF through SIRT1 signaling pathway. PMID- 28910975 TI - Emerging role of HuR in inflammatory response in kidney diseases. AB - Human antigen R (HuR) is a member of the embryonic lethal abnormal vision (ELAV) family which can bind to the A/U rich elements in 3' un-translated region of mRNA and regulate mRNA splicing, transportation, and stability. Unlike other members of the ELAV family, HuR is ubiquitously expressed. Early studies mainly focused on HuR function in malignant diseases. As researches proceed, more and more proofs demonstrate its relationship with inflammation. Since most kidney diseases involve pathological changes of inflammation, HuR is now suggested to play a pivotal role in glomerular nephropathy, tubular ischemia-reperfusion damage, renal fibrosis and even renal tumors. By regulating the mRNAs of target genes, HuR is causally linked to the onset and progression of kidney diseases. Reports on this topic are steadily increasing, however, the detailed function and mechanism of action of HuR are still not well understood. The aim of this review article is to summarize the present understanding of the role of HuR in inflammation in kidney diseases, and we anticipate that future research will ultimately elucidate the therapeutic value of this novel target. PMID- 28910976 TI - Isochlorogenic acid A promotes melanin synthesis in B16 cell through the beta catenin signal pathway. AB - Isochlorogenic acid A, also called 3,5-dicaffeoylquinic acid (3,5-diCQA), is a widespread phenolic compound in the plant. Recent studies have shown that it has antioxidant and anti-inflammatory activity. In addition, oxidative stress and inflammation induced by solar ultraviolet radiation is a very significant reason for skin depigmentation. Therefore, in this study, we evaluated the effect of 3,5 diCQA on B16 cells and explored its molecular mechanism. Results showed that 3,5 diCQA upregulated intracellular melanin production in a time- and dose-dependent manner. Tyrosinase (TYR) activity was also increased after treatment with 3,5 diCQA in a dose-dependent manner. Expressions of TYR, TYR-related protein1, TYR related protein2, and microphthalmia-associated transcription factor were upregulated in a dose-dependent manner after 48 h of treatment with 3,5-diCQA. Results also showed that 3,5-diCQA promoted the phosphorylation of Akt at Thr308 and glycogen synthase kinase-3beta at Ser 9. Moreover, 3,5-diCQA increased the content of beta-catenin in cell cytoplasm and nucleus by reducing the content of phosphorylated beta-catenin (p-beta-catenin). All these results suggest that 3,5 diCQA may mediate the acceleration of melanin synthesis by the beta-catenin signal pathway. PMID- 28910977 TI - Bisphenol A induced apoptosis and transcriptome differences of spermatogonial stem cells in vitro. AB - Bisphenol A (BPA) is widely used as an industrial plasticizer, which is also an endocrine disruptor and considered to have adverse effects on reproduction. In male mammals, the long-term production of billions of spermatozoa relies on the regulated proliferation and differentiation of spermatogonial stem cells (SSCs). However, little is known about the effects of BPA on the viability of SSCs. To investigate the influence of BPA exposure on SSCs in vitro, we isolated SSCs from mouse and successfully established in vitro propagation of SSCs. After BPA treatment, we found that BPA reduced the viability of SSCs and induced SSC apoptosis. For revealing the transcriptome differences of the BPA-treated SSCs, we performed high-throughput RNA sequencing and found that 860 genes were differentially expressed among 18,272 observed genes. The gene ontology (GO) terms, regulation of programmed cell death and apoptotic process, were enriched in the differentially expressed genes (DEGs). Among the cluster of DEGs associated with the kyoto encyclopedia of genes and genomes (KEGG) apoptosis pathway, activating transcription factor 4 (Atf4) and DNA damage inducible transcript 3 (Ddit3) genes were significantly up-regulated in BPA-treated SSCs, which were proved by qPCR. Taken together, these findings suggest that BPA can increase the mRNA expression of pro-apoptosis genes and reduce the viability of SSCs by inducing apoptosis. PMID- 28910978 TI - DNA-binding properties of FOXP3 transcription factor. AB - FOXP3, a lineage-specific forkhead (FKH) transcription factor, plays essential roles in the development and function of regulatory T cells. However, the DNA binding properties of FOXP3 are not well understood. In this study, FOXP3 fragments containing different domains were purified, and their DNA-binding properties were investigated using electrophoretic mobility shift assay and isothermal titration calorimetry (ITC). Both the FKH and leucine-zipper domains were required for optimal DNA binding for FOXP3. FOXP3 protein not only binds with DNA sequences containing one FKH consensus sequence, but also binds with DNA sequences with two direct repeats of consensus sequences separated by three nucleotides (DRE3). Our results shed lights on the mechanisms by which FOXP3 recognizes cognate DNA elements, and would facilitate further structural and functional studies of FOXP3. PMID- 28910979 TI - CRISPR/Cas9-based efficient genome editing in Staphylococcus aureus. AB - Staphylococcus aureus is an important pathogenic bacterium prevalent in nosocomial infections and associated with high morbidity and mortality rates, which arise from the significant pathogenicity and multi-drug resistance. However, the typical genetic manipulation tools used to explore the relevant molecular mechanisms of S. aureus have multiple limitations: leaving a scar in the genome, comparatively low gene-editing efficiency, and prolonged experimental period. Here, we present a single-plasmid based on the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system which allows rapid and efficient chromosomal manipulation in S. aureus. The plasmid carries the cas9 gene under the control of the constitutive promoter Pxyl/tet, a single guide RNA-encoding sequence transcribed via a strong promoter Pspac, and donor DNA used to repair the double strand breaks. The function of the CRISPR/Cas9 vector was demonstrated by deleting the tgt gene and the rocA gene, and by inserting the erm R cassette in S. aureus. This research establishes a CRISPR/Cas9 genome editing tool in S. aureus, which enables marker-free, scarless and rapid genetic manipulation, thus accelerating the study of gene function in S. aureus. PMID- 28910980 TI - Neuroprotective effect of deferoxamine on N-methyl-d-aspartate-induced excitotoxicity in RGC-5 cells. AB - Many N-methyl-d-aspartate (NMDA) receptor antagonists have been used to treat neurodegenerative diseases induced by glutamate excitotoxicity in clinics. However, the universality of the glutamic acid neurotransmitter system makes the glutamic acid receptor blockers inefficient and unsafe. Thus, regulating the downstream signaling pathway in the excitotoxicity of glutamic acid may be a more effective and safer way to antagonize the glutamic acid receptor. In this study, we investigated the effect of deferoxamine (DFO), an iron chelator, on the NMDA induced excitotoxicity. RGC-5 cells were cultured and identified in vitro, and the NMDA-induced injury was assessed. Then the MTT assay was used to estimate the cell survival and JC-1 staining was performed to detect changes in mitochondrial membrane potential. Immunofluorescent staining and western blot analysis were used to analyze the expressions of respiratory chain proteins. It was found that DFO increased the survival rate of RGC-5 cells and that this effect was positively correlated with the concentration of DFO and the treatment time. The mitochondrial membrane potential and the expression levels of succinate dehydrogenase subunit A and cytochrome c oxidase subunit IV were also increased after DFO treatment, while NMDA reduced their expression levels. These data demonstrate that DFO has significant neuroprotective activity against NMDA induced excitotoxicity in RGC-5 cells. PMID- 28910981 TI - Distinct transcription profile of genes involved in carotenoid biosynthesis among six different color carrot (Daucus carota L.) cultivars. AB - Carotenoid, a group of lipophilic molecules, is widely distributed in nature, and is important for plant photosynthesis and photoprotection. In carrot taproot, different types of dominant carotenoid accumulation lead to yellow, orange, and red colors. In this study, six different carrot cultivars were used to simultaneously analyze carotenoid contents by high performance liquid chromatography. The expression levels of genes involved in carotenoid biosynthesis of carrot were also detected by real-time quantitative PCR. It was found that genes involved in xanthophyll formation were expressed at high levels in yellow carrot cultivars. However, these genes were expressed at low levels in orange carrot cultivars. The contents of alpha- and beta-carotene accounted for a large proportion in total carotenoid contents in orange carrot cultivars. These results indicate that alpha-carotene accumulation and xanthophyll formation may be related to the expression levels of carotene hydroxylase genes in carrot. PMID- 28910982 TI - Exosomes containing miR-21 transfer the characteristic of cisplatin resistance by targeting PTEN and PDCD4 in oral squamous cell carcinoma. AB - Resistance to chemotherapy remains a major obstacle for the effective treatment of oral squamous cell carcinoma (OSCC). Evidence for the involvement of exosomes as important regulators of cisplatin chemoresistance in OSCC is still poorly understood. Our objective of this study was to explore the roles for exosomes in modulating key cellular pathways mediating response to chemotherapy. We first developed the cisplatin-resistant cell lines (HSC-3-R and SCC-9-R) and found that the conditioned media from cisplatin-resistant OSCC cells enhanced the chemoresistance of parental OSCC cell. The release of exosomes was blocked by inhibitor (GW4869) and exosomes were found to be involved in the chemoresistance of parental OSCC cell transferred from resistant cells. The exosomes derived from resistant cells and parental cells were isolated. Then, the isolated exosomes were characterized and quantified by electron microscopy, qNano analysis, and western blot analysis. Exosomes derived from cisplatin-resistant OSCC cells were found to enhance the chemoresistance of OSCC cell and decrease the DNA damage signaling in response to cisplatin. It was also found that exosomes derived from cisplatin-resistant OSCC cells transferred miR-21 to OSCC parental cells and induced cisplatin resistance by targeting phosphatase and tensin homolog and programmed cell death 4. Furthermore, the roles of cisplatin-resistant OSCC cells derived exosomes in vivo were confirmed by subcutaneous xenograft mouse model. Collectively, the results suggest that exosomes released from cisplatin-resistant OSCC cells transmit miR-21 to induce cisplatin resistance of OSCC cells. PMID- 28910983 TI - Quantitative proteomic analysis of host responses triggered by Mycobacterium tuberculosis infection in human macrophage cells. AB - Macrophages are primary host of Mycobacterium tuberculosis (M.tb) and the central effector of in vivo innate immune responses against bacteria. Though the interaction between macrophages and mycobacteria has been widely investigated, the molecular mechanisms of M.tb pathogenesis in macrophages are still not clear. In this work, we investigated the altered protein expression profiles of macrophages after virulent H37Rv strain and avirulent H37Ra strain infection by tandem mass tag-based quantitative proteomics. Among 6762 identified proteins of macrophages, the expression levels of 235 proteins were significantly altered, which is supposed to be related to the infection of different strains. By bioinformatics analysis at systems level, we found that these proteins are mainly involved in the biological process of apoptosis, blood coagulation, oxidative phosphorylation, and others. The enormous variation in protein profiles between macrophages infected with H37Ra and H37Rv suggests the existence of four different immunity mechanisms that decide the fates of macrophages and M.tb. These data may provide a better understanding of M.tb pathogenesis within the host, which contributes to the prevention and clinical treatment of tuberculosis. PMID- 28910984 TI - Genomic and transcriptomic analysis of Saccharomyces cerevisiae isolates with focus in succinic acid production. AB - Succinic acid is a platform chemical that plays an important role as precursor for the synthesis of many valuable bio-based chemicals. Its microbial production from renewable resources has seen great developments, specially exploring the use of yeasts to overcome the limitations of using bacteria. The objective of the present work was to screen for succinate-producing isolates, using a yeast collection with different origins and characteristics. Four strains were chosen, two as promising succinic acid producers, in comparison with two low producers. Genome of these isolates was analysed, and differences were found mainly in genes SDH1, SDH3, MDH1 and the transcription factor HAP4, regarding the number of single nucleotide polymorphisms and the gene copy-number profile. Real-time PCR was used to study gene expression of 10 selected genes involved in the metabolic pathway of succinic acid production. Results show that for the non-producing strain, higher expression of genes SDH1, SDH2, ADH1, ADH3, IDH1 and HAP4 was detected, together with lower expression of ADR1 transcription factor, in comparison with the best producer strain. This is the first study showing the capacity of natural yeast isolates to produce high amounts of succinic acid, together with the understanding of the key factors associated, giving clues for strain improvement. PMID- 28910985 TI - Yeast-bacteria competition induced new metabolic traits through large-scale genomic rearrangements in Lachancea kluyveri. AB - Large-scale chromosomal rearrangements are an important source of evolutionary novelty that may have reshaped the genomes of existing yeast species. They dramatically alter genome organization and gene expression fueling a phenotypic leap in response to environmental constraints. Although the emergence of such signatures of genetic diversity is thought to be associated with human exploitation of yeasts, less is known about the driving forces operating in natural habitats. Here we hypothesize that an ecological battlefield characteristic of every autumn when fruits ripen accounts for the genomic innovations in natural populations. We described a long-term cross-kingdom competition experiment between Lachancea kluyveri and five species of bacteria. Now, we report how we further subjected the same yeast to a sixth species of bacteria, Pseudomonas fluorescens, resulting in the appearance of a fixed and stably inherited large-scale genomic rearrangement in two out of three parallel evolution lines. The 'extra-banded' karyotype, characterized by a higher fitness and an elevated fermentative capacity, conferred the emergence of new metabolic traits in most carbon sources and osmolytes. We tracked down the event to a duplication and translocation event involving a 261-kb segment. Such an experimental setup described here is an attractive method for developing industrial strains without genetic engineering strategies. PMID- 28910986 TI - Elimination of the last reactions in ergosterol biosynthesis alters the resistance of Saccharomyces cerevisiae to multiple stresses. AB - The sterol composition of membranes is known to influence many phenotypes of yeast. However, a systematic study of the relationship between sterol composition and stress resistances has not been conducted. Here, we therefore constructed single or double gene deletion mutants of the last four enzymes in ergosterol biosynthesis in a prototrophic genetic background of Saccharomyces cerevisiae. Identification of the sterol composition of these mutants revealed a high flexibility of the sterol-processing steps instead of the previously proposed sequential conversion. Compared with the wild type, the mutants showed altered resistances to different exogenous stresses regarding the specific growth rate and duration of lag phase. The erg5 deletion mutant whose sterol has a saturated side chain exhibited overall robust growth under the tested stress conditions. The thermotolerant phenotype of erg5 deletion mutant was reproduced in filamentous fungus Penicillium oxalicum. These results highlight the important role of sterols in the response of yeast cells to environmental stresses, and suggest the possibility of improving the robustness of industrial yeast strains by engineering their sterol composition. PMID- 28910987 TI - Management of combined injuries of the posterior cruciate ligament and posterolateral corner of the knee: a systematic review. AB - Background: Approximately 60% of posterior cruciate ligament (PCL) injury are associated with a posterolateral corner (PLC) tear. Sources of data: We performed a systematic review of the literature according to the PRISMA guidelines. The following key words were searched on Medline, Cochrane, EMBASE, Google Scholar, and Ovid: 'posterior cruciate ligament' or 'PCL' with 'posterolateral corner' or 'PLC' and 'chronic'; 'injury'; 'management'; 'reconstruction'; 'outcomes'; 'complications'. Areas of agreement: There was a statistically significant improvement of all clinical scores after surgery regardless of the procedure performed to reconstruct both PCL and PLC. Areas of controversy: No randomized control trials were identified on the topic. Standardized methods of functional outcomes assessment are necessary to improve communication on the functional results of the management of PC-PLC. Growing points: Single stage surgical reconstruction of PCL and PLC is recommended in patients with posterolateral rotatory instability of the knee. Areas timely for developing research: Adequately powered randomized trials with appropriate subjective and objective outcome measures are necessary to reach definitive conclusions. PMID- 28910988 TI - Anticoagulation after coronary stenting: a systemic review. AB - Introduction or background: Anticoagulant therapy is mainly used to prevent patients from suffering coronary and systemic thromboembolism after stenting. Many studies have been done to formulate an optimized regimen of a post-PCI or long-time anticoagulant therapy. Recent advances in the selection and duration of anticoagulant agents will be conducive to the management of patients who are considered to need anticoagulant therapy after stenting. Sources of data: Key recent published literature, including international guidelines and relevant reviews. Areas of agreement: Anticoagulant therapy has been acknowledged to improve the prognosis of patients after stenting by reducing the risk of coronary and systemic thromboembolism. Areas of controversy: Firstly, the benefit-risk ratio of post-PCI parenteral anticoagulation to prevent stent thrombosis locally in the coronary artery is still unclear. Secondly, the efficacy and safety of bivalirudin deserve to be discussed. Furthermore, the recommendation to use long time oral anticoagulant therapy to prevent systemic thromboembolism after stenting should also be emphasized. Growing points: Studies of anticoagulant therapy in patients after stenting add to the understanding of an optimized anticoagulant regimen and contribute to improving clinical outcomes. Areas for developing research: The safety and efficacy of bivalirudin, a direct thrombin inhibitor, need to be further investigated by more large-scale randomized clinical trials.Based on the widespread use of ticagrelor and prasugrel for patients who need long-time oral anticoagulant therapy, further study is needed to find an optimal strategy that balances the risk of bleeding and ischemic events after coronary stenting. PMID- 28910989 TI - Dystonia. AB - Introduction: Dystonia is a clinically heterogeneous group of hyperkinetic movement disorders. Recent advances have provided a better understanding of these conditions with significant clinical impact. Sources of data: Peer reviewed journals and reviews. PubMed.gov. Areas of agreement: A recent consensus classification, including the assessment of phenomenology and identification of the dystonia syndromes, has provided a helpful tool for the clinical assessment. New forms of monogenic dystonia have been recently identified. Areas of controversy: Despite recent advances in the understanding of dystonia, treatment remains symptomatic in most patients. Growing points: Recent advances in genetics have provided a better understanding of the potential pathogenic mechanisms involved in dystonia. Deep brain stimulation has shown to improve focal and combined forms of dystonia and its indications are constantly expanding. Areas timely for developing research: Growing understanding of the disease mechanisms involved will allow the development of targeted and disease-modifying therapies in the future. PMID- 28910990 TI - The contribution of genetics and environment to obesity. AB - Background: Obesity is a global health problem mainly attributed to lifestyle changes such as diet, low physical activity or socioeconomics factors. However, several evidences consistently showed that genetics contributes significantly to the weight-gain susceptibility. Sources of data: A systematic literature search of most relevant original, review and meta-analysis, restricted to English was conducted in PubMed, Web of Science and Google scholar up to May 2017 concerning the contribution of genetics and environmental factors to obesity. Areas of agreement: Several evidences suggest that obesogenic environments contribute to the development of an obese phenotype. However, not every individual from the same population, despite sharing the same obesogenic environment, develop obesity. Areas of controversy: After more than 10 years of investigation on the genetics of obesity, the variants found associated with obesity represent only 3% of the estimated BMI-heritability, which is around 47-80%. Moreover, genetic factors per se were unable to explain the rapid spread of obesity prevalence. Growing points: The integration of multi-omics data enables scientists having a better picture and to elucidate unknown pathways contributing to obesity. Areas timely for developing research: New studies based on case-control or gene candidate approach will be important to identify new variants associated with obesity susceptibility and consequently unveiling its genetic architecture. This will lead to an improvement of our understanding about underlying mechanisms involved in development and origin of the actual obesity epidemic. The integration of several omics will also provide insights about the interplay between genes and environments contributing to the obese phenotype. PMID- 28910991 TI - Pricing as a means of controlling alcohol consumption. AB - Background: Reducing the affordability of alcohol, by increasing its price, is the most effective strategy for controlling alcohol consumption and reducing harm. Sources of data: We review meta-analyses and systematic reviews of alcohol tax/price effects from the past decade, and recent evaluations of tax/price policies in the UK, Canada and Australia. Areas of agreement: While the magnitudes of price effects vary by sub-group and alcoholic beverage type, it has been consistently shown that price increases lead to reductions in alcohol consumption. Areas of controversy: There remains, however, a lack of consensus on the most appropriate taxation and pricing policy in many countries because of concerns about effects by different consumption level and income level and disagreement on policy design between parts of the alcoholic beverage industries. Growing points: Recent developments in the research highlight the importance of obtaining accurate alcohol price data, reducing bias in estimating price responsiveness, and examining the impact on the heaviest drinkers. Areas timely for developing research: There is a need for further research focusing on the substitution effects of taxation and pricing policies, estimation of the true tax pass-through rates, and empirical analysis of the supply-side response (from alcohol producers and retailers) to various alcohol pricing strategies. PMID- 28910992 TI - Physician-assisted suicide-a clean bill of health? AB - Background: Physician-assisted suicide (PAS) laws have been enacted in five US States and, along with physician-administered euthanasia, in Canada and the Netherlands. Sources of data: Annual reports of the Oregon Health Authority and published research papers. Areas of agreement: Not all recipients of lethal drugs use them to end their lives. Improvements in palliative care provision. Areas of controversy: Rising numbers of deaths from PAS. Emergence of 'doctor shopping' and multiple-prescribing. Absence of qualitative scrutiny of assessment process. No re-assessment or oversight when prescribed drugs are ingested. Recent pressures to extend Oregon's PAS law. Growing points: Reasons given for seeking PAS indicate this is a societal rather than a clinical issue and raise the question whether adjudicating on requests for legalized PAS is an appropriate role for doctors. Areas for timely research: Research into quality of decision making in requests for PAS and into potential role of doctors as expert witnesses rather than judges in requests for PAS. PMID- 28910993 TI - Transtendon repair in partial articular supraspinatus tendon tear. AB - Introduction: Partial thickness rotator cuff tears (PTRCTs) are common, with an incidence between 17% and 37%, and a high prevalence in throwing athletes. Different surgical procedures are suggested when partial tears involve the articular portion of the rotator cuff, including arthroscopic debridement of the tear, debridement with acromioplasty, tear completion and repair, and lately transtendon repair. This systematic review describes the transtendon repair and examines indications, contraindications, complications and clinical outcome. Source of data: We identified clinical studies listed in the Pubmed Google Scholar, CINAHL, Cochrane Central and Embase Biomedical databases in English and Italian concerning the clinical outcomes following treatment of partial articular supraspinatus tendon tear using transtendon surgical repair. Areas of agreement: Eighteen studies fulfilled our inclusion criteria. All were published between 2005 and 2016, three were retrospective, and 15 prospective. The total number of patients was 507 with a mean age of 50.8 years. Areas of controversy: Tear completion and repair and transtendon repair alone produce similar results. Growing points: Transtendon surgical repair allows to obtain good-excellent results in the treatment of partial articular supraspinatus tendon tears. Areas timely for developing research: Further studies are needed to produce clear guidelines in the treatment of partial articular supraspinatus tendon tears. Level of evidence: IV. PMID- 28910994 TI - Paediatric and maternal schistosomiasis: shifting the paradigms. AB - Background: In endemic areas, schistosomiasis causes both overt and subclinical disease in young children and their mothers, as well as in returned travellers. Sources of data: Key recently published literature. Areas of agreement: An action plan for paediatric schistosomiasis and female genital schistosomiasis (FGS) is needed with expanded access to praziquantel (PZQ) treatment required. Areas of controversy: Schistosomiasis-related morbidity is underappreciated. Present and future demand for PZQ treatment is bottlenecked, imbalanced and inequitable. Current dosing, treatment algorithms and access plans are suboptimal with treatment stalled during pregnancy. Growing points: Raised dosing of PZQ (>40 mg/kg) is being explored in young children. Surveillance of female genital schistosomiasis FGS is increasing. Use of PZQ in pregnancy is safe and preventive chemotherapy guidelines are being revised in morbidity- and transmission-control settings. Areas timely for developing research: Shifting focus of population level control to individual-case management. Detection and prevention of FGS within general health services and integration of PZQ treatment for women and children in antenatal clinics. Feasibility studies assessing alternative and expanded access to PZQ treatment to at-risk children and mothers and pregnant women. PMID- 28910995 TI - Genomic medicine and data sharing. AB - Introduction: Effective data sharing does not occur in the UK despite being essential for the delivery of high-quality genomic services to patients across clinical specialities and to optimize advances in genomic medicine. Sources of data: Original papers, reviews, guidelines, policy papers and web-resources. Areas of agreement: Data sharing for genomic medicine requires appropriate infrastructure and policies, together with acceptance by health professionals and the public of the necessity of data sharing for clinical care. Areas of controversy: There is ongoing debate around the different technical approaches and safeguards that could be used to facilitate data sharing while minimizing the risks to individuals of identification. Lack of consensus undermines trust and confidence. Growing points: Ongoing policy developments around genomics and health data create opportunities to ensure systems and policies are in place to support proportionate, effective and safeguarded data sharing. Areas timely for developing research: Mechanisms to improve public trust. PMID- 28910996 TI - Think adult-think child! Why should staff caring for dying adults ask what the death means for children in the family? AB - Introduction: Bereaved children and young people in the UK are 'hidden mourners'. Sources of data: Review of primary and secondary evidence on childhood bereavement. Area of agreement: Children experience grief that varies according to the circumstance of death and their cognitive ability. Voluntary organizations can be supportive, but provision is patchy and vulnerable to austerity. Areas of concern: Adult-centric denial of the importance and long-term consequences of childhood grief; uncertainty in how best to relate to bereaved children in faiths and in schools. Growing points: Increased awareness of the immediate and long term consequences of childhood bereavement; even young children can experience loss through death. Areas timely for research: Better knowledge of the numbers of affected children; longitudinal data to track experiences and outcomes; measuring effectiveness of different approaches; identifying risk factors for early intervention in complicated or prolonged grief; the importance of faith and rituals around death; mapping the provision of services to monitor the impact of austerity. Recommendations: 'Think adult-think child' means that all staff caring for dying adults should take responsibility for asking what the death means for the children in the family, with schools, primary care and faith organizations having protocols and expertise available to support grieving children; recent catastrophes expose need for agencies to have management plans that focus on vulnerable children and young people. PMID- 28910997 TI - Paediatric nuclear medicine imaging. AB - Background: Nuclear medicine imaging explores tissue viability and function by using radiotracers that are taken up at cellular level with different mechanism. This imaging technique can also be used to assess blood flow and transit through tubular organs. Nuclear medicine imaging has been used in paediatrics for decades and this field is continuously evolving. Sources of data: The data presented comes from clinical experience and some milestone papers on the subject. Areas of agreement: Nuclear medicine imaging is well-established in paediatric nephro urology in the context of urinary tract infection, ante-natally diagnosed hydronephrosis and other congenital renal anomalies. Also, in paediatric oncology, I-123-meta-iodobenzyl-guanidine has a key role in the management of children with neuroblastic tumours. Bone scintigraphy is still highly valuable to localize the source of symptoms in children and adolescents with bone pain when other imaging techniques have failed. Thyroid scintigraphy in neonates with congenital hypothyroidism is the most accurate imaging technique to confirm the presence of ectopic functioning thyroid tissue. Areas of controversy: Radionuclide transit studies of the gastro-intestinal tract are potentially useful in suspected gastroparesis or small bowel or colonic dysmotility. However, until now a standardized protocol and a validated normal range have not been agreed, and more work is necessary. Research is ongoing on whether magnetic resonance imaging (MRI), with its great advantage of great anatomical detail and no ionizing radiations, can replace nuclear medicine imaging in some clinical context. On the other hand, access to MRI is often difficult in many district general hospitals and general anaesthesia is frequently required, thus adding to the complexity of the examination. Growing points: Patients with bone pain and no cause for it demonstrated on MRI can benefit from bone scintigraphy with single photon emission tomography and low-dose computed tomography. This technique can identify areas of mechanical stress at cortical bone level, difficult to demonstrate on MRI, which can act as pain generators. Positron emission tomography (PET) is being tested in the staging, response assessment and at the end of treatment of several paediatric malignancies. PET is becoming more widely utilized in neurology in the pre-surgical assessment of some children with drug resistant epilepsy. Areas timely for developing research: The use of PET/MRI scanners is very attractive as it combines benefits of MR imaging with the assessment of cellular viability and metabolism with PET in one examination. This imaging technique will allow important research on tumour in-vivo metabolism (possible applications include lymphomas, neuroblastomas, malignant germ cell tumours andbrain tumours), with the aim of offering a personalized biological profile of the tumour in a particular patient. Ground-breaking research is also envisaged in neurosciences, especially in epilepsy, using PET tracers that would enable a better identification of the epileptogenic focus, and in psychiatry, with the use of radiolabeled neurotransmitters. In paediatric nephro-urology, the identification of the asymptomatic child with ante-natally diagnosed hydronephrosis at risk of losing renal parenchymal function if left untreated is another area of active research involving radionuclide renography. PMID- 28910998 TI - Abnormal uterine bleeding. AB - Introduction: It is not uncommon for a woman to suffer from abnormal uterine bleeding (AUB) or heavy menstrual bleeding (HMB) at some point during her lifetime. Once pathology is excluded, in practice, management needs to be individualised, taking into account the improvement of the woman's symptoms and quality of life. Sources of data: Peer-reviewed journals, governmental and professional society publications. Areas of agreement: There is now agreement on a structured, universal approach to the diagnosis of AUB, with the aide memoirs PALM (polyps, adenomyosis, leiomyoma, malignancy) and COEIN (coagulopathies, ovulatory dysfunction, endometrial, iatrogenic, not otherwise classified). Once malignancy and significant pelvic pathology have been ruled out, medical treatment is an effective first-line therapeutic option, with surgery, including endometrial ablation and hysterectomy, offered when medical management has failed to resolve symptoms and fertility is no longer desired. Areas of controversy: There remains controversy around the management of the types and subtypes of adenomyosis and leiomyoma, and understanding their impact on clinical reproductive outcomes. Areas currently under development: Standardised assessment tools for measuring outcomes of AUB are being developed. Areas timely for developing research: Novel diagnostic and monitoring tools should be developed to help stratify treatment for women with AUB, particularly relating to 'unclassified' and 'endometrial' causes. PMID- 28910999 TI - Infection with Opisthorchis felineus induces intraepithelial neoplasia of the biliary tract in a rodent model. AB - The liver fluke Opisthorchis felineus is a member of the triad of epidemiologically relevant species of the trematode family Opisthorchiidae, and the causative agent of opisthorchiasis felinea over an extensive range that spans regions of Eurasia. The International Agency for Research on Cancer classifies the infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis as group 1 agents and a major risk factor for cholangiocarcinoma. However, the carcinogenic potential of the infection with O. felineus is less clear. Here, we present findings that support the inclusion of O. felineus in the Group 1 list of biological carcinogens. Two discrete lines of evidence support the notion that infection with this liver fluke is carcinogenic. First, novel oxysterol-like metabolites detected by liquid chromatography-mass spectroscopy in the egg and adult developmental stages of O. felineus, and in bile, sera, and urine of liver fluke-infected hamsters exhibited marked similarity to oxysterol like molecules known from O. viverrini. Numerous oxysterols and related DNA adducts detected in the liver fluke eggs and in bile from infected hamsters suggested that infection-associated oxysterols induced chromosomal lesions in host cells. Second, histological analysis of liver sections from hamsters infected with O. felineus confirmed portal area enlargement, inflammation with severe periductal fibrosis and changes in the epithelium of the biliary tract characterized as biliary intraepithelial neoplasia, BilIN. The consonance of these biochemical and histopathological changes revealed that O. felineus infection in this rodent model induced precancerous lesions conducive to malignancy. PMID- 28911000 TI - Dicer regulates non-homologous end joining and is associated with chemosensitivity in colon cancer patients. AB - DNA double-strand break (DSB) repair is an important mechanism underlying chemotherapy resistance in human cancers. Dicer participates in DSB repair by facilitating homologous recombination. However, whether Dicer is involved in non homologous end joining (NHEJ) remains unknown. Here, we addressed whether Dicer regulates NHEJ and chemosensitivity in colon cancer cells. Using our recently developed NHEJ assay, we found that DSB introduction by I-SceI cleavage leads to Dicer upregulation. Dicer knockdown increased SIRT7 binding and decreased the level of H3K18Ac (acetylated lysine 18 of histone H3) at DSB sites, thereby repressing the recruitment of NHEJ factors to DSB sites and inhibiting NHEJ. Dicer overexpression reduced SIRT7 binding and increased the level of H3K18Ac at DSB sites, promoting the recruitment of NHEJ factors to DSBs and moderately enhancing NHEJ. Dicer knockdown and overexpression increased and decreased, respectively, the chemosensitivity of colon cancer cells. Dicer protein expression in colon cancer tissues of patients was directly correlated with chemoresistance. Our findings revealed a function of Dicer in NHEJ-mediated DSB repair and the association of Dicer expression with chemoresistance in colon cancer patients. PMID- 28911001 TI - Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile. AB - Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li Fraumeni family. PMID- 28911002 TI - Intratumor heterogeneity predicts metastasis of triple-negative breast cancer. AB - Even with the identical clinicopathological features, the ability for metastasis is vastly different among triple-negative breast cancer (TNBC) patients. Intratumor heterogeneity (ITH), which is common in breast cancer, may be a key mechanism leading to the tumor progression. In this study, we studied whether a quantitative genetic definition of ITH can predict clinical outcomes in patients with TNBC. We quantified ITH by calculating Shannon index, a measure of diversity in a population, based on Myc, epidermal growth factor receptor/centromeric probe 7 (EGFR/CEP7) and cyclin D1/centromeric probe 11 (CCND1/CEP11) copy number variations (CNVs) in 300 cells at three different locations of a tumor. Among 75 TNBC patients, those who developed metastasis had significantly higher ITH, that is Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs. Higher Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs were significantly associated with the development of metastasis and were predictive of significantly worse metastasis-free survival (MFS). Regional heterogeneity, defined as the difference in copy numbers of Myc, EGFR or CCND1 at different locations, was found in 52 patients. However, the presence of regional heterogeneity did not correlate with metastasis or MFS. Our findings demonstrate that higher ITH of EGFR/CEP7 and CCND1/CEP11 CNVs is predictive of metastasis and is associated with significantly worse MFS in TNBC patients, suggesting that ITH is a very promising novel prognostic factor in TNBC. PMID- 28911003 TI - Personal exposure to fine particulate matter and benzo[a]pyrene from indoor air pollution and leukocyte mitochondrial DNA copy number in rural China. AB - Households in Xuanwei and Fuyuan, China, possess hazardous levels of fine particulate matter with an aerodynamic diameter <2.5 microns (PM2.5) and polycyclic aromatic hydrocarbons (PAHs) from coal combustion. Previous studies found that increased exposure to PM2.5 and benzo[a]pyrene (BaP; a PAH) were associated with decreased mitochondrial DNA copy number (mtDNAcn), a marker of oxidative stress. We further evaluated these associations in a cross-sectional study of 148 healthy non-smoking women from Xuanwei and Fuyuan. Personal exposure to PM2.5 and BaP was measured using portable devices. MtDNAcn was measured using qPCR amplification of leukocyte DNA that was collected after air measurements. Linear regression models were used to estimate the associations between personal exposure to PM2.5 and BaP, and mtDNAcn adjusted for age, body mass index (BMI) and fuel type. We found inverse associations between exposure to PM2.5 and BaP, and mtDNAcn. Each incremental log-MUg/m3 increase in PM2.5 was associated with a significant decrease in mtDNAcn of -10.3 copies per cell [95% confidence interval (95% CI): -18.6, -2.0; P = 0.02]. Additionally, each log-ng/m3 increase in BaP was associated with a significant decrease in mtDNAcn of -5.4 copies per cell (95% CI: -9.9, -0.8, P = 0.02). Age, BMI, fuel type and coal mine type were not significantly associated with mtDNAcn. Exposure to PM2.5 and BaP may alter mitochondrial dynamics in non-smoking Chinese women. MtDNAcn may be a potential mediator of indoor air pollution on chronic disease development. PMID- 28911004 TI - Inherent aerobic capacity-dependent differences in breast carcinogenesis. AB - Although regular physical activity is associated with improvement in aerobic capacity and lower breast cancer risk, there are heritable sets of traits that affect improvement in aerobic capacity in response to physical activity. Although aerobic capacity segregates risk for a number of chronic diseases, the effect of the heritable component on cancer risk has not been evaluated. Therefore, we investigated breast carcinogenesis in rodent models of heritable fitness in the absence of induced physical activity. Female offspring of N:NIH rats selectively bred for low (LIAC) or high (HIAC) inherent aerobic capacity were injected intraperitoneally with 1-methyl-1-nitrosurea (70 mg/kg body wt). At study termination 33 weeks post-carcinogen, cancer incidence (14.0 versus 47.3%; P < 0.001) and multiplicity (0.18 versus 0.85 cancers per rat; P < 0.0001) were significantly decreased in HIAC versus LIAC rats, respectively. HIAC had smaller visceral and subcutaneous body fat depots than LIAC and activity of two proteins that regulated the mammalian target of rapamycin, protein kinase B (Akt), and adenosine monophosphate-activated protein kinase were suppressed and activated, respectively, in HIAC. Although many factors distinguish between HIAC and LIAC, it appears that the protective effect of HIAC against breast carcinogenesis is mediated, at least in part, via alterations in core metabolic signaling pathways deregulated in the majority of human breast cancers. PMID- 28911005 TI - OCIAD2 suppressed tumor growth and invasion via AKT pathway in Hepatocelluar carcinoma. AB - Hepatocellular carcinoma (HCC) is an aggressive tumor and the third leading cause of cancer-related death worldwide. Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) has been found frequently methylated in various cancers, including HCC. The aim of the present study was to investigate the role of OCIAD2 in HCC progression. We analyzed liver hepatocellular carcinoma patients' data from the Cancer Genome Atlas (TCGA), including data extracted from 371 HCC tissues and 50 adjacent normal liver tissues. The RNA sequencing and DNA methylation data revealed that OCIAD2 were significantly hypermethylated and its expression level in the tumor tissues was much lower than that in the corresponding adjacent normal tissues. The methylation level in the promoter was negatively correlated with the expression level of OCAID2. Treatment of HCC cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycitydine (5-Aza) induced a significant increase in the OCIAD2 mRNA and protein. Knocking-down OCIAD2 led to an increased colony formation, migration and invasion dramatically, accompanying with an enhanced expression of MMP9 and activation of AKT and FAK. Inhibition of AKT signaling restored OCIAD2-mediated changes in HCC cell clonogenic growth, migration and invasion. Survival analysis of HCC patient's data indicated patients with a higher expression ratio of OCIAD2/MMP9 had a shorter overall survival than those with a lower expression ratio of OCIAD2/MMP9. Overall, our data indicate that reduced expression of OCIAD2 by DNA hypermethylation plays an important role in HCC tumor growth and invasion. Hypermethylation of OCIAD2 may contribute to HCC treatment development. PMID- 28911006 TI - Ghrelin Serum Concentrations Are Associated with Treatment Response During Lithium Augmentation of Antidepressants. AB - Background: Lithium augmentation of antidepressants is an effective strategy in treatment-resistant depression. The proteohormone ghrelin is thought to be involved in the pathophysiology of depression. The purpose of this study was to investigate the association of treatment response with the course of ghrelin levels during lithium augmentation. Method: Ghrelin serum concentrations and severity of depression were measured in 85 acute depressive patients before and after 4 weeks of lithium augmentation. Results: In a linear mixed model analysis, we found a significant effect of response*time interaction (F1.81=9.48; P=.0028): under treatment, ghrelin levels increased in nonresponders and slightly decreased in responders to lithium augmentation. The covariate female gender had a significant positive effect (F1.83=4.69; P=.033), whereas time, response, appetite, and body mass index (kg/m2) did not show any significant effect on ghrelin levels (P>.05). Conclusion: This is the first study showing that the course of ghrelin levels separates responders and nonresponders to lithium augmentation. Present results support the hypothesis that ghrelin serum concentrations might be involved in response to pharmacological treatment of depression. PMID- 28911007 TI - Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain. AB - Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain. PMID- 28911008 TI - Maternal Dietary L-Arginine and Adverse Birth Outcomes in Dar es Salaam, Tanzania. AB - The amino acid arginine is a physiological precursor to nitric oxide, which is a key mediator of embryonic survival, fetal growth, and pregnancy maintenance. We evaluated the association between consumption of the amino acid arginine and the rate of adverse birth outcomes using data from a double-blind, randomized, placebo-controlled micronutrient supplementation trial among pregnant women in Dar es Salaam, Tanzania (2001-2004). Dietary intakes of arginine were assessed using repeated 24-hour recalls that were administered throughout pregnancy. Participants (n = 7,591) were monitored by research midwives throughout follow-up to assess pregnancy outcomes. Cubic-restricted splines and multivariable log Poisson regression with empirical standard errors were used to estimate the continuous and categorical associations between arginine intake and adverse birth outcomes. Compared with women within the lowest quintile of arginine intake, those within the highest quintile had 0.79 times the risk of preterm birth before 37 weeks (95% confidence interval: 0.63, 1.00; P = 0.03). The continuous associations of arginine intake with preterm birth before 37 weeks and with preterm birth before 34 weeks were characterized by an initial rapid decrease in risk with increasing intake (P for nonlinearity < 0.01). Arginine intake was not associated with fetal loss or giving birth to infants who were born small for their gestational ages. This data suggest that the association between dietary arginine intake and preterm birth warrants further investigation. PMID- 28911009 TI - Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles. AB - Environmental or social challenges can stimulate a cascade of coordinated physiological changes in stress response systems. Unfortunately, chronic activation of these adaptations under conditions such as low socioeconomic status (SES) can have negative consequences for long-term health. While there is substantial evidence tying low SES to increased disease risk and reduced life expectancy, the underlying biology remains poorly understood. Using pilot data on 120 older adults from the Health and Retirement Study (United States, 2002-2010), we examined the associations between SES and gene expression levels in adulthood, with particular focus on a gene expression program known as the conserved transcriptional response to adversity. We also used a bioinformatics-based approach to assess the activity of specific gene regulation pathways involved in inflammation, antiviral responses, and stress-related neuroendocrine signaling. We found that low SES was related to increased expression of conserved transcriptional response to adversity genes and distinct patterns of proinflammatory, antiviral, and stress signaling (e.g., sympathetic nervous system and hypothalamic-pituitary-adrenal axis) transcription factor activation. PMID- 28911010 TI - Evaluating the Effectiveness of New York City Health Policy Initiatives in Reducing Cardiovascular Disease Mortality, 1990-2011. AB - Beginning in 2002, New York City (NYC) implemented numerous policies and programs targeting cardiovascular disease (CVD) risk factors. Using death certificates, we analyzed trends in NYC-specific and US mortality rates from 1990 to 2011 for all causes, any CVD, atherosclerotic CVD (ACVD), coronary artery disease (CAD), and stroke. Joinpoint analyses quantified annual percent change (APC) and evaluated whether decreases in CVD mortality accelerated after 2002 in either NYC or the total US population. Our analyses included 1,149,217 NYC decedents. The rates of decline in mortality from all causes, any CVD, and stroke in NYC did not change after 2002. Among men, the decline in ACVD mortality accelerated during 2002-2011 (APC = -4.8%, 95% confidence interval (CI): -6.1, -3.4) relative to 1990-2001 (APC = -2.3%, 95% CI: -3.1, -1.5). Among women, ACVD rates began declining more rapidly in 1993 (APC = -3.2%, 95% CI: -3.8, -2.7) and again in 2006 (APC = -6.6%, 95% CI: -8.9, -4.3) as compared with 1990-1992 (APC = 1.6%, 95% CI: -2.7, 6.0). In the US population, no acceleration of mortality decline was observed in either ACVD or CAD mortality rates after 2002. Relative to 1990-2001, atherosclerotic CVD and CAD rates began to decline more rapidly during the 2002-2011 period in both men and women-a pattern not observed in the total US population, suggesting that NYC initiatives might have had a measurable influence on delaying or reducing ACVD mortality. PMID- 28911011 TI - Evaluating the Relationship Between Birth Weight for Gestational Age and Adult Blood Pressure Using Participants From a Cohort of Same-Sex Siblings, Discordant on Birth Weight Percentile. AB - Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005-2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04-mm Hg decrement in adult systolic BP (95% confidence interval (CI): -2.14, 0.06) and a 0.63-mm Hg decrement in diastolic BP (95% CI: -1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to -0.90 mm Hg (95% CI: -1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., -1.22 mm Hg (95% CI: -5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited. PMID- 28911012 TI - Particulate Matter and Risk of Hospital Admission in the Kathmandu Valley, Nepal: A Case-Crossover Study. AB - Air pollution is known to lead to a substantial health burden, but the majority of evidence is based on data from North America and Europe. Despite rising pollution levels, very limited information is available for South Asia. We investigated the impact of particulate matter with an aerodynamic diameter less than or equal to 10 MUm (PM10) on hospitalization, by cause and subpopulation, in the Kathmandu Valley, an understudied and rapidly urbanizing region in Nepal. Individual-level daily inpatient hospitalization data (2004-2007) were collected from each of 6 major hospitals, as Nepal has no central data collection system. Time-stratified case-crossover analysis was used with interaction terms for potential effect modifiers (e.g., age, sex, and socioeconomic status), with adjustment for day of the week and weather. Daily PM10 concentrations averaged 120 MUg/m3, with the daily maximum reaching 403 MUg/m3. A 10-MUg/m3 increase in PM10 level was associated with increased risks of hospitalization of 1.00% (95% confidence interval (CI): 0.62, 1.38), 1.70% (95% CI: 0.18, 3.25), and 2.29% (95% CI: 0.18, 4.43) for total, respiratory, and cardiovascular admissions, respectively. We did not find strong evidence of effect modification by age, sex, or socioeconomic status. These results, in combination with the high levels of exposure, indicate a potentially serious human health burden from air pollution in the Kathmandu Valley. PMID- 28911014 TI - RE: "SMOKELESS TOBACCO USE AND THE RISK OF HEAD AND NECK CANCER: POOLED ANALYSIS OF US STUDIES IN THE INHANCE CONSORTIUM". PMID- 28911013 TI - Invited Commentary: Integrating Genomics and Social Epidemiology-Analysis of Late Life Low Socioeconomic Status and the Conserved Transcriptional Response to Adversity. AB - Socially disadvantaged children face increased morbidity and mortality as they age. Understanding mechanisms through which social disadvantage becomes biologically embedded and devising measurements that can track this embedding are critical priorities for research to address social gradients in health. The analysis by Levine et al. (Am J Epidemiol. 2017;186(5):503-509) of genome-wide gene expression in a subsample of US Health and Retirement Study participants suggests important new directions for the field. Specifically, findings suggest promise in integrating gene expression data into population studies and provide further evidence for the conserved transcriptional response to adversity as a marker of biological embedding of social disadvantage. The study also highlights methodological issues related to the analysis of gene expression data and social gradients in health and a need to examine the conserved transcriptional response to adversity alongside other proposed measurements of biological embedding. Looking to the future, advances in genome science are opening new opportunities for sociogenomic epidemiology. PMID- 28911015 TI - THE AUTHORS REPLY. PMID- 28911016 TI - Quantifying rooting at depth in a wheat doubled haploid population with introgression from wild emmer. AB - Background and Aims: The genetic basis of increased rooting below the plough layer, post-anthesis in the field, of an elite wheat line (Triticum aestivum 'Shamrock') with recent introgression from wild emmer (T. dicoccoides), is investigated. Shamrock has a non-glaucous canopy phenotype mapped to the short arm of chromosome 2B (2BS), derived from the wild emmer. A secondary aim was to determine whether genetic effects found in the field could have been predicted by other assessment methods. Methods: Roots of doubled haploid (DH) lines from a winter wheat ('Shamrock' * 'Shango') population were assessed using a seedling screen in moist paper rolls, in rhizotrons to the end of tillering, and in the field post-anthesis. A linkage map was produced using single nucleotide polymorphism markers to identify quantitative trait loci (QTLs) for rooting traits. Key Results: Shamrock had greater root length density (RLD) at depth than Shango, in the field and within the rhizotrons. The DH population exhibited diversity for rooting traits within the three environments studied. QTLs were identified on chromosomes 5D, 6B and 7B, explaining variation in RLD post anthesis in the field. Effects associated with the non-glaucous trait on RLD interacted significantly with depth in the field, and some of this interaction mapped to 2BS. The effect of genotype was strongly influenced by the method of root assessment, e.g. glaucousness expressed in the field was negatively associated with root length in the rhizotrons, but positively associated with length in the seedling screen. Conclusions: To our knowledge, this is the first study to identify QTLs for rooting at depth in field-grown wheat at mature growth stages. Within the population studied here, our results are consistent with the hypothesis that some of the variation in rooting is associated with recent introgression from wild emmer. The expression of genetic effects differed between the methods of root assessment. PMID- 28911017 TI - Uncertain pollination environment promotes the evolution of a stable mixed reproductive system in the self-incompatible Hypochaeris salzmanniana (Asteraceae). AB - Background and aims: The transition from outcrossing to selfing is a repeated pattern in angiosperm diversification and according to general theory this transition should occur quickly and mixed reproductive systems should be infrequent. However, a large proportion of flowering plants have mixed reproductive systems, even showing inbreeding depression. Recently, several theoretical studies have shown that mixed mating systems can be stable, but empirical studies supporting these assumptions are still scarce. Methods: Hypochaeris salzmanniana, an annual species with populations differing in their self-incompatibility expression, was used as a study case to assess the stability of its mixed reproductive system. Here a descriptive study of the pollination environment was combined with measurements of the stability of the self incompatibility system, outcrossing rate, reproductive assurance and inbreeding depression in four populations for two consecutive years. Key Results: The reproductive system of populations exhibited a geographical pattern: the proportion of plants decreased from west to east. Pollinator environment also varied geographically, being less favourable from west to east. The self incompatibility expression of some populations changed markedly in only one year. After selfing, progeny was mainly self-compatible, while after outcrossing both self-incompatible and self-compatible plants were produced. In general, both reproductive assurance and high inbreeding depression were found in all populations and years. The lowest values of inbreeding depression were found in 2014 in the easternmost populations, which experienced a marked increase in self compatibility in 2015. Conclusions: The mixed reproductive system of H. salzmanniana seems to be an evolutionarily stable strategy, with selfing conferring reproductive assurance when pollinator attendance is low, but strongly limited by inbreeding depression. The fact that the highest frequencies of self compatible plants appeared in the environments most unfavourable to pollination suggests that these plants are selected in these sites, although high rates of inbreeding depression should impede the complete loss of self-incompatibility. In H. salzmanniana, year-to-year changes in the frequency of self-incompatible individuals are directly derived from the balance between reproductive assurance and inbreeding depression. PMID- 28911018 TI - Wilted cucumber plants infected by Fusarium oxysporum f. sp. cucumerinum do not suffer from water shortage. AB - Background and Aims: Fusarium wilt is primarily a soil-borne disease and results in yield loss and quality decline in cucumber (Cucumis sativus). The main symptom of fusarium wilt is the wilting of entire plant, which could be caused by a fungal toxin(s) or blockage of water transport. To investigate whether this wilt arises from water shortage, the physiological responses of hydroponically grown cucumber plants subjected to water stress using polyethylene glycol (PEG, 6000) were compared with those of plants infected with Fusarium oxysporum f. sp. cucumerinum (FOC). Methods: Parameters reflecting plant water status were measured 8d after the start of treatment. Leaf gas exchange parameters and temperature were measured with a LI-COR portable open photosynthesis system and by thermal imaging. Chlorophyll fluorescence and chloroplast structures were assessed by imaging pulse amplitude-modulated fluorometry and transmission electron microscopy, respectively. Key Results: Cucumber water balance was altered after FOC infection, with decreased water absorption and hydraulic conductivity. However, the responses of cucumber leaves to FOC and PEG differed in leaf regions. Under water stress, measures of lipid peroxidation (malondialdehyde) and chlorophyll fluorescence indicated that the leaf edge was more seriously injured, with a higher leaf temperature and disrupted leaf water status compared with the centre. Here, abscisic acid (ABA) and proline were negatively correlated with water potential. In contrast, under FOC infection, membrane damage and a higher temperature were observed in the leaf centre while ABA and proline did not vary with water potential. Cytologically, FOC-infected cucumber leaves exhibited circular chloroplasts and swelled starch grains in the leaf centre, in which they again differed from PEG-stressed cucumber leaves. Conclusions: This study illustrates the non-causal relationship between fusarium wilt and water transport blockage. Although leaf wilt occurred in both water stress and FOC infection, the physiological responses were different, especially in leaf spatial distribution. PMID- 28911020 TI - Plant Cuttings: news in Botany. PMID- 28911019 TI - Early Arabidopsis root hair growth stimulation by pathogenic strains of Pseudomonas syringae. AB - Background and Aims: Selected beneficial Pseudomonas spp. strains have the ability to influence root architecture in Arabidopsis thaliana by inhibiting primary root elongation and promoting lateral root and root hair formation. A crucial role for auxin in this long-term (1week), long-distance plant-microbe interaction has been demonstrated. Methods: Arabidopsis seedlings were cultivated in vitro on vertical plates and inoculated with pathogenic strains Pseudomonas syringae pv. maculicola (Psm) and P. syringae pv. tomato DC3000 (Pst), as well as Agrobacterium tumefaciens (Atu) and Escherichia coli (Eco). Root hair lengths were measured after 24 and 48h of direct exposure to each bacterial strain. Several Arabidopsis mutants with impaired responses to pathogens, impaired ethylene perception and defects in the exocyst vesicle tethering complex that is involved in secretion were also analysed. Key Results: Arabidopsis seedling roots infected with Psm or Pst responded similarly to when infected with plant growth promoting rhizobacteria; root hair growth was stimulated and primary root growth was inhibited. Other plant- and soil-adapted bacteria induced similar root hair responses. The most compromised root hair growth stimulation response was found for the knockout mutants exo70A1 and ein2. The single immune pathways dependent on salicylic acid, jasmonic acid and PAD4 are not directly involved in root hair growth stimulation; however, in the mutual cross-talk with ethylene, they indirectly modify the extent of the stimulation of root hair growth. The Flg22 peptide does not initiate root hair stimulation as intact bacteria do, but pretreatment with Flg22 prior to Psm inoculation abolished root hair growth stimulation in an FLS2 receptor kinase-dependent manner. These early response phenomena are not associated with changes in auxin levels, as monitored with the pDR5::GUS auxin reporter. Conclusions: Early stimulation of root hair growth is an effect of an unidentified component of living plant pathogenic bacteria. The root hair growth response is triggered in the range of hours after bacterial contact with roots and can be modulated by FLS2 signalling. Bacterial stimulation of root hair growth requires functional ethylene signalling and an efficient exocyst-dependent secretory machinery. PMID- 28911021 TI - Effects of Lifestyle Modification on an Exaggerated Blood Pressure Response to Exercise in Normotensive Females. AB - BACKGROUND: This study was designed to examine the effects of a lifestyle modification on the improvement in an exaggerated systolic blood pressure (SBP) response to exercise in normotensive females. METHODS: The subjects were 78 normotensive females with (n = 25) and without (n = 53) an exaggerated SBP response to exercise who were not taking any medications. An exaggerated SBP response to exercise was defined according to the criteria of the Framingham Study (peak SBP: >=190 mm Hg). A lifestyle modification program consisting of aerobic exercise and diet counseling was conducted for 12 weeks. The brachial ankle pulse wave velocity (baPWV), plasma nitrate/nitrite (NOx), plasma thiobarbituric acid-reactive substances (TBARS), high-sensitivity C-reactive protein, fibrinogen levels, and the white blood cell (WBC) counts were measured before and after 12-week intervention. RESULTS: After 12-week intervention, the exercise-induced SBP elevation decreased in an exaggerated SBP response group (P < 0.05). In addition, the plasma NOx significantly increased, and the WBC counts and plasma TBARS decreased in an exaggerated SBP response group (P < 0.05). In an exaggerated SBP response group, a stepwise multiple regression analysis showed that the percent change in exercise-induced SBP elevation was independently associated with the percent changes in the plasma NOx level and baPWV (r2 = 0.647, P < 0.0001). CONCLUSIONS: These results suggest that a lifestyle modification is considered to be important for reducing an exaggerated SBP response to exercise by improving the arterial stiffness and nitric oxide bioavailability. PMID- 28911022 TI - Hypertensive Cardiovascular Risk: Pulsatile Hemodynamics, Gender, and Therapeutic Implications. AB - PURPOSE: In recent years, the predictive value of 2 pulsatile parameters has been extensively studied in hypertension: aortic stiffness and pulse pressure (PP) amplification. Aortic stiffness is an index of aortic rigidity and PP amplification is the ratio between central and brachial PP, an indirect evaluation of wave reflections. Both are safe, independent, noninvasive predictors of overall and cardiovascular risk. Our purpose is to determine the validity of these parameters in 2 different circumstances: gender and therapeutic implications. AGE EFFECT: Studies have shown that whereas steady mean arterial pressure is significantly higher in men than in women, pulsatile pressure largely predominates in women, mostly in older age and as a consequence of short stature. Gender differences require more extensive investigation due to the disparities of dose-response ranging among populations and the contribution of ethnic factors, frequently based on individual origin. REGARDING THERAPEUTIC IMPLICATIONS: Many questions have yet to be resolved. First, the prognosis of antihypertensive therapy is largely based on blood pressure reduction but also requires evaluation of arterial rigidity and wave reflections to achieve adequate therapeutic "de stiffening." The most effective approach appears to be the combination of angiotensin- and calcium-channel blockade, in certain cases associated with diuretic compounds. Second, antialdosterone drugs can be useful, but it is their antifibrotic more than their antihypertensive effect that appears effective. Third, prevention of comorbidities, such as those associating hypertension, diabetes, and/or kidney damage, should become primary targets for drug treatment. PMID- 28911023 TI - Using Carbon Monoxide Releasing Molecules in Models of Preeclampsia: When Should We Be Monitoring Vascular Effects? PMID- 28911024 TI - Ambulatory Pulse Pressure Predicts the Development of Left Ventricular Diastolic Dysfunction in Over 20 Years of Follow-up. AB - BACKGROUND: Ambulatory blood pressure (ABP) has been shown to have an association with left ventricular diastolic dysfunction (LVDD) in cross-sectional assessments. We evaluated the association between ABP measurement (ABPM) and the development of LVDD during over 20 years of follow up in 414 middle-aged subjects from OPERA cohort. METHODS: ABPM, clinical, and anthropometric measurements were performed in baseline. Echocardiographic measurements were performed at baseline and during follow-up and E/E' >=15 was considered indicating significant LVDD. RESULTS: Several baseline clinical characteristics (age, female gender, short stature, body mass index, prevalence of diabetes, in-office systolic BP (SBP), in office pulse pressure (PP), N-terminal pro-atrial natriuretic peptide, and the use of antihypertensive therapy) were associated with the development of LVDD. Baseline 24-hour mean, daytime mean or nighttime mean SBP or diastolic BP were not associated with the development of LVDD, neither were different circadian BP profiles. Instead 24-hour mean, daytime mean and nighttime mean PP showed significant association with the development of LVDD (P from <0.001 to 0.001) even after adjustment with significant baseline clinical characteristics (P from 0.001 to 0.016). CONCLUSION: These findings suggest that ambulatory PP has an independent predictive value in the development of LVDD during over 20 years of follow-up. PMID- 28911025 TI - Home Blood Pressure Variability From the Stored Memory Is Correlated With Albuminuria, but From the Logbook Is not. AB - BACKGROUND: The aim of this study was to evaluate whether the mean and the variability of home blood pressure (HBP) from the logbook correlate with albuminuria as well as HBP from the stored memory in patients with type 2 diabetes. METHODS: This study is a post hoc analysis of a cross-sectional multicenter study. HBP measurements were performed for 14 consecutive days in 276 patients with type 2 diabetes. Patients were requested to write down their HBP values in logbooks and were not informed about the memory function of their BP monitoring devices. RESULTS: HBP values from the logbook were significantly lower and less variable than those from the stored memory. The mean of morning systolic BP (SBP) from the logbook (adjusted beta = 0.326, P < 0.001) as well as that from the stored memory (adjusted beta = 0.336, P < 0.0001) was significantly associated with logarithm of urinary albumin excretion (UAE). The SD of morning SBP (adjusted beta = 0.134, P = 0.017) from the stored memory was significantly associated with logarithm of UAE, in contrast, the SD of morning SBP (adjusted beta = 0.104, P = 0.057) from the logbook was not associated with logarithm of UAE. CONCLUSIONS: Patients with type 2 diabetes might report inaccurate HBP measurements and, as a result, the variability of HBP from the logbook is underestimated and poorly correlates with albuminuria. The use of stored BP measurements is recommended to accurately evaluate the relationship with diabetic nephropathy. PMID- 28911026 TI - Response to: Using Carbon Monoxide Releasing Molecules in Models of Pre Eclampsia: When Should We Be Monitoring Vascular Effects? PMID- 28911027 TI - Green nail syndrome. PMID- 28911028 TI - Laundry Blues: a case of methemoglobinemia with laundry detergent and Tylenol ingestion. PMID- 28911029 TI - Necrotizing fasciitis caused by genogroup * Neisseria meningitidis. PMID- 28911030 TI - Whole-genome sequencing identifies nosocomial transmission of extra-pulmonary M. tuberculosis-response. PMID- 28911032 TI - After the Fukushima nuclear disaster of 2011-is Japan better prepared-perhaps not. PMID- 28911031 TI - Flecainide overdose-induced Brugada electrocardiogram pattern. PMID- 28911033 TI - Formulation of chitosan with the polyepitope HIV-1 protein candidate vaccine efficiently boosts cellular immune responses in mice. AB - Human immunodeficiency virus-1 (HIV-1) continues to be a major global public health issue and priority. Despite the variety of antiretroviral therapies, it seems that an effective vaccine against HIV-1 is still very necessary. An ideal HIV-1 vaccine should be able to elicit both humoral and cellular immunities. In this respect, polyepitope vaccines, incorporated from several conserved regions of HIV-1 proteins, have received much attention recently. Herein, the immunogenicity of the HIV-1 polyepitope protein-based candidate vaccines was evaluated in BALB/c mice. Following the plasmid (pET23a-HIV-1-tat/pol/gag/env) preparation and transformation, the recombinant protein expression was optimized in Escherichia coli BL21 (DE3) host cells. After the HIV-1-top4 protein purification, chitosan and alum adjuvants were added to the vaccines formulations to reinforce the immunogenicity of the candidate vaccines. Mice were subcutaneously immunized three times at 2-week intervals with the candidate vaccines and the elicitation of both humoral and cellular immune responses were investigated. Taken together, the results showed that chitosan adjuvanted candidate vaccine conferred a stronger immunogenicity and elicited higher cellular responses than other candidate vaccines (P < 0.05). Thereby, it seems that co-utilizing of potent adjuvants with the HIV-1 polyepitope protein vaccines can help to open new avenues for strategies for HIV/AIDS vaccine design. PMID- 28911034 TI - Planktonic free-living amoebae susceptibility to dental unit waterlines disinfectants. AB - A high diversity of microorganisms is encountered inside dental unit waterlines (DUWL). Among those the presence of free-living amoebae (FLA) appears currently underestimated, although human infections may occur due to contact with FLA contaminated water during dental cares. In order to limit microbial DUWL contamination, disinfectants are provided by dental unit manufacturer, however, with limited documentation on their activities against FLA. The aim of this study was to evaluate the efficiency of three commercial DUWL disinfectants: the Calbenium(c) (Airel, Champigny-sur-Marne, France), the Oxygenal 6(c) (Kavo, Biberach, Germany) and the Sterispray(c) (Gammasonic, Billom, France), against two FLA species, i.e. Acanthamoeba castellanii and Vermamoeba vermiformis alone or co-cultured with Pseudomonas aeruginosa and Candida albicans at concentrations ranging from 0% to 5% (v/v). Results showed varied efficacies of disinfectants: the Oxygenal 6(c) did not exhibit FLA killing activity, while the Sterispray(c) and the Calbenium(c) displayed concentration- and species-dependent activities with a maximum eradication rates of 100% and 86%, and 79% and 97% for A. castellani and V. vermiformis, respectively. None of the disinfectants were able to totally eradicate FLA at concentrations recommended by manufacturers. Present results highlight unsatisfactory anti-FLA activities of 3 DUWL disinfectant preparations advocating deeper investigation of antimicrobial spectra of commercial disinfectants in use for DUWL maintenance. PMID- 28911035 TI - Evaluation of PE_PGRS33 as a potential surface target for humoral responses against Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) PE_PGRS33 is a surface-exposed protein that was shown to interact with Toll-like receptor 2 on host macrophages to induce inflammatory signals and promote entry in macrophages. In this study, we investigated PE_PGRS33 as a potential target of a humoral response aimed at hampering key processes in tuberculosis pathogenesis. PE_PGRS33 protein was successfully expressed and purified under native condition in Escherichia coli. The purified protein retained its native functional and biological properties, showing the ability to elicit proinflammatory signals in murine and human macrophages. Interestingly, a polyclonal antiserum raised against native PE_PGRS33 showed no cross-reactions with other mycobacterial proteins. The anti PE_PGRS33 serum was also able to inhibit Mtb entry into macrophages, but it did not reduce entry of the MtbDeltape_pgrs33 strain. Addition of native recombinant PE_PGRS33 to the MtbDeltape_pgrs33 strain during infection restored the Mtb wild type entry phenotype in macrophage. Moreover, the anti-PE_PGRS33 serum was able to neutralize the proinflammatory activity of PE_PGRS33 in vitro. Furthermore, mice immunized with native recombinant PE_PGRS33, but not with a DNA vaccine expressing PE_PGRS33, were able to restrict M. smegmatis in vivo. These results highlight the potential use of PE_PGRS33 as a target of a neutralizing humoral response against tuberculosis. PMID- 28911036 TI - High-fat-diet-induced obesity upregulates the expression of lymphoid chemokines and promotes the formation of gastric lymphoid follicles after Helicobacter suis infection. AB - Helicobacter suis colonizes the stomachs of a variety of animals, including humans, and is more likely than other Helicobacter species to induce gastric mucosa-associated lymphoid tissue lymphoma. Obesity is a low-grade chronic inflammatory state in which the induction of a chemokine network contributes to a variety of diseases. However, the effect of obesity on the development of gastric MALT in the presence of H. suis infection remains unclear. Here, we reveal that high-fat-diet-induced obesity upregulates the expression of lymphoid chemokines in the stomach and accelerates the H. suis infection-induced formation of gastric lymphoid follicles, potentially via a mechanism that involves the activation of the nuclear factor kappa B (NF-kappaB) signaling pathway. These findings provide novel insight into the pathogenesis of obesity-related diseases, especially those induced by Helicobacter infection. PMID- 28911037 TI - A biologically conjugated polysaccharide vaccine delivered by attenuated Salmonella Typhimurium provides protection against challenge of avian pathogenic Escherichia coli O1 infection. AB - Avian pathogenic Escherichia coli (APEC) causes avian airsacculitis and colibacillosis, resulting in significant economic loss to the poultry industry. O1, O2 and O78 are the three predominant serotypes. O-antigen of lipopolysaccharide is serotype determinant and highly immunogenic, and O-antigen polysaccharide-based vaccines have great potential for preventing bacterial infections. In this study, we utilized a novel yeast/bacterial shuttle vector pSS26 to clone the 10.8 kb operon synthesizing APEC O1 O-antigen polysaccharide. The resulting plasmid was introduced into attenuated Salmonella vaccines to deliver this O-antigen polysaccharide. O1 O-antigen was stably synthesized in attenuated Salmonella Typhimurium, demonstrated by slide agglutination, silver staining and western blot. Our results also showed that APEC O1 O-antigen produced in the Salmonella vaccines was attached to bacterial cell surfaces, and the presence of heterologous O-antigen did not alter the resistance to surface acting agents. Furthermore, birds immunized orally or intramuscularly provided protection against the virulent O1 APEC challenge. Salmonella vaccines carrying APEC O1 O-antigen gene cluster also induced high IgG and IgA immune responses against lipopolysaccharide from the APEC O1 strain. The use of our novel shuttle vector facilitates cloning of large DNA fragments, and this strategy could pave the way for production of Salmonella-vectored vaccines against prevalent APEC serotypes. PMID- 28911038 TI - Spliceman2: a computational web server that predicts defects in pre-mRNA splicing. AB - Summary: Most pre-mRNA transcripts in eukaryotic cells must undergo splicing to remove introns and join exons, and splicing elements present a large mutational target for disease-causing mutations. Splicing elements are strongly position dependent with respect to the transcript annotations. In 2012, we presented Spliceman, an online tool that used positional dependence to predict how likely distant mutations around annotated splice sites were to disrupt splicing. Here, we present an improved version of the previous tool that will be more useful for predicting the likelihood of splicing mutations. We have added industry-standard input options (i.e. Spliceman now accepts variant call format files), which allow much larger inputs than previously available. The tool also can visualize the locations-within exons and introns-of sequence variants to be analyzed and the predicted effects on splicing of the pre-mRNA transcript. In addition, Spliceman2 integrates with RNAcompete motif libraries to provide a prediction of which trans -acting factors binding sites are disrupted/created and links out to the UCSC genome browser. In summary, the new features in Spliceman2 will allow scientists and physicians to better understand the effects of single nucleotide variations on splicing. Availability and implementation: Freely available on the web at http://fairbrother.biomed.brown.edu/spliceman2 . Website implemented in PHP framework-Laravel 5, PostgreSQL, Apache, and Perl, with all major browsers supported. Contact: william_fairbrother@brown.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28911039 TI - Methodological Approaches to Assessing Tobacco Health Warnings. PMID- 28911040 TI - Future Research Priorities in Fungal Resistance. AB - Improved understanding of basic mycological, pharmacological, and immunological processes has led to important advances in the diagnosis and treatment of invasive fungal infections. However, the rise of fungi that are resistant to existing antifungal agents poses a substantial threat to human health. Addressing this expanding problem is an urgent priority for the international research community. In this article, we highlight important diagnostic and therapeutic advances that address the rise of resistant fungi as well as new public health initiatives that warrant further investigation to help curb the spread of these potentially lethal organisms. PMID- 28911041 TI - Culture-Independent Molecular Methods for Detection of Antifungal Resistance Mechanisms and Fungal Identification. AB - Resistance to azoles and echinocandins has emerged as a significant factor affecting the clinical management of patients with invasive fungal infections. Immunosuppressed patients at high risk for invasive fungal infections often have prolonged or repeated exposure to antifungals resulting in either the well documented selection of naturally occurring, less susceptible fungal species, or the in situ development of specific resistance mechanisms. Nucleic acid-based molecular diagnostics are particularly well suited for the rapid detection of low abundance fungal pathogens and identification of the infecting pathogen to the genus and species levels, as well as assessment of resistance mechanisms. A wide range of molecular probing technologies involving real-time polymerase chain reaction (PCR) assays that facilitate direct analysis of a single infecting genome in a sterile blood specimen are available and have recently been commercialized (eg, Roche LightCycler SeptiFast and T2 Biosystems T2Candida). One of the exciting applications of molecular technology is the direct detection of specific resistance mechanisms that evolve during therapy. In principle, the detection of resistance mechanisms that have been independently validated to cause resistance provides a culture-independent biomarker for potential therapeutic failure. The emergence of real-time PCR assays utilizing allele specific molecular detection technology that is highly sensitive, robust, and high-throughput has the potential to improve patient care by providing faster detection of drug-resistant infecting strains and to help inform therapeutic management. PMID- 28911042 TI - Novel Agents and Drug Targets to Meet the Challenges of Resistant Fungi. AB - The emergence of drug-resistant fungi poses a major threat to human health. Despite advances in preventive, diagnostic, and therapeutic interventions, resistant fungal infections continue to cause significant morbidity and mortality in patients with compromised immunity, underscoring the urgent need for new antifungal agents. In this article, we review the challenges associated with identifying broad-spectrum antifungal drugs and highlight novel targets that could enhance the armamentarium of agents available to treat drug-resistant invasive fungal infections. PMID- 28911043 TI - Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment. AB - Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. PMID- 28911044 TI - Antifungal Resistance: An Emerging Reality and A Global Challenge. PMID- 28911045 TI - Azole-Resistant Aspergillosis: Epidemiology, Molecular Mechanisms, and Treatment. AB - Aspergillus fumigatus remains the most common species in all pulmonary syndromes, followed by Aspergillus flavus which is a common cause of allergic rhinosinusitis, postoperative aspergillosis and fungal keratitis. The manifestations of Aspergillus infections include invasive aspergillosis, chronic pulmonary aspergillosis and bronchitis. Allergic manifestations of inhaled Aspergillus include allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Triazoles are the mainstay of therapy against Aspergillus infections for treatment and prophylaxis. Lately, increased azole resistance in A. fumigatus has become a significant challenge in effective management of aspergillosis. Earlier studies have brought to light the contribution of non-cyp51 mutations along with alterations in cyp51A gene resulting in azole-resistant phenotypes of A. fumigatus. This review highlights the magnitude of azole-resistant aspergillosis and resistance mechanisms implicated in the development of azole-resistant A. fumigatus and address the therapeutic options available. PMID- 28911046 TI - Animal Models for Studying Triazole Resistance in Aspergillus fumigatus. AB - Infections caused by triazole-resistant Aspergillus fumigatus are associated with a higher probability of treatment failure and mortality. Because clinical experience in managing these infections is still limited, mouse models of invasive aspergillosis fulfill a critical void for studying treatment regimens designed to overcome resistance. The type of immunosuppression, the route of infection, the timing of antifungal administration, and the end points used to assess antifungal activity affect the interpretation of data from these models. Nevertheless, these models provide important insights that help guide treatment decisions in patients with triazole-resistant invasive aspergillosis. Animal models confirmed that a high triazole minimal inhibitory concentration corresponded with triazole treatment failure and that the efficacy of other classes of drugs, such as the polyenes and echinocandins, was not affected by the presence of triazole resistance mutations. Furthermore, the feasibility of triazole dose escalation, combination therapy, and prophylaxis were explored as strategies to overcome resistance. PMID- 28911047 TI - The Role of In Vitro Susceptibility Testing in the Management of Candida and Aspergillus. AB - Antifungal susceptibility testing has evolved from a research technique to a standardized and well-validated tool for the clinical management of fungal infections and for epidemiological studies. Genetic mutations and phenotypic resistance in vitro have been shown to correlate with clinical outcomes and treatment failures, and this in turn has led to the creation of clinical breakpoints and, more recently, epidemiological cutoff values for clinically relevant fungal pathogens. Resistance mechanisms for Candida and Aspergillus species have been extensively described and their corresponding genetic mutations can now be readily detected. Epidemiological studies have been able to detect the emergence of regional clonal and nonclonal resistance in several countries. The clinical microbiology laboratory is expected to transition from culture and traditional susceptibility testing to molecular methods for detection, identification, and resistance profiling over the next 5-10 years. PMID- 28911048 TI - What Can Different Motor Circuits Tell Us About Psychosis? An RDoC Perspective. AB - Signs of motor dysfunction are evidenced across a range of psychiatric disorders including schizophrenia. Historically, these features have been neglected but emerging theoretical and methodological advancements have shed new light on the utility of considering movement abnormalities. Indeed, the National Institute of Mental Health Research Domain Criteria initiative has recently met to develop a Motor Systems Domain. This reflects a growing appreciation for the enhanced reliability and validity that can come along with evaluating disturbances relevant to psychiatric illnesses from multiple levels of analysis, and conceptualizing these domains with respect to the complexity of their role in a broader integrated system (ie, weighing contributions and interactions between the cognitive, affective, and motor domains). This article discusses motor behaviors and seeks to explain how research into basal ganglia, cerebellar, and cortico-motor circuit function/dysfunction, grounded in brain circuit-motor behavior relationships, can elucidate our understanding of pathophysiology, provide vital links to other key systems of interest, significantly improve identification and classification, and drive development of targeted individualized treatments. PMID- 28911049 TI - Aberrant Hyperconnectivity in the Motor System at Rest Is Linked to Motor Abnormalities in Schizophrenia Spectrum Disorders. AB - Motor abnormalities are frequently observed in schizophrenia and structural alterations of the motor system have been reported. The association of aberrant motor network function, however, has not been tested. We hypothesized that abnormal functional connectivity would be related to the degree of motor abnormalities in schizophrenia. In 90 subjects (46 patients) we obtained resting stated functional magnetic resonance imaging (fMRI) for 8 minutes 40 seconds at 3T. Participants further completed a motor battery on the scanning day. Regions of interest (ROI) were cortical motor areas, basal ganglia, thalamus and motor cerebellum. We computed ROI-to-ROI functional connectivity. Principal component analyses of motor behavioral data produced 4 factors (primary motor, catatonia and dyskinesia, coordination, and spontaneous motor activity). Motor factors were correlated with connectivity values. Schizophrenia was characterized by hyperconnectivity in 3 main areas: motor cortices to thalamus, motor cortices to cerebellum, and prefrontal cortex to the subthalamic nucleus. In patients, thalamocortical hyperconnectivity was linked to catatonia and dyskinesia, whereas aberrant connectivity between rostral anterior cingulate and caudate was linked to the primary motor factor. Likewise, connectivity between motor cortex and cerebellum correlated with spontaneous motor activity. Therefore, altered functional connectivity suggests a specific intrinsic and tonic neural abnormality in the motor system in schizophrenia. Furthermore, altered neural activity at rest was linked to motor abnormalities on the behavioral level. Thus, aberrant resting state connectivity may indicate a system out of balance, which produces characteristic behavioral alterations. PMID- 28911051 TI - Developing a Motor Systems Domain for the NIMH RDoC Program. PMID- 28911052 TI - Alternative Perspectives on Police Encounters and Psychotic Experiences [Invited Commentary on DeVylder et al, "Psychotic Experiences in the Context of Police Victimization"]. PMID- 28911053 TI - Co-ordination of NDH and Cup proteins in CO2 uptake in cyanobacterium Synechocystis sp. PCC 6803. AB - High and low affinity CO2-uptake systems containing CupA (NDH-1MS) and CupB (NDH 1MS'), respectively, have been identified in Synechocystis sp. PCC 6803, but it is yet unknown how the complexes function in CO2 uptake. In this work, we found that deletion of cupB significantly lowered the growth of cells, and deletion of both cupA and cupB seriously suppressed the growth below pH 7.0 even under 3% CO2. The rate of photosynthetic oxygen evolution was decreased slightly by deletion of cupA but significantly by deletion of cupB and more severely by deletion of both cupA and cupB, especially in response to changed pH conditions under 3% CO2. Furthermore, we found that assembly of CupB into NDH-1MS' was dependent on NdhD4 and NdhF4. NDH-1MS' was not affected in the NDH-1MS degradation mutant and NDH-1MS was not affected in the NDH-1MS'-degradation mutants, indicating the existence of independent CO2-uptake systems under high CO2 conditions. The light-induced proton gradient across thylakoid membranes was significantly inhibited in ndhD-deletion mutants, suggesting that NdhDs functions in proton pumping. The carbonic anhydrase activity was suppressed partly in the cupA- or cupB-deletion mutant but severely in the mutant with both cupA and cupB deletion, indicating that CupA and CupB function in conversion of CO2 to HCO3-. In turn, deletion of cup genes lowered the transthylakoid membrane proton gradient and deletion of ndhDs decreased the CO2 hydration. Our results suggest that NDH-1M provides an alkaline region to activate Cup proteins involved in CO2 uptake. PMID- 28911054 TI - The algal pyrenoid: key unanswered questions. AB - The confinement of Rubisco in a chloroplast microcompartment, or pyrenoid, is a distinctive feature of most microalgae, and contributes to perhaps ~30 Pg of carbon fixed each year, yet our understanding of pyrenoid composition, regulation, and function remains fragmentary. Recently, significant progress in understanding the pyrenoid has arisen from studies using mutant lines, mass spectrometric analysis of isolated pyrenoids, and advanced ultrastructural imaging of the microcompartment in the model alga Chlamydomonas. The emergence of molecular details in other lineages provides a comparative framework for this review, and evidence that most pyrenoids function similarly, even in the absence of a common ancestry. The objective of this review is to explore pyrenoid diversity throughout key algal lineages and discuss whether common ultrastructural and cellular features are indicative of common functional processes. By characterizing pyrenoid origins in terms of mechanistic and structural parallels, we hope to provide key unanswered questions which will inform future research directions. PMID- 28911050 TI - Motor Abnormalities: From Neurodevelopmental to Neurodegenerative Through "Functional" (Neuro)Psychiatric Disorders. AB - Background: Motor abnormalities (MAs) of severe mental disorders have been traditionally neglected both in clinical practice and research, although they are an increasing focus of attention because of their clinical and neurobiological relevance. For historical reasons, most of the literature on MAs has been focused to a great extent on schizophrenia, and as a consequence their prevalence and featural properties in other psychiatric or neuropsychiatric disorders are poorly known. In this article, we evaluated the extent to which catatonic, extrapyramidal and neurological soft signs, and their associated clinical features, are present transdiagnostically. Methods: We examined motor-related features in neurodevelopmental (schizophrenia, obsessive compulsive disorder, autism spectrum disorders), "functional" (nonschizophrenic nonaffective psychoses, mood disorders) and neurodegenerative (Alzheimer's disease) disorders. Examination of the literature revealed that there have been very few comparisons of motor-related features across diagnoses and we had to rely mainly in disorder specific studies to compare it transdiagnostically. Results: One or more motor domains had a substantial prevalence in all the diagnoses examined. In "functional" disorders, MAs, and particularly catatonic signs, appear to be markers of episode severity; in chronic disorders, although with different degree of strength or evidence, all motor domains are indicators of both disorder severity and poor outcome; lastly, in Alzheimer's disease they are also indicators of disorder progression. Conclusions: MAs appear to represent a true transdiagnostic domain putatively sharing neurobiological mechanisms of neurodevelopmental, functional or neurodegenerative origin. PMID- 28911055 TI - Pyrenoid loss in Chlamydomonas reinhardtii causes limitations in CO2 supply, but not thylakoid operating efficiency. AB - The pyrenoid of the unicellular green alga Chlamydomonas reinhardtii is a microcompartment situated in the centre of the cup-shaped chloroplast, containing up to 90% of cellular Rubisco. Traversed by a network of dense, knotted thylakoid tubules, the pyrenoid has been proposed to influence thylakoid biogenesis and ultrastructure. Mutants that are unable to assemble a pyrenoid matrix, due to expressing a vascular plant version of the Rubisco small subunit, exhibit severe growth and photosynthetic defects and have an ineffective carbon-concentrating mechanism (CCM). The present study set out to determine the cause of photosynthetic limitation in these pyrenoid-less lines. We tested whether electron transport and light use were compromised as a direct structural consequence of pyrenoid loss or as a metabolic effect downstream of lower CCM activity and resulting CO2 limitation. Thylakoid organization was unchanged in the mutants, including the retention of intrapyrenoid-type thylakoid tubules, and photosynthetic limitations associated with the absence of the pyrenoid were rescued by exposing cells to elevated CO2 levels. These results demonstrate that Rubisco aggregation in the pyrenoid functions as an essential element for CO2 delivery as part of the CCM, and does not play other roles in maintenance of photosynthetic membrane energetics. PMID- 28911056 TI - Carbon-concentrating mechanisms in seagrasses. AB - Seagrasses are unique angiosperms that carry out growth and reproduction submerged in seawater. They occur in at least three families of the Alismatales. All have chloroplasts mainly in the cells of the epidermis. Living in seawater, the supply of inorganic carbon (Ci) to the chloroplasts is diffusion limited, especially under unstirred conditions. Therefore, the supply of CO2 and bicarbonate across the diffusive boundary layer on the outer side of the epidermis is often a limiting factor. Here we discuss the evidence for mechanisms that enhance the uptake of Ci into the epidermal cells. Since bicarbonate is plentiful in seawater, a bicarbonate pump might be expected; however, the evidence for such a pump is not strongly supported. There is evidence for a carbonic anhydrase outside the outer plasmalemma. This, together with evidence for an outward proton pump, suggests the possibility that local acidification leads to enhanced concentrations of CO2 adjacent to the outer tangential epidermal walls, which enhances the uptake of CO2, and this could be followed by a carbon-concentrating mechanism (CCM) in the cytoplasm and/or chloroplasts. The lines of evidence for such an epidermal CCM are discussed, including evidence for special 'transfer cells' in some but not all seagrass leaves in the tangential inner walls of the epidermal cells. It is concluded that seagrasses have a CCM but that the case for concentration of CO2 at the site of Rubisco carboxylation is not proven. PMID- 28911057 TI - Cyanobacteria vs green algae: which group has the edge? PMID- 28911058 TI - Overcoming adversity through diversity: aquatic carbon concentrating mechanisms. PMID- 28911059 TI - Forcing the vicious circle: sarcopenia increases toxicity, decreases response to chemotherapy and worsens with chemotherapy. AB - Sarcopenia has recently emerged as a new condition that, independently from malnutrition, may adversely affect the prognosis of cancer patients. Purpose of this narrative review is to define the prevalence of sarcopenia in different primaries, its role in leading to chemotherapy toxicity and decreased compliance with the oncological therapy and the effect of some drugs on the onset of sarcopenia. Finally, the review aims to describe the current approaches to restore the muscle mass through nutrition, exercise and anti-inflammatory agents or multimodal programmes with a special emphasis on the results of randomized controlled trials. The examination of the computed tomography scan at the level of the third lumbar vertebra-a common procedure for staging many tumours-has allowed the oncologist to evaluate the muscle mass and to collect many retrospective data on the prevalence of sarcopenia and its clinical consequences. Sarcopenia is a condition affecting a high percentage of patients with a range depending on type of primary tumour and stage of disease. It is noteworthy that patients may be sarcopenic even if their nutritional status is apparently maintained or they are obese. Sarcopenic patients exhibited higher chemotherapy toxicity and poorer compliance with oncological treatments. Furthermore, several antineoplastic drugs appeared to worsen the sarcopenic status. Therapeutic approaches are several and this review will focus on those validated by randomized controlled trials. They include the use of omega-3-enriched oral nutritional supplements and orexigenic agents, the administration of adequate high-protein regimens delivered enterally or parenterally, and programmes of physical exercise. Better results are expected combining different procedures in a multimodal approach. In conclusion, there are several premises to prevent/treat sarcopenia. The oncologist should coordinate this multimodal approach by selecting priorities and sequences of treatments and then involving a nutrition health care professional or a physical therapist depending on the condition of the single patient. PMID- 28911060 TI - Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire. AB - Background: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. Patients and methods: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). Results: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. Conclusion: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo SCT for NHL. PMID- 28911062 TI - TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial. AB - Background: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. Methods: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. Results: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. Conclusions: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation. PMID- 28911063 TI - Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. AB - Background: The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. Materials and methods: We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. Results: Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. Conclusion: A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors. PMID- 28911061 TI - International cancer seminars: a focus on esophageal squamous cell carcinoma. AB - The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts. PMID- 28911064 TI - Cancer mortality predictions for 2017 in Latin America. AB - Background: From most recent available data, we predicted cancer mortality statistics in selected Latin American countries for the year 2017, with focus on lung cancer. Materials and methods: We obtained death certification data from the World Health Organization and population data from the Pan American Health Organization database for all neoplasms and selected cancer sites. We derived figures for Argentina, Brazil, Chile, Colombia, Cuba, Mexico and Venezuela. Using a logarithmic Poisson count data joinpoint model, we estimated number of deaths and age-standardized (world population) mortality rates in 2017. Results: Total cancer mortality rates are predicted to decline in all countries. The highest mortality rates for 2017 are in Cuba, i.e. 132.3/100 000 men and 93.3/100 000 women. Mexico had the lowest predicted rates, 64.7/100 000 men and 60.6/100 000 women. In contrast, the total number of cancer deaths is expected to rise due to population ageing and growth. Men showed declines in lung cancer trends in all countries and age groups considered, while only Colombian and Mexican women had downward trends. Stomach and (cervix) uteri rates are predicted to continue their declines, though mortality from these neoplasms remains comparatively high. Colorectal, breast and prostate cancer rates were predicted to decline moderately, as well as leukaemias. There was no clear pattern for pancreatic cancer. Between 1990 and 2017 about 420 000 cancer deaths were avoided in 5 of the 7 countries, no progress was observed in Brazil and Cuba. Conclusion: Cancer mortality rates for 2017 in seven selected Latin American countries are predicted to decline, though there was appreciable variability across countries. Mortality from major cancers-including lung and prostate-and all cancers remains comparatively high in Cuba, indicating the need for improved prevention and management. PMID- 28911065 TI - Development of an integrated electronic platform for patient self-report and management of adverse events during cancer treatment. AB - Background: Significant adverse events (AE) during cancer therapy disrupt treatment and escalate to emergency admissions. Approaches to improve the timeliness and accuracy of AE reporting may improve safety and reduce health service costs. Reporting AE via patient reported outcomes (PROs), can improve clinician-patient communication and making data available to clinicians in 'real time' using electronic PROs (ePROs) could potentially transform clinical practice by providing easily accessible records to guide treatment decisions. This manuscript describes the development of eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice) is a National Institute for Health Research-funded programme, a system for patients to self-report and manage AE online during and after cancer treatment. Materials and methods: A multidisciplinary team of IT experts, staff and patients developed using agile principles a secure web application interface (QStore) between an existing online questionnaire builder (QTool) displaying real-time ePRO data to clinicians in the electronic patient record at Leeds Teaching Hospitals NHS Trust. Hierarchical algorithms were developed corresponding to Common Terminology Criteria for Adverse Events grading using the QTool question dependency function. Patient advocates (N = 9), patients (N = 13), and staff (N = 19) usability tested the system reporting combinations of AE. Results: The eRAPID system allows patients to report AE from home on PC, tablet or any web enabled device securely during treatment. The system generates immediate self-management advice for low or moderate AE and for severe AE advice to contact the hospital immediately. Clinicians can view patient AE data in the electronic patient record and receive email notifications when patients report severe AE. Conclusions: Evaluation of the system in a randomised controlled trial in breast, gynaecological and colorectal cancer patients undergoing systemic therapy is currently underway. To adapt eRAPID for different treatment groups, pilot studies are being undertaken with patients receiving pelvic radiotherapy and upper gastrointestinal surgery. ISRCTN88520246. PMID- 28911066 TI - Prevention of chemotherapy toxicity by agents that neutralize or degrade cell free chromatin. AB - Background: Toxicity associated with chemotherapy is a major therapeutic challenge and is caused by chemotherapy-induced DNA damage and inflammation. We have recently reported that cell-free chromatin (cfCh) fragments released from dying cells can readily enter into healthy cells of the body to integrate into their genomes and induce DNA double-strand breaks, apoptosis and inflammation in them. We hypothesized that much of the toxicity of chemotherapy might be due to release of large quantities of cfCh from dying cells that could trigger an exaggerated DNA damage, apoptotic and inflammatory response in healthy cells over and above that caused by the drugs themselves. Methods: We tested this hypothesis by administering cfCh neutralizing/degrading agents namely, anti-histone antibody complexed nanoparticles, DNase I and a novel DNA degrading agent-Resveratrol-Cu concurrently with five different chemotherapeutic agents to examine if chemotherapy-induced toxicity could be minimized. Results: We observed (i) significant reduction in chemotherapy-induced surge of cfCh in blood; (ii) significant reduction in chemotherapy-induced surge of inflammatory cytokines CRP, IL-6, IFNgamma and TNFalpha in blood; (iii) abolition of chemotherapy induced tissue DNA damage (gammaH2AX), apoptosis (active caspase-3) and inflammation (NFkappaB and IL-6) in multiple organs and peripheral blood mononuclear cells; (iv) prevention of prolonged neutropenia following a single injection of adriamycin and (v) significant reduction in death following a lethal dose of adriamycin. Conclusion: Our results suggest that toxicity of chemotherapy is caused to a large extent by cfCh released from dying cells and can be prevented by concurrent treatment with cfCh neutralizing/degrading agents. PMID- 28911067 TI - Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. AB - Background: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. Patients and methods: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. Results: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. Conclusions: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF mutant tumours. ClinicalTrials.gov number: NCT00442637. PMID- 28911068 TI - Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG). AB - Background: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. Patients and methods: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. Results: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. Conclusion: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach. PMID- 28911069 TI - Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment. AB - Background: While tumor-tissue remains the 'gold standard' for genetic analysis in cancer patients, it is challenged with the advent of circulating cell-free tumor DNA (ctDNA) analysis from blood samples. Here, we broaden our previous study on the clinical validation of plasma DNA in metastatic colorectal cancer patients, by evaluating its clinical utility under standard management care. Patients and methods: Concordance and data turnaround-time of ctDNA when compared with tumor-tissue analysis were studied in a real-time blinded prospective multicenter clinical study (n = 140 metastatic colorectal patients). Results are presented according to STARD criteria and were discussed in regard with clinical outcomes of patients. Results: Much more mutations were found by ctDNA analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctDNA analysis instead of 44%, 8.8% and 7.2% by tumor-tissue analysis. Median tumor-tissue data turnaround-time was 16 days while 2 days for ctDNA analysis. Discordant samples analysis revealed that use of biopsy, long delay between tumor tissue and blood collection and resection of the tumor at time of blood draw, tumor site, or type of tissue analyzed seem to affect concordance. Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response (RAS status) and the prognosis (BRAF status) of those discordant patients do not appear contradictory to the mutational status as determined by plasma analysis. Lastly, we present the first distribution profile of the RAS and BRAF hotspot mutations as determined by ctDNA analysis (n = 119), revealing a high proportion of patients with multiple mutations (45% of the population and up to 5 mutations) and only 24% of WT scored patients for both genes. Mutation profile as determined from ctDNA analysis with using various detection thresholds highlights the importance of the test sensitivity. Conclusion: Our study showed that ctDNA could replace tumor-tissue analysis, and also clinical utility of ctDNA analysis by considerably reducing data turnaround time. PMID- 28911071 TI - Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling. AB - Background: Preoperative chemoradiotherapy followed by surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas. Yet, predicting that patients will respond to treatment remains an unmet clinical challenge. Experimental design: Using laser-capture microdissection we isolated RNA from stroma and tumour glands from prospective pre-treatment samples (n = 15). Transcriptomic profiles were obtained hybridising PrimeView Affymetrix arrays. We modelled a carcinoma-associated fibroblast-specific genes filtering data using GSE39396. Results: The analysis of differentially expressed genes of stroma/tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment; codifying mainly for extracellular matrix and ribosomal components. We built a carcinoma-associated fibroblast (CAF) specific classifier with genes showing changes in expression according to the tumour regression grade (FN1, COL3A1, COL1A1, MMP2 and IGFBP5). We assessed these five genes at the protein level by means of immunohistochemical staining in a patient's cohort (n = 38). For predictive purposes we used a leave one-out cross-validated model with a positive predictive value (PPV) of 83.3%. Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the leave-one-out cross-validated regression model improved the classification performance with a PPV of 93.3%. An independent cohort was used for classifier validation (n = 36), achieving a PPV of 88.2%. In a multivariate analysis, the two-protein classifier proved to be the only independent predictor of response. Conclusion: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer. PMID- 28911070 TI - Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. AB - Background: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. Materials and methods: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). Results: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. Conclusions: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. Clinical Trial Number: NCT01086826, www.clinicaltrials.gov. PMID- 28911073 TI - Treating cancer cachexia: an evolving landscape. PMID- 28911072 TI - Oncologist use and perception of large panel next-generation tumor sequencing. AB - Background: Genomic profiling is increasingly incorporated into oncology research and the clinical care of cancer patients. We sought to determine physician perception and use of enterprise-scale clinical sequencing at our center, including whether testing changed management and the reasoning behind this decision-making. Patients and methods: All physicians who consented patients to MSK-IMPACT, a next-generation hybridization capture assay, in tumor types where molecular profiling is not routinely performed were asked to complete a questionnaire for each patient. Physician determination of genomic 'actionability' was compared to an expertly curated knowledgebase of somatic variants. Reported management decisions were compared to chart review. Results: Responses were received from 146 physicians pertaining to 1932 patients diagnosed with 1 of 49 cancer types. Physicians indicated that sequencing altered management in 21% (331/1593) of patients in need of a treatment change. Among those in whom treatment was not altered, physicians indicated the presence of an actionable alteration in 55% (805/1474), however, only 45% (362/805) of these cases had a genomic variant annotated as actionable by expert curators. Further evaluation of these patients revealed that 66% (291/443) had a variant in a gene associated with biologic but not clinical evidence of actionability or a variant of unknown significance in a gene with at least one known actionable alteration. Of the cases annotated as actionable by experts, physicians identified an actionable alteration in 81% (362/445). In total, 13% (245/1932) of patients were enrolled to a genomically matched trial. Conclusion: Although physician and expert assessment differed, clinicians demonstrate substantial awareness of the genes associated with potential actionability and report using this knowledge to inform management in one in five patients. Clinical Trial number: NCT01775072. PMID- 28911074 TI - Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease. AB - Background: Current standard treatment, including non-anthracycline-based chemotherapy and optimal combining of radiotherapy, has dramatically improved outcomes of patients with extranodal natural killer/T-cell lymphoma (ENKTL) during the last decade. This study was conducted to investigate the clinical outcome of ENKTL patients with relapsed or progressive disease after initial current standard therapy. Patients and methods: We retrospectively reviewed patients diagnosed with ENKTL at six centers in four countries (China, France, Singapore, and South Korea) from 1997 to 2015 and analyzed 179 patients who had relapsed or progressed after initial current standard therapy. Results: After a median follow-up of 58.6 months (range 27.9-89.2), the median second progression free survival (PFS) was 4.1 months [95% confidence interval (CI) 3.04-5.16] and overall survival (OS) was 6.4 months (95% CI 4.36-8.51). Multivariate Cox regression analysis revealed that elevated lactate dehydrogenase, multiple extranodal sites (>=2), and presence of B symptoms were associated with inferior OS (P < 0.05). OS and PFS were significantly different according to both prognostic index of natural killer lymphoma (PINK) and PINK-E (Epstein-Barr virus) models. Salvage chemotherapy with l-asparaginase (l-Asp)-based regimens showed a significantly better clinical benefit to response rate and PFS, although it did not lead to OS improvement. First use of l-Asp in the salvage setting and l-Asp rechallenge at least 6 months after initial treatment were the best candidates for salvage l-Asp containing chemotherapy. Conclusions: Most patients with relapsed or refractory ENKTL had poor prognosis with short survival. Further studies are warranted to determine the optimal treatment of patients with relapsed or refractory ENKTL. PMID- 28911075 TI - Metastasis of cancer: when and how? PMID- 28911076 TI - Stromal inflammation, necrosis and HER2 overexpression in ductal carcinoma in situ of the breast: another causality dilemma? PMID- 28911077 TI - Proton therapy in mediastinal Hodgkin lymphoma: moving from dosimetric prediction to clinical evidence. PMID- 28911078 TI - Revival of PI3K inhibitors in non-Hodgkin's lymphoma. PMID- 28911079 TI - Do not throw the baby out with the bathwater: SELECT a personalized, de-escalated lenvatinib schedule allows response in locally advanced DTC while controlling major drug-related bleeding. PMID- 28911080 TI - Rituximab for nivolumab plus ipilimumab-induced encephalitis in a small-cell lung cancer patient. PMID- 28911081 TI - Survival advantage for etoposide/cisplatin over paclitaxel/carboplatin concurrent chemoradiation in patients with inoperable stage III NSCLC: a subgroup analysis for ECOG 2 patients would be of great interest. PMID- 28911082 TI - Borderline resectable pancreatic cancer: an evolving concept. PMID- 28911083 TI - Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis. AB - Background: Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. Patients and methods: We conducted high-depth whole exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. Results: CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. Conclusions: In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis. PMID- 28911084 TI - The 'critical mass' survey of palliative care programme at ESMO designated centres of integrated oncology and palliative care. AB - Background: The ESMO Designated Centres (ESMO-DCs) of Integrated Oncology and Palliative Care (PC) Incentive Programme has grown steadily. We aimed to characterise the level of PC clinical services, education and research at ESMO DCs. Methods: We sent all 184 ESMO-DCs an electronic survey consisting of 78 questions examining the DC characteristics, palliative care clinical programme (structure, processes, and outcomes), primary PC delivery by oncologists, education, research and attitudes and beliefs towards the ESMO-DC programme. Results: The response rate was 83% (152/184). 115 (76%) ESMO-DCs were from Europe, 87 (57%) were tertiary care centres. 136 (90%) had inpatient consultation teams, 135 (89%) had outpatient PC clinics, 107 (71%) had dedicated acute care beds, and 75 (50%) offered community-based PC. An estimated 70% (interquartile range [IQR] 28-80%) of patients with advanced cancer had a PC consultation before death, occurring 90 days before death (median, IQR 40-150 days) for outpatients and 21 days (IQR 14-45 days) for inpatients. 59 (39%) offered PC fellowship programme; 47 (32%) had mandatory PC rotations for oncology fellows. Ninety-nine (65%) had double-boarded palliative oncologists. 118 (78%) of the ESMO-DCs reported that routine symptom screening was offered in the oncology clinic and 30% of patients had documented end-of-life discussions by their oncologists. Most centres (>80%) perceived the ESMO-DC programme to increase their status. Conclusions: The ESMO-DCs had a high level of PC infrastructure and provided access to a large proportion of patients with advanced cancer. The survey supports that the 13 criteria required for ESMO designation set a robust framework for integration, stimulated investment of resources into some palliative care programmes prior to accreditation, and raised the interest about palliative care among clinicians, trainees and patients. PMID- 28911085 TI - A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer. AB - Background: Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC). Patients and methods: Patients with advanced NSCLC who had received >=2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate. Results: Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95-1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90-1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%). Conclusion: This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC. Trial registration ID: www.ClinicalTrials.gov; NCT01454934. PMID- 28911086 TI - Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions. AB - Background: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Patients and methods: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. Results: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/ul with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. Conclusions: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor. PMID- 28911087 TI - An antisense oligonucleotide targeting TGF-beta2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages. AB - Background: The transforming growth factor (TGF)-beta pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-beta pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-beta isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-beta2. Materials and methods: We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis. Results: We observed that ISTH0047 is able to significantly reduce TGF-beta2 mRNA and protein levels without altering the levels of TGF-beta1 and TGF-beta3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-beta2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86. Conclusion: Overall, our data point to TGF-beta2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages. PMID- 28911088 TI - Chemotherapy-induced toxicity-a secondary effect caused by released DNA? PMID- 28911089 TI - The Italian Collaborative Group sets a standard for the treatment of locally advanced head and neck cancer. PMID- 28911090 TI - Maintenance therapy in advanced colorectal cancer, yes or no? Ask the laboratory. PMID- 28911091 TI - A phase III trial comparing oral S-1/cisplatin and intravenous 5 fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. AB - Background: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naive patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. Patients and methods: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. Results: Overall, 361 patients were randomized (S 1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had >=1 grade 3/4 treatment-emergent adverse event or >=1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. Conclusions: These data suggest that S 1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. ClinicalTrial.gov registration number: NCT01285557. PMID- 28911093 TI - Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma. AB - Background: We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL). Patients and methods: From June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15-36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20-45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6-57). Overall, 42% were pediatric (<=18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5-92 months). Results: The 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date. Conclusion: Consolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical. PMID- 28911092 TI - Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT. AB - Background: Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. Design and methods: We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Results: Distributions of several clinico pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Conclusion: Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. Clinicaltrials.gov: NCT00066690 and NCT00066703. PMID- 28911094 TI - Structure/cleavage-based insights into helical perturbations at bulge sites within T. thermophilus Argonaute silencing complexes. AB - We have undertaken a systematic structural study of Thermus thermophilus Argonaute (TtAgo) ternary complexes containing single-base bulges positioned either within the seed segment of the guide or target strands and at the cleavage site. Our studies establish that single-base bulges 7T8, 5A6 and 4A5 on the guide strand are stacked-into the duplex, with conformational changes localized to the bulge site, thereby having minimal impact on the cleavage site. By contrast, single-base bulges 6'U7' and 6'A7' on the target strand are looped-out of the duplex, with the resulting conformational transitions shifting the cleavable phosphate by one step. We observe a stable alignment for the looped-out 6'N7' bulge base, which stacks on the unpaired first base of the guide strand, with the looped-out alignment facilitated by weakened Watson-Crick and reversed non canonical flanking pairs. These structural studies are complemented by cleavage assays that independently monitor the impact of bulges on TtAgo-mediated cleavage reaction. PMID- 28911095 TI - Understanding mutational effects in digenic diseases. AB - To further our understanding of the complexity and genetic heterogeneity of rare diseases, it has become essential to shed light on how combinations of variants in different genes are responsible for a disease phenotype. With the appearance of a resource on digenic diseases, it has become possible to evaluate how digenic combinations differ in terms of the phenotypes they produce. All instances in this resource were assigned to two classes of digenic effects, annotated as true digenic and composite classes. Whereas in the true digenic class variants in both genes are required for developing the disease, in the composite class, a variant in one gene is sufficient to produce the phenotype, but an additional variant in a second gene impacts the disease phenotype or alters the age of onset. We show that a combination of variant, gene and higher-level features can differentiate between these two classes with high accuracy. Moreover, we show via the analysis of three digenic disorders that a digenic effect decision profile, extracted from the predictive model, motivates why an instance was assigned to either of the two classes. Together, our results show that digenic disease data generates novel insights, providing a glimpse into the oligogenic realm. PMID- 28911096 TI - Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases. AB - Polyadenylation of nascent RNA by poly(A) polymerase (PAP) is important for 3' end maturation of almost all eukaryotic mRNAs. Most mammalian genes harbor multiple polyadenylation sites (PASs), leading to expression of alternative polyadenylation (APA) isoforms with distinct functions. How poly(A) polymerases may regulate PAS usage and hence gene expression is poorly understood. Here, we show that the nuclear canonical (PAPalpha and PAPgamma) and non-canonical (Star PAP) PAPs play diverse roles in PAS selection and gene expression. Deficiencies in the PAPs resulted in perturbations of gene expression, with Star-PAP impacting lowly expressed mRNAs and long-noncoding RNAs to the greatest extent. Importantly, different PASs of a gene are distinctly regulated by different PAPs, leading to widespread relative expression changes of APA isoforms. The location and surrounding sequence motifs of a PAS appear to differentiate its regulation by the PAPs. We show Star-PAP-specific PAS usage regulates the expression of the eukaryotic translation initiation factor EIF4A1, the tumor suppressor gene PTEN and the long non-coding RNA NEAT1. The Star-PAP-mediated APA of PTEN is essential for DNA damage-induced increase of PTEN protein levels. Together, our results reveal a PAS-guided and PAP-mediated paradigm for gene expression in response to cellular signaling cues. PMID- 28911097 TI - Structural accommodation of ribonucleotide incorporation by the DNA repair enzyme polymerase Mu. AB - While most DNA polymerases discriminate against ribonucleotide triphosphate (rNTP) incorporation very effectively, the Family X member DNA polymerase MU (Pol MU) incorporates rNTPs almost as efficiently as deoxyribonucleotides. To gain insight into how this occurs, here we have used X-ray crystallography to describe the structures of pre- and post-catalytic complexes of Pol MU with a ribonucleotide bound at the active site. These structures reveal that Pol MU binds and incorporates a rNTP with normal active site geometry and no distortion of the DNA substrate or nucleotide. Moreover, a comparison of rNTP incorporation kinetics by wildtype and mutant Pol MU indicates that rNTP accommodation involves synergistic interactions with multiple active site residues not found in polymerases with greater discrimination. Together, the results are consistent with the hypothesis that rNTP incorporation by Pol MU is advantageous in gap filling synthesis during DNA double strand break repair by nonhomologous end joining, particularly in nonreplicating cells containing very low deoxyribonucleotide concentrations. PMID- 28911098 TI - The SmAP2 RNA binding motif in the 3'UTR affects mRNA stability in the crenarchaeum Sulfolobus solfataricus. AB - Sm and Sm-like proteins represent an evolutionarily conserved family with key roles in RNA metabolism in Pro- and Eukaryotes. In this study, a collection of 53 mRNAs that co-purified with Sulfolobus solfataricus (Sso) SmAP2 were surveyed for a specific RNA binding motif (RBM). SmAP2 was shown to bind with high affinity to the deduced consensus RNA binding motif (SmAP2-cRBM) in vitro. Residues in SmAP2 interacting with the SmAP2-cRBM were mapped by UV-induced crosslinking in combination with mass-spectrometry, and verified by mutational analyses. The RNA binding site on SmAP2 includes a modified uracil binding pocket containing a unique threonine (T40) located on the L3 face and a second residue, K25, located in the pore. To study the function of the SmAP2-RBM in vivo, three authentic RBMs were inserted in the 3'UTR of a lacS reporter gene. The presence of the SmAP2-RBM in the reporter-constructs resulted in decreased LacS activity and reduced steady state levels of lacS mRNA. Moreover, the presence of the SmAP2-cRBM in and the replacement of the lacS 3'UTR with that of Sso2194 encompassing a SmAP2-RBM apparently impacted on the stability of the chimeric transcripts. These results are discussed in light of the function(s) of eukaryotic Lsm proteins in RNA turnover. PMID- 28911100 TI - Genome-wide analysis of influenza viral RNA and nucleoprotein association. AB - Influenza A virus (IAV) genomes are composed of eight single-stranded RNA segments that are coated by viral nucleoprotein (NP) molecules. Classically, the interaction between NP and viral RNA (vRNA) is depicted as a uniform pattern of 'beads on a string'. Using high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP), we identified the vRNA binding profiles of NP for two H1N1 IAV strains in virions. Contrary to the prevailing model for vRNA packaging, NP does not bind vRNA uniformly in the A/WSN/1933 and A/California/07/2009 strains, but instead each vRNA segment exhibits a unique binding profile, containing sites that are enriched or poor in NP association. Intriguingly, both H1N1 strains have similar yet distinct NP binding profiles despite extensive sequence conservation. Peaks identified by HITS-CLIP were verified as true NP binding sites based on insensitivity to DNA antisense oligonucleotide-mediated RNase H digestion. Moreover, nucleotide content analysis of NP peaks revealed that these sites are relatively G-rich and U-poor compared to the genome-wide nucleotide content, indicating an as-yet unidentified sequence bias for NP association in vivo. Taken together, our genome-wide study of NP-vRNA interaction has implications for the understanding of influenza vRNA architecture and genome packaging. PMID- 28911099 TI - Bacillus subtilis RecA with DprA-SsbA antagonizes RecX function during natural transformation. AB - Bacillus subtilis DprA and RecX proteins, which interact with RecA, are crucial for efficient chromosomal and plasmid transformation. We showed that RecA, in the rATP.Mg2+ bound form (RecA.ATP), could not compete with RecX, SsbA or SsbB for assembly onto single-stranded (ss)DNA, but RecA.dATP partially displaced these proteins from ssDNA. RecX promoted reversible depolymerization of preformed RecA.ATP filaments. The two-component DprA-SsbA mediator reversed the RecX negative effect on RecA filament extension, but not DprA or DprA and SsbB. In the presence of DprA-SsbA, RecX added prior to RecA.ATP inhibited DNA strand exchange, but this inhibition was reversed when RecX was added after RecA. We propose that RecA nucleation is more sensitive to RecX action than is RecA filament growth. DprA-SsbA facilitates formation of an active RecA filament that directly antagonizes the inhibitory effects of RecX. RecX and DprA enable chromosomal transformation by altering RecA filament dynamics. DprA-SsbA and RecX proteins constitute a new regulatory network of RecA function. DprA-SsbA contributes to the formation of an active RecA filament and directly antagonizes the inhibitory effects of RecX during natural transformation. PMID- 28911101 TI - Information transduction capacity reduces the uncertainties in annotation-free isoform discovery and quantification. AB - The automated transcript discovery and quantification of high-throughput RNA sequencing (RNA-seq) data are important tasks of next-generation sequencing (NGS) research. However, these tasks are challenging due to the uncertainties that arise in the inference of complete splicing isoform variants from partially observed short reads. Here, we address this problem by explicitly reducing the inherent uncertainties in a biological system caused by missing information. In our approach, the RNA-seq procedure for transforming transcripts into short reads is considered an information transmission process. Consequently, the data uncertainties are substantially reduced by exploiting the information transduction capacity of information theory. The experimental results obtained from the analyses of simulated datasets and RNA-seq datasets from cell lines and tissues demonstrate the advantages of our method over state-of-the-art competitors. Our algorithm is an open-source implementation of MaxInfo. PMID- 28911102 TI - FANCJ helicase controls the balance between short- and long-tract gene conversions between sister chromatids. AB - The FANCJ DNA helicase is linked to hereditary breast and ovarian cancers as well as bone marrow failure disorder Fanconi anemia (FA). Although FANCJ has been implicated in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), the molecular mechanism underlying the tumor suppressor functions of FANCJ remains obscure. Here, we demonstrate that FANCJ deficient human and hamster cells exhibit reduction in the overall gene conversions in response to a site-specific chromosomal DSB induced by I-SceI endonuclease. Strikingly, the gene conversion events were biased in favour of long-tract gene conversions in FANCJ depleted cells. The fine regulation of short- (STGC) and long-tract gene conversions (LTGC) by FANCJ was dependent on its interaction with BRCA1 tumor suppressor. Notably, helicase activity of FANCJ was essential for controlling the overall HR and in terminating the extended repair synthesis during sister chromatid recombination (SCR). Moreover, cells expressing FANCJ pathological mutants exhibited defective SCR with an increased frequency of LTGC. These data unravel the novel function of FANCJ helicase in regulating SCR and SCR associated gene amplification/duplications and imply that these functions of FANCJ are crucial for the genome maintenance and tumor suppression. PMID- 28911103 TI - Prediction of genome-wide DNA methylation in repetitive elements. AB - DNA methylation in repetitive elements (RE) suppresses their mobility and maintains genomic stability, and decreases in it are frequently observed in tumor and/or surrogate tissues. Averaging methylation across RE in genome is widely used to quantify global methylation. However, methylation may vary in specific RE and play diverse roles in disease development, thus averaging methylation across RE may lose significant biological information. The ambiguous mapping of short reads by and high cost of current bisulfite sequencing platforms make them impractical for quantifying locus-specific RE methylation. Although microarray based approaches (particularly Illumina's Infinium methylation arrays) provide cost-effective and robust genome-wide methylation quantification, the number of interrogated CpGs in RE remains limited. We report a random forest-based algorithm (and corresponding R package, REMP) that can accurately predict genome wide locus-specific RE methylation based on Infinium array profiling data. We validated its prediction performance using alternative sequencing and microarray data. Testing its clinical utility with The Cancer Genome Atlas data demonstrated that our algorithm offers more comprehensively extended locus-specific RE methylation information that can be readily applied to large human studies in a cost-effective manner. Our work has the potential to improve our understanding of the role of global methylation in human diseases, especially cancer. PMID- 28911104 TI - Synthesis and incorporation of 13C-labeled DNA building blocks to probe structural dynamics of DNA by NMR. AB - We report the synthesis of atom-specifically 13C-modified building blocks that can be incorporated into DNA via solid phase synthesis to facilitate investigations on structural and dynamic features via NMR spectroscopy. In detail, 6-13C-modified pyrimidine and 8-13C purine DNA phosphoramidites were synthesized and incorporated into a polypurine tract DNA/RNA hybrid duplex to showcase the facile resonance assignment using site-specific labeling. We also addressed micro- to millisecond dynamics in the mini-cTAR DNA. This DNA is involved in the HIV replication cycle and our data points toward an exchange process in the lower stem of the hairpin that is up-regulated in the presence of the HIV-1 nucleocapsid protein 7. As another example, we picked a G-quadruplex that was earlier shown to exist in two folds. Using site-specific 8-13C 2'deoxyguanosine labeling we were able to verify the slow exchange between the two forms on the chemical shift time scale. In a real-time NMR experiment the re equilibration of the fold distribution after a T-jump could be monitored yielding a rate of 0.012 min-1. Finally, we used 13C-ZZ-exchange spectroscopy to characterize the kinetics between two stacked X-conformers of a Holliday junction mimic. At 25 degrees C, the refolding process was found to occur at a forward rate constant of 3.1 s-1 and with a backward rate constant of 10.6 s-1. PMID- 28911105 TI - A novel nucleoid-associated protein coordinates chromosome replication and chromosome partition. AB - We searched for regulators of chromosome replication in the cell cycle model Caulobacter crescentus and found a novel DNA-binding protein (GapR) that selectively aids the initiation of chromosome replication and the initial steps of chromosome partitioning. The protein binds the chromosome origin of replication (Cori) and has higher-affinity binding to mutated Cori-DNA that increases Cori-plasmid replication in vivo. gapR gene expression is essential for normal rapid growth and sufficient GapR levels are required for the correct timing of chromosome replication. Whole genome ChIP-seq identified dynamic DNA binding distributions for GapR, with the strongest associations at the partitioning (parABS) locus near Cori. Using molecular-genetic and fluorescence microscopy experiments, we showed that GapR also promotes the first steps of chromosome partitioning, the initial separation of the duplicated parS loci following replication from Cori. This separation occurs before the parABS dependent partitioning phase. Therefore, this early separation, whose mechanisms is not known, coincides with the poorly defined mechanism(s) that establishes chromosome asymmetry: C. crescentus chromosomes are partitioned to distinct cell poles which develop into replicating and non-replicating cell-types. We propose that GapR coordinates chromosome replication with asymmetry-establishing chromosome separation, noting that both roles are consistent with the phylogenetic restriction of GapR to asymmetrically dividing bacteria. PMID- 28911106 TI - Unencumbered Pol beta lyase activity in nucleosome core particles. AB - Packaging of DNA into the nucleosome core particle (NCP) is considered to exert constraints to all DNA-templated processes, including base excision repair where Pol beta catalyzes two key enzymatic steps: 5'-dRP lyase gap trimming and template-directed DNA synthesis. Despite its biological significance, knowledge of Pol beta activities on NCPs is still limited. Here, we show that removal of the 5'-dRP block by Pol beta is unaffected by NCP constraints at all sites tested and is even enhanced near the DNA ends. In contrast, strong inhibition of DNA synthesis is observed. These results indicate 5'-dRP gap trimming proceeds unperturbed within the NCP; whereas, gap filling is strongly limited. In the absence of additional factors, base excision repair in NCPs will stall at the gap filling step. PMID- 28911107 TI - Web-based NGS data analysis using miRMaster: a large-scale meta-analysis of human miRNAs. AB - The analysis of small RNA NGS data together with the discovery of new small RNAs is among the foremost challenges in life science. For the analysis of raw high throughput sequencing data we implemented the fast, accurate and comprehensive web-based tool miRMaster. Our toolbox provides a wide range of modules for quantification of miRNAs and other non-coding RNAs, discovering new miRNAs, isomiRs, mutations, exogenous RNAs and motifs. Use-cases comprising hundreds of samples are processed in less than 5 h with an accuracy of 99.4%. An integrative analysis of small RNAs from 1836 data sets (20 billion reads) indicated that context-specific miRNAs (e.g. miRNAs present only in one or few different tissues / cell types) still remain to be discovered while broadly expressed miRNAs appear to be largely known. In total, our analysis of known and novel miRNAs indicated nearly 22 000 candidates of precursors with one or two mature forms. Based on these, we designed a custom microarray comprising 11 872 potential mature miRNAs to assess the quality of our prediction. MiRMaster is a convenient-to-use tool for the comprehensive and fast analysis of miRNA NGS data. In addition, our predicted miRNA candidates provided as custom array will allow researchers to perform in depth validation of candidates interesting to them. PMID- 28911108 TI - The third restriction-modification system from Thermus aquaticus YT-1: solving the riddle of two TaqII specificities. AB - Two restriction-modification systems have been previously discovered in Thermus aquaticus YT-1. TaqI is a 263-amino acid (aa) Type IIP restriction enzyme that recognizes and cleaves within the symmetric sequence 5'-TCGA-3'. TaqII, in contrast, is a 1105-aa Type IIC restriction-and-modification enzyme, one of a family of Thermus homologs. TaqII was originally reported to recognize two different asymmetric sequences: 5'-GACCGA-3' and 5'-CACCCA-3'. We previously cloned the taqIIRM gene, purified the recombinant protein from Escherichia coli, and showed that TaqII recognizes the 5'-GACCGA-3' sequence only. Here, we report the discovery, isolation, and characterization of TaqIII, the third R-M system from T. aquaticus YT-1. TaqIII is a 1101-aa Type IIC/IIL enzyme and recognizes the 5'-CACCCA-3' sequence previously attributed to TaqII. The cleavage site is 11/9 nucleotides downstream of the A residue. The enzyme exhibits striking biochemical similarity to TaqII. The 93% identity between their aa sequences suggests that they have a common evolutionary origin. The genes are located on two separate plasmids, and are probably paralogs or pseudoparalogs. Putative positions and aa that specify DNA recognition were identified and recognition motifs for 6 uncharacterized Thermus-family enzymes were predicted. PMID- 28911109 TI - Selective tumor cell death induced by irradiated riboflavin through recognizing DNA G-T mismatch. AB - Riboflavin (vitamin B2) has been thought to be a promising antitumoral agent in photodynamic therapy, though the further application of the method was limited by the unclear molecular mechanism. Our work reveals that riboflavin was able to recognize G-T mismatch specifically and induce single-strand breaks in duplex DNA targets efficiently under irradiation. In the presence of riboflavin, the photo irradiation could induce the death of tumor cells that are defective in mismatch repair system selectively, highlighting the G-T mismatch as potential drug target for tumor cells. Moreover, riboflavin is a promising leading compound for further drug design due to its inherent specific recognition of the G-T mismatch. PMID- 28911110 TI - Two-tailed RT-qPCR: a novel method for highly accurate miRNA quantification. AB - MicroRNAs are a class of small non-coding RNAs that serve as important regulators of gene expression at the posttranscriptional level. They are stable in body fluids and pose great potential to serve as biomarkers. Here, we present a highly specific, sensitive and cost-effective system to quantify miRNA expression based on two-step RT-qPCR with SYBR-green detection chemistry called Two-tailed RT qPCR. It takes advantage of novel, target-specific primers for reverse transcription composed of two hemiprobes complementary to two different parts of the targeted miRNA, connected by a hairpin structure. The introduction of a second probe ensures high sensitivity and enables discrimination of highly homologous miRNAs irrespectively of the position of the mismatched nucleotide. Two-tailed RT-qPCR has a dynamic range of seven logs and a sensitivity sufficient to detect down to ten target miRNA molecules. It is capable to capture the full isomiR repertoire, leading to accurate representation of the complete miRNA content in a sample. The reverse transcription step can be multiplexed and the miRNA profiles measured with Two-tailed RT-qPCR show excellent correlation with the industry standard TaqMan miRNA assays (r2 = 0.985). Moreover, Two-tailed RT qPCR allows for rapid testing with a total analysis time of less than 2.5 hours. PMID- 28911111 TI - Combinatorial ensemble miRNA target prediction of co-regulation networks with non prediction data. AB - MicroRNAs (miRNAs) are key regulators of cell-fate decisions in development and disease with a vast array of target interactions that can be investigated using computational approaches. For this study, we developed metaMIR, a combinatorial approach to identify miRNAs that co-regulate identified subsets of genes from a user-supplied list. We based metaMIR predictions on an improved dataset of human miRNA-target interactions, compiled using a machine-learning-based meta-analysis of established algorithms. Simultaneously, the inverse dataset of negative interactions not likely to occur was extracted to increase classifier performance, as measured using an expansive set of experimentally validated interactions from a variety of sources. In a second differential mode, candidate miRNAs are predicted by indicating genes to be targeted and others to be avoided to potentially increase specificity of results. As an example, we investigate the neural crest, a transient structure in vertebrate development where miRNAs play a pivotal role. Patterns of metaMIR-predicted miRNA regulation alone partially recapitulated functional relationships among genes, and separate differential analysis revealed miRNA candidates that would downregulate components implicated in cancer progression while not targeting tumour suppressors. Such an approach could aid in therapeutic application of miRNAs to reduce unintended effects. The utility is available at http://rna.informatik.uni-freiburg.de/metaMIR/. PMID- 28911112 TI - Integrative and conjugative elements and their hosts: composition, distribution and organization. AB - Conjugation of single-stranded DNA drives horizontal gene transfer between bacteria and was widely studied in conjugative plasmids. The organization and function of integrative and conjugative elements (ICE), even if they are more abundant, was only studied in a few model systems. Comparative genomics of ICE has been precluded by the difficulty in finding and delimiting these elements. Here, we present the results of a method that circumvents these problems by requiring only the identification of the conjugation genes and the species' pan genome. We delimited 200 ICEs and this allowed the first large-scale characterization of these elements. We quantified the presence in ICEs of a wide set of functions associated with the biology of mobile genetic elements, including some that are typically associated with plasmids, such as partition and replication. Protein sequence similarity networks and phylogenetic analyses revealed that ICEs are structured in functional modules. Integrases and conjugation systems have different evolutionary histories, even if the gene repertoires of ICEs can be grouped in function of conjugation types. Our characterization of the composition and organization of ICEs paves the way for future functional and evolutionary analyses of their cargo genes, composed of a majority of unknown function genes. PMID- 28911113 TI - MCbiclust: a novel algorithm to discover large-scale functionally related gene sets from massive transcriptomics data collections. AB - The potential to understand fundamental biological processes from gene expression data has grown in parallel with the recent explosion of the size of data collections. However, to exploit this potential, novel analytical methods are required, capable of discovering large co-regulated gene networks. We found current methods limited in the size of correlated gene sets they could discover within biologically heterogeneous data collections, hampering the identification of multi-gene controlled fundamental cellular processes such as energy metabolism, organelle biogenesis and stress responses. Here we describe a novel biclustering algorithm called Massively Correlated Biclustering (MCbiclust) that selects samples and genes from large datasets with maximal correlated gene expression, allowing regulation of complex networks to be examined. The method has been evaluated using synthetic data and applied to large bacterial and cancer cell datasets. We show that the large biclusters discovered, so far elusive to identification by existing techniques, are biologically relevant and thus MCbiclust has great potential in the analysis of transcriptomics data to identify large-scale unknown effects hidden within the data. The identified massive biclusters can be used to develop improved transcriptomics based diagnosis tools for diseases caused by altered gene expression, or used for further network analysis to understand genotype-phenotype correlations. PMID- 28911114 TI - Coupling transcriptional activation of CRISPR-Cas system and DNA repair genes by Csa3a in Sulfolobus islandicus. AB - CRISPR-Cas system provides the adaptive immunity against invading genetic elements in prokaryotes. Recently, we demonstrated that Csa3a regulator mediates spacer acquisition in Sulfolobus islandicus by activating the expression of Type I-A adaptation cas genes. However, links between the activation of spacer adaptation and CRISPR transcription/processing, and the requirement for DNA repair genes during spacer acquisition remained poorly understood. Here, we demonstrated that de novo spacer acquisition required Csa1, Cas1, Cas2 and Cas4 proteins of the Sulfolobus Type I-A system. Disruption of genes implicated in crRNA maturation or DNA interference led to a significant accumulation of acquired spacers, mainly derived from host genomic DNA. Transcriptome and proteome analyses showed that Csa3a activated expression of adaptation cas genes, CRISPR RNAs, and DNA repair genes, including herA helicase, nurA nuclease and DNA polymerase II genes. Importantly, Csa3a specifically bound the promoters of the above DNA repair genes, suggesting that they were directly activated by Csa3a for adaptation. The Csa3a regulator also specifically bound to the leader sequence to activate CRISPR transcription in vivo. Our data indicated that the Csa3a regulator couples transcriptional activation of the CRISPR-Cas system and DNA repair genes for spacer adaptation and efficient interference of invading genetic elements. PMID- 28911115 TI - The IRES5'UTR of the dicistrovirus cricket paralysis virus is a type III IRES containing an essential pseudoknot structure. AB - Cricket paralysis virus (CrPV) is a dicistrovirus. Its positive-sense single stranded RNA genome contains two internal ribosomal entry sites (IRESs). The 5' untranslated region (5'UTR) IRES5'UTR mediates translation of non-structural proteins encoded by ORF1 whereas the well-known intergenic region (IGR) IRESIGR is required for translation of structural proteins from open reading frame 2 in the late phase of infection. Concerted action of both IRES is essential for host translation shut-off and viral translation. IRESIGR has been extensively studied, in contrast the IRES5'UTR remains largely unexplored. Here, we define the minimal IRES element required for efficient translation initiation in drosophila S2 cell free extracts. We show that IRES5'UTR promotes direct recruitment of the ribosome on the cognate viral AUG start codon without any scanning step, using a Hepatitis C virus-related translation initiation mechanism. Mass spectrometry analysis revealed that IRES5'UTR recruits eukaryotic initiation factor 3, confirming that it belongs to type III class of IRES elements. Using Selective 2'-hydroxyl acylation analyzed by primer extension and DMS probing, we established a secondary structure model of 5'UTR and of the minimal IRES5'UTR. The IRES5'UTR contains a pseudoknot structure that is essential for proper folding and ribosome recruitment. Overall, our results pave the way for studies addressing the synergy and interplay between the two IRES from CrPV. PMID- 28911116 TI - Mechanistic features of the atypical tRNA m1G9 SPOUT methyltransferase, Trm10. AB - The tRNA m1G9 methyltransferase (Trm10) is a member of the SpoU-TrmD (SPOUT) superfamily of methyltransferases, and Trm10 homologs are widely conserved throughout Eukarya and Archaea. Despite possessing the trefoil knot characteristic of SPOUT enzymes, Trm10 does not share the same quaternary structure or key sequences with other members of the SPOUT family, suggesting a novel mechanism of catalysis. To investigate the mechanism of m1G9 methylation by Trm10, we performed a biochemical and kinetic analysis of Trm10 and variants with alterations in highly conserved residues, using crystal structures solved in the absence of tRNA as a guide. Here we demonstrate that a previously proposed general base residue (D210 in Saccharomyces cerevisiae Trm10) is not likely to play this suggested role in the chemistry of methylation. Instead, pH-rate analysis suggests that D210 and other conserved carboxylate-containing residues at the active site collaborate to establish an active site environment that promotes a single ionization that is required for catalysis. Moreover, Trm10 does not depend on a catalytic metal ion, further distinguishing it from the other known SPOUT m1G methyltransferase, TrmD. These results provide evidence for a non canonical tRNA methyltransferase mechanism that characterizes the Trm10 enzyme family. PMID- 28911117 TI - Structure-based domain assignment in Leishmania infantum EndoG: characterization of a pH-dependent regulatory switch and a C-terminal extension that largely dictates DNA substrate preferences. AB - Mitochondrial endonuclease G from Leishmania infantum (LiEndoG) participates in the degradation of double-stranded DNA (dsDNA) during parasite cell death and is catalytically inactive at a pH of 8.0 or above. The presence, in the primary sequence, of an acidic amino acid-rich insertion exclusive to trypanosomatids and its spatial position in a homology-built model of LiEndoG led us to postulate that this peptide stretch might act as a pH sensor for self-inhibition. We found that a LiEndoG variant lacking residues 145-180 is indeed far more active than its wild-type counterpart at pH values >7.0. In addition, we discovered that (i) LiEndoG exists as a homodimer, (ii) replacement of Ser211 in the active-site SRGH motif with the canonical aspartate from the DRGH motif of other nucleases leads to a catalytically deficient enzyme, (iii) the activity of the S211D variant can be restored upon the concomitant replacement of Ala247 with Arg and (iv) a C terminal extension is responsible for the observed preferential cleavage of single-stranded DNA (ssDNA) and ssDNA-dsDNA junctions. Taken together, our results support the view that LiEndoG is a multidomain molecular machine whose nuclease activity can be subtly modulated or even abrogated through architectural changes brought about by environmental conditions and interaction with other binding partners. PMID- 28911118 TI - Multimerization rules for G-quadruplexes. AB - G-quadruplexes can multimerize under certain conditions, but the sequence requirements of such structures are not well understood. In this study, we investigated the ability of all possible variants of the central tetrad in a monomeric, parallel-strand G-quadruplex to form higher-order structures. Although most of these 256 variants existed primarily as monomers under the conditions of our screen, ~10% formed dimers or tetramers. These structures could form in a wide range of monovalent and divalent metal ions, and folding was highly cooperative in both KCl and MgCl2. As was previously shown for G-quadruplexes that bind GTP and promote peroxidase reactions, G-quadruplexes that form dimers and tetramers have distinct sequence requirements. Some mutants could also form heteromultimers, and a second screen was performed to characterize the sequence requirements of these structures. Taken together, these experiments provide new insights into the sequence requirements and structures of both homomultimeric and heteromultimeric G-quadruplexes. PMID- 28911119 TI - A snoRNA modulates mRNA 3' end processing and regulates the expression of a subset of mRNAs. AB - mRNA 3' end processing is an essential step in gene expression. It is well established that canonical eukaryotic pre-mRNA 3' processing is carried out within a macromolecular machinery consisting of dozens of trans-acting proteins. However, it is unknown whether RNAs play any role in this process. Unexpectedly, we found that a subset of small nucleolar RNAs (snoRNAs) are associated with the mammalian mRNA 3' processing complex. These snoRNAs primarily interact with Fip1, a component of cleavage and polyadenylation specificity factor (CPSF). We have functionally characterized one of these snoRNAs and our results demonstrated that the U/A-rich SNORD50A inhibits mRNA 3' processing by blocking the Fip1-poly(A) site (PAS) interaction. Consistently, SNORD50A depletion altered the Fip1-RNA interaction landscape and changed the alternative polyadenylation (APA) profiles and/or transcript levels of a subset of genes. Taken together, our data revealed a novel function for snoRNAs and provided the first evidence that non-coding RNAs may play an important role in regulating mRNA 3' processing. PMID- 28911120 TI - PhiReX: a programmable and red light-regulated protein expression switch for yeast. AB - Highly regulated induction systems enabling dose-dependent and reversible fine tuning of protein expression output are beneficial for engineering complex biosynthetic pathways. To address this, we developed PhiReX, a novel red/far-red light-regulated protein expression system for use in Saccharomyces cerevisiae. PhiReX is based on the combination of a customizable synTALE DNA-binding domain, the VP64 activation domain and the light-sensitive dimerization of the photoreceptor PhyB and its interacting partner PIF3 from Arabidopsis thaliana. Robust gene expression and high protein levels are achieved by combining genome integrated red light-sensing components with an episomal high-copy reporter construct. The gene of interest as well as the synTALE DNA-binding domain can be easily exchanged, allowing the flexible regulation of any desired gene by targeting endogenous or heterologous promoter regions. To allow low-cost induction of gene expression for industrial fermentation processes, we engineered yeast to endogenously produce the chromophore required for the effective dimerization of PhyB and PIF3. Time course experiments demonstrate high-level induction over a period of at least 48 h. PMID- 28911121 TI - Engineering human PrimPol into an efficient RNA-dependent-DNA primase/polymerase. AB - We have developed a straightforward fluorometric assay to measure primase polymerase activity of human PrimPol (HsPrimPol). The sensitivity of this procedure uncovered a novel RNA-dependent DNA priming-polymerization activity (RdDP) of this enzyme. In an attempt to enhance HsPrimPol RdDP activity, we constructed a smart mutant library guided by prior sequence-function analysis, and tested this library in an adapted screening platform of our fluorometric assay. After screening less than 500 variants, we found a specific HsPrimPol mutant, Y89R, which displays 10-fold higher RdDP activity than the wild-type enzyme. The improvement of RdDP activity in the Y89R variant was due mainly to an increased in the stabilization of the preternary complex (protein:template:incoming nucleotide), a specific step preceding dimer formation. Finally, in support of the biotechnological potential of PrimPol as a DNA primer maker during reverse transcription, mutant Y89R HsPrimPol rendered up to 17-fold more DNA than with random hexamer primers. PMID- 28911122 TI - Data exploration, quality control and statistical analysis of ChIP-exo/nexus experiments. AB - ChIP-exo/nexus experiments rely on innovative modifications of the commonly used ChIP-seq protocol for high resolution mapping of transcription factor binding sites. Although many aspects of the ChIP-exo data analysis are similar to those of ChIP-seq, these high throughput experiments pose a number of unique quality control and analysis challenges. We develop a novel statistical quality control pipeline and accompanying R/Bioconductor package, ChIPexoQual, to enable exploration and analysis of ChIP-exo and related experiments. ChIPexoQual evaluates a number of key issues including strand imbalance, library complexity, and signal enrichment of data. Assessment of these features are facilitated through diagnostic plots and summary statistics computed over regions of the genome with varying levels of coverage. We evaluated our QC pipeline with both large collections of public ChIP-exo/nexus data and multiple, new ChIP-exo datasets from Escherichia coli. ChIPexoQual analysis of these datasets resulted in guidelines for using these QC metrics across a wide range of sequencing depths and provided further insights for modelling ChIP-exo data. PMID- 28911123 TI - A systematic comparison of error correction enzymes by next-generation sequencing. AB - Gene synthesis, the process of assembling gene-length fragments from shorter groups of oligonucleotides (oligos), is becoming an increasingly important tool in molecular and synthetic biology. The length, quality and cost of gene synthesis are limited by errors produced during oligo synthesis and subsequent assembly. Enzymatic error correction methods are cost-effective means to ameliorate errors in gene synthesis. Previous analyses of these methods relied on cloning and Sanger sequencing to evaluate their efficiencies, limiting quantitative assessment. Here, we develop a method to quantify errors in synthetic DNA by next-generation sequencing. We analyzed errors in model gene assemblies and systematically compared six different error correction enzymes across 11 conditions. We find that ErrASE and T7 Endonuclease I are the most effective at decreasing average error rates (up to 5.8-fold relative to the input), whereas MutS is the best for increasing the number of perfect assemblies (up to 25.2-fold). We are able to quantify differential specificities such as ErrASE preferentially corrects C/G transversions whereas T7 Endonuclease I preferentially corrects A/T transversions. More generally, this experimental and computational pipeline is a fast, scalable and extensible way to analyze errors in gene assemblies, to profile error correction methods, and to benchmark DNA synthesis methods. PMID- 28911125 TI - Differences in survival among adults with HIV-associated Kaposi's sarcoma during routine HIV treatment initiation in Zomba district, Malawi: a retrospective cohort analysis. AB - Background: The HIV epidemic is a major public health concern throughout Africa. Malawi is one of the worst affected countries in sub-Saharan Africa with a 2014 national HIV prevalence currently estimated at 10% (9.3-10.8%) by UNAIDS. Study reports, largely in the African setting comparing outcomes in HIV patients with and without Kaposi's sarcoma (KS) indicate poor prognosis and poor health outcomes amongst HIV+KS patients. Understanding the mortality risk in this patient group could help improve patient management and care. Methods: Using data for the 559 adult HIV+KS patients who started ART between 2004 and September 2011 at Zomba clinic in Malawi, we estimated relative hazard ratios for all-cause mortality by controlling for age, sex, TB status, occupation, date of starting treatment and distance to the HIV+KS clinic. Results: Patients with tuberculosis (95% CI: 1.05-4.65) and patients who started ART before 2008 (95% CI: 0.34-0.81) were at significantly greater risk of dying. A random-effects Cox model with Log Gaussian frailties adequately described the variation in the hazard for mortality. Conclusion: The year of starting ART and TB status significantly affected survival among HIV+KS patients. A sub-population analysis of this kind can inform an efficient triage system for managing vulnerable patients. PMID- 28911124 TI - Assessment of quality of antiretroviral therapy services in India, 2014-2015. AB - Background: Following a decade of provision of free antiretroviral therapy (ART) in India, a nationwide assessment of ART services was conducted to review quality of care at ART centers. This paper presents the methods and defines replicable model of undertaking large scale assessments. Methods: During the period January 2014-March 2015, 357 ART centers were reviewed under four domains, namely, operations, technical, monitoring and evaluation (M&E), and logistics. Mixed methods, comprising of desk review and on-site facility assessment; random sample of records, interviews with both health-care staff and people living with HIV (PLHIV) were used. Grading for each of the domain was done on a scale of 5, with 1 (Very poor) being the lowest and 5 (Excellent) as highest. Results: 1720 health care staff and 1762 beneficiaries were interviewed; 34 600 patient cards were reviewed. Of the 357 centers assessed 60, 169 and 128 scored Excellent, Average and Poor, respectively, in operations domain; 147, 176, 34 in Technical domain; 215, 115, 27 in M&E domain; 263, 71, 23 centers in logistics domain scored Excellent, Average and Poor, respectively. About 95% (1698/1785) of PLHIV were satisfied with the care provided at ART centers. Conclusion: The methodology used for the assessment of ART centers in India yielded insights on the different domains that impact implementation and quality of service delivery. The design of this exercise may inform other researchers and managers planning similar large scale assessments. PMID- 28911126 TI - Diabetes in the Cape Coast metropolis of Ghana: an assessment of risk factors, nutritional practices and lifestyle changes. AB - Background: Despite the significant increase in the incidence of diabetes in Ghana, research in this area has been lagging. The purpose of the study was to assess the risk factors associated with diabetes in the Cape Coast metropolis of Ghana, and to describe nutritional practices and efforts toward lifestyle change. Methods: A convenient sample of 482 adults from the Cape Coast metropolis was surveyed using a self-reported questionnaire. The survey collected information on the demographic, socioeconomic characteristics, health status and routine nutritional practices of respondents. The aims of the study were addressed using multivariable regression analyses. Results: A total of 8% of respondents reported that they had been diagnosed with diabetes. Older age and body weight were found to be independently associated with diabetes. Individuals living with diabetes were no more likely than those without diabetes to have taken active steps at reducing their weight. Conclusion: The percentage of self-reported diabetes in this population was consistent with what has been reported in previous studies in Ghana. The findings from this study highlight the need for more patient education on physical activity and weight management. PMID- 28911127 TI - Nutritional status of children from low-income countries arriving in Spain. AB - Background: Nutritional problems, anaemia and infectious diseases are the main causes of morbidity and mortality in children and adolescents in tropical and subtropical areas. The main objective of this study was to determine the nutritional status in children from low-income countries who migrated to Spain and the value of the usual biochemistry markers of nutrition in these children, as well as to evaluate the nutritional status associated with imported infectious diseases. Moreover, we evaluated the association between anaemia and nutrition problems. Methods: We prospectively evaluated immigrants younger than 18 years of age, from tropical or subtropical areas, who were referred on suspicion of or screening for imported diseases. Detailed medical records and physical and oral examinations were obtained. Blood count and biochemical measures of micronutrients and nutritional biomarkers were performed. We included microbiological methods for diagnosing imported infectious diseases according to the region of origin and clinical setting. Results: 373 minors were evaluated, including 250 (67.0%) from sub-Saharan Africa, 67 (18.0%) from North Africa and 56 (15.0%) from Latin America. The mean BMI of the subjects was 19.8+/-0.2. BMI increased by 0.02 for each month of stay in Spain. Nineteen patients (6.8%) had a nutritional risk of growth problems, and 50 (17.8%) were overweight. The time since arrival was longer in patients who were overweight (p<0.05). Twenty-one minors (5.7%) had a haemoglobin count less than 11.5 g/dL. Children infected with intestinal helminthiasis had anaemia more frequently than uninfected patients, and children infected with intestinal protozoa had anaemia more frequently than uninfected patients (OR=2.7 I.C 1.1-7.0, p<0.05). Conclusions: Immigrant children in Spain have a low prevalence of growth problem, and being overweight is a frequent nutritional issue. A low level of ferritin is the most frequently detected nutritional problem and the main cause of anaemia. PMID- 28911128 TI - Charting a path forward: policy analysis of China's evolved DRG-based hospital payment system. AB - Background: At present, the diagnosis-related groups-based prospective payment system (DRG-PPS) that has been implemented in China is merely a prototype called the simplified DRG-PPS, which is known as the 'ceiling price for a single disease'. Given that studies on the effects of a simplified DRG-PPS in China have usually been controversial, we aim to synthesize evidence examining whether DRGs can reduce medical costs and length of stay (LOS) in China. Methods: Data were searched from both Chinese [Wan Fang and China National Knowledge Infrastructure Database (CNKI)] and international databases (Web of Science and PubMed), as well as the official websites of Chinese health departments in the 2004-2016 period. Only studies with a design that included both experimental (with DRG-PPS implementation) and control groups (without DRG-PPS implementation) were included in the review. Results: The studies were based on inpatient samples from public hospitals distributed in 12 provinces of mainland China. Among them, 80.95% (17/21) revealed that hospitalization costs could be reduced significantly, and 50.00% (8/16) indicated that length of stay could be decreased significantly. In addition, the government reports showed the enormous differences in pricing standards and LOS in various provinces, even for the same disease. Conclusions: We conclude that the simplified DRGs are useful in controlling hospitalization costs, but they fail to reduce LOS. Much work remains to be done in China to improve the simplified DRG-PPS. PMID- 28911129 TI - A comparative study on the efficacy of praziquantel and albendazole in the treatment of urinary schistosomiasis in Adim, Cross River State, Nigeria. AB - Background: Praziquantel (PZQ) is the current drug of choice for the treatment of urinary schistosomiasis in endemic areas. It is very efficacious, although the potential for the development of resistance has been reported in some endemic areas among human subjects and in animal studies. Its' limitation include high cost and administration of multiple numbers of tablets. Albendazole (ALB) is used in the treatment of intestinal helminths infection. It is a broad-spectrum single dose antihelminthic with an excellent cure rate and safety criteria. Currently, it is not routinely used for the treatment of urinary schistosomiasis. Methods: Urine samples collected from 596 pupils aged between 2 and 16 years were processed and examined for the presence of ova of Schistosoma haematobium using a standard filtration technique. A total of 100 infected subjects were treated with a standard dose of PZQ (40 mg/kg body weight), while another group of 96 infected subjects were treated with ALB (400 mg for individuals above 3 years). A post treatment study was conducted 1 month after treatment to assess their cure rate. Results: The prevalence of S. haematobium infection in the study area was 32.8% (196/596). More males were infected (44.2%) (122/276) than females (23.1%) (74/320). The difference in the prevalence rate of infection by gender was statistically significant (X2=15.7>3.841, p<0.05). The highest prevalence of infection was observed among subjects aged 14-16 years (42.1%) (32/76), while those aged 5-7 years had the least prevalence (23.7%) (38/160). There was no statistically significant difference in the prevalence of urinary schistosomiasis by age of the subjects (X2=5.99<9.5, p>0.05). PZQ gave a higher cure rate of 78.0% (78/100) compared with ALB (68.7%) (66/96). There was no statistically significant difference in the cure rate obtained with both drugs (X2=0.355>0.282, p>0.05). The intensity of egg excretion was greatly reduced in subjects who were not cured by the two drugs. Conclusion: The findings of this study suggest the use of ALB for the treatment of urinary schistosomiasis. We recommend further assessment of the efficacy of the drug in an area with higher morbidity of urinary schistosomiasis than the present study area. PMID- 28911130 TI - On the ferries: the unmet health care needs of transiting refugees in Greece. AB - Background: In 2015, over 850 000 refugees, asylum seekers and migrants arrived in Greece. In response to an overwhelming need for access to healthcare for them, Doctors of the World established the Refugee Ferry Project, which comprised of a clinic providing primary health care, and integrated mental health and psychosocial support on board a commercial ferry. Methods: Of the 1405 service users, 87.5% (1229/1405) originated from Syria, Afghanistan and Iraq. The majority were women 801/1405 (57%) and children 511/1405 (36%), including 50 pregnant women and 19 unaccompanied minors. Results: The most common diagnoses were respiratory tract infections, dehydration, nausea and vomiting, and musculoskeletal pain with 39.4% of the disease burden being classified as non communicable. Exposure to violence was associated with an increased risk of developing mental health issues. Conclusions: Humanitarian actors face huge challenges trying to respond to the needs of transiting populations. It is only by continuous reassessment and having the capacity to mobilize and adapt to an ever-evolving situation that we can try to meet these needs. Having an integrated, flexible and multidisciplinary approach remains crucial, despite the shift from a transit to static population. With over 62 000 refugees stranded in Greece, the need to develop innovative ways to respond to their needs is greater than ever. PMID- 28911131 TI - Addressing challenges to human health in the Anthropocene epoch-an overview of the findings of the Rockefeller/Lancet Commission on Planetary Health. PMID- 28911132 TI - The Neglected Diseases: Will a 'New World Order' Reverse Global Gains? PMID- 28911134 TI - Thyroid Function and Premature Delivery in TPO Antibody-Negative Women: The Added Value of hCG. AB - Context: Human chorionic gonadotropin (hCG) stimulates thyroid function during pregnancy. We recently showed that thyroid autoimmunity severely attenuated the thyroidal response to hCG stimulation and that this may underlie the higher risk of premature delivery in thyroperoxidase antibody (TPOAb)-positive women. We hypothesized that a lower thyroidal response to hCG stimulation in TPOAb-negative women is also associated with a higher risk of premature delivery and preterm premature rupture of membranes (pPROM). Design, Setting, and Participants: Thyrotropin (TSH), free thyroxine (FT4), and hCG concentrations were available in 5644 TPOAb-negative women from a prospective cohort. We tested for interaction between TSH or FT4 and hCG in linear regression models for duration of pregnancy and logistic regression models for premature delivery/pPROM. Accordingly, analyses were stratified per TSH percentile (TSH >= 85th percentile) and hCG per 10,000 IU/L. Results: Women with high TSH and low hCG concentrations did not have a higher risk of premature delivery or pPROM, with protective effect estimates. In contrast, women with a high TSH concentration despite a high hCG concentration had twofold to 10-fold higher risk of premature delivery (Pdifference = 0.022) and an up to fourfold higher risk of pPROM (Pdifference = 0.079). hCG concentrations were not associated with premature delivery or pPROM. Conclusion: In TPOAb-negative women with high-normal TSH concentrations, only women with high hCG concentrations had a higher risk of premature delivery or pPROM. These results suggest a lower thyroidal response to hCG stimulation is also associated with premature delivery in TPOAb-negative women and that an additional measurement of hCG may improve thyroid-related risk assessments during pregnancy. PMID- 28911133 TI - Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit. AB - Context: The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown. Objective: To determine the role of kisspeptin in the developing HFA. Design: Experiments using H295R and primary HFA cells as in vitro models of the fetal adrenal. Association of plasma kisspeptin levels with HFA size in a longitudinal clinical study. Setting: Academic research center and tertiary fetal medicine unit. Participants: Thirty-three healthy pregnant women were recruited at their 12-week routine antenatal ultrasound scan. Main Outcome Measures: The spatiotemporal expression of Kiss1R in the HFA. The production of dehydroepiandrosterone sulfate (DHEAS) from HFA cells after kisspeptin treatment, alone or in combination with adrenocorticotropic hormone or corticotropin-releasing hormone. Fetal adrenal volume (FAV) and kisspeptin levels at four antenatal visits (~20, 28, 34, and 38 weeks' gestation). Results: Expression of Kiss1R was present in the HFA from 8 weeks after conception to term and was shown in the inner fetal zone. Kisspeptin significantly increased DHEAS production in H295R and second-trimester HFA cells. Serial measurements of kisspeptin confirmed a correlation with FAV growth in the second trimester, independent of sex or estimated fetal weight. Conclusions: Kisspeptin plays a key role in the regulation of the HFA and thus the fetoplacental unit, particularly in the second trimester of pregnancy. PMID- 28911135 TI - Is It Me or My Hormones? Neuroendocrine Activation Profiles to Visual Food Stimuli Across the Menstrual Cycle. AB - Context: Homeostatic energy balance is controlled via the hypothalamus, whereas regions controlling reward and cognitive decision-making are critical for hedonic eating. Eating varies across the menstrual cycle peaking at the midluteal phase. Objective: To test responses of females with regular cycles during midfollicular and midluteal phase and of users of monophasic oral contraception pills (OCPs) to visual food cues. Design: Participants performed a functional magnetic resonance imaging while exposed to visual food cues in four time points: fasting and fed conditions in midfollicular and midluteal phases. Patients: Twenty females with regular cycles and 12 on monophasic OCP, aged 18 to 35 years. Main Outcome Measures: Activity in homeostatic (hypothalamus), reward (amygdala, putamen and insula), frontal (anterior cingulate cortex, dorsolateral prefrontal cortex), and visual regions (calcarine and lateral occipital cortex). Setting: Tertiary hospital. Results: In females with regular cycles, brain regions associated with homeostasis but also the reward system, executive frontal areas, and afferent visual areas were activated to a greater degree during the luteal compared with the follicular phase. Within the visual areas, a dual effect of hormonal and prandial state was seen. In females on monophasic OCPs, characterized by a permanently elevated progesterone concentration, activity reminiscent of the luteal phase was found. Androgen, cortisol, testosterone, and insulin levels were significantly correlated with reward and visual region activation. Conclusions: Hormonal mechanisms affect the responses of women's homeostatic, emotional, and attentional brain regions to food cues. The relation of these findings to eating behavior throughout the cycle needs further investigation. PMID- 28911136 TI - Protein-Rich Food Ingestion Stimulates Mitochondrial Protein Synthesis in Sedentary Young Adults of Different BMIs. AB - Context: Excess fat mass may diminish the anabolic potency of protein-rich food ingestion to stimulate muscle protein subfractional synthetic responses. However, the impact of adiposity on mitochondrial protein synthesis (MPS) rates after protein-rich food ingestion has not been thoroughly examined in vivo in humans. Objective: We compared basal and postprandial MPS and markers of muscle inflammation [toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) protein content] in young adults with different body mass indices (BMIs). Methods: Ten normal-weight (NW; BMI = 22.7 +/- 0.4 kg/m2), 10 overweight (OW; BMI = 27.1 +/- 0.5 kg/m2), and 10 obese (OB; BMI = 35.9 +/- 1.3 kg/m2) adults received primed continuous L-[ring-13C6]phenylalanine infusions, blood sampling, and skeletal muscle biopsies before and after the ingestion of 170 g of pork. Results: Pork ingestion increased muscle TLR4 and MyD88 protein content in the OB group (P < 0.05), but not in the NW or OW groups. Basal MPS was similar between groups (P > 0.05). Pork ingestion stimulated MPS (P < 0.001; 0 to 300 minutes) in the NW (2.5- +/- 0.6-fold above baseline values), OW (1.7- +/- 0.3-fold), and OB groups (2.4- +/- 0.5-fold) with no group differences (P > 0.05). Conclusions: Protein-dense food ingestion promotes muscle inflammatory signaling only in OB adults. However, the consumption of a dinner sized amount of protein strongly stimulated a postprandial MPS response irrespective of BMI. Our data suggest that alterations in postprandial MPS are unlikely to contribute to compromised muscle macronutrient metabolism witnessed with obesity. PMID- 28911137 TI - Cardiovascular Diseases and Life Expectancy in Adults With Type 2 Diabetes: A Korean National Sample Cohort Study. AB - Objective: Although type 2 diabetes is a strong risk factor for cardiovascular disease and mortality, information on its association with mortality and life expectancy according to cardiovascular comorbidities is limited, especially in Asia. Thus, this study assessed mortality and reductions in life expectancy associated with cardiometabolic multimorbidity. Design and Methods: A total of 569,831 participants older than 30 years from Korean National Health Insurance Service-National Sample Cohort were enrolled between 2002 and 2006 and followed for a median of 12.0 years. They were categorized into five mutually exclusive groups according to baseline disease status, as follows: none (reference group); diabetes only; diabetes and stroke; diabetes and myocardial infarction (MI); and diabetes, stroke, and MI. Mortality rates and hazard ratios (HRs), reductions of life expectancy, and age-specific contributions to life expectancy were calculated by constructing life tables. Results: The mortality rates per 1000 person-years were 6.85, 19.86, 67.17, 66.34, and 115.52 in the reference, diabetes only; diabetes and stroke; diabetes and MI; and diabetes, stroke, and MI groups, respectively. The corresponding HRs for all-cause mortality were 1.70 [95% confidence interval (CI), 1.66 to 1.75], 3.66 (95% CI, 3.32 to 4.03), 3.56 (95% CI, 3.06 to 4.14), and 4.79 (95% CI, 3.05 to 7.50) compared with the reference group. The estimated reductions in life expectancy were greater at younger ages and markedly increased with more cardiometabolic comorbidities. Conclusion: Young Asians with type 2 diabetes, especially those with cardiovascular comorbidity, did not live as long than their nondiabetic equivalents. Thus, these individuals require special attention to prevent further reductions in life expectancy. PMID- 28911138 TI - Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion. AB - Context: Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. Objective: We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. Design, Setting, and Participants: In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index-matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11beta-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Results: Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 pm to 10 pm [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 pm to 2 am (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 pm and 250 mg at 10 pm, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 pm to 10 pm (AUC difference: -0.06 nmol/L/h; P = 0.85); 10 pm to 2 am (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 pm to 2 pm (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. Conclusions: In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6. PMID- 28911140 TI - Parity and Risk of Thyroid Autoimmunity Based on the NHANES (2001-2002, 2007 2008, 2009-2010, and 2011-2012). AB - Context: Autoimmune thyroid disease is more common in women than in men. Fetal microchimerism has been implicated as a potential explanation for this disparity. Objective: The objective of this study was to evaluate the relationship between parity and thyroid autoimmunity in the US population. Design, Setting, Patients: The National Health and Nutrition Examination Survey was used to identify females with antithyroperoxidase (TPOAb) and antithyroglobulin antibody (TgAb) measurements and parity data. Subjects (n = 4864) were categorized as never pregnant (n = 909) or previously pregnant (n = 3955). The association of parity with thyroid autoantibodies was examined both qualitatively and quantitatively. Thyroid autoimmunity was defined as TPOAb and/or TgAb titers above the reference limits. Results: Previous pregnancy carried an odds ratio (OR) of 1.55 [95% confidence interval (CI): 1.26 to 1.91] for thyroid autoimmunity compared with never pregnant. Number of pregnancies was associated with thyroid autoimmunity: OR = 1.37 (95% CI: 1.02 to 1.84); 1.4 (95% CI: 1.08 to 1.81); 1.52 (95% CI: 1.18 to 1.96); and 1.73 (95% CI: 1.38 to 2.18) for 1, 2, 3, and >=4 pregnancies, respectively. Because ever-pregnant women differed in several variables-age, race, smoking status, history of thyroid disease, and urinary iodine level-from never-pregnant women (P < 0.001), a multivariate regression analysis was performed, which showed no association of pregnancy with thyroid autoimmunity. The association was further examined utilizing an age-matched analysis, which confirmed the absence of an association between thyroid autoimmunity and parity. Conclusion: Although we initially observed a strong association between parity and thyroid autoimmunity, after controlling for age and other variables, we were unable to identify an association. PMID- 28911139 TI - Preeclampsia Downregulates MicroRNAs in Fetal Endothelial Cells: Roles of miR 29a/c-3p in Endothelial Function. AB - Context: Preeclampsia is a leading cause of fetal and maternal morbidity and mortality during pregnancy. Although the etiology of preeclampsia is unknown, preeclampsia offspring have increased risks of developing cardiovascular disorders in adulthood, implicating that preeclampsia programs fetal vasculature in utero. Objective: We hypothesize that preeclampsia alters expression profiles of endothelial microRNAs (miRNAs) in fetal endothelial cells and disturbs the vascular endothelial growth factor A (VEGFA)- and fibroblast growth factor 2 (FGF2)-induced endothelial function. Design and Setting: Unpassaged (P0) human umbilical vein endothelial cells (HUVECs) were isolated immediately after cesarean-section delivery from normotensive (NT) and preeclamptic (PE) pregnancies. Differentially expressed miRNAs between P0-HUVECs from NT and PE pregnancies were identified using a miRNA polymerase chain reaction (PCR) array and confirmed using reverse transcription quantitative PCR. To determine the function of these differentially expressed miRNAs, miRNAs of interest were knocked down in NT-HUVECs following by cell functional assays. Results: Sixteen miRNAs, including miR-29a/c-3p, were downregulated in P0-HUVECs from the PE group compared with the NT group. Bioinformatics analysis predicted the PI3K-v-akt murine thymoma viral oncogene homolog 1 (AKT) signaling pathway was dysregulated in P0-HUVECs from the PE group, which was associated with the miR-29a/c-3p downregulation. We further demonstrated that miR-29a/c-3p knockdown inhibited the VEGFA- and FGF2-induced endothelial migration as well as FGF2-induced AKT1 phosphorylation in HUVECs. However, miR-29a/c-3p knockdown did not alter the extracellular signal-regulated kinase 1/2 phosphorylation, cell proliferation, and endothelial monolayer integrity in response to VEGFA and FGF2 in HUVECs. Conclusions: Preeclampsia-downregulated miR-29a/c-3p may impair fetal endothelial function by disturbing the FGF2-activated PI3K-AKT signaling pathway, hence inhibiting endothelial cell migration. PMID- 28911141 TI - Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins. AB - Context: Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well defined. Objective: The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. Materials and Methods: In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. Results: Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. Conclusions: Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway. PMID- 28911142 TI - Deficient Endogenous Glucose Production During Exercise After Total Pancreatectomy/Islet Autotransplantation. AB - Context: Total pancreatectomy followed by intrahepatic islet autotransplantation (TP/IAT) is performed to alleviate severe, unrelenting abdominal pain caused by chronic pancreatitis, to improve quality of life, and to prevent diabetes. Objective: To determine the cause of exercise-induced hypoglycemia that is a common complaint in TP/IAT recipients. Design: Participants completed 1 hour of steady-state exercise. Setting: Hospital research unit. Patients and Other Participants: We studied 14 TP/IAT recipients and 10 age- and body mass index matched control subjects. Interventions: Peak oxygen uptake (VO2) was determined via a symptom-limited maximal cycle ergometer test. Fasted subjects then returned for a primed [6,6-2H2]-glucose infusion to measure endogenous glucose production while completing 1 hour of bicycle exercise at either 40% or 70% peak VO2. Main Outcome Measures: Blood samples were obtained to measure glucose metabolism and counterregulatory hormones before, during, and after exercise. Results: Although the Borg Rating of Perceived Exertion did not differ between recipients and control subjects, aerobic capacity was significantly higher in controls than in recipients (40.4 +/- 2.0 vs 27.2 +/- 1.4 mL/kg per minute; P < 0.001). This difference resulted in workload differences between control subjects and recipients to reach steady-state exercise at 40% peak VO2 (P = 0.003). Control subjects significantly increased their endogenous glucose production from 12.0 +/ 1.0 to 15.2 +/- 1.0 umol/kg per minute during moderate exercise (P = 0.01). Recipients did not increase endogenous glucose production during moderate exercise (40% peak VO2) but succeeded during heavy exercise, from 10.1 +/- 0.4 to 14.8 +/- 2.0 umol/kg per minute (70% peak VO2; P = 0.001). Conclusions: Failure to increase endogenous glucose production during moderate exercise may be a key contributor to the hypoglycemia TP/IAT recipients experience. PMID- 28911144 TI - Randomized Trial Comparing Two Algorithms for Levothyroxine Dose Adjustment in Pregnant Women With Primary Hypothyroidism. AB - Context: Regulation of maternal thyroid hormones during pregnancy is crucial for optimal maternal and fetal outcomes. There are no specific guidelines addressing maternal levothyroxine (LT4) dose adjustments throughout pregnancy. Objective: To compare two LT4 dose-adjustment algorithms in hypothyroid pregnant women. Design: Thirty-three women on stable LT4 doses were recruited at <10 weeks gestation during 38 pregnancies and randomized to one of two dose-adjustment groups. Group 1 (G1) used an empiric two-pill/week dose increase followed by subsequent pill per-week dose adjustments. In group 2 (G2), LT4 dose was adjusted in an ongoing approach in micrograms per day based on current thyroid stimulating hormone (TSH) level and LT4 dose. TSH was monitored every 2 weeks in trimesters 1 and 2 and every 4 weeks in trimester 3. Setting: Academic endocrinology clinics in Washington, DC. Main Outcome Measure: Proportion of TSH values within trimester specific goal ranges. Results: Mean gestational age at study entry was 6.4 +/- 2.1 weeks. Seventy-five percent of TSH values were within trimester-specific goal ranges in G1 compared with 81% in G2 (P = 0.09). Similar numbers of LT4 dose adjustments per pregnancy were required in both groups (G1, 3.1 +/- 2.0 vs G2, 4.1 +/- 3.2; P = 0.27). Women in G1 were more likely to have suppressed TSH <0.1 mIU/L in trimester 1 (P = 0.01). Etiology of hypothyroidism, but not thyroid antibody status, was associated with proportion of goal TSH values. Conclusions: We compared two options for LT4 dose adjustment and showed that an ongoing adjustment approach is as effective as empiric dose increase for maintaining goal TSH in hypothyroid women during pregnancy. PMID- 28911143 TI - Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma. AB - Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with overall poor prognosis. The Ki67 labeling index (LI) has a major prognostic role in localized ACC after complete resection, but its estimates may suffer from considerable intra- and interobserver variability. VAV2 overexpression induced by increased Steroidogenic Factor-1 dosage is an essential factor driving ACC tumor cell invasion. Objective: To assess the prognostic role of VAV2 expression in ACC by investigation of a large cohort of patients. Design, Setting, and Participants: A total of 171 ACC cases (157 primary tumors, six local recurrences, eight metastases) from seven European Network for the Study of Adrenal Tumors centers were studied. Outcome Measurements: H-scores were generated to quantify VAV2 expression. VAV2 expression was divided into two categories: low (H-score, <2) and high (H-score, >=2). The Ki67 LI retrieved from patients' pathology records was also categorized into low (<20%) and high (>=20%). Clinical and immunohistochemical markers were correlated with progression-free survival (PFS) and overall survival (OS). Results: VAV2 expression and Ki67 LI were significantly correlated with each other and with PFS and OS. Heterogeneity of VAV2 expression inside the same tumor was very low. Combined assessment of VAV2 expression and Ki67 LI improved patient stratification to low-risk and high-risk groups. Conclusion: Combined assessment of Ki67 LI and VAV2 expression improves prognostic prediction in ACC. PMID- 28911145 TI - Bone Mineral Density After Cessation of GH Treatment in Young Adults Born SGA: A 5-Year Longitudinal Study. AB - Context: Short children born small for gestational age (SGA) have below-average bone mineral density (BMD). Growth hormone (GH) treatment improves height and BMD in short SGA children. Longitudinal data on BMD in adults born SGA, after GH cessation (GH-stop), are lacking. Objective: To determine BMD in young adults born SGA during 5 years after GH-stop. Methods: In 173 GH-treated adults born SGA (SGA-GH), BMD of total body (BMDTB) and bone mineral apparent density of lumbar spine (BMADLS) were measured longitudinally at adult height (AH) and 6 months, 2 years, and 5 years thereafter. At 5 years after GH-stop (age 21 years), data were compared with 45 untreated short SGA adults (SGA-S), 59 SGA adults with spontaneous catch-up (SGA-CU), and 81 adults born appropriate for gestational age (AGA). Results: At GH-stop (mean age 16.4 years), estimated mean (standard error) BMDTB standard deviation score (SDS) was -0.40 (0.1) in males and -0.51 (0.1) in females, followed by a trend toward a decrease of BMDTB in males to -0.59 (0.1) at 5 years after GH-stop (P = 0.06), whereas it remained stable in females [-0.57 (0.1); P = 0.33]. At GH-stop, BMADLS SDS was -0.01 (0.1) in males and -0.29 (0.1) in females, followed by a decrease in males and females to -0.38 and -0.55, respectively, at 5 years after GH-stop (P < 0.001). At 5 years after GH-stop, BMDTB and BMADLS in SGA-GH were similar compared with SGA-S, SGA-CU, and AGA. Conclusion: After GH-stop, there is a gradual decline of BMADLS, but at the age of 21 years, BMDTB and BMADLS are similar as in untreated short SGA adults. PMID- 28911146 TI - Anemia in Patients With Resistance to Thyroid Hormone alpha: A Role for Thyroid Hormone Receptor alpha in Human Erythropoiesis. AB - Context: Patients with resistance to thyroid hormone (TH) alpha (RTHalpha) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHalpha patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)alpha in erythropoiesis. Objective: To investigate whether a defect in TRalpha affects the maturation of red blood cells in RTHalpha patients. Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHalpha patients (n = 11) harboring different inactivating mutations in TRalpha (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points. Results: After ~14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHalpha-derived cells differentiated more slowly. During spontaneous differentiation, RTHalpha-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHalpha-derived progenitors did not correlate with severity of underlying TRalpha defect. Both control and RTHalpha-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHalpha patient-derived HEPs. Conclusions: Inactivating mutations in human TRalpha affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTHalpha patients. PMID- 28911147 TI - KIF5B/RET Rearrangement in a Carcinoma of the Thyroid Gland: A Case Report of a Fatal Disease. AB - Background: The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC. Case: An advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases. The patient died after 6 months from the initial diagnosis. The histological revision of the thyroid tumor confirmed the diagnosis of DSV-PTC, and its molecular analysis revealed a KIF5B/RET rearrangement that, until now, was described only in a minority of lung adenocarcinoma. Other 18 cases of DSV-PTC were then studied for the presence of KIF5B/RET rearrangement, but all of them were negative. Conclusions: This was a case of DSV-PTC positive for KIF5B/RET rearrangement, but considering that this alteration has been described only in lung adenocarcinoma and that the clinical course was more typical of lung carcinoma, we cannot completely rule out the possibility that this was a metastatic lesion from a lung tumor mimicking a DSV-PTC. As an alternative, we can also hypothesize that this was a case of fusion of two tumoral tissues deriving from a DSV-PTC and a metastasis of a KIF5B/RET positive lung adenocarcinoma. The question of whether the molecular findings, particularly when specifically reported only in some subtypes of human tumors, can overcome the morphological diagnosis is a matter of discussion. PMID- 28911148 TI - Age-Related Anabolic Resistance of Myofibrillar Protein Synthesis Is Exacerbated in Obese Inactive Individuals. AB - Context: A diminished muscle anabolic response to protein nutrition may underpin age-associated muscle loss. Objective: To determine how chronological and biological aging influence myofibrillar protein synthesis (MyoPS). Design: Cross sectional comparison. Setting: Clinical research facility. Participants: Ten older lean [OL: 71.7 +/- 6 years; body mass index (BMI) <=25 kg ? m-2], 7 older obese (OO: 69.1 +/- 2 years; BMI >=30 kg ? m-2), and 18 young lean (YL) individuals (25.5 +/- 4 years; BMI <=25 kg ? m-2). Intervention: Skeletal muscle biopsies obtained during a primed-continuous infusion of l-[ring-13C6] phenylalanine. Main Outcome Measures: Anthropometrics, insulin resistance, inflammatory markers, habitual diet, physical activity, MyoPS rates, and fiber type characteristics. Results: Fat mass, insulin resistance, inflammation, and type II fiber intramyocellular lipid were greater, and daily step count lower, in OO compared with YL and OL. Postprandial MyoPS rates rose above postabsorptive values by ~81% in YL (P < 0.001), ~38% in OL (P = 0.002, not different from YL), and ~9% in OO (P = 0.11). Delta change in postprandial MyoPS from postabsorptive values was greater in YL compared with OL (P = 0.032) and OO (P < 0.001). Absolute postprandial MyoPS rates and delta postprandial MyoPS change were associated with step count (r2 = 0.33; P = 0.015) and leg fat mass (r2 = 0.4; P = 0.006), respectively, in older individuals. Paradoxically, lean mass was similar between groups, and muscle fiber area was greater in OO vs OL (P = 0.002). Conclusion: Age-related muscle anabolic resistance is exacerbated in obese inactive individuals, with no apparent detriment to muscle mass. PMID- 28911149 TI - Insulin-Like Growth Factor Bioactivity, Stanniocalcin-2, Pregnancy-Associated Plasma Protein-A, and IGF-Binding Protein-4 in Pleural Fluid and Serum From Patients With Pulmonary Disease. AB - Context: Members of the insulin-like growth factor (IGF) system are primarily produced in the liver and secreted into the circulation, but they are also produced, recruited, and activated locally in tissues. Objective: To compare activity and concentrations of IGF system components in pleural fluid and blood. Design: Pathological pleural fluid, secondary to lung cancer or nonmalignant disease, and matching blood samples were collected from 24 patients ages 66.7 to 81.9 years. Methods: IGF-related proteins and cytokine levels were measured by immunoassays or immunoblotting. Bioactive IGF was measured by an IGF-1 receptor phosphorylation assay. Results: Total IGF-1 concentration did not differ between the compartments, but concentrations of free IGF-1 and bioactive IGF were more than threefold higher in pleural fluid than in corresponding serum samples (P = 0.0004), regardless of etiology. Median pregnancy-associated plasma protein-A (PAPP-A) and interleukin (IL)-6 levels were increased 47-fold and 143-fold, respectively, in pleural fluid compared with plasma (P < 0.0001). PAPP-A and IL-6 concentrations correlated positively (r = 0.46; P = 0.02). In pleural fluid, levels of PAPP-A-generated IGF binding protein-4 fragments correlated inversely with that of stanniocalcin-2 (r <= -0.42; P <= 0.05), a PAPP-A inhibitor; such correlations were absent in plasma. Conclusion: Pathological pleural fluid is characterized by increased in vitro IGF bioactivity and elevated concentrations of PAPP-A, an IGF-activating proteinase. Thus, the tissue activity of the IGF system may differ substantially from that of the circulating IGF system. The correlation between IL-6 and PAPP-A indicates that inflammation plays a role in promoting local tissue IGF activity. PMID- 28911150 TI - Provider and Site-Level Determinants of Testosterone Prescribing in the Veterans Healthcare System. AB - Context: Testosterone prescribing rates have increased substantially in the past decade. However, little is known about the context within which such prescriptions occur. Objective: We evaluated provider- and site-level determinants of receipt of testosterone and of guideline-concordant testosterone prescribing. Design: This study was cross-sectional in design. Setting: This study was conducted at the Veterans Health Administration (VA). Participants: Study participants were a national cohort of male patients who had received at least one outpatient prescription within the VA during fiscal year (FY) 2008 to FY 2012. A total of 38,648 providers and 130 stations were associated with these patients. Main Outcome Measure: This study measured receipt of testosterone and guideline-concordant testosterone prescribing. Results: Providers ranging in age from 31 to 60 years, with less experience in the VA [all adjusted odds ratio (AOR), <2; P < 0.01] and credentialed as medical doctors in endocrinology (AOR, 3.88; P < 0.01) and urology (AOR, 1.48; P < 0.01) were more likely to prescribe testosterone compared with older providers, providers of longer VA tenure, and primary care providers, respectively. Sites located in the West compared with the Northeast [AOR, 1.75; 95% confidence interval (CI), 1.45-2.11] and care received at a community-based outpatient clinic compared with a medical center (AOR, 1.22; 95% CI, 1.20-1.24) also predicted testosterone use. Although they were more likely to prescribe testosterone, endocrinologists were also more likely to obtain an appropriate workup before prescribing compared with primary care providers (AOR, 2.14; 95% CI, 1.54-2.97). Conclusions: Our results highlight the opportunity to intervene at both the provider and the site levels to improve testosterone prescribing. This study also provides a useful example of how to examine contributions to prescribing variation at different levels of the health care system. PMID- 28911151 TI - Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1. AB - Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results: We identified 112 patients with APS 1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-omega were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1. PMID- 28911153 TI - Estrogen Receptor alpha, a Sex-Dependent Predictor of Aggressiveness in Nonfunctioning Pituitary Adenomas: SSTR and Sex Hormone Receptor Distribution in NFPA. AB - Context: Nonfunctioning pituitary adenomas (NFPAs) are fairly common and require a multidisciplinary approach. Reliable markers of a clinically aggressive course are lacking. Medical treatment is not available, and transsphenoidal surgery is the preferred primary treatment. Objective: We aimed to characterize the somatostatin, estrogen, and progesterone receptor distribution for NFPAs and compare it with factors of tumor aggressiveness. Design: Tumor samples for immunohistochemistry (n = 145) and quantitative reverse transcription polymerase chain reaction (n = 106) analyses of somatostatin receptor (SSTR) 1, SSTR2, SSTR3, SSTR5, estrogen receptor alpha (ERalpha), and progesterone receptor (PR) were measured by immunoreactive score (IRS) and messenger RNA relative quantity and retrospectively compared with variables of aggressiveness. Setting: All patients were operated at the same tertiary referral center. Participants: A total of 164 patients with NFPA and tumor tissue from the primary operation were included. Results: SSTR3 was expressed abundantly by immunohistochemistry in all NFPAs. The IRS of ERalpha correlated with that of SSTR2 in male patients only (males, P < 0.001; females, P = 0.8). Low ERalpha level was linked to a higher reintervention rate (P = 0.001) and earlier reintervention (P = 0.004) in male patients only (females, P = 0.95 and P = 0.65, respectively). Absence of ERalpha together with age provided a good prediction model for reintervention in male patients with gonadotroph adenomas. Conclusions: SSTR3 is expressed abundantly in NFPAs and is therefore a possible target for medical treatment. Absence of ERalpha together with young age may predict tumor recurrence in groups of NFPAs. Further validation in systematic prospective studies is needed. PMID- 28911152 TI - Hypothalamic Glucose Transport in Humans During Experimentally Induced Hypoglycemia-Associated Autonomic Failure. AB - Context: Upregulated brain glucose transport in response to recurrent hypoglycemia may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) and impaired awareness of hypoglycemia. Whether recurrent hypoglycemia alters glucose transport in the hypothalamus is unknown. Objective: To test the hypothesis that hypothalamic glucose transport will increase in healthy volunteers preconditioned with recurrent hypoglycemia to induce HAAF. Setting: University medical center. Design and Participants: Thirteen healthy subjects underwent paired euglycemic and hypoglycemic preconditioning studies separated by at least 1 month. Following preconditioning, hypothalamic glucose transport was measured by magnetic resonance spectroscopy (MRS) in the afternoon on day 2 of each preconditioning protocol. Outcome Measure: The ratio of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRglc), obtained from MRS-measured glucose in the hypothalamus as a function of plasma glucose. Results: HAAF was successfully induced based on lower epinephrine, glucagon, and cortisol during the third vs first hypoglycemic preconditioning clamp (P <= 0.01). Hypothalamic glucose transport was not different following recurrent euglycemia vs hypoglycemia (Tmax/CMRglc 1.62 +/- 0.09 after euglycemia preconditioning and 1.75 +/- 0.14 after hypoglycemia preconditioning; P was not significant). Hypothalamic glucose concentrations measured by MRS were not different following the two preconditioning protocols. Conclusions: Glucose transport kinetics in the hypothalamus of healthy humans with experimentally induced HAAF were not different from those measured without HAAF. Future studies of patients with diabetes and impaired awareness of hypoglycemia will be necessary to determine if the existence of the diabetes state is required for this adaptation to hypoglycemia to occur. PMID- 28911154 TI - Prognostic Significance of Circulating RET M918T Mutated Tumor DNA in Patients With Advanced Medullary Thyroid Carcinoma. AB - Context: Interpretation of calcitonin measurement to predict the prognosis of medullary thyroid carcinoma (MTC) requires multiple measurements over an extended time period, making it an imperfect biomarker for evaluating prognosis or disease behavior. Single circulating cell-free DNA (cfDNA) values have been shown to be a valuable prognostic marker for several solid tumors. Objective: We tested the hypothesis that cfDNA containing the RET M918T mutation could be detected in the blood of patients with advanced MTC whose tumor harbored an M918T mutation and would be able to predict overall survival more reliably than calcitonin. Design: The level of cfDNA containing RET M918T mutation was measured in the plasma of patients with MTC via droplet digital polymerase chain reaction. Patients: Patients had a confirmed sporadic MTC diagnosis, a serum calcitonin measurement >100 pg/mL, and tumor tissue biopsy results providing RET M918T mutation status. There were 75 patients included in this study, 50 of whom harbored an RET M918T mutation by tissue biopsy. Results: RET M918T cfDNA was detected in 16 of 50 patients (32%) with a positive tissue biopsy. The detection of RET M918T cfDNA strongly correlated with worse overall survival and more accurately predicted a worse outcome than calcitonin doubling time. Conclusions: Liquid biopsy is able to detect RET M918T mutations in patient plasma with high specificity but low sensitivity. In patients with established somatic RET M918T mutations, the allelic fraction of circulating tumor DNA is prognostic for overall survival and may play a role in monitoring response to treatment. PMID- 28911156 TI - Letter to the Editor: Including the Zona Reticularis in the Definition of Hypoadrenalism and Hyperadrenalism. PMID- 28911155 TI - Differential Associations of Inflammatory Markers With Insulin Sensitivity and Secretion: The Prospective METSIM Study. AB - Context: Low-grade inflammation is involved in the development of type 2 diabetes and cardiovascular disease (CVD); however, prospective studies evaluating inflammatory markers as predictors of changes in insulin secretion and insulin sensitivity are lacking. Objective: We investigated the associations of glycoprotein acetyls (GlycA), interleukin-1 receptor antagonist (IL-1RA), and high-sensitivity C-reactive protein (hs-CRP) with insulin secretion, insulin sensitivity, incident type 2 diabetes, hypertension, CVD events, and total mortality in the prospective Metabolic Syndrome in Men (METSIM) study. Design: A prospective study. Participants: The cross-sectional METSIM study included 8749 nondiabetic Finnish men aged 45 to 73 years, who had been randomly selected from the population register of Kuopio, Finland. A total of 5401 men participated in the 6.8-year follow-up study. Main Outcome Measures: Changes in insulin secretion, insulin sensitivity, and cardiometabolic traits during the follow-up period and the incidence of type 2 diabetes, hypertension, CVD events, and total mortality. Results: During the follow-up period, GlycA was associated with impaired insulin secretion, hyperglycemia, incident type 2 diabetes (hazard ratio, 1.37; 95% confidence interval, 1.29 to 1.46) and CVD (hazard ratio, 1.21; 95% confidence interval, 1.12 to 1.32). IL-1RA and hs-CRP were associated with adverse changes in insulin sensitivity and obesity-related traits and with total mortality (hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.20; and hazard ratio, 1.08; 95% confidence interval, 1.04 to 1.11, respectively). Conclusions: Inflammatory markers differentially predicted changes in insulin secretion and insulin sensitivity. GlycA predicted impaired insulin secretion, and IL-1RA and hs-CRP predicted changes in insulin sensitivity. Combining the three markers improved the prediction of disease outcomes, suggesting that they capture different aspects of low-grade inflammation. PMID- 28911157 TI - Letter to the Editor: "Hypoparathyroidism: Less Severe Hypocalcemia With Treatment With Vitamin D2 Compared With Calcitriol". PMID- 28911158 TI - Letter to the Editor: "Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness". PMID- 28911159 TI - Letter to the Editor: "Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study". PMID- 28911160 TI - Response to Letter: "Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High Risk RET Mutations Do Not Predict Disease Aggressiveness". PMID- 28911161 TI - Letter to the Editor: Genetics and Vitamin D Supplementation in Pregnancy. PMID- 28911162 TI - Response to Letter: "Hypoparathyroidism: Less Severe Hypocalcemia With Treatment With Vitamin D2 Compared With Calcitriol". PMID- 28911163 TI - Response to Letter: "Calcium and Bone Turnover Markers in Acromegaly: A Prospective, Controlled Study". PMID- 28911164 TI - Response to Letter: Genetics and Vitamin D Supplementation in Pregnancy. PMID- 28911165 TI - Cellular Retinoic Acid-Binding Protein 1 Modulates Stem Cell Proliferation to Affect Learning and Memory in Male Mice. AB - Retinoic acid (RA) is the active ingredient of vitamin A. It exerts its canonical activity by binding to nuclear RA receptors (RARs) to regulate gene expression. Increasingly, RA is also known to elicit nongenomic RAR-independent activities, most widely detected in activating extracellular regulated kinase (ERK)1/2. This study validated the functional role of cellular retinoic acid-binding protein 1 (Crabp1) in mediating nongenomic activity in RA, specifically activating ERK1/2 to rapidly augment the cell cycle by expanding the growth 1 phase and slowing down embryonic stem cell and neural stem cell (NSC) proliferation. The study further uncovered the physiological activity of Crabp1 in modulating NSC proliferation and animal behavior. In the Crabp1 knockout mouse hippocampus, where Crabp1 is otherwise detected in the subgranular zone, neurogenesis and NSC proliferation increased and hippocampus-dependent brain functions such as learning and memory correspondingly improved. This study established the physiological role of Crabp1 in modulating stem cell proliferation and hippocampus-dependent brain activities such as learning and memory. PMID- 28911166 TI - Hormonal and Growth Regulation of Epithelial and Stromal Cells From the Normal and Malignant Endometrium by Pigment Epithelium-Derived Factor. AB - We discovered that pigment epithelium-derived factor (PEDF)-null mice have endometrial hyperplasia, the precursor to human type I endometrial cancer (ECA), which is etiologically linked to unopposed estrogen (E2), suggesting that this potent antiangiogenic factor might contribute to dysregulated growth and the development of type I ECA. Treatment of both ECA cell lines and primary ECA cells with recombinant PEDF dose dependently decreased cellular proliferation via an autocrine mechanism by blocking cells in G1 and G2 phases of the cell cycle. Consistent with the known opposing effects of E2 and progesterone (Pg) on endometrial proliferation, Pg increases PEDF protein synthesis and release, whereas E2 has the converse effect. Using PEDF luciferase promoter constructs containing two Pg and one E2 response elements, E2 reduced and Pg increased promoter activity due to distal response elements. Furthermore, E2 decreases and Pg increases PEDF secretion into conditioned media (CM) by both normal endometrial stromal fibroblasts (ESFs) and cancer-associated fibroblasts (CAFs), but only CM from ESFs mediated growth-inhibitory activity of primary endometrial epithelial cells (EECs). In addition, in cocultures with primary EECs, Pg-induced growth inhibition is mediated by ESFs, but not CAFs. This is consistent with reduced levels of Pg receptors on CAFs surrounding human malignant glands in vivo. Taken together, the data suggest that PEDF is a hormone-regulated negative autocrine mediator of endometrial proliferation, and that paracrine growth inhibition by soluble factors, possibly PEDF, released by ESFs in response to Pg, but not CAFs, exemplifies a tumor microenvironment that contributes to the pathogenesis of ECA. PMID- 28911167 TI - In Utero Exposure to a High-Fat Diet Programs Hepatic Hypermethylation and Gene Dysregulation and Development of Metabolic Syndrome in Male Mice. AB - Exposure to a high-fat (HF) diet in utero is associated with increased incidence of cardiovascular disease, diabetes, and metabolic syndrome later in life. However, the molecular basis of this enhanced susceptibility for metabolic disease is poorly understood. Gene expression microarray and genome-wide DNA methylation analyses of mouse liver revealed that exposure to a maternal HF milieu activated genes of immune response, inflammation, and hepatic dysfunction. DNA methylation analysis revealed 3360 differentially methylated loci, most of which (76%) were hypermethylated and distributed preferentially to hotspots on chromosomes 4 [atherosclerosis susceptibility quantitative trait loci (QTLs) 1] and 18 (insulin-dependent susceptibility QTLs 21). Interestingly, we found six differentially methylated genes within these hotspot QTLs associated with metabolic disease that maintain altered gene expression into adulthood (Arhgef19, Epha2, Zbtb17/Miz-1, Camta1 downregulated; and Ccdc11 and Txnl4a upregulated). Most of the hypermethylated genes in these hotspots are associated with cardiovascular system development and function. There were 140 differentially methylated genes that showed a 1.5-fold increase or decrease in messenger RNA levels. Many of these genes play a role in cell signaling pathways associated with metabolic disease. Of these, metalloproteinase 9, whose dysregulation plays a key role in diabetes, obesity, and cardiovascular disease, was upregulated 1.75 fold and hypermethylated in the gene body. In summary, exposure to a maternal HF diet causes DNA hypermethylation, which is associated with long-term gene expression changes in the liver of exposed offspring, potentially contributing to programmed development of metabolic disease later in life. PMID- 28911168 TI - Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Mediators of Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep. AB - Prenatal testosterone (T) excess in sheep leads to peripheral insulin resistance (IR), reduced adipocyte size, and tissue-specific changes, with liver and muscle but not adipose tissue being insulin resistant. To determine the basis for the tissue-specific differences in insulin sensitivity, we assessed changes in negative (inflammation, oxidative stress, and lipotoxicity) and positive mediators (adiponectin and antioxidants) of insulin sensitivity in the liver, muscle, and adipose tissues of control and prenatal T-treated sheep. Because T excess leads to maternal hyperinsulinemia, fetal hyperandrogenism, and functional hyperandrogenism and IR in their female offspring, prenatal and postnatal interventions with antiandrogen, flutamide, and the insulin sensitizer rosiglitazone were used to parse out the contribution of androgenic and metabolic pathways in programming and maintaining these defects. Results showed that (1) peripheral IR in prenatal T-treated female sheep is related to increases in triglycerides and 3-nitrotyrosine, which appear to override the increase in high molecular-weight adiponectin; (2) liver IR is a function of the increase in oxidative stress (3-nitrotyrosine) and lipotoxicity; (3) muscle IR is related to lipotoxicity; and (4) the insulin-sensitive status of visceral adipose tissue appears to be a function of the increase in antioxidants that likely overrides the increase in proinflammatory cytokines, macrophages, and oxidative stress. Prenatal and postnatal intervention with either antiandrogen or insulin sensitizer had partial effects in preventing or ameliorating the prenatal T induced changes in mediators of insulin sensitivity, suggesting that both pathways are critical for the programming and maintenance of the prenatal T induced changes and point to potential involvement of estrogenic pathways. PMID- 28911169 TI - Obesity-Induced Infertility in Male Mice Is Associated With Disruption of Crisp4 Expression and Sperm Fertilization Capacity. AB - Approximately 15% of human couples of reproductive age have impaired fertility, and the male component accounts for about half of these cases. The etiology is usually unknown, but high correlation with the increase in obesity rates is documented. In this study, we show that diet-induced and genetically obese mice display copulatory behavior comparable to controls, but the number of females impregnated by obese males is remarkably low. Screening for changes in gene expression in the male reproductive tract showed decreased Crisp4 expression in testis and epididymis of obese mice. Lack of CRISP4 in the luminal membrane of epididymal cells indicated inadequate secretion. Consistent with CRISP4 action in acrosome reaction, sperm from mice fed a high-fat diet (HFD) had decreased fertilization capacity. CRISP4 treatment of sperm from HFD mice prior to in vitro fertilization improved fertilization rate. In leptin-deficient obese and infertile mice, leptin's effect to restore CRISP4 expression and function required gonadal hormones. Our findings indicate that the obesity-induced decline in sperm motility and fertilization capacity results in part from the disruption of epididymal CRISP4 expression and secretion. PMID- 28911170 TI - Sertoli Cell Number Defines and Predicts Germ and Leydig Cell Population Sizes in the Adult Mouse Testis. AB - Sertoli cells regulate differentiation and development of the testis and are essential for maintaining adult testis function. To model the effects of dysregulating Sertoli cell number during development or aging, we have used acute diphtheria toxin-mediated cell ablation to reduce Sertoli cell population size. Results show that the size of the Sertoli cell population that forms during development determines the number of germ cells and Leydig cells that will be present in the adult testis. Similarly, the number of germ cells and Leydig cells that can be maintained in the adult depends directly on the size of the adult Sertoli cell population. Finally, we have used linear modeling to generate predictive models of testis cell composition during development and in the adult based on the size of the Sertoli cell population. This study shows that at all ages the size of the Sertoli cell population is predictive of resulting testicular cell composition. A reduction in Sertoli cell number/proliferation at any age will therefore lead to a proportional decrease in germ cell and Leydig cell numbers, with likely consequential effects on fertility and health. PMID- 28911171 TI - Sirtuin-3 Promotes Adipogenesis, Osteoclastogenesis, and Bone Loss in Aging Male Mice. AB - Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice. Bone marrow stromal cells (BMSCs) from Sirt3Tg mice displayed an enhanced ability to differentiate into adipocytes compared with control BMSCs. We found a 2.5-fold increase in the number of osteoclasts on the bone surface in Sirt3Tg mice compared with control mice (P < 0.03), and increased osteoclastogenesis in vitro. Importantly, Sirt3 activates the mechanistic target of rapamycin (mTOR) pathway to regulate osteoclastogenesis. Sirt3Tg male mice exhibited a significant reduction in cortical thickness at the tibiofibular junction (P < 0.05). In summary, Sirt3 activity in bone marrow cells is associated with increased adipogenesis, increased osteoclastogenesis through activation of mTOR signaling, and reduced bone mass. Interestingly, Sirt3 expression in bone marrow cells increases during aging, suggesting that Sirt3 promotes age-related adipogenesis and osteoclastogenesis associated with bone loss. These findings identify Sirt3 as an important regulator of adipogenesis and skeletal homeostasis in vivo and identify Sirt3 as a potential target for the treatment of osteoporosis. PMID- 28911172 TI - Androgens Mediate Sex-Dependent Gonadotropin Expression During Late Prenatal Development in the Mouse. AB - Central organization of the hypothalamic-pituitary-gonadal axis is initiated during fetal life. At this critical time, gonadal hormones mediate sex-specific development of the hypothalamic-pituitary axis, which then dictates reproductive physiology and behavior in adulthood. Although studies have investigated the effects of prenatal androgens on central factors influencing gonadotropin releasing hormone (GnRH) release, the impact of fetal androgens on gonadotrope function has been overlooked. In the current study, we demonstrated that gonadotropin gene expression and protein production were robustly elevated in female mice compared with males during late fetal development and that this sex difference was dependent on fetal androgens. Treatment of dams from embryonic day (E)15.5 to E17.5 with testosterone, dihydrotestosterone (DHT), or the androgen antagonist flutamide eliminated the sex difference at E18.5. Specifically, flutamide relieved the suppression in male gene expression, elevating the level to that of females, whereas testosterone or DHT attenuated female gene expression to male levels. The gonadotrope population is equivalent in males and females, and gonadotropic cells in both sexes express androgen receptors, suggesting that androgen-dependent transcriptional regulation can occur in these cells in either sex. Studies using mouse models lacking GnRH signaling show that GnRH is necessary for enhanced gonadotropin expression in females and is therefore required to observe the sex difference. Collectively, these data suggest that circuits controlling GnRH input to the fetal pituitary are unrestrained in females yet robustly inhibited in males via circulating androgens and demonstrate plasticity in gonadotropin synthesis and secretion in both sexes depending on the androgen milieu during late prenatal development. PMID- 28911173 TI - Lithium Chloride Increases COX-2 Expression and PGE2 Production in a Human Granulosa-Lutein SVOG Cell Line Via a GSK-3beta/beta-Catenin Signaling Pathway. AB - Lithium chloride (LiCl) is widely prescribed for the treatment of bipolar disorders and is associated with a higher incidence of reproductive adverse effects. Cyclooxygenase (COX)-2 and its derivative, prostaglandin E2 (PGE2), play regulatory roles in the human ovulatory process. Whether LiCl affects ovulation by regulating COX2 expression and PGE2 production in the human ovary is still largely unknown. The aim of this study was to investigate the effect of LiCl on the expression of COX-2 and production of PGE2 in human granulosa-lutein (hGL) cells, as well as the mechanisms underlying this effect. Both immortalized and primary hGL cells were used as research models. Using dual inhibition approaches, our results show that LiCl initiates the hGL cellular action by inhibiting the activity of glycogen synthase kinase-3beta [GSK-3beta (phosphorylation of GSK 3beta)] and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not by affecting protein kinase B or cAMP response element binding protein signaling. Additionally, the phosphorylation of GSK-3beta, but not ERK1/2, resulted in the stabilization and nuclear localization of beta-catenin. Furthermore, knockdown of either beta-catenin or GSK-3beta reversed the LiCl induced upregulation of COX-2 expression. These results indicate that LiCl upregulates the expression of COX-2 and the subsequent production of PGE2 through the canonical GSK-3beta/beta-catenin signaling pathway in hGL cells. PMID- 28911174 TI - Sex Reversal and Comparative Data Undermine the W Chromosome and Support Z-linked DMRT1 as the Regulator of Gonadal Sex Differentiation in Birds. AB - The exact genetic mechanism regulating avian gonadal sex differentiation has not been completely resolved. The most likely scenario involves a dosage mechanism, whereby the Z-linked DMRT1 gene triggers testis development. However, the possibility still exists that the female-specific W chromosome may harbor an ovarian determining factor. In this study, we provide evidence that the universal gene regulating gonadal sex differentiation in birds is Z-linked DMRT1 and not a W-linked (ovarian) factor. Three candidate W-linked ovarian determinants are HINTW, female-expressed transcript 1 (FET1), and female-associated factor (FAF). To test the association of these genes with ovarian differentiation in the chicken, we examined their expression following experimentally induced female-to male sex reversal using the aromatase inhibitor fadrozole (FAD). Administration of FAD on day 3 of embryogenesis induced a significant loss of aromatase enzyme activity in female gonads and masculinization. However, expression levels of HINTW, FAF, and FET1 were unaltered after experimental masculinization. Furthermore, comparative analysis showed that FAF and FET1 expression could not be detected in zebra finch gonads. Additionally, an antibody raised against the predicted HINTW protein failed to detect it endogenously. These data do not support a universal role for these genes or for the W sex chromosome in ovarian development in birds. We found that DMRT1 (but not the recently identified Z linked HEMGN gene) is male upregulated in embryonic zebra finch and emu gonads, as in the chicken. As chicken, zebra finch, and emu exemplify the major evolutionary clades of birds, we propose that Z-linked DMRT1, and not the W sex chromosome, regulates gonadal sex differentiation in birds. PMID- 28911175 TI - Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance. AB - Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females. PMID- 28911177 TI - Deoxycorticosterone/Salt-Mediated Cardiac Inflammation and Fibrosis Are Dependent on Functional CLOCK Signaling in Male Mice. AB - Activation of the mineralocorticoid receptor (MR) promotes inflammation, fibrosis, and hypertension. Clinical and experimental studies show that MR antagonists have significant therapeutic benefit for all-cause heart failure; however, blockade of renal MRs limits their widespread use. Identification of key downstream signaling mechanisms for the MR in the cardiovascular system may enable development of targeted MR antagonists with selectivity for pathological MR signaling and lower impact on physiological renal electrolyte handling. One candidate pathway is the circadian clock, the dysregulation of which is associated with cardiovascular diseases. We have previously shown that the circadian gene Per2 is dysregulated in hearts with selective deletion of cardiomyocyte MR. We therefore investigated MR-mediated cardiac inflammation and fibrosis in mice that lack normal regulation and oscillation of the circadian clock in peripheral tissues, that is, CLOCKDelta19 mutant mice. The characteristic cardiac inflammatory/fibrotic response to a deoxycorticosterone (DOC)/salt for 8 weeks was significantly blunted in CLOCKDelta19 mice when compared with wild-type mice, despite a modest increase at "baseline" for fibrosis and macrophage number in CLOCKDelta19 mice. In contrast, cardiac hypertrophy in response to DOC/salt was significantly greater in CLOCKDelta19 vs wild-type mice. Markers for renal inflammation and fibrosis were similarly attenuated in the CLOCKDelta19 mice given DOC/salt. Moreover, increased CLOCK expression in H9c2 cardiac cells enhanced MR-mediated transactivation of Per1, suggesting cooperative signaling between these transcription factors. This study demonstrates that the full development of MR-mediated cardiac inflammation and fibrosis is dependent on intact signaling by the circadian protein CLOCK. PMID- 28911176 TI - New Insights Into the Role of Estrogens in Male Fertility Based on Findings in Aromatase-Deficient Zebrafish. AB - It has been demonstrated that estrogens are indispensable for male fertility in mammals. Aromatase (encoded by CYP19) catalyzes the final step of estradiol biosynthesis. However, less is known about the role of aromatase in male fertility in nonmammalian species. Fish aromatase is encoded by two separate genes: the gonad-specific cyp19a1a and the brain-specific cyp19a1b. In a recent study, we used transcription activatorlike effector nucleases to systematically generate cyp19a1a and cyp19a1b mutant lines and a cyp19a1a;cyp19a1b double-mutant line in zebrafish and demonstrated that cyp19a1a was indispensable for sex differentiation. In this study, we focused on male fertility in these aromatase deficient zebrafish. Our results showed that all aromatase-deficient male fish had normal fertility even at 1 year after fertilization. Interestingly, we observed more spermatozoa in the cyp19a1a and double-mutant males than in the wild-type and cyp19a1b mutant males. The whole-body androgen levels, follicle stimulating hormone beta and luteinizing hormone beta protein levels in the pituitary, and transcript levels of genes known to be involved in spermatogenesis and steroidogenesis in the testes were significantly higher in the cyp19a1a mutant and aromatase double-mutant males than in the wild-type and cyp19a1b mutant males. These results might explain why more spermatozoa were observed in these fish. Collectively, our findings indicate that estrogens are not needed to achieve and maintain normal fertility in male zebrafish. This finding challenges the traditional view that estrogens are indispensable for male fertility. PMID- 28911178 TI - Naturally Occurring Amino Acids in Helix 10 of the Thyroid Hormone Receptor Mediate Isoform-Specific TH Gene Regulation. AB - Thyroid hormone (TH) action is mediated by the products of two genes, TH receptor (THR)alpha (THRA) and THRbeta (THRB) that encode several closely related receptor isoforms with differing tissue distributions. The vast majority of THR isoform specific effects are thought to be due to tissue-specific differences in THR isoform expression levels. We investigated the alternative hypothesis that intrinsic functional differences among THR isoforms mediate these tissue-specific effects. To achieve the same level of expression of each isoform, we created tagged THR isoforms and tested their DNA and functional properties in vitro. We found significant homodimerization and functional differences among the THR isoforms. THRA1 was unable to form homodimers on direct repeat separated by 4 bp DNA elements and was also defective in TH-dependent repression of Tshb and Rxrg in a thyrotroph cell line, TalphaT1.1. In contrast, THRB2 was both homodimer sufficient and fully functional on these negatively regulated genes. Using domain exchanges and individual amino acid switches between THRA1 and THRB2, we identified three amino acids in helix 10 of the THRB2 ligand-binding domain that are required for negative regulation and are absent in THRA1. PMID- 28911179 TI - Deciphering the Function of the Blunt Circadian Rhythm of Melatonin in the Newborn Lamb: Impact on Adrenal and Heart. AB - Neonatal lambs, as with human and other neonates, have low arrhythmic endogenous levels of melatonin for several weeks until they start their own pineal rhythm of melatonin production at approximately 2 weeks of life. During pregnancy, daily rhythmic transfer of maternal melatonin to the fetus has important physiological roles in sheep, nonhuman primates, and rats. This melatonin rhythm provides a circadian signal and also participates in adjusting the physiology of several organs in preparation for extrauterine life. We propose that the ensuing absence of a melatonin rhythm plays a role in neonatal adaptation. To test this hypothesis, we studied the effects of imposing a high-amplitude melatonin rhythm in the newborn lamb on (1) clock time-related changes in cortisol and plasma variables and (2) clock time-related changes of gene expression of clock genes and selected functional genes in the adrenal gland and heart. We treated newborn lambs with a daily oral dose of melatonin (0.25 mg/kg) from birth to 5 days of age, recreating a high-amplitude melatonin rhythm. This treatment suppressed clock time-related changes of plasma adrenocorticotropic hormone, cortisol, clock gene expression, and functional genes in the newborn adrenal gland. In the heart, it decreased heart/body weight ratio, increased expression of Anp and Bnp, and resulted in different heart gene expression from control newborns. The interference of this postnatal melatonin treatment with the normal postnatal pattern of adrenocortical function and heart development support a physiological role for the window of flat postnatal melatonin levels during the neonatal transition. PMID- 28911180 TI - Central Oxytocin and Energy Balance: More Than Feelings. PMID- 28911181 TI - High-Fat Diet and Pregnancy: Are You Ready To Take Risks for Your Offspring? PMID- 28911182 TI - Retinoid Actions: A New Horizon. PMID- 28911183 TI - CORRIGENDUM FOR "A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes". PMID- 28911184 TI - Subcellular localization and function study of a secreted phospholipase C from Nocardia seriolae. AB - Fish nocardiosis is a chronic systemic granulomatous disease, and Nocardia seriolae is the main pathogen that causes it. The pathogenesis and virulence factors of N. seriolae are not fully understood. A phospholipase C (PLC), which is likely to be a secreted protein targeting host cell mitochondria, was found by a bioinformatics analysis of the whole genome sequence of N. seriolae. In order to determine the subcellular localization and study the preliminary function of PLC from N. seriolae (NsPLC), in this study gene cloning, secreted protein identification, subcellular localization in host cells and apoptosis detection of NsPLC were carried out. Mass spectrometry analysis of extracellular products from N. seriolae showed that NsPLC was a secreted protein. Subcellular localization of NsPLC-GFP fusion protein in fathead minnow (FHM) cells revealed that the green fluorescence exhibited a punctate distribution near the nucleus and did not co localize with mitochondria. In addition, an apoptosis assay suggested that apoptosis was induced in FHM cells by the overexpression of NsPLC. This study may lay the foundations for further studies on the function of NsPLC and promote the understanding of the virulence factors and pathogenic mechanism of N. seriolae. PMID- 28911185 TI - Identification of a new gene yecC involved in threonine export in Escherichia coli. AB - Threonine (Thr), an essential amino acid for mammals, has expanded its application to industries with fast-growing market demand. One factor that limits the production of L-threonine by microbial fermentation is the lack of an effective export system. This study proposes a method based on isobaric tags for relative and absolute quantification (iTRAQ) to determine potential Thr excretion proteins. Proteomics analysis revealed that an ABC family transport protein named YecC was upregulated in response to Thr addition. When the yecC gene or yecC-yecS fliY is overexpressed in Escherichia coli DH5alpha, a phenotype resistant to inhibitory concentrations of Thr was observed in the strains. In addition, Thr production was increased when the yecC gene and yecC-yecS-fliY were overexpressed in the Thr producers in which rthA or rthBC was deleted separately or in combination. Therefore, YecC protein could facilitate Thr efflux in E. coli and be suitable for application in engineering microbial cells to produce Thr. PMID- 28911186 TI - Isolation of proteolytic bacteria from mealworm (Tenebrio molitor) exoskeletons to produce chitinous material. AB - The use of insects as a source of protein is becoming an important factor for feeding an increasing population. After protein extraction for food use, the insect exoskeleton may offer the possibility for the production of added value products. Here, the aim was to isolate bacteria from the surface of farmed mealworms (Tenebrio molitor Linnaeus, 1758) for the production of chitinous material from insect exoskeletons using microbial fermentation. Isolates were screened for proteases and acid production that may aid deproteination and demineralisation of insects through fermentation to produce chitin. Selected isolates were used single-step (isolated bacteria only) or two-step fermentations with Lactobacillus plantarum (DSM 20174). Two-step fermentations with isolates from mealworm exoskeletons resulted in a demineralisation of 97.9 and 98.5% from deproteinated mealworm fractions. Attenuated total reflectance-Fourier- transform infrared spectroscopy analysis showed that crude chitin was produced. However, further optimisation is needed before the process can be upscaled. This is, to our knowledge, the first report using microbial fermentation for the extraction of chitin from insects. PMID- 28911187 TI - Genome analysis of food-processing stressful-resistant probiotic Bifidobacterium animalis subsp. lactis BF052, and its potential application in fermented soymilk. AB - In this study, Bifidobacterium animalis subsp. lactis BF052 was demonstrated the growth capability in soymilk and could be thus supplemented as a probiotic starter that employed soymilk as one of its food vehicles. The complete genome sequence of BF052 was therefore determined to understand the genetic basis of BF052 as a technological and functional probiotic starter. The whole genome sequence of BF052 consists of a circular genome of 1938 624 bp with a G+C content of 60.50%. This research highlights relevant genes involving in its adaptive responses to industrial and/or environmental stresses and utilization of alpha galacto-oligosaccharides in BF052 strain compared with other representative bifidobacterial genomes. PMID- 28911188 TI - Diversity of Ochrobactrum species in food animals, antibiotic resistance phenotypes and polymorphisms in the blaOCH gene. AB - Twenty-six lactose non-fermenting, oxidase, urease and citrate-positive Gram negative rods, isolated from broiler chickens, pigs and cattle at slaughter, were subjected to the matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry and 16S rDNA sequencing for identification. Susceptibility to 14 antimicrobials was determined by the disc diffusion method. Ochrobactrum isolates resistant to third-generation cephalosporins were PCR-screened for the presence of the Ochrobactrum anthropi ampC gene (blaOCH). A 547-bp internal segment of blaOCH in the Ochrobactrum spp isolates was amplified with a newly designed primer set, and a phylogenetic reconstruction based on the complete amino acid sequence of blaOCH obtained from nine Ochrobactrum strains in our collection and 20 O. anthropi available in the GenBank was undertaken. All the Ochrobactrum isolates were resistant to the expanded-spectrum beta-lactams and streptomycin. None of the isolates was resistant to imipenem while 41.7% to 50.0% of them were resistant to fluoroquinolones. The blaOCH gene was detected in 16 (66.7%) and 20 (83.3%) of the 24 Ochrobactrum isolates (O. intermedium/O. tritici species), using primers designed for O. anthropi and the newly designed primer set, respectively. Six blaOCH variants grouped into two divergent clusters were identified. This is the first report of the complete nucleotide sequence of the blaOCH gene in non-antropi Ochrobactrum species. PMID- 28911190 TI - Do long working hours predispose to atrial fibrillation? PMID- 28911191 TI - My atrial fibrillation is not your atrial fibrillation. PMID- 28911192 TI - European Heart Journal: Case Reports. PMID- 28911193 TI - The search for a new assay of myocardial necrosis. PMID- 28911189 TI - Long working hours as a risk factor for atrial fibrillation: a multi-cohort study. AB - Aims: Studies suggest that people who work long hours are at increased risk of stroke, but the association of long working hours with atrial fibrillation, the most common cardiac arrhythmia and a risk factor for stroke, is unknown. We examined the risk of atrial fibrillation in individuals working long hours (>=55 per week) and those working standard 35-40 h/week. Methods and results: In this prospective multi-cohort study from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium, the study population was 85 494 working men and women (mean age 43.4 years) with no recorded atrial fibrillation. Working hours were assessed at study baseline (1991-2004). Mean follow-up for incident atrial fibrillation was 10 years and cases were defined using data on electrocardiograms, hospital records, drug reimbursement registers, and death certificates. We identified 1061 new cases of atrial fibrillation (10-year cumulative incidence 12.4 per 1000). After adjustment for age, sex and socioeconomic status, individuals working long hours had a 1.4-fold increased risk of atrial fibrillation compared with those working standard hours (hazard ratio = 1.42, 95% CI = 1.13-1.80, P = 0.003). There was no significant heterogeneity between the cohort-specific effect estimates (I2 = 0%, P = 0.66) and the finding remained after excluding participants with coronary heart disease or stroke at baseline or during the follow-up (N = 2006, hazard ratio = 1.36, 95% CI = 1.05-1.76, P = 0.0180). Adjustment for potential confounding factors, such as obesity, risky alcohol use and high blood pressure, had little impact on this association. Conclusion: Individuals who worked long hours were more likely to develop atrial fibrillation than those working standard hours. PMID- 28911194 TI - British Cardiovascular Society Conference 2017. PMID- 28911195 TI - Peter Juni from Switzerland to Canada. PMID- 28911196 TI - Risk factors and consequences of atrial fibrillation: genetics, blood pressure, working hours, and cognitive decline. PMID- 28911197 TI - Contribution of TLR2 pathway in the pathogenesis of vulvovaginal candidiasis. AB - Candida albicans is the prevalent etiological agent in acute vulvovaginal infection and the most severe chronic condition known as recurrent vulvovaginal candidiasis (VVC). A critical role of local innate immunity in defense and pathogenesis of vaginal infection by Candida is proposed. The fungal recognition by the innate immune receptor is an essential step for the induction of local responses including cytokines and antimicrobial peptides (AMPs) production for host protection. Using TLR2-deficient mice, we characterized the early innate immune response during VVC. Intravaginal challenge of TLR2-/- mice with C. albicans demonstrated that in response to the initial massive penetration, a strong local inflammatory reaction with recruitment of polymorphonuclear neutrophils was developed. Both interleukin 1beta (IL1beta)-regarded as the hallmark of VVC immunopathogenesis-and IL6 were increased in vaginal lavage. Murine beta defensin 1 (mBD1), a constitutive AMP with fungicidal and chemotactic activity, was significantly upregulated in wild type (WT) animals in response to infection. Interestingly, in the absence of TLR2 recognition, levels of mBD1 RNA more than twice higher than those in WT infected animals were observed. Interestingly, our results demonstrate that TLR2 signaling is important to control the fungal burden in the vaginal tract. These finding provide new evidence about the role of this innate receptor during VVC. PMID- 28911198 TI - Loss of native alpha-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. AB - alpha-Synuclein (alphaS) forms round cytoplasmic inclusions in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence suggests a physiological function of alphaS in vesicle trafficking and release. In contrast to earlier tenets, recent work indicates that alphaS normally exists in cells in a dynamic equilibrium between monomers and tetramers/multimers. We engineered alphaS mutants incapable of multimerization, leading to excess monomers at vesicle membranes. By EM, such mutants induced prominent vesicle clustering, leading to round cytoplasmic inclusions. Immunogold labeling revealed abundant alphaS intimately associated with vesicles of varied size. Fluorescence microscopy with marker proteins showed that the alphaS-associated vesicles were of diverse endocytic and secretory origin. An alphaS '3K' mutant (E35K + E46K + E61K) that amplifies the PD/DLB-causing E46K mutation induced alphaS-rich vesicle clusters resembling the vesicle-rich areas of Lewy bodies, supporting pathogenic relevance. Mechanistically, E46K can increase alphaS vesicle binding via membrane induced amphipathic helix formation, and '3K' further enhances this effect. Another engineered alphaS variant added hydrophobicity to the hydrophobic half of alphaS helices, thereby stabilizing alphaS-membrane interactions. Importantly, substituting charged for uncharged residues within the hydrophobic half of the stabilized helix not only reversed the strong membrane interaction of the multimer-abolishing alphaS variant but also restored multimerization and prevented the aberrant vesicle interactions. Thus, reversible alphaS amphipathic helix formation and dynamic multimerization regulate a normal function of alphaS at vesicles, and abrogating multimers has pathogenic consequences. PMID- 28911199 TI - Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function. AB - Inactivating mutations in the Armadillo repeat-containing 5 (ARMC5) gene have recently been discovered in primary macronodular adrenal hyperplasia (PMAH), a cause of Cushing syndrome. Biallelic ARMC5 inactivation in PMAH suggested that ARMC5 may have tumor suppressor functions in the adrenal cortex. We generated and characterized a new mouse model of Armc5 deficiency. Almost all Armc5 knockout mice died during early embryonic development, around 6.5 and 8.5 days. Knockout embryos did not undergo gastrulation, as demonstrated by the absence of mesoderm development at E7.5. Armc5 heterozygote mice (Armc5+/-) developed normally but at the age of 1 year, their corticosterone levels decreased; this was associated with a decrease of protein kinase A (PKA) catalytic subunit alpha (Calpha) expression both at the RNA and protein levels that were also seen in human patients with PMAH and ARMC5 defects. However, this was transient, as corticosterone levels normalized later, followed by the development of hypercorticosteronemia in one-third of the mice at 18 months of age, which was associated with increases in PKA and Calpha expression. Adrenocortical tissue analysis from Armc5+/- mice at 18 months showed an abnormal activation of the Wnt/beta-catenin signaling pathway in a subset of zona fasciculata cells. These data confirm that Armc5 plays an important role in early mouse embryonic development. Our new mouse line can be used to study tissue-specific effects of Armc5. Finally, Armc5 haploinsufficiency leads to Cushing syndrome in mice, but only later in life, and this involves PKA, its catalytic subunit Calpha, and the Wnt/beta-catenin pathway. PMID- 28911200 TI - Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death. AB - Eukaryotic elongation factor 1A (EEF1A), is encoded by two distinct isoforms, EEF1A1 and EEF1A2; whereas EEF1A1 is expressed almost ubiquitously, EEF1A2 expression is limited such that it is only detectable in skeletal muscle, heart, brain and spinal cord. Currently, the role of EEF1A2 in normal cardiac development and function is unclear. There have been several reports linking de novo dominant EEF1A2 mutations to neurological issues in humans. We report a pair of siblings carrying a homozygous missense mutation p.P333L in EEF1A2 who exhibited global developmental delay, failure to thrive, dilated cardiomyopathy and epilepsy, ultimately leading to death in early childhood. A third sibling also died of a similar presentation, but DNA was unavailable to confirm the mutation. Functional genomic analysis was performed in S. cerevisiae and zebrafish. In S. cerevisiae, there was no evidence for a dominant-negative effect. Previously identified putative de novo mutations failed to complement yeast strains lacking the EEF1A ortholog showing a major growth defect. In contrast, the introduction of the mutation seen in our family led to a milder growth defect. To evaluate its function in zebrafish, we knocked down eef1a2 expression using translation blocking and splice-site interfering morpholinos. EEF1A2-deficient zebrafish had skeletal muscle weakness, cardiac failure and small heads. Human EEF1A2 wild-type mRNA successfully rescued the morphant phenotype, but mutant RNA did not. Overall, EEF1A2 appears to be critical for normal heart function in humans, and its deficiency results in clinical abnormalities in neurologic function as well as in skeletal and cardiac muscle defects. PMID- 28911201 TI - Gene expression profiling of puberty-associated genes reveals abundant tissue and sex-specific changes across postnatal development. AB - The timing of human puberty is highly variable, sexually dimorphic, and associated with adverse health outcomes. Over 20 genes carrying rare mutations have been identified in known pubertal disorders, many of which encode critical components of the hypothalamic-pituitary-gonadal (HPG) axis. Recent genome-wide association studies (GWAS) have identified more than 100 candidate genes at loci associated with age at menarche or voice breaking in males. We know little about the spatial, temporal or postnatal expression patterns of the majority of these puberty-associated genes. Using a high-throughput and sensitive microfluidic quantitative PCR strategy, we profiled the gene expression patterns of the mouse orthologs of 178 puberty-associated genes in male and female mouse HPG axis tissues, the pineal gland, and the liver at five postnatal ages spanning the pubertal transition. The most dynamic gene expression changes were observed prior to puberty in all tissues. We detected known and novel tissue-enhanced gene expression patterns, with the hypothalamus expressing the largest number of the puberty-associated genes. Notably, over 40 puberty-associated genes in the pituitary gland showed sex-biased gene expression, most of which occurred peri puberty. These sex-biased genes included the orthologs of candidate genes at GWAS loci that show sex-discordant effects on pubertal timing. Our findings provide new insight into the expression of puberty-associated genes and support the possibility that the pituitary plays a role in determining sex differences in the timing of puberty. PMID- 28911202 TI - Pathogenicity of a novel missense variant associated with choroideremia and its impact on gene replacement therapy. AB - Choroideremia (CHM) is an inherited retinal dystrophy characterised by progressive degeneration of photoreceptors, retinal pigment epithelium (RPE) and underlying choroid. It is caused by loss-of-function mutations in CHM, which has an X-linked inheritance, and is thus an ideal candidate for gene replacement strategies. CHM encodes REP1, which plays a key role in the prenylation of Rab GTPases. We recently showed that an induced pluripotent stem cell (iPSc)-derived RPE model for CHM is fully functional and reproduces the underlying prenylation defect. This criterion can thus be used for testing the pathogenic nature of novel variants. Until recently, missense variants were not associated with CHM. Currently, at least nine such variants have been reported but only two have been shown to be pathogenic. We report here the characterisation of the third pathogenic missense CHM variant, p.Leu457Pro. Clinically, the associated phenotype is indistinguishable from that of loss-of-function mutations. By contrast, this missense variant results in wild type CHM expression levels and detectable levels of mutant protein. The prenylation status of patient-specific fibroblasts and iPSc-derived RPE is within the range observed for loss-of function mutations, consistent with the clinical phenotype. Lastly, considering the current climate of CHM gene therapy, we assayed whether the presence of mutant REP1 could interfere with a gene replacement strategy by testing the prenylation status of patient-specific iPSc-derived RPE following AAV-mediated gene transfer. Our results show that correction of the functional defect is possible and highlight the predictive value of these models for therapy screening prior to inclusion in clinical trials. PMID- 28911203 TI - Mutations of conserved non-coding elements of PITX2 in patients with ocular dysgenesis and developmental glaucoma. AB - Mutations in FOXC1 and PITX2 constitute the most common causes of ocular anterior segment dysgenesis (ASD), and confer a high risk for secondary glaucoma. The genetic causes underlying ASD in approximately half of patients remain unknown, despite many of them being screened by whole exome sequencing. Here, we performed whole genome sequencing on DNA from two affected individuals from a family with dominantly inherited ASD and glaucoma to identify a 748-kb deletion in a gene desert that contains conserved putative PITX2 regulatory elements. We used CRISPR/Cas9 to delete the orthologous region in zebrafish in order to test the pathogenicity of this structural variant. Deletion in zebrafish reduced pitx2 expression during development and resulted in shallow anterior chambers. We screened additional patients for copy number variation of the putative regulatory elements and found an overlapping deletion in a second family and in a potentially-ancestrally-related index patient with ASD and glaucoma. These data suggest that mutations affecting conserved non-coding elements of PITX2 may constitute an important class of mutations in patients with ASD for whom the molecular cause of their disease have not yet been identified. Improved functional annotation of the human genome and transition to sequencing of patient genomes instead of exomes will be required before the magnitude of this class of mutations is fully understood. PMID- 28911204 TI - Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution. AB - Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases. PMID- 28911205 TI - A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination. AB - X-linked adrenoleukodystrophy (ALD) is a devastating inherited neurodegenerative disease caused by defects in the ABCD1 gene and affecting peripheral and central nervous system myelin. ABCD1 encodes a peroxisomal transmembrane protein required for very long chain fatty acid (VLCFA) metabolism. We show that zebrafish (Danio rerio) Abcd1 is highly conserved at the amino acid level with human ABCD1, and during development is expressed in homologous regions including the central nervous system and adrenal glands. We used TALENs to generate five zebrafish abcd1 mutant allele lines introducing premature stop codons in exon 1, as well as obtained an abcd1 allele from the Zebrafish Mutation Project carrying a point mutation in a splice donor site. Similar to patients with ALD, zebrafish abcd1 mutants have elevated VLCFA levels. Interestingly, we found that CNS development of the abcd1 mutants is disrupted, with hypomyelination in the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death. By day of life five abcd1 mutants demonstrate impaired motor function, and overall survival to adulthood of heterozygous and homozygous mutants is decreased. Expression of human ABCD1 in oligodendrocytes rescued apoptosis in the abcd1 mutant. In summary, we have established a zebrafish model of ALD that recapitulates key features of human disease pathology and which reveals novel features of underlying disease pathogenesis. PMID- 28911206 TI - Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia. AB - Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome gives rise to unregulated protein-induced insulin secretion from pancreatic beta-cells, fasting hypoglycemia and elevated plasma ammonia levels. Mutations associated with HI/HA were identified in the Glud1 gene, encoding for glutamate dehydrogenase (GDH). We aimed at identifying the molecular causes of dysregulation in insulin secretion and ammonia production conferred by the most frequent HI/HA mutation Ser445Leu. Following transduction with adenoviruses carrying the human GDH-wild type or GDH S445L-mutant gene, immunoblotting showed efficient expression of the transgenes in all the investigated cell types. Enzymatic activity tested in INS-1E beta cells revealed that the mutant was much more sensitive to the allosteric activator ADP, rendering it highly responsive to substrates. INS-1E cells expressing either the wild type or mutant GDH responded similarly to glucose stimulation regarding mitochondrial activation and insulin secretion. However, at basal glucose glutamine stimulation increased mitochondrial activity and insulin release only in the mutant cells. In mouse and human islets, expression of mutant GDH resulted in robust elevation of insulin secretion upon glutamine stimulation, not observed in control islets. Hepatocytes expressing either the wild type or mutant GDH produced similar levels of ammonia when exposed to glutamine, although alanine response was strongly elevated with the mutant form. In conclusion, the GDH-S445L mutation confers hyperactivity to this enzyme due to higher sensitivity to ADP allosteric activation. This renders beta-cells responsive to amino acid stimulation, explaining protein-induced hypoglycemia secondary to non physiological insulin release. Hepatocytes carrying mutant GDH produced more ammonia upon alanine exposure, which underscores hyperammonemia developed by the patients. PMID- 28911208 TI - HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia. PMID- 28911207 TI - Trans-ethnic meta-regression of genome-wide association studies accounting for ancestry increases power for discovery and improves fine-mapping resolution. AB - Trans-ethnic meta-analysis of genome-wide association studies (GWAS) across diverse populations can increase power to detect complex trait loci when the underlying causal variants are shared between ancestry groups. However, heterogeneity in allelic effects between GWAS at these loci can occur that is correlated with ancestry. Here, a novel approach is presented to detect SNP association and quantify the extent of heterogeneity in allelic effects that is correlated with ancestry. We employ trans-ethnic meta-regression to model allelic effects as a function of axes of genetic variation, derived from a matrix of mean pairwise allele frequency differences between GWAS, and implemented in the MR MEGA software. Through detailed simulations, we demonstrate increased power to detect association for MR-MEGA over fixed- and random-effects meta-analysis across a range of scenarios of heterogeneity in allelic effects between ethnic groups. We also demonstrate improved fine-mapping resolution, in loci containing a single causal variant, compared to these meta-analysis approaches and PAINTOR, and equivalent performance to MANTRA at reduced computational cost. Application of MR-MEGA to trans-ethnic GWAS of kidney function in 71,461 individuals indicates stronger signals of association than fixed-effects meta-analysis when heterogeneity in allelic effects is correlated with ancestry. Application of MR MEGA to fine-mapping four type 2 diabetes susceptibility loci in 22,086 cases and 42,539 controls highlights: (i) strong evidence for heterogeneity in allelic effects that is correlated with ancestry only at the index SNP for the association signal at the CDKAL1 locus; and (ii) 99% credible sets with six or fewer variants for five distinct association signals. PMID- 28911210 TI - A20, an essential component of the ubiquitin-editing protein complex, is a negative regulator of inflammation in human myometrium and foetal membranes. AB - STUDY QUESTION: Does A20 regulate mediators involved in the terminal processes of human labour in primary myometrial and amnion cells? SUMMARY ANSWER: A20 is a nuclear factor-kappa B (NF-kappaB) responsive gene that acts as a negative regulator of NF-kappaB-induced expression of pro-labour mediators. WHAT IS KNOWN ALREADY: Inflammation is commonly implicated in spontaneous preterm birth and the processes involved in rupture of foetal membranes and uterine contractions. In myometrium and foetal membranes, the pro-inflammatory transcription factor NF kappaB regulates the transcription of pro-labour mediators in response to inflammatory stimuli. In non-gestational tissues, A20 is widely recognised as an anti-inflammatory protein that inhibits inflammation-induced NF-kappaB signalling. STUDY DESIGN, SIZE, DURATION: Primary human amnion and myometrial cells were used to determine the effect of pro-inflammatory mediators on A20 expression and the effect of A20 siRNA on the expression and secretion of pro labour mediators. The expression of A20 was assessed in myometrium and foetal membranes from non-labouring and labouring women at preterm and or term (n = 8 or nine samples per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: The effects of pro-inflammatory mediators and of A20 siRNA in cell cultures were determined by quantitative RT-PCR (qRT-PCR), western blots, immunoassays, gelatin zymography and luciferase assays. A20 expression in tissue samples was assessed by qRT-PCR. Statistical significance was ascribed to a P value < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: In primary cells isolated from myometrium and or amnion, the pro inflammatory cytokines IL1B and TNF, the bacterial products flagellin and fsl-1, and the viral double stranded RNA analogue poly(I:C) significantly increased A20 mRNA expression via NF-kappaB. A20 siRNA studies in primary myometrial and amnion cells demonstrated an augmentation of inflammation-induced expression and or secretion of pro-inflammatory cytokines (IL1A, IL6), chemokines (CXCL1, CXCL8, CCL2), adhesion molecules (ICAM1, VCAM1), contraction-associated proteins (PTGS2, PTGFR, PGF2alpha) and the extracellular matrix degrading enzyme MMP9, as well as NF-kappaB activation. Inhibition of NF-kappaB activity significant attenuated inflammation-induced expression of pro-labour mediators in A20 siRNA transfected cells. Finally, A20 mRNA expression was decreased in myometrium and foetal membranes with labour, and in foetal membranes with chorioamnionitis. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The conclusions of this study are solely reliant on the data from in vitro experiments using cells isolated from myometrium and amnion. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study raise the possibility that targeting A20 may be a therapeutic approach to reduce inflammation associated with spontaneous preterm birth. STUDY FUNDING AND COMPETING INTEREST(S): Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Funding for this study was provided by the NHMRC (grant no. 1058786), Norman Beischer Medical Research Foundation and the Mercy Research Foundation. There are no competing interests. PMID- 28911211 TI - Are there intracellular Ca2+ oscillations correlated with flagellar beating in human sperm? A three vs. two-dimensional analysis. AB - STUDY QUESTION: Are there intracellular Ca2+ ([Ca2+]i) oscillations correlated with flagellar beating in human sperm? SUMMARY ANSWER: The results reveal statistically significant [Ca2+]i oscillations that are correlated with the human sperm flagellar beating frequency, when measured in three-dimensions (3D). WHAT IS KNOWN ALREADY: Fast [Ca2+]i oscillations that are correlated to the beating flagellar frequency of cells swimming in a restricted volume have been detected in hamster sperm. To date, such findings have not been confirmed in any other mammalian sperm species. An important question that has remained regarding these observations is whether the fast [Ca2+]i oscillations are real or might they be due to remaining defocusing effects of the Z component arising from the 3D beating of the flagella. STUDY DESIGN, SIZE, DURATION: Healthy donors whose semen samples fulfill the WHO criteria between the age of 18-28 were selected. Cells from at least six different donors were utilized for analysis. Approximately the same number of experimental and control cells were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Motile cells were obtained by the swim up technique and were loaded with Fluo-4 (Ca2+ sensitive dye) or with Calcein (Ca2+ insensitive dye). Ni2+ was used as a non-specific plasma membrane Ca2+ channel blocker. Fluorescence data and flagella position were acquired in 3D. Each cell was recorded for up to 5.6 s within a depth of 16 microns with a high speed camera (coupled to an image intensifier) acquiring at a rate of 3000 frames per second, while an oscillating objective vibrated at 90 Hz via a piezoelectric device. From these samples, eight experimental and nine control sperm cells were analyzed in both 2D and 3D. MAIN RESULTS AND THE ROLE OF CHANCE: We have implemented a new system that allows [Ca2+]i measurements of the human sperm flagellum beating in 3D. These measurements reveal statistically significant [Ca2+]i oscillations that correlate with the flagellar beating frequency. These oscillations may arise from intracellular sources and/or Ca2+ transporters, as they were insensitive to external Ni2+, a non-specific plasma membrane Ca2+ channel blocker. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Analysis in 3D needs a very fast image acquisition rate to correctly sample a volume containing swimming sperm. This condition requires a very short exposure time per image making it necessary to use an image intensifier which also increases noise. The lengthy analysis time required to obtain reliable results limited the number of cells that could be analyzed. WIDER IMPLICATIONS OF THE FINDINGS: The possibility of recording flagellar [Ca2+]i oscillations described here may open a new avenue to better understand ciliary and flagellar beating that are fundamental for mucociliary clearance, oocyte transport, fertilization, cerebrospinal fluid pressure regulation and developmental left-right symmetry breaking in the embryonic node. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by Consejo Nacional de Ciencia y Tecnologia (CONACyT) (grants 253952 to G.C.; 156667 to F.M.M. and Fronteras 71 39908-Q to A.D. and Post doctoral scholarships 366844 to P.H.-H. and 291028 to F.M.) and the Direccion General de Asuntos del Personal Academico of the Universidad Nacional Autonoma de Mexico (DGAPA-UNAM) (grants CJIC/CTIC/4898/2016 to F.M. and IN205516 to A.D.). There are no conflicts of interest to declare. PMID- 28911209 TI - Intracellular activation of ovastacin mediates pre-fertilization hardening of the zona pellucida. AB - STUDY QUESTION: How and where is pro-ovastacin activated and how does active ovastacin regulate zona pellucida hardening (ZPH) and successful fertilization? STUDY FINDING: Ovastacin is partially active before exocytosis and pre-hardens the zona pellucida (ZP) before fertilization. WHAT IS KNOWN ALREADY: The metalloproteinase ovastacin is stored in cortical granules, it cleaves zona pellucida protein 2 (ZP2) upon fertilization and thereby destroys the ZP sperm ligand and triggers ZPH. Female mice deficient in the extracellular circulating ovastacin-inhibitor fetuin-B are infertile due to pre-mature ZPH. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We isolated oocytes from wild-type and ovastacin deficient (Astlnull) FVB mice before and after fertilization (in vitro and in vivo) and quantified ovastacin activity and cleavage of ZP2 by immunoblot. We assessed ZPH by measuring ZP digestion time using alpha-chymotrypsin and by determining ZP2 cleavage. We determined cellular distribution of ovastacin by immunofluorescence using domain-specific ovastacin antibodies. Experiments were performed at least in triplicate with a minimum of 20 oocytes. Data were pre analyzed using Shapiro-Wilk test. In case of normal distribution, significance was determined via two-sided Student's t-test, whereas in case of non-normal distribution via Mann-Whitney U-test. MAIN RESULTS AND THE ROLE OF CHANCE: Metaphase II (MII) oocytes contained both inactive pro-ovastacin and activated ovastacin. Immunoblot and ZP digestion assays revealed a partial cleavage of ZP2 even before fertilization in wild-type mice. Partial cleavage coincided with germinal-vesicle breakdown and MII, despite the presence of fetuin-B protein, an endogenous ovastacin inhibitor, in the follicular and oviductal fluid. Upon exocytosis, part of the C-terminal domain of ovastacin remained attached to the plasmalemma, while the N-terminal active ovastacin domain was secreted. This finding may resolve previously conflicting data showing that ovastacin acts both as an oolemmal receptor termed SAS1B (sperm acrosomal SLLP1 binding protein; SLLP, sperm lysozyme like protein) and a secreted protease mediating ZP2 cleavage. LIMITATIONS, REASONS FOR CAUTION: For this study, only oocytes isolated from wild-type and ovastacin-deficient FVB mice were investigated. Some experiments involved oocyte activation by the Ca2+ ionophore A23187 to trigger ZPH. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a detailed spatial and temporal view of pre-mature cleavage of ZP2 by ovastacin, which is known to adversely affect IVF rate in mice and humans. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by the Center of Natural Sciences and Medicine and by a start-up grant of the Johannes Gutenberg University Mainz to W.S., and by a grant from Deutsche Forschungsgemeinschaft and by the START program of the Medical Faculty of RWTH Aachen University to J.F. and W.J.D. There are no competing interests to declare. PMID- 28911212 TI - Apposition to endometrial epithelial cells activates mouse blastocysts for implantation. AB - STUDY QUESTION: How do interactions between blastocyst-stage embryos and endometrial epithelial cells regulate the early stages of implantation in an in vitro model? SUMMARY ANSWER: Mouse blastocyst apposition with human endometrial epithelial cells initiates trophectoderm differentiation to trophoblast, which goes on to breach the endometrial epithelium. WHAT IS KNOWN ALREADY: In vitro models using mouse blastocysts and human endometrial cell lines have proven invaluable in the molecular characterisation of embryo attachment to endometrial epithelium at the onset of implantation. Genes involved in embryonic breaching of the endometrial epithelium have not been investigated in such in vitro models. STUDY DESIGN, SIZE, DURATION: This study used an established in vitro model of implantation to examine cellular and molecular interactions during blastocyst attachment to endometrial epithelial cells. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mouse blastocysts developed from embryonic day (E) 1.5 in vitro were hatched and co-cultured with confluent human endometrial adenocarcinoma-derived Ishikawa cells in serum-free medium. A scale of attachment stability based on blastocyst oscillation upon agitation was devised. Blastocysts were monitored for 48 h to establish the kinetics of implantation, and optical sectioning using fluorescence microscopy revealed attachment and invasion interfaces. Quantitative PCR was used to determine blastocyst gene expression. Data from a total of 680 mouse blastocysts are reported, with 3-6 experimental replicates. T-test and ANOVA analyses established statistical significance at P < 0.05, P < 0.01 and P < 0.001. MAIN RESULTS AND THE ROLE OF CHANCE: Hatched E4.5 mouse blastocysts exhibited weak attachment to confluent Ishikawa cells over the first 24 h of co culture, with intermediate and stable attachment occurring from 28 h (E5.5 + 4 h) in a hormone-independent manner. Attached embryos fixed after 48 h (E6.5) frequently exhibited outgrowths, characterised morphologically and with antibody markers as trophoblast giant cells (TGCs), which had breached the Ishikawa cell layer. Beginning co-culture at E5.5 also resulted in intermediate and stable attachment from E5.5 + 4 h; however, these embryos did not go on to breach the Ishikawa cell layer, even when co-culture was extended to E7.5 (P < 0.01). Blastocysts cultured from E4.5 in permeable transwell inserts above Ishikawa cells before transfer to direct co-culture at E5.5 went on to attach but failed to breach the Ishikawa cell layer by E6.5 (P < 0.01). Gene expression analysis at E5.5 demonstrated that direct co-culture with Ishikawa cells from E4.5 resulted in downregulation of trophectoderm transcription factors Cdx2 (P < 0.05) and Gata3 (P < 0.05) and upregulation of the TGC transcription factor Hand1 (P < 0.05). Co-culture with non-endometrial human fibroblasts did not alter the expression of these genes. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The in vitro model used here combines human carcinoma-derived endometrial cells with mouse embryos, in which the cellular interactions observed may not fully recapitulate those in vivo. The data gleaned from such models can be regarded as hypothesis-generating, and research is now needed to develop more sophisticated models of human implantation combining multiple primary endometrial cell types with surrogate and real human embryos. WIDER IMPLICATIONS OF THE FINDINGS: This study implicates blastocyst apposition to endometrial epithelial cells as a critical step in trophoblast differentiation required for implantation. Understanding this maternal regulation of the embryonic developmental programme may lead to novel treatments for infertility. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by funds from the charities Wellbeing of Women (RG1442) and Diabetes UK (15/0005207), and studentship support for SCB from the Anatomical Society. No conflict of interest is declared. PMID- 28911213 TI - Effects of oncotherapy on testicular stem cells and niche. PMID- 28911216 TI - Environment, health and infrastructure: troubling questions. PMID- 28911215 TI - NICE public health guidance update. PMID- 28911217 TI - Promoting the ethics of promoting the public's health: a call for papers; a call for debate. PMID- 28911218 TI - A new public health, tiered approach to improving musculoskeletal health through physical activity provision. PMID- 28911214 TI - Growth regulation by estrogen in breast cancer 1 (GREB1) is a novel progesterone responsive gene required for human endometrial stromal decidualization. AB - STUDY QUESTION: Is Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) required for progesterone-driven endometrial stromal cell decidualization? SUMMARY ANSWER: GREB1 is a novel progesterone-responsive gene required for progesterone-driven human endometrial stromal cell (HESC) decidualization. WHAT IS KNOWN ALREADY: Successful establishment of pregnancy requires HESCs to transform from fibroblastic to epithelioid cells in a process called decidualization. This process depends on the hormone progesterone, but the molecular mechanisms by which it occurs have not been determined. STUDY DESIGN, SIZE, DURATION: Primary and transformed HESCs in which GREB1 expression was knocked down were decidualized in culture for up to 6 days. Wild-type and progesterone receptor (PR) knockout mice were treated with progesterone, and their uteri were assessed for levels of GREB1 expression. PARTICIPANTS/MATERIALS, SETTING, METHODS: Analysis of previous data included data mining of expression profile data sets and in silico transcription factor-binding analysis. Endometrial biopsies obtained from healthy women of reproductive age during the proliferative phase (Days 8-12) of their menstrual cycle were used for isolating HESCs. Experiments were carried out with early passage (no more than four passages) HESCs isolated from at least three subjects. Transcript levels of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were detected by quantitative RT-PCR as readouts for HESC decidualization. Cells were also imaged by phase-contrast microscopy. To assess the requirement for GREB1, PR and SRC-2, cells were transfected with specifically targeted small interfering RNAs. Results are shown as mean and SE from three replicates of one representative patient-derived primary endometrial cell line. Experiments were also conducted with transformed HESCs. MAIN RESULTS AND THE ROLE OF CHANCE: Progesterone treatment of mice and transformed HESCs led to an ~5-fold (5.6 +/- 0.81, P < 0.05, and 5.2 +/- 0.26, P < 0.01, respectively) increase in GREB1 transcript levels. This increase was significantly reduced in the uteri of PR knock-out mice (P < 0.01), in HESCs treated with the PR antagonist RU486 (P < 0.01), or in HESCs in which PR expression was knocked down (P < 0.05). When GREB1 expression was knocked down, progesterone-driven decidualization markers in both immortalized and primary HESCs was significantly reduced (P < 0.05 and P < 0.01). Finally, GREB1 knock down signficantly reduced expression of the PR target genes WNT4 and FOXOA1 (P < 0.05 and P < 0.01, respectively). LARGE SCALE DATA: This study used the Nuclear Receptor Signaling Atlas. LIMITATIONS, REASONS FOR CAUTION: Although in vitro cell culture studies indicate that GREB1 is required for endoemtrial decidualization, the in vivo role of GREB1 in endometrial function and dysfunction should be assessed by using knock-out mouse models. WIDER IMPLICATIONS OF THE FINDINGS: Identification and functional analysis of GREB1 as a key molecular mediator of decidualization may lead to improved diagnosis and clinical management of women with peri-implantation loss due to inadequate endometrial decidualization. STUDY FUNDING AND COMPETING INTEREST(S): This research was funded in part by: a National Institutes of Health (NIH)/ National Institute of Child Health and Human Development (NICHD) grant (R00 HD080742) and Washington University School of Medicine start-up funds to R.K., an NIH/NICHD grant (RO1 HD-07857) to B.W.O.M., and a NIH/NICHD grant (R01 HD-042311) to J.P.L. The authors declare no conflicts of interests. PMID- 28911219 TI - Abrasion of eroded and sound enamel by a dentifrice containing diamond abrasive particles AB - Eroded enamel is more susceptible to abrasive wear than sound enamel. New toothpastes utilizing diamond particles as abrasives have been developed. The present study investigated the abrasive wear of eroded enamel by three commercially available toothpastes (one containing diamond particles) and compared it to the respective wear of sound enamel caused by these toothpastes. Seventy-two bovine enamel samples were randomly allocated to six groups (S1-S3 and E1-E3; n=12). Samples were submitted to an abrasive (S1-S3) or erosion plus abrasion (E1-E3) cycling. Per cycle, all samples were brushed (abrasion; 20 brushing stokes) with the following toothpastes: S1/E1: Signal WHITE SYSTEM, S2/E2: elmex KARIESSCHUTZ and S3-E3: Candida WHITE DIAMOND (diamond particles). Groups E1-E3 were additionally eroded with HCl (pH 3.0) for 2 min before each brushing procedure. After 30, 60 and 90 cycles enamel wear was measured by surface profilometry. Within the same toothpaste and same number of cycles, enamel wear due to erosion plus abrasion was significantly higher than due to mere abrasion. After 30, 60 and 90 cycles, no significant difference in the wear in groups S1 and S2 was observed while the wear in group E1 was significantly (p<0.05, ANOVA, Scheffecyc) lower than that in group E2. After 90 cycles, wear in group S3 was about 5 times higher than that in group S2, while wear in group E3 was about 1.3 times higher than that in group E2. As compared to the other two investigated toothpastes, the dentifrice containing diamond particles caused slightly higher abrasive wear of eroded enamel and distinctly higher wear of sound enamel compared to the conventional toothpastes under investigation. PMID- 28911220 TI - Contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI RADS) 2017 - a review of important differences compared to the CT/MRI system. AB - Medical imaging plays an important role in the diagnosis and management of hepatocellular carcinoma (HCC). The Liver Imaging Reporting and Data System (LI RADS) was initially created to standardize the reporting and data collection of CT and MR imaging for patients at risk for HCC. As contrast-enhanced ultrasound (CEUS) has been widely used in clinical practice, it has recently been added to the LI-RADS. While CEUS LI-RADS shares fundamental concepts with CT/MRI LI-RADS, there are key differences between the modalities reflecting dissimilarities in the underlying methods of image acquisition and types of contrast material. This review introduces a recent update of CEUS LI-RADS and explains the key differences from CT/MRI LI-RADS. PMID- 28911222 TI - Ratiometric Fluorescent Probe for Imaging of Pantetheinase in Living Cells. AB - Pantetheinase, which catalyzes the cleavage of pantetheine to pantothenic acid (vitamin B5) and cysteamine, is involved in the regulation of oxidative stress, pantothenate recycling and cell migration. However, further elucidating the cellular function of this enzyme is largely limited by the lack of a suitable fluorescence imaging probe. By conjugating pantothenic acid with cresyl violet, herein we develop a new fluorescence probe CV-PA for the assay of pantetheinase. The probe not only possesses long analytical wavelengths but also displays linear ratiometric (I628/582 nm) fluorescence response to pantetheinase in the range of 5-400 ng/mL with a detection limit of 4.7 ng/mL. This probe has been used to evaluate the efficiency of different inhibitors and quantitatively detect pantetheinase in serum samples, revealing that pantetheinase in fetal bovine serum and new born calf serum is much higher than that in normal human serum. Notably, with the probe the ratiometric imaging and in situ quantitative comparison of pantetheinase in different living cells (LO2 and HK-2) have been achieved for the first time. It is found that the level of pantetheinase in LO2 cells is much larger than that in HK-2 cells, as further validated by Western blot analysis. The proposed probe may be useful to better understand the specific function of pantetheinase in the pantetheinase-related pathophysiological processes. PMID- 28911221 TI - Chemical Basis for Deuterium Labeling of Fat and NADPH. AB - Much understanding of metabolism is based on monitoring chemical reactions in cells with isotope tracers. For this purpose, 13C is well suited due to its stable incorporation into biomolecules and minimal kinetic isotope effect. For redox reactions, deuterium tracing can provide additional information. To date, studies examining NADPH production with deuterated carbon sources have failed to account for roughly half of NADPH's redox active hydrogen. We show the missing hydrogen is the result of enzyme-catalyzed H-D exchange between water and NADPH. Though isolated NADPH does not undergo H-D exchange with water, such exchange is catalyzed by Flavin enzymes and occurs rapidly in cells. Correction for H-D exchange is required for accurate assessment of biological sources of NADPH's high energy electrons. Deuterated water (D2O) is frequently used to monitor fat synthesis in vivo, but the chemical pathway of the deuterons into fat remains unclear. We show D2O labels fatty acids primarily via NADPH. Knowledge of this route enables calculation, without any fitting parameters, of the mass isotopomer distributions of fatty acids from cells grown in D2O. Thus, knowledge of enzyme catalyzed H-D exchange between water and NADPH enables accurate interpretation of deuterium tracing studies of redox cofactor and fatty acid metabolism. PMID- 28911223 TI - Direct Sampling and Analysis of Atmospheric Particulate Organic Matter by Proton Transfer-Reaction Mass Spectrometry. AB - We report on a new method for analyzing atmospheric submicrometer particulate organic matter which combines direct particle sampling and volatilization with online chemical ionization mass spectrometric analysis. Technically, the method relies on the combined use of a CHARON ("Chemical Analysis of Aerosol Online") particle inlet and a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF-MS). Laboratory studies on target analytes showed that the ionization conditions in the PTR-ToF-MS lead to extensive fragmentation of levoglucosan and cis-pinonic acid, while protonated oleic acid and 5alpha-cholestane molecules remain intact. Potential problems and biases in quantitative and qualitative analyses are discussed. Side-by-side atmospheric comparison measurements of total particulate organic mass and levoglucosan with an aerosol mass spectrometer (AMS) were in good agreement. Complex and clearly distinct organic mass spectra were obtained from atmospheric measurements in three European cities (Lyon, Valencia, Innsbruck). Data visualization in reduced-parameter frameworks (e.g., oxidation state of carbon vs carbon number) revealed that the CHARON-PTR-ToF-MS technique adds significant analytical capabilities for characterizing particulate organic carbon in the Earth's atmosphere. Positive matrix factorization (PMF) was used for apportioning sources of atmospheric particles in late fall in Innsbruck. The m/z signatures of known source marker compounds (levoglucosan and resin acids, polycyclic aromatic hydrocarbons, nicotine) in the mass spectra were used to assign PMF factors to biomass burning, traffic, and smoking emission sources. PMID- 28911224 TI - Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper Catalyzed Thiolane Assembly. AB - An asymmetric total synthesis of (+)-6-hydroxythiobinupharidine (1b) and (-)-6 hydroxythionuphlutine (2b), a set of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies of the Nuphar genus, is described. The central bis-spirocyclic tetrahydrothiophene ring was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ from the coupling of a copper-carbene with a spirocyclic thietane. This strategy diverges both from the proposed biosynthesis1 and previous syntheses of this family of alkaloids,2,3 all of which employ dimerization of symmetric monomers to form the aforementioned thiaspirane. The coupling of unsymmetrical monomers allowed access to the unsymmetrically oxidized product 2b for the first time. PMID- 28911226 TI - Identification of the Ubiquitous Antioxidant Tripeptide Glutathione as a Fruit Fly Semiochemical. AB - Many insects mark their oviposition sites with a host marking pheromone (HMP) to deter other females from overexploiting these sites. Previous studies have identified and used HMPs to manage certain fruit fly species; however, few are known for African indigenous fruit flies. The HMP of the African fruit fly, Ceratitis cosyra, was identified as the ubiquitous plant and animal antioxidant tripeptide, glutathione (GSH). GSH was isolated from the aqueous extract of adult female fecal matter and characterized by LC-QTOF-MS. GSH level increased with increasing age of female fecal matter, with highest concentration detected from 2 week-old adult females. Additionally, GSH levels were 5-10-times higher in fecal matter than in the ovipositor or hemolymph extracts of females. In bioassays, synthetic GSH reduced oviposition responses in conspecifics of C. cosyra and the heterospecific species C. rosa, C. fasciventris, C. capitata, and Zeugodacus cucurbitae. These results represent the first report of a ubiquitous antioxidant as a semiochemical in insects and its potential use in fruit fly management. PMID- 28911225 TI - Validating the Water Flooding Approach by Comparing It to Grand Canonical Monte Carlo Simulations. AB - The study of the function of proteins on a quantitative level requires consideration of the water molecules in and around the protein. This requirement presents a major computational challenge due to the fact that the insertion of water molecules can have a very high activation barrier and would require a long simulation time. Recently, we developed a water flooding (WF) approach which is based on a postprocessing Monte Carlo ranking of possible water configurations. This approach appears to provide a very effective way for assessing the insertion free energies and determining the most likely configurations of the internal water molecules. Although the WF approach was used effectively in modeling challenging systems that have not been addressed reliably by other microscopic approaches, it was not validated by a comparison to the more rigorous grand canonical Monte Carlo (GCMC) method. Here we validate the WF approach by comparing its performance to that of the GCMC method. It is found that the WF approach reproduces the GCMC results in well-defined test cases but does so much faster. This established the WF approach as a useful strategy for finding correct water configurations in proteins and thus to provide a powerful way for studies of the functions of proteins. PMID- 28911227 TI - Fluorescence Assay for Ribonuclease H Based on Nonlabeled Substrate and DNAzyme Assisted Cascade Amplification. AB - As a highly conserved damage repair protein, RNase H can specifically hydrolyze RNA in DNA-RNA chimeric strands. DNAzyme, a synthetic single-stranded DNA consisting of binding and catalytic sites, can cleave RNA in the presence of cofactors. In this study, we establish a highly sensitive RNase H assay assisted with DNAzyme's cleavage property. A DNA-RNA chimeric strand, which contains DNAzyme sequences, is used as the hydrolysis substrate of RNase H. The RNase H hydrolysis of the chimeric substrate results in the release of DNAzyme. Subsegment DNAzyme digest, a molecular beacon, causes a "turn-on" fluorescence signal by disrupting its hairpin structure. Furthermore, the fluorescence signal is amplified by cyclic digestion of DNAzyme to the substrate of molecular beacon. Under the optimal conditions, the detection limit of RNase H is 0.01 U/mL, which is superior to those of several alternative approaches. Additionally, the method was further used for RNase H detection in heterogeneous biological samples as well as to investigate the effects of natural compounds on this enzyme. In summary, these results show that the method not only provides a universal platform for monitoring RNase H activity but also shows great potential in biomedical studies and drug screening. PMID- 28911233 TI - Targeting Specificity of the CRISPR/Cas9 System. AB - CRISPR/Cas9 system has accelerated research across many fields since its demonstration for genome editing. CRISPR also offers vast therapeutic potential, but an important hurdle of this technology is the off-target mutations it can induce. In this viewpoint, we will discuss recent strategies for improving CRISPR specificity, emphasizing how a complete mechanistic understanding of CRISPR/Cas9 can benefit such efforts. We also propose that agreeing upon a consensus protocol with the highest specificity could benefit researchers working on CRISPR-based therapies. In addition to improving CRISPR/Cas9 specificity, accurate detection of off-target events is also crucial, and we will discuss various unbiased off target detection methods in terms of their advantages and disadvantages. We suggest that using a combination of cell-based and cell-free methods can prove more useful. In addition, we point out that improving predictive algorithms for off-target sites would require pooling of the available off-target analysis data and standardization of the protocols used for obtaining the data. Moreover, we highlight the risk of insertional mutagenesis for gene correction applications requiring the use of donor DNA. We conclude by discussing future prospects for the field, as well as steps that can be taken to overcome the aforementioned challenges. PMID- 28911234 TI - Mucopolysaccharidosis IIIB (Sanfilippo syndrome B) in a commercial emu (Dromaius novaehollandiae) flock. AB - Clinicopathological diagnosis of mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B), an inherited autosomal recessive lysosomal storage disease, as a cause of losses in a commercial emu flock and screening breeders using a mutation-specific DNA test are described. Between 2012 and 2015, ~5-10 juvenile emus from a few weeks to several months of age developed progressive neurological signs and died while others in the flock remained healthy. Necropsy of two affected siblings revealed multiple sites of haemorrhage, cytoplasmic periodic acid-Schiff and Luxol fast blue-positive inclusions in neurons, and aggregates of foamy macrophages in visceral organs. Affected emus were homozygous for the two-base deletion in the alpha-N-acetylglucosaminidase gene that causes MPS IIIB in emus. Mutation-specific DNA tests for MPS IIIB in emus were developed. Screening blood samples from 78 breeding emus revealed 14 (18%; 9 males, 4 females, and 1 unknown gender) carriers; an overall 0.09 mutant alpha-N acetylglucosaminidase allele frequency. A "test and cull male carriers" programme, in which carrier males are culled but carrier females are retained, was proposed to avoid breeding affected emus together, ultimately eliminating the disease from future broods, and preserving the gene pool with as much breeding stock as possible. Molecular genetic diagnostic tests are simple, precise, and permit screening of all breeders for the mutant allele in any flock and can be used to eliminate MPS IIIB-related emu losses through informed breeding. PMID- 28911235 TI - Health and politics: war by other means on the Palestinian minority in Israel. PMID- 28911236 TI - Comments on: Effects of yoga versus hydrotherapy training on health-related quality of life and exercise capacity in patients with heart failure: A randomized controlled study. PMID- 28911237 TI - Moving on. PMID- 28911238 TI - Talking about sunbed tanning in online discussion forums: Assertions and arguments. AB - OBJECTIVE: There is increasing evidence of both health and appearance risks associated with sunbed use. At the same time, the sunbed industry promotes the benefits of using sunbeds, and the image of a tanned skin as attractive and healthy arguably remains embedded within contemporary western culture. These tensions are played out in everyday conversations, and this paper reports a study which explored how sunbed users manage them within online discussion forums. DESIGN: A total of 556 posts from 13 sunbed-related threads, taken from six different UK-based online forums, were analysed thematically followed by techniques from discourse analysis. MAIN OUTCOME MEASURES: Informed by social representations theory and discursive-rhetorical psychology, the way social representations of sunbed use are constructed, debated and disputed in online discussion forums were explored. RESULTS: Sunbed users drew upon numerous representations to distance and protect themselves from negativity they were confronted with in the forums, utilising a range of rhetorical, discursive strategies to help them. CONCLUSION: Theoretical contributions and potential practical implications of the findings are discussed. Findings indicate, for example, that those working on campaigns and interventions in this area need to consider the wider negativity and argumentative orientation of sunbed users' responses. PMID- 28911239 TI - Controlled release of liposome-encapsulated temozolomide for brain tumour treatment by convection-enhanced delivery. AB - Convection-enhanced delivery (CED) is a promising technique for the delivery of drugs directly into the central nervous system (CNS) and, more specifically, the brain. CED can increase drug concentration within a brain tumour, thereby improving the therapeutic efficacy and limiting the systemic toxicity of tumoricidal agents. In this study, we evaluated a drug-liposome construct in vitro and in vivo using U87 tumour-bearing nude mice. Dipalmitoylphosphatidylcholine (DPPC)-based liposomes were designed to deliver a lipophilic temozolomide (TMZ) formulation (LipoTMZ). The LipoTMZ displayed good release of TMZ in vitro over a suitable range of time and temperatures. Encapsulating the TMZ into liposomes enhanced its tumoricidal activity against U87MG human glioma cells. The LipoTMZ also displayed good release and distribution of TMZ when delivered intracerebrally to U87MG tumour-bearing mice by CED infusion. Histological examination revealed that CED did not damage normal brain tissue. Our data indicate that CED was an effective method to deliver LipoTMZ to U87MG tumour-bearing mice, significantly inhibiting tumour growth without evidence of systemic toxicity. PMID- 28911240 TI - Understanding the prevalence and correlates of implicit theories of weight in the United States: Insights from a nationally representative sample. AB - OBJECTIVES: The primary aim of this research is to understand how mindsets about weight controllability in the United States relate to population health. We examined the distribution of people's implicit theories of weight, from an incremental (controllable) to an entity (not controllable) mindset, in a nationally representative sample, as well as their relation to: sociodemographic factors, beliefs about behaviour and genetics as causes of obesity and engagement in weight management-relevant behaviours. METHODS: We report data from the National Cancer Institute's Health Information National Trends Survey 4. RESULTS: A majority of respondents endorsed an incremental mindset of body weight, but endorsement of this mindset was stronger among younger, white respondents, and those with a higher income and more educational attainment. A stronger incremental mindset was related to stronger behaviour and weaker genetic causal beliefs about obesity, as well as a tendency to report increased engagement in weight management-relevant behaviours. CONCLUSIONS: Our research provides evidence that although incremental mindsets are more common overall and associated with engagement in health behaviours that can contribute to or detract from population health, incremental mindsets are less common among individuals from more marginalised groups. PMID- 28911241 TI - Correction to: Boztas et al., Effects of different doses of remifentanil on hemodynamic response to anesthesia induction in healthy elderly patients. PMID- 28911242 TI - European validation of The Comprehensive International Classification of Functioning, Disability and Health Core Set for Osteoarthritis from the perspective of patients with osteoarthritis of the knee or hip. AB - PURPOSE: To validate the International Classification of Functioning, Disability and Health Comprehensive Core Set for Osteoarthritis from the patient perspective in Europe. MATERIALS AND METHODS: This multicenter cross-sectional study involved 375 patients with knee or hip osteoarthritis. Trained health professionals completed the Comprehensive Core Set, and patients completed the Short-Form 36 questionnaire. Content validity was evaluated by calculating prevalences of impairments in body function and structures, limitations in activities and participation and environmental factors, which were either barriers or facilitators. Convergent construct validity was evaluated by correlating the International Classification of Functioning, Disability and Health categories with the Short-Form 36 Physical Component Score and the SF-36 Mental Component Score in a subgroup of 259 patients. RESULTS: The prevalences of all body function, body structure and activities and participation categories were >40%, >32% and >20%, respectively, and all environmental factors were relevant for >16% of patients. Few categories showed relevant differences between knee and hip osteoarthritis. All body function categories and all but two activities and participation categories showed significant correlations with the Physical Component Score. Body functions from the ICF chapter Mental Functions showed higher correlations with the Mental Component Score than with the Physical Component Score. CONCLUSIONS: This study supports the validity of the International Classification of Functioning, Disability and Health Comprehensive Core Set for Osteoarthritis. Implications for Rehabilitation Comprehensive International Classification of Functioning, Disability and Health Core Sets were developed as practical tools for application in multidisciplinary assessments. The validity of the Comprehensive International Classification of Functioning, Disability and Health Core Set for Osteoarthritis in this study supports its application in European patients with osteoarthritis. The differences in results between this Europe validation study and a previous Singaporean validation study underscore the need to validate the International Classification of Functioning, Disability and Health Core Sets in different regions of the world. PMID- 28911243 TI - An Investigation of a Video-Based Preference Assessment of Social Interactions. AB - We examined the use of a paired-stimulus, video-based preference assessment (VPA) to identify high- and low-preference social interactions for three children with autism spectrum disorder. We conducted two VPAs with each participant: one with access to the interaction contingent on each selection and one without access. We also conducted a concurrent-operant reinforcer assessment to evaluate the accuracy of the VPAs in identifying reinforcers. For two participants, the VPAs corresponded strongly and the results of the reinforcer assessment suggest that the high-preference interaction produced more of the target response than the low preference interaction. For the other participant, the VPAs identified different high- and low-preference interactions, and the results of the reinforcer assessment suggest that the VPA without access may have been more accurate in identifying a reinforcer. PMID- 28911244 TI - Exploring strategies used to deliver physical activity experiences to Veterans with a physical disability. AB - PURPOSE: Physical activity is an important method of rehabilitation used to promote positive physical and psychosocial outcomes among military personnel, including Veterans, with a physical disability. However, minimal research has explored physical activity program implementation strategies, particularly how these strategies may foster positive rehabilitation outcomes, and quality participation experiences among Veterans post-injury. The purpose of the current study is to document strategies used to deliver physical activity programs to Veterans with a physical disability. RESEARCH METHODS: Semi-structured interviews were conducted with program staff from three Veteran physical activity programs, and program documentation was collected. Data were analyzed using a thematic analysis. RESULTS: Four themes were identified representing strategies used for delivering physical activity programming: (1) foster social connections; (2) challenge participants; (3) tailor programs and outcomes to match participant needs; and (4) include knowledgeable coaches/instructors. CONCLUSIONS: The study provides researchers and practitioners (e.g., rehabilitation professionals, program facilitators, coaches) with evidence of strategies for delivering physical activity programming for Veterans post-injury, thus assisting with future program development and evaluation. The findings also provide preliminary insight regarding the potential relationships between physical activity programming and elements of quality participation. Implications for Rehabilitation Physical activity is a popular method of rehabilitation for military personnel post-injury. Findings highlight four strategies used to deliver physical activity experiences to Veterans with a physical disability. Strategies highlighted provide insight as to how rehabilitation specialists can promote quality experiences for Veterans with a physical disability during physical activity programming. PMID- 28911245 TI - Recent advances on conversion and co-production of acetone-butanol-ethanol into high value-added bioproducts. AB - Butanol is an important bulk chemical and has been regarded as an advanced biofuel. Large-scale production of butanol has been applied for more than 100 years, but its production through acetone-butanol-ethanol (ABE) fermentation process by solventogenic Clostridium species is still not economically viable due to the low butanol titer and yield caused by the toxicity of butanol and a by product, such as acetone. Renewed interest in biobutanol as a biofuel has spurred technological advances to strain modification and fermentation process design. Especially, with the development of interdisciplinary processes, the sole product or even the mixture of ABE produced through ABE fermentation process can be further used as platform chemicals for high value added product production through enzymatic or chemical catalysis. This review aims to comprehensively summarize the most recent advances on the conversion of acetone, butanol and ABE mixture into various products, such as isopropanol, butyl-butyrate and higher molecular mass alkanes. Additionally, co-production of other value added products with ABE was also discussed. PMID- 28911246 TI - Dual targeting of l-carnitine-conjugated nanoparticles to OCTN2 and ATB0,+ to deliver chemotherapeutic agents for colon cancer therapy. AB - l-Carnitine, obligatory for oxidation of fatty acids, is transported into cells by the Na+-coupled transporter OCTN2 and the Na+/Cl--coupled transporter ATB0,+. Here we investigated the potential of L-carnitine-conjugated poly(lactic-co glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) to deliver chemotherapeutic drugs into cancer cells by targeting the nanoparticles to both OCTN2 and ATB0,+. The cellular uptake of LC-PLGA NPs in the breast cancer cell line MCF7 and the colon cancer cell line Caco-2 was increased compared to unmodified nanoparticles, but decreased in the absence of co-transporting ions (Na+ and/or Cl-) or in the presence of competitive substrates for the two transporters. Studies with fluorescently labeled nanoparticles showed their colocalization with both OCTN2 and ATB0,+, confirming the involvement of both transporters in the cellular uptake of LC-PLGA NPs. As the expression levels of OCTN2 and ATB0,+ are higher in colon cancer cells than in normal colon cells, LC-PLGA NPs can be used to deliver chemotherapeutic drugs selectively into cancer cells for colon cancer therapy. With 5-fluorouracil-loaded LC-PLGA NPs, we were able to demonstrate significant increases in the uptake efficiency and cytotoxicity in colon cancer cells that were positive for OCTN2 and ATB0,+. In a 3D spheroid model of tumor growth, LC PLGA NPs showed increased uptake and enhanced antitumor efficacy. These findings indicate that dual-targeting LC-PLGA NPs to OCTN2 and ATB0,+ has great potential to deliver chemotherapeutic drugs for colon cancer therapy. Dual targeting LC PLGA NPs to OCTN2 and ATB0,+ can selectively deliver chemotherapeutics to colon cancer cells where both transporters are overexpressed, preventing targeting to normal cells and thus avoiding off-target side effects. PMID- 28911247 TI - Metabolic pathways and pharmacokinetics of natural medicines with low permeability. AB - Drug metabolism plays an important role in the drug disposal process. Differences in pharmacokinetics among individuals are the basis for personalized medicine. Natural medicines, formed by long-term evolution of nature, prioritize the action of a target protein with a drug. Natural medicines are valued for structural diversity, low toxicity, low cost, and definite biological activities. Metabolic pathway and pharmacokinetic research of natural medicines is highly beneficial for clinical dose adjustment and the development of personalized medicine. This review was performed using a systematic search of all available literature. It provides an overview and discussion of metabolic pathways and the pharmacokinetics of natural medicines with low permeability. The related enzymes and factors affecting them are analyzed. The series of metabolic reactions, including phase I reactions(oxidation hydrolysis, and reduction reactions) and phase II reactions (binding reactions), catalyzed by intracellular metabolic enzymes (such as CYP450, esterase, SULT, and UGT enzymes) in tissues (such as liver and gastro-intestinal tract) or in the body fluid environment were examined. The administration route, drug dose, and delivery system had a large influence on absorption, metabolism, and pharmacokinetics. Natural medicines with low permeability had distinctive metabolisms and pharmacokinetics. The metabolic and in vivo kinetic properties were favorably modified by choosing suitable drug delivery systems, administration routes and drug doses, among other variables. This study provides valuable information for clinicians and pharmacists to guide patients safe, effective, and rational drug use. The research of metabolism and pharmacokinetics is significant in guiding personalized clinical medicine. PMID- 28911248 TI - Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice. AB - Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model. PMID- 28911249 TI - Transcriptome analysis reveals the molecular mechanism of hepatic fat metabolism disorder caused by Muscovy duck reovirus infection. AB - : The aim of this work was to clarify the molecular mechanism underlying the fatty degeneration of livers infected with Muscovy duck reovirus (MDRV), which produces obvious white necrotic foci in the liver. Transcriptome data for MDRV infected Muscovy duck livers and control livers were sequenced, assembled, and annotated with Illumina(r) HiSeq 2000. The differentially expressed genes were screened and their functions were analysed. We also determined and confirmed the molecular mechanism of the hepatic fat metabolism disorder caused by MDRV infection. The expression of 4190 genes was higher in the infected livers than in the control livers, and the expression of 1113 genes was reduced. A Gene Ontology analysis showed that these genes were involved in 48 biological functions, and were significantly enriched in 237 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The free fatty acid content was significantly higher in the livers of infected Muscovy ducks than in the control livers (P < 0.01). The KEGG analysis showed that MDRV infection inhibited the cholesterol efflux from hepatic cells and reduced the expression of key enzymes involved in fatty acid degradation (scavenger receptor class b type 1, ABCG8, and APOA4), leading to the accumulation of fatty acids and cholesterol in the liver cells. In this study, we have identified the genes differentially expressed in livers infected by MDRV, from which we inferred the genes associated with lipodystrophia, and elucidated the molecular mechanism of the hepatic steatosis induced by MDRV. ABBREVIATIONS: ABC: ATP binding cassette transport; ACADVL: acyl-CoA dehydrogenase, very long chain; ACAT: mitochondrial-like acetyl-CoA acetyltransferase A; ACAT2: acetyl-CoA acyltransferase 2; ACNAT2: acyl-coenzyme A amino acid N-acyltransferase 2-like; ACOT1: acyl-CoA thioesterase 1; ACOT7: acyl-CoA thioesterase 7; ACOX1: acyl-CoA oxidase 1, palmitoyl; ACSBG2: acyl-CoA synthetase bubblegum family member 2; ACSL1: acyl-CoA synthetase long-chain family member 1; ADH1: alcohol dehydrogenase 1; APOA4: apolipoprotein A-IV; ARV: avian reovirus; cDNA: complementary deoxyribonucleic acid; COG: Clusters of Orthologous Groups; DEG: differentially expressed gene; DGAT: diacylgycerol acyltransferase; DNA: deoxyribonucleic acid; ECI2: enoyl-CoA delta isomerase 2; EHHADH: enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase; FDR: false discovery rate; GCDH: Pseudopodoces humilis glutaryl-CoA dehydrogenase; GO: Gene Ontology; HADHA: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit; I-FABP: intestinal fatty acid binding protein; KEGG: Kyoto Encyclopedia of Genes and Genomes; L-FABP: liver fatty acid binding protein; MDRV: Muscovy duck reovirus; MOI: multiplicity of infection; NPC1L1: Niemann-Pick C1-like 1; qPCR: real-time quantitative polymerase chain reaction; RNA: ribonucleic acid; RNase: ribonuclease; RNA-seq: RNA sequencing technology; RPKM: reads per kilobase per million mapped reads; SR-B1: scavenger receptor class b type 1. PMID- 28911251 TI - Patient Enablement After a Single Appointment With a GP: Analysis of Finnish QUALICOPC Data. AB - BACKGROUND: Patient enablement is described as patient's ability to understand and cope with illness after a consultation. The purpose of this study was to analyze factors associated with enablement in Finnish primary health care. An additional aim was to evaluate whether a single question could be used to measure enablement. METHODS: A questionnaire survey was addressed to Finnish general practitioners (GPs) within the Quality and Costs of Primary Care in Europe (QUALICOPC) study framework. A trained fieldworker contacted nine patients for every participating GP. Two to 9 patients per GP (median 9 patients) completed the questionnaire. Patient enablement was measured by a single question based on the Patient Enablement Instrument questionnaire. Multivariate and multilevel analyses were performed to find variables that have an independent association with patient enablement. RESULTS: A total of 1196 patients completed the QUALICOPC questionnaire. A total of 898 patients (75.1%) agreed that they felt better able to cope with their health problem or illness after an appointment with a GP, reflecting patient enablement. In the theme group analyses, 11 factors were found to have a statistically significant ( P < .05) association with enablement. In the final multivariable model, positive perceptions of doctor patient communication and patient satisfaction were positively associated with enablement. CONCLUSIONS: The results, using a single question to measure enablement, are comparable to previous findings on factors associated with enablement. Further research is needed and these results should be regarded as preliminary. PMID- 28911252 TI - Investigation of binding properties of two ethidium derivatives with serum albumins: spectral and computational approach. AB - The interaction mechanisms of two ethidium derivatives, 3,8-dibenzoylamino-5 ethyl-6-phenylphenantridinium chloride (E2) and 3,8-diphenylacetylamino-5-ethyl-6 phenylphenantridinium chloride (E3) with serum albumins (BSA and HSA) have been investigated by a combined experimental and computational approach. Fluorescence quenching and UV-vis results revealed that the interaction of derivatives with albumins resulted in formation of ground-state complexes and the obtained Stern Volmer quenching constants designate the presence of a static component in the quenching mechanisms. Thermodynamic parameters (DeltaH and DeltaS values) point out the ionic interactions play the major role in E2-BSA, E2-HSA and E3-HSA complexes. The van der Waals interactions are dominant forces in E3-BSA complex. Moreover, the obtained results in this study were supported with computational analyzes which have same tendency. PMID- 28911253 TI - Comment on: Maternal pre-eclampsia as a risk factor for necrotizing enterocolitis. PMID- 28911254 TI - Acceptance of home blood glucose monitoring by owners of recently diagnosed diabetic cats and impact on quality of life changes in cat and owner. AB - Objectives This study aimed to evaluate the acceptance of home blood glucose monitoring (HBGM) by owners of recently diagnosed diabetic cats, and the impact of choosing HBGM on the quality of life (QoL) changes of cat and owner, in addition to glycaemic changes during 6 months of follow-up. Methods Owners of cats diagnosed with diabetes mellitus (DM) and treated with insulin for 6-20 weeks were divided into an HBGM group and a non-HBGM group, based on their ability and willingness to perform HBGM after a standardised instruction session. The HBGM acceptance level and reasons for acceptance failure were documented; a questionnaire evaluated owners' experiences. For the following 6 months, changes in QoL, measured using the validated DIAQoL-pet quantification tool, and changes in glycaemic control parameters (clinical signs, serum fructosamine, blood glucose curve average/minimal/maximal/pre-insulin blood glucose) were compared between HBGM and non-HBGM groups at months 1, 3 and 6, as well as within the groups between baseline and months 1, 3 and 6. Results Thirty-eight cats were enrolled; 28 (74%) entered the HBGM group. There was no significant difference between groups in overall DIAQoL-pet score or glycaemic control parameters at any time point apart from the maximal blood glucose at month 6 (lower in the HBGM group). However, the DIAQoL-pet score, including indicators of owner worry about DM, worry about hypoglycaemia and costs, as well as glycaemic parameters, improved at all time points within the HBGM group but not within the non-HBGM group. Remission occurred in 9/28 (32%) HBGM group cats and 1/10 (10%) non-HBGM group cats ( P = 0.236). Conclusions and relevance HBGM was adopted successfully by most diabetic cat owners. Despite the extra task, positive changes in QoL parameters occurred in the HBGM group and not in the non-HBGM group. Although no difference was found in glycaemic control between the HBGM and non-HBGM groups during the 6 months of follow-up, significant glycaemic improvements were documented in the HBGM group. PMID- 28911255 TI - Downward finger displacement distinguishes Parkinson disease dementia from Alzheimer disease. AB - : Purpose/Aim of the study: To study finger displacement in patients with Parkinson disease dementia (PDD) and in patients with Alzheimer disease (AD). METHODS: We examined 56 patients with PDD and 35 with AD. Patients were examined during their regular outpatient clinic visit. Finger displacement was measured by observers not actively involved in the study using a creative grid ruler for all PDD and AD patients. Finger displacement was examined by asking patients to point their index fingers toward the grid ruler with the nails facing upward. Patients were asked to maintain the pointing position for 15 s. After 15 s, patients were asked to close their eyes for another 15 s while maintaining the same position. A positive result was downward index finger displacement of >=5 cm within the 15 second time window with eyes closed. RESULTS: Of the 56 PDD patients, 53 had bilateral finger displacement of >5 cm. In comparison, of the 35 AD patients, only 1 patient had minimal displacement. CONCLUSIONS: Results of the non-invasive finger displacement test may provide insight, on an outpatient basis, of the integrity of subcortical-cortical circuits. Downward finger displacement, especially bilateral downward displacement, may signal the extensive disruption of subcortical-cortical circuits that occurs in PDD patients. ABBREVIATIONS: AChE: acetylcholinesterase; AD: Alzheimer disease; DLB: dementia with Lewy bodies; ET: essential tremor; MDS-UPDRS: Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination; PD: Parkinson disease; PDD: Parkinson disease dementia. PMID- 28911257 TI - Fatigue in multiple sclerosis: The contribution of resting-state functional connectivity reorganization. AB - OBJECTIVES:: To investigate resting-state functional connectivity (RS-FC) of the default-mode network (DMN) and of sensorimotor network (SMN) network in relapsing remitting (RR) multiple sclerosis (MS) patients with fatigue (F) and without fatigue(NF). METHODS:: In all, 59 RRMS patients and 29 healthy controls (HC) underwent magnetic resonance imaging (MRI) protocol including resting-state fMRI (RS-fMRI). Functional connectivity of the DMN and SMN was evaluated by independent component analysis (ICA). A linear regression analysis was performed to explore whether fatigue was mainly driven by changes observed in the DMN or in the SMN. Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). RESULTS:: Compared to HC, F-MS patients showed a stronger RS-FC in the posterior cingulate cortex (PCC) and a reduced RS-FC in the anterior cingulated cortex (ACC) of the DMN. F-MS patients, compared to NF-MS patients, revealed (1) an increased RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN and (2) an increased RS-FC in the primary motor cortex and in the supplementary motor cortex of the SMN. The regression analysis suggested that fatigue is mainly driven by RS-FC changes of the DMN. CONCLUSIONS:: Fatigue in RRMS is mainly associated to a functional rearrangement of non-motor RS networks. PMID- 28911256 TI - Immune Reconstitution Inflammatory Syndrome in Patients with AIDS and Disseminated Coccidioidomycosis: A Case Series and Review of the Literature. AB - Coccidioidomycosis causes substantial morbidity and mortality in endemic areas, and dissemination is frequent in patients with impaired cellular immunity such as AIDS. Immune reconstitution inflammatory syndrome (IRIS) is paradoxical clinical worsening after initiation of antiretroviral therapy (ART) in a patient with HIV and a simultaneous opportunistic infection (OI). Immune reconstitution inflammatory syndrome has been well described for a host of mycobacterial, viral, and fungal OIs and malignancies such as Kaposi sarcoma. To date, only 3 cases of IRIS due to coccidioidomycosis have been reported in the literature. At our institution, we report 4 cases of IRIS in HIV-infected patients with disseminated coccidioidomycosis. Unfortunately, all 4 patients died of worsening coccidioidal infection after initiating ART. The optimal timing of ART in patients with AIDS and coccidioidomycosis remains to be elucidated. PMID- 28911258 TI - Effect of Cryopreservation on Cell-Laden Hydrogels: Comparison of Different Cryoprotectants. AB - Cell encapsulation in hydrogels is a technique that offers a variety of applications, ranging from drug delivery to biofabrication of three-dimensional scaffolds. The assembly of cell-laden hydrogel building blocks aims to generate complex biological constructs by manipulating microscale units. An important issue for the clinical implementation of this technique is the long-term storage of a large stock of cell/hydrogel building blocks. In this work, the impact of cryopreservation on the viability and functionality of cells encapsulated in alginate matrices is presented comparing different cryoprotective agents (CPAs). Human osteosarcoma MG63 cells were encapsulated in sodium alginate fiber constructs with wetspinning method and exposed to different formulations of cryopreservation media, containing dimethyl sulfoxide (DMSO), glycerol, and trehalose. The cell-laden fibers were subsequently slow-cooled down to -80 degrees C and stored in liquid nitrogen. After thawing, viability and death pathway of encapsulated cells were investigated, and metabolic activity and proliferative capacity of cells released from the alginate matrix were evaluated. The viability of MG63 cells encapsulated in alginate matrix ranged from 71% +/- 4% to 85% +/- 2%, depending on the cryoprotective media formulation with no protracted harmful effects from the CPAs. On the other side, cells cryopreserved in encapsulated conditions and released from the hydrogel showed larger metabolic activity and proliferative capacity in tissue culture plate compared to cells cryopreserved in suspension, in particular when DMSO and glycerol were used as CPAs. Results have been correlated with the viscoelastic properties and water content changes of the alginate constructs loaded with the different CPAs. PMID- 28911259 TI - A rare case of ovarian cancer in a pregnant woman with metastatic non-small cell lung cancer. PMID- 28911260 TI - Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis. AB - BACKGROUND: Amiselimod, an oral selective sphingosine-1-phosphate 1 receptor modulator, suppressed disease activity dose-dependently without clinically relevant bradyarrhythmia in a 24-week phase 2, placebo-controlled study in relapsing-remitting multiple sclerosis. OBJECTIVE: To assess safety and efficacy of amiselimod over 96 weeks. METHODS: After completing the core study, patients on amiselimod continued at the same dose, whereas those on placebo were randomised 1:1:1 to amiselimod 0.1, 0.2 or 0.4 mg for another 72 weeks. Most patients receiving 0.1 mg were re-randomised to 0.2 or 0.4 mg upon availability of the core study results. RESULTS: Of 415 patients randomised in the core study, 367 (88.4%) entered and 322 (77.6%) completed the extension. One or more adverse events were reported in 303 (82.6%) of 367 patients: 'headache', 'lymphocyte count decreased', 'nasopharyngitis' and 'MS relapse' were most common (14.7% 16.9%). No serious opportunistic infection, macular oedema or malignancy was reported and no bradyarrhythmia of clinical concern was observed by Holter or 12 lead electrocardiogram. The dose-dependent effect of amiselimod on clinical and magnetic resonance imaging-related outcomes from the core study was sustained in those continuing on amiselimod and similarly observed after switching to active drug. CONCLUSION: For up to 2 years of treatment, amiselimod was well tolerated and dose-dependently effective in controlling disease activity. PMID- 28911262 TI - Alleviation by gamma amino butyric acid supplementation of chronic heat stress induced degenerative changes in jejunum in commercial broiler chickens. AB - High ambient temperature adversely influences poultry production. In the present study, gamma amino butyric acid (GABA) supplementation was used to alleviate the adverse changes due to heat stress (HS) in a broiler chicken strain (Ross 308). At 21 days of age, the birds were divided into four groups of 13. Two groups were housed under normal room temperature, one group was given orally 0.2 ml 0.9% physiological saline (CN) daily, the other group received 0.2 ml of 0.5% GABA solution orally (GN). A third group was exposed to environmental HS (33 +/- 1 degrees C lasting for 2 weeks) + physiological saline (CH) and a fourth group was exposed to HS + GABA supplementation (GH). GABA supplementation during HS significantly reduced the birds' increased body temperature (p <.0001) and increased their body weight gain (p <.0001). This effect was associated with increases in the heat stress-induced reductions in jejunal villus length, crypt depth and mucous membrane thickness, and decreases in the vascular changes occurred due to HS. Additionally, GABA supplementation significantly modulated HS induced changes in glucose facilitated transporter 2 (GLUT2), peptide transporter 1 (PEPT1) and heat shock protein 70 (HSP70) mRNA expression in the jejunal mucosa (p < .0001). GABA supplementation also significantly elevated the triiodothyronine (T3) hormone level and hemoglobin levels and decreased the heterophil-lymphocyte ratio (H/L ratio) (p <.0001). Furthermore, it induced higher hepatic glutathione peroxidase enzyme (GSH-Px) activities and decreased the malondialdehyde dehydrogenase (MDA) content. These results indicate that GABA supplementation during HS may be used to alleviate HS-related changes in broiler chickens. PMID- 28911264 TI - Corrigendum. PMID- 28911263 TI - Potential Role of OCT4 in Leukemogenesis. AB - Embryonic stem cells typically show properties of long-term self-renewal and lack of differentiation. When appropriately stimulated, they are able to differentiate into all cell lineages, and lose their self-renewal characteristics. These properties are controlled by a series of genes encoding several transcription factors, including OCT4, the product of POU5F1 gene. OCT4 is expressed in germ cell tumors but also aberrantly in cancers developing in differentiated tissues. In a previous study, we observed a high expression of OCT4 in acute myeloid cell lines and primary cells, regardless of the acute myeloid leukemia (AML) subtype. In this study, we investigated the putative oncogenic role of OCT4 in proliferation and differentiation arrest. OCT4 expression was assessed in a panel of myeloid cell lines, together with clonogenic and proliferation properties, before and after differentiation in the presence of retinoic acid (RA). Same experiments were performed under short hairpin RNA (shRNA)-mediated OCT4 inhibition. In the presence of RA, we observed a decrease of OCT4 expression, associated with a loss of clonogenic and proliferation capacities, cell cycle arrest, and upregulation of p21, in HL60, NB4, KASUMI, and Me-1 cell lines. This effect was absent in the KG1a cell line, which did not differentiate. Downregulation of OCT4 by shRNA resulted in the same pattern of differentiation and loss of proliferation. Although KG1a did not differentiate, a decrease in proliferation was observed. Our findings suggest that OCT4 is implicated in the differentiation arrest at least in some types of AML, and that it also plays a role in cell proliferation through different oncogenic mechanisms. OCT4 might be a potential new target for antileukemic treatments. PMID- 28911261 TI - Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy. AB - Cardio-oncology is a new and rapidly expanding field that merges cancer and cardiovascular disease. Cardiovascular disease is an omnipresent side effect of cancer therapy; in fact, it is the second leading cause of death in cancer survivors after recurrent cancer. It has been well documented that many cancer chemotherapeutic agents cause cardiovascular toxicity. Nonetheless, the underlying cause of cancer therapy-induced cardiovascular toxicity is largely unknown. In this review, we discuss the potential role of damage-associated molecular patterns (DAMPs) as an underlying contributor to cancer therapy-induced cardiovascular toxicity. With an increasing number of cancer patients, as well as extended life expectancy, understanding the mechanisms underlying cancer therapy induced cardiovascular disease is of the utmost importance to ensure that cancer is the only disease burden that cancer survivors have to endure. PMID- 28911265 TI - Mental health and chronic diseases: a challenge to be faced from a new perspective. PMID- 28911266 TI - Behavioral and brain oscillatory correlates of affective processing in subclinical depression. AB - Named among the most dangerous diseases of the modern era, depression is characterized primarily by distortions in the affective sphere. Despite extensive investigations of underlying the neural background, mechanisms of the distortion still remain unknown. The current study analyzed brain oscillatory dynamics in different frequencies during resting state and presentation of affective stimuli in nonclinical individuals with high Beck Depression Inventory-II (BDI-II) scores (HB) versus controls. Both behavioral and electrocortical "markers" of clinical depression were apparent at subclinical level. A resting-state electroencephalogram (EEG) of HB revealed increased power in low frequencies, predominantly in the frontal cortical areas, that is in accordance with a "spatio temporal dysfunction" model of depression. Related to that, transition from an eyes-closed to eyes-open condition was associated with diminished alpha blockade in HB, suggesting difficulties with the relocation of attention focus from inner processes toward environmental stimuli. Subsequently, independently of a sign of emotion, five out of six discrete emotions were evaluated as less valenced and four out of six as less intense by HB than by controls, corroborating the view of emotion context insensitivity (ECI) associated with depression. Underlying brain oscillatory dynamics revealed that depression was associated with deficits in the early, implicit, processing stages of emotional stimuli. Later processing stages were characterized by prominent power surges in low and alpha frequencies, presumably indicating emotion upregulation processes and increased engagement of cognitive mechanisms in affective tasks. The study provides brain oscillatory based mechanisms of emotion processing distortions associated with depression. PMID- 28911267 TI - The behavioral and molecular evaluation of effects of social instability stress as a model of stress-related disorders in adult female rats. AB - The study aimed to test the hypotheses that chronic social instability stress (CSIS) alters behavioral and physiological parameters and expression of selected genes important for stress response and social behaviors. Adult female Sprague Dawley rats were subjected to the 4-week CSIS procedure, which involves unpredictable rotation between phases of isolation and overcrowding. Behavioral analyses (Experiment 1) were performed on the same rats before and after CSIS (n = 16) and physiological and biochemical measurements (Experiment 2) were made on further control (CON; n = 7) and stressed groups (CSIS; n = 8). Behaviors in the open field test (locomotor and exploratory activities) and elevated-plus maze (anxiety-related behaviors) indicated anxiety after CSIS. CSIS did not alter the physiological parameters measured, i.e. body weight gain, regularity of estrous cycles, and circulating concentrations of stress hormones and sex steroids. QRT PCR analysis of mRNA expression levels was performed on amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus. The main finding is that CSIS alters the mRNA levels for the studied genes in a region-specific manner. Hence, expression of POMC (pro-opiomelanocortin), AVPR1a (arginine vasopressin receptor), and OXTR (oxytocin receptor) significantly increased in the amygdala following CSIS, while in PFC and/or hypothalamus, POMC, AVPR1a, AVPR1b, OXTR, and ERbeta (estrogen receptor beta) expression decreased. CSIS significantly reduced expression of CRH-R1 (corticotropin-releasing hormone receptor type 1) in the hippocampus. The directions of change in gene expression and the genes and regions affected indicate a molecular basis for the behavior changes. In conclusion, CSIS may be valuable for further analyzing the neurobiology of stress related disorders in females. PMID- 28911268 TI - Apathy, not depressive symptoms, as a predictor of semantic and phonemic fluency task performance in stroke and transient ischemic attack. AB - OBJECTIVES: This study examined the relationship between apathy and cognition in patients with cerebrovascular disease. Apathy may result from damage to frontal subcortical circuits causing dysexecutive syndromes, but apathy is also related to depression. We assessed the ability of apathy to predict phonemic fluency and semantic fluency performance after controlling for depressive symptoms in 282 individuals with stroke and/or transient ischemic attack. METHOD: Participants (N = 282) completed the Phonemic Fluency Test, Semantic Fluency Test, Center for Epidemiologic Studies Depression Scale, and Apathy Evaluation Scale. A cross sectional correlational design was utilized. RESULTS: Using hierarchical linear regressions, apathy scores significantly predicted semantic fluency performance (beta = -.159, p = .020), but not phonemic fluency performance (beta = -.112, p = .129) after scaling scores by age and years of education and controlling for depressive symptoms. Depressive symptoms entered into the first step of both hierarchical linear regressions did not predict semantic fluency (beta = -.035, p = .554) or phonemic fluency (beta = -.081, p = .173). Apathy and depressive symptoms were moderately correlated, r(280) = .58, p < .001. CONCLUSIONS: The results of this study are consistent with research supporting a differentiation between phonemic and semantic fluency tasks, whereby phonemic fluency tasks primarily involve frontal regions, and semantic fluency tasks involve recruitment of more extended networks. The results also highlight a distinction between apathy and depressive symptoms and suggest that apathy may be a more reliable predictor of cognitive deficits than measures of mood in individuals with cerebrovascular disease. Apathy may also be more related to cognition due to overlapping motivational and cognitive frontal subcortical circuitry. Future research should explore whether treatments for apathy could be a novel target for improving cognitive outcomes after stroke. PMID- 28911269 TI - Applicability of two-dimensional surface model in bacterial biosorption system: an advanced approach in bioremediation of metal ions. AB - The surface of Bacillus VMSDCM (accession no. HQ108109) has been characterized at various pH values of the experimental solution. The boundary values of conditional parameter were used to develop a mathematical six lumped stochastic model for studying the surface chemistry of the bacterium cells. The results of the model were statistically analyzed to understand the strength of the proposed model. The simulation of the model was performed in Turbo C++ interface. The convergence values of the model were recorded and all the asymptotic points were neglected. The optimum values of model were reiterated to identify the intermittent values of maximum number of active sites, concentration of hydrides and hydroxides of calcium and magnesium and difference between the theoretical and experimental count of active sites. The values of zeta potential indicated towards the ionization of negatively charged surface functional groups at higher values of pH. The results of the present investigation revealed the fact that changes in the values of conditional parameter (pH) may create a drift in design parameters of a batch or continuous column reactor, fabricated for biosorption cum-bioaccumulation of metal ions (Ca2+ and Mg2+) across liquid phase. PMID- 28911270 TI - Effective partial nitrification of ammonia in a fluidized bed bioreactor. AB - A lab-scale fluidized bed bioreactor with high-density polyethylene as biofilm carrier media was operated to study partial nitrification (PN) performance with high ammonia concentrations. The system was run at nitrogen loading rates (NLRs) from 1.2 to 4.8 kg N/(m3 d) with empty bed contact time of 2.0 and 2.7 h and four different influent ammonia concentrations of 100, 200, 300 and 400 mg/L. Dissolved oxygen concentration and temperature were maintained around 1.3 mg/L and 35 degrees C, respectively. Stable PN was successfully achieved during the whole period with low effluent NO3-N concentration at less than 15 mg/L, due to effective suppression of nitrite-oxidizing bacteria activity at high concentrations of free ammonia (5.3-27.3 mg N/L) and low alkalinity-to-ammonia ratio. At the NLR of 3.6 kg N/(m3 d), NH4-N conversion and NO2-N accumulation ratios were 57.8% and 53.9%, respectively, which could be further used in the anaerobic ammonium oxidation process (ANAMMOX) as the effluent NO2-N/NH4-N ratio was 1.27. PMID- 28911271 TI - Chitosan modification persimmon tannin bioadsorbent for highly efficient removal of Pb(II) from aqueous environment: the adsorption equilibrium, kinetics and thermodynamics. AB - Lead (Pb) pollution has triggered a great threat to ecological system as well as public health due to its highly toxic and mutagenic properties. In this study, chitosan surface modified persimmon tannin (PT-CS) biomass composite as an environmental-friendly bioadsorbent for highly efficient removal of Pb(II) from aqueous solutions was investigated. Fourier-transform infrared spectroscopy, X ray diffraction, scanning electron microscope, Brunauer-Emmett-Teller, X-ray photoelectron spectroscopy and Zeta potential were used to elucidate the adsorption mechanism. Combining oxidation reaction, electrostatic interaction and chelation reaction, PT-CS exhibited fine adsorption to Pb(II). The maximum adsorption capacity was 179.3 mg/g. Equilibrium isotherm for the adsorption of Pb(II) was analyzed by the Langmuir, Freundlich and Temkin models, and the Langmuir isotherm (R2 > 0.99) was the best. The pseudo-first-order, pseudo-second order and intraparticle diffusion equations were used to analyze the kinetic data of the adsorption process and the pseudo-second-order kinetic (Rs2 > 0.98) model was fitted well. Moreover, thermodynamic parameters including DeltaG0 < 0, DeltaH0 (150.57 KJ/mol) > 0 and DeltaS0 (456.13 J/mol K) > 0 showed that the process of Pb(II) adsorption by PT-CS was spontaneous and endothermic. All these results illustrated that PT-CS would be a promising and low-cost alternative bioadsorbent of Pb(II) in wastewater treatment. PMID- 28911272 TI - Exploring health navigating design: momentary contentment in a cancer context. AB - PURPOSE: The technocratic and medicalized model of healthcare is rarely optimal for patients. By connecting two different studies we explore the possibilities of increasing quality of life in cancer care. METHODS: The first study captures survival strategies in a historically isolated Arctic village in Norway resulting in Momentary contentment theory, which emerged from analysing four years of participant observation and interview data. The second study conceptualizes everyday life of cancer patients based on in-depth interviews with 19 cancer patients; this was conceptualized as Navigating a new life situation. Both studies used classic grounded theory methodology. The connection between the studies is based on a health design approach. RESULTS: We found a fit between cancer patients challenging life conditions and harsh everyday life in an Arctic village. Death, treatments and dependence have become natural parts of life where the importance of creating spaces-of-moments and a Sense of Safety is imminent to well-being. While the cancer patients are in a new life situation, the Arctic people show a natural ability to handle uncertainties. CONCLUSION: By innovation theories connected to design thinking, Momentary contentment theory modified to fit cancer care would eventually be a way to improve cancer patients' quality of life. PMID- 28911273 TI - Memory enhancement of fresh ginseng on deficits induced by chronic restraint stress in mice. AB - OBJECTIVES: Chronic stress exposure can disrupt the balance of organisms, result in learning and memory impairments and induce oxidative stress. However, there is a lack of safe and effective long-term therapeutic agents for stress-related injuries. Fresh ginseng (FG), an unprocessed raw root of ginseng, has antioxidant and neuroprotective activities and has been used as functional health food in Asian countries for many years. The aim of this study was to verify the protective effects of FG on chronic restraint stress (CRS)-induced learning and memory impairments as well as oxidative stress damage in mice. METHODS: Animals were subjected to object location recognition test (OLRT) and novel object recognition test (NORT) to evaluate discriminative ability and spatial learning and memory, and Morris water maze test (MWMT) was used to evaluate the acquisition and retention of spatial memory. In addition, oxidative stress parameters were assessed by measuring the malondialdehyde (MDA) and total antioxidant reactivity levels in serum. RESULTS: Experimental results demonstrated that CRS-induced mice exhibited significantly decreased discrimination index (DI) in OLRT and NORT, longer escape latency and swimming distance, and decreased crossing numbers in MWMT. FG (2 and 6 g/kg) treatment markedly enhanced the discriminative ability by elevating DI in OLRT and NORT, improved the acquisition and retention of spatial memory by decreasing escape latency and swimming distance in the acquisition phase, and increased the crossing numbers in the probe phase of MWMT. Administration of FG (2 and 6 g/kg) significantly reduced the elevated MDA level caused by CRS. DISCUSSION: Our results suggest that FG treatment could improve CRS-induced learning and memory impairments and oxidative stress damage. FG is an intriguing therapeutic agent and functional health food in stress-related dementia. PMID- 28911274 TI - Participation and support - associations with Swedish pupils' positive health. AB - From the perspective of salutogenesis, schools have opportunities to create supportive environments for health and well-being, but there is a need for more knowledge about positive health determinants in the school setting. The aim of this study was to analyse adolescents' self-reported positive health and its association with supportive factors in the school environment. Data was derived from a cross-sectional study in which pupils were aged 12-16 (n=1527). A positive health scale was used to examine the association of positive health with the following determinants: classroom participation; teacher support; peer support; parental support; and personal relative affluence. Data was analysed with multiple logistic regression. The results showed that positive health was associated with classroom participation and support from teachers and parents more commonly among boys than girls. All determinants were significantly associated with pupils' positive health. The conclusion is that students' positive health is strongly associated with support from the school. Classroom participation and support are major concerns for the health of pupils, and it is essential to develop these aspects of the school environment. PMID- 28911275 TI - Associations between retirement reasons, chronic pain, athletic identity, and depressive symptoms among former professional footballers. AB - BACKGROUND: Retirement from professional sport has been recognised as a major psychological stressor, and there is a need to identify factors that increase the risk of mental health problems after career termination. The current study examined associations between career-ending injury, chronic pain, athletic identity, and depressive symptomology in retired professional footballers. METHODS: A cross-sectional study was performed with 307 retired male footballers who had played within a professional United Kingdom league. Participants completed measures of depressive symptoms (Short Depression-Happiness Scale), chronic pain (Pain Intensity Numerical Rating Scale), and athletic identity (Athletic Identity Measurement Scale), and reported their reasons for retirement. RESULTS: A total of 48 participants (16%) met the cut-off score for possible cases of clinically relevant depression. These participants were more recently retired, and had higher athletic identity than those without depressive symptoms. Former players with depressive symptoms were more likely to cite injury as a retirement reason, and report higher levels of ongoing injury-related pain. Multivariate logistic regression revealed that the presence of depressive symptoms was independently associated with retirement through injury (OR = 3.44; 95% CI = 1.39, 8.51), higher pain levels (OR = 1.38; 95% CI = 1.02, 1.86), and increased athletic identity (OR = 1.28; 95% CI = 1.14, 1.44). CONCLUSIONS: Career ending injury is strongly associated with higher odds of depressive symptomology during retirement, while experiencing chronic pain, and maintaining a high sense of athletic identity, are additional potential contributors. PMID- 28911276 TI - High G flight: physiological effects and countermeasures. PMID- 28911277 TI - Analysis of Different Melatonin Secretion Patterns in Children With Sleep Disorders: Melatonin Secretion Patterns in Children. AB - The objective of this study was to analyze circadian patterns of urinary 6 sulphatoxymelatonin (aMT6s) excretion in children with primary sleep disorders in comparison with healthy controls. A total of 124 control children and 124 patients (aged 4-14 years) diagnosed with diverse primary sleep disorders were recruited. aMT6s concentrations were measured in diurnal and nocturnal urine, as well as in 24-hour urine. aMT6s levels were significantly higher and showed significantly more evident circadian variations in the control group ( P < .001). Four different melatonin (aMT) production and excretion patterns were distinguished in the group with sleep disorders: (1) standard aMT production pattern, (2) low aMT production pattern, (3) aMT production pattern with absence of circadian variation, and (4) aMT hyperproduction pattern. This study highlights the importance of analyzing specific alterations of aMT secretion in each sleep disorder and provides evidences to explain why not all children with sleep disturbances do respond to aMT treatment. PMID- 28911278 TI - Measurement of Sedentary Behaviors or "Downtime" in Rett Syndrome. AB - This study aimed to validate measures of sedentary time in individuals with Rett syndrome. Twenty-six individuals (median [IQR] age 16.0 (9.4-20.6) years) wore an activPAL accelerometer during video-taped activities and agreement was determined between sedentary time determined by the activPAL and observation. For 11 individuals (median [IQR] age 14.5 (11.5-25.6) years), linear regression was used to determine the relationship between sedentary time recorded on the modified Bouchard activity record diary card and measured using the activPAL. In comparison to observation, the activPAL accurately measured duration of sedentary time with a mean difference (limit of agreement) of -1.0 (6.3) minutes. The duration of Bouchard activity record downtime accounted for 73% of the variance of sedentary time measured by the activPAL (coefficient 0.762, 95% CI 0.413 to 1.111). These data provide clinicians and caregivers with capacity to investigate strategies that would aim to increase activity in the nonexercise component of the activity continuum. PMID- 28911280 TI - Adrenaline-a therapeutic history. PMID- 28911281 TI - Can the timing of perioperative fluids affect hospital length of stay? PMID- 28911282 TI - What are we injecting with our drugs? AB - In preparation for a case, an anaesthetist opened a 20 ml glass vial of propofol and aspirated the propofol into a syringe via a blunt drawing-up needle. Increased resistance was felt with aspiration. On inspection, a shard of glass was found at the tip of the drawing-up needle. The shard was presumed to be from the propofol ampoule, and to have fallen into the solution upon snapping open its glass tip. This illustrative case raises the issue of contamination of drugs by particles introduced during the drawing-up process. It also highlights the possibility that during the drawing-up process, intravenous drugs may become contaminated not just with particles, but with microorganisms on the surface of the particles. In this article, we discuss relevant recent research of the implications of this type of drug contamination. We draw attention to the need for meticulous care in drawing up and administering intravenous drugs during anaesthesia, particularly propofol. PMID- 28911283 TI - Australian and New Zealand Anaesthetic Allergy Group Perioperative Anaphylaxis Investigation Guidelines. AB - These guidelines are a consensus document developed by a working party of the Australian and New Zealand Anaesthetic Allergy Group (ANZAAG) to provide an approach to the investigation of perioperative anaphylaxis. They focus primarily on the use of skin testing as it is the investigation with the greatest clinical utility for the identification of the likely causative agent and potentially safer alternatives. The practicalities and process of skin testing, its limitations, and the place of other tests are discussed. These guidelines also address the roles of graded challenge and in vitro testing. The implications of anaphylaxis associated with neuromuscular blocking agents, beta-lactam antibiotics, local anaesthetic agents and chlorhexidine are discussed. Evidence for the recommendations is derived from literature searches using the words skin test, allergy, anaphylaxis, anaesthesia, and each of the individual agents listed in these guidelines. The individual articles were then reviewed for suitability for inclusion in these guidelines. Where evidence was not strong, as is the situation for many perioperative agents, expert consensus from the ANZAAG working party was used. These guidelines are intended for use by specialists involved in the investigation of perioperative allergy. They have been approved following peer review by members of ANZAAG and are available on the ANZAAG website: http://www.anzaag.com/anaphylaxis-management/testing-guidelines.pdf. PMID- 28911284 TI - Effect of nicotine replacement therapy on mortality, delirium, and duration of therapy in critically ill smokers: a systematic review and meta-analysis. AB - Nicotine replacement therapy is widely used in critically ill smokers and its effect on delirium, mortality and duration of intensive care unit (ICU) admission is unknown. The aims of this review were to determine whether the management of nicotine withdrawal with nicotine replacement therapy reduces delirium, mortality or length of stay in critically ill smokers in ICU. The primary outcome was incidence of author-defined ICU delirium. Secondary outcomes were ICU or hospital mortality, ICU-free days at day 28, and ICU or hospital length of stay. We conducted a systematic review and meta-analysis of the data sources MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews for randomised controlled trials and observational studies. Clinical trials, observational studies and systematic reviews comparing nicotine replacement therapy with placebo or no treatment were included. Case reports, case series, non-systematic reviews and studies that involved children were excluded. Eight studies were eligible (n=2,636) for inclusion in the data synthesis. In a meta-analysis of observational studies, nicotine replacement therapy was associated with increased delirium (three studies; n=908; I2=0%; finite element method: odds ratio 4.03 [95% confidence interval 2.64, 6.15]; P <0.001). There was no difference in ICU mortality (three studies; n=1,309; P=0.10, I2=44%; finite element method: odds ratio 0.58; 95% confidence intervals 0.31-1.10) and hospital mortality or 28-day ICU-free days. In the absence of high-quality data, nicotine replacement therapy cannot currently be recommended for routine use to prevent delirium or to reduce hospital or ICU mortality in critically ill smokers. PMID- 28911285 TI - In vitro evaluation of the effect of haemodilution with dextran 40 on coagulation profile as measured by thromboelastometry and multiple electrode aggregometry. AB - We evaluated the effects of haemodilution with either dextran 40 or 0.9% normal saline on coagulation in vitro using rotational thromboelastometry (ROTEM(r), Pentapharm Co., Munich, Germany) and multiple electrode aggregometry (Multiplate(r) Platelet Function Analyser, Dynabyte, Munich, Germany). Venous blood samples obtained from 20 healthy volunteers were diluted in vitro with dextran 40 or normal saline by 5%, 10% and 15%. Fibrinogen concentration, ROTEM EXTEM(r) (screening test for the extrinsic coagulation pathway), FIBTEM(r) (an EXTEM-based assay of the fibrin component of clot) parameters including coagulation time, clot formation time, alpha angle, maximum clot firmness and lysis index were measured in the undiluted sample and at each level of haemodilution. Dextran 40 at 15% haemodilution significantly prolonged coagulation time, clot formation time and significantly decreased the alpha angle and maximal clot firmness (EXTEM amplitude at five minutes [A5] and ten minutes [A10]) compared with normal saline. The FIBTEM assay (maximal clot firmness and FIBTEM A5 and A10) showed a marked decrease in maximal clot firmness at all dilutions suggesting impaired fibrinogen activity and a risk of bleeding. Multiple electrode aggregometry did not demonstrate any platelet dysfunction. Haemodilution with dextran 40 causes significant impairment in clot formation and strength compared to saline haemodilution and undiluted blood. At the levels of in vitro haemodilution designed to reflect the clinical use of dextran infusions, no significant fibrinolysis or platelet inhibition was observed. PMID- 28911286 TI - The effect of a surgery-specific cardiac output-guided haemodynamic algorithm on outcomes in patients undergoing pancreaticoduodenectomy in a high-volume centre: a retrospective comparative study. AB - In this retrospective observational study performed in a high-volume hepatobiliary-pancreatic unit, we evaluated the effect of a surgery-specific goal directed therapy (GDT) physiologic algorithm on complications and length of hospital stay. We compared patients who underwent pancreaticoduodenectomy with either a standardised Enhanced Recovery After Surgery program (usual care group), or a standardised Enhanced Recovery After Surgery program in combination with a surgery-specific cardiac output-guided algorithm (GDT group). We included 145 consecutive patients: 47 in the GDT group and 98 in the usual care group. Multivariable associations between GDT and lengths of stay and complications were investigated using negative binomial regression. Postoperative complications were common and occurred at similar frequencies amongst the GDT and usual care groups: 64% versus 68% respectively, P=0.71; odds ratio 0.82; (95% confidence interval 0.39-1.70). There were fewer cardiorespiratory complications in the GDT group. Median (interquartile range) length of hospital stay was ten days (8.0-14.0) in the GDT group compared to 13 days (8.8-21.3) in the usual care group, P=0.01. Median (interquartile range) total intraoperative fluid was 3,000 ml (2,050 4,175) in the GDT group compared to 4,500 ml (3,275-5,325) in the usual care group, P <0.0001; but by day one, the median (interquartile range) fluid balance was similar (1,198 ml [700-1,729] in the GDT group versus 977 ml [419-2,044] in the usual care group, P=0.96). Use of vasoactive medications was higher in the GDT group. In our patients undergoing pancreaticoduodenectomy, GDT was associated with restrictive intraoperative fluid intervention, fewer cardiorespiratory complications and a shorter hospital length of stay compared to usual care. However, we could not exclude an influence of surgical caseload, which we have previously found to be an important variable. We also could not relate the increased hospital length of stay to cardiorespiratory complications in individual patients. Therefore, these observational retrospective findings would require confirmation in a prospective randomised study. PMID- 28911287 TI - Effect of sugammadex versus neostigmine/atropine combination on postoperative cognitive dysfunction after elective surgery. AB - This study aimed to assess the effects of sugammadex and neostigmine/atropine on postoperative cognitive dysfunction (POCD) in adult patients after elective surgery. A randomised, double-blind controlled trial was carried out on 160 American Society of Anesthesiologists physical status I to III patients who were >40 years. The Mini-Mental State Evaluation, clock-drawing test and the Isaacs Set test were used to assess cognitive function at three timepoints: 1) preoperatively, 2) one hour postoperatively, and 3) at discharge. The anaesthetic protocol was the same for all patients, except for the neuromuscular block reversal, which was administered by random allocation using either sugammadex or neostigmine/atropine after the reappearance of T2 in the train-of-four sequence. POCD was defined as a decline >=1 standard deviation in >=2 cognitive tests. The incidence of POCD was similar in both groups at one hour postoperatively and at discharge (28% and 10%, in the neostigmine group, 23% and 5.4% in the sugammadex group, P=0.55 and 0.27 respectively). In relation to individual tests, a significant decline of clock-drawing test in the neostigmine group was observed at one hour postoperatively and at discharge. For the Isaacs Set test, a greater decline was found in the sugammadex group. These findings suggest that there are no clinically important differences in the incidence of POCD after neostigmine or sugammadex administration. PMID- 28911288 TI - Impact of thrombelastography in paediatric intensive care. AB - We assessed the clinical impact of thrombelastography (TEG(r)) results (TEG(r) 5000, Haemonetics Corporation, Braintree, MA, USA) by measuring their ability to cause changes in a theoretical treatment plan and contribute to the understanding of haemostasis. We prospectively included paediatric intensive care unit (PICU) patients who had standard tests of haemostasis and TEG ordered and had an arterial catheter or extracorporeal access port in situ. Blood for standard tests and TEG was taken simultaneously. Independent of patient care, general patient information and results of standard laboratory tests were presented to five clinicians who were asked to document their theoretical treatment plan. Clinicians were then shown TEG results and asked if they caused a change in their plan, if they confirmed initial standard laboratory test results, if they enabled a better understanding of haemostasis and if they provided additional information. Inter-rater agreement between the clinicians was determined. Forty two TEG results were obtained from 34 patients. Overall, the inclusion of TEG results led to a change in treatment plan in 97 of 207 occasions (47%), confirmed standard laboratory test results in 177 of 204 occasions (87%), enabled a better understanding of haemostasis in 140 of 204 occasions (69%) and provided additional information in 131 of 204 occasions (64%). Variation existed between clinicians, seemingly due to individual differences, with poor inter-rater agreement. We conclude that TEG results led to changes in treatment plans almost half the time, confirmed findings of standard tests and provided a better understanding of haemostasis, but randomised controlled trials are required to determine the role and influence of TEG results on patient outcome. PMID- 28911289 TI - Incidence of elevated procalcitonin and presepsin levels after severe trauma: a pilot cohort study. AB - Procalcitonin (PCT) and presepsin (PSEP) are useful biomarkers for diagnosing sepsis; however, elevated PCT and PSEP levels may be observed in conditions other than sepsis. We hypothesised that PCT and PSEP levels could increase after severe traumatic injuries. Trauma patients with an Injury Severity Score of >=16 from October 2013 to September 2015 were enrolled in our study. We examined PCT and PSEP levels and their positive rates on days 0 and 1. PCT and PSEP levels on days 0 and 1 were compared. Risk factors for increasing sepsis biomarker levels were identified by multivariate logistic regression analyses. In this study, 75 patients were included. PCT levels on days 0 and 1 were 0.1+/-0.4 and 1.8+/-6.3 ng/ml, respectively (P=0.02). PSEP levels on days 0 and 1 were 221+/-261 and 222+/-207 pg/ml, respectively (P=0.98). As per multivariate logistic regression analyses, packed red blood cell (PRBC) transfusion was the only independent risk factor for higher PCT levels on day 1 (P=0.04). Using PCT to diagnose sepsis in trauma patients on day 1 requires caution. PRBC transfusion was found to be a risk factor for increasing PCT levels. On the other hand, PSEP levels were not affected by trauma during the early phases. PMID- 28911290 TI - Outcomes of telemedicine intervention in a regional intensive care unit: a before and after study. AB - Telemedicine consultations in remote intensive care units (ICUs) overseas were found to be effective in reducing mortality and hospital length of stay (LOS). In Australia, there were anecdotal reports of these clinical outcomes. This retrospective before and after study assessed the improvement in patient outcomes with the implementation of a telemedicine program in a regional high dependency unit. Daily virtual consultations were conducted between the rural facility and the intensivists at the regional centre. A total of 525 patients received intensive care support between 2010 and 2015. Hospital and High Dependency Unit mortality showed no evidence of significant differences between the telemedicine group and the baseline (relative risk 1.02, 95% confidence interval [CI] 0.99 1.06, P=0.25 and relative risk 1.00, 95% CI 0.98-1.03, P=0.67 respectively). The hospital LOS was lower in the baseline group by 1.5 days. There was no significant difference in High Dependency Unit LOS. To adjust for the covariates in LOS, log linear regression analysis was performed. The telemedicine intervention, Acute Physiology and Chronic Health Evaluation II scores and inter hospital transfers were found to contribute significantly to hospital LOS. The most important result of the study was that the proportion of inter-hospital transfers was lower in the telemedicine group (relative risk 0.88, 95% CI 0.80 0.98, P=0.03) compared to baseline. This means that critically ill patients in our regional centre can continue to receive specialist care remotely through tele ICU consultations thus avoiding the need for patient transport. However, further study is needed to establish the benefits and risks of telemedicine intervention in ICUs in Australia. PMID- 28911291 TI - Administration of anaesthetic triggering agents to patients tested malignant hyperthermia normal and their relatives in New Zealand: an update. AB - Testing for malignant hyperthermia in New Zealand involves two tests-in vitro contracture testing of excised lateral quadriceps muscle and DNA analysis. In vitro contracture testing is regarded as the gold standard in malignant hyperthermia diagnosis but several publications have questioned the reliability of a normal result. Analysis of 479 anaesthetic records in 280 patients or their descendants throughout New Zealand who had tested negative for malignant hyperthermia, demonstrated there was no evidence of malignant hyperthermia episodes in this group who had been administered anaesthetic triggering agents. A wide range of anaesthetics were used over the study period. Analysis of each anaesthetic record was undertaken using the malignant hyperthermia grading scale which determines the likelihood that an anaesthetic event represents a malignant hyperthermia episode. Confirmation of the negative results was further supported by normal DNA analysis of patients in 48% of anaesthetics. There are advantages to using inhalational agents in certain situations and although demonstrating a zero risk of a malignant hyperthermia episode is not statistically possible, evidence in this large series suggests that the risk of an episode in these patients is extremely low and may be negligible. We suggest that anaesthetic triggering agents can be used safely in patients with normal in vitro contracture tests, and in their descendants. PMID- 28911292 TI - A retrospective observational study of patients with dilated cardiomyopathy undergoing non-cardiac surgery. AB - The perioperative risks and factors associated with adverse cardiac outcomes in patients with dilated cardiomyopathy undergoing non-cardiac surgery are unknown. Interrogation of the Nelson Hospital transthoracic echocardiogram database identified 127 patients with dilated cardiomyopathy who satisfied the study criteria and underwent non-cardiac surgery between June 1999 and July 2013. Demographic and clinical data along with postoperative death within 30 days or a major adverse cardiac event were retrieved and analysed. The mean age was 75.9 years. Seventy-one percent of the patients had severe impairment of left ventricular function and 35% had a severely dilated left ventricle. A major adverse cardiac event occurred in 18.1% of patients and 5.5% of patients died within 30 days of surgery. Increased surgical risk and absence of cerebrovascular disease were associated with adverse outcome (P <0.001, P <0.05, respectively). Forty-three and a half percent (43.5%) of patients undergoing high-risk surgery had an adverse outcome compared to 36.1% and 5.9% for moderate and low-risk surgery, respectively. A major adverse cardiac event was observed in 26.7% of patients with cardiovascular disease compared to 9.8% of patients without cardiovascular disease. We were unable to exclude an influence of other potential risk factors due to the retrospective observational nature of the study. These findings highlight a potential increase in complications with moderate or high surgical risk, whilst are reassuring in demonstrating the relative safety of low risk surgery in this group of high-risk patients. PMID- 28911293 TI - A survey of the sequelae of memorable anaesthetic drug errors from the anaesthetist's perspective. AB - Drug errors amongst anaesthetists are common. Although there has been previous work on the system factors involved with drug error, there has been little research on the sequelae of a drug error from the anaesthetist's perspective. To clarify this issue, we surveyed anaesthetists regarding their most memorable drug error to identify associated factors and personal sequelae regarding their professional practice after the event. An online survey was sent anonymously to 989 Australian and New Zealand College of Anaesthetists (ANZCA) Fellows in March 2016 and the results were collected over the following two months. There were 295 completed surveys (29.8% response). The majority of respondents were male consultants, aged over 45 years. Reported drug errors occurred most frequently during normal working hours, and the most common drugs involved were non depolarising muscle relaxants. In 34% of the errors, another anaesthetist was present, and their presence was felt to have contributed in 40.7% of these cases. About 20% of respondents reported that they did not receive adequate support after the event. Sleep patterns were affected in 14.4% of respondents, although very few found that the error had affected their capacity to function at work. These findings suggest that memorable drug errors can be significant enough to have adverse sequelae to anaesthetists, even if no patient harm occurs. PMID- 28911294 TI - Potential for inadvertent airway delivery of carbon dioxide with humidified high flow oxygen circuit. PMID- 28911295 TI - Echocardiography Time Audit study. PMID- 28911296 TI - A brief safety assessment of active self-warming blankets; too hot to handle? PMID- 28911297 TI - Fungal coronary embolus while on extracorporeal membrane oxygenation. PMID- 28911298 TI - Veno-arterial extracorporeal membrane oxygenation for severe cardiogenic shock secondary to phaeochromocytoma crisis. PMID- 28911299 TI - In Silico Models for Nanomedicine: Recent Developments. AB - Nanomedicine is a recent promising setting for the advancement of current medical therapies, in particular for cancer. Nanoparticle-mediated therapies are aimed to tackle extremely complex phenomena, involving different biochemical, mechanical and biophysical factors. Computational models can contribute to medical research by helping the understanding of biological mechanisms and by providing quantitative analyses. In this work, we report on computational models that address four main issues related to the use of nanoparticles in anti-cancer therapies, namely the delivery of nanoparticles, their uptake by cells, the release of drugs from nano-platforms and nanoparticle-based therapeutics. In silico approaches constitute a valuable tool to aid clinical studies, guiding the rational design of new nanoparticle formulations and identifying the optimal strategies for existing treatments. PMID- 28911300 TI - Editorial: Non-Communicable Diseases: Gender Differences in Therapy. PMID- 28911301 TI - Editorial: Targeting Drug-resistant and Metastatic Tumors by Interference with Tumor and Microenvironment-related Alterations. PMID- 28911302 TI - What is the Real Efficacy of Beta-Blockers for the Treatment of Essential Hypertension? AB - OBJECTIVE: This review covers the pharmacokinetics and pharmacodynamic of beta blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third generation beta-blockers beyond hypertension. BACKGROUND: The efficacy and safety of beta-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of beta-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that beta-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating beta-blockers (atenolol and metoprolol) are inferior to first line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism. CONCLUSION: New vasodilating beta-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs nonvasodilating beta-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation beta-blockers are superior to conventional beta-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation beta-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group. PMID- 28911303 TI - Role of Protein Kinases and Their Inhibitors in Radiation Response of Tumor Cells. AB - Phosphorylation, the addition of a phosphate group to a molecule, is an effective way of regulating the biological properties of that molecule. Protein phosphorylation is a post-translational modification of proteins and affects cellular signaling transduction. Protein kinases induce phosphorylation by catalyzing the transfer of phosphate groups to serine, threonine, and tyrosine residues on protein substrates. Consistent with their roles in cancer, protein kinases have emerged as one of the most clinically useful target molecules in pharmacological cancer therapy. Intrinsic or acquired resistance of cancers against anti-cancer therapeutics, such as ionizing radiation, is a major obstacle for the effective treatment of many cancers. In this review, we describe key aspects of various kinases acting on proteins. We also discuss the roles of protein kinases in the pathophysiology and treatment of cancer. Because protein kinases correlate with radiation resistance in various types of cancer, we focus on several kinases responsible for radiation resistance and/or sensitivity and their therapeutic implications. Finally, we suggest some ongoing radiation sensitization strategies using genetic loss and/or kinase inhibitors that can counteract radiation resistance-related protein kinases. PMID- 28911304 TI - Sialidases: Therapeutic and Antiatherogenic Potential. AB - This review focuses on the biological role and clinical relevance of relatively poor studied enzymes known as sialidases. We describe structure and function of sialic acid, in particular as a component of gangliosides and plasma lipoproteins. Several types of sialidases are known in mammals, of which trans sialidase is of special interest, since it is capable of removing sialic acid from low density lipoprotein (LDL) particles and transferring it to different acceptors in blood plasma. Desialylation of LDL, in turn, endows it a capacity to accumulate in the smooth muscle cells of human aortic intima, and therefore is important for atherogenesis. Moreover, sialidases appear to be involved in a variety of pathological processes, including viral infections and cancer, which makes these enzymes an attractive therapeutic target. PMID- 28911305 TI - Alginate-Based Cell Microencapsulation for Tissue Engineering and Regenerative Medicine. AB - Increasing numbers of requests for transplantable organs and their scarcity has led to a pressing need to find alternative solutions to standard transplantation. An appealing but challenging proposal came from the fields of tissue engineering and regenerative medicine, the purpose of which is to build tissues/organs from scratch in the laboratory and use them as either permanent substitutes for direct implantation into the patient's body, or as temporary substitutes to bridge patients until organ regeneration or transplantation. Using bioartificial constructs requires administration of immunosuppressant therapies to prevent rejection by the recipient. Microencapsulation has been identified as promising technology for immunoisolating biological materials from immune system attacks by the patient. It is based on entrapping cellular material within a spherical semipermeable polymeric scaffold. This latter defines the boundary between the internal native-like environment and the external "aggressive" one. The scaffold thus acts like a selective filter that makes possible an appropriate supply of nutrients and oxygen to the cellular constructs, while blocking the passage for adverse molecules. Alginate, which is a natural polymer, is the main biomaterial used in this context. Its excellent properties and mild gelation ability provide suitable conditions for supporting viability and preserving the functionalities of the cellular- engineered constructs over long periods. Although much remains to be done before bringing microencapsulated constructs into clinical practice, an increasing number of applications for alginate-based microencapsulation in numerous medical areas confirm the considerable potential for this technology in providing a cure for transplant in patients that excludes immunosuppressive therapies. PMID- 28911306 TI - Management of Blood Pressure and Heart Rate in Patients with Diabetes Mellitus. AB - BACKGROUND: In patients with diabetes mellitus (DM) there is a clear association between blood pressure (BP) levels and macrovascular and microvascular complications. However, the BP targets that need to be achieved for optimal outcomes remain controversial. METHODS: The purpose of this narrative review is to discuss BP targets and management in patients with DM. The subject of elevated heart rate, which has been associated with mortality in many populations, and which is observed in some patients with DM will also be addressed. RESULTS: Most guidelines recommend a target BP in patients with DM of <140/90 mmHg. Most consistently recommended first-line pharmacotherapy for the treatment of hypertension in non-black patients with DM is an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) while for black patients a calcium channel blocker or a thiazide diuretic. Newer antidiabetic drugs, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium glucose co-transporter-2 (SGLT2) inhibitors lower not only blood glucose but also BP levels. The SGLT2 inhibitor-associated decrease in BP is not accompanied by an increase in heart rate, which is observed however with GLP-1 receptor agonists. CONCLUSION: The most widely accepted BP target for patients with DM among guidelines is <140/90 mmHg and the most widely accepted pharmacotherapy to achieve these goals are ACE inhibitors and ARBs. Newer antidiabetic medications have been shown to also lower BP and decrease cardiovascular events, thus representing a promising new therapeutic option for patients with DM and hypertension. PMID- 28911307 TI - Tumor Targeting of Polymeric Nanoparticles Conjugated with Peptides, Saccharides, and Small Molecules for Anticancer Drugs. AB - Targeting drugs or pharmaceutical compounds to tumor site increases cancer treatment efficiency and therapeutic outcome. Nanoparticles are unique delivery systems for site-targeting within an organism. Many novel technologies have been established in drug research and development area. Nanotechnology now offers nanometer size polymeric nanoparticles and these particles direct drugs to their targets, protect drugs against degradation, and release the drug in a controlled manner. Modification of nanoparticle surface by molecules leads to prolonged retention and accumulation in the target area of the organism. Current efforts of designing polymeric nanoparticles include drug activation in the target area, controlled drug release at the site upon stimulation, and increased drug loading capacity of drug polymer conjugates. Recent progress in molecular mechanism elucidation of cancer cell and rising research in nanoparticle designs may provide efficient cancer treatment modality and innovative nanoparticle designs in the near future. Recent years have seen many developments in the field of innovative peptide based drug nanoparticles. Although none of them approved to be used in clinics yet, peptides are promising structures due to their simple and nonantigenic nature. Biodegradable materials are also preferred materials in drug delivery. Polysaccharide-based micelle systems improve hydrophobic drug and protein delivery. Ease of saccharide structure modification improves pharmacokinetic and pharmacodynamic properties of drug molecules as well as their delivery to a specific site in a controlled manner and sustained rate. Small molecules, especially drugs, conjugated to nanoparticles and several nanoparticles of this type are in the clinical trials and at the market. This review provides recent developments of polymeric nanoparticles conjugated with peptides, saccharides, and small molecules in cancer theraphy. PMID- 28911308 TI - Why Not All Hypertensive Patients Are Tachycardic at Rest? AB - BACKGROUND: The importance of increased resting heart rate in hypertensive patients was highlighted in the European Society of Hypertension statement on the identification and management of hypertensive patient with elevated heart rate. METHODS: Review of the available literature. RESULTS: Increased heart rate is an independent predictor of cardiovascular morbidity and mortality even after adjustment for other conventional cardiovascular risk factors. Resting heart rate is correlated with blood pressure and prospectively related to the development of hypertension, as shown in numerous general population and hypertensive cohorts. Patients with hypertension may be characterized by increased sympathetic activation, and increased heart rate is considered a simple marker of increased sympathetic nervous activity. The definition of tachycardia is debatable as in clinical practice, tachycardia is generally defined as resting heart rate over 100 beats per minute (bpm) but this definition does not take into account epidemiological data and risk related to increased heart rate. Available evidence suggests that a lower threshold defining an increased resting heart rate should be adopted. In large hypertensive cohorts, approximately one third of the studied subjects had resting heart rate above 80-85 bpm and many of these patients had features of the metabolic/insulin resistance syndrome. Furthermore, the prevalence of hypertension increases with age and the hemodynamic pattern of hypertension in older subjects is not characterized by increased heart rate. CONCLUSIONS: These reasons, in addition to the fact that heart rate is variable and depends on multiple factors, may explain why not all patients with hypertension are tachycardic at rest. PMID- 28911309 TI - Formulation, Quality Control and Safety Issues of Nanocarriers Used for Cancer Treatment. AB - Cancer is becoming a leading cause of death in the last years. Although we have seen great advances, most human cancers remain incurable because many patients either do not respond or relapse to treatment. Several lines of research are disclosing new therapeutic targets which lead to new active drugs. However, there are still unsolved problems related to stabilization of the pharmaceutical ingredient in aqueous and biological media, pharmacokinetic and pharmacodynamic profiles and cellular uptake to name just a few. In this context, nanotechnology with the emerging tools of nanoengineering offers many possibilities to guide the design of new products with improved safety and efficacy. The presence of several reacting groups and the sensitivity of their properties to small changes in composition make nanocarriers tunable not only to modify their stability in a particular environment but also to respond to changes in biological situations in the right place and time frame. This review summarizes the main preparation methods and formulation strategies of nano and microcarriers designed for drug delivery applications for cancer treatment and will attempt to give a glimpse on how their structure, shape, physico-chemical properties and chemical composition may affect their overall stability and interactions with biological systems. We will also cover aspects of nanoengineering that are opening new opportunities for the development of more effective nanomedicines, emphasizing on the challenges that have to be kept in mind when dealing with biological activities of nanocarriers that depend not only on their chemical composition but also on those of the structures formed by them and by their interactions with biological systems. From this, a very important issue that emerges is that nanocarriers frequently display an intrinsic bioactivity (i.e.: immunomodulatory). Therefore, it should be stressed that nanocarriers cannot be considered as inert, biocompatible excipients. Furthermore, their biological activity will mostly depend on the physical and chemical properties of the structures of the nanoparticles that are presented to living systems. As an approach to the rational design of new pharmaceutical products, nanoengineering is providing new tools for the precise control of the properties of nanocarriers for cancer treatment. PMID- 28911310 TI - How to Treat Patients with Essential Hypertension and Peripheral Arterial Disease. AB - BACKGROUND: Arterial hypertension (AH) and peripheral arterial disease (PAD) frequently coincide. While significant attention is paid to AH, PAD is often underestimated. It is known that both AH and PAD present high cardiovascular risks for ischemic events. To date, the use of the most common anti-hypertensive drugs in PAD patients is still under debate. METHODS: Data from studies of large populations and minor cohorts of patients show AH and PAD together or PAD alone. RESULTS: cardiovascular and renal outcomes for PAD patients show lowered arterial pressure. We cannot rank the class of anti-hypertensive drugs recommended for PAD patients with AH. However, optimum targeted anti-hypertensive therapy is strongly recommended by cardiology guidelines. CONCLUSION: comprehensive cardiovascular protection is the most important goal in using anti-AH drugs in PAD together with other drugs such as anti-platelets and statins. PMID- 28911311 TI - PLANTS IN THE CRISPR. AB - Sarah Webb explores how researchers are using CRISPR/Cas9 to solve agricultural problems. PMID- 28911312 TI - PERSISTENT EPIGENETIC MEMORY. AB - Nematodes transmit environmental information, such as temperature or food availability, across generations. Amber Dance looks at how this is possible. PMID- 28911313 TI - [Letter to the Editor] Incorrect assignment of affected nucleotides in footprinting/probing experiments. AB - Address correspondence to Sergey Belikov or Lars Wieslander, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden. E-mail: sergey.belikov@su.se or lars.wieslander@su.se. PMID- 28911314 TI - Construction of a combinatorial library of chimeric tumor-specific promoters. AB - Gene therapy is a fast-developing field of molecular medicine. New, effective, and cancer-specific promoters are in high demand by researchers seeking to treat cancer through expression of therapeutic genes. Here, we created a combinatorial library of tumor-specific chimeric promoter modules for identifying new promoters with desired functions. The library was constructed by randomly combining promoter fragments from eight human genes involved in cell proliferation control. The pool of chimeric promoters was inserted into a lentiviral expression vector upstream of the CopGFP reporter gene, transduced into A431 cells, and enriched for active promoters by cell sorting. The enriched library contained a remarkably high proportion of active and tumor-specific promoters. This approach to generating combinatorial libraries of chimeric promoters may serve as a useful tool for selecting highly specific and effective promoters for cancer research and gene therapy. PMID- 28911315 TI - Direct quantification of protein glycan phosphorylation. AB - Phosphorylation is an important post-translational modification (PTM) of proteins and a critical quality attribute for protein therapeutics, especially if it is required for protein function or sub-cellular targeting. Most current methods to quantify phosphorylation are time-consuming, indirect, or require specific instrumentation and technical skills. Here, we report the adaptation of a phosphate-specific binding dye and common laboratory instruments for quantification of relative amounts of phosphorylated glycans as well as phosphorylation of amino acid residues on the backbones of proteins. Our results show that quantification of phosphorylation using the new method agrees with published data on the number of phosphorylated glycosylation sites for two lysosomal enzymes: beta-glucuronidase (GUS) and cathepsin D. PMID- 28911316 TI - Optimizing T4 DNA polymerase conditions enhances the efficiency of one-step sequence- and ligation-independent cloning. AB - Previously, we developed a one-step sequence- and ligation-independent cloning (SLIC) method that is simple, fast, and cost-effective. However, although one step SLIC generally works well, its cloning efficiency is occasionally poor, potentially due to formation of stable secondary structures within the single stranded DNA (ssDNA) region generated by T4 DNA polymerase during the 2.5 min treatment at room temperature. To overcome this problem, we developed a modified thermo-regulated one-step SLIC approach by testing shorter T4 DNA polymerase treatment durations (5 s-2.5 min) over a wide range of temperatures (25-75 degrees C). The highest cloning efficiency resulted when inserts with homology lengths <20 bases were treated with T4 DNA polymerase for 30 s at 50 degrees C. This briefer T4 polymerase treatment at a higher temperature helps increase cloning efficiency for inserts with strong secondary structures at their ends, increasing the utility of one-step SLIC for the cloning of short fragments. PMID- 28911317 TI - Generation of iPS-derived model cells for analyses of hair shaft differentiation. AB - Biological evaluation of hair growth/differentiation activity in vitro has been a formidable challenge, primarily due to the lack of relevant model cell systems. To solve this problem, we generated a stable model cell line in which successive differentiation via epidermal progenitors to hair components is easily inducible and traceable. Mouse induced pluripotent stem (iPS) cell-derived cells were selected to stably express a tetracycline (Tet)-inducible bone morphogenic protein-4 (BMP4) expression cassette and a luciferase reporter driven by a hair specific keratin 31 gene (krt31) promoter (Tet-BMP4-KRT31-Luc iPS). While Tet- BMP4-KRT31-Luc iPS cells could be maintained as stable iPS cells, the cells differentiated to produce luciferase luminescence in the presence of all-trans retinoic acid (RA) and doxycycline (Dox), and addition of a hair differentiation factor significantly increased luciferase fluorescence. Thus, this cell line may provide a reliable cell-based screening system to evaluate drug candidates for hair differentiation activity. PMID- 28911318 TI - Development and Optimization of a High Titer Recombinant Lentivirus System. AB - To enable simple and effective high titer recombinant lentivirus production, we examined key parameters for the generation of lentivirus including: transfection optimization, media change, incubation time and DNA vector selection. These results illustrate the importance of optimizing transfection processes for high titer recombinant lentivirus production. PMID- 28911320 TI - Practicing governance towards equity in health systems: LMIC perspectives and experience. AB - The unifying theme of the papers in this series is a concern for understanding the everyday practice of governance in low- and middle-income country (LMIC) health systems. Rather than seeing governance as a normative health system goal addressed through the architecture and design of accountability and regulatory frameworks, these papers provide insights into the real-world decision-making of health policy and system actors. Their multiple, routine decisions translate policy intentions into practice - and are filtered through relationships, underpinned by values and norms, influenced by organizational structures and resources, and embedded in historical and socio-political contexts. These decisions are also political acts - in that they influence who accesses benefits and whose voices are heard in decision-making, reinforcing or challenging existing institutional exclusion and power inequalities. In other words, the everyday practice of governance has direct impacts on health system equity.The papers in the series address governance through diverse health policy and system issues, consider actors located at multiple levels of the system and draw on multi-disciplinary perspectives. They present detailed examination of experiences in a range of African and Indian settings, led by authors who live and work in these settings. The overall purpose of the papers in this series is thus to provide an empirical and embedded research perspective on governance and equity in health systems. PMID- 28911321 TI - Q&A: The brain under a mesoscope: the forest and the trees. AB - Neurons relevant to a particular behavior are often widely dispersed across the brain. To record activity in groups of individual neurons that might be distributed across large distances, neuroscientists and optical engineers have been developing a new type of microscope called a mesoscope. Mesoscopes have high spatial resolution and a large field of view. This Q&A will discuss this exciting new technology, highlighting a particular instrument, the two-photon random access mesoscope (2pRAM). PMID- 28911322 TI - Sharing fishers' ethnoecological knowledge of the European pilchard (Sardina pilchardus) in the westernmost fishing community in Europe. AB - BACKGROUND: With the present difficulties in the conservation of sardines in the North Atlantic, it is important to investigate the local ecological knowledge (LEK) of fishermen about the biology and ecology of these fish. The ethnoecological data of European pilchard provided by local fishermen can be of importance for the management and conservation of this fishery resource. Thus, the present study recorded the ethnoecological knowledge of S. pilchardus in the traditional fishing community of Peniche, Portugal. METHODS: This study was based on 87 semi-structured interviews conducted randomly from June to September 2016 in Peniche. The interview script contained two main points: Profile of fishermen and LEK on European pilchard. The ethnoecological data of sardines were compared with the scientific literature following an emic-etic approach. Data collected also were also analysed following the union model of the different individual competences and carefully explored to guarantee the objectivity of the study. RESULTS: The profile of the fishermen was investigated and measured. Respondents provided detailed informal data on the taxonomy, habitat, behaviour, migration, development, spawning and fat accumulation season of sardines that showed agreements with the biological data already published on the species. The main uses of sardines by fishermen, as well as beliefs and food taboos have also been mentioned by the local community. CONCLUSIONS: The generated ethnoecological data can be used to improve the management of this fishery resource through an adaptive framework among the actors involved, in addition to providing data that can be tested in further ecological studies. Therefore, this local knowledge may have the capacity to contribute to more effective conservation actions for sardines in Portugal. PMID- 28911323 TI - Exploring how different modes of governance act across health system levels to influence primary healthcare facility managers' use of information in decision making: experience from Cape Town, South Africa. AB - BACKGROUND: Governance, which includes decision-making at all levels of the health system, and information have been identified as key, interacting levers of health system strengthening. However there is an extensive literature detailing the challenges of supporting health managers to use formal information from health information systems (HISs) in their decision-making. While health information needs differ across levels of the health system there has been surprisingly little empirical work considering what information is actually used by primary healthcare facility managers in managing, and making decisions about, service delivery. This paper, therefore, specifically examines experience from Cape Town, South Africa, asking the question: How is primary healthcare facility managers' use of information for decision-making influenced by governance across levels of the health system? The research is novel in that it both explores what information these facility managers actually use in decision-making, and considers how wider governance processes influence this information use. METHODS: An academic researcher and four facility managers worked as co-researchers in a multi-case study in which three areas of management were served as the cases. There were iterative cycles of data collection and collaborative analysis with individual and peer reflective learning over a period of three years. RESULTS: Central governance shaped what information and knowledge was valued - and, therefore, generated and used at lower system levels. The central level valued formal health information generated in the district-based HIS which therefore attracted management attention across the levels of the health system in terms of design, funding and implementation. This information was useful in the top-down practices of planning and management of the public health system. However, in facilities at the frontline of service delivery, there was a strong requirement for local, disaggregated information and experiential knowledge to make locally appropriate and responsive decisions, and to perform the people management tasks required. Despite central level influences, modes of governance operating at the subdistrict level had influence over what information was valued, generated and used locally. CONCLUSIONS: Strengthening local level managers' ability to create enabling environments is an important leverage point in supporting informed local decision-making, and, in turn, translating national policies and priorities, including equity goals, into appropriate service delivery practices. PMID- 28911324 TI - Leadership and governance of community health worker programmes at scale: a cross case analysis of provincial implementation in South Africa. AB - BACKGROUND: National community health worker (CHW) programmes are returning to favour as an integral part of primary health care systems, often on the back of pre-existing community based initiatives. There are significant challenges to the integration and support of such programmes, and they require coordination and stewardship at all levels of the health system. This paper explores the leadership and governance tasks of large-scale CHW programmes at sub-national level, through the case of national reforms to South Africa's community based sector, referred to as the Ward Based Outreach Team (WBOT) strategy. METHODS: A cross case analysis of leadership and governance roles, drawing on three case studies of adoption and implementation of the WBOTs strategy at provincial level (Western Cape, North West and Gauteng) was conducted. The primary case studies mapped system components and assessed implementation processes and contexts. They involved teams of researchers and over 200 interviews with stakeholders from senior to frontline, document reviews and analyses of routine data. The secondary, cross case analysis specifically focused on the issues and challenges facing, and strategies adopted by provincial and district policy makers and managers, as they engaged with the new national mandate. From this key sub national leadership and governance roles were formulated. RESULTS: Four key roles are identified and discussed: 1. Negotiating a fit between national mandates and provincial and district histories and strategies of community based services 2. Defining new organisational and accountability relationships between CHWs, local health services, communities and NGOs 3. Revising and developing new aligned and integrated planning, human resource, financing and information systems 4. Leading change by building new collective visions, mobilising political, including budgetary, support and designing implementation strategies. CONCLUSIONS: This analysis, from real-life systems, adds to understanding of the processes involved in developing CHW programmes at scale, and specifically the negotiated and multilevel nature of leadership and governance in such programmes, spanning analytic, managerial, technical and political roles. PMID- 28911325 TI - How does decentralisation affect health sector planning and financial management? a case study of early effects of devolution in Kilifi County, Kenya. AB - BACKGROUND: A common challenge for health sector planning and budgeting has been the misalignment between policies, technical planning and budgetary allocation; and inadequate community involvement in priority setting. Health system decentralisation has often been promoted to address health sector planning and budgeting challenges through promoting community participation, accountability, and technical efficiency in resource management. In 2010, Kenya passed a new constitution that introduced 47 semi-autonomous devolved county governments, and a substantial transfer of responsibility for healthcare from the central government to these counties. METHODS: This study analysed the effects of this major political decentralization on health sector planning, budgeting and overall financial management at county level. We used a qualitative, case study design focusing on Kilifi County, and were guided by a conceptual framework which drew on decentralisation and policy analysis theories. Qualitative data were collected through document reviews, key informant interviews, and participant and non participant observations conducted over an eighteen months' period. RESULTS: We found that the implementation of devolution created an opportunity for local level prioritisation and community involvement in health sector planning and budgeting hence increasing opportunities for equity in local level resource allocation. However, this opportunity was not harnessed due to accelerated transfer of functions to counties before county level capacity had been established to undertake the decentralised functions. We also observed some indication of re-centralisation of financial management from health facility to county level. CONCLUSION: We conclude by arguing that, to enhance the benefits of decentralised health systems, resource allocation, priority setting and financial management functions between central and decentralised units are guided by considerations around decision space, organisational structure and capacity, and accountability. In acknowledging the political nature of decentralisation polices, we recommend that health sector policy actors develop a broad understanding of the countries' political context when designing and implementing technical strategies for health sector decentralisation. PMID- 28911326 TI - Borrelia infection and risk of celiac disease. AB - BACKGROUND: Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease. METHODS: Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease. RESULTS: Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up. CONCLUSIONS: Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease. PMID- 28911327 TI - Negotiating power relations, gender equality, and collective agency: are village health committees transformative social spaces in northern India? AB - BACKGROUND: Participatory health initiatives ideally support progressive social change and stronger collective agency for marginalized groups. However, this empowering potential is often limited by inequalities within communities and between communities and outside actors (i.e. government officials, policymakers). We examined how the participatory initiative of Village Health, Sanitation, and Nutrition Committees (VHSNCs) can enable and hinder the renegotiation of power in rural north India. METHODS: Over 18 months, we conducted 74 interviews and 18 focus groups with VHSNC members (including female community health workers and local government officials), non-VHSNC community members, NGO staff, and higher level functionaries. We observed 54 VHSNC-related events (such as trainings and meetings). Initial thematic network analysis supported further examination of power relations, gendered "social spaces," and the "discourses of responsibility" that affected collective agency. RESULTS: VHSNCs supported some re-negotiation of intra-community inequalities, for example by enabling some women to speak in front of men and perform assertive public roles. However, the extent to which these new gender dynamics transformed relations beyond the VHSNC was limited. Furthermore, inequalities between the community and outside stakeholders were re entrenched through a "discourse of responsibility": The comparatively powerful outside stakeholders emphasized community responsibility for improving health without acknowledging or correcting barriers to effective VHSNC action. In response, some community members blamed peers for not taking up this responsibility, reinforcing a negative collective identity where participation was futile because no one would work for the greater good. Others resisted this discourse, arguing that the VHSNC alone was not responsible for taking action: Government must also intervene. This counter-narrative also positioned VHSNC participation as futile. CONCLUSIONS: Interventions to strengthen participation in health systems can engender social transformation. However they must consider how changing power relations can be sustained outside participatory spaces, and how discourse frames the rationale for community participation. PMID- 28911328 TI - Devolution and its effects on health workforce and commodities management - early implementation experiences in Kilifi County, Kenya. AB - BACKGROUND: Decentralisation is argued to promote community participation, accountability, technical efficiency, and equity in the management of resources, and has been a recurring theme in health system reforms for several decades. In 2010, Kenya passed a new constitution that introduced 47 semi-autonomous county governments, with substantial transfer of responsibility for health service delivery from the central government to these counties. Focusing on two key elements of the health system, Human Resources for Health (HRH) and Essential Medicines and Medical Supplies (EMMS) management, we analysed the early implementation experiences of this major governance reform at county level. METHODS: We employed a qualitative case study design, focusing on Kilifi County, and adapted the decision space framework developed by Bossert et al., to guide our inquiry and analysis. Data were collected through document reviews, key informant interviews, and participant and non-participant observations between December 2012 and December 2014. RESULTS: As with other county level functions, HRH and EMMS management functions were rapidly transferred to counties before appropriate county-level structures and adequate capacity to undertake these functions were in place. For HRH, this led to major disruptions in staff salary payments, political interference with HRH management functions and confusion over HRH management roles. There was also lack of clarity over specific roles and responsibilities at county and national government, and of key players at each level. Subsequently health worker strikes and mass resignations were witnessed. With EMMS, significant delays in procurement led to long stock-outs of essential drugs in health facilities. However, when the county finally managed to procure drugs, health facilities reported a better order fill-rate compared to the period prior to devolution. CONCLUSION: The devolved government system in Kenya has significantly increased county level decision-space for HRH and EMMS management functions. However, harnessing the full potential benefits of this increased autonomy requires targeted interventions to clarify the roles and responsibilities of different actors at all levels of the new system, and to build capacity of the counties to undertake certain specific HRH and EMMS management tasks. Capacity considerations should always be central when designing health sector decentralisation policies. PMID- 28911329 TI - Psoriasis-associated vascular disease: the role of HDL. AB - Psoriasis is a chronic inflammatory systemic disease with a prevalence of 2-3%. Overwhelming evidence show an epidemiological association between psoriasis, cardiovascular disease and atherosclerosis. Cardiovascular disease is the most frequent cause of death in patients with severe psoriasis. Several cardiovascular disease classical risk factors are also increased in psoriasis but the psoriasis associated risk persists after adjusting for other risk factors.Investigation has focused on finding explanations for these epidemiological data. Several studies have demonstrated significant lipid metabolism and HDL composition and function alterations in psoriatic patients. Altered HDL function is clearly one of the mechanisms involved, as these particles are of the utmost importance in atherosclerosis defense. Recent data indicate that biologic therapy can reverse both structural and functional HDL alterations in psoriasis, reinforcing their therapeutic potential. PMID- 28911330 TI - Extensive transcriptomic and epigenomic remodelling occurs during Arabidopsis thaliana germination. AB - BACKGROUND: Seed germination involves progression from complete metabolic dormancy to a highly active, growing seedling. Many factors regulate germination and these interact extensively, forming a complex network of inputs that control the seed-to-seedling transition. Our understanding of the direct regulation of gene expression and the dynamic changes in the epigenome and small RNAs during germination is limited. The interactions between genome, transcriptome and epigenome must be revealed in order to identify the regulatory mechanisms that control seed germination. RESULTS: We present an integrated analysis of high resolution RNA sequencing, small RNA sequencing and MethylC sequencing over ten developmental time points in Arabidopsis thaliana seeds, finding extensive transcriptomic and epigenomic transformations associated with seed germination. We identify previously unannotated loci from which messenger RNAs are expressed transiently during germination and find widespread alternative splicing and divergent isoform abundance of genes involved in RNA processing and splicing. We generate the first dynamic transcription factor network model of germination, identifying known and novel regulatory factors. Expression of both microRNA and short interfering RNA loci changes significantly during germination, particularly between the seed and the post-germinative seedling. These are associated with changes in gene expression and large-scale demethylation observed towards the end of germination, as the epigenome transitions from an embryo-like to a vegetative seedling state. CONCLUSIONS: This study reveals the complex dynamics and interactions of the transcriptome and epigenome during seed germination, including the extensive remodelling of the seed DNA methylome from an embryo-like to vegetative-like state during the seed-to-seedling transition. Data are available for exploration in a user-friendly browser at https://jbrowse.latrobe.edu.au/germination_epigenome . PMID- 28911332 TI - "We are toothless and hanging, but optimistic": sub county managers' experiences of rapid devolution in coastal Kenya. AB - BACKGROUND: In March 2013, Kenya transitioned from a centralized to a devolved system of governance. Within the health sector, this entailed the transfer of service provision functions to 47 newly formed semi-autonomous counties, while policy and regulatory functions were retained at the national level. The devolution process was rapid rather than progressive. METHODS: We conducted qualitative research within one county to examine the early experiences of devolution in the health sector. We specifically focused on the experience of change from the perspective of sub-county managers, who form the link between county level managers and health facility managers. We collected data by observing a diverse range of management meetings, support supervision visits and outreach activities involving sub-county managers between May 2013 and June 2015, conducting informal interviews wherever we could. Informal observations and interviews were supplemented by fifteen tape recorded in depth interviews with purposively selected sub-county managers from three sub-counties. RESULTS: We found that sub county managers as with many other health system actors were anxious about and ill-prepared for the unexpectedly rapid devolution of health functions to the newly created county government. They experienced loss of autonomy and resources in addition to confused lines of accountability within the health system. However, they harnessed individual, team and stakeholder resources to maintain their jobs, and continued to play a central role in supporting peripheral facility managers to cope with change. CONCLUSIONS: Our study illustrates the importance in accelerated devolution contexts for: 1) mid-level managers to adopt new ways of working and engagement with higher and lower levels in the system; 2) clear lines of communication during reforms to these actors and 3) anticipating and managing the effect of change on intangible software issues such as trust and motivation. More broadly, we show the value of examining organisational change from the perspective of key actors within the system, and highlight the importance in times of rapid change of drawing upon and working with those already in the system. These actors have valuable tacit knowledge, but tapping into and building on this knowledge to enable positive response in times of health system shocks requires greater attention to sustained software capacity building within the health system. PMID- 28911331 TI - Dynamic DNA methylation reconfiguration during seed development and germination. AB - BACKGROUND: Unlike animals, plants can pause their life cycle as dormant seeds. In both plants and animals, DNA methylation is involved in the regulation of gene expression and genome integrity. In animals, reprogramming erases and re establishes DNA methylation during development. However, knowledge of reprogramming or reconfiguration in plants has been limited to pollen and the central cell. To better understand epigenetic reconfiguration in the embryo, which forms the plant body, we compared time-series methylomes of dry and germinating seeds to publicly available seed development methylomes. RESULTS: Time-series whole genome bisulfite sequencing reveals extensive gain of CHH methylation during seed development and drastic loss of CHH methylation during germination. These dynamic changes in methylation mainly occur within transposable elements. Active DNA methylation during seed development depends on both RNA-directed DNA methylation and heterochromatin formation pathways, whereas global demethylation during germination occurs in a passive manner. However, an active DNA demethylation pathway is initiated during late seed development. CONCLUSIONS: This study provides new insights into dynamic DNA methylation reprogramming events during seed development and germination and suggests possible mechanisms of regulation. The observed sequential methylation/demethylation cycle suggests an important role of DNA methylation in seed dormancy. PMID- 28911333 TI - Profiling bacterial communities by MinION sequencing of ribosomal operons. AB - BACKGROUND: An approach utilizing the long-read capability of the Oxford Nanopore MinION to rapidly sequence bacterial ribosomal operons of complex natural communities was developed. Microbial fingerprinting employs domain-specific forward primers (16S rRNA subunit), reverse primers (23S rRNA subunit), and a high-fidelity Taq polymerase with proofreading capabilities. Amplicons contained both ribosomal subunits for broad-based phylogenetic assignment (~ 3900 bp of sequence), plus the intergenic spacer (ITS) region (~ 300 bp) for potential strain-specific identification. RESULTS: To test the approach, bacterial rRNA operons (~ 4200 bp) were amplified from six DNA samples employing a mixture of farm soil and bioreactor DNA in known concentrations. Each DNA sample mixture was barcoded, sequenced in quadruplicate (n = 24), on two separate 6-h runs using the MinION system (R7.3 flow cell; MAP005 and 006 chemistry). From nearly 90,000 MinION reads, roughly 33,000 forward and reverse sequences were obtained. This yielded over 10,000 2D sequences which were analyzed using a simplified data analysis pipeline based on NCBI Blast and assembly with Geneious software. The method could detect over 1000 operational taxonomic units in the sample sets in a quantitative manner. Global sequence coverage for the various rRNA operons ranged from 1 to 1951x. An iterative assembly scheme was developed to reconstruct those rRNA operons with > 35x coverage from a set of 30 operational taxonomic units (OTUs) among the Proteobacteria, Actinobacteria, Acidobacteria, Firmicutes, and Gemmatimonadetes. Phylogenetic analysis of the 16S rRNA and 23S rRNA genes from each operon demonstrated similar tree topologies with species/strain-level resolution. CONCLUSIONS: This sequencing method represents a cost-effective way to profile microbial communities. Because the MinION is small, portable, and runs on a laptop, the possibility of microbiota characterization in the field or on robotic platforms becomes realistic. PMID- 28911334 TI - Slow-release praziquantel for dogs: presentation of a new formulation for echinococcosis control. AB - BACKGROUND: Echinococcosis is a serious, zoonotic, parasitic disease with worldwide distribution. According to a epidemiological survey in 2012 in China, there are 20,000 infected patients and more than 50 million people at the risk. As the dog is the main, definitive host, the Government of China encourages monthly praziquantel treatment of every dog. However, this is difficult to achieve in geographically challenging areas, such as the Tibetan plateau, where there are also many dogs without owners. To overcome these problems, we investigated the transmission blocking capacity of a slow-release formulation of praziquantel administered by subcutaneous injection. METHODS: The impact of a slow-release preparation of two pharmacokinetically stereoselective praziquantel enantiomers, i.e., R-(-)-praziquantel (R-PZQ) and S-(+)-praziquantel (S-PZQ) absorbed into a biodegradable polymer was studied in beagle dogs (N = 6). The preparation was given by subcutaneous injection using a single dose of 100 mg/kg. Chiral-selective, high-performance liquid chromatography (HPLC) and high resolution mass spectrometry (HRMS) were applied to measure the praziquantel enantiomers in the plasma of the dogs. The lower limit for estimating plasma concentrations accurately for R-PZQ was 4 ng/ml and for S-PZQ 20 ng/ml. The pharmacokinetic parameters were calculated by a noncompartmental analysis model using Drug Analyze System (DAS) software 2.0. The SPSS 19.0 software was used for statistical analysis, and the statistical comparison between enantiomers was assessed using the two-tailed t-test. RESULTS: Two hours after administration, peak concentrations of R-PZQ and S-PZQ: 321 +/- 26 and 719 +/- 263 ng/ml, respectively, were achieved. After 180 days, the average plasma concentration of R-PZQ in the six dogs had decreased to 13 ng/ml. The average concentration value of S-PZQ was higher than that of R-PZQ in the first 90-day period but fell afterwards and could not be accurately estimated when dropping below 20 ng/ml (the lower methodological limit for this enantiomer). Taking all the dogs into account, the average maximum concentration (Cmax) of S-PZQ in plasma over the first 3 months was higher than that of R-PZQ by 114.0% (P < 0.05), while the average mean retention time (MRT) of R-PZQ in plasma was higher than that of S PZQ by 96.3% (P < 0.05). CONCLUSIONS: Praziquantel given as an in situ slow release formulation by subcutaneous injection resulted in concentrations of the active principle in beagle dogs, which should be capable of resisting new Echinococcus infections for at least 6 months. The new formulation of praziquantel represents a potential, alternative way of presenting medication against tapeworm infections in dogs. PMID- 28911335 TI - Mammary phyllodes tumor with six episodes of a relapse: a case report. AB - BACKGROUND: Phyllodes tumor is a rare breast mass. Most phyllodes tumors are benign, but occasionally some show malignancy. Even if the tumors are benign, they can easily show recurrence. CASE PRESENTATION: We report a case of a 48-year old Asian woman, who had previously undergone a tumorectomy of her left breast 12 years before, with a pathological diagnosis of fibroadenoma. Five years after the initial tumorectomy, the patient presented with an abnormally enlarged left breast. A biopsy determined the growth to be a phyllodes tumor; subsequently, a partial mastectomy was conducted. However, the patient's left breast showed rapid enlargement in the next 5 months. The treating physicians suspected a relapse and subsequently consulted with our hospital. The breast mass was resected at our institution. After this surgery, the patient had repeated episodes of relapse and underwent four additional operations. Since then, the patient has not had any additional relapse so far. CONCLUSIONS: We present a case of a phyllodes tumor with multiple episodes of relapse. Although phyllodes tumors commonly show relapse, this case was unique because of the number of episodes of relapse. This case highlights the need to carry out tumorectomy with adequate margins with subsequent careful observation to check for relapse. PMID- 28911336 TI - Genome build information is an essential part of genomic track files. AB - Genomic locations are represented as coordinates on a specific genome build version, but the build information is frequently missing when coordinates are provided. We show that this information is essential to correctly interpret and analyse the genomic intervals contained in genomic track files. Although not a substitute for best practices, we also provide a tool to predict the genome build version of genomic track files. PMID- 28911337 TI - Postings and transfers in the Ghanaian health system: a study of health workforce governance. AB - BACKGROUND: Decision-making on postings and transfers - that is, the geographic deployment of the health workforce - is a key element of health workforce governance. When poorly managed, postings and transfers result in maldistribution, absenteeism, and low morale. At stake is managing the balance between organisational (i.e., health system) and individual (i.e., staff preference) needs. The negotiation of this potential convergence or divergence of interests provides a window on practices of postings and transfers, and on the micro-practices of governance in health systems more generally. This article explores the policies and processes, and the interplay between formal and informal rules and norms which underpin postings and transfers practice in two rural districts in the Greater Accra Region of Ghana. METHODS: Semi-structured interviews were conducted with eight district managers and 87 frontline staff from the district health administration, district hospital, polyclinic, health centres and community outreach compounds across two districts. Interviews sought to understand how the postings and transfers process works in practice, factors in frontline staff and district manager decision-making, personal experiences in being posted, and study leave as a common strategy for obtaining transfers. RESULTS: Differential negotiation-spaces at regional and district level exist and inform postings and transfers in practice. This is in contrast to the formal cascaded rules set to govern decision-making authority for postings and transfers. Many frontline staff lack policy clarity of postings and transfers processes and thus 'test' the system through informal staff lobbying, compounding staff perception of the postings and transfers process as being unfair. District managers are also challenged with limited decision-space embedded in broader policy contexts of systemic hierarchy and resource dependence. This underscores the negotiation process as ongoing, rather than static. CONCLUSIONS: These findings point to tensions between individual and organisational goals. This article contributes to a burgeoning literature on postings and transfers as a distinct dynamic which bridges the interactions between health systems governance and health workforce development. Importantly, this article helps to expand the notion of health systems governance beyond 'good' governance towards understanding governance as a process of negotiation. PMID- 28911339 TI - Emerging treatments for the behavioral and psychological symptoms of dementia. AB - Dementia is referred to a loss of memory and decline in other mental abilities at levels critical enough to hinder performance of daily activities. It can be of several types, depending on the underlying pathophysiology. The behavioral and psychological symptoms of dementia (BPSD) are various, but the most clinically significant are depression, apathy, and anxiety. Other BPSD include agitation, aberrant motor behavior, elation, hallucinations, and alterations in sleep and appetite. About 90% of sufferers of dementia are affected by BPSD during the course of the illness. These symptoms occur in demented patients irrespective of the dementia subtype. However, there has not been significant development in the areas of disease-modifying pharmacotherapeutics for dementia. Therefore, tackling BPSD has emerged as a research avenue in the recent past. Existing antidepressants, antipsychotics, and cholinergic agents have been extensively used in the treatment of BPSD, independently and in different combinations. However, these agents have not successful in completely alleviating such symptoms. Research in this field is going on globally, but it is still limited by various factors. There is a strong need to develop new entities and test them clinically. This review focuses on emerging treatments for the management of clinically significant BPSD. PMID- 28911338 TI - Organisational culture and trust as influences over the implementation of equity oriented policy in two South African case study hospitals. AB - BACKGROUND: This paper uses the concepts of organisational culture and organisational trust to explore the implementation of equity-oriented policies - the Uniform Patient Fee Schedule (UPFS) and Patients' Rights Charter (PRC) - in two South African district hospitals. It contributes to the small literatures on organisational culture and trust in low- and middle-income country health systems, and broader work on health systems' people-centeredness and "software". METHODS: The research entailed semi-structured interviews (Hospital A n = 115, Hospital B n = 80) with provincial, regional, district and hospital managers, as well as clinical and non-clinical hospital staff, hospital board members, and patients; observations of policy implementation, organisational functioning, staff interactions and patient-provider interactions; and structured surveys operationalising the Competing Values Framework for measuring organisational culture (Hospital A n = 155, Hospital B n = 77) and Organisational Trust Inventory (Hospital A n = 185, Hospital B n = 92) for assessing staff-manager trust. RESULTS: Regarding the UPFS, the hospitals' implementation approaches were similar in that both primarily understood it to be about revenue generation, granting fee exemptions was not a major focus, and considerable activity, facility management support, and provincial support was mobilised behind the UPFS. The hospitals' PRC paths diverged quite significantly, as Hospital A was more explicit in communicating and implementing the PRC, while the policy also enjoyed stronger managerial support in Hospital A than Hospital B. Beneath these experiences lie differences in how people's values, decisions and relationships influence health system functioning and in how the nature of policies, culture, trust and power dynamics can combine to create enabling or disabling micro-level implementation environments. CONCLUSIONS: Achieving equity in practice requires managers to take account of "unseen" but important factors such as organisational culture and trust, which are key aspects of the organisational context that can profoundly influence policies. In addition to implementation "hardware" such as putting in place necessary staff and resources, it emphasises "software" implementation tasks such as relationship management and the negotiation of values, where equity-oriented policies might be interpreted as challenging health workers' status and values, and paying careful attention to how policies are practically framed and translated into practice, to ensure key equity aspects are not neglected. PMID- 28911340 TI - Ursolic Acid Attenuates TGF-beta1 Induced Epithelial-Mesenchymal Transition in NSCLC by Targeting Integrin alphaVbeta5/MMPs Signaling. AB - Transforming growth factor-beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT) of non-small-cell carcinoma (NSCLC) may contribute to tumor metastasis. TGF-beta1-induced EMT in H1975 cells (a human NSCLC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-beta1-integrin signaling pathway. Ursolic acid has been previously reported to inhibit tumor growth and metastasis in several cancers. However, whether ursolic acid can attenuate TGF-beta1-induced EMT in H1975 cells and its underlying mechanisms remains unknown. In this study, ursolic acid significantly attenuated the TGF-beta1-induced decrease in E-cadherin level and elevated the level of N-cadherin. Furthermore, ursolic acid inhibited the mesenchymal-like responses in H1975 cells, including cell migration, invasion and activity of matrix metallopeptidase (MMP)-2 and -9. Finally, our new findings provided evidence that, ursolic acid could inhibit EMT in NSCLC through TGF-beta1 signaling pathway mediated integrinalphaVbeta5 expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in NSCLC. We conclude that ursolic acid attenuated TGF-beta1-induced EMT in H1975 cells and might be a promising therapeutic agent for treating NSCLC. PMID- 28911341 TI - Rapid Detection of Staphylococcus aureus and Related Species Isolated from Food, Environment, Cosmetics, a Medical Device, and Clinical Samples Using the VITEK MS Microbial Identification System. AB - Staphylococcus spp. is considered as one of the most common human-pathogenic bacteria, causing illnesses ranging from nonthreatening skin infections to lethal diseases, including sepsis, pneumonia, bloodstream infections, and food poisoning. The emergence of methicillin-resistant Staphylococcus aureus strains has increased morbidity and mortality and resulted in a major healthcare burden worldwide. Single and multilocus sequence typing have been extensively used in the identification of Staphylococcus species. Nevertheless, these assays are relatively time-consuming and require high-quality DNA. Matrix-assisted laser desorption ionization-time-of-flight has been used recently for the rapid identification of several bacterial species. In this study, we have examined 47 Staphylococcus isolates recovered from food, environment, clinical samples, cosmetic products, and a medical device and 3 American Type Culture Collection Staphylococcus reference isolates using bioMerieux VITEK MS and VITEK 2 systems to determine isolate identity. Sequencing of the 16S ribosomal RNA gene was performed to confirm and compare the species identification data generated by VITEK 2 and VITEK MS systems. Although the VITEK 2 system could not identify one of the isolates, VITEK MS identified all 50 Staphylococcus spp. isolates tested. Results of this study clearly suggest that VITEK MS can be used in the rapid identification of Staphylococcus isolates of public health importance. PMID- 28911343 TI - Validation Study of MaxSignal(r) Histamine Enzymatic Assay for the Detection of Histamine in Fish/Seafood. AB - Bioo Scientific Corp. has developed a rapid enzymatic quantitative assay for the determination of histamine in seafood. Fresh/frozen tuna, canned tuna, pouched tuna, and frozen mahi mahi samples were used for the validation study under the specific guidelines of the AOAC Research Institute Performance Tested MethodsSM program. Recoveries ranged from 82 to 107% at concentrations ranging from 6 to 72 ppm, with RSDr values between 0.8 and 6.5% (6-72 ppm). The linearity of the assay ranged from 0 to 108 ppm, with R2 values exceeding 0.99. The LOD was 0.9 ppm and the LOQ was 2.6 ppm for frozen tuna, which gave the lowest background level of contaminant. Cross-reactivity of the assay was tested against 14 other biogenic amines and was found to be minimal for all (<0.5%), except for agmatine (4.1%) and putrescine (0.9%). There was no observable interference from any tested biogenic amines. Product consistency was verified by validating lot-to-lot variations and variations within the same lot. Overall recoveries for all tested matrixes were within the acceptable range (80-120%). A 1-year claimed shelf life of the kit at 4 degrees C was verified by accelerated stability study data collected on days 1, 15, and 32 at 25 degrees C and by real-time stability testing at 1-month, 6-month, and 1-year at 4 degrees C. No difference in histamine detection was observed in ruggedness testing, in which minor changes were introduced to the assay protocol. Good agreement was observed between AOAC Official MethodSM 977.13 and the MaxSignal(r) Histamine Enzymatic Assay method. Independent laboratory testing demonstrated that the MaxSignal method works with the same precision in the hands of minimally trained technicians as with the expert method developers. This study validates the performance of Bioo Scientific's rapid enzymatic method. PMID- 28911342 TI - Efficacy and Safety of Transcatheter Arterial Chemoembolization and Transcatheter Arterial Chemotherapy Infusion in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. AB - Hepatocellular carcinoma (HCC) is a worldwide health threat with increasing incidence and a high mortality rate. Most HCC patients are diagnosed at an advanced stage and are unable to undergo potential curative surgery. Transcatheter arterial chemoembolization (TACE) and transcatheter arterial chemotherapy infusion (TACI) are two of the main palliative treatments for advanced HCC patients. The clinical efficacy and safety of TACE and TACI are controversial. For this reason, we conducted a systematic review and meta analysis to summarize the current evidence. We searched for randomized controlled trials (RCTs) and cohort studies that compared the clinical outcomes and adverse effects in HCC patients who received TACE or TACI treatments. The database search was performed and last updated on November 1, 2016. Overall survival and clinical response were compared using a hazard ratio (HR) with a 95% confidence interval (CI). A total of 11 clinical studies that included 13,090 patients were included based on the inclusion/exclusion criteria, of which 9 were cohort studies and 2 were RCTs. TACE was associated with a 23% lower hazard of death compared to TACI (pooled HR = 0.77, 95% CI = 0.67-0.88, p = 0.0002). Patients receiving TACE had a 28% higher disease control rate (DCR) and 162% higher objective response rate (ORR). Only the increase in ORR associated with TACE was statistically significant [DCR: odds ratio (OR) = 1.28, 95% CI = 0.35-4.64, p = 0.71; ORR: OR = 2.62, 95% CI = 1.33-5.15, p = 0.002]. TACE is associated with more favorable survival and response rate than TACI in patients with intermediate or advanced HCC. PMID- 28911344 TI - Comparison of Spectrophotometric Methods for the Determination of Copper in Sugar Cane Spirit. AB - Three spectrophotometric methods were developed for the determination of copper (Cu) in sugar cane spirit using the chromogenic reagents neocuproine, cuprizone, and bathocuproine. Experimental conditions, such as reagent concentration, reducer concentration, pH, buffer concentration, the order of addition of reagents, and the stability of the complexes, were optimized. The work range was established from 1.0 to 10.0 ug/mL, with correlation coefficients of >0.999 for all three optimized methods. The methods were evaluated regarding accuracy by addition and recovery tests at five concentration levels, and the obtained recoveries ranged from 91 to 105% (n = 3). Precision was expressed as RSD (relative standard deviation), with values ranging from 0.01 to 0.17% (n = 10). The method using the chromogenic reagent cuprizone presented the greatest molar absorptivity, followed by bathocuproine and neocuproine. The methods were applied for the determination of Cu in sugar cane spirit, and the results were compared with a reference method by flame atomic absorption spectrometry (FAAS). Calibration curve solutions for FAAS analysis were prepared in a 40% (v/v) alcohol medium in a range of concentrations from 0.5 up to 5 ug/mL. Measurements for Cu determination were carried out at a wavelength of 324.7 nm. The concentrations obtained for Cu in sugar cane spirit samples from Brazil were between 1.99 and 12.63 ug/mL, and about 75% of the samples presented Cu concentrations above the limit established by Brazilian legislation (5.0 ug/mL or 5.0 mg/L). PMID- 28911345 TI - Tuberculosis, human rights and ethics. PMID- 28911346 TI - Strategic partnerships towards tuberculosis elimination. PMID- 28911347 TI - Post-implementation blues: the unfulfilled potential of Xpert. PMID- 28911348 TI - Asthma: the increasing, unchecked epidemic. PMID- 28911349 TI - Tuberculosis, human rights and ethics considerations along the route of a highly vulnerable migrant from sub-Saharan Africa to Europe. AB - Migrant health is a critical public health issue, and in many countries attention to this topic has focused on the link between migration and communicable diseases, including tuberculosis (TB). When creating public health policies to address the complex challenges posed by TB and migration, countries should focus these policies on evidence, ethics, and human rights. This paper traces a commonly used migration route from sub-Saharan Africa to Europe, identifying situations at each stage in which human rights and ethical values might be affected in relation to TB care. This illustration provides the basis for discussing TB and migration from the perspective of human rights, with a focus on the right to health. We then highlight three strands of discussion in the ethics and justice literature in an effort to develop more comprehensive ethics of migrant health. These strands include theories of global justice and global health ethics, the creation of 'firewalls' to separate enforcement of immigration law from protection of human rights, and the importance of non-stigmatization to health justice. The paper closes by reflecting briefly on how TB programs can better incorporate human rights and ethical principles and values into public health practice. PMID- 28911350 TI - Applying the Care Group model to tuberculosis control: findings from a community based project in Mozambique. AB - BACKGROUND: We describe the effectiveness of an innovative community-based social mobilization approach called Care Groups to improve the effectiveness of the national tuberculosis (TB) program by increasing TB testing and improving treatment outcomes in six districts of rural Mozambique. METHODS: The Care Group approach, which was implemented in a population of 218 191, enabled a facilitator to meet every 6 months with 10-12 community health volunteers (forming a Care Group) to share key TB messages and then for them to convey these messages over the subsequent 6 months to 10-12 households. Three household surveys were performed over 5 years to measure population-level changes in knowledge and behaviors. Data from village TB, laboratory, and district registers were also used to monitor activities and outcomes. RESULTS: There were substantial improvements in TB-related knowledge and behaviors in the number of patients initiating treatment, in the percentage of patients receiving directly observed treatment, in treatment success, and in TB-related mortality. CONCLUSION: Care Groups are uniquely suited to address some of the challenges of TB control. This project sheds light on a new strategy for engaging communities to address not only TB, but other health priorities as well. PMID- 28911351 TI - Comprehensive understanding of health-seeking behaviour among pulmonary tuberculosis patients in China. AB - SETTING: In China, there were 918 000 tuberculosis (TB) cases in 2015 alone. The primary challenge facing TB control is the allocation of limited health care resources. OBJECTIVE: To gain a comprehensive understanding of the first choice of health care facility among Chinese patients with suspected pulmonary TB (PTB) and the number of visits required to make the diagnosis. DESIGN: Relevant full text articles in three Chinese and one English literature databases up to November 2016 were reviewed. Meta-analyses were performed using Stata v12.0. RESULTS: Among 1257 potentially relevant selected articles, 27 cross-sectional studies involving 9891 patients were included in the final analyses. Most PTB patients chose county-level hospitals (40%, 95%CI 33-46) and village clinics (34%, 95%CI 27-42); only 13% (95%CI 10-16) of patients chose to visit PTB dispensaries first. Before obtaining the correct diagnosis, 28% (95%CI 11-44) of patients had to visit health facilities more than three times. CONCLUSION: Patients with suspicion of PTB were more likely to visit low-level facilities than dispensaries. Repeated visits resulted in both overall delay and high risk of PTB transmission. These findings suggest that a shift in government policy for PTB is required. PMID- 28911352 TI - Missed opportunities for earlier diagnosis of rifampicin-resistant tuberculosis despite access to Xpert(r) MTB/RIF. AB - OBJECTIVE: To assess the proportion of rifampicin-resistant tuberculosis (RR-TB) patients with potential earlier RR-TB diagnoses in Khayelitsha, South Africa. DESIGN: We conducted a retrospective analysis among RR-TB patients diagnosed from 2012 to 2014. Patients were considered to have missed opportunities for earlier diagnosis if 1) they were incorrectly screened according to the Western Cape diagnostic algorithm; 2) the first specimen was not tested using Xpert(r) MTB/RIF; 3) no specimen was ever tested; or 4) the initial Xpert test showed a negative result, but no subsequent specimen was sent for follow-up testing in human immunodeficiency virus-positive patients. RESULTS: Among 543 patients, 386 (71%) were diagnosed with Xpert and 112 (21%) had had at least one presentation at a health care facility within the 6 months before the presentation at which RR TB was diagnosed. Overall, 95/543 (18%) patients were screened incorrectly at some point: 48 at diagnostic presentation only, 38 at previous presentation only, and 9 at both previous and diagnostic presentations. CONCLUSIONS: These data show that a significant proportion of RR-TB patients might have been diagnosed earlier, and suggest that case detection could be improved if diagnostic algorithms were followed more closely. Further training and monitoring is required to ensure the greatest benefit from universal Xpert implementation. PMID- 28911353 TI - Persistently high early mortality despite rapid diagnostics for drug-resistant tuberculosis cases in South Africa. AB - OBJECTIVE: To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. DESIGN: We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. RESULTS: Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naive patients (aHR 3.40, 95%CI 2.90 3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). CONCLUSION: In EDRweb, mortality is highest in the first few weeks after MDR/RR TB treatment initiation. PMID- 28911354 TI - Drug resistance patterns among extra-pulmonary tuberculosis cases in a tertiary care centre in North India. AB - BACKGROUND: xtra-pulmonary tuberculosis (EPTB) is a growing public health concern, and data on drug resistance are limited. MATERIAL AND METHODS: Specimens from 2468 clinically diagnosed EPTB patients received at the Intermediate Reference Laboratory (IRL) of a tertiary centre in India were subjected to Ziehl Neelsen staining, Xpert(r) MTB/RIF testing, liquid culture and drug susceptibility testing (DST) using automated BACTEC MGITTM 960TM. Line-probe assay (LPA) was performed on all culture-positive isolates. Gene sequencing was performed on rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB) and phenotypic/genotypic discrepant isolates. RESULTS: The culture positivity rate was 18.9% (483/2553). The sensitivity and specificity of Xpert in diagnosing EPTB were respectively 70.8% (95%CI 66.5-74.8) and 97.7% (95%CI 96.9-98.3), with liquid culture as the reference standard. Prevalence of RR/MDR-TB was 10.1% (49/483). Prevalence of pre-extensively drug-resistant TB (pre-XDR-TB) was 18.4% (09/49), whereas the prevalence of XDR-TB among MDR-TB patients was 2% (01/49). The sensitivity of genotypic DST for the detection of rifampicin resistance was 92.7% (95%CI 81.1-98.5) and specificity was 99.3% (95%CI 97.5-99.9), with 100% concordance between Xpert and LPA. CONCLUSION: The burden of drug resistance, including M/XDR-TB, among EPTB patients is high. Novel molecular tests can help in early diagnosis and treatment to prevent disease progression and amplification of resistance. PMID- 28911355 TI - Latent tuberculous infection testing among HIV-infected persons in clinical care, United States, 2010-2012. AB - SETTING: Current guidelines recommend latent tuberculous infection (LTBI) testing at the time of human immunodeficiency virus (HIV) diagnosis and annually thereafter for persons at high risk of LTBI. OBJECTIVES: To estimate LTBI testing prevalence and describe the characteristics of HIV-infected persons who would benefit from annual LTBI testing. DESIGN: We estimated the proportions of LTBI testing among a nationally representative sample of HIV-infected adults in care between 2010 and 2012, and compared the patient characteristics of those with a positive LTBI test result to those with a negative result using chi2 tests. RESULTS: Among 2772 patients, 68.8% had been tested for LTBI at least once since HIV diagnosis, and 39.4% had been tested during the previous 12 months. Among patients tested at least once, 6.9% tested positive, 80.7% tested negative, and 12.4% had an indeterminate or undocumented result. Patients with a positive test were significantly more likely to be foreign-born, have lower educational attainment, and a household income at or below the federal poverty level. CONCLUSIONS: More than 30% of HIV-infected patients had never been tested for LTBI. Providers should test all patients for LTBI at the time of HIV diagnosis. The patient characteristics associated with a positive LTBI test result may guide provider decisions about annual testing. PMID- 28911356 TI - High completion rates of isoniazid preventive therapy among persons living with HIV in Swaziland. AB - SETTING: Five human immunodeficiency virus (HIV) care facilities in Swaziland. OBJECTIVE: To assess adherence and treatment completion of a 6-month course of isoniazid preventive therapy (IPT) provided to HIV-infected patients through a self-selected model of facility-based, community-based or peer-supported IPT delivery coordinated with antiretroviral refills. DESIGN: Prospective cohort study. RESULTS: Between February and August 2015, we enrolled 908 patients, with follow-up until February 2016. Most were female (66.2%), with a median age of 38 years (interquartile range 31-45). Most (n = 797, 87.8%) chose facility-based delivery, 111 (12.2%) selected community-based delivery, and none selected peer supported delivery. Adherence was high in both cohorts; among those with available data, 794 (94.8%) reported taking at least 80% of their IPT (P > 0.05). Twenty-two patients screened positive for tuberculosis (TB) at any visit; all had TB excluded and most continued IPT. In total, 812 (89.4%) patients completed treatment: 711 (89.2%) were on facility-based and 111 (91.0%) on community-based IPT (P > 0.05). No confirmed treatment failures occurred. Few patients discontinued IPT (6.3%) or were lost to follow-up (4.1%). CONCLUSION: Self selected IPT delivery aligned with HIV care achieved high rates of adherence and treatment completion. This model may improve outcomes by simplifying clinic visits and conferring agency to the patient, and may be readily implemented in similar high TB-HIV burden settings. PMID- 28911357 TI - Pulmonary tuberculosis diagnostic practices among people living with the human immunodeficiency virus in Lesotho. AB - SETTING: Twelve health facilities in Berea District, Lesotho, that participated in the Start TB Patients on ART and Retain on Treatment (START) Study, a mixed methods cluster-randomized trial evaluating a combination intervention package to improve early initiation of antiretroviral therapy (ART) and anti-tuberculosis treatment success among patients with tuberculosis (TB) and human immunodeficiency virus (HIV). OBJECTIVE: To assess TB and HIV diagnostic practices among TB-HIV patients. DESIGN: A standardized survey assessed services at each facility at baseline. Routine clinical data were abstracted for all newly registered adult TB-HIV patients during the study period. Descriptive statistics were used to assess TB diagnostic practices, timing of the HIV diagnosis, and ART status at TB treatment initiation. RESULTS: Between April 2013 and March 2015, 1233 TB-HIV patients were enrolled. Among 1215 patients with available data, 87.2% had pulmonary TB, of which 34.8% were bacteriologically confirmed, 40.9% tested negative and 24.3% were not tested. Among 1138 patients with available data, 53.3% had an existing HIV diagnosis, of whom 39.3% were ART-naive. CONCLUSIONS: The majority of pulmonary TB patients were clinically diagnosed, and many were unaware of their HIV status or were ART-naive despite known status. The Test and Treat Strategy holds promise to prevent TB and reduce TB-related mortality among people living with HIV; however, enhanced TB diagnostic capacity and improved HIV case detection are urgently needed. PMID- 28911358 TI - Performance of nested RT-PCR on CSF for tuberculous meningitis diagnosis in HIV infected patients. AB - SETTING: Timely diagnosis of tuberculous meningitis (TBM) in patients with human immunodeficiency virus (HIV) infection remains a challenge. Despite the current scale-up of the Xpert(r) MTB/RIF assay, other molecular diagnostic tools are necessary, particularly in referral centres in low- and middle-income countries without Xpert testing. OBJECTIVE: To determine the diagnostic performance of nested real-time polymerase chain reaction (nRT-PCR) in HIV-infected TBM patients categorised according to standardised clinical case definitions. DESIGN: Based on clinical, laboratory and imaging data, HIV-infected patients with suspected TBM were prospectively categorised as 'definite TBM', 'probable TBM', 'possible TBM' or 'not TBM'. We evaluated nRT-PCR sensitivity and specificity in diagnosing TBM among definite TBM cases, and among definite + probable TBM cases. RESULTS: Ninety-two participants were enrolled in the study. nRT-PCR sensitivity for definite TBM (n = 8) was 100% (95%CI 67-100) and 86% (95%CI 60-96) for both definite and probable TBM (n = 6). Assuming that 'not TBM' patients (n = 74) were true-negatives, nRT-PCR specificity was 100% (95%CI 95-100). The possible TBM group (n = 4) had no nRT-PCR positives. CONCLUSIONS: The nRT-PCR is a useful rule in test for HIV-infected patients with TBM according to international consensus case definitions. As nRT-PCR cannot exclude TBM, studies comparing and combining nRT-PCR with other assays are necessary for a rule-out test. PMID- 28911359 TI - Interferon-gamma response to the treatment of active pulmonary and extra pulmonary tuberculosis. AB - BACKGROUND: Interferon-gamma (IFN-gamma) release assays (IGRAs) are used to diagnose tuberculosis (TB) but not to measure treatment response. OBJECTIVE: To measure IFN-gamma response to active anti-tuberculosis treatment. DESIGN: Patients from the Henan Provincial Chest Hospital, Henan, China, with TB symptoms and/or signs were enrolled into this prospective, observational cohort study and followed for 6 months of treatment, with blood and sputum samples collected at 0, 2, 4, 6, 8, 16 and 24 weeks. The QuantiFERON(r) TB-Gold assay was run on collected blood samples. Participants received a follow-up telephone call at 24 months to determine relapse status. RESULTS: Of the 152 TB patients enrolled, 135 were eligible for this analysis: 118 pulmonary (PTB) and 17 extra-pulmonary TB (EPTB) patients. IFN-gamma levels declined significantly over time among all patients (P = 0.002), with this decline driven by PTB patients (P = 0.001), largely during the initial 8 weeks of treatment (P = 0.019). IFN-gamma levels did not change among EPTB patients over time or against baseline culture or drug resistance status. CONCLUSION: After 6 months of effective anti-tuberculosis treatment, IFN-gamma levels decreased significantly in PTB patients, largely over the initial 8 weeks of treatment. IFN-gamma concentrations may offer some value for monitoring anti-tuberculosis treatment response among PTB patients. PMID- 28911360 TI - Evaluation of the TB-LAMP assay for the rapid diagnosis of pulmonary tuberculosis in Northern India. AB - SETTING: A tertiary care hospital in North India. OBJECTIVE: To evaluate a commercial kit-based loop-mediated isothermal amplification (TB-LAMP) assay for the diagnosis of pulmonary tuberculosis (PTB). DESIGN: A total of 530 patients presenting with PTB symptoms were enrolled and one sputum sample was collected from each patient. The TB-LAMP assay (LoopampTM MTBC Detection kit) was performed on the raw sputum sample. The remaining sample was used for smear microscopy and mycobacterial culture. A cartridge-based nucleic acid amplification test (NAAT, Xpert(r) MTB/RIF assay) was also performed on the processed pellet. RESULTS: The sensitivity and specificity of the TB-LAMP assay in culture-positive samples obtained from 453 patients presenting with PTB symptoms (77 specimens were excluded) were respectively 100% (95%CI 94.7-100) and 99.2% (95%CI 97.8-99.8). The sensitivity and specificity of Xpert in culture-positive samples were respectively 82.6% (95%CI 71.5-90.6) and 94.9% (95%CI 92.2-96.8). A concordance of 0.75 was obtained between the two NAATs (TB-LAMP assay and Xpert) using the kappa statistic. CONCLUSION: The TB-LAMP assay showed high sensitivity and specificity with limited requirement of testing infrastructure, and is thus a promising diagnostic tool for TB diagnosis in resource-poor settings. PMID- 28911361 TI - Detecting Mycobacterium tuberculosis using the loop-mediated isothermal amplification test in South Africa. AB - SETTING: In South Africa, KwaZulu-Natal is the epicentre of the human immunodeficiency virus (HIV) epidemic, where approximately 70% of people with tuberculosis (TB) are co-infected with HIV. Undiagnosed TB contributes to high mortality in HIV-infected patients. Delays in diagnosing TB and treatment initiation result in prolonged transmission and increased infectiousness. OBJECTIVE: To evaluate the LoopampTM MTBC Detection kit (TB-LAMP; based on the loop-mediated isothermal amplification assay), smear microscopy and Xpert test with the gold standard of mycobacterial culture. METHODS: Sputum samples were collected from 705 patients with symptoms of pulmonary TB attending a primary health care clinic. RESULTS: The TB-LAMP assay had significantly higher sensitivity than smear microscopy (72.6% vs. 45.4%, P < 0.001), whereas specificity was slightly lower (99% vs. 96.8%, P = 0.05), but significantly higher than Xpert (92.9%, P = 0.004). There was no significant difference in sensitivity of smear-positive, culture-positive and smear-negative, culture positive sputum samples using TB-LAMP vs. Xpert (respectively 95.9%/55.9% vs. 97.6%/66.1%; P =0.65, P = 0.27). The positive predictive value of TB-LAMP was significantly higher than that of Xpert (87.5% vs. 77.0%; P = 0.02), but similar to that of smear microscopy (94.2%; P = 0.18). The negative predictive value was respectively 91.9%, 92.5% (P = 0.73) and 83.1% (P = 0.0001). CONCLUSION: Given its ease of operability, the TB-LAMP assay could be implemented as a point-of care test in primary health care settings, and contribute to reducing treatment waiting times and TB prevalence. PMID- 28911362 TI - Assessment of the quality of anti-tuberculosis medicines in Almaty, Kazakhstan, 2014. AB - SETTING: In 2009, the World Health Organization (WHO) conducted a survey of the quality of four anti-tuberculosis drugs in the former Soviet Union countries. Kazakhstan had the highest proportion of substandard drugs. OBJECTIVE: To assess the quality of anti-tuberculosis drugs used in Kazakhstan in 2014. DESIGN: Fourteen anti-tuberculosis drugs from the Almaty Interdistrict TB Dispensary were randomly selected and screened for quality using Global Pharma Health Fund MinilabTM testing. First, the product and packaging were physically inspected to determine whether tablets/capsules were intact (i.e., whether they contained the full amount of the drug, and whether the packaging was genuine). Second, the tablets/capsules were dissolved in water to test whether they could be adequately absorbed by the body. Finally, semi-quantitive analyses were undertaken using thin-layer chromatography to verify the presence and concentration of the active pharmaceutical ingredient and to detect impurities. RESULTS: We discovered no counterfeit medicines. However, 163 (19%) of the 854 anti-tuberculosis drugs sampled failed at least one of the three tests. These samples were found among 24/50 (48%) batches of 14 anti-tuberculosis drugs. CONCLUSION: Our study identified a high proportion of poor-quality first- and second-line anti tuberculosis drugs. Use of these medicines may lead to treatment failure and the development of drug resistance. Confirmatory testing should be performed to determine if they should be removed from the market. PMID- 28911363 TI - Bronchial angles are associated with nodular bronchiectatic non-tuberculous mycobacteria lung disease. AB - BACKGROUND: The nodular bronchiectatic (NB) form of non-tuberculous mycobacteria (NTM) lung disease usually involves the right middle lobe (RML) and the left upper lobe lingular segment. However, the reason underlying this preference is not known. METHODS: Fifty patients with NB NTM lung disease who had both positive NTM culture(s) and NB lesions in the RML or lingular segment on computed tomography (CT) of the chest, and 100 healthy subjects matched for sex, age, height and body weight with normal chest CT, were randomly selected. Using reconstructed curved multiplanar reformation (MPR) images, the lengths, diameters and angles of the RML and lingular bronchi were measured. RESULTS: Of the 150 individuals, 64% were female; the mean age was 55 years. The angles of the bronchi were significantly more acute in patients than in healthy subjects, both in the RML (patients, mean 46.75 degrees +/- standard deviation 8.87 degrees vs. healthy subjects, mean 51.73 degrees +/- 7.76 degrees ; P = 0.001) and in the lingular segments (patients, mean 26.94 degrees +/- 8.16 degrees vs. healthy subjects, mean 34.65 degrees +/- 9.75 degrees ; P < 0.001). In addition, the angles of the bronchi in the involved segments were more acute than those in the non-involved segments, both in the RML and the lingular segments. There were no differences in the lengths and bronchi diameters between groups. CONCLUSIONS: An acute angle (obtuse slope) of RML/lingular bronchi could be an anatomical risk factor for NB NTM lung disease. PMID- 28911364 TI - TB-IRIS presenting with haemophagocytic lymphohistiocytosis in a non-HIV-infected male. PMID- 28911365 TI - Osteomyelitis and arthritis caused by Mycobacterium intracellulare: an underestimated diagnosis. PMID- 28911366 TI - Lophomonas blattarum co-infection in a patient with multidrug-resistant tuberculosis. PMID- 28911369 TI - 9th BIC International Conference: Rome (Italy), 15-17 September 2017. PMID- 28911368 TI - Systemic adiponectin treatment reverses polycystic ovary syndrome-like features in an animal model. AB - The present study examined the efficacy of adiponectin for regulating the reproductive, metabolic and fertility status of mice with polycystic ovary syndrome (PCOS). PCOS was induced in prepubertal (21- to 22-day-old) mice using dehydroepiandrosterone (6mg 100g-1day-1 for 25days), after which mice were administered either a low or high dose of adiponectin (5 or 15ugmL-1, s.c., respectively). PCOS mice exhibited typical features, including the presence of numerous cystic follicles, increased circulating androgens, increased body mass, altered steroidogenesis, decreased insulin receptor expression and increased serum triglycerides, serum glucose, Toll-like receptor (TLR)-4 (a marker of inflammation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis). These parameters were significantly correlated with a reduction in adiponectin in PCOS mice compared with vehicle-treated control mice. Exogenous adiponectin treatment of PCOS mice restored body mass and circulating androgen, triglyceride and glucose levels. Adiponectin also restored ovarian expression of steroidogenic markers (LH receptors, steroidogenic acute regulatory protein and 3beta-hydroxysteroid dehydrogenase), insulin receptor, TLR-4 and VEGF levels in control mice. Adiponectin restored ovulation in PCOS mice, as indicated by the presence of a corpus luteum and attainment of pregnancy. These findings suggest that adiponectin effectively facilitates fertility in anovulatory PCOS. We hypothesise that systemic adiponectin treatment may be a promising therapeutic strategy for the management of PCOS. PMID- 28911370 TI - Introduction to Dr. Jerzy Leszczynski. PMID- 28911371 TI - Amino substituted nitrogen heterocycle ureas as kinase insert domain containing receptor (KDR) inhibitors: Performance of structure-activity relationship approaches. AB - A quantitative structure-activity relationship (QSAR) study was performed on a set of amino-substituted nitrogen heterocyclic urea derivatives. Two novel approaches were applied: (1) the simplified molecular input-line entry systems (SMILES) based optimal descriptors approach; and (2) the fragment-based simplex representation of molecular structure (SiRMS) approach. Comparison with the classic scheme of building up the model and balance of correlation (BC) for optimal descriptors approach shows that the BC scheme provides more robust predictions than the classic scheme for the considered pIC50 of the heterocyclic urea derivatives. Comparison of the SMILES-based optimal descriptors and SiRMS approaches has confirmed good performance of both techniques in prediction of kinase insert domain containing receptor (KDR) inhibitory activity, expressed as a logarithm of inhibitory concentration (pIC50) of studied compounds. PMID- 28911372 TI - Reactivity and stability of selected flavor compounds. AB - Flavor is the most important aspect of food. Based on the complex matrix of the food system and the flavor structure themselves, one important factor that plays a key role in the quality attribute of food is flavor stability. Not surprisingly, there is a large volume of published research investigating the stability of different food flavor compounds, since understanding flavor stability is crucial to creating greater awareness of dietary flavor application. This review presents a variety of factors that are thought to be involved in the stability of several selected important flavor compounds and the approach to improve the stability of different flavors. Some mechanisms of chemical degradation of flavor compounds were also provided. PMID- 28911373 TI - Recent developments in blood glucose sensors. AB - Diabetes has recently become a leading cause of death worldwide. To date, although there is no means to cure or prevent diabetes, appropriate medication and blood sugar monitoring can enhance treatment efficiency, alleviate the symptoms, and diminish the complications of the condition. This review article deals with current growth areas in the market for blood glucose sensors and possible future alternatives, which are generally considered to be the point sample test and the continuous glucose monitor (CGM). Most glucose sensors are enzyme-based, whereas others are enzyme-free. The former class is sensitive and some products are extensively employed for daily self-sensing and in hospital environments as reliable diagnostic tools. The latter class, particularly the boronic acid fluorescent sensor, is facile and extremely promising. Practicality demands that all types of sensors offer accuracy, specificity, and real-time detection. PMID- 28911374 TI - Physicochemical properties of Terminalia catappa seed oil as a novel dietary lipid source. AB - Terminalia catappa Linn (TC) is an ornamental tree planted extensively in many countries. It has been known for a long time that the seeds are edible but no research has focused on the realm of its use as food. Our previous data showed that the seed contains high levels of oil content (600 g/kg) and possesses the optimum fatty acid balance indicated in fat dietary guidelines. This study aims to investigate the physical and chemical properties and the possibility of using TC seed oil as a new dietary lipid. The effects of extraction conditions, partial refining process, and storage stability on TC oil properties were conducted compared with soybean oil. The results showed that physicochemical properties including the density, refractive index, melting point, acidity, free fatty acid, saponification value, unsaponifiable, peroxide, and fatty acid composition of the extracted oil were comparable with soybean oil and their values followed the dietary standard of edible oil. PMID- 28911375 TI - Effects of enzymatic extraction on anthocyanins yield of saffron tepals (Crocos sativus) along with its color properties and structural stability. AB - An aqueous solution of Pectinex (containing cellulase, hemicellulase, and pectinase) at 1%, 2.5%, 5%, 7%, and 10% concentrations and 40 degrees C was used to extract anthocyanins (Acys) of saffron tepals at 20, 40, 60, 120 and 180 min reaction times and compared with ethanol solvent under similar conditions. The Acys of the Pectinex solution reached 6.7 mg/g of tepal powder (~40% more than the ethanol method) when the enzyme concentrations and extraction times were, respectively, 5% and 60 min. The Acys of aqueous enzymes had three times slower degradation rates and 50% more attractive chroma color than the ones recovered by ethanol solution after 3 h of extraction time. Additionally, the Acys of the ethanol solution lost its content sharply (>45%) and its chroma changed quickly (due to the browning and polymerization). High performance liquid chromatography (HPLC) analysis showed that Acys extracted with mixed enzymes had about 80% more cyanidin 3-glucosides and 20% less pelargonidin 3,5-glucosides than with the ethanol method. Most probably, the high content of cyanidin 3-glycosides in enzyme-extracted Acys of saffron tepals was the key factor for its high stability. PMID- 28911376 TI - Development and validation of a high-performance thin layer chromatography method for the determination of cholesterol concentration. AB - An accurate, sensitive, precise, reliable, and quick method for the determination of cholesterol content by high-performance thin layer chromatography is developed. In this method, aluminum-backed precoated silica gel 60 F254 plates were used as the stationary phase and the samples were sprayed with the help of CAMAG sample applicator Linomat 5. The chromatogram was developed with the mobile phase consisting of chloroform:methanol (9.5:0.5, v/v). The samples were detected using CAMAG Scanner 4 and evaluated using the method developed on winCATS software. Densitometric analysis of cholesterol was performed in absorbance mode at 200 nm. In this solvent system, cholesterol gave a compact spot with an Rf value of 0.63 +/- 0.03. The linear regression analysis of data for the calibration curve showed good linearity over a concentration range of 2-7 MUg/spot with a regression value of 0.99933 and standard deviation of 1.44%. The limit of detection and limit of quantification were found to be 100 ng/spot and 500 ng/spot, respectively. Using the developed method, the concentration of cholesterol in the saponified and unsaponified egg yolk sample was determined. This method was found to be reproducible and can even be used for samples containing complex matrices. PMID- 28911377 TI - By-product of Lavandula latifolia essential oil distillation as source of antioxidants. AB - The objective of this work was to evaluate the antioxidant properties of Lavandula latifolia waste obtained after essential oil distillation. Samples of 12 wild populations of the Lavandula genus collected between 2009 and 2010 were hydrodistilled and their by-products were analyzed using the Folin-Ciocalteu, free radical scavenging activity (2,2-diphenyl-1-picrylhydrazyl), and the ferric reducing antioxidant power (FRAP) methods. Rosmarinic acid, apigenin, and luteolin contents were analyzed by high-performance liquid chromatography-diode array detection. The mean of total phenolic content ranged from 1.89 +/- 0.09 mg gallic acid equivalents/g dry weight to 3.54 +/- 0.22 mg gallic acid equivalents/g dry weight. The average value of the half maximal effective concentration (EC50) for scavenging activity ranged from 5.09 +/- 0.17 mg/mL to 14.30 +/- 1.90 mg/mL and the variability of the EC50 in FRAP ranged from 3.72 +/- 0.12 mg/mL to 18.55 +/- 0.77 mg/mL. Annual variation was found among this samples and the environmental conditions of 2009 were found to be more favorable. The plants collected from Sedano showed the highest antioxidant power. Our results show that rosmarinic acid and apigenin in L. latifolia contributed to the antioxidant properties of the waste. In conclusion, the by-product of the distillation industry could be valorizing as a source of natural antioxidants. PMID- 28911378 TI - Interaction of gallic acid with trypsin analyzed by spectroscopy. AB - The interactions between trypsin and gallic acid (GA) were investigated by means of fluorescence spectroscopy, UV-vis absorption spectroscopy, resonance light scattering (RLS) spectroscopy, synchronous fluorescence spectroscopy, and enzymatic inhibition assay. It was found that GA can cause the fluorescence quenching of trypsin during the process of formation of GA-trypsin complex, resulting in inhibition of trypsin activity (IC50 = 3.9 * 10-6 mol/L). The fluorescence spectroscopic data showed that the quenching efficiency can reach about 80%. The binding constants were 1.9371 * 104 L/mol, 1.8192 * 104 L/mol, and 1.7465 * 104 L/mol at three temperatures, respectively. The thermodynamic parameters revealed that hydrogen bonds, van der Waals, hydrophobic, and electrostatic interactions were involved in the binding process of GA to trypsin. Molecular modeling studies illustrated a specific display of binding information and explained most of the experiment phenomena. The microenvironments of tryptophan and tyrosine residue in trypsin were changed by the GA. Results indicated that GA was a strong quencher and inhibitor of trypsin. PMID- 28911379 TI - Temperature-dependent studies on the total phenolics, flavonoids, antioxidant activities, and sugar content in six onion varieties. AB - Heating effect on total phenol, flavonoids, antioxidant activity, and sugar content of six onion varieties has been quantitatively investigated to explore the effect of different temperatures. The onion varieties comprised one red skinned variety, two white-skinned varieties, and three yellow-skinned varieties. The heating temperature was scanned at 80 degrees C, 100 degrees C, 120 degrees C, and 150 degrees C for 30 minutes each, and quantitative analysis was performed relative to the powdered onion at ambient temperature. Quercetin, glucosides and sugar content were analyzed using high-performance liquid chromatography. The total phenolic and antioxidant content increased in all six varieties. The total flavonoid levels showed a considerable change. On heating the onion samples at 120 degrees C for 30 minutes, the red-skinned variety showed the highest level of total phenolic content [13712.67 +/- 1034.85 MUg of gallic acid equivalent/g dry weight (MUg GAE/g DW)] and total flavonoids [3456.00 +/- 185.82 MUg of quercetin equivalents/g dry weight (MUg Q/g DW)], whereas the content of total phenolics and total flavonoids were 13611.83 +/- 341.61 MUg GAE/g DW and 3482.87 +/- 117.17 MUg Q/g DW, respectively, for the yellow-skinned (Sunpower) variety. Quercetin and its glucoside contents increased up to 120 degrees C and then decreased at 150 degrees C, whereas the sugar content continuously decreased with heating. All cultivars showed the same pattern in the heating effect, and the predominant flavonoids were destroyed at higher temperatures. Therefore, it is improper to expose onion powder to a temperature higher than 120 degrees C. PMID- 28911380 TI - Chemical compositions of the volatile extracts from seeds of Dendranthema nankingense and Borago officinalis. AB - Volatile extracts from the seeds of Dendranthema nankingense Hand.-Mazz. and Borago officinalis L. were prepared using simultaneous distillation and extraction, and analyzed with gas chromatography-mass spectrometry on two capillary gas chromatography columns of different polarity. Ninety-five volatile compounds were identified in D. nankingense seeds, with hexanal, benzeneacetaldehyde, borneol, (-)-camphor, and 3-methyl-1-butanol being the predominant species. Sixty-five volatile compounds were identified in B. officinalis seeds, with 2-pentanone, 2,3-dihydro-benzofuran, 3-methyl butanal, and hexanal being the most abundant species. Thirty-three compounds, including short-chain aliphatic aldehydes, alcohols, and ketones, were common to both seeds. The volatile composition of both seeds varied significantly depending on their respective origins. The volatile terpenoids borneol and (-)-camphor could be key bioactive contributors to the characteristic flavor and cooling effects of D. nankingense. For the first time, coumaran was identified as an abundant species in plant seeds. PMID- 28911381 TI - The effects of methadone maintenance treatment on heroin addicts with response inhibition function impairments: Evidence from event-related potentials. AB - Response inhibition has been a core issue in addictive behavior. Many previous studies have found that response inhibition abilities are damaged in those with drug dependence. However, whether heroin addicts who are treated with methadone maintenance have an abnormal response inhibition ability is not clear. In order to investigate the response inhibition functions in heroin addicts who were treated with methadone maintenance, electroencephalography (EEG) was used to examine 14 heroin addicts treated with methadone maintenance (HDM), 17 heroin addicts (HD), and 18 healthy controls (HC) in an equiprobability Go?NoGo task. The reaction times (RTs) for the Go stimuli in the HD group were slower than those in the HDM and HC groups. Event-related potential (ERP) measurements showed that NoGo stimuli elicited larger N2 amplitudes than Go stimuli in the HDM and HC groups. However, for the HD group, the N2 amplitudes were similar for the two conditions. In addition, the HDM and HD groups were associated with longer P3 latencies. Our results demonstrated that methadone maintenance treatment might ease the deficits in response inhibition that result from long-term drug abuse. However, compared to normal people, HDM patients have serious problems evaluating and inhibiting inappropriate behaviors. PMID- 28911382 TI - Simultaneous determination of 2 aconitum alkaloids and 12 ginsenosides in Shenfu injection by ultraperformance liquid chromatography coupled with a photodiode array detector with few markers to determine multicomponents. AB - A method with few markers to determine multicomponents was established and validated to evaluate the quality of Shenfu injection by ultraperformance liquid chromatography coupled with a photodiode array detector. The separations were performed on an ACQUITY UPLC BEH C18 (2.1 * 50 mm2, 1.7 MUm) column. Methanol and 0.1% formic acid aqueous solution were used as the mobile phase. The flow rate was 0.3 mL/min. 2 aconitum alkaloids and 12 ginsenosides could be perfectly separated within 15 minutes. Ginsenoside Rg1 and benzoylmesaconine, the easily available active components, were employed as the maker components to calculate the relative correction factors of other components in Shenfu injection, Panax ginseng and Aconitum carmichaeli. The external standard method was also established to validate the feasibility of the method with few markers to determine multicomponents. Parameter p and the principal component analysis method were employed to investigate the disparities among batches for the effective quality control of Shenfu injection. The results demonstrated that the ultraperformance liquid chromatography coupled with a photodiode array detector method with few markers to determine multicomponents could be used as a powerful tool for the quality evaluation of traditional Chinese medicines and their preparations. PMID- 28911383 TI - Gold nanoparticles grafted modified silica gel as a new stationary phase for separation and determination of steroid hormones by thin layer chromatography. AB - A new thin layer chromatographic layer using gold nanoparticles grafted 3 triethoxysilyl propylamine modified silica gel (Au NPs-APTS modified silica gel) was developed as a stationary phase for separation and determination of two steroid hormones, namely progesterone and testosterone. Acetone-n-hexane 25:75 (v/v) was used as the mobile phase, and the results were compared with those obtained using plain (i.e., unmodified) silica gel plates. Some chromatographic parameters used for separation of the two steroids on an Au NPs-APTS modified silica gel plate as well as on a plain silica gel plate, including DeltaRF, separation factor (alpha), and resolution (RS), were evaluated and compared. The reproducibility of RF values was also determined by analysis of the two steroids in 7 consecutive days on both plates. Validity of the method was investigated, and a wide linear range of 1-200 ng per spot, and low detection limits of 0.16 ng and 0.13 ng per spot, low quantification limits of 0.51 ng and 0.40 ng per spot, and good precision (expressed as percent relative standard deviation) lower than 3.1% and 2.7% were obtained for progesterone and testosterone, respectively. As the results revealed, the proposed method is rapid and sensitive, and it is applicable to separation and determination of progesterone and testosterone in biological matrices such as urine samples. PMID- 28911384 TI - Ca2+ and aminoguanidine on gamma-aminobutyric acid accumulation in germinating soybean under hypoxia-NaCl stress. AB - Gamma-aminobutyric acid (GABA), a nonproteinous amino acid with some benefits on human health, is synthesized by GABA-shunt and the polyamine degradation pathway in plants. The regulation of Ca2+ and aminoguanidine on GABA accumulation in germinating soybean (Glycine max L.) under hypoxia-NaCl stress was investigated in this study. Exogenous Ca2+ increased GABA content significantly by enhancing glutamate decarboxylase gene expression and its activity. Addition of ethylene glycol tetra-acetic acid into the culture solution reduced GABA content greatly due to the inhibition of glutamate decarboxylase activity. Aminoguanidine reduced over 85% of diamine oxidase activity, and 33.28% and 36.35% of GABA content in cotyledon and embryo, respectively. Under hypoxia-NaCl stress, the polyamine degradation pathway contributed 31.61-39.43% of the GABA formation in germinating soybean. PMID- 28911385 TI - Antioxidant activities and contents of flavonoids and phenolic acids of Talinum triangulare extracts and their immunomodulatory effects. AB - In this study, leaves and stems of Talinum triangulare were sequentially extracted with phosphate buffer solution to obtain PTL and PTS (phosphate buffered extracts of T. triangulare leaves and stems), with 75% ethanol to obtained ETL and ETS (ethanol extracts of T. triangulare leaves and stems), or with 90 degrees C boiling water to obtain WTL and WTS (water extracts of T. triangulare leaves and stems). We investigated the antioxidant activities of various T. triangulare extracts, analyzed the extracts' stimulations on human mononuclear cell (MNC) growth and secretion of cytokines (interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha) and nitric oxide, and then assayed their subsequent inhibitions on human leukemic U937 cell growth. Results indicated that extracts of T. triangulare showed significant antioxidant activities. Among these extracts, WTS showed the highest stimulatory effect on human MNC growth. The secretion levels of interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha in the conditioned medium, wherein human MNC was treated with 500 MUg/mL WTS for 72 hours, were 1275, 859, and 2222 pg/mL, respectively. All conditioned media obtained from human MNCs cultured with various T. triangulare extracts showed significant inhibition against U937 cell growth of over 40%. These results suggest that T. triangulare extracts may be used in health foods for their immunomodulatory potential. PMID- 28911386 TI - Analysis of major antioxidants from extracts of Myrmecodia pendans by UV/visible spectrophotometer, liquid chromatography/tandem mass spectrometry, and high performance liquid chromatography/UV techniques. AB - In the present work, heat reflux extraction with ethanol/water (80:20; v/v) as the solvent was used to extract antioxidants from Myrmecodia pendans. The crude extract (CE) was fractionated using hexane and ethyl acetate. Ethyl acetate fraction (EAF) and aqueous fraction were collected. Antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl-radical radical and ferric reducing power of the CE, EAF, and aqueous fraction were evaluated. EAF showed comparable antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl-radical radical and ferric reducing power to those of the CE. UV/visible, liquid chromatography/electrospray ionization/tandem mass spectrometry, and high-performance liquid chromatography were employed for identifying the major antioxidant compounds in the EAF. Three major phenolic compounds (rosmarinic acid, procyanidin B1, and polymer of procyanidin B1) were identified. The first two compounds were confirmed and quantified by high-performance liquid chromatography using authentic standards, but confirmation of the third compound was hampered by a lack of commercial standard. Concentrations of rosmarinic acid and procyanidin B1 in the EAF were found to be 20.688 +/- 1.573 mg/g dry sample and 3.236 +/- 0.280 mg/g dry sample, respectively. All these three compounds are reported for the first time in sarang semut. PMID- 28911387 TI - Hepatoprotective effects of kaempferol 3-O-rutinoside and kaempferol 3-O glucoside from Carthamus tinctorius L. on CCl4-induced oxidative liver injury in mice. AB - Safflower (Carthamus tinctorius L.) is a traditional medicinal and edible herb with a long history of use in China. In this study, a model of hepatotoxicity induced by carbon tetrachloride (CCl4) in mice was used to investigate the hepatoprotective effects of kaempferol 3-O-rutinoside (K-3-R) and kaempferol 3-O glucoside (K-3-G), two kaempferol glycosides isolated from C. tinctorius L. K-3-R and K-3-G, at doses of 200 mg/kg and 400 mg/kg, were given orally to male mice once/d for 7 days before they received CCl4 intraperitoneally. Our results showed that K-3-R and K-3-G treatment increased the level of total protein (TP) and prevented the CCl4-induced increases in serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and hepatic malondialdehyde (MDA) levels. Additionally, mice treated with K-3-R and K-3-G had significantly restored glutathione (GSH) levels and showed normal catalase (CAT) and superoxide dismutase (SOD) activities, compared to CCl4-treated mice. K-3-R and K-3-G also mitigated the CCl4-induced liver histological alteration, as indicated by histopathological evaluation. These findings demonstrate that K-3-R and K-3-G have protective effects against acute CCl4-induced oxidative liver damage. PMID- 28911388 TI - Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1 hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives. AB - Pyrrolizidine alkaloid-containing plants are widespread in the world and probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolic activation to form dehydropyrrolizidine alkaloids that bind to cellular proteins and DNA leading to hepatotoxicity, genotoxicity, and tumorigenicity. At present, it is not clear how dehydropyrrolizidine alkaloids bind to cellular amino acids and proteins to induced toxicity. We previously reported that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl 5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts that upon reaction with phenyl isothiocyanate (PITC) formed four DHP-valine-PITC adduct isomers. In this study, we report the absolute configuration and stability of DHP-valine and DHP valine-PITC adducts, and the mechanism of interconversion between DHP-valine-PITC adducts. PMID- 28911389 TI - Beverage-induced enhanced bioavailability of carbamazepine and its consequent effect on antiepileptic activity and toxicity. AB - The present study was undertaken to investigate the food-drug interaction of carbamazepine (CBZ). Common fruit juices [grapefruit juice (GFJ), lime juice (LJ)], known to inhibit the enzyme cytochrome P450 3A4 (CYP3A4), and some widely consumed beverages [milk (M), black tea (BT)] were involved in this study in the presence of CBZ, as might happen during clinical therapy. The effects of the beverages on the pharmacokinetics and drug-induced toxicity of CBZ was observed after concomitant administration for a period of 28 days. Accordingly, the influence of altered bioavailability of CBZ on its antiepileptic activity was investigated. A significant shift in the Cmax as well as Tmax of CBZ was observed in the presence of LJ and GFJ. This increase in bioavailability significantly enhanced hepatotoxicity and delayed the onset of tremor and piloerection against pentylene tetrazole (PTZ)-induced seizure in experimental animals. However, increased toxicity of CBZ was found to be absent with BT. Thus, from our observation, LJ or GFJ in the presence of CBZ significantly increased the bioavailability of CBZ, which might lead to increased toxicity and antiepileptic activity of the drug. PMID- 28911390 TI - The histamine content of dried flying fish products in Taiwan and the isolation of halotolerant histamine-forming bacteria. AB - Thirty dried flying fish products were purchased from fishing village stores in Taiwan and tested to detect the presence of histamine and histamine-forming bacteria. Except for histamine and cadaverine, the average content of various biogenic amines in the tested samples was less than 3.5 mg/100 g. Eight (26.6%) dried flying fish samples had histamine levels greater than the United States Food and Drug Administration guideline of 5 mg/100 g for scombroid fish and/or scombroid products, whereas four (13.3%) samples contained more than the hazard action level of 50 mg/100 g. One histamine-producing bacterial isolate was identified as Staphylococcus xylosus by 16S rDNA sequencing with polymerase chain reaction amplification. This isolate was capable of producing 507.8 ppm of histamine in trypticase soy broth supplemented with 1.0% l-histidine (TSBH). The S. xylosus isolate was a halotolerant bacterium that had a consistent ability to produce more than 300 ppm of histamine at 3% sodium chloride concentration in TSBH medium after 72 hours. PMID- 28911391 TI - Perspectives on genetically modified crops and food detection. AB - Genetically modified (GM) crops are a major product of the global food industry. From 1996 to 2014, 357 GM crops were approved and the global value of the GM crop market reached 35% of the global commercial seed market in 2014. However, the rapid growth of the GM crop-based industry has also created controversies in many regions, including the European Union, Egypt, and Taiwan. The effective detection and regulation of GM crops/foods are necessary to reduce the impact of these controversies. In this review, the status of GM crops and the technology for their detection are discussed. As the primary gap in GM crop regulation exists in the application of detection technology to field regulation, efforts should be made to develop an integrated, standardized, and high-throughput GM crop detection system. We propose the development of an integrated GM crop detection system, to be used in combination with a standardized international database, a decision support system, high-throughput DNA analysis, and automated sample processing. By integrating these technologies, we hope that the proposed GM crop detection system will provide a method to facilitate comprehensive GM crop regulation. PMID- 28911392 TI - Isolation of eugenyl beta-primeveroside from Camellia sasanqua and its anticancer activity in PC3 prostate cancer cells. AB - Most studies of tea trees have focused on their ornamental properties, there are fewer published studies on their medical values. The purpose of this study was to compare the chemical constituents and the biological potential of the water extract of leaves in eight species of Camellia including Camellia sinensis. Among eight Camellia species, Camellia sasanqua showed potent anticancer activities in prostate cancer PC3 cells. In addition to catechins, the major component, eugenyl beta-primeveroside was detected in C. sasanqua. Eugenyl beta-primeveroside blocked the progression of cell cycle at G1 phase by inducing p53 expression and further upregulating p21 expression. Moreover, eugenyl beta-primeveroside induced apoptosis in PC3 prostate cancer cells. Our results suggest that C. sasanqua may have anticancer potential. PMID- 28911393 TI - Exploring in vitro neurobiological effects and high-pressure liquid chromatography-assisted quantitation of chlorogenic acid in 18 Turkish coffee brands. AB - The hydroalcoholic extracts of the Turkish traditional coffee samples from 18 commercial brands were tested for their neurobiological effects through enzyme inhibition based on enzyme-linked immunosorbance microtiter assays against acetylcholinesterase, butyrylcholinesterase, and tyrosinase, linked to Alzheimer's and Parkinson's diseases. The extracts were also subjected to several antioxidant test systems to define their antiradical, metal-chelation capacity, and reducing power. Total phenol and flavonoid contents in the extracts were delineated by spectrophotometric methods, while chlorogenic acid in the coffee samples was quantified by high-pressure liquid chromatography. The extracts displayed low to moderate inhibition (from 2.13 +/- 0.01% to 36.12 +/- 1.07% at 200 MUg/mL) against the tested enzymes, whereas they had notable 2,2'-diphenyl-1 picrylhydrazyl radical scavenging activity up to 56.15 +/- 2.03% at 200 MUg/mL. The extracts exerted a remarkable ferric-reducing antioxidant power values, while chlorogenic acid was found to range between 0.288 +/- 0.005% and 2.335 +/- 0.010%. PMID- 28911394 TI - Pacific oyster-derived polysaccharides attenuate allergen-induced intestinal inflammation in a murine model of food allergy. AB - Oyster-derived polysaccharides (OPS) have been shown to modulate the T helper (Th)1/Th2 immunobalance toward the Th1-dominant direction in antigen-primed splenocytes. In the present study, we hypothesized that OPS might attenuate intestinal inflammation associated with food allergy, a Th2-dominant immune disorder. BALB/c mice were sensitized twice with ovalbumin (OVA) absorbed to alum and then repeatedly challenged with intragastric OVA to induce intestinal allergic responses. The mice were administered by gavage with OPS and/or vehicle (distilled water) once/d during the two sensitization phases, and once every other day during the challenge phase. Administration with OPS attenuated OVA challenge-elicited diarrhea, and the infiltration of mast cells in the intestine. OPS demonstrated a protective effect on the reduced ratio of villus length over crypt depth of the intestine in allergic mice. Furthermore, OPS administration markedly attenuated the intestinal expression of the Th2 signature cytokine interleukin-4 (IL-4). Collectively, these results demonstrated the in vivo antiallergic activity of OPS, which is associated with the suppression of allergen-induced intestinal Th2 responses and mast cell activation. PMID- 28911395 TI - Microspheres as carriers for lipase inhibitory substances to reduce dietary triglyceride absorption in mice. AB - The present study intends to use microspheres as a delivery system of chlorogenic acid (CGA) to investigate the influences of CGA microspheres on dietary fat absorption and fecal triglyceride excretion in a mice model. Microspheres have an average particle size of about 53.3 MUm. Results indicated that the microspheres were capable of gradually releasing the preloaded CGA into the surrounding medium. Their bioadhesive property might help prolong the gastrointestinal transit time in mice, and render a better mixing and contact between CGA and triglyceride. Consumption of CGA microspheres resulted in a significantly higher level of fecal triglyceride (119-144%) as compared with the corresponding control groups. A microsphere would be a desirable vehicle for CGA to improve its efficacy along the intestine. PMID- 28911396 TI - Myrciaria cauliflora extracts attenuate diabetic nephropathy involving the Ras signaling pathway in streptozotocin/nicotinamide mice on a high fat diet. AB - Diabetic nephropathy (DN) is a major cause of end-stage renal disease and its mortality is continuously increasing worldwide. Previous studies indicate that reactive oxygen species play an important role in high glucose-induced renal injury. Myrciaria cauliflora has been reported as a functional food rich in anthocyanins possessing anti-oxidative and anti-inflammatory properties. This study examined whether M. cauliflora extracts (MCE) can attenuate diabetic nephropathy progression in type 2 diabetes mellitus mice. First, the composition of the anthocyanins and polyphenols of MCE were determined by high-performance liquid chromatography and spectrophotometry. One hundred mg/kg of streptozotocin and 240 mg/kg nicotinamide were administered to C57BL/6J mice fed a high fat diet and varied concentrations of MCE. The plasma glucose concentration, body weight, oral glucose tolerance, blood pressure, renal ultrasound ultrasonic wave were monitored every 2 weeks. Following euthanasia, the kidneys of the mice were analyzed using hematoxylin-eosin, periodic acid Schiff, Masson's trichrome, and immunohistochemistry staining. The results showed that MCE stabilized the plasma glucose and indirectly improved insulin sensitivity in diabetic mice. In addition, diabetes-caused glomerular atrophy, accumulation of saccharide, and formation of collagen IV were recovered or reduced under treatment with MCE in diabetic mice. Our results indicate that MCE has beneficial effects in DN and the mechanism has been confirmed to inhibit Ras/PI3K/Akt and kidney fibrosis related proteins. This work illustrates the potential of MCE rich in anthocyanins and polyphenols as a natural food to inhibit DN. PMID- 28911397 TI - Mycotoxin monitoring for commercial foodstuffs in Taiwan. AB - Mycotoxins are toxic food contaminants that are naturally produced by certain fungi. They induce negative effects on human health by making food unsafe for consumption. In this study, analyses were performed to determine the levels and incidence of aflatoxins (AFs) in peanut products, tree nuts, spices, and Coix seeds; ochratoxin A (OTA) in wheat and roasted coffee, as well as OTA and AFs in rice; and citrinin (CIT) in red yeast rice (RYR) products. A total of 712 samples from nine different food categories were collected between 2012 and 2013. The samples were analyzed over 2 years for AFs, OTA, and CIT by methods recommended by the Ministry of Health and Welfare. These official analytical methods were extensively validated in-house and through interlaboratory trials. The analytical values of suspected contaminated specimens were confirmed by liquid chromatography - tandem mass spectrometry analysis to identify the specific mycotoxin present in the sample. We show that 689 samples (96.8%) complied with the regulations set by the Ministry of Health and Welfare. AFs were found in four peanut-candy products, one peanut-flour product, one pistachio product, one Sichuan-pepper product, and one Coix seed product. All had exceeded the maximum levels of 15 parts per billion for peanut and 10 parts per billion for other food products. Furthermore, 14 RYR samples contained CIT above 5 parts per million, and one RYR tablet exceeded the maximum amount allowed. Instances of AFs in substandard Sichuan pepper and Coix seeds were first detected in Taiwan. Measures were taken by the relevant authorities to remove substandard products from the market in order to decrease consumer exposure to mycotoxin. Border control measures were applied to importing food commodities with a higher risk of mycotoxin contamination, such as peanut, Sichuan pepper, and RYR products. Declining trends were observed in the noncompliance rate of AFs in peanut products, as well as that of CIT in RYR raw materials monitored from 2010 to 2013. PMID- 28911398 TI - Nanomaterial-based sensors for detection of foodborne bacterial pathogens and toxins as well as pork adulteration in meat products. AB - Food safety draws considerable attention in the modern pace of the world owing to rapid-changing food recipes and food habits. Foodborne illnesses associated with pathogens, toxins, and other contaminants pose serious threat to human health. Besides, a large amount of money is spent on both analyses and control measures, which causes significant loss to the food industry. Conventional detection methods for bacterial pathogens and toxins are time consuming and laborious, requiring certain sophisticated instruments and trained personnel. In recent years, nanotechnology has emerged as a promising field for solving food safety issues in terms of detecting contaminants, enabling controlled release of preservatives to extend the shelf life of foods, and improving food-packaging strategies. Nanomaterials including metal oxide and metal nanoparticles, carbon nanotubes, and quantum dots are gaining a prominent role in the design of sensors and biosensors for food analysis. In this review, various nanomaterial-based sensors reported in the literature for detection of several foodborne bacterial pathogens and toxins are summarized highlighting their principles, advantages, and limitations in terms of simplicity, sensitivity, and multiplexing capability. In addition, the application through a noncross-linking method without the need for any surface modification is also presented for detection of pork adulteration in meat products. PMID- 28911399 TI - Reduction of histamine and biogenic amines during salted fish fermentation by Bacillus polymyxa as a starter culture. AB - Bacillus polymyxa D05-1, isolated from salted fish product and possessing amine degrading activity, was used as a starter culture in salted fish fermentation in this study. Fermentation was held at 35 degrees C for 120 days. The water activity in control samples (without starter culture) and inoculated samples (inoculated with B. polymyxa D05-1) remained constant throughout fermentation, whereas the pH value rose slightly during fermentation. Salt contents in both samples were constant in the range of 17.5-17.8% during the first 60 days of fermentation and thereafter increased slowly. The inoculated samples had considerably lower levels of total volatile basic nitrogen (p < 0.05) than control samples at each sampling time during 120 days of fermentation. Aerobic bacterial counts in inoculated samples were retarded during the first 60 days of fermentation and thereafter increased slowly, whereas those of control samples increased rapidly with increased fermentation time. However, the aerobic bacterial counts of control samples were significantly higher (p < 0.05) than those of inoculated samples after 40 days of fermentation. In general, overall biogenic amine contents (including histamine, putrescine, cadaverine, and tyramine) in the control samples were markedly higher (p < 0.05) than those of the inoculated samples throughout fermentation. After 120 days of fermentation, the histamine and overall biogenic amine contents in the inoculated samples were reduced by 34.0% and 30.0%, respectively, compared to control samples. These results emphasize that the application of starter culture with amines degrading activity in salted fish products was effective in reducing biogenic amine accumulation. PMID- 28911400 TI - Effects of calcium supplements on the quality and acrylamide content of puffed shrimp chips. AB - The quality and acrylamide content of deep-fried and microwave-puffed shrimp chips fortified with 0.1%, 0.5%, or 1.0% calcium salts (calcium lactate, calcium carbonate, calcium citrate, or calcium acetate) were investigated. Microwave puffed shrimp chips contained higher amounts of acrylamide (130.43 ppb) than did deep-fried shrimp chips. The greatest mitigation of acrylamide formation in overfried chips was obtained with 0.1% calcium lactate. All browning indexes of fortified shrimp chips, whether deep-fried or microwave-puffed, were reduced. L* values of microwave-puffed shrimp chips were higher than those of deep-fried shrimp chips, whereas a* and b* values and browning indexes were lower. Color differences (DeltaE) between deep-fried puffed shrimp chips fortified with calcium salts and a control sample were higher than 5, and the sensory scores of shrimp chips were significantly decreased by the addition of calcium lactate. PMID- 28911401 TI - Chemical quality evaluation of Antrodia cinnamomea fruiting bodies using phytomics similarity index analysis. AB - The fruiting body of Antrodia cinnamomea is used as a medicinal mushroom in Taiwan and is found on the inner cavity of the endemic species Cinnamomum kanehirai. In this study, phytomics similarity index (PSI) analysis was employed for the chemical quality evaluation of the A. cinnamomea fruiting bodies from different strains, and grown on various substrates. The results indicated that the different types of A. cinnamomea fruiting bodies contain eight index compounds, and that it was difficult to discriminate between them solely on the basis of those index compounds. In our research, we used PSI scores to assess the metabolite similarity of the fruiting bodies of A. cinnamomea. It was revealed that fruiting bodies from various A. cinnamomea strains grown on different culture substrates produce distinct PSI scores. We concluded that PSI analysis had good selectivity on the different types of A. cinnamomea fruiting bodies. PMID- 28911402 TI - Antioxidant and antidiabetic activities of 11 herbal plants from Hyrcania region, Iran. AB - In the present study, 2,2-diphenyl-1-picrylhydrazyl radical scavenging, alpha amylase and alpha-glucosidase inhibition activities, and total phenolic contents of n-hexane, ethyl acetate, and methanol extracts of various parts of Allium paradoxum, Buxus hyrcana, Convolvulus persicus, Eryngium caucasicum, Heracleum persicum, Pimpinella affinis, Parrotia persica, Primula heterochroma, Pyrus boissieriana, Ruscus hyrcanus, and Smilax excelsa were investigated. These plants, which mostly serve as food flavoring, were collected from Hyrcania region, Sari, Iran. Some extracts of H. persicum, S. excels, P. boissieriana, P. persica, and P. heterochroma exhibited significant antidiabetic activities in alpha-amylase and alpha-glucosidase assays, more effective than acarbose (concentrations that cause 50% inhibition = 75.7 MUg/mL and 6.1 MUg/mL against alpha-amylase and alpha-glucosidase, respectively). Also, C. persicus, P. boissieriana, and P. heterochroma showed strong antioxidant activities, compared with butylated hydroxytoluene (concentration that causes 50% inhibition = 16.7 MUg/mL). In conclusion, this study can recommend these plants as good candidates for further investigations to find potent antidiabetic natural products or probable lead compounds. Statistical analysis showed significant correlation between the 2,2-diphenyl-1-picrylhydrazyl scavenging activity and total phenolic contents (r = 0.711, p < 0.001). PMID- 28911403 TI - Determination of the levels of two types of neurotransmitter and the anti migraine effects of different dose-ratios of Ligusticum chuanxiong and Gastrodia elata. AB - Ligusticum chuanxiong (LC)-Gastrodia elata (GE) compatibility is widely used in the clinic for the treatment of migraine. It has been shown that the changes of neurotransmitters in the central nervous system are closely related to the pathogenesis of migraine; whether LC-GE compatibility might affect the neurotransmitters in migraine rats has not yet been studied. In this study, high performance liquid chromatography-fluorescence detector methods for quantification of serotonin (5-hydroxytryptamine, 5-HT) and excitatory amino acids (EAAs) in rat brain were developed. The 5-HT was measured directly, while EAAs were determined by using dansyl chloride as precolumn derivative reagent. The validation of the methods, including selectivity, linearity, sensitivity, precision, accuracy, recoveries, and stability were carried out and demonstrated to meet the requirements of quantitative analysis. Compared with the model group, the expression of 5-HT in migraine rat brain was enhanced from 30 minutes to 120 minutes and glutamate (L-Glu) was suppressed from 30 minutes to 60 minutes in an LC-GE (4:3) group compared with the model group (p < 0.05, p < 0.01, respectively). These findings showed that the analytical methods were simple, sensitive, selective, and low cost, and LC-GE 4:3 compatibility could have better efficacy for treating migraine through upregulating 5-HT levels and downregulating L-Glu levels. PMID- 28911404 TI - The analytical determination and electrochemiluminescence behavior of amoxicillin. AB - A novel electrochemiluminescence (ECL) luminophor of amoxicillin was studied and found to generate ECL following the oxidation or reduction of amoxicillin. The amoxicillin oxidation state was also found to eliminate the reduction state, generating ECL. When solutions of amoxicillin were scanned between +1.5 V and 1.0 V with a graphite electrode in the presence of cetyltrimethyl ammonium bromide using KC1 as the supporting electrolyte, ECL emissions were observed at potentials of -0.7 V and +0.5 V. The ECL intensity at -0.7 V was enhanced by H2O2. Based on these findings, an ECL method for the determination of the amoxicillin concentration is proposed. The ECL intensities were linear with amoxicillin concentrations in the range of 1.8 * 10-8 g/mL to 2.5 * 10-7 g/mL, and the limit of detection (signal/noise = 3) was 5 * 10-9 g/mL. The florescence of amoxicillin had the greatest emission intensity in a neutral medium, with the emission wavelength dependent on the excitation wavelength. The experiments on the ECL mechanism for amoxicillin found that the electrochemical oxidation products of dissolved oxygen and active oxygen species contributed to the ECL process. The data also suggest that the hydroxyl group of amoxicillin contributed to its ECL emission. PMID- 28911405 TI - Chemopreventive effect of myrtenal on bacterial enzyme activity and the development of 1,2-dimethyl hydrazine-induced aberrant crypt foci in Wistar Rats. AB - Colon cancer remains as a serious health problem around the world despite advances in diagnosis and treatment. Dietary fibers are considered to reduce the risk of colon cancer as they are converted to short chain fatty acids by the presence of anaerobic bacteria in the intestine, but imbalanced diet and high fat consumption may promote tumor formation at different sites, including the large bowel via increased bacterial enzymes activity. The present study was conducted to characterize the inhibitory action of myrtenal on bacterial enzymes and aberrant crypt foci (ACF). Experimental colon carcinogenesis induced by 1,2 dimethylhydrazine is histologically, morphologically, and anatomically similar to human colonic epithelial neoplasm. Discrete microscopic mucosal lesions such as ACF and malignant tumors function as important biomarkers in the diagnosis of colon cancer. Methylene blue staining was carried out to visualize the impact of 1,2-dimethylhydrazine and myrtenal. Myrtenal-treated animals showed decreased levels of bacterial enzymes such as beta-glucuronidase, beta-glucosidase, and mucinase. Characteristic changes in the colon were noticed by inhibiting ACF formation in the colon. In conclusion, treatment with myrtenal provided altered pathophysiological condition in colon cancer-bearing animals with evidence of decreased crypt multiplicity and tumor progression. PMID- 28911406 TI - Quantitative analysis of insulin in total parenteral nutrition bag in Taiwan. AB - Regular insulin can reduce hyperglycemia when directly added to total parenteral nutrition (TPN) solutions. Insulin is not routinely added to all TPN solutions. For patients who require insulin prior to the initiation of TPN supplement, one third to one-half of the usual total daily dose can be added to the TPN bag as regular human insulin. However, an incorrect dose or an interaction between insulin and the TPN bag material may affect blood sugar control in clinical practice. Therefore, it is important to quantitatively determine the final dose of insulin in the TPN bag. High performance liquid chromatography is a very powerful technique for determining the purity of proteins. The goal of this study was to use high-performance liquid chromatography to perform quantitative analysis of insulin in a TPN bag. The analysis was performed under different light conditions (UV, fluorescent, and darkness) and different temperatures (25 degrees C and 2-8 degrees C). The results show that adsorption of insulin on an ethylene vinyl acetate TPN bag is significantly higher than that on glass. Based on the results, it is evident that regular insulin should be administered separately from TPN to reduce cost and eliminate wasteful disposal of TPN solutions. PMID- 28911407 TI - Use, history, and liquid chromatography/mass spectrometry chemical analysis of Aconitum. AB - Aconitum and its products have been used in Asia for centuries to treat various ailments, including arthritis, gout, cancer, and inflammation. In general, their preparations and dispensing have been restricted to qualified folk medicine healers due to their low safety index and reported toxicity. In the past few decades, official guidelines have been introduced in Asian pharmacopeias to control Aconitum herbal products. However, these guidelines were based on primitive analytical techniques for the determination of the whole Aconitum alkaloids and were unable to distinguish between toxic and nontoxic components. Recent advances in analytical techniques, especially high performance liquid chromatography (HPLC) and electrophoresis coupled with highly sensitive detectors, allowed rapid and accurate determination of Aconitum secondary metabolites. Reports focusing on liquid chromatography/mass spectrometry analysis of Aconitum and its herbal products are discussed in the current review. This review can be used by the health regulatory authorities for updating pharmacopeial guidelines of Aconitum and its herbal products. PMID- 28911408 TI - Determination of Pb (Lead), Cd (Cadmium), Cr (Chromium), Cu (Copper), and Ni (Nickel) in Chinese tea with high-resolution continuum source graphite furnace atomic absorption spectrometry. AB - The contents of lead, cadmium, chromium, copper, and nickel were determined in 25 tea samples from China, including green, yellow, white, oolong, black, Pu'er, and jasmine tea products, using high-resolution continuum source graphite furnace atomic absorption spectrometry. The methods used for sample preparation, digestion, and quantificational analysis were established, generating satisfactory analytical precisions (represented by relative standard deviations ranging from 0.6% to 2.5%) and recoveries (98.91-101.32%). The lead contents in tea leaves were 0.48-10.57 mg/kg, and 80% of these values were below the maximum values stated by the guidelines in China. The contents of cadmium and chromium ranged from 0.01 mg/kg to 0.39 mg/kg and from 0.27 mg/kg to 2.45 mg/kg, respectively, remaining in compliance with the limits stipulated by China's Ministry of Agriculture. The copper contents were 7.73-63.71 mg/kg; only 64% of these values complied with the standards stipulated by the Ministry of Agriculture. The nickel contents ranged from 2.70 mg/kg to 13.41 mg/kg. Consequently, more attention must be paid to the risks of heavy metal contamination in tea. The quantitative method established in this work lays a foundation for preventing heavy metal toxicity in human from drinking tea and will help establish regulations to control the contents of heavy metals in tea. PMID- 28911409 TI - Comparing determination methods of detection and quantification limits for aflatoxin analysis in hazelnut. AB - Hazelnut is a type of plant that grows in wet and humid climatic conditions. Adverse climatic conditions result in the formation of aflatoxin in hazelnuts during the harvesting, drying, and storing processes. Aflatoxin is considered an important food contaminant, which makes aflatoxin analysis important in the international produce trade. For this reason, validation is important for the analysis of aflatoxin in hazelnuts. The limit of detection (LOD) and limit of quantification (LOQ) are two important parameters in validation. In this study, the LOD and LOQ values have been determined using the Association of Official Agricultural Chemists (AOAC) Method 991.31, which is one of the most viable high performance liquid chromatography analysis methods in the analysis of aflatoxin in hazelnuts. Several approaches can be used to calculate LOD and LOQ values. In this study, to calculate the LOD and LOQ values, the visual evaluation (empirical) method, the signal-to-noise method, and calibration curve approaches were applied. The most appropriate approaches were compared. Our conclusion is that the visual evaluation method provided much more realistic LOD and LOQ values. PMID- 28911410 TI - Determination of histamine in milkfish stick implicated in food-borne poisoning. AB - An incident of food-borne poisoning causing illness in 37 victims due to ingestion of fried fish sticks occurred in September 2014, in Tainan city, southern Taiwan. Leftovers of the victims' fried fish sticks and 16 other raw fish stick samples from retail stores were collected and tested to determine the occurrence of histamine and histamine-forming bacteria. Two suspected fried fish samples contained 86.6 mg/100 g and 235.0 mg/100 g histamine; levels that are greater than the potential hazard action level (50 mg/100 g) in most illness cases. Given the allergy-like symptoms of the victims and the high histamine content in the suspected fried fish samples, this food-borne poisoning was strongly suspected to be caused by histamine intoxication. Moreover, the fish species of suspected samples was identified as milkfish (Chanos chanos), using polymerase chain reaction direct sequence analysis. In addition, four of the 16 commercial raw milkfish stick samples (25%) had histamine levels greater than the US Food & Drug Administration guideline of 5.0 mg/100 g for scombroid fish and/or products. Ten histamine-producing bacterial strains, capable of producing 373 1261 ppm of histamine in trypticase soy broth supplemented with 1.0% L-histidine, were identified as Enterobacter aerogenes (4 strains), Enterobacter cloacae (1 strain), Morganella morganii (2 strains), Serratia marcescens (1 strain), Hafnia alvei (1 strain), and Raoultella orithinolytica (1 strain), by 16S ribosomal DNA sequencing with polymerase chain reaction amplification. PMID- 28911411 TI - Fabrication of a novel electrochemical sensor for determination of hydrogen peroxide in different fruit juice samples. AB - A new hydrogen peroxide (H2O2) sensor is fabricated based on a multiwalled carbon nanotube-modified glassy carbon electrode (MWCNT-GCE) and reactive blue 19 (RB). The charge transfer coefficient, alpha, and the charge transfer rate constant, ks, of RB adsorbed on MWCNT-GCE were calculated and found to be 0.44 +/- 0.01 Hz and 1.9 +/- 0.05 Hz, respectively. The catalysis of the electroreduction of H2O2 by RB-MWCNT-GCE is described. The RB-MWCNT-GCE shows a dramatic increase in the peak current and a decrease in the overvoltage of H2O2 electroreduction in comparison with that seen at an RB modified GCE, MWCNT modified GCE, and activated GCE. The kinetic parameters such as alpha and the heterogeneous rate constant, k', for the reduction of H2O2 at RB-MWCNT-GCE surface were determined using cyclic voltammetry. The detection limit of 0.27MUM and three linear calibration ranges were obtained for H2O2 determination at the RB-MWCNT-GCE surface using an amperometry method. In addition, using the newly developed sensor, H2O2 was determined in real samples with satisfactory results. PMID- 28911412 TI - Analysis of aroma compounds and nutrient contents of mabolo (Diospyros blancoi A. DC.), an ethnobotanical fruit of Austronesian Taiwan. AB - Diospyros blancoi A. DC. is an evergreen tree species of high-quality wood. Mabolo, the fruit of this plant, is popular among the natives in Taiwan, but its potential in economic use has not been fully explored. Mabolo has a rich aroma. Of the 39 different volatile compounds isolated, its intact fruit and peel were found to both contain 24 compounds, whereas the pulp contained 28 compounds. The most important aroma compounds were esters and alpha-farnesene. Our data show that mabolo is rich in dietary fiber (3.2%), and the contents of other nutrients such as malic acid, vitamin B2, vitamin B3, folic acid, pantothenic acid, and choline chloride were 227.1 mg/100 g, 0.075 mg/100 g, 0.157 mg/100 g, 0.623 mg/100 g, 0.19 mg/100 g, and 62.52 mg/100 g, respectively. Moreover, it is rich in calcium and zinc; the contents of which were found to be 42.8 mg/100 g and 3.6 mg/100 g, respectively. Our results show that D. blancoi has the potential to be bred for a novel fruit. PMID- 28911413 TI - Development of standardized methodology for identifying toxins in clinical samples and fish species associated with tetrodotoxin-borne poisoning incidents. AB - Tetrodotoxin (TTX) is a naturally occurring toxin in food, especially in puffer fish. TTX poisoning is observed frequently in South East Asian regions. In TTX derived food poisoning outbreaks, the amount of TTX recovered from suspicious fish samples or leftovers, and residual levels from biological fluids of victims are typically trace. However, liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry methods have been demonstrated to qualitatively and quantitatively determine TTX in clinical samples from victims. Identification and validation of the TTX-originating seafood species responsible for a food poisoning incident is needed. A polymerase chain reaction-based method on mitochondrial DNA analysis is useful for identification of fish species. This review aims to collect pertinent information available on TTX-borne food poisoning incidents with a special emphasis on the analytical methods employed for TTX detection in clinical laboratories as well as for the identification of TTX-bearing species. PMID- 28911414 TI - Rapid confirmatory analysis of avermectin residues in milk by liquid chromatography tandem mass spectrometry. AB - Our study developed a quick method for confirmatory analysis of avermectins (abamectin B1a, doramectin, ivermectin B1a, eprinomectin B1a, and moxidectin) in bovine milk according to the European Commission Decision 2002/657/EC requirements. Avermectins were liquid-liquid extracted with acetonitrile, followed by an evaporation step, and then analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry in the negative ion mode. An in-house method validation was performed and the data reported on specificity, linearity, recovery, limit of detection, limit of quantitation, decision limit, and detection capability. The advantage of this method is that low levels of avermectins are detectable and quantitatively confirmed at a rapid rate in milk. PMID- 28911415 TI - High performance liquid chromatography (HPLC) fingerprints and primary structure identification of corn peptides by HPLC-diode array detection and HPLC electrospray ionization tandem mass spectrometry. AB - Corn peptides (CPs) are reported to have many biological functions, such as facilitating alcohol metabolism, antioxidation, antitumor, antihypertension, and hepatoprotection. To develop a method for quality control, the high-performance liquid chromatography (HPLC) system was applied. Twenty-eight common peaks were found in all the CPs of corn samples from Enshi, China, based on which, a fingerprinting chromatogram was established for use in quality control in future research. Subsequently, the major chemical constituents of these common peaks were identified respectively using the HPLC-diode-array detection electrospray ionization tandem mass spectrometry (DAD-ESI-MS/MS) system, and 48 peptide fractions were determined ultimately. This was the first time for the majority of these peptides to be reported, and many of them contained amino acids of glutamine (Q), L and A, which might play an important role in the exhibition of the bioactivities of CPs. Many peptides had a similar primary structure to the peptides which had been proven to be bioactive such as facilitating alcohol metabolism, scavenging free radicals, and inhibiting lipid peroxidation. This systematical analysis of the primary structure of CPs facilitated subsequent studies on the relationship between the structures and functions, and could accelerate holistic research on CPs. PMID- 28911416 TI - Development and validation of a simple reversed-phase HPLC-UV method for determination of oleuropein in olive leaves. AB - A simple, precise, accurate, and selective method is developed and validated for the determination of oleuropein, which is the main phenolic compound in olive leaves. Separation was achieved on a reversed-phase C18 column (5 MUm, 150 * 4.6 mm inner diameter) using a mobile phase consisting of acetonitrile/phosphate buffer pH 3.0 (20:80, v/v), at a flow rate of 1.0 mL/minute and UV detection at 280 nm. This method is validated according to the requirements for new methods, which include accuracy, precision, selectivity, robustness, limit of detection, limit of quantitation, linearity, and range. The current method demonstrates good linearity over the range of 3-1000 ppm of oleuropein, with r2 > 0.999. The recovery of oleuropein in olive leaves ranges from 97.7% to 101.1%. The method is selective, in that oleuropein is well separated from other compounds of olive leaves with good resolution. The method is also precise-the relative standard deviation of the peak areas of replicate injections of oleuropein standard solution is <1%. The degree of reproducibility of the results obtained as a result of small deliberate variations in the method parameters and by changing analytical operators has proven that the method is robust and rugged. The low limit of detection and limit of quantitation of oleuropein when using this method enable the detection and quantitation of oleuropein at low concentrations. PMID- 28911417 TI - Flavonoid compositions and antioxidant activity of calamondin extracts prepared using different solvents. AB - Calamondin has been demonstrated to exhibit antioxidant function and tyrosinase inhibitory activity, which might be attributed to its flavonoid compounds. To improve their application, the flavonoid compositions and antioxidant activity of calamondin extracts, prepared by different solvents, were investigated. The results showed that total phenolic and flavonoid contents of extracts from peel of calamondin were higher than that from pulp, except the flavonoid content in hot water extract. The flavonoids found in extracts of calamondin were 3',5'-di-C beta-glucopyranosylphloretin (DGPP), naringin, hesperidin, nobiletin, tangeretin, and diosmin. DGPP exhibited the highest quantity, while naringin and hesperidin were the other two major flavonoids. The content of DGPP in hot water extract of peel was higher than in extracts of organic solvents, however, the contents of nobiletin and tangeretin were found only in extracts of organic solvents. The highest levels of total flavonoids and DGPP were obtained in hot water extract from peel at 90 degrees C. The extracts of hot water and ethyl acetate showed higher 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging potency than that of ethanol and methanol. A positive relationship existed between total phenolic contents and DPPH scavenging potency (p < 0.01), while total flavonoid compositions also showed correlation (p < 0.05). Thus, DGPP, naringin, and hesperidin might contribute to antioxidant activity. Collectively, the hot water extract of calamondin peel might have potential for health food and cosmetic applications due to its good antioxidant activity and high level of DGPP. PMID- 28911419 TI - Catechin content and the degree of its galloylation in oolong tea are inversely correlated with cultivation altitude. AB - The taste quality of oolong tea generated from leaves of Camellia sinensis L. cultivated in the same mountain area is positively correlated to the cultivation altitude, partly due to the inverse correlation with the astringency of the tea infusion. The astringency of oolong tea mostly results from the presence of polyphenolic compounds, mainly catechins and their derivatives. Four catechins, ( )-epicatechin (EC) and (-)-epigallocatechin (EGC) together with their gallate derivatives (with relatively high astringency), (-)-EC gallate (ECG) and (-)-EGC gallate (EGCG), were detected as major compounds in oolong tea. The degrees of catechin galloylation, designated as ECG/(EC + ECG) and EGCG/(EGC + EGCG), in both oolong tea infusions and their fresh tea leaves, were found to be inversely correlated to the cultivation altitude at 200 m, 800 m, and 1300 m. A similar inverse correlation was observed when seven more oolong tea infusions and seven more fresh leaves harvested at altitude ranging from 170 m to 1600 m were recruited for the analyses. Moreover, catechin contents in oolong tea infusions were also found to be inversely correlated to the cultivation altitude. It is proposed that catechin content and the degree of its galloylation account for, at least partly, the inverse correlation between the astringency of oolong tea and the cultivation altitude. PMID- 28911418 TI - Effect of extraction solvent on total phenol content, total flavonoid content, and antioxidant activity of Limnophila aromatica. AB - Limnophila aromatica is commonly used as a spice and a medicinal herb in Southeast Asia. In this study, water and various concentrations (50%, 75%, and 100%) of methanol, ethanol, and acetone in water were used as solvent in the extraction of L. aromatica. The antioxidant activity, total phenolic content, and total flavonoid content of the freeze-dried L. aromatica extracts were investigated using various in vitro assays. The extract obtained by 100% ethanol showed the highest total antioxidant activity, reducing power and DPPH (2,2 diphenyl-1-picrylhydrazyl) radical scavenging activity. The same extract also exhibited the highest phenolic content (40.5 mg gallic acid equivalent/g of defatted L. aromatica) and the highest flavonoid content (31.11 mg quercetin equivalent/g of defatted L. aromatica). The highest extraction yield was obtained by using 50% aqueous acetone. These results indicate that L. aromatica can be used in dietary applications with a potential to reduce oxidative stress. PMID- 28911420 TI - Effect of roasting on the volatile constituents of Trichosanthes kirilowii seeds. AB - Roasted Trichosanthes kirilowii seeds have much more intense flavor than the raw seeds, and are commonly used as food and in the preparations of many medicinal formulations. Volatile constituents in the raw and roasted T. kirilowii seeds were separated by simultaneous distillation and extraction, and analyzed by gas chromatography-mass spectrometry on two capillary gas chromatography columns of different polarities (DB-WAX and HP-1). A total of 40 volatile compounds were identified in the raw seeds, with pentanal, 2-pentanol, styrene, (Z)-2-heptenal, (+)-calarene, and alpha-muurolene being the predominant compounds; 40 volatile compounds were also identified in the roasted seeds, with 3-methylbutanal, ethanol, 2-butanol, 2,3-butanediol, (E,E)-2,4-nonadienal, and 2-isopropyl-5 methyl-9-methylene-bicyclo[4.4.0]dec-1-ene being the most abundant compounds. A total of 15 compounds, mostly aldehydes, were common in both seeds. Roasting of T. kirilowii seeds resulted in a significant decrease in the levels of sesquiterpenes and short-chain aliphatic aldehydes. By contrast, high concentrations of 3-methylbutanal, ethanol, 2-butanol, and alkyl pyrazines were generated, which was responsible for the unique flavor of the roasted seeds. The study results may be useful for optimizing the roasting process and oil processing of T. kirilowii seeds. PMID- 28911421 TI - Detection of 10 sweeteners in various foods by liquid chromatography/tandem mass spectrometry. AB - The analytical method for sweeteners in various food matrixes is very important for food quality control and regulation enforcement. A simple and rapid method for the simultaneous determination of 10 sweeteners [acesulfame potassium (ACS K), aspartame (ASP), cyclamate (CYC), dulcin (DUL), glycyrrhizic acid (GA), neotame (NEO), neohesperidin dihydrochalcone (NHDC), saccharin (SAC), sucralose (SCL), and stevioside (STV)] in various foods by liquid chromatography/tandem mass chromatography (LC-MS/MS) was developed. The chromatographic separation was performed on a Phenomenex Luna Phenyl-Hexyl (5 MUm, 4.6 mm * 150 mm) column with gradient elution of 10 mM ammonium acetate in water and 10 mM ammonium acetate in methanol. The recoveries of the 10 sweeteners were between 75% and 120%, and the coefficients of variation were less than 20%. The limits of quantification were 0.5 MUg/kg for NHDC and SCL. For the other sweeteners, the limits of quantification were 0.1 MUg/kg. Compared to the traditional high-performance liquid chromatography method, the LC-MS/MS method could provide better sensitivity, higher throughput, enhanced specificity, and more sweeteners analyzed in a single run. The samples included 27 beverages (16 alcoholic and 11 nonalcoholic beverages) and 15 pickled foods (1 pickled pepper, 3 candies, and 11 candied fruits). Two remanufactured wines were found to contain 7.2, 8.5 MUg/g SAC and 126.5, 123 MUg/g CYC, respectively. ACS-K, ASP, SCL, and NEO were detected in five beverages and drinks. The pickled peppers and candied fruits were found to contain SAC, GA, CYC, ASP, STV, NEO, and ACS-K. The wine with sweeteners detected was remanufactured wine, not naturally fermented wine. Therefore, the ingredient label for the sweeteners of remanufactured wine should be regulated by the proper authority for inspection of sweeteners. PMID- 28911422 TI - Determination of the food dye carmine in milk and candy products by differential pulse polarography. AB - As a basis for the development of a sensitive analytical method for the determination of carmine food dye, a study of the differential pulse polarographic reduction of carminic acid (CA) on a dropping mercury electrode was performed. For the analytical differential pulse polarographic method running at pH 2.0 Britton-Robinson (B-R) buffer solution (peak at -489 mV), the relationship between the peak current and CA concentration was linear in the range of 1 MUM to 90 MUM with a detection limit of 0.16 MUM. The proposed electrochemical procedure was successfully applied to the determination of carmine food dye in spiked commercially available strawberry flavored milk. The method was extended to the determination of CA in candy and results were in agreement with that obtained by a spectrophotometric comparison method. A cyclic voltammogram of CA in 2.0 B-R buffer electrolyte was obtained on the dropping mercury electrode at pH 2.0 during potential scans from 0.00 mV to 1000 mV versus Ag/AgCl. From repetitive cyclic voltammograms, one cathodic peak at -500 mV and three anodic peaks on the reverse scan between approximately -340 mV and -460 mV were recorded. The influences of some other commonly found inorganic and organic salts on the determination of CA were also examined. The sufficiently good recoveries and low standard deviations for the data reflect the high accuracy and precision of the proposed differential pulse polarographic method. PMID- 28911423 TI - Integration of independent component analysis with near-infrared spectroscopy for analysis of bioactive components in the medicinal plant Gentiana scabra Bunge. AB - Independent component (IC) analysis was applied to near-infrared spectroscopy for analysis of gentiopicroside and swertiamarin; the two bioactive components of Gentiana scabra Bunge. ICs that are highly correlated with the two bioactive components were selected for the analysis of tissue cultures, shoots and roots, which were found to distribute in three different positions within the domain [two-dimensional (2D) and 3D] constructed by the ICs. This setup could be used for quantitative determination of respective contents of gentiopicroside and swertiamarin within the plants. For gentiopicroside, the spectral calibration model based on the second derivative spectra produced the best effect in the wavelength ranges of 600-700 nm, 1600-1700 nm, and 2000-2300 nm (correlation coefficient of calibration = 0.847, standard error of calibration = 0.865%, and standard error of validation = 0.909%). For swertiamarin, a spectral calibration model based on the first derivative spectra produced the best effect in the wavelength ranges of 600-800 nm and 2200-2300 nm (correlation coefficient of calibration = 0.948, standard error of calibration = 0.168%, and standard error of validation = 0.216%). Both models showed a satisfactory predictability. This study successfully established qualitative and quantitative correlations for gentiopicroside and swertiamarin with near-infrared spectra, enabling rapid and accurate inspection on the bioactive components of G. scabra Bunge at different growth stages. PMID- 28911424 TI - Simultaneous determination of ranitidine and metronidazole in pharmaceutical formulations at poly(chromotrope 2B) modified activated glassy carbon electrodes. AB - A simple and sensitive electrochemical method for the simultaneous and quantitative detection of ranitidine (RT) and metronidazole (MT) was developed, based on a poly(chromotrope 2B) modified activated glassy carbon electrode (PCHAGCE). The PCHAGCE showed excellent electrocatalytic activity toward the reduction of both RT and MT in 0.1 mol/L phosphate buffer solution (pH 6.0). The peak-to-peak separations for the simultaneous detection of RT and MT between the two reduction waves in cyclic voltammetry were increased significantly from ~0.1 V at activated GCE, to ~0.55 V at PCHAGCE. By differential pulse voltammetry techniques, the reduction peak currents of RT and MT were both linear over the range of 1.0 * 10-5-4.0*10-4 mol/L. The detection limits (S/N = 3) were 5.4 * 10 7 mol/L and 3.3 * 10-7 mol/L for RT and MT, respectively. The modified electrode was successfully applied to the determination of RT and MT in pharmaceutical preparations and human serum as real samples with stable and reliable recovery data. PMID- 28911425 TI - 5-Aminolevulinic acid induced photodynamic inactivation on Staphylococcus aureus and Pseudomonas aeruginosa. AB - The aim of the present study was to develop a simple and fast screening technique to directly evaluate the bactericidal effects of 5-aminolevulinic acid (ALA) mediated photodynamic inactivation (PDI) and to determine the optimal antibacterial conditions of ALA concentrations and the total dosage of light in vitro. The effects of PDI on Staphylococcus aureus and Pseudomonas aeruginosa in the presence of various concentrations of ALA (1.0 mM, 2.5 mM, 5.0 mM, 10.0 mM) were examined. All bacterial strains were exponentially grown in the culture medium at room temperature in the dark for 60 minutes and subsequently irradiated with 630 +/- 5 nm using a light-emitting diode (LED) red light device for accumulating the light doses up to 216 J/cm2. Both bacterial species were susceptible to the ALA-induced PDI. Photosensitization using 1.0 mM ALA with 162 J/cm2 light dose was able to completely reduce the viable counts of S. aureus. A significant decrease in the bacterial viabilities was observed for P. aeruginosa, where 5.0 mM ALA was photosensitized by accumulating the light dose of 162 J/cm2. We demonstrated that the use of microplate-based assays-by measuring the apparent optical density of bacterial colonies at 595 nm-was able to provide a simple and reliable approach for quickly choosing the parameters of ALA-mediated PDI in the cell suspensions. PMID- 28911426 TI - Correlation of antituberculosis drug-related liver injury and liver function monitoring: A 12-year experience of the Taiwan Drug Relief Foundation. AB - Antituberculosis drug-related liver injury (ATLI) is the most prevalent hepatotoxicity in many countries. Whether monitoring liver tests is beneficial to prevent this potentially grave adverse drug reaction (ADR) is open to debate. The Taiwan Drug Relief Foundation (TDRF) was established by the Taiwan Food and Drug Administration to collect severe cases of ADR and carry out drug injury relief tasks. Our intention was to explore the role of monitoring liver tests in the susceptibility and severity of ATLI from the database of this foundation. All cases of suspected ATLI collected by the TDRF from 1999 to 2012 were reviewed. The basic demographic data, clinical course, and laboratory data of these patients were analyzed. A total of 57 cases with severe ATLI were verified and enrolled into this study. There was a high mortality (71.9%) in this cohort. Twenty-four cases (42.1%) were chronic viral hepatitis B carriers, who had higher baseline serum aminotransferase level than noncarriers. The patients without monitoring liver tests had higher peak serum alanine aminotransferase, bilirubin levels, and mortality (adjusted odds ratio, 8.87; 95% confidence interval = 1.32 59.41; p = 0.024) than those with monitoring liver tests. In conclusion, patients with severe ATLI whose records were collected by the TDRF have a high mortality. Patients without follow-up monitoring liver tests had more severe liver injuries and higher mortality than those with monitoring live tests. To alleviate this potentially grave ADR, checking of liver biochemical tests prior to antituberculosis treatment and periodic monitoring of these tests thereafter are highly suggested. PMID- 28911427 TI - Electrochemical oxidation behavior of hydrochlorothiazide on a glassy carbon electrode and its voltammetric determination in pharmaceutical formulations and biological fluids. AB - The electrochemical oxidation behavior of hydrochlorothiazide (HCT) on a glassy carbon as a working electrode was investigated in Britton-Robinson (B-R) buffer pH 3, by using anodic stripping voltammetry (ASV) and cyclic voltammetry (CV). This drug gave a well-defined voltammetric oxidation peak at + 1200 mV versus an Ag/AgCl reference electrode. The electrochemical oxidation process was shown to be irreversible and diffusion controlled, with adsorption characterized over the entire pH range. The optimized conditions, such as accumulation time and potential, scan rate, frequency, pulse amplitude, varying of working electrodes, and instrumental parameters were studied. The calibration graph for HCT was obtained from 4 * 10-6 to 4 * 10-5 M (correlation coefficient = 0.997) using the developed electroanalytical method (ASV). The detection limit of this drug was 4.3 * 10-9 M. ASV and CV techniques with adequate precision and accuracy have been developed and applied for direct determination of HCT in commercial tablets without separation or extraction procedures and biological fluids such as urine and plasma. PMID- 28911428 TI - Quantitative determination of salvinorin A, a natural hallucinogen with abuse liability, in Internet-available Salvia divinorum and endemic species of Salvia in Taiwan. AB - In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum and its related concentrated extract products are available via the Internet. Besides S. divinorum, there are many endemic Salvia species whose salvinorin A content is yet unknown. To understand the abuse liability of these products, the aim of this study was to assess the concentration of salvinorin A in endemic Salvia species and Internet-available salvinorin A-related products. Samples of S. divinorum were purchased via the Internet and samples of eight endemic species of Salvia were collected in Taiwan, including S. arisanensis Hayata, S. coccinea Juss. ex Murr, S. hayatana Makino ex Hayata, S. japonica Thumb. ex Murr, S. nipponica Miq. Var. formosana (Hayata) Kudo, S. scapiformis Hance, S. tashiroi Hayata. Icon. PI. Formosan, and S. keitaoensis Hayata. The content of salvinorin A was determined by high performance liquid chromatography (HPLC). Salvinorin A was extracted from the dry leaves of S. divinorum and endemic species of Salvia with methanol and analyzed on a C-18 column by isocratic elution with a mobile phase of acetonitrile-water. Salvinorin A was detected in S. divinorum, but not in the endemic Salvia species of Taiwan. Therefore, endemic species of Salvia in Taiwan may not possess hallucinogenic potential. However, the potential harm from S. divinorum available via the Internet should be thoroughly assessed in Taiwan, and control measures similar to those implemented in many other countries should be considered. PMID- 28911429 TI - Comparison of free radical formation induced by baicalein and pentamethyl hydroxychromane in human promyelocytic leukemia cells using electron spin resonance. AB - Baicalein and pentamethyl-hydroxychromane (PMC) have been investigated for use as antioxidants. However, antioxidants may stimulate free radical formation under certain conditions. The aim of our study was to determine whether PMC and baicalein exhibit both pro-oxidant and antioxidant activities in human promyelocytic leukemia (HL-60) cells. In this study, electron spin resonance spectrometry was used to investigate the effects of baicalein and PMC on free radical formation. In HL-60 cells, baicalein and PMC produced hydroxyl and phenoxyl radicals, respectively, but each inhibited radical formation by the other. The PMC pro-oxidant activity required H2O2, whereas baicalein produced hydroxyl radicals during the cell resting state only. The antioxidant effect of baicalein on PMC-induced oxidative stress in HL-60 cells may involve myeloperoxidase inhibition, which produces the myeloperoxidase-protein radical. Our investigation of the antioxidant effects of baicalein on arachidonic acid (AA)-induced oxidative stress in HL-60 cells showed that the baicalein-phenoxyl radical was the primary product, and that either carbon-centered or acyl radicals were the secondary products. However, the antioxidant effects of PMC on AA induced oxidative stress produced only nonradical products. In conclusion, we showed that baicalein displayed both pro-oxidant and antioxidant activities in HL 60 cells. PMC exhibited no pro-oxidant activity during the cells' resting state but produced the PMC-phenoxyl radical in the presence of H2O2.The reaction of baicalein with AA in HL-60 cells produced baicalein-derived phenoxyl radicals that may initiate various pro-oxidative reactions. However, PMC does not produce radicals when it acts as an antioxidant. Thus, PMC is more beneficial as an antioxidant than baicalein. PMID- 28911430 TI - The implementation of HACCP management system in a chocolate ice cream plant. AB - To guarantee the safety of chocolate ice cream production, the Hazard Analysis Critical Control Points (HACCP) system was applied to the production process. The biological, chemical, and physical hazards that may exist in every step of chocolate ice cream production were identified. In addition, the critical control points were selected and the critical limits, monitoring, corrective measures, records, and verifications were established. The critical control points, which include pasteurization and freezing, were identified. Implementing the HACCP system in food manufacturing can effectively ensure food safety and quality, expand the market, and improve the manufacturers' management level. PMID- 28911431 TI - Efficacy and safety of tumor necrosis factor-alpha blockers for ulcerative colitis: A systematic review and meta-analysis of published randomized controlled trials. AB - To evaluate the efficacy and safety of TNF-alpha blockers for ulcerative colitis. A systematic search for randomized controlled trials (RCTs) of TNF-alpha blockers for treatment of ulcerative colitis (UC) were performed in PubMed, Web of Science, Embase and cochrane clinical trial. We estimated Pooled estimates of the odds ratio (OR) and relevant 95% confidence interval (CI) using fixed effects model or random effects model as appropriate. Heterogeneity, publication bias, and subgroup analyses were conducted. Nine randomized controlled studies met the selection criteria with a total of 2518 patients. Five studies compared Infliximab with placebo. Two studies compared Infliximab to corticosteroids. Two studies compared Adalimumab to placebo. One study compared subcutaneous golimumab to placebo. Short-term response, short-term remission, long-term remission and mucosal healing were better in the TNF-alpha blocker group than in the control group (p < 0.05). TNF-alpha blockers decreased the colectomy rate and serious adverse reactions (p < 0.05). The TNF-alpha blockers were superior to controls in achieving short-term clinical response/remission, long-term remission and mucosal healing and decreased the colectomy rate and serious adverse reactions. PMID- 28911432 TI - Antioxidant, antimicrobial, antitumor, and cytotoxic activities of an important medicinal plant (Euphorbia royleana) from Pakistan. AB - The aim of present study was to evaluate antioxidant, antimicrobial, and antitumor activities of methanol, hexane, and aqueous extracts of fresh Euphorbia royleana. Total phenolic and flavonoid contents were estimated as gallic acid and querectin equivalents, respectively. Antioxidant activity was assessed by scavenging of free 2,2'- diphenyl-1-picrylhydrazyl radicals and reduction of ferric ions, and it was observed that inhibition values increase linearly with increase in concentration of extract. The results of ferric reducing antioxidant power assay showed that hexane extract has maximum ferric reducing power (12.70 +/- 0.49 mg gallic acid equivalents/g of plant extract). Maximum phenolic (47.47 +/- 0.71 MUg gallic acid equivalents/mg of plant extract) and flavonoid (63.68 +/ 0.43 MUg querectin equivalents/mg of plant extract) contents were also found in the hexane extract. Furthermore, we examined antimicrobial activity of the three extracts (methanol, hexane, aqueous) against a panel of microorganisms (Escherichia coli, Bacillus subtillis, Pasteurella multocida, Aspergillus niger, and Fusarium solani) by disc-diffusion assay, and found the hexane extract to be the best antimicrobial agent. Hexane extract was also observed as to be most effective in a potato disc assay. As hexane extract showed potent activity in all the investigated assays, it was targeted for cytotoxic assessment. Maximum cytotoxicity (61.66%) by hexane extract was found at 800 MUg/mL. It is concluded that investigated extracts have potential for isolation of antioxidant and antimicrobial compounds for the pharmaceutical industry. PMID- 28911433 TI - Possible molecular targets for therapeutic applications of caffeic acid phenethyl ester in inflammation and cancer. AB - Of the various derivatives of caffeic acid, caffeic acid phenethyl ester (CAPE) is a hydrophobic, bioactive polyphenolic ester obtained from propolis extract. The objective in writing this review article was to summarize all published studies on therapeutics of CAPE in inflammation and cancer to extract direction for future research. The possible molecular targets for the action of CAPE, include various transcription factors such as nuclear factor-kappaB, tissue necrosis factor-alpha, interleukin-6, cyclooxygenase-2, Nrf2, inducible nitric oxide synthase, nuclear factor of activated T cells, hypoxia-inducible factor 1alpha, and signal transducers and activators of transcription. Based on the valuable data on its therapeutics in inflammation and cancer, clinical studies of CAPE should also be conducted to explore its toxicities, if any. PMID- 28911434 TI - Significant elevation of antiviral activity of strictinin from Pu'er tea after thermal degradation to ellagic acid and gallic acid. AB - Compared with abundant catechins, strictinin is a minor constituent in teas and has been demonstrated to possess inhibitory potency on influenza virus. In this study, strictinin was found as the major phenolic compound in Pu'er teas produced from leaves and buds of wild trees. Due to its thermal instability, strictinin, in tea infusion or in an isolated form, was completely decomposed to ellagic acid and gallic acid after being autoclaved for 7 minutes. A plaque reduction assay was employed to compare the relative inhibitory potency between strictinin and its thermally degraded products against human influenza virus A/Puerto Rico/8/34. The results showed that the antiviral activity of ellagic acid regardless of the presence or absence of gallic acid was significantly higher than that of strictinin. Thermal degradation of strictinin to ellagic acid and gallic acid seems to be beneficial for the preparation of Pu'er teas in terms of enhancing antiviral activity. PMID- 28911435 TI - In vitro anti-diabetic effect and chemical component analysis of 29 essential oils products. AB - Twenty-nine commercial essential oil (EO) products that were purchased from the Taiwan market, including three different company-made Melissa officinalis essential oils, were assayed on their glucose consumption activity and lipid accumulation activity on 3T3-L1 adipocytes. The EOs of M. officinalis were significantly active in both model assays. By contrast, EOs of peppermint, lavender, bergamot, cypress, niaouli nerolidol, geranium-rose, and revensara did not increase glucose consumption activity from media, but displayed inhibited lipid accumulation activity (65-90% of lipid accumulation vs. the control 100%). Because of the promising activity of M. officinalis EOs, three different products were collected and compared for their gas chromatography chemical profiles and bioactivity. The Western blot data suggest that the key factors of the adenosine monophosphate-activated protein kinase/acetyl-CoA carboxylase pathway can be mediated by M. officinalis EOs. Together with biodata, gas chromatography-mass spectrometry profiles suggested mixtures of citrals and minor compounds of M. officinalis EOs may play an important role on effect of antidiabetes. PMID- 28911436 TI - Quality assessment of Fritillariae Thunbergii Bulbus sold in Taiwan markets using a validated HPLC-UV method combined with hierarchical clustering analysis. AB - The present paper describes the development of a high performance liquid chromatography-ultraviolet (HPLC-UV) detection method for quantitative determination of peimine and peiminine in Fritillariae Thunbergii Bulbus (FTB). Separation was achieved using a conventional XBridgeTM Shield RP 18 column (250 mm * 4.6 mm, internal diameter 3.5 MUm) with photodiode array detection at 190 400 nm for UV spectra and 220 nm for quantification. The mobile phase consisted of (A) 0.03% diethylamine aqueous solution and (B) acetonitrile eluted by an isocratic procedure at 45:55 (A:B) over 25 minutes. The method was validated for linearity, limits of detection (LOD) and quantification (LOQ), inter- and intra day precisions, repeatability, stability, and recovery. All the validation results were satisfactory. The developed method was then applied to assay the contents of the two chemical markers in all the FTB samples collected. Based on the contents of the two analytes, hierarchical clustering analysis (HCA) was performed to reveal the similarities and differences of the samples. PMID- 28911437 TI - Preparation of total flavonoids from loquat flower and its protective effect on acute alcohol-induced liver injury in mice. AB - This study aimed to research the preparation techniques of total flavones from loquat flower (TFLF), its anti-oxidation capacity, and its protective effect on hepatic injury. The best extraction parameters by orthogonal experimentation were water at 100 degrees C, extraction time 2.5 hours, solid/liquid ratio 1:20, and three decoctions. The chromogenic reaction to the flavones showed that loquat flowers mainly contained flavone, flavonol, and flavanone compounds combining ortho-phenolic hydroxyl group structure in the 10-30% ethanol fraction. The anti oxidant capacity of O2-. was 26.09% and of OH-.was 83.01% by salicylic acid and pyrogallol auto-oxidation. Compared with the model group, TFLF lowered the levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, and malondialdehyde and liver index significantly, and upregulated the expression of adipose triglyceride lipase and Heine oxygenase-1 mRNA. The present findings suggest that TFLF has protective effect on acute alcoholinduced liver injury in mice and may be related to its antioxidant and free-radical scavenging activity. PMID- 28911438 TI - Quality analysis of Polygala tenuifolia root by ultrahigh performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. AB - Polygala tenuifolia root is used as a functional food due to its attractive health benefits. In this study, ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) were utilized to characterize the bioactive compounds in P. tenuifolia root. The UPLC-MS/MS information revealed 36 bioactive compounds, including oligosaccharide esters, polygalasaponins, and polygalaxanthones. GC-MS identified 34 volatile compounds with fatty acids as the main chemicals. The leading compound judged by UPLC-MS/MS was tenuifoliside A, and oleic acid was the leading volatile from GC-MS profiles. All samples tested showed similar bioactive compound compositions, but the level of each compound varied. Principal component analysis revealed the principal bioactive compounds with significant level variations between samples. These principal chemicals could be used for quality judgment of P. tenuifolia root, instead of measuring the levels of all compositional compounds. PMID- 28911439 TI - Effects of indium chloride exposure on sperm morphology and DNA integrity in rats. AB - Indium, a Group IIIA element of the periodic chart and a rare earth metal characterized by high plasticity, corrosion resistance, and a low melting point, is widely used in the electronics industry where released streams can contaminate the environment. Consequently, indium can reach humans mainly by natural ways, which could result in a health hazard. Although reproductive toxicities have been surveyed in some studies in animal models, the infertility effects of sperm function induced by indium compounds have not been greatly investigated. We designed a study to investigate the toxicities of subacute exposure to indium compounds on male sperm function and the process of spermatogenesis in a rodent model. Fourteen Sprague-Dawley rats on postnatal Day (PND) 84 were randomly divided into exposure and control groups, and weekly received intraperitoneal injections of indium chloride (1.5 mg/kg body weight) and normal saline, respectively, for 8 weeks. Cauda epididymal sperm count, motility, morphology, chromatin DNA integrity, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, and testis DNA content were investigated. The indium chloride exposed group showed significant toxicity to sperm function, as well as an increased percentage of sperm morphological abnormality and chromatin DNA damage. Furthermore, positive correlations between abnormal sperm morphology, chromatin DNA damage, and superoxide anion generation were also noted. The results of this study demonstrated the toxic effect of subacute low dose indium exposure during sexual maturation on sperm function, resulting in sperm chromatin DNA damage through an increase in sperm ROS generation in a rodent model. PMID- 28911440 TI - Border inspections of imported food and related products in Taiwan from 2011 to 2013. PMID- 28911441 TI - Current development in medical devices postmarket surveillance in Taiwan. PMID- 28911442 TI - The development of alcohol policy in contemporary China. AB - Over recent years, an increase in alcohol-related problems has been noted in China. Taking effective measures against the problem requires clear reviewing and understanding of the evolution of the Chinese alcohol policy. This study is aimed to evaluate the alcohol policy with special focus on reviewing the alcohol production and consumption situation in China and assessing the changes in Chinese alcohol policy along with other related fields. This article finishes with a set of recommended policy changes that could help solve the recent alcohol related problems and analyze the major impediments. PMID- 28911443 TI - Authenticity analysis of citrus essential oils by HPLC-UV-MS on oxygenated heterocyclic components. AB - Citrus essential oils are widely applied in food industry as the backbone of citrus flavors. Unfortunately, due to relatively simple chemical composition and tremendous price differences among citrus species, adulteration has been plaguing the industry since its inception. Skilled blenders are capable of making blends that are almost indistinguishable from authentic oils through conventional gas chromatography analysis. A reversed-phase high performance liquid chromatography (HPLC) method was developed for compositional study of nonvolatile constituents in essential oils from major citrus species. The nonvolatile oxygenated heterocyclic components identified in citrus oils were proved to be more effective as markers in adulteration detection than the volatile components. Authors are hoping such an analysis procedure can be served as a routine quality control test for authenticity evaluation in citrus essential oils. PMID- 28911444 TI - Characterization and determination of antioxidant components in the leaves of Camellia chrysantha (Hu) Tuyama based on composition-activity relationship approach. AB - Camellia chrysantha (Hu) Tuyama (CCT), an ornamental plant possessing antioxidant activity, has been infused as tea and drank for its health benefits. The antioxidant components in CCT, however, had not been clearly characterized. To quickly identify the antioxidant constituents of CCT, a composition-activity relationship strategy based on ultra high-pressure liquid chromatography coupled with linear ion trap hybrid orbitrap mass spectrometry and orthogonal partial least-squares method has been applied. As a result, 16 variables were found to make significant contributions to the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. Six of them were identified as catechin (1), epicatechin (5), vitexin (8), isovitexin (10), quercetin-7-O-beta-D-glucopyranoside (12) and kaempferol (16). The strength of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity was found to be 12 > 1 > 5 > 16 > 8 > 10 by validation test. Meanwhile, a liquid chromatography-electrospray ionization-mass spectrometry method was established for quantitative determination of six marker compounds in CCT samples from different preparations. The validation of the method, including linearity, sensitivity (limitation of detection and limitation of quantification), repeatability, precision, stability, and recoveries, was carried out and demonstrated to meet the requirements of quantitative analysis. This is the first report on the comprehensive characterization and determination of chemical constituents in CCT by ultra high-pressure liquid chromatography coupled with linear ion trap hybrid orbitrap mass spectrometry. The results indicate that the composition-activity relationship approach may be a useful method for the discovery of active constituents in natural plants and the quality control of medicinal herbs. PMID- 28911445 TI - Inhibitory activity of Sargassum hemiphyllum sulfated polysaccharide in arachidonic acid-induced animal models of inflammation. AB - Sargassum hemiphyllum is a common plant found on the coasts of Taiwan; it has been used as an anti-inflammatory agent in traditional herbal medicine. This study aimed to evaluate the anti-inflammatory effects of S. hemiphyllum sulfated polysaccharide (SHSP) using two different mouse models. In both arachidonic acid induced ear inflammatory gavage and paint models, SHSP decreased ear swelling and erythema. In addition, SHSP decreased the production of myeloperoxidase, nitric oxide, interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in a dose-dependent manner. Histological examination results showed that SHSP reduced the area of neutrophilic infiltration in inflamed ears. The anti-inflammatory activity of SHSP has already been demonstrated in vitro. In this study, SHSP extracted from the same species of brown seaweed exhibited anti-inflammatory activity in both oral and topical applications in vivo. Therefore, SHSP may play a role in the treatment of inflammatory diseases. PMID- 28911446 TI - Antioxidant and antiacetylcholinesterase activities of Sorbus torminalis (L.) Crantz (wild service tree) fruits. AB - In this study, the antioxidant and antiacetylcholinesterase activities of Sorbus torminalis (L.) Crantz fruits were evaluated. Total phenolic and flavonoid compounds, 2,2'-azino-bis (3-ethylbenzothioazoline-6-sulfonic acid), 2,2' diphenyl-1-picrylhydrazyl, and superoxide anion radicals scavenging activities and ferric-reducing antioxidant power of water, ethyl acetate, acetone, and methanol extracts were determined for the measurement of the antioxidant activity. Quercetin and alpha-tocopherol were used as standard antioxidants. The inhibitory effect of the water extract on acetylcholinesterase (AChE) was evaluated using the Ellman method and galantamine was used as a standard. Water extract had the highest total phenolic concentration and the strongest antioxidant activity followed by ethyl acetate and acetone extracts whereas methanol extract has the lowest phenolics and weakest antioxidant activity. Moreover, water extract showed moderate ability to inhibit AChE. It was concluded that fruits of S. torminalis have antioxidant and anti-AChE activities and that the plant might be a natural source of antioxidants and AChE inhibitors. PMID- 28911447 TI - Finding of polysaccharide-peptide complexes in Cordyceps militaris and evaluation of its acetylcholinesterase inhibition activity. AB - Acetylcholinesterase (AChE) inhibition enhances learning and cognitive ability for treatment of Alzheimer's disease. Polysaccharide-peptide complexes were identified in Cordyceps militaris (CPSPs) and characterized for their AChE inhibitory properties. Three polymers (CPSP-F1, -F2, and -F3) were extracted and separated by ultrasound-assisted extraction and diethylaminoethanol (DEAE) Sepharose CL-6B column chromatography. Polysaccharide-peptide complexes were identified by DEAE-Sepharose CL-6B column chromatography and high-performance gel filtration chromatography, Fourier transform infrared spectra, amino sugar composition analysis, and beta-elimination reaction to identify polysaccharide peptide bond categories. Separation of CPSP can increase AChE inhibitory activity from the crude polysaccharide of C. militaris. CPSP-F1 and CPSP-F2 exhibited half maximal inhibitory concentrations of 32.2 +/- 0.2 mg/mL and 5.3 +/- 0.0 mg/mL. Thus, we identified polysaccharide-peptide complexes from C. militaris and suggest CPSP has great potential in AChE inhibition bioassay. PMID- 28911448 TI - Analysis of lipophilic compounds of tea coated on the surface of clay teapots. AB - The surface of a clay teapot tends to be coated with a waterproof film after constant use for tea preparation. The waterproof films of two kinds of teapots (zisha and zhuni) used for preparing oolong tea and old oolong tea were extracted and subjected to gas chromatography-mass spectrometry analysis. The results showed that comparable constituents were detected in these films; they were primarily fatty acids and linear hydrocarbons that were particularly rich in palmitic acid and stearic acid. To explore the source of these two abundant fatty acids, the fatty acid compositions of fresh tea leaves, granules, infusion, and vapor of infusion were analyzed by gas chromatography. Fresh tea leaves were rich in palmitic acid (C-16:0), unsaturated linolenic acid (C-18:3), linoleic acid (C 18:2), and oleic acid (C-18:1), which were presumably from the phospholipid membrane. During the process of manufacturing oolong tea, the three unsaturated fatty acids may be substantially degraded or oxidized to stearic acid (C-18:0), which was enriched with palmitic acid in the tea granules and in the infusion. The vapor of the tea infusion is primarily composed of palmitic acid and stearic acid. Thus, the coated films of teapots mostly originated from the lipophilic compounds of the tea infusions. PMID- 28911449 TI - Development of two reference materials for all trans-retinol, retinyl palmitate, alpha- and gamma-tocopherol in milk powder and infant formula. AB - Vitamins are important food constituents that can be present in almost every foodstuff. Food quality and safety depends on food surveillance by reliable quantitative analysis enabled by appropriate quality control. Certified matrix reference materials are versatile tools to support quality assurance and control. However, in the case of vitamins, which are important in various foods, there is a lack of matrix reference materials. Two certified reference materials for the determination of all-trans-retinol, retinyl palmitate, and alpha- and gamma tocopherol in milk powder and infant formula have been developed by the National Institute of Standards, Egypt. This article presents the preparation, characterization, homogeneity, and stability testing as well as statistical treatment of data and certified value assignment. The assignment of the certified values and associated uncertainties in the prepared natural-matrix reference materials were based on the widely used approach of combining data from independent and reliable analytical methods. PMID- 28911450 TI - Major flavonoid constituents and short-term effects of Chun Mee tea in rats. AB - Chun Mee tea is a kind of green tea produced in China mainly for export purposes. Foam quantity is usually used as an index for evaluating the quality of Chun Mee tea. In the current study, we compared the concentrations of total saponin and flavonoids between foamy and low-foam Chun Mee tea. Our research confirmed that the total saponin and O-glycosylated flavonoid concentrations were related to the foam quantity of Chun Mee teas. We also studied the short-term safety effects of extract supplementation with foamy and low-foam Chun Mee tea in rats by routine blood tests and analysis of liver and kidney function, and blood lipids. Our results showed that both types of tea extract supplementations did not cause any observable adverse effects or impair either liver or kidney function. Additionally, this study confirmed the beneficial effects of Chun Mee tea extract supplementation on the decrease of total plasma cholesterol. PMID- 28911451 TI - Safety assessment of menaquinone-7 for use in human nutrition. AB - Vitamin K occurs widely in foods and has been shown to have a beneficial effect on the cardiovascular system, as well as anticancer, anti-inflammatory, and antiosteoporosis properties. A previous study indicates that long-chain menaquinone-7 may be more bioavailable than vitamin K and short-chain menaquinones. In the present study, acute, subacute toxicity and genotoxicity assays were carried out to evaluate the safety of oral menaquinone-7 in albino Wistar rats. Oral administration of menaquinone-7, at a concentration of 2000 mg/kg, did not cause toxic symptoms in either male or female rats. A subacute toxicity study also proved the safety and tolerance of prolonged treatment (for 90 days) with menaquinone-7 in rats, as evidenced by biochemical, hematological, and urine parameters as well as by histopathological analysis. Genotoxicity and mutagenicity studies were performed by comet, micronucleus, and Ames tests on Salmonella typhimurium strains, which showed cellular safety and nonmutagenicity of menaquinone-7. The results indicate the safety of menaquinone-7 for human consumption. PMID- 28911452 TI - A review of quality surveillance projects on cosmetics in Taiwan. AB - The Food and Drug Administration in Taiwan is responsible for the quality regulation and control of cosmetics. In order to have a clear understanding of the trends in the product quality monitoring outcomes and the regulatory control measures over the past years, this study has put together the reports of nine cosmetic surveillance projects conducted between 1982 and 2012. The findings can be used as a reference in developing a more solid quality monitoring plan and management system for cosmetic products. Results show that permanent wave products, hair dye products, and phthalate esters in cosmetic products have the highest average noncompliance rates at 39.2%, 14.2%, and 11.2%, respectively. These are followed by the average noncompliance rates of mercury in products, sunscreen products, and microorganisms in products, at 8.5%, 7.1%, and 5.5%, respectively, and the remaining three projects averaging below 4.1%. Since 1997, when new standards were announced and assistance to manufacturers was reinforced, the noncompliance rates of permanent wave products decreased annually, until 2007, when it was fully qualified for the standards. Overall, the study showed that the noncompliance rates of permanent wave products and for levels of phthalate esters, mercury, and hydroquinone in cosmetic products have all decreased in the previous years. The results of surveillance projects conducted after 2005 revealed only one noncompliance sample with lead, arsenic, and cadmium, whereas the surveillance projects on permanent wave products and chloroform- and 1,4-dioxane-containing products revealed full compliance with regulation standards. However, the noncompliance rates for microorganisms in cosmetics and the ingredients in hair dye products and sunscreen products were still high. These high-risk products must be monitored. These surveillance projects are conducted to ensure the safety of cosmetics in the market. PMID- 28911453 TI - Linearity study on detection and quantification limits for the determination of avermectins using linear regression. AB - In this study, linear relationships between response and concentration were used to estimate the detection limit (DL) and quantification limit (QL) for five avermectins: emamectin, abamectin, doramectin, moxidectin, and ivermectin. Estimation of DL and QL was based on the standard deviation of residual and y intercept of the regression line at low concentrations of avermectins, using the dispersive solid-phase extraction procedure. Avermectin extracts were analyzed using liquid chromatography tandem mass spectrometry. Based on the regression slope, DL and QL were higher at concentrations of 0.3-0.4 MUg/kg and 1 MUg/kg, respectively, for all avermectin compounds. Linearity assessment was performed by linear regression, which incorporated a regression model, outlier rejection, and evaluation of the assumption with a significant test. For all avermectins, there is a significant correlation between response and concentration in the range 1-15 MUg/kg, and the y-intercept passes through origin (zero). PMID- 28911454 TI - Potentiometric monitoring of cobalt in beer sample by solid contact ion selective electrode. AB - A new solid contact cobalt selective electrode was constructed with 4-tert butylthiacalix[4]arene as ionophore. The best performance was observed with the membrane having an ionophore/polyvinyl chloride/sodium tetraphenylborate/nitrophenyl octyl ether ratio of 3.5:33:1.5:62 (w/w; mg). The electrode, under steady-state conditions, exhibited a working concentration range of 1 * 10-1 - 1 * 10-6 mol/L with a near-Nernstian slope of 25.3 mV/decade and a detection limit of 3.5 * 10-7 mol/L. The electrode had a very short response time (<10 seconds) and good reproducibility at a working pH range of 4.0-6.5. The electrode was used for 4 months without any significant change in its sensitivity. The potentiometric performance of the electrode in partially nonaqueous medium [up to 20 % (v/v) alcohol] was found satisfactory. The performance of the prepared electrode for the analysis of beer samples using direct potentiometric method is very encouraging. PMID- 28911455 TI - Ionic liquid-based hollow fiber-supported liquid-phase microextraction enhanced electrically for the determination of neutral red. AB - A method of ionic liquid-based hollow fiber liquid-phase microextraction enhanced electrically was successfully developed and applied to the extraction and determination of neutral red (NR) dye, which was selected as the model analyte. A room temperature ionic liquid, 1-octyl-3-methylimidazolium hexafluorophosphate ([C8mim][PF6]), was placed in the pores of a polytetrafluoethylene hollow fiber, which acts as a liquid membrane and the acceptor solution. The extraction parameters affecting the enrichment factor of NR, such as pH, extraction time, elution time, stirring rate, and the voltage were optimized. In addition, UV Visible (UV-Vis) or electrochemiluminescence spectra were also determined. The extraction rate and capacity of NR could be improved significantly by cathodic polarization. Under the optimized extraction conditions (organic liquid microextraction phase [C8mim][PF6], pH 7, stirring rate 300 rpm, extraction time 20 minutes, ultrasonic-assisted elution time 3 minutes, voltage -70 V), the detection limit of 0.38 MUg/L and linear correlation coefficient of r > 0.99 were obtained. The established method was successfully applied to the analysis of three soft drink samples, which were spiked with NR standards at the concentrations of 0.1, 1.0, and 5.0 mg/L, and satisfactory results were obtained. PMID- 28911456 TI - Sulfur compounds identification and quantification from Allium spp. fresh leaves. AB - BACKGROUND: Pyruvic acid concentration is a critical factor in determining Allium spp. pungency. This study was initiated to accurately measure the background pyruvic acid levels in Romanian Allium spp. From the pungency point of view, all analyzed plant varieties in this study are considered low pungent cultivars based on the enzymatically produced pyruvate level (between 42 MUmol/g and 222 MUmol/g fresh wt). Chromatographic analysis was carried out for the different varieties of the most popular fresh leaves (Allium cepa var. "Diamant", Allium cepa var. "Rubiniu", and Allium ursinum L.) in order to identify the sulfur compounds. The thin layer chromatography analysis led to the identification of allicin, with Rf = 0.377-0.47, as an important sulfur compound. The gas chromatography-mass spectrometry analysis of the leaves' extracts detected disulfides as the major sulfur compounds. Principal component analysis was performed to establish the differences in plant composition. These studies suggest the potential good uses of the fresh leaves of Romanian Allium spp. as condiment, ingredient, or preservative in the food industry. PMID- 28911457 TI - Characterization of odor-active compounds in cooked meat of farmed obscure puffer (Takifugu obscurus) using gas chromatography-mass spectrometry-olfactometry. AB - The volatile and odor-active compounds in cooked meat of farmed obscure puffer (Takifugu obscurus) were analyzed by gas chromatography-mass spectrometry olfactometry (GC-MS-O). The volatile compounds were extracted by the simultaneous distillation-extraction (SDE) method, then separated and identified by GC-MS. Odor-active compounds in the SDE extract were characterized by GC-MS-O. A total of 68 volatile compounds were found, including 23 aldehydes, 10 alcohols, nine ketones, 17 N- or S-containing compounds and aromatics, three acids, three alkanes, and three esters. Of these, 31 odor-active compounds were detected and identified. Trimethylamine (fishy), octanal (grassy, leafy, green), (E)-2-octenal (roast, fatty), 1-octen-3-ol (fishy, fatty, mushroom, grassy), 2-ethyl-1 hexanethiol (cooked fish), (E,E)-2,4-octadienal (cooked meat, sweet), 2 acetylthiazole (meaty, roast, nutty, sulfur), 2-acetylpyrrole (nutty, walnut, bread) were identified as the key odorants in the cooked meat of farmed obscure puffer based on posterior intensity and time-intensity methods. PMID- 28911458 TI - Total nutritional capacity and inflammation inhibition effect of Acalypha alnifolia Klein ex wild-An unexplored wild leafy vegetable. AB - Investigation of the nutritional as well as trace elements of a wild leafy vegetable, Acalypha alnifolia, and evaluation of the analgesic, anti inflammatory, and antipyretic properties of acetone and methanol leaf extracts are the main objectives of the present study. The powdered A. alnifolia leaf sample was subjected to nutritional and mineral analysis. Plant leaves were extracted (using the Soxhlet apparatus) as successive solvent extractions. The extract doses of 200 and 400 mg/kg of acetone and methanol extracts were used for pharmacology study. The analgesic, anti-inflammatory, and antipyretic experiments were carried out by using animal models. The obtained result proves that the plant possesses essential nutritive values and useful biological properties. The higher dose of acetone extract has significant potency when compared with methanol extract at p < 0.005. On the whole, the plant is rich in minerals and has good biological properties; hence, this plant is suggested for cultivation and regular use for nutritional supplement. PMID- 28911459 TI - Clove (Syzygium aromaticum) ingredients affect lymphocyte subtypes expansion and cytokine profile responses: An in vitro evaluation. AB - Clove (Syzygium aromaticum) has been used in folk medicine in many disorders. The present work aimed to investigate effects of clove essential oil as eugenol and water soluble ingredients on mouse splenocytes. Clove extracts were harvested and in different concentrations (0.001-1000 MUg/mL) were affected to splenocytes and also phytohemagglutinin (PHA = 5 MUg/mL) and lipopolysaccharide (LPS = 10 MUg/mL) activated splenocytes; then splenocytes proliferation assayed using the MTT ([3 (4, 5-dimethylthiazole-2-yl) -2, 5-diphenyl tetrazolium bromide]) method were done. On the culture supernatant interferon (IFN)-gamma, interleukin (IL)-4, IL 10, and transforming growth factor (TGF)-beta cytokines were measured. Clove ingredients (100 MUg/mL and 1000 MUg/mL) reduced PHA stimulated splenocytes proliferation and enhanced LPS stimulated cells expansion. Treated splenocytes showed suppression of IFN-gamma release and induction of IL-4, IL-10, and TGF beta secretion (in the range of 0.1-1000 MUg/mL). The results of this study suggest clove extracts could suppress the T cell cellular immunity and enhance humoral immune responses. In clove affection cytokine pattern shifted toward modulatory and Th2 responses and accelerator of humoral immunity cytokines. PMID- 28911460 TI - Dolichos biflorus exhibits anti-inflammatory and antioxidant properties in an acute inflammatory model. AB - Dolichos biflorus (Muthira) is a branched, suberect, and downing herb, native to most parts of India, and found at altitudes of up to 1000 m, whose seeds can be cooked and eaten. Nutrition plays a key role in building immunity and preventing noncommunicable diseases to a certain extent. The purpose of this study was to evaluate the anti-inflammatory and antioxidant effects of 70% methanolic extract of seeds of D. biflorus (DME) in carrageenan-induced inflammation. DME exhibited maximum percentage of oedema inhibition at a dose of 50 mg/kg at the 3rd hour of carrageenan induction. The effect was higher than that of the standard drug Voveran. The activities of cyclooxygenase, lipoxygenase, nitric oxide synthase, myeloperoxidase, and malondialdehyde showed significant (p < 0.05) reduction whereas the activities of antioxidant enzymes, vitamins C, and reduced glutathione level were increased significantly (p < 0.05) on treatment with DME. Also levels of the acute phase protein, ceruloplasmin, were brought to their normal range in DME-treated rats. Phytochemical analysis showed that the extract contains alkaloids, flavonoids, carbohydrates, proteins, and tannins, which may contribute to its anti-inflammatory and antioxidant activity. Thus the results demonstrate the potential beneficiary effect of DME on carrageenan-induced inflammation in rats. PMID- 28911461 TI - Regulation of human cytokines by Cordyceps militaris. AB - Cordyceps (Cordyceps militaris) exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits). In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses) on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor alpha, and a significant downregulation of interleukin-12(p70), interferon-gamma inducible protein 10, and macrophage inflammatory protein-1beta activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines. PMID- 28911462 TI - Optimization of fermentation process of Cordyceps militaris and antitumor activities of polysaccharides in vitro. AB - The influence of medium composition and cultural conditions on simultaneous yield of mycelia, intracellular polysaccharide, adenosine, and mannitol by Cordyceps militaris CGMCC 2909 was investigated with desirability functions in this study. An optimization strategy based on the desirability function approach, together with response surface methodology (RSM) has been used to optimize medium composition, and the optimal medium was obtained via the desirability as follows: yeast extract 10.33 g/L, sucrose 27.24 g/L, KH2PO4 5.60 g/L and the optimal culture conditions are initial pH 6, 25 degrees C, rotation speed 150 r/minute, inoculum size 4%(v/v), and medium capacity 40 mL/250 mL. Under these conditions, the yield of mycelia, intracellular polysaccharide, adenosine and mannitol reached 12.19 g/L, 0.6 g/L, 61.84 mg/L, and 1.38 g/L, respectively, and the D value was 0.77. Furthermore, the polysaccharides showed significant antitumor activities against HeLa and HepG2 in vitro in a dose-dependent manner in 72 hours. At a concentration of 1000 mg/mL, the inhibition rate of polysaccharides was 92.38% and 98.79%. The IC50 for HeLa and HepG2 were 70.91 MUg/mL and 97.63 MUg/mL, respectively. PMID- 28911463 TI - Hypocholesterolemic properties of grapefruit (Citrus paradisii) and shaddock (Citrus maxima) juices and inhibition of angiotensin-1-converting enzyme activity. AB - Grapefruit (Citrus paradisii) and shaddock (Citrus maxima) juices are used in folk medicine for the management of hypertension and other cardiovascular diseases, but the mechanism of action by which they exert their therapeutic action is unclear. The aim of this study was to investigate the effect of grapefruit and shaddock juices on angiotensin-1-converting enzyme (ACE) activity in vitro and the hypocholesterolemic properties of the juices in rats fed a high cholesterol diet. Grapefruit juice had higher total phenol and flavonoid contents than shaddock juice, while both juices inhibited ACE activity in a dose-dependent manner. Furthermore, administration of the juices to rats fed a high-cholesterol diet caused a significant reduction in plasma total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels and an increase in high-density lipoprotein-cholesterol levels. The inhibition of ACE activity in vitro and in vivo hypocholesterolemic effect of the juices could explain the use of the juices in the management of cardiovascular diseases. PMID- 28911464 TI - Effect of gamma-aminobutyric acid and nattokinase-enriched fermented beans on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats. AB - In this study we have evaluated the changes in arterial blood pressure in spontaneously hypertensive rats (SHR) caused by the short-term intake of Bacillus subtilis B060-fermented beans with significant gamma-aminobutyric acid (GABA) and nattokinase activity. After being weaned, 7-week-old male SHR and 7-week-old male Wistar-Kyoto (WKY) rats were randomized into seven groups. Until the 8th week of life, the rats in each group were given one of the following: Group 1, high dose of GABA and nattokinase in the SHR (SHD); Group 2, medium dose of GABA and nattokinase in the SHR (SMD); Group 3, low dose of GABA and nattokinase in the SHR (SLD); Group 4, negative control in the SHR (SD); Group 5, positive control in the SHR (SM); Group 6, high dose of GABA and nattokinase in the WKY (WHD); and Group 7, negative control in the WKY (WD). Distilled water served as the negative control, and captopril (50 mg/kg), a known ACE inhibitor, served as the positive control. Systolic blood pressure and diastolic blood pressure values were measured weekly from the 8th week to the 16th week of life using the tail-cuff method. A definite decrease in systolic and diastolic blood pressure values could be observed in the rats treated with captopril and in the rats that received GABA and nattokinase. The greatest antihypertensive effect was observed when the pharmacological treatment was administered. The effect of the daily intake of fermented beans containing GABA and nattokinase may be helpful in controlling blood pressure levels in hypertensive model animals. The fermentation of beans with B. subtilis B060 may therefore constitute a successful strategy for producing a functional food with antihypertensive activity. PMID- 28911465 TI - Extraction of water-soluble polysaccharide and the antioxidant activity from Semen cassiae. AB - Water-soluble polysaccharide was isolated from Semen cassiae using water for extraction and ethanol for deposition. The optimized conditions for polysaccharide isolation by orthogonal experiments were a sample to liquid ratio of 1:30 at 80 degrees C for 3.5 hours; the yield of polysaccharide from Semen cassiae under these conditions was 5.46%. Different polysaccharides (SCPW-1, SCPW 2, SCPW-3, SCPW-4, SCPW-5, SCPS-1, SCPS-2) were obtained from the extract (i.e., crude polysaccharide) by DEAE-cellulose column chromatography. The polysaccharides obtained showed different structures by Fourier transform infrared therein the five elected from the seven kinds separated. The antioxidant activities of the extract were evaluated. The scavenging rates of the present extract on hydroxyl and superoxide were 43.32% and 64.97%, respectively, at a concentration of polysaccharide of 94.03 MUg/mL, which was better than vitamin C at the same concentration. The scavenging rate of the present extract on 1,1 diphenyl-2-picrylhydrazyl was 13.33% at a polysaccharide concentration of 94.03 MUg/mL, which was less than vitamin C at the same concentration. PMID- 28911466 TI - Application of ion mobility spectrometry for the determination of tramadol in biological samples. AB - In this study, a simple and rapid ion mobility spectrometry (IMS) method has been described for the determination of tramadol. The operating instrumental parameters that could influence IMS were investigated and optimized (temperature; injection: 220 and IMS cell: 190 degrees C, flow rate; carrier: 300 and drift: 600 mL/minute, voltage; corona: 2300 and drift: 7000 V, pulse width: 100 MUs). Under optimum conditions, the calibration curves were linear within two orders of magnitude with R2 >= 0.998 for the determination of tramadol in human plasma, saliva, serum, and urine samples. The limits of detection and the limits of quantitation were between 0.1 and 0.3 and 0.3 and 1 ng/mL, respectively. The relative standard deviations were between 7.5 and 8.8%. The recovery results (90 103.9%) indicate that the proposed method can be applied for tramadol analysis in different biological samples. PMID- 28911467 TI - Antioxidant effects of Camellia sinensis L. extract in patients with type 2 diabetes. AB - The prevalence of diabetes mellitus (DM) has dramatically increased in the past decade. Furthermore, increasing evidence from research shows that oxidative stress (OS) plays a crucial role in the pathogenesis of diabetes and in its complications. A search for ways to reduce oxidative damage has become the focus of interest for the majority of scientists. In this study, we determined the radical scavenging activity of single green tea constituents by using an on-line high performance liquid chromatography (HPLC)-2,2-diphenyl-1-picrylhydrazyl (DPPH) method and evaluated the antioxidant effects on type 2 diabetic patients by performing a double-blind, placebo-controlled study. Epigallocatechin gallate was identified as the most potent antioxidant, contributing approximately 50% of the total antioxidant capacity of green tea extract. We also found a statistically significant decrement of lipid peroxidation markers in patients treated with green tea extract after 9 months or after 18 months of follow-up. Overall, these findings are attractive for diabetic patients, helping them to keep a high level of performance and well-being, which ultimately may delay the time of disability and reduce mortality. PMID- 28911468 TI - Voltammetric determination of chlorogenic acid in pharmaceutical products using poly(aminosulfonic acid) modified glassy carbon electrode. AB - In this work, a poly(aminosulfonic acid) modified glassy carbon electrode was fabricated and the electrochemical behavior of chlorogenic acid (CGA) was studied by cyclic voltammetry. Compared with a bare glassy carbon electrode, the modified electrode exhibits excellent catalytic effect on the electrochemical redox of CGA. Utilizing this catalytic effect, a sensitive and selective electrochemical method for the determination of CGA was developed. The analytical parameters were optimized. Under the optimized conditions, the oxidation peak current is linearly proportional to the concentration of CGA in the range from 4.00 * 10-7 to 1.20 * 10-5 mol/L and the detection limit is 4.00 * 10-8 mol/L. Further, the performance of the proposed method has been validated in terms of linearity (r = 0.9995), recovery (96.3-102.8%), reproducibility (RSD < 4.0%, n = 6) and robustness. The developed method has been successfully applied for the determination of CGA in a variety of pharmaceutical products. PMID- 28911469 TI - Analytical method development and validation of simultaneous estimation of rabeprazole, pantoprazole, and itopride by reverse-phase high-performance liquid chromatography. AB - A simple, selective, rapid, and precise reverse-phase high-performance liquid chromatography (RP-HPLC) method for the simultaneous estimation of rabeprazole (RP), pantoprazole (PP), and itopride (IP) has been developed. The compounds were well separated on a Phenomenex C18 (Luna) column (250 mm * 4.6 mm, dp = 5 MUm) with C18 guard column (4 mm * 3 mm * 5 MUm) with a mobile phase consisting of buffer containing 10 mM potassium dihydrogen orthophosphate (adjusted to pH 6.8): acetonitrile (70:30 v/v) at a flow rate of 1.0 mL/min and ultraviolet detection at 288 nm. The retention time of RP, PP, and IP were 5.35, 7.92, and 11.16 minutes, respectively. Validation of the proposed method was carried out according to International Conference on Harmonisation (ICH) guidelines. Linearity range was obtained for RP, PP, and IP over the concentration range of 2.5-25, 1-30, and 3-35 MUg/mL and the r2 values were 0.994, 0.978, and 0.991, respectively. The calculated limit of detection (LOD) values were 1, 0.3, and 1 MUg/mL and limit of quantitation (LOQ) values were 2.5, 1, and 3 MUg/mL for RP, PP, and IP correspondingly. Thus, the current study showed that the developed reverse-phase liquid chromatography method is sensitive and selective for the estimation of RP, PP, and IP in combined dosage form. PMID- 28911470 TI - Electrochemistry and determination of cefdinir by voltammetric and computational approaches. AB - The oxidation and reduction behavior of cefdinir (CEF) was studied by experimental methods and computational calculations at B3LYP/6-31+G (d)//AM1. Voltammetric studies were carried out based on two irreversible reduction peaks at approximately -0.5 and -1.2 V on a hanging mercury drop electrode (HMDE) and on one irreversible oxidation peak at approximately 1.0 V on a glassy carbon electrode (GCE) versus Ag/AgCl, KCl (3.0M) in Britton-Robinson (BR) buffer at pH 4.2 and 5.0, respectively. Differential pulse adsorptive stripping voltammetric methods have been developed and validated for determination of CEF in different samples. The linear range was established as 0.25-40.0 MUM for HMDE and 0.40-10.0 MUM for GCE. Limit of quantification was calculated to be 0.20 and 0.26 MUM for HMDE and GCE, respectively. These methods were successfully applied to assay the drug in tablets and human serum with good recoveries between 92.7% and 107.3% having relative standard deviation less than 10%. PMID- 28911471 TI - Determination of L-arginine content in Radix isatidis by a composite fluorescent probe of Pd (II). AB - In the presence of Britton-Robinson buffer solution (pH = 9.5) and surfactant of Tween-80, fluorescence intensity of calcein was quenched by Pd2+. However, the fluorescence intensity can be enhanced after adding a certain concentration of L arginine, and the rate of the enhancement showed a good liner relationship with the added amount of L-arginine. We then established a fluorescence spectrometry for the determination of L-arginine. In addition, the linear range, along with detection limit, was different when the slit width changed. Thus, we could use a different slit width to meet our requirements according to the samples we treated. By testing actual samples and the reliability of our method, we found that our method was reliable for determining the content of L-arginine in Radix isatidis. PMID- 28911472 TI - Formulation and evaluation of controlled-release of telmisartan microspheres: In vitro/in vivo study. AB - The aim of this work was to design a controlled-release drug-delivery system for the angiotensin-II receptor antagonist drug telmisartan. Telmisartan was encapsulated with different EUDRAGIT polymers by an emulsion solvent evaporation technique and the physicochemical properties of the formulations were characterized. Using a solvent evaporation method, white spherical microspheres with particle sizes of 629.9-792.1 MUm were produced. The in vitro drug release was studied in three different pH media (pH 1.2 for 2 hours, pH 6.8 for 4 hours, and pH 7.4 for 18 hours). The formulations were then evaluated for their pharmacokinetic parameters. The entrapment efficiency of these microspheres was between 58.6% and 90.56%. The obtained microspheres showed good flow properties, which were evaluated in terms of angle of repose (15.29-26.32), bulk and tapped densities (0.37-0.53 and 0.43-0.64, respectively), Carr indices and Hausner ratio (12.94-19.14% and 1.14-1.23, respectively). No drug release was observed in the simulated gastric medium up to 2 hours; however, a change in pH from 1.2 to 6.8 increased the drug release. At pH 7.4, formulations with EUDRAGIT RS 100 showed a steady drug release. The microsphere formulation TMRS-3 (i.e., microspheres containing 2-mg telmisartan) gave the highest Cmax value (6.8641 MUg/mL) at 6 hours, which was three times higher than Cmax for telmisartan oral suspension (TOS). Correspondingly, the area under the curve for TMRS-3 was 8.5 times higher than TOS. Particle size and drug release depended on the nature and content of polymer used. The drug release mechanism of the TMRS-3 formulation can be explained using the Higuchi model. The controlled release of drug from TMRS-3 also provides for higher plasma drug content and improved bioavailability. PMID- 28911473 TI - Binding interactions of niclosamide with serum proteins. AB - A study of the binding of niclosamide (NC) to serum proteins such as human serum albumin, hemoglobin, and globulin was carried out using fluorescence and UV visible spectroscopy. Interactions between NC and these proteins were estimated by Stern-Volmer and van't Hoff equations. The binding constants and the thermodynamic parameters, DeltaH, DeltaS, and DeltaG at different temperatures were also determined by using these equations. Data showed that NC may exhibit a static quenching mechanism with all proteins. The thermodynamic parameters were calculated. Data showed that van der Waals interactions and hydrogen bonds are the main forces for human serum albumin and hemoglobin. Globulin, however, bound to NC via hydrophobic interaction. The spectral changes of synchronous fluorescence suggested that both the microenvironment of NC and the conformation of the proteins changed in relation to their concentrations during NC's binding. PMID- 28911474 TI - Use of a failure probability constraint to suggest an initial dose in a phase I cancer clinical trial. AB - The primary objective of a Phase I cancer clinical trial is to determine the maximum tolerated dose of a drug. The "failure probability" was proposed and used as a constraint to help identify a suitable initial dose range. The maximum tolerated dose was then determined based on a 3 + 3 cohort-based escalation scheme. Multiple simulations were conducted, and the method was evaluated according to the required sample size and accuracy and precision of maximum tolerated dose estimate. The results indicated that the median of the initial dose range suggested using a failure probability is a suitable initial dose regardless of the dose escalation sequence used for a cancer Phase I study. This initial dose required a smaller sample size and resulted in less bias of the estimated maximum tolerated dose compared with a commonly used initial dose, that is, 10% of the lethal dose. We tested our approach using real dose and toxicity outcome data from two published Phase I studies. These results indicate that adding a failure probability constraint into the calculation of the initial dose range will improve the efficiency of Phase I cancer trials. PMID- 28911475 TI - Recent trends in specialty pharma business model. AB - The recent rise of specialty pharma is attributed to its flexible, versatile, and open business model while the traditional big pharma is facing a challenging time with patent cliff, generic threat, and low research and development (R&D) productivity. These multinational pharmaceutical companies, facing a difficult time, have been systematically externalizing R&D and some even establish their own corporate venture capital so as to diversify with more shots on goal, with the hope of achieving a higher success rate in their compound pipeline. Biologics and clinical Phase II proof-of-concept (POC) compounds are the preferred licensing and collaboration targets. Biologics enjoys a high success rate with a low generic biosimilar threat, while the need is high for clinical Phase II POC compounds, due to its high attrition/low success rate. Repurposing of big pharma leftover compounds is a popular strategy but with limitations. Most old compounds come with baggage either in lackluster clinical performance or short in patent life. Orphan drugs is another area which has gained popularity in recent years. The shorter and less costly regulatory pathway provides incentives, especially for smaller specialty pharma. However, clinical studies on orphan drugs require a large network of clinical operations in many countries in order to recruit enough patients. Big pharma is also working on orphan drugs starting with a small indication, with the hope of expanding the indication into a blockbuster status. Specialty medicine, including orphan drugs, has become the growth engine in the pharmaceutical industry worldwide. Big pharma is also keen on in-licensing technology or projects from specialty pharma to extend product life cycles, in order to protect their blockbuster drug franchises. Ample opportunities exist for smaller players, even in the emerging countries, to collaborate with multinational pharmaceutical companies provided that the technology platforms or specialty medicinal products are what the big pharma wants. The understanding of intellectual properties and international drug regulations are the key for specialty pharma to have a workable strategy for product registration worldwide. PMID- 28911476 TI - Camel milk as a potential therapy for controlling diabetes and its complications: A review of in vivo studies. AB - Diabetes is a condition in which there is an elevation of blood glucose. Insulin, which is produced by the pancreas, is an important hormone needed by the body because it enables glucose to be transported into cells. Under the diabetic condition, the cells may not respond properly to insulin or the body does not produce a sufficient amount of insulin, or both. This situation will cause glucose accumulation in the blood that leads to major complications. Oral insulin therapy has been used for many years; however, coagulation in an acidic environment decreases the efficacy of insulin by neutralizing its actions. Several researchers have found that camel milk can be an adjunct to insulin therapy. It appears to be safe and effective in improving long-term glycemic control. Therefore, the aim of this study was to review in vivo studies on the effect of camel milk as a potential therapy for controlling diabetes and its complications such as high cholesterol levels, liver and kidney disease, decreased oxidative stress, and delayed wound healing. PMID- 28911477 TI - Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review. AB - Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug loaded nanoparticles are applied. PMID- 28911478 TI - Separation and speciation analysis of zinc from Flammulina velutipes. AB - Orthogonal experiment was applied to optimize the water extraction parameters of zinc from Flammulina velutipes, and then the extracts were separated by membrane filter (0.45 MUm) and D101 macroporous resin. Six different species of Zn were obtained and the Zn content of various species were determined by flame atomic absorption spectrometry. The optimized conditions for the extraction of Zn were: ratio of dried material to water, 1:30; extraction temperature, 75 degrees C; extraction time, 120 minutes. About 34.43 MUg Zn was extracted from 1 g dried F. velutipes powder under the optimal conditions. The recovery value for Zn was 96.5% with a low relative standard deviation. In addition, the content of the organic state of Zn was more than that of the inorganic state, and most of the organic state Zn was found in the polysaccharide and protein fractions. PMID- 28911479 TI - Determination of cholesterol and four phytosterols in foods without derivatization by gas chromatography-tandem mass spectrometry. AB - In this study, a method for determination of cholesterol and four phytosterols by gas chromatography coupled with electron impact ionization mode-tandem mass spectrometry without derivatization in general food was developed. The sample was saponified with 7.5% KOH in methanol. After heating on hot plate and reflux for 60 minutes, the saponified portion was extracted with n-hexane/petroleum ether (50:50, v/v). The extracts were evaporated with rotary evaporator and then redissolved with tetrahydrofuran. The tetrahydrofuran layer was transferred into an injection vial and analyzed by gas chromatography on a 30 m VF-5 column. Limit of quantification was 2 mg/kg. Recoveries of cholesterol and four phytosterols from general food were between 91% and 100%. PMID- 28911480 TI - Determination of oligosaccharides and monosaccharides in Hakka rice wine by precolumn derivation high-performance liquid chromatography. AB - This article presents a precolumn derivatization procedure with 1-phenyl-3-methyl 5-pyrazolone (PMP) reagent to detect oligosaccharides and monosaccharides in Hakka rice wine. The subsequent separation of the derivatized glucose-PMP also was performed using a mobile phase consisting of the molar ratio of acetonitrile to ammonium acetate buffer (0.1M) of 22:78 at a flow rate of 1.0 mL/min with the column temperature of 35 degrees C, and the pH of ammonium acetate buffer at 5.5. The optimum derivation conditions were as follows: reaction temperature, 70 degrees C; reaction time, 30 minutes; molar ratio of PMP to glucose, 10:1 (v/v); molar ratio of sodium hydroxide to glucose, 3:1 (v/v). The recovery rates were between 93.13% and 102.08% with relative standard deviation of 0.96-2.48%. The established method provides sufficient sensitivity with values of limit of detection of 0.09-0.26 mg/L and limit of quantification of 0.27-0.87 mg/L for determination of oligosaccharides and monosaccharides. PMID- 28911481 TI - A rapid and sensitive spectrophotometric method for the determination of benzoyl peroxide in wheat flour samples. AB - A simple, rapid, and sensitive spectrophotometric method for the determination of benzoyl peroxide (BPO) in wheat flour samples was developed. The detection principle is based on BPO reacted with 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS) to obtain a blue-green colored product that was detected at 415 nm by spectrophotometry. The effect of factors influencing the color reaction was investigated. Under the selected conditions, the linear range for quantification of BPO was observed between 0.2-1.0 mg L-1 with r2 = 0.998. The limit of detection (LOD) was 0.025 mg L-1. The developed method obtained superior precision (relative standard deviation < 2%) using 11 repeatability at 0.2 mg L 1, 0.6 mg L-1, and 0.8 mg L-1. The proposed methodology was successfully applied to determine BPO in wheat flour samples. PMID- 28911482 TI - Identification of biosynthetic intermediates of teaghrelins and teaghrelin-like compounds in oolong teas, and their molecular docking to the ghrelin receptor. AB - Teaghrelins are unique acylated flavonoid tetraglycosides found in Chin-shin oolong tea, and have been demonstrated to be promising oral ghrelin analogues. The biosynthetic pathway of teaghrelins from quercetin-3-O-rutinoside (rutin) or kaempferol-3-O-rutinoside (nicotiflorin) was proposed to comprise three enzymatic steps according to the identification of putative intermediates in Chin-shin oolong tea. In addition to the two known teaghrelins in Chin-shin oolong tea, four teaghrelin-like compounds with different attachments of glycosides were identified in various oolong teas. Molecular modeling and docking were used to evaluate theoretically whether the putative biosynthetic intermediates of teaghrelins and the four teaghrelin-like compounds could be potential candidates of ghrelin analogues. The results showed that the attachment of a coumaroyl group was crucial for these tea compounds to bind to the ghrelin receptor. However, the additional attachment of a rhamnosyl glycoside to the flavonoid backbone of teaghrelin-like compounds at C-7 significantly reduced their binding affinity with the ghrelin receptor. PMID- 28911483 TI - Evaluation of iron-binding activity of collagen peptides prepared from the scales of four cultivated fishes in Taiwan. AB - Iron deficiency is one of the most concerning deficiency problems in the world. It may generate several adverse effects such as iron deficiency anemia (IDA) and reduced physical and intellectual working capacity. The aim of this study is to evaluate the Fe(II)-binding activity of collagen peptides from fishery by products. Lates calcarifer, Mugil cephalus, Chanos chanos, and Oreochromis spp are four major cultivated fishes in Taiwan; thousands of scales of these fish are wasted without valuable utilization. In this study, scales of these fish were hydrolyzed by papain plus flavourzyme. Collagen peptides were obtained and compared for their Fe(II)-binding activity. Collagen peptides from Chanos chanos showed the highest Fe(II)-binding activity, followed by those from Lates calcarifer and Mugil cephalus; that from Oreochromis spp exhibited the lowest one. Fe(II)-binding activity of collagen peptides from fish scales was also confirmed with a dialysis method. Molecular weight (MW) distributions of the collagen peptides from scales of four fish are all < 10 kDa, and averaged 1.3 kDa. Hydrolysates of fish scales were further partially purified with ion exchange chromatography. Fractions having Fe(II)-binding activity were obtained and their activity compared. Data obtained showed that collagen peptides from fish scales did have Fe(II)-binding activity. This is the first observation elucidating fish scale collagen possessing this functionality. The results from this study also indicated that collagen peptides from fish scales could be applied in industry as a bioresource. PMID- 28911485 TI - Quercetin uptake and metabolism by murine peritoneal macrophages in vitro. AB - Quercetin (Q), a bioflavonoid ubiquitously distributed in vegetables, fruits, leaves, and grains, can be absorbed, transported, and excreted after oral intake. However, little is known about Q uptake and metabolism by macrophages. To clarify the puzzle, Q at its noncytotoxic concentration (44MUM) was incubated without or with mouse peritoneal macrophages for different time periods. Medium alone, extracellular, and intracellular fluids of macrophages were collected to detect changes in Q and its possible metabolites using high-performance liquid chromatography. The results showed that Q was unstable and easily oxidized in either the absence or the presence of macrophages. The remaining Q and its metabolites, including isorhamnetin and an unknown Q metabolite [possibly Q- (O semiquinone)], might be absorbed by macrophages. The percentage of maximal Q uptake by macrophages was found to be 2.28% immediately after incubation; however, Q uptake might persist for about 24 hours. Q uptake by macrophages was greater than the uptake of its methylated derivative isorhamnetin. As Q or its metabolites entered macrophages, those compounds were metabolized primarily into isorhamnetin, kaempferol, or unknown endogenous Q metabolites. The present study, which aimed to clarify cellular uptake and metabolism of Q by macrophages, may have great potential for future practical applications for human health and immunopharmacology. PMID- 28911484 TI - Oxidant stress evoked damage in rat hepatocyte leading to triggered nitric oxide synthase (NOS) levels on long term consumption of aspartame. AB - This study investigates how long-term (40 mg/kg b.wt) consumption of aspartame can alter the antioxidant status, stress pathway genes, and apoptotic changes in the liver of Wistar albino rats. Numerous controversial reports are available on the use of aspartame as it releases methanol as one of its metabolites during metabolism. To mimic the human methanol metabolism the methotrexate treated rats were included to study the aspartame effects. The aspartame treated methotrexate (MTX animals showed a marked significant increase in the superoxide dismutase (SOD), catalase (CAT), lipid peroxidation (LPO), and Glutathione peroxidase (GPx) activity in the liver from control and MTX control animals, and showed a significant decrease in reduced glutathione (GSH) and protein thiol in aspartame treated animals. The aspartame treated MTX animals showed a marked significant decrease in the body weight, brain, and liver weight. The aspartame treated MTX animals showed a marked increase in the inducible nitric oxide (iNOS), neuronal nitric oxide (nNOS), c-fos, Heat shock protein (Hsp) 70 Tumour necrosis Factor (TNF)alpha, caspase 8, c-jun N terminal kinases (JNK) 3 and Nuclear factor kappa B (NFkB) gene expression in the liver from control and MTX control animals. The aspartame treated MTX animals showed a marked increase in the c-fos, Hsp 70, iNOS Caspase 8, and JNK 3 protein expression in the liver from control and MTX control animals indicating the enhancement of stress and apoptosis. The aspartame treated MTX animals showed a streak of marked DNA fragmentation in the liver. On immunohistochemical analysis aspartame treated animals showed brown colored positive hepatocytes indicating the stress specific and apoptotic protein expression. Since aspartame consumption is on the rise among people, it is essential to create awareness regarding the usage of this artificial sweetener. PMID- 28911486 TI - Effects of drying on caffeoylquinic acid derivative content and antioxidant capacity of sweet potato leaves. AB - Caffeoylquinic acid (CQA) derivatives are known to possess antioxidative potential and have many beneficial effects on human health. The present study compared the CQA contents and antioxidant activities of aerial parts of sweet potato plants. The effects of drying methods (freeze drying, and drying at 30 degrees C, 70 degrees C, and 100 degrees C) on these two parameters of the first fully expanded leaves were also assessed. The results indicated that the CQA derivatives were detectable in leaves, stem, and flowers of sweet potato plants (varied from 39.34 mg/g dry weight to 154.05 mg/g dry weight), with the leaves (particularly expanding and first fully expanded leaves) containing more CQA derivatives than other aerial plant parts. The expanding and first fully expanded leaves also exhibited greater antioxidant activities than other aerial plant parts, possibly due to their higher contents of CQA derivatives. Drying method significantly affected the content of CQA derivatives in dried sweet potato leaf tissues. Drying treatments at both 70 degrees C and 100 degrees C significantly reduced the CQA derivative content and antioxidant activity in the first fully expanded leaves. Among the tested drying methods, the freeze-drying method demonstrated the preservation of the highest amount of CQA derivatives (147.84 mg/g) and antioxidant property. However, 30 degrees C cool air drying was also a desirable choice (total CQA derivative content was reduced to only 129.52 mg/g), compared to 70 degrees C and 100 degrees C hot air drying, for commercial-scale processing of sweet potato leaves, if the higher operation cost of freeze drying was a major concern. PMID- 28911487 TI - Effects of blending wheatgrass juice on enhancing phenolic compounds and antioxidant activities of traditional kombucha beverage. AB - Traditional kombucha is a fermented black tea extract and sugar. Sweetened black tea (10% w/v) and wheatgrass juice (WGJ) were mixed in various ratios and used as fermentation substrate for enhancing phenolic compounds and antioxidant activity. Starter, comprising of yeast (Dekkera bruxellensis) and acetic acid bacteria (Gluconacetobacter rhaeticus and Gluconobacter roseus), was inoculated at 20% (v/v), and fermented statically at 29 +/- 1 degrees C for 12 days. The results showed that the total phenolic and flavonoid contents and antioxidant activity of the modified kombucha were higher than those of traditional preparations. All WGJ blended kombucha preparations were characterized as having higher concentrations of various phenolic compounds such as gallic acid, catechin, caffeic acid, ferulic acid, rutin, and chlorogenic acid as compared to traditional ones. Addition of WGJ resulted in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability of kombucha being > 90%, while the oxygen radical absorbance capacity increased from 5.0 MUmol trolox equivalents/mL to 12.8 MUmol trolox equivalents/mL as the ratio of WGJ increased from 0% to 67% (v/v). The highest antioxidant activity was obtained using a 1:1 (v/v) black tea decoction to WGJ ratio and 3 days of fermentation, producing various types of phenolic acids. These results suggest that intake of fermented black tea enhanced with wheatgrass juice is advantageous over traditional kombucha formulas in terms of providing various complementary phenolics and might have more potential to reduce oxidative stress. PMID- 28911488 TI - Effects of red mold dioscorea with pioglitazone, a potentially functional food, in the treatment of diabetes. AB - The prevalence of type 2 diabetes mellitus is increasing rapidly, and its treatment with pioglitazone is likely to induce rhabdomyolysis. We aimed to determine the effect of cotreatment with pioglitazone and red mold dioscorea (RMD) produced by Monascus purpureus NTU 568 on pancreas function in streptozotocin (STZ)-induced diabetic rats. In diabetic rats fed RMD, RMD with pioglitazone, and pioglitazone alone, insulin concentrations increased significantly by 18.6-40.4%, 64.0-100.0%, and 52.8%, respectively, compared with that in the diabetic group (p < 0.05). Oral glucose tolerance was impaired in the STZ-induced diabetic group within 4 weeks, however, oral glucose tolerance in rats treated with RMD or RMD with pioglitazone improved after 4 weeks, 6 weeks, and 8 weeks. Findings from this study might lend support to the use of RMD as a novel functional food for the prevention of diabetes. PMID- 28911489 TI - Effects of electrode settings on chlorine generation efficiency of electrolyzing seawater. AB - Electrolyzed water has significant disinfection effects, can comply with food safety regulations, and is environmental friendly. We investigated the effects of immersion depth of electrodes, stirring, electrode size, and electrode gap on the properties and chlorine generation efficiency of electrolyzing seawater and its storage stability. Results indicated that temperature and oxidation-reduction potential (ORP) of the seawater increased gradually, whereas electrical conductivity decreased steadily in electrolysis. During the electrolysis process, pH values and electric currents also decreased slightly within small ranges. Additional stirring or immersing the electrodes deep under the seawater significantly increased current density without affecting its electric efficiency and current efficiency. Decreasing electrode size or increasing electrode gap decreased chlorine production and electric current of the process without affecting its electric efficiency and current efficiency. Less than 35% of chlorine in the electrolyzed seawater was lost in a 3-week storage period. The decrement trend leveled off after the 1st week of storage. The electrolyzing system is a convenient and economical method for producing high-chlorine seawater, which will have high potential applications in agriculture, aquaculture, or food processing. PMID- 28911490 TI - Effects of process conditions on chlorine generation and storage stability of electrolyzed deep ocean water. AB - Electrolyzed water is a sustainable disinfectant, which can comply with food safety regulations and is environmentally friendly. We investigated the effects of platinum plating of electrode, electrode size, cell potential, and additional stirring on electrolysis properties of deep ocean water (DOW) and DOW concentration products. We also studied the relationships between quality properties of electrolyzed DOW and their storage stability. Results indicated that concentrating DOW to 1.7 times increased chlorine level in the electrolyzed DOW without affecting electric and current efficiencies of the electrolysis process. Increasing magnesium and potassium levels in DOW decreased chlorine level in the electrolyzed DOW as well as electric and current efficiencies of the electrolysis process. Additional stirring could not increase electrolysis efficiency of small electrolyzer. Large electrode, high electric potential and/or small electrolyzing cell increased chlorine production rate but decreased electric and current efficiencies. High electrolysis intensity decreased storage stability of the electrolyzed seawater and the effects of electrolysis on DOW gradually subsided in storage. DOW has similar electrolysis properties to surface seawater, but its purity and stability are better. Therefore, electrolyzed DOW should have better potential for applications on postharvest cleaning and disinfection of ready-to-eat fresh produce. PMID- 28911491 TI - Nutritional and nutraceutical characteristics of Sageretia theezans fruit. AB - The fruit of Sageretia theezans is one of many underutilized edible fruits that grow along the southern seashores of East Asia. In this study, to evaluate the nutritional and nutraceutical values of S. theezans fruit, the composition of minerals, organic acids, and proximate and fatty acids, the total phenolic, total flavonoid, and total anthocyanin content, and the antioxidant and antidiabetic activities of S. theezans fruit were analyzed. The results indicate that S. theezans fruit could be classified as a potential potassium-, malic acid-, and linoleic/oleic acid-rich fruit. In addition, The ethyl acetate (EtOAc) fraction of the 70% ethanol (EtOH) crude extract exhibited strong antioxidant activities including free radical scavenging and reducing power activities compared with the same concentration of butylated hydroxytoluene. Furthermore, the EtOAc fraction showed significant inhibition of alpha-glucosidase activity. The analysis of the total phenolic and flavonoid content suggested that the remarkable antioxidant and antidiabetic activities of the EtOAc fraction are due to the presence of high levels of polyphenolic compounds. PMID- 28911492 TI - Antioxidation, angiotensin converting enzyme inhibition activity, nattokinase, and antihypertension of Bacillus subtilis (natto)-fermented pigeon pea. AB - Because of the high incidence of cardiovascular diseases in Asian countries, traditional fermented foods from Asia have been increasingly investigated for antiatherosclerotic effects. This study investigated the production of nattokinase, a serine fibrinolytic enzyme, in pigeon pea by Bacillus subtilis fermentation. B. subtilis 14714, B. subtilis 14715, B. subtilis 14716, and B. subtilis 14718 were employed to produce nattokinase. The highest nattokinase activity in pigeon pea was obtained using B. subtilis 14715 fermentation for 32 hours. In addition, the levels of antioxidants (phenolics and flavonoids) and angiotensin converting enzyme inhibitory activity were increased in B. subtilis 14715-fermented pigeon pea, compared with those in nonfermented pigeon pea. In an animal model, we found that both water extracts of pigeon pea (100 mg/kg body weight) and water extracts of B. subtilis-fermented pigeon pea (100 mg/kg body weight) significantly improved systolic blood pressure (21 mmHg) and diastolic blood pressure (30 mmHg) in spontaneously hypertensive rats. These results suggest that Bacillus-fermented pigeon pea has benefits for cardiovascular health and can be developed as a new dietary supplement or functional food that prevents hypertension. PMID- 28911493 TI - Red algae (Gelidium amansii) reduces adiposity via activation of lipolysis in rats with diabetes induced by streptozotocin-nicotinamide. AB - Gelidium amansii (GA) is an edible red algae that is distributed mainly in northeastern Taiwan. This study was designed to investigate the effects of GA on plasma glucose, lipids, and adipocytokines in rats with streptozotocin nicotinamide-induced diabetes. Rats were divided into four groups: (1) rats without diabetes fed a high-fat diet (control group); (2) rats with diabetes fed a high-fat diet; (3) rats with diabetes fed a high-fat diet with thiazolidinedione in the diet; and (4) rats with diabetes fed a high-fat diet and GA. The experimental diet and drinking water were available ad libitum for 11 weeks. After the 11-week feeding study, plasma glucose, triglyceride, and cholesterol concentrations were lower in rats with diabetes fed the GA diet than in animals with diabetes fed the control diet. In addition, cholesterol and triglyceride excretion were significantly higher in rats with diabetes fed the GA diet. Moreover, GA feeding induced lipolysis in both paraepididymal and perirenal adipose tissues. Adipose tissue (paraepididymal and perirenal) weight and triglyceride contents were lower after GA treatment. Plasma adipocytokines including tumor necrosis factor-alpha, interleukin-6, and plasminogen activator inhibitor-1 were reduced by GA feeding in rats with diabetes. The results of the current study suggest that GA feeding may regulate plasma glucose and lipid levels and prevent adipose tissue accumulation in rats with diabetes. PMID- 28911494 TI - Antioxidant activity and growth inhibition of human colon cancer cells by crude and purified fucoidan preparations extracted from Sargassum cristaefolium. AB - Fucose-containing sulfated polysaccharides, also termed "fucoidans", which are known to possess antioxidant, anticoagulant, anticancer, antiviral, and immunomodulating properties, are normally isolated from brown algae via various extraction techniques. In the present study, two methods (SC1 and SC2) for isolation of fucoidan from Sargassum cristaefolium were compared, with regard to the extraction yields, antioxidant activity, and inhibition of growth of human colon cancer cells exhibited by the respective extracts. SC1 and SC2 differ in the number of extraction steps and concentration of ethanol used, as well as the obtained sulfated polysaccharide extracts, namely, crude fucoidan preparation (CFP) and purified fucoidan preparation (PFP), respectively. Thin layer chromatography, Fourier transform infrared analysis, and measurements of fucose and sulfate contents revealed that the extracts were fucoidan. There was a higher extraction yield for CFP, which contained less fucose and sulfate but more uronic acid, and had weaker antioxidant activity and inhibition of growth in human colon cancer cells. In contrast, there was a lower extraction yield for PFP, which contained more fucose and sulfate but less uronic acid, and had stronger antioxidant activity and inhibition of growth in human colon cancer cells. Thus, since the difference in bioactive activities between CFP and PFP was not remarkable, the high extraction yield of SC1 might be favored as a method in industrial usage for extracting fucoidan. PMID- 28911495 TI - Food suppliers' perceptions and practical implementation of food safety regulations in Taiwan. AB - The relationships between the perceptions and practical implementation of food safety regulations by food suppliers in Taiwan were evaluated. A questionnaire survey was used to identify individuals who were full-time employees of the food supply industry with at least 3 months of experience. Dimensions of perceptions of food safety regulations were classified using the constructs of attitude of employees and corporate concern attitude for food safety regulation. The behavior dimension was classified into employee behavior and corporate practice. Food suppliers with training in food safety were significantly better than those without training with respect to the constructs of perception dimension of employee attitude, and the constructs of employee behavior and corporate practice associated with the behavior dimension. Older employees were superior in perception and practice. Employee attitude, employee behavior, and corporate practice were significantly correlated with each other. Satisfaction with governmental management was not significantly related to corporate practice. The corporate implementation of food safety regulations by suppliers was affected by employees' attitudes and behaviors. Furthermore, employees' attitudes and behaviors explain 35.3% of corporate practice. Employee behavior mediates employees' attitudes and corporate practices. The results of this study may serve as a reference for governmental supervision and provide training guidelines for workers in the food supply industry. PMID- 28911496 TI - Is it possible to rapidly and noninvasively identify different plants from Asteraceae using electronic nose with multiple mathematical algorithms? AB - Many plants originating from the Asteraceae family are applied as herbal medicines and also beverage ingredients in Asian areas, particularly in China. However, they may be confused due to their similar odor, especially when ground into powder, losing their typical macroscopic characteristics. In this paper, 11 different multiple mathematical algorithms, which are commonly used in data processing, were utilized and compared to analyze the electronic nose (E-nose) response signals of different plants from Asteraceae family. Results demonstrate that three-dimensional plot scatter figure of principal component analysis with less extracted components could offer the identification results more visually; simultaneously, all nine kinds of artificial neural network could give classification accuracies at 100%. This paper presents a rapid, accurate, and effective method to distinguish Asteraceae plants based on their response signals in E-nose. It also gives insights to further studies, such as to find unique sensors that are more sensitive and exclusive to volatile components in Chinese herbal medicines and to improve the identification ability of E-nose. Screening sensors made by other novel materials would be also an interesting way to improve identification capability of E-nose. PMID- 28911497 TI - Antifungal and antioxidant activities of organic and aqueous extracts of Annona squamosa Linn. leaves. AB - An increasing demand for natural additives has shifted the attention from synthetic to natural antioxidants and antifungal agents. This study was carried out to evaluate the antifungal and antioxidant activities of methanol, chloroform, and aqueous extracts of Annona squamosa Linn. leaves. The antifungal activities of all extracts of A. squamosa leaves against five different strains of fungi (Alternaria alternata, Candida albicans, Fusarium solani, Microsporum canis, and Aspergillus niger) were evaluated by the agar well diffusion method and the minimum inhibitory concentration of each extract was assessed by antifungal susceptibility using the broth microdilution method. The antioxidant potential of each extract was determined by free radicals (1,1-diphenyl-2 picrylhydrazyl, nitric oxide, and hydrogen peroxide) scavenging activity and reducing power property of A. squamosa leaves. Both organic and aqueous extracts were found to express dose-dependent inhibition against all tested fungi strains in both agar well diffusion and broth dilution methods. The free radical scavenging activity and reducing power property of all extracts were found to be concentration dependent, with the methanol extract exhibiting higher antioxidant activity than the chloroform extract, which was more effective than the aqueous extract of A. squamosa leaves. Results of phytochemical analysis of extracts showed the presence of glycosides, saponins, tannins, flavonoids, phenols, etc. The results obtained from in vitro studies of antifungal and antioxidant activities clearly suggest that the methanol, chloroform, and aqueous extracts of A. squamosa leaves possess antifungal and antioxidant activity. PMID- 28911498 TI - Method development and validation for the high-performance liquid chromatography assay of gastrodin in water extracts from different sources of Gastrodia elata Blume. AB - Gastrodia elata Blume is commonly used as a medical herb in China for ameliorating headaches, dizziness, and convulsions. In previous studies, water extracts of G. elata Bl. (WGE) have demonstrated potential to act as therapeutic agents to improve depression-like symptoms in rats. As gastrodin (GAS) is a major active compound in WGE, its quantitation in WGE is important for quality control. The objective of this study was to develop an optimized and validated reversed phase high-performance liquid chromatography method for the analysis of GAS in different sources of WGE. We evaluated the GAS content in varieties of G. elata Bl. including G. elata Bl. f. glauca S. Chow and G. elata Bl. f. elata. We also evaluated the GAS content of the latter variety from two different origins, Yun nan and Hu-nan. The results indicate that the amount of GAS analyzed in WGE from G. elata Bl. f. glauca S. Chow is five times higher than that of G. elata Bl. f. elata from Yun-nan and Hu-nan. A significant difference in GAS content was observed between varieties of G. elata Bl., although not between locations of origin. PMID- 28911499 TI - Chemical material basis study of Xuefu Zhuyu decoction by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Xuefu Zhuyu decoction, a classic prescription in traditional Chinese medicine, has been widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. In order to profile the chemical material basis of this formula, an ultra-performance liquid chromatography (UPLC) coupled with quadrupole time-of-flight mass spectrometry (Q/TOF MS) method has been established for rapid separation and structural characterization of compounds in the decoction. As a result, 103 compounds including phenolic acids, spermidines, C-glycosyl quinochalcones, terpenoids, flavonoids, saponins, and others were detected; 35 of them were unambiguously identified, and 68 were tentatively characterized by comparing the retention time, MS data, characteristic MS fragmentation pattern and retrieving the literature. In conclusion, the UPLC coupled with quadrupole time-of-flight mass spectrometry method developed in this work is an efficient approach to perform chemical material basis studies of traditional Chinese medicine formulae. PMID- 28911500 TI - Flavone glycosides from commercially available Lophatheri Herba and their chromatographic fingerprinting and quantitation. AB - Lophatheri Herba (Danzhuye; LH), the dried leaves of Lophatherum gracile Brongn (Poaceae), is commonly used in Chinese herbal medicine as an antipyretic, antibacterial, and diuretic. Chemical analysis has been conducted to isolate and identify seven major flavonoid glycosides, including a new flavone C-glycoside, luteolin 6-C-beta-D-glucuronopyranosyl-(1->2)-beta-D-glucopyranoside (1), isoorientin (2), swertiajaponin (3), luteolin 6-C-beta-D-glucuronopyranosyl-(1 >2)-alpha-L-arabinopyranoside (4), isovitexin (5), swertisin (6), luteolin 7-O beta-D-glucopyranoside (7), and luteolin 6-C-alpha-L-arabinopyranoside (8), from commercially available LHs in Taiwan. The structure of the new compound (1), the maximum component, was determined by extensive one- (1D-) and two-dimensional (2D ) nuclear magnetic resonance (NMR), and MS spectral analyses. The 1H and 13C-NMR of two rotameric pairs of 3 and 6 were also assigned. To establish the quality control platform of LH, we developed a simultaneous determination of multiple components in 10 commercially available LHs, collected from different areas of Taiwan, by high performance liquid chromatography (HPLC) and ultra performance liquid chromatography (UPLC), as well as quantitative measurement of the major components 1-4, and 8. All isolated major compounds showed good linear regression (R2 >= 0.9993) within the test ranges and high reproducibility. These methods are readily accessible for the quality control of LH. PMID- 28911501 TI - Effect of high-pressure homogenization preparation on mean globule size and large diameter tail of oil-in-water injectable emulsions. AB - The effect of different high pressure homogenization energy input parameters on mean diameter droplet size (MDS) and droplets with > 5 MUm of lipid injectable emulsions were evaluated. All emulsions were prepared at different water bath temperatures or at different rotation speeds and rotor-stator system times, and using different homogenization pressures and numbers of high-pressure system recirculations. The MDS and polydispersity index (PI) value of the emulsions were determined using the dynamic light scattering (DLS) method, and large-diameter tail assessments were performed using the light-obscuration/single particle optical sensing (LO/SPOS) method. Using 1000 bar homogenization pressure and seven recirculations, the energy input parameters related to the rotor-stator system will not have an effect on the final particle size results. When rotor stator system energy input parameters are fixed, homogenization pressure and recirculation will affect mean particle size and large diameter droplet. Particle size will decrease with increasing homogenization pressure from 400 bar to 1300 bar when homogenization recirculation is fixed; when the homogenization pressure is fixed at 1000 bar, the particle size of both MDS and percent of fat droplets exceeding 5 MUm (PFAT5) will decrease with increasing homogenization recirculations, MDS dropped to 173 nm after five cycles and maintained this level, volume-weighted PFAT5 will drop to 0.038% after three cycles, so the "plateau" of MDS will come up later than that of PFAT5, and the optimal particle size is produced when both of them remained at plateau. Excess homogenization recirculation such as nine times under the 1000 bar may lead to PFAT5 increase to 0.060% rather than a decrease; therefore, the high-pressure homogenization procedure is the key factor affecting the particle size distribution of emulsions. Varying storage conditions (4-25 degrees C) also influenced particle size, especially the PFAT5. PMID- 28911502 TI - Degradation of histamine by Bacillus polymyxa isolated from salted fish products. AB - Histamine is the causative agent of scombroid poisoning, a foodborne chemical hazard. Histamine is degraded by the oxidative deamination activity of certain microorganisms. In this study, eight histamine-degrading bacteria isolated from salted fish products were identified as Rummeliibacillus stabekisii (1 isolate), Agrobacterium tumefaciens (1 isolate), Bacillus cereus (2 isolates), Bacillus polymyxa (1 isolate), Bacillus licheniformis (1 isolate), Bacillus amyloliquefaciens (1 isolate), and Bacillus subtilis (1 isolate). Among them, B. polymyxa exhibited the highest activity in degrading histamine than the other isolates. The ranges of temperature, pH, and salt concentration for growth and histamine degradation of B. polymyxa were 25-37 degrees C, pH 5-9, and 0.5-5% NaCl, respectively. B. polymyxa exhibited optimal growth and histamine-degrading activity at 30 degrees C, pH 7, and 0.5% NaCl in histamine broth for 24 hours of incubation. The histamine-degrading isolate, B. polymyxa, might be used as a starter culture in inhibiting histamine accumulation during salted fish product fermentation. PMID- 28911503 TI - Correction. PMID- 28911505 TI - Correction. PMID- 28911504 TI - Correction. PMID- 28911507 TI - More Appropriate Cardiovascular Risk Screening Through Understanding Complex Phenotypes: Mind the Gap. PMID- 28911506 TI - Metabolically Healthy Obese and Incident Cardiovascular Disease Events Among 3.5 Million Men and Women. AB - BACKGROUND: Previous studies have been unclear about the cardiovascular risks for metabolically healthy obese individuals. OBJECTIVES: This study examined the associations among metabolically healthy obese individuals and 4 different presentations of incident cardiovascular disease in a contemporary population. METHODS: We used linked electronic health records (1995 to 2015) in The Health Improvement Network (THIN) to assemble a cohort of 3.5 million individuals, 18 years of age or older and initially free of cardiovascular disease. We created body size phenotypes defined by body mass index categories (underweight, normal weight, overweight, and obesity) and 3 metabolic abnormalities (diabetes, hypertension, and hyperlipidemia). The primary endpoints were the first record of 1 of 4 cardiovascular presentations (coronary heart disease [CHD], cerebrovascular disease, heart failure, and peripheral vascular disease). RESULTS: During a mean follow-up of 5.4 years, obese individuals with no metabolic abnormalities had a higher risk of CHD (multivariate-adjusted hazard ratio [HR]: 1.49; 95% confidence interval [CI]: 1.45 to 1.54), cerebrovascular disease (HR: 1.07; 95% CI: 1.04 to 1.11), and heart failure (HR: 1.96; 95% CI: 1.86 to 2.06) compared with normal weight individuals with 0 metabolic abnormalities. Risk of CHD, cerebrovascular disease, and heart failure in normal weight, overweight, and obese individuals increased with increasing number of metabolic abnormalities. CONCLUSIONS: Metabolically healthy obese individuals had a higher risk of coronary heart disease, cerebrovascular disease, and heart failure than normal weight metabolically healthy individuals. Even individuals who are normal weight can have metabolic abnormalities and similar risks for cardiovascular disease events. PMID- 28911509 TI - Exploration of PCSK9 as a Cardiovascular Risk Factor: Is There a Link to the Platelet? PMID- 28911508 TI - Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation. AB - BACKGROUND: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available. OBJECTIVES: This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B2 (11-dh-TxB2), a marker of platelet activation. METHODS: We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB2 (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis. RESULTS: The mean age of patients was 73.5 +/- 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB2 were significantly correlated (Spearman's rho: 0.665; p < 0.001). CONCLUSIONS: Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB2 suggests PCSK9 as a mechanism potentially implicated in platelet activation. PMID- 28911511 TI - A Natural Biomarker Deserving Attention: Gasping Following Primary Cardiac Arrest. PMID- 28911510 TI - Long-Term Prognostic Value of Gasping During Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Gasping is a natural reflex that enhances oxygenation and circulation during cardiopulmonary resuscitation (CPR). OBJECTIVES: This study sought to assess the relationship between gasping during out-of-hospital cardiac arrest and 1-year survival with favorable neurological outcomes. METHODS: The authors prospectively collected incidence of gasping on all evaluable subjects in a multicenter, randomized, controlled, National Institutes of Health-funded out-of hospital cardiac arrest clinical trial from August 2007 to July 2009. The association between gasping and 1-year survival with favorable neurological function, defined as a Cerebral Performance Category (CPC) score <=2 was estimated using multivariable logistic regression. RESULTS: The rates of 1-year survival with a CPC score of <=2 were 5.4% (98 of 1,827) overall, and 20% (36 of 177) and 3.7% (61 of 1,643) for individuals with and without spontaneous gasping or agonal respiration during CPR, respectively. In multivariable analysis, 1-year survival with CPC <=2 was independently associated with younger age (odds ratio [OR] for 1 SD increment 0.57; 95% confidence interval [CI]: 0.43 to 0.76), gasping during CPR (OR: 3.94; 95% CI: 2.09 to 7.44), shockable initial recorded rhythm (OR: 16.50; 95% CI: 7.40 to 36.81), shorter CPR duration (OR: 0.31; 95% CI: 0.19 to 0.51), lower epinephrine dosage (OR: 0.47; 95% CI: 0.25 to 0.87), and pulmonary edema (OR: 3.41; 95% CI: 1.53 to 7.60). Gasping combined with a shockable initial recorded rhythm had a 57-fold higher OR (95% CI: 23.49 to 136.92) of 1-year survival with CPC <=2 versus no gasping and no shockable rhythm. CONCLUSIONS: Gasping during CPR was independently associated with increased 1-year survival with CPC <=2, regardless of the first recorded rhythm. These findings underscore the importance of not terminating resuscitation prematurely in gasping patients and the need to routinely recognize, monitor, and record data on gasping in all future cardiac arrest trials and registries. PMID- 28911513 TI - Delivering Instant Heat: Shocking the Heart. PMID- 28911514 TI - Defibrillation for Ventricular Fibrillation: A Shocking Update. AB - Cardiac arrest is defined as the termination of cardiac activity associated with loss of consciousness, of spontaneous breathing, and of circulation. Sudden cardiac arrest and sudden cardiac death (SCD) are terms often used interchangeably. Most patients with out-of-hospital cardiac arrest have shown coronary artery disease or symptoms during the hour before the event. Cardiac arrest is potentially reversible by cardiopulmonary resuscitation, defibrillation, cardioversion, cardiac pacing, or treatments targeted at the underlying disease (e.g., acute coronary occlusion). We restrict SCD hereafter to cardiac arrest due to ventricular fibrillation, including rhythms shockable by an automatic external defibrillator (AED), implantable cardioverter-defibrillator (ICD), or wearable cardioverter-defibrillator (WCD). We summarize the state of the art related to defibrillation in treating SCD, including a brief history of the evolution of defibrillation, technical characteristics of modern AEDs, strategies to improve AED access and increase survival, ancillary treatments, and use of ICDs or WCDs. PMID- 28911512 TI - Cardioprotective Effects of HSP72 Administration on Ischemia-Reperfusion Injury. AB - BACKGROUND: Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. OBJECTIVES: This study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. METHODS: A left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken. RESULTS: Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv HSP72-treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72 treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits. CONCLUSIONS: Single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction. PMID- 28911515 TI - Chronic Chagas Heart Disease Management: From Etiology to Cardiomyopathy Treatment. AB - Trypanosoma cruzi (T. cruzi) infection is endemic in Latin America and is becoming a worldwide health burden. It may lead to heterogeneous phenotypes. Early diagnosis of T. cruzi infection is crucial. Several biomarkers have been reported in Chagas heart disease (ChHD), but most are nonspecific for T. cruzi infection. Prognosis of ChHD patients is worse compared with other etiologies, with sudden cardiac death as an important mode of death. Most ChHD patients display diffuse myocarditis with fibrosis and hypertrophy. The remodeling process seems to be associated with etiopathogenic mechanisms and neurohormonal activation. Pharmacological treatment and antiarrhythmic therapy for ChHD is mostly based on results for other etiologies. Heart transplantation is an established, valuable therapeutic option in refractory ChHD. Implantable cardioverter-defibrillators are indicated for prevention of secondary sudden cardiac death. Specific etiological treatments should be revisited and reserved for select patients. Understanding and management of ChHD need improvement, including development of randomized trials. PMID- 28911516 TI - Diversity Matters. PMID- 28911518 TI - ABIM/ACC Competency-Based Education Pilot in Internal Medicine and Cardiovascular Disease. PMID- 28911517 TI - Effect of the FDA Regulatory Approach on the 0/1-h Algorithm for Rapid Diagnosis of MI. PMID- 28911519 TI - Bioresorbable Scaffold Thrombosis: A Multifactorial Phenomenon Also Involving Hypersensitivity Inflammation? PMID- 28911520 TI - Reply: Bioresorbable Scaffold Thrombosis: A Multifactorial Phenomenon Also Involving Hypersensitivity Inflammation? PMID- 28911521 TI - Left Ventricle Assist Device Recovery Should Include Recovery of Ventilatory and Autonomic Nervous System Abnormalities. PMID- 28911522 TI - Reply: Left Ventricle Assist Device Recovery Should Include Recovery of Ventilatory and Autonomic Nervous System Abnormalities. PMID- 28911524 TI - Correction. PMID- 28911523 TI - Toward Multiple SNP Motif Analyses of Loci Associated With Phenotypic Traits. PMID- 28911525 TI - Correction. PMID- 28911526 TI - Introduction to the Special Issue: Dietary Natural Compounds. PMID- 28911528 TI - Macrophages in oxidative stress and models to evaluate the antioxidant function of dietary natural compounds. AB - Antioxidant testing of natural products has attracted increasing interest in recent years, mainly due to the fact that an antioxidant-rich diet might provide health benefits. Activated macrophages are a major source of reactive oxygen species, reactive nitrogen species, and peroxynitrite generated through the so called respiratory burst. Constitutively released proinflammatory cytokine, especially tumor necrosis factor-alpha, triggers nuclear factor-kappaB, and activator protein-1 translocation leading to the over production of reactive oxygen species and reactive nitrogen species in macrophages. Activation of transcription factors in the long-lived tissue-resident macrophages and/or monocyte-derived macrophages, trigger epigenetic modifications leading to the pathogenesis of chronic diseases. Nutraceuticals including lipid raft structure disruption agent, cholesterol depletion agent, farnesyltransferase inhibitor, nuclear factor-kappaB blocker (alpha,beta-unsaturated carbonyl compounds), glucocorticoid receptor agonist, and peroxisome proliferator-activated receptor gamma agonist have long been used to inactive macrophage. The inhibition effects on the formation of nitric oxide, superoxide, and nitrite peroxide may be responsible for the anti-inflammatory functionalities. Activated macrophage models could be used to identify the active components for functional diets development through a multiple targets strategy. PMID- 28911529 TI - An apple a day to prevent cancer formation: Reducing cancer risk with flavonoids. AB - The purpose of this review is to update and discuss key findings from in vitro and in vivo studies on apple and its biocompounds, with a special focus on its anticancer role. Several studies have proposed that apple and its extracts exhibit a variety of biological functions that may contribute to health benefits including beneficial effects against chronic heart and vascular disorders, respiratory and pulmonary dysfunction, diabetes, obesity, and cancer. In this review, we summarize the molecular mechanism(s) of various components in apple, as established in previous studies that indicated their growth-inhibitory effects in various cancer cell types. Moreover, an attempt is made to delineate the direction of future studies that could lead to the development of apple components as a potent chemopreventive/chemotherapeutic agent against cancer. PMID- 28911527 TI - Cellular models for the evaluation of the antiobesity effect of selected phytochemicals from food and herbs. AB - Dietary phytochemicals from food and herbs have been studied for their health benefits for a long time. The incidence of obesity has seen an incredible increase worldwide. Although dieting, along with increased physical activity, seems an easy method in theory to manage obesity, it is hard to apply in real life. Obesity treatment drugs and surgery are not successful or targeted for everyone and can have significant side effects. This low rate of success is the major reason that the overweight as well as the pharmaceutical industry seek alternative methods, including phytochemicals. Therefore, more and more research has focused on the role of phytochemicals to alleviate lipid accumulation or enhance energy expenditure in adipocytes. This review discusses selected phytochemicals from food and herbs and their effects on adipogenesis, lipogenesis, lipolysis, oxidation of fatty acids, and browning in 3T3-L1 preadipocytes. PMID- 28911530 TI - Autophagy-inducing effect of pterostilbene: A prospective therapeutic/preventive option for skin diseases. AB - Pterostilbene is a naturally occurring analog of resveratrol with many health benefits. These health benefits are associated with its antioxidant activity, anti-inflammatory effects, and chemopreventive effects attributed to its unique structure. The skin cancer chemopreventive potential of pterostilbene is supported by a variety of mechanistic studies confirming the anti-inflammatory effects in skin cancer models. Molecular biological studies have identified that pterostilbene targets pleotropic signaling pathways, including those involved in mitogenesis, cell cycle regulation, and apoptosis. Recently, pterostilbene has been reported to induce autophagy in cancer and normal cells. Through autophagy induction, the inflammatory-related skin diseases can be attenuated. This finding suggests the potential use of pterostilbene in the treatment and prevention of skin disorders via alleviating inflammatory responses by autophagy induction. This review summarizes the protective and therapeutic benefits of pterostilbene in skin diseases from the viewpoint of its antioxidant, anti-inflammatory, and autophagy-inducing effects. Novel underlying mechanisms regarding these effects are discussed. We proposed that pterostilbene, a promising natural product, can be used as a preventive and therapeutic agent for inflammation-related skin disorders through induction of autophagy. PMID- 28911531 TI - Biological actions and molecular effects of resveratrol, pterostilbene, and 3' hydroxypterostilbene. AB - Stilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans resveratrol, pterostilbene, and 3'-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans resveratrol, pterostilbene, and 3'-hydroxypterostilbene. PMID- 28911532 TI - Bioactive phytochemicals in barley. AB - Epidemiological studies have consistently shown that regular consumption of whole grain barley reduces the risk of developing chronic diseases. The presence of barley fiber, especially beta-glucan in whole grain barley, has been largely credited for these health benefits. However, it is now widely believed that the actions of the fiber component alone do not explain the observed health benefits associated with the consumption of whole grain barley. Whole grain barley also contains phytochemicals including phenolic acids, flavonoids, lignans, tocols, phytosterols, and folate. These phytochemicals exhibit strong antioxidant, antiproliferative, and cholesterol lowering abilities, which are potentially useful in lowering the risk of certain diseases. Therefore, the high concentration of phytochemicals in barley may be largely responsible for its health benefits. This paper reviews available information regarding barley phytochemicals and their potential to combat common nutrition-related diseases including cancer, cardiovascular disease, diabetes, and obesity. PMID- 28911533 TI - Techniques and methods to study functional characteristics of emulsion systems. AB - With the growing popularity of the functional food market, bioactive ingredients from natural sources are discovered one after another for their ability to promote better health and prevent chronic diseases. Emulsion, widely occurring in many food systems, has become a popular vehicle to facilitate the incorporation of bioactive components into the food system. Depending on the designated functionality, an emulsion can be developed with various physical and chemical properties. To ensure the successful development of a high-quality emulsion-based system to serve their purpose in food, knowledge of the analytical methods that could efficiently evaluate their quality parameters is important for investigators who work in this field. In this work, important emulsion properties are overviewed, and techniques that are commonly used to assess them are provided. Discussions and recommendations are also included to make suggestions on advantages and disadvantages when selecting suitable techniques and methods to characterize these quality parameters of emulsion systems. PMID- 28911534 TI - Phenolic compounds and biological activities of small-size citrus: Kumquat and calamondin. AB - Kumquat and calamondin are two small-size citrus fruits. Owing to their health benefits, they are traditionally used as folk medicine in Asian countries. However, the research on flavonoids and biological activities of kumquat and calamondin have received less attention. This review summarizes the reported quantitative and qualitative data of phenolic compositions in these two fruits. Effects of maturity, harvest time, various solvent extractions and heat treatment of phenolic compositions, and bioactivities were discussed; distributions of the forms of phenolic compounds existing in kumquat and calamondin were also summarized. Furthermore, biological activities, including antioxidant, antityrosinase, antimicrobial, antitumor, and antimetabolic disorder effects, have also been discussed. Effective phenolic components were proposed for a certain bioactivity. It was found that C-glycoside flavonoids are dominant phenolic compounds in kumquat and calamondin, unlike in other citrus fruits. Up to now, biological activities and chemical characteristics of C-glycoside flavonoids in kumquat and calamondin are largely unknown. PMID- 28911535 TI - Chemopreventive effect of natural dietary compounds on xenobiotic-induced toxicity. AB - Contaminants (or pollutants) that affect human health have become an important issue, spawning a myriad of studies on how to prevent harmful contaminant-induced effects. Recently, a variety of biological functions of natural dietary compounds derived from consumed foods and plants have been demonstrated in a number of studies. Natural dietary compounds exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis. Contaminant-induced toxicity and carcinogenesis are mostly attributed to the mutagenic activity of reactive metabolites and the disruption of normal biological functions. Therefore, the metabolic regulation of hazardous chemicals is key to reducing contaminant-induced adverse health effects. Moreover, promoting contaminant excretion from the body through Phase I and II metabolizing enzymes is also a useful strategy for reducing contaminant-induced toxicity. This review focuses on summarizing the natural dietary compounds derived from common dietary foods and plants and their possible mechanisms of action in the prevention/suppression of contaminant-induced toxicity. PMID- 28911536 TI - Biopharmaceutical potentials of Prosopis spp. (Mimosaceae, Leguminosa). AB - Prosopis is a commercially important plant genus, which has been used since ancient times, particularly for medicinal purposes. Traditionally, Paste, gum, and smoke from leaves and pods are applied for anticancer, antidiabetic, anti inflammatory, and antimicrobial purposes. Components of Prosopis such as flavonoids, tannins, alkaloids, quinones, or phenolic compounds demonstrate potentials in various biofunctions, such as analgesic, anthelmintic, antibiotic, antiemetic, microbial antioxidant, antimalarial, antiprotozoal, antipustule, and antiulcer activities; enhancement of H+, K+, ATPases; oral disinfection; and probiotic and nutritional effects; as well as in other biopharmaceutical applications, such as binding abilities for tablet production. The compound juliflorine provides a cure in Alzheimer disease by inhibiting acetylcholine esterase at cholinergic brain synapses. Some indirect medicinal applications of Prosopis spp. are indicated, including antimosquito larvicidal activity, chemical synthesis by associated fungal or bacterial symbionts, cyanobacterial degradation products, "mesquite" honey and pollens with high antioxidant activity, etc. This review will reveal the origins, distribution, folk uses, chemical components, biological functions, and applications of different representatives of Prosopis. PMID- 28911537 TI - Functional study of Cordyceps sinensis and cordycepin in male reproduction: A review. AB - Cordyceps sinensis has various biological and pharmacological functions, and it has been claimed as a tonic supplement for sexual and reproductive dysfunctions for a long time in oriental society. In this article, the in vitro and in vivo effects of C. sinensis and cordycepin on mouse Leydig cell steroidogenesis are briefly described, the stimulatory mechanisms are summarized, and the recent findings related to the alternative substances regulating male reproductive functions are also discussed. PMID- 28911538 TI - Corrigendum to "Hydrolysis of isoflavone in black soy milk using cellulose bead as enzyme immobilizer" [J Food Drug Anal 24 (2016) 788-795]. PMID- 28911539 TI - Corrigendum to "Assessment of the pharmacokinetics, removal rate of hemodialysis, and safety of lactulose in hemodialysis patients" [J Food Drug Anal 24 (2016) 876 880]. PMID- 28911540 TI - Extraction, bioavailability, and bioefficacy of capsaicinoids. AB - Capsaicinoids are active constituents responsible for the pungent and spicy flavor in chili peppers. During the past few decades, various extraction methods of capsaicinoids from peppers have been developed with high yields. Through biological studies, pharmacological benefits have been reported such as pain relief, antiinflammation, anticancer, cardio-protection, as well as weight loss. In this paper, the extraction methods and bioavailability of capsaicinoids are reviewed and discussed. In addition, the pharmacological effects and their underlying mechanisms are also studied. PMID- 28911541 TI - Food macromolecule based nanodelivery systems for enhancing the bioavailability of polyphenols. AB - Diet polyphenols-primarily categorized into flavonoids (e.g., flavonols, flavones, flavan-3-ols, anthocyanidins, flavanones, and isoflavones) and nonflavonoids (with major subclasses of stilbenes and phenolic acids)-are reported to have health-promoting effects, such as antioxidant, antiinflammatory, anticarcinoma, antimicrobial, antiviral, and cardioprotective properties. However, their applications in functional foods or medicine are limited because of their inefficient systemic delivery and poor oral bioavailability. Epigallocatechin-3-gallate, curcumin, and resveratrol are the well-known representatives of the bioactive diet polyphenols but with poor bioavailability. Food macromolecule based nanoparticles have been fabricated using reassembled proteins, crosslinked polysaccharides, protein-polysaccharide conjugates (complexes), as well as emulsified lipid via safe procedures that could be applied in food. The human gastrointestinal digestion tract is the first place where the food grade macromolecule nanoparticles exert their effects on improving the bioavailability of diet polyphenols, via enhancing their solubility, preventing their degradation in the intestinal environment, elevating the permeation in small intestine, and even increasing their contents in the bloodstream. We contend that the stability and structure behaviors of nanocarriers in the gastrointestinal tract environment and the effects of nanoencapsulation on the metabolism of polyphenols warrant more focused attention in further studies. PMID- 28911542 TI - Classification and regulatory perspectives of dietary fiber. AB - This review discusses the history and evolution of the state of dietary fiber (DF) with account of refinements in extraction methods and legal definitions subsequent to the launch of DF hypothesis. For a long time, defining and regulating DFs relied heavily on their chemical compositions and analytical methods. Although chemical compositions and analytical methods still play an important role in the definition of DF, physiological activity has also been taken into consideration. The precise definition of DF is still evolving, particularly whether oligosaccharides degrees of polymerization (DP) 3-9 should be considered as DF or not. Decades of scientific research have initiated the expansion of the term DF to include indigestible oligosaccharides with their DP between 3 and 9; hence responding to the positive health benefits of DF as well as fulfilling the needs in food labeling regulations. PMID- 28911543 TI - Chemistry and bioactivity of Gardenia jasminoides. AB - Gardenia jasminoides, grown in multiple regions in China, was commonly used as a natural yellow dye but has been one of the popular traditional Chinese medicines since the discovery of its biological property a few decades ago. It has been reported that G. jasminoides possess multiple biological activities, such as antioxidant properties, hypoglycemic effect, inhibition of inflammation, antidepression activity, and improved sleeping quality. In this review, our aim was to have a comprehensive summary of its phytochemistry including the extraction, isolation, and characterization of volatiles and bioactive molecules in G. jasminoides, focusing on the two major phytochemicals, genipin and crocin, which possess potent medicinal properties. Furthermore, this study attempted to establish a structure-activity relationship between the two major series of molecules with two pharmcophores and their biological activities, which would serve further exploration of the properties of phytocompounds in G. jasminoides as potential functional foods and medicines. PMID- 28911544 TI - Black garlic: A critical review of its production, bioactivity, and application. AB - Black garlic is obtained from fresh garlic (Allium sativum L.) that has been fermented for a period of time at a controlled high temperature (60-90 degrees C) under controlled high humidity (80-90%). When compared with fresh garlic, black garlic does not release a strong offensive flavor owing to the reduced content of allicin. Enhanced bioactivity of black garlic compared with that of fresh garlic is attributed to its changes in physicochemical properties. Studies concerning the fundamental findings of black garlic, such as its production, bioactivity, and applications, have thus been conducted. Several types of black garlic products are also available in the market with a fair selling volume. In this article, we summarize the current knowledge of changes in the components, bioactivity, production, and applications of black garlic, as well as the proposed future prospects on their possible applications as a functional food product. PMID- 28911545 TI - Chemistry and health effects of furanocoumarins in grapefruit. AB - Furanocoumarins are a specific group of secondary metabolites that commonly present in higher plants, such as citrus plants. The major furanocoumarins found in grapefruits (Citrus paradisi) include bergamottin, epoxybergamottin, and 6',7' dihydroxybergamottin. During biosynthesis of these furanocoumarins, coumarins undergo biochemical modifications corresponding to a prenylation reaction catalyzed by the cytochrome P450 enzymes with the subsequent formation of furan rings. Because of undesirable interactions with several medications, many studies have developed methods for grapefruit furanocoumarin quantification that include high-performance liquid chromatography coupled with UV detector or mass spectrometry. The distribution of furanocoumarins in grapefruits is affected by several environmental conditions, such as processing techniques, storage temperature, and packing materials. In the past few years, grapefruit furanocoumarins have been demonstrated to exhibit several biological activities including antioxidative, -inflammatory, and -cancer activities as well as bone health promotion both in vitro and in vivo. Notably, furanocoumarins potently exerted antiproliferative activities against cancer cell growth through modulation of several molecular pathways, such as regulation of the signal transducer and activator of transcription 3, nuclear factor-kappaB, phosphatidylinositol-3-kinase/AKT, and mitogen-activated protein kinase expression. Therefore, based on this review, we suggest furanocoumarins may serve as bioactive components that contribute, at least in part, to the health benefits of grapefruit. PMID- 28911546 TI - Polyphenols with antiglycation activity and mechanisms of action: A review of recent findings. AB - Advanced glycation end products (AGEs) are substances composed of amino groups of proteins and reducing sugars. The initial and propagation phases of the glycation process are accompanied by the production of a large amount of free radicals, carbonyl species, and reactive dicarbonyl species, of which, methylglyoxal (MG) is the most reactive and can cause dicarbonyl stress, influencing normal physiological functions. In the advanced phase, the production of AGEs and the interaction between AGEs and their receptor, RAGE, are also considered to be among the causes of chronic diseases, oxidative stress, and inflammatory reaction. Till date, multiple physiological activities of polyphenols have been confirmed. Recently, there have been many studies discussing the ability of polyphenols to suppress the MG and AGEs formation, which was also confirmed in some in vivo studies. This review article collects recent literatures concerning the effects of polyphenols on the generation of MG and AGEs through different pathways and discusses the feasibility of the inhibition of glycative stress and dicarbonyl stress by polyphenols. PMID- 28911547 TI - Multifunctions of dietary polyphenols in the regulation of intestinal inflammation. AB - Food for specified health use is a type of functional food approved by the Japanese government, with more than 1250 products in 10 health-claim categories being approved as of April 2016. Polyphenols are currently used as functional ingredients in seven of the 10 categories. Although they have not yet been used for the food-for-specified-health-use category of "gut health promotion," polyphenols are expected to contribute to the future development of gut modulating food. Intestinal functions include digestion/absorption, acting as a barrier, recognition of external factors, and signal transduction. Owing to incessant exposure to external stress factors including food substances, bacteria, and environmental chemicals, intestines are always inflammatory to some extent, which may cause damage to and dysfunction of intestinal tissues depending on the situation. We identified food factors that could suppress immoderate inflammation in the intestines. In addition to certain amino acids and peptides, polyphenols such as chlorogenic acid and isoflavones were found to suppress inflammation in intestinal cells. Intestinal inflammation is caused by various factors in diverse mechanisms. Recent studies revealed that activation of pattern recognition receptors, such as Toll-like receptors and nucleotide-binding oligomerization domain proteins, in epithelial cells triggers intestinal inflammation. Intracellular receptors or signaling molecules controlling the intestinal detoxification system are also involved in the regulation of inflammation. Differentiation of regulatory T cells by activating a transcription factor Foxp-3 is known to suppress intestinal inflammation. A variety of phytochemicals including polyphenols modulate these receptors and signaling molecules, and are thus anti-inflammatory. Polyphenols affect epigenetic changes occurring in intestinal tissues by interacting with the enzymes responsible for DNA methylation and histone acetylation. New types of anti-inflammatory food factors may be discovered by examining dietary substances that interact with the abovementioned target molecules. PMID- 28911548 TI - Corrigendum to "Guava fruit extract and its triterpene constituents have osteoanabolic effect: stimulation of osteoblast differentiation by activation of mitochondrial respiration via the Wnt/beta-catenin signalling". PMID- 28911549 TI - Determination of naturally occurring estrogenic hormones in cow's and river buffalo's meat by HPLC-FLD method. AB - This study was performed to measure and compare the levels of steroid hormones [estrone (E1), 17beta-estradiol (E2), and estriol (E3)] and their conjugated metabolites in cow's and river buffalo's meat in two distinct follicular and luteal phases. Moreover, the possible effect of a heating process on steroid hormone concentration was also investigated. The collected meat (biceps femoris muscle) samples were subjected to liquid extraction, enzymatical deconjugation, and C18 solid-phase extraction. Estrogens were analyzed using high performance liquid chromatography equipped with a fluorescence detector. In the follicular phase the levels of steroid hormones (E1 and E2) in either tested species were higher than the luteal phase. Moreover, in the present study, E1 concentration (free and deconjugated value, 16.2 +/- 1.1 ng/L) was found to be the highest phenolic estrogen in beef, while the dominant estrogen in muscle of river buffalo was E2 (free and deconjucated value, 23.3 +/- 1.3 ng/L). The study revealed that animal species influenced the concentration of hormones (E1 and E2) in the samples. The heating process did not significantly change (p > 0.05) the levels of estrogens. The further findings of the present study showed that E3 (deconjugated form) was only detected in the buffalo's meat (15.8 +/- 1.9 ng/L). These data suggest that although meat is one of the valuable nutrient sources for humans, there are, however, increasing concerns about the safety of meat due to the excessive presence of steroid hormones. PMID- 28911550 TI - Essential oils from Taiwan: Chemical composition and antibacterial activity against Escherichia coli. AB - The chemical compositions of seven essential oils from Taiwan were analyzed by gas chromatography-mass spectrometry. The eluates were identified by matching the mass fragment patents to the National Institute of Standards and Technology (NIST) 08 database. The quantitative analysis showed that the major components of lemon verbena are geranial (26.9%) and neral (23.1%); those of sweet marjoram are gamma-terpinene (18.5%), thymol methyl ether (15.5%), and terpinen-4-ol (12.0%); those of clove basil are eugenol (73.6%), and beta-(Z)-ocimene (15.4%); those of patchouli are carvacrol (47.5%) and p-cymene (15.2%); those of rosemary are alpha pinene (54.8%) and 1,8-cineole (22.2%); those of tea tree are terpinen-4-ol (33.0%) and 1,8-cineole (27.7%); and those of rose geranium are citronellol (28.9%) and 6,9-guaiadiene (20.1%). These components are somewhat different from the same essential oils that were obtained from other origins. Lemon verbena has the same major components everywhere. Tea tree, rose geranium, and clove basil have at least one major component throughout different origins. The major components and their amounts in sweet marjoram, patchouli, and rosemary vary widely from one place to another. These results demonstrate that essential oils have a large diversity in their composition in line with their different origins. The antibacterial activity of essential oils against Escherichia coli was evaluated using the optical density method (turbidimetry). Patchouli is a very effective inhibitor, in that it completely inhibits the growth of E. coli at 0.05%. Clove basil and sweet marjoram are good inhibitors, and the upper limit of their minimum inhibitory concentration is 0.1%. PMID- 28911551 TI - Assessment of the key aroma compounds in rose-based products. AB - In this study, headspace solid phase microextraction-gas chromatography-mass spectrometry and GC-olfactometry were used to analyze the key aroma compounds in three types of rose-based products, including low-temperature extracts (LTEs), high-temperature extracts (HTEs), and rose drinks (RDs). In combination with the Guadagni theory, it was confirmed that the key aroma components of LTE were beta phenyl ethyl alcohol, citronellol, geraniol, and eugenol. The main aroma compounds in HTE were beta-phenyl ethyl alcohol, citronellol, geraniol, eugenol, linalool, and rose oxide. The four key aroma compounds in RDs were beta-phenyl ethyl alcohol, eugenol, geraniol, and linalool. PMID- 28911552 TI - Evaluation of metal concentration and antioxidant, antimicrobial, and anticancer potentials of two edible mushrooms Lactarius deliciosus and Macrolepiota procera. AB - This study is designed for the determination of metal concentrations, antioxidant, antimicrobial, and anticancer potential of two edible mushrooms Lactarius deliciosus and Macrolepiota procera. Concentrations of nine metals are determined and all metals are present in the allowable concentrations in the tested mushrooms except Cd in M. procera. Antioxidant activity was evaluated by free radical scavenging and reducing power. M. procera extract had more potent free radical scavenging activity (IC50=311.40 MUg/mL) than L. deliciosus extract. Moreover, the tested extracts had effective reducing power. The total content of phenol in the extracts was examined using Folin-Ciocalteu reagent and obtained values expressed as pyrocatechol equivalents. Further, the antimicrobial potential was determined with a microdilution method on 15 microorganisms. Among the tested species, extract of L. deliciosus showed a better antimicrobial activity with minimum inhibitory concentration values ranging from 2.5 mg/mL to 20 mg/mL. Finally, the cytotoxic activity was tested using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method on human epithelial carcinoma HeLa cells, human lung carcinoma A549 cells, and human colon carcinoma LS174 cells. Extract of both mushrooms expressed similar cytotoxic activity with IC50 values ranging from 19.01 MUg/mL to 80.27 MUg/mL. PMID- 28911553 TI - Rapid determination of trace level copper in tea infusion samples by solid contact ion selective electrode. AB - A new solid contact copper selective electrode with a poly (vinyl chloride) (PVC) membrane consisting of o-xylylenebis(N,N-diisobutyldithiocarbamate) as ionophore has been prepared. The main novelties of constructed ion selective electrode concept are the enhanced robustness, cheapness, and fastness due to the use of solid contacts. The electrode exhibits a rapid (< 10 seconds) and near-Nernstian response to Cu2+ activity from 10-1 to 10-6 mol/L at the pH range of 4.0-6.0. No serious interference from common ions was found. The electrode characterizes by high potential stability, reproducibility, and full repeatability. The electrode was used as an indicator electrode in potentiometric titration of Cu(II) ions with EDTA and for the direct assay of tea infusion samples by means of the calibration graph technique. The results compared favorably with those obtained by the atomic absorption spectroscopy (AAS). PMID- 28911554 TI - Quantitation of curcuminoid contents, dissolution profile, and volatile oil content of turmeric capsules produced at some secondary government hospitals. AB - The aim of this work was to validate the simple and rapid isocratic reversed phase-high performance liquid chromatography using a C-18 column for the determination of curcuminoid contents, dissolution profile, and volatile oil content of turmeric capsules produced at three secondary government hospitals. The validated reversed phase-high performance liquid chromatography method for three curcuminoids (bisdemethoxycurcumin, demethoxycurcumin, and curcumin) had a good linearity (R2 > 0.9990), accuracy (% recovery was 99.96-101.14%, 97.42 102.23%, and 98.01-99.12% for bisdemethoxycurcumin, demethoxycurcumin, and curcumin, respectively), precision (% relative standard deviation < 2% and < 5% for intraday and interday precision, respectively), including limit of detection, limit of quantitation, and system suitability. We found that turmeric capsules had a higher content of curcumin than bisdemethoxycurcumin and demethoxycurcumin. The total curcuminoid contents of all lots ranged from 12.02%w/w to 14.36%w/w. Dissolution profiles of curcuminoids were fitted with Higuchi model. Moreover, volatile oil content, determined using the hydrodistillation method, ranged from 7.00%v/w to 8.00%v/w. In conclusion, all nine lots of turmeric capsules from three secondary government hospitals met the standard criteria of the Thai Herbal Pharmacopoeia in the topic of curcuminoid contents, dissolution, and volatile oil content. PMID- 28911555 TI - Effect of shaking process on correlations between catechins and volatiles in oolong tea. AB - Shaking the tea leaves is the key manipulation to making oolong tea. It contributes to the formation of flavor and fragrance in oolong tea. The dynamic variations of catechins and volatile organic compounds (VOCs) during the shaking process were investigated. The results showed that the contents of epicatechin, epigallocatechin, epicatechin gallate (ECG), and epigallocatechin gallate (EGCG) first decreased after the shaking and then increased to the initial value before the next shaking. Geraniol, linalool and its oxides, and phenylethyl alcohol showed similar variations. The contents of trans-beta-ocimene, 1H-indole, and 3 hexenyl hexanoate increased after the second or third shaking (the late fermentation stage). However, the contents of aldehydes showed an opposite trend to other VOCs. The abundance of phenylethyl alcohol was positively related to the content of ECG and EGCG during fermentation, whereas the abundance of cis-3 hexenal was negatively related to the content of ECG. The correlations between catechin and VOCs indicated that shaking affected the chemical transformation of the compounds in oolong tea. PMID- 28911556 TI - Studies on physicochemical and nutritional properties of aerial parts of Cassia occidentalis L. AB - In the present, work chemical composition and nutritional value of aerial parts of Cassia occidentalis L. was studied. The aerial parts of C. occidentalis possess favorable physicochemical properties with good nutritional value, such as high energy value, crude fibers, and vitamin levels. The X-ray fluorescence spectrophotometry data revealed that the sample is rich in minerals, especially in Fe, Ca, K, and Mn. Further, minerals such as Mg, Zn, Cu, Na, P, and S are present in good amount and depicted the nutritional value of the selected material. The plant sample is rich in phytochemicals such as flavonoids, alkaloids, lignin, tannins, and phenols. The presence of phytochemical constituents was confirmed by gas chromatography-mass spectrometry profile and high-performance thin layer chromatography fingerprinting techniques. The findings stimulate the on-farm cultivation of C. occidentalis on a large scale to relieve the iron deficiency in local community, and it can be used as a dietary supplement to treat anemia. PMID- 28911557 TI - Antihyperlipidemic activity of Allium chinense bulbs. AB - Allium chinense is a medicinal plant and nutritional food commonly used in Eastern Asia. In this study, we investigated the in vitro antioxidant activity (scavenging of alpha,alpha-diphenyl-beta-picrylhydrazyl free radical, total phenol content, reducing power, and total antioxidant activity) and constituents of various extracts from A. chinense. Moreover, we also studied the in vivo hypolipidemic effects of extracts on high-fat-diet Wistar rats. Ethanol extracts from A. chinense showed notable antioxidant activity, and its high-dose essential oil extract both significantly reduced serum and hepatic total cholesterol, triglyceride, and low-density lipoprotein levels and increased serum high-density lipoprotein levels in high-fat-diet Wistar rats compared with those observed following treatment with the control drug probucol. Additionally, visceral fat in high-fat-diet Wistar rats was reduced. Furthermore, groups with high doses of essential-oil and residue extracts showed protective effects associated with histopathological liver alteration. These results suggested that A. chinense is a valuable plant worthy of further investigation as a potential dietary supplement or botanical drug. PMID- 28911558 TI - Inhibitory effects of polyphenol-enriched extract from Ziyang tea against human breast cancer MCF-7 cells through reactive oxygen species-dependent mitochondria molecular mechanism. AB - A polyphenol-enriched extract from selenium-enriched Ziyang green tea (ZTP) was selected to evaluate its antitumor effects against human breast cancer MCF-7 cells. In ZTP, (-)-epigallocatechin gallate (28.2%) was identified as the major catechin, followed by (-)-epigallocatechin (5.7%) and (-)-epicatechin gallate (12.6%). ZTP was shown to inhibit MCF-7 cell proliferation (half maximal inhibitory concentration, IC50 = 172.2 MUg/mL) by blocking cell-cycle progression at the G0/G1 phase and inducing apoptotic death. Western blotting assay indicated that ZTP induced cell-cycle arrest by upregulation of p53 and reduced the expression of CDK2 in MCF-7 cells. ZTP-caused cell apoptosis was associated with an increase in Bax/Bcl-2 ratio, and activation of caspase-3 and -9. MCF-7 cells treated with ZTP also showed an overproduction of reactive oxygen species, suggesting that reactive oxygen species played an important role in the induction of apoptosis in MCF-7 cells. This is the first report showing that ZTP is a potential novel dietary agent for cancer chemoprevention or chemotherapy. PMID- 28911559 TI - Extracts of Agrimonia eupatoria L. as sources of biologically active compounds and evaluation of their antioxidant, antimicrobial, and antibiofilm activities. AB - In this study, we determined the concentration of total phenols, flavonoids, tannins, and proanthocyanidins in the water, diethyl ether, acetone, and ethanol extracts of Agrimonia eupatoria L. We also investigated the antioxidant activity of these extracts using two methods [2,2-diphenyl-1-picrylhydrazyl (DPPH) and reducing power] and their in vitro antimicrobial (antibacterial and antifungal) activity on some selected species of bacteria and fungi. In addition, the effects of the acetone and water extracts on the inhibition of biofilm formation of Proteus mirabilis and Pseudomonas aeruginosa were investigated using the crystal violet method. The concentration of total phenols was measured according to the Folin-Ciocalteu method and the values obtained ranged from 19.61 mgGA/g to 220.31 mgGA/g. The concentration of flavonoids was examined by the aluminum chloride method and the values obtained ranged from 20.58 mgRU/g to 97.06 mgRU/g. The total tannins concentration was measured by the polyvinylpolypyrrolidone method and the values obtained ranged from 3.06 mgGA/g to 207.27 mgGA/g. The concentration of proanthocyanidins was determined by the butanol-HCl method and the values obtained ranged from 4.15 CChE/g to 103.72 CChE/g. Among the various extracts studied, the acetone extract exhibited good antioxidant activity (97.13%, as determined by the DPPH method). The acetone extract was active in the absorbance value range from 2.2665 to 0.2495 (as determined by the reducing power method). The strongest antimicrobial activity was detected on G+ bacteria, especially on probiotic species, and the acetone extract demonstrated the highest activity. Biofilm inhibitory concentration required to reduce biofilm coverage by 50% values for acetone extract was 4315 MUg/mL for P. mirabilis and 4469.5 MUg/mL for P. aeruginosa. The results provide a basis for further research of this plant species. PMID- 28911560 TI - Extraction temperature affects the activities of antioxidation, carbohydrate digestion enzymes, and angiotensin-converting enzyme of Pleurotus citrinopileatus extract. AB - Extraction temperature can potentially affect the chemical compositions and bioactivities of the extracts obtained. The objective of this study was to investigate the effect of extraction temperature on the distribution of bioactive compounds and the bioactivities of Pleurotus citrinopileatus. The antioxidant activities (2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid)+ scavenging capabilities) and the inhibitory capabilities on pancreatic alpha-amylase, intestinal alpha glucosidase, and hypertension-linked angiotensin-converting enzyme of hot water P. citrinopileatus extract and cold water P. citrinopileatus extract were determined. The results showed that the antioxidant capabilities and inhibitory effects on alpha-amylase, alpha-glucosidase, and angiotensin-converting enzyme of cold water P. citrinopileatus extract were significantly higher than those of hot water P. citrinopileatus extract. The cold water P. citrinopileatus extracted was further precipitated with 100% ammonium sulfate to obtain a polysaccharide fraction or with 75% ethanol to obtain a protein fraction. The inhibitory activities of the protein fraction of the cold water P. citrinopileatus extract on alpha-amylase, alpha-glucosidase, and angiotensin-converting enzyme were significantly higher than those of the polysaccharide fraction. In conclusion, the protein fraction of the cold water P. citrinopileatus extract could be responsible for its bioactivities. PMID- 28911561 TI - Thymol reduces oxidative stress, aortic intimal thickening, and inflammation related gene expression in hyperlipidemic rabbits. AB - Atherosclerosis plays a key role in the development of cardiovascular diseases, and is often associated with oxidative stress and local inflammation. Thymol, a major polyphenolic compound in thyme, exhibits antioxidant and anti-inflammatory properties. In this study, we measured the in vitro antioxidant activity of thymol, and investigated the effect of thymol on high-fat-diet-induced hyperlipidemia and atherosclerosis. New Zealand white rabbits were fed with regular chow, high-fat and high-cholesterol diet (HC), T3, or T6 (HC with thymol supplementation at 3 mg/kg/d or 6 mg/kg/d, respectively) for 8 weeks. Aortic intimal thickening, serum lipid parameters, multiple inflammatory markers, proinflammatory cytokines, and atherosclerosis-associated indicators were significantly increased in the HC group but decreased upon thymol supplementation. In summary, thymol exhibits antioxidant activity, and may suppress the progression of high-fat-diet-induced hyperlipidemia and atherosclerosis by reducing aortic intimal lipid lesion, lowering serum lipids and oxidative stress, and alleviating inflammation-related responses. PMID- 28911562 TI - Bioactive compounds and antioxidative activity of colored rice bran. AB - The profiles of bioactive compounds (including phenolics and flavonoids in free and bound fractions, anthocyanins, proanthocyanidins, vitamin E, and gamma oryzanol) of outer and inner rice bran from six colored rice samples collected from local markets were investigated. Proanthocyanidins could only be detected in red rice bran but not in black rice bran. The free fraction of the extracts dominated the total phenolics (72-92%) and the total flavonoids (72-96%) of colored rice bran. Most of the phenolic acids (83-97%) in colored rice bran were present in the bound form. Protocatechualdehyde was identified for the first time in the bound fraction of red rice bran by high performance liquid chromatography photodiode array/electrospray ionization tandem mass spectrometry. The antioxidative activities of the free fraction of the colored rice bran were attributed to the proanthocyanidins in red colored rice and anthocyanins in black rice, while that of the bound fraction was mainly due to the phenolic acids. PMID- 28911563 TI - Effects of electrode gap and electric potential on chlorine generation of electrolyzed deep ocean water. AB - Electrolyzed water is a sustainable disinfectant, which can comply with food safety regulations and is environmentally friendly. A two-factor central composite design was adopted for studying the effects of electrode gap and electric potential on chlorine generation efficiency of electrolyzed deep ocean water. Deep ocean water was electrolyzed in a glass electrolyzing cell equipped with platinum-plated titanium anode and cathode. Results showed high electric efficiency at a low cell potential, and a high current density and high chlorine concentration at a high cell potential and low electrode gap. Current efficiency of the system was not significantly affected by electrode gap and electric potential. A small electrode gap reduced the required cell potential and resulted in high energy efficiency. The optimal choice of electrode gap and cell potential depends on the chlorine level of the electrolyzed deep ocean water to be produced, and a small electrode gap is preferred. PMID- 28911564 TI - Trace residue analysis of dicyandiamide, cyromazine, and melamine in animal tissue foods by ultra-performance liquid chromatography. AB - An effective sample preparation procedure using an accelerated solvent extraction (ASE) procedure, followed by cleaning with melamine molecularly imprinted polymers solid-phase extraction (MISPE) was developed. A novel and highly sensitive ASE-MISPE-ultra-performance liquid chromatography (UPLC) method was developed for effective separation and simultaneous determination of dicyandiamide (DCD), cyromazine (CYR), and melamine (MEL) in complex animal tissue foods. Under optimized conditions, good linearity was achieved with a correlation coefficient (r) of 0.9999 in the range of at least two orders of magnitude. The limit of quantification of the method was 1.7 MUg/kg, 5.0 MUg/kg, and 3.2 MUg/kg for DCD, MEL, and CYR, which was three orders of magnitude smaller than the maximum residue limits (MRLs). The intra- and inter-day precisions (in terms of the relative standard deviation, RSD) of the three analytes were in the range of 1.7-3.1% and 3.1-6.3%, respectively. The average recoveries of analytes from blank chicken, beef, mutton, pork, and pig liver samples spiked with the three levels varied from 91.2% to 107% with RSD of 1.7-8.3% for DCD, 89.0-104% with RSD of 2.1-6.1% for CYR, and 94.8-105% with RSD of 1.1-6.6% for MEL. The proposed method has the characteristics of speed, sensitivity, and accuracy, and can be used for the routine determination of DCD, CYR, and MEL at the MUg/kg level in complex animal tissue foods. PMID- 28911565 TI - Renoprotective effect of Caralluma fimbriata against high-fat diet-induced oxidative stress in Wistar rats. AB - The current study was designed to evaluate the renoprotective effect of hydro alcoholic extract of Caralluma fimbriata (CFE) against high-fat diet-induced oxidative stress in Wistar rats. Male Wistar rats were randomly divided into five groups: control (C), control treated with CFE (C + CFE), high-fat diet fed (HFD), high-fat diet fed treated with CFE (HFD + CFE), and high-fat diet fed treated with metformin (HFD + metformin). CFE was orally administered (200 mg/kg body weight) to Groups C + CFE and HFD + CFE rats for 90 days. Renal functional markers such as, urea, uric acid, and creatinine levels in plasma were quantified during the experimental period. At the end of the experimental period, activities of transaminases and oxidative stress markers, i.e., reduced glutathione (GSH), lipid peroxidation, protein oxidation, and activities of antioxidant enzymes were assayed in renal tissue. Coadministration of CFE along with HF-diet in Group HFD + CFE prevented the rise in the levels of plasma urea, uric acid, and creatinine, and elevated activities of renal transaminases with decreased protein content of Group HFD (p < 0.05). Establishment of oxidative stress in Group HFD, as evident from elevated lipid peroxidation, protein oxidation levels with depleted levels of GSH, and decreased activities of GSH dependent and independent antioxidant enzymes, was prevented in Groups HFD + CFE and HFD + metformin rats. Further, there were no deviations in the studied parameters but there was improved antioxidant status of Group C + CFE from Group C which revealed the nontoxic nature of CFE even under chronic treatment. Thus, CFE treatment effectively alleviated the HF-diet induced renal damage. Hence, this plant could be used as an adjuvant therapy for the prevention and/or management of HF-diet induced renal damage. PMID- 28911566 TI - Effects of herbal mixture extracts on obesity in rats fed a high-fat diet. AB - The aim of this study was to investigate and compare the effects of three herbal mixture extracts on obesity induced by high-fat diet (HFD) in rats. The prescriptions-Pericarpium citri reticulatae and Fructus crataegi-were used as matrix components and mixed with Ampelopsis grossedentata, Salvia miltiorrhiza, and epigallocatechin-3-gallate (EGCG) to form T1, T2, and T3 complexes, respectively. Results revealed that HFD feeding significantly increased body weight gain, fat deposition, plasma lipid profiles, hepatic lipid accumulation, and hepatic vacuoles formation, but decreased plasma levels of adiponectin in rats. Only the T1 complex showed the tendency, although not significantly so, for decreased HFD-induced body weight gain. T1 and T3 complexes significantly reduced HFD-induced fat deposition, and plasma levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Only the T1 complex significantly increased HFD-reduced adiponectin levels in plasma, but decreased HFD-increased triglyceride content in liver tissues. All complexes effectively inhibited HFD induced vacuoles formation. The content of dihydromyricetin, salvianolic acid B, and EGCG in T1, T2, and T3 complexes was 18.25 +/- 0.07%, 22.20 +/- 0.10%, and 18.86 +/- 0.04%, respectively. In summary, we demonstrated that herbal mixture extracts, especially T1 complex, exhibit antiobesity activity in HFD-fed rats. PMID- 28911567 TI - Chemical composition and anti-inflammatory activities of essential oil from Trachydium roylei. AB - Chemical composition, anti-inflammatory activity, and cytotoxicity of essential oils obtained from the aerial parts of Trachydium roylei were investigated in this study. The chemical composition of T. roylei essential oil was analyzed using gas chromatography mass spectrometry. Fifty-nine components, representing 98.87% of the oils, were characterized. The oils were predominated by aromatic compounds and monoterpene hydrocarbons, and the main components were myristicin (25.35%), beta-phellandrene (22.95%), elemicine (7.69%), isoelemicin (5.48%), and cedrol (5.26%). The anti-inflammatory activity of the oil in lipopolysaccharide stimulated murine RAW 264.7 cells was evaluated. The oils downregulated the production of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6, and significantly increased the anti inflammatory cytokine IL-10 levels. Results indicated that the oils effectively inhibited the secretion of nitric oxide and prostaglandin E2 in lipopolysaccharide-stimulated macrophages. Western blot analyses were performed to determine whether the inhibitory effects of the oils on proinflammatory mediators (nitric oxide and prostaglandin E2) were related to the modulation of inducible nitric oxide synthase and cyclooxygenase-2 expression. These findings suggest that T. roylei essential oils exert an anti-inflammatory effect by regulating the expression of inflammatory cytokines. PMID- 28911568 TI - Validated high-performance thin-layer chromatographic (HPTLC) method for simultaneous determination of nadifloxacin, mometasone furoate, and miconazole nitrate cream using fractional factorial design. AB - A high-performance thin-layer chromatographic method for simultaneous determination of nadifloxacin, mometasone furoate, and miconazole nitrate was developed and validated as per International Conference on Harmonization guidelines. High-performance thin-layer chromatographic separation was performed on aluminum plates precoated with silica gel 60F254 and methanol:ethyl acetate:toluene: acetonitrile:3M ammonium formate in water (1:2.5:6.0:0.3:0.2, % v/v) as optimized mobile phase at detection wavelength of 224 nm. The retardation factor (Rf) values for nadifloxacin, mometasone furoate, and miconazole nitrate were 0.23, 0.70, and 0.59, respectively. Percent recoveries in terms of accuracy for the marketed formulation were found to be 98.35-99.76%, 99.36-99.65%, and 99.16-100.25% for nadifloxacin, mometasone furoate, and miconazole nitrate, respectively. The pooled percent relative standard deviation for repeatability and intermediate precision studies was found to be < 2% for three target analytes. The effect of four independent variables, methanol content in total mobile phase, wavelength, chamber saturation time, and solvent front, was evaluated by fractional factorial design for robustness testing. Amongst all four factors, volume of methanol in mobile phase appeared to have a possibly significant effect on retention factor of miconazole nitrate compared with the other two drugs nadifloxacin and mometasone furoate, and therefore it was important to be carefully controlled. In summary, a novel, simple, accurate, reproducible, and robust high-performance thin-layer chromatographic method was developed, which would be of use in quality control of these cream formulations. PMID- 28911569 TI - Tumor cell culture on collagen-chitosan scaffolds as three-dimensional tumor model: A suitable model for tumor studies. AB - Tumor cells naturally live in three-dimensional (3D) microenvironments, while common laboratory tests and evaluations are done in two-dimensional (2D) plates. This study examined the impact of cultured 4T1 cancer cells in a 3D collagen chitosan scaffold compared with 2D plate cultures. Collagen-chitosan scaffolds were provided and passed confirmatory tests. 4T1 tumor cells were cultured on scaffolds and then tumor cells growth rate, resistance to X-ray radiation, and cyclophosphamide as a chemotherapy drug were analyzed. Furthermore, 4T1 cells were extracted from the scaffold model and were injected into the mice. Tumor growth rate, survival rate, and systemic immune responses were evaluated. Our results showed that 4T1 cells infiltrated the scaffolds pores and constructed a 3D microenvironment. Furthermore, 3D cultured tumor cells showed a slower proliferation rate, increased levels of survival to the X-ray irradiation, and enhanced resistance to chemotherapy drugs in comparison with 2D plate cultures. Transfer of extracted cells to the mice caused enhanced tumor volume and decreased life span. This study indicated that collagen-chitosan nanoscaffolds provide a suitable model of tumor that would be appropriate for tumor studies. PMID- 28911570 TI - Influence of gallic acid on alpha-amylase and alpha-glucosidase inhibitory properties of acarbose. AB - Acarbose is an antidiabetic drug which acts by inhibiting alpha-amylase and alpha glucosidase activities but with deleterious side effects. Gallic acid (GA) is a phenolic acid that is widespread in plant foods. We therefore investigated the influence of GA on alpha-amylase and alpha-glucosidase inhibitory properties of acarbose (in vitro). Aqueous solutions of acarbose and GA were prepared to a final concentration of 25MUM each. Thereafter, mixtures of the samples (50% acarbose + 50% GA; 75% acarbose+25% GA; and 25% acarbose+75% GA) were prepared. The results revealed that the combination of 50% acarbose and 50% GA showed the highest alpha-glucosidase inhibitory effect, while 75% acarbose+25% GA showed the highest alpha-amylase inhibitory effect. Furthermore, all the samples caused the inhibition of Fe2+-induced lipid peroxidation (in vitro) in rat pancreatic tissue homogenate, with the combination of 50% acarbose and 50% GA causing the highest inhibition. All the samples also showed antioxidant properties (reducing property, 2,2'-azino-bis (-3-ethylbenzthiazoline-6-sulphonate [ABTS*] and 1,1 diphenyl-2-picrylhydrazyl [DPPH] free radicals scavenging abilities, and Fe2+ chelating ability). Therefore, combinations of GA with acarbose could be employed as antidiabetic therapy, with a possible reduction of side effects of acarbose; nevertheless, the combination of 50% acarbose and 50% GA seems the best. PMID- 28911571 TI - Fungal flora and aflatoxin contamination in Pakistani wheat kernels (Triticum aestivum L.) and their attribution in seed germination. AB - This study aimed to isolate fungal pathogens and to subsequently quantify aflatoxin (AF; B1 + B2 + G1 + G2) contamination in wheat crops grown in Pakistan. Accordingly, a total of 185 wheat samples were collected from different areas of Pakistan and numerous potent fungal pathogens were isolated. AF contamination attributed to the presence of intoxicating fungal pathogens and resulting metabolic activities were quantified using a high performance liquid chromatography-fluorescence detector coupled with postcolumn derivatization. Additionally, the effect of fungal pathogens on seed germination was also examined. The results obtained showed that 50% of tested wheat samples were found to be contaminated with a diverse range of fungal species. The rate of recurrence of fungal pathogens were Aspergillus 31%, Penicillium 9%, Fusarium 8%, Rhizopus 3%, and Alternaria 2%. The presence of Tilletia indica and Claviceps purpurea species was found to be inevident in all tested wheat samples. AFB1 contamination was detected in 48 (26.0%) samples and AFB2 in 13 (7.0%) samples. AFG1 and AFG2 were not found in any of the tested samples. The contamination range of AFB1 and AFB2 was 0.05-4.78 MUg/kg and 0.02-0.48 MUg/kg, respectively. The total amount of AFs (B1 + B2) found in 48 (26.0%) samples had a mean level of 0.53 +/- 0.40 MUg/kg and a contamination range of 0.02-5.26 MUg/kg. The overall results showed that in 137 (74.0%) samples, AFs were not found within detectable limits. Furthermore, in 180 (97.2%) samples, AF levels were found to be below the maximum tolerated levels (MTL) recommended by the European Union (4 MUg/kg). In five (2.7%) samples, AF contamination was higher than the MTL of the European Union. However, these samples were fit for human consumption with reference to the MTL (20 MUg/kg) assigned by the USA (Food and Drug Administration and Food and Agriculture Organization) and Pakistan (Pakistan Standards and Quality Control Authority). Germination rates in healthy and contaminated wheat kernels were 84.6% and 45.2%, respectively. Based on the obtained results, it was concluded that the levels of fungal pathogen and AF contamination in Pakistani-grown wheat are not a potential threat to consumer health. However, control procedures along with a strict monitoring policy are mandatory to further minimize the prevalence of fungal carriers and the potency of AFs in crops cultivated in Pakistan. PMID- 28911572 TI - Temporal trend of polychlorinated dibenzo-p-dioxin/polychlorinated dibenzofuran and dioxin like-polychlorinated biphenyl concentrations in food from Taiwan markets during 2004-2012. AB - The levels of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) or polychlorinated biphenyl (PCB) in foodstuffs have decreased over the past decade in many countries. However, the trend for the levels of these compounds in foodstuffs in Taiwan remains unknown. In this study, we compared the distribution of PCDD/F and PCB in nine foodstuff categories acquired from Taiwan markets from 2004 to 2012. The levels expressed as World Health Organization toxic equivalents (WHO-TEQs) in the different foodstuffs tested were as follows: fish, average 0.463 pg WHO98-TEQ/g sample > seafood, 0.163 pg WHO98-TEQ/g > eggs, 0.150 pg WHO98-TEQ/g > oils, 0.126 pg WHO98-TEQ/g > meats, 0.095 pg WHO98-TEQ/g > dairy products, 0.054 pg WHO98-TEQ/g > cereals, 0.017 pg WHO98-TEQ/g > vegetables, 0.013 pg WHO98-TEQ/g > fruits, 0.009 pg WHO98 TEQ/g. Levels were particularly high in crab (average: 0.6 pg WHO98-TEQ/g sample (1.243 pg WHO98-TEQ/g sample) and large marine fish (0.6). In Taiwan, a decreasing trend of PCDD/Fs or dioxin-like PCBs (dl-PCBs) was observed in meat, dairy, eggs, and vegetables, whereas an elevated trend was observed in cereals or the levels were nearly equal in fruits and oils at alternative time shift. Dl PCBs contributed to 60-65% toxicity equivalence levels in fish and seafood, but only to 13-40% in meat and cereal samples. The decreasing trend was consistent with the results in other countries; however, the trends in cereals, fruits, and oils were in contrast to previous results reported in other countries. Cereals and fruits are important crops in southern Taiwan, and the local pollution generated by industries or incinerators may seriously affect the distribution of PCDD/Fs and dl-PCBs. To ensure food safety, a risk assessment for residents living in different areas should be adopted for all food categories simultaneously in the future. PMID- 28911574 TI - Corrigendum to "Characterizing diversity based on nutritional and bioactive compositions of yam germplasm (Dioscorea spp.) commonly cultivated in China" [J Food Drug Anal 24 (2016) 367-375]. PMID- 28911573 TI - Hepatoprotective and antidiabetic effects of Pistacia lentiscus leaf and fruit extracts. AB - Pistacia lentiscus (Anacardiaceae) is commonly used in folk medicine to treat various diseases. The aim of the present study was to evaluate the hepatoprotective and antioxidant activities of extracts of P. lentiscus leaves (PL) and fruits (PF) against experimentally induced liver damage. Furthermore, characterization of extracts was attempted by a spectroscopic methodology (Fourier transform infrared spectroscopy) and high-performance liquid chromatography with diode array detection analysis. A hepatoprotective potential against paracetamol [165 mg/kg body weight (b.w.)] toxicity was noticed in mice pretreated with the same dose of PL or PF extract (125 mg/kg b.w.) or a combination of both (PL/PF 63/63 mg/kg b.w.), as revealed by an analysis of biochemical parameters (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activities and total bilirubin). These results were confirmed by histological examination of the liver, which revealed significant protection against paracetamol-induced hepatic necrosis. Furthermore, PF extract exhibited a promising antidiabetic activity in streptozotocin-induced diabetic rats, similar to the reference drug glibenclamide (0.91 g/L), a result confirmed by in vitro inhibition of alpha-amylase. We demonstrated that the leaf crude extract showed the best effect in all tested methods, compared to its fruit counterpart, probably due to the presence of higher amounts of phenolic compounds, as determined by phytochemical and Fourier transform infrared spectroscopy analyses. Moreover, high-performance liquid chromatography with diode array detection led to the identification of six compounds for each part of the plant. Gallic acid, a characteristic compound of Pistacia species, was most abundant in leaves and fruits, while luteolin was detected for the first time in fruits. Obtained activities of P. lentiscus extracts may well be due, at least in part, to the presence of the above compounds. PMID- 28911575 TI - Recent progress on the traditional Chinese medicines that regulate the blood. AB - In traditional Chinese medicine, the herbs that regulate blood play a vital role. Here, nine herbs including Typhae Pollen, Notoginseng Root, Common Bletilla Tuber, India Madder Root and Rhizome, Chinese Arborvitae Twig, Lignum Dalbergiae Oderiferae, Chuanxiong Rhizoma, Corydalis Tuber, and Motherwort Herb were selected and reviewed for their recent studies on anti-tumor, anti-inflammatory and cardiovascular effects. Besides, the analytical methods developed to qualify or quantify the active compounds of the herbs are also summarized. PMID- 28911576 TI - Dietary antioxidants and their indispensable role in periodontal health. AB - Periodontitis is an increasing area of interest due to its global prevalence. This inflammatory condition results due to the loss of the critical balance between the virulence factors produced by microorganisms and the inflammatory host response. A number of efforts have been made in the past to address this condition and regain periodontal health. Targeting the root cause by nonsurgical debridement has been considered the gold standard. However, research has shown the possible effects of nutrient deficiency and an imbalanced diet on the periodontium. Therefore, an effort toward the maintenance of optimal conditions as well as improvement of the oral health necessities the introduction of adjunctive nutritional therapy, which can benefit the patients. Antioxidants in the diet have some remarkable benefits and valuable properties that play an irreplaceable role in the maintenance of periodontal health. These have emerged as excellent adjuncts that can enhance the outcomes of conventional periodontal therapy. The aim of this review article is to highlight some of these dietary antioxidants that can make a notable difference by striking a balance between health and disease. PMID- 28911577 TI - Chemical constituents and bioactivity of Formosan lauraceous plants. AB - Taiwan is rich in lauraceous plants. A review of 197 references based on the chemical analysis and bioactivity of indigenous lauraceous plants carried out by native scientists from 1963 to 2014 has been compiled. About 303 new compounds and thousands of known compounds comprising alkaloids and non-alkaloids with diverse structures have been isolated or identified from indigenous plants belonging to the 11 lauraceous genera. The volatile components, however, have been excluded from this review. This review provides an overview of the past efforts of Taiwan scientists working on secondary metabolites and their bioactivity in native lauraceous plants. The potential of lauraceous plants worthy of further study is also noted. The contents will be helpful for the chemotaxonomy of Lauraceae and be of value for the development of native Formosan lauraceous plants. PMID- 28911578 TI - Application of hollow fiber liquid phase microextraction and dispersive liquid liquid microextraction techniques in analytical toxicology. AB - The recent developments in hollow fiber liquid phase microextraction and dispersive liquid-liquid microextraction are reviewed. Applications of these newly emerging developments in extraction and preconcentration of a vast category of compounds including heavy metals, pesticides, pharmaceuticals and abused drugs in complex matrices (environmental and biological matrices) are reviewed and discussed. The new developments in these techniques including the use of solvents lighter than water, ionic liquids and supramolecular solvents are also considered. Applications of these new solvents reduce the use of toxic solvents and eliminate the centrifugation step, which reduces the extraction time. PMID- 28911579 TI - Rapid screening of toxic salbutamol, ractopamine, and clenbuterol in pork sample by high-performance liquid chromatography-UV method. AB - A rapid and simple high-performance liquid chromatography-UV method was developed for the separation and quantification of salbutamol, ractopamine, and clenbuterol in pork. A mixture of acetonitrile-formic acid-ammonium acetate was used as the mobile phase to separate three beta-agonists on a C18 column with gradient. The effects of the addition of formic acid and ammonium acetate to mobile phases on the separation of beta-agonists were investigated. These additives can greatly improve the resolution and sensitivity. Under the optimized chromatographic condition, this separation does not need extra sample preparation. Complete baseline separation of three beta-agonists was achieved in < 20 minutes; the linear range is 0.2-50 MUg/L with a correlation coefficient R2 value of > 0.99. Excellent method reproducibility was found by intra- and interday precisions with a relative standard deviation of < 3%. The detection limit (S/N = 3) was found to be <0.05 MUg/L; this method can be used for routine screening of the beta-agonist residues in foods of animal origin before being identified by confirmatory methods. PMID- 28911580 TI - Evaluation of boldenone as a growth promoter in broilers: safety and meat quality aspects. AB - The object of this study was to evaluate the safety and meat quality criteria in broilers following intramuscular injection of boldenone. Twenty-four broiler chicks, divided into two groups, were used in the present study. Boldenone was injected intramuscularly at a single-dose level of 5 mg/kg body weight into 12 broiler chicks at 2 weeks old; the other 12 chicks were injected with sesame oil and kept as controls. Blood samples were collected from the wing and metatarsal veins after 1, 2, and 3 weeks through the experimental course for hematological and clinic-chemical safety parameters. On the last day, chicks were humanely sacrificed and livers and kidneys were removed for histopathological examination. Breast muscles were also removed to assess meat-quality parameters. Boldenone significantly (p < 0.05) increased total erythrocytic count and hemoglobin and hematocrit values, while mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration indices decreased. Leukogram showed leukopenia, lymphopenia, and granulocytosis (p < 0.05) as compared to control. Hepatorenal biomarkers, including alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, urea, and creatinine were significantly (p < 0.05) higher than the corresponding control values. Additionally, boldenone significantly (p < 0.05) increased metabolic markers, including total protein, globulins, cholesterol, triacylglycerols, and glucose, with parallel decreases in albumin and albumin/globulin ratio. Degenerative changes were recorded in liver and kidney tissues from chicks treated with boldenone. Muscle samples exhibited raised pH values and higher microbial counts as compared to the corresponding control. These data may discourage the use of boldenone as a growth promoter in broilers due to safety and meat quality reasons. PMID- 28911581 TI - Characterization of nine polyphenols in fruits of Malus pumila Mill by high performance liquid chromatography. AB - Polyphenols are important bioactive substances in apple. To explore the profiles of the nine representative polyphenols in this fruit, a high-performance liquid chromatography method has been established and validated. The validated method was successfully applied for the simultaneous characterization and quantification of these nine apple polyphenols in 11 apple extracts, which were obtained from six cultivars from Shaanxi Province, China. The results showed that only abscission of the Fuji apple sample was rich in the nine apple polyphenols, and the polyphenol contents of other samples varied. Although all the samples were collected in the same region, the contents of nine polyphenols were different. The proposed method could serve as a prerequisite for quality control of Malus products. PMID- 28911582 TI - Aroma transition from rosemary leaves during aromatization of olive oil. AB - The aroma profile of aromatized olive oil was determined in this study. The primary objective was to investigate the transition of major aroma compounds from rosemary and olive fruit during the kneading step of olive oil production by response surface methodology. For this purpose, temperature, time, and amount of rosemary leaves were determined as independent variables. The results indicated that temperature and time did not affect the transition of target compounds, but rosemary leaves addition had a strong influence on transition, especially for characteristic aroma compounds of this herb. Adequacies of developed models were found to be high enough to predict each aromatic component of interest. PMID- 28911583 TI - Histamine production by Raoultella ornithinolytica in mahi-mahi meat at various storage temperatures. AB - Mahi-mahi meat was inoculated with Raoultella ornithinolytica at 5.0 log CFU/g and stored at -20 degrees C, 4 degrees C, 15 degrees C, 25 degrees C, or 37 degrees C to investigate bacterial growth and formation of total volatile base nitrogen and histamine in mahi-mahi meat. R. ornithinolytica grew rapidly in samples stored at temperature above 15 degrees C. The histamine contents quickly increased to higher than 50 mg/100 g in samples stored at 25 degrees C and 37 degrees C within 12 hours as well as those stored at 15 degrees C within 48 hours. The total volatile base nitrogen contents increased to higher than the index level (30 mg/100 g) for fish decomposition at 25 degrees C within 48 hours and 37 degrees C within 24 hours. However, bacterial growth and histamine formation were controlled by cold storage of the samples at 4 degrees C or below. Once the frozen mahi-mahi samples stored at -20 degrees C for 2 months were thawed and stored at 25 degrees C after 24 hours, histamine started to accumulate rapidly (>50 mg/100 g of fish). PMID- 28911584 TI - Analysis of N-nitrosodiethylamine by ion chromatography coupled with UV photolysis pretreatment. AB - Nitrosamines such as N-nitrosodiethylamine (NDEA) are commonly detected by spectrophotometry after photolysis and Griess reaction (PG) in food industries for lower cost. Results of this research indicate that NDEA decays rapidly under UV irradiation, and concentrations of the generated NO2- and NO3- ions vary with photolysis conditions. Thus, the measurement of the PG method may be inconsistent because it is based on the amount of photoproduced NO2-. In addition, more errors may be present in the PG method since NO3- cannot be measured colorimetrically using Griess reagent. In this work, the sum of the concentrations of photoproduced NO2- and NO3- was found to be equivalent to the initial NDEA before photolysis, and a photolysis-ion chromatography method was validated, which may serve as a feasible and accurate method to determine nitrosamines. PMID- 28911585 TI - Characterization of myrtle seed (Myrtus communis var. baetica) as a source of lipids, phenolics, and antioxidant activities. AB - This study aimed to characterize the chemical composition and antioxidant activity of the oil and the methanolic extract of Myrtus communis var. baetica seed. The oil yield of myrtle seed was 8.90%, with the amount of neutral lipid, especially triacylglycerol, being the highest, followed by phospholipids and glycolipids. Total lipids and all lipid classes were rich in linoleic acid. The content of total phenols, flavonoids, tannins, and proanthocyanidins of the methanolic extract and the oil from myrtle seed was determined using spectrophotometric methods. Antioxidant activities of the oil and the methanolic extract from myrtle seed were evaluated using 1,1-diphenyl-2-picrylhydrazyl radical scavenging, beta-carotene-linoleic acid bleaching, and reducing power and metal chelating activity assays. In all tests, the methanolic extract of myrtle seed showed better antioxidant activity than oil. This investigation could suggest the use of myrtle seed in food, industrial, and biomedical applications for its potential metabolites and antioxidant abilities. PMID- 28911586 TI - Phytochemical standardization, antioxidant, and antibacterial evaluations of Leea macrophylla: A wild edible plant. AB - In Ayurveda, Leea macrophylla Roxb. ex Hornem. (Leeaceae) is indicated in worm infestation, dermatopathies, wounds, inflammation, and in symptoms of diabetes. The present study aims to determine the antioxidant and antibacterial potential of ethanolic extract and its different fractions of Leea macrophylla root tubers using phytochemical profiling which is still unexplored. Quantitative estimations of different phytoconstituents along with characterization of ethanol extract using high performance liquid chromatography (HPLC) were performed using chlorogenic acid as a marker compound for the first time. The extract and its successive fractions were also evaluated for in vitro antioxidant activity using different models. The extract was further tested against a few Gram-positive and Gram-negative bacteria for its antibacterial activity. Phytochemical screening and quantitative estimations revealed the extract to be rich in alkaloid, flavonoid, phenols, and tannins, whereas chlorogenic acid quantified by HPLC in ethanol extract was 9.01% w/w. The results also indicated potential antioxidant and antibacterial activity, which was more prominent in the extract followed by its butanol fraction. PMID- 28911587 TI - Biochemical characterization of a novel antioxidant and angiotensin I-converting enzyme inhibitory peptide from Struthio camelus egg white protein hydrolysis. AB - A peptide from ostrich (Struthio camelus) egg white protein hydrolysate (OEWPH) was purified, characterized, and its antioxidant and enzyme inhibitory properties were evaluated. The OEWPH was prepared using pepsin and pancreatin, and then fractionated using reversed-phase high performance liquid chromatography. The antioxidant activity of the WG-9 peptide was investigated based on its scavenging capacity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 2,20-azinobis (3 ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), superoxide (O2*-), hydroxyl (OH*-), and lipid peroxidation inhibition. The angiotensin-converting enzyme (ACE) inhibitory activity and kinetic parameters of the peptide were determined using N-[3-(2-Furyl)acryloyl]-L-phenylalanyl-glycyl-glycine (FAPGG) as a substrate. Tandem mass spectrometry analysis of the purified peptide revealed a sequence of WESLSRLLG (MW: 1060 Da; WG-9). This peptide inhibited linoleic acid oxidation and acted as a DPPH (IC50 = 15 +/- 0.4 MUg/mL), ABTS (IC50 = 130 +/- 4.5 MUg/mL), superoxide (IC50 = 160 +/- 6.4 MUg/mL), and hydroxyl (IC50 = 150 +/- 6.7 MUg/mL) radical scavenger. The ACE-inhibitory activity and kinetic parameters of the WG-9 peptide were determined, showing an ACE inhibitory activity with IC50 of 46.7 +/- 1.4 MUg/mL. The parameters of peptide/ACE interactions were investigated by molecule docking. Furthermore, viability assays showed that the identified peptide had no cytotoxicity against an HFLF-PI-5 cell line. In conclusion, the WG-9 peptide showed potent antioxidant and ACE-inhibitory activity. PMID- 28911588 TI - Comparing the functional components, SOD-like activities, antimutagenicity, and nutrient compositions of Phellinus igniarius and Phellinus linteus mushrooms. AB - Many species of the genus Phellinus possess beneficial properties, including antioxidant, immune-enhancing, and antimutagenic effects. Phenolic compounds and polysaccharides are two kinds of bioactive compounds; however, few studies have compared the differences between Phellinus igniarius and Phellinus linteus in their functional components, functional activities, and nutrient compositions. Herein, the proximate compositions and microelements of the fruiting body of P. igniarius and P. linteus were determined. The fruiting body of P. igniarius and P. linteus were extracted by boiling water [water extract of P. igniarius (WEPI) and P. linteus (WEPL)]. The contents of total phenolics and polysaccharides, as well as superoxide dismutase (SOD)-like and antimutagenic activities of WEPI and WEPL, were compared. We found that WEPI was rich in phenolics and polysaccharides and had higher SOD-like activity than WEPL. Nutrient compositions were mainly different in minerals, whereas anitmutagenicity was similar. All of these results suggested that P. igniarius has greater potential for the development of antioxidant and immunomodulating food products than P. linteus. PMID- 28911589 TI - Effect of an avocado oil-enhanced diet (Persea americana) on sucrose-induced insulin resistance in Wistar rats. AB - A number of studies have been conducted to evaluate the effects of vegetable oils with varying percentages of monounsaturated and polyunsaturated fatty acids on insulin resistance. However, there is no report on the effect of avocado oil on this pathologic condition. The aim of this work was to evaluate the effect of avocado oil on sucrose-induced insulin resistance in Wistar rats. An experimental study was carried out on Wistar rats that were randomly assigned into six groups. Each group received a different diet over an 8-week period (n = 11 in each group): the control group was given a standard diet, and the other five groups were given the standard feed plus sucrose with the addition of avocado oil at 0%, 5%, 10%, 20%, and 30%, respectively. Variables were compared using Student t test and analysis of variance. Statistically significant difference was considered when p < 0.05. Rats that were given diets with 10% and 20% avocado oil showed lower insulin resistance (p = 0.022 and p = 0.024, respectively). Similar insulin resistance responses were observed in the control and 30% avocado oil addition groups (p = 0.85). Addition of 5-30% avocado oil lowered high sucrose diet induced body weight gain in Wistar rats. It was thus concluded that glucose tolerance and insulin resistance induced by high sucrose diet in Wistar rats can be reduced by the dietary addition of 5-20% avocado oil. PMID- 28911590 TI - Cholinesterase inhibitory activity and chemical constituents of Stenochlaena palustris fronds at two different stages of maturity. AB - Stenochlaena palustris fronds are popular as a vegetable in Southeast Asia. The objectives of this study were to evaluate the anticholinesterase properties and phytochemical profiles of the young and mature fronds of this plant. Both types of fronds were found to have selective inhibitory effect against butyrylcholinesterase compared with acetylcholinesterase. However, different sets of compounds were responsible for their activity. In young fronds, an antibutyrylcholinesterase effect was observed in the hexane extract, which was comprised of a variety of aliphatic hydrocarbons, fatty acids, and phytosterols. In the mature fronds, inhibitory activity was observed in the methanol extract, which contained a series of kaempferol glycosides. Our results provided novel information concerning the ability of S. palustris to inhibit cholinesterase and its phytochemical profile. Further research to investigate the potential use of this plant against Alzheimer's disease is warranted, however, young and mature fronds should be distinguished due to their phytochemical differences. PMID- 28911591 TI - Characterizing diversity based on nutritional and bioactive compositions of yam germplasm (Dioscorea spp.) commonly cultivated in China. AB - Yams (Dioscorea spp.) are widely cultivated as edible resources and medical materials in China. Characterizing chemical compositions in yam germplasm is crucial to determine their diversity and suitability for food and medicine applications. In this study, a core germplasm containing 25 yam landraces was used to create an effective classification of usage by characterizing their nutritive and medicinal compositions. All studied landraces exhibited high contents of starch from 60.7% to 80.6% dry weight (DW), protein (6.3-12.2% DW), minerals (especially Mg 326.8-544.7 mg/kg DW), and essential amino acids. Allantoin and dioscin varied considerably, with values of 0.62-1.49% DW and 0.032 0.092% DW, respectively. The quality variability of 25 yam landraces was clearly separated in light of UPGMA clustering and principal component analysis (PCA). Using an eigenvalue >=1 as the cutoff, the first three principal components accounted for most of the total variability (62.33%). Classification was achieved based on the results of the measured parameters and principal component analysis scores. The results are of great help in determining appropriate application strategies for yam germplasm in China. PMID- 28911592 TI - Purification and identification of anti-inflammatory peptides derived from simulated gastrointestinal digests of velvet antler protein (Cervus elaphus Linnaeus). AB - The objective of this study was to identify anti-inflammatory peptides from simulated gastrointestinal digest (pepsin-pancreatin hydrolysate) of velvet antler protein. The hydrolysate was purified using ultrafiltration and consecutive chromatographic methods. The anti-inflammatory activity of the purified fraction was evaluated by the inhibition of NO production in lipopolysaccharide-induced RAW 264.7 macrophages. Four anti-inflammatory peptides, VH (Val-His), LAN (Leu-Ala-Asn), AL (Ala-Leu), and IA (Ile-Ala), were identified by liquid chromatography/tandem mass spectrometry. Each of these peptides demonstrated a U-shaped dose-effect relationship. VH, LAN, AL and IA showed the strongest anti-inflammatory activities at 200 MUg/mL, that is, 15.5%, 13.0%, 16.0% and 11.2% inhibition of lipopolysaccharide-induced NO production, respectively. Additionally, the enhanced NO inhibitory activity was observed for the peptides mixture, indicating the possible synergistic effects. These results suggested that the peptides derived from velvet antler protein could potentially be used as a promising ingredient in functional foods or nutraceuticals against inflammatory diseases. PMID- 28911593 TI - Anti-inflammatory effects, nuclear magnetic resonance identification, and high performance liquid chromatography isolation of the total flavonoids from Artemisia frigida. AB - The aerial parts of Artemisia frigida Willd. are used to treat joint swelling, renal heat, abnormal menstruation, and sore carbuncle. The anti-inflammatory effects of A. frigida have been well-known in folk medicine, suggesting that components extracted from A. frigida could potentially treat inflammatory disease. With the aim of discovering bioactive compounds, in this study, we extracted total flavonoids from the aerial parts of A. frigida and investigated their anti-inflammatory effects against inflammation induced by carrageenan and egg albumin in rats. At the doses studied, total flavonoids (100 mg/kg, 200 mg/kg, and 400 mg/kg) and some isolated compounds (30 mg/kg) showed significant and dose-dependent anti-inflammatory effects. According to the high-performance liquid chromatography analysis of the total flavonoids from A. frigida, there are five major compounds, namely, 5-hydroxy-3',4'-dimethoxy-7-O-beta-d-glucuronide (F1), 5-hydroxy-3',4',5'-trimethoxy-7-O-beta-d-glucuronide (F2), 5,7,3' trihydroxy-6,4'-dimethoxyflavone (F3), 5,3'-dihydroxy-6,7,4'-trimethoxyflavone (F4), and 5,3'-dihydroxy-3,6,7,4'-tetramethoxyflavone (F5), which may explain the anti-inflammatory activity. PMID- 28911594 TI - Determination of scutellarin in breviscapine preparations using quantitative proton nuclear magnetic resonance spectroscopy. AB - The objective of the present study was to develop the selection criteria of proton signals for the determination of scutellarin using quantitative nuclear magnetic resonance (qNMR), which is the main bioactive compound in breviscapine preparations for the treatment of cerebrovascular disease. The methyl singlet signal of 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt was selected as the internal standard for quantification. The molar concentration of scutellarin was determined by employing different proton signals. To obtain optimum proton signals for the quantification, different combinations of proton signals were investigated according to two selection criteria: the recovery rate of qNMR method and quantitative results compared with those obtained with ultra performance liquid chromatography. As a result, the chemical shift of H-2' and H 6' at delta 7.88 was demonstrated as the most suitable signal with excellent linearity range, precision, and recovery for determining scutellarin in breviscapine preparations from different manufacturers, batch numbers, and dosage forms. Hierarchical cluster analysis was employed to evaluate the determination results. The results demonstrated that the selection criteria of proton signals established in this work were reliable for the qNMR study of scutellarin in breviscapine preparations. PMID- 28911595 TI - Determination of urea content in urea cream by centrifugal partition chromatography. AB - The objective of this study is to establish a centrifugal partition chromatography (CPC) method for determination of the urea ingredient in urea cream. The mechanism of this method is that urea is determined by UV detector at 430 nm after being extracted from the cream and derivatized on line via Ehrlich reaction in rotor of CPC, where the reaction products dissolve in the mobile phase and the cream matrix retains in the stationary phase. The mixed solvent consisting of n-hexane, methanol, hydrochloric acid and p dimethylaminobenzaldehyde with a ratio of 1000 mL:1000 mL:18 mL:2.0 g is used for solvent system of CPC. The CPC method proposed offers good precision and convenience without complex sample pretreatment processes. PMID- 28911596 TI - Delphinidin immobilized on silver nanoparticles for the simultaneous determination of ascorbic acid, noradrenalin, uric acid, and tryptophan. AB - In the present study, the fabrication of a new modified electrode for electrocatalytic oxidation of noradrenalin, based on the delphinidin immobilized on silver nanoparticles modified glassy carbon electrode. Cyclic voltammetry was used to investigate the redox properties of this modified electrode. The surface charge transfer rate constant (ks) and the charge transfer coefficient (alpha) for the electron transfer between the glassy carbon electrode and the immobilized delphinidin were calculated. The differential pulse voltammetry exhibited two linear dynamic ranges and a detection limit of 0.40MUM for noradrenalin determination. Moreover, the present electrode could separate the oxidation peak potentials of ascorbic acid, noradrenalin, uric acid, and tryptophan in a mixture. The usefulness of this nanosensor was also investigated for the determination of ascorbic acid, noradrenalin, and uric acid in pharmaceutical and biological fluid samples with satisfactory results. PMID- 28911597 TI - Antioxidant activity and protective effects of cocoa and kola nut mistletoe (Globimetula cupulata) against ischemia/reperfusion injury in Langendorff perfused rat hearts. AB - Protection against cardiomyocyte damage following ischemia/reperfusion (I/R) injury is highly desirable in patients with ischemic heart disease. Hydromethanol extracts of Globimetula cupulata (mistletoe) growing on cocoa (CGCE) and kola nut (KGCE) trees were assessed for antioxidant content and cardioprotective potential against I/R. Graded concentrations (1-50 MUg/mL) of CGCE or KGCE were tested on Langendorff-perfused rat hearts to evaluate the effects on the flow rate, heart rate, and force of cardiac contraction, while another set of hearts were subjected to biochemical analyses. Both extracts showed good antioxidant content and activity, but KGCE (EC50: 24.8+/-1.8 MUg/mL) showed higher hydroxyl radical scavenging activity than CGCE (70.2+/-4.5 MUg/mL). Both extracts at 3 MUg/mL reversed (p < 0.001) membrane peroxidation and the significant decrease in nitrite level, coronary flow rate, and superoxide dismutase and catalase activity caused by the I/R cycle. It is concluded that G. cupulata protects against ischemia-reperfusion injury in rat hearts via augmenting endogenous antioxidants and significant restoration of altered hemodynamic parameters. PMID- 28911598 TI - Correlation between drug-drug interaction-induced Stevens-Johnson syndrome and related deaths in Taiwan. AB - Concomitant use of some drugs can lead to interactions between them resulting in severe adverse effects. To date, there are few reports of incidences of Stevens Johnson syndrome (SJS) associated with combination drug administration. Therefore, we studied the relationship between drug combinations and SJS-related mortality, with the hope that a retrospective study of this nature would provide information crucial for the prevention of future drug-drug interaction related deaths attributable to SJS. This retrospective longitudinal study used mortality cases from 1999 to 2008 that were diagnosed as erythema multiforme (International Classification of Diseases, Ninth Revision, Clinical Modification 695.1) from the National Health Insurance database in Taiwan. Statistical comparisons of the results were performed using analysis of variance (ANOVA), independent sample t tests, and odds ratio (OR). In this way, the relationship between combinations of SJS-inducing drugs and mortality could be determined. A total of 111 patients who had died, including 63 males and 48 females (66.0 +/- 20 and 70.0 +/- 17.7 years, respectively), were suspected of having experienced drug-drug interaction-related adverse effects. The associated drug combinations included allopurinol and ampicillin (p = 0.049), carbamazepine and sulfamethoxazole/trimethoprim (TMP) (p < 0.0001), carbamazepine and phenytoin (p < 0.0001), sulfamethoxazole/TMP and phenytoin (p = 0.015), sulfadoxine and piroxicam (p = 0.045), phenobarbital and cephalexin (p < 0.0001), ampicillin and erythromycin (p < 0.0001), erythromycin and minocycline (p < 0.0001), and vancomycin and ethambutol (p < 0.0001) administered 1 month before the patients' deaths. Caution should be exercised when administering any drugs that may possibly induce SJS. In addition, attention should be paid to ensure prompt identification of possible drug-drug interactions, and patients should be closely monitored. Furthermore, medications should be immediately discontinued at the first sign or symptom suggesting the occurrence of drug-related SJS, and then prompt, adequate supportive care should be provided. PMID- 28911599 TI - Statistical optimization of lovastatin and confirmation of nonexistence of citrinin under solid-state fermentation by Monascus sanguineus. AB - Lovastatin is a well-known natural statin, which is used for lowering plasma cholesterol levels by inhibiting 3-hydroxy-3-methyl glutaryl coenzyme A reductase. Different strains of Aspergillus and Monascus sp. have been exploited for statin production but Monascus sanguineus is still unexplored. In this study, lovastatin production from Monascus sanguineus under solid state fermentation was optimized using response surface methodology. The optimized value of the lovastatin yield was 20.04 mg/gds with soybean concentration of 20 g/L, CaCl2 concentration of 2.5 g/L, acetic acid concentration of 25 MUL and inoculum size of 3.4 mL. This study also documented spectrometric characterization and fragment pattern of lovastatin with the help of Fourier transfer infrared spectrometry and mass spectrometry. Citrinin was not detected in any of the samples used for this study. PMID- 28911600 TI - Fast separation and quantification of three anti-glaucoma drugs by high performance liquid chromatography UV detection. AB - In this study, a simple and accurate high-performance liquid chromatography method was developed and validated for fast separation of three anti-glaucoma drugs: timolol maleate (TM), brimonidine tartrate (BM), and latanoprost (LP). Separation of the three drugs was achieved in < 6 minutes using a BDS Hypersil phenyl column and a mobile phase consisting of acetonitrile: 25mM phosphate buffer, pH 4.0 (50: 50, v/v) at 1.2 mL/min with UV detection at 210 nm. The method was linear over the concentration ranges of 5.0-200.0 MUg/mL, 2.0-80.0 MUg/mL and 1.0-25.0 MUg/mL with lower detection limits of 0.21 MUg/mL, 0.10 MUg/mL and 0.11 MUg/mL for TM, BM and LP, respectively. The method was applied for the determination of two fixed-dose combination eye drops for the treatment of glaucoma, containing TM together with either BM or LP. Commercial samples of single-ingredient ophthalmic solutions containing the studied drugs were also successfully analyzed. The results obtained by the proposed method were favorably compared with those obtained by the comparison methods using Student's t test and the variance ratio F test. PMID- 28911601 TI - Acute pancreatitis in patients with type 2 diabetes mellitus treated with dipeptidyl peptidase-4 inhibitors. AB - Dipeptidyl peptidase (DPP)-4 inhibitors are approved for use in monotherapy or in combination therapy for patients with type 2 diabetes mellitus for <1 decade. However, numerous reports of DPP-4 inhibitors induced acute pancreatitis were made through the US Food and Drug Administration Adverse Event Reporting System, and this led to a revision in the prescribing information for these drugs. Therefore, this study is designed to evaluate DPP-4 inhibitors induced acute pancreatitis via the spontaneous adverse drug reactions (ADRs) reporting system in a medical center. In four of 2305 ADR cases, it is suspected that DPP-4 inhibitors induced moderate to serious acute pancreatitis. Beyond drugs, other factors also contribute to acute pancreatitis and affect the possibility of ADRs assessed using the Naranjo algorithm. Finally, our results indicate that the incidence of DPP-4 inhibitors induced acute pancreatitis is low. PMID- 28911602 TI - Corrigendum to "Evaluation of a health-promoting school program to enhance correct medication use in Taiwan" [J Food Drug Anal 22 (2014) 271-278]. PMID- 28911603 TI - Corrigendum to "Flavone glycosides from commercially available Lophatheri Herba and their chromatographic fingerprinting and quantitation" [J Food Drug Anal 23 (2015) 821-827]. PMID- 28911604 TI - Nanotechnology in food science: Functionality, applicability, and safety assessment. AB - Rapid development of nanotechnology is expected to transform many areas of food science and food industry with increasing investment and market share. In this article, current applications of nanotechnology in food systems are briefly reviewed. Functionality and applicability of food-related nanotechnology are highlighted in order to provide a comprehensive view on the development and safety assessment of nanotechnology in the food industry. While food nanotechnology offers great potential benefits, there are emerging concerns arising from its novel physicochemical properties. Therefore, the safety concerns and regulatory policies on its manufacturing, processing, packaging, and consumption are briefly addressed. At the end of this article, the perspectives of nanotechnology in active and intelligent packaging applications are highlighted. PMID- 28911605 TI - 7-N-Acetylcysteine-pyrrole conjugate-A potent DNA reactive metabolite of pyrrolizidine alkaloids. AB - Plants containing pyrrolizidine alkaloids (PAs) are widespread throughout the world and are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form reactive dehydropyrrolizidine alkaloids (dehydro-PAs) that are capable of alkylating cellular DNA and proteins, form (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA and DHP protein adducts, and lead to cytotoxicity, genotoxicity, and tumorigenicity. In this study, we determined that the metabolism of riddelliine and monocrotaline by human and rat liver microsomes in the presence of N-acetylcysteine both produced 7-N-acetylcysteine-DHP (7-NAC-DHP) and DHP. Reactions of 7-NAC-DHP with 2' deoxyguanosine (dG), 2'-deoxyadenosine (dA), and calf thymus DNA in aqueous solution followed by enzymatic hydrolysis yielded DHP-dG and/or DHP-dA adducts. These results indicate that 7-NAC-DHP is a reactive metabolite that can lead to DNA adduct formation. PMID- 28911606 TI - Inhibitory mechanism against oxidative stress of caffeic acid. AB - The purpose of this article is to summarize the reported antioxidant activities of a naturally abundant bioactive phenolic acid, caffeic acid (CA, 3,4 dihydroxycinnamic acid), so that new avenues for future research involving CA can be explored. CA is abundantly found in coffee, fruits, vegetables, oils, and tea. CA is among the most potential and abundantly found in nature, hydroxycinnamic acids with the potential of antioxidant behavior. Reactive oxygen species produced as a result of endogenous processes can lead to pathophysiological disturbances in the human body. Foods containing phenolic substances are a potential source for free radical scavenging; these chemicals are known as antioxidants. This review is focused on CA's structure, availability, and potential as an antioxidant along with its mode of action. A brief overview of the literature published about the prooxidant potential of caffeic acid as well as the future perspectives of caffeic acid research is described. CA can be effectively employed as a natural antioxidant in various food products such as oils. PMID- 28911607 TI - Certification of caffeine reference material purity by ultraviolet/visible spectrophotometry and high-performance liquid chromatography with diode-array detection as two independent analytical methods. AB - Caffeine reference material certified for purity is produced worldwide, but no research work on the details of the certification process has been published in the literature. In this paper, we report the scientific details of the preparation and certification of pure caffeine reference materials. Caffeine was prepared by extraction from roasted and ground coffee by dichloromethane after heating in deionized water mixed with magnesium oxide. The extract was purified, dried, and bottled in dark glass vials. Stratified random selection was applied to select a number of vials for homogeneity and stability studies, which revealed that the prepared reference material is homogeneous and sufficiently stable. Quantification of caffeine purity % was carried out using a calibrated UV/visible spectrophotometer and a calibrated high-performance liquid chromatography with diode-array detection method. The results obtained from both methods were combined to drive the certified value and its associated uncertainty. The certified value of the reference material purity was found to be 99.86% and its associated uncertainty was +/-0.65%, which makes the candidate reference material a very useful calibrant in food and drug chemical analysis. PMID- 28911608 TI - Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats. AB - Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 +/- 25.1 vs. 128.8 +/- 8.9 units/L) and aspartate aminotransferase (174.7 +/- 31.5 vs. 296.4 +/- 56.4 units/L, p<0.01) compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 +/- 4.1 vs. 128.8 +/- 8.9 units/L, p<0.01) and aspartate aminotransferase (128.8 +/- 8.54 vs. 296.4 +/- 56.4 units/L, p<0.001) levels in Group IV (goat milk 40 mL/kg) compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg) was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 +/- 2 vs. 89.88 +/- 2.42 MUmol/mL of tissue homogenate, p<0.001 and 69.7 +/- 0.78 vs. 89.88 +/- 2.42 MUmol/mL of tissue homogenate, p<0.001, respectively). Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 +/- 0.29 vs. 3.1 +/- 0.288 units/mL, p<0.001 and 7.8 +/- 0.392 vs. 3.1 +/- 0.288 units/mL, p<0.001) compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent. PMID- 28911609 TI - Antibacterial and laxative activities of strictinin isolated from Pu'er tea (Camellia sinensis). AB - Strictinin, the major phenolic compound in Pu'er teas produced from young leaves and buds of wild trees, was isolated to evaluate its antibacterial and laxative activities. The minimum inhibitory concentrations of strictinin against Propionibacterium acnes and Staphylococcus epidermidis were determined as 250 MUM and 2000 MUM, respectively, apparently higher than those of several antibiotics commonly used for bacterial infections. The additive and synergistic effects on the inhibitory activities of strictinin combined with other commercial antibiotics were observed in two bacteria tested in this study via the analysis of fractional inhibitory concentrations. Laxative activity was observed on defecation of the rats fed with strictinin. Further analysis showed that the laxative effect of strictinin was presumably caused by accelerating small intestinal transit, instead of enhancing gastric emptying, increasing food intake, or inducing diarrhea in the rats. Taken together with the antiviral activities demonstrated previously, it is suggested that strictinin is one of the active ingredients responsible for the antiviral, antibacterial, and laxative effects of wild Pu'er tea, and has the potential to be developed as a mild natural substitute for antibiotics and laxatives. PMID- 28911610 TI - Myrciaria cauliflora extract improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-nicotinamide mice. AB - Myrciaria cauliflora is a functional food rich in anthocyanins, possessing antioxidative and anti-inflammatory properties. Our previous results demonstrated M. cauliflora extract (MCE) had beneficial effects in diabetic nephropathy (DN) and via the inhibition of Ras/PI3K/Akt and kidney fibrosis-related proteins. The purpose of this study was to assess the benefit of MCE in diabetes associated with kidney inflammation and glycemic regulation in streptozotocin-nicotinamide (STZ/NA)-induced diabetic mice. Compared with the untreated diabetic group, MCE significantly improved blood glucose and serum biochemical characteristic levels. Exposure to MCE increased antioxidative enzyme activity and diminished reactive oxygen synthesis. Mice receiving MCE supplementation had reduced intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), colony stimulating factor 1 (CSF-1), interleukin-1beta (IL-1beta), IL-6 and tumor necrosis factor alpha (TNF-alpha) levels compared to the untreated diabetic mice. Inflammatory and fibrotic related proteins such as collagen IV, fibronectin, Janus kinase (JAK), phosphorylated signal transducer and activator of transcription 3 (STAT3), protein kinase C beta (PKC-beta), and nuclear factor kappa B (NF-kappaB) were also inhibited by MCE treatment in STZ/NA mice. These results suggest that MCE may be used as a hypoglycemic agent and antioxidant in Type 2 diabetic mice. PMID- 28911611 TI - Antifatigue and increasing exercise performance of Actinidia arguta crude alkaloids in mice. AB - Actinidia arguta (Siebold et Zucc.) Planch. ex. Miq. is one of the most recently domesticated fruit species with increasing commercial production worldwide. It is a well-known traditional Chinese medicine and is used to reduce blood glucose and treat atopic dermatitis. In addition, it possesses antioxidant, anticancer, and antiallergic properties. In this study, we investigated the physical antifatigue and exercise performance effects of A. arguta crude alkaloids (AACA) extracted with 70% ethanol. Four groups of male Kunming mice (n = 16) were orally administered AACA at doses of 0 mg/kg/d (vehicle), 50 mg/kg/d (AACA-50), 100 mg/kg/d (AACA-100), or 200 mg/kg/d (AACA-200) for 28 days. The effect of AACA treatment on exercise performance was studied using the forelimb grip strength experiment and by the measurement of the weight-loaded swimming time. The antifatigue effect is evaluated based on fatigue-associated biochemical parameters, hepatic and muscular glycogen levels, and changes in the morphology of transverse and longitudinal sections of skeletal muscle. The results showed that AACA could elevate the endurance and grip strength in mice. The exhaustive swimming time of the AACA-50, AACA-100, and AACA-200 groups was significantly (p < 0.05) increased compared with the vehicle. The swimming time of the AACA-100 group was the longest among all groups studied. Mice in the AACA-treated groups had decreased levels of lactate, ammonia, and creatine kinase after a physical challenge compared with the vehicle group. The tissue glycogen, an important energy source during exercise, significantly increased with AACA. The morphology of transverse and longitudinal sections of skeletal muscle did not change in the vehicle group. Overall, these findings suggest that AACA possesses antifatigue effects and increases exercise performance in mice. Therefore, A. arguta may be developed as an antifatigue dietary supplement in the category of functional foods. PMID- 28911612 TI - Effects of carbonyl iron powder on iron deficiency anemia and its subchronic toxicity. AB - Carbonyl iron powder (CIP) has been used as a food additive or mineral supplement. However, the effects of CIP on iron deficiency anemia (IDA) and its subchronic toxicity have not been investigated. We found that oral administration of CIP at a dose of 2.96 mg/kg recovered the hemoglobin concentration of erythrocytes of IDA rats to the normal level after 8 days. The no observed adverse effect level of CIP in rats was considered to be > 200 mg/kg. The hematological and serum biochemical parameters of the rats did not differ significantly between the control and treated groups. There were no morphological changes observed in the organs including liver, kidneys, spleen, testes, stomach and intestine. Therefore, CIP might be a safe iron supplement. PMID- 28911613 TI - Proteomic changes associated with metabolic syndrome in a fructose-fed rat model. AB - Metabolic syndrome (MetS), characterized by a constellation of disorders such as hyperglycemia, insulin resistance, and hypertension, is becoming a major global public health problem. Fructose consumption has increased dramatically over the past several decades and with it the incidence of MetS. However, its molecular mechanisms remain to be explored. In this study, we used male Sprague-Dawley (SD) rats to study the pathological mechanism of fructose induced MetS. The SD rats were fed a 60% high-fructose diet for 16 weeks to induce MetS. The induction of MetS was confirmed by blood biochemistry examination. Proteomics were used to investigate the differential hepatic protein expression patterns between the normal group and the MetS group. Proteomic results revealed that fructose-induced MetS induced changes in glucose and fatty acid metabolic pathways. In addition, oxidative stress and endoplasmic reticulum stress-related proteins were modulated by high-fructose feeding. In summary, our results identify many new targets for future investigation. Further characterization of these proteins and their involvement in the link between insulin resistance and metabolic dyslipidemia may bring new insights into MetS. PMID- 28911614 TI - Hygienic quality, adulteration of pork and histamine production by Raoultella ornithinolytica in milkfish dumpling. AB - Ten milkfish dumpling products purchased from retail stores in southern Taiwan were collected to determine the occurrence of biogenic amines, histamine-forming bacteria, and adulteration of pork. This study showed the high contents of aerobic plate count (APC), total coliforms (TC) and Escherichia coli in tested milkfish dumpling samples, whereas the average content of various biogenic amines in all tested samples was < 1.6 mg/100 g (< 0.05 to 1.54 mg/100 g). Three histamine-producing bacterial strains (2 isolates of Raoultella ornithinolytica and 1 isolate of Enterobacter aerogenes) isolated from tested samples produced 276.6 ppm to 561.8 ppm of histamine in trypticase soy broth supplemented with 1.0% L-histidine (TSBH). Assay of multiplex polymerase chain reaction (PCR) revealed that the adulteration rates were 50% (5/10) for pork in milkfish dumplings. In addition, milkfish dumpling stuffing was inoculated with R. ornithinolytica at 5.0 log colony forming units (CFU)/g and stored at various temperatures from 4 degrees C to 37 degrees C to investigate bacterial growth and formation of histamine. The histamine contents quickly increased to higher than 50 mg/100 g in samples stored at 37 degrees C and 25 degrees C within 24 hours and 36 hours, respectively, as well as stored at 15 degrees C within 48 hours. Therefore, bacterial growth and histamine formation were controlled by cold storage of the samples at 4 degrees C. PMID- 28911615 TI - Investigation of aluminum content of imported candies and snack foods in Taiwan. AB - Candies, chewing gums, dried fruits, jellies, chocolate, and shredded squid pieces imported from 17 countries were surveyed for their aluminum content. The samples were bought from candy shops, supermarkets, and convenience stores, and through online shopping. Sample selection focused on imported candies and snacks. A total of 67 samples, including five chewing gums, seven dried fruits, 13 chocolates, two jellies, two dried squid pieces, and 38 candies, were analyzed. The content of aluminum was analyzed by inductively coupled plasma optical emission spectrometry (ICP OES). The limit of quantitation for aluminum was 1.53 mg/kg. The content of aluminum ranged from not detected (ND) to 828.9 mg/kg. The mean concentrations of aluminum in chewing gums, dried fruits, chocolate, jellies, dried squid pieces, and candies were 36.62 mg/kg, 300.06 mg/kg, 9.1 mg/kg, 2.3 mg/kg, 7.8 mg/kg, and 24.26 mg/kg, respectively. Some samples had relatively high aluminum content. The highest aluminum content of 828.9 mg/kg was found in dried papaya threads imported from Thailand. Candies imported from Thailand and Vietnam had aluminum contents of 265.7 mg/kg and 333.1 mg/kg, respectively. Exposure risk assessment based on data from the Taiwan National Food Consumption Database was employed to calculate the percent provisional tolerable weekly intake (%PTWI). The percent provisional tolerable weekly intake of aluminum for adults (19-50 years) and children (3-6 years) based on the consumption rate of the total population showed that candies and snacks did not contribute greatly to aluminum exposure. By contrast, in the exposure assessment based on the consumers-only consumption rate, the estimated values of weekly exposure to aluminum from dried papaya threads in adults (19-50 years) and children (3-6 years) were 4.18 mg/kg body weight (bw)/wk and 7.93 mg/kg bw/wk, respectively, for 50th percentile consumers, and 6.26 mg/kg bw/wk and 12.88 mg/kg bw/wk, respectively, for 95th percentile consumers. PMID- 28911616 TI - Production of a monoclonal antibody against aflatoxin M1 and its application for detection of aflatoxin M1 in fortified milk. AB - Aflatoxin M1 (AFM1) is a toxic metabolite of the fungal product aflatoxin found in milk. For food safety concern, maximum residual limits of AFM1 in milk and dairy products have been differently enforced in many countries. A suitable detection method is required to screen a large number of product samples for the AFM1 contamination. In this study, monoclonal antibodies (MAbs) against AFM1 were generated using a conventional somatic cell fusion technique. After screening, five MAbs (AFM1-1, AFM1-3, AFM1-9, AFM1-11, and AFM1-17) were obtained that showed cross-reactivity with aflatoxin B1 (AFB1) and aflatoxin G1 (AFG1) but with no other tested compounds. An indirect competitive enzyme-linked immunosorbent assay (ELISA) using a partially purified MAb and antigen-coated plates yielded the best sensitivity with the 50% inhibition concentration (IC50) and the limit of detection (LOD) values of 0.13 ng/mL and 0.04 ng/mL, respectively. This indirect competitive ELISA was used to quantify the amount of fortified AFM1 in raw milk. The precision and accuracy in terms of % coefficient of variation (CV) and % recovery of the detection was investigated for both intra- (n = 6) and inter- (n = 12) variation assays. The % CV was found in the range of 3.50-15.8% and 1.32-7.98%, respectively, while the % recovery was in the range of 92-104% and 100-103%, respectively. In addition, the indirect ELISA was also used to detect AFM1 fortified in processed milk samples. The % CV and % recovery values were in the ranges of 0.1-33.0% and 91-109%, respectively. Comparison analysis between the indirect ELISA and high performance liquid chromatography was also performed and showed a good correlation with the R2 of 0.992 for the concentration of 0.2-5.0 ng/mL. These results indicated that the developed MAb and ELISA could be used for detection of AFM1 in milk samples. PMID- 28911617 TI - Hydrolysis of isoflavone in black soy milk using cellulose bead as enzyme immobilizer. AB - The establishment of a catalytic system to enrich isoflavone aglycones in black soybean milk was investigated in this study. Beta-glucosidase, which was covalently immobilized onto cellulose beads, exhibited a significant efficiency for the conversion of 4-nitrophenyl beta-d-glucuronide to p-nitrophenol over the sol-gel method. The Michaelis constant (Km) of the cellulose bead enzymatic system was determined to be 1.50+/-0.10 mM. Operational reusability of the cellulose bead enzymatic system was justified for more than 10 batch reactions in black soy milk. Moreover, the storage stability verification indicated that the cellulose bead catalytic system was able to sustain its highest catalytic activity for 10 days. High-performance liquid chromatography results demonstrated that this enzymatic system required only 30 minutes to achieve complete isoflavone deglycosylation, and the aglycone content in the total isoflavones in black soy milk was enriched by 67% within 30 minutes by the cellulose bead enzymatic system. PMID- 28911618 TI - Green synthesis of silver nanoparticles using onion extract and their application for the preparation of a modified electrode for determination of ascorbic acid. AB - A high-quality method for one-pot biosynthesis of silver nanoparticles (AgNPs) using onion extracts as reductant and stabilizer is reported. The synthesized AgNPs were characterized by ultraviolet-visible spectroscopy (UV-Vis), X-ray powder diffraction (XRD), and transmission electron microscopy (TEM). UV-Vis spectroscopy results showed that the AgNP absorption band was located at a peak of 397 nm in aqueous solution. Both XRD and TEM results confirmed that the AgNPs were mainly spherical with average diameters of 6.0 nm by TEM and about 5.3-10.2 nm calculated using XRD data. The ability of AgNPs to reduce charge transfer resistance was also investigated using electrochemical impedance spectroscopy. Finally, the effect of synthesized NPs on ascorbic acid signal was investigated by square wave voltammetry. The peak current of square wave voltammograms of ascorbic acid increased linearly with its concentration in the range of 0.4 450.0MUM. The detection limit for ascorbic acid was 0.1MUM. PMID- 28911619 TI - Characterization of yogurts made with milk solids nonfat by rheological behavior and nuclear magnetic resonance spectroscopy. AB - The effect of adding milk solids nonfat (MSNF) on the physical properties and microstructure of yogurts was investigated. The physical properties of fat free yogurt, fat free with MSNF yogurt, whole fat yogurt, and whole fat with MSNF yogurt were analyzed using shear viscosity, viscoelasticity, and texture analysis. The two yogurts with MSNF had higher consistency coefficient (K), storage modulus (G'), yield stress, and hardness. To gain insight into the multiphase system, nuclear magnetic resonance (NMR) and brightfield microscope images were acquired. The addition of MSNF significantly modified NMR relaxation time; T1 values were reduced significantly. Brightfield microscope images showed that the size of the protein network of the two yogurts with MSNF added was greater than that of the two yogurts without MSNF added. The microstructural information supported the physical information. The results showed that the increase in MSNF contributed positively to strengthening the physical/mechanical properties of yogurt. PMID- 28911620 TI - Composition of Asarum heterotropoides var. mandshuricum radix oil from different extraction methods and activities against human body odor-producing bacteria. AB - In this study, oils from Asarum heterotropoides were extracted by traditional solvent extraction and supercritical CO2 (SC-CO2) extraction methods and their antioxidant activities along with antimicrobial and inhibitory activities against five human body odor-producing bacteria (Staphylococcus epidermidis, Propionibacterium freudenreichii, Micrococcus luteus, Corynebacterium jeikeium, and Corynebacterium xerosis) were evaluated. The oil was found to contain 15 components, among which the most abundant component was methyl eugenol (37.6%), which was identified at every condition studied in different extraction methods. The oil extracted with n-hexane and ethanol mixture exhibited a strong antioxidant activity (92% +/- 2%) and the highest ABTS and 2,2-diphenyl-1 picrylhydrazyl scavenging activities (89% +/- 0.2%). The highest amounts of total phenolic content and total flavonoid content were 23.1+/-0.4 mg/g and 4.9+/-0.1 mg/g, respectively, in the traditional method. In the SC-CO2 method performed at 200 bar/50 degrees C using ethanol as an entrainer, the highest inhibition zone was recorded against all the aforementioned bacteria. In particular, strong antibacterial activity (38+/-2 mm) was found against M. luteus. The minimum inhibitory concentration (MIC) for the oil against bacteria ranged from 10.1+/ 0.1 MUg/mL to 46+/-2 MUg/mL. The lowest MIC was found against M. luteus. Methyl eugenol was found to be one of the major compounds working against human body odor-producing bacteria. PMID- 28911621 TI - In vitro prebiotic effects and quantitative analysis of Bulnesia sarmienti extract. AB - Prebiotics are used to influence the growth, colonization, survival, and activity of probiotics, and enhance the innate immunity, thus improving the health status of the host. The survival, growth, and activity of probiotics are often interfered with by intrinsic factors and indigenous microbes in the gastrointestinal tract. In this study, Bulnesia sarmienti aqueous extract (BSAE) was evaluated for the growth-promoting activity of different strains of Lactobacillus acidophilus, and a simple, precise, cost-effective high-performance liquid chromatography (HPLC) method was developed and validated for the determination of active prebiotic ingredients in the extract. Different strains of L. acidophilus (probiotic) were incubated in de Man, Rogosa, and Sharpe (MRS) medium with the supplementation of BSAE in a final concentration of 0.0%, 1.0%, and 3.0% (w/v) as the sole carbon source. Growth of the probiotics was determined by measuring the pH changes and colony-forming units (CFU/mL) using the microdilution method for a period of 24 hours. The HPLC method was designed by optimizing mobile-phase composition, flow rate, column temperature, and detection wavelength. The method was validated according to the requirements of a new method, including accuracy, precision, linearity, limit of detection, limit of quantitation, and specificity. The major prebiotic active ingredients in BSAE were determined using the validated HPLC method. The rapid growth rate of different strains of L. acidophilus was observed in growth media with BSAE, whereas the decline of pH values of cultures varied in different strains of probiotics depending on the time of culture. (+)-Catechin and (-)-epicatechin were identified on the basis of their retention time, absorbance spectrum, and mass spectrometry fragmentation pattern. The developed method met the limit of all validation parameters. The prebiotic active components, (+)-catechin and (-) epicatechin, were quantified as 1.27% and 0.71% (w/w), respectively, in crude extract, and 6.36+/-0.06 MUg/mL and 4.47+/-0.41 MUg/mL (mean+/-standard deviation), respectively, in a prebiotic capsule of BSAE by HPLC analysis. BSAE contains the active components of prebiotics and enhances the growth of L. acidophilus. PMID- 28911622 TI - Sedative and hypnotic effects of supercritical carbon dioxide fluid extraction from Schisandra chinensis in mice. AB - Schisandra chinensis is a traditional Chinese medicine that has been used for treating insomnia and neurasthenia for centuries. Lignans, which are considered to be the bioactive components, are apt to be extracted by supercritical carbon dioxide. This study was conducted to investigate the sedative and hypnotic activities of the supercritical carbon dioxide fluid extraction of S. chinensis (SFES) in mice and the possible mechanisms. SFES exhibited an obvious sedative effect on shortening the locomotor activity in mice in a dose-dependent (10-200 mg/kg) manner. SFES (50 mg/kg, 100 mg/kg, and 200 mg/kg, intragstrically) showed a strong hypnotic effect in synergy with pentobarbital in mouse sleep, and reversal of insomnia induced by caffeine, p-chlorophenylalanine and flumazenil by decreasing sleep latency, sleep recovery, and increasing sleeping time. In addition, it produced a synergistic effect with 5-hydroxytryptophan (2.5 mg/kg, intraperitoneally). The behavioral pharmacological results suggest that SFES has significant sedative and hypnotic activities, and the mechanisms might be relevant to the serotonergic and gamma-aminobutyric acid (GABA)ergic system. PMID- 28911623 TI - A comparative study of three tissue-cultured Dendrobium species and their wild correspondences by headspace gas chromatography-mass spectrometry combined with chemometric methods. AB - : Plant tissue culture technique is widely used in the conservation and utilization of rare and endangered medicinal plants and it is crucial for tissue culture stocks to obtain the ability to produce similar bioactive components as their wild correspondences. In this paper, a headspace gas chromatography-mass spectrometry method combined with chemometric methods was applied to analyze and evaluate the volatile compounds in tissue-cultured and wild Dendrobium huoshanense Cheng and Tang, Dendrobium officinale Kimura et Migo and Dendrobium moniliforme (Linn.) Sw. In total, 63 volatile compounds were separated, with 53 being identified from the three Dendrobium spp. SAMPLES: Different provenances of Dendrobiums had characteristic chemicals and showed remarkable quantity discrepancy of common compositions. The similarity evaluation disclosed that the accumulation of volatile compounds in Dendrobium samples might be affected by their provenance. Principal component analysis showed that the first three components explained 85.9% of data variance, demonstrating a good discrimination between samples. Gas chromatography-mass spectrometry techniques, combined with chemometrics, might be an effective strategy for identifying the species and their provenance, especially in the assessment of tissue-cultured Dendrobium quality for use in raw herbal medicines. PMID- 28911624 TI - Bovine serum albumin adsorbed on eremomycin and grafted on silica as new mixed binary chiral sorbent for improved enantioseparation of drugs. AB - A new silica-based, mixed-binary chiral sorbent grafted with the macrocyclic antibiotic eremomycin and bovine serum albumin (BSA) was obtained. The sorbent filled high-performance liquid chromatography column was capable of enantioseparation of racemic drugs, such as profens, in reversed-phase chromatography mode. The mixed-binary eremomycin-BSA-sorbent showed better capability for profens enantioseparation as compared with a sorbent containing eremomycin only. BSA grafted onto the sorbent surface significantly reduced retention times of other proteins from the analyte solution, and free proteins (including BSA) injected as analytes were not retained on the column, and subsequently eluted with a dead volume. The drastic difference observed in the binding of profens and other proteins using the sorbent was tested for determination and enantioseparation of profens in artificial-urine solutions. PMID- 28911625 TI - Suppression of ERK1/2 and hypoxia pathways by four Phyllanthus species inhibits metastasis of human breast cancer cells. AB - Chemotherapies remain far from ideal due to drug resistance; therefore, novel chemotherapeutic agents with higher effectiveness are crucial. The extracts of four Phyllanthus species, namely Phyllanthus niruri, Phyllanthus urinaria, Phyllanthus watsonii, and Phyllanthus amarus, were shown to induce apoptosis and inhibit metastasis of breast carcinoma cells (MCF-7). The main objective of this study was to determine the pathways utilized by these four Phyllanthus species to exert anti-metastatic activities. A cancer 10-pathway reporter was used to investigate the pathways affected by the four Phyllanthus species. Results indicated that these Phyllanthus species suppressed breast carcinoma metastasis and proliferation by suppressing matrix metalloprotein 2 and 9 expression via inhibition of the extracellular signal-related kinase (ERK) pathway. Additionally, inhibition of hypoxia-inducible factor 1-alpha in the hypoxia pathway caused reduced vascular endothelial growth factor and inducible nitric oxide synthase expression, resulting in anti-angiogenic effects and eventually anti-metastasis. Two-dimensional gel electrophoresis identified numerous proteins suppressed by these Phyllanthus species, including invasion proteins, anti apoptotic protein, protein-synthesis proteins, angiogenic and mobility proteins, and various glycolytic enzymes. Our results indicated that ERK and hypoxia pathways are the most likely targets of the four Phyllanthus species for the inhibition of MCF-7 metastasis. PMID- 28911626 TI - High-throughput liquid chromatography tandem mass spectrometry method for simultaneous determination of fampridine, paroxetine, and quinidine in rat plasma: Application to in vivo perfusion study. AB - A selective and high-throughput liquid chromatography-mass spectrometry method has been developed and validated for the simultaneous quantification of paroxetine, fampridine, and quinidine in rat plasma using imipramine as an internal standard. Following protein precipitation extraction, the analytes and internal standard were run on XBridge C18 column (150 mm * 4.6 mm, 5 MUm) using a gradient mobile phase consisting of 5mM ammonium formate in water (pH 9.0) and acetonitrile in a flow gradience program. The precursor and product ions of the drugs were monitored on a triple quadrupole instrument operated in the positive ionization mode. The method was validated over a concentration range of 0.1-100 ng/mL for all the three analytes, with relative recoveries ranging from 69% to 82%. The intra- and interbatch precision (percent coefficient of variation) across four validation runs were less than 13.4%. The accuracy determined at four quality control (QC) levels (lower limit of quantitation, low QC, medium QC, and high QC) was within +/-6.5% of coefficient of variation values. The method proved highly reproducible and sensitive, and was successfully applied in a pharmacokinetic study after single-dose oral administration to rats and also in perfusion study sample analysis. PMID- 28911627 TI - Assessment of the pharmacokinetics, removal rate of hemodialysis, and safety of lactulose in hemodialysis patients. AB - Lactulose is often used to treat hepatic encephalopathy or constipation, and also exhibits benefits to chronic renal insufficiency due to reduce nitrogen-related products in serum. The present study investigated the pharmacokinetics of lactulose, its removal rate through dialysis, and safety by administering lactulose 6.5 g (Lagnos Jelly Divided Pack 16.05 g) orally to six hemodialysis patients who resided in Taiwan. As a result, the means of maximum plasma concentrations (Cmax) and Time to reach Cmax (Tmax) were 3090 +/- 970 ng/mL and 6.5 +/- 2.3 hours, respectively. The mean plasma concentration was 2220 +/- 986 ng/mL after administration for 24 hours. Sequentially, the mean plasma concentration reduced to 307 +/- 117 ng/mL after the application of 4-hour dialysis. Area under the plasma concentration-time curve from zero to 24 h post dose (AUC0-24h) were 56,200 +/- 21,300 ng h/mL and the AUC0-28h was 61,200 +/- 23,300 ng h/mL. The rate of lactulose removal by dialysis was 83.6+/-8.9%. In addition, the multiple doses of lactulose using a simulated model suggested that no plasma accumulation would be expected while coordinating with dialysis. Good tolerability was confirmed, while the mild adverse effect of diarrhea was observed in one case during the study period. No death or serious adverse effect was reported. Based on the present study, we demonstrated the pharmacokinetic transition with respect to plasma levels of lactulose in patients with impaired renal excretion treated with hemodialysis. PMID- 28911628 TI - Antifungal activity of Momordica charantia seed extracts toward the pathogenic fungus Fusarium solani L. AB - Momordica charantia L., a vegetable crop with high nutritional value, has been used as an antimutagenic, antihelminthic, anticancer, antifertility, and antidiabetic agent in traditional folk medicine. In this study, the antifungal activity of M. charantia seed extract toward Fusarium solani L. was evaluated. Results showed that M. charantia seed extract effectively inhibited the mycelial growth of F. solani, with a 50% inhibitory rate (IC50) value of 108.934 MUg/mL. Further analysis with optical microscopy and fluorescence microscopy revealed that the seed extract led to deformation of cells with irregular budding, loss of integrity of cell wall, as well as disruption of the fungal cell membrane. In addition, genomic DNA was also severely affected, as small DNA fragments shorter than 50 bp appeared on agarose gel. These findings implied that M. charantia seed extract containing alpha-momorcharin, a typical ribosome-inactivating protein, could be an effective agent in the control of fungal pathogens, and such natural products would represent a sustainable alternative to the use of synthetic fungicides. PMID- 28911629 TI - A survey of aflatoxin M1 in cow milk in Southern Iran. AB - The competitive enzyme-linked immunosorbent assay technique was used to evaluate aflatoxin M1 (AFM1) levels in 168 samples of raw milk (135 samples and 33 samples from bulk tanks of farms and milk collection centers, respectively) and 12 samples of pasteurized milk in Fars province, Southern Iran. AFM1 was found in 55.56% of the samples with a mean concentration of 21.31 ng/L. The concentration of AFM1 in raw milk samples from farms was significantly (p<0.05) lower than that in samples from collection centers and pasteurized milk. The concentration of AFM1 was not influenced by season, location, or type of farm. The concentrations of AFM1 in all samples were lower than the Iranian national standard limit (100 ng/L), but in 30% of raw cow milk samples they were higher than the maximum tolerance limit accepted by the European Union (50 ng/L); therefore, more effort is needed to control AFM1 levels in milk produced in Southern Iran. PMID- 28911630 TI - Nonenzymatic glucose sensor based on disposable pencil graphite electrode modified by copper nanoparticles. AB - A nonenzymatic glucose sensor based on a disposable pencil graphite electrode (PGE) modified by copper nanoparticles [Cu(NP)] was prepared for the first time. The prepared Cu(NP) exhibited an absorption peak centered at ~562 nm using UV visible spectrophotometry and an almost homogenous spherical shape by scanning electron microscopy. Cyclic voltammetry of Cu(NP)-PGE showed an adsorption controlled charge transfer process up to 90.0 mVs-1. The sensor was applied for the determination of glucose using an amperometry technique with a detection limit of [0.44 (+/-0.01) MUM] and concentration sensitivity of [1467.5 (+/-1.3) MUA/mMcm-2]. The preparation of the Cu(NP)-PGE sensor was reproducible (relative standard deviation = 2.10%, n = 10), very simple, fast, and inexpensive, and the Cu(NP)-PGE is suitable to be used as a disposable glucose sensor. PMID- 28911631 TI - New psychoactive substances of natural origin: A brief review. AB - Plant-based drugs of abuse are as old as recorded human history. Although traditional addictive substances, such as opium, cannabis and coca, have been controlled by the United Nations anti-drug conventions, many, if not most, natural plants with addictive or abuse liability remain elusive. Therefore, the United Nations Office on Drugs and Crime (UNODC) has warned the emerging threat from new psychoactive substances (NPS), which are mostly derived or modified from the constituents of natural origin. For example, synthetic cannabinoids and synthetic cathinones are derived from the cannabis and khat plant, respectively. In this review, we briefly discussed the chemistry, pharmacology and toxicology of five common NPS of natural origin, i.e., khat, kratom, salvia, magic mushroom and mandrake. Through the review, we hope that professionals and general public alike can pay more attention to the potential problems caused by natural NPS, and suitable control measures will be taken. PMID- 28911632 TI - Determination of urea in milk based on N-bromosuccinimide-dichlorofluorescein postchemiluminescence method. AB - A new postchemiluminescence (PCL) reaction was observed when urea was injected into the reaction mixture after the CL reaction of N-bromosuccinimide and dichlorofluorescein. A possible reaction mechanism was proposed based on the studies of the CL kinetic characteristics, CL spectra, fluorescence spectra, and other experiments. A new flow injection CL method for the determination of urea was established based on the PCL reaction. The relative standard deviation for the determination of urea was 1.3% (n = 11, c = 5.0 * 10-8 g/mL). The CL intensity responded linearly to the concentration of urea in the range 2.0 * 10-9 1.0 * 10-6 g/mL (r = 0.9992). The detection limit was 7 * 10-10 g/mL. The method had been applied to the determination of urea in milk with satisfactory results. PMID- 28911633 TI - An analysis method for flavan-3-ols using high performance liquid chromatography coupled with a fluorescence detector. AB - Procyanidins belong to a family of flavan-3-ols, which consist of monomers, (+) catechin and (-)-epicatechin, and their oligomers and polymers, and are distributed in many plant-derived foods. Procyanidins are reported to have many beneficial physiological activities, such as antihypertensive and anticancer effects. However, the bioavailability of procyanidins is not well understood owing to a lack of convenient and high-sensitive analysis methods. The aim of this study was to develop an improved method for determining procyanidin content in both food materials and biological samples. High performance liquid chromatography (HPLC) coupled with a fluorescence detector was used in this study. The limits of detection (LODs) of (+)-catechin, (-)-epicatechin, procyanidin B2, procyanidin C1, and cinnamtannin A2 were 3.0*10-3 ng, 4.0*10-3 ng, 14.0*10-3 ng, 18.5*10-3 ng, and 23.0*10-3 ng, respectively; the limits of quantification (LOQs) were 10.0*10-3 ng, 29.0*10-3 ng, 28.5*10-3 ng, 54.1*10-3 ng, and 115.0*10-3 ng, respectively. The LOD and LOQ values indicated that the sensitivity of the fluorescence detector method was around 1000 times higher than that of conventional HPLC coupled with a UV-detector. We applied the developed method to measure procyanidins in black soybean seed coat extract (BE) prepared from soybeans grown under three different fertilization conditions, namely, conventional farming, basal manure application, and intertillage. The amount of flavan-3-ols in these BEs decreased in the order intertillage > basal manure application > conventional farming. Commercially available BE was orally administered to mice at a dose of 250 mg/kg body weight, and we measured the blood flavan-3-ol content. Data from plasma analysis indicated that up to the tetramer oligomerization, procyanidins were detectable and flavan-3-ols mainly existed in conjugated forms in the plasma. In conclusion, we developed a highly sensitive and convenient analytical method for the analysis of flavan-3-ols, and applied this technique to investigate the bioavailability of flavan-3-ols in biological samples and to measure flavan-3-ol content in food material and plants. PMID- 28911634 TI - Extraction and quantification of polyphenols from kinnow (Citrus reticulate L.) peel using ultrasound and maceration techniques. AB - An investigation was carried out to extract polyphenols from the peel of kinnow (Citrus reticulate L.) by maceration and ultrasound-assisted extraction (UAE) techniques. The antioxidant potential of these polyphenols was evaluated using ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and superoxide radical scavenging assays; and their antimicrobial activity was assessed against bacterial strains Staphyloccoccus aureus, Bacillus cereus, and Salmonella typhimurium. The highest extraction yield was obtained through the solvent ethanol at 80% concentration level, whereas UAE was a more efficient technique and yielded comparatively higher polyphenol contents than maceration. Maximum polyphenols were extracted with 80% methanol [32.48 mg gallic acid equivalent (GAE)/g extract] using UAE, whereas minimum phenolics (8.64 mg GAE/g extract) were obtained with 80% ethyl acetate through the maceration technique. Elevated antioxidant activity of kinnow peel extracts was exhibited in three antioxidant assays, where 80% methanolic extracts showed the highest antioxidant activity (27.67+/-1.11mM/100 g for FRAP) and the highest scavenging activity, 72.83+/-0.65% and 64.80+/-0.91% for DPPH and superoxide anion radical assays, respectively. Strong correlations between total polyphenols and antioxidant activity were recorded. Eleven phenolic compounds-including five phenolic acids and six flavonoids-were identified and quantified by high performance liquid chromatography. Ferulic acid and hesperidin were the most abundant compounds whereas caffeic acid was the least abundant phenolic compound in kinnow peel extracts. Maximum inhibition zone was recorded against S. aureus (16.00+/-0.58 mm) whereas minimum inhibition zone was noted against S. typhimurium (9.00+/-1.16 mm). It was concluded that kinnow mandarin peels, being a potential source of phenolic compounds with antioxidant and antimicrobial properties, may be used as an ingredient for the preparation of functional foods. PMID- 28911635 TI - Validation and assessment of matrix effect and uncertainty of a gas chromatography coupled to mass spectrometry method for pesticides in papaya and avocado samples. AB - In this paper a method of using the "quick, easy, cheap, effective, rugged, and safe" (QuEChERS) extraction and gas chromatography coupled to mass spectrometry detection (GC-MS) was developed for the analysis of five frequently applied pesticides in papaya and avocado. The selected pesticides, ametryn, atrazine, carbaryl, carbofuran, and methyl parathion, represent the most commonly used classes (carbamates, organophosphorous, and triazines). Optimum separation achieved the analysis of all pesticides in < 6.5 minutes. Validation using papaya and avocado samples established the proposed method as linear, accurate, and precise. In this sense, the correlation coefficients were > 0.99. The limits of detection (LOD) and quantification (LOQ) in papaya ranged from 0.03 mg/kg to 0.35 mg/kg and from 0.06 mg/kg to 0.75 mg/kg, respectively. Meanwhile for avocado, LOD values varied from 0.14 mg/kg to 0.28 mg/kg and LOQ values ranged from 0.22 mg/kg to 0.40 mg/kg. Recoveries obtained for each pesticide in both matrices ranged between 60.6% and 104.3%. The expanded uncertainty of the method was < 26% for all the pesticides in both fruits. Finally, the method was applied to other fruits. PMID- 28911636 TI - Novel electrochemical xanthine biosensor based on chitosan-polypyrrole-gold nanoparticles hybrid bio-nanocomposite platform. AB - The aim of this study was the electrochemical detection of the adenosine-3 phosphate degradation product, xanthine, using a new xanthine biosensor based on a hybrid bio-nanocomposite platform which has been successfully employed in the evaluation of meat freshness. In the design of the amperometric xanthine biosensor, chitosan-polypyrrole-gold nanoparticles fabricated by an in situ chemical synthesis method on a glassy carbon electrode surface was used to enhance electron transfer and to provide good enzyme affinity. Electrochemical studies were carried out by the modified electrode with immobilized xanthine oxidase on it, after which the biosensor was tested to ascertain the optimization parameters. The Biosensor exhibited a very good linear range of 1-200 MUM, low detection limit of 0.25 MUM, average response time of 8 seconds, and was not prone to significant interference from uric acid, ascorbic acid, glucose, and sodium benzoate. The resulting bio-nanocomposite xanthine biosensor was tested with fish, beef, and chicken real-sample measurements. PMID- 28911637 TI - Safety of frozen liver for human consumption. AB - The objective of this study was to ensure and evaluate the safety of imported frozen beef liver traded in supermarkets of Kafr El-Sheikh Governorate, Egypt, through detection of Salmonella typhimurium, Salmonella enteritidies, Escherichia coli O157:H7, antibiotic residues, and aflatoxin B1 residue. Fifty samples of imported frozen liver were randomly collected from different shops at Kafr El Sheikh Governorate for isolation of S. typhimurium, S. enteritidies, and E. coli O157:H7. The results revealed that for both microorganisms 4% of the examined samples presumed to contain Salmonella and E. coli O157:H7 organisms, according to the colonial character on Harlequin Salmonella ABC agar media and Harlequin SMAC-BCIG agar media. According to biochemical and serological identifications, both organisms could not be detected in the examined samples. A total of 29 (58%) samples were positive for antibiotic residues, using the Premi test (a broad spectrum screening test for the detection of antibiotic residues in meat) at or below the maximum residue limits. In addition, aflatoxin B1 was detected in one (2%) samples with a concentration of 1.1 MUg/kg. The results reflect that there was good hygiene practice for handling and preparation of frozen liver while selling to consumers. However, a high percentage of antibiotic residues reflect ignorance of withdrawal time before slaughtering of animals as well as misuse of antibiotics in veterinary fields. Furthermore, aflatoxin B1 residue was detected in examined frozen liver samples at a concentration below the maximum residual level, which is not enough to cause threat to humans, but it is enough to cause problem if it is eaten regularly reflect contamination of animal feed with aflatoxins. PMID- 28911638 TI - Assessment of antibacterial drug residues in milk for consumption in Kosovo. AB - The objective of this study was to assess the occurrence of drug residues in the raw milk collected from individual farms and milk collection points during 2009 2010 in six different major regions of Kosovo (Prishtine, Gjilan, Mitrovice, Peje, Gjakove, Prizren). In the present study, a total of 1734 raw milk samples were collected, and qualitatively screened with two different tests, the Delvotest SP assay and an enzyme-linked receptor-binding assay (SNAP). Overall, 106 (6.11%) out of 1734 samples examined with Delvotest SP contained possible drug residues (5.12% and 7.51% of samples from 2009 and 2010, respectively). All suspect samples were further analyzed by three distinct enzyme-linked receptor binding assays specific for beta-lactams (new beta-lactam test), tetracyclines (SNAP tetracycline test), and sulfonamides (SNAP sulfamethazine test). Only the new SNAP beta-lactam test detected residues in 40 out of 52 samples in 2009 and 54 out of 54 suspect samples in 2010. A confirmatory method based on liquid chromatography-tandem mass spectrometry was used to confirm the presence of beta lactam drug residues in samples detected by the enzyme-linked receptor-binding assay. Amoxicillin, penicillin G, and cloxacillin were the most frequently detected residues and were in a concentration range between 2.1 MUg/kg and 1973 MUg/kg. Seventeen of the positive samples exceeded the maximum residue levels for one or more beta-lactam drug. The highest number of positive milk samples came from the Peje Region (58.8%) and Gjakove Region (23.5%), and the lowest number of positive samples originated from Gjilan (5.88%), with no positive samples detected in two regions, Mitrovice and Prizren. PMID- 28911639 TI - Designing primers and evaluation of the efficiency of propidium monoazide - Quantitative polymerase chain reaction for counting the viable cells of Lactobacillus gasseri and Lactobacillus salivarius. AB - The purpose of this study is to evaluate the efficiency of using propidium monoazide (PMA) real-time quantitative polymerase chain reaction (qPCR) to count the viable cells of Lactobacillus gasseri and Lactobacillus salivarius in probiotic products. Based on the internal transcription spacer and 23S rRNA genes, two primer sets specific for these two Lactobacillus species were designed. For a probiotic product, the total deMan Rogosa Sharpe plate count was 8.65+/-0.69 log CFU/g, while for qPCR, the cell counts of L. gasseri and L. salivarius were 8.39+/-0.14 log CFU/g and 8.57+/-0.24 log CFU/g, respectively. Under the same conditions, for its heat-killed product, qPCR counts for L. gasseri and L. salivarius were 6.70+/-0.16 log cells/g and 7.67+/-0.20 log cells/g, while PMA-qPCR counts were 5.33+/-0.18 log cells/g and 5.05+/-0.23 log cells/g, respectively. For cell dilutions with a viable cell count of 8.5 log CFU/mL for L. gasseri and L. salivarius, after heat killing, the PMA-qPCR count for both Lactobacillus species was near 5.5 log cells/mL. When the PMA-qPCR counts of these cell dilutions were compared before and after heat killing, although some DNA might be lost during the heat killing, significant qPCR signals from dead cells, i.e., about 4-5 log cells/mL, could not be reduced by PMA treatment. Increasing PMA concentrations from 100 MUM to 200 MUM or light exposure time from 5 minutes to 15 minutes had no or, if any, only minor effect on the reduction of qPCR signals from their dead cells. Thus, to differentiate viable lactic acid bacterial cells from dead cells using the PMA-qPCR method, the efficiency of PMA to reduce the qPCR signals from dead cells should be notable. PMID- 28911640 TI - Long-term feeding of red algae (Gelidium amansii) ameliorates glucose and lipid metabolism in a high fructose diet-impaired glucose tolerance rat model. AB - This study was designed to investigate the effect of Gelidium amansii (GA) on carbohydrate and lipid metabolism in rats with high fructose (HF) diet (57.1% w/w). Five-week-old male Sprague-Dawley rats were fed a HF diet to induce glucose intolerance and hyperlipidemia. The experiment was divided into three groups: (1) control diet group (Con); (2) HF diet group (HF); and (3) HF with GA diet group (HF + 5% GA). The rats were fed the experimental diets and drinking water ad libitum for 23 weeks. The results showed that GA significantly decreased retroperitoneal fat mass weight of HF diet-fed rats. Supplementation of GA caused a decrease in plasma glucose, insulin, tumor necrosis factor-alpha, and leptin. HF diet increased hepatic lipid content. However, intake of GA reduced the accumulation of hepatic lipids including total cholesterol (TC) and triglyceride contents. GA elevated the excretion of fecal lipids and bile acid in HF diet-fed rats. Furthermore, GA significantly decreased plasma TC, triglyceride, low density lipoprotein plus very low density lipoprotein cholesterol, and TC/high density lipoprotein cholesterol ratio in HF diet-fed rats. HF diet induced an in plasma glucose and an impaired glucose tolerance, but GA supplementation decreased homeostasis model assessment equation-insulin resistance and improved impairment of glucose tolerance. Taken together, these results indicate that supplementation of GA can improve the impairment of glucose and lipid metabolism in an HF diet-fed rat model. PMID- 28911641 TI - Evaluation of the prebiotic effects of citrus pectin hydrolysate. AB - Citrus pectin enzyme hydrolysate (PEH) of different hydrolysis time intervals (6 hours, PEH-6; 12 hours, PEH-12; 24 hours, PEH-24; or 48 hours, PEH-48) or concentrations (1%, 2%, and 4%) was tested for its growth stimulation effect on two probiotics, Bifidobacterium bifidum and Lactobacillus acidophilus. Higher monosaccharide concentrations and smaller molecular weights of PEHs were obtained by prolonging the hydrolysis time. In addition, higher PEH concentrations resulted in significantly higher (p < 0.05) probiotic populations, pH reduction, and increase in total titratable acidity than the glucose-free MRS negative control. Furthermore, significantly higher populations in the low pH environment and longer survival time in nonfat milk (p < 0.05) were observed when the two probiotics were incubated in media supplemented with 2% PEH-24, than in glucose and the negative control. In comparison with other prebiotics, addition of 2% PEH 24 resulted in a more significant increase in the probiotic population (p < 0.05) than in the commercial prebiotics. This study demonstrated that PEH derived from citrus pectin could be an effective prebiotic to enhance the growth, fermentation, acid tolerance, and survival in nonfat milk for the tested probiotics. PMID- 28911642 TI - Lactobacillus pentosus GMNL-77 inhibits skin lesions in imiquimod-induced psoriasis-like mice. AB - Psoriasis, which is regarded as a T-cell-mediated chronic inflammatory skin disease, is characterized by hyperproliferation and poor differentiation of epidermal keratinocytes. In this study, we aimed to determine the in vivo effect of a potentially probiotic strain, Lactobacillus pentosus GMNL-77, in imiquimod induced epidermal hyperplasia and psoriasis-like skin inflammation in BALB/c mice. Oral administration of L. pentosus GMNL-77 significantly decreased erythematous scaling lesions. Real-time polymerase chain reaction showed that treatment with L. pentosus GMNL-77 significantly decreased the mRNA levels of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, and the IL-23/IL-17A axis-associated cytokines (IL-23, IL-17A/F, and IL 22) in the skin of imiquimod-treated mice. In addition, we found that L. pentosus GMNL-77 decreased the spleen weights of the imiquimod-treated group and reduced the numbers of IL-17- and IL-22-producing CD4+ T cells in the spleen. In conclusion, the present study provides insight into the potential use of L. pentosus GMNL-77 in the future treatment of psoriasis. PMID- 28911643 TI - Cytotoxic and antioxidant capacity of camel milk peptides: Effects of isolated peptide on superoxide dismutase and catalase gene expression. AB - Peptides from natural sources such as milk are shown to have a wide spectrum of biological activities. In this study, three peptides with antioxidant capacity were identified from camel milk protein hydrolysate. Pepsin and pancreatin were used for hydrolysis of milk proteins. Ultrafiltration and reverse-phase high performance liquid chromatography were used for the concentration and purification of the hydrolysate, respectively. Sequences of the three peptides, which were determined by matrix-assisted laser desorption/ionization time-of flight spectrophotometry, were LEEQQQTEDEQQDQL [molecular weight (MW): 1860.85 Da, LL-15], YLEELHRLNAGY (MW: 1477.63 Da, YY-11), and RGLHPVPQ (MW: 903.04 Da, RQ 8). The 3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate the cytotoxicity of these chemically synthesized peptides against HepG2 cells. In vitro analysis showed antioxidant properties and radical scavenging activities of these peptides on 2,2-diphenyl-1-picrylhydrazyl, 2,2' azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)+, O2-, and OH- free radicals. HepG2 cells were treated with YY-11 peptide for 48 hours, and the expression of superoxide dismutase and catalase genes was examined using real-time polymerase chain reaction. The results revealed a significant increase in the expression of superoxide dismutase and catalase genes in treated HepG2 cells. PMID- 28911644 TI - Nephroprotective effect of Paeonia emodi via inhibition of advanced glycation end products and oxidative stress in streptozotocin-nicotinamide induced diabetic nephropathy. AB - The present study aimed to evaluate the effect of alcohol (PA) and hydroalcohol (PHA) extract of Paeonia emodi Royale roots in treatment of streptozotocin nicotinamide induced diabetic nephropathy. Diabetes mellitus was induced in male Wistar rats by streptozotocin (65 mg/kg intraperitoneally) 15 minutes after nicotinamide (230 mg/kg, intraperitoneally) administration and diabetic nephropathy was assessed by measuring serum glucose, renal parameters (urea, uric acid, creatinine, and blood urea nitrogen level) and lipid profile. The rats were treated with different doses of extracts (100 mg/kg, 200 mg/kg, and 400 mg/kg) for 45 days. Oxidative stress was assessed by measuring tissue antioxidant enzymes level along with the formation of advanced glycation end-products (AGEs) in kidney. PA and PHA (400 mg/kg) produced significant attenuation in the serum glucose level (165.08 +/- 3.353 mg/dL and 154.27 +/- 2.209 mg/dL, respectively) as compared to control. Elevated renal parameters, lipid levels, tissue antioxidant enzymes and AGE formation were also restored in a dose-dependent manner. These findings suggest that by amelioration of oxidative stress and formation of AGEs, PA and PHA significantly inhibited the progression diabetic nephropathy in rats. PMID- 28911645 TI - Antibiofilm activity of cashew juice pulp against Staphylococcus aureus, high performance liquid chromatography/diode array detection and gas chromatography mass spectrometry analyses, and interference on antimicrobial drugs. AB - The epidemiology of Staphylococcus aureus infections has evolved in recent years, as this species is a major Gram-positive pathogen associated with healthcare services. The antimicrobial resistance of this species raises an urgent need for new treatment strategies. Fruits play important nutritional and economic roles in society, but their biological and pharmacological features are poorly explored when compared to nonedible parts of plants such as barks and leaves. In this study, we show that the cashew apple juice [cashew juice pulp (CJP)] extract is active against the planktonic cells of S. aureus strains, and for the first time, we show that CJP is also active against S. aureus biofilms. High performance liquid chromatography and gas chromatography-mass spectrometry analyses were conducted to prospect for polyphenols and free carbohydrates, respectively. Cashew apple juice, which is rich in nutrients, is widely consumed in Brazil; therefore, the quality attributes of CJPs were investigated. Samples were evaluated for pH, total titratable acidity, vitamin C levels, and total soluble solids. We also detected an antagonistic interference of CJP when it was combined with different antimicrobial drugs. PMID- 28911646 TI - Evaluating the urate-lowering effects of different microbial fermented extracts in hyperuricemic models accompanied with a safety study. AB - Uric acid (UA) is an end product of purine metabolism by the enzyme xanthine oxidase (XOD). Hyperuricemia is characterized by the accumulation of serum UA and is an important risk factor for gout and many chronic disorders. XOD inhibitors or uricase (catalyzes UA to the more soluble end product) can prevent these chronic diseases. However, currently available hypouricemic agents induce severe side effects. Therefore, we developed new microbial fermented extracts (MFEs) with substantial XOD inhibition activity from Lactobacillus (MFE-21) and Acetobacter (MFE-25), and MFE-120 with high uricase activity from Aspergillus. The urate-lowering effects and safety of these MFEs were evaluated. Our results showed that MFE-25 exerts superior urate-lowering effects in the therapeutic model. In the preventive model, both MFE-120 and MFE-25 significantly reduced UA. The results of the safety study showed that no organ toxicity and no treatment related adverse effects were observed in mice treated with high doses of MFEs. Taken together, the results showed the effectiveness of MFEs in reducing hyperuricemia without systemic toxicity in mice at high doses, suggesting that they are safe for use in the treatment and prevention of hyperuricemia. PMID- 28911647 TI - Characterization and hepatoprotective activity of anthocyanins from purple sweet potato (Ipomoea batatas L. cultivar Eshu No. 8). AB - The hepatoprotective activity of anthocyanin-rich purple sweet potato extract (APSPE) was demonstrated. Sixty mice were randomly divided into six groups: control group [without carbon tetrachloride (CCl4) or APSPE]; model group (with CCl4 only); positive control group (50 mg/kg body weight silymarin); low-dose group (100 mg/kg body weight APSPE); medium-dose group (200 mg/kg body weight APSPE); and high-dose group (400 mg/kg body weight APSPE). After 10 days intragastric administration of the respective supplements, the mice in all groups except control were injected intraperitoneally with CCl4 (0.15% in arachis oil, 10 mL/kg body weight, intravenous). Twelve hours after CCl4 injection, the mice were measured in terms of liver index, levels of aspartate aminotransferase and alanine aminotransferase in serum, as well as glutathione, superoxide dismutase, and malondialdehyde in liver homogenate. Additionally, the livers of mice were stained with hematoxylin and eosin and sectioned for observation. Nineteen purple sweet potato anthocyanins were identified from the purple sweet potato cultivar Eshu No. 8 and analyzed by liquid chromatography- electrospray ionization-tandem mass spectrometry. Peonidin 3-coumaryl-p-hydroxybenzoyl sophoroside-5-glucoside was first identified in purple sweet potato. The results showed that anthocyanins in Eshu No. 8 had good hepatoprotective activity. PMID- 28911648 TI - Induction of G2/M arrest and apoptosis through mitochondria pathway by a dimer sesquiterpene lactone from Smallanthus sonchifolius in HeLa cells. AB - Dimer sesquiterpene lactones (SLs), uvedafolin and enhydrofolin, against four monomer SLs isolated from yacon, Smallanthus sonchifolius, leaf were the most cytotoxic substances on HeLa cells (IC50 values 2.96-3.17 MUM at 24 hours). However, the cytotoxic mechanism of dimer SL has not been elucidated yet. Therefore, in this study, we clarified the in vitro cytotoxic mechanism of uvedafolin on the HeLa cells, and evaluated the cytotoxicity against NIH/3T3 cells which were used as normal cells. In consequence, the dimer SLs had low toxicity for the NIH/3T3 cells (IC50 4.81-4.98 MUM at 24 hours) and then the uvedafolin mediated cell cycle arrest at the G2/M phase and induced apoptosis on the HeLa cells evidenced by appearance of a subG1 peak. Uvedafolin induced apoptosis was attributed to caspase-9 and caspase-3/7 activities. An effectively induced apoptosis pathway was demonstrated from mitochondria membrane potential change and cytochrome c release to cytosol. These results reveal that uvedafolin induced apoptosis via the mitochondria pathway. The present results indicate the potential of uvedafolin as a leading compound of new anticancer agents. PMID- 28911649 TI - Long-chain bases from sea cucumber mitigate endoplasmic reticulum stress and inflammation in obesity mice. AB - Endoplasmic reticulum (ER) stress and inflammation can induce hyperglycemia. Long chain bases (LCBs) from sea cucumber exhibit antihyperglycemic activities. However, their effects on ER stress and inflammation are unknown. We investigated the effects of LCBs on ER stress and inflammatory response in high-fat, fructose diet-induced obesity mice. Reactive oxygen species and free fatty acids were measured. Inflammatory cytokines in serum and their mRNA expressions in epididymal adipose tissues were investigated. Hepatic ER stress-related key genes were detected. c-Jun NH2-terminal kinase and nuclear factor kappaB inflammatory pathways were also evaluated in the liver. Results showed that LCBs reduced serum and hepatic reactive oxygen species and free fatty acids concentrations. LCBs decreased serum proinflammatory cytokines levels, namely interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6, macrophage inflammatory protein 1, and c reactive protein, and increased anti-inflammatory cytokine IL-10 concentration. The mRNA and protein expressions of these cytokines in epididymal adipose tissues were regulated by LCBs as similar to their circulatory contents. LCBs inhibited phosphorylated c-Jun NH2-terminal kinase and inhibitor kappa kinase beta, and nuclear factor kappaB nuclear translocation. LCBs also inhibited mRNA expression of ER stress markers glucose regulated protein, activating transcription factor 6, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, and X-box binding protein 1, and phosphorylation of eukaryotic initiation factor-alpha and inositol requiring enzyme 1alpha. These results indicate that LCBs can alleviate ER stress and inflammatory response. Nutritional supplementation with LCBs may offer an adjunctive therapy for RE stress associated inflammation. PMID- 28911650 TI - Time course effects of fermentation on fatty acid and volatile compound profiles of Cheonggukjang using new soybean cultivars. AB - In this study, we investigated the effects of the potential probiotic Bacillus subtilis CSY191 on the fatty acid profiles of Cheonggukjang, a fermented soybean paste, prepared using new Korean brown soybean cultivars, protein-rich cultivar (Saedanbaek), and oil-rich cultivar (Neulchan). Twelve fatty acids were identified in the sample set-myristic, palmitic, palmitoleic, stearic, oleic, vaccenic, linoleic, alpha-linolenic, arachidic, gondoic, behenic, and lignoceric acids-yet, no specific changes driven by fermentation were noted in the fatty acid profiles. To further explore the effects of fermentation of B. subtilis CSY191, complete profiles of volatiles were monitored. In total, 121, 136, and 127 volatile compounds were detected in the Saedanbaek, Daewon (control cultivar), and Neulchan samples, respectively. Interestingly, the content of pyrazines-compounds responsible for pungent and unpleasant Cheonggukjang flavors was significantly higher in Neulchan compared to that in Saedanbaek. Although the fermentation period was not a strong factor affecting the observed changes in fatty acid profiles, we noted that profiles of volatiles in Cheonggukjang changed significantly over time, and different cultivars represented specific volatile profiles. Thus, further sensory evaluation might be needed to determine if such differences influence consumers' preferences. Furthermore, additional studies to elucidate the associations between B. subtilis CSY191 fermentation and other nutritional components (e.g., amino acids) and their health-promoting potential are warranted. PMID- 28911651 TI - Microencapsulation of fish oil using supercritical antisolvent process. AB - In order to improve the encapsulation process, a newly supercritical antisolvent process was developed to encapsulate fish oil using hydroxypropyl methyl cellulose as a polymer. Three factors, namely, temperature, pressure, and feed emulsion rate were optimized using response surface methodology. The suitability of the model for predicting the optimum response value was evaluated at the conditions of temperature at 60 degrees C, pressure at 150 bar, and feed rate at 1.36 mL/min. At the optimum conditions, particle size of 58.35 MUm was obtained. The surface morphology of the micronized fish oil was also evaluated using field emission scanning electron microscopy where it showed that particles formed spherical structures with no internal voids. Moreover, in vitro release of oil showed that there are significant differences of release percentage of oil between the formulations and the results proved that there was a significant decrease in the in vitro release of oil from the powder when the polymer concentration was high. PMID- 28911652 TI - Microbiological, histological, and biochemical evidence for the adverse effects of food azo dyes on rats. AB - In this study, 120 lactic acid bacterial strains from different fermented dairy products as well as 10 bacterial intestinal isolates were evaluated for in vitro and in vivo degradation of various food azo dyes. Of these isolates, lactic acid bacteria (LAB) strains 13 and 100 and the intestinal isolates Ent2 and Eco5 exhibited 96-98% degradation of the tested food azo dyes within 5-6 hours. High performance liquid chromatography mass spectra of sunset yellow (E110) and carmoisine (E122) anaerobic degradation products by the intestinal isolates showed that they were structurally related to toxic aromatic amines. For an in vivo study, eight groups of rats were treated for 90 days with either the food azo dyes or their degradation products. All groups were kept for a further 30 days as recovery period and then dissected at 120 days. Hematological, histopathological, and protein markers were assessed. Rats treated with either E110/E122 or their degradation products exhibited highly significant changes in red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and white blood cell count. In addition, alanine and aspartate aminotransferases, amylase, total bilirubin, blood urea nitrogen, creatinine, glucose, total protein, and globulins were significantly increased. Furthermore, marked histopathological alterations in the liver, kidney, spleen, and small intestine were observed. Significant decreases in inflammation and a noticeable improvement in the liver, kidney, spleen, and small intestine of rats treated with LAB and food azo dyes simultaneously were observed. Finally, these results provide a reliable basis for not only a better understanding of the histological and biochemical effects of food additives, but also for early diagnostics. In addition, LAB strains 13 and 100 may play an important role as potential probiotics in food and dairy technology as a probiotic lactic acid starter. PMID- 28911653 TI - Assessment of rosehips based on the content of their biologically active compounds. AB - In this study, an in-depth analysis of the unique set of rosehip samples from 71 Rosa genotypes was conducted with the aim to identify the most suitable ones for applications in the food and pharmaceutical industries based on the content of biologically active compounds. In the first part of our experiments, the antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl assay and the genotypes with the highest values were selected for the follow-up analysis. In the second part of experiments, the major classes of biologically active compounds in rosehips such as carotenoids, tocopherols, flavonoids, and triterpenoic acids were further quantified using liquid chromatography-based techniques. Large variation was observed among all the analyzed compounds with intraspecific variation often hiding interspecific or intersectional differences. The compounds studied herein thus do not provide a sharp tool for chemotaxonomic resolution of the genus Rosa. High intraspecific variation indicates the necessity to screen and utilize individual rose genotypes rather than representatives of the species when searching for sources of biologically active compounds. In the final stage of the study, 10 genotypes were selected for further cultivation and use, based on the highest concentrations of the analyzed biologically active compounds. PMID- 28911654 TI - Extraction optimization of gallic acid, (+)-catechin, procyanidin-B2, (-) epicatechin, (-)-epigallocatechin gallate, and (-)-epicatechin gallate: their simultaneous identification and quantification in Saraca asoca. AB - The objective of the present investigation was to optimize extraction conditions for maximum recovery of bioactive phenolics from different parts of Saraca asoca. Extraction recovery was optimized using a mixture of methanol and water in different proportions. For identification and quantification of six analytes, a rapid reversed phase ultra-performance liquid chromatography (UPLC) photo diode array detection method was developed. UPLC separation was achieved in a gradient elution mode on a C18 column with acetonitrile and aqueous phosphoric acid (0.1%, pH = 2.5). Extraction solvent for maximum recovery of analytes varied depending on the nature of matrices. The developed UPLC method was validated in accordance with International Council for Harmonisation (ICH) guidelines. Wide linearity range, sensitivity, accuracy, short retention time, and simple mobile phase composition implied that the method could be suitable for routine analysis of all six analytes with high precision and accuracy. The uniqueness of this study is the determination of the distribution of these compounds in the various parts of S. asoca. PMID- 28911655 TI - Therapeutic effects of D-aspartate in a mouse model of multiple sclerosis. AB - Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis. EAE is mainly mediated by adaptive and innate immune responses that leads to an inflammatory demyelization and axonal damage. The aim of the present research was to examine the therapeutic efficacy of D-aspartic acid (D-Asp) on a mouse EAE model. EAE induction was performed in female C57BL/6 mice by myelin 40 oligodendrocyte glycoprotein (35-55) in a complete Freund's adjuvant emulsion, and D-Asp was used to test its efficiency in the reduction of EAE. During the course of study, clinical evaluation was assessed, and on Day 21, post immunization blood samples were taken from the heart of mice for the evaluation of interleukin 6 and other chemical molecules. The mice were sacrificed, and their brain and cerebellum were removed for histological analysis. Our findings indicated that D-Asp had beneficial effects on EAE by attenuation in the severity and delay in the onset of the disease. Histological analysis showed that treatment with D-Asp can reduce inflammation. Moreover, in D-Asp-treated mice, the serum level of interleukin 6 was significantly lower than that in control animals, whereas the total antioxidant capacity was significantly higher. The data indicates that D-Asp possess neuroprotective property to prevent the onset of the multiple sclerosis. PMID- 28911656 TI - Physicochemical analysis and nonisothermal kinetic study of sertraline-lactose binary mixtures. AB - In the present study the physicochemical stability of sertraline with lactose was evaluated in drug-excipient binary mixtures. Different physicochemical methods such as differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy, and mass spectrometry were applied to confirm the incompatibility. The final aim of this study was to evaluate the kinetic parameters using a fast and sensitive DSC method. Solid-state kinetic parameters were derived from nonisothermally stressed physical mixtures using different thermal models such as Friedman, Flynn-Wall-Ozawa, and Kissinger-Akahira-Sunose. Overall, the instability of sertraline with lactose was successfully evaluated. Further confirmation was made by tracking the Maillard reaction product of sertraline and lactose by mass spectrometry. DSC scans provided important information about the stability of sertraline in solid-state condition and also revealed the related thermokinetic parameters in order to understand the nature of the chemical instability. PMID- 28911657 TI - Convenient UV-spectrophotometric determination of citrates in aqueous solutions with applications in the pharmaceutical analysis of oral electrolyte formulations. AB - Herein, we present a convenient method for quantitative spectrophotometric determination of citrate ions in aqueous solutions in the middle-UV range. It involves measuring the absorbance of citric acid at 209 nm under suppressed dissociation at pH < 1.0 in the presence of hydrochloric acid. Validation of the method was performed according to the guidelines of the International Conference on Harmonization. A very good linear dependence of the absorbance on concentration (r2 = 0.9999) was obtained in a citrate concentration range of 0.5 5.0 mmol/L. This method is characterized by excellent precision and accuracy; the coefficient of variation in each case is below the maximal permissible value (%RSD < 2). The proposed analytical procedure has been successfully applied to the determination of citrates in oral electrolyte formulations. PMID- 28911658 TI - Identification of an exposure risk to heavy metals from pharmaceutical-grade rubber stoppers. AB - Exposure to low concentrations of heavy metals and metalloids represents a well documented risk to animal and human health. However, current standards (European Pharmacopeia [EP], United States Pharmacopoeia [USP], International Organization for Standardization [ISO], YBB concerned with rubber closures) only require testing for Zn in pharmaceutical-grade rubber stoppers and then using only pure water as a solvent. We extracted and quantified heavy metals and trace elements from pharmaceutical-grade rubber stoppers under conditions that might occur during the preparation of drugs. Pure water, saline, 10% glucose, 3% acetic acid (w/v), 0.1 mol/L hydrochloric acid, and diethylenetriaminepentaacetic acid (4 mg/mL, 0.4 mg/mL, and 0.04 mg/mL) were used as extraction agents. We quantified the extracted arsenic, lead, antimony, iron, magnesium, aluminum, and zinc using inductively coupled plasma mass spectrometry. The concentration of extracted metals varied depending on the different extraction solutions used and between the different rubber stopper manufacturers. Rubber stoppers are ubiquitously used in the pharmaceutical industry for the storage and preparation of drugs. Extraction of heavy metals during the manufacturing and preparation of drugs represents a significant risk, suggesting a need for industry standards to focus on heavy metal migration from rubber stoppers. PMID- 28911659 TI - The detoxifying effects of structural elements of persimmon tannin on Chinese cobra phospholipase A2 correlated with their structural disturbing effects well. AB - The effects of persimmon tannin (PT) characteristic structural elements on Naja atra phospholipase A2 (PLA2)-induced lethality, myotoxicity, and hemolysis in mice models were determined. In addition, methods including surface plasmon resonance, dynamic light scattering, and Fourier transform infrared spectroscopy were explored to uncover the possible detoxifying mechanisms of PT on snake venom PLA2. Our results revealed that PT characteristic elements (EGCG, ECG, A-type EGCG dimer, and A-type ECG dimer) could neutralize the lethality, myotoxicity, and hemolysis of PLA2. Moreover, the detoxifying effects of the four structural elements correlated with their structural disturbing effects well. Our results proved that A-type EGCG dimer and A-type ECG dimer may be structural requirements for the detoxifying effects of PT. We propose that the high affinity of A-type EGCG dimer and A-type ECG dimer for PLA2 and the considerable spatial structural disturbance of PLA2 induced by the dimers may be responsible for their antilethality, antimyotoxicity, and antihemolysis on Chinese cobra PLA2in vivo. PMID- 28911660 TI - An ecofriendly green liquid chromatographic method for simultaneous determination of nicotinamide and clindamycin phosphate in pharmaceutical gel for acne treatment. AB - A new green micellar liquid chromatographic method was developed and validated for the quantitative estimation of nicotinamide (NICO) and clindamycin phosphate (CLD) in bulk and pharmaceutical gel formulation. The analytes are well resolved in less than 6.0 minutes using micellar mobile phase consisting of 0.10M sodium dodecyl sulfate (SDS), 0.3% triethylamine, and 10% 2-propanol in 0.02M orthophosphoric acid at pH 3.0, running through an Eclipse XDB-C8 column (150 mm*4.6 mm, 5 MUm particle size) with flow rate 1.0 mL/min. The effluent was monitored with diode array detection at 210 nm. The retention times of NICO and CLD were 3.8 minutes and 5.6 minutes, respectively. The method was validated according to the International Conference on Harmonisation (ICH) guidelines in terms of linearity, limit of detection, limit of quantification, accuracy, precision, robustness, and specificity to prove its reliability. Linear correlation was achieved by plotting the peak area of each drug against its concentration. It was found to be rectilinear in the ranges of 1.0-40.0 MUg/mL and 0.5-15.0 MUg/mL with limits of detection of 0.06 MUg/mL and 0.03 MUg/mL and limits of quantification of 0.19 MUg/mL and 0.09 MUg/mL for NICO and CLD, respectively. The method was successfully implemented for the simultaneous determination of the analytes in their bulk powder and combined gel formulation with high % recoveries. The ease of sample treatment facilitates and greatly expedites the treatment with reduced cost and improved accuracy of the procedure. PMID- 28911661 TI - Corrigendum to "Biopharmaceutical potentials of Prosopis spp. (Mimosaceae, Leguminosa)" [J Food Drug Anal 25 (2017) 187-196]. PMID- 28911662 TI - Pharmacokinetic interactions of herbal medicines for the treatment of chronic hepatitis. AB - Chronic liver disease is a serious global health problem, and an increasing number of patients are seeking alternative medicines or complementary treatment. Herbal medicines account for 16.8% of patients with chronic liver disease who use complementary and alternative therapies. A survey of the National Health Insurance Research Database in Taiwan reported that Long-Dan-Xie-Gan-Tang, Jia Wei-Xia-Yao-San, and Xiao-Chai-Hu-Tang (Sho-saiko-to) were the most frequent formula prescriptions for chronic hepatitis used by traditional Chinese medicine physicians. Bioanalytical methods of herbal medicines for the treatment of chronic hepatitis were developed to investigate pharmacokinetics properties, but multicomponent herbal formulas have been seldom discussed. The pharmacokinetics of herbal formulas is closely related to efficacy, efficiency, and patient safety of traditional herbal medicines. Potential herbal formula-drug interactions are another essential issue during herbal formula administration in chronic hepatitis patients. In a survey with the PubMed database, this review article evaluates the existing evidence-based data associated with the documented pharmacokinetics profiles and potential herbal-drug interactions of herbal formulas for the treatment of chronic hepatitis. In addition, the existing pharmacokinetic profiles were further linked with clinical practice to provide insight for the safety and specific use of traditional herbal medicines. PMID- 28911663 TI - Recent advances in oral delivery of drugs and bioactive natural products using solid lipid nanoparticles as the carriers. AB - Chemical and enzymatic barriers in the gastrointestinal (GI) tract hamper the oral delivery of many labile drugs. The GI epithelium also contributes to poor permeability for numerous drugs. Drugs with poor aqueous solubility have difficulty dissolving in the GI tract, resulting in low bioavailability. Nanomedicine provides an opportunity to improve the delivery efficiency of orally administered drugs. Solid lipid nanoparticles (SLNs) are categorized as a new generation of lipid nanoparticles consisting of a complete solid lipid matrix. SLNs used for oral administration offer several benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. The nontoxic excipients and sophisticated material engineering of SLNs tailor the controllable physicochemical properties of the nanoparticles for GI penetration via mucosal or lymphatic transport. In this review, we highlight the recent progress in the development of SLNs for disease treatment. Recent application of oral SLNs includes therapies for cancers, central nervous system-related disorders, cardiovascular-related diseases, infection, diabetes, and osteoporosis. In addition to drugs that may be active cargos in SLNs, some natural compounds with pharmacological activity are also suitable for SLN encapsulation to enhance oral bioavailability. In this article, we systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for drug- and natural compound-loaded SLNs. PMID- 28911664 TI - Smog induces oxidative stress and microbiota disruption. AB - Smog is created through the interactions between pollutants in the air, fog, and sunlight. Air pollutants, such as carbon monoxide, heavy metals, nitrogen oxides, ozone, sulfur dioxide, volatile organic vapors, and particulate matters, can induce oxidative stress in human directly or indirectly through the formation of reactive oxygen species. The outermost boundary of human skin and mucous layers are covered by a complex network of human-associated microbes. The relation between these microbial communities and their human host are mostly mutualistic. These microbes not only provide nutrients, vitamins, and protection against other pathogens, they also influence human's physical, immunological, nutritional, and mental developments. Elements in smog can induce oxidative stress to these microbes, leading to community collapse. Disruption of these mutualistic microbiota may introduce unexpected health risks, especially among the newborns and young children. Besides reducing the burning of fossil fuels as the ultimate solution of smog formation, advanced methods by using various physical, chemical, and biological means to reduce sulfur and nitrogen contains in fossil fuels could lower smog formation. Additionally, information on microbiota disruption, based on functional genomics, culturomics, and general ecological principles, should be included in the risk assessment of prolonged smog exposure to the health of human populations. PMID- 28911665 TI - Nanostructures: Current uses and future applications in food science. AB - Recent developments in nanoscience and nanotechnology intend novel and innovative applications in the food sector, which is rather recent compared with their use in biomedical and pharmaceutical applications. Nanostructured materials are having applications in various sectors of the food science comprising nanosensors, new packaging materials, and encapsulated food components. Nanostructured systems in food include polymeric nanoparticles, liposomes, nanoemulsions, and microemulsions. These materials enhance solubility, improve bioavailability, facilitate controlled release, and protect bioactive components during manufacture and storage. This review highlights the applications of nanostructured materials for their antimicrobial activity and possible mechanism of action against bacteria, including reactive oxygen species, membrane damage, and release of metal ions. In addition, an overview of nanostructured materials, and their current applications and future perspectives in food science are also presented. PMID- 28911666 TI - Fast and simple method for semiquantitative determination of calcium propionate in bread samples. AB - Calcium propionate has been widely used as a preservative in bakery and in bread. It is sometimes not carefully used, or a high concentration is added to preserve products. High consumption of calcium propionate can lead to several health problems. This study aims to develop a fast and simple semiquantitative method based on color complex formation for the determination of calcium propionate in a bread sample. A red-brown complex was obtained from the reaction of ferric ammonium sulfate and propionate anion. The product was rapidly formed and easily observed with the concentration of propionate anion >0.4 mg/mL. A high performance liquid chromatography (HPLC) method was also developed and validated for comparison. Twenty-two bread samples from three markets near Bangkok were randomly selected and assayed for calcium propionate using the above two developed methods. The results showed that 19/22 samples contained calcium propionate >2000 mg/kg. The results of the complex formation method agreed with the HPLC method. PMID- 28911667 TI - DNA barcode and identification of the varieties and provenances of Taiwan's domestic and imported made teas using ribosomal internal transcribed spacer 2 sequences. AB - The major aim of made tea identification is to identify the variety and provenance of the tea plant. The present experiment used 113 tea plants [Camellia sinensis (L.) O. Kuntze] housed at the Tea Research and Extension Substation, from which 113 internal transcribed spacer 2 (ITS2) fragments, 104 trnL intron, and 98 trnL-trnF intergenic sequence region DNA sequences were successfully sequenced. The similarity of the ITS2 nucleotide sequences between tea plants housed at the Tea Research and Extension Substation was 0.379-0.994. In this polymerase chain reaction-amplified noncoding region, no varieties possessed identical sequences. Compared with the trnL intron and trnL-trnF intergenic sequence fragments of chloroplast cpDNA, the proportion of ITS2 nucleotide sequence variation was large and is more suitable for establishing a DNA barcode database to identify tea plant varieties. After establishing the database, 30 imported teas and 35 domestic made teas were used in this model system to explore the feasibility of using ITS2 sequences to identify the varieties and provenances of made teas. A phylogenetic tree was constructed using ITS2 sequences with the unweighted pair group method with arithmetic mean, which indicated that the same variety of tea plant is likely to be successfully categorized into one cluster, but contamination from other tea plants was also detected. This result provides molecular evidence that the similarity between important tea varieties in Taiwan remains high. We suggest a direct, wide collection of made tea and original samples of tea plants to establish an ITS2 sequence molecular barcode identification database to identify the varieties and provenances of tea plants. The DNA barcode comparison method can satisfy the need for a rapid, low-cost, frontline differentiation of the large amount of made teas from Taiwan and abroad, and can provide molecular evidence of their varieties and provenances. PMID- 28911668 TI - Determination of multiresidue analysis of beta-agonists in muscle and viscera using liquid chromatograph/tandem mass spectrometry with Quick, Easy, Cheap, Effective, Rugged, and Safe methodologies. AB - The official analytical method of the Taiwan Food and Drug Administration, Ministry of Health and Welfare for testing for veterinary drug residues in foods is the multiresidue analysis of beta-agonists. Samples are pretreated through liquid-liquid extraction and solid-phase extraction. This method is time consuming and requires the intensive use of solvents. To improve analytical efficiency and reduce costs, our study incorporated QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) techniques to establish a new method of multiresidue analysis of beta-agonists in animal muscle and viscera. The pretreatment time was shortened and solvent usage was minimized. The modified analysis was conducted using liquid chromatography/tandem mass spectrometry (LC-MS/MS) and quantification was performed using multiple reaction monitoring. The results demonstrated that the correlation coefficients of the tissue calibration curve were higher than 0.99 and the limit of quantification (LOQ) was 1 ppb. The average recoveries in spiked samples varied from 70% to 120%, and the relative difference between duplicated analysis results was lower than 10%. On the basis of the results, the proposed method was concluded to be an appropriate procedure for determining the presence of beta-agonists, and demonstrated the advantages of high recovery rates in spiked samples, high precision, reduced analysis time and solvent usage, and lower costs. PMID- 28911669 TI - Simultaneous determination of ascorbic acid and caffeine in commercial soft drinks using reversed-phase ultraperformance liquid chromatography. AB - A new reversed-phase ultraperformance liquid chromatography method with a photodiode array detector was developed for the quantification of ascorbic acid (AA) and caffeine (CAF) in 11 different commercial drinks consisting of one energy drink and 10 ice tea drinks. Separation of the analyzed AA and CAF with an internal standard, caffeic acid, was performed on a Waters BEH C18 column (100 mm * 2.1 mm, 1.7 MUm i.d.), using a mobile phase consisting of acetonitrile and 0.2M H3PO4 (11:89, v/v) with a flow rate of 0.25 mL/min and an injection volume of 1.0 MUL. Calibration graphs for AA and CAF were computed from the peak area ratio of AA/internal standard and CAF/internal standard detected at 244.0 nm and 273.6 nm, respectively. The developed reversed-phase ultraperformance liquid chromatography method was validated by analyzing standard addition samples. The proposed reversed-phase ultraperformance liquid chromatography method gave us successful results for the quantitative analysis of commercial drinks containing AA and CAF substances. PMID- 28911670 TI - Voltammetric sensor for tartrazine determination in soft drinks using poly (p aminobenzenesulfonic acid)/zinc oxide nanoparticles in carbon paste electrode. AB - Zinc oxide nanoparticles (ZnO NPs) and p-aminobenzenesulfonic acid (p-ABSA) were used to fabricate a modified electrode, as a highly sensitive and selective voltammetric sensor, for the determination of tartrazine. A fast and easy method for the fabrication of poly p-ABSA (Pp-ABSA)/ZnO NPs-carbon paste electrode (Pp ABSA/ZnO NPs-CPE) by cyclic voltammetry was used. By combining the benefits of Pp ABSA, ZnO NPs, and CPE, the resulted modified electrode exhibited outstanding electrocatalytic activity in terms of tartrazine oxidation by giving much higher peak currents than those obtained for the unmodified CPE and also other constructed electrodes. The effects of various experimental parameters on the voltammetric response of tartrazine were investigated. At the optimum conditions, the sensor has a linear response in the concentration range of 0349-5.44 MUM, a good detection sensitivity (2.2034 MUA/MUM), and a detection limit of 80 nM of tartrazine. The proposed electrode was used for the determination of tartrazine in soft drinks with satisfactory results. PMID- 28911671 TI - Albendazole residues in goat's milk: Interferences in microbial inhibitor tests used to detect antibiotics in milk. AB - Albendazole (ABZ) residues in goat's milk and their effect on the response of microbial inhibitor tests used for screening antibiotics were evaluated. A total of 18 Murciano-Granadina goats were treated with ABZ and individually milked once a day over a 7-day period. ABZ quantification was performed by high performance liquid chromatography. The ABZ parent drug was not detected. The maximum concentration of its metabolites (ABZ sulfoxide, ABZ sulfone, and ABZ 2 aminosulfone) was reached on the 1st day post treatment (260.0 +/- 70.1 MUg/kg, 112.8 +/- 28.7 MUg/kg, 152.0 +/- 23.6 MUg/kg, respectively), decreasing to lower than the maximum residue limit (MRL, 100 MUg/kg) on the 3rd day post treatment. Milk samples were also analyzed by microbial tests [Brilliant Black Reduction Test (BRT) MRL, Delvotest SP-NT MCS and Eclipse 100], and only one positive result was found for Delvotest SP-NT MCS and Eclipse 100. However, a high occurrence of positive outcomes was obtained for BRT MRL during 6 days post treatment, whereas ABZ residues were not detected from the 4th day post administration, suggesting that factors other than the antiparasitic agent might affect the microbial test response. PMID- 28911672 TI - Rapid investigation of alpha-glucosidase inhibitory activity of Phaleria macrocarpa extracts using FTIR-ATR based fingerprinting. AB - Phaleria macrocarpa, known as "Mahkota Dewa", is a widely used medicinal plant in Malaysia. This study focused on the characterization of alpha-glucosidase inhibitory activity of P. macrocarpa extracts using Fourier transform infrared spectroscopy (FTIR)-based metabolomics. P. macrocarpa and its extracts contain thousands of compounds having synergistic effect. Generally, their variability exists, and there are many active components in meager amounts. Thus, the conventional measurement methods of a single component for the quality control are time consuming, laborious, expensive, and unreliable. It is of great interest to develop a rapid prediction method for herbal quality control to investigate the alpha-glucosidase inhibitory activity of P. macrocarpa by multicomponent analyses. In this study, a rapid and simple analytical method was developed using FTIR spectroscopy-based fingerprinting. A total of 36 extracts of different ethanol concentrations were prepared and tested on inhibitory potential and fingerprinted using FTIR spectroscopy, coupled with chemometrics of orthogonal partial least square (OPLS) at the 4000-400 cm-1 frequency region and resolution of 4 cm-1. The OPLS model generated the highest regression coefficient with R2Y = 0.98 and Q2Y = 0.70, lowest root mean square error estimation = 17.17, and root mean square error of cross validation = 57.29. A five-component (1+4+0) predictive model was build up to correlate FTIR spectra with activity, and the responsible functional groups, such as -CH, -NH, -COOH, and -OH, were identified for the bioactivity. A successful multivariate model was constructed using FTIR attenuated total reflection as a simple and rapid technique to predict the inhibitory activity. PMID- 28911673 TI - Impact of different partitioned solvents on chemical composition and bioavailability of Sasa quelpaertensis Nakai leaf extract. AB - The leaves of Sasa quelpaertensis Nakai were extracted with 80% ethanol and further partitioned with n-hexane, chloroform, ethyl acetate, n-butanol, and aqueous fractions to evaluate the biological activity through assessment via various in vitro assays, including total phenol content; 1,1-diphenyl-1 picrylhydrazyl (DPPH) and 2,2-azino-bis-(3-ethylbenzothiazothiazoline-6-sulfornic acid (ABTS) radical scavenging; reducing power; alpha-glucosidase and tyrosinase inhibitory; and alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) activity assays. The highest activity was found in the ethyl acetate fraction for all assays and showed stronger DPPH radical scavenging, reducing power, and tyrosinase inhibitory activity than the positive controls (butylated hydroxytoluene, alpha-tocopherol, and arbutin, respectively). When compared to the ethyl acetate fraction, the n-butanol fraction had lower rates, but it still demonstrated relatively high activity. The activity of the n-hexane fraction was high for DPPH and ABTS radical scavenging activity and contained significant amounts of phenol content, whereas the chloroform fraction possessed the highest reducing power, tyrosinase inhibitory, and ADH and ALDH activity, despite having the lowest phenol content when compared to the other fractions. These findings clearly indicate that S. quelpaertensis Nakai leaves can be a good natural source of antioxidants and tyrosinase inhibitors, as well as ADH and ALDH activity inducers, suggesting that may have potential for treating various diseases and improving human health. PMID- 28911674 TI - Phytochemical composition and antibacterial activity of the essential oils from different parts of sea buckthorn (Hippophae rhamnoides L.). AB - Essential oils from the seed, pulp, and leaf of sea buckthorn were obtained with hydrodistillation, and their phytochemical composition was analyzed through gas chromatography-mass spectrometry. Furthermore, the antibacterial activity of the oils was tested on five food-borne bacteria by spectrometry and evaluated in terms of minimum inhibitory concentration. The results indicate that the composition of all essential oils is dominated by free fatty acids, esters, and alkanes. Minimum inhibitory concentration values on each bacterium were obtained for oils from different parts. The oils from different parts exhibited nearly equal inhibitory effect on Staphylococcus aureus. The pulp oil was found to be the most effective for the rest of bacteria tested except Escherichia coli, on which seed oil shows twice the inhibitory effect to that of leaf or pulp oil. Three natural inhibitory examples were found comparable with or even better than the positive control: pulp oil on Bacillus subtilis, and pulp oil and leaf oil on Bacillus coagulans. PMID- 28911675 TI - Phenolic constituents of Pulicaria undulata (L.) C.A. Mey. sub sp. undulata (Asteraceae): Antioxidant protective effects and chemosystematic significances. AB - One new naturally isoflavone compound, 5,7,2',3',4' penta hydroxyl isoflavone-4' O-beta-glucopyranoside (1) was isolated from the aqueous methanol extract (AME) of Pulicaria undulata subsp. undulata, together with seven known compounds: kaempferol (2), kaempferol 3-O-beta-glucoside (3), quercetin (4), quercetin 3-O beta-glucoside (5), quercetin 3-O-beta-galactoside (6), quercetin 3,7-di OCH3 (7), and caffeic acid (8). Their structures were established through chemical (acid hydrolysis) and spectral analysis (UV, NMR, and ESIM). The AME and some isolated compounds were evaluated as protective agents. Free radical scavenging using a microscaled 2,2-diphenyl-1-picrylhydrazyl assay was used to assess the direct antioxidant properties that were evaluated by the ability to protect murine Hepa1c1c7 liver cells against damage induced by the organic peroxide tert butyl hydroperoxide. The neutral red uptake assay (NRU) was used to record the activity. Results of the 2,2-diphenyl-1-picrylhydrazyl assay recorded differential scavenging properties in ascending order: 5,7,2',3',4' penta hydroxyl isoflavone-4'-O-beta-glucopyranoside>quercetin>quercetin 3-O galactoside>caffeic acid>quercetin 3,7-di-OCH3>kaempferol with 50% inhibitory concentrations of 3.9 MUM, 7.5 MUM, 11.4 MUM, 12.2 MUM, 78.1 MUM, and 252.3 MUM, respectively. The antioxidative potential reveals the potency of AME, quercetin, and quercetin 3,7-di-OCH3. The latter compound showed full protection at 100 MUM (33 MUg/mL) against the induced toxicant effect where the 50% effective concentration was calculated as 33.6+/-1.7 MUM (11.1 MUg/mL). In addition to quercetin, which was extensively shown previously as a cytoprotective agent, AME was less potent; it was capable of protecting 75% at 100 MUg/mL with 50% effective concentration of 92.3+/-4 MUg/mL. Moreover, the isolated flavonoids were found to be significantly chemosystematic markers. PMID- 28911676 TI - Composition analysis and antioxidant properties of black garlic extract. AB - Black garlic produced from fresh garlic under controlled high temperature and humidity has strong antioxidant properties. To determine these compounds, five fractions (from F1 to F5) were separated and purified by elution with chloroform:methanol at different ratios (8:1, 6:1, 4:1, 2:1, and 0:1; v/v). The antioxidant activity of each fraction was analyzed. The results showed that F3 and F4 had higher phenolic contents and stronger 2,2-diphenyl-2-picrylhydrazyl radical scavenging activity than the others. Seven purified individual components were further separated using semipreparation high-performance liquid chromatography from these two intensely antioxidant fractions (F3 and F4), their structures were elucidated by high-performance liquid chromatography coupled to diode array detection, electrospray ionization, mass spectrometry, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance spectrometry. Three compounds including adenosine, uridine, and 2-acetylpyrrole were first identified in black garlic, except for 5-hydroxymethylfurfural, (1S, 3S)-1-methyl-1,2,3,4 tetrahydro-beta-carboline-3-carboxylic acid, and (1R, 3S)-1-methyl-1,2,3,4 tetrahydro-beta-carboline-3-carboxylic acid. The cellular antioxidant activities of uridine, adenosine, carboline alkaloids, 5-hydroxymethylfurfural, and ethyl acetate extracts were consistent with the results of in vitro experimental antioxidant properties. The results provide useful information for understanding the health benefits of black garlic products. PMID- 28911677 TI - Antioxidant and antimicrobial phenolic compounds from extracts of cultivated and wild-grown Tunisian Ruta chalepensis. AB - The antioxidant and antibacterial activities of phenolic compounds from cultivated and wild Tunisian Ruta chalepensis L. leaves, stems, and flowers were assessed. The leaves and the flowers exhibited high but similar total polyphenol, flavonoid, and tannin content. Moreover, two organs showed strong, although not significantly different, total antioxidant activity, 2,2-diphenyl-1 picrylhydrazyl scavenging ability, and reducing power. Investigation of the phenolic composition showed that vanillic acid and coumarin were the major compounds in the two organs, with higher percentages in the cultivated organs than in the spontaneous organs. Furthermore, R. chalepensis extracts showed marked antibacterial properties against human pathogen strains, and the activity was organ- and origin-dependent. Spontaneous stems had the strongest activity against Pseudomonas aeruginosa. From these results, it was concluded that domestication of Ruta did not significantly affect its chemical composition and consequently the possibility of using R. chalpensis organs as a potential source of natural antioxidants and as an antimicrobial agent in the food industry. PMID- 28911678 TI - Averrhoa bilimbi fruits attenuate hyperglycemia-mediated oxidative stress in streptozotocin-induced diabetic rats. AB - Hyperglycemia-mediated oxidative stress plays a major role in the development of diabetic complications. Averrhoa bilimbi Linn. (Oxalidaceae) is a medicinal plant with fruits reported to possess antidiabetic activity. This study evaluated the beneficial effects of the ethyl acetate fraction of A. bilimbi fruit (ABAEE) on the antioxidant/oxidant status in diabetes mellitus. Diabetic rats were treated orally with the ethyl acetate fraction of A. bilimbi fruits at a dose of 25 mg/kg body weight for 60 days. Serum glucose, glycated hemoglobin, plasma insulin, hepatic toxicity markers, antioxidant enzymes, lipid peroxidation products, and liver histopathology were assayed checked after 60 days of extract treatment. Diabetic rats administered ABAEE showed a significant decline in serum glucose, glycated hemoglobin, and also significantly increases the level of plasma insulin, as well as a notable attenuation in thiobarbituric acid-reactive substances, conjugated dienes, and hydroperoxides. ABAEE also modulated hepatic antioxidant potential by significantly increasing the activities of catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and reducing glutathione content. The results associated with ABAEE were more significant than those observed following treatment with the standard drug metformin. Histopathological observations showed that ABAEE effectively rescued hepatocytes from oxidative damage without affecting cellular function and structural integrity. High-performance liquid chromatography analysis of ABAEE indicated the presence of phenolic compound, quercetin, indicating that the antidiabetic effect of the extract might be related to quercetin. These results demonstrated the potential beneficial effect of ABAEE on streptozotocin-induced diabetes in rats. PMID- 28911679 TI - Assessment of bacterial quality of honey produced in Tamale metropolis (Ghana). AB - The bacterial quality of honey from different production sites within Tamale metropolis, Ghana, was estimated using standard microbiological methods. Honey samples were bought from six different production sites within Tamale metropolis and labeled. Samples that were taken from location B recorded the least mean bacterial count of 6.0*104 colony forming units/mL with samples taken from location D showing the highest, 1.1*105 colony forming units/mL. However, samples from production sites E and F recorded no bacteria growth. Bacteria isolated included Escherichia coli, Staphylococcus spp., Shigella spp., Streptococcus spp., and Bacillus spp. The pH values of honey samples from the various locations were found to be directly correlated to the average bacteria load. The variation in bacteria load and species at the various production sites and the absence of bacteria growth in two production sites is an indication of the differences in production practices, as well as hygienic conditions at these sites. The presence of these isolates is a cause for concern as pathogenic strains of these bacteria can cause serious health related problems. PMID- 28911680 TI - Effect of storage temperature and time on the nutritional quality of walnut male inflorescences. AB - The objective of this study was to investigate the effect of storage temperature and time on nutrients, bioactive compounds, and antioxidant activities of walnut male inflorescences. The results showed that the moisture, saccharides, fat, protein, amino acids, ascorbic acid, phenolic and flavonoid compound contents, and antioxidant activities of walnut male inflorescences were markedly influenced by storage temperature, and different degrees of decrease in these parameters were observed during the entire storage period. Moreover, higher storage temperature had a more significant effect on the nutrients, bioactive compounds, and antioxidant activities of walnut male flowers, and the loss rate of these components at 25 degrees C was higher than that determined at 4 degrees C. However, the results also presented that the ash and mineral contents did not appear to be influenced significantly by the storage temperature, and slightly significant changes were observed in crude fiber throughout storage, which indicated that the influence of storage on the individual mineral and crude fiber content was minimal. Based on the findings in this study, in order to maximize nutrients concentration, walnut male inflorescences should be kept at 4 degrees C for <6 days and be consumed as fresh as possible. PMID- 28911681 TI - Study on the interaction of bioactive compound S-allyl cysteine from garlic with serum albumin. AB - Multispectroscopic techniques were used to investigate the interaction of S-allyl cysteine (SAC) from garlic with human serum albumin (HSA). UV-Vis absorption measurements prove the formation of the HSA-SAC complex. An analysis of fluorescence spectra revealed that in the presence of SAC, the quenching mechanism of HSA is considered static. The quenching rate constant Kq, KSV, and the binding constant KA were estimated. According to the Van't Hoff equation, the thermodynamic parameters enthalpy change (DeltaH) and entropy change (DeltaS) were calculated to be -1.00*105 J/mol and -255 J/mol/K, respectively. These indicate that hydrogen bonds and van der Waals forces are the major forces between SAC and HSA. The changes in the secondary structure of HSA, which was induced by SAC, were determined by circular dichroism spectroscopy. Energy transfer was confirmed and the distance between donor and acceptor was calculated to be 2.83 nm. PMID- 28911682 TI - Relation between salt tolerance and biochemical changes in cumin (Cuminum cyminum L.) seeds. AB - In this study, the effects of salinity on growth, fatty acid, essential oil, and phenolic composition of cumin (Cuminum cyminum L.) seeds as well as the antioxidant activities of their extracts were investigated. Plants were treated with different concentrations of NaCl treatment: 0, 50, 75, and 125 mmoL. Plant growth was significantly reduced with the severity of saline treatment. This also caused important reductions in the seed yield and yield components. Besides, NaCl treatments affected fatty acid composition. Petroselinic and linoleic acids proportions diminished consistently with the increase in NaCl concentration, whereas palmitic acid proportion increased. Furthermore, NaCl enhanced essential oil production in C. cyminum seeds and induced marked changes on the essential oil quality. Essential oil chemotype was modified from gamma-terpinene/1-phenyl 1,2 ethanediol in control to gamma-terpinene/beta-pinene in salt stressed plants. Total polyphenol content was higher in treated seeds, and salinity improved the amount of individual phenolic compounds. Moreover, antioxidant activities of the extracts were determined by four different test systems, namely 2,2-diphenyl-1 picrylhydrazyl, beta-carotene/linoleic acid chelating, and reducing power assays. The highest antioxidant activities were reveled in severe stressed plants. In this case, cumin seeds produced under saline conditions may function as a potential source of essential oil and antioxidant compounds, which could support the utilization of this plant in a large field of applications such as food industry. PMID- 28911683 TI - Antibacterial activity and interactions of plant essential oil combinations against Gram-positive and Gram-negative bacteria. AB - The aim of this study was to compare the antibacterial effects of several essential oils (EOs) alone and in combination against different Gram-positive and Gram-negative bacteria associated with food products. Parsley, lovage, basil, and thyme EOs, as well as their mixtures (1:1, v/v), were tested against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella typhimurium. The inhibitory effects ranged from strong (thyme EO against E. coli) to no inhibition (parsley EO against P. aeruginosa). Thyme EO exhibited strong (against E. coli), moderate (against S. typhimurium and B. cereus), or mild inhibitory effects (against P. aeruginosa and S. aureus), and basil EO showed mild (against E. coli and B. cereus) or no inhibitory effects (against S. typhimurium, P. aeruginosa, and S. aureus). Parsley and lovage EOs revealed no inhibitory effects against all tested strains. Combinations of lovage/thyme and basil/thyme EOs displayed antagonistic effects against all bacteria, parsley/thyme EOs against B. cereus, S. aureus, P. aeruginosa, and E. coli, and lovage/basil EOs against B. cereus and E. coli. Combinations of parsley/lovage and parsley/basil EOs exhibited indifferent effects against all bacteria. The combination of lovage/basil EO showed indifferent effect against S. aureus, P. aeruginosa, and S. typhimurium, and the combination parsley/thyme EO against S. typhimurium. Thyme EO has the highest percentage yield and antibacterial potential from all tested formulations; its combination with parsley, lovage, and basil EOs determines a reduction of its antibacterial activity. Hence, it is recommended to be used alone as the antibacterial agent. PMID- 28911684 TI - A randomized, double-blind clinical study to determine the effect of ANKASCIN 568 plus on blood glucose regulation. AB - Diabetes is the fourth major cause of death in Taiwan. High blood glucose can lead to macrovascular diseases, small vessel diseases (retinopathy, kidney disease), and neuropathy. This study aimed to investigate whether Monascus fermented products (ANKASCIN 568 plus) can regulate blood glucose and blood lipids. This study enrolled 39 patients with a fasting blood glucose level between 100 mg/dL and 180 mg/dL, and a glycated hemoglobin (HbA1c) level of <9%. All patients were randomly divided into placebo (n=20) and experimental (n=19) groups. Each patient received two placebo capsules (maltodextrin) or ANKASCIN 568 plus capsules daily for 12 weeks. The patients were screened during follow-up 4 weeks after the administration of sample or placebo had been discontinued. Blood and urine samples were collected at the initial, 6th week, 12th week, and 16th week. The anthropometric indicators of blood pressure, fasting plasma glucose level, postprandial plasma glucose level, insulin level, insulin resistance, blood lipid changes, and liver, kidney, and thyroid function indices were measured. After 6 weeks, changes in fasting blood glucose, low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels showed that ANKASCIN 568 plus had a more favorable effect than the placebo. Compared to baseline, a statistically significant decrease of 8.5%, 10.3%, and 7.5% was observed in fasting blood glucose, LDL-C and, TC levels, respectively (p<0.05 for all pairs). Therefore, ANKASCIN 568 plus produced by Monascus purpureus NTU 568 fermentation may be a potentially useful agent for the regulation of blood glucose and blood lipids and for treatment of coronary artery diseases. PMID- 28911685 TI - Simultaneous characterization and quantification of 17 main compounds in Rabdosia rubescens by high performance liquid chromatography. AB - Rabdosia rubescens is a healthy herbal tea and well-known Chinese medicinal herb. To evaluate the quality of R. rubescens from China, a high performance liquid chromatography method with dual-wavelength detection was developed and validated. The method was successfully applied for the simultaneous characterization and quantification of 17 main constituents from four different cultivation regions in China. Under optimal conditions, analysis was performed on a Luna C-18 column and gradient elution with a solvent system of acetonitrile and 0.5% (v/v) acetic acid water at a flow rate of 1.0 mL/min and wavelength of 220 nm and 280 nm. All standard calibration curves exhibited good linearity (r2 > 0.9992) within the test ranges. The precision was evaluated by intraday and interday tests, which revealed relative standard deviation values within the ranges of 0.57-2.35% and 0.52-3.40%, respectively. The recoveries were in the range of 96.37-101.66%. The relative standard deviation values for stability and repeatability were < 5%. The contents of some compounds were low and varied with different cultivars. The proposed method could serve as a prerequisite for quality control of R. rubescens materials and products. PMID- 28911686 TI - Development of validated high-performance thin layer chromatography for quantification of aristolochic acid in different species of the Aristolochiaceae family. AB - This study was undertaken to isolate and quantify aristolochic acid in Aristolochia indica stem and Apama siliquosa root. Aristolochic acid is an important biomarker component present in the Aristolochiaceae family. The isolation method involved simple solvent extraction, precipitation and further purification, using recrystallization. The structure of the compound was confirmed using infrared spectroscopy, mass spectrometry and nuclear magnetic resonance. A specific and rapid high-performance thin layer chromatography (HPTLC) method was developed for analysis of aristolochic acid. The method involved separation on the silica gel 60 F254 plates using the single solvent system of n-hexane: chloroform: methanol. The method showed good linear relationship in the range 0.4-2.0 MUg/spot with r2 = 0.998. The limit of detection and limit of quantification were 62.841 ng/spot and 209.47 ng/spot, respectively. The proposed validated HPTLC method was found to be an easy to use, accurate and convenient method that could be successfully used for standardization and quality assessment of herbal material as well as formulations containing different species of the Aristolochiaceae family. PMID- 28911687 TI - Simultaneous separation of antihyperlipidemic drugs by green ultrahigh performance liquid chromatography-diode array detector method: Improving the health of liquid chromatography. AB - Statins in combination with fibrates show beneficial effects on the lipoprotein profile of patients because they have positive complimentary effects on lipid profile. A new green ultrahigh-performance liquid chromatography-diode array detector method for simultaneous analysis of simvastatin (SMV) and fenofibrate (FNF) in standard form, marketed formulations, and self-emulsifying drug delivery system formulations was developed and validated in the present investigation. The method utilized C18 as stationary phase and a combination of methanol:water (8:2) as an eluent. It was found that selected eluent provided short run time (2.5 minutes), better peak symmetry and satisfactory values of other chromatographic parameters such as resolution (Rs=2.325), capacity factor (k, 3.0 and 4.2 for SMV and FNF, respectively), selectivity (alpha =1.4), and number of theoretical plates (N, 4265 and 5285 for SMV and FNF, respectively). An excellent linear relationship (r2 0.998 and 0.997 for SMV and FNF, respectively) was observed for linear regression data for the calibration plots. The developed system was validated for accuracy, precision, robustness (? 2% for both drugs) and recovery (98-102% for both drugs). Results obtained from the statistical treatment of the values obtained for different parameters proved that the method is suitable, reproducible, and selective for the simultaneous analysis of SMV and FNF in bulk, marketed, and self-emulsifying drug delivery system formulations. The replacement of commonly applied toxic solvents with innocuous and environmentally benign solvents provides a better option than the more toxic processes in drug analysis. PMID- 28911688 TI - Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney. AB - In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd) and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6): saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05). However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes) and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO). However, co treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats. PMID- 28911689 TI - Effect of oleuropein against chemotherapy drug-induced histological changes, oxidative stress, and DNA damages in rat kidney injury. AB - Cisplatin-based chemotherapy is responsible for a large number of renal failures, and it is still associated with high rates of mortality today. Oleuropein (OLE) presents a plethora of pharmacological beneficial properties. In this study we investigated whether OLE could provide sufficient protection against cisplatin induced nephrotoxicity. With this aim, Sprague-Dawley rats were divided into eight groups: control; 7 mg/kg/d cisplatin, 50 mg/kg, 100 mg/kg, and 200 mg/kg OLE; and treatment with OLE for 3 days starting at 24 hours following cisplatin injection. After exposure to the chemotherapy agent and OLE, oxidative DNA damage was quantitated in the renal tissue of experimental animals by measuring the amount of 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts. Malondialdehyde (MDA) level, total oxidative stress (TOS), and total antioxidant status (TAS) were assessed to determine the oxidative injury in kidney cells. The histology of the kidney was examined using four different staining methods: hematoxylin-eosin (H&E), periodic acid Schiff (PAS), Masson trichrome, and amyloid. In addition, the blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE) levels were established. Our experimental data showed that tissue 8-OHdG levels were significantly higher in the cisplatin group when compared to the control group. The glomerular cells were sensitive to cisplatin as tubular cells. In addition, treatment with cisplatin elevated the levels of BUN, UA, CRE, and TOS, but lowered the level of TAS compared to the control group. The OLE therapy modulated oxidative stress in order to restore normal kidney function and reduced the formation of 8-OHdG induced by cisplatin. Furthermore, the OLE treatment significantly reduced pathological findings in renal tissue. We demonstrate for the first time that OLE presents significant cytoprotective properties against cisplatin-induced genotoxicity by restoring the antioxidant system of the renal tissue. According to our findings, OLE is a promising novel natural source for the prevention of serious kidney damage in current chemotherapies. PMID- 28911690 TI - A review on the analysis of ingredients with health care effects in health food in Taiwan. AB - This review article discusses the analysis of ingredients with health care effects in health food in Taiwan. The top 10 items on the list of registered health food products up to 2014 in Taiwan are described, including monocolin K, omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid), beta glucans, inulin, catechins, oligosaccharides, resistant maltodextrin, amino acids, medium chain fatty acids, and polysaccharides. Some analytical methods for the analysis of ingredients with health care effects are announced to the public on the website of health food section of the Taiwan Food and Drug Administration for the application and the postmarket surveillance of health food. Each application of health food should include the appropriate analytical method for the analysis of the ingredient or specific compound that has the health care effect, for the sake of quality assurance. Self-management of each applicant is required for regulation, the reputation of its own, and social responsibility to the consumers. PMID- 28911691 TI - Application of polymeric nanoparticles and micelles in insulin oral delivery. AB - Diabetes mellitus is an endocrine disease in which the pancreas does not produce sufficient insulin or the body cannot effectively use the insulin it produces. Insulin therapy has been the best choice for the clinical management of diabetes mellitus. The current insulin therapy is via subcutaneous injection, which often fails to mimic the glucose homeostasis that occurs in normal individuals. This provokes numerous attempts to develop a safe and effective noninvasive route for insulin delivery. Oral delivery is the most convenient administration route. However, insulin cannot be well absorbed orally because of its rapid enzymatic degradation in the gastrointestinal tract. Therefore, nanoparticulate carriers such as polymeric nanoparticles and micelles are employed for the oral delivery of insulin. These nanocarriers protect insulin from degradation and facilitate insulin uptake via a transcellular and/or paracellular pathway. This review article focuses on the application of nanoparticles and micelles in insulin oral delivery. The recent advances in this topic are also reviewed. PMID- 28911692 TI - Rhodiola plants: Chemistry and biological activity. AB - Rhodiola is a genus of medicinal plants that originated in Asia and Europe and are used traditionally as adaptogens, antidepressants, and anti-inflammatory remedies. Rhodiola plants are rich in polyphenols, and salidroside and tyrosol are the primary bioactive marker compounds in the standardized extracts of Rhodiola rosea. This review article summarizes the bioactivities, including adaptogenic, antifatigue, antidepressant, antioxidant, anti-inflammatory, antinoception, and anticancer activities, and the modulation of immune function of Rhodiola plants and its two constituents, as well as their potential to prevent cardiovascular, neuronal, liver, and skin disorders. PMID- 28911693 TI - Rice bran oil prevents neuroleptic-induced extrapyramidal symptoms in rats: Possible antioxidant mechanisms. AB - Tardive dyskinesia (TD) is one of the serious side effects of long-term antipsychotic treatment. Chronic treatment with neuroleptic leads to the development of abnormal oral movements called vacuous chewing movements (VCMs). The oxidative stress hypothesis of TD is one of the possible pathophysiologic models for TD. Preclinical and clinical studies of this hypothesis indicate that neurotoxic free radical production is likely to be a consequence of antipsychotic medication and is related to occurrence of TD. Oxidative stress is implicated in the pathophysiology of TD. Rats chronically treated with haloperidol orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs, which increased in a time-dependent manner as the treatment continued for 5 weeks. Motor coordination impairment started after the 1st week and was maximally impaired after 3 weeks and gradually returned to the 1st week value. Motor activity in an open field or home cage (activity box) not altered. Administration of rice bran oil (antioxidant) by oral tubes at a dose of 0.4 mL/day prevented the induction of haloperidol-elicited VCMs as well impairment of motor coordination. The results are discussed in the context of a protective role of antioxidant of rice bran oil in the prevention of haloperidol-induced extrapyramidal symptoms. PMID- 28911694 TI - Evaluation of antioxidant, anti-inflammatory, and antiulcer properties of Vaccinium leschenaultii Wight: A therapeutic supplement. AB - In folklore systems of medicine, bilberry fruit and leaf extracts have been used for the treatment of diarrhoea, dysentery, diabetes, inflammation, and ulcer. The present study was to determine antioxidant, anti-inflammatory, and antiulcerogenic activities of Vaccinium leschenaultii Wight leaf and fruit. The phenolic, tannin, and flavonoid contents of V. leschenaultii leaf and fruit were quantified and were subjected to assess their antioxidant potential using various in vitro systems such as 1, 1 diphenyl-2-picrylhydrazyl, 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) radical scavenging, phosphomolybdenum, and ferric reducing antioxidant power reduction activities. Based on the antioxidant potential, acetone and methanol extracts of leaf and fruit were used to evaluate the anti-inflammatory activity and protective effect against ethanol-induced gastric damage in a rat model. The quantification of secondary metabolites shows that the phenolic, flavonoid, and tannin contents are higher in methanol extracts of fruit and leaf. The results of antioxidant assays exhibited that the methanol extracts of leaf possesses better 1, 1 diphenyl-2-picrylhydrazyl radical scavenging and ferric reducing power activity. Oral administration of the acetone fruit and leaf extracts of V. leschenaultii were capable of reducing the edema formation in rats against carrageenan and egg albumin induced inflammation. Moreover, leaf and fruit acetone extracts at the dose of 400 mg/kg highly inhibited ulcer formation. The study concluded that the plant substances such as total phenols, flavonoids along with appreciable antioxidant potential could be the supportive evidence to prove both the anti-inflammatory and antiulcer activities of V. leschenaultii. The traditional importance of this plant will help to reveal the potential of plant to provide alternative phytotherapeutics for human health. PMID- 28911695 TI - Antioxidant capacity and bioactive compounds of four Brazilian native fruits. AB - The purpose of this study was to evaluate the bioactive compounds and antioxidant activity of extracts from araca (Psidium cattleianum), butia (Butia eriospatha), and pitanga (Eugenia uniflora) fruits with different flesh colors (i.e., purple, red, and orange), and blackberries (Rubus sp.; cv. Xavante and Cherokee) collected in the southern region of Brazil. The content of ascorbic acid, total carotenoids, and phenolics were determined. The profile of the phenolic compounds was assessed by high-performance liquid chromatography combined with diode array detection (HPLC-DAD). The antioxidant activity was determined using the ferric reducing antioxidant power (FRAP) assay, 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) assay, total reactive antioxidant potential (TRAP) assay, and total antioxidant reactivity (TAR) assay. The Xavante blackberry and purple-fleshed pitanga showed the highest total phenolic content [816.50 mg gallic acid equivalents (GAE)/100g and 799.80 mg GAE/100g, respectively]. The araca and red fleshed pitanga showed the highest carotenoid content (6.27 ug beta-carotene/g and 5.86 ug beta-carotene/g, respectively). The fruits contained several phenolic compounds such as quercetin derivatives, quercitrin, isoquercitrin, and cyanidin derivatives, which may contribute differentially to the antioxidant capacity. The highest scavenging activity in the DPPH assay was found for purple-fleshed pitanga (IC50 36.78 mg/L), blackberries [IC50 44.70 (Xavante) and IC50 78.25 mg/L (Cherokee)], and araca (IC50 48.05 mg/L), which also showed the highest FRAP, followed by orange- and red-fleshed pitanga. Our results revealed that some fruits grown in southern Brazil such as purple-fleshed pitanga, blackberries, and araca are rich sources of phenolic compounds and have great antioxidant activity. PMID- 28911696 TI - Sweet potato leaf extract inhibits the simulated in vitro gastrointestinal digestion of native starch. AB - Several studies have reported the therapeutic use of caffeoylquinic acid (CQA) derivatives in the management of hyperglycemia. This study used a simulated in vitro gastrointestinal digestion model to assess the inhibitory effects of CQA derivatives-rich sweet potato leaf extract (SPLE) and a commercially produced green coffee bean extract (GCBE), each with total polyphenols contents of 452 mg g-1 and 278 mg g-1, respectively, against starch digestion. The changes in the amounts of total polyphenols and total CQA derivatives during in vitro gastrointestinal digestion were also examined. The results indicated that both extracts contained substantial levels of CQA derivatives (136 mg g-1 and 83.5 mg g-1 of extract for SPLE and GCBE, respectively). The amounts of total polyphenols and total CQA derivatives in 20 mg of SPLE and GCBE samples decreased from 9.04 mg to 0.58 mg and from 5.56 mg to 0.58 mg, and from 2.72 mg to 0.16 mg and from 1.67 mg to 0.10 mg, respectively, following in vitro gastrointestinal digestion and subsequent dialysis. When SPLE and GCBE were accompanied with starch for in vitro digestion test, they both exhibited inhibitory effect against starch digestion during simulated intestinal digestion, with estimated half maximal inhibitory concentration (IC50) values of 4.91 mg and 6.06 mg polyphenols, respectively. The amount of glucose permeated through dialysis membrane also decreased significantly in comparison with the extract-negative control. Thus, both SPLE and GCBE were capable of modulating the release of glucose from starch digestion in simulated intestinal tract. The observed inhibitory effects against glucose release were presumably due in part to the presence of CQA derivatives in the tested extracts. The SPLE had higher inhibitory effect against in vitro starch digestion than the commercially prepared reference GCBE. Therefore, the SPLE might be used to manage hyperglycemia over the long term. PMID- 28911697 TI - Anthocyanin-rich tea Sunrouge upregulates expressions of heat shock proteins in the gastrointestinal tract of ICR mice: A comparison with the conventional tea cultivar Yabukita. AB - Sunrouge is an anthocyanin-rich, new tea cultivar that contains similar levels of catechins as Yabukita, the most popular tea cultivar consumed in Japan. Interestingly, Sunrouge preparations have previously been shown to have more pronounced acetylcholinesterase inhibitory and anticolitis activities than those of Yabukita. In this study, we examined their effects on expressions of self defensive molecules, including heat shock proteins (HSPs), which are molecular chaperones involved in homeostasis and longevity. Hot water extract from freeze dried Sunrouge significantly upregulated messenger RNA (mRNA) expressions of HSP40, HSP70, and HSP32 (heme oxygenase-1), with grades greater than those shown by Yabukita. Oral administration of freeze-dried preparation of Sunrouge to male ICR mice at a dose of 1% in the basal diet for 1 month resulted in marked upregulations of several HSP mRNA expressions in mucosa from the gastrointestinal tract, especially the upper small intestine. Again, its efficacy was remarkably higher than that of Yabukita. Moreover, exposure of Caenorhabditis elegans to Sunrouge conferred thermoresistant phenotype, and also resulted in a significant life-span elongation. Taken together, our results suggest that Sunrouge is a unique and promising tea cultivar for regulating self-defense systems. PMID- 28911698 TI - Melilotus albus and Dorycnium herbaceum extracts as source of phenolic compounds and their antimicrobial, antibiofilm, and antioxidant potentials. AB - Melilotus albus Medic. and Dorycnium herbaceum Vill. (Fabaceae) acetone, ethyl acetate, and ethanol extracts were investigated for their in vitro antimicrobial, antibiofilm, and antioxidant activity with quantification of phenolic compound contents. In general, D. herbaceum extracts showed better antibacterial and antioxidant activity than M. albus extracts. Bacteria Bacillus subtilis, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa, and Proteus mirabilis were the most susceptible with the minimum inhibitory concentrations (MICs), determined by microdilution method, between 1.25-10 mg/mL. Antifungal activity was lower with the detectable MICs at 10 mg/mL and 20 mg/mL. The plant extracts, using the crystal violet assay, inhibit P. aeruginosa biofilm formation in concentration range from 5 mg/mL to 20 mg/mL whereas the effect on mature bacterial biofilm was lower. The antioxidant activity was evaluated using 2, 2 diphenyl-1-picrylhydrazyl (DPPH) radicals scavenging and reducing power model systems. The intensity of DPPH radicals scavenging activity, expressed as half maximal effective concentration (EC50) values, was from 84.33 MUg/mL to >1000 MUg/mL. The extracts demonstrated reduced power in a concentration-dependent manner, with ethanol extract as the most active. The total phenols, flavonoids, and proanthocyanidins were determined spectrophotometrically while total extractable tannins were obtained by precipitation method. The phenolic compounds showed differences in their total contents depending on solvents polarities and plant species. Although the plants M. albus and D. herbaceum have not yet been fully explored, these results contribute better understanding of their biotic properties and potential application as antimicrobial and antioxidant agents. PMID- 28911699 TI - Effects of extracts from Gynura bicolor (Roxb. & Willd.) DC. on iron bioavailability in rats. AB - Gynura bicolor (Roxb. & Willd.) DC. is widely distributed in certain areas of Asia and is very popular in vegetarian cuisine in Taiwan. This study investigates the effects of G. bicolor extracts with different polarities of 80 mg/kg body weight (BW) G. bicolor alcohol extract, 80 mg/kg BW G. bicolor water extract, and 80 mg/kg BW G. bicolor ether extract on Fe bioavailability using the hemoglobin repletion efficiency assay. Wistar rats were assigned to five groups: a group receiving an iron-deficient (ID) diet; a group receiving an ID diet supplemented with ferrous sulfate (20 mg Fe/kg BW); and three groups receiving ID diets supplemented with ferrous sulfate and one of G. bicolor alcohol extract, G. bicolor water extract, or G. bicolor water extract. The results indicated that the levels of hemoglobin, serum iron, serum ferritin, liver ferritin, hemoglobin regeneration efficiency, relative biological value, and hepcidin all were significantly higher than those of the ID diet group. Besides, the iron transporter divalent metal transporter-1 was significantly reduced, but iron release protein expression of ferroportin was significantly increased. It was concluded that G. bicolor extracts may promote iron bioavailability and regulate the expressions of divalent metal transporter-1 and ferroportin. PMID- 28911700 TI - Effect of storage time on metabolite profile and alpha-glucosidase inhibitory activity of Cosmos caudatus leaves - GCMS based metabolomics approach. AB - Cosmos caudatus, which is a commonly consumed vegetable in Malaysia, is locally known as "Ulam Raja". It is a local Malaysian herb traditionally used as a food and medicinal herb to treat several maladies. Its bioactive or nutritional constituents consist of a wide range of metabolites, including glucosinolates, phenolics, amino acids, organic acids, and sugars. However, many of these metabolites are not stable and easily degraded or modified during storage. In order to investigate the metabolomics changes occurring during post-harvest storage, C. caudatus samples were subjected to seven different storage times (0 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours) at room temperature. As the model experiment, the metabolites identified by gas chromatography-mass spectrometry (GC-MS) were correlated with alpha-glucosidase inhibitory activity analyzed with multivariate data analysis (MVDA) to find out the variation among samples and metabolites contributing to the activity. Orthogonal partial least squares (OPLS) analysis was applied to investigate the metabolomics changes. A profound chemical alteration, both in primary and secondary metabolites, was observed. The alpha-tocopherol, catechin, cyclohexen-1 carboxylic acid, benzoic acid, myo-inositol, stigmasterol, and lycopene compounds were found to be the discriminating metabolites at early storage; however, sugars such as sucrose, alpha-d-galactopyranose, and turanose were detected, which was attributed to the discriminating metabolites for late storage. The result shows that the MVDA method is a promising technique to identify biomarker compounds relative to storage at different times. PMID- 28911701 TI - Effective extraction method through alkaline hydrolysis for the detection of starch maleate in foods. AB - A high-performance liquid chromatography (HPLC) method was developed for the determination of maleic acid which was released from starch maleate (SM) through the alkaline hydrolysis reaction. The proper alkaline hydrolysis conditions and LC separation are reported in this study. The starch samples were treated with 50% methanol for 30 minutes, and then hydrolyzed by 0.5N KOH for 2 hours to release maleic acid. A C18 column and gradient mobile phase consisting of 0.1% phosphoric acid and methanol at a flow rate of 1.0 mL/minute were used for separation. The method showed a good linearity in the range of 0.01-1.0 ig/mL, with a limit of quantification (LOQ) at 10 mg/kg in starch. The recoveries in corn starch, noodle, and fish balls were between 93.9% and 108.4%. The relative standard deviation (RSD) of precision was <4.9% (n = 3). This valid method was rapid, sensitive, precise, and suitable for routine monitoring of the illegal adulteration of SM in foods. PMID- 28911702 TI - Simultaneous determination of some common food dyes in commercial products by digital image analysis. AB - A simple and relatively fast image-analysis method using digital images, obtained with a flatbed scanner, has been described. The method was used for the simultaneous determination of four common food dyes, namely, carmoisine, brilliant blue, sunset yellow, and quinoline yellow, in binary mixtures in commercial products without a need for any prior separation steps. The results obtained were validated against a standard high-performance liquid chromatography method and a good agreement was obtained. The parameters affecting the experimental results were optimized. Under the optimal conditions, the method provided acceptable linear ranges (20-250 mg/L) with correlation coefficients higher than 0.998, suitable precision (relative standard deviation <= 4.5%), and limits of detection between 4.82 and 8.05 mg/L. PMID- 28911703 TI - Determination of 20 synthetic dyes in chili powders and syrup-preserved fruits by liquid chromatography/tandem mass spectrometry. AB - A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method is developed to simultaneously determine 20 synthetic dyes (New Coccine, Indigo Carmine, Erythrosine, Tartrazine, Sunset Yellow FCF, Fast Green FCF, Brilliant Blue FCF, Allura Red AC, Amaranth, Dimethyl Yellow, Fast Garnet GBC, Para Red, Sudan I, Sudan II, Sudan III, Sudan IV, Sudan Orange G, Sudan Red 7B, Sudan Red B, and Sudan Red G) in food samples. This method offers high sensitivity and selectivity through the selection of two fragment ion transitions under multiple reaction monitoring mode to satisfy the requirements of both quantitation and qualitation. Using LC-MS/MS, the newly developed extraction protocol used in this study is rapid and simple and does not require the use of solid-phase extraction cartridges. The linearities and recoveries of the method are observed at the concentration range of 0.10-200 MUg/kg and more than 90% for all dyes, respectively. The method has been successfully applied to screen 18 commercial chili powders and six commercial syrup-preserved fruits purchased from retail establishments in Taipei City. The results show that three legal food dyes, Tartrazine, and/or Sunset Yellow FCF, and/or New Coccine, are present in some syrup-preserved fruits. Amaranth, an illegal food dye in certain countries but declared illegal in Taiwan, is found in an imported syrup-preserved fruit. PMID- 28911704 TI - Electrochemical determination of paraquat in citric fruit based on electrodeposition of silver particles onto carbon paste electrode. AB - Carbon paste electrodes (CPEs) modified with silver particles present an interesting tool in the determination of paraquat (PQ) using square wave voltammetry. Metallic silver particle deposits have been obtained via electrochemical deposition in acidic media using cyclic voltammetry. Scanning electron microscopy and X-ray diffraction measurements show that the silver particles are deposited onto carbon surfaces in aggregate form. The response of PQ with modified electrode (Ag-CPE) related to Ag/CP loading, preconcentration time, and measuring solution pH was investigated. The result shows that the increase in the two cathodic peak currents (Peak 1 and Peak 2), under optimized conditions, was linear with the increase in PQ concentration in the range 1.0 * 10-7 mol/L to 1.0 * 10-3 mol/L. The detection limit and quantification limit were 2.01 * 10-8 mol/L and 6.073 * 10-8 mol/L, respectively for Peak 1. The precision expressed as relative standard deviation for the concentration level 1.0 * 10-5 mol/L (n = 8) was found to be 1.45%. The methodology was satisfactorily applied for the determination of PQ in citric fruit cultures. PMID- 28911705 TI - Determination of the concentration of alum additive in deep-fried dough sticks using dielectric spectroscopy. AB - The concentration of alum additive in deep-fried dough sticks (DFDSs) was investigated using a coaxial probe method based on dielectric properties in the 0.3-10-GHz frequency range. The dielectric spectra of aqueous solutions with different concentrations of alum, sodium bicarbonate, and mixtures thereof were used. The correspondence between dielectric loss and alum concentration was thereby revealed. A steady, uniform correspondence was successfully established by introducing omega.epsilon"(omega), the sum of dielectric loss and conductor loss (i.e., total loss), according to the electrical conductivity of the alum containing aqueous solutions. Specific, resonant-type dielectric dispersion arising from alum due to atomic polarization was identified around 1 GHz. This was used to discriminate the alum additive in the DFDS from other ingredients. A quantitative relationship between alum and sodium bicarbonate concentrations in the aqueous solutions and the differential dielectric loss Deltaepsilon"(omega) at 0.425 GHz was also established with a regression coefficient over 0.99. With the intention of eliminating the effects of the chemical reactions with sodium bicarbonate and the physical processes involved in leavening and frying during preparation, the developed technique was successfully applied to detect the alum dosage in a commercial DFDS (0.9942 g/L). The detected value agreed well with that determined using graphite furnace atomic absorption spectrometry (0.9722 g/L). The relative error was 2.2%. The results show that the proposed dielectric differential dispersion and loss technique is a suitable and effective method for determining the alum content in DFDSs. PMID- 28911706 TI - Detection of viable Salmonella in ice cream by TaqMan real-time polymerase chain reaction assay combining propidium monoazide. AB - Real-time polymerase chain reaction (PCR) allows rapid detection of Salmonella in frozen dairy products, but it might cause a false positive detection result because it might amplify DNA from dead target cells as well. In this study, Salmonella-free frozen ice cream was initially inoculated with heat-killed Salmonella Typhimurium cells and stored at -18 degrees C. Bacterial DNA extracted from the sample was amplified using TaqMan probe-based real-time PCR targeting the invA gene. Our results indicated that DNA from the dead cells remained stable in frozen ice cream for at least 20 days, and could produce fluorescence signal for real-time PCR as well. To overcome this limitation, propidium monoazide (PMA) was combined with real-time PCR. PMA treatment can effectively prevent PCR amplification from heat-killed Salmonella cells in frozen ice cream. The PMA real time PCR assay can selectively detect viable Salmonella at as low as 103 CFU/mL. Combining 18 hours of pre-enrichment with the assay allows for the detection of viable Salmonella at 100 CFU/mL and avoiding the false-positive result of dead cells. The PMA real-time PCR assay provides an alternative specifically for detection of viable Salmonella in ice cream. However, when the PMA real-time PCR assay was evaluated in ice cream subjected to frozen storage, it obviously underestimated the contamination situation of viable Salmonella, which might lead to a false negative result. According to this result, the use of enrichment prior to PMA real-time PCR analysis remains as the more appropriate approach. PMID- 28911707 TI - Concentrations and solubility of selected trace metals in leaf and bagged black teas commercialized in Poland. AB - The objective of this study was to determine the concentrations of heavy metals in bagged and leaf black teas of the same brand and evaluate the percentage transfer of metals to tea infusion to assess the consumer exposure. Ten leaf black teas and 10 bagged black teas of the same brand available in Poland were analyzed for Zn, Mn, Cd, Pb, Ni, Co, Cr, Al, and Fe concentrations both in dry material and their infusion. The bagged teas contained higher amounts of Pb, Mn, Fe, Ni, Al, and Cr compared with leaf teas of the same brand, whereas the infusions of bagged tea contained higher levels of Mn, Ni, Al, and Cr compared with leaf tea infusions. Generally, the most abundant trace metals in both types of tea were Al and Mn. There was a wide variation in percentage transfer of elements from the dry tea materials to the infusions. The solubility of Ni and Mn was the highest, whereas Fe was insoluble and only a small portion of this metal content may leach into infusion. With respect to the acceptable daily intake of metals, the infusions of both bagged and leaf teas analyzed were found to be safe for human consumption. PMID- 28911708 TI - The effect of pineapple core fiber on dough rheology and the quality of mantou. AB - The consumption of dietary fiber offers the health benefit of lowering the risk of many chronic diseases. Pineapple core fiber (PCF) in this study was extracted and incorporated into dough and mantou (i.e., steamed bread). The effects of PCF substitution and fiber size on textural and rheological properties of dough and mantou were evaluated by a texture analyzer. The substitution of wheat flour by PCF resulted in a stiffer and less extensible dough with or without fermentation. The hardness and gumminess of mantou significantly increased as the PCF substitution increased from 0% to 15%, but the cohesiveness, specific volume, and elasticity significantly decreased with the fiber substitution. Ten percent PCF enriched dough and mantou with various fiber sizes had similar rheological and textural properties, except for the k1 and k2 values. By sensory evaluation, 5% PCF-enriched mantou and the control bread had better acceptability in texture, color, odor, and overall acceptability, compared to mantous enriched with 10% or 15% PCF. Significant correlations existed between the rheological properties of dough and textural parameters of mantou and between the sensory quality and textural parameters of mantou. Therefore, we suggest that fiber-enriched mantou can be prepared with 5% PCF substitution to increase the intake of dietary fiber and maintain the quality of mantou. PMID- 28911709 TI - Alleviative effects of litchi (Litchi chinensis Sonn.) flower on lipid peroxidation and protein degradation in emulsified pork meatballs. AB - To avoid or retard the lipid peroxidation of meat products, antioxidants are commonly added. Considering the safety and health of additives in meat products, consumers prefer natural antioxidants rather than synthetic ones. Gentisic acid and epicatechin were identified as the major phenolic acid and flavonoid, respectively, of litchi flowers (LFs). The physicochemical properties of pork meatballs with or without dried LF powders (0.5%, 1.0%, and 1.5%, w/w) and tert butylhydroquinone (TBHQ; 0.01%, w/w) were analyzed during a 4-week frozen storage period. LF and TBHQ decreased (p < 0.05) thiobarbituric acid reactive substance (TBARS) values but increased (p < 0.05) thiol group contents in meatballs. LF added to meatballs improved (p < 0.05) texture and water-holding capacity (centrifugation/purge losses) more than in the control group upon the storage. Although LF powders made meatballs redder and darker (p < 0.05) than the control and TBHQ groups, they did not affect the preference of panelists. The addition of 0.5% LF powders exhibited the best (p < 0.05) overall sensory panel acceptance. LFs may be an effective natural antioxidant to reduce lipid and protein oxidation for frozen cooked meat products. PMID- 28911710 TI - The implementation of a Hazard Analysis and Critical Control Point management system in a peanut butter ice cream plant. AB - To ensure the safety of the peanut butter ice cream manufacture, a Hazard Analysis and Critical Control Point (HACCP) plan has been designed and applied to the production process. Potential biological, chemical, and physical hazards in each manufacturing procedure were identified. Critical control points for the peanut butter ice cream were then determined as the pasteurization and freezing process. The establishment of a monitoring system, corrective actions, verification procedures, and documentation and record keeping were followed to complete the HACCP program. The results of this study indicate that implementing the HACCP system in food industries can effectively enhance food safety and quality while improving the production management. PMID- 28911711 TI - Effects of aqueous extract of Ruta graveolens and its ingredients on cytochrome P450, uridine diphosphate (UDP)-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H)-quinone oxidoreductase in mice. AB - Ruta graveolens (the common rue) has been used for various therapeutic purposes, including relief of rheumatism and treatment of circulatory disorder. To elucidate the effects of rue on main drug-metabolizing enzymes, effects of an aqueous extract of the aerial part of rue and its ingredients on cytochrome P450 (P450/CYP), uridine diphosphate (UDP)-glucuronosyltransferase, and reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H):quinone oxidoreductase were studied in C57BL/6JNarl mice. Oral administration of rue extract to males increased hepatic Cyp1a and Cyp2b activities in a dose-dependent manner. Under a 7-day treatment regimen, rue extract (0.5 g/kg) induced hepatic Cyp1a and Cyp2b activities and protein levels in males and females. This treatment increased hepatic UDP-glucuronosyltransferase activity only in males. However, NAD(P)H:quinone oxidoreductase activity remained unchanged. Based on the contents of rutin and furanocoumarins of mouse dose of rue extract, rutin increased hepatic Cyp1a activity and the mixture of furanocoumarins (Fmix) increased Cyp2b activities in males. The mixture of rutin and Fmix increased Cyp1a and Cyp2b activities. These results revealed that rutin and Fmix contributed at least in part to the P450 induction by rue. PMID- 28911712 TI - Optimization of ultrasonic extraction by response surface methodology combined with ultrafast liquid chromatography-ultraviolet method for determination of four iridoids in Gentiana rigescens. AB - Gentiana rigescens is a rich source of iridoids and is commonly used as a folk medicine for treatment of hepatitis and cholecystitis for over 1000 years. A rapid ultrafast liquid chromatography-ultraviolet method was developed for simultaneous determination of four major iridoid glycosides in G. rigescens. Response surface methodology based on the Box-Behnken design was applied to optimize the extraction conditions of iridoid glycosides. Using the Shim-Pack XR ODS III, four iridoid glycosides were efficiently separated with an acetonitrile:0.1% formic acid aqueous solution gradient at a flow rate of 0.25 mL/min for 8 minutes. All the regression equations revealed a good linear relationship (R2 > 0.9995). The intraday and interday variations were <1.95%. The recoveries ranged from 99.7% to 103.2%. The optimal extraction conditions were as follows: methanol concentration, 82%; the ratio of liquid to solid material, 68:1 (mL/g); and extraction time, 32 minutes. The yield of the four iridoid glycosides under the optimal process was found to be 63.08 mg/g, which was consistent with the predicted yield. In addition, the total content of 50 cultivated samples from Lincang, Yunnan, China, was within the range of 33.6-113.26 mg/g, which provides a more reasonable foundation for utilization of G. rigescens. PMID- 28911713 TI - Dynamics of phytoestrogen, isoflavonoids, and its isolation from stems of Pueraria lobata (Willd.) Ohwi growing in Democratic People's Republic of Korea. AB - Four isoflavonoids were isolated from stems of Pueraria lobata (Willd.) Ohwi growing in Democratic People's Republic of Korea and identified as daidzein (1), genistin (2), daidzin (3), and puerarin (4), structures, which were elucidated by means of spectroscopic analysis. Isoflavonoids were isolated using silica gel chromatography and purified with organic solvents. Isoflavonoid contents in P. lobata were determined using reliable high-performance liquid chromatography. The results indicated that the contents of puerarin and genistin in the roots are higher than those in the stems (6.19% and 0.04% vs. 1.15% and 0.02%), whereas the stems have higher contents of daidzin and daidzein than the roots (3.17% and 0.06% vs. 1.72% and 0.05%). Accordingly, the root part of the plant is useful for the isolation of puerarin and the stem part for daidzin. This study suggests that the stem of P. lobata is useful as an alternative source of puerarin, daidzin, genistin, and daidzein. In addition, collection of the stem will not sacrifice the plant and thus is beneficial to the natural ecosystems. PMID- 28911714 TI - Investigation of impact of storage conditions on Hypericum perforatum L. dried total extract. AB - Hypericum perforatum L. (Hypericaceae) has been widely prescribed for mild to moderate depression following the release of promising results in clinical trials. However, it is known that its constituents may be affected by milieu. The stability complexities of the constituents of H. perforatum have gained interest in recent years. The aim of the present study was to examine the impact of storage conditions on H. perforatum total extract simultaneously under different storage conditions. Temperature, humidity, and light conditions were evaluated. Comparative analyses of methanol extracts were conducted using high performance liquid chromatography-diode array detection for chlorogenic acid, rutin, hyperoside, isoquercitrin, quercitrin, quercetin, amentoflavone, pseudohypericin, hyperforin, and hypericin. Analysis and extraction were performed using a validated method. The fluctuation of the constituents of the plant extract has been demonstrated. Among these components, chlorogenic acid was the most stable. Hyperforin, hypericin, and pseudohypericin were more stable than the flavonoids at -20 degrees C, in the 6th month. As estimated, decay was lowest at -20 degrees C and highest at 40 degrees C-75% relative humidity for the analyzed constituents. Except for hyperforin, light protection decreased the breakdown of components within 4 months. However, at the 6th month, equivalent changes were seen for all constituents. Degradation of the constituents at -20 degrees C indicates the importance of stability tests in analysis studies covering time and storage conditions. PMID- 28911715 TI - Gas chromatographic method for the determination of lumefantrine in antimalarial finished pharmaceutical products. AB - A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O-bis(trimethyl-silyl)trifluoro-acetamide at 70 degrees C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length * 0.32 mm i.d., 0.25 MUm film thickness) column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD) = 1.0%], linearity (=0.9986), precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%), and high sensitivity with detection limits of 0.01 MUg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products. PMID- 28911716 TI - Formulation of essential oil-loaded chitosan-alginate nanocapsules. AB - Naturally occurring polymers such as alginate (AL) and chitosan (CS) are widely used in biomedical and pharmaceutical fields in various forms such as nanoparticles, capsules, and emulsions. These polymers have attractive applications in drug delivery because of their biodegradability, biocompatibility, and nontoxic nature. The pharmaceutical applications of essential oils such as turmeric oil and lemongrass oil are well-known, and their active components, ar-turmerone and citral, respectively, are known for their antibacterial, antifungal, antioxidant, antimutagenic, and anticarcinogenic properties. However, these essential oils are unstable, volatile, and insoluble in water, which limits their use for new formulations. Therefore, this study focuses on developing a CS-AL nanocarrier for the encapsulation of essential oils. The effects of process parameters such as the effect of heat and the concentrations of AL and CS were investigated. Various physicochemical characterization techniques such as scanning electron microscopy, Fourier transform infrared spectroscopy, and ultraviolet-visible spectroscopy were performed. Results of characterization studies showed that 0.3 mg/mL AL and 0.6 mg/mL CS produced minimum-sized particles (<300 nm) with good stability. It was also confirmed that the oil-loaded nanocapsules were hemocompatible, suggesting their use for future biomedical and pharmaceutical applications. Furthermore, the antiproliferative activity of turmeric oil- and lemongrass oil-loaded nanocapsules was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay in A549 cell lines and it was found that both the nanoformulations had significant antiproliferative properties than the bare oil. PMID- 28911717 TI - New ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of irbesartan in human plasma. AB - With the objective of reducing analysis time and maintaining good efficiency, there has been substantial focus on high-speed chromatographic separations and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is a preeminent analytical tool for rapid biomedical analysis. In this study a simple, rapid, sensitive, and specific ultra-performance liquid chromatography MS/MS method was developed and validated for quantification of the angiotensin II receptor antagonist, irbesartan (IRB), in human plasma. After a simple protein precipitation using methanol and acetonitrile, IRB and internal standard (IS) telmisartan were separated on Acquity UPLC BEH C18 column (50 mm * 2.1 mm, i.d. 1.7 MUm, Waters, Milford, MA, USA) using a mobile phase consisted of acetonitrile: methanol: 10 mM ammonium acetate (70: 15: 15 v/v/v) with a flow rate of 0.4 mL/min and detected MS/MS in negative ion mode. The ion transitions recorded in multiple reaction monitoring mode were m/z 427.2->193.08 for IRB and m/z 513.2->469.3 for IS. The assay exhibited a linear dynamic range of 2-500 ng/mL for IRB in human plasma with good correlation coefficient of (0.995) and with a lower limit of quantitation of 2 ng/mL. The intra- and interassay precisions were satisfactory; the relative standard deviations did not exceed 9.91%. The proposed UPLC-MS/MS method is simple, rapid, and highly sensitive, and hence it could be reliable for pharmacokinetic and toxicokinetic study in both animals and humans. PMID- 28911718 TI - Synthesis and phototoxicity of isomeric 7,9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation. AB - Pyrrolizidine alkaloids (PAs) are hepatotoxic, genotoxic, and carcinogenic in experimental animals. Because of their widespread distribution in the world, PA containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Upon metabolism, PAs generate reactive dehydro PAs and other pyrrolic metabolites that lead to toxicity. Dehydro-PAs are known to react with glutathione (GSH) to form 7-GSH-(+/-)-6,7-dihydro-7-hydroxy-1 hydroxymethyl-5H-pyrrolizine (7-GS-DHP) in vivo and in vitro and 7,9-diGS-DHP in vitro. To date, the phototoxicity of GS-DHP adducts has not been well studied. In this study, we synthesized 7-GS-DHP, a tentatively assigned 9-GS-DHP, and two enantiomeric 7,9-diGS-DHP adducts by reaction of dehydromonocrotaline with GSH. The two 7,9-diGS-DHPs were separated by high performance liquid chromatography (HPLC) and their structures were characterized by 1H nuclear magnetic resonance (NMR) and 1H-1H correlation spectroscopy (COSY) NMR spectral analysis. Photoirradiation of 7-GS-DHP, 9-GS-DHP, and the two 7,9-diGS-DHPs as well as dehydromonocrotaline, dehydroheliotrine, and the 7-R enantiomer of DHP (DHR), by UVA light at 0 J/cm2, 14 J/cm2, and 35 J/cm2 in the presence of a lipid, methyl linoleate, all resulted in lipid peroxidation in a light dose-responsive manner. The levels of lipid peroxidation induced by the two isomeric 7,9-diGS-DHPs were significantly higher than that by 7-GS-DHP and 9-GS-DHP. When 7,9-diGS-DHP was irradiated in the presence of sodium azide (NaN3), the level of lipid peroxidation decreased; lipid peroxidation was enhanced when methanol was replaced by deuterated methanol. These results suggest that singlet oxygen is a product induced by the irradiation of 7,9-diGS-DHP. When irradiated in the presence of superoxide dismutase (SOD), the level of lipid peroxidation decreased, indicating that lipid peroxidation is also mediated by superoxide. These results indicate that lipid peroxidation is mediated by reactive oxygen species (ROS). These results suggest that 7,9-diGS-DHPs are phototoxic, generating lipid peroxidation mediated by ROS. PMID- 28911719 TI - Analysis of titanium dioxide and zinc oxide nanoparticles in cosmetics. AB - There have been rapid increases in consumer products containing nanomaterials, raising concerns over the impact of nanoparticles (NPs) to humankind and the environment, but little information has been published about mineral filters in commercial sunscreens. It is urgent to develop methods to characterize the nanomaterials in products. Titanium dioxide (TiO2) and zinc oxide (ZnO) NPs in unmodified commercial sunscreens were characterized by laser scanning confocal microscopy, atomic force microscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). The results showed that laser scanning confocal microscopy evaluated primary particle aggregates and dispersions but could not size NPs because of the diffraction limited resolution of optical microscopy (200 nm). Atomic force microscopy measurements required a pretreatment of the sunscreens or further calibration in phase analysis, but could not provide their elemental composition of commercial sunscreens. While XRD gave particle size and crystal information without a pretreatment of sunscreen, TEM analysis required dilution and dispersion of the commercial sunscreens before imaging. When coupled with energy-dispersive X-ray spectroscopy, TEM afforded particle size information and compositional analysis. XRD characterization of six commercial sunscreens labeled as nanoparticles revealed that three samples contained TiO2 NPs, among which two listed ZnO and TiO2, and displayed average particle sizes of 15 nm, 21 nm, and 78 nm. However, no nanosized ZnO particles were found in any of the samples by XRD. In general, TEM can resolve nanomaterials that exhibit one or more dimensions between 1 nm and 100 nm, allowing the identification of ZnO and TiO2 NPs in all six sunscreens and ZnO/TiO2 mixtures in two of the samples. Overall, the combination of XRD and TEM was suitable for analyzing ZnO and TiO2 NPs in commercial sunscreens. PMID- 28911720 TI - Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5]. PMID- 28911721 TI - Erratum to A.C. Crespo et al., "Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation". PMID- 28911722 TI - Erratum to "Exploratory analysis of seven Alzheimer's disease genes: disease progression" [Neurobiol. Aging 34 (2013) 1310.e1-1310.e7]. PMID- 28911723 TI - Preface. PMID- 28911724 TI - Radioactive iodine (RAI) therapy for metastatic differentiated thyroid cancer. AB - Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. It usually has a comparatively benign course. If properly executed, radioiodine therapy can provide an effective treatment of even advanced, metastatic DTC. A major problem in determining the right RAI for a patient with metastatic disease is a comparative lack of evidence. There are no reports on randomized controlled trials in this patient group which can aid us in determining which way to treat which patient. Few non-randomized prospective observational studies have been performed. Most available evidence is based on retrospective analyses which, although often informative, still are hampered by the selection bias inherent to retrospective studies on a small, preselected sample of the total DTC population. The aim of the present review is to provide an overview of the relevant literature on the issues pertinent to the execution of RAI. Radioiodine therapy of metastatic DTC in patients can be an effective treatment modality which will contribute significantly to a patients' life expectancy. However, much is unclear in the management of this malignancy, including which activity to use, how to determine this activity (empiric vs. dosimetric approach) as well as the potential long-term complications. In pediatric patients, special considerations apply with regard to weight-adaptation of activities as well the risk of pulmonary fibrosis in patients with diffuse miliary metastases. PMID- 28911725 TI - Which patient with thyroid cancer deserves systemic therapy and when? AB - Distant metastases from differentiated thyroid cancer (DTC) are a rare event, occurring in less than 10% of patients with persistent or recurrent clinical disease. About 50% of these patients do respond to radioiodine (RAI) therapy, either with complete remission or stabilization of the disease on a long term period. Unfortunately, another 50% of these patients are refractory to the treatment with RAI, either from the first appearance of distant metastases or during follow-up. Overall, these patients represent 4-5 new cases/year/million. After the discovery of RAI-refractory disease, the 10-year survival rate is usually less than 10% and the mean life expectancy is 3-5 years (Durante et al., 2006). Tyrosine hinase inhibitors (TKI) have been introduced in the clinical practice based on the results of several phase III clinical trial, which brought to the approval from competent authorities in USA and Europe of two specific drugs: sorafenib and lenvatinib. Both of them, have shown objective response rates improving the progression-free survival rates, although no overall survival benefit has been demonstrated yet (Schlumberger et al., 2015; Brose et al., 2014) [2,3]. The most challenging issue in RAI-refractory thyroid cancer is when a patient should be considered RAI-refractory and when to initiate treatment with TKI. PMID- 28911726 TI - Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer. AB - Multitargeted kinase inhibitors have been shown to improve progression-free survival in patients with structurally progressive, radioactive iodine refractory differentiated thyroid cancer. While the inclusion criteria for phase 3 clinical trials and clinical practice guidelines provide guidance with regard to the minimal requirements that need to be met prior to initiation of a multitargeted kinase inhibitor, a better way to integrate the rate of structural disease progression with the size of the metastatic foci to more precisely define the optimal time to recommend initiation of therapy for individual patients is needed. In this manuscript we describe how to use assessments of tumor size and growth rates (structural disease doubling times) to define the critical point in time when the volume and rate of progression of metastatic structural disease merits consideration for initiation of systemic therapy (the inflection point). PMID- 28911728 TI - Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life. AB - The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided. PMID- 28911729 TI - Chemotherapy and tyrosine-kinase inhibitors for medullary thyroid cancer. AB - Medullary thyroid cancer (MTC) represents 3% of all clinical thyroid cancers and arises from thyroid C cells that produce calcitonin. Locally advanced or metastatic MTC requires a careful work-up including measurement of serum calcitonin and carcinoembryonic antigen, determination of their doubling time and comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for treatment. Cytotoxic chemotherapy can control tumor burden in some patients with response rates of around 20% in old series. For the last 10 years, systemic therapy for MTC patients with large tumor burden and documented progression of the disease has involved the use of tyrosine kinase inhibitors targeting VEGFR and ret. Progression-free survival benefits have been demonstrated for both vandetanib and cabozantinib, as compared to placebo. Although these molecules are effective, they also have specific toxicity profiles which require a thorough clinical management in specialized centers. In the present review, we describe the work-up and treatment modalities of patients with advanced or metastatic medullary thyroid cancer with a focus on chemotherapy and targeted therapy results. PMID- 28911727 TI - The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer. AB - RET receptor tyrosine kinase acts as a mutated oncogenic driver in several human malignancies and it is over-expressed in other cancers. Small molecule compounds with RET tyrosine kinase inhibitory activity are being investigated for the targeted treatment of these malignancies. Multi-targeted compounds with RET inhibitory concentration in the nanomolar range have entered clinical practice. This review summarizes mechanisms of RET oncogenic activity and properties of new compounds that, at the preclinical stage, have demonstrated promising anti-RET activity. PMID- 28911730 TI - Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients. AB - Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed. PMID- 28911731 TI - Science, pseudoscience, evidence-based practice and post truth. PMID- 28911732 TI - Imaging cell biology and physiology in vivo using intravital microscopy. PMID- 28911733 TI - Time-lapsed, large-volume, high-resolution intravital imaging for tissue-wide analysis of single cell dynamics. AB - Pathologists rely on microscopy to diagnose disease states in tissues and organs. They utilize both high-resolution, high-magnification images to interpret the staining and morphology of individual cells, as well as low-magnification overviews to give context and location to these cells. Intravital imaging is a powerful technique for studying cells and tissues in their native, live environment and can yield sub-cellular resolution images similar to those used by pathologists. However, technical limitations prevent the straightforward acquisition of low-magnification images during intravital imaging, and they are hence not typically captured. The serial acquisition, mosaicking, and stitching together of many high-resolution, high-magnification fields of view is a technique that overcomes these limitations in fixed and ex vivo tissues. The technique however, has not to date been widely applied to intravital imaging as movements caused by the living animal induce image distortions that are difficult to compensate for computationally. To address this, we have developed techniques for the stabilization of numerous tissues, including extremely compliant tissues, that have traditionally been extremely difficult to image. We present a novel combination of these stabilization techniques with mosaicked and stitched intravital imaging, resulting in a process we call Large-Volume High-Resolution Intravital Imaging (LVHR-IVI). The techniques we present are validated and make large volume intravital imaging accessible to any lab with a multiphoton microscope. PMID- 28911734 TI - Both point mutations and low expression levels of the nicotinic acetylcholine receptor beta1 subunit are associated with imidacloprid resistance in an Aphis gossypii (Glover) population from a Bt cotton field in China. AB - Aphis gossypii Glover is a destructive pest of numerous crops throughout the world. Although the expansion of Bt cotton cultivation has helped to control some insect pests, the damage from cotton aphids has not been mitigated. The evolution of aphid resistance to imidacloprid has made its chemical control more difficult since its introduction in 1991. Field populations of A. gossypii that were collected from different transgenic (Bt) cotton planting areas of China in 2014 developed different levels of resistance to imidacloprid. The IMI_R strain has developed high resistance to imidacloprid with the resistance ratio >1200-fold. Compared with the susceptible IMI_S strain, the IMI_R strain also developed a high level cross resistance to sulfoxaflor and acetamiprid. The limited synergism with either PBO or DEF suggests that resistance may be due to the site mutation of molecular target rather than to enhanced detoxification. Three target-site mutations within the nicotinic acetylcholine receptor (nAChR) beta1 subunit were detected in the IMI_R strain. The R81T mutation has been reported to be responsible for imidacloprid resistance in A. gossypii and M. persicae. Both V62I and K264E were first detected in A. gossypii. These point mutations are also present in field populations, suggesting that they play a role in the resistance to imidacloprid. Furthermore, the expression level of transcripts encoding beta1 subunit was decreased significantly in the IMI_R strain compared with the IMI_S strain, suggesting that both point mutations and the down-regulation of nAChR beta1 subunit expression may be involved in the resistance mechanism for imidacloprid in A. gossypii. These results should be useful for the management of imidacloprid-resistant cotton aphids in Bt cotton fields in China. PMID- 28911735 TI - Antifungal activity of sterols and dipsacus saponins isolated from Dipsacus asper roots against phytopathogenic fungi. AB - The in vivo antifungal activity of crude extracts of Dipsacus asper roots was evaluated against the phytopathogenic fungi Botrytis cinerea, Colletotrichum coccodes, Blumeria graminis f. sp. hordei, Magnaporthe grisea, Phytophthora infestans, Puccinia recondita and Rhizoctonia solani using a whole-plant assay method. Ethyl acetate and acetone extracts, at 1000MUg/mL, suppressed the development of tomato gray mold (TGM) and tomato late blight (TLB) by 90%. Through bioassay-guided isolation, five antifungal substances were isolated from the D. asper roots and identified as beta-sitosterol (1), campesterol (2), stigmasterol (3), cauloside A (4) and a novel dipsacus saponin, named colchiside (3-O-beta-d-xylopyranosyl-23-O-beta-d-glucopyranosyl-28-O-beta-d-(6-O-acetyl) glucopyranosyl hederagenin) (5). Of those, cauloside A (4) displayed the greatest antifungal efficacy against rice blast, TGM and TLB. Colchiside (5) moderately suppressed the development of TLB, but exhibited little effect against the other diseases. The synergistic effects of the isolated compounds against TLB were also assessed. Synergistic and additive interactions were observed between several of the sterol compounds. This study indicated that the crude extracts of, and bioactive substances from, the roots of D. asper suppress TGM and TLB. In addition, cauloside A (4) and colchiside (5) could be used as antifungal lead compounds. PMID- 28911736 TI - Exposure to 2,4-dichlorophenoxyacetic acid induces oxidative stress and apoptosis in mouse testis. AB - The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is used worldwide. It has been associated with a variety of toxicities in rodents. In this study, male mice were orally administered 2,4-D at 50, 100 or 200mg/kg/day to investigate testicular toxicity and the possible mechanisms of action. Exposure to 2,4-D at high concentrations (100 and 200mg/kg/day) for 14 consecutive days caused spermatogenic disruption and seminiferous epithelial destruction. Furthermore, 2,4-D administration (100 and 200mg/kg/day) increased the formation of the lipid peroxidation product malondialdehyde and decreased activities of the antioxidant enzymes superoxide dismutase and catalase in the testis. Moreover, 2,4-D exposure up-regulated the expression of p53 and Bax protein and down-regulated the expression of Bcl-2 protein in the testis. These results demonstrate that oxidative stress and apoptosis may be involved in testicular toxicity induced by high concentrations of 2,4-D in mice. PMID- 28911737 TI - Glutathione transferase-mediated benzimidazole-resistance in Fusarium graminearum. AB - Fusarium graminearum laboratory mutants moderately (MR) and highly (HR) benzimidazole-resistant, carrying or not target-site mutations at the beta2 tubulin gene were utilized in an attempt to elucidate the biochemical mechanism(s) underlying the unique BZM-resistance paradigm of this fungal plant pathogen. Relative expression analysis in the presence or absence of carbendazim (methyl-2-benzimidazole carbamate) using a quantitative Real Time qPCR (RT-qPCR) revealed differences between resistant and the wild-type parental strain although no differences in expression levels of either beta1- or beta2-tubulin homologue genes were able to fully account for two of the highly resistant phenotypes. Glutathione transferase (GST)-mediated detoxification was shown to be -at least partly- responsible for the elevated resistance levels of a HR isolate bearing the beta2-tubulin Phe200Tyr resistance mutation compared with another MR isolate carrying the same mutation. This benzimidazole-resistance mechanism is reported for the first time in F. graminearum. No indications of detoxification involved in benzimidazole resistance were found for the rest of the isolates as revealed by GST and glutathione peroxidase (GPx) activities and bioassays using monoxygenase and hydrolase detoxification enzyme inhibiting synergists. Interestingly, besides the Phe200Tyr mutation-carrying HR isolate, the remaining highly-carbendazim resistant phenotypes could not be associated with any of the target site modification/overproduction, detoxification or reduced uptake increased efflux mechanisms. PMID- 28911738 TI - Effects of introducing theanine or glutamic acid core to tralopyril on systemicity and insecticidal activity. AB - Tralopyril was the active agent of a pro-insecticide chlorfenapyr. To simultaneously solve the problems of the phytotoxicity and non-systemic insecticidal activity of tralopyril, four new tralopyril conjugates containing theanine or glutamic acid moieties were designed and synthesized. Their phytotoxicity to tea shoot, phloem systemicity, and insecticidal activity were evaluated. Phytotoxic symptoms were not observed after the tea shoots were exposed to the four conjugates at concentrations of 2mM. The phloem mobility test on Ricinus communis L. seedlings confirmed that all four conjugates were mobile in the sieve tubes. Results of insecticidal activity against the third-instar larvae of Plutella xylostella showed that only conjugate 20 exhibited activity with an LC50 value of 0.5882+/-0.0504mM. After root application to tea seedlings, conjugate 20 showed obviously systemic insecticidal activity against Dendrothrips minowai Priesner, while chlorfenapyr showed no attribute of that. A new conjugate as potential phloem mobile pro-insecticide candidate was provided and so a novel strategy of pro-insecticide for improved phloem systemicity was proposed. PMID- 28911739 TI - Role of inward rectifier potassium channels in salivary gland function and sugar feeding of the fruit fly, Drosophila melanogaster. AB - The arthropod salivary gland is of critical importance for horizontal transmission of pathogens, yet a detailed understanding of the ion conductance pathways responsible for saliva production and excretion is lacking. A superfamily of potassium ion channels, known as inward rectifying potassium (Kir) channels, is overexpressed in the Drosophila salivary gland by 32-fold when compared to the whole body mRNA transcripts. Therefore, we aimed to test the hypothesis that pharmacological and genetic depletion of salivary gland specific Kir channels alters the efficiency of the gland and reduced feeding capabilities using the fruit fly Drosophila melanogaster as a model organism that could predict similar effects in arthropod disease vectors. Exposure to VU041, a selective Kir channel blocker, reduced the volume of sucrose consumption by up to 3.2-fold and was found to be concentration-dependent with an EC50 of 68MUM. Importantly, the inactive analog, VU937, was shown to not influence feeding, suggesting the reduction in feeding observed with VU041 is due to Kir channel inhibition. Next, we performed a salivary gland specific knockdown of Kir1 to assess the role of these channels specifically in the salivary gland. The genetically depleted fruit flies had a reduction in total volume ingested and an increase in the time spent feeding, both suggestive of a reduction in salivary gland function. Furthermore, a compensatory mechanism appears to be present at day 1 of RNAi-treated fruit flies, and is likely to be the Na+-K+-2Cl- cotransporter and/or Na+-K+-ATPase pumps that serve to supplement the inward flow of K+ ions, which highlights the functional redundancy in control of ion flux in the salivary glands. These findings suggest that Kir channels likely provide, at least in part, a principal potassium conductance pathway in the Drosophila salivary gland that is required for sucrose feeding. PMID- 28911740 TI - Effect of drimenol and synthetic derivatives on growth and germination of Botrytis cinerea: Evaluation of possible mechanism of action. AB - The aim of this study was to determine the antifungal activity of Drimenol (1) and its synthetic derivatives, nordrimenone (2), drimenyl acetate (3), and drimenyl-epoxy-acetate (4), and to establish a possible mechanism of action for drimenol. For that, the effect of each compound on mycelial growth of Botrytis cinerea was assessed. Our results showed that compounds 1, 2, 3 and 4 are able to affect Botrytis cinerea growth with EC50 values of 80, 92, 80 and 314ppm, respectively. These values suggest that the activity of these compounds is mainly determined by presence of the double bond between carbons 7 and 8 of the drimane ring. In addition, germination of B. cinerea in presence of 40 and 80ppm of drimenol is reduced almost to a half of the control value. Finally, in order to elucidate a possible mechanism by which drimenol is affecting B. cinerea, the determination of membrane integrity, reactive oxygen species production and gene expression studies of specific genes were performed. PMID- 28911741 TI - Growth, hydrolases and ultrastructure of Fusarium oxysporum as affected by phenolic rich extracts from several xerophytic plants. AB - Fusarium oxysporum, the causal agent of rot and wilt diseases, is one of the most detrimental phytopathogens for the productivity of many economic crops. The present study was conducted to evaluate the potentiality of some xerophytic plants as eco-friendly approach for management of F. oxysporum. Phenolic rich extracts from five plants namely: Horwoodia dicksoniae, Citrullus colocynthis, Gypsophila capillaris, Pulicaria incisa and Rhanterium epapposum were examined in vitro. The different extracts showed high variability in their phenolic and flavonoid contents as well as total antioxidant capacity. A strong positive correlation existed between the antifungal activity of the tested extracts and their contents of both total phenolics and flavonoids (r values are 0.91 and 0.82, respectively). Extract of P. incisa was the most effective in reducing the mycelial growth (IC50=0.92mg/ml) and inhibiting the activities of CMCase, pectinase, amylase and protease by 36, 42, 58 and 55%, respectively. The high performance liquid chromatography analysis of P. incisa extract revealed the presence of eight phenolic acids along with five polyphenolic compounds. The flavonol, quercetin and its glycosides rutin and quercetrin were the most abundant followed by the phenolic acids, t-cinnamic, caffeic, ferulic and vanillic. P. incisa extract not only affects the growth and hydrolases of F. oxysporum but also induces ultrastructure changes in the mycelium, as revealed by transmission electron microscopy. To our knowledge, this is the first study to investigate the mechanisms underlying the antifungal activity of P. incisa. PMID- 28911742 TI - Inheritance and stability of mevinphos-resistance in Plutella xylostella (L.), with special reference to mutations of acetylcholinesterase 1. AB - Diamondback moth (Plutella xylostella L.) causes enormous damage on cruciferous vegetables and can rapidly develop resistance to all kinds of insecticides. To effectively manage the insecticide resistance of P. xylostella, an understanding of its inheritance and stability is essential. Here we investigated the phenotypic and genotypic basis of mevinphos resistance by crossing two genetically pure lines of P. xylostella, an SHggt wild-type strain and an SHMTCN resistant strain carrying 892T/T, 971C/C, and 1156T/G (TCN) mutations of the acetylcholinesterase 1 gene (Pxace1). Similar median lethal concentrations and degrees of dominance in the reciprocal cross progeny, and no plateau on the log concentration-probit line of F1 backcross and self-cross progeny, suggest that the mevinphos-resistance in P. xylostella is inherited as an autosomal and incomplete dominant trait governed by more than one gene. In the absence of mevinphos exposure, the resistance ratio and Pxace1 mutation frequency declined concomitantly in the SHMTCN strain. After 20-generation relaxation, the mevinphos resistance decreased from 52- to 6-fold and the Pxace1 mutation frequency of the TCN haplotype pair decreased from 100% to 0%. A good correlation was found between the resistance ratio and TCN frequency within the range of 12.5- to 25 fold resistance. Since there was no TCN haplotype pair detected below a resistance level of 12.5-fold, we speculate that resistance mechanisms other than target site insensitivity may exist. These observations are important for the prediction and management of mevinphos and related organophosphate resistance in field populations of P. xylostella. PMID- 28911743 TI - Effects of a NTG-based chemical mutagenesis on the propamocarb-tolerance of the nematophagous fungus Lecanicillium attenuatum. AB - Lecanicillium attenuatum is an important nematophagous fungus with potential as a biopesticide for control of plant-pathogenic nematodes. However, relatively low fungicide-tolerance limits its application in the field. To improve the propamocarb-tolerance of L. attenuatum, a NTG-based mutagenesis system was established. Among different combinations of NTG concentration and treatment time in the first-round NTG treatment, the treatment of 1.0mg/ml NTG for 60min gave a proper conidial lethality rate of 84.6% and the highest positive mutation rate of 7.7%, and then produced the highest propamocarb-tolerant mutant LA-C-R1-T4-M whose EC50 value reached to 1050.0MUg/ml. The positive mutation range was 105.1% in the first-round NTG treatment. Multiple-round NTG treatment was further employed to enhance the propamocarb tolerance of L. attenuatum. The positive mutation range was significantly accumulated to 179.3% on the third-round NTG treatment, and then appeared to level-off and remained constant. These results indicated that multiple-round NTG treatment had a significant accumulative effect on fungal tolerance to propamocarb. Among all chemical-mutants, the LA-C-R3-M was the highest tolerant to propamocarb, whose EC50 value was increased 2.79-fold compared to the wild-type strain, and it was mitotic stable after 20 passages on PDA medium. Colony growth, conidia yield and conidial germination on plates, and parasitism of nematode eggs of M. incognita and H. glycines were not significantly changed by the NTG-based mutagenesis compared to the wild-type strain in either single- or multiple-round NTG treatment. In conclusion, we succeeded in improving the propamocarb tolerance of L. attenuatum via the optimized NTG-based mutagenesis system. The improved strain LA-C-R3-M could be potentially applied with propamocarb in the field. PMID- 28911744 TI - Identification of two novel P450 genes and their responses to deltamethrin in the cabbage moth, Mamestra brassicae Linnaeus. AB - Cytochrome P450 monooxygenases, found in virtually all living organisms, play an important role in the metabolism of xenobiotics such as drugs, pesticides, and plant toxins. In this study, we identified two novel cytochrome P450 genes from the cabbage moth, Mamestra brassicae Linnaeus. They were named CYP4M51 and CYP6AB56 (GenBank Accession Nos.: KX008607 and JQ901385, respectively) by the P450 Nomenclature Committee. Real-time quantitative reverse transcription revealed that CYP4M51 and CYP6AB56 were highly expressed in the fat bodies and were differentially expressed at different larval developmental stages. Expression levels of these two cytochrome P450 genes were up-regulated by deltamethrin. Analyses of their detoxification roles using RNA interference followed by a deltamethrin bioassay showed that larvae mortalities increased by 11.4% and 21.6%, respectively, after CYP4M51 and CYP6AB56 were partially silenced. These results suggest that inhibition of the novel cytochrome P450 genes CYP4M51 and CYP6AB56 could be used to increase the efficacy of cabbage moth control by deltamethrin. PMID- 28911745 TI - Investigation of resistance levels and mechanisms to nicosulfuron conferred by non-target-site mechanisms in large crabgrass (Digitaria sanguinalis L.) from China. AB - Large crabgrass is a major grass weed widely distributed across China. This weed infests maize fields and has evolved resistance to the acetolactate synthase (ALS)-inhibiting herbicide nicosulfuron due to continuous and intensive use. In this study, a total of 25 out of 26 large crabgrass populations collected from maize field demonstrated resistance to nicosulfuron. Amino acid modifications in ALS known to confer resistance to ALS-inhibiting herbicides in other weeds, were not found in the 9 tested resistant populations. The P450 inhibitor malathion significantly reversed resistance to nicosulfuron in 3 tested populations, indicating one or more P450s may be involved. Nicosulfuron was metabolized more rapidly in one resistant large crabgrass population than in a susceptible biotype. This demonstrates that the metabolic resistance mechanisms involving one or more P450s may be responsible for large crabgrass resistance to nicosulfuron in this biotype. PMID- 28911746 TI - Plant growth regulator-mediated anti-herbivore responses of cabbage (Brassica oleracea) against cabbage looper Trichoplusia ni Hubner (Lepidoptera: Noctuidae). AB - Plant elicitors can be biological or chemical-derived stimulators of jasmonic acid (JA) or salicylic acid (SA) pathways shown to prime the defenses in many crops. Examples of chemical elicitors of the JA and SA pathways include methyl jasmonate and 1,2,3-benzothiadiazole-7-carbothioate (BTH or the commercial plant activator Actigard 50WG, respectively). The use of specific elicitors has been observed to affect the normal interaction between JA and SA pathways causing one to be upregulated and the other to be suppressed, often, but not always, at the expense of the plant's herbivore or pathogen defenses. The objective of this study was to determine whether insects feeding on Brassica crops might be negatively affected by SA inducible defenses combined with an inhibitor of detoxification and anti-oxidant enzymes that regulate the insect response to the plant's defenses. The relative growth rate of cabbage looper Trichoplusia ni Hubner (Lepidoptera: Noctuidae) fed induced cabbage Brassica oleraceae leaves with the inhibitor, quercetin, was significantly less than those fed control cabbage with and without the inhibitor. The reduced growth was related to the reduction of glutathione S-transferases (GSTs) by the combination of quercetin and increased levels of indole glucosinolates in the cabbage treated with BTH at 2.6* the recommended application rate. These findings may offer a novel combination of elicitor and synergist that can provide protection from plant disease and herbivores in cabbage and other Brassica crops. PMID- 28911747 TI - Error-prone PCR mutation of Ls-EPSPS gene from Liriope spicata conferring to its enhanced glyphosate-resistance. AB - Liriope spicata (Thunb.) Lour has a unique LsEPSPS structure contributing to the highest-ever-recognized natural glyphosate tolerance. The transformed LsEPSPS confers increased glyphosate resistance to E. coli and A. thaliana. However, the increased glyphosate-resistance level is not high enough to be of commercial value. Therefore, LsEPSPS was subjected to error-prone PCR to screen mutant EPSPS genes capable of endowing higher resistance levels. A mutant designated as ELs EPSPS having five mutated amino acids (37Val, 67Asn, 277Ser, 351Gly and 422Gly) was selected for its ability to confer improved resistance to glyphosate. Expression of ELs-EPSPS in recombinant E. coli BL21 (DE3) strains enhanced resistance to glyphosate in comparison to both the LsEPSPS-transformed and untransformed controls. Furthermore, transgenic ELs-EPSPS A. thaliana was about 5.4 fold and 2-fold resistance to glyphosate compared with the wild-type and the Ls-EPSPS-transgenic plants, respectively. Therefore, the mutated ELs-EPSPS gene has potential value for has potential for the development of glyphosate-resistant crops. PMID- 28911748 TI - The pattern of shikimate pathway and phenylpropanoids after inhibition by glyphosate or quinate feeding in pea roots. AB - The shikimate pathway is a metabolic route for the biosynthesis of aromatic amino acids (AAAs) (i.e. phenylalanine, tyrosine, and tryptophan). A key enzyme of shikimate pathway (5-enolpyruvylshikimate-3-phosphate synthase, EPSPS) is the target of the widely used herbicide glyphosate. Quinate is a compound synthesized in plants through a side branch of the shikimate pathway. Glyphosate provokes quinate accumulation and exogenous quinate application to plants shows a potential role of quinate in the toxicity of the herbicide glyphosate. Based on this, we hypothesized that the role of quinate accumulation in the toxicity of the glyphosate would be mediated by a deregulation of the shikimate pathway. In this study the effect of the glyphosate and of the exogenous quinate was evaluated in roots of pea plants by analyzing the time course of a full metabolic map of several metabolites of shikimate and phenylpropanoid pathways. Glyphosate application induced an increase of the 3-deoxy-D-arabino-heptulosonate-7 phosphate synthase (DAHPS, first enzyme of the shikimate pathway) protein and accumulation of metabolites upstream of the enzyme EPSPS. No common effects on the metabolites and regulation of shikimate pathway were detected between quinate and glyphosate treatments, supporting that the importance of quinate in the mode of action of glyphosate is not mediated by a common alteration of the regulation of the shikimate pathway. Contrary to glyphosate, the exogenous quinate supplied was probably incorporated into the main trunk from the branch pathway and accumulated in the final products, such as lignin, concomitant with a decrease in the amount of DAHPS protein. PMID- 28911749 TI - Effect of participatory women's groups and counselling through home visits on children's linear growth in rural eastern India (CARING trial): a cluster randomised controlled trial. AB - BACKGROUND: Around 30% of the world's stunted children live in India. The Government of India has proposed a new cadre of community-based workers to improve nutrition in 200 districts. We aimed to find out the effect of such a worker carrying out home visits and participatory group meetings on children's linear growth. METHODS: We did a cluster-randomised controlled trial in two adjoining districts of Jharkhand and Odisha, India. 120 clusters (around 1000 people each) were randomly allocated to intervention or control using a lottery. Randomisation took place in July, 2013, and was stratified by district and number of hamlets per cluster (0, 1-2, or >=3), resulting in six strata. In each intervention cluster, a worker carried out one home visit in the third trimester of pregnancy, monthly visits to children younger than 2 years to support feeding, hygiene, care, and stimulation, as well as monthly women's group meetings to promote individual and community action for nutrition. Participants were pregnant women identified and recruited in the study clusters and their children. We excluded stillbirths and neonatal deaths, infants whose mothers died, those with congenital abnormalities, multiple births, and mother and infant pairs who migrated out of the study area permanently during the trial period. Data collectors visited each woman in pregnancy, within 72 h of her baby's birth, and at 3, 6, 9, 12, and 18 months after birth. The primary outcome was children's length-for-age Z score at 18 months of age. Analyses were by intention to treat. Due to the nature of the intervention, participants and the intervention team were not masked to allocation. Data collectors and the data manager were masked to allocation. The trial is registered as ISCRTN (51505201) and with the Clinical Trials Registry of India (number 2014/06/004664). RESULTS: Between Oct 1, 2013, and Dec 31, 2015, we recruited 5781 pregnant women. 3001 infants were born to pregnant women recruited between Oct 1, 2013, and Feb 10, 2015, and were therefore eligible for follow-up (1460 assigned to intervention; 1541 assigned to control). Three groups of children could not be included in the final analysis: 147 migrated out of the study area (67 in intervention clusters; 80 in control clusters), 77 died after the neonatal period and before 18 months (31 in intervention clusters; 46 in control clusters), and seven had implausible length for-age Z scores (<-5 SD; one in intervention cluster; six in control clusters). We measured 1253 (92%) of 1362 eligible children at 18 months in intervention clusters, and 1308 (92%) of 1415 eligible children in control clusters. Mean length-for-age Z score at 18 months was -2.31 (SD 1.12) in intervention clusters and -2.40 (SD 1.10) in control clusters (adjusted difference 0.107, 95% CI -0.011 to 0.226, p=0.08). The intervention did not significantly affect exclusive breastfeeding, timely introduction of complementary foods, morbidity, appropriate home care or care-seeking during childhood illnesses. In intervention clusters, more pregnant women and children attained minimum dietary diversity (adjusted odds ratio [aOR] for women 1.39, 95% CI 1.03-1.90; for children 1.47, 1.07-2.02), more mothers washed their hands before feeding children (5.23, 2.61-10.5), fewer children were underweight at 18 months (0.81, 0.66-0.99), and fewer infants died (0.63, 0.39-1.00). INTERPRETATION: Introduction of a new worker in areas with a high burden of undernutrition in rural eastern India did not significantly increase children's length. However, certain secondary outcomes such as self reported dietary diversity and handwashing, as well as infant survival were improved. The interventions tested in this trial can be further optimised for use at scale, but substantial improvements in growth will require investment in nutrition-sensitive interventions, including clean water, sanitation, family planning, girls' education, and social safety nets. FUNDING: UK Medical Research Council, Wellcome Trust, UK Department for International Development (DFID). PMID- 28911751 TI - Facing forwards along the Health Silk Road. PMID- 28911750 TI - Effect of counselling on health-care-seeking behaviours and rabies vaccination adherence after dog bites in Haiti, 2014-15: a retrospective follow-up survey. AB - BACKGROUND: Haiti has an integrated bite case management (IBCM) programme to counsel animal-bite victims on the risk of rabies and appropriate treatment, as well as the Haiti Animal Rabies Surveillance Program (HARSP) to examine the animals. We assessed the usefulness of the IBCM programme to promote best practices for rabies prophylaxis after exposure in a low-income rabies-endemic setting. METHODS: We did a retrospective follow-up survey of randomly selected bite victims who were counselled by Haiti's IBCM programme between May 15, 2014, and Sept 15, 2015. We classified participants by HARSP decisions of confirmed, probable, suspected, or non-rabies exposures. We compared health-care outcomes in people who sought medical care before IBCM counselling with those in people who sought care after counselling. We used decision trees to estimate the probability of actions taken in the health-care system, and thereby human deaths. FINDINGS: During the study period, 1478 dog bites were reported to HARSP for assessment. 37 (3%) were confirmed exposures, 76 (5%) probable exposures, 189 (13%) suspected exposures, and 1176 (80%) non-rabies exposures. 115 of these cases were followed up in the survey. IBCM counselling was associated with a 1.2 times increase in frequency of bite victims seeking medical care and of 2.4 times increase in vaccination uptake. We estimated that there would be four human rabies deaths among the 1478 people assessed by IBCM during the survey period, and 11 in the absence of this programme, which would equate to a 65% decrease in rabies deaths. Among three people dead at the time of the follow-up survey, one was deemed to be due to rabies after a probable rabies exposure. INTERPRETATION: Adherence to medical providers' recommendations might be improved through counselling provided by IBCM programmes. FUNDING: None. PMID- 28911752 TI - Gaps and challenges underpinning the first analysis of global coverage of early antenatal care. PMID- 28911753 TI - Respiratory syncytial virus mortality among young children. PMID- 28911754 TI - Hepatitis D virus in Africa: several unmet needs. PMID- 28911755 TI - Women's participatory groups and nurturing child care. PMID- 28911756 TI - Substantial reductions in rabies, but still a lot to be done. PMID- 28911757 TI - Task shifting in health care: the risks of integrated medicine in India. PMID- 28911758 TI - Medical Education Partnership Initiative gives birth to AFREhealth. PMID- 28911759 TI - Can reverse innovation catalyse better value health care? PMID- 28911760 TI - Updated estimates of typhoid fever burden in sub-Saharan Africa. PMID- 28911761 TI - Model citizen. PMID- 28911762 TI - Model citizen - Authors' reply. PMID- 28911763 TI - Early antenatal care visit: a systematic analysis of regional and global levels and trends of coverage from 1990 to 2013. AB - BACKGROUND: The timing of the first antenatal care visit is paramount for ensuring optimal health outcomes for women and children, and it is recommended that all pregnant women initiate antenatal care in the first trimester of pregnancy (early antenatal care visit). Systematic global analysis of early antenatal care visits has not been done previously. This study reports on regional and global estimates of the coverage of early antenatal care visits from 1990 to 2013. METHODS: Data were obtained from nationally representative surveys and national health information systems. Estimates of coverage of early antenatal care visits were generated with linear regression analysis and based on 516 logit transformed observations from 132 countries. The model accounted for differences by data sources in reporting the cutoff for the early antenatal care visit. FINDINGS: The estimated worldwide coverage of early antenatal care visits increased from 40.9% (95% uncertainty interval [UI] 34.6-46.7) in 1990 to 58.6% (52.1-64.3) in 2013, corresponding to a 43.3% increase. Overall coverage in the developing regions was 48.1% (95% UI 43.4-52.4) in 2013 compared with 84.8% (81.6 87.7) in the developed regions. In 2013, the estimated coverage of early antenatal care visits was 24.0% (95% UI 21.7-26.5) in low-income countries compared with 81.9% (76.5-87.1) in high-income countries. INTERPRETATION: Progress in the coverage of early antenatal care visits has been achieved but coverage is still far from universal. Substantial inequity exists in coverage both within regions and between income groups. The absence of data in many countries is of concern and efforts should be made to collect and report coverage of early antenatal care visits to enable better monitoring and evaluation. FUNDING: Department of Reproductive Health and Research, WHO and UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. PMID- 28911766 TI - Juvenile Dermatomyositis: Key Roles of Muscle Magnetic Resonance Imaging and Early Aggressive Treatment. AB - Juvenile dermatomyositis is a rare systemic connective tissue disease with onset during childhood. It presents clinically with proximal muscle weakness and characteristic skin involvement. Diagnosis is based on the Bohan and Peter criteria, though many authors are now substituting biopsy with muscle magnetic resonance imaging (MRI) for both diagnosis and follow-up. Without intensive early treatment, complications such as calcinosis cutis and lipodystrophy can develop in the chronic phases of the disease. Early recognition is therefore key to management. We present a series of 5 patients who were diagnosed with Juvenile dermatomyositis on muscle MRI without undergoing muscle biopsy and who received early treatment. We draw attention to the usefulness of muscle MRI for the diagnosis of muscle involvement and to the importance of early initiation of intensive treatment to prevent complications. PMID- 28911764 TI - Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. METHODS: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. FINDINGS: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5.0 months (IQR 2.3-11.0) in low income or lower middle-income countries, 4.0 years (2.0-10.0) in upper middle income countries, and 7.0 years (3.6-16.8) in high-income countries. INTERPRETATION: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation. PMID- 28911765 TI - Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: Hepatitis D virus (also known as hepatitis delta virus) can establish a persistent infection in people with chronic hepatitis B, leading to accelerated progression of liver disease. In sub-Saharan Africa, where HBsAg prevalence is higher than 8%, hepatitis D virus might represent an important additive cause of chronic liver disease. We aimed to establish the prevalence of hepatitis D virus among HBsAg-positive populations in sub-Saharan Africa. METHODS: We systematically reviewed studies of hepatitis D virus prevalence among HBsAg positive populations in sub-Saharan Africa. We searched PubMed, Embase, and Scopus for papers published between Jan 1, 1995, and Aug 30, 2016, in which patient selection criteria and geographical setting were described. Search strings included sub-Saharan Africa, the countries therein, and permutations of hepatitis D virus. Cohort data were also added from HIV-positive populations in Malawi and Ghana. Populations undergoing assessment in liver disease clinics and those sampled from other populations (defined as general populations) were analysed. We did a meta-analysis with a DerSimonian-Laird random-effects model to calculate a pooled estimate of hepatitis D virus seroprevalence. FINDINGS: Of 374 studies identified by our search, 30 were included in our study, only eight of which included detection of hepatitis D virus RNA among anti-hepatitis D virus seropositive participants. In west Africa, the pooled seroprevalence of hepatitis D virus was 7.33% (95% CI 3.55-12.20) in general populations and 9.57% (2.31 20.43) in liver-disease populations. In central Africa, seroprevalence was 25.64% (12.09-42.00) in general populations and 37.77% (12.13-67.54) in liver-disease populations. In east and southern Africa, seroprevalence was 0.05% (0.00-1.78) in general populations. The odds ratio for anti-hepatitis D virus detection among HBsAg-positive patients with liver fibrosis or hepatocellular carcinoma was 5.24 (95% CI 2.74-10.01; p<0.0001) relative to asymptomatic controls. INTERPRETATION: Findings suggest localised clusters of hepatitis D virus endemicity across sub Saharan Africa. Epidemiological data are needed from southern and east Africa, and from patients with established liver disease. Further studies should aim to define the reliability of hepatitis D virus testing methods, identify risk factors for transmission, and characterise the natural history of the infection in the region. FUNDING: Wellcome Trust, Royal Society. PMID- 28911767 TI - Binding Isotope Effects for Interrogating Enzyme-Substrate Interactions. AB - Equilibrium binding isotope effects (BIEs) report on the bond vibrational status of enzyme substrates in the Michaelis complex prior to the transition state and how they differ from the solution state. Accordingly, BIEs provide an experimental means of interrogating enzyme-substrate interactions and inform on the influence of enzyme-mediated atomic distortions in modulating substrate reactivity. In this chapter, we outline a rapid equilibrium dialysis method that our lab has used to measure BIEs for several enzyme systems. Implementation of the rapid equilibrium dialysis approach is described in the context of our recent studies on the substrate bonding environment for the human protein lysine N methyltransferase NSD2. A summary of BIE effects provides context for the range of experimental values. PMID- 28911768 TI - Natural Isotope Abundance in Metabolites: Techniques and Kinetic Isotope Effect Measurement in Plant, Animal, and Human Tissues. AB - The natural isotope abundance in bulk organic matter or tissues is not a sufficient base to investigate physiological properties, biosynthetic mechanisms, and nutrition sources of biological systems. In fact, isotope effects in metabolism lead to a heterogeneous distribution of 2H, 18O, 13C, and 15N isotopes in metabolites. Therefore, compound-specific isotopic analysis (CSIA) is crucial to biological and medical applications of stable isotopes. Here, we review methods to implement CSIA for 15N and 13C from plant, animal, and human samples and discuss technical solutions that have been used for the conversion to CO2 and N2 for IRMS analysis, derivatization and isotope effect measurements. It appears that despite the flexibility of instruments used for CSIA, there is no universal method simply because the chemical nature of metabolites of interest varies considerably. Also, CSIA methods are often limited by isotope effects in sample preparation or the addition of atoms from the derivatizing reagents, and this implies that corrections must be made to calculate a proper delta-value. Therefore, CSIA has an enormous potential for biomedical applications, but its utilization requires precautions for its successful application. PMID- 28911769 TI - Measurement of Kinetic Isotope Effects in an Enzyme-Catalyzed Reaction by Continuous-Flow Mass Spectrometry. AB - Kinetic isotope effects (KIEs) provide powerful probes of the mechanisms of enzyme-catalyzed reactions. In this chapter, we describe the use of continuous flow mass spectrometry to determine the deuterium KIE for the enzyme N acetylpolyamine oxidase based on the ratio of labeled and unlabeled products in mass spectra of whole reaction mixtures. PMID- 28911770 TI - Primary Deuterium Kinetic Isotope Effects From Product Yields: Rationale, Implementation, and Interpretation. AB - A simple and convenient method is described to determine primary deuterium kinetic isotope effects (1 degrees DKIEs) on reactions where the hydron incorporated into the reaction product is derived from solvent water. The 1 degrees DKIE may be obtained by 1H NMR analyses as the ratio of the yields of H- and D-labeled products from a reaction in 50:50 (v/v) HOH/DOD. The procedures for these 1H NMR analyses are reviewed. This product deuterium isotope effect (PDIE) is defined as 1/phiEL for fractionation of hydrons between solvent and the transition state for the reaction examined. When the solvent is not the direct hydron donor, it is necessary to correct the PDIE for the fractionation factor phiEL for partitioning of the hydron between the solvent and the direct donor EL. This method was used to determine the 1 degrees DKIE on decarboxylation reactions catalyzed by wild-type orotidine 5'-monophosphate decarboxylase (OMPDC) and by mutants of OMPDC, and then in the determination of the 1 degrees DKIE on the decarboxylation reaction catalyzed by 5-carboxyvanillate decarboxylase. The experimental procedures used in studies on OMPDC and the rationale for these procedures are described. PMID- 28911771 TI - Measurement and Prediction of Chlorine Kinetic Isotope Effects in Enzymatic Systems. AB - Approaches to determine chlorine kinetic isotope effects (Cl-KIEs) on enzymatic dehalogenations are discussed and illustrated by representative examples. Three aspects are considered. First methodology for experimental measurement of Cl KIEs, with stress being on FAB-IRMS technique developed in our laboratory, is described. Subsequently, we concentrate our discussion on the consequences of reaction complexity in the interpretation of experimental values, a problem especially important in cases of polychlorinated reactants. The most fruitful studies of enzymatic dehalogenations by Cl-KIEs require their theoretical evaluation, hence the computational focus of the second part of this chapter. PMID- 28911773 TI - Chemical Ligation and Isotope Labeling to Locate Dynamic Effects. AB - Heavy isotope labeling of enzymes slows protein motions without disturbing the electrostatics and can therefore be used to probe the role of dynamics in enzyme catalysis. To identify the structural elements responsible for dynamic effects, individual segments of an enzyme can be labeled and the resulting effect on the kinetics of the reaction can be measured. Such hybrid isotopomers can be constructed by expressed protein ligation, in which complementary labeled and unlabeled peptide segments are prepared by recombinant gene expression and linked by means of chemical ligation. The construction of such hybrid isotopomers is exemplified here with the paradigmatic enzyme dihydrofolate reductase (DHFR) from Escherichia coli. PMID- 28911774 TI - Use of Isotopes and Isotope Effects for Investigations of Diiron Oxygenase Mechanisms. AB - Isotope effects of four broad and overlapping categories have been applied to the study of the mechanisms of chemical reaction and regulation of nonheme diiron cluster-containing oxygenases. The categories are: (a) mass properties that allow substrate-to-product conversions to be tracked, (b) atomic properties that allow specialized spectroscopies, (c) mass properties that impact primarily vibrational spectroscopies, and (d) bond dissociation energy shifts that permit dynamic isotope effect studies of many types. The application of these categories of isotope effects is illustrated using the soluble methane monooxygenase system and CmlI, which catalyzes the multistep arylamine to arylnitro conversion in the biosynthetic pathway for chloramphenicol. PMID- 28911772 TI - Kinetic Deuterium Isotope Effects in Cytochrome P450 Reactions. AB - Cytochrome P450 (P450, CYP) research provides many opportunities for the application of kinetic isotope effect (KIE) strategies. P450s collectively catalyze oxidations of more substrates than any other group of enzymes, and CH bond cleavage is a major feature in a large fraction of these reactions. The presence of a significant primary deuterium KIE is evidence that hydrogen abstraction is at least partially rate-limiting in the reactions, and this appears to be the case in many P450 reactions. The first report of a KIE in (P450 linked) drug metabolism appeared in 1961 (for morphine N-demethylation), and in a number of cases, it has been possible to modulate the in vivo metabolism or toxicity of chemicals by deuterium substitution. A number of efforts are in progress to utilize deuterium substitution to alter the metabolism of drugs in an advantageous manner. PMID- 28911775 TI - Characterization of Substrate, Cosubstrate, and Product Isotope Effects Associated With Enzymatic Oxygenations of Organic Compounds Based on Compound Specific Isotope Analysis. AB - Enzymatic oxygenations are among the most important biodegradation and detoxification reactions of organic pollutants. In the environment, however, such natural attenuation processes are extremely difficult to monitor. Changes of stable isotope ratios of aromatic pollutants at natural isotopic abundances serve as proxies for isotope effects associated with oxygenation reactions. Such isotope fractionations offer new avenues for revealing the pathway and extent of pollutant transformation and provide new insights into the mechanisms of catalysis by Rieske non-heme ferrous iron oxygenases. Based on compound-specific C, H, N, and O isotope analysis, we present a comprehensive methodology with which isotope effects can be derived from the isotope fractionation measured in substrates, the cosubstrate O2, and organic oxygenation products. We use dioxygenation of nitrobenzene and 2-nitrotoluene by nitrobenzene dioxygenase as illustrative examples to introduce different mathematical procedures for deriving apparent substrate and product isotope effects. We present two experimental approaches to control reactant and product turnover for isotope fractionation analysis in experimental systems containing purified enzymes, E. coli clones, and pure strains of environmental microorganisms. Finally, we present instrumental procedures and sample treatment instructions for analysis of C, H, and N isotope analysis in organic compounds and O isotope analysis in aqueous O2 by gas and liquid chromatography coupled to isotope ratio mass spectrometry. PMID- 28911776 TI - pH-Free Measurement of Relative Acidities, Including Isotope Effects. AB - A powerful pH-free multicomponent NMR titration method can measure relative acidities, even of closely related compounds, with excellent accuracy. The history of the method is presented, along with details of its implementation and a comparison with earlier NMR titrations using a pH electrode. Many of its areas of applicability are described, especially equilibrium isotope effects. The advantages of the method, some practical considerations, and potential pitfalls are considered. PMID- 28911777 TI - Isotope Ratio Monitoring 13C Nuclear Magnetic Resonance Spectrometry for the Analysis of Position-Specific Isotope Ratios. AB - Studies of changes in isotope ratios in a given molecule caused by an enzyme reaction can give considerable insight into mechanism. Similarly, cascades of enzymes-pathways-can also introduce fractionation that can be used to characterize the type of metabolism being exploited. In both cases, classical studies have used enrichment techniques that have allowed the determination of isotope fractionation. More recent approaches, however, allow such studies to be carried out on substrates in which the isotope ratios are in the natural abundance range. This has the advantage of avoiding potentially demanding synthesis of specifically labeled compounds as well as allowing multipositional isotope ratio determinations. The downside can be that considerable quantities of analyte are required. In this chapter, we present the use of isotope ratio monitoring by NMR spectrometry as a means to access positional isotope ratios, potentially for all positions in the target molecule(s). It should be noted that, while the approach is generic, in that the general conditions for obtaining the required data follow the same protocol, no single protocol exists for all applications. The chapter is therefore split into two parts: general comments pertinent to the approach followed by a number of examples illustrating how different questions can be approached. PMID- 28911779 TI - Measurement of Enzyme Isotope Effects. AB - Enzyme isotope effects, or the kinetic effects of "heavy" enzymes, refer to the effect of isotopically labeled protein residues on the enzyme's activity or physical properties. These effects are increasingly employed in the examination of the possible contributions of protein dynamics to enzyme catalysis. One hypothesis assumed that isotopic substitution of all 12C, 14N, and nonexchangeable 1H by 13C, 15N, and 2H, would slow down protein picosecond to femtosecond dynamics without any effect on the system's electrostatics following the Born-Oppenheimer approximation. It was suggested that reduced reaction rates reported for several "heavy" enzymes accords with that hypothesis. However, numerous deviations from the predictions of that hypothesis were also reported. Current studies also attempt to test the role of individual residues by site specific labeling or by labeling a pattern of residues on activity. It appears that in several systems the protein's fast dynamics are indeed reduced in "heavy" enzymes in a way that reduces the probability of barrier crossing of its chemical step. Other observations, however, indicated that slower protein dynamics are electrostatically altered in isotopically labeled enzymes. Interestingly, these effects appear to be system dependent, thus it might be premature to suggest a general role of "heavy" enzymes' effect on catalysis. PMID- 28911778 TI - Applications of Isotope Ratio Mass Spectrometry in Sports Drug Testing Accounting for Isotope Fractionation in Analysis of Biological Samples. AB - The misuse of anabolic-androgenic steroids (AAS) in sports aiming at enhancing athletic performance has been a challenging matter for doping control laboratories for decades. While the presence of a xenobiotic AAS or its metabolite(s) in human urine immediately represents an antidoping rule violation, the detection of the misuse of endogenous steroids such as testosterone necessitates comparably complex procedures. Concentration thresholds and diagnostic analyte ratios computed from urinary steroid concentrations of, e.g., testosterone and epitestosterone have aided identifying suspicious doping control samples in the past. These ratios can however also be affected by confounding factors and are therefore not sufficient to prove illicit steroid administrations. Here, carbon and, in rare cases, hydrogen isotope ratio mass spectrometry (IRMS) has become an indispensable tool. Importantly, the isotopic signatures of pharmaceutical steroid preparations commonly differ slightly but significantly from those found with endogenously produced steroids. By comparing the isotope ratios of endogenous reference compounds like pregnanediol to that of testosterone and its metabolites, the unambiguous identification of the urinary steroids' origin is accomplished. Due to the complex urinary matrix, several steps in sample preparation are inevitable as pure analyte peaks are a prerequisite for valid IRMS determinations. The sample cleanup encompasses steps such as solid phase or liquid-liquid extraction that are presumably not accompanied by isotopic fractionation processes, as well as more critical steps like enzymatic hydrolysis, high-performance liquid chromatography fractionation, and derivatization of analytes. In order to exclude any bias of the analytical results, each step of the analytical procedure is optimized and validated to exclude, or at least result in constant, isotopic fractionation. These efforts are explained in detail. PMID- 28911780 TI - Kinetic Isotope Effect Analysis of RNA 2'-O-Transphosphorylation. AB - The breaking of RNA strands by 2'-O-transphosphorylation is a ubiquitous reaction in biology, and enzymes that catalyze this reaction play key roles in RNA metabolism. The mechanisms of 2'-O-transphosphorylation in solution are relatively well studied, but complex and can involve different transition states depending on how the reaction is catalyzed. Because of this complexity and the lack of experimental information on transition-state structure, pinning down the chemical details of enzyme-catalyzed RNA strand cleavage has been difficult. Kinetic isotope effects (KIEs) provide information about changes in bonding as a reaction proceeds from ground state to transition state, and therefore they provide a powerful tool for revealing mechanistic detail. Application of kinetic isotope analyses to RNA 2'-O-transphosphorylation faces three fundamental challenges: synthesis of RNA substrate isotopomers with 18O substitutions at the 2'-O, 5'-O and nonbridging phosphoryl oxygens; determination of the 18O/16O ratios in the residual unreacted substrate or product RNAs; and analyzing these data to allow calculation of the KIEs for use in evaluating different mechanistic scenarios. In this chapter, we outline methods for surmounting these challenges for solution RNA 2'-O-transphosphorylation reactions, and we describe their initial application to understand nonenzymatic solution reactions and reactions catalyzed by the enzyme ribonuclease A. PMID- 28911781 TI - Theory and Application of the Relationship Between Steady-State Isotope Effects on Enzyme Intermediate Concentrations and Net Rate Constants. AB - Steady-state kinetic isotope effects on enzyme-catalyzed reactions are often interpreted in terms of the microscopic rate constants associated with the elementary reactions of interest. Unfortunately, this approach can lead to confusion, especially when more than one elementary reaction is isotopically sensitive, because it forces one to consider the full catalytic cycle one step at a time rather than as a complete whole. Herein we argue that shifting focus from intrinsic effects to net rate constants and enzyme intermediate concentrations provides a more natural and holistic interpretation by which the effects of partial rate limitation are more easily understood. In doing so, we demonstrate how the experimental determination of isotope effects on enzyme intermediate concentrations allows a direct determination of isotope effects on net rate constants. The chapter is divided into three main sections. The first outlines the basic theory and its interpretation. The second discusses an application of the theory in the study of the radical SAM enzyme DesII. The final section then provides the complete mathematical treatment. PMID- 28911782 TI - Determining Carbon Kinetic Isotope Effects Using Headspace Analysis of Evolved CO2. AB - Isotope ratio mass spectrometry (IRMS) provides accurate measurements of relative abundance of isotopes of heavy atoms for reactions that are subject to kinetic isotope effects (KIEs). The recent development of compound-specific isotope analysis (CSIA) allows the use of multiple time points that provide data for a rate plot as well as isotope ratios. Utilizing CSIA in enzymology presents opportunities for obtaining heavy atom KIEs in diverse areas. PMID- 28911783 TI - Kinetic Isotope Effect Studies to Elucidate the Reaction Mechanism of RNA Modifying Enzymes. AB - The synthesis of specifically deuterated uridine, its incorporation into an RNA oligonucleotide substrate, and the use of the labeled substrate to determine the deuterium kinetic isotope effect for the reaction catalyzed by the pseudouridine synthases (enzymes that isomerize uridine to pseudouridine in RNA) are described. Both enzymes-TruB and RluA-display a primary kinetic isotope effect, which indicates the formation of a glycal intermediate in the ribose ring during turnover. Although the details of the protocols are specific to these two enzymes, the general methodology is readily adaptable to the synthesis and incorporation of other labeled nucleosides into any RNA molecule by in vitro transcription. PMID- 28911784 TI - Measurement of Kinetic Isotope Effects by Continuously Monitoring Isotopologue Ratios Using NMR Spectroscopy. AB - Nuclear magnetic spectroscopic (NMR) methods are discussed for the measurement of heavy atom (13C, 18O, 15N) and secondary deuterium kinetic isotope effects. The discussion focuses primarily on the NMR methods that enable the measurement of quantitative spectra and not on methods to make labeled substrates. Two main techniques are considered: single-point determinations on natural abundance material and the continuous monitoring of isotopically enriched materials. The second method is described in more detail, and we include a discussion of the current state of instrumentation and computer programs for data acquisition and analysis. PMID- 28911785 TI - Extracting Kinetic Isotope Effects From a Global Analysis of Reaction Progress Curves. AB - Enzyme reaction progress curves, or time course datasets, are often rich in information, yet their analysis typically reduces their information content to a single parameter, the initial velocity. An alternative approach is described here, where the time course is described by a model constructed from rate equations. In combination with global nonlinear regression, intrinsic rate and/or equilibrium constants can be directly obtained by fitting these data. This method can be greatly enhanced when combined with the measurement of (usually deuterium) isotope effects, which selectively perturb individual step(s) within the reaction, allowing better separation of fitted parameters and more robust model testing. This chapter focuses on practical considerations when using analytical and/or numerically integrated rate equations to model enzyme reactions. The emphasis is on the underlying methodology, which is demonstrated with specific examples alongside recommendations of suitable software. PMID- 28911786 TI - Preface. PMID- 28911787 TI - Pulmonary embolism severity assessment and prognostication. AB - For patients who have acute symptomatic pulmonary embolism (PE), risk of short term death and adverse outcomes should drive the initial treatment decisions. Practice guidelines recommend that patients who have a high-risk of PE-related death and adverse outcomes, determined by the presence of haemodynamic instability (i.e., shock or hypotension), should receive systemically administered thrombolytic therapy. Intermediate-high risk patients might benefit from close observation, and some should undergo escalation of therapy beyond standard anticoagulation, particularly if haemodynamic deterioration occurs. Low risk for adverse outcomes should lead to early hospital discharge or full treatment at home. Validated prognostic tools (i.e., clinical prognostic scoring systems, imaging studies, and cardiac laboratory biomarkers) assist with risk classification of patients who have acute symptomatic PE. PMID- 28911788 TI - Correction. PMID- 28911789 TI - A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome. AB - Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients. PMID- 28911791 TI - Three-tier five-level preventive strategy for domestic violence and sexual violence prevention in Taiwan. PMID- 28911790 TI - Microchimerism: Defining and redefining the prepregnancy context - A review. AB - Bidirectional transplacental exchange characterizes human pregnancy. Cells exchanged between mother and fetus can durably persist as microchimerism and may have both short- and long-term consequences for the recipient. The amount, type, and persistence of microchimerism are influenced by obstetric characteristics, pregnancy complications, exposures to infection, and other factors. A reproductive-aged woman enters pregnancy harboring previously acquired microchimeric "grafts," which may influence her preconception health and her subsequent pregnancy outcomes. Many questions remain to be answered about microchimerism with broad-ranging implications. This review will summarize key aspects of this field of research and propose important questions to be addressed moving forward. PMID- 28911792 TI - Facial profile and frontal changes after bimaxillary surgery in patients with mandibular prognathism. AB - BACKGROUND/PURPOSE: Patients are always concerned about their postoperative appearance before surgery for facial deformity correction. The present study investigated the facial profile and frontal changes following two-jaw surgery. METHODS: Forty patients who underwent two-jaw surgery were divided by the amount of mandibular setback (group I: <=8 mm and group II: >8 mm). Cephalometric radiograms (lateral and frontal) were collected and analyzed at three intervals: preoperatively (T1), immediately postoperatively (T2), and final follow-up (T3). The following points were identified: cheek points (C1-C5), pronasale (Prn, tip of the nose), anterior nasal spine (ANS), subnasal (Sn), point A, labrale superius (Ls), incision superius (Is), labrale inferius (Li), incision inferius (Ii), point B, labiomental sulcus (Si), pogonion (Pog), soft tissue pogonion (PogS), ramus point (RP), and gonion (Go). The immediate postoperative changes (T21), final postoperative changes (T32), and final stability (T31) were calculated and analyzed. RESULTS: In T31, the cheek line showed significant advancements of 2.3 mm (group I) and 1.6 mm (group II). The soft:hard tissue ratios were significantly correlated: Prn:ANS (0.37:1), Prn:A (0.39:1), Sn:A (0.85:1), C3:A (0.82:1), Ls:Is (0.92:1), Li:Ii (0.91:1), Si:B (0.88:1), and PogS:Pog (group I, 0.78:1 and group II, 0.93:1). The intercondylion and intergonial widths of group II (T31) significantly increased 1.8 and 4 mm, respectively. Regarding the postoperative skeletal stability (T32), group I showed significant correlations between amounts of mandibular setback, but group II did not. CONCLUSION: In the facial profile, the cheek line showed significant advancement postoperatively. The frontal mandibular transverse dimensions were significantly increased. PMID- 28911793 TI - Passive air sampling of polybrominated diphenyl ethers in New Delhi, Kolkata, Mumbai and Chennai: Levels, homologous profiling and source apportionment. AB - Several studies in the recent past reported new sources for industrial persistent organic pollutants (POPs) from metropolitan cities of India. To fill the data gap for atmospheric polybrominated diphenyl ethers (PBDEs), polyurethane foam disk passive air sampling (PUF-PAS) was conducted along urban-suburban-rural transects in four quadrilateral cities viz., New Delhi, Kolkata, Mumbai and Chennai from northern, eastern, western and southern India respectively. Average concentration of Sigma8PBDEs in pg/m3 for New Delhi, Kolkata, Mumbai and Chennai were 198, 135, 264 and 144 respectively. We observed a distinct urban > suburban > rural trend for atmospheric PBDEs in Mumbai. Principal component analysis (PCA) attributed three different source types. BDE-47, -99, -100, -153 and -154 loaded in the first component were relatively high in the sites where industrial and informal electronic waste (e-waste) recycling activities were prevalent. Penta congener, BDE-99 and tetra congener, BDE-47 contributed 50%-75% of total PBDEs. Ratio of BDE-47 and -99 in Indian cities reflected the usage of penta formulations like Bromkal -70DE and DE-71 in the commercial and electrical products. PC-2 was loaded with BDE-28 and -35. Percentage of BDE-28 and BDE-35 (>10%) were comparatively much higher than commercial penta products. Abundance of BDE-28 in majority sites can be primarily due to re-emission from surface soil. PC-3 was loaded with BDE-183 and elevated levels were observed mostly in the industrial corridor of Indian cities. BDE-183 was notably high in the urban industrial sites of New Delhi. We suspect this octa-BDE congener resulted from recycling process of plastic products containing octa-BDE formulation used as flame retardants. PMID- 28911794 TI - Response of extracellular polymeric substances to thermal treatment in sludge dewatering process. AB - Sludge dewatering is an important process in municipal wastewater treatment and critically influences the subsequent transportation and disposal. Thermal treatment coupled with other chemical processes has been widely used to improve sludge dewaterability. However, information about the response of sludge extracellular polymeric substances (EPS) to thermal treatment and its role in sludge dewatering is still limited. In this work, the effects of thermal treatment on anaerobic and aerobic sludges were investigated with an emphasis on the colloid properties of released EPS in sludge dewatering process. The results indicate that sludge dewaterability became deteriorated with the increased temperature in the range of 30-170 degrees C, which was ascribed to the disintegration of sludge flocs and change of EPS characteristics. Disintegrated sludge induced the release of the negatively charged EPS, resulting in the weakened bridging interaction and lower compactness. After thermal treatment, the EPS with a higher average molecular weight and stretched coil configuration retained more water. In addition, difference in dewaterability between anaerobic and aerobic sludges was found to be attributed to their different contents and structures of EPS components. These results provide an insight into thermal dependent sludge dewatering process and are useful to facilitate water-sludge separation. PMID- 28911795 TI - Spatial variations in the occurrence of potentially genotoxic disinfection by products in drinking water distribution systems in China. AB - We investigated the occurrence of disinfection by-products (DBPs) with genotoxic potential in plant effluent and distribution water samples from four drinking water treatment plants in two Chinese cities using comprehensive two-dimensional gas chromatography-quadrupole mass spectrometry. We tested the samples for 37 DBPs with genotoxic potential, which we had previously identified and prioritized in water under controlled laboratory conditions. Thirty of these DBPs were found in the water samples at detection frequencies of between 10% and 100%, and at concentrations between 3.90 and 1.77 * 103 ng/L. Of the DBPs detected, the concentrations of 1,1,1-trichloropropan-2-one were highest, and ranged from 299 to 1.77 * 103 ng/L with an average of 796 ng/L. The concentrations of 6-chloro-2 N-propan-2-yl-1,3,5-triazine-2,4-diamine and 2,6-ditert-butylcyclohexa-2,5-diene 1,4-dione were also much higher, and ranged from 107 to 721 ng/L, and from 152 to 504 ng/L, respectively. Concentrations of 1,1,1-trichloropropan-2-one, 2-chloro-1 phenylethanone, 2,2-dichloro-1-phenylethanone and 6-chloro-2-N-propan-2-yl-1,3,5 triazine-2,4-diamine were highest at or near the treatment plants and decreased with increasing distance from the plants. Patterns in the concentrations of benzaldehyde, 2-phenylpropan-2-ol, and 1-methylnaphthalene differed between plants. The levels of DBPs such as 4-ethylbenzaldehyde, (E)-non-2-enal, and 1 phenylethanone were relatively constant within the distribution systems, even at the furthest sampling points (20 km < d < 30 km). A risk assessment showed that there was no risk to human health. It is, however, important to note that, because of limited availability of toxicity data, only five DBPs were evaluated in this study. The risks to health associated with exposure to the target potentially genotoxic DBPs should not be ignored because of their prolonged existence in drinking water. PMID- 28911797 TI - Correction. PMID- 28911796 TI - Spontaneous uterine rupture at 19 weeks of gestation. PMID- 28911798 TI - Development and evaluation of multiplex real-time PCR for diagnosis of HSV-1, VZV, CMV, and Toxoplasma gondii in patients with infectious uveitis. AB - Infectious uveitis is a vision threatening inflammatory ocular disease wherein early diagnosis may prevent the loss of vision. The purpose of this study was to develop a multiplex real-time PCR for the diagnosis of Herpes simplex virus-1, Varicella zoster virus, cytomegalovirus and Toxoplasma gondii in patients with suspected infectious uveitis. A total of 126 intraocular samples (aqueous and vitreous humor) were collected and subjected to multiplex real-time PCR. Overall 26.2% (33/126) patients were found to be positive for one or more of the pathogens tested. The overall positivity for VZV, HSV, CMV and T. gondii was found to be 16 (12.7%), 7 (5.6%), 5 (3.9%), and 9 (7.1%); with mean pathogen load of 5.07*105, 9.5*104, 1.08*104 and 394 (copies/MUl) respectively. The development of highly sensitive and specific assay for early differentiation of pathogens is important for the early initiation of treatment thereby preventing irreversible damage to the ocular structures. PMID- 28911799 TI - Effects of glucocorticoids on stratum corneum lipids and function in human skin-A detailed lipidomic analysis. AB - BACKGROUND: Topical glucocorticoids (GCs) are known to induce atrophy of human skin including thinning of epidermal and dermal compartments by influencing keratinocyte proliferation and synthesis of extracellular matrix proteins. GCs are also known to reduce skin barrier integrity but little is known about the changes in lipid composition in human skin following topical administration of GCs. OBJECTIVE: This study investigated the effects of GCs on stratum corneum (SC) function and lipid profile of human skin in vivo. METHOD: Over a period of 4 weeks, 16 healthy volunteers were treated on the forearms once daily with topical clobetasol proprionate (CP), betamethasone diproprionate (BDP) or vehicle. One day after last application (Day 29) SC lipids were collected by tape stripping and analysed by a high sensitivity liquid chromatography-mass spectrometry method. Gene expression was analysed in skin biopsies. The full skin, epidermal and SC thickness were assessed by ultrasound, optical coherence tomography and confocal microscopy, respectively, and barrier integrity was assessed by measuring transepidermal water loss (TEWL). RESULTS: Compared to vehicle controls, GCs induced significant alterations in SC lipid profiles. CP caused a reduction in 98 lipids of 226 analysed while BDP treatment only resulted in a significant change of 29 lipids. Most pronounced changes occurred among long chain, ester-linked, ceramide classes while other ceramide classes were much less affected. Almost the complete profile of triacylglycerols (TGs) was significantly decreased by CP while more modest changes were observed in free fatty acids. Topical GCs reduced the thickness of skin layers and increased TEWL. GC treatment also induced changes in expression of genes coding for extracellular markers and enzymes involved in lipid synthesis. CONCLUSIONS: This study shows a reduction in specific SC lipid classes following topical GC treatment of human skin and contributes to the characterisation of the barrier disruption in human skin induced by topical steroids. PMID- 28911800 TI - Evolution of the sex ratio and effective number under gynodioecy and androdioecy. AB - We address the evolution of effective number of individuals under androdioecy and gynodioecy. We analyze dynamic models of autosomal modifiers of weak effect on sex expression. In our zygote control models, the sex expressed by a zygote depends on its own genotype, while in our maternal control models, it depends on the genotype of its maternal parent. Our analysis unifies full multi-dimensional local stability analysis with the Li-Price equation, which for all its heuristic appeal, describes evolutionary change over a single generation. We define a point in the neighborhood of a fixation state from which a single-generation step indicates the asymptotic behavior of the frequency of a modifier allele initiated at an arbitrary point near the fixation state. A concept of heritability appropriate for the evolutionary modification of sex emerges from the Li Priceframework. We incorporate our theoretical analysis into our previously developed Bayesian inference framework to develop a new method for inferring the viability of gonochores (males or females) relative to hermaphrodites. Applying this approach to microsatellite data derived from natural populations of the gynodioecious plant Schiedea salicaria and the androdioecious killifish Kryptolebias marmoratus, we find that while female and hermaphrodite S. salicaria appear to have similar viabilities, male K. marmoratus appear to survive to reproductive age at less than half the rate of hermaphrodites. PMID- 28911801 TI - Mental Health Screening, Treatment, and Referral During the Perinatal Period. PMID- 28911802 TI - Transient gestational exposure to drinking water containing excess hexavalent chromium modifies insulin signaling in liver and skeletal muscle of rat progeny. AB - Chromium (Cr), an essential micronutrient potentiates insulin action, whereas excess hexavalent Cr (CrVI) acts as an endocrine disruptor. Pregnant mothers living in areas abutting industries using the metal and chromite ore dumps are exposed to ground water contaminated with Cr. Nevertheless, the impact of prenatal exposure to excess CrVI on insulin signaling in the progeny remains obscure. We tested the hypothesis "transient gestational exposure to drinking water containing excess CrVI may modify insulin signaling during postnatal life". Pregnant Wistar rats were given drinking water containing 50, 100 and 200 ppm CrVI (K2Cr2O7) from gestational day 9-14 encompassing the period of organogenesis; the male progenies were tested at postnatal day 60. Neither fasting blood glucose nor oral glucose tolerance was altered in CrVI treated progeny. Nevertheless, western blot detection pointed out attenuated expression level of insulin receptor (IR), its downstream signaling molecules (IRS-1, pIRS 1Tyr632, Akt and pAktSer473) and organ specific glucose transporters (GLUT2 in liver and GLUT4 in gastrocnemius muscle), along with a significant increase in serum insulin level in male progenies exposed to CrVI. While 14C-2-deoxy glucose uptake increased in the liver, the same decreased in the skeletal muscle whereas, 14C-glucose oxidation recorded a consistent decrease in both tissues of CrVI exposed rats. These findings support our hypothesis and suggest that transient gestational exposure to excess CrVI may affect insulin signaling and glucose oxidation in the progeny, predictably rendering them vulnerable to insulin resistance. PMID- 28911803 TI - Sensory overload and imbalance: Resting-state vestibular connectivity in PTSD and its dissociative subtype. AB - BACKGROUND: The vestibular system integrates multisensory information to monitor one's bodily orientation in space, and is influenced by interoceptive awareness. Post-traumatic stress disorder (PTSD) involves typically alterations in interoceptive and bodily self-awareness evidenced by symptoms of hyperarousal, as well as of emotional detachment, including emotional numbing, depersonalization, and derealization. These alterations may disrupt vestibular multisensory integration between the brainstem (vestibular nuclei) and key vestibular cortical regions (parieto-insular vestibular cortex, prefrontal cortex). Accordingly, this study examined functional connectivity of the vestibular system in PTSD and its dissociative subtype. METHODS: Using resting-state fMRI data in SPM12 and PickAtlas, a seed-based analysis was employed to examine vestibular nuclei functional connectivity differences among PTSD (n = 60), PTSD dissociative subtype (PTSD + DS, n = 41) and healthy controls (n = 40). RESULTS: Increased vestibular nuclei functional connectivity with the parieto-insular vestibular cortex and the dorsolateral prefrontal cortex (dlPFC) was observed in PTSD and in controls as compared to PTSD + DS, and greater connectivity with the posterior insula was observed in controls as compared to PTSD. Interestingly, whereas PTSD symptom severity correlated negatively with dlPFC connectivity, clinical measures of depersonalization/derealization correlated negatively with right supramarginal gyrus connectivity. DISCUSSION: Taken together, decreased vestibular nuclei functional connectivity with key cortical vestibular regions in the PTSD + DS as compared to PTSD group, and its negative correlations with PTSD and dissociative symptoms, suggest that dysregulation of vestibular multisensory integration may contribute to the unique symptom profiles of each group. Further research examining disruption of vestibular system neural circuitry in PTSD and its dissociative subtype will be critical in capturing the neurophenomenology of PTSD symptoms and in identifying psychotherapeutic techniques that target dysfunction related to the vestibular system. PMID- 28911804 TI - Case report: Left ventricular noncompaction cardiomyopathy and RASopathies. AB - The following is a case report of 6 patients with Noonan syndrome (NS) and/or a related RASsopathy that also have evidence of left ventricular noncompaction cardiomyopathy (LVNC). Noonan syndrome,a type of RASopathy, is an autosomal dominant disorder that is typically associated with congenital heart defects and hypertrophic cardiomyopathy. There have been minimal reports of Noonan syndrome or other RASopathy and the association of LVNC. This report promulgates 6 nonrelated cases of Noonan syndrome or unspecified RASopathy and LVNC. PMID- 28911806 TI - Comparison of characteristics and fibril-forming ability of skin collagen from barramundi (Lates calcarifer) and tilapia (Oreochromis niloticus). AB - The present study isolated and characterized the barramundi (Lates calcarifer) skin collagen (BC) and tilapia (Oreochromis niloticus) skin collagen (TC). The yields of BC and TC by enzymatic extraction were 47.3+/-3.7% and 52.6+/-6.1% respectively, dry weight. The SDS-PAGE profile indicated both collagens were mainly type I with two different alpha chains. FTIR spectra and X-ray diffraction confirmed that the triple helical structure of both collagens was not affected by pepsin digestion. The denaturation (Td) and melting temperature (Tm) were 36.8 and 109.6 degrees C for BC, 37.6 and 113.7 degrees C for TC, measured by rheometer and DSC. This high thermal stability could be attributed to the high imino acid content (205.9 and 210.9 residues/1000 residues) of BC and TC. Fibril forming studies indicated BC exhibited higher ability than (p<0.05) that of TC, especially under the effect of NaCl. One major characteristic of this result showed that NaCl had the markedly effects of promoting collagen forming fibrils, and electron microscopic observation corroborated this phenomenon. In general, barramundi and tilapia skin collagen with high thermal stability and good fibril forming ability may be suitable for use as an alternative to mammalian-derived collagen in biomaterials, pharmaceuticals and cosmetics. PMID- 28911807 TI - Cellulose nanofibrils (CNFs) from Ammophila arenaria, a natural and a fast growing grass plant. AB - The production of cellulose nanofibrils (CNFs) with a high yield from Ammophila arenariahas been explored and the ensuing CNFs were characterized in terms of morphology, crystallinity and rheological properties. Ammophila arenaria (marram grass) is a perennial grass plant with high tolerance to drought, which is growing naturally in nutritionally poor sand with low organic matter. Fibers were extracted from the plant by conventional alkaline pulping and bleaching with a yield around 50% based on the dry weight of the plant. A TEMPO-mediated oxidation and a cationization with glycidyltrimethylammonium chloride were performed as a pretreament to facilitate the fibrillation process and produced stable CNF suspension with high yield and controlled surface charge. High pressure homogenization was used for the mechanical disintegration of the pretreated fibers and nanosized CNFs with width around 5-8nm were produced with a yield exceeding 80%. PMID- 28911808 TI - Renal Transplantation After Treatment for a Urological Cancer: Who and When? Does Evidence Help for a Challenge? PMID- 28911805 TI - Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications. AB - The CRISPR-Cas9 genome-editing system is a part of the adaptive immune system in archaea and bacteria to defend against invasive nucleic acids from phages and plasmids. The single guide RNA (sgRNA) of the system recognizes its target sequence in the genome, and the Cas9 nuclease of the system acts as a pair of scissors to cleave the double strands of DNA. Since its discovery, CRISPR-Cas9 has become the most robust platform for genome engineering in eukaryotic cells. Recently, the CRISPR-Cas9 system has triggered enormous interest in therapeutic applications. CRISPR-Cas9 can be applied to correct disease-causing gene mutations or engineer T cells for cancer immunotherapy. The first clinical trial using the CRISPR-Cas9 technology was conducted in 2016. Despite the great promise of the CRISPR-Cas9 technology, several challenges remain to be tackled before its successful applications for human patients. The greatest challenge is the safe and efficient delivery of the CRISPR-Cas9 genome-editing system to target cells in human body. In this review, we will introduce the molecular mechanism and different strategies to edit genes using the CRISPR-Cas9 system. We will then highlight the current systems that have been developed to deliver CRISPR-Cas9 in vitro and in vivo for various therapeutic purposes. PMID- 28911809 TI - Taxonomy, ecology and biotechnological applications of thraustochytrids: A review. AB - Thraustochytrids were first discovered in 1934, and since the 1960's they have been increasingly studied for their beneficial and deleterious effects. This review aims to provide an enhanced understanding of these protists with a particular emphasis on their taxonomy, ecology and biotechnology applications. Over the years, thraustochytrid taxonomy has improved with the development of modern molecular techniques and new biochemical markers, resulting in the isolation and description of new strains. In the present work, the taxonomic history of thraustochytrids is reviewed, while providing an up-to-date classification of these organisms. It also describes the various biomarkers that may be taken into consideration to support taxonomic characterization of the thraustochytrids, together with a review of traditional and modern techniques for their isolation and molecular identification. The originality of this review lies in linking taxonomy and ecology of the thraustochytrids and their biotechnological applications as producers of docosahexaenoic acid (DHA), carotenoids, exopolysaccharides and other compounds of interest. The paper provides a summary of these aspects while also highlighting some of the most important recent studies in this field, which include the diversity of polyunsaturated fatty acid metabolism in thraustochytrids, some novel strategies for biomass production and recovery of compounds of interest. Furthermore, a detailed overview is provided of the direct and current applications of thraustochytrid-derived compounds in the food, fuel, cosmetic, pharmaceutical, and aquaculture industries and of some of the commercial products available. This review is intended to be a source of information and references on the thraustochytrids for both experts and those who are new to this field. PMID- 28911810 TI - Exercise VE/VCO2 Slope: An Endurance Marker of Prognosis Also in Patients with HFpEF and Pulmonary Hypertension, at Least! PMID- 28911812 TI - Relationships between residue Voronoi volume and sequence conservation in proteins. AB - BACKGROUND: Functional and biophysical constraints can cause different levels of sequence conservation in proteins. Previously, structural properties, e.g., relative solvent accessibility (RSA) and packing density of the weighted contact number (WCN), have been found to be related to protein sequence conservation (CS). The Voronoi volume has recently been recognized as a new structural property of the local protein structural environment reflecting CS. However, for surface residues, it is sensitive to water molecules surrounding the protein structure. Herein, we present a simple structural determinant termed the relative space of Voronoi volume (RSV); it uses the Voronoi volume and the van der Waals volume of particular residues to quantify the local structural environment. METHODS: RSV (range, 0-1) is defined as (Voronoi volume-van der Waals volume)/Voronoi volume of the target residue. The concept of RSV describes the extent of available space for every protein residue. RESULTS: RSV and Voronoi profiles with and without water molecules (RSVw, RSV, VOw, and VO) were compared for 554 non-homologous proteins. RSV (without water) showed better Pearson's correlations with CS than did RSVw, VO, or VOw values. The mean correlation coefficient between RSV and CS was 0.51, which is comparable to the correlation between RSA and CS (0.49) and that between WCN and CS (0.56). CONCLUSIONS: RSV is a robust structural descriptor with and without water molecules and can quantitatively reflect evolutionary information in a single protein structure. Therefore, it may represent a practical structural determinant to study protein sequence, structure, and function relationships. PMID- 28911811 TI - An intergenerational effect of neuroendocrine metabolic programming alteration induced by prenatal ethanol exposure in rats. AB - Prenatal ethanol exposure (PEE) induces hypothalamic-pituitary-adrenal (HPA) axis related neuroendocrine metabolic programming alteration in the first generation (F1) rats. In this study, the HPA hormones and glucose/lipid phenotypes under basal state and stressed condition induced by a fortnight ice-water swimming were examined in F2 to verify the intergenerational effect. Under the basal state, serum corticosterone (CORT) and glucose of some PEE groups were lowered while those of serum triglycerides (TG) were increased comparing with controls. Following chronic stress, the percentage increase in CORT from the basal state tended to be greater for some PEE groups compared with controls while the percentage reduction of glucose and percentage elevation of TG were smaller. These results revealed that the low basal activity and hyper-responsiveness of the HPA axis as well as glucocorticoid-associated glucose and lipid phenotypic alterations were partially retained in F2, which indicates PEE-induced neuroendocrine metabolic programming alteration may have an intergenerational effect. PMID- 28911813 TI - Functional dynamics in cyclic nucleotide signaling and amyloid inhibition. AB - It is now established that understanding the molecular basis of biological function requires atomic resolution maps of both structure and dynamics. Here, we review several illustrative examples of functional dynamics selected from our work on cyclic nucleotide signaling and amyloid inhibition. Although fundamentally diverse, a central aspect common to both fields is that function can only be rationalized by considering dynamic equilibria between distinct states of the accessible free energy landscape. The dynamic exchange between ground and excited states of signaling proteins is essential to explain auto inhibition and allosteric activation. The dynamic exchange between non-toxic monomeric species and toxic oligomers of amyloidogenic proteins provides a foundation to understand amyloid inhibition. NMR ideally probes both types of dynamic exchange at atomic resolution. Specifically, we will show how NMR was utilized to reveal the dynamical basis of cyclic nucleotide affinity, selectivity, agonism and antagonism in multiple eukaryotic cAMP and cGMP receptors. We will also illustrate how NMR revealed the mechanism of action of plasma proteins that act as extracellular chaperones and inhibit the self association of the prototypical amyloidogenic Abeta peptide. The examples outlined in this review illustrate the widespread implications of functional dynamics and the power of NMR as an indispensable tool in molecular pharmacology and pathology. PMID- 28911814 TI - The effect of patient gender on outcomes after reverse total shoulder arthroplasty. AB - BACKGROUND: Gender differences may exist for patients undergoing shoulder arthroplasty. Limited data suggest that women may have worse preoperative disability and outcomes. Our objective was to determine whether gender influences preoperative disability and patient-reported outcomes after reverse total shoulder arthroplasty. METHODS: Data were prospectively collected for patients who underwent reverse total shoulder arthroplasty for rotator cuff arthropathy or osteoarthritis with a rotator cuff tear at a single institution between 2009 and 2015. Range of motion, visual analog scale, 12-Item Short Form Health Survey (SF 12), and American Shoulder and Elbow Surgeons (ASES) scores were collected at the preoperative, 1-year, and 2-year postoperative time points. Data were analyzed using multivariate mixed-effect regression analysis. RESULTS: There were 117 patients included. Men and women had similar demographics, preoperative range of motion, pain, and function. Length of stay was similar (men, 2.32 days; women, 2.58 days; P = .18). Controlling for patient variables, men achieved higher ASES function (P = .009) and SF-12 Physical Component Summary (P = .008) scores compared with women. There was no difference between men and women in ASES pain and SF-12 Mental Component Summary scores, visual analog scale score, or range of motion. CONCLUSION: Improvements in pain and range of motion were similar in men and women; however, men achieved higher ASES function and SF-12 Physical Component Summary scores. Women may be more functionally impaired on the basis of differences in activities of daily living. These results may be used to guide discussion about expected benefits after reverse shoulder arthroplasty. PMID- 28911815 TI - Haemocytes from Crassostrea gigas and OsHV-1: A promising in vitro system to study host/virus interactions. AB - Since 2008, mass mortality outbreaks associated with the detection of particular variants of OsHV-1 have been reported in Crassostrea gigas spat and juveniles in several countries. Recent studies have reported information on viral replication during experimental infection. Viral DNA and RNA were also detected in the haemolymph and haemocytes suggesting that the virus could circulate through the circulatory system. However, it is unknown if the virus is free in the haemolymph, passively associated at the surface of haemocytes, or able to infect and replicate inside these cells inducing (or not) virion production. In the present study, we collected haemocytes from the haemolymphatic sinus of the adductor muscle of healthy C. gigas spat and exposed them in vitro to a viral suspension. Results showed that viral RNAs were detectable one hour after contact and the number of virus transcripts increased over time in association with an increase of viral DNA detection. These results suggested that the virus is able to initiate replication rapidly inside haemocytes maintained in vitro. These in vitro trials were also used to carry out a dual transcriptomic study. We analyzed concomitantly the expression of some host immune genes and 15 viral genes. Results showed an up regulation of oyster genes currently studied during OsHV-1 infection. Additionally, transmission electron microscopy examination was carried out and did not allow the detection of viral particles. Moreover, All the results suggested that the in vitro model using haemocytes can be valuable for providing new perspective on virus-oyster interactions. PMID- 28911816 TI - Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system. AB - Protein degradation is critical for proteostasis, and the addition of polyubiquitin chains to a substrate is necessary for its recognition by the 26S proteasome. Therapeutic intervention in the ubiquitin proteasome system has implications ranging from cancer to neurodegeneration. Novel screening methods and chemical biology tools for targeting E1-activating, E2-conjugating and deubiquitinating enzymes will be discussed in this review. Approaches for targeting E3 ligase-substrate interactions as well as the proteasome will also be covered, with a focus on recently described approaches. PMID- 28911817 TI - Natural neuro-inflammatory inhibitors from Caragana turfanensis. AB - Because of the critical role of over-activated microglia in the progress of neurodegenerative diseases, it has been selected as a potential therapeutic target for drug discovery. In order to find natural neuroinflammatory inhibitors, we carried out a bioactivity-oriented phytochemical research of Caragana turfanensis Kom. (Krassn.), which is a folk medicine widely distributed in Xinjiang. As a result, a new coumarin lactone caraganolide A (1) and 35 known components were characterized from the effective extract of C. turfanensis. Furthermore, their anti-neuroinflammatory effects were evaluated in LPS-induced BV2 microglial cells using Griess assay to determine the release of nitric oxide (NO). Compounds 1, 2, 4-6, 9, 13-15, 20, 29 and 30 exhibited significant inhibitory activities and no obvious cytotoxicities were observed at their effective concentrations. It is noteworthy, the new compound caraganolide A (1) (IC50 1.01+/-1.57uM) and 3',7,8-trihydroxy-4'-methoxyisoflavone (5) (IC506.87+/ 2.23uM) exhibited more excellent action than that of positive control minocycline (IC50 9.07+/-0.86MUM). PMID- 28911818 TI - Anti-fatigue activity of a Lachnum polysaccharide and its carboxymethylated derivative in mice. AB - The present study was designed to evaluate the anti-fatigue activity of an exopolysaccharide LEP-1b and its carboxymethylated derivative CLEP-1b from a Lachnum sp. Carboxymethylation was confirmed through FT-IR and 13C NMR spectroscopies, which showed that the (-CH2COOH) group was attached to an oxygen (O) atom of the hydroxyl group on (C-3) of LEP-1b. Each treatment group LEP-1b and CLEP-1b at doses (50, 100, 200mg/kg, respectively) ameliorated physical fatigue and extended exhaustive swimming time in mice. Results of the fatigue related biochemical markers showed that LEP-1b and CLEP-1b at doses (50, 100, 200mg/kg, respectively) increased the content of hepatic glycogen and decreased the level of serum urea nitrogen and lactic acid. Additionally, LEP-1b and CLEP 1b enhanced the antioxidant enzymes' activities and reduced the lipid peroxidation. Moreover, results revealed that CLEP-1b had higher anti-fatigue activity than LEP-1b at same doses but without statistical significance, especially CLEP-1b (200mg/kg) had strong anti-fatigue effects. Therefore, LEP-1b and CLEP-1b can potentially be exploited as a kind of healthcare compound to combat fatigue and to boost physical strength. PMID- 28911820 TI - Regulation of pannexin channels in the central nervous system by Src family kinases. AB - Pannexins form single membrane channels that regulate the passage of ions, small molecules and metabolites between the intra- and extracellular compartments. In the central nervous system, these channels are integrated into numerous signaling cascades that shape brain physiology and pathology. Post-translational modification of pannexins is complex, with phosphorylation emerging as a prominent form of functional regulation. While much is still not known regarding the specific kinases and modified amino acids, recent reports support a role for Src family tyrosine kinases (SFK) in regulating pannexin channel activity. This review outlines the current evidence supporting SFK-dependent pannexin phosphorylation in the CNS and examines the importance of these modifications in the healthy and diseased brain. PMID- 28911819 TI - Non-Neurogenic Language Disorders: A Preliminary Classification. AB - BACKGROUND: Few publications deal with non-neurogenic language disorders (NNLDs), distinct from psychogenic speech disorders such as psychogenic dysphonia or stuttering. NNLDs are alterations in language owing to psychosomatic preoccupations, conversion disorder, psychiatric disorders, or other psychological reasons. OBJECTIVE: To identify and classify the range of NNLDs and their characteristics. METHODS: This review summarizes the literature on disturbances in language, broadly defined as the use of symbols for communication, which may have a psychogenic or psychiatric etiology. RESULTS: The literature suggests a classification for NNLDs that includes psychogenic aphasia with dysgrammatism; psychogenic "lalias" including oxylalia and agitolalia, palilalia and echolalia, xenolalia, glossolalia, and coprolalia; psychologically mediated word usage; psychotic language; and psychogenic forms of the foreign accent syndrome. CONCLUSIONS: Clinicians and researchers have insufficiently emphasized the presence of NNLDs, their characteristics, and their identification. Yet, these disorders may be the first or predominant manifestation of a psychologically-mediated illness. There are 2 steps to recognition. The first is to know how to distinguish NNLDs from the manifestations of neurogenic language impairments after a neurological evaluation. The second step is awareness of specific associated and examination features that suggest the presence of a NNLD. PMID- 28911822 TI - Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. AB - There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs. Computer-aided drug design (CADD) tools added a benefit to the design and development of new CDK inhibitors by studying the binding pattern of the inhibitors to the ATP binding domain of CDKs. Herein, we have attempted a comparative analysis of structural differences between several CDKs ATP binding sites and their inhibitor specificity by depicting the important ligand-receptor interactions for a particular CDK to be targeted. This perspective provides futuristic implications in the design of inhibitors considering the spatial features and structural insights of the specific CDK. PMID- 28911821 TI - On the occurrence and enigmatic functions of mixed (chemical plus electrical) synapses in the mammalian CNS. AB - Electrical synapses with diverse configurations and functions occur at a variety of interneuronal appositions, thereby significantly expanding the physiological complexity of neuronal circuitry over that provided solely by chemical synapses. Gap junctions between apposed dendritic and somatic plasma membranes form "purely electrical" synapses that allow for electrical communication between coupled neurons. In addition, gap junctions at axon terminals synapsing on dendrites and somata allow for "mixed" (dual chemical+electrical) synaptic transmission. "Dual transmission" was first documented in the autonomic nervous system of birds, followed by its detection in the central nervous systems of fish, amphibia, and reptiles. Subsequently, mixed synapses have been detected in several locations in the mammalian CNS, where their properties and functional roles remain undetermined. Here, we review available evidence for the presence, complex structural composition, and emerging functional properties of mixed synapses in the mammalian CNS. PMID- 28911823 TI - Towards antibody-drug conjugates and prodrug strategies with extracellular stimuli-responsive drug delivery in the tumor microenvironment for cancer therapy. AB - The design of innovative anticancer chemotherapies with superior antitumor efficacy and reduced toxicity continues to be a challenging endeavor. Recently, the success of Adcetris(r) and Kadcyla(r) made antibody-drug conjugates (ADCs) serious contenders to reach the envied status of Paul Ehrlich's "magic bullet". However, ADCs classically target overexpressed and internalizing antigens at the surface of cancer cells, and in solid tumors are associated with poor tumor penetration, insufficient targeting in heterogeneous tumors, and appearance of several resistance mechanisms. In this context, alternative non-internalizing ADCs and prodrugs have been developed to circumvent these limitations, in which the drug can be selectively released by an extracellular stimulus in the tumor microenvironment. Each strategy and method of activation will be discussed as potential alternatives to internalizing ADCs for cancer therapy. PMID- 28911824 TI - [DRESS and viruses]. PMID- 28911825 TI - Paving the Rho in cancer metastasis: Rho GTPases and beyond. AB - Malignant carcinomas are often characterized by metastasis, the movement of carcinoma cells from a primary site to colonize distant organs. For metastasis to occur, carcinoma cells first must adopt a pro-migratory phenotype and move through the surrounding stroma towards a blood or lymphatic vessel. Currently, there are very limited possibilities to target these processes therapeutically. The family of Rho GTPases is an ubiquitously expressed division of GTP-binding proteins involved in the regulation of cytoskeletal dynamics and intracellular signaling. The best characterized members of the Rho family GTPases are RhoA, Rac1 and Cdc42. Abnormalities in Rho GTPase function have major consequences for cancer progression. Rho GTPase activation is driven by cell surface receptors that activate GTP exchange factors (GEFs) and GTPase-activating proteins (GAPs). In this review, we summarize our current knowledge on Rho GTPase function in the regulation of metastasis. We will focus on key discoveries in the regulation of epithelial-mesenchymal-transition (EMT), cell-cell junctions, formation of membrane protrusions, plasticity of cell migration and adaptation to a hypoxic environment. In addition, we will emphasize on crosstalk between Rho GTPase family members and other important oncogenic pathways, such as cyclic AMP mediated signaling, canonical Wnt/beta-catenin, Yes-associated protein (YAP) and hypoxia inducible factor 1alpha (Hif1alpha) and provide an overview of the advancements and challenges in developing pharmacological tools to target Rho GTPase and the aforementioned crosstalk in the context of cancer therapeutics. PMID- 28911826 TI - Immunoproteasome-selective and non-selective inhibitors: A promising approach for the treatment of multiple myeloma. AB - The ubiquitin-proteasome system (UPS) is the major non-lysosomal proteolytic system for the degradation of abnormal or damaged proteins no longer required. The proteasome is involved in degradation of numerous proteins which regulate the cell cycle, indicating a role in controlling cell proliferation and maintaining cell survival. Defects in the UPS can lead to anarchic cell proliferation and to tumor development. For these reasons UPS inhibition has become a significant new strategy for drug development in cancer treatment. In addition to the constitutive proteasome, which is expressed in all cells and tissues, higher organisms such as vertebrates possess two immune-type proteasomes, the thymoproteasome and the immunoproteasome. The thymoproteasome is specifically expressed by thymic cortical epithelial cells and has a role in positive selection of CD8+ T cells, whereas the immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell-mediated immunity. Recent studies demonstrated that the immunoproteasome has a preservative role during oxidative stress and is up regulated in a number of pathological disorders including cancer, inflammatory and autoimmune diseases. As a consequence, immunoproteasome-selective inhibitors are currently the focus of anticancer drug design. At present, the commercially available proteasome inhibitors bortezomib and carfilzomib which have been validated in multiple myeloma and other model systems, appear to target both the constitutive and immunoproteasomes, indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents, such as peripheral neuropathy and gastrointestinal effects, which may be due to targeting of the constitutive proteasome in these tissues. In contrast, by selectively inhibiting the immunoproteasome, it may be possible to maintain the antimyeloma and antilymphoma efficacy while reducing these toxicities, thereby increasing the therapeutic index. This review article will be focused on the discussion of the most promising immunoproteasome specific inhibitors which have been developed in recent years. Particular attention will be devoted to the description of their mechanism of action, their structure-activity relationship, and their potential application in therapy. PMID- 28911827 TI - Single-Site Robot-Assisted Laparoscopic Staging Surgery for Presumed Clinically Early-Stage Ovarian Cancer. AB - STUDY OBJECTIVE: To present the demonstration of robotic-assisted laparoendoscopic single-site (R-LESS) staging surgery in presumed clinically early-stage ovarian cancer. DESIGN: A step-by-step presentation of the procedure using video (Canadian Task Force classification III). SETTING: A university hospital. PATIENT: A 29-year-old woman was referred from a local clinic for an 8 * 6 cm left ovarian tumor suggesting malignancy. Her serum cancer antigen 125 level was 1636 U/mL. There was no evidence of a metastatic tumor or lymph node enlargement on magnetic resonance imaging or positron emission tomographic/computed tomographic imaging. INTERVENTION: Under general anesthesia, a 2-cm vertical intraumbilical incision was made, and a Lap Single trocar (Sejong Medical, Ltd, Gyeonggi-do, South Korea) was applied. The entire abdominal cavity was clear without any seeding tumor or adhesion. We performed laparoendoscopic single-site left salpingo-oophorectomy. On frozen section, high-grade epithelial malignancy was diagnosed. We started R-LESS staging surgery with the Da Vinci Xi system (Intuitive Surgical, Inc, Sunnyvale, CA). Fenestrated bipolar forceps and a permanent cautery hook were introduced. Both pelvic and inferior mesenteric para-aortic lymphadenectomy was performed. The patient was tilted in a reverse Trendelenburg position while performing infracolic omentectomy. MAIN RESULTS: The total operation took 280 minutes, and the console time was 135 minutes. The estimated blood loss was 100 mL. The patient was discharged on the next day after surgery. Histopathologic evaluation revealed a poorly differentiated endometrioid carcinoma. A total of 15 pelvic lymph nodes and 7 para-aortic lymph nodes were retrived. Among them, 2 para-aortic lymph nodes showed malignancy. CONCLUSION: We could successfully perform R-LESS staging surgery for presumed clinically early stage ovarian cancer without any complications. PMID- 28911828 TI - Laparoscopic Sentinel Lymph Node Mapping with Indocyanine Green Using the iSpies Platform: Initial Experience Argentina. AB - STUDY OBJECTIVE: To demonstrate the initial experience in Argentina using the iSpies indocyanine green (ICG) platform in sentinel lymph node mapping in patients with early-stage cervical cancer. DESIGN: Step-by-step demonstration of the technique using a video and pictures (educative video) (Canadian Task Force classification III). SETTING: Laparoscopic and robotic sentinel lymph node mapping using ICG has been shown to be safe and feasible; however, in developing countries, the opportunities to use fluorescent imaging through a minimally invasive approach are very limited, given the cost restrictions of acquiring the near-infrared technology and the fluorescent dyes. INTERVENTION: A 47-year-old woman presented with a stage IB1 squamous cervical cancer. Physical examination revealed a 1.5-cm tumor without evidence of parametrial involvement. Magnetic resonance imaging did not show any evidence of metastatic disease. The patient underwent laparoscopic radical hysterectomy with sentinel lymph node mapping. On laparoscopic exposure of the pelvic spaces, a cervical injection of ICG (1 mL superficial and deep) was administered using a spinal needle at the 3 o'clock and 9 o'clock positions. Sentinel lymph node mapping was then performed using the ICG (Pulsion Medical Systems, Feldkirchen, Germany) and an iSpies near-infrared camera (Karl Storz Endoskope, Tuttlingen, Germany). Bilateral sentinel lymph nodes were detected on the left external iliac artery and in the right obturator space. Both were confirmed ex vivo. The total operative time was 170 minutes. No intraoperative or postoperative complications were reported, and the patient was discharged at 48 hours after surgery. Estimated blood loss was minimal. Sentinel lymph node mapping alone is not the standard of care in our institution, and thus bilateral lymphadenectomy was performed. Ultrastaging is routinely performed when a sentinel lymph node is evaluated. Final pathology revealed a tumor confined to the cervix, with tumor-free margins, and a total of 10 lymph nodes that were negative for any evidence of disease. Disadvantages of this technology compared with the Pinpoint ICG system (Novadaq Technologies; Bonita Springs, FL) is the lack of simultaneous white vision and fluorescence ICG detection, and the to manually change normal vision to infrared vision. An advantage of the Storz iSpies system is its availability in our country, considering that the technology developed by Novadaq is not yet approved in Argentina. CONCLUSION: Although ICG sentinel lymph node mapping is becoming a standard of care [1,2], a lack of ICG dye or laparoscopic near-infrared technologies could be a deterrent to its use in developing countries. A focus on expanding this technology in countries with limited resources would allow patients the opportunity to avoid the morbidity associated with full lymphadenectomy. PMID- 28911829 TI - Influenza in Older Adults. AB - Annually, influenza viruses cause significant disease in older adults, varying with the virulence of the circulating strain, prior exposure to circulating strain, and influenza vaccine effectiveness. Older adults often present atypically (eg, without fever) and with complications of influenza infection such as chronic obstructive pulmonary disease and congestive heart failure exacerbations. Prevention methods include antiviral medications and vaccines. Current influenza vaccines have moderate effectiveness for the prevention of hospitalization, but newer more immunogenic vaccines designed for adults 65 years of age and older have been licensed. PMID- 28911830 TI - Norovirus Infection in Older Adults: Epidemiology, Risk Factors, and Opportunities for Prevention and Control. AB - Norovirus is the leading cause of acute gastroenteritis. In older adults, it is responsible for an estimated 3.7 million illnesses; 320,000 outpatient visits; 69,000 emergency department visits; 39,000 hospitalizations; and 960 deaths annually in the United States. Older adults are particularly at risk for severe outcomes, including prolonged symptoms and death. Long-term care facilities and hospitals are the most common settings for norovirus outbreaks in developed countries. Diagnostic platforms are expanding. Several norovirus vaccines in clinical trials have the potential to reap benefits. This review summarizes current knowledge on norovirus infection in older adults. PMID- 28911832 TI - Association of silent infarcts in sickle cell anemia with decreased annexin A5 resistance. AB - BACKGROUND: Sickle cell anemia (SCA) is characterized by abnormally shaped, adhesive RBCs that interact with white blood cells and the endothelium, leading to chronic hemolysis, vasculopathy and a prothrombotic state. About 10% of subjects with a thrombotic event in the general population will have an associated antiphospholipid (aPL) antibody. One proposed mechanism for the thrombophilic nature of aPL antibodies is the disruption of the potent anticoagulant annexin A5 or Annexin A5 resistance (A5R). We designed a pilot study assessing the presence of aPL antibodies and disruption of A5R in pediatric sickle cell subjects. METHODS: 39 subjects with SCA participated in this study. A5R, DRVVT, anti-beta2GP1, anti-beta2GP1, anti-phosphatidylserine and anti cardiolipin antibody assays were performed. RESULTS: There was a high prevalence of abnormal A5R despite a low prevalence of antiphospholipid antibodies. Multivariate logistic regression analyses showed an association with silent infarcts (p=0.015), lower hemoglobin (p=0.037), older age (p=0.047) and abnormal A5R. CONCLUSION: We report an association between annexin A5 resistance and presence of silent infarct, low hemoglobin, and older age in a subgroup of SCA subjects. A potential role for perturbed A5R in the pathophysiology of SCA needs to be evaluated further. PMID- 28911831 TI - Prenatal and postnatal polybrominated diphenyl ether (PBDE) exposure and measures of inattention and impulsivity in children. AB - Exposure to polybrominated diphenyl ethers (PBDEs) during fetal development may be associated with deficits in attention and impulse control. However, studies examining postnatal PBDE exposures and inattention and impulsivity have been inconsistent. Using data from 214 children in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort with enrollment from 2003 to 2006 in the Greater Cincinnati Area, we investigated the relationship of both prenatal and postnatal PBDE exposures with attention and impulse control. Serum PBDEs were measured at 16+/-3weeks of gestation and during childhood at 1, 2, 3, 5, and 8years. We assessed children's attention and impulse control using the Conners' Continuous Performance Test-Second Edition (CPT-II) at 8years. We used multiple informant models to estimate associations of repeated PBDE measures with inattention and impulsivity. There was a pattern of associations between PBDEs and poorer performance on CPT-II measures of attention. For BDE-153, adverse associations extended to exposures at preschool and kindergarten ages; ten-fold increases in exposure were associated with higher omission errors (BDE-153 at 3years: beta=4.0 [95% CI: -2.4, 10.5]; at 5years: beta=4.6 [95% CI: -2.8, 12.0]; at 8years: beta=4.1 [95% CI: -3.4, 11.5]). Longer hit reaction times, indicated by the exponential part of the hit reaction curve, were also observed with 10-fold increases in BDE-153 during the prenatal period and throughout childhood (Prenatal: beta=15.0 milliseconds (ms) [95% CI: -15.8, 45.8]; 5years: beta=20.6ms [95% CI: -20.8, 61.9]; 8years: beta=28.6ms [95% CI: 12.1, 69.4]). Significant impairment in discriminability, as indicated by detectability (d'), between targets and non-targets was also noted with 5 and 8 year PBDE concentrations. Associations between PBDEs and inattention significantly differed by child sex, with males performing more poorly than females with regard to omission errors and measures of reaction times. Collectively, these results do not strongly support that PBDEs are associated with poorer impulse and attention control among 8year old children. However, there may be a possible relationship between prenatal and concurrent PBDEs and inattention, which requires additional research. PMID- 28911833 TI - Development of the Nurses' Care Coordination Competency Scale for mechanically ventilated patients in critical care settings in Japan: Part 2 Validation of the scale. AB - OBJECTIVES: To confirm the validity and reliability of the nurses' care coordination competency draft scale for mechanically ventilated patients in Japan. DESIGN/METHOD: In this cross sectional observational study, a draft scale measuring care coordination was distributed to 2189 nurses from 73 intensive care units in Japan from February-March 2016. Based on the valid 887 responses, we examined construct validity including structural validity (exploratory and confirmatory factor analysis), convergent and discriminant validity and internal consistency reliability. SETTINGS: 73 Intensive care units. RESULTS: Exploratory factor analyses yielded four factors with 22 items: 1) promoting team cohesion, 2) understanding care coordination needs, 3) aggregating and disseminating information, 4) devising and clearly articulating the care vision. The four factor model was confirmed using a confirmatory factor analysis (confirmatory fit index=0.942, root mean square error of approximation=0.062). Scale scores positively correlated with team leadership and clearly identified and discriminated nurses' attributes. Cronbach's alpha coefficient for each subscale was between 0.812 and 0.890, and 0.947 for the total scale. CONCLUSIONS: The Nurses' Care Coordination Competency Scale with four factors and 22 items had sufficient validity and reliability. The scale could make care coordination visible in nursing practice. Future research on the relationship between this scale and patient outcomes is needed. PMID- 28911834 TI - How swimming affects plasma insulin and glucose concentration in Thoroughbreds: A pilot study. AB - Low intensity exercise increases insulin-stimulated glucose uptake in skeletal muscle and decreases its plasma concentration. In this study, plasma insulin and glucose concentrations were evaluated 5min before and 5, 15, 25, 35, 45 and 60min after an IV bolus of glucose in 12 Thoroughbreds before and after 1 month of submaximal aquatraining exercise, monitored using heart rate and blood lactate. Plasma glucose concentrations were evaluated using a colorimetric enzymatic method, and plasma insulin concentrations with a solid-phase radioimmunoassay method. Pre-training plasma glucose concentrations at 15, 25 and 35min, area under the glucose curve and peak glucose concentration were significantly higher than post-training values (P<0.05). Baseline pre-training plasma insulin concentrations were significantly lower than in the post-training period, and plasma insulin was significantly higher at 45 and 60min in the pre-training period than the post-training period. These results indicate that aquatraining could improve insulin-glucose metabolism in horses. PMID- 28911835 TI - Molecular characterisation of equine group A rotaviruses in Ireland (2011-2015). AB - The molecular epidemiology of equine group A rotaviruses (RVAs) in Ireland from 2011 to 2015 was investigated. Of 438 diagnostic specimens submitted from foals with enteric disease, 102 (23.3%) were positive for RVA using an immunochromatographic assay. G genotypes were determined for 76 equine RVAs, of which 68 (89.5%) were G3 and eight (10.5%) were G14. Of 18 RVAs (12 G3 and six G14) characterised by P genotyping, all were P[12]. G3P[12] and G14P[12] were the most prevalent genotypes of RVA in foals in Ireland, similar to other countries and consistent with previous studies in Ireland from 1999 to 2005. Phylogenetic analysis showed that G3P[12] and G14P[12] RVAs were related to equine RVAs recently detected in Europe, Brazil and South Africa, and to the vaccine strain H 2. PMID- 28911836 TI - Implementation of an algorithm for selection of antimicrobial therapy for diarrhoeic calves: Impact on antimicrobial treatment rates, health and faecal microbiota. AB - This study evaluated the impact of an algorithm targeting antimicrobial therapy of diarrhoeic calves on the incidence of diarrhoea, antimicrobial treatment rates, overall mortality, mortality of diarrhoeic calves and changes in the faecal microbiota. The algorithm was designed to target antimicrobial therapy in systemically ill calves from on two dairy farms. Retrospective (farm 1: 529 calves; farm 2: 639 calves) and prospective (farm 1: 639 calves; farm 2: 842 calves) cohorts were examined for 12 months before and after implementation of the algorithm. The Mantel-Haenszel test and Kaplan-Meier survival curves were used to assess the cumulative incidence risk (CIR) and time to development of each outcome before and after implementation of the algorithm. The CIR of antimicrobial treatment rates was 80% lower after implementation of the algorithm on both farms (CIR 0.19, 95% confidence interval 0.17-0.21). There was no difference in the CIR of overall mortality, but the CRI for mortality of diarrhoeic calves was lower in the period after implementation of the algorithm on one farm. The faecal microbiota of 15 healthy calves from both farms at each time period were characterised using a sequencing platform targeting the V4 region of the 16S rRNA gene. On both farms, there were significant differences in community membership and structure (parsimony P<0.001). Use of the algorithm for treatment of diarrhoeic calves reduced antimicrobial treatment rates without a negative impact on the health of calves. However, the experimental design did not take into account the potential confounding effects of dietary changes between the study periods. PMID- 28911837 TI - Quantifying center of pressure variability in chondrodystrophoid dogs. AB - The center of pressure (COP) position reflects a combination of proprioceptive, motor and mechanical function. As such, it can be used to quantify and characterize neurologic dysfunction. The aim of this study was to describe and quantify the movement of COP and its variability in healthy chondrodystrophoid dogs while walking to provide a baseline for comparison to dogs with spinal cord injury due to acute intervertebral disc herniations. Fifteen healthy adult chondrodystrophoid dogs were walked on an instrumented treadmill that recorded the location of each dog's COP as it walked. Center of pressure (COP) was referenced from an anatomical marker on the dogs' back. The root mean squared (RMS) values of changes in COP location in the sagittal (y) and horizontal (x) directions were calculated to determine the range of COP variability. Three dogs would not walk on the treadmill. One dog was too small to collect interpretable data. From the remaining 11 dogs, 206 trials were analyzed. Mean RMS for change in COPx per trial was 0.0138 (standard deviation, SD 0.0047) and for COPy was 0.0185 (SD 0.0071). Walking speed but not limb length had a significant effect on COP RMS. Repeat measurements in six dogs had high test retest consistency in the x and fair consistency in the y direction. In conclusion, COP variability can be measured consistently in dogs, and a range of COP variability for normal chondrodystrophoid dogs has been determined to provide a baseline for future studies on dogs with spinal cord injury. PMID- 28911839 TI - Keeping joints healthy: The Goldilocks effect of exercise. PMID- 28911838 TI - Efficacy of a single oral dose of a live bivalent E. coli vaccine against post weaning diarrhea due to F4 and F18-positive enterotoxigenic E. coli. AB - F4- and F18-positive enterotoxigenic E. coli strains (F4-ETEC and F18-ETEC) are important causes of post-weaning diarrhea (PWD) in pigs. F4 (antigenic variant ac) and F18 (ab and ac) fimbriae are major antigens that play an important role in the early stages of infection. Herein, the efficacy of a live oral vaccine consisting of two non-pathogenic E. coli strains, one F4ac- and one F18ac positive, was evaluated using F4ac-ETEC and F18ab-ETEC challenge models. A randomized, masked, placebo-controlled, block design, parallel-group confirmatory study with two different vaccination-challenge intervals (7 and 21 days) was conducted for each challenge model. The vaccine was administered in one dose, to >=18-day-old piglets via drinking water. Efficacy was assessed by evaluating diarrhea, clinical observations, weight gain and fecal shedding of F4-ETEC or F18 ETEC. Anti-F4 and anti-F18 immunoglobulins in blood were measured. The vaccination resulted in significant reductions in clinical PWD and fecal shedding of F4-ETEC and F18-ETEC after the 7- and 21-day-post-vaccination heterologous challenges, except for after the 21-day-post-vaccination F4-ETEC challenge, when the clinical PWD was too mild to demonstrate efficacy. A significant reduction of mortality and weight loss by vaccination were observed following the F18-ETEC challenge. The 7-day protection was associated with induction of anti-F4 and anti F18 IgM, whereas the 21-day protection was mainly associated with anti-F4 and anti-F18 IgA. The 7-day onset and 21-day duration of protection induced by this vaccine administered once in drinking water to pigs of at least 18days of age were confirmed by protection against F4-ETEC and F18-ETEC, and induction of F4 and F18-specific immunity. Cross protection of the vaccine against F18ab-E. coli was demonstrated for both the 7- and 21-day F18-ETEC challenges. PMID- 28911840 TI - Compartmental resection of peripheral nerve tumours with limb preservation in 16 dogs (1995-2011). AB - Peripheral nerve tumours (PNTs) affecting the limbs may lead to chronic pain, lameness and/or monoparesis that is refractory to medical treatment. The most common radical therapy for PNTs has been surgical excision with limb amputation. However, compartmental resection with preservation of the limb has been performed by the authors with favourable clinical results and therefore this bi institutional retrospective study was undertaken to assess limb function, survival and recurrence. Sixteen dogs that had been diagnosed with PNTs between 1995 and 2011 met the inclusion criteria for this study. In the majority of the cases, good to excellent limb function was achieved. The overall median survival time (MST) was 1303days (42.8 months; range, 14 days-4639 days, [0.5-152.4 months]), with two dogs still alive at time of evaluation. Non-infiltrated margins were the best prognostic indicator; dogs with non-infiltrated margins had a MST of 2227days (P<0.001) compared to dogs with infiltrated margins (MST of 487 days). The 1-year calculated survival rate was 68.8% and the 2- and 3-year calculated survival rates were 62.5%. Surgical treatment with tumour removal and limb spare for proximal and distal PNTs can be successful. Compartmental excision can lead to good limb function, producing survival comparable to limb amputation, and should therefore be considered as an alternative to limb amputation in canine PNTs. PMID- 28911841 TI - The consistency and influence of environmental and animal factors on exhaled breath condensate hydrogen peroxide, pH and leukotriene B4 in horses. AB - This study was performed to determine the consistency of exhaled breath condensate (EBC) hydrogen peroxide (H2O2), pH and leukotriene B4 (LTB4) measurements in asymptomatic horses and to define the influence of environmental and animal factors on these variables. Intra- and inter-day consistency for both H2O2 and pH measurements were adequate, with intraclass correlation coefficients >=0.8, whereas the consistency for LTB4 was poor. H2O2 was influenced by ambient temperature (TA), humidity, time of day and collection location (all P<0.01), while pH was influenced by respiratory rate during EBC collection and TA (both P<0.001). The consistency of EBC H2O2 and pH measurements may be sufficient for use as diagnostic biomarkers in horses. However, the influence of identified environmental and animal factors should be considered. PMID- 28911842 TI - Genetic correlations of hip dysplasia scores for Golden retrievers and Labrador retrievers in France, Sweden and the UK. AB - In order to reduce the prevalence of inherited diseases in pedigree dogs, the feasibility of implementation of an international breeding program was investigated. One prerequisite is a strong genetic correlation between countries and our objective was to estimate this correlation for canine hip dysplasia (HD) across three countries to evaluate the feasibility of an international genetic evaluation. Data were provided by the Societe Centrale Canine (SCC, France), Svenska Kennelklubben (SKK, Sweden) and The Kennel Club (KC, UK) on Golden retriever and Labrador retriever dogs. Trivariate analysis on the three different modes of scoring HD in France, Sweden and the UK was performed using a mixed linear animal model. Heritability, genetic correlation, number of common sires, genetic similarity, selection differentials and accuracy of selection were calculated. The estimated heritabilities of Golden retrievers (Labrador retrievers) for HD scores were 0.28 (0.15), 0.28 (0.29) and 0.41 (0.34) in France, Sweden and the UK, respectively. The feasibility of performing a genetic evaluation of HD across countries was indicated by the favourable genetic correlations estimated between score modes (ranged from 0.48 to 0.99). The accuracy of selection for the most recent birth year cohorts of male dogs was not improved by international evaluation compared to national evaluation. Improvement in genetic progress can however be achieved by selection across populations in different countries, particularly for small populations, which were indicated by the large difference between selection differentials based on the national and international evaluations. PMID- 28911843 TI - The effect of a cannula milk sampling technique on the microbiological diagnosis of bovine mastitis. AB - Two methods of collecting milk samples from mastitic bovine mammary quarters were compared. Samples were taken in a consistent order in which standard aseptic technique sampling was done first, followed by insertion of a sterile cannula through the teat canal and collection of a second sample. Microbiological results of those two sampling techniques were compared. Milk samples were analysed using multiplex real-time polymerase chain reaction (PCR). The cannula technique produced a reduced number of microbial species or groups of species per sample compared with conventional sampling. Staphylococcus spp. were the most common species identified and were detected more often during conventional sampling than with cannula sampling. Staphylococcus spp. identified in milk samples could also have originated from the teat canal without being present in the milk. The number of samples positive for Trueperella pyogenes or yeasts in the conventional samples was twice as high as in the cannula samples, indicating that the presence of Trueperella pyogenes and yeast species should not necessarily be interpreted as being the causative agents of bovine intra-mammary infections (IMI). PMID- 28911844 TI - Serologic responses to peptides of Anaplasma phagocytophilum and Borrelia burgdorferi in dogs infested with wild-caught Ixodes scapularis. AB - Anaplasma phagocytophilum and Borrelia burgdorferi are both transmitted by Ixodes spp. and are associated with clinical illness in some infected dogs. This study evaluated canine antibody responses to the A. phagocytophilum p44 peptides APH-1 and APH-4 as well as the B. burgdorferi C6 peptide before and after doxycycline treatment. A total of eight dogs were infested with wild-caught I. scapularis for 1 week. Blood was collected prior to tick attachment and from Days 3-77 to 218 302 with doxycycline treatment beginning on Day 218. Blood was assayed for A. phagocytophilum DNA by PCR assay. Sera was assessed for antibodies by immunofluorescent antibody (IFA) test and ELISA. Anaplasma phagocytophilum DNA was amplified from blood of all dogs by Day 7. Antibodies to APH-4 were detected in serum as early as 14days after tick exposure and six dogs had APH-4 antibodies detected 3-7 days before antibodies against APH-1. All dogs were seropositive for A. phagocytophilum from Days 218 to 302. Antibodies to B. burgdorferi were detected in 6/8 dogs beginning 21days after I. scapularis infestation. Among the five dogs that remained seropositive at Day 218, C6 antibody levels declined on average 81% within 84days of initiating treatment. The results suggest that the APH-4 peptide may be more useful than APH-1 for detecting antibodies earlier in the course of an A. phagocytophilum infection. After doxycycline administration, C6 antibody levels but not APH-1 or APH-4 antibody levels decreased, suggesting a treatment effect on C6 antibody production. PMID- 28911845 TI - Age associated changes in peripheral airway smooth muscle mass of healthy horses. AB - Peripheral airway smooth muscle (ASM) mass is increased in severe equine asthma, but no information is available on age related changes in ASM. In this study, peripheral ASM dimensions were determined in healthy horses of different ages. The thickness of the peripheral ASM layer was constant in horses of different ages, but ASM occupied a greater proportion of the inner wall area in young horses compared to older horses. This finding suggests that equine airways experience a decrease in the relative abundance of ASM with age. PMID- 28911846 TI - Protein Folding Mediated by Trigger Factor and Hsp70: New Insights from Single Molecule Approaches. AB - Chaperones assist in protein folding, but what this common phrase means in concrete terms has remained surprisingly poorly understood. We can readily measure chaperone binding to unfolded proteins, but how they bind and affect proteins along folding trajectories has remained obscure. Here we review recent efforts by our labs and others that are beginning to pry into this issue, with a focus on the chaperones trigger factor and Hsp70. Single-molecule methods are central, as they allow the stepwise process of folding to be followed directly. First results have already revealed contrasts with long-standing paradigms: rather than acting only "early" by stabilizing unfolded chain segments, these chaperones can bind and stabilize partially folded structures as they grow to their native state. The findings suggest a fundamental redefinition of the protein folding problem and a more extensive functional repertoire of chaperones than previously assumed. PMID- 28911847 TI - Analysis of Structural Features Contributing to Weak Affinities of Ubiquitin/Protein Interactions. AB - Ubiquitin is a small protein that enables one of the most common post translational modifications, where the whole ubiquitin molecule is attached to various target proteins, forming mono- or polyubiquitin conjugations. As a prototypical multispecific protein, ubiquitin interacts non-covalently with a variety of proteins in the cell, including ubiquitin-modifying enzymes and ubiquitin receptors that recognize signals from ubiquitin-conjugated substrates. To enable recognition of multiple targets and to support fast dissociation from the ubiquitin modifying enzymes, ubiquitin/protein interactions are characterized with low affinities, frequently in the higher MUM and lower mM range. To determine how structure encodes low binding affinity of ubiquitin/protein complexes, we analyzed structures of more than a hundred such complexes compiled in the Ubiquitin Structural Relational Database. We calculated various structure based features of ubiquitin/protein binding interfaces and compared them to the same features of general protein-protein interactions (PPIs) with various functions and generally higher affinities. Our analysis shows that ubiquitin/protein binding interfaces on average do not differ in size and shape complementarity from interfaces of higher-affinity PPIs. However, they contain fewer favorable hydrogen bonds and more unfavorable hydrophobic/charge interactions. We further analyzed how binding interfaces change upon affinity maturation of ubiquitin toward its target proteins. We demonstrate that while different features are improved in different experiments, the majority of the evolved complexes exhibit better shape complementarity and hydrogen bond pattern compared to wild-type complexes. Our analysis helps to understand how low affinity PPIs have evolved and how they could be converted into high-affinity PPIs. PMID- 28911848 TI - Detecting weak position fluctuations from encoder signal using singular spectrum analysis. AB - Mechanical fault or defect will cause some weak fluctuations to the position signal. Detection of such fluctuations via encoders can help determine the health condition and performance of the machine, and offer a promising alternative to the vibration-based monitoring scheme. However, besides the interested fluctuations, encoder signal also contains a large trend and some measurement noise. In applications, the trend is normally several orders larger than the concerned fluctuations in magnitude, which makes it difficult to detect the weak fluctuations without signal distortion. In addition, the fluctuations can be complicated and amplitude modulated under non-stationary working condition. To overcome this issue, singular spectrum analysis (SSA) is proposed for detecting weak position fluctuations from encoder signal in this paper. It enables complicated encode signal to be reduced into several interpretable components including a trend, a set of periodic fluctuations and noise. A numerical simulation is given to demonstrate the performance of the method, it shows that SSA outperforms empirical mode decomposition (EMD) in terms of capability and accuracy. Moreover, linear encoder signals from a CNC machine tool are analyzed to determine the magnitudes and sources of fluctuations during feed motion. The proposed method is proven to be feasible and reliable for machinery condition monitoring. PMID- 28911849 TI - Eight new phenylethanoid glycoside derivatives possessing potential hepatoprotective activities from the fruits of Forsythia suspensa. AB - In our study to investigate components with hepatoprotective activities, eight new phenylethanoid glycoside derivatives (1-8) were isolated from the 75% EtOH H2O extract of the fruits of Forsythia suspensa along with six known compounds (9 14). These new structures were elucidated through HRESIMS and extensive NMR spectroscopic techniques. The absolute configurations of their sugars were determined by GC analysis. The pharmacological assay showed that compounds 2, 3, and 9-11 displayed remarkable hepatoprotective activities against N-acetyl-p aminophenol (APAP)-induced HepG2 cell damage at the concentration of 10MUM (Bicyclol as positive contrast). PMID- 28911850 TI - Activation of indoleamine 2, 3- dioxygenase pathway by olanzapine augments antidepressant effects of venlafaxine in mice. AB - Recent clinical studies report antipsychotics as a better option to augment the action of antidepressants in treatment resistant cases. However, the proper mechanisms underlying the antidepressant effect of antipsychotics is still not clear. Indolamine 2, 3 dioxygenase (IDO) pathway is considered to be an important pathway in pro-inflammatory cytokine associated stress-induced depression. The present study investigated the antidepressant effect of venlafaxine, olanzapine and their combinations in chronic forced-swim stress-induced depression in mice. In addition, the role of pro-inflammatory cytokines and IDO-mediated pathway was investigated. Swiss albino mice were subjected to chronic forced-swim stress and evaluation for antidepressant-like activity was performed on 7th, 14th and 21st day following which serum levels of pro-inflammatory cytokines (IL-1beta and IL-6 levels) and the levels of hippocampal kynurenine (KYN), tryptophan (TRP) and serotonin (5HT) were estimated. The combination exhibited augmentation of antidepressant-like activity of venlafaxine by olanzapine in chronic forced-swim stress model. Further, it reversed the enhanced serum IL-1beta and IL-6 and reverted the increased activity of IDO as measured by ratio of hippocampal KYN/TRP and 5HT/TRP in stressed mice. Augmentation of antidepressant effect of venlafaxine by olanzapine is thus mediated by normalising the shift from KYN to TRP pathway in chronic forced swim induced stressed mice. PMID- 28911851 TI - Cortisol awakening response in patients with bipolar disorder during acute episodes and partial remission: A pilot study. AB - This exploratory study examined the cortisol awakening response (CAR) in patients with bipolar disorder (BPD) at acute phases and partial remission of manic or depressive episodes. Saliva samples of twenty-seven BPD inpatients and 25 healthy controls were collected to determine the CAR patterns, and 12 patients were sampled again at partial remission. BPD patients exhibited a non-enhanced CAR pattern. Lower cortisol expression and a blunted CAR distinguished bipolar depressive patients from the controls. The intra-individual follow-up for both patient groups revealed a non-significant improvement in CAR patterns, indicating a trend of a normalized CAR after partial remission for BPD patients. PMID- 28911853 TI - Rebuttal of Atkins et al. (2017) critique of the Ost (2014) meta-analysis of ACT. AB - Atkins et al. strongly criticize my (Ost, 2014) systematic review and meta analysis of ACT. The bulk of their re-examination of my article is divided into four parts: a) Selection of studies, b) Ratings of methodological quality, c) Meta-analysis, and d) Judgments of quality of evidence. It is evident from my paper that I have refuted their claims regarding each of these parts. Regarding a) Selection of studies I showed that only four studies had a cell size of less than 10 and their inclusion did not change the mean effect size or increased variability. Concerning b) Ratings of methodological quality I have showed that my ratings were reliable and had accuracy. As for c) Meta-analysis, I have demonstrated that I got very similar results to those of A-Tjak et al. (2015) that Atkins et al. describes as a much better meta-analysis. Regarding d) Judgments of quality of evidence, Atkins et al. brought up 23 studies for which they argued that I have done an incorrect evaluation but for every single study I have disproved their arguments and maintain my 2014 evaluation of the evidence base of ACT. Thus, there is no reason to follow Atkins et al. suggestion that my review "should now be set aside in making decisions regarding the treatment efficacy of ACT." PMID- 28911852 TI - Molecular epidemiology, resistance, and virulence properties of Pseudomonas aeruginosa cross-colonization clonal isolates in the non-outbreak setting. AB - Pseudomonas aeruginosa is the predominant opportunistic pathogen leading to nosocomial infection and outbreak in hospitals. Hospitalized patients may be infected with this bacterium through close contact with contaminated environmental media. However, the molecular epidemiology, resistance, and virulence properties of Pseudomonas aeruginosa cross-colonization isolates has received limited attention in the non-outbreak setting. This study aims to investigate the epidemiological relationship of clinical and environmental P. aeruginosa isolates and to characterize the resistance and virulence properties of clonal clusters and sporadic strains in a non-outbreak setting. A total of 436 patients were screened for P. aeruginosa during hospitalization, and environmental samples were taken from their immediate ward media, including faucets, doorknobs, bedrails, pillows, quilts, and mattresses. As a result, 100 P. aeruginosa isolates were obtained, including 74 clinical strains and 26 environmental strains. By using Pulsed-Field Gel Electrophoresis, the fingerprint displayed 20 distinct clusters and 44 sporadic strains. According to identical genotypes, there were clear P. aeruginosa cross-colonization processes from the ward media to inpatients, indicating faucets, bedrails, and pillows as the main propagation media that had been contaminated by clonal isolates previously detected in other patients. In addition, there were P. aeruginosa transmission processes between inpatients that were unexplained for lack of epidemiological evidence. As compared to sporadic strains of P. aeruginosa, clonal clusters are more capable of producing high-level biofilm, developing multi-drug resistance and inducing high-degree cytotoxicity. Among P. aeruginosa clonal clusters, there was a strong positive correlation between antibiotic resistance and biofilm production. We conclude that constant cross-colonization of P. aeruginosa clonal isolates will pose a long-term serious threat in terms of nosocomial outbreaks. Thus, strict disinfection and sterilization procedures should be implemented for ward media, and P. aeruginosa in environments and patients should be closely monitored, especially those strains with strong resistance and virulence. PMID- 28911854 TI - Resumption of ovarian function, the metabolic profile and body condition in Brahman cows (Bos indicus) is not affected by the combination of calf separation and progestogen treatment. AB - To evaluate the effect of different calf separation procedures after a progestogen treatment on the resumption of ovarian function, body condition and metabolic profile, 59 multiparous Brahman cows grazing on a mixed grass pasture were studied. No supplementation was given at any time. Body condition score (BCS), fat thickness (FAT) and blood metabolites were measured fortnightly from the beginning of the last trimester of gestation until 96days postpartum. At 30days postpartum all animals received a progesterone (P4)-releasing device (CIDR) which was withdrawn 9days later when prostaglandin F2alpha was applied. At this time, treatments TW (n=28), where calves were separated from their dams for 48h; RS (n=21), calves were allowed to suckle once a day for 1h; and continuous suckling (CS; n=10). Ovarian function was assessed by blood concentrations of progesterone on days -14, -9, 10, 13, 30 and 33 after CIDR removal. At the end of the experimental period, an average of 20% of the cows had not initiated estrous cycles. There were no changes of FAT or BCS during the last trimester of pregnancy in all cows (P>0.05). During the postpartum period cows of all groups lost (P<0.05) BCS and FAT with a nadir at 60-80days postpartum, regardless of treatment. At 10days after CIDR withdrawal the percentage of cows having ovulations was 75, 61 and 80 (P>0.05) for TW, RS and CS groups. Blood metabolites follow a similar pattern in the three groups. With the conditions of the present study, the method of calf separation after a progestogen treatment, does not affect the resumption of ovarian function or metabolic profile. PMID- 28911856 TI - Correction. PMID- 28911857 TI - New mouse model for inducing and evaluating unilateral vestibular deafferentation syndrome. AB - BACKGROUND: Unilateral vestibular deafferentation syndrome (uVDS) holds a particular place in the vestibular pathology domain. Due to its suddenness, the violence of its symptoms that often result in emergency hospitalization, and its associated original neurophysiological properties, this syndrome is a major source of questioning for the otoneurology community. Also, its putative pathogenic causes remain to be determined. There is currently a strong medical need for the development of targeted and effective countermeasures to improve the therapeutic management of uVDS. NEW METHODS: The present study reports the development of a new mouse model for inducing and evaluating uVDS. Both the method for generating controlled excitotoxic-type peripheral vestibular damages, through transtympanic administration of the glutamate receptors agonist kainate (TTK), and the procedure for evaluating the ensuing clinical signs are detailed. COMPARISON WITH EXISTING METHODS: Through extensive analysis of the clinical symptoms characteristics, this new animal model provides the opportunity to better follow the temporal evolution of various uVDS specific symptoms, while better appreciating the different phases that composed this syndrome. RESULTS: The uVDS evoked in the TTK mouse model displays two main phases distinguishable by their kinetics and amplitudes. Several parameters of the altered vestibular behaviour mimic those observed in the human syndrome. CONCLUSION: This new murine model brings concrete information about how uVDS develops and how it affects global behaviour. In addition, it opens new opportunity to decipher the etiopathological substrate of this pathology by authorizing the use of genetically modified mouse models. PMID- 28911855 TI - Conformationally constrained peptides target the allosteric kinase dimer interface and inhibit EGFR activation. AB - Although EGFR is a highly sought-after drug target, inhibitor resistance remains a challenge. As an alternative strategy for kinase inhibition, we sought to explore whether allosteric activation mechanisms could effectively be disrupted. The kinase domain of EGFR forms an atypical asymmetric dimer via head-to-tail interactions and serves as a requisite for kinase activation. The kinase dimer interface is primarily formed by the H-helix derived from one kinase monomer and the small lobe of the second monomer. We hypothesized that a peptide designed to resemble the binding surface of the H-helix may serve as an effective disruptor of EGFR dimerization and activation. A library of constrained peptides was designed to mimic the H-helix of the kinase domain and interface side chains were optimized using molecular modeling. Peptides were constrained using peptide "stapling" to structurally reinforce an alpha-helical conformation. Peptide stapling was demonstrated to notably enhance cell permeation of an H-helix derived peptide termed EHBI2. Using cell-based assays, EHBI2 was further shown to significantly reduce EGFR activity as measured by EGFR phosphorylation and phosphorylation of the downstream signaling substrate Akt. To our knowledge, this is the first H-helix-based compound targeting the asymmetric interface of the kinase domain that can successfully inhibit EGFR activation and signaling. This study presents a novel, alternative targeting site for allosteric inhibition of EGFR. PMID- 28911858 TI - Corrigendum to "What affects public acceptance of recycled and desalinated water?" [Water Res. 45 (2) (2011) pp. 933-943]. PMID- 28911859 TI - Recent development of signaling pathways inhibitors of melanogenesis. AB - Human skin, eye and hair color rely on the production of melanin, depending on its quantity, quality, and distribution, Melanin plays a monumental role in protecting the skin against the harmful effect of ultraviolet radiation and oxidative stress from various environmental pollutants. However, an excessive production of melanin causes serious dermatological problems such as freckles, solar lentigo (age spots), melasma, as well as cancer. Hence, the regulation of melanin production is important for controlling the hyper-pigmentation. Melanogenesis, a biosynthetic pathway to produce melanin pigment in melanocyte, involves a series of intricate enzymatic and chemical catalyzed reactions. Several extrinsic factors include ultraviolet radiation and chemical drugs, and intrinsic factors include molecules secreted by surrounding keratinocytes or melanocytes, and fibroblasts, all of which regulate melanogenesis. This article reviews recent advances in the development of melanogenesis inhibitors that directly/indirectly target melanogenesis-related signaling pathways. Efforts have been made to provide a description of the mechanism of action of inhibitors on various melanogenesis signaling pathways. PMID- 28911860 TI - Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal. AB - Low glucose stimulated phosphorylation of pregnane X receptor (PXR) at Ser350 in correlation with an increased gluconeogenesis in human hepatoma-derived HepG2 cells. Only glucose, but neither insulin nor glucagon, stimulated this phosphorylation. Here, serine/threonine kinase, vaccinia related kinase 1 (VRK1) mediated phosphorylation of PXR is now defined as this glucose-elicited novel signal. In low glucose conditions, VRK1 directly phosphorylates PXR at Ser350, enabling PO3-PXR to scaffold protein phosphatase PP2Calpha. This PP2Calpha dephosphorylates serine/threonine kinase 2 (SGK2) at Thr193. This dephosphorylation dissociates SGK2 from and actives the phosphoenolpyruvate carboxykinase 1 (PCK1) gene as phosphorylated SGK2 binds and represses the gene. Conversely, VRK1 self-represses its activity to phosphorylate PXR through cyclin dependent kinase 2 (CDK2) in high glucose conditions, resulting in the repression of the PCK1 gene. This PXR phosphorylation was also observed in fasting mouse livers. Thus, the VRK1-CDK2-PXR-PP2Calpha-SGK2 pathway can be a novel physiological cell signaling that regulates gluconeogenesis in response to glucose. PMID- 28911861 TI - The perspective of the person in healthcare: Listening to and engaging persons in healthcare. PMID- 28911862 TI - Fatty acid binding protein (Fabp) 5 interacts with the calnexin cytoplasmic domain at the endoplasmic reticulum. AB - Calnexin is a type 1 integral endoplasmic reticulum membrane molecular chaperone with an endoplasmic reticulum luminal chaperone domain and a highly conserved C terminal domain oriented to the cytoplasm. Fabp5 is a cytoplasmic protein that binds long-chain fatty acids and other lipophilic ligands. Using a yeast two hybrid screen, immunoprecipitation, microscale thermophoresis analysis and cellular fractionation, we discovered that Fabp5 interacts with the calnexin cytoplasmic C-tail domain at the endoplasmic reticulum. These observations identify Fabp5 as a previously unrecognized calnexin binding partner. PMID- 28911863 TI - The crystal structure of the Pyrococcus abyssi mono-functional methyltransferase PaTrm5b. AB - The wyosine hypermodification found exclusively at G37 of tRNAPhe in eukaryotes and archaea is a very complicated process involving multiple steps and enzymes, and the derivatives are essential for the maintenance of the reading frame during translation. In the archaea Pyrococcus abyssi, two key enzymes from the Trm5 family, named PaTrm5a and PaTrm5b respectively, start the process by forming N1 methylated guanosine (m1G37). In addition, PaTrm5a catalyzes the further methylation of C7 on 4-demethylwyosine (imG-14) to produce isowyosine (imG2) at the same position. The structural basis of the distinct methylation capacities and possible conformational changes during catalysis displayed by the Trm5 enzymes are poorly studied. Here we report the 3.3 A crystal structure of the mono-functional PaTrm5b, which shares 32% sequence identity with PaTrm5a. Interestingly, structural superposition reveals that the PaTrm5b protein exhibits an extended conformation similar to that of tRNA-bound Trm5b from Methanococcus jannaschii (MjTrm5b), but quite different from the open conformation of apo PaTrm5a or well folded apo-MjTrm5b reported previously. Truncation of the N terminal D1 domain leads to reduced tRNA binding as well as the methyltransfer activity of PaTrm5b. The differential positioning of the D1 domains from three reported Trm5 structures were rationalized, which could be attributable to the dissimilar inter-domain interactions and crystal packing patterns. This study expands our understanding on the methylation mechanism of the Trm5 enzymes and wyosine hypermodification. PMID- 28911864 TI - Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps. AB - Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a transmembrane domain, a signal-transducing HAMP domain, a dimerization and histidine phospho-acceptor sub-domain (DHp) and a catalytic and ATP-binding subdomain (CA). The key activation event involves the rearrangement of the HAMP DHp helical core and translation of the CA towards the acceptor histidine, which presumably results in an autokinase-competent complex. In the present work we integrate coarse-grained, all-atom, and hybrid QM-MM computer simulations to probe the large-scale conformational reorganization that takes place from the inactive to the autokinase-competent state (conformational step), and evaluate its relation to the autokinase reaction itself (chemical step). Our results highlight a tight coupling between conformational and chemical steps, underscoring the advantage of CA walking along the DHp core, to favor a reactive tautomeric state of the phospho-acceptor histidine. The results not only represent an example of multiscale modelling, but also show how protein dynamics can promote catalysis. PMID- 28911865 TI - 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) ameliorated dexamethasone induced hepatic gluconeogenesis through activation of Akt/FoxO1 pathway. AB - 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) is identified as a selective SphK2 inhibitor. It was previously reported as an anti-tumor agent, in this study we demonstrated that K145 was able to regulate hepatic gluconeogenesis and improve glucose intolerance in mice. C57BL/6 mice treated with dexamethasone injection were used as experimental animals, which exhibited impaired glucose tolerance and increased gluconeogenetic enzymes. After K145 treatment, we found that the impairment of glucose tolerance and gluconeogenetic genes mRNA expression were improved. Besides, both in vivo and in votro studies suggested that K145 stimulated insulin dependent Akt phosphorylation and subsequently activates FoxO1 phosphorylation therefore inhibited gluconeogenetic genes expression including PEPCK and G6pase. Our study figures out a potential extent increase the value of developing K145 as therapeutic candidate for diabetes. PMID- 28911866 TI - Molecular dynamics simulations of stratum corneum lipid mixtures: A multiscale perspective. AB - The lipid matrix of the stratum corneum (SC) layer of skin is essential for human survival; it acts as a barrier to prevent rapid dehydration while keeping potentially hazardous material outside the body. While the composition of the SC lipid matrix is known, the molecular-level details of its organization are difficult to infer experimentally, hindering the discovery of structure-property relationships. To this end, molecular dynamics simulations, which give molecular level resolution, have begun to play an increasingly important role in understanding these relationships. However, most simulation studies of SC lipids have focused on preassembled bilayer configurations, which, owing to the slow dynamics of the lipids, may influence the final structure and hence the calculated properties. Self-assembled structures would avoid this dependence on the initial configuration, however, the size and length scales involved make self assembly impractical to study with atomistic models. Here, we report on the development of coarse-grained models of SC lipids designed to study self assembly. Building on previous work, we present the interactions between the headgroups of ceramide and free fatty acid developed using the multistate iterative Boltzmann inversion method. Validation of the new interactions is performed with simulations of preassembled bilayers and good agreement between the atomistic and coarse-grained models is found for structural properties. The self-assembly of mixtures of ceramide and free fatty acid is investigated and both bilayer and multilayer structures are found to form. This work therefore represents a necessary step in studying SC lipid systems on multiple time and length scales. PMID- 28911867 TI - Population dynamics of neural progenitor cells during aging in the cerebral cortex. AB - Recent studies indicate that adult neurogenesis occurs in the cerebral cortex of rodents. Neural progenitor cells (NPCs) have been found in the adult cerebral cortex. These cells are expected to be regulated by various stimuli, including environmental enrichment, exercise, learning, and stress. However, it is unclear what stimuli can regulate cortical NPCs. In this study, we examined whether aging has an impact on population dynamics of NPCs in the murine cerebral cortex, using immunohistological staining for NPCs. The density of NPCs was kept from 5- to 12 month-old, dramatically decreased at 17-month-old, and thereafter maintained the same level until 24-month-old. Comparing the densities of NPCs in the cortical areas, such as the cingulate, primary motor, primary somatosensory, and insular cortices, we found that the degrees of decreased densities of NPCs in the cingulate and insular cortices were significantly smaller than those in the primary motor and somatosensory cortices. NPCs in aged cortex produced new neurons by ischemia. These results indicate that in aged mice, NPCs exist and produce new neurons in the cerebral cortex. Additionally, the extent of reduction of the density of NPCs in the cortices with higher cognitive functions may be less than that in the primary motor and somatosensory cortices. PMID- 28911868 TI - Central and peripheral expression sites of phoenixin-14 immunoreactivity in rats. AB - Phoenixin is a pleiotropic peptide involved in reproduction, anxiety and recently also implicated in the control of food intake. Besides the 20-amino acid phoenixin, the 14-amino acid phoenixin-14 also shows bioactive properties. However, the expression sites of phoenixin-14 in the brain and peripheral tissues are not yet described in detail. Therefore, a mapping of the brain and peripheral tissues from male and female Sprague-Dawley rats with a specific phoenixin-14 antibody was performed using western blot and immunohistochemistry. High density of phoenixin-14 immunoreactivity was detected in the medial division of the brain central amygdaloid nucleus, in the spinal trigeminal tract and in the spinocerebellar tract as well as in cells between the crypts of duodenum, jejunum and ileum. Medium density immunoreactivity was observed in the bed nucleus of the stria terminalis, in the area postrema, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve as well as in the peripheral parts of the islets of Langerhans in the pancreas. A low density of phoenixin-14 immunoreactivity was detected in the arcuate nucleus, the supraoptic nucleus and the raphe pallidus. After pre-absorption of the antibody with phoenixin-14 peptide, no immunosignals were observed indicating specificity of the antibody. Taken together, the widespread distribution of phoenixin-14 immunoreactivity gives additional rise to the pleiotropic functions of the peptide such as possible effects in gastrointestinal motility, immune functions and glucose homeostasis. PMID- 28911869 TI - Degradation of nuclear Ubc9 induced by listeriolysin O is dependent on K+ efflux. AB - Listeriolysin O (LLO) is a pore-forming toxin produced by L. monocytogenes, and is belonged to a protein family of cholesterol-dependent cytolysins (CDCs). Previous studies have demonstrated that LLO triggers Ubc9 degradation and disrupts host SUMOylation to facilitate bacterial infection. However, the underlying mechanism of Ubc9 degradation is unclear. Here we show that LLO induced down-regulation of Ubc9 is independent of Ubc9-SUMO interaction, however, it may involve phosphorylation signaling. Additionally, LLO exerts its effects primarily on nuclear Ubc9 and this process is mediated by K+ efflux. Interestingly, for intracellular CDCs such as pneumolysin and suilysin, blockage of K+ efflux enhances degradation of nuclear Ubc9, suggesting that extracellular and intracellular pathogens may exploit different mechanisms to modulate host SUMOylation system. Furthermore, up-regulation of SUMOylation by stable expression of SUMO-1 or SUMO-2 shows a delay in membrane perforation by LLO, indicating that SUMO modification of host proteins may act at the frontline for the defense response against LLO. Taken together, our study provides insights to the understanding of host-pathogen interactions. PMID- 28911871 TI - Correction. PMID- 28911872 TI - Correction. PMID- 28911870 TI - Microplastics releasing from personal care and cosmetic products in China. AB - Microplastics (MPs) have become a major global issue; their release from various products affects the aquatic environment, especially marine ecosystems. As a primary source of MPs, personal care and cosmetics products (PCCPs) containing MPs contribute to this environmental risk. We visited several supermarket chains in Beijing, China to identify PCCPs containing MPs. Overall, 7.1% of facial cleansers contained MPs, with an average weight of 25.04+/-10.69mgMP/g and average size of 313+/-130MUm; whereas, 2.2% of shower gel products contained an average weight of 17.80+/-7.50mgMPs/g with an average size of 422+/-185MUm. The majority of MPs were made of polyethylene, based on Raman and Fourier transform infrared spectra analyses, while only a few were made of walnut shells and carbon particles. Finally, estimated 39tons MPs were released into the environment based on PCCPs use in China based on available data. PMID- 28911873 TI - Correction. PMID- 28911875 TI - Letter on the article "Supplementation with 80,000 UI vitamin D3/month between November and April corrects vitamin D insufficiency without overdosing: Effect on serum 25-hydroxyvitamin D serum concentrations". PMID- 28911874 TI - Childhood adversity predicts reduced physiological flexibility during the processing of negative affect among adolescents with major depression histories. AB - BACKGROUND: Adversity during early development has been shown to have enduring negative physiological consequences. In turn, atypical physiological functioning has been associated with maladaptive processing of negative affect, including its regulation. The present study therefore explored whether exposure to adverse life events in childhood predicted maladaptive (less flexible) parasympathetic nervous system functioning during the processing of negative affect among adolescents with depression histories. METHODS: An initially clinic-referred, pediatric sample (N=189) was assessed at two time points. At Time 1, when subjects were 10.17years old (SD=1.42), on average, and were depressed, parents reported on adverse life events the offspring experienced up to that point. At Time 2, when subjects were 17.18years old (SD=1.28), and were remitted from depression, parents again reported on adverse life events in their offspring's lives for the interim period. At time 2, subjects' parasympathetic nervous system functioning (quantified as respiratory sinus arrhythmia) also was assessed at rest, during sad mood induction, and during instructed mood repair. RESULTS: Extent of adverse life events experienced by T1 (but not events occurring between T1 and T2) predicted less flexible RSA functioning 7years later during the processing of negative affect. Adolescents with more extensive early life adversities exhibited less vagal withdrawal following negative mood induction and tended to show less physiological recovery following mood repair. CONCLUSIONS: Early adversities appear to be associated with less flexible physiological regulatory control during negative affect experience, when measured later in development. Stress related autonomic dysfunction in vulnerable youths may contribute to the unfavorable clinical prognosis associated with juvenile-onset depression. PMID- 28911876 TI - Immunoglobulin isotype switching of antibodies to vimentin is associated with development of transplant glomerulopathy following human renal transplantation. AB - BACKGROUND: Immune responses to tissue-restricted self-antigens are thought to play a role in chronic rejection after solid organ transplantation. De novo development of antibodies (Abs) to vimentin have been reported to be associated with interstitial fibrosis/tubular atrophy after kidney transplant, and it has been suggested that immunoglobulin isotype switching of Abs to vimentin may occur during this process. We aimed to determine the correlation between immunoglobulin isotype switching of Abs to vimentin and development of transplant glomerulopathy (TG) after kidney transplant, and to determine whether citrullinated modification of vimentin is required for de novo anti-vimentin development. METHODS: Sera were collected from 24 patients with TG (diagnosed on biopsy), 24 matched stable kidney transplant recipients (KTxRs) and 22 normal healthy subjects who did not undergo transplant. Serum vimentin Abs concentrations were measured using enzyme linked immunosorbent assay (ELISA). Immunoglobulin isotypes of anti-vimentin were determined using isotype-specific Abs conjugated with horseradish peroxidase. Samples were considered positive to vimentin Abs if the values were above mean+2* standard deviations of the levels in the healthy control subjects. Specificities of anti-vimentin for mutated citrullinated vimentin and anti-mutated citrullinated vimentin were measured by ELISA. RESULTS: In this retrospective analysis of 24 KTxRs with TG, 16/24 (67%) patients with biopsy-proven TG developed Abs to vimentin (645+/-427ng/ml). In contrast, only 4/24 (17%) stable KTxRs had detectable Abs to vimentin (275+/-293ng/ml; p=0.001). Of the patients with TG, 15/24 (63%) developed Abs to vimentin of IgG isotype (572+/-276ng/ml), whereas only 6/24 (25%) stable KTxRs (310+/-288ng/ml) had anti-vimentin of IgG isotype (p=0.002). However, no significant difference was noted in the concentration of IgM isotype anti-vimentin between KTxRs with TG (9/24 [38%], 407+/-401ng/ml) and stable KTxRs (5/24 [21%], 348+/-439ng/ml; p=0.631). The serum concentration of Abs specific for the mutated form of citrullinated vimentin was not significantly different between KTxRs with TG and stable KTxRs. CONCLUSIONS: Patients with biopsy-proven TG demonstrated significantly increased levels of anti-vimentin Abs of the IgG isotype compared with stable KTxRs. Anti-vimentin in stable KTxRs was primarily of IgM isotype. Therefore, the observed isotype switching of anti-vimentin from IgM to IgG isotype strongly suggests ongoing immune responses to vimentin in KTxRs diagnosed with TG. Furthermore, as opposed to patients with rheumatoid arthritis (who develop immune responses primarily to citrullinated vimentin), KTxRs diagnosed with TG developed immune responses to non-citrullinated vimentin, suggesting that modification of vimentin protein via citrullination is not required for the de novo anti-vimentin response seen in patients with TG. PMID- 28911877 TI - Validity and reliability of naturalistic driving scene categorization Judgments from crowdsourcing. AB - A common challenge with processing naturalistic driving data is that humans may need to categorize great volumes of recorded visual information. By means of the online platform CrowdFlower, we investigated the potential of crowdsourcing to categorize driving scene features (i.e., presence of other road users, straight road segments, etc.) at greater scale than a single person or a small team of researchers would be capable of. In total, 200 workers from 46 different countries participated in 1.5days. Validity and reliability were examined, both with and without embedding researcher generated control questions via the CrowdFlower mechanism known as Gold Test Questions (GTQs). By employing GTQs, we found significantly more valid (accurate) and reliable (consistent) identification of driving scene items from external workers. Specifically, at a small scale CrowdFlower Job of 48 three-second video segments, an accuracy (i.e., relative to the ratings of a confederate researcher) of 91% on items was found with GTQs compared to 78% without. A difference in bias was found, where without GTQs, external workers returned more false positives than with GTQs. At a larger scale CrowdFlower Job making exclusive use of GTQs, 12,862 three-second video segments were released for annotation. Infeasible (and self-defeating) to check the accuracy of each at this scale, a random subset of 1012 categorizations was validated and returned similar levels of accuracy (95%). In the small scale Job, where full video segments were repeated in triplicate, the percentage of unanimous agreement on the items was found significantly more consistent when using GTQs (90%) than without them (65%). Additionally, in the larger scale Job (where a single second of a video segment was overlapped by ratings of three sequentially neighboring segments), a mean unanimity of 94% was obtained with validated-as-correct ratings and 91% with non-validated ratings. Because the video segments overlapped in full for the small scale Job, and in part for the larger scale Job, it should be noted that such reliability reported here may not be directly comparable. Nonetheless, such results are both indicative of high levels of obtained rating reliability. Overall, our results provide compelling evidence for CrowdFlower, via use of GTQs, being able to yield more accurate and consistent crowdsourced categorizations of naturalistic driving scene contents than when used without such a control mechanism. Such annotations in such short periods of time present a potentially powerful resource in driving research and driving automation development. PMID- 28911878 TI - Comparison of proposed countermeasures for dilemma zone at signalized intersections based on cellular automata simulations. AB - The Type II dilemma zone describes the road segment to a signalized intersection where drivers have difficulties to decide either stop or go at the onset of yellow signal. Such phenomenon can result in an increased crash risk at signalized intersections. Different types of warning systems have been proposed to help drivers make decisions. Although the warning systems help to improve drivers' behavior, they also have several disadvantages such as increasing rear end crashes or red-light running (RLR) violations. In this study, a new warning system called pavement marking with auxiliary countermeasure (PMAIC) is proposed to reduce the dilemma zone and enhance the traffic safety at signalized intersections. The proposed warning system integrates the pavement marking and flashing yellow system which can provide drivers with better suggestions about stop/go decisions based on their arriving time and speed. In order to evaluate the performance of the proposed warning system, this paper presents a cellular automata (CA) simulation study. The CA simulations are conducted for four different scenarios in total, including the typical intersection without warning system, the intersection with flashing green countermeasure, the intersection with pavement marking, and the intersection with the PMAIC warning system. Before the specific CA simulation analysis, a logistic regression model is calibrated based on field video data to predict drivers' general stop/go decisions. Also, the rules of vehicle movements in the CA models under the influence by different warning systems are proposed. The proxy indicators of rear-end crash and potential RLR violations were estimated and used to evaluate safety levels for the different scenarios. The simulation results showed that the PMAIC countermeasure consistently offered best performance to reduce rear-end crash and RLR violation. Meanwhile, the results indicate that the flashing-green countermeasure could not effectively reduce either rear-end crash risk or RLR violations. Also, it is found that the pavement-marking countermeasure has positive effects on reducing the rear-end risk while it may increase the probability of RLR violation. Lastly, the implementation of the proposed warning system is discussed with the consideration of connected-vehicle technology. It is expected that the dilemma zone issues can be efficiently addressed if the proposed countermeasure can be employed within connected vehicle technology. PMID- 28911879 TI - Corrigendum to "Biosynthesis and chemical transformation of benzoxazinoids in rye during seed germination and the identification of a rye Bx6-like gene" [Phytochemistry 140 (2017) 95-107]. PMID- 28911880 TI - Pelvic exenteration for gynecologic malignancies: Postoperative complications and oncologic outcomes. AB - INTRODUCTION AND OBJECTIVE: To evaluate complications, morbidity and oncologic outcomes of pelvic exenteration as treatment for gynecologic malignancies. MATERIALS AND METHODS: Between 2008 and 2015, a total of 35 patients underwent pelvic exenteration, due to recurrence of gynecological cancer. Surgical outcomes, early and late postoperative complications, and recurrence/survival outcomes were assessed. RESULTS: Mean patient age was 53.8 years. Anterior exenteration was done in 20 patients, while 15 were total exenterations. Ileal conduit was done in 24 patients, while 8 received a neobladder and 3 a cutaneous ureterostomy. Postoperative complications were divided in 2groups, early (<30 days) and late complications (>30 days). A total of 25 patients (71.4%) had one or more early complications; 16 (45.7%) had fever due to a urinary tract infection, pyelonephritis or intra-abdominal collection; 2 (5.7%) developed a vesicovaginal fistula; 4 (11.4%) a rectovaginal fistula; 3 (8.5%) acute kidney failure and one (2.85%) uronephrosis. Regarding to late complications, 8patients (22.8%) had fever. Six (17%) presented with uronephrosis, and 5 (14.2%) with ureteral-pouch stricture. Five patients (14.2%) had acute renal insufficiency, 3 (8,6%) rectovaginal fistula and one (2.85%) urinary fistula. Mean follow up time was 20.3 month (2-60). A total of 22patients (62.8%) were free of disease. Another 13 (37.1%) patients relapsed. Only 4 (11.4%) patients died after pelvic exenteration due to underlying disease. CONCLUSION: Pelvic exenteration has a high rate of complications and morbidity, but can be the last curative opportunity in patients with recurrent or persistent gynecologic malignancies. This procedure should be performed by multidisciplinary, experienced teams in a tertiary medical center. PMID- 28911881 TI - Tailoring the orthopaedic consultation: How perceived patient characteristics influence surgeons' communication. AB - OBJECTIVE: To investigate whether and how orthopaedic surgeons tailor communication during medical consultations based on perceived patient characteristics. METHODS: Seven orthopaedic surgeons were repeatedly interviewed following an approach based on ecological momentary assessment. Qualitative content analysis was used to analyse the eighty short interviews. The association between patient characteristics and tailoring approaches was explored in a correspondence analysis of the counted codes. RESULTS: Surgeons estimate patients' competence (illness management and communication abilities), autonomy, and interpersonal behaviour. They report tailoring communication in two-thirds of the consultations. The surgeons' perception was associated with the employment of specific approaches to communication: (1) high patient competence with extensive information provision or no changes in communication, (2) less autonomy and less competence with reassurance and direction, (3) high autonomy with discussions about pace and expectations, and (4) high sociability with communication about personal circumstances and wishes. CONCLUSION: The surgeon's perception of a patient influences communication during consultations. Future research should address whether these intuitively employed approaches are appropriate, effective, and generalizable to other medical specialists. PRACTICE IMPLICATIONS: Tailoring physician-patient communication can improve its quality. The novel approaches identified in this study can be used to formulate and test formal guidelines for tailored communication. PMID- 28911882 TI - Aromatase inhibitors: A new approach for controlling ovarian function in cattle. AB - Numerous treatments and protocols have been used to control the reproductive cycle in cattle, with varying effectiveness and many involving the administration of steroid hormones. Steroid hormones, such as estradiol, are perceived as having a negative impact on consumer health. This internationally shared opinion has led to a ban on the use of steroid hormones in food producing animals in many countries (i.e., European Union, New Zealand, and Australia). Letrozole, a non steroidal aromatase inhibitor, inactivates the aromatase enzyme responsible for the synthesis of estrogens by reversibly binding to the "heme" group of the P450 subunit. Letrozole is approved as an adjuvant or first-line treatment for hormone dependent breast cancer in post-menopausal women, but has been used increasingly for ovulation induction in the treatment of infertility in women. Using the bovine model to determine the effects on ovarian function, letrozole treatment was found to extend the lifespan of the dominant follicle and thereby delay emergence of the next follicle wave and/or ovulation. Letrozole treatment also had a luteotrophic effect; that is, larger CL and/or higher circulating concentrations of progesterone were detected in letrozole-treated heifers. Results of the initial studies in cattle provided the impetus for the development of aromatase inhibitor-based synchronization and fertility treatment in cattle. Biologically active concentrations of letrozole were achieved via intravenous, intramuscular or intravaginal administration, but the intravaginal route of administration is of particular interest because it permits extended and defined treatment periods, is minimally invasive, and reduces animal handling. Recent results revealed that irrespective of the stage of the cycle, a 4-day letrozole based protocol induced ovulation in a significantly greater proportion of animals and with significantly greater synchrony than the control treatment. Evidence and reasons for the increasing use of programmed breeding and fixed-time artificial insemination are discussed in this review as a background to current development of an innovative aromatase inhibitor-based protocol as a safe and effective method of controlling the estrous cycle and ovulation in cattle. PMID- 28911885 TI - Yours, Mine, Ours......data sharing in clinical research. PMID- 28911883 TI - TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection in vivo. AB - We have studied the role of the tumor necrosis factor superfamily member APRIL in the development of embryonic mouse midbrain dopaminergic neurons in vitro and in vivo. In culture, soluble APRIL enhanced axon growth during a window of development between E12 and E14 when nigrostriatal axons are growing to their targets in the striatum in vivo. April transcripts were detected in both the striatum and midbrain during this period and at later stages. The axon growth enhancing effect of APRIL was similar to that of glial cell-derived neurotrophic factor (GDNF), but in contrast to GDNF, APRIL did not promote the survival of midbrain dopaminergic neurons. The effect of APRIL on axon growth was prevented by function-blocking antibodies to one of its receptors, BCMA (TNFRSF13A), but not by function-blocking antibodies to the other APRIL receptor, TACI (TNFRSF13B), suggesting that the effects of APRIL on axon growth are mediated by BCMA. In vivo, there was a significant reduction in the density of midbrain dopaminergic projections to the striatum in April-/- embryos compared with wild type littermates at E14. These findings demonstrate that APRIL is a physiologically relevant factor for the nigrostriatal projection. Given the importance of the degeneration of dopaminergic nigrostriatal connections in the pathogenesis and progression of Parkinson's disease, our findings contribute to our understanding of the factors that establish nigrostriatal integrity. PMID- 28911884 TI - Anti-VEGF treatment improves neurological function in tumors of the nervous system. AB - Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas. PMID- 28911886 TI - Implementation of the Practice Standards for Specialist Critical Care Nurses in Australia. PMID- 28911887 TI - Response to "Implementation of the Practice Standards for Specialist Critical Care Nurses in Australia". PMID- 28911888 TI - Postoperative imaging of orthopaedic hardware in the hand and wrist: is there an added value for tomosynthesis? AB - AIM: To prospectively investigate digital tomosynthesis (DTS) as an alternative to digital radiography (DR) for postoperative imaging of orthopaedic hardware after trauma or arthrodesis in the hand and wrist. MATERIALS AND METHODS: Thirty six consecutive patients (12 female, median age 36 years, range 19-86 years) were included in this institutional review board approved clinical trial. Imaging was performed with DTS in dorso-palmar projection and DR was performed in dorso palmar, lateral, and oblique views. Images were evaluated by two independent radiologists for qualitative and diagnosis-related imaging parameters using a four-point Likert scale (1=excellent, 4not diagnostic) and nominal scale. Interobserver agreement between the two readers was assessed with Cohen's kappa (k). Differences between DTS and CR were tested with Wilcoxon's signed-rank test. A p-value <0.05 was considered statistically significant. RESULTS: Regarding image quality, interobserver agreement was higher for DTS compared to DR, especially for fracture-related parameters (delineation osteosynthesis material [OSM]: KDTS0.96 versus KDR0.45; delineation fracture margins: KDTS0.78 versus KDR0.35). Delineation of fracture margins and delineation of adjacent joint spaces scored significant better for DTS compared to DR (delineation fracture margins: DTS1.54, DR2.28, p0.001; delineation adjacent joint spaces: DTS1.31, DR2.24, p0.001). Regarding diagnosis-related findings, interobserver agreement was almost equal. DTS showed a significant higher sharpness of fracture margins (DTS1.94, DR2.33, p0.04). Mean dose area product (DAP) for DTS was significant higher compared to DR (mean DR0.219 Gy.cm2, mean DTS0.903 Gy.cm2, p0.001). CONCLUSION: Fracture healing is more visible and interobserver agreement is higher for DTS compared to DR in the postoperative assessment of orthopaedic hardware in the hand and wrist. PMID- 28911890 TI - Three-dimensional imaging, an important factor of decision in breast augmentation. AB - INTRODUCTION: Since the beginning of the 21st century, three-dimensional imaging systems have been used more often in plastic surgery, especially during preoperative planning for breast surgery and to simulate the postoperative appearance of the implant in the patient's body. The main objective of this study is to assess the patients' attitudes regarding 3D simulation for breast augmentation. METHOD: A study was conducted, which included women who were operated on for primary breast augmentation. During the consultation, a three dimensional simulation with Crisalix was done and different sized implants were fitted in the bra. RESULTS: Thirty-eight women were included. The median age was 29.4, and the median prosthesis volume was 310mL. The median rank given regarding the final result was 9 (IQR: 8-9). Ninety percent of patients agreed (66% absolutely agreed, and 24% partially agreed) that the final product after breast augmentations was similar to the Crisalix simulation. Ninety-three percent of the patients believed that the three-dimensional simulation helped them choose their prosthesis (61% a lot and 32% a little). After envisaging a breast enlargement, patients estimated that the Crisalix system was absolutely necessary (21%), very useful (32%), useful (45%), or unnecessary (3%). Regarding prosthesis choice, an equal number of women preferred the 3D simulation (19 patients) as preferred using different sizes of implants in the bra (19 patients). CONCLUSION: The present study demonstrated that 3D simulation is actually useful for patients in order to envisage a breast augmentation. But it should be used as a complement to the classic method of trying different sized breast implants in the bra. PMID- 28911889 TI - [Benefits of volumetric to facial rejuvenation. Part 2: Dermal fillers]. AB - Injectable substances known as fillers are used to palliate age-related atrophy and ptosis, and for their so-called "pseudo-lifting" action. They do not replace face and neck lift, but allow it to be postponed or, when injected after surgical lifting, make the result durable. Hyaluronic acid has a predominant and unchallenged place among fillers, well ahead of poly-L-lactic acid or calcium hydroxyapatite. Approaches and injection methods are the same for all fillers, corresponding to those for autologous fat injection, the reference substance, with a few particularities. The substance used, the level of hyaluronic acid reticulation, and the depth of the injection depend on the injection site and intended effect. Effects range from smoothing superficial wrinkles to remodeling whole parts of the face. Complications related to such fillers are well known, especially in the case of hyaluronic acid, where overcorrection is the most frequent. To limit the risk of complications and also to offer each patient the most individually adapted corrections, before any procedure, the plastic surgeon needs to question the patient and perform precise medical examination. PMID- 28911891 TI - Erratum to "A novel mutation in the PSEN2 gene (N141Y) associated with early onset autosomal dominant Alzheimer's disease in a Chinese Han family" [Neurobiol. Aging 35 (2014) 2420.e1-2420.e5]. PMID- 28911892 TI - Erratum to "Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome" [Neurobiol. Aging 35 (2014) 1513.e1-1513.e5]. PMID- 28911893 TI - Treatment recommendations for non-infectious anterior uveitis. AB - BACKGROUND AND OBJECTIVE: To develop recommendations on the use of immunodepressors in patients with non-infectious, non-neoplastic anterior uveitis (AU) based on best evidence and experience. MATERIAL AND METHODS: A multidisciplinary panel of five experts was established, who, in the first nominal group meeting defined the scope, users, and chapters of the document. A systematic literature review was performed to assess the efficacy and safety of immunosuppressors in patients with non-infectious, non-neoplastic AU. All the above was discussed in a second nominal group meeting and 33 recommendations were generated. Through the Delphi methodology, the degree of agreement with the recommendations was tested also by 25 more experts. Recommendations were voted on from one (total disagreement) to 10 (total agreement). We defined agreement if at least 70% voted >=7. The level of evidence and degree of recommendation was assessed using the Oxford Centre for Evidence-based Medicine's Levels of Evidence. RESULTS: The 33 recommendations were accepted. They include specific recommendations on patients with non-infectious, non-neoplastic AU, as well as different treatment lines. CONCLUSIONS: In patients with non-infectious, non neoplastic AU, these recommendations on the use of immunosuppressors might be a guide in order to help in the treatment decision making, due to the lack of robust evidence or other globally accepted algorithms. PMID- 28911894 TI - Response: The Evolution of Lung Transplant Anesthesia. PMID- 28911895 TI - Con: Dynamic Left Ventricular Outflow Tract Obstruction Should Be Considered an "Unexpected" Finding in Patients With End-Stage Liver Disease Undergoing Dobutamine Stress Echocardiography in Preparation for Liver Transplantation. PMID- 28911896 TI - Patient Selection and Outcomes of Transfemoral Transcatheter Aortic Valve Replacement Performed with Monitored Anesthesia Care Versus General Anesthesia. AB - OBJECTIVE: The aim of this study was to compare outcomes of monitored anesthesia care (MAC) versus general anesthesia (GA) for transfemoral transcatheter aortic valve replacement (TF-TAVR) and to describe a selection process for the administration of MAC. DESIGN: Retrospective analysis of patients who underwent TF-TAVR under MAC or GA. SETTING: Department of Cardiac Anesthesia, Albany Medical Center, a tertiary university hospital. PARTICIPANTS: Patients selected for TF-TAVR. INTERVENTIONS: Patients were divided into those who underwent MAC and those who underwent GA. MEASUREMENTS AND MAIN RESULTS: The study comprised 104 consecutive patients (55% male, mean age 83 years) who underwent TF-TAVR under MAC (n = 60) or GA (n = 37) from 2014 to 2015. Seven patients were converted from MAC to GA and were omitted from analysis. There was no statistically significant difference between 30-day mortality and complications between the 2 groups. The MAC group had a significantly shorter median intensive care unit length of stay (48 h v 74 h, p = 0.0002). The MAC group also demonstrated reduced procedural time (45.5 min v 62 min, p = 0.003); operating room time (111 min v 153 min, p = <0.001); and fluoroscopy time (650 s v 690 s, p = 0.03). CONCLUSIONS: Patient selection for TF-TAVR with MAC can be formalized and implemented successfully. MAC allows for the minimizing of patient exposure to unnecessary interventions and improving resource utilization in suitable TAVR patients. Selection requires a multidisciplinary clinical decision-making process. MAC demonstrates good outcomes compared with GA, yet it is important to have a cardiac anesthesiologist present in the event of emergency conversion to GA. PMID- 28911897 TI - Perioperative Point-of-Care Ultrasound in Pediatric Anesthesiology: A Case Series Highlighting Intraoperative Diagnosis of Hemodynamic Instability and Alteration of Management. PMID- 28911898 TI - Challenge of Pregnancy in Patients With Pre-Capillary Pulmonary Hypertension: Veno-Arterial Extracorporeal Membrane Oxygenation as an Innovative Support for Delivery. PMID- 28911899 TI - A Rare Iatrogenic Atrial-Esophageal Fistula and Anesthetic Considerations for Primary Surgical Repair. PMID- 28911900 TI - Authors' Response: Unplanned reintubation following cardiac surgery: Incidence, timing, risk factors, and outcomes. PMID- 28911901 TI - Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder With Oppositional Defiant Disorder. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia, and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of comorbid oppositional defiant disorder (ODD) (comorbidity rates up to 60%) on these neuroanatomical differences is scarcely studied, while ODD (in combination with conduct disorder) has been associated with structural abnormalities of the frontal lobe, amygdala, and insula. The aim of this study was to investigate the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD. METHODS: Three groups, 16 +/- 3.5 years of age (mean +/- SD; range 7-29 years), were studied on volumetric and cortical thickness characteristics using structural magnetic resonance imaging (surface-based morphometry): ADHD+ODD (n = 67), ADHD-only (n = 243), and control subjects (n = 233). Analyses included the moderators age, gender, IQ, and scan site. RESULTS: ADHD+ODD and ADHD-only showed volumetric reductions in total gray matter and (mainly) frontal brain areas. Stepwise volumetric reductions (ADHD+ODD < ADHD-only < control subjects) were found for mainly frontal regions, and ADHD+ODD was uniquely associated with reductions in several structures (e.g., the precuneus). In general, findings remained significant after accounting for ADHD symptom severity. There were no group differences in cortical thickness. Exploratory voxelwise analyses showed no group differences. CONCLUSIONS: ADHD+ODD and ADHD-only were associated with volumetric reductions in brain areas crucial for attention, (working) memory, and decision-making. Volumetric reductions of frontal lobes were largest in the ADHD+ODD group, possibly underlying observed larger impairments in neurocognitive functions. Previously reported striatal abnormalities in ADHD may be caused by comorbid conduct disorder rather than ODD. PMID- 28911902 TI - The impact of 10-valent and 13-valent pneumococcal conjugate vaccines on hospitalization for pneumonia in children: A systematic review and meta-analysis. AB - BACKGROUND: This systematic review and meta-analysis aimed at summarizing available data on the impact of PCV10 and PCV13 in reducing the incidence of CAP hospitalizations in children aged <5years. METHODS: A systematic search of the literature was conducted. We included time-series analyses and before-after studies, reporting the incidence of hospitalization for pneumonia in the periods before and after the introduction of PCV10 or PCV13 into the immunization program. Pooled estimates of Incidence Rate Ratio (IRR) were calculated by using a random-effects meta-analytic model. Results were stratified according to age groups (<24months and 24-59months) and case definitions of pneumonia (clinically and radiologically confirmed pneumonia). RESULTS: A total of 1533 potentially relevant articles were identified. Of these, 12 articles were included in the analysis. In children aged <24months, the meta-analysis showed a reduction of 17% (95%CI: 11-22%, p-value<0.001) an of 31% (95%CI: 26-35%, p-value<0.001) in the hospitalization rates respectively for clinically and radiologically confirmed pneumonia, respectively, after the introduction of the novel PCVs. In children aged 24-59months, the meta-analysis showed a reduction of 9% (95%CI: 5-14%, p value<0.001) and of 24% (95%CI: 12-33%, p-value<0.001) in the hospitalization rates for clinically and radiologically confirmed pneumonia, respectively, after the introduction of the novel PCVs. High heterogeneity was detected among studies evaluating the hospitalization rate for clinically and radiologically confirmed pneumonia. CONCLUSIONS: The results of this study revealed a significant impact of PCV10 and PCV13 in reducing the hospitalizations for pneumonia, particularly in children aged <24months and for radiologically confirmed disease. Further appropriately designed studies, comparing the impact of PCV10 and PCV13, are needed in order to obtain solid data on which to establish future immunization strategies. PMID- 28911903 TI - The vaccines and antibodies associated with Als3p for treatment of Candida albicans infections. AB - Candida albicans is the most common fungal microorganism in healthy individuals, as well as the cause of high mortality infections in high-risk hosts such as immunocompromised patients. Antifungal vaccines and monoclonal antibodies useful for active or passive immunizations have recently generated considerable excitement for the treatment of fungal infections. The cell wall proteins of C. albicans, which are crucial for virulence and pathogenicity, are attractive target antigens. Als3p, a member of the C. albicans agglutinin-like sequence (ALS) family, is a hyphal-specific glycophosphatidylinositol cell wall protein that plays a key role in the interaction with host cells. The abundance of Als3p on the hyphal surface makes it an attractive target. For example, the NDV-3 vaccine, targeted at the N-terminus of Als3p, has entered a preparation of Phase 2 clinical trial. The Als3p-specific antibodies include monoclonal antibodies (MAbs) 3-A5, MAb 113, and scFv3. In addition, MAb C7, MAb 3D9.3 and MAb 2G8, which were supposed to be identifying other targets, have also provided good protection by recognizing Als3p. In this review, we summarize the functions of Als3p and highlight the development of the vaccines and the antibodies that are associated, directly or indirectly, with this protein. PMID- 28911904 TI - Functional characterization of candidate antigens of Hyalomma anatolicum and evaluation of its cross-protective efficacy against Rhipicephalus microplus. AB - Hyalomma anatolicum and Rhipicephalus microplus seriously affect dairy animals and immunization of host is considered as a sustainable option for the management of the tick species. Identification and validation of protective molecules are the major challenges in developing a cross-protective vaccine. The subolesin (SUB), calreticulin (CRT) and cathepsin L-like cysteine proteinase (CathL) genes of H. anatolicum were cloned, sequenced and analysed for sequence homology. Both Ha-SUB and Ha-CRT genes showed very high level of homogeneity within the species (97.6-99.4% and 98.2-99.7%) and among the tick species (77.3-99.3% and 85.1 99.7%) while for Ha-CathL the homogeneity was lower among ticks (57.5-89.5%). Besides tick species, both Ha-SUB and Ha- CRT genes showed high level of homogeneity with dipterans (47.2-53.4% and 72.0-74.4%) and nematodes (64.0% by CRT). The level of expression of the conserved genes in different stages of the tick species was studied. The differences in fold change of expression (FCE) of the targeted genes in life stages of tick were not statistically significant except Ha-SUB in eggs and in frustrated females, Ha-CRT in fed male and Ha-CathL in unfed and frustrated females where highest FCE was recorded. The functional properties of the genes were studied by RNAi technology and a significant level of gene suppression (p<0.05) resulted in very low percentage of engorgement of treated ticks viz., 3.7%, 11.1% and 30.0% in Ha-SUB, Ha-CRT and Ha-CathL respectively, in comparison to control was recorded. The recombinant proteins rHa SUB, rHa-CRT and rHa-CathL encoded by the genes were expressed in prokaryotic expression system. They were evaluated for cross-protective efficacy and found to be respectively, 65.4%, 41.3% and 30.2% protective against H. anatolicum and 54.0%, 37.6% and 22.2%, against R. microplus infestations. PMID- 28911905 TI - Gaussian process classification of superparamagnetic relaxometry data: Phantom study. AB - MOTIVATION: Superparamagnetic relaxometry (SPMR) is an emerging technology that holds potential for use in early cancer detection. Measurement of the magnetic field after the excitation of cancer-bound superparamagnetic iron oxide nanoparticles (SPIONs) enables the reconstruction of SPIONs spatial distribution and hence tumor detection. However, image reconstruction often requires solving an ill-posed inverse problem that is computationally challenging and sensitive to measurement uncertainty. Moreover, an additional image processing module is required to automatically detect and localize the tumor in the reconstructed image. OBJECTIVE: Our goal is to examine the use of data-driven machine learning technique to detect a weak signal induced by a small cluster of SPIONs (surrogate tumor) in presence of background signal and measurement uncertainty. We aim to investigate the performance of both data-driven and image reconstruction models to characterize situations that one can replace the computationally-challenging reconstruction technique by the data-driven model. METHODS: We utilize Gaussian process (GP) classification model and a physics-based image reconstruction method, tailored to SPMR datasets that are obtained from (i) in silico simulations designed based on mouse cancer models and (ii) phantom experiments using MagSense system (Imagion Biosystems, Inc.). We investigate the performance of the GP classifier against the reconstruction technique, for different levels of measurement noise, different scenarios of SPIONs distribution, and different concentrations of SPIONs at the surrogate tumor. RESULTS: In our in silico source detection analysis, we were able to achieve high sensitivity results using GP model that outperformed the image reconstruction model for various choices of SPIONs concentration at the surrogate tumor and measurement noise levels. Moreover, in our phantom studies we were able to detect the surrogate tumor phantoms with 5% and 7.3% of the total used SPIONs, surrounded by 9 low concentration phantoms with accuracies of 87.5% and 96.4%, respectively. CONCLUSIONS: The GP framework provides acceptable classification accuracies when dealing with in silico and phantom SPMR datasets and can outperform an image reconstruction method for binary classification of SPMR data. PMID- 28911906 TI - Identification of novel biomarkers for MLL-translocated acute myeloid leukemia. AB - Acute myeloid leukemias (AMLs) with translocations of the mixed lineage leukemia (MLL/KMT2A) gene are common in young patients and are generally associated with poor clinical outcomes. The molecular biology of MLL fusion genes remains incompletely characterized and is complicated by the fact that more than 100 different partner genes have been identified in fusions with MLL. The continuously growing list of MLL fusions also represents a clinical challenge with respect to identification of novel fusions and tracking of the fusions to monitor progression of the disease after treatment. Recently, we have developed a novel single-donor model leukemia system that permits the development of human AML from normal cord blood cells. Gene expression analysis of this model and of MLL-AML patient samples has identified a number of candidate biomarker genes with highly biased expression on leukemic cells. Here, we present data demonstrating the potential clinical utility of several of these candidate genes for identifying known and novel MLL fusions. PMID- 28911907 TI - MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice. AB - MicroRNA-22 (miR-22) is a highly conserved microRNA that can regulate cell proliferation, oncogenesis, and cell maturation, especially during stress. In hematopoietic stem cells (HSCs), miR-22 has been reported to be involved in the regulation of key self-renewal factors, including Tet2. Recent work demonstrates that miR-22 also participates in regulation of the interferon (IFN) response, and expression profiling studies suggest that it is variably expressed at different stages in erythroid differentiation. We thus hypothesized that miR-22 regulates maturation of erythroid progenitors during stress hematopoiesis through its interaction with IFN. We compared the blood and bone marrow of wild-type (WT) and miR-22-deficient mice at baseline and upon infectious challenge with systemic lymphochoriomeningitis (LCMV) virus. miR-22-deficient mice maintained platelet counts better than WT mice during infection, but they showed significantly reduced red blood cells and hemoglobin. Analysis of bone marrow progenitors demonstrated better overall survival and improved HSC homeostasis in infected miR 22-null mice compared with WT, which was attributable to a blunted IFN response to LCMV challenge in the miR-22-null mice. We found that miR-22 was expressed exclusively in stage II erythroid precursors and downregulated upon infection in WT mice. Our results indicate that miR-22 promotes the IFN response to viral infection and that it functions at baseline as a brake to slow erythroid differentiation and maintain adequate erythroid potential. Impaired regulation of erythrogenesis in the absence of miR-22 can lead to anemia during infection. PMID- 28911909 TI - COUNTERPOINT: Should Continuous Venovenous Hemofiltration Always Be the Preferred Mode of Renal Replacement Therapy for the Patient With Acute Brain Injury? No. PMID- 28911908 TI - Enhancement of mouse hematopoietic stem/progenitor cell function via transient gene delivery using integration-deficient lentiviral vectors. AB - Integration-deficient lentiviruses (IdLVs) deliver genes effectively to tissues but are lost rapidly from dividing cells. This property can be harnessed to express transgenes transiently to manipulate cell biology. Here, we demonstrate the utility of short-term gene expression to improve functional potency of hematopoietic stem and progenitor cells (HSPCs) during transplantation by delivering HOXB4 and Angptl3 using IdLVs to enhance the engraftment of HSPCs. Constitutive overexpression of either of these genes is likely to be undesirable, but the transient nature of IdLVs reduces this risk and those associated with unsolicited gene expression in daughter cells. Transient expression led to increased multilineage hematopoietic engraftment in in vivo competitive repopulation assays without the side effects reported in constitutive overexpression models. Adult stem cell fate has not been programmed previously using IdLVs, but we demonstrate that these transient gene expression tools can produce clinically relevant alterations or be applied to investigate basic biology. PMID- 28911910 TI - POINT: Should Continuous Venovenous Hemofiltration Always Be the Preferred Mode of Renal Replacement Therapy for the Patient With Acute Brain Injury? Yes. PMID- 28911911 TI - Rebuttal From Drs Niemi and Stoff. PMID- 28911912 TI - Rebuttal From Drs Osgood and Muehlschlegel. PMID- 28911914 TI - Changes in the level of Long Non-Coding RNA Gomafu gene expression in schizophrenia patients before and after antipsychotic medication. PMID- 28911913 TI - Phosphatidic Acid and Cardiolipin Coordinate Mitochondrial Dynamics. AB - Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases. Moreover, lipid-modifying enzymes such as phospholipases and lipid phosphatases may organize local lipid composition to spatially and temporarily coordinate a balance between fusion and division to establish mitochondrial morphology. PMID- 28911915 TI - Risk factors of compliance with self-harm command hallucinations in individuals with affective and non-affective psychosis. AB - Clinicians are often left with the difficult task of assessing and managing the risk of violent behaviors in individuals having command hallucinations, which may result in substantial rates of false positive or false negative. Moreover, findings on the association between command hallucinations and suicidal behaviors are limited. In an attempt to better understand compliance to this hallucinatory phenomenon, our objective was to identify the risk factors of compliance with self-harm command hallucinations. Secondary analyses from the MacArthur Study were performed on 82 participants with psychosis reporting such commands. Univariate logistic regression was used to examine the classification value of each characteristic associated with compliance with such commands. Seriousness and frequency of childhood physical abuse, a current comorbid substance use disorder, emotional distress, general symptomatology, history of compliance, and belief about compliance in the future were found to be significant risk factors of compliance with self-harm commands in the week preceding psychiatric inpatient. Multivariate analyses revealed that severity of childhood physical abuse, belief about compliance in the future, and a current comorbid substance use disorder were independent risk factors. The final model showed excellent classification accuracy as suggest by the receiver operating characteristic curve (AUC=0.84, 95% CI: 0.75-0.92, p<0.001). Our results suggest considerable clinical implications in regard to the assessment of risk of compliance to self-harm command hallucinations in individuals with psychosis. PMID- 28911916 TI - Transformational thinking about asthma. PMID- 28911917 TI - After asthma: airways diseases need a new name and a revolution. PMID- 28911918 TI - Ian Pavord: engaging with the eosinophil. PMID- 28911919 TI - Andrew Bush: a broad portfolio in paediatric respirology. PMID- 28911921 TI - Using data to tackle the burden of amputation in diabetes. PMID- 28911920 TI - After asthma: redefining airways diseases. PMID- 28911922 TI - Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open label, single-arm, single-center, phase 2 study. AB - BACKGROUND: Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). PATIENTS AND METHODS: After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: <=0.20 and H1: >=0.40, with a type I and type II error of 5% and 10%, respectively. RESULTS: From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9-58.9); pT <= 1 in 25 (54.3%, 95% CI: 39.0-69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6-NR), nor was median overall survival (interquartile range: 30.3-NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT <= 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT <= 1 response (P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. CONCLUSIONS: SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy. PMID- 28911923 TI - Secondary data sources for health services research in urologic oncology. AB - BACKGROUND: Though secondary data analyses of large datasets may reduce logistical and financial barriers required to perform significant and innovative work, such research requires specialized skills in data handling and statistical techniques as well as thorough and detailed knowledge of the data sources being used. OBJECTIVES: To provide an overview of several common types of secondary data, focusing on strengths, weaknesses and examples of how these data may be used for health services research. RESULTS: Secondary data comprise a broad and heterogeneous category. This review covers several large categories of such data with examples of their use and discussions about their strengths and weaknesses. Sources include administrative data, claims-based datasets, electronic health records health surveys, patient or disease or both registries, quality improvement initiatives, as well as data from existing trials. Linkages of different types of data may expand the scope of questions answerable using secondary data analysis. Specific strengths and weaknesses of each type of dataset are discussed along with examples from the recent urologic literature. CONCLUSIONS: Choice of the appropriate data source should be tailored to the specific research question as well as the research resources and expertise available. Appropriate decisions about which data to use are the foundation for valid, high-impact research using secondary data. PMID- 28911924 TI - Sialyl-Tn identifies muscle-invasive bladder cancer basal and luminal subtypes facing decreased survival, being expressed by circulating tumor cells and metastases. AB - OBJECTIVES: To evaluate the potential of sialyl-Tn (STn), a cancer-associated glycan antigen present in membrane glycoproteins, to improve a recent molecular model for stratification and prognostication of advanced stage bladder tumors based on keratins (KRT14, 5, and 20) expression. In addition, determine the association between STn and disease dissemination based on the evaluation of circulating tumor cells (CTCs) and the metastasis, which is a critical matter to improve patient management. PATIENTS AND METHODS: A retrospective series of 80 muscle-invasive primary bladder tumors and associated metastasis were screened for KRT14, 5, and 20 and STn by real-time polymerase chain reaction and immunohistochemistry. Peripheral blood was collected in a patients' subset, CTCs were isolated through a size-based microfluidic chip and screened for KRTs and STn. RESULTS: Basal-like lesions presented worse cancer-specific and disease-free survival compared to luminal tumors. STn antigen inclusion discriminated patients with worst survival in each subgroup (P = 0.047 for luminal; P = 0.027 for basal like tumors). STn expression in CTCs and distant metastasis was also demonstrated. CONCLUSION: This work reinforces the potential of the KRT-based model for bladder cancer management and the association of STn with aggressiveness, supporting its inclusion in predictive molecular models toward patient-tailored precision medicine. Moreover, we describe for the first time that CTCs and the metastasis present a basal phenotype and express the STn antigen, highlighting its link with disease dissemination. Future studies should focus on determining the biological and clinical significance of these observations in the context of liquid biopsies. Given the membrane nature of STn, highly specific targeted therapeutics may also be envisaged. PMID- 28911926 TI - Severe ovarian hyperstimulation syndrome modifies early maternal serum beta-human chorionic gonadotropin kinetics, but obstetrical and neonatal outcomes are not impacted. AB - OBJECTIVE: To study the impact of severe ovarian hyperstimulation syndrome (OHSS) on beta-hCG kinetics and obstetrical and neonatal outcomes. DESIGN: Retrospective single-center case-control study. SETTING: University tertiary referral center. PATIENT(S): A total of 77 patients who presented a clinical pregnancy after IVF and had been hospitalized for severe OHSS were included in this study and compared with 231 controls presenting an IVF-induced clinical pregnancy without OHSS and matched for the year of pregnancy and the number of gestational sacs. INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): The outcome of pregnancy (miscarriage, medical abortion, or delivery), beta-hCG values, obstetrical, and neonatal outcomes. RESULT(S): After multivariate analysis adjusted for parity, tobacco smoking, presence of polycystic ovary syndrome, age, and body mass index, outcomes of pregnancies were not altered by OHSS. However, there was a trend toward a lower early miscarriage rate in the OHSS group (7.8%) than in the control group (16%). Maternal serum beta-hCG values at different time points of the pregnancy and fold changes of beta-hCG values were lower in OHSS than in controls (268 +/- 160 vs. 389 +/- 215 IU/L at day 16; and 4.8 +/- 1.5 vs. 5.4 +/- 1.4 fold change between day 16 and day 20). Beta-hCG also correlated negatively with the number of oocytes retrieved. Incidence of gestational diabetes, gestational hypertension, intrauterine growth restriction, premature birth, and low birth weight did not differ between groups. CONCLUSION(S): Although early maternal serum beta-hCG kinetics were modified in women after severe OHSS, the outcomes of these pregnancies remained comparable to those of IVF pregnancies without OHSS. According to these data, pregnancies after severe OHSS do not require particular care compared with IVF pregnancies, but differences in beta hCG levels and kinetics should be taken into account when interpreting these results. PMID- 28911925 TI - Ethinylestradiol 20 MUg/drospirenone 3 mg in a flexible extended regimen for the management of endometriosis-associated pelvic pain: a randomized controlled trial. AB - OBJECTIVE: To investigate the efficacy and safety of ethinylestradiol 20 MUg/drospirenone 3 mg in a flexible extended regimen (FlexibleMIB) compared with placebo to treat endometriosis-associated pelvic pain (EAPP). DESIGN: A phase 3, randomized, double-blind, placebo-controlled, parallel-group study, consisting of a 24-week double-blind treatment phase followed by a 28-week open-label extension phase with an unblinded reference arm. SETTING: Thirty-two centers. PATIENT(S): A total of 312 patients with endometriosis. INTERVENTION(S): Patients were randomized to FlexibleMIB, placebo, or dienogest. The FlexibleMIB and placebo arms received 1 tablet per day continuously for 120 days, with a 4-day tablet free interval either after 120 days or after >=3 consecutive days of spotting and/or bleeding on days 25-120. After 24 weeks, placebo recipients were changed to FlexibleMIB. Patients randomized to dienogest received 2 mg/d for 52 weeks in an unblinded reference arm. MAIN OUTCOME MEASURE(S): Absolute change in the most severe EAPP based on visual analog scale scores from the baseline observation phase to the end of the double-blind treatment phase. RESULT(S): Compared with placebo, FlexibleMIB significantly reduced the most severe EAPP (mean difference in visual analog scale score: -26.3 mm). FlexibleMIB also improved other endometriosis-associated pain and gynecologic findings and reduced the size of endometriomas. CONCLUSION(S): FlexibleMIB improved EAPP and was well tolerated, suggesting it may be a new alternative for managing endometriosis. CLINICAL TRIALS REGISTRATION NUMBER: NCT01697111. PMID- 28911927 TI - Dynamic expression of PGRMC1 and SERBP1 in human endometrium: an implication in the human decidualization process. AB - OBJECTIVE: To characterize PGRMC1 and SERBP1 in human endometrium and to investigate the putative role of PGRMC1 in endometrial decidualization. DESIGN: The PGRMC1 and SERBP1 expression in human endometrium was determined throughout the menstrual cycle. We analyzed the colocalization of PGRMC1 and SERBP1. Then, endometrial stromal cells (ESCs) were isolated to investigate the functional effect of PGRMC1 overexpression on decidualization. SETTING: IVI clinic. PATIENT(S): Endometrial biopsies were collected from fertile volunteers (n = 61) attending the clinic as ovum donors. INTERVENTION(S): Endometrial samples of 61 healthy fertile women. MAIN OUTCOME MEASURE(S): In vivo localization of PGRMC1 and SERBP1 was assessed by immunohistochemistry. The PGRMC1/SERBP1 colocalization was investigated in vitro and in vivo. Decidualization effect of PGRMC1 overexpression was evaluated in primary ESC cultures. RESULT(S): The PGRMC1 was detected in the endometrial stroma throughout the menstrual cycle, but decreased in the late secretory phase. The SERBP1 immunostaining was present in stroma and increased in the entire the menstrual cycle. The PGRMC1 and SERBP1 colocalized in the cytoplasmic fractions of nondecidualized and decidualized ESC. The PGRMC1 overexpression significantly inhibited in vitro decidualization. CONCLUSION(S): Our results suggest that classic P receptors (PRs) are not the only kind playing a role in the normal physiology of the endometrium. The human decidualization process could be altered by the overexpression or mislocalization of PGRMC1 in ESC. PMID- 28911928 TI - Introduction: Contemporary approaches to alternative ovarian stimulation strategies for in vitro fertilization. AB - In the current practice of IVF, the vast majority of cycles use some form of controlled ovarian stimulation before egg retrieval to increase the number of embryos available for transfer or cryopreservation. However, the optimal stimulation regimen has not been established. This month's Views and Reviews presents five different approaches to alternative ovarian stimulation strategies. These include mild stimulation regimens, modified natural cycles, stimulation with oral agents, in vitro maturation (in the absence of stimulation), and finally, a proposal for patient-tailored ovarian stimulation. As the treatment of infertility becomes more personalized, it is likely that standard, heavy-handed stimulation protocols will give way to simpler strategies, specifically tailored to each patient's individual characteristics and needs. PMID- 28911929 TI - Clomiphene citrate at 50: the dawning of assisted reproduction. PMID- 28911930 TI - Low fertility awareness in United States reproductive-aged women and medical trainees: creation and validation of the Fertility & Infertility Treatment Knowledge Score (FIT-KS). AB - OBJECTIVE: To create, validate, and use a fertility awareness survey based on current U.S. DATA: DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Phase 1 included U.S. women ages 18-45; phase 2 included female medical students and obstetrics and gynecology trainees at two urban academic programs. INTERVENTION(S): Survey including demographics, the Fertility & Infertility Treatment Knowledge Score (FIT-KS) instrument, and General Nutrition Knowledge Questionnaire. MAIN OUTCOME MEASURE(S): Knowledge of natural fertility and infertility treatments. RESULT(S): The FIT-KS was validated through detailed item and validity analyses. In phase 1, 127 women participated; their median age was 31 years, and 43.7% had children. Their mean FIT-KS score was 16.2 +/- 3.5 (55.9% correct). In phase 2, 118 medical trainees participated; their median age was 25 years, and 12.4% had children. Their mean FIT-KS score was 18.8 +/- 2.1 (64.9% correct), with year of training correlating to a higher score (r=0.40). Participant awareness regarding lifestyle factors varied, but it was particularly low regarding the effects of lubricants. The majority underestimated the spontaneous miscarriage rate and overestimated the fecundability of 40-year-old women. There was general overestimation of success rates for assisted reproductive technologies, particularly among medical trainees. CONCLUSION(S): The FIT-KS is validated to current U.S. data for use in both general and medical populations as a quick assessment of fertility knowledge. The knowledge gaps demonstrated in this study correlate with national trends in delayed childbearing and time to initiate treatment. For medical trainees, these results raise concerns about the quality of fertility counseling they may be able to offer patients. Greater educational outreach must be undertaken to enhance fertility awareness. PMID- 28911931 TI - A validated measure for fertility awareness: an essential step toward informed reproductive decision-making. PMID- 28911932 TI - Varicocelectomy to "upgrade" semen quality to allow couples to use less invasive forms of assisted reproductive technology. AB - OBJECTIVE: To determine the magnitude of improvement in semen parameters after a varicocelectomy and the fraction that have improvements such that couples needing IVF or IUI are "upgraded" to needing less invasive assisted reproductive technology (ART). DESIGN: Retrospective review of prospectively collected data. SETTING: Academic medical centers. PATIENT(S): Men presenting for a fertility evaluation with a clinical varicocele. INTERVENTION(S): Varicocele repair (surgical or embolization). MAIN OUTCOME MEASURE(S): Total motile sperm count (TMSC) before and after repair, and the proportion of men considered candidates for: natural pregnancy (NP) >9 million, IUI 5-9 million, or IVF < 5 million. RESULT(S): A total of 373 men underwent varicocele repair. The TMSC increased from 18.22 +/- 38.32 to 46.72 +/- 210.92 (P=.007). The most pronounced increase was with baseline TMSC <5 million, from 2.32 +/- 1.50 to 15.97 +/- 32.92 (P=.0000002); 58.8% of men were upgraded from IVF candidacy to IUI or NP. For baseline TMSC 5-9 million, the mean TMSC increased from 6.96 +/- 1.16 to 24.29 +/ 37.17 (P=.0004), allowing 64.9% of men to become candidates for NP. For baseline TMSC of >9 million, TMSC increased from 36.26 +/- 52.08 to 81.80 +/- 310.83 (P=.05). CONCLUSION(S): Varicocele repair has an important role in the treatment of infertility. Even for low TMSCs, a varicocelectomy may reduce the need for IVF. Varicocele repair (by embolization or microsurgery) potentially reduces the need for IVF and IUI. PMID- 28911933 TI - Pain cognition versus pain intensity in patients with endometriosis: toward personalized treatment. AB - OBJECTIVE: To explore how pain intensity and pain cognition are related to health related quality of life (HRQoL) in women with endometriosis. DESIGN: Cross sectional questionnaire-based survey. SETTING: Multidisciplinary referral center. PATIENT(S): Women with laparoscopically and/or magnetic resonance imaging-proven endometriosis (n = 50) and healthy control women (n = 42). INTERVENTION(S): For HRQoL, two questionnaires: the generic Short Form Health Survey (SF-36) and the Endometriosis Health Profile 30 (EHP-30). For pain cognition, three questionnaires: the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), and the Pain Anxiety Symptoms Scale (PASS). For pain intensity, the verbal Numeric Rating Scale (NRS). MAIN OUTCOME MEASURE(S): Association between pain intensity and pain cognition with HRQoL in women with endometriosis, and the differences in HRQoL and pain cognition between women with endometriosis and healthy controls. RESULT(S): Health-related quality of life was statistically significantly impaired in women with endometriosis as compared with healthy control women. The variables of pain intensity and pain cognition were independent factors influencing the HRQoL of women with endometriosis. Patients with endometriosis had statistically significantly more negative pain cognition as compared with controls. They reported more pain anxiety and catastrophizing, and they were hypervigilant toward pain. CONCLUSION(S): Pain cognition is independently associated with the HRQoL in endometriosis patients. Clinicians should be aware of this phenomenon and may consider treating pain symptoms in a multidimensional, individualized way in which the psychological aspects are taken into account. In international guidelines on management of women with endometriosis more attention should be paid to the psychological aspects of care. PMID- 28911934 TI - Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study. AB - OBJECTIVE: To evaluate the efficacy and safety of dienogest (DNG), a progestational 19-norsteroid, in patients with symptomatic adenomyosis. DESIGN: Phase III, randomized, double-blind, multicenter, placebo-controlled study. SETTING: Clinical study sites in Japan. PATIENT(S): Sixty-seven patients with adenomyosis. INTERVENTION(S): Patients were randomly assigned to receive DNG (2 mg/d, orally) or placebo for 16 weeks. In cases of complicated anemia, patients were treated for anemia before randomization. MAIN OUTCOME MEASURE(S): The primary end point was the change from baseline to after treatment pain score, using zero- to three-point verbal rating scales that defined pain severity according to limited ability to work and need for analgesics. The visual analogue scale was used as another pain parameter. RESULT(S): Decreases from baseline in the pain score and the visual analogue scale at the end of treatment were significantly more in the DNG group than in the placebo group (P<.001). During the treatment period, almost all of the patients treated with DNG experienced irregular uterine bleeding and one patient had mild anemia. No severe cases of anemia were observed. CONCLUSION(S): These results suggest that DNG is effective and well tolerated in the treatment for painful symptoms associated with adenomyosis not complicated by severe uterine enlargement or severe anemia. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-142642(en). PMID- 28911935 TI - Obesity discrimination in healthcare. PMID- 28911936 TI - Exercise training in patients with pulmonary and systemic hypertension: A unique therapy for two different diseases. AB - Pulmonary hypertension is a potentially life-threatening condition. Given its evolving definition, the incidence and prevalence of the disease is difficult to define, but registries suggest an increased global awareness. The management of patients with pulmonary arterial hypertension is highly specialised and requires multi-disciplinary input from a range of healthcare professionals, including cardiologists, respiratory physicians, rheumatologists, rehabilitation physicians and cardio-pulmonary physiotherapists. Historically, exercise training in pulmonary hypertension has not been recommended because of safety concerns. However, an increasing number of studies have demonstrated the benefit of exercise training on exercise capacity, peak oxygen consumption and quality of life. Systemic hypertension is one of the most important risk factors for cardiovascular disease, and has been ranked as the leading cause for death and disability worldwide: therefore, adequate control of blood pressure is important for public health. Lowering of blood pressure and prevention of hypertension is in first instance preferable by lifestyle changes. These include weight loss, moderation of alcohol intake, a diet with increased fresh fruit and vegetables, reduced saturated fat, reduced salt intake, reduced stress, and, finally, increased physical activity. With regard to the latter, former guidelines predominantly recommended aerobic exercises such as walking, jogging, and cycling for lowering blood pressure. The main focus of this narrative overview paper is to briefly examine and summarize the benefit of exercise training in patients with pulmonary and systemic hypertension, suggest mechanisms by which exercise may improve symptoms and function and provide evidence-based recommendations regarding the frequency and intensity of exercise in these patients. PMID- 28911937 TI - [Vaccination study of children in the North department, France]. PMID- 28911938 TI - [Families' experiences and satisfaction with a pediatric emergency service]. AB - OBJECTIVE: Today, pediatric emergency services receive a rising number of "non urgent" cases, which are due to parental anxiety or a miscomprehension of medical explanations. The aim of this study was therefore to understand what those families experience and need when they consult in such cases, in order to respond with adapted solutions. METHODS: Semi-structured interviews and questionnaires with parents, after the consultation or in the waiting room. RESULTS: Based on the families' narratives, we present the results in six steps, which correspond to the steps they experience from the decision to go to the hospital to the consultation. Families' experiences are very satisfactory regarding the quality of medical care, the relationship between staff and children, and the staff's overall attitude. Critical points concern practical aspects (parking, food, and play facilities); the waiting time and the lack of information; and the communication between the medical staff and the parents, most particularly related to their anxiety and waiting time. DISCUSSION: The results show first that parents have multiple preoccupations: many stress factors and organizational difficulties are added to their child's disease. These preoccupations are mostly related to the lack of information about the waiting time, information that they would need to organize their day and their time in the hospital. Second, the results show that parental anxiety influences their decision to come to the emergency department, their experience of care and of the waiting time, and their judgment about the quality of the medical care. Considering this, families requested practical improvements (i.e., more toys in the waiting room), and suggest more communication and presence from the medical staff. Based on their demands, we suggest an agenda of care in four steps: a waiting time, a time for sharing, a time for information giving, and a validation time. CONCLUSIONS: Overall, parents are stressed and anxious when they come to the emergency department and request more reassurance, attention, and explanations from the healthcare staff. We propose a final "validation time" to verify that the medical explanations are understood as well as the emotional state of the family. In this way, we can ensure good follow-up care at home, avoid unnecessary readmissions, and promote parental health education. PMID- 28911939 TI - Evaluation of airborne sensory irritants for setting exposure limits or guidelines: A systematic approach. AB - Sensory irritation of eyes and upper airways is an important endpoint for setting occupational exposure limits (OELs) and indoor air guidelines. Sensory irritants cause a painful burning, stinging and itching sensation. Controlled chamber studies are the "golden standard" for evaluations. Well conducted workplace studies offer another possibility. For generalization, the number of participants and their age, smoking, gender, and prior exposure, experience and mood has to be considered. Exposure assessments have to be reliable and exposure duration sufficiently long to establish time-response relationships. A potential confounding by odour has to be assessed. For workplace exposures, mixed exposure and healthy worker effects have to be evaluated. The "Alarie test" is the only validated animal bioassay for prediction of sensory irritation in humans. The mouse bioassay uses the trigeminal reflex-induced decrease in the respiratory rate. The 50% decrease (RD50) has been correlated with OELs set for sensory irritants; predicted OELs for sensory irritants are 0.03xRD50. Evaluation of the bioassay comprises the number of mice and the strain, the reliability of the exposure concentrations and exposure-response relationships, and the similar mode of-action in mice and humans. These approaches can be used for quality assurance of reported data to set air quality guidelines. PMID- 28911940 TI - Anthracenyl polar embedded stationary phases with enhanced aromatic selectivity. Part II: A density functional theory study. AB - New polar embedded aromatic stationary phases (mono- and trifunctional versions) that contain an amide-embedded group coupled with a tricyclic aromatic moiety were developed for chromatographic applications and described in the first paper of this series. These phases offered better separation performance for PAHs than for alkylbenzene homologues, and an enhanced ability to differentiate aromatic planarity to aromatic tridimensional conformation, especially for the trifunctional version and when using methanol instead of acetonitrile. In this second paper, a density functional theory study of the retention process is reported. In particular, it was shown that the selection of the suitable computational protocol allowed for describing rigorously the interactions that could take place, the solvent effects, and the structural changes for the monofunctional and the trifunctional versions. For the first time, the experimental data coupled with these DFT results provided a better understanding of the interaction mechanisms and highlighted the importance of the multimodal character of the designed stationary phases: alkyl spacers for interactions with hydrophobic solutes, amide embedded groups for dipole-dipole and hydrogen-bond interactions, and aromatic terminal groups for pi-pi interactions. PMID- 28911941 TI - Headspace solid-phase microextraction coupled to comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry for the analysis of aerosol from tobacco heating product. AB - A method involving headspace solid-phase microextraction (HS-SPME) and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC-TOFMS) was developed and optimised to elucidate the volatile composition of the particulate phase fraction of aerosol produced by tobacco heating products (THPs). Three SPME fiber types were studied in terms of extraction capacity and precision measurements. Divinylbenzene polydimethylsiloxane appeared as the most efficient coating for these measurements. A central composite design of experiment was utilised for the optimization of the extraction conditions. Qualitative and semi-quantitative analysis of the headspace above THP aerosol condensate was carried out using optimised extraction conditions. Semi-quantitative analyses of detected constituents were performed by assuming that their relative response factors to the closest internal standard (itR) were equal to 1. Using deconvoluted mass spectral data (library similarity and reverse match >750) and linear retention indices (match window of +/-15 index units), 205 peaks were assigned to individual compounds, 82 of which (including 43 substances previously reported to be present in tobacco) have not been reported previously in tobacco aerosol. The major volatile fraction of the headspace contained ketones, alcohols, aldehydes, alicyclic hydrocarbons alkenes, and alkanes. The method was further applied to compare the volatiles from the particulate phase of aerosol composition of THP with that of reference cigarette smoke and showed that the THP produced a less complex chemical mixture. This new method showed good efficiency and precision for the peak areas and peak numbers from the volatile fraction of aerosol particulate phase for both THP and reference cigarettes. PMID- 28911942 TI - Future perspectives in high efficient and ultrafast chiral liquid chromatography through zwitterionic teicoplanin-based 2-MUm superficially porous particles. AB - With the aim of pushing forward the limits of high efficient and ultrafast chiral liquid chromatography, a new Chiral Stationary Phase (CSP) has been prepared by covalently bonding the teicoplanin selector on 2.0MUm Superficially Porous Particles (SPPs). An already validated bonding protocol, which permits to achieve teicoplanin-based CSPs exhibiting zwitterionic behaviour, has been employed to prepare not only the 2.0MUm version of the CSP but also two other analogous CSPs based, respectively, on 2.7MUm SPPs and 1.9MUm Fully Porous Particles (FPPs). The kinetic performance of these CSPs has been compared through the analysis of both van Deemter curves and kinetic plots by employing in-house packed columns of 4.6mm internal diameter and different lengths (20, 50 and 100mm). In particular on the columns packed with 2.0MUm SPPs, extremely large efficiencies were observed for both achiral (>310,000 theoretical plates/meter, N/m; hr: 1.61) and chiral compounds (>290,000 N/m; hr: 1.72) in HILIC conditions. Thanks to their efficiency and enantioselectivity, these CSPs were successfully employed in ultrafast chiral separations. As an example, the enantiomers of haloxyfop were baseline resolved in about 3s, with a resolution higher than 2.0, (flow rate: 8mL/min) on a 2cm long column packed with the 2.0MUm chiral SPPs. PMID- 28911943 TI - Heterozygous deletion of AKT1 rescues cardiac contractility, but not hypertrophy, in a mouse model of Noonan Syndrome with Multiple Lentigines. AB - Noonan Syndrome with Multiple Lentigines (NSML) is associated with congenital heart disease in form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Genetically, NSML is primarily caused by mutations in the non-receptor protein tyrosine phosphatase SHP2. Importantly, certain SHP2 mutations such as Q510E can cause a particularly severe form of HCM with heart failure in infancy. Due to lack of insight into the underlying pathomechanisms, an effective custom tailored therapy to prevent heart failure in these patients has not yet been found. SHP2 regulates numerous signaling cascades governing cell growth, differentiation, and survival. Experimental models have shown that NSML mutations in SHP2 cause dysregulation of downstream signaling, in particular involving the protein kinase AKT. AKT, and especially the isoform AKT1, has been shown to be a major regulator of cardiac hypertrophy. We therefore hypothesized that hyperactivation of AKT1 is required for the development of Q510E-SHP2-induced HCM. We previously generated a transgenic mouse model of NSML-associated HCM induced by Q510E-SHP2 expression in cardiomyocytes starting before birth. Mice display neonatal-onset HCM with initially preserved contractile function followed by functional decline around 2months of age. As a proof-of-principle study, our current goal was to establish to which extent a genetic reduction in AKT1 rescues the Q510E-SHP2-induced cardiac phenotype in vivo. AKT1 deletion mice were crossed with Q510E-SHP2 transgenic mice and the resulting compound mutant offspring analyzed. Homozygous deletion of AKT1 greatly reduced viability in our NSML mouse model, whereas heterozygous deletion of AKT1 in combination with Q510E-SHP2 expression was well tolerated. Despite normalization of pro-hypertrophic signaling downstream of AKT, heterozygous deletion of AKT1 did not ameliorate cardiac hypertrophy induced by Q510E-SHP2. However, the functional decline caused by Q510E-SHP2 expression was effectively prevented by reducing AKT1 protein. This demonstrates that AKT1 plays an important role in the underlying pathomechanism. Furthermore, the functional rescue was associated with an increase in the capillary-to-cardiomyocyte ratio and normalization of capillary density per tissue area in the compound mutant offspring. We therefore speculate that limited oxygen supply to the hypertrophied cardiomyocytes may contribute to the functional decline observed in our mouse model of NSML-associated HCM. PMID- 28911945 TI - Long-term follow-up and survivorship of single-radius, posterior-stabilized total knee arthroplasty. AB - BACKGROUND: We sought to determine the 10-year survivorship of single-radius, posterior-stabilized total knee arthroplasty (TKA) in Asian patients. We also aimed to determine whether the long-term clinical and radiographic results differed between patients with and without patellar resurfacing. METHODS: This retrospective study included 148 (115 patients) consecutive single-radius, posterior-stabilized TKAs. Ten-year survivorship analysis was performed using the Kaplan-Meier method with additional surgery for any reason as the end-point. Furthermore, long-term clinical and radiographic results of 109 knees (74%; 84 patients) with more than 10-year follow-up were analyzed. Ten-year survivorship and long-term outcomes after surgery were determined, and outcomes were compared between patients with and without patellar resurfacing. RESULTS: The cumulative survival rate of the single-radius posterior-stabilized TKA of 148 knees was 97.7% (95% confidence interval, 93.1%-99.3%) at 10 years after surgery. Three knees required additional surgery during the 10-year follow-up because of one case of instability and two cases of periprosthetic infections. Mean postoperative Knee Society knee score and function score were 97 points and 75 points, respectively. There were no cases of aseptic loosening of the prosthesis, even though a non-progressive radiolucent line was found in 10 (9%) knees. There were no differences in postoperative scores and degree of patellar tilt and displacement between patients with and without patellar resurfacing. CONCLUSIONS: Single-radius, posterior-stabilized TKA showed satisfactory long-term clinical and radiographic outcomes in Asian patients regardless of patellar resurfacing, with comparable survivorship to that reported in westerners. PMID- 28911944 TI - Assessing the mechanisms of cholesteryl ester transfer protein inhibitors. AB - Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD. PMID- 28911946 TI - Suboptimal Agreement Among Cytopathologists in Diagnosis of Malignancy Based on Endoscopic Ultrasound Needle Aspirates of Solid Pancreatic Lesions: A Validation Study. AB - BACKGROUND & AIMS: Despite the widespread use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter-observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS-FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. METHODS: We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter-observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS-FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter-observer agreement (IOA) was calculated using multi-rater kappa (kappa) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. RESULTS: The IOA for final diagnoses, based on cytologic analysis, was moderate (kappa = 0.56; 95% CI, 0.43-0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (kappa = 0.007; 95% CI, -0.03 to -0.04) and qualitative parameters (kappa = 0.5; 95% CI, 0.47-0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1-26.89). CONCLUSIONS: There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists. PMID- 28911948 TI - Pearly Esophageal Papules: An Innocent Bystander in the Evaluation of Dysphagia. PMID- 28911947 TI - Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial. AB - BACKGROUND & AIMS: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial. METHODS: We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels. RESULTS: The patients' mean model for end-stage disease score was 20.9 +/- 6.6. The primary end point (albumin >=30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 +/- 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded. CONCLUSIONS: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014 002300-24 and ISRCTN14174793. PMID- 28911950 TI - Reply. PMID- 28911949 TI - Postprandial High-Resolution Impedance Manometry Identifies Mechanisms of Nonresponse to Proton Pump Inhibitors. AB - BACKGROUND & AIMS: Recognition of rumination and supragastric belching is often delayed as symptoms may be mistakenly attributed to gastroesophageal reflux disease. However, distinct from gastroesophageal reflux disease, rumination and supragastric belching are more responsive to behavioral interventions than to acid-suppressive and antireflux therapies. Postprandial high-resolution impedance manometry (PP-HRIM) is an efficient method to identify rumination and belches. We investigated the distribution of postprandial profiles determined by PP-HRIM, and identified patient features associated with postprandial profiles among patients with nonresponse to proton pump inhibitors (PPIs). METHODS: We performed a retrospective analysis of PP-HRIM studies performed on 94 adults (mean age, 50.6 y; 62% female) evaluated for PPI nonresponsiveness at an esophageal referral center, from January 2010 through May 2016. Following a standard esophageal manometry protocol, patients ingested a solid refluxogenic test meal (identified by patients as one that induces symptoms) with postprandial monitoring up to 90 minutes (median, 50 min). Patients were assigned to 1 of 4 postprandial profiles: normal; reflux only (>6 transient lower esophageal sphincter relaxations (TLESRs)/h); supragastric belch (>2 supragastric belches/h), with or without TLESR; or rumination (>=1 rumination episode/h) with or without TLESR and supragastric belching. The primary outcome was postprandial profile. RESULTS: Of the study participants, 24% had a normal postprandial profile, 14% had a reflux only profile, 42% had a supragastric belch profile, and 20% had a rumination profile. In multinomial regression analysis, the rumination group most frequently presented with regurgitation, the supragastric belch and rumination groups were younger in age, and the reflux-only group had a lower esophagogastric junction contractile integral. The number of weakly acidic reflux events measured by impedance-pH monitoring in patients receiving PPI therapy was significantly associated with frequency of rumination episodes and supragastric belches. CONCLUSIONS: In a retrospective analysis of 94 nonresponders to PPI therapy evaluated by PP-HRIM, we detected an abnormal postprandial pattern in 76% of cases: 42% of these were characterized as supragastric belching, 20% as rumination, and 14% as reflux only. Age, esophagogastric junction contractility, impedance-pH profiles, and symptom presentation differed significantly among groups. PP-HRIM can be used in the clinic to evaluate mechanisms of PPI nonresponse. PMID- 28911951 TI - Anniversary Tribute From the Editors of Clinical Gastroenterology and Hepatology. PMID- 28911952 TI - Trends in food insecurity among California residents from 2001 to 2011: Inequities at the intersection of immigration status and ethnicity. AB - Although immigrants are healthier than non-immigrants on numerous outcomes, the reverse appears to be true with regards to food insecurity. Most studies ignore heterogeneity in the risk for food insecurity within immigration status and by ethnicity, even though significant variation likely exists. We consider how immigration status and ethnicity are related to trends in food insecurity among Latinos and Asians in California from 2001 through 2011. Data come from the 2001 to 2011 restricted California Health Interview Survey (n=245,679). We categorized Latinos and Asians as US-born, naturalized/legal permanent residents (naturalized/LPR), and non-LPRs (students, temporary workers, refugees, and undocumented persons). Multivariable weighted logistic regression analyses assessed temporal trends over the 10-year period after adjustment for demographics, socioeconomic characteristics, and program participation. Across this period, US-born Asians reported similar levels of food insecurity as US-born Whites. Conversely, Latinos, regardless of immigration status or nativity, and Asian immigrants (i.e., naturalized/LPR and non-LPR) reported greater food insecurity than US-born Whites. Further, from 2001 through 2009, non-LPR Latinos reported higher risk of food insecurity than naturalized/LPR Latinos. Thus, food insecurity differs between ethnic groups, but also differs within ethnic group by immigration status. Efforts to reduce food insecurity should consider the additional barriers to access that are faced by immigrants, particularly those without legal permanent residency. PMID- 28911953 TI - Associations between complementary medicine utilization and influenza/pneumococcal vaccination: Results of a national cross-sectional survey of 9151 Australian women. AB - Influenza and pneumococcal vaccination is recommended for all adults, with older adults considered a high-risk group for targeted intervention. As such it is important for factors affecting vaccine uptake in this group to be examined. Complementary medicine (CM) use has been suggested as a possible factor associated with lower vaccination uptake. To determine if associations exist between influenza and pneumococcal vaccine uptake in older Australian women and the use of CM, data from women aged 62-67years surveyed as part of the Australian Longitudinal Study on Women's Health (ALSWH) were analyzed in 2013 regarding their health and health care utilization. Associations between the uptake of influenza and pneumococcal vaccinations and the use of CM were analyzed in 2016 using chi-squared tests and multiple logistic regression modelling. Of the 9151 women, 65.6% and 17.7% reported that they had influenza and pneumococcal vaccination within the past 3years respectively. Regression analyses show that women who consulted naturopaths/herbalists (OR=0.64) and other CM practitioners (OR=0.64) were less likely to have vaccination (influenza only), as were women who used yoga (OR=0.77-0.80) and herbal medicines (OR=0.78-0.83) (influenza and pneumococcal). Conversely, women using vitamin supplements were more likely to receive either vaccination (OR=1.17-1.24) than those not using vitamin supplements. The interface between CM use and influenza and pneumococcal vaccination uptake in older women appears complex, multi-factorial and often highly individualized and there is a need for further research to provide a rich examination of the decision-making and motivations of stakeholders around this important public health topic. PMID- 28911954 TI - Erratum of "Hearing thresholds at high frequency in patients with cystic fibrosis: a systematic review". PMID- 28911955 TI - Somatic Mutations and Ancestry Markers in Hispanic Lung Cancer Patients. AB - INTRODUCTION: To address the lack of genomic data from Hispanic/Latino (H/L) patients with lung cancer, the Latino Lung Cancer Registry was established to collect patient data and biospecimens from H/L patients. METHODS: This retrospective observational study examined lung cancer tumor samples from 163 H/L patients, and tumor-derived DNA was subjected to targeted-exome sequencing (>1000 genes, including EGFR, KRAS, serine/threonine kinase 11 gene [STK11], and tumor protein p53 gene [TP53]) and ancestry analysis. Mutation frequencies in this H/L cohort were compared with those in a similar cohort of non-Hispanic white (NHW) patients and correlated with ancestry, sex, smoking status, and tumor histologic type. RESULTS: Of the adenocarcinomas in the H/L cohort (n = 120), 31% had EGFR mutations, versus 17% in the NHW control group (p < 0.001). KRAS (20% versus 38% [p = 0.002]) and STK11 (8% versus 16% [p = 0.065]) mutations occurred at lower frequency, and mutations in TP53 occurred at similar frequency (46% versus 40% [p = 0.355]) in H/L and NHW patients, respectively. Within the Hispanic cohort, ancestry influenced the rate of TP53 mutations (p = 0.009) and may have influenced the rate of EGFR, KRAS, and STK11 mutations. CONCLUSIONS: Driver mutations in H/L patients with lung adenocarcinoma differ in frequency from those in NHW patients associated with their indigenous American ancestry. The spectrum of driver mutations needs to be further assessed in the H/L population. PMID- 28911956 TI - ALK and ROS1 Double-Rearranged Lung Squamous Cell Carcinoma Responding to Crizotinib Treatment: A Case Report. PMID- 28911957 TI - A double blind randomized experimental study on the use of IgM-enriched polyclonal immunoglobulins in an animal model of pneumonia developing shock. AB - BACKGROUND: Patients with severe pneumonia often develop septic shock. IgM enriched immunoglobulins have been proposed as a potential adjuvant therapy for septic shock. While in vitro data are available on the possible mechanisms of action of IgM-enriched immunoglobulins, the results of the in vivo experimental studies are non-univocal and, overall, unconvincing. We designed this double blinded randomized controlled study to test whether IgM-enriched immunoglobulins administered as rescue treatment in a pneumonia model developing shock, could either limit lung damage and/or contain systemic inflammatory response. METHODS: Thirty-eight Sprague Dawley rats were ventilated with injurious ventilation for 30min to prime the lung. The rats were subsequently randomized to received intratracheal instillation of either lipopolysaccharide (LPS) (12mg/kg) or placebo followed by 3.5h of protective mechanical ventilation. IgM-enriched immunoglobulins at 25mg/h (0.5mL/h) or saline were intravenously administered in the last hour of mechanical ventilation. During the experiment, gas exchange and hemodynamic measurements were recorded. Thereafter, the animals were sacrificed, and blood and organs were stored for cytokines measurements. RESULTS: Despite similar lung and hemodynamic findings, the administration of IgM-enriched immunoglobulins compared to placebo significantly modulates the inflammatory response by increasing IL-10 levels in the bloodstream and by decreasing TNF alpha in bronchoalveolar lavage (BAL) fluid. Furthermore, in vitro data suggest that IgM-enriched immunoglobulins induce monocytes production of IL-10 after LPS stimulation. CONCLUSIONS: In an in vivo model of pneumonia developing shock, IgM enriched immunoglobulins administered as rescue treatment enhance the anti inflammatory response by increasing blood levels of IL-10 and reducing TNF-alpha in BAL fluid. PMID- 28911958 TI - Application of Real-Time Surgical Navigation for Zygomatic Implant Insertion in Patients With Severely Atrophic Maxilla. AB - PURPOSE: Computer-aided treatment technology has extended its applications to oral implantology. This report describes the authors' initial clinical experience on the application of a commercially available navigation system (VectorVision) in zygomatic implant (ZI) insertion in the severely atrophic maxilla. MATERIALS AND METHODS: This was a retrospective longitudinal study. Eligible patients with maxillary edentulism who were treated with ZI placement were enrolled. Treatment planning was performed on the computer based on previously obtained 3-dimensional imaging data. The surgical procedure was carried out under the guidance of a surgical navigation system. The outcome variable was safety and additional variables were ZI survival rate and radiologic bone-to-implant contact (rBIC) area in the zygoma. Statistical analysis was performed with SPSS 16.0 for Windows (SPSS, Inc, Chicago, IL). RESULTS: Fifteen patients (8 men, 7 women; age range, 30 to 69 yr; average age, 43 +/- 3.5 yr) were eligible for the study and were enrolled from May 2015 through September 2016. Of the included patients, each of 4 patients received 1 ZI on each side of the zygomatic bone and 2 to 4 standard implants in the edentulous anterior maxilla; the other 11 received a ZI "quad approach" without standard implant insertion. All ZIs were anchored in the site of the maxillary alveolar process and zygomatic bone, and no critical anatomic structure injuries occurred during insertion and postoperative radiographic examination. All ZIs achieved osseointegration, for an overall survival rate of 100% after early healing. The overall rBIC area of ZIs in the study was 4.1 to 24.7 mm (average, 14.5 +/- 4.6 mm). CONCLUSION: For the limited clinical cases treated in this study, the procedure for ZI placement was feasible and reliable with the guidance of the surgical navigation system. In addition, the potential risk of complications was minimized and ZIs were placed to make the best possible use of the available bone volume. PMID- 28911959 TI - Histological Changes in the Periosteum Following Subperiosteal Expansion in Rabbit Scalp. AB - PURPOSE: In intraoral bone grafting, tension-free coverage of the recipient site with periosteal flap results in optimal wound closure. Tissue expansion could be a suitable modality to obtain soft tissue in the oral cavity. The aim of this study was to assess the histology of the periosteum after subperiosteal expansion in the rabbit scalp. MATERIALS AND METHODS: In this animal study, 6 rectangular tissue expanders were placed in the skulls of 6 male white New Zealand rabbits; in 6 control rabbits, an incision was made to the periosteum but no expansion was performed. Three months after the surgeries, the rabbits were sacrificed and tissue samples were stained with hematoxylin and eosin and Masson trichrome. RESULTS: The number of osteoblasts, fibroblasts, and blood vessels and the density of collagen fibers were significantly increased in the experimental group compared with the control group (P < .001). CONCLUSIONS: Subperiosteal tissue expansion in the rabbit scalp markedly increased the histologic components of the periosteum involved in bone regeneration. PMID- 28911960 TI - Characterization of the adrenocorticotrophic hormone - induced mouse model of resistance to antidepressant drug treatment. AB - Approximately 30-60% of patients treated with existing antidepressants fail to achieve remission of depressive symptoms leading to Treatment Resistant Depression (TRD). There is an urgent need to develop novel medications, which is highly limited by the non-availability of relevant animal models with good predictive validity. ACTH administration has been shown to result in the resistance to acute and chronic effects of imipramine. However, the pharmacology of the model and the mechanisms contributing to the resistance are not completely understood. Furthermore, it is not known whether the ACTH administered animals show signs of depression-like behavior. Accordingly, we characterized the behavioral profile and sensitivity to antidepressants in BALB/c mice treated with ACTH and to evaluate some of the mechanisms responsible for the behavioral effects. Daily treatment with ACTH for 14, 21 or 28days failed to produce a depression-like phenotype in the sucrose preference test, voluntary wheel running or FST. In contrast, the acute antidepressant response in the FST was no longer observed in ACTH mice treated with fluoxetine, imipramine, duloxetine or bupropion. Interestingly, the combination of fluoxetine and a low dose of olanzapine, or the combination of fluoxetine and bupropion was efficacious in ACTH treated mice. Further, the sensitivity to a GluN2B receptor antagonist, radiprodil was retained in the ACTH model. To understand the mechanism responsible for the diminished response in these mice, we evaluated p11 (S100A10) mRNA expression and 5-HT2A protein expression. p11 expression was decreased and 5 HT2A protein content increased in ACTH treated mice. In summary, this model may have utility for the identification of novel treatments for TRD. PMID- 28911961 TI - Sociocultural Considerations in Juvenile Arthritis: A Review. AB - PROBLEM: Juvenile Arthritis (JA) is one of the most common autoimmune diseases in children. A variety of sociocultural factors that influence health outcomes in children with JA have been examined in previous research. However, clinical guidelines to guide the care of these children lack support because this research has not been systematically examined and synthesized. ELIGIBILITY CRITERIA: Primary research articles from five internet databases were included if they were peer-reviewed articles in English of studies conducted in the U.S. or Canada and referenced one or more determinants of health, quality of life, socioeconomic status, or health disparities in children with JA. SAMPLE: The final sample included 16 articles representing 2139 children and 939 parents. RESULTS: Topics covered in the studies included medication compliance, electronic medical records, environmental risk factors, economic hardship, parental coping, leisure activities, and their effects on patient outcomes including disability and quality of life. Patients with Medicaid experienced more severe outcomes than patients with private insurance despite equivalent levels of healthcare utilization. Other important topics, such as effects of the physical environment and alcohol use, were missing from the literature. CONCLUSIONS: Five categories of health determinants were found to influence outcomes: biology, individual behaviors, social environment, physical environment, and health services. Disparities continue to exist for racial and ethnic minority children with JA and those of low socioeconomic status. IMPLICATIONS: Sociocultural factors should be taken into consideration when developing care plans, research studies, and policies in order to remove barriers and promote the best outcomes for this vulnerable population. PMID- 28911962 TI - Development and psychometric validation of a questionnaire to evaluate nurses' adherence to recommendations for preventing pressure ulcers (QARPPU). AB - AIM OF THE STUDY: The main objective of this work is the development and psychometric validation of an instrument to evaluate nurses' adherence to the main recommendations issued for preventing pressure ulcers. MATERIAL AND METHODS: An instrument was designed based on the main recommendations for the prevention of pressure ulcers published in various clinical practice guides. Subsequently, it was proceeded to evaluate the face and content validity of the instrument by an expert group. It has been applied to 249 Spanish nurses took part in a cross sectional study to obtain a psychometric evaluation (reliability and construct validity) of the instrument. The study data were compiled from June 2015 to July 2016. RESULTS: From the results of the psychometric analysis, a final 18-item, 4 factor questionnaire was derived, which explained 60.5% of the variance and presented the following optimal indices of fit (CMIN/DF: 1.40 p < 0.001; GFI: 0.93; NFI: 0.92; CFI: 0.98; TLI: 0.97; RMSEA: 0.04 (90% CI 0.025-0.054). CONCLUSIONS: The results obtained show that the instrument presents suitable psychometric properties for evaluating nurses' adherence to recommendations for the prevention of pressure ulcers. PMID- 28911963 TI - Evolution of Computed Tomography Imaging the First Year after Endovascular Sealing of Infrarenal Aortic Aneurysms Using the Nellix Device. AB - BACKGROUND: The Nellix endovascular aneurysm sealing (EVAS) system is an alternative endovascular treatment option for infrarenal aortic aneurysms (AAAs), with a unique appearance on computed tomography angiography (CTA). Normal evolution of post-EVAS CTA appearance follow-up is still largely unknown and important to timely detect eventual complications. The objective is to assess the normal appearance of CTA images 30 days and 1 year after EVAS in 50 consecutive patients. METHODS: Fifty patients treated with Nellix EVAS for an infrarenal AAA were included from 3 hospitals. Using dedicated software, a total of 150 CTA scans were analyzed by predetermined variables per anatomical segment. RESULTS: Thirty days post-EVAS, there was a slight, but not statistically significant, increase in AAA diameter that returned to the preoperative value after 1 year. A shift in total aortic volume distribution was observed without changing aortic diameter, including a trend toward a decreased thrombus volume (85.6 +/- 49.1 mL and 78.8 +/- 35.5 mL at 30 days and 1 year, respectively, P < 0.242) and a slight, but statistically significant, increase in polymer volume (68.2 +/- 34.1 mL and 71.9 +/- 35.2 mL at 30 days and 1 year, respectively, P < 0.001). The beta angle (P = 0.06) and iliac artery angulation (P < 0.001) decreased after implant. The latter returned to its original state after 1 year, whereas the neck straightening remained. Over time, there was a significant decrease in radiodensity in the middle of the polymer-filled endobags with an increase at its edges (P < 0.05). Thrombus radiodensity significantly increased over the first year (P < 0.05). Diameters of the infrarenal neck and common iliac arteries remained unchanged, no endoleaks were observed, and the position of the device was stable. CONCLUSIONS: Change of CT appearance after EVAS is unique, and as such, the judgment of these images requires experience. The appearance of the endobags in respect to volume and radiodensity differ from classic EVAR. Normal changes over time are observed in aortoiliac angulation, volumes, and radiodensities. PMID- 28911964 TI - Adventitial Cystic Disease: Complicated and Uncomplicated. AB - Three cases of adventitial cystic disease of popliteal artery are reported; 1 complicated with associated thrombosis of the popliteal artery and 2 uncomplicated. Operative management and follow-up are described. PMID- 28911966 TI - Fluoxetine administration during adolescence attenuates cognitive and synaptic deficits in adult 3*TgAD mice. AB - Fluoxetine (FLX) has broad neurobiological functions and neuroprotective effects; however, the preventive effects of FLX on cognitive impairments in Alzheimer's disease (AD) have not been reported. Here, we studied whether adolescent administration of fluoxetine can prevent memory deficits in AD transgenic mice that harbour PS1m146v, APPswe and TauP301L mutations (3 * TgAD). FLX was applied through peritoneal injection to the mice at postnatal day 35 (p35) for 15 consecutive days, and the effects of FLX were observed at 6-month. We found that adolescent administration of FLX improved learning and memory abilities in 6 month-old 3 * TgAD mice. FLX exposure also increased the sizes of the hippocampal CA1, dentate gyrus (DG) and extensive cortex regions, with increased numbers of neurons and higher dendritic spine density. Meanwhile, the synaptic plasticity of neurons in the hippocampus was remodelled, and the expression levels of synaptic related proteins were increased along with activation of the cyclic AMP response element-binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signalling pathway. Finally, we found that FLX effectively prevented the increase of beta-amyloid (Abeta) levels. These data suggest that adolescent administration of the antidepressant drug FLX can efficiently preserve cognitive functions and improve pathologies in 3*Tg AD mice. PMID- 28911965 TI - Physiological roles of CNS muscarinic receptors gained from knockout mice. AB - Because the five muscarinic acetylcholine receptor subtypes have overlapping distributions in many CNS tissues, and because ligands with a high degree of selectivity for a given subtype long remained elusive, it has been difficult to determine the physiological functions of each receptor. Genetically engineered knockout mice, in which one or more muscarinic acetylcholine receptor subtype has been inactivated, have been instrumental in identifying muscarinic receptor functions in the CNS, at the neuronal, circuit, and behavioral level. These studies revealed important functions of muscarinic receptors modulating neuronal activity and neurotransmitter release in many brain regions, shaping neuronal plasticity, and affecting functions ranging from motor and sensory function to cognitive processes. As gene targeting technology evolves including the use of conditional, cell type specific strains, knockout mice are likely to continue to provide valuable insights into brain physiology and pathophysiology, and advance the development of new medications for a range of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and addictions, as well as non opioid analgesics. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'. PMID- 28911967 TI - Applications of nuclear magnetic resonance in lipid analyses: An emerging powerful tool for lipidomics studies. AB - The role of lipids in cell, tissue, and organ physiology is crucial; as many diseases, including cancer, diabetes, neurodegenerative, and infectious diseases, are closely related to absorption and metabolism of lipids. Mass spectrometry (MS) based methods are the most developed powerful tools to study the synthetic pathways and metabolic networks of cellular lipids in biological systems; leading to the birth of an emerging subject lipidomics, which has been extensively reviewed. Nuclear magnetic resonance (NMR), another powerful analytical tool, which allows the visualization of single atoms and molecules, is receiving increasing attention in lipidomics analyses. However, very little work focusing on lipidomic studies using NMR has been critically reviewed. This paper presents a first comprehensive summary of application of 1H, 13C &31P NMR in lipids and lipidomics analyses. The scientific basis, principles and characteristic diagnostic peaks assigned to specific atoms/molecular structures of lipids are presented. Applications of 2D NMR in mapping and monitoring of the components and their changes in complex lipids systems, as well as alteration of lipid profiling over disease development are also reviewed. The applications of NMR lipidomics in diseases diagnosis and food adulteration are exemplified. PMID- 28911968 TI - Macrodislocation of cardiac pacemaker electrodes prior to surgery for renal tumour. PMID- 28911969 TI - Airway management of saber-sheath trachea using single use flexible videoscope. PMID- 28911971 TI - The effects of house dust mite sublingual immunotherapy tablet on immunologic biomarkers and nasal allergen challenge symptoms. PMID- 28911970 TI - Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways. AB - BACKGROUND: Oxidative stress-induced mitochondrial dysfunction can contribute to inflammation and remodeling in patients with chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. OBJECTIVE: We sought to examine the effect of induced pluripotent stem cell-derived mesenchymal stem cells (iPSC MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. METHODS: ASMCs were cocultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (DeltaPsim), and apoptosis were measured. Conditioned medium from iPSC MSCs and transwell cocultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyperresponsiveness in ozone-exposed mice was also investigated. RESULTS: Coculture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis, and DeltaPsim loss in ASMCs. iPSC-MSC-conditioned medium or transwell cocultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not DeltaPsim or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct coculture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyperresponsiveness, and inflammation in mouse lungs. CONCLUSION: iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs while reducing airway inflammation and hyperresponsiveness. These effects are, at least in part, dependent on cell-cell contact, which allows for mitochondrial transfer, and paracrine regulation. Therefore iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases, such as COPD. PMID- 28911972 TI - Sex-specific effects of developmental lead exposure on the immune-neuroendocrine network. AB - The environmental toxicant lead (Pb) has long been known to induce neurological deficits. The 1st century Greek physician Pedanius Dioscorides noted that "lead makes the mind give way". Current studies are suggesting the effects of Pb on behaviors may involve the immune system and conversely some immunomodulatory changes may be due to Pb effects in the central nervous system. Although Pb induced disorders do not appear to discriminate among females and males, this report discusses the differences observed in human and animal studies regarding differential gender effects on gene expression after Pb exposure. The overall ill health outcomes are apparent with variant levels of Pb exposure and exposures at different times in development. However, the consensus is that doses leading to blood lead levels>5MUg/dl and prenatal exposures are most pathogenic. Although the general detriments induced by Pb may be similar in females and males, there are sex specific outcomes on health and behavior. It is suggested that Pb induces more oxidative stress in females and more upregulation of genes responding to oxidative stress, while males have more proteolytic destruction; but in both cases, there is generation of altered/denatured self-constituents causing inflammation and loss of homeostasis of neuronal and immune functions. The higher estrogen levels of females are indicated as the reason for more Pb-induced reactive oxygen species in females. This review describes some of the different genes involved in female and male responses to Pb exposure and involved pathways. PMID- 28911973 TI - Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress. AB - Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1-(2,2-dimethyltetrahydrofuro[2,3][1,3]dioxol-5-yl)ethane-1,2-diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia-induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose-induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na+/K+-ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca2+ level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na+/K+-ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose-induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM-associated complications. PMID- 28911974 TI - Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons. AB - The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q<0.05; enrichment range 1.40-9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting beta-cells and neurons and underline the existence of trans-nosology pathways in diabetes and its co morbidities. PMID- 28911975 TI - Selection shapes the patterns of codon usage in three closely related species of genus Misgurnus. AB - Neutrality plots revealed that selection probably dominates codon bias, whereas mutation plays only a minor role, in shaping the codon bias in three loaches, Misgurnus anguillicaudatus, M. mohoity, and M. bipartitus. These three species also clearly showed similar tendencies in the preferential usage of codons. Nineteen, nine, and 14 preferred codon pairs and 179, 182, and 173 avoided codon pairs were also detected in M. anguillicaudatus, M. bipartitus, and M. mohoity, respectively, and the most frequently avoided type of cP3-cA1 dinucleotide in these species was nnUAnn. The expression-linked patterns of codon usage revealed that higher expression was associated with higher GC3, lower ENC, and a smaller proportion of amino acids with high size/complexity (S/C) scores in these three species. These results elucidate selectively driven codon bias in Misgurnus species, and reveal the potential importance of expression-mediated selection in shaping the genome evolution of fish. PMID- 28911976 TI - Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study. AB - AIMS: We assessed the long-term risk of cataract following a pregnancy complicated by gestational diabetes. METHODS: We carried out a longitudinal cohort study of 1,108,541 women who delivered infants between 1989-2013 in Quebec, Canada, with follow-up extending up to 25years later. The cohort included 71,862 women with gestational diabetes and 5247 with cataracts. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of gestational diabetes with subsequent risk of cataract, adjusted for age, parity, socioeconomic status, time period, comorbidity, and type 2 diabetes. RESULTS: Women with gestational diabetes had an elevated incidence of cataract (22.6 per 1000) compared with no gestational diabetes (15.1 per 1000), with 1.15 times the risk (95% CI 1.04-1.28). Women with gestational diabetes who subsequently developed type 2 diabetes had a higher risk of cataract compared with no gestational and type 2 diabetes (HR 3.62, 95% CI 3.01-4.35), but women with gestational diabetes who did not develop type 2 diabetes continued to be at risk (HR 1.12, 95% CI 1.00-1.25). CONCLUSIONS: Gestational diabetes may be an independent risk factor for cataract later in life, although risks are greatest for women who subsequently develop type 2 diabetes. PMID- 28911977 TI - Screening for sexual dissatisfaction among people with type 2 diabetes in primary care. AB - AIMS: The identification and discussion of sexual care needs in people with type 2 diabetes mellitus (T2DM) in primary care is currently insufficient. The objective of this study was to determine the prevalence of sexual dissatisfaction, sexual problems and need for help by using a screening instrument among people with T2DM in primary care. METHODS: Data were collected in 45 general practices in the Netherlands from January 2015 to February 2016. The Brief Sexual Symptom Checklist (BSSC) was used to screen among 40-75 year old men and women. RESULTS: In total, 786 people with T2DM (66.5% men) were screened. The prevalence of sexual dissatisfaction was 36.6%, significantly higher among men than among women (41.1% vs. 27.8%). Sexually dissatisfied men most often reported erectile dysfunction (71.6%); for sexually dissatisfied women, low sexual desire (52.8%) and lubrication problems (45.8%) were most common. More than half of all dissatisfied people had a need for care (61.8%), significantly more men than women (66.8% vs. 47.2%). CONCLUSIONS: One third of people with T2DM is sexually dissatisfied and more than half of these people report a need for help. The BSSC could be used a tool to proactively identify sexually dissatisfied people in primary care. PMID- 28911978 TI - Effect of 12-month resistance and endurance training on quality, quantity, and function of skeletal muscle in older adults requiring long-term care. AB - Older adults requiring long-term care will experience age-associated deterioration of the quality and quantity of skeletal muscle if no interventions are performed. Long-term training is considered a typical intervention method and is effective for improvement of both muscle quantity and physical function. However, how such training affects muscle quality [i.e., fat-to-muscle ratio as determined by echo intensity (EI)] in older adults requiring long-term care remains unclear. The purpose of this study was to investigate the effects of a 12 month physical training intervention on the quality and quantity of skeletal muscle, physical function, and blood chemistry in older adults requiring long term care. Seventeen older adults requiring long-term care (Tr-group) and 15 healthy older adults (Cont-group) participated in this study. Patients in the Tr group performed exercises consisting of resistance and endurance training once or twice a week for 12months. The EI and muscle thickness of the thigh were calculated from the rectus femoris and biceps femoris using B-mode transverse ultrasound images. Physical functions (isometric knee extension peak torque, sit to-stand test, 5-m normal/maximal speed walking, handgrip strength, and timed up and go test) and blood lipid components including adipocytokines were measured at three points, i.e. baseline and 6 and 12months after. The thigh EI was significantly lower after 6months of training than baseline, and it returned to the initial level after 12months of training (baseline, 70.2+/-8.3a.u.; 6months, 64.1+/-11.2a.u.; 12months, 72.3+/-7.2a.u.). The thigh muscle thickness, 5-m maximal speed walking, and knee extension torque were significantly improved after 12months of training (P<0.05). The blood chemistry parameters did not significantly change. These results demonstrate that a 12-month training intervention contributes to improvement of muscle quantity and function with tentative changes in muscle quality but has no effect on blood chemistry in older adults requiring long-term care. We conclude that this type of training has the potential to restore the muscle functional abilities of older adults requiring long-term care. PMID- 28911979 TI - Opening Pandora's Box: Mechanisms of Mycobacterium tuberculosis Resuscitation. AB - Mycobacterium tuberculosis (Mtb) characteristically causes an asymptomatic infection. While this latent tuberculosis infection (LTBI) is not contagious, reactivation to active tuberculosis disease (TB) causes the patient to become infectious. A vaccine has existed for TB for a century, while drug treatments have been available for over 70 years; despite this, TB remains a major global health crisis. Understanding the factors which allow the bacillus to control responses to host stress and mechanisms leading to latency are critical for persistence. Similarly, molecular switches which respond to reactivation are important. Recently, research in the field has sought to focus on reactivation, employing system-wide approaches and animal models. Here, we describe the current work that has been done to elucidate the mechanisms of reactivation and stop reactivation in its tracks. PMID- 28911981 TI - Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke. AB - Experimental stroke leads to microglia activation and progressive neuronal loss at sites of secondary neurodegeneration (SND). These lesions are remote from, but synaptically connected to, primary infarction sites. Previous studies have demonstrated that immune cells are present in sites of infarction in the first hours and days after stroke, and are associated with increased neurodegeneration in peri-infarct regions. However, it is not known whether immune cells are also present in more distal sites where SND occurs. Our study aimed to investigate whether immune cells are present in sites of SND and, if so, how these cell populations compare to those in the peri-infarct zone. Cells were isolated from the thalamus, the main site of SND, and remaining brain tissue 14days post stroke. Analysis was performed using flow cytometry to quantify microglia, myeloid cell and lymphocyte numbers. We identified a substantial infiltration of immune cells in the ipsilateral (stroked) compared to the contralateral (control) thalamus, with a significant increase in the percentage of CD4+ and CD8+ T cells. This result was further quantified using immunofluorescent labelling of fixed tissue. In the remaining ipsilateral hemisphere tissue, there were significant increases in the frequency of CD4+ and CD8+ T lymphocytes, B lymphocytes, Ly6G+ neutrophils and both Ly6G-Ly6CLO and Ly6G-Ly6CHI monocytes. Our results indicate that infiltrating immune cells persist in ischemic tissue after the acute ischemic phase, and are increased in sites of SND. Importantly, immune cells have been shown to play pivotal roles in both damage and repair processes after stroke. Our findings indicate that immune cells may also be involved in the pathogenesis of SND and further clinical studies are warranted to characterise the nature of inflammatory cell infiltrates in human disease. PMID- 28911980 TI - Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction. AB - It is well-established that psychological distress reduces natural killer cell immune function and that this reduction can be due to the stress-induced release of glucocorticoids. Glucocorticoids are known to alter epigenetic marks associated with immune effector loci, and are also known to influence chromatin organization. The purpose of this investigation was to assess the effect of glucocorticoids on natural killer cell chromatin organization and to determine the relationship of chromatin organization to natural killer cell effector function, e.g. interferon gamma production. Interferon gamma production is the prototypic cytokine produced by natural killer cells and is known to modulate both innate and adaptive immunity. Glucocorticoid treatment of human peripheral blood mononuclear cells resulted in a significant reduction in interferon gamma production. Glucocorticoid treatment also resulted in a demonstrable natural killer cell nuclear phenotype. This phenotype was localization of the histone, post-translational epigenetic mark, H3K27me3, to the nuclear periphery. Peripheral nuclear localization of H3K27me3 was directly related to cellular levels of interferon gamma. This nuclear phenotype was determined by direct visual inspection and by use of an automated, high through-put technology, the Amnis ImageStream. This technology combines the per-cell information content provided by standard microscopy with the statistical significance afforded by large sample sizes common to standard flow cytometry. Most importantly, this technology provides for a direct assessment of the localization of signal intensity within individual cells. The results demonstrate glucocorticoids to dysregulate natural killer cell function at least in part through altered H3K27me3 nuclear organization and demonstrate H3K27me3 chromatin organization to be a predictive indicator of glucocorticoid induced immune dysregulation of natural killer cells. PMID- 28911982 TI - Upper aerodigestive tract cancer and oral health status before radiotherapy: A cross-sectional study of 154 patients. AB - OBJECTIVES: We aimed to determine primarily the oral health status of patients with upper aerodigestive tract cancer before radiotherapy, and secondarily the prevalence of risk factors for poor oral status. METHODS: A cross-sectional study was conducted in Marseille University hospital. Assessment criteria were the Decay, Missing and Filled (DMF) Index and periodontal status. RESULTS: One hundred and fifty-four patients, mean age 60.9years, were included. The most common sites of primary tumors were the larynx (28.6%) and oral cavity (26.6%). Current or past smokers accounted for 80.5% of patients and 67% were alcohol abusers. Most patients (83.8%) did not have xerostomia. They ate three meals a day (61%), with sugar consumption in 40%. The median number of daily tooth brushings was 2, with a manual toothbrush (81.2%). Few patients used dental floss or interproximal brushes. Individual DMF index was 17.6 (D=2.3, M=9.3, F=6.0) and was higher in patients with xerostomia and alcohol abusers (P=0.01). Osseous level was 62.3% and 57.8% of patients had osseous infections, which were more common with poor hygiene (P=0.04). Most patients (85.7%) had periodontal disease, but incidence did not significantly differ according to risk factors. DISCUSSION: The DMF index was higher in presence of periodontal disease and osseous infections. Alcohol and xerostomia were associated with a high individual DMF index and osseous infections were more frequent in patients with poor hygiene. Patients with upper aerodigestive tract cancer are at high risk of osteoradionecrosis if they do not receive dental treatment before radiotherapy. PMID- 28911983 TI - Does the association between early life growth and later obesity differ by race/ethnicity or socioeconomic status? A systematic review. AB - PURPOSE: Rapid growth during infancy predicts higher risk of obesity later in childhood. The association between patterns of early life growth and later obesity may differ by race/ethnicity or socioeconomic status (SES), but prior evidence syntheses do not consider vulnerable subpopulations. METHODS: We systemically reviewed published studies that explored patterns of early life growth (0-24 months of age) as predictors of later obesity (>24 months) that were either conducted in racial/ethnic minority or low-SES study populations or assessed effect modification of this association by race/ethnicity or SES. Literature searches were conducted in PubMed and SocINDEX. RESULTS: Ten studies met the inclusion criteria. Faster growth during the first 2 years of life was consistently associated with later obesity irrespective of definition and timing of exposure and outcome measures. Associations were strongest in populations composed of greater proportions of racial/ethnic minority and/or low-SES children. For example, ORs ranged from 1.17 (95% CI: 1.11, 1.24) in a heterogeneous population to 9.24 (95% CI: 3.73, 22.9) in an entirely low-SES nonwhite population. CONCLUSIONS: The impact of rapid growth in infancy on later obesity may differ by social stratification factors such as race/ethnicity and family income. More robust and inclusive studies examining these associations are needed. PMID- 28911984 TI - A multiplex protein-free lateral flow assay for detection of microRNAs based on unmodified molecular beacons. AB - Lateral flow assays (LFAs) have promising potentials for point-of-care applications. Recently, many LFAs have been reported that are based on hybridization of oligonucleotide strands. Mostly, biotinylated capture DNAs are immobilized on the surface of a nitrocellulose membrane via streptavidin interactions. During the assay, stable colorful complexes get formed that are visible by naked eyes. Here, we present an inexpensive and unique design of LFA that applies unmodified oligonucleotides at capture lines. The presented LFA do not utilize streptavidin or any other affinity protein. We employ structural switch of molecular beacons (MB) in combination with base stacking hybridization (BSH) phenomenon. The unique design of the reported LFA provided high selectivity for target oligonucleotides. We validated potential applications of the system for detection of DNA mimics of two microRNAs in multiplex assays. PMID- 28911985 TI - Moving forward in carcinogenicity assessment: Report of an EURL ECVAM/ESTIV workshop. AB - There is an increased need to develop novel alternative approaches to the two year rodent bioassay for the carcinogenicity assessment of substances where the rodent bioassay is still a basic requirement, as well as for those substances where animal use is banned or limited or where information gaps are identified within legislation. The current progress in this area was addressed in a EURL ECVAM- ESTIV workshop held in October 2016, in Juan les Pins. A number of initiatives were presented and discussed, including data-driven, technology driven and pathway-driven approaches. Despite a seemingly diverse range of strategic developments, commonalities are emerging. For example, providing insight into carcinogenicity mechanisms is becoming an increasingly appreciated aspect of hazard assessment and is suggested to be the best strategy to drive new developments. Thus, now more than ever, there is a need to combine and focus efforts towards the integration of available information between sectors. Such cross-sectorial harmonisation will aid in building confidence in new approach methods leading to increased implementation and thus a decreased necessity for the two-year rodent bioassay. PMID- 28911987 TI - Aortitis in giant cell arteritis: diagnosis with FDG PET/CT and agreement with CT angiography. AB - OBJECTIVES: To assess the detection rate of aortitis in giant cell arteritis (GCA) with fluorodeoxyglucose positron emission tomography/computed tomography (PET) and to compare the findings with CT angiography (CTA). METHODS: Fifty-two GCA patients and 27 controls were included. GCA patients had a PET scan at diagnosis (35/52) or during relapse (17/52). Concomitant CTA was performed in 35/52 patients. Aortitis was defined as FDG uptake higher than the liver for PET and wall thickness>=3mm for CTA. Agreement between PET and CTA was evaluated by the kappa coefficient and Spearman correlation coefficient. RESULTS: Aortitis was diagnosed using PET in 40% (14/35) of patients at diagnosis and in 0% of controls (0/27). Agreement was perfect between PET and CT at a patient-based level, and very good at a vascular segment-based level (kappa: 0.72 to 1). PET was positive in 35% (6/17) of patients scanned during GCA relapse, showing aortitis (n=4) and/or articular uptake (n=4). Discrepancies between PET and CT were observed only in relapsing GCA (n=3). Correlation between the maximum standardized uptake value and wall thickness was moderate at diagnosis (r: 0.57 to 0.7) and not statistically significant during relapse. CONCLUSIONS: The detection rate of aortitis in GCA patients using PET is 40%, approximately in the range of CTA rates, suggesting that the two techniques have similar sensitivity. PET seems valuable in relapsing GCA, allowing the detection of vascular and articular activities. PMID- 28911986 TI - Virtual Cell Based Assay simulations of intra-mitochondrial concentrations in hepatocytes and cardiomyocytes. AB - In order to replace the use of animals in toxicity testing, there is a need to predict human in vivo toxic doses from concentrations that cause adverse effects in in vitro test systems. The virtual cell based assay (VCBA) has been developed to simulate intracellular concentrations as a function of time, and can be used to interpret in vitro concentration-response curves. In this study we refine and extend the VCBA model by including additional target-organ cell models and by simulating the fate and effects of chemicals at the organelle level. In particular, we describe the extension of the original VCBA to simulate chemical fate in liver (HepaRG) cells and cardiomyocytes (ICell cardiomyocytes), and we explore the effects of chemicals at the mitochondrial level. This includes a comparison of: a) in vitro results on cell viability and mitochondrial membrane potential (mmp) from two cell models (HepaRG cells and ICell cardiomyocytes); and b) VCBA simulations, including the cell and mitochondrial compartment, simulating the mmp for both cell types. This proof of concept study illustrates how the relationship between intra cellular, intra mitochondrial concentration, mmp and cell toxicity can be obtained by using the VCBA. PMID- 28911988 TI - Primary thromboprophylaxis with low-dose aspirin and antiphospholipid antibodies: Pro's and Con's. AB - Whether primary prophylaxis should be prescribed in individuals with antiphospholipid antibodies (aPL) remains controversial due to the lack of relevant evidence-based data. Indeed, it is unclear whether the benefit of LDA outweighs the risk of major bleeding associated with LDA in a low-risk population. On the contrary, stratification of aPL-positive subjects according to their aPL profile (combination, isotype and titer), presence of other concomitant risk factors for thrombosis and coexistence of an underling autoimmune disease is essential to decide whether primary prophylactic therapy should be prescribed. Additionally, the management of modifiable thrombotic risk factors is a necessary strategy, and the use of transient prophylaxis is crucial during high-risk periods. Specifically designed prospective trials are urgently needed to determine the real prophylactic impact of aspirin, as well as of alternative or concomitant therapeutic strategies such as hydroxychloroquine, statins or DOACS in aPL positive patients. PMID- 28911989 TI - U-47700: A Clinical Review of the Literature. AB - BACKGROUND: U-47700 is a synthetic opioid developed by The Upjohn Company in the 1970s, which has recently appeared in the news and medical literature due to its toxicity. Currently, there are no clinical trial data assessing the safety of U 47700. OBJECTIVE: To describe the signs and symptoms of ingestion, laboratory testing, and treatment modalities for U-47700 intoxication. DISCUSSION: We searched PubMed, Embase, Web of Science, and EBSCO for articles using the term "U 47700" and "47700." The following inclusion criteria were used: had to be in English; full text; must involve humans; must be either a randomized control trial, prospective trial, retrospective analysis, case series, or case report; and must include clinical findings at presentation. We identified and extracted data from relevant articles. Ten relevant articles were included with 16 patients. Patients that died after overdose with U-47700 typically presented to the hospital with pulmonary edema. Patients who survived an overdose presented with decreased mental status and decreased respiratory rate suggestive of an opioid toxidrome. Patients also commonly had tachycardia. Immunoassays failed to identify U-47700, and the identification of U-47700 required the use of chromatographic and spectral techniques. CONCLUSION: We report the first clinical review of U-47700 intoxication. PMID- 28911990 TI - Peri-dome Choroidal Deepening in Highly Myopic Eyes With Dome-Shaped Maculas. AB - PURPOSE: To determine characteristics of peri-dome choroidal deepening (PDCD) surrounding dome-shaped maculas (DSMs) in highly myopic eyes. DESIGN: Observational case series. METHODS: Applying swept-source optical coherence tomography, we examined the posterior pole of highly myopic eyes with DSMs. RESULTS: The study included 91 highly myopic eyes (67 patients; mean age: 60.0 +/ 15.1 years; mean axial length: 30.0 +/- 7.4 mm) with a mean dome height of the DSM of 232 +/- 132 MUm. PDCDs were detected in 53 (58%) eyes. Subfoveal choroidal thickness was significantly thinner in eyes with vs without PDCDs (35 +/- 29 MUm vs 62 +/- 48 MUm; P = .016), while both groups did not vary significantly (all P >= .25) in age, axial length, and dome height. In contrast to peripapillary intrachoroidal cavitations (ICCs), PDCDs consisted of a widened choroid without large low-reflective suprachoroidal spaces. Unlike peripapillary ICCs or macular ICCs, PDCDs were not associated with caving of the overlying retina or backward bowing of the sclera. In the region of the PDCDs, the Bruch membrane (BM) was shorter than the inner scleral surface. Defects of the BM overlying the PDCDs were detected in 20 (38%) eyes. CONCLUSIONS: PDCDs were common findings in highly myopic eyes with DSMs. PDCDs may be associated with a dome-induced inward push of the BM at the top of the DSM, leading to a compression of the subfoveal choroid and, owing to an increased strain of the BM on the dome's slopes, to a relative detachment of BM in the peri-dome region. PMID- 28911991 TI - A Randomized Controlled Trial Comparing Outcomes of Cataract Surgery in Nanophthalmos With and Without Prophylactic Sclerostomy. AB - PURPOSE: To prospectively evaluate visual outcomes and complications during and after cataract surgery with or without prophylactic sclerostomy in nanophthalmic eyes with visually significant cataract. STUDY DESIGN: Randomized controlled trial. METHODS: Sixty nanophthalmic eyes of 60 patients with visually significant cataract were randomly assigned to cataract surgery alone (control group, n = 31) or cataract surgery with concomitant prophylactic sclerostomy (sclerostomy group, n = 29). Surgery was performed using phacoemulsification or manual small-incision cataract surgery (SICS) based on the LOCS III grading score. Group differences in intraoperative and postoperative complications were analyzed and risk factors assessed. RESULTS: Fewer complications were noted in eyes receiving sclerostomy (5/29, 17.2%) as compared to control group eyes (12/31, 38.7%), though differences were marginally significant (P = .065). Four control group, but no sclerostomy group, eyes developed postoperative uveal effusions (P = .04). In multivariable models, sclerostomy decreased the odds of an intraoperative or postoperative complication by 80% (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.04-0.92, P = .039); SICS was associated with a significantly higher risk of complications as compared to phacoemulsification (OR = 5.95, 95% CI = 1.49 23.73, P = .012), while high preoperative intraocular pressure (OR = 4.54, 95% CI = 0.99-20.9, P = .052) and greater lens thickness (OR = 3.38, 95% CI = 0.88 12.91, P = .075) demonstrated a marginally significant association. CONCLUSIONS: Cataract surgery in eyes with nanophthalmos is associated with a high risk for vision-threatening complications. Performing a simultaneous prophylactic sclerostomy with cataract surgery reduces complication rates, particularly uveal effusions. Cataract surgery at earlier stages by phacoemulsification may be more beneficial than undergoing manual SICS. PMID- 28911992 TI - Is Corneal Arcus Independently Associated With Incident Cardiovascular Disease in Asians? AB - PURPOSE: To examine the longitudinal relationship between baseline corneal arcus (CA) and incident cardiovascular disease (CVD) in ethnic Indian and Malay adults in Singapore. DESIGN: Population-based cohort study. METHODS: Indian and Malay adults aged 40-80 years were recruited for baseline and 6-year follow-up visits between 2004-2009 and 2010-2015, respectively (follow-up response rate 73.9%). CA was assessed by ophthalmologists using slit-lamp biomicroscopy. The main outcome was self-reported incident CVD, defined as new myocardial infarction, angina pectoris, or stroke, which developed between baseline and follow-up. Multivariable logistic regression models assessed independent associations between baseline CA and incident CVD, adjusting for traditional CVD risk factors including age, sex, serum cholesterol, hypertension, diabetes, and smoking. We further conducted sex-stratified analyses to identify possible effect modifications. RESULTS: Of the total 3637 participants (overall mean [SD] age: 56 [9] years, 46% male) with available follow-up data, without history of CVD at baseline, 208 (5.7%) incident CVD cases were reported. Participants with CA were more likely to have incident CVD (7.5%) than those without (4.9%). After controlling for traditional CVD risk factors, CA was independently associated with incident CVD (odds ratio [95% confidence interval]: 1.52 [1.07-2.16]) in adjusted models. In sex-stratified models, associations between CA and incident CVD were seen in men (1.73 [1.12-2.67]) and not in women (1.05 [0.56-1.97]). CONCLUSIONS: CA is associated with incident CVD, independent of serum lipids and traditional CVD risk factors, in ethnic Malay and Indian men. Our finding suggests that CA is an additional observable indicator of CVD in men. PMID- 28911993 TI - Ocular Manifestations of Familial Transthyretin Amyloidosis. AB - PURPOSE: Among patients with familial amyloidosis, mutation in the transthyretin (TTR) protein is the most common type. Patients with TTR amyloidosis have been noted to have ocular, especially vitreous, involvement. In this report, an analysis of the types and frequency of ocular manifestations in TTR amyloidosis is presented. DESIGN: Observational case series. METHODS: Two hundred and sixty three patients who presented to Mayo Clinic with TTR amyloidosis between January 1, 1970, and November 1, 2014, consented to be included in the Mayo Clinic amyloidosis database maintained by the Department of Hematology. Fifty-four patients had ocular examinations at a mean of 4.25 +/- 3.93 months after systemic symptoms. RESULTS: Of 108 examined eyes in 54 patients with TTR amyloidosis, there were 26 eyes (24%) in 13 patients with ocular involvement. Patients with ocular involvement were more likely to be women than those without ocular involvement (46% vs 15%, respectively, P = .008) and have significantly worse visual acuity (VA) at presentation (logMAR 0.24 [Snellen equivalent 20/30] vs logMAR 0.00 [Snellen equivalent 20/20], P = .017). The ophthalmic findings included vitreous amyloid (26/26, 100%), neurotrophic keratitis (2/26, 8%), glaucoma (5/26, 19%), and tortuous retinal vessels (4/26, 15%). The glaucoma was classified as open-angle (2/26), exfoliative (2/26), and neovascular following central retinal vein occlusion from amyloidosis (1/26). Ten patients underwent vitrectomy for visually significant vitreous amyloidosis, which significantly improved VA from a baseline of logMAR 0.70 (Snellen equivalent 20/100) to logMAR 0.05 (Snellen equivalent ~20/20), P = .003. Three TTR mutations, Glu89Lys, Gly47Arg, and homozygous Gly6Ser, not previously described, were associated with vitreous amyloid. CONCLUSION: In this large cohort of patients with TTR amyloidosis, female sex and decreased VA were associated with ocular amyloid. Three mutations that have not been previously reported to have vitreous involvement were described: Glu89Lys, Gly47Arg, and homozygous Gly6Ser. PMID- 28911994 TI - Assessment of Optical Coherence Tomography Color Probability Codes in Myopic Glaucoma Eyes After Applying a Myopic Normative Database. AB - PURPOSE: To evaluate the optical coherence tomography (OCT) color probability codes based on a myopic normative database and to investigate whether the implementation of the myopic normative database can improve the OCT diagnostic ability in myopic glaucoma. DESIGN: Comparative validity study. METHODS: In this study, 305 eyes (154 myopic healthy eyes and 151 myopic glaucoma eyes) were included. A myopic normative database was obtained based on myopic healthy eyes. We evaluated the agreement between OCT color probability codes after applying the built-in and myopic normative databases, respectively. Another 120 eyes (60 myopic healthy eyes and 60 myopic glaucoma eyes) were included and the diagnostic performance of OCT color codes using a myopic normative database was investigated. RESULTS: The mean weighted kappa (Kw) coefficients for quadrant retinal nerve fiber layer (RNFL) thickness, clock-hour RNFL thickness, and ganglion cell-inner plexiform layer (GCIPL) thickness were 0.636, 0.627, and 0.564, respectively. The myopic normative database showed a higher specificity than did the built-in normative database in quadrant RNFL thickness, clock-hour RNFL thickness, and GCIPL thickness (P < .001, P < .001, and P < .001, respectively). The receiver operating characteristic curve values increased when using the myopic normative database in quadrant RNFL thickness, clock-hour RNFL thickness, and GCIPL thickness (P = .011, P = .004, P < .001, respectively). CONCLUSION: The diagnostic ability of OCT color codes for detection of myopic glaucoma significantly improved after application of the myopic normative database. The implementation of a myopic normative database is needed to allow more precise interpretation of OCT color probability codes when used in myopic eyes. PMID- 28911995 TI - Ocular Dysfunctions Presenting in Tacrolimus-Induced Posterior Reversible Encephalopathy Syndrome: A Case Presentation. AB - : The constellation of ocular symptoms known as Balint syndrome is a rare disorder seen in bilateral parieto-occipital lesions and is most frequently due to arterial occlusive disease or acute hypertension. Here we present the case of a patient with tacrolimus-induced posterior reversible encephalopathy syndrome (PRES) who presented with optic ataxia, simultanagnosia, and ocular apraxia. These ocular findings, consistent with Balint syndrome, are rarely the initial presentation of PRES. This case highlights the importance of early recognition of this unusual phenomenon, as well as the importance of an individualized rehabilitation plan to maximize functional independence in these patients. LEVEL OF EVIDENCE: V. PMID- 28911996 TI - Accessibility to Tertiary Stroke Centers in Hokkaido, Japan: Use of Novel Metrics to Assess Acute Stroke Care Quality. AB - BACKGROUND: Both the accessibility and availability of stroke specialists are major determinants of patient outcomes following acute ischemic stroke (AIS). The purpose of this study was to implement novel metrics to assess the accessibility of tertiary stroke centers as well as to evaluate regional disparities in stroke specialists. METHODS: Using network analysis in a geographic information system, we calculated areas within 30- and 60-minute travel times to facilities providing intravenous recombinant tissue-type plasminogen activator and mechanical thrombectomy. We further evaluated the accessibility for the proportion of the population aged 65 years or older that resided outside of these areas. Uniformity in the geographical distribution of stroke specialists was then evaluated using optimal statistical analysis. RESULTS: Accessibility varied widely from region to region, with low accessibility being concentrated in rural areas with low population density. Accessibility to facilities providing mechanical thrombectomy was especially low, and 17.8% of elderly individuals lived >=60 minutes from treatment facilities. In addition, the distribution of stroke specialists was uneven compared with the distribution of hospital beds and full-time medical doctors. CONCLUSION: The results of this study revealed regional disparities in the spatial accessibility to treatment facilities, as well as in the distribution of stroke specialists in Hokkaido. These findings provide useful information that could be employed to appropriately allocate resources toward the formation of a medical supply system for patients with AIS. PMID- 28911997 TI - Heart-type fatty acid-binding protein in cardiovascular disease: A systemic review. AB - Fatty acid-binding proteins, whose clinical applications have been studied, are a family of proteins that reflect tissue injury. Heart-type fatty acid-binding protein (H-FABP) is a marker of ongoing myocardial damage and useful for early diagnosis of acute myocardial infarction (AMI). In the past decade, compared to other cardiac enzymes, H-FABP has shown more promise as an early detection marker for AMI. However, the role of H-FABP is being re-examined due to recent refinement in the search for newer biomarkers, and greater understanding of the role of high-sensitivity troponin. We discuss the current role of H-FABP as an early marker for AMI in the era of high sensitive troponin. H-FABP is highlighted as a prognostic marker for a broad spectrum of fatal diseases, viz., AMI, heart failure, arrhythmia, and pulmonary embolism that could be associated with poor clinical outcomes. Because the cut-off value of what constitutes an abnormal H FABP potentially differs for each cardiovascular event and depends on the clinical setting, an optimal cut-off value has not been clearly established. Of note, several factors such as age, gender, and cardiovascular risk factors, which affect H-FABP levels need to be considered in this context. In this review, we discuss the clinical applications of H-FABP as a prognostic marker in various clinical settings. PMID- 28911998 TI - Establishing age-specific reference intervals for anti-Mullerian hormone in adult Chinese women based on a multicenter population. AB - AIM OF THIS STUDY: Anti-Mullerian hormone (AMH) is useful for the assessment of ovarian reserve and treatment of individualized in vitro fertilization (IVF). The aim of this study is to establish AMH reference interval for adult Chinese women on the Beckman Beckman DxI 800 platform. MATERIAL AND METHODS: From May to September 2013, serum from 1169 apparently healthy adult females from five representative cities in China (Beijing, Hangzhou, Guangzhou, Dalian and Urumqi) were collected, and AMH was analyzed on the platform of Beckman DxI 800 automated chemiluminescence immunoassay. Multiple regression analysis was used to investigate the effects of region, sex, age, body mass index (BMI), systolic blood pressure (SBP), exercise on AMH. Age specific reference interval for AMH was established. RESULTS: The main factor affecting AMH levels was age (B=-0.756, P<0.001). The AMH reference intervals for adult Chinese women aged 19-24years, 25 29years, 30-34years, 35-39years, 40-44years, 45-49years and >=50years were 0.74 16.06, 0.67-11.64, 0.50-9.99, 0.09-8.33, 0.04-4.09, 0.01-1.46 and <0.01 0.18ng/ml, respectively. The linear, quadratic and cubic models could either provide good fit regression model to describe the decline of AMH with age (R2=0.40). CONCLUSION: This study firstly established age-specific reference intervals for AMH in Chinese women based on multicenter population. PMID- 28912000 TI - Not enough I say! Expand the remit of living systematic reviews to inform future research. PMID- 28912001 TI - Controversy and debate on clinical genomics sequencing-paper 3: response to "clinical genome-wide sequencing: do not throw out the baby with the bathwater". PMID- 28911999 TI - Living systematic reviews: 4. Living guideline recommendations. AB - While it is important for the evidence supporting practice guidelines to be current, that is often not the case. The advent of living systematic reviews has made the concept of "living guidelines" realistic, with the promise to provide timely, up-to-date and high-quality guidance to target users. We define living guidelines as an optimization of the guideline development process to allow updating individual recommendations as soon as new relevant evidence becomes available. A major implication of that definition is that the unit of update is the individual recommendation and not the whole guideline. We then discuss when living guidelines are appropriate, the workflows required to support them, the collaboration between living systematic reviews and living guideline teams, the thresholds for changing recommendations, and potential approaches to publication and dissemination. The success and sustainability of the concept of living guideline will depend on those of its major pillar, the living systematic review. We conclude that guideline developers should both experiment with and research the process of living guidelines. PMID- 28912002 TI - Living systematic review: 1. Introduction-the why, what, when, and how. AB - Systematic reviews are difficult to keep up to date, but failure to do so leads to a decay in review currency, accuracy, and utility. We are developing a novel approach to systematic review updating termed "Living systematic review" (LSR): systematic reviews that are continually updated, incorporating relevant new evidence as it becomes available. LSRs may be particularly important in fields where research evidence is emerging rapidly, current evidence is uncertain, and new research may change policy or practice decisions. We hypothesize that a continual approach to updating will achieve greater currency and validity, and increase the benefits to end users, with feasible resource requirements over time. PMID- 28912005 TI - Proximal radial artery arteriovenous fistula for hemodialysis vascular access. AB - OBJECTIVE: This study reviewed our experience with proximal radial artery-based arteriovenous fistulas (PRA-AVFs) for hemodialysis vascular access, evaluating characteristics of the patients, functional patency, risk of steal syndrome, survival of the patient, and technical considerations. METHODS: We retrospectively analyzed our database of consecutive patients, identifying those individuals with a PRA-AVF created during a 12-year period. In addition to physical examination, all patients underwent ultrasound vessel mapping by the operating surgeon, identifying the PRA-AVF configuration and outflow target most likely to succeed. RESULTS: PRA-AVFs were created in 1396 individuals during the 12-year study period. The mean age was 59 years (standard deviation, +/-15.9 years); 717 (51%) patients were women, 819 (59%) were diabetic, and 394 (28%) were obese. A transposition procedure was required in 400 patients, and 189 (47%) of these were completed in two-staged operations. Preoperative characteristics with a negative impact on PRA-AVF cumulative patency included female gender (hazard ratio, 1.90; 95% confidence interval, 1.37-2.65), obesity (hazard ratio, 1.92; 95% confidence interval, 1.40-2.65), and younger age. Dialysis-associated steal syndrome (DASS) requiring an intervention occurred in 39 (2.8%) patients, and 85% of these were diabetic. The most common procedures required to restore hand perfusion while preserving the AVF were banding and outflow branch ligation or coil occlusion to decrease access flow. DASS emerged spontaneously in 15 (1.1%) of the patients, and 24 (1.7%) individuals developed hand ischemia requiring intervention after fistulography with balloon angioplasty of the PRA AVF anastomosis during the first years of the study period. Limiting angioplasty balloon size for such patients avoided these uncommon angioplasty-induced DASS events in later years. Primary, primary assisted, and cumulative (secondary) patency rates were 60%, 90%, and 93% at 12 months and 47%, 86%, and 91% at 24 months, respectively. Follow-up was 0.7 to 127 months (median, 25 months). CONCLUSIONS: PRA-AVFs offer excellent functional patency with low risk of dialysis access-related steal syndrome. The antecubital site has a wide range of venous outflow options for both direct PRA-AVFs and transposition procedures. PMID- 28912003 TI - Living systematic reviews: 2. Combining human and machine effort. AB - New approaches to evidence synthesis, which use human effort and machine automation in mutually reinforcing ways, can enhance the feasibility and sustainability of living systematic reviews. Human effort is a scarce and valuable resource, required when automation is impossible or undesirable, and includes contributions from online communities ("crowds") as well as more conventional contributions from review authors and information specialists. Automation can assist with some systematic review tasks, including searching, eligibility assessment, identification and retrieval of full-text reports, extraction of data, and risk of bias assessment. Workflows can be developed in which human effort and machine automation can each enable the other to operate in more effective and efficient ways, offering substantial enhancement to the productivity of systematic reviews. This paper describes and discusses the potential-and limitations-of new ways of undertaking specific tasks in living systematic reviews, identifying areas where these human/machine "technologies" are already in use, and where further research and development is needed. While the context is living systematic reviews, many of these enabling technologies apply equally to standard approaches to systematic reviewing. PMID- 28912004 TI - Living systematic reviews: 3. Statistical methods for updating meta-analyses. AB - A living systematic review (LSR) should keep the review current as new research evidence emerges. Any meta-analyses included in the review will also need updating as new material is identified. If the aim of the review is solely to present the best current evidence standard meta-analysis may be sufficient, provided reviewers are aware that results may change at later updates. If the review is used in a decision-making context, more caution may be needed. When using standard meta-analysis methods, the chance of incorrectly concluding that any updated meta-analysis is statistically significant when there is no effect (the type I error) increases rapidly as more updates are performed. Inaccurate estimation of any heterogeneity across studies may also lead to inappropriate conclusions. This paper considers four methods to avoid some of these statistical problems when updating meta-analyses: two methods, that is, law of the iterated logarithm and the Shuster method control primarily for inflation of type I error and two other methods, that is, trial sequential analysis and sequential meta analysis control for type I and II errors (failing to detect a genuine effect) and take account of heterogeneity. This paper compares the methods and considers how they could be applied to LSRs. PMID- 28912006 TI - Predictors of late aortic intervention in patients with medically treated type B aortic dissection. AB - BACKGROUND: Patients with medically managed type B aortic dissection (TBAD) have a high incidence of aorta-related complications over time. Whereas early thoracic endovascular aortic repair (TEVAR) to seal the entry tear can promote aortic remodeling and prevent late aneurysm formation, there are sparse data as to which patients will benefit from such therapy. The goal of this study was to identify clinical and anatomic factors that are associated with the need for subsequent aortic intervention in patients who present with uncomplicated TBAD. These factors could guide the selection of patients who will benefit from TEVAR in the subacute phase. METHODS: Patients who presented with acute uncomplicated TBAD and were initially managed medically from January 2000 to December 2013 were included in the study. Timing of intervention was stratified into early (within 180 days of initial presentation) and late (181 days and later) cohorts. All patients had follow-up axial imaging studies. These imaging studies were reviewed for anatomic criteria in a retrospective fashion. Predictors of aortic intervention were determined using Cox regression analyses. RESULTS: There were 254 patients (65% men) with medically managed acute TBAD. The average age at presentation was 66.3 years, and 82.5% had a history of hypertension. Mean follow-up was 6.8 years (range, 0.1-13.6 years). There were a total of 97 (38%) patients who required an aortic intervention during follow-up; 30 (12%) patients required an early intervention, and 67 (26%) were treated during late follow-up (100% for aneurysmal degeneration). Predictors of late aortic intervention included entry tear >10 mm (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.5-3.8; P = .03), total aortic diameter >40 mm at time of presentation (OR, 2.2; 95% CI, 1.8 4.3; P = .02), false lumen diameter >20 mm (OR, 1.8; 95% CI, 1.3-4.7; P = .03), and increase in total aortic diameter >5 mm between serial imaging studies (OR, 2.3; 95% CI, 1.3-3.5; P = .02). Complete thrombosis of the false lumen was protective against late operative intervention (OR, 0.22; 95% CI, 0.11-0.48; P < .01). CONCLUSIONS: Nearly 40% of patients who present with an uncomplicated TBAD will ultimately require an aortic intervention. All of the late interventions were performed for aneurysmal degeneration. A variety of readily available anatomic features can predict the need for eventual operative intervention in TBAD; accordingly, these parameters can guide the desirability of early TEVAR. PMID- 28912007 TI - Adventitial adipogenic degeneration is an unidentified contributor to aortic wall weakening in the abdominal aortic aneurysm. AB - OBJECTIVE: The processes driving human abdominal aortic aneurysm (AAA) progression are not fully understood. Although antiinflammatory and proteolytic strategies effectively quench aneurysm progression in preclinical models, so far all clinical interventions failed. These observations hint at an incomplete understanding of the processes involved in AAA progression and rupture. Interestingly, strong clinical and molecular associations exist between popliteal artery aneurysms (PAAs) and AAAs; however, PAAs have an extremely low propensity to rupture. We thus reasoned that differences between these aneurysms may provide clues toward (auxiliary) processes involved in AAA-related wall debilitation. A better understanding of the pathophysiologic processes driving AAA growth can contribute to pharmaceutical treatments in the future. METHODS: Aneurysmal wall samples were collected during open elective and emergency repair. Control perirenal aorta was obtained during kidney transplantation, and reference popliteal tissue obtained from the anatomy department. This study incorporates various techniques including (immuno)histochemistry, Western Blot, quantitative polymerase chain reaction, microarray, and cell culture. RESULTS: Histologic evaluation of AAAs, PAAs, and control aorta shows extensive medial (PAA) and transmural fibrosis (AAA), and reveals abundant adventitial adipocytes aggregates as an exclusive phenomenon of AAAs (P < .001). Quantitative polymerase chain reaction, immunohistochemistry, Western blotting, and microarray analysis showed enrichment of adipogenic mediators (C/EBP family P = .027; KLF5 P < .000; and peroxisome proliferator activated receptor-gamma, P = .032) in AAA tissue. In vitro differentiation tests indicated a sharply increased adipogenic potential of AAA adventitial mesenchymal cells (P < .0001). Observed enrichment of adipocyte related genes and pathways in ruptured AAA (P < .0003) supports an association between the extent of fatty degeneration and rupture. CONCLUSIONS: This translational study identifies extensive adventitial fatty degeneration as an ignored and distinctive feature of AAA disease. Enrichment of adipocyte genesis and adipocyte-related genes in ruptured AAA point to an association between the extent of fatty degeneration and rupture. This observation may (partly) explain the failure of medical therapy and could provide a lead for pharmaceutical alleviation of AAA progression. PMID- 28912008 TI - Dietary inflammatory index and mental health: A cross-sectional analysis of the relationship with depressive symptoms, anxiety and well-being in adults. AB - BACKGROUND & AIMS: The relationship between diet, inflammation and mental health is of increasing interest. However, limited data regarding the role of dietary inflammatory potential in this context exist. Therefore the aim of this work was to examine associations between the inflammatory potential of habitual diet and mental health outcomes in a cross-sectional sample of 2047 adults (50.8% female). METHODS: Diet was assessed using a self-completed food frequency questionnaire from which dietary inflammatory index (DII(r)) scores were determined. Depressive symptoms, anxiety and well-being were assessed using the CES-D, HADS-A and WHO-5 screening tools. RESULTS: Logistic regression analyses revealed that higher energy-adjusted DII (E-DII(r)) scores, reflecting a more pro-inflammatory diet, were associated with increased risk of depressive symptoms (odds ratios (OR) 1.70, 95% confidence intervals (CI) 1.23-2.35, p = 0.001) and anxiety (OR 1.60, 95% CI 1.15-2.24, p = 0.006) and lower likelihood of well-being (OR 0.62, 95% CI 0.46-0.83, p = 0.001), comparing highest to lowest tertile of E-DII. In gender stratified analyses associations were noted in women only. Women with the highest E-DII scores were at elevated risk of depressive symptoms (OR 2.29, 95% CI 1.49 3.51, p < 0.001) and anxiety (OR 2.00, 95% CI 1.30-3.06, p = 0.002), while likelihood of reporting good well-being was lower (OR 0.55, 95% CI 0.36-0.79, p = 0.002), relative to those with the lowest E-DII scores. CONCLUSIONS: These findings, which suggest that a pro-inflammatory diet is associated with adverse mental health, may be of clinical and public health significance regarding the development of novel nutritional psychiatry approaches to promote good mental health. PMID- 28912009 TI - An inflammation-based prognostic score, the C-reactive protein/albumin ratio predicts the morbidity and mortality of patients on parenteral nutrition. AB - BACKGROUND: There is no "gold standard" score for predicting poor-nutrition related outcomes. The objective of this study was to identify the optimal predictive score, based on inflammatory parameters, for the clinical outcomes of parenteral nutrition (PN). MATERIAL AND METHODS: This was a 4-year retrospective observational study of 460 patients treated with PN. C-reactive protein (CRP), prealbumin, albumin, CRP/prealbumin and CRP/albumin were studied as potential prognostic scores at the beginning of PN for clinical outcomes during PN. Three different statistical approaches were developed: 1) A univariate analysis of each of the 5 prognostic scores and 5 multivariate models for CRP/albumin and CRP/prealbumin to study their association with exitus, infection, sepsis, liver failure, renal impairment, cancer, intensive care unit stay, mechanical ventilation; 2) Univariate and multivariate survival analysis of PN length, intensive care unit (ICU) length of saty and days of mechanical ventilation vs CRP/albumin and CRP/prealbumin; 3) A ROC analysis of the prognostic accuracy of CRP/albumin and CRP/prealbumin over morbidity/mortality. RESULTS: 1) CRP, albumin and CRP/albumin gave more information about morbidity/mortality than prealbumin and CRP/prealbumin. CRP/albumin was statistically significant for exitus (OR 1.85; CI 95%: 1.00-3.45), infection (OR 2.15; CI 95%: 1.22-3.80), sepsis (OR 2.82; CI 95%: 1.69-4.70) and liver failure (OR 2.66; CI 95%: 1.55-4.58). CRP/prealbumin for sepsis was (OR 2.21; CI 95%: 1.34-3.64) and for liver failure (OR 2.04; CI 95%: 1.17-3.53); 2) CRP/albumin and CRP/prealbumin significantly predict PN duration, days in ICU and days on mechanical ventilation; 3) and are related to exitus, infection, sepsis and liver failure. CONCLUSION: The CRP/albumin score at the beginning of PN treatment has more prognostic capability than CRP/prealbumin, albumin or prealbumin. The systematic use of this score could help to identify those patients with higher risk. PMID- 28912010 TI - First week weight dip and reaching growth targets in early life in preterm infants. AB - BACKGROUND & AIMS: Aggressive parenteral nutritional practices were implemented in clinical practice over a decade ago to prevent early growth retardation in preterm infants. We aimed to study adherence to current nutritional recommendations in a population of very preterm infants, and to evaluate growth in early life. METHODS: Preterm infants (gestational age <30 weeks and birth weight <1500 g) were included in a prospective observational cohort study. Data on parenteral and enteral intake were collected on days 1-7, 14, 21 and 28 (d28) of life. Growth data were collected at birth, at moment of maximal weight loss (dip), and either at discharge from the neonatal intensive care unit or at d28, whichever came first. Nutritional intakes were compared to recommendations of current guidelines. The target growth rate was 15-20 g/kg/d. RESULTS: Fifty-nine infants (63% male) were included. Median gestational age was 27 3/7 (interquartile range 25 6/7;28 4/7), and birth weight was 920 g (720;1200). Median macronutrient intakes were within or above the targets on all study days, but energy targets were not met before day 5. Median growth rates were 9.5 and 18.1 g/kg/d, when calculated from respectively birth and dip to discharge/d28. Eight (14%) versus 46 (78%) infants met the growth targets, when evaluated from respectively birth and dip to discharge/d28. CONCLUSIONS: In this cohort, only energy intake up to day 5 was lower than recommended. Growth targets were achieved in the majority of the infants, but only when evaluated from dip onward, not from birth. PMID- 28912011 TI - Cell-line dependent antiviral activity of sofosbuvir against Zika virus. AB - The recent epidemic of Zika virus (ZIKV) in the Americas and its association with fetal and neurological complications has shown the need to develop a treatment. Repurposing of drugs that are already FDA approved or in clinical development may shorten drug development timelines in case of emerging viral diseases like ZIKV. Initial studies have shown conflicting results when testing sofosbuvir developed for treatment of infections with another Flaviviridae virus, hepatitis C virus. We hypothesized that the conflicting results could be explained by differences in intracellular processing of the compound. We assessed the antiviral activity of sofosbuvir and mericitabine against ZIKV using Vero, A549, and Huh7 cells and measured the level of the active sofosbuvir metabolite by mass spectrometry. Mericitabine did not show activity, while sofosbuvir inhibited ZIKV with an IC50 of ~4 MUM, but only in Huh7 cells. This correlated with differences in intracellular concentration of the active triphosphate metabolite of sofosbuvir, GS-461203 or 007-TP, which was 11-342 times higher in Huh7 cells compared to Vero and A549 cells. These results show that a careful selection of cell system for repurposing trials of prodrugs is needed for evaluation of antiviral activity. Furthermore, the intracellular levels of 007-TP in tissues and cell types that support ZIKV replication in vivo should be determined to further investigate the potential of sofosbuvir as anti-ZIKV compound. PMID- 28912012 TI - The effects of aerobic exercise on depression-like, anxiety-like, and cognition like behaviours over the healthy adult lifespan of C57BL/6 mice. AB - Preclinical studies have demonstrated exercise improves various types of behaviours such as anxiety-like, depression-like, and cognition-like behaviours. However, these findings were largely conducted in studies utilising short-term exercise protocols, and the effects of lifetime exercise on these behaviours remain unknown. This study investigates the behavioural effects of lifetime exercise in normal healthy ageing C57BL/6 mice over the adult lifespan. 12 week old C57BL/6 mice were randomly assigned to voluntary wheel running or non exercise (control) groups. Exercise commenced at aged 3 months and behaviours were assessed in young adult (Y), early middle age (M), and old (O) mice (n=11 17/group). The open field and elevated zero maze examined anxiety-like behaviours, depression-like behaviours were quantified with the forced swim test, and the Y maze and Barnes maze investigated cognition-like behaviours. The effects of lifetime exercise were not simply an extension of the effects of chronic exercise on anxiety-like, depression-like, and cognition-like behaviours. Exercise tended to reduce overt anxiety-like behaviours with ageing, and improved recognition memory and spatial learning in M mice as was expected. However, exercise also increased anxiety behaviours including greater freezing behaviour that extended spatial learning latencies in Y female mice in particular, while reduced distances travelled contributed to longer spatial memory and cognitive flexibility latencies in Y and O mice. Lifetime exercise may increase neurogenesis-associated anxiety. This could be an evolutionary conserved adaptation that nevertheless has adverse impacts on cognition-like function, with particularly pronounced effects in Y female mice with intact sex hormones. These issues require careful investigation in future rodent studies. PMID- 28912013 TI - Acid-sensing ion channel 1 contributes to normal olfactory function. AB - Acid-sensing ion channels (ASICs) are cation channels activated by protons. ASIC1a, a primary ASIC subunit in the brain, was recently characterized in the olfactory bulb. The present study tested the hypothesis that ASIC1a is essential for normal olfactory function. Olfactory behavior of wild-type (WT) and ASIC1-/- mice was evaluated by using three standard olfactory tests: (1) the buried food test, (2) the olfactory habituation test, and (3) the olfactory preference test. In buried food test, ASIC1-/- mice had significantly longer latency to uncover buried food than WT mice. In olfactory habituation test, ASIC1-/- mice had increased sniffing time with acidic odorants. In olfactory preference test, ASIC1 /- mice did not exhibit normal avoidance behavior for 2, 5- dihydro-2, 4, 5 trimethylthiazoline (TMT). Consistent with ASIC1 knockout, ASIC1 inhibition by nasal administration of PcTX1 increased the latency for WT mice to uncover the buried food. Together, these findings suggest a key role for ASIC1a in normal olfactory function. PMID- 28912014 TI - Acute alerting effects of light: A systematic literature review. AB - Periodic, well timed exposure to light is important for our health and wellbeing. Light, in particular in the blue part of the spectrum, is thought to affect alertness both indirectly, by modifying circadian rhythms, and directly, giving rise to acute effects. We performed a systematic review of empirical studies on direct, acute effects of light on alertness to evaluate the reliability of these effects. In total, we identified 68 studies in which either light intensity, spectral distribution, or both were manipulated, and evaluated the effects on behavioral measures of alertness, either subjectively or measured in reaction time performance tasks. The results show that increasing the intensity of polychromatic white light has been found to increase subjective ratings of alertness in a majority of studies, though a substantial proportion of studies failed to find significant effects, possibly due to small sample sizes or high baseline light intensities. The effect of the color temperature of white light on subjective alertness is less clear. Some studies found increased alertness with higher color temperatures, but other studies reported no detrimental effects of filtering out the short wavelengths from the spectrum. Similarly, studies that used monochromatic light exposure showed no systematic pattern for the effects of blue light compared to longer wavelengths. Far fewer studies investigated the effects of light intensity or spectrum on alertness as measured with reaction time tasks and of those, very few reported significant effects. In general, the small sample sizes used in studies on acute alerting effects of light make it difficult to draw definitive conclusions and better powered studies are needed, especially studies that allow for the construction of dose-response curves. PMID- 28912015 TI - Stem cell-based peripheral vascular regeneration. AB - Chronic critical limb ischemia (CLI) represents an end-stage manifestation of peripheral arterial disease (PAD). CLI patients are at very high risk of amputation and cardiovascular complications, leading to severe morbidity and mortality. Because many patients with CLI are ineligible for conventional revascularization procedures, it is urgently needed to explore alternative strategies to improve blood supply in the ischemic tissue. Although researchers initially focused on gene/protein therapy using proangiogenic growth factors/cytokines, recent discovery of somatic stem/progenitor cells including bone marrow (BM)-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) has drastically developed the field of therapeutic angiogenesis for CLI. Overall, early phase clinical trials demonstrated that stem/progenitor cell therapies may be safe, feasible and potentially effective. However, only few late phase clinical trials have been conducted. This review provides an overview of the preclinical and clinical reports to demonstrate the usefulness and the current limitations of the cell-based therapies. PMID- 28912016 TI - Arabidopsis thaliana miRNAs promote embryo pattern formation beginning in the zygote. AB - miRNAs are essential regulators of cell identity, yet their role in early embryo development in plants remains largely unexplored. To determine the earliest stage at which miRNAs act to promote pattern formation in embryogenesis, we examined a series of mutant alleles in the Arabidopsis thaliana miRNA biogenesis enzymes DICER-LIKE 1 (DCL1), SERRATE (SE), and HYPONASTIC LEAVES 1 (HYL1). Cellular and patterning defects were observed in dcl1, se and hyl1 embryos from the zygote through the globular stage of embryogenesis. To identify miRNAs that are expressed in early embryogenesis, we sequenced mRNAs from globular stage Columbia wild type (wt) and se-1 embryos, and identified transcripts potentially corresponding to 100 miRNA precursors. Considering genome location and transcript increase between wt and se-1, 39 of these MIRNAs are predicted to be bona fide early embryo miRNAs. Among these are conserved miRNAs such as miR156, miR159, miR160, miR161, miR164, miR165, miR166, miR167, miR168, miR171, miR319, miR390 and miR394, as well as miRNAs whose function has never been characterized. Our analysis demonstrates that miRNAs promote pattern formation beginning in the zygote, and provides a comprehensive dataset for functional studies of individual miRNAs in Arabidopsis embryogenesis. PMID- 28912017 TI - Indoleamine 2,3-Dioxygenase 1, Increased in Human Gastric Pre-Neoplasia, Promotes Inflammation and Metaplasia in Mice and Is Associated With Type II Hypersensitivity/Autoimmunity. AB - BACKGROUND & AIMS: Chronic gastrointestinal inflammation increases the risk of cancer by mechanisms that are not well understood. Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-binding enzyme that regulates the immune response via catabolization and regulation of tryptophan availability for immune cell uptake. IDO1 expression is increased during the transition from chronic inflammation to gastric metaplasia. We investigated whether IDO1 contributes to the inflammatory response that mediates loss of parietal cells leading to metaplasia. METHODS: Chronic gastric inflammation was induced in Ido1-/- and CB57BL/6 (control) mice by gavage with Helicobacter felis or overexpression of interferon gamma in gastric parietal cells. We also performed studies in Jh-/- mice, which are devoid of B cells. Gastric tissues were collected and analyzed by flow cytometry, immunostaining, and real-time quantitative polymerase chain reaction. Plasma samples were analyzed by enzyme-linked immunosorbent assay. Gastric tissues were obtained from 20 patients with gastric metaplasia and 20 patients without gastric metaplasia (controls) and analyzed by real-time quantitative polymerase chain reaction; gastric tissue arrays were analyzed by immunohistochemistry. We collected genetic information on gastric cancers from The Cancer Genome Atlas database. RESULTS: H felis gavage induced significantly lower levels of pseudopyloric metaplasia in Ido1-/- mice, which had lower frequencies of gastric B cells, than in control mice. Blood plasma from H felis-infected control mice had increased levels of autoantibodies against parietal cells, compared to uninfected control mice, but this increase was lower in Ido1-/- mice. Chronically inflamed stomachs of Ido1-/- mice had significantly lower frequencies of natural killer cells in contact with parietal cells, compared with stomachs of control mice. Jh-/- mice had lower levels of pseudopyloric metaplasia than control mice in response to H felis infection. Human gastric pre-neoplasia and carcinoma specimens had increased levels of IDO1 messenger RNA compared with control gastric tissues, and IDO1 protein colocalized with B cells. Co-clustering of IDO1 messenger RNA with B-cell markers was corroborated by The Cancer Genome Atlas database. CONCLUSIONS: IDO1 mediates gastric metaplasia by regulating the B-cell compartment. This process appears to be associated with type II hypersensitivity/autoimmunity. The role of autoimmunity in the progression of pseudopyloric metaplasia warrants further investigation. PMID- 28912018 TI - Association Between Germline Mutations in BRF1, a Subunit of the RNA Polymerase III Transcription Complex, and Hereditary Colorectal Cancer. AB - BACKGROUND & AIMS: Although there is a genetic predisposition to colorectal cancer (CRC), few of the genes that affect risk have been identified. We performed whole-exome sequence analysis of individuals in a high-risk family without mutations in genes previously associated with CRC risk to identify variants associated with inherited CRC. METHODS: We collected blood samples from 3 relatives with CRC in Spain (65, 62, and 40 years old at diagnosis) and performed whole-exome sequence analyses. Rare missense, truncating or splice-site variants shared by the 3 relatives were selected. We used targeted pooled DNA amplification followed by next generation sequencing to screen for mutations in candidate genes in 547 additional hereditary and/or early-onset CRC cases (502 additional families). We carried out protein-dependent yeast growth assays and transfection studies in the HT29 human CRC cell line to test the effects of the identified variants. RESULTS: A total of 42 unique or rare (population minor allele frequency below 1%) nonsynonymous genetic variants in 38 genes were shared by all 3 relatives. We selected the BRF1 gene, which encodes an RNA polymerase III transcription initiation factor subunit for further analysis, based on the predicted effect of the identified variant and previous association of BRF1 with cancer. Previously unreported or rare germline variants in BRF1 were identified in 11 of 503 CRC families, a significantly greater proportion than in the control population (34 of 4300). Seven of the identified variants (1 detected in 2 families) affected BRF1 mRNA splicing, protein stability, or expression and/or function. CONCLUSIONS: In an analysis of families with a history of CRC, we associated germline mutations in BRF1 with predisposition to CRC. We associated deleterious BRF1 variants with 1.4% of familial CRC cases, in individuals without mutations in high-penetrance genes previously associated with CRC. Our findings add additional evidence to the link between defects in genes that regulate ribosome synthesis and risk of CRC. PMID- 28912020 TI - Intestinal Dysbiosis Featuring Abundance of Ruminococcus gnavus Associates With Allergic Diseases in Infants. AB - BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with development of allergies in infants. However, it is not clear what microbes might contribute to this process. We investigated what microbe(s) might be involved in analyses of infant twins and mice. METHODS: We studied fecal specimens prospectively in a twin cohort (n = 30) and age-matched singletons (n = 14) born at National Taiwan University Children's Hospital, Taipei, Taiwan, from April 2011 to March 2013. Clinical parameters (gestational age, birth body weight, mode of delivery and feeding, immunizations, and medical events) were recorded. Fecal samples were collected beginning immediately after birth and for 1 year; the children were followed until 3 years of age and allergic symptoms (repetitive and continuous for at least 6 months) were noted. A skin prick test was used to ascertain atopy. Bacterial communities in fecal samples were profiled by 16S ribosomal RNA-based polymerase chain reaction-temporal temperature gradient gel electrophoresis and next-generation sequencing. BALB/c mice without and with ovalbumin sensitization/challenge were infected with candidate bacteria by oral gauge intragastric intubation. Fecal, serum, lung, and colon tissue samples were collected from mice and analyzed for mechanisms of allergy development. RESULTS: During the investigation period, 20 children (45.5%) developed allergic diseases, including respiratory (allergic rhinitis and asthma) and skin (atopic dermatitis and eczema) allergies. Lachnospiraceae were detected at significantly higher frequency in allergic infants than nonallergic infants (P < .004); the high fecal count of Lachnospiraceae in allergic subjects appeared at 2 months of age and persisted until 12 months of age. The enrichment of Lachnospiraceae in allergic infants was attributed to the overgrowth of Ruminococcus gnavus, which tended to have a low frequency in nonallergic subjects (P = .0004). Increased R gnavus was observed before the onset of allergic manifestations, and was associated with respiratory allergies (P < .002) or respiratory allergies coexistent with atopic eczema (P < .001). In mice, endogenous R gnavus grew rapidly after sensitization and challenge with ovalbumin. Mice gavaged with purified R gnavus developed airway hyper responsiveness and had histologic evidence of airway inflammation (asthma). Expansion of R gnavus in mice stimulated secretion of cytokines (interleukin [IL] 25, IL33, and thymic stromal lymphopoietin) by colon tissues, which activated type 2 innate lymphoid cells and dendritic cells to promote differentiation of T helper 2 cells and production of their cytokines (IL4, IL5, and IL13). This led to infiltration of the colon and lung parenchyma by eosinophils and mast cells. CONCLUSIONS: In a study of a twin cohort (some infants with, some without allergies), we associated development of allergies, particularly respiratory allergies, with increased fecal abundance of R gnavus. Mice fed R gnavus developed airway inflammation, characterized by expansion of T-helper 2 cells in the colon and lung, and infiltration of colon and lung parenchyma by eosinophils and mast cells. PMID- 28912019 TI - A Nigro-Vagal Pathway Controls Gastric Motility and Is Affected in a Rat Model of Parkinsonism. AB - BACKGROUND & AIMS: In most patients with Parkinson's disease, gastrointestinal (GI) dysfunctions, such as gastroparesis and constipation, are prodromal to the cardinal motor symptoms of the disease. Sporadic Parkinson's disease has been proposed to develop after ingestion of neurotoxicants that affect the brain-gut axis via the vagus nerve, and then travel to higher centers, compromising the substantia nigra pars compacta (SNpc) and, later, the cerebral cortex. We aimed to identify the pathway that connects the brainstem vagal nuclei and the SNpc, and to determine whether this pathway is compromised in a rat model of Parkinsonism. METHODS: To study this neural pathway in rats, we placed tracers in the dorsal vagal complex or SNpc; brainstem and midbrain were examined for tracer distribution and neuronal neurochemical phenotype. Rats were given injections of paraquat once weekly for 3 weeks to induce features of Parkinsonism, or vehicle (control). Gastric tone and motility were recorded after N-methyl-d-aspartate microinjection in the SNpc and/or optogenetic stimulation of nigro-vagal terminals in the dorsal vagal complex. RESULTS: Stimulation of the SNpc increased gastric tone and motility via activation of dopamine 1 receptors in the dorsal vagal complex. In the paraquat-induced model of Parkinsonism, this nigro-vagal pathway was compromised during the early stages of motor deficit development. CONCLUSIONS: We identified and characterized a nigro-vagal monosynaptic pathway in rats that controls gastric tone and motility. This pathway might be involved in the prodromal gastric dysmotility observed in patients with early-stage Parkinson's disease. PMID- 28912021 TI - Association between spinal immobilization and survival at discharge for on-scene blunt traumatic cardiac arrest: A nationwide retrospective cohort study. AB - INTRODUCTION: Spinal immobilization has been indicated for all blunt trauma patients suspected of having cervical spine injury. However, for traumatic cardiac arrest (TCA) patients, rapid transportation without compromising potentially reversible causes is necessary. Our objective was to investigate the temporal trend of spinal immobilization for TCA patients and to examine the association between spinal immobilization and survival. METHODS: We conducted a retrospective cohort study using the Japan Trauma Data Bank 2004-2015 registry data. Our study population consisted of adult blunt TCA patients encountered at the scene of a trauma. The primary outcome was the survival proportion at hospital discharge, and the secondary outcome was the proportion achieving return of spontaneous circulation (ROSC). We examined the association between spinal immobilization and these outcomes using a logistic regression model based on imputed data sets with the multiple imputation method to account for missing data. RESULTS: Among 4313 patients who met the inclusion criteria, 3307 (76.7%) were immobilized. The proportion of patients that underwent spinal immobilization gradually decreased from 82.7% in 2004-2006 to 74.0% in 2013-2015. 1.0% of immobilized and 0.9% of non-immobilized patients had severe cervical spine injury. Spinal immobilization was significantly associated with lower survival at discharge (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.42 to 0.98) and ROSC by admission (OR, 0.48; 95%CI, 0.27 to 0.87). There was no significant sub group difference of the association between spinal immobilization and survival at discharge by patients with or without cervical spine injury (p for interaction 0.73). CONCLUSION: Spinal immobilization is widely used even for blunt TCA patients, even though it is associated with a lower rate of survival at discharge and ROSC by admission. According to these results, we suggest that spinal immobilization should not be routinely recommended for all blunt TCA patients. PMID- 28912022 TI - When does intraoperative 3D-imaging play a role in transpedicular C2 screw placement? AB - INTRODUCTION: The stabilization of an atlantoaxial (C1-C2) instability is demanding due to a complex atlantoaxial anatomy with proximity to the spinal cord, a variable run of the vertebral artery (VA) and narrow C2 pedicles. We perfomed the Goel & Harms fusion in combination with an intraoperative 3D imaging to ensure correct screw placement in the C2 pedicle. We hypothesized, that narrow C2 pedicles lead to a higher malposition rate of screws by perforation of the pedicle wall. The purpose of this study was to describe a certain pedicle size, under which the perforation rate rises. PATIENTS AND METHODS: In this retrospective study, all patients (n=30) were operated in the Goel & Harms technique. The isthmus height and pedicle diameter of C2 were measured. The achieved screw position in C2 was evaluated according to Gertzbein & Robbin classification (GRGr). RESULTS: A statistically significant correlation was found between the pedicles size (isthmus height/pedicle diameter) and the achieved GRGr for the right (p=0.002/p=0.03) and left side (p=0.018/p=0.008). The ROC analysis yielded a Cut Off value for the pedicle size to distinguish between an intact or perforated pedicle wall (GRGr 1 or >=2). The Cut-Off value was identified for the isthmus height (right 6.1mm, left 5.4mm) and for the pedicle diameter (6.6mm both sides). CONCLUSION: The hypothesis, that narrow pedicles lead to a higher perforation rate of the pedicle wall, can be accepted. Pedicles of <6.6mm turned out to be a risk factor for a perforation of the pedicle wall (GRGr 2 or higher). Intraoperative 3D imaging is a feasible tool to confirm optimal screw position, which becomes even more important in cases with thin pedicles. The rising risk of VA injury in these cases support the additional use of navigation. PMID- 28912023 TI - Avoiding over-telescoping to improve outcomes in cephalomedullary nailing. PMID- 28912024 TI - Correction. PMID- 28912025 TI - Correction. PMID- 28912026 TI - Influence of various therapeutic strategies on right ventricular morphology, function and hemodynamics in pulmonary arterial hypertension. AB - BACKGROUND: In idiopathic pulmonary arterial hypertension (IPAH) treatment goals include improving right ventricular (RV) function, hemodynamics and symptoms to move patients to a low-risk category for adverse clinical outcomes. No data are available on the effect of upfront combination therapy on RV improvement as compared with monotherapy. The aim of this study was to evaluate echocardiographic RV morphology and function in patients affected by IPAH and treated with different strategies. METHODS: Sixty-nine consecutive, treatment naive IPAH patients treated with first-line upfront combination therapy at 10 centers were retrospectively evaluated and compared with 2 matched cohorts treated with monotherapy after short-term follow-up. Evaluation included clinical, hemodynamic and echocardiographic parameters. RESULTS: At 155 +/- 65 days after baseline evaluation, patients in the oral+prostanoid group (Group 1) had the most clinical and hemodynamic improvement compared with the double oral group (Group 2), the oral monotherapy group (Group 3) and the prostanoid monotherapy group (Group 4). The more extensive reduction of pulmonary vascular resistance in Groups 1, 2 and 4 was associated with significant improvement in all RV echocardiographic parameters compared with Group 3. Considering the number of patients who reached the target goals suggested by established guidelines, 8 of 27 (29.6%) and 7 of 42 (16.7%) patients in Groups 1 and 2, respectively, achieved low-risk status, as compared with 2 of 69 (2.8%) and 6 of 27 (22.2%) in Groups 3 and 4, respectively. CONCLUSIONS: In advanced treatment-naive IPAH patients, an upfront combination therapy strategy seems to significantly improve hemodynamics and RV morphology and function compared with oral monotherapy. The most significant results seem to be achieved with prostanoids plus oral drug, whereas the use of the double oral combination and prostanoids as monotherapy seem to produce similar results. PMID- 28912028 TI - Corrigendum to "Cyclical strain modulates metalloprotease and matrix gene expression in human tenocytes via activation of TGFbeta" [Biochim. Biophys. Acta (2013) 2596-2607]. PMID- 28912027 TI - Factor analysis in optimization of formulation of high content uniformity tablets containing low dose active substance. AB - Warfarin is intensively discussed drug with narrow therapeutic range. There have been cases of bleeding attributed to varying content or altered quality of the active substance. Factor analysis is useful for finding suitable technological parameters leading to high content uniformity of tablets containing low amount of active substance. The composition of tabletting blend and technological procedure were set with respect to factor analysis of previously published results. The correctness of set parameters was checked by manufacturing and evaluation of tablets containing 1-10mg of warfarin sodium. The robustness of suggested technology was checked by using "worst case scenario" and statistical evaluation of European Pharmacopoeia (EP) content uniformity limits with respect to Bergum division and process capability index (Cpk). To evaluate the quality of active substance and tablets, dissolution method was developed (water; EP apparatus II; 25rpm), allowing for statistical comparison of dissolution profiles. Obtained results prove the suitability of factor analysis to optimize the composition with respect to batches manufactured previously and thus the use of metaanalysis under industrial conditions is feasible. PMID- 28912029 TI - Inclusion of Highest Glasgow Coma Scale Motor Component Score in Mortality Risk Adjustment for Benchmarking of Trauma Center Performance. AB - BACKGROUND: The Glasgow Coma Scale (GCS) is the most widely used measure of traumatic brain injury (TBI) severity. Currently, the arrival GCS motor component (mGCS) score is used in risk-adjustment models for external benchmarking of mortality. However, there is evidence that the highest mGCS score in the first 24 hours after injury might be a better predictor of death. Our objective was to evaluate the impact of including the highest mGCS score on the performance of risk-adjustment models and subsequent external benchmarking results. STUDY DESIGN: Data were derived from the Trauma Quality Improvement Program analytic dataset (January 2014 through March 2015) and were limited to the severe TBI cohort (16 years or older, isolated head injury, GCS <=8). Risk-adjustment models were created that varied in the mGCS covariates only (initial score, highest score, or both initial and highest mGCS scores). Model performance and fit, as well as external benchmarking results, were compared. RESULTS: There were 6,553 patients with severe TBI across 231 trauma centers included. Initial and highest mGCS scores were different in 47% of patients (n = 3,097). Model performance and fit improved when both initial and highest mGCS scores were included, as evidenced by improved C-statistic, Akaike Information Criterion, and adjusted R squared values. Three-quarters of centers changed their adjusted odds ratio decile, 2.6% of centers changed outlier status, and 45% of centers exhibited a >=0.5-SD change in the odds ratio of death after including highest mGCS score in the model. CONCLUSIONS: This study supports the concept that additional clinical information has the potential to not only improve the performance of current risk adjustment models, but can also have a meaningful impact on external benchmarking strategies. Highest mGCS score is a good potential candidate for inclusion in additional models. PMID- 28912030 TI - Liver Function Assessment Using Technetium 99m-Galactosyl Single-Photon Emission Computed Tomography/CT Fusion Imaging: A Prospective Trial. AB - BACKGROUND: The prediction of postoperative liver function remains a largely subjective practice based on CT volumetric analysis. However, future liver volume after a hepatectomy is not the only factor that contributes to postoperative liver function and outcomes. STUDY DESIGN: In this prospective trial, 185 consecutive patients who underwent liver operations between 2014 and 2015 were studied. Volumetric and functional rates of remnant liver were measured using technetium 99m-galactosyl human serum albumin single-photon emission computed tomography/CT fusion imaging to evaluate post-hepatectomy remnant liver function. Remnant indocyanine green clearance rate using galactosyl (KGSA) (KGSA * functional rate) was used to predict future remnant liver function. Hepatectomy was considered safe for patients with remnant KGSA values >=0.05, and the primary end point was to determine the accuracy and reliability of this criteria. The prediction of the 90-day major complication and mortality rates was assessed. RESULTS: Median hospital stay was 9 days and median ICU stay was 1 day, with only 1 in-hospital death (90-day mortality rate 0.5%). Overall morbidity rate evaluated according to the Clavien-Dindo classification was 9%. For post hepatectomy liver failure definitions, the International Study Group of Liver Surgery definition was fulfilled in 14 patients (8%), with the majority being grade B (50%), compared with 2 patients (1%) fulfilling the "50-50" criteria, and 0 patients (0%) fulfilling the PeakBili >7 criteria. CONCLUSIONS: Results of this study showed that remnant KGSA provided information that allowed us to predict remnant liver function. This information will be important for surgeons when deciding on a treatment plan for patients with liver diseases. (ClinicalTrials.gov ID: NCT02013895). PMID- 28912031 TI - Hormones and the Coolidge effect. AB - The Coolidge effect is the renewal of sexual behavior after the presentation of a novel sexual partner and possibly occurs as the result of habituation and dishabituation processes. This re-motivation to copulate is well studied in males and is commonly related to sexual satiety, which involves several neurobiological changes in steroid receptors and their mRNA expression in the CNS. On the other hand, there are few reports studying sexual novelty in females and have been limited to behavioral aspects. Here we report that the levels of rat proceptive behavior, a sign of sexual motivation, declines after 4 h of continuous mating, particularly in females that were unable to regulate the time of mating. Such reduction was not accompanied by changes in lordosis, suggesting that they were not due to the vanishing of the endocrine optimal milieu necessary for the expression of both components of sexual behavior in the female rat. These and previous data support important differences between sexual behavior in both sexes that would result in natural divergences in the Coolidge effect expression. We here also review some reports in humans showing peculiarities between the pattern of habituation and dishabituation in women and men. This is a growing research field that needs emphasis in female subjects. PMID- 28912032 TI - Androgens and androgen receptor action in skin and hair follicles. AB - Beyond sexual functions, androgens exert their action in skin physiology and pathophysiology. Skin cells are able to synthesize most active androgens from gonadal or adrenal precursors and the enzymes involved in skin steroidogenesis are implicated both in normal or pathological processes. Even when the role of androgens and androgen receptor (AR) in skin pathologies has been studied for decades, their molecular mechanisms in skin disorders remain largely unknown. Here, we analyze recent studies of androgens and AR roles in several skin-related disorders, focusing in the current understanding of their molecular mechanisms in androgenetic alopecia (AGA). We review the molecular pathophysiology of type 2 5alpha-reductase, AR coactivators, the paracrine factors deregulated in dermal papillae (such as TGF-beta, IGF 1, WNTs and DKK-1) and the crosstalk between AR and Wnt signaling in order to shed some light on new promising treatments. PMID- 28912033 TI - Dissecting the CD93-Multimerin 2 interaction involved in cell adhesion and migration of the activated endothelium. AB - The glycoprotein CD93 has recently been recognized to play an important role in the regulation of the angiogenic process. Moreover, CD93 is highly expressed in the endothelial cells of tumor blood vessel and faintly expressed in the non proliferating endothelium. Much evidence suggests that CD93 mediates adhesion in the endothelium. Here we identify Multimerin 2 (MMRN2), a pan-endothelial extracellular matrix protein, as a specific ligand for CD93. We found that CD93 and MMRN2 are co-expressed in the blood vessels of various human tumors. Moreover, disruption of the CD93-MMRN2 interaction reduced endothelial cell adhesion and migration, making the interaction of CD93 with MMRN2 an ideal target to block pathological angiogenesis. Model structures and docking studies served to envisage the region of CD93 and MMRN2 involved in the interaction. Site directed mutagenesis identified different residue hotspots either directly or indirectly involved in the binding. We propose a molecular model in which the coiled-coil domain of MMRN2 is engaged by F238 of CD93. Altogether, these studies identify the key interaction surfaces of the CD93-MMRN2 complex and provide a framework for exploring how to inhibit angiogenesis by hindering the CD93-MMRN2 interaction. PMID- 28912034 TI - Sleep deprivation induces spatial memory impairment by altered hippocampus neuroinflammatory responses and glial cells activation in rats. AB - We aimed to investigate the glial cells activation as a potential mechanism involved in the sleep deprivation (SD) induced cognitive impairment through changes in inflammatory cytokines. We analyzed the spatial memory, inflammatory cytokine levels, and gliosis during SD. SD induced spatial memory impairment, imbalance of inflammatory (increased pro- and decreased anti-) cytokines in both hippocampus and plasma in association with glial cells activation in the hippocampus of sleep-deprived rats were observed. Further analysis of the data presented a correlation between spatial memory impairment and activated microglia induced increased pro-inflammatory cytokines after 48h of SD. PMID- 28912035 TI - Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis. AB - Myasthenia gravis (MG) is caused by autoantibodies, the majority of which target the muscle acetylcholine receptor (AChR). Plasmapheresis and IgG-immunoadsorption are useful therapy options, but are highly non-specific. Antigen-specific immunoadsorption would remove only the pathogenic autoantibodies, reducing the possibility of side effects while maximizing the benefit. We have extensively characterized such adsorbents, but in vivo studies are missing. We used rats with experimental autoimmune MG to perform antigen-specific immunoadsorptions over three weeks, regularly monitoring symptoms and autoantibody titers. Immunoadsorption was effective, resulting in a marked autoantibody titer decrease while the immunoadsorbed, but not the mock-treated, animals showed a dramatic symptom improvement. Overall, the procedure was found to be efficient, suggesting the subsequent initiation of clinical trials. PMID- 28912036 TI - Dual effects of the PI3K inhibitor ZSTK474 on multidrug efflux pumps in resistant cancer cells. AB - ZSTK474 is a potent phosphoinositide 3-kinase (PI3K) inhibitor that reduces cell proliferation via G1-arrest. However, there is little information on the susceptibility of this anticancer drug to resistance conferred by the multidrug pumps P-glycoprotein (ABCB1) and ABCG2. We have demonstrated that ZSTK474 generated cytotoxicity in cells over-expressing either pump with potency similar to that in drug sensitive cells. In addition, the co-administration of ZSTK474 with the cytotoxic anti-cancer drugs vinblastine and mitoxantrone caused a potentiated cytotoxic effect in both drug sensitive and efflux pump expressing cells. These observations suggest that ZSTK474 is unaffected by the presence of multidrug efflux pumps and may circumvent their activities. Indeed, ZSTK474 increased the cellular accumulation of calcein-AM and mitoxantrone in cells expressing ABCB1 and ABCG2, respectively. ZSTK474 treatment also resulted in reduced expression of both efflux pumps in multidrug resistant cancer cells. Measurement of ABCB1 or ABCG2 mRNA levels demonstrated that the reduction was not due to altered transcription. Similarly, inhibitor studies showed that the proteasomal degradation pathway for ABCB1 and the lysosomal route for ABCG2 degradation were unaffected by ZSTK474. Thus the mechanism underlying reduced ABCB1 and ABCG2 levels caused by ZSTK474 was due to a reduction in overall protein synthesis; a process influenced by the PI3K pathway. In summary, ZSTK474 is not susceptible to efflux by the resistance mediators ABCB1 and ABCG2. Moreover, it inhibits the drug transport function of the pumps and leads to a reduction in their cellular expression levels. Our observations demonstrate that ZSTK474 is a powerful anticancer drug. PMID- 28912037 TI - The role of mental imagery in mood amplification: An investigation across subclinical features of bipolar disorders. AB - Vivid emotional mental imagery has been identified across a range of mental disorders. In bipolar spectrum disorders - psychopathologies characterized by mood swings that alternate between depression and mania, and include irritability and mixed affect states - mental imagery has been proposed to drive instability in both 'positive' and 'negative' mood. That is, mental imagery can act as an "emotional amplifier". The current experimental study tested this hypothesis and investigated imagery characteristics associated with mood amplification using a spectrum approach to psychopathology. Young adults (N = 42) with low, medium and high scores on a measure of subclinical features of bipolar disorder (BD), i.e., hypomanic-like experiences such as overly 'positive' mood, excitement and hyperactivity, completed a mental imagery generation training task using positive picture-word cues. Results indicate that (1) mood amplification levels were dependent on self-reported hypomanic-like experiences. In particular, (2) engaging in positive mental imagery led to mood amplification of both positive and negative mood in those participants higher in hypomanic-like experiences. Further, (3) in participants scoring high for hypomanic-like experiences, greater vividness of mental imagery during the experimental task was associated with greater amplification of positive mood. Thus, for individuals with high levels of hypomanic-like experiences, the generation of emotional mental imagery may play a causal role in their mood changes. This finding has implications for understanding mechanisms driving mood amplification in bipolar spectrum disorders, such as targeting imagery vividness in therapeutic interventions. PMID- 28912038 TI - Proton Pump Inhibitor Use Is Associated With a Reduced Risk of Infection with Intestinal Protozoa. AB - OBJECTIVE: Proton pump inhibitors (PPIs) can kill some human protozoan parasites in cell culture better than the drug metronidazole. Clinical data showing an antiprotozoal effect for PPIs are lacking. The objective of the study is to determine if PPI use is associated with a reduced risk of having intestinal parasites. METHODS: We obtained electronic medical record data for all persons who received a stool ova and parasite (O & P) examination at our tertiary care academic medical center in Cleveland, Ohio, between January 2000 and September 2014. We obtained the person's age, whether they were taking a PPI at the time of the O & P examination, and whether the pathology report indicated the presence of any parasites. chi2 with Yates correction was used to determine if PPI use was associated with stool protozoa. RESULTS: Three intestinal protozoa were identified in 1199 patients taking a PPI (0.3%), and 551 intestinal parasites were identified in the 14,287 patients not taking a PPI (3.9%). There was a statistically significant lower likelihood of finding protozoa in the stool of a person taking a PPI compared with those not taking a PPI (P < .0001). CONCLUSIONS: Patients taking a PPI were statistically less likely to have an intestinal protozoa reported on stool O & P examination compared with those not taking a PPI. PMID- 28912039 TI - Acquired Heart Disease Superimposed on Congenital Heart Disease. AB - A 50-year-old man with a murmur since birth developed systemic arterial hypertension as an adult. He came to the hospital because of dyspnea. He had a pulmonic valve ejection click and a murmur of pulmonic stenosis. His echocardiogram showed biventricular hypertrophy, a flat ventricular septum, a D shaped left ventricle, systolic doming of the pulmonic valve, and Doppler evidence of a 70 mm Hg peak systolic pressure gradient across the pulmonic valve and a peak right ventricular systolic pressure of 100 mm Hg. His electrocardiograms showed no evidence of the right ventricular and right atrial enlargement so evident on echocardiogram, presumably because it was obscured by the marked changes of left ventricular hypertrophy. Three years later, when he was admitted for sepsis and worsening heart failure with anasarca, the voltage changes of left ventricular hypertrophy had virtually disappeared, likely due to the large amount of fluid between the heart and the electrodes. PMID- 28912040 TI - Inaccuracy of Right Atrial Pressure Estimates Through Inferior Vena Cava Indices. AB - The precision of echocardiography in estimating pulmonary pressures has been debated. A value of right atrial pressure (RAP) is needed for pulmonary pressure estimation, and it could be partly responsible for the estimation error. Several schemes based on the inferior vena cava (IVC) are commonly used in clinical practice and in experimental studies for RAP estimation. However, the majority lack proper validation, and thus far, no study has compared them all. In this prospective, blinded study, a comprehensive transthoracic echocardiography was performed on 200 patients referred for right heart catheterization. The IVC was measured in different views and RAP was estimated according to 6 different schemes. One hundred ninety patients were suitable for analysis. IVC measurements were significantly but poorly associated with invasive RAP. All RAP schemes showed poor accuracy compared with invasive RAP (average accuracy 34%). None of the schemes showed a clear superiority over the others. No echocardiographic or clinical variables showed a relevant impact on the estimation error. In conclusion, RAP estimation based on the IVC is highly inaccurate irrespective of the method used and should be avoided whenever possible. Whether adding estimated RAP values affects the estimation of pulmonary pressures is yet to be determined. PMID- 28912042 TI - Aptamer micelles targeting fractalkine-expressing cancer cells in vitro and in vivo. AB - In this work we hypothesized that the chemokine fractalkine can serve as a cancer molecular target. We engineered aptamer micelles functionalized with an outer poly(ethylene glycol) (PEG) corona, and investigated the extent and efficacy of using them as a targeting tool against fractalkine-expressing colon adenocarcinoma cells. In vitro cell binding results showed that aptamer micelles bound and internalized to fractalkine-expressing cancer cells with the majority of the micelles found free in the cytoplasm. Minimal surface binding was observed by healthy cells. Even though partial PEGylation did not prevent serum adsorption, micelles were highly resistant to endonuclease and exonuclease degradation. In vivo biodistribution studies and confocal studies demonstrated that even though both aptamer and control micelles showed tumor accumulation, only the aptamer micelles internalized into fractalkine-expressing cancer cells, thus demonstrating the potential of the approach and showing that fractalkine may serve as a specific target for nanoparticle delivery to cancer cells. PMID- 28912041 TI - Postoperative B-type natriuretic peptide monitoring for the assessment of the magnitude of shunting through Blalock-Taussig anastomoses. AB - BACKGROUND: The Modified Blalock-Taussig shunt (MBTS) is the most common palliative operation performed in patients with complex cardiac defects. Postoperative morbidity and mortality rates are high, mainly due to shunt thrombosis and over-shunting. Over-shunting may be difficult to identify postoperatively based on conventional criteria. Since plasma B-type natriuretic peptide (BNP) concentrations correlate with the magnitude of shunting in various left-to-right shunt cardiac defects, we investigated its ability to identify postoperative MBTS over-shunting. METHODS AND RESULTS: This retrospective, observational study included 42 consecutive patients (median age 9.50days, IQR: 6.00-58.25) undergoing MBTS for obstruction of the pulmonary blood flow at a tertiary referral pediatric cardiac center. The BNP threshold concentrations which accurately predicted outcome and MBTS over-shunting were derived using the ROC methodology. 443 BNP concentrations were analysed. The presence of atrio ventricular valve regurgitation was the most important component of overall variance (72.75%). In 34 patients without regurgitation, BNP concentrations were predictive of a duration of mechanical ventilation >8days and of intensive care stay >11days, with ROC areas of 0.655 [0.597-0.719], 0.650 [0.589-0.711], a negative predictive value for the >1035pgmL-1 threshold of 0.93 and 0.96 respectively. SaO2 was less accurate for the prediction of both outcomes. In patients in whom the pulmonary flow was entirely MBTS-supplied, a BNP concentrations >1052pgmL-1 was predictive of a pulmonary-to-systemic ratio>2. CONCLUSION: In MBTS patients without atrio-ventricular valve regurgitation, maintaining BNP below 1000pgmL-1 may represent a therapeutic target to avoid over shunting. PMID- 28912043 TI - Abnormal segments of right uncinate fasciculus and left anterior thalamic radiation in major and bipolar depression. AB - Differential brain structural abnormalities between bipolar disorder (BD) and major depressive disorder (MDD) may reflect different pathological mechanisms underlying these two brain disorders. However, few studies have directly compared the brain structural properties, especially in white matter (WM) tracts, between BD and MDD. Using automated fiber-tract quantification (AFQ), we utilized diffusion tensor images (DTI) from 67 unmedicated depressed patients, including 31 BD and 36 MDD, and 45 healthy controls (HC) to create fractional anisotropy (FA) tract profiles along 20 major WM tracts. Then, we compared between-group differences in FA values at each node along the fiber tracts. To differentiate the BD and the MDD, we enrolled the diffusion measures of the tract profiles into support vector machine (SVM), a type of machine learning algorithm. The BD showed lower FA in the insular cortex portion of the right uncinate fasciculus (UF) compared to the MDD and in the prefrontal lobe portion of the right UF compared to the HC. The MDD showed lower FA in the prefrontal lobe portion of the left anterior thalamic radiation (ATR) compared to the HC. Using the SVM approach, we found the FA tract profile of the left ATR can be used to differentiate the BD and the MDD at an accuracy up to 68.33% (p=0.018). These findings suggested that the BD and the MDD may be characterized by different abnormalities in specific segments of brain WM tracts, especially in two frontal-situated tracts, the right UF and the left ATR. PMID- 28912044 TI - Sex estimation in a contemporary Turkish population based on CT scans of the calcaneus. AB - Building a reliable biological profile from decomposed remains depends heavily on the accurate estimation of sex. A variety of methods based on every single skeletal element have been developed over the years for different populations employing both osteological and virtual methods. The latter seem to be a reasonable alternative in countries lacking osteological reference collections. The current study used 3D virtual models of calcanei from CT scans of living adults to develop a sex estimation method for contemporary Turkish. Four hundred and twenty eight calcanei CT scans were analysed. The sample was divided in two subsamples: an original (N=348) and a validation sample (N=80) with similar distribution of males and females. Nine classical measurements were taken using the 3D models of the calcanei and two different statistical methods (Discriminant function analysis and Binary logistic regression) were used. Classification accuracy ranged from 82% to 98% for the validation sample and it was consistently high using any of the two methods. Sex bias seems to be lower for most of the logistic regression equations compared to the discriminant functions. These results, however, need further testing to be verified. Based on the results of this study we recommend the use of both methods for sex estimation from the measurements of the calcaneus bone in a Turkish population. PMID- 28912045 TI - Sulfate-reducing bacteria stimulate gut immune responses and contribute to inflammation in experimental colitis. AB - The intestinal microbiota is critical for mammalian immune system development and homeostasis. Sulfate-reducing bacteria (SRB) are part of the normal gut microbiota, but their increased levels may contribute to colitis development, likely in association with hydrogen sulfide (H2S) production. Here, we investigated the effects of SRB in the gut immune response in germ-free mice, and in experimental colitis. After 7days of colonization with Desulfovibrio indonesiensis or with a human SRB consortium (from patients with colitis), germ free mice exhibited alterations in the colonic architecture, with increased cell infiltration in the lamina propria. SRB colonization upregulated the Th17 and Treg profiles of cytokine production/cell activation, in T cells from mesenteric lymph nodes. These alterations were more pronounced in mice colonized with the human SRB consortium, although D. indonesiensis colonization produced higher levels of H2S. Importantly, the colon of C57BL/6 mice with colitis induced by TNBS or oxazolone had increased SRB colonization, and the administration of D. indonesiensis to mice with TNBS-induced colitis clearly exacerbated the alterations in colonic architecture observed in the established disease, and also increased mouse weight loss. We conclude that SRB contribute to immune response activation in the gut and play an important role in colitis development. PMID- 28912046 TI - Seasonal expression of luteinizing hormone receptor and follicle stimulating hormone receptor in testes of the wild ground squirrels (Citellus dauricus Brandt). AB - The objective of this study was to evaluate whether luteinizing hormone (LH), follicle stimulating hormone (FSH) and their receptors luteinizing hormone receptor (LHR) and follicle stimulating hormone receptor (FSHR) play roles in the seasonal spermatogenesis of the wild ground squirrels. To that end, we characterized the testicular immunolocalization of LHR and FSHR, their expression on both mRNA and protein levels, as well as serum concentrations of LH and FSH in male wild ground squirrels throughout the annual reproductive cycle. Histologically, all types of spermatogenic cells including mature spermatozoa were identified in the breeding season (April), while spermatogonia and primary spermatocytes were observed in the non-breeding season (June), and spermatogonia, primary spermatocytes and secondary spermatocytes were found in pre-hibernation (September). LHR was present in Leydig cells during the whole periods with more intense staining in the breeding season; Stronger immunostaining of FSHR was observed in Sertoli cells during the breeding season compared to the non-breeding season and pre-hibernation. Consistently, the mRNA and protein levels of LHR and FSHR were higher in testes of the breeding season, and then decreased to a relatively lower level in the non-breeding season and pre-hibernation. Meanwhile, serum LH and FSH concentrations were significantly higher in the breeding season than those in the non-breeding season and pre-hibernation. These results suggested that gonadotropins and its receptors, LHR and FSHR may be involved in the regulation of seasonal changes in testicular functions of the wild ground squirrels. PMID- 28912047 TI - Analytical and diagnostic aspects of carbohydrate deficient transferrin (CDT): A critical review over years 2007-2017. AB - The need for investigating alcohol abuse by means of objective tools is worldwide accepted. Among the currently available biomarkers of chronic alcohol abuse, carbohydrate-deficient transferrin (CDT) is one of the most used indicator, mainly because of its high specificity. However, some CDT analytical and interpretation aspects are still under discussion, as witnessed by numerous research papers and reviews. The present article presents a critical review of the literature on CDT appeared in the period from 2007 to 2017 (included). The article is organized in the following sections: (1) introduction, (2) pre analytical aspects (3) analytical aspects (4) diagnostic aspects (5) concluding remarks. As many as 139 papers appeared in the international literature and retrieved by the search engines PubMed, Web of Science and Scopus are quoted. PMID- 28912048 TI - Effectiveness and safety of robotic-assisted versus laparoscopic hepatectomy for liver neoplasms: A meta-analysis of retrospective studies. AB - This meta-analysis aimed to investigate the effectiveness and safety of RAH and LLR for liver neoplasms. A systematic search was performed in PubMed, EMbase, the Cochrane Library, Web of science, and China Biology Medicine disc up to July 2016 for studies that provided comparisons between the surgical outcomes of RAH and LLR for liver neoplasms. WMD, OR and 95% CI were calculated and data combined using the random-effect model. The quality of the evidence was assessed using GRADE methods. A total of 17 studies were included in the meta-analysis, in which 487 patients were in the RAH group and 902 patients were in the LLR group. The meta-analysis results indicated: compared to LLR, RAH was associated with more estimated blood loss, longer operative time, and longer time to first nutritional intake (p < 0.05). There was no significant difference in length of hospital stay, conversion rate during operation, R0 resection rate, complications and mortality (p > 0.05). Three studies reported the total cost, and the result showed a higher cost in the RAH group when compared with the LLR group (p < 0.05). This meta-analysis indicated that RAH and LLR display similar effectiveness and safety in hepatectomy. Considering the lack of high quality original studies, prospective clinical trials should be conducted to provide strong evidence for clinical guidelines formation, and the insurance coverage policies should be established to promote the application of robotic surgery in the future. PMID- 28912049 TI - Two novel mutations in ZAP70 gene that result in human immunodeficiency. PMID- 28912050 TI - Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. STUDY DESIGN: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days. RESULTS: Children treated with PERT for 28 days did not gain more weight than controls (13.7 +/- 9.0% in controls vs 15.3 +/- 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P <.01). Although the study was not powered to detect differences in mortality, mortality was significantly lower in the intervention group treated with pancreatic enzymes (18.6% vs 37.8%; P < .05). Children who died had low fecal fatty acid split ratios at admission. Exocrine pancreatic insufficiency was not improved by PERT, but children receiving PERT were more likely to be discharged with every passing day (P = .02) compared with controls. CONCLUSIONS: PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function. TRIAL REGISTRATION: ISRCTN.com: 57423639. PMID- 28912051 TI - The Relationship between Coronary Artery Disease Risk Factors and Carotid Intima Media Thickness in Children. AB - OBJECTIVE: To determine the number of coronary artery disease risk factors and the individual coronary artery disease risk factors that have a negative influence on carotid intima-media thickness in children. STUDY DESIGN: One hundred and nineteen children (mean age 10.51 +/- 0.52 years; 51% female) participated. Each subject was assessed for carotid intima-media thickness, total cholesterol, high-density lipoprotein cholesterol (HDL-C), glucose, body mass index (BMI), and resting blood pressure. Surveys assessed family history of cardiovascular disease, and physical activity. Ultrasound assessment was completed on the right and left common carotid arteries. Statistical analyses included the t test, chi2 test, one-way ANOVA, and stepwise regression. RESULTS: An increase in carotid intima-media thickness was observed with 2 vs 0 coronary artery disease risk factors for left carotid intima-media thickness (P < .001). With 3+ vs 0 coronary artery disease risk factors, increases in left (P < .001) and combined left and right carotid intima-media thickness (P < .05) were observed. BMI independently predicted carotid intima-media thickness (r = 0.410; P < .01), but HDL-C did not. However, HDL-C was significantly inversely related to BMI (r = -0.534; P < .01). Combining BMI and HDL-C provided the strongest prediction of carotid intima-media thickness (r = 0.451; adjusted R2 = 0.190). Compared with children with a healthy and overweight BMI, children in the obese category had greater right (P < .00), left (P < .001), and combined right and left carotid intima-media thickness (P < .001). CONCLUSIONS: Carotid intima-media thickness is negatively influenced by 2+ coronary artery disease risk factors. Weight status appears to have the greatest negative impact on carotid intima media thickness in children. These findings support the need for strategies to lower BMI in children. PMID- 28912053 TI - Erratum Regarding "Food Insecurity, CKD, and Subsequent ESRD in US Adults" (Am J Kidney Dis. 2017;70[1]:38-47). PMID- 28912055 TI - Data Without Numbers. PMID- 28912054 TI - Effectiveness of Pharmacist Interventions on Cardiovascular Risk in Patients With CKD: A Subgroup Analysis of the Randomized Controlled RxEACH Trial. AB - BACKGROUND: Affecting a substantial proportion of adults, chronic kidney disease (CKD) is considered a major risk factor for cardiovascular (CV) events. It has been reported that patients with CKD are underserved when it comes to CV risk reduction efforts. STUDY DESIGN: Prespecified subgroup analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Adults with CKD and at least 1 uncontrolled CV risk factor were enrolled from 56 pharmacies across Alberta, Canada. INTERVENTION: Patient, laboratory, and individualized CV risk assessments; treatment recommendations; prescription adaptation(s) and/or initiation as necessary; and regular monthly follow-up for 3 months. OUTCOMES: The primary outcome was change in estimated CV risk from baseline to 3 months after randomization. Secondary outcomes were change between baseline and 3 months after randomization in individual CV risk factors (ie, low-density lipoprotein cholesterol, blood pressure, and hemoglobin A1c), risk for developing end-stage renal disease, and medication use and dosage; tobacco cessation 3 months after randomization for those who used tobacco at baseline; and the impact of rural versus urban residence on the difference in change in estimated CV risk. MEASUREMENTS: CV risk was estimated using the Framingham, UK Prospective Diabetes Study, and international risk assessment equations depending on the patients' comorbid conditions. RESULTS: 290 of the 723 participants enrolled in RxEACH had CKD. After adjusting for baseline values, the difference in change in CV risk was 20% (P<0.001). Changes of 0.2mmol/L in low-density lipoprotein cholesterol concentration (P=0.004), 10.5mmHg in systolic blood pressure (P<0.001), 0.7% in hemoglobin A1c concentration (P<0.001), and 19.6% in smoking cessation (P=0.04) were observed when comparing the intervention and control groups. There was a larger reduction in CV risk in patients living in rural locations versus those living in urban areas. LIMITATIONS: The 3-month follow-up period can be considered relatively short. It is possible that larger reduction in CV risk could have been observed with a longer follow up period. CONCLUSIONS: This subgroup analysis demonstrated that a community pharmacy-based intervention program reduced CV risk and improved control of individual CV risk factors. This represents a promising approach to identifying and managing patients with CKD that could have important public health implications. PMID- 28912052 TI - Assessing Children's Report of Stool Consistency: Agreement Between the Pediatric Rome III Questionnaire and the Bristol Stool Scale. AB - OBJECTIVES: To assess the agreement between the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III (QPGS-RIII) and the Bristol Stool Scale (BSS) in evaluating stool consistency and the diagnosis of functional constipation in children. STUDY DESIGN: Children aged 8-18 years were asked to describe their stool consistency in the previous month according to the QPGS-RIII and the BSS. Stool consistency according to both instruments was categorized into 3 categories: "hard," "normal," and "liquid." The children's reported stool consistency using the QPGS-RIII and the BSS were compared, and the intrarater agreement between the 2 instruments was measured using the Cohen kappa coefficient (kappa). The diagnosis of functional constipation was based on the Rome III criteria, incorporating the assessment of stool consistency according to the QPGS-RIII and the BSS. RESULTS: A total of 1835 children were included. Only slight agreement existed between the QPGS-RIII and the BSS for assessing stool consistency (kappa = .046; P = .022). Significantly more children reported hard stools on the BSS compared to the QPGS-RIII (18.0% vs 7.1%; P = .000). The prevalence of functional constipation was 8.6% using the QPGS-RIII and 9.3% using the BSS (P = .134). CONCLUSIONS: Only slight agreement exists between the QPGS RIII and the BSS in the evaluation of stool consistency in children. Better instruments are needed to assess the consistency of stools with a high degree of reliability, both in research and in the clinical setting. PMID- 28912056 TI - Revisiting unplanned extubation in the pediatric intensive care unit: What's new? AB - In 2010, recommendations for preventing unplanned extubations (UEs) in pediatric patients were published based on a literature review. Since then, there have been an increasing number of publications related to UE focusing on children. If the introduction of care bundles and larger body of evidence on UE had impact on UE occurrence, this would have important implications on clinical practice. We searched for relevant publications published between Jan 1, 2010 and Jun 30, 2016 in the MEDLINE, EMBASE, and Cochrane systems. Eight articles were eligible for data abstraction. Three studies were of high methodological quality. The mean contemporaneous incidence of UEs was 1.19 UEs/100 intubation days. The primary risk factors were as follows: caregiver bedside procedures/manipulation, agitation, and endotracheal tube care. The ideal incidence of UEs remains unknown. Key areas identified in the current review may be amenable to changes in unit processes by implementing a care bundle strategy. PMID- 28912057 TI - Apnoeic oxygenation during intubation in the intensive care unit: A systematic review and meta-analysis. AB - Hypoxaemia increases the risk of cardiac arrest and mortality during intubation. The reduced physiological reserve and reduced efficacy of pre-oxygenation in intensive care patients makes their intubation particularly dangerous. Apnoeic oxygenation is a promising means of preventing hypoxaemia in this setting. We sought to ascertain whether apnoeic oxygenation reduces the incidence of hypoxaemia when used during endotracheal intubation in the intensive care unit (ICU). A systematic review of five databases for all relevant studies published up to November 2016 was performed. Eligible studies investigated apnoeic oxygenation during intubation in the ICU, irrespective of design. All studies were assessed for risk of bias and level of evidence. A meta-analysis was performed on all data using Revman 5.3. Six studies including 518 patients were retrieved. The study found level 1 evidence of a significant reduction in the incidence of critical desaturation (RR = 0.69, CI = 0.48-1.00, p = 0.05) and a significant increase in the lowest SpO2 value by 2.83% (CI = 2.28-3.38, p < 0.00001). There was a significant reduction in ICU stay (WMD = -2.89, 95%CI = 3.25 to -2.51, p < 0.00001). There was no significant difference between groups regarding mortality (RR = 0.77, 95%CI = 0.59-1.03, p = 0.08), first pass intubation success (RR = 1.17, 95%CI = 0.67 to 2.03, p = 0.58), arrhythmia during intubation (RR = 0.58, 95%CI = 0.08 to 4.29, p = 0.60), cardiac arrest during intubation (RR = 0.33, 95%CI = 0.01 to 7.84, p = 0.49) and duration of ventilation (WMD = -1.97, 95%CI = -5.89 to 1.95, p = 0.32). Apnoeic oxygenation reduces patient hypoxaemia during intubation performed in the ICU. This meta analysis found evidence that apnoeic oxygenation may significantly reduce the incidence of critical desaturation and significantly raises the minimum recorded SpO2 in this setting. We recommend apnoeic oxygenation be incorporated into ICU intubation protocol. PMID- 28912058 TI - Translation and cultural adaptation of the quality of communication questionnaire for ICU family members in Korea. AB - BACKGROUND: There are no Korean instruments to assess the concepts associated with end-of-life communication quality. OBJECTIVES: To translate and culturally adapt the Quality of Communication (QOC) questionnaire into Korean and evaluate its acceptability and internal consistency. METHODS: We first translated the QOC from English into Korean, then back-translated from Korean to English, and evaluated the cultural appropriateness of the items. We pretested and refined the Korean version of the QOC with 11 ICU family members. Subsequently, the Korean version of the QOC was administered to 62 family members of chronically critically ill patients recruited from 10 ICUs to evaluate its internal consistency. RESULTS: Participants completed the Korean QOC without difficulty during the pretest, and it showed acceptable internal consistency (Cronbach's alpha >=0.85). CONCLUSION: This study provided preliminary evidence of the acceptability and reliability of the Korean QOC in ICU family members. Nonetheless, further evaluation, including item relevance and other psychometric properties, is warranted. PMID- 28912060 TI - Conservative management of a first spontaneous hyphema secondary to iris vascular tufts. PMID- 28912059 TI - Piracetam inhibits ethanol (EtOH)-induced memory deficit by mediating multiple pathways. AB - Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown. In this study, we found that Pir inhibited ethanol induced memory deficit by mediating multiple pathways. Treatment with EtOH could cause cognitive deficit in juvenile rats, and triggered the alteration of synaptic plasticity. Administration with Pir significantly increased long-term potentiation and protected hippocampus neurons from EtOH neurotoxicity. Pir intervention ameliorated EtOH-induced cell apoptosis and inhibited the activation of Caspase-3 in vitro, suggesting that Pir protected neurons by anti-apoptotic effects. Pir could decrease the expression of LC3-II and Beclin-1 induced by EtOH, and increase the phosphorylation of mTOR and reduce the phosphorylation of Akt, which suggested that the protective effect of Pir was involved in regulation of autophagic process and mTOR/Akt pathways. In conclusion, we speculate that Pir reduces EtOH-induced neuronal damage by regulation of apoptotic action and autophagic action, and our research offers preclinical evidence for the application of Pir in ethanol toxicity. PMID- 28912061 TI - [Wide field OCT-angiography of a patient with proliferative diabetic retinopathy]. PMID- 28912062 TI - Simulation of a dynamical ecotourism system with low carbon activity: A case from western China. AB - Currently, sustainable tourism is becoming more and more important in developing ecological economies. To achieve low-carbon development, some industries, such as logistics and municipal solid waste, have already taken action, but tourism has not attached sufficient importance to this issue. This paper designs an ecotourism system including tourism, carbon waste (solid waste and sewage), and ecology (water supply and green areas) to simulate low-carbon ecotourism through a quantitative approach. This paper explores the tourism system as well as some interactive factors and studies their quantitative relationship based on historical data. A feedback-loop dynamical system model is designed to simulate tourism, waste carbon, and ecology simultaneously. Finally, a case study applying the feedback-loop dynamical system model to Leshan City, a typical travel destination with colorful natural resources in western China, is conducted to indicate the development of ecotourism in an environmentally friendly economy, which verifies the positive effects of the model. Results show a coordinating upward tendency of tourism, solid waste carbon, and ecology from the dynamical model. When tourism increases, solid waste accumulation increases; however, the amount of sewage dumped directly into nature decreases sharply. After analysis of investment policy scenarios, the research indicates that more funds for sewage treatment will attract more tourists. To maintain the equilibrium of carbon waste, more funds shall be invested in solid waste treatment in the long term. Some discussions about local policy are included. PMID- 28912063 TI - Differential expression by chromatin modifications of alcohol dehydrogenase 1 of Chorispora bungeana in cold stress. AB - Epigenetic modifications regulate plant genes to cope with a variety of environmental stresses. Chorispora bungeana is an alpine subnival plant with strong tolerance to multiple abiotic stresses, especially cold stress. In this study, we characterized the alcohol dehydrogenase 1 gene from Chorispora bungeana, CbADH1, that is up-regulated in cold conditions. Overexpression of CbADH1 in Arabidopsis thaliana improved cold tolerance, as indicated by a decreased lethal temperature (LT50). Chromatin immunoprecipitation assays showed that histone H3 is removed from the promoter region and the middle-coding region of the gene. H3K9 acetylation and H3K4 trimethylation increased throughout the gene and in the proximal promoter region, respectively. Moreover, increased Ser5P and Ser2P polymerase II accumulation further indicated changes in the transcription initiation and elongation of CbADH1 were due to the cold stress. Taken together, our results suggested that CbADH1 is highly expressed during cold stress, and is regulated by epigenetic modifications. This study expands our understanding of the regulation of gene expression by epigenetic modifications in response to environmental cues. PMID- 28912064 TI - Cell cycle and histone modification genes were decreased in placenta tissue from unexplained early miscarriage. AB - Genetic defect is a major cause of early miscarriage, but still in many cases the etiology are not fully understood. Recent studies have shown that dysregulation of genes in placenta tissue are participated in the pathogenesis of unexplained early miscarriage. The aim of our study is to explore mRNA expression profile in placental chorionic villi and to reveal the underlying mechanism of unexplained early miscarriage. Chorionic villous were isolated and extracted from early miscarriage (n=3) and control pregnancy (n=3) placenta with normal chromosome karyotype using MLPA assay, and then mRNA expression profiles were determined by microarray. For verification the reproducibility of the microarray, three up regulated genes and six down-regulated genes were chosen and examined by real time PCR (n=30). A total of 81 genes were up-regulated and 231 genes were down regulated when compared to the control group, and the differences were reached statistically significances (P<0.05). After Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we found that almost down-regulation genes are associated with cell cycle and histone modification, and these genes are participated in several important physiological processes, such as cell proliferation, nuclear division, chromatic assembly, DNA packing and modification. These results indicated that cell cycle and histone modification genes, and related signaling pathway maybe contribute to the genesis and development of unexplained early miscarriage. Further studies and validations are necessary to elucidate the exact roles of these genes in miscarriage pathogenesis, which can develop tools for early detection and management. PMID- 28912065 TI - Taino and African maternal heritage in the Greater Antilles. AB - Notwithstanding the general interest and the geopolitical importance of the island countries in the Greater Antilles, little is known about the specific ancestral Native American and African populations that settled them. In an effort to alleviate this lacuna of information on the genetic constituents of the Greater Antilles, we comprehensively compared the mtDNA compositions of Cuba, Dominican Republic, Haiti, Jamaica and Puerto Rico. To accomplish this, the mtDNA HVRI and HVRII regions, as well as coding diagnostic sites, were assessed in the Haitian general population and compared to data from reference populations. The Taino maternal DNA is prominent in the ex-Spanish colonies (61.3%-22.0%) while it is basically non-existent in the ex-French and ex-English colonies of Haiti (0.0%) and Jamaica (0.5%), respectively. The most abundant Native American mtDNA haplogroups in the Greater Antilles are A2, B2 and C1. The African mtDNA component is almost fixed in Haiti (98.2%) and Jamaica (98.5%), and the frequencies of specific African haplogroups vary considerably among the five island nations. The strong persistence of Taino mtDNA in the ex-Spanish colonies (and especially in Puerto Rico), and its absence in the French and English excolonies is likely the result of different social norms regarding mixed marriages with Taino women during the early years after the first contact with Europeans. In addition, this article reports on the results of an integrative approach based on mtDNA analysis and demographic data that tests the hypothesis of a southward shift in raiding zones along the African west coast during the period encompassing the Transatlantic Slave Trade. PMID- 28912066 TI - The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells. AB - 3',5'-Cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. Here, we have investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2'-O-Me-cAMP) increased cytoplasmic Ca2+ concentration ([Ca2+]c) in <=30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC). However, these drugs did not modify [Ca2+]c in fluo-4 loaded HUVEC monolayers. In DAF-2-loaded HUVEC monolayers, forskolin, PKA and Epac activators significantly increased NO release, and the forskolin effect was reduced by inhibition of PKA (Rp-cAMPs), Epac (ESI-09), eNOS (L-NAME) or phosphoinositide 3-kinase (PI3K; LY-294,002). On the other hand, inhibition of CaMKII (KN-93), AMPK (Compound C), or total absence of Ca2+, was without effect. In Western blot experiments, Serine 1177 phosphorylated-eNOS was significantly increased in HUVEC by cAMP-elevating agents and PKA or Epac activators. In isolated rat aortic rings LY-294,002, but not KN-93 or Compound C, significantly reduced the vasorelaxant effects of forskolin in the presence of endothelium. Our results suggest that Epac and PKA activate eNOS via Ser 1177 phosphorylation by activating the PI3K/Akt pathway, and independently of AMPK or CaMKII activation or [Ca2+]c increase. This action explains, in part, the endothelium-dependent vasorelaxant effect of cAMP. PMID- 28912067 TI - Farnesoid X receptor regulates SULT1E1 expression through inhibition of PGC1alpha binding to HNF4alpha. AB - Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity. The inhibitory effect was potentiated by FXR overexpression but attenuated by FXR knockdown, confirming FXR-dependent regulation of SULT1E1. Surprisingly, direct regulation of SULT1E1 by FXR was unlikely because FXR did not bind to SULT1E1 promoter or enhancer as revealed by chromatin immunoprecipitation (ChIP). Interestingly, SULT1E1 regulation was abolished when HNF4alpha (hepatocyte nuclear factor 4alpha, a known activator of SULT1E1) was silenced, supporting a critical role for HNF4alpha in FXR regulation of SULT1E1. Furthermore, a combination of ChIP, luciferase reporter and co-immunoprecipitation assays showed that FXR inhibited HNF4alpha transactivation of SULT1E1 by suppressed binding of the co-activator PGC1alpha (peroxisome proliferator-activated receptor-gamma coactivator 1alpha) to HNF4alpha. In conclusion, FXR transcriptionally regulates SULT1E1 through inhibition of PGC1alpha binding to HNF4alpha. Targeting the FXR SULT1E1 axis may represent a promising approach for management of estrogen related diseases. PMID- 28912069 TI - Generation of a novel human cytomegalovirus bacterial artificial chromosome tailored for transduction of exogenous sequences. AB - The study of herpesviruses, including human cytomegalovirus (HCMV), is complicated by viral genome complexity and inefficient methods for genetic manipulation in tissue culture. Reverse genetics of herpesviruses has been facilitated by propagating their genomes in E. coli as bacterial artificial chromosomes (BACs), which enables complex and precise genetic manipulation using bacterial recombinational systems. Internal capsid volume imposes a strict limit on the length of genome that can be packaged efficiently. This necessitates deletion of presumably nonessential segments of the viral genome to allow for incorporation of the E. coli mini-F plasmid propagation sequence. To avoid deleting viral genes, several BACs utilize a Cre/LoxP system to self-excise the mini-F sequence upon reconstitution of virus in tissue culture. Here, we describe the adaptation of Cre/LoxP to modify the mini-F sequence of the HCMV TB40/E BAC, thus generating a new self-excisable BAC, TB40/E/Cre. After excision of the E. coli propagation sequence, a 2.7 kbp genome length deficit is created due to a preexisting deletion within the US2-US6 coding region. We exploited this deficit and an FKBP12 protein destabilization domain (ddFKBP) to create a novel gene transduction system for studying exogenous proteins during HCMV infection. Using TB40/E/Cre, we: i) found genome length-associated differences in growth and ii) demonstrated its utility as a system capable of efficient transduction of exogenous proteins and regulation of their accumulation over periods as short as 2h. TB40/E/Cre is a powerful tool of broad applicability that can be adapted to study HCMV replication and cell biology in a variety of contexts. PMID- 28912070 TI - Recombinant influenza H7 hemagglutinin containing CFLLC minidomain in the transmembrane domain showed enhanced cross-protection in mice. AB - Since February 2013, H7N9 influenza virus, causing human infections with high mortality in China, has been a potential pandemic threat. The H7N9 viruses are found to diverge into distinct genotypes as other influenza viruses; thus a vaccine that can provide sufficient cross-protection against different genotypes of H7N9 viruses is urgently needed. Our previous studies demonstrated that the HA based structural design approach by introducing a CFLLC minidomain into transmembrane domain (TM) of H1, H5 or H9 hemagglutinin (HA) proteins by replacing with H3 subtype HA TM could enhance their cross-protection. In this study, we used Sf9 insect cell expression system to express recombinant H7 HA proteins H7-53WT, in which HA gene was derived from H7N9-53 strain, and H7-53TM containing CFLLC minidomian by replacing its TM domain with H3 HA TM. We investigated whether introduction of CFLLC minidomain into H7 HA (H7-53TM) could increase its cross-reactivity and cross-protection against different genotypes of H7N9 viruses. The results showed that the H7-53TM either with or without squalene adjuvant induced increased HI antibodies, serum IgG antibodies, and IFN-gamma production to a panel of 7 H7N9 viruses in mice. Vaccinated animals with H7-53TM alone showed complete protection against challenge with heterologous H7N9-MCX strain, while H7-53WT alone showed incomplete protection (80%). Furthermore, mice vaccinated with H7-53TM HA showed less body weight loss and less pulmonary lesions and inflammation after challenge with homologous or heterologous H7N9 viruses, comparing to H7-53WT. In summary, this study presents a better subunit vaccine candidate (H7-53TM) against potential H7N9 pandemic. PMID- 28912068 TI - Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy. AB - Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt 1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy. PMID- 28912071 TI - Sentinel node biopsy after primary chemotherapy in cT2 N0/1 breast cancer patients: Long-term results of a retrospective study. AB - BACKGROUND: It is controversial whether sentinel node biopsy (SNB) is adequate in breast cancer patients who become cN0 after primary chemotherapy. To address this we retrospectively compared outcomes in T2 cases given primary chemotherapy, comparing those given axillary dissection (AD) with those given SNB but no AD if sentinel nodes were clinically negative post-chemotherapy. METHODS: We examined overall survival (OS), disease-free survival (DFS), and axillary failure in 317 consecutive cT2 cN0/1 patients given primary chemotherapy followed by quadrantectomy/mastectomy, between January 2002 and December 2007. The approach to the axilla changed over time allowing division into three groups: 101 (31.9%) given upfront AD; 139 (43.8%) given SNB + AD; and 77 (24.3%) given SNB only because the SNs were negative. RESULTS: After median follow-ups of 92 (AD), 99 (SNB + AD) and 72 months (SNB-only), OS (p = 0.131) and DFS (p = 0.087) did not differ between the 3 groups, or between SNB-only and the ypN1 and ypN0 subgroups of SNB + AD, or between the cN0 and cN1 subgroups (before chemotherapy) of the SNB-only group. No SNB-only patient had axillary failure. OS (p = 0.004) and DFS (p = 0.002) were better in patients with complete response than those with partial response or stable/progressive disease. CONCLUSIONS: SNB is adequate in T2 patients who are cN0 after primary chemotherapy, irrespective of axillary status before. Better outcomes after complete pathological remission confirm the prognostic importance of response to primary chemotherapy, and suggest that all T2 patients should receive primary chemotherapy. PMID- 28912072 TI - Suprapubic approach for robotic complete mesocolic excision in right colectomy: Oncologic safety and short-term outcomes of an original technique. AB - INTRODUCTION: Right-sided colon cancer has a worse prognosis than left-sided colon cancer. Complete mesocolic excision (CME) with central vessels ligation (CVL) reduces local recurrence, but is technically demanding, particularly with a laparoscopic approach. Aim of this study is to describe a new robotic approach to right colectomy with CME and CVL and to report oncologic safety and short term outcomes. METHODS: Twenty consecutive patients were included. All patients had a right colon adenocarcinoma and underwent right colectomy with a suprapubic approach. Surgery was realized with the Da Vinci Xi(r) system and all trocars were placed along a horizontal line 3-6 cm above the pubis. CME with CVL was realized in all the patients. Data analysed were: duration of surgery, conversions to open surgery, intraoperative and postoperative complication by Clavien Dindo classification, margins of resections, length of specimen and number of lymph nodes retrieved. RESULTS: Patients median age was 69 years, median body mass index was 27 kg/m2. Median operative time was 249 min, blood loss was negligible, no conversions to open or laparoscopic surgery occurred. Median hospital stay was six days; two postoperative grade IIIa Clavien-Dindo complications occurred, no 30-days postoperative death was registered. Resection margins were negative in all patients; median tumour diameter was 3.6 cm, median specimen length was 40 cm, median number of harvested lymph nodes was 40. CONCLUSIONS: Robotic right colectomy with CME using a suprapubic approach is a feasible and safe technique that allows for an extended lymphadenectomy and provides high quality surgical specimens. PMID- 28912073 TI - Mapping of ventricular arrhythmias using a novel noninvasive epicardial and endocardial electrophysiology system. AB - INTRODUCTION: The aim of this study was to assess the use of a novel noninvasive epicardial and endocardial electrophysiology system (NEEES) for mapping of ventricular arrhythmias. METHODS: Eight patients (2 females, mean age 50+/-17 years) with ischemic (n=3) and nonischemic (n=5) cardiomyopathy and inducible ventricular arrhythmias during electrophysiology study were enrolled. Noninvasive mapping of ventricular arrhythmias was performed using the NEEES based on body surface electrocardiograms and computed tomography imaging data. Arrhythmia patterns were analyzed using noninvasive phase mapping. RESULTS: Macro-reentrant VT circuits were observed in 3 ischemic and 1 nonischemic cardiomyopathy patient, respectively. In the remaining 4 patients, phase mapping revealed relatively stable rotor activity and multiple wavelets. CONCLUSIONS: Noninvasive cardiac mapping was able to visualize the macro-reentrant circuits in patients with scar related VT. In patients without myocardial scar only polymorphic VT or VF was inducible, and rotor activity and multiple wavelets were observed. PMID- 28912074 TI - Heart rate dependency of JT interval sections. AB - BACKGROUND: Little experience exists with the heart rate correction of J-Tpeak and Tpeak-Tend intervals. METHODS: In a population of 176 female and 176 male healthy subjects aged 32.3+/-9.8 and 33.1+/-8.4years, respectively, curve-linear and linear relationship to heart rate was investigated for different sections of the JT interval defined by the proportions of the area under the vector magnitude of the reconstructed 3D vectorcardiographic loop. RESULTS: The duration of the JT sub-section between approximately just before the T peak and almost the T end was found heart rate independent. Most of the JT heart rate dependency relates to the beginning of the interval. The duration of the terminal T wave tail is only weakly heart rate dependent. CONCLUSIONS: The Tpeak-Tend is only minimally heart rate dependent and in studies not showing substantial heart rate changes does not need to be heart rate corrected. For any correction formula that has linear additive properties, heart rate correction of JT and JTpeak intervals is practically the same as of the QT interval. However, this does not apply to the formulas in the form of Int/RRa since they do not have linear additive properties. PMID- 28912075 TI - Ventricular repolarization disturbances after high dose intravenous methylprednisolone Theraphy. AB - OBJECTIVE: There are no randomized trials evaluating the effects of pulse steroid treatment on cardiac electrophysiologic functions. The data are limited only to case series. In this study, we sought to evaluate the effects of high dose intravenous methylprednisolone therapy on indices of ventricular repolarization. METHODS: Fifty patients with various autoimmune and inflammatory disorders were enrolled to the study. Electrocardiography (ECG) was obtained 4h before and 12h after the pulse steroid treatment. All ECGs were thoroughly evaluated by an experienced electrophysiologist. Indices of ventricular repolarization including QTc, JT, Tp-Te, Tp-Te/QTc were measured and compared with before and after treatment ECGs. RESULTS: There were 36 female and 14 male patients. Mean age was 36+/-13years. Heart rate was significantly reduced after the therapy (87,16+/ 17,45bpm vs 73,86+/-17,45 p:0,001). QT interval (361,0+/-29,91 vs 388,20+/-42,84 p:0,001) and corrected QT interval (QTc) was significantly prolonged (401,60+/ 19,79 vs 413,72+/-26,38 p:0,01) after pulse steroid therapy. Also, JT interval (273,0+/-28,73 vs. 299,60+/-45,66 p:0,001) and JT interval index (JTI%) was significantly prolonged (118,18+/-17,54 vs. 110,56+/-13,92 p:0,01). Tp-e interval was significantly prolonged after high-dose steroid treatment (74,60+/-13,12 vs. 83,80+/-13,68 p:0.001). The ratio of Tp-Te to QTc was also significantly increased after pulse steroid therapy (0,18+/-0,03 vs 0,20+/-0,03 p:0,009). CONCLUSION: Our study shows that indices of ventricular repolarization are significantly prolonged after pulse steroid treatment. These findings indicate an increased risk of arrhythmias related to high dose intravenous methylprednisolone therapy. PMID- 28912076 TI - Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis. AB - Combined cognitive and physical exercise interventions have potential to elicit cognitive benefits in older adults with mild cognitive impairment (MCI) or dementia. This meta-analysis aims to quantify the overall effect of these interventions on global cognitive functioning in older adults with MCI or dementia. Ten randomized controlled trials that applied a combined cognitive physical intervention with cognitive function as an outcome measure were included. For each study effect sizes were computed (i.e., post-intervention standardized mean difference (SMD) scores) and pooled, using a random-effects meta-analysis. The primary analysis showed a small-to-medium positive effect of combined cognitive-physical interventions on global cognitive function in older adults with MCI or dementia (SMD[95% confidence interval]=0.32[0.17;0.47], p<0.00). A combined intervention was equally beneficial in patients with dementia (SMD=0.36[0.12;0.60], p<0.00) and MCI (SMD=0.39[0.15;0.63], p<0.05). In addition, the analysis showed a moderate-to-large positive effect after combined cognitive physical interventions for activities of daily living (ADL) (SMD=0.65[0.09;1.21], p<0.01)and a small-to-medium positive effect for mood (SMD=0.27[0.04;0.50], p<0.01). These functional benefits emphasize the clinical relevance of combined cognitive and physical training strategies. PMID- 28912077 TI - Electron receptor addition enhances butanol synthesis in ABE fermentation by Clostridium acetobutylicum. AB - The techniques for enhancing butanol production in ABE fermentation by Clostridium acetobutylicum generally focus on adding electron carrier to strengthen NADH synthesis, repressing hydrogenase by aerating CO, supplementing butyrate, etc. However, those methods suffer from the problems of total solvent decrease, high purification cost, using expensive supplemental substances, etc. In this study, we added small amount of electron receptors (Na2SO4/CaSO4, 2g/L) into ABE fermentation broth: to alter electron/proton distributions in the intracellular electron transport shuttle system, directing more electron/proton pairs into NADH synthesis route; to stimulate intracellular accumulation of those amino acids favorable for cells survival/butanol synthesis. In ABE fermentation in a 7L fermentor, adding 2g/L Na2SO4 could raise butanol concentration to a higher level of 12.96g/L, which was 34.8% higher than that of the control. Addition of tiny amount cheap electron receptor would provide a new way to enhance bio-butanol production. PMID- 28912078 TI - Effect of 5-hydroxymethylfurfural (5-HMF) on high-rate continuous biohydrogen production from galactose. AB - This study investigated the effect of 5-hydroxymethylfurfural (5-HMF) on high rate continuous fermentative H2 production in a lab-scale fixed bed reactor (FBR) inoculated with mixed culture granules and fed with 15g/L galactose at a hydraulic retention time of 6h and at 37 degrees C. During the 83days of operation, 5-HMF up to 2.4g/L was spiked into the feedstock. The maximum hydrogen production performance of 26.6L/L-d and 2.9mol H2/mol galactoseadded were achieved at 5-HMF concentration of 0.6g/L. 5-HMF concentration exceeding 0.9g/L not only inhibited hydrogen production but also affected the biofilm structure and microbial community population. However, when 5-HMF was eliminated from the feedstock, the performance and microbial community population were rapidly recovered. PMID- 28912079 TI - Solid anaerobic digestion: State-of-art, scientific and technological hurdles. AB - In this paper, a state-of-art about solid anaerobic digestion (AD), focused on recent progress and trends of research is proposed. Solid anaerobic digestion should be the most appropriate process for degradation of by-products with high total solid (TS) content, especially lignocellulosic materials like agricultural waste (straw, manure), household waste and food waste. Solid AD is already widely used in waste water treatment plant for treating plant for sewage sludge but could be more developed for lignocellulosic materials with high TS content. Many research works were carried out in Europe on solid AD, focused on current hurdles (BMP, codigestion, inhibition, microbial population, rheology, water transfers, inoculum, etc.) in order to optimize the solid AD process. In conclusion, hurdles of solid AD process should and must be solved in order to propose better productivity and profitability of such system operating with high TS content (>15%), favouring reliable industrial processes. PMID- 28912080 TI - Induced prodrug activation by conditional protein degradation. AB - Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation Directed Enzyme Prodrug Therapy (DDEPT). Herein, we use traceless shielding (TShld), a mechanism that degrades a protein of interest unless it is rescued by the addition of rapamycin, to test this concept. We demonstrated that TShld rapidly yielded only native protein products within 1h after rapamycin addition. The rapid protection phenotype of TShld was further adapted to rescue yeast cytosine deaminase, a prodrug converting enzyme. As expected, cell viability was adversely affected only in the presence of both 5-fluorocytosine (5-FC) and rapamycin. We believe that the DDEPT system can be easily combined with other targeting strategies to further increase the safety of prodrug therapies. PMID- 28912081 TI - Towards understanding rTMS mechanism of action: Stimulation of the DLPFC causes network-specific increase in functional connectivity. AB - Transcranial magnetic stimulation (TMS) is a powerful non-invasive technique for the modulation of brain activity. While the precise mechanism of action is still unknown, TMS is applied in cognitive neuroscience to establish causal relationships between stimulation and subsequent changes in cerebral function and behavioral outcome. In addition, TMS is an FDA-approved therapeutic agent in psychiatric disorders, especially major depression. Successful repetitive TMS in such disorders is usually applied over the left dorso-lateral prefrontal cortex (DLPFC) and treatment response mechanism was therefore supposed to be based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. However, mechanistic evidence for the direct effects of rTMS over DLPFC is sparse. Here we show the specificity and temporal evolution of rTMS effects by comparing connectivity changes within 20 common independent components in a sham controlled study. Using an unbiased whole-brain resting-state network (RSN) approach, we successfully demonstrate that stimulation of left DLPFC modulates anterior cingulate cortex (ACC) connectivity in one specific meso-cortico-limbic network, while all other networks are neither influenced by rTMS nor by sham treatment. The results of this study show that the neural correlates of TMS treatment response are also traceable in DLPFC stimulation of healthy brains and therefore represent direct effects of the stimulation procedure. PMID- 28912082 TI - MAPK signalling pathway in cancers: Olive products as cancer preventive and therapeutic agents. AB - The mitogen-activated protein kinases (MAPKs) are fundamental in inflammation and cancer control, through the crosstalk between the redox regulated nuclear factor E2-related factor 2 (Nrf2) and nuclear factor-kB (NFkappaB) gene expression. MAPKs regulate various cellular activities involved in cancer progression, including proliferation, apoptosis and immune escape and blockade of upstream kinases is a current therapeutic strategy. However, these therapies are associated with some adverse effects and with the paradoxical activation of the MAPKs pathway. In the context of cancer prevention and treatment, it has been suggested that dietary factors are able to modulate cancer initiation and progression by interacting with the MAPKs. Within these dietary factors, virgin olive oil (VOO) is of particular interest due to its content in squalene, already used as drug delivery system in cancer therapy. The aim of this review is to discuss the studies pointing to the effects of olive-derived foodstuff and nutraceuticals on MAPKs signalling cascades. The reviewed experimental studies suggest that the stress-activated JNK and p38 MAPKs could be targets of olive derived nutraceuticals. The latter, including phytochemicals from olive cultivation and processing wastes, could be adjuvants in chemotherapies, whereas VOO could be considered a "natural delivery system" of bioactive phytochemicals due to its high content in squalene. PMID- 28912083 TI - Nasogastric decompression not associated with a reduction in surgery or bowel ischemia for acute small bowel obstruction. AB - OBJECTIVES: Small bowel obstructions (SBOs) occur 300,000 times annually leading to $1.3 billion in cost. Approximately 20% of patients require a laparotomy to manage the obstruction and either prevent or treat intestinal ischemia. Early management may play a role in reducing these complications. Nasogastric decompression is commonly used for early management. Our primary objective was to determine if NGD was associated with lower rates of surgery, bowel ischemia or length of stay. METHODS: We retrospectively enrolled 181 ED patients with SBO from 9/2013 to 9/2015 in order to determine if nasogastric decompression was associated with a reduction in rates of surgery, bowel ischemia or hospital length of stay. RESULTS: Our subject population was 46% female, median age of 60.27% of patients received surgery. Nasogastric decompression was used in 51% of patients. There was no association with a reduction in rates of surgery (p=0.20) or bowel resection (p=0.41) with patients receiving Nasogastric decompression, and no difference in baseline characteristics. Nasogastric decompression was associated with a two-day increase in hospital length of stay. Factors that were significantly associated with surgical exploration of SBO were: female (OR 2.32 (95% CI: 1.01-5.31)) and "definite SBO" on CT (OR 3.29 (95% CI: 1.18-9.20)). Abnormal vital signs, obstipation, and lab values were not predictors of surgery. CONCLUSION: Nasogastric decompression is not associated with a reduction in need for surgery or bowel resection, but is associated with a 2-day increase in median LOS. Women were more likely to receive surgery than men. PMID- 28912084 TI - Patients' outcomes after cardiac arrest based on age: Methodological issues. PMID- 28912085 TI - The evaluation of the sensitivity and specificity of wrist examination findings for predicting fractures. AB - BACKGROUND: The aim of this study was to evaluate the sensitivity and specificity of physical examination findings and functional tests in adult acute wrist trauma patients who presented to the emergency department (ED) and to create a reliable and practical clinical decision rule for determining the necessity of radiography in wrist trauma. METHODS: This prospective observational study was conducted in a tertiary ED. Each patient was checked for 18 physical examination findings and functional tests. Patients with suspected fracture were enrolled consecutively. Antero-posterior and lateral wrist views were performed for each patient. All radiographical studies were interpreted by an orthopedic surgeon. The prevalence, sensitivity and specificity, negative and positive predictive values of each finding were calculated. A modeling for predicting fractures was created using computer. RESULTS: 207 patients were evaluated and 69 patients (33.3%) had fractures. The most common encounterd fracture site was distal radius (29.5%). The most sensitive examination finding was pain in dorsiflexion (95.7%) and the most specific finding was ecchymosis (97.8%). Wrist edema, deformity and pain aggravated by pronation were found to be strong predictors of fracture. The area under the receiver operating characteristic curve at internal validation for a prediction model based on these three predictors was 0.88 (95% CI: 0.83-0,93). The overall sensitivity and specificity of this model were 94% (95% CI: 85-98%) and 51% (95% CI 43-60%) respectively. According to the model created in this study, 34% of acute blunt wrist trauma patients do not require any X-ray imaging. CONCLUSIONS: This triple modeling may be used as an effective decision rule for predicting all wrist fractures in the ED and in the disaster setting. PMID- 28912087 TI - Endocannabinoid mechanism in amphetamine-type stimulant use disorders: A short review. AB - Recent evidence shows that the endocannabinoid system is involved in amphetamine type stimulants (ATS) use disorders. To elucidate the role of the endocannabinoid system in ATS addiction, we reviewed results of studies using cannabinoid receptor agonists, antagonists as well as knockout model. The endocannabinoid system seems to play a role in reinstatement and relapse of ATS addiction and ATS induced psychiatric symptoms. The molecular mechanisms of this system remains unclear, the association with dopamine system in nucleus accumbens is most likely involved. However, the function of the endocannabinoid system in anxiety and anti anxiety effects induced by ATS is more complicated. These findings suggest that the endocannabinoid system may play an important role in the mechanism of ATS addiction and provide new idea for treating ATS addiction. PMID- 28912086 TI - G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling. AB - Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated GRK4-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of GRK4 halted cell proliferation. Cells expressing GRK4 (GRK4(+)) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-beta-galactosidase (SA-beta-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in GRK4(+) cells (>= 2 fold, p < 0.05). Among these, 9 genes - AKT1, p16INK4, p27KIP1, p19INK4, IGFBP3, MAPK14, PLAU, THBS1, TP73 - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, CDK2, CDK6, ETS1, NBN, RB1, SIRT1, were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins (MAPK14) was validated by immunoblotting. Neither p53 nor p21Waf1/Cip1 protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of GRK4 on triggering a p53-independent cellular senescence, which involves an intricate signaling network. PMID- 28912088 TI - Sip and spit or sip and swallow: Choice of method differentially alters taste intensity estimates across stimuli. AB - While the myth of the tongue map has been consistently and repeatedly debunked in controlled studies, evidence for regional differences in suprathreshold intensity has been noted by multiple research groups. Given differences in physiology between the anterior and posterior tongue (fungiform versus foliate and circumvallate papillae) and differences in total area stimulated (anterior only versus whole tongue, pharynx, and epiglottis), small methodological changes (sip and spit versus sip and swallow) have the potential to substantially influence data. We hypothesized instructing participants to swallow solutions would result in greater intensity ratings for taste versus expectorating the solutions, particularly for umami and bitter, as these qualities were previously found to elicit regional differences in perceived intensity. Two experiments were conducted: one with model taste solutions [sucrose (sweet), a monosodium glutamate/inosine monophosphate (MSG/IMP) mixture (savory/umami), isolone (a bitter hop extract), and quinine HCl (bitter)], and a second with actual food products (grapefruit juice, salty vegetable stock, savory vegetable stock, iced coffee, and a green tea sweetened with acesulfame-potassium and sucralose). In a counterbalanced crossover design, participants (n=66 in experiment 1 and 64 in experiment 2) rated the stimuli for taste intensities both when swallowing and when spitting out the stimuli. Results suggest swallowing may lead to greater reported bitterness versus spitting out the stimulus, but that this effect was not consistent across all samples. Thus, explicit instructions to spit out or swallow samples should be given to participants in studies investigating differences in taste intensities, as greater intensity may sometimes, but not always, be observed when swallowing various taste stimuli. PMID- 28912089 TI - Vocal correlates of emotional reactivity within and across contexts in domestic pigs (Sus scrofa). AB - Vocalizations have long been recognized to encode information about an individual's emotional state and, as such, have contributed to the study of emotions in animals. However, the potential of vocalizations to also encode information about an individual's emotional reactivity has received much less attention. In this study, we aimed to test whether the vocalizations of domestic pigs contain correlates of emotional reactivity that are consistent between different contexts. We recorded vocalizations of 120 young female pigs in an experimental arena in two consecutive recording contexts, social isolation and an encounter with a familiar human. Simultaneously, we measured their heart rate and behaviour to determine their emotional reactivity in the same context (within context). In addition, we aimed to determine the subjects' emotional reactivity in other contexts (across-context) by measuring their behaviour in four common tests of emotional reactivity, the human approach test, the open door test, the open field test and the novel object test. Using a cluster analysis, we identified four different call types. Significant inter-context correlations were found for all call types, suggesting that pig vocalizations are consistent within an individual across contexts. The call rate and the proportions of the individual call types were found to correlate significantly with indices of emotional reactivity both within and across contexts. Thereby, we found more significant correlations to indices of emotional reactivity within context (behavioural and physiological response during recording) compared to across context (behavioural response in the four emotional reactivity tests). The consistency of the vocal correlates to emotional reactivity between the different contexts depended on the call type. While we found moderate evidence that the high grunt is indicative of more active, more explorative and less fearful individuals both within as well as across contexts, the other call types provided less consistent results. Thus, it seems that some call types are better suited to provide information on a caller's emotional reactivity than others, and further research is needed to clarify the underlying influential factors. PMID- 28912090 TI - Immuno-oncology and Its Opportunities for Interventional Radiologists: Immune Checkpoint Inhibition and Potential Synergies with Interventional Oncology Procedures. AB - Immunotherapy, specifically the use of immune checkpoint inhibitors, offers a new approach to fighting cancer. Although the results of treatment with immune checkpoint inhibition alone have been remarkable for certain cancers, these results are not universal. Preclinical and early clinical studies indicate the potential for synergistic effects when immune checkpoint inhibition is combined with immunogenic local therapies such as ablation and embolization. This review offers an overview of immunology as it relates to immune checkpoint inhibition and the possibilities for synergy when combined with interventional radiology treatments. PMID- 28912091 TI - Is hippocampal neurogenesis modulated by the sensation of self-motion encoded by the vestibular system? AB - It is now well accepted that physical exercise stimulates hippocampal neurogenesis and may promote cognitive ability. Less clear are the mechanisms by which this process occurs. One potential contributing influence, that is usually neglected, is the vestibular system, which by its very nature must be activated during physical exercise and which essentially cannot be turned off without complete bilateral vestibular lesions. This paper reviews a small literature that demonstrates that bilateral vestibular loss (BVL) in rats modulates cell proliferation in the dentate gyrus (DG) and that artificial electrical activation of the vestibular system, using galvanic vestibular stimulation, does also. Although there are only a few piecemeal studies of this subject, because of the way that they were controlled, it is likely that the vestibular system has a regulatory role in cell proliferation in the DG and therefore possibly in neurogenesis, which needs to be taken into account in the interpretation of neurogenesis studies. PMID- 28912092 TI - Comparison of gut microbiota in adult patients with type 2 diabetes and healthy individuals. AB - Recent studies indicate that inflammatory reactions leading to the development of type 2 diabetes mellitus (T2DM) may also contribute to variations in the composition of the intestinal microbiota, suggesting a relation between T2DM and bacterial residents in the intestinal tract. This case-control study was designed to evaluate the composition of the gut microbiota dominant bacterial groups in patients with T2DM compared to the healthy people. A total of 36 adult subjects (18 patients diagnosed with T2DM and 18 healthy persons) were included in the study. The intestinal microbiota composition was investigated by quantitative real-time polymerase chain reaction (qPCR) method using bacterial 16S rRNA gene. The quantities of two groups of bacteria were meaningfully different among T2DM patients and healthy individuals. While, the level of Lactobacillus was significantly higher in the patients with T2DM (P value < 0.001), Bifidobacterium was significantly more frequent in the healthy people (P value < 0.001). The quantities of Prevotella (P value = 0.0.08) and Fusobacterium (P value = 0.99) genera in faecal samples were not significantly different between the two groups. The significant alterations in dominant faecal bacterial genera found in T2DM patients participating in the current study highlight the link between T2DM disease and compositional variation in intestinal flora. These findings may be valuable for developing approaches to control T2DM by modifying the gut microbiota. More investigations with focus on various taxonomic levels (family, genus and species) of bacteria are necessary to clarify the exact relevance of changes in the gut microbial communities with the progression of T2DM disorder. PMID- 28912093 TI - Lentiviral gene delivery to plasmolipin-expressing cells using Mus caroli endogenous retrovirus envelope protein. AB - Gene therapy is a promising method for treating malignant diseases. One of the main problems is target delivery of therapeutic genes. Here we show that lentiviral vector particles pseudotyped with Mus caroli endogenous retrovirus (McERV) envelope protein can be used for selective transduction of PLLP expressing cells. As a therapeutic gene in McERV-pseudotyped vector particles we used miniSOG encoding the cytotoxic FMN-binding protein, which can generate reactive oxygen species under illumination. Significant cytotoxic effect (up to 80% of dead cells in population) was observed in PLLP-expressing cells transduced with McERV-pseudotyped vector particles and subjected to illumination. We demonstrated that the McERV-pseudotyped HIV-1 based lentiviral vector particles are an effective tool for selective photoinduced destruction of PLLP-expressing cells. PMID- 28912094 TI - Selection of PD1/PD-L1 X-Aptamers. AB - Specific, chemically modified aptamers (X-Aptamers) were identified against two immune checkpoint proteins, recombinant Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1). Selections were performed using a bead-based X-Aptamer (XA) library containing several different amino acid functional groups attached to dU at the 5-position. The binding affinities and specificities of the selected XA-PD1 and XA-PDL1 were validated by hPD-1 and hPD-L1 expression cells, as well as by binding to human pancreatic ductal adenocarcinoma tissue. The selected PD1 and PDL1 XAs can mimic antibody functions in in vitro assays. PMID- 28912095 TI - Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo. AB - Gliomas are the most recurrently occurring primary malignancies in the central nervous system. Despite surgical interventions, chemo- and radiotherapy, the results are unfortunately poor. Therefore, there is pressing need to explore more effective and efficient treatment options for treatment of glioma. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 MUM against glioma U87 cells as against the IC50 of 65 MUM against human astrocytes. The molecule exerted its anticancer activity through induction of apoptosis as evident from the Bid-, and Bax controlled cytochrome c and Omi/HtrA2 release, XIAP suppression, and caspase-9 and 3 signalling cascade. Additionally, it also caused cell cycle arrest of human glioma U87 cancer cells in the S phase of the cell cycle. Interestingly, globularifolin also caused significant inhibition of Akt/mTOR/p70S6K and MEK/ERK pathways. Globularifolin also inhibits cell migration and invasion by regulating the expression of matrix metalloproteinases (MMPs) in U87 glioma cells. We further investigated whether globularifolin exhibits the same effectiveness against glioma cell xenografts in nude mice in vivo and it was observed that globularifolin significantly reduced the tumor growth and volume in vivo indicating the potential of globularifolin as lead molecule for glioma chemotherapy. PMID- 28912096 TI - Analytical verification and method comparison of the ADVIA Centaur(r) Intact Parathyroid Hormone assay. AB - OBJECTIVES: This study is the first verification of the novel iPTH Siemens ADVIA Centaur(r) Intact Parathyroid Hormone (iPTHm) chemiluminescence immunoassay based on monoclonal antibodies. We also compared the iPTH results obtained using this assay with the previous ADVIA Centaur(r) Parathyroid Hormone assay (iPTHp) based on polyclonal antibodies. DESIGN AND METHODS: The analytical performance study of iPTHm assay included LoD, LoQ, intra- and inter-assay reproducibility, and linearity. A comparison study was performed on 369 routine plasma samples. The results were analyzed independently for patients with normal and abnormal GFR, as well as patients on hemodialysis. In addition, clinical concordance between assays was assessed. Finally, we studied PTH stability of plasma samples at 4 degrees C. RESULTS: For the iPTHm assay LoD and LoQ were 0.03pmol/L and 0.10pmol/L, respectively. Intra- and inter-assay CV were between 2.3% and 6.2%. Linearity was correct in the range from 3.82 to 203.08pmol/L. Correlation studies showed a good correlation (r=0.99) between iPTHm and iPTHp, with bias of -2.55% (IC -3.48% to -1.62%) in the range from 0.32 to 117.07pmol/L. Clinical concordance, assessed by Kappa Index, was 0.874. The stability study showed that differences compared to basal iPTH concentration did not exceed 20% in any of the samples analyzed. CONCLUSIONS: The iPTHm assay demonstrated acceptable performance and a very good clinical concordance with iPTHp assay, currently used in our laboratory. Thus, the novel iPTHm assay can replace the previous iPTHp assay, since results provided by both assays are very similar. In our study, the stability of iPTH is not affected by storage up to 14days. PMID- 28912097 TI - IgG subclasses quantitation: Analytical performance of The Binding Site SPAPLUS(r) human assay and comparison with Siemens BNII(r) assay. AB - OBJECTIVES: Accurate evaluation of analyzers is highly recommended before these devices are broadly introduced for routine testing. Concerning quantification of IgG subclasses (IgGSc), standardization has not yet been reached and thus different assays might lead to different results. Here we report the analytical performances of The Binding Site (TBS) SPAPLUS(r) human IgGSc assay and the concordance with the Siemens BNII(r) human IgGSc assay. DESIGN AND METHODS: We evaluated precision, LoB, LoD and linearity of TBS SPAPLUS(r) human IgGSc immunoassay. Quantitation of IgGSc in 53 patients' serum samples was performed in parallel on both analyzers. Results from both assays were compared. RESULTS: Analytical performances of the TBS SPAPLUS(r) human IgGSc assay are acceptable for routine clinical use. According to the method comparison study, TBS assay measures lower values than Siemens assay for IgG1 and IgG4, whereas for IgG2 and IgG3 TBS provides greater values. All assays present a proportional bias, greater in the case of IgG3 and IgG4 assays. Individual subclass agreement, based on the classification of samples within three categories (low, normal and high) according to assay-specific reference intervals, range from 75% (IgG1) to 92% (IgG2). However, total classification agreement over all four subclasses only account for 55% of samples. CONCLUSION: Results obtained from both assays are not interchangeable. Standardization of IgGSc assay and review of the reference ranges must be accomplished in order to achieve a higher degree of agreement between different methods. PMID- 28912098 TI - Melatonin-mediated upregulation of Sirt3 attenuates sodium fluoride-induced hepatotoxicity by activating the MT1-PI3K/AKT-PGC-1alpha signaling pathway. AB - Mitochondrial reactive oxygen species (ROS) production has been implicated in the pathogenesis of fluoride toxicity in liver. Melatonin, an indolamine synthesized in the pineal gland, was previously shown to protect against sodium fluoride (NaF)-induced hepatotoxicity. This study investigated the protective effects of melatonin pretreatment on NaF-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Reducing mitochondrial ROS by melatonin substantially attenuated NaF-induced NADPH oxidase 4 (Nox4) upregulation and cytotoxicity in L-02 cells. Melatonin exerted its hepatoprotective effects by upregulating Sirtuin 3 (Sirt3) expression level and its activity. Melatonin increased the activity of manganese superoxide dismutase (SOD2) by promoting Sirt3-mediated deacetylation and promoted SOD2 expression through Sirt3-regulated DNA-binding activity of forkhead box O3 (FoxO3a), thus inhibiting the production of mitochondrial ROS induced by NaF. Notably, increased peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) by melatonin activated the Sirt3 expression, which was regulated by an estrogen related receptor (ERR) binding element (ERRE) mapped to Sirt3 promoter region. Analysis of the cell signaling pathway profiling systems and specific pathway inhibition indicated that melatonin enhances PGC-1alpha expression by activating the PI3K/AKT signaling pathway. Importantly, inhibition of melatonin receptor (MT)-1 blocked the melatonin-activated PI3K/AKT-PGC-1alpha-Sirt3 signaling. Mechanistic study revealed that the protective effects of melatonin were associated with down-regulation of JNK1/2 phosphorylation. Our findings provided a theoretical basis that melatonin mitigated NaF-induced hepatotoxicity, which, in part, was mediated through the activation of the Sirt3 pathway. PMID- 28912099 TI - Antimicrobial peptides are degraded by the cytosolic proteases of human erythrocytes. AB - Well-studied and promising antimicrobial peptides (AMPs), with potent bactericidal activity, in vitro, have yet to have a significant impact in human medicine beyond topical applications. We previously showed that interactions of AMPs with concentrated human erythrocytes inhibit many of them, and suggested that screens and assays should be done in their presence to mimic host cell inhibition. Here, we use AMPs to characterize the activity of proteases that are associated with human erythrocytes. The representative AMPs, ARVA and indolicidin, are degraded significantly during incubation with dilute, washed erythrocytes and yield a variety of degradation products, suggesting significant exopeptidase activity. Comparison of these fragments with those obtained from incubation with serum shows that the proteolytic activity associated with cells yields unique products that are not explained by residual serum proteases. By separately testing the membrane and cytosolic fractions, we show that erythrocyte proteolytic activity is found only in the cytosol. Finally, we incubated a diverse cross-section of natural and synthetic linear AMPs with human erythrocyte cytosolic extracts and observed degradation of all of them. These results show that, in addition to cell binding, proteolysis can also contribute significantly to host cell inhibition of AMPs in vitro and possibly also in vivo. PMID- 28912100 TI - Influence of omega-3 fatty acids on bovine luteal cell plasma membrane dynamics. AB - Fish oil is a rich source of omega-3 fatty acids which disrupt lipid microdomain structure and affect mobility of the prostaglandin F2alpha (FP) receptor in bovine luteal cells. The objectives of this study were to determine the effects of individual omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on 1) membrane fatty acid composition, 2) lipid microdomain structure, and 3) lateral mobility of the FP receptor in bovine luteal cells. Ovaries were collected from a local abattoir (n=5/experiment). The corpus luteum was resected and enzymatically digested using collagenase to generate a mixed luteal cell population. In all experiments, luteal cells were treated with 0, 1, 10 or 100MUM EPA or DHA for 72h to allow incorporation of fatty acids into membrane lipids. Results from experiment 1 show that culturing luteal cells in the presence of EPA or DHA increased these luteal fatty acids. In experiment 2, both EPA and DHA increased spatial distribution of lipid microdomains in a dose-dependent manner. Single particle tracking results from experiment 3 show that increasing both EPA and DHA concentrations increased micro and macro-diffusion coefficients, increased domain size, and decreased residence time of FP receptors. Collectively, results from this study demonstrate similar effects of EPA and DHA on lipid microdomain structure and lateral mobility of FP receptors in cultured bovine luteal cells. Moreover, only 10MUM of either fatty acid was needed to mimic the effects of fish oil. PMID- 28912102 TI - Cholesterol affects the interaction between an ionic liquid and phospholipid vesicles. A study by differential scanning calorimetry and nanoplasmonic sensing. AB - The present work aims at studying the interactions between cholesterol-rich phosphatidylcholine-based lipid vesicles and trioctylmethylphosphonium acetate ([P8881][OAc]), a biomass dissolving ionic liquid (IL). The effect of cholesterol was assayed by using differential scanning calorimetry (DSC) and nanoplasmonic sensing (NPS) measurement techniques. Cholesterol-enriched dipalmitoyl phosphatidylcholine vesicles were exposed to different concentrations of the IL, and the derived membrane perturbation was monitored by DSC. The calorimetric data could suggest that the binding and infiltration of the IL are delayed in the vesicles containing cholesterol. To clarify our findings, NPS was applied to quantitatively follow the resistance of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine incorporating 0, 10, and 50mol% of cholesterol toward the IL exposure over time. The membrane perturbation induced by different concentrations of IL was found to be a concentration dependent process on cholesterol-free lipid vesicles. Moreover, our results showed that lipid depletion in cholesterol enriched lipid vesicles is inversely proportional to the increasing amount of cholesterol in the vesicles. These findings support that cholesterol-rich lipid bilayers are less susceptible toward membrane disrupting agents as compared to membranes that do not incorporate any sterols. This probably occurs because cholesterol tightens the phospholipid acyl chain packing of the plasma membranes, increasing their resistance and reducing their permeability. PMID- 28912101 TI - Importance of the REM (Ras exchange) domain for membrane interactions by RasGRP3. AB - RasGRP comprises a family of guanine nucleotide exchange factors, regulating the dissociation of GDP from Ras GTPases to enhance the formation of the active GTP bound form. RasGRP1 possesses REM (Ras exchange), GEF (catalytic), EF-hand, C1, SuPT (suppressor of PT), and PT (plasma membrane-targeting) domains, among which the C1 domain drives membrane localization in response to diacylglycerol or phorbol ester and the PT domain recognizes phosphoinositides. The homologous family member RasGRP3 shows less plasma membrane localization. The objective of this study was to explore the role of the different domains of RasGRP3 in membrane translocation in response to phorbol esters. The full-length RasGRP3 shows limited translocation to the plasma membrane in response to PMA, even when the basic hydrophobic cluster in the PT domain, reported to be critical for RasGRP1 translocation to endogenous activators, is mutated to resemble that of RasGRP1. Moreover, exchange of the C-termini (SuPT-PT domain) of the two proteins had little effect on their plasma membrane translocation. On the other hand, while the C1 domain of RasGRP3 alone showed partial plasma membrane translocation, truncated RasGRP3 constructs, which contain the PT domain and are missing the REM, showed stronger translocation, indicating that the REM of RasGRP3 was a suppressor of its membrane interaction. The REM of RasGRP1 failed to show comparable suppression of RasGRP3 translocation. The marked differences between RasGRP3 and RasGRP1 in membrane interaction necessarily will contribute to their different behavior in cells and are relevant to the design of selective ligands as potential therapeutic agents. PMID- 28912103 TI - Membrane perturbing activities and structural properties of the frog-skin derived peptide Esculentin-1a(1-21)NH2 and its Diastereomer Esc(1-21)-1c: Correlation with their antipseudomonal and cytotoxic activity. AB - Antimicrobial peptides (AMPs) represent new alternatives to cope with the increasing number of multi-drug resistant microbial infections. Recently, a derivative of the frog-skin AMP esculentin-1a, Esc(1-21), was found to rapidly kill both the planktonic and biofilm forms of the Gram-negative bacterium Pseudomonas aeruginosa with a membrane-perturbing activity as a plausible mode of action. Lately, its diastereomer Esc(1-21)-1c containing two d-amino acids i.e. DLeu14 and DSer17 revealed to be less cytotoxic, more stable to proteolytic degradation and more efficient in eradicating Pseudomonas biofilm. When tested in vitro against the free-living form of this pathogen, it displayed potent bactericidal activity, but this was weaker than that of the all-l peptide. To investigate the reason accounting for this difference, mechanistic studies were performed on Pseudomonas spheroplasts and anionic or zwitterionic membranes, mimicking the composition of microbial and mammalian membranes, respectively. Furthermore, structural studies by means of optical and nuclear magnetic resonance spectroscopies were carried out. Our results suggest that the different extent in the bactericidal activity between the two isomers is principally due to differences in their interaction with the bacterial cell wall components. Indeed, the lower ability in binding and perturbing anionic phospholipid bilayers for Esc(1-21)-1c contributes only in a small part to this difference, while the final effect of membrane thinning once the peptide is inserted into the membrane is identical to that provoked by Esc(1-21). In addition, the presence of two d-amino acids is sufficient to reduce the alpha-helical content of the peptide, in parallel with its lower cytotoxicity. PMID- 28912104 TI - Dissection of membrane-binding and -remodeling regions in two classes of bacterial phospholipid N-methyltransferases. AB - Bacterial phospholipid N-methyltransferases (Pmts) catalyze the formation of phosphatidylcholine (PC) via successive N-methylation of phosphatidylethanolamine (PE). They are classified into Sinorhizobium-type and Rhodobacter-type enzymes. The Sinorhizobium-type PmtA protein from the plant pathogen Agrobacterium tumefaciens is recruited to anionic lipids in the cytoplasmic membrane via two amphipathic helices called alphaA and alphaF. Besides its enzymatic activity, PmtA is able to remodel membranes mediated by the alphaA domain. According to the Heliquest program, alphaA- and alphaF-like amphipathic helices are also present in other Sinorhizobium- and Rhodobacter-type Pmt enzymes suggesting a conserved architecture of alpha-helical membrane-binding regions in these methyltransferases. As representatives of the two Pmt families, we investigated the membrane binding and remodeling capacity of Bradyrhizobium japonicum PmtA (Sinorhizobium-type) and PmtX1 (Rhodobacter-type), which act cooperatively to produce PC in consecutive methylation steps. We found that the alphaA regions in both enzymes bind anionic lipids similar to alphaA of A. tumefaciens PmtA. Membrane binding of PmtX1 alphaA is enhanced by its substrate monomethyl-PE indicating a substrate-controlled membrane association. The alphaA regions of all investigated enzymes remodel spherical liposomes into tubular filaments suggesting a conserved membrane-remodeling capacity of bacterial Pmts. Based on these results we propose that the molecular details of membrane-binding and remodeling are conserved among bacterial Pmts. PMID- 28912105 TI - High BMI and male sex as risk factor for increased short-term renal impairment in living kidney donors - Retrospective analysis of 289 consecutive cases. AB - BACKGROUND: Kidney transplantation represents the treatment of choice for end stage renal disease (ESRD). However, nephrectomy bears certain short- as well as long-term risks for the healthy, voluntary donor. As obesity is increasing and is a known risk factor for surgical complications, we wanted to assess the impact of BMI on perioperative complication rates and renal function. MATERIALS AND METHODS: We retrospectively assessed patients undergoing living donor kidney nephrectomy at our institution. We identified 289 donors that underwent unilateral nephrectomy between January 2006 and December 2015. Donors were categorized according to their BMI (BMI <25 kg/m2, BMI >=25/<30 kg/m2, BMI >=30 kg/m2). Where indicated, analysis of variance (ANOVA) was used to compare groups, a stepwise linear regression model was used to assess impact of BMI on the change of eGFR. RESULTS: 126 donors (43.6%) had a BMI <25 while 120 (41.5%) had a BMI >=25/<30 and 43 (14.9%) were obese with a BMI >=30. BMI had no statistically significant influence on the percentage of laparoscopic approach (86.5% vs. 83.3% vs. 88.4%, p = 0.6564), on conversion rates (0% vs. 2.0% vs. 2.6%, p = 0.2879) or postoperative complication rates defined as Clavien Dindo >= II (8.7% vs. 13.3% vs. 14.0%, respectively; p = 0.4474). Notably, there were no Grade III or higher complications in any group. There was no difference in pre-operative kidney function, postoperative surgical site infection or systemic infection. BMI and male sex had a statistically significant influence on short-term decline of eGFR. CONCLUSION: Obese donors do not suffer from an increased risk of intraoperative or perioperative complication rates. However, male sex and high BMI are associated with a more pronounced short-term decline in renal function. The impact of BMI on long-term consequences for kidney donors needs to be defined in larger prospective cohorts. PMID- 28912107 TI - A short food literacy questionnaire (SFLQ) for adults: Findings from a Swiss validation study. AB - The short food literacy questionnaire (SFLQ) was developed to measure a broad range of skills including functional, interactive, and critical elements of FL. This study evaluated SFLQ measurement properties. We used a workplace intervention trial to reduce salt intake in Switzerland to explore the underlying structure of the questionnaire with 350 respondents and identify the ideal number of SFLQ items to capture the different elements of FL. Exploratory factor analysis showed a unidimensional structure of the final 12-item questionnaire. A sum score based on all 12 items (Cronbach's alpha = 0.82) showed expected positive associations with health literacy and knowledge of recommended salt intake. The findings indicate the SFLQ is a feasible and reliable tool to assess FL among adults that can be helpful in public health practices focusing on FL. PMID- 28912106 TI - Vascular activation of K+ channels and Na+-K+ ATPase activity of estrogen deficient female rats. AB - The goal of the present study was to evaluate vascular potassium channels and Na+ K+-ATPase activity in estrogen deficient female rats. Female rats that underwent ovariectomy were assigned to receive daily treatment with placebo (OVX) or estrogen replacement (OVX+E2, 1mg/kg, once a week, i.m.). Aortic rings were used to examine the involvement of K+ channels and Na+-K+-ATPase in vascular reactivity. Acetylcholine (ACh)-induced relaxation was analyzed in the presence of L-NAME (100MUM) and K+ channels blockers: tetraethylammonium (TEA, 5mM), 4 aminopyridine (4-AP, 5mM), iberiotoxin (IbTX, 30nM), apamin (0.5mM), charybdotoxin (ChTX, 0.1mM) and iberiotoxin plus apamin. When aortic rings were pre-contracted with KCl (60mM) or pre-incubated with TEA (5mM), 4-aminopyridine (4-AP, 5mM) and iberiotoxin (IbTX, 30nM) plus apamin (0.5MUM), the ACh-induced relaxation was less effective in the ovariectomized group. Additionally, 4-AP and IbTX decreased the relaxation by sodium nitroprusside in all groups but this reduction was greater in the ovariectomized group. Estrogen deficiency also increased aortic functional Na+-K+ ATPase activity evaluated by K+-induced relaxation. L-NAME or endothelium removal were not able to block the increase in aortic functional Na+-K+ ATPase activity, however, TEA (5mM) restored this increase to the control level. We also found that estrogen deficiency increased superoxide anion production and reduced nitric oxide release in aortic ring from ovariectomized animals. In summary, our results emphasize that the process underlying ACh-induced relaxation is preserved in ovariectomized animals due to the activation of K+ channels and increased Na+-K+ ATPase activity. PMID- 28912108 TI - Leptospira borgpetersenii hybrid leucine-rich repeat protein: Cloning and expression, immunogenic identification and molecular docking evaluation. AB - Leptospirosis is an important zoonotic disease, and the major outbreak of this disease in Thailand in 1999 was due largely to the Leptospira borgpetersenii serovar Sejroe. Identification of the leucine-rich repeat (LRR) LBJ_2271 protein containing immunogenic epitopes and the discovery of the LBJ_2271 ortholog in Leptospira serovar Sejroe, KU_Sej_R21_2271, led to further studies of the antigenic immune properties of KU_Sej_LRR_2271. The recombinant hybrid (rh) protein was created and expressed from a hybrid PCR fragment of KU_Sej_R21_2271 fused with DNA encoding the LBJ_2271 signal sequence for targeting protein as a membrane-anchoring protein. The fusion DNA was cloned into pET160/GW/D-TOPO(r) to form the pET160_hKU_R21_2271 plasmid. The plasmid was used to express the rhKU_Sej_LRR_2271 protein in Escherichia coli BL21 StarTM (DE3). The expressed protein was immunologically detected by Western blotting and immunoreactivity detection with hyperimmune sera, T cell epitope prediction by HLA allele and epitope peptide binding affinity, and potential T cell reactivity analysis. The immunogenic epitopes of the protein were evaluated and verified by HLA allele and epitope peptide complex structure molecular docking. Among fourteen best allele epitopes of this protein, binding affinity values of 12 allele epitopes remained unchanged compared to LBJ_2271. Two epitopes for alleles HLA-A0202 and -A0301 had higher IC50 values, while T cell reactivity values of these peptides were better than values from LBJ_2271 epitopes. Eight of twelve epitope peptides had positive T-cell reactivity scores. Although the molecular docking of two epitopes, 3FPLLKEFLV11/47FPLLKEFLV55 and 50KLSTVPEGV58, into an HLA-A0202 model revealed a good fit in the docked structures, 50KLSTVPEGV58 and 94KLSTVPEEV102 are still considered as the proteins' best epitopes for allele HLA-A0202. The results of this study showed that rhKU_Sej_LRR_2271 protein contained natural immunological properties that should be further examined with respect to antigenic immune stimulation for vaccine development to prevent prevalent leptospiral serovar infection in Thailand. PMID- 28912109 TI - A label-free biosensor based on localized surface plasmon resonance for diagnosis of tuberculosis. AB - A biosensor based on localized surface plasmon resonance (LSPR) was developed to detect the antibody of Mycobacterium tuberculosis using the fusion protein CFP10 ESAT6 as an antigen. To explore the diagnostic potential of the biosensor for tuberculosis (TB), the fusion protein CFP10-ESAT6 was immobilized on gold nanorods (Au NRs) by chemical modification, and the functionalized Au NRs were subsequently incubated with serums collected from TB patients, non-tuberculous pulmonary disease patients or healthy individuals. The change in the LSPR properties of Au NRs from the specific interaction between the antigen and antibody was monitored, and detection of the target antibody was completed based on the proposed biosensor. Serum analysis showed that the sensitivity of the biosensor was 79% and the specificity was 92%. Therefore, the LSPR biosensor is a valuable tool for serodiagnosis of TB. PMID- 28912110 TI - The genetics of congenitally small brains. AB - Primary microcephaly (PM) refers to a congenitally small brain, resulting from insufficient prenatal production of neurons, and serves as a model disease for brain volumic development. Known PM genes delineate several cellular pathways, among which the centriole duplication pathway, which provide interesting clues about the cellular mechanisms involved. The general interest of the genetic dissection of PM is illustrated by the convergence of Zika virus infection and PM gene mutations on congenital microcephaly, with CENPJ/CPAP emerging as a key target. Physical (protein-protein) and genetic (digenic inheritance) interactions of Wdr62 and Aspm have been demonstrated in mice, and should now be sought in humans using high throughput parallel sequencing of multiple PM genes in PM patients and control subjects, in order to categorize mutually interacting genes, hence delineating functional pathways in vivo in humans. PMID- 28912111 TI - CRISPR/Cas9 mediated G4946E substitution in the ryanodine receptor of Spodoptera exigua confers high levels of resistance to diamide insecticides. AB - Diamide insecticides selectively activate insect ryanodine receptors (RyRs), inducing uncontrolled release of calcium ions, and causing muscle contraction, paralysis and eventually death. The RyRG4946E substitution associated with diamide resistance has been identified in three lepidopteran pests, Plutella xylostella, Tuta absoluta and Chilo suppressalis. Recently, the T. absoluta RyRG4946V mutation was knocked into the model insect Drosophila melanogaster by CRISPR/Cas9 mediated genome editing and provided in vivo functional confirmation for its role in diamide resistance. In the present study, we successfully introduced the RyRG4946E mutation with CRISPR/Cas9 technology into a lepidopteran pest of global importance, Spodoptera exigua. The genome-edited strain (named 4946E) homozygous for the SeRyRG4946E mutation exhibited 223-, 336- and >1000 fold resistance to chlorantraniliprole, cyantraniliprole and flubendiamide, respectively when compared to the wild type strain (WHS) of S. exigua. Reciprocal crossing experiments revealed that the target-site resistance in strain 4946E underlies an autosomal and almost recessive mode of inheritance for anthranilic diamides, whereas it was completely recessive for flubendiamide. Our results not only provided in vivo functional validation of the RyRG4946E mutation in conferring high levels of resistance to diamide insecticides for the first time in a controlled genetic background of a lepidopteran pest, but also revealed slight differences on the level of resistance between anthranilic diamides (chlorantraniliprole and cyantraniliprole) and flubendiamide conferred by the SeRyRG4946E mutation. PMID- 28912112 TI - Molecular basis of peripheral olfactory sensing during oviposition in the behavior of the parasitic wasp Anastatus japonicus. AB - Anastatus japonicus is a parasitic wasp and natural enemy of the litchi pest Tessaratoma papillosa, and for decades in China, A. japonicus has been mass reared inside the eggs of Antheraea pernyi to control T. papillosa. A series of experiments was performed to explore the olfactory mechanism underlying the oviposition behavior of A. japonicus. First, a transcriptomic analysis was performed on the antennae of A. japonicus, and the resulting assemblies led to the generation of 70,473 unigenes. Subsequently, 21,368 unigenes were matched to known proteins, 48 odorant receptors (ORs) (including Orco) and 13 antennal ionotropic receptors (IRs) (including the co-receptors IR8a and IR25a) were identified and predicted to form complete open reading frames (ORFs). The FPKM (fragments per Kb per million reads) values and RT-PCR results showed that AjapOrco, AjapOR10, AjapOR27, AjapOR33 and AjapOR35 were either highly abundant or expressed specifically in the olfactory organs. Furthermore, AjapOrco silencing resulted in a significant decrease in both the parasitism rate and the host-seeking time of A. japonicus, whereas dsRNA injection showed that IR8a and IR25a did not produce significant behavioral changes, suggesting that the oviposition behavior of A. japonicus is more reliant on OR-based pathways than IR based pathways. Our previous GC-MS data derived twenty-nine compounds which were abundent from these host plants and host insects. We performed electrophysiological and oviposition assays on A. japonicus, and eight odorants were found to elicit a significant electroantennogram (EAG) response. Among these odorants, beta-Caryophyllene, Undecane, (E)-alpha-Farnesene (+)-Aromadendrene and Cis-3-Hexen-ol had strong attractant effects on oviposition, whereas 2-Ethyl-1 Hexan-ol, Ethyl Acetate and alpha-Caryophyllene had a strong repellant effects. Thus, these chemicals might influence oviposition guidance/repulsion behavior in A. japonicus. To further explore the target ORs that are tuned to the functional odorants, the nine candidate ORs described above were silenced by RNA interference, and the results showed that a large decrease in the EAG response of all the tested functional odorants in the AjapOrco-silencing group. In addition, the AjapOR35-silencing group showed a significant decrease in the EAG response to beta-Caryophyllene and (E)-alpha-Farnesene, indicating that AjapOR35 is tuned to these two oviposition attractants beta-Caryophyllene and (E)-alpha-Farnesene. Further binary-choice oviposition assays showed that the oviposition attractant effect of beta-Caryophyllene and (E)-alpha-Farnesene vanished after AjapOR35 was silenced, indicating that the emission of these attractants from host plants can guide A. japonicus to locate eggs for ovipositioning and indicated that AjapOR35 is correlated with the olfactory detection oviposition behavior of this species. This study provides a better understanding of the molecular basis and functional chemicals underlying the oviposition behavior of A. japonicus, and the results may help improve biocontrol approaches. PMID- 28912113 TI - Mobile Augmented Reality as a Feature for Self-Oriented, Blended Learning in Medicine: Randomized Controlled Trial. AB - BACKGROUND: Advantages of mobile Augmented Reality (mAR) application-based learning versus textbook-based learning were already shown in a previous study. However, it was unclear whether the augmented reality (AR) component was responsible for the success of the self-developed app or whether this was attributable to the novelty of using mobile technology for learning. OBJECTIVE: The study's aim was to test the hypothesis whether there is no difference in learning success between learners who employed the mobile AR component and those who learned without it to determine possible effects of mAR. Also, we were interested in potential emotional effects of using this technology. METHODS: Forty-four medical students (male: 25, female: 19, mean age: 22.25 years, standard deviation [SD]: 3.33 years) participated in this study. Baseline emotional status was evaluated using the Profile of Mood States (POMS) questionnaire. Dermatological knowledge was ascertained using a single choice (SC) test (10 questions). The students were randomly assigned to learn 45 min with either a mobile learning method with mAR (group A) or without AR (group B). Afterwards, both groups were again asked to complete the previous questionnaires. AttrakDiff 2 questionnaires were used to evaluate the perceived usability as well as pragmatic and hedonic qualities. For capturing longer term effects, after 14 days, all participants were again asked to complete the SC questionnaire. All evaluations were anonymous, and descriptive statistics were calculated. For hypothesis testing, an unpaired signed-rank test was applied. RESULTS: For the SC tests, there were only minor differences, with both groups gaining knowledge (average improvement group A: 3.59 [SD 1.48]; group B: 3.86 [SD 1.51]). Differences between both groups were statistically insignificant (exact Mann Whitney U, U=173.5; P=.10; r=.247). However, in the follow-up SC test after 14 days, group A had retained more knowledge (average decrease of the number of correct answers group A: 0.33 [SD 1.62]; group B: 1.14 [SD 1.30]). For both groups, descriptively, there were only small variations regarding emotional involvement, and learning experiences also differed little, with both groups rating the app similar for its stimulating effect. CONCLUSIONS: We were unable to show significant effects for mAR on the immediate learning success of the mobile learning setting. However, the similar level of stimulation being noted for both groups is inconsistent with the previous assumption of the success of mAR-based approach being solely attributable to the excitement of using mobile technology, independent of mAR; the mAR group showed some indications for a better long-term retention of knowledge. Further studies are needed to examine this aspect. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): 00012980; http://www.drks.de/drks_web/navigate.do? navigationId=trial.HTML&TRIAL_ID=DRKS00012980 (Archived by WebCite at http://www.webcitation.org/ 6tCWoM2Jb). PMID- 28912114 TI - Understanding the Natural Progression of Spina Bifida: Prospective Study. AB - BACKGROUND: Spina bifida (SB) is monitored through birth defects surveillance across the United States and in most developed countries. Although much is known about the management of SB and its many comorbid conditions in affected individuals, there are few systematic, longitudinal studies on population-based cohorts of children or adults. The natural history of SB across the life course of persons with this condition is not well documented. Earlier identification of comorbidities and secondary conditions could allow for earlier intervention that might enhance the developmental trajectory for children with SB. OBJECTIVE: The purpose of this project was to assess the development, health, and condition progression by prospectively studying children who were born with SB in Arizona and Utah. In addition, the methodology used to collect the data would be evaluated and revised as appropriate. METHODS: Parents of children with SB aged 3 6 years were eligible to participate in the study, in English or Spanish. The actual recruitment process was closely documented. Data on medical history were collected from medical records; family functioning, child behaviors, self-care, mobility and functioning, and health and well-being from parent reports; and neuropsychological data from testing of the child. RESULTS: In total, 152 individuals with SB were identified as eligible and their parents were contacted by site personnel for enrollment in the study. Of those, 45 (29.6%) declined to participate and 6 (3.9%) consented but did not follow through. Among 101 parents willing to participate, 81 (80.2%) completed the full protocol and 20 (19.8%) completed the partial protocol. Utah enrolled 72.3% (73/101) of participants, predominately non-Hispanic (60/73, 82%) and male (47/73, 64%). Arizona enrolled 56% (28/50) of participants they had permission to contact, predominately Hispanic (18/28, 64%) and male (16/28, 57%). CONCLUSIONS: We observed variance by site for recruitment, due to differences in identification and ascertainment of eligible cases and the required institutional review board processes. Restriction in recruitment and the proportion of minorities likely impacted participation rates in Arizona more than Utah. PMID- 28912115 TI - System-Wide Inpatient Portal? Implementation: Survey of Health Care Team Perceptions. AB - BACKGROUND: Inpatient portals, a new type of patient portal tailored specifically to the hospital setting, can allow patients to access up-to-date health information and exchange secure communications with their care team. As such, inpatient portals present an opportunity for patients to increase engagement in their care during a time of acute crisis that emphasizes focus on a patient's health. While there is a large body of research on patient portals in the outpatient setting, questions are being raised specifically about inpatient portals, such as how they will be incorporated into the flow of patient care in hectic, stressed, team-based hospital settings. OBJECTIVE: Our aim is to improve understanding about hospital care team members' perceptions of the value of an interactive patient portal for admitted patients, as well as to ascertain staff orientation toward this new technology. METHODS: Throughout the course of 2016, an inpatient portal, MyChart Bedside (MCB) was implemented across a five-hospital health system. The portal is a tablet-based app that includes a daily schedule, lab/test results, secure messaging with the care team, a place to take notes, and access to educational materials. Within a month of initial rollout, hospital care team members completed a 5-minute, anonymous online survey to assess attitudes and perceptions about MCB use and staff training for the new technology. RESULTS: Throughout the health system, 686 staff members completed the survey: 193 physicians (23.6%), 439 nurses (53.7%), and 186 support staff (22.7%). Questions about the importance of MCB, self-efficacy in using MCB with patients, and feelings about sufficient training and resources showed that an average of 40-60% of respondents in each group reported a positive orientation toward the MCB technology and training received. This positive orientation was highest among support staff, lower among nurses, and lowest for physicians (all differences by staff role were statistically significant at P<.001). Additionally, 62.0% of respondents reported "not enough" training. CONCLUSIONS: Despite the robust training effort, similar to that used in previous health information technology implementations at this health system, hospital care team members reported only a moderately positive orientation toward MCB and its potential, and the majority wanted more training. We propose that due to the unique elements of the inpatient portal-interactive features used by patients and providers requiring explanation and collaboration-traditional training approaches may be insufficient. Introduction of the inpatient portal as a new collaborative tool may thus require new methods of training to support enhanced engagement between patients and their care team. PMID- 28912117 TI - Sample Size Calculations for Population Size Estimation Studies Using Multiplier Methods With Respondent-Driven Sampling Surveys. AB - BACKGROUND: While guidance exists for obtaining population size estimates using multiplier methods with respondent-driven sampling surveys, we lack specific guidance for making sample size decisions. OBJECTIVE: To guide the design of multiplier method population size estimation studies using respondent-driven sampling surveys to reduce the random error around the estimate obtained. METHODS: The population size estimate is obtained by dividing the number of individuals receiving a service or the number of unique objects distributed (M) by the proportion of individuals in a representative survey who report receipt of the service or object (P). We have developed an approach to sample size calculation, interpreting methods to estimate the variance around estimates obtained using multiplier methods in conjunction with research into design effects and respondent-driven sampling. We describe an application to estimate the number of female sex workers in Harare, Zimbabwe. RESULTS: There is high variance in estimates. Random error around the size estimate reflects uncertainty from M and P, particularly when the estimate of P in the respondent-driven sampling survey is low. As expected, sample size requirements are higher when the design effect of the survey is assumed to be greater. CONCLUSIONS: We suggest a method for investigating the effects of sample size on the precision of a population size estimate obtained using multipler methods and respondent-driven sampling. Uncertainty in the size estimate is high, particularly when P is small, so balancing against other potential sources of bias, we advise researchers to consider longer service attendance reference periods and to distribute more unique objects, which is likely to result in a higher estimate of P in the respondent-driven sampling survey. PMID- 28912116 TI - Reliability of an e-PRO Tool of EORTC QLQ-C30 for Measurement of Health-Related Quality of Life in Patients With Breast Cancer: Prospective Randomized Trial. AB - BACKGROUND: Breast cancer represents the most common malignant disease in women worldwide. As currently systematic palliative treatment only has a limited effect on survival rates, the concept of health-related quality of life (HRQoL) is gaining more and more importance in the therapy setting of metastatic breast cancer. One of the major patient-reported outcomes (PROs) for measuring HRQoL in patients with breast cancer is provided by the European Organization for Research and Treatment of Cancer (EORTC). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. Facing the possibilities associated with evolving digitalization in medicine, validation of electronic versions of well-established PRO is essential in order to contribute to comprehensive and holistic oncological care and to ensure high quality in cancer research. OBJECTIVE: The aim of this study was to analyze the reliability of a tablet-based measuring application for EORTC QLQ-C30 in German language in patients with adjuvant and (curative) metastatic breast cancer. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female patients with adjuvant and metastatic breast cancer recruited as part of the e-PROCOM study. All patients were required to complete the electronic- (e-PRO) and paper-based versions of the HRQoL EORTC QLQ-C30 questionnaire. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability [Wilcoxon test] and test of internal consistency [Spearman rho and agreement rates for single items, Pearson correlation and Kendall tau for each scale]) were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patient's response behavior between paper- and electronic-based questionnaires. Regarding the test of parallel forms reliability, no significant differences were found in 27 of 30 single items and in 14 of 15 scales, whereas a statistically significant correlation in the test of consistency was found in all 30 single items and all 15 scales. CONCLUSIONS: The evaluated e-PRO version of the EORTC QLQ-C30 is reliable for patients with both adjuvant and metastatic breast cancer, showing a high correlation in almost all questions (and in many scales). Thus, we conclude that the validated paper-based PRO assessment and the e-PRO tool are equally valid. However, the reliability should also be analyzed in other prospective trials to ensure that usability is reliable in all patient groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT03132506; https://clinicaltrials.gov/ct2/show/NCT03132506 (Archived by WebCite at http://www.webcitation.org/6tRcgQuou). PMID- 28912118 TI - Topically Applied Carvedilol Attenuates Solar Ultraviolet Radiation Induced Skin Carcinogenesis. AB - In previous studies, the beta-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P+ cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV induced neoplastic transformation. Both carvedilol and 4-OHC (1 MUmol/L) blocked transformation induced by chronic UV (15 mJ/cm2) exposure for 8 weeks. However, EGF-mediated transformation was inhibited by only carvedilol but not by 4-OHC. Carvedilol (1 and 5 MUmol/L), but not 4-OHC, attenuated UV-induced AP-1 and NF kappaB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single-dose UV (200 mJ/cm2)-induced skin inflammation mouse model, carvedilol (10 MUmol/L), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL1beta, IL6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm2) three times a week for 25 weeks, topical administration of carvedilol (10 MUmol/L) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect. These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer. Cancer Prev Res; 10(10); 598-606. (c)2017 AACR. PMID- 28912119 TI - Lower-extremity symmetry influences knee abduction moments during sidestepping in rugby. PMID- 28912120 TI - Profiling movement and gait quality using accelerometry in children's physical activity: consider quality, not just quantity. PMID- 28912122 TI - GPs earned an average of L90 100 in 2015-16. PMID- 28912121 TI - Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction. AB - RATIONALE: Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early-stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. OBJECTIVE: To determine whether post-MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. METHODS AND RESULTS: Female Gottingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia-reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n=9; 2*107 cells total) or placebo (vehicle; n=9) through NOGA-guided transendocardial injections. 5-ethynyl-2'deoxyuridine (EdU)-a thymidine analog-containing minipumps were inserted at the time of MI induction. At 72 hours (n=8), initial injury and cell retention were assessed. At 3 months post-MI, cardiac structure and function were evaluated by serial echocardiography and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72 hours post-MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC-treated hearts had significantly reduced scar size, smaller myocytes, and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular volumes and ejection fraction were significantly more preserved in CBSC-treated hearts, and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU+ cardiac myocytes was increased in CBSC- versus vehicle- treated animals. CONCLUSIONS: CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves left ventricular functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction. PMID- 28912123 TI - Type VI secretion system MIX-effectors carry both antibacterial and anti eukaryotic activities. AB - Most type VI secretion systems (T6SSs) described to date are protein delivery apparatuses that mediate bactericidal activities. Several T6SSs were also reported to mediate virulence activities, although only few anti-eukaryotic effectors have been described. Here, we identify three T6SSs in the marine bacterium Vibrio proteolyticus and show that T6SS1 mediates bactericidal activities under warm marine-like conditions. Using comparative proteomics, we find nine potential T6SS1 effectors, five of which belong to the polymorphic MIX effector class. Remarkably, in addition to six predicted bactericidal effectors, the T6SS1 secretome includes three putative anti-eukaryotic effectors. One of these is a MIX-effector containing a cytotoxic necrotizing factor 1 domain. We demonstrate that T6SS1 can use this MIX-effector to target phagocytic cells, resulting in morphological changes and actin cytoskeleton rearrangements. In conclusion, the V. proteolyticus T6SS1, a system homologous to one found in pathogenic vibrios, uses a suite of polymorphic effectors that target both bacteria and eukaryotic neighbors. PMID- 28912124 TI - Kindlin-2 recruits paxillin and Arp2/3 to promote membrane protrusions during initial cell spreading. AB - Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to the extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell adhesion and membrane protrusion by directly binding and recruiting paxillin to nascent adhesions. Here, we report that kindlin-2 has a dual role during initial cell spreading: it binds paxillin via the pleckstrin homology and F0 domains to activate Rac1, and it directly associates with the Arp2/3 complex to induce Rac1-mediated membrane protrusions. Consistently, abrogation of kindlin-2 binding to Arp2/3 impairs lamellipodia formation and cell spreading. Our findings identify kindlin-2 as a key protein that couples cell adhesion by activating integrins and the induction of membrane protrusions by activating Rac1 and supplying Rac1 with the Arp2/3 complex. PMID- 28912126 TI - Atypical Altered Mental Status in a Toddler. PMID- 28912125 TI - BLM helicase regulates DNA repair by counteracting RAD51 loading at DNA double strand break sites. AB - The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. We find that in cells expressing a mutant version of BRCA1, an essential HR factor, ablation of BLM rescues genomic integrity and cell survival in the presence of DNA double strand breaks. Improved genomic integrity in these cells is linked to a substantial increase in the stability of RAD51 at DNA double-strand break sites and in the overall efficiency of HR. Ablation of BLM also rescues RAD51 foci and HR in cells lacking BRCA2 or XRCC2. These results indicate that the anti recombinase activity of BLM is of general importance for normal retention of RAD51 at DNA break sites and regulation of HR. PMID- 28912127 TI - Painful red eyes in a contact lens wearer. PMID- 28912128 TI - Aging modifies the effect of cardiac output on middle cerebral artery blood flow velocity. AB - An association between cerebral blood flow (CBF) and cardiac output (CO) has been established in young healthy subjects. As of yet it is unclear how this association evolves over the life span. To that purpose, we continuously recorded mean arterial pressure (MAP; finger plethysmography), CO (pulse contour; CO trek), mean blood flow velocity in the middle cerebral artery (MCAV; transcranial Doppler ultrasonography), and end-tidal CO2 partial pressure (PetCO2) in healthy young (19-27 years), middle-aged (51-61 years), and elderly subjects (70-79 years). Decreases and increases in CO were accomplished using lower body negative pressure and dynamic handgrip exercise, respectively. Aging in itself did not alter dynamic cerebral autoregulation or cerebrovascular CO2 reactivity. A linear relation between changes in CO and MCAVmean was observed in middle-aged (P < 0.01) and elderly (P = 0.04) subjects but not in young (P = 0.45) subjects, taking concurrent changes in MAP and PetCO2 into account. These data imply that with aging, brain perfusion becomes increasingly dependent on CO. PMID- 28912129 TI - The efficacy of unsupervised home-based exercise regimens in comparison to supervised laboratory-based exercise training upon cardio-respiratory health facets. AB - Supervised high-intensity interval training (HIIT) can rapidly improve cardiorespiratory fitness (CRF). However, the effectiveness of time-efficient unsupervised home-based interventions is unknown. Eighteen volunteers completed either: laboratory-HIIT (L-HIIT); home-HIIT (H-HIIT) or home-isometric hand-grip training (H-IHGT). CRF improved significantly in L-HIIT and H-HIIT groups, with blood pressure improvements in the H-IHGT group only. H-HIIT offers a practical, time-efficient exercise mode to improve CRF, away from the laboratory environment. H-IHGT potentially provides a viable alternative to modify blood pressure in those unable to participate in whole-body exercise. PMID- 28912130 TI - Near-infrared spectroscopy of superficial and deep rectus femoris reveals markedly different exercise response to superficial vastus lateralis. AB - To date our knowledge of skeletal muscle deoxygenation as measured by near infrared spectroscopy (NIRS) is predicated almost exclusively on sampling of superficial muscle(s), most commonly the vastus lateralis (VL-s). Recently developed high power NIRS facilitates simultaneous sampling of deep (i.e., rectus femoris, RF-d) and superficial muscles of RF (RF-s) and VL-s. Because deeper muscle is more oxidative with greater capillarity and sustains higher blood flows than superficial muscle, we used time-resolved NIRS to test the hypotheses that, following exercise onset, the RF-d has slower deoxy[Hb+Mb] kinetics with reduced amplitude than superficial muscles. Thirteen participants performed cycle exercise transitions from unloaded to heavy work rates. Within the same muscle (RF-s vs. RF-d) deoxy[Hb+Mb] kinetics (mean response time, MRT) and amplitudes were not different. However, compared with the kinetics of VL-s, deoxy[Hb+Mb] of RF-s and RF-d were slower (MRT: RF-s, 51 +/- 23; RF-d, 55 +/- 29; VL-s, 18 +/- 6 s; P < 0.05). Moreover, the amplitude of total[Hb+Mb] was greater for VL-s than both RF-s and RF-d (P < 0.05). Whereas pulmonary VO2 kinetics (i.e., on vs. off) were symmetrical in heavy exercise, there was a marked on-off asymmetry of deoxy[Hb+Mb] for all three sites i.e., MRT-off > MRT-on (P < 0.05). Collectively these data reveal profoundly different O2 transport strategies, with the RF-s and RF-d relying proportionately more on elevated perfusive and the VL-s on diffusive O2 transport. These disparate O2 transport strategies and their temporal profiles across muscles have previously been concealed within the "global" pulmonary VO2 response. PMID- 28912131 TI - Imaging the halogen bond in self-assembled halogenbenzenes on silver. AB - Halogens are among the most electronegative elements, and the variations in size and polarizability of halogens require different descriptions of the intermolecular bonds they form. Here we use the inelastic tunneling probe (itProbe) to acquire real-space imaging of intermolecular-bonding structures in the two-dimensional self-assembly of halogenbenzene molecules on a metal surface. Direct visualization is obtained for the intermolecular attraction and the "windmill" pattern of bonding among the fully halogenated molecules. Our results provide a hitherto missing understanding of the nature of the halogen bond. PMID- 28912132 TI - Mitotic transcription and waves of gene reactivation during mitotic exit. AB - Although the genome is generally thought to be transcriptionally silent during mitosis, technical limitations have prevented sensitive mapping of transcription during mitosis and mitotic exit. Thus, the means by which the interphase expression pattern is transduced to daughter cells have been unclear. We used 5 ethynyluridine to pulse-label transcripts during mitosis and mitotic exit and found that many genes exhibit transcription during mitosis, as confirmed with fluorescein isothiocyanate-uridine 5'-triphosphate labeling, RNA fluorescence in situ hybridization, and quantitative reverse transcription polymerase chain reaction. The first round of transcription immediately after mitosis primarily activates genes involved in the growth and rebuilding of daughter cells, rather than cell type-specific functions. We propose that the cell's transcription pattern is largely retained at a low level through mitosis, whereas the amplitude of transcription observed in interphase is reestablished during mitotic exit. PMID- 28912133 TI - Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. AB - Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations. PMID- 28912135 TI - Editorial expression of concern. PMID- 28912134 TI - ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. AB - Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a "split-SIM" SUMO2 engagement platform. These findings uncover a ZATT-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc. PMID- 28912136 TI - Tumor Resection Recruits Effector T Cells and Boosts Therapeutic Efficacy of Encapsulated Stem Cells Expressing IFNbeta in Glioblastomas. AB - Purpose: Despite tumor resection being the first-line clinical care for glioblastoma (GBM) patients, nearly all preclinical immune therapy models intend to treat established GBM. Characterizing cytoreductive surgery-induced immune response combined with the administration of immune cytokines has the potential of offering a new treatment paradigm of immune therapy for GBMs.Experimental Design: We developed syngeneic orthotopic mouse GBM models of tumor resection and characterized the immune response of intact and resected tumors. We also created a highly secretable variant of immune cytokine IFNbeta to enhance its release from engineered mouse mesenchymal stem cells (MSC-IFNbeta) and assessed whether surgical resection of intracranial GBM tumor significantly enhanced the antitumor efficacy of targeted on-site delivery of encapsulated MSC-IFNbeta.Results: We show that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSC) and simultaneous recruitment of CD4/CD8 T cells. This immune response significantly enhanced the antitumor efficacy of locally delivered encapsulated MSC-IFNbeta via enhanced selective postsurgical infiltration of CD8 T cells and directly induced cell-cycle arrest in tumor cells, resulting in increased survival of mice. Utilizing encapsulated human MSC IFNbeta in resected orthotopic tumor xenografts of patient-derived GBM, we further show that IFNbeta induces cell-cycle arrest followed by apoptosis, resulting in increased survival in immunocompromised mice despite their absence of an intact immune system.Conclusions: This study demonstrates the importance of syngeneic tumor resection models in developing cancer immunotherapies and emphasizes the translational potential of local delivery of immunotherapeutic agents in treating cancer. Clin Cancer Res; 23(22); 7047-58. (c)2017 AACR. PMID- 28912137 TI - Enhanced Cancer Immunotherapy by Chimeric Antigen Receptor-Modified T Cells Engineered to Secrete Checkpoint Inhibitors. AB - Purpose: Despite favorable responses of chimeric antigen receptor (CAR) engineered T-cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR T cells secreting checkpoint inhibitors (CPI) targeting PD-1 (CAR.alphaPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model.Experimental Design: To evaluate the effector function and expansion capacity of CAR.alphaPD1-T cells in vitro, we measured the production of IFNgamma and T-cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.alphaPD1-T cells, CAR T cells, and CAR T cells combined with anti-PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs.Results: Human anti-PD-1 CPIs secreted by CAR.alphaPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T-cell function. PD-1 blockade by continuously secreted anti-PD-1 attenuated the inhibitory T-cell signaling and enhanced T-cell expansion and effector function both in vitro and in vivo In the xenograft mouse model, we demonstrated that the secretion of anti-PD-1 enhanced the antitumor activity of CAR T cells and prolonged overall survival.Conclusions: With constitutive anti-PD-1 secretion, CAR.alphaPD1-T cells are more functional and expandable, and more efficient at tumor eradication than parental CAR T cells. Collectively, our study presents an important and novel strategy that enables CAR T cells to achieve better antitumor immunity, especially in the treatment of solid tumors. Clin Cancer Res; 23(22); 6982-92. (c)2017 AACR. PMID- 28912138 TI - Sarcomatoid Renal Cell Carcinoma: The Apple Doesn't Fall Far from the Tree. AB - The most comprehensive sequencing effort of sarcomatoid renal cell carcinoma (sRCC) to date reinforces the notion that the sarcomatoid component is closely related to the epithelial component of the cancer. This work also challenges the notion that sRCC evolves from low-grade RCC and identifies potential mediators of sarcomatoid differentiation. Clin Cancer Res; 23(21); 6381-3. (c)2017 AACRSee related article by Wang et al., p. 6686. PMID- 28912139 TI - A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer. AB - Purpose: Mutation of the Kirsten ras sarcoma viral oncogene homolog (KRAS) and loss of p53 function are commonly seen in patients with non-small cell lung cancer (NSCLC). Combining therapeutics targeting these tumor-defensive pathways with cisplatin in a single-nanoparticle platform are rarely developed in clinic.Experimental Design: Cisplatin was encapsulated in liposomes, which multiple polyelectrolyte layers, including siKRAS and miR-34a were built on to generate multifunctional layer-by-layer nanoparticle. Structure, size, and surface charge were characterized, in addition to in vitro toxicity studies. In vivo tumor targeting and therapy was investigated in an orthotopic lung cancer model by microCT, fluorescence imaging, and immunohistochemistry.Results: The singular nanoscale formulation, incorporating oncogene siKRAS, tumor-suppressor stimulating miR-34a, and cisplatin, has shown enhanced toxicity against lung cancer cell line, KP cell. In vivo, systemic delivery of the nanoparticles indicated a preferential uptake in lung of the tumor-bearing mice. Efficacy studies indicated prolonged survival of mice from the combination treatment.Conclusions: The combination RNA-chemotherapy in an LbL formulation provides an enhanced treatment efficacy against NSCLC, indicating promising potential in clinic. Clin Cancer Res; 23(23); 7312-23. (c)2017 AACR. PMID- 28912140 TI - Downregulation of SAFB Sustains the NF-kappaB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer. AB - Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-beta-activated kinase 1 (TAK1) and NF-kappaB signaling by SAFB The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-kappaB signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1- and NF-kappaB-related genes.Conclusions: Our results show that SAFB regulated the activity of NF-kappaB signaling in CRC by targeting TAK1 This novel mechanism provides a comprehensive understanding of both SAFB and the NF-kappaB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-kappaB axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108 18. (c)2017 AACR. PMID- 28912142 TI - Pioneering pharmacist and medication errors researcher Kenneth N. Barker dies at age 80. PMID- 28912143 TI - The relation between promotional spending on drugs and their therapeutic gain: a cohort analysis. AB - BACKGROUND: Whether drug promotion helps or hinders appropriate prescribing by physicians is debated. This study examines the most heavily promoted drugs and the therapeutic value of those drugs to help determine whether doctors should be using promotional material to inform themselves about drugs. METHODS: Lists were constructed of the 50 most heavily promoted drugs (amount of money spent on journal advertisements and visits by sales representatives) and the 50 top selling drugs (by dollar value) for 2013, 2014 and 2015. Therapeutic gain was determined by examining ratings from the Patented Medicine Prices Review Board and the French drug bulletin Prescrire International and was categorized as major, moderate or little to none. For each of the 3 years, the number of drugs in the 3 therapeutic categories for drugs in both groups was compared. The amount and proportion of money spent on promotion for drugs in each of the 3 therapeutic categories for the 3 years was also determined. RESULTS: Therapeutic ratings were available for 42 of 79 of the most heavily promoted drugs over the 3 years and for 40 of 61 of the top-selling drugs. Nearly all the money spent on promotion in each of the 3 years went to drugs with little to no therapeutic gain. The distribution of therapeutic gain for drugs in both groups was statistically significantly different only in 2013 (p = 0.04). INTERPRETATION: Most of the money spent on promotion went to drugs that offer little to no therapeutic gain. This result calls into question whether doctors should read journal advertisements or see sales representatives to acquire information about important medical therapies. PMID- 28912141 TI - Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival. AB - Purpose: Bevacizumab, a humanized monoclonal antibody to VEGF, is used routinely in the treatment of patients with recurrent glioblastoma (GBM). However, very little is known regarding the effects of bevacizumab on the cells in the perivascular space in tumors.Experimental Design: Established orthotopic xenograft and syngeneic models of GBM were used to determine entry of monoclonal anti-VEGF-A into, and uptake by cells in, the perivascular space. Based on the results, we examined CD133+ cells derived from GBM tumors in vitro Bevacizumab internalization, trafficking, and effects on cell survival were analyzed using multilabel confocal microscopy, immunoblotting, and cytotoxicity assays in the presence/absence of inhibitors.Results: In the GBM mouse models, administered anti-mouse-VEGF-A entered the perivascular tumor niche and was internalized by Sox2+/CD44+ tumor cells. In the perivascular tumor cells, bevacizumab was detected in the recycling compartment or the lysosomes, and increased autophagy was found. Bevacizumab was internalized rapidly by CD133+/Sox2+-GBM cells in vitro through macropinocytosis with a fraction being trafficked to a recycling compartment, independent of FcRn, and a fraction to lysosomes. Bevacizumab treatment of CD133+ GBM cells depleted VEGF-A and induced autophagy thereby improving cell survival. An inhibitor of lysosomal acidification decreased bevacizumab-induced autophagy and increased cell death. Inhibition of macropinocytosis increased cell death, suggesting macropinocytosis of bevacizumab promotes CD133+ cell survival.Conclusions: We demonstrate that bevacizumab is internalized by Sox2+/CD44+-GBM tumor cells residing in the perivascular tumor niche. Macropinocytosis of bevacizumab and trafficking to the lysosomes promotes CD133+ cell survival, as does the autophagy induced by bevacizumab depletion of VEGF-A. Clin Cancer Res; 23(22); 7059-71. (c)2017 AACR. PMID- 28912144 TI - Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies. AB - In addition to the well-known estrogen receptor (ER) and human epidermal growth factor receptor 2, the androgen receptor (AR) is also a potential drug target in breast cancer treatment. Whole-body imaging can provide information across lesions within a patient. ER expression in tumor lesions can be visualized by 18F fluoroestradiol (18F-FES) PET, and AR expression has been visualized in prostate cancer patients with 18F-fluorodihydrotestosterone (18F-FDHT) PET. Our aim was to assess the concordance between 18F-FDHT and 18F-FES PET and tumor AR and ER expression measured immunohistochemically in patients with metastatic breast cancer. Methods: Patients with ER-positive metastatic breast cancer were eligible for the study, irrespective of tumor AR status. The concordance of 18F-FDHT and 18F-FES uptake on PET with immunohistochemical expression of AR and ER in biopsies of corresponding metastases was analyzed. Patients underwent 18F-FDHT PET and 18F-FES PET. A metastasis was biopsied within 8 wk of the PET procedures. Tumor samples with more than 10% and 1% nuclear tumor cell staining were considered, respectively, AR- and ER-positive. Correlations between PET uptake and semiquantitative immunohistochemical scoring (percentage positive cells * intensity) were calculated. The optimum threshold of SUV to discriminate positive and negative lesions for both AR and ER was determined by receiver-operating characteristic analysis. Results: In the 13 evaluable patients, correlation (R2 ) between semiquantitative AR expression and 18F-FDHT uptake was 0.47 (P = 0.01) and between semiquantitative ER expression and 18F-FES uptake 0.78 (P = 0.01). The optimal cutoff for AR-positive lesions was an SUVmax of 1.94 for 18F-FDHT PET, yielding a sensitivity of 91% and a specificity of 100%; the optimal cutoff was an SUVmax of 1.54 for 18F-FES PET, resulting in a sensitivity and specificity of 100% for ER. Conclusion:18F-FDHT and 18F-FES uptake correlate well with AR and ER expression levels in representative biopsies. These results show the potential use of whole-body imaging for receptor status assessment, particularly in view of biopsy-associated sampling errors and heterogeneous receptor expression in breast cancer metastases. PMID- 28912145 TI - Dynamic 18F-FDG PET Lymphography for In Vivo Identification of Lymph Node Metastases in Murine Melanoma. AB - Positron lymphography using 18F-FDG followed by Cerenkov-guided resection of lymph nodes in healthy mice has previously been introduced by our group. Our aim in this study was to further assess the technique's potential beyond merely localizing sentinel lymph nodes. We now aimed to evaluate the potential of positron lymphography to characterize the nodes with respect to their tumor status in order to identify metastatic lymph nodes. We explored whether metastatic nodes could be distinguished from normal nodes via dynamic 18F-FDG lymphography, to then be resected under Cerenkov imaging guidance. Methods: A murine melanoma cell line highly metastatic to lymph nodes (B16F10) was implanted subcutaneously on the dorsal hind paw of C57 mice while the tumor-free contralateral leg served as an intraindividual control. A model of reactive lymph nodes after concanavalin A challenge served as an additional control to provide nonmalignant inflammatory lymphadenopathy. Dynamic PET/CT imaging was performed immediately after injection of 18F-FDG around the tumor or intracutaneously in the contralateral footpad. Furthermore, PET/CT and Cerenkov studies were performed repeatedly over time to follow the course of metastatic spread. In selected mice, popliteal lymph nodes underwent Cerenkov luminescence imaging. Hematoxylin and eosin staining was done to verify the presence of lymphatic melanoma infiltration. Results: Positron lymphography using 18F-FDG was successfully performed on tumor-bearing and non-tumor-bearing mice, as well as on controls bearing sites of inflammation; the results clearly identified the sentinel lymph node basin and delineated the lymphatic drainage. Significantly prolonged retention of activity was evident in metastatic nodes as compared with controls without tumor. On the basis of these results, the contrast in detection and identification of metastatic lymph nodes was distinct and could be used for guided lymph node resection, such as by using Cerenkov luminescence imaging. However, retention after 18F-FDG lymphography was also seen in acute inflammatory lymphadenopathy. Conclusion: In a tumor model, significantly longer retention of the radiotracer during 18F-FDG lymphography was seen in metastatic than nonmetastatic lymph nodes, allowing for differentiation between the two and for selective resection of tumor-bearing nodes using Cerenkov imaging. Inflammation can be better differentiated in a subacute state. PMID- 28912146 TI - Cerenkov-Activated Sticky Tag for In Vivo Fluorescence Imaging. AB - A big challenge in the clinical use of Cerenkov luminescence (CL) imaging is its low signal intensity, which is several orders of magnitude below ambient light. Consequently, highly sensitive cameras, sufficient shielding from background light, and long acquisition times are required. To alleviate this problem, we hypothesized a strategy to convert the weak CL signal into a stronger fluorescence signal by using CL-activated formation of nitrenes from azides to locally fix a fluorescent probe in tissue by the formation of a covalent bond. CL activated drug delivery was also evaluated using the same azide chemistry. The specific delivery of the CL-activated drug to cancer cells could reduce systemic toxicity, which is a limitation in chemotherapy. Methods: A cyanine-class near infrared fluorescent dye, Cy7, and doxorubicin were synthetically attached to polyfluorinated aryl azide to form Cy7 azide and DOX azide, respectively. Fibrosarcoma cells were incubated with 18F-FDG and exposed to Cy7 azide with subsequent fluorescence imaging. For CL-activated tagging in vivo, tumor-bearing mice were injected first with 90Y-DOTA-RGD, targeting alphavbeta3 integrins, and then with the Cy7 azide. Fluorescence signal was imaged over time. Breast cancer cells were incubated with DOX azide and 68Ga, after which cell viability was quantified using an assay. Results: CL photoactivation of Cy7 azide in vitro showed significantly higher fluorescence signal from 18F-FDG-treated than untreated cells. In vivo, CL photoactivation could be shown by using the tumor specific, integrin-targeting 90Y-DOTA-RGD and the localized activation of Cy7 azide. Here, localized CL-induced fluorescence was detected in the tumors and remained significantly higher over several days than in tumors without CL. We also established as a next step CL-activated drug delivery of DOX azide by showing significantly decreasing cell viability of breast cancer cells in a CL dose-dependent manner in vitro using CL photoactivation of DOX azide. Conclusion: We were able to develop a CL-activated "sticky tag" that converts the low CL signal into a stable and long-lasting, highly intense fluorescence signal. This fluorescent footprint of the radioactive signal might be clinically used for intraoperative surgery. The CL-targeted drug delivery strategy may potentially be used for dual-step targeted therapy. PMID- 28912147 TI - Performance of a PET Insert for High-Resolution Small-Animal PET/MRI at 7 Tesla. AB - We characterize a compact MR-compatible PET insert for simultaneous preclinical PET/MRI. Although specifically designed with the strict size constraint to fit inside the 114-mm inner diameter of the BGA-12S gradient coil used in the BioSpec 70/20 and 94/20 series of small-animal MRI systems, the insert can easily be installed in any appropriate MRI scanner or used as a stand-alone PET system. Methods: The insert consists of a ring of 16 detector-blocks each made from depth of-interaction-capable dual-layer-offset arrays of cerium-doped lutetium-yttrium oxyorthosilicate crystals read out by silicon photomultiplier arrays. Scintillator crystal arrays are made from 22 * 10 and 21 * 9 crystals in the bottom and top layers, respectively, with respective layer thicknesses of 6 and 4 mm, arranged with a 1.27-mm pitch, resulting in a useable field of view 28 mm long and about 55 mm wide. Results: Spatial resolution ranged from 1.17 to 1.86 mm full width at half maximum in the radial direction from a radial offset of 0 15 mm. With a 300- to 800-keV energy window, peak sensitivity was 2.2% and noise equivalent count rate from a mouse-sized phantom at 3.7 MBq was 11.1 kcps and peaked at 20.8 kcps at 14.5 MBq. Phantom imaging showed that features as small as 0.7 mm could be resolved. 18F-FDG PET/MR images of mouse and rat brains showed no signs of intermodality interference and could excellently resolve substructures within the brain. Conclusion: Because of excellent spatial resolvability and lack of intermodality interference, this PET insert will serve as a useful tool for preclinical PET/MR. PMID- 28912149 TI - Regarding "18F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low Background Detection of Thrombi". PMID- 28912148 TI - Thermal Imaging Is a Noninvasive Alternative to PET/CT for Measurement of Brown Adipose Tissue Activity in Humans. AB - Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilizes glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by the current standard method of assessing BAT-PET/CT-as it requires exposure to high doses of ionizing radiation. Infrared thermography (IRT) is a potential noninvasive, safe alternative, although direct corroboration with PET/CT has not been established. Methods: IRT and 18F-FDG PET/CT data from 8 healthy men subjected to water-jacket cooling were directly compared. Thermal images were geometrically transformed to overlay PET/CT-derived maximum intensity projection (MIP) images from each subject, and the areas with the most intense temperature and glucose uptake within the supraclavicular regions were compared. Relationships between supraclavicular temperatures (TSCR) from IRT and the metabolic rate of glucose uptake (MR(gluc)) from PET/CT were determined. Results: Glucose uptake on MR(gluc)MIP was found to correlate positively with a change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5% +/- 5.1%. Prolonged cooling, for 60 min, was associated with a further TSCR rise, compared with cooling for 10 min. Conclusion: The supraclavicular hotspot identified on IRT closely corresponded to the area of maximal uptake on PET/CT derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations for whom PET/CT is not feasible, practical, or repeatable. PMID- 28912150 TI - 18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment. AB - Accurate differential diagnosis of parkinsonism is of paramount therapeutic and prognostic importance. In addition, with the development of invasive therapies and novel disease-specific therapies, strategies for patient enrichment in trial populations are of growing importance. Imaging disease-specific patterns of regional glucose metabolism with PET and 18F-FDG allows for a highly accurate distinction between Parkinson disease (PD) and atypical parkinsonian syndromes, including multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration. On the basis of a preliminary metaanalysis of currently available studies with inclusion of multiple disease groups, we estimated that the diagnostic sensitivity and specificity for visual PET readings supported by voxel-based statistical analyses for diagnosis of atypical parkinsonian syndromes are 91.4% and 90.6%, respectively. The diagnostic specificity of 18F-FDG PET for diagnosing multiple-system atrophy, progressive supranuclear palsy, and corticobasal degeneration was consistently shown to be high (>90%), whereas sensitivity was more variable (>75%). It is increasingly acknowledged that cognitive impairment represents a major challenge in PD, with mild cognitive impairment being a prodromal stage of PD with dementia (PDD). In line with clinical and neuropsychologic studies, recent PET studies demonstrated that posterior cortical dysfunction in nondemented PD patients precedes cognitive decline and the development of PDD by several years. Taken together, the current literature underscores the utility of 18F-FDG PET for diagnostic evaluation of parkinsonism and the promising role of 18F-FDG PET for assessment and risk stratification of cognitive impairment in PD. PMID- 28912151 TI - In Vitro Evaluation of Molecular Tumor Targets in Nuclear Medicine: Immunohistochemistry Is One Option, but Under Which Conditions? AB - The identification of new molecular targets for diagnostic and therapeutic applications using in vitro methods is an important challenge in nuclear medicine. One such method is immunohistochemistry, increasingly popular because it is easy to perform. This review presents the case for conducting receptor immunohistochemistry to evaluate potential molecular targets in human tumor tissue sections. The focus is on the immunohistochemistry of G-protein-coupled receptors, one of the largest families of cell surface proteins, representing a major class of drug targets and thus playing an important role in nuclear medicine. This review identifies common pitfalls and challenges and provides guidelines on performing such immunohistochemical studies. An appropriate validation of the target is a prerequisite for developing robust and informative new molecular probes. PMID- 28912152 TI - Distinct Effects of Body Mass Index and Waist/Hip Ratio on Risk of Breast Cancer by Joint Estrogen and Progestogen Receptor Status: Results from a Case-Control Study in Northern and Eastern China and Implications for Chemoprevention. AB - BACKGROUND: Obesity is a consideration in the pharmacologic intervention for estrogen receptor (ER) positive (ER+) breast cancer risk. Body mass index (BMI) and waist/hip ratio (WHR) have demonstrated different effects on breast cancer risk in relation to estrogen receptor (ER) status, but the results have been inconsistent. Furthermore, the situation in Chinese women remains unclear. MATERIALS AND METHODS: We conducted a case-control study including 1,439 breast cancer cases in Northern and Eastern China. Both ER and progesterone receptor (PR) statuses were available for 1,316 cases. Associations between body size related factors and breast cancer risk defined by receptor status were assessed by multiple polytomous unconditional logistic regression analysis. RESULTS: Body mass index and WHR were positively associated with overall breast cancer risk. Body mass index was positively associated with both ER+/PR positive (PR+) and ER negative (ER-)/PR negative(PR-) subtype risks, although only significantly for ER+/PR+ subtype. Waist-hip ratio was only positively correlated with ER-/PR- subtype risk, although independent of BMI. Body mass index was positively associated with risk of ER+/PR+ and ER-/PR- subtypes in premenopausal women, whereas WHR was inversely correlated with ER+/PR- and positively with ER-/PR- subtype risks. Among postmenopausal women, WHR >0.85 was associated with increased risk of ER-/PR- subtype. CONCLUSION: Both general and central obesity contribute to breast cancer risk, with different effects on specific subtypes. General obesity, indicated by BMI, is more strongly associated with ER+/PR+ subtype, especially among premenopausal women, whereas central obesity, indicated by WHR, is more specific for ER-/PR- subtype, independent of menopausal status. These results suggest that different chemoprevention strategies may be appropriate in selected individuals. IMPLICATIONS FOR PRACTICE: The results of this study suggest that general and central obesity may play different roles in different breast cancer subtypes, supporting the hypothesis that obesity affects breast carcinogenesis via complex molecular interconnections, beyond the impact of estrogens. The results also imply that different chemoprevention strategies may be appropriate for selected individuals, highlighting the need to be particularly aware of women with a high waist/hip ratio but normal body mass index. Given the lack of any proven pharmacologic intervention for estrogen receptor negative breast cancer, stricter weight-control measures may be advised in these individuals. PMID- 28912153 TI - Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures. AB - BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). RESULTS: In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4 ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases). CONCLUSION: Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. IMPLICATIONS FOR PRACTICE: By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors. PMID- 28912155 TI - Visual Motion Discrimination by Propagating Patterns in Primate Cerebral Cortex. AB - Visual stimuli can evoke waves of neural activity that propagate across the surface of visual cortical areas. The relevance of these waves for visual processing is unknown. Here, we measured the phase and amplitude of local field potentials (LFPs) in electrode array recordings from the motion-processing medial temporal (MT) area of anesthetized male marmosets. Animals viewed grating or dot field stimuli drifting in different directions. We found that, on individual trials, the direction of LFP wave propagation is sensitive to the direction of stimulus motion. Propagating LFP patterns are also detectable in trial-averaged activity, but the trial-averaged patterns exhibit different dynamics and behaviors from those in single trials and are similar across motion directions. We show that this difference arises because stimulus-sensitive propagating patterns are present in the phase of single-trial oscillations, whereas the trial averaged signal is dominated by additive amplitude effects. Our results demonstrate that propagating LFP patterns can represent sensory inputs at timescales relevant to visually guided behaviors and raise the possibility that propagating activity patterns serve neural information processing in area MT and other cortical areas.SIGNIFICANCE STATEMENT Propagating wave patterns are widely observed in the cortex, but their functional relevance remains unknown. We show here that visual stimuli generate propagating wave patterns in local field potentials (LFPs) in a movement-sensitive area of the primate cortex and that the propagation direction of these patterns is sensitive to stimulus motion direction. We also show that averaging LFP signals across multiple stimulus presentations (trial averaging) yields propagating patterns that capture different dynamic properties of the LFP response and show negligible direction sensitivity. Our results demonstrate that sensory stimuli can modulate propagating wave patterns reliably in the cortex. The relevant dynamics are normally masked by trial averaging, which is a conventional step in LFP signal processing. PMID- 28912154 TI - Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia. AB - Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Deltap35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Deltap35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Deltap35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Abeta accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Deltap35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Deltap35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems. PMID- 28912157 TI - Approaching the Ground Truth: Revealing the Functional Organization of Human Multisensory STC Using Ultra-High Field fMRI. AB - Integrating inputs across sensory systems is a property of the brain that is vitally important in everyday life. More than two decades of fMRI research have revealed crucial insights on multisensory processing, yet the multisensory operations at the neuronal level in humans have remained largely unknown. Understanding the fine-scale spatial organization of multisensory brain regions is fundamental to shed light on their neuronal operations. Monkey electrophysiology revealed that the bimodal superior temporal cortex (bSTC) is topographically organized according to the modality preference (visual, auditory, and bimodal) of its neurons. In line with invasive studies, a previous 3 Tesla fMRI study suggests that the human bSTC is also topographically organized according to modality preference (visual, auditory, and bimodal) when analyzed at 1.6 * 1.6 * 1.6 mm3 voxel resolution. However, it is still unclear whether this resolution is able to unveil an accurate spatial organization of the human bSTC. This issue was addressed in the present study by investigating the spatial organization of functional responses of the bSTC in 10 participants (from both sexes) at 1.5 * 1.5 * 1.5 mm3 and 1.1 * 1.1 * 1.1 mm3 using ultra-high field fMRI (at 7 Tesla). Relative to 1.5 * 1.5 * 1.5 mm3, the bSTC at 1.1 * 1.1 * 1.1 mm3 resolution was characterized by a larger selectivity for visual and auditory modalities, stronger integrative responses in bimodal voxels, and it was organized in more distinct functional clusters indicating a more precise separation of underlying neuronal clusters. Our findings indicate that increasing the spatial resolution may be necessary and sufficient to achieve a more accurate functional topography of human multisensory integration.SIGNIFICANCE STATEMENT The bimodal superior temporal cortex (bSTC) is a brain region that plays a crucial role in the integration of visual and auditory inputs. The aim of the present study was to investigate the fine-scale spatial organization of the bSTC by using ultra-high magnetic field fMRI at 7 Tesla. Mapping the functional topography of bSTC at a resolution of 1.1 * 1.1 * 1.1 mm3 revealed more accurate representations than at lower resolutions. This result indicates that standard resolution fMRI may lead to wrong conclusions about the functional organization of the bSTC, whereas high spatial resolution is essential to more accurately approach neuronal operations of human multisensory integration. PMID- 28912156 TI - Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration. AB - Wallerian degeneration (WD) is considered an essential preparatory stage to the process of axonal regeneration. In the peripheral nervous system, infiltrating monocyte-derived macrophages, which use the chemokine receptor CCR2 to gain entry to injured tissues from the bloodstream, are purportedly necessary for efficient WD. However, our laboratory has previously reported that myelin clearance in the injured sciatic nerve proceeds unhindered in the Ccr2-/- mouse model. Here, we extensively characterize WD in male Ccr2-/- mice and identify a compensatory mechanism of WD that is facilitated primarily by neutrophils. In response to the loss of CCR2, injured Ccr2-/- sciatic nerves demonstrate prolonged expression of neutrophil chemokines, a concomitant extended increase in the accumulation of neutrophils in the nerve, and elevated phagocytosis by neutrophils. Neutrophil depletion substantially inhibits myelin clearance after nerve injury in both male WT and Ccr2-/- mice, highlighting a novel role for these cells in peripheral nerve degeneration that spans genotypes.SIGNIFICANCE STATEMENT The accepted view in the basic and clinical neurosciences is that the clearance of axonal and myelin debris after a nerve injury is directed primarily by inflammatory CCR2+ macrophages. However, we demonstrate that this clearance is nearly identical in WT and Ccr2-/- mice, and that neutrophils replace CCR2+ macrophages as the primary phagocytic cell. We find that neutrophils play a major role in myelin clearance not only in Ccr2-/- mice but also in WT mice, highlighting their necessity during nerve degeneration in the peripheral nervous system. These degeneration studies may propel improvements in nerve regeneration and draw critical parallels to mechanisms of nerve degeneration and regeneration in the CNS and in the context of peripheral neuropathies. PMID- 28912158 TI - Visual Responses in FEF, Unlike V1, Primarily Reflect When the Visual Context Renders a Receptive Field Salient. AB - When light falls within a neuronal visual receptive field (RF) the resulting activity is referred to as the visual response. Recent work suggests this activity is in response to both the visual stimulation and the abrupt appearance, or salience, of the presentation. Here we present a novel method for distinguishing the two, based on the timing of random and nonrandom presentations. We examined these contributions in frontal eye field (FEF; N = 51) and as a comparison, an early stage in the primary visual cortex (V1; N = 15) of male monkeys (Macaca mulatta). An array of identical stimuli was presented within and outside the neuronal RF while we manipulated salience by varying the time between stimulus presentations. We hypothesized that the rapid presentation would reduce salience (the sudden appearance within the visual field) of a stimulus at any one location, and thus decrease responses driven by salience in the RF. We found that when the interstimulus interval decreased from 500 to 16 ms there was an approximate 79% reduction in the FEF response compared with an estimated 17% decrease in V1. This reduction in FEF response for rapid presentation was evident even when the random sequence preceding a stimulus did not stimulate the RF for 500 ms. The time course of these response changes in FEF suggest that salience is represented much earlier (<100 ms following stimulus onset) than previously estimated. Our results suggest that the contribution of salience dominates at higher levels of the visual system.SIGNIFICANCE STATEMENT The neuronal responses in early visual processing [e.g., primary visual cortex (V1)] reflect primarily the retinal stimulus. Processing in higher visual areas is modulated by a combination of the visual stimulation and contextual factors, such as salience, but identifying these components separately has been difficult. Here we quantified these contributions at a late stage of visual processing [frontal eye field (FEF)] and as a comparison, an early stage in V1. Our results suggest that as visual information continues through higher levels of processing the neural responses are no longer driven primarily by the visual stimulus in the receptive field, but by the broader context that stimulus defines-very different from current views about visual signals in FEF. PMID- 28912160 TI - Dopamine D2 Receptors Modulate Pyramidal Neurons in Mouse Medial Prefrontal Cortex through a Stimulatory G-Protein Pathway. AB - Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage dependent currents (e.g., NMDAR-mediated Ca2+ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or beta-arrestin knock-out, and mimicked by Gs-DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with Gs, rather than the Gi/o-associated mechanisms that have classically been ascribed to D2Rs.SIGNIFICANCE STATEMENT Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been implicated in schizophrenia, Tourette syndrome, and bipolar disorder. Recently, we described a new mechanism through which D2R activation can enhance the excitability of pyramidal neurons in the PFC. Here, we explore the underlying cellular mechanisms. Surprisingly, although D2Rs are classically assumed to signal through Gi/o-coupled G-proteins and/or scaffolding proteins, such as beta-arrestin, we find that the effects of D2Rs on prefrontal pyramidal neurons are actually mediated by pathways associated with Gs-mediated signaling. Furthermore, we show how, via this D2R-dependent phenomenon, synaptic input can enhance the excitability of prefrontal neurons over timescales on the order of seconds. These results elucidate cellular mechanisms underlying a novel signaling pathway downstream of D2Rs that may contribute to prefrontal function under normal and pathological conditions. PMID- 28912159 TI - Oscillatory Reinstatement Enhances Declarative Memory. AB - Declarative memory recall is thought to involve the reinstatement of neural activity patterns that occurred previously during encoding. Consistent with this view, greater similarity between patterns of activity recorded during encoding and retrieval has been found to predict better memory performance in a number of studies. Recent models have argued that neural oscillations may be crucial to reinstatement for successful memory retrieval. However, to date, no causal evidence has been provided to support this theory, nor has the impact of oscillatory electrical brain stimulation during encoding and retrieval been assessed. To explore this we used transcranial alternating current stimulation over the left dorsolateral prefrontal cortex of human participants [n = 70, 45 females; age mean (SD) = 22.12 (2.16)] during a declarative memory task. Participants received either the same frequency during encoding and retrieval (60 60 or 90-90 Hz) or different frequencies (60-90 or 90-60 Hz). When frequencies matched there was a significant memory improvement (at both 60 and 90 Hz) relative to sham stimulation. No improvement occurred when frequencies mismatched. Our results provide support for the role of oscillatory reinstatement in memory retrieval.SIGNIFICANCE STATEMENT Recent neurobiological models of memory have argued that large-scale neural oscillations are reinstated to support successful memory retrieval. Here we used transcranial alternating current stimulation (tACS) to test these models. tACS has recently been shown to induce neural oscillations at the frequency stimulated. We stimulated over the left dorsolateral prefrontal cortex during a declarative memory task involving learning a set of words. We found that tACS applied at the same frequency during encoding and retrieval enhances memory. We also find no difference between the two applied frequencies. Thus our results are consistent with the proposal that reinstatement of neural oscillations during retrieval supports successful memory retrieval. PMID- 28912161 TI - Disruption of Bmal1 Impairs Blood-Brain Barrier Integrity via Pericyte Dysfunction. AB - Circadian rhythm disturbances are well established in neurological diseases. However, how these disruptions cause homeostatic imbalances remains poorly understood. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) is a major circadian clock transcriptional activator, and Bmal1 deficiency in male Bmal1nestin-/- mice induced marked astroglial activation without affecting the number of astrocytes in the brain and spinal cord. Bmal1 deletion caused blood-brain barrier (BBB) hyperpermeability with an age-dependent loss of pericyte coverage of blood vessels in the brain. Using Nestin-green fluorescent protein (GFP) transgenic mice, we determined that pericytes are Nestin-GFP+ in the adult brain. Bmal1 deletion caused Nestin-GFP+ pericyte dysfunction, including the downregulation of platelet-derived growth factor receptor beta (PDGFRbeta), a protein necessary for maintaining BBB integrity. Knockdown of Bmal1 downregulated PDGFRbeta transcription in the brain pericyte cell line. Thus, the circadian clock component Bmal1 maintains BBB integrity via regulating pericytes.SIGNIFICANCE STATEMENT Circadian rhythm disturbances may play a role in neurodegenerative disorders, such as Alzheimer's disease. Our results revealed that one of the circadian clock components maintains the integrity of the blood-brain barrier (BBB) by regulating vascular-embedded pericytes. These cells were recently identified as a vital component for the control of BBB permeability and cerebral blood flow. Our present study demonstrates the involvement of circadian clock component Bmal1 in BBB homeostasis and highlights the role of Bmal1 dysfunction in multiple neurological diseases. PMID- 28912162 TI - Regional Cellular Environment Shapes Phenotypic Variations of Hippocampal and Neocortical Chandelier Cells. AB - Different cortical regions processing distinct information, such as the hippocampus and the neocortex, share common cellular components and circuit motifs but form unique networks by modifying these cardinal units. Cortical circuits include diverse types of GABAergic interneurons (INs) that shape activity of excitatory principal neurons (PNs). Canonical IN types conserved across distinct cortical regions have been defined by their morphological, electrophysiological, and neurochemical properties. However, it remains largely unknown whether canonical IN types undergo specific modifications in distinct cortical regions and display "regional variants." It is also poorly understood whether such phenotypic variations are shaped by early specification or regional cellular environment. The chandelier cell (ChC) is a highly stereotyped IN type that innervates axon initial segments of PNs and thus serves as a good model with which to address this issue. Here, we show that Cadherin-6 (Cdh6), a homophilic cell adhesion molecule, is a reliable marker of ChCs and Cdh6-CreER mice (both sexes) provide genetic access to hippocampal ChCs (h-ChCs). We demonstrate that, compared with neocortical ChCs (nc-ChCs), h-ChCs cover twice as much area and innervate twice as many PNs. Interestingly, a subclass of h-ChCs exhibits calretinin (CR) expression, which is not found in nc-ChCs. Furthermore, we find that h-ChCs appear to be born earlier than nc-ChCs. Surprisingly, despite the difference in temporal origins, ChCs display host-region-dependent axonal/synaptic organization and CR expression when transplanted heterotopically. These results suggest that local cellular environment plays a critical role in shaping terminal phenotypes of regional IN variants in the hippocampus and the neocortex.SIGNIFICANCE STATEMENT Canonical interneuron (IN) types conserved across distinct cortical regions such as the hippocampus and the neocortex are defined by morphology, physiology, and gene expression. However, it remains unknown whether they display phenotypic variations in different cortical regions. In addition, it is unclear whether terminal phenotypes of regional IN variants belonging to a canonical IN type are determined intrinsically or extrinsically. Our results provide evidence of striking differences in axonal/synaptic organization and calretinin expression between hippocampal chandelier cells (ChCs) and neocortical ChCs. They also reveal that local cellular environment in distinct cortical regions regulates these terminal phenotypes. Therefore, our study suggests that local cortical environment shapes the phenotypes of regional IN variants, which may be required for unique circuit operations in distinct cortical regions. PMID- 28912164 TI - Highs and lows of diabetic care: lessons from a national audit. PMID- 28912163 TI - Neonatal resuscitation using a laryngeal mask airway: a randomised trial in Uganda. AB - OBJECTIVE: Mortality rates from birth asphyxia in low-income countries remain high. Face mask ventilation (FMV) performed by midwives is the usual method of resuscitating neonates in such settings but may not always be effective. The i gel is a cuffless laryngeal mask airway (LMA) that could enhance neonatal resuscitation performance. We aimed to compare LMA and face mask (FM) during neonatal resuscitation in a low-resource setting. SETTING: Mulago National Referral Hospital, Kampala, Uganda. DESIGN: This prospective randomised clinical trial was conducted at the labour ward operating theatre. After a brief training on LMA and FM use, infants with a birth weight >2000 g and requiring positive pressure ventilation at birth were randomised to resuscitation by LMA or FM. Resuscitations were video recorded. MAIN OUTCOME MEASURES: Time to spontaneous breathing. RESULTS: Forty-nine (24 in the LMA and 25 in the FM arm) out of 50 enrolled patients were analysed. Baseline characteristics were comparable between the two arms. Time to spontaneous breathing was shorter in LMA arm than in FM arm (mean 153 s (SD+/-59) vs 216 s (SD+/-92)). All resuscitations were effective in LMA arm, whereas 11 patients receiving FM were converted to LMA because response to FMV was unsatisfactory. There were no adverse effects. CONCLUSION: A cuffless LMA was more effective than FM in reducing time to spontaneous breathing. LMA seems to be safe and effective in clinical practice after a short training programme. Its potential benefits on long-term outcomes need to be assessed in a larger trial. CLINICAL TRIAL REGISTRY: This trial was registered in https://clinicaltrials.gov, with registration number NCT02042118. PMID- 28912166 TI - Breastfeeding and vitamin D. PMID- 28912167 TI - Adult Nursing. AB - EBN Perspectives bring together key issues from the commentaries in one of our nursing topic themes. PMID- 28912165 TI - Holistic care of complicated tuberculosis in healthcare settings with limited resources. AB - In recent years, most of the focus on improving the quality of paediatric care in low-income countries has been on improving primary care using the Integrated Management of Childhood Illness, and improving triage and emergency treatment in hospitals aimed at reducing deaths in the first 24 hours. There has been little attention paid to improving the quality of care for children with chronic or complex diseases. Children with complicated forms of tuberculosis (TB), including central nervous system and chronic pulmonary TB, provide examples of acute and chronic multisystem paediatric illnesses that commonly present to district-level and second-level referral hospitals in low-income countries. The care of these children requires a holistic clinical and continuous quality improvement approach. This includes timely decisions on the commencement of treatment often when diagnoses are not certain, identification and management of acute respiratory, neurological and nutritional complications, identification and treatment of comorbidities, supportive care, systematic monitoring of treatment and progress, rehabilitation, psychological support, ensuring adherence, and safe transition to community care. New diagnostics and imaging can assist this, but meticulous attention to clinical detail at the bedside and having a clear plan for all aspects of care that is communicated well to staff and families are essential for good outcomes. The care is multidimensional: biomedical, rehabilitative, social and economic, and multidisciplinary: medical, nursing and allied health. In the era of the Sustainable Development Goals, approaches to these dimensions of healthcare are needed within the reach of the poorest people who access district hospitals in low-income countries. PMID- 28912169 TI - Joined-up planning across the whole system is essential to improve mental health. PMID- 28912168 TI - Alternative Polyadenylation of PRELID1 Regulates Mitochondrial ROS Signaling and Cancer Outcomes. AB - Disruption of posttranscriptional gene regulation is a critical step in oncogenesis that can be difficult to observe using traditional molecular techniques. To overcome this limitation, a modified polyadenylation site sequencing (PAS-seq) protocol was used to generate a genome-wide map of alternative polyadenylation (APA) events in human primary breast tumor specimens and matched normal tissue. This approach identified an APA event in the PRELID1 mRNA that enhances its steady-state level and translational efficiency, and is a strong breast cancer subtype-dependent predictor of patient clinical outcomes. Furthermore, it has been demonstrated that PRELID1 regulates stress response and mitochondrial reactive oxygen species (ROS) production in a cell type-specific manner. Modulation of PRELID1 expression, including its posttranscriptional control, appears to be a common stress response across different cancer types. These data reveal that PRELID1 mRNA processing is an important regulator of cell type-specific responses to stress used by multiple cancers and is associated with patient outcomes.Implications: This study suggests that the regulation of PRELID1 expression, by APA and other mechanisms, plays a role in mitochondrial ROS signaling and represents a novel prognostic factor and therapeutic target in cancer. Mol Cancer Res; 15(12); 1741-51. (c)2017 AACR. PMID- 28912170 TI - Liver disease mortality varies widely across England. PMID- 28912171 TI - Headache and papilloedema in a 10 year old. PMID- 28912173 TI - Secondary malignant neoplasms, progression-free survival and overall survival in patients treated for Hodgkin lymphoma: a systematic review and meta-analysis of randomized clinical trials. AB - Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta analyzed using Peto's method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow up. PMID- 28912175 TI - In vitro evidence of complement activation in patients with sickle cell disease. PMID- 28912174 TI - Senescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells. AB - Transcriptional deregulation caused by epigenetic or genetic alterations is a major cause of leukemic transformation. The Spi1/PU.1 transcription factor is a key regulator of many steps of hematopoiesis, and limits self-renewal of hematopoietic stem cells. The deregulation of its expression or activity contributes to leukemia, in which Spi1 can be either an oncogene or a tumor suppressor. Herein we explored whether cellular senescence, an anti-tumoral pathway that restrains cell proliferation, is a mechanism by which Spi1 limits hematopoietic cell expansion, and thus prevents the development of leukemia. We show that Spi1 overexpression triggers cellular senescence both in primary fibroblasts and hematopoietic cells. Erythroid and myeloid lineages are both prone to Spi1-induced senescence. In hematopoietic cells, Spi1-induced senescence requires its DNA-binding activity and a functional p38MAPK14 pathway but is independent of a DNA-damage response. In contrast, in fibroblasts, Spi1-induced senescence is triggered by a DNA-damage response. Importantly, using our well established Spi1 transgenic leukemia mouse model, we demonstrate that Spi1 overexpression also induces senescence in erythroid progenitors of the bone marrow in vivo before the onset of the pre-leukemic phase of erythroleukemia. Remarkably, the senescence response is lost during the progression of the disease and erythroid blasts do not display a higher expression of Dec1 and CDKN1A, two of the induced senescence markers in young animals. These results bring indirect evidence that leukemia develops from cells which have bypassed Spi1-induced senescence. Overall, our results reveal senescence as a Spi1-induced anti proliferative mechanism that may be a safeguard against the development of acute myeloid leukemia. PMID- 28912172 TI - RNA-binding proteins in neurodegeneration: mechanisms in aggregate. AB - Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens. PMID- 28912177 TI - Rac1 functions downstream of miR-142 in regulation of erythropoiesis. PMID- 28912176 TI - Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms. AB - Nearly one-third of patients with acute myeloid leukemia have FMS-like tyrosine kinase 3 mutations and thus have poor survival prospects. Receptor tyrosine kinase anexelekto is critical for FMS-like tyrosine kinase 3 signaling and participates in FMS-like tyrosine kinase 3 inhibitor resistance mechanisms. Thus, strategies targeting anexelekto could prove useful for acute myeloid leukemia therapy. ONO-7475 is an inhibitor with high specificity for anexelekto and MER tyrosine kinase. Herein, we report that ONO-7475 potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3. MER tyrosine kinase-lacking MOLM13 cells were sensitive to ONO-7475, while MER tyrosine kinase expressing OCI-AML3 cells were resistant, suggesting that the drug acts via anexelekto in acute myeloid leukemia cells. Reverse phase protein analysis of ONO-7475 treated cells revealed that cell cycle regulators like cyclin dependent kinase 1, cyclin B1, polo-like kinase 1, and retinoblastoma were suppressed. ONO-7475 suppressed cyclin dependent kinase 1, cyclin B1, polo-like kinase 1 gene expression suggesting that anexelekto may regulate the cell cycle, at least in part, via transcriptional mechanisms. Importantly, ONO-7475 was effective in a human FMS-like tyrosine kinase 3 with internal tandem duplication mutant murine xenograft model. Mice fed a diet containing ONO-7475 exhibited significantly longer survival and, interestingly, blocked leukemia cell infiltration in the liver. In summary, ONO 7475 effectively kills acute myeloid leukemia cells in vitro and in vivo by mechanisms that involve disruption of diverse survival and proliferation pathways. PMID- 28912178 TI - Cardiomyopathies: An Overview. AB - The nonischemic cardiomyopathies are a diverse group of cardiac disorders that frequently cause heart failure and death and are now recognized with increasing frequency. There has been substantial progress in the clinical recognition and understanding of the natural history of these conditions. Well-established and new techniques of cardiac imaging are also helpful in this regard. Basic scientists are elucidating the pathogenesis and pathobiology of individual cardiomyopathies. In this compendium, some of the most important advances in this field are reviewed. Scientific opportunities to enhance further collaborative research to accelerate progress are identified. PMID- 28912179 TI - Classification, Epidemiology, and Global Burden of Cardiomyopathies. AB - In the past 25 years, major advances were achieved in the nosography of cardiomyopathies, influencing the definition and taxonomy of this important chapter of cardiovascular disease. Nearly, 50% of patients dying suddenly in childhood or adolescence or undergoing cardiac transplantation are affected by cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic, restrictive, and noncompacted) and added to update the World Health Organization classification. Myocarditis has also been named inflammatory cardiomyopathy. Extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed establishment of dilated cardiomyopathy as mostly cytoskeleton, force transmission disease; hypertrophic-restrictive cardiomyopathies as sarcomeric, force generation disease; and arrhythmogenic cardiomyopathy as desmosome, cell junction disease. Channelopathies (short and long QT, Brugada, and catecholaminergic polymorphic ventricular tachycardia syndromes) should also be considered cardiomyopathies because of electric myocyte dysfunction. Cardiomyopathies are easily diagnosed but treated only with palliative pharmacological or invasive therapy. Curative therapy, thanks to insights into the molecular pathogenesis, has to target the fundamental mechanisms involved in the onset and progression of these conditions. PMID- 28912182 TI - Hypertrophic Obstructive Cardiomyopathy: Surgical Myectomy and Septal Ablation. AB - Hypertrophic cardiomyopathy is a genetic disorder characterized by marked hypertrophy of the myocardium. It is frequently accompanied by dynamic left ventricular outflow tract obstruction and symptoms of dyspnea, angina, and syncope. The initial therapy for symptomatic patients with obstruction is medical therapy with beta-blockers and calcium antagonists. However, there remain a subset of patients who have continued severe symptoms, which are unresponsive to medical therapy. These patients can be treated with septal reduction therapy, either surgical septal myectomy or alcohol septal ablation. When performed by experienced operators working in high-volume centers, septal myectomy is highly effective with a >90% relief of obstruction and improvement in symptoms. The perioperative mortality rate for isolated septal myectomy in most centers is <1%. Alcohol septal ablation is a less invasive treatment. In many patients, the hemodynamic and clinical results are comparable to that of septal myectomy. However, the results of alcohol septal ablation are dependent on the septal perforator artery supplying the area of the contact between the hypertrophied septum and the anterior leaflet of the mitral valve. There are some patients, particularly younger patients with severe hypertrophy, who do not uniformly experience complete relief of obstruction and symptoms. Both techniques of septal reduction therapy are highly operator dependent. The final decision as to which approach should be selected in any given patient is dependent up patient preference and the availability and experience of the operator and institution at which the patient is being treated. PMID- 28912180 TI - Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. AB - Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management. PMID- 28912183 TI - Arrhythmogenic Cardiomyopathy. AB - Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder, predisposing to sudden cardiac death, particularly in young patients and athletes. Pathological features include loss of myocytes and fibrofatty replacement of right ventricular myocardium; biventricular involvement is often observed. It is a cell-to-cell junction cardiomyopathy, typically caused by genetically determined abnormalities of cardiac desmosomes, which leads to detachment of myocytes and alteration of intracellular signal transduction. The diagnosis of arrhythmogenic cardiomyopathy does not rely on a single gold standard test but is achieved using a scoring system, which encompasses familial and genetic factors, ECG abnormalities, arrhythmias, and structural/functional ventricular alterations. The main goal of treatment is the prevention of sudden cardiac death. Implantable cardioverter defibrillator is the only proven lifesaving therapy; however, it is associated with significant morbidity because of device related complications and inappropriate implantable cardioverter defibrillator interventions. Selection of patients who are the best candidates for implantable cardioverter defibrillator implantation is one of the most challenging issues in the clinical management. PMID- 28912184 TI - Inflammatory Cardiomyopathic Syndromes. AB - Inflammatory activation occurs in nearly all forms of myocardial injury. In contrast, inflammatory cardiomyopathies refer to a diverse group of disorders in which inflammation of the heart (or myocarditis) is the proximate cause of myocardial dysfunction, causing injury that can range from a fully recoverable syndrome to one that leads to chronic remodeling and dilated cardiomyopathy. The most common cause of inflammatory cardiomyopathies in developed countries is lymphocytic myocarditis most commonly caused by a viral pathogenesis. In Latin America, cardiomyopathy caused by Chagas disease is endemic. The true incidence of myocarditis is unknown to the limited utilization and the poor sensitivity of endomyocardial biopsies (especially for patchy diseases such as lymphocytic myocarditis and sarcoidosis) using the gold-standard Dallas criteria. Emerging immunohistochemistry criteria and molecular diagnostic techniques are being developed that will improve diagnostic yield, provide additional clues into the pathophysiology, and offer an application of precision medicine to these important syndromes. Immunosuppression is recommended for patients with cardiac sarcoidosis, giant cell myocarditis, and myocarditis associated with connective tissue disorders and may be beneficial in chronic viral myocarditis once virus is cleared. Further trials of immunosuppression, antiviral, and immunomodulating therapies are needed. Together, with new molecular-based diagnostics and therapies tailored to specific pathogeneses, the outcome of patients with these disorders may improve. PMID- 28912185 TI - Restrictive Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. AB - Restrictive cardiomyopathy (RCM) is characterized by nondilated left or right ventricle with diastolic dysfunction. The restrictive cardiomyopathies are a heterogenous group of myocardial diseases that vary according to pathogenesis, clinical presentation, diagnostic evaluation and criteria, treatment, and prognosis. In this review, an overview of RCMs will be presented followed by a detailed discussion on 3 major causes of RCM, for which tailored interventions are available: cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis. Each of these 3 RCMs is challenging to diagnose, and recognition of each disease entity is frequently delayed. Clinical clues to promote recognition of cardiac amyloidosis, cardiac sarcoidosis, and cardiac hemochromatosis and imaging techniques used to facilitate diagnosis are discussed. Disease-specific therapies are reviewed. Early recognition remains a key barrier to improving survival in all RCMs. PMID- 28912181 TI - Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. AB - Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetrical with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third. The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding beta myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ~50% of the HCM families. In ~40% of HCM patients, the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents. PMID- 28912186 TI - Cardiomyopathies Due to Left Ventricular Noncompaction, Mitochondrial and Storage Diseases, and Inborn Errors of Metabolism. AB - The normal function of the human myocardium requires the proper generation and utilization of energy and relies on a series of complex metabolic processes to achieve this normal function. When metabolic processes fail to work properly or effectively, heart muscle dysfunction can occur with or without accompanying functional abnormalities of other organ systems, particularly skeletal muscle. These metabolic derangements can result in structural, functional, and infiltrative deficiencies of the heart muscle. Mitochondrial and enzyme defects predominate as disease-related etiologies. In this review, left ventricular noncompaction cardiomyopathy, which is often caused by mutations in sarcomere and cytoskeletal proteins and is also associated with metabolic abnormalities, is discussed. In addition, cardiomyopathies resulting from mitochondrial dysfunction, metabolic abnormalities, storage diseases, and inborn errors of metabolism are described. PMID- 28912188 TI - Modern Imaging Techniques in Cardiomyopathies. AB - Modern advanced imaging techniques have allowed increasingly more rigorous assessment of the cardiac structure and function of several types of cardiomyopathies. In contemporary cardiology practice, echocardiography and cardiac magnetic resonance imaging are widely used to provide a basic framework in the evaluation and management of cardiomyopathies. Echocardiography is the quintessential imaging technique owing to its unique ability to provide real-time images of the beating heart with good temporal resolution, combined with its noninvasive nature, cost-effectiveness, availability, and portability. Cardiac magnetic resonance imaging provides data that are both complementary and uniquely distinct, thus allowing for insights into the disease process that until recently were not possible. The new catchphrase in the evaluation of cardiomyopathies is multimodality imaging, which is purported to be the efficient integration of various methods of cardiovascular imaging to improve the ability to diagnose, guide therapy, or predict outcomes. It usually involves an integrated approach to the use of echocardiography and cardiac magnetic resonance imaging for the assessment of cardiomyopathies, and, on occasion, single-photon emission computed tomography and such specialized techniques as pyrophosphate scanning. PMID- 28912189 TI - Associations between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis, and between MIF gene polymorphisms and disease susceptibility: a meta-analysis. AB - AIM: To systematically review evidence regarding the relationship between circulating macrophage migration inhibitory factor (MIF) levels and rheumatoid arthritis (RA), and the association between MIF gene polymorphisms and RA susceptibility. DESIGN: We performed a meta-analysis on data of serum/plasma MIF levels in patients with RA and in controls, and on associations between the MIF 173 C/G and -794CATT5-8 polymorphisms and RA susceptibility. PATIENTS: Twelve studies, comprising a total of 362 RA cases and 531 controls evaluated for MIF levels, and 2367 RA cases and 2395 controls evaluated for MIF polymorphisms, were included. RESULTS: MIF levels were significantly higher in the RA group than in the control group (standardised mean difference (95% CI) 0.923 (0.766 to 1.080), p<0.001). Stratification by ethnicity revealed significantly higher MIF levels in the RA group in Caucasian, Asian and Latin American populations. MIF levels were significantly higher in patients with RA, regardless of adjustment, sample size or data type evaluated. RA was identified to be significantly associated with the MIF-173 C allele (OR (95% CI) 1.271 (1.141 to 1.416), p<0.001), as well as with the -794CATT7 allele (OR (95% CI) 1.229 (1.084 to 1.415), p=0.002) and the 794CATT7-MIF-173C haplotype RA (OR (95% CI) 1.433 (1.138 to 1.805), p=0.002). CONCLUSIONS: Our meta-analyses revealed significantly higher circulating MIF levels in patients with RA, and found evidence of associations between the MIF 173 C/G and -794CATT5-8 polymorphisms and RA susceptibility. PMID- 28912190 TI - Invitations received from potential predatory publishers and fraudulent conferences: a 12-month early-career researcher experience. AB - PURPOSE OF THE STUDY: This study aims to describe all unsolicited electronic invitations received from potential predatory publishers or fraudulent conferences over a 12-month period following the first publication as a corresponding author of a junior academician. STUDY DESIGN: Unsolicited invitations received at an institutional email address and perceived to be sent by predatory publishers or fraudulent conferences were collected. RESULTS: A total of 502 invitations were included of which 177 (35.3%) had subject matter relevant to the recipient's research interests and previous work. Two hundred and thirty-seven were invitations to publish a manuscript. Few disclosed the publication fees (32, 13.5%) but they frequently reported accepting all types of manuscripts (167, 70.5%) or emphasised on a deadline to submit (165, 69.6%). Invitations came from 39 publishers (range 1 to 87 invitations per publisher). Two hundred and ten invitations from a potential fraudulent conference were received. These meetings were held in Europe (97, 46.2%), North America (65, 31.0%), Asia (20.4%) or other continents (5, 2.4%) and came from 18 meeting organisation groups (range 1 to 137 invitations per organisation). Becoming an editorial board member (30), the editor-in-chief (1), a guest editor for journal special issue (6) and write a book chapter (11) were some of the roles offered in the other invitations included while no invitation to review a manuscript was received. CONCLUSIONS: Young researchers are commonly exposed to predatory publishers and fraudulent conferences following a single publication as a corresponding author. Academic institutions worldwide need to educate and inform young researchers of this emerging problem. PMID- 28912187 TI - Pediatric Cardiomyopathies. AB - : Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.1 to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common; restrictive, noncompaction, and mixed cardiomyopathies occur infrequently; and arrhythmogenic right ventricular cardiomyopathy is rare. Pediatric cardiomyopathies can result from coronary artery abnormalities, tachyarrhythmias, exposure to infection or toxins, or secondary to other underlying disorders. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies often occur in the absence of comorbidities, such as atherosclerosis, hypertension, renal dysfunction, and diabetes mellitus; as a result, they offer insights into the primary pathogenesis of myocardial dysfunction. Large international registries have characterized the epidemiology, cause, and outcomes of pediatric cardiomyopathies. Although adult and pediatric cardiomyopathies have similar morphological and clinical manifestations, their outcomes differ significantly. Within 2 years of presentation, normalization of function occurs in 20% of children with dilated cardiomyopathy, and 40% die or undergo transplantation. Infants with hypertrophic cardiomyopathy have a 2-year mortality of 30%, whereas death is rare in older children. Sudden death is rare. Molecular evidence indicates that gene expression differs between adult and pediatric cardiomyopathies, suggesting that treatment response may differ as well. Clinical trials to support evidence-based treatments and the development of disease-specific therapies for pediatric cardiomyopathies are in their infancy. This compendium summarizes current knowledge of the genetic and molecular origins, clinical course, and outcomes of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02549664 and NCT01912534. PMID- 28912192 TI - Mechanical cervicAl ripeninG for women with PrOlongedPregnancies (MAGPOP): protocol for a randomised controlled trial of a silicone double balloon catheter versus the Propess system for the slow release of dinoprostone for cervical ripening of prolonged pregnancies. AB - INTRODUCTION: Induction of labour for prolonged pregnancies (PP) when the cervix is unfavourable is a challenging situation. Cervical ripening by pharmacological or mechanical techniques before oxytocin administration is used to increase the likelihood of vaginal delivery. Both techniques are equally effective in achieving vaginal delivery but excessive uterine activity, which induces fetal heart rate (FHR) anomalies, is more frequent after the pharmacological intervention. We hypothesised that mechanical cervical ripening could reduce the caesarean rate for non-reassuring FHR especially in PP where fetuses are already susceptible to this. METHODS AND ANALYSIS: A multicentre, superiority, open label, parallel-group, randomised controlled trial that aims to compare cervical ripening with a mechanical device (Cervical Ripening Balloon, Cook-Medical Europe, Ireland) inserted in standardised manner for 24 hours to pharmacological cervical ripening (Propess system for slow release system of 10 mg of dinoprostone, Ferring SAS, France) before oxytocin administration. Women (n=1220) will be randomised in a 1:1 ratio in 15 French units. Participants will be women with a singleton pregnancy, a vertex presentation, a term >=41+0 and<=42+0 week's gestation, and for whom induction of labour is planned. Women with a Bishop score >=6, a prior caesarean delivery, premature rupture of membranes or with any contraindication for vaginal delivery will be excluded. The primary endpoint is the caesarean rate for non-reassuring FHR. Secondary outcomes are related to delivery and perinatal morbidity. As study investigators and patients cannot be masked to treatment assignment, to compensate for the absence of blinding, an independent endpoint adjudication committee, blinded to group allocation, will determine whether the caesarean for non-reassuring FHR was justified. ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants. The Tours Research ethics committee has approved this study (2016-R23, 29 November 2016). Study findings will be submitted for publication and presented at relevant conferences. TRIAL REGISTRATION NUMBER: NCT02907060; pre-results. PMID- 28912191 TI - High versus low energy administration in the early phase of acute pancreatitis (GOULASH trial): protocol of a multicentre randomised double-blind clinical trial. AB - INTRODUCTION: Acute pancreatitis (AP) is an inflammatory disease with no specific treatment. Mitochondrial injury followed by ATP depletion in both acinar and ductal cells is a recently discovered early event in its pathogenesis. Importantly, preclinical research has shown that intracellular ATP delivery restores the physiological function of the cells and protects from cell injury, suggesting that restoration of energy levels in the pancreas is therapeutically beneficial. Despite several high quality experimental observations in this area, no randomised trials have been conducted to date to address the requirements for energy intake in the early phase of AP. METHODS/DESIGN: This is a randomised controlled two-arm double-blind multicentre trial. Patients with AP will be randomly assigned to groups A (30 kcal/kg/day energy administration starting within 24 hours of hospital admission) or B (low energy administration during the first 72 hours of hospital admission). Energy will be delivered by nasoenteric tube feeding with additional intravenous glucose supplementation or total parenteral nutrition if necessary. A combination of multiorgan failure for more than 48 hours and mortality is defined as the primary endpoint, whereas several secondary endpoints such as length of hospitalisation or pain will be determined to elucidate more detailed differences between the groups. The general feasibility, safety and quality checks required for high quality evidence will be adhered to. ETHICS AND DISSEMINATION: The study has been approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (55961-2/2016/EKU). This study will provide evidence as to whether early high energy nutritional support is beneficial in the clinical management of AP. The results of this trial will be published in an open access way and disseminated among medical doctors. TRIAL REGISTRATION: The trial has been registered at the ISRCTN (ISRTCN 63827758). PMID- 28912193 TI - Effectiveness of a multifactorial intervention based on an application for smartphones, heart-healthy walks and a nutritional workshop in patients with type 2 diabetes mellitus in primary care (EMID): study protocol for a randomised controlled trial. AB - INTRODUCTION: New information and communication technologies (ICTs) may promote lifestyle changes, but no adequate evidence is available on their combined effect of ICTs with multifactorial interventions aimed at improving diet and increasing physical activity in patients with type 2 diabetes mellitus (DM2). The primary objective of this study is to assess the effect of a multifactorial intervention to increase physical activity and adherence to Mediterranean diet in DM2. METHODS AND ANALYSIS: Study scope and population: The study will be conducted at 'La Alamedilla' primary care research unit in Salamanca (Spain). 200 patients with DM2 of both sexes, aged 25-70 years and who meet the inclusion criteria and sign the informed consent will be recruited. Each participant will attend the clinic at baseline and 3 and 12 months after intervention. INTERVENTION: Both groups will be given short advice on diet and physical activity. The intervention group will also take five heart-healthy walks and attend a group session on diet education and will be trained on use of an application for smartphone (EVIDENT II) for 3 months. VARIABLES AND MEASUREMENT INSTRUMENTS: The main study endpoints will be changes in physical activity, as assessed by a pedometer and the International Physical Activity Questionnaire, and adherence to the Mediterranean diet, as evaluated by an adherence questionnaire and the Diet Quality Index. Anthropometric parameters and laboratory values, lifestyles and quality of life will also be assessed. ETHICS AND DISSEMINATION: It was approved by the Clinical Research Ethics Committee of Salamanca on 28/11/2016. TRIAL REGISTRATION: NCT02991079; Pre-results. PMID- 28912194 TI - Assessing oral medication adherence among patients with type 2 diabetes mellitus treated with polytherapy in a developed Asian community: a cross-sectional study. AB - OBJECTIVES: The disease burden of type 2 diabetes mellitus (T2DM) is rising due to suboptimal glycaemic control leading to vascular complications. Medication adherence (MA) directly influences glycaemic control and clinical consequences. This study aimed to assess the MA of patients with T2DM and identify associated factors. DESIGN: Analysis of data from a cross-sectional survey and electronic medical records. SETTING: Primary care outpatient clinic in Singapore. PARTICIPANTS: Adult patients with T2DM. MAIN OUTCOME MEASURES: MA to each prescribed oral hypoglycaemic agent (OHA) was measured using the five-question Medication Adherence Report Scale (MARS-5). Low MA is defined as a MARS-R score of <25. Demographic data, clinical characteristics and investigation results were collected to identify factors that are associated with low MA. RESULTS: The study population comprised 382 patients with a slight female predominance (53.4%) and a mean+/-SD age of 62.0+/-10.4 years. 57.1% of the patients had low MA to at least one OHA. Univariate analysis showed that patients who were younger, of Chinese ethnicity, married or widowed, self-administering their medications or taking fewer (four or less) daily medications tended to have low MA to OHA. Logistic regression revealed that younger age (OR 0.97; 95% CI 0.95 to0.99), Chinese ethnicity (OR 2.80; 95% CI 1.53 to5.15) and poorer glycaemic control (HbA1c level) (OR 1.27; 95% CI 1.06 to1.51) were associated with low MA to OHA. CONCLUSIONS: Younger patients with T2DM and of Chinese ethnicity were susceptible to low MA to OHA, which was associated with poorer glycaemic control. Polytherapy was not associated with low MA. PMID- 28912196 TI - Correction: In patients presenting to the emergency department with skin and soft tissue infections what is the diagnostic accuracy of point-of-care ultrasonography for the diagnosis of abscess compared to the current standard of care? A systematic review and meta-analysis. PMID- 28912195 TI - Associations between participation in organised physical activity in the school or community outside school hours and neighbourhood play with child physical activity and sedentary time: a cross-sectional analysis of primary school-aged children from the UK. AB - OBJECTIVES: To assess the extent to which participation in organised physical activity in the school or community outside school hours and neighbourhood play was associated with children's physical activity and sedentary time. DESIGN: Cross-sectional study. SETTING: Children were recruited from 47 state-funded primary schools in South West England. PARTICIPANTS: 1223 children aged 8-9 years old. OUTCOME MEASURES: Accelerometer-assessed moderate-to-vigorous-intensity physical activity (MVPA) and sedentary time. METHODS: Children wore an accelerometer, and the mean minutes of MVPA and sedentary time per day were derived. Children reported their attendance at organised physical activity in the school or community outside school hours and neighbourhood play using a piloted questionnaire. Cross-sectional linear and logistic regression were used to examine if attendance frequency at each setting (and all settings combined) was associated with MVPA and sedentary time. Multiple imputation methods were used to account for missing data and increase sample size. RESULTS: Children who attended clubs at school 3-4 days per week obtained an average of 7.58 (95% CI 2.7 to 12.4) more minutes of MVPA per day than children who never attended. Participation in the three other non-school-based activities was similarly associated with MVPA. Evidence for associations with sedentary time was generally weaker. Associations were similar in girls and boys. When the four different contexts were combined, each additional one to two activities participated in per week increased participants' odds (OR: 1.18, 95% CI 1.12 to 1.25) of meeting the government recommendations for 60 min of MVPA per day. CONCLUSION: Participating in organised physical activity at school and in the community is associated with greater physical activity and reduced sedentary time among both boys and girls. All four types of activity contribute to overall physical activity, which provides parents with a range of settings in which to help their child be active. PMID- 28912197 TI - Standard admission order sets promote ordering of unnecessary investigations: a quasi-randomised evaluation in a simulated setting. PMID- 28912198 TI - Frequency of low-value care in Alberta, Canada: a retrospective cohort study. AB - OBJECTIVE: To determine how frequently 10 low-value services highlighted by Choosing Wisely are done and what factors influence their provision. METHODS: This is a retrospective cohort study using routinely collected health data from five linked data sets from 2012 to 2015 in the Canadian province of Alberta to determine the frequency with which 10 low-value services were provided. RESULTS: Between 2012 and 2015, 162 143 people (4% of all 3 814 536 adult Albertans and 5% of the 3 423 135 who saw a physician at least once in that time frame) received at least one of the 10 low-value services, including 29.8% of Albertans older than 75 years (57 811 of 194 068). The proportion of adults receiving low-value services ranged from carotid artery imaging in 0.1% of asymptomatic adults without cerebrovascular disease, to prostate-specific antigen (PSA) testing in 55.5% of men 75 years or older without a history of prostate cancer. Although age, Charlson scores and frequency of primary care visits were associated with low-value service provision, the directions of the association differed across services; however, higher socioeconomic status, increased frequency of specialist contact and higher ratio of specialists to primary care physicians in the patient's region were associated with an increased risk of receiving all of the low-value services we examined. The low-value services which resulted in the greatest costs to the healthcare system were cervical cancer screening in women older than 65 without history of cervical dysplasia or genital cancer, PSA testing in men older than 75 without history of prostate cancer and preoperative stress testing/cardiac imaging before non-cardiac surgery. CONCLUSIONS: Even within a universal coverage healthcare system, the proportion of patients receiving low-value services varied widely (from <0.1% to 56%). Increased use was associated with higher socioeconomic status, increased frequency of specialist contact and higher ratio of specialists to primary care physicians. PMID- 28912199 TI - Preprints and Cardiovascular Science: Prescient or Premature? PMID- 28912200 TI - Development and Validation of Electronic Quality Measures to Assess Care for Patients With Transient Ischemic Attack and Minor Ischemic Stroke. AB - BACKGROUND: Despite interest in using electronic health record (EHR) data to assess quality of care, the accuracy of such data is largely unknown. We sought to develop and validate transient ischemic attack and minor ischemic stroke electronic quality measures (eQMs) using EHR data. METHODS AND RESULTS: A random sample of patients with transient ischemic attack or minor ischemic stroke, cared for in Veterans Health Administration facilities (fiscal year 2011), was identified. We constructed 31 eQMs based on existing quality measures. Chart review was the criterion standard for validating the eQMs. To evaluate eQMs in terms of eligibility, we calculated the proportion of patients who were genuinely not eligible to receive a process (based on chart review) and who were correctly identified as not eligible by the EHR data (specificity). To assess eQMs about classification of whether patients received a process, we calculated the proportion of patients who actually received the process (based on chart review) and who were classified correctly by the EHR data as passing (sensitivity). Seven hundred sixty-three patients were included. About eligibility, specificity varied from 25% (brain imaging; carotid imaging) to 99% (anticoagulation quality). About pass rates, sensitivity varied from 30% (antihypertensive class) to 100% (coronary risk assessment; international normalized ratio measured). The 16 eQMs with >=70% specificity in eligibility and >=70% sensitivity in pass rates included coronary risk assessment, international normalized ratio measured, HbA1c measurement, speech language pathology consultation, anticoagulation for atrial fibrillation, discharge on statin, lipid management, neurology consultation, Holter, deep vein thrombosis prophylaxis, oral hypoglycemic intensification, cholesterol medication intensification, antihypertensive intensification, antihypertensive class, carotid stenosis intervention, and substance abuse referral for alcohol. CONCLUSIONS: It is feasible to construct valid eQMs for processes of transient ischemic attack and minor ischemic stroke care. Healthcare systems with EHRs should consider using electronic data to evaluate care for their patients with transient ischemic attack and to complement and expand quality measurement programs currently focused on patients with stroke. PMID- 28912201 TI - Race and Socioeconomic Differences Associated With Changes in Statin Eligibility Under the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines. AB - BACKGROUND: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines expanded eligibility criteria for statins. We examined race and socioeconomic differences associated with these changes. METHODS AND RESULTS: This was an observational study of adults between 40 and 75 years of age using data from the National Health and Nutrition Examination Surveys between 2005 and 2012. Change in eligibility for statins was assessed based on the third adult treatment panel criteria and the 2013 ACC/AHA guidelines. Differences relating to self-reported race, income, education, and insurance status were assessed in models that were adjusted for age and each of the other factors. Statin eligibility increased among all race, education, and income groups. Becoming newly eligible for statins was more likely for black people (25.8% newly eligible; adjusted odds ratio, 3.8; P<0.001), people of other races (18.7%; adjusted odds ratio, 2.5; P<0.001), those with no more than high-school education (17.3%; adjusted odds ratio, 1.7; P=0.001), and those with no health insurance (17.6%; adjusted odds ratio, 1.5; P<0.001) compared with white people (14.5%), those who completed college (13.0%), and those with health insurance (15.6%). Income differences were not significant after adjusting for age, race, and education. These differences were driven by the prevalence of elevated predicted cardiac risk and diabetes mellitus. Among the US adults who were newly eligible for statins, 12.4 million (66.3%) were nonwhite, had lower education or lower income, and 3.0 million (16.1%) had no health insurance. Race and socioeconomic differences in statin eligibility were more pronounced under the 2013 ACC/AHA guidelines than under third adult treatment panel. If treatment disparities remain unchanged, the 2013 ACC/AHA guidelines increase the number of US adults who are eligible but do not receive statins by 3.0 million nonwhites, 3.6 million with no more than high-school education, and 4.1 million in the lowest 2 income quartiles. CONCLUSIONS: The 2013 ACC/AHA guidelines increase statin eligibility most among adults with nonwhite race, socioeconomic disadvantage, and no health insurance. Without improving access to healthcare, the potential gains from expanding indications for cardioprotective medications will not be realized. PMID- 28912202 TI - Blockchain Technology: Applications in Health Care. PMID- 28912203 TI - Can Electronic Health Records Make Quality Measurement Fast and Easy? PMID- 28912204 TI - Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis. PMID- 28912205 TI - Epicardial Breakthrough Waves During Sinus Rhythm: Depiction of the Arrhythmogenic Substrate? AB - BACKGROUND: Epicardial breakthrough waves (EBW) during atrial fibrillation are important elements of the arrhythmogenic substrate and result from endo epicardial asynchrony, which also occurs to some degree during sinus rhythm (SR). We examined the incidence and characteristics of EBW during SR and its possible value in the detection of the arrhythmogenic substrate associated with atrial fibrillation. METHODS AND RESULTS: Intraoperative epicardial mapping (interelectrode distances 2 mm) of the right atrium, Bachmann's bundle, the left atrioventricular groove, and the pulmonary vein area was performed during SR in 381 patients (289 male, 67+/-10 years) with ischemic or valvular heart disease. EBW were referred to as sinus node breakthrough waves if they were the earliest right atrial activated site. A total of 218 EBW and 57 sinus node breakthrough waves were observed in 168 patients (44%). EBW mostly occurred at right atrium (N=105, 48%) and left atrioventricular groove (N=67, 31%), followed by Bachmann's bundle (N=27, 12%) and pulmonary vein area (N=19, 9%; P<0.001). EBW occurred most often in ischemic heart disease patients (N=114, 49%) compared with (ischemic and) valvular heart disease patients (N=26, 17%; P<0.001). EBW electrograms most often consisted of double and fractionated potentials (N=137, 63%). In case of single potentials, an R wave was observed in 88% (N=71) of EBW, as opposed to 21% of sinus node breakthrough waves (N=5; P<0.001). Fractionated EBW potentials were more often observed at the right atrium and Bachmann's bundle (P<0.001). CONCLUSIONS: During SR, EBW are present in over a third of patients, particularly in thicker parts of the atrial wall. Features of SR EBW indicate that muscular connections between endo- and epicardium underlie EBW and that a slight degree of endo-epicardial asynchrony required for EBW to occur is already present in some areas during SR. Hence, an anatomic substrate is present, which may enhance the occurrence of EBW during atrial fibrillation, thereby promoting atrial fibrillation persistence. PMID- 28912206 TI - Clinical Yield of Familial Screening After Sudden Death in Young Subjects: The French Experience. AB - BACKGROUND: After sudden cardiac death with negative autopsy, clinical screening of relatives identifies a high proportion of inherited arrhythmia syndrome. However, the efficacy of this screening in families not selected by autopsy has never been assessed. We aim to investigate the value of clinical screening in relatives of all subjects who died suddenly before 45 years of age. METHODS AND RESULTS: One hundred and three consecutive families who experienced unexplained sudden cardiac death before 45 years of age were included from May 2009 to December 2014 in a prospective multicenter registry. Clinical screening was provided to all relatives and performed in 64 families (230 relatives, 80 unexplained sudden cardiac death). Diagnosis was established in 16 families (25%), including Brugada syndrome (7), long QT syndromes (5), dilated cardiomyopathy (2), and hypertrophic cardiomyopathy (2). The diagnostic yield was mainly dependent on the number of screened relatives (3.8+/-3.4 screened relatives in diagnosed families versus 2.0+/-1.5; P<0.005) rising to 47% with at least 3 relatives. It additionally increased from 3 of 32 (9%) to 9 of 22 (41%) when both parents were screened (P=0.01). Diagnostic performance was also dependent on the exhaustiveness of screening (70% of complete screening in the diagnosed families versus 25%; P<0.0001) with 17 Brugada syndromes and 15 long QT syndromes diagnosed based on pharmacological tests. CONCLUSIONS: Even without autopsy, familial screening after sudden death in young patients is effective. Broad screening of relatives and systematic tests, including pharmacological challenges, greatly increases the likelihood of diagnosis in families. PMID- 28912207 TI - Propagation of Sinus Waves in the Atrial Architecture: When Laminar Electrical Fluxes Turn Turbulent. PMID- 28912208 TI - Efficacy of Familial Screening After Sudden Cardiac Death in Young Adults Irrespective of Postmortem Analysis: Implication of a Pharmacological Challenge as a First Step of Screening. PMID- 28912209 TI - Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification. PMID- 28912210 TI - Sex Differences in Clinical Characteristics, Psychosocial Factors, and Outcomes Among Patients With Stable Coronary Heart Disease: Insights from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial. AB - BACKGROUND: Greater understanding of differences between men and women with coronary heart disease is needed. METHODS AND RESULTS: In this post hoc analysis of the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, we described psychosocial factors, treatments, and outcomes of men versus women with stable coronary heart disease and explored the association of sex with psychosocial characteristics and cardiovascular risk. Cox proportional hazards models were used to assess the relationship between sex and outcomes. Interactions among sex, psychosocial factors, and the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were tested. Of 15 828 patients, 2967 (19%) were women. Among women, 21.2% felt often or always stressed at home (versus 9.8% of men), and 19.2% felt often or always sad or depressed (versus 10.1% of men; all P<0.0001). The median duration of follow-up was 3.7 years (25th-75th percentiles: 3.5-3.8 years). Use of evidence based medications for coronary heart disease at baseline and 24 months was similar between sexes, as were event rates for all outcomes analyzed. In the multivariable model including psychosocial measures, female sex was associated with lower cardiovascular risk. There was a statistically significant interaction (P=0.03) such that the lower risk in women varied by depressive symptom frequency, whereby women who were more depressed had a risk similar to men. CONCLUSIONS: Female sex was independently associated with better long-term clinical outcomes, although this was modified by frequency of depressive symptoms. This suggests that emotional state may be an important target for improving outcomes in patients with coronary heart disease, specifically in women. CLINICAL TRIAL REGISTRATION: STABILITY ClinicalTrials.gov number (NCT00799903). PMID- 28912211 TI - Body Mass Index Is Associated With Microvascular Endothelial Dysfunction in Patients With Treated Metabolic Risk Factors and Suspected Coronary Artery Disease. AB - BACKGROUND: Obesity is key feature of the metabolic syndrome and is associated with high cardiovascular morbidity and mortality. Obesity is associated with macrovascular endothelial dysfunction, a determinant of outcome in patients with coronary artery disease. Here, we compared the influence of obesity on microvascular endothelial function to that of established cardiovascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and smoking in patients with suspected coronary artery disease. METHODS AND RESULTS: Endothelial function was assessed during postocclusive reactive hyperemia of the brachial artery and downstream microvascular beds in 108 patients who were scheduled for coronary angiography. In all patients, microvascular vasodilation was assessed using peripheral arterial tonometry; laser Doppler flowmetry and digital thermal monitoring were performed. Body mass index was significantly associated with decreased endothelium-dependent vasodilatation measured with peripheral arterial tonometry (r=0.23, P=0.02), laser Doppler flowmetry (r=0.30, P<0.01), and digital thermal monitoring (r=0.30, P<0.01). In contrast, hypertension, hypercholesterolemia, and smoking had no influence on microvascular vasodilatation. Especially in diabetic patients, endothelial function was not significantly reduced (control versus diabetes mellitus, mean+/-SEM or median [interquartile range], peripheral arterial tonometry: 1.90+/-0.20 versus 1.67+/ 0.20, P=0.19, laser Doppler flowmetry: 728% [interquartile range, 427-1110] versus 589% [interquartile range, 320-1067] P=0.28, and digital thermal monitoring: 6.6+/-1.0% versus 2.5+/-1.7%, P=0.08). In multivariate linear regression analysis, body mass index was the only risk factor that significantly attenuated endothelium-dependent vasodilatation using all 3 microvascular function tests. CONCLUSIONS: Higher body mass index is associated with reduced endothelial function in patients with suspected coronary artery disease, even after adjustment for treated diabetes mellitus, hypertension, hypercholesterolemia, and smoking. PMID- 28912213 TI - Comment on "The complex effects of ocean acidification on the prominent N2-fixing cyanobacterium Trichodesmium". AB - Hong et al (Reports, 5 May 2017, p. 527) suggested that previous studies of the biogeochemically significant marine cyanobacterium Trichodesmium showing increased growth and nitrogen fixation at projected future high CO2 levels suffered from ammonia or copper toxicity. They reported that these rates instead decrease at high CO2 when contamination is alleviated. We present and discuss results of multiple published studies refuting this toxicity hypothesis. PMID- 28912212 TI - Risk Stratification Using the CHA2DS2-VASc Score in Takotsubo Syndrome: Data From the Takotsubo Italian Network. AB - BACKGROUND: The CHA2DS2-VASc score predicts stroke in patients with atrial fibrillation and has been reported to have a prognostic role even in acute coronary syndrome patients. The Takotsubo syndrome is a condition that mimics acute coronary syndrome and may present several complications including stroke. We sought to assess the ability of CHA2DS2-VASc score to predict adverse events in Takotsubo syndrome patients. METHODS AND RESULTS: Overall, 371 Takotsubo syndrome patients were enrolled in a prospective registry. Patients were divided into 3 groups according to the CHA2DS2-VASc score: Group A (<=1), B (2-3), and C (>=4). The median CHA2DS2-VASc score was 3 (interquartile range: 2-4). Overall, 9%, 42%, and 49% were included in Group A, B, and C, respectively. Follow-up length was 26+/-20 months. The mortality rate was 6%, 7%, and 17% in Group A, B, and C, respectively (P=0.011). The stroke rate was 3% and not different among the 3 groups. Estimated major adverse cardiac and cerebrovascular events (the composite of death, myocardial infarction, and stroke) rates in the 3 groups were 6%, 9%, and 17% in Group A, B, and C, respectively (P=0.033). The CHA2DS2-VASc score resulted as a predictor of major adverse cardiac and cerebrovascular events (odds ratio 2.1, 95% confidence interval, 1.2-3.6; P=0.01) and all-cause mortality (odds ratio 1.5, 95% confidence interval, 1.2-1.9; P=0.001). CONCLUSIONS: In Takotsubo syndrome, the CHA2DS2-VASc score allows prediction of cardiovascular events and mortality at long-term follow-up. PMID- 28912214 TI - Response to Comment on "The complex effects of ocean acidification on the prominent N2-fixing cyanobacterium Trichodesmium". AB - Hutchins et al question the validity of our results showing that under fast growth conditions, the beneficial effect of high CO2 on Trichodesmium is overwhelmed by the deleterious effect of the concomitant decrease in ambient and cellular pH. The positive effect of acidification reported by Hutchins and co workers is likely caused by culture conditions that support suboptimal growth rates. PMID- 28912217 TI - Cover stories: Making the neutrino scattering cover. PMID- 28912215 TI - The form and function of channelrhodopsin. AB - Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable for photosynthesis and survival. These plant behavioral responses were initially investigated more than 150 years ago. Recently, major principles of function for light-gated ion channels have been elucidated by creating channelrhodopsins with kinetics that are accelerated or slowed over orders of magnitude, by discovering and designing channelrhodopsins with altered spectral properties, by solving the high-resolution channelrhodopsin crystal structure, and by structural model-guided redesign of channelrhodopsins for altered ion selectivity. Each of these discoveries not only revealed basic principles governing the operation of light-gated ion channels, but also enabled the creation of new proteins for illuminating, via optogenetics, the fundamentals of brain function. PMID- 28912216 TI - A cargo-sorting DNA robot. AB - Two critical challenges in the design and synthesis of molecular robots are modularity and algorithm simplicity. We demonstrate three modular building blocks for a DNA robot that performs cargo sorting at the molecular level. A simple algorithm encoding recognition between cargos and their destinations allows for a simple robot design: a single-stranded DNA with one leg and two foot domains for walking, and one arm and one hand domain for picking up and dropping off cargos. The robot explores a two-dimensional testing ground on the surface of DNA origami, picks up multiple cargos of two types that are initially at unordered locations, and delivers them to specified destinations until all molecules are sorted into two distinct piles. The robot is designed to perform a random walk without any energy supply. Exploiting this feature, a single robot can repeatedly sort multiple cargos. Localization on DNA origami allows for distinct cargo sorting tasks to take place simultaneously in one test tube or for multiple robots to collectively perform the same task. PMID- 28912220 TI - Bot-hunters eye mischief in German election. PMID- 28912218 TI - Science of preparedness. PMID- 28912221 TI - NIH quietly shelves gun research program. PMID- 28912223 TI - Unusual quake rattles Mexico. PMID- 28912222 TI - 'Supergenes' drive evolution. PMID- 28912224 TI - Pay up or retract? Drug survey spurs conflict. PMID- 28912225 TI - Papua New Guinea's genetic diversity withstood farming. PMID- 28912226 TI - PETA targets early-career wildlife researcher. PMID- 28912227 TI - Keeping the faith. PMID- 28912228 TI - Neurons that drive and quench thirst. PMID- 28912229 TI - The refrigerant is also the pump. PMID- 28912230 TI - DNA robots sort as they walk. PMID- 28912231 TI - Crystal-clear memories of a bacterium. PMID- 28912232 TI - Scattering neutrinos caught in the act. PMID- 28912233 TI - Microbial mass movements. PMID- 28912234 TI - Without inclusion, diversity initiatives may not be enough. PMID- 28912236 TI - China must lead on emissions trading. PMID- 28912235 TI - Not just Salk. PMID- 28912237 TI - Carbon footprint of China's belt and road. PMID- 28912238 TI - Biological fabrication of cellulose fibers with tailored properties. AB - Cotton is a promising basis for wearable smart textiles. Current approaches that rely on fiber coatings suffer from function loss during wear. We present an approach that allows biological incorporation of exogenous molecules into cotton fibers to tailor the material's functionality. In vitro model cultures of upland cotton (Gossypium hirsutum) are incubated with 6-carboxyfluorescein-glucose and dysprosium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-glucose, where the glucose moiety acts as a carrier capable of traveling from the vascular connection to the outermost cell layer of the ovule epidermis, becoming incorporated into the cellulose fibers. This yields fibers with unnatural properties such as fluorescence or magnetism. Combining biological systems with the appropriate molecular design offers numerous possibilities to grow functional composite materials and implements a material-farming concept. PMID- 28912239 TI - DNA sequence-directed shape change of photopatterned hydrogels via high-degree swelling. AB - Shape-changing hydrogels that can bend, twist, or actuate in response to external stimuli are critical to soft robots, programmable matter, and smart medicine. Shape change in hydrogels has been induced by global cues, including temperature, light, or pH. Here we demonstrate that specific DNA molecules can induce 100-fold volumetric hydrogel expansion by successive extension of cross-links. We photopattern up to centimeter-sized gels containing multiple domains that undergo different shape changes in response to different DNA sequences. Experiments and simulations suggest a simple design rule for controlled shape change. Because DNA molecules can be coupled to molecular sensors, amplifiers, and logic circuits, this strategy introduces the possibility of building soft devices that respond to diverse biochemical inputs and autonomously implement chemical control programs. PMID- 28912240 TI - Highly efficient electrocaloric cooling with electrostatic actuation. AB - Solid-state refrigeration offers potential advantages over traditional cooling systems, but few devices offer high specific cooling power with a high coefficient of performance (COP) and the ability to be applied directly to surfaces. We developed a cooling device with a high intrinsic thermodynamic efficiency using a flexible electrocaloric (EC) polymer film and an electrostatic actuation mechanism. Reversible electrostatic forces reduce parasitic power consumption and allow efficient heat transfer through good thermal contacts with the heat source or heat sink. The EC device produced a specific cooling power of 2.8 watts per gram and a COP of 13. The new cooling device is more efficient and compact than existing surface-conformable solid-state cooling technologies, opening a path to using the technology for a variety of practical applications. PMID- 28912241 TI - Soft x-ray excitonics. AB - The dynamic response of excitons in solids is central to modern condensed-phase physics, material sciences, and photonic technologies. However, study and control have hitherto been limited to photon energies lower than the fundamental band gap. Here we report application of attosecond soft x-ray and attosecond optical pulses to study the dynamics of core-excitons at the L2,3 edge of Si in silicon dioxide (SiO2). This attosecond x-ray absorption near-edge spectroscopy (AXANES) technique enables direct probing of the excitons' quasiparticle character, tracking of their subfemtosecond relaxation, the measurement of excitonic polarizability, and observation of dark core-excitonic states. Direct measurement and control of core-excitons in solids lay the foundation of x-ray excitonics. PMID- 28912242 TI - Fabrication of fillable microparticles and other complex 3D microstructures. AB - Three-dimensional (3D) microstructures created by microfabrication and additive manufacturing have demonstrated value across a number of fields, ranging from biomedicine to microelectronics. However, the techniques used to create these devices each have their own characteristic set of advantages and limitations with regards to resolution, material compatibility, and geometrical constraints that determine the types of microstructures that can be formed. We describe a microfabrication method, termed StampEd Assembly of polymer Layers (SEAL), and create injectable pulsatile drug-delivery microparticles, pH sensors, and 3D microfluidic devices that we could not produce using traditional 3D printing. SEAL allows us to generate microstructures with complex geometry at high resolution, produce fully enclosed internal cavities containing a solid or liquid, and use potentially any thermoplastic material without processing additives. PMID- 28912243 TI - Thirst-associated preoptic neurons encode an aversive motivational drive. AB - Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic labeling to characterize neurons activated by water deprivation in the hypothalamic median preoptic nucleus (MnPO). Single-cell transcriptional profiling revealed that dehydration-activated MnPO neurons consist of a single excitatory cell type. After optogenetic activation of these neurons, mice drank water and performed an operant lever-pressing task for water reward with rates that scaled with stimulation frequency. This stimulation was aversive, and instrumentally pausing stimulation could reinforce lever-pressing. Activity of these neurons gradually decreased over the course of an operant session. Thus, the activity of dehydration-activated MnPO neurons establishes a scalable, persistent, and aversive internal state that dynamically controls thirst motivated behavior. PMID- 28912246 TI - The sustainable scientist. PMID- 28912245 TI - A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea. AB - New Guinea shows human occupation since ~50 thousand years ago (ka), independent adoption of plant cultivation ~10 ka, and great cultural and linguistic diversity today. We performed genome-wide single-nucleotide polymorphism genotyping on 381 individuals from 85 language groups in Papua New Guinea and find a sharp divide originating 10 to 20 ka between lowland and highland groups and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 thousand years, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in Papua New Guinea is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies. PMID- 28912244 TI - Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. AB - Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDL expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria. PMID- 28912247 TI - miR-212 mediates counter-regulation on CRH expression and HPA axis activity in male mice. AB - The mechanisms of hypothalamic-pituitary-adrenal (HPA) axis regulation have been studied persistently but still are not elucidated. Considering the emerging roles of microRNA in stress response, we conducted a microRNA microarray in mice hypothalamus to identify the potential role of microRNAs in regulating the HPA axis. In total, 41 microRNAs changed during heat stress in which we found that miR-212 contains a binding sequence with corticotropin-releasing hormone (Crh) 3'UTR according to a sequence analysis. We observed that miR-212 expression in the hypothalamus was escalated by repeated heat and restraint stress. By overexpression or inhibition of miR-212 and the dual-luciferase reporter assay, we proved that miR-212 could bind with Crh 3'UTR to regulate its expression in mice hypothalamus primary cells and in the hippocampus neuron cell line HT-22. In addition, we injected miR-212 agomir or antagomir in mice hypothalamus to overexpress or inhibit miR-212, which leads to alterations of CRH expression and HPA axis activity in vivo Furthermore, miR-212 and CRH were both transcribed by the cAMP response element-binding protein (CREB). Overexpression and inhibition of miR-212 affect CREB-dependent CRH expression. Taken together, our results suggest an inhibitory role of miR-212 on the HPA axis, which acts in a counter regulatory manner. PMID- 28912248 TI - Multi-Disciplinary Vascular Access Care and Access Outcomes in People Starting Hemodialysis Therapy. AB - BACKGROUND AND OBJECTIVES: Fistulas, the preferred form of hemodialysis access, are difficult to establish and maintain. We examined the effect of a multidisciplinary vascular access team, including nurses, surgeons, and radiologists, on the probability of using a fistula catheter-free, and rates of access-related procedures in incident patients receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined vascular access outcomes in the first year of hemodialysis treatment before (2004-2005, preteam period) and after the implementation of an access team (2006-2008, early-team period; 2009 2011, late-team period) in the Calgary Health Region, Canada. We used logistic regression to study the probability of fistula creation and the probability of catheter-free fistula use, and negative binomial regression to study access related procedure rates. RESULTS: We included 609 adults (mean age, 65 [+/-15] years; 61% men; 54% with diabetes). By the end of the first year of hemodialysis, 102 participants received a fistula in the preteam period (70%), 196 (78%) in the early-team period (odds ratios versus preteam, 1.47; 95% confidence interval, 0.92 to 2.35), and 139 (66%) in the late-team period (0.85; 0.54 to 1.35). Access team implementation did not affect the probability of catheter-free use of the fistula (odds ratio, 0.87; 95% confidence interval, 0.52 to 1.43, for the early; and 0.89; 0.52 to 1.53, for the late team versus preteam period). Participants underwent an average of 4-5 total access-related procedures during the first year of hemodialysis, with higher rates in women and in people with comorbidities. Catheter-related procedure rates were similar before and after team implementation; relative to the preteam period, fistula-related procedure rates were 40% (20%-60%) and 30% (10%-50%) higher in the early-team and late-team periods, respectively. CONCLUSION: Introduction of a multidisciplinary access team did not increase the probability of catheter-free fistula use, but resulted in higher rates of fistula-related procedures. PMID- 28912249 TI - Preoperative staging of cholangiocarcinoma and biliary carcinoma using 18F fluorodeoxyglucose positron emission tomography: a meta-analysis. AB - This meta-analysis was performed to determine the diagnostic accuracy of 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in assessing primary cholangiocarcinoma (CCA) and CCA with lymph node and distant metastasis. A literature search for studies reporting the use of 18F-FDG-PET for preoperative work-up/staging in patients with CCA was performed. Diagnostic OR (DOR) was used as an index of diagnostic performance of FDG-PET/CT in predicting primary CCA, lymph node metastases, and distant metastases. The pooled DOR was 9.34 (95% CI 4.27 to 20.42) and the area under the summary receiver operating characteristic (SROC) curve was 0.8643 (SE=0.0362), indicating overall good discriminatory test performance in predicting primary CCA. Subgroup analyses based on the primary tumor site showed better diagnostic performance for intrahepatic CCA (DOR=54.44, 95% CI 13.44 to 220.49), both intrahepatic and extrahepatic CCA (DOR=32.96, 95% CI 1.41 to 768.80) and gallbladder cancer (DOR=12.93, 95% CI 1.97 to 84.80), than for extrahepatic CCA (DOR=2.55, 95% CI 0.71 to 9.20) and hilar CCA (DOR=2.75, 95% CI 0.17 to 43.72). The pooled DOR for the prediction of lymph nodes metastases in 10 studies was 11.34 (95% CI 4.79 to 26.80), with moderate heterogeneity (Cochran Q=15.14, p=0.0872, I2=40.5%). The area under the SROC curve was 0.8584 (SE=0.0729). In conclusion, 18F-FDG-PET and PET/CT were found to be accurate in the evaluation of primary tumors, lymph node metastasis, and distant metastasis in patients with CCA. PMID- 28912251 TI - Neuroimmune interaction and the regulation of intestinal immune homeostasis. AB - Many essential gastrointestinal functions, including motility, secretion, and blood flow, are regulated by the autonomic nervous system (ANS), both through intrinsic enteric neurons and extrinsic (sympathetic and parasympathetic) innervation. Recently identified neuroimmune mechanisms, in particular the interplay between enteric neurons and muscularis macrophages, are now considered to be essential for fine-tuning peristalsis. These findings shed new light on how intestinal immune cells can support enteric nervous function. In addition, both intrinsic and extrinsic neural mechanisms control intestinal immune homeostasis in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. In this mini-review, we discuss recent insights on immunomodulation by intrinsic enteric neurons and extrinsic innervation, with a particular focus on intestinal macrophages. In addition, we discuss the relevance of these novel mechanisms for intestinal immune homeostasis in physiological and pathological conditions, mainly focusing on motility disorders (gastroparesis and postoperative ileus) and inflammatory disorders (colitis). PMID- 28912250 TI - Role of MicroRNA-423-5p in posttranscriptional regulation of the intestinal riboflavin transporter-3. AB - Riboflavin (RF) is essential for normal cellular functions and health. Humans obtain RF from exogenous sources via intestinal absorption that involves a highly specific carrier-mediated process. We have recently established that the riboflavin transporter-3 (RFVT3) is vital for the normal intestinal RF uptake process and have characterized certain aspects of its transcriptional regulation. Little is known, however, about how this transporter is regulated at the posttranscriptional level. We address this issue by focusing on the role of microRNAs. Using bioinformatics, we identified two potential interacting miRNAs with the human (h) RFVT3-3'-UTR, and showed (using pmirGLO-hRFVT3-3'-UTR) that the hRFVT3-3'-UTR is, indeed, a target for miRNA effect. Of the two putative miRNAs identified, miR-423-5p was found to be highly expressed in intestinal epithelial cells and that its mimic affected luciferase reporter activity of the pmirGLO-hRFVT3-3'-UTR construct, and also led to inhibition in RF uptake by intestinal epithelial Caco-2 and HuTu-80 cells. Furthermore, cells transfected with mutated seed sequences for miR-423-5p showed an abrogation in inhibitory effect of the miR-423-5p mimic on luciferase activity. While miR-423-5p did not affect the level of expression of the hRFVT3 mRNA, it did lead to a significant inhibition in the level of expression of its protein. Similarly, miR-423-5p was found to affect the level of expression of the mouse RFVT3 in cultured intestinal enteroids. These findings demonstrate, for the first time, that the RFVT3 is a target for posttranscriptional regulation by miRNAs in intestinal epithelial cells and that this regulation has functional consequences on intestinal RF uptake.NEW & NOTEWORTHY Our findings show for the first time that RFVT3 is a target for posttranscriptional regulation by miR-423-5p in intestinal epithelial cells, and this regulation has functional consequences on intestinal riboflavin (RF) uptake process. PMID- 28912252 TI - Time for action on deprivation in accessing cancer treatment in the UK. PMID- 28912253 TI - Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions. AB - Panobinostat (Farydak) is an orally active hydroxamic acid-derived histone deacetylase inhibitor used for the treatment of relapsed or refractory multiple myeloma. Based on recombinant cytochrome P450 (P450) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was mediated primarily by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also an in vitro reversible and time-dependent inhibitor of CYP3A4/5 and a reversible inhibitor of CYP2D6 and CYP2C19. Based on a previous clinical drug drug interaction study with ketoconazole (KTZ), the contribution of CYP3A4 in vivo was estimated to be ~40%. Using clinical pharmacokinetic (PK) data from several trials, including the KTZ drug-drug interaction (DDI) study, a physiologically based pharmacokinetic (PBPK) model was built to predict panobinostat PK after single and multiple doses (within 2-fold of observed values for most trials) and the clinical DDI with KTZ (predicted and observed area under the curve ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer rifampin (RIF) and the sensitive CYP3A4 substrate midazolam (MDZ) in lieu of clinical trials. Panobinostat exposure was predicted to decrease in the presence of RIF (65%) and inconsequentially increase MDZ exposure (4%). Additionally, PBPK modeling was used to examine the effects of stomach pH on the absorption of panobinostat in humans and determined that absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies were incorporated into the Food and Drug Administration-approved product label, providing guidance for panobinostat dosing recommendations when it is combined with other drugs. PMID- 28912255 TI - Sex hormones and the development of sexual size dimorphism: 5alpha dihydrotestosterone inhibits growth in a female-larger lizard (Sceloporus undulatus). AB - Sexual differences in adult body size [sexual size dimorphism (SSD)] and color (sexual dichromatism) are widespread, and both male- and female-biased dimorphisms are observed even among closely related species. A growing body of evidence indicates testosterone can regulate growth, thus the development of SSD, and sexual dichromatism. However, the mechanism(s) underlying these effects are conjectural, including possible conversions of testosterone to estradiol (E2) or 5alpha-dihydrotestosterone (DHT). In the present study, we hypothesized that the effects of testosterone are physiological responses mediated by androgen receptors, and we tested two specific predictions: (1) that DHT would mimic the effects of testosterone by inhibiting growth and enhancing coloration, and (2) that removal of endogenous testosterone via surgical castration would stimulate growth. We also hypothesized that females share downstream regulatory networks with males and predicted that females and males would respond similarly to DHT. We conducted experiments on eastern fence lizards (Sceloporus undulatus), a female-larger species with striking sexual dichromatism. We implanted Silastic(r) tubules containing 150 ug DHT into intact females and intact and castrated males. We measured linear growth rates and quantified color for ventral and dorsal surfaces. We found that DHT decreased growth rate and enhanced male-typical coloration in both males and females. We also found that, given adequate time, castration alone is sufficient to stimulate growth rate in males. The results presented here suggest that: (1) the effects of testosterone on growth and coloration are mediated by androgen receptors without requiring aromatization of testosterone into E2, and (2) females possess the androgen-receptor-mediated regulatory networks required for initiating male-typical inhibition of growth and enhanced coloration in response to androgens. PMID- 28912256 TI - Mitochondrial capacity, oxidative damage and hypoxia gene expression are associated with age-related division of labor in honey bee (Apis mellifera L.) workers. AB - During adult life, honey bee workers undergo a succession of behavioral states. Nurse bees perform tasks inside the nest, and when they are about 2-3 weeks old they initiate foraging. This switch is associated with alterations in diet, and with the levels of juvenile hormone and vitellogenin circulating in hemolymph. It is not clear whether this behavioral maturation involves major changes at the cellular level, such as mitochondrial activity and the redox environment in the head, thorax and abdomen. Using high-resolution respirometry, biochemical assays and RT-qPCR, we evaluated the association of these parameters with this behavioral change. We found that tissues from the head and abdomen of nurses have a higher oxidative phosphorylation capacity than those of foragers, while for the thorax we found the opposite situation. As higher mitochondrial activity tends to generate more H2O2, and H2O2 is known to stabilize HIF-1alpha, this would be expected to stimulate hypoxia signaling. The positive correlation that we observed between mitochondrial activity and hif-1alpha gene expression in abdomen and head tissue of nurses would be in line with this hypothesis. Higher expression of antioxidant enzyme genes was observed in foragers, which could explain their low levels of protein carbonylation. No alterations were seen in nitric oxide (NO) levels, suggesting that NO signaling is unlikely to be involved in behavioral maturation. We conclude that the behavioral change seen in honey bee workers is reflected in differential mitochondrial activities and redox parameters, and we consider that this can provide insights into the underlying aging process. PMID- 28912257 TI - Nurse honeybee workers tend capped brood, which does not require feeding, around the clock. AB - 'Nurse' honeybees tend brood around the clock with attenuated or no circadian rhythms, but the brood signals inducing this behavior remain elusive. We first tested the hypothesis that worker circadian rhythms are regulated by brood pheromones. We monitored locomotor activity of individually isolated nurse bees that were exposed to either various doses of larval extract or synthetic brood ester pheromone (BEP). Bees orally treated with larval extract showed attenuated circadian rhythms in one of four tested colonies; a similar but statistically non significant trend was seen in two additional colonies. Nurse bees treated with synthetic BEP showed rhythm attenuation in one of three tested colonies. Next, we tested the hypothesis that capped brood, which does not require feeding, nevertheless induces around-the-clock activity in nurses. By combining a new protocol that enables brood care by individually isolated nurse bees, detailed behavioral observations and automatic high-resolution monitoring of locomotor activity, we found that isolated nurses tended capped brood around the clock with attenuated circadian rhythms. Bees individually isolated in similar cages but without brood showed strong circadian rhythms in locomotor activity and rest. This study shows for the first time that the need to feed hungry larvae is not the only factor accounting for around-the-clock activity in nurse bees. Our results further suggest that the transition between activity with and without circadian rhythms is not a simple switch triggered by brood pheromones. Around the-clock tending may enhance brood development and health in multiple ways that include improved larval feeding, thermoregulation or hygienic behavior. PMID- 28912258 TI - Frank-Starling mechanism and short-term adjustment of cardiac flow. AB - The Frank-Starling law of the heart is a filling-force mechanism (FFm), a positive relationship between the distension of a ventricular chamber and its force of ejection, and such a mechanism is found across all the studied vertebrate lineages. The functioning of the cardiovascular system is usually described by means of the cardiac and vascular functions, the former related to the contractility of the heart and the latter related to the afterload imposed on the ventricle. The crossing of these functions is the so-called 'operation point', and the FFm is supposed to play a stabilizing role for the short-term variations in the working of the system. In the present study, we analyze whether the FFm is truly responsible for such a stability within two different settings: one-ventricle and two-ventricle hearts. To approach the query, we linearized the region around an arbitrary operation point and put forward a dynamical system of differential equations to describe the relationship among volumes in face of blood flows governed by pressure differences between compartments. Our results show that the FFm is not necessary to give stability to an operation point. Thus, which forces selected and maintained such a mechanism in all vertebrates? The present results indicate three different and complementary roles for the FFm: (1) it decreases the demands of a central controlling system over the circulatory system; (2) it smooths out perturbations in volumes; and (3) it guarantees faster transitions between operation points, i.e. it allows for rapid changes in cardiac output. PMID- 28912259 TI - NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis. AB - BACKGROUND: The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS: Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3 induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1beta (interleukin-1beta) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS: NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis. PMID- 28912260 TI - Decoupling Between Diastolic Pulmonary Artery Pressure and Pulmonary Capillary Wedge Pressure as a Prognostic Factor After Continuous Flow Ventricular Assist Device Implantation. AB - BACKGROUND: A cohort of heart failure (HF) patients receiving left ventricular assist devices (LVADs) has decoupling of their diastolic pulmonary artery pressure and pulmonary capillary wedge pressure. However, the clinical implications of this decoupling remain unclear. METHODS AND RESULTS: In this prospective study, patients with LVADs underwent routine invasive hemodynamic ramp testing with right heart catheterization, during which LVAD speeds were adjusted. Inappropriate decoupling was defined as a >5 mm Hg difference between diastolic pulmonary artery pressure and pulmonary capillary wedge pressure. The primary outcomes of survival and heart failure readmission rates after ramp testing were assessed. Among 63 LVAD patients (60+/-12 years old and 25 female [40%]), 27 patients (43%) had inappropriate decoupling at their baseline speed. After adjustment of their rotation speed during ramp testing, 30 patients (48%) had inappropriate decoupling. Uni/multivariable Cox analyses demonstrated that decoupling was the only significant predictor for the composite end point of death and heart failure readmission during the 1 year following the ramp study (total of 18 events; hazards ratio, 1.09; 95% confidence interval, 1.04-1.24; P<0.05). Furthermore, normalization of decoupling (n=8) during ramp testing was significantly associated with higher 1-year heart failure readmission-free survival rate compared with the non-normalized group (n=19, 100% versus 53%; P=0.035). CONCLUSIONS: The presence of inappropriate decoupling was associated with worse outcomes in patients with LVADs. Prospective, large-scale multicenter studies to validate the result are warranted. PMID- 28912261 TI - Preoperative Pectoralis Muscle Quantity and Attenuation by Computed Tomography Are Novel and Powerful Predictors of Mortality After Left Ventricular Assist Device Implantation. AB - BACKGROUND: Skeletal muscle mass decreases in end-stage heart failure and is predictive of clinical outcomes in several disease states. Skeletal muscle attenuation and quantity as quantified on preoperative chest computed tomographic scans may be predictive of mortality after continuous flow (CF) left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: A single-center continuous flow-LVAD database (n=354) was used to identify patients with chest computed tomographies performed in the 3 months before LVAD implantation (n=143). Among patients with computed tomography data available, unilateral pectoralis muscle mass indexed to body surface area and attenuation (approximated by mean Hounsfield units [PHUm]) were measured in each patient with a high intrarater and inter-rater reliability (intraclass correlation coefficients 0.98 and 0.97, respectively). Multivariate Cox regression analyses were performed, censoring at cardiac transplantation, to assess the impact of preoperative pectoralis muscle index and pectoralis muscle mean Hounsfield unit on survival after LVAD implantation. Each unit increase in pectoralis muscle index was associated with a 27% reduction in the hazard of death after LVAD (adjusted hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P=0.007). Each 5-U increase in pectoralis muscle mean Hounsfield unit was associated with a 22% reduction in the hazard of death after LVAD (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.89; P<0.0001). Pectoralis muscle index and pectoralis muscle mean Hounsfield unit outperformed other traditional measures in the data set, including the HeartMate II risk score. CONCLUSIONS: Pectoralis muscle size and attenuation were powerful predictors of outcomes after LVAD implantation in this data set. This one time, repeatable, internal assessment of patient substrate added valuable prognostic information that was not available on standard preoperative testing. PMID- 28912262 TI - Diastolic Pressure Difference to Classify Pulmonary Hypertension in the Assessment of Heart Transplant Candidates. AB - BACKGROUND: The diastolic pressure difference (DPD) is recommended to differentiate between isolated postcapillary and combined pre-/postcapillary pulmonary hypertension (Cpc-PH) in left heart disease (PH-LHD). However, in usual practice, negative DPD values are commonly calculated, potentially related to the use of mean pulmonary artery wedge pressure (PAWP). We used the ECG to gate late diastolic PAWP measurements. We examined the method's impact on calculated DPD, PH-LHD subclassification, hemodynamic profiles, and mortality. METHODS AND RESULTS: We studied patients with advanced heart failure undergoing right heart catheterization to assess cardiac transplantation candidacy (N=141). Pressure tracings were analyzed offline over 8 to 10 beat intervals. Diastolic pulmonary artery pressure and mean PAWP were measured to calculate the DPD as per usual practice (diastolic pulmonary artery pressure-mean PAWP). Within the same intervals, PAWP was measured gated to the ECG QRS complex to calculate the QRS gated DPD (diastolic pulmonary artery pressure-QRS-gated PAWP). Outcomes occurring within 1 year were collected retrospectively from chart review. Overall, 72 of 141 cases demonstrated PH-LHD. Within PH-LHD, the QRS-gated DPD yielded higher calculated DPD values (3 [-1 to 6] versus 0 [-4 to 3] mm Hg; P<0.01) and a greater proportion of Cpc-PH (24% versus 8%; P<0.01) versus the usual practice DPD. Cases reclassified as Cpc-PH based on QRS-gated DPD demonstrated higher pulmonary arterial pressures versus isolated postcapillary pulmonary hypertension (P<0.05). One-year mortality was similar between PH-LHD groups. CONCLUSIONS: The DPD calculated in usual practice is underestimated in PH LHD, which may classify Cpc-PH patients as isolated postcapillary pulmonary hypertension. The QRS-gated DPD reclassifies a subset of PH-LHD patients from isolated postcapillary pulmonary hypertension to Cpc-PH, which is characterized by an adverse hemodynamic profile. PMID- 28912263 TI - Hemodynamic Phenotyping of Pulmonary Hypertension in Left Heart Failure. AB - Increased pulmonary venous pressure secondary to left heart disease is the most common cause of pulmonary hypertension (PH). The diagnosis of PH due to left heart disease relies on a clinical probability assessment followed by the invasive measurements of a mean pulmonary artery pressure (PAP) >=25 mm Hg and mean wedged PAP (PAWP) >15 mm Hg. A combination of mean PAP and mean PAWP defines postcapillary PH. Postcapillary PH is generally associated with a diastolic pulmonary pressure gradient (diastolic PAP minus mean PAWP) <7 mm Hg, a transpulmonary pressure gradient (mean PAP minus mean PAWP) <12 mm Hg, and pulmonary vascular resistance <=3 Wood units (WU). This combination of criteria defines isolated postcapillary PH. Postcapillary PH with elevated vascular gradients and pulmonary vascular resistance defines combined post- and precapillary PH (Cpc-PH). Postcapillary PH is associated with a decreased survival in proportion to increased pulmonary vascular gradients, decreased pulmonary arterial compliance, and reduced right ventricular function. The Cpc-PH subcategory occurs in 12% to 13% of patients with PH due to left heart disease. Patients with Cpc-PH have severe PH, with higher diastolic pulmonary pressure gradient, transpulmonary pressure gradient, and pulmonary vascular resistance and more pronounced ventilatory responses to exercise, lower pulmonary arterial compliance, depressed right ventricular ejection fraction, and shorter life expectancy than isolated postcapillary PH. Cpc-PH bears similarities to pulmonary arterial hypertension. Whether Cpc-PH is amenable to therapies targeting the pulmonary circulation remains to be tested by properly designed randomized controlled trials. PMID- 28912264 TI - What We Talk About When We Talk About the Wedge Pressure. PMID- 28912265 TI - Editor's Perspective. PMID- 28912266 TI - Lysine trimethylation regulates 78-kDa glucose-regulated protein proteostasis during endoplasmic reticulum stress. AB - The up-regulation of chaperones such as the 78-kDa glucose-regulated protein (GRP78, also referred to as BiP or HSPA5) is part of the adaptive cellular response to endoplasmic reticulum (ER) stress. GRP78 is widely used as a marker of the unfolded protein response, associated with sustained ER stress. Here we report the discovery of a proteostatic mechanism involving GRP78 trimethylation in the context of ER stress. Using mass spectrometry-based proteomics, we identified two GRP78 fractions, one homeostatic and one induced by ER stress. ER stress leads to de novo biosynthesis of non-trimethylated GRP78, whereas homeostatic, METTL21A-dependent lysine 585-trimethylated GRP78 is reduced. This proteostatic mechanism, dependent on the posttranslational modification of GRP78, allows cells to differentially regulate specific protein abundance during cellular stress. PMID- 28912267 TI - Antitumor immunity is defective in T cell-specific microRNA-155-deficient mice and is rescued by immune checkpoint blockade. AB - MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional KO mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote IFNgamma production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage expression of IFNgamma-inducible genes. We also found that immune checkpoint-blocking (ICB) antibodies against programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) restored antitumor immunity in miR-155 T cell-conditional KO mice. We noted that these ICB antibodies rescued the levels of IFNgamma-expressing T cells, expression of multiple activation and effector genes expressed by tumor-infiltrating CD8+ and CD4+ T cells, and tumor associated macrophage activation. Moreover, the ICB approach partially restored expression of several derepressed miR-155 targets in tumor-infiltrating, miR-155 deficient CD8+ T cells, suggesting that miR-155 and ICB regulate overlapping pathways to promote antitumor immunity. Taken together, our findings highlight the multifaceted role of miR-155 in T cells, in which it promotes antitumor immunity. These results suggest that the augmentation of miR-155 expression could be used to improve anticancer immunotherapies. PMID- 28912268 TI - Structural and functional diversity in Listeria cell wall teichoic acids. AB - Wall teichoic acids (WTAs) are the most abundant glycopolymers found on the cell wall of many Gram-positive bacteria, whose diverse surface structures play key roles in multiple biological processes. Despite recent technological advances in glycan analysis, structural elucidation of WTAs remains challenging due to their complex nature. Here, we employed a combination of ultra-performance liquid chromatography-coupled electrospray ionization tandem-MS/MS and NMR to determine the structural complexity of WTAs from Listeria species. We unveiled more than 10 different types of WTA polymers that vary in their linkage and repeating units. Disparity in GlcNAc to ribitol connectivity, as well as variable O-acetylation and glycosylation of GlcNAc contribute to the structural diversity of WTAs. Notably, SPR analysis indicated that constitution of WTA determines the recognition by bacteriophage endolysins. Collectively, these findings provide detailed insight into Listeria cell wall-associated carbohydrates, and will guide further studies on the structure-function relationship of WTAs. PMID- 28912269 TI - Glycoprotein A repetitions predominant (GARP) positively regulates transforming growth factor (TGF) beta3 and is essential for mouse palatogenesis. AB - Glycoprotein A repetitions predominant (GARP) (encoded by the Lrrc32 gene) plays important roles in cell-surface docking and activation of TGFbeta. However, GARP's role in organ development in mammalian systems is unclear. To determine the function of GARP in vivo, we generated a GARP KO mouse model. Unexpectedly, the GARP KO mice died within 24 h after birth and exhibited defective palatogenesis without apparent abnormalities in other major organs. Furthermore, we observed decreased apoptosis and SMAD2 phosphorylation in the medial edge epithelial cells of the palatal shelf of GARP KO embryos at embryonic day 14.5 (E14.5), indicating a defect in the TGFbeta signaling pathway in the GARP-null developing palates. Of note, the failure to develop the secondary palate and concurrent reduction of SMAD phosphorylation without other defects in GARP KO mice phenocopied TGFbeta3 KO mice, although GARP has not been suggested previously to interact with TGFbeta3. We found that GARP and TGFbeta3 co-localize in medial edge epithelial cells at E14.5. In vitro studies confirmed that GARP and TGFbeta3 directly interact and that GARP is indispensable for the surface expression of membrane-associated latent TGFbeta3. Our findings indicate that GARP is essential for normal morphogenesis of the palate and demonstrate that GARP plays a crucial role in regulating TGFbeta3 signaling during embryogenesis. In conclusion, we have uncovered a novel function of GARP in positively regulating TGFbeta3 activation and function. PMID- 28912270 TI - The periplasmic transaminase PtaA of Pseudomonas fluorescens converts the glutamic acid residue at the pyoverdine fluorophore to alpha-ketoglutaric acid. AB - The periplasmic conversion of ferribactin to pyoverdine is essential for siderophore biogenesis in fluorescent pseudomonads, such as pathogenic Pseudomonas aeruginosa or plant growth-promoting Pseudomonas fluorescens The non ribosomal peptide ferribactin undergoes cyclizations and oxidations that result in the fluorophore, and a strictly conserved fluorophore-bound glutamic acid residue is converted to a range of variants, including succinamide, succinic acid, and alpha-ketoglutaric acid residues. We recently discovered that the pyridoxal phosphate-containing enzyme PvdN is responsible for the generation of the succinamide, which can be hydrolyzed to succinic acid. Based on this, a distinct unknown enzyme was postulated to be responsible for the conversion of the glutamic acid to alpha-ketoglutaric acid. Here we report the identification and characterization of this enzyme in P. fluorescens strain A506. In silico analyses indicated a periplasmic transaminase in fluorescent pseudomonads and other proteobacteria that we termed PtaA for "periplasmic transaminase A" An in frame-deleted ptaA mutant selectively lacked the alpha-ketoglutaric acid form of pyoverdine, and recombinant PtaA complemented this phenotype. The ptaA/pvdN double mutant produced exclusively the glutamic acid form of pyoverdine. PtaA is homodimeric and contains a pyridoxal phosphate cofactor. Mutation of the active site lysine abolished PtaA activity and affected folding as well as Tat-dependent transport of the enzyme. In pseudomonads, the occurrence of ptaA correlates with the occurrence of alpha-ketoglutaric acid forms of pyoverdines. As this enzyme is not restricted to pyoverdine-producing bacteria, its catalysis of periplasmic transaminations is most likely a general tool for specific biosynthetic pathways. PMID- 28912271 TI - The complex structure and function of Mediator. AB - In eukaryotes, RNA polymerase II (pol II) transcribes all protein-coding genes and many noncoding RNAs. Whereas many factors contribute to the regulation of pol II activity, the Mediator complex is required for expression of most, if not all, pol II transcripts. Structural characterization of Mediator is challenging due to its large size (~20 subunits in yeast and 26 subunits in humans) and conformational flexibility. However, recent studies have revealed structural details at higher resolution. Here, we summarize recent findings and place in context with previous results, highlighting regions within Mediator that are important for regulating its structure and function. PMID- 28912272 TI - The transcription factor HOXB7 regulates ERK kinase activity and thereby stimulates the motility and invasiveness of pancreatic cancer cells. AB - HOX genes encode transcription factors that function as sequence-specific transcription factors that are involved in cellular proliferation, differentiation, and death. The aim of this study was to investigate the role of a HOX family protein, HOXB7, in the motility and invasiveness of pancreatic cancer cells. We previously identified a HOXB7 transcript that is one of a number of transcripts that are preferentially translated in membrane protrusions in pancreatic cancer cells. Immunocytochemistry showed that HOXB7 was localized to the cell protrusions of migrating pancreatic cancer cells. Knockdown of HOXB7 by transfection with HOXB7-specific siRNA decreased these protrusions and inhibited the motility and invasiveness of the cells. Transfection of a HOXB7-rescue construct into the HOXB7-knockdown cells restored peripheral actin structures in cell protrusions and abrogated the HOXB7 knockdown-induced decrease in cell protrusions. It is generally accepted that the Rho family of GTPases regulate the organization of actin filaments and contribute to the formation of cell protrusions. The levels of the active Rho GTPases were not influenced by HOXB7 in the cells; however, HOXB7 knockdown decreased the level of phosphorylated ERK1/2. This inactivation of ERK1/2 decreased cell protrusions, thereby inhibiting the invasiveness of pancreatic cancer cells. Further investigation showed that HOXB7/ERK1/2 signaling selectively stimulated JNK and HSP27 phosphorylation and thereby increased the motility and invasiveness of pancreatic cancer cells. These results suggested that HOXB7 stimulates ERK1/2 phosphorylation and provided evidence that HOXB7, besides its role in transcriptional regulation, also promotes cell motility and invasiveness. PMID- 28912273 TI - Neuroligin 4 regulates synaptic growth via the bone morphogenetic protein (BMP) signaling pathway at the Drosophila neuromuscular junction. AB - The neuroligin (Nlg) family of neural cell adhesion molecules is thought to be required for synapse formation and development and has been linked to the development of autism spectrum disorders in humans. In Drosophila melanogaster, mutations in the neuroligin 1-3 genes have been reported to induce synapse developmental defects at neuromuscular junctions (NMJs), but the role of neuroligin 4 (dnlg4) in synapse development has not been determined. Here, we report that the Drosophila neuroligin 4 (DNlg4) is different from DNlg1-3 in that it presynaptically regulates NMJ synapse development. Loss of dnlg4 results in reduced growth of NMJs with fewer synaptic boutons. The morphological defects caused by dnlg4 mutant are associated with a corresponding decrease in synaptic transmission efficacy. All of these defects could only be rescued when DNlg4 was expressed in the presynapse of NMJs. To understand the basis of DNlg4 function, we looked for genetic interactions and found connections with the components of the bone morphogenetic protein (BMP) signaling pathway. Immunostaining and Western blot analyses demonstrated that the regulation of NMJ growth by DNlg4 was due to the positive modulation of BMP signaling by DNlg4. Specifically, BMP type I receptor thickvein (Tkv) abundance was reduced in dnlg4 mutants, and immunoprecipitation assays showed that DNlg4 and Tkv physically interacted in vivo Our study demonstrates that DNlg4 presynaptically regulates neuromuscular synaptic growth via the BMP signaling pathway by modulating Tkv. PMID- 28912274 TI - Structure, mechanism, and regulation of polycomb-repressive complex 2. AB - Polycomb repressive complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this Minireview, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials. We conclude by exploring unresolved questions and future directions for inquiry regarding PRC2 structure and function. PMID- 28912275 TI - NMR reveals the intrinsically disordered domain 2 of NS5A protein as an allosteric regulator of the hepatitis C virus RNA polymerase NS5B. AB - Non-structural protein 5B (NS5B) is the RNA-dependent RNA polymerase that catalyzes replication of the hepatitis C virus (HCV) RNA genome and therefore is central for its life cycle. NS5B interacts with the intrinsically disordered domain 2 of NS5A (NS5A-D2), another essential multifunctional HCV protein that is required for RNA replication. As a result, these two proteins represent important targets for anti-HCV chemotherapies. Despite this importance and the existence of NS5B crystal structures, our understanding of the conformational and dynamic behavior of NS5B in solution and its relationship with NS5A-D2 remains incomplete. To address these points, we report the first detailed NMR spectroscopic study of HCV NS5B lacking its membrane anchor (NS5BDelta21). Analysis of constructs with selective isotope labeling of the delta1 methyl groups of isoleucine side chains demonstrates that, in solution, NS5BDelta21 is highly dynamic but predominantly adopts a closed conformation. The addition of NS5A-D2 leads to spectral changes indicative of binding to both allosteric thumb sites I and II of NS5BDelta21 and induces long-range perturbations that affect the RNA-binding properties of the polymerase. We compared these modifications with the short- and long-range effects triggered in NS5BDelta21 upon binding of filibuvir, an allosteric inhibitor. We demonstrate that filibuvir-bound NS5BDelta21 is strongly impaired in the binding of both NS5A-D2 and RNA. NS5A-D2 induces conformational and functional perturbations in NS5B similar to those triggered by filibuvir. Thus, our work highlights NS5A-D2 as an allosteric regulator of the HCV polymerase and provides new insight into the dynamics of NS5B in solution. PMID- 28912277 TI - Advantages of 70-kV CT Angiography for the Visualization of the Adamkiewicz Artery: Comparison with 120-kV Imaging. AB - BACKGROUND AND PURPOSE: Preprocedural identification of the Adamkiewicz artery is crucial in patients with aortic diseases. This study aimed to compare 70-kV CTA with conventional 120-kV CTA for the identification of the Adamkiewicz artery, examining differences in radiation dose and image quality. MATERIALS AND METHODS: We retrospectively analyzed 2 equal groups of 60 patients who had undergone 70-kV or 120-kV CTA to detect the Adamkiewicz artery before aortic repair. Size specific dose estimate, the CT number of the aorta, and the contrast-to-noise ratio of the anterior spinal artery to the spinal cord were recorded. Furthermore, detectability of the Adamkiewicz artery was evaluated by using a 4 point continuity score (3, definite to 0, undetectable). RESULTS: There was significantly lower radiation exposure with 70-kV CTA than 120-kV CTA (median size-specific dose estimate, 23.1 versus 61.3 mGy, respectively; P < .001). CT number and contrast-to-noise ratio were both significantly higher in the 70-kV CTA group than the 120-kV group (999.1 HU compared with 508.7 HU, and 5.6 compared with 3.4, respectively; P < .001 for both). Detectability of the Adamkiewicz artery was not impaired in the 70-kV CTA group (90.0% versus 83.3% in the 120-kV group, P = .28). Moreover, the Adamkiewicz artery was detected with greater confidence with 70-kV CTA, reflected by a significantly superior continuity score (median, 3) compared with 120-kV CTA (median, 2; P = .001). CONCLUSIONS: Seventy-kilovolt CTA has substantial advantages for the identification of the Adamkiewicz artery before aortic repair, with a significantly lower radiation exposure and superior image quality than 120-kV CTA. PMID- 28912276 TI - Cavin-2 regulates the activity and stability of endothelial nitric-oxide synthase (eNOS) in angiogenesis. AB - Angiogenesis is a highly regulated process for formation of new blood vessels from pre-existing ones. Angiogenesis is dysregulated in various pathologies, including age-related macular degeneration, arthritis, and cancer. Inhibiting pathological angiogenesis therefore represents a promising therapeutic strategy for treating these disorders, highlighting the need to study angiogenesis in more detail. To this end, identifying the genes essential for blood vessel formation and elucidating their function are crucial for a complete understanding of angiogenesis. Here, focusing on potential candidate genes for angiogenesis, we performed a morpholino-based genetic screen in zebrafish and identified Cavin-2, a membrane-bound phosphatidylserine-binding protein and critical organizer of caveolae (small microdomains in the plasma membrane), as a regulator of angiogenesis. Using endothelial cells, we show that Cavin-2 is required for in vitro angiogenesis and also for endothelial cell proliferation, migration, and invasion. We noted a high level of Cavin-2 expression in the neovascular tufts in the mouse model of oxygen-induced retinopathy, suggesting a role for Cavin-2 in pathogenic angiogenesis. Interestingly, we also found that Cavin-2 regulates the production of nitric oxide (NO) in endothelial cells by controlling the stability and activity of the endothelial nitric-oxide synthase (eNOS) and that Cavin-2 knockdown cells produce much less NO than WT cells. Also, mass spectrometry, flow cytometry, and electron microscopy analyses indicated that Cavin-2 is secreted in endothelial microparticles (EMPs) and is required for EMP biogenesis. Taken together, our results indicate that in addition to its function in caveolae biogenesis, Cavin-2 plays a critical role in endothelial cell maintenance and function by regulating eNOS activity. PMID- 28912278 TI - Pituitary Macroadenoma and Visual Impairment: Postoperative Outcome Prediction with Contrast-Enhanced FIESTA. AB - BACKGROUND AND PURPOSE: Contrast-enhanced FIESTA can depict anterior optic pathways in patients with large suprasellar tumors. We assessed whether the degree of kink in the optic nerve at the optic canal orifice on contrast-enhanced FIESTA correlates with the postoperative improvement of visual impairment in patients with pituitary macroadenoma. MATERIALS AND METHODS: Thirty-one patients with pituitary macroadenoma who underwent preoperative MR imaging and an operation were evaluated. We measured the optic nerve kinking angle on sagittal oblique contrast-enhanced FIESTA parallel to the optic nerve; the optic nerve kinking angle was defined as the angle between a line parallel to the planum sphenoidale and a line parallel to the intracranial optic nerve at the optic canal orifice. We used logistic regression analyses to determine whether the clinical (sex, age, and duration of symptoms) and imaging (tumor height, chiasmal compression severity, hyperintense optic nerve on T2WI, and optic nerve kinking angle) characteristics were associated with the postoperative improvement (good versus-little improvement) of visual acuity disturbance and visual field defect. RESULTS: There were 53 impaired sides before the operation: 2 sides with visual acuity disturbance alone, 25 with visual field defect alone, and 26 with both. After the operation, good improvement was found in 17 of the 28 sides with visual acuity disturbance and in 32 of the 51 sides with visual field defects. Only the optic nerve kinking angle was significantly associated with good improvement of the visual acuity disturbance (P = .011) and visual field defect (P = .002). CONCLUSIONS: The degree of the optic nerve kinking angle was an independent predictor of postoperative improvement, indicating that irreversible damage to the optic nerve may be associated with its kinking at the optic canal orifice. PMID- 28912279 TI - Differences in Morphologic and Hemodynamic Characteristics for "PHASES-Based" Intracranial Aneurysm Locations. AB - BACKGROUND AND PURPOSE: Several recent prospective studies have found that unruptured intracranial aneurysms at various anatomic locations have different propensities for future rupture. This study aims to uncover the lack of understanding regarding rupture-prone characteristics, such as morphology and hemodynamic factors, associated with different intracranial aneurysm location. MATERIALS AND METHODS: We investigated the characteristics of 311 unruptured aneurysms at our center. Based on the PHASES study, we separated and compared morphologic and hemodynamic characteristics among 3 aneurysm location groups: 1) internal carotid artery; 2) middle cerebral artery; and 3) anterior communicating, posterior communicating, and posterior circulation arteries. RESULTS: A mixed model statistical analysis showed that size ratio, low wall shear stress area, and pressure loss coefficient were different between the intracranial aneurysm location groups. In addition, a pair-wise comparison showed that ICA aneurysms had lower size ratios, lower wall shear stress areas, and lower pressure loss coefficients compared with MCA aneurysms and compared with the group of anterior communicating, posterior communicating, and posterior circulation aneurysms. There were no statistical differences between MCA aneurysms and the group of anterior communicating, posterior communicating, and posterior circulation aneurysms for morphologic or hemodynamic characteristics. CONCLUSIONS: ICA aneurysms may be subjected to less rupture-prone morphologic and hemodynamic characteristics compared with other locations, which could explain the decreased rupture propensity of intracranial aneurysms at this location. PMID- 28912280 TI - Added Value of Arterial Spin-Labeling MR Imaging for the Differentiation of Cerebellar Hemangioblastoma from Metastasis. AB - BACKGROUND AND PURPOSE: In adults with only cerebellar masses, hemangioblastoma and metastasis are the 2 most important differential diagnoses. Our aim was to investigate the added value of arterial spin-labeling MR imaging for differentiating hemangioblastoma from metastasis in patients with only cerebellar masses. MATERIALS AND METHODS: This retrospective study included a homogeneous cohort comprising patients with only cerebellar masses, including 16 hemangioblastomas and 14 metastases. All patients underwent enhanced MR imaging, including arterial spin-labeling. First, the presence or absence of a hyperperfused mass was determined. Next, in the hyperperfused mass, relative tumor blood flow (mean blood flow in the tumor divided by blood flow measured in normal-appearing cerebellar tissue) and the size ratio (size in the arterial spin labeling images divided by size in the postcontrast T1WI) were measured. To validate the arterial spin-labeling findings, 2 observers independently evaluated the conventional MR images and the combined set of arterial spin-labeling images. RESULTS: All patients with hemangioblastomas and half of the patients with metastases presented with a hyperperfused mass (P < .001). The size ratio and relative tumor blood flow were significantly larger for hemangioblastomas than for metastases (P < .001 and P = .039, respectively). The size ratio revealed excellent diagnostic power (area under the curve = 0.991), and the relative tumor blood flow demonstrated moderate diagnostic power (area under the curve = 0.777). The diagnostic accuracy of both observers was significantly improved after the addition of arterial spin-labeling; the area under the curve improved from 0.574 to 0.969 (P < .001) for observer 2 and from 0.683 to 1 (P < .001) for observer 2. CONCLUSIONS: Arterial spin-labeling imaging can aid in distinguishing hemangioblastoma from metastasis in patients with only cerebellar masses. PMID- 28912281 TI - Bring Back the Joy in Neuroradiology. PMID- 28912282 TI - Apparent Diffusion Coefficient Histograms of Human Papillomavirus-Positive and Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma: Assessment of Tumor Heterogeneity and Comparison with Histopathology. AB - BACKGROUND AND PURPOSE: Head and neck squamous cell carcinoma associated with human papillomavirus infection represents a distinct tumor entity. We hypothesized that diffusion phenotypes based on the histogram analysis of ADC values reflect distinct degrees of tumor heterogeneity in human papillomavirus positive and human papillomavirus-negative head and neck squamous cell carcinomas. MATERIALS AND METHODS: One hundred five consecutive patients (mean age, 64 years; range, 45-87 years) with primary oropharyngeal (n = 52) and oral cavity (n = 53) head and neck squamous cell carcinoma underwent MR imaging with anatomic and diffusion-weighted sequences (b = 0, b = 1000 s/mm2, monoexponential ADC calculation). The collected tumor voxels from the contoured ROIs provided histograms from which position, dispersion, and form parameters were computed. Histogram data were correlated with histopathology, p16-immunohistochemistry, and polymerase chain reaction for human papillomavirus DNA. RESULTS: There were 21 human papillomavirus-positive and 84 human papillomavirus-negative head and neck squamous cell carcinomas. At histopathology, human papillomavirus-positive cancers were more often nonkeratinizing (13/21, 62%) than human papillomavirus negative cancers (19/84, 23%; P = .001), and their mitotic index was higher (71% versus 49%; P = .005). ROI-based mean and median ADCs were significantly lower in human papillomavirus-positive (1014 +/- 178 * 10-6 mm2/s and 970 +/- 187 * 10-6 mm2/s, respectively) than in human papillomavirus-negative tumors (1184 +/- 168 * 10-6 mm2/s and 1161 +/- 175 * 10-6 mm2/s, respectively; P < .001), whereas excess kurtosis and skewness were significantly higher in human papillomavirus-positive (1.934 +/- 1.386 and 0.923 +/- 0.510, respectively) than in human papillomavirus negative tumors (0.643 +/- 0.982 and 0.399 +/- 0.516, respectively; P < .001). Human papillomavirus-negative head and neck squamous cell carcinoma had symmetric normally distributed ADC histograms, which corresponded histologically to heterogeneous tumors with variable cellularity, high stromal component, keratin pearls, and necrosis. Human papillomavirus-positive head and neck squamous cell carcinomas had leptokurtic skewed right histograms, which corresponded to homogeneous tumors with back-to-back densely packed cells, scant stromal component, and scattered comedonecrosis. CONCLUSIONS: Diffusion phenotypes of human papillomavirus-positive and human papillomavirus-negative head and neck squamous cell carcinomas show significant differences, which reflect their distinct degree of tumor heterogeneity. PMID- 28912283 TI - Reaction Time Is Negatively Associated with Corpus Callosum Area in the Early Stages of CADASIL. AB - BACKGROUND AND PURPOSE: Reaction time was recently recognized as a marker of subtle cognitive and behavioral alterations in the early clinical stages of CADASIL, a monogenic cerebral small-vessel disease. In unselected patients with CADASIL, brain atrophy and lacunes are the main imaging correlates of disease severity, but MR imaging correlates of reaction time in mildly affected patients are unknown. We hypothesized that reaction time is independently associated with the corpus callosum area in the early clinical stages of CADASIL. MATERIALS AND METHODS: Twenty-six patients with CADASIL without dementia (Mini-Mental State Examination score > 24 and no cognitive symptoms) and without disability (modified Rankin Scale score <= 1) were compared with 29 age- and sex-matched controls. Corpus callosum area was determined on 3D-T1 MR imaging sequences with validated methodology. Between-group comparisons were performed with t tests or chi2 tests when appropriate. Relationships between reaction time and corpus callosum area were tested using linear regression modeling. RESULTS: Reaction time was significantly related to corpus callosum area in patients (estimate = 7.4 * 103, standard error = 3.3 * 103, P = .03) even after adjustment for age, sex, level of education, and scores of depression and apathy (estimate = -12.2 * 103, standard error = 3.8 * 103, P = .005). No significant relationship was observed in controls. CONCLUSIONS: Corpus callosum area, a simple and robust imaging parameter, appears to be an independent correlate of reaction time at the early clinical stages of CADASIL. Further studies will determine whether corpus callosum area can be used as an outcome in future clinical trials in CADASIL or in more prevalent small-vessel diseases. PMID- 28912286 TI - Association of Developmental Venous Anomalies with Demyelinating Lesions in Patients with Multiple Sclerosis. AB - We present 5 cases of demyelination in patients diagnosed with multiple sclerosis that are closely associated with a developmental venous anomaly. Although the presence of a central vein is a known phenomenon with multiple sclerosis plaques, demyelination occurring around developmental venous anomalies is an underreported phenomenon. Tumefactive demyelination can cause a diagnostic dilemma because of its overlapping imaging findings with central nervous system neoplasm. The relationship of a tumefactive plaque with a central vein can be diagnostically useful, and we suggest that if such a lesion is closely associated with a developmental venous anomaly, an inflammatory or demyelinating etiology should be a leading consideration. PMID- 28912284 TI - T1-Weighted Dynamic Contrast-Enhanced MR Perfusion Imaging Characterizes Tumor Response to Radiation Therapy in Chordoma. AB - BACKGROUND AND PURPOSE: Chordomas notoriously demonstrate a paucity of changes following radiation therapy on conventional MR imaging. We hypothesized that dynamic contrast-enhanced MR perfusion imaging parameters of chordomas would change significantly following radiation therapy. MATERIALS AND METHODS: Eleven patients with pathology-proved chordoma who completed dynamic contrast-enhanced MR perfusion imaging pre- and postradiation therapy were enrolled. Quantitative tumor measurements were obtained by 2 attending neuroradiologists. ROIs were used to calculate vascular permeability and plasma volume and generate dynamic contrast-enhancement curves. Quantitative analysis was performed to determine mean and maximum plasma volume and vascular permeability values, while semiquantitative analysis on averaged concentration curves was used to determine the area under the curve. A Mann-Whitney U test at a significance level of P < .05 was used to assess differences of the above parameters between pre- and postradiation therapy. RESULTS: Plasma volume mean (pretreatment mean = 0.82; posttreatment mean = 0.42), plasma volume maximum (pretreatment mean = 3.56; posttreatment mean = 2.27), and vascular permeability mean (pretreatment mean = 0.046; posttreatment mean = 0.028) in the ROIs significantly decreased after radiation therapy (P < .05); this change thereby demonstrated the potential for assessing tumor response. Area under the curve values also demonstrated significant differences (P < .05). CONCLUSIONS: Plasma volume and vascular permeability decreased after radiation therapy, suggesting that these dynamic contrast-enhanced MR perfusion parameters may be useful for monitoring chordoma growth and response to radiation therapy. Additionally, the characteristic dynamic MR signal intensity-time curve of chordoma may provide a radiographic means of distinguishing chordoma from other spinal lesions. PMID- 28912287 TI - Public reason and the limited right to conscientious objection: a response to Magelssen. AB - In a recent article for this journal, Morten Magelssen argues that the right to conscientious objection in healthcare is grounded in the moral integrity of healthcare professionals, a good for both professionals and society. In this paper, I argue that there is no right to conscientious objection in healthcare, at least as Magelssen conceives of it. Magelssen's conception of the right to conscientious objection is too expansive in nature. Although I will assume that there is a right to conscientious objection, it does not extend to objections that are purely religious in nature. i Thus, this right is considerably more restricted than Magelssen thinks. In making my case, I draw on John Rawls's later work in arguing for the claim that conscientious objection based on purely religious considerations fails to benefit society in the appropriate way. PMID- 28912285 TI - Predictors of Incomplete Occlusion following Pipeline Embolization of Intracranial Aneurysms: Is It Less Effective in Older Patients? AB - BACKGROUND AND PURPOSE: Flow diversion with the Pipeline Embolization Device (PED) for the treatment of intracranial aneurysms is associated with a high rate of aneurysm occlusion. However, clinical and radiographic predictors of incomplete aneurysm occlusion are poorly defined. In this study, predictors of incomplete occlusion at last angiographic follow-up after PED treatment were assessed. MATERIALS AND METHODS: A retrospective analysis of consecutive aneurysms treated with the PED between 2009 and 2016, at 3 academic institutions in the United States, was performed. Cases with angiographic follow-up were selected to evaluate factors predictive of incomplete aneurysm occlusion at last follow-up. RESULTS: We identified 465 aneurysms treated with the PED; 380 (81.7%) aneurysms (329 procedures; median age, 58 years; female/male ratio, 4.8:1) had angiographic follow-up, and were included. Complete occlusion (100%) was achieved in 78.2% of aneurysms. Near-complete (90%-99%) and partial (<90%) occlusion were collectively achieved in 21.8% of aneurysms and defined as incomplete occlusion. Of aneurysms followed for at least 12 months (211 of 380), complete occlusion was achieved in 83.9%. Older age (older than 70 years), nonsmoking status, aneurysm location within the posterior communicating artery or posterior circulation, greater aneurysm maximal diameter (>=21 mm), and shorter follow-up time (<12 months) were significantly associated with incomplete aneurysm occlusion at last angiographic follow-up on univariable analysis. However, on multivariable logistic regression, only age, smoking status, and duration of follow-up were independently associated with occlusion status. CONCLUSIONS: Complete occlusion following PED treatment of intracranial aneurysms can be influenced by several factors related to the patient, aneurysm, and treatment. Of these factors, older age (older than 70 years) and nonsmoking status were independent predictors of incomplete occlusion. While the physiologic explanation for these findings remains unknown, identification of factors predictive of incomplete aneurysm occlusion following PED placement can assist in patient selection and counseling and might provide insight into the biologic factors affecting endothelialization. PMID- 28912288 TI - Sometimes, not always, not never: a response to Pickard and Pearce. AB - This paper provides a response to Hanna Pickard and Stephen Pearce's paper 'Balancing costs and benefits: a clinical perspective does not support a harm minimisation approach for self-injury outside of community settings.' This paper responded to my article 'Should healthcare professionals sometimes allow harm? The case of self-injury.' There is much in the paper that I would agree with, but I feel it is important to respond to a number of the criticisms of my paper in order to clarify my position and to facilitate ongoing debate in relation to this important issue. PMID- 28912289 TI - Using best interests meetings for people in a prolonged disorder of consciousness to improve clinical and ethical management. AB - Current management of people with prolonged disorders of consciousness is failing patients, families and society. The causes include a general lack of concern, knowledge and expertise; a legal and professional framework which impedes timely and appropriate decision-making and/or enactment of the decision; and the exclusive focus on the patient, with no legitimate means to consider the broader consequences of healthcare decisions. This article argues that a clinical pathway based on the principles of (a) the English Mental Capacity Act 2005 and (b) using time-limited treatment trials could greatly improve patient management and reduce stress on families. There needs to be early and continuing use of formal best interests meetings, starting between 7 and 21 days after onset of unconsciousness (from any cause, including progressive disorders). The treatment options need to evolve as the clinical state and prognosis becomes more certain. A formal discussion of treatment withdrawal should occur when the upper bound of predicted recovery falls below a level the patient would have considered acceptable, and it should always be discussed when the condition is considered permanent. Any decision to stop treatment should be contingent on a formal second opinion from an independent expert who should review the clinical situation and expected prognosis, but not the best interests decision. The article also asks how, if at all, the adverse effects on the family and the resource implications of long-term care of people left in a prolonged state of unconsciousness should be incorporated in the process. PMID- 28912290 TI - Achieving high-quality care: a view from NICE. AB - The National Institute for Health and Care Excellence (NICE) was established in 1999 to provide evidence-based guidance. The task of producing guidance by reviewing primary research data and using an advisory committee to develop evidence-based recommendations, is not straightforward. Guidance production is, however, less challenging than the task of putting evidence-based recommendations into practice.NICE is very sensitive to this challenge as, since 1999, over 1500 pieces of NICE guidance have been published. A number of pieces of guidance relate to heart disease, including pharmaceutical agents, new medical technologies and clinical guidelines. Examples include guidelines on acute heart failure and atrial fibrillation, and advice on technologies including edoxaban and implantable cardioverter defibrillators.The research evidence is clear that a change in practice rarely comes about as a result of simply disseminating guidance on best practice. Simple dissemination is particularly ineffective if the guidance has not been produced by a well-respected, credible organisation. It is also clear from the literature that implementation is more successful when more than one approach is taken, and when there is alignment between efforts at organisational, local and national levels.At an organisational level, there should be support from the Board for quality improvement, with ongoing measurement of progress. Resources should be provided for targeted change programmes, particularly where new guidance suggests improvements are required. A systematic process for putting change in place should include identifying barriers to change, agreeing interventions to overcome the barriers and drive forward improvement and planning for implementation and evaluation. PMID- 28912291 TI - High-risk DLBCL: interim PET? Not yet. PMID- 28912292 TI - Gene therapy: WAS (not) just for kids. PMID- 28912293 TI - tPA and anger management for macrophages. PMID- 28912294 TI - Brentuximab: is it time for a new "B" in ABVD? PMID- 28912295 TI - Erdheim-Chester disease: the "targeted" revolution. PMID- 28912296 TI - Exuberant nodal proliferation of mature plasmacytoid dendritic cells in a patient with chronic myelomonocytic leukemia. PMID- 28912297 TI - Cyclin D1-negative mantle cell lymphoma with aberrant CD3 expression. PMID- 28912298 TI - Empowering lay bystanders to respond to medical emergencies. PMID- 28912299 TI - The Test Your Memory for Mild Cognitive Impairment (TYM-MCI). AB - BACKGROUND: To validate a short cognitive test: the Test Your Memory for Mild Cognitive Impairment (TYM-MCI) in the diagnosis of patients with amnestic mild cognitive impairment or mild Alzheimer's disease (aMCI/AD). METHODS: Two hundred and two patients with mild memory problems were recruited. All had 'passed' the Mini-Mental State Examination (MMSE). Patients completed the TYM-MCI, the Test Your Memory test (TYM), MMSE and revised Addenbrooke's Cognitive Examination (ACE R), had a neurological examination, clinical diagnostics and multidisciplinary team review. RESULTS: As a single test, the TYM-MCI performed as well as the ACE R in the distinction of patients with aMCI/AD from patients with subjective memory impairment with a sensitivity of 0.79 and specificity of 0.91. Used in combination with the ACE-R, it provided additional value and identified almost all cases of aMCI/AD. The TYM-MCI correctly classified most patients who had equivocal ACE-R scores. Integrated discriminant improvement analysis showed that the TYM-MCI added value to the conventional memory assessment. Patients initially diagnosed as unknown or with subjective memory impairment who were later rediagnosed with aMCI/AD scored poorly on their original TYM-MCI. CONCLUSION: The TYM-MCI is a powerful short cognitive test that examines verbal and visual recall and is a valuable addition to the assessment of patients with aMCI/AD. It is simple and cheap to administer and requires minimal staff time and training. PMID- 28912300 TI - [18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia. AB - INTRODUCTION: Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [18F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies. METHODS AND RESULTS: Seven patients (five with svPPA and two with 'right' semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [18F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BPND (non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BPND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [18F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity. CONCLUSIONS: [18F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non tau target for [18F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed 'off target' binding sites for [18F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [18F]AV 1451 to differentiate and track different types of frontotemporal lobar degeneration. PMID- 28912301 TI - Early-onset drug-induced parkinsonism after exposure to offenders implies nigrostriatal dopaminergic dysfunction. AB - OBJECTIVES: The onset of parkinsonism in patients with drug-induced parkinsonism (DIP) exhibits extensive individual variability following exposure to offending drugs. We investigated whether the individual variations in the onset time of parkinsonism reflected the underlying subtle dopaminergic dysfunction in DIP. METHODS: We enrolled 71 patients with DIP who had visually normal striatal dopamine transporter (DAT) availability in 18F-FP-CIT positron emission tomography scans. According to their exposure durations to the offending drugs prior to onset of the parkinsonism, the patients were divided into the early onset group (duration <=6 months; n=35) and delayed-onset group (duration >6 months; n=36). We performed the quantitative analysis of the DAT availability in each striatal subregion between the groups. RESULTS: No patients with DIP had DAT availability that was more than 2 SD below the normal mean of DAT availability. Compared with the delayed-onset group, the early-onset DIP group had decreased DAT availability in the striatal subregions including the posterior putamen (p=0.018), anterior putamen (p=0.011), caudate (p=0.035) and ventral striatum (p=0.027). After adjusting for age, sex and cross-cultural smell identification test scores, a multivariate analysis revealed that the DAT availability in the striatal subregions of the patients with DIP was significantly and positively associated with the natural logarithm of the duration of drug exposure. CONCLUSIONS: These results suggest that a short exposure to the offending drugs before the development of parkinsonism would be associated with subtle nigrostriatal dopaminergic dysfunction in patients with DIP. PMID- 28912303 TI - GPR62 constitutively activates cAMP signaling but is dispensable for male fertility in mice. AB - G-protein-coupled receptors (GPCRs) participate in diverse physiological functions and are promising targets for drug discovery. However, there are still over 140 orphan GPCRs whose functions remain to be elucidated. Gpr62 is one of the orphan GPCRs that is expressed in the rat and human brain. In this study, we found that Gpr62 is also expressed in male germ cells in mice, and its expression increases along with sperm differentiation. GPR62 lacks the BBXXB and DRY motifs, which are conserved across many GPCRs, and it was able to induce cAMP signaling in the absence of a ligand. These structural and functional features are conserved among mammals, and the mutant analysis of GPR62 has revealed that lacking of these motifs is involved in the constitutive activity. We also found that GPR62 can homooligomerize, but it is not sufficient for its constitutive activity. We further investigated its physiological function by using Gpr62 knockout (Gpr62-/-) mice. Gpr62-/- mice were born normally and did not show any abnormality in growth and behavior. In addition, both male and female Gp62-/- mice were fertile, and the differentiation and motility of spermatozoa were normal. We also found that Gpr61, the gene most similar to Gpr62 in the GPCR family shows a constitutive activity and an expression pattern similar to those of Gpr62 Our results suggest that GPR62 constitutively activates the cAMP pathway in male germ cells but is dispensable for male fertility, which is probably due to its functional redundancy with GPR61. PMID- 28912302 TI - Prevention of renal apoB retention is protective against diabetic nephropathy: role of TGF-beta inhibition. AB - Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr-/- mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-beta (TGF-beta), in some experiments mice were injected with either the TGF-beta-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ~30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF beta. Use of 1D11 led to sustained suppression of TGF-beta for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-beta inhibition is nephroprotective. PMID- 28912304 TI - E-cadherin and ZEB2 modulate trophoblast cell differentiation during placental development in pigs. AB - It is one of the important events that trophoblast cells within the placental folds differentiate into two types that differ in cell shape during placental development in pigs. This study showed that all the trophoblast cells were of similar shape between Yorkshire and Chinese Meishan pigs on day 26 of gestation; thereafter, the trophoblast cells located at the top of the placental folds became high columnar, while those cells at the base of the placental folds were cuboidal on day 50 of gestation. Additionally, on day 95 of gestation, all the trophoblast cells in Meishan pigs became cuboidal, but the trophoblast cells located at the top of the placental folds in Yorkshire pigs still remained columnar. The membranous E-cadherin and beta-catenin were strongly co-expressed by the high columnar trophoblast cells but very weakly expressed by those cuboidal cells. Consistently, the expression pattern of ZEB2, the E-cadherin repressor, was inversely correlated with that of E-cadherin in the two types of trophoblast cells in the two breeds. Furthermore, electrophoretic mobility shift assays demonstrated the binding of ZEB2 to the E-cadherin promoter in nuclear extracts from porcine placental tissue. These findings suggest a ZEB2-dependent mechanism of trophoblast cell differentiation during placental development in pigs. PMID- 28912306 TI - Complete Nucleotide Sequence of Klebsiella pneumoniae Bacteriophage vB_KpnM_KpV477. AB - The double-stranded DNA (dsDNA) bacteriophage vB_KpnM_KpV477, with a broad spectrum of lytic activity against Klebsiella pneumoniae, including strains of capsular serotypes K1, K2, and K57, was isolated from a clinical sample. The phage genome comprises 168,272 bp, with a G+C content of 39.3%, and it contains 275 putative coding sequences (CDSs) and 17 tRNAs. PMID- 28912305 TI - Effects of Liraglutide on Weight Loss, Fat Distribution, and beta-Cell Function in Obese Subjects With Prediabetes or Early Type 2 Diabetes. AB - OBJECTIVE: Obesity is associated with an increased risk of type 2 diabetes and cardiovascular complications. The risk depends significantly on adipose tissue distribution. Liraglutide, a glucagon-like peptide 1 analog, is associated with weight loss, improved glycemic control, and reduced cardiovascular risk. We determined whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese subjects with prediabetes or early type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixty-two metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes, were randomized to liraglutide (1.8 mg/day) or lifestyle counseling. Changes in SAT and VAT levels (determined by abdominal MRI), insulin sensitivity (according to the Matsuda index), and beta cell function (beta-index) were assessed during a multiple-sampling oral glucose tolerance test; and circulating levels of IGF-I and IGF-II were assessed before and after a comparable weight loss (7% of initial body weight). RESULTS: After comparable weight loss, achieved by 20 patients per arm, and superimposable glycemic control, as reflected by HbA1c level (P = 0.60), reduction in VAT was significantly higher in the liraglutide arm than in the lifestyle arm (P = 0.028), in parallel with a greater improvement in beta-index (P = 0.021). No differences were observed in SAT reduction (P = 0.64). IGF-II serum levels were significantly increased (P = 0.024) only with liraglutide administration, and the increase in IGF-II levels correlated with both a decrease in VAT (rho = -0.435, P = 0.056) and an increase in the beta-index (rho = 0.55, P = 0.012). CONCLUSIONS: Liraglutide effects on visceral obesity and beta-cell function might provide a rationale for using this molecule in obese subjects in an early phase of glucose metabolism dysregulation natural history. PMID- 28912307 TI - Genome Sequence of Staphylococcus aureus PX03, an Acetoin-Producing Strain with a Small-Sized Genome. AB - Staphylococcus aureus PX03 can produce acetoin efficiently. Here, we present a 2.38-Mb assembly of its genome sequence, which might provide further insights into the molecular mechanism of its acetoin biosynthesis to further improve its biotechnological applications. PMID- 28912308 TI - Draft Genome Sequence of Epilithonimonas sp. FP211-J200, Isolated from an Outbreak Episode on a Rainbow Trout (Oncorhynchus mykiss) Farm. AB - Here, we report the draft genome sequence of Epilithonimonas sp. FP211-J200, isolated from rainbow trout head kidney cells. The size of the genome is 4,110,772 bp, with a G+C content of 37.1%. The Epilithonimonas sp. FP211-J200 genome has genes related to tetracycline and beta-lactam resistance. This is the first reported Epilithonimonas species genome isolated from a fish host. PMID- 28912309 TI - First Whole-Genome Shotgun Sequence of a Promising Cellulase Secretor, Trichoderma koningiopsis Strain POS7. AB - Trichoderma koningiopsis strain POS7 produces significantly large amounts of cellulase enzymes in solid-state fermentation. The Illumina-based sequence analysis reveals an approximate genome size of 36.6 Mbp, with a G+C content of 48.82% for T. koningiopsis POS7. Based on ab initio prediction, 12,661 coding genes were annotated. PMID- 28912310 TI - Draft Genome Sequence of Prevotella copri Isolated from the Gut of a Healthy Indian Adult. AB - Prevotella copri, a Gram-negative anaerobic rod-shaped bacterium, is frequently associated with the human gastrointestinal tract and influences host physiology, immunity, and metabolic pathways. In the present study, we report the draft genome sequence of P. copri isolated from the gut of a healthy Indian adult. PMID- 28912311 TI - Draft Genome Sequence of the Human-Pathogenic Fungus Scedosporium boydii. AB - The opportunistic fungal pathogen Scedosporium boydii is the most common Scedosporium species in French patients with cystic fibrosis. Here we present the first genome report for S. boydii, providing a resource which may enable the elucidation of the pathogenic mechanisms in this species. PMID- 28912312 TI - Draft Genome Sequence of Corynebacterium kefirresidentii SB, Isolated from Kefir. AB - The genus Corynebacterium includes Gram-positive species with a high G+C content. We report here a novel species, Corynebacterium kefirresidentii SB, isolated from kefir grains collected in Germany. Its draft genome sequence was remarkably dissimilar (average nucleotide identity, 76.54%) to those of other Corynebacterium spp., confirming that this is a unique novel species. PMID- 28912313 TI - Complete Genome Sequence of a Shiga Toxin-Producing Enterobacter cloacae Clinical Isolate. AB - Enterobacter cloacae strain M12X01451 was isolated from a patient with mild diarrhea. This strain produces a novel subtype of Shiga toxin 1, Stx1e. The Stx1e converting prophage in strain M12X01451 is stable and can infect other bacteria following induction. Here we report the complete genome sequence and annotation of strain M12X01451. PMID- 28912314 TI - Complete Genome Sequence of Dehalobacterium formicoaceticum Strain DMC, a Strictly Anaerobic Dichloromethane-Degrading Bacterium. AB - Dehalobacterium formicoaceticum utilizes dichloromethane as the sole energy source in defined anoxic bicarbonate-buffered mineral salt medium. The products are formate, acetate, inorganic chloride, and biomass. The bacterium's genome was sequenced using PacBio, assembled, and annotated. The complete genome consists of one 3.77-Mb circular chromosome harboring 3,935 predicted protein-encoding genes. PMID- 28912315 TI - Complete Genome Sequence of Ralstonia solanacearum FJAT-91, a High-Virulence Pathogen of Tomato Wilt. AB - Ralstonia solanacearum FJAT-91, which displays higher virulence toward plants belonging to the family Solanaceae, was isolated from a wilted tomato plant vessel in Fujian province, southeast China. Here, we report the complete genome sequence of R. solanacearum FJAT-91 using long-read single-molecule PacBio sequencing technology. The genome comprises a 3,873,214-bp circular chromosome and a 2,000,873-bp circular megaplasmid with an overall G+C content of 66.85%. PMID- 28912316 TI - Draft Genome Sequence of Bacillus thuringiensis subsp. aizawai HD133. AB - We report here the 6,512,057-bp draft genome sequence of Bacillus thuringiensis subsp. aizawai HD133. This strain contains at least 6 cry genes and 13 candidate biosynthetic gene clusters. PMID- 28912317 TI - Complete Genome Sequence of Nervous Necrosis Virus Isolated from Orange-Spotted Grouper (Epinephelus coioides) in Taiwan. AB - The genome sequence of nervous necrosis virus strain KS1 isolated from orange spotted grouper (Epinephelus coioides) was cloned and analyzed. The viral genome is composed of two single-stranded positive-sense RNA molecules, RNA1 and RNA2. Phylogenetic analysis shows that the virus strain KS1 belongs to the red-spotted grouper nervous necrosis virus genotype. PMID- 28912318 TI - Chromosome and Large Linear Plasmid Sequences of a Borrelia miyamotoi Strain Isolated from Ixodes pacificus Ticks from California. AB - Borrelia miyamotoi, a relapsing fever group spirochete, is an emerging tick-borne pathogen. It has been identified in ixodid ticks across the Northern Hemisphere, including the West Coast of the United States. We describe the chromosome and large linear plasmid sequence of a B. miyamotoi isolate cultured from a California field-collected Ixodes pacificus tick. PMID- 28912319 TI - Complete Genome Sequence of Mycobacterium chimaera SJ42, a Nonoutbreak Strain from an Immunocompromised Patient with Pulmonary Disease. AB - Mycobacterium chimaera, a nontuberculous mycobacterium (NTM) belonging to the Mycobacterium avium complex (MAC), is an opportunistic pathogen that can cause respiratory and disseminated disease. We report the complete genome sequence of a strain, SJ42, isolated from an immunocompromised male presenting with MAC pneumonia, assembled from Illumina and Oxford Nanopore data. PMID- 28912320 TI - Complete Genome Sequence of Spiroplasma corruscae EC-1T (DSM 19793), a Bacterium Isolated from a Lampyrid Beetle (Ellychnia corrusca). AB - Spiroplasma corruscae EC-1T (DSM 19793) was isolated from the gut of a lampryid beetle (Ellychnia corrusca) collected in Beltsville, MD, USA, in 1983. Here, we report the complete genome sequence of this bacterium to facilitate the investigation of its biology and the comparative genomics among Spiroplasma species. PMID- 28912321 TI - Draft Genome Sequence of the Plant Pathogen Streptomyces sp. Strain 11-1-2. AB - Streptomyces sp. strain 11-1-2 is a Gram-positive filamentous bacterium that was isolated from a common scab lesion on a potato tuber. The strain is highly pathogenic to plants but does not produce the virulence-associated Streptomyces phytotoxin thaxtomin A. Here, we report the draft genome sequence of Streptomyces sp. 11-1-2. PMID- 28912322 TI - Draft Genome Sequence of Streptomyces sp. XY006, an Endophyte Isolated from Tea (Camellia sinensis). AB - Streptomyces sp. XY006 is an endophytic bacterium isolated from the young leaf material of the tea plant (Camellia sinensis). The draft genome consists of 8.2 Mb and encodes 7,415 putative open reading frames. This strain is found to contain a high capacity for the production of natural products. PMID- 28912323 TI - Complete Genome Sequences of Bordetella pertussis Isolates with Novel Pertactin Deficient Deletions. AB - Clinical isolates of the respiratory pathogen Bordetella pertussis in the United States have become predominantly deficient for the acellular vaccine immunogen pertactin through various independent mutations. Here, we report the complete genome sequences for four B. pertussis isolates that harbor novel deletions responsible for pertactin deficiency. PMID- 28912324 TI - Permanent Draft Genome Sequence of Photorhabdus temperata Strain Hm, an Entomopathogenic Bacterium Isolated from Nematodes. AB - Photorhabdus temperata strain Hm is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. Here, we report a 5.0-Mbp draft genome sequence for P. temperata strain Hm with a G+C content of 44.1% and containing 4,226 candidate protein-encoding genes. PMID- 28912325 TI - Draft Genome Sequence of the Vaginal Isolate Corynebacterium amycolatum ICIS 9. AB - Corynebacterium amycolatum ICIS 9 was isolated from a vaginal smear of a healthy woman. Here, we report the draft genome sequence of C. amycolatum ICIS 9, which will be useful for further studies of specific genetic features of this strain and for understanding its probiotic properties. PMID- 28912326 TI - Complete Genome Sequence of a Novel Subgenotype of Porcine Reproductive and Respiratory Syndrome Virus Strain JX/CH/2016, Isolated in Jiangxi, China. AB - We sequenced the complete genome of porcine reproductive and respiratory syndrome virus (PRRSV) strain JX/CH/2016. Phylogenetic analysis based on the sequences of the open reading frame 5 (ORF5) gene revealed that this strain belongs to subgenotype IV. This is the first report of the complete genome sequence of PRRSV IV. PMID- 28912327 TI - Whole-Genome Sequence of the First Sequence Type 27 Brucella ceti Strain Isolated from European Waters. AB - Brucella spp. that cause marine brucellosis are becoming more important, as the disease appears to be more widespread than originally thought. Here, we report a whole and annotated genome sequence of Brucella ceti CRO350, a sequence type 27 strain isolated from a bottlenose dolphin carcass found in the Croatian part of the northern Adriatic Sea. PMID- 28912328 TI - Complete Genome Sequence of Salmonella enterica subsp. enterica Serovar Paratyphi B Sequence Type 28 Harboring mcr-1. AB - In 2015, plasmid-mediated colistin resistance was reported to be caused by a mobilized phosphoethanolamine transferase gene (mcr-1) in Enterobacteriaceae Here, we announce the complete genome sequence of the earliest d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B isolate harboring mcr-1 from the collection of the German National Reference Laboratory for Salmonella. PMID- 28912330 TI - Genome Sequence of Grapevine Virus T, a Novel Foveavirus Infecting Grapevine. AB - Here, we report the genome sequence of grapevine virus T (GVT), a novel single stranded RNA virus identified from a transcriptome of grapevine. The genome of GVT is 8,701 nucleotides in length and encodes five open reading frames. GVT is a putative member of the genus Foveavirus in the family Betaflexiviridae. PMID- 28912329 TI - Genome Sequence of Grapevine Virus K, a Novel Vitivirus Infecting Grapevine. AB - Here, we report the genome sequence of grapevine virus K (GVK), a novel single stranded RNA virus identified from a transcriptome of grapevine. The genome of GVK is 7,476 nucleotides in length and encodes 5 open reading frames. GVK is a putative member of the genus Vitivirus in the family Betaflexiviridae. PMID- 28912331 TI - Complete Genome Sequences of Two Vesicular Stomatitis Virus Isolates Collected in Mexico. AB - We report two full-genome sequences of vesicular stomatitis New Jersey virus (VSNJV) obtained by Illumina next-generation sequencing of RNA isolated from epithelial suspensions of cattle naturally infected in Mexico. These genomes represent the first full-genome sequences of vesicular stomatitis New Jersey viruses circulating in Mexico deposited in the GenBank database. PMID- 28912332 TI - Complete Genome Sequence of Acute Hepatopancreatic Necrosis Disease-Causing Vibrio campbellii LA16-V1, Isolated from Penaeus vannamei Cultured in a Latin American Country. AB - We report here the complete genome sequence of Vibrio campbellii, isolated from Penaeus vannamei cultured in a Latin American country. The Tn3-like transposon and pirAB genes were encoded on the plasmid pLA16-2. These data support the geographical variations in the virulence plasmid found among acute hepatopancreatic necrosis disease (AHPND)-causing Vibrio isolates from Latin America and Asia. PMID- 28912333 TI - Draft Genome Sequence of the Type Strain Sphingopyxis bauzanensis DSM 22271. AB - We present here the draft genome sequence of Sphingopyxis bauzanensis DSM 22271. The assembly contains 4,258,005 bp in 28 scaffolds and has a GC content of 63.3%. A series of specific genes involved in the catabolism or transport of aromatic compounds was identified. PMID- 28912334 TI - Draft Genome Sequence of Paenibacillus sp. XY044, a Potential Plant Growth Promoter Isolated from a Tea Plant. AB - Paenibacillus sp. XY044 is an endophytic bacterium isolated from the stem of a tea plant (Camellia sinensis cv. Maoxie). Here, we present the draft genome sequence of XY044, which includes genes encoding features related to plant growth promotion and biocontrol. PMID- 28912335 TI - Draft Genome Sequence of Klebsiella pneumoniae OK8, a Multidrug-Resistant Mouse and Human Pathogen. AB - We report here the draft genome sequence of Klebsiella pneumoniae OK8, a multidrug-resistant strain which was isolated in 1976 from a human and is known to be a mouse pathogen. PMID- 28912336 TI - Elevated semaphorin 5A in patients with Hashimoto's thyroiditis: a case-control study. AB - OBJECTIVE: Hashimoto's thyroiditis (HT) is characterized by elevated specific auto-antibodies, including TgAb and TPOAb. Increasing evidence has demonstrated the essential role of Th17 cells in HT. However, the underlying mechanism is still unclear. Semaphorin 5A (Sema 5A) is involved in several autoimmune diseases through the regulation of immune cells. The aim of the present study was to explore the role of Sema 5A in HT. METHODS: We measured serum Sema 5A levels in HT (n = 92) and healthy controls (n = 111) by enzyme-linked immunosorbent assay (ELISA). RNA levels of Sema 5A and their receptors (plexin-A1 and plexin-B3), as well as several cytokines (IFN-gamma, IL-4 and IL-17), were detected by real-time polymerase chain reaction in peripheral blood mononuclear cells from 23 patients with HT and 31 controls. In addition, we investigated the relationship between serum Sema 5A and HT. RESULTS: Serum Sema 5A in HT increased significantly compared with healthy controls (P < 0.001). Moreover, serum Sema 5A levels were positively correlated with TgAb (r = 0.511, P < 0.001), TPOAb (r = 0.423, P < 0.001), TSH (r = 0.349, P < 0.001) and IL-17 mRNA expression (r = 0.442, P < 0.001). Increased Sema 5A RNA expression was observed (P = 0.041) in HT compared with controls. In receiver-operating characteristic (ROC) analysis, serum Sema 5A predicted HT with a sensitivity of 79.35% and specificity of 96.40%, and the area under the curve of the ROC curve was 0.836 (95% CI: 0.778-0.884, P < 0.001). CONCLUSIONS: These data demonstrated elevated serum Sema 5A in HT patients for the first time. Serum Sema 5A levels were correlated with thyroid auto-antibodies and IL-17 mRNA expression. Sema 5A may be involved in immune response of HT patients. PMID- 28912337 TI - Adrenal hyperandrogenism does not deteriorate insulin resistance and lipid profile in women with PCOS. AB - OBJECTIVE: The aim of this study was to investigate the impact of adrenal hyperandrogenism on insulin resistance and lipid profile in women with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: We studied 372 women with PCOS according to the NIH criteria. 232 age- and BMI-matched women served as controls in order to define adrenal hyperandrogenism (DHEA-S >95th percentile). Then, patients with PCOS were classified into two groups: with adrenal hyperandrogenism (PCOS-AH, n = 108) and without adrenal hyperandrogenism (PCOS-NAH, n = 264). Anthropometric measurements were recorded. Fasting plasma glucose, insulin, lipid profile, sex hormone-binding globulin (SHBG) and androgen (TT, Delta4A, DHEA-S) concentrations were assessed. Free androgen index (FAI) and homeostatic model assessment-insulin resistance (HOMA-IR) index were calculated. RESULTS: Women with PCOS-AH were younger than PCOS-NAH (P < 0.001), but did not differ in the degree and type of obesity. No differences were found in HOMA-IR, total cholesterol, HDL-c, LDL-c and triglyceride concentrations (in all comparisons, P > 0.05). These metabolic parameters did not differ between the two groups even after correction for age. Women with PCOS-AH had lower SHBG (29.2 +/- 13.8 vs 32.4 +/- 11.8 nmol/L, P = 0.025) and higher TT (1.0 +/- 0.2 vs 0.8 +/- 0.4 ng/mL, P = 0.05) and Delta4A (3.9 +/- 1.2 vs 3.4 +/- 1.0 ng/mL, P = 0.007) concentrations, as well as FAI (14.1 +/- 8.0 vs 10.2 +/- 5.0, P < 0.001). These results were confirmed by a multiple regression analysis model in which adrenal hyperandrogenism was negatively associated with age (P < 0.001) and SHBG concentrations (P = 0.02), but not with any metabolic parameter. CONCLUSIONS: Women with PCOS and adrenal hyperandrogenism do not exhibit any deterioration in insulin resistance and lipid profile despite the higher degree of total androgens. PMID- 28912338 TI - Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing's disease. AB - PURPOSE: Transsphenoidal surgery (TSS) is the primary treatment modality for Cushing's disease (CD). However, the predictors of post-operative remission and recurrence remain debatable. Thus, we studied the post-operative remission and long-term recurrence rates, as well as their respective predictive factors. METHODS: A retrospective analysis of case records of 230 CD patients who underwent primary microscopic TSS at our tertiary care referral centre between 1987 and 2015 was undertaken. Demographic features, pre- and post-operative hormonal values, MRI findings, histopathological features and follow-up data were recorded. Remission and recurrence rates as well as their respective predictive factors were studied. RESULTS: Overall, the post-operative remission rate was 65.6% (early remission 46%; delayed remission 19.6%), while the recurrence rate was 41% at mean follow-up of 74 +/- 61.1 months (12-270 months). Significantly higher early remission rates were observed in patients with microadenoma vs macroadenoma (51.7% vs 30.6%, P = 0.005) and those with unequivocal vs equivocal MRI for microadenoma (55.8% vs 38.5%, P = 0.007). Patients with invasive macroadenoma had poorer (4.5% vs 45%, P = 0.001) remission rates. Recurrence rates were higher in patients with delayed remission than those with early remission (61.5% vs 30.8%, P = 0.001). Duration of post-operative hypocortisolemia >=13 months predicted sustained remission with 100% specificity and 46.4% sensitivity. Recurrence could be detected significantly earlier (27.7 vs 69.2 months, P < 0.001) in patients with available serial follow-up biochemistry as compared to those with infrequent follow-up after remission. CONCLUSION: In our study, remission and recurrence rates were similar to that of reported literature, but proportion of delayed remission was relatively higher. Negative/equivocal MRI findings and presence of macroadenoma, especially those with cavernous sinus invasion were predictors of poor remission rates. In addition to early remission, longer duration of post-operative hypocortisolism is an important predictor of sustained remission. Regular biochemical surveillance may help in identifying recurrence early. PMID- 28912339 TI - Reproductive and metabolic features during puberty in sons of women with polycystic ovary syndrome. AB - CONTEXT: Intrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty. METHODS: Sixty-nine PCOS sons (PCOSs) and 84 control sons of 7-18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17alpha-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample. RESULTS: Waist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II-III. In Tanner stages II-III and IV-V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups. CONCLUSIONS: Sons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls. PMID- 28912340 TI - Donor-Recipient Identification in Para- and Poly-phyletic Trees Under Alternative HIV-1 Transmission Hypotheses Using Approximate Bayesian Computation. AB - Diversity of the founding population of Human Immunodeficiency Virus Type 1 (HIV 1) transmissions raises many important biological, clinical, and epidemiological issues. In up to 40% of sexual infections, there is clear evidence for multiple founding variants, which can influence the efficacy of putative prevention methods, and the reconstruction of epidemiologic histories. To infer who-infected whom, and to compute the probability of alternative transmission scenarios while explicitly taking phylogenetic uncertainty into account, we created an approximate Bayesian computation (ABC) method based on a set of statistics measuring phylogenetic topology, branch lengths, and genetic diversity. We applied our method to a suspected heterosexual transmission case involving three individuals, showing a complex monophyletic-paraphyletic-polyphyletic phylogenetic topology. We detected that seven phylogenetic lineages had been transmitted between two of the individuals based on the available samples, implying that many more unsampled lineages had also been transmitted. Testing whether the lineages had been transmitted at one time or over some length of time suggested that an ongoing superinfection process over several years was most likely. While one individual was found unlinked to the other two, surprisingly, when evaluating two competing epidemiological priors, the donor of the two that did infect each other was not identified by the host root-label, and was also not the primary suspect in that transmission. This highlights that it is important to take epidemiological information into account when analyzing support for one transmission hypothesis over another, as results may be nonintuitive and sensitive to details about sampling dates relative to possible infection dates. Our study provides a formal inference framework to include information on infection and sampling times, and to investigate ancestral node-label states, transmission direction, transmitted genetic diversity, and frequency of transmission. PMID- 28912342 TI - A Powerful Variant-Set Association Test Based on Chi-Square Distribution. AB - Detecting the association between a set of variants and a given phenotype has attracted a large amount of attention in the scientific community, although it is a difficult task. Recently, several related statistical approaches have been proposed in the literature; powerful statistical tests are still highly desired and yet to be developed in this area. In this paper, we propose a powerful test that combines information from each individual single nucleotide polymorphism (SNP) based on principal component analysis without relying on the eigenvalues associated with the principal components. We compare the proposed approach with some popular tests through a simulation study and real data applications. Our results show that, in general, the new test is more powerful than its competitors considered in this study; the gain in detecting power can be substantial in many situations. PMID- 28912341 TI - The Role of Blm Helicase in Homologous Recombination, Gene Conversion Tract Length, and Recombination Between Diverged Sequences in Drosophilamelanogaster. AB - DNA double-strand breaks (DSBs) are a particularly deleterious class of DNA damage that threatens genome integrity. DSBs are repaired by three pathways: nonhomologous-end joining (NHEJ), homologous recombination (HR), and single strand annealing (SSA). Drosophila melanogaster Blm (DmBlm) is the ortholog of Saccharomyces cerevisiae SGS1 and human BLM, and has been shown to suppress crossovers in mitotic cells and repair mitotic DNA gaps via HR. To further elucidate the role of DmBlm in repair of a simple DSB, and in particular recombination mechanisms, we utilized the Direct Repeat of white (DR-white) and Direct Repeat of whitewith mutations (DR-white.mu) repair assays in multiple mutant allele backgrounds. DmBlm null and helicase-dead mutants both demonstrated a decrease in repair by noncrossover HR, and a concurrent increase in non-HR events, possibly including SSA, crossovers, deletions, and NHEJ, although detectable processing of the ends was not significantly impacted. Interestingly, gene conversion tract lengths of HR repair events were substantially shorter in DmBlm null but not helicase-dead mutants, compared to heterozygote controls. Using DR-white.mu, we found that, in contrast to Sgs1, DmBlm is not required for suppression of recombination between diverged sequences. Taken together, our data suggest that DmBlm helicase function plays a role in HR, and the steps that contribute to determining gene conversion tract length are helicase-independent. PMID- 28912343 TI - Diversification of Transcriptional Regulation Determines Subfunctionalization of Paralogous Branched Chain Aminotransferases in the Yeast Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae harbors BAT1 and BAT2 paralogous genes that encode branched chain aminotransferases and have opposed expression profiles and physiological roles . Accordingly, in primary nitrogen sources such as glutamine, BAT1 expression is induced, supporting Bat1-dependent valine-isoleucine-leucine (VIL) biosynthesis, while BAT2 expression is repressed. Conversely, in the presence of VIL as the sole nitrogen source, BAT1 expression is hindered while that of BAT2 is activated, resulting in Bat2-dependent VIL catabolism. The presented results confirm that BAT1 expression is determined by transcriptional activation through the action of the Leu3-alpha-isopropylmalate (alpha-IPM) active isoform, and uncovers the existence of a novel alpha-IPM biosynthetic pathway operating in a put3Delta mutant grown on VIL, through Bat2-Leu2-Leu1 consecutive action. The classic alpha-IPM biosynthetic route operates in glutamine through the action of the leucine-sensitive alpha-IPM synthases. The presented results also show that BAT2 repression in glutamine can be alleviated in a ure2Delta mutant or through Gcn4-dependent transcriptional activation. Thus, when S. cerevisiae is grown on glutamine, VIL biosynthesis is predominant and is preferentially achieved through BAT1; while on VIL as the sole nitrogen source, catabolism prevails and is mainly afforded by BAT2. PMID- 28912345 TI - A Novel Bibenzyl Compound (20C) Protects Mice from 1-Methyl-4-Phenyl-1,2,3,6 Tetrahydropyridine/Probenecid Toxicity by Regulating the alpha-Synuclein-Related Inflammatory Response. AB - The novel bibenzyl compound 2-[4-hydroxy-3-(4- hydroxyphenyl) benzyl]-4-(4- hydroxyphenyl) phenol (20C) plays a neuroprotective role in vitro, but its effects in vivo have not yet been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine, and neuron and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected the blood-brain barrier (BBB) structure, ameliorated alpha-synuclein dysfunction, suppressed glial activation, and regulated both nuclear factor kappaB (NF-kappaB) signaling and the NOD-like receptor protein (NLRP) 3 inflammasome pathway. Our results indicated that 20C may prevent neurodegeneration in the MPTP/p mouse model by targeting alpha-synuclein and regulating alpha-synuclein-related inflammatory responses, including BBB damage, glial activation, NF-kappaB signaling, and the NLRP3 inflammasome pathway. PMID- 28912344 TI - Parasex Generates Phenotypic Diversity de Novo and Impacts Drug Resistance and Virulence in Candida albicans. AB - Candida albicans is a diploid fungus that is a frequent cause of mucosal and systemic infections in humans. This species exhibits an unusual parasexual cycle in which mating produces tetraploid cells that undergo a nonmeiotic program of concerted chromosome loss to return to a diploid or aneuploid state. In this work, we used a multipronged approach to examine the capacity of parasex to generate diversity in C. albicans First, we compared the phenotypic properties of 32 genotyped progeny and observed wide-ranging differences in fitness, filamentation, biofilm formation, and virulence. Strikingly, one parasexual isolate displayed increased virulence relative to parental strains using a Galleria mellonella model of infection, establishing that parasex has the potential to enhance pathogenic traits. Next, we examined parasexual progeny derived from homothallic, same-sex mating events, and reveal that parasex can generate diversity de novo from identical parental strains. Finally, we generated pools of parasexual progeny and examined resistance of these pools to environmental stresses. Parasexual progeny were generally less fit than control strains across most test conditions, but showed an increased ability to grow in the presence of the antifungal drug fluconazole (FL). FL-resistant progeny were aneuploid isolates, often being diploid strains trisomic for both Chr3 and Chr6. Passaging of these aneuploid strains frequently led to loss of the supernumerary chromosomes and a concomitant decrease in drug resistance. These experiments establish that parasex generates extensive phenotypic diversity de novo, and that this process has important consequences for both virulence and drug resistance in C. albicans populations. PMID- 28912347 TI - Intrafamily Protein Interactions Contribute to DNA Localization. PMID- 28912346 TI - The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis. AB - 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) has been linked to pro hypertensive and anti-hypertensive actions through its ability to promote vasoconstriction and inhibit Na transport in the ascending limb of the loop of Henle, respectively. In this study, we assessed the effects of 20-HETE blockade on blood pressure, renal hemodynamics, and urinary sodium excretion in Cyp4a14(-/ ) male mice, which display androgen-driven 20-HETE-dependent hypertension. Administration of 2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyicosa 6(Z),15(Z)-dienoate (20-SOLA), a water-soluble 20-HETE antagonist, in the drinking water normalized the blood pressure of male Cyp4a14(-/-) hypertensive mice (+/-124 vs. +/-153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(-/-) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(-/-) male mice treated with 20-SOLA displayed increased urinary sodium excretion that was paralleled by the reduction of blood pressure suggestive of an antinatriuretic activity of endogenous 20-HETE in the hypertensive mice. This interpretation is in line with the observation that the natriuretic response to acute isotonic saline loading in hypertensive Cyp4a14(-/-) male mice was significantly impaired relative to that in WT mice; this impairment was corrected by 20-SOLA treatment. Hence, endogenous 20-HETE appears to promote sodium conservation in hypertensive Cyp4a14(-/-) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption. PMID- 28912348 TI - A Time to Divide and a Time to Expand: Histone Deacetylases Flip a Gibberellin Oxidase-Mediated Switch in Root Meristem Cells. PMID- 28912349 TI - NHS not ready to take on UK pensioners abroad if Brexit talks stall, peers are told. PMID- 28912350 TI - Reply to Nash: Color terms are lost, despite missing data. PMID- 28912351 TI - Reply to Jin and Zhu: PINOID-mediated COP1 phosphorylation matters in photomorphogenesis in Arabidopsis. PMID- 28912352 TI - Role of PINOID-mediated COP1 phosphorylation in Arabidopsis photomorphogenesis is overemphasized. PMID- 28912353 TI - Loss of color terms not demonstrated. PMID- 28912354 TI - Well below 2 degrees C: Mitigation strategies for avoiding dangerous to catastrophic climate changes. AB - The historic Paris Agreement calls for limiting global temperature rise to "well below 2 degrees C." Because of uncertainties in emission scenarios, climate, and carbon cycle feedback, we interpret the Paris Agreement in terms of three climate risk categories and bring in considerations of low-probability (5%) high-impact (LPHI) warming in addition to the central (~50% probability) value. The current risk category of dangerous warming is extended to more categories, which are defined by us here as follows: >1.5 degrees C as dangerous; >3 degrees C as catastrophic; and >5 degrees C as unknown, implying beyond catastrophic, including existential threats. With unchecked emissions, the central warming can reach the dangerous level within three decades, with the LPHI warming becoming catastrophic by 2050. We outline a three-lever strategy to limit the central warming below the dangerous level and the LPHI below the catastrophic level, both in the near term (<2050) and in the long term (2100): the carbon neutral (CN) lever to achieve zero net emissions of CO2, the super pollutant (SP) lever to mitigate short-lived climate pollutants, and the carbon extraction and sequestration (CES) lever to thin the atmospheric CO2 blanket. Pulling on both CN and SP levers and bending the emissions curve by 2020 can keep the central warming below dangerous levels. To limit the LPHI warming below dangerous levels, the CES lever must be pulled as well to extract as much as 1 trillion tons of CO2 before 2100 to both limit the preindustrial to 2100 cumulative net CO2 emissions to 2.2 trillion tons and bend the warming curve to a cooling trend. PMID- 28912355 TI - Diverse p53/DNA binding modes expand the repertoire of p53 response elements. AB - The tumor suppressor protein p53 acts as a transcription factor, binding sequence specifically to defined DNA sites, thereby activating the expression of genes leading to diverse cellular outcomes. Canonical p53 response elements (REs) are made of two decameric half-sites separated by a variable number of base pairs (spacers). Fifty percent of all validated p53 REs contain spacers between 1 and 18 bp; however, their functional significance is unclear at present. Here, we show that p53 forms two different tetrameric complexes with consensus or natural REs, both with long spacers: a fully specific complex where two p53 dimers bind to two specific half-sites, and a hemispecific complex where one dimer binds to a specific half-site and the second binds to an adjacent spacer sequence. The two types of complexes have comparable binding affinity and specificity, as judged from binding competition against bulk genomic DNA. Structural analysis of the p53 REs in solution shows that these sites are not bent in both their free and p53 bound states when the two half-sites are either abutting or separated by spacers. Cell-based assay supports the physiological relevance of our findings. We propose that p53 REs with long spacers comprise separate specific half-sites that can lead to several different tetrameric complexes. This finding expands the universe of p53 binding sites and demonstrates that even isolated p53 half-sites can form tetrameric complexes. Moreover, it explains the manner in which p53 binds to clusters of more than one canonical binding site, common in many natural REs. PMID- 28912356 TI - Biomarkers of disease can be detected in mice as early as 4 weeks after initiation of exposure to third-hand smoke levels equivalent to those found in homes of smokers. AB - Third-hand smoke (THS) is a newly discovered environmental health hazard that results from accumulation and aging of second-hand smoke (SHS) toxins on surfaces where smoking has occurred. Our objective was to determine whether there is a time-dependent effect of THS exposure on health. Using an in vivo exposure mouse system that mimics exposure of humans to THS, we investigated its effects on biomarkers found in serum, and in liver and brain tissues. Mice were exposed to THS for 1, 2, 4, or 6 months and brain, liver, and serum were collected. We found that THS exposure, as early as 1 month, resulted in increased circulating inflammatory cytokines, tumor necrosis factor by an order of magnitude of 2 and granulocyte macrophage colony-stimulating factor by an order of magnitude of 1.5 and in increases in the stress hormone epinephrine and the liver damage biomarker aspartate aminotransferase (AST), increased in magnitude 1.5 and 2.5 times compared with controls, respectively. THS exposure for 2 months resulted in further damage and at 4 and 6 months, many factors related to oxidative stress were altered and caused molecular damage. We also found that the mice became hyperglycemic and hyperinsulinimic suggesting that insulin resistance (IR) may be a significant consequence of long-term exposure to THS. In conclusion, time dependent THS exposure has a significant effect on health as early as 1 month after initiation of exposure and these alterations progressively worsen with time. Our studies are important because virtually nothing is known about the effects of increased THS exposure time, they can serve to educate the public on the dangers of THS, and the biomarkers we identified can be used in the clinic, once verified in exposed humans. PMID- 28912357 TI - Grazing limits natural biological controls of woody encroachment in Inner Mongolia Steppe. AB - Woody encroachment in grasslands has become increasingly problematic globally. Grazing by domestic animals can facilitate woody encroachment by reducing competition from herbaceous plants and fire frequency. Herbivorous insects and parasitic plants can each exert forces that result in the natural biological control of encroaching woody plants through reducing seeding of their host woody plants. However, the interplay of grazing and dynamics of herbivorous insects or parasitic plants, and its effects on the potential biological control of woody encroachment in grasslands remains unclear. We investigated the flower and pod damage by herbivorous insects, and the infection rates of a parasitic plant on the shrub Caragana microphylla, which is currently encroaching in Inner Mongolia Steppe, under different grazing management treatments (33-year non-grazed, 7-year non-grazed, currently grazed). Our results showed that Caragana biomass was highest at the currently grazed site, and lowest at the 33-year non-grazed site. Herbaceous plant biomass followed the opposite pattern, suggesting that grazing is indeed facilitating the encroachment of Caragana plants in Inner Mongolia Steppe. Grazing also reduced the abundance of herbivorous insects per Caragana flower, numbers of flowers and pods damaged by insect herbivores, and the infection rates of the parasitic plant on Caragana plants. Our results suggest that grazing may facilitate woody encroachment in grasslands not only through canonical mechanisms (e.g. competitive release via feeding on grasses, reductions in fires, etc.), but also by limiting natural biological controls of woody plants (herbivorous insects and parasitic plants). Thus, management efforts must focus on preventing overgrazing to better protect grassland ecosystems from woody encroachment. PMID- 28912358 TI - Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial. AB - OBJECTIVE: We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). DESIGN: We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 MUg of ethinylestradiol and 150 MUg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008-004531-38). METHODS: The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. RESULTS: Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6 6.7), total testosterone (1.1 nmol/L, 0.4-1.7), free testosterone (25 pmol/L, 12 39), androstenedione (5.5 nmol/L, 1.8-9.2) and dehydroepiandrosterone sulfate (2.7 MUmol/L, 1.4-4.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02-0.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7-4.4), dyslipidemia (OR: 0.6, 95% CI: 0.2-1.8) or hypertension (OR: 0.3, 95% CI: 0.5 2.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments. CONCLUSIONS: COC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors. PMID- 28912359 TI - Left ventricular strain rate is reduced during voluntary apnea in healthy humans. AB - During an apneic event, sympathetic nerve activity increases resulting in subsequent increases in left ventricular (LV) afterload and myocardial work. It is unknown how cardiac mechanics are acutely impacted by the increased myocardial work during an apneic event. Ten healthy individuals (23 +/- 3 yr) performed multiple voluntary end-expiratory apnea (VEEA) maneuvers exposed to room air, while a subset ( n = 7) completed multiple VEEA exposed to hyperoxic air (100% [Formula: see text]). Beat-by-beat blood pressure, heart rate, and stroke volume were measured continuously. Effective arterial elastance (EA) was calculated as an index of cardiac afterload, and myocardial work was calculated as the rate pressure product (RPP). Tissue Doppler echocardiography was used to measure LV tissue velocities, deformation via strain, and strain rate (SR). Systolic blood pressure (Delta18 +/- 13 mmHg, P < 0.01), EA (Delta0.13 +/- 0.10 mmHg/ml, P < 0.01), and RPP (Delta9 +/- 10 beats/min * mmHg 10-2, P < 0.01) significantly increased with room air VEEA. This occurred in parallel with decreases in peak longitudinal systolic (Delta-0.62 +/- 0.41 cm/s, P < 0.01) and early LV filling (Delta-2.81 +/- 1.99 cm/s, P < 0.01) myocardial velocities. Longitudinal SR (Delta-0.30 +/- 0.32 1/s, P = 0.01) was significantly decreased during room air VEEA. VEEA with hyperoxia did not alter ( P > 0.18) EA or RPP and attenuated the systolic blood pressure response compared with room air. Myocardial velocities and LV strain rate response to VEEA were unchanged ( P = 0.30) with hyperoxia. Consistent with our hypotheses, VEEA-induced increases in EA and myocardial work impact LV mechanics, which may depend, in part, on stimulation of peripheral chemoreceptors. NEW & NOTEWORTHY Transient increases in arterial blood pressure and systemic vascular resistance occur during sleep apnea events and may contribute to the associated daytime hypertension and risk of overt cardiovascular disease. To date, the link between this apnea pressor response and acute changes in left ventricular function remains poorly understood. We demonstrate that in parallel to increases in cardiac afterload a depressed left ventricular systolic function occurs at end apnea. PMID- 28912360 TI - Influence of past injurious exercise on fiber type-specific acute anabolic response to resistance exercise in skeletal muscle. AB - We investigated the influence of past injurious exercise on anabolic response of skeletal muscle fibers to resistance exercise (RE). Wistar rats were divided into exercise (E) and exercise-after-injury (I-E) groups. At age 10 wk, the right gastrocnemius muscle in each rat in the I-E group was subjected to strenuous eccentric contractions. Subsequently, RE was imposed on the same muscle of each rat at 14 wk of age in both groups. Peak joint torque and total force generation per body mass during RE were similar between the groups. Muscle protein synthesis (MPS) in the I-E group was higher than that in the E group 6 h after RE. Furthermore, levels of phospho-p70S6 kinase (Thr389) and phospho-ribosomal protein S6 (phospho-rpS6) (Ser240/244), a downstream target of p70S6 kinase, were higher in the I-E group than in the E group. For the anabolic response in each fiber type, the I-E group showed a higher MPS response in type IIb, IIa, and I fibers and a higher phospho-rpS6 response in type IIx, IIa, and I fibers than the E group. In the I-E group, the relative content of myosin heavy chain (MHC) IIa was higher and that of MHC IIb was lower than those in the E group. In addition, type IIa fibers showed a lower MPS response to RE than type IIb fibers in the I-E group. In conclusion, the past injurious exercise enhanced the MPS and phospho rpS6 responses in type IIb, IIa, and I fibers and type IIx, IIa, and I fibers, respectively. NEW & NOTEWORTHY Past injurious exercise increased the muscle protein synthesis (MPS) response and mammalian target of rapamycin complex 1 (mTORC1) signaling activation to resistance exercise. In the responses of each fiber type, the past injurious exercise increased the MPS and phosphorylation ribosomal protein (Ser240/244) responses in type IIb, IIa, and I fibers and type IIx, IIa, and I fibers, respectively. PMID- 28912361 TI - Impact of sleep restriction on local immune response and skin barrier restoration with and without "multinutrient" nutrition intervention. AB - Systemic immune function is impaired by sleep restriction. However, the impact of sleep restriction on local immune responses and to what extent any impairment can be mitigated by nutritional supplementation is unknown. We assessed the effect of 72-h sleep restriction (2-h nightly sleep) on local immune function and skin barrier restoration of an experimental wound, and determined the influence of habitual protein intake (1.5 g.kg-1.day-1) supplemented with arginine, glutamine, zinc sulfate, vitamin C, vitamin D3, and omega-3 fatty acids compared with lower protein intake (0.8 g.kg-1.day-1) without supplemental nutrients on these outcomes. Wounds were created in healthy adults by removing the top layer of less than or equal to eight forearm blisters induced via suction, after adequate sleep (AS) or 48 h of a 72-h sleep restriction period (SR; 2-h nightly sleep). A subset of participants undergoing sleep restriction received supplemental nutrients during and after sleep restriction (SR+). Wound fluid was serially sampled 48 h postblistering to assess local cytokine responses. The IL-8 response of wound fluid was higher for AS compared with SR [area-under-the-curve (log10), 5.1 +/- 0.2 and 4.9 +/- 0.2 pg/ml, respectively; P = 0.03]; and both IL-6 and IL-8 concentrations were higher for SR+ compared with SR ( P < 0.0001), suggestive of a potentially enhanced early wound healing response. Skin barrier recovery was shorter for AS (4.2 +/- 0.9 days) compared with SR (5.0 +/- 0.9 days) ( P = 0.02) but did not differ between SR and SR+ ( P = 0.18). Relatively modest sleep disruption delays wound healing. Supplemental nutrition may mitigate some decrements in local immune responses, without detectable effects on wound healing rate. NEW & NOTEWORTHY The data herein characterizes immune function in response to sleep restriction in healthy volunteers with and without nutrition supplementation. We used a unique skin wound model to show that sleep restriction delays skin barrier recovery, and nutrition supplementation attenuates decrements in local immune responses produced by sleep restriction. These findings support the beneficial effects of adequate sleep on immune function. Additional studies are necessary to characterize practical implications for populations where sleep restriction is unavoidable. PMID- 28912362 TI - Sympathetic function during whole body cooling is altered in hypertensive adults. AB - During moderate cold exposure, cardiovascular-related morbidity and mortality increase disproportionately in hypertensive adults (HTN); however, the mechanisms underlying this association are not well defined. We hypothesized that whole body cold stress would evoke exaggerated increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in HTN compared with normotensive adults (NTN) and that sympathetic baroreflex function would be altered during cooling in HTN. MSNA (peroneal microneurography) and beat-to-beat BP (Finometer) were measured continuously in 10 NTN (6 men/4 women; age 53 +/- 3 yr; resting BP 125 +/- 3/79 +/- 1 mmHg) and 13 HTN (7 men/6 women; age 58 +/- 2 yr; resting BP 146 +/- 5/88 +/- 2 mmHg) during whole body cooling-induced reductions in mean skin temperature (Tsk; water-perfused suit) from 34.0 to 30.5 degrees C. During cooling, the increase in mean arterial pressure was greater in HTN (NTN: Delta6 +/- 2 vs. HTN: Delta11 +/- 1 mmHg; P = 0.02) and accompanied by exaggerated increases in MSNA (NTN: Delta8 +/- 3 vs. HTN: Delta20 +/- 3 bursts/100 heart beats; P < 0.01). The slope of the relation between MSNA and diastolic BP did not change during cooling in NTN (Tsk 34.0 degrees C: -4.4 +/- 0.8 vs. Tsk 30.5 degrees C: -5.0 +/- 0.3 bursts.100 heart beats-1.mmHg-1; P = 0.47) but increased in HTN (Tsk 34.0 degrees C: -3.6 +/- 0.4 vs. Tsk 30.5 degrees C: -5.4 +/- 0.4 bursts.100 heart beats) 1.mmHg-1; P = 0.02). These findings demonstrate that the cooling-induced increases in BP and MSNA are exaggerated in HTN. Furthermore, during cooling, sympathetic baroreflex sensitivity increases in HTN, but not NTN, presumably to allow for baroreflex-mediated buffering of excessive cooling-induced increases in BP. Collectively, these findings suggest that sympathetic function is altered during whole body cooling in hypertension. NEW & NOTEWORTHY These novel findings demonstrate that whole body cooling-induced reductions in mean skin temperature elicited greater increases in blood pressure and muscle sympathetic nerve activity in hypertensive adults. In addition, during moderate cold exposure, sympathetic baroreflex sensitivity increased in hypertensive, but not normotensive, adults. PMID- 28912363 TI - TGFbeta (Transforming Growth Factor-beta) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm. AB - OBJECTIVE: Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFbeta (transforming growth factor-beta) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. APPROACH AND RESULTS: Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFbeta using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFbeta blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1beta or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1beta after disease initiation has no effect on AAA progression to rupture. CONCLUSIONS: Endogenous TGFbeta activity is required for the healing of AAA. TGFbeta blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets. PMID- 28912364 TI - Novel Pathological Role of hnRNPA1 (Heterogeneous Nuclear Ribonucleoprotein A1) in Vascular Smooth Muscle Cell Function and Neointima Hyperplasia. AB - OBJECTIVE: hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) plays a variety of roles in gene expression. However, little is known about the functional involvement of hnRNPA1 in vascular smooth muscle cell (VSMC) function and neointima hyperplasia. In this study, we have attempted to investigate the functional roles of hnRNPA1 in the contexts of VSMC function, injury-induced vessel remodeling, and human atherosclerotic lesions, as well as discern the molecular mechanisms involved. APPROACH AND RESULTS: hnRNPA1 expression levels were consistently modulated during VSMC phenotype switching and neointimal lesion formation induced by wire injury. Functional studies showed that VSMC-specific gene expression, proliferation, and migration were regulated by hnRNPA1. Our data show that hnRNPA1 exerts its effects on VSMC functions through modulation of IQGAP1 (IQ motif containing GTPase activating protein 1). Mechanistically, hnRNPA1 regulates IQGAP1 mRNA degradation through 2 mechanisms: upregulating microRNA-124 (miR-124) and binding to AU-rich element of IQGAP1 gene. Further evidence suggests that hnRNPA1 upregulates miR-124 by modulating miR-124 biogenesis and that IQGAP1 is the authentic target gene of miR-124. Importantly, ectopic overexpression of hnRNPA1 greatly reduced VSMC proliferation and inhibited neointima formation in wire-injured carotid arteries. Finally, lower expression levels of hnRNPA1 and miR-124, while higher expression levels of IQGAP1, were observed in human atherosclerotic lesions. CONCLUSIONS: Our data show that hnRNPA1 is a critical regulator of VSMC function and behavior in the context of neointima hyperplasia, and the hnRNPA1/miR-124/IQGAP1 regulatory axis represents a novel therapeutic target for the prevention of cardiovascular diseases. PMID- 28912366 TI - Lower Plasma Fetuin-A Levels Are Associated With a Higher Mortality Risk in Patients With Coronary Artery Disease. AB - OBJECTIVE: The present study was designed to evaluate the association of circulating fetuin-A with cardiovascular disease (CVD) and all-cause mortality. APPROACH AND RESULTS: We measured plasma fetuin-A in 1620 patients using an enzyme-linked immunosorbent assay kit. The patients were members of the Guangdong coronary artery disease cohort and were recruited between October 2008 and December 2011. Cox regression models were used to estimate the association between plasma fetuin-A and the risk of mortality. A total of 206 deaths were recorded during a median follow-up of 5.9 years, 146 of whom died from CVD. The hazard ratios for the second and third tertiles of the fetuin-A levels (using the first tertile as a reference) were 0.65 (95% confidence interval, 0.44-0.96) and 0.51 (95% confidence interval, 0.33-0.78) for CVD mortality (P=0.005) and 0.65 (95% confidence interval, 0.47-0.91) and 0.48 (95% confidence interval, 0.33 0.70) for all-cause mortality (P<0.001), respectively. CONCLUSIONS: Lower plasma fetuin-A levels were associated with an increased risk of all-cause and CVD mortality in patients with coronary artery disease independently of traditional CVD risk factors. PMID- 28912367 TI - Lessons From Pediatric HIV: A Case for Curative Intent in Pediatric Cancer in LMICs. PMID- 28912365 TI - D-Dimer in African Americans: Whole Genome Sequence Analysis and Relationship to Cardiovascular Disease Risk in the Jackson Heart Study. AB - OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, beta=0.284, P=3.24*10-11). The rs2022030 effect size was nearly 3* larger among women (beta=0.373, P=9.06*10-13) than among men (beta=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (beta=0.507, P=1.41*10-14), and this association was successfully replicated in 1933 AAs (P=2.3*10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs. PMID- 28912368 TI - Neurodevelopment of HIV-Exposed and HIV-Unexposed Uninfected Children at 24 Months. AB - BACKGROUND: We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana. METHODS: HIV-infected and uninfected mothers enrolled in a prospective observational study ("Tshipidi") in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics. RESULTS: We evaluated 670 children (313 HEU, 357 HUU) with >=1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small. CONCLUSIONS: HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring. PMID- 28912370 TI - Private patients treated by rogue breast surgeon will be compensated under L37m fund. PMID- 28912369 TI - Customized Viral Immunotherapy for HPV-Associated Cancer. AB - The viral-transforming proteins E6 and E7 make human papillomavirus-positive (HPV+) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8+ T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 * 106 E7-specific CD8+ T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV+ murine model TC1 clears large tumors in a CD8+-dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV+ cancer, as demonstrated by marked infection of HPV+ patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV+ cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847-59. (c)2017 AACR. PMID- 28912371 TI - Preprints and Cardiovascular Science: Prescient or Premature? PMID- 28912372 TI - Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity. AB - DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers. PMID- 28912374 TI - Collagen-Embedded Tumor Transplantations in Xenopus laevis Tadpoles. AB - The Xenopus laevis tadpole provides a valuable model for studying tumorigenesis and tumor immunity by intravital real-time microscopy. Using well-characterized thymic lymphoid tumor lines (15/0 and ff-2) that are transplantable into their compatible hosts (LG-15 isogenic clones and the F inbred strain, respectively), a system of semisolid tumor engraftment has been designed. Because these lymphoid tumor cell lines are not adherent and grow in suspension, they are first immobilized in a matrix of type I rat tail collagen before transplantation as a semisolid tumor graft under the transparent dorsal skin in the head region of a tadpole. This semisolid tumor engraftment is amenable to manipulation and permits real-time visualization of tumor growth, neovascularization, collagen rearrangements, immune cell infiltration, and formation of the tumor microenvironment. PMID- 28912375 TI - Organ Culture of the Xenopus Tadpole Intestine. AB - During Xenopus metamorphosis, most tadpole organs remodel from the larval to adult form to prepare for adaptation to terrestrial life. Organ culture serves as an important tool for studying larval-to-adult organ remodeling independent of the effects of other parts of the body. Here, I introduce a protocol for organ culture in vitro using the Xenopus laevis tadpole intestine before metamorphic climax. During culture in the absence of exogenous 3,3',5-triiodo-l-thyronine (T3), the most potent natural thyroid hormone, the intestine remains in its larval state without any metamorphic changes. In contrast, when T3 is added to the culture medium, the larval epithelium undergoes apoptosis, whereas adult stem cells appear, actively proliferate, and finally generate the differentiated adult epithelium within a week. At the same time, the surrounding nonepithelial tissues also develop. Thus, this culture model is useful for clarifying the control mechanisms of apoptosis in larval tissues, formation of adult stem cells, and cell proliferation and differentiation of adult tissues, all of which occur in harmony during natural metamorphosis. Moreover, a procedure for tissue recombination combined with organ culture provides a platform for investigating complex tissue interactions during organ remodeling. Such tissue recombination experiments will help to reveal the important role of nonepithelial tissues in larval epithelial apoptosis and/or adult stem cell development in the X. laevis intestine. PMID- 28912373 TI - The Association of Sleep Duration and Quality with CKD Progression. AB - Evidence suggests that sleep disorders are common in individuals with CKD, but the influence of sleep duration and quality on CKD progression is unknown. We examined the association of habitual sleep duration and quality with CKD progression in 431 Chronic Renal Insufficiency Cohort (CRIC) Study participants, of whom 48% were women and 50% had diabetes (mean age of 60 years old, mean eGFR =38 ml/min per 1.73 m2, and median urine protein-to-creatinine ratio [UPCR] =0.20 g/g). We assessed sleep duration and quality by 5-7 days of wrist actigraphy and self-report. Primary outcomes were incident ESRD, eGFR slope, log-transformed UPCR slope, and all-cause death. Participants slept an average of 6.5 hours per night; mean sleep fragmentation was 21%. Over a median follow-up of 5 years, we observed 70 ESRD events and 48 deaths. In adjusted analyses, greater sleep fragmentation associated with increased ESRD risk (hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.07 per 1% increase in fragmentation). In adjusted mixed effects regression models, shorter sleep duration (per hour less) and greater sleep fragmentation (per 1% more) each associated with greater eGFR decline (-1.12 and -0.18 ml/min per 1.73 m2 per year, respectively; P=0.02 and P<0.01, respectively) and greater log UPCR slope (0.06/yr and 0.01/yr, respectively; P=0.02 and P<0.001, respectively). Self-reported daytime sleepiness associated with increased risk for all-cause death (hazard ratio, 1.11; 95% confidence interval, 1.02 to 1.20 per one-point increase in the Epworth Sleepiness Scale score). These findings suggest that short and poor-quality sleep are unrecognized risk factors for CKD progression. PMID- 28912377 TI - Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission. AB - The incidence of thyroid cancers has been steadily increasing worldwide over the past few decades. Although five-year survival rates for differentiated thyroid cancers are upwards of 90%, clinical outcomes for patients with undifferentiated, recurrent and/or metastatic disease are often dismal despite conventional interventions. As such, there is a demand for novel treatment options. Cancer immunotherapy represents the ultimate form of personalized medicine by leveraging the specificity and potency of a patient's immune system to kill their tumor. The thyroid cancer microenvironment is rich in immunological cells, making it a reasonable candidate for immunotherapy. This review maps out the immunological features of thyroid cancers and how these can be modulated. There are surprising immunological consequences of conventional therapies that demand attention. Also, hormonal modulation of the immune system is highlighted as a unique and confounding feature of thyroid cancers. A variety of cutting-edge immune-based therapies are discussed, with an emphasis placed on how these can be integrated with the current standard of care. Several high priority areas in need of research are also highlighted. PMID- 28912376 TI - Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura. AB - Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (Cmax [U/mL]) and area under the concentration-time curve (AUC [h?U/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13 mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084. PMID- 28912378 TI - Systematic Mutagenesis of Serine Hydroxymethyltransferase Reveals an Essential Role in Nematode Resistance. AB - Rhg4 is a major genetic locus that contributes to soybean cyst nematode (SCN) resistance in the Peking-type resistance of soybean (Glycine max), which also requires the rhg1 gene. By map-based cloning and functional genomic approaches, we previously showed that the Rhg4 gene encodes a predicted cytosolic serine hydroxymethyltransferase (GmSHMT08); however, the novel gain of function of GmSHMT08 in SCN resistance remains to be characterized. Using a forward genetic screen, we identified an allelic series of GmSHMT08 mutants that shed new light on the mechanistic aspects of GmSHMT08-mediated resistance. The new mutants provide compelling genetic evidence that Peking-type rhg1 resistance in cv Forrest is fully dependent on the GmSHMT08 gene and demonstrates that this resistance is mechanistically different from the PI 88788-type of resistance that only requires rhg1 We also demonstrated that rhg1-a from cv Forrest, although required, does not exert selection pressure on the nematode to shift from HG type 7, which further validates the bigenic nature of this resistance. Mapping of the identified mutations onto the SHMT structural model uncovered key residues for structural stability, ligand binding, enzyme activity, and protein interactions, suggesting that GmSHMT08 has additional functions aside from its main enzymatic role in SCN resistance. Lastly, we demonstrate the functionality of the GmSHMT08 SCN resistance gene in a transgenic soybean plant. PMID- 28912379 TI - Element-based prognostics of occupational pneumoconiosis using micro-proton induced X-ray emission analysis. AB - Pneumoconiosis is an occupational disease accompanied by long-term lung impairment, for which prediction of prognosis is poorly understood because of the complexity of the inhaled particles. Micro-proton-induced X-ray emission (micro PIXE) analysis, which is advantageous for high-sensitivity, two-dimensional element mapping of lung tissues, was used to investigate element-based predictive factors of prognosis in Chinese patients with welder's and coal miner's pneumoconiosis. Chest radiographs and lung function tests showed that most of the coal miners deteriorated, whereas symptoms in some welders were alleviated after 5 yr, as determined by comparing percent vital capacity (%VC) and forced expiratory volume in the 1st second over forced vital capacity (FEV1.0/FVC) to values taken at the initial diagnosis. Micro-PIXE analysis suggested that the most abundant particulates in welder's pneumoconiosis were Fe, Mn, and Ti (metallic oxide),which were accompanied by particulates containing Si, Al, and Ca (aluminum silicate) or only Si (SiO2); the most abundant particulates in coal miner's pneumoconiosis were composed of C, Si, Al, K, and Ti, which were accompanied by particulates containing Ca or Fe. Particulates containing Al, Si, S, K, Ca, and Ti (orthoclase and anorthite) were correlated with severity of fibrosis. Multivariable linear regression suggested that long-term FEV1.0/FVC decrease was independently associated with Si and smoking index, whereas %VC decrease was associated with Si and Ti. A risk index comprised of these factors was developed to predict the prognosis of pneumoconiosis. Micro-PIXE analysis is feasible for the evaluation of elemental composition and dust exposure, especially for patients whose exposure is mixed or uncertain. PMID- 28912380 TI - Exposure of neonatal mice to bromine impairs their alveolar development and lung function. AB - The halogen bromine (Br2) is used extensively in industry and stored and transported in large quantities. Its accidental or malicious release into the atmosphere has resulted in significant casualties. The pathophysiology of Br2 induced lung injury has been studied in adult animals, but the consequences of Br2 exposure to the developing lung are completely unknown. We exposed neonatal mouse littermates on postnatal day 3 (P3) to either Br2 at 400 ppm for 30 min (400/30), to Br2 at 600 ppm for 30 min (600/30), or to room air, then returned them to their dams and observed until P14. Mice exposed to Br2 had decreased survival (S) and had decreased weight (W) at P14 in the 400/30 group (S = 63.5%, W = 6.67 +/- 0.08) and in the 600/30 group (S = 36.1%, W = 5.13 +/- 0.67) as compared with air breathing mice (S = 100%, W = 7.96 +/- 0.30). Alveolar development was impaired, as evidenced by increased mean linear intercept at P14. At P14, Br2 exposed mice also exhibited a decrease of arterial partial pressure of oxygen, decreased quasi-static lung compliance, as well as increased alpha smooth muscle actin mRNA and protein and increased mRNA for IL-1beta, IL-6, CXCL1, and TNFalpha. Global gene expression, evaluated by RNA sequencing and Ingenuity Pathway Analysis, revealed persistent abnormalities in gene expression profiles at P14 involving pathways of "formation of lung" and "pulmonary development." The data indicate that Br2 inhalation injury early in life results in severe lung developmental consequences, wherein persistent inflammation and global altered developmental gene expression are likely mechanistic contributors. PMID- 28912381 TI - Invariant natural killer T cells promote immunogenic maturation of lung dendritic cells in mouse models of asthma. AB - Our previous study showed that invariant natural killer T (iNKT) cells might act as an adjuvant to promote Th2 inflammatory responses in an OVA-induced mouse model of allergic asthma, but the mechanism remains unknown. To clarify the underlying mechanism through which iNKT cells promote Th2 inflammatory responses, we investigated the modulatory influence of iNKT cells on phenotypic and functional maturation of lung dendritic cells (LDCs) using iNKT cell-knockout mice, specific iNKT cell activation, coculture experiments, and adoptive transfer of iNKT cells in mouse models of asthma. Our data showed that iNKT cell deficiency could downregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from a mouse model of asthma. However, elevated activation of iNKT cells by alpha-galactosylceramide and adoptive transfer of iNKT cells could upregulate surface maturation markers and proinflammatory cytokine secretion of LDCs from mouse models of asthma. Meanwhile, iNKT cells significantly influenced the function of LDCs, markedly enhancing Th2 responses in vivo and in vitro. In addition, iNKT cell can induce LDCs expression of CD206 and RELM-alpha, reflecting alternative activation of LDCs in a mouse model of asthma. alpha-Galactosylceramide treatment significantly enhanced expression of CD40L of lung iNKT cells from a mouse model of asthma, and the coculture experiment of LDCs with iNKT cells showed that the blockade of CD40L strongly suppressed surface maturation markers and proinflammatory cytokine production by LDCs. Our data suggest that iNKT cells can promote immunogenic maturation of LDCs to enhance Th2 responses in mouse models of asthma. PMID- 28912383 TI - Physiotherapists as detectives: investigating clues and plots in the clinical encounter. AB - This article investigates the clinical reasoning process of physiotherapists working with patients with chronic muscle pain. The article demonstrates how physiotherapists work with clues and weigh up different plots as they seek to build consistent stories about their patient's illness. The material consists of interviews with 10 Norwegian physiotherapists performed after the first clinical encounter with a patient. Using a narrative approach and Lonergan's theory of interpretation, the study highlights how, like detectives, the therapists work with clues by asking a number of interpretive questions of their data. They interrogate what they have observed and heard during the first session, they also question how the patient's story was told, including the contextual and relation aspects of clue production, and they ask why the patient's story was told to them in this particular way at this particular time. The article shows how the therapists configure clues into various plots on the basis of their experience of working with similar cases and how their detective work is pushed forward by uncertainty and persistent questioning of the data. PMID- 28912384 TI - [Fracture Liaison Service and Osteoporosis Liaison Service.] AB - Fracture Liaison Service(FLS)was initiated in the late 1990s in Europe then afterwards spread to North America and Australia. The aim of FLS is to prevent secondary fractures after fragility fractures. Because of its usefulness it has become a global success through proof of its high efficacy and cost effectiveness. The Japan Osteoporosis Society(JOS)initiated Osteoporosis Liaison Service(OLS)in Japan. FLS and OLS have the same aim-to prevent secondary fractures; however, OSL also aims to prevent primary fractures in clinics and the community. JOS created the role of Osteoporosis Manager(OM), which is a coordinator for OLS, and a total of 1,867 OMs have been approved as of March 2017. PMID- 28912382 TI - Versican is produced by Trif- and type I interferon-dependent signaling in macrophages and contributes to fine control of innate immunity in lungs. AB - Growing evidence suggests that versican is important in the innate immune response to lung infection. Our goal was to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. We first defined the signaling events that regulate versican expression, using bone marrow derived macrophages (BMDMs) from mice lacking specific Toll-like receptors (TLRs), TLR adaptor molecules, or the type I interferon receptor (IFNAR1). We show that LPS and polyinosinic-polycytidylic acid [poly(I:C)] trigger a signaling cascade involving TLR3 or TLR4, the Trif adaptor, type I interferons, and IFNAR1, leading to increased expression of versican by macrophages and implicating versican as an interferon-stimulated gene. The signaling events regulating versican are distinct from those for hyaluronan synthase 1 (HAS1) and syndecan-4 in macrophages. HAS1 expression requires TLR2 and MyD88. Syndecan-4 requires TLR2, TLR3, or TLR4 and both MyD88 and Trif. Neither HAS1 nor syndecan-4 is dependent on type I interferons. The importance of macrophage-derived versican in lungs was determined with LysM/Vcan-/- mice. These studies show increased recovery of inflammatory cells in the bronchoalveolar lavage fluid of poly(I:C) treated LysM/Vcan-/- mice compared with control mice. IFN-beta and IL-10, two important anti-inflammatory molecules, are significantly decreased in both poly(I:C)-treated BMDMs from LysM/Vcan-/- mice and bronchoalveolar lavage fluid from poly(I:C)-treated LysM/Vcan-/- mice compared with control mice. In short, type I interferon signaling regulates versican expression, and versican is necessary for type I interferon production. These findings suggest that macrophage-derived versican is an immunomodulatory molecule with anti inflammatory properties in acute pulmonary inflammation. PMID- 28912385 TI - [Primary fracture prevention through the Osteoporosis Liaison Service.] AB - It is difficult to prevent primary fragility fractures because the subjects have not yet experienced a fracture. The offers of the community Osteoporosis Liaison Service are important for primary prevention of fragility fractures. The prevention, education, enlightenment, and the offer of osteoporosis examinations are included in this service. It is necessary to deliver the prevention services and osteoporosis education according to the age of the subjects. Hence, for young people, it is effective to include in school education that getting high peak bone mass is important, and for the middle-aged population, it is necessary to include education on the maintenance of bone quantity and the impact on risk factors such as smoking and excessive alcohol consumption. Furthermore, early detection of osteoporosis is important, with an osteoporosis check-up being one of the few opportunities for assessing the bone mineral density(BMD)in elderly women. However, there are some problems with osteoporosis check-ups in Japan. First, the implementation and participation rates of osteoporosis check-ups are low. Second, only BMD is set as the most important value for the assessment. Third, the subjects are limited to women in the range of 40-70 years of age with the knot age set at every 5 years. Finally, the setting of the BMD measuring apparatus is low. We adopted Fracture Risk Assessment Tool(FRAX)and loco-check for check-ups at Asahi-machi in the Toyama Prefecture to resolve the above problems and have reported its usefulness. Action by the Osteoporosis Liaison Service to enforce osteoporosis check-ups is expected. Various types of professional medical staff participate in the Osteoporosis Liaison Service as osteoporosis managers. It is desired that the managers will cooperate and function as an osteoporosis project team in the community. PMID- 28912386 TI - [Implementation of Fracture Liaison Service for a secondary prevention of fragility fracture.] AB - Secondary fracture prevention in aged people is most important issue for the reduction of fragility fractures. Implemetation of fractuire liaison service play a key role to achieve secondary fracture prevention with continuous and comprehensive care for fracture patients. Fracture Liaison Service are spread in world-wide, and demonstrated the effects for fracture incidence and economical aspects. PMID- 28912387 TI - [Osteoporosis Liaison Service and exercise regimens, based on Locomotive Syndrome.] AB - The purpose of Osteoporosis Liaison Service(OLS)is primary and secondary prevention of osteoporosis and fragility fracture by multiple medical occupations. Exercise instruction and exercise intervention are important factors in OLS. Exercise has effects of increasing bone density and preventing falls. In OLS, it is also necessary to disseminate knowledge on osteoporosis and fractures to the public. Main measures against locomotive syndrome(LS), meaning weakening of ambulatory ability, are exercise and nutrition, and the LS prevention campaign is thought to lead to prevention of falls. In addition, LS is in common with OLS because it aims to spread such preventive measures widely. Exercise for LS prevention can be used safely and effectively at hospitals and workshops, as well as regional comprehensive care system. PMID- 28912388 TI - [Osteoporosis Liaison Service and nutrition counseling and education.] AB - Nutritional counseling as part of the Osteoporosis Liaison Service(OLS)should provide active nutritional counseling and lifestyle guidance by referring to the detailed methods for conducting "nutritional status assessments", an item of OLS 7, a detailed activity outcome measure of the OLS. After conducting adequate nutritional assessments, the goals for each stage of behavior change should be established, aiming to set roughly one goal for a specified period of time and increasing the goals once improvements have been made. Incorporating feedback in the next improvement plan becomes very important. Good nutritional counseling will surely lead to achieving the OLS goals(improvement in treatment rates and treatment continuation rates). Moreover, it will contribute to decreasing the number of patients with fractures, eliminating sequential fractures and prolonging a healthy life expectancy in Japan. PMID- 28912389 TI - [Osteoporosis Liaison Service and Medication Instruction.] AB - The goals of the osteoporosis liaison service are to prevent the disease more effectively, to diagnose it properly and to provide a higher quality treatment for it as well as to increase healthy life- span and to minimize the gap in health status by offering raising awareness activities. Pharmacist can play an important role in achieving both of goals. "The family pharmacist system", which was introduced by the Pharmaceuticals and Medical Devices Law(Yakkiho)in 2016, is expected to contribute to achieve the former goal while "Health supporting pharmacy" is expected to strive for the latter goal. It is also necessary to build a patient-centered collaborative relationship between hospital pharmacists and those of insurance pharmacy by sharing the information on the patients' medication. In that sense, it seems that osteoporosis managers who have a license for a pharmacist can play a significant role as a collaboration hub in the service and they can be expected to help prevent osteoporosis bone fracture and repeated fracture by supporting them in life in the community. It seems their role as a connector among all pharmacists will be more important. PMID- 28912390 TI - [Osteoporosis Liaison Service and multi medical staff cooperation.] AB - A place of the activity of Osteoporosis Liaison Service (OLS) is classified into the in-hospital and the out-hospital. "Kotsu-Kotsu approach" is performed in our hospital for fracture inpatients as OLS. "Kotsu-Kotsu approach" can be able to performed the various and comprehensive assessment for the patients by multi medical staff, especially Osteoporosis managers. The construction of the cooperation with other facilities is propelled for activity of out-hospital. Ministry of Health, Labour and Welfare impel to establish community-based integrated care systems. Importance adds to OLS under the multi medical staff cooperation that I included the care in the community in more and more from now on. To that end, the leadership of the doctor is required. PMID- 28912391 TI - [Sarcopenia, frailty and osteoporosis.] AB - Skeletal muscle mass declines and muscular strength also weakens with age. This is sarcopenia. Bone shows similar age-dependent changes leading to osteoporosis. Thus, the aging change of muscle and bone shows a similar change. Anatomically, skeletal muscle and bone are closely related. Sarcopenia and osteoporosis are risks of falls and fractures, and the risk for disability is also high. In addition, it is considered that vitamin D is involved in all of its etiologies, and attention to vitamin D is necessary. Along with these similarities, there is a difference between sarcopenia and osteoporosis, which is a gender difference. That is, while osteoporosis tends to occur in postmenopausal women, the decrease in skeletal muscle is more likely to occur in men. In this article, we will explain sarcopenia along with frailty which is likely to be caused by aging, and describe the diagnosis method and the treatment method from the pathophysiology. PMID- 28912392 TI - [Refracture prevention and rehabilitation.] AB - Osteoporosis Liaison Service(OLS)is not only the fracture prevention of the onset, and the refracture prevention holds important positioning. For OLS activity in the hospitals of the fracture risk by FRAX grasp it, and it is important to evaluate the fall risk. What an interval, a motor function including the lower limbs muscular strength evaluate in a fall risk evaluation and TUG and walking speed temporarily for a fall risk evaluation for, the eye opening single leg right time to leave is desirable. It is a problem that an evaluation and treatment for osteoporosis are insufficient by recent DPC induction. PMID- 28912393 TI - [Cost-effectiveness of implementing Osteoporosis Liaison Service program.] AB - Facing with swelling medical expenses, bringing a viewpoint of cost-effectiveness to disease management of osteoporosis has become important. Previous economic evaluations from the UK and the USA have reported that implementing a Fracture Liaison Service program reduces refracture rates and results in healthcare cost savings. In recent years, a model-based cost-effectiveness analysis has been performed in Japan and reported Secondary fracture prevention by Osteoporosis Liaison Service program is cost-effective in Japanese women with osteoporosis who have suffered a hip fracture. In addition, secondary fracture prevention is less expensive than no therapy in high-risk patients with multiple risk factors. PMID- 28912394 TI - [HPV Vaccination Program - The History and Recent Progress]. AB - Four years have passed since HPV vaccination "crisis" occurred in June 2013. In Japan,a publicly funded HPV vaccination program for adolescent females aged 12-16 years began in December 2010. However,the Japanese government withdrew its recommendation for HPV vaccination in June, 2013 because news reports on potential adverse effects of HPV vaccines without any medical evidence appeared repeatedly. The vaccination coverage among adolescent females decreased quickly from around 70%in females born between 1994 and 1999 to only 1%in females born since 2001 over the country. The suspension of recommendation for vaccination has continued to the present,though there is no scientific or epidemiologic evidence to demonstrate the causal linkage between post-vaccination symptoms and the HPV vaccines. Very recently,an ecological investigation reported that similar symptoms also occur in unvaccinated adolescents in Japan. Medical organizations in Japan are also calling for a resumption of the HPV vaccination program. Now,the resumption of the recommendation needs a political judgment. PMID- 28912395 TI - [Cytotoxic Agents and Immune Checkpoint Inhibitors]. AB - It has been reported that favorable influences of cytotoxic agents to anti-tumor immune response included immunogenic cell death and suppression of regulatory T cell and myeloid-derived suppressor cell. Some clinical trials showed that the addition of immune checkpoint inhibitor to standard chemotherapy improved efficacy in patients with non-small-cell lung cancer or malignant melanoma in first-line settings. Phase III trials of the combination of immune checkpoint inhibitor and chemotherapy in several malignancies are ongoing. PMID- 28912396 TI - [Immune-Checkpoint Inhibitors for Lung Cancer with EGFR Mutation]. AB - Recent clinical evidence that anti-PD-1/PD-L1 antibody therapy is superior to cytotoxic chemotherapy for patients with non-small cell lung cancer(NSCLC)that expresses PD-L1 has lead to a paradigm shift in treatment strategies for those patients. However, efficacy of anti-PD-1/PD-L1 antibodies for patients with NSCLC harboring EGFR mutation is generally poor. This lack ofresponse is at least partially attributed to suppression oftumor infiltrating lymphocytes caused by EGFR pathway activation or to low non-synonymous mutation load in NSCLC with EGFR mutation. However, anti-PD-1/PD-L1 antibodies may play some roles in patients who acquired resistance against EGFR tyrosine kinase inhibitors. In this review, relationship between patients with EGFR mutation and treatment using immune checkpoint inhibitors is summarized. PMID- 28912397 TI - [Combination Therapy of Immune Checkpoint Inhibitors]. AB - Recently, monotherapies of immune checkpoint inhibitor have been approved for some malignant tumors such as advanced melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin lymphoma, head and neck cancer in Japan. As the next step, to aim improvement of the clinical benefit, development of combination immunotherapies including immune checkpoint inhibitors are ongoing. In this chapter, recent strategies of clinical development of combination immunotherapy are described. PMID- 28912398 TI - [Therapeutic Cancer Vaccine and Immune Checkpoint Inhibitor]. AB - Therapeutic cancer vaccine enhances a specific immune response against tumor cells in vivo, resulting in exertion of antitumor effects. On the other hand, immune checkpoint inhibitors promote the induction of tumor-specific T cells and also enhance the cytotoxic abilityof these T cells in tumor microenvironment. There is a possibilitythat immune checkpoint inhibitors enhance tumor immune responses induced bytherapeutic cancer vaccine, and it is expected that additive or synergistic effects will be obtained bythe combination of them. Moreover, according to previous reports, we should use an immune checkpoint inhibitor to enhance the cytotoxic ability of tumor-specific T cells as the combination for therapeutic cancer vaccine. Furthermore, the combination of a specific antibodyagainst newlyidentified co-inhibitoryreceptors (Lag-3, Tim-3, TIGIT, etc)and a therapeutic cancer vaccine is also one of newlyexpected treatments in the future. PMID- 28912399 TI - [Adoptive Cell Therapy with Immune Checkpoint Blockade]. AB - Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene modified T cells in recent years. The effector cells mostly express PD-1, therefore the cytotoxic reactivity of the effector cells are inhibited by PD-L1. The combination of the adoptive cell therapy and the immune checkpoint blockade is expected to enhance efficacy. On the other hand, the immune-related adverse events may also be enhanced, therefore, it is needed to develop the combination therapy carefully, improving the cancer antigen-specificity or dealing with the cytokine release syndrome. PMID- 28912400 TI - [Upper G. I. Cancer]. PMID- 28912401 TI - [I. Immunotherapy for Gastroenterological Cancer]. PMID- 28912402 TI - [II. The Role of Extended Surgery for Advanced Gastric Cancer]. PMID- 28912403 TI - [III. Peri-Operative Chemotherapy for Gastric Cancer]. PMID- 28912404 TI - Significance of UICC Activities in Global Health Initiatives on Cancer Looking Towards the Future of Cooperative Networks for Cancer Care in Asia - A Dialogue with the Union for International Cancer Control(UICC). AB - At the 24th Asia Pacific Cancer Conference held in Seoul, Korea from 22 to 24 June 2017, a dialogue with Dr.Cary Adams, CEO of the Union for International Cancer Control(UICC)was held to discuss the significance of UICC activities in global health initiatives on cancer and pathways for cooperation on cancer control and care.UICC is engaged in a wide range of capacity building, advocacy and convening initiatives and is increasingly focusing on multi-sectoral approaches.In Japan activities are still predominantly focused on scientific and clinical research and this dialogue provided an opportunity to discuss the possibilities for expanding cooperation in Asia, using the UICC Asia Regional Office(UICC-ARO)as a platform.Discussion also covered UICC's new C/Can 2025: City Cancer Challenge, a new multi-sectoral initiative that has the potential to bring multiple stakeholders together. PMID- 28912405 TI - [Exploring the Possibility of New Biomarkers of Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer (NSCLC)]. AB - Mutation burden in a tumor, presumably involving neo-antigens in the tumor tissue, is also thought to be one of the better predictors for the efficacy of immune checkpoint inhibitors. However, it is difficult to analyze the mutation burden routinely in the clinic. Here, we describe more convenient factors that can be used as surrogate markers of mutation burden. Ninety-four patients with NSCLC who underwent resection in our institution were recruited for this study. Mutation burden and major gene alterations were analyzed by using next generation sequencing. Several immunological parameters were also assessed using immunohistochemistry. Statistical analysis was performed on mutation burden, major gene alternations, immunohistochemistry, and clinical parameters. The median mutation load was 54 mutations(range, 10-363 mutations). Squamous cell carcinoma, EGFRmutation -negativity, and TP53 alteration-positivity were closely connected with higher mutation burden. Multiple regression analysis showed that mutation burden in the tumor could be associated with EGFRmutation and TP53 alteration status. PMID- 28912406 TI - [A Retrospective Study Analyzing the Clinical Course of Patients with Non-Small Cell Lung Cancer Receiving Local or Systemic Therapy after Post-Operative Recurrence]. AB - BACKGROUND: While systemic therapy is one of the therapeutic options available for post-operative recurrence of non-small cell lung cancer, efficacy of local therapy for locoregional recurrence or limited metastatic lesions has also been reported. OBJECTIVE: We aimed to evaluate the clinical course of patients with post-operative recurrence(locoregional or limited metastatic lesion)after receiving local or systemic therapy. METHODS: Clinical data were retrospectively analyzed and survival duration was compared using the logrank test. RESULTS: A total of 22 patients were included. Median progression-free survival in patients receiving local therapy, systemic chemotherapy, or a combination of both therapies was 15.1 months, 6.3 months, and 13 months, respectively. Two patients receiving treatment with EGFR-TKI did not show disease progression at 41.3 months and 45.8 months(p=0.265). Median overall survivals in patients receiving local therapy, systemic chemotherapy, or a combination of both therapies were 26.5 months, 20 months, and 37.9 months, respectively(p=0.510). After the treatment, 6 patients showed regrowth of the recurrent lesion, 8 patients showed remote metastases, and 2 patients showed both regrowth of the recurrent lesion and remote metastases. CONCLUSION: Patients who received treatment including local therapy showed longer survival duration, but statistical significance was not detected. Our study suggested that regrowth of the recurrent lesion and remote metastases can be equally observed after treatment. PMID- 28912407 TI - Diagnostic Efficacy of Percutaneous Renal Tumor Biopsy - Concomitant Use of Frozen Section to Accurately Diagnose Renal Tumor with Necrosis. AB - OBJECTIVES: To evaluate the diagnostic efficacy of percutaneous renal tumor biopsy. METHODS: We retrospectively investigated 23 patients who underwent percutaneous renal tumor biopsy since 2008 at Department of Renal and Urologic Surgery, Asahikawa Medical University Hospital. We examined indications of biopsy, diagnostic concordance rate between urologists, radiologists and biopsy findings, pathological findings and biopsy-related complications. RESULTS: Renal tumor biopsy was performed under ultrasonography guidance in 21 patients and computed tomography guidance in 2. The most frequent indication to perform biopsy was to determine histological subtype of renal cell carcinoma(RCC)before treatment. The second indication was to clarify the nature of renal tumor. Biopsy findings revealed RCC in 17 patients and urothelial carcino- ma(UC)in 6. Diagnostic concordance rate between urologist's diagnosis and biopsy findings was 91%(21/23), which showed the same result between radiologists and biopsy findings. Biopsy-related adverse event included needle tract implantation in 1 patient with UC. Another patient who had central necrosis in the tumor showed insufficient material causing repeat biopsy with frozen section. Except this patient, initial renal tumor biopsy was successful in all patients by concomitant use of frozen section for tumor with central necrosis. The overall diagnostic rate of initial biopsy was 95.7%(22/23). CONCLUSIONS: Despite a small number of patients and a retrospective nature, the present study shows that renal tumor biopsy plays an important role in diagnosis of renal tumor. Concomitant use of frozen section might be considered at the time of renal tumor biopsy in patients with necrotic renal tumor to avoid repeat biopsy. However, we should take into consideration that there are some possible risks of needle tract implantation in cases with UC when we perform percutaneous renal tumor biopsy. PMID- 28912408 TI - [Results of a Drug Use Survey of Filgrastim Biosimilar 1(Filgrastim BS Syringe for Inj. "MOCHIDA"and "F")]. AB - With the aim of evaluating the safety and efficacy of filgrastim biosimilar 1(Filgrastim BS syringe for Inj. "MOCHIDA"and "F"), we conducted a drug use results survey of this product for its indications, including mobilization of hematopoietic stem cells into peripheral blood and chemotherapy-induced neutropenia. Of the 518 cases enrolled between August 2013 and July 2015, 495 were selected to be subjects of our safety and efficacy evaluations. 37 cases (7.47%)experienced side effects, which were mainly lower back pain(19, 3.84%), fever(8, 1.62%)and bone pain(3, 0.61%). As for serious side effects, interstitial pneumonia was reported in 2 cases, but this disorder has already been ecognized as being associated with the use of filgrastim originator, and there were no reports of unknown side effects calling for immediate attention. In addition, we investigated hypersensitivity reactions(such as nettle rash and anaphylactic shock)and diminished drug effects, both of which are considered to be attributable to immunogenicity, and found that non-serious nettle rash was reported in 2 cases. However, there have been no reports of anaphylactic shock or diminished drug effects. The efficacy rate based on physicians' clinical observations was 97.98%. This study confirmed that there are no problems with the clinical use of filgrastim biosimilar 1. PMID- 28912409 TI - [A Case of Pneumocystis Pneumonia during Adjuvant Dose-Dense Chemotherapy for Breast Cancer]. AB - A 47-year-old woman received adjuvant chemotherapy for breast cancer. On the 13th day of 4 courses of dose-dense AC therapy, she developed a fever. She was orally administered an antibioticfor febrile neutropenia treatment. She showed no improvement of symptoms and gradually presented with new symptoms, including a non-productive cough and dyspnea. After admission, she underwent a further examination, and was provided a diagnosis of pneumocystis pneumonia. It is reported that patients receiving chemotherapy for solid tumors are less likely to develop opportunistic infections. However, patients receiving dose-dense chemotherapy may have a higher risk for developing opportunistic infections than those receiving conventional chemotherapy. PMID- 28912410 TI - [Psoriasis and Psoriatic Arthritis Induced by Nivolumab in a Patient with Advanced Non-Small-Cell Lung Cancer]. AB - BACKGROUND: Immune checkpoint-blocking antibodies may induce specific side effects known as immune-relatedad verse events. CASE PRESENTATION: A 66-year oldman without any history of autoimmune disease was referredto our hospital for treatment of lung cancer in the right upper lobe. The tumor was diagnosed as Stage III A non-small-cell lung cancer by using bronchoscopic biopsy, computedtomography, andFDG -PET. After a single course of cisplatin andpemetrexed , the tumor size increasedremarkably andthe regimen was changedto nivolumab(3mg/kg every 2 weeks). Psoriasis andpsoriatic arthritis were observed after 4 courses of nivolumab. Nivolumab treatment continued, and the oral administration of predni- solone(20mg/day)couldimprove psoriasis andpsoriatic arthritis. However, the lung cancer showedprogressive disease after the 11th course of nivolumab. CONCLUSION: Psoriasis andpsoriatic arthritis were inducedby nivolumab in the patient without any history of autoimmune disease. It is unclear how prednisolone affected nivolumab for the treatment of lung cancer. PMID- 28912411 TI - [Early VATS(Video-Assisted Thoracoscopic Surgery)Was Effective for a Case of Chylothorax after Lung Cancer Excision]. AB - A 66-year-old man underwent a right upper lobectomy and lymph node dissection for lung cancer. We confirmed a milky white pleural effusion after diet initiation on the first postoperative day, and a chylothorax was diagnosed. The patient began a f at-restricted diet; however, the pleural effusion did not decrease. Therefore, we performed VATS(video-assisted thoracoscopic surgery)1 week after surgery with good results. Early VATS for a postoperative chylothorax was useful. PMID- 28912412 TI - [A Case of Advanced Neuroendocrine Cell Carcinoma of the Stomach Treated with S-1 and Cisplatin Chemotherapy]. AB - A 69-year-old man presented to our hospital because of epigastric pain. A type 2 lesion was seen in the lesser curvature of the antrum of the stomach. A moderately differentiated adenocarcinoma(human epidermal growth factor receptor 2 negative) was diagnosed by biopsy. Abdominal computed tomography showed a mass shadow 52mm in diameter in the pyloric region invading the surrounding organs, but no evidence of distant metastasis. Chemotherapy with S-1 and cisplatin(SP therapy)was initiated because of a diagnosis of locally advanced gastric cancer. After 2 courses of chemotherapy, the tumor shrinkage rate was 70%, confirming that treatment was effective. However, severe skin disorders developed, precluding the continuation of chemotherapy. Staging laparoscopy showed no evidence of peritoneal dissemination, but invasion into the superior mesenteric vein was noted. The tumor was resected by pancreaticoduodenectomy with partial resection of the venous wall. Pathological examination of the resected specimens provided a definite diagnosis of neuroendocrine cell carcinoma. As of 1 year and 7 months after surgery, there has been no observation of metastasis or recurrence. SP therapy was suggested to be a useful regimen for preoperative chemotherapy in patients with locally advanced neuroendocrine cell carcinoma. PMID- 28912413 TI - [A Case of Alcoholic Liver Disease Presenting as Prominent Accumulation of Ascites Associated with Liver Damage Due to CapeOX]. AB - A 75-year-old man with rectal cancer had consumed an average of6 6 g of alcohol per day for 47 years. However, his liver function was within normal limits and his Child-Pugh classification was A before initiation of therapy. He underwent neoadjuvant chemoradiation and a low anterior resection. The patient then received CapeOX as an adjuvant therapy. During the fourth cycle of CapeOX, computed tomography(CT)showed massive ascites. The chemotherapy was discontinued and treatment including a diuretic agent was initiated. The ascites gradually decreased and 8 months after the discontinuation of CapeOX, CT showed neither the presence ofascites nor recurrence ofthe cancer or metastasis. When a patient has a history ofexcessive alcohol intake, even iftest results for liver function are within normal limits, we should be aware ofthe hepatic toxicity ofCapeOX. PMID- 28912414 TI - Polish Experience with Liver Transplantation and Post-Transplant Outcomes in Children with Urea Cycle Disorders. AB - BACKGROUND Liver transplantation (LT) is recommended for various metabolic diseases, including urea cycle disorders (UCDs). The aim of this study was to determine indications and outcomes of LT for UCDs in the tertiary reference Children's Hospital in Warsaw, Poland. MATERIAL AND METHODS Medical charts of children with UCD who underwent LT between 2008 and July 2016 were retrospectively reviewed. The following parameters were analyzed: symptoms at time of diagnosis, age at diagnosis, age at transplantation, graft characteristics and survival, postsurgical complications, and biochemical and laboratory results before and after transplantation. RESULTS Twelve patients with UCD who underwent LT at a mean age of 5 y (0.5-14 y) received a total of 14 liver grafts. Four children (33%) received a living donor graft, while 8 (68%) got a deceased donor liver graft. A total number of transplanted organs consisted of 9 (64%) whole-liver grafts and 5 (36%) reduced-size grafts. The 30-day post transplant patient survival rate was 100% and graft survival rate was 93% (13/14). For those with a post-transplant follow-up of at least 1 year (n=10/12), the 1-year patient survival rate was 100% and the graft survival rate was 85.7% (12/14). Median peak of blood ammonia at presentation was 653 (159-2613) ug/dL (normal <80 ug/dl), and median peak of blood glutamine was 1273.2 umol/l (964 3900 umol/l). There was 1 episode of hyperammonemia following LT, but it was not due to UCD. Six (50%) patients were diagnosed with some degree of developmental delay/neurological impairment before transplantation, which remained stable or slightly improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at follow-up. CONCLUSIONS LT leads to eradication of hyperammonemia, withdrawal of dietary restrictions with low-protein diet, and potentially improved neurocognitive development. PMID- 28912415 TI - Targeting Overexpressed Activating Transcription Factor 1 (ATF1) Inhibits Proliferation and Migration and Enhances Sensitivity to Paclitaxel In Esophageal Cancer Cells. PMID- 28912416 TI - A Case of Tranexamic Acid as Adjunctive Treatment for Chronic Subdural Hematoma with Multiple Recurrences. AB - BACKGROUND Chronic subdural hematoma (CSDH) is a common neurosurgical condition that is treated using a cranial burr hole evacuation procedure, but recurrence is common. The use of anticoagulant therapy can increase the risk of developing a recurrent subdural hematoma. We present a challenging case of a patient on long term anticoagulant therapy following previous aortic and aortic valve surgery who had CSDH with multiple recurrences and was ultimately treated with tranexamic acid as an adjunct to surgery. CASE REPORT A male patient in his mid-sixties presented with a headache and bilateral CSDH. Apart from a mechanical heart valve, he was otherwise healthy. A standard burr hole evacuation was performed, but the left hematoma and symptoms recurred after three months, and he presented with additional symptoms of aphasia and right-hand weakness. He had an additional three procedures followed by recurrences over a period of six weeks. Following his fifth and final surgical procedure, he was given postoperative intravenous tranexamic acid 10 mg/kg four times during the first 24 hours with dalteparin sodium 9,500 international units (IU) twice daily. His symptoms resolved, and after nine months he had no residual hematoma, and no thromboembolic complications occurred. CONCLUSIONS This case has demonstrated that tranexamic acid can be used as an adjunctive treatment to surgery when dealing with recurring CSDH, even in patients who require concomitant anticoagulant therapy. Although clinical trials are underway to evaluate tranexamic acid as a medical treatment for CSDH, this case report may support further studies that include patients with risk factors for thromboembolic disease. PMID- 28912417 TI - Comparison of Leukocyte Esterase Testing of Synovial Fluid with Synovial Histology for the Diagnosis of Periprosthetic Joint Infection. AB - BACKGROUND Periprosthetic joint infection (PJI) is a complication of total joint arthroplasty (TJA). The leukocyte esterase (LE) strip test and histology are diagnostic methods for PJI. The aims of this study were to determine the sensitivity and specificity of the LE strip test and to compare it with histology in the diagnosis of PJI. MATERIAL AND METHODS Between January and December 2015, 93 patients who underwent TJA with PJI were enrolled in the study. Synovial fluid samples were tested with an LE strip, and three synovial tissue samples from each patient underwent frozen section and formalin-fixed histology. Recent criteria from the Musculoskeletal Infection Society (MSIS) were used for the diagnosis of PJI. RESULTS Ninety-three patients studied included 38 cases of PJI and 55 non infected cases. Sensitivity and specificity of the LE strip test were 92.1% (95% CI, 77.5-97.9%) and 96.4% (95% CI, 86.4-99.4%), respectively. There was no significant difference in sensitivity (p=0.249) or specificity (p=0.480) between frozen and paraffin sections for histology; the two methods were strongly correlated (phi=0.892). Comparison of the LE test results with histology showed a strong correlation (phi=0.758, and phi=0.840). CONCLUSIONS The findings of this preliminary study have shown that the LE strip test on synovial fluid showed similar sensitivity and specificity as histology for the diagnosis of PJI, indicating that that further controlled clinical studies should be performed to investigate the role of the LE strip test for the early diagnosis of PJI. PMID- 28912418 TI - Genesis of ultra-high-Ni olivine in high-Mg andesite lava triggered by seamount subduction. AB - The Kamchatka Peninsula is a prominent and wide volcanic arc located near the northern edge of the Pacific Plate. It has highly active volcanic chains and groups, and characteristic lavas that include adakitic rocks. In the north of the peninsula adjacent to the triple junction, some additional processes such as hot asthenospheric injection around the slab edge and seamount subduction operate, which might enhance local magmatism. In the forearc area of the northeastern part of the peninsula, monogenetic volcanic cones dated at <1 Ma were found. Despite their limited spatiotemporal occurrence, remarkable variations were observed, including primitive basalt and high-Mg andesite containing high-Ni (up to 6300 ppm) olivine. The melting and crystallization conditions of these lavas indicate a locally warm slab, facilitating dehydration beneath the forearc region, and a relatively cold overlying mantle wedge fluxed heterogeneously by slab-derived fluids. It is suggested that the collapse of a subducted seamount triggered the ascent of Si-rich fluids to vein the wedge peridotite and formed a peridotite pyroxenite source, causing the temporal evolution of local magmatism with wide compositional range. PMID- 28912419 TI - Identifying topologically associating domains and subdomains by Gaussian Mixture model And Proportion test. AB - The spatial organization of the genome plays a critical role in regulating gene expression. Recent chromatin interaction mapping studies have revealed that topologically associating domains and subdomains are fundamental building blocks of the three-dimensional genome. Identifying such hierarchical structures is a critical step toward understanding the three-dimensional structure-function relationship of the genome. Existing computational algorithms lack statistical assessment of domain predictions and are computationally inefficient for high resolution Hi-C data. We introduce the Gaussian Mixture model And Proportion test (GMAP) algorithm to address the above-mentioned challenges. Using simulated and experimental Hi-C data, we show that domains identified by GMAP are more consistent with multiple lines of supporting evidence than three state-of-the-art methods. Application of GMAP to normal and cancer cells reveals several unique features of subdomain boundary as compared to domain boundary, including its higher dynamics across cell types and enrichment for somatic mutations in cancer.Spatial organization of the genome plays a crucial role in regulating gene expression. Here the authors introduce GMAP, the Gaussian Mixture model And Proportion test, to identify topologically associating domains and subdomains in Hi-C data. PMID- 28912420 TI - Room-temperature 2D semiconductor activated vertical-cavity surface-emitting lasers. AB - Two-dimensional (2D) semiconductors are opening a new platform for revitalizing widely spread optoelectronic applications. The realisation of room-temperature vertical 2D lasing from monolayer semiconductors is fundamentally interesting and highly desired for appealing on-chip laser applications such as optical interconnects and supercomputing. Here, we present room-temperature low-threshold lasing from 2D semiconductor activated vertical-cavity surface-emitting lasers (VCSELs) under continuous-wave pumping. 2D lasing is achieved from a 2D semiconductor. Structurally, dielectric oxides were used to construct the half wavelength-thick cavity and distributed Bragg reflectors, in favour of single mode operation and ultralow optical loss; in the cavity centre, the direct bandgap monolayer WS2 was embedded as the gain medium, compatible with the planar VCSEL configuration and the monolithic integration technology. This work demonstrates 2D semiconductor activated VCSELs with desirable emission characteristics, which represents a major step towards practical optoelectronic applications of 2D semiconductor lasers.Two-dimensional materials have recently emerged as interesting materials for optoelectronic applications. Here, Shang et al. demonstrate two-dimensional semiconductor activated vertical-cavity surface emitting lasers where both the gain material and the lasing characteristics are two-dimensional. PMID- 28912421 TI - Pollination of Ficus elastica: India rubber re-establishes sexual reproduction in Singapore. AB - Ficus elastica, otherwise known as India Rubber (although its geographical origins are unclear), was an important source of latex in the early 19th century and was widely cultivated in tropical Asia. Like all figs, F. elastica is dependent on tiny, highly specific wasps for pollination, and detailed studies based out of Singapore in the 1930s suggested that through the loss of its pollinator F. elastica was extinct in the wild. However, around 2005 wild seedlings of F. elastica began appearing in Singapore. We identified the pollinator as Platyscapa clavigera, which was originally described from F. elastica in Bogor in 1885. A visit to Bogor Botanical Gardens revealed that not only was F. elastica being pollinated by P. clavigera in the gardens, but there was clear evidence it had been reproducing naturally there over many decades. Although Singapore has a native fig flora of over 50 species, F. elastica went unpollinated for at least 70 years and probably from the time it was introduced during the 19th century. These observations illustrate the extraordinary specificity of this interaction and, through the fig's ability to wait for its pollinators, demonstrates one way in which such highly specific interactions can be evolutionarily stable. PMID- 28912422 TI - Children and adults with Attention-Deficit/Hyperactivity Disorder cannot move to the beat. AB - Children and adults with Attention-Deficit Hyperactivity Disorder (ADHD) fail in simple tasks like telling whether two sounds have different durations, or in reproducing single durations. The deficit is linked to poor reading, attention, and language skills. Here we demonstrate that these timing distortions emerge also when tracking the beat of rhythmic sounds in perceptual and sensorimotor tasks. This contrasts with the common observation that durations are better perceived and produced when embedded in rhythmic stimuli. Children and adults with ADHD struggled when moving to the beat of rhythmic sounds, and when detecting deviations from the beat. Our findings point to failure in generating an internal beat in ADHD while listening to rhythmic sounds, a function typically associated with the basal ganglia. Rhythm-based interventions aimed at reinstating or compensating this malfunctioning circuitry may be particularly valuable in ADHD, as already shown for other neurodevelopmental disorders, such as dyslexia and Specific Language Impairment. PMID- 28912423 TI - The Chinese herbal formula Free and Easy Wanderer ameliorates oxidative stress through KEAP1-NRF2/HO-1 pathway. AB - Posttraumatic stress disorder (PTSD) gains a lot of attention due to high prevalence and strong psychological upset, but the etiology remains undefined and effective treatment is quite limited. Growing studies demonstrated the involvement of oxidative stress in various psychiatry diseases, suggesting anti oxidation therapy might be a strategy for PTSD treatment. Free and Easy Wanderer (FAEW) is a poly-herbal drug clinically used in China for hundreds of years in the treatment of psychiatric disorder. We hypothesized that FAEW exerts clinical effects through the activity against oxidative stress with fluoxetine as antidepressant control drug. Our results revealed that FAEW significantly reduced both endogenous and H2O2-induced exogenous ROS levels in the human glioblastoma T98G and neuroblastoma SH-SY5Y cell lines. Transcriptome-wide microarray analysis indicated NRF2/HO-1 as the common target of FAEW and fluoxetine. Western blotting assay proved that the two drugs promoted NRF2 release from KEAP1 in the cytoplasm and translocation to the nuclei in a KEAP1-dependent manner, the expression of the protein HO-1 increased accordingly, suggesting the participation of KEAP1 NRF2/HO-1 pathway. The chemical constituents of FAEW (i.e. paeoniflorin, baicalin) bound to KEAP1 in silico, which hence might be the effective substances of FAEW. In conclusion, FAEW counteracted H2O2-induced oxidative stress through KEAP1-NRF2/HO-1 pathway. PMID- 28912424 TI - Electric field and aging effects of uniaxial ferroelectrics Sr x Ba1-x Nb2O6 probed by Brillouin scattering. AB - Static and dynamic heterogeneity of disordered system is one of the current topics in materials science. In disordered ferroelectric materials with random fields, dynamic polar nanoregions (PNRs) appear at Burns temperature and freeze into nanodomain state below Curie temperature (T C). This state is very sensitive to external electric field and aging by which it gradually switches into macrodomain state. However, the role of PNRs in such states below T C is still a puzzling issue of materials science. Electric field and aging effects of uniaxial ferroelectric Sr x Ba1-x Nb2O6 (x = 0.40, SBN40) single crystals were studied using Brillouin scattering to clarify the critical nature of PNRs in domain states below T C. On field heating, a broad anomaly in longitudinal acoustic (LA) velocity at low temperature region was due to an incomplete alignment of nanodomains caused by the interaction between PNRs. A sharp anomaly near T C was attributed to the complete switching of nanodomain to macrodomain state owing to the lack of interaction among PNRs. After isothermal aging below T C, the noticeable increase of LA velocity was observed. It was unaffected by cyclic temperature measurements up to T C, and recovered to initial state outside of a narrow temperature range above and below aging temperature. PMID- 28912425 TI - Predictive models of minimal hepatic encephalopathy for cirrhotic patients based on large-scale brain intrinsic connectivity networks. AB - We aimed to find the most representative connectivity patterns for minimal hepatic encephalopathy (MHE) using large-scale intrinsic connectivity networks (ICNs) and machine learning methods. Resting-state fMRI was administered to 33 cirrhotic patients with MHE and 43 cirrhotic patients without MHE (NMHE). The connectivity maps of 20 ICNs for each participant were obtained by dual regression. A Bayesian machine learning technique, called Graphical Model-based Multivariate Analysis, was applied to determine ICN regions that characterized group differences. The most representative ICNs were evaluated by the performance of three machine learning methods (support vector machines (SVMs), multilayer perceptrons (MLP), and C4.5). The clinical significance of these potential biomarkers was further tested. The temporal lobe network (TLN), and subcortical network (SCN), and sensorimotor network (SMN) were selected as representative ICNs. The distinct functional integration patterns of the representative ICNs were significantly correlated with behavior criteria and Child-Pugh scores. Our findings suggest the representative ICNs based on GAMMA can distinguish MHE from NMHE and provide supplementary information to current MHE diagnostic criteria. PMID- 28912426 TI - Deconvolution of DNA methylation identifies differentially methylated gene regions on 1p36 across breast cancer subtypes. AB - Breast cancer is a complex disease consisting of four distinct molecular subtypes. DNA methylation-based (DNAm) studies in tumors are complicated further by disease heterogeneity. In the present study, we compared DNAm in breast tumors with normal-adjacent breast samples from The Cancer Genome Atlas (TCGA). We constructed models stratified by tumor stage and PAM50 molecular subtype and performed cell-type reference-free deconvolution to control for cellular heterogeneity. We identified nineteen differentially methylated gene regions (DMGRs) in early stage tumors across eleven genes (AGRN, C1orf170, FAM41C, FLJ39609, HES4, ISG15, KLHL17, NOC2L, PLEKHN1, SAMD11, WASH5P). These regions were consistently differentially methylated in every subtype and all implicated genes are localized to the chromosomal cytoband 1p36.3. Seventeen of these DMGRs were independently validated in a similar analysis of an external data set. The identification and validation of shared DNAm alterations across tumor subtypes in early stage tumors advances our understanding of common biology underlying breast carcinogenesis and may contribute to biomarker development. We also discuss evidence of the specific importance and potential function of 1p36 in cancer. PMID- 28912427 TI - DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma. AB - Epigenetic deregulation is a hallmark of cancer characterized by frequent acquisition of new DNA methylation in CpG islands. To gain insight into the methylation changes of canine DLBCL, we investigated the DNA methylome in primary DLBCLs in comparison with control lymph nodes by genome-wide CpG microarray. We identified 1,194 target loci showing different methylation levels in tumors compared with controls. The hypermethylated CpG loci included promoter, 5'-UTRs, upstream and exonic regions. Interestingly, targets of polycomb repressive complex in stem cells were mostly affected suggesting that DLBCL shares a stem cell-like epigenetic pattern. Functional analysis highlighted biological processes strongly related to embryonic development, tissue morphogenesis and cellular differentiation, including HOX, BMP and WNT. In addition, the analysis of epigenetic patterns and genome-wide methylation variability identified cDLBCL subgroups. Some of these epigenetic subtypes showed a concordance with the clinical outcome supporting the hypothesis that the accumulation of aberrant epigenetic changes results in a more aggressive behavior of the tumor. Collectively, our results suggest an important role of DNA methylation in DLBCL where aberrancies in transcription factors were frequently observed, suggesting an involvement during tumorigenesis. These findings warrant further investigation to improve cDLBCL prognostic classification and provide new insights on tumor aggressiveness. PMID- 28912428 TI - IL-37 is associated with osteoarthritis disease activity and suppresses proinflammatory cytokines production in synovial cells. AB - The objective of this study is to investigate the correlation between IL-37 level and osteoarthritis activity and to determine the anti-inflammatory effects of IL 37 in peripheral blood mononuclear cells (PBMCs) and synovial cells (SCs) from osteoarthritis (OA) patients, which including 32 patients with erosive inflammatory OA (EIOA) and 40 patients with primary generalized OA (PGOA), 40 age and sex matched healthy volunteers were recruited as healthy controls (HCs). The protein and relative mRNA levels of IL-37 were significant increased in the blood of EIOA patients compared with those of PGOA patients and HCs. Serum IL-37 levels of OA patients were positively correlated with VAS score, as well as with CRP, ESR in blood. Positive correlations were also observed among IL-37 with IL-1beta, TNF-alpha and IL-6 in synovial cells. Furthermore, the expression of IL-1beta, TNF-alpha and IL-6 in PBMCs and SCs from EIOA patients was suppressed by IL-37 in vitro. In conclusion, our results indicated that IL-37 increased in EIOA patients and was positively correlated with disease activity, the pro-inflammatory cytokines such as IL-1beta, TNF-alpha and IL-6 in PBMCs and synovial cells from EIOA patients were restrained by recombinant IL-37. Thus, IL-37 may serve as a novel therapeutic target for the treatment of OA inflammation. PMID- 28912429 TI - Production and Characteristics of a Novel Xylose- and Alkali-tolerant GH 43 beta xylosidase from Penicillium oxalicum for Promoting Hemicellulose Degradation. AB - beta-xylosidase is a pivotal enzyme for complete degradation of xylan in hemicelluloses of lignocelluloses, and the xylose- and alkali-tolerant beta xylosidase with high catalytic activity is very attractive for promoting enzymatic hydrolysis of alkaline-pretreated lignocellulose. In this study, a novel intracellular glycoside hydrolase family 43 beta-xylosidase gene (xyl43) from Penicillium oxalicum 114-2 was successfully high-level overexpressed in Pichia pastoris, and the secreted enzyme was characterized. The beta-xylosidase Xyl43 exhibited great pH stability and high catalytic activity in the range of pH 6.0 to 8.0, and high tolerance to xylose with the Ki value of 28.09 mM. The Xyl43 could effectively promote enzymatic degradation of different source of xylan and hemicellulose contained in alkaline-pretreated corn stover, and high conversion of xylan to xylose could be obtained. PMID- 28912430 TI - STIM1-dependent Ca2+ signaling regulates podosome formation to facilitate cancer cell invasion. AB - The clinical significance of STIM proteins and Orai Ca2+ channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca2+ signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca2+ entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1-/-) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca2+ microdomain that is the molecular basis for Ca2+ sensitivity controlling podosome formation. PMID- 28912431 TI - Phylogeography of the sand dollar genus Encope: implications regarding the Central American Isthmus and rates of molecular evolution. AB - Vicariant events have been widely used to calibrate rates of molecular evolution, the completion of the Central American Isthmus more extensively than any other. Recent studies have claimed that rather than the generally accepted date of ~3 million years ago (Ma), the Isthmus was effectively complete by the middle Miocene, 13 Ma. We present a fossil calibrated phylogeny of the new world sand dollar genus Encope, based on one nuclear and four mitochondrial genes, calibrated with fossils at multiple nodes. Present day distributions of Encope are likely the result of multiple range contractions and extinction events. Most species are now endemic to a single region, but one widely distributed species in each ocean is composed of morphotypes previously described as separate species. The most recent separation between eastern Pacific and Caribbean extant clades occurred at 4.90 Ma, indicating that the Isthmus of Panama allowed genetic exchange until the Pliocene. The rate of evolution of mitochondrial genes in Encope has been ten times slower than in the closely related genera Mellita and Lanthonia. This large difference in rates suggests that splits between eastern Pacific and Caribbean biota, dated on the assumption of a "universal" mitochondrial DNA clock are not valid. PMID- 28912432 TI - Mitigating Motor Neuronal Loss in C. elegans Model of ALS8. AB - ALS8 is a late-onset familial autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS) caused by a point mutation (P56S) in the VAPB gene (VAMP associated protein isoform B). Here, we generated two C. elegans models of the disease: a transgenic model where human VAPB wild-type (WT) or P56S mutant was expressed in a subset of motor neurons, and a second model that targeted inducible knockdown of the worm's orthologue, vpr-1. Overexpression of human VAPB in DA neurons caused a backward locomotion defect, axonal misguidance, and premature neuronal death. Knockdown of vpr-1 recapitulated the reduction in VAPB expression associated with sporadic cases of human ALS. It also caused backward locomotion defects as well as an uncoordinated phenotype, and age-dependent, progressive motor neuronal death. Furthermore, inhibiting phosphatidylinositol-4 (PtdIns 4)-kinase activity with PIK-93 reduced the incidence of DA motor neuron loss and improved backward locomotion. This supports the loss of VAPB function in ALS8 pathogenesis and suggests that reducing intracellular PtdIns4P might be an effective therapeutic strategy in delaying progressive loss of motor neurons. PMID- 28912433 TI - Electron beam detection of a Nanotube Scanning Force Microscope. AB - Atomic Force Microscopy (AFM) allows to probe matter at atomic scale by measuring the perturbation of a nanomechanical oscillator induced by near-field interaction forces. The quest to improve sensitivity and resolution of AFM forced the introduction of a new class of resonators with dimensions at the nanometer scale. In this context, nanotubes are the ultimate mechanical oscillators because of their one dimensional nature, small mass and almost perfect crystallinity. Coupled to the possibility of functionalisation, these properties make them the perfect candidates as ultra sensitive, on-demand force sensors. However their dimensions make the measurement of the mechanical properties a challenging task in particular when working in cavity free geometry at ambient temperature. By using a focused electron beam, we show that the mechanical response of nanotubes can be quantitatively measured while approaching to a surface sample. By coupling electron beam detection of individual nanotubes with a custom AFM we image the surface topography of a sample by continuously measuring the mechanical properties of the nanoresonators. The combination of very small size and mass together with the high resolution of the electron beam detection method offers unprecedented opportunities for the development of a new class of nanotube-based scanning force microscopy. PMID- 28912434 TI - Food-grade filler particles as an alternative method to modify the texture and stability of myofibrillar gels. AB - A series of food grade particles were characterized for their potential as fillers in myofibrillar gels. The fillers were separated into (i) hydrophilic, insoluble, crystalline particles and (ii) starch granules. The particles used were microcrystalline cellulose, oat fiber and walnut shell flour, as well as potato and tapioca starches. Crystalline particles increased hardness and decreased recovery properties. Although all of these fillers decreased the T2 relaxation time of water, this was dependent on particle type and size. An increase in gel strength was observed with increasing filler content, which was attributed to particle crowding. Native potato starch was the most efficient at increasing liquid retention, while native tapioca was the least effective. Gel strength increased significantly only for the native potato and modified tapioca starches, but no effect on recovery attributes were observed for any of the starch varieties. The potato starches became swollen and hydrated to a similar extent during the protein gelation process, while the native tapioca starch gelatinized at higher temperatures, and the modified tapioca showed little evidence of swelling. T2 relaxometry supported this finding, as the meat batters containing native potato starch displayed two water populations, while the remaining starches displayed only a single population. PMID- 28912435 TI - Turning behaviors of T cells climbing up ramp-like structures are regulated by myosin light chain kinase activity and lamellipodia formation. AB - T cells navigate diverse microenvironments to perform immune responses. Micro scale topographical structures within the tissues, which may inherently exist in normal tissues or may be formed by inflammation or injury, can influence T cell migration, but how T cell migration is affected by such topographical structures have not been investigated. In this study, we fabricated ramp-like structures with a 5 MUm height and various slopes, and observed T cells climbing up the ramp like structures. T cells encountering the ramp-like structures exhibited MLC accumulation near head-tail junctions contacting the ramp-like structures, and made turns to the direction perpendicular to the ramp-like structures. Pharmacological study revealed that lamellipodia formation mediated by arp2/3 and contractility regulated by myosin light chain kinase (MLCK) were responsible for the intriguing turning behavior of T cells climbing the ramp-like structures. Arp2/3 or MLCK inhibition substantially reduced probability of T cells climbing sharp-edged ramp-like structures, indicating intriguing turning behavior of T cells mediated by lamellipodia formation and MLCK activity may be important for T cells to access inflamed or injured tissues with abrupt topographical changes. PMID- 28912436 TI - Distributed Acoustic Sensing for Seismic Monitoring of The Near Surface: A Traffic-Noise Interferometry Case Study. AB - Ambient-noise-based seismic monitoring of the near surface often has limited spatiotemporal resolutions because dense seismic arrays are rarely sufficiently affordable for such applications. In recent years, however, distributed acoustic sensing (DAS) techniques have emerged to transform telecommunication fiber-optic cables into dense seismic arrays that are cost effective. With DAS enabling both high sensor counts ("large N") and long-term operations ("large T"), time-lapse imaging of shear-wave velocity (V S ) structures is now possible by combining ambient noise interferometry and multichannel analysis of surface waves (MASW). Here we report the first end-to-end study of time-lapse V S imaging that uses traffic noise continuously recorded on linear DAS arrays over a three-week period. Our results illustrate that for the top 20 meters the V S models that is well constrained by the data, we obtain time-lapse repeatability of about 2% in the model domain-a threshold that is low enough for observing subtle near-surface changes such as water content variations and permafrost alteration. This study demonstrates the efficacy of near-surface seismic monitoring using DAS-recorded ambient noise. PMID- 28912437 TI - Voice selectivity in the temporal voice area despite matched low-level acoustic cues. AB - In human listeners, the temporal voice areas (TVAs) are regions of the superior temporal gyrus and sulcus that respond more to vocal sounds than a range of nonvocal control sounds, including scrambled voices, environmental noises, and animal cries. One interpretation of the TVA's selectivity is based on low-level acoustic cues: compared to control sounds, vocal sounds may have stronger harmonic content or greater spectrotemporal complexity. Here, we show that the right TVA remains selective to the human voice even when accounting for a variety of acoustical cues. Using fMRI, single vowel stimuli were contrasted with single notes of musical instruments with balanced harmonic-to-noise ratios and pitches. We also used "auditory chimeras", which preserved subsets of acoustical features of the vocal sounds. The right TVA was preferentially activated only for the natural human voice. In particular, the TVA did not respond more to artificial chimeras preserving the exact spectral profile of voices. Additional acoustic measures, including temporal modulations and spectral complexity, could not account for the increased activation. These observations rule out simple acoustical cues as a basis for voice selectivity in the TVAs. PMID- 28912438 TI - Malignancy risk stratification of thyroid nodules: comparisons of four ultrasound Thyroid Imaging Reporting and Data Systems in surgically resected nodules. AB - To compare the efficiency of four different ultrasound (US) Thyroid Imaging Reporting and Data Systems (TI-RADS) in malignancy risk stratification in surgically resected thyroid nodules (TNs). The study included 547 benign TNs and 464 malignant TNs. US images of the TNs were retrospectively reviewed and categorized according to the TI-RADSs published by Horvath E et al. (TI-RADS H), Park et al. (TI-RADS P), Kwak et al. (TI-RADS K) and Russ et al. (TI-RADS R). The diagnostic performances for the four TI-RADSs were then compared. At multivariate analysis, among the suspicious US features, marked hypoechogenicity was the most significant independent predictor for malignancy (OR: 15.344, 95% CI: 5.313 44.313) (P < 0.05). Higher sensitivity was seen in TI-RADS H, TI-RADS K, TI-RADS R comparing with TI-RADS P (P < 0.05 for all), whereas the specificity, accuracy and area under the ROC curve (Az) of TI-RADS P were the highest (all P < 0.05). Higher specificity, accuracy and Az were seen in TI-RADS K compared with TI-RADS R (P = 0.003). With its higher sensitivity, TI-RADS K, a simple predictive model, is practical and convenient for the management of TNs in clinical practice. The study indicates that there is a good concordance between TI-RADS categories and histopathology. PMID- 28912439 TI - Association between cognitive deficits and suicidal ideation in patients with major depressive disorder. AB - The role of cognitive function in suicidal ideation in patients with major depressive disorder (MDD) has not been adequately explored. This research sought to measure the relationship between suicidal ideation and cognitive function. Therefore, in this study, the association between cognitive function and suicidal ideation in patients with MDD was assessed. Cognitive function was evaluated in 233 patients with MDD using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS). Suicidal ideation was assessed using item 3 of the Hamilton Depression Rating Scale. Approximately 59.2% of the patients (138/233) expressed suicidal ideation. Among the BACS subtests, only the executive function scores were significantly lower in patients with MDD with than in those without (p < 0.005). In addition, the executive function, motor speed function, and composite scores correlated negatively with the severity of suicidal ideation in these patients. These results suggest that executive function, motor speed function, and global neuropsychological function are associated with suicidal ideation in patients with MDD and that the BACS neuropsychological battery is an efficient instrument for monitoring these characteristics. Moreover, specific BACS scores can potentially serve as cognitive biomarkers of suicide risk in patients with MDD. PMID- 28912440 TI - The Generalization of Auditory Accommodation to Altered Spectral Cues. AB - The capacity of healthy adult listeners to accommodate to altered spectral cues to the source locations of broadband sounds has now been well documented. In recent years we have demonstrated that the degree and speed of accommodation are improved by using an integrated sensory-motor training protocol under anechoic conditions. Here we demonstrate that the learning which underpins the localization performance gains during the accommodation process using anechoic broadband training stimuli generalize to environmentally relevant scenarios. As previously, alterations to monaural spectral cues were produced by fitting participants with custom-made outer ear molds, worn during waking hours. Following acute degradations in localization performance, participants then underwent daily sensory-motor training to improve localization accuracy using broadband noise stimuli over ten days. Participants not only demonstrated post training improvements in localization accuracy for broadband noises presented in the same set of positions used during training, but also for stimuli presented in untrained locations, for monosyllabic speech sounds, and for stimuli presented in reverberant conditions. These findings shed further light on the neuroplastic capacity of healthy listeners, and represent the next step in the development of training programs for users of assistive listening devices which degrade localization acuity by distorting or bypassing monaural cues. PMID- 28912441 TI - Broadband acoustic skin cloak based on spiral metasurfaces. AB - A skin cloak based on the acoustic metasurface made of graded spiral units is proposed and numerically investigated. The presented skin cloak is an acoustical layer consisting of 80 subwavelength-sized unit cells, which provide precise local phase modulation and hence resort the disturbed sound filed in such a way to hide the object to acoustic wave. Numerical simulations show that the suggested skin cloak both work well under normal and small-angled incidences. By taking the advantage of the spiral-typed metasurface, the suggested skin cloak is rather thin with thickness in the order around 1/7 of the wavelength of target frequency, moreover, the intrinsic characteristics of modest dispersion ensure the skin cloak provides remarkable acoustic invisibility in a broad frequency ranging from 2500 Hz to 3600 Hz. PMID- 28912442 TI - The association between respiratory tract infection incidence and localised meningitis epidemics: an analysis of high-resolution surveillance data from Burkina Faso. AB - Meningococcal meningitis epidemics in the African meningitis belt consist of localised meningitis epidemics (LME) that reach attack proportions of 1% within a few weeks. A meningococcal serogroup A conjugate vaccine was introduced in meningitis belt countries from 2010 on, but LME due to other serogroups continue to occur. The mechanisms underlying LME are poorly understood, but an association with respiratory pathogens has been hypothesised. We analysed national routine surveillance data in high spatial resolution (health centre level) from 13 districts in Burkina Faso, 2004-2014. We defined LME as a weekly incidence rate of suspected meningitis >=75 per 100,000 during >=2 weeks; and high incidence episodes of respiratory tract infections (RTI) as the 5th quintile of monthly incidences. We included 10,334 health centre month observations during the meningitis season (January-May), including 85 with LME, and 1891 (1820) high incidence episodes of upper (lower) RTI. In mixed effects logistic regression accounting for spatial structure, and controlling for dust conditions, relative air humidity and month, the occurrence of LME was strongly associated with high incidence episodes of upper (odds ratio 23.9, 95%-confidence interval 3.1-185.3), but not lower RTI. In the African meningitis belt, meningitis epidemics may be triggered by outbreaks of upper RTI. PMID- 28912443 TI - Graphite Oxide Improves Adhesion and Water Resistance of Canola Protein-Graphite Oxide Hybrid Adhesive. AB - Protein derived adhesives are extensively explored as a replacement for synthetic ones, but suffers from weak adhesion and water resistance. Graphite oxide (GO) has been extensively used in nanocomposites, but not in adhesives applications. The objectives of this study were to prepare functionally improved protein adhesive by exfoliating GO with different oxidation levels, and to determine the effect of GO on adhesion mechanism. GO were prepared by oxidizing graphite for 0.5, 2, and 4 h (GO-A, GO-B and GO-C, respectively). Increasing oxidation time decreased C/O ratio; while the relative proportion of C-OH, and C = O groups initially increased up to 2 h of oxidation, but reduced upon further oxidation. Canola protein-GO hybrid adhesive (CPA-GO) was prepared by exfoliating GO at a level of 1% (w/w). GO significantly increased (p < 0.05) adhesion; where GO-B addition showed the highest dry, and wet strength of 11.67 +/- 1.00, and 4.85 +/- 0.61 MPa, respectively. The improvements in adhesion was due to the improved exfoliation of GO, improved adhesive and cohesive interactions, increased hydrogen bonding, increased hydrophobic interactions and thermal stability of CPA GO. GO, as we proposed for the first time is easier to process and cost-effective in preparing protein-based adhesives with significantly improved functionalities. PMID- 28912444 TI - Pan-genomic and transcriptomic analyses of Leuconostoc mesenteroides provide insights into its genomic and metabolic features and roles in kimchi fermentation. AB - The genomic and metabolic features of Leuconostoc (Leu) mesenteroides were investigated through pan-genomic and transcriptomic analyses. Relatedness analysis of 17 Leu. mesenteroides strains available in GenBank based on 16S rRNA gene sequence, average nucleotide identity, in silico DNA-DNA hybridization, molecular phenotype, and core-genome indicated that Leu. mesenteroides has been separated into different phylogenetic lineages. Pan-genome of Leu. mesenteroides strains, consisting of 999 genes in core-genome, 1,432 genes in accessory-genome, and 754 genes in unique genome, and their COG and KEGG analyses showed that Leu. mesenteroides harbors strain-specifically diverse metabolisms, probably representing high evolutionary genome changes. The reconstruction of fermentative metabolic pathways for Leu. mesenteroides strains showed that Leu. mesenteroides produces various metabolites such as lactate, ethanol, acetate, CO2, mannitol, diacetyl, acetoin, and 2,3-butanediol through an obligate heterolactic fermentation from various carbohydrates. Fermentative metabolic features of Leu. mesenteroides during kimchi fermentation were investigated through transcriptional analyses for the KEGG pathways and reconstructed metabolic pathways of Leu. mesenteroides using kimchi metatranscriptomic data. This was the first study to investigate the genomic and metabolic features of Leu. mesenteroides through pan-genomic and metatranscriptomic analyses, and may provide insights into its genomic and metabolic features and a better understanding of kimchi fermentations by Leu. mesenteroides. PMID- 28912445 TI - Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation. AB - Amyloid beta (Abeta) accumulation is an early event in the pathogenesis of Alzheimer's disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Abeta deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Abeta induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53 responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway. PMID- 28912447 TI - Development and Validation of a Nomogram for Predicting Survival in Patients with Advanced Pancreatic Ductal Adenocarcinoma. AB - This study aimed to develop and validate an effective prognostic nomogram for advanced PDAC patients. We conducted a prospective multicenter cohort study involving 1,526 advanced PDAC patients from three participating hospitals in China between January 1, 2004 and December 31, 2013. Two thirds of the patients were randomly assigned to the training set (n = 1,017), and one third were assigned to the validation set (n = 509). Multivariate cox regression analysis was performed to identify significant prognostic factors for overall survival to develop the nomogram. Internal and external validation using C-index and calibration curve were conducted in the training set and validation set respectively. As results, seven independent prognostic factors were identified: age, tumor stage, tumor size, ALT (alanine aminotransferase), ALB (albumin), CA 19-9, HBV infection status, and these factors were entered into the nomogram. The proposed nomogram showed favorable discrimination and calibration both in the training set and validation set. The C-indexes of the training set and validation set were 0.720 and 0.696 respectively, which were both significantly higher than that of the staging system (C-index = 0.613, P < 0.001). In conclusion, the proposed nomogram may be served as an effective tool for prognostic evaluation of advanced PDAC. PMID- 28912449 TI - Red and green colors emitting spherical-shaped calcium molybdate nanophosphors for enhanced latent fingerprint detection. AB - We report the synthesis of spherical-shaped rare-earth (Eu3+ and Tb3+) ions doped CaMoO4 nanoparticles in double solvents (IPA and H2O) with the help of autoclave. The X-ray diffraction patterns well match with the standard values and confirm the crystallization in a tetragonal phase with an I41/a (88) space group. The luminescence spectra exhibit the strong red and green emissions from Eu3+ and Tb3+ ions doped samples, respectively. The X-ray photoelectron spectroscopy results show the oxidation states of all the elements present in the sample. The temperature-dependent luminescence spectra reveal the stability of Eu3+ and Tb3+ ions doped samples. The red- and green-emitting Eu3+ and Tb3+ ions doped CaMoO4 samples were used for detection and enhancement of latent fingerprints which are the common evidences found at crime scenes. The enhanced latent fingerprints obtained on different surfaces have high contrast with low background interference. The minute details of the fingerprint which are useful for individualization are clearly observed with the help of these nanopowders. PMID- 28912446 TI - An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. AB - The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle for tissue repair in central nervous system (CNS). Here we report that injection of imidazole-poly(organophosphazenes) (I-5), a hydrogel with thermosensitive sol-gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model. Cystic cavities are bridged by fibronectin-rich extracellular matrix. The fibrotic extracellular matrix remodeling is mediated by matrix metalloproteinase-9 expressed in macrophages within the fibrotic extracellular matrix. A poly(organophosphazenes) hydrogel lacking the imidazole moiety, which physically interacts with macrophages via histamine receptors, exhibits substantially diminished bridging effects. I-5 injection improves coordinated locomotion, and this functional recovery is accompanied by preservation of myelinated white matter and motor neurons and an increase in axonal reinnervation of the lumbar motor neurons. Our study demonstrates that dynamic interactions between inflammatory cells and injectable biomaterials can induce beneficial extracellular matrix remodeling to stimulate tissue repair following CNS injuries.The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle. Here the authors show an injection of imidazole poly(organophosphazenes), a hydrogel with thermosensitive sol-gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model. PMID- 28912448 TI - A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-beta-lactamases. AB - Carbapenem-resistant Enterobacteriaceae threaten human health, since carbapenems are last resort drugs for infections by such organisms. Metallo-beta-lactamases (MbetaLs) are the main mechanism of resistance against carbapenems. Clinically approved inhibitors of MBLs are currently unavailable as design has been limited by the incomplete knowledge of their mechanism. Here, we report a biochemical and biophysical study of carbapenem hydrolysis by the B1 enzymes NDM-1 and BcII in the bi-Zn(II) form, the mono-Zn(II) B2 Sfh-I and the mono-Zn(II) B3 GOB-18. These MbetaLs hydrolyse carbapenems via a similar mechanism, with accumulation of the same anionic intermediates. We characterize the Michaelis complex formed by mono Zn(II) enzymes, and we identify all intermediate species, enabling us to propose a chemical mechanism for mono and binuclear MbetaLs. This common mechanism open avenues for rationally designed inhibitors of all MbetaLs, notwithstanding the profound differences between these enzymes' active site structure, beta-lactam specificity and metal content.Carbapenem-resistant bacteria pose a major health threat by expressing metallo-beta-lactamases (MbetaLs), enzymes able to hydrolyse these life-saving drugs. Here the authors use biophysical and computational methods and show that different MbetaLs share the same reaction mechanism, suggesting new strategies for drug design. PMID- 28912450 TI - New molecular insights into the tyrosyl-tRNA synthase inhibitors: CoMFA, CoMSIA analyses and molecular docking studies. AB - Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q 2 = 0.611, r 2pred = 0.933, r 2m = 0.954) and CoMSIA model (q 2 = 0.546, r 2pred = 0.959, r 2m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4 hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities. PMID- 28912451 TI - Unveiling CO2 heterogeneous freezing plumes during champagne cork popping. AB - Cork popping from clear transparent bottles of champagne stored at different temperatures (namely, 6, 12, and 20 degrees C) was filmed through high-speed video imaging in the visible light spectrum. During the cork popping process, a plume mainly composed of gaseous CO2 with traces of water vapour freely expands out of the bottleneck through ambient air. Most interestingly, for the bottles stored at 20 degrees C, the characteristic grey-white cloud of fog classically observed above the bottlenecks of champagne stored at lower temperatures simply disappeared. It is replaced by a more evanescent plume, surprisingly blue, starting from the bottleneck. We suggest that heterogeneous freezing of CO2 occurs on ice water clusters homogeneously nucleated in the bottlenecks, depending on the saturation ratio experienced by gas-phase CO2 after adiabatic expansion (indeed highly bottle temperature dependent). Moreover, and as observed for the bottles stored at 20 degrees C, we show that the freezing of only a small portion of all the available CO2 is able to pump the energy released through adiabatic expansion, thus completely inhibiting the condensation of water vapour found in air packages adjacent to the gas volume gushing out of the bottleneck. PMID- 28912453 TI - Measuring critical transitions in financial markets. AB - Tipping points in complex systems are structural transitions from one state to another. In financial markets these critical points are connected to systemic risks, which have led to financial crisis in the past. Due to this, researchers are studying tipping points with different methods. This paper introduces a new method which bridges the gap between real-world portfolio management and statistical facts in financial markets in order to give more insight into the mechanics of financial markets. PMID- 28912452 TI - Endogenous omega-3 Fatty Acid Production by fat-1 Transgene and Topically Applied Docosahexaenoic Acid Protect against UVB-induced Mouse Skin Carcinogenesis. AB - The present study was intended to explore the effects of endogenously produced omega-3 polyunsaturated fatty acids (PUFAs) on ultraviolet B (UVB)-induced skin inflammation and photocarcinogenesis using hairless fat-1 transgenic mice harboring omega-3 desaturase gene capable of converting omega-6 to omega-3 PUFAs. Upon exposure to UVB irradiation, fat-1 transgenic mice exhibited a significantly reduced epidermal hyperplasia, oxidative skin damage, and photocarcinogenesis as compared to wild type mice. The transcription factor, Nrf2 is a master regulator of anti-inflammatory and antioxidant gene expression. While the protein expression of Nrf2 was markedly enhanced, the level of its mRNA transcript was barely changed in the fat-1 transgenic mouse skin. Topical application of docosahexaenoic acid (DHA), a representative omega-3 PUFA, in wild type hairless mice induced expression of the Nrf2 target protein, heme oxygenase-1 in the skin and protected against UVB-induced oxidative stress, inflammation and papillomagenesis. Furthermore, transient overexpression of fat-1 gene in mouse epidermal JB6 cells resulted in the enhanced accumulation of Nrf2 protein. Likewise, DHA treated to JB6 cells inhibited Nrf2 ubiquitination and stabilized it. Taken together, our results indicate that functional fat-1 and topically applied DHA potentiate cellular defense against UVB-induced skin inflammation and photocarcinogenesis through elevated activation of Nrf2 and upregulation of cytoprotective gene expression. PMID- 28912454 TI - Resilience of electricity grids against transmission line overloads under wind power injection at different nodes. AB - A steadily increasing fraction of renewable energy sources for electricity production requires a better understanding of how stochastic power generation affects the stability of electricity grids. Here, we assess the resilience of an IEEE test grid against single transmission line overloads under wind power injection based on the dc power flow equations and a quasi-static grid response to wind fluctuations. Thereby we focus on the mutual influence of wind power generation at different nodes. We find that overload probabilities vary strongly between different pairs of nodes and become highly affected by spatial correlations of wind fluctuations. An unexpected behaviour is uncovered: for a large number of node pairs, increasing wind power injection at one node can increase the power threshold at the other node with respect to line overloads in the grid. We find that this seemingly paradoxical behaviour is related to the topological distance of the overloaded line from the shortest path connecting the wind nodes. In the considered test grid, it occurs for all node pairs, where the overloaded line belongs to the shortest path. PMID- 28912455 TI - A CRISPR screen identifies genes controlling Etv2 threshold expression in murine hemangiogenic fate commitment. AB - The ETS transcription factor Etv2 is necessary and sufficient for the generation of hematopoietic and endothelial cells. However, upstream regulators of Etv2 in hemangiogenesis, generation of hematopoietic and endothelial cells, have not been clearly addressed. Here we track the developmental route of hemangiogenic progenitors from mouse embryonic stem cells, perform genome-wide CRISPR screening, and transcriptome analysis of en route cell populations by utilizing Brachyury, Etv2, or Scl reporter embryonic stem cell lines to further understand the mechanisms that control hemangiogenesis. We identify the forkhead transcription factor Foxh1, in part through Eomes, to be critical for the formation of FLK1+ mesoderm, from which the hemangiogenic fate is specified. Importantly, hemangiogenic fate is specified not simply by the onset of Etv2 expression, but by a threshold-dependent mechanism, in which VEGF-FLK1 signaling plays an instructive role by promoting Etv2 threshold expression. These studies reveal comprehensive cellular and molecular pathways governing the hemangiogenic cell lineage development.How haematopoietic and endothelial cell lineages are specified is unclear. Here, the authors identify the forkhead transcription factor Foxh1 as regulating FLK1+ mesoderm formation in mouse embryonic stem cells, which in turn specifies hemangiogenic fate via Etv2. PMID- 28912456 TI - Physiological activity in calm thermal indoor environments. AB - Indoor environmental comfort has previously been quantified based on the subjective assessment of thermal physical parameters, such as temperature, humidity, and airflow velocity. However, the relationship of these parameters to brain activity remains poorly understood. The objective of this study was to determine the effect of airflow on brain activity using electroencephalograms (EEG) of participants in a living environment under different airflow conditions. Before the recording, the room was set to a standardised air temperature and humidity. During the recording, each participant was required to perform a simple time-perception task that involved pressing buttons after estimating a 10-second interval. Cooling and heating experiments were conducted in summer and winter, respectively. A frequency analysis of the EEGs revealed that gamma and beta activities showed lower amplitudes under conditions without airflow than with airflow, regardless of the season (i.e., cooling or heating). Our results reveal new neurophysiological markers of the response to airflow sensation. Further, based on the literature linking gamma and beta waves to less anxious states in calm environments, we suggest that airflow may alter the feelings of the participants. PMID- 28912457 TI - Photoelectrolysis Using Type-II Semiconductor Heterojunctions. AB - The solar-powered production of hydrogen for use as a renewable fuel is highly desirable for the world's future energy infrastructure. However, difficulties in achieving reasonable efficiencies, and thus cost-effectiveness, have hampered significant research progress. Here we propose the use of semiconductor nanostructures to create a type-II heterojunction at the semiconductor-water interface in a photoelectrochemical cell (PEC) and theoretically investigate it as a method of increasing the maximum photovoltage such a cell can generate under illumination, with the aim of increasing the overall cell efficiency. A model for the semiconductor electrode in a PEC is created, which solves the Schrodinger, Poisson and drift-diffusion equations self-consistently. From this, it is determined that ZnO quantum dots on bulk n-InGaN with low In content x is the most desirable system, having electron-accepting and -donating states straddling the oxygen- and hydrogen-production potentials for x < 0.26, though large variance in literature values for certain material parameters means large uncertainties in the model output. Accordingly, results presented here should form the basis for further experimental work, which will in turn provide input to refine and develop the model. PMID- 28912458 TI - Y Chromosome, Mitochondrial DNA and Childhood Behavioural Traits. AB - Many psychiatric traits are sexually dimorphic in terms of prevalence, age of onset, progression and prognosis; sex chromosomes could play a role in these differences. In this study we evaluated the association between Y chromosome and mitochondrial DNA haplogroups with sexually-dimorphic behavioural and psychiatric traits. The study sample included 4,211 males and 4,009 females with mitochondrial DNA haplogroups and 4,788 males with Y chromosome haplogroups who are part of the Avon Longitudinal Study of Parents and Children (ALSPAC) based in the United Kingdom. Different subsets of these populations were assessed using measures of behavioural and psychiatric traits with logistic regression being used to measure the association between haplogroups and the traits. The majority of behavioural traits in our cohort differed between males and females; however Y chromosome and mitochondrial DNA haplogroups were not associated with any of the variables. These findings suggest that if there is common variation on the Y chromosome and mitochondrial DNA associated with behavioural and psychiatric trait variation, it has a small effect. PMID- 28912459 TI - Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. AB - Immune cells such as macrophages are drivers and biomarkers of most cancers. Scoring macrophage infiltration in tumor tissue provides a prognostic assessment that is correlated with disease outcome and therapeutic response, but generally requires invasive biopsy. Routine detection of hemosiderin iron aggregates in macrophages in other settings histologically and in vivo by MRI suggests that similar assessments in cancer can bridge a gap in our ability to assess tumor macrophage infiltration. Quantitative histological and in vivo MRI assessments of non-heme cellular iron revealed that preclinical prostate tumor models could be differentiated according to hemosiderin iron accumulation-both in tumors and systemically. Monitoring cellular iron levels during "off-label" administration of the FDA-approved iron chelator deferiprone evidenced significant reductions in tumor size without extensive perturbation to these iron deposits. Spatial profiling of the iron-laden infiltrates further demonstrated that higher numbers of infiltrating macrophage iron deposits was associated with lower anti-tumor chelation therapy response. Imaging macrophages according to their innate iron status provides a new phenotypic window into the immune tumor landscape and reveals a prognostic biomarker associated with macrophage infiltration and therapeutic outcome. PMID- 28912460 TI - Elemental and Molecular Segregation in Oil Paintings due to Lead Soap Degradation. AB - The formation of Pb, Zn, and Cu carboxylates (soaps) has caused visible deterioration in hundreds of oil paintings dating from the 15th century to the present. Through transport phenomena not yet understood, free fatty acids in the oil binding medium migrate through the paint and react with pigments containing heavy metals to form soaps. To investigate the complex correlation among the elemental segregation, types of chemical compounds formed, and possible mechanisms of the reactions, a paint sample cross-section from a 15th century oil painting was examined by synchrotron X-ray techniques. X-ray fluorescence (XRF) microscopy, quantified with elemental correlation density distribution, showed Pb and Sn segregation in the soap-affected areas. X-ray absorption near edge structure (XANES) around the Pb-L3 absorption edge showed that Pb pigments and Pb soaps can be distinguished while micro-XANES gave further information on the chemical heterogeneity in the paint film. The advantages and limitations of these synchrotron-based techniques are discussed and compared to those of methods routinely used to analyze paint samples. The results presented set the stage for improving the information extracted from samples removed from works of art and for correlating observations in model paint samples to those in the naturally aged samples, to shed light onto the mechanism of soap formation. PMID- 28912461 TI - Vimentin knockout results in increased expression of sub-endothelial basement membrane components and carotid stiffness in mice. AB - Intermediate filaments are involved in stress-related cell mechanical properties and in plasticity via the regulation of focal adhesions (FAs) and the actomyosin network. We investigated whether vimentin regulates endothelial cells (ECs) and vascular smooth muscle cells (SMCs) and thereby influences vasomotor tone and arterial stiffness. Vimentin knockout mice (Vim-/-) exhibited increased expression of laminin, fibronectin, perlecan, collagen IV and VE-cadherin as well as von Willebrand factor deposition in the subendothelial basement membrane. Smooth muscle (SM) myosin heavy chain, alpha-SM actin and smoothelin were decreased in Vim-/- mice. Electron microscopy revealed a denser endothelial basement membrane and increased SM cell-matrix interactions. Integrin alphav, talin and vinculin present in FAs were increased in Vim-/- mice. Phosphorylated FA kinase and its targets Src and ERK1/2 were elevated in Vim-/- mice. Knockout of vimentin, but not of synemin, resulted in increased carotid stiffness and contractility and endothelial dysfunction, independently of blood pressure and the collagen/elastin ratio. The increase in arterial stiffness in Vim-/- mice likely involves vasomotor tone and endothelial basement membrane organization changes. At the tissue level, the results show the implication of FAs both in ECs and vascular SMCs in the role of vimentin in arterial stiffening. PMID- 28912462 TI - Impacts of light limitation on corals and crustose coralline algae. AB - Turbidity associated with elevated suspended sediment concentrations can significantly reduce underwater light availability. Understanding the consequences for sensitive organisms such as corals and crustose coralline algae (CCA), requires an understanding of tolerance levels and the time course of effects. Adult colonies of Acropora millepora and Pocillopora acuta, juvenile P. acuta, and the CCA Porolithon onkodes were exposed to six light treatments of ~0, 0.02, 0.1, 0.4, 1.1 and 4.3 mol photons m-2 d-1, and their physiological responses were monitored over 30 d. Exposure to very low light (<0.1 mol photons m-2 d-1) caused tissue discoloration (bleaching) in the corals, and discolouration (and partial mortality) of the CCA, yielding 30 d EI10 thresholds (irradiance which results in a 10% change in colour) of 1.2-1.9 mol photons m-2 d 1. Recent monitoring studies during dredging campaigns on a shallow tropical reef, have shown that underwater light levels very close (~500 m away) from a working dredge routinely fall below this value over 30 d periods, but rarely during the pre-dredging baseline phase. Light reduction alone, therefore, constitutes a clear risk to coral reefs from dredging, although at such close proximity other cause-effect pathways, such as sediment deposition and smothering, are likely to also co-occur. PMID- 28912463 TI - Physical activity is prospectively associated with spinal pain in children (CHAMPS Study-DK). AB - ABSTARCT: Spinal pain and physical inactivity are critical public health issues. We investigated the prospective associations of physical activity intensity with spinal pain in children. Physical activity was quantified with accelerometry in a cohort of primary school students. Over 19 months, parents of primary school students reported children's spinal pain status each week via text-messaging (self-reported spinal pain). Spinal pain reports were followed-up by trained clinicians who diagnosed each child's complaint and classified the pain as non traumatic or traumatic. Associations were examined with logistic regression modeling using robust standard errors and reported with odds ratios (OR). Children (n = 1205, 53.0% female) with mean +/- SD age of 9.4 +/- 1.4 years, participated in 75,180 weeks of the study. Nearly one-third (31%) of children reported spinal pain, and 14% were diagnosed with a spinal problem. Moderate intensity physical activity was protectively associated with self-reported [OR(95%CI) = 0.84(0.74, 0.95)], diagnosed [OR(95%CI) = 0.79(0.67, 0.94)] and traumatic [OR(95%CI) = 0.77(0.61, 0.96)] spinal pain. Vigorous intensity physical activity was associated with increased self-reported [OR(95%CI) = 1.13(1.00, 1.27)], diagnosed [OR(95%CI) = 1.25(1.07, 1.45)] and traumatic [OR(95%CI) = 1.28(1.05, 1.57)] spinal pain. The inclusion of age and sex covariates weakened these associations. Physical activity intensity may be a key consideration in the relationship between physical activity behavior and spinal pain in children. PMID- 28912464 TI - On current transients in MoS2 Field Effect Transistors. AB - We present an experimental investigation of slow transients in the gate and drain currents of MoS2-based transistors. We focus on the measurement of both the gate and drain currents and, from the comparative analysis of the current transients, we conclude that there are at least two independent trapping mechanisms: trapping of charges in the silicon oxide substrate, occurring with time constants of the order of tens of seconds and involving charge motion orthogonal to the MoS2 sheet, and trapping at the channel surface, which occurs with much longer time constants, in particular when the device is in a vacuum. We observe that the presence of such slow phenomena makes it very difficult to perform reliable low frequency noise measurements, requiring a stable and repeatable steady-state bias point condition, and may explain the sometimes contradictory results that can be found in the literature about the dependence of the flicker noise power spectral density on gate bias. PMID- 28912465 TI - Inhomogeneous phases in coupled electron-hole bilayer graphene sheets: Charge Density Waves and Coupled Wigner Crystals. AB - Recently proposed accurate correlation energies are used to determine the phase diagram of strongly coupled electron-hole graphene bilayers. The control parameters of the phase diagram are the charge carrier density and the insulating barrier thickness separating the bilayers. In addition to the electron-hole superfluid phase we find two new inhomogeneous ground states, a one dimensional charge density wave phase and a coupled electron-hole Wigner crystal. The elementary crystal structure of bilayer graphene plays no role in generating these new quantum phases, which are completely determined by the electrons and holes interacting through the Coulomb interaction. The experimental parameters for the new phases lie within attainable ranges and therefore coupled electron hole bilayer graphene presents itself as an experimental system where novel emergent many-body phases can be realized. PMID- 28912466 TI - Using a Novel Microfabricated Model of the Alveolar-Capillary Barrier to Investigate the Effect of Matrix Structure on Atelectrauma. AB - The alveolar-capillary barrier is composed of epithelial and endothelial cells interacting across a fibrous extracelluar matrix (ECM). Although remodeling of the ECM occurs during several lung disorders, it is not known how fiber structure and mechanics influences cell injury during cyclic airway reopening as occurs during mechanical ventilation (atelectrauma). We have developed a novel in vitro platform that mimics the micro/nano-scale architecture of the alveolar microenvironment and have used this system to investigate how ECM microstructural properties influence epithelial cell injury during airway reopening. In addition to epithelial-endothelial interactions, our platform accounts for the fibrous topography of the basal membrane and allows for easy modulation of fiber size/diameter, density and stiffness. Results indicate that fiber stiffness and topography significantly influence epithelial/endothelial barrier function where increased fiber stiffness/density resulted in altered cytoskeletal structure, increased tight junction (TJ) formation and reduced barrier permeability. However, cells on rigid/dense fibers were also more susceptible to injury during airway reopening. These results indicate that changes in the mechanics and architecture of the lung microenvironment can significantly alter cell function and injury and demonstrate the importance of implementing in vitro models that more closely resemble the natural conditions of the lung microenvironment. PMID- 28912467 TI - Highly chromophoric Cy5-methionine for N-terminal fluorescent tagging of proteins in eukaryotic translation systems. AB - Despite significant advances on fluorescent labeling of target proteins to study their structural dynamics and function, there has been need for labeling with high quantum yield ensuring high sensitivity and selectivity without sacrificing the biological function of the protein. Here as a technical advancement over non canonical amino acid incorporation, we provided a conceptual design of the N terminal fluorescent tagging of proteins. Cy5-labeled methionine (Cy5-Met) was chemically synthesized, and then the purified Cy5-Met was coupled with synthetic human initiator tRNA by methionine tRNA synthetase. Cy5-Met-initiator tRNA (Cy5 Met-tRNAi) was purified and transfected into HeLa cells with HIV-Tat plasmid, resulting in an efficient production of Cy5-labeled HIV-Tat protein. Based on the universal requirement in translational initiation, the approach provides co translational incorporation of N-terminal probe to a repertoire of proteins in the eukaryote system. This methodology has potential utility in the single molecule analysis of human proteins in vitro and in vivo for addressing to their complex biological structural and functional dynamics. PMID- 28912468 TI - Cytokine-based Predictive Models to Estimate the Probability of Chronic Periodontitis: Development of Diagnostic Nomograms. AB - Although a distinct cytokine profile has been described in the gingival crevicular fluid (GCF) of patients with chronic periodontitis, there is no evidence of GCF cytokine-based predictive models being used to diagnose the disease. Our objectives were: to obtain GCF cytokine-based predictive models; and develop nomograms derived from them. A sample of 150 participants was recruited: 75 periodontally healthy controls and 75 subjects affected by chronic periodontitis. Sixteen mediators were measured in GCF using the Luminex 100TM instrument: GMCSF, IFNgamma, IL1alpha, IL1beta, IL2, IL3, IL4, IL5, IL6, IL10, IL12p40, IL12p70, IL13, IL17A, IL17F and TNFalpha. Cytokine-based models were obtained using multivariate binary logistic regression. Models were selected for their ability to predict chronic periodontitis, considering the different role of the cytokines involved in the inflammatory process. The outstanding predictive accuracy of the resulting smoking-adjusted models showed that IL1alpha, IL1beta and IL17A in GCF are very good biomarkers for distinguishing patients with chronic periodontitis from periodontally healthy individuals. The predictive ability of these pro-inflammatory cytokines was increased by incorporating IFN gamma and IL10. The nomograms revealed the amount of periodontitis-associated imbalances between these cytokines with pro-inflammatory and anti-inflammatory effects in terms of a particular probability of having chronic periodontitis. PMID- 28912469 TI - Softening non-metallic crystals by inhomogeneous elasticity. AB - High temperature structural materials must be resistant to cracking and oxidation. However, most oxidation resistant materials are brittle and a significant reduction in their yield stress is required if they are to be resistant to cracking. It is shown, using density functional theory, that if a crystal's unit cell elastically deforms in an inhomogeneous manner, the yield stress is greatly reduced, consistent with observations in layered compounds, such as Ti3SiC2, Nb2Co7, W2B5, Ta2C and Ta4C3. The mechanism by which elastic inhomogeneity reduces the yield stress is explained and the effect demonstrated in a complex metallic alloy, even though the electronegativity differences within the unit cell are less than in the layered compounds. Substantial changes appear possible, suggesting this is a first step in developing a simple way of controlling plastic flow in non-metallic crystals, enabling materials with a greater oxidation resistance and hence a higher temperature capability to be used. PMID- 28912470 TI - The sensitivity of a radical pair compass magnetoreceptor can be significantly amplified by radical scavengers. AB - Birds have a remarkable ability to obtain navigational information from the Earth's magnetic field. The primary detection mechanism of this compass sense is uncertain but appears to involve the quantum spin dynamics of radical pairs formed transiently in cryptochrome proteins. We propose here a new version of the current model in which spin-selective recombination of the radical pair is not essential. One of the two radicals is imagined to react with a paramagnetic scavenger via spin-selective electron transfer. By means of simulations of the spin dynamics of cryptochrome-inspired radical pairs, we show that the new scheme offers two clear and important benefits. The sensitivity to a 50 MUT magnetic field is greatly enhanced and, unlike the current model, the radicals can be more than 2 nm apart in the magnetoreceptor protein. The latter means that animal cryptochromes that have a tetrad (rather than a triad) of tryptophan electron donors can still be expected to be viable as magnetic compass sensors. Lifting the restriction on the rate of the spin-selective recombination reaction also means that the detrimental effects of inter-radical exchange and dipolar interactions can be minimised by placing the radicals much further apart than in the current model. PMID- 28912472 TI - Honeycomb-like ZnO Mesoporous Nanowall Arrays Modified with Ag Nanoparticles for Highly Efficient Photocatalytic Activity. AB - A new structure of honeycomb-like ZnO mesoporous nanowall arrays (MNWAs) with highly efficient photocatalytic activity was designed and successfully synthesized on Al foil by hydrothermal method. The nanowalls of ZnO-MNWAs have mesopores, which possess a large surface area. The visible light absorption of ZnO-MNWAs was efficiently stronger than ZnO nanowire, resulting in that the photocatalytic activity of ZnO-MNWAs, whose bandgap energy was 3.12 eV, was 5.97 times than that of ZnO nanowires in the degradation of methyl orange. Besides, Al foil acted as a good electron conductor which was beneficial to the separation of photo-induced electron-hole pairs. After modifying ZnO-MNWAs with a proper amount of Ag nanoparticles (NPs), photocatalytic activity could be further enhanced. The photocatalytic activity of ZnO-MNWAs with the optimal amount of Ag NPs was 9.08 times than that of ZnO nanowires and 1.52 times than that of pure ZnO-MNWAs. PMID- 28912471 TI - Protein-driven RNA nanostructured devices that function in vitro and control mammalian cell fate. AB - Nucleic acid nanotechnology has great potential for future therapeutic applications. However, the construction of nanostructured devices that control cell fate by detecting and amplifying protein signals has remained a challenge. Here we design and build protein-driven RNA-nanostructured devices that actuate in vitro by RNA-binding-protein-inducible conformational change and regulate mammalian cell fate by RNA-protein interaction-mediated protein assembly. The conformation and function of the RNA nanostructures are dynamically controlled by RNA-binding protein signals. The protein-responsive RNA nanodevices are constructed inside cells using RNA-only delivery, which may provide a safe tool for building functional RNA-protein nanostructures. Moreover, the designed RNA scaffolds that control the assembly and oligomerization of apoptosis-regulatory proteins on a nanometre scale selectively kill target cells via specific RNA protein interactions. These findings suggest that synthetic RNA nanodevices could function as molecular robots that detect signals and localize target proteins, induce RNA conformational changes, and programme mammalian cellular behaviour.Nucleic acid nanotechnology has great potential for future therapeutic applications. Here the authors build protein-driven RNA nanostructures that can function within mammalian cells and regulate the cell fate. PMID- 28912473 TI - Fine-scale harbour seal usage for informed marine spatial planning. AB - High-resolution distribution maps can help inform conservation measures for protected species; including where any impacts of proposed commercial developments overlap the range of focal species. Around Orkney, northern Scotland, UK, the harbour seal (Phoca vitulina) population has decreased by 78% over 20 years. Concern for the declining harbour seal population has led to constraints being placed on tidal energy generation developments. For this study area, telemetry data from 54 animals tagged between 2003 and 2015 were used to produce density estimation maps. Predictive habitat models using GAM-GEEs provided robust predictions in areas where telemetry data were absent, and were combined with density estimation maps, and then scaled to population levels using August terrestrial counts between 2008 and 2015, to produce harbour seal usage maps with confidence intervals around Orkney and the North coast of Scotland. The selected habitat model showed that distance from haul out, proportion of sand in seabed sediment, and annual mean power were important predictors of space use. Fine-scale usage maps can be used in consenting and licensing of anthropogenic developments to determine local abundance. When quantifying commercial impacts through changes to species distributions, usage maps can be spatially explicitly linked to individual-based models to inform predicted movement and behaviour. PMID- 28912474 TI - Rhus coriaria increases protein ubiquitination, proteasomal degradation and triggers non-canonical Beclin-1-independent autophagy and apoptotic cell death in colon cancer cells. AB - Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. Here, we investigated the anticancer effect of Rhus coriaria extract (RCE) on HT 29 and Caco-2 human colorectal cancer cells. We found that RCE significantly inhibited the viability and colony growth of colon cancer cells. Moreover, RCE induced Beclin-1-independent autophagy and subsequent caspase-7-dependent apoptosis. Blocking of autophagy by chloroquine significantly reduced RCE-induced cell death, while blocking of apoptosis had no effect on RCE-induced cell death. Mechanistically, RCE inactivated the AKT/mTOR pathway by promoting the proteasome dependent degradation of both proteins. Strikingly, we also found that RCE targeted Beclin-1, p53 and procaspase-3 to degradation. Proteasome inhibition by MG-132 not only restored these proteins to level comparable to control cells, but also reduced RCE-induced cell death and blocked the activation of autophagy and apoptosis. The proteasomal degradation of mTOR, which occurred only 3 hours post RCE treatment was concomitant with an overall increase in the level of ubiquitinated proteins and translated stimulation of proteolysis by the proteasome. Our findings demonstrate that Rhus coriaria possesses strong anti colon cancer activity through stimulation of proteolysis as well as induction of autophagic and apoptotic cell death, making it a potential and valuable source of novel therapeutic cancer drug. PMID- 28912476 TI - Enstrophy transport conditional on local flow topologies in different regimes of premixed turbulent combustion. AB - Enstrophy is an intrinsic feature of turbulent flows, and its transport properties are essential for the understanding of premixed flame-turbulence interaction. The interrelation between the enstrophy transport and flow topologies, which can be assigned to eight categories based on the three invariants of the velocity-gradient tensor, has been analysed here. The enstrophy transport conditional on flow topologies in turbulent premixed flames has been analysed using a Direct Numerical Simulation database representing the corrugated flamelets (CF), thin reaction zones (TRZ) and broken reaction zones (BRZ) combustion regimes. The flame in the CF regime exhibits considerable flame generated enstrophy, and the dilatation rate and baroclinic torque contributions to the enstrophy transport act as leading order sink and source terms, respectively. Consequently, flow topologies associated with positive dilatation rate values, contribute significantly to the enstrophy transport in the CF regime. By contrast, enstrophy decreases from the unburned to the burned gas side for the cases representing the TRZ and BRZ regimes, with diminishing influences of dilatation rate and baroclinic torque. The enstrophy transport in the TRZ and BRZ regimes is governed by the vortex-stretching and viscous dissipation contributions, similar to non-reacting flows, and topologies existing for all values of dilatation rate remain significant contributors. PMID- 28912475 TI - The Impact of Young Age for Prognosis by Subtype in Women with Early Breast Cancer. AB - Young age (<=40 years) use to be considered an independent risk factor for the prognosis of women with early-stage breast cancer. We conducted a retrospective analysis to investigate this claim in a population of young patients who were stratified by molecular subtype. We identified 2,125 women with stage I to III breast cancer from the Fujian Medical University Union Hospital. Multivariable Cox proportional hazards models were used to analyze the relationship between age groups stratified by molecular subtype and 5-year disease-free survival (DFS), 5 year distant metastasis-free survival (DMFS), and 5-year breast cancer-specific survival (BCSS). Median follow-up time was 77 months. Patients <=40 years of age presented with a significantly worse 5-year DFS and 5-year DMFS. In stratified analyses, young women with luminal A subtype disease were associated with a worse 5-year DFS, 5-year DMFS, and 5-year BCSS. Women with luminal B (Her2-) tumors showed a decrease in 5-year DFS and 5-year DMFS. Our findings support the hypothesis that young age seems to be an independent risk factor for the prognosis for breast cancer patients with the luminal A and luminal B (Her2-) subtypes but not in those with luminal B (Her2+), Her2 over-expression, and triple-negative disease. PMID- 28912477 TI - Brain barriers and functional interfaces with sequential appearance of ABC efflux transporters during human development. AB - Adult brain is protected from entry of drugs and toxins by specific mechanisms such as ABC (ATP-binding Cassette) efflux transporters. Little is known when these appear in human brain during development. Cellular distribution of three main ABC transporters (ABCC1, ABCG2, ABCB1) was determined at blood-brain barriers and interfaces in human embryos and fetuses in first half of gestation. Antibodies against claudin-5 and -11 and antibodies to alpha-fetoprotein were used to describe morphological and functional aspects of brain barriers. First exchange interfaces to be established, probably at 4-5 weeks post conception, are between brain and embryonic cerebrospinal fluid (eCSF) and between outer surface of brain anlage and primary meninx. They already exclude alpha-fetoprotein and are immunopositive for both claudins, ABCC1 and ABCG2. ABCB1 is detectable within a week of blood vessels first penetrating into brain parenchyma (6-7 weeks post conception). ABCC1, ABCB1 and ABCG2 are present at blood-CSF barrier in all choroid plexuses from first appearance (7 weeks post conception). Outer CSF-brain interfaces are established between 9-11 weeks post conception exhibiting immunoreactivity for all three transporters. Results provide evidence for sequential establishment of brain exchange interfaces and spatial and temporal timetable for three main ABC transporters in early human brain. PMID- 28912478 TI - The molecular epidemiology of HIV-1 in the Comunidad Valenciana (Spain): analysis of transmission clusters. AB - HIV infections are still a very serious concern for public heath worldwide. We have applied molecular evolution methods to study the HIV-1 epidemics in the Comunidad Valenciana (CV, Spain) from a public health surveillance perspective. For this, we analysed 1804 HIV-1 sequences comprising protease and reverse transcriptase (PR/RT) coding regions, sampled between 2004 and 2014. These sequences were subtyped and subjected to phylogenetic analyses in order to detect transmission clusters. In addition, univariate and multinomial comparisons were performed to detect epidemiological differences between HIV-1 subtypes, and risk groups. The HIV epidemic in the CV is dominated by subtype B infections among local men who have sex with men (MSM). 270 transmission clusters were identified (>57% of the dataset), 12 of which included >=10 patients; 11 of subtype B (9 affecting MSMs) and one (n = 21) of CRF14, affecting predominately intravenous drug users (IDUs). Dated phylogenies revealed these large clusters to have originated from the mid-80s to the early 00 s. Subtype B is more likely to form transmission clusters than non-B variants and MSMs to cluster than other risk groups. Multinomial analyses revealed an association between non-B variants, which are not established in the local population yet, and different foreign groups. PMID- 28912480 TI - Genome-wide RAD sequencing data provide unprecedented resolution of the phylogeny of temperate bamboos (Poaceae: Bambusoideae). AB - The temperate bamboos (tribe Arundinarieae, Poaceae) are strongly supported as monophyly in recent molecular studies, but taxonomic delineation and phylogenetic relationships within the tribe lack resolution. Here, we sampled 39 species (36 temperate bamboos and 3 outgroups) for restriction-site associated DNA sequencing (RAD-seq) with an emphasis on Phyllostachys clade and related clades. Using the largest data matrix for the bamboos to date, we were able to infer phylogenetic relationships with unparalleled resolution. The Phyllostachys, Shibataea, and Arundinaria clades defined from plastid phylogeny, were not supported as monophyletic group. However, the RAD-seq phylogeny largely agreed with the morphology-based taxonomy, with two clades having leptomorph rhizomes strongly supported as monophyletic group. We also explored two approaches, BWA-GATK (a mapping system) and Stacks (a grouping system), for differences in SNP calling and phylogeny inference. For the same level of missing data, the BWA-GATK pipeline produced much more SNPs in comparison with Stacks. Phylogenetic analyses of the largest data matrices from both pipelines, using concatenation and coalescent methods provided similar tree topologies, despite the presence of missing data. Our study demonstrates the utility of RAD-seq data for elucidating phylogenetic relationships between genera and higher taxonomic levels in this important but phylogenetically challenging group. PMID- 28912479 TI - Late-stage differentiation of embryonic pancreatic beta-cells requires Jarid2. AB - Jarid2 is a component of the Polycomb Repressor complex 2 (PRC2), which is responsible for genome-wide H3K27me3 deposition, in embryonic stem cells. However, Jarid2 has also been shown to exert pleiotropic PRC2-independent actions during embryogenesis. Here, we have investigated the role of Jarid2 during pancreas development. Conditional ablation of Jarid2 in pancreatic progenitors results in reduced endocrine cell area at birth due to impaired endocrine cell differentiation and reduced prenatal proliferation. Inactivation of Jarid2 in endocrine progenitors demonstrates that Jarid2 functions after endocrine specification. Furthermore, genome-wide expression analysis reveals that Jarid2 is required for the complete activation of the insulin-producing beta-cell differentiation program. Jarid2-deficient pancreases exhibit impaired deposition of RNAPII-Ser5P, the initiating form of RNAPII, but no changes in H3K27me3, at the promoters of affected endocrine genes. Thus, our study identifies Jarid2 as a fine-tuner of gene expression during late stages of pancreatic endocrine cell development. These findings are relevant for generation of transplantable stem cell-derived beta-cells. PMID- 28912481 TI - Analytical Property of Scattering Matrix:Spectroscopy Phenomena and Sharp Overlapping Autoionization Resonances. AB - An extended atomic data base with sufficiently high precision is required in astrophysics studies and the energy researches. For example, there are "infinite" energy levels in discrete energy region as well as overlapping resonances in autoionization region. We show in this paper the merits of our relativistic eigenchannel R-matrix method R-R-Eigen based on the analytical continuation properties of scattering matrices for the calculations of the energy levels, overlapping resonances and the related transitions. Using Ne+ as an illustration example, the scattering matrices of Ne+ in both discrete and continuum energy regions are calculated by our R-R-Eigen method directly. Based on our proposed projected high dimensional quantum-defect graph (symmetrized), one can readily determine the accuracies of the calculated scattering matrices using the experimental energy levels in a systematical way. The calculated resonant photoionization cross sections in the autoionization region are in excellent agreement with the benchmark high resolution experiments. With the scattering matrices checked/calibrated against spectroscopy data in both discrete and continuum energy regions, the relevant dynamical processes should be calculated with adequate accuracies. It should then satisfy the needs of the astrophysical and energy researches. PMID- 28912482 TI - Strong coupling of magnons in a YIG sphere to photons in a planar superconducting resonator in the quantum limit. AB - We report measurements made at millikelvin temperatures of a superconducting coplanar waveguide resonator (CPWR) coupled to a sphere of yttrium-iron garnet. Systems hybridising collective spin excitations with microwave photons have recently attracted interest for their potential quantum information applications. In this experiment the non-uniform microwave field of the CPWR allows coupling to be achieved to many different magnon modes in the sphere. Calculations of the relative coupling strength of different mode families in the sphere to the CPWR are used to successfully identify the magnon modes and their frequencies. The measurements are extended to the quantum limit by reducing the drive power until, on average, less than one photon is present in the CPWR. Investigating the time dependent response of the system to square pulses, oscillations in the output signal at the mode splitting frequency are observed. These results demonstrate the feasibility of future experiments combining magnonic elements with planar superconducting quantum devices. PMID- 28912483 TI - Thermal properties of Zn2(C8H4O4)2*C6H12N2 metal-organic framework compound and mirror symmetry violation of dabco molecules. AB - Thermal properties of Zn2(C8H4O4)2*C6H12N2 metal-organic framework compound at 8 300 K suggest the possibility of subbarrier tunnelling transitions between left twisted (S) and right-twisted (R) forms of C6H12N2 dabco molecules with D3 point symmetry. The data agree with those obtained for the temperature behavior of nuclear spin-lattice relaxation times. It is shown that there is a temperature range where the transitions are stopped. Therefore, Zn2(C8H4O4)2*C6H12N2 and related compounds are interesting objects to study the effect of spontaneous mirror-symmetry breaking and stabilization of chiral isomeric molecules in solids at low temperatures. PMID- 28912484 TI - Evaluation of therapeutic potential of the silver/silver chloride nanoparticles synthesized with the aqueous leaf extract of Rumex acetosa. AB - Silver nanoparticles were green synthesized with the aqueous leaf extract of the widely consumed green leafy vegetable, Rumex acetosa (sorrel) and the obtained silver nanoparticles (Ag NPs) were tested for their in vitro antioxidant potential, cytotoxicity against human osteosarcoma (HOS) cell lines and antibacterial effects against sixteen human pathogenic clinical isolates. Different analytical techniques viz. UV-vis, FTIR, XRD, SEM-EDX and TEM were employed to characterize the synthesized Ag NPs. Surface Plasmon spectra for the Ag NPs with brownish black color were centered approximately at 448 nm. FTIR analysis revealed the presence of reactive N-H and O-H groups that are effective in reducing Ag(I) ions to Ag(0) which then reacted with the contents of the extract to AgCl/Ag2C2O4. From SEM and TEM analyses, the particles were found to be predominantly spherical in shape and ranged in size from 5 nm to 80 nm, but were largely in the range of 15 nm to 20 nm. Ag NPs showed considerable antioxidant activity, and all the sixteen clinical isolates of human pathogens tested were significantly inhibited. Also, HOS cell lines were significantly (p < 0.05) inhibited at 25% concentration of the Ag NPs extract, while showing a marginal revival at 50% and 100% concentrations. PMID- 28912486 TI - The Homologous Recombination Machinery Orchestrates Post-replication DNA Repair During Self-renewal of Mouse Embryonic Stem Cells. AB - Embryonic stem (ES) cells require homologous recombination (HR) to cope with genomic instability caused during self-renewal. Here, we report expression dynamics and localization of endogenous HR factors in DNA break repair of ES cells. In addition, we analyzed gene expression patterns of HR-related factors at the transcript level with RNA-sequencing experiments. We showed that ES cells constitutively expressed diverse HR proteins throughout the cell cycle and that HR protein expression was not significantly changed even in the DNA damaging conditions. We further analyzed that depleting Rad51 resulted in the accumulation of larger single-stranded DNA (ssDNA) gaps, but did not perturb DNA replication, indicating that ES cells were able to enter the G2-phase in the presence of unrepaired DNA gaps, consistent with the possibility that post-replication repair helps avoid stalling at the G2/M checkpoint. Interestingly, caffeine treatment inhibited the formation of Rad51 or Rad54 foci, but not the formation of gammaH2AX and Exo1 foci, which led to incomplete HR in ssDNA, thus increasing DNA damage sensitivity. Our results suggested that ES cells possess conserved HR promoting machinery to ensure effective recruitment of the HR proteins to DNA breaks, thereby driving proper chromosome duplication and cell cycle progression in ES cells. PMID- 28912485 TI - Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons. AB - Historically, room-temperature structure determination was succeeded by cryo crystallography to mitigate radiation damage. Here, we demonstrate that serial millisecond crystallography at a synchrotron beamline equipped with high viscosity injector and high frame-rate detector allows typical crystallographic experiments to be performed at room-temperature. Using a crystal scanning approach, we determine the high-resolution structure of the radiation sensitive molybdenum storage protein, demonstrate soaking of the drug colchicine into tubulin and native sulfur phasing of the human G protein-coupled adenosine receptor. Serial crystallographic data for molecular replacement already converges in 1,000-10,000 diffraction patterns, which we collected in 3 to maximally 82 minutes. Compared with serial data we collected at a free-electron laser, the synchrotron data are of slightly lower resolution, however fewer diffraction patterns are needed for de novo phasing. Overall, the data we collected by room-temperature serial crystallography are of comparable quality to cryo-crystallographic data and can be routinely collected at synchrotrons.Serial crystallography was developed for protein crystal data collection with X-ray free electron lasers. Here the authors present several examples which show that serial crystallography using high-viscosity injectors can also be routinely employed for room-temperature data collection at synchrotrons. PMID- 28912487 TI - CScape: a tool for predicting oncogenic single-point mutations in the cancer genome. AB - For somatic point mutations in coding and non-coding regions of the genome, we propose CScape, an integrative classifier for predicting the likelihood that mutations are cancer drivers. Tested on somatic mutations, CScape tends to outperform alternative methods, reaching 91% balanced accuracy in coding regions and 70% in non-coding regions, while even higher accuracy may be achieved using thresholds to isolate high-confidence predictions. Positive predictions tend to cluster in genomic regions, so we apply a statistical approach to isolate coding and non-coding regions of the cancer genome that appear enriched for high confidence predicted disease-drivers. Predictions and software are available at http://CScape.biocompute.org.uk/ . PMID- 28912488 TI - Gene Expression and Methylation Analyses Suggest DCTD as a Prognostic Factor in Malignant Glioma. AB - Malignant glioma is the most common brain cancer with dismal outcomes. Individual variation of the patients' survival times is remarkable. Here, we investigated the transcriptome and promoter methylation differences between patients of malignant glioma with short (less than one year) and the patients with long (more than three years) survival in CGGA (Chinese Glioma Genome Atlas), and validated the differences in TCGA (The Cancer Genome Atlas) to identify the genes whose expression levels showed high concordance with prognosis of glioma patients, as well as played an important role in malignant progression. The gene coding a key enzyme in genetic material synthesis, dCMP deaminase (DCTD), was found to be significantly correlated with overall survival and high level of DCTD mRNA indicated shorter survival of the patients with malignant glioma in different databases. Our finding revealed DCTD as an efficient prognostic factor for malignant glioma. As DCTD inhibitor gemcitabine has been proposed as an adjuvant therapy for malignant glioma, our finding also suggests a therapeutic value of gemcitabine for the patients with high expression level of DCTD. PMID- 28912489 TI - Incoherent digital holograms acquired by interferenceless coded aperture correlation holography system without refractive lenses. AB - We present a lensless, interferenceless incoherent digital holography technique based on the principle of coded aperture correlation holography. The acquired digital hologram by this technique contains a three-dimensional image of some observed scene. Light diffracted by a point object (pinhole) is modulated using a random-like coded phase mask (CPM) and the intensity pattern is recorded and composed as a point spread hologram (PSH). A library of PSHs is created using the same CPM by moving the pinhole to all possible axial locations. Intensity diffracted through the same CPM from an object placed within the axial limits of the PSH library is recorded by a digital camera. The recorded intensity this time is composed as the object hologram. The image of the object at any axial plane is reconstructed by cross-correlating the object hologram with the corresponding component of the PSH library. The reconstruction noise attached to the image is suppressed by various methods. The reconstruction results of multiplane and thick objects by this technique are compared with regular lens-based imaging. PMID- 28912490 TI - The interdependent network of gene regulation and metabolism is robust where it needs to be. AB - Despite being highly interdependent, the major biochemical networks of the living cell-the networks of interacting genes and of metabolic reactions, respectively have been approached mostly as separate systems so far. Recently, a framework for interdependent networks has emerged in the context of statistical physics. In a first quantitative application of this framework to systems biology, here we study the interdependent network of gene regulation and metabolism for the model organism Escherichia coli in terms of a biologically motivated percolation model. Particularly, we approach the system's conflicting tasks of reacting rapidly to (internal and external) perturbations, while being robust to minor environmental fluctuations. Considering its response to perturbations that are localized with respect to functional criteria, we find the interdependent system to be sensitive to gene regulatory and protein-level perturbations, yet robust against metabolic changes. We expect this approach to be applicable to a range of other interdependent networks.Although networks of interacting genes and metabolic reactions are interdependent, they have largely been treated as separate systems. Here the authors apply a statistical framework for interdependent networks to E. coli, and show that it is sensitive to gene and protein perturbations but robust against metabolic changes. PMID- 28912491 TI - Meiotic arrest with roscovitine and follicular fluid improves cytoplasmic maturation of porcine oocytes by promoting chromatin de-condensation and gene transcription. AB - The developmental capacity of in vitro matured oocytes is inferior to that of the in vivo matured ones due to insufficient cytoplasmic maturation. Although great efforts were made to accomplish better cytoplasmic maturation by meiotic arrest maintenance (MAM) before in vitro maturation (IVM), limited progress has been achieved in various species. This study showed that MAM of porcine oocytes was better achieved with roscovitine than with dibutyryl cyclic adenosine monophosphate (db-cAMP) or 3-isobutyl-1-methylxanthine. Oocyte developmental competence after IVM was significantly improved following MAM in 199 + FF medium (TCM-199 containing 10% porcine follicular fluid and 25 uM roscovitine) to a level even higher than that in control oocytes matured without pre-MAM. Observations on other markers further confirmed the positive effects of MAM in 199 + FF on oocyte cytoplasmic maturation. During MAM culture in 199 + FF, re decondensation (RDC) of condensed chromatin occurred, and transcription of genes beneficial to cytoplasmic maturation was evident in some of the oocytes with surrounded nucleoli (SN). However, MAM with db-cAMP neither induced RDC nor improved oocyte developmental potential. Together, the results suggest that MAM in the presence of FF and roscovitine improved the developmental competence of porcine oocytes by promoting a pre-GVBD chromatin de-condensation and expression of beneficial genes. PMID- 28912492 TI - Epicutaneous allergen application preferentially boosts specific T cell responses in sensitized patients. AB - The effects of epicutaneous allergen administration on systemic immune responses in allergic and non-allergic individuals has not been investigated with defined allergen molecules. We studied the effects of epicutaneous administration of rBet v 1 and rBet v 1 fragments on systemic immune responses in allergic and non allergic subjects. We conducted a clinical trial in which rBet v 1 and two hypoallergenic rBet v 1 fragments were applied epicutaneously by atopy patch testing (APT) to 15 birch pollen (bp) allergic patients suffering from atopic dermatitis, 5 bp-allergic patients suffering from rhinoconjunctivitis only, 5 patients with respiratory allergy without bp allergy and 5 non-allergic individuals. Epicutaneous administration of rBet v 1 and rBet v 1 fragments led to strong and significant increases of allergen-specific T cell proliferation (CLA+ and CCR4+T cell responses) only in bp-allergic patients with a positive APT reaction. There were no relevant changes of Bet v 1-specific IgE and IgG responses. No changes were noted in allergic subjects without bp allergy and in non-allergic subjects. Epicutaneous allergen application boosts specific T cell but not antibody responses mainly in allergic, APT-positive patients suggesting IgE-facilitated allergen presentation as mechanism for its effects on systemic allergen-specific immune responses. PMID- 28912493 TI - Synthesis of flower-like magnetite nanoassembly: Application in the efficient reduction of nitroarenes. AB - A facile approach for the synthesis of magnetite microspheres with flower-like morphology is reported that proceeds via the reduction of iron(III) oxide under a hydrogen atmosphere. The ensuing magnetic catalyst is well characterized by XRD, FE-SEM, TEM, N2 adsorption-desorption isotherm, and Mossbauer spectroscopy and explored for a simple yet efficient transfer hydrogenation reduction of a variety of nitroarenes to respective anilines in good to excellent yields (up to 98%) employing hydrazine hydrate. The catalyst could be easily separated at the end of a reaction using an external magnet and can be recycled up to 10 times without any loss in catalytic activity. PMID- 28912494 TI - Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders. AB - Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p < 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p < 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed. PMID- 28912496 TI - A Magnetometer Based on a Spin Wave Interferometer. AB - We describe a magnetic field sensor based on a spin wave interferometer. Its sensing element consists of a magnetic cross junction with four micro-antennas fabricated at the edges. Two of these antennas are used for spin wave excitation while two other antennas are used for detection of the inductive voltage produced by the interfering spin waves. Two waves propagating in the orthogonal arms of the cross may accumulate significantly different phase shifts depending on the magnitude and direction of the external magnetic field. This phenomenon is utilized for magnetic field sensing. The sensitivity attains its maximum under the destructive interference condition, where a small change in the external magnetic field results in a drastic increase of the inductive voltage, as well as in the change of the output phase. We report experimental data obtained for a micrometer scale Y3Fe2(FeO4)3 cross structure. The change of the inductive voltage near the destructive interference point exceeds 40 dB per 1 Oe. The phase of the output signal exhibits a pi-phase shift within 1 Oe. The data are collected at room temperature. Taking into account the low thermal noise in ferrite structures, we estimate that the maximum sensitivity of the spin wave magnetometer may exceed attotesla. PMID- 28912495 TI - Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins. AB - The global organization of protein binding sites is analyzed by constructing a weighted network of binding sites based on their structural similarities and detecting communities of structurally similar binding sites based on the minimum description length principle. The analysis reveals that there are two central binding site communities that play the roles of the network hubs of smaller peripheral communities. The sizes of communities follow a power-law distribution, which indicates that the binding sites included in larger communities may be older and have been evolutionary structural scaffolds of more recent ones. Structurally similar binding sites in the same community bind to diverse ligands promiscuously and they are also embedded in diverse domain structures. Understanding the general principles of binding site interplay will pave the way for improved drug design and protein design. PMID- 28912497 TI - Selective antibody activation through protease-activated pro-antibodies that mask binding sites with inhibitory domains. AB - Systemic injection of therapeutic antibodies may cause serious adverse effects due to on-target toxicity to the antigens expressed in normal tissues. To improve the targeting selectivity to the region of disease sites, we developed protease activated pro-antibodies by masking the binding sites of antibodies with inhibitory domains that can be removed by proteases that are highly expressed at the disease sites. The latency-associated peptide (LAP), C2b or CBa of complement factor 2/B were linked, through a substrate peptide of matrix metalloproteinase-2 (MMP-2), to an anti-epidermal growth factor receptor (EGFR) antibody and an anti tumor necrosis factor-alpha (TNF-alpha) antibody. Results showed that all the inhibitory domains could be removed by MMP-2 to restore the binding activities of the antibodies. LAP substantially reduced (53.8%) the binding activity of the anti-EGFR antibody on EGFR-expressing cells, whereas C2b and CBa were ineffective (21% and 9.3% reduction, respectively). Similarly, LAP also blocked 53.9% of the binding activity of the anti-TNF-alpha antibody. Finally, molecular dynamic simulation showed that the masking efficiency of LAP, C2b and CBa was 33.7%, 10.3% and -5.4%, respectively, over the binding sites of the antibodies. This strategy may aid in designing new protease-activated pro-antibodies that attain high therapeutic potency yet reduced systemic on-target toxicity. PMID- 28912498 TI - Reproducible and scalable purification of extracellular vesicles using combined bind-elute and size exclusion chromatography. AB - Extracellular vesicles (EVs) play a pivotal role in cell-to-cell communication and have been shown to take part in several physiological and pathological processes. EVs have traditionally been purified by ultracentrifugation (UC), however UC has limitations, including resulting in, operator-dependant yields, EV aggregation and altered EV morphology, and moreover is time consuming. Here we show that commercially available bind-elute size exclusion chromatography (BE SEC) columns purify EVs with high yield (recovery ~ 80%) in a time-efficient manner compared to current methodologies. This technique is reproducible and scalable, and surface marker analysis by bead-based flow cytometry revealed highly similar expression signatures compared with UC-purified samples. Furthermore, uptake of eGFP labelled EVs in recipient cells was comparable between BE-SEC and UC samples. Hence, the BE-SEC based EV purification method represents an important methodological advance likely to facilitate robust and reproducible studies of EV biology and therapeutic application. PMID- 28912499 TI - Role of Dopamine D2 Receptor in Stress-Induced Myelin Loss. AB - Dopaminergic systems play a major role in reward-related behavior and dysregulation of dopamine (DA) systems can cause several mental disorders, including depression. We previously reported that dopamine D2 receptor knockout (D2R-/-) mice display increased anxiety and depression-like behaviors upon chronic stress. Here, we observed that chronic stress caused myelin loss in wild type (WT) mice, while the myelin level in D2R-/- mice, which was already lower than that in WT mice, was not affected upon stress. Fewer mature oligodendrocytes (OLs) were observed in the corpus callosum of stressed WT mice, while in D2R-/- mice, both the control and stressed group displayed a decrease in the number of mature OLs. We observed a decrease in the number of active beta-catenin (ABC) expressing and TCF4-expressing cells among OL lineage cells in the corpus callosum of stressed WT mice, while such regulation was not found in D2R-/- mice. Administration of lithium normalized the behavioral impairments and myelin damage induced by chronic stress in WT mice, and restored the number of ABC-positive and TCF4-positive OLs, while such effect was not found in D2R-/- mice. Together, our findings indicate that chronic stress induces myelin loss through the Wnt/beta catenin signaling pathway in association with DA signaling through D2R. PMID- 28912500 TI - Dynamic Changes in the Splenic Transcriptome of Chickens during the Early Infection and Progress of Marek's Disease. AB - Gallid alphaherpesvirus 2 (GaHV2) is an oncogenic avian herpesvirus inducing Marek's disease (MD) and rapid-onset T-cell lymphomas. To reveal molecular events in MD pathogenesis and tumorigenesis, the dynamic splenic transcriptome of GaHV2 infected chickens during early infection and pathogenic phases has been determined utilizing RNA-seq. Based on the significant differentially expressed genes (DEGs), analysis of gene ontology, KEGG pathway and protein-protein interaction network has demonstrated that the molecular events happening during GaHV2 infection are highly relevant to the disease course. In the 'Cornell Model' description of MD, innate immune responses and inflammatory responses were established at early cytolytic phase but persisted until lymphoma formation. Humoral immunity in contrast began to play a role firstly in the intestinal system and started at late cytolytic phase. Neurological damage caused by GaHV2 is first seen in early cytolytic phase and is then sustained throughout the following phases over a long time period. During the proliferative phase many pathways associated with transcription and/or translation were significantly enriched, reflecting the cell transformation and lymphoma formation. Our work provides an overall view of host responses to GaHV2 infection and offers a meaningful basis for further studies of MD biology. PMID- 28912501 TI - Transcription regulation of CDKN1A (p21/CIP1/WAF1) by TRF2 is epigenetically controlled through the REST repressor complex. AB - We observed extra-telomeric binding of the telomere repeat binding factor TRF2 within the promoter of the cyclin-dependent kinase CDKNIA (p21/CIP1/WAF1). This result in TRF2 induced transcription repression of p21. Interestingly, p21 repression was through engagement of the REST-coREST-LSD1-repressor complex and altered histone marks at the p21 promoter in a TRF2-dependent fashion. Furthermore, mutational analysis shows p21 repression requires interaction of TRF2 with a p21 promoter G-quadruplex. Physiologically, TRF2-mediated p21 repression attenuated drug-induced activation of cellular DNA damage response by evading G2/M arrest in cancer cells. Together these reveal for the first time role of TRF2 in REST- repressor complex mediated transcription repression. PMID- 28912502 TI - Caloric restriction delays age-related methylation drift. AB - In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7-14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals.Caloric restriction has been shown to increase lifespan in mammals. Here, the authors provide evidence that age-related methylation drift correlates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation of age-related methylation drift. PMID- 28912503 TI - Systematic review and meta-analysis of differentially expressed miRNAs in experimental and human temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is a common chronic neurological disease in humans. A number of studies have demonstrated differential expression of miRNAs in the hippocampus of humans with TLE and in animal models of experimental epilepsy. However, the dissimilarities in experimental design have led to largely discordant results across these studies. Thus, a comprehensive comparison is required in order to better characterize miRNA profiles obtained in various post status epilepticus (SE) models. We therefore created a database and performed a meta-analysis of differentially expressed miRNAs across 3 post-SE models of epileptogenesis (electrical stimulation, pilocarpine and kainic acid) and human TLE with hippocampal sclerosis (TLE-HS). The database includes data from 11 animal post-SE studies and 3 human TLE-HS studies. A total of 378 differentially expressed miRNAs were collected (274 up-regulated and 198 down-regulated) and analyzed with respect to the post-SE model, time point and animal species. We applied the novel robust rank aggregation method to identify consistently differentially expressed miRNAs across the profiles. It highlighted common and unique miRNAs at different stages of epileptogenesis. The pathway analysis revealed involvement of these miRNAs in key pathogenic pathways underlying epileptogenesis, including inflammation, gliosis and deregulation of the extracellular matrix. PMID- 28912504 TI - Qubit-mediated deterministic nonlinear gates for quantum oscillators. AB - Quantum nonlinear operations for harmonic oscillator systems play a key role in the development of analog quantum simulators and computers. Since strong highly nonlinear operations are often unavailable in the existing physical systems, it is a common practice to approximate them by using conditional measurement-induced methods. The conditional approach has several drawbacks, the most severe of which is the exponentially decreasing success rate of the strong and complex nonlinear operations. We show that by using a suitable two level system sequentially interacting with the oscillator, it is possible to resolve these issues and implement a nonlinear operation both nearly deterministically and nearly perfectly. We explicitly demonstrate the approach by constructing self-Kerr and cross-Kerr couplings in a realistic situation, which require a feasible dispersive coupling between the two-level system and the oscillator. PMID- 28912505 TI - Biomimetic Silica Nanoparticles Prepared by a Combination of Solid-Phase Imprinting and Ostwald Ripening. AB - Herein we describe the preparation of molecularly imprinted silica nanoparticles by Ostwald ripening in the presence of molecular templates immobilised on glass beads (the solid-phase). To achieve this, a seed material (12 nm diameter silica nanoparticles) was incubated in phosphate buffer in the presence of the solid phase. Phosphate ions act as a catalyst in the ripening process which is driven by differences in surface energy between particles of different size, leading to the preferential growth of larger particles. Material deposited in the vicinity of template molecules results in the formation of sol-gel molecular imprints after around 2 hours. Selective washing and elution allows the higher affinity nanoparticles to be isolated. Unlike other strategies commonly used to prepare imprinted silica nanoparticles this approach is extremely simple in nature and can be performed under physiological conditions, making it suitable for imprinting whole proteins and other biomacromolecules in their native conformations. We have demonstrated the generic nature of this method by preparing imprinted silica nanoparticles against targets of varying molecular mass (melamine, vancomycin and trypsin). Binding to the imprinted particles was demonstrated in an immunoassay (ELISA) format in buffer and complex media (milk or blood plasma) with sub-nM detection ability. PMID- 28912506 TI - Role of tumor necrosis factor-alpha and its receptors in diesel exhaust particle induced pulmonary inflammation. AB - Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung. However, the underlying mechanisms remain to be elucidated. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that operates by binding to tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2). The role of TNF-alpha signaling and the importance of either TNFR1 or TNFR2 in the DEP-induced inflammatory response has not yet been elucidated. TNF-alpha knockout (KO), TNFR1 KO, TNFR2 KO, TNFR1/TNFR2 double KO (TNFR-DKO) and wild type (WT) mice were intratracheally exposed to saline or DEP. Pro-inflammatory cells and cytokines were assessed in the bronchoalveolar lavage fluid (BALF). Exposure to DEP induced a dose-dependent inflammation in the BALF in WT mice. In addition, levels of TNF-alpha and its soluble receptors were increased upon exposure to DEP. The DEP-induced inflammation in the BALF was decreased in TNF-alpha KO, TNFR-DKO and TNFR2 KO mice. In contrast, the inflammatory response in the BALF of DEP-exposed TNFR1 KO mice was largely comparable with WT controls. In conclusion, these data provide evidence for a regulatory role of TNF-alpha in DEP-induced pulmonary inflammation and identify TNFR2 as the most important receptor in mediating these inflammatory effects. PMID- 28912507 TI - Fast-track development of an in vitro 3D lung/immune cell model to study Aspergillus infections. AB - To study interactions of airborne pathogens, e.g. Aspergillus (A.) fumigatus with upper and lower respiratory tract epithelial and immune cells, we set up a perfused 3D human bronchial and small airway epithelial cell system. Culturing of normal human bronchial or small airway epithelial (NHBE, SAE) cells under air liquid interphase (ALI) and perfusion resulted in a significantly accelerated development of the lung epithelia associated with higher ciliogenesis, cilia movement, mucus-production and improved barrier function compared to growth under static conditions. Following the accelerated differentiation under perfusion, epithelial cells were transferred into static conditions and antigen-presenting cells (APCs) added to study their functionality upon infection with A. fumigatus. Fungi were efficiently sensed by apically applied macrophages or basolaterally adhered dendritic cells (DCs), as illustrated by phagocytosis, maturation and migration characteristics. We illustrate here that perfusion greatly improves differentiation of primary epithelial cells in vitro, which enables fast-track addition of primary immune cells and significant shortening of experimental procedures. Additionally, co-cultured primary DCs and macrophages were fully functional and fulfilled their tasks of sensing and sampling fungal pathogens present at the apical surface of epithelial cells, thereby promoting novel possibilities to study airborne infections under conditions mimicking the in vivo situation. PMID- 28912508 TI - Use of anthropogenic linear features by two medium-sized carnivores in reserved and agricultural landscapes. AB - Many carnivores are threatened by habitat loss and fragmentation. These changes create linear features and habitat edges that can facilitate foraging and/or travel. To understand the significance of anthropogenic linear features in the ecology of carnivores, fine-scaled studies are needed. We studied two medium sized carnivores: the endangered Tasmanian devil (Sarcophilus harrisii) and the near threatened spotted-tailed quoll (Dasyurus maculatus), in a mixed landscape of conservation and agricultural land. Using GPS tracking, we investigated their use of intact habitat versus linear features such as roads, fences and the pasture/cover interface. Both species showed a positive selection for anthropogenic linear features, using the pasture/cover interface for foraging and roads for movement and foraging. Devils travelled along fence lines, while quolls showed little preference for them. Otherwise, both species foraged in forest and travelled through pasture. While devils and quolls can utilise anthropogenic linear features, we suggest that their continued survival in these habitats may depend on the intensity of other threats, e.g. persecution, and providing that sufficient intact habitat remains to sustain their ecological needs. We suggest that the management of both species and probably many other species of carnivores should focus on controlling mortality factors associated with human use of landscapes. PMID- 28912509 TI - Aspirin inhibits LPS-induced macrophage activation via the NF-kappaB pathway. AB - Aspirin (acetylsalicylic acid, ASA) has been shown to improve bone marrow mesenchymal stem cell-based calvarial bone regeneration by promoting osteogenesis and inhibiting osteoclastogenesis. However, it remains unknown whether aspirin influences other immune cells during bone formation. In the present study, we investigated whether ASA treatment influenced macrophage activation during the LPS inducement. We found that ASA could downregulate the expressions of iNOS and TNF-alpha both in mouse peritoneum macrophages and RAW264.7 cells induced by LPS via the IkappaK/IkappaB/NF-kappaB pathway and a COX2/PGE2/EP2/NF-kappaB feedback loop, without affecting the expressions of FIZZ/YM-1/ARG1 induced by IL-4. Furthermore, we created a rat mandibular bone defect model and showed that ASA treatment improved bone regeneration by inhibiting LPS-induced macrophage activation in the early stages of inflammation. Taken together, our results indicated that ASA treatment was a feasible strategy for improving bone regeneration, particularly in inflammatory conditions. PMID- 28912510 TI - The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease. AB - Radiotherapy can result in lung diseases pneumonitis or fibrosis dependent on patient susceptibility. Herein we used inbred and genetically altered mice to investigate whether the tissue adaptive immune response to radiation injury influences the development of radiation-induced lung disease. Six inbred mouse strains were exposed to 18 Gy whole thorax irradiation and upon respiratory distress strains prone to pneumonitis with fibrosis presented an increased pulmonary frequency of Thelper (Th)17 cells which was not evident in strains prone solely to pneumonitis. The contribution of Th17 cells to fibrosis development was supported as the known enhanced fibrosis of toll-like receptor 2&4 deficient mice, compared to C57BL/6J mice, occurred with earlier onset neutrophilia, and with increased levels of pulmonary Th17, but not Th1, cells following irradiation. Irradiated Il17-/- mice lacked Th17 cells, and were spared both fibrosis and pneumonitis, as they survived to the end of the experiment with a significantly increased pulmonary Th1 cell frequency, only. Interferon-gamma-/- mice, deficient in Th1 cells, developed a significantly enhanced fibrosis response compared to that of C57BL/6J mice. The tissue adaptive immune response influences the pulmonary disease response to radiotherapy, as an increased Th17 cell frequency enhanced and a Th1 response spared, fibrosis in mice. PMID- 28912511 TI - Outcomes of adjuvant epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment for EGFR-mutant non-small-cell lung cancer: a propensity score analysis. AB - Small molecule tyrosine kinase inhibitors (TKIs) have transformed the management of advanced non-small-cell lung cancer (NSCLC) harboring activating epithelial growth factor receptor (EGFR) mutations, while the efficacy of TKIs in the adjuvant setting remains unclear. We collected the data of 209 EGFR-mutant NSCLC patients receiving complete resection from 2010 to 2013. Study end points were disease-free survival (DFS) and overall survival (OS). Among the eligible patients, 41 (19.6%) received EGFR TKIs in the adjuvant treatment. The 3-year DFS of adjuvant EGFR TKIs treatment group (70.5%, 95% CI, 54.6-86.4%) was significantly superior that control group (50.2%, 95% CI, 40-60.4%; log-rank P = 0.014). TKIs treatment (HR, 0.51; 95% CI, 0.29-0.97; P = 0.04) was significantly associated with improved DFS in multivariate Cox analysis. No significant difference was observed in 3-year OS between two groups (73.1% [58.0-88.2%] vs 61.8% [52.2-71.4%], log-rank P = 0.21). Propensity-score matching further confirmed that adjuvant TKIs treatment extended the DFS (log-rank P = 0.024), but did not improve OS (log-rank P = 0.40). Our analysis revealed that adjuvant EGFR TKIs treatment was beneficial for early-stage NSCLC patients harboring activating EGFR mutations after complete resection. PMID- 28912512 TI - Assessing individual risk for AMD with genetic counseling, family history, and genetic testing. AB - PurposeThe goal was to develop a simple model for predicting the individual risk profile for age-related macular degeneration (AMD) on the basis of genetic information, disease family history, and smoking habits.Patients and methodsThe study enrolled 151 AMD patients following specific clinical and environmental inclusion criteria: age >55 years, positive family history for AMD, presence of at least one first-degree relative affected by AMD, and smoking habits. All of the samples were genotyped for rs1061170 (CFH) and rs10490924 (ARMS2) with a TaqMan assay, using a 7500 Fast Real Time PCR device. Statistical analysis was subsequently employed to calculate the real individual risk (OR) based on the genetic data (ORgn), family history (ORf), and smoking habits (ORsm).Results and conclusionThe combination of ORgn, ORf, and ORsm allowed the calculation of the Ort that represented the realistic individual risk for developing AMD. In this report, we present a computational model for the estimation of the individual risk for AMD. Moreover, we show that the average distribution of risk alleles in the general population and the knowledge of parents' genotype can be decisive to assess the real disease risk. In this contest, genetic counseling is crucial to provide the patients with an understanding of their individual risk and the availability for preventive actions. PMID- 28912513 TI - Comment on 'A review of 145 234 ophthalmic patient episodes lost to follow-up'. PMID- 28912514 TI - Retinal changes following rapid ascent to a high-altitude environment. AB - PurposeTo determine what impact rapid ascension to a high-altitude environment has on the retina with the aim of preventing and treating high-altitude oculopathy.Patients and methodsParticipants in the study were members of the Chinese military assigned to the high-altitude environment of the Tibetan plateau. Ninety-one participants were enrolled in the study. Optical coherence tomography was used to measure the thickness of retina-related indicators. Measurements were taken before and after exposure to the high-altitude environment and upon return to the baseline altitude.ResultsFollowing exposure to the high-altitude environment in Tibet, there was a significant increase in retinal nerve fiber layer (RNFL) thickness in the temporal and nasal quadrants of the optic disc, whilst a significant decrease in RNFL thickness in the inferior optic disc was also observed. A significant increase in RNFL thickness in the superior and inferior macula was also evident, along with a significant increase in the ganglion cell layer thickness in the superior macula. Upon return to the baseline altitude, all measurements returned to baseline levels except for the RNFL of the inferior macula, which was significantly thicker. Pathological changes were also documented in the eyes of nine participants upon returning to baseline altitude, including ischemic optic neuropathy, myopia, and cortical amaurosis.ConclusionsThe high-altitude environment can have a negative impact on the health of the retina and may contribute to the incidence of various eye diseases. This study deepens the understanding of what impact a high-altitude environment has on retina and provides reliable data for blindness prevention and treatment. PMID- 28912515 TI - Screening for vision-threatening diabetic retinopathy in South India: comparing portable non-mydriatic and standard fundus cameras and clinical exam. AB - PurposeTo evaluate the sensitivity and specificity of a portable non-mydriatic fundus camera to diagnose vision-threatening diabetic retinopathy (VTDR).Patients and methodsA prospective, single-site, comparative instrument validation study was undertaken at the Aravind Eye Care System. Overall, 155 subjects with and without diabetes were recruited. Images from 275 eyes were obtained with the (1) non-mydriatic Smartscope, (2) mydriatic Smartscope, and (3) mydriatic table-top camera of the macular, nasal, and superotemporal fields. A retina specialist performed a dilated fundus examination (DFE), (reference standard). Two masked retina specialists graded the images. Sensitivity and specificity to detect VTDR with the undilated Smartscope was calculated compared to DFE.ResultsGraders 1 and 2 had a sensitivity of 93% (95% confidence interval (CI): 87-97%) and 88% (95% CI: 81-93%) and a specificity of 84% (95% CI: 77-89%) and 90% (95% CI: 84-94%), respectively, in diagnosing VTDR with the undilated Smartscope compared to DFE. Compared with the dilated Topcon images, graders 1 and 2 had sensitivity of 88% (95% CI: 81-93%) and 82% (95% CI: 73-88%) and specificity of 99% (95% CI: 96 100%) and 99% (95% CI: 95-100%).ConclusionsRemote graders had high sensitivity and specificity in diagnosing VTDR with undilated Smartscope images, suggesting utility where portability is a necessity. PMID- 28912516 TI - Choroidal thickness measurements in children with isolated growth hormone deficiency. AB - PurposeThe aim of this study was to determine the choroidal thickness measurement values in cases with isolated growth hormone deficiency (IGHD), to compare them with the healthy control group by using enhanced depth imaging optical coherence tomography (EDI-OCT), and to evaluate the effect of growth hormone (GH) treatment on choroid.Patients and methodsIn this study, 23 cases who were diagnosed with IGHD as a study group and 46 healthy subjects as a control group were included. All patients and controls underwent a complete ophthalmologic examination, including an examination with EDI-OCT. Choroidal thickness (CT) was measured at the fovea and at 1000 MUm intervals from the foveal center in both temporal and nasal directions.ResultsThe mean subfoveal choroidal thickness (SFCT) was 329.04+/-88.49 MUm in the cases with IGHD and 365.35+/-50.48 MUm in the control group (P=0.033). The mean CT at temporal 1 and 2 mm were thinner in the IGHD group than that of control group (P=0.033 and P=0.043, respectively). Nasal quadrant measurements were also found to be thinner in the IGHD cases than that of control group, but the difference was not statistically significant. We found a significant positive correlation between pubertal staging and SFCT (rs=0.607, P=0.006). There was no statistically significant difference in CT values of the study group between before and 12 months after GH treatment (P>0.05).ConclusionThis study shows patients with IGHD has a thinner CT when compared with healthy pediatric cases. GH treatment seems to be not associated with the choroidal development. PMID- 28912517 TI - Reply to Anitua et al: Searching for the best blood-derived eye drops. PMID- 28912519 TI - Response to: 'Comment on A review of 145 234 ophthalmic patient episodes lost to follow-up'. PMID- 28912518 TI - Trainee-led research networks in ophthalmology: is this the way forward? PMID- 28912520 TI - Intraoperative intorsional traction test of the inferior oblique. AB - PurposeWe present a novel variation of the traction test of the inferior oblique (IO) muscle. We demonstrate the correlation between the traction test and clinically graded IO overaction and describe the utility of this test to confirm IO weakening.MethodsWe performed a retrospective chart review on all patients who underwent IO surgery and intraoperative intorsion traction tests by a single surgeon over a 10-year period. We compared the traction test results, in 'clock hours' of freedom, before and after IO surgery. We correlated the torsion test at start of surgery with clinical observed IO overaction (scale 0 to +4) in 67 IO operations (56 myectomies, 6 anterior transpositions, 4 myotomies, and 1 recession) and compared to a control group of 23 eyes with minimal or no IO overaction.ResultsThe mean intorsion freedom in the eyes undergoing IO surgery was less than in control eyes (1.63 vs 1.89 clock hour; P<0.00005). There was a significant inverse relationship between grading of clinical IO action and the intorsion test result (Pearson rank coefficient, (r=-0.45; P<0.00001)). Myectomy produced the greatest change in torsion freedom (mean 1.32 clock hour), with all myectomies showing at least 1 clock hour extra freedom after the surgery.ConclusionsThe intorsion traction test confirmed that the IO stiffness correlated with pre-operative IO overaction grade. While it can be helpful in confirming that the entire IO muscle was weakened, it does not substitute for the careful inspection at the end of surgery to ensure there are no remaining IO fibers. PMID- 28912521 TI - Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury. AB - Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy. PMID- 28912522 TI - Human histone deacetylase 6 shows strong preference for tubulin dimers over assembled microtubules. AB - Human histone deacetylase 6 (HDAC6) is the major deacetylase responsible for removing the acetyl group from Lys40 of alpha-tubulin (alphaK40), which is located lumenally in polymerized microtubules. Here, we provide a detailed kinetic analysis of tubulin deacetylation and HDAC6/microtubule interactions using individual purified components. Our data unequivocally show that free tubulin dimers represent the preferred HDAC6 substrate, with a K M value of 0.23 uM and a deacetylation rate over 1,500-fold higher than that of assembled microtubules. We attribute the lower deacetylation rate of microtubules to both longitudinal and lateral lattice interactions within tubulin polymers. Using TIRF microscopy, we directly visualized stochastic binding of HDAC6 to assembled microtubules without any detectable preferential binding to microtubule tips. Likewise, indirect immunofluorescence microscopy revealed that microtubule deacetylation by HDAC6 is carried out stochastically along the whole microtubule length, rather than from the open extremities. Our data thus complement prior studies on tubulin acetylation and further strengthen the rationale for the correlation between tubulin acetylation and microtubule age. PMID- 28912523 TI - Enhanced paramagnetism of mesoscopic graphdiyne by doping with nitrogen. AB - The new two-dimensional graphitic material, graphdiyne, has attracted great interest recently due to the superior intrinsic semiconductor properties. Here we investigate the magnetism of pure graphdiyne material and find it demonstrating a remarkable paramagnetic characteristic, which can be attributed to the appearance of special sp-hybridized carbon atoms. On this basis, we further introduce nitrogen with 5.29% N/C ratio into graphdiyne followed by simply annealing in a dopant source and realize a twofold enhancement of saturation moment at 2 K. Associate with the density of states calculation, we investigate the influence of the nitrogen atom doping sites on paramagnetism, and further reveal the important role of doped nitrogen atom on benzene ring in improving local magnetic moment. These results can not only help us deeply understand the intrinsic magnetism of graphdiyne, but also open an efficient way to improve magnetism of graphdiyne by hetero atom doping, like nitrogen doping, which may promote the potential application of graphdiyne in spintronics. PMID- 28912524 TI - Precise insertion and guided editing of higher plant genomes using Cpf1 CRISPR nucleases. AB - Precise genome editing of plants has the potential to reshape global agriculture through the targeted engineering of endogenous pathways or the introduction of new traits. To develop a CRISPR nuclease-based platform that would enable higher efficiencies of precise gene insertion or replacement, we screened the Cpf1 nucleases from Francisella novicida and Lachnospiraceae bacterium ND2006 for their capability to induce targeted gene insertion via homology directed repair. Both nucleases, in the presence of a guide RNA and repairing DNA template flanked by homology DNA fragments to the target site, were demonstrated to generate precise gene insertions as well as indel mutations at the target site in the rice genome. The frequency of targeted insertion for these Cpf1 nucleases, up to 8%, is higher than most other genome editing nucleases, indicative of its effective enzymatic chemistry. Further refinements and broad adoption of the Cpf1 genome editing technology have the potential to make a dramatic impact on plant biotechnology. PMID- 28912525 TI - Pulse Transit Time Based Continuous Cuffless Blood Pressure Estimation: A New Extension and A Comprehensive Evaluation. AB - Cuffless technique enables continuous blood pressure (BP) measurement in an unobtrusive manner, and thus has the potential to revolutionize the conventional cuff-based approaches. This study extends the pulse transit time (PTT) based cuffless BP measurement method by introducing a new indicator - the photoplethysmogram (PPG) intensity ratio (PIR). The performance of the models with PTT and PIR was comprehensively evaluated in comparison with six models that are based on sole PTT. The validation conducted on 33 subjects with and without hypertension, at rest and under various maneuvers with induced BP changes, and over an extended calibration interval, respectively. The results showed that, comparing to the PTT models, the proposed methods achieved better accuracy on each subject group at rest state and over 24 hours calibration interval. Although the BP estimation errors under dynamic maneuvers and over extended calibration interval were significantly increased for all methods, the proposed methods still outperformed the compared methods in the latter situation. These findings suggest that additional BP-related indicator other than PTT has added value for improving the accuracy of cuffless BP measurement. This study also offers insights into future research in cuffless BP measurement for tracking dynamic BP changes and over extended periods of time. PMID- 28912526 TI - MPZL1 forms a signalling complex with GRB2 adaptor and PTPN11 phosphatase in HER2 positive breast cancer cells. AB - HER2/ErbB2 is overexpressed in a significant fraction of breast tumours and is associated with a poor prognosis. The adaptor protein GRB2 interacts directly with activated HER2 and is sufficient to transmit oncogenic signals. However, the consequence of HER2 activation on global GRB2 signalling networks is poorly characterized. We performed GRB2 affinity purification combined with mass spectrometry analysis of associated proteins in a HER2+ breast cancer model to delineate GRB2-nucleated protein interaction networks. We report the identification of the transmembrane protein MPZL1 as a new GRB2-associated protein. Our data show that the PTPN11 tyrosine phosphatase acts as a scaffold to bridge the association between GRB2 and MPZL1 in a phosphotyrosine-dependent manner. We further demonstrate that the formation of this MPZL1-PTPN11-GRB2 complex is triggered by cell attachment to fibronectin. Thus, our data support the importance of this new signalling complex in the control of cell adhesion of HER2+ breast cancer cells, a key feature of the metastatic process. PMID- 28912527 TI - Treatment with Caffeic Acid and Resveratrol Alleviates Oxidative Stress Induced Neurotoxicity in Cell and Drosophila Models of Spinocerebellar Ataxia Type3. AB - Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death. Here we show that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro-oxidant tert butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3. Furthermore, CA and Res improved survival and locomotor activity and decreased mutant ataxin-3 and ROS levels in tBH-treated SCA3 Drosophila. CA and Res also altered p53 and nuclear factor-kappaB (NF-kappaB) activation and expression in tBH-treated cell and fly models of SCA3, respectively. Blockade of NF-kappaB activation annulled the protective effects of CA and Res on apoptosis, ROS, and p53 activation in tBH-treated SK-N-SH-MJD78 cells, which suggests the importance of restoring NF-kappaB activity by CA and Res. Our findings suggest that CA and Res may be useful in the management of oxidative stress induced neuronal apoptosis in SCA3. PMID- 28912528 TI - Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival. AB - We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4+CD25- regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro, without needing cell-to-cell contact, and induced kidney allograft survival prolongation in-vivo. Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administered in-vivo, dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation. PMID- 28912529 TI - Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2. AB - The Musashi family of RNA binding proteins act to promote stem cell self-renewal and oppose cell differentiation predominantly through translational repression of mRNAs encoding pro-differentiation factors and inhibitors of cell cycle progression. During tissue development and repair however, Musashi repressor function must be dynamically regulated to allow cell cycle exit and differentiation. The mechanism by which Musashi repressor function is attenuated has not been fully established. Our prior work indicated that the Musashi1 isoform undergoes site-specific regulatory phosphorylation. Here, we demonstrate that the canonical Musashi2 isoform is subject to similar regulated site-specific phosphorylation, converting Musashi2 from a repressor to an activator of target mRNA translation. We have also characterized a novel alternatively spliced, truncated isoform of human Musashi2 (variant 2) that lacks the sites of regulatory phosphorylation and fails to promote translation of target mRNAs. Consistent with a role in opposing cell cycle exit and differentiation, upregulation of Musashi2 variant 2 was observed in a number of cancers and overexpression of the Musashi2 variant 2 isoform promoted cell transformation. These findings indicate that alternately spliced isoforms of the Musashi protein family possess distinct functional and regulatory properties and suggest that differential expression of Musashi isoforms may influence cell fate decisions. PMID- 28912530 TI - ROS induced distribution of mitochondria to filopodia by Myo19 depends on a class specific tryptophan in the motor domain. AB - The role of the actin cytoskeleton in relation to mitochondria function and dynamics is only recently beginning to be recognized. Myo19 is an actin-based motor that is bound to the outer mitochondrial membrane and promotes the localization of mitochondria to filopodia in response to glucose starvation. However, how glucose starvation induces mitochondria localization to filopodia, what are the dynamics of this process and which enzymatic adaptation allows the translocation of mitochondria to filopodia are not known. Here we show that reactive oxygen species (ROS) mimic and mediate the glucose starvation induced phenotype. In addition, time-lapse fluorescent microscopy reveals that ROS induced Myo19 motility is a highly dynamic process which is coupled to filopodia elongation and retraction. Interestingly, Myo19 motility is inhibited by back-to consensus-mutation of a unique residue of class XIX myosins in the motor domain. Kinetic analysis of the purified mutant Myo19 motor domain reveals that the duty ratio (time spent strongly bound to actin) is highly compromised in comparison to that of the WT motor domain, indicating that Myo19 unique motor properties are necessary to propel mitochondria to filopodia tips. In summary, our study demonstrates the contribution of actin-based motility to the mitochondrial localization to filopodia by specific cellular cues. PMID- 28912531 TI - TGF-a1-induced miR-503 controls cell growth and apoptosis by targeting PDCD4 in glioblastoma cells. AB - Aberrant expression of microRNAs hae been shown to be closely associated with glioblastoma cell proliferation, apoptosis and drug resistance. However, mechanisms underlying the role of mcroRNAs in glioblastoma cell growth and apoptosis are not fully understood. In this study, we report that miR-503 is overexpressed in glioblastoma tissue compared with normal human brain tissue. Mechanistically, miR-503 can be induced by TGF-a1 at the transcriptional level by binding the smad2/3 binding elements in the promoter. Ectopic overexpression of miR-503 promotes cell growth and inhibits apoptosis by targeting PDCD4. In contrast, inhibition of miR-503 reduces cell growth. Furthermore, miR-503 inhibitor augments the growth inhibitory effect of temozolomide in glioblastoma cells. These results establish miR-503 as a promising molecular target for glioblastoma therapy. PMID- 28912532 TI - Chronic kidney disease is associated with poorer in-hospital outcomes in patients hospitalized with infections: Electronic record analysis from China. AB - Predominantly based on studies from high-income countries, reduced estimated glomerular filtration rate (eGFR) has been associated with increased risk of infections and infection-related hospitalizations (IRHs). We here explore in hospital outcomes of IRHs in patients with different kidney function. A total of 6,283 adults, not on renal replacement therapy, with a discharge diagnosis of infection, and with an eGFR 1-12 months before index hospitalization, were included from four hospitals in China. We compared in-hospital outcomes (death, intensive care unit (ICU) admission, length of hospital stay (LOHS) and medical expenses), between patients with and without chronic kidney disease (CKD, defined as eGFR <= 60 ml/min per 1.73 m2 of body surface area) by mixed-effects logistic regression model or generalized linear model. The odds for in-hospital mortality (adjusted odds ratios (OR) = 1.41; 95% CI 1.02-1.96) and ICU admission (OR = 2.18; 95% CI 1.64-2.91) were higher among patients with CKD. The median LOHS was significantly higher for CKD patients (11 days vs. 10 days in non-CKD, P < 0.001), and inferred costs were 20.0% higher adjusted for inflation rate based on costs in 2012 (P < 0.001). Patients with CKD hospitalized with infections are at increased risk of poorer in-hospital outcomes, conveying higher medical costs. PMID- 28912533 TI - Oral fibroblasts modulate the macrophage response to bacterial challenge. AB - Tissue damage in chronic periodontal disease is driven by the host response to a dysbiotic microbiota, and not by bacteria directly. Among chronic inflammatory diseases of the oral cavity, inflammation and tissue damage around dental implants (peri-implantitis) is emerging as a major clinical challenge, since it is more severe and less responsive to treatment compared to inflammation around natural teeth. We tested whether oral fibroblasts from the periodontal ligament (PDLF), which are present around natural teeth but not around dental implants, actively regulate inflammatory responses to bacterial stimulation. We show that human PDLF down-regulate TNF-alpha post-transcriptionally in macrophages stimulated with the oral pathogen Porphyromonas gingivalis. Cell contact and secretion of IL-6 and IL-10 contribute to the modulation of inflammatory cytokine production. Although fibroblasts decreased TNF-alpha secretion, they enhanced the ability of macrophages to phagocytose bacteria. Surprisingly, donor matched oral fibroblasts from gingival tissues, or fibroblasts from peri-implant inflamed tissues were at least as active as PDLF in regulating macrophage responses to bacteria. In addition, priming fibroblasts with inflammatory mediators enhanced PDLF regulatory activity. A further understanding of the spectrum of fibroblast activities in inflammatory lesions is important in order to design ways to control inflammatory tissue damage. PMID- 28912534 TI - Multisegmented Nanowires: a Step towards the Control of the Domain Wall Configuration. AB - Cylindrical nanowires synthesized by controlled electrodeposition constitute excellent strategic candidates to engineer magnetic domain configurations. In this work, multisegmented CoNi/Ni nanowires are synthesized for tailoring a periodic magnetic structure determined by the balance between magnetocrystalline and magnetostatic energies. High-resolution Transmission Electron Microscopy confirms the segmented growth and the sharp transition between layers. Although both CoNi and Ni segments have similar fcc cubic crystal symmetry, their magnetic configuration is quite different as experimentally revealed by Magnetic Force Microscopy (MFM) imaging. While the Ni segments are single domain with axial magnetization direction, the CoNi segments present two main configurations: a single vortex state or a complex multivortex magnetic configuration, which is further interpreted with the help of micromagnetic simulations. This original outcome is ascribed to the tight competition between anisotropies. The almost monocrystalline fcc structure of the CoNi segments, as revealed by the electron diffraction patterns, which is atypical for its composition, contributes to balance the magnetocrystalline and shape anisotropies. The results of MFM measurements performed under in-plane magnetic field demonstrate that it is possible to switch from the multivortex configuration to a single vortex configuration with low magnetic fields. PMID- 28912535 TI - Molecular mechanisms underlying the involvement of the sigma-1 receptor in methamphetamine-mediated microglial polarization. AB - Our previous study demonstrated that the sigma-1 receptor is involved in methamphetamine-induced microglial apoptosis and death; however, whether the sigma-1 receptor is involved in microglial activation as well as the molecular mechanisms underlying this process remains poorly understood. The aim of this study is to demonstrate the involvement of the sigma-1 receptor in methamphetamine-mediated microglial activation. The expression of sigma-1R, iNOS, arginase and SOCS was examined by Western blot; activation of cell signaling pathways was detected by Western blot analysis. The role of sigma-1R in microglial activation was further validated in C57BL/6 N WT and sigma-1 receptor knockout mice (male, 6-8 weeks) injected intraperitoneally with saline or methamphetamine (30 mg/kg) by Western blot combined with immunostaining specific for Iba-1. Treatment of cells with methamphetamine (150 MUM) induced the expression of M1 markers (iNOS) with concomitant decreased the expression of M2 markers (Arginase) via its cognate sigma-1 receptor followed by ROS generation. Sequential activation of the downstream MAPK, Akt and STAT3 pathways resulted in microglial polarization. Blockade of sigma-1 receptor significantly inhibited the generation of ROS and activation of the MAPK and Akt pathways. These findings underscore the critical role of the sigma-1 receptor in methamphetamine-induced microglial activation. PMID- 28912536 TI - Predictive and prognostic value of intravoxel incoherent motion (IVIM) MR imaging in patients with advanced cervical cancers undergoing concurrent chemo radiotherapy. AB - By using the intravoxel incoherent motion (IVIM) model, the diffusion-related coefficient (D) and the perfusion-related parameter (f) can be obtained simultaneously. Here, we explored the application of IVIM MR imaging in predicting long-term prognosis in patients with advanced cervical cancers treated with concurrent chemo-radiotherapy (CCRT). In this study, pelvic MR examinations including an IVIM sequence were performed on 30 women with advanced cervical cancers at three time points (within 2 weeks before, as well as 2 and 4 weeks after, the initiation of CCRT). The performance of tumour size and IVIM-derived parameters in predicting long-term prognosis was evaluated. After a median follow up of 24 months (range, 10~34 months), 25/30 (83.33%) patients were alive, and 21/30 (70.00%) remained free of disease. A shrinkage rate of maximum diameter (time point 1 vs. 3) >= 58.31% was useful in predicting a good long-term prognosis. The IVIM-derived apparent diffusion coefficient (ADCIVIM) value at time point 2 and the ADCIVIM and f values at time point 3 also performed well in predicting a good prognosis, with AUC of 0.767, 0.857 and 0.820, respectively. IVIM MR imaging has great potential in predicting long-term prognosis in patients with advanced cervical cancers treated with CCRT. PMID- 28912537 TI - Hybrid Ag nanowire transparent conductive electrodes with randomly oriented and grid-patterned Ag nanowire networks. AB - To improve the electrical properties of silver nanowire (Ag NW) transparent conductive electrodes (TCEs), the density of Ag NW networks should be increased, to increase the number of percolation paths. However, because of the inverse relationship between optical transmittance and electrical resistivity, the optical properties of Ag NW TCEs deteriorate with increasing density of the Ag NW network. In this study, a hybrid Ag NW electrode composed of randomly oriented and grid-patterned Ag NW networks is demonstrated. The hybrid Ag NW electrodes exhibit significantly improved sheet resistances and slightly decreased transmittances compared to randomly oriented Ag NW networks. Hybrid Ag NW TCEs show excellent mechanical flexibilities and durabilities in bending tests with a 5 mm radius of curvature. Moreover, flexible transparent film heaters (TFHs) based on the hybrid Ag NW electrodes show elevated maximum temperatures relative to TFHs based on randomly oriented Ag NW electrodes, when operated at the same input voltages. PMID- 28912538 TI - Decoupled dynamic magnetic field measurements improves diffusion-weighted magnetic resonance images. AB - Field probes are miniature receiver coils with localized NMR-active samples inside. They are useful in monitoring magnetic field. This information can be used to improve magnetic resonance image quality. While field probes are coupled to each other marginally in most applications, this coupling can cause incorrect resonance frequency estimates and image reconstruction errors. Here, we propose a method to reduce the coupling between field probes in order to improve the accuracy of magnetic field estimation. An asymmetric sensitivity matrix describing the coupling between channels of field probes and NMR active droplets within field probes was empirically measured. Localized signal originating from each probe was derived from the product of the inverse of the sensitivity matrix and the coupled probe measurements. This method was used to estimate maps of dynamic magnetic fields in diffusion weighted MRI. The estimated fields using decoupled probe measurement led to images more robust to eddy currents caused by diffusion sensitivity gradients along different directions. PMID- 28912539 TI - Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity. AB - Indiscriminate use of antibiotics globally has lead to an increase in emergence of drug-resistant pathogens under both nosocomial, as well as more worryingly, in community setting as well. Further, a decrease in the corporate interest and financial commitment has exerted increasing pressure on a rapidly dwindling antimicrobial drug discovery and developmental program. In this context, we have screened the Library of Pharmacologically Active Compounds (LOPAC, Sigma) against Staphylococcus aureus and Mycobacterium tuberculosis to identify potent novel antimicrobial molecules amongst non-antibiotic molecules. Microplate-based whole cell growth assay was performed to analyze the antimicrobial potency of the compounds against Staphylococcus aureus and Mycobacterium tuberculosis. We identified diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase, as a broad-spectrum antibiotic potently active against drug resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis. Intriguingly, the diphenyleneiodonium chloride was also very effective against slow-growing non replicating Mtb persisters. FIC index demonstrated a strongly synergistic interaction between diphenyleneiodonium chloride and Rifampicin while it did not interact with INH. The antimicrobial property of the diphenyleneiodonium chloride was further validated in vivo murine neutropenic thigh S. aureus infection model. Taken together, these findings suggest that Diphenyleneiodonium chloride can be potentially repurposed for the treatment of tuberculosis and staphylococcal infections. PMID- 28912540 TI - SOX9 Regulates Cancer Stem-Like Properties and Metastatic Potential of Single Walled Carbon Nanotube-Exposed Cells. AB - Engineered nanomaterials hold great promise for the future development of innovative products but their adverse health effects are a major concern. Recent studies have indicated that certain nanomaterials, including carbon nanotubes (CNTs), may be carcinogenic. However, the underlying mechanisms behind their potential malignant properties remain unclear. In this study, we linked SOX9, a stem cell associated transcription factor, to the neoplastic-like properties of human lung epithelial cells chronically exposed to a low-dose of single-walled carbon nanotubes (SWCNTs). We found that SOX9 is upregulated in SWCNT-exposed cells, which is consistent with their abilities to induce tumor formation and metastasis in vivo. We therefore hypothesized that SOX9 overexpression may be responsible for the neoplastic-like phenotype observed in our model. Indeed, SOX9 knockdown inhibited anchorage-independent cell growth in vitro and lung colonization in vivo in a mouse xenograft model. SOX9 depletion also suppressed the formation of cancer stem-like cells (CSCs), as determined by tumor sphere formation and aldehyde dehydrogenase (ALDH) activity (Aldefluor) assays. Furthermore, SOX9 knockdown suppressed tumor metastasis and the expression of the stem cell marker ALDH1A1. Taken together, our findings provide a mechanistic insight into SWCNT-induced carcinogenesis and the role of SOX9 in CSC regulation and metastasis. PMID- 28912541 TI - Coprophagous features in carnivorous Nepenthes plants: a task for ureases. AB - Most terrestrial carnivorous plants are specialized on insect prey digestion to obtain additional nutrients. Few species of the genus Nepenthes developed mutualistic relationships with mammals for nitrogen supplementation. Whether dietary changes require certain enzymatic composition to utilize new sources of nutrients has rarely been tested. Here, we investigated the role of urease for Nepenthes hemsleyana that gains nitrogen from the bat Kerivoula hardwickii while it roosts inside the pitchers. We hypothesized that N. hemsleyana is able to use urea from the bats' excrements. In fact, we demonstrate that 15N-enriched urea provided to Nepenthes pitchers is metabolized and its nitrogen is distributed within the plant. As ureases are necessary to degrade urea, these hydrolytic enzymes should be involved. We proved the presence and enzymatic activity of a urease for Nepenthes plant tissues. The corresponding urease cDNA from N. hemsleyana was isolated and functionally expressed. A comprehensive phylogenetic analysis for eukaryotic ureases, including Nepenthes and five other carnivorous plants' taxa, identified them as canonical ureases and reflects the plant phylogeny. Hence, this study reveals ureases as an emblematic example for an efficient, low-cost but high adaptive plasticity in plants while developing a further specialized lifestyle from carnivory to coprophagy. PMID- 28912542 TI - Transcranial direct current stimulation (tDCS) applied to the left dorsolateral premotor cortex (dPMC) interferes with rhythm reproduction. AB - Movement timing in the sub-second range engages a brain network comprising cortical and sub-cortical areas. The present study aims at investigating the functional significance of the left dorsolateral premotor cortex (dPMC) for precise movement timing as determined by sensorimotor synchronization and rhythm reproduction. To this end, 18 healthy volunteers performed an auditorily paced synchronization-continuation task with the right hand. A simple reaction time task served as control condition. Transcranial direct current stimulation (tDCS) was applied over the left dPMC in order to modulate cortical excitability either with anodal or cathodal polarity or as sham stimulation. TDCS was applied for 10 minutes, respectively on separate days. For the continuation task the analysis revealed significantly smaller inter-tap intervals (ITIs) following cathodal tDCS suggesting movement hastening as well as a trend towards larger ITIs following anodal stimulation suggesting movement slowing. No significant effect was found following sham stimulation. Neither for synchronization nor for reaction time tasks significant polarity-specific effects emerged. The data suggest the causal involvement of the dPMC in temporally precisereproduction of isochronous rhythms rather than sensorimotor synchronization. The present findings support the hypothesis that different cortical brain areas within the motor-control-network distinctively contribute to movement timing in the sub-second range. PMID- 28912543 TI - Inhibition of fucosylation by 2-fluorofucose suppresses human liver cancer HepG2 cell proliferation and migration as well as tumor formation. AB - Core fucosylation is one of the most important glycosylation events in the progression of liver cancer. For this study, we used an easily handled L-fucose analog, 2-fluoro-L-fucose (2FF), which interferes with the normal synthesis of GDP-fucose, and verified its potential roles in regulating core fucosylation and cell behavior in the HepG2 liver cancer cell line. Results obtained from lectin blot and flow cytometry analysis clearly showed that 2FF treatment dramatically inhibited core fucosylation, which was also confirmed via mass spectrometry analysis. Cell proliferation and integrin-mediated cell migration were significantly suppressed in cells treated with 2FF. We further analyzed cell colony formation in soft agar and tumor xenograft efficacy, and found that both were greatly suppressed in the 2FF-treated cells, compared with the control cells. Moreover, the treatment with 2FF decreased the core fucosylation levels of membrane glycoproteins such as EGF receptor and integrin beta1, which in turn suppressed downstream signals that included phospho-EGFR, -AKT, -ERK, and -FAK. These results clearly described the roles of 2FF and the importance of core fucosylation in liver cancer progression, suggesting 2FF shows promise for use in the treatment of hepatoma. PMID- 28912544 TI - Development of chloroplast genome resources for peanut (Arachis hypogaea L.) and other species of Arachis. AB - ABSRACT: Peanut (Arachis hypogaea L.) is an important oilseed and cash crop worldwide. Wild Arachis spp. are potental sources of novel genes for the genetic improvement of cultivated peanut. Understanding the genetic relationships with cultivated peanut is important for the efficient use of wild species in breeding programmes. However, for this genus, only a few genetic resources have been explored so far. In this study, new chloroplast genomic resources have been developed for the genus Arachis based on whole chloroplast genomes from seven species that were sequenced using next-generation sequencing technologies. The chloroplast genomes ranged in length from 156,275 to 156,395 bp, and their gene contents, gene orders, and GC contents were similar to those for other Fabaceae species. Comparative analyses among the seven chloroplast genomes revealed 643 variable sites that included 212 singletons and 431 parsimony-informative sites. We also identified 101 SSR loci and 85 indel mutation events. Thirty-seven SSR loci were found to be polymorphic by in silico comparative analyses. Eleven highly divergent DNA regions, suitable for phylogenetic and species identification, were detected in the seven chloroplast genomes. A molecular phylogeny based on the complete chloroplast genome sequences provided the best resolution of the seven Arachis species. PMID- 28912545 TI - The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Cav3.2 channels. AB - Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Cav3.2 III-IV linker alters the Cav3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T type calcium conductance in GAERS. PMID- 28912546 TI - Phosphoenolpyruvate Carboxykinase Maintains Glycolysis-driven Growth in Drosophila Tumors. AB - Tumors frequently fail to pass on all their chromosomes correctly during cell division, and this chromosomal instability (CIN) causes irregular aneuploidy and oxidative stress in cancer cells. Our objective was to test knockdowns of metabolic enzymes in Drosophila to find interventions that could exploit the differences between normal and CIN cells to block CIN tumor growth without harming the host animal. We found that depleting by RNAi or feeding the host inhibitors against phosphoenolpyruvate carboxykinase (PEPCK) was able to block the growth of CIN tissue in a brat tumor explant model. Increasing NAD+ or oxidising cytoplasmic NADH was able to rescue the growth of PEPCK depleted tumors, suggesting a problem in clearing cytoplasmic NADH. Consistent with this, blocking the glycerol-3-phosphate shuttle blocked tumor growth, as well as lowering ROS levels. This work suggests that proliferating CIN cells are particularly vulnerable to inhibition of PEPCK, or its metabolic network, because of their compromised redox status. PMID- 28912548 TI - Phylogenetic implications of nuclear rRNA IGS variation in Stipa L. (Poaceae). AB - The article takes up the problem of deficiency of molecular marker, which could illustrate molecular variability as well as phylogenetic relation within the genus of Stipa L. (Poaceae). Researches made so far hadn't delivered sufficient information about relationships between particular taxa from the genus of Stipa. In the present study, we analyzed variability and phylogenetic informativeness of nuclear ribosomal DNA in six species from the genus against five other species from Poaceae including a division of this region into functional elements and domains. Our results showed that the intergenic spacer region, and especially its part adjacent to 26 S nrDNA, is a molecular marker giving a real chance for a phylogeny reconstruction of Stipa. The region seems to be the most phylogenetically informative for Stipa from all the chloroplast and nuclear markers tested so far. Comparative analysis of nrDNA repeat units from Stipa to other representatives of Poaceae showed that their structure does not deviate from the general scheme. However, the rate of evolution within the inter-repeats in the IGS region is extremely high and therefore it predestines the region for phylogenetic analyses of Stipa at genus level or in shallower taxonomic scale. PMID- 28912547 TI - A systematic exploration of the interactions between bacterial effector proteins and host cell membranes. AB - Membrane-bound organelles serve as platforms for the assembly of multi-protein complexes that function as hubs of signal transduction in eukaryotic cells. Microbial pathogens have evolved virulence factors that reprogram these host signaling responses, but the underlying molecular mechanisms are poorly understood. Here we test the ability of ~200 type III and type IV effector proteins from six Gram-negative bacterial species to interact with the eukaryotic plasma membrane and intracellular organelles. We show that over 30% of the effectors localize to yeast and mammalian cell membranes, including a subset of previously uncharacterized Legionella effectors that appear to be able to regulate yeast vacuolar fusion. A combined genetic, cellular, and biochemical approach supports that some of the tested bacterial effectors can bind to membrane phospholipids and may regulate membrane trafficking. Finally, we show that the type III effector IpgB1 from Shigella flexneri may bind to acidic phospholipids and regulate actin filament dynamics.Microbial pathogens secrete effector proteins into host cells to affect cellular functions. Here, the authors use a yeast-based screen to study around 200 effectors from six bacterial species, showing that over 30% of them interact with the eukaryotic plasma membrane or intracellular organelles. PMID- 28912549 TI - Synthesis of ammonia using sodium melt. AB - Research into inexpensive ammonia synthesis has increased recently because ammonia can be used as a hydrogen carrier or as a next generation fuel which does not emit CO2. Furthermore, improving the efficiency of ammonia synthesis is necessary, because current synthesis methods emit significant amounts of CO2. To achieve these goals, catalysts that can effectively reduce the synthesis temperature and pressure, relative to those required in the Haber-Bosch process, are required. Although several catalysts and novel ammonia synthesis methods have been developed previously, expensive materials or low conversion efficiency have prevented the displacement of the Haber-Bosch process. Herein, we present novel ammonia synthesis route using a Na-melt as a catalyst. Using this route, ammonia can be synthesized using a simple process in which H2-N2 mixed gas passes through the Na-melt at 500-590 degrees C under atmospheric pressure. Nitrogen molecules dissociated by reaction with sodium then react with hydrogen, resulting in the formation of ammonia. Because of the high catalytic efficiency and low-cost of this molten-Na catalyst, it provides new opportunities for the inexpensive synthesis of ammonia and the utilization of ammonia as an energy carrier and next generation fuel. PMID- 28912550 TI - Calcium-Mediated Adhesion of Nanomaterials in Reservoir Fluids. AB - Globally, a small percentage of oil is recovered from reservoirs using primary and secondary recovery mechanisms, and thus a major focus of the oil industry is toward developing new technologies to increase recovery. Many new technologies utilize surfactants, macromolecules, and even nanoparticles, which are difficult to deploy in harsh reservoir conditions and where failures cause material aggregation and sticking to rock surfaces. To combat these issues, typically material properties are adjusted, but recent studies show that adjusting the dispersing fluid chemistry could have significant impact on material survivability. Herein, the effect of injection fluid salinity and composition on nanomaterial fate is explored using atomic force microscopy (AFM). The results show that the calcium content in reservoir fluids affects the interactions of an AFM tip with a calcite surface, as surrogates for nanomaterials interacting with carbonate reservoir rock. The extreme force sensitivity of AFM provides the ability to elucidate small differences in adhesion at the pico-Newton (pN) level and provides direct information about material survivability. Increasing the calcium content mitigates adhesion at the pN-scale, a possible means to increase nanomaterial survivability in oil reservoirs or to control nanomaterial fate in other aqueous environments. PMID- 28912551 TI - The antipsychotic drugs olanzapine and haloperidol modify network connectivity and spontaneous activity of neural networks in vitro. AB - Impaired neural synchronization is a hallmark of psychotic conditions such as schizophrenia. It has been proposed that schizophrenia-related cognitive deficits are caused by an unbalance of reciprocal inhibitory and stimulatory signaling. This supposedly leads to decreased power of induced gamma oscillations during the performance of cognitive tasks. In light of this hypothesis an efficient antipsychotic treatment should modify the connectivity and synchronization of local neural circuits. To address this issue, we investigated a model of hippocampal neuronal networks in vitro. Inhibitory and excitatory innervation of GABAergic and glutamatergic neurons was quantified using immunocytochemical markers and an automated routine to estimate network connectivity. The first generation (FGA) and second generation (SGA) antipsychotic drugs haloperidol and olanzapine, respectively, differentially modified the density of synaptic inputs. Based on the observed synapse density modifications, we developed a computational model that reliably predicted distinct changes in network activity patterns. The results of computational modeling were confirmed by spontaneous network activity measurements using the multiple electrode array (MEA) technique. When the cultures were treated with olanzapine, overall activity and synchronization were increased, whereas haloperidol had the opposite effect. We conclude that FGAs and SGAs differentially affect the balance between inhibition and excitation in hippocampal networks. PMID- 28912552 TI - Under-ice availability of phytoplankton lipids is key to freshwater zooplankton winter survival. AB - Shortening winter ice-cover duration in lakes highlights an urgent need for research focused on under-ice ecosystem dynamics and their contributions to whole ecosystem processes. Low temperature, reduced light and consequent changes in autotrophic and heterotrophic resources alter the diet for long-lived consumers, with consequences on their metabolism in winter. We show in a survival experiment that the copepod Leptodiaptomus minutus in a boreal lake does not survive five months under the ice without food. We then report seasonal changes in phytoplankton, terrestrial and bacterial fatty acid (FA) biomarkers in seston and in four zooplankton species for an entire year. Phytoplankton FA were highly available in seston (2.6 ug L-1) throughout the first month under the ice. Copepods accumulated them in high quantities (44.8 ug mg dry weight-1), building lipid reserves that comprised up to 76% of body mass. Terrestrial and bacterial FA were accumulated only in low quantities (<2.5 ug mg dry weight-1). The results highlight the importance of algal FA reserve accumulation for winter survival as a key ecological process in the annual life cycle of the freshwater plankton community with likely consequences to the overall annual production of aquatic FA for higher trophic levels and ultimately for human consumption. PMID- 28912553 TI - Polarization-independent, wide-incident-angle and dual-band perfect absorption, based on near-field coupling in a symmetric metamaterial. AB - We numerically and experimentally investigated a dual-band metamaterial perfect absorber (MPA), utilizing the near-field coupling of double split-ring resonators (DSRRs). Owing to the near-field coupling between resonators, two arms in each DSRR resonate in different phases, leading to a dual-band perfect absorption. The proposed MPA also exhibits polarization-insensitive behavior and maintains the high absorption above 90% up to a wide range of incident angle more than 45 degrees . Finally, to further consolidate our approach, a multi-band absorption is also studied by exploiting the near-field coupling among a larger number of DSRRs. Our work is expected to be applied to future broadband devices using MPA. PMID- 28912554 TI - Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons. AB - In addition to the regulation of social and emotional behaviors, the hypothalamic neuropeptide oxytocin has been shown to stimulate neurogenesis in adult dentate gyrus; however, the mechanisms underlying the action of oxytocin are still unclear. Taking advantage of the conditional knockout mouse model, we show here that endogenous oxytocin signaling functions in a non-cell autonomous manner to regulate survival and maturation of newly generated dentate granule cells in adult mouse hippocampus via oxytocin receptors expressed in CA3 pyramidal neurons. Through bidirectional chemogenetic manipulations, we also uncover a significant role for CA3 pyramidal neuron activity in regulating adult neurogenesis in the dentate gyrus. Retrograde neuronal tracing combined with immunocytochemistry revealed that the oxytocin neurons in the paraventricular nucleus project directly to the CA3 region of the hippocampus. Our findings reveal a critical role for oxytocin signaling in adult neurogenesis.Oxytocin (OXT) has been implicated in adult neurogenesis. Here the authors show that CA3 pyramidal cells in the adult mouse hippocampus express OXT receptors and receive inputs from hypothalamic OXT neurons; activation of OXT signaling in CA3 pyramidal cells promotes the survival and maturation of newborn neurons in the dentate gyrus in a non-cell autonomous manner. PMID- 28912555 TI - New taxa of freshwater mussels (Unionidae) from a species-rich but overlooked evolutionary hotspot in Southeast Asia. AB - Southeast Asia harbors a unique and diverse freshwater fauna of Mesozoic origin, which is under severe threat of extinction because of rapid economic development and urbanization. The largest freshwater basins of the region are certainly the primary evolutionary hotspots and they attract the most attention as key biodiversity areas for conservation. In contrast, medium-sized rivers are considered low-importance areas with secondary biodiversity, whose faunas originated via founder events from larger basins during the Pleistocene, although such a scenario has never been tested by using a phylogenetic approach. In this investigation, we used freshwater mussels (Unionidae) as a model to estimate the levels of endemism within the Sittaung, a little-known remote basin in Myanmar, compared with the surrounding larger rivers (Irrawaddy, Salween and Mekong). We discovered that the Sittaung represents an exceptional evolutionary hotspot with numerous endemic taxa of freshwater mussels. On the basis of our extensive dataset, we describe two new tribes, two genera, seven species and a subspecies of Unionidae. Our results highlight that medium-sized basins may represent separate evolutionary hotspots that harbor a number of endemic lineages. These basins should therefore be a focus of special conservation efforts alongside the largest Southeast Asian rivers. PMID- 28912556 TI - Synthesis and in-vitro anticancer evaluation of polyarsenicals related to the marine sponge derived Arsenicin A. AB - In the light of the promising bioactivity of the tetraarsenic marine metabolite arsenicin A, the dimethyl analogue 2 and four isomeric methylene homologues (including the natural product itself) were obtained using a one-pot microwave assisted synthesis, starting from arsenic (III) oxide. Due to the poor diagnostic value of the NMR technique in the structural elucidation of these molecules, they were fully characterized by mass spectrometry and infrared (IR)-spectroscopy, comparing density functional theory (DFT) simulated and experimental spectra. This synthetic procedure provided a fast and efficient access to the cytotoxicity evaluation of organoarsenical leads of the natural hit molecule. From in vitro screening, each tested compound resulted in being more active than the FDA approved arsenic trioxide, with the most lipophilic molecule in the series showing the best growth inhibition of both leukemia and solid tumor cell lines. These results may open promising perspectives in the development of new more potent and selective arsenical drugs against solid tumors. PMID- 28912557 TI - A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine. AB - N-methyl-D-aspartate-receptors (NMDARs) are ionotropic glutamate receptors that function in synaptic transmission, plasticity and cognition. Malfunction of NMDARs has been implicated in a variety of nervous system disorders, making them attractive therapeutic targets. Overexpression of functional NMDAR in non neuronal cells results in cell death by excitotoxicity, hindering the development of cell-based assays for NMDAR drug discovery. Here we report a plate-based, high throughput approach to study NMDAR function. Our assay enables the functional study of NMDARs with different subunit composition after activation by glycine/D serine or glutamate and hence presents the first plate-based, high throughput assay that allows for the measurement of NMDAR function in glycine/D-serine and/or glutamate sensitive modes. This allows to investigate the effect of small molecule modulators on the activation of NMDARs at different concentrations or combinations of the co-ligands. The reported assay system faithfully replicates the pharmacology of the receptor in response to known agonists, antagonists, positive and negative allosteric modulators, as well as the receptor's sensitivity to magnesium and zinc. We believe that the ability to study the biology of NMDARs rapidly and in large scale screens will enable the identification of novel therapeutics whose discovery has otherwise been hindered by the limitations of existing cell based approaches. PMID- 28912558 TI - An omniphobic lubricant-infused coating produced by chemical vapor deposition of hydrophobic organosilanes attenuates clotting on catheter surfaces. AB - ABSTARCT: Catheter associated thrombosis is an ongoing problem. Omniphobic coatings based on tethering biocompatible liquid lubricants on self-assembled monolayers of hydrophobic organosilanes attenuate clotting on surfaces. Herein we report an efficient, non-invasive and robust process for coating catheters with an antithrombotic, omniphobic lubricant-infused coating produced using chemical vapor deposition (CVD) of hydrophobic fluorine-based organosilanes. Compared with uncoated catheters, CVD coated catheters significantly attenuated thrombosis via the contact pathway of coagulation. When compared with the commonly used technique of liquid phase deposition (LPD) of fluorine-based organosilanes, the CVD method was more efficient and reproducible, resulted in less disruption of the outer polymeric layer of the catheters and produced greater antithrombotic activity. Therefore, omniphobic coating of catheters using the CVD method is a simple, straightforward and non-invasive procedure. This method has the potential to not only prevent catheter thrombosis, but also to prevent thrombosis on other blood-contacting medical devices. PMID- 28912559 TI - Inherent aggressive character of invasive and non-invasive cells dictates the in vitro migration pattern of multicellular spheroid. AB - Cellular migration, a process relevant to metastasis, is mostly studied in the conventional 2D condition. However, cells cultured in the 3D condition assumed to mimic the in vivo conditions better. The current study is designed to compare an invasive and non-invasive adenocarcinoma cell with an invasive fibrosarcoma cell to understand the migration pattern of the multicellular spheroid. It is observed that conventional haplotaxis, chemotactic and pseudo-3D migration assay cannot distinguish between the invasive and non-invasive cells conclusively under 2D condition. Invasive spheroids migrate rapidly in sprouting assay in comparison to non-invasive spheroids. Effects of cytochalasin B, marimastat and blebbistatin are tested to determine the influence of different migration modality namely actin polymerization, matrix metalloprotease and acto-myosin in both culture conditions. Altered mRNA profile of cellular migration related genes (FAK, Talin, Paxillin, p130cas and Vinculin) is observed between 2D and 3D condition followed by the changed expression of matrix metallo proteases. A distinct difference is observed in distribution and formation of focal adhesion complex under these culture conditions. This study demonstrates the efficacy of multicellular spheroids in identifying the intrinsic aggressive behavior of different cell lines as a proof of concept and recognizes the potential of spheroids as a migration model. PMID- 28912560 TI - The SRGAP2 SNPs, their haplotypes and G * E interactions on serum lipid traits. AB - Maonan nationality is a relatively conservative and isolated minority in China. Little is known about the association of the Slit-Robo Rho GTPase activating protein 2 gene (SRGAP2) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese populations. This study was performed to clarify the association of the SRGAP2 rs2483058 and rs2580520 SNPs and their haplotypes with serum lipid traits in the Maonan and Han populations. Genotyping of the 2 SNPs was performed in 2444 unrelated subjects (Han, 1210 and Maonan, 1234) by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The allelic (rs2483058) and genotypic (rs2483058 and rs2580520) frequencies were different between the two ethnic groups. Four haplotypes were identified in our populations, and the rs2483058G-rs2580520C haplotype was the commonest one. The rs2483058C-rs2580520G haplotype was associated with an increased risk of dyslipidemia, and showed consistent association with serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1 levels, and the ApoA1/ApoB ratio. These results indicated that the SRGAP2 SNPs and their haplotypes were associated with serum lipid levels. Their haplotypes can explain much more serum lipid variation than any single SNP alone, especially for serum TC, HDL-C and ApoA1 levels. PMID- 28912561 TI - Luminophore Configuration and Concentration-Dependent Optoelectronic Characteristics of a Quantum Dot-Embedded DNA Hybrid Thin film. AB - To be useful in optoelectronic devices and sensors, a platform comprising stable fluorescence materials is essential. Here we constructed quantum dots (QDs) embedded DNA thin films which aims for stable fluorescence through the stabilization of QDs in the high aspect ratio salmon DNA (SDNA) matrix. Also for maximum luminescence, different concentration and configurations of core- and core/alloy/shell-type QDs were embedded within SDNA. The QD-SDNA thin films were constructed by drop-casting and investigated their optoelectronic properties. The infrared, UV-visible and photoluminescence (PL) spectroscopies confirm the embedment of QDs in the SDNA matrix. Absolute PL quantum yield of the QD-SDNA thin film shows the ~70% boost due to SDNA matrix compared to QDs alone in aqueous phase. The linear increase of PL photon counts from few to order of 5 while increasing [QD] reveals the non-aggregation of QDs within SDNA matrix. These systematic studies on the QD structure, absorbance, and concentration- and thickness-dependent optoelectronic characteristics demonstrate the novel properties of the QD-SDNA thin film. Consequently, the SDNA thin films were suggested to utilize for the generalised optical environments, which has the potential as a matrix for light conversion and harvesting nano-bio material as well as for super resolution bioimaging- and biophotonics-based sensors. PMID- 28912562 TI - Flexible supercapacitor electrodes based on real metal-like cellulose papers. AB - The effective implantation of conductive and charge storage materials into flexible frames has been strongly demanded for the development of flexible supercapacitors. Here, we introduce metallic cellulose paper-based supercapacitor electrodes with excellent energy storage performance by minimizing the contact resistance between neighboring metal and/or metal oxide nanoparticles using an assembly approach, called ligand-mediated layer-by-layer assembly. This approach can convert the insulating paper to the highly porous metallic paper with large surface areas that can function as current collectors and nanoparticle reservoirs for supercapacitor electrodes. Moreover, we demonstrate that the alternating structure design of the metal and pseudocapacitive nanoparticles on the metallic papers can remarkably increase the areal capacitance and rate capability with a notable decrease in the internal resistance. The maximum power and energy density of the metallic paper-based supercapacitors are estimated to be 15.1 mW cm-2 and 267.3 MUWh cm-2, respectively, substantially outperforming the performance of conventional paper or textile-type supercapacitors.With ligand-mediated layer-by layer assembly between metal nanoparticles and small organic molecules, the authors prepare metallic paper electrodes for supercapacitors with high power and energy densities. This approach could be extended to various electrodes for portable/wearable electronics. PMID- 28912563 TI - A cell cycle-independent mode of the Rad9-Dpb11 interaction is induced by DNA damage. AB - Budding yeast Rad9, like its orthologs, controls two aspects of the cellular response to DNA double strand breaks (DSBs) - signalling of the DNA damage checkpoint and DNA end resection. Rad9 binds to damaged chromatin via modified nucleosomes independently of the cell cycle phase. Additionally, Rad9 engages in a cell cycle-regulated interaction with Dpb11 and the 9-1-1 clamp, generating a second pathway that recruits Rad9 to DNA damage sites. Binding to Dpb11 depends on specific S/TP phosphorylation sites of Rad9, which are modified by cyclin dependent kinase (CDK). Here, we show that these sites additionally become phosphorylated upon DNA damage. We define the requirements for DNA damage-induced S/TP phosphorylation of Rad9 and show that it is independent of the cell cycle or CDK activity but requires prior recruitment of Rad9 to damaged chromatin, indicating that it is catalysed by a chromatin-bound kinase. The checkpoint kinases Mec1 and Tel1 are required for Rad9 S/TP phosphorylation, but their influence is likely indirect and involves phosphorylation of Rad9 at S/TQ sites. Notably, DNA damage-induced S/TP phosphorylation triggers Dpb11 binding to Rad9, but the DNA damage-induced Rad9-Dpb11 interaction is dispensable for recruitment to DNA damage sites, indicating that the Rad9-Dpb11 interaction functions beyond Rad9 recruitment. PMID- 28912565 TI - Real-time Image Processing for Microscopy-based Label-free Imaging Flow Cytometry in a Microfluidic Chip. AB - Imaging flow cytometry (IFC) is an emerging technology that acquires single-cell images at high-throughput for analysis of a cell population. Rich information that comes from high sensitivity and spatial resolution of a single-cell microscopic image is beneficial for single-cell analysis in various biological applications. In this paper, we present a fast image-processing pipeline (R-MOD: Real-time Moving Object Detector) based on deep learning for high-throughput microscopy-based label-free IFC in a microfluidic chip. The R-MOD pipeline acquires all single-cell images of cells in flow, and identifies the acquired images as a real-time process with minimum hardware that consists of a microscope and a high-speed camera. Experiments show that R-MOD has the fast and reliable accuracy (500 fps and 93.3% mAP), and is expected to be used as a powerful tool for biomedical and clinical applications. PMID- 28912564 TI - Transcriptome analysis of developing lens reveals abundance of novel transcripts and extensive splicing alterations. AB - Lens development involves a complex and highly orchestrated regulatory program. Here, we investigate the transcriptomic alterations and splicing events during mouse lens formation using RNA-seq data from multiple developmental stages, and construct a molecular portrait of known and novel transcripts. We show that the extent of novelty of expressed transcripts decreases significantly in post-natal lens compared to embryonic stages. Characterization of novel transcripts into partially novel transcripts (PNTs) and completely novel transcripts (CNTs) (novelty score >= 70%) revealed that the PNTs are both highly conserved across vertebrates and highly expressed across multiple stages. Functional analysis of PNTs revealed their widespread role in lens developmental processes while hundreds of CNTs were found to be widely expressed and predicted to encode for proteins. We verified the expression of four CNTs across stages. Examination of splice isoforms revealed skipped exon and retained intron to be the most abundant alternative splicing events during lens development. We validated by RT-PCR and Sanger sequencing, the predicted splice isoforms of several genes Banf1, Cdk4, Cryaa, Eif4g2, Pax6, and Rbm5. Finally, we present a splicing browser Eye Splicer ( http://www.iupui.edu/~sysbio/eye-splicer/ ), to facilitate exploration of developmentally altered splicing events and to improve understanding of post transcriptional regulatory networks during mouse lens development. PMID- 28912566 TI - Enhancement of the Device Performance and the Stability with a Homojunction structured Tungsten Indium Zinc Oxide Thin Film Transistor. AB - Tungsten-indium-zinc-oxide thin-film transistors (WIZO-TFTs) were fabricated using a radio frequency (RF) co-sputtering system with two types of source/drain (S/D)-electrode material of conducting WIZO (homojunction structure) and the indium-tin oxide (ITO) (heterojunction structure) on the same WIZO active-channel layer. The electrical properties of the WIZO layers used in the S/D electrode and the active-channel layer were adjusted through oxygen partial pressure during the deposition process. To explain enhancements of the device performance and stability of the homojunction-structured WIZO-TFT, a systematic investigation of correlation between device performance and physical properties at the interface between the active layer and the S/D electrodes such as the contact resistance, surface/interfacial roughness, interfacial-trap density, and interfacial energy level alignments was conducted. The homojunction-structured WIZO-TFT exhibited a lower contact resistance, smaller interfacial-trap density, and flatter interfacial roughness than the WIZO-TFT with the heterojunction structure. The 0.09 eV electron barrier of the homojunction-structured WIZO-TFT is lower than the 0.21 eV value that was obtained for the heterojunction-structured WIZO-TFT. This reduced electron barrier may be attributed to enhancements of device performance and stability, that are related to the carrier transport. PMID- 28912567 TI - Structural and dynamical characteristics of flow units in metallic glasses. AB - The metallic glasses (MGs) are conjectured to be heterogeneous-their microscopic structures are embedded with localized, soft and loosely packed atomic regions, which are termed as flow units (FUs). Detailed knowledges on the structure and dynamical features of FUs are essential for understanding the plasticity of MGs. In our study, by performing dynamical tests on MGs in molecular dynamics simulations, we show that mechanical hysteretic loops are formed in the strain stress curves due to the undergoing plastic events. By analyzing the activated times of each atom in different dynamical tests, we map the exact locations of FUs and the distribution of their activation probability in the initial structure of MGs. More importantly, we demonstrate that the FUs are indeed liquid-like according to the Lindemann criterion of melting. PMID- 28912568 TI - Intrinsic neural network dysfunction in quiescent Crohn's Disease. AB - Psychological factors and comorbidities play an important role in inflammatory bowel diseases. Such comorbidity could be associated with a specific neural phenotype. Brain regions associated with emotion regulation and self-referential processing, including areas assigned to the "default mode network" (DMN), could be promising candidates in this regard. We investigated the functional integrity of multiple intrinsic neural networks in remitted patients with Crohn's disease (CD) and sought to establish relationships between neural network connectivity and psychiatric symptoms. Fifteen CD patients in remission and 14 controls were investigated. We employed resting-state functional magnetic resonance imaging (fMRI) at 3 Tesla followed by a spatial Independent Component Analysis for fMRI data. Abnormal connectivity in CD patients was observed in DMN subsystems only (p < 0.05, cluster-corrected). Increased connectivity was found in the anterior cingulate and left superior medial frontal gyrus (aDMN) and the middle cingulate cortex (pDMN). Middle cingulate activity showed a significant association with anxiety scores in patients (p = 0.029). This study provides first evidence of selectively disrupted intrinsic neural network connectivity in CD and suggests abnormalities of self-referential neural networks. An increased sensitivity to self-related affective and somatic states in CD patients could account for these findings and explain a higher risk for anxiety symptoms. PMID- 28912569 TI - Two-dimensional Dirac particles in a Poschl-Teller waveguide. AB - We obtain exact solutions to the two-dimensional (2D) Dirac equation for the one dimensional Poschl-Teller potential which contains an asymmetry term. The eigenfunctions are expressed in terms of Heun confluent functions, while the eigenvalues are determined via the solutions of a simple transcendental equation. For the symmetric case, the eigenfunctions of the supercritical states are expressed as spheroidal wave functions, and approximate analytical expressions are obtained for the corresponding eigenvalues. A universal condition for any square integrable symmetric potential is obtained for the minimum strength of the potential required to hold a bound state of zero energy. Applications for smooth electron waveguides in 2D Dirac-Weyl systems are discussed. PMID- 28912571 TI - Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation. AB - Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications. PMID- 28912570 TI - A focus on extracellular Ca2+ entry into skeletal muscle. AB - The main task of skeletal muscle is contraction and relaxation for body movement and posture maintenance. During contraction and relaxation, Ca2+ in the cytosol has a critical role in activating and deactivating a series of contractile proteins. In skeletal muscle, the cytosolic Ca2+ level is mainly determined by Ca2+ movements between the cytosol and the sarcoplasmic reticulum. The importance of Ca2+ entry from extracellular spaces to the cytosol has gained significant attention over the past decade. Store-operated Ca2+ entry with a low amplitude and relatively slow kinetics is a main extracellular Ca2+ entryway into skeletal muscle. Herein, recent studies on extracellular Ca2+ entry into skeletal muscle are reviewed along with descriptions of the proteins that are related to extracellular Ca2+ entry and their influences on skeletal muscle function and disease. PMID- 28912573 TI - Low-Magnitude High-Frequency Vibration Accelerated the Foot Wound Healing of n5 streptozotocin-induced Diabetic Rats by Enhancing Glucose Transporter 4 and Blood Microcirculation. AB - Delayed wound healing is a Type 2 diabetes mellitus (DM) complication caused by hyperglycemia, systemic inflammation, and decreased blood microcirculation. Skeletal muscles are also affected by hyperglycemia, resulting in reduced blood flow and glucose uptake. Low Magnitude High Frequency Vibration (LMHFV) has been proven to be beneficial to muscle contractility and blood microcirculation. We hypothesized that LMHFV could accelerate the wound healing of n5-streptozotocin (n5-STZ)-induced DM rats by enhancing muscle activity and blood microcirculation. This study investigated the effects of LMHFV in an open foot wound created on the footpad of n5-STZ-induced DM rats (DM_V), compared with no-treatment DM (DM), non DM vibration (Ctrl_V) and non-DM control rats (Ctrl) on Days 1, 4, 8 and 13. Results showed that the foot wounds of DM_V and Ctrl_V rats were significantly reduced in size compared to DM and Ctrl rats, respectively, at Day 13. The blood glucose level of DM_V rats was significantly reduced, while the glucose transporter 4 (GLUT4) expression and blood microcirculation of DM_V rats were significantly enhanced in comparison to those of DM rats. In conclusion, LMHFV can accelerate the foot wound healing process of n5-STZ rats. PMID- 28912572 TI - Follistatin N terminus differentially regulates muscle size and fat in vivo. AB - Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno associated viral vector (AAV). Overexpression of wild-type FST in normal mice greatly increased muscle mass while decreasing fat accumulation, whereas overexpression of an N terminus mutant or N terminus-deleted FST had no effect on muscle mass but moderately decreased fat mass. In contrast, FST-I-I containing the complete N terminus and double domain I without domain II and III had no effect on fat but increased skeletal muscle mass. The effects of different constructs on differentiated C2C12 myotubes were consistent with the in vivo finding. We hypothesized that ND was critical for myostatin blockade, mediating the increase in muscle mass, and was less pivotal for activin binding, which accounts for the decrease in the fat tissue. An in vitro TGF-beta1-responsive reporter assay revealed that FST-I-I and N terminus-mutated or -deleted FST showed differential responses to blockade of activin and myostatin. Our study provided direct in vivo evidence for a role of the ND of FST, shedding light on future potential molecular designs for FST-based gene therapy. PMID- 28912574 TI - Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer. AB - Colorectal cancer (CRC) is a heterogeneous disease and recent advances in subtype classification have successfully stratified the disease using molecular profiling. The contribution of bacterial species to CRC development is increasingly acknowledged, and here, we sought to analyse CRC microbiomes and relate them to tumour consensus molecular subtypes (CMS), in order to better understand the relationship between bacterial species and the molecular mechanisms associated with CRC subtypes. We classified 34 tumours into CRC subtypes using RNA-sequencing derived gene expression and determined relative abundances of bacterial taxonomic groups using 16S rRNA amplicon metabarcoding. 16S rRNA analysis showed enrichment of Fusobacteria and Bacteroidetes, and decreased levels of Firmicutes and Proteobacteria in CMS1. A more detailed analysis of bacterial taxa using non-human RNA-sequencing reads uncovered distinct bacterial communities associated with each molecular subtype. The most highly enriched species associated with CMS1 included Fusobacterium hwasookii and Porphyromonas gingivalis. CMS2 was enriched for Selenomas and Prevotella species, while CMS3 had few significant associations. Targeted quantitative PCR validated these findings and also showed an enrichment of Fusobacterium nucleatum, Parvimonas micra and Peptostreptococcus stomatis in CMS1. In this study, we have successfully associated individual bacterial species to CRC subtypes for the first time. PMID- 28912575 TI - Thermodynamics of nanodisc formation mediated by styrene/maleic acid (2:1) copolymer. AB - Styrene/maleic acid copolymers (SMA) have recently attracted great interest for in vitro studies of membrane proteins, as they self-insert into and fragment biological membranes to form polymer-bounded nanodiscs that provide a native-like lipid-bilayer environment. SMA copolymers are available in different styrene/maleic acid ratios and chain lengths and, thus, possess different charge densities, hydrophobicities, and solubilisation properties. Here, we studied the equilibrium solubilisation properties of the most commonly used copolymer, SMA(2:1), by monitoring the formation of nanodiscs from phospholipid vesicles using 31P nuclear magnetic resonance spectroscopy, dynamic light scattering, and differential scanning calorimetry. Comparison of SMA(2:1) phase diagrams with those of SMA(3:1) and diisobutylene/maleic acid (DIBMA) revealed that, on a mass concentration scale, SMA(2:1) is the most efficient membrane solubiliser, despite its relatively mild effects on the thermotropic phase behaviour of solubilised lipids. In contrast with previous kinetic studies, our equilibrium experiments demonstrate that the solubilisation of phospholipid bilayers by SMA(2:1) is most efficient at moderately alkaline pH values. This pH dependence was also observed for the solubilisation of native Escherichia coli membranes, for which SMA(2:1) again turned out to be the most powerful solubiliser in terms of the total amounts of membrane proteins extracted. PMID- 28912576 TI - Interrogating open issues in cancer medicine with patient-derived xenografts. AB - This corrects the article DOI: 10.1038/nrc.2016.140. PMID- 28912579 TI - Interference-exact radiative transfer equation. AB - The Purcell effect, i.e., the modification of the spontaneous emission rate by optical interference, profoundly affects the light-matter coupling in optical resonators. Fully describing the optical absorption, emission, and interference of light hence conventionally requires combining the full Maxwell's equations with stochastic or quantum optical source terms accounting for the quantum nature of light. We show that both the nonlocal wave and local particle features associated with interference and emission of propagating fields in stratified geometries can be fully captured by local damping and scattering coefficients derived from the recently introduced quantized fluctuational electrodynamics (QFED) framework. In addition to describing the nonlocal optical interference processes as local directionally resolved effects, this allows reformulating the well known and widely used radiative transfer equation (RTE) as a physically transparent interference-exact model that extends the useful range of computationally efficient and quantum optically accurate interference-aware optical models from simple structures to full optical devices. PMID- 28912580 TI - PTPRJ Inhibits Leptin Signaling, and Induction of PTPRJ in the Hypothalamus Is a Cause of the Development of Leptin Resistance. AB - Leptin signaling in the hypothalamus plays a crucial role in the regulation of body weight. Leptin resistance, in which leptin signaling is disrupted, is a major obstacle to the improvement of obesity. We herein demonstrated that protein tyrosine phosphatase receptor type J (Ptprj) is expressed in hypothalamic neurons together with leptin receptors, and that PTPRJ negatively regulates leptin signaling by inhibiting the activation of JAK2, the primary tyrosine kinase in leptin signaling, through the dephosphorylation of Y813 and Y868 in JAK2 autophosphorylation sites. Leptin signaling is enhanced in Ptprj-deficient mice, and they exhibit lower weight gain than wild-type mice because of a reduced food intake. Diet-induced obesity and the leptin treatment up-regulated PTPRJ expression in the hypothalamus, while the overexpression of PTPRJ induced leptin resistance. Thus, the induction of PTPRJ is a factor contributing to the development of leptin resistance, and the inhibition of PTPRJ may be a potential strategy for improving obesity. PMID- 28912578 TI - Tumour acidosis: from the passenger to the driver's seat. AB - The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed. PMID- 28912581 TI - Secretory phospholipase A2-IIA overexpressing mice exhibit cyclic alopecia mediated through aberrant hair shaft differentiation and impaired wound healing response. AB - Secretory phospholipase A2 Group-IIA (sPLA2-IIA) is involved in lipid catabolism and growth promoting activity. sPLA2-IIA is deregulated in many pathological conditions including various cancers. Here, we have studied the role of sPLA2-IIA in the development of cyclic alopecia and wound healing response in relation to complete loss of hair follicle stem cells (HFSCs). Our data showed that overexpression of sPLA2-IIA in homozygous mice results in hyperproliferation and terminal epidermal differentiation followed by hair follicle cycle being halted at anagen like stage. In addition, sPLA2-IIA induced hyperproliferation leads to compl pathological conditions including various cancers. Here ete exhaustion of hair follicle stem cell pool at PD28 (Postnatal day). Importantly, sPLA2-IIA overexpression affects the hair shaft differentiation leading to development of cyclic alopecia. Molecular investigation study showed aberrant expression of Sox21, Msx2 and signalling modulators necessary for proper differentiation of inner root sheath (IRS) and hair shaft formation. Further, full-thickness skin wounding on dorsal skin of K14-sPLA2-IIA homozygous mice displayed impaired initial healing response. Our results showed the involvement of sPLA2-IIA in regulation of matrix cells differentiation, hair shaft formation and complete loss of HFSCs mediated impaired wound healing response. These novel functions of sPLA2-IIA may have clinical implications in alopecia, cancer development and ageing. PMID- 28912577 TI - Classifying the evolutionary and ecological features of neoplasms. AB - Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research. PMID- 28912582 TI - Evolution of gag and gp41 in Patients Receiving Ritonavir-Boosted Protease Inhibitors. AB - Several groups have proposed that genotypic determinants in gag and the gp41 cytoplasmic domain (gp41-CD) reduce protease inhibitor (PI) susceptibility without PI-resistance mutations in protease. However, no gag and gp41-CD mutations definitively responsible for reduced PI susceptibility have been identified in individuals with virological failure (VF) while receiving a boosted PI (PI/r)-containing regimen. To identify gag and gp41 mutations under selective PI pressure, we sequenced gag and/or gp41 in 61 individuals with VF on a PI/r (n = 40) or NNRTI (n = 20) containing regimen. We quantified nonsynonymous and synonymous changes in both genes and identified sites exhibiting signal for directional or diversifying selection. We also used published gag and gp41 polymorphism data to highlight mutations displaying a high selection index, defined as changing from a conserved to an uncommon amino acid. Many amino acid mutations developed in gag and in gp41-CD in both the PI- and NNRTI-treated groups. However, in neither gene, were there discernable differences between the two groups in overall numbers of mutations, mutations displaying evidence of diversifying or directional selection, or mutations with a high selection index. If gag and/or gp41 encode PI-resistance mutations, they may not be confined to consistent mutations at a few sites. PMID- 28912583 TI - Cleavage of 3'-terminal adenosine by archaeal ATP-dependent RNA ligase. AB - Methanothermobacter thermoautotrophicus RNA ligase (MthRnl) catalyzes formation of phosphodiester bonds between the 5'-phosphate and 3'-hydroxyl termini of single-stranded RNAs. It can also react with RNA with a 3'-phosphate end to generate a 2',3'-cyclic phosphate. Here, we show that MthRnl can additionally remove adenosine from the 3'-terminus of the RNA to produce 3'-deadenylated RNA, RNA(3'-rA). This 3'-deadenylation activity is metal-dependent and requires a 2' hydroxyl at both the terminal adenosine and the penultimate nucleoside. Residues that contact the ATP/AMP in the MthRnl crystal structures are essential for the 3'-deadenylation activity, suggesting that 3'-adenosine may occupy the ATP binding pocket. The 3'-end of cleaved RNA(3'-rA) consists of 2',3'-cyclic phosphate which protects RNA(3'-rA) from ligation and further deadenylation. These findings suggest that ATP-dependent RNA ligase may act on a specific set of 3'-adenylated RNAs to regulate their processing and downstream biological events. PMID- 28912584 TI - Niche harmony search algorithm for detecting complex disease associated high order SNP combinations. AB - Genome-wide association study is especially challenging in detecting high-order disease-causing models due to model diversity, possible low or even no marginal effect of the model, and extraordinary search and computations. In this paper, we propose a niche harmony search algorithm where joint entropy is utilized as a heuristic factor to guide the search for low or no marginal effect model, and two computationally lightweight scores are selected to evaluate and adapt to diverse of disease models. In order to obtain all possible suspected pathogenic models, niche technique merges with HS, which serves as a taboo region to avoid HS trapping into local search. From the resultant set of candidate SNP-combinations, we use G-test statistic for testing true positives. Experiments were performed on twenty typical simulation datasets in which 12 models are with marginal effect and eight ones are with no marginal effect. Our results indicate that the proposed algorithm has very high detection power for searching suspected disease models in the first stage and it is superior to some typical existing approaches in both detection power and CPU runtime for all these datasets. Application to age-related macular degeneration (AMD) demonstrates our method is promising in detecting high-order disease-causing models. PMID- 28912585 TI - Matrisome Profiling During Intervertebral Disc Development And Ageing. AB - Intervertebral disc (IVD) degeneration is often the cause of low back pain. Degeneration occurs with age and is accompanied by extracellular matrix (ECM) depletion, culminating in nucleus pulpous (NP) extrusion and IVD destruction. The changes that occur in the disc with age have been under investigation. However, a thorough study of ECM profiling is needed, to better understand IVD development and age-associated degeneration. As so, iTRAQ LC-MS/MS analysis of foetus, young and old bovine NPs, was performed to define the NP matrisome. The enrichment of Collagen XII and XIV in foetus, Fibronectin and Prolargin in elder NPs and Collagen XI in young ones was independently validated. This study provides the first matrisome database of healthy discs during development and ageing, which is key to determine the pathways and processes that maintain disc homeostasis. The factors identified may help to explain age-associated IVD degeneration or constitute putative effectors for disc regeneration. PMID- 28912586 TI - Three-dimensional combined biomarkers assay could improve diagnostic accuracy for gastric cancer. AB - So far, stomach-specific biomarkers, gastric cancer(GC)-related environmental factors, and cancer-associated biomarkers are three major classes of serological biomarkers with GC warning potential, joint detection of which is expected to increase the diagnosis efficiency. We investigated whether the combination of serum pepsinogens(PGs), IgG anti-Helicobacter pylori (HpAb), and osteopontin (OPN) can be used as a panel for GC diagnose. Serum was collected from 365 GC patients and 729 healthy individuals,furtherly 332 cases and 332 age- and sex matched controls were selected for the matched analysis. Serum levels were measured by ELISA. Logistic regression and receiver operator characteristic curve (ROC) were used to assess the associations of biomarkers with GC and the discriminative performance of biomarkers for GC. The area under ROC from three dimensional combination of PGI/II-HpAb-OPN (0.826) was significantly higher than two-dimensional combination of PGI/II-HpAb (0.786, P < 0.001), PGI/II-OPN (0.787, P < 0.001), and OPN-HpAb (0.801, P = 0.006), as well as one-biomarker of PGI/II (0.735, P < 0.001), HpAb (0.737, P < 0.001) and OPN(0.713, P < 0.001), respectively. The combination of PGI/II-HpAb-OPN, yielded a sensitivity of 70.2% and specificity of 78.3% at the predicted probability of 0.493 as the optimal cutoff point. Three-dimensional combined biomarkers assay could improve diagnostic accuracy for gastric cancer. PMID- 28912587 TI - Tuning electromagnetic properties of SrRuO3 epitaxial thin films via atomic control of cation vacancies. AB - Elemental defect in transition metal oxides is an important and intriguing subject that result in modifications in variety of physical properties including atomic and electronic structure, optical and magnetic properties. Understanding the formation of elemental vacancies and their influence on different physical properties is essential in studying the complex oxide thin films. In this study, we investigated the physical properties of epitaxial SrRuO3 thin films by systematically manipulating cation and/or oxygen vacancies, via changing the oxygen partial pressure (P(O2)) during the pulsed laser epitaxy (PLE) growth. Ru vacancies in the low-P(O2)-grown SrRuO3 thin films induce lattice expansion with the suppression of the ferromagnetic T C down to ~120 K. Sr vacancies also disturb the ferromagnetic ordering, even though Sr is not a magnetic element. Our results indicate that both A and B cation vacancies in an ABO3 perovskite can be systematically engineered via PLE, and the structural, electrical, and magnetic properties can be tailored accordingly. PMID- 28912588 TI - Lipopolysaccharide-initiated persistent rhinitis causes gliosis and synaptic loss in the olfactory bulb. AB - The olfactory mucosa (OM) is exposed to environmental agents and therefore vulnerable to inflammation. To examine the effects of environmental toxin initiated OM inflammation on the olfactory bulb (OB), we induced persistent rhinitis in mice and analyzed the spatial and temporal patterns of histopathological changes in the OM and OB. Mice received unilateral intranasal administration of lipopolysaccharide (LPS) or saline three times per week, and were immunohistologically analyzed at 1, 3, 7, 14 and 21 days after the first administration. LPS administration induced an inflammatory response in the OM, including the infiltration of Ly-6G-, CD11b-, Iba-1- and CD3-positive cells, the production of interleukin-1beta by CD11b- and Iba-1-positive cells, and loss of olfactory sensory neurons (OSNs). In the OB, we observed activation of microglia and astrocytes and decreased expression of tyrosine hydroxylase in periglomerular cells, vesicular glutamate transporter 1, a presynaptic protein, in mitral and tufted projection neurons, and 5T4 in granule cells. Thus, the OM inflammation exerted a detrimental effect, not only on OSNs, but also on OB neurons, which might lead to neurodegeneration. PMID- 28912589 TI - Microbial diversity in the hypersaline Lake Meyghan, Iran. AB - Lake Meyghan is one of the largest and commercially most important salt lakes in Iran. Despite its inland location and high altitude, Lake Meyghan has a thalassohaline salt composition suggesting a marine origin. Inputs of fresh water by rivers and rainfall formed various basins characterized by different salinities. We analyzed the microbial community composition of three basins by isolation and culturing of microorganisms and by analysis of the metagenome. The basins that were investigated comprised a green ~50 g kg-1 salinity brine, a red ~180 g kg-1 salinity brine and a white ~300 g kg-1 salinity brine. Using different growth media, 57 strains of Bacteria and 48 strains of Archaea were isolated. Two bacterial isolates represent potential novel species with less than 96% 16S rRNA gene sequence identity to known species. Abundant isolates were also well represented in the metagenome. Bacteria dominated the low salinity brine, with Alteromonadales (Gammaproteobacteria) as a particularly important taxon, whereas the high salinity brines were dominated by haloarchaea. Although the brines of Lake Meyghan differ in geochemical composition, their ecosystem function appears largely conserved amongst each other while being driven by different microbial communities. PMID- 28912590 TI - The importance of simulated lung fluid (SLF) extractions for a more relevant evaluation of the oxidative potential of particulate matter. AB - Particulate matter (PM) induces oxidative stress in vivo, leading to adverse health effects. Oxidative potential (OP) of PM is increasingly studied as a relevant metric for health impact (instead of PM mass concentration) as much of the ambient particle mass do not contribute to PM toxicity. Several assays have been developed to quantify PM oxidative potential and a widely used one is the acellular dithiothreitol (DTT) assay. However in such assays, particles are usually extracted with methanol or Milli-Q water which is unrepresentative of physiological conditions. For this purpose, OPDTT measurements after simulated lung fluids (SLF) extraction, in order to look at the impact of simulated lung fluid constituents, were compared to Milli-Q water extraction measurements. Our major finding is a significant decrease of the OPDTT when the artificial lysosomal fluid (ALF) solution was used. Indeed, ligand compounds are present in the SLF solutions and some induce a decrease of the OP when compared to water extraction. Our results suggest that the effect of ligands and complexation in lining fluids towards PM contaminants probably has been underestimated and should be investigated further. PMID- 28912591 TI - Inter-individual differences in heart rate variability are associated with inter individual differences in mind-reading. AB - In the present study, we investigated whether inter-individual differences in vagally-mediated cardiac activity (high frequency heart rate variability, HF-HRV) would be associated with inter-individual differences in mind-reading, a specific aspect of social cognition. To this end, we recorded resting state HF-HRV in 49 individuals before they completed the Reading the Mind in the Eyes Test, a test that required the identification of mental states on basis of subtle facial cues. As expected, inter-individual differences in HF-HRV were associated with inter individual differences in mental state identification: Individuals with high HF HRV were more accurate in the identification of positive but not negative states than individuals with low HF-HRV. Individuals with high HF-HRV may, thus, be more sensitive to positive states of others, which may increase the likelihood to detect cues that encourage approach and affiliative behavior in social contexts. Inter-individual differences in mental state identification may, thus, explain why individuals with high HF-HRV have been shown to be more successful in initiating and maintaining social relationships than individuals with low HF-HRV. PMID- 28912592 TI - Accurate immune repertoire sequencing reveals malaria infection driven antibody lineage diversification in young children. AB - Accurately measuring antibody repertoire sequence composition in a small amount of blood is challenging yet important for understanding repertoire responses to infection and vaccination. We develop molecular identifier clustering-based immune repertoire sequencing (MIDCIRS) and use it to study age-related antibody repertoire development and diversification before and during acute malaria in infants (< 12 months old) and toddlers (12-47 months old) with 4-8 ml of blood. Here, we show this accurate and high-coverage repertoire-sequencing method can use as few as 1000 naive B cells. Unexpectedly, we discover high levels of somatic hypermutation in infants as young as 3 months old. Antibody clonal lineage analysis reveals that somatic hypermutation levels are increased in both infants and toddlers upon infection, and memory B cells isolated from individuals who previously experienced malaria continue to induce somatic hypermutations upon malaria rechallenge. These results highlight the potential of antibody repertoire diversification in infants and toddlers.Somatic hypermutation of antibodies can occur in infants but are difficult to track. Here the authors present a new method called MIDCIRS for deep quantitative repertoire sequencing with few cells, and show infants as young as 3 months can expand antibody lineage complexity in response to malaria infection. PMID- 28912593 TI - Effect of palm-based tocotrienols and tocopherol mixture supplementation on platelet aggregation in subjects with metabolic syndrome: a randomised controlled trial. AB - Tocotrienols, the unsaturated form of vitamin E, were reported to modulate platelet aggregation and thrombotic mechanisms in pre-clinical studies. Using a Food and Drug Administration (FDA)-approved cartridge-based measurement system, a randomised, double-blind, crossover and placebo-controlled trial involving 32 metabolic syndrome adults was conducted to investigate the effect of palm-based tocotrienols and tocopherol (PTT) mixture supplementation on platelet aggregation reactivity. The participants were supplemented with 200 mg (69% tocotrienols and 31% alpha-tocopherol) twice daily of PTT mixture or placebo capsules for 14 days in a random order. After 14 days, each intervention was accompanied by a postprandial study, in which participants consumed 200 mg PTT mixture or placebo capsule after a meal. Blood samples were collected on day 0, day 14 and during postprandial for the measurement of platelet aggregation reactivity. Subjects went through a 15-day washout period before commencement of subsequent intervention. Fasting platelet aggregation reactivity stimulated with adenosine diphosphate (ADP) did not show substantial changes after supplementation with PTT mixture compared to placebo (p = 0.393). Concomitantly, changes in postprandial platelet aggregation reactivity remained similar between PTT mixture and placebo interventions (p = 0.408). The results of this study highlight the lack of inhibitory effect on platelet aggregation after short-term supplementation of PTT mixture in participants with metabolic syndrome. PMID- 28912594 TI - Quantification of Aquaporin-Z reconstituted into vesicles for biomimetic membrane fabrication. AB - Aquaporin incorporated biomimetic membranes are anticipated to offer unprecedented desalination capabilities. However, the lack of accurate methods to quantify the reconstituted aquaporin presents a huge hurdle in investigating aquaporin performance and optimizing membrane fabrication. Herein, we present three quantification methods to determine the Aquaporin-Z reconstituted into E. coli lipid vesicles: 1) nanogold labeling with transmission electron microscopy (TEM) visualization, 2) nickel labeling with inductively coupled plasma-mass spectrometry (ICP-MS) and 3) gel electrophoresis. The TEM method serves as a quick way to determine if aquaporin has been reconstituted, but is not quantitative. The numerical results from quantitative methods, ICP-MS and gel electrophoresis, correlate closely, showing that 60 +/- 20% vs 66 +/- 4% of Aquaporin-Z added is successfully reconstituted into vesicles respectively. These methods allow more accurate determination of Aquaporin-Z reconstituted and loss during reconstitution, with relatively commonly available equipment and without complex sample handling, or lengthy data analysis. These would allow them to be widely applicable to scientific studies of protein function in the biomimetic environment and engineering studies on biomimetic membrane fabrication. PMID- 28912595 TI - Analysis of VSV pseudotype virus infection mediated by rubella virus envelope proteins. AB - Rubella virus (RV) generally causes a systemic infection in humans. Viral cell tropism is a key determinant of viral pathogenesis, but the tropism of RV is currently poorly understood. We analyzed various human cell lines and determined that RV only establishes an infection efficiently in particular non-immune cell lines. To establish an infection the host cells must be susceptible and permissible. To assess the susceptibility of individual cell lines, we generated a pseudotype vesicular stomatitis virus bearing RV envelope proteins (VSV RV/CE2E1). VSV-RV/CE2E1 entered cells in an RV envelope protein-dependent manner, and thus the infection was neutralized completely by an RV-specific antibody. The infection was Ca2+-dependent and inhibited by endosomal acidification inhibitors, further confirming the dependency on RV envelope proteins for the VSV-RV/CE2E1 infection. Human non-immune cell lines were mostly susceptible to VSV-RV/CE2E1, while immune cell lines were much less susceptible than non-immune cell lines. However, susceptibility of immune cells to VSV-RV/CE2E1 was increased upon stimulation of these cells. Our data therefore suggest that immune cells are generally less susceptible to RV infection than non-immune cells, but the susceptibility of immune cells is enhanced upon stimulation. PMID- 28912596 TI - Complete reperfusion is required for maximal benefits of mechanical thrombectomy in stroke patients. AB - A mTICI 2b or a mTICI 3 score are currently considered success following mechanical thrombectomy (MT) in acute stroke but is undetermined whether the two scores translate equivalent outcomes. We present a single-center, retrospective cohort of patients with anterior circulation stroke treated with MT and achieving a final mTICI score 2b or 3. A multimodal CT at baseline and a multimodal MRI at 24 hours assessed the growth of the infarct, and the modified Rankin Scale (mRS) assessed functional outcome at 90 days. The primary outcome was the shift analysis of the mRS at day 90 in ordinal regression adjusted for covariates (age, sex, pretreatment NIHSS score, target occlusion, infarct core, pretreatment alteplase), and the collateral score. Infarct growth was explored in a similarly adjusted multiple linear regression model. MT was started within a median of 285 minutes of symptom onset; 51 (41%) patients achieved a mTICI 2b, and 74 (59%), a mTICI 3. mTICI 3 resulted in better mRS score transitions than mTICI 2b (odds ratio 2.018 [95% CI 1.033-3.945], p = 0. 040), and reduced infarct growth (p = 0.002). We conclude that in patients with acute stroke receiving MT, success should be redefined as achieving a mTICI 3 score. PMID- 28912597 TI - Angle-resolved stochastic photon emission in the quantum radiation-dominated regime. AB - Signatures of stochastic effects in the radiation of a relativistic electron beam interacting with a counterpropagating superstrong short focused laser pulse are investigated in a quantum regime when the electron's radiation dominates its dynamics. We consider the electron-laser interaction at near-reflection conditions when pronounced high-energy gamma-ray bursts arise in the backward emission direction with respect to the initial motion of the electrons. The quantum stochastic nature of the gamma-photon emission is exhibited in the angular distributions of the radiation and explained in an intuitive picture. Although, the visibility of the stochasticity signatures depends on the laser and electron beam parameters, the signatures are of a qualitative nature and robust. The stochasticity, a fundamental quantum property of photon emission, should thus be measurable rather straightforwardly with laser technology available in near future. PMID- 28912598 TI - Synthetic lethality screens point the way to new cancer drug targets. PMID- 28912599 TI - Market watch: Upcoming market catalysts in Q4 2017. PMID- 28912600 TI - The human microbiome: opportunity or hype? PMID- 28912601 TI - PHF7, a novel male gene influences female fecundity and population growth in Nilaparvata lugens Stal (Hemiptera: Delphacidae). AB - PHF7 exhibits male-specific expression in early germ cells, germline stem cells and spermatogonia in insects, and its expression promotes spermatogenesis in germ cells when they are present in a male soma. However, the influence of male specific PHF7 on female reproductive biology via mating remains unclear. Thus, we investigated the potential impacts of male PHF7, existed in seminal fluid of Nilaparvata lugens (NlPHF7), on fecundity and population growth via mating. Our results revealed that suppressing male NlPHF7 expression by RNAi led to decreases in body weight, soluble accessory gland protein content, arginine content, and reproductive organ development in males, resulting in significant reduction of oviposition periods and fecundity in females, and significant decrease in body weight, fat body and ovarian protein content, yeast-like symbionts abundance, ovarian development and vitellogenin gene expression in their female mating partners. Similarly, suppression of NlPHF7 expression in males mated with the control female reduced population growth and egg hatching rate, but did not influence gender ratio. We infer that NlPHF7 play a role important in stimulating female fecundity via mating. This study provides valuable information by identifying a potentially effective target gene for managing BPH population through RNAi. PMID- 28912602 TI - Kinetic adaptation of human Myo19 for active mitochondrial transport to growing filopodia tips. AB - Myosins are actin-based molecular motors which are enzymatically adapted for their cellular functions such as transportation and membrane tethering. Human Myo19 affects mitochondrial motility, and promotes their localization to stress induced filopodia. Therefore, studying Myo19 enzymology is essential to understand how this motor may facilitate mitochondrial motility. Towards this goal, we have purified Myo19 motor domain (Myo19-3IQ) from a human-cell expression system and utilized transient kinetics to study the Myo19-3IQ ATPase cycle. We found that Myo19-3IQ exhibits noticeable conformational changes (isomerization steps) preceding both ATP and ADP binding, which may contribute to nucleotide binding r egulation. Notably, the ADP isomerization step and subsequent ADP release contribute significantly to the rate-limiting step of the Myo19-3IQ ATPase cycle. Both the slow ADP isomerization and ADP release prolong the time Myo19-3IQ spend in the strong actin binding state and hence contribute to its relatively high duty ratio. However, the predicted duty ratio is lower than required to support motility as a monomer. Therefore, it may be that several Myo19 motors are required to propel mitochondria movement on actin filaments efficiently. Finally, we provide a model explaining how Myo19 translocation may be regulated by the local ATP/ADP ratio, coupled to the mitochondria presence in the filopodia. PMID- 28912603 TI - Novel insight into streptozotocin-induced diabetic rats from the protein misfolding perspective. AB - Protein folding is a process of self-assembly defined by the sequence of the amino acids of the protein involved. Additionally, proteins tend to unfold, misfold and aggregate due to both intrinsic and extrinsic causes. Human islet amyloid polypeptide (hIAPP) aggregation is an early step in diabetes mellitus. However, the aggregation of rat IAPP (rIAPP) remains an open question. Adult female Sprague-Dawley rats weighing 150-250 g were divided into two groups. The experimental group (streptozotocin [STZ]) (n = 21) received an intraperitoneal injection of a single dose of 40 mg/kg STZ. We used the mouse anti-IAPP antibody and the anti-amyloid oligomer antibody to study the temporal course of rIAPP oligomerization during STZ-induced diabetes using a wide array of methods, strategies and ideas derived from biochemistry, cell biology, and proteomic medicine. Here, we demonstrated the tendency of rIAPP to aggregate and trigger cooperative processes of self-association or hetero-assembly that lead to the formation of amyloid oligomers (trimers and hexamers). Our results are the first to demonstrate the role of rIAPP amyloid oligomers in the development of STZ induced diabetes in rats. The IAPP amyloid oligomers are biomarkers of the onset and progression of diabetes and could play a role as therapeutic targets. PMID- 28912604 TI - Oral health promotion in the community pharmacy: an evaluation of a pilot oral health promotion intervention. AB - Introduction Poor oral health is a significant public health concern, costing the NHS in England L3.4 billion annually. Community pharmacies are easily accessible, frequently visited by patients and the community pharmacy contractual framework requires pharmacies to provide healthy living advice to patients - therefore offering a little explored avenue for the delivery of oral health interventions.Methodology A pilot oral health promotion intervention was introduced in five pharmacies in deprived areas of County Durham between September and December 2016. A mixed methods approach to the evaluation was performed, utilising a patient evaluation questionnaire and semi-structured qualitative interviews with pharmacy staff.Results One thousand and eighty-nine participants received the intervention. Following the intervention 72% of participants perceived their knowledge of oral health as much better, 66% definitely intended to change their oral health habits and 64% definitely thought a pharmacy was the right place to receive advice about oral health. Three themes emerged from the qualitative data: (1) intervention feedback, (2) knowledge gap and (3) service development.Discussion The data demonstrated the acceptability of patients to a community pharmacy based oral health intervention, with most patients reporting intentions to change their oral healthcare habits after receiving the intervention. Previous literature has identified a willingness of pharmacy staff to become involved with oral health; this study provides evidence that patients are also receptive to such services being delivered in the community pharmacy setting. Further work is required to assess the benefits of a community pharmacy based oral health intervention and the potential for further growth of this role.Conclusion A community pharmacy is perceived by patients as an acceptable provider of oral health interventions and has the potential to provide positive changes to the oral health of the population. PMID- 28912606 TI - Profiling of cocaine using ratios of GC-MS peaks. AB - Illicit cocaine seizures are often compared to each other by using gas chromatography-mass spectrometry (GC-MS) data from cocaine alkaloid compounds to determine whether two specimens originate from the same production batch or not. This can provide intelligence or investigative information at the early stages of an investigation or evidence in court. Traditional classification methods assume high stability of all alkaloids, use all of them to calculate the correlation between two profiles and use a threshold to classify samples. Unstable alkaloids will have a strong influence on the performance. We show that comparing each alkaloid target compound individually improves the classification. Unfortunately, it requires normalization and is also sensitive to the stability. Instead we suggest to use ratios of all possible pairwise combinations of the GC-MS peaks. These ratios are scale free and directly comparable between samples. The peaks can be given different weights in the comparison of profiles using appropriate classification methods and we show that randomForest classification using these ratios have a high and reproducible performance in comparison with other methods. The performance of this method is not affected by noise, transformation or normalization and should be considered for future comparison of chromatographic profiles in general. PMID- 28912605 TI - Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15. AB - CD4+CD8+ T lymphocytes account for 1-2% of circulating human T lymphocytes, but their frequency is augmented in several diseases. The phenotypic and functional properties of these T lymphocytes are still ill-defined. We performed an ex vivo characterization of CD4+CD8+ T lymphocytes from the blood of healthy individuals. We observed that CD4+CD8+ T lymphocytes exhibit several characteristics associated with memory T lymphocytes including the expression of chemokine receptors (e.g. CCR7, CXCR3, CCR6) and activation markers (e.g. CD57, CD95). Moreover, we showed that a greater proportion of CD4+CD8+ T lymphocytes have an enhanced capacity to produce cytokines (IFNgamma, TNFalpha, IL-2, IL-4, IL-17A) and lytic enzymes (perforin, granzyme B) compared to CD4+ and/or CD8+ T lymphocytes. Finally, we assessed the impact of three key cytokines in T cell biology on these cells. We observed that IL-2, IL-7 and IL-15 triggered STAT5 phosphorylation in a greater proportion of CD4+CD8+ T lymphocytes compared to CD4 and CD8 counterparts. We demonstrate that CD4+CD8+ T lymphocytes from healthy donors exhibit a phenotypic profile associated with memory T lymphocytes, an increased capacity to produce cytokines and lytic enzymes, and a higher proportion of cells responding to key cytokines implicated in T cell survival, homeostasis and activation. PMID- 28912607 TI - 'Nobody could possibly misunderstand what a group is': a study in early twentieth century group axiomatics. AB - In the early years of the twentieth century, the so-called 'postulate analysis' the study of systems of axioms for mathematical objects for their own sake-was regarded by some as a vital part of the efforts to understand those objects. I consider the place of postulate analysis within early twentieth-century mathematics by focusing on the example of a group: I outline the axiomatic studies to which groups were subjected at this time and consider the changing attitudes towards such investigations. PMID- 28912609 TI - The Biomonitoring of Great Lakes Populations Program. PMID- 28912608 TI - Structural features of the carbon-sulfur chemical bond: a semi-experimental perspective. AB - In this work semi-experimental and theoretical equilibrium geometries of 10 sulfur-containing organic molecules, as well as 4 oxygenated ones, are determined by means of a computational protocol based on density functional theory. The results collected in the present paper further enhance our online database of accurate semi-experimental equilibrium molecular geometries, adding 13 new molecules containing up to 8 atoms, for 12 of which the first semi-experimental equilibrium structure is reported, to the best of our knowledge. We focus in particular on sulfur-containing compounds, aiming both to provide new accurate data on some rather important chemical moieties, only marginally represented in the literature of the field, and to examine the structural features of carbon sulfur bonds in the light of the previously presented linear regression approach. The structural changes issuing from substitution of oxygen by sulfur are discussed to get deeper insights on how modifications in electronic structure and nuclear potential can affect equilibrium geometries. With respect to our previous works, we perform non-linear constrained optimizations of equilibrium SE structures with a new general and user-friendly software under development in our group with updated definition of useful statistical indicators. PMID- 28912610 TI - A guide for religious for end-of-life decision making. PMID- 28912611 TI - Our Lady Undoer of Knots. PMID- 28912612 TI - Homily for the Memorial of Our Lady of Lourdes. PMID- 28912613 TI - Is medicine losing its way? A firm foundation for medicine as a real therapeia. AB - : Is medicine losing its way? This question may seem to imply a serious warning, one needing a further explanation. What I mean to say by the title of this paper is that we can detect an undeniable shift in medicine in the last forty to fifty years. Medicine used to focus on what we call "health care" in a classical sense, that is, the treatment of people suffering from diseases, injuries or handicaps, or the alleviation of pain and other symptoms. In addition to this, in the last half century, it has begun to offer more and more treatments aiming to perfect the qualities of people who are otherwise healthy. SUMMARY: Due to the rapid progress of research in the biomedical field, medicine is already and will ever more be able not only to cure diseases, but also to improve the characteristics of healthy human persons. This seems to be justifiable from the point of view of the contemporary view of man. This considers the mind as the actual human person and the body as an object of which he may dispose as he likes. However, serious and convincing objections exist against this view, because it does not do justice to the fact that we experience ourselves as a unity. Aristotelian-Thomist anthropology explains man as a substantial unity of a spiritual and a material dimension, of body and soul, which implies that the body is an essential dimension of man, participates in his intrinsic dignity and is never to be instrumentalized in order to improve the characteristics of healthy people. Medicine should apply all new medical techniques availed, but remain true health care. PMID- 28912614 TI - Spiritual care of the sick. AB - : In the Gospel we see how people bring the sick to Christ to be healed. As physicians, nurses, and chaplains we are God's instruments bringing physical and spiritual healing to the sick. It is important for those of us who care for the sick to ask them about their religious affiliation and spiritual needs, and then following their cues and in a respectful way to encourage them to pray and, in the case of Catholics, to receive the sacraments. We should also pray for our patients, and when we think they would like it, to pray with them. SUMMARY: Physicians and nurses, not only chaplains, should ask patients about their religious beliefs, offer to find spiritual assistance for them, and when appropriate pray with them. PMID- 28912615 TI - Why the moratorium on human-animal chimera research should not be lifted. AB - The National Institutes of Health (NIH) announced its plans to lift its moratorium on funding research that involves injecting human embryonic stem cells into animal embryos, which would allow for the creation of part-human and part animal organisms known as chimeras. The NIH allowed only one month to receive public comments in the midst of a presidential election campaign. Lifting the moratorium means that, for the first time, the federal government will begin spending taxpayer dollars on the creation and manipulation of new organisms that would blur the line between humans and animals. Interestingly, this government effort is creating an uncommon coalition between pro-life groups and animal rights activists that oppose this medical research on ethical grounds; the former seeking to ensure the welfare of human embryos and the latter seeking to protect the well-being of animals. Unlike the issue of abortion, this research is complex. Yet, it is important that the pro-life laity and clergy be adequately informed on some of the basic science and ethics that surround this research. To fully understand why this research is unethical and why the NIH is pursuing this particular research, it is important to understand the ethical tenets governing human-subject research and why secular scientists are pursuing this scientific field. PMID- 28912616 TI - Decision making in neonatal end-of-life scenarios in low-income settings1. AB - : The challenge of decision making in end-of-life scenarios is exacerbated when the patient is a newborn and in a low-income setting. The principle of proportionate care is a helpful guide but needs to be applied. The complex interplay of benefit, burden, and cost of various treatments all need to be considered. In patients with severe neonatal encephalopathy, prognosis can be hard to determine, and a team approach to decision making can help. In low-income settings, or where there are limited resources, the ideal care needs to be incarnated in the real context. Issues of social justice also arise as finite resources need to be used prudently. SUMMARY: Decisions regarding medical care become difficult when the patient is a seriously ill newborn baby. In the developing world, scarce medical facilities and minimal economic resources also limit possible treatment options. The Catholic Church offers practical ethical principles which can help the medical team and family to strive to do what is morally best in these difficult situations. PMID- 28912617 TI - Pulmonary hypertension: Clinical parameters of a difficult case in pregnancy. AB - : Treatment of pulmonary hypertension in pregnancy with a prostacyclin analogue iloprost and/or calcium channel antagonists appears to improve outcomes and survival. These medications could have been administered to the patient and the response monitored. If the patient did not respond to therapy, this patient may have had either a referral to or transfer to another high risk center with more experience in this type of pregnant patient. There is no literature to support termination of pregnancy improving maternal survival outcomes in these patients, even though termination is recommended by all obstetrical textbooks. Maternal survival, rather, appears to be related to response to therapy, type of therapy, and continuation of therapy. SUMMARY: A patient who is pregnant with pulmonary hypertension (increased right-sided heart pressures) may be managed with medications. There is no literature to support termination of pregnancy improving maternal survival outcomes in patients with pulmonary hypertension, even though termination is recommended by all obstetrical textbooks. Maternal survival, rather, appears to be related to response to therapy, type of therapy, and continuation of therapy. PMID- 28912618 TI - Moral theological analysis of direct versus indirect abortion. AB - : Cases of a vital conflict, where the lives of both the mother and child are at risk during pregnancy, have been the subject of recent vigorous debate. The basic principles put forth in the Ethical and Religious Directives are reviewed, as is the principle of double effect. An illustrative case of severe cardiomyopathy in a pregnant woman is described and it is noted that the principle of double effect would not apply. Counter arguments are noted, focusing on Martin Rhonheimer who posits that in the case of vital conflicts, such as performing a craniotomy on a baby stuck in the birth canal, taking the baby's life does not constitute a direct abortion because moral norms do not apply in the extreme conflict situation where both mother and child will die. He states that the death of the fetus is not intentional in these cases. He overlooks "how the life is being saved" and that a choice has been made, which implies a moral act, not just a physical one. Rhonheimer wants to make his moral judgment solely on the basis of intention, prescinding from what actually occurs in the physical world of cause and effect. This is clearly against the teaching in Evangelium vitae. Ethics deal with the deliberate chosen actions in space and time of embodied human beings; it deals inescapably with material actions, with specifications of intentions. Rhonheimer states, "a killing or an abortion is 'direct,' not because the death of the fetus is caused in some physically direct way, but because it is willed as the means to an end." However the death of the child cannot be excluded from the act and is therefore of necessity included in it. What the acting person chooses includes what happens physically in this act. If the action theory proposed by Rhonheimer is accepted, it could be very difficult to avoid death-dealing actions from taking place in Catholic hospitals. SUMMARY: This is a moral analysis of cases of "vital conflicts," where the lives of both the mother and child are at risk during a pregnancy. It is stated by some ethicists that directly killing the baby to save the life of the mother is morally justified, even when the direct action of the doctor is to kill the baby. Examples are provided to illustrate how Catholic moral principles apply. It is concluded that direct killing, regardless of the intention, is not justified. The doctor should always work to try and save the lives of both the mother and the child. One should never be directly killed even if the intention is to save the life of the other. PMID- 28912619 TI - What moral character is and is not. AB - : Louise Mitchell discusses character in "Integrity and virtue: The forming of good character" (The Linacre Quarterly 82, no. 2: 149-169). I argue that she is mistaken in identifying character as a potency and that it is rather the sum of one's moral habits and dispositions. I establish this by showing that if one correctly applies the division Aristotle presents in the text that Mitchell relies on, it follows that character belongs in the category of habit. I further support this conclusion by considering how people commonly speak of moral character. I then show that the text from the Summa Theologiae Mitchell relies on concerns sacramental character and not moral character; moreover, if we apply the reasoning contained there to moral character, we are again led to see that it should be categorized as a habit. Lastly, I explain that a human being's potency for character lies in the soul's rational powers. SUMMARY: I defend the common sense view that moral character is the sum of one's moral habits and dispositions in response to Louise Mitchell who maintains that moral character is a potency. I do so by applying Aristotle's threefold division of things that exist in the soul namely, potency, habit, and emotion-and also by examining how Aristotle speaks about character and how the average person speaks about character. In addition, I show why humans are the only animals that have the potential to develop character, and how this potential lies in the rational faculties of our soul. PMID- 28912621 TI - FAQs from the 2012 CMA Annual Conference. PMID- 28912620 TI - Hormonal contraception and the development of autoimmunity: A review of the literature. AB - : Estrogens and progestins are known to have profound effects on the immune system and may modulate the susceptibility to autoimmune diseases. A comprehensive literature search was carried out using PubMed for any of 153 autoimmune disease terms and the terms contraception, contraceptive, or their chemical components with limits of Humans + Title or Abstract. Over 1,800 titles were returned and scanned, 352 papers retrieved and reviewed in depth and an additional 70 papers retrieved from the bibliographies. Based on this review, substantial evidence exists linking the use of combined oral contraceptives to a lower incidence of hyperthyroidism, an increase in multiple sclerosis, ulcerative colitis, Crohn's disease, Systemic Lupus Erythematosus, and interstitial cystitis. Progesterone only contraceptives are linked to progesterone dermatitis and in one large developing world concurrent cohort study are associated with increases in arthropathies and related disorders, eczema and contact dermatitis, pruritis and related conditions, alopecia, acne, and urticaria. Hormonal contraceptives modulate the immune system and may influence the susceptibility to autoimmune diseases with significant increases in risk for several autoimmune diseases. SUMMARY: Hormonal contraceptives (HCs), such as the "pill," Norplant, and vaginal rings, are very potent hormones that have effects on the immune system, which is made up of white blood cells and lymph nodes and normally defends the body against invading bacteria, viruses and parasites. This review looked at the association of HC use to the development of autoimmune diseases, where the immune system turns against the body and causes damage to organs. There is good evidence that HC use is associated with an increased risk of several serious autoimmune diseases such as Crohn's disease (which causes inflammation of the bowels), Lupus (which causes inflammation in many organs), and interstitial cystitis (which causes inflammation in the bladder). Several other rarer autoimmune diseases are also linked to HC use. People contemplating the use of HCs should be informed of these risks. PMID- 28912622 TI - Local and Systemic Immune Responses to Influenza A Virus Infection in Pneumonia and Encephalitis Mouse Models. AB - OBJECTIVE: To compare local and systemic profiles between different disease pathologies (pneumonia and encephalitis) induced by influenza A virus (IAV). METHODS: An IAV pneumonia model was created by intranasal inoculation of C57BL/6 mice with influenza A/WSN/33 (H1N1) virus. Lung lavage and blood collection were performed on day 3 after IAV inoculation. Similarly, an IAV encephalitis mouse model was created by direct intracranial IAV inoculation. Cerebrospinal fluid (CSF) and blood collection were conducted according to the same schedule. Cytokine/chemokine profiles were produced for each collected sample. Then the data were compared visually using radar charts. RESULTS: Serum cytokine profiles were similar in pneumonia and encephalitis models, but local responses between the bronchoalveolar lavage fluid (BALF) in the pneumonia model and CSF in the encephalitis model differed. Moreover, to varying degrees, the profiles of local cytokines/chemokines differed from those of serum in both the pneumonia and encephalitis models. CONCLUSION: Investigating local samples such as BALF and CSF is important for evaluating local immune responses, providing insight into pathology at the primary loci of infection. Serum data alone might be insufficient to elucidate local immune responses and might not enable clinicians to devise the most appropriate treatment strategies. PMID- 28912624 TI - Corrigendum to "Expression and Clinical Significance of Cancer Stem Cell Markers CD24, CD44, and CD133 in Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis". AB - [This corrects the article DOI: 10.1155/2017/3276806.]. PMID- 28912623 TI - Measurement of Serum Klotho in Systemic Sclerosis. AB - BACKGROUND: The aim of our study was to evaluate the serum concentration of klotho in a cohort of systemic sclerosis (SSc) patients compared to that of healthy controls and to correlate its levels with the degree and the kind of organ involvement. METHODS: Blood samples obtained from both patients and controls were collected and analysed by an ELISA test for the determination of human soluble klotho. Scleroderma patients were evaluated for disease activity through clinical, laboratory, and instrumental assessment. RESULTS: Our cohort consisted of 81 SSc patients (74 females, mean age 63.9 +/- 13.1 years) and 136 healthy controls (78 females, mean age 50.5 +/- 10.7 years). When matched for age, serum klotho concentration significantly differed between controls and patients (p < 0.001). However, in SSc patients, we did not find any significant association between serum klotho and clinical, laboratory, and instrumental findings. Lower serum levels of klotho were detected in 4 patients who were anticitrullinated peptide antibody (ACPA) positive (p = 0.005). CONCLUSIONS: Our data show a lower concentration of klotho in the serum of SSc patients compared to that of healthy controls, without any significant association with clinical manifestations and laboratory and instrumental findings. The association between serum klotho and ACPA positivity requires further investigation. PMID- 28912625 TI - Cognitive Impairment in Relapsing-Remitting Multiple Sclerosis Patients with Very Mild Clinical Disability. AB - Cognitive dysfunction affects 40-65% of multiple sclerosis (MS) patients and can occur in the early stages of the disease. This study aimed to explore cognitive functions by means of the Italian version of the minimal assessment of cognitive function in MS (MACFIMS) in relapsing-remitting MS (RRMS) patients with very mild clinical disability to identify the primarily involved cognitive functions. Ninety-two consecutive RRMS patients with Expanded Disability Status Scale (EDSS) scores <= 2.5 and forty-two healthy controls (HC) were investigated. Our results show that 51.1% of MS patients have cognitive dysfunction compared to HC. An impairment of verbal and visual memory, working memory, and executive functions was found in the RRMS group. After subgrouping RRMS by EDSS, group 1 (EDSS <= 1.5) showed involvement of verbal memory and executive functions; moreover, group 2 (2 <= EDSS <= 2.5) patients were also impaired in information processing speed and visual memory. Our results show that utilizing a comprehensive neuropsychological assessment, approximately half of MS patients with very mild physical disability exhibit cognitive impairment with a primary involvement of prefrontal cognitive functions. Detecting impairment of executive functions at an early clinical stage of disease could be useful to promptly enroll MS patients in targeted rehabilitation. PMID- 28912626 TI - Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer. AB - Breast cancer metastasizes to lymph nodes or other organs, which determine the prognosis of patients. It is difficult to cure the breast cancer patients with distant metastasis due to resistance to drug therapies. Elucidating the underlying mechanisms of breast cancer metastasis and drug resistance is expected to provide new therapeutic targets. Sphingosine-1-phosphate (S1P) is a pleiotropic, bioactive lipid mediator that regulates many cellular functions, including proliferation, migration, survival, angiogenesis/lymphangiogenesis, and immune responses. S1P is formed in cells by sphingosine kinases and released from them, which acts in an autocrine, paracrine, and/or endocrine manner. S1P in extracellular space, such as interstitial fluid, interacts with components in the tumor microenvironment, which may be important for metastasis. Importantly, recent translational research has demonstrated an association between S1P levels in breast cancer patients and clinical outcomes, highlighting the clinical importance of S1P in breast cancer. We suggest that S1P is one of the key molecules to overcome the resistance to the drug therapies, such as hormonal therapy, anti-HER2 therapy, or chemotherapy, all of which are crucial aspects of a breast cancer treatment. PMID- 28912627 TI - IL-25 Could Be Involved in the Development of Allergic Rhinitis Sensitized to House Dust Mite. AB - BACKGROUND AND PURPOSE: When house dust mite (HDM), a common allergen, comes into the mucosal membrane, it may stimulate innate immunity. However, the precise role of interleukin- (IL-) 25 in the development of HDM-induced nasal allergic inflammation is still unclear. Therefore, we investigated the role of IL-25 in allergic rhinitis (AR) patients sensitized to HDM. METHODS: To confirm the production of IL-25 in human nasal epithelial cells (HNECs), we stimulated HNECs. IL-25 expression in the nasal mucosa from control, non-AR (NAR) patients, and HDM sensitized AR patients was assessed using immunohistochemistry, and quantitative reverse transcription PCR. Correlations between IL-25 and other inflammatory markers were explored. RESULTS: An in vitro study showed significantly elevated concentrations of IL-25 in the HNEC samples with highest doses of HDM. Nasal tissues from AR patients sensitized to HDM showed significantly higher IL-25 expression, compared to those from the control or NAR patients. Moreover, the expression of IL-25 in nasal tissues from AR patients sensitized to HDM was positively associated with Th2 markers, such as ECP and GATA3. CONCLUSIONS: IL-25 expression increased with high-dose HDM stimulation and was related to Th2 markers. Therefore, IL-25 neutralization might offer a new strategy for treating patients with HDM-sensitized AR. PMID- 28912628 TI - The future of orthopedic manual therapy: what are we missing? PMID- 28912629 TI - Spinal manipulation does not affect pressure pain thresholds in the absence of neuromodulators: a randomized controlled trial. AB - BACKGROUND: Measurement of pressure pain threshold (PPT) is a way to determine one of the many potential treatment effects of spinal manipulative therapy. OBJECTIVE: To determine how multiple spinal manipulations administered in a single-session affected PPTs at local and distal sites in asymptomatic individuals. METHODS: Participants were randomly assigned into one of three groups: Group one (n = 18) received a lumbar manipulation followed by a cervical manipulation. Group two (n = 17) received a cervical manipulation followed by a lumbar manipulation. The control group (n = 19) received two bouts of five minutes of rest. At baseline and after each intervention or rest period, each participant's PPTs were obtained using a handheld algometer. The PPTs were tested bilaterally over the lateral epicondyles of the humerus and over the mid-bellies of the upper trapezius, lumbar paraspinal, and the tibialis anterior muscles. This study was registered with ClinicalTrials.gov, and its Identifier is NCT02828501. RESULTS: Repeated-measures ANOVAs and Kruskal-Wallis tests showed no significant within- or between-group differences in PPT. Within-group effect sizes in the changes of PPT ranged from -.48 at the left paraspinal muscles to .24 at the left lateral humeral epicondyle. Statistical power to detect significant differences at alpha of 0.05 was calculated to be 0.94. CONCLUSIONS: This study suggests that in young adults who do not have current or recent symptoms of spinal pain, multiple within-session treatments of cervical and lumbar spinal manipulation fail to influence PPTs. Changes in PPT that are observed in symptomatic individuals are likely to be primarily influenced by pain related neuromodulators rather than by an isolated, mechanical effect of spinal manipulation. PMID- 28912630 TI - Inter-tester reliability of selected clinical tests for long-lasting temporomandibular disorders. AB - OBJECTIVE: Clinical tests used to examine patients with temporomandibular disorders vary in methodological quality, and some are not tested for reliability. The purpose of this cross-sectional study was to evaluate inter tester reliability of clinical tests and a cluster of tests used to examine patients with long-lasting temporomandibular disorders. METHODS: Forty patients with pain in the temporomandibular area treated by health-professionals were included. They were between 18-70 years, had 65 symptomatic (33 right/32 left) and 15 asymptomatic joints. Two manual therapists examined all participants with selected tests. Percentage agreement and the kappa coefficient (k) with 95% confidence interval (CI) were used to evaluate the tests with categorical outcomes. For tests with continuous outcomes, the relative inter-tester reliability was assessed by the intraclass-correlation-coefficient (ICC3,1, 95% CI) and the absolute reliability was calculated by the smallest detectable change (SDC). RESULTS: The best reliability among single tests was found for the dental stick test, the joint-sound test (k = 0.80-1.0) and range of mouth-opening (ICC3,1 (95% CI) = 0.97 (0.95-0.98) and SDC = 4 mm). The reliability of cluster of tests was excellent with both four and five positive tests out of seven. CONCLUSION: The reliability was good to excellent for the clinical tests and the cluster of tests when performed by experienced therapists. The tests are feasible for use in the clinical setting. They require no advanced equipment and are easy to perform. PMID- 28912631 TI - Subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder manual therapy plus exercise intervention in individuals with subacromial impingement syndrome: a prospective, randomized controlled clinical trial pilot study. AB - OBJECTIVES: To determine the subacute effects of cervicothoracic spinal thrust/non-thrust in addition to shoulder non-thrust plus exercise in patients with subacromial pathology. METHODS: This was a randomized, single blinded controlled trial pilot study. This trial was registered at ClinicalTrials.gov (NCT01753271) and reported according to Consolidated Standards of Reporting Trials requirements. Patients were randomly assigned to either shoulder treatment plus cervicothoracic spinal thrust/non-thrust or shoulder treatment-only group. Primary outcomes were average pain intensity (Numeric Pain Rating Scale) and physical function (Shoulder Pain and Disability Index) at 2 weeks, 4 weeks, and patient discharge. RESULTS: 18 patients, mean age 43.1(15.8) years satisfied the eligibility criteria and were analyzed for follow-up data. Both groups showed statistically significant improvements in both pain and function at 2 weeks, 4 weeks, and discharge. The between-group differences for changes in pain or physical function were not significant at any time point. DISCUSSION: The addition of cervicothoracic spinal thrust/non-thrust to the shoulder treatment only group did not significantly alter improvement in pain or function in patients with subacromial pathology. Both approaches appeared to provide an equally notable benefit. Both groups improved on all outcomes and met the criteria for clinical relevance for both pain and function. LEVEL OF EVIDENCE: 2b. PMID- 28912632 TI - The intra-rater reliability of a revised 3-point grading system for accessory joint mobilizations. AB - OBJECTIVES: Joint mobilizations are often quantified using a 4-point grading system based on the physiotherapist's detection of resistance. It is suggested that the initial resistance to joint mobilizations is imperceptible to physiotherapists, but that at some point through range becomes perceptible, a point termed R1. Grades of mobilization traditionally hinge around this concept and are performed either before or after R1. Physiotherapists, however, show poor reliability in applying grades of mobilization. The definition of R1 is ambiguous and dependent on the skills of the individual physiotherapist. The aim of this study is to test a revised grading system where R1 is considered at the beginning of range, and the entire range, as perceived by the physiotherapists maximum force application, is divided into three, creating 3 grades of mobilization. METHOD: Thirty-two post-registration physiotherapists and nineteen pre registration students assessed end of range (point R2) and then applied 3 grades of AP mobilizations, over the talus, in an asymptomatic models ankle. Vertical forces were recorded through a force platform. Intra-class Correlation Coefficients, Standard Error of Measurement, and Minimal Detectable Change were calculated to explore intra-rater reliability on intra-day and inter-day testing. T-tests determined group differences. RESULTS: Intra-rater reliability was excellent for intra-day testing (ICC 0.96-0.97), and inter-day testing (ICC 0.85 0.93). No statistical difference was found between pre- and post-registration groups. DISCUSSION: Standardizing the definition of grades of mobilization, by moving R1 to the beginning of range and separating grades into thirds, results in excellent intra-rater reliability on intra-day and inter-day tests. LEVEL OF EVIDENCE: 3b. PMID- 28912633 TI - A preliminary case series evaluating the safety and immediate to short-term clinical benefits of joint mobilization in hemophilic arthritis of the lower limb. AB - OBJECTIVES: Arthritis resulting from recurrent intra-articular bleeding in individuals with hemophilia can be severely debilitating due to joint pain and stiffness with subsequent loss of mobility and function. Very limited studies have investigated the potential benefits of joint mobilization for this condition. This case series is a preliminary investigation of safety, as well as immediate and short-term clinical benefits, associated with gentle knee and ankle joint mobilization in people with hemophilic arthropathy. METHODS: A single intervention of joint mobilization was applied to the affected knees and/or ankles of 16 individuals with severe or moderate hemophilia within a public hospital setting. Adverse events, as well as immediate (pain-free passive joint range, Timed Up and Go Test with maximum pain numerical rating scale) and short term (Lower Extremity Functional Scale) effects of the intervention were evaluated with a repeated measures ANOVA. RESULTS: There were no adverse events. An immediate significant increase was observed in pain-free passive ankle joint range of motion (p < 0.05) following the joint mobilization intervention. DISCUSSION: The findings of this case series suggest that gentle joint mobilization techniques may be safely considered as part of a multimodal management approach for hemophilic arthropathy. PMID- 28912634 TI - Posterior hip instability relocation testing: a resident's case report. AB - BACKGROUND: Micro-instability (non-radiographic clinical instability) continues to gain recognition as a problem at the hip. Although most research has been directed to anterior hip instability, posterior hip instability (PHI) has also garnered attention. PHI is under recognized, difficult to identify, and confused with other hip pathologies such as a simple sprain or strain. A novel clinical test is introduced that may have helped identify PHI in this patient. Additionally, a conservative rehabilitation approach emphasizing stabilization exercises is described. CASE DESCRIPTION: A 29-year-old female presented with complaints of posterior lateral and anterior hip pain of 1.5 years duration. Upon initiating an aggressive stretching program, her pain worsened. Examination revealed limited and painful hip flexion, and positive anterior impingement testing for femoroacetabular impingement. Both tests were significantly less painful with more motion when retested with manual repositioning of the femoral head from posterior to anterior, referred to as posterior relocation testing. The patient was instructed to discontinue stretching. A stabilization plan was established including strengthening of the deep external rotators with trunk and lower quarter neuromuscular re-education. OUTCOME: The patient completed 12 appointments over 2.5 months. At discharge, the patient reported improvements with pain and function. The Lower Extremity Functional Scale improved from 64/80 to 77/80 and Oswestry Disability Questionnaire improved from 8 to 0%. DISCUSSION: PHI may have contributed to this patient's symptoms. The posterior relocation test may assist clinicians with identification of PHI, thus directing treatment toward stabilization and neuromuscular control rather than interventions designed to increase mobility. LEVEL OF EVIDENCE: 4. PMID- 28912635 TI - Profile of Justice-Involved Marijuana and Other Substance Users: Demographics, Health and Health Care, Family, and Justice System Experiences. AB - Substance users are more likely to have co-occurring health problems, and this pattern is intensified among those involved with the criminal justice system. Interview data for 1977 incarcerated men in 5 states from the Multi-site Family Study on Incarceration, Parenting, and Partnering that was conducted between December 2008 and August 2011 were analyzed to compare pre-incarceration substance use patterns and health outcomes between men who primarily used marijuana, primarily used alcohol, primarily used other drugs, and did not use any illicit substances during that time. Using regression modeling, we examined the influence of substance use patterns on physical and mental health. Primary marijuana users comprised the largest portion of the sample (31.5%), closely followed by nonusers (30.0%), and those who primarily used other drugs (30.0%); primary alcohol users comprised the smallest group (19.6%). The substance user groups differed significantly from the nonuser group on many aspects of physical and mental health. Findings suggest that even among justice-involved men who are not using "hard" drugs, substance use merits serious attention. Expanding the availability of substance use treatment during and after incarceration might help to promote physical and mental health during incarceration and reentry. PMID- 28912636 TI - Should Emergency Endoscopy be Performed in All Patients With Suspected Colonic Diverticular Hemorrhage? AB - OBJECTIVE: We attempted to develop a scoring system for facilitating decision making regarding the performance of emergency endoscopy in patients with colonic diverticular hemorrhage. METHODS: This study involved analysis of the data of 178 patients who presented with hematochezia and were diagnosed as having colonic diverticular hemorrhage by colonoscopy. The patients were divided into 2 groups depending on whether the bleeding source was identified or not at the initial endoscopy (source-identified and source-not-identified groups), and on the basis of the results obtained, we established a scoring system for predicting successful identification of the bleeding source. RESULTS: The percentages of patients on oral anticoagulant therapy or with a Charlson comorbidity index of >=6, serum C-reactive protein level of >=1 mg/dL, or extravasation of contrast medium visualized on contrast-enhanced computed tomographic (CT) images were all significantly higher in the identified than in the nonidentified group. Multivariate analysis identified extravasation of contrast medium on contrast enhanced CT images (odds ratio [OR]: 10.6; 95% confidence interval [CI]: 2.7 42.2) and use of anticoagulants (OR: 4.5; 95% CI: 1.5-13.5) as independent predictors of successful identification of the bleeding source at the initial endoscopy in patients with colonic diverticular hemorrhage. On the basis of these results, we established a scoring system, which showed a sensitivity of 80% and specificity of 81% for successful identification of the bleeding source at the initial endoscopy. CONCLUSIONS: Herein, we propose a scoring system as a useful tool for determining whether emergency endoscopy is indicated in individual patients with suspected colonic diverticular hemorrhage. PMID- 28912637 TI - Prognostic Impact of Extracapsular Lymph Node Invasion and Myofibroblastic Activity in Extrahepatic Bile Duct Cancer. AB - Extrahepatic bile duct carcinoma is a potentially malignant gastrointestinal lesion. Cancer cells spread via the lymphatic system to regional lymph nodes and help in tumor progression. However, there are no reports on the prognostic impact of extracapsular lymph node invasion and myofibroblastic activity in this cancer. Hence, we classified the histopathologic patterns of lymph nodes into 2 patterns: extracapsular lymph node invasion or not. Based on this, we investigated 32 cases of extrahepatic bile duct cancer with lymph node metastasis and classified 21 cases as positive and 11 cases as negative. The extracapsular lymph node invasion cases were associated with poor disease-free survival and overall survival. The myofibroblast density of the metastatic foci was significantly higher in the extracapsular lymph node invasion cases. This is the first study to demonstrate that extracapsular lymph node invasion cases were associated with poor prognosis and that the myofibroblast distribution contributed to malignancy. PMID- 28912638 TI - Chronic Pain Assessments in Children and Adolescents: A Systematic Literature Review of the Selection, Administration, Interpretation, and Reporting of Unidimensional Pain Intensity Scales. AB - BACKGROUND: Advances in pain assessment approaches now indicate which measures should be used to capture chronic pain experiences in children and adolescents. However, there is little guidance on how these tools should best be administered and reported, such as which time frames to use or how pain scores are categorised as mild, moderate, or severe. OBJECTIVE: To synthesise current evidence on unidimensional, single-item pain intensity scale selection, administration, interpretation, and reporting. METHODS: Databases were searched (inception: 18 January 2016) for studies in which unidimensional pain intensity assessments were used with children and adolescents with chronic pain. Ten quality criteria were developed by modifying existing recommendations to evaluate the quality of administration of pain scales most commonly used with children. RESULTS: Forty six studies met the inclusion criteria. The highest score achieved was 7 out of a possible 10 (median: 5; IQR: 4-6). Usage of scales varied markedly in administrator/completer, highest anchors, number of successive assessments, and time referent periods used. CONCLUSIONS: Findings suggest these scales are selected, administered, and interpreted inconsistently, even in studies of the same type. Furthermore, methods of administration are rarely reported or justified making it impossible to compare findings across studies. This article concludes by recommending criteria for the future reporting of paediatric chronic pain assessments in studies. PMID- 28912640 TI - Spike Frequency Adaptation in Neurons of the Central Nervous System. AB - Neuronal firing patterns and frequencies determine the nature of encoded information of the neurons. Here we discuss the molecular identity and cellular mechanisms of spike-frequency adaptation in central nervous system (CNS) neurons. Calcium-activated potassium (KCa) channels such as BKCa and SKCa channels have long been known to be important mediators of spike adaptation via generation of a large afterhyperpolarization when neurons are hyper-activated. However, it has been shown that a strong hyperpolarization via these KCa channels would cease action potential generation rather than reducing the frequency of spike generation. In some types of neurons, the strong hyperpolarization is followed by oscillatory activity in these neurons. Recently, spike-frequency adaptation in thalamocortical (TC) and CA1 hippocampal neurons is shown to be mediated by the Ca2+-activated Cl- channel (CACC), anoctamin-2 (ANO2). Knockdown of ANO2 in these neurons results in significantly reduced spike-frequency adaptation accompanied by increased number of spikes without shifting the firing mode, which suggests that ANO2 mediates a genuine form of spike adaptation, finely tuning the frequency of spikes in these neurons. Based on the finding of a broad expression of this new class of CACC in the brain, it can be proposed that the ANO2-mediated spike-frequency adaptation may be a general mechanism to control information transmission in the CNS neurons. PMID- 28912639 TI - Comparison of the Perioperative and Postoperative Effects of Levobupivacaine and of Levobupivacaine + Adrenaline in Pediatric Tonsillectomy: A Double-Blind Randomized Study. AB - OBJECTIVES: We aimed to assess the effects of levobupivacaine and of levobupivacaine + adrenaline administered during pediatric tonsillectomy on the postoperative period. METHODS: A total of 90 patients between the ages of five and twelve were divided randomly into two groups before tonsillectomy: levobupivacaine only (0.5%) 0.4 mg.kg-1 or levobupivacaine (0.5%) 0.4 mg.kg-1 + adrenaline (1 : 200.000) administered by means of peritonsillar infiltration. Primary outcomes were postoperative pain scores recorded at various intervals until 24 hours postoperatively. Secondary outcomes included postoperative nausea and vomiting (PONV), time to first oral intake, time to the first administration of analgesics and total consumption of analgesics, and the amount of bleeding for all children. RESULTS: In both groups, patients had the same postoperative pain scores and PONV rates, and equal amounts of analgesics were consumed up to 24 hours postoperatively. The two groups also had the same time until first oral intake, recovery time and time to the first analgesic request, and amount of bleeding. CONCLUSIONS: Perioperative levobupivacaine infiltration on its own is a valid alternative to the combination of levobupivacaine + adrenaline for perioperative and postoperative effectiveness in pediatric tonsillectomy. This trial is registered with Australian New Zealand Clinical Trial Registry ACTRN: ACTRN12617001167358. PMID- 28912641 TI - Toll-like Receptor 2: A Novel Therapeutic Target for Ischemic White Matter Injury and Oligodendrocyte Death. AB - Despite paramount clinical significance of white matter stroke, there is a paucity of researches on the pathomechanism of ischemic white matter damage and accompanying oligodendrocyte (OL) death. Therefore, a large gap exists between clinical needs and laboratory researches in this disease entity. Recent works have started to elucidate cellular and molecular basis of white matter injury under ischemic stress. In this paper, we briefly introduce white matter stroke from a clinical point of view and review pathophysiology of ischemic white matter injury characterized by OL death and demyelination. We present a series of evidence that Toll-like receptor 2 (TLR2), one of the membranous pattern recognition receptors, plays a cell-autonomous protective role in ischemic OL death and ensuing demyelination. Moreover, we also discuss our recent findings that its endogenous ligand, high-mobility group box 1 (HMGB1), is released from dying OLs and exerts autocrine trophic effects on OLs and myelin sheath under ischemic condition. We propose that modulation of TLR2 and its endogenous ligand HMGB1 can be a novel therapeutic target for ischemic white matter disease. PMID- 28912643 TI - Decreased Glial GABA and Tonic Inhibition in Cerebellum of Mouse Model for Attention-Deficit/Hyperactivity Disorder (ADHD). AB - About 5~12% of school-aged children suffer from the Attention Deficit/Hyperactivity Disorder (ADHD). However, the core mechanism of ADHD remains unclear. G protein-coupled receptor kinase-interacting protein-1 (GIT1) has recently been reported to be associated with ADHD in human and the genetic deletion of GIT1 result in ADHD-like behaviors in mice. Mice lacking GIT1 shows a shift in neuronal excitation/inhibition (E/I) balance. However, the pricise mechanism for E/I imbalance and the role of neuron-glia interaction in GIT1 knockout (KO) mice have not been studied. Especially, a possible contribution of glial GABA and tonic inhibition mediated by astrocytic GABA release in the mouse model for ADHD remains unexplored. Therefore, we investigated the changes in the amount of GABA and degree of tonic inhibition in GIT1 KO mice. We observed a decreased glial GABA intensity in GIT1 KO mice compared to wild type (WT) mice and an attenuation of tonic current from cerebellar granule cells in GIT1 KO mice. Our study identifies the previously unknown mechanism of reduced astrocytic GABA and tonic inhibition in GIT1 lacking mice as a potential cause of hyperactivity disorder. PMID- 28912642 TI - NOX Inhibitors - A Promising Avenue for Ischemic Stroke. AB - NADPH-oxidase (NOX) mediated superoxide originally found on leukocytes, but now recognized in several types of cells in the brain. It has been shown to play an important role in the progression of stroke and related cerebrovascular disease. NOX is a multisubunit complex consisting of 2 membrane-associated and 4 cytosolic subunits. NOX activation occurs when cytosolic subunits translocate to the membrane, leading to transport electrons to oxygen, thus producing superoxide. Superoxide produced by NOX is thought to function in long-term potentiation and intercellular signaling, but excessive production is damaging and has been implicated to play an important role in the progression of ischemic brain. Thus, inhibition of NOX activity may prove to be a promising treatment for ischemic brain as well as an adjunctive agent to prevent its secondary complications. There is mounting evidence that NOX inhibition in the ischemic brain is neuroprotective, and targeting NOX in circulating immune cells will also improve outcome. This review will focus on therapeutic effects of NOX assembly inhibitors in brain ischemia and stroke. However, the lack of specificity and toxicities of existing inhibitors are clear hurdles that will need to be overcome before this class of compounds could be translated clinically. PMID- 28912644 TI - TLR5 Activation through NF-kappaB Is a Neuroprotective Mechanism of Postconditioning after Cerebral Ischemia in Mice. AB - Postconditioning has been shown to protect the mouse brain from ischemic injury. However, the neuroprotective mechanisms of postconditioning remain elusive. We have found that toll-like receptor 5 (TLR5) plays an integral role in postconditioning-induced neuroprotection through Akt/nuclear factor kappa B (NF kappaB) activation in cerebral ischemia. Compared to animals that received 30 min of transient middle cerebral artery occlusion (tMCAO) group, animals that also underwent postconditioning showed a significant reduction of up to 60.51% in infarct volume. Postconditioning increased phospho-Akt (p-Akt) levels and NF kappaB translocation to the nucleus as early as 1 h after tMCAO and oxygen glucose deprivation. Furthermore, inhibition of Akt by Akt inhibitor IV decreased NF-kappaB promoter activity after postconditioning. Immunoprecipitation showed that interactions between TLR5, MyD88, and p-Akt were increased from postconditioning both in vivo and in vitro. Similar to postconditioning, flagellin, an agonist of TLR5, increased NF-kappaB nuclear translocation and Akt phosphorylation. Our results suggest that postconditioning has neuroprotective effects by activating NF-kappaB and Akt survival pathways via TLR5 after cerebral ischemia. Additionally, the TLR5 agonist flagellin can simulate the neuroprotective mechanism of postconditioning in cerebral ischemia. PMID- 28912646 TI - Student Misbehavior in Physical Education: The Role of 2 * 2 Achievement Goals and Moral Disengagement. AB - This study aimed to determine whether goal orientations were related to students' self-reported misbehaviors in physical education and to examine whether the effects were mediated by moral disengagement. A two-study project employing structural equation modeling was conducted with high school students (Study 1, n = 287; Study 2, n = 296). In Study 1, the results showed that mastery-avoidance goals were unable to predict five misbehaviors (i.e., aggressive behavior, low engagement, failure to follow directions, poor self-management, and distracting behavior). Mastery-approach goals negatively predicted low engagement, failure to follow directions, and poor self-management. Performance-approach goals positively predicted aggressive and distracting behaviors, while performance avoidance goals positively predicted all five misbehaviors. In Study 2, the results indicated that the positive relationships between performance-approach goals and misbehaviors and between performance-avoidance goals and misbehaviors were mediated by moral disengagement. These results are discussed in terms of the model of achievement goals, and implications for physical education are also highlighted. PMID- 28912645 TI - Anti-inflammatory Effect of Glucagon Like Peptide-1 Receptor Agonist, Exendin-4, through Modulation of IB1/JIP1 Expression and JNK Signaling in Stroke. AB - Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which block inactivation of GLP-1, are currently in clinical use for type 2 diabetes mellitus. Recently, GLP-1 has also been reported to have neuroprotective effects in cases of cerebral ischemia. We therefore investigated the neuroprotective effects of GLP-1 receptor (GLP-1R) agonist, exendin-4 (ex-4), after cerebral ischemia-reperfusion injury. Transient middle cerebral artery occlusion (tMCAO) was induced in rats by intracerebroventricular (i.c.v.) administration of ex-4 or ex9-39. Oxygen-glucose deprivation was also induced in primary neurons, bEnd.3 cells, and BV-2. Ischemia reperfusion injury reduced expression of GLP-1R. Additionally, higher oxidative stress in SOD2 KO mice decreased expression of GLP-1R. Downregulation of GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4, which resulted in significant reduction of infarct volume. Levels of intracellular cyclic AMP, a second messenger of GLP-1R, were also increased by 2.7-fold as a result of high GLP-1R expression. Moreover, our results showed that ex-4 attenuated pro inflammatory cyclooxygenase-2 (COX-2) and prostaglandin E2 after MCAO. C-Jun NH2 terminal kinase (JNK) signaling, which stimulates activation of COX-2, was 36% inhibited by i.c.v. injection of ex-4 at 24 h. Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7-fold increased by ex-4. GLP-1R activation by ex-4 resulted in reduction of COX-2 through increasing IB1 expression, resulting in anti-inflammatory neuroprotection during stroke. Our study suggests that the anti inflammatory action of GLP-1 could be used as a new strategy for the treatment of neuroinflammation after stroke accompanied by hyperglycemia. PMID- 28912647 TI - Accelerometery and Heart Rate Responses of Professional Fast-Medium Bowlers in One-Day and Multi-Day Cricket. AB - The physical demands of fast-medium bowling are increasingly being recognised, yet comparative exploration of the differing demands between competitive formats (i.e. one-day [OD] versus multi-day [MD] matches) remain minimal. The aim of this study was to describe in-match physiological profiles of professional fast-medium bowlers from England across different versions of competitive matches using a multivariable wearable monitoring device. Seven professional cricket fast-medium bowlers wore the BioharnessTM monitoring device during matches, over three seasons (>80 hours in-match). Heart Rate (HR) and Acceleromety (ACC) was compared across match types (OD, MD) and different in-match activity states (Bowling, Between over bowling, Fielding). Peak acceleration during OD bowling was significantly higher in comparison to MD cricket ([OD vs. MD] 234.1 +/- 57.9 vs 226.6 +/- 32.9 ct.episode-1, p < 0.05, ES = 0.11-0.30). Data for ACC were also higher during OD than MD fielding activities (p < 0.01, ES = 0.11-.30). OD bowling stimulated higher mean HR responses (143 +/- 14 vs 137 +/- 16 beats.min 1, p < 0.05, ES = 0.21) when compared to MD matches. This increase in OD cricket was evident for both between over (129 +/- 9 vs 120 +/- 13 beats.min-1,p < 0.01, ES = 0.11-0.50) and during fielding (115 +/- 12 vs 106 +/- 12 beats.min-1, p < 0.01, ES = 0.36) activity. The increased HR and ACC evident in OD matches suggest greater acute physical loads than MD formats. Therefore, use of wearable technology and the findings provided give a valuable appreciation of the differences in match loads, and thus required physiological preparation and recovery in fast-medium bowlers. PMID- 28912648 TI - A Motivational Model of Physical Education and Links to Enjoyment, Knowledge, Performance, Total Physical Activity and Body Mass Index. AB - The present paper examined the full sequence of the Hierarchical Model of Motivation in physical education (PE) including motivational climate, basic psychological needs, intrinsic motivation, and related links to contextual enjoyment, knowledge, performance, and total moderate to vigorous physical activity (MVPA). Gender differences and correlations with body mass index (BMI) were also analyzed. Cross-sectional data was represented by self-reports and objective assessments of 770 middle school students (52% of girls) in North-East Finland. The results showed that task-involving climate in girls' PE classes was related to enjoyment and knowledge through physical competence and intrinsic motivation, whereas task-involving climate was associated with enjoyment and knowledge via competence and autonomy, and total MVPA via autonomy, intrinsic motivation, and knowledge within boys. This may indicate that girls and boys perceive PE classes in a different way. Graded PE assessments appeared to be essential in motivating both girls and boys to participate in greater total MVPA, whereas BMI was negatively linked with competence and social relatedness only among girls. Although, the current and previous empirical findings supported task involving teaching methods in PE, in some cases, ego-involving climate should be considered. Therefore, both task- and ego-involving teaching practices can be useful ways of developing preferred behaviors in PE classes. PMID- 28912649 TI - Does "Live High-Train Low (and High)" Hypoxic Training Alter Running Mechanics In Elite Team-sport Players? AB - This study aimed to investigate if "Live High-Train Low (and High)" hypoxic training alters constant-velocity running mechanics. While residing under normobaric hypoxia (>=14 h.d-1; FiO2 14.5-14.2%) for 14 days, twenty field hockey players performed, in addition to their usual training in normoxia, six sessions (4 * 5 * 5-s maximal sprints; 25 s passive recovery; 5 min rest) under either normobaric hypoxia (FiO2 ~14.5%, n = 9) or normoxia (FiO2 20.9%, n = 11). Before and immediately after the intervention, their running pattern was assessed at 10 and 15 km.h-1 as well as during six 30-s runs at ~20 km.h-1 with 30-s passive recovery on an instrumented motorised treadmill. No clear changes in running kinematics and spring-mass parameters occurred globally either at 10, 15 or ~20 km.h-1, with also no significant time * condition interaction for any parameters (p > 0.14). Independently of the condition, heart rate (all p < 0.05) and ratings of perceived exertion decreased post-intervention (only at 15 km.h-1, p < 0.05). Despite indirect signs for improved psycho-physiological responses, no forthright change in stride mechanical pattern occurred after "Live High-Train Low (and High)" hypoxic training. PMID- 28912650 TI - The Effects Combining Cryocompression Therapy following an Acute Bout of Resistance Exercise on Performance and Recovery. AB - Compression and cold therapy used separately have shown to reduce negative effects of tissue damage. The combining compression and cold therapy (cryocompression) as a single recovery modality has yet to be fully examined. To examine the effects of cryocompression on recovery following a bout of heavy resistance exercise, recreationally resistance trained men (n =16) were recruited, matched, and randomly assigned to either a cryocompression group (CRC) or control group (CON). Testing was performed before and then immediately after exercise, 60 minutes, 24 hours, and 48 hours after a heavy resistance exercise workout (barbell back squats for 4 sets of 6 reps at 80% 1RM, 90 sec rest between sets, stiff legged deadlifts for 4 sets of 8 reps at 1.0 X body mass with 60 sec rest between sets, 4 sets of 10 eccentric Nordic hamstring curls, 45 sec rest between sets). The CRC group used the CRC system for 20-mins of cryocompression treatment immediately after exercise, 24 hours, and 48 hours after exercise. CON sat quietly for 20-mins at the same time points. Muscle damage [creatine kinase], soreness (visual analog scale, 0-100), pain (McGill Pain Q, 0-5), fatigue, sleep quality, and jump power were significantly (p < 0.05) improved for CRC compared to CON at 24 and 48 hours after exercise. Pain was also significantly lower for CRC compared to CON at 60-mins post exercise. These findings show that cryocompression can enhance recovery and performance following a heavy resistance exercise workout. PMID- 28912652 TI - Objectively Measured Physical Activity Levels among Ethnic Minority Children Attending School-Based Afterschool Programs in a High-Poverty Neighborhood. AB - Ethnic minority children living in high poverty neighborhoods are at high risk of having insufficient physical activity (PA) during school days and, thus, the importance of school as a place to facilitate PA in these underserved children has been largely emphasized. This study examined the levels and patterns of PA in minority children, with particular focus on the relative contributions of regular physical education (PE) and school-based afterschool PA program in promoting moderate- and vigorous-intensity PA (MVPA) during school days. PA data were repeatedly measured using a Polar Active accelerometer across multiple school days (M = 5.3 days per child), from seventy-five ethnic minority children attending a Title I public elementary school in a high-poverty neighborhood in the US. The minutes and percentage of MVPA accumulated during school, PE, and afterschool PA program were compared to the current recommendations (>=30-min of MVPA during school hours; and >=50% of MVPA during PE or afterschool PA program) as well as by the demographic characteristics including sex, grade, ethnicity, and weight status using a general linear mixed model that accounts for repeated observations. On average, children spent 41.6 mins (SE = 1.8) of MVPA during school hours and of those, 14.1 mins (SE = 0.6) were contributed during PE. The average proportion of time spent in MVPA during PE was 31.3% (SE = 1.3), which was significantly lower than the recommendation (>=50% of MVPA), whereas 54.2% (SE = 1.2) of time in afterschool PA program were spent in MVPA. The percentage of monitoring days meeting current recommendations were 69.5% (SE = 0.03), 20.8% (SE = 0.02), and 59.6% (SE = 0.03) for during school, PE, and afterschool PA program, respectively. Our findings highlighted that school-based afterschool PA, in addition to regular PE classes, could be of great benefit to promote PA in minority children during school days. Further research and practice are still needed to increase MVPA during school hours, particularly during PE classes. PMID- 28912651 TI - Manual Resistance versus Conventional Resistance Training: Impact on Strength and Muscular Endurance in Recreationally Trained Men. AB - Manual resistance training (MRT) has been widely used in the field of physical therapy. It has also been used as a strength training method due to the accommodating resistance nature of this modality. The aim of the present study was to compare the effects of an 8-week MRT program on maximum strength and muscular endurance in comparison to conventional resistance training in recreationally trained men. Twenty healthy recreationally trained male subjects were recruited and divided into a MRT training group and a conventional training (CT) group. CT group performed bench press and lat pull-down exercises, and the MRT group performed similar movements with resistance provided by a personal trainer. Both groups completed similar training protocol and training load: 2 training sessions weekly for 3 sets of 8 repetitions at an intensity of 8 to 10 on the perceived exertion scale of 0-10. Initial maximum strength differences were not significant between the groups. Neither group showed significant changes in muscular strength or endurance. Despite the statistically non-significant pre- to post differences, a trend for improvement was observed and effect size (ES) calculations indicated greater magnitude of effects for strength and endurance changes in the MRT group in lat pulldown (g=0.84) compared to CT group. Effectiveness of MRT is similar to CT for improving muscular strength and endurance. MRT can be used as a supplemental or alternative strength training modality for recreationally trained subjects, or be considered by personal trainers especially in low equipped facility conditions. PMID- 28912653 TI - Validity of a Newly-Designed Rectilinear Stepping Ergometer Submaximal Exercise Test to Assess Cardiorespiratory Fitness. AB - The maximum oxygen uptake (VO2 max), determined from graded maximal or submaximal exercise tests, is used to classify the cardiorespiratory fitness level of individuals. The purpose of this study was to examine the validity and reliability of the YMCA submaximal exercise test protocol performed on a newly designed rectilinear stepping ergometer (RSE) that used up and down reciprocating vertical motion in place of conventional circular motion and giving precise measurement of workload, to determine VO2 max in young healthy male adults. Thirty-two young healthy male adults (32 males; age range: 20-35 years; height: 1.75 +/- 0.05 m; weight: 67.5 +/- 8.6 kg) firstly participated in a maximal effort graded exercise test using a cycle ergometer (CE) to directly obtain measured VO2 max. Subjects then completed the progressive multistage test on the RSE beginning at 50W and including additional stages of 70, 90, 110, 130, and 150W, and the RSE YMCA submaximal test consisting of a workload increase every 3 minutes until the termination criterion was reached. A metabolic equation was derived from the RSE multistage exercise test to predict oxygen consumption (VO2) from power output (W) during the submaximal exercise test (VO2 (mL.min-1 )=12.4 *W(watts)+3.5 mL.kg-1.min-1*M+160mL.min-1, R2= 0.91, standard error of the estimate (SEE) = 134.8mL.min-1). A high correlation was observed between the RSE YMCA estimated VO2 max and the CE measured VO2 max (r=0.87). The mean difference between estimated and measured VO2 max was 2.5 mL.kg-1.min-1, with an SEE of 3.55 mL.kg-1.min-1. The data suggest that the RSE YMCA submaximal exercise test is valid for predicting VO2 max in young healthy male adults. The findings show that the rectilinear stepping exercise is an effective submaximal exercise for predicting VO2 max. The newly-designed RSE may be potentially further developed as an alternative ergometer for assessing cardiorespiratory fitness and the promotion of personalized health interventions for health care professionals. PMID- 28912654 TI - Reduced Spanish Version of Participation Motives Questionnaire for Exercise and Sport: Psychometric Properties, Social/Sport Differences. AB - Understanding the motives that influence physical activity participation is important in order to orientate physical activity promotion and increase physical activity levels of practice of the population. Although many instruments been created and validated to measure motives to perform physical activity, one of the most frequently used scales during years is the Participation of Motives Questionnaire (PMQ) by Gill et al. (1983). Unfortunately, despite being so used and translated into many languages, there is no psychometric support for some factors about due to a low internal consistency. The purpose of this research was to present a reduced model of the Spanish version of the PMQ and to analyze the motives for sports participation. The Spanish version of PMQ was applied to participants of both sexes with ages between 12 and 60 years (M = 19.20; SD = 6.37). Factorial validity of the questionnaire was checked using exploratory and confirmatory analyses. Analysis of items and internal consistency of the factors were carried out. Reduced version measures seven dimensions (competition, status, teamwork, energy release, family/peers, skill development and health/fitness) with good values of validity and reliability (Cronbach's Alpha were between 0.713 and 0.879). Different reasons for exercise and sport by sociodemographic variables were found. For example, females practice for exercise and sports for competition and teamwork than males Elite athletes practice more exercise and sport also for teamwork, skills development and health/fitness than amateurs. Finally those who have more experience, practice more physical activity and sport for competition, status and health/fitness. PMID- 28912655 TI - Chronic Eccentric Exercise and Antioxidant Supplementation: Effects on Lipid Profile and Insulin Sensitivity. AB - Eccentric exercise has been shown to exert beneficial effects in both lipid profile and insulin sensitivity. Antioxidant supplementation during chronic exercise is controversial as it may prevent the physiological training-induced adaptations. The aim of this study was to investigate: 1) the minimum duration of the eccentric exercise training required before changes on metabolic parameters are observed and 2) whether antioxidant supplementation during training would interfere with these adaptations. Sixteen young healthy men were randomized into the Vit group (1 g of vitamin C and 400 IU vitamin E daily) and the placebo (PL) group. Subjects received the supplementation for 9 weeks. During weeks 5-9 all participants went through an eccentric exercise training protocol consisting of two exercise sessions (5 sets of 15 eccentric maximal voluntary contractions) per week. Plasma triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoproteins (Apo A1, Apo B and Lpa) and insulin sensitivity (HOMA) were assessed before the supplementation (week 0), at weeks 5, 6, 7, 8 and 9. TG, TC and LDL were significantly lower compared to pre supplementation at both weeks 8 and 9 (P<0.05) in both groups. HDL was significantly elevated after 4 weeks of training (p < 0.005) in both groups. There was no effect of the antioxidant supplementation in any of the variables. There was no effect of either the training or the supplementation protocol in apolipoproteins levels and insulin sensitivity. A minimum duration of 3 weeks of eccentric exercise training is required before beneficial effects in lipid profile can be observed in healthy young men. Concomitant antioxidant supplementation does not interfere with the training-induced adaptations. PMID- 28912656 TI - Do Maximal Roller Skiing Speed and Double Poling Performance Predict Youth Cross Country Skiing Performance? AB - The aims of the current study were to analyze whether specific roller skiing tests and cycle length are determinants of youth cross-country (XC) skiing performance, and to evaluate sex specific differences by applying non-invasive diagnostics. Forty-nine young XC skiers (33 boys; 13.8 +/- 0.6 yrs and 16 girls; 13.4 +/- 0.9 yrs) performed roller skiing tests consisting of both shorter (50 m) and longer durations (575 m). Test results were correlated with on snow XC skiing performance (PXC) based on 3 skating and 3 classical distance competitions (3 to 6 km). The main findings of the current study were: 1) Anthropometrics and maturity status were related to boys', but not to girls' PXC; 2) Significant moderate to acceptable correlations between girls' and boys' short duration maximal roller skiing speed (double poling, V2 skating, leg skating) and PXC were found; 3) Boys' PXC was best predicted by double poling test performance on flat and uphill, while girls' performance was mainly predicted by uphill double poling test performance; 4) When controlling for maturity offset, boys' PXC was still highly associated with the roller skiing tests. The use of simple non-invasive roller skiing tests for determination of PXC represents practicable support for ski clubs, schools or skiing federations in the guidance and evaluation of young talent. PMID- 28912657 TI - Moderate Intensity Cycling Exercise after Upper Extremity Resistance Training Interferes Response to Muscle Hypertrophy but Not Strength Gains. AB - The purpose of the present study was to examine the effect of 30-min moderate intensity cycling exercise immediately after upper-body resistance training on the muscle hypertrophy and strength gain. Fourteen subjects were randomly divided between two groups. One group performed moderate intensity (55% of maximum oxygen consumption [VO2max], 30 min) cycle training immediately after arm resistance training as concurrent training (CT; n = 7, age: 21.8 +/- 0.7 years, height: 1.68 +/- 0.06 m, weight: 60.3 +/- 7.4 kg); the second group performed the same endurance and arm RT on separate days as control group (SEP; n=7, age: 22.1 +/- 0.7 years, height: 1.76 +/- 0.05 m, weight: 63.8 +/- 3.6 kg). The supervised progressive RT program was designed to induce muscular hypertrophy (3-5 sets of 10 repetitions) with bilateral arm-curl exercise using 75% of the one repetition maximum (1RM) with 2-min rest intervals. The RT program was performed for 8 weeks, twice per week. Muscle cross-sectional area (CSA), 1RM, and VO2max were measured pre- and post-training. Significant increases in muscle CSA from pre- to post-training were observed in both the SEP (p = 0.001, effect size [ES] = 0.84) and the CT groups (p = 0.004, ES = 0.45). A significant increase in 1RM from pre- to post-training was observed in the SEP (p = 0.025, ES = 0.91) and CT groups (p = 0.001, ES = 2.38). There were no interaction effects (time * group) for CSA, 1RM, or VO2max. A significantly higher percentage change of CSA was observed in the SEP group (12.1 +/- 4.9%) compared to the CT group (5.0 +/- 2.7%, p = 0.029), but no significant difference was observed in the 1RM (SEP: 19.8 +/- 16.8%, CT: 24.3 +/- 11.1%). The data suggest that significant improvement of CSA and strength can be expected with progressive resistance training with subsequent endurance exercise performed immediately or on a different day. Changes in CSA might be affected by subsequent cycling exercise after 8 weeks of training. PMID- 28912658 TI - A Systematic Method to Detect the Metabolic Threshold from Gas Exchange during Incremental Exercise. AB - Incremental exercise consists of three domains of exercise intensity demarcated by two thresholds. The first of these thresholds, derived from gas exchange measurements, is defined as the metabolic threshold (VO2theta) above which lactate accumulates. Correctly and reliably identified, VO2theta is a non invasive, sub-maximal marker of aerobic function with practical value. This investigation compared variability in selection of VO2theta among interpreters with different levels of experience as well as from auto-detection algorithms employed by a commercially available metabolic cart (MC). Ten healthy young men performed three replicates of incremental cycle exercise during which gas exchange measurements were collected breath-by-breath. Two experienced interpreters (E) and four novice interpreters (N) determined VO2theta from plots of specific response variables. Interpreters noted methods used and confidence in their selections. VO2theta was automatically determined by the MC. Interclass correlations indicated that E agreed with each other (mean difference, 21 mL.min 1) and with the MC (23 mL.min-1), but not with N (-664 to 364 mL.min-1); N did not agree among themselves. Despite good overall agreement between E and MC, differences >500 mL.min-1 were seen in 50% of individual cases. N expressed unduly higher confidence and used different VO2theta selection strategies compared with E. Experience and use of a systematic approach is essential for correctly identifying VO2theta. Current guidelines for exercise testing and interpretation do not include recommendations for such an approach. Data from this study suggests that this may be a serious shortcoming. Until an alternative schema for VO2theta detection is developed prospectively, strategies based on the present study will give practitioners a systematic and consistent approach to threshold detection. PMID- 28912659 TI - Power-Time Curve Comparison between Weightlifting Derivatives. AB - This study examined the power production differences between weightlifting derivatives through a comparison of power-time (P-t) curves. Thirteen resistance trained males performed hang power clean (HPC), jump shrug (JS), and hang high pull (HHP) repetitions at relative loads of 30%, 45%, 65%, and 80% of their one repetition maximum (1RM) HPC. Relative peak power (PPRel), work (WRel), and P-t curves were compared. The JS produced greater PPRel than the HPC (p < 0.001, d = 2.53) and the HHP (p < 0.001, d = 2.14). In addition, the HHP PPRel was statistically greater than the HPC (p = 0.008, d = 0.80). Similarly, the JS produced greater WRel compared to the HPC (p < 0.001, d = 1.89) and HHP (p < 0.001, d = 1.42). Furthermore, HHP WRel was statistically greater than the HPC (p = 0.003, d = 0.73). The P-t profiles of each exercise were similar during the first 80-85% of the movement; however, during the final 15-20% of the movement the P-t profile of the JS was found to be greater than the HPC and HHP. The JS produced greater PPRel and WRel compared to the HPC and HHP with large effect size differences. The HHP produced greater PPRel and WRel than the HPC with moderate effect size differences. The JS and HHP produced markedly different P-t profiles in the final 15-20% of the movement compared to the HPC. Thus, these exercises may be superior methods of training to enhance PPRel. The greatest differences in PPRel between the JS and HHP and the HPC occurred at lighter loads, suggesting that loads of 30-45% 1RM HPC may provide the best training stimulus when using the JS and HHP. In contrast, loads ranging 65-80% 1RM HPC may provide an optimal stimulus for power production during the HPC. PMID- 28912660 TI - Effects of Whole Body Vibration on the Neuromuscular Amplitude of Vastus Lateralis Muscle. AB - The aim of this study was to investigate the effects of whole-body vibration (WBV) on vastus lateralis (VL) surface electromyographic (sEMG) amplitude during an isometric semi-squat exercise, using two different frequencies, and to verify the influence of additional filters on the analyzed sEMG signal's characteristics. Forty physically active women were randomly divided into two groups with 20 members each: one group performed an isometric semi-squat exercise at 30 Hz - while the other group performed the same exercise protocol at 50 Hz. The sEMG amplitude of the VL muscle was recorded during the exercise protocols in two conditions: with and without vibration. After removing vibration-induced artifacts using digital filters, sEMG amplitude of VL increased significantly (p < 0.05) without differences between the frequencies. The results of this study suggest that WBV at 30 Hz and 50 Hz increased the sEMG amplitude of the VL muscle during an isometric semi-squat exercise. Furthermore, applying sEMG filters during signal processing of WBV is necessary, because motion artifacts from the vibration frequencies may contribute to the contamination of the sEMG amplitude. PMID- 28912661 TI - Effectiveness of Movement Therapy Interventions and Training Modifications for Preventing Running Injuries: A Meta-Analysis of Randomized Controlled Trials. AB - Runners are at relatively high risk for sustaining an overuse injury. While many risk factors have been documented so far, previous reviews have mostly failed to identify effective interventions to lower injury risk in runners. To review the high-quality evidence on two types of preventive interventions - movement therapy interventions and training-modification interventions, regarding running-related injury prevention. Pubmed (MEDLINE), PEDro and Cochrane Central Register of Controlled Trials databases were searched in April 2017, with no date or language restrictions, using following search terms: running injury prevention, running injury therapy, running injury incidence, running injury exercise and running injury risk. Studies were included if they were a randomized controlled trial or prospective cohort study, investigated the effects of movement therapy or training modification interventions, contained a population of runners or other populations, involved in running (e.g. military recruits), and reported lower extremity injury incidence rates specific to running. In total, 4935 citations were identified, 69 of which were retrieved for full-text evaluation. Seven articles met the inclusion criteria and were included in meta-analysis. Two separate meta-analyses were carried out for both intervention types. First meta analysis showed no preventive effects of movement therapy interventions, with an overall risk ratio of 0.98 (p = 0.81, I2 = 42 %). The second meta-analysis showed no overall preventive effect of training modifications, with an overall risk ratio of 0.78 (p = 0.35, I2 = 79%). No evidence was found to support the preventive effects of movement therapy or training modification. This may primarily be due to non-optimal intervention designs, such as using inappropriate placebo exercises. Preventive programs may also be more effective when carried out prior to running program onset. PMID- 28912663 TI - Performance Enhancement by Brain Stimulation. PMID- 28912662 TI - Long Term Changes in Muscles around the Knee Joint after ACL Resection in Rats: Comparisons of ACL-Resected, Contralateral and Normal Limb. AB - The purpose of this study was to investigate the long-term effects of anterior cruciate ligament (ACL) resection on the morphological and contractile characteristics of rectus femoris (RF) and semimembranosus (SM) muscles in both injured and contralateral hindlimbs in rats. Wistar male rats (8-week old) were used. Rats were divided into two groups; ACL-resected and (sham-operated) control groups. Furthermore, right and left limbs of rats in the ACL-resected group were assigned as ACL-resected and contralateral groups, respectively, at 1 day, 1, 4, and 48 weeks after ACL resection. No ACL-resection-associated changes in the mass of both muscles were observed 1 week after ACL resection. On the other hand, ACL resection-associated reduction on mean fiber cross-sectional area (fiber CSA) in RF muscle lasted 48 weeks after ACL resection. Furthermore, ACL-resection associated increase in fiber composition of type I fiber in RF muscle in contralateral limbs. In addition, long-term effects of ACL resection were observed in both ACL-resected and contralateral limbs. Evidences from this study suggested that ACL resection may cause to change in the morphological (fiber CSA) and contractile (distribution of fiber types) properties of skeletal muscles around the knee joint in not only injured but also contralateral limb. Rehabilitation for quantitative and qualitative muscle changes by ACL resection may be required a special care for a long-term period. PMID- 28912664 TI - Modified Tuck Jump Assessment: Reliability and Training of Raters. PMID- 28912665 TI - Multimodal Approach of Pulmonary Artery Intimal Sarcoma: A Single-Institution Experience. AB - INTRODUCTION: Pulmonary artery sarcoma (PAS) is a rare tumor, whose therapeutic approach is mainly based on surgery, either pneumonectomy or pulmonary endarterectomy (PEA). The prognosis reported in published series is very poor, with survival of 1.5 months without any kind of treatment. PATIENTS AND METHODS: From January 2010 to January 2016, 1027 patients were referred to our hospital for symptoms of acute or chronic pulmonary thromboembolic disease. Twelve patients having a confirmed diagnosis of PAS underwent PEA. Median age was 64.5 years. Most patients had a long history of symptoms, having a median time of 7.5 months from onset of symptoms to surgery. RESULTS: Following PEA and cardiopulmonary rehabilitation, 10 patients received conventional chemotherapy with doxorubicin and ifosfamide, starting at a median of 42 days from surgery. Four patients also received radiotherapy. Four patients have died due to disease progression, while 7 are still alive, with 5 being disease-free at 4-55+ months from diagnosis. CONCLUSIONS: In patients with PAS, a multimodal approach including PEA, CT, and RT is feasible but it should be evaluated individually, according to the tumor extension and the patient's clinical condition. Apart from improving quality of life mainly by reducing or delaying symptoms due to PH, it may improve life expectancy. PMID- 28912666 TI - Prevalence of low back pain in Iranian nurses: a systematic review and meta analysis. AB - BACKGROUND: Low back pain (LBP) as a musculoskeletal disorder is one of the most common occupational injuries in nurses but there isn't any valid measure of the prevalence of LBP in Iranian nursing. In order to increase the power and improve the estimates of the prevalence of LBP in Iranian nurses, a comprehensive meta analysis was carried out. A summary measure of all studies conducted in this field was found and distributions of LBP were evaluated based on different variables. METHODS: Inclusion criteria included articles with prevalence of LBP in Iranian nurses, who had at least six months of work experience without any trauma, injuries to spine, or any underlying disease. The keywords"prevalence, low back pain, nurses", and "Iran" were used as part of this search. Databases such as Pubmed, Web of Science, Science direct, Scopus, IranMedex, Irandoc, Magiran, SID, CIVILICA, IMEMR and Google scholar were searched up to and including 15 June 2016. For data extraction a form was designed that included the following variables: Author names, province, sample size, age, gender, marital status, work experience, body mass index, job type, smoking status, work schedule, year of publication, type of standard questionnaire, prevalence of LBP, studies' quality score and climate classifications. Data analysis was carried out using fixed and random effects model. Heterogeneity between studies was assessed by using the I2 and Q tests. RESULTS: In all 1250 articles were identified and 22 articles with 9347 participants met the inclusion criteria for meta-analyses after filtering. The prevalence of low back pain during their working life and during the last year, was estimated at 63% (95% Confidence Interval (CI): 57.4 68.5) and 61.2% (95% CI: 55.7-66.7) respectively. The prevalence rate of this disorder was 58.7% (95% CI: 35.8-81.7) and 60.4% (95% CI: 52.2-68.6) among men and women respectively. Furthermore, prevalence's of LBP were 59.5% in wards nurses, 50.3% in operating room technicians, and 39.4% in aid nurses. CONCLUSIONS: The results showed the high prevalence of LBP injury in nurses, especially female nurses. The effect of musculoskeletal disorders such as LBP may be reduced by considering proper observation of the principles of ergonomics in the workplace, performing physical examinations on a regular basis, identifying risk factors in the advancement of musculoskeletal disorders and then trying to fix them. PMID- 28912667 TI - How do nurse consultant job characteristics impact on job satisfaction? An Australian quantitative study. AB - BACKGROUND: There is a direct link between job satisfaction, nurses' job performance and improved patient outcomes. Understanding what job characteristics influence job satisfaction is vital if health organizations are to optimize individual employee satisfaction and performance. This is particularly necessary in the Nurse Consultant role, which is a multifaceted role that has evolved to meet the dynamic and changing needs of health services. This study aims to examine how job characteristics influence Nurse Consultant job satisfaction and identify differences across metropolitan and rural contexts. METHODS: This paper presents quantitative findings that are part of a larger prospective cross sectional mixed method study. An online survey consisting of a variety of job characteristic factors was administered to all NCs working in a large Local Health District in New South Wales, Australia over an 8-week period in 2010. Descriptive analysis identified NC's perceptions of job satisfaction and job characteristics in their current role and factor and regression analysis identified relationships between these factors. RESULTS: Job satisfaction was identified as high (mean 4.3) and is strongly correlated with job autonomy, role clarity, role conflict and job support. A high level of role clarity has a moderating effect on the relationship between job autonomy and job satisfaction. CONCLUSIONS: Study findings inform how we prepare nurses for the NC role and how managers engage with and support NCs in their role taking into account context. Understanding the factors that influence job satisfaction and role effectiveness gives managers valuable information to assist in positioning and supporting these roles to maximize effectiveness across integrated and contemporary models of health care delivery. PMID- 28912668 TI - The prognostic values of the expression of Vimentin, TP53, and Podoplanin in patients with cervical cancer. AB - PURPOSE: Epithelial-mesenchymal transition (EMT), TP53, and Podoplanin have been implicated in the tumorigenesis and metastasis of human cancers. Nevertheless, the clinical significance of these markers in cancer patients is still not clear. In this study, we sought to determine the prognostic values of Vimentin, TP53, and Podoplanin in patients with cervical cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were performed to determine the messenger RNA and protein expression levels of Vimentin, TP53, and Podoplanin, respectively, in cervical squamous cell carcinoma and adjacent normal cervical tissues. Additionally, the expression levels of Podoplanin were also measured in 130 cervical cancer patients (FIGO stages Ib1-IIa2) using immunohistochemistry (IHC) staining. RESULTS: The mRNA expression levels of Vimentin, TP53, and Podoplanin were considerably elevated in cervical cancer tissues, compared with those in the adjacent normal cervical tissues. Additionally, the protein expression levels of Vimentin were closely correlated with the age of onset (P = 0.007), lymph node metastasis (P = 0.007), lymphatic invasion (P = 0.024), disease recurrence (P < 0.001), and the clinical prognosis of patients with cervical cancer (P < 0.001). Our multivariate analysis also suggests that Vimentin is an independent marker for survival in cervical cancer patients. Furthermore, the expression levels of Vimentin are negatively correlated with the proliferation marker Ki67 expression. CONCLUSIONS: Our data show that Vimentin can serve as an independent prognostic marker for cervical cancer patients with primary surgery. Registration number ChiCTR-TRC-06000236 Registered 15 December 2006. PMID- 28912669 TI - Identification of novel mutations in congenital afibrinogenemia patients and molecular modeling of missense mutations in Pakistani population. AB - BACKGROUND: Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder that was first described in 1920. It is transmitted as an autosomal recessive trait that is characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in a higher number of cases of congenital fibrinogen deficiency in their respective populations. This study focused on the detection of mutations in fibrinogen genes using DNA sequencing and molecular modeling of missense mutations in all three genes [Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG)] in Pakistani patients. METHODS: This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency were screened for mutations in the Fibrinogen alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this study. RESULTS: Ten patients had mutations in FGA followed by three mutations in FGB and three mutations in FGG, respectively. Twelve of these mutations were novel. The missense mutations were predicted to result in a loss of stability because they break ordered regions and cause clashes in the hydrophobic core of the protein. CONCLUSIONS: Congenital afibrinogenemia is a rapidly growing problem in regions where consanguinity is frequently practiced. This study illustrates that mutations in FGA are relatively more common in Pakistani patients and molecular modeling of the missense mutations has shown damaging protein structures which has profounding effect on phenotypic bleeding manifestations in these patients. PMID- 28912670 TI - The Role of Real Time Endoscopic Ultrasound Guided Elastography for Targeting EUS FNA of Suspicious Pancreatic Masses: A Review of the Literature and A Single Center Experience. AB - BACKGROUND: Endoscopic ultrasound guided elastography is an imaging modality that can be used to evaluate tissue stiffness and to assess solid pancreatic lesions. It can also assist in optimizing the diagnostic yield of endoscopic ultrasound guided fine needle aspiration biopsies. AIMS: To review the literature on solid pancreatic lesions, the use of EUS guided fine needle aspiration and endoscopic ultrasound guided elastography and to present a single center experience using elastography to direct fine needle aspiration biopsies of solid pancreatic lesions. METHODS: We present a review of the literature and a single center experience describing the use of EUS guided elastography in directing fine needle aspiration biopsies of solid pancreatic lesions. RESULTS: Thirteen male veterans with an average age of 62.3 (SD+/-11.8) years were enrolled in the study. The mean pancreatic mass size on EUS was 5.1*5.2 (SD+/-4.4*4.5) cm. A total of 13 lesions were identified during elastography. The lesions were most commonly found in the body (n=5), followed by multifocal lesions (n=4), pancreatic head (n=3) and tail (n=1). The seven concerning pancreatic lesions were stratified based on color pattern identified on EUS and EUS-elastography. Three lesions were homogenously blue, and four lesions were heterogeneously blue. The remaining six lesions which were less concerning were predominantly green. Of the three lesions, that were homogenously blue, two were diagnosed as adenocarcinoma (n=2) and chronic pancreatitis (n=1) respectively. Of the four heterogeneously blue lesions two were adenocarcinomas, while the other two represented a large B-cell lymphoma and chronic pancreatitis. Patients whose lesions were characterized as homogenous or heterogeneous green were benign and remained disease free after a median of two years of regular follow up. LIMITATIONS: Relatively small number of patients studied. CONCLUSIONS: In our single center experience we found that the use of real time endoscopic ultrasound guided elastography for targeting fine needle aspiration of suspicious pancreatic lesions may be beneficial as an adjunct modality to complement conventional EUS. Larger prospective studies need to be conducted to evaluate the utility of this modality in targeting pancreatic lesions. PMID- 28912671 TI - Brownian Optogenetic-Noise-Photostimulation on the Brain Amplifies Somatosensory Evoked Field Potentials. AB - Stochastic resonance (SR) is an inherent and counter-intuitive mechanism of signal-to-noise ratio (SNR) facilitation in biological systems associated with the application of an intermediate level of noise. As a first step to investigate in detail this phenomenon in the somatosensory system, here we examined whether the direct application of noisy light on pyramidal neurons from the mouse-barrel cortex expressing a light-gated channel channelrhodopsin-2 (ChR2) can produce facilitation in somatosensory evoked field potentials. Using anesthetized Thy1 ChR2-YFP transgenic mice, and a new neural technology, that we called Brownian optogenetic-noise-photostimulation (BONP), we provide evidence for how BONP directly applied on the barrel cortex modulates the SNR in the amplitude of whisker-evoked field potentials (whisker-EFP). In all transgenic mice, we found that the SNR in the amplitude of whisker-EFP (at 30% of the maximal whisker-EFP) exhibited an inverted U-like shape as a function of the BONP level. As a control, we also applied the same experimental paradigm, but in wild-type mice, as expected, we did not find any facilitation effects. Our results show that the application of an intermediate intensity of BONP on the barrel cortex of ChR2 transgenic mice amplifies the SNR of somatosensory whisker-EFPs. This result may be relevant to explain the improvements found in sensory detection in humans produced by the application of transcranial-random-noise-stimulation (tRNS) on the scalp. PMID- 28912672 TI - Maximizing the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective. AB - Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilize scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape [Alzheimer's, Parkinson's, frontotemporal degeneration, amyotrophic lateral sclerosis (ALS), Lewy-body and vascular dementia] were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online. PMID- 28912673 TI - Improving the Delivery of SOD1 Antisense Oligonucleotides to Motor Neurons Using Calcium Phosphate-Lipid Nanoparticles. AB - Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting the upper and lower motor neurons in the motor cortex and spinal cord. Abnormal accumulation of mutant superoxide dismutase I (SOD1) in motor neurons is a pathological hallmark of some forms of the disease. We have shown that the orderly progression of the disease may be explained by misfolded SOD1 cell-to cell propagation, which is reliant upon its active endogenous synthesis. Reducing the levels of SOD1 is therefore a promising therapeutic approach. Antisense oligonucleotides (ASOs) can efficiently silence proteins with gain-of-function mutations. However, naked ASOs have a short circulation half-life and are unable to cross the blood brain barrier (BBB) warranting the use of a drug carrier for effective delivery. In this study, calcium phosphate lipid coated nanoparticles (CaP-lipid NPs) were developed for delivery of SOD1 ASO to motor neurons. The most promising nanoparticle formulation (Ca/P ratio of 100:1), had a uniform spherical core-shell morphology with an average size of 30 nm, and surface charge (zeta-potential) of -4.86 mV. The encapsulation efficiency of ASO was 48% and stability studies found the particle to be stable over a period of 20 days. In vitro experiments demonstrated that the negatively charged ASO-loaded CaP-lipid NPs could effectively deliver SOD1-targeted ASO into a mouse motor neuron-like cell line (NSC-34) through endocytosis and significantly down-regulated SOD1 expression in HEK293 cells. The CaP-lipid NPs exhibited a pH-dependant dissociation, suggesting that that the acidification of lysosomes is the likely mechanism responsible for facilitating intracellular ASO release. To demonstrate tissue specific delivery and localization of these NPs we performed in vivo microinjections into zebrafish. Successful delivery of these NPs was confirmed for the zebrafish brain, the blood stream, and the spinal cord. These results suggest that CaP-lipid NPs could be an effective and safe delivery system for the improved delivery of SOD1 ASOs to motor neurons. Further in vivo evaluation in transgenic mouse models of SOD1 ALS are therefore warranted. PMID- 28912674 TI - A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system (PNS) that drastically alter quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness of distal extremities, and/or oversensitivity to thermal or mechanical stimuli. This adverse side effect often requires a reduction in chemotherapy dosage or even discontinuation of treatment. Currently there are no effective treatment options for CIPN. While the underlying mechanisms for CIPN are not understood, current data identify a "dying back" axon degeneration of distal nerve endings as the major pathology in this disorder. Therefore, mechanistic understanding of axon degeneration will provide insights into the pathway and molecular players responsible for CIPN. Here, we review recent findings that expand our understanding of the pathogenesis of CIPN and discuss pathways that may be shared with the axonal degeneration that occurs during developmental axon pruning and during injury-induced Wallerian degeneration. These mechanistic insights provide new avenues for development of therapies to prevent or treat CIPN. PMID- 28912675 TI - Deceptive but Not Honest Manipulative Actions Are Associated with Increased Interaction between Middle and Inferior Frontal gyri. AB - The prefrontal cortex is believed to be responsible for execution of deceptive behavior and its involvement is associated with greater cognitive efforts. It is also generally assumed that deception is associated with the inhibition of default honest actions. However, the precise neurophysiological mechanisms underlying this process remain largely unknown. The present study was aimed to use functional magnetic resonance imaging to reveal the underlying functional integration within the prefrontal cortex during the task which requires that subjects to deliberately mislead an opponent through the sequential execution of deceptive and honest claims. To address this issue, we performed psychophysiological interaction (PPI) analysis, which allows for statistical assessment of changes in functional relationships between active brain areas in changing psychological contexts. As a result the whole brain PPI-analysis established that both manipulative honest and deceptive claiming were associated with an increase in connectivity between the left middle frontal gyrus and right temporo-parietal junction (rTPJ). Taking into account the role played by rTPJ in processes associated with the theory of mind the revealed data can reflect possible influence of socio-cognitive context on the process of selecting manipulative claiming regardless their honest or deceptive nature. Direct comparison between deceptive and honest claims revealed pattern enhancement of coupling between the left middle frontal gyrus and the left inferior frontal gyrus. This finding provided evidence that the execution of deception relies to a greater extent on higher-order hierarchically-organized brain mechanisms of executive control required to select between two competing deceptive or honest task sets. PMID- 28912676 TI - Chemical Exchange Saturation Transfer MRI Signal Loss of the Substantia Nigra as an Imaging Biomarker to Evaluate the Diagnosis and Severity of Parkinson's Disease. AB - The early diagnosis of Parkinson's disease (PD) and the accurate evaluation of disease severity are crucial for intervention and treatment in PD patients. In this study, we applied chemical exchange saturation transfer (CEST) imaging to patients at different stages of PD and explored the clinical value of the CEST signal loss of the substantia nigra as an imaging biomarker of PD. The measured CEST signal intensities (including amide proton transfer-weighted or APTw, and total CEST or CESTtotal) of the substantia nigra in PD patients showed a significantly decreased tendency with PD progression. Compared to normal controls, the APTw and CEST total intensities of PD patients significantly decreased at both the early and advanced or late stages. These APTw and CESTtotal values of the substantia nigra were also significantly lower in advanced or late stage PD patients than in early stage PD patients. For PD patients with unilateral symptoms, the APTw and CESTtotal values in the substantia nigra on the affected side were significantly lower than those in normal controls. Both the APTw and CESTtotal values of PD were significantly correlated with the severity of disease and disease duration. Our findings suggest that the CEST MRI signal of the substantia nigra is a potential imaging biomarker for the diagnosis and monitoring of the severity of PD. PMID- 28912677 TI - Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice. AB - Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration. PMID- 28912678 TI - IL-17A Enhances Microglial Response to OGD by Regulating p53 and PI3K/Akt Pathways with Involvement of ROS/HMGB1. AB - Cerebral ischemia-reperfusion injury (IRI) has a complex pathogenesis, and interleukin-17 (IL-17) is a newly identified class of the cytokine family that plays an important role in ischemic inflammation. An oxygen-glucose deprivation (OGD) model showed that IL-17A expression was significantly up-regulated in microglial cells. After IL-17A siRNA transfection, the inhibition of proliferation, and the increased apoptosis in microglial cells, induced by OGD/reperfusion, was improved, and the elevation of Caspase-3, Caspase-8, Caspase 9, and poly ADP ribose polymerase (PARP) activities was inhibited. Mass spectrometry demonstrated that IL-17A functioned through a series of factors associated with oxidative stress and apoptosis and regulated Caspase-3 activity and apoptosis in microglial cells via the p53 and PI3K/Akt signaling pathways. IL 17A, HMGB1, and ROS were regulated mutually to exhibit a synergistic effect in the OGD model of microglial cells, but the down-regulation of IL-17A or HMGB1 expression did not completely inhibit the production of ROS. These findings demonstrated that ROS might be located upstream of IL-17A and HMGB1 so that ROS can regulate HMGB1/IL-17A expression to affect the p53 and PI3K/Akt signaling pathways and therefore promote the occurrence of apoptosis in microglial cells. These findings provide a novel evidence for the role of IL-17A in ischemic cerebral diseases. PMID- 28912679 TI - Proteomic Differences in Blood Plasma Associated with Antidepressant Treatment Response. AB - The current inability of clinical psychiatry to objectively select the most appropriate treatment is a major factor contributing to the severity and clinical burden of major depressive disorder (MDD). Here, we have attempted to identify plasma protein signatures in 39 MDD patients to predict response over a 6-week treatment period with antidepressants. LC-MS/MS analysis showed that differences in the levels of 29 proteins at baseline were found in the group with a favorable treatment outcome. Most of these proteins were components of metabolism or immune response pathways as well as multiple components of the coagulation cascade. After 6 weeks of treatment, 43 proteins were altered in responders of which 2 (alpha-actinin and nardilysin) had been identified at baseline. In addition, 46 proteins were altered in non-responders and 9 of these (alpha-actinin, alpha-2 macroglobulin, apolipoprotein B-100, attractin, C-reactive protein, fibrinogen alpha chain, fibrinogen beta chain, nardilysin and serine/threonine-protein kinase Chk1) had been identified at baseline. However, it should be stressed that the small sample size precludes generalization of the main results. Further studies to validate these as potential biomarkers of antidepressant treatment response are warranted considering the potential importance to the field of psychiatric disorders. This study provides the groundwork for development of novel objective clinical tests that can help psychiatrists in the clinical management of MDD through improved prediction and monitoring of patient responses to antidepressant treatments. PMID- 28912680 TI - Fyn Signaling Is Compartmentalized to Dopamine D1 Receptor Expressing Neurons in the Dorsal Medial Striatum. AB - The tyrosine kinase Fyn plays an important role in synaptic plasticity, learning, and memory. Here we report that Fyn is activated in response to 15 min D1 receptor (D1R) but not D2 receptor (D2R) stimulation specifically in the dorsomedial striatum (DMS) of mice but not in the other substriatal regions, the dorsolateral striatum (DLS), and the nucleus accumbens (NAc). Once activated Fyn phosphorylates its substrate GluN2B, and we show that GluN2B is phosphorylated only in the DMS but not in the other striatal regions. Striatal neurons are divided into D1R expressing medium spiny neurons (MSNs) and D2R expressing MSNs. Thus, to explore the cell-type specificity of this signaling pathway in the DMS, we developed a Cre-dependent Flip Excision (FLEX) approach to knockdown Fyn in D1R MSNs or D2R MSNs, and proved that the D1R-dependent Fyn activation is localized to DMS D1R MSNs. Importantly, we provide evidence to suggest that the differential association of Fyn and GluN2B with the scaffolding RACK1 is due to the differential localization of Fyn in lipid rafts.Our data further suggest that the differential cholesterol content in the three striatal regions may determine the region specificity of this signaling pathway. Together, our data show that the D1R-dependent Fyn/GluN2B pathway is selectively activated in D1R expressing MSNs in the DMS, and that the brain region specificity of pathway depends on the molecular and cellular compartmentalization of Fyn and GluN2B. PMID- 28912681 TI - Divergence in Morris Water Maze-Based Cognitive Performance under Chronic Stress Is Associated with the Hippocampal Whole Transcriptomic Modification in Mice. AB - Individual susceptibility determines the magnitude of stress effects on cognitive function. The hippocampus, a brain region of memory consolidation, is vulnerable to stressful environments, and the impact of stress on hippocampus may determine individual variability in cognitive performance. Therefore, the purpose of this study was to define the relationship between the divergence in spatial memory performance under chronically unpredictable stress and an associated transcriptomic alternation in hippocampus, the brain region of spatial memory consolidation. Multiple strains of BXD (B6 * D2) recombinant inbred mice went through a 4-week chronic variable stress (CVS) paradigm, and the Morris water maze (MWM) test was conducted during the last week of CVS to assess hippocampal dependent spatial memory performance and grouped animals into low and high performing groups based on the cognitive performance. Using hippocampal whole transcriptome RNA-sequencing data, differential expression, PANTHER analysis, WGCNA, Ingenuity's upstream regulator analysis in the Ingenuity Pathway Analysis(r) and phenotype association analysis were conducted. Our data identified multiple genes and pathways that were significantly associated with chronic stress-associated cognitive modification and the divergence in hippocampal dependent memory performance under chronic stress. Biological pathways associated with memory performance following chronic stress included metabolism, neurotransmitter and receptor regulation, immune response and cellular process. The Ingenuity's upstream regulator analysis identified 247 upstream transcriptional regulators from 16 different molecule types. Transcripts predictive of cognitive performance under high stress included genes that are associated with a high occurrence of Alzheimer's and cognitive impairments (e.g., Ncl, Eno1, Scn9a, Slc19a3, Ncstn, Fos, Eif4h, Copa, etc.). Our results show that the variable effects of chronic stress on the hippocampal transcriptome are related to the ability to complete the MWM task and that the modulations of specific pathways are indicative of hippocampal dependent memory performance. Thus, the divergence in spatial memory performance following chronic stress is related to the unique pattern of gene expression within the hippocampus. PMID- 28912683 TI - Nano-scale Biophysical and Structural Investigations on Intact and Neuropathic Nerve Fibers by Simultaneous Combination of Atomic Force and Confocal Microscopy. AB - The links between neuropathies of the peripheral nervous system (PNS), including Charcot-Marie-Tooth1A and hereditary neuropathy with liability to pressure palsies, and impaired biomechanical and structural integrity of PNS nerves remain poorly understood despite the medical urgency. Here, we present a protocol describing simultaneous structural and biomechanical integrity investigations on isolated nerve fibers, the building blocks of nerves. Nerve fibers are prepared from nerves harvested from wild-type and exemplary PNS neuropathy mouse models. The basic principle of the designed experimental approach is based on the simultaneous combination of atomic force microscopy (AFM) and confocal microscopy. AFM is used to visualize the surface structure of nerve fibers at nano-scale resolution. The simultaneous combination of AFM and confocal microscopy is used to perform biomechanical, structural, and functional integrity measurements at nano- to micro-scale. Isolation of sciatic nerves and subsequent teasing of nerve fibers take ~45 min. Teased fibers can be maintained at 37 degrees C in a culture medium and kept viable for up to 6 h allowing considerable time for all measurements which require 3-4 h. The approach is designed to be widely applicable for nerve fibers from mice of any PNS neuropathy. It can be extended to human nerve biopsies. PMID- 28912682 TI - Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases. AB - Extracellular vesicles (EVs) can be classified into apoptotic bodies, microvesicles (MVs), and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM), neuroblastoma (NB), medulloblastoma (MB), and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis. PMID- 28912684 TI - Distinct Activities of Tfap2A and Tfap2B in the Specification of GABAergic Interneurons in the Developing Cerebellum. AB - GABAergic inhibitory neurons in the cerebellum are subdivided into Purkinje cells and distinct subtypes of interneurons from the same pool of progenitors, but the determinants of this diversification process are not well defined. To explore the transcriptional regulation of the development of cerebellar inhibitory neurons, we examined the role of Tfap2A and Tfap2B in the specification of GABAergic neuronal subtypes in mice. We show that Tfap2A and Tfap2B are expressed in inhibitory precursors during embryonic development and that their expression persists into adulthood. The onset of their expression follows Ptf1a and Olig2, key determinants of GABAergic neuronal fate in the cerebellum; and, their expression precedes Pax2, an interneuron-specific factor. Tfap2A is expressed by all GABAergic neurons, whereas Tfap2B is selectively expressed by interneurons. Genetic manipulation via in utero electroporation (IUE) reveals that Tfap2B is necessary for interneuron specification and is capable of suppressing the generation of excitatory cells. Tfap2A, but not Tfap2B, is capable of inducing the generation of interneurons when misexpressed in the ventricular neuroepithelium. Together, our results demonstrate that the differential expression of Tfap2A and Tfap2B defines subtypes of GABAergic neurons and plays specific, but complementary roles in the specification of interneurons in the developing cerebellum. PMID- 28912685 TI - Neural Code-Neural Self-information Theory on How Cell-Assembly Code Rises from Spike Time and Neuronal Variability. AB - A major stumbling block to cracking the real-time neural code is neuronal variability - neurons discharge spikes with enormous variability not only across trials within the same experiments but also in resting states. Such variability is widely regarded as a noise which is often deliberately averaged out during data analyses. In contrast to such a dogma, we put forth the Neural Self Information Theory that neural coding is operated based on the self-information principle under which variability in the time durations of inter-spike-intervals (ISI), or neuronal silence durations, is self-tagged with discrete information. As the self-information processor, each ISI carries a certain amount of information based on its variability-probability distribution; higher-probability ISIs which reflect the balanced excitation-inhibition ground state convey minimal information, whereas lower-probability ISIs which signify rare-occurrence surprisals in the form of extremely transient or prolonged silence carry most information. These variable silence durations are naturally coupled with intracellular biochemical cascades, energy equilibrium and dynamic regulation of protein and gene expression levels. As such, this silence variability-based self information code is completely intrinsic to the neurons themselves, with no need for outside observers to set any reference point as typically used in the rate code, population code and temporal code models. Moreover, temporally coordinated ISI surprisals across cell population can inherently give rise to robust real time cell-assembly codes which can be readily sensed by the downstream neural clique assemblies. One immediate utility of this self-information code is a general decoding strategy to uncover a variety of cell-assembly patterns underlying external and internal categorical or continuous variables in an unbiased manner. PMID- 28912686 TI - Roles of Microglial Phagocytosis and Inflammatory Mediators in the Pathophysiology of Sleep Disorders. AB - Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation. PMID- 28912687 TI - Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats. AB - Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in humans, and is often developed after an initial precipitating brain injury. This form of epilepsy is frequently resistant to pharmacological treatment; therefore, the prevention of TLE is the prospective approach to TLE therapy. The lithium pilocarpine model in rats replicates some of the main features of TLE in human, including the pathogenic mechanisms of cell damage and epileptogenesis after a primary brain injury. In the present study, we investigated changes in the properties of glutamatergic transmission during the first 3 days after pilocarpine-induced acute seizures in Wistar rats (PILO-rats). Using RT-PCR and electrophysiological techniques, we compared the changes in the temporal cortex (TC) and hippocampus, brain areas differentially affected by seizures. On the first day, we found a transient increase in a ratio of alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) and N-methyl d-aspartate (NMDA) receptors in the excitatory synaptic response in pyramidal neurons of the CA1 area of the dorsal hippocampus, but not in the TC. This was accompanied by an increase in the slope of input-output (I/O) curves for fEPSPs recorded in CA1, suggesting an enhanced excitability in AMPARs in this brain area. There was no difference in the AMPA/NMDA ratio in control rats on the third day. We also revealed the alterations in NMDA receptor subunit composition in PILO-rats. The GluN2B/GluN2A mRNA expression ratio increased in the dorsal hippocampus but did not change in the ventral hippocampus or the TC. The kinetics of NMDA-mediated evoked EPSCs in hippocampal neurons was slower in PILO-rats compared with control animals. Ifenprodil, a selective antagonist of GluN2B-containing NMDARs, diminished the area and amplitude of evoked EPSCs in CA1 pyramidal cells more efficiently in PILO-rats compared with control animals. These results demonstrate that PILO induced seizures lead to more severe alterations in excitatory synaptic transmission in the dorsal hippocampus than in the TC. Seizures affect the relative contribution of AMPA and NMDA receptor conductances in the synaptic response and increase the proportion of GluN2B-containing NMDARs in CA1 pyramidal neurons. These alterations disturb normal circuitry functions in the hippocampus, may cause neuron damage, and may be one of the important pathogenic mechanisms of TLE. PMID- 28912690 TI - RING Finger Protein 38 Is a Neuronal Protein in the Brain of Nile Tilapia, Oreochromis niloticus. AB - Really interesting new gene (RING) finger protein is a type of zinc-binding motif found in a large family of functionally distinct proteins. RING finger proteins are involved in diverse cellular processes including apoptosis, DNA repair, cell cycle, signal transduction, tumour suppressor, vesicular transport, and peroxisomal biogenesis. RING finger protein 38 (RNF38) is a member of the family whose functions remain unknown. To gain insight into the putative effects of RNF38 in the central nervous system, we localised its expression. The aim of this study was to identify the neuroanatomical location(s) of rnf38 mRNA and its peptide, determine the type of RNF38-expressing cells, and measure rnf38 gene expression in the brain of male tilapia. The distributions of rnf38 mRNA and its peptide were visualised using in situ hybridisation with digoxigenin-labelled RNA antisense and immunocytochemistry, respectively. Both were identically distributed throughout the brain, including the telencephalon, preoptic area, optic tectum, hypothalamus, cerebellum, and the hindbrain. Double-labelling immunocytochemistry for RNF38 and the neuronal marker HuC/D showed that most but not all RNF38 protein was expressed in neuronal nuclei. Quantitative real-time polymerase chain reaction showed the highest level of rnf38 mRNA in the midbrain, followed by the preoptic area, cerebellum, optic tectum, telencephalon, hindbrain and hypothalamus. These findings reveal a differential spatial pattern of RNF38 in the tilapia brain, suggesting that it has potentially diverse functions related to neuronal activity. PMID- 28912691 TI - The Brain of the Black (Diceros bicornis) and White (Ceratotherium simum) African Rhinoceroses: Morphology and Volumetrics from Magnetic Resonance Imaging. AB - The morphology and volumetrics of the understudied brains of two iconic large terrestrial African mammals: the black (Diceros bicornis) and white (Ceratotherium simum) rhinoceroses are described. The black rhinoceros is typically solitary whereas the white rhinoceros is social, and both are members of the Perissodactyl order. Here, we provide descriptions of the surface of the brain of each rhinoceros. For both species, we use magnetic resonance images (MRI) to develop a description of the internal anatomy of the rhinoceros brain and to calculate the volume of the amygdala, cerebellum, corpus callosum, hippocampus, and ventricular system as well as to determine the gyrencephalic index. The morphology of both black and white rhinoceros brains is very similar to each other, although certain minor differences, seemingly related to diet, were noted, and both brains evince the general anatomy of the mammalian brain. The rhinoceros brains display no obvious neuroanatomical specializations in comparison to other mammals previously studied. In addition, the volumetric analyses indicate that the size of the various regions of the rhinoceros brain measured, as well as the extent of gyrification, are what would be predicted for a mammal with their brain mass when compared allometrically to previously published data. We conclude that the brains of the black and white rhinoceros exhibit a typically mammalian organization at a superficial level, but histological studies may reveal specializations of interest in relation to rhinoceros behavior. PMID- 28912688 TI - A Shift from a Pivotal to Supporting Role for the Growth-Associated Protein (GAP 43) in the Coordination of Axonal Structural and Functional Plasticity. AB - In a number of animal species, the growth-associated protein (GAP), GAP-43 (aka: F1, neuromodulin, B-50, G50, pp46), has been implicated in the regulation of presynaptic vesicular function and axonal growth and plasticity via its own biochemical properties and interactions with a number of other presynaptic proteins. Changes in the expression of GAP-43 mRNA or distribution of the protein coincide with axonal outgrowth as a consequence of neuronal damage and presynaptic rearrangement that would occur following instances of elevated patterned neural activity including memory formation and development. While functional enhancement in GAP-43 mRNA and/or protein activity has historically been hypothesized as a central mediator of axonal neuroplastic and regenerative responses in the central nervous system, it does not appear to be the crucial substrate sufficient for driving these responses. This review explores the historical discovery of GAP-43 (and associated monikers), its transcriptional, post-transcriptional and post-translational regulation and current understanding of protein interactions and regulation with respect to its role in axonal function. While GAP-43 itself appears to have moved from a pivotal to a supporting factor, there is no doubt that investigations into its functions have provided a clearer understanding of the biochemical underpinnings of axonal plasticity. PMID- 28912692 TI - Calsyntenins Are Expressed in a Dynamic and Partially Overlapping Manner during Neural Development. AB - Calsyntenins form a family of linker proteins between distinct populations of vesicles and kinesin motors for axonal transport. They were implicated in synapse formation and synaptic plasticity by findings in worms, mice and humans. These findings were in accordance with the postsynaptic localization of the Calsyntenins in the adult brain. However, they also affect the formation of neural circuits, as loss of Calsyntenin-1 (Clstn1) was shown to interfere with axonal branching and axon guidance. Despite the fact that Calsyntenins were discovered originally in embryonic chicken motoneurons, their distribution in the developing nervous system has not been analyzed in detail so far. Here, we summarize our analysis of the temporal and spatial expression patterns of the cargo-docking proteins Clstn1, Clstn2 and Clstn3 during neural development by comparing the dynamic distribution of their mRNAs by in situ hybridization in the spinal cord, the cerebellum, the retina and the tectum, as well as in the dorsal root ganglia (DRG). PMID- 28912689 TI - Monoamine Release in the Cat Lumbar Spinal Cord during Fictive Locomotion Evoked by the Mesencephalic Locomotor Region. AB - Spinal cord neurons active during locomotion are innervated by descending axons that release the monoamines serotonin (5-HT) and norepinephrine (NE) and these neurons express monoaminergic receptor subtypes implicated in the control of locomotion. The timing, level and spinal locations of release of these two substances during centrally-generated locomotor activity should therefore be critical to this control. These variables were measured in real time by fast cyclic voltammetry in the decerebrate cat's lumbar spinal cord during fictive locomotion, which was evoked by electrical stimulation of the mesencephalic locomotor region (MLR) and registered as integrated activity in bilateral peripheral nerves to hindlimb muscles. Monoamine release was observed in dorsal horn (DH), intermediate zone/ventral horn (IZ/VH) and adjacent white matter (WM) during evoked locomotion. Extracellular peak levels (all sites) increased above baseline by 138 +/- 232.5 nM and 35.6 +/- 94.4 nM (mean +/- SD) for NE and 5-HT, respectively. For both substances, release usually began prior to the onset of locomotion typically earliest in the IZ/VH and peaks were positively correlated with net activity in peripheral nerves. Monoamine levels gradually returned to baseline levels or below at the end of stimulation in most trials. Monoamine oxidase and uptake inhibitors increased the release magnitude, time-to-peak (TTP) and decline-to-baseline. These results demonstrate that spinal monoamine release is modulated on a timescale of seconds, in tandem with centrally-generated locomotion and indicate that MLR-evoked locomotor activity involves concurrent activation of descending monoaminergic and reticulospinal pathways. These gradual changes in space and time of monoamine concentrations high enough to strongly activate various receptors subtypes on locomotor activated neurons further suggest that during MLR-evoked locomotion, monoamine action is, in part, mediated by extrasynaptic neurotransmission in the spinal cord. PMID- 28912693 TI - Octopamine Underlies the Counter-Regulatory Response to a Glucose Deficit in Honeybees (Apis mellifera). AB - An animal's internal state is a critical parameter required for adaptation to a given environment. An important aspect of an animal's internal state is the energy state that is adjusted to the needs of an animal by energy homeostasis. Glucose is one essential source of energy, especially for the brain. A shortage of glucose therefore triggers a complex response to restore the animal's glucose supply. This counter-regulatory response to a glucose deficit includes metabolic responses like the mobilization of glucose from internal glucose stores and behavioral responses like increased foraging and a rapid intake of food. In mammals, the catecholamines adrenalin and noradrenalin take part in mediating these counter-regulatory responses to a glucose deficit. One candidate molecule that might play a role in these processes in insects is octopamine (OA). It is an invertebrate biogenic amine and has been suggested to derive from an ancestral pathway shared with adrenalin and noradrenalin. Thus, it could be hypothesized that OA plays a role in the insect's counter-regulatory response to a glucose deficit. Here we tested this hypothesis in the honeybee (Apis mellifera), an insect that, as an adult, mainly feeds on carbohydrates and uses these as its main source of energy. We investigated alterations of the hemolymph glucose concentration, survival, and feeding behavior after starvation and examined the impact of OA on these processes in pharmacological experiments. We demonstrate an involvement of OA in these three processes in honeybees and conclude there is an involvement of OA in regulating a bee's metabolic, physiological, and behavioral response following a phase of prolonged glucose deficit. Thus, OA in honeybees acts similarly to adrenalin and noradrenalin in mammals in regulating an animal's counter-regulatory response. PMID- 28912694 TI - From Cortical Blindness to Conscious Visual Perception: Theories on Neuronal Networks and Visual Training Strategies. AB - Homonymous hemianopia (HH) is the most common cortical visual impairment leading to blindness in the contralateral hemifield. It is associated with many inconveniences and daily restrictions such as exploration and visual orientation difficulties. However, patients with HH can preserve the remarkable ability to unconsciously perceive visual stimuli presented in their blindfield, a phenomenon known as blindsight. Unfortunately, the nature of this captivating residual ability is still misunderstood and the rehabilitation strategies in terms of visual training have been insufficiently exploited. This article discusses type I and type II blindsight in a neuronal framework of altered global workspace, resulting from inefficient perception, attention and conscious networks. To enhance synchronization and create global availability for residual abilities to reach visual consciousness, rehabilitation tools need to stimulate subcortical extrastriate pathways through V5/MT. Multisensory bottom-up compensation combined with top-down restitution training could target pre-existing and new neuronal mechanisms to recreate a framework for potential functionality. PMID- 28912696 TI - Swing Boat: Inducing and Recording Locomotor Activity in a Drosophila melanogaster Model of Alzheimer's Disease. AB - Recent studies indicate that physical activity can slow down progression of neurodegeneration in humans. To date, automated ways to induce activity have been predominantly described in rodent models. To study the impact of activity on behavior and survival in adult Drosophila melanogaster, we aimed to develop a rotating tube device "swing boat" which is capable of monitoring activity and sleep patterns as well as survival rates of flies. For the purpose of a first application, we tested our device on a transgenic fly model of Alzheimer's disease (AD). Activity of flies was recorded in a climate chamber using the Drosophila Activity Monitoring (DAM) System connected to data acquisition software. Locomotor activity was induced by a rotating tube device "swing boat" by repetitively tilting the tubes for 30 min per day. A non-exercising group of flies was used as control and activity and sleep patterns were obtained. The GAL4 /UAS system was used to drive pan-neuronal expression of human Abeta42 in flies. Immunohistochemical stainings for Abeta42 were performed on paraffin sections of adult fly brains. Daily rotation of the fly tubes evoked a pronounced peak of activity during the 30 min exercise period. Pan-neuronal expression of human Abeta42 in flies caused abnormalities in locomotor activity, reduction of life span and elevated sleep fragmentation in comparison to wild type flies. Furthermore, the formation of amyloid accumulations was observed in the adult fly brain. Gently induced activity over 12 days did not evoke prominent effects in wild type flies but resulted in prolongation of median survival time by 7 days (32.6%) in Abeta42-expressing flies. Additionally, restoration of abnormally decreased night time sleep (10%) and reduced sleep fragmentation (28%) were observed compared to non-exercising Abeta42-expressing flies. On a structural level no prominent effects regarding prevalence of amyloid aggregations and Abeta42 RNA expression were detected following activity induction. The rotating tube device successfully induced activity in flies shown by quantitative activity analysis. Our setup enabled quantitative analysis of activity and sleep patterns as well as of survival rates. Induced activity in a Drosophila model of Alzheimer's disease improved survival and ameliorated sleep phenotypes. PMID- 28912695 TI - Region- and Cell-Specific Expression of Transmembrane Collagens in Mouse Brain. AB - Unconventional collagens are nonfribrillar proteins that not only contribute to the structure of extracellular matrices but exhibit unique bio-activities. Although roles for unconventional collagens have been well-established in the development and function of non-neural tissues, only recently have studies identified roles for these proteins in brain development, and more specifically, in the formation and refinement of synaptic connections between neurons. Still, our understanding of the full cohort of unconventional collagens that are generated in the mammalian brain remains unclear. Here, we sought to address this gap by assessing the expression of transmembrane collagens (i.e., collagens XIII, XVII, XXIII and XXV) in mouse brain. Using quantitative PCR and in situ hybridization (ISH), we demonstrate both region- and cell-specific expression of these unique collagens in the developing brain. For the two most highly expressed transmembrane collagens (i.e., collagen XXIII and XXV), we demonstrate that they are expressed by select subsets of neurons in different parts of the brain. For example, collagen XXIII is selectively expressed by excitatory neurons in the mitral/tufted cell layer of the accessory olfactory bulb (AOB) and by cells in the inner nuclear layer (INL) of the retina. On the other hand, collagen XXV, which is more broadly expressed, is generated by subsets of excitatory neurons in the dorsal thalamus and midbrain and by inhibitory neurons in the retina, ventral thalamus and telencephalon. Not only is col25a1 expression present in retina, it appears specifically enriched in retino-recipient nuclei within the brain (including the suprachiasmatic nucleus (SCN), lateral geniculate complex, olivary pretectal nucleus (OPN) and superior colliculus). Taken together, the distinct region- and cell-specific expression patterns of transmembrane collagens suggest that this family of unconventional collagens may play unique, yet-to-be identified roles in brain development and function. PMID- 28912697 TI - Brains in Competition: Improved Cognitive Performance and Inter-Brain Coupling by Hyperscanning Paradigm with Functional Near-Infrared Spectroscopy. AB - Hyperscanning brain paradigm was applied to competitive task for couples of subjects. Functional Near-Infrared Spectroscopy (fNIRS) and cognitive performance were considered to test inter-brain and cognitive strategy similarities between subjects (14 couples) during a joint-action. We supposed increased brain-to-brain coupling and improved cognitive outcomes due to joint-action and the competition. As supposed, the direct interaction between the subjects and the observed external feedback of their performance (an experimentally induced fictitious feedback) affected the cognitive performance with decreased Error Rates (ERs), and Response Times (RTs). In addition, fNIRS measure (oxyhemoglobin, O2Hb) revealed an increased brain activity in the prefrontal cortex (PFC) in post feedback more than pre-feedback condition. Moreover, a higher inter-brain similarity was found for the couples during the task, with higher matched brain response in post-feedback condition than pre-feedback. Finally, a significant increased prefrontal brain lateralization effect was observed for the right hemisphere. Indeed the right PFC was more responsive with similar modalities within the couple during the post-feedback condition. The joined-task and competitive context was adduced to explain these cognitive performance improving, synergic brain responsiveness within the couples and lateralization effects (negative emotions). PMID- 28912698 TI - Altered Rich-Club and Frequency-Dependent Subnetwork Organization in Mild Traumatic Brain Injury: A MEG Resting-State Study. AB - Functional brain connectivity networks exhibit "small-world" characteristics and some of these networks follow a "rich-club" organization, whereby a few nodes of high connectivity (hubs) tend to connect more densely among themselves than to nodes of lower connectivity. The Current study followed an "attack strategy" to compare the rich-club and small-world network organization models using Magnetoencephalographic (MEG) recordings from mild traumatic brain injury (mTBI) patients and neurologically healthy controls to identify the topology that describes the underlying intrinsic brain network organization. We hypothesized that the reduction in global efficiency caused by an attack targeting a model's hubs would reveal the "true" underlying topological organization. Connectivity networks were estimated using mutual information as the basis for cross-frequency coupling. Our results revealed a prominent rich-club network organization for both groups. In particular, mTBI patients demonstrated hyper-synchronization among rich-club hubs compared to controls in the delta band and the delta-gamma1, theta-gamma1, and beta-gamma2 frequency pairs. Moreover, rich-club hubs in mTBI patients were overrepresented in right frontal brain areas, from theta to gamma1 frequencies, and underrepresented in left occipital regions in the delta-beta, delta-gamma1, theta-beta, and beta-gamma2 frequency pairs. These findings indicate that the rich-club organization of resting-state MEG, considering its role in information integration and its vulnerability to various disorders like mTBI, may have a significant predictive value in the development of reliable biomarkers to help the validation of the recovery from mTBI. Furthermore, the proposed approach might be used as a validation tool to assess patient recovery. PMID- 28912699 TI - Effects of Scene Properties and Emotional Valence on Brain Activations: A Fixation-Related fMRI Study. AB - Temporal and spatial characteristics of fixations are affected by image properties, including high-level scene characteristics, such as object-background composition, and low-level physical characteristics, such as image clarity. The influence of these factors is modulated by the emotional content of an image. Here, we aimed to establish whether brain correlates of fixations reflect these modulatory effects. To this end, we simultaneously scanned participants and measured their eye movements, while presenting negative and neutral images in various image clarity conditions, with controlled object-background composition. The fMRI data were analyzed using a novel fixation-based event-related (FIBER) method, which allows the tracking of brain activity linked to individual fixations. The results revealed that fixating an emotional object was linked to greater deactivation in the right lingual gyrus than fixating the background of an emotional image, while no difference between object and background was found for neutral images. We suggest that deactivation in the lingual gyrus might be linked to inhibition of saccade execution. This was supported by fixation duration results, which showed that in the negative condition, fixations falling on the object were longer than those falling on the background. Furthermore, increase in the image clarity was correlated with fixation-related activity within the lateral occipital complex, the structure linked to object recognition. This correlation was significantly stronger for negative images, presumably due to greater deployment of attention towards emotional objects. Our eye-tracking results are in line with these observations, showing that the chance of fixating an object rose faster for negative images over neutral ones as the level of noise decreased. Overall, our study demonstrated that emotional value of an image changes the way that low and high-level scene properties affect the characteristics of fixations. The fixation-related brain activity is affected by the low-level scene properties and this impact differs between negative and neutral images. The high-level scene properties also affect brain correlates of fixations, but only in the case of the negative images. PMID- 28912700 TI - Action Direction of Muscle Synergies in Voluntary Multi-Directional Postural Control. AB - A muscle synergy is a coordinative structure of muscles that has been proposed as a strategy to reduce the number of variables that the central nervous system (CNS) has to address in motor tasks. In this article, the mechanical contribution of muscle synergies and coordinative structures of muscles in voluntary multi directional postural control were investigated. The task for healthy, young subjects was to shift and align their center of pressure (COP) to targets dispersed in 12 different directions in the horizontal plane by leaning their bodies for 10 s. Electromyograms (EMGs) of 18 muscles and COPs were recorded in the experiment. Muscle synergies were extracted using non-negative matrix factorization (NMF), and the structure of coordinative modules to keep the posture leaning toward various directions was disclosed. Then the directional properties, such as the mechanical role (i.e., action directions, we use ADs as abbreviation below), of muscle synergies and muscles were estimated using an electromyogram-weighted averaging (EWA) method, which is based on a cross correlation between the fluctuations in the activation of muscle synergies and the COP. The results revealed that the ADs of muscle synergies were almost uniformly distributed in the task space in most of the subjects, which indicates that mechanical characteristics reduce the redundancy in postural control. In terms of the composition of muscle synergies and the ADs of individual muscles, we confirmed that muscle synergies in multi-directional postural control comprised a combination of several muscles, including various ADs, that generate torque at different joints. PMID- 28912701 TI - Spectral Entropy Can Predict Changes of Working Memory Performance Reduced by Short-Time Training in the Delayed-Match-to-Sample Task. AB - Spectral entropy, which was generated by applying the Shannon entropy concept to the power distribution of the Fourier-transformed electroencephalograph (EEG), was utilized to measure the uniformity of power spectral density underlying EEG when subjects performed the working memory tasks twice, i.e., before and after training. According to Signed Residual Time (SRT) scores based on response speed and accuracy trade-off, 20 subjects were divided into two groups, namely high performance and low-performance groups, to undertake working memory (WM) tasks. We found that spectral entropy derived from the retention period of WM on channel FC4 exhibited a high correlation with SRT scores. To this end, spectral entropy was used in support vector machine classifier with linear kernel to differentiate these two groups. Receiver operating characteristics analysis and leave-one out cross-validation (LOOCV) demonstrated that the averaged classification accuracy (CA) was 90.0 and 92.5% for intra-session and inter-session, respectively, indicating that spectral entropy could be used to distinguish these two different WM performance groups successfully. Furthermore, the support vector regression prediction model with radial basis function kernel and the root-mean-square error of prediction revealed that spectral entropy could be utilized to predict SRT scores on individual WM performance. After testing the changes in SRT scores and spectral entropy for each subject by short-time training, we found that 16 in 20 subjects' SRT scores were clearly promoted after training and 15 in 20 subjects' SRT scores showed consistent changes with spectral entropy before and after training. The findings revealed that spectral entropy could be a promising indicator to predict individual's WM changes by training and further provide a novel application about WM for brain-computer interfaces. PMID- 28912702 TI - Altered White Matter Integrity in Smokers Is Associated with Smoking Cessation Outcomes. AB - Smoking is a significant cause of preventable mortality worldwide. Understanding the neural mechanisms of nicotine addiction and smoking cessation may provide effective targets for developing treatment strategies. In the present study, we explored whether smokers have white matter alterations and whether these alterations are related to cessation outcomes and smoking behaviors. Sixty-six smokers and thirty-seven healthy non-smokers were enrolled. The participants underwent magnetic resonance imaging scans and smoking-related behavioral assessments. After a 12-week treatment with varenicline, 28 smokers succeeded in quitting smoking and 38 failed. Diffusion parameter maps were compared among the non-smokers, future quitters, and relapsers to identify white matter differences. We found that the future relapsers had significantly lower fractional anisotropy (FA) in the orbitofrontal area than non-smokers, and higher FA in the cerebellum than non-smokers and future quitters. The future quitters had significantly lower FA in the postcentral gyrus compared to non-smokers and future relapsers. Compared to non-smokers, pooled smokers had lower FA in bilateral orbitofrontal gyrus and left superior frontal gyrus. In addition, regression analysis showed that the left orbitofrontal FA was correlated with smoking-relevant behaviors. These results suggest that white matter alterations in smokers may contribute to the formation of aberrant brain circuits underlying smoking behaviors and are associated with future smoking cessation outcomes. PMID- 28912703 TI - The Influence of External Forces on Wrist Proprioception. AB - Proprioception combines information from cutaneous, joint, tendon, and muscle receptors for maintaining a reliable internal body image. However, it is still a matter of debate, in both neurophysiology and psychology, to what extent such body image is modified or distorted by a changing haptic environment. In particular, what is worth investigating is the contribution of external forces on our perception of body and joint configuration. The proprioceptive acuity of fifteen young participants was tested with a Joint Position Matching (JPM) task, performed with the dominant wrist under five different external forces, in order to understand to what extent they affect proprioceptive acuity. Results show that accuracy and precision in target matching do not change in a significant manner as a function of the loading condition, suggesting that the multi-sensory integration process is indeed capable of discriminating different sub-modalities of proprioception, namely the joint position sense and the sense of force. Furthermore, results indicate a preference for target undershooting when movements are performed in a viscous or high resistive force field, rather than passive or null fields in which subjects did not show any predominance for under/over estimation of their position. PMID- 28912705 TI - Corrigendum: Multi-Kernel Learning with Dartel Improves Combined MRI-PET Classification of Alzheimer's Disease in AIBL Data: Group and Individual Analyses. AB - [This corrects the article on p. 380 in vol. 11, PMID: 28790908.]. PMID- 28912706 TI - Dynamic Neural Fields with Intrinsic Plasticity. AB - Dynamic neural fields (DNFs) are dynamical systems models that approximate the activity of large, homogeneous, and recurrently connected neural networks based on a mean field approach. Within dynamic field theory, the DNFs have been used as building blocks in architectures to model sensorimotor embedding of cognitive processes. Typically, the parameters of a DNF in an architecture are manually tuned in order to achieve a specific dynamic behavior (e.g., decision making, selection, or working memory) for a given input pattern. This manual parameters search requires expert knowledge and time to find and verify a suited set of parameters. The DNF parametrization may be particular challenging if the input distribution is not known in advance, e.g., when processing sensory information. In this paper, we propose the autonomous adaptation of the DNF resting level and gain by a learning mechanism of intrinsic plasticity (IP). To enable this adaptation, an input and output measure for the DNF are introduced, together with a hyper parameter to define the desired output distribution. The online adaptation by IP gives the possibility to pre-define the DNF output statistics without knowledge of the input distribution and thus, also to compensate for changes in it. The capabilities and limitations of this approach are evaluated in a number of experiments. PMID- 28912704 TI - Reliability of EEG Measures of Interaction: A Paradigm Shift Is Needed to Fight the Reproducibility Crisis. AB - Measures of interaction (connectivity) of the EEG are at the forefront of current neuroscientific research. Unfortunately, test-retest reliability can be very low, depending on the measure and its estimation, the EEG-frequency of interest, the length of the signal, and the population under investigation. In addition, artifacts can hamper the continuity of the EEG signal, and in some clinical situations it is impractical to exclude artifacts. We aimed to examine factors that moderate test-retest reliability of measures of interaction. The study involved 40 patients with a range of neurological diseases and memory impairments (age median: 60; range 21-76; 40% female; 22 mild cognitive impairment, 5 subjective cognitive complaints, 13 temporal lobe epilepsy), and 20 healthy controls (age median: 61.5; range 23-74; 70% female). We calculated 14 measures of interaction based on the multivariate autoregressive model from two EEG recordings separated by 2 weeks. We characterized test-retest reliability by correlating the measures between the two EEG-recordings for variations of data length, data discontinuity, artifact exclusion, model order, and frequency over all combinations of channels and all frequencies, individually for each subject, yielding a correlation coefficient for each participant. Excluding artifacts had strong effects on reliability of some measures, such as classical, real valued coherence (~0.1 before, ~0.9 after artifact exclusion). Full frequency directed transfer function was highly reliable and robust against artifacts. Variation of data length decreased reliability in relation to poor adjustment of model order and signal length. Variation of discontinuity had no effect, but reliabilities were different between model orders, frequency ranges, and patient groups depending on the measure. Pathology did not interact with variation of signal length or discontinuity. Our results emphasize the importance of documenting reliability, which may vary considerably between measures of interaction. We recommend careful selection of measures of interaction in accordance with the properties of the data. When only short data segments are available and when the signal length varies strongly across subjects after exclusion of artifacts, reliability becomes an issue. Finally, measures which show high reliability irrespective of the presence of artifacts could be extremely useful in clinical situations when exclusion of artifacts is impractical. PMID- 28912707 TI - Methodological Choices in Muscle Synergy Analysis Impact Differentiation of Physiological Characteristics Following Stroke. AB - Muscle synergy analysis (MSA) is a mathematical technique that reduces the dimensionality of electromyographic (EMG) data. Used increasingly in biomechanics research, MSA requires methodological choices at each stage of the analysis. Differences in methodological steps affect the overall outcome, making it difficult to compare results across studies. We applied MSA to EMG data collected from individuals post-stroke identified as either responders (RES) or non responders (nRES) on the basis of a critical post-treatment increase in walking speed. Importantly, no clinical or functional indicators identified differences between the cohort of RES and nRES at baseline. For this exploratory study, we selected the five highest RES and five lowest nRES available from a larger sample. Our goal was to assess how the methodological choices made before, during, and after MSA affect the ability to differentiate two groups with intrinsic physiologic differences based on MSA results. We investigated 30 variations in MSA methodology to determine which choices allowed differentiation of RES from nRES at baseline. Trial-to-trial variability in time-independent synergy vectors (SVs) and time-varying neural commands (NCs) were measured as a function of: (1) number of synergies computed; (2) EMG normalization method before MSA; (3) whether SVs were held constant across trials or allowed to vary during MSA; and (4) synergy analysis output normalization method after MSA. MSA methodology had a strong effect on our ability to differentiate RES from nRES at baseline. Across all 10 individuals and MSA variations, two synergies were needed to reach an average of 90% variance accounted for (VAF). Based on effect sizes, differences in SV and NC variability between groups were greatest using two synergies with SVs that varied from trial-to-trial. Differences in SV variability were clearest using unit magnitude per trial EMG normalization, while NC variability was less sensitive to EMG normalization method. No outcomes were greatly impacted by output normalization method. MSA variability for some, but not all, methods successfully differentiated intrinsic physiological differences inaccessible to traditional clinical or biomechanical assessments. Our results were sensitive to methodological choices, highlighting the need for disclosure of all aspects of MSA methodology in future studies. PMID- 28912708 TI - Remodeling Pearson's Correlation for Functional Brain Network Estimation and Autism Spectrum Disorder Identification. AB - Functional brain network (FBN) has been becoming an increasingly important way to model the statistical dependence among neural time courses of brain, and provides effective imaging biomarkers for diagnosis of some neurological or psychological disorders. Currently, Pearson's Correlation (PC) is the simplest and most widely used method in constructing FBNs. Despite its advantages in statistical meaning and calculated performance, the PC tends to result in a FBN with dense connections. Therefore, in practice, the PC-based FBN needs to be sparsified by removing weak (potential noisy) connections. However, such a scheme depends on a hard-threshold without enough flexibility. Different from this traditional strategy, in this paper, we propose a new approach for estimating FBNs by remodeling PC as an optimization problem, which provides a way to incorporate biological/physical priors into the FBNs. In particular, we introduce an L1-norm regularizer into the optimization model for obtaining a sparse solution. Compared with the hard-threshold scheme, the proposed framework gives an elegant mathematical formulation for sparsifying PC-based networks. More importantly, it provides a platform to encode other biological/physical priors into the PC-based FBNs. To further illustrate the flexibility of the proposed method, we extend the model to a weighted counterpart for learning both sparse and scale-free networks, and then conduct experiments to identify autism spectrum disorders (ASD) from normal controls (NC) based on the constructed FBNs. Consequently, we achieved an 81.52% classification accuracy which outperforms the baseline and state-of-the art methods. PMID- 28912709 TI - Extending XNAT Platform with an Incremental Semantic Framework. AB - Informatics increases the yield from neuroscience due to improved data. Data sharing and accessibility enable joint efforts between different research groups, as well as replication studies, pivotal for progress in the field. Research data archiving solutions are evolving rapidly to address these necessities, however, distributed data integration is still difficult because of the need of explicit agreements for disparate data models. To address these problems, ontologies are widely used in biomedical research to obtain common vocabularies and logical descriptions, but its application may suffer from scalability issues, domain bias, and loss of low-level data access. With the aim of improving the application of semantic models in biobanking systems, an incremental semantic framework that takes advantage of the latest advances in biomedical ontologies and the XNAT platform is designed and implemented. We follow a layered architecture that allows the alignment of multi-domain biomedical ontologies to manage data at different levels of abstraction. To illustrate this approach, the development is integrated in the JPND (EU Joint Program for Neurodegenerative Disease) APGeM project, focused on finding early biomarkers for Alzheimer's and other dementia related diseases. PMID- 28912712 TI - Effect of Cognitive Demand on Functional Visual Field Performance in Senior Drivers with Glaucoma. AB - : Purpose: To investigate the effect of cognitive demand on functional visual field performance in drivers with glaucoma. Method: This study included 20 drivers with open-angle glaucoma and 13 age- and sex-matched controls. Visual field performance was evaluated under different degrees of cognitive demand: a static visual field condition (C1), dynamic visual field condition (C2), and dynamic visual field condition with active driving (C3) using an interactive, desktop driving simulator. The number of correct responses (accuracy) and response times on the visual field task were compared between groups and between conditions using Kruskal-Wallis tests. General linear models were employed to compare cognitive workload, recorded in real-time through pupillometry, between groups and conditions. Results: Adding cognitive demand (C2 and C3) to the static visual field test (C1) adversely affected accuracy and response times, in both groups (p < 0.05). However, drivers with glaucoma performed worse than did control drivers when the static condition changed to a dynamic condition [C2 vs. C1 accuracy; glaucoma: median difference (Q1-Q3) 3 (2-6.50) vs. CONTROLS: 2 (0.50 2.50); p = 0.05] and to a dynamic condition with active driving [C3 vs. C1 accuracy; glaucoma: 2 (2-6) vs. CONTROLS: 1 (0.50-2); p = 0.02]. Overall, drivers with glaucoma exhibited greater cognitive workload than controls (p = 0.02). Conclusion: Cognitive demand disproportionately affects functional visual field performance in drivers with glaucoma. Our results may inform the development of a performance-based visual field test for drivers with glaucoma. PMID- 28912710 TI - Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation. AB - Alzheimer's disease (AD) is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-beta (Abeta) peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Abeta production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV) would react differentially from the 2 DIV cells upon treatment with 1000 nM Abeta1-42 for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after Abeta treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2) and milk fat globule-EGF factor 8 protein (MFG-E8) levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1) and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2), TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1) cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9) was marked in 16 DIV cells. Increased senescence associated beta-galactosidase (SA-beta-gal) and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by Abeta in 2 DIV microglia. Additionally, Abeta downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while increased the number of CD86+ cells in 16 DIV microglia. Simultaneous M1 and M2 markers were found after Abeta treatment, but at lower expression in the in vitro aged microglia. Data show key aging associated responses by microglia when incubated with Abeta, with a loss of reactivity from the 2 DIV to the 16 DIV cells, which course with a reduced phagocytosis, migration and lower expression of inflammatory miRNAs. These findings help to improve our understanding on the heterogeneous responses that microglia can have along the progression of AD disease and imply that therapeutic approaches may differ from early to late stages. PMID- 28912713 TI - Meta-Analysis for Clinical Evaluation of Xingnaojing Injection for the Treatment of Cerebral Infarction. AB - Objective: Xingnaojing injection (XNJ) is derived from An-Gong-Niu-Huang pill, a well-known traditional Chinese patent medicine, which is widely used for stroke. To evaluate the therapeutic effect of XNJ on cerebral infarction, an extensive meta-analysis was used. Methods: Six major electronic databases including the Chinese Biomedical Database (CBM), Wanfang, the VIP medicine information system (VMIS) and the China National Knowledge Infrastructure (CNKI), PubMed, Embase, and the Cochrane Library were examined to retrieve randomized controlled trials designed to evaluate the clinical efficacy of XNJ in treating CI before November 26, 2016. Results: There were 53 randomized controlled trials with 4915 participants in this study. The results reflected that compared with the conventional therapy (CT) alone, XNJ could significantly improve the overall response rate (OR = 3.56, 95% CI [2.94, 4.32], P < 0.00001), and clinical symptom (including increasing activities of daily living (ADL, MD = 10.23, 95% CI [9.47, 10.99], P < 0.00001), and reduce infarction size (MD = -1.83, 95% CI [-2.49, 1.16], P < 0.00001)). However, there was no significant difference between the XNJ treatment and conventional therapy in Glasgow Coma Scale (GCS, P = 0.32). Neurological deficit score demonstrated that XNJ could significantly reduce the score in two different evaluation criterions as National Institutes of Health Stroke Scale (NIHSS, MD = -3.44, 95% CI [-4.52, -2.36], P < 0.00001), and the Chinese Stroke Scale (CSS, MD = -5.72, 95% CI [-6.94, -4.50], P < 0.00001). Additionally, serum MMPs, including MMP-2 and MMP-9 were significantly reduced by XNJ treatment compared with conventional therapy (MD = -11.24, 95% CI [-20.83, 1.65], P = 0.02; MD = -25.08, 95% CI [-35.49, -14.67], P < 0.00001, respectively). Moreover, XNJ was able to improve hemorrheology in reducing whole blood viscosity, plasma viscosity, and hematocrit (MD = -1.44, 95% CI [-2.18, 0.70], P = 0.001; MD = -0.22, 95% CI [-0.37, -0.07], P = 0.003; MD = -3.63, 95% CI [-6.23, -1.03], P = 0.006, respectively). The therapeutic efficacy of XNJ was found associated with improving hemodynamics (increasing peak-flow rate, and average velocity) (MD = 12.66, 95% CI [10.50, 14.81], P < 0.00001; MD = 9.90, 95% CI [8.63, 11.17], P < 0.00001). XNJ was also related to reducing cholesterol and triglyceride (MD = -1.06, 95% CI [-1.21, -0.92], P < 0.00001; MD = -1.05, 95% CI [-1.12, -0.97], P < 0.00001). Conclusion: Despite the sample size and the poor quality of the included studies of this review, the results of the research showed that XNJ might be a beneficial therapeutic method for the treatment of cerebral infarction. PMID- 28912711 TI - Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice. AB - Memory decline during aging or accompanying neurodegenerative diseases, represents a major health problem. Neurotrophins have long been considered relevant to the mechanisms of aging-associated cognitive decline and neurodegeneration. Mature Brain-Derived Neurotrophic Factor (BDNF) and its precursor (proBDNF) can both be secreted in response to neuronal activity and exert opposing effects on neuronal physiology and plasticity. In this study, biochemical analyses revealed that increased levels of proBDNF are present in the aged mouse hippocampus relative to young and that the level of hippocampal proBDNF inversely correlates with the ability to perform in a spatial memory task, the water radial arm maze (WRAM). To ascertain the role of increased proBDNF levels on hippocampal function and memory we performed infusions of proBDNF into the CA1 region of the dorsal hippocampus in male mice trained in the WRAM paradigm: In well-performing aged mice, intra-hippocampal proBDNF infusions resulted in a progressive and significant impairment of memory performance. This impairment was associated with increased p-cofilin levels, an important regulator of dendritic spines and synapse physiology. On the other hand, in poor performers, intra-hippocampal infusions of TAT-Pep5, a peptide which blocks the interaction between the p75 Neurotrophin Receptor (p75NTR) and RhoGDI, significantly improved learning and memory, while saline infusions had no effect. Our results support a role for proBDNF and its receptor p75NTR in aging-related memory impairments. PMID- 28912714 TI - Anti-inflammatory and Analgesic Effects of Polygonum orientale L. Extracts. AB - Background and Purpose:Polygonum orientale L. (family: Polygonaceae), named Hongcao in China, is a Traditional Chinese Medicinal and has long been used for rheumatic arthralgia and rheumatoid arthritis. However, no pharmacological and mechanism study to confirm these clinic effects have been published. In this investigation, the anti-inflammatory, analgesic effects and representative active ingredient compounds of P. orientale have been studied. Methods: Dried small pieces of the stems and leaves of P. orientale were decocted with water and partitioned successively to obtain ethyl acetate and ethyl ether extract of P. orientale (POEa and POEe). Chemical compositions of them were analyzed by UPLC-Q Exactive HRMS. Anti-inflammatory and analgesic effects of POEa and POEe were evaluated using xylene induced ear edema, carrageenan induced paw edema, Freunds' complete adjuvant induced arthritis, and formaldehyde induced pain in rat. Their mechanisms of anti-inflammatory and analgesic effects were also studied via assays of TNF-alpha, IL-1beta, IL-6, and PGE2 in serum. Results: UPLC-Q-Exactive HRMS analysis showed that POEa and POEe mainly contained flavonoids including orientin, isoorientin, vitexin, luteolin, and quercetin. Furthermore, anti inflammatory effects of POEa and POEe were evident in xylene induced ear edema. The paw edema in Freund's complete adjuvant and carrageenan were significantly (P < 0.05, 0.01) inhibited by POEa (5, 7.5 g/kg). POEe (7.5 g/kg) was significantly (P < 0.05, 0.01) inhibited Freunds' complete adjuvant induced paw edema and cotton pellet induced granuloma formation. Similarly, POEe significantly (P < 0.05, 0.01) inhibited the pain sensation in acetic acid induced writhing test. POEa (5, 7.5 g/kg) significantly (P < 0.05, 0.01) inhibited formaldehyde induced pain in both phases. POEa (7.5 g/kg) markedly (P < 0.05) prolonged the latency period of hot plate test after 30 and 60 min. The concentrations of TNF-alpha, IL 1beta, IL-6, and PGE2 were significantly (P < 0.01) decreased by POEa (3.75, 5 g/kg). Conclusion: POEa and POEe have anti-inflammatory and analgesic effects, which was mainly relevant to the presence of flavonoids, including orientin, isoorientin, vitexin, luteolin, and quercetin. The mechanism of anti-inflammatory and analgesic effects of POEa may be to decrease the concentrations of TNF-alpha, IL-1beta, IL-6, and PGE2 in serum. PMID- 28912716 TI - A Meta-Analysis of Folic Acid in Combination with Anti-Hypertension Drugs in Patients with Hypertension and Hyperhomocysteinemia. AB - Folic acid is generally used to lower homocysteine concentrations and prevent stroke and cardiovascular disease (CVD) at present. However, the efficacy of therapies that lower homocysteine concentrations in reducing the risk of CVD and stroke remains controversial. Our objective was to do a meta-analysis of relevant randomized controlled trials (RCTs) to evaluate the efficacy of folic acid supplementation among patients with hypertension and Hyperhomocysteinemia (HT/HHcy). We included RCTs examining the effects of folic acid plus antihypertensive therapy compared to antihypertensive alone. Weighted Mean Difference (WMD) and Relative risk (RR) were used as a measure of the effect of folic acid on the outcome measures with a random effect model. Sixty-five studies including 7887 patients met all inclusion criteria. Among them, 49 trials reported significant effect of combination therapy for reducing SBP (systolic Blood Pressure) and DBP (Diastolic Blood Pressure) levels compared with antihypertensive alone (WMD = -7.85, WMD = -6.77, respectively). Meanwhile, folic acid supplementation apparently reduced the level of total homocysteine (WMD = 5.5). In addition, folic acid supplementation obviously reduced the risk of cardiovascular and cerebrovascular events (CVCE) by 12.9% compared with control groups. In terms of the stratified analyses, a bigger beneficial effect was seen in those RCTs with treatment duration of more than 12 weeks, a decrease in the concentration of total homocysteine of more than 25%, with folic acid fortification. Our findings indicated that folic acid supplementation was effective in the primary prevention of CVCE among HT/HHcy patients, as well as reducing the blood pressure and total homocysteine levels. PMID- 28912717 TI - Global Metabolomics Reveals the Metabolic Dysfunction in Ox-LDL Induced Macrophage-Derived Foam Cells. AB - Atherosclerosis (AS) is a chronic disorder of large arteries that is a major risk factors of high morbidity and mortality. Oxidative modification LDL is one of the important contributors to atherogenesis. Macrophages take up ox-LDL and convert into foam cells, which is the hallmark of AS. To advance the understanding of the metabolic perturbation involved in ox-LDL induced macrophage-derived foam cells and discover the potential biomarkers of early AS, a global metabolomics approach was applied based on UHPLC-QTOF/MS. Multivariate statistical analyses identified five metabolites (25-azacholesterol, anandamide, glycocholate, oleoyl ethanolamide, and 3-oxo-4, 6-choladienoate) for distinguishing foamy macrophages from controls. Among the six main metabolic pathways, the unsaturated fatty acid, especially arachidonic acid metabolism, contributed importantly to early AS. A new biomarker, anandamide (AEA), whose synthesis and metabolism in macrophages are disturbed by overloaded ox-LDL, results in metabolic obstruction. This study is the first to investigate the metabolic disturbance in macrophage-derived foam cells induced by ox-LDL and screen potential biomarkers and metabolic pathways associated with early AS. Our findings provide a new insight in the underlying pathophysiological mechanisms and also help to identify novel targets for the intervention of AS. PMID- 28912715 TI - Anti-fibrotic Potential of AT2 Receptor Agonists. AB - There are a number of therapeutic targets to treat organ fibrosis that are under investigation in preclinical models. There is increasing evidence that stimulation of the angiotensin II type 2 receptor (AT2R) is a novel anti-fibrotic strategy and we have reviewed the published in vivo preclinical data relating to the effects of compound 21 (C21), which is the only nonpeptide AT2R agonist that is currently available for use in chronic preclinical studies. In particular, the differential influence of AT2R on extracellular matrix status in various preclinical fibrotic models is discussed. Collectively, these studies demonstrate that pharmacological AT2R stimulation using C21 decreases organ fibrosis, which has been most studied in the setting of cardiovascular and renal disease. In addition, AT2R-mediated anti-inflammatory effects may contribute to the beneficial AT2R-mediated anti-fibrotic effects seen in preclinical models. PMID- 28912719 TI - Population-Based Case-Control Study Assessing the Association between Statins Use and Pulmonary Tuberculosis in Taiwan. AB - Background and Objectives: Little evidence is available about the relationship between statins use and pulmonary tuberculosis in Taiwan. The aim of the study was to explore this issue. Methods: Using the database of the Taiwan National Health Insurance Program, we conducted a population-based case-control study to identify 8,236 subjects aged 20 years and older with newly diagnosed pulmonary tuberculosis from 2000 to 2013 as the cases. We randomly selected 8,236 sex matched and age-matched subjects without pulmonary tuberculosis as the controls. Subjects who had at least one prescription of statins before the index date were defined as "ever use." Subjects who never had one prescription of statins before the index date were defined as "never use." The odds ratio (OR) and 95% confidence interval (CI) for pulmonary tuberculosis associated with statins use was estimated by a multivariable logistic regression model. Results: After adjustment for co-variables, the adjusted OR of pulmonary tuberculosis was 0.67 for subjects with ever use of statins (95% CI 0.59, 0.75). In a sub-analysis, the adjusted ORs of pulmonary tuberculosis were 0.87 (95% CI 0.69, 1.10) for subjects with cumulative duration of statins use <3 months, 0.77 (95% CI 0.58, 1.03) for 3 6 months, and 0.59 (95% CI 0.51, 0.68) for >=6 months, compared with subjects with never use of statins. Conclusions: Statins use correlates with a small but statistically significant risk reduction of pulmonary tuberculosis. The protective effect is stronger for longer duration of statins use. Due to a case control design, a causal-relationship cannot be established in our study. A prospective cohort design is needed to confirm our findings. PMID- 28912718 TI - Technical Improvement and Application of Hydrodynamic Gene Delivery in Study of Liver Diseases. AB - Development of an safe and efficient in vivo gene delivery method is indispensable for molecular biology research and the progress in the following gene therapy. Over the past few years, hydrodynamic gene delivery (HGD) with naked DNA has drawn increasing interest in both research and potential clinic applications due to its high efficiency and low risk in triggering immune responses and carcinogenesis in comparison to viral vectors. This method, involving intravenous injection (i.v.) of massive DNA in a short duration, gives a transient but high in vivo gene expression especially in the liver of small animals. In addition to DNA, it has also been shown to deliver other substance such as RNA, proteins, synthetic small compounds and even viruses in vivo. Given its ability to robustly mimic in vivo hepatitis B virus (HBV) production in liver, HGD has become a fundamental and important technology on HBV studies in our group and many other groups. Recently, there have been interesting reports about the applications and further improvement of this technology in other liver research. Here, we review the principle, safety, current application and development of hydrodynamic delivery in liver disease studies, and discuss its future prospects, clinical potential and challenges. PMID- 28912720 TI - A Single Angiotensin II Hypertensive Stimulus Is Associated with Prolonged Neuronal and Immune System Activation in Wistar-Kyoto Rats. AB - Activation of autonomic neural pathways by chronic hypertensive stimuli plays a significant role in pathogenesis of hypertension. Here, we proposed that even a single acute hypertensive stimulus will activate neural and immune pathways that may be important in initiation of memory imprinting seen in chronic hypertension. We investigated the effects of acute angiotensin II (Ang II) administration on blood pressure, neural activation in cardioregulatory brain regions, and central and systemic immune responses, at 1 and 24 h post-injection. Administration of a single bolus intra-peritoneal (I.P.) injection of Ang II (36 MUg/kg) resulted in a transient increase in the mean arterial pressure (MAP) (by 22 +/- 4 mmHg vs saline), which returned to baseline within 1 h. However, in contrast to MAP, neuronal activity, as measured by manganese-enhanced magnetic resonance (MEMRI), remained elevated in several cardioregulatory brain regions over 24 h. The increase was predominant in autonomic regions, such as the subfornical organ (SFO; ~20%), paraventricular nucleus of the hypothalamus (PVN; ~20%) and rostral ventrolateral medulla (RVLM; ~900%), among others. Similarly, systemic and central immune responses, as evidenced by circulating levels of CD4+/IL17+ T cells, and increased IL17 levels and activation of microglia in the PVN, respectively, remained elevated at 24 h following Ang II challenge. Elevated Fos expression in the PVN was also present at 24 h (by 73 +/- 11%) following Ang II compared to control saline injections, confirming persistent activation of PVN. Thus, even a single Ang II hypertensive stimulus will initiate changes in neuronal and immune cells that play a role in the developing hypertensive phenotype. PMID- 28912721 TI - Physical and Chemical Processes and the Morphofunctional Characteristics of Human Erythrocytes in Hyperglycaemia. AB - Background: This study examines the effect of graduated hyperglycaemia on the state and oxygen-binding ability of hemoglobin, the correlation of phospholipid fractions and their metabolites in the membrane, the activity of proteolytic enzymes and the morphofunctional state of erythrocytes. Methods: Conformational changes in the molecule of hemoglobin were determined by Raman spectroscopy. The structure of the erythrocytes was analyzed using laser interference microscopy (LIM). To determine the activity of NADN-methemoglobinreductase, we used the P.G. Board method. The degree of glycosylation of the erythrocyte membranes was determined using a method previously described by Felkoren et al. Lipid extraction was performed using the Bligh and Dyer method. Detection of the phospholipids was performed using V. E. Vaskovsky method. Results: Conditions of hyperglycaemia are characterized by a low affinity of hemoglobin to oxygen, which is manifested as a parallel decrease in the content of hemoglobin oxyform and the growth of deoxyform, methemoglobin and membrane-bound hemoglobin. The degree of glycosylation of membrane proteins and hemoglobin is high. For example, in the case of hyperglycaemia, erythrocytic membranes reduce the content of all phospholipid fractions with a simultaneous increase in lysoforms, free fatty acids and the diacylglycerol (DAG). Step wise hyperglycaemia in incubation medium and human erythrocytes results in an increased content of peptide components and general trypsin-like activity in the cytosol, with a simultaneous decreased activity of MU-calpain and caspase 3. Conclusions: Metabolic disorders and damage of cell membranes during hyperglycaemia cause an increase in the population of echinocytes and spherocytes. The resulting disorders are accompanied with a high probability of intravascular haemolysis. PMID- 28912722 TI - Repeated Mandibular Extension in Rat: A Procedure to Modulate the Cerebral Arteriolar Tone. AB - Previous data have shown both in the rat and in the human that a single mandibular extension lasting 10 min induces a significant important and prolonged reduction in blood pressure and heart rate, affecting also rat pial microcirculation by the release of endothelial factors. In the present work, we assessed whether repeated mandibular extension could further prolong these effects. We performed two mandibular extensions, the second mandibular extension being applied 10 min after the first one. The second mandibular extension produced a reduction in blood pressure and heart rate for at least 240 min. As in the case of a single mandibular extension, pial arterioles dilated persisting up to 140 min after the second extension. Spectral analysis on 30 min recordings under baseline conditions and after repetitive mandibular extensions showed that the pial arterioles dilation was associated with rhythmic diameter changes sustained by an increase in the frequency components related to endothelial, neurogenic, and myogenic activity while a single mandibular extension caused, conversely, an increase only in the endothelial activity. In conclusion, repetitive mandibular extension prolonged the effects of a single mandibular extension on blood pressure, heart rate and vasodilation and induced a modulation of different frequency components responsible of the pial arteriolar tone, in particular increasing the endothelial activity. PMID- 28912723 TI - Increased Hemodynamic Load in Early Embryonic Stages Alters Myofibril and Mitochondrial Organization in the Myocardium. AB - Normal blood flow is essential for proper heart formation during embryonic development, as abnormal hemodynamic load (blood pressure and shear stress) results in cardiac defects seen in congenital heart disease (CHD). However, the detrimental remodeling processes that relate altered blood flow to cardiac malformation and defects remain unclear. Heart development is a finely orchestrated process with rapid transformations that occur at the tissue, cell, and subcellular levels. Myocardial cells play an essential role in cardiac tissue maturation by aligning in the direction of stretch and increasing the number of contractile units as hemodynamic load increases throughout development. This study elucidates the early effects of altered blood flow on myofibril and mitochondrial configuration in the outflow tract myocardium in vivo. Outflow tract banding was used to increase hemodynamic load in the chicken embryo heart between Hamburger and Hamilton stages 18 and 24 (~24 h during tubular heart stages). 3D focused ion beam scanning electron microscopy analysis determined that increased hemodynamic load induced changes in the developing myocardium, characterized by thicker myofibril bundles that were more disbursed in circumferential orientation, and mitochondria that organized in large clusters around the nucleus. Proteomic mass-spectrometry analysis quantified altered protein composition after banding that is consistent with altered myofibril thin filament assembly and function, and mitochondrial maintenance and organization. Additionally, pathway analysis of the proteomics data identified possible activation of signaling pathways in response to banding, including the renin angiotensin system (RAS). Imaging and proteomic data combined indicate that myofibril and mitochondrial arrangement in early embryonic stages is a critical developmental process that when disturbed by altered blood flow may contribute to cardiac malformation and defects. PMID- 28912724 TI - Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia. AB - Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC) and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy proline, and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates. PMID- 28912725 TI - Enhanced Strength and Sprint Levels, and Changes in Blood Parameters during a Complete Athletics Season in 800 m High-Level Athletes. AB - The purpose of this study was to analyze changes in sprint, strength, hematological, and hormonal parameters in high-level 800 m athletes during a complete athletics season. Thirteen male athletes of national and international level in 800 m (personal best ranging from 1:43 to 1:58 min:ss) participated in this study. A total of 5 tests were conducted during a complete athletics season. Athletes performed sprint tests (20 and 200 m), countermovement jump (CMJ), jump squat (JS), and full squat (SQ) tests. Blood samples (red and white blood profile) and hormones were collected in test 1 (T1), test 3 (T3), and test 5 (T5). A general increase in the performance of the strength and sprint parameters analyzed (CMJ, JS, SQ, 20 m, and 200 m) during the season was observed, with a significant time effect in CMJ (P < 0.01), SQ (P < 0.01), and 200 m (P < 0.05). This improvement was accompanied by a significant enhancement of the 800 m performance from T3 to T5 (P < 0.01). Significant changes in some hematological variables: hematocrit (Hct) (P < 0.01), mean corpuscular volume (MCV) (P < 0.001), mean corpuscular hemoglobin content (MCHC) (P < 0.001), white blood cells count (WBC) (P < 0.05), neutrophils (P < 0.05), monocytes (P < 0.05), and mean platelet volume (MPV) (P < 0.05) were observed throughout the season. The hormonal response and creatin kinase (CK) did not show significant variations during the season, except for insulin-like growth factor I (IGF-1) (P < 0.05). In conclusion, our results suggest the importance of strength levels in middle distance athletes. On the other hand, variations in some hematological parameters and a depression of the immune system occurred during the season. Therefore, monitoring of the mechanical, hematological and hormonal response in athletes may help coaches and athletes to optimize the regulation of training contents and may be useful to diagnose states of overreaching or overtraining in athletes throughout the season. PMID- 28912726 TI - Cardiovascular and Muscular Consequences of Work-Matched Interval-Type of Concentric and Eccentric Pedaling Exercise on a Soft Robot. AB - Eccentric types of endurance exercise are an acknowledged alternative to conventional concentric types of exercise rehabilitation for the cardiac patient, because they reduce cardiorespiratory strain due to a lower metabolic cost of producing an equivalent mechanical output. The former contention has not been tested in a power- and work-matched situation of interval-type exercise under identical conditions because concentric and eccentric types of exercise pose specific demands on the exercise machinery, which are not fulfilled in current practice. Here we tested cardiovascular and muscular consequences of work-matched interval-type of leg exercise (target workload of 15 sets of 1-min bipedal cycles of knee extension and flexion at 30 rpm with 17% of maximal concentric power) on a soft robotic device in healthy subjects by concomitantly monitoring respiration, blood glucose and lactate, and power during exercise and recovery. We hypothesized that interval-type of eccentric exercise lowers strain on glucose related aerobic metabolism compared to work-matched concentric exercise, and reduces cardiorespiratory strain to levels being acceptable for the cardiac patient. Eight physically active male subjects (24.0 years, 74.7 kg, 3.4 L O2 min 1), which power and endurance performance was extensively characterized, completed the study, finalizing 12 sets on average. Average performance was similar during concentric and eccentric exercise (p = 0.75) but lower than during constant load endurance exercise on a cycle ergometer at 75% of peak aerobic power output (126 vs. 188 Watt) that is recommended for improving endurance capacity. Peak oxygen uptake (-17%), peak ventilation (-23%), peak cardiac output (-16%), and blood lactate (-37%) during soft robotic exercise were lower during eccentric than concentric exercise. Glucose was 8% increased after eccentric exercise when peak RER was 12% lower than during concentric exercise. Muscle power and RFD were similarly reduced after eccentric and concentric exercise. The results highlight that the deployed interval-type of eccentric leg exercise reduces metabolic strain of the cardiovasculature and muscle compared to concentric exercise, to recommended levels for cardio-rehabilitation (i.e., 50 70% of peak heart rate). Increases in blood glucose concentration indicate that resistance to contraction-induced glucose uptake after the deployed eccentric protocol is unrelated to muscle fatigue. PMID- 28912727 TI - A Hybrid EMD-Kurtosis Method for Estimating Fetal Heart Rate from Continuous Doppler Signals. AB - Monitoring of fetal heart rate (FHR) is an important measure of fetal wellbeing during the months of pregnancy. Previous works on estimating FHR variability from Doppler ultrasound (DUS) signal mainly through autocorrelation analysis showed low accuracy when compared with heart rate variability (HRV) computed from fetal electrocardiography (fECG). In this work, we proposed a method based on empirical mode decomposition (EMD) and the kurtosis statistics to estimate FHR and its variability from DUS. Comparison between estimated beat-to-beat intervals using the proposed method and the autocorrelation function (AF) with respect to RR intervals computed from fECG as the ground truth was done on DUS signals from 44 pregnant mothers in the early (20 cases) and late (24 cases) gestational weeks. The new EMD-kurtosis method showed significant lower error in estimating the number of beats in the early group (EMD-kurtosis: 2.2% vs. AF: 8.5%, p < 0.01, root mean squared error) and the late group (EMD-kurtosis: 2.9% vs. AF: 6.2%). The EMD-kurtosis method was also found to be better in estimating mean beat-to beat with an average difference of 1.6 ms from true mean RR compared to 19.3 ms by using the AF method. However, the EMD-kurtosis performed worse than AF in estimating SNDD and RMSSD. The proposed EMD-kurtosis method is more robust than AF in low signal-to-noise ratio cases and can be used in a hybrid system to estimate beat-to-beat intervals from DUS. Further analysis to reduce the estimated beat-to-beat variability from the EMD-kurtosis method is needed. PMID- 28912728 TI - "You're Only as Strong as Your Weakest Link": A Current Opinion about the Concepts and Characteristics of Functional Training. PMID- 28912730 TI - Diagnosis of Swimming Induced Pulmonary Edema-A Review. AB - Swimming induced pulmonary edema (SIPE) is a complication that can occur during exercise with the possibility of misdiagnosis and can quickly become life threatening; however, medical literature infrequently describes SIPE. Therefore, the aim of this review was to analyse all individual cases diagnosed with SIPE as reported in scientific sources, with an emphasis on the diagnostic pathways and the key facts resulting in its diagnosis. Due to a multifactorial and complicated pathophysiology, the diagnosis could be difficult. Based on the actual literature, we try to point out important findings regarding history, conditions, clinical findings, and diagnostic testing helping to confirm the diagnosis of SIPE. Thirty-eight cases from seventeen articles reporting the diagnosis of SIPE were selected. We found remarkable differences in the individual described diagnostic pathways. A total of 100% of the cases suffered from an acute onset of breathing problems, occasionally accompanied by hemoptysis. A total of 73% showed initial hypoxemia. In most of the cases (89%), an initial chest X-Ray or chest CT was available, of which one-third (71%) showed radiological signs of pulmonary edema. The majority of the cases (82%) experienced a rapid resolution of symptoms within 48 h, the diagnostic hallmark of SIPE. Due to a foreseeable increase in participation in swimming competitions and endurance competitions with a swimming component, diagnosis of SIPE will be important, especially for medical teams caring for these athletes. PMID- 28912729 TI - Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection. AB - Even today two bacterial lung infections, namely pneumonia and tuberculosis, are among the 10 most frequent causes of death worldwide. These infections still lack effective treatments in many developing countries and in immunocompromised populations like infants, elderly people and transplanted patients. The interaction between bacteria and the host is a complex system of interlinked intercellular and the intracellular processes, enriched in regulatory structures like positive and negative feedback loops. Severe pathological condition can emerge when the immune system of the host fails to neutralize the infection. This failure can result in systemic spreading of pathogens or overwhelming immune response followed by a systemic inflammatory response. Mathematical modeling is a promising tool to dissect the complexity underlying pathogenesis of bacterial lung infection at the molecular, cellular and tissue levels, and also at the interfaces among levels. In this article, we introduce mathematical and computational modeling frameworks that can be used for investigating molecular and cellular mechanisms underlying bacterial lung infection. Then, we compile and discuss published results on the modeling of regulatory pathways and cell populations relevant for lung infection and inflammation. Finally, we discuss how to make use of this multiplicity of modeling approaches to open new avenues in the search of the molecular and cellular mechanisms underlying bacterial infection in the lung. PMID- 28912732 TI - Transcriptome Identified lncRNAs Associated with Renal Fibrosis in UUO Rat Model. AB - Renal fibrosis represents a final common outcome of many renal diseases and has attracted a great deal of attention. To better understand whether lncRNAs could be a player in this process or be a biomarker for renal fibrosis diagnosis, we compared transcriptome sequencing data on renal tissues and urine respectively between UUO (unilateral ureteral obstruction) and shamed (Sham) rat model. Numerous genes including lncRNAs with significant changes in their expression were identified. 24 lncRNAs were up-regulated and 79 lncRNAs were down-regulated in the renal tissues of the UUO rats. 625 lncRNAs were up-regulated and 177 lncRNAs were down-regulated in urines of the UUO rats. Among the lncRNAs upregulated in renal tissue of UUO rats, 19 lncRNAs were predicted containing several conserved Smad3 binding motifs in the promoter. Among them, lncRNAs with putative promoter containing more than 4 conserved Smad3 binding motifs were demonstrated to be induced by TGF-beta significantly in normal rat renal tubular epithelial NRK-52E cells. We further confirmed that lncRNA TCONS_00088786 and TCONS_01496394 were regulated by TGF-beta stimulation and also can influence the expression of some fibrosis-related genes through a feedback loop. Based on transcriptome sequencing data, bioinformatics analysis and qRT-PCR detection, we also demonstrated lncRNA in urine are detectable and might be a novel biomarker of renal fibrosis. These results provide new information for the involvement of lncRNAs in renal fibrosis, indicating that they may serve as candidate biomarkers or therapeutic targets in the future. PMID- 28912731 TI - Long-Term Athletic Development in Youth Alpine Ski Racing: The Effect of Physical Fitness, Ski Racing Technique, Anthropometrics and Biological Maturity Status on Injuries. AB - Alpine ski racing is known to be a sport with a high risk of injuries. Because most studies have focused mainly on top-level athletes and on traumatic injuries, limited research exists about injury risk factors among youth ski racers. The aim of this study was to determine the intrinsic risk factors (anthropometrics, biological maturity, physical fitness, racing technique) for injury among youth alpine ski racers. Study participants were 81 youth ski racers attending a ski boarding school (50 males, 31 females; 9-14 years). A prospective longitudinal cohort design was used to monitor sports-related risk factors over two seasons and traumatic (TI) and overuse injuries (OI). At the beginning of the study, anthropometric characteristics (body height, body weight, sitting height, body mass index); biological maturity [status age at peak height velocity (APHV)]; physical performance parameters related to jump coordination, maximal leg and core strength, explosive and reactive strength, balance and endurance; and ski racing technique were assessed. Z score transformations normalized the age groups. Multivariate binary logistic regression (dependent variable: injury yes/no) and multivariate linear regression analyses (dependent variable: injury severity in total days of absence from training) were calculated. T-tests and multivariate analyses of variance were used to reveal differences between injured and non-injured athletes and between injury severity groups. The level of significance was set to p < 0.05. Relatively low rates of injuries were reported for both traumatic (0.63 TI/athlete) and overuse injuries (0.21 OI/athlete). Athletes with higher body weight, body height, and sitting height; lower APHV values; better core flexion strength; smaller core flexion:extension strength ratio; shorter drop jump contact time; and higher drop jump reactive strength index were at a lower injury risk or more vulnerable for fewer days of absence from training. However, significant differences between injured and non-injured athletes were only observed with respect to the drop jump reactive strength index. Regular documentation of anthropometric characteristics, biological maturity and physical fitness parameters is crucial to help to prevent injury in youth ski racing. The present findings suggest that neuromuscular training should be incorporated into the training regimen of youth ski racers to prevent injuries. PMID- 28912733 TI - Resilience and Cognitive Bias in Chinese Male Medical Freshmen. AB - BACKGROUND: Psychological resilience has become a hot issue in positive psychology research. However, little is known about cognitive bias difference of individuals with different resilience levels. This study aimed to explore the characteristics of cognitive bias and its role in Chinese medical freshmen with different resilience levels. METHODS: 312 Chinese medical freshmen were surveyed by the Chinese version of Connor-Davidson Resilience Scale, 92 of whom were, respectively, allocated into high (n = 46) and low (n = 46) resilient group to complete computerized tests using an attentional shifting task and an emotional picture recognition task. RESULTS: All participants had the highest recognition accuracy toward negative pictures compared to neutral and positive ones. By comparison, it was found that the high-resilient group had a longer recognition response time toward positive emotional pictures, but a shorter response time toward negative emotional pictures, while the low-resilient group had a longer response time toward negative emotional pictures. CONCLUSION: This study pointed to the association between resilience and cognitive bias. Medical freshmen with different resilience levels showed significant differences in the cognitive bias toward emotional pictures, suggesting that reducing negative cognitive bias and promoting positive cognitive bias could be important targets to increase resilience. PMID- 28912734 TI - Malmo Treatment Referral and Intervention Study-High 12-Month Retention Rates in Patients Referred from Syringe Exchange to Methadone or Buprenorphine/Naloxone Treatment. AB - BACKGROUND: Heroin dependence is associated with high mortality. Opioid agonist treatment (OAT) with methadone or buprenorphine has strong evidence for treatment of this relapsing condition. In our setting, OAT has been associated with strict and demanding intake procedures, often with requirements of social stability, but also high, approximately 80 percent 12-month retention rates. In a recent randomized controlled trial, we demonstrated high rates of successful rapid referral from a syringe exchange programme (SEP) to treatment with methadone or buprenorphine, including actual treatment initiation. The objectives of this study were to assess 12-month retention rates, in order to assess whether a novel referral program of current drug users at a SEP would achieve retention rates comparable to more traditional intake procedures. METHODS: The present report is a 12-month follow-up of 71 patients who successfully started treatment with methadone or buprenorphine/naloxone. Patient data from baseline and at 12 months were collected. RESULTS: Out of the 71 patients who started treatment, 58 (82%) were still in treatment after 12 months. CONCLUSION: This was a population, referred from a SEP, with a high drug use severity on admission and no pretreatment requirement for social stability, but there were still high retention rates at 12 months comparable to regular opioid agonist clinics in our setting. PMID- 28912735 TI - Development and Preliminary Validation of the Scale for Evaluation of Psychiatric Integrative and Continuous Care-Patient's Version. AB - This pilot study aimed to evaluate and examine an instrument that integrates relevant aspects of cross-sectoral (in- and outpatients) mental health care, is simply to use and shows satisfactory psychometric properties. The development of the scale comprised literature research, held 14 focus groups and 12 interviews with patients and health care providers, item-pool generation, content validation by a scientific expert panel, and face validation by 90 patients. The preliminary scale was tested on 385 patients across seven German hospitals with cross sectoral mental health care (CSMHC) as part of their treatment program. Psychometric properties of the scale were evaluated using genuine and transformed data scoring. To check reliability and postdictive validity of the scale, Cronbach's alpha coefficient and multivariable linear regression were used. This development process led to the development of an 18-item scale called the "Scale for Evaluation of Psychiatric Integrative and Continuous Care (SEPICC)" with a two-point and five-point response options. The scale consists of two sections. The first section assesses the presence or absence of patients' experiences with various CSMHC' relevant components such as home treatment, flexibility of treatments' switching, case management, continuity of care, cross-sectoral therapeutic groups, and multidisciplinary teams. The second section evaluates the patients' opinions about these relevant components. Using raw and transformed scoring resulted into comparable results. However, data distribution using transformed scoring showed a smaller deviation from normality. For the overall scale, the Cronbach's alpha coefficient was 0.82. Self-reported experiences with relevant components of the CSMHC were positively associated with the patients approval of these components. In conclusion, the new scale provides a good starting point for further validation. It can be used as a tool to evaluate CSMHC. Methodologically, using transformed data scoring appeared to be preferable because of a smaller deviation from normality and a higher reliability measured by Cronbach's alpha. PMID- 28912736 TI - Understanding the Uncanny: Both Atypical Features and Category Ambiguity Provoke Aversion toward Humanlike Robots. AB - Robots intended for social contexts are often designed with explicit humanlike attributes in order to facilitate their reception by (and communication with) people. However, observation of an "uncanny valley"-a phenomenon in which highly humanlike entities provoke aversion in human observers-has lead some to caution against this practice. Both of these contrasting perspectives on the anthropomorphic design of social robots find some support in empirical investigations to date. Yet, owing to outstanding empirical limitations and theoretical disputes, the uncanny valley and its implications for human-robot interaction remains poorly understood. We thus explored the relationship between human similarity and people's aversion toward humanlike robots via manipulation of the agents' appearances. To that end, we employed a picture-viewing task (Nagents = 60) to conduct an experimental test (Nparticipants = 72) of the uncanny valley's existence and the visual features that cause certain humanlike robots to be unnerving. Across the levels of human similarity, we further manipulated agent appearance on two dimensions, typicality (prototypic, atypical, and ambiguous) and agent identity (robot, person), and measured participants' aversion using both subjective and behavioral indices. Our findings were as follows: (1) Further substantiating its existence, the data show a clear and consistent uncanny valley in the current design space of humanoid robots. (2) Both category ambiguity, and more so, atypicalities provoke aversive responding, thus shedding light on the visual factors that drive people's discomfort. (3) Use of the Negative Attitudes toward Robots Scale did not reveal any significant relationships between people's pre-existing attitudes toward humanlike robots and their aversive responding-suggesting positive exposure and/or additional experience with robots is unlikely to affect the occurrence of an uncanny valley effect in humanoid robotics. This work furthers our understanding of both the uncanny valley, as well as the visual factors that contribute to an agent's uncanniness. PMID- 28912738 TI - Prejudice and Health Anxiety about Radiation Exposure from Second-Generation Atomic Bomb Survivors: Results from a Qualitative Interview Study. AB - The effect of atomic bomb radiation exposure on the survivors and their children has been a worrisome problem since soon after the 1945 Hiroshima and Nagasaki bombings. Researchers have examined physical and genetic effects; however, no research has focused on second-generation survivors' (SGS) psychological effects. Consequently, this study shed light on the SGS' experience of discrimination and prejudice and their anxiety concerning the genetic effects of radiation exposure. This study utilized semi-structured interviews with 14 SGS (10 women, mean age = 56 +/- 6.25 years, range = 46-68 years). Data were analyzed using a modified version of the grounded theory approach. Three categories were extracted: low awareness as an SGS, no health anxiety regarding the effect of radiation, and health anxiety regarding the effect of radiation. The results did not reveal that SGS who grew up in the bombed areas experienced discrimination or prejudice. They had little health anxiety from childhood to adolescence. In this study, some of the SGS developed health anxiety about their third-generation children, but only among female participants. Perhaps the transgenerational transmission of anxiety concerning the genetic effects of radiation exposure causes stress, particularly among women with children. However, a change was seen in adulthood health anxiety regarding the effects of radiation, suggesting the possibility that changes in the psychological experiences of SGS can be observed throughout their lifetimes and that their own health status, and that of their children, the third generation survivors, affects their health anxiety regarding radiation. PMID- 28912737 TI - Neuropsychological Profile of Specific Executive Dysfunctions in Patients with Deficit and Non-deficit Schizophrenia. AB - Objectives: Although it has been shown that there are more profound deficits present in deficit schizophrenia (DS) patients than in non-deficit schizophrenia (NDS) patients, there still remain some matters requiring further investigation. In this context, we formulated three research aims: (1) to compare executive functions between the investigated groups, (2) to determine the relationship between particular aspects of executive functions within the groups, and (3) to draw up a neuropsychological profile for executive functions. Methods: The study involved 148 schizophrenia patients divided into two groups on the basis of the Schedule for the Deficit Syndrome: DS (n = 70) and NDS (n = 78). Patients were matched for sex, age, years of education, and overall cognitive functioning. For assessing executive functions we used the Wisconsin Card Sorting Test (WCST), the Trail Making Test (TMT), the Phonemic Verbal Fluency Test (VFT P), the Stroop Color and Word Test (SCWT), and the Go/No Go task (GNG). Results: Deficit schizophrenia patients scored lower on the WCST and TMT (relative flexibility) than did the NDS patients. There were no inter-group differences in the VFT P, SCWT (relative inhibition), or GNG. There were significant correlations between WCST and TMT scores in both groups. The general neuropsychological profiles were similar in both groups. Conclusion: Deficit schizophrenia patients exhibited slightly greater interference with concept formation and non-verbal cognitive flexibility. Therefore, such problems may be specific to this particular type of schizophrenia. These results may be useful for the development of neuropsychological diagnostic methods for patients with schizophrenia. PMID- 28912739 TI - Contextual Cueing Effect in Spatial Layout Defined by Binocular Disparity. AB - Repeated visual context induces higher search efficiency, revealing a contextual cueing effect, which depends on the association between the target and its visual context. In this study, participants performed a visual search task where search items were presented with depth information defined by binocular disparity. When the 3-dimensional (3D) configurations were repeated over blocks, the contextual cueing effect was obtained (Experiment 1). When depth information was in chaos over repeated configurations, visual search was not facilitated and the contextual cueing effect largely crippled (Experiment 2). However, when we made the search items within a tiny random displacement in the 2-dimentional (2D) plane but maintained the depth information constant, the contextual cueing was preserved (Experiment 3). We concluded that the contextual cueing effect was robust in the context provided by 3D space with stereoscopic information, and more importantly, the visual system prioritized stereoscopic information in learning of spatial information when depth information was available. PMID- 28912740 TI - The Dark Triad Traits from a Life History Perspective in Six Countries. AB - Work on the Dark Triad traits has benefited from the use of a life history framework but it has been limited to primarily Western samples and indirect assessments of life history strategies. Here, we examine how the Dark Triad traits (i.e., psychopathy, Machiavellianism, and narcissism) relate to two measures of individual differences in life history strategies. In Study 1 (N = 937), we replicated prior observed links between life history strategies, as measured by the Mini-K, and the Dark Triad traits using samples recruited from three countries. In Study 2 (N = 1032), we measured life history strategies using the Consideration of Future Consequences Scale and correlated it with the Dark Triad traits in samples recruited from three additional countries. While there was some variability across participants' sex and country, the results were generally consistent in that psychopathy and (to a lesser extent) Machiavellianism were related to faster life history strategies and narcissism was related to slower life history strategies. These results add cross-cultural data and the use of two measures of life history speed to understand the Dark Triad traits from a life history perspective. PMID- 28912741 TI - Daily Use of Energy Management Strategies and Occupational Well-being: The Moderating Role of Job Demands. AB - We examine the relationships among employees' use of energy management strategies and two occupational well-being outcomes: job satisfaction and emotional exhaustion. Based on conservation of resources theory, it was hypothesized that employees with high job demands would benefit more from using energy management strategies (i.e., including prosocial, organizing, and meaning-related strategies), compared to employees with low job demands. We tested this proposition using a quantitative diary study. Fifty-four employees provided data twice daily across one work week (on average, 7 daily entries). Supporting the hypotheses, prosocial energy management was positively related to job satisfaction. Moreover, employees with high job demands were less emotionally exhausted when using prosocial strategies. Contrary to predictions, when using organizing strategies, employees with low job demands had higher job satisfaction and lower emotional exhaustion. Under high job demands, greater use of organizing strategies was associated with lower job satisfaction and higher emotional exhaustion. Finally, use of meaning-related strategies was associated with higher emotional exhaustion when job demands were low. With this research, we position energy management as part of a resource investment process aimed at maintaining and improving occupational well-being. Our findings show that this resource investment will be more or less effective depending on the type of strategy used and the existing drain on resources (i.e., job demands). This is the first study to examine momentary effects of distinct types of work-related energy management strategies on occupational well-being. PMID- 28912742 TI - Perception, Action, and Cognition of Football Referees in Extreme Temperatures: Impact on Decision Performance. AB - Different professional domains require high levels of physical performance alongside fast and accurate decision-making. Construction workers, police officers, firefighters, elite sports men and women, the military and emergency medical professionals are often exposed to hostile environments with limited options for behavioral coping strategies. In this (mini) review we use football refereeing as an example to discuss the combined effect of intense physical activity and extreme temperatures on decision-making and suggest an explicative model. In professional football competitions can be played in temperatures ranging from -5 degrees C in Norway to 30 degrees C in Spain for example. Despite these conditions, the referee's responsibility is to consistently apply the laws fairly and uniformly, and to ensure the rules are followed without waning or adversely influencing the competitiveness of the play. However, strenuous exercise in extreme environments imposes increased physiological and psychological stress that can affect decision-making. Therefore, the physical exertion required to follow the game and the thermal strain from the extreme temperatures may hinder the ability of referees to make fast and accurate decisions. Here, we review literature on the physical and cognitive requirements of football refereeing and how extreme temperatures may affect referees' decisions. Research suggests that both hot and cold environments have a negative impact on decision-making but data specific to decision-making is still lacking. A theoretical model of decision-making under the constraint of intense physical activity and thermal stress is suggested. Future naturalistic studies are needed to validate this model and provide clear recommendations for mitigating strategies. PMID- 28912743 TI - Act on Numbers: Numerical Magnitude Influences Selection and Kinematics of Finger Movement. AB - In the past decade hand kinematics has been reliably adopted for investigating cognitive processes and disentangling debated topics. One of the most controversial issues in numerical cognition literature regards the origin - cultural vs. genetically driven - of the mental number line (MNL), oriented from left (small numbers) to right (large numbers). To date, the majority of studies have investigated this effect by means of response times, whereas studies considering more culturally unbiased measures such as kinematic parameters are rare. Here, we present a new paradigm that combines a "free response" task with the kinematic analysis of movement. Participants were seated in front of two little soccer goals placed on a table, one on the left and one on the right side. They were presented with left- or right-directed arrows and they were instructed to kick a small ball with their right index toward the goal indicated by the arrow. In a few test trials participants were presented also with a small (2) or a large (8) number, and they were allowed to choose the kicking direction. Participants performed more left responses with the small number and more right responses with the large number. The whole kicking movement was segmented in two temporal phases in order to make a hand kinematics' fine-grained analysis. The Kick Preparation and Kick Finalization phases were selected on the basis of peak trajectory deviation from the virtual midline between the two goals. Results show an effect of both small and large numbers on action execution timing. Participants were faster to finalize the action when responding to small numbers toward the left and to large number toward the right. Here, we provide the first experimental demonstration which highlights how numerical processing affects action execution in a new and not-overlearned context. The employment of this innovative and unbiased paradigm will permit to disentangle the role of nature and culture in shaping the direction of MNL and the role of finger in the acquisition of numerical skills. Last but not least, similar paradigms will allow to determine how cognition can influence action execution. PMID- 28912744 TI - The Effect of Psychological Suzhi on Problem Behaviors in Chinese Adolescents: The Mediating Role of Subjective Social Status and Self-esteem. AB - In this study, we examined subjective social status (SSS) and self-esteem as potential mediators between the association of psychological suzhi and problem behaviors in a sample of 1271 Chinese adolescents (44.5% male, grades 7-12). The results showed that SSS and self-esteem were fully mediating the relationship between psychological suzhi and problem behaviors. Moreover, the indirect effect was stronger via self-esteem than via SSS. These findings perhaps provide insight into the preliminary effect that SSS and self-esteem underlie psychological suzhi's effect on adolescents' problem behaviors, and also are important in helping school-teachers and administrators to develop a better understanding of problem behaviors in their schools as a pre-requisite to the development of more effective behaviors management practices from the perspective of psychological suzhi. Implications and limitations in the present study have also been discussed. PMID- 28912745 TI - Emotional Empathic Responses to Dynamic Negative Affective Stimuli Is Gender Dependent. AB - Empathy entails the ability to recognize emotional states in others and feel for them. Since empathy does not take place in a static setting, paradigms utilizing more naturalistic, dynamic stimuli instead of static stimuli are perhaps more suited to grasp the origin of this highly complex social skill. The study was set up to test the effect of stimulus dynamics and gender on empathic responses. Participants were 80 healthy volunteers (N = 40 males) aged 22.5 years on average. Behavioral empathy was tested with the multifaceted empathy test, including static emotional stimuli, and the multidimensional movie empathy test (MMET), including dynamic stimuli. Findings showed emotional empathy (EE) responses were higher to negative emotional stimuli in both tasks, i.e., using static as well as dynamic stimuli. Interestingly a gender-dependent response was only seen in the MMET using dynamic stimuli. It was shown that females felt more aroused and were more concerned with people in negative affective states. It was concluded that the MMET is suited to study gender differences in EE. PMID- 28912746 TI - The Role of Slow Speech Amplitude Envelope for Speech Processing and Reading Development. AB - This study examined the putative link between the entrainment to the slow rhythmic structure of speech, speech intelligibility and reading by means of a behavioral paradigm. Two groups of 20 children (Grades 2 and 5) were asked to recall a pseudoword embedded in sentences presented either in quiet or noisy listening conditions. Half of the sentences were primed with their syllabic and prosodic amplitude envelope to determine whether a boost in auditory entrainment to these speech features enhanced pseudoword intelligibility. Priming improved pseudoword recall performance only for the older children both in a quiet and a noisy listening environment, and such benefit from the prime correlated with reading skills and pseudoword recall. Our results support the role of syllabic and prosodic tracking of speech in reading development. PMID- 28912748 TI - Editorial: Age-Related Vestibular Loss: Current Understanding and Future Research Directions. PMID- 28912747 TI - Decreasing Risk of Fatal Subarachnoid Hemorrhage and Other Epidemiological Trends in the Era of Coiling Implementation in Australia. AB - BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is associated with a high risk of mortality and disability in survivors. We examined the epidemiology and burden of SAH in our population during a time services were re-organized to facilitate access to evidence-based endovascular coiling and neurosurgical care. METHODS: SAH hospitalizations from 2001 to 2009, in New South Wales, Australia, were linked to death registrations to June 30, 2010. We assessed the variability of admission rates, fatal SAH rates and case fatality over time and according to patient demographic characteristics. RESULTS: There were 4,945 eligible patients admitted to hospital with SAH. The risk of fatal SAH significantly decreased by 2.7% on average per year (95% CI = 0.3-4.9%). Case fatality at 2, 30, 90, and 365 days significantly declined over time. The average annual percentage reduction in mortality ranged from 4.4% for 30-day mortality (95% CI -6.1 to -2.7) (P < 0.001) to 4.7% for mortality within 2 days (-7.1 to -2.2) (P < 0.001) (Table 3). Three percent of patients received coiling at the start of the study period, increasing to 28% at the end (P-value for trend <0.001). Females were significantly more likely to be hospitalized for a SAH compared to males [incident rate ratio (IRR) = 1.33, 95% CI = 1.23-1.44] (P < 0.001) and to die from SAH (IRR = 1.40, 95% CI = 1.24-1.59) (P < 0.001). People born in South-East Asia and the Oceania region had a significantly increased risk of SAH, while the risk of fatal SAH was greater in South-East and North-East Asian born residents. People residing in areas of least disadvantage had the lowest risk of hospitalization (IRR = 0.83, 95% CI = 0.74 0.92) and also the lowest risk of fatal SAH (0.81, 95% CI = 0.66-1.00) (P < 0.001 and P = 0.003, respectively). For every 100 SAH admissions, 20 and 15 might be avoided in males and females, respectively, if the risk of SAH in our population equated to that of the most socio-economically advantaged. CONCLUSION: Our study reports reductions in mortality risk in SAH corresponding to identifiable changes in health service delivery and evolving treatments such as coiling. Addressing inequities in SAH risk and mortality may require the targeting of prevalent and modifiable risk factors to improve population outcomes. PMID- 28912749 TI - Functional Connectivity of the Corpus Callosum in Epilepsy Patients with Secondarily Generalized Seizures. AB - The corpus callosum (CC) plays an important role in generalization of seizure activity. We used resting-state function magnetic resonance imaging (rs-fMRI) to investigate the regional and interregional functional connectivity of CC in patients with magnetic resonance imaging (MRI)-negative and secondarily generalized seizures. We measured the multi-regional coherences of blood oxygen level-dependent (BOLD) signals via rs-fMRI, cortical thickness via high resolution T1-weighted MRI, and white matter (WM) integrity via diffusion-tensor imaging in 16 epilepsy patients as well as in 16 age- and gender-matched healthy subjects. All patients had non-lesional MRI, medically well-controlled focal epilepsy and history of secondarily generalized convulsions. Individuals with epilepsy had significant differences in regional and interregional hypersynchronization of BOLD signals intrahemispherically and interhemispherically, but no difference in cortical thickness and WM integrity. The only area with increased regional hypersynchrony in WM was over the anterior CC, which also exhibited lower activation of neighboring resting-state networks. The present study revealed abnormal local and distant synchronization of spontaneous neural activities in epileptic patients with secondarily generalized seizures. PMID- 28912751 TI - Decreased Secondary Lesion Growth and Attenuated Immune Response after Traumatic Brain Injury in Tlr2/4-/- Mice. AB - Danger-associated molecular patterns are released by damaged cells and trigger neuroinflammation through activation of non-specific pattern recognition receptors, e.g., toll-like receptors (TLRs). Since the role of TLR2 and 4 after traumatic brain injury (TBI) is still unclear, we examined the outcome and the expression of pro-inflammatory mediators after experimental TBI in Tlr2/4-/- and wild-type (WT) mice. Tlr2/4-/- and WT mice were subjected to controlled cortical injury and contusion volume and brain edema formation were assessed 24 h thereafter. Expression of inflammatory markers in brain tissue was measured by quantitative PCR 15 min, 3 h, 6 h, 12 h, and 24 h after controlled cortical impact (CCI). Contusion volume was significantly attenuated in Tlr2/4-/- mice (29.7 +/- 0.7 mm3 as compared to 33.5 +/- 0.8 mm3 in WT; p < 0.05) after CCI while brain edema was not affected. Only interleukin (IL)-1beta gene expression was increased after CCI in the Tlr2/4-/- relative to WT mice. Inducible nitric oxide synthetase, TNF, IL-6, and COX-2 were similar in injured WT and Tlr2/4-/- mice, while the increase in high-mobility group box 1 was attenuated at 6 h. TLR2 and 4 are consequently shown to potentially promote secondary brain injury after experimental CCI via neuroinflammation and may therefore represent a novel therapeutic target for the treatment of TBI. PMID- 28912750 TI - Current and Emerging Technologies for Probing Molecular Signatures of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available techniques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype. PMID- 28912753 TI - Food Addiction in Patients with Newly Diagnosed Type 2 Diabetes in Northeast China. AB - AIM: The aim of the study was to explore the prevalence of food addiction (FA) in individuals with newly diagnosed type 2 diabetes mellitus (T2DM) in China and to analyze risk factors of FA. METHODS: A total of 624 subjects [312 individuals with newly diagnosed T2DM, 312 age-matched and body mass index (BMI)-matched healthy participants] were recruited. All participants were asked to complete the Yale Food Addiction Scale (YFAS) and received physical and lab examinations. The T2DM group was further divided into a FA group and a non-FA group. RESULTS: Of the patients with newly diagnosed T2DM, 8.6% (27/312) met the FA diagnostic criteria proposed by the YFAS (7.6% in men and 10.1% in women, P = 0.43), while 1.3% (4/312) met the criteria in the control group. Logistic regression analysis showed that FA in the T2DM group was positively related to BMI and negatively related to age. T2DM with FA had a significantly higher uric acid (UA). CONCLUSION: Both men and women with newly diagnosed T2DM, especially in northeast China, were more likely to suffer from FA. T2DM patients with FA were younger and had higher UA. PMID- 28912752 TI - Disparities in Cardiovascular Disease and Type 2 Diabetes Risk Factors in Blacks and Whites: Dissecting Racial Paradox of Metabolic Syndrome. AB - Cardiovascular diseases (CVD) remain as the leading cause of mortality in the western world and have become a major health threat for developing countries. There are several risk factors that account for the CVD and the associated mortality. These include genetics, type 2 diabetes (T2DM), obesity, physical inactivity, hypertension, and abnormal lipids and lipoproteins. The constellation of these risk factors has been termed metabolic syndrome (MetS). MetS varies among racial and ethnic populations. Thus, race and ethnicity account for some of the differences in the MetS and the associated CVD and T2DM. Furthermore, the relationships among traditional metabolic parameters and CVD differ, especially when comparing Black and White populations. In this regard, the greater CVD in Blacks than Whites have been partly attributed to other non-traditional CVD risk factors, such as subclinical inflammation (C-reactive protein), homocysteine, increased low-density lipoprotein oxidation, lipoprotein a, adiponectin, and plasminogen activator inhibitor-1, etc. Thus, to understand CVD and T2DM differences in Blacks and Whites with MetS, it is essential to explore the contributions of both traditional and non-traditional CVD and T2DM risk factors in Blacks of African ancestry and Whites of Europoid ancestry. Therefore, in this mini review, we propose that non-traditional risk factors should be integrated in defining MetS as a predictor of CVD and T2DM in Blacks in the African diaspora in future studies. PMID- 28912754 TI - The Gambian Bone and Muscle Ageing Study: Baseline Data from a Prospective Observational African Sub-Saharan Study. AB - The Gambian Bone and Muscle Ageing Study is a prospective observational study investigating bone and muscle ageing in men and women from a poor, subsistence farming community of The Gambia, West Africa. Musculoskeletal diseases, including osteoporosis and sarcopenia, form a major part of the current global non communicable disease burden. By 2050, the vast majority of the world's ageing population will live in low- and middle-income countries with an estimated two fold rise in osteoporotic fracture. The study design was to characterise change in bone and muscle outcomes and to identify possible preventative strategies for fracture and sarcopenia in the increasing ageing population. Men and women aged >=40 years from the Kiang West region of The Gambia were recruited with stratified sampling by sex and age. Baseline measurements were completed in 488 participants in 2012 who were randomly assigned to follow-up between 1.5 and 2 years later. Follow-up measurements were performed on 465 participants approximately 1.7 years after baseline measurements. The data set comprises a wide range of measurements on bone, muscle strength, anthropometry, biochemistry, and dietary intake. Questionnaires were used to obtain information on health, lifestyle, musculoskeletal pain, and reproductive status. Baseline cross sectional data show preliminary evidence for bone mineral density and muscle loss with age. Men had greater negative differences in total body lean mass with age than women following adjustments for body size. From peripheral quantitative computed tomography scans, greater negative associations between bone outcomes and age at the radius and tibia were shown in women than in men. Ultimately, the findings from The Gambian Bone and Muscle Ageing Study will contribute to the understanding of musculoskeletal health in a transitioning population and better characterise fracture and sarcopenia incidence in The Gambia with an aim to the development of preventative strategies against both. PMID- 28912755 TI - Editorial: A Multidisciplinary Look at Stenotrophomonas maltophilia: An Emerging Multi-Drug-Resistant Global Opportunistic Pathogen. PMID- 28912757 TI - In situ Occurrence, Prevalence and Dynamics of Parvilucifera Parasitoids during Recurrent Blooms of the Toxic Dinoflagellate Alexandrium minutum. AB - Dinoflagellate blooms are natural phenomena that often occur in coastal areas, which in addition to their large number of nutrient-rich sites are characterized by highly restricted hydrodynamics within bays, marinas, enclosed beaches, and harbors. In these areas, massive proliferations of dinoflagellates have harmful effects on humans and the ecosystem. However, the high cell density reached during blooms make them vulnerable to parasitic infections. Under laboratory conditions parasitoids are able to exterminate an entire host population. In nature, Parvilucifera parasitoids infect the toxic dinoflagellate Alexandrium minutum during bloom conditions but their prevalence and impact remain unexplored. In this study, we evaluated the in situ occurrence, prevalence, and dynamics of Parvilucifera parasitoids during recurrent blooms of A. minutum in a confined site in the NW Mediterranean Sea as well as the contribution of parasitism to bloom termination. Parvilucifera parasitoids were recurrently detected from 2009 to 2013, during seasonal outbreaks of A. minutum. Parasitic infections in surface waters occurred after the abundance of A. minutum reached 104-105 cells L-1, suggesting a density threshold beyond which Parvilucifera transmission is enhanced and the number of infected cells increases. Moreover, host and parasitoid abundances were not in phase. Instead, there was a lag between maximum A. minutum and Parvilucifera densities, indicative of a delayed density-dependent response of the parasitoid to host abundances, similar to the temporal dynamics of predator-prey interactions. The highest parasitoid prevalence was reached after a peak in host abundance and coincided with the decay phase of the bloom, when a maximum of 38% of the A. minutum population was infected. According to our estimates, Parvilucifera infections accounted for 5 18% of the total observed A. minutum mortality, which suggested that the contribution of parasitism to bloom termination is similar to that of other biological factors, such as encystment and grazing. PMID- 28912756 TI - FixK2 Is the Main Transcriptional Activator of Bradyrhizobium diazoefficiens nosRZDYFLX Genes in Response to Low Oxygen. AB - The powerful greenhouse gas, nitrous oxide (N2O) has a strong potential to drive climate change. Soils are the major source of N2O and microbial nitrification and denitrification the main processes involved. The soybean endosymbiont Bradyrhizobium diazoefficiens is considered a model to study rhizobial denitrification, which depends on the napEDABC, nirK, norCBQD, and nosRZDYFLX genes. In this bacterium, the role of the regulatory cascade FixLJ-FixK2-NnrR in the expression of napEDABC, nirK, and norCBQD genes involved in N2O synthesis has been previously unraveled. However, much remains to be discovered regarding the regulation of the respiratory N2O reductase (N2OR), the key enzyme that mitigates N2O emissions. In this work, we have demonstrated that nosRZDYFLX genes constitute an operon which is transcribed from a major promoter located upstream of the nosR gene. Low oxygen was shown to be the main inducer of expression of nosRZDYFLX genes and N2OR activity, FixK2 being the regulatory protein involved in such control. Further, by using an in vitro transcription assay with purified FixK2 protein and B. diazoefficiens RNA polymerase we were able to show that the nosRZDYFLX genes are direct targets of FixK2. PMID- 28912758 TI - The N-terminal Region of Nisin Is Important for the BceAB-Type ABC Transporter NsrFP from Streptococcus agalactiae COH1. AB - Lantibiotics are (methyl)-lanthionine-containing antimicrobial peptides produced by several Gram-positive bacteria. Some human pathogenic bacteria express specific resistance proteins that counteract this antimicrobial activity of lantibiotics. In Streptococcus agalactiae COH1 resistance against the well-known lantibiotic nisin is conferred by, the nisin resistance protein (NSR), a two component system (NsrRK) and a BceAB-type ATP-binding cassette (ABC) transporter (NsrFP). The present study focuses on elucidating the function of NsrFP via its heterologous expression in Lactococcus lactis. NsrFP is able to confer a 16-fold resistance against wild type nisin as determined by growth inhibition experiments and functions as a lantibiotic exporter. Several C-terminal nisin mutants indicated that NsrFP recognizes the N-terminal region of nisin. The N-terminus harbors three (methyl)-lanthionine rings, which are conserved in other lantibiotics. PMID- 28912759 TI - Seasonality Affects the Diversity and Composition of Bacterioplankton Communities in Dongjiang River, a Drinking Water Source of Hong Kong. AB - Water quality ranks the most vital criterion for rivers serving as drinking water sources, which periodically changes over seasons. Such fluctuation is believed associated with the state shifts of bacterial community within. To date, seasonality effects on bacterioplankton community patterns in large rivers serving as drinking water sources however, are still poorly understood. Here we investigated the intra-annual bacterial community structure in the Dongjiang River, a drinking water source of Hong Kong, using high-throughput pyrosequencing in concert with geochemical property measurements during dry, and wet seasons. Our results showed that Proteobacteria, Actinobacteria, and Bacteroidetes were the dominant phyla of bacterioplankton communities, which varied in composition, and distribution from dry to wet seasons, and exhibited profound seasonal changes. Actinobacteria, Bacteroidetes, and Cyanobacteria seemed to be more associated with seasonality that the relative abundances of Actinobacteria, and Bacteroidetes were significantly higher in the dry season than those in the wet season (p < 0.01), while the relative abundance of Cyanobacteria was about 10 fold higher in the wet season than in the dry season. Temperature and [Formula: see text]-N concentration represented key contributing factors to the observed seasonal variations. These findings help understand the roles of various bacterioplankton and their interactions with the biogeochemical processes in the river ecosystem. PMID- 28912760 TI - Immunization with Live Human Rhinovirus (HRV) 16 Induces Protection in Cotton Rats against HRV14 Infection. AB - Human rhinoviruses (HRVs) are the main cause of cold-like illnesses, and currently no vaccine or antiviral therapies against HRVs are available to prevent or mitigate HRV infection. There are more than 150 antigenically heterogeneous HRV serotypes, with ~90 HRVs belonging to major group species A and B. Development of small animal models that are susceptible to infection with major group HRVs would be beneficial for vaccine research. Previously, we showed that the cotton rat (Sigmodon hispidus) is semi-permissive to HRV16 (major group, species HRV-A virus) infection, replicating in the upper and lower respiratory tracts with measurable pathology, mucus production, and expression of inflammatory mediators. Herein, we report that intranasal infection of cotton rats with HRV14 (major group, species HRV-B virus) results in isolation of infectious virus from the nose and lung. Similar to HRV16, intramuscular immunization with live HRV14 induces homologous protection that correlated with high levels of serum neutralizing antibodies. Vaccination and challenge experiments with HRV14 and HRV16 to evaluate the development of cross-protective immunity demonstrate that intramuscular immunization with live HRV16 significantly protects animals against HRV14 challenge. Determination of the immunological mechanisms involved in heterologous protection and further characterization of infection with other major HRV serotypes in the cotton rat could enhance the robustness of the model to define heterotypic relationships between this diverse group of viruses and thereby increase its potential for development of a multi-serotype HRV vaccine. PMID- 28912761 TI - Preliminary Characterization of MEDLE-2, a Protein Potentially Involved in the Invasion of Cryptosporidium parvum. AB - Cryptosporidium spp. are important causes of diarrhea in humans, ruminants, and other mammals. Comparative genomic analysis indicated that genetically related and host-adapted Cryptosporidium species have different numbers of subtelomeric genes encoding the Cryptosporidium-specific MEDLE family of secreted proteins, which could contribute to differences in host specificity. In this study, a Cryptosporidium parvum-specific member of the protein family MEDLE-2 encoded by cgd5_4590 was cloned and expressed in Escherichia coli. Immunofluorescent staining with antibodies generated from the recombinant protein showed the expression of the protein in sporozoites and development stages. In vitro neutralization assay with the antibodies partially blocked the invasion of sporozoites. These results support the potential involvement of MEDLE-2 in the invasion of host cells. PMID- 28912762 TI - Comparative Study of Transcriptome Profiles of Mouse Livers and Skins Infected by Fork-Tailed or Non-Fork-Tailed Schistosoma japonicum. AB - Schistosoma japonicum (S. japonicum) is a worldwide spread pathogen which penetrates host skin and then induces several diseases in infected host, such as fibrosis, formation of granulomas, hepatocirrhosis, and hepatomegaly. In present study, for the first time, transcriptomic profiles of mouse livers and skins infected by fork-tailed S. japonicum cercaria or non-fork-tailed S. japonicum cercaria were analyzed by using RNA-seq. The present findings demonstrated that transcriptomic landscapes of livers and skins infected by fork-tailed S. japonicum cercaria or non-fork-tailed S. japonicum cercaria were different. S. japonicum has great influence on hepatic metabolic processes. Fork-tailed S. japonicum cercaria upregulated hepatic metabolic processes, while non-fork-tailed S. japonicum cercaria downregulated hepatic metabolic processes. For the metabolism process or the metabolism enzyme expressional change, the pharmacokinetics of host could be changed during S. japonicum infection, regardless the biotypes of S. japonicum cercariae. The changes of infected skins focused on upregulation of immune response. During the S. japonicum skin infection period, fork-tailed S. japonicum cercaria infection induced stronger immune response comparing with that immune response triggered by non-fork-tailed S. japonicum cercaria. The transcription factor enrichment analysis showed that Irf7, Stat1 and Stat2 could play important roles in gene regulation during fork tailed S. japonicum cercaria infection. PMID- 28912763 TI - The Microbial Community Dynamics during the Vitex Honey Ripening Process in the Honeycomb. AB - The bacterial and fungal communities of vitex honey were surveyed by sequencing the 16S rRNA gene and the internal transcribed spacer region of ribosomal DNA. Vitex honey samples were analyzed at different stage of ripening; the vitex flower was also analyzed, and the effect of the chemical composition in the experimental setup was assessed. The results confirmed the presence of dominant Bacillus spp. as the dominant bacterial in honey, and yeast related genera was the main fungal in the honey, respectively. Lactococcus and Enterococcus were detected for the first time in honey. The proportion of most of the fungal community decreased during the honey ripening process. Multivariate analyses also showed that the fungal community of 5, 10, and 15 days honey samples tended to cluster together and were completely separated from the 1 day honey sample. The change in the fungal community showed a correlation with the variation in the chemical components, such as moisture and phenolic compounds. Together, these results suggest that ripening of honey could change its microbial composition, and decrease the potential risk of microbiology. PMID- 28912765 TI - Biology and Genomics of an Historic Therapeutic Escherichia coli Bacteriophage Collection. AB - We have performed microbiological and genomic characterization of an historic collection of nine bacteriophages, specifically infecting a K1 E. coli O18:K1:H7 ColV+ strain. These phages were isolated from sewage and tested for their efficacy in vivo for the treatment of systemic E. coli infection in a mouse infection model by Smith and Huggins (1982). The aim of the study was to identify common microbiological and genomic characteristics, which co-relate to the performance of these phages in in vivo study. These features will allow an informed selection of phages for use as therapeutic agents. Transmission electron microscopy showed that six of the nine phages were Podoviridae and the remaining three were Siphoviridae. The four best performing phages in vivo belonged to the Podoviridae family. In vitro, these phages exhibited very short latent and rise periods in our study. In agreement with their microbiological profiles, characterization by genome sequencing showed that all six podoviruses belong to the Autographivirinae subfamily. Of these, four were isolates of the same species (99% identity), whereas two had divergent genomes compared to other podoviruses. The Siphoviridae phages, which were moderate to poor performers in vivo, exhibited longer latent and rise periods in vitro. Two of the three siphoviruses were closely related to each other (99% identity), but all can be associated with the Guernseyvirinae subfamily. Genome sequence comparison of both types of phages showed that a gene encoding for DNA-dependent RNA polymerase was only present in phages with faster replication cycle, which may account for their better performance in vivo. These data define a combination of microbiological, genomic and in vivo characteristics which allow a more rational evaluation of the original in vivo data and pave the way for the selection of phages for future phage therapy trails. PMID- 28912764 TI - Resistance to Antibiotics, Biocides, Preservatives and Metals in Bacteria Isolated from Seafoods: Co-Selection of Strains Resistant or Tolerant to Different Classes of Compounds. AB - Multi-drug resistant bacteria (particularly those producing extended-spectrum beta-lactamases) have become a major health concern. The continued exposure to antibiotics, biocides, chemical preservatives, and metals in different settings such as the food chain or in the environment may result in development of multiple resistance or co-resistance. The aim of the present study was to determine multiple resistances (biocides, antibiotics, chemical preservatives, phenolic compounds, and metals) in bacterial isolates from seafoods. A 75.86% of the 87 isolates studied were resistant to at least one antibiotic or one biocide, and 6.90% were multiply resistant to at least three biocides and at least three antibiotics. Significant (P < 0.05) moderate or strong positive correlations were detected between tolerances to biocides, between antibiotics, and between antibiotics with biocides and other antimicrobials. A sub-set of 30 isolates selected according to antimicrobial resistance profile and food type were identified by 16S rDNA sequencing and tested for copper and zinc tolerance. Then, the genetic determinants for biocide and metal tolerance and antibiotic resistance were investigated. The selected isolates were identified as Pseudomonas (63.33%), Acinetobacter (13.33%), Aeromonas (13.33%), Shewanella, Proteus and Listeria (one isolate each). Antibiotic resistance determinants detected included sul1 (43.33% of tested isolates), sul2 (6.66%), blaTEM (16.66%), blaCTX-M (16.66%), blaPSE (10.00%), blaIMP (3.33%), blaNDM-1 (3.33%), floR (16.66%), aadA1 (20.0%), and aac(6')-Ib (16.66%). The only biocide resistance determinant detected among the selected isolates was qacEDelta1 (10.00%). A 23.30 of the selected isolates were able to grow on media containing 32 mM copper sulfate, and 46.60% on 8 mM zinc chloride. The metal resistance genes pcoA/copA, pcoR, and chrB were detected in 36.66, 6.66, and 13.33% of selected isolates, respectively. Twelve isolates tested positive for both metal and antibiotic resistance genes, including one isolate positive for the carbapenemase gene blaNDM-1 and for pcoA/copA. These results suggest that exposure to metals could co-select for antibiotic resistance and also highlight the potential of bacteria on seafoods to be involved in the transmission of antimicrobial resistance genes. PMID- 28912766 TI - Environmental Bacteriophages of the Emerging Enterobacterial Phytopathogen, Dickeya solani, Show Genomic Conservation and Capacity for Horizontal Gene Transfer between Their Bacterial Hosts. AB - Dickeya solani is an economically important phytopathogen widespread in mainland Europe that can reduce potato crop yields by 25%. There are no effective environmentally-acceptable chemical systems available for diseases caused by Dickeya. Bacteriophages have been suggested for use in biocontrol of this pathogen in the field, and limited field trials have been conducted. To date only a small number of bacteriophages capable of infecting D. solani have been isolated and characterized, and so there is a need to expand the repertoire of phages that may have potential utility in phage therapy strategies. Here we describe 67 bacteriophages from environmental sources, the majority of which are members of the viral family Myoviridae. Full genomic sequencing of two isolates revealed a high degree of DNA identity with D. solani bacteriophages isolated in Europe in the past 5 years, suggesting a wide ecological distribution of this phage family. Transduction experiments showed that the majority of the new environmental bacteriophages are capable of facilitating efficient horizontal gene transfer. The possible risk of unintentional transfer of virulence or antibiotic resistance genes between hosts susceptible to transducing phages cautions against their environmental use for biocontrol, until specific phages are fully tested for transduction capabilities. PMID- 28912767 TI - Shifts in Host Mucosal Innate Immune Function Are Associated with Ruminal Microbial Succession in Supplemental Feeding and Grazing Goats at Different Ages. AB - Gastrointestinal microbiota may play an important role in regulating host mucosal innate immune function. This study was conducted to test the hypothesis that age (non-rumination, transition and rumination) and feeding type [Supplemental feeding (S) vs. Grazing (G)] could alter ruminal microbial diversity and maturation of host mucosal innate immune system in goat kids. MiSeq sequencing was applied to investigate ruminal microbial composition and diversity, and RT PCR was used to test expression of immune-related genes in ruminal mucosa. Results showed that higher (P < 0.05) relative abundances of Prevotella, Butyrivibrio, Pseudobutyrivibrio, Methanobrevibacter.gottschalkii, Neocallimastix, Anoplodinium-Diplodinium, and Polyplastron, and lower relative abundance of Methanosphaera (P = 0.042) were detected in the rumen of S kids when compared to those in G kids. The expression of genes encoding TLRs, IL1alpha, IL1beta and TICAM2 was down-regulated (P < 0.01), while expression of genes encoding tight junction proteins was up-regulated (P < 0.05) in the ruminal mucosa of S kids when compared to that in G kids. Moreover, irrespective of feeding type, relative abundances of ruminal Prevotella, Fibrobacter, Ruminococcus, Butyrivibrio, Methanobrevibacter, Neocallimastix, and Entodinium increased with age. The expression of most genes encoding TLRs and cytokines increased (P < 0.05) from day 0 to 7, while expression of genes encoding tight junction proteins declined with age (P < 0.05). This study revealed that the composition of each microbial domain changed as animals grew, and these changes might be associated with variations in host mucosal innate immune function. Moreover, supplementing goat kids with concentrate could modulate ruminal microbial composition, enhance barrier function and decrease local inflammation. The findings provide useful information in interpreting microbiota and host interactions, and developing nutritional strategies to improve the productivity and health of rumen during early life. PMID- 28912768 TI - Linseed Oil Supplementation of Lambs' Diet in Early Life Leads to Persistent Changes in Rumen Microbiome Structure. AB - Diet has been shown to have a significant impact on microbial community composition in the rumen and could potentially be used to manipulate rumen microbiome structure to achieve specific outcomes. There is some evidence that a window may exist in early life, while the microbiome is being established, where manipulation through diet could lead to long-lasting results. The aim of this study was to test the hypothesis that dietary supplementation in early life will have an effect on rumen microbial composition that will persist even once supplementation is ceased. Twenty-seven new-born lambs were allocated to one of three dietary treatments; a control group receiving standard lamb meal, a group receiving lamb meal supplemented with 40 g kg-1 DM of linseed oil and a group receiving the supplement pre-weaning and standard lamb meal post-weaning. The supplement had no effect on average daily feed intake or average daily weight gain of lambs. Bacterial and archaeal community composition was significantly (p = 0.033 and 0.005, respectively) different in lambs fed linseed oil throughout the study compared to lambs on the control diet. Succinivibrionaceae, succinate producers, and Veillonellaceae, propionate producers, were in a higher relative abundance in the lambs fed linseed oil while Ruminococcaceae, a family linked with high CH4 emitters, were in a higher relative abundance in the control group. The relative abundance of Methanobrevibacter was reduced in the lambs receiving linseed compared to those that didn't. In contrast, the relative abundance of Methanosphaera was significantly higher in the animals receiving the supplement compared to animals receiving no supplement (40.82 and 26.67%, respectively). Furthermore, lambs fed linseed oil only in the pre-weaning period had a bacterial community composition significantly (p = 0.015) different to that of the control group, though archaeal diversity and community structure did not differ. Again, Succinivibrionaceae and Veillonellaceae were in a higher relative abundance in the group fed linseed oil pre-weaning while Ruminococcaceae were in a higher relative abundance in the control group. This study shows that lambs fed the dietary supplement short-term had a rumen microbiome that remained altered even after supplementation had ceased. PMID- 28912769 TI - Adaptation of Surface-Associated Bacteria to the Open Ocean: A Genomically Distinct Subpopulation of Phaeobacter gallaeciensis Colonizes Pacific Mesozooplankton. AB - The marine Roseobacter group encompasses numerous species which occupy a large variety of ecological niches. However, members of the genus Phaeobacter are specifically adapted to a surface-associated lifestyle and have so far been found nearly exclusively in disjunct, man-made environments including shellfish and fish aquacultures, as well as harbors. Therefore, the possible natural habitats, dispersal and evolution of Phaeobacter spp. have largely remained obscure. Applying a high-throughput cultivation strategy along a longitudinal Pacific transect, the present study revealed for the first time a widespread natural occurrence of Phaeobacter in the marine pelagial. These bacteria were found to be specifically associated to mesoplankton where they constitute a small but detectable proportion of the bacterial community. The 16S rRNA gene sequences of 18 isolated strains were identical to that of Phaeobacter gallaeciensis DSM26640T but sequences of internal transcribed spacer and selected genomes revealed that the strains form a distinct clade within P. gallaeciensis. The genomes of the Pacific and the aquaculture strains were highly conserved and had a fraction of the core genome of 89.6%, 80 synteny breakpoints, and differed 2.2% in their nucleotide sequences. Diversification likely occurred through neutral mutations. However, the Pacific strains exclusively contained two active Type I restriction modification systems which is commensurate with a reduced acquisition of mobile elements in the Pacific clade. The Pacific clade of P. gallaeciensis also acquired a second, homolog phosphonate transport system compared to all other P. gallaeciensis. Our data indicate that a previously unknown, distinct clade of P. gallaeciensis acquired a limited number of clade-specific genes that were relevant for its association with mesozooplankton and for colonization of the marine pelagial. The divergence of the Pacific clade most likely was driven by the adaptation to this novel ecological niche rather than by geographic isolation. PMID- 28912770 TI - Infectious Agents As Markers of Human Migration toward the Amazon Region of Brazil. AB - Infectious agents are common companions of humans and since ancient times they follow human migration on their search for a better place to live. The study of paleomicrobiology was significantly improved in its accuracy of measurement with the constant development of better methods to detect and analyze nucleic acids. Human tissues are constantly used to trace ancient infections and the association of anthropological evidences are important to confirm the microbiological information. Infectious agents which establish human persistent infections are particularly useful to trace human migrations. In the present article, the evidence of infection by viral agents such as human T-lymphotropic virus 1, human T-lymphotropic virus 2, human herpes virus-8, JC virus, and a bacterium, Chlamydia trachomatis, was described using different methodologies for their detection. Their presence was further used as biomarkers associated with anthropological and other relevant information to trace human migration into the Amazon region of Brazil. The approach also evidenced their microbiological origin, emergence, evolution, and spreading. The information obtained confirms much of the archeological information available tracing ancient and more recent human migration into this particular geographical region. In this article, the paleomicrobiological information on the subject was summarized and reviewed. PMID- 28912771 TI - Selection of Functional Quorum Sensing Systems by Lysogenic Bacteriophages in Pseudomonas aeruginosa. AB - Quorum sensing (QS) in Pseudomonas aeruginosa coordinates the expression of virulence factors, some of which are used as public goods. Since their production is a cooperative behavior, it is susceptible to social cheating in which non cooperative QS deficient mutants use the resources without investing in their production. Nevertheless, functional QS systems are abundant; hence, mechanisms regulating the amount of cheating should exist. Evidence that demonstrates a tight relationship between QS and the susceptibility of bacteria against the attack of lytic phages is increasing; nevertheless, the relationship between temperate phages and QS has been much less explored. Therefore, in this work, we studied the effects of having a functional QS system on the susceptibility to temperate bacteriophages and how this affects the bacterial and phage dynamics. We find that both experimentally and using mathematical models, that the lysogenic bacteriophages D3112 and JBD30 select QS-proficient P. aeruginosa phenotypes as compared to the QS-deficient mutants during competition experiments with mixed strain populations in vitro and in vivo in Galleria mellonella, in spite of the fact that both phages replicate better in the wild-type background. We show that this phenomenon restricts social cheating, and we propose that temperate phages may constitute an important selective pressure toward the conservation of bacterial QS. PMID- 28912772 TI - An Anthropocentric View of the Virosphere-Host Relationship. AB - For over a century, viruses have been known as the most abundant and diverse group of organisms on Earth, forming a virosphere. Based on extensive meta analyses, we present, for the first time, a wide and complete overview of virus host network, covering all known viral species. Our data indicate that most of known viral species, regardless of their genomic category, have an intriguingly narrow host range, infecting only 1 or 2 host species. Our data also show that the known virosphere has expanded based on viruses of human interest, related to economical, medical or biotechnological activities. In addition, we provide an overview of the distribution of viruses on different environments on Earth, based on meta-analyses of available metaviromic data, showing the contrasting ubiquity of head-tailed phages against the specificity of some viral groups in certain environments. Finally, we uncovered all human viral species, exploring their diversity and the most affected organic systems. The virus-host network presented here shows an anthropocentric view of the virology. It is therefore clear that a huge effort and change in perspective is necessary to see more than the tip of the iceberg when it comes to virology. PMID- 28912773 TI - Hirsutine, an Indole Alkaloid of Uncaria rhynchophylla, Inhibits Late Step in Dengue Virus Lifecycle. AB - Dengue virus (DENV) is transmitted to humans by Aedes mosquitoes and is a public health issue worldwide. No antiviral drugs specific for treating dengue infection are currently available. To identify novel DENV inhibitors, we analyzed a library of 95 compounds and 120 extracts derived from crude drugs (herbal medicines). In the primary screening, A549 cells infected with DENV-1 were cultured in the presence of each compound and extract at a final concentration of 10 MUM (compound) and 100 MUg/mL (extract), and reduction of viral focus formation was assessed. Next, we eliminated compounds and extracts which were cytotoxic using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hirsutine, an indole alkaloid of Uncaria rhynchophylla, was identified as a potent anti-DENV compound exhibiting high efficacy and low cytotoxicity. Hirsutine showed antiviral activity against all DENV serotypes. Time-of-drug addition and time-of-drug-elimination assays indicated that hirsutine inhibits the viral particle assembly, budding, or release step but not the viral translation and replication steps in the DENV lifecycle. A subgenomic replicon system was used to confirm that hirsutine does not restrict viral genome RNA replication. Hirsutine is a novel DENV inhibitor and potential candidate for treating dengue fever. PMID- 28912774 TI - Therapeutic Antibodies to KIR3DL2 and Other Target Antigens on Cutaneous T-Cell Lymphomas. AB - KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide-linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs. Beside its expression on NK cells, it is also found on rare circulating T lymphocytes, mainly CD8+. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class I molecules is essential for NK development by promoting phenomena such as licensing and driving NK cell maturation. For KIR3DL2, this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition, KIR3DL2 binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal toll like receptor 9 that promotes cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T cell lymphomas such as Sezary syndrome, CD30+ cutaneous lymphoma, and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies (mAbs) directed against KIR3DL2 has been helpful in the diagnosis, follow-up, and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T-cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review, we discuss the various aspects of KIR3DL2 on the functions of CD4+ T cells and how targeting this receptor helps to develop innovative therapeutic strategies. PMID- 28912775 TI - Shared and Distinct Phenotypes and Functions of Human CD161++ Valpha7.2+ T Cell Subsets. AB - Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of Valpha7.2-Jalpha33/Jalpha20/Jalpha12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ Valpha7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ Valpha7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ Valpha7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ Valpha7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ Valpha7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ Valpha7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ Valpha7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo. PMID- 28912776 TI - Human CD5+ Innate Lymphoid Cells Are Functionally Immature and Their Development from CD34+ Progenitor Cells Is Regulated by Id2. AB - Innate lymphoid cells (ILCs) have emerged as a key cell type involved in surveillance and maintenance of mucosal tissues. Mouse ILCs rely on the transcriptional regulator Inhibitor of DNA-binding protein 2 (Id2) for their development. Here, we show that Id2 also drives development of human ILC because forced expression of Id2 in human thymic progenitors blocked T cell commitment, upregulated CD161 and promyelocytic leukemia zinc finger (PLZF), and maintained CD127 expression, markers that are characteristic for human ILCs. Surprisingly CD5 was also expressed on these in vitro generated ILCs. This was not an in vitro artifact because CD5 was also found on ex vivo isolated ILCs from thymus and from umbilical cord blood. CD5 was also expressed on small proportions of ILC2 and ILC3. CD5+ ILCs were functionally immature, but could further differentiate into mature CD5- cytokine-secreting ILCs. Our data show that Id2 governs human ILC development from thymic progenitor cells toward immature CD5+ ILCs. PMID- 28912777 TI - Class A CpG Oligonucleotide Priming Rescues Mice from Septic Shock via Activation of Platelet-Activating Factor Acetylhydrolase. AB - Sepsis is a life-threatening, overwhelming immune response to infection with high morbidity and mortality. Inflammatory response and blood clotting are caused by sepsis, which induces serious organ damage and death from shock. As a mechanism of pathogenesis, platelet-activating factor (PAF) induces excessive inflammatory responses and blood clotting. In this study, we demonstrate that a Class A CpG oligodeoxynucleotide (CpG-A1585) strongly induced PAF acetylhydrolase, which generates lyso-PAF. CpG-A1585 rescued mice from acute lethal shock and decreased fibrin deposition, a hallmark of PAF-induced disseminated intravascular coagulation. Furthermore, CpG-A1585 improved endotoxin shock induced by lipopolysaccharide, which comprises the cell wall of Gram-negative bacteria and inhibits inflammatory responses induced by cytokines such as interleukin-6 and tumor necrosis factor-alpha. These results suggest that CpG-A1585 is a potential therapeutic target to prevent sepsis-related induction of PAF. PMID- 28912778 TI - Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats. AB - Resolution agonists, including lipid mediators and peptides such as annexin A1 (ANXA1), are providing novel approaches to treat inflammatory conditions. Surgical trauma exerts a significant burden on the immune system that can affect and impair multiple organs. Perioperative cerebral injury after cardiac surgery is associated with significant adverse neurological outcomes such as delirium and postoperative cognitive dysfunction. Using a clinically relevant rat model of cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA), we tested the pro-resolving effects of a novel bioactive ANXA1 tripeptide (ANXA1sp) on neuroinflammation and cognition. Male rats underwent 2 h CPB with 1 h DHCA at 18 degrees C, and received vehicle or ANXA1sp followed by timed reperfusion up to postoperative day 7. Immortalized murine microglial cell line BV2 were treated with vehicle or ANXA1sp and subjected to 2 h oxygen-glucose deprivation followed by timed reoxygenation. Microglial activation, cell death, neuroinflammation, and NF-kappaB activation were assessed in tissue samples and cell cultures. Rats exposed to CPB and DHCA had evident neuroinflammation in various brain areas. However, in ANXA1sp-treated rats, microglial activation and cell death (apoptosis and necrosis) were reduced at 24 h and 7 days after surgery. This was associated with a reduction in key pro-inflammatory cytokines due to inhibition of NF-kappaB activation in the brain and systemically. Treated rats also had improved neurologic scores and shorter latency in the Morris water maze. In BV2 cells treated with ANXA1sp, similar protective effects were observed including decreased pro-inflammatory cytokines and cell death. Notably, we also found increased expression of ANXA1, which binds to NF-kappaB p65 and thereby inhibits its transcriptional activity. Our findings provide evidence that treatment with a novel pro-resolving ANXA1 tripeptide is neuroprotective after cardiac surgery in rats by attenuating neuroinflammation and may prevent postoperative neurologic complications. PMID- 28912779 TI - Vgamma4+gammadeltaT Cells Aggravate Severe H1N1 Influenza Virus Infection-Induced Acute Pulmonary Immunopathological Injury via Secreting Interleukin-17A. AB - The influenza A (H1N1) pdm09 virus remains a critical global health concern and causes high levels of morbidity and mortality. Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the major outcomes among severely infected patients. Our previous study found that interleukin (IL)-17A production by humans or mice infected with influenza A (H1N1) pdm09 substantially contributes to ALI and subsequent morbidity and mortality. However, the cell types responsible for IL-17A production during the early stage of severe influenza A (H1N1) pdm09 infection remained unknown. In this study, a mouse model of severe influenza A (H1N1) pdm09 infection was established. Our results show that, in the lungs of infected mice, the percentage of gammadeltaT cells, but not the percentages of CD4+Th and CD8+Tc cells, gradually increased and peaked at 3 days post-infection (dpi). Further analysis revealed that the Vgamma4+gammadeltaT subset, but not the Vgamma1+gammadeltaT subset, was significantly increased among the gammadeltaT cells. At 3 dpi, the virus induced significant increases in IL 17A in the bronchoalveolar lavage fluid (BALF) and serum. IL-17A was predominantly secreted by gammadeltaT cells (especially the Vgamma4+gammadeltaT subset), but not CD4+Th and CD8+Tc cells at the early stage of infection, and IL 1beta and/or IL-23 were sufficient to induce IL-17A production by gammadeltaT cells. In addition to secreting IL-17A, gammadeltaT cells secreted interferon (IFN)-gamma and expressed both an activation-associated molecule, natural killer group 2, member D (NKG2D), and an apoptosis-associated molecule, FasL. Depletion of gammadeltaT cells or the Vgamma4+gammadeltaT subset significantly rescued the virus-induced weight loss and improved the survival rate by decreasing IL-17A secretion and reducing immunopathological injury. This study demonstrated that, by secreting IL-17A, lung Vgamma4+gammadeltaT cells, at least, in part mediated influenza A (H1N1) pdm09-induced immunopathological injury. This mechanism might serve as a promising new target for the prevention and treatment of ALI induced by influenza A (H1N1) pdm09. PMID- 28912780 TI - Inflammatory Markers for Arterial Stiffness in Cardiovascular Diseases. AB - Arterial stiffness predicts an increased risk of cardiovascular events. Inflammation plays a major role in large arteries stiffening, related to atherosclerosis, arteriosclerosis, endothelial dysfunction, smooth muscle cell migration, vascular calcification, increased activity of metalloproteinases, extracellular matrix degradation, oxidative stress, elastolysis, and degradation of collagen. The present paper reviews main mechanisms explaining the crosstalk between inflammation and arterial stiffness and the most common inflammatory markers associated with increased arterial stiffness, considering the most recent clinical and experimental studies. Diverse studies revealed significant correlations between the severity of arterial stiffness and inflammatory markers, such as white blood cell count, neutrophil/lymphocyte ratio, adhesion molecules, fibrinogen, C-reactive protein, cytokines, microRNAs, and cyclooxygenase-2, in patients with a broad variety of diseases, such as metabolic syndrome, diabetes, coronary heart disease, peripheral arterial disease, malignant and rheumatic disorders, polycystic kidney disease, renal transplant, familial Mediterranean fever, and oral infections, and in women with preeclampsia or after menopause. There is strong evidence that inflammation plays an important and, at least, partly reversible role in the development of arterial stiffness, and inflammatory markers may be useful additional tools in the assessment of the cardiovascular risk in clinical practice. Combined assessment of arterial stiffness and inflammatory markers may improve non-invasive assessment of cardiovascular risk, enabling selection of high-risk patients for prophylactic treatment or more regular medical examination. Development of future destiffening therapies may target pro-inflammatory mechanisms. PMID- 28912782 TI - The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B. AB - Saliva of the blood feeding sand fly Lutzomyia longipalpis was previously shown to inhibit the alternative pathway (AP) of the complement system. Here, we have identified Lufaxin, a protein component in saliva, as the inhibitor of the AP. Lufaxin inhibited the deposition of C3b, Bb, Properdin, C5b, and C9b on agarose coated plates in a dose-dependent manner. It also inhibited the activation of factor B in normal serum, but had no effect on the components of the membrane attack complex. Surface plasmon resonance (SPR) experiments demonstrated that Lufaxin stabilizes the C3b-B proconvertase complex when passed over a C3b surface in combination with factor B. Lufaxin was also shown to inhibit the activation of factor B by factor D in a reconstituted C3b-B, but did not inhibit the activation of C3 by reconstituted C3b-Bb. Proconvertase stabilization does not require the presence of divalent cations, but addition of Ni2+ increases the stability of complexes formed on SPR surfaces. Stabilization of the C3b-B complex to prevent C3 convertase formation (C3b-Bb formation) is a novel mechanism that differs from previously described strategies used by other organisms to inhibit the AP of the host complement system. PMID- 28912783 TI - Sex Differences in Asthma: A Key Role of Androgen-Signaling in Group 2 Innate Lymphoid Cells. AB - Infectious diseases, autoimmune diseases, and also allergy differentially affect women and men. In general, women develop strongest immune responses and thus the proportion of infected individuals and the severity of many viral, bacterial, or parasitic infections are increased in men. However, heightened immunity in women makes them more susceptible than men to autoimmunity and allergy. While sex differences in immunity are well documented, little is known about the cellular and molecular mechanisms underlying these immunological differences, particularly in allergic asthma. Asthma is a chronic inflammation of the airways mediated by exacerbated type 2 immune responses. Sex differences have been reported in the incidence, prevalence, and severity of asthma. While during childhood, males are more susceptible to asthma than females, there is a switch at the onset of puberty as for many other allergic diseases. This decrease of asthma incidence around puberty in males suggests that hormonal mediators could play a protective role in the susceptibility to allergic responses in male. Group 2 innate lymphoid cells (ILC2s) have recently emerged as critical players in the initiation of allergic responses, but also in the resolution of parasitic infection, through their capacity to rapidly and potently produce type 2 cytokines. This review will cover the current understanding of the impact of sex-linked factors in allergic inflammation, with a particular focus on the role of sex hormones on the development and function of tissue-resident ILC2s. PMID- 28912781 TI - MicroRNA: Dynamic Regulators of Macrophage Polarization and Plasticity. AB - The ability of a healthy immune system to clear the plethora of antigens it encounters incessantly relies on the enormous plasticity displayed by the comprising cell types. Macrophages (MPhis) are crucial member of the mononuclear phagocyte system (MPS) that constantly patrol the peripheral tissues and are actively recruited to the sites of injury and infection. In tissues, infiltrating monocytes replenish MPhi. Under the guidance of the local micro-milieu, MPhi can be activated to acquire specialized functional phenotypes. Similar to T cells, functional polarization of macrophage phenotype viz., inflammatory (M1) and reparative (M2) is proposed. Equipped with diverse toll-like receptors (TLRs), these cells of the innate arm of immunity recognize and phagocytize antigens and secrete cytokines that activate the adaptive arm of the immune system and perform key roles in wound repair. Dysregulation of MPhi plasticity has been associated with various diseases and infection. MicroRNAs (miRNAs) have emerged as critical regulators of transcriptome output. Their importance in maintaining health, and their contribution toward disease, encompasses virtually all aspects of human biology. Our understanding of miRNA-mediated regulation of MPhi plasticity and polarization can be utilized to modulate functional phenotypes to counter their role in the pathogenesis of numerous disease, including cancer, autoimmunity, periodontitis, etc. Here, we provide an overview of current knowledge regarding the role of miRNA in shaping MPhi polarization and plasticity through targeting of various pathways and genes. Identification of miRNA biomarkers of diagnostic/prognostic value and their therapeutic potential by delivery of miRNA mimics or inhibitors to dynamically alter gene expression profiles in vivo is highlighted. PMID- 28912784 TI - Comparison of the Protective Efficacy of Neutralizing Epitopes of 2009 Pandemic H1N1 Influenza Hemagglutinin. AB - The 2009 H1N1 influenza (Pdm09) pandemic has been referred to as the first influenza pandemic of the twenty-first century. There is a marked difference in antigenicity between the pandemic H1N1 virus and past seasonal H1N1 viruses, which allowed the pandemic virus to spread rapidly in humans. Antibodies (Abs) against hemagglutinin (HA), especially neutralizing Abs against epitopes in the head of HA, play critical roles in defending the host against the virus. Some preexisting neutralizing Abs that recognize neutralizing epitopes of Pdm09 HA, thereby affording cross-protection, have been reported. To better understand the protective effects of epitopes in Pdm09 HA, we constructed a series of plasmid DNAs (DNA vaccines) by cloning various combinations of Pdm09 neutralizing epitopes into the HA backbone derived from A/PR/8/1934 (H1N1). We subsequently compared the protective immune responses induced by these various forms of HA in a mouse model. We found that the plasmid DNAs with epitope substitutions provided better protection against lethal virus challenge and induced higher strain specific antibody titers, with epitope Sa being the most effective. Moreover, the combination of epitopes Sa and Sb provided almost complete protection in mice. These findings provide new insights into the protective efficacy of neutralizing epitopes of influenza HA. PMID- 28912785 TI - Genotyping-by-Sequencing (GBS) Revealed Molecular Genetic Diversity of Iranian Wheat Landraces and Cultivars. AB - Background: Genetic diversity is an essential resource for breeders to improve new cultivars with desirable characteristics. Recently, genotyping-by-sequencing (GBS), a next-generation sequencing (NGS) technology that can simplify complex genomes, has now be used as a high-throughput and cost-effective molecular tool for routine breeding and screening in many crop species, including the species with a large genome. Results: We genotyped a diversity panel of 369 Iranian hexaploid wheat accessions including 270 landraces collected between 1931 and 1968 in different climate zones and 99 cultivars released between 1942 to 2014 using 16,506 GBS-based single nucleotide polymorphism (GBS-SNP) markers. The B genome had the highest number of mapped SNPs while the D genome had the lowest on both the Chinese Spring and W7984 references. Structure and cluster analyses divided the panel into three groups with two landrace groups and one cultivar group, suggesting a high differentiation between landraces and cultivars and between landraces. The cultivar group can be further divided into four subgroups with one subgroup was mostly derived from Iranian ancestor(s). Similarly, landrace groups can be further divided based on years of collection and climate zones where the accessions were collected. Molecular analysis of variance indicated that the genetic variation was larger between groups than within group. Conclusion: Obvious genetic diversity in Iranian wheat was revealed by analysis of GBS-SNPs and thus breeders can select genetically distant parents for crossing in breeding. The diverse Iranian landraces provide rich genetic sources of tolerance to biotic and abiotic stresses, and they can be useful resources for the improvement of wheat production in Iran and other countries. PMID- 28912786 TI - Co-infection of Sweet Orange with Severe and Mild Strains of Citrus tristeza virus Is Overwhelmingly Dominated by the Severe Strain on Both the Transcriptional and Biological Levels. AB - Citrus tristeza is one of the most destructive citrus diseases and is caused by the phloem-restricted Closterovirus, Citrus tristeza virus. Mild strain CTV-B2 does not cause obvious symptoms on indicators whereas severe strain CTV-B6 causes symptoms, including stem pitting, cupping, yellowing, and stiffening of leaves, and vein corking. Our laboratory has previously characterized changes in transcription in sweet orange separately infected with CTV-B2 and CTV-B6. In the present study, transcriptome analysis of Citrus sinensis in response to double infection by CTV-B2 and CTV-B6 was carried out. Four hundred and eleven transcripts were up-regulated and 356 transcripts were down-regulated prior to the onset of symptoms. Repressed genes were overwhelmingly associated with photosynthesis, and carbon and nucleic acid metabolism. Expression of genes related to the glycolytic, oxidative pentose phosphate (OPP), tricarboxylic acid cycle (TCA) pathways, tetrapyrrole synthesis, redox homeostasis, nucleotide metabolism, protein synthesis and post translational protein modification and folding, and cell organization were all reduced. Ribosomal composition was also greatly altered in response to infection by CTV-B2/CTV-B6. Genes that were induced were related to cell wall structure, secondary and hormone metabolism, responses to biotic stress, regulation of transcription, signaling, and secondary metabolism. Transport systems dedicated to metal ions were especially disturbed and ZIPs (Zinc Transporter Precursors) showed different expression patterns in response to co-infection by CTV-B2/CTV-B6 and single infection by CTV-B2. Host plants experienced root decline that may have contributed to Zn, Fe, and other nutrient deficiencies. Though defense responses, such as, strengthening of the cell wall, alteration of hormone metabolism, secondary metabolites, and signaling pathways, were activated, these defense responses did not suppress the spread of the pathogens and the development of symptoms. The mild strain CTV-B2 did not provide a useful level of cross-protection to citrus against the severe strain CTV-B6. PMID- 28912787 TI - Effect of Light Availability on the Interaction between Maritime Pine and the Pine Weevil: Light Drives Insect Feeding Behavior But Also the Defensive Capabilities of the Host. AB - Light is a major environmental factor that may determine the interaction between plants and herbivores in several ways, including top-down effects through changes in herbivore behavior and bottom-up effects mediated by alterations of plant physiology. Here we explored the relative contribution of these two regulation processes to the outcome of the interaction of pine trees with a major forest pest, the pine weevil (Hylobius abietis). We studied to what extent light availability influence insect feeding behavior and/or the ability of pines to produce induced defenses in response to herbivory. For this purpose, 3-year old Pinus pinaster plants from three contrasting populations were subjected to 6 days of experimental herbivory by the pine weevil under two levels of light availability (complete darkness or natural sunlight) independently applied to the plant and to the insect in a fully factorial design. Light availability strongly affected the pine weevil feeding behavior. The pine weevil fed more and caused larger feeding scars in darkness than under natural sunlight. Besides, under the more intense levels of weevil damage (i.e., those registered with insects in darkness), light availability also affected the pine's ability to respond to insect feeding by producing induced resin defenses. These results were consistent across the three studied populations despite they differed in weevil susceptibility and inducibility of defenses. Morocco was the most damaged population and the one that induced more defensive compounds. Overall, results indicate that light availability modulates the outcome of the pine-weevil interactions through both bottom-up and top-down regulation mechanisms. PMID- 28912788 TI - Development and Genetic Characterization of Advanced Backcross Materials and An Introgression Line Population of Solanum incanum in a S. melongena Background. AB - Advanced backcrosses (ABs) and introgression lines (ILs) of eggplant (Solanum melongena) can speed up genetics and genomics studies and breeding in this crop. We have developed the first full set of ABs and ILs in eggplant using Solanum incanum, a wild eggplant that has a relatively high tolerance to drought, as a donor parent. The development of these ABs and IL eggplant populations had a low efficiency in the early stages, because of the lack of molecular markers and genomic tools. However, this dramatically improved after performing genotyping-by sequencing in the first round of selfing, followed by high-resolution-melting single nucleotide polymorphism genotyping in subsequent selection steps. A set of 73 selected ABs covered 99% of the S. incanum genome, while 25 fixed immortal ILs, each carrying a single introgressed fragment in homozygosis, altogether spanned 61.7% of the S. incanum genome. The introgressed size fragment in the ILs contained between 0.1 and 10.9% of the S. incanum genome, with a mean value of 4.3%. Sixty-eight candidate genes involved in drought tolerance were identified in the set of ILs. This first set of ABs and ILs of eggplant will be extremely useful for the genetic dissection of traits of interest for eggplant, and represents an elite material for introduction into the breeding pipelines for developing new eggplant cultivars adapted to the challenges posed by the climate change scenario. PMID- 28912789 TI - Alignment of Common Wheat and Other Grass Genomes Establishes a Comparative Genomics Research Platform. AB - Grass genomes are complicated structures as they share a common tetraploidization, and particular genomes have been further affected by extra polyploidizations. These events and the following genomic re-patternings have resulted in a complex, interweaving gene homology both within a genome, and between genomes. Accurately deciphering the structure of these complicated plant genomes would help us better understand their compositional and functional evolution at multiple scales. Here, we build on our previous research by performing a hierarchical alignment of the common wheat genome vis-a-vis eight other sequenced grass genomes with most up-to-date assemblies, and annotations. With this data, we constructed a list of the homologous genes, and then, in a layer-by-layer process, separated their orthology, and paralogy that were established by speciations and recursive polyploidizations, respectively. Compared with the other grasses, the far fewer collinear outparalogous genes within each of three subgenomes of common wheat suggest that homoeologous recombination, and genomic fractionation should have occurred after its formation. In sum, this work contributes to the establishment of an important and timely comparative genomics platform for researchers in the grass community and possibly beyond. Homologous gene list can be found in Supplemental material. PMID- 28912790 TI - Development and Evaluation of Glycine max Germplasm Lines with Quantitative Resistance to Sclerotinia sclerotiorum. AB - Sclerotinia sclerotiorum, the causal agent of Sclerotinia stem rot, is a devastating fungal pathogen of soybean that can cause significant yield losses to growers when environmental conditions are favorable for the disease. The development of resistant varieties has proven difficult. However, poor resistance in commercial cultivars can be improved through additional breeding efforts and understanding the genetic basis of resistance. The objective of this project was to develop soybean germplasm lines that have a high level of Sclerotinia stem rot resistance to be used directly as cultivars or in breeding programs as a source of improved Sclerotinia stem rot resistance. Sclerotinia stem rot-resistant soybean germplasm was developed by crossing two sources of resistance, W04-1002 and AxN-1-55, with lines exhibiting resistance to Heterodera glycines and Cadophora gregata in addition to favorable agronomic traits. Following greenhouse evaluations of 1,076 inbred lines derived from these crosses, 31 lines were evaluated for resistance in field tests during the 2014 field season. Subsequently, 11 Sclerotinia stem rot resistant breeding lines were moved forward for field evaluation in 2015, and seven elite breeding lines were selected and evaluated in the 2016 field season. To better understand resistance mechanisms, a marker analysis was conducted to identify quantitative trait loci linked to resistance. Thirteen markers associated with Sclerotinia stem rot resistance were identified on chromosomes 15, 16, 17, 18, and 19. Our markers confirm previously reported chromosomal regions associated with Sclerotinia stem rot resistance as well as a novel region of chromosome 16. The seven elite germplasm lines were also re-evaluated within a greenhouse setting using a cut petiole technique with multiple S. sclerotiorum isolates to test the durability of physiological resistance of the lines in a controlled environment. This work presents a novel and comprehensive classical breeding method for selecting lines with physiological resistance to Sclerotinia stem rot and a range of agronomic traits. In these studies, we identify four germplasm lines; 91-38, 51-23, SSR51-70, and 52-82B exhibiting a high level of Sclerotinia stem rot resistance combined with desirable agronomic traits, including high protein and oil contents. The germplasm identified in this study will serve as a valuable source of physiological resistance to Sclerotinia stem rot that could be improved through further breeding to generate high-yielding commercial soybean cultivars. PMID- 28912791 TI - Mycorrhizal Associations and Trophic Modes in Coexisting Orchids: An Ecological Continuum between Auto- and Mixotrophy. AB - Two distinct nutritional syndromes have been described in temperate green orchids. Most orchids form mycorrhizas with rhizoctonia fungi and are considered autotrophic. Some orchids, however, associate with fungi that simultaneously form ectomycorrhizas with surrounding trees and derive their carbon from these fungi. This evolutionarily derived condition has been called mixotrophy or partial mycoheterotrophy and is characterized by 13C enrichment and high N content. Although it has been suggested that the two major nutritional syndromes are clearly distinct and tightly linked to the composition of mycorrhizal communities, recent studies have challenged this assumption. Here, we investigated whether mycorrhizal communities and nutritional syndromes differed between seven green orchid species that co-occur under similar ecological conditions (coastal dune slacks). Our results showed that mycorrhizal communities differed significantly between orchid species. Rhizoctonia fungi dominated in Dactylorhiza sp., Herminium monorchis, and Epipactis palustris, which were autotrophic based on 13C and N content. Conversely, Liparis loeselii and Epipactis neerlandica associated primarily with ectomycorrhizal fungi but surprisingly, 13C and N content supported mixotrophy only in E. neerlandica. This, together with the finding of some ectomycorrhizal fungi in rhizoctonia associated orchids, suggests that there exists an ecological continuum between the two syndromes. The presence of a large number of indicator species associating with individual orchid species further confirms previous findings that mycorrhizal fungi may be important factors driving niche-partitioning in terrestrial orchids and therefore contribute to orchid coexistence. PMID- 28912792 TI - Genotypic Variation in Yield, Yield Components, Root Morphology and Architecture, in Soybean in Relation to Water and Phosphorus Supply. AB - Water shortage and low phosphorus (P) availability limit yields in soybean. Roots play important roles in water-limited and P-deficient environment, but the underlying mechanisms are largely unknown. In this study we determined the responses of four soybean [Glycine max (L.) Merr.] genotypes [Huandsedadou (HD), Bailudou (BLD), Jindou 21 (J21), and Zhonghuang 30 (ZH)] to three P levels [applied 0 (P0), 60 (P60), and 120 (P120) mg P kg-1 dry soil to the upper 0.4 m of the soil profile] and two water treatment [well-watered (WW) and water stressed (WS)] with special reference to root morphology and architecture, we compared yield and its components, root morphology and root architecture to find out which variety and/or what kind of root architecture had high grain yield under P and drought stress. The results showed that water stress and low P, respectively, significantly reduced grain yield by 60 and 40%, daily water use by 66 and 31%, P accumulation by 40 and 80%, and N accumulation by 39 and 65%. The cultivar ZH with the lowest daily water use had the highest grain yield at P60 and P120 under drought. Increased root length was positively associated with N and P accumulation in both the WW and WS treatments, but not with grain yield under water and P deficits. However, in the WS treatment, high adventitious and lateral root densities were associated with high N and P uptake per unit root length which in turn was significantly and positively associated with grain yield. Our results suggest that (1) genetic variation of grain yield, daily water use, P and N accumulation, and root morphology and architecture were observed among the soybean cultivars and ZH had the best yield performance under P and water limited conditions; (2) water has a major influence on nutrient uptake and grain yield, while additional P supply can modestly increase yields under drought in some soybean genotypes; (3) while conserved water use plays an important role in grain yield under drought, root traits also contribute to high nutrient uptake efficiency and benefit yield under drought. PMID- 28912793 TI - Diverse Rice Landraces of North-East India Enables the Identification of Novel Genetic Resources for Magnaporthe Resistance. AB - North-East (NE) India, the probable origin of rice has diverse genetic resources. Many rice landraces of NE India were not yet characterized for blast resistance. A set of 232 landraces of NE India, were screened for field resistance at two different hotspots of rice blast, viz., IIRR-UBN, Hyderabad and ICAR-NEH, Manipur in two consecutive seasons. The phenotypic evaluation as well as gene profiling for 12 major blast resistance genes (Pitp, Pi33, Pi54, Pib, Pi20, Pi38, Pita2, Pi1, Piz, Pi9, Pizt, and Pi40) with linked as well as gene-specific markers, identified 84 resistant landraces possessing different gene(s) either in singly or in combinations and also identified seven resistant landraces which do not have the tested genes, indicating the valuable genetic resources for blast resistance. To understand the molecular diversity existing in the population, distance and model based analysis were performed using 120 SSR markers. Results of both analyses are highly correlated by forming two distinct subgroups and the existence of high diversity (24.9% among the subgroups; 75.1% among individuals of each subgroup) was observed. To practically utilize the diversity in the breeding program, a robust core set having an efficiency index of 0.82 which consists of 33 landraces were identified through data of molecular, blast phenotyping, and important agro-morphological traits. The association of eight novel SSR markers for important agronomic traits which includes leaf and neck blast resistance was determined using genome-wide association analysis. The current study focuses on identifying novel resources having field resistance to blast as well as markers which can be explored in rice improvement programs. It also entails the development of a core set which can aid in representing the entire diversity for efficiently harnessing its properties to broaden the gene pool of rice. PMID- 28912794 TI - Histological and Transcriptomic Analysis during Bulbil Formation in Lilium lancifolium. AB - Aerial bulbils are an important propagative organ, playing an important role in population expansion. However, the detailed gene regulatory patterns and molecular mechanism underlying bulbil formation remain unclear. Triploid Lilium lancifolium, which develops many aerial bulbils on the leaf axils of middle-upper stem, is a useful species for investigating bulbil formation. To investigate the mechanism of bulbil formation in triploid L. lancifolium, we performed histological and transcriptomic analyses using samples of leaf axils located in the upper and lower stem of triploid L. lancifolium during bulbil formation. Histological results indicated that the bulbils of triploid L. lancifolium are derived from axillary meristems that initiate de novo from cells on the adaxial side of the petiole base. Transcriptomic analysis generated ~650 million high quality reads and 11,871 differentially expressed genes (DEGs). Functional analysis showed that the DEGs were significantly enriched in starch and sucrose metabolism and plant hormone signal transduction. Starch synthesis and accumulation likely promoted the initiation of upper bulbils in triploid L. lancifolium. Hormone-associated pathways exhibited distinct patterns of change in each sample. Auxin likely promoted the initiation of bulbils and then inhibited further bulbil formation. High biosynthesis and low degradation of cytokinin might have led to bulbil formation in the upper leaf axil. The present study achieved a global transcriptomic analysis focused on gene expression changes and pathways' enrichment during upper bulbil formation in triploid L. lancifolium, laying a solid foundation for future molecular studies on bulbil formation. PMID- 28912795 TI - Different Growth and Physiological Responses of Six Subtropical Tree Species to Warming. AB - Quantifying changes in interspecific plant growth and physiology under climate warming will facilitate explanation of the shifts in community structure in subtropical forest. We evaluated the effects of 3 years climate warming (ca. 1 degrees C, 2012-2015) on plant growth and physiological parameters of six subtropical tree species by translocating seedlings and soil from a higher to a lower elevation site. We found that an increase in soil/air temperature had divergent effects on six co-occurring species. Warming increased the biomass of Schima superba and Pinus massoniana, whereas it decreased their specific leaf area and intrinsic water use efficiency compared to other species. Warming decreased the foliar non-structural carbohydrates for all species. Our findings demonstrated that a warmer climate would have species-specific effects on the physiology and growth of subtropical trees, which may cause changes in the competitive balance and composition of these forests. PMID- 28912796 TI - A Low-Cost Imaging Method for the Temporal and Spatial Colorimetric Detection of Free Amines on Maize Root Surfaces. AB - Plant root exudates are important mediators in the interactions that occur between plants and microorganisms in the soil, yet much remains to be learned about spatial and temporal variation in their production. This work outlines a method utilizing a novel colorimetric paper to detect spatial and temporal changes in the production of nitrogen-containing compounds on the root surface. While existing methods have made it possible to conduct detailed analysis of root exudate composition, relatively less is known about where in the root system exudates are produced and how this localization changes as the root grows. Furthermore, there is much to learn about how exudate localization and composition varies in response to stress. Root exudates are chemically diverse secretions composed of organic acids, amino acids, proteins, sugars, and other metabolites. The sensor utilized for the method, ninhydrin, is a colorless substance in solution that reacts with free amino groups to form a purple dye. A detection paper was developed by formulating ninhydrin into a print solution that was uniformly deposited onto paper with a commercial ink jet printer. This "ninhydrin paper" was used to analyze the chemical makeup of root surfaces from maize seedlings grown vertically on germination paper. Through contact between the ninhydrin paper and seedling root surfaces, combined with images of both the seedlings and dried ninhydrin papers captured using a standard flatbed scanner, nitrogen-containing substances on the root surface can be localized and concentration of signal estimated for over 2 weeks of development. The method was found to be non-inhibiting to plant growth over the analysis period although damage to root hairs was observed. The method is sensitive in the detection of free amines at concentrations as little as 140 MUM. Furthermore, ninhydrin paper is stable, showing consistent color changes up to 2 weeks after printing. This relatively simple, low-cost method could contribute to a better understanding of root exudates and mechanisms used by plants to interact with the complex soil environment during growth and development. PMID- 28912797 TI - Corrigendum: Expression Level of the DREB2-Type Gene, Identified with Amplifluor SNP Markers, Correlates with Performance, and Tolerance to Dehydration in Bread Wheat Cultivars from Northern Kazakhstan. AB - [This corrects the article on p. 1736 in vol. 7, PMID: 27917186.]. PMID- 28912799 TI - Triportheus albus Cope, 1872 in the Blackwater, Clearwater, and Whitewater of the Amazon: A Case of Phenotypic Plasticity? AB - The Amazon basin includes 1000s of bodies of water, that are sorted according to their color in three types: blackwater, clearwater, and whitewater, which significantly differ in terms of their physicochemical parameters. More than 3,000 species of fish live in the rivers of the Amazon, among them, the sardine, Triportheus albus, which is one of the few species that inhabit all three types of water. The purpose of our study was to analyze if the gene expression of T. albus is determined by the different types of water, that is, if the species presents phenotypic plasticity to live in blackwater, clearwater, and whitewater. Gills of T. albus were collected at well-characterized sites for each type of water. Nine cDNA libraries were constructed, three biological replicates of each condition and the RNA was sequenced (RNA-Seq) on the MiSeq(r) Platform (Illumina(r)). A total of 51.6 million of paired-end reads, and 285,456 transcripts were assembled. Considering the FDR <= 0.05 and fold change >= 2, 13,754 differentially expressed genes were detected in the three water types. Two mechanisms related to homeostasis were detected in T. albus that live in blackwater, when compared to the ones in clearwater and whitewater. The acidic blackwater is a challenging environment for many types of aquatic organisms. The first mechanism is related to the decrease in cellular permeability, highlighting the genes coding for claudin proteins, actn4, itgb3b, DSP, Gap junction protein, and Ca2+-ATPase. The second with ionic and acid-base regulation [rhcg1, slc9a6a (NHE), ATP6V0A2, Na+/K+-ATPase, slc26a4 (pedrin) and slc4a4b]. We suggest T. albus is a good species of fish for future studies involving the ionic and acid base regulation of Amazonian species. We also concluded that, T. albus, shows well defined phenotypic plasticity for each water type in the Amazon basin. PMID- 28912800 TI - Gaze Estimation Method Using Analysis of Electrooculogram Signals and Kinect Sensor. AB - A gaze estimation system is one of the communication methods for severely disabled people who cannot perform gestures and speech. We previously developed an eye tracking method using a compact and light electrooculogram (EOG) signal, but its accuracy is not very high. In the present study, we conducted experiments to investigate the EOG component strongly correlated with the change of eye movements. The experiments in this study are of two types: experiments to see objects only by eye movements and experiments to see objects by face and eye movements. The experimental results show the possibility of an eye tracking method using EOG signals and a Kinect sensor. PMID- 28912798 TI - Comparative Genomic Analysis of the Human Gut Microbiome Reveals a Broad Distribution of Metabolic Pathways for the Degradation of Host-Synthetized Mucin Glycans and Utilization of Mucin-Derived Monosaccharides. AB - The colonic mucus layer is a dynamic and complex structure formed by secreted and transmembrane mucins, which are high-molecular-weight and heavily glycosylated proteins. Colonic mucus consists of a loose outer layer and a dense epithelium attached layer. The outer layer is inhabited by various representatives of the human gut microbiota (HGM). Glycans of the colonic mucus can be used by the HGM as a source of carbon and energy when dietary fibers are not sufficiently available. Both commensals and pathogens can utilize mucin glycans. Commensals are mostly involved in the cleavage of glycans, while pathogens mostly utilize monosaccharides released by commensals. This HGM-derived degradation of the mucus layer increases pathogen susceptibility and causes many other health disorders. Here, we analyzed 397 individual HGM genomes to identify pathways for the cleavage of host-synthetized mucin glycans to monosaccharides as well as for the catabolism of the derived monosaccharides. Our key results are as follows: (i) Genes for the cleavage of mucin glycans were found in 86% of the analyzed genomes, which significantly higher than a previous estimation. (ii) Genes for the catabolism of derived monosaccharides were found in 89% of the analyzed genomes. (iii) Comparative genomic analysis identified four alternative forms of the monosaccharide-catabolizing enzymes and four alternative forms of monosaccharide transporters. (iv) Eighty-five percent of the analyzed genomes may be involved in potential feeding pathways for the monosaccharides derived from cleaved mucin glycans. (v) The analyzed genomes demonstrated different abilities to degrade known mucin glycans. Generally, the ability to degrade at least one type of mucin glycan was predicted for 81% of the analyzed genomes. (vi) Eighty two percent of the analyzed genomes can form mutualistic pairs that are able to degrade mucin glycans and are not degradable by any of the paired organisms alone. Taken together, these findings provide further insight into the inter microbial communications of the HGM as well as into host-HGM interactions. PMID- 28912801 TI - Efficient Multiple Kernel Learning Algorithms Using Low-Rank Representation. AB - Unlike Support Vector Machine (SVM), Multiple Kernel Learning (MKL) allows datasets to be free to choose the useful kernels based on their distribution characteristics rather than a precise one. It has been shown in the literature that MKL holds superior recognition accuracy compared with SVM, however, at the expense of time consuming computations. This creates analytical and computational difficulties in solving MKL algorithms. To overcome this issue, we first develop a novel kernel approximation approach for MKL and then propose an efficient Low Rank MKL (LR-MKL) algorithm by using the Low-Rank Representation (LRR). It is well-acknowledged that LRR can reduce dimension while retaining the data features under a global low-rank constraint. Furthermore, we redesign the binary-class MKL as the multiclass MKL based on pairwise strategy. Finally, the recognition effect and efficiency of LR-MKL are verified on the datasets Yale, ORL, LSVT, and Digit. Experimental results show that the proposed LR-MKL algorithm is an efficient kernel weights allocation method in MKL and boosts the performance of MKL largely. PMID- 28912802 TI - Chaotic Image Encryption Algorithm Based on Bit Permutation and Dynamic DNA Encoding. AB - With the help of the fact that chaos is sensitive to initial conditions and pseudorandomness, combined with the spatial configurations in the DNA molecule's inherent and unique information processing ability, a novel image encryption algorithm based on bit permutation and dynamic DNA encoding is proposed here. The algorithm first uses Keccak to calculate the hash value for a given DNA sequence as the initial value of a chaotic map; second, it uses a chaotic sequence to scramble the image pixel locations, and the butterfly network is used to implement the bit permutation. Then, the image is coded into a DNA matrix dynamic, and an algebraic operation is performed with the DNA sequence to realize the substitution of the pixels, which further improves the security of the encryption. Finally, the confusion and diffusion properties of the algorithm are further enhanced by the operation of the DNA sequence and the ciphertext feedback. The results of the experiment and security analysis show that the algorithm not only has a large key space and strong sensitivity to the key but can also effectively resist attack operations such as statistical analysis and exhaustive analysis. PMID- 28912803 TI - Optimal Parameter Selection for Support Vector Machine Based on Artificial Bee Colony Algorithm: A Case Study of Grid-Connected PV System Power Prediction. AB - Predicting the output power of photovoltaic system with nonstationarity and randomness, an output power prediction model for grid-connected PV systems is proposed based on empirical mode decomposition (EMD) and support vector machine (SVM) optimized with an artificial bee colony (ABC) algorithm. First, according to the weather forecast data sets on the prediction date, the time series data of output power on a similar day with 15-minute intervals are built. Second, the time series data of the output power are decomposed into a series of components, including some intrinsic mode components IMFn and a trend component Res, at different scales using EMD. The corresponding SVM prediction model is established for each IMF component and trend component, and the SVM model parameters are optimized with the artificial bee colony algorithm. Finally, the prediction results of each model are reconstructed, and the predicted values of the output power of the grid-connected PV system can be obtained. The prediction model is tested with actual data, and the results show that the power prediction model based on the EMD and ABC-SVM has a faster calculation speed and higher prediction accuracy than do the single SVM prediction model and the EMD-SVM prediction model without optimization. PMID- 28912804 TI - Assessment of Nutritional Status, Digestion and Absorption, and Quality of Life in Patients with Locally Advanced Pancreatic Cancer. AB - BACKGROUND AND AIM: To provide a comprehensive quantitative assessment of nutritional status, digestion and absorption, and quality of life (QoL) in patients with locally advanced pancreatic cancer (LAPC). METHODS: Sixteen patients with LAPC were prospectively assessed for weight loss (WL), body mass index (BMI), fat-free mass index (FFMI), handgrip strength (HGS), dietary macronutrient intake, serum vitamin levels, resting and total energy expenditure (REE and TEE, indirect calorimetry), intestinal absorption capacity and fecal losses (bomb calorimetry), exocrine pancreatic function (fecal elastase-1 (FE1)), and gastrointestinal quality of life (GIQLI). RESULTS: Two patients had a low BMI, 10 patients had WL > 10%/6 months, 8 patients had a FFMI < P10, and 8 patients had a HGS < P10. Measured REE was 33% higher (P = 0.002) than predicted REE. TEE was significantly higher than daily energy intake (P = 0.047). Malabsorption (<85%) of energy, fat, protein, and carbohydrates was observed in, respectively, 9, 8, 12, and 10 patients. FE1 levels were low (<200 MUg/g) in 13 patients. Total QoL scored 71% (ample satisfactory). CONCLUSION: Patients with LAPC have a severely impaired nutritional status, most likely as a result of an increased REE and malabsorption due to exocrine pancreatic insufficiency. The trial is registered with PANFIRE clinicaltrials.gov NCT01939665. PMID- 28912805 TI - Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model. AB - The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days. The rats were then sacrificed to harvest blood and liver tissue samples in order to determine blood and tissue MDA, serum ALT, plasma TNF-alpha, TGF-beta, and PTX3 levels. Histological specimens were examined via light microscopy. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by relatively worse histopathological scores and increased biochemical marker levels. Lactulose treatment significantly reduced the liver enzyme ALT, plasma TNF-alpha, TGF-beta, PTX3, and MDA levels and also decreased histological changes in the liver tissue with MTX-induced hepatotoxicity in the rat model. We suggest that lactulose has anti-inflammatory and antifibrotic effects on an MTX-induced liver injury model. These effects can be due to the impact of intestinal microbiome. PMID- 28912806 TI - Associations of Fatty Liver Disease with Hypertension, Diabetes, and Dyslipidemia: Comparison between Alcoholic and Nonalcoholic Steatohepatitis. AB - Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are representative types of fatty liver disease (FLD) and have similar histologic features. In this study, we aimed to compare the associations of the two FLD types with hypertension (HT), diabetes mellitus (DM), and dyslipidemia (DL). A nationwide survey investigating FLD status included 753 Japanese subjects (median age 55 years; male 440, female 313) with biopsy-proven ASH (n = 172) or NASH (n = 581). We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. Older age and a higher body mass index were significant factors associated with HT. Older age, female sex, a higher body mass index, advanced liver fibrosis, and the NASH type of FLD (odds ratio 2.77; 95% confidence interval 1.78-4.31; P < 0.0001) were significant factors associated with DM. Finally, the NASH type of FLD (odds ratio 4.05; 95% confidence interval 2.63-6.24; P < 0.0001) was the only significant factor associated with DL. Thus, the associations of NASH with DM and DL were stronger than those of ASH with DM and DL. In the management of FLD subjects, controlling DM and DL is particularly important for NASH subjects. PMID- 28912807 TI - A Meta-Analysis and Systematic Review of the Efficacy of Twice Daily PPIs versus Once Daily for Treatment of Gastroesophageal Reflux Disease. AB - BACKGROUND: To investigate whether PPIs BID is superior to QD for treatment of GERD in a short time. METHODS: We searched PubMed, Cochrane Library, Scopus, EMBASE, Ovid, EBSCO, and Web of Science databases (from 1998 to May 2016) to select RCTs, which compared the efficacy of PPIs BID versus QD for GERD. The primary outcomes were symptom relief or esophageal mucosal healing at weeks 4 and 8. The M-H method with fixed-effect or random-effect model was used to calculate RR and 95% CIs. RESULTS: Seven RCTs were enrolled. The esophageal healing rates were higher in PPIs BID group (P = 0.01), and rabeprazole 20 mg BID can achieve better mucosal healing than 20 mg QD after 8 weeks (P < 0.05). However, no significant differences were observed in heartburn relief (P = 0.27), sustained symptom relief rates at week 4 (P = 0.05), 24 h pH monitoring after treatment (P = 0.11), endoscopic response at week 4 (P = 0.22), and adverse events (P = 0.18). CONCLUSION: PPIs BID more effectively improve endoscopic healing rate at week 8 than PPIs QD. But there are no significant differences in symptom relief, 24 h pH monitoring, sustained symptom relief, and endoscopic response at week 4. PMID- 28912808 TI - Association of Polymorphisms in Toll-Like Receptors 4 and 9 with Autoimmune Thyroid Disease in Korean Pediatric Patients. AB - BACKGROUND: Toll-like receptors (TLRs) have been suggested to be associated with the development of AITD. METHODS: Fifteen single-nucleotide polymorphisms in 7 TLR genes were analyzed in 104 Korean children (girls = 86, boys = 18) with AITD (Hashimoto disease (HD) = 44, Graves' disease (GD) = 60, thyroid-associated ophthalmopathy (TAO) = 29, and non-TAO = 31) with 183 controls. RESULTS: GD showed higher frequencies of the TLR4 rs1927911 C allele than control. TAO showed a lower frequency of the TLR4 rs1927911 CT genotype and non-TAO showed a higher frequency of the TLR4 rs1927911 CC genotype than control. The frequency of the TLR9 rs187084 CC genotype in TAO was higher than that in non-TAO. GD females showed a higher frequency of the TLR4 rs10759932 T allele, rs1927911 CC genotype, and the rs1927911 C allele than controls. GD males showed a higher frequency of the TLR4 rs10759932 CC genotype and rs1927911 TT genotype and lower frequency of the rs1927911 CT genotype than control. The frequency of the TLR4 rs10759932 CC genotype, C allele and rs1927911 TT genotype, and T allele in a GD female were lower than in a GD male. CONCLUSIONS: Our results suggest that TLR4 and 9 polymorphisms might contribute to the pathogenesis of GD and TAO. PMID- 28912809 TI - The Biphasic Effect of Vitamin D on the Musculoskeletal and Cardiovascular System. AB - This narrative review summarizes beneficial and harmful vitamin D effects on the musculoskeletal and cardiovascular system. Special attention is paid to the dose response relationship of vitamin D with clinical outcomes. In infants and adults, the risk of musculoskeletal diseases is highest at circulating 25-hydroxyvitamin D (25OHD) concentrations below 25 nmol/L and is low if 40-60 nmol/L are achieved. However, evidence is also accumulating that in elderly people the risk of falls and fractures increases again at circulating 25OHD levels > 100 nmol/L. Cohort studies report a progressive increase in cardiovascular disease (CVD) events at 25OHD levels < 50 nmol/L. Nevertheless, meta-analyses of randomized controlled trials suggest only small beneficial effects of vitamin D supplements on surrogate parameters of CVD risk and no reduction in CVD events. Evidence is accumulating for adverse vitamin D effects on CVD outcomes at 25OHD levels > 100 nmol/L, but the threshold may be influenced by the level of physical activity. In conclusion, dose-response relationships indicate deleterious effects on the musculoskeletal system and probably on the cardiovascular system at circulating 25OHD levels < 40-60 nmol/L and >100 nmol/L. Future studies should focus on populations with 25OHD levels < 40 nmol/L and should avoid vitamin D doses achieving 25OHD levels > 100 nmol/L. PMID- 28912811 TI - Corrigendum to "In Vitro Antioxidant Treatment of Semen Samples in Assisted Reproductive Technology: Effects of Myo-Inositol on Nemaspermic Parameters". AB - [This corrects the article DOI: 10.1155/2016/2839041.]. PMID- 28912810 TI - Latent Inflammation and Insulin Resistance in Adipose Tissue. AB - Obesity is a growing problem in modern society and medicine. It closely associates with metabolic disorders such as type 2 diabetes mellitus (T2DM) and hepatic and cardiovascular diseases such as nonalcoholic fatty liver disease, atherosclerosis, myocarditis, and hypertension. Obesity is often associated with latent inflammation; however, the link between inflammation, obesity, T2DM, and cardiovascular diseases is still poorly understood. Insulin resistance is the earliest feature of metabolic disorders. It mostly develops as a result of dysregulated insulin signaling in insulin-sensitive cells, as compared to inactivating mutations in insulin receptor or signaling proteins that occur relatively rare. Here, we argue that inflammatory signaling provides a link between latent inflammation, obesity, insulin resistance, and metabolic disorders. We further hypothesize that insulin-activated PI3-kinase pathway and inflammatory signaling mediated by several IkappaB kinases may constitute negative feedback leading to insulin resistance at least in the fat tissue. Finally, we discuss perspectives for anti-inflammatory therapies in treating the metabolic diseases. PMID- 28912812 TI - The Influence of Sweet Taste Perception on Dietary Intake in Relation to Dental Caries and BMI in Saudi Arabian Schoolchildren. AB - OBJECTIVES: The aim of the study was to evaluate the influence of sweet taste perception on dietary habits in Saudi schoolchildren. In addition, the relationship between dietary habits and both caries and BMI was studied. METHODS: A cross-sectional observational study comprising 225 schoolchildren aged 13-15 years from Jeddah, Saudi Arabia, was conducted. The consumption frequency of certain food items was analysed from a beverage and snack questionnaire and a three-day estimated dietary record was obtained. The sweet taste perception level was determined as sweet taste threshold (TT) and sweet taste preference (TP). Children were grouped into low, medium, and high, according to their sweet taste perception level. ICDAS and DMFS indices were used for caries registration and anthropometric measurements using BMI were collected. RESULTS: Sweet taste perception was found to be negatively correlated to the number of main meals and positively correlated to both snack and sweet intake occasions. Statistically significant differences were found between the TT and TP groups with regard to the number of main meals and sweet intake (p <= 0.01). No significant correlation between the dietary variables and caries or BMI was found. CONCLUSIONS: The dietary habits and sweet intake were found to be influenced by the sweet taste perception level, while the relation between the dietary habits and the caries and BMI was found insignificant. PMID- 28912813 TI - Silicone Substrate with Collagen and Carbon Nanotubes Exposed to Pulsed Current for MSC Osteodifferentiation. AB - Autologous human adipose tissue-derived mesenchymal stem cells (MSCs) have the potential for clinical translation through their induction into osteoblasts for regeneration. Bone healing can be driven by biophysical stimulation using electricity for activating quiescent adult stem cells. It is hypothesized that application of electric current will enhance their osteogenic differentiation, and addition of conductive carbon nanotubes (CNTs) to the cell substrate will provide increased efficiency in current transmission. Cultured MSCs were seeded and grown onto fabricated silicone-based composites containing collagen and CNT fibers. Chemical inducers, namely, glycerol phosphate, dexamethasone, and vitamin C, were then added to the medium, and pulsatile submilliampere electrical currents (about half mA for 5 cycles at 4 mHz, twice a week) were applied for two weeks. Calcium deposition indicative of MSC differentiation and osteoblastic activity was quantified through Alizarin Red S and spectroscopy. It was found that pulsed current significantly increased osteodifferentiation on silicone collagen films without CNTs. Under no external current, the presence of 10% (m/m) CNTs led to a significant and almost triple upregulation of calcium deposition. Both CNTs and current parameters did not appear to be synergistic. These conditions of enhanced osteoblastic activities may further be explored ultimately towards future therapeutic use of MSCs. PMID- 28912814 TI - Effect of Antioxidant Water on the Bioactivities of Cells. AB - It has been reported that water at the interface of a hydrophilic thin film forms an exclusion zone, which has a higher density than ordinary water. A similar phenomenon was observed for a hydrated hydrophilic ceramic powder, and water turns into a three-dimensional cell-like structure composed of high density water and low density water. This structured water appears to have a stimulative effect on plant growth. This report outlines our study of antioxidant properties of this structured water and its effect on cell bioactivities. Culturing media which were prepared utilizing this antioxidant structured water promoted the viability of RAW 264.7 macrophage cells by up to three times. The same tendency was observed for other cells including IEC-6, C2C12, and 3T3-L1. Also, the cytokine expression of the splenocytes taken from a mouse spleen increased in the same manner. The water also appears to suppress the viability of cancer cell, MCF-7. These results strongly suggest that the structured water helps the activities of normal cells while suppressing those of malignant cells. PMID- 28912815 TI - Feasibility of Metatranscriptome Analysis from Infant Gut Microbiota: Adaptation to Solid Foods Results in Increased Activity of Firmicutes at Six Months. AB - Newborns are rapidly colonized by microbes and their intestinal tracts contain highly dynamic and rapidly developing microbial communities in the first months of life. In this study, we describe the feasibility of isolating mRNA from rapidly processed faecal samples and applying deep RNA-Seq analysis to provide insight into the active contributors of the microbial community in early life. Specific attention is given to the impact of removing rRNA from the mRNA on the phylogenetic and transcriptional profiling and its analysis depth. A breastfed baby was followed in the first six months of life during adaptation to solid food, dairy products, and formula. It was found that, in the weaning period, the total transcriptional activity of Actinobacteria, mainly represented by Bifidobacterium, decreased while that of Firmicutes increased over time. Moreover, Firmicutes and Actinobacteria, including the canonical Bifidobacteria as well as Collinsella, were found to be important contributors to carbohydrate fermentation and vitamin biosynthesis in the infant intestine. Finally, the expression of Lactobacillus rhamnosus-like genes was detected, likely following transfer from the mother who consumed L. rhamnosus GG. The study indicates that metatranscriptome analysis of the infant gut microbiota is feasible on infant stool samples and can be used to provide insight into the core activities of the developing community. PMID- 28912816 TI - Review of Current Immunologic Therapies for Hidradenitis Suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1-4% of the population. The disease is more common in women and patients of African American descent and approximately one-third of patients report a family history. Obesity and smoking are known risk factors, but associations with other immune disorders, especially inflammatory bowel disease, are also recognized. The pathogenesis of HS is poorly understood and host innate or adaptive immune response, defective keratinocyte function, and the microbial environment in the hair follicle and apocrine gland have all been postulated to play a role in disease activity. While surgical interventions can be helpful to reduce disease burden, there is a high recurrence rate. Increasingly, data supports targeted immune therapy for HS, and longitudinal studies suggest benefit from these agents, both when used alone and as an adjunct to surgical treatments. The purpose of this review is to outline the current data supporting use of targeted immune therapy in HS management. PMID- 28912817 TI - The Effects of Vitamin D Supplement on Prevention of Recurrence of Preeclampsia in Pregnant Women with a History of Preeclampsia. AB - INTRODUCTION: Preeclampsia is a pregnancy-specific syndrome. One of the hypotheses concerning the etiology of preeclampsia is vitamin D deficiency during pregnancy. METHOD AND MATERIALS: The present study is a randomized controlled clinical trial which aims to determine the effect of vitamin D supplement on reducing the probability of recurrent preeclampsia. 72 patients were placed in control group while 70 patients were randomized to the intervention group. The intervention group received a 50000 IU pearl vitamin D3 once every two weeks. The control group was administered placebo. Vitamin D or placebo was given until the 36th week of pregnancy. RESULTS: The patients in intervention group have significantly lower (P value = 0.036) probability of preeclampsia than patients in the control group. The risk of preeclampsia for the control group was 1.94 times higher than that for the intervention group (95% CI 1.02, 3.71). CONCLUSION: The intended intervention (i.e., prescription of vitamin D) has a protective effect against recurrent preeclampsia. Vitamin D supplementation therapy in pregnancy could help in reducing the incidence of gestational hypertension/preeclampsia. REGISTRATION: This study has been registered in Iranian Registry of Clinical Trials (IRCT) site with ID number IRCT2017010131695N1. PMID- 28912818 TI - A Successfully Treated Case of Gastrointestinal Stromal Tumor Causing Severe Anemia and Localized Peritonitis Showing Angina Pectoris Resulting in Watershed Cerebral Infarction. AB - Ischemic stroke following acute myocardial infarction is a rare but a serious complication. Because the pathophysiology of stroke is dynamic, it is often hard to identify the cause of stroke. Here, we present the case of a 75-year-old man with ischemic stroke following angina pectoris caused by severe anemia and localized peritonitis due to gastrointestinal stromal tumor of small intestine. On admission, he showed consciousness disturbance, fever, and left hemiplegia. The electrocardiogram on admission showed ST-segment depression in V2 to V6 which was normalized 4 hours later. The ultrasound cardiogram showed the mild hypokinesis in the apical portion of left ventricle which was also normalized later. The magnetic resonance imaging and angiography showed ischemic stroke in watershed area between right anterior and middle cerebral arteries area and stenosis of distal portion of right middle cerebral artery. The computed tomography of abdomen showed a mass of small intestine. We decided to perform curative surgery after transfusion and successfully resected the mass of the small intestine, which was revealed to be a gastrointestinal stromal tumor (GIST). This is a successfully treated case of GIST in which the complicated pathophysiology of watershed cerebral infarction following angina pectoris might be clearly revealed. PMID- 28912819 TI - Large Subcapsular Splenic Hematoma with a Large Pancreatic Pseudocyst Was Successfully Treated with Splenic Arterial Embolization and Ultrasound-Guided Percutaneous Drainage of Pancreatic Pseudocyst. AB - Subcapsular splenic hematoma is a rare complication of pancreatitis. The management for subcapsular splenic hematoma remains controversial. We herein report a case of a large subcapsular splenic hematoma with a large pancreatic pseudocyst, which was successfully treated with splenic arterial embolization and ultrasound- (US-) guided percutaneous drainage of pancreatic pseudocyst, for the first time. A 44-year-old male suffered from recurrent abdominal pain for more than two years. He had previous 3 episodes of pancreatitis. A subcapsular splenic hematoma (16.0 * 16.0 * 7.6 cm) with pancreatic pseudocyst (13.5 * 10.0 * 8.0 cm) was shown on abdominal computed tomography (CT). He underwent splenic arterial embolization to decrease the blood supply of the spleen and then ultrasound guided percutaneous drainage of the large pancreatic pseudocyst. After 2 weeks, the repeated CT-Abdomen showed the disappearance of pancreatic pseudocyst and multiple areas of infarction on the spleen, while the splenic subcapsular hematoma had also significantly reduced. The patient was discharged after almost a month of his hospital admission with the drainage tube attached, and about 2 weeks later the drainage tube was removed upon CT scan confirmation of decrease in the volume of the subcapsular hematoma. Patient had no abdominal symptoms at the 1.5-year follow-up. PMID- 28912820 TI - Granulomatosis with Polyangiitis with Myocarditis and Ventricular Tachycardia. AB - Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is a pulmonary-renal syndrome affecting small and medium sized blood vessels. The disease has a prevalence in studies ranging from 3 to 15.7 cases per 100,000, with a noted increasing incidence and prevalence in more recent studies. Pulmonary manifestations include hemorrhage, lung cavitary lesions, and pulmonary fibrosis. Within the kidney, GPA is known to cause rapidly progressive pauci-immune crescentic glomerulonephritis. Rare and severe cardiovascular manifestations include pericarditis, arrhythmias, myocarditis, and aortic valve disease. Our patient is a 43-year-old female with typical pulmonary and renal lesions from GPA and also acute myocarditis, multiple episodes of ventricular tachycardia, and a severe reactive thrombocytosis. PMID- 28912821 TI - Thyrotoxicosis and Choledocholithiasis Masquerading as Thyroid Storm. AB - A 26-year-old female, thirteen months postpartum, presented to the emergency department for four weeks of epigastric abdominal pain, pruritus, new onset jaundice, and 11.3 kgs (25 lbs) unintentional weight loss. On examination, she was afebrile, tachycardic, alert, and oriented and had jaundice with scleral icterus. Labs were significant for undetectable TSH, FT4 that was too high to measure, and elevated total bilirubin, direct bilirubin, alkaline phosphatase, and transaminases. Abdominal ultrasound revealed cholelithiasis without biliary ductal dilation. Treatment for presumed thyroid storm was initiated. Further work up with magnetic resonance cholangiopancreatography (MRCP) revealed an obstructing cholelith within the distal common bile duct. With the presence of choledocholithiasis explaining the jaundice and abdominal pain, plus the absence of CNS alterations, the diagnosis of thyroid storm was revised to thyrotoxicosis complicated by choledocholithiasis. Endoscopic retrograde cholangiopancreatogram (ERCP) with sphincterotomy was performed to alleviate the biliary obstruction, with prompt symptomatic improvement. Thyroid storm is a rare manifestation of hyperthyroidism with a high rate of morbidity and mortality. The diagnosis of thyroid storm is based on clinical examination, and abnormal thyroid function tests do not correlate with disease severity. Knowledge of the many manifestations of thyroid storm will facilitate a quick and accurate diagnosis and treatment. PMID- 28912822 TI - A Rare Case of Cavitary Lesion of the Lung Caused by Mycoplasma pneumoniae in an Immunocompetent Patient. AB - Mycoplasma pneumoniae is an atypical bacterium that most commonly causes upper respiratory tract infections, but it can also cause pneumonia, referred to as "walking pneumonia." Although cavitary lesions are present in a wide variety of infectious and noninfectious processes, those attributable to M. pneumoniae are extremely uncommon; thus, to date, epidemiological studies are lacking. Here, we present a rare case of a 20-year-old male, referred to us from a psychiatric facility for evaluation of a cough, who was found to have a cavitary lesion in the right upper lobe. An extensive workup for cavitary lesion was negative, but his mycoplasma IgM level was high. A computed tomography (CT) of the chest confirmed the presence of a cavitary lesion. After treatment with levofloxacin antibiotics, a follow-up CT showed complete resolution of the lesion. Our case is a rare presentation of mycoplasma pneumonia as a cavitary lesion in a patient without any known risk factors predisposing to mycoplasma infection. Early recognition and treatment with an appropriate antibiotic may lead to complete resolution of the cavitary lesion. PMID- 28912823 TI - Assessment of Environmental Attitudes and Risk Perceptions among University Students in Mersin, Turkey. AB - BACKGROUND: Environmental destruction is one of the most important problems in this century. OBJECTIVE: The aim of the study was to determine the environmental attitudes and perceived risks associated with environmental factors of the students. METHODS: This cross-sectional study was conducted in 7 faculties of Mersin University. The research data were collected using a questionnaire. The questionnaire included sociodemographic characteristics, the "Environmental Attitudes Scale," and the "Environmental Risk Perception Scale." 774 students who filled out questionnaires were evaluated. RESULTS: The sample included 55.8% females. Environmental Attitudes Scale mean scores of students were identified as 81.1 +/- 11.3. The highest perceived risk was release of radioactive materials associated with nuclear power generation. The environmental attitudes and risk perception scores were higher in Health Sciences than in the other faculties. Females were more positive towards the environment and had higher risk perceptions than the men. There is a negative correlation between age and resource depletion risk and global environmental risk score. CONCLUSION: Students had a positive attitude to the environment and had moderate-level risk perception about the environment. Environmental awareness of students, especially those studying in the Social Sciences, should be increased. The environmental education curriculum should be revised throughout all the courses. PMID- 28912824 TI - Prevalence and Correlates of Complementary and Alternative Medicine Use among Patients with Lung Cancer: A Cross-Sectional Study in Beirut, Lebanon. AB - Patients with lung cancer are increasingly seeking complementary and alternative medicine (CAM) to improve their physiological and psychological well-being. This study aimed to assess CAM use among lung cancer patients in Lebanon. Using a cross-sectional design, 150 lung cancer patients attending the Basile Cancer Institute at the American University of Beirut Medical Center were interviewed. Participants completed a questionnaire addressing sociodemographic characteristics, lung cancer condition, and use of CAM. The main outcome of interest was "use of any CAM therapy since diagnosis." Prevalence of CAM use was 41%. The most commonly used CAM modality among study participants was "dietary supplements/special foods." Results of the multiple logistic regression analyses showed that CAM use was positively associated with Lebanese nationality and paying for treatment out of pocket and was negatively associated with unemployment and having other chronic diseases. About 10% of patients used CAM on an alternative base, 58% did not disclose CAM use to their physician, and only 2% cited health professionals as influencing their choice of CAM. This study revealed a prevalent CAM use among lung cancer patients in Lebanon, with a marginal role for physicians in guiding this use. Promoting an open-communication and a patient-centered approach regarding CAM use is warranted. PMID- 28912825 TI - Randomised and non-randomised studies to estimate the effect of community-level public health interventions: definitions and methodological considerations. AB - BACKGROUND: The preferred method to evaluate public health interventions delivered at the level of whole communities is the cluster randomised trial (CRT). The practical limitations of CRTs and the need for alternative methods continue to be debated. There is no consensus on how to classify study designs to evaluate interventions, and how different design features are related to the strength of evidence. ANALYSIS: This article proposes that most study designs for the evaluation of cluster-level interventions fall into four broad categories: the CRT, the non-randomised cluster trial (NCT), the controlled before-and-after study (CBA), and the before-and-after study without control (BA). A CRT needs to fulfil two basic criteria: (1) the intervention is allocated at random; (2) there are sufficient clusters to allow a statistical between-arm comparison. In a NCT, statistical comparison is made across trial arms as in a CRT, but treatment allocation is not random. The defining feature of a CBA is that intervention and control arms are not compared directly, usually because there are insufficient clusters in each arm to allow a statistical comparison. Rather, baseline and follow-up measures of the outcome of interest are compared in the intervention arm, and separately in the control arm. A BA is a CBA without a control group. CONCLUSION: Each design may provide useful or misleading evidence. A precise baseline measurement of the outcome of interest is critical for causal inference in all studies except CRTs. Apart from statistical considerations the exploration of pre/post trends in the outcome allows a more transparent discussion of study weaknesses than is possible in non-randomised studies without a baseline measure. PMID- 28912826 TI - Can yesterday's smoking research inform today's shiftwork research? Epistemological consequences for exposures and doses due to circadian disruption at and off work. AB - In 1950, landmark epidemiology studies by Wynder & Graham and Doll & Hill contributed to identifying smoking as a potent carcinogen. In 2007, IARC classified shiftwork involving circadian disruption (CD) as probably carcinogenic; however, epidemiological evidence in regards to the carcinogenicity of shiftwork that involves nightwork is conflicting. We hypothesize that shiftwork research is lacking chronobiological and methodological rigor and that lessons can be learned from comparison with smoking research. Herein, we provide a factual view at, and a fictional case study of, 1940s smoking research which serves as an analogy for current shiftwork research dilemmas. This analogy takes the form of limiting counting cigarettes to a particular time window (i.e. at work) rather than assessing exposures to, and doses of, accumulated smoking over 24 h, highlighting the importance of exposure and dose. Simply put, smoking insights could have been delayed or even disallowed. In conclusion, CD may be similar to smoking insofar as for quantitative measures of cumulative doses, exposures both at and off work may have to be considered. Future work must explore whether such similarity factually exists and whether CD is a cancer hazard in IARC terms. PMID- 28912827 TI - Development of TaqMan probes targeting the four major celiac disease epitopes found in alpha-gliadin sequences of spelt (Triticum aestivum ssp. spelta) and bread wheat (Triticum aestivum ssp. aestivum). AB - BACKGROUND: Celiac disease (CD) is caused by specific sequences of gluten proteins found in cereals such as bread wheat (Triticum aestivum ssp. aestivum) and spelt (T. aestivum ssp. spelta). Among them, the alpha-gliadins display the highest immunogenicity, with four T-cell stimulatory epitopes. The toxicity of each epitope sequence can be reduced or even suppressed according to the allelic form of each sequence. One way to address the CD problem would be to make use of this allelic variability in breeding programs to develop safe varieties, but tools to track the presence of toxic epitopes are required. The objective of this study was to develop a tool to accurately detect and quantify the immunogenic content of expressed alpha-gliadins of spelt and bread wheat. RESULTS: Four TaqMan probes that only hybridize to the canonical-i.e. toxic-form of each of the four epitopes were developed and their specificity was demonstrated. Six TaqMan probes targeting stable reference genes were also developed and constitute a tool to normalize qPCR data. The probes were used to measure the epitope expression levels of 11 contrasted spelt accessions and three ancestral diploid accessions of bread wheat and spelt. A high expression variability was highlighted among epitopes and among accessions, especially in Asian spelts, which showed lower epitope expression levels than the other spelts. Some discrepancies were identified between the canonical epitope expression level and the global amount of expressed alpha-gliadins, which makes the designed TaqMan probes a useful tool to quantify the immunogenic potential independently of the global amount of expressed alpha-gliadins. CONCLUSIONS: The results obtained in this study provide useful tools to study the immunogenic potential of expressed alpha-gliadin sequences from Triticeae accessions such as spelt and bread wheat. The application of the designed probes to contrasted spelt accessions revealed a high variability and interesting low canonical epitope expression levels in the Asian spelt accessions studied. PMID- 28912828 TI - Dendritic Immunotherapy Improvement for an Optimal Control Murine Model. AB - Therapeutic protocols in immunotherapy are usually proposed following the intuition and experience of the therapist. In order to deduce such protocols mathematical modeling, optimal control and simulations are used instead of the therapist's experience. Clinical efficacy of dendritic cell (DC) vaccines to cancer treatment is still unclear, since dendritic cells face several obstacles in the host environment, such as immunosuppression and poor transference to the lymph nodes reducing the vaccine effect. In view of that, we have created a mathematical murine model to measure the effects of dendritic cell injections admitting such obstacles. In addition, the model considers a therapy given by bolus injections of small duration as opposed to a continual dose. Doses timing defines the therapeutic protocols, which in turn are improved to minimize the tumor mass by an optimal control algorithm. We intend to supplement therapist's experience and intuition in the protocol's implementation. Experimental results made on mice infected with melanoma with and without therapy agree with the model. It is shown that the dendritic cells' percentage that manages to reach the lymph nodes has a crucial impact on the therapy outcome. This suggests that efforts in finding better methods to deliver DC vaccines should be pursued. PMID- 28912829 TI - Mental health leadership and patient access to care: a public-private initiative in South Africa. AB - BACKGROUND: Mental health leadership is a critical component of patient access to care. More specifically, the ability of mental health professionals to articulate the needs of patients, formulate strategies and engage meaningfully at the appropriate level in pursuit of resources. This is not a skill set routinely taught to mental health professionals. METHODS: A public-private mental health leadership initiative, emanating from a patient access to care programme, was developed with the aim of building leadership capacity within the South African public mental health sector. The express aim was to equip health care professionals with the requisite skills to more effectively advocate for their patients. The initiative involved participants from various sites within South Africa. Inclusion was based on the proposal of an ongoing "project", i.e. a clinician-initiated service development with a multidisciplinary focus. The projects were varied in nature but all involved identification of and a plan for addressing an aspect of the participants' daily professional work which negatively impacted on patient care due to unmet needs. Six such projects were included and involved 15 participants, comprising personnel from psychiatry, psychology, occupational therapy and nursing. Each project group was formally mentored as part of the initiative, with mentors being senior professionals with expertise in psychiatry, public health and nursing. The programme design thus provided a unique practical dimension in which skills and learnings were applied to the projects with numerous and diverse outcomes. RESULTS: Benefits were noted by participants but extended beyond the individuals to the health institutions in which they worked and the patients that they served. Participants acquired both the skills and the confidence which enabled them to sustain the changes that they themselves had initiated in their institutions. The initiative gave impetus to the inclusion of public mental health as part of the curriculum for specialist training. CONCLUSIONS: Despite the significant adverse social and economic costs of mental illness, psychiatric and related services receive a low level of priority within the health care system. Ensuring that mental health receives the recognition and the resources it deserves requires that mental health care professionals become effective advocates through mental health leadership. PMID- 28912831 TI - Genome sequencing and transcriptome analysis of Trichoderma reesei QM9978 strain reveals a distal chromosome translocation to be responsible for loss of vib1 expression and loss of cellulase induction. AB - BACKGROUND: The hydrolysis of biomass to simple sugars used for the production of biofuels in biorefineries requires the action of cellulolytic enzyme mixtures. During the last 50 years, the ascomycete Trichoderma reesei, the main source of industrial cellulase and hemicellulase cocktails, has been subjected to several rounds of classical mutagenesis with the aim to obtain higher production levels. During these random genetic events, strains unable to produce cellulases were generated. Here, whole genome sequencing and transcriptomic analyses of the cellulase-negative strain QM9978 were used for the identification of mutations underlying this cellulase-negative phenotype. RESULTS: Sequence comparison of the cellulase-negative strain QM9978 to the reference strain QM6a identified a total of 43 mutations, of which 33 were located either close to or in coding regions. From those, we identified 23 single-nucleotide variants, nine InDels, and one translocation. The translocation occurred between chromosomes V and VII, is located upstream of the putative transcription factor vib1, and abolishes its expression in QM9978 as detected during the transcriptomic analyses. Ectopic expression of vib1 under the control of its native promoter as well as overexpression of vib1 under the control of a strong constitutive promoter restored cellulase expression in QM9978, thus confirming that the translocation event is the reason for the cellulase-negative phenotype. Gene deletion of vib1 in the moderate producer strain QM9414 and in the high producer strain Rut-C30 reduced cellulase expression in both cases. Overexpression of vib1 in QM9414 and Rut-C30 had no effect on cellulase production, most likely because vib1 is already expressed at an optimal level under normal conditions. CONCLUSION: We were able to establish a link between a chromosomal translocation in QM9978 and the cellulase-negative phenotype of the strain. We identified the transcription factor vib1 as a key regulator of cellulases in T. reesei whose expression is absent in QM9978. We propose that in T. reesei, as in Neurospora crassa, vib1 is involved in cellulase induction, although the exact mechanism remains to be elucidated. The data presented here show an example of a combined genome sequencing and transcriptomic approach to explain a specific trait, in this case the QM9978 cellulase-negative phenotype, and how it helps to better understand the mechanisms during cellulase gene regulation. When focusing on mutations on the single base-pair level, changes on the chromosome level can be easily overlooked and through this work we provide an example that stresses the importance of the big picture of the genomic landscape during analysis of sequencing data. PMID- 28912830 TI - In vitro oxidative decarboxylation of free fatty acids to terminal alkenes by two new P450 peroxygenases. AB - BACKGROUND: P450 fatty acid decarboxylases represented by the unusual CYP152 peroxygenase family member OleTJE have been receiving great attention recently since these P450 enzymes are able to catalyze the simple and direct production of 1-alkenes for potential applications in biofuels and biomaterials. To gain more mechanistic insights, broader substrate spectra, and improved decarboxylative activities, it is demanded to discover and investigate more P450 fatty acid decarboxylases. RESULTS: Here, we describe for the first time the expression, purification, and in vitro biochemical characterization of two new CYP152 peroxygenases, CYP-Aa162 and CYP-Sm46Delta29, that are capable of decarboxylating straight-chain saturated fatty acids. Both enzymes were found to catalyze the decarboxylation and hydroxylation of a broad range of free fatty acids (C10-C20) with overlapping substrate specificity, yet distinct chemoselectivity. CYP Sm46Delta29 works primarily as a fatty (lauric) acid decarboxylase (66.1 +/- 3.9% 1-undecene production) while CYP-Aa162 more as a fatty (lauric) acid hydroxylase (72.2 +/- 0.9% hydroxy lauric acid production). Notably, the optical spectroscopic analysis of functional CYP-Sm46Delta29 revealed no characteristic P450 band, suggesting a unique heme coordination environment. Active-site mutagenesis analysis showed that substitution with the proposed key decarboxylation-modulating residues, His85 and Ile170, enhanced the decarboxylation activity of CYP-Aa162 and P450BSbeta, emphasizing the importance of these residues in directing the decarboxylation pathway. Furthermore, the steady-state kinetic analysis of CYP-Aa162 and CYP-Sm46Delta29 revealed both cooperative and substrate inhibition behaviors which are substrate carbon chain length dependent. CONCLUSIONS: Our data identify CYP-Sm46Delta29 as an efficient OleTJE-like fatty acid decarboxylase. Oxidative decarboxylation chemoselectivity of the CYP152 decarboxylases is largely dependent upon the carbon chain length of fatty acid substrates and their precise positioning in the enzyme active site. Finally, the kinetic mode analysis of the enzymes could provide important guidance for future process design. PMID- 28912832 TI - Unique organization and unprecedented diversity of the Bacteroides (Pseudobacteroides) cellulosolvens cellulosome system. AB - BACKGROUND: (Pseudo) Bacteroides cellulosolvens is an anaerobic, mesophilic, cellulolytic, cellulosome-producing clostridial bacterium capable of utilizing cellulose and cellobiose as carbon sources. Recently, we sequenced the B. cellulosolvens genome, and subsequent comprehensive bioinformatic analysis, herein reported, revealed an unprecedented number of cellulosome-related components, including 78 cohesin modules scattered among 31 scaffoldins and more than 200 dockerin-bearing ORFs. In terms of numbers, the B. cellulosolvens cellulosome system represents the most intricate, compositionally diverse cellulosome system yet known in nature. RESULTS: The organization of the B. cellulosolvens cellulosome is unique compared to previously described cellulosome systems. In contrast to all other known cellulosomes, the cohesin types are reversed for all scaffoldins i.e., the type II cohesins are located on the enzyme integrating primary scaffoldin, whereas the type I cohesins are located on the anchoring scaffoldins. Many of the type II dockerin-bearing ORFs include X60 modules, which are known to stabilize type II cohesin-dockerin interactions. In the present work, we focused on revealing the architectural arrangement of cellulosome structure in this bacterium by examining numerous interactions between the various cohesin and dockerin modules. In total, we cloned and expressed 43 representative cohesins and 27 dockerins. The results revealed various possible architectures of cell-anchored and cell-free cellulosomes, which serve to assemble distinctive cellulosome types via three distinct cohesin dockerin specificities: type I, type II, and a novel-type designated R (distinct from type III interactions, predominant in ruminococcal cellulosomes). CONCLUSIONS: The results of this study provide novel insight into the architecture and function of the most intricate and extensive cellulosomal system known today, thereby extending significantly our overall knowledge base of cellulosome systems and their components. The robust cellulosome system of B. cellulosolvens, with its unique binding specificities and reversal of cohesin dockerin types, has served to amend our view of the cellulosome paradigm. Revealing new cellulosomal interactions and arrangements is critical for designing high-efficiency artificial cellulosomes for conversion of plant-derived cellulosic biomass towards improved production of biofuels. PMID- 28912833 TI - Perspectives for biocatalytic lignin utilization: cleaving 4-O-5 and Calpha-Cbeta bonds in dimeric lignin model compounds catalyzed by a promiscuous activity of tyrosinase. AB - BACKGROUND: In the biorefinery utilizing lignocellulosic biomasses, lignin decomposition to value-added phenolic derivatives is a key issue, and recently biocatalytic delignification is emerging owing to its superior selectivity, low energy consumption, and unparalleled sustainability. However, besides heme containing peroxidases and laccases, information about lignolytic biocatalysts is still limited till date. RESULTS: Herein, we report a promiscuous activity of tyrosinase which is closely associated with delignification requiring high redox potentials (>1.4 V vs. normal hydrogen electrode [NHE]). The promiscuous activity of tyrosinase not only oxidizes veratryl alcohol, a commonly used nonphenolic substrate for assaying ligninolytic activity, to veratraldehyde but also cleaves the 4-O-5 and Calpha-Cbeta bonds in 4-phenoxyphenol and guaiacyl glycerol-beta guaiacyl ether (GGE) that are dimeric lignin model compounds. Cyclic voltammograms additionally verified that the promiscuous activity oxidizes lignin related high redox potential substrates. CONCLUSION: These results might be applicable for extending the versatility of tyrosinase toward biocatalytic delignification as well as suggesting a new perspective for sustainable lignin utilization. Furthermore, the results provide insight for exploring the previously unknown promiscuous activities of biocatalysts much more diverse than ever thought before, thereby innovatively expanding the applicable area of biocatalysis. PMID- 28912834 TI - Molecular and clinical characterization of new patient with 1,08 Mb deletion in 10p15.3 region. AB - BACKGROUND: Three distinct contiguous gene deletion syndromes are located at 10p chromosomal region. The deletion, involving 10p15.3 region, has been characterized by (DeScipio et al., Am J Med Genet A 158A:2152-61, 2012). However, because of the variation in size of the described deletions and lack of knowledge about the involved genes, the correlation between genotypes and patients' phenotypes remains unknown. CASE PRESENTATION: We describe female patient with de novo 1,08 Mb deletion in 10p15.3 region, similar to the patient nr seven reported by (DeScipio et al., Am J Med Genet A 158A:2152-61, 2012) but with more severe clinical features. Our patient demonstrated speech and motor delay, dysmorphic features, brain abnormalities and Tetralogy of Fallot with pulmonary atresia. CONCLUSIONS: This case shows the importance of collection of more patients with deletion in order to obtain a more precise physical map of 10p region. PMID- 28912835 TI - A unique set of complex chromosomal abnormalities in an infant with myeloid leukemia associated with Down syndrome. AB - BACKGROUND: Children with Down syndrome (DS) have an enhanced risk of developing acute leukemia, with the most common subtype being acute megakaryoblastic leukemia (AMKL). Myeloid leukemia in Down syndrome (ML-DS) is considered a disease with distinct clinical and biological features. There are few studies focusing on the clonal cytogenetic changes during evolution of ML-DS. CASE PRESENTATION: Here, we describe a complex karyotype involving a previously unreported set of chromosomal abnormalities acquired during progression of ML-DS in an infant boy: derivative der(1)t(1;15)(q24;q23), translocation t(4;5)(q26;q33) and derivative der(15)t(7;15)(p21;q23). Different molecular cytogenetic probes and probesets including whole chromosome painting (WCP) and locus specific probes, as well as, multicolor-FISH and multicolor chromosome banding (MCB) were performed in order to characterize the chromosomal abnormalities involved in this complex karyotype. The patient was treated according to the acute myeloid leukemia-Berlin-Frankfurt-Munich-2004 (AML-BFM 2004) treatment protocol for patients with Down syndrome; however, he experienced a poor clinical outcome. CONCLUSION: The molecular cytogenetic studies performed, allowed the characterization of novel chromosomal abnormalities in ML-DS and possible candidate genes involved in the leukemogenic process. Our findings suggest that the complex karyotype described here was associated with the poor prognosis. PMID- 28912836 TI - Methods for enhancing the reproducibility of biomedical research findings using electronic health records. AB - BACKGROUND: The ability of external investigators to reproduce published scientific findings is critical for the evaluation and validation of biomedical research by the wider community. However, a substantial proportion of health research using electronic health records (EHR), data collected and generated during clinical care, is potentially not reproducible mainly due to the fact that the implementation details of most data preprocessing, cleaning, phenotyping and analysis approaches are not systematically made available or shared. With the complexity, volume and variety of electronic health record data sources made available for research steadily increasing, it is critical to ensure that scientific findings from EHR data are reproducible and replicable by researchers. Reporting guidelines, such as RECORD and STROBE, have set a solid foundation by recommending a series of items for researchers to include in their research outputs. Researchers however often lack the technical tools and methodological approaches to actuate such recommendations in an efficient and sustainable manner. RESULTS: In this paper, we review and propose a series of methods and tools utilized in adjunct scientific disciplines that can be used to enhance the reproducibility of research using electronic health records and enable researchers to report analytical approaches in a transparent manner. Specifically, we discuss the adoption of scientific software engineering principles and best-practices such as test-driven development, source code revision control systems, literate programming and the standardization and re-use of common data management and analytical approaches. CONCLUSION: The adoption of such approaches will enable scientists to systematically document and share EHR analytical workflows and increase the reproducibility of biomedical research using such complex data sources. PMID- 28912837 TI - Carbuncle due to Salmonella Enteritidis: a novel presentation. AB - BACKGROUND: Salmonella Enteritidis causes intestinal and extra-intestinal infections, but rarely cutaneous infections. It has never been reported to cause carbuncle (a collection of interconnected furuncles with multiple pustular openings). We report a case of carbuncle due to S. Enteritidis. CASE PRESENTATION: An adult Bangladeshi patient with type 2 diabetes presented with a carbuncle on the left-side of his neck. A pure culture of S. Enteritidis was grown from the pus of the carbuncle. The patient was successfully treated with ciprofloxacin to which the isolate was susceptible. Whole genome sequencing of the strain showed that it possessed three additional virulence genes-pef (for plasmid-encoded fimbriae), spv (for salmonella plasmid virulence), rck (for resistance to complement killing) -responsible for systemic infections that were absent in the genome of a reference S. Enteritidis strain. In phylogenetic analysis, the strain clustered with other S. Enteritidis strains from different parts of the world. CONCLUSIONS: A weakened immune system of the patient due to diabetes mellitus and the additional virulence genes of the isolate may have contributed to the unusual presentation of carbuncle. The possibility of S. Enteritidis to cause carbuncle should be considered. PMID- 28912838 TI - Phylogenomics of Colombian Helicobacter pylori isolates. AB - BACKGROUND: During the Spanish colonisation of South America, African slaves and Europeans arrived in the continent with their corresponding load of pathogens, including Helicobacter pylori. Colombian strains have been clustered with the hpEurope population and with the hspWestAfrica subpopulation in multilocus sequence typing (MLST) studies. However, ancestry studies have revealed the presence of population components specific to H. pylori in Colombia. The aim of this study was to perform a thorough phylogenomic analysis to describe the evolution of the Colombian urban H. pylori isolates. RESULTS: A total of 115 genomes of H. pylori were sequenced with Illumina technology from H. pylori isolates obtained in Colombia in a region of high risk for gastric cancer. The genomes were assembled, annotated and underwent phylogenomic analysis with 36 reference strains. Additionally, population differentiation analyses were performed for two bacterial genes. The phylogenetic tree revealed clustering of the Colombian strains with hspWestAfrica and hpEurope, along with three clades formed exclusively by Colombian strains, suggesting the presence of independent evolutionary lines for Colombia. Additionally, the nucleotide diversity of horB and vacA genes from Colombian isolates was lower than in the reference strains and showed a significant genetic differentiation supporting the hypothesis of independent clades with recent evolution. CONCLUSIONS: The presence of specific lineages suggest the existence of an hspColombia subtype that emerged from a small and relatively isolated ancestral population that accompanied crossbreeding of human population in Colombia. PMID- 28912839 TI - Addition of nonalbumin proteinuria to albuminuria improves prediction of type 2 diabetic nephropathy progression. AB - BACKGROUND: Albuminuria is generally accepted as a sensitive marker of diabetic nephropathy but has limitations in predicting its progression. The aim of this study was to evaluate the use of nonalbumin proteinuria in addition to albuminuria for predicting the progression of type 2 diabetic nephropathy. METHODS: In this retrospective observational study, the urine albumin-to creatinine ratio (ACR) and the nonalbumin protein-to-creatinine ratio (NAPCR) were measured in 325 patients with type 2 diabetes and estimated glomerular filtration rates (eGFR) >=30 mL/min/1.73 m2. The patients were divided into four groups based on the cutoff points for the urinary ACR (30 mg/g) and NAPCR (120 mg/g). The renal outcomes were chronic kidney disease (CKD) progression and accelerated eGFR decline. RESULTS: During the 4.3-year follow-up period, 25 (7.7%) patients showed CKD progression and 69 (21.2%) patients showed accelerated eGFR decline. After adjusting for nine clinical parameters, the group with a NAPCR greater than 120 mg/g exhibited higher cumulative incidences of CKD progression (hazard ratio 6.84; P = 0.001) and accelerated eGFR decline (hazard ratio 1.95; P = 0.011) than the group with a NAPCR < 120 mg/g. In patients with normoalbuminuria, the group with NAPCR levels greater than 120 mg/g also exhibited a higher cumulative incidence than that with NAPCR levels <120 mg/g of CKD progression (hazard ratio 21.82; P = 0.005). The addition of NAPCR to ACR improved the model fit for CKD progression and accelerated eGFR decline. CONCLUSION: Nonalbumin proteinuria showed additional value over and above that of albuminuria for predicting the progression of CKD in patients with type 2 diabetes. PMID- 28912840 TI - The relationship between insulin sensitivity and heart rate-corrected QT interval in patients with type 2 diabetes. AB - BACKGROUND: Reduced insulin sensitivity not only contributes to the pathogenesis of type 2 diabetes but is also linked to multiple metabolic risk factors and cardiovascular diseases (CVD). A prolonged heart rate-corrected QT interval (QTc interval) is related to ventricular arrhythmias and CVD mortality and exhibits a high prevalence among type 2 diabetes patients. The aim of the study was to investigate the relationship between insulin sensitivity and the QTc interval in patients with type 2 diabetes. METHODS: This cross-sectional observational study recruited 2927 patients with type 2 diabetes who visited the Affiliated Haian Hospital and Second Affiliated Hospital of Nantong University. The insulin sensitivity index (Matsuda index, ISIMatsuda) derived from 75-g OGTT and other metabolic risk factors were examined in all patients. The QTc interval was estimated using a resting 12-lead electrocardiogram, and an interval longer than 440 ms was considered abnormally prolonged. RESULTS: The QTc interval was significantly and negatively correlated with the ISIMatsuda (r = -0.296, p < 0.001), and when the multiple linear regression analysis was adjusted for anthropometric parameters, metabolic risk factors, and current antidiabetic treatments, the QTc interval remained significantly correlated with the ISIMatsuda (beta = -0.23, t = -12.63, p < 0.001). The proportion of patients with prolonged QTc interval significantly increased from 12.1% to 17.9%, 25.6% and 37.9% from the fourth to third, second and first quartile of the ISIMatsuda, respectively. After adjusting for anthropometric parameters by multiple logistic regression analysis, the corresponding odd ratios (ORs) for prolonged QTc interval of the first, second and third quartiles versus the fourth quartile of ISIMatsuda were 3.11 (95% CI 2.23-4.34), 2.09 (1.51-2.88) and 1.53 (1.09-2.14), respectively, and p for trend was <0.001. CONCLUSIONS: Reduced insulin sensitivity is associated with an increase in the QTc interval in patients with type 2 diabetes. PMID- 28912841 TI - Bioinformatics method identifies potential biomarkers of dilated cardiomyopathy in a human induced pluripotent stem cell-derived cardiomyocyte model. AB - Dilated cardiomyopathy (DCM) is the most common type of cardiomyopathy that account for the majority of heart failure cases. The present study aimed to reveal the underlying molecular mechanisms of DCM and provide potential biomarkers for detection of this condition. The public dataset of GSE35108 was downloaded, and 4 normal induced pluripotent stem cell (iPSC)-derived cardiomyocytes (N samples) and 4 DCM iPSC-derived cardiomyocytes (DCM samples) were utilized. Raw data were preprocessed, followed by identification of differentially expressed genes (DEGs) between N and DCM samples. Crucial functions and pathway enrichment analysis of DEGs were investigated, and protein protein interaction (PPI) network analysis was conducted. Furthermore, a module network was extracted from the PPI network, followed by enrichment analysis. A set of 363 DEGs were identified, including 253 upregulated and 110 downregulated genes. Several biological processes (BPs), such as blood vessel development and vasculature development (FLT1 and MMP2), cell adhesion (CDH1, ITGB6, COL6A3, COL6A1 and LAMC2) and extracellular matrix (ECM)-receptor interaction pathway (CDH1, ITGB6, COL6A3, COL6A1 and LAMC2), were significantly enriched by these DEGs. Among them, MMP2, CDH1 and FLT1 were hub nodes in the PPI network, while COL6A3, COL6A1, LAMC2 and ITGB6 were highlighted in module 3 network. In addition, PENK and APLNR were two crucial nodes in module 2, which were linked to each other. In conclusion, several potential biomarkers for DCM were identified, such as MMP2, FLT1, CDH1, ITGB6, COL6A3, COL6A1, LAMC2, PENK and APLNR. These genes may serve significant roles in DCM via involvement of various BPs, such as blood vessel and vasculature development and cell adhesion, and the ECM-receptor interaction pathway. PMID- 28912842 TI - A reliable method for the sorting and identification of ALDHhigh cancer stem cells by flow cytometry. AB - Cancer stem cells (CSCs) are a rare tumorigenic population of cells found in multiple types of cancer. It has been suggested that CSCs are responsible for cancer drug resistance, metastasis and recurrence. Therefore, it is important to develop techniques to correctly sort and identify CSCs. In the current study, the sorting and identification of aldehyde dehydrogenase high (ALDHhigh) CSCs was performed using flow cytometry. Cells from three colon cancer cell lines were cultured in serum-free medium to obtain CSCs-enriched spheroid cells. Subsequently, two subpopulations of ALDHhigh CSCs were isolated by flow cytometry either with the use of propidium iodide (PI) or not, respectively. The two subpopulations of ALDHhigh CSCs exhibited distinct characteristics, including stem cell related gene expression, self-renewal capacity and tumorigenicity in vitro and in vivo. Key regulators of the epithelial-mesenchymal transition (EMT), including vimentin, snail and slug were highly expressed in ALDHhigh CSCs. Therefore, the current study indicates that PI staining prior to the sorting of ALDHhigh CSCs by flow cytometry is an appropriate system for the study of CSCs. The current study also demonstrated that there was partial overlap between the transcriptional programs underlying the EMT and CSCs. PMID- 28912843 TI - MicroRNA-210 contributes to peripheral nerve regeneration through promoting the proliferation and migration of Schwann cells. AB - Peripheral nerve injury impacts the daily life of affected individuals. MicroRNA (miR)-210 is a multifunctional miR and has effects on the proliferation, migration and differentiation of cells. However, whether miR-210 has effects on peripheral nerve regeneration has remained elusive. In the present study, the miR 210 levels in a rat model of sciatic nerve injury were evaluated by reverse transcription quantitative PCR and the effects of miR-210 on the proliferation and migration of Schwann cells were explored. Elevated miR-210 levels were discovered in the sciatic nerve injury rat model. miR-210 mimics were found to promote the proliferation and migration of Schwann cells, while miR-210 inhibitor was found to inhibit the proliferation and migration of Schwann cells. Further study showed that miR-210 had effects on the expression of growth-associated protein-43, myelin-associated glycoprotein and myelin basic protein. These results showed that miR-210 had effects on the proliferation and migration of Schwann cells and may be involved in the peripheral nerve regeneration. PMID- 28912844 TI - Triptolide inhibits CD4+ memory T cell-mediated acute rejection and prolongs cardiac allograft survival in mice. AB - There have been numerous investigations into the immunosuppressive effects of triptolide; however, its inhibitory effects on memory T cells remain to be elucidated. Using a cluster of differentiation (CD)4+ memory T-cell transfer model, the aim of the present study was to determine the inhibitory effects of triptolide on CD4+ memory T cell-mediated acute rejection and to determine the potential underlying mechanisms. At 4 weeks after skin transplantation, mouse cervical heart transplantation was performed following the transfer of CD4+ memory T cells. Mice were divided into two groups: A Control [normal saline, 30 ml/kg/day; intraperitoneal injection (ip)] and a triptolide group (triptolide, 3 mg/kg/day; ip). Graft survival, pathological examination and the corresponding International Society for Heart & Lung Transplantation (ISHLT) scores were assessed 5 days following heart transplantation, and levels of interleukin (IL) 2, interferon-gamma (IFN-gamma), IL-10 and transforming growth factor beta1 (TGF beta1) in cardiac grafts and peripheral blood were assessed using reverse transcription-quantitative polymerase chain reaction and ELISA. The duration of cardiac graft survival in the triptolide group was significantly increased compared with the control group (14.3+/-0.4 vs. 5.3+/-0.2 days; P<0.001). Further pathological examinations revealed that the infiltration of inflammatory cells and myocardial damage in the cardiac grafts was notably reduced by triptolide, and the corresponding ISHLT scores in the triptolide group were significantly lower than those of the control group (grade 2.08+/-0.15 vs. 3.67+/-0.17; P<0.001). In addition, triptolide was able to significantly reduce IL-2 and IFN gamma secretion (P<0.01), significantly increase TGF-beta1 secretion in the cardiac grafts and peripheral blood (P<0.01) and increase IL-10 secretion in the cardiac grafts. Therefore, the present study suggests that triptolide inhibits CD4+ memory T cell-mediated acute rejection and prolongs cardiac allograft survival in mice. This effect may be mediated by the inhibition of cytokine secretion by type 1 T helper cells and promotion of regulatory T cell proliferation. PMID- 28912845 TI - Forkhead box C1 is targeted by microRNA-133b and promotes cell proliferation and migration in osteosarcoma. AB - Forkhead box C1 (FOXC1) has been demonstrated to act as an oncogene in a number of malignant tumors, though its underlying mechanism of action in osteosarcoma (OS) remains unknown. The present study evaluated the expression and regulatory role of FOXC1 in OS. Reverse transcription-quantitative polymerase chain reaction and western blot data indicated that FOXC1 was significantly upregulated in OS tissues and cell lines when compared with adjacent non-tumor tissues (P<0.001) and normal human osteoblast cells (P<0.01), respectively. Moreover, levels of FOXC1 expression were significantly higher in OS at advanced clinical stage (III IV) when compared with that at low clinical stage (I-II; P<0.001). Knockdown of FOXC1 expression caused a significant decrease in the proliferation and migration of OS U2OS cells (P<0.01), while overexpression of FOXC1 significantly promoted U2OS cell proliferation and migration (P<0.01), relative to control U2OS cells. Furthermore, FOXC1 was identified as a direct target of microRNA (miR)-133b, a reported tumor-suppressive miR in OS. The protein expression of FOXC1 was negatively regulated by miR-133b in U2OS cells (P<0.01), and miR-133b expression was inversely correlated with FOXC1 expression in OS. In conclusion, the present study demonstrated that FOXC1, targeted by miR-133b, may promote cell proliferation and migration in OS. Thus, FOXC1 may be a potential therapeutic target in the treatment of OS. PMID- 28912846 TI - The role of mTOR signaling pathway on cognitive functions in cerebral ischemia reperfusion. AB - The role and mechanism of the mTOR signaling pathway in the impaired cognitive function in cerebral ischemia-reperfusion were examined in the present study. Sprague-Dawley (SD) rats were divided into the sham operation, cerebral ischemia, cerebral ischemia-reperfusion and cerebral ischemia-reperfusion adaptive groups. A Morris water maze test was carried out in the different treatment groups at 2 weeks after surgery to detect cognitive function. After the experimental animals were sacrificed, fluorescent quantitative PCR test was used to detect the key signaling molecules in the mTOR signaling pathway in the different treatment groups, such as mTOR, p-mTOR, AKT and p-AKT gene mRNA expression. The protein expression was determined by enzyme-linked immunosorbent assay and western blotting. mTOR expression and localization in the different treatment groups was detected by immunohistochemistry, and the positive cell rate was determined. Compared with the sham operation group, the levels of mTOR, p-mTOR, AKT and p-AKT mRNAs and hippocampal proteins were significantly lower in the cerebral ischemia group and cerebral ischemia-reperfusion group (P<0.05). Levels of mTOR, p-mTOR, AKT and p-AKT mRNAs and proteins in the cerebral ischemia-reperfusion adaptive group decreased but did not show significant differences (P>0.05). The Morris water maze results showed that, the adaptive ability and the cognitive functions were improved significantly in the cerebral ischemia-reperfusion adaptive group when compared with the cerebral ischemia and cerebral ischemia-reperfusion groups (P<0.05). The number of mTOR-positive cells in hippocampus was significantly higher in the sham operation and cerebral ischemia-reperfusion adaptive groups, but there was no difference between these groups. In conclusion, mTOR signaling pathway improves the cognitive function in cerebral ischemia-reperfusion in rats. PMID- 28912848 TI - Changes in the anterior cornea during the early stages of severe myopia prior to and following LASIK, as detected by confocal microscopy. AB - The present study aimed to assess the microscopic changes of the epithelium and Bowman's layer under confocal microscopy during the early stages of severe myopia following laser in situ keratomileusis (LASIK). The study comprised 54 patients (54 eyes) with severe myopia and 65 patients (65 eyes) with low and moderate myopia, who underwent LASIK surgery at Tianjin Medical University Eye Hospital (Tianjin, China). In all patients, the epithelium, Bowman's layer and anterior stroma were examined prior to and 1, 7, 30, 90 and 180 days after the surgery, using in vivo confocal microscopy. Six (6 eyes) of the 54 patients with severe myopia (11.1%) exhibited corneal epithelial changes following the surgery, as examined by a slit lamp. Three patients (3 eyes) exhibited epithelial changes under confocal microscopy. In 40 eyes (74.1%) with severe myopia, brown yellow changes were observed at the epithelial layer and in the central part of the cornea 6 months after the surgery; the same was observed in 35 eyes (53.8%) with low and moderate myopia. Microfolds in the Bowman's layer of eyes with severe myopia were detected in 48 eyes (88.9%), and in 54 eyes (100.0%) in the anterior stroma following LASIK, whereas microfolds were observed in 51 (78.5%) and 65 eyes (100%), respectively, in patients with low to moderate myopia. In the severe myopia group, 54 eyes (100%) exhibited nerve fibers below the epithelium that were detectable 1 day post-surgery; in 16 eyes (29.6%), 1 or 2 sub-epithelial nerve fibers were detected 7 days after the surgery, and in 24 eyes (44.4%), 1 or 2 sub-epithelial nerve fibers were observed 6 months after the surgery. In eyes with low and moderate myopia, the figures were 100, 38.5 and 64.8%, respectively. The nerves of neither group returned to the pre-operative level. In conclusion, neurotrophic epitheliopathy, microfolds in Bowman's layer and anterior stroma were detected in the present patients with severe myopia of the cornea following LASIK, and the recovery of nerve fibers required an extended period of time. PMID- 28912847 TI - Identification of microRNAs involved in gefitinib resistance of non-small-cell lung cancer through the insulin-like growth factor receptor 1 signaling pathway. AB - Multiple clinical and experimental studies have suggested that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) may be effective at treating advanced non-small cell lung cancer (NSCLC), however, the molecular basis of primary resistance to EGFR-TKIs in NSCLC remains unclear. In the current study, the insulin-like growth factor 1 receptor (IGF-1R) gene in the gefitinib resistant human lung adenocarcinoma epithelial cell line A549 (A549/GR) was silenced using small interfering RNA (siRNA) in order to determine the role of microRNA (miRNA) in the development of resistance against epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinoma. The relative gefitinib-resistant capacity in A549 and A549/GR cells was determined using a cell counting kit 8. A549/GR cells were transfected with chemically synthesized siRNA to silence the IGF-1R gene. A total of 48 h after siRNA transfection, IGF-1R expression in A549/GR cells was evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. miRNA expression in A549/GR cells and A549/GR cells with silenced IGF 1R was analyzed using a miRNA microarray. The microarray results of 10 miRNAs were then compared with the results of RT-qPCR. The results demonstrated that the gefitinib-resistance capacity of A549/GR cells was six times higher than that of A549 cells. Additionally, RT-qPCR and western blotting demonstrated that the IGF 1R gene in A549/GR cells was successfully silenced by siRNA. The highest silencing rate (72%) of the IGF-1R gene was obtained using siRNA-2. The microarray identified 72 miRNAs with significantly different expression in A549/GR cells with silenced IGF-1R compared with A549/GR cells. Of the 72 differentially expressed miRNAs, 13 miRNAs (including miR-497-3p and miR-1273c) were up-regulated and 59 miRNAs (including miR-361-3p and miR-345-3p) were down regulated in A549/GR cells with silenced IGF-1R compared with A549/GR cells. The changes in the expression of 10 different miRNAs were confirmed by RT-qPCR. Thus, the present study successfully established an A549/GR cell line with silenced IGF 1R. The results suggest that a number of miRNAs associated with the IGF-1R signaling pathway, including miR-497-3p and miR-144-5p, were involved in the development of resistance against EGFR-TKIs in A549 cells. These miRNAs may provide novel targets to treat lung adenocarcinoma exhibiting resistance against EGFR-TKIs. PMID- 28912849 TI - MicroRNA-93 inhibits inflammatory responses and cell apoptosis after cerebral ischemia reperfusion by targeting interleukin-1 receptor-associated kinase 4. AB - The present study aimed to investigate changes in the expression of interleukin (IL)-1 receptor-associated kinase 4 (IRAK4) and microRNA (miRNA or miR)-93 in mice with cerebral ischemia reperfusion (CIR) injury, as well as the association and regulatory mechanism between IRAK4 and miR-93. The CIR mouse model was constructed and mouse microglia BV2 cells were transfected with miR-93 mimic or miR-93 inhibitor. Quantitative polymerase chain reaction was used to measure the expression of mRNA and miR-93. Western blotting was performed to determine protein expression. Enzyme-linked immunosorbent assays were performed to measure the concentrations pro-inflammatory factors. The expression of miR-93 in CIR mice brains was significantly reduced, while Ago-miR-93 (a type of miRNA analog) increased its expression. Ago-miR-93 alleviated neurological deficits and reduced cerebral infarction volume in the mice. Furthermore, Ago-miR-93 inhibited inflammatory responses following CIR. Ago-miR-93 decreased the rate of cell apoptosis following CIR. In addition, miR-93 downregulated IRAK4 protein expression, but did not alter its mRNA expression levels in BV2 cells. miR-93 expression reduced the expression of pro-inflammatory factors in BV2 cells. Ago miR-93 inhibited IRAK4 expression in the brain tissues of CIR mice. The present study demonstrated that miR-93 inhibits inflammatory responses and cell apoptosis following CIR by targeting the IRAK4 signaling pathway. PMID- 28912850 TI - Effects of leukotriene B4 on interleukin-32, interferon-gamma and chemokines in rats with rheumatoid arthritis. AB - The objective of this study was to investigate the effects of leukotriene B4 (LTB4) on the expression of interleukin-32 (IL-32) interferon-gamma (IFN-gamma) and chemokine monocyte chemoattractant protein (MCP-1) and macrophage inhibitory protein (MIP-1alpha) in rheumatoid arthritis (RA). The rat model of RA collagen induced-arthritis (CIA) was established. The levels of LTB4, interleukin-32, IFN gamma and chemokines MCP-1 and MIP-1alpha in CIA rats were detected by ELISA. After the rat synovial cells were isolated and treated with different concentrations of LTB4, the effect of LTB4 the expression of IL-32, IFN-gamma and chemokines MCP-1 and MIP-1alpha mRNA in synovial cells was detected by real-time quantitative PCR, the effect of LTB4 on protein expression was detected by immunoblotting. The effects of different concentrations of LTB4 on the viability and apoptosis of synovial cells were detected by LDH and cell proliferation reagent WST-1. Compared with the control group, the levels of LTB4, IL-32, IFN gamma and chemokines MCP-1 and MIP-1alpha were significantly increased in the serum of the CIA group. After treatment of CIA rat synovial cells with different concentrations of LTB4, the expression of IL-32, IFN-gamma and chemokines MCP-1 and MIP-1alpha mRNA and protein were increased with significant differences among groups. WST-1 and flow cytometry showed that LTB4 had significant toxic effects on synovial cells and promoted apoptosis. In conclusion, LTB4 promotes the expression of interleukin-32, IFN-gamma and chemokines MCP-1 and MIP-1alpha in synovial cells and facilitates apoptosis of synovial cells. PMID- 28912851 TI - Molecular mechanism of miR-181b in heart disease due to pregnancy-induced hypertension syndrome. AB - The present study aimed to investigate the molecular mechanisms of microRNA (miR) 181b in heart disease due to hypertensive disorders complicating pregnancy (HDCP) through regulating the expression of metallopeptidase inhibitor 3 (TIMP3). miR 181b expression was detected by reverse transcription-quantitative polymerase chain reaction in peripheral blood samples from patients with HDCP. These samples were analyzed for clinical pathological characteristics. The primary cardiomyocytes of rats were cultured in hypoxic conditions for 24 h, in which miR 181b expression was detected at different time points. The expression of TIMP3 was assessed in normal rat cardiomyocytes following transfection with miR-181b mimics by western blot analysis. The TIMP3 protein was also detected in cardiomyocytes following transfection with TIMP3 short interfering-RNA. The apoptosis rate of transfected cardiomyocytes was detected by flow cytometry following 24 h of culture in a hypoxic environment. Luciferase assay was applied to validate whether miR-181b binds to the 3' untranslated region of TIMP3 mRNA. miR-181b expression was significantly downregulated in the peripheral blood of patients with HDCP and the miR-181b expression was negatively associated with the grades of hypertension (P<0.05). The results of luciferase assay indicated that miR-181b directly targets TIMP3. The apoptosis rates of rat cardiomyocytes in the group transfected with miR-181b or TIMP3 siRNA was significantly lower than the normal control group (P<0.05). miR-181b may inhibit apoptosis of cardiomyocytes to protect myocardial cells through directly targeting TIMP3 genes, which serve important roles in HDCP. PMID- 28912852 TI - Baicalein reduces endometriosis by suppressing the viability of human endometrial stromal cells through the nuclear factor-kappaB pathway in vitro. AB - The aim of the present study was to evaluate the effects of baicalein on human endometrial stromal cells in vitro. Ectopic endometrium samples were obtained from 6 female patients with ovarian endometriosis who underwent laparoscopic surgical procedures from July to September 2015. After culturing the cells, immunocytochemistry was performed to verify the purity and homogeneity of the endometrial stromal cells, and a Cell Counting Kit-8 assay was used to evaluate cell viability. In addition, cell cycle progression was analyzed using flow cytometry, and the effects of baicalein on the expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), proliferating cell nuclear antigen (PCNA) and cyclin D1 in endometrial stromal cells were evaluated using western blot analysis. The related signaling pathways were also investigated by incubating cells with inhibitors of signaling pathways, prior to adding 40 uM baicalein for 48 h, followed by analysis of cell viability using a Cell Counting Kit-8 assay. The results indicated that treatment with baicalein significantly induced a dose-dependent decrease (P<0.05) in the viability of human endometrial stromal cells, which was abolished by inhibition of the nuclear factor (NF) kappaB signaling pathway. However, baicalein treatment did not induce a time dependent decrease in viability, as cell viabilities between the 24, 48 and 72 h treatment groups did not differ significantly. The number of cells in the G0/G1 phase significantly increased following treatment with baicalein (P<0.05), while the number of cells in the S and G2/M phases significantly decreased (P<0.05). Baicalein-treated cells also exhibited significantly reduced expression of Bcl-2, PCNA and cyclin D1 compared with control cells (P<0.05). These results suggested that baicalein may suppress the viability of human endometrial stromal cells through the NF-kappaB signaling pathway in vitro, and may induce apoptosis and promote cell cycle arrest at the G0/G1 phase. Thus, baicalein may provide a novel treatment option for endometriosis. PMID- 28912853 TI - Efficacy research of salazosulfamide in ankylosing spondylitis and NAT1 gene polymorphism. AB - The aim of this study was to explore the correlation of salazosulfamide efficacy on ankylosing spondylitis and N-acetyltransferase 1 (NAT1) gene polymorphism. Thirty-two patients with ankylosing spondylitis were recruited in the experimental group and 36 normal individuals were recruited to the control group. The experimental group received 8.0 mg of salazosulfamide (MTX) per week and the control group received isodose of normal saline. Twenty-six patients in the experimental group responded to the salazosulfamide treatment and 6 did not show response. Morning stiffness time of patients in the experimental group who responded to salazosulfamide was significantly lower than that of patients with no reaction to salazosulfamide, and similar to patients in the control group. The average tender joint count of patients in the experimental group that responded to salazosulfamide was lower than in patients with no response to treatment, and similar to patients in the control group. NAT1 gene sequencing determined that the patients sensitive to salazosulfamide treatment manifested as AA/AG at 263 locus, whereas patients not sensitive to salazosulfamide were GG. NAT1 expression was comparable between the different genotypes at the mRNA level. However, there was a significant difference of NAT1 protein between groups. Overall, salazosulfamide demonstrates curative activity for ankylosing spondylitis and we believe that NAT1 AA/GG genotype at 263 locus can promote salazosulfamide effectiveness on ankylosing spondylitis. PMID- 28912854 TI - Comparative proteomics analysis of primary cutaneous amyloidosis. AB - Primary cutaneous amyloidosis (PCA) is a localized skin disorder that is characterized by the abnormal deposition of amyloid in the extracellular matrix (ECM) of the dermis. The pathogenesis of PCA is poorly understood. The objective of the present study was to survey proteome changes in PCA lesions in order to gain insight into the molecular basis and pathogenesis of PCA. Total protein from PCA lesions and normal skin tissue samples were extracted and analyzed using the isobaric tags for relative and absolute quantitation technique. The function of differentially expressed proteins in PCA were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction analysis. The proteins that were most upregulated in PCA lesions were further analyzed by immunohistochemistry. A total of 1,032 proteins were identified in PCA lesions and control skin samples, with 51 proteins differentially expressed in PCA lesions, of which 27 were upregulated. In PCA lesions, the upregulated proteins were primarily extracellulary located. In addition, GO analysis indicated that the upregulated proteins were significantly enriched in the biological processes of epidermal development, collagen fiber organization and response to wounding (adjusted P<0.001). KEGG analysis indicated that the upregulated proteins were significantly enriched in the signaling pathways of cell communication, ECM receptor interaction and focal adhesion (adjusted P<0.001). Furthermore, the upregulated proteins were enriched in the molecular function of calcium ion binding, and the calcium binding proteins calmodulin-like protein 5, S100 calcium-binding protein A7 (S100A7)/fatty-acid binding protein and S100A8/A9 exhibited the highest levels of upregulation in PCA. This analysis of differentially expressed proteins in PCA suggests that increased focal adhesion, differentiation and wound healing is associated with the pathogenesis of PCA. PMID- 28912855 TI - Effect of transoral endoscopic adenoidectomy on peripheral blood T-lymphocyte subsets in children with obstructive sleep apnea-hypopnea syndrome and its treatment strategy. AB - The objective of the present study was to investigate the effect of transoral endoscopic adenoidectomy on peripheral blood T lymphocyte subsets in pediatric patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and its treatment strategy. Ninety-eight pediatric patients with adenoidal hypertrophy associated with OSAHS admitted to the Department of Otolaryngology, Xuzhou Children's Hospital were selected. After admission, patients received perfected 24 h polysomnogram monitoring, routine blood examination, fasting blood biochemistry examination, T-lymphocyte subset count, 24 h ambulatory blood pressure monitoring, and nasopharyngeal computed tomography. After patients were diagnosed with adenoidal hypertrophy associated with OSAHS, they underwent transoral endoscopic adenoidectomy with a power microdebrider. Patients were evaluated at 3 , 6- and 12-week follow-up visits. The CD3+, CD4+, and CD8+ T-cell counts, CD4+/CD8+ T lymphocyte ratio, and changes of 24 h ambulatory blood pressure before and after surgery were recorded. After the 6-week follow-up visit, the mean CD4+ T lymphocyte count in patients was increased significantly compared with that before surgery, the CD4+/CD8+ T lymphocyte ratio increased gradually, and the differences were statistically significant (P<0.05). The frequency of nocturnal awakening of patients was decreased significantly after surgery and the duration of nocturnal sleep was extended significantly (P<0.05). Through analysis of the preoperative and postoperative clinical data of pediatric patients, the CD4+/CD8+ T lymphocyte ratio was negatively correlated with mean arterial pressure (MAP) (r=-1.06, P=0.003). In conclusion, adenoidectomy can significantly decrease the MAP in pediatric patients with OSAHS and increase the duration of nocturnal sleep. The peripheral blood CD4+/CD8+ T lymphocyte ratio in pediatric patients was significantly negatively correlated with MAP. PMID- 28912856 TI - Blood purification treatment initiated at the time of sepsis diagnosis effectively attenuates serum HMGB1 upregulation and improves patient prognosis. AB - The aim of the present study was to investigate the increase in serum and urine levels of high mobility group box protein 1 (HMGB1) during sepsis and the effect of blood purification treatments on HMGB1 levels and patient prognosis. A total of 40 intensive care patients with sepsis were randomly assigned to different groups (n=10 per group): A control group (sepsis group), a continuous renal replacement treatment (CRRT) group, a hemoperfusion (HP) group and an HP+CRRT group. The blood purification treatments using HP and/or CRRT were performed immediately after the diagnosis of sepsis. HMGB1 levels were measured using ELISA, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores and 30-day survival rates were evaluated. Relative to a healthy control group (n=10), HMGB1 levels were observed to be significantly upregulated during sepsis (P<0.05). Following the initiation of sepsis, serum HMGB1 continued to increase in the sepsis group and was significantly elevated at 24 h (P<0.05), whereas urine HMGB1 levels decreased significantly at 12 and 24 h (P<0.05). Serum HMGB1 levels were significantly positively correlated with APACHE II scores (r=0.7284, P<0.01) and significantly negatively correlated with urine HMGB1 levels (r= 0.5103, P=0.026). Serum HMGB1 levels were significantly reduced in the HP and HP+CRRT groups by 12 and 24 h following the initiation of treatment (both P<0.05). Changes in the urine HMGB1 level differed in each group. Relative to the sepsis group, the APACHE II scores of all blood purification groups were significantly reduced (P<0.05) and the 30-day survival rate of the HP+CRRT group was significantly increased (P=0.0107). The results of the present study indicate that blood purification initiated at the point of diagnosis in patients with sepsis may attenuate serum HMGB1 upregulation, promote urinary excretion of HMGB1 and improve the prognosis of sepsis. PMID- 28912857 TI - Overexpression of transcription factor activating enhancer binding protein 4 (TFAP4) predicts poor prognosis for colorectal cancer patients. AB - Transcription factor activating enhancer binding protein 4 (TFAP4) is an important regulator in the genesis and progression of human cancers. Overexpression of TFAP4 has been found to be correlated with several malignancies. The present study assessed the clinical importance of TFAP4 in colorectal cancer (CRC). First, immunohistochemistry was used to analyze TFAP4 expression and the association of TFAP4 expression with clinicopathological features on a tissue microarray containing 208 CRC patients. The results revealed that TFAP4 protein expression was significantly upregulated in CRC tissues compared with that in normal colon tissues (P<0.001). Of note, statistical analysis revealed that TFAP4 expression was significantly correlated with a high pathological grade (P=0.034), advanced clinical stage (P=0.024), enhanced tumor invasion (P=0.002) and lymph node metastasis (P=0.041). In addition, the Cancer Genome Atlas dataset further validated that TFAP4 mRNA levels were increased in CRC with advanced clinical stage (P=0.026), lymph node metastasis (P=0.018) and vascular invasion (P=0.046). Kaplan-Meier survival analysis demonstrated that CRC patients with high TFAP4 expression had shorter overall survival compared with those with low TFAP4 expression (P=0.011). Importantly, overexpression of TFAP4 was a valuable independent prognostic factor for CRC patients (hazard ratio, 8.200; 95% confidence interval, 1.838-36.591; P=0.006). In summary, TFAP4 may have an important role in CRC progression and upregulation of TFAP4 may be a predictor of poor prognosis for CRC patients. PMID- 28912858 TI - Cordycepin induces apoptosis of human acute monocytic leukemia cells via downregulation of the ERK/Akt signaling pathway. AB - The aim of the present study was to examine the apoptotic effect of cordycepin (COR) on human THP-1 acute monocytic leukemia cells. THP-1 cells were exposed to different concentrations of COR for 24, 48, 72 or 96 h. The cell viability and apoptotic rate were analyzed. The gene expression of Akt1, Akt2, Akt3, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were assessed by reverse transcription quantitative PCR. Western blot analysis was used to detect the protein levels of phosphorylated (p)-Akt, p-extracellular signal-regulated kinase (ERK) and cleaved caspase-3. It was found that the viability of THP-1 cells was inhibited by COR in a dose- and time-dependent manner. After treatment with 200 uM COR for 24 h, the percentage of apoptotic cells was significantly increased. COR also downregulated the levels of Bcl-2, Akt1, Akt2 and Akt3, and elevated the expression of Bax. The protein levels of p-Akt and p-ERK were suppressed and cleaved caspase-3 was increased after treatment of COR. In conclusion, COR was found to induce apoptosis of THP-1 acute monocytic leukemia cells through downregulation of ERK/Akt signaling. PMID- 28912859 TI - Multidisciplinary therapy for the treatment of malocclusion in a patient with chronic periodontitis with a five-year follow-up: A case report. AB - Multidisciplinary therapy is essential in dental practice to achieve optimized outcomes. The present case report describes the application of periodontal surgery with a five-year follow-up in a patient with malocclusion and chronic periodontitis. In the presence of periodontal inflammation, orthodontic therapy may result in further periodontal breakdown due to plaque accumulation. In order to prevent this progression, scaling and root planning with a periodontal endoscope was applied, and continuous clinical monitoring and risk assessment was performed every 3 months using a Florida Probe. This combined treatment supports the long-term maintenance of periodontal conditions, functional occlusion and harmony of the facial profile. PMID- 28912860 TI - Effects of HV-CRRT on PCT, TNF-alpha, IL-4, IL-6, IL-8 and IL-10 in patients with pancreatitis complicated by acute renal failure. AB - The aim of the study was to investigate the effects of high-volume continuous renal replacement therapy (HV-CRRT) on procalcitonin (PCT), tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4), IL-6, IL-8 and IL-10 in acute pancreatitis complicated by acute renal failure. Eighty-six patients with acute pancreatitis complicated with acute renal failure were selected from September 2014 to September 2016 in our hospital, and were treated by continuous veno venous hemofiltration (CVVH). The patients were randomly divided into the observation group, treated by the HV-CVVH model with a displacement rate of 4 l/h, and the control group, treated by the normal capacity model with a displacement rate of 2 l/h. The levels of PCT, TNF-alpha, IL-4, IL-6, IL-8, and IL-10 in serum were measured by ELISA before and 2, 6 and 12 h after treatment, and 12 h after CVVH. The serum PCT and TNF-alpha levels in the two groups were decreased at 2 h after treatment. The lowest levels appeared at 6 h after treatment, and then recovered, but remained lower than those before treatment (p<0.05). The levels of IL-4, IL-6, IL-8 and IL-10, as well as PCT and TNF-alpha in the two groups were significantly lower than those before treatment, and the decreases in the observation group were more obvious than those in the control group (p<0.05). In conclusion, compared with the standard volume method, HV-CRRT can more effectively remove various inflammatory factors and reduce the levels of serum PCT for the treatment of pancreatitis complicated by acute renal failure. Additionally, replacement of the blood filter at appropriate time-points can improve the treatment efficacy. PMID- 28912861 TI - Phascolarctobacterium faecium abundant colonization in human gastrointestinal tract. AB - Phascolarctobacterium can produce short-chain fatty acids, including acetate and propionate, and can be associated with the metabolic state and mood of the host. The present study investigated the colonization characteristics of Phascolarctobacterium faecium in healthy individuals <1-80 years old in Southern China. A total of 150 fresh fecal samples were collected, and bacterial DNA was isolated from these samples for quantitative polymerase chain reaction analysis. Phascolarctobacterium faecium demonstrated a high colonization rate and abundant colonization in the human gastrointestinal tract. The colonization rate varied between 43.33-93.33%, and the abundance of Phascolarctobacterium faecium ranged between 3.22-5.76 log cells g-1 (<1 years old) and 3.06-9.33 log cells g-1 (>1 year old). The permillage of Phascolarctobacterium faecium in total bacteria ranged between 0.004-1.479. There was presence of Phascolarctobacterium faecium like bacteria in younger individuals with a gradual increase in the number of bacteria maintained at a high level with increasing ages (between 1 and 60 years old), but with a decrease in elderly individuals (>60 years old). The results of the present study demonstrated that Phascolarctobacterium faecium is abundantly colonized in the human gastrointestinal tract. PMID- 28912862 TI - Astragalus polysaccharides combined with ibuprofen exhibit a therapeutic effect on septic rats via an anti-inflammatory cholinergic pathway. AB - The aim of the present study was to investigate the effects of Astragalus polysaccharides (APS) in combination with ibuprofen (IBU) in the treatment of sepsis and the underlying mechanism. The combined drug treatment was evaluated in a rat model of cecal ligation and puncture (CLP). The serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and acetylcholine (ACh) were determined. Nicotinic acetylcholine (nAChR) alpha7 receptor expression and histopathological changes in the lung tissue were also observed. When compared with untreated rats and rats treated with either component alone, the combined treatment significantly decreased the production of TNF-alpha and IL-6 (P<0.05), and increased nAChR alpha7 receptor mRNA expression and the release of ACh in the serum (P<0.05). These results demonstrated that APS combined with IBU can effectively reduce the generation of inflammatory mediators in the serum of CLP induced septic rats. These effects may be mediated via a cholinergic anti inflammatory pathway involving nAChR alpha7. PMID- 28912863 TI - A novel mutation in the hepatocyte nuclear factor-1beta gene in maturity onset diabetes of the young 5 with multiple renal cysts and pancreas hypogenesis: A case report. AB - A 17-year-old Chinese male was hospitalized exhibiting hyperglycemia and increased serum urea nitrogen and creatinine levels in addition to weight loss. The patient was treated with gliclazide. The patient was 150 cm tall, weighed 35 kg and had no family history of diabetes or kidney disease. Physical examination revealed cephalus quadratus, rachitic rosary and a visible toe-out gait. Laboratory examinations revealed that the patient's fasting plasma glucose and glycosylated hemoglobin levels were markedly increased, fasting plasma C-peptide level was slightly increased and no peak 2 h postprandial was observed. Diabetic autoimmune antibodies [islet cell cytoplasmic autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), isulinoma-2-associated autoantibodies (IA2A) and insulin autoantibodies (IAA)] were negative. Levels of serum electrolytes decreased, uric acid and parathyroid hormone increased, mild albuminuria was detected and there was a low proportion of urine. The patient also presented with low bone mass and cataracts. Abdominal computed tomography (CT) revealed a bilateral atrophic kidney with multiple renal cysts, primarily located at the junction of renal cortex and medulla, with a diameter of 0.3-0.7 cm. CT also revealed hypogenesis of the body and tail of the pancreas. In an oral glucose tolerance test, the mother and paternal uncle of the patient were diagnosed with type II diabetes and the patient's sister, maternal uncle and paternal grandpa were diagnosed with glucose tolerance impairment. Genetic testing revealed an unreported amino acid mutation in exon 2 of hepatocyte nuclear factor 1beta (c.391C>T), a nonsense mutation of CAA to TAA at codon 131. This mutation was identified in the proband but not in any other family members. PMID- 28912864 TI - Evaluation of the chondroprotective action of N-acetylglucosamine in a rat experimental osteoarthritis model. AB - It has been demonstrated that oral administration of N-acetylglucosamine (GlcNAc) alleviates the symptoms of osteoarthritis (OA). The aim of the present study was to elucidate the molecular mechanisms for the chondroprotective action of GlcNAc in OA. Biomarkers for type II collagen degradation and synthesis were evaluated, as were histopathological changes, using a rat anterior cruciate ligament transection (ACLT)-induced OA model. Changes in the expression of genes in the cartilage were assessed via DNA microarray and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results indicated that ACLT induced histopathological changes of articular cartilage, whereas oral administration of GlcNAc (1,000 mg/kg/day for 28 days) significantly suppressed these changes. Additionally, GlcNAc significantly decreased levels of a type II collagen degradation marker in sera compared with that in the ACLT group, although there were no significant changes in the levels of a type II collagen synthesis marker. Furthermore, DNA microarray and reverse transcription-quantitative polymerase chain reaction results demonstrated that GlcNAc treatment downregulated the expression of periostin, which is likely involved in the degradation of cartilage, whereas GlcNAc upregulated the expression of lipocalin 2, which is involved in the regulation of chondrocyte proliferation and differentiation. In conclusion, the results of the present study suggest that GlcNAc is able to suppress the histopathological changes induced by OA and exhibits a chondroprotective action by inhibiting type II collagen degradation in the articular cartilage, possibly via modulation of the expression of inflammatory and chondroprotective molecules, including periostin and lipocalin 2. PMID- 28912865 TI - Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus. AB - The aim of the present study was to determine the levels of soluble fractalkine (sFKN) and expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus (NPSLE). Disease activity of SLE was assessed using the SLE Disease Activity Index (SLEDAI). The mRNA expression levels of CX3CR1 and FKN were quantified using reverse transcription-quantitative polymerase chain reaction. Levels of sFKN in the serum and cerebrospinal fluid (CSF) were measured using enzyme-linked immunosorbent assays. The mRNA expression levels of CX3CR1 in peripheral blood mononuclear cells from patients with NPSLE, non-NPSLE and Behcet's disease were significantly higher than that of rheumatoid arthritis and healthy persons. Levels of sFKN in the serum and CSF of cells with diffuse NPSLE (DNPSLE) were significantly higher than those of focal NPSLE (FNPSLE) cells. Serum levels of sFKN were higher in patients with NPSLE or non-NPSLE than heathy persons. sFKN in CSF were significantly higher in DNPSLE than non-NPSLE cells, but there were no significant difference between FNPSLE and control. Treatment reduced sFKN in serum and CSF in patients with NPSLE. There was significant correlation between sFKN in the serum of patients with SLE and the SLEDAI. sFKN levels were correlated with IgG in CSF from patients with NPSLE. The mRNA expression levels of CX3CR1 in the brain tissue of lupus mice were significantly higher than normal mice; however, the mRNA expression of FKN was lower than normal mice. These results suggest that sFKN and CX3CR1 may be involved in vasculitis and SLE, particularly in DNPSLE, which may occur by damaging the blood-brain barrier or recruiting expression microglial cells of CX3CR1. Additionally, sFKN appears to be a serological marker in patients with SLE, and may be useful for the diagnosis and treatment of NPSLE. PMID- 28912866 TI - Compositional analysis of various layers of upper urinary tract stones by infrared spectroscopy. AB - The objective of the present study was to determine the composition of various layers of upper urinary stones and assess the mechanisms of stone nucleation and aggregation. A total of 40 integrated urinary tract stones with a diameter of >0.8 cm were removed from the patients. All of the stones were cut in half perpendicularly to the longitudinal axis. Samples were selected from nuclear, internal and external layers of each stone. Fourier transform infrared spectroscopy (FT-IR) was adopted for qualitative and quantitative analysis of all of the fragments and compositional differences among nuclear, internal and external layers of various types of stone were subsequently investigated. A total of 25 cases of calcium oxalate (CaOx) stones and 10 cases of calcium phosphate (CaP) stones were identified to be mixed stones, while 5 uric acid (UA) calculi were pure stones (purity, >95%). In addition, the contents of CaOx and carbapatite (CA.AP) crystals in various layers of the mixed stones were found to be variable. In CaOx stones, the content of CA.AP in nuclear layers was significantly higher than that of the outer layers (32.0 vs. 6.8%; P<0.05), while the content of CaOx was lower in the inner than in the outer layers (57.6 vs. 86.6%; P<0.05). In CaP stones, the content of CA.AP in the nuclear layers was higher than that in the outer layers (74.0 vs. 47.3%; P<0.05), while the content of CaOx was lower in the inner than in the outer layers (7.0 vs. 40.0%; P<0.05). The UA stones showed no significant differences in their composition among different layers. In conclusion, FT-IR analysis of various layers of human upper urinary tract stones revealed that CaOx and CaP stones showed differences in composition between their core and surface, while all of the UA calculi were pure stones. The composition showed a marked variation among different layers of the stones, indicating that metabolism has an important role in different phases of the evolution of stones. The present study provided novel insight into the pathogenesis of urinary tract stones and may contribute to their prevention and treatment. PMID- 28912867 TI - Protective effect of controlled release of cytokine response modifier A from chitosan microspheres on rat chondrocytes from interleukin-1beta induced inflammation and apoptosis. AB - The aim of the present study was to investigate the protective effect of cytokine response modifier A (CrmA) released from chitosan (CS) microspheres in a controlled manner on interleukin (IL)-1beta-induced inflammation and apoptosis in chondrocytes. The CrmA release kinetics were characterized by an initial burst release, which was reduced to a linear release over 8 days. Furthermore, chondrocytes were isolated from 1-week-old Sprague Dawley rats. The cell culture was established by stimulation with 10 ng/ml IL-1beta and subsequent incubation with CS-CrmA microspheres. Following stimulation with IL-1beta, the viability of chondrocytes was decreased. However, the cell viability was attenuated by CS-CrmA microspheres as revealed by a cell counting kit-8 assay. CS-CrmA microspheres significantly inhibited IL-1beta-induced inflammation in chondrocytes by attenuating increases in the gene expression levels of inducible nitric oxide synthase and cyclooxygenase-2, as well as the concentrations of nitric oxide and prostaglandin E2. CS-CrmA microspheres significantly decreased the number of apoptotic chondrocytes induced by IL-1beta as indicated by a terminal deoxyribonucleotide transferase deoxyuridine triphosphate nick-end labeling assay. In addition, CS-CrmA microspheres blocked IL-1beta-induced chondrocyte apoptosis by increasing B-cell lymphoma 2 (Bcl-2) and decreasing Bcl-2-associated X protein, caspase-3 and poly adenosine diphosphate-ribose polymerase expression at the mRNA and protein levels, as indicated by reverse-transcription quantitative polymerase chain reaction and western blot analysis, respectively. The results of the present study revealed that CS-CrmA microspheres, as a controlled release system of CrmA, may protect rat chondrocytes from IL-1beta induced inflammation and apoptosis via regulating inflammatory and apoptosis associated genes. PMID- 28912868 TI - Bax is involved in the anticancer activity of Velcade in colorectal cancer. AB - Numerous chemotherapeutic agents promote tumor cell death by activating the intrinsic apoptosis signaling pathway. This pathway is regulated by mitochondrial dysfunction, which occurs through an intricate process controlled by complex interactions between B-cell lymphoma 2 (Bcl-2) family members and other cellular proteins. Bcl-2-associated X protein (Bax) is a proapoptotic protein that is an essential component of the intrinsic apoptosis signaling pathway. Patients lacking Bax may be less sensitive to chemotherapy due to an impaired intrinsic apoptosis signaling pathway. The present study demonstrated that Bax expression in colorectal cancer (CRC) tissues was typically increased compared with that in adjacent normal tissues. Furthermore, Bax-/- HCT-116 cells exhibited reduced proliferation and colony formation ability compared with Bax+/+ HCT116 cells, although the rate of apoptosis of these cells remained unchanged. However, Bax-/- HCT116 cells became more resistant to apoptosis when treated with Velcade. The results of the present study provide novel insights into the relevance of Bax expression to the prognosis of CRC. PMID- 28912869 TI - Association of ANK1 variants with new-onset type 2 diabetes in a Han Chinese population from northeast China. AB - Previous studies have identified three loci (rs4737009, rs515071 and rs516946) in ankyrin 1 (ANK1) that are associated with type 2 diabetes mellitus (T2DM) in a number of ethnic groups. However, the impact of single nucleotide polymorphisms (SNPs) of ANK1 on T2DM in a Han Chinese population from northeast China has not yet been studied. The present study was undertaken to investigate the relationship between the ANK1 gene and new-onset T2DM in northeastern China. Three widely studied variants were genotyped and analyzed for T2DM susceptibility in 1,962 Chinese subjects (996 with T2DM and 966 healthy controls). Genotyping was performed using SNPscanTM. The single-locus analysis, identified differences in the expression of rs515071 and rs516946 between cases and controls, with an odds ratio (OR) of 1.31 [95% confidence interval (CI), 1.10-1.55; P=0.002] and 1.32 (95% CI, 1.09-1.61; P=0.005) respectively, while there were no differences in the expression of rs4737009 between the groups. For the SNP of rs515071, the presence of AA or GA significantly reduced the risk of T2DM compared with GG (adjusted P=0.019, OR=0.78; 95% CI, 0.63-0.96). With respect to rs516946, individuals carrying TT or CT exhibited a decreased risk of T2DM compared with those with the CC allele (adjusted P=0.040, OR=0.79; 95% CI, 0.63-0.99). Furthermore, haplotype analysis indicated that the haplotype frequency of GC in T2DM cases was significantly higher than in controls (P=0.002, OR=1.31; 95% CI, 1.10-1.55). Furthermore, the rs516946-CC genotype was associated with a larger waist circumference (P=0.031). The present data indicated that ANK1 was a potential T2DM susceptibility gene in a Han Chinese population from northeastern China. PMID- 28912870 TI - Eosinophilic biomarkers for detection of acute exacerbation of chronic obstructive pulmonary disease with or without pulmonary embolism. AB - Eosinophilia has been implicated in the pathophysiology of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the role of eosinophil activation in the development of AECOPD remains unclear. In the present study, the reliability of plasma levels of eosinophil activation markers, including eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPX), were measured and used as diagnostic biomarkers of AECOPD with or without pulmonary embolism (PE). A total of 47 patients with AECOPD, 30 patients with AECOPD/PE and 35 healthy adults were enrolled in the present study. Plasma levels of ECP, EDN, EPX and MBP were measured using commercial ELISA kits. The mean concentrations of plasma ECP, EDN, EPX and MBP in the patients with AECOPD was significantly 2.87-, 3.06-, 1.60- and 1.92-fold higher, respectively, compared with the control group (P<0.05). Similar results were obtained in patients with AECOPD/PE, for whom plasma levels of ECP, EDN, EPX and MBP were significantly 2.06-, 2.21-, 1.42- and 2.42-fold higher, respectively, compared with the controls (P<0.05). No significant differences were observed in the levels of these proteins between patients with AECOPD or AECOPD/PE. Among the four potential markers, ECP was determined to be the optimal marker for distinguishing patients with AECOPD or AECOPD/PE from the controls. No significant correlation was observed between marker concentrations and gender, age or disease severity. The results of the present study may have clinical applications in the diagnosis of AECOPD using these novel biomarkers. PMID- 28912871 TI - Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy induced apoptosis due to downregulation of the phosphatidylinositol-3 kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor. AB - Radiotherapy is a vital and effective method to treat solid tumors. However, in many tumor types, development of resistance of cancer cells and cytotoxicity in normal tissues presents a major therapeutic problem. It is therefore crucial to identify and develop novel sensitizing agents that may improve the response to radiation therapy without causing any adverse effects. The present study aimed to investigate whether paeonol, a bioactive flavonoid, was able to confer sensitivity to radiation in human ovarian cancer cells. The human ovarian cancer cell lines SKOV-3 and OVCAR-3 were exposed to varying doses of radiation (2, 4 or 6 Gy) in the presence or absence of paeonol (25, 50 or 100 uM). Radiosensitivity was assessed by measuring cell viability using a CCK-8 assay and Annexin V/PI staining. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), proteins of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway and apoptotic pathway proteins [caspase-3, Bcl-2 associated death promoter, B-cell lymphoma (Bcl)-2, Bcl-2-associated X and Bcl extra large (Bcl-xL)] were also assessed. Paeonol treatment enhanced apoptosis of SKOV-3 and OVCAR-3 cells that were exposed to radiation. The expression of Bcl-2 and Bcl-xL were markedly upregulated in these cells. Treatment with paeonol concentrations of 50 and 100 uM caused a significant downregulation of VEGF, HIF 1alpha and PI3K/Akt pathway proteins. Paeonol effectively enhanced the sensitivity of ovarian cancer cells to radiation by significantly altering regulation of the proteins of the PI3K/Akt pathway, in addition to downregulating VEGF and HIF-1alpha. PMID- 28912872 TI - Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma. AB - Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor beta, RET and KIT. Cellular immunotherapy has the potential to be a highly targeted treatment, with low toxicity to normal tissues and a high capacity to eradicate tumor tissue. The present study assessed the safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lenvatinib and cellular immunotherapy in a murine model of renal cell carcinoma (RCC). The present study used a therapeutic dose of 0.12 mg lenvatinib and/or 104 rat uterine cancer adenocarcinoma (RuCa)-sensitized lymphocytes administered once daily continuously in 7-day cycles. Tumor regression was observed in mice with RCC following treatment with lenvatinib and 104 RuCa-sensitized lymphocytes. MTD was established as once daily administration of 0.18 mg lenvatinib and 106 RuCa sensitized lymphocytes. The most common treatment-related adverse effects observed were fatigue (40%), mucosal inflammation (30%), proteinuria, diarrhea, vomiting, hypertension and nausea (all 40%). Combination therapy using lenvatinib and cellular immunotherapy enhanced the antitumor effect induced by single treatments and prolonged the survival of mice with RCC compared with either of the single treatments. Treatment with lenvatinib (0.12 mg) combined with 104 RuCa sensitized lymphocytes was associated with manageable toxicity consistent with individual agents. Further evaluation of this combination therapy in mice with advanced RCC is required. In conclusion, cellular immunotherapy and oncolytic therapy for cancer may be improved by the synergistic effects of lenvatinib and sensitized lymphocytes. In the present study, the inherent antineoplastic and immune stimulatory properties of the two agents were enhanced when used in combination, which may provide a basis for clinical treatment of patients with RCC. PMID- 28912873 TI - Phospholemman, a major regulator of skeletal muscle Na+/K+-ATPase, is not mutated in probands with hypokalemic periodic paralysis. AB - The pathogenesis of hypokalemic periodic paralysis (HypoPP) remains unclear. Though some mutations in skeletal muscle ion channels were revealed previously, the exact mechanism remains to be fully elucidated. Increased Na+/K+-ATPase activity in skeletal muscle is postulated to contribute to attacks of HypoPP. Before the link between Na+/K+-ATPase dysfunction and these ion channel mutations is established, mutations in Na+/K+-ATPase and their regulators are the first to be excluded. Phospholemman, which is a protein encoded by the FXYD domain containing ion transport regulator 1 (FXYD1) gene, is predominantly expressed in skeletal muscle and is the major regulator of Na+/K+-ATPase. Therefore, the aim of the present study was to determine the genetic involvement of phospholemman in HypoPP development. Genomic DNA was extracted from the peripheral blood of five HypoPP probands with typical manifestations. The coding exons of FXYD1, exons 2 7, were polymerase chain reaction (PCR)-amplified and sequenced. No mutations were detected in FXYD1 in any of the subjects studied. To conclude, mutations in phospholemman encoding genes may not be involved with HypoPP and the relationship between phospholemman and Na+/K+-ATPase dysfunction in attacks of HypoPP requires further study. PMID- 28912874 TI - Dietary vitamin B6 modulates the gene expression of myokines, Nrf2-related factors, myogenin and HSP60 in the skeletal muscle of rats. AB - Previous studies have suggested that vitamin B6 is an ergogenic factor. However, the role of dietary vitamin B6 in skeletal muscle has not been widely researched. The aim of the present study was to investigate the effects of dietary vitamin B6 on the gene expression of 19 myokines, 14 nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated factors, 8 myogenesis-related factors and 4 heat shock proteins (HSPs), which may serve important roles in skeletal muscles. Rats were fed a diet containing 1 (marginal vitamin B6 deficiency), 7 (recommended dietary level) or 35 mg/kg of pyridoxine (PN) HCl/ for 6 weeks. Gene expressions were subsequently analysed using reverse transcription-quantitative polymerase chain reaction. Food intake and growth were unaffected by this dietary treatment. The rats in the 7 and 35 mg/kg PN HCl groups exhibited a significant increase in the concentration of pyridoxal 5'-phosphate in the gastrocnemius muscle compared with the 1 mg/kg PN HCl diet (P<0.01). The expressions of myokines, such as IL-7, IL 8, secreted protein acidic and rich in cysteine, IL-6, growth differentiation factor 11, myonectin, leukaemia inhibitory factor, apelin and retinoic acid receptor responder (tazarotene induced) 1, the expression of Nrf2 and its regulated factors, such as heme oxygenase 1, superoxide dismutase 2, glutathione peroxidase 1 and glutathione S-transferase, and the expression of myogenin and HSP60 were significantly elevated in the 7 mg/kg PN HCl group compared with the 1 mg/kg PN HCl diet (P<0.05). No significant differences in levels of these genes were observed between the 35 and 1 mg/kg PN HCl, with the exception of GDF11 and myonectin, whose expressions were significantly increased in the 35 mg/kg PN HCl (P<0.05). Notably, the majority of gene expressions that were affected responded to dietary supplemental vitamin B6 in a similar manner. The results suggest that compared with the marginal vitamin B6 deficiency, the recommended dietary intake of vitamin B6 upregulates the gene expression of a number of factors that promote the growth and repair of skeletal muscle. PMID- 28912875 TI - Inhibitory effect of burdock leaves on elastase and tyrosinase activity. AB - Burdock (Arctium lappa L.) leaves generate a considerable amount of waste following burdock root harvest in Taiwan. To increase the use of burdock leaves, the present study investigated the optimal methods for producing burdock leaf extract (BLE) with high antioxidant polyphenolic content, including drying methods and solvent extraction concentration. In addition, the elastase and tyrosinase inhibitory activity of BLE was examined. Burdock leaves were dried by four methods: Shadow drying, oven drying, sun drying and freeze-drying. The extract solution was then subjected to total polyphenol content analysis and the method that produced BLE with the highest amount of total antioxidant components was taken forward for further analysis. The 1,1-diphenyl-2-pycrylhydrazyl scavenging, antielastase and antityrosinase activity of the BLE were measured to enable the evaluation of the antioxidant and skin aging-associated enzyme inhibitory activities of BLE. The results indicated that the total polyphenolic content following extraction with ethanol (EtOH) was highest using the freeze drying method, followed by the oven drying, shadow drying and sun drying methods. BLE yielded a higher polyphenol content and stronger antioxidant activity as the ratio of the aqueous content of the extraction solvent used increased. BLE possesses marked tyrosinase and elastase inhibitory activities, with its antielastase activity notably stronger compared with its antityrosinase activity. These results indicate that the concentration of the extraction solvent was associated with the antioxidant and skin aging-associated enzyme inhibitory activity of BLE. The reactive oxygen species scavenging theory of skin aging may explain the tyrosinase and elastase inhibitory activity of BLE. In conclusion, the optimal method for obtaining BLE with a high antioxidant polyphenolic content was freeze-drying followed by 30-50% EtOH extraction. In addition, the antielastase and antityrosinase activities of the BLE produced may be aid in the development of skincare products with antiwrinkle and skin-evening properties. PMID- 28912876 TI - Effect of intercostal nerve block combined with general anesthesia on the stress response in patients undergoing minimally invasive mitral valve surgery. AB - The aim of the present study was to investigate the effect of intercostal nerve block combined with general anesthesia on the stress response and postoperative recovery in patients undergoing minimally invasive mitral valve surgery (MIMVS). A total of 30 patients scheduled for MIMVS were randomly divided into two groups (n=15 each): Group A, which received intercostal nerve block combined with general anesthesia and group B, which received general anesthesia alone. Intercostal nerve block in group A was performed with 0.5% ropivacaine from T3 to T7 prior to anesthesia induction. In each group, general anesthesia was induced using midazolam, sufentanil, propofol and vecuronium. Central venous blood samples were collected to determine the concentrations of cortisol, glucose, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) at the following time points: During central venous catheterization (T1), 5 min prior to cardiopulmonary bypass (T2), perioperative (T3) and 24 h following surgery (T4). Clinical data, including parameters of opioid (sufentanil) consumption, time of mechanical ventilation, duration of intensive care unit (ICU) stay, visual analog scale scores and any complications arising from intercostal nerve block, were recorded. Levels of cortisol, glucose, IL-6 and TNF-alpha in group A were significantly lower than those in group B at T2 (all P<0.001; cortisol, P<0.05), T3 (all P<0.001) and T4 (all P<0.001; glucose, P<0.05), suggesting that intercostal nerve block combined with general anesthesia may inhibit the stress response to MIMVS. Additionally, intercostal nerve block combined with general anesthesia may significantly reduce sufentanil consumption (P<0.001), promote early tracheal extubation (P<0.001), shorten the duration of ICU stay (P<0.01) and attenuate postoperative pain (P<0.001), compared with general anesthesia alone. Thus, these results suggest that intercostal nerve block combined with general anesthesia conforms to the concept of rapid rehabilitation surgery and may be suitable for clinical practice. PMID- 28912877 TI - FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells. AB - Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor alpha (ERalpha), and upregulated ERalpha-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERalpha were decreased, and trastuzumab-induced ERalpha target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERalpha target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer. PMID- 28912878 TI - Triterpenoids from Ganoderma lucidum inhibit the activation of EBV antigens as telomerase inhibitors. AB - Nasopharyngeal carcinoma (NPC) is a malignant disease that threatens the health of humans. To find effective agents for the inhibition of Epstein-Barr virus (EBV) infection, which is associated with NPC, a phytochemical investigation of Ganoderma lucidum was carried out in the present study. Five triterpenoids were identified, including ganoderic acid A (compound 1), ganoderic acid B (compound 2), ganoderol B (compound 3), ganodermanontriol (compound 4), and ganodermanondiol (compound 5), on the basis of spectroscopic analysis. An inhibition of EBV antigens activation assay was implemented to elucidate the triterpenoids from G. lucidum and potentially prevent NPC. All the triterpenoids showed significant inhibitory effects on both EBV EA and CA activation at 16 nmol. At 3.2 nmol, all the compounds moderately inhibited the activation of the two antigens. The activity of telomerase was inhibited by these triterpenoids at 10 uM. Molecular docking demonstrated that compound 1 was able to inhibit telomerase as a ligand. In addition, the physicochemical properties of these compounds were calculated to elucidate their drug-like properties. These results provided evidence for the application of these triterpenoids and whole G. lucidum in the treatment of NPC. PMID- 28912879 TI - A crossover study of the combination therapy of metformin and exenatide or biphasic insulin aspart 30 in overweight or obese patients newly diagnosed with type 2 diabetes mellitus. AB - The aim of the present study was to explore the effects of various combinations of exenatide, metformin (MET) and biphasic insulin aspart 30 (BIA30) on type 2 diabetes mellitus (T2DM). Two hundred overweight or obese patients newly diagnosed with T2DM were evenly randomized into two groups: A (twice daily for all: Phase I, 5 ug exenatide + 0.5 g MET for 4 weeks, then 10 ug exenatide + 0.5 g MET for 8 weeks; Phase II, 0.5 g MET for 12 weeks; Phase III, 0.3-0.4 U/kg/day BIA30 + 0.5 g MET for 12 weeks) and B (Phases I, II, III matched the phases III, II and I in group A). In groups A and B a significant decrease and increase, respectively, in glycated hemoglobin (HbAlc) and body mass index (BMI) was noted during Phase I. A 3.2+/-0.4-kg decrease in body weight in group A and a 2.6+/-0.3 kg increase in group B was observed. In Phase II, HbAlc was significantly increased in both groups (P<0.05). In Phase III, the BMI was increased in group A and reduced in group B (P<0.05). There was a 3.8+/-0.4-kg weight decrease in group B and 4.2+/-0.5-kg increase in group A (P<0.05). The combination of exenatide and MET promoted weight loss, glycemic control, beta-cell function index, C peptide and adiponectin levels. These results suggested that the combination of exenatide and MET is better than the combination of BIA and MET for the therapy of overweight or obese patients newly diagnosed with T2DM. PMID- 28912881 TI - Immune regulation of miR-30 on the Mycobacterium tuberculosis-induced TLR/MyD88 signaling pathway in THP-1 cells. AB - The present study aimed to examine the expression of microRNA (miR)-30 family members in THP-1 human monocytes cells during Mycobacterium tuberculosis (MTB) H37Rv infection, and to investigate the role of miR-30 in the regulation of MTB induced Toll-like receptor (TLR)/myeloid differentiation factor 88 (MyD88) activation and cytokine expression. The THP-1 cells were infected with MTB H37Rv and the expression of miR-30 family members was determined by reverse transcription-quantitative polymerase chain reaction analysis. In addition, miR 30a and miR-30e mimics were transfected into THP-1 cells to overexpress miR-30a and miR-30e. The expression of TLR2, TLR4 and MyD88 was determined by western blot analysis, and the expression of the cytokines tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 was determined using ELISA assays. A luciferase reporter assay was used to identify the target gene of miR-30a. MTB infection was demonstrated to significantly induce miR-30a and miR-30e expression in THP-1 cells in a time-dependent manner. Forced overexpression of miR-30a, but not miR 30e, exhibited an inhibitory effect on TLR/MyD88 activation and cytokine expression in the uninfected and MTB-infected THP-1 cells. The luciferase reporter assay demonstrated that miR-30a directly regulates the transcriptional activity of the MyD88 3'-untranslated region. In conclusion, the present study, to the best of our knowledge, is the first to demonstrate that miR-30a suppresses TLR/MyD88 activation and cytokine expression in THP-1 cells during MTB H37Rv infection, and that MyD88 is a direct target of miR-30a. The current study may aid in the development of novel therapeutic approaches for treating MTB. PMID- 28912880 TI - Spectroscopic analysis and docking simulation on the recognition and binding of TEM-1 beta-lactamase with beta-lactam antibiotics. AB - The interaction between TEM-1 beta-lactamase and antibiotics is very important in the hydrolysis of antibiotics. In the present study, the recognition and binding of TEM-1 beta-lactamase with three beta-lactam antibiotics, including penicillin G, cefalexin and cefoxitin, was investigated by fluorescence and ultraviolet visible absorption spectra in combination with molecular docking in the temperature range of 278-288 K and under simulated physiological conditions. The results demonstrated that the fluorescence emissions of TEM-1 beta-lactamase were extinguished by static quenching and the energy of TEM-1 beta-lactamase was transferred in a non-radioactive manner. The binding of TEM-1 beta-lactamase with the three antibiotics was a spontaneously exothermic process, with binding constants of 1.41*107, 7.81*106 and 5.43*104 at 278 K. Furthermore, binding was driven by enthalpy change and the binding forces between them were mainly hydrogen bonding and Van der Waals forces. A TEM-1 beta-lactamase only bound with one antibiotic at a time and the binding capacity between them was closely associated with the functional groups and flexibility in the antibiotics. In addition, a conformational change occurred in the TEM-1 beta-lactamases when they bound with the three antibiotics and TEM-1 beta-lactamase-antibiotic complexes were formed. The present study provided an insight into the recognition and binding of TEM-1 beta-lactamase with beta-lactam antibiotics, which may be helpful for designing a novel substrate for TEM-1 beta-lactamase and developing novel antibiotics that are resistant to the enzyme. PMID- 28912882 TI - Atorvastatin alleviates iodinated contrast media-induced cytotoxicity in human proximal renal tubular epithelial cells. AB - Contrast media (CM)-induced nephropathy (CIN) is a serious complication of intravascularly applied radiocontrast media. At present, no drugs have been approved for the prevention of CIN. The present study aimed to explore the effects and potential mechanisms of atorvastatin on iodinated CM-induced cytotoxicity in the human proximal renal tubular epithelial cells. The cytotoxic effect of iohexol (50, 100 and 200 mg I/ml) and the protective effect of atorvastatin pretreatment (1, 20 and 40 uM) were assessed. The cytotoxicity of iohexol was evaluated via the MTT cell viability and lactate dehydrogenase assays. The amount of apoptotic cells was determined by flow cytometry. Morphological changes in HK-2 cells were observed via transmission electron microscopy. The mRNA expression of NOX4 and p22phox was measured through reverse transcription-quantitative polymerase chain reaction analysis. The cytotoxicity was induced by iohexol in HK-2 cells. Atorvastatin was identified to significantly alleviate the suppression of cell viability induced by iohexol. Notably, 40 uM atorvastatin also significantly reduced the mRNA expression of intracellular NOX4 and p22phox, and the percentage of apoptotic cells. Furthermore, morphological changes characteristic of injured cells were alleviated by atorvastatin pretreatment. These results suggest that atorvastatin exhibits a protective effect on HK-2 cells against iohexol-induced cytotoxicity through the downregulation of NOX4 and p22phox. Thus, atorvastatin is a potential therapeutic agent for the prevention of CIN and required further study. PMID- 28912883 TI - Tirofiban facilitates the reperfusion process during endovascular thrombectomy in ICAS. AB - The aim of the present study was to assess the use of tirofiban injections for rescue therapy following artery reocclusion due to intra-luminal thrombosis during endovascular thrombectomy in patients with acute ischemic stroke (AIS). A total of seven cases of patients treated with adjunctive tirofiban injections following failed endovascular thrombectomy due to instant intra-luminal thrombosis were retrospectively assessed. A Solitaire stent was used as the primary thrombectomy device in all patients. Tirofiban was injected intra arterially via a temporarily deployed Solitaire stent with continuous intravenous infusion for the subsequent 24 h; half of the conventionally recommended dose was employed. Outcome measures included angiographic reperfusion (mTICI), symptomatic intracranial hemorrhage, mortality and functional independence at 90 days (modified Rankin Scale, 0-2). Six patients had occlusions in the middle cerebral artery and one patient had occlusions in the basilar artery. Of the seven patients, five exhibited successful reperfusion (mTICI 2b-3) and achieved functional independence following 90 days. Reperfusion failed in the remaining two patients, who succumbed within 90 days of therapy. No intracranial or extracranial hemorrhage cases were identified. The results of the present study suggest that tirofiban facilitates reperfusion and ameliorates long-term prognosis in patients with AIS undergoing endovascular thrombectomy, and may be safe for those receiving intravenous tissue plasminogen activator therapy. PMID- 28912884 TI - Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo. AB - Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant beta1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting. PMID- 28912885 TI - Brusatol-Mediated Inhibition of c-Myc Increases HIF-1alpha Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia. AB - HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying brusatol-induced HIF-1alpha degradation and cell death in colorectal cancer under hypoxia (0.5% O2). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1alpha degradation and cancer cell death in a dose dependent manner. This effect was mediated by activation of prolyl hydroxylases (PHDs), as evidenced by the block of brusatol-induced HIF-1alpha degradation and cancer cell death by both pharmacological inhibition and siRNA-mediated knockdown of PHDs. In addition, a ferrous iron chelator (2,2'-bypyridyl) blocked brusatol induced degradation of HIF-1alpha and cancer cell death in hypoxia by inhibiting PHD activation. We further found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF 1alpha and cancer cell death by increasing mitochondrial ROS production and subsequent ROS-mediated transition of ferrous iron to ferric iron. Consistent with these results, treatment of tumor-bearing mice with brusatol significantly suppressed tumor growth by promoting PHD-mediated HIF-1alpha degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1alpha degradation by promoting PHD activity and induces cell death in colorectal cancer under hypoxia. PMID- 28912886 TI - The pH-Triggered Triblock Nanocarrier Enabled Highly Efficient siRNA Delivery for Cancer Therapy. AB - Small interfering RNA (siRNA) therapies have been hampered by lack of delivery systems in the past decades. Nowadays, a few promising vehicles for siRNA delivery have been developed and it is gradually revealed that enhancing siRNA release from endosomes into cytosol is a very important factor for successful delivery. Here, we designed a novel pH-sensitive nanomicelle, PEG-PTTMA-P(GMA-S DMA) (PTMS), for siRNA delivery. Owing to rapid hydrolysis in acidic environment, PTMS NPs underwent hydrophobic-to-hydrophilic transition in endosomes that enabled combination of proton sponge effect and raised osmotic pressure in endosomes, resulting in vigorous release of siRNAs from endosomes into cytosol. In vitro results demonstrated that PTMS/siRNA complexes exhibited excellent gene silencing effects in several cell lines. Their gene silencing efficiency could reach ~91%, ~87% and ~90% at the N/P ratio of 50/1 in MDA-MB-231, A549 and Hela cells respectively, which were better than that obtained with Lipofectamine 2000. The highly efficient gene silencing was then proven from enhanced siRNA endosomal release, which is mainly attributed to pH-triggered degradation of polymer and acid-accelerated siRNA release. In vivo experiments indicated that NPs/siRNA formulation rapidly accumulated in tumor sites after i.v. injection. Tumor growth was effectively inhibited and ~45% gene knockdown efficacy was determined at the siRRM2 dose of 1mg/kg. Meanwhile, no significant toxicity was observed during the whole treatment. We also found that PTMS/siRNA formulations could lead to significant gene silencing effects in liver (~63%) and skin (~80%) when injected by i.v. and s.c., respectively. This research work gives a rational strategy to optimize siRNA delivery systems for tumor treatments. PMID- 28912887 TI - rSj16 Protects against DSS-Induced Colitis by Inhibiting the PPAR-alpha Signaling Pathway. AB - Background: Epidemiologic studies and animal model experiments have shown that parasites have significant modulatory effects on autoimmune disorders, including inflammatory bowel disease (IBD). Recombinant Sj16 (rSj16), a 16-kDa secreted protein of Schistosoma japonicum (S.japonicum) produced by Escherichia coli (E. coli), has been shown to have immunoregulatory effects in vivo and in vitro. In this study, we aimed to determine the effects of rSj16 on dextran sulfate sodium (DSS)-induced colitis. Methods: DSS-induced colitis mice were treated with rSj16. Body weight loss, disease activity index (DAI), myeloperoxidase (MPO) activity levels, colon lengths, macroscopic scores, histopathology findings, inflammatory cytokine levels and regulatory T cell (Treg) subset levels were examined. Moreover, the differential genes expression after treated with rSj16 were sequenced, analyzed and identified. Results: rSj16 attenuated clinical activity of DSS-induced colitis mice, diminished pro-inflammatory cytokine production, up regulated immunoregulatory cytokine production and increased Treg percentages in DSS-induced colitis mice. Moreover, DSS-induced colitis mice treated with rSj16 displayed changes in the expression levels of specific genes in the colon and show the crucial role of peroxisome proliferator activated receptor alpha (PPAR alpha) signaling pathway. PPAR-alpha activation diminished the therapeutic effects of rSj16 in DSS-induced colitis mice, indicating that the PPAR-alpha signaling pathway plays a crucial role in DSS-induced colitis development. Conclusions: rSj16 has protective effects on DSS-induced colitis, effects mediated mainly by PPAR-alpha signaling pathway inhibition. The findings of this study suggest that rSj16 may be useful as a therapeutic agent and that PPAR-alpha may be a new therapeutic target in the treatment of IBD. PMID- 28912888 TI - Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells. AB - Cancer cells are characterized by genetic and epigenetic alterations and phytochemicals, epigenetic modulators, are considered as promising candidates for epigenetic therapy of cancer. In the present study, we have investigated cancer cell fates upon stimulation of breast cancer cells (MCF-7, MDA-MB-231, SK-BR-3) with low doses of sulforaphane (SFN), an isothiocyanate. SFN (5-10 uM) promoted cell cycle arrest, elevation in the levels of p21 and p27 and cellular senescence, whereas at the concentration of 20 uM, apoptosis was induced. The effects were accompanied by nitro-oxidative stress, genotoxicity and diminished AKT signaling. Moreover, SFN stimulated energy stress as judged by decreased pools of ATP and AMPK activation, and autophagy induction. Anticancer effects of SFN were mediated by global DNA hypomethylation, decreased levels of DNA methyltransferases (DNMT1, DNMT3B) and diminished pools of N6-methyladenosine (m6A) RNA methylation. SFN (10 uM) also affected microRNA profiles, namely SFN caused upregulation of sixty microRNAs and downregulation of thirty two microRNAs, and SFN promoted statistically significant decrease in the levels of miR-23b, miR-92b, miR-381 and miR-382 in three breast cancer cells. Taken together, we show for the first time that SFN is an epigenetic modulator in breast cancer cells that results in cell cycle arrest and senescence, and SFN may be considered to be used in epigenome-focused anticancer therapy. PMID- 28912889 TI - CBX8 Suppresses Tumor Metastasis via Repressing Snail in Esophageal Squamous Cell Carcinoma. AB - The poor clinical outcome and prognosis of esophageal squamous cell carcinoma (ESCC) is mainly attributed to its highly invasive and metastatic nature, making it urgent to further elicit the molecular mechanisms of the metastasis of ESCC. The function of each polycomb chromobox (CBX) protein in cancer is cell-type dependent. Although CBX8 has been reported to promote the esophageal squamous cell carcinoma (ESCC) tumorigenesis, its role in ESCC metastasis has not been explored yet. In this study, we report that the inhibition of cell migration, invasion, and metastasis in ESCC requires CBX8-mediated repression of Snail, a key transcription factor that induces epithelial-to-mesenchymal transition (EMT), and that CBX8 inversely correlated with Snail in the ESCC tissues. Moreover, this novel function of CBX8 is dependent on its binding with the Snail promoter, which in turn suppresses the transcription of Snail. Collectively, CBX8 may play paradoxical roles in ESCC, inhibiting metastasis while promoting cell proliferation. PMID- 28912890 TI - Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery. AB - Malignant glioma is one of the most untreatable cancers because of the formidable blood-brain barrier (BBB), through which few therapeutics can penetrate and reach the tumors. Biologics have been booming in cancer therapy in the past two decades, but their application in brain tumor has long been ignored due to the impermeable nature of BBB against effective delivery of biologics. Indeed, it is a long unsolved problem for brain delivery of macromolecular drugs, which becomes the Holy Grail in medical and pharmaceutical sciences. Even assisting by targeting ligands, protein brain delivery still remains challenging because of the synthesis difficulties of ligand-modified proteins. Herein, we propose a rocket-like, multistage booster delivery system of a protein toxin, trichosanthin (TCS), for antiglioma treatment. TCS is a ribosome-inactivating protein with the potent activity against various solid tumors but lack of specific action and cell penetration ability. To overcome the challenge of its poor druggability and site specific modification, intein-mediated ligation was applied, by which a gelatinase-cleavable peptide and cell-penetrating peptide (CPP)-fused recombinant TCS toxin can be site-specifically conjugated to lactoferrin (LF), thus constructing a BBB-penetrating, gelatinase-activatable cell-penetrating nanohybrid TCS toxin. This nanohybrid TCS system is featured by the multistage booster strategy for glioma dual-targeting delivery. First, LF can target to the BBB-overexpressing low-density lipoprotein receptor-related protein-1 (LRP-1), and assist with BBB penetration. Second, once reaching the tumor site, the gelatinase-cleavable peptide acts as a separator responsive to the glioma associated matrix metalloproteinases (MMPs), thus releasing to the CPP-fused toxin. Third, CPP mediates intratumoral and intracellular penetration of TCS toxin, thereby enhancing its antitumor activity. The BBB penetration and MMP-2 activability of this delivery system were demonstrated. The antiglioma activity was evaluated in the subcutaneous and orthotopic animal models. Our work provides a useful protocol for improving the druggability of such class of protein toxins and promoting their in-vivo application for targeted cancer therapy. PMID- 28912892 TI - Real-time In vivo Diagnosis of Nasopharyngeal Carcinoma Using Rapid Fiber-Optic Raman Spectroscopy. AB - We report the utility of a simultaneous fingerprint (FP) (i.e., 800-1800 cm-1) and high-wavenumber (HW) (i.e., 2800-3600 cm-1) fiber-optic Raman spectroscopy developed for real-time in vivo diagnosis of nasopharyngeal carcinoma (NPC) at endoscopy. A total of 3731 high-quality in vivo FP/HW Raman spectra (normal=1765; cancer=1966) were acquired in real-time from 204 tissue sites (normal=95; cancer=109) of 95 subjects (normal=57; cancer=38) undergoing endoscopic examination. FP/HW Raman spectra differ significantly between normal and cancerous nasopharyngeal tissues that could be attributed to changes of proteins, lipids, nucleic acids, and the bound water content in NPC. Principal components analysis (PCA) and linear discriminant analysis (LDA) together with leave-one subject-out, cross-validation (LOO-CV) were implemented to develop robust Raman diagnostic models. The simultaneous FP/HW Raman spectroscopy technique together with PCA-LDA and LOO-CV modeling provides a diagnostic accuracy of 93.1% (sensitivity of 93.6%; specificity of 92.6%) for nasopharyngeal cancer identification, which is superior to using either FP (accuracy of 89.2%; sensitivity of 89.9%; specificity of 88.4%) or HW (accuracy of 89.7%; sensitivity of 89.0%; specificity of 90.5%) Raman technique alone. Further receiver operating characteristic (ROC) analysis reconfirms the best performance of the simultaneous FP/HW Raman technique for in vivo diagnosis of NPC. This work demonstrates for the first time that simultaneous FP/HW fiber-optic Raman spectroscopy technique has great promise for enhancing real-time in vivo cancer diagnosis in the nasopharynx during endoscopic examination. PMID- 28912891 TI - Bioengineering of Artificial Antigen Presenting Cells and Lymphoid Organs. AB - The immune system protects the body against a wide range of infectious diseases and cancer by leveraging the efficiency of immune cells and lymphoid organs. Over the past decade, immune cell/organ therapies based on the manipulation, infusion, and implantation of autologous or allogeneic immune cells/organs into patients have been widely tested and have made great progress in clinical applications. Despite these advances, therapy with natural immune cells or lymphoid organs is relatively expensive and time-consuming. Alternatively, biomimetic materials and strategies have been applied to develop artificial immune cells and lymphoid organs, which have attracted considerable attentions. In this review, we survey the latest studies on engineering biomimetic materials for immunotherapy, focusing on the perspectives of bioengineering artificial antigen presenting cells and lymphoid organs. The opportunities and challenges of this field are also discussed. PMID- 28912893 TI - The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction. AB - Rationale: Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies, is associated with additional myonecrosis, and is linked to worse prognosis, including death. We have shown, both in in vitro and in vivo models, that ultrasound (US) and microbubble (MB) therapy (termed "sonoreperfusion" or "SRP") is a theranostic approach that relieves MVO and restores perfusion, but the underlying mechanisms remain to be established. Objective: In this study, we investigated the role of nitric oxide (NO) during SRP. Methods and results: We first demonstrated in plated cells that US-stimulated MB oscillations induced a 6 fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation in vitro. We then monitored the kinetics of intramuscular NO and perfusion flow rate responses following 2-min of SRP therapy in the rat hindlimb muscle, with and without blockade of eNOS with LNAME. Following SRP, we found that starting at 6 minutes, intramuscular NO increased significantly over 30 min and was higher than baseline after 13 min. Concomitant contrast enhanced burst reperfusion imaging confirmed that there was a marked increase in perfusion flow rate at 6 and 10 min post SRP compared to baseline (>2.5 fold). The increases in intramuscular NO and perfusion rate were blunted with LNAME. Finally, we tested the hypothesis that NO plays a role in SRP by assessing reperfusion efficacy in a previously described rat hindlimb model of MVO during blockade of eNOS. After US treatment 1, microvascular blood volume was restored to baseline in the MB+US group, but remained low in the LNAME group. Perfusion rates increased in the MB+US group after US treatment 2 but not in the MB+US+LNAME group. Conclusions: These data strongly support that MB oscillations can activate the eNOS pathway leading to increased blood perfusion and that NO plays a significant role in SRP efficacy. PMID- 28912894 TI - Genetically Encoded Photoactuators and Photosensors for Characterization and Manipulation of Pluripotent Stem Cells. AB - Our knowledge of pluripotent stem cell biology has advanced considerably in the past four decades, but it has yet to deliver on the great promise of regenerative medicine. The slow progress can be mainly attributed to our incomplete understanding of the complex biologic processes regulating the dynamic developmental pathways from pluripotency to fully-differentiated states of functional somatic cells. Much of the difficulty arises from our lack of specific tools to query, or manipulate, the molecular scale circuitry on both single-cell and organismal levels. Fortunately, the last two decades of progress in the field of optogenetics have produced a variety of genetically encoded, light-mediated tools that enable visualization and control of the spatiotemporal regulation of cellular function. The merging of optogenetics and pluripotent stem cell biology could thus be an important step toward realization of the clinical potential of pluripotent stem cells. In this review, we have surveyed available genetically encoded photoactuators and photosensors, a rapidly expanding toolbox, with particular attention to those with utility for studying pluripotent stem cells. PMID- 28912896 TI - Investigation of the Safety of Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Natural Canine Model of Aging. AB - Rationale: Ultrasound-mediated opening of the Blood-Brain Barrier(BBB) has shown exciting potential for the treatment of Alzheimer's disease(AD). Studies in transgenic mouse models have shown that this approach can reduce plaque pathology and improve spatial memory. Before clinical translation can occur the safety of the method needs to be tested in a larger brain that allows lower frequencies be used to treat larger tissue volumes, simulating clinical situations. Here we investigate the safety of opening the BBB in half of the brain in a large aged animal model with naturally occurring amyloid deposits. Methods: Aged dogs naturally accumulate plaques and show associated cognitive declines. Low frequency ultrasound was used to open the BBB unilaterally in aged beagles (9 11yrs, n=10) in accordance with institutionally approved protocols. Animals received either a single treatment or four weekly treatments. Magnetic resonance imaging(MRI) was used to guide the treatments and assess the tissue effects. The animals underwent neurological testing during treatment follow-up, and a follow up MRI exam 1 week following the final treatment. Results: The permeability of the BBB was successfully increased in all animals (mean enhancement: 19+/-11% relative to untreated hemisphere). There was a single adverse event in the chronic treatment group that resolved within 24 hrs. Follow-up MRI showed the BBB to be intact with no evidence of tissue damage in all animals. Histological analysis showed comparable levels of microhemorrhage between the treated and control hemispheres in the prefrontal cortex (single/repeat treatment: 1.0+/-1.4 vs 0.4+/-0.5/5.2+/-1.8 vs. 4.0+/-2.0). No significant differences were observed in beta-amyloid load (single/repeat: p=0.31/p=0.98) although 3/5 animals in each group showed lower Abeta loads in the treated hemisphere. Conclusion: Whole hemisphere opening of the BBB was well tolerated in the aged large animal brain. The treatment volumes and frequencies used are clinically relevant and indicate safety for clinical translation. Further study is warranted to determine if FUS has positive effects on naturally occurring amyloid pathology. PMID- 28912897 TI - Genomic Analysis of Tumor Microenvironment Immune Types across 14 Solid Cancer Types: Immunotherapeutic Implications. AB - We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number. The mutational and neoepitope features of the tumor were compared according to the four TMITs. We found that PD-L1/CD8A/CYT subgroups could not distinguish different mutation and neoantigen numbers in certain tumor types such as glioblastoma multiforme, prostate adenocarcinoma, and head and neck and lung squamous cell carcinoma. For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma. In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers. Our findings show that the TMIT stratification proposed could serve as a favorable approach for tailoring optimal immunotherapeutic strategies in certain tumor types. Going forward, it will be important to test the clinical practicability of TMIT based on quantification of immune infiltrates using mRNA-seq to predict clinical response to these and other immunotherapeutic strategies in more different tumors. PMID- 28912895 TI - Mass spectrometry-assisted gel-based proteomics in cancer biomarker discovery: approaches and application. AB - There is a critical need for the discovery of novel biomarkers for early detection and targeted therapy of cancer, a major cause of deaths worldwide. In this respect, proteomic technologies, such as mass spectrometry (MS), enable the identification of pathologically significant proteins in various types of samples. MS is capable of high-throughput profiling of complex biological samples including blood, tissues, urine, milk, and cells. MS-assisted proteomics has contributed to the development of cancer biomarkers that may form the foundation for new clinical tests. It can also aid in elucidating the molecular mechanisms underlying cancer. In this review, we discuss MS principles and instrumentation as well as approaches in MS-based proteomics, which have been employed in the development of potential biomarkers. Furthermore, the challenges in validation of MS biomarkers for their use in clinical practice are also reviewed. PMID- 28912898 TI - Inhibition of Bone Marrow-Derived Mesenchymal Stem Cells Homing Towards Triple Negative Breast Cancer Microenvironment Using an Anti-PDGFRbeta Aptamer. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs) are shown to participate in tumor progression by establishing a favorable tumor microenvironment (TME) that promote metastasis through a cytokine networks. However, the mechanism of homing and recruitment of BM-MSCs into tumors and their potential role in malignant tissue progression is poorly understood and controversial. Here we show that BM MSCs increase aggressiveness of triple-negative breast cancer (TNBC) cell lines evaluated as capability to migrate, invade and acquire stemness markers. Importantly, we demonstrate that the treatment of BM-MSCs with a nuclease resistant RNA aptamer against platelet-derived growth factor receptor beta (PDGFRbeta) causes the inhibition of receptor-dependent signaling pathways thus drastically hampering BM-MSC recruitment towards TNBC cell lines and BM-MSCs trans-differentiation into carcinoma-associated fibroblast (CAF)-like cells. Moreover, in vivo molecular imaging analysis demonstrated the aptamer ability to prevent BM-MSCs homing to TNBC xenografts. Collectively, our results indicate the anti-PDGFRbeta aptamer as a novel therapeutic tool to interfere with BM-MSCs attraction to TNBC providing the rationale to further explore the aptamer in more complex pre-clinical settings. PMID- 28912899 TI - Earwax as an alternative specimen for forensic analysis. AB - In this work, we presented, for the first time, earwax as an alternative forensic specimen for detecting 12 neuropsychotic drugs employing liquid chromatography tandem mass spectrometry in positive and negative ion modes after straightforward extraction with methanol. The method was validated and standard curves were established by external calibration with correlation coefficients >0.99. All precision, accuracy, matrix effects, extraction recoveries, and carryover were within acceptable limits; limits of quantification were sufficiently low to quantify almost all the samples tested. To confirm the feasibility of the study, earwax specimens were collected from actual patients treated with different combinations of the 12 drugs and analyzed by our method; the 12 drugs could be quantified from the earwax specimens of the users successfully, showing usefulness of earwax specimens, because of its noninvasive sampling and the storage of drug(s) for relatively long time together with its being relatively less contaminated by environmental impurities. This study is pioneering; many detailed studies on earwax as an alternative specimen remain to be explored. PMID- 28912900 TI - Open Label Trial of the Efficacy and Safety Profile of Rikkunshito used for the Treatment of Gastrointestinal Symptoms in Patients with Parkinson's Disease: A Pilot Study. AB - BACKGROUND: Patients with Parkinson's disease (PD) usually experience distress related not only to motor dysfunction, but also to nonmotor symptoms, including gastrointestinal dysfunction. OBJECTIVE: The purpose of this pilot study was to evaluate the efficacy and safety profile of a traditional Japanese medicine, rikkunshito (RKT), used for the treatment of gastrointestinal symptoms, associated with anorexia and dyspepsia, in patients with PD. METHODS: Patients were randomly assigned to either Group A (4-week treatment period with 7.5 g/d RKT followed by a 4-week off-treatment period) or Group B (4-week off-treatment period followed by a 4-week treatment period with 7.5 g/d RKT). Appetite, quality of life for gastrointestinal symptoms, and depression were assessed using a visual analog scale, the Gastrointestinal Symptom Rating Scale and the Self Rating Depression Scale, respectively. The gastric emptying examination and assay of plasma acylated ghrelin level were performed using the 13C-acetate breath test and commercially available assay kits, respectively. RESULTS: RKT treatment produced a significant increase in the appetite score (1.84 [2.34]; P < 0.05), compared to a decrease in the score over the off-treatment period (-1.36 [2.94]). The mean score for abdominal pain, on the Gastrointestinal Symptom Rating Scale, and for self-reported depression, on the Self-Rating Depression Scale, also decreased significantly with RKT treatment (P < 0.05), compared with the off treatment period scores. No effect of RKT on plasma acylated ghrelin level and rate of gastric emptying was identified. CONCLUSIONS: RKT may improve anorexia in patients with PD. The positive effects of RKT on depression and anorexia may improve the overall quality of life of these patients. The benefits of RKT identified in our pilot study will need to be confirmed in a randomized, double blind, controlled trial. UMIN Clinical Trial Registry identifier: UMIN000009626. PMID- 28912901 TI - Can a Selective Serotonin Reuptake Inhibitor Act as a Glutamatergic Modulator? AB - Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin reuptake inhibitors whose antidepressant mechanism of action is classically attributed to an elevation of the extracellular levels of serotonin in the synaptic cleft. However, the biological effects of these drugs seem to be more complex than their traditionally described mechanism of action. Among their actions is the inhibition of different types of Na+ and K+ channels, as well as of glutamate uptake activity. The clearance of extracellular glutamate is essential to maintain the central nervous system within physiological conditions, and this excitatory neurotransmitter is removed from the synaptic cleft by astrocyte transporters. This transport depends upon a hyperpolarized membrane potential in astrocytes that is mainly maintained by Kir4.1 K+ channels. The impairment of the Kir4.1 channel activity reduces driving force for the glutamate transporter, resulting in an accumulation of extracellular glutamate. It has been shown that sertraline and fluoxetine inhibit Kir4.1 K+ channels. Recently, we demonstrated that sertraline reduces glutamate uptake in human platelets, which contain a high affinity Na+-dependent glutamate uptake system, with kinetic and pharmacological properties similar to astrocytes in the central nervous system. Considering these similarities between human platelets and astrocytes, one might ask if sertraline could potentially reduce glutamate clearance in the synaptic cleft and consequently modulate glutamatergic transmission. This possibility merits investigation, since it may provide additional information regarding the mechanism of action and perhaps the side effects of these antidepressants. PMID- 28912902 TI - Effects of Dapagliflozin on Body Composition and Liver Tests in Patients with Nonalcoholic Steatohepatitis Associated with Type 2 Diabetes Mellitus: A Prospective, Open-label, Uncontrolled Study. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease. Risk factors for NASH include type 2 diabetes mellitus (T2DM) and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors used to treat T2DM prevent glucose reabsorption in the kidney and increase glucose urinary excretion. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications associated with NASH in rodent models. OBJECTIVE: To assess the efficacy and safety profile of dapagliflozin for the treatment of NASH associated with T2DM. METHODS: In this single-arm, nonrandomized, open-label study, 16 patients with percutaneous liver biopsy-confirmed NASH and T2DM were enrolled to be prescribed dapagliflozin 5 mg/d for 24 weeks. Of these, 11 patients were evaluable. Patients with chronic liver disease other than NASH were excluded. Body composition, laboratory variables related to liver tests and metabolism, and glucose homeostasis were assessed at baseline and periodically during the study. Changes from baseline were evaluated with the Wilcoxon signed rank test. RESULTS: Administration of dapagliflozin for 24 weeks was associated with significant decreases in body mass index (P < 0.01), waist circumference (P < 0.01), and waist-to-hip ratio (P < 0.01). Changes in body composition were driven by reductions in body fat mass (P < 0.01) and percent body fat (P < 0.01), without changes in lean mass or total body water. Liver tests (ie, serum concentrations of aspartate aminotransferase, alanine aminotransferase, ferritin, and type IV collagen 7S) also significantly improved during the study. Insulin concentrations decreased (P < 0.01 by Week 24) in combination with significant reductions in fasting plasma glucose (P < 0.01) and glycated hemoglobin (P < 0.01) levels and increases in adiponectin (P < 0.01) levels from Week 4 onward. CONCLUSIONS: Dapagliflozin was associated with improvements in body composition, most likely a reduction in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH associated with T2DM. UMIN Clinical Trial Registry identifier: UMIN000023574. PMID- 28912903 TI - What Did I Do? Practitioner Awareness of Ethical Issues in Scientific Publishing. AB - Massage therapy practice as well as research in massage therapy is guided by ethical principles and boundaries of professional behavior. Scientific publishing is also guided by a set of ethical standards, about which all aspiring scientific authors should be aware. Honesty, integrity, and conflicts of interest are issues in science and these issues can also impact scientific publishing. Historical ethical issues and current events are discussed. PMID- 28912905 TI - A Case for Mixed Methods Research in Massage Therapy. PMID- 28912904 TI - Fasciatherapy and Reflexology compared to Hypnosis and Music Therapy in Daily Stress Management. AB - BACKGROUND: Patients suffering from stress symptoms due to every-day life who are looking for a non-pharmacological response to their relief expectation are many. Furthermore, early reckoning of the day-to-day stress which may lead to clinical diagnosis is the best way of preventing the stress-related diseases. Among the many alternative medicinal options, there is little evidence that fasciatherapy (Fs) and reflexology (Rf) are effective in this field. PURPOSE: assess incidence of fasciatherapy Danis Bois Method (DBM) and of reflexology on patients' stress level in everyday-life, and provide a more informed choice among the numerous mind and body techniques by comparing them with hypnosis (Hp) and music therapy (Mt). SETTINGS: Specialized Complementary and Alternative Medicine (CAM) centres for outpatients. PARTICIPANTS: 308 individuals (average age = 50.53 SD 14.37, 93 males, 215 females) going to the centres for health care, but free from serious diseases and not heavily medicated respecting the inclusion criteria and providing valid forms. RESEARCH DESIGN: Four armed, non-randomized observational pragmatic trial with pretest-posttest repeated measures, on separate samples of natural groups. INTERVENTION: According to the centre participants where they used to be treated, they were exposed to a single semi-standardized session of a technique of their choice: Fs, Rf, Hp, Mt. Volunteers had a controlled non intervention resting (Rt) session. MAIN OUTCOME MEASURES: Mean STAI-Y assessing anxiety as reflecting the stress level: MANCOVA and ANCOVA performed with Tukey's HSD. RESULTS: MANCOVA indicates a significant reduction of anxiety (p < .01) in each condition, resting included. ANCOVA performance adjusting on stress level in T0 (41.73) and on the mean sumscore of the trait (44.89), Fs (-13.92), Rf ( 15.92), and Hp (-15.88) were equally effective on the stress level decrease. Mt ( 10.0) and Rt (-6.38) showed the same level of effectiveness. CONCLUSIONS: The results suggest fasciatherapy DBM, hypnosis, and reflexology could be used as non pharmacological and safe interventions in stress management. Though showing a lesser efficiency, music therapy could be useful in different circumstances. PMID- 28912906 TI - Constipation Is Related to Small Bowel Disturbance Rather Than Colonic Enlargement in Acquired Chagasic Megacolon. AB - BACKGROUND: Constipation is the main symptom of acquired chagasic megacolon. However, a number of patients with Chagas disease without colon involvement also have the same complain. This study evaluated the role of small bowel in constipated patients with Chagas disease with and without megacolon. METHODS: Orocecal transit time (OCTT) and oral glucose tolerance test (OGTT) in constipated non-chagasic and chagasic patients with and without megacolon were performed. One hundred fifteen patients were included in this study and were divided into two groups based on the presence or absence of constipation, which is defined as at least 7 days without bowel movements for more than 1 year. These two groups were further divided into three subgroups based on the serology test results for Trypanosoma cruzi and the presence and absence of megacolon on barium enema. All patients were subjected to OCTT and OGTT. RESULTS: Among 70 constipated patients, 64.3% had OCTT longer than 120 min, higher than the non constipated patients (31.1%, P < 0.000). The proportion of patients within the three subgroups in the non-constipated group was not different from each other (P = 0.345). Among the constipated subgroup, 94.44% of the chagasic megacolon subgroup had OCTT longer than 120 min, higher than the other two subgroups (P = 0.005). Chagas patients with constipation, without or without megacolon, showed higher blood glucose levels at 30, 60, and 90 min after oral ingestion of 70 g glucose than normal subjects with or without constipation. CONCLUSIONS: Constipated, either non-chagasic or chagasic, patients have a prolonged OCTT. This result suggests that slow small bowel transit may be a significant factor for constipation. PMID- 28912907 TI - Long-Term Follow-Up of Autonomic and Enteric Measures in Patients Undergoing Vertical Banded Gastroplasty for Morbid Obesity. AB - BACKGROUND: A multi-component model of autonomic and enteric factors may correlate with ultimate weight loss or gain after restrictive obesity surgery. This study aimed to determine relevant parameters to predict successful long-term weight loss. METHODS: Thirty-nine patients (four males and 35 females) with a mean age of 37.2 years were followed for over 15 years after vertical banded gastroplasty. Baseline adrenergic: postural adjustment ratio (PAR) and vasoconstriction (VC); cholinergic: electrocardiogram R-to-R interval (RRI) and enteric measure: electrogastrogram (EGG) were utilized by a discriminant function analysis to classify patients as a long-term loser or gainer. Using latest weight compared to baseline, patients were divided as 10 gainers and 29 losers. RESULTS: A discriminate model successfully predicted ultimate weight gain in 8/10 (80%) of patients who subsequently gained weight and weight loss in 24/29 (83%) of patients who lost weight for a total correct classification of 32/39 (82%). The same model with data at 3 months postoperatively predicted weight gain in 9/10 (90%) of patients and weight loss in 24/29 (83%) of patients, for a total correct classification of 34/39 (87%). CONCLUSIONS: A multi-component model at baseline and 3 months postoperative can predict long-term weight outcome from restrictive obesity surgery. PMID- 28912908 TI - Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis. AB - BACKGROUND: Gastrin-releasing peptide (GRP) is a pluripotent peptide that has been implicated in both gastrointestinal inflammatory states and classical chronic metabolic diseases such as diabetes. Abnormal glucose metabolism (AGM) after pancreatitis, an exemplar inflammatory disease involving the gastrointestinal tract, is associated with persistent low-grade inflammation and altered secretion of pancreatic and gut hormones as well as cytokines. While GRP is involved in secretion of many of them, it is not known whether GRP has a role in AGM. Therefore, we aimed to investigate the association between GRP and AGM following pancreatitis. METHODS: Fasting blood samples were collected to measure GRP, blood glucose, insulin, amylin, glucagon, pancreatic polypeptide (PP), somatostatin, cholecystokinin, gastric-inhibitory peptide (GIP), gastrin, ghrelin, glicentin, glucagon-like peptide-1 and 2, oxyntomodulin, peptide YY (PYY), secretin, vasoactive intestinal peptide, tumor necrosis factor-alpha (TNF alpha), monocyte chemoattractant protein (MCP)-1, and interleukin-6. Modified Poisson regression analysis and linear regression analyses were conducted. Four statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. RESULTS: A total of 83 individuals after an episode of pancreatitis were recruited. GRP was significantly associated with AGM, consistently in all four models (P -trend < 0.05), and fasting blood glucose contributed 17% to the variance of GRP. Further, GRP was significantly associated with glucagon (P < 0.003), MCP-1 (P < 0.025), and TNF-alpha (P < 0.025) - consistently in all four models. GRP was also significantly associated with PP and PYY in three models (P < 0.030 for both), and with GIP and glicentin in one model (P = 0.001 and 0.024, respectively). Associations between GRP and other pancreatic and gut hormones were not significant. CONCLUSION: GRP is significantly increased in patients with AGM after pancreatitis and is associated with increased levels of pro-inflammatory cytokines, as well as certain pancreatic and gut hormones. Detailed mechanistic studies are now warranted to investigate the exact role of GRP in derangements of glucose homeostasis following pancreatitis. PMID- 28912909 TI - The Use of Tranexamic Acid for Upper Gastrointestinal Bleeding by Medical and Surgical Intensivists: A Single Center Experience. AB - BACKGROUND: Tranexamic acid (TXA) may be beneficial in the management of upper gastrointestinal bleeding (UGIB). We sought to investigate how frequently intensivists at our academic institution use TXA for patients with UGIB, and to investigate whether the utilization rate of TXA differs between surgical and medical intensivists, and provide an updated literature review on the subject. METHODS: We performed a retrospective cohort study of patients admitted for UGIB to the surgical intensive care unit (SICU) and the medical intensive care unit (MICU) at our academic healthcare facility (University of Florida Health - Shands Hospital) from January 1, 2013 to December 31, 2016. The patients were categorized as receiving or not receiving TXA. The overall utilization rate of TXA was calculated, and the utilization rates for the MICU and SICU were compared using a two-sample test for equality of two proportions with continuity correction. RESULTS: The study cohort included a total of 1,829 patients with a diagnosis of UGIB. Of those, 988 were treated in the MICU and 841 were treated in the SICU. Of the 988 patients in the MICU, six received TXA (0.61%), while 10 (1.19%) of the 841 patients in the SICU received TXA. The overall utilization rate of TXA was 0.87%. The odds of receiving TXA in the SICU were 1.97 times greater than in the MICU (odds ratio (OR): 1.97, 95% confidence interval (CI): 0.74 - 5.2, P = 1.83). CONCLUSIONS: Our study suggests that TXA may be underused in the management of UGIB, and that the utilization rate does not differ significantly between surgical and medical intensivists. PMID- 28912910 TI - Prognostic Significance of Elevated Cardiac Troponin in Acute Gastrointestinal Bleeding. AB - BACKGROUND: Acute gastrointestinal bleeding (AGIB) is responsible for over 140,000 hospitalizations annually. Cardiovascular-related deaths account for 30% of the patients surviving the initial episode of AGIB. The purpose of this study was to identify the impact of elevated troponin on short-term mortality and length of stay (LOS) of these patients. METHODS: From July 2013 to July 2016, 290 patients admitted with a diagnosis of AGIB and who had cardiac troponin I measured within 24 h of presentation were retrospectively reviewed. Clinical variables including 30-day mortality, 30-day readmission and LOS were then compared between the groups of troponin elevation and no troponin elevation. RESULTS: The overall 30-day mortality among patients with AGIB was 6.5% (19/290). Cardiac troponin was elevated in 10% of patients (29/290). Among patients with normal troponin, 5% (13/261) died within 30 days. In patients with troponin elevation, 21% died in the same period (6/29, P = 0.001). The LOS was also higher in patients with troponin elevation (6 vs. 5 days, P = 0.02). There was no difference in 30-day readmission among the two groups. Past history of coronary artery disease, congestive heart failure, hypertension, aspirin use and elevated creatinine was more common in patients with troponin elevation. On multivariate analysis, troponin elevation on presentation is associated with increased mortality (odds: 5.50, CI: 1.73 - 17.47, P = 0.004). CONCLUSION: In patients admitted to the inpatient service with AGIB, elevated troponin I on presentation is associated with high short-term mortality and longer hospital stay. PMID- 28912911 TI - Doxycycline-Induced Acute Pancreatitis: A Rare Adverse Event. AB - Doxycycline is a broad-spectrum antibiotic belonging to the tetracycline group which acts by inhibiting bacterial protein synthesis. It is considered to be a relatively safe drug. We report a case of doxycycline-induced acute pancreatitis (DIAP) in an adult female patient who was started on the usual therapeutic dose 1 week before for acne vulgaris. The WHO causality assessment was possible, and the Naranjo scale confirmed it as "definite" adverse drug reaction. A brief literature review on case reports previously reporting DIAP has also been summarized. PMID- 28912912 TI - Splenic Abscess: An Unusual Complication of Colon Cancer. AB - Colon cancer is among the common malignancies. Common cancer-related complications are regional tumor extension, obstruction, and tumor perforation. Abscess formation is among the rare complications. We report a case of a 60-year old female who presented with shortness of breath and left upper quadrant pain and was diagnosed with splenic abscess associated with colon cancer. This type of presentation necessitates an early surgical intervention. PMID- 28912913 TI - Paraneoplastic Dermatomyositis Syndrome Presenting as Dysphagia. AB - Dermatomyositis (DM) is a rare autoimmune condition which predominantly affects females in the fifth and sixth decades of life. DM presents acutely or progressively as painless proximal skeletal muscle weakness and can be associated with a heliotropic rash around the eyes, and Gottron's papules on extensor surfaces of the hands. While the pathophysiology of DM is still unclear, abnormal T- and B-cell immune activity has been reported. DM has been associated with malignancy and has been shown to appear before, concurrently with, or after diagnosis of cancer. We report a 72-year-old female with renal clear cell carcinoma, breast cancer, and papillary serous carcinoma of the uterus, who presented with progressive weakness, 30 pound weight loss, and dysphagia over the past 3 months. She also reported difficulty in ambulating, facial rash, and inability to extend her fingers. Left bicep muscle biopsy and staining with nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) identified frequent myofibers with targetoid-like changes consistent with DM. Despite immunosuppression with intravenous corticosteroids, she did not respond to the treatment and a percutaneous gastrostomy tube was placed for enteral feeding. PMID- 28912914 TI - Intraductal Ultrasonography as a Local Assessment Before Magnetic Compression Anastomosis for Obstructed Choledochojejunostomy. AB - Magnetic compression anastomosis (MCA) has been developed as a non-surgical alternative treatment for biliary obstruction without serious complications. A 70 year-old woman who had undergone pancreaticoduodenectomy with modified Child reconstruction for pancreatic head cancer suffered from obstructed choledochojejunostomy with no recurrent findings 4 months after the operation. Cholangiography using the percutaneous transhepatic cholangiographic drainage (PTCD) and fluoroscopy revealed complete obstruction of the upper common bile duct, and the length of the obstruction was 7 mm. Intraductal ultrasonography (IDUS) showed fibrous heterogenous hyperechoic appearance without fluid collection, vessels or foreign bodies at the site of the obstruction. We performed choledochojejunostomy using the MCA technique. One magnet was inserted into the obstruction of the hepatic side through the PTCD fistula. Another was delivered endoscopically to the obstruction of the jejunal side. The two magnets were immediately attracted towards each other transmurally, and reanastomosis was confirmed 7 days after starting the compression. The magnets were easily retrieved endoscopically. A 16-Fr indwelling drainage tube was placed in the jejunum through the PTCD. The internal tube is still in place 6 months after reanastomosis, and no MCA-related complications have been observed. In conclusion, MCA is a safe, effective, low-invasive treatment for biliary obstruction, and IDUS is useful for the pretreatment assessment of feasibility and safety. PMID- 28912915 TI - Gastrointestinal Bleeding Successfully Treated Using Interventional Radiology. AB - Gastrointestinal (GI) bleeding is an emergency medical condition that leads to hemorrhagic shock or circulatory instability if left untreated. A mainstay for treating GI bleeding is endoscopic therapy; more than 90% of GI bleeding can be staunched by endoscopic hemostasis. However, patients with unstable hemodynamics or GI bleeding that cannot be controlled by endoscopy require transcatheter embolization or surgical intervention. The development of several devices and embolization agents that are used in interventional radiology (IVR) leads to safe and accessible treatment via IVR. If endoscopic treatment fails, IVR is the second strategy. Herein, we report cases of GI bleeding that were successfully treated by IVR and discuss the therapeutic strategy. PMID- 28912916 TI - Acute Liver Failure in a Patient Travelling From Asia: The Other Face of the Coin of Infectious Disease. AB - We present a case of a 63-year-old male who had travelled from South India to United Kingdom (UK) visiting relatives. He had developed episodes of diarrhea, vomiting and fevers while travelling and on assessment in hospital, mild abdominal distension was noted with rapid deterioration to hypovolemic shock. Initial blood test showed a low platelet count with deranged liver function tests (LFTs). It was noted that during admission to intensive care unit (ICU), blood continued to ooze from a previous surgical laparoscopy wound, central and arterial line access sites. Blood results revealed ongoing derangement of clotting and LFT. Computed tomography (CT) scan showed possible acute cholecystitis and a laparoscopy showed an ischemic-looking liver and gut but no significant gallbladder abnormality. The virology screen was positive for dengue virus antibodies IgM and IgG. The patient developed multi-organ failure and deteriorated despite intensive support. Post mortem showed fulminant hepatic failure and acute tubular necrosis of kidneys. PMID- 28912917 TI - The Low-Dose (7.5 mg/day) Pioglitazone Therapy. AB - Pioglitazone is one of thiazolidinedione derivatives, which stimulates nuclear peroxisome proliferator-activated receptor gamma and improves glucose and lipid metabolism and insulin sensitivity. A recent systematic review and meta-analysis showed that pioglitazone therapy was associated with a lower risk of major adverse cardiovascular events in patients with pre-diabetes and diabetes. Further, in a cohort study of patients with type 2 diabetes, pioglitazone therapy was associated with a statistically significant decrease in the risk of all-cause mortality. Despite these beneficial effects, the meta-analysis showed that pioglitazone therapy had higher risks of heart failure, bone fractures, edema and weight gain. To find out the efficacy and safety of the low-dose (7.5 mg/day) pioglitazone therapy, we reviewed the dose-response of pioglitazone on favorable effects and adverse effects due to pioglitazone, by searching the reports on effects of daily dose of 7.5 mg and/or 15 mg and/or 30 mg of pioglitazone. The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism, fatty liver, insulin resistance, and adiponectin as the standard- and high-dose pioglitazone therapy. Furthermore, the low-dose pioglitazone therapy may also show less adverse effects on weight gain, edema and heart failure as compared with the standard- and high-dose pioglitazone therapy. PMID- 28912918 TI - Prospective Identification of Oligoclonal/Abnormal Band of the Same Immunoglobulin Type as the Malignant Clone by Differential Location of M-Spike and Oligoclonal Band. AB - BACKGROUND: Serum and urine protein electrophoreses and immunofixation electrophoreses are the gold standards in diagnosing monoclonal gammopathy. Identification of oligoclonal bands in post-treatment patients has emerged as an important issue and recording the location of the malignant monoclonal peak may facilitate prospective identification of a new "monoclonal" spike as being distinct from the malignant peak. METHODS: We recorded the locations of monoclonal spikes in descriptive terms, such as being in the cathodal region, mid gamma region, anodal region, and beta region. The location of monoclonal or restricted heterogeneity bands in subsequent protein electrophoreses was compared to the location of the original malignant spike. RESULTS: In a patient with plasma cell myeloma, the original monoclonal IgG kappa band was located at the anodal end of gamma region. Post-treatment, an IgG kappa band was noted in mid gamma region and the primary malignant clone was not detectable by serum protein immunofixation electrophoresis (SIFE) in post-treatment sample. Even though the kappa/lambda ratio remained abnormal, we were able to recognize stringent complete response by noting the different location of the new IgG kappa band as a benign regenerative process. CONCLUSIONS: Recording the location of the malignant monoclonal spike facilitates the identification of post-treatment oligoclonal bands, prospectively. Recognizing the regenerative, benign, bands in post transplant patients facilitates the determination of stringent complete response despite an abnormal kappa/lambda ratio. PMID- 28912919 TI - Intravenous Carnitine Administration in Addition to Parenteral Nutrition With Lipid Emulsion May Decrease the Inflammatory Reaction in Postoperative Surgical Patients. AB - BACKGROUND: A prospective randomized study was performed to investigate the validity of intravenous carnitine administration during postoperative parenteral nutrition (PN) with lipid emulsion. METHODS: Patients undergoing surgery for gastric or colorectal cancer were enrolled in the study and were randomly divided into two groups (n = 8 in each group): 1) group L, who received a peripheral PN (PPN) solution of 7.5% glucose, 30% amino acid, and 20% lipid emulsion; and 2) group LC, who received the same PPN solution, as well as carnitine intravenously. PPN was performed from postoperative day (POD) 1 to POD4. Clinical and laboratory parameters were compared between the two groups; statistical significance was set at P < 0.05. RESULTS: Serum carnitine concentrations were significantly higher in group LC on POD3 (P < 0.01) and POD7 (P = 0.01). Postoperative changes in laboratory parameters and morbidity were comparable between the two groups. However, the decrease in C-reactive protein from POD3 to POD7 was significantly greater in group LC than in group L (P = 0.011). CONCLUSION: The results show that intravenous carnitine administration in addition to PN is safe and may be beneficial for recovery from postoperative inflammatory reactions. PMID- 28912920 TI - Microalbuminuria: Correlation With Prevalence and Severity of Coronary Artery Disease in Non-Diabetics. AB - BACKGROUND: Previous studies have shown that microalbuminuria (MAU) is an independent risk factor for cardiovascular diseases in diabetics, hypertensive patients and in the general population. However, the correlation of MAU with the severity of coronary artery disease (CAD) in non-diabetic patients has not been addressed in detail. This study aimed to investigate the relationship between MAU and severity of angiographically confirmed CAD in non-diabetic patients. METHODS: This was a cross-sectional study, which included 90 non-diabetic patients with documented CAD by coronary angiography. The ratio of urine albumin to creatinine was used to define MAU and severity of CAD was estimated using SYNTAX score. Patients were divided into two groups: group I that included patients without MAU and group II that included patients with MAU. RESULTS: Out of 90 non-diabetic CAD patients, 62 (68.9%) were in group I (MAU negative) and 28 (31.1%) were in group II (MAU positive). There was statistically significant difference in the median SYNTAX score between the groups (21 vs. 28, P < 0.001). The prevalences of double vessel CAD and triple vessel CAD were significantly higher in MAU positive group. There was a strong relationship between the presence of MAU and the extent and complexity of CAD (r = 0.094; P < 0.001). CONCLUSION: Thus, we conclude that patients with MAU have more severe angiographically detected CAD than those without MAU, and MAU exhibits a significant association with the presence and severity of CAD. PMID- 28912921 TI - Validation of Skeletal Muscle Volume as a Nutritional Assessment in Patients With Gastric or Colorectal Cancer Before Radical Surgery. AB - BACKGROUND: Recently, some studies have reported the importance of sarcopenia as a prognostic factor in patients with gastrointestinal cancer who have undergone surgery. We aimed to examine skeletal muscle volume for use in nutritional assessment of preoperative patients, and to compare the results with those of other conventional methods of nutritional assessment, such as biochemical or body composition values. METHODS: This was an open cohort study which examined skeletal muscle volume for use in nutritional assessment of preoperative patients. A total of 121 patients with gastrointestinal cancer who underwent radical surgery were enrolled in this study between June 1, 2008 and December 31, 2012. There were 39 and 82 patients with gastric and colorectal cancer, respectively. The primary outcome of this study was postoperative overall survival. The secondary outcomes were postoperative survival from cancer-related deaths, recurrences of cancer after surgery, postoperative complications, and postoperative hospital inpatient stay (measured in days). Univariate and multivariate analyses were used to identify the relevant factors for postoperative outcomes mentioned above. RESULTS: Skeletal muscle volume was a significant (hazard ratio (HR): 3.34, 95% confidence interval (CI): 1.21 - 9.17, P = 0.020) independent prognostic factor for cancer-related deaths in patients with gastric or colorectal cancer who had undergone surgery, and a marginally independent (HR: 2.48, 95% CI: 0.91 - 6.81, P = 0.077) factor that negatively contributed to overall survival in these patients. In contrast, the preoperative skeletal muscle volume was not correlated with the recurrence of cancer, and was not significantly correlated with the occurrence of severe complications after surgery or prolongation of hospitalization. CONCLUSIONS: The preoperative skeletal muscle volume was a significant prognostic factor in patients with gastric or colorectal cancers. Therefore, the estimation of skeletal muscle volume may be important for stable, long-term nutritional assessment in patients with gastrointestinal cancers. PMID- 28912922 TI - Obstetric Outcomes of Twin Pregnancies in Japanese Women Aged 40 and Older. AB - BACKGROUND: The aim of this study was to compare the obstetric outcomes of twin pregnancies between Japanese women aged >= 40 years and their younger counterparts aged 25 - 29. METHODS: This was a retrospective study of twin pregnancies managed at Japanese Red Cross Katsushika Maternity Hospital between 2002 and 2016. Women aged 40 and older at delivery (n = 117) were compared with women aged 25 - 29 at delivery (n = 536). RESULTS: Although the women >= 40 years old were more likely to have increased risks of HELLP (hemolytic, elevated liver enzymes and low platelet) syndrome and very low birth weight neonates, there were no measurable differences in obstetric outcomes such as hypertensive disorders, premature delivery and neonatal asphyxia between the two groups. CONCLUSION: Advanced maternal age did not seem to affect obstetric outcomes in twin pregnancies seriously. PMID- 28912923 TI - Lack of Needs Assessment in Cancer Survivorship Care and Rehabilitation in Hospitals and Primary Care Settings. AB - BACKGROUND: Formalized and systematic assessment of survivorship care and rehabilitation needs is prerequisite for ensuring cancer patients sufficient help and support through their cancer trajectory. Patients are often uncertain as to how to express and address their survivorship care and rehabilitation needs, and little is known about specific, unmet needs and the plans necessary to meet them. There is a call for both ensuring survivorship care and rehabilitation for cancer patients in need and further for documenting the specific needs related to the cancer disease and its treatment. Thus the aim of this study was to describe specific survivorship care and rehabilitation needs and plans as stated by patients with cancer at hospitals when diagnosed and when primary care survivorship care and rehabilitation begins. METHODS: Needs assessment forms from cancer patients at two hospitals and two primary care settings were analyzed. The forms included stated needs and survivorship care and rehabilitation plans. All data were categorized using the International Classification of Functioning, Disability and Health (ICF). RESULTS: Eighty-nine patients at hospitals and 99 in primary care, stated their needs. Around 50% of the patients completed a survivorship care and rehabilitation plan. In total, 666 (mean 7.5) needs were stated by hospital patients and 836 (mean 8.0) by those in primary care. The needs stated were primarily within the ICF component "body functions and structure", and the most frequent needs were (hospitals/primary care) fatigue (57%/67%), reduced muscle strength (55%/67%) and being worried (37%/36%). CONCLUSIONS: The results underpin an urgent need for a systematic procedure to assess needs in clinical practice where cancer patients are being left without survivorship care and rehabilitation needs assessment. Gaining knowledge on needs assessment and the detailed description of needs and plans can facilitate targeted interventions. The findings indicate an urgent need to change the practice culture to be systematic in addressing and identifying survivorship care needs among patients with cancer. Further the findings call for considering the development of a new needs assessment form with involvement of both patients and healthcare professionals. PMID- 28912924 TI - Relationship Between Serum Total Testosterone Concentration and Augmentation Index at Radial Artery in Japanese Postmenopausal Patients. AB - BACKGROUND: The significance of testosterone as a risk factor for cardiovascular disease (CVD) in females is controversial. This cross-sectional study aimed to elucidate the relationship between serum total testosterone concentration (T-T) and augmentation index at the radial artery (r-AIx) as a marker of arterial function in Japanese postmenopausal patients. METHODS: A total of 447 postmenopausal patients with traditional cardiovascular risk factors and/or a history of CVD (age (mean +/- standard deviation (SD)), 73 +/- 10 years) were enrolled. r-AIx was measured using tonometry, and the association between r-AIx and various clinical parameters, including T-T, was determined. RESULTS: r-AIx significantly increased (CVD vs. non-CVD: 99+/-11% vs. 91+/-11%, P < 0.001) and T T significantly decreased (CVD vs. non-CVD: 0.31 +/- 0.13 ng/mL vs. 0.49 +/- 0.23 ng/mL, P < 0.001) in patients with CVD than in those without CVD. A significant negative correlation (r = -0.48; P < 0.001) between r-AIx and T-T was observed. Furthermore, multiple regression analysis indicated that T-T (t value = -7.7; P < 0.001), height (t value = -5.3; P < 0.001), d-ROMs test as a marker of oxidative stress in vivo (t value = 3.2; P < 0.001), CVD (t value = 2.9; P < 0.01), and pulse rate (t value = -2.7; P < 0.01) were independent variables for r-AIx as a subordinate factor. CONCLUSION: This study revealed that low T-T is an important determining factor for an increase in r-AIx in Japanese postmenopausal patients. A prospective multicenter study with a large sample size is required to confirm the results of this study. PMID- 28912926 TI - A Rare Case of Atrial Metastasis From a Rectal Adenocarcinoma. AB - Colorectal cancers typically metastasize to the lymph nodes, liver or lungs. Metastasis to the heart is rare and although a few cases of cardiac metastases from colon cancer are described in the literature, cases of metastatic rectal cancer to the heart are far fewer. A 69-year-old woman with a history of rectal adenocarcinoma treated with neo-adjuvant chemotherapy and radiation, followed by resection and adjuvant chemotherapy, presented with increasing dyspnea on exertion and lower extremity edema 5 years after oncology follow-up. Echocardiography revealed a mass within the right atrium, which was biopsied and found to be consistent with metastatic rectal adenocarcinoma and a thrombus. The patient was deemed to be a poor surgical candidate given her co-morbidities and overall prognosis. Chemotherapy was offered and refused by the patient. The medical literature has a paucity of similar cases of rectal adenocarcinoma metastasizing to the right atrium. Further studies are needed to help guide standardized treatment options. PMID- 28912925 TI - Incretin Kinetics Before and After Miglitol in Japanese Patients With Late Dumping Syndrome. AB - BACKGROUND: In patients with late dumping syndrome following gastrectomy, it has been reported that hypoglycemia occurs due to inhibition of glucagon secretion as a result of excessive insulin production facilitated by an increase in glucagon like peptide-1 (GLP-1). METHODS: To determine the kinetics of incretins in Japanese patients with late dumping syndrome, an oral glucose tolerance test was carried out before and after miglitol administration, and the kinetics of insulin and incretins were analyzed. RESULTS: After miglitol administration, there was improvement of hypoglycemia and early phase insulin secretion, with persistent excessive insulin secretion being minimized. These findings revealed that miglitol inhibited rapid excessive influx of carbohydrates into the blood and persistent elevation of GLP-1, resulting in improvement of early phase insulin secretion and minimizing persistent excessive insulin secretion. CONCLUSIONS: Eating frequent small meals is generally effective for late dumping syndrome, but patients often find it difficult to continue such a regimen. Based on the present analysis of incretin kinetics, miglitol may be a useful treatment option for late dumping syndrome. PMID- 28912927 TI - The Sixth Vital Sign: Body Mass Index in Patients With Sickle Cell Disease. PMID- 28912928 TI - Method to Increase Undergraduate Laboratory Student Confidence in Performing Independent Research. PMID- 28912929 TI - Student Misconceptions about Plants - A First Step in Building a Teaching Resource. AB - Plants are ubiquitous and found in virtually every ecosystem on Earth, but their biology is often poorly understood, and inaccurate ideas about how plants grow and function abound. Many articles have been published documenting student misconceptions about photosynthesis and respiration, but there are substantially fewer on such topics as plant cell structure and growth; plant genetics, evolution, and classification; plant physiology (beyond energy relations); and plant ecology. The available studies of misconceptions held on those topics show that many are formed at a very young age and persist throughout all educational levels. Our goal is to begin building a central resource of plant biology misconceptions that addresses these underrepresented topics, and here we provide a table of published misconceptions organized by topic. For greater utility, we report the age group(s) in which the misconceptions were found and then map them to the ASPB - BSA Core Concepts and Learning Objectives in Plant Biology for Undergraduates, developed jointly by the American Society of Plant Biologists and the Botanical Society of America. PMID- 28912930 TI - Pedigree Go Fish. PMID- 28912931 TI - Laboratory Activity to Promote Student Understanding of UV Mutagenesis and DNA Repair. PMID- 28912932 TI - Engaging College Students by Singing the Science. PMID- 28912933 TI - A Model Approach to Public Engagement Training for Students in Developing Countries. PMID- 28912934 TI - Using Anthropomorphism and Fictional Story Development to Enhance Student Learning. PMID- 28912936 TI - Combination of Q-Switched Nd:YAG and Fractional Erbium:YAG Lasers in Treatment of Melasma: A Randomized Controlled Clinical Trial. AB - Introduction: Ablative and nonablative lasers have been used to treat melasma. We aimed to assess and compare the combining Q-switched Nd:YAG laser (QSNYL) and fractional erbium:YAG laser (FEYL) with QSNYL alone in treatment of melasma. Methods: This randomized controlled clinical trial was performed in our Research Center during 2013-2014. Women with melasma and without a history of keloid formation, hypersensitivity to hydroquinone, or pigmentary changes due to laser therapy were randomly allocated to receive four sessions of either QSNYL-FEYL combination or QSNYL alone. All patients received topical treatment with Kligman's formula. Before laser therapy and 4 weeks after the last treatment session, patients' skin was assessed for changes in skin color, melanin content, and erythema intensity of melasma lesions quantitatively. Results: Finally, 21 patients in QSNYL-FEYL and 20 in QSNYL group (mean age, 38.57 [5.60] and 42.60 [8.44] years, respectively) completed study. The skin color had become lighter in both groups (mean [SD] percentage change of 56.95 [40.29] and 29.25 [13.20] in QSNYL-FEYL and QSNYL groups, respectively) with significantly better results in QSNYL-FEYL group (P = 0.006). Percentage of decrease of melanin content was significantly higher in QSNYL-FEYL group (22.01 [10.67] vs. 7.69 [4.75]; P < 0.001). After adjustment for baseline values, the post treatment intensity of erythema was significantly lower in QSNYL-FEYL group (P < 0.001). The patients reported no adverse events. Conclusion: QSNYL-FEYL was significantly more effective in decreasing melanin content of lesions than QSNYL and led to a lighter skin. PMID- 28912937 TI - Relieving Pain in Oral Lesions of Pemphigus Vulgaris Using the Non-ablative, Non thermal, CO2 Laser Therapy (NTCLT): Preliminary Results of a Novel Approach. AB - Introduction: Pemphigus vulgaris (PV) is a chronic, serious autoimmune mucocutaneous bullous disease. Oral lesions in PV may be extremely painful. This pain may adversely affect the patients' oral intake and quality of life. This before-after clinical trial was designed to assess the pain relieving effects of single session of non-ablative, non-thermal CO2 laser therapy (NTCLT) in oral lesions of PV. Methods: Fifty painful oral lesions of fourteen patients with PV were illuminated by CO2 laser (power: 1 W, scanning the lesions with rapid circular motion of the handpiece) passing through a thick layer of transparent gel with high water content. The pain severity of the oral lesions was reported by the patients up to the fourth postoperative day. They were also asked to continue their existing systemic treatment during the course of this study as a precondition for the participation. Results: The severity of contact and non stimulate (non-contact) pain declined immediately and significantly after NTCLT (P < 0.001). The pain relieving effect was sustained during the four successive days of follow-up. The procedure was pain free and no kind of analgesics was required. Following NTCLT, there were no visible thermal complications such as destruction, ablation or irritation of the oral lesions. Conclusion: The results of the trial proposed that single session of NTCLT could immediately and significantly relieve pain in oral lesions of PV, without any visible thermal complications. PMID- 28912935 TI - Baicalin Attenuates Subarachnoid Hemorrhagic Brain Injury by Modulating Blood Brain Barrier Disruption, Inflammation, and Oxidative Damage in Mice. AB - In subarachnoid hemorrhagic brain injury, the early crucial events are edema formation due to inflammatory responses and blood-brain barrier disruption. Baicalin, a flavone glycoside, has antineuroinflammatory and antioxidant properties. We examined the effect of baicalin in subarachnoid hemorrhagic brain injury. Subarachnoid hemorrhage was induced through filament perforation and either baicalin or vehicle was administered 30 min prior to surgery. Brain tissues were collected 24 hours after surgery after evaluation of neurological scores. Brain tissues were processed for water content, real-time PCR, and immunoblot analyses. Baicalin improved neurological score and brain water content. Decreased levels of tight junction proteins (occludin, claudin-5, ZO-1, and collagen IV) required for blood-brain barrier function were restored to normal level by baicalin. Real-time PCR data demonstrated that baicalin attenuated increased proinflammatory cytokine (IL-1beta, IL-6, and CXCL-3) production in subarachnoid hemorrhage mice. In addition to that, baicalin attenuated microglial cell secretion of IL-1beta and IL-6 induced by lipopolysaccharide (100 ng/ml) dose dependently. Finally, baicalin attenuated induction of NOS-2 and NOX-2 in SAH mice at the mRNA and protein level. Thus, we demonstrated that baicalin inhibited microglial cell activation and reduced inflammation, oxidative damage, and brain edema. PMID- 28912938 TI - Comparison of Endovenous Laser and Radiofrequency Ablation in Treating Varices in the Same Patient. AB - Introduction: To compare endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in different legs in the same individual in patients with venous insufficiency. Methods: Sixty patients with bilateral saphenous vein insufficiency were included. EVLA or RFA was applied to one of the patient's legs and RFA or EVLA to the other leg. Results: EVLA and RFA complications were hyperemia at 20.7% and 31.0%, ecchymosis at 31.0% and 51.7% and edema at 27.6% and 65.5%, respectively. The rate of recanalization was 6.8% in the RFA group. No recanalization was observed in EVLA group. The level of patients satisfied with EVLA was 51.7%, compared to 31.0% for RFA, while 17.2% of patients were satisfied with both procedures. Times to return to daily activity were 0.9 days in the EVLA group and 1.3 days in the RFA group. Conclusion: EVLA procedure may be superior to RFA in certain respects. PMID- 28912939 TI - Effect of Er:YAG Laser and Sandblasting in Recycling of Ceramic Brackets. AB - Introduction: This study was performed to determine the shear bond strength of rebonded mechanically retentive ceramic brackets after recycling with Erbium Doped Yttrium Aluminum Garnet (Er:YAG) laser or sandblasting. Methods: Twenty eight debonded ceramic brackets plus 14 intact new ceramic brackets were used in this study. Debonded brackets were randomly divided into 2 groups of 14. One group was treated by Er:YAG laser and the other with sandblasting. All the specimens were randomly bonded to 42 intact human upper premolars. The shear bond strength of all specimens was determined with a universal testing machine at a crosshead speed of 0.5 mm/min until bond failure occurred. The recycled bracket base surfaces were observed under a scanning electron microscope (SEM). Analysis of variance (ANOVA) and Tukey tests were used to compare the shear bond strength of the 3 groups. Fisher exact test was used to evaluate the differences in adhesive remnant index (ARI) scores. Results: The highest bond strength belonged to brackets recycled by Sandblasting (16.83 MPa). There was no significant difference between the shear bond strength of laser and control groups. SEM photographs showed differences in 2 recycling methods. The laser recycled bracket appeared to have as well-cleaned base as the new bracket. Although the sandblasted bracket photographs showed no remnant adhesives, remarkable micro roughening of the base of the bracket was apparent. Conclusion: According to the results of this study, both Er:YAG laser and sandblasting were efficient to mechanically recondition retentive ceramic brackets. Also, Er:YAG laser did not change the design of bracket base while removing the remnant adhesives which might encourage its application in clinical practice. PMID- 28912940 TI - Technical Report on the Modification of 3-Dimensional Non-contact Human Body Laser Scanner for the Measurement of Anthropometric Dimensions: Verification of its Accuracy and Precision. AB - Introduction: Three-dimensional (3D) scanners are widely used in medicine. One of the applications of 3D scanners is the acquisition of anthropometric dimensions for ergonomics and the creation of an anthropometry data bank. The aim of this study was to evaluate the precision and accuracy of a modified 3D scanner fabricated in this study. Methods: In this work, a 3D scan of the human body was obtained using DAVID Laser Scanner software and its calibration background, a linear low-power laser, and one advanced webcam. After the 3D scans were imported to the Geomagic software, 10 anthropometric dimensions of 10 subjects were obtained. The measurements of the 3D scanner were compared to the measurements of the same dimensions by a direct anthropometric method. The precision and accuracy of the measurements of the 3D scanner were then evaluated. The obtained data were analyzed using an independent sample t test with the SPSS software. Results: The minimum and maximum measurement differences from three consecutive scans by the 3D scanner were 0.03 mm and 18 mm, respectively. The differences between the measurements by the direct anthropometry method and the 3D scanner were not statistically significant. Therefore, the accuracy of the 3D scanner is acceptable. Conclusion: Future studies will need to focus on the improvement of the scanning speed and the quality of the scanned image. PMID- 28912941 TI - The Effect of Er:YAG Laser Irradiation and Different Concentrations of Sodium Hypochlorite on Shear Bond Strength of Composite to Primary Teeth's Dentin. AB - Introduction: The aim of this study was to evaluate the effect of various concentrations of NaOCl on shear bond strength of composite resin to dentin of primary teeth, prepared with laser and bur. Methods: In this in vitro study, 48 primary molars were sectioned at mesiodistal direction and were randomly divided into 6 groups; G1: bur, G2: bur + NaOCl 2.5%, G3: bur + NaOCl 5.25%, G4: laser, G5: laser + NaOCl 2.5%, G6: laser + NaOCl 5.25%. One-Step Plus adhesive was applied after phosphoric acid gel and NaOCl over the dentin surfaces for all groups, and composite resin cylinders were bonded to the samples. After thermocycling, shear bond strengths of composite resin to dentin were measured and statistical analyses were done by means of t test and analysis of variance (ANOVA). Results: The mean shear bond strength showed no significant difference between the groups prepared with bur (13.82 +/- 3.49) and laser (14.18 +/- 3.65) (P > 0.05). The mean difference of shear bond strength between three groups G1, G2 and G3 and between G4, G5 and G6 were not statistically significant (P > 0.05). Scanning electron microscopy (SEM) figures showed an irregular surface in laser groups and fairly complete removal of smear layer from the orifices of the dentinal tubules, in the group in which NaOCl was used. Conclusion: The application of different concentrations of NaOCl does not significantly improve the bond strength in dentin surfaces prepared with laser or bur. PMID- 28912942 TI - Efficacy of Sodium Hypochlorite Activated With Laser in Intracanal Smear Layer Removal: An SEM Study. AB - Introduction: The purpose of the present study was to evaluate the different concentrations of sodium hypochlorite activated with laser in removing of the smear layer in the apical, middle, and coronal segments of root canal walls by scanning electron microscopy analysis. Methods: Sixty single-rooted human mandibular teeth were decoronated to a standardized length. The samples were prepared by using Race rotary system to size 40, 0.04 taper and divided into 4 equal groups (n = 15). Group 1, irrigated with EDTA 17% and 5.25% NaOCl, groups 2, 3 and 4, 1%, 2.5%, and 5% NaOCl activated with Nd:YAG laser, respectively. Teeth were split longitudinally and subjected to scanning electron microscope (SEM). Data were analyzed by Kruskal-Wallis, Mann-Whitney tests. P value of <0.05 was considered statistically significant. Results: Five percent NaOCl LAI (laser activated irrigation) showed best smear layer removal in test groups and the difference was statistically significant (P < 0.001). Control group (EDTA 17% and 5.25% NaOCl irrigation) showed significantly better outcomes in comparative with test groups (P < 0.001). In the apical third, compared to coronal and middle third, the canal walls were often contaminated by inorganic debris and smear layer. Conclusion: All different concentrations of sodium hypochlorite activated with laser have a positive effect on removing of smear layer. Sodium hypochlorite activated with laser removed smear layer more effectively at the coronal and middle third compared to the apical third. PMID- 28912943 TI - Assessment of Low-Level Laser Therapy Effects After Extraction of Impacted Lower Third Molar Surgery. AB - Introduction: The aim of this study was to assess the effect of low-level laser therapy (LLLT) on pain, swelling and maximum mouth opening in patients undergoing third molar surgery. Methods: A prospective, randomized double-blind study was undertaken on 44 patients at the Dental School, Ahvaz Jundishapur University of Medical Sciences, in 2015. A low-level laser was randomly applied on one of the two sides after surgery of 15 patients. The experimental side received 18 J/cm2 of energy density, wavelength of 980 nm, and output power of 1.8 W. On the control side, a hand-piece was applied intra-orally, but laser was not activated. In addition, in order to evaluate trismus, 13 patients were treated by unilateral laser therapy and 16 patients did not receive laser therapy at all. The laser was administered intraorally on two points of vestibular and lingual sides at 1 cm from the surgery site, and extraorally at the emergence of the masseter muscle, immediately after surgery, and repeated 24 hours later. The pain, swelling and maximum mouth opening (MMO) were compared between the two groups at 24 hours and a week after surgery. Results: The mean score of pain 24 hours after surgery in the laser therapy group (2.3 +/- 3.5) was significantly lower than the mean score of pain in the drug therapy (4.19 +/- 3.09) (P = 0.036). Moreover, the mean score of pain at one week after surgery in the laser therapy group (0.13 +/- 2.33) was significantly lower than the drug therapy group (1.43 +/- 2.45) (P = 0.046). The amount of swelling according to different measurements did not significantly differ between the two groups neither at 24 hours nor at 1 week after surgery. Conclusion: Our findings showed that LLLT was useful in reducing pain and could slightly reduce swelling compared to drug therapy in impacted third molar surgery. PMID- 28912944 TI - Photodynamic Therapy With Bengal Rose and Derivatives Against Leishmania amazonensis. AB - Introduction: The treatment of cutaneous leishmaniasis (CL) is based primarily on the use of pentavalent antimonials, which may lead to many side effects limiting their use. Photodynamic therapy (PDT) is an alternative for the treatment of CL, and some xanthene dyes have the potential for use in PDT. Methods: The xanthenes rose bengal B (RB) and its derivatives rose bengal methyl ester (RBMET), and butyl ester (RBBUT) were analyzed for leishmanicidal activity against promastigotes and intracellular amastigotes of Leishmania amazonensis. Cytotoxicity was assessed in J774.A1 macrophages. Results: RB derivates RBMET (IC50 9.83 MUM), and RBBUT (IC50 45.08 MUM) showed leishmanicidal activity, however, were toxic to J774.A1 macrophages, resulting in low selectivity index. Conclusion: The RBMET and RBBUT showed to be effective against the L. amazonensis and the low selectivity index presented may not be a limitation for their use in PDT to CL treatment. PMID- 28912945 TI - Comparison of Er:YAG Laser and Ultrasonic Scaler in the Treatment of Moderate Chronic Periodontitis: A Randomized Clinical Trial. AB - Introduction: Periodontitis is an inflammatory periodontal disease that leads to tooth loss. Recently laser has been introduced as an alternative treatment for periodontitis. The aim of the present study was to compare the effect of Erbium doped Yttrium Aluminum Garnet (Er:YAG) laser with ultrasonic scaler in patients with moderate chronic periodontitis. Methods: In this randomized single-blind clinical trial, 27 patients with moderate chronic periodontitis were selected. One quadrant of the patients was treated by Er:YAG laser and the other one by ultrasonic scaler. Clinical parameters, including periodontal pocket depth (PPD), papillary bleeding index (PBI) and clinical attachment level (CAL) were measured before, as well as 6 and 12 weeks after treatment. Data were analyzed by SPSS 20 software using Friedman test, paired t test, independent t test and Mann-Whitney test. The significance level was set at 0.05. Results: The means of clinical parameters in both groups were significantly improved in the first and second follow-ups (P < 0.001). Although the means of PPD, PBI and CAL were slightly higher in the laser group than in the ultrasonic group, the differences were not statistically significant between these two groups (P > 0.05). Conclusion: Although both ultrasonic scaler and Er:YAG laser could effectively improve clinical periodontal parameters, the results did not reveal the superiority of Er:YAG laser over ultrasonic scaler or vice versa. PMID- 28912946 TI - Crosslinking method of hyaluronic-based hydrogel for biomedical applications. AB - In the field of tissue engineering, there is a need for advancement beyond conventional scaffolds and preformed hydrogels. Injectable hydrogels have gained wider admiration among researchers as they can be used in minimally invasive surgical procedures. Injectable gels completely fill the defect area and have good permeability and hence are promising biomaterials. The technique can be effectively applied to deliver a wide range of bioactive agents, such as drugs, proteins, growth factors, and even living cells. Hyaluronic acid is a promising candidate for the tissue engineering field because of its unique physicochemical and biological properties. Thus, this review provides an overview of various methods of chemical and physical crosslinking using different linkers that have been investigated to develop the mechanical properties, biodegradation, and biocompatibility of hyaluronic acid as an injectable hydrogel in cell scaffolds, drug delivery systems, and wound healing applications. PMID- 28912947 TI - Friction massage versus kinesiotaping for short-term management of latent trigger points in the upper trapezius: a randomized controlled trial. AB - BACKGROUND: Latent trigger points in the upper trapezius muscle may disrupt muscle movement patterns and cause problems such as cramping and decreased muscle strength. Because latent trigger points may spontaneously become active trigger points, they should be addressed and treated to prevent further problems. In this study we compared the short-term effect of kinesiotaping versus friction massage on latent trigger points in the upper trapezius muscle. METHODS: Fifty-eight male students enrolled with a stratified sampling method participated in this single blind randomized clinical trial (Registration ID: IRCT2016080126674N3) in 2016. Pressure pain threshold was recorded with a pressure algometer and grip strength was recorded with a Collin dynamometer. The participants were randomly assigned to two different treatment groups: kinesiotape or friction massage. Friction massage was performed daily for 3 sessions and kinesiotape was used for 72 h. One hour after the last session of friction massage or removal of the kinesiotape, pressure pain threshold and grip strength were evaluated again. RESULTS: Pressure pain threshold decreased significantly after both friction massage (2.66 +/- 0.89 to 2.25 +/- 0.76; P = 0.02) and kinesiotaping (2.00 +/- 0.74 to 1.71 +/- 0.65; P = 0.01). Grip strength increased significantly after friction massage (40.78 +/- 9.55 to 42.17 +/- 10.68; P = 0.03); however there was no significant change in the kinesiotape group (39.72 +/- 6.42 to 40.65 +/- 7.3; P = 0.197). There were no significant differences in pressure pain threshold (2.10 +/- 0.11 & 1.87 +/- 0.11; P = 0.66) or grip strength (42.17 +/- 10.68 & 40.65 +/- 7.3; P = 0.53) between the two study groups. CONCLUSIONS: Friction massage and kinesiotaping had identical short-term effects on latent trigger points in the upper trapezius. Three sessions of either of these two interventions did not improve latent trigger points. TRIAL REGISTRATION: Registration ID in IRCT: IRCT2016080126674N3. PMID- 28912948 TI - Outbreak of Fusarium oxysporum infections in children with cancer: an experience with 7 episodes of catheter-related fungemia. AB - BACKGROUND: Fusarium species are widely spread in nature as plant pathogens but are also able to cause opportunistic fungal infections in humans. We report a cluster of Fusarium oxysporum bloodstream infections in a single pediatric cancer center. METHODS: All clinical and epidemiological data related to an outbreak involving seven cases of fungemia by Fusarium oxysporum during October 2013 and February 2014 were analysed. All cultured isolates (n = 14) were identified to species level by sequencing of the TEF1 and RPB2 genes. Genotyping of the outbreak isolates was performed by amplified fragment length polymorphism fingerprinting. RESULTS: In a 5-month period 7 febrile pediatric cancer patients were diagnosed with catheter-related Fusarium oxysporum bloodstream infections. In a time span of 11 years, only 6 other infections due to Fusarium were documented and all were caused by a different species, Fusarium solani. None of the pediatric cancer patients had neutropenia at the time of diagnosis and all became febrile within two days after catheter manipulation in a specially designed room. Extensive environmental sampling in this room and the hospital did not gave a clue to the source. The outbreak was terminated after implementation of a multidisciplinary central line insertion care bundle. All Fusarium strains from blood and catheter tips were genetically related by amplified fragment length polymorphism fingerprinting. All patients survived the infection after prompt catheter removal and antifungal therapy. CONCLUSION: A cluster with, genotypical identical, Fusarium oxysporum strains infecting 7 children with cancer, was most probably catheter-related. The environmental source was not discovered but strict infection control measures and catheter care terminated the outbreak. PMID- 28912949 TI - A comprehensive analysis on child mortality and its determinants in Bangladesh using frailty models. AB - BACKGROUND: Bangladesh has experienced a significant reduction of child mortality over the past decades which helped achieve the Millennium Development Goal 4 (MDG 4) target. But the mortality among under-5 aged children is still relatively high and it needs a substantial effort to achieve the Sustainable Development Goal (SDG) target and decelerate the current rate of under-5 mortality. At this stage, it is hence important to explore the trend and determinants of under-5 mortality in order to reduce the vulnerability of child's survival. The aim of this study is to explore the trends and identify the factors associated with mortality in children aged less than 5 years in Bangladesh. METHODS: Data from three repeatedly cross-sectional Bangladesh Demographic and Health Surveys (BDHSs) for the year 2007, 2011 and 2014 were used. A stratified two-stage sampling method was used to collect information on child and maternal health in these surveys. Cox's proportional hazards models with community and mother level random effects (or frailty models) were fitted to identify the associated factors with under five mortality. RESULTS: Our study reveals that urban-rural disparity in child mortality has decreased over the time. The frailty models revealed that the combined effect of birth order and preceding birth interval length, sex of the child, maternal age at birth, mother's working status, parental education were the important determinants associated with risk of child mortality. The risk of mortality also varied across divisions with Sylhet division being the most vulnerable one. Moreover, significant and sizable frailty effects were found which indicates that the estimations of the unmeasured and unobserved mother and community level factors on the risk of death were substantively important. CONCLUSION: Our study suggests that community-based educational programs and public health interventions focused on birth spacing may turn out to be the most effective. Moreover, unobserved community and familial effects need to be considered along with significant programmable determinants while planning for the child survival program. PMID- 28912950 TI - Quality improvement regarding handoff. AB - BACKGROUND AND OBJECTIVES: Previous studies have emphasized the importance of effectual communication during patient handoffs. The objectives of this study were to (1) implement a resident-driven quality improvement project to improve handoffs by including key elements that are necessary for a safe and effective handoff. We chose to use the IPASS (illness severity, patient summary, action items, situation awareness and contingency planning, synthesis by receiver) mnemonic as our standardized handoff model; (2) Consider balancing measures in an effort to be aware of any negative effects of our interventions on resident satisfaction with the system. METHODS: A senior resident established a quality improvement team which developed an AIM statement (a written, measurable, and time-sensitive description of the goal of a quality improvement team) and key drivers. A survey was administered to residents regarding their opinions about the handoff process. Tracking of whether or not handoffs included the component IPASS elements was performed over an 11-month period. During this time frame, three Plan-Do-Study-Act cycles were conducted. The first was an educational series involving lecture and role playing. The second was printed cards listing appropriate handoff elements. Intervention three was development of a tool and method to decrease nurse interruptions during handoff. RESULTS: Inclusion of six key elements of handoffs improved as follows. Illness severity improved from 5% to 97%, diagnosis from 60% to 100%, patient summary from 71% to 100%, contingency planning from 10% to 100%, action list from 23% to 100%, and receiver synthesis from 0% to 97%. Balancing measures showed the residents were more satisfied with the new system and found it to be more effective at providing a safe transition of care. CONCLUSION: Implementation of a resident-driven multidisciplinary IPASS handoff system resulted in improved inclusion of key handoff elements and increased resident satisfaction. PMID- 28912951 TI - The frequency and severity of epistaxis in children with sickle cell anaemia in eastern Uganda: a case-control study. AB - BACKGROUND: There are a paucity of data on epistaxis as it pertains to sickle cell anaemia. Some case studies suggest epistaxis to be a significant complication in patients with sickle cell anaemia in sub-Saharan Africa; however, no robust studies have sought to establish the epidemiology or pathophysiology of this phenomenon. METHODS: We conducted a case-control study with the aim of investigating the importance of epistaxis among children presenting with sickle cell anaemia at the Mbale Regional Referral Hospital in eastern Uganda. Cases were children aged 2-15 years with an existing diagnosis of laboratory confirmed sickle cell anaemia, while controls were children without sickle cell anaemia who were frequency matched to cases on the basis of age group and gender. The frequency and severity of epistaxis was assessed using a structured questionnaire developed specifically for this study. Odds ratios controlled for age group and gender were calculated using unconditional logistic regression. RESULTS: A total of 150 children were included, 73 children with sickle cell anaemia and 77 children without sickle cell anaemia. The overall prevalence of epistaxis among children with sickle cell anaemia and children without sickle cell anaemia was 32.9 and 23.4% respectively. The case-control odds ratios for epistaxis, recurrent epistaxis and severe epistaxis were, 1.6 (95%CI 0.8-3.4; p = 0.2), 7.4 (1.6-34.5; 0.01), and 8.3 (1.0-69.8; 0.05) respectively. CONCLUSIONS: Our results suggest that in eastern Uganda, children with sickle cell anaemia experience epistaxis more frequently and with greater severity than children without sickle cell anaemia. Further studies are indicated to confirm this conclusion and investigate aetiology. PMID- 28912952 TI - Noncontiguous finished genome sequences and descriptions of 'Paenibacillus bouchesdurhonensis,' 'Paenibacillus rubinfantis,' 'Paenibacillus senegalimassiliensis' and 'Paenibacillus tuaregi' identified by culturomics. AB - Microbial culturomics represents a completely new approach to investigate microbial diversity by using different optimized culture conditions, mass spectrometry, genome sequencing and annotation and phenotypic description that allow for an extensive characterization of new species and the study of the human microbiome. Here we present four new species within the genus Paenibacillus: 'Paenibacillus bouchesdurhonensis' strain Marseille-P3071T, 'Paenibacillus rubinfantis' strain MT18T, 'Paenibacillus senegalimassiliensis' strain SIT18T and 'Paenibacillus tuaregi' strain Marseille-P2472T, which are all facultatively aerobic and Gram-positive bacilli. PMID- 28912953 TI - Psychological effects of a disastrous hydrogen fluoride spillage on the local community. AB - BACKGROUND: On September 27, 2012, at 3:43 pm, a hydrogen fluoride spill occurred in a manufacturing plant located at the 4th complex of the Gumi National Industrial Complex in Gumi City, South Korea. The present study aimed to evaluate the psychological effects of the hydrogen fluoride spill on the members of the community and to investigate their relationships with physical symptoms and changes in psychological effects occurring as time passed after the accident. METHODS: The 1st phase involved a survey of 1359 individuals that was conducted 1 month after the spill, and the 2nd phase involved a survey of 711 individuals that was conducted 7 months after the accident. The questionnaires included items for assessing demographic characteristics, hydrogen fluoride exposure level, physical symptoms, and psychological status. Physical symptoms were assessed to determine the persistence of irritations. Psychological status was assessed to investigate the impact of event level using the Impact of Event Scale - Revised Korean version (IES-R-K), and the anxiety level was assessed using the Beck Anxiety Inventory (BAI). RESULTS: As the hydrogen fluoride exposure level increased, the impact of event and anxiety levels increased significantly both 1 and 7 months after the accident (p < 0.05). The mean score of the impact of event levels decreased significantly from 33.33 +/- 14.64 at 1 month after the accident to 28.68 +/- 11.80 at 7 months after the accident (p < 0.05). The mean score of the anxiety levels increased significantly from 5.16 +/- 6.59 at 1 month after the accident to 6.79 +/- 8.41 at 7 months after the accident (p < 0.05). The risk of persistent physical symptoms at 7 months after the accident was significantly higher in females. The risk of persistent physical symptoms also increased significantly, with increasing age, hydrogen fluoride exposure, and impact of event levels (p < 0.05). CONCLUSIONS: The present study found that the impact of event level and anxiety level increased with increasing hydrogen fluoride exposure. Anxiety levels persisted even after time passed. The risk of persistent physical symptoms at 7 months after the accident was higher in females, and it increased with increasing age, hydrogen fluoride exposure level, and impact of event levels. PMID- 28912954 TI - Evaluation of the current landscape of respiratory nurse specialists in the UK: planning for the future needs of patients. AB - INTRODUCTION: The National Health Service currently faces significant challenges and must optimise effective workforce planning and management. There are increasing concerns regarding poor workforce planning for respiratory medicine; a greater understanding of the role of respiratory nurse specialists will inform better workforce planning and management. METHODS: This was a survey study. Two surveys were administered: an organisational-level survey and an individual respiratory nurse survey. RESULTS: There were 148 and 457 respondents to the organisational and individual nurse survey, respectively. Four main themes are presented: (1) breadth of service provided; (2) patient care; (3) work environment; and (4) succession planning. The majority of work conducted by respiratory nurse specialists relates to patient care outside the secondary care setting including supporting self-management in the home, supporting patients on home oxygen, providing hospital-at-home services and facilitating early discharge from acute care environments. Yet, most respiratory nursing teams are employed by secondary care trusts and located within acute environments. There was evidence of multidisciplinary working, although integrated care was not prominent in the free-text responses. High workload was reported with one-quarter of nursing teams short-staffed. Respiratory nurses reported working unpaid extra hours and a lack of administrative support that often took them away from providing direct patient care. Nearly half of the present sample either plan to retire or are eligible for retirement within 10 years. CONCLUSIONS: This survey report provides a current snapshot of the respiratory nurse specialist workforce in the UK. This workforce is an ageing population; the results from this survey can be used to inform succession planning and to ensure a viable respiratory nurse specialist workforce in future. PMID- 28912956 TI - Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus. AB - BACKGROUND: The cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM). METHODS: Fifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross over trial and received 28 days of oral SRT2104 (2.0 g/day) or placebo. Forearm vasodilatation (measured during intrabrachial bradykinin, acetylcholine and sodium nitroprusside infusions) as well as markers of glycaemic control, lipid profile, plasma fibrinolytic factors, and markers of platelet-monocyte activation, were measured at baseline and at the end of each treatment period. RESULTS: Lipid profile and platelet-monocyte activation were similar in both treatment arms (p>0.05 for all). Forearm vasodilatation was similar on exposure to acetylcholine and sodium nitroprusside (p>0.05, respectively). Bradykinin induced vasodilatation was less during treatment with SRT2104 versus placebo (7.753vs9.044, respectively, mean difference=-1.291,(95% CI -2.296 to -0.285, p=0.012)). Estimated net plasminogen activator inhibitor type 1 antigen release was reduced in the SRT2104 arm versus placebo (mean difference=-38.89 ng/100 mL tissue/min, (95% CI -75.47, to -2.305, p=0.038)). There were no differences in other plasma fibrinolytic factors (p>0.05 for all). After 28 days, SRT2104 exposure was associated with weight reduction (-0.93 kg (95% CI -1.72 to -0.15), p=0.0236), and a rise in glycated haemoglobin (5 mmol/mol or 0.48% (0.26 to 0.70), p=0.004). CONCLUSIONS: In people with T2DM, SRT2104 had inconsistent, predominantly neutral effects on endothelial and fibrinolytic function, and no discernible effect on lipids or platelet function. In contrast, weight loss was induced along with deterioration in glycaemic control, suggestive of potentially important metabolic effects. CLINICAL TRIAL REGISTRATION: NCT01031108; Results. PMID- 28912957 TI - Characteristics of rare and private deletions identified in phenotypically normal individuals. AB - Genomic copy number variations (CNVs) identified through chromosomal microarray testing must be validated to confirm whether they are pathogenically and functionally relevant to their respective clinical features. Although larger deletions have a higher probability to be pathogenic, this is not always true. Phenotypically normal individuals showed five CNV deletions larger than 1.5 Mb. The genes related to autosomal dominant trait were absent within these CNV deletions. PMID- 28912955 TI - Targeting aspirin resistance with nutraceuticals: a possible strategy for reducing cardiovascular morbidity and mortality. PMID- 28912958 TI - A nurse-delivered mental health intervention for obstetric fistula patients in Tanzania: results of a pilot randomized controlled trial. AB - BACKGROUND: Obstetric fistula has severe psychological consequences, but no evidence-based interventions exist to improve mental health in this population. This pilot trial evaluated a psychological intervention for women receiving surgical care for obstetric fistula. METHODS: A parallel two-armed pilot RCT was conducted between 2014 and 2016. The intervention was six individual sessions, based on psychological theory and delivered by a nurse facilitator. The study was conducted at a tertiary hospital in Moshi, Tanzania. Women were eligible if they were over age 18 and admitted to the hospital for surgical repair of an obstetric fistula. Sixty participants were randomized to the intervention or standard of care. Surveys were completed at baseline, post-treatment (before discharge), and 3 months following discharge. Standardized scales measured depression, anxiety, traumatic stress, and self-esteem. Feasibility of an RCT was assessed by participation and retention. Feasibility and acceptability of the intervention were assessed by fidelity, attendance, and participant ratings. Potential efficacy was assessed by exploratory linear regression and clinical significance analysis. RESULTS: Eighty-five percent met criteria for mental health dysfunction at enrollment. All eligible patients enrolled, with retention 100% post and 73% at 3 months. Participants rated the intervention acceptable and beneficial. There were sharp and meaningful improvements in mental health outcomes over time, with no evidence of differences by condition. CONCLUSIONS: A nurse-delivered mental health intervention was feasible to implement as part of in-patient clinical care and regarded positively. Mental health treatment in this population is warranted given high level of distress at presentation to care. TRIAL REGISTRATION: ClinicalTrials.Gov NCT01934075. PMID- 28912959 TI - Research protocol for a complex intervention to support hearing and vision function to improve the lives of people with dementia. AB - BACKGROUND: Hearing and vision impairments are among the most common and disabling comorbidities in people living with dementia. Intervening to improve sensory function could be a means by which the lives of people living with dementia may be improved. However, very few studies have tried to ameliorate outcomes in dementia by improving sensory function. This paper describes the multi-step development of a new intervention designed to support hearing and vision function in people living with dementia in their own homes. At the end of the development programme, it is anticipated that a 'sensory support' package will be ready for testing in a full scale randomised controlled trial. METHODS: This programme is based on the process of 'intervention mapping' and comprises four integrated steps, designed to address the following: (1) scoping the gaps in understanding, awareness and service provision for the hearing and/or vision impairment care needs of people with dementia using a systematic literature review and Expert Reference Group; (2) investigating the support care needs through a literature search, stakeholder surveys, focus groups, semi-structured interviews and an Expert Reference Group, leading to a prototype sensory support package; (3) refining the prototype by additional input from stakeholders using focus groups and semi-structured interviews; and (4) field testing the draft intervention using an open-labelled, non-randomised feasibility study, integrating feedback from people with dementia and their significant others to develop the final intervention ready for full scale definitive trialling. Input from the 'patient and public voice' is a cornerstone of the work and will interlink with each step of the development process. The programme will take place in study centres in Manchester, Nicosia and Bordeaux. DISCUSSION: Quantitative and qualitative data analyses will be employed, dependent upon the sub-studies in question. Data from the steps will be integrated with consideration given to weighting of evidence for each step of the programme. This programme represents the logical development of a complex intervention to fulfil an unmet need. It is based on a theoretical framework and will lead to a subsequent full scale efficacy trial. The challenges in integrating the data and addressing the contextual issues across study sites will be scrutinised. PMID- 28912960 TI - Influence of disease activity on RA treatment choices in countries with restricted access to expensive, innovative drugs: a discrete choice experiment among rheumatologists. AB - OBJECTIVE: To assess the influence of disease activity of patients with rheumatoid arthritis on treatment choices of rheumatologists in countries with restricted access to expensive, innovative drugs. METHODS: Rheumatologists from Hungary, Romania and UK were invited to complete two consecutive discrete choice experiments with hypothetical drug treatments for two different patient profiles: high and moderate disease activity. Rheumatologists were asked to choose repeatedly between two unlabelled treatment options that differed in five attributes: efficacy (expected improvement and achieved disease activity state), safety (probability of serious adverse events), patient's preference (level of agreement), total medication costs and cost-effectiveness. A heteroscedastic discrete choice model using interaction terms between attribute levels and patient profiles (binary variable) was used to assess the preferences of rheumatologists towards each attribute and the influence of the patient profile. RESULTS: Overall, 148 rheumatologists completed the survey (46% females, mean age 49 years, 49% academic). For both patient profiles, efficacy dominated the treatment choice over patient's preference, safety and economic aspects. However, for patients with high compared with moderate disease activity, the importance of drug efficacy significantly increased (from 48% for moderate to 57% for high disease activity), whereas the importance of patient's preference significantly decreased (from 15% to 11%). No significant differences were observed for economic and safety considerations. CONCLUSION: Rheumatologists were willing to give up some efficacy to account for patient's preference when choosing treatments for patients with moderate compared to high disease activity. Disease activity however did not influence importance of economic aspects in treatment choices. PMID- 28912961 TI - TRPA1 expression is downregulated by dexamethasone and aurothiomalate in human chondrocytes: TRPA1 as a novel factor and drug target in arthritis. PMID- 28912962 TI - Gene panel sequencing in Brazilian patients with retinitis pigmentosa. AB - BACKGROUND: Retinal dystrophies constitute a group of diseases characterized by clinical variability and pronounced genetic heterogeneity. Retinitis pigmentosa is the most common subtype of hereditary retinal dystrophy and is characterized by a progressive loss of peripheral field vision (Tunnel Vision), eventual loss of central vision, and progressive night blindness. The characteristics of the fundus changes include bone-spicule formations, attenuated blood vessels, reduced and/or abnormal electroretinograms, changes in structure imaged by optical coherence tomography, and subjective changes in visual function. The different syndromic and nonsyndromic forms of retinal dystrophies can be attributed to mutations in more than 250 genes. Molecular diagnosis for patients with retinitis pigmentosa has been hampered by extreme genetic and clinical heterogeneity between retinitis pigmentosa and other forms of retinal dystrophies. Next generation sequencing (NGS) technologies are among the most promising techniques to identify pathogenic variations in retinal dystrophies. PURPOSE: The purpose of this study was to discover the molecular diagnosis for Brazilian patients clinically diagnosed with a retinitis pigmentosa pattern of inheritance by using NGS technologies. MATERIALS AND METHODS: Sixteen patients with the clinical diagnosis of retinitis pigmentosa were included in the study. Their DNA was sequenced in a panel with 132 genes related to retinal dystrophies using the Illumina(r) platform. Sequence analysis and variation calling was performed using Soft Genetics(r), NextGene, and Geneticist Assistant software. The criteria for pathogenicity analysis were established according to the results of prediction programs (Polyphen 2, Mutation taster and MetaCoreTM) and comparison of pathogenic variations found with databases. RESULTS: The identified potentially pathogenic variations were all confirmed by Sanger sequencing. There were 89 variations predicted as pathogenic, but only 10 of them supported the conclusion of the molecular diagnosis. Five of the nine patients were autosomal dominant RP (56%), two (22%) were autosomal recessive RP, and two (22%) were X-linked RP. Nine of the 16 patients (56%) had probably positive or positive results. CONCLUSION: The Next Generation Sequencing used in this study allowed the molecular diagnosis to be confirmed in 56% of the patients and clarified the inheritance pattern of the patient's retinal dystrophies. PMID- 28912963 TI - Hallmarks of glioblastoma: a systematic review. AB - Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained unchanged since the implementation of the STUPP regimen in 2005 with concomitant radio-/chemotherapy and adjuvant chemotherapy with temozolomide. In the context of Hanahan and Weinberg's six hallmarks and two emerging hallmarks of cancer, we discuss up-to-date status and recent research in the biology of GBM. We discuss the clinical impact of the research results with the most promising being in the hallmarks 'enabling replicative immortality', 'inducing angiogenesis', 'reprogramming cellular energetics' and 'evading immune destruction'. This includes the importance of molecular diagnostics according to the new WHO classification and how next generation sequencing is being implemented in the clinical daily life. Molecular results linked together with clinical outcome have revealed the importance of the prognostic biomarker isocitratedehydrogenase (IDH), which is now part of the diagnostic criteria in brain tumours. IDH is discussed in the context of the hallmark 'reprogramming cellular energetics'. O-6-methylguanine-DNA methyltransferase status predicts a more favourable response to treatment and is thus a predictive marker. Based on genomic aberrations, Verhaak et al have suggested a division of GBM into three subgroups, namely, proneural, classical and mesenchymal, which could be meaningful in the clinic and could help guide and differentiate treatment decisions according to the specific subgroup. The information achieved will develop and improve precision medicine in the future. PMID- 28912965 TI - Medically Important Parasites Carried by Cockroaches in Melong Subdivision, Littoral, Cameroon. AB - Cockroaches have been recognized as mechanical vectors of pathogens that can infest humans or animals. A total of 844 adult cockroaches (436 males and 408 females) were caught. In the laboratory, cockroaches were first washed in saturated salt solution to remove ectoparasites and then rinsed with 70% alcohol, dried, and dissected for endoparasites. An overall transport rate of 47.39% was recorded. Six genera of parasites were identified. These were Ascaris (33.76%), Trichuris (11.97%), Capillaria (6.16%), Toxocara (4.86%), Hook Worm (4.86%), and Eimeria (2.73%). The parasites were more recorded on the external surface (54.27%) of cockroaches than in the internal surface (GIT, 38.51%). The same tendency was obtained between sexes with female cockroaches having a higher transport rate (36.69%). Cockroaches caught in toilets carried more parasites (31.99%) as compared to those from kitchens (22.63%) and houses (11.14%). Almost all encountered parasites were recognized as responsible of zoonosis and they can be consequently released in nature by hosts and easily disseminated by cockroaches as mechanical vectors. Sanitary education, reenforcement of worms' eradication programs, and the fight against these insects remain a necessity in the Melong Subdivision. PMID- 28912964 TI - Is the South African Triage Scale valid for use in Afghanistan, Haiti and Sierra Leone? AB - OBJECTIVE: To assess the validity of the South African Triage Scale (SATS) in four Medecins Sans Frontieres (MSF)-supported emergency departments (ED, two trauma-only sites, one mixed site (both medical and trauma cases) and one paediatric-only site) in Afghanistan, Haiti and Sierra Leone. METHODS: This was a retrospective cohort study conducted between June 2013 and June 2014. Validity was assessed by comparing patients' SATS ratings with their final ED outcome (ie, hospital admission, death or discharge). RESULTS: In the two trauma settings, the SATS demonstrated good validity: it accurately predicted an increase in the likelihood of mortality and hospitalisation across incremental acuity levels (p<0.001) and ED outcomes for 'green' and 'red' patients matched the predicted ED outcomes in 84%-99% of cases. In the mixed ED, the SATS was able to predict an incremental increase in hospitalisation (p<0.001) across both trauma and non trauma cases. In the paediatric-only settings, SATS was able to predict an incremental increase in hospitalisation in the non-trauma cases only (p<0.001). However, 87% (non-trauma) and 94% (trauma) of 'red' patients in the mixed-medical setting were overtriaged and 76% (non-trauma) and 100% (trauma) of 'green' patients in the paediatric settings were undertriaged. CONCLUSION: The SATS is a valid tool for trauma-only settings in low-resource countries. Its use in mixed settings seems justified, but context-specific assessments would seem prudent. Finally, in paediatric settings with endemic malaria, adding haemoglobin level to the SATS discriminator list may help to improve the undertriage of patients with malaria. PMID- 28912966 TI - ABCC6 Gene Analysis in 20 Japanese Patients with Angioid Streaks Revealing Four Frequent and Two Novel Variants and Pseudodominant Inheritance. AB - PURPOSE: To report the spectrum of ABCC6 variants in Japanese patients with angioid streaks (AS). PATIENTS AND METHODS: This was a single-center cohort study. The medical records of 20 patients with AS from 18 unrelated Japanese families were retrospectively reviewed. Screening of the ABCC6 gene (exons 1 to 31) was performed using PCR-based Sanger sequencing. RESULTS: Eight ABCC6 variants were identified as candidate disease-causing variants. These eight variants included five known variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, and p.R1357W), one previously reported variant (p.N428S) of unknown significance, and two novel variants (c.1939C>T [p.H647Y] and c.3374C>T [p.S1125F]); the three latter variants were determined to be variants of significance. The following four variants were frequently identified: p.V848CfsX83 (14/40 alleles, 35.0%), p.Q378X (7/40 alleles, 17.5%), p.R1357W (6/40 alleles, 15.0%), and p.R419Q (4/40 alleles, 10.0%). The ABCC6 variants were identified in compound heterozygous or homozygous states in 13 of 18 probands. Two families showed a pseudodominant inheritance pattern. Pseudoxanthoma elasticum was seen in 15 of 17 patients (88.2%) who underwent dermatological examination. CONCLUSIONS: We identified disease-causing ABCC6 variants that were in homozygous or compound heterozygous states in 13 of 18 families (72.2%). Our results indicated that ABCC6 variants play a significant role in patients with AS in the Japanese population. PMID- 28912967 TI - Correlation of Macular Focal Electroretinogram with Ellipsoid Zone Extension in Stargardt Disease. AB - Stargardt disease (STGD1) is the most common cause of inherited juvenile macular degeneration. This disease is characterized by a progressive accumulation of lipofuscin in the outer retina and subsequent loss of photoreceptors and retinal pigment epithelium. The aim of this study was to evaluate the relationship between cone photoreceptor function and structure in STGD1. Macular function was assessed by visual acuity measurement and focal electroretinogram (FERG) recording while spectral domain optical coherence tomography (SD-OCT) imaging was performed to evaluate the integrity of photoreceptors. FERG amplitude was significantly reduced in patients with Stargardt disease (p < 0.0001). The amplitude of FERG showed a negative relationship with interruption of ellipsoid zone (EZ) (R2 = 0.54, p < 0.0001) and a positive correlation with average macular thickness (AMT). Conversely, visual acuity was only weakly correlated with central macular thickness (CMT) (R2 = 0.12, p = 0.04). In conclusion, this study demonstrates that FERG amplitude is a reliable indicator of macular cone function while visual acuity reflects the activity of the foveal region. A precise assessment of macular cone function by FERG recording may be useful to monitor the progression of STGD1 and to select the optimal candidates to include in future clinical trials to treat this disease. PMID- 28912968 TI - Bimanual Microincision Cataract Surgery versus Coaxial Microincision Cataract Surgery: A Meta-Analysis of Randomized Controlled Trials and Cohort Studies. AB - PURPOSE: This meta-analysis was conducted to compare the intraoperative and postoperative outcomes of bimanual microincision cataract surgery (B-MICS) and coaxial microincision cataract surgery (C-MICS). METHODS: Three databases were searched for papers that compared B-MICS and C-MICS from inception to June 2016. The following intraoperative and postoperative outcomes were included in the final meta-analysis: ultrasound time (UST), effective phacoemulsification time (EPT), balanced salt solution use (BSS use), mean surgery time, best-corrected visual acuity (BCVA), central corneal thickness (CCT), and increased CCT. RESULTS: There were no statistically significant differences in mean surgery time, UST, BSS use, BCVA, CCT, or increased CCT (one subgroup at postoperative day 7-8 and another subgroup at postoperative day 30). However, there was less EPT needed during surgery (p < 0.01) and lower levels of increased CCT at postoperative day 1 (p = 0.02) in the B-MICS group compared with the C-MICS group. CONCLUSIONS: The EPT was shorter and increased CCT was less at postoperative day 1 in the B-MICS group. There were no statistically significant differences in other intraoperative and postoperative outcomes between the B-MICS group and the C-MICS group. B-MICS is an efficient and safe cataract surgery procedure. PMID- 28912969 TI - Migration-Related Stressors and Their Effect on the Severity Level and Symptom Pattern of Depression among Vietnamese in Germany. AB - OBJECTIVES: Vietnamese in Germany represent a scarcely researched and vulnerable group for mental health problems, especially under exposure to migration-related stressors (MRS). This study analyzes the effect of those MRS on the severity level and symptom pattern of depression. DESIGN: We analyzed the data of 137 depressed Vietnamese patients utilizing Germany's first Vietnamese psychiatric outpatient clinic. Hierarchical linear regression models were applied to investigate how the quantity of MRS influenced (1) the overall severity of self reported depression symptoms; (2) the cognitive, affective, and somatic BDI-II subscale; and (3) the single BDI-II items of these subscales. RESULTS: A greater number of MRS were related to a higher severity level of depression in general, as well as to a higher level on the cognitive depression subscale in particular. The BDI-II single items pessimism, past failure, guilt feelings, punishment feelings, and suicidal thoughts were particularly associated with a higher quantity of perceived MRS. CONCLUSION: Among depressed Vietnamese migrants in Germany, a higher number of reported MRS were associated with higher overall depression severity. Within the domains of depression, particularly the cognitive domain was linked to perceived MRS. The association between MRS and suicidal thoughts is clinically highly relevant. PMID- 28912970 TI - Knowledge, Practice, and Associated Factors of Home-Based Management of Diarrhea among Caregivers of Children Attending Under-Five Clinic in Fagita Lekoma District, Awi Zone, Amhara Regional State, Northwest Ethiopia, 2016. AB - INTRODUCTION: In Ethiopia, it is the second cause for clinical presentation among under five-year child population. OBJECTIVE: The main aim of this study was to assess knowledge, practice, and associated factors of home-based management of diarrhea among caregivers of children attending the under-five clinic. METHODS: Institution based quantitative cross-sectional study was carried out from March 1, 2016, to April 22, 2016. RESULTS: Two hundred eight (56.2%) of them had good knowledge and one hundred thirty-nine (37.6%) of them had the good practice of home management of diarrhea, specifically, primary education (AOR: 5.384, 95% CI: 2.008, 14.438), secondary and above education (AOR: 11.769, 95% CI: 3.527, 39.275), daily laborer (AOR: 0.208, 95% CI: 0.054, 0.810), and no information about diarrhea (AOR: 0.139, 95% CI: 0.054, 0.354). Moreover, age range of 25-35 (AOR: 4.091, 95% CI: 1.741, 9.616) and 36-45 (AOR: 3.639, 95% CI: 1.155, 11.460), being single (AOR: 0.111, 95% CI: 0.013, 0.938), being divorced (AOR: 0.120, 95% CI: 0.024, 0.598), illiteracy (AOR: 0.052, 95% CI: 0.017, 0.518), primary education (AOR: 0.143, CI: 0.046, 0.440), and no information about diarrhea (AOR: 0.197, 95% CI: 0.057, 0.685) were significantly associated variables with the outcome variables in multivariate regression. CONCLUSION: Caregivers had slightly adequate knowledge but poor practice. PMID- 28912971 TI - Sleep Parameters in Short Daily versus Conventional Dialysis: An Actigraphic Study. AB - Previous studies have observed worse sleep quality in patients undergoing conventional dialysis as compared to daily dialysis. Our aim was to compare the sleep parameters of patients undergoing daily or conventional dialysis using an objective measure (actigraphy). This cross-sectional study was performed in three dialysis centers, including a convenience sample (nonprobability sampling) of 73 patients (36 patients on daily hemodialysis and 37 patients on conventional hemodialysis). The following parameters were evaluated: nocturnal total sleep time (NTST), expressed in minutes; wake time after sleep onset (WASO), expressed in minutes; number of nighttime awakenings; daytime total sleep time (DTST), expressed in minutes; number of daytime naps; and nighttime percentage of sleep (% sleep). The Mini-Mental State Examination and the Beck Depression Inventory were also administered. The mean age was 53.4 +/- 17.0 years. After adjustment of confounding factors using multiple linear regression analysis, no difference in actigraphy parameters was detected between the groups: NTST (p = 0.468), WASO (p = 0.88), % sleep (p = 0.754), awakenings (p = 0.648), naps (p = 0.414), and DTST (p = 0.805). Different from previous studies employing qualitative analysis, the present assessment did not observe an influence of hemodialysis modality on objective sleep parameters in chronic renal patients. PMID- 28912972 TI - Denosumab for Male Hemodialysis Patients with Low Bone Mineral Density: A Case Control Study. AB - Denosumab increases bone mineral density (BMD) in patients not receiving hemodialysis therapy. However, limited data are available in the literature concerning the use of denosumab in hemodialysis patients. We treated male hemodialysis patients with low radius BMD with denosumab therapy for 1 year and evaluated its effect on radius BMD. Seventeen patients were treated with denosumab 60 mg every 6 months, and 20 patients were not treated with denosumab (control group). At seven days, the mean corrected calcium level decreased from 9.2 +/- 0.5 mg to 8.5 +/- 0.5 mg (P < 0.01), and mean serum phosphorus decreased from 5.0 +/- 1.3 mg/dl to 4.2 +/- 0.9 mg/dl (P < 0.01). At 1 month, the corrected calcium and serum phosphorus levels were 9.2 +/- 0.9 mg/dl and 4.0 +/- 1.1 mg/dl, respectively. At 1 year, BMD increased by 2.6% +/- 4.4% in the denosumab group and decreased by 4.5% +/- 7.7% in the control group (P < 0.001). In our observational study, denosumab therapy represents an effective treatment for male dialysis patients with low BMD. PMID- 28912973 TI - Clinical Characteristics in Patients with Triple Negative Breast Cancer. AB - PURPOSE: The purpose of this study was to compare and contrast the clinical characteristics of the triple negative breast cancer (TNBC) and non-TNBC patients, with a particular focus on genetic susceptibility and risk factors prior to diagnosis. METHODS: Our institutional database was queried for all patients diagnosed with invasive breast cancer between January 2010 and May 2016. RESULTS: Out of a total of 1964 patients, 190 (10%) patients had TNBC. The median age for both TNBC and non-TNBC was 59 years. There was a significantly higher proportion of African American and Asian patients with TNBC (p = 0.0003) compared to patients with non-TNBC. BRCA1 and BRCA2 were significantly associated with TNBC (p < 0.0001, p = 0.0007). A prior history of breast cancer was significantly associated with TNBC (p = 0.0003). There was no relationship observed between TNBC and a history of chemoprevention or patients who had a history of AH or LCIS. CONCLUSIONS: We found that having Asian ancestry, a prior history of breast cancer, and a BRCA1 or BRCA2 mutation all appear to be positively associated with TNBC. In order to develop more effective treatments, better surveillance, and improved prevention strategies, it is necessary to improve our understanding of the population at risk for TNBC. PMID- 28912974 TI - Comment on "Interrelationship between Sleep and Exercise: A Systematic Review". PMID- 28912975 TI - An Incidentally Detected Right Ventricular Pseudoaneurysm. AB - Ventricular pseudoaneurysm is an uncommon, potentially fatal complication that has been associated with myocardial infarction, cardiac surgery, chest trauma, and infectious processes. Diagnosis can be challenging, as cases are rare and slowly progressing and typically lack identifiable features on clinical presentation. As a result, advanced imaging techniques have become the hallmark of identification. Ahead, we describe a patient who presents with acute decompensated heart failure and was incidentally discovered to have a large right ventricular pseudoaneurysm that developed following previous traumatic anterior rib fracture. PMID- 28912976 TI - Electromagnetic Interference from Swimming Pool Generator Current Causing Inappropriate ICD Discharges. AB - Electromagnetic interference (EMI) includes any electromagnetic field signal that can be detected by device circuitry, with potentially serious consequences: incorrect sensing, pacing, device mode switching, and defibrillation. This is a unique case of extracardiac EMI by alternating current leakage from a submerged motor used to recycle chlorinated water, resulting in false rhythm detection and inappropriate ICD discharge. A 31-year-old female with arrhythmogenic right ventricular cardiomyopathy and Medtronic dual-chamber ICD placement presented after several inappropriate ICD shocks at the public swimming pool. Patient had never received prior shocks and device was appropriate at all regular follow-ups. Intracardiac electrograms revealed unique, high-frequency signals at exactly 120 msec suggestive of EMI from a strong external source of alternating current. Electrical artifact was incorrectly sensed as a ventricular arrhythmia which resulted in discharge. ICD parameters including sensing, pacing thresholds, and impedance were all normal suggesting against device malfunction. With device failure and intracardiac sources excluded, EMI was therefore strongly suspected. Avoidance of EMI source brought complete resolution with no further inappropriate shocks. After exclusion of intracardiac interference, device malfunction, and abnormal settings, extracardiac etiologies such as EMI must be thoughtfully considered and excluded. Elimination of inappropriate shocks is to "first, do no harm." PMID- 28912977 TI - Isolated Persistent Left Superior Vena Cava, Sick Sinus Syndrome, and Challenging Pacemaker Implantation. AB - Persistent left superior vena cava with absent right superior vena cava is a very rare venous anomaly and is known as isolated PLSVC. It is usually an asymptomatic anomaly and is mostly detected during difficult central venous access or pacemaker implantation, though it could also be associated with an increased incidence of congenital heart disease, arrhythmias, and conduction disturbances. Herein, we describe a dual-chamber pacemaker implantation in a patient with isolated PLSVC and sick sinus syndrome. PMID- 28912978 TI - Anoxic Brain Injury Presenting as Pseudosubarachnoid Hemorrhage in the Medical Intensive Care Unit. AB - Anoxic encephalopathy is frequently encountered in the medical intensive care unit (ICU). Cerebral edema as a result of anoxic brain injury can result in increased attenuation in the basal cisterns and subarachnoid spaces on computerized tomography (CT) scans of the head. These findings can mimic those seen in acute subarachnoid hemorrhage (SAH) and are referred to as pseudosubarachnoid hemorrhage (pseudo-SAH). Pseudo-SAH is a diagnosis critical care physicians should be aware of as they treat and evaluate their patients with presumed SAH, which is a medical emergency. This lack of awareness could have important clinical implications on outcomes and impact management decisions if patients with anoxic brain injury are inappropriately treated for SAH. We describe three patients who presented to the hospital with anoxic brain injury. Subsequent CT head suggested SAH, which was subsequently proven to be pseudo-SAH. PMID- 28912979 TI - The Protocol of Fixed Reconstruction for Severely Worn Teeth Combined with Anterior Deep Bite. AB - Full mouth reconstruction is one of the most effective methods to restore severe worn teeth that have suffered reduced vertical dimension. Although the use of the overlay splint restoration for a trial period allowing the patient to adapt to an increased vertical dimension is the recognized method, the specific protocol from the transitional splint to the fixed reconstruction is yet to be established. This case report describes a 50-year-old female patient who has severely worn teeth combined with an anterior deep bite and chewing pain. The protocol of the treatment process is described. PMID- 28912980 TI - Sporotrichoid-Like Spread of Cutaneous Mycobacterium chelonae in an Immunocompromised Patient. AB - Mycobacterium chelonae is a rapidly growing mycobacterium found in water and soil that can cause local cutaneous infections in immunocompetent hosts but more frequently affects immunocompromised patients. Typically, patients will present with painful subcutaneous nodules of the joints or soft tissues from traumatic inoculation. However, exhibiting a sporotrichoid-like pattern of these nodules is uncommon. Herein, we report a case of sporotrichoid-like distribution of cutaneous Mycobacterium chelonae in a patient with systemic lupus erythematosus on significant immunosuppressive medications. Clinicians treating immunocompromised patients should be cognizant of their propensity to develop unusual infections and atypical presentations. PMID- 28912981 TI - Physician Beware: Severe Cyanide Toxicity from Amygdalin Tablets Ingestion. AB - Despite the risk of cyanide toxicity and lack of efficacy, amygdalin is still used as alternative cancer treatment. Due to the highly lethal nature of cyanide toxicity, many patients die before getting medical care. Herein, we describe the case of a 73-year-old female with metastatic pancreatic cancer who developed cyanide toxicity from taking amygdalin. Detailed history and physical examination prompted rapid clinical recognition and treatment with hydroxocobalamin, leading to resolution of her cyanide toxicity. Rapid clinical diagnosis and treatment of cyanide toxicity can rapidly improve patients' clinical outcome and survival. Inquiries for any forms of ingestion should be attempted in patients with clinical signs and symptoms suggestive of poisoning. PMID- 28912982 TI - Severe Thyrotoxicosis Secondary to Povidone-Iodine from Peritoneal Dialysis. AB - A 73-year-old male on home peritoneal dialysis (PD) with recent diagnosis of atrial fibrillation presented with fatigue and dyspnea. Hyperthyroidism was diagnosed with TSH < 0.01 mIU/L and FT4 > 100 pmol/L. He had no personal or family history of thyroid disease. There had been no exposures to CT contrast, amiodarone, or iodine. Technetium thyroid scan showed diffusely decreased uptake. He was discharged with a presumptive diagnosis of thyroiditis. Three weeks later, he had deteriorated clinically. Possible iodine sources were again reviewed, and it was determined that povidone-iodine solution was used with each PD cycle. Methimazole 25 mg daily was initiated; however, he had difficulty tolerating the medication and continued to clinically deteriorate. He was readmitted to hospital where methimazole was restarted at 20 mg bid with high dose prednisone 25 mg and daily plasma exchange (PLEX) therapy. Biochemical improvement was observed with FT4 dropping to 48.5 pmol/L by day 10, but FT4 rebounded to 67.8 pmol/L after PLEX was discontinued. PLEX was restarted and thyroidectomy was performed. Pathology revealed nodular hyperplasia with no evidence of thyroiditis. Preoperative plasma iodine levels were greater than 5 times the upper limit of normal range. We hypothesize that the patient had underlying autonomous thyroid hormone production exacerbated by exogenous iodine exposure from a previously unreported PD-related source. PMID- 28912983 TI - Metastatic Melanoma of the Gallbladder in an Asymptomatic Patient. AB - Malignant Melanoma (MM) is among the most dangerous malignancies with some of the least known survival rates. Melanoma most commonly metastasizes to regional lymph nodes, the lungs, and brain. Metastatic disease of the gallbladder (GB) is exceptionally rare making it difficult to diagnose. The fact that typically patients do not present until they are symptomatic-only after widespread metastatic disease has already occurred-is further complicating the diagnosis of MM of the GB. For this reason, MM of the GB is rarely discovered in living patients. In fact, review of the literature showed only 40 instances in which metastatic disease of the GB was reported in living patients. We describe the presentation and management of a patient who had metastatic disease of the GB. However, our case is unique because his malignancy was discovered incidentally while he was asymptomatic. He was successfully treated with an open cholecystectomy. We have presented this case in order to make the necessity of meticulous investigation of potential metastasis in patients with a known history of cutaneous melanoma clear. PMID- 28912984 TI - Caecal Perforation from Primary Intestinal Tuberculosis in Pregnancy. AB - The incidence of tuberculosis (TB) is rising worldwide, despite the efficacy of the BCG vaccination. Populations at greatest risk of contracting TB are migrant communities, as well as immunocompromised individuals. The diagnosis of extrapulmonary TB (EPTB) can often present as a diagnostic conundrum, due to its nonspecific and varied presentation, often mimicking inflammatory bowel disease or malignancy. We present a case of caecal TB in pregnancy, which resulted in caecal perforation, a right hemicolectomy, and severe preterm delivery. The aim of this case report is to discuss the diagnosis of extrapulmonary TB, as well as its subsequent management in pregnancy. PMID- 28912985 TI - Isolated Splenic Cold Abscesses with Perisplenic Extension: Treated Successfully without Splenectomy. AB - Splenic tuberculosis (TB) in the form of multiple splenic cold abscesses with perisplenic extensions is a rare disease, especially in an immunocompetent host. It demonstrates diagnostic complexity, which makes identification of the disease difficult. We report a case of an immunocompetent adult male who presented with fever, pain in the left lower chest, decreased appetite, and significant weight loss. On physical examination, he had tenderness in the left lower infra-axillary region and Traube's space dullness without palpable spleen. Ultrasound-guided aspiration of the abscess fluid revealed Mycobacterium tuberculosis (MTB) by polymerase chain reaction (PCR). No primary focus of the infection was detected in the lungs or any other organs. The patient was successfully treated with antitubercular therapy (ATT). PMID- 28912986 TI - Transmission of Donor-Derived Trypanosoma cruzi and Subsequent Development of Chagas Disease in a Lung Transplant Recipient. AB - Donor infection status should be considered when accepting an organ for transplant. Here we present a case of Chagas disease developing after a lung transplant where the donor was known to be Trypanosoma cruzi antibody positive. The recipient developed acute Trypanosoma cruzi infection with reactivation after treatment. Chagas disease-positive donors are likely to be encountered in the United States; donor targeted screening is needed to guide decisions regarding organ transplant and posttransplant monitoring. PMID- 28912987 TI - Cerebellar Involvement in an Immunocompetent Patient Presenting with Progressive Multifocal Leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the JC virus, a polyomavirus that can be reactivated under certain immunosuppressive conditions, such as AIDS, immunomodulatory therapy, and haematological malignancies. However, a few cases of immunocompetent patients have been reported in which no immunodeficiency was present. We describe the case of an 83-year-old immunocompetent man who presented with severe cerebellar symptoms with an MRI scan suggestive of severe demyelinating disease. We were not able to identify any occult immunosuppression or malignancy in our patient. PMID- 28912988 TI - Accidental Intrathecal Administration of Digoxin in an Elderly Male with End Stage Renal Disease. AB - The systemic effects of digoxin toxicity have been well-known. However, there has been no case citing the effects of intrathecal digoxin in light of end-stage renal disease in the elderly. Here, we report on the case of the successful management of accidental intrathecal digoxin administration in an elderly male with end-stage renal disease. PMID- 28912989 TI - Vaginal Urinary Calculi Formation Secondary to Vaginal Mesh Exposure with Urinary Incontinence. AB - BACKGROUND: Vaginal stones may form in the setting of mesh exposure with urinary incontinence. This report serves to help understand the presentation, evaluation, and management of vaginal urinary stones. CASE: A 68-year-old female presented with a vaginal calculus. She had a history of anterior and posterior polypropylene mesh placement for prolapse 7 years earlier and urinary incontinence. The stone was identified on a portion of exposed mesh and removed in office. Pathology confirmed urinary etiology. The exposed mesh resolved with topical estrogen. Cystourethroscopy excluded urinary fistula and bladder mesh erosion. CONCLUSIONS: When identified, a vaginal calculus should be removed and evaluated for composition. Cystourethroscopy should be performed to assess potential urinary tract fistulas and mesh erosion. Additional imaging should be considered. PMID- 28912990 TI - Triple Synchronous Primary Neoplasms of the Cervix, Endometrium, and Ovary: A Rare Case Report and Summary of All the English PubMed-Indexed Literature. AB - The incidence rate of triple or more synchronous primary neoplasms of the female genital system is exceedingly uncommon. To the best of our knowledge, only 13 such cases have been reported in the PubMed-indexed English literature. Herein, we report a single case of triple synchronous primary neoplasms of the cervix, endometrium, and left ovary with three distinct histological patterns that were not reported previously. Moreover, we briefly present a summary table of all the English PubMed-indexed cases of triple or more synchronous primary neoplasms of the female genital system (n = 13). PMID- 28912991 TI - T Cell Histiocyte Rich Large B Cell Lymphoma Presenting as Hemophagocytic Lymphohistiocytosis: An Uncommon Presentation of a Rare Disease. AB - T cell histiocyte rich large B cell lymphoma (THRLBCL) is a rare subtype of non Hodgkin's lymphoma characterized by malignant B cells with reactive T lymphocytes. The pathophysiology is thought to involve cytokine-mediated evasion of T cell immune response by malignant B cells. It usually presents at an advanced stage with extranodal involvement. An extremely unusual manifestation of the disease is hemophagocytic lymphohistiocytosis (HLH) which is a hyperinflammatory disorder. We present a case of a 43-year-old male who presented with recurrent fever and recent radiologic imaging showing splenomegaly and right inguinal lymphadenopathy. On presentation, he had a fever of 105 degrees F. Laboratory work-up was consistent with pancytopenia, elevated lactate dehydrogenase, elevated D-dimer, and a ferritin of 24,247 ng/mL. The patient was started on steroid therapy. An excisional biopsy of the right inguinal lymph node was consistent with a diagnosis of THRLBCL and the patient subsequently received six cycles of chemotherapy with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) after which a PET-CT scan showed no evidence of biologically active disease and ferritin was down to 822 ng/mL. We discuss the clinical manifestations and diagnostic and therapeutic considerations of this rare disease along with a review of reported cases in the literature. PMID- 28912992 TI - Giant Conjunctival Nevus in a 12-Year-Old Child. AB - We describe a case of a giant conjunctival nevus presented in a 12-year-old girl with suspicious clinicomorphological appearance. The lesion was noticed by the parents at the age of 3 years as a "fleshy spot" on the bulbar conjunctiva. The lesion remained unchanged until approx. 6 months before recent admission. On slit lamp examination, a large conjunctival lesion with variegate pigmentation and indistinct margins was detected on the superonasal part of the bulbar conjunctiva of the left eye. Intralesional cysts and vessels were detected with AS-OCT examination. Wide excision and cryotherapy to the scleral bed were performed and amniotic membrane graft was used to restore the ocular surface. Histopathological examination revealed compound type conjunctival nevus and disclosed any sign of malignancy. Although giant conjunctival nevus is a rare entity, precise diagnosis and adequate management are very important as it can be confused with malignant melanoma. PMID- 28912993 TI - Bilateral Peritonsillar Abscess in an Infant: An Unusual Presentation of Sore Throat. AB - INTRODUCTION: Peritonsillar abscess is considered a suppurative complication of acute tonsillitis. It is usually unilateral and clinically evident bilateral presentation is uncommon. The condition affects mainly children older than 10 years and young adults. Herein we present a rare case of bilateral peritonsillar abscess in an infant. PRESENTATION OF CASE: A 1-year-old boy presented with a two day history of worsening sore throat, loss of appetite, vomiting, and fever. Examination of the oral cavity and oropharynx revealed enlarged and inflamed tonsils and a bilaterally congested and bulging soft palate. CT scan confirmed the hypothesis of bilateral peritonsillar abscess. Antibiotic therapy was instituted and after 5 days only slight regression of swelling of the soft palate was observed. He underwent a surgical procedure for draining the abscesses. After the procedure, he presented good clinical and laboratory evolution and was discharged home. DISCUSSION: Although peritonsillar abscesses are considered common complications of acute tonsillitis bilateral cases are extremely rare, especially in early childhood. The diagnosis is based on history and physical examination and the treatment remains controversial among otolaryngologists. CONCLUSION: Bilateral peritonsillar abscess should be diagnosed and treated promptly and adequately to prevent respiratory obstruction and to avoid dissemination into the deep neck spaces. PMID- 28912994 TI - Jitteriness/Anxiety Syndrome Developing Immediately following Initiation of Oral Administration of Sertraline. AB - Here, we report our experience with patients in whom jitteriness/anxiety syndrome developed immediately following the start of oral sertraline administration. Administration was discontinued in these patients on day 2, and the jitteriness/anxiety syndrome improved the following day. Jitteriness/anxiety syndrome may develop immediately following oral administration of even low doses of sertraline, and improvement can be expected if sertraline is promptly discontinued. PMID- 28912995 TI - Coprophagia and Entomophagia in a Patient with Alcohol Related Dementia. AB - Coprophagia and entomophagia are two phenomena not commonly reported in the medical literature and their occurrence is usually associated with mental disorders. We present the case of a 59-year-old man with a history of alcohol abuse who was evaluated due to cognitive deterioration and disturbed eating habits including feces and living insects. Organic causes were ruled out and an important cognitive impairment became evident on neuropsychological formal test. The behavior remitted after antipsychotic pharmacologic therapy and alcohol detoxification, leaving the diagnostic impression of alcohol related dementia. This report shows a rare association of these two conditions in a patient with dementia. PMID- 28912996 TI - A Rare Cause of Obstructive Sleep Apnea Syndrome: Retropharyngeal Lipoma. AB - Lipoma is the most common benign mesenchymal neoplasm. About 16% of lipomas arise in the head and neck region, especially in the posterior neck. Large lipomas that originate from the retropharyngeal space may cause dyspnea, dysphagia, and snoring and occasionally may lead to obstructive sleep apnea syndrome (OSAS). Herein, we report a 45-year-old male patient with OSAS caused by a giant retropharyngeal lipoma with emphasis on CT findings. PMID- 28912997 TI - Laparoscopic Repair of Diaphragmatic Rupture: A Case Report with Radiological and Surgical Correlation. AB - The leading cause of diaphragmatic rupture is penetrating abdominal trauma, including gunshot- and stab-related wounds; however, diaphragmatic rupture can also result from blunt trauma to the abdomen. The diagnosis can be difficult to make as the physical examination may be unremarkable, and imaging, that is, a conventional chest X-ray and/or CT imaging, may initially fail to reveal the injury. Failure to recognize diaphragmatic rupture can result in a delayed presentation, sometimes years later, with a potential catastrophic outcome. Therefore, prompt and swift diagnosis is critical to avoid this potential harmful scenario. Traditionally, repair is performed through a laparotomy or a thoracotomy incision. Owing to the many advances made in minimally invasive surgery, not only has laparoscopy become the modality of choice to diagnose diaphragmatic rupture due to its high degree of sensitivity and specificity, but it can provide simultaneous therapeutic intervention as well. We report a case of laparoscopic repair of a diaphragmatic rupture in a 22-year-old female who sustained blunt abdominal trauma during a motor vehicle accident. PMID- 28912998 TI - IgG4-Related Kidney Disease: Report of a Case Presenting as a Renal Mass. AB - IgG4-related disease (IgG4-RD) is a nosological entity defined as a chronic immune-mediated fibro-inflammatory condition characterized by a tendency to form tumefactive, tissue-destructive lesions or by organ failure. Urologic involvement in IgG4-RD has been described in some short series of patients and in isolated case reports, most often involving the kidneys in so-called IgG4-related kidney disease (IgG4-RKD). The disease can occasionally mimic malignancies and is at risk of being misdiagnosed due to its rarity. We report the case of a 56-year-old man presenting with a right renal mass suspected of being malignant. Laboratory tests showed normal creatinine levels, a high erythrocyte sedimentation rate, and high levels of C-reactive protein and microalbuminuria. The patient underwent radical right nephroureterectomy and histopathologic examination revealed features proving IgG4-RKD. He was therefore referred to immunologists. Typical clinical presentation of IgG4-RKD includes altered renal function with inconstant or no radiologic findings. Conversely, in the case we presented, a single nodule was detected upon imaging evaluation, thus mimicking malignancy. This raises the issue of a proper differential diagnosis. A multidisciplinary approach can be useful, although in clinical practice the selection of patients suspected of having IgG4-RKD is critical in the cases presenting with a renal mass that mimics malignancy. PMID- 28912999 TI - Tacrolimus Aggravated Tube Feeding Syndrome with Acute Renal Failure in a Pediatric Liver Transplant Recipient. AB - Acute renal failure can be caused by calcineurin inhibitors (CNIs), due to arteriolopathy and altered tubular function. Within this context, we present the case of a 14-month-old liver transplant recipient who suffered an acute polyuric renal failure during a short episode of hypercaloric feeding. In our case, CNI induced distal RTA led to nephrocalcinosis and therefore to secondary nephrogenic diabetes insipidus. The diet with high renal solute load consequently resulted in an acute polyuric renal failure with severe hypernatremic dehydration. In conclusion, a hypercaloric diet in children with potentially impaired renal function due to therapy with CNIs requires precise calculation of the potential renal solute load and the associated fluid requirements. PMID- 28913000 TI - Lipolymphedema Associated with Idiopathic Cyclic Edema: A Therapeutic Approach. AB - Idiopathic cyclic edema is a type of generalized edema that mainly affects women. Diagnosis is made by the patient's clinical history and an evaluation of the accumulation of weight during the day. The objective of this study is to report the clinical control of lymphedema associated with idiopathic cyclic edema using calcium dobesilate. A 55-year-old female patient reported generalized edema for years in that she woke up in the morning with her legs swollen and the edema worsened during the day. The physical examination revealed generalized edema. After four days of treatment with calcium dobesilate, the patient returned to the Clinica Godoy, Brazil, with less edema and reductions in body weight and the amount of extracellular and intracellular fluid. With further treatment, there was a total reduction of the edema. It is concluded that calcium dobesilate helps to control lymphedema secondary to idiopathic cyclic edema. PMID- 28913001 TI - Methamphetamine Use and Emergency Department Utilization: 20 Years Later. AB - BACKGROUND: Methamphetamine (MAP) users present to the emergency department (ED) for myriad reasons, including trauma, chest pain, and psychosis. The purpose of this study is to determine how their prevalence, demographics, and resource utilization have changed. METHODS: Retrospective review of MAP patients over 3 months in 2016. Demographics, mode of arrival, presenting complaints, disposition, and concomitant cocaine/ethanol use were compared to a 1996 study at the same ED. RESULTS: 638 MAP-positive patients, 3,013 toxicology screens, and 20,203 ED visits represented an increase in prevalence compared to 1996: 461 MAP positive patients, 3,102 screens, and 32,156 visits. MAP patients were older compared to the past. Mode of arrival was most frequently by ambulance but at a lower proportion than 1996, as was the proportion of MAP patients with positive cocaine toxicology screens and ethanol coingestion. Admission rate was lower compared to the past, as was discharge to jail. The proportion of MAP patients presenting with blunt trauma was lower compared to the past and higher for chest pain. CONCLUSION: A significant increase in the prevalence of MAP-positive patients was found. Differences in presenting complaints and resource utilization may reflect the shifting demographics of MAP users, as highlighted by an older patient population relative to the past. PMID- 28913002 TI - Corrigendum to "Mikkeli Osteoporosis Index Identifies Fracture Risk Factors and Osteoporosis and Intervention Thresholds Parallel with FRAX". AB - [This corrects the article DOI: 10.4061/2011/732560.]. PMID- 28913003 TI - Corrigendum to "The Relationship between Population T4/TSH Set Point Data and T4/TSH Physiology". AB - [This corrects the article DOI: 10.1155/2016/6351473.]. PMID- 28913004 TI - Hypermetabolic Thyroid Incidentaloma on Positron Emission Tomography: Review of Laboratory, Radiologic, and Pathologic Characteristics. AB - INTRODUCTION: Incidental hypermetabolic thyroid lesions on Positron Emission Tomography have significant clinical value and may harbor malignancy. In this study we evaluated laboratory, radiologic, and pathologic characteristics of incidental hypermetabolic thyroid lesions. MATERIALS AND METHODS: We evaluated 18 patients prospectively with various malignancies and hypermetabolic thyroid incidentaloma. The thyroid function tests, ultrasound assessment, and guided FNA biopsy were performed on all cases. RESULTS: We included 9 male and 9 female patients with mean age of 51 years. Most common malignancy was colon cancer. Metabolic activity quantification using maximum standard uptake value demonstrated range between 1.4 and 65.4 with mean value of 9.4. We found highest metabolic activity in patients with lung adenocarcinoma, B-cell lymphoma, and colon adenocarcinoma. On ultrasound exam most thyroid lesions were of solid, hypoechoic, noncalcified nature with either normal or peripheral increased vascularity. FNA biopsy report was benign in 15 cases and malignant or highly suggestive for malignancy in 3 other cases. Two of the three malignant cases demonstrated metabolic activity higher than average SUV max. CONCLUSION: Most thyroid hypermetabolic incidentalomas are benign lesions, while higher values of SUV max are in favor of malignancy. This mandates further evaluation of incidentally found thyroid hypermetabolic lesions on routine PET/CT scans. PMID- 28913006 TI - UHPLC-PDA Assay for Simultaneous Determination of Vitamin D3 and Menaquinone-7 in Pharmaceutical Solid Dosage Formulation. AB - A newly developed method based on ultrahigh performance liquid chromatography (UHPLC) was optimized for the simultaneous determination of vitamin D3 and menaquinone-7 (MK-7) in tablet formulation in the present study. UHPLC separation of vitamin D3 and MK-7 was performed with ACE Excel 2 C18-PFP column (2 MUm, 2.1 * 100 mm) at 0.6 mL min-1 flow rate, whereas the mobile phase consisted of methanol/water (19 : 1, v/v, phase A) and isopropyl alcohol (99.9%, phase B) containing 0.5% triethylamine. Isocratic separation of both the analytes was performed at 40 degrees C by pumping the mobile phases A and B in the ratio of 50 : 50 (v/v, pH, 6.0). Both analytes were detected at a wavelength of 265 nm and the injection volume was 1.0 MUL. The overall runtime per sample was 4.5 min with retention time of 1.26 and 3.64 min for vitamin D3 and MK-7, respectively. The calibration curve was linear from 5.0 to 100 MUg mL-1 for vitamin D3 and MK-7 with a coefficient of determination (R2) >= 0.9981, while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.46 and 2.21%, respectively. The proposed HPLC method was demonstrated to be simple and rapid for the determination of vitamin D3 and MK-7 in tablets. PMID- 28913007 TI - The role of unexplained high serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels in the second trimester to determine poor obstetric outcomes. AB - OBJECTIVE: To investigate the relationship between gestational complications and high levels of maternal serum alfa-fetoprotein (MSAFP) and/or beta human chorionic gonadotropin (hCG) and to determine whether these markers are effective predictors of poor pregnancy outcomes. MATERIALS AND METHODS: In this study, we enrolled a total of 679 women at 15-20 gestational weeks with MSAFP and hCG below or above 2.0 multiples of the median (MoM); of those, 200 women with normal MSAFP and hCG MoM formed the control group. Pre-eclampsia, intrauterine growth retardation (IUGR), preterm labor, preterm delivery, placental abruption, placenta previa, placenta accreta, preterm premature rupture of the membranes (PPROM), intrauterine fetal death, as well as neonatal and perinatal morbidity rates were evaluated. RESULTS: A significant relationship was found between adverse pregnancy outcomes and abnormal elevation of hCG and AFP levels in the second trimester. In cases of isolated elevation of hCG, preeclampsia and preterm labor/spontaneous preterm birth rate were slightly higher than in the control group (p=0.043, p=0.015), while IUGR, PPROM, placental abruption, and intrauterine fetal death rates were all similar (p=0.063, p=0.318, p=1.00, p=0.556). In case having an elevation in both markers, increased rate of obstetric complications have been observed. A significant relationship was found between the high levels of maternal serum AFP and hCG MoM and poor pregnancy outcomes like preeclampsia, IUGR, PPROM, intrauterine fetal death (p=0.003, p=0.001, p=0.040, p=0.006). CONCLUSION: To our knowledge, up to now, no definitive follow-up and treatment protocols have been established for patients at increased risk. In light of these findings, it is recommended to inform and educate patients about the most likely signs and symptoms of complications, to make more often antenatal visits, to perform more frequent ultrasound examination (fetal growth, AFI, etc.), NST, arterial/venous doppler, biophysical profile, and cervical length measurements in high-risk group. PMID- 28913008 TI - Intrahepatic cholestasis of pregnancy: Relationship between bile acid levels and maternal and fetal complications. AB - OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) complicates pregnancies which is characterized by elevated serum bile acid levels. ICP increases maternal and fetal morbidities. This study was designed to determine the association of maternal and fetal complications and serum bile acid levels. MATERIAL AND METHOD: Maternal and fetal characteristics were analyzed from the medical records of 61 patients who gave birth following a pregnancy complicated with ICP between 2009 and 2013. RESULTS: Eighty seven percent of 61 cases were singletons, and 13% of them were twins. Mean SBA level was 36 MUmol/L. Preterm birth rate among singletons and twin pregnancies were 24.5% and 62.5%, respectively. Mean SBA level in preterm birth group was statistically higher with respect to the term birth group (100.8 MUmol/L and 25.61 MUmol/L, respectively; p=0.001). No perinatal mortality associated with ICP was detected in the study group. CONCLUSION: Pregnant women with the ICP compose high-risk group in regard to fetal and maternal risks. Close follow-up of these patients is required due to increased risks such as preterm delivery, meconium staining and fetal death. PMID- 28913005 TI - Chaperone-Based Therapies for Disease Modification in Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of pathological intracellular aggregates primarily composed of misfolded alpha-synuclein. This pathology implicates the molecular machinery responsible for maintaining protein homeostasis (proteostasis), including molecular chaperones, in the pathobiology of the disease. There is mounting evidence from preclinical and clinical studies that various molecular chaperones are downregulated, sequestered, depleted, or dysfunctional in PD. Current therapeutic interventions for PD are inadequate as they fail to modify disease progression by ameliorating the underlying pathology. Modulating the activity of molecular chaperones, cochaperones, and their associated pathways offers a new approach for disease modifying intervention. This review will summarize the potential of chaperone-based therapies that aim to enhance the neuroprotective activity of molecular chaperones or utilize small molecule chaperones to promote proteostasis. PMID- 28913009 TI - Evaluation of female sexual function index and associated factors among married women in North Eastern Black Sea region of Turkey. AB - OBJECTIVE: The aim of this study was detection of Female Sexual Function Index (FSFI) scores of married women living in North Eastern Black Sea region of Turkey and comparison with demographic data. MATERIALS AND METHODS: A cross-sectional, descriptive study conducted at a University Hospital, gynecology and obstetrics outpatient clinic. Married women between 18-50 years of age, without any complaint enrolled in the study and participants were asked to fill out the form of FSFI. Age, gravidity and number of living children, duration of marriage, education and income levels, employment status, and contraceptive methods has been questioned. Sexual desire, arousal, lubrication, orgasm, satisfaction, pain subscales, and total score of FSFI were determined and compared with demographic data. RESULTS: Lower FSFI levels were detected from 70.9% of the respondents. Age, duration of marriage and number of children were adversely affected the FSFI scores. Intermediate education level and usage of a contraceptive method were related with higher FSFI scores. Pain scores were high in all participants independently from other parameters. CONCLUSIONS: For identification of women's sexual dysfunction, increasing the knowledge level and awareness about sexuality are required. PMID- 28913010 TI - Does the serum E2 level change following coasting treatment strategy to prevent ovarian hyperstimulation syndrome impact cycle outcomes during controlled ovarian hyperstimulation and in vitro fertilization procedure? AB - OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) remains as a clinical problem for hyperresponder patients during controlled ovarian hyperstimulation and in vitro fertilization (COH-IVF) procedure. Herein, we aimed to evaluate the COH-IVF outcomes in hyperresponder patients managed with coasting treatment strategy for OHSS prevention regarding the establishment of clinical pregnancy as an endpoint of the treatment cycle. MATERIALS AND METHODS: The medical records related to the COH-IVF outcome in 119 hyperresponder patients who have exhibited a serum estradiol level greater than or equal to 3000 pg/mL were evaluated. The study was conducted on a total of 119 patients, 98 of whom have been treated by coasting or coasting with GnRH antagonist co-treatment strategies, while the remaining 21 women (control group) have not been managed with coasting treatment. The COH and IVF-ET outcomes in the 119 patients were compared based on the coasting treatment situation. RESULTS: Among the women who received coasting treatment, the number of patients demonstrating E2 level decrement and also E2 level decrement rate after coasting were similar between patients with and without clinical pregnancy. Total gonadotropin dose, 2PN number, embryo number, and fertilization rate were significantly higher in the patients with a clinical pregnancy. CONCLUSION: The coasting treatment is a clinically useful preventive strategy for OHSS avoidance. GnRH antagonist co-treatment decreases the duration of coasting although any detrimental or ameliorating impact of this effect on pregnancy rates have not been seen. The E2 level decrement or increment following coasting treatment seems not to be related to cycle outcomes. PMID- 28913011 TI - Analysis of non-squamous vulvar cancer cases: A 21-year experience in a single center. AB - OBJECTIVE: To evaluate the patients with non-squamous cell type of vulvar cancer who were treated in our clinic within 21 years. MATERIALS AND METHODS: We assessed the data of 14 patients who were treated for non-squamous cancer of the vulva between January 1992 and August 2013. The age of patients, histopathological diagnosis of the tumor, tumor size, tumor location, medical or surgical treatment, response to the treatment, recurrence, and survival rates were analyzed. RESULTS: The mean age of the patients was 53 years. The main complaint was vulvar pruritus (71%). Mean tumor size was 2.4 cm (range: 0.5-6 cm). In 65% of cases, the tumor was localized in the labia majora. The histopathologic diagnosis of the patients was as follows: malignant melanoma in 5 patients, basal cell carcinoma in 5 patients, mucinous type adenocarcinoma in 2 patients, apocrine gland carcinoma in one patients, and malign peripheral nerve sheath tumor in 1 patient. For 11 patients, surgery was the primary treatment. Radical vulvectomy and bilateral inguinofemoral lymphadenectomy were performed in 8 patients. Local excision alone without lymphadenectomy was performed in other 3 patients. Five of eight patients (62.5%), who undergone radical surgery, had lymph node metastases. Of these 5 patients, two had bilateral lymph node metastasis. Mean follow-up time was 49.2 months (range 12 to 72 months). Eight (57.1%) patients had suffered first recurrence. In those patients, the mean time to recurrence was 19.5 months (range, 6-48 months). CONCLUSION: Non-squamous cell vulvar cancer is a rare disease and comprises a heterogeneous group of tumors. Malignant melanoma is the most aggressive one. Multicenter prospective studies are necessary in order to standardize the treatment of these rare tumors. PMID- 28913012 TI - Opinion of women about elective abortion. AB - OBJECTIVE: The aim of this study was to investigate the opinions of women who presented to the hospital for elective abortion. MATERIALS AND METHODS: This descriptive study was designed and conducted at our university hospital between March 2013-April 2013 by the method of face-to-face interviews with 500 women who presented to the hospital as patient or relatives of patients. Poll consisted of 6 questions about demographic characteristics and 14 questions evaluating the opinions and attitudes about abortion. RESULTS: The age of the women who participated in the study was ranging between 18 and 75 years with the mean age of 31.5+/-11.9 years. Twenty-six women (5.2%) were illiterate, while 109 (21.8%) were university graduates. 70.8% of women stated that they were against elective abortion. Among the reasons against abortion on request were: "forbidden by the religion"-53.1% of women, "against human rights"-35.3%, and "unhealthy for the mother"-7.1% of women. About the prohibition of abortion, 82.4% of women said that "it may be performed under necessary conditions", 9.6% "it should be completely forbidden", and 8% stated that "it should never be forbidden". CONCLUSION: A large number of respondents reported that they have negative attitude towards elective abortion, however, in case of medical necessity, abortion should be performed. During the legal arrangements done about situations that may affect the public health, such as abortion regulations, we believe it would be useful to assess the perspective of the society on this issue. PMID- 28913013 TI - Prevalence of pelvic organ prolapse and related factors in a general female population. AB - OBJECTIVE: The aim of this study was to assess the prevalence and the related factors of pelvic organ prolapse (POP) in a female population to whom health care services are offered. MATERIALS AND METHODS: 1354 of the 3000 women admitted to the outpatient clinic between June 2008 and December 2008 were enrolled as they accepted to participate to the study. 34 of these patients with a history of previous hysterectomy and/or any kind of pelvic reconstructive surgery were excluded. Baseline characteristics, as well as medical and obstetric history of the patients were recorded. All women underwent vaginal examination to determine the degree of prolapse by pelvic organ prolapse quantification (POPQ) system. POP Q stages >=2 were defined as prolapse. Women with and without prolapse were compared. Regression analysis was used in order to determine the independent predictors. RESULTS: Prolapse (stage >=2) was detected in 358 patients (27.1%). Patients with prolapse were found to be significantly older and heavier. They had a higher waist to hip ratio and had a higher parity. Compared to women without prolapse, cesarean rate was significantly lower in women with prolapse (10.6% vs. 20.8%; p<0.001), and the mean birth weight of the babies of the women with prolapse was significantly higher (3584+/-574 vs. 3490+/-389 g, p=0.004). Prevalence of prolapse was found to be decreased as the level of education increased. Waist to hip ratio (OR:46.2, CI: 3.3-655, p=0.005), parity (OR:1.5, CI:1.3-1.7, p<0.001), vaginal delivery (OR:1.5, CI: 0.3-0.8, p=0.005), and menopausal status (OR:1.2, CI: 1.1-1.4, p=0.005) were found to be independent predictors of development of POP. CONCLUSION: In the present study, POP was found to be associated with waist to hip ratio, parity, vaginal delivery, and menopausal status. PMID- 28913014 TI - Recent advances in the diagnosis and management of gestational diabetes. AB - Gestational diabetes is a condition which is seen in 7% of pregnancies and have potential risks for both mother and fetus. Despite its importance, there is not any golden standard approaches to the diagnosis and management of the disease. The aim of this review was to investigate the advances in the diagnosis and management of gestational diabetes in recent years. PMID- 28913015 TI - Long-term survival after total pelvic exenteration in a patient with recurrent cervical carcinoma: A case report. AB - The management of recurrent cervical cancer depends mainly on previous treatment as well as on the site and extent of recurrence. Pelvic exenteration usually represents the only therapeutic approach with curative intent for women with central pelvic relapse who have previously received irradiation. In the present report, we share our experience regarding survival outcome in a patient with recurrent endocervical carcinoma who underwent total pelvic exenteration. PMID- 28913016 TI - Rudimentary horn pregnancy in the first trimester; importance of ultrasound and clinical suspicion in early diagnosis: A case report. AB - We aimed to present 7-8 weeks rudimentary horn pregnancy detected preoperatively. A 37-year-old woman, gravida 3, para 2, at 7-8 weeks' gestation referred to our clinic with a complaint of abdominal pain. The patient was primarily infertile, and she had unicornuate uterus detected during infertility investigation. Due to abnormal ultrasonographic image, rudimentary horn pregnancy was considered. Accurate diagnosis was made by laparoscopy, and rudimentary horn excision was performed. Prerupture diagnosis is very difficult in rudimentary horn pregnancies. The key role in preoperative diagnosis is suspicion. Ultrasonographic examination and clinical suspicion are sufficient in most cases. PMID- 28913017 TI - Successful medical treatment of fetal supraventricular tachycardia that cause hydrops fetalis. AB - Supraventricular tachycardia (SVT) is the most frequent fetal tachyarrhythmia. Diagnosis is established with M-mode ultrasound and/or Doppler investigation. Untreated cases may develop fetal heart failure and hydrops. Even these cases should not be left untreated - maternal administration of anti-arrhythmic drugs should be undertaken. In this manuscript, we describe a successful treatment with maternal administration of sotalol and digoxin in a fetus that developed hydrops because of SVT. PMID- 28913018 TI - Low-grade fibromyxoid sarcoma of the vagina: A tumor, not previously reported at this site. AB - This report presents the first case of low-grade fibromyxoid sarcoma (LGFMS) arising from the vaginal wall (a rare soft-tissue sarcoma of subfascial planes) and draws attention to differential diagnosis of masses arising from the vaginal wall. A patient presenting with abdominal pain to emergency department was diagnosed to have an ovarian mass filling the Douglas space. At laparoscopy, the origin of the mass was identified as the posterior vaginal wall. After vaginal excision of the gelatinous mass, pathologic diagnosis revealed a rare tumor, LGFMS. We discussed the differential diagnosis of vaginal LGFMS. PMID- 28913019 TI - What should be the protocol selection after failure of in-vitro fertilization at normoresponder patients: Agonist or antagonist? AB - OBJECTIVE: Evaluation of the impact of agonist or antagonist protocol selection on pregnancy outcomes after failure of in-vitro fertilization (IVF) treatment cycles which were down regulated with Gonadotropin Releasing Hormone (GnRH) agonist. MATERIALS AND METHODS: This was a retrospective study. Two hundred and sixty nine patients who were treated with GnRH agonist protocol between years 2002-2012 at an IVF unit and underwent a second attempt following one year period after failure of IVF enrolled in the study. Age, basal FSH levels, antral follicle counts, duration of induction, the number of yielded oocytes, the number of transferred embryos and the transfer days, clinical and ongoing pregnancy rates were evaluated for each treatment cycle. RESULTS: Normoresponder patients were separated into two groups according to the agonist or antagonist protocol selection at the second attempt and the results of two consequent IVF cycles were compared. There were no statistically significant difference between the groups for the dosage of administered gonadotropin, duration of induction, the count of yielded oocytes, the day and the number of transferred embryos (p>0.05). Furthermore the fertilization rate, clinical and ongoing pregnancy rates were similar in two groups. CONCLUSION: The selection of antagonist treatment is effective as agonist protocols at normoresponder patients after failure of IVF. PMID- 28913020 TI - Comparison of long GnRH agonist versus GnRH antagonist protocol in poor responders. AB - OBJECTIVE: To compare long GnRH agonist with GnRH antagonist protocol in poor responders. MATERIALS AND METHODS: Medical charts of 531 poor responder women undergoing in-vitro fertilization (IVF) cycle at Zeynep Kamil Maternity and Children's Hospital, IVF Center were retrospectively analysed. Those who received at least 300 IU/daily gonadotropin and had <=3 oocytes retrieved were enrolled in the study. Poor responders were categorized into two groups as those who received long GnRH agonist or GnRH antagonist regimen. RESULTS: Treatment duration and total gonadotropin dosage were significantly higher in women undergoing the long GnRH agonist regimen compared with the GnRH antagonist regimen (p<0.001 for both). Although the number of total and mature oocytes retrieved was similar between the groups, good quality embryos were found to be higher in the GnRH antagonist regimen. The day of embryo transfer and number of transferred embryos were similar in the groups. No statistically significant differences were detected in pregnancy (10.5% vs 14.1%), clinical pregnancy (7.7% vs 10.6%) and early pregnancy loss rates (27.2% vs 35%) between the groups. CONCLUSION: GnRH antagonist regimen may be preferable to long GnRH regimen as it could decrease the cost and treatment duration in poor responders. PMID- 28913021 TI - The effect of first chromosome long arm duplication on survival of endometrial carcinoma. AB - OBJECTIVE: The aim of this study is to investigate the effect of first chromosome long arm duplication (dup(1q)) in cases with endometrial carcinoma detected with array based comperative genomic hybridization (aCGH) on survival from the cancer. MATERIALS AND METHODS: A total of 53 patients with the diagnosis of endometrial carcinom due to endometrial biopsy and who have been operated for this reason have been allocated in the study. Frozen section biopsy and staging surgery have been performed for all the cases. Samples obtained from the tumoral mass have been investigated for chromosomal aberrations with aCGH method. Kaplan-Meier and Cox-regression analysis have been performed for survival analysis. RESULTS: Among 53 cases with endometrial carcinomas, dup(1q) was diagnosed in 14 (26.4%) of the cases. For the patient group that has been followed-up for 24 months (3-33 months), dup(1q) (p=.01), optimal cytoreduction (p<.001), lymph node positivity (p=.006), tumor stage >1 (p=.006) and presence of high risk tumor were the factors that were associated with survival. Cox-regression analysis has revealed that optimal cytoreduction was the most important prognostic factor (p=.02). CONCLUSION: Presence of 1q duplication can be used as a prognostic factor in the preoperative period. PMID- 28913022 TI - Prediction of tumor grade and stage in endometrial carcinoma by preoperative assessment of sonographic endometrial thickness: Is it possible? AB - OBJECTIVE: To evaluate preopertive accuracy of endometrial thickness for assesment of histologic grade and stage of endometrial carcinoma and also determining a cut-off value for the determination of grade of endometrial carcinoma. MATERIALS AND METHODS: Clinical data of 105 patients who underwent surgical staging with endometrial carcinoma were reviewed retrospectively. Preoperatively endometrial thickness were recorded and correlated with pathologic information. RESULTS: A statistically significant correlation was found in between endometrial thickness and grade of the disease (r=0.746, p=0.001). Besides, no correlation was found between endometrial thickness and stage (r=0.153, p=0.119). The endometrial thickness at 9 mm revealed the optimal sensitivity and specificity (93.33 and 26.2, respectively) for turning through grade1 to grade 2 with 68.2% positive predictive value and 66.7% negative predictive value. We indicated the endometrial thickness at 27 mm as the optimal value with sensitivity and specificity (27.27 and 95.65, respectively) for turning through grade 2 to grade 3 with 66.7% positive predictive value and 77.5% negative predictive value. CONCLUSION: In conlusion, sonographic evaluation of the endometrial thickness is economical, simple and can be used as a prognostic tool for endometrial cancer grading. The operating team may have the chance to get prepared before the operation and may have the chance to inform the patient about the operation. PMID- 28913023 TI - Assessment of thickened endometrium in tamoxifen therapy. AB - OBJECTIVE: Aim of this study was to evaluate role of hysteroscopy in thickened endometrium (>5 mm) associated with tamoxifen therapy. MATERIALS AND METHODS: We performed dilatation and curettage (D&C) and hysteroscopic biopsy to patients for evaluation of thickened endometrium in tamoxifen therapy. One hundred and nine asymptomatic patients with estrogen receptor positive breast cancer treated with tamoxifen 20 mg daily. We performed hysteroscopic biopsy or D&C to patients who have thickened endometrium at transvaginal sonography. We correlate pathology report results of D&C and hysteroscopic biopsy. RESULTS: Fifty-nine of 103 patients have thickened endometrium.Thirty-five of 59 patients diagnosed with D&C (19 inactive endometrium, 15 endometrial polyp, 1 endometrial hyperplasia). D&C couldn't get material 24 of these patients. Hysteroscopic biopsy diagnosed endometrial polyp 11 (45.8%) of these patients. CONCLUSION: We can state that D&C does not seem accurate enough for detection of intrauterin pathologies in thickened endometrium associated with tamoxifen therapy. We therefore believe it is reasonable to perform hysteroscopic biopsy in asymptomatic tamoxifen treated patients who have thickened endometrium. PMID- 28913024 TI - The influence of dexamethasone on postoperative nausea and vomiting in patients undergoing gynecologic laparoscopic surgeries: A randomised, controlled, double blind trial. AB - OBJECTIVE: Dexamethasone, as a part of multimodal approach, can decrease nausea and vomiting following laparoscopy in high risk patients. We performed this study to find out whether the dexamethasone can improve postoperative nausea and vomiting (PONV) in patients undergoing gynecology laparoscopic surgeries. MATERIALS AND METHODS: In this double-blind randomized clinical trial, 91 patients who underwent gynecologic laparoscopic surgery in Rasool Akram hospital in Tehran during 2011-2014 were enrolled. Fourty-four patients received 8 mg dexamethasone (study group) and 47 patients received 10 mg metochlopramide (control group) intravenously after intubation. Outcome parameters including age, weight, height, cause of hospitalization, drugs, Last Menstrual Period (LMP), Blood Pressure (BP), Heart Rate (HR), Respiratory Rate (RR) and oxygen saturation, Visual Analogue Scale (VAS) score, nausea and vomiting were entered to SPSS (v.16) and were analyzed. RESULTS: Eighyt-eight American Society of Anesthesiology (ASA) class 1-2 patients between 25-39 years old were analyzed. There was no difference in vital signs during and post operation (BP, HR, RR and O2 saturation) between these two groups (p value>0.05). There was no significant difference between VAS score at 4 and 24 hours after the operation (14% vs. 17.8% and 7% vs. 6.7%, respectively, p>0.05). Incidence of PONV in 4 hours was significantly lower in dexamethasone group (11.6% vs. 55.6% p<0.0001), while there was no significant difference in 24 hours (23.3% vs. 22.2%, p>0.05) and also need to anti-emetic drugs wasn't significantly lower in study group (p>0.05). CONCLUSION: We conclude that dexamethasone can relieve PONV after gynecologic laparoscopic surgery. PMID- 28913025 TI - Comparison of total laparoscopic hysterectomy and abdominal hysterectomy. AB - OBJECTIVE: The aim of this prospective study is to evaluate and compare to the outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH) who performed in our clinic. MATERIALS AND METHODS: We performed surgical procedures at Necmettin Erbakan University Faculty of Medicine, Department of Obstetrics and Gynecology between January 2013 and April 2014. Forty patients who underwent TLH (group 1) compared to 40 patients who underwent TAH (group 2). The mean age of the cases, body mass index (BMI), duration of operation, the amount of blood loss, rates of complications and post operative hospital stay were compared for two groups. RESULTS: There were no statistically significant differences between the two groups regarding age, body mass index (BMI), specimen weight, pre-operative hemoglobin (Hb) value and rates of the complications. The mean post-operative Hb value was significantly higher in group 1 than group 2 (11.5+/-0.8 gr/dl vs. 10.8+/-1.7, p=0.02). The mean time of operation was significantly longer in group 1 than in group 2 (105.4+/-22.9 minutes vs. 74+/-18, p<0.001). The mean duration of hospital stay was statistically shorter in group 1 compared to the group 2 (2.48+/-0.6 days vs. 4.88+/-1.2, p<0.001). CONCLUSION: Total laparoscopic hysterectomy is safe and feasible method for gynecological diseases. TLH may offer specific benefits for properly selected patients. Its advantages are lower peri-operative morbidity, improvement of quality of life, shorter hospital stay and faster return to activity. PMID- 28913026 TI - Can we use as a marker the maternal serum levels of D-dimer and fibrinogen to predict intra uterin growth restriction? AB - OBJECTIVE: The purpose of the present study was to assess the effect of D-dimer and fibrinogen levels in maternal serum as a marker for detection of intrauterine growth restriction (IUGR). MATERIALS AND METHODS: Two hundred-thirty four pregnant women who get pregnancy follow-up and delivery in the tertiary hospital between January 2011 and December 2011 were admitted to the study. Pregnant women were divided into two groups; group-1: 117 pregnants complicated with IUGR and group-2: 117 healthy pregnants without IUGR as control. Serum D-dimer and fibrinogen levels of all pregnant women were measured in the third trimester. The levels of D-dimer and fibrinogen were compared between two groups. RESULTS: There is no significant difference between the groups for age, body mass index before pregnancy, smoking and gestational weeks (p>0.05). Gravidity, parity, number of children and maternal serum fibrinogen level were detected significantly different between the groups (p<0.001). D-dimer level was not significantly different between the groups (p=0.183), but fibrinogen level in group-1 was found higher than group-2. CONCLUSION: Serum fibrinogen level was found higher in pregnant women complicated with IUGR but D-dimer level was not different between the groups. Although serum D-dimer should not be used as a marker for detection of IUGR, serum fibrinogen may be used. PMID- 28913028 TI - Recurrent massive haemoperitoneum associated with ruptured corpus luteum in women with congenital afibrinogenemia; case report. AB - Massive hemoperitoneum secondary to ruptured corpus luteum is a rare but serious and life-threatening complication for women with congenital bleeding disorders and may lead to surgical interventions and even oophorectomy. Congenital afibrinogenemia is a rare inherited coagulation disorder. As it can be asymptomatic, its clinical manifestations vary from minimal tendency of bleeding to life-threatening bleedings. Intraabdominal bleeding due to ovulation is very rare in these patients and only a few cases of corpus luteum rupture and hemoperitoneum in afibrinogenemic patients have been described. We report on a 28 year-old woman with congenital afibrinogenemia with recurrent massive intraabdominal bleeding due to ovulation as the presenting clinical sign. The first episode was managed with fresh frozen plasma, cryoprecipitate and blood transfusions; exploratory laparotomy and excision of the ruptured follicle was performed at the second episode; the third episode was managed with fresh frozen plasma, cryoprecipitate and blood transfusions; exploratory laparotomy and right salphingooopherectomy was performed at the fourth episode; fifth episode was managed with fresh frozen plasma, cryoprecipitate and blood transfusions. Conservative management is crucial for patients with congenital bleeding disorders. These case demonstrate that preservation of ovarian function is possible with a conservative approach and recurrent episodes may be prevented by suppression of ovulation. PMID- 28913027 TI - Current approaches on non-invasive prenatal diagnosis: Prenatal genomics, transcriptomics, personalized fetal diagnosis. AB - Recent developments in molecular genetics improved our knowledge on fetal genome and physiology. Novel scientific innovations in prenatal diagnosis have accelerated in the last decade changing our vision immensely. Data obtained from fetal genomic studies brought new insights to fetal medicine and by the advances in fetal DNA and RNA sequencing technology novel treatment strategies has evolved. Non-invasive prenatal diagnosis found ground in genetics and the results are widely studied in scientific arena. When Lo and colleges proved fetal genetic material can be extracted from maternal plasma and fetal DNA can be isolated from maternal serum, the gate to many exciting discoveries was open. Microarray technology and advances in sequencing helped fetal diagnosis as well as other areas of medicine. Today it is a very crucial prerequisite for physicians practicing prenatal diagnosis to have a profound knowledge in genetics. Prevailing practical use and application of fetal genomic tests in maternal and fetal medicine mandates obstetricians to update their knowledge in genetics. The purpose of this review is to assist physicians to understand and update their knowledge in fetal genetic testing from maternal blood, individualized prenatal counseling and advancements on the subject by sharing our experiences as Istanbul University Fetal Nucleic Acid Research Group. PMID- 28913029 TI - Intracranial foreign body (bullet) during pregnancy. AB - Intracranial foreign bodies during pregnancy is a very rare condition, however its maternal and fetal outcomes are very crucial with regard to morbidity and mortality. Furthermore wounding by firearms is still a public health problem particularly in our country. Intracranial foreign bodies during pregnancy is high risk pregnancy and must be managed with care and multidisciplinary approach. During this course and labour avoiding the increase in intracranial pressure is the most important key point. In this case report we present the follow-up and outcome of a patient with bullet in brain after intracranial injury caused by firearm. PMID- 28913030 TI - Vaginal cuff dehiscence with bowel evisceration after robotic hysterectomy. AB - Vaginal cuff dehisence with bowel evisceration after hysterectomy is a very rare complication. However, the incidance of this complication appears to be increased with the widely used techniques of laparoscopic surgery especially with robotic hysterectomy. In this case report we aimed to evaluate the risk factors and treatment methods for this complication. PMID- 28913031 TI - Vaginal breech deliveries: Trend in the past 30 years. PMID- 28913032 TI - Factors affecting general sleep pattern and quality of sleep in pregnant women. AB - OBJECTIVE: To investigate factors affecting general sleep pattern and sleep quality in pregnant women. MATERIALDS AND METHODS: We assessed all pregnant women applied to Department of Obstetrics and Gynecology in Training and Research Hospital, School of Medicine, Kahramanmaras Sutcu Imam University between 01 January 2014 and 01 March 2014. The participants were informed prior to the study and 100 pregnant women who gave their informed consent were included in the study. Questionnaires consisting sociodemographic characteristics, pregnancy history and the Epworth sleepiness scale were applied to the patients. Factors affecting general sleep pattern and sleep quality in pregnant women were compared. RESULTS: The mean age of 100 pregnant women was 27.9 years (min=16, max=42). The mean gestational age of participants was found to be 24.8 weeks (min=5, max=40). In obstetric history, 9% of women previously had a stillbirth and also 25% of women previously had curettage performed. There were tobacco use in 6% of participants and 6% of patients previously had been to the hospital due to a sleep disorder. The mean excessive daytime sleepiness scale score of pregnant women were found to be 4.56. There were no significant difference among the patients regarding regular exercise (p=0.137), tobacco use (p=0.784), accompanying disease (p=0.437) and excessive daytime sleepiness scale score. CONCLUSION: In our study, patients who had a complaint of sleep disorder before and who were previously admitted to a health center for this problem, were also found to suffer from the same problem during pregnancy. Treatment of sleep disorders in preconception period for women planning pregnancy is important in terms of mother and the baby's health. Pregnant women should be informed about factors reducing sleep quality during pregnancy. PMID- 28913033 TI - The effect of preserving prepared sperm samples at room temperature or at 37 degrees C before intrauterine insemination (IUI) on clinical pregnancy rate. AB - OBJECTIVE: The comparison of the effect of preserving prepared sperm samples at room temperature or at 37 degrees C before intrauterine insemination (IUI) on clinical pregnancy rate. MATERIALS AND METHODS: Retrospective clinical research. University hospital, infertility clinic. Patients with one or two follicles, between the ages of 20 and 40, whose infertility period was less than 6 years and the injected total motile sperm count was more than 10 million. Preserving sperm samples prepared for IUI at 37 oC or at room temperature before IUI. The clinical pregnancy rate of IUI cycles between 1st of January 2004 and 1st of December 2011 in which prepared sperm samples were preserved at 37 oC and the clinical pregnancy rate of IUI cycles between 1st of December 2011 and 31st of May 2014 in which prepared sperm samples preserved at room temperature. RESULTS: Clinical pregnancy rates were similar in IUI cycles in which prepared sperm samples were preserved at 37 oC and at room temperature (9.3% vs. 8.9%). Clinical pregnancy rates in IUI cycles with 2 follicles were higher than IUI cycles with 1 follicle (10.8% vs. 7.6%) (p=0.002). Further statistical analysis after splitting data according to the number of the follicles revealed that there was no statistical difference between clinical pregnancy rates after IUI cycles in which prepared sperm samples were preserved at 37 oC or at room temperature in both one follicle (7.6% vs. 7.6%), and two follicle cycles (11.5% vs. 10.1%). CONCLUSIONS: Preserving prepared sperm samples at room temperature had no negative effect on clinical pregnancy rates when compared with reserving prepared sperm samples at 37 oC during IUI cycles. PMID- 28913034 TI - A comparison between stabilization exercises and pelvic floor muscle training in women with pelvic organ prolapse. AB - OBJECTIVE: This study aimed to compare the effectiveness of stabilization exercises and pelvic floor muscle training in women with stage 1 and 2 pelvic organ prolapse. MATERIALS AND METHODS: In a total 38 women with pelvic organ prolapse whose average age was 45.60 years, pelvic floor muscles were evaluated with electromyography, and prolapse with pelvic organ prolapse quantification system, and the quality of life with prolapse quality of life questionnaire. Afterwards, the subjects were divided into two groups; stabilization exercise group (n=19) and pelvic floor muscle training group (n=19). Stabilization exercise group were given training for 8 weeks, 3 times a week. Pelvic floor muscle training group were given eight-week home exercises. Each group was assessed before training and after eight weeks. RESULTS: An increase was found in the pelvic muscle activation response in the 2 groups (p<=0.05). There was no difference in EMG activity values between the groups (p>0.05). A difference was found in the values Aa, Ba and C in subjects of each group (p<=0.05), and the TVL, Ap, Bp and D values of subjects in pelvic floor muscle training group (p<=0.05) in the before and after pelvic organ prolapse quantification system assessment, however, no difference was found between the groups (p<=0.05). A positive difference was found in the effect of prolapse sub parameter in each of the two groups, and in general health perception sub parameter in subjects of stabilization exercise group (p<0.05) in the prolapse quality of life questionnaire. CONCLUSIONS: It was concluded that both training programs increased the pelvic floor muscle strength, provided a decline in prolapse stages. Stabilization exercise has increased general health perception unlike home training, thus, these exercises can be added to the treatment of women with prolapse. PMID- 28913035 TI - The relationship between Polycystic ovary syndrome and vitamin D levels. AB - OBJECTIVE: The main aim of this study was to determine the association of serum 25-hydroxyvitamin D (25-OH D) levels with hormonal, clinical and metabolic profile in patients with and without Polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: Forty-eight normal-weight (body mass index (BMI) of 19-24.99 kg/m2) women with PCOS, 36 overweight (BMI of 25-29.9 kg/m2) women with PCOS and 56 normal-weight controls participated in the study. Blood samples were collected in the early follicular phase (between day 2 and day 5 of the menstrual cycle) at 9:00 am after an overnight fast. Circulating concentrations of 25-OH D, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, TSH, free testosterone, dehydroepiandrosterone sulphate (DHEA-SO4), 17 hydroxyprogesterone, sex hormone-binding globulin (SHBG), fasting insulin, fasting glucose, and lipid profile were assessed. RESULTS: Normal weight (BMI 19 24.99 kg/m2) and overweight (BMI 25-29.99 kg/m2) women with PCOS were compared with normal-weight controls and lower 25-OH D levels were found in both PCOS groups (p<0.05 and p<0.01, respectively 25-OH D significantly negatively correlated with waist circumference (WC), waist-to-hip ratio (WHR), free testosterone and modified Ferriman-Gallwey scores, however, there was a positive correlation between 25-OH D and SHBG levels (p<0.05). CONCLUSION: Our findings suggest that PCOS is associated with hypovitaminosis D. PMID- 28913036 TI - What is the fate of scientific abstracts? The publication rates of abstracts presented at the 7th National Congress of Gynecology and Obstetrics. AB - OBJECTIVE: Oral and poster presentations held at national and international congresses are recognized as valuable tools for sharing current scientific data and experience among physicians. However, a large proportion of these works fail to be published in scientific journals. We have designed a study to identify the publication rate of presentations held at the 7th National Congress of Obstetrics and Gynecology in 2009. MATERIALS AND METHODS: A systematic search of databases was performed using author names and key words from the abstract title to locate publications in peer-reviewed journals corresponding to the presentations held at the 7th National Congress of Obstetrics and Gynecology. Information regarding mode of presentation, topic, type of affiliation, name and impact factor of the scientific journal, change in author names and time elapsed between presentation and publication were recorded and analyzed statistically. RESULTS: Of 243 abstracts that were presented at the congress, 45 papers (18.5%) were published in international peer-reviewed journals, whereas 39 (16%) were published in national journals. The mean time to publication was 17+/-2 months for international and 11+/-4 months for national journals (p=0.102). The international publication rate of oral presentations was significantly higher than that of poster presentations (50% vs. 16.2%; p<0.03). The manuscripts were published in a total of 21 journals, with four journals accounting for 49% of the publications. The comparison of the publication rates of the universities with other institutions has yielded no significant difference. CONCLUSION: Alltough a significant proportion of the abstracts presented in the 7th National Gynecology and Obstetrics Congress have been succesfully converted to publication overall, only a limited percentage of all abstracts have been published in international peer-reviewed journals. The relatively higher conversion to international publication rate of the oral presentations show that they are of higher interest and clinical relevance. PMID- 28913037 TI - Predictive factors for latency period in viable pregnancies complicated by preterm premature rupture of the membranes. AB - OBJECTIVE: In this study, we aimed to evaluate some laboratory and clinical factors in the prediction of latency period for pregnant patients complicated with preterm premature rupture of the membranes. MATERIALS AND METHODS: Sixty five pregnant patients between 24 and 34 weeks of gestation, who were admitted to University of Cukurova School of Medicine Hospital with the diagnosis of preterm premature rupture of the membranes (PPROM) between January 01, 2013 and December 31, 2013, were included in this study. Serum CRP, procalcitonin, sedimentation rate, leukocyte count and cervical length (measured with transvaginal ultrasound) of patients were analyzed for the correlation with the latency period. RESULTS: None of the parameters were found to be correlated with the latency period. However, patients with cervical length of <25 mm were found to have shorter duration of latency. CONCLUSION: Although preterm premature rupture of the membranes is thought to be either an infection-based disease or a disease increasing the risk of infectious complications, major infection markers are not found to be helpful criteria for the prediction of latency period. Patients with a cervical length of <25 mm can be expected to deliver earlier and, therefore, can be referred to a tertiary center earlier. PMID- 28913038 TI - The effect of magnesium sulphate on postoperative analgesia requirements in gynecological surgeries. AB - OBJECTIVE: Recent studies have shown the positive effect of magnesium sulphate (MgSO4) on pain reduction and postoperative analgesic requirements in patients undergoing surgery. We assessed the effect of MgSO4 on intra-operative and postoperative analgesic requirements in patients undergoing lower abdominal gynecological laparotomy. MATERIALS AND METHODS: This randomized clinical trial was conducted on 30 female patients at Rasool-e-Akram (referral and academic) hospital in Tehran from August 2012 to March 2013. The patients who were candidates for gynecologic surgeries (hysterectomy and/or myomectomy) were randomized into study (n=15) and control (n=15) groups. Same anesthetic technique was used in all patients. Besides induction of the anesthesia in the study group, we administered MgSO4 50 mg/kg/hr intravenously (IV) for analgesic purposes as a bolus dose and then 8 mg/kg IV as maintenance dose. Control group received the same anesthetic agents and the same amount of isotonic saline instead of MgSO4. Analgesic consumption was measured in both groups postoperatively within 24 hours. The visual analog scale (VAS) was used for the evaluation of postoperative pain in both groups. RESULTS: There was a decrease in analgesic consumption and pain in the group receiving MgSO4, in comparison to control group. Pain severity assessment, 24 hours post operatively showed similar results in both groups. There was a statistically significant difference in prescribed dose of pethidine between study and control groups (p=<0.0001). CONCLUSION: Intra-operative MgSO4 is effective in postoperative pain control following lower abdominal laparotomy. Further studies with larger sample sizes and longer follow-up should be performed to obtain more information about safety and to determine whether doses of MgSO4 can provide postoperative analgesic benefits. PMID- 28913039 TI - Uterus transplantation: Experimental animal models and recent experience in humans. AB - Uterus transplantation has been considered as an alternative management modality in the last few years for adoption or gestational surrogacy for women with absence of uterus due to congenital or acquired reasons. Surrogacy is legal in only a few countries because of ethical, social and legal issues. Up to date, a total of 11 uterus transplantation cases have been reported in which uteri were harvested from ten live donors and one donor with brain death. After unsuccessful attempt of first uterus transplantation, many studies have been conducted in animals and these experimental models enabled our knowledge to increase on this topic. First experimental studies were performed in rodents; later uterus transplantation was accomplished in sheep, pigs and rabbits. Recently, researches in non-human primates have led the experience regarding transplantation technique and success to improve. In this review, we reviewed the experimental animal researches in the area of uterus transplantation and recent experience in humans. PMID- 28913041 TI - Uterine inversion as an extremely rare cause of secondary infertility: A case report. AB - Today, infertility takes a major place in gynecology practice. Non-puerperal uterine inversion is a rare event and usually accompanies submucous myoma, leiomyosarcoma, rhabdomyosarcoma, malignant mixed Mullerian tumour, and endometrial polyp. Herein, we report a 39-year-old woman who suffered from secondary infertility together with uterine inversion, which is an extremely rare co-existence. PMID- 28913040 TI - Factors affecting age of onset of menopause and determination of quality of life in menopause. AB - Menopause is a process in the climacteric period, characterized by a reduction in ovarian activity, a fall in the fertility rate, and a range of symptoms including irregular menstruation intervals. Most women enter menopause in their 40s, but this can vary from one individual to another. Although there are many factors affecting the age of menopause onset, there is no general agreement on them. Studies have shown many factors to affect the age of menopause, such as the mother's age at menopause, the age at menarche, gestational age, use of oral contraceptives, irregular menstrual cycle, number of pregnancies, body mass index, use of tobacco and alcohol, physical activity, unilateral oophorectomy, serum lead levels, consumption of polyunsaturated fat, socioeconomic status and educational level. During this period, hormonal and biochemical changes give rise to various symptoms in the woman's body. In menopause period, physical, psychological, social and sexual changes have a negative effect on quality of life in women. Recently, different measures have been used to assess women's quality of life in this period of change. The purpose of this review was to examine the factors affecting the onset age of menopause and the measures of quality of life related to menopause. PMID- 28913042 TI - Mitotically active cellular fibroma of the ovary: A case report. AB - Fibromas are classified in a spectrum from fibromas to fibrosarcomas according to the number of mitosis they include. Malignant fibrosarcomas which have aggressive pattern show higher mitotic activity and nuclear atypia. Cellular fibromas with less than 4 mitotic figures under 10 high power fields (HPF) are benign. "Mitotically active cellular fibromas" that are classified between the cellular fibromas and fibrosarcomas, have >=4 mitotic figures in 10 HPF but do not have nuclear atypia. A very few cases of mitotically active cellular fibromas have been reported in the literature. In this report, we present the case of mitotically active cellular fibroma in a patient who applied to our clinic with the complaint of pelvic mass. PMID- 28913043 TI - Wilson's disease presenting with HELLP syndrome; A case report. AB - Wilson's disease (WD) is an autosomal recessive disorder. It is characterized by toxic accumulation of copper mainly in the liver and brain but also in cornea and kidney due to a defect in biliary excretion of copper. The hepatic manifestation of WD is diverse and may include asymptomatic elevation of aminotransferase, chronic hepatitis, cirrhosis, or acute/fulminant hepatic failure. Characteristic of acute hepatic failure in WD is concomitance of acute intravascular hemolytic anemia. Acute intravascular hemolytic anemia and thrombocytopenia in WD may be interpreted as a feature of Hemolysis, Elevated Liver Enzymes, Low Platelet Count (HELLP) syndrome besides acute liver failure. The differential diagnosis may be very difficult. Here, WD in pregnancy presenting with clinical symptoms of HELLP syndrome and developing acute liver failure in postpartum period is discussed. PMID- 28913045 TI - Do the interactions between coital frequency, cervical length, and urogenital infection affect obstetric outcomes? AB - OBJECTIVE: To determine whether interactions between coital frequency, cervical length, and urogenital infection affect obstetric outcomes. MATERIALS AND METHODS: A total of 268 unselected pregnant women were recruited in the study. The study population consisted of four groups of women: group 1 (n=203) screened negative for bacterial vaginosis (BV) both in the first and second trimesters; group 2 (n=18) screened negative for BV in the first trimester but positive in the second trimester; group 3 (n=33) screened positive for BV in the first trimester but negative in the second trimester; and group 4 (n=14) screened positive for BV both in the first and second trimesters. Urine culture, cervico vaginal cultures, and bacterial vaginosis were screened between 11-14 weeks and 20-24 weeks. RESULTS: Two hundred fifty women were eligible for analysis in the study after lost-to-follow up patients were excluded. Previous abortion >=1 and previous preterm delivery at 24-34 weeks >=1 were statistically significantly higher in group 2. The number of patients who were diagnosed as having preterm premature rupture of membranes (PPROM) was statistically significantly higher in group 4. Sexual intercourse during the first trimester, cervical length during the second trimester, and history of preterm birth (PTB) were statistically significant risk factors for preterm birth <37 weeks (1.27; (1.12-1.44); 5.33; (1.84-15.41); 6.95; (1.58-30.54), respectively). CONCLUSION: Presence or treatment of BV did not influence rates of PTB. The probability of PPROM would be higher in patients who are BV positive both in the first and second trimesters. PMID- 28913044 TI - The combination of dehydroepiandrosterone, transdermal testosterone, and growth hormone as an adjuvant therapy in assisted reproductive technology cycles in patients aged below 40 years with diminished ovarian reserve. AB - OBJECTIVE: To evaluate to the efficacy of testosterone, dehydroepiandrosterone (DHEA) and growth hormone (GH) supplementations in patients with diminished ovarian reserve (DOR) in assisted reproductive technology (ART) cycles. MATERIALS AND METHODS: A retrospective cohort including 33 women with 81 ART cycles were aged and ovarian reserve matched 52 women with 102 conventional in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) protocol. Administration of DHEA for 12 weeks and transdermal testosterone for 4 weeks as pretreatment adjuvant and luteal start GH in DOR patient treatment arm compared to conventional IVF/ICSI cycles. RESULTS: The number of follicles >14 mm, number of oocytes, number of metaphase 2 oocytes and fertilisation rate were significantly higher in ISIK protocol (IP). The clinical pregnancy rate (CPR) per embryo transfer of the IP was 38.2% (13/34). The cancellation rate of cycles decreased significantly from 54.5 % (24/44) to 8.1% (3/37) with the IP, while the OPR was 35.3% (12/34). CONCLUSIONS: Our study has shown that even the poorest responders could achieve clinical pregnancy after inducing ovarian folliculogenesis with a combination of transdermal testosterone, DHEA and GH. PMID- 28913046 TI - Six-year incidence and some features of cases of brachial plexus injury in a tertiary referral center. AB - OBJECTIVE: To present some features and incidence of cases of brachial plexus injury in deliveries at the Department of Obstetrics and Gynecology of Zeynep Kamil Maternity and Children's Training and Research Hospital, from January 2010 through December 2014. MATERIALS AND METHODS: In total, 38.896 deliveries in the Department of Obstetrics and Gynecology of Zeynep Kamil Maternity and Children's Training and Research Hospital, from January 2010 through December 2014 were screened from a prospectively collected database. We recorded gravidity, parity, body mass index, maternal diabetes, labor induction, gestational age at delivery, operative deliveries, malpresentations, prolonged second stage of deliveries, shoulder dystocies, clavicle and humerus fructures, estimated fetal weight, biparietal diameter, abdominal circumference, femur length, fetal sex, route of delivery, maternal age, and fetal anomalies. RESULTS: There were 28 (72/100.000) cases of brachial plexus injury among 38.896 deliveries. In the 6-year study period, there were 18.363 deliveries via c-section, whereas 20.533 were vaginal deliveries. CONCLUSION: Sonographic fetal weight estimation and clinical examination performed by experienced obstetricians, and active appropriate management of shoulder dystocias seemed to attenuate the incidence of brachial plexus injury in the at risk population in our tertiary referral center. PMID- 28913047 TI - What is Turkish women's opinion about vaginal delivery? AB - OBJECTIVE: To determine Turkish women's opinion about vaginal birth. MATERIALS AND METHODS: This prospective cohort study was conducted in Department of Obstetrics and Gynecology of Suleymaniye Maternity Research and Training Hospital in Istanbul, Turkey, between February 2015 and April 2015. The participants of this study were 100 primiparous pregnant women who had vaginal deliveries. The women were interviewed face-to-face after the birth. Data were collected through a socio-demographic and clinical questionnaire. RESULTS: Ninety percent of the women reported vaginal birth as the ideal mode of delivery route; a minority of the women (10%) had decided on cesarean birth before having a vaginal birth. Anxiety of pain was the major factor that influenced choice of delivery type before giving birth. After vaginal birth, 84% of women were satisfied with vaginal birth and reported that they would prefer vaginal birth for their next pregnancy. However, 16% reported that they would prefer cesarean birth for their next pregnancy due to pain of labor, pain of episiotomy, anxiety, and prolonged duration of labor. CONCLUSION: The results suggest the majority of women prefer to give birth vaginally and reported vaginal birth as the ideal choice. PMID- 28913048 TI - Seroprevalence of Toxoplasma, Rubella, and Cytomegalovirus among pregnant women in Van. AB - OBJECTIVE: To determine the seroprevalence of anti-Toxoplasma, anti-Rubella, and anti-Cytomegalovirus (CMV) antibodies among pregnant women receiving prenatal care at Van Training and Research Hospital. MATERIALS AND METHODS: In developing countries, various infectious agents encountered in the gestational period are important because they influence both maternal and fetal health. Among these, Toxoplasma gondii, Rubella and CMV are quite prevalent. In the present study, anti-Toxoplasma, anti-Rubella and anti-CMV antibodies were analyzed in the serum samples obtained from women receiving prenatal care at Van Training and Research Hospital between June 2012 and July 2013, and positive serum samples were retrospectively evaluated. Anti-Toxoplasma, anti-Rubella and anti-CMV antibodies were analyzed using ELISA with Cobas 4000 e411 (Roche, Germany) and Architect i2000SR (Abbott Diagnostics, Germany) analyzers. RESULTS: Over the course of the study period, the results of a total of 9809 patients were investigated in terms of anti-Toxoplasma, anti-Rubella, and anti-CMV antibodies. Anti-Toxoplasma, anti Rubella, and anti-CMV IgM and IgG antibody positivity rates were 1.1%, 0.5% and 2.6%, and 37.6%, 86.5% and 100%, respectively. CONCLUSION: Anti-Toxoplasma IgG antibody positivity rates determined in the present study were lower as compared with the results of the other studies reported from Turkey. However, CMV IgM and IgG antibody positivity rates were be higher as compared with those reported in the literature. PMID- 28913049 TI - Primary carcinoma of the fallopian tubes: Analysis of sixteen patients. AB - OBJECTIVE: The aim of this study was to review patients with tubal carcinoma who underwent surgery in our clinic due to primary carcinoma of the fallopian tubes, a very rare gynecologic malignancy. MATERIALS AND METHODS: Sixteen patients who were diagnosed as having primary carcinoma of the fallopian tubes and underwent surgery in Zeynep Kamil Research and Training Hospital between January 2007 and December 2014 were included in the study. Demographic data such as age, gravidity, parity, menopausal condition, symptoms, adjuvant therapy, recurrence of tumor, as well as time and type of operation were extracted from patient epicrisis reports and oncology files. Patient information was extracted from the patients' current files and phone calls were made with patients and their relatives. RESULTS: The mean age of patients was 59.6 (range, 43-78) years. Seventy-five percent of the women were menopausal at admission; the mean menopause duration was 10 years (range, 1-20 years). None of the patients were nulliparous and mean parity was 4.3 (2-8). The most common presenting symptom was abdominopelvic pain, followed by abnormal uterine bleeding. The most common histopathologic type was high-grade serous carcinoma. The mean follow-up duration was 23.7 months (range, 2-53 months). During follow-up, recurrence was seen in 4 (25%) patients. One patient left the study during follow-up. The mean disease free survival was 48 months. No relation was found between disease-free survival, age, stage, grade, and histologic type in univariate logistic regression analysis. CONCLUSION: Primary carcinoma of the fallopian tubes is a rare gynecologic tumor that is seen in older patients, has no specific signs, and usually cannot be diagnosed before surgery. Therefore, we think that large series, multi-centered studies with long-term follow-up duration are needed to define its etiopathogenesis and treatment strategies for the disease. PMID- 28913050 TI - Evaluation of dietary habits during pregnancy. AB - OBJECTIVE: Pregnancy is a special period of increased nutritional needs during which conscious nutritional support is required. Insufficient and imbalanced nutrition in this period of life causes serious conditions that affect both child and mother. This study aimed to evaluate the relationship between pregnancy and nutrition/nutritional habits during pregnancy. MATERIALS AND METHODS: In this descriptive study, a questionnaire was conducted on a voluntary basis to pregnant women who were admitted to the Pregnancy Outpatient Clinic of Obstetrics and Gynecology Department at Ankara Numune Training and Research Hospital. Questions about general information, pregnancy-related information, thoughts and knowledge about breastfeeding, nutritional habits, and meal frequency were asked to pregnant women. Three hundred fourteen questionnaires were assessed in the study. SPSS for Windows Version 16.0 and MS-Excel 2007 were used for statistical evaluations. P<0.05 was accepted as statistical significance. RESULTS: There was a statistically significant relationship between pre-pregnancy body mass index (BMI) and number of pregnancies; level of education and income levels; number of children and history of caesarian section as an additional problem within previous pregnancies. The change of nutritional habits during pregnancy was examined; we found that consumption of fruits (51%) and vegetables (40.8%) increased the most, while intake of tea (26.1%) and redmeat (21%) mainly decreased during pregnancy. It was found that during pregnancy 20.4% of pregnant women had never consumed fish, 13.1% abstained from red meat, and 12.4% excluded white meat from their diet. CONCLUSIONS: We believe that this study will help to raise awareness about adequate and balanced nutrition during pregnancy and to define special nutritional recommendations. PMID- 28913051 TI - Gonadotropin-releasing hormone agonist triggering of oocyte maturation in assisted reproductive technology cycles. AB - Gonadotropin-releasing hormone agonists (GnRHa) have gained increasing attention in the last decade as an alternative trigger for oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS). They provide a short luteinizing hormone (LH) peak that limits the production of vascular endothelial growth factor, which is the key mediator leading to increased vascular permeability, the hallmark of OHSS. Initial studies showed similar oocyte yield and embryo quality compared with conventional human chorionic gonadotropin (hCG) triggering; however, lower pregnancy rates and higher miscarriage rates were alarming in GnRHa triggered groups. Therefore, two approaches have been implemented to rescue the luteal phase in fresh transfers. Intensive luteal phase support (iLPS) involves administiration of high doses of progesterone and estrogen and active patient monitoring. iLPS has been shown to provide satisfactory fertilization and clinical pregnancy rates, and to be especially useful in patients with high endogenous LH levels, such as in polycystic ovary syndrome. The other method for luteal phase rescue is low-dose hCG administiration 35 hours after GnRHa trigger. Likewise, this method results in statistically similar ongoing pregnancy rates (although slightly lower than) to those of hCG triggered cycles. GnRHa triggering decreased OHSS rates dramatically, however, none of the rescue methods prevent OHSS totally. Cases were reported even in patients who underwent cryopreservation and did not receive hCG. GnRH triggering induces a follicle stimulating hormone (FSH) surge, similar to natural cycles. Its possible benefits have been investigated and dual triggering, GnRHa trigger accompanied by a simultaneous low-dose hCG injection, has produced promising results that urge further exploration. Last of all, GnRHa triggering is useful in fertility preservation cycles in patients with hormone sensitive tumors. In conclusion, GnRHa triggering accompanied by appropriate luteal phase rescue protocols is a relatively safe option for patients at high risk for OHSS. PMID- 28913053 TI - Pregnancy with sigmoid volvulus: A case report with literature review. AB - Sigmoid volvulus refers to torsion of a segment of the alimentary tract, which often leads to bowel obstruction and ischemic changes. Sigmoid volvulus is an acute surgical emergency because delay in diagnosis and management can cause adverse maternal and fetal complications. Sigmoid volvulus typically presents with acute-on-chronic abdominal distension that may develop slowly over 3-4 days. An early and effective resuscitation with fluid replacement, electrolyte balance correction, prophylactic antibiotics and nasogastric decompression is necessary. The standard goals of treatment are to relieve the obstruction, avoid colonic ischemia, and prevent recurrence either by endoscopic decompression or resection with primary anastomosis. A pregnant woman with sigmoid volvulus at 34 weeks and 1 day of gestation presented to our hospital with abdominal pain, vomiting, and constipation. The patient was jointly surgically managed with laparotomy, cesarean section, and detorsion of the sigmoid volvulus, and was discharged in a healthy state on the 5th postoperative day. PMID- 28913052 TI - The risk factors, consequences, treatment, and importance of gestational depression. AB - Nowadays, mental problems have become an important health issue, the most frequent of which in pregnancy is depression. Gestational depression is known to increase gestational complications and negatively affect maternal and fetal health. The frequency of gestational depression and depressive symptoms are 10 30%. Risk factors vary according to genetic, psychologic, environmental, social, and biologic factors. Maternal morbidity and mortality rates increase in pregnant women who do not receive treatment, obstetric complications and negative fetal consequences are seen, and the incidence of postpartum depression increases. Due to all these important consequences, healthcare providers who manage pregnant women should be informed about the frequency, symptoms, and screening methods of postpartum depression, the significance of the consequences of undiagnosed and untreated depression on the health of mother and baby, and the importance of early diagnosis. Pregnant women who are at risk should be screened and detected, and directed to related centers. In this review, we briefly review the definition of gestational depression, its frequency, risk factors, complications, screening, treatments, and the procedures that need to be performed the diagnostic process. PMID- 28913054 TI - Renal angiomyolipoma during pregnancy: Case report and literature review. AB - Renal angiomyolipoma is a rare tumor that can be either sporadic or found together with tuberous sclerosis or pulmonary lymphangioleiomyomatosis. These tumors are hormone sensitive and therefore tend to grow during pregnancy and their main complication is the risk of rupture. Optimal management is still controversial because there are very few cases reported in the literature. We expect that the case of our patient, who delivered her baby vaginally at 36 weeks of gestation and underwent definitive treatment (nephrectomy) thereafter, to further enhance the knowledge about the management of these rare tumors during pregnancy. PMID- 28913055 TI - Postmenopausal spontaneous uterine perforation: Case report. AB - Spontaneous uterine rupture and generalized peritonitis caused by pyometra occurs rarely with high morbidity and mortality. A correct and definite diagnosis can be made with laparotomy or laparoscopy. The clinical findings of perforated pyometra are similar to perforation of the gastrointestinal tract and gynecologic symptoms are less frequent, which makes preoperative diagnosis difficult. We report a case of a patient aged 82 years who underwent surgery for spontaneous uterine rupture and generalized peritonitis as a result of pyometra. PMID- 28913056 TI - The effects of thalidomide in a rat model of surgically-induced endometriosis. AB - OBJECTIVE: The aim of the study was to analyze the anti-angiogenic role of thalidomide and to assess whether thalidomide had any influence on a rat model of surgically-induced endometriosis. MATERIALS AND METHODS: Endometriosis was induced through surgical induction and homologous transplantation in 16 rats. The rats were randomly separated into two groups as thalidomide (n=8) and control (n=8) groups. Using oral gavage, 100 mg/kg thalidomide 0.5 ml was administered to the first group and saline 0.5 ml to the control group. Histopathologic findings and volume analysis of implants were evaluated after 4 weeks. Vascular endothelial growth factor-A (VEGF-A) and oxidative markers were run from the fluid through peritoneal lavage. RESULTS: The average implant volume decreased significantly in the thalidomide administrated group after treatment (53.3 and 22.9 mm3 respectively, p=0.012). Significant differences observed in the histopathologic scores of the thalidomide group (3 and 1 respectively, p=0.012) were not observed in the control group. Significant decreases were observed in the levels of VEGF-A and myeloperoxidase (MPO) from oxidative markers (p=0.004, p=0.037, respectively). CONCLUSION: Thalidomide provides volumetric and histopathologic recovery in implants particularly because the VEGF inhibition and anti-angiogenic effect, which suggests that it could be effective in the treatment of endometriosis. PMID- 28913057 TI - The effects of fresh embryo transfers and elective frozen/thawed embryo transfers on pregancy outcomes in poor ovarian responders as defined by the Bologna criteria. AB - OBJECTIVE: To compare the effects of fresh embryo transfers (ET) and elective frozen/thawed embryo transfers (eFET) on implantation, clinical pregnancy, and live birth rates in poor ovarian responders, as defined by the Bologna criteria. MATERIALS AND METHODS: All electronic databases of embryo transfers between January 2011 and January 2014 were retrospectively reviewed. Two hundred fifty nine of all the fresh ET and 96 of all eFET were included into the study. An antagonist protocol with letrozole was used for the controlled ovarian hyperstimulation (COH) in all participants. RESULTS: The mean age was 36.9 years (range, 21-43 years) in the fresh ET arm and 37.2 years (range, 21-43 years) in the eFET arm (p=0.45). The clinical pregnancy rate was 35% (90/259) versus 29% (28/96); the abortion rate was 27% (20/75) versus 36% (9/25); and the live birth rate was 21% (55/259) versus 17% (16/99). There were no significant differences between groups and p values were 0.32, 0.52, and 0.42, respectively. The mean E2 level was 389 (range, 50-2055 pg/mL) in the fresh ET group (on hCG day) and 418 pg/mL (range, 121-3073 pg/mL) in the eFET group (on day 14 of cycle) (p=0.122). No differences were found between the two groups with respect to the total number of retrieved oocytes (p=0.55) and number of metaphase II (MII) oocytes (p=0.81). The number of embryo transfers was statistically different (p=0.005). The effects of age, total number of retrieved oocytes, number of MII oocytes, type of treatment, number of ET, and the day of ET and E2 level to live birth outcomes were investigated using binary logistic regresion analyses, and no stastical effect was determined by any of the parameters. P values were p=0.50, 0.66, 0.45, 0.30, 0.30, 0.08, and 0.90, respectively. CONCLUSION: E2 levels tend to be lower in poor responders, thus the receptivity of the endometrium may be damaged less than normal, which may explain why pregnancy results are the same between eFET and ET groups. PMID- 28913058 TI - Laparoscopic staging of endometrial cancer: Does it have any impact on survival? AB - OBJECTIVE: To assess whether laporoscopic approach to endometrial cancer is associated with survival. MATERIALS AND METHODS: In total, 158 patients with endometrial cancer underwent staging surgery at a tertiary referral center, 30 of whom underwent laparoscopy, whereas the remainder received treatment with a conventional approach. Survival between groups was analyzed. RESULTS: The comparison of the groups revealed similar disease-free survival (p=0.791). Histology, cervical, adnexal and serosal involvement were found to be significantly correlated with recurrence in the laparoscopically staged group, whereas CA 125, histology, tumor grade, tumor diameter, cervical involvement, degree of myometrial invasion, adnexal and serosal involvement, and pelvic metastasis were significanly correlated with recurrence in the conventionally managed group. CONCLUSION: Laparoscopic approach to endometrial cancer, along with its widely accepted postoperative advantages, has similar disease-free survival but different variables affect recurrence rates. PMID- 28913059 TI - Should we add unilateral sacrospinous ligament fixation to vaginal hysterectomy in management of stage 3 and stage 4 pelvic organ prolapse? AB - OBJECTIVE: To compare ''vaginal hysterectomy alone'' with ''vaginal hysterectomy with prophylactic unilateral sacrospinous ligament fixation'' in terms of intraoperative complications and 1-year anatomic outcomes and symptoms in patients aged over 50 years who presented with stage 3 or 4 pelvic organ prolapse (POP). MATERIALS AND METHODS: Thirty-five patients underwent vaginal hysterectomy alone and 32 patients underwent vaginal hysterectomy with unilateral sacrospinous ligament fixation because of benign pathology between January 2012, and June 2014, were retrospectively analyzed in this study. The patients' demographic data and preoperative and intraoperative findings were obtained from the hospital records and noted. The patients were invited by phone to a follow-up visit to assess their 1-year anatomic outcomes and symptoms. RESULTS: There was no significant demographic difference between the patients who underwent vaginal hysterectomy alone and those who had a vaginal hysterectomy with sacrospinous ligament fixation. Both length of operation and hospital stay were significantly longer in the patients who underwent vaginal hysterectomy with sacrospinous ligament fixation (p<0.001); intraoperative complications requiring blood transfusion were also significantly more frequent in these patients compared with the patients who underwent vaginal hysterectomy only (p=0.048). Recurrence of vaginal vault prolapse was significantly more frequent in the patients with vaginal hysterectomy alone compared with those who had both vaginal hysterectomy and sacrospinous ligament fixation (p=0.035). CONCLUSION: Unilateral sacrospinous ligament fixation might be added to vaginal hysterectomy in patients with stage 3 or 4 POP who are predicted to have long survival times. However, further studies with a larger sample size are needed in this area of research. PMID- 28913060 TI - Neither early nor late for becoming pregnant: Comparison of the perinatal outcomes of adolescent, reproductive age, and advanced maternal age pregnancies. AB - OBJECTIVE: To compare perinatal and short-term neonatal outcomes of adolescent, reproductive age, and advanced maternal age (AMA) pregnancies in a low-income region of Istanbul. MATERIALS AND METHODS: Three hundred six adolescents, 301 reproductive age, and 303 AMA pregnant women who delivered in Suleymaniye Education and Research Hospital between January 1st 2007, and January 31st 2015, were recruited to the study population. The clinical, obstetric and short-term neonatal outcomes of the women were analyzed retrospectively. RESULTS: Adolescent and AMA pregnancies were associated with severe adverse perinatal and short-term neonatal outcomes compared with reproductive-age women. Adolescent and AMA pregnancies had quite similar risks in obstetric outcomes. Adolescent pregnancies were related with severe adverse short-term neonatal outcomes when compared with advanced maternal age pregnancies. CONCLUSION: Adolescent and AMA pregnancies should be defined as high-risk pregnancies. Our research indicated that healthcare providers such as obstetricians, midwives, and family physicians should be alert in these populations. PMID- 28913062 TI - Efficacy of endocervical curettage and CA-125 measurement in endometrial serous carcinoma: A case series and literature review. AB - OBJECTIVE: This is a case series and literature review of patients with endometrial serous carcinoma (ESC) in which endocervical curettage (ECC) and CA 125 measurement were utilized as a diagnostic procedure in preoperative staging. MATERIALS AND METHODS: The patients were treated in the gynecologic oncology clinic of Istanbul University Faculty of Medicine between January 2005, and January 2015. A total of 37 patients were included in the final analysis. RESULTS: ECC accurately predicted ESC in 22 patients (59.5%). The mean pre operative serum CA-125 level was 73.24+/-3.30 IU/mL; pre-operative serum CA-125 levels were elevated above 35 IU/mL in 25 patients (69%). CONCLUSION: ECC is an acceptable diagnostic tool to predict the presence or absence of cervical involvement in endometrial cancer. On the other hand, its accuracy in specific subgroups requires further analysis in carefully designed prospective studies. Furthermore, pre-operative serum CA-125 levels may be important for management and counseling in the subgroup of women with ESC. PMID- 28913061 TI - An analysis of 37 patients with uterine leiomyosarcoma at a high-volume cancer center. AB - OBJECTIVE: To evaluate the clinicopathologic characteristics, treatment methods, survival, and prognosis of uterine leiomyosarcoma (ULMS). MATERIALS AND METHODS: All patients with ULMS who were treated between January 1998 and October 2012 were retrospectively reviewed. A total of 37 women who met the inclusion criteria were included in the present study. Univariate and multivariate analyses were used to identify the risk factors for overall survival (OS) and progression-free survival (PFS). RESULTS: The majority of patients had stage 1 disease (IA, n=9 (24.3%); IB, n=23 (62.1%)). All patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Additionally, only pelvic, and pelvic plus para-aortic lymphadenectomy was performed in 5 (13.5%) and 8 (21.6%) women, respectively. Adjuvant treatment was administered to 27 (72.9%) patients. Patients who did not receive adjuvant therapy had stage 1 disease. Recurrences occurred in 5 (13.5%) patients. The median follow-up period was 71 months (range 1-158 months). The 5-year PFS and OS rates were 68% and 74%, for all patients. The 5-year OS rates for women with stage 1 and >= stage 2 disease were 82% and 27%, respectively. Multivariate analysis confirmed stage 1 disease as the only independent predictor of both PFS (Odds ratio (OR) 10.955, 95% confidence interval (CI) 1.686-71.181, (p=0.012)) and OS (OR 57.429, 95% CI 3.287-1003.269, (p=0.006)). CONCLUSIONS: Extensive surgery is not associated with prognosis and stage 1 disease is the only independent good prognostic factor for survival in patients with ULMS. PMID- 28913063 TI - Uterine sparing surgical methods in pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is defined as the protrusion of pelvic organs to the vagen and is an important health problem in patients of older age. Today, most women with POP prefer uterine sparing surgery due to the changes in lifestyle, beliefs, pregnancy desire, and understanding the role of the uterus and cervix in sexual function. Therefore, the need for newer surgical procedures that involve less invasive surgery, reduced intraoperative and postoperative risks, and a faster healing time in POP surgery have gained importance. Vaginal, abdominal, laparoscopic, and robotic methods are defined in uterine preserving surgery but there is not yet a consensus on which of them should be chosen. In choosing the proper technique, the patient's general status, accompanying disease, correct indication, and the surgeon's experience are all important. In our practice we prefer laparoscopic mesh sacrohysteropexy in patients who prefer to preserve their uterus because of the lower costs and high success rates compared with abdominal and robotic techniques. PMID- 28913064 TI - Diagnosis and treatment of iron deficiency anemia during pregnancy and the postpartum period: Iron deficiency anemia working group consensus report. AB - According to the World Health Organization (WHO), anemia is the most common disease, affecting >1.5 billion people worldwide. Furthermore, iron deficiency anemia (IDA) accounts for 50% of cases of anemia. IDA is common during pregnancy and the postpartum period, and can lead to serious maternal and fetal complications. The aim of this report was to present the experiences of a multidisciplinary expert group, and to establish reference guidelines for the optimal diagnosis and treatment of IDA during pregnancy and the postpartum period. Studies and guidelines on the diagnosis and treatment of IDA published in Turkish and international journals were reviewed. Conclusive recommendations were made by an expert panel aiming for a scientific consensus. Measurement of serum ferritin has the highest sensitivity and specificity for diagnosis of IDA unless there is a concurrent inflammatory condition. The lower threshold value for hemoglobin (Hb) in pregnant women is <11 g/dL during the 1st and 3rd trimesters, and <10.5 g/dL during the 2nd trimester. In postpartum period a Hb concentration <10 g/dL indicates clinically significant anemia. Oral iron therapy is given as the first-line treatment for IDA. Although current data are limited, intravenous (IV) iron therapy is an alternative therapeutic option in patients who do not respond to oral iron therapy, have adverse reactions, do not comply with oral iron treatment, have a very low Hb concentration, and require rapid iron repletion. IV iron preparations can be safely used for the treatment of IDA during pregnancy and the postpartum period, and are more beneficial than oral iron preparations in specific indications. PMID- 28913065 TI - Laparoscopic systemic devascularization of uterine cornu for cornual resection in interstitial pregnancy. AB - Cornual pregnancies carry a greater maternal mortality risk than ampullary ectopic pregnancies and they may cause significant hemorrhage. A woman aged 36 years with a six-week history of amenorrhea, slight vaginal bleeding, and low abdominal pain of three days duration presented to our clinic. A diagnosis of right cornual ectopic pregnancy was made using ultrasonographic findings. Laparoscopic exploration confirmed the diagnosis. We occluded the uterine artery at its origin and also transected vessels within the mesosalpinx and uteroovarian ligament to successfully accomplish avascularization of a cornual pregnancy. Occlusion of the uterine arteries is reported to be a safe and blood-sparing technique. Severe hemorragia may occur during the operation; therefore, techniques to minimize blood loss are reported. In our case, occlusion of the uterine artery and transection of the mesosalpinx and uteroovarian vessels provided a bloodless operation and there was no need to bilaterally occlude vessels. PMID- 28913066 TI - Primitive uterine neuroectodermal tumours: Two case reports. AB - Primitive neuroectodermal tumor (PNET) arise from Kulchitsky cells and are rarely seen in the female genital tract. Differential diagnosis of PNET can be made based on immunohistochemical profiles and genetic analyses. Genital tract pNETs are very aggressive pathologies with different clinical and molecular manifestations and there are no standard guidelines for treatment. We aimed to present two cases of uterine PNETs with different symptomatology and clinical findings. PMID- 28913067 TI - Uterine rupture in pregnancy after robotic myomectomy. AB - Uterine rupture in pregnancy is a rare and often catastrophic complication with a high incidence of fetal and maternal morbidity. A gravida 2 para 1 woman aged 40 years who was 33-34 weeks pregnant presented to our clinic with serious abdominal pain, nausea and vomiting that had begun 6 hours previously. Her past surgical history included a robotic myomectomy 2 years ago in our unit. Obstetric ultrasonography revealed a 33-week fetus without a heartbeat whereupon she underwent emergency laparotomy and we found a 4 cm rupture on the anterior wall of the uterus. Uterine rupture should always be kept in mind, especially in patients with history of uterine surgery. PMID- 28913068 TI - HIV/AIDS epidemic in Turkey and use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. AB - OBJECTIVE: To evaluate changes in epidemiologic characteristics for HIV/AIDS in Turkey since 1985, management of HIV-positive pregnancies, and how new-borns and infants would be protected by anti-viral therapy (AVT). MATERIALS AND METHODS: The World Health Organization (WHO) progress reports, 2013 UNAIDS Global AIDS epidemic reports, Turkish Ministry of Health HIV/AIDS reports, and distribution tables that we published for specific time frames (1985-2013) according to sex, age, age groups, and possible transmission routes were used and the groups were compared. RESULTS: Although there were 35.3 (32.2-38.8) million people who were HIV(+) in the world as of 2013, only 9.7 million received AVTs. In Turkey, the total number of people with HIV/AIDS reported between 1985-2013 was 7050. There was a dramatic upward trend, with a peak in 2012 (n=1068). Sexually transmitted infection was the most common, and 4 drug use and blood transfusions showed a proportional increase. A total of 77 infections passed from mother to baby; seven cases have been reported in the last two years. CONCLUSION: Turkey is obliged to create an effective surveillance system for the prevention of HIV. The WHO proposed a new treatment protocol (option B+) in 2013 to prevent HIV mother-child transmission. PMID- 28913069 TI - Is anti-Mullerian hormone a good diagnostic marker for adolescent and young adult patients with Polycystic ovary syndrome? AB - OBJECTIVE: To evaluate serum anti-Mullerian hormone (AMH) levels in adolescent and young adult (AYA) Turkish patients with Polycystic ovary syndrome (PCOS), and to determine whether it had a diagnostic value. MATERIALS AND METHODS: A total of 90 AYA patients were recruited for this study. The study group consisted of 43 patients diagnosed as having PCOS, and the control group comprised 47 age-matched patients. The diagnosis of PCOS was made in accordance with the recent Amsterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine PCOS consensus workshop group's proposal that all three of the Rotterdam criteria for diagnosing PCOS in adolescents be present. In all patients, serum AMH levels were measured using enzyme-linked immunosorbent assay. Receiver operator characteristics (ROC) curve analysis was performed to reveal diagnostic potential of AMH. RESULTS: Serum AMH levels were higher in the PCOS group compared with controls, but the difference was not statistically significant (10.1+/-6.9 ng/mL vs. 9.4+/-5.5 ng/mL, p=0.198). There was a significant age-related decrease in AMH levels in both the study and control groups (r=-0.331, p=0.001). There was also a significant inverse correlation between serum AMH and follicle-stimulating hormone levels in all patients (r= 0.227, p=0.031). ROC analyses demonstrated that the area under the curve indicative of AMH value for discriminating PCOS was 0.579 with a 95% confidence interval of 0.453-0.705 (p=0.198). The cut-off value according to the highest Youden index was calculated to be 14.0 ng/mL with a sensitivity of 48.8% and specificity of 77.1%. CONCLUSION: Serum AMH levels are slightly higher in AYA patients with PCOS than in controls. However, AMH is not a good marker for the diagnosis of PCOS in AYA patients. PMID- 28913070 TI - Female sexual distress in infertile Turkish women. AB - OBJECTIVE: To evaluate the effect of infertility on sexual distress in women attending the infertility clinic. MATERIALS AND METHODS: In a cross-sectional study we evaluated sexual distress among 88 women who attended the infertility clinic in our institute between January and June 2015. All women who were experiencing primary or secondary infertility during the study sampling were included in the sudy. Sexual distress was measured using the Female sexual distress scale-revised (FSDS-R), a cross-validated patient-reported outcomes measure. Correlations of FSDS-R with patient characteristics and laboratory measurements were calculated using Spearman's rank correlation tests. RESULTS: With the exceptions of the age of couples and serum anti-mullerian hormone (AMH) levels, no predictor of high sexual distress was found in the univariate analysis when comparing groups with regard to the FSDS-R cut-off score. The mean age of the sexually distressed women (33.6+/-5.8 years vs. 29.3+/-5.1 years) and their partners (35.4+/-4.8 years vs. 31.6+/-4.2 years) was significantly higher than those of the non distressed women, according to a FSDS-R score over 11 (p<0.05). The serum level of AMH was significantly lower in infertile women with high total sexual distress scores (1.4 vs. 7.6 ng/mL (p<0.001)). CONCLUSION: In infertile women, age of woman, age of partner, and serum AMH levels are related with the hope of women to have a child despite an association with sexual distress. Serum AMH, which is perceived as necessary for fertility, had a significant inverse correlation with levels of sexual stress. PMID- 28913071 TI - The effect of education given before surgery on self-esteem and body image in women undergoing hysterectomy. AB - OBJECTIVE: To evaluate the effect of information provided before surgery on the self-esteem and body image of women undergoing hysterectomy. MATERIALS AND METHODS: The study had a semi-experimental design with pre-post tests. A total of 60 women were included in the study and divided into two groups, the intervention group (n=30) and control group (n=30). A questionnaire, the Rosenberg self-esteem scale, and the body image scale were used to collect data. RESULTS: The pre- and post-test body image scores were similar in the intervention group patients, but the post-test scores were significantly higher in the control group (p<0.05). The pre- and post-test self-esteem scores were again similar in the intervention group, but the post-test scores were significantly lower in the control group (p<0.05). CONCLUSION: This study revealed that health education given to patients prior to hysterectomy protects body image and consequently self-esteem. PMID- 28913072 TI - Retrospective analysis of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy. AB - OBJECTIVE: Detection of factors that affect the success of single-dose methotrexate treatment in ectopic pregnancy. MATERIALS AND METHODS: We investigated 99 patients who had been treated with single-dose methotrexate for ectopic pregnancy in our clinic between January 2009 and June 2014. Demographic, clinical, and laboratory results of possible factors that affect treatment success were retrospectively analyzed. Successfully and unsuccessfully treated patients were compared based on their pre-treatment results. RESULTS: The success rate of single-dose methotrexate treatment was found to be 70.7%. No significant difference was found between succesfully and unsuccessfully treated patients before treatment in terms of factors such as gestational weeks, mass size, presence of yolk sac, and presence of free fluid (p=0.224, p=0.201, p=0.200, p=0.200). Serum beta-hCG values in patients whose treatment was unsuccessful was found to be higher compared with the successfully treated group (mean beta-hCG value of unsuccessful group: 4412+/-3501 mIU/mL; mean beta-hCG value of successful group: 1079+/-942 mIU/mL; p<0.001). CONCLUSION: Single-dose methotrexate treatment is an effective and reliable method in the treatment of ectopic pregnancy. Elevation of serum beta-hCG value stands as the main prognostic factor that affects the success of single-dose methotrexate treatment. PMID- 28913073 TI - Analysis of the effectiveness of ultrasound and clinical examination methods in fetal weight estimation for term pregnancies. AB - OBJECTIVE: To compare the accuracy of clinical and ultrasonographic (USG) estimation of fetal weight in non-complicated, term pregnancies. MATERIALS AND METHODS: Two hundred term pregnant women were included in the study. We used three formulae for the estimation of fetal weight at term; the Hadlock formula for the USG method, and two different formulas for clinical methods, maternal symphysis-fundal height and abdominal circumference at the level of umbilicus. Accuracy was determined by mean percentage error, mean absolute percentage error and proportion of estimates within 10% of actual birth weight (birth weight +/ 10%). Patients were divided into two groups according to actual birth weight, the normal birth weight group (2500-3999 g) and high birth weight group (>=4000 g). RESULTS: All three methods statistically overestimated birth weight for the high and normal birth weight groups (p<0.001, p=1.000, p=0.233) (p=0.037, p<0.001, and p<0.001). For both groups, the mean absolute percentage errors of USG were smaller than for the other two clinical methods and the number of estimates were within 10% of actual birth weight for USG was greater than for the clinical methods; the differences were statistically significant (p<0.001). No statistically significant difference of accuracy was observed for all three methods for the high birth weight group (p=0.365, p=0.768, and p=0.540). However, USG systematically underestimated birth weight in this group. CONCLUSION: For estimation of fetal birth weight in term pregnancies, ultrasonography is better than clinical methods. In the suspicion of macrosomia, it must be remembered that no method is better than any other. In addition, if ultrasonography is used, careful management is recommended because ultrasonography overestimates in this group. PMID- 28913074 TI - Single intrauterine demise in twin pregnancies: Analysis of 29 cases. AB - OBJECTIVE: To evaluate the maternal and fetal demographic features and clinical aspects of twin pregnancies with single intrauterine demise. MATERIALS AND METHODS: This retrospective study was conducted in Dicle University Faculty of Medicine, Department of Gynecology and Obstetrics between January 2008 and December 2013. There were a total of 594 twin deliveries in our hospital between the given dates. Twenty-nine of these cases were referred to our hospital by another health center because of a preliminary diagnosis of single intrauterine demise. Maternal age, parity, chorionicity, week of fetal death, gestational week at delivery, mode of delivery, birth weight, Activity, pulse, grimace, appearance, respiration scores, maternal fibrinogen levels at delivery and during pregnancy, stay in the neonatal intensive care unit, and obstetric complications were explored in these 29 cases of single intrauterine demise. RESULTS: The mean age of the 29 patients who were provided antenatal follow-up and delivery services in our hospital was 29.9+/-6.5 years. Thirteen (44.8%) of the patients were monochorionic, whereas 16 (55.2%) were dichorionic. Intrauterine fetal death occurred in the first trimester in 6 pateints and in the second or third trimester in 23. In addition, 20 (69%) patients underwent cesarean section, whereas 9 (31%) had spontaneous vaginal delivery. Lastly, none of the patients had a maternal coagulation disorder. CONCLUSION: Twin pregnancies with single intrauterine death can lead to various complications for both the surviving fetus and the mother. Close maternal and fetal monitoring, and proper care and management can minimize complications. PMID- 28913075 TI - Problems of modern approaches to management of early pregnancy failure. AB - In the last 20 to 30 years, early diagnosis of pregnancy has markedly decreased ectopic pregnancy-related maternal mortality, and the necessity for surgical treatment. With modern approaches in the treatment of ectopic pregnancy, surgical therapy has been replaced by medical therapy and medical treatment by spontaneous follow-up in appropriate cases. However, this current trend has led to some problems, including the maximization of ultrasonographic interpretations, misunderstandings in serial human koryonik gonadotropin hormon measurements, and complications due to inappropriate methotrexate use. The aim of the present study was to review the literature relating to the diagnosis and follow-up of early pregnancies, to underline some of the important considerations, and to help avoid possible iatrogenic errors. PMID- 28913076 TI - Genomic, proteomic and lipidomic evaluation of endometrial receptivity. AB - Endometrial receptivity is a complex phenomenon that plays a vital role in infertility. Although quality of embryo can be evaluated for a successful implantation, endometrial receptivity is still an unknown factor. With advances in technology, the microarray approach has provided an 'omic' tool to evaluate endometrial receptivity. In Latin, 'omic' means the whole family. The genomic, proteomic, and lipidomic evaluations of endometrium mean a wholesome evaluation of the genes, lipids and proteins of the endometrium. Evaluation of receptivity with this three-way approach may provide insight to the potential markers of implantation. Genomic analysis has been limited to date because not every gene alteration affects protein expression. Lipidomic analysis has recently gained popularity because lipids are strictly controlled during the implantation period. In summary, with the recent advances in microarray technology, genomic, lipidomic, and proteomic analyses of the endometrium may provide 'optimal' evaluation tools and criteria to assess receptivity in the near future. PMID- 28913077 TI - Mullerian adenosarcoma of the uterus associated with tamoxifen treatment for breast cancer. AB - Mullerian adenosarcoma following tamoxifen therapy is a rare condition. Our aim was to report the youngest patient in the literature with uterine mullerian adenosarcoma who was undergoing tamoxifen therapy for breast cancer. A premenopausal woman aged 38 years who was undergoing tamoxifen therapy for breast cancer, was admitted with symptoms of lower abdominal pain and irregular vaginal bleeding and malodorous vaginal discharge that had continued for at least 6 months. A pelvic examination revealed a large and malodorous polypoid mass protruding through the cervix and an enlarged uterus. A biopsy from the protruding polypoid mass was reported as a large area of necrosis with neoplastic mesenchymal cells. The patient underwent a total abdominal hysterectomy, bilateral salpingo-oopherectomy, pelvic-paraaortic lymph node dissection, and omentectomie. The histologic diagnosis was Mullerian adenosarcoma. As a result, she was discharged to the oncology department. The woman is alive and her chemoradiotherapy treatment is ongoing. The role of tamoxifen therapy in the development of endometrial neoplasms remains unclear, but all cases of endometrial thickening and vaginal bleeding must be investigated for Mullerian adenosarcoma in tamoxifen users. PMID- 28913078 TI - Reimplantation of an autoamputated ovary in the omentum: A case report. AB - Autoamputation is one of the complications of ovarian torsion. In many cases, ovarian torsion develops as a result of mature cystic teratoma. Herein, we present a woman aged 27 years whose right ovary was autoamputated and reimplanted in the omentum. It should be noted that autoamputated ovaries can reimplant in surrounding tissues by revascularization and present as mobile abdominal masses with atypical localization. PMID- 28913079 TI - Parasitic omental ovarian dermoid tumour mimicking an adnexal mass: A report of two very unusual cases. AB - The differential diagnosis of cystic adnexal masses includes various pathologies, some placed extragonadally. Herein, we present two different cases of omental ovarian dermoid tumours that were diagnosed using ultrasonography and removed with surgery. The greater part of the omental teratomas appear to have developed from self-amputation of cysts in the ovary, followed by their re-implantation into the omentum. Omental teratomas can be located in the pelvis, where they might be mistaken for an adnexal mass, an upper abdominal mass, or a periumbilical mass. The location of omental teratomas might slightly change from one examination to another. In such cases, preoperative diagnostic imaging methods may not provide adequate information to physicians. Gynecologists should always keep in mind the possibility of intraabdominal ovarian parasitic cystic teratomas in the differential diagnosis of suspicious adnexal masses during surgery. Awareness among gynecologic surgeons of such masses may help prevent misdiagnosis, delayed surgery, or the use of wrong surgical approaches. PMID- 28913080 TI - Characteristics and outcomes of in vitro fertilization in different phenotypes of polycystic ovary syndrome. AB - OBJECTIVE: The aim of this study was to investigate whether polycystic ovary syndrome (PCOS) phenotype without polycystic ovaries (PCO) differs in terms of in vitro fertilization (IVF) outcomes compared with classic phenotypes. MATERIALS AND METHODS: This retrospective controlled study included 262 patients who underwent IVF treatment with an indication of unexplained or tubal factor infertility (control group), ovulatory patients with PCO morphology (group 1), PCOS phenotype with oligoanovulation and hyperandrogenemia (group 2), PCOS phenotype with PCO morphology and oligoanovulation (group 3). Outcomes and baseline characteristics of IVF-embryo transfer treatments were compared among all groups. RESULTS: PCOS phenotype without PCO morphology had similar IVF stimulation characteristics compared with classic phenotypes; however, a higher total gonadotropin dose was needed to achieve similar results compared with patients with PCO morphology with or without PCOS. Basal follicle-stimulating hormone level (beta coefficient=0.207, p=0.003), group (beta coefficient=-0.305, p<0.001) and age (beta coefficient=0.311, p<0.001) were significantly associated with the total gonadotropin dose. The number of good quality embryo on transfer day was significantly lower in patients with isolated PCO morphology and PCO morphology with oligoanovulation than in those with PCOS phenotype without PCO morphology. CONCLUSION: PCO morphology provides easier stimulation, whereas hyperandrogenemia provides better results as good quality embryos. However, the end point is similar in terms of biochemical, clinical, and ongoing pregnancy rates. PMID- 28913081 TI - The outcomes of controlled ovarian hyperstimulation/intrauterine insemination in patients with unilateral tubal occlusion on hysterosalpingograph. AB - OBJECTIVE: The aim of the present study was to evaluate the pregnancy rates of intrauterine insemination (IUI) and controlled ovarian hyperstimulation (COH) in patients with one-sided tubal occlusion on hysterosalpingography (HSG). MATERIALS AND METHODS: Patients who underwent COH/IUI were enrolled into this retrospective cohort study. The patients with one-sided tubal occlusion diagnosed under HSG who met the inclusion criteria were accepted into the study group. The control group consisted of patients with unexplained infertility. The outcomes of COH/IUI were compared between the study and control groups. RESULTS: Ninety-seven patients in the study group (n=44) and control group (n=53) who underwent COH/IUI treatment were included into study. The biochemical, clinical, and ongoing pregnancy rates were similar between patients with unilateral occlusion diagnosed under HSG and those with unexplained infertility. The spontaneous pregnancy rate within one year was higher in patients with normal HSG than in patients with unilateral tubal occlusion, but the difference did not show statistical significance. CONCLUSION: Infertile patients with one-sided tubal occlusion in HSG can be managed as with patients with unexplained infertility and normal HSG findings. In addition, COH/IUI may be considered as the first-line treatment option in the management of these patients. PMID- 28913082 TI - Does screening for vaginal infection have an impact on pregnancy rates in intracytoplasmic sperm injection cycles? AB - OBJECTIVE: Assisted reproduction techniques have become widespread worldwide. Considering their costs, physicians endeavor to improve pregnancy rates. Infections are one of the disrupting problems in this arena. We aimed to investigate the effects of screening for vaginal infection on pregnancy rates in intracytoplasmic sperm injection cycles. MATERIALS AND METHODS: One hundred twenty patients randomized into two groups for this study. Patients were screened for vaginal infections in group 1, and no screening was performed in group 2. The assisted reproduction outcomes were investigated and compared between the two groups. RESULTS: There was no significant difference between ages, or durations and causes of infertility of patients who conceived and of those who did conceive. Forty-five patients in group 1, and 40 patients in group 2 reached the embryo transfer stage. The rates of conception were 23.5% (n=4) in culture positive patients (n=17), and 42.9% (n=12) in culture-negative patients (n=28) in group 1. There was no significant difference among patients who were not screened, screen-positive, and screen-negative, in terms of pregnancy rates. None of the patients had Neisseria gonorrhoeae or Trichomonas vaginalis. Bacterial vaginosis was detected in 13 patients, and both bacterial vaginosis and Chlamydia trachomatis were detected in 4 patients. Three of 4 patients who conceived screen positive and 8 of 12 patients who conceived screen-negative delivered healthily at term. CONCLUSION: No significant difference was found between patients who were sampled for culture and patients who were not sampled in terms of pregnancy rates. Also, no difference was found between the patients who were culture negative and patients who were treated with antimicrobials after a culture positive result. Further larger studies are warranted to clarify this issue. PMID- 28913083 TI - What is the optimal strategy in the management of patients with preterm premature rupture of membranes before 32 weeks of gestation? AB - OBJECTIVE: Our aim was to compare the outcomes of expectant management of pregnancy or immediate delivery in patients with preterm premature rupture of membranes (PPROM) between 24+0 and 32+0 weeks of pregnancy. MATERIALS AND METHODS: This is a retrospective cohort study conducted at a tertiary medical center. Patients who were diagnosed as having PPROM between 24+0 and 32+0 weeks of gestation were selected from an electronic database. Thirty-one patients with expectant management and 22 patients with spontaneous immediate delivery were analyzed. Birth weight, Apgar score, duration of stay in the neonatal intensive care unit (NICU), composite adverse outcomes, and mortality rates of groups were compared. Binary logistic regression analysis with backward stepwise elimination was used to determine confounding factors for antenatal complications and neonatal composite adverse outcomes. RESULTS: Gestational age at admission was smaller in the expectant management group. The median latency period was 6 days (range, 2-58 days). Although gestational age at delivery was similar, birth weights were smaller in expectant management group compared with the immediate delivery group (p=0.264 and p<0.05, respectively). Apgar scores, duration in the NICU, composite adverse outcomes, and neonatal mortality rates were similar in each group. Antenatal complication in the expectant management group was higher (p<0.05). Gestational age at delivery and serum C-reactive protein levels were two confounding factors for antenatal complication and gestational age at delivery was the only factor affecting composite adverse outcome. CONCLUSION: Expectant management in patients with PPROM at 24 to 32 gestational weeks might be considered as a good alternative. PMID- 28913084 TI - Vitamin D deficiency in pregnancy is not associated with diabetes mellitus development in pregnant women at low risk for gestational diabetes. AB - OBJECTIVE: We aimed to investigate the effect of vitamin D deficiency as a risk factor for the development of gestational diabetes mellitus (GDM) among pregnant women without known risk factors. MATERIALS AND METHODS: The study was conducted on pregnant women who had been under regular follow-up and had low risk for GDM development. The patients were divided into two groups according to the presence of GDM; GDM and no GDM (control) group. Body mass index (BMI), sociodemographic data including level of education and nutritional habits were recorded. Serum 25 (OH) vitamin D3 levels, hemoglobin, hematocrit, and mean corpuscular volume (MCV) values were measured. An oral glucose tolerance test was performed, between 24 and 28 weeks of pregnancy. RESULTS: GDM ratio was calculated as 4.6%. The false positive rate of 50 g oral glucose load screening test was found to be 16.5%. The BMI levels of women diagnosed as having GDM and those with no GDM group at the beginningof the pregnancy period were calculated as 24.3+/-2.6 and 22.8+/-1.6 kg/m2 respectively, exhibiting a statistically significant difference between the two groups (p=0.001). Hemoglobin, hematocrit, and MCV values did not show a statistically significant difference between the two groups (p>0.05). The levels of 25 (OH) vitamin D3 of the study groups were found comparable in both groups (p=0.13). CONCLUSION: Plasma levels of vitamin D may not be a contributing factor for the development of GDM in women with a low risk for GDM. PMID- 28913085 TI - Conventional 22- and 20-gauge needle for second trimester amniocentesis: A comparison of short term outcomes. AB - OBJECTIVE: To compare the short-term outcomes of two different-sized needles for genetic amniocentesis. MATERIALS AND METHODS: A total of 271 amniocentesis were retrospectively evaluated in 2 groups concerning the size of the needles used during the procedure: Conventional 20-gauge (G) (n=164) and 22G (n=107). Periprocedural complications and cost-effectiveness were compared across the groups. RESULTS: There were no differences between groups concerning complications within 15 days after the procedure (fetal loss, 0.6% versus 0.9%, and amniotic fluid leak 1.2% versus 1.8%, p=0.99 for each). The 22G needle was significantly more cost efficient (p<0.0001). CONCLUSION: The 22 G spinal needle is convenient for second trimester amniocentesis with similar complication rate and has a favorable cost profile. PMID- 28913086 TI - Prevalence of endometrial polyps coexisting with uterine fibroids and associated factors. AB - OBJECTIVE: The aim of the study was to investigate the prevalence of endometrial polyps in patients with uterine fibroids and associated factors of coexistence of these two pathologies. MATERIALS AND METHODS: The medical records of 772 patients who underwent hysterectomy because of uterine fibroids were retrospectively reviewed. Patients were divided into two groups according to the presence of endometrial polyps in the histopathologic examination. Demographic, clinical and histopathologic findings of the patients with and without endometrial polyps were compared. Student's t-test, Mann-Whitney U test, Pearson's Chi-square test, and logistic regression analysis were used for statistical analysis. RESULTS: The prevalence of the endometrial polyps in uterine fibroid cases was found 20.1% (n=155). Age >=45 years (odds ratio [OR] 1.61; 95% confidence interval [CI]: [1.06-2.44]; p=0.014), presence of hypertension (23.9% vs. 17.5%; p=0.047), endometrial hyperplasia (OR 4.00; 95% CI: [1.92-8.33]; p<0.001) and cervical polyps (OR 3.13; 95% CI: [1.69-5.88]; p<0.001) were significantly associated with the coexistence of endometrial polyps and uterine fibroids. Endometrial polyps were more common in patients with >=2 fibroids (p=0.023) and largest fibroid <8 cm (p=0.009). A negative correlation was found between condom use and endometrial polyps (8.1% vs. 3.9%; p=0.044). CONCLUSIONS: The prevalence of the endometrial polyps coexisting with uterine fibroids was 20.1%. Age, hypertension, endometrial hyperplasia, cervical polyps, and number of fibroids were positively correlated; condom use and size of largest fibroid were negatively correlated with the coexistence of these two pathologies. PMID- 28913087 TI - Utilization of Wilms' tumor 1 antigen in a panel for differential diagnosis of ovarian carcinomas. AB - OBJECTIVE: Ovarian metasteses are often mistaken for primary adenocarcinoma. Studies conducted in recent years have focused on a search for an immunohistochemical marker to aid the differential diagnosis primary and metastatic ovarian carcinoma. Our study objective was to study the usefulness of Wilms tumor 1 (WT 1) antigen in this context. MATERIALS AND METHODS: The study was conducted at the pathology clinic of Lutfi Kirdar Training and Research Hospital. Deparaffinated blocks of 40 epithelial ovarian tumors, 40 colon adenocarcinomas, and 35 cases of omentum metastases were studied. Cytokeratin 7 (CK 7), cytokeratin 20 (CK 20), and WT 1 were applied to all specimens. RESULTS: All ovarian adenocarcinomas were stained with CK 7 (100%). Colorectal adenocarcinomas were stained positive with CK 20 in 87.5% of cases. Primary ovarian adenocarcinomas stained positive with WT 1 in 82.5% of the cases and none of the colorectal adenocarcinomas showed staining with WT 1 (0%). CONCLUSION: WT 1 can be used in conjuction with CK 7 in the differential diagnosis of ovarian carcinomas. PMID- 28913088 TI - A novel approach for congenital absence of the uterine cervix: Office hysteroscopic versapoint canalization using real-time trans-abdominal sonography guidance. AB - Herein, we report a novel technique for cervical agenesis via office hysteroscopy using Versapoint using real-time trans-abdominal sonography guidance. Fourteen days after the canalization procedure, a second hysteroscopy was performed to remove the silicone catheter and insert a Cupper T380a intrauterine device, which aimed to prevent a neocervical canal occlusion. This is the first case report of a patient with congenital cervical agenesis undergoing canalization with Versapoint in an office hysteroscopy; laparoscopy was not performed for assistance. PMID- 28913089 TI - Vesicocutaneus fistula after cesarean section-a curious complication: Case report and review. AB - Vesicocutaneous fistulas are very rare pathologies in the urinary tract. We present the second case of a vesicocutaneus fistula after cesarean section, and discuss strategies for prevention, diagnosis, and treatment of this exceptional complication. A woman with a vesicocutaneous fistula after cesarean delivery was admitted and diagnostic tests including fluoroscopy, magnetic resonance imaging (MRI), and reconstructed MRI revealed the fistula tract and an urachal anomaly. The patient was treated through excision of the fistula tract. Laparotomy should be performed carefully, and the surgeon should be aware of the urachus. Inadvertent trauma to the urachus during laparotomy might cause serious unexpected complications. Possible etiologic factors for vesicocutaneous fistulae, prevention, and treatment methods are discussed. PMID- 28913090 TI - Prenatal diagnosis of sirenomelia in the first trimester: A case report. AB - Sirenomelia or "mermaid syndrome" is a rare congenital syndrome characterized by the anomalous development of the caudal region of the body. We present a case of sirenomelia diagnosed in the first trimester using two-dimensional and three dimensional ultrasonographic examination. A nulliparous woman aged thirty years was referred to our perinatology unit for evaluation because of oligohydramnios at 12 weeks of gestation. Her medical history was unremarkable. There was no family history of genetic abnormalities. We identified a single lower extremity and severe oligohydramnios, which are characteristics of sirenomelia. Sirenomelia, a developmental defect involving the caudal region of the body, is associated with several internal visceral anomalies. Sirenomelia is fatal in most cases due to the characteristic pulmonary hypoplasia and renal agenesia. Prenatal diagnosis of sirenomelia may be difficult in the second or third trimester because of the severe oligohydramnios; it should be easier to diagnose sirenomelia in the first trimester. PMID- 28913091 TI - A 27-kg mucinous cystadenoma of the ovary presenting with deep vein thrombosis. AB - Giant ovarian adenomas are rarely observed today because of early diagnosis and treatment. Mucinous cystadenomas is a kind of tumor that mostly causes the ovary to enlarge. Theu can present with various and non-specific clinical manifestations such as deep vein thrombosis. The primary symptoms of giant ovarian tumors are abdominal enlargement and distension. Therefore, making the correct preoperative diagnosis is sometimes difficult. The appropriate treatment must include oncologic procedures and a multidisciplinary approach to minimalize complications and save the patient's life. Herein, we report a woman aged 53 years with a 27-kg ovarian mucinous cystadenoma that presented as a left popliteal vein thrombosis. PMID- 28913092 TI - The relationship between estradiol-progesterone alterations after ovulation trigger and treatment success in intrauterine insemination cycles. AB - OBJECTIVE: To assess the relationship between the estrogen-progesterone alterations before and after ovulation trigger and treatment success in intrauterine insemination (IUI) cycles. MATERIALS AND METHODS: Two hundred fifty one women with infertility underwent ovulation induction followed by IUI. For all subjects, estradiol and progesterone concentrations were evaluated on the trigger and IUI day. The results were analyzed to assess the relationship between hormone levels and positive pregnancy test. RESULTS: There were 34 women with a positive pregnancy test following controlled ovarian stimulation and IUI cycle. Estradiol and progesterone levels on the trigger day and the day of IUI were compared within groups with and without positive pregnancy tests. The comparison revealed significantly increased levels of progesterone after trigger in both groups; however, although there were estradiol level drops in both groups, the drop in the group with negative pregnancy tests was statistically significant. CONCLUSION: Significant drops in estradiol concentrations after ovulation trigger are associated with IUI cycle treatment failure. PMID- 28913093 TI - The value of urea, creatinine, prolactin, and beta sub-unit of human chorionic gonadotropin of vaginal fluid in the diagnosis of premature preterm rupture of membranes in pregnancy. AB - OBJECTIVE: To evaluate the effectiveness of urea, creatinine, prolactin, and the beta sub-unit of human chorionic gonadotropin (beta-hCG) of vaginal fluid in the diagnosis premature preterm rupture of membranes (PROM). MATERIALS AND METHODS: In this observational study, 160 pregnant women with gestational age of 28 to 40 weeks were divided into two equal groups: investigation (documented PROM) and control (intact membrane) groups. Five cubic centimeters of normal saline was poured into the vagina of all participants and the liquid was extracted after a few minutes using a syringe. The liquid was sent to a laboratory for examination. Data were analyzed using a t-test. RESULTS: The volume of urea, creatinine, prolactin, and beta-hCG was significantly different in the two groups (p<0.001). Based on receiver operating characteristic curve and cut-off point, sensitivity, specificity, positive and negative predictive values of beta-hCG for detecting PROM were 87.5%, 86%, 86.4%, and 87.3%, respectively. Also, the same factors for urea in detecting PROM were 79.7%, 82.5%, 81.8%, and 80.4%, respectively. Creatinine had 74.6% sensitivity, 85% specificity, and 83% and 77.2% positive and negative predictive values for detecting PROM. Finally, prolactin had 87.5% sensitivity, 90% specificity, and 90% positive and 88% negative predictive values for detecting PROM. CONCLUSION: Prolactin and beta-hCG have more diagnostic value than urea and creatinine in detecting PROM, and can be used in suspected cases. PMID- 28913094 TI - Changes of intraocular pressure in different trimesters of pregnancy among Syrian refugees in Turkey: A cross-sectional study. AB - OBJECTIVE: To evaluate the physiologic changes in intraocular pressure associated with pregnancy in healthy Syrian refugee women in Turkey. MATERIALS AND METHODS: In this cross-sectional study, intraocular pressures were measured using a Goldmann tonometer in 235 patients in the first, second, and third trimester of pregnancy and puerperium among Syrian refugees in Turkey. RESULTS: Mean intraocular pressures values of the right eye were 15.5+/-2.5 mmHg, 14.4+/-1.4 mmHg, 13.9+/-1.6 and 14.7+/-1.9 mmHg in the three trimesters and puerperium, respectively. Mean intraocular pressures values of the left eye were 15.3+/-1.6 mmHg, 14.3+/-1.4 mmHg, 13.9+/-1.6 and 15.3+/-2.2 mmHg in the three trimesters and puerperium, respectively. The mean intraocular pressures values measured from both eyes were significantly higher in first trimester and puerperal period than in the third trimester (p<0.001). CONCLUSION: Changes in the intraocular pressure in pregnancy are common and temporary. This study shows the baseline changes in the intraocular pressure during pregnancy in healthy women. Therefore, we cannot extrapolate the results to the whole eye. A decrease in intraocular pressures was shown in healthy pregnant women. PMID- 28913095 TI - Association of first trimester serum uric acid levels gestational diabetes mellitus development. AB - OBJECTIVE: To investigate the association of first trimester serum uric acid levels with the development of gestational diabetes mellitus (GDM) in low-risk pregnant women. MATERIALS AND METHODS: In this retrospective data analysis, the results of pregnant women who completed both first trimester biochemical panel and two-step GDM screening were compared with an age-, body mass index, and gestational age-matched control group. The women were grouped as either GDM or impaired glucose tolerance (IGT) according to 100-g oral glucose challenge results. Uric acid levels were compared between the groups and diagnostic utility was tested with receiver-operating characteristics curves. RESULTS: Sixty-six women in GDM group and 358 women in the IGT group were compared against 202 healthy pregnant women. The groups did not differ significantly in terms of parity, pre-gestational body mass index and gestational age. Serum samples for uric acid levels were obtained. The mean serum uric acid levels were significantly higher in the GDM and IGT groups (5.95 mg/dL (+/-0.97 mg/dL) and 4.76 mg/dL (+/-1.51 mg/dL), respectively) compared with the control group (3.76 mg/dL (+/-1.07 mg/dL) (p<0.001). The area under the curve for uric acid levels was 0.92 (95% confidence interval 0.88-0.95) for diagnosis of GDM. At a diagnostic threshold of 3.95 mg/dL, uric acid levels predicted development of GDM with 60% specificity and 100% sensitivity. CONCLUSION: First trimester serum uric acid has a linear association with the development of GDM and IGT. PMID- 28913096 TI - First trimester fetal aortic Doppler for hemoglobinopathies. AB - OBJECTIVE: To evaluate fetal aortic Doppler for the prenatal diagnosis of hemoglobinopathies in the first trimester of pregnancy. MATERIALS AND METHODS: Between January and November 2014, a total of 108 patients were enrolled in the study. The couples were carriers of either alpha/beta thalassemia, sickle cell disease or combined carriers of these and were admitted to Cukurova University Faculty of Medicine, Department of Obstetrics and Gynecology Prenatal Diagnosis Center. One hour before the chorionic villus sampling (CVS), patients were evaluated using fetal aortic Doppler. Pulsatility index, peak systolic velocity, and heart rate were noted. RESULTS: There were no statistically significant differences in Doppler indices between different groups of CVS results when compared with the healthy controls. CONCLUSION: Fetal aortic Doppler investigation was found to be ineffective for the prenatal diagnosis of hemoglobinopathies. PMID- 28913097 TI - Prediction of adverse pregnancy outcomes using uterine artery Doppler imaging at 22-24 weeks of pregnancy: A North Indian experience. AB - OBJECTIVE: The aim of this study was to assess the predictive value of uterine artery Doppler imaging at 22-24 weeks of gestation for adverse pregnancy outcomes. MATERIALS AND METHODS: This was a prospective study in which uterine artery Doppler was performed at 22-24 weeks of gestation in 165 pregnant women with singleton pregnancies. A pulsatility index (PI) more than 1.45 or bilateral uterine notching was labeled as abnormal Doppler. The pregnancy outcome was assessed in terms of normal outcome, preeclampsia, fetal growth restriction (FGR), low birth weight, spontaneous preterm delivery, oligohydramnios, fetal loss or at least one adverse outcome. RESULTS: Out of 165 patients, 35 (21.2%) had abnormal second trimester uterine artery Doppler. In pregnancies that resulted in preeclampsia (PE), (n=21), FGR, (n=21), and low birth weight (n=39), the median uterine artery PI was higher (1.52, 1.41, and 1.27 respectively). In the presence of abnormal Doppler, the risk of PE [OR=10.7, 95% confidence interval (CI): (3.91-29.1); p<0.001], FGR [OR=4.34, 95% CI: (1.62-11.6); p=0.002], low birth weight [OR=6.39, 95% CI: (3.16-12.9); p<0.001] and the risk of at least one obstetric complication [OR=8.73, 95% CI: (3.5-21.3); p<0.001] was significantly high. The positive predictive value of abnormal uterine artery Doppler was highest for preeclampsia (36.84%) among all adverse pregnancy outcomes assessed. CONCLUSION: Uterine artery Doppler ultrasonography at 22-24 weeks of gestation is a significant predictor of at least one adverse pregnancy outcome, with the highest prediction for preeclampsia. PMID- 28913098 TI - A comparison of the effects of the most commonly used tocolytic agents on maternal and fetal blood flow. AB - OBJECTIVE: To investigate the effects of two tocolytics, nifedipine and magnesium sulfate, on Doppler indices in maternal and fetal vessels. MATERIALS AND METHODS: We recruited 100 pregnant women with preterm birth between 24-36 gestational weeks who were admitted to our tertiary center over a two-year period. Patients were allocated to nifedipine (n=49) and magnesium sulfate (n=51) groups and Doppler indices of umbilical, middle cerebral, uterine arteries, and ductus venosus were measured before and after tocolysis. RESULTS: There were no differences between the groups in terms of maternal age, gestational week, body mass indexes, cervical dilation, effacement at admission, birth weights and latency periods until birth. Nifedipine decreased resistance indexes in uterine arteries but magnesium sulfate increased resistance especially in the right uterine artery. Nifedipine significantly decreased systole to diastole and resistance index in the umbilical artery, magnesium sulfate increased systole to diastole and resistance index but this was not statistically significant. Nifedipine acted variably on resistance index and pulsatility index in the ductus venosus; however, magnesium sulfate increased resistance. Nifedipine decreased pulsatility index in the middle cerebral artery, contrary to magnesium sulfate with which it increased. CONCLUSION: Nifedipine had favorable effects on maternal and fetal vessel indexes but magnesium sulfate increased resistance. Despite the proposed neuroprotective benefits of magnesium sulfate, nifedipine seems to be a better and safer tocolytic agent than magnesium sulfate due to its positive beneficial effects on maternal and fetal vessels. PMID- 28913099 TI - Luteal phase support in intrauterine insemination cycles. AB - Intrauterine insemination (IUI) treatment aims to increase the rate of conception by increasing the chances that the maximum number of healthy sperm reach the site of fertilization. IUI with controlled ovarian stimulation is frequently used in assisted reproduction practice. Although widely used, the efficacy of luteal support in IUI remains controversial. In this article, we aimed to review what we know regarding luteal support in IUI cycles and to adjudicate about the clinical use and benefits of this treatment. Based on the study results available in the literature, it appears to be beneficial to supplement the luteal phase in gonadotropin-stimulated IUI cycles that yield more than one follicle. PMID- 28913100 TI - Live birth after transfer of a tripronuclear embryo: An intracytoplasmic sperm injection as a combination of microarray and time-lapse technology. AB - Although around 1-4% of human zygotes have been found to be tripronuclear, there is little information about the subsequent development and chromosomal composition of embryos that derive from these zygotes. Herein, we report a pregnancy and subsequent delivery of a healthy newborn after the transfer of a blastocyst that developed from a tripronuclear zygote that had a euploid microarray result. PMID- 28913101 TI - Amphricrine carcinoma of the cervix-adeno neuroendocrine tumor: A case report. AB - Adenoneuroendocrine carcinoma is a very rare form of cervical carcinoma that includes both endocrine and exocrine components. In general terms, these carcinomas progress aggressively and show early metastases due to the neuroendocrine component. The most important criteria related to prognosis is the stage of the disease. Without clearly determined therapeutic protocols this carcinoma is generally seen at earlier ages and causes high mortality. Many radiotherapy and multidrug chemotherapy protocols are used after surgical intervention. Detection of the neuroendocrine component of cervical tumors is achieved through immunohistochemical staining. Herein, we present a woman aged 50 years who was admitted to the hospital with abdominal pain and postmenopausal vaginal bleeding whose examination revealed a cervical tumor. A pathologic examination after surgery resulted as "adenocarcinoma and large cell neuroendocrine carcinoma." Afterwards, a combined chemotherapy regimen (cisplatin + etoposid) was administered to the patient and 6 months of progress is evaluated in this report. PMID- 28913102 TI - Do preeclampsia symptoms resolve after intrauterine death of a fetus? AB - : We present two cases of twin pregnancies without resolution of preeclamptic symptoms after intrauterine death of one twin. CASE 1: A nulliparous woman aged 37 years was referred at 26 weeks of gestation because of arterial hypertension, edema, and growth restriction in one twin. Three weeks later the restricted twin died. During the following three weeks, ultrasound examinations showed a reduced growth velocity of the surviving fetus and reversed umbilical flow. At the end of the 34th week of gestation, cesarean section was performed and a healthy female infant was delivered. CASE 2: A nulliparous woman aged 33 years with a 27-week twin pregnancy was referred because of arterial hypertension and discordant growth. The restricted twin died at 31 weeks of gestation. Following the death, within two weeks the growth of the co-twin started to slow down and reversed end diastolic flow presented. At the end of the 33rd week of gestation, cesarean section was performed and a healthy female infant was delivered. : The interesting point of these cases was the secondary effects on the co-twins. During the time after intrauterine deaths of one twin, the surviving fetuses started to show a reduced growth velocity and reversed umbilical flow and mothers had increased blood pressure and proteinuria again. We think that both cases are evidence of late on-set systemic maternal effects (such as systemic maternal endothelial activation and/or systemic maternal inflammatory response) depends on preeclampsia. PMID- 28913103 TI - Early prenatal diagnosis of thoraco-omphalopagus twins at ten weeks of gestation by ultrasound. AB - Early prenatal diagnosis of conjoined twins, an extreme form of monozygotic twinning, is very important for the further management and counselling of parents because they are associated with high perinatal mortality. We present a case of thoraco-omphalopagus twins diagnosed at ten weeks and four days of gestation by two-dimensional Doppler ultrasound, which was then terminated. PMID- 28913104 TI - Role of inflammation and oxidative stress in the etiology of primary ovarian insufficiency. AB - OBJECTIVE: The aim of this study was to elucidate the etiology and treatment of primary ovarian insufficiency, which is of unknown cause in 95% of the cases. MATERIALS AND METHODS: Thirty patients aged 18-40 years who presented to Dicle University Faculty of Medicine Clinic of Obstetrics and Gynecology between June 2012 and January 2014 and were diagnosed as having primary ovarian insufficiency based on their clinical and endocrinologic data, and 30 healthy controls were included in this study. RESULTS: No significant differences were found between patients with primary ovarian insufficiency and control subjects in demographic data and lipid profile levels, thyroid- stimulating hormone, prolactin, and glucose. However, the neutrophil to lymphocyte ratio and levels of follicle stimulating hormone, luteinizing hormone, total antioxidant status, total oxidant status, and oxidative stress index were significantly higher in patients with primary ovarian insufficiency than in control subjects. In the correlation analysis, follicle-stimulating hormone exhibited a positive correlation with total oxidant status, oxidative stress index, and the neutrophil to lymphocyte ratio (r=0.573** p<0.001, r=0.584** p<0.001, r=0.541 p<0.001, respectively) and correlated negatively with total antioxidant status (r=-0.437** p<0.001). CONCLUSION: The neutrophil to lymphocyte ratio, total oxidant status, and oxidative stress index levels are elevated in primary ovarian insufficiency. Therefore, anti-oxidative and anti-inflammatory treatment might be administered to patients in the early stage of primary ovarian insufficiency. However, larger studies are needed to clarify whether these elevated levels are a cause or a consequence of primary ovarian insufficiency. PMID- 28913105 TI - Non-invasive prediction of implantation window in controlled hyperstimulation cycles: Can the time from the menstrual day at embryo transfer to expected menstrual cycle give a clue? AB - OBJECTIVE: The aim of this study was to assess whether the time from the menstrual day at embryo transfer to expected menstrual cycle (TETEMC) is associated with the implantation in women with regular cycles or not. MATERIALS AND METHODS: Forty women with successful implantation and forty women without implantation with regular cycles were randomly selected from prospectively collected database of assisted reproductive technology clinic of Zeynep Kamil Women And Children's Health Training and Research Hospital. TETEMC was calculated for each case to assess relationship with the successful implantation. RESULTS: Comparison of groups revealed significant differences with regard to TETEMC and the menstrual period (p<0.05). In ROC analyses both the TETEMC (AUC=0.824, p<0.001) and the menstrual period (AUC=0.797, p<0.001) were significant predictors for clinical pregnancy. Cut off value for the menstrual period was found to be 27.5 days with 82.6% sensitivity and 65% specificity. Cut off value for TETEMC was 11.5 days with 75% sensitivity and 63.2% specificity. CONCLUSION: Longer menstrual cycle and the TETEMC seem to be associated with the implantation failure. PMID- 28913107 TI - The views of nulliparous pregnant women on the types of delivery. AB - OBJECTIVE: To evaluate the relevant thoughts of nulliparous pregnant women in the second trimester without an absolute indication for cesarean on delivery preferences. MATERIALS AND METHODS: This study was conducted on pregnant women who presented to the Ankara University Faculty of Medicine, Department of Obstetrics and Gynecology Pregnant Outpatients Department for antenatal follow-up between May 2014 and February 2015. A total of 237 nulliparous patients voluntarily completed the survey form and the data were evaluated using various parameters. Parameters consistent with normal distribution were evaluated using the t-test, and parameters that were not normally distributed were evaluated using the Mann-Whitney U test. Parameters with a p value <0.05 were considered significant. RESULTS: We found that 221 (93.2%) of the 237 nulliparous pregnant women preferred vaginal delivery and the remaining 16 (6.8%) preferred delivery by cesarean section. CONCLUSION: Women should be informed on the type of birth and both methods should be explained in a realistic and scientific manner in terms of benefit and risk. An effort is being made to increase vaginal birth rates worldwide and the same effort should be made in Turkey. PMID- 28913106 TI - Do vitamin D and high-sensitivity-C reactive protein levels differ in patients with hyperemesis gravidarum? A preliminary study. AB - OBJECTIVES: The high sensitivity-C reactive protein (hs-CRP) is an inflammatory marker and vitamin D is an immune modulator that might play a critical role in the pathogenesis of hyperemesis gravidarum. Therefore, in the current study, we tested the hypothesis that suggests women with hyperemesis gravidarum have lower 25-hydroxyvitamin D levels and higher hs-CRP levels, compared to controls. MATERIALS AND METHODS: This prospective case-control study included 30 women with hyperemesis gravidarum (study group) and 30 age- and body mass index-matched healthy women (control group). The levels of 25-hydroxyvitamin D and hs-CRP were compared between two groups. RESULTS: Both the serum 25-hydroxyvitamin D (5.30 MUg/L vs. 6.44 MUg/L; p=0.09) and hs-CRP levels (0.29 mg/dL vs. 0.47 mg/dL; p=0.93) were not significantly different between the study and control groups. Vitamin D deficiency was present in 27 (90.0%) women in the study group and 22 (73.3%) women in the control group (p=0.181). There was also no correlation between 25-hydroxyvitamin D and hs-CRP levels in both groups. CONCLUSION: Although it did not reach statistical significance, vitamin D levels were lower in the study group compared with controls. Therefore, vitamin D might be speculated to play a crucial role in controlling the inflammatory status associated with hyperemesis gravidarum. Larger studies are required to clarify whether there is a relation between vitamin D deficiency and hyperemesis gravidarum. PMID- 28913108 TI - The optimal analgesic method in saline infusion sonogram: A comparison of two effective techniques with placebo. AB - OBJECTIVE: Operations performed with local anesthesia can sometimes be extremely painful and uncomfortable for patients. Our aim was to investigate the optimal analgesic method in saline infusion sonograms. MATERIALS AND METHODS: This study was performed in our Clinic of Obstetrics and Gynecology between March and August 2011. Ninety-six patients were included. Patients were randomly divided into groups that received saline (controls, group 1), paracervical block (group 2), or paracervical block + intrauterine lidocaine (group 3). In all groups, a visual analogue scale score was performed during the tenaculum placement, while saline was administered, and 30 minutes after the procedure. RESULTS: When all the patients were evaluated, the difference in the visual analogue scale scores in premenopausal patients during tenaculum placement, during the saline infusion into the cavity, and 30 minutes following the saline infusion sonography were statistically different between the saline and paracervical block groups, and between the saline and paracervical block + intrauterine lidocaine group. However, there was no statistically significant difference between paracervical block and paracervical block + intrauterine lidocaine groups. CONCLUSION: As a result of our study, paracervical block is a safe method to use in premenopausal patients to prevent pain during saline infusion sonography. The addition of intrauterine lidocaine to the paracervical block does not increase the analgesic effect; moreover, it increases the cost and time that the patient stays in the dorsolithotomy position by 3 minutes. PMID- 28913109 TI - A comparison of clinico-pathologic characteristics of patients with serous and clear cell carcinoma of the uterus. AB - OBJECTIVE: Serous carcinoma and clear cell carcinomas account for 10% and 3% of endometrial cancers but are responsible for 39% and 8% of cancer deaths, respectively. In this study, we aimed to compare serous carcinoma and clear cell carcinoma regarding the surgico-pathologic and clinical characteristics, and survival, and to detect factors that affected recurrence and survival. MATERIALS AND METHODS: We retrospectively analyzed patients with clear cell and serous endometrial cancer who underwent surgery between January 1993 and December 2013 in our clinic. We used Kaplan-Meier estimator to analyze survival. RESULTS: The tumor type in 49 patients was clear cell carcinomas and was serous uterine carcinoma in 51 patients. Advanced stage (stage III and IV) disease was present in 42% of the patients in the clear cell group, whereas this rate was 62% in the serous group (p=0.044). Lymph node metastasis was detected in 37% of the patients with clear cell carcinomas and 51% of the patients with serous carcinoma (p=0.17). The adjuvant therapies used did not differ significantly between the groups (p=0.192). The groups had similar recurrence patterns. Five-year progression-free survival and the 5-year overall survival were 60.6% and 85.8%, 45.5% and 67.8% in the patients with clear cell carcinomas and serous tumor, respectively. CONCLUSION: With the exception that more advanced stages were observed in patients with serous carcinoma endometrial cancers at presentation, the surgico-pathologic features, recurrence rates and patterns, and survival rates did not differ significantly between the groups with clear cell carcinoma and serous carcinoma endometrial cancers. PMID- 28913110 TI - Long- and short-term complications of episiotomy. AB - Although extensively applied in obstetrics practice to facilitate delivery by increasing the vaginal birth conduit, most episiotomy studies are in the context of short- or medium-term outcomes, and the number of studies investigating the long-term effects is insufficient. Episiotomy is often considered associated with urinary and/or anal incontinence and dyspareunia; however, there is no concrete evidence for this issue. Current meta-analyses and reviews that assessed the studies available in the literature revealed that episiotomy does not decrease the rates of urinary incontinence, perineal pain, and sexual dysfunction and that routine episiotomy does not prevent pelvic floor damage; thus, the recommended use of mediolateral episiotomy is restricted, rather than routine. According to the limited number of studies on sexual function, there seems to be a linear relationship between the degree of perineal laceration and postpartum dyspareunia. It is still not clear whether episiotomy has any impact on pelvic floor relaxation, pelvic organ prolapse, and sexual dysfunction in the long term. PMID- 28913111 TI - The role of ADAMTS genes in preeclampsia. AB - Preeclampsia is a complex disease that increases both maternal and fetal morbidity and mortality in both developed and developing countries. It complicates around 5-10% of all pregnancies..The pathophysiology of preeclampsia includes both maternal and fetal/placental factors. Implantation of embryo and placentation are crucial steps for development of pregnancy involving trophoblast invasion. Abnormalities of spiral artery invasion, trophoblast function, inflammatory process, and biologic functions of angiogenic/anti-angiogenic factors early in pregnancy result in pregnancy diseases, including preeclampsia. ADAMTS genes are members of the family of matrix metalloproteinase, which have important tasks in extracellular matrix (ECM) degradation and repair processes. The roles of ADAMTS in preeclampsia may include regulation of spiral artery invasion and ECM arrangement of the placenta. PMID- 28913112 TI - Clitoral keloids after female genital mutilation/cutting. AB - We aimed to describe the presentation of long-term complications of female genital mutilation/cutting and the surgical management of clitoral keloids secondary to female genital mutilation/cutting. Twenty-seven women who underwent surgery because of clitoral keloid between May 2014 and September 2015 in Sudan Nyala Turkish Hospital were evaluated in this retrospective descriptive case series study. The prevalence of type 1, type 2, and type 3 female genital mutilation/cutting were 3.7%, 22.2%, and 74.1%, respectively (type 1: 1/27, type 2: 6/27, and type 3: 20/27). All patients had long-term health problems (dysuria, chronic pelvic pain, vaginal discharge, and chronic pruritus) and sexual dysfunction. Keloids were removed by surgical excision. There were no postoperative complications in any patient. Although clitoral keloid lesions can be seen after any type of female genital mutilation/cutting, they usually develop after type 3 female genital mutilation/cutting. Most of these keloids were noticed after menarche. Keloids can be removed by surgical excision and this procedure can alleviate some long-term morbidities of female genital mutilation/cutting. PMID- 28913113 TI - Prenatal diagnosis of pectus excavatum. AB - Pectus excavatum (PE) is the depression of the lower part of manubrium sterni and xiphoid process. The main problem of PE depends on the cardiopulmonary morbidity caused by the narrowing of the thoracic space. To date, prenatal diagnosis of this deformity has been reported only once and was associated with Down syndrome. We present another case which we diagnosed as PE during a second-trimester fetal anatomic scan. The pectus severity index is used for these patients in postnatal life; however, prenatal adaption of this index is reported for the first time in our case. PMID- 28913114 TI - Placental, hepatic, and supraclavicular lymph node metastasis in pancreatic adenocarcinoma during pregnancy: A case report. AB - The occurrence of coexisting cancer in pregnant women is not a common phenomenon. It complicates approximately 1 in 1000 to 1500 pregnancies. We present a multiparous woman aged 27 years in her 28th week of pregnancy who was admitted to our clinic with right upper quadrant pain and was finally revealed to have multiple metastatic pancreatic adenocarcinoma. To the best of our knowledge, this is the first documented case of pancreatic adenocarcinoma to metastasize both to the placenta and multiple maternal sites (liver, supraclavicular, para-aortic lymph nodes) in a pregnant patient. Unpredictable metastases to the placenta may be encountered and may even lead to definitive diagnosis, as in our case. Therefore, the placenta in any patient with known malignancy should be sent for pathologic evaluation. PMID- 28913115 TI - Unusual uterine metastasis of invasive ductal carcinoma: A case report. AB - Metastatic carcinoma of the uterus usually originates from other genital sites. Extragenital metastases such as breast are rare. A woman aged 34 years with a history of breast cancer was referred to the gynecology outpatient clinic for routine follow-up. Diagnostic tests and gynecologic examination revealed a uterine mass, which was removed with laparotomy. The pathologic investigation revealed metastasis of invasive lobular breast cancer. Chemotherapy was given and the patient has been under follow-up for 3 years with normal imaging on comput erized tomographic examination and positron-emission tomography-computerized tomographic. It should be kept in mind that patients with breast cancer who have received tamoxifen may develop primary endometrial cancers, and may also demonstrate uterine metastases. With successful treatment these patients can obtain dis-ease-free survival. PMID- 28913116 TI - Evaluation of sleep disorder and its effect on sexual dysfunction in patients with Fibromyalgia syndrome. AB - OBJECTIVE: Sexual problems are commonly seen in women with fibromyalgia syndrome (FMS). The objective of this study was to reveal the relationship between the severity of symptoms, sleep disorder, and sexual dysfunction in women with FMS. MATERIALS AND METHODS: A total of 140 sexually active women with FMS aged 17-67 years who presented to our physical medicine and rehabilitation outpatient clinic between January 2016 and June 2016 were enrolled in the study. The patients' age, height, body weight, body mass index (BMI), and general pain score [visual analogue scale, (VAS)] for the last 1 week were recorded. The patients were given three different sets of questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Fibromyalgia Impact Questionnaire (FIQ), and Female Sexual Function Index (FSFI). RESULTS: The mean age of the patients was 40.3+/-8.5 years; the mean BMI was 27.1+/-4.4 kg/m2, VAS (last 1 week) was 6.9+/-2 cm, the mean PSQI was 24.8+/ 10.8 (one patient with PSQI <=5), FIQ was 65.9+/-19.2, and FSFI was 19.0+/-6.9. No significant relationship was observed between the mean PSQI and BMI values (p=0.401), whereas a significant relationship was found between the mean values of VAS, FIQ, and FSFI (p=0.03; p=0.034; p<0.001, respectively). In Pearson's correlation analysis, a positive correlation was noted between PSQI and VAS (r=0.324; p<0.001) and FIQ values (r=0.271; p=0.001). A significant relationship was found between the FIQ and VAS values (p<0.001). P less than 0.005 was considered statistically significant. CONCLUSION: Sleep disorder is regarded as the underlying cause for many signs and symptoms in FMS. Sexual dysfunction may develop in women with FMS, based on the severity of the disease and poor sleep quality. We found that sleep dysfunction was significantly related with the severity of disease, pain, and sexual disfunction. We also found a positive correlation between VAS and PSQI. PMID- 28913117 TI - Evaluation of the efficacy of transobturator tape surgery in the treatment of stress urinary incontinence using urodynamics and questionnaires. AB - OBJECTIVE: To measure the efficiency of transobturator tape (TOT) surgery using urodynamics and questionnaires in stress urinary incontinence. MATERIALS AND METHODS: Ninety-two patients with stress and mixed urinary incontinency who underwent TOT surgery were selected for the study. We retrospectively examined the patients' urodynamics, ultrasonography, demographic characteristics, incontinency surveys, life quality scores [incontinence impact questionnaire, (IQ 7) and urinary distress inventory (UDI-6)], diagnostic findings, Q-type test, surgical records, and complications. Patients treatment adherence, life quality scores, and urodynamics were evaluated as per the findings and complications following discharge of the patients between 12 and 36 months. Patients with a surgical history as the result of incontinence were excluded from the study. RESULTS: Prior to surgery, 57 (61%, 95) patients had stress urinary incontinence (SUI), and 35 (38%, 05) patients had mixed urinary incontinence (MUI). During surgery, 45 (48%, 91) patients underwent extra pelvic surgical intervention. The mean follow-up time was 22.17+/-7.55 months. Our subjective success rate was 91%, 3 and the objective success rate was 78%, 3. In the life quality evaluation, a statistically significant improvement was found between IIQ-7 and UDI-6 scores. Parity over 4 was an important failure reason. Two (2%, 17) patients developed vaginal erosion, 2 (2%, 17) of the patients developed temporary urine retention, and 1 (1%, 08) patient developed nova urge incontinence. CONCLUSION: Our study demonstrates that TOT surgery provides high objective and subjective success and has a positive impact on life quality. The ease of application and lower complication rate makes TOT a valuable alternative for other treatment approaches in the surgical treatment of SUI. PMID- 28913118 TI - The course and outcomes of complicated gallstone disease in pregnancy: Experience of a tertiary center. AB - OBJECTIVE: To evaluate the course and outcomes of pregnant patients with complicated gallstone disease and to reveal the experience of a tertiary center. MATERIALS AND METHODS: The records of 92.567 patients were evaluated using searches for diagnoses with the terms of pregnant, pregnancy, gallstone, cholecystitis, cholangitis, choledocholithiasis, pancreatitis, and endoscopic retrograde cholangiopancreatography in pregnancy in the hospital database. Patients' age, week of gestation, parity, body mass index, definitive diagnosis, attack episodes, treatment modalities, and obstetric and neonatal complications were evaluated. RESULTS: Overall, 59 women were diagnosed as having complicated gallstone disease in pregnancy. Acute cholecystitis was the most commonly diagnosed complicated gallbladder disease (62.7%). Cholecystectomy was performed in 15 women during gestation. Perinatal outcomes were as follows: one (1.7%) maternal death, 4 (6.8%) preterm deliveries, 5 (8.5%) low-birth-weight fetuses, and 1 (1.7%) missed abortion were encountered. No fetal abnormalities were encountered. CONCLUSION: A significant proportion of women experience biliary disease during pregnancy. Herein, we presented our clinical experience because the diagnosis, course, and management of complicated gallstone disease in pregnancy is complicated. PMID- 28913119 TI - Hysteroscopy: A necessary method for detecting uterine pathologies in post menopausal women with abnormal uterine bleeding or increased endometrial thickness. AB - OBJECTIVE: To investigate the histologic and hysteroscopic findings of post menopausal women with uterine bleeding and asymptomatic women with increased endometrial thickness equal or more than 5 mm. MATERIALS AND METHODS: This cross sectional study was performed between May 2014 and June 2015 on 110 post menopausal women aged 40-82 years. The women were divided into two groups: Women with abnormal uterine bleeding (AUB group) and asymptomatic women with increased endometrial thickness (asymptomatic group). RESULTS: Among the participants, 67 women had AUB and 43 women were asymptomatic. In the AUB group sensitivity, specificity, and positive and negative predictive values of hysteroscopy for normal findings were 98%, 100%, 100% and 90%, respectively. In the asymptomatic group, the same parameters were 98%, 100%, 100% and 85%, respectively. The sensitivity, specificity, and positive and negative predictive values of hysteroscopy for polyps and myomas were 100%. Also, the sensitivity, specificity, and positive and negative predictive values were 100% in hyperplasia cases found during hysteroscopy in both groups. CONCLUSION: Increased endometrial thickness in postmenopausal women with or without AUB is mostly due to benign lesions such as polyps and submucosal myomas. Hysteroscopy is a safe and reliable method for evaluating and treating these lesions. PMID- 28913120 TI - Effects of the morbid obesity and skin incision choices on surgical outcomes in patients undergoing total abdominal hysterectomy. AB - OBJECTIVE: This study aimed to evaluate the effect of obesity on surgical outcomes in patients who underwent gynecologic surgery. MATERIALS AND METHODS: In total, we evaluated 132 patients who underwent total abdominal hysterectomy with or without salpingo-oophorectomy for benign gynecologic procedures at our tertiary referral gynaecology clinic. RESULTS: The non-morbid obese group [body mass index (BMI) <40 kg/m2] included 94 patients, and the morbid obese group (BMI >=40 kg/m2) included 38 patients. The perioperative outcomes of the groups were compared. The mean operative time was significantly longer for morbid obese patients than non-morbid obese patients (p<0.05). Estimated blood loss, the need for blood transfusion, postoperative hemoglobin values, and the need for an intraabdominal drain were similar between the groups. Early and late postoperative complications were significantly more frequent in the morbid obese group than the other group (p<0.05, for each). Early postoperative complications in patients who underwent vertical skin incision were significantly more frequent than in patients who underwent pfannenstiel incision (p<0.05). Late complications were comparable between the two types of skin incision. CONCLUSION: Morbid obesity significantly increases the mean operative times and the postoperative complication rates of abdominal hysterectomy operations. PMID- 28913121 TI - The impact of abdominal and laparoscopic hysterectomies on women's sexuality and psychological condition. AB - OBJECTIVE: To investigate whether there were any differences in the quality of life, sexual function, and self-esteem of patients who underwent total laparoscopic hysterectomy (TLH) (n=42) and total abdominal hysterectomy (TAH) (n=42). MATERIALS AND METHODS: All premenopausal patients who underwent TLH or TAH because of benign uterine disorders were enrolled. The sexual function and quality of life status were assessed preoperatively and 6 months postoperatively using three standardized validated questionnaires: the Arizona Sexual Experiences Scale (ASEX), the Symptom Checklist-90-Revised (SCL-90-R), and the Rosenberg Self Esteem Scale (RSES). RESULTS: Preoperative ASEX, SCL-90-R and RSES scores were not different among the hysterectomy subgroups. The postoperative SCL-90-R scores were also not different among the hysterectomy subgroups. The postoperative RSES scores were significantly lower (p<0.05) than the preoperative scores for all procedures (indicating improved self-esteem) but did not differ among the groups. The postoperative ASEX scores were significantly decreased (p<0.01) as compared with the preoperative scores (indicating improved sexual function). When the average score of each item of the ASEX score was compared in both groups, significant differences were observed in sexual drive and arousal in the laparoscopy group (p<0.01). CONCLUSION: Women undergoing TLH for benign uterine disease may have better outcomes related to certain sexual function parameters than women undergoing TAH. PMID- 28913122 TI - Impact of laparoscopic ovarian drilling on serum anti-mullerian hormone levels in patients with anovulatory Polycystic Ovarian syndrome. AB - OBJECTIVES: Anti-mullerian hormone (AMH) is a marker of the activity of recruitable ovarian follicles. It is useful in the prediction of ovarian reserve. Women with polycystic ovarian syndrome (PCOS) have elevated circulating and intrafollicular AMH levels. Laparoscopic ovarian drilling (LOD) in patients with PCOS destroys ovarian androgen-producing tissue and reduces their peripheral conversion to estrogens. Identifying factors that determine the response of patients with PCOS to LOD will help in selecting the patients who would likely benefit from this treatment. AMH is one such marker that can predict the response to LOD. To evaluate the effect of LOD on serum AMH levels among PCOS responders and non-responders and the usefulness of AMH as a tool in predicting the response to LOD, and to whether there was loss of ovarian function after LOD. MATERIALS AND METHODS: This is a prospective cohort study including 30 clomiphene-resistant women with anovulatory PCOS undergoing LOD. Statistical analysis was performed to evaluate the effect of LOD on serum levels of AMH on these women. RESULTS: A significant fall in the levels of AMH was observed after LOD in both responders and non-responders (p<0.001). Women with AMH >8.3 ng/mL showed a significantly lower ovulation rate (33.3%). LOD was not associated with a risk of diminished ovarian reserve. CONCLUSION: LOD is an effective first-line treatment for women with PCOS who are clomiphene resistant. LOD has no negative effect on ovarian reserve. AMH is a useful marker in predicting the outcome of LOD. PMID- 28913123 TI - True management of Obstructed Hemi-vagina and Ipsilateral Renal Anomaly syndrome. AB - Herlyn-Werner-Wunderlich syndrome is an unusual congenital anomaly of the female genitourinary system, which is described as uterine didelphys with Obstructed Hemi-vagina and Ipsilateral Renal Anomaly (OHIRA), also known as OHVIRA syndrome. Typical symptoms are pelvic pain, tenderness, pelvic mass due to blood collection in the obstructed hemi-vagina and uterus, and dysmenorrhea that usually begins shortly after menarche. Clinical suspicion is very important for diagnosis and correct management avoids both short- and long-term complications. Surgical removal of the vaginal septum is the main treatment method. Herein, we describe the evaluation and surgical management of a patient with OHVIRA syndrome who was diagnosed using magnetic resonance imaging and pelvic ultrasound. PMID- 28913124 TI - Postpartum aortic dissection in a patient without Marfan's syndrome. AB - Aortic dissection can occur in pregnancy or during the postpartum period without pre-existing disease and it is a rare but potentially life-threatening event. Herein, we present a young woman without Marfan's syndrome who developed a postpartum ascending aortic dissection 5 days after cesarean section. PMID- 28913125 TI - Bilateral ovarian metastasis of a Klatskin tumor: A rare case. AB - Metastatic carcinomas of the ovary have an important place in all ovarian cancers and tumors. They can originate from many organs and systems and may metastasize to the ovary. The most common primary origin of metastasis is the gastrointestinal tract and then breast tissue. Cholangiocellular carcinomas involving the junction of the right and left bile ducts are called Klatskin tumors, and their metastases to the ovaries are very rare. A woman aged 54 years who had been treated previously for Klatskin tumor was admitted to our clinic due to bilateral ovarian masses and high serum calcium 19-9 levels. The preoperative approach, operative, and postoperative management of Klatskin tumor is presented. PMID- 28913126 TI - Angular pregnancy. AB - Angular pregnancy is a rare condition in which the embryo is implanted in the lateral angle of the uterine cavity, medial to the uterotubal junction and round ligament, and causes life-threatening obstetric complications. It is important to differentiate this condition from interstitial and cornual pregnancy because they all result in emergency conditions. Although angular pregnancy can progress to term pregnancy, it may be associated with major obstetric complications such as uterine rupture, placental retention, postpartum hemorrhage, or may need further surgery and hysterectomy. This report describes a case of angular pregnancy from the 6th gestational week and continued until delivery in the 32nd gestational week. Sonographic findings, follow-up, and delivery concerns are described in this manuscript. PMID- 28913127 TI - Severe methotrexate toxicity after treatment for ectopic pregnancy: A case report. AB - Severe methotrexate toxicity due to medical treatment of an ectopic pregnancy is presented. The feasibility of low-dose use and success of methotrexate makes it the first drug in the medical treatment of ectopic pregnancies. Besides its advantages, it should be used with caution and severe toxicity should be kept in mind. PMID- 28913128 TI - Early initiation and exclusive breastfeeding: Factors influencing the attitudes of mothers who gave birth in a baby-friendly hospital. AB - OBJECTIVE: To investigate the initation time of breastfeeding, exclusive breastfeeding rates, and complementary feeding practices during the first six months of life among mothers who gave birth in a baby-friendly hospital. MATERIALS AND METHODS: A cross-sectional study was conducted with 350 mothers. Demographic characteristics, obstetric history and information about breastfeeding initiation were collected at the hospital. Information about factors affecting breastfeeding duration and feeding practices of the infants were obtained at the end of six months. RESULTS: Some 97.4% of the mothers initiated breastfeeding, 60.1% within the first hour. Exclusive breastfeeding was maintained for six months in 38.9%. Low education levels of mother/father, random breastfeeding, rare breastfeeding at night, nipple problems, bottle/pacifier use, and lack of social support were found associated with early cessation. Planned pregnancy [odds ratio (OR=2.02)] and vaginal delivery (OR=0.3) were found as the most important factors in early initiation, whereas antepartum breastfeeding education (OR=7.17) was the most important factor for exclusive breastfeeding duration in the logistic analysis. More than half (61.1%) of the infants were partially/bottle fed for six months; the most common reason was the belief that breast milk was insufficient. CONCLUSION: Efforts to encourage mothers and society to breastfeed exclusively should be made as part of a primary public health strategy to prevent early cessation of breastfeeding. PMID- 28913129 TI - Evaluating the content and quality of intrapartum care in vaginal births: An example of a state hospital. AB - OBJECTIVE: The purpose of the research was to assess the content and quality of the intrapartum care offered in vaginal births in Turkey, based on the example of a state hospital. MATERIALS AND METHODS: This cross-sectional study was conducted between January 1st, 2013 and December 31st, 2014 at Aydin Maternity and Children's Hospital. The study sample consisted of 303 women giving vaginal birth, who were recruited into the study using the method of convenience sampling. Research data were collected with a questionnaire created by the researchers and assessed using the Bologna score. Numbers and percentages were assessed in the data analysis. RESULTS: The mean age of the women was 25.14+/ 5.37 years and 40.5% had given one live birth. Of the women, 45.2% were admitted to hospital in the latent phase, 76.6% were administered an enema, 3.3% had epidural anesthesia, 2.6% delivered using vacuum extraction, and 54.1% underwent an episiotomy. Some 23.8% of the women experienced spontaneous laceration that needed sutures. The babies of two women exhibited an Apgar score below 7 in the fifth minute. When the quality of the intrapartum care given to the women was assessed with the Bologna score, it was found that 92.7% went into labor spontaneously, 100% of the births were supervised by midwives and doctors, 97.7% of the women had no supporting companion, and the nonsupine position was only used in 0.3% of the women. A partogram was used to follow up on the birth process in 72.6% of the women, and 82.5% achieved contact with their babies within the first hour after birth. Induction was applied in 76.6% of the women and fundal pressure in 27.4%. CONCLUSION: The study revealed that the quality of intrapartum care in vaginal births was inadequate. Reformulating the guidelines regarding intrapartum care in accordance with World Health Organization recommendations and evidence-based practices may contribute to improving mother and infant health. PMID- 28913130 TI - Prevalence of gestational diabetes mellitus according to the different criterias. AB - OBJECTIVE: The two-step approach recommended by the National Diabetes Data Group (NDDG), Carpenter and Coustan (C&C), and O'Sullivan, and the single-step approach recommended by the International Association of Diabetes and Pregnancy Study Group (IADPSG) are used to diagnose gestational diabetes mellitus (GDM). We aimed to determine GDM prevalence and to compare the two-step and single-step approaches used in the southeastern region of Turkey. MATERIALS AND METHODS: In total, 3048 records of pregnant women screened for GDM between 2008 and 2014 were retrospectively extracted from our laboratory information system. GDM was defined according to the criteria of NDDG, C&C, and O'Sullivan between in 2008 and 2011, and according to those of the IADPSG between 2012 and 2014. Demographic variables were compared using student's t-test. The linear trends in GDM prevalence with age were calculated using logistic regression. RESULTS: GDM prevalence was found as 4.8%, 8%, and 13.4% using the NDDG, C&C, and O'Sullivan two-step approach, respectively, and 22.3% with the IADPSG single-step approach. GDM prevalence increased with increasing age in both approaches. CONCLUSION: GDM prevalence was higher using the single-step approach than with the two-step approach. There was a significant increase in GDM prevalence using the IADPSG criteria. PMID- 28913131 TI - The significance of reverse flow in ductus venosus between sixteen and twenty weeks' gestation. AB - OBJECTIVE: To evaluate the correlation between reversed a-wave in ductus venosus at 16-20 weeks' gestation and trisomy 21 and adverse perinatal outcomes. MATERIALS AND METHODS: Our study included 174 pregnant women who were under follow-up at a tertiary center between May and September 2010. Ductus venosus Doppler (DVD) measurements were obtained throughout the 6-month period from women who underwent amniocentesis procedures due to increased risk for trisomy 21 in terms of first or second trimester screening test results. These women were followed up for enrollment of subsequent data about perinatal outcomes. RESULTS: In 13 of 174 cases, Doppler studies indicated a reversed a-wave in the ductus venosus. Of these fetuses, 3 were diagnosed as having trisomy 21 after amniocentesis, which related to 60% (3 of 5 fetuses) of all fetuses with trisomy 21. The pregnant women with reversed a-wave in DVD also had an increased rate of preeclampsia (15%) and gestational diabetes mellitus (GDM) (23%) in late pregnancy. CONCLUSION: Reversed a-wave in ductus venosus between 16-20 weeks' gestation is associated with increased risk of trisomy 21, preeclampsia, and GDM. If further prospective studies confirm its utility, DVD interrogation for trisomy 21 may be extended until 20 weeks' gestation. PMID- 28913132 TI - The incidence, risk factors, and mortality of preterm neonates: A prospective study from Jordan (2012-2013). AB - OBJECTIVE: To explore the incidence of preterm delivery, maternal risk factors for having a preterm neonate, and preterm neonates' mortality in Jordan. MATERIALS AND METHODS: A cross-sectional population-based design was applied. Socio-demographic, perinatal, delivery risk factors, and survival information were gathered in pre- and post-hospital discharge interviews with 21075 women who gave birth to live neonates at >=20 weeks of gestation in 18 hospitals in Jordan. Women were interviewed between 2012 and 2013. The sample was limited to singleton women who gave birth to live neonates. Women who gave birth to stillborn babies were excluded. RESULTS: Preterm delivery incidence was 5.8%, of which 85% were in 32-36 gestational weeks. Male sex, primigravidity, hypertension, preeclampsia, and diabetes were significantly associated with an increased risk of preterm delivery. Women aged 20-35 years had the lowest risk of preterm delivery. Mother's weight <50 kg, hospitalization at 24-34 gestational weeks, lack of antenatal care visits or <8 visits during pregnancy, a history of preterm delivery, and a history of stillbirth/neonatal death were associated with increased risks of preterm delivery. The neonatal mortality rate was 4/1000 live births among full-term and 123/1000 live births among preterm babies. Prematurity, congenital anomalies, and maternal diseases were the causes of 84% of preterm neonatal deaths. CONCLUSION: The mortality rate was considerably higher among preterm neonates than among term neonates; discrepancies between Jordan and other countries existed. Systematic prenatal risk assessment and quality postnatal health care improvements are required to improve the survival rates of preterm neonates. PMID- 28913133 TI - The relationship between fecal incontinence and vaginal delivery in the postmenopausal stage. AB - OBJECTIVE: Obstetric anal sphincter injuries are one of the most significant complications of vaginal delivery that give way to fecal incontinence, which is defined as the involuntary leakage of gas, fluid or solid stool. Although sphincter injuries are seen in 0.5-9% of all deliveries. It has been reported that 20-41% of women who had vaginal deliveries had occult anal sphincter injuries as endoanal ultrasonography began to be used by physicians. The aim of our study was to investigate the relationship between fecal incontinence, whose incidence increases dramatically during the postmenopausal stage, and occult anal sphincter injuries. MATERIALS AND METHODS: Two hundred healthy female patients with no history of anal sphincter injury, aged between 18 and 70 years were included in the study. The participants were divided into 4 groups according to their menopausal stages and mode of delivery; premenopausal (group 1) and postmenopausal (group 2) vaginal delivery, and premenopausal (group 3) and postmenopausal (group 4) cesarean section. Wexner incontinence scores were determined. The participants' defects were assessed using endoanal ultrasound and their status of fecal incontinence using anorectal manometric measurements. RESULTS: Anorectal manometric measurement results were found significantly lower in group 1 than in group 3 (p<0.01). The Wexner scores of groups 1 and 3 were similar. The anorectal manometric measurement results of group 2 were significantly lower than those of group 4, and the Wexner score of group 2 was significantly higher than other groups (p=0.03). CONCLUSION: Anal sphincter injuries formed after vaginal delivery may be one of the reasons that increase the incidence of postmenopausal fecal incontinence and cause the formation of fecal incontinence symptoms in women. PMID- 28913134 TI - Management of vesicovaginal fistulas after gynecologic surgery. AB - OBJECTIVE: In developed nations, surgery, especially gynecologic procedures, is the major cause of vesicovaginal fistulas (VVFs). We retrospectively evaluated our treatment modalities for VVF repair caused by a gynecologic surgery, and discussed the reasons of selecting certain surgical techniques and their outcomes. MATERIALS AND METHODS: We compared the surgical procedure preferences of surgeons and their results with patient and surgeon characteristics for the management of VVFs after an inciting gynecologic surgery in Suleyman Demirel University Hospital, Isparta over a 10-year period. The surgical procedures were undertaken in departments of urology and obstetrics and gynecology. RESULTS: Abdominal repair was chosen for 65%, vaginal repair for 25%, and laparoscopic repair for 10% of patients. For the 75% of the patients that urologists operated, they chose the abdominal route. The mean parity number of patients who underwent abdominal repair was lower than that for vaginal repairs (p<0.05). For the patients managed with the vaginal route, 20% had a Martius flap, and 80% had a simple excision and repair. For patients operated via the abdominal route, 18% needed omental flap; no tissue interposition was used for the rest. The mean hospitalization time was less in patients managed with transvaginal repair (3.4 days) compared with transabdominal repair (9.2 days) (p<0.05). CONCLUSION: The choice of repair method depends on surgeon's training (gynecology vs. urology). The vaginal route should be the first choice because it does not compromise the success rate and the mean hospitalization time is less. For the transvaginal approach, access to the lesion is the most important factor for the success of the procedure. No flap is needed for tissues that appear well vascularized. PMID- 28913135 TI - Prognostic risk factors for lymph node involvement in patients with endometrial cancer. AB - OBJECTIVE: We aimed to analyze variables affecting lymph node (LN) involvement and to assess the need for systematic lymphadenectomy in patients with endometrial cancer (EC). MATERIALS AND METHODS: A single centre retrospective analysis was conducted in a total of 128 consecutive patients with EC who underwent systematic pelvic or combined pelvic and paraaortic lymphadenectomy between 2009 and 2012. Mann-Whitney U, chi-square, and Fisher's exact test were used for univariate analyses when appropriate. Variables with a p value <0.05 in the univariate analysis were included into a multivariate logistic regression analysis. The effects of variables on LN involvement are reported using adjusted odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: In univariate analysis, grade 2-3, tumor size >=3 cm, deep (>=50%) myometrial invasion, presence of cervical, adnexal or omental involvement, positive peritoneal cytology, open surgical approach (laparotomy), combined pelvic and paraaortic lymphadenectomy and number of total LNs removed (>30) were found associated with LN involvement. However, the number of total LNs removed (>30) was the only independent variable that predict LN involvement in multivariate analysis [OR: 15.08; 95% CI: (1.28-177.59); p=0.03]. CONCLUSION: This study demonstrates that the more LNs removed during staging of EC, the greater the probability of finding LN metastasis. PMID- 28913136 TI - Clinical analyses of successful and previously failed intracytoplasmic sperm injection cycle parameters in patients with poor ovarian reserve. AB - OBJECTIVE: To determine some major characteristic differences between two consecutive successful and unsuccessful intracytoplasmic sperm injection (ICSI) cycles in poor responders. MATERIALS AND METHODS: Sixty women with poor ovarian response as determined using the Bologna criteria underwent ICSI cycles following an unsuccessful trial. Some parameters of both cycles including age, body mass index (BMI), serum follicle-stimulating hormone (FSH) and estradiol levels, antral follicle count, gonadotropin dosage, duration of stimulation, antagonist starting day, duration of antagonist administration, endometrial thickness at trigger day, number of total and fertilized oocytes, embryo transfer day, number of embryo cells, and fertilization rate were compared in the same patients to identify predictors of cycles with clinical pregnancy. RESULTS: The mean age, BMI, serum FSH, estradiol concentrations, and antral follicle count were 35.9 years (range, 30-42 years), 25.9 kg/m2 (range, 18.4-33.5 kg/m2), 10.9 IU/mL (range, 7-13 IU/mL), 52.9 pg/mL (range, 11.6-75 pg/mL), and 4.7 (range, 2-10), respectively. A comparison of cycle characteristics showed a significantly higher total number of mature and fertilized oocytes in successful cycles. The fertilization rate was also significantly higher in cycles with clinical pregnancy. Early initiation of antagonist was shown to result in favorable outcomes. A comparison of embryo characteristics showed that transfer of higher stage embryos and embryos with higher numbers of cells had a significant impact on cycle outcomes. CONCLUSION: Our comparison of parameters of failed and successful ICSI cycles in poor responders revealed significantly earlier antagonist initiation, higher total number of mature and fertilized oocytes, fertilization rate, and significantly higher stage of embryo development and cell numbers at transfer in cycles that resulted in clinical pregnancy. PMID- 28913137 TI - Intra-cesarean insertion and fixation of frameless intrauterine devices. AB - Various contraceptive methods are available to postpartum women including hormonal and nonhormonal barriers, as well as injectable forms. Of all the available birth control methods, intrauterine devices (IUD) are felt by many to be the near-ideal form of contraception, and are recommended by advocacy groups, physicians, and gynecological organizations worldwide. Immediate postpartum IUD insertion deserves greater attention because it can provide immediate contraception, prevents repeat unintended pregnancies, and may serve to reduce the incidence or need for secondary cesarean delivery; however, insertion of conventional T-shape IUDs immediately post placenta delivery is limited by their high expulsion and displacement rates. Anchoring of frameless-design IUDs that lack conventional cross-arms to the uterine fundal surfaces has been medically and commercially available throughout Europe for many years. The placement technique is simple, has minimal patient discomfort, and high long-term patient acceptance due to its high degree of uterine compatibility as a consequence of its small size and segmented design. Frameless-design IUD implantation appears to represent a major advance, suitable for general use, due to its lack of timing restraints and its simplicity of attachment, which only requires limited training. PMID- 28913138 TI - Chondrosarcoma mimicking an adnexal mass: A very rare case report. AB - Chondrosarcoma is considered as a common primary bone sarcoma. These sarcomas can form large masses without any specific symptoms because there are no barriers in pelvic anatomy to prevent the enlargement of tumors, and can mimic ovarian masses. We present a pelvic chondrosarcoma in a woman aged 37 years who was misdiagnosed as having an ovarian mass due to the limited information obtained from imaging studies. Pelvic chondrosarcoma should be considered in patients who have pelvic masses with solid components. It should be kept in mind that interventions should be performed at centers where there are orthopedic surgeons with experience of this subject. PMID- 28913139 TI - Mayer-Rokitansky-Kuster-Hauser syndrome associated with rectovestibular fistula. AB - A female neonate with two openings in the introitus and an absent anal opening at the anal site presents a diagnostic challenge. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome associated with rectovestibular fistula, though rare, should be kept in mind as a differential diagnosis of this presentation. We present such a case in a one-year-old female child with MRKH syndrome and rectovestibular fistula. PMID- 28913140 TI - A rare case of complete penoscrotal transposition with hypospadias in a newborn. PMID- 28913141 TI - Outcome of intracytoplasmic sperm injection after preinstillation of a gonadotropin releasing hormone agonist in the uterine cavity just before embryo transfer. AB - OBJECTIVE: To evaluate the effects of a gonadotropin releasing hormone agonist (GnRHa) injection prior to embryo transfer on implantation and pregnancy rate. MATERIALS AND METHODS: We performed a retrospective analysis of patients undergoing in vitro fertilization (IVF) therapy with and without GnRHa preinstallation into the uterine cavity just before embryo transfer between January 2012 and March 2013 in a single IVF center of a university hospital. Patients were evaluated based upon implantation, pregnancy, live birth, and miscarriage rates. RESULTS: GnRHa was injected into the uterine cavity of 108 patients prior to embryo transfer which were regarded as study group. One thousand forty-seven patients who were not injected GnRHa were regarded as the control group. Pregnancy rates were 44.4% and 41.7% in the GnRHa and control groups, respectively. Live birth rates were 27.8% and 26.1%, miscarriage rates were 15.7% and 15.7%, and implantation rates were 31% and 30%, respectively and there were no difference between groups statistically (p>0.05). CONCLUSION: No statistically significant differences in implantation, pregnancy, live birth, or miscarriage rates were observed in patients treated with GnRHa prior to embryo transfer, relative to the controls. Therefore, GnRHa injection into the uterine cavity prior to embryo transfer is not recommended as a means of increasing implantation or pregnancy rates in IVF. However, prospective randomized controlled studies are needed to clarify the effect of GnRHa instillation in the uterine cavity for embryo implantation in IVF. PMID- 28913142 TI - Day 3 embryo transfer versus day 5 blastocyst transfers: A prospective randomized controlled trial. AB - OBJECTIVE: This study aimed to show whether transferring day 5 embryos resulted in higher implantation and pregnancy rates than transferring day 3 embryos in Turkish women undergoing an intracytoplasmic sperm injection (ICSI) cycle. MATERIALS AND METHODS: A total of 190 women who had ICSI after retrieval of more than four oocytes on the day of fertilization check were randomly assigned to undergo embryo transfer either on day 3 or day 5. RESULTS: Day 3 and day 5 transfers were statistically similar with respect to the age of woman (p=0.107), duration of infertility (p=0.528), cause of infertility (p=0.850), number of collected oocytes (p=0.119), number of metaphase II oocytes (p=0.178), number of fertilized oocytes (p=0.092), and number of transferred embryos (p=0.556). The number of grade 1 embryos was significantly higher in day 5 transfers than in day 3 transfers (p=0.001). Day 3 and day 5 embryo transfers had statistically similar implantation, clinical pregnancy, twinning, and live birth rates (p=0.779, p=0.771, p=0.183, and p=0.649, respectively). The live birth rates in singleton pregnancies conceived after day 3 and day 5 embryo transfers were statistically similar (p=0.594). CONCLUSION: The efficacy of blastocyst transfer is not inferior to that of embryo transfer on cleavage stage. Performing blastocyst transfer may have benefits because it is associated with acceptable pregnancy rates and morphologic assessment on day 3 has limited predictive value for subsequent embryonic development. PMID- 28913143 TI - Role of osteocalcin, tumor necrosis factor-alpha and adiponectin in polycystic ovary syndrome patients with insulin resistance. AB - OBJECTIVE: Insulin resistance (IR) seems to be the main pathogenic factor in polycystic ovary syndrome (PCOS). Adiponectin and tumor necrosis factor-alpha (TNF-alpha) are important in IR. The aim of this study was to evaluate the correlations of osteocalcin, adiponectin, and TNF-alpha with IR in PCOS. MATERIALS AND METHODS: A total of 60 women were divided into two groups. The first group constituted 44 patients with PCOS and the control group comprised 16 healthy women. Osteocalcin, adiponectin, TNF-alpha levels, body mass index (BMI), and IR in the fasting state were assessed and correlations of these parameters were evaluated. RESULTS: Homeostasis model assessment (HOMA)-IR, adiponectin, osteocalcin, and androstenedione levels were significantly increased in the PCOS group. A moderate positive correlation between BMI and HOMA-IR, a moderate negative correlation between TNF-alpha and osteocalcin, and a mild negative correlation between adiponectin and BMI were detected in PCOS. CONCLUSION: Osteocalcin may have impact on adiponectin, TNF-alpha, and IR levels in PCOS. Different osteocalcin levels in patients with PCOS may be responsible for explaining PCOS heterogeneity. PMID- 28913144 TI - Effect of pigtail catheter application on obstetric outcomes in in vitro fertilization/intracytoplasmic sperm injection pregnancies following hyperstimulation syndrome. AB - OBJECTIVE: To evaluate the effects of percutaneous pigtail catheter drainage on the outcomes of intracytoplasmic sperm injection (ICSI) pregnancies following moderate or severe ovarian hyperstimulation syndrome (OHSS). MATERIALS AND METHODS: This retrospective study included 189 patients hospitalized for OHSS following ICSI treatment in a tertiary in vitro fertilization unit between 2006 and 2014. Pigtail catheters were applied in 63 patients; the other 126 patients did not need that treatment. The obstetric reports of 173 patients could be accessed and were examined to investigate the pregnancy outcomes of those with and without catheters. RESULTS: No complications such as infection or vascular or intra-abdominal organ trauma were observed related to the pigtail application. There were no differences in abortus, preterm labor, gestational diabetes mellitus, and preeclampsia ratio between the pigtail and control groups (p>0.05). The rate of readmission to hospital for OHSS was lower in the pigtail group than in the control group although not statistically significant (p=0.08). CONCLUSION: Pigtail application is a safe and effective method for draining ascites in patients with OHSS after ICSI treatment. The use of pigtail catheters had no adverse effects on the perinatal outcomes of patients hospitalized with OHSS who became pregnant after ICSI treatment. In addition, the percutaneous drainage of ascites via a pigtail catheter helped prevent the readmission of patients with moderate or severe OHSS. PMID- 28913145 TI - Subclinical hypothyroidism: Is it important in intracytoplasmic sperm injection cycles? AB - OBJECTIVE: To compare intracytoplasmic sperm injection (ICSI) outcomes of women with subclinical hypothyroidism with those of euthyroid women. MATERIALS AND METHODS: A retrospective case-control study was conducted. Out of 2529 ICSI cycles evaluated, 41 women with hypothyroidism, 28 women with hyperthyroidism, and 128 women with subclinical hyperthyroidism were excluded, and 2336 cycles were analyzed. Women were identified as having subclinical hypothyroidism (case group, n=105) in the presence of a thyroid-stimulating hormone level >4.5 mU/L and normal free T4 and compared with euthyroid controls (n=2231). RESULTS: The mean age, body mass index, day 3 follicle-stimulating hormone level, and antral follicle count of the study patients were similar to the control group (p>0.5). The cycle cancellation rate of the study group was similar to the control group (13.3% vs. 7.6%, p=0.1). The clinical pregnancy rate was 21.2% in the study group, which was significantly lower than the 35.8% in the control group (p=0.04). The take-home baby rate was also significantly lower in the study group compared with the control groups (13.5% vs. 31.4% respectively, p=0.01). CONCLUSION: Both the clinical pregnancy rate and the take-home baby rate is lower in women with subclinical hypothyroidism at the time of ICSI cycle. PMID- 28913146 TI - Fetomaternal outcomes in pregnant women with hepatitis E infection; still an important fetomaternal killer with an unresolved mystery of increased virulence in pregnancy. AB - OBJECTIVE: Hepatitis is a prevalent infection in developing countries. While hepatitis B and C are deepening their roots in the developed world, hepatitis A and E are common in the developing world. The uniqueness of hepatitis is in its transformation from a relatively self-limiting disease in the non-pregnant state, to a highly virulent disease during pregnancy. MATERIALS AND METHODS: This retrospective observational study was conducted in the Department of Obstetrics and Gynecology, King George's Medical University, Lucknow, for a period of six months from June 2016 to November 2016 [probably during an endemic peak of hepatitis E virus (HEV)] to observe the clinical outcomes in HEV-infected pregnant women. RESULTS: A total of 32 anti-HEV immunoglobulin M-positive pregnant women were included, and fetomaternal outcomes were analyzed. Hepatitis E positivity was significantly associated with maternal mortality, intrauterine demise with prematurity, and premature rupture of membranes was the most common fetal complication noted. CONCLUSION: The difference in extent of virulence of infection and variations in maternal morbidity, mortality, and rates of intrauterine demise, signify the presence of some factors that play a role and need to be further studied and evaluated. PMID- 28913147 TI - Summary of 2185 prenatal invasive procedures in a single center: A retrospective analysis. AB - OBJECTIVE: To determine the frequency, indications, and outcomes of diagnostic invasive prenatal procedures (DIPP) performed in a university hospital. MATERIALS AND METHODS: This retrospective, observational study included 2185 cases of DIPP (chorionic villus sampling, amniocentesis, and cordocentesis) performed at the department of obstetrics and gynecology of a university hospital between 2010 and 2016. We included all DIPP cases performed between 11 and 24 weeks of gestation. We compared the different types of DIPP performed in our hospital. RESULTS: Two thousand one hundred eighty-five procedures were performed (1853 amniocenteses, 326 chorionic villus sampling, and 6 cordocenteses). The main indication for performing invasive procedures was abnormal results of aneuploidy screening for trisomy 21, followed by maternal age, and fetal structural abnormality. The fetal karyotype was altered in 154 (26.1%) cases. Trisomy 21 was the most common aneuploidy followed by trisomy 18, monosomy X, and trisomy 13. Fetal karyotype could not be revealed in 42 (2%) cases due to maternal contamination in 18 cases, inadequate sampling in 4 cases, and failure of cell culture in 27 cases. There were 2 pregnancy losses due to the invasive procedure (only in amniocentesis). CONCLUSION: The ideal approach to pregnancies with a detected chromosomal abnormality should be tailored according to the individual choice of the couples regarding whether they decide for or against a child with a known chromosomal abnormality. PMID- 28913148 TI - The effect of pelvic organ prolapse type on sexual function, muscle strength, and pelvic floor symptoms in women: A retrospective study. AB - OBJECTIVE: This retrospective research was planned to investigate the effect of pelvic organ prolapse (POP) type on sexual function, muscle strength, and pelvic floor symptoms in symptomatic women. MATERIALS AND METHODS: Data on POP type and stages as assessed using the Pelvic Organ Prolapse-Quantification system of 721 women who presented to the women's health unit between 2009 and 2016 were collected retrospectively. POP types were recorded as asymptomatic, anterior, apical, and posterior compartment prolapses. Sexual function was assessed using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short-form (PISQ-12), pelvic floor muscle strength was assessed through vaginal pressure measurement, and pelvic floor symptoms and quality of life were assessed using the Pelvic Floor Distress Inventory-20 (PFDI-20). RESULTS: Among 168 women who met the inclusion criteria, 96 had anterior compartment prolapses, 20 had apical compartment prolapses, 16 had posterior compartment prolapses, and 36 women were asymptomatic. There was no difference between the groups in their PISQ-12 total and subscales scores, PFDI-20 total and two subscale (colorectal/anal, urinary) scores, and muscle strength (p>0.05). In the Pelvic Organ Prolapse Distress Inventory-6, another subscale of PFDI-20, it was determined that there was a difference between asymptomatic women and those with anterior compartment prolapses (p=0.044) and apical compartment prolapses (p=0.011). CONCLUSION: This research found that POP type did not affect sexual function, muscle strength, and colorectal and urinary symptoms in our cohort. There were more prolapse symptoms and complaints in women with anterior and apical compartment prolapses. PMID- 28913149 TI - Comparison of libido, Female Sexual Function Index, and Arizona scores in women who underwent laparoscopic or conventional abdominal hysterectomy. AB - OBJECTIVE: The aim of the present study was to compare female sexual function between women who underwent conventional abdominal or laparoscopic hysterectomy. MATERIALS AND METHODS: Seventy-seven women who were scheduled to undergo hysterectomy without oophorectomy for benign gynecologic conditions were included in the study. The women were assigned to laparoscopic or open abdominal hysterectomy according to the surgeons preference. Women with endometriosis and symptomatic prolapsus were excluded. Female sexual function scores were obtained before and six months after the operation from each participant by using validated questionnaires. RESULTS: Pre- and postoperative scores of three different quationnaires were found as comparable in the group that underwent laparoscopic hysterectomy (p>0.05). Scores were also found as comparable in the group that underwent laparotomic hysterectomy (p>0.05). Pre- and postoperative values were compared between the two groups and revealed similar results with regard to all three scores (p>0.05). CONCLUSION: Our data showed comparable pre- and the postoperative scores for the two different hysterectomy techniques. The two groups were also found to have similar pre- and postoperative score values. PMID- 28913150 TI - Features of ovarian Brenner tumors: Experience of a single tertiary center. AB - OBJECTIVE: Brenner tumors are rare neoplasms of the ovary. The aim of this study was to investigate the clinical features of Brenner tumors. MATERIALS AND METHODS: The clinical features of 22 patients who were treated in Ankara University Faculty of Medicine Obstetrics and Gynecology Department between 2005 and 2015 were evaluated retrospectively from hospital medical records. RESULTS: The patients were aged 34 to 79 years at the time of diagnosis and the mean age was 55.1 years. Two (9.1%) patients were pre-menopausal, five (22.7%) were peri menopausal, and 25 (68.2%) patients were postmenopausal. One patient was pregnant. Twenty of the neoplasms were benign, one was malignant, and one was both malignant and benign. There was no recurrence in the malignant cases. Six (27.2%) patients had mixed tumors consisting of Brenner tumor and another ovarian pathology. Specifically, the other component of these tumors was mucinous cystadenoma in four patients, endometriosis externa in one patient, and high grade serous papillary cyst adenocarcinoma in one patient. CONCLUSION: Brenner tumors are usually incidental benign pathologic findings of surgical procedures in postmenopausal women. They can be found with other ovarian pathologies such as mucinous ovarian tumors and can coexist with other female genital tumors. Further studies are needed to completely understand the clinical features of Brenner tumors. PMID- 28913151 TI - Harlequin ichthyosis: A rare case. AB - Harlequin ichthyosis is a very rare condition that affects the skin of newborns. It is associated with poor barrier function of the skin leading to dehydration and leaves newborns prone to infections. It is due to mutations in adenosine triphosphate binding cassette A12 gene transmitted as an autosomal recessive disorder. The prognosis is very poor in these cases. Here, we report one such rare case. PMID- 28913152 TI - Early vulvar and umbilical incisional scar recurrence of cervical squamous cell carcinoma: Earlier than usually expected. AB - Cutaneous metastasis is considered as a hazardous condition depending on the mean survival around 9 months, which usually originates from cancers of the breast, lung, ovary, colon, and rarely from the cervix. The crucial prognostic factor of cutaneous metastasis depends on the period between the primary malignancy and cutaneous metastasis. We report two cases of the unusual presentation of squamous cell cancer of the cervix that developed vulvar and umbilical metastasis in the 5th month of primary treatment. Both of our patients survived for 11 months following the primary treatment. In addition, our first case is the earliest vulvar recurrence of cervical carcinoma in the English literature following appropriate medical and surgical management. PMID- 28913153 TI - Quantitative analysis of 18F-NaF dynamic PET/CT cannot differentiate malignant from benign lesions in multiple myeloma. AB - A renewed interest has been recently developed for the highly sensitive bone seeking radiopharmaceutical 18F-NaF. Aim of the present study is to evaluate the potential utility of quantitative analysis of 18F-NaF dynamic PET/CT data in differentiating malignant from benign degenerative lesions in multiple myeloma (MM). 80 MM patients underwent whole-body PET/CT and dynamic PET/CT scanning of the pelvis with 18F-NaF. PET/CT data evaluation was based on visual (qualitative) assessment, semi-quantitative (SUV) calculations, and absolute quantitative estimations after application of a 2-tissue compartment model and a non compartmental approach leading to the extraction of fractal dimension (FD). In total 263 MM lesions were demonstrated on 18F-NaF PET/CT. Semi-quantitative and quantitative evaluations were performed for 25 MM lesions as well as for 25 benign, degenerative and traumatic lesions. Mean SUVaverage for MM lesions was 11.9 and mean SUVmax was 23.2. Respectively, SUVaverage and SUVmax for degenerative lesions were 13.5 and 20.2. Kinetic analysis of 18F-NaF revealed the following mean values for MM lesions: K1 = 0.248 (1/min), k3 = 0.359 (1/min), influx (Ki) = 0.107 (1/min), FD = 1.382, while the respective values for degenerative lesions were: K1 = 0.169 (1/min), k3 = 0.422 (1/min), influx (Ki) = 0.095 (1/min), FD = 1. 411. No statistically significant differences between MM and benign degenerative disease regarding SUVaverage, SUVmax, K1, k3 and influx (Ki) were demonstrated. FD was significantly higher in degenerative than in malignant lesions. The present findings show that quantitative analysis of 18F NaF PET data cannot differentiate malignant from benign degenerative lesions in MM patients, supporting previously published results, which reflect the limited role of 18F-NaF PET/CT in the diagnostic workup of MM. PMID- 28913154 TI - PET/CT imaging of the diapeutic alkylphosphocholine analog 124I-CLR1404 in high and low-grade brain tumors. AB - CLR1404 is a cancer-selective alkyl phosphocholine (APC) analog that can be radiolabeled with 124I for PET imaging, 131I for targeted radiotherapy and/or SPECT imaging, or 125I for targeted radiotherapy. Studies have demonstrated avid CLR1404 uptake and prolonged retention in a broad spectrum of preclinical tumor models. The purpose of this pilot trial was to demonstrate avidity of 124I CLR1404 in human brain tumors and develop a framework to evaluate this uptake for use in larger studies. 12 patients (8 men and 4 women; mean age of 43.9 +/- 15.1 y; range 23-66 y) with 13 tumors were enrolled. Eleven patients had suspected tumor recurrence and 1 patient had a new diagnosis of high grade tumor. Patients were injected with 185 MBq +/- 10% of 124I-CLR1404 followed by PET/CT imaging at 6-, 24-, and 48-hour. 124I-CLR1404 PET uptake was assessed qualitatively and compared with MRI. After PET image segmentation SUV values and tumor to background ratios were calculated. There was no significant uptake of 124I CLR1404 in normal brain. In tumors, uptake tended to increase to 48 hours. Positive uptake was detected in 9 of 13 lesions: 5/5 high grade tumors, 1/2 low grade tumors, 1/1 meningioma, and 2/4 patients with treatment related changes. 124I-CLR1404 uptake was not detected in 1/2 low grade tumors, 2/4 lesions from treatment related changes, and 1/1 indeterminate lesion. For 6 malignant tumors, the average tumor to background ratios (TBR) were 9.32 +/- 4.33 (range 3.46 to 15.42) at 24 hours and 10.04 +/- 3.15 (range 5.17 to 13.17) at 48 hours. For 2 lesions from treatment related change, the average TBR were 5.05 +/- 0.4 (range 4.76 to 5.33) at 24 hours and 4.88 +/- 1.19 (range 4.04 to 5.72) at 48 hours. PET uptake had areas of both concordance and discordance compared with MRI. 124I CLR1404 PET demonstrated avid tumor uptake in a variety of brain tumors with high tumor-to-background ratios. There were regions of concordance and discordance compared with MRI, which has potential clinical relevance. Expansion of these studies is required to determine the clinical significance of the 124I-CLR1404 PET findings. PMID- 28913155 TI - Hepatic metabolism of 11C-methionine and secretion of 11C-protein measured by PET in pigs. AB - Hepatic amino acid metabolism and protein secretion are essential liver functions that may be altered during metabolic stress, e.g. after surgery. We wished to develop a dynamic liver PET method using the radiolabeled amino acid 11C methionine to examine this question. Eleven 40-kg pigs were allocated to either laparotomy or pneumoperitoneum. 24 hours after surgery a 70-min dynamic PET scanning of the liver with arterial blood sampling was performed immediately after intravenous injection of 11C-methionine. Time course of arterial plasma 11C methionine concentration was used as input function and that of liver tissue 11C concentration as output function in an extended Patlak analysis that accounted for irreversible metabolism of 11C-methionine (hepatic systemic metabolic clearance Kmet) and secretion of 11C-protein + 11C-metabolites into blood (rate constant kloss). Appearance of 11C-proteins in arterial plasma was measured during the experiment. There were no statistically significant differences between the laparotomy group and the pneumoperitoneum group in any of the calculated parameters. Average mean hepatic systemic metabolic clearance Kmet was 0.212 mL plasma/mL liver tissue/min, secretion rate constant from liver to blood kloss 0.0054 min-1, flux of methionine Fflux 3.59 MUmol methionine/mL liver tissue/min, and the appearance rate of 11C-proteins in plasma Rprot 0.048 kBq/mL plasma/min. There was significant correlation between Kmet and Rprot. In conclusion, the hepatic systemic metabolic clearance of 11C-methionine was significantly correlated to the appearance rate of 11C-proteins in plasma. It would be interesting to translate the present method to human studies for the development of a clinical quantitative test of hepatic protein secretion. PMID- 28913156 TI - Head and neck PET/CT therapy response interpretation criteria (Hopkins criteria) external validation study. AB - Qualitative assessment of PET/CT results in post therapy is very important to provide a reproducible and systemic reporting. A recently introduced response criteria, known as the Hopkins criteria showed promising results. Our aim is to externally validate the Hopkins interpretation system to assess therapy response in head and neck squamous cell cancer (HNSCC). The study included 69 biopsy proven HNSCC patients who underwent post therapy PET/CT between 5-24 weeks after completion of therapy. PET/CT images were interpreted by one nuclear medicine physician and one nuclear radiologist, independently. The studies were scored according to the Hopkins criteria for right neck, left neck, primary tumor site, and overall assessment. Scores 1, 2, 3 were considered as negative and scores 4 and 5 were considered as positive for tumors. Inter-reader variability was assessed using percent agreement and Kappa statistics. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and analyzed using Cox proportional hazards regression. Of the 69 patients, 59 (85.5%) were males, with a mean age of 62.8 years. The percent agreement between readers for overall, right neck, left neck, and primary tumor site were 91.3%, 97.6%, 97.6%, 91.3% respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of the overall therapy assessment were 66.7%, 87.3%, 33%, 96.5% respectively. Cox univariate regression analysis showed positive primary tumor site scores and overall scores were associated with a higher risk of progression (p<0.05). External validation of Hopkins criteria showed excellent inter-reader agreement and prediction of PFS in HNSCC patients. PMID- 28913157 TI - Non-functioning gastroenteropancreatic (GEP) tumors: a 111In-Pentetreotide SPECT/CT diagnostic study. AB - In a retrospective study performed in non-functioning GEP tumor patients we further investigated 111In-Pentetreotide SPECT/CT usefulness in diagnosis, staging and follow-up also evaluating whether the procedure may give more information than conventional imaging procedures (CIP), such as CT, MRI, US. We enrolled 104 consecutive patients with non-functioning GEP tumors, 30 in initial diagnosis and staging phases (IDS) and 74 in follow-up (FU). All patients underwent somatostatin receptor scintigraphy (SRS) whole body scan at 4, 24 and, if necessary, 48 hours followed by abdominal and chest SPECT/CT after 111In Pentetreotide 148-222 MBq i.v. injection. The patients previously underwent 2 to 3 CIP. At both CIP and SPECT/CT, 34/104 patients were classified as no evidence of disease (NED); in 70/104 patients, neoplastic lesions were ascertained and 12 IDS and 17 FU were classified as not operable and treated with octeotride or chemotherapy. SPECT/CT and CIP were concordantly positive in 44 patients, while only CIP was positive in 6 cases and only SPECT/CT in 20. Both per-patient sensitivity and accuracy of SPECT/CT (91.4 and 94.2%, respectively) were higher than CIP (71.4 and 80.8%, respectively), but not significantly. Globally, 292 lesions were ascertained: 141 hepatic, 78 abdominal extra-hepatic and 73 extra abdominal. CIP detected 191/292 (65.4%) lesions in 50 patients, while SPECT/CT 244/292 (83.6%) in 64, the difference being significant (p<0.0001). No false positive results were found at both SPECT/CT and CIP. Both SPECT/CT sensitivity and accuracy were higher than CIP in G1, G2, neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC) patients, but significantly only for G1. Globally, SPECT/CT incremental value than CIP was 35.6%. SPECT/CT correctly modified CIP classification and patient management in 27.9% of cases, while it down-staged the disease than CIP in 9.6% of cases. However, the two procedures combined use could achieve the highest accuracy value. 111In-Pentetreotide SRS, acquired as SPECT/CT, showing high sensitivity and accuracy values, more elevated than CIP in the present study, can still have a wide employment in the routine diagnostic protocol of non-functioning GEP tumors with significant impact on patient management and therapy planning. The procedure is simple to perform, has limited cost and wide availability in all Nuclear Medicine Centers. PMID- 28913158 TI - Dosimetry and first human experience with 89Zr-panitumumab. AB - 89Zr-panitumumab is a novel immuno-PET radiotracer. A fully humanized IgG2 antibody, panitumumab binds with high affinity to the extracellular ligand binding domain of EGFR. Immuno-PET with radiolabeled panitumumab is a non invasive method that could characterize EGFR expression in tumors and metastatic lesions. It might also assist in selecting patients likely to benefit from targeted therapy as well as monitor response and drug biodistribution for dosing guidance. Our objective was to calculate the maximum dosing for effective imaging with minimal radiation exposure in a small subset. Three patients with metastatic colon cancer were injected with approximately 1 mCi (37 MBq) of 89Zr-panitumumab IV. Whole body static images were then obtained at 2-6 hours, 1-3 days and 5-7 days post injection. Whole organ contours were applied to the liver, kidneys, spleen, stomach, lungs, bone, gut, heart, bladder and psoas muscle. From these contours, time activity curves were derived and used to calculate mean resident times which were used as input into OLINDA 1.1 software for dosimetry estimates. The whole body effective dose was estimated between 0.264 mSv/MBq (0.97 rem/mCi) and 0.330 mSv/MBq (1.22 rem/mCi). The organ which had the highest dose was the liver which OLINDA estimated between 1.9 mGy/MBq (7.2 rad/mCi) and 2.5 mGy/MBq (9 rad/mCi). The effective dose is within range of extrapolated estimates from mice studies. 89Zr-panitumumab appears safe and dosimetry estimates are reasonable for clinical imaging. PMID- 28913159 TI - Enzymatic characterization of a recombinant carbonyl reductase from Acetobacter sp. CCTCC M209061. AB - BACKGROUND: Acetobacter sp. CCTCC M209061 could catalyze carbonyl compounds to chiral alcohols following anti-Prelog rule with excellent enantioselectivity. Therefore, the enzymatic characterization of carbonyl reductase (CR) from Acetobacter sp. CCTCC M209061 needs to be investigated. RESULTS: A CR from Acetobacter sp. CCTCC M209061 (AcCR) was cloned and expressed in E. coli. AcCR was purified and characterized, finding that AcCR as a dual coenzyme-dependent short-chain dehydrogenase/reductase (SDR) was more preferred to NADH for biocatalytic reactions. The AcCR was activated and stable when the temperature was under 35 degrees C and the pH range was from 6.0 to 8.0 for the reduction of 4'-chloroacetophenone with NADH as coenzyme, and the optimal temperature and pH were 45 degrees C and 8.5, respectively, for the oxidation reaction of isopropanol with NAD+. The enzyme showed moderate thermostability with half-lives of 25.75 h at 35 degrees C and 13.93 h at 45 degrees C, respectively. Moreover, the AcCR has broad substrate specificity to a range of ketones and ketoesters, and could catalyze to produce chiral alcohol with e.e. >99% for the majority of tested substrates following the anti-Prelog rule. CONCLUSIONS: The recombinant AcCR exhibited excellent enantioselectivity, broad substrate spectrum, and highly stereoselective anti-Prelog reduction of prochiral ketones. These results suggest that AcCR is a powerful catalyst for the production of anti-Prelog alcohols.Graphical abstractThe biocatalytic reactions conducted with the recombinant AcCR. PMID- 28913160 TI - Pancoast tumor approach through oesophagus. AB - Patient with Pancoast Tumor usually present in advanced stage of the disease which requires chemotherapy and radiotherapy as options of treatment. Histologic confirmation is a key for further treatment of these patients. Normally in bronchoscopy the lesion can't be visualised and in result making biopsy difficult to perform. Transthoracic biopsy through computed tomography poses anatomic difficulties and not always the pulmonary lesion can be reached. We report a case of pancoast tumor in a 68 year old male who presented with left arm pain and upper lobe increased density mass in chest x ray. Computed tomography confirmed an upper lobe mass of the left lung with invasion of the chest wall. It was successfully diagnosed with biopsy taken through the oesophagus of intrapulmonary mass with the EBUS bronchoscope (EUS- B FNA). No complication were observed during and after the procedure. To our knowledge this is the first case of making the diagnosis of lung carcinoma Pancoast tumor using EBUS bronchoscope with approach through oesophagus (EUS-B FNA). There may be a role in using EBUS specifically to diagnose a pancoast tumor in the right patient population. PMID- 28913161 TI - A young immunocompetent patient with spontaneous Aspergillus empyema who developed severe eosinophilia. AB - Aspergillus empyema is usually reported as a complication of surgical procedures, and spontaneous cases are quite rare. Here, we describe the case of a 16-year-old man who suddenly developed dyspnea despite previously being healthy. Chest computed tomography showed multiple mass-containing cavity lesions, pneumothorax, and pleural effusion in the left thorax. Within 2 weeks, Aspergillus fumigatus grew from his pleural effusion, thus he was diagnosed with Aspergillus empyema. He also developed severe eosinophilia after admission, and was treated with anti fungal drugs. Although there are many factors that can cause eosinophilia, we suspect that infection with Aspergillus fumigatus was the major cause of the eosinophilia in this patient. The lack of bronchial symptoms and lesions were not consistent with a diagnosis of allergic bronchopulmonary aspergillosis. As far as we know, this is the first case of spontaneous Aspergillus empyema resulting in severe eosinophilia. PMID- 28913162 TI - Endobronchial hamartoma; a rare structural cause of chronic cough. AB - Pulmonary hamartomas are rare benign tumors consisting of multiple mesenchymal cell lines like cartilage, bone and fat. We discuss an interesting case of a 53 year-old male patient, who was referred to our clinic for persistent cough. Chest X-ray revealed a left suprahilar density associated with plate like atelectasis, which on chest CT was found to be a densely calcified nodule, causing narrowing of the left upper lobe (LUL) bronchus with calcified bilateral hilar lymph nodes. A bronchoscopy revealed a smooth endobronchial mass with calcification, which was removed. Histopathology revealed pulmonary hamartoma. PMID- 28913163 TI - General and selective brain connectivity alterations in essential tremor: A resting state fMRI study. AB - Although essential tremor is the most common movement disorder, there is little knowledge about the pathophysiological mechanisms of this disease. Therefore, we explored brain connectivity based on slow spontaneous fluctuations of blood oxygenation level dependent (BOLD) signal in patients with essential tremor (ET). A cohort of 19 ET patients and 23 healthy individuals were scanned in resting condition using functional magnetic resonance imaging (fMRI). General connectivity was assessed by eigenvector centrality (EC) mapping. Selective connectivity was analyzed by correlations of the BOLD signal between the preselected seed regions and all the other brain areas. These measures were then correlated with the tremor severity evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTS). Compared to healthy subjects, ET patients were found to have lower EC in the cerebellar hemispheres and higher EC in the anterior cingulate and in the primary motor cortices bilaterally. In patients, the FTMTS score correlated positively with the EC in the putamen. In addition, the FTMTS score correlated positively with selective connectivity between the thalamus and other structures (putamen, pre-supplementary motor area (pre-SMA), parietal cortex), and between the pre-SMA and the putamen. We observed a selective coupling between a number of areas in the sensorimotor network including the basal ganglia and the ventral intermediate nucleus of thalamus, which is widely used as neurosurgical target for tremor treatment. Finally, ET was marked by suppression of general connectivity in the cerebellum, which is in agreement with the concept of ET as a disorder with cerebellar damage. PMID- 28913164 TI - Haemoprotozoa: Making biological sense of molecular phylogenies. AB - A range of protistan parasites occur in the blood of vertebrates and are transmitted by haematophagous invertebrate vectors. Some 48 genera are recognized in bood primarily on the basis of parasite morphology and host specificity; including extracellular kinetoplastids (trypanosomatids) and intracellular apicomplexa (haemogregarines, haemococcidia, haemosporidia and piroplasms). Gene sequences are available for a growing number of species and molecular phylogenies often link parasite and host or vector evolution. This review endeavours to reconcile molecular clades with biological characters. Four major trypanosomatid clades have been associated with site of development in the vector: salivarian or stercorarian for Trypanosoma, and supra- or peri-pylorian for Leishmania. Four haemogregarine clades have been associated with acarine vectors (Hepatozoon A and B, Karyolysus, Hemolivia) and another two with leeches (Dactylosoma, Haemogregarina sensu stricto). Two haemococcidian clades (Lankesterella, Schellackia) using leeches and mosquitoes (as paratenic hosts!) were paraphyletic with monoxenous enteric coccidia. Two major haemosporidian clades have been associated with mosquito vectors (Plasmodium from mammals, Plasmodium from birds and lizards), two with midges (Hepatocystis from bats, Parahaemoproteus from birds) and two with louse-flies and black-flies (Haemoproteus and Leucocytozoon from birds). Three major piroplasm clades were recognized: one associated with transovarian transmission in ticks (Babesia sensu stricto); one with pre erythrocytic schizogony in vertebrates (Theileria/Cytauxzoon); and one with neither (Babesia sensu lato). Broad comparative studies with allied groups suggest that trypanosomatids and haemogregarines evolved first in aquatic and then terrestrial environments, as evidenced by extant lineages in invertebrates and their radiation in vertebrates. In contrast, haemosporidia and haemococcidia are thought to have evolved first in vertebrates from proto-coccidia and then incorporated invertebrate vectors. Piroplasms are thought to have evolved in ticks and diversified into mammals. More molecular studies are required on more parasite taxa to refine current thought, but ultimately transmission studies are mandated to determine the vectors for many haemoprotozoa. PMID- 28913165 TI - Molecular characterization of Babesia peircei and Babesia ugwidiensis provides insight into the evolution and host specificity of avian piroplasmids. AB - There are 16 recognized species of avian-infecting Babesia spp. (Piroplasmida: Babesiidae). While the classification of piroplasmids has been historically based on morphological differences, geographic isolation and presumed host and/or vector specificities, recent studies employing gene sequence analysis have provided insight into their phylogenetic relationships and host distribution and specificity. In this study, we analyzed the sequences of the 18S rRNA gene and ITS-1 and ITS-2 regions of two Babesia species from South African seabirds: Babesia peircei from African penguins (Spheniscus demersus) and Babesia ugwidiensis from Bank and Cape cormorants (Phalacrocorax neglectus and P. capensis, respectively). Our results show that avian Babesia spp. are not monophyletic, with at least three distinct phylogenetic groups. B. peircei and B. ugwidiensis are closely related, and fall within the same phylogenetic group as B. ardeae (from herons Ardea cinerea), B. poelea (from boobies Sula spp.) and B. uriae (from murres Uria aalge). The validity of B. peircei and B. ugwidiensis as separate species is corroborated by both morphological and genetic evidence. On the other hand, our results indicate that B. poelea might be a synonym of B. peircei, which in turn would be a host generalist that infects seabirds from multiple orders. Further studies combining morphological and molecular methods are warranted to clarify the taxonomy, phylogeny and host distribution of avian piroplasmids. PMID- 28913166 TI - Anisakidae nematodes isolated from the flathead grey mullet fish (Mugil cephalus) of Buenaventura, Colombia. AB - Anisakiasis is a parasitic infection caused by larval stages of nematodes of the genus Anisakis, Pseudoterranova and Contracaecum, of the Anisakidae family. The lifecycle of these nematodes develops in aquatic organisms and their final hosts are marine mammals. However, humans can act as accidental hosts and become infected with infective stage larvae (L3) by consuming raw or undercooked fish or shellfish carrying the parasite. Of this group of parasites, the genus Anisakis is the most studied: its presence in humans is associated with non-specific gastrointestinal symptoms or allergic responses that can trigger anaphylactic shock. The lack of studies in anisakiasis and Anisakis in Colombia has resulted in this infection being little-known by medical practitioners and therefore potentially underreported. The objective of this study was to identify anisakid nematodes in the flathead grey mullet fish (Mugil cephalus), caught by artisanal fishing methods and commercialized in Buenaventura. Morphological identification was carried out by classical taxonomy complemented by microscopy study using the histochemical technique Hematoxylin-Eosin. Nematodes of the genus Anisakis were found in the host M. cephalus. The Prevalence of Anisakis larvae in flathead grey mullet fish was 33%. The findings confirm the presence of Anisakis sp. in fish for human consumption in the Colombian Pacific region, a justification for further investigation into a possible emerging disease in this country. PMID- 28913167 TI - Ictal conduction aphasia and ictal angular gyrus syndrome as rare manifestations of epilepsy: The importance of ictal testing during video-EEG monitoring. AB - The aim of these two case reports is to demonstrate that a predefined, structured, multimodal clinical bed-side testing during seizures in a long-term video-EEG monitoring setting facilitates diagnosis of complex neuropsychological syndromes. To the best of our knowledge, we present the first case of conduction aphasia as the sole ictal semiology, and a patient with focal seizures producing an angular gyrus syndrome in the speech dominant hemisphere. The relevance of diagnosing ictal aphasic and angular gyrus syndromes and localizing the symptomatogenic zone is discussed. Current pathophysiological concepts are presented regarding conduction aphasia and Gerstmann's syndrome. PMID- 28913168 TI - Feasibility of photoacoustic/ultrasound imaging of synovitis in finger joints using a point-of-care system. AB - We evaluate a portable ultrasound and photoacoustic imaging (PAI) system for the feasibility of a point-of-care assessment of clinically evident synovitis. Inflamed and non-inflamed proximal interphalangeal joints of 10 patients were examined and compared with joints from 7 healthy volunteers. PAI scans, ultrasound power Doppler (US-PD), and clinical examination were performed. We quantified the amount of photoacoustic (PA) signal using a region of interest (ROI) drawn over the hypertrophic joint space. PAI response was increased 4 to 10 fold when comparing inflamed with contralateral non-inflamed joints and with joints from healthy volunteers (p < 0.001 for both). US-PD and PAI were strongly correlated (Spearman's rho = 0.64, with 95% CI: 0.42, 0.79). Hence, PAI using a compact handheld probe is capable of detecting clinically evident synovitis. This motivates further investigation into the predictive value of PAI, including multispectral PAI, with other established modalities such as US-PD or MRI. PMID- 28913169 TI - A semi-virtual two dimensional gel electrophoresis: IF-ESI LC-MS/MS. AB - A method for increasing the productivity of ESI LC-MS/MS (electrospray ionization liquid chromatography-tandem mass spectrometry) was proposed and applied. After IF (isoelectric focusing) of the sample using IPG (immobilized pH gradient) strip, the strip was cut to sections, and every section was treated according to trypsinolysis protocol for MS/MS analysis. The peptides produced were further analyzed by ESI LC-MS/MS. The procedure allows to: *identify many more proteins and proteoforms compared to shotgun analysis of extracts.*build a semi-virtual 2DE map of identified proteins. PMID- 28913170 TI - Comparison of tissue processing methods for microvascular visualization in axolotls. AB - The vascular system, the pipeline for oxygen and nutrient delivery to tissues, is essential for vertebrate development, growth, injury repair, and regeneration. With their capacity to regenerate entire appendages throughout their lifespan, axolotls are an unparalleled model for vertebrate regeneration, but they lack many of the molecular tools that facilitate vascular imaging in other animal models. The determination of vascular metrics requires high quality image data for the discrimination of vessels from background tissue. Quantification of the vasculature using perfused, cleared specimens is well-established in mammalian systems, but has not been widely employed in amphibians. The objective of this study was to optimize tissue preparation methods for the visualization of the microvascular network in axolotls, providing a basis for the quantification of regenerative angiogenesis. To accomplish this aim, we performed intracardiac perfusion of pigment-based contrast agents and evaluated aqueous and non-aqueous clearing techniques. The methods were verified by comparing the quality of the vascular images and the observable vascular density across treatment groups. Simple and inexpensive, these tissue processing techniques will be of use in studies assessing vascular growth and remodeling within the context of regeneration. Advantages of this method include: *Higher contrast of the vasculature within the 3D context of the surrounding tissue *Enhanced detection of microvasculature facilitating vascular quantification *Compatibility with other labeling techniques. PMID- 28913172 TI - Finding tuberculosis in prisons in India: who benefits? PMID- 28913171 TI - Development of capacity for research ethics review in low- and middle-income countries: need for a systems approach. PMID- 28913173 TI - 'Leaving no-one behind': how community health workers can contribute to achieving the Sustainable Development Goals. PMID- 28913174 TI - Research ethics committees in the Pacific Islands: gaps and opportunities for health sector strengthening. AB - There has been a range of developments in recent years to stimulate increasing public health research activity throughout the Pacific. Development of local capacity for ethics committee review and oversight is, however, frequently underdeveloped. This is reflected in the number of Pacific Island nations where ethics committees have not been established or where only informal processes exist for ethics review and oversight. This is problematic for the optimal development of relevant and culturally appropriate research, and building up local ethics committees should be part of continued research development in the Pacific. Three areas in which local ethics committees may add value are 1) offering better capacity to reflect local priorities, 2) providing broader benefits for research capacity building, and 3) assisting to strengthen systems beyond research ethics. This article considers benefits and challenges for ethics committees in the Pacific, and suggests directions for regional development to further strengthen public health research activity. PMID- 28913176 TI - Propensity Score Matched Comparison of Intensity Modulated Radiation Therapy vs Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Survival Analysis from the National Cancer Database. AB - PURPOSE: No direct comparisons between extreme hypofractionation and conventional fractionation have been reported in randomized trials for the treatment of localized prostate cancer. The goal of this study is to use a propensity score matched (PSM) analysis with the National Cancer Database (NCDB) for the comparison of stereotactic body radiation therapy (SBRT) and intensity modulated radiation therapy (IMRT) for organ confined prostate cancer. METHODS: Men with localized prostate cancer treated with radiation dose >=72 Gy for IMRT and >=35 Gy for SBRT to the prostate only were abstracted from the NCDB. Men treated with previous surgery, brachytherapy, or proton therapy were excluded. Matching was performed to eliminate confounding variables via PSM. Simple 1-1 nearest neighbor matching resulted in a matched sample of 5,430 (2,715 in each group). Subset analyses of men with prostate-specific antigen (PSA) > 10, GS = 7, and GS > 7 yielded matched samples of 1,020, 2,194, and 247, respectively. RESULTS: No difference in survival was noted between IMRT and SBRT at 8 years (p = 0.65). Subset analyses of higher risk men with PSA > 10 or GS = 7 histology or GS > 7 histology revealed no difference in survival between IMRT and SBRT (p = 0.58, p = 0.68, and p = 0.62, respectively). Variables significant for survival for the matched group included: age (p < 0.0001), primary payor (p = 0.0001), Charlson/Deyo Score (p = 0.0002), PSA (p = 0.0013), Gleason score (p < 0.0001), and use of hormone therapy (p = 0.02). CONCLUSION: Utilizing the NCDB, there is no difference in survival at 8 years comparing IMRT to SBRT in the treatment of localized prostate cancer. Subset analysis confirmed no difference in survival even for intermediate- and high-risk patients based on Gleason Score and PSA. PMID- 28913175 TI - Regulation of Endoplasmic Reticulum-Mitochondria Ca2+ Transfer and Its Importance for Anti-Cancer Therapies. AB - Inter-organelle membrane contact sites are emerging as major sites for the regulation of intracellular Ca2+ concentration and distribution. Here, extracellular stimuli operate on a wide array of channels, pumps, and ion exchangers to redistribute intracellular Ca2+ among several compartments. The resulting highly defined spatial and temporal patterns of Ca2+ movement can be used to elicit specific cellular responses, including cell proliferation, migration, or death. Plasma membrane (PM) also can directly contact mitochondria and endoplasmic reticulum (ER) through caveolae, small invaginations of the PM that ensure inter-organelle contacts, and can contribute to the regulation of numerous cellular functions through scaffolding proteins such as caveolins. PM and ER organize specialized junctions. Here, many components of the receptor dependent Ca2+ signals are clustered, including the ORAI1-stromal interaction molecule 1 complex. This complex constitutes a primary mechanism for Ca2+ entry into non-excitable cells, modulated by intracellular Ca2+. Several contact sites between the ER and mitochondria, termed mitochondria-associated membranes, show a very complex and specialized structure and host a wide number of proteins that regulate Ca2+ transfer. In this review, we summarize current knowledge of the particular action of several oncogenes and tumor suppressors at these specialized check points and analyze anti-cancer therapies that specifically target Ca2+ flow at the inter-organelle contacts to alter the metabolism and fate of the cancer cell. PMID- 28913177 TI - Big Data in Designing Clinical Trials: Opportunities and Challenges. AB - Emergence of big data analytics resource systems (BDARSs) as a part of routine practice in Radiation Oncology is on the horizon. Gradually, individual researchers, vendors, and professional societies are leading initiatives to create and demonstrate use of automated systems. What are the implications for design of clinical trials, as these systems emerge? Gold standard, randomized controlled trials (RCTs) have high internal validity for the patients and settings fitting constraints of the trial, but also have limitations including: reproducibility, generalizability to routine practice, infrequent external validation, selection bias, characterization of confounding factors, ethics, and use for rare events. BDARS present opportunities to augment and extend RCTs. Preliminary modeling using single- and muti-institutional BDARS may lead to better design and less cost. Standardizations in data elements, clinical processes, and nomenclatures used to decrease variability and increase veracity needed for automation and multi-institutional data pooling in BDARS also support ability to add clinical validation phases to clinical trial design and increase participation. However, volume and variety in BDARS present other technical, policy, and conceptual challenges including applicable statistical concepts, cloud-based technologies. In this summary, we will examine both the opportunities and the challenges for use of big data in design of clinical trials. PMID- 28913179 TI - Management of Elderly Patients with Glioblastoma after CE.6. PMID- 28913178 TI - Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment. AB - Investigating the role of intrinsic cell heterogeneity emerging from variations in cell-cycle parameters and apoptosis is a crucial step toward better informing drug administration. Antimitotic agents, widely used in chemotherapy, target exclusively proliferative cells and commonly induce a prolonged mitotic arrest followed by cell death via apoptosis. In this paper, we developed a physiologically motivated mathematical framework for describing cancer cell growth dynamics that incorporates the intrinsic heterogeneity in the time individual cells spend in the cell-cycle and apoptosis process. More precisely, our model comprises two age-structured partial differential equations for the proliferative and apoptotic cell compartments and one ordinary differential equation for the quiescent compartment. To reflect the intrinsic cell heterogeneity that governs the growth dynamics, proliferative and apoptotic cells are structured in "age," i.e., the amount of time remaining to be spent in each respective compartment. In our model, we considered an antimitotic drug whose effect on the cellular dynamics is to induce mitotic arrest, extending the average cell-cycle length. The prolonged mitotic arrest induced by the drug can trigger apoptosis if the time a cell will spend in the cell cycle is greater than the mitotic arrest threshold. We studied the drug's effect on the long-term cancer cell growth dynamics using different durations of prolonged mitotic arrest induced by the drug. Our numerical simulations suggest that at confluence and in the absence of the drug, quiescence is the long-term asymptotic behavior emerging from the cancer cell growth dynamics. This pattern is maintained in the presence of small increases in the average cell-cycle length. However, intermediate increases in cell-cycle length markedly decrease the total number of cells and can drive the cancer population to extinction. Intriguingly, a large "switch on/switch-off" increase in the average cell-cycle length maintains an active cell population in the long term, with oscillating numbers of proliferative cells and a relatively constant quiescent cell number. PMID- 28913180 TI - Developmental Cycle and Genome Analysis of Protochlamydia massiliensis sp. nov. a New Species in the Parachlamydiacae Family. AB - Amoeba-associated microorganisms (AAMs) are frequently isolated from water networks. In this paper, we report the isolation and characterization of Protochlamydia massiliensis, an obligate intracellular Gram-negative bacterium belonging to the Parachlamydiaceae family in the Chlamydiales order, from a cooling water tower. This bacterium was isolated on Vermamoeba vermiformis. It has a multiple range of hosts among amoeba and is characterized by a typical replication cycle of Chlamydiae with a particularity, recently shown in some chlamydia, which is the absence of inclusion vacuoles in the V. vermiformis host, adding by this a new member of Chlamydiae undergoing developmental cycle changes in the newly adapted host V. vermiformis. Draft genome sequencing revealed a chromosome of 2.86 Mb consisting of four contigs and a plasmid of 92 Kb. PMID- 28913181 TI - Clinical Experience of Sturdy Elevation of the Reconstructed Auricle. AB - BACKGROUND: The ear is composed of elastic cartilage as its framework, and is covered with a thin layer of skin. Auricular reconstruction using autogenous cartilage in microtia patients requires delicacy. This paper reports clinical experiences related to elevation of reconstructed ear in the last 11 years. METHODS: This study was based on 68 congenital microtia patients who underwent auricular elevation in our hospital. Among these 68 patients, 47 patients were recruited. We compared the differences in the ear size, auriculocephalic angle, and conchal depth with those in the opposite ear, and the patients' satisfaction levels were investigated using a survey. RESULTS: The difference in the sizes of the two ears was less than or equal to 5 mm in 32 patients, 5 to 10 mm in 10 patients, and greater than or equal to 10 mm in 5 patients. The difference in the auriculocephalic angles of the two ears was less than or equal to 10 degrees in 14 patients, 10 to 20 degrees in 26 patients, and greater than or equal to 20 degrees in 7 patients. The difference in the conchal depths of the two ears was less than or equal to 5 mm in 24 patients, 5 to 10 mm in 19 patients, and greater than or equal to 10 mm in 4 patients. The average grade of 3.9 points out of 5 points was obtained by the patients with satisfactory surveys. CONCLUSION: We could make enough protrusion and maintain the three-dimensional shape for a long time to satisfy our patients. PMID- 28913182 TI - Comparison between Z-plasty and V-Y Advancement for the Surgical Correction of Cryptotia. AB - BACKGROUND: Cryptotia correction by V-Y advancement of a temporal triangular flap was introduced in 2005. However, despite the several advantages of V-Y advancement, visible scars at the donor site are problematic. As a result, a Z plasty technique was considered for skin deficiency in mild cases. Therefore, we introduce a new surgical scheme for cryptotia correction based on considerations of techniques and complications that arose in our clinic. METHODS: Between 2000 and 2013, 26 patients (35 cases) of cryptotia were treated. Seventeen patients had unilateral cryptotia and nine had bilateral cryptotia. Two corrective methods were used, Z-plasty or V-Y advancement, based on the severity. In mild cases, Z plasty was used for correction and in severe cases, V-Y flap advancement was used for more skin supplement. RESULTS: Follow-up periods ranged from 6 months to 1.5 years. The results obtained were relatively favorable. Nine cases of mild deformity were corrected by Z-plasty, and the other 26 cases with mild or severe deformities were corrected by V-Y advancement. In Z-plasty cases, there was one hypertrophic scar and in V-Y advancement cases, seven resulted in visible scarring and three in skin sloughing. CONCLUSION: The main advantage of Z-plasty is a lower likelihood of visible scarring at the donor site. In mild cases, Z plasty may be a good alternative, but in severe cases, V-Y advancement is probably the best option for more skin supplement. PMID- 28913183 TI - Acellular Dermal Matrix to Treat Full Thickness Skin Defects: Follow-Up Subjective and Objective Skin Quality Assessments. AB - BACKGROUND: There are several options for replacement of the dermal layer in full thickness skin defects. In this study, we present the surgical outcomes of reconstruction using acellular dermal substitutes by means of objective and subjective scar assessment tools. METHODS: We retrospectively reviewed the medical records of 78 patients who had undergone autologous split-thickness skin graft with or without concomitant acellular dermal matrix (CGDerm or AlloDerm) graft. We examined graft survival rate and evaluated postoperative functional skin values. Individual comparisons were performed between the area of skin graft and the surrounding normal skin. Nine months after surgery, we compared the skin qualities of CGDerm graft group (n=25), AlloDerm graft group (n=8) with skin graft only group (n=23) each other using the objective and subjective measurements. RESULTS: The average of graft survival rate was 93% for CGDerm group, 92% for AlloDerm group and 86% for skin graft only group. Comparing CGDerm grafted skin to the surrounding normal skin, mean elasticity, hydration, and skin barrier values were 87%, 86%, and 82%, respectively. AlloDerm grafted skin values were 84%, 85%, and 84%, respectively. There were no statistical differences between the CGDerm and AlloDerm groups with regard to graft survival rate and skin functional analysis values. However, both groups showed more improvement of skin quality than skin graft only group. CONCLUSION: The new dermal substitute (CGDerm) demonstrated comparable results with regard to elasticity, humidification, and skin barrier effect when compared with conventional dermal substitute (AlloDerm). PMID- 28913184 TI - Characteristics of Dermoid Cyst of the Auricle. AB - BACKGROUND: Dermoid cysts of the auricular area are extremely rare. We report on six cases of auricular dermoid and epidermoid cyst, and differentiate dermoid cyst from epidermal cyst along with a review of the literature. METHODS: Three cases involved a gradually enlarging mass of the superior and anterior aspect of the helix of their ear. Another two cases were located in the posterior aspect of the ear. RESULTS: During the operation, a tumor was found just under the skin, not fixed mastoid or adjacent cartilage. Histologically, all specimens contained desquamated squamous epithelium and keratin in the lumen. However, two cases of posterior masses showed the presence of adnexal structures and three cases did not. CONCLUSION: A key in diagnosis of the dermoid cyst is the presence of adnexal structures. If the wall does not bear adnexal structures, the term epidermoid or keratin cyst is applied. Acquired cysts are most commonly of traumatic origin and result from an implantation or downward displacement of an epidermal fragment. Finally, the congenital epidermoid cyst grew at the upper part of the auricle; however, the dermoid cyst grew at the lower and posterior part of the auricle. PMID- 28913185 TI - Intraparotid Facial Nerve Schwannoma. AB - Intraparotid facial nerve schwannoma is a rare benign neoplasm. Due to its rarity, it is not usually a prioritized diagnosis before surgery and may therefore lead to an unintentional treatment error. In this article, we report a single case of intraparotid facial nerve schwannoma. We were able to make a diagnosis with frozen biopsy. A complete resection of the mass while preserving the facial nerve was performed. Herein we present our clinical experience with regards to the treatment process of intraparotid facial nerve schwannoma. PMID- 28913186 TI - A Case of Rapidly Growing Extraocular Sebaceous Carcinoma. AB - Sebaceous carcinoma is a rare malignant tumor differentiated from the adnexal epithelium of sebaceous glands and forms less than 1% of all cutaneous malignancies. We present a case of a 93-year-old woman with a rapidly growing mass on the right cheek. Initial histiopathologic finding was basal cell carcinoma. The mass was widely excised and superficial parotidectomy was performed while preserving the facial nerve branches. The resulting defect was covered with a transposition flap from the ipsilateral posterior auricular area and the donor site was closed primarily. However, histopathologic examination of the excised mass showed a poorly differentiated sebaceous carcinoma with a clear resection margin. The diagnosis of sebaceous carcinoma can be difficult to make at initial presentation. This report describes a rare case of a rapidly growing extraocular sebaceous carcinoma, which resulted in a good treatment outcome, and provides a review of relevant literature. PMID- 28913187 TI - Leiomyosarcoma of the Face. AB - Leiomyosarcoma is a rare form of soft tissue neoplasm, with only 1% to 5% occurring in the head and neck region. Current recommended treatment suggests surgical excision with a wide lateral margin, but no definite guidelines regarding excisional margin have been established yet. Recently, complete excision with a narrow surgical margin has been recommended, and the authors present a case of cutaneous leiomyosarcoma on the face that was successfully managed by complete removal with a narrow excisional margin. A 74-year-old woman presented with a 3 cm sized, rapidly growing cutaneous mass on her right preauricular area. Preoperative biopsy of the skin lesion suggested a cutaneous leiomyosarcoma. The authors performed complete surgical excision with a 1 cm lateral margin, and the resulting skin defect was repaired with bilateral V-Y advancement local flaps. Histopathology and immunohistochemistry evaluation confirmed a moderately differentiated cutaneous leiomyosarcoma, with negative margin involvement. The patient refused of any additional treatment, but showed no locoregional recurrence during the 1.5 years of postoperative follow-up period. With a regular postoperative follow-up, cutaneous leiomyosarcomas may be successfully treated with a narrow surgical margin. PMID- 28913188 TI - Ganglion Cyst of the Sternoclavicular Joint in an Adult. AB - Ganglion cysts are most common on the dorsum of the hand or wrist, but they can occur in any part of the body. There have been few papers reporting ganglion cysts originating from the sternoclavicular joint, with most of these cases developing in children. A 76-year-old woman was referred to our department because of a painless mass over the right sternoclavicular joint. The mass was excised along with the portion of the sternoclavicular joint capsule surrounding the stalk. Histopathologic examination showed the cyst wall to be composed of compressed collagen fibers without evidence of an epithelial or synovial lining, which was consistent with ganglion cyst. To our knowledge, this is the first report of such a cyst in an adult. We consider this to be a useful report for surgeons that treat mass lesions occurring in almost any part of the body surface. PMID- 28913189 TI - Nodular Fasciitis of the Periorbital Area. AB - Nodular fasciitis is a reactive, non-neoplastic lesion that is most commonly found in the subcutaneous or superficial fascia of the extremities and trunk. Head and neck lesions are relatively uncommon and reports vary from 7% to 15% depending on the authors. Nodular fasciitis grows quickly, and shows a pleomorphic spindle cell pattern with increased mitotic activity. Such factors lead to cases where the lesion is mistaken for a malignancy such as fibrosarcoma and the case may end up with unnecessarily aggressive treatments. The intent of this paper is to report a relatively rare case of nodular fasciitis occurring in the periorbital area and also to highlight the importance of accurate diagnosis and non-aggressive management of this benign lesion. PMID- 28913190 TI - Effectiveness of Helmet Cranial Remodeling in Older Infants with Positional Plagiocephaly. AB - BACKGROUND: Management of positional plagiocephaly by wearing a cranial molding helmet has become a matter of growing medical interest. Some research studies reported that starting helmet therapy early (age 5 to 6 months) is important and leads to a significantly better outcome in a shorter treatment time. The aim of the present study was to evaluate the effectiveness of cranial remodeling treatment with wearing helmet for older infants (>=18 months). METHODS: We conducted a retrospective study of 27 infants with positional plagiocephaly without synostosis, who were started from 2008 to 2012. Every child underwent a computerized tomography (CT) before starting helmet therapy to exclude synostosis of the cranial sutures and had CT performed once again after satisfactory completion of therapy. Anthropometric measurements were taken on using spreading calipers in every child. The treatment effect was compared using cranial vault asymmetry (CVA) and the cranial vault asymmetry index (CVAI), which were obtained from diagonal measurements before and after therapy. RESULTS: The discrepancy of CVA and CVAI of all the patients significantly decreased after cranial molding helmet treatment in older infants (>=18 months) 7.6 mm from 15.6 mm to 8 mm and 4.51% from 9.42% to 4.91%. Six patients had confirmed successful outcome, and all subjects were good compliance patients. The treatment lasted an average of 16.4 months, was well tolerated, and had no complication. Additionally, the rate of the successful treatment (final CVA <=5 mm) significantly decreased when the wearing time per was shorter. CONCLUSION: This study showed that treatment by cranial remodeling orthosis was effective if the patient could wear the helmet longer and treatment duration was somewhat longer than in younger patients, well tolerated in older infants and had no morbidity. This therapeutic option is available and indicated in these older infants before other cranial remodeling surgery. PMID- 28913191 TI - Microplate Fixation without Maxillomandibular Fixation in Double Mandibular Fractures. AB - BACKGROUND: Maxillomandibular fixation (MMF) is usually used to treat double mandibular fractures. However, advancements in reduction and fixation techniques may allow recovery of the premorbid dental arch and occlusion without the use of MMF. We investigated whether anatomical reduction and microplate fixation without MMF could provide secure immobilization and correct occlusion in double mandibular fractures. METHODS: Thirty-four patients with double mandibular fractures were treated with open reduction and internal fixation without MMF. Both fracture sites were surgically treated. For bony fixations, we used microplates with or without wire. After reduction, each fracture site was fixed at two or three points to maintain anatomical alignment of the mandible. Interdental wiring was used to reduce the fracture at the superior border and to enhance stability for 6 weeks. Mouth opening was permitted immediately. RESULTS: No major complications were observed, including infection, plate exposure, non union, or significant malocclusion. Five patients experienced minor complications, among whom the only one patient experienced a persistant but mild malocclusion with no need for additional management. CONCLUSION: This study showed that double mandibular fractures correction with two- or three-point fixation without MMF simplified the surgical procedure, increased patient comfort, and reduced complications, due to good stability and excellent adaptation. PMID- 28913192 TI - Effectiveness of Dual-Maneuver Using K-Wire and Dingman Elevator for the Reduction of Unstable Zygomatic Arch Fracture. AB - BACKGROUND: The zygoma is the most prominent portion of the face. Almost all simple zygomatic arch fractures are treated in a closed fashion with a Dingman elevator. However, the open approach should be considered for unstable zygomatic arch fractures. The coronal approach for a zygomatic arch fracture has complications. In this study, we introduce our method to reduce a special type of unstable zygomatic fracture. METHODS: We retrospectively reviewed zygomatic arch view and facial bone computed tomography scans of 424 patients who visited the Wonju Severance Christian Hospital from 2007 to 2010 with zygomaticomaxillary fractures, among whom 15 patients met the inclusion criteria. RESULTS: We used a Dingman elevator and K-wire simultaneously to manage this type of zygomatic arch fracture. Simple medial rotation force usually collapses the posterior fractured segment, and the fracture becomes unstable. Thus, the posterior fracture segment must be concurrently elevated with a Dingman elevator through Keen's approach with rotation force applied through the K-wire. All fractures were reduced without any instability using this method. CONCLUSION: We were able to reduce unstable and difficult zygomatic arch fractures without an open incision or any external fixation device. PMID- 28913193 TI - Acute Bone Remodeling after Reduction of Nasal Bone Fracture on Computed Tomography Imaging. AB - BACKGROUND: A number of studies have reported complication after reduction of nasal bone fractures. Among complicated cases, some showed improvement in shape of the nose with passage of time. Therefore, we examined these changes using computed tomography (CT) images taken over intervals. METHODS: CT scans of 50 patients with new nasal bone fractures were reviewed, and the images were compared amongst preoperative, immediately postoperative, and one month scans. Changes in nasal bone shape, were evaluated based on the angle of nasal bone arch between the nasal bone and frontal process of maxilla, overall shape of arch, mal alignment of fracture segments involving bony irregularity or bony displacement. These evaluations were used to separate postoperative outcomes into 5 groups: excellent, good, fair, poor, and very poor. RESULTS: Immediate postoperative nasal shape was excellent in 10 cases, good in 31 cases, fair in 8 cases, and poor results in a single case. Postoperative shape at one month was excellent in 37 cases, good in 12 cases, fair in a single case. CONCLUSION: The overall shape of nasal bone after fracture reduction tended to improve with passage of time. PMID- 28913194 TI - Palatal Mucoperiosteal Island Flaps for Palate Reconstruction. AB - BACKGROUND: Many options are available to cover a palatal defect, including local or free flaps. The objective of this study was to evaluate the usefulness of palatal mucoperiosteal island flap in covering a palatal defect after tumor excision. METHODS: Between October 2006 and July 2013, we identified 19 patients who underwent palatal reconstruction using a palatal mucoperiosteal island flap after tumor excision. All cases were retrospectively analyzed by defect location, size, tumor pathology, type of reconstruction, and functional outcomes. Speech and swallowing functions were evaluated using a 7-point visual analog scale (VAS) score. RESULTS: Among the 19 patients, there were 7 men and 12 women with an age range of 25 to 74 years (mean, 52.5+/-14.3 years). The size of flaps was 2-16 cm2 (mean, 9.4+/-4.2 cm2). Either unilateral or bilateral palatal island flaps were used depending on the size of defect. During the follow-up period (mean, 32.7+/ 21.4 months), four patients developed a temporary oronasal fistula, which healed without subsequent operative. The donor sites were well re-epithelized. Speech and swallowing function scores were 6.63+/-0.5 and 6.58+/-0.69 on the 7-point VAS, indicating the ability to eat solid foods and communicate verbally without significant disability. CONCLUSION: The palatal mucoperiosteal island flap is a good reconstruction modality for palatal defects if used under appropriate indications. The complication rates and donor site morbidity are low, with good functional outcomes. PMID- 28913195 TI - Comparison of Mechanical Stability between Fibular Free Flap Reconstruction versus Locking Mandibular Reconstruction Plate Fixation. AB - BACKGROUND: The fibular free flap has been used as the standard methods of segmental mandibular reconstruction. The objective of mandibular reconstruction not only includes restored continuity of the mandible but also the recovery of optimal function. This paper emphasizes the advantage of the fibular free flap reconstruction over that of locking mandibular reconstruction plate fixation. METHODS: The hospital charts of all patients (n=20) who had a mandibular reconstruction between 1994 and 2013 were retrospectively reviewed. Eight patients had plate-only fixation of the mandible, and the remaining 12 had vascularized fibular free flap reconstruction. Complications and outcomes were reviewed and compared between the 2 groups via statistical analysis. RESULTS: Overall complication rates were significantly lower in the fibular flap group (8.3%) than in the plate fixation group (87.5%; p =0.001). Most (7/8) patients in the plate fixation group had experienced plate-related late complications, including plate fracture or exposure. In the fibular flap group, no complications were observed, except for a single case of donor-site wound dehiscence (1/12). CONCLUSION: The fibular free flap provides a more stable support and additional soft tissue support for the plate, thereby minimizing the risk of plate-related complications. Fibular free flap is the most reliable option for mandibular reconstruction, and we believe that the flap should be performed primarily whenever possible. PMID- 28913196 TI - Dual Plane Augmentation Genioplasty Using Gore-Tex Chin Implants. AB - BACKGROUND: The chin shape and position is important in determining the general shape of the face, and augmentation genioplasty is performed alone or in combination with other aesthetic procedures. However, augmentation genioplasty using osteotomy is an invasive and complex procedure with the potential to damage mentalis muscle and mental nerve, to affect chin growth, and prolonged recovery. Our aim was to present our experience with a modified augmentation genioplasty procedure for hypoplastic chins using a Gore-Tex implant. METHODS: Two vertical slit incisions were made at the canine level to create a supraperiosteal pocket between the incisions, preserving the periosteum and mentalis muscle. Minimal sub periosteal dissection was performed lateral to the incisions along the mandibular border. The both wings of implant were inserted under the periosteum to achieve a stable dual plane implantation. RESULTS: In total, 47 patients underwent dual plane chin augmentation using a Gore-Tex implant between January 2008 and May 2013. The mean age at operation was 25.77 years (range, 15-55 years). There were 3 cases of infection; one patient was treated with antibiotics, the others underwent implant removal. Additionally, two patients complained of postoperative parasthesia that spontaneously improved without any additional treatment. Most patients were satisfied with the postoperative outcomes, and no chin growth problems were observed among the younger patients. CONCLUSION: Dual plane Gore Tex chin augmentation is a minimally-invasive operation that is simple and safe. All implants yielded satisfactory results with no significant complications such as mental nerve injury, lower lip incompetence, or chin growth limitation. PMID- 28913197 TI - Hemifacial Transplantation Model in Rats. AB - BACKGROUND: To refine facial transplantation techniques and achieve sound results, it is essential to develop a suitable animal model. Rat is a small animal and has many advantages over other animals that have been used as transplantation models. The purpose of this study was to describe a rat hemifacial transplantation model and to verify its convenience and reproducibility. METHODS: Animals used in this study were Lewis rats (recipients) and Lewis-Brown Norway rats (donors). Nine transplantations were performed, requiring 18 animals. The hemifacial flap that included the ipsilateral ear was harvested based on the unilateral common carotid artery and external jugular vein and was transferred as a single unit. Cyclosporine A therapy was initiated 24 hours after transplantation and lasted for 2 weeks. Signs of rejection responses were evaluated daily. RESULTS: The mean transplantation time was 1 hour 20 minutes. The anatomy of common carotid artery and external jugular vein was consistent, and the vessel size was appropriate for anastomosis. Six of nine allografts remained good viable without vascular problems at the conclusion of study (postoperative 2 weeks). CONCLUSION: The rat hemifacial transplantation model is suitable as a standard transplantation training model. PMID- 28913198 TI - Correction of Unilateral Nostril Hypoplasia with Z-Plasty in a Child. AB - Unilateral nostril hypoplasia is an extremely rare congenital malformation of unknown etiology, and only a few cases have been reported in literature. Owing to variability and complexity of the deformity, surgical correction of unilateral nostril hypoplasia represents one of the most significant reconstructive challenges to reconstructive plastic surgeons. We report a 7-year-old Vietnamese child with nasal and periocular deformity resembling a craniofacial cleft. Grossly, the right nostril was patent but with alar rim deformity, and the left nostril was not readily identifiable. A dystopic medial canthus was present on the left side as well. Closer inspection and palpation of the left side of nose revealed a patency through the soft tissue and underlying bony structure, Thus, a new alar rim were reconstructed with an irregularly shaped Z-plasty to create patency on the involved side. Simulatneously, a second Z-plasty was performed to address the medial canthal deformity. Postoperative appearance and function was sastisfactory at one-year follow up visit. In the treatment of patients with nostril hypoplasia, a careful preoperative physical examination is a prerequisite, and Z-plasty can be a valuable option for surgical correction. PMID- 28913199 TI - Unusual Sjogren's Syndrome with Bilateral Parotid Cysts. AB - Sjogren's syndrome is a chronic autoimmune exocrinopathy that destroys salivary and lacrimal gland tissue. We report an unusual case of this disease in a 54-year old woman who presented with multiple and bilateral parotid cystic masses. The multiple, small, bead-like cysts were clearly evident in the computed tomography sections in this patient, a visible reminder that this may be the initial presentation in a patient with Sjogren's syndrome. As the case illustrates, Sjogren's syndrome should be included in the differential diagnosis of multiple and bilateral cystic parotid lesions. PMID- 28913200 TI - Spindle Cell Lipoma: A Rare, Misunderstood Entity. AB - Spindle cell lipoma, a rare variant of lipoma, is a benign tumor found in the posterior neck and shoulder. A 24-year-old man with a close family history of malignant lymphoma had presented with a large, firm, nodular mass found in the right supraclavicular area. Excision of the deeply located mass revealed a pale yellow, rubbery nodule which grossly resembled an enlarged lymph node, with a variant of lymphoma as a primary suspect. However, pathological studies revealed the lesion to be a spindle cell lipoma. Although atypical in location, spindle cell lipoma should always be kept in differential diagnosis of a newly-noted soft tissue mass, as this entity may be easily cured by simple excision. PMID- 28913201 TI - Half-and-Half Palatoplasty. AB - A 14-month-old child was diagnosed with a Veau Class II cleft palate. Von Langenbeck palatoplasty was performed for the right palate, and V-Y pushback palatoplasty was performed for the left palate. The child did not have a special problem during the surgery, and the authors were able to elongate the cleft by 10 mm. Contrary to preoperative concerns regarding the hybrid use of palatoplasties, the uvula and midline incisions remained balanced in the middle. The authors named this combination method "half-and-half palatoplasty" and plan to conduct a long-term follow up study as a potential solution that minimizes the complications of palatoplasty. PMID- 28913202 TI - Analysis of Facial Asymmetry in Deformational Plagiocephaly Using Three Dimensional Computed Tomographic Review. AB - BACKGROUND: Infants with deformational plagiocephaly (DP) usually present with cranial vault deformities as well as facial asymmetry. The purpose of this study was to use three-dimensional anthropometric data to evaluate the influence of cranial deformities on facial asymmetry. METHODS: We analyzed three-dimensional computed tomography data for infants with DP (n=48) and without DP (n=30, control). Using 16 landmarks and 3 reference planes, 22 distance parameters and 2 angular parameters were compared. This cephalometric assessment focused on asymmetry of the orbits, nose, ears, maxilla, and mandible. We then assessed the correlation between 23 of the measurements and cranial vault asymmetry (CVA) for statistical significance using relative differences and correlation analysis. RESULTS: With the exception of few orbital asymmetry variables, most measurements indicated that the facial asymmetry was greater in infants with DP. Mandibular and nasal asymmetry was correlated highly with severity of CVA. Shortening of the ipsilateral mandibular body was particularly significant. There was no significant deformity in the maxilla or ear. CONCLUSION: This study demonstrated that the cranial vault deformity in DP is associated with facial asymmetry. Compared with the control group, the infants with DP were found to have prominent asymmetry of the nose and mandible. PMID- 28913203 TI - Clinical Characteristics of the Forehead Lipoma. AB - BACKGROUND: Lipomas can be categorized into deep and superficial lipomas according to anatomical depth. Many cases of forehead lipomas are reported to be deep to the muscle layer. We analyze ultrasound in delineating depth of forehead lipomas. METHODS: A retrospective review was performed for all patients who underwent excision of forehead lipomas between January 2008 and March 2013 and for whom preoperative ultrasound study was available. Sensitivity and specificity of ultrasound imaging was evalauted against depth finding at the time of surgical excision. RESULTS: The review identified 42 patients who met the inclusion criteria. Preoperative ultrasound reading was 18 as deep lipomas and 24 as superficial. However, intraoperative finding revealed 2 of the 18 deep lipomas to be superficial and 13 of the 24 superficial lipomas to be deep lipomas. Overall, ultrasonography turned out to be 69% (29/42) accurate in correctly delineating superficial versus deep lipomas. CONCLUSION: Lipomas of the forehead tend to be located in deeper tissue plane compared to lipomas found elsewhere in the body. Preoperative ultrasonography of lipomas can be helpful, but was not accurate in identifying the depth of forehead lipomas in our patient population. Even if a forehead lipoma is found to be superficial on ultrasound, operative planning should include the possibility of deep lipomas. PMID- 28913204 TI - Venous Occlusion Detected by Caregiver with Implantable Doppler in a Buried Free Flap. AB - The use of the implantable Doppler device eases the burden of free flap monitoring, and allows caregivers to notify healthcare personnel of a potential vascular event. A 24-year-old female patient underwent anterolateral thigh adipofascial flap surgery to provide a buried flap on the left temporal area for a depressed and infected skull wound. The author was able to salvage the flap from two venous occlusions, which was made possible by early notifications from the caregiver who reported changes in the Doppler signal. PMID- 28913205 TI - Malignant Peripheral Nerve Sheath Tumor in Frontal Sinus, Orbital Cavity and Ethmoid Cavity. AB - Malignant peripheral nerve sheath tumors are extremely rare soft tissue sarcomas. Among various locations, the trunk and extremities are the most commonly involved sites, with only 15% of such lesions occuring in head and neck region. Here, we report a case of a 74-year-old male who presented with forehead swelling and right eye deviation. Computed tomography images revealed a tumor involving the frontal sinus, ethmoid sinus, and the orbital cavity. The patient underwent a surgical excision of the lesion, which histopathological examination revealed to be a malignant peripheral nerve sheath tumor. PMID- 28913206 TI - Aesthetic Correction of a Protrusive Forehead through Repositioning of the Anterior Wall of the Frontal Sinus. AB - Facial skeletal remodeling was revolutionized more than 30 years ago, by the work of Tessier and other craniofacial surgeons. However, the need to correct the skeleton in the upper third of the face is not frequently diagnosed or treated in aesthetic facial surgery. Here, we report on the aesthetic correction of a protrusive forehead. A patient visited our hospital for aesthetic contouring with a prominent forehead. The anterior wall of the frontal sinus was removed with a craniotome via the bicoronal approach. After the excised bone was repositioned, it was fixed with a titanium mesh plate and screws. An electric burr was used to contour the supraorbital rim and frontal bone. Once the desired shape was achieved, the periosteum was replaced, and the wound was closed in layers. When performed properly, frontal sinus contouring could significantly improve the appearance in patients with a prominent forehead. Plastic surgeons must carefully evaluate patients with a prominent forehead for skeletal remodeling that involves the accurate and safe repositioning of the anterior wall of the frontal sinus. PMID- 28913207 TI - Reconstruction of Full Thickness Ala Defect with Nasolabial Fold and Septal Mucosal Hinge Flap. AB - Reconstruction of a full-thickness alar defect requires independent blood supplies to the inner and outer surfaces. Because of this, secondary operations are commonly needed for the division of skin flap from its origin. Here, we report a single-stage reconstruction of full-thickness alar defect, which was made possible by the use of a nasolabial island flap and septal mucosal hinge flap. A 49-year-old female had presented with a squamous cell carcinoma of the right ala which was invading through the mucosa. The lesion was excised with a 5 mm free margin through the full-thickness of ala. The lining and cartilage was restored using a septal mucosa hinge flap and a conchal cartilage from the ipsilateral ear. The superficial surface was covered with a nasolabial island flap based on a perforator from the angular artery. The three separate tissue layers were reconstructed as a single subunit, and no secondary operations were necessary. Single-stage reconstruction of the alar subunit was made possible by the use of a nasolabial island flap and septal mucosal hinge flap. Further studies are needed to compare long-term outcomes following single-stage and multi stage reconstructions. PMID- 28913208 TI - Importance of Accurate Diagnosis in Pyoderma Gangrenosum. AB - Pyoderma gangrenosum is a rare inflammatory reactive dermatosis marked by painful cutaneous ulcers. Diagnosis of pyoderma gangrenosum is usually made based on past medical history and after the exclusion of other possible diseases based on the clinical manifestations of the lesion. Diseases that show rapid progression to necrosis and that should not be misdiagnosed as pyoderma gangrenosum include malignant neoplasms and necrotizing fasciitis. Immunosuppressive agents such as steroids and cyclosporine are considered first-line therapy. Surgical removal of the necrotic tissues is contraindicated, as it may further induce immune reaction and promote ulcer to enlarge. Here, we present a case to encourage plastic surgeons to consider pyodermagangrenosum in the differential diagnosis of idiopathic ulcers. Satisfactory outcomes for patients with pyodermagangrenosum may be expected when using steroids and immunosuppressive agents during the early stage of the disease. PMID- 28913209 TI - A Recurrent Giant Pilomatricoma on the Back. PMID- 28913210 TI - Multiple Skin Cancers Following Psoralen and Ultraviolet A Treatment of Psoriasis. PMID- 28913211 TI - Analysis of Facial Asymmetry. AB - Facial symmetry is an important component of attractiveness. However, functional symmetry is favorable to aesthetic symmetry. In addition, fluctuating asymmetry is more natural and common, even if patients find such asymmetry to be noticeable. However, fluctuating asymmetry remains difficult to define. Several studies have shown that a certain level of asymmetry could generate an unfavorable image. A natural profile is favorable to perfect mirror-image profile, and images with canting and differences less than 3 degrees -4 degrees and 3-4 mm, respectively, are generally not recognized as asymmetry. In this study, a questionnaire survey among 434 medical students was used to evaluate photos of Asian women. The students preferred original images over mirror images. Facial asymmetry was noticed when the canting and difference were more than 3 degrees and 3 mm, respectively. When a certain level of asymmetry is recognizable, correcting it can help to improve social life and human relationships. Prior to any operation, the anatomical component for noticeable asymmetry should be understood, which can be divided into hard tissues and soft tissue. For diagnosis, two-and three-dimensional (3D) photogrammetry and radiometry are used, including photography, laser scanner, cephalometry, and 3D computed tomography. PMID- 28913212 TI - Skull Reconstruction with Custom Made Three-Dimensional Titanium Implant. AB - BACKGROUND: Source material used to fill calvarial defects includes autologous bones and synthetic alternatives. While autologous bone is preferable to synthetic material, autologous reconstruction is not always feasible due to defect size, unacceptable donor-site morbidity, and other issues. Today, advanced three-dimensional (3D) printing techniques allow for fabrication of titanium implants customized to the exact need of individual patients with calvarial defects. In this report, we present three cases of calvarial reconstructions using 3D-printed porous titanium implants. METHODS: From 2013 through 2014, three calvarial defects were repaired using custommade 3D porous titanium implants. The defects were due either to traumatic subdural hematoma or to meningioma and were located in parieto-occipital, fronto-temporo-parietal, and parieto-temporal areas. The implants were prepared using individual 3D computed tomography (CT) data, Mimics software, and an electron beam melting machine. For each patient, several designs of the implant were evaluated against 3D-printed skull models. All three cases had a custom-made 3D porous titanium implant laid on the defect and rigid fixation was done with 8 mm screws. RESULTS: The custom-made 3D implants fit each patient's skull defect precisely without any dead space. The operative site healed without any specific complications. Postoperative CTs revealed the implants to be in correct position. CONCLUSION: An autologous graft is not a feasible option in the reconstruction of large calvarial defects. Ideally, synthetic materials for calvarial reconstruction should be easily applicable, durable, and strong. In these aspects, a 3D titanium implant can be an optimal source material in calvarial reconstruction. PMID- 28913213 TI - Transfacial Surgical Approaches to Secure Wide Exposure of the Skull Base. AB - BACKGROUND: Treatment of skull base tumors is challenging due to limited access and presence of important neurovascular structures nearby. The success of a complete tumor resection depends on the extent of tumor exposure and secure field of view. While these tumors are often removed by transcranial endoscopic access, transfacial approach is sometimes required depending on the location and size of the tumor. This study describes various transfacial approaches in patients undergoing skull base tumor resection. METHODS: From March to November 2013, 15 patients underwent skull base tumor resection via transfacial accesses at a tertiary institution. Data were reviewed for patient demographics, type of access used, completeness of tumor resection, surgical outcome, and postoperative complications. RESULTS: Two clivus tumor patients underwent transmaxillary approach; three tuberculum- sellae and suprasellar-hypothalamus tumor patients underwent transbasal approach; three clinoid and retrobulbar intraconal orbital tumor patients underwent orbitozygomatic approach; and seven petroclival-area, pons, cavernous sinus, and lateral-sphenoid-wing tumor patients underwent zygomatic approach. In all cases, the upper and lower margins of the tumor were visible. Complete tumor removal consisted of 10 cases, and partial tumor removal in 5. There were no immediate major complications observed for the transfacial portion of the operations. The overall cosmetic results were satisfactory. CONCLUSION: Plastic surgeons can use various transfacial approaches according to the location and size of skull base tumors to secure a sufficient field of view for neurosurgeons. PMID- 28913214 TI - Simple Aesthetic Correction for Patients with Acute Auriculocephalic Angle. AB - BACKGROUND: Acute auriculocephalic angle refers to an ear with helix that is spaced closely to the cranium. An increasing number of patients with acute auriculocephalic angle wish to undergo corrective operation for aesthetic purposes. However, there is a paucity of data regarding acute auriculocephalic angle. This paper proposes a treatment protocol for patients with acute auriculocephalic angle. METHODS: We performed a retrospective analysis of patients undergoing acute auriculocephalic angle (4 patients, 6 ears). Patient records were reviewed for demographic data as well as auricular measurements at preoperative, immediate postoperative and final follow-up evaluations. RESULTS: All of the patients were men with a mean age of 36.5 years (range, 23-52 years). The mean follow-up period was 47.5 months (range, 28-60 months). Postoperative auriculocephalic angle was close to the normal auriculocephalic angle (25 degrees -30 degrees ) without notable scars. Moreover, the patients had minimal contractions of the skin flaps without any hematoma or relapse. CONCLUSION: We propose the following three treatment protocols for patients with acute auriculocephalic angle: the posterior auricular muscle should be sufficiently released, the mastoid area should be augmented using implants, the skin should be repositioned with a superior auricular flap. PMID- 28913215 TI - Application of Hand Towel Drape over Dingman Mouth Gag. AB - In cleft palate surgery, the environment is especially critical when suturing. Encum-bered, obstructive space in the environment can hinder a suture while using the Dingman mouth gag. We introduced a novel but simple draping technique. A simple hand towel is placed over the gag. A hole is cut out in the middle according to each patient's mouth. After making the hole, the hand towel is soaked in water and gently squeezed. Then the towel is properly placed over the Dingman mouth gag. Dripping water on the hand towel during the suture helps keep it in place. Using this draping technique, we cut 14 minutes of operation time compared to the average operation time of the past 2 years. There were several disadvantages in previous draping method. First, long suture material may easily get caught. Second, the operation field can easily be contaminated. Third, focusing on the operation becomes difficult due to the obstruction. This draping technique can compensate for the disadvantages of the previous Dingman mouth gag. PMID- 28913216 TI - Complex Correction of Complete Cleft Lip with Severe Prominent Premaxilla using Lip Adhesion and Nasoalveolar Molding Device. AB - Nasoalveolar molding (NAM) device is an effective treatment for protruding maxilla in infants with cleft palate. However, only a few studies have investigated the effect of NAM devices on the treatment of protruding maxilla in infants with cleft lip only. We have designed a combination treatment using NAM devices prior to cheiloplasy for cleft lip-only patients with severe anterior protrusion of the premaxilla. Three cleft lip-only infants with 1-cm or more of premaxilla protrusion were included. Definitive cheiloplasty was performed at 6 months of age without any preoperative correction in infant 1. Cheiloplasty was performed in conjunction with the use of NAM device and lip adhesion in infants 2 and 3. Postoperative columella length and anterior-posterior dimension of the protruding premaxilla were compared amongst the infants. We were able to obtain satisfactory postoperative columella length and general nasal appearance. PMID- 28913217 TI - Delayed Orbital Hemorrhage around Alloplastic Implants after Blowout Fracture Reduction. AB - Alloplastic implants have been used to repair orbital wall fractures in most cases. Orbital hemorrhage is a rare complication of these implants and has been reported rarely in Korea. The purpose of this article is to report a late complication case focusing on their etiology and management. A 20-year-old male patient underwent open reduction with Medpor (porous polyethylene) insertion for bilateral orbital floor fractures. The initial symptom occurred with proptosis in the right side as well as vertical dystopia, which had started 4 days earlier, 8 months after surgery. Any trauma history after the surgery was not present. We performed an exploration and removal of hematoma with Medpor titanium meshed alloplastic implant. A case of delayed orbital hematoma following alloplastic implant insertion was identified. It occurred within the pseudocapsule of the implant. One week after surgery, overall symptoms improved successfully, and no complications were reported during the 11-month follow-up period. Although rare, orbital hemorrhage is a potential complication of alloplastic orbital floor implants, which may present many years after surgery. As in the case presented, delayed hematoma should be included in the differential diagnosis of late proptosis or orbital dystopia. PMID- 28913218 TI - Actinomycosis and Sialolithiasis in Submandibular Gland. AB - Actinomycosis is a subacute or chronic suppurative infection caused by Actinomyces species, which are anaerobic Gram-positive bacteria that normally colonize the human mouth and digestive and urogenital tracts. Cervicofacial actinomycosis is the most frequent clinical form of actinomycosis, and is associated with odontogenic infection. Characterized by an abscess and mandibular involvement with or without fistula, but the cervicofacial form of actinomycosis is often misdiagnosed because the presentation is not specific and because it can mimic numerous infectious and non-infectious diseases, including malignant tumors. We report a rare case of actinomycosis infection with coexisting submandibular sialolithiasis. The patient presented with a 1*1 cm abscess-like lesion below the lower lip. Punch biopsy of the lesion revealed atypical squamous cell proliferation with infiltrative growth, suggestive of squamous cell carcinoma. The patient underwent wide excision of this lesion, where the lesion was found to be an abscess formation with multiple submandibular sialolithiases. The surgical specimen was found to contain Actinomyces without any evidence of a malignant process. We assumed that associated predisposing factors such as poor oral hygiene may have caused a dehydrated condition of the oral cavity, leading to coexistence of actinomycosis and sialolithiasis. PMID- 28913219 TI - Microcystic Adnexal Carcinoma Misdiagnosed as Desmoplastic Trichoepithelioma on Preoperative Biopsy. AB - Microcystic adnexal carcinoma is a rare type of tumor, with about 300 cases reported globally. Due to its similar histology with other tumors, it is occasionally misdiagnosed as desmoplastic trichoepithelioma, basal cell carcinoma, syringoma, and so on. We present a patient with a mass on the perioral area who was preoperatively diagnosed with trichoepithelioma. Microcystic adnexal carcinoma was diagnosed after excisional biopsy and a wide excision. Defects were reconstructed with a mucosal advancement flap. There was no recurrence and there were no significant complications during the 18-month follow-up period. Because superficial punch biopsy has limitations in width and depth, surgeons should always consider the possibility of malignancy of a mass even if a biopsy shows a benign result. PMID- 28913220 TI - My Hopes for 2015: Letter from the President of Korean Cleft Palate-Craniofacial Association. PMID- 28913221 TI - Management of Alveolar Cleft. AB - The alveolar cleft has not received as much attention as labial or palatal clefts, and the management of this cleft remains controversial. The management of alveolar cleft is varied, according to the timing of operation, surgical approach, and the choice of graft material. Gingivoperiosteoplasty does not yet have a clear concensus among surgeons. Primary bone graft is associated with maxillary retrusion, and because of this, secondary bone graft is the most widely adopted. However, a number of surgeons employ presurgical palatal appliance prior to primary alveolar bone graft and have found ways to minimize flap dissection, which is reported to decrease the rate of facial growth attenuation and crossbite. In this article, the authors wish to review the literature regarding various advantages and disadvantages of these approaches. PMID- 28913223 TI - Morphology of the Aging Forehead: A Three-Dimensional Computed Tomographic Study. AB - BACKGROUND: Age-related changes have been studied for lower and middle facial bones. Although the forehead comprises one-third of the facial area, no studies have investigated age-related changes in the upper part of the face or forehead. The purpose of this study was to use three-dimensional computed tomography (3D CT) to investigate age-related changes in the frontal bone. METHODS: A retrospective review was performed for patients who underwent 3D CT scan of facial bones. Patients were divided by gender and age (20 to 40 years, 41 to 60 years, and above 60 years). The frontal bone curvature was evaluated by the length of frontal bone and by two frontal bone angles in relation to the Frankfurt horizon. RESULTS: In both genders, aging was associated with increasing lower slope length. In elderly men (>60 years), the upper slope angle was significantly higher when compared to younger male subjects. Women demonstrated similar age-related changes, but the differences were only statistically significant for the middle and older age groups. CONCLUSION: This study demonstrates quantifiable age-related changes in the frontal bone. These findings contribute to the understanding of age-related changes of the facial soft tissues. The mean measurements in each age group can be used as a reference when planning forehead reconstruction. PMID- 28913222 TI - Quantitative Assessment of Orbital Volume and Intraocular Pressure after Two-Wall Decompression in Thyroid Ophthalmopathy. AB - BACKGROUND: Surgical outcomes after orbital wall decompression have focused on the degree of exophthalmos and intraocular pressure. The aim of this research was to evaluate intraorbital volume using computed tomography (CT) images following two-wall decompression using a combined subcilliary and endoscopic approaches. METHODS: A retrospective review was performed for all patients who had undergone the two-wall decompression method. The pre/postoperative CT images were used to evaluate changes in intraocular volume. Intraocular pressure was evaluated using applanation tonometry. Surgical details are discussed within the body of text. RESULTS: Two-wall decompression thru the medial wall and floor was associated with an average intraorbital volume change of 7.3 cm3, with maximal accommodation up to 13 cm3. Changes in intraocular pressures were not statistically significant. CONCLUSION: Two-wall decompression was effective in accommodation of up to 13 cm3 of soft tissue herniation. There was no statistically significant association between changes in volume to pressure. PMID- 28913224 TI - A Surgical Technique for Congenital Preauricular Sinus. AB - BACKGROUND: Preauricular sinuses represent a common congenital abnormality in children. Classically, a preauricular sinus manifests as a small opening, usually near the anterior limb of ascending helix. The difficulty in the surgical treatment of preauricular sinus is the high recurrence rate. The aim of this article is to review the outcomes of preauricular sinus and to introduce our surgical technique and its prognosis. METHODS: A single-institutional retrospective review was performed for all patients who had undergone excision of congenital periauricular sinus between October 2007 and April 2014. Medical records were reviewed for demographic information, wound complication, and recurrence rate. The sinus tract was visualized with the aid of preoperative dye instillation and intraoperative probe insertion. The skin next to the sinus opening was incised elliptically, and the tract itself was dissected medially to the end of the sinus tract and posteriorly to the cartilage of the ascending helix. RESULTS: The review identified 44 patients for a total of 57 preauricular sinus tracts. The mean age at time of operation was 16.3 years with a range from 9 months to 65 years. Unilateral preauricular sinus tract was present in 31 patients (11 right and 20 left preauricular tract), and 13 patients had bilateral sinus tract. None of the patients had experienced wound issues postoperative, and there were no recurrent sinus tract formation or infection. CONCLUSION: Using a combination of dye instillation, probe insertion, and modified dissection, we were able to achieve a recurrence free series of preauricular sinus tract excision among a heterogenous group of patients. A large patient series is necessary to replicate the results of this study. PMID- 28913225 TI - Schwannoma of the Orbit. AB - BACKGROUND: A schwannoma is a benign, slow-growing peripheral nerve sheath tumor that originates from Schwann cells. Orbital schwannomas are rare, accounting for only 1% of all orbital neoplasms. In this study, we retrospectively review orbital schwannomas and characterize clinical, radiologic, and histologic features of this rare entity. METHODS: A retrospective review was performed to identify patients with histologically confirmed orbital schwannoma, among a list of 437 patients who had visited our hospital with soft tissue masses within the orbit as the primary presentation between 2010 and 2014. Patient charts and medical records were reviewed for demographic information, relevant medical and family history, physical examination findings relating to ocular and extraocular sensorimotor function, operative details, postoperative complications, pathologic report, and recurrence. RESULTS: Five patients (5/437, 1.1%) were identified as having histologically confirmed orbital schwannoma and underwent complete excision. Both computed tomography (CT) and magnetic resonance imaging (MRI) studies were not consistent in predicting histologic diagnosis. There were no complications, and none of the patients experienced significant scar formation. In two cases, patients exhibited a mild postoperative numbness of the forehead, but the patients demonstrated full recovery of sensation within 3 months after the operation. None of the five patients have experienced recurrence. CONCLUSION: Orbital schwannomas are relatively rare tumors. Preoperative diagnosis is difficult because of its variable presentation and location. Appropriate early assessment of orbital tumors by CT or MRI and prompt management is warranted to prevent the development of severe complications. Therefore, orbital schwannomas should be considered in the differential diagnosis of slow-growing orbital masses. PMID- 28913227 TI - Reconstruction of Chronic Complicated Scalp and Dural Defects Using Acellular Human Dermis and Latissimus Dorsi Myocutaneous Free flap. AB - We present reconstruction of a complicated scalp-dura defect using acellular human dermis and latissimus dorsi myocutaneous free flap. A 62-year-old female had previously undergone decompressive craniectomy for intracranial hemorrhage. The cranial bone flap was cryopreserved and restored to the original location subsequently, but necessitated removal for a methicillin-resistant Staphylococcal infection. However, the infectious nidus remained in a dermal substitute that was left over the cerebrum. Upon re-exploration, this material was removed, and frank pus was observed in the deep space just over the arachnoid layer. This was carefully irrigated, and the dural defect was closed with acellular dermal matrix in a watertight manner. The remaining scalp defect was covered using a free latissimus dorsi flap with anastomosis between the thoracodorsal and deep temporal arteries. The wound healed well without complications, and the scalp remained intact without any evidence of cerebrospinal fluid leak or continued infection. PMID- 28913226 TI - Comparison of Prostaglandin E1 and Sildenafil Citrate Administration on Skin Flap Survival in Rats. AB - BACKGROUND: Alprostadil and sildenafil are known vasodilators used independently to improve flap survival in animal models. In this study, we investigate whether these agents act synergistically to decrease flap necrosis in rat models. METHODS: After acclimation period, 4 groups of 10 male white rats were given a modified McFarlane skin flap. The postoperative treatment included saline control (Group A), sildenafil citrate-only (Group B), alprostadil-only (Group C), and both sildenafil and alprostadil (Group D). The flaps were observed on postoperative days 1, 3, 5 and 7. The animals were euthenized on postoperative day 7, and the flaps were evaluated for inflammation and neovascularization. RESULTS: At each observation, the mean necrotic index was significantly lower for all three treatment groups (Groups A, B, C) and was the lowest for the combined treatment group. On histologic evaluations, combined treatment was associated with decreased inflammation and increased capillary vessel formation, when compared with control group. CONCLUSION: Both sildenafil-only and alprostadil treatments were independently associated with increased flap survival rate. Sildenafil citrate and alprostadil had a synergistic effect in increasing flap survival rate. PMID- 28913228 TI - Surgical Treatment of Polyotia. AB - Polyotia is an extremely rare type of the auricular malformation that is characterized by a large accessory ear. A 3-year-old girl presented to us with bilateral auricular abnormalities and underwent two-stage corrective operation for polyotia. In this report, we present the surgical details and postoperative outcomes of polyotia correction in the patient. Relevant literature is reviewed. PMID- 28913229 TI - Improvement of Congenital Muscular Torticollis with Mild Symptoms in Non-Treated Adult after Simple Surgical Myotomy of Sternocleidomastoid Muscle under Local Anesthesia. AB - In adult congenital muscular torticollis (CMT) patients, physical therapy is not as effective because the development of sternocleidomastoid muscle (SCM) muscle is complete. While surgical release can address CMT in adult patients, the risk of general anesthesia and visible postoperative scar is a concern, expecially in patients with mild symptoms. In this paper, we report our experience in treating such patients with minimal-incision myotomy under local anesthesia. A review was performed for all adult patients who had undergone the simple myotomy procedure. Surgical indication was reserved for patients with mild fibrotic band in the SCM muscle with minimal lengthdiscrepancybetween the muscles. All patients had recognizable head tiltand palpation of fibrotic band on affected side of the neck. Surgical details are described in the main body of text. Three female patients had undergone the procedure. Torticollis was resolve in all patients with complete restoration of ranage of motion. There were no postoperative complications, and patient satisfaction was high. We have reported three cases of mild CMT in adult female patients, who had undergone minimal-incision myotomy under local anesthesia. Outcomes were satisafactory with no morbidity to report. With careful patient selection, this method offers an alternate treatment option for adult CMT patients with mild symptoms. PMID- 28913230 TI - A Giant Keratoacanthoma Treated with Surgical Excision. AB - A keratoacanthoma is a rapidly growing cutaneous tumor that spontaneously involutes in most instances. A giant keratoacanthoma is a rare variant and are characterized by lesions larger than 20 mm in diameter. We report a 56-year-old man with a rapidly growing tumor of the right cheek, which was diagnosed as keratoacanthoma. The mass was excised completely under general anesthesia, followed by Limberg flap for reconstruction. Intraoperative frozen section histology suggested the lesion to be a well-differentiated squamous cell carcinoma, whereas final histopathology was consistent with keratoacanthoma. We herein report the first case of a giant keratoacanthoma treated with surgical excision in Korea and discuss the clinical and histopathological features of keratoacanthoma, with a review of the literature. PMID- 28913231 TI - Use of a Y-Shaped Plate for Intermaxillary Fixation. AB - Maxillomandibular fractures usually require intermaxillary fixation as a means to immobilize and stabilize the fracture and to re-establish proper occlusion. Arch bars or intermaxillary fixation screws cannot be used for edentulous patients or for patients who have poor dental health. Here, we present a case of repeated intermaxillary fixation failure in a patient weak alveolar rigidity secondary to multiple dental implants. Because single-point fixation screws were not strong enough to maintain proper occlusion, we have used Y-shaped plates to provide more rigid anchoring points for the intermaxillary wires. We suggest that this method should be considered for patients in whom conventional fixation methods are inappropriate or have failed. PMID- 28913232 TI - Intermuscular Lipoma in the Posterior Triangle of the Neck. PMID- 28913233 TI - A Comment on Application of Hand Towel Drape over Dingman Mouth Gag. PMID- 28913234 TI - Reconstructive Trends in Post-Ablation Patients with Esophagus and Hypopharynx Defect. AB - The main challenge in pharyngoesophageal reconstruction is the restoration of swallow and speech functions. The aim of this paper is to review the reconstructive options and associated complications for patients with head and neck cancer. A literature review was performed for pharynoesophagus reconstruction after ablative surgery of head and neck cancer for studies published between January 1980 to July 2015 and listed in the PubMed database. Search queries were made using a combination of 'esophagus' and 'free flap', 'microsurgical', or 'free tissue transfer'. The search query resulted in 123 studies, of which 33 studies were full text publications that met inclusion criteria. Further review into the reference of these 33 studies resulted in 15 additional studies to be included. The pharyngoesophagus reconstruction should be individualized for each patient and clinical context. Fasciocutaneous free flap and pedicled flap are effective for partial phayngoesophageal defect. Fasciocutaneous free flap and jejunal free flap are effective for circumferential defect. Pedicled flaps remain a safe option in the context of high surgical risk patients, presence of fistula. Among free flaps, anterolateral thigh free flap and jejunal free flap were associated with superior outcomes, when compared with radial forearm free flap. Speech function is reported to be better for the fasciocutaneous free flap than for the jejunal free flap. PMID- 28913235 TI - Inferior Blow-Out Fracture Reduction Using Two Urinary Balloon Catheters. AB - BACKGROUND: The reduction of orbital blowout fracture primarily aims to normalize the extra-ocular movement by returning the herniated orbital soft tissue into the original position, and to prevent enophthalmos by normalizing the orbital cavity volume. We introduce a balloon catheter-assisted orbital floor reduction technique. METHODS: A retrospective review was performed for all patients with orbital floor fracture who underwent the technique described in the main body of this text. Medical records were reviewed for demographic data, clinical presentation and course, degree of enophthalmos, intraorbital volume on computed tomography scan, and postoperative outcomes. The enophthalmos and intraorbital volume of the injured site were compared to the uninjured eye and orbit. RESULTS: The review identified 14 patients (11 male, 3 female). The mean preoperative difference in en-exopthalmos was 2.13 mm, while the mean orbital volume was 116%. The mean postoperative difference in en-exophthalmos had improved to 0.61 mm with a mean orbital volume of 101.85%. At the time of catheter removal at 10 days, three patients experienced diplopia (n=1), extra-ocular movement disorder (1), or enophthalmos (1). All of these had resolved by the 6-month follow-up visit. CONCLUSION: Balloon catheter-assisted reduction of the orbital floor fractures was associated with improvements in intraorbital volume and enopthalmos in the 14 patients. Notable complications included diplopia, enophthalmos, and limited extra-ocular movement, all of which were transient in the early postoperative period and had resolved by 6-month follow up. PMID- 28913236 TI - Kirschner Wire Fixation for the Treatment of Comminuted Zygomatic Fractures. AB - BACKGROUND: The Kirschner wire (K-wire) technique allows stable fixation of bone fragments without periosteal dissection, which often lead to bone segment scattering and loss. The authors used the K-wire fixation to simplify the treatment of laborious comminuted zygomatic bone fracture and report outcomes following the operation. METHODS: A single-institution retrospective review was performed for all patients with comminuted zygomatic bone fractures between January 2010 and December 2013. In each patient, the zygoma was reduced and fixed with K-wire, which was drilled from the cheek bone and into the contralateral nasal cavity. For severely displaced fractures, the zygomaticofrontal suture was first fixated with a microplate and the K-wire was used to increase the stability of fixation. Each wire was removed approximately 4 weeks after surgery. Surgical outcomes were evaluated for malar eminence, cheek symmetry, Kwire site scar, and complications (based on a 4-point scale from 0 to 3, where 0 point is 'poor' and 3 points is 'excellent'). RESULTS: The review identified 25 patients meeting inclusion criteria (21 men and 4 women). The mean age was 52 years (range, 15-73 years). The mean follow up duration was 6.2 months. The mean operation time was 21 minutes for K-wire alone (n=7) and 52 minutes for K-wire and plate fixation (n=18). Patients who had received K-wire only fixation had severe underlying diseases or accompanying injuries. The mean postoperative evaluation scores were 2.8 for malar contour and 2.7 for K-wire site scars. The mean patient satisfaction was 2.7. There was one case of inflammation due to the K-wire. CONCLUSION: The use of K-wire technique was associated with high patient satisfaction in our review. K-wire fixation technique is useful in patient who require reduction of zygomatic bone fractures in a short operating time. PMID- 28913237 TI - Medial Wall Orbital Reconstruction using Unsintered Hydroxyapatite Particles/Poly L-Lactide Composite Implants. AB - BACKGROUND: Poly-L-lactide materials combined with hydroxyapatite (u-HA /PLLA) have been developed to overcome the drawbacks of absorbable materials, such as radiolucency and comparably less implant strength. This study was designed to evaluate the usefulness of u-HA/PLLA material in the repair of orbital medial wall defects. METHODS: This study included 10 patients with pure medial wall blow out fractures. The plain radiographs were taken preoperatively, immediately after, and 2 months after surgery. The computed tomography scans were performed preoperatively and 2 months after surgery. Patients were evaluated for ease of manipulation, implant immobility, rigidity and complications with radiologic studies. RESULTS: None of the patients had postoperative complications, such as infection or enophthalmos. The u-HA/PLLA implants had adequate rigidity, durability, and stable position on follow-up radiographic studies. On average, implants were thawed 3.4 times and required 14 minutes of handling time. CONCLUSION: The u-HA/PLLA implants are safe and reliable for reconstruction of orbital medial wall in terms of rigidity, immobility, radiopacity, and cost effectiveness. These thin yet rigid implants can be useful where wide periosteal dissection is difficult due to defect location or size. Since the u-HA/PLLA material is difficult to manipulate, these implants are not suitable for use in complex 3-dimensional defects. PMID- 28913238 TI - Wire or Hook Traction for Reducing Zygomatic Fracture. AB - BACKGROUND: Variable methods have been introduced for reduction of the zygomatic fractures. The Dingman elevator is used widely to reduce these fractures but is inappropriate in certain types of fractures which require atypical traction vectors. We introduce and examine an alternate method of reducing zygomatic fractures using wire and hook traction. METHODS: A retrospective study was performed for all zygomatic fracture patients admitted between 2008 and 2014. Medially rotated fractures were reduced by using a wire looped through an intermaxillary screw secured on the medial side of the zygoma. Laterally rotated fractures were reduced using a hook introduced through an infrazygomatic skin incision. RESULTS: No accidental bleeding or incomplete reduction was observed in any of the cases. Postoperative imaging demonstrated proper reduction immediately after the operation. Follow-up computed tomography study at 1 month after operation also demonstrated proper reduction and healthy union across the previous site of fracture. CONCLUSION: The hook and wire method allowed precise application of traction forces across zygomatic fractures. The fractured bone fragment could be pulled in the direction precisely opposite to the vector of impact at the time of trauma. Soft tissue damage due to dissection was minimized. In particular, this method was effective in reducing rotated bone fragments and can be an alternative option to using the zygoma elevator. PMID- 28913239 TI - A Retrospective Analysis of 303 Cases of Facial Bone Fracture: Socioeconomic Status and Injury Characteristics. AB - BACKGROUND: The incidence and etiology of facial bone fracture differ widely according to time and geographic setting. Because of this, prevention and management of facial bone fracture requires ongoing research. This study examines the relationship between socioeconomic status and the incidence of facial bone fractures in patients who had been admitted for facial bone fractures. METHODS: A retrospective study was performed for all patients admitted for facial bone fracture at the National Medical Center (Seoul, Korea) from 2010 to 2014. We sought correlations amongst age, gender, fracture type, injury mechanism, alcohol consumption, and type of medical insurance. RESULTS: Out of the 303 patients meeting inclusion criteria, 214 (70.6%) patients were enrolled in National Health Insurance (NHI), 46 (15.2%) patients had Medical Aid, and 43 (14.2%) patients were homeless. The main causes of facial bone fractures were accidental trauma (51.4%), physical altercation (23.1%), and traffic accident (14.2%). On Pearson's chi-square test, alcohol consumption was correlated significantly with accidental trauma (p<0.05). And, the ratio of alcohol consumption leading to facial bone fractures differed significantly in the homeless group compared to the NHI group and the Medical Aid group (p<0.05). CONCLUSION: We found a significant inverse correlation between economic status and the incidence of facial bone fractures caused by alcohol consumption. Our findings indicate that more elaborate guidelines and prevention programs are needed for socioeconomically marginalized populations. PMID- 28913240 TI - Direct Open Venous Drainage: An Alternative Choice for Flap Congestion Salvage. AB - In this report, we present a scalp defect reconstruction with lateral arm free flap. We highlight the difficulty in obtaining a recipient vein and the venous drainage managed through an open end of the donor vein. A 52-year-old woman presented with a pressure sore on the left scalp. A lateral arm free flap was transferred to cover this 8*6 cm defect. The arterial anastomosis was successful, but no recipient vein could be identified within the wound bed. Instead, we used a donor venous end for the direct open venous drainage. In order to keep this exposed venous end patent, we applied heparin-soaked gauze dressing to the wound. Also, the vein end was mechanically dilated and irrigated with heparin solution at two hour intervals. Along with fluid management and blood transfusion, this management was continued for the five days after the operation. The flap survived well without any complication. Through this case, we were able to demonstrate that venous congestion can be avoided by drainage of the venous blood through an open vessel without the use of leeches. PMID- 28913241 TI - Unusual Bilateral Impalement Injury with Rusted Iron Bars on Face and Neck. AB - Impalement injury is the subset of penetrating trauma, defined as fixed, elongated objects penetrate and remain in the human body cavity or region by relatively low velocity. We report an unusual case of facial and neck impalement where two dirty rusted iron bars penetrated forehead bilaterally and exited neck and ear respectively without causing major organ injuries. After thorough radiologic and physical evaluation, the patient got medical and surgical treatment. The patient was discharged without complication after four day of delayed wound closure. There have been no complications and sequelaes related with trauma, wound infection and scar contracture at 3-year follow-up. According to affected organs and pattern of impalement, individualized and multidisciplinary surgical approach should be considered. Following these guidelines as in this case, it was possible to achieve excellent clinical outcome in impalement injury. PMID- 28913242 TI - Usefulness of Ultrasonography-Assisted Closed Reduction for Nasal Fracture under Local Anesthesia. AB - Closed reduction is the treatment of choice for most nasal bone fractures. In this technique, the nasal bone cannot be directly visualized, proper reduction is confirmed by palpation of the bony contour. This confirmation-via-palpation is in most cases too uncomfortable or painful for patients, and this is the reason why most closed reductions of nasal bone fractures are performed under general anesthesia. Recently, ultrasonography has been adopted as a useful diagnostic method and operative adjunct. In this report, we report the use of ultrasonography as a means to provide palpation-less confirmation of proper reduction, which in turn allows for nasal bone reduction under local anesthesia. PMID- 28913243 TI - Absorbable Plate-Related Infection after Facial Bone Fracture Reduction. AB - Absorbable plates are used widely for fixation of facial bone fractures. Compared to conventional titanium plating systems, absorbable plates have many favorable traits. They are not palpable after plate absorption, which obviates the need for plate removal. Absorbable plate-related infections are relatively uncommon at less than 5% of patients undergoing fixation of facial bone fractures. The plates are made from a mixture of poly-L-lactic acid and poly-DL-lactic acid or poly-DL lactic acid and polyglycolic acid, and the ratio of these biodegradable polymers is used to control the longevity of the plates. Degradation rate of absorbable plate is closely related to the chance of infection. Low degradation is associated with increased accumulation of plate debris, which in turn can increase the chance of infection. Predisposing factors for absorbable plate related infection include the presence of maxillary sinusitis, plate proximity to incision site, and use of tobacco and significant amount of alcohol. Using short screws in fixating maxillary fracture accompanied maxillary sinusitis will increase the rate of infection. Avoiding fixating plates near the incision site will also minimize infection. Close observation until complete absorption of the plate is crucial, especially those who are smokers or heavy alcoholics. The management of plate infection is varied depending on the clinical situation. Severe infections require plate removal. Wound culture and radiologic exam are essential in treatment planning. PMID- 28913244 TI - Clinical Analysis of Lobular Keloid after Ear Piercing. AB - BACKGROUND: Lobular keloid appears to be a consequence of hypertrophic inflammation secondary to ear piercings performed under unsterile conditions. We wish to understand the pathogenesis of lobular keloids and report operative outcomes with a literature review. METHODS: A retrospective review identified 40 cases of lobular keloids between January, 2005 and December, 2010. Patient records were reviewed for preclinical factors such as presence of inflammation after ear piercing prior to keloid development, surgical management, and histopathologic correlation to recurrence. RESULTS: The operation had been performed by surgical core extirpation or simple excision, postoperative lobular compression, and scar ointments. Perivascular infiltration was noted in intra- and extra-keloid tissue in 70% of patients. The postoperative recurrence rate was 10%, and most of the patients satisfied with treatment outcomes. CONCLUSION: Histological perivascular inflammation is a prominent feature of lobular keloids. Proper surgical treatment, adjuvant treatments, and persistent follow-up observation were sufficient in maintaining a relatively low rates of recurrence. PMID- 28913245 TI - Anthropometric Analysis of Facial Foramina in Korean Population: A Three Dimensional Computed Tomographic Study. AB - BACKGROUND: Position of the facial foramina is important for regional block and for various maxillofacial surgical procedures. In this study, we report on anthropometry and morphology of these foramina using three-dimensional computed tomography (3D-CT) data. METHODS: A retrospective review was performed for all patients who have undergone 3D-CT scan of the facial skeleton for reasons other than fracture or deformity of the facial skeleton. Anthropometry of the supraorbital, infraorbital, and mental foramina (SOF, IOF, MF) were described in relation to facial midline, inferior orbital margin, and inferior mandibular margin (FM, IOM, IMM). This data was analyzed according to sex and age. Additionally, infraorbital and mental foramen were classified into 5 positions based on the anatomic relationships to the nearest perpendicular dentition. RESULTS: The review identified 137 patients meeting study criteria. Supraorbital foramina was more often in the shape of a foramen (62%) than that of a notch (38%). The supraorbital, infraorbital, and mental foramina were located 33.7 mm, 37.1 mm, and 33.7 mm away from the midline. The mean vertical distance between IOF and IOM was 13.4 mm. The mean distance between MF and IMM was 21.0 mm. The IOF and MF most commonly coincided with upper and lower second premolar dentition, respectively. Between the sex, the distance between MF and IMM was significantly higher for males than for female. In a correlation analysis, SOF FM, IOF-FM and MF-FM values were significantly increased with age, but IOF-IOM values were significantly decreased with age. CONCLUSION: In the current study, we have reported anthropometric data concerning facial foramina in the Korean population, using a large-scale data analysis of three-dimensional computed tomography of facial skeletons. The correlations made respect to patient sex and age will provide help to operating surgeons when considering nerve blocks and periosteal dissections around the facial foramina. PMID- 28913246 TI - Reduction of Nasal Bone Fracture using Ultrasound Imaging during Surgery. AB - BACKGROUND: Most nasal bone fractures are corrected using non-invasive methods. Often, patients are dissatisfied with surgical outcomes following such closed approach. In this study, we compare surgical outcomes following blind closed reduction to that of ultrasound-guided reduction. METHODS: A single-institutional prospective study was performed for all nasal fracture patients (n=28) presenting between May 2013 and November 2013. Upon research consent, patients were randomly assigned to either the control group (n=14, blind reduction) or the experimental group (n=14, ultrasound-guided reduction). Surgical outcomes were evaluated using preoperative and 3-month postoperative X-ray images by two independent surgeons. Patient satisfaction was evaluated using a questionnaire survey. RESULTS: The experimental group consisted of 4 patients with Plane I fracture and 10 patients with Plane II fracture. The control group consisted of 3 patients with Plane I fracture and 11 patients with Plane II fracture. The mean surgical outcomes score and the mean patient dissatisfaction score were found not to differ between the experimental and the control group in Plane I fracture (p=0.755, 0.578, respectively). In a subgroup analysis consisting of Plane II fractures only, surgeons graded outcomes for ultrasound-guided reduction higher than that for the control group (p=0.007). Likewise, among the Plane II fracture patients, those who underwent ultrasound-guided reduction were less dissatisfied than those who underwent blind reduction (p=0.043). CONCLUSION: Our study result suggests that ultrasound-guided closed reduction is superior to blind closed reduction in those patients with Plane II nasal fractures. PMID- 28913247 TI - Silicone Implant-Based Paranasal Augmentation for Mild Midface Concavity. AB - BACKGROUND: Midface concavity is a relatively common facial feature in East Asian populations. Paranasal augmentation is becoming an increasingly popular procedure for patients with mild concavity and normal occlusion. In this study, we evaluate clinical outcomes following a series of paranasal augmentation. METHODS: A retrospective review was performed for patients with Class I occlusion who had undergone bilateral paranasal augmentation using custom-made silicone implants, between October 2005 and September 2013. Patient charts were reviewed for demographic information, concomitant operations, and postoperative complications. Preoperative and postoperative (1-month) photographs were used to evaluate operative outcome. RESULTS: The review identified a total of 93 patients meeting study criteria. Overall, aesthetic outcomes were satisfactory. Five-millimeter thick silicone implant was used in 81 cases, and the mean augmentation was 4.26 mm for this thickness. Among the 93 patients, 2 patients required immediate implant removal due to discomfort. An additional 3 patients experienced implant migration without any extrusion. Nine patients complained of transient paresthesia, which had resolved by 2 weeks. There were no cases of hematoma or infection. All patients reported improvement in their lateral profile and were pleased at follow-up. Complications that arose postoperatively included 9 cases of numbness in the upper lip and 3 cases of implant migration. All cases yielded satisfactory results without persisting complications. Sensations were fully restored postoperatively after 1 to 2 weeks. CONCLUSION: Paranasal augmentation with custom-made silicone implants is a simple, safe, and inexpensive method that can readily improve the lateral profile of a patient with normal occlusion. When combined with other aesthetic procedures, paranasal augmentation can synergistically improve outcome and lead to greater patient satisfaction. PMID- 28913248 TI - Cutaneous Horn in Premalignant and Malignant Conditions. AB - Cutaneous horns are conical, circumscribed protuberances formed by densely layered keratin. These lesions originate from basal keratinocytes and may manifest as benign, premalignant, or malignant cutaneous pathology in chronically sun-damaged areas. Complete surgical excision with histologic examination is needed for potential malignancy. In this report, we describe two elderly women presenting with solitary facial cutaneous horns, which were respectively diagnosed as actinic keratosis and squamous cell carcinoma. PMID- 28913249 TI - Massive Hemorrhage Facial Fracture Patient Treated by Embolization. AB - Major maxillofacial bone injury itself can be life threatening from both cardiovascular point of view, as well as airway obstruction. Significant hemorrhage from facial fracture is an uncommon occurrence, and there is little in the literature to guide the management of these patients. We report a 73-year-old male driver who was transported to our hospital after a motor vehicle collision. The patient was hypotensive and tachycardic at presentation and required active fluid resuscitation and transfusion. The patient was intubated to protect the airway. All external attempts to control the bleeding, from packing to fracture reduction, were unsuccessful. Emergency angiogram revealed the bleeding to originate from terminal branches of the sphenopalatine artery, which were embolized. This was associated with cessation of bleeding and stabilization of vital signs. Despite the age and severity of injury, the patient recovered well and was discharged home at 3 months with full employment. In facial trauma patients with intractable bleeding, transcatheter arterial embolization should be considered early in the course of management to decrease mortality rate. PMID- 28913250 TI - Cutaneous Rosai-Dorfman Disease Confused with Vascular Mass. AB - Rosai-Dorfman disease is a rare histiocytic disorder, clinically characterized by massive, bilateral painless cervical lymphadenopathy with potential for extranodal manifestations. We report a 45-year-old male patient who presented with a slowly growing erythematous nodule of the left chin. The mass appeared non vascular on computed tomography study, but ultrasonogram was suggestive of a vascular lesion. The lesion was excised with presumptive diagnosis of a hemangioma. However, histopathologic examination of the surgical biopsy revealed histiocytic infiltration with emperipolesis, which was pathognomic for Rosai Dorfman disease. Additional imaging studies did not reveal lymph node enlargement or other extranodal manifestation. The patient was diagnosed with cutaneous form of the Rosai-Dorfman disease and was discharged home. He remains free of local recurrence at 8 months. PMID- 28913251 TI - Recurrent Chondroid Syringoma of the Alar Rim. AB - Chondroid synringoma (CS), pleomorphic adenoma of skin, is a benign tumor found in the head and neck region. CS was first reported in 1859 by Billorth for the salivary gland tumor. The usual presentation is an slowly growing, asymptomatic mass. A 53-year-old female with a history of chondroid synringoma had presented with multiple firm, nodular masses found in the left nostril area. The lesion had been excised 8 years prior and was diagnosed histopathologically, but had gradually recurred. Excision of the mass located in subcutaneous layer revealed four whitish, firm tumors surrounded with capsular tissue. Neither recurrence nor complications occurred during the 18 months follow-up period. In the head and neck region, chondroid syringoma should always be considered in differential diagnosis of soft tissue masses despite its rare incidence. For that reason, excisional biopsy with clear margin is the optimal diagnostic as well as therapeutic choice. We report a case of recurred chondroid syringoma on the nose in female patient. PMID- 28913252 TI - Forehead Osteoma Excision by Anterior Hairline Incision with Subcutaneous Dissection. AB - Forehead osteomas are benign but can pose aesthetic and functional problems. These osteomas are resected via bicoronal or endoscopic approach. However, large osteomas cannot be removed via endoscopic approach, and bicoronal approach can result in damage to the supraorbital nerve with resultant numbness in the forehead. We present a new approach to resection of forehead osteomas, with access provided by an anterior hairline incision and subcutaneous dissection. Three patients underwent resection of the forehead osteoma through an anterior hairline incision. The dissection was carried in the subcutaneous plane, and the frontalis muscle and periosteum were divided parallel to the course of supraorbital nerve. The resulting bony defect was re-contoured using Medpor(r). All three patients recovered without any postoperative infection or complication and symptoms. Scalp sensory was preserved. Aesthetic outcomes were satisfactory. Patients remain free of recurrence for 12 months of follow up. The anterior hair line approach with subcutaneous dissection is an effective method for removal of forehead osteoma, since it offers broad visualization and hides the scar in the hairline. In addition, the dissection in the subcutaneous plane avoids inadvertent injury to the deep nerve branches and helps to maintains scalp sensation. PMID- 28913253 TI - Spring Update: A Letter from the President of the Korean Cleft Palate Craniofacial Association. PMID- 28913254 TI - Oral and Oropharyngeal Reconstruction with a Free Flap. AB - Extensive surgical resection of the aerodigestive track can result in a large and complex defect of the oropharynx, which represents a significant reconstructive challenge for the plastic surgery. Development of microsurgical techniques has allowed for free flap reconstruction of oropharyngeal defects, with superior outcomes as well as decreases in postoperative complications. The reconstructive goals for oral and oropharyngeal defects are to restore the anatomy, to maintain continuity of the intraoral surface and oropharynx, to protect vital structures such as carotid arteries, to cover exposed portions of internal organs in preparation for adjuvant radiation, and to preserve complex functions of the oral cavity and oropharynx. Oral and oropharyngeal cancers should be treated with consideration of functional recovery. Multidisciplinary treatment strategies are necessary for maximizing disease control and preserving the natural form and function of the oropharynx. PMID- 28913255 TI - Delayed Reduction of Nasal Bone Fractures. AB - BACKGROUND: Nasal bone fractures are managed by closed reduction within the 2 week period, and are managed by secondary correction after this time. There is little literature on the delayed reduction for nasal bone fractures beyond the 2 week duration. We report our experience with nasal fractures, which were reduced beyond this period. METHODS: A retrospective review was performed for all patients who had undergone closed reduction of isolated nasal bone fracture. Patients were included for having undergone reduction of nasal bone fractures at or more than 2 weeks after the injury. Medical records were reviewed for demographic information, injury mechanism, fracture type, delay in treatment, and cause for delay. Postoperative outcomes were evaluated using computed tomography images. RESULTS: The review identified 10 patients. The average reduction time was 22.1 days. Five of patients underwent reduction between days 15 and 20, and the remaining five patients underwent reduction between days 21 and 41. The postoperative outcomes were excellent in 8 patients and good in 2 patients. CONCLUSION: Outcomes were superior for nasal fractures with displaced end plates and multiple fracture segments. Our study results appears to support delayed reduction of isolated nasal fractures in the presence of factors that delay bony reunion. PMID- 28913256 TI - A Retrospective Clinical View of Basal Cell Carcinoma and Squamous Cell Carcinoma in the Head and Neck Region: A Single Institution's Experience of 247 Cases over 19 Years. AB - BACKGROUND: The two most common skin cancers are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The purpose of this study was to describe the detailed clinical behavior of BCC and SCC in the head and neck region over 19 years at a single institution. METHODS: A retrospective analysis was performed for all patients with non-melanoma skin cancer who had undergone surgical resection over an 18-year period. Patient charts were reviewed for demographic information, tumor size, onset-to-diagnosis, anatomic location, clinical subtype, histologic differentiation, method of surgical treatment, and recurrence. RESULTS: The review identified 265 cases of either BCC or SCC in 226 patients. Of the 226 patients, 80 (35.4%) were men and 146 (64.6%) were women. BCC (n=138, 55.9%) was more frequent than SCC (109, 44.1%). The most frequent age group was 70-to-79 year olds (45 patients, 35.2%) for BCC and 80-to-89 year olds (41 patients, 41.8%) for SCC. By aesthetic units of the face, the most common location was the nasal unit (44 cases, 31.9%) for BCC and the buccal unit (23 cases, 21.1%) for SCC. The most common clinical subtype of BCC was the nodular type (80 cases, 58.0%). Local flaps were most commonly used to cover surgical defects (136 cases, 55.1%). Recurrent rates were 2.2% for BCC and 5.5% for SCC. CONCLUSION: In our study, many characteristics of BCC and SCC were compared to previously published reports were generally similar, except the ratio of BCC to SCC. Further study can help to establish the characteristics of BCC and SCC. PMID- 28913257 TI - Use of Triamcinolone Acetonide to Treat Lower Eyelid Malposition after the Subciliary Approach. AB - BACKGROUND: The subciliary approach is commonly used for reconstruction of orbital wall or zygomaticomaxillary fractures. However, this approach is associated with postoperative complications, especially lower eyelid malposition. We report the experience of managing postoperative lower eyelid malposition with triamcinolone acetonide. METHODS: A retrospective review was performed for all traumatic facial fractures requiring surgery via the subciliary approach at Chosun University Hospital in 2014. For each patient meeting inclusion criteria, the medical chart was reviewed for demographic information and postoperative course, including the presence of postoperative eyelid malposition or scleral show. RESULTS: The review identified 189 cases in which the subciliary approach was used, and postoperative lower eyelid malposition was found in 7 cases (3.7%). For these 7 patients, the mean therapeutic period (interval to correction of the malposition) was 10.5 weeks (range, 8 to 14 weeks). On average, patients received 3 injections of triamcinolone. In all cases, degrees of the malposition were improved, and none of the patients required an operative intervention to correct the malposition. CONCLUSION: Triamcinolone injection is an appropriate treatment modality for lower eyelid malposition after subciliary approach. Treatment duration is relatively short, requiring fewer than 4 outpatient clinic visits, with relatively earlier recovery compared to conservative "wait-and-see" management. PMID- 28913258 TI - Risk Acceptance and Expectations of Scalp Allotransplantation. AB - BACKGROUND: In scalp allotransplantation, the scalp from a brain-dead donor, including hair, is transferred to a recipient with scalp defects. Opinions differ on the appropriateness of scalp allotransplantation. In order to maintain graft function and cosmetic outcomes, scalp transplantation recipients would need to receive lifelong immunosuppression treatments. The risks of this immunosuppression have to be balanced against the fact that receiving a scalp allotransplant does not extend lifespan or restore a physical function. Therefore, the present study aimed to investigate risk acceptance and expectations regarding scalp allotransplantation in different populations. METHODS: A questionnaire survey study was conducted. A total of 300 subjects participated; survey was conducted amongst the general public (n=100), kidney transplantation recipients (n=50), a group of patient who required scalp reconstruction due to tumor or trauma (n=50), and physicians (n=100). The survey was modified by using the Korean version of the Louisville instrument for transplantation questionnaire. RESULTS: Risk acceptance and expectations for scalp transplantation varied widely across the groups. Kidney transplantation recipients revealed the highest risk acceptance and expectations, whereas the physicians were most resistant to the risks of scalp transplantation. CONCLUSION: Our study demonstrates that, in specific groups, scalp allotransplantation and the need for immunosuppression carries an acceptable risk despite the lack of lifeextending benefits. Our results suggest that scalp allotransplantation can be an acceptable alternative to existing scalp reconstruction surgeries in patients with pre-existing need for immunosuppression. PMID- 28913259 TI - Improvement of Infraorbital Rim contour Using Medpor. AB - BACKGROUND: Asymmetry of the infraorbital rim can be caused by trauma, congenital or acquired disease, or insufficient reduction during a previous operation. Such asymmetry needs to be corrected because the shape of the infraorbital rim or midfacial skeleton defines the overall midfacial contour. METHODS: The study included 5 cases of retruded infraorbital rim. All of the patient underwent restoration of the deficient volume using polyethylene implants between June 2005 and June 2011. The infraorbital rim was accessed through a subciliary approach, and the implants were placed in subperiosteal space. Surgical outcomes were evaluated using preoperative and postoperative computed tomography studies. RESULTS: Implant based augmentation was associated with a mean projection of 4.6 mm enhancement. No postoperative complications were noted during the 30-month follow-up period. CONCLUSION: Because of the safeness, short recovery time, effectiveness, reliability, and potential application to a wide range of facial disproportion problems, this surgical technique can be applied to midfacial retrusion from a variety of etiologies, such as fracture involving infraorbital rim, congenital midfacial hypoplasia, lid malposition after blepharoplasty, and skeletal changes due to aging. PMID- 28913260 TI - Aesthetic Facial Correction of Cleidocranial Dysplasia. AB - We report two cases of cleidocranial dysplasia, which was managed without significant craniofacial osteotomy. A mother and daughter, both of normal intelligence, presented with central forehead depression, mid-face hypoplasia, and blepharoptosis. The fact that they have an identically deformed face implied a genetic basis. In both patients, radiologic evaluation revealed the underdeveloped maxilla, persistent fontanelle opening, and cleidal aplasia. Clinical findings and radiologic studies were consistent with the diagnosis of cleidocranial dysplasia. Both patients underwent forehead plasty via bicoronal approach, augmentation rhinoplasty using tip plasty, and epicanthoplasty. In addition, the mother underwent malar augmentation using Medpor implantation and reduction genioplasty. The patients did not experience any postoperative complication and remained satisfied with the operation at 6-year follow-up. PMID- 28913261 TI - Malignant Skin Tumor Misdiagnosed as a Benign Skin Lesion. AB - Despite the fact that benign skin lesions can undergo malignant transformation, the necessity and timing of the surgical resection have yet to be established. In this study, we analyse three cases of benign-appearing skin lesions, which were found to be carcinomatous on histologic examination and review the literature regarding the importance of prophylactic removal of benign-appearing skin lesion. The first and second cases were female patients wishing for cosmetic surgery. The first patient had a benign-appearing lesion on dorsum nasi, and the second patient had an inconspicuous lesion right along the right nasolabial fold. The third patient was a middle-aged male with a pigmented lesion on the left cheek, who presented to the clinic only after having met the operating surgeon through an acquaintance outside the hospital setting. All of the lesions were suspected to be of benign nature and were excised for cosmesis only. However, histologic examination of these lesions showed that the first two tumors were basal cell carcinoma with the last tumor being squamouse cell carcinoma. Thus, it is considered that removal of benign like skin lesion will result in good prognosis of patients scheduled to undergo other surgery. PMID- 28913262 TI - Recurrent Pleomorphic Adenoma of the Parotid Gland. AB - Pleomorphic adenoma is the most common type of salivary gland tumor and the most common tumor of the parotid gland. Because of its propensity for invasion, pleomorphic adenoma of the parotid requires superficial parotidectomy or total parotidectomy to minimize the risk of tumor recurrence. We report a case of pleomorphic adenoma of the parotid gland with repeated recurrences. A 23-year-old male patient presented with a protruding neck mass. Six years prior to this presentation, the patient had undergone superficial parotidectomy for the removal of pleomorphic adenoma of the right parotid gland at our institution. The patient experienced recurrence at 17 months after the initial resection, which required a total parotidectomy with partial resection of the facial nerve. Pathologic examination revealed histologic findings consistent with pleomorphic adenoma across the surgical specimen from all three of the operations. The patient suffered from facial nerve paralysis, with facial expressions partially recovered over a year. PMID- 28913263 TI - Sebaceoma Arising from Nevus Sebaceous with Early Focal Carcinomatous Area. PMID- 28913264 TI - Compound Type Odontoma at Maxilla. PMID- 28913265 TI - Cranioplasty with Methylmethacrylate in Plagiocephaly. PMID- 28913266 TI - Secondary Reconstruction of Frontal Sinus Fracture. AB - Fractures of frontal sinus account for 5%-12% of all fractures of facial skeleton. Inadequately treated frontal sinus injuries may result in malposition of sinus structures, as well as subsequent distortion of the overlying soft tissue. Such inappropriate treatment can result in aesthetic complaints (contour deformity) as well as medical complications (recurrent sinusitis, mucocele or mucopyocele, osteomyelitis of the frontal bone, meningitis, encephalitis, brain abscess or thrombosis of the cavernous sinus) with potentially fatal outcomes. Frontal contour deformity warrants surgical intervention. Although deformities should be corrected by the deficiency in tissue type, skin and soft tissue correction is considered better choice than bone surgery because of minimal invasiveness. Development of infection in the postoperative period requires all secondary operations to be delayed, pending the resolution of infectious symptoms. The anterior cranial fossa must be isolated from the nasal cavity to prevent infectious complications. Because most of the complications are related to infection, frontal sinus fractures require extensive surgical debridement and adequate restructuring of the anatomy. The authors suggest surgeons to be familiar with various methods of treatment available in the prevention and management of complications following frontal sinus fractures, which is helpful in making the proper decision for secondary frontal sinus fracture surgery. PMID- 28913267 TI - Orbital Floor Fracture. AB - The medial wall and floor of the bony orbit are frequently fractured because of the delicate anatomy. To optimize functional and aesthetic results, reconstructive surgeons should understand the anatomy and pathophysiology of orbital fractures. Appropriate treatment involves optimal timing of intervention, proper indications for operative repair, incision and dissection, release of herniated tissue, implant material and placement, and wound closure. The following review will discuss the management of orbital floor fractures, with the operative method preferred by the author. Special considerations in operation technique and the complication are also present in this article. PMID- 28913268 TI - Transconjuctival Incision with Lateral Paracanthal Extension for Corrective Osteotomy of Malunioned Zygoma. AB - BACKGROUND: Conventional correction of malunioned zygoma requires complete regional exposure through a bicoronal flap combined with a lower eyelid incision and an upper buccal sulcus incision. However, there are many potential complications following bicoronal incisions, such as infection, hematoma, alopecia, scarring and nerve injury. We have adopted a zygomaticofrontal suture osteotomy technique using transconjunctival incision with lateral paracanthal extension. We performed a retrospective review of clinical cases underwent correction of malunioned zygoma with the approach to evaluate outcomes following this method. METHODS: Between June 2009 and September 2015, corrective osteotomies were performed in 14 patients with malunioned zygoma by a single surgeon. All 14 patients received both upper gingivobuccal and transconjunctival incisions with lateral paracanthal extension. The mean interval from injury to operation was 16 months (range, 12 months to 4 years), and the mean follow-up was 1 year (range, 4 months to 3 years). RESULTS: Our surgical approach technique allowed excellent access to the infraorbital rim, orbital floor, zygomaticofrontal suture and anterior surface of the maxilla. Of the 14 patients, only 1 patient suffered a complication-oral wound dehiscence. Among the 6 patients who received infraorbital nerve decompression, numbness was gradually relieved in 4 patients. Two patients continued to experience persistent numbness. CONCLUSION: Transconjunctival incision with lateral paracanthal extension combined with upper gingivobuccal sulcus incision offers excellent exposure of the zygoma-orbit complex, and could be a valid alternative to the bicoronal approach for osteotomy of malunioned zygoma. PMID- 28913269 TI - Ocular Complications in Assault-Related Blowout Fracture. AB - BACKGROUND: Blowout fracture is one of the most common facial fractures, and patients usually present with accompanying ocular complications. Many studies have looked into the frequency of persistent ocular symptoms, but there is no study on assault patients and related ocular symptoms. We evaluated the incidence of residual ocular symptoms in blow-out fractures between assaulted and non assaulted patients, and sought to identify any connection among the degree of enophthalmos, defect size, and assault-related injury. METHODS: A retrospective review was performed for any patient who sustained a unilateral blowout fracture between January 2010 to December 2014. The collected data included information such as age, gender, etiology, and clinical ocular symptoms as examined by an ophthalmologist. This data was analyzed between patients who were injured through physical altercation and patients who were injured through other means. RESULTS: The review identified a total of 182 patients. Out of these, 74 patients (40.7%) have been struck by a fist, whereas 108 patients (59.3%) have sustained non assault related injuries. The average age was 36.1 years, and there was a male predominance in both groups (70 patients [94.6%] in the assaulted group and 87 patients [80.6%] in the non-assault group). Diplopia and enophthalmos were more frequent in patients with assault history than in non-assaulted patients (p<0.05). Preoperatively, 25 patients (33.8%) with assault history showed diplopia, whereas 20 patients (18.5%) showed diplopia in the non-assaulted group (p<0.05). Preoperative enophthalmos was present in 34 patients (45.9%) with assault history, whereas 31 patients (28.7%) showed enophthalmos in the non assaulted group (p<0.05). CONCLUSION: Patients with an assault history due to a fist blow experienced preoperative symptoms more frequently than did patients with non-assault-related trauma history. Preoperative diplopia and enophthalmos occurred at a higher rate for patients who were assaulted. Surgeons should take into account such characteristics in the management of assaulted patients. PMID- 28913270 TI - The Efficacy of Bioabsorbable Mesh in Craniofacial Trauma Surgery. AB - BACKGROUND: The ultimate goal of craniofacial reconstructive surgery is to achieve the most complete restoration of facial functions. A bioabsorbable fixation system which does not need secondary operation for implant removal has been developed in the last decade. The purpose of this study is to share the experience of authors and to demonstrate the efficacy of bioabsorbable mesh in a variety of craniofacial trauma operations. METHODS: Between October 2008 and February 2015, bioabsorbable meshes were used to reconstruct various types of craniofacial bone fractures in 611 patients. Any displaced bone fragments were detached from the fracture site and fixed to the mesh. The resulting bone-mesh complex was designed and molded into an appropriate shape by the immersion in warm saline. The mesh was molded once again under simultaneous warm saline irrigation and suction. RESULTS: In all patients, contour deformities were restored completely, and bone segments were fixed properly. The authors found that the bioabsorbable mesh provided rigid fixation without any evidence of integrity loss on postoperative computed tomography scans. CONCLUSION: Because bioabsorbable meshes are more flexible than bioabsorbable plates, they can be molded and could easily reconstruct the facial bone in three dimensions. Additionally, it is easy to attach bone fragments to the mesh. Bioabsorbable mesh and screws is effective and can be easily applied for fixation in various craniofacial trauma reconstructive scenarios. PMID- 28913271 TI - The Clinical Analysis of the Nasal Septal Cartilage by Measurement Using Computed Tomography. AB - BACKGROUND: The nasal septal cartilage is often used as a donor graft in rhinoplasty operations but can vary widely in size across the patient population. As such, preoperative estimation of the cartilaginous area is important for patient counseling as well as operating planning. We aim to estimate septal cartilage area by using facial computed tomography (CT) studies. METHODS: The study was performed using facial CT images taken from 200 patients between January 2012 to July 2015. Using the mid-sagittal image, the boundary of cartilaginous septum was delineated from soft tissue using the mean difference in signal intensity (or brightness). The area within this boundary was calculated. The calculated area for septal cartilage was then compared across age groups and sexes. RESULTS: Overall, the mean area of nasal septal cartilage was 8.18 cm2 with the maximum of 12.42 cm2 and the minimum of 4.89 cm2. The cartilage areas were measured to be larger in men than in women (p<0.05). The area decreased with advancing age (p<0.05). CONCLUSION: Measuring the size of septal cartilage using brightness difference is more precise and reliable than previously reported methods. This method can be utilized as the standard for prevention of postoperative complication. PMID- 28913272 TI - Application of Rapid Prototyping Technique and Intraoperative Navigation System for the Repair and Reconstruction of Orbital Wall Fractures. AB - BACKGROUND: Restoring the orbital cavity in large blow out fractures is a challenge for surgeons due to the anatomical complexity. This study evaluated the clinical outcomes and orbital volume after orbital wall fracture repair using a rapid prototyping (RP) technique and intraoperative navigation system. METHODS: This prospective study was conducted on the medical records and radiology records of 12 patients who had undergone a unilateral blow out fracture reconstruction using a RP technique and an intraoperative navigation system from November 2014 to March 2015. The surgical results were assessed by an ophthalmic examination and a comparison of the preoperative and postoperative orbital volume ratio (OVR) values. RESULTS: All patients had a successful treatment outcome without complications. Volumetric analysis revealed a significant decrease in the mean OVR from 1.0952+/-0.0662 (ranging from 0.9917 to 1.2509) preoperatively to 0.9942+/-0.0427 (ranging from 0.9394 to 1.0680) postoperatively. CONCLUSION: The application of a RP technique for the repair of orbital wall fractures is a useful tool that may help improve the clinical outcomes by understanding the individual anatomy, determining the operability, and restoring the orbital cavity volume through optimal implant positioning along with an intraoperative navigation system. PMID- 28913273 TI - Transient Anisocoria during Medial Blowout Fracture Surgery. AB - Transient anisocoria is rare during blowout fracture reconstruction. We report a case of transient anisocoria occurring during medial blowout fracture reconstruction and review the relevant literature. A 54-year-old woman was struck in the face and was admitted for a medial blowout fracture of the left eye. During the operation, persistent bleeding occurred. To control this bleeding, a 1% lidocaine solution with 1:200,000 epinephrine was applied to the orbital wall with cotton pledgets. In total, 40 mL of local anesthetic was used for the duration of the operation. After approximately three hours of the surgery, the ipsilateral pupil was observed to be dilated, with sluggish response to light. By 3 hours after the operation, the mydriasis had resolved with normal light reflex. In conclusion, neurological and ophthalmologic evaluation must be performed prior to blowout fracture surgery. Preoperative ophthalmic evaluation is simple and essential in ruling out any preexisting neurologic condition. Moreover, surgeons must be aware of the fact that excessive injection of lidocaine with epinephrine for hemostasis during orbital wall surgery can result in intraoperative anisocoria. Anisocoria-related situations must be addressed in a proficient manner through sufficient understanding of the mechanism controlling the pupillary response to various stimuli. PMID- 28913274 TI - Primary Cutaneous Mucinous Carcinoma Treated with Narrow Surgical Margin. AB - Primary cutaneous mucinous carcinoma (PCMC) is a rare malignant tumor of eccrine origin. Clinically, the carcinoma presents as a solitary, slow growing, and painless nodule. For this reason, this tumor is often considered to be a benign mass in the preoperative setting. The lesion is, however, malignant in nature and has a tendency for local recurrence and infrequent metastasis. Wide local excision is the treatment of choice. However, few reports exist with information regarding surgical margins and clinical outcomes. Herein, we report a case of PCMC excised with a narrow surgical margin and review the relevant literature. A 49-year-old man presented with a small cutaneous nodule of the right cheek. The mass was excised without any margin, but pathologic examination revealed histology of mucinous carcinoma. Because of this, the operative site was re excised with a 5-mm margin, and the wound was closed using a V-Y advancement flap. Systemic work-up did not reveal other potential metastatic primary, for a final diagnosis of PCMC. We report this case of PCMC, treated with relatively narrow margin in a patient with good prognostic factors. PMID- 28913275 TI - Stafne Bone Cavity of the Mandible. AB - Stafne bone cavity is a rare mandibular defect that was first reported by Edward C. Stafne in 1942. It commonly presents with a well-demarcated, asymptomatic, unilateral radiolucency that indicates lingual invagination of the cortical bone. A 52-year-old female patient who with nasal bone fracture, visited the hospital. During facial bone computed tomography (CT) for facial area evaluation, a well shaped cystic lesion was accidentally detected on the right side of the mandible. Compared to the left side, no swelling or deformity was observed in the right side of the oral lesion, and no signs of deformity caused by mucosal inflammation. 3D CT scans, and mandible series x-rays were performed, which showed a well-ossified radiolucent oval lesion. Axial CT image revealed a cortical defect containing soft tissue lesion, which has similar density as the submandibular gland on the lingual surface of the mandible. The fact that Stafne cavity is completely surrounded by the bone is the evidence to support the hypothesis that embryonic salivary gland is entrapped by the bone. In most cases, Stafne bone cavity does not require surgical treatment. We believe that the mechanical pressure from the salivary gland could have caused the defect. PMID- 28913276 TI - Recurrent Extranodal NK/T-Cell Lymphoma Presenting as a Perforating Palatal Ulcer and Oro-Nasal Fistula. AB - Nasal-type extranodal natural killer/T-cell lymphoma (ENKTL) is a rare disease presenting with non-specific symptoms, typically originating in the nasal cavity, palate, or midfacial region. Oral cavity is an extremely rare site for this type of lymphoma. In this report, we present a case of palatal perforation and oro nasal fistula as a manifestation of recurrent ENKTL. Complicated disease entity should be considered when surgeons deal with palatal perforation and oro-nasal fistula. PMID- 28913277 TI - Atypical Facial Filler Granuloma: Comparative Histologic Analysis with Paraffinoma. AB - Dermal fillers are generally accepted as safe and well-tolerable cosmetic tools. However, adverse reactions have been reported in the literature. Here, we present a case of atypical facial filler granuloma and compare its histologic features with those of the classic paraffinoma. PMID- 28913278 TI - Chondroid Syringoma on Face. AB - Chondroid syringoma is a rare mixed tumor of the skin which is composed of both mesenchymal and epithelial cells. Its incidence at less than 0.1% and is frequently located on the head and neck. Chondroid syringoma is easily confused with epidermal cysts. Since malignant forms of chondroid syringoma have been reported, accurate and timely diagnosis is important for proper management. We report clinical and histological features of chondroid syringoma in 5 patients treated at our institution. In most of the cases, chondroid syringoma presented as a round, firm, nodular or cystic lesion that had well marginated heterogeneity in sonography. Clinically, all of the lesions were removed by simple excision. Microscopically, all five tumors were well circumscribed and consisted of epithelial, myoepithelial, and stromal components. The epithelial component formed tubules lined by one or more rows of eosinophilic epithelial cells. The outer layer of tubules appeared to be flattened myoepithelial cells. The stroma is myxoid and contained spindle shaped myoepithelial cells. We expect that the clinical, sonographic, and histological data from our report may help clinicians who are confronted with various kinds of analogous facial lesions to decide the most proper management for their patients. PMID- 28913279 TI - Primary Cutaneous Mucinous Carcinoma of the Eyelid. AB - Primary cutaneous mucinous carcinoma (PCMC) is a rare low-grade malignant neoplasm derived from the eccrine glands. PCMC most commonly arises in the head and neck, with the eyelid being the most common site of origin. This case report describes a 51-year-old male with a painless, pigmented superficial nodular lesion over his right lower eyelid. The lesion was considered to be benign, and the initial treatment was simple excision with a 3-mm margin. However, histologic examination revealed the diagnosis of PCMC, and the patient underwent re-excision of the tumor site with an additional 3-mm margin from the initial scar. Histologic study of this second margin was free of any malignant cells. The patient experienced no postoperative complication or recurrence after 2 years. In our case, the skin lesion had benign morphologic findings and was strongly suspected to be a benign mass. Physicians should be aware of this tumor and be able to differentiate it from benign cystic or solid eyelid lesions. PMID- 28913280 TI - Panfacial Bone Fracture and Medial to Lateral Approach. AB - Panfacial bone fracture is challenging. Even experienced surgeons find restoration of original facial architecture difficult because of the severe degree of fragmentation and loss of reference segments that could guide the start of facial reconstruction. To restore the facial contour, surgeons usually follow a general sequence for panfacial bone reduction. Among the sequences, the bottom to-top and outside-in sequence is reported to be the most widely used in recent publications. However, a single sequence cannot be applied to all cases of panfacial fractures because of the variations in panfacial bone fracture patterns. In this article, we intend to find the reference and discuss the efficacy of inside-out sequence in facial bone fracture reconstruction. PMID- 28913281 TI - A Review of Subbrow Approach in the Management of Non-Complicated Anterior Table Frontal Sinus Fracture. AB - Frontal sinus fractures, particularly anterior sinus fractures, are relatively common facial fractures. Many agree on the general principles of frontal fracture management; however, the optimal methods of reduction are controversial. The subbrow approach enables accurate reduction and internal fixation of the fractures in the anterior table of the frontal sinus by allowing direct visualization of the fracture. Given the surgical success in reduction and rigid fixation, patient satisfaction, and aesthetic benefits, the transcutaneous approach through a subbrow incision is superior to other reduction techniques used in the management of an anterior table frontal sinus fracture. PMID- 28913282 TI - The Versatility of Cheek Rotation Flaps. AB - BACKGROUND: The cheek rotation flap has sufficient blood flow and large flap size and it is also flexible and easy to manipulate. It has been used for reconstruction of defects on cheek, lower eyelid, or medial and lateral canthus. For the large defects on central nose, paramedian forehead flap has been used, but patients were reluctant despite the remaining same skin tone on damaged area because of remaining scars on forehead. However, the cheek flap is cosmetically superior as it uses the adjacent large flap. Thus, the study aims to demonstrate its versatility with clinical practices. METHODS: This is retrospective case study on 38 patients who removed facial masses and reconstructed by the cheek rotation flap from 2008 to 2015. It consists of defects on cheek (16), lower eyelid (12), nose (3), medial canthus (3), lateral canthus (2), and preauricle (2). Buccal mucosa was used for the reconstruction of eyelid conjunctiva, and skin graft was processed for nasal mucosa reconstruction. RESULTS: The average defect size was 6.4 cm2, and the average flap size was 47.3 cm2. Every flap recovered without complications such as abnormal slant, entropion or ectropion in lower eyelid, but revision surgery required in three cases of nasal side wall reconstruction due to the occurrence of dog ear on nasolabial sulcus. CONCLUSION: The cheek rotation flap can be applicable instead of paramedian forehead flap for the large nasal sidewall defect reconstruction as well as former medial and lateral canthal defect reconstruction. PMID- 28913283 TI - Reduction of Zygomatic Arch Isolated Fracture Using Ultra Sound and Needle Marking. AB - BACKGROUND: Zygomatic arch is a bony arch constituting the lateral midface, which consists of 25% of all midface fractures. There are a number of ways to evaluate the extent of zygomatic arch fracture. Some authors have reported successful treatment outcomes using ultrasound (U/S). To add to the previous methods, we have considered ways to accurately display the location of the fracture line while using U/S with 23 gauge needle marking. We introduce our method, which provided satisfactory results for reduction using a portable U/S, and it can evaluate the fracture line simultaneously when reduction of an isolated zygomatic arch fracture is necessary, and needle marking, which can easily point out the fracture line on U/S. METHODS: We studied 21 patients with an isolated zygomatic arch fracture who underwent closed reduction using U/S and needle marking between 2013 and 2015. RESULTS: We achieved satisfactory results in all our cases with respect to reduction by using the Dingman elevator after performing a temporal approach incision, while confirming relative positioning between needle marking and zygomatic fracture at the same time, after insertion of a 23 gauge needle in the skin above the zygomatic arch fracture line parallel to it. CONCLUSION: We treated 21 patients with an isolated zygomatic arch fracture using U/S and the needle marking method, which provided satisfactory results because the extent of reduction of the fracture could be evaluated in real-time during the operation and exposure to radiation was reduced. PMID- 28913284 TI - Comparison Study of the Use of Absorbable Materials as Internal Splints with Airway Silicone Splint and Absorbable Materials as Internal Splints Alone. AB - BACKGROUND: Packing after closed reduction of nasal fracture causes uncomfortable nasal obstruction in patients. We packed the superior meatus with synthetic polyurethane foam (SPF) to support the nasal bone, and packed the middle nasal meatus with a nasal airway splint (NAS) and SPF. The aim of this article is prospectively to compare the subjective patient discomfort of SPF (Nasopore Forte plus) packing alone and SPF with NAS. METHODS: We compared the prospectively subjective patient discomfort of SPF packing alone (group A) and SPF with NAS (group B) via visual analog scale (VAS; 0, no symptom; 100, most severe symptom). RESULTS: At first postoperative day group B showed significant lower scores in dry mouth, sleep disturbance, conversation difficulty. However at third postoperative day, VAS scores of each group had no statistically significant differences. Moreover at fifth postoperative day group A had statistically significant lower scores for nasal pain, dry mouth than the group B. CONCLUSION: Combination method of using NAS and SPF have some advantage on the patient comfort from first postoperative day to third postoperative day. PMID- 28913285 TI - Surgical Methods of Zygomaticomaxillary Complex Fracture. AB - BACKGROUND: Zygoma is a major buttress of the midfacial skeleton, which is frequently injured because of its prominent location. Zygoma fractures are classified according to Knight and North based on the direction of anatomic displacement and the pattern created by the fracture. In zygomaticomaxillary complex (ZMC) fracture many incisions (lateral eyebrow, lateral upper blepharoplasty, transconjunctival, subciliary, subtarsal, intraoral, direct percutaneous approach) are useful. We reviewed various approaches for the treatment of ZMC fractures and discussed about incisions and fixation methods. METHODS: A retrospective review was conducted of patients with ZMC fracture at a single institution from January 2005 to December 2014. Patients with single zygomatic arch fracture were excluded. RESULTS: The identified 694 patients who were admitted for zygomatic fractures from which 192 patients with simple arch fractures were excluded. The remaining 502 patients consisted of 439 males and 63 females, and total 532 zygomatic bone was operated. Orbital fracture was the most common associated fracture. According to the Knight and North classification the most frequent fracture was Group IV. Most fractures were fixated at two points (73%). CONCLUSION: We reviewed our cases over 10 years according to fracture type and fixation methods. In conclusion, minimal incision, familiar approach and fixation methods of the surgeon are recommended. PMID- 28913286 TI - Treatment of Nonsyndromic Craniosynostosis Using Multi-Split Osteotomy and Rigid Fixation with Absorbable Plates. AB - BACKGROUND: Nonsyndromic craniosynostosis is a relatively common craniofacial anomaly and various techniques were introduced to achieve its operative goals. Authors found that by using smaller bone fragments than that used in conventional cranioplasty, sufficiently rigid bone union and effective regeneration capacity could be achieved with better postoperative outcome, only if their stable fixation was ensured. METHODS: Through bicoronal incisional approach, involved synostotic cranial bone together with its surrounding areas were removed. The resected bone flap was split into as many pieces as possible. The extent of this 'multi-split osteotomy' depends on the degree of dysmorphology, expectative volume increment after surgery and probable dead space caused by bony gap between bone segments. Rigid interosseous fixation was performed with variable types of absorbable plate and screw. In all cases, the pre-operational three-dimensional computed tomography (3D CT) was checked and brain CT was taken immediately after the surgery. Also about 12 months after the operation, 3D CT was checked again to see postoperative morphology improvement, bone union, regeneration and intracranial volume change. RESULTS: The bony gaps seen in the immediate postoperative brain CT were all improved as seen in the 3D CT after 12 months from the surgery. No small bone fragment resorption was observed. Brain volume increase was found to be made gradually, leaving no case of remaining epidural dead space. CONCLUSION: We conclude that it is meaningful in presenting a new possibility to be applied to not only nonsyndromic craniosynostosis but also other reconstructive cranial vault surgeries. PMID- 28913287 TI - Cryptogenic Temporal Hollowing. AB - Temporal hollowing is a common complication that occurs after coronal approach surgeries. However, temporal hollowing without previous nerve damage or trauma history is rare. Herein, we present a patient with cryptogenic temporal hollowing. A 22-year-old man without any history of craniofacial interventions or trauma presented with temporal hallowing. Magnetic resonance imaging revealed fatty degeneration of the left temporalis muscle. Electromyography and nerve conduction study showed no signs of neurologic abnormalities. The patient received autologous fat injection of 30 mL harvested from the left thigh using the modified Coleman technique. Temporal hollowing is commonly caused by atrophy of the superficial temporal fat pad. Its incidence is reported to be as high as 6% after coronal approach operation. Augmentation using porous hydroxyapatite or titanium mesh is a treatment option. Autologous fat graft can also be an option for mild to moderate temporal hollowing. In this case, a patient with no history of trauma, surgery, or myogenic disease developed temporal hollowing. Further study of the littleknown cryptogenic form of temporal hollowing is warranted. PMID- 28913288 TI - Rare Giant Upper Lip Epidermal Cyst in a Patient Wearing a Denture. AB - Epidermal cysts are intradermal or subcutaneous cystic tumors that frequently occur in the face, scalp, neck, and body trunk. Acquired cases of epidermal cyst commonly occur as a result of various surgical operations, chronic irritation, or trauma, all of which may trigger the occurrence of the invagination of squamous epithelium. A 57-year-old man presented with a palpable mass 7 cm*2 cm in size in the upper lip. The patient had a 3-year history of wearing a denture to restore missing bilateral maxillary central and lateral incisors, accompanied by inflammatory findings on the buccal mucosa due to chronic lip irritation. The resected oval-shaped cyst had a size of 5.5 cm*3.0 cm*2.5 cm, and it was an encapsulated mass with a well-defined margin. The histopathology was typical of epidermal cyst. This case of a rare giant upper lip epidermal cyst in a patient wearing a denture may be of interest to clinicians. PMID- 28913289 TI - Communicating Hydrocephalus Onset Following a Traumatic Tension Pneumocephalus. AB - The entrapment of intracranial air from the check valve system results in a tension pneumocephalus. It should be distinguished from simple pneumocephalus because they are intracranial space-occupying masses that can threaten life. Communicating hydrocephalus is a serious and frequent complication of post traumatic head injury. Head injury is one of the most common causes in etiopathogenesis of communicating hydrocephalus. Here, we describe a case of a 65 year-old man who developed communicating hydrocephalus after a post-traumatic tension pneumocephalus. To the best of our knowledge, this is the first reported case of communicating hydrocephalus developed after a post-traumatic tension pneumocephalus. Although the exact pathogenic mechanisms underlying the cascade following trauma remain unclear, communicating hydrocephalus after a tension pneumocephalus could be considered a possible complication. PMID- 28913290 TI - Delayed-Onset Methicillin-Resistant Staphylococcus aureus Infection at 18 Months after Absorbable Plate Fixation for Zygomaticomaxillary Complex Fracture. AB - None of the reports of delayed infection mentioned a latent period exceeding 13 months. we report an infection that developed 18 months after implantation of an absorbable plate. A 16-year-old adolescent girl had undergone reduction and fixation with an absorbable plate for Lefort I and zygomaticomaxillary complex fractures 18 months prior at our hospital. In her most recent hospital visit as an outpatient, abscess was observed in periocular area. Computed tomography revealed sinusitis with an abscess above the infraorbital rim. Wound culture yielded methicillin-resistant Staphylococcus aureus . Despite conservative treatments, wound state did not improve. Therefore, our department decided to perform surgery. Absorbable plate had been mostly absorbed but remained a bit. Bony depression of infraorbital rim and mucosal exposure of maxillary sinus anterior wall were observed. After the surgery, the patient recovered. We believe that the reason the wound infection and sinusitis manifested at the same time is because of several factor such as alcohol abuse, smoking, and mucosal exposure of maxillary sinus anterior wall. Absorbable plate takes 9 months to 3 years to be completely absorbed, thus we suggest studies with a follow-up of at least 3 years be undertaken to determine the outcomes of patients with many risk factors. PMID- 28913291 TI - Immediate Near-Total Scalp Reconstruction with Artificial Dermis on Exposed Calvarium. AB - Scalp defect management is complicated secondary to reduced laxity in the scalp and forehead area. For reconstruction of larger defects with exposed bone and loss of the periosteal layer, free flap reconstruction is one option for single stage surgery, although the procedure is lengthy and includes the possibility of flap loss. We successfully performed a single-stage reconstruction of a large scalp defect using a combination of artificial dermis, split-thickness skin graft, and full-thickness skin graft following wide excision of a cutaneous angiosarcoma, and present our method as one option for the treatment of large oncologic surgical defects in patients who are poor candidates for free flap surgery. PMID- 28913292 TI - The Effect of Botulinum Toxin on an Iatrogenic Sialo-Cutaneous Fistula. AB - A sialo-cutaneous fistula is a communication between the skin and a salivary gland or duct discharging saliva. Trauma and iatrogenic complications are the most common causes of this condition. Treatments include aspiration, compression, and the administration of systemic anticholinergics; however, their effects are transient and unsatisfactory in most cases. We had a case of a patient who developed an iatrogenic sialo-cutaneous fistula after wide excision of squamous cell carcinoma in the parotid region that was not treated with conventional management, but instead completely resolved with the injection of botulinum toxin. Based on our experience, we recommend the injection of botulinum toxin into the salivary glands, especially the parotid gland, as a conservative treatment option for sialo-cutaneous fistula. PMID- 28913293 TI - Facial Flap Repositioning in Posttraumatic Facial Asymmetry. AB - Perfect facial and body symmetry is an important aesthetic concept which is very difficult, if not impossible, to achieve. Yet, facial asymmetries are commonly encountered by plastic and reconstructive surgeons. Here, we present a case of posttraumatic facial asymmetry successfully treated with a unique concept of facial flap repositioning. A 25-year-old male patient visited our department with severe posttraumatic facial asymmetry. There was deviated nasal bone and implant to the right, and the actual facial appearance asymmetry was much more severe compared to the computed tomography, generally shifted to the right. After corrective rhinoplasty, we approached through intraoral incision, and much adhesion from previous surgeries was noted. We meticulously elevated the facial flap of both sides, mainly involving the cheeks. The elevated facial flap was shifted to the left, and after finding the appropriate location, we sutured the middle portion of the flap to the periosteum of anterior nasal spine for fixation. We successfully freed the deviated facial tissues and repositioned it to improve symmetry in a single stage operation. We conclude that facial flap repositioning is an effective technique for patients with multiple operation history, and such method can successfully apply to other body parts with decreased tissue laxity. PMID- 28913294 TI - Approach to Frontal Sinus Outflow Tract Injury. AB - Frontal sinus outflow tract (FSOT) injury may occur in cases of frontal sinus fractures and nasoethmoid orbital fractures. Since the FSOT is lined with mucosa that is responsible for the path from the frontal sinus to the nasal cavity, an untreated injury may lead to complications such as mucocele formation or chronic frontal sinusitis. Therefore, evaluation of FSOT is of clinical significance, with FSOT being diagnosed mostly by computed tomography or intraoperative dye. Several options are available to surgeons when treating FSOT injury, and they need to be familiar with these options to take the proper treatment measures in order to follow the treatment principle for FSOT, which is a safe sinus, and to reduce complications. This paper aimed to examine the surrounding anatomy, diagnosis, and treatment of FSOT. PMID- 28913295 TI - Management of Le Fort I fracture. AB - Among the classification of maxillary fracture, the Le Fort classification is the best-known categorization. Le Fort (1901) completed experiments that determined the maxilla areas of structural weakness which he designated as the "lines of weakness". According to these results, there are three basic fracture line patterns (transverse, pyramidal and craniofacial disjunction). A transverse fracture is a Le Fort I fracture that is above the level of the apices of the maxillary teeth section, including the entire alveolar process of the maxilla, vault of the palate and inferior ends of the pterygoid processes in a single block from the upper craniofacial skeleton. Le Fort fractures result in both a cosmetic and a functional deficit if treated inappropriately. In this article, authors review the management of a Le Fort I fracture with a case-based discussion. PMID- 28913296 TI - Effect of Relaxin Expressing Adenovirus on Scar Remodeling: A Preliminary Study. AB - BACKGROUND: Relaxin is a transforming growth factor beta1 antagonist. To determine the effects of relaxin on scar reduction, we investigated the scar remodeling process by injecting relaxin-expressing adenoviruses using a pig scar model. METHODS: Scars with full thickness were generated on the backs of Yorkshire pigs. Scars were divided into two groups (relaxin [RLX] and Control). Adenoviruses were injected into the RLX (expressing relaxin) and Control (not expressing relaxin) groups. Changes in the surface areas, color index and pliability of scars were compared. RESULTS: Fifty days after treatment, the surface areas of scars decreased, the color of scars was normalized, and the pliability of scars increased in RLX group. CONCLUSION: Relaxin-expressing adenoviruses improved the surface area, color, and pliability of scars. The mechanism of therapeutic effects on scar formation should be further investigated. PMID- 28913297 TI - Pyogenic Granuloma: A Retrospective Analysis of Cases Treated Over a 10-Year. AB - BACKGROUND: Pyogenic granuloma (PG) is a benign vascular lesion of the mucosa and skin. Recent studies of the epidemiology of PG are rare. We aimed to retrospectively analyze characteristics of PG cases in South Korea. METHODS: We reviewed the medical records of 155 patients treated for PG between March 2005 and May 2014. The male-to-female ratio was 1:1.2 (70 males, 85 females). The mean age of patients was 35.3 years. RESULTS: A high occurrence was observed in the first and third decades in males, and the fourth to fifth decades in females. There was a statistically significant difference between genders according to age group (p<0.05). The average lesion diameter was 0.84+/-0.46 cm (long axis). The most frequently involved site was the face (n=47). Bleeding was the primary complication (n=41). PG was mostly treated with excisional biopsy (n=74). The recurrence rate was 7.7% (n=12). CONCLUSION: We concluded that most common site of PG was the face, the age of female with PG is higher than previous studies, and finger is associated with trauma more than other sites. The most recent epidemiological information on PG of this study will support the treatment and diagnosis of PG and future research objectives. PMID- 28913298 TI - The Unnecessity of Positron Emission Tomography Computed Tomography in the Etiologic Evaluation of Neurodevelopmental Delay in Craniosynostosis Patients. AB - BACKGROUND: In evaluation of craniosynostosis patients in terms of neurodevelopmental delay, positron emission tomography computed tomography (PET CT) scan can be used to assess brain abnormalities through glucose metabolism. We aimed to determine the unnecessity of PET-CT in this study. METHODS: Thirty-eight patients diagnosed with craniosynostosis who underwent distraction osteogenesis from October, 2010 to November, 2013 were reviewed. Magnetic resonance imaging (MRI) and PET-CT scan were carried out for evaluation of the brain structure and function, whereas X-ray and CT scan were taken for evaluation of the skull. RESULTS: Nine patients reported abnormal MRI findings which were not significant, and five patients showed local problem on brain on PET-CT scan. No correlation was found among them. CONCLUSION: PET-CT evaluation of possible abnormal brain findings do not affect surgical planning or require additional therapy. Preoperative PET-CT scan is not the essential study to get any etiologic information of the disease consequences or to establish the treatment plan. PMID- 28913299 TI - Correlation between Operation Result and Patient Satisfaction of Nasal Bone Fracture. AB - BACKGROUND: Many authors have evaluated the post-reduction result of nasal bone fracture through patient satisfaction or postoperative complications. However, these results are limited because they are subjective. The aim of this study was to correlate an objective operation result with patient satisfaction and postoperative complications according to the type of nasal bone fractures. METHODS: Our study included 313 patients who had isolated nasal bone fractures and had undergone a closed reduction. Postoperative outcomes were evaluated objectively using computed tomographic (CT) images, while patient satisfaction was evaluated one month after the operation. The correlation of the operation result with patient satisfaction was then evaluated. RESULTS: The correlation between the operation result and patient satisfaction was highest for the lateral impact group type I (LI) type of fracture and lowest for the comminuted fracture group (C) type of fracture. However, there were no statistically significant differences in correlation between the overall result and patient satisfaction by fracture type. The complication rate of lateral impact group type II (LII), C, and frontal impact group type I (FI) fractures were statistically significantly higher than that of frontal impact group type II (FII) and LI fractures. There were no statistically significant relationships between the prevalence of complications and septal fracture or deviation according to the fracture type. In the total group, however, there was a statistically significant difference in complication rate by septal fracture. CONCLUSION: We found that the CT outcomes correlated with patient satisfaction. The complication rate of LII, C, and FI fractures were statistically significantly higher than that of FII and LI fractures. Septal fracture/deviation increased the postoperative complication in the total group. PMID- 28913300 TI - Objective Outcomes of Closed Reduction According to the Type of Nasal Bone Fracture. AB - BACKGROUND: Nasal fractures have a tendency of resulting in structural or functional complications, and the results can vary according to the type of nasal bone fracture. The aim of this study was to evaluate the objective postoperative results according to the type of nasal bone fractures. METHODS: We reviewed 313 patients who had a closed reduction of nasal bone fracture. The classification of nasal bone fracture by Stranc and Robertson was used to characterize the fracture type: frontal impact group type I (FI), frontal impact group type II (FII), lateral impact group type I (LI), lateral impact group type II (LII), and comminuted fracture group (C). For each patient, we tried to use the same axial image section of computed tomographic (CT) scans before and immediately after operation. Postoperative outcomes were classified into 4 grades: excellent (E), good (G), fair (F), and poor (P). We also analyzed postoperative complications by fracture type. RESULTS: Regarding the postoperative CT images, 189 subjects showed E results, 99 subjects showed G, 18 subjects showed F, and 7 subjects showed P reduction. The rate of operation results graded as E by each fracture type was 66.67% in FI, 52.0% in FII, 64.21% in LI, 62.79% in LII, and 21.74% in C. Complications of FI (7.14%), LII (13.95%), and C (13.04%) groups occurred more than in the FII (4.00%) and LI (4.21%) groups. CONCLUSION: It seems that the operation result by fracture type was better in the FI, LI, and LII type than the FII and C type; after one month, however, LII type showed more complications than other types. The septal fracture can be thought to affect early reduction results in nasal bone fractures. PMID- 28913301 TI - Concordant Surgical Treatment: Non-melanocytic Skin Cancer of the Head and Neck. AB - BACKGROUND: Skin cancer is the most common type of cancer. Of the 4 million skin lesions excised annually worldwide, approximately 2 million are considered cancerous. In this study, we aimed to describe a regional experience with skin cancers treated by a single senior surgeon and to provide a treatment algorithm. METHODS: The medical records of 176 patients with head and neck non-melanocytic skin cancer (NMSC) who were treated by a single surgeon at our institution between January 2010 and May 2016 were retrospectively reviewed, and their data (age, sex, pathological type, tumor location/size, treatment modality) were analyzed. Patients with cutaneous squamous cell carcinoma (cSCC) who were classified as a high-risk group for nodal metastasis underwent sentinel node mapping according to the National Comprehensive Cancer Network guidelines. RESULTS: Among the patients with NMSC who were treated during this period, basal cell carcinoma (BCC; n=102, 57.9%) was the most common pathological type, followed by cSCC (n=66, 37.5%). Most lesions were treated by complete excision, with tumor-free surgical margins determined via frozen section pathology. Thirty one patients with high-metastasis-risk cSCC underwent sentinel node mapping, and 17 (54.8%) exhibited radiologically positive sentinel nodes. Although these nodes were pathologically negative for metastasis, 2 patients (6.5%) later developed lymph node metastases. CONCLUSION: In our experience, BCC treatment should comprise wide excision with tumor-free surgical margins and proper reconstruction. In contrast, patients with cSCC should undergo lymphoscintigraphy, as nodal metastases are a possibility. Proper diagnosis and treatment could reduce the undesirably high morbidity and mortality rates. PMID- 28913302 TI - Eccrine Poroma of the Postauricular Area. AB - Eccrine poroma is a common benign cutaneous tumor that originates in an intraepidermal eccrine duct. This tumor exhibits acral distribution (sole, palm), and is rarely encountered in the head and neck area. In fact eccrine poroma in the postauricular area has only been rarely reported. A 55-year-old female visited our hospital with a main complaint of a mass that first developed in the left postauricular area about a year previously. The mass was painless, soft, protruding, domed, and dark red in color, and had slowly enlarged (at presentation it measured 1*1 cm). Excisional biopsy was performed. Histological examination showed distinct features, and eccrine poroma was diagnosed. Follow-up at 6 months postoperatively showed no recurrence. The frequency of eccrine poroma is dependent on eccrine sweat glands density, and thus, usually occurs on the palms or soles. For eccrine poroma in the head and neck region, the differential diagnosis must rule out other masses, such as nevus, skin tag, pyogenic granuloma, cyst, basal cell carcinoma, and seborrheic keratosis. Importantly, 18% of poromas show malignant transformation, and can develop into porocarcinoma. For these reasons, an eccrine poroma in the facial area requires histological examination, complete excision, and follow-up. PMID- 28913303 TI - Simultaneous Development of Three Different Neoplasms of Trichilemmoma, Desmoplastic Trichilemmoma and Basal Cell Carcinoma Arising from Nevus Sebaceus. AB - Nevus sebaceus is a hamartoma of the sebaceous gland that occurs congenitally, from which various secondary tumors can arise with a prevalence of 5%-6%. Benign neoplasms commonly arise from nevus sebaceous, but they have a very low malignant potential. Two neoplasms may occasionally arise within the same lesion, but it is rare for three or more neoplasms to occur in a nevus sebaceus simultaneously. A 61-year-old male patient was admitted to our hospital for a 4 cm*2.5 cm growing tumor in a verrucous form arising within a periauricular nevus sebaceus in the post auricle of the left ear that had developed 30 years earlier. The nodule was diagnosed as 3 different types of tumors: trichilemmoma, desmoplastic trichilemmoma, and basal cell carcinoma. To our knowledge, this is the first report of the coexistence of three different tumors arising from nevus sebaceous. It contain malignant neoplasm also. Surgeons should be aware of the need for close monitoring and early complete surgical excision of sebaceous nevus in order to improve patient outcomes. PMID- 28913304 TI - Trichilemmal Carcinoma from Proliferating Trichilemmal Cyst on the Posterior Neck. AB - Trichilemmal cysts are common fluid-filled growths that arise from the isthmus of the hair follicle. They can form rapidly multiplying trichilemmal tumors-, also called proliferating trichilemmal cysts, which are typically benign. Rarely, proliferating trichilemmal cysts can become cancerous. Here we report the case of a patient who experienced this series of changes. The 27-year-old male patient had been observed to have a 1*1 cm cyst 7 years ago. Eight months prior to presentation at our institution, incision and drainage was performed at his local clinic. However, the size of the mass had gradually increased. At our clinic, he presented with a 5*4 cm hard mass that had recurred on the posterior side of his neck. The tumor was removed without safety margin, and the skin defect was covered with a split-thickness skin graft. The pathologic diagnosis was a benign proliferating trichilemmal cyst. The mass recurred after 4months, at which point, a wide excision (1.3-cm safety margin) and split-thickness skin graft were performed. The biopsy revealed a trichilemmal carcinoma arising from a proliferating trichilemmal cyst. This clinical experience suggests that clinicians should consider the possibility of malignant changes when diagnosing and treating trichilemmal cysts. PMID- 28913305 TI - Treatment of Tongue Lymphangioma with Intralesional Combination Injection of Steroid, Bleomycin and Bevacizumab. AB - Lymphangioma is a congenital malformed lymphatic tumor that rarely involves the tongue. In our clinic, a 10-year-old female presented with lymphangioma circumscriptum involving the right two-thirds of the tongue. We administered an intralesional combination injection of triamcinolone, bleomycin, and bevacizumab as a treatment. Almost complete remission after combination therapy was achieved without complications such as edema, swallowing difficulties or recurrence. Bevacizumab, an inhibitor of vascular endothelial growth factor, was effective for the treatment of lymphangioma of the tongue in this case. No recurrence was noted at the 1-year follow up. PMID- 28913306 TI - Silicone Implant Sandwiched between Intact Nasal Bones with Fractured Nasal Bone Segments. AB - As the number of people who have undergone augmentation rhinoplasty has increased recently, nasal fractures are becoming more common after rhinoplasty. A silicone implant can affect the nasal fracture pattern, but there is no significant difference in treatment methods commonly. A 28-year-old female who had undergone augmentation visited our clinic with a nasal fracture. Computed tomography revealed that the silicone implant was sandwiched between the intact nasal bones with fractured bone fragments. In this case, open reduction was inevitable and a new silicone implant was inserted after reduction. Migration of the silicone implant beneath the nasal bone is a very rare phenomenon, but its accurate prevention and diagnosis is important because a closed reduction is impossible. PMID- 28913307 TI - Solitary Piloleiomyoma in the Scalp. AB - Cutaneous leiomyomas can be classified into three types according to the site of origin: piloleiomyoma, angioleiomyoma, and dartoic (genital) leiomyoma. It might be expected that leiomyomas are commonly found on the scalp because there are many arrector pili muscles and vessels. However, leiomyomas are actually rarely reported in the scalp. Recently, we observed a case of cutaneous leiomyoma in the scalp and present our experience along with a literature review. PMID- 28913308 TI - New Treatment in Facial Nerve Palsy Caused by Sagittal Split Ramus Osteotomy of Mandible. AB - A 25-years-old woman with mandibular prognathism underwent a mandibular setback by way of mandibular sagittal split ramus osteotomy (MSSRO). After 2 days of operation, she developed difficulty of closing her right eye. The blink reflex test and motor nerve conduction study of the right orbicularis oris muscle were revealed right facial neuropathy of unknown origin and House-Brackmann facial nerve grading system (HBFNGS) grade V. For treatment, we initially prescribed oral prednisolone and nimodipine including physical therapy. The samples consisted of 11 facial nerve palsy patients caused by MSSRO and were analysed about onset of facial nerve palsy, postoperative HBFNGS, final HBFNGS, treatment method and recovery time. At 10 weeks of treatment of nimodipine, she had completely regained normal function (HBFNGS grade I) of the right facial nerve. The clinical results lead to assume a fast recovery of facial nerve function by the nimodipine medication, whereas average time of recovery is 16.32 weeks in references. Despite of the limited one patient treated, the result was very promising with respect to a faster recovery of the facial nerve function. Considering the use of nimodipine treatment for peripheral facial nerve palsy following a surgical approach with an anatomically preserved nerve can be recommended. PMID- 28913309 TI - 2017 Spring Update: A Letter from the President of the Korean Cleft Palate Craniofacial Association. PMID- 28913310 TI - Treatment of Mandibular Angle Fractures. AB - The management of mandibular angle fractures is often challenging and results in the highest complication rate among fractures of the mandible. In addition, the optimal treatment modality for angle fractures remains controversial. Traditional treatment protocols for angle fractures have involved rigid fixation with intraoperative maxillomandibular fixation (MMF) to ensure absolute stability. However, more recently, non-compression miniplates have gained in popularity and the use of absolute intraoperative MMF as an adjunct to internal fixation has become controversial. In this article, the history of, and current trends in, the treatment of mandibular angle fractures will be briefly reviewed. In addition, issues regarding the management of the third molar tooth will be discussed. PMID- 28913311 TI - Usefulness of a Transconjunctival Approach in the Reconstruction of the Medial Blow-Out Wall Fracture. AB - BACKGROUND: A transcaruncular approach is typically used for reconstructions of medial wall fractures. However, others reported that a transconjunctival approach was conducive for securing an adequate surgical field of view. In this study, we aimed to examine the extent of repair of medial wall fracture via a transconjunctival approach. METHODS: We retrospectively reviewed the medical records of 50 patients diagnosed as having medial wall fracture via preoperative computed tomography and who underwent surgery between March 2011 and February 2014. The fracture location was defined by dividing each of the anterior posterior and superior-inferior distances into three compartments. RESULTS: A transcaruncular approach was used in 7 patients, while the transconjunctival approach was performed in the remaining 43 patients. The transconjunctival approach enabled a relatively broad range of repair that partially included the front and back of the medial wall, and was successful in 86% of the entire study population. CONCLUSION: It is known that more than 50% of total cases of the medial wall fracture occur mainly in the middle-middle portion, a majority of which can be reconstructed via a transconjunctival approach. We used a transconjunctival approach in identifying the location of the fracture on image scans except for cases including the fracture of the superior portion in patients with medial wall fracture. If it is possible to identify the location of the fracture, a transconjunctival approach would be an useful method for the reconstruction in that it causes no damages to the lacrimal system and is useful in confirming the overall status of the floor. PMID- 28913312 TI - The Efficacy of Coblator in Turbinoplasty. AB - BACKGROUND: Turbinate hypertrophy is one of the common causes of chronic nasal obstruction. In principle, therapeutic guidelines recommend medical treatment. Failure to treat turbinate thickening despite drug therapy may indicate the need for surgery. The main aim of this study was to determine the effect of radiofrequency surgery, among various other surgical procedures, on people with both nasal septal deviation and turbinate hypertrophy. METHODS: Among people with nasal deviation who visited the subject hospital between July 2008 to July 2014, 21 people with nasal septal deviation and severe turbinate hypertrophy before their surgery had undergone septoplasty with turbinoplasty using radiofrequency combined with septoplasty. The degree of the turbinate's hypertrophy was appraised in all the patients before and after the surgery using the rhinoscopy, and acoustic rhinometry was objectively carried out. The subjective effect of the turbinoplasty using radiofrequency was explored through the visual analog scale (VAS) score. RESULTS: The degree of contraction of the nasal mucosa after the rhinoscopy changed from Grades 3 and 4 (100%) to Grades 1 and 2 (95.2%) and Grades 3 (4.8%). The minimal cross-sectional area significantly increased from 0.44+/-0.07 to 0.70+/-0.07 cm2 (p<0.05). The nasal cavity volume increased from 4.79+/-0.49 to 6.76+/-0.55 cm2 (p<0.05). The subjective symptoms evaluated with VAS score a year after the surgery significantly improved (p<0.05). CONCLUSION: Turbinoplasty using Coblator with septoplasty is an effective treatment method because it expands nasal cavity, has a low incidence of complications, subjectively improves symptoms, and has short treatment duration. PMID- 28913313 TI - A Statistical Analysis of Superior Orbital Fissure Width in Korean Adults using Computed Tomography Scans. AB - BACKGROUND: The superior orbital fissure is a small area that connects the middle cranial fossa and the orbit. Many studies have measured the size of the superior orbital fissure. However, there is no standard value for the size of the superior orbital fissure. Therefore, we conducted this study to provide the average size of the superior orbital fissure in Korean adults. METHODS: We measured the widths of the superior orbital fissures of 142 patients using computed tomography scans. Because the width of the superior orbital fissure varies at different locations, we measured the superior orbital fissure width at the level of the optic canal. RESULTS: In the males, the width of the superior orbital fissure on both sides was 3.79+/-0.93 mm, and these values were 3.79+/-0.96 mm for the left side and 3.783+/-0.92 mm for the right side. In the females, the widths of the superior orbital fissures were 3.62+/-1.35 mm on the left side, 3.69+/-1.18 mm on the right side, and 3.65+/-1.26 mm across both sides. CONCLUSION: There were no significant differences between the males and females or between the left and right sides. The present study suggests that we may accept the hypothesis that a congenitally narrow superior orbital fissure may be a risk factor for the superior orbital fissure syndrome. Surgeons should take precaution with patients who have narrow superior orbital fissures during the perioperative period. PMID- 28913314 TI - Olfactory Dysfunction in Nasal Bone Fracture. AB - BACKGROUND: All nasal bone fractures have the potential for worsening of olfactory function. However, few studies have studied the olfactory outcomes following reduction of nasal bone fractures. This study evaluates posttraumatic olfactory dysfunction in patients with nasal bone fracture before and after closed reduction. METHODS: A prospective study was conducted for all patients presenting with nasal bone fracture (n=97). Each patient consenting to the study underwent the Korean version of Sniffin' Sticks test (KVSS II) before operation and at 6 month after closed reduction. The nasal fractures were divided according to the nasal bone fracture classification by Haug and Prather (Types I-IV). The olfactory scores were compared across fracture types and between preoperative and postoperative settings. RESULTS: Olfactory dysfunction was frequent after nasal fracture (45/97, 46.4%). Our olfactory assessment using the KVSS II test revealed that fracture reduction was not associated with improvements in the mean test score in Type I or Type II fractures. More specifically, the mean posttraumatic Threshold, discrimination and identification score decreased from 28.8 points prior to operation to 23.1 point at 6 months for Type II fracture with septal fracture. CONCLUSION: Our study has revealed two alarming trends regarding post nasal fracture olfactory dysfunction. First, our study demonstrated that almost half (46.4%) of nasal fracture patients experience posttraumatic olfactory dysfunction. Second, closed reduction of these fractures does not lead to improvements olfaction at 6 months, which suggest that olfactory dysfunction is probably due to factors other than the fracture itself. The association should be further explored between injuries that lead to nasal fracture and the mechanism behind posttraumatic olfactory dysfunction. PMID- 28913315 TI - The Algorithm-Oriented Management of Nasal Bone Fracture according to Stranc's Classification System. AB - BACKGROUND: Nasal bone fracture is one of the most common facial bone fracture types, and the surgical results exert a strong influence on the facial contour and patient satisfaction. Preventing secondary deformity and restoring the original bone state are the major goals of surgeons managing nasal bone fracture patients. In this study, a treatment algorithm was established by applying the modified open reduction technique and postoperative care for several years. METHODS: This article is a retrospective chart review of 417 patients who had been received surgical treatment from 2014 to 2015. Using prepared questionnaires and visual analogue scale, several components (postoperative nasal contour; degree of pain; minor complications like dry mouth, sleep disturbance, swallowing difficulty, conversation difficulty, and headache; and degree of patient satisfaction) were evaluated. RESULTS: The average scores for the postoperative nasal contour given by three experts, and the degree of patient satisfaction, were within the "satisfied" (4) to "very satisfied" (5) range (4.5, 4.6, 4.5, and 4.2, respectively). The postoperative degree of pain was sufficiently low that the patients needed only the minimum dose of painkiller. The scores for the minor complications (dry mouth, sleep disturbance, swallowing difficulty, conversation difficulty, headache) were relatively low (36.4, 40.8, 65.2, 32.3, and 34 out of the maximum score of 100, respectively). CONCLUSION: Satisfactory results were obtained through the algorithm-oriented management of nasal bone fracture. The degree of postoperative pain and minor complications were considerably low, and the degree of satisfaction with the nasal contour was high. PMID- 28913316 TI - Metastatic Squamous Cell Carcinoma of the Lower Lip: Analysis of the 5-Year Survival Rate. AB - OBJECTIVES: The author analyse the impact of extracapsular lymph node spread and bone engagement in the ipsilateral neck of patients suffering squamous cell carcinoma (SCC) of the lower lip. METHODS: The data of 56 neck dissections performed in patients suffering SCC of the lower lip between January 2000 and December 2008 were retrospectively analysed. Statistical analysis was performed with the Kaplan-Meier life table method, and the survival rate was investigated with the log rank statistic and significance test. The values were considered statistically significant at p<0.05. RESULTS: Nine patients took advantage from simultaneous treatment of tumor and prophylactic neck dissection (level I-III), reaching 100% survival rate. Patients suffering metastasized disease, who received radical neck dissection at the time of tumor treatment, presented 83.3% survival rate. Patients who underwent previous surgery and radiotherapy presented worse prognosis although radical neck dissection in case of extra-capsular spread only (24.7%) and osseous engagement (22.2%). CONCLUSION: Prophylactic neck dissection (level I-III) is recommended in T3-T4 N0 SCC. Simultaneous treatment of tumor and cervical lymph nodes provides a better prognosis as respect to delayed nodal management. Extra-capsular spread with or without bone engagement represents independent risk factor responsible for high mortality rate of SCC of the lower lip. PMID- 28913317 TI - Reconstruction of a Complex Scalp Defect after the Failure of Free Flaps: Changing Plans and Strategy. AB - The ideal scalp reconstruction involves closure of the defect with similar hair bearing local tissue in a single step. Various reconstructions can be used including primary closure, secondary healing, skin grafts, local flaps, and microvascular tissue transfer. A 53-year-old female patient suffered glioblastoma, which had recurred for the second time. The neurosurgeons performed radial debridement and an additional resection of the tumor, followed by reconstruction using a serratus anterior muscle flap with a split-thickness skin graft. Unfortunately, the flap became completely useless and a bilateral rotation flap was used to cover the defect. Two month later, seroma with infection was found due to recurrence of the tumor. Additional surgery was performed using multiple perforator based island flap. The patient was discharged two weeks after surgery without any complications, but two months later, the patient died. Radical surgical resection of tumor is the most important curative option, followed by functional and aesthetic reconstruction. We describe a patient with a highly malignant tumor that required multiple resections and subsequent reconstruction. Repeated recurrences of the tumor led to the failure of reconstruction and our strategy inevitably changed, from reconstruction to palliative treatment involving fast and stable wound closure for the patient's comfort. PMID- 28913318 TI - Modified Anterior Craniofacial Osteotomy Using Partial Nasal Bone Division and Reconstruction in Frontoethmoidal Sinus Meningioma. AB - Typical transcranial approaches are insufficient for adequate visualization and resection of skull base tumors. Different approaches with multiple modifications have been attempted. Here, we describe a new approach for a lesion that is central and hard to treat by conventional craniotomy and successful reconstruction with calvarial bone graft and titanium mesh plate. A 69-year-old female patient presented with recurrent meningioma. The tumor had invaded the frontal lobe, right supraorbital rim, and ethmoidal bone. We performed a modified anterior craniofacial approach that fully exposed the tumor and invaded bone. In consideration of the patient's age and cosmetic result, the tumor and invaded bone was resected and the defect area was reconstructed with titanium mesh and calvarial bone graft. At 6 months postoperative the patient had no complications and was satisfied with the esthetic result. We report this case to demonstrate the successful approach and reconstruction using this technique. PMID- 28913319 TI - Rare Location of Castleman's Disease in the Temporal Region: A Case Report Involving a Young Korean Woman and Review of the Literature. AB - Castleman's disease (CD) is an uncommon benign lymphoproliferative disorder of unknown etiology. Histopathologically, it is divided into three types: hyaline vascular, plasma cellular, and multicentric CD. The mass usually presents asymptomatically; however, it can cause non-specific symptoms such as fever and fatigue. Although CD can be found wherever lymph nodes are present, 75% of cases are reported in the mediastinum, and occurrence in the head and neck is rare. Herein, we report a rare case of CD presenting as a superficial mass in the temporal region. To the best of our knowledge, this is the first report of temporal CD in Korea involving a young patient. PMID- 28913320 TI - Pediatric Orbital Medial Wall Trapdoor Fracture with Normal Computed Tomography Findings. AB - With advances in diagnostic technology, radiologic diagnostic methods have been used more frequently, and physical examination may be neglected. The authors report a case of pediatric medial orbital trapdoor fracture in which the surgery was delayed because computed tomography (CT) findings did not indicate bone displacement, incarceration of rectus muscle, or soft tissue herniation. A healthy 6-year-old boy was admitted to the emergency room for right eyebrow laceration. We could not check eyeball movement or diplopia, because the patient was irritable. Thus, we performed facial CT under sedation, but there was normal CT finding. Seven days later, the patient visited our hospital due to persistent nausea and dizziness. We were able to perform a physical examination this time. Lateral gaze of right eye was limited. CT still did not show any findings suggestive of fracture, but we decided to perform exploratory surgery. We performed exploration, and found no bone displacement, but discovered entrapped soft tissue. We returned the soft tissue to its original position. The patient fully recovered six weeks later. To enable early detection and treatment, thorough physical examination and CT reading are especially needed when the patient shows poor compliance, and frequent follow-up observations are also necessary. PMID- 28913321 TI - Mixed Tumor in Deep Lobe and Versatility of Acellular Dermal Matrix. AB - Frey's syndrome and infra-auricular depressed deformities are the ones of the most common complications that can occur after total parotidectomy. We report 1 case of pleomorphic adenoma occurred in the deep lobe that obtained good results from using acellular dermal matrix (ADM) after total parotidectomy. A 24-year-old man visited the hospital with oval shape mass in right mandibular angle which of 4 cm in size was found in the deep lobe of right parotid gland from Magnetic resonance imaging scanning and a pleomorphic adenoma was suspected. A total parotidectomy was performed while preserving the facial nerve. The material known as ADM were placed in the depressed part from where the mass was removed, and the site was sutured. The surgery site was healed well without any complications such as Frey's syndrome or infra-auricular depressed deformities. The pathological result was confirmed as pleomorphic adenoma. In addition to these advantages, it does not have little potential of deformation by the gravity after the surgery, and there is no restraint on circulation, which makes fabrication free and each deformation into various shapes can be described as another advantage of the reconstruction using the ADM. PMID- 28913322 TI - Late Complication of a Silicone Implant Thirty Years after Orbital Fracture Reconstruction. AB - Alloplastic materials used for orbital fracture reconstruction can induce complications, such as infection, migration, extrusion, intraorbital hemorrhage, and residual diplopia. Silicone is one of the alloplastic materials that has been widely used for decades. The author reports a rare case of spontaneous extrusion of a silicone implant that was used for orbital fracture reconstruction 30 years earlier. A 50-year-old man was admitted to the emergency room for an exposed substance in the lower eyelid area of the left eye, which began as a palpable hard nodule a week earlier. The exposed material was considered to be implant used for previous surgery. Under general anesthesia, the implant and parts of the fibrous capsule tissue were removed. Several factors hinder the diagnosis of implant extrusions that occur a long period after the surgery. So, surgeons must be aware that complications with implants can still arise several decades following orbital fracture reconstruction, even without specific causes. PMID- 28913323 TI - Cutaneous Basal Cell Carcinoma Arising in Odontogenic Cutaneous Fistula. AB - An odontogenic cutaneous fistula is a pathological communication between the outer skin surface of the face and the oral cavity. Facial cutaneous fistula is a complication of odontogenic infection that is often misdiagnosed with skin infection. We report a rare case, which was diagnosed as basal cell carcinoma based on the biopsy of skin lesions in the patient who had been diagnosed with odontogenic cutaneous fistula. A 64-year-old male patient presented with a cutaneous odontogenic fistula. The patient had undergone surgical extraction of fistula tract and loose tooth before dermatology or plastic surgery consultation. With the biopsy and computed tomography, it was confirmed that fistula and basal cell carcinoma. However, the connection between the fistula and skin cancer was not clear. Positron emission tomography-computed tomography scan was performed and was not detected as other local or distant metastasis. After that, wide excision of the skin lesion was performed. Although skin cancer is not commonly observed, it is necessary to rule out this disease entity by performing biopsy of skin lesions. PMID- 28913324 TI - Cutaneous Leiomyosarcoma of the Face. AB - Cutaneous leiomyosarcoma is an uncommon superficial soft tissue sarcoma and mainly found in the middle aged to elderly males. It can occur in any part of the body, mostly affecting the extremities and rarely affecting the face. It grows relatively slowly, can be diagnosed by biopsy and is treated by surgical excision. It needs to be distinguished from other spindle cell neoplasms, and immunohistochemical markers are usually required to attain an accurate diagnosis. We report a case of cutaneous leiomyosarcoma appeared on the left cheek within 6 month of a 73-year-old female patient suspected with malignant melanoma before surgery. PMID- 28913325 TI - Bone Loss Prevention of Bisphosphonates in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of bisphosphonates in improving bone mineral density (BMD) and decreasing the occurrence rate of fractures and adverse events in patients with inflammatory bowel disease (IBD). METHODS: Randomized controlled trials (RCTs) which use bisphosphonates in IBD patients were identified in PubMed, MEDLINE database, EMBASE database, Web of Knowledge, and the Cochrane Databases between 1990 and June 2016. People received bisphosphonate or placebos with a follow-up of at least one year were also considered. STATA 12.0 software was used for the meta analysis. RESULTS: Eleven randomized clinical trials were included in the meta analysis. The data indicated that the percentage change in the increased BMD in the bisphosphonates groups was superior to that of the control groups at the lumbar spine and total hip. At the femoral neck, there was no significant difference between the two groups. The incidence of new fractures during follow up showed significant reduction. The adverse event analysis revealed no significant difference between the two groups. CONCLUSION: Our results demonstrate that bisphosphonates therapy has an effect on bone loss in patients with IBD but show no evident efficiency at increasing the incidence of adverse events. PMID- 28913326 TI - Improvement in White Matter Tract Reconstruction with Constrained Spherical Deconvolution and Track Density Mapping in Low Angular Resolution Data: A Pediatric Study and Literature Review. AB - INTRODUCTION: Diffusion-weighted magnetic resonance imaging (DW-MRI) allows noninvasive investigation of brain structure in vivo. Diffusion tensor imaging (DTI) is a frequently used application of DW-MRI that assumes a single main diffusion direction per voxel, and is therefore not well suited for reconstructing crossing fiber tracts. Among the solutions developed to overcome this problem, constrained spherical deconvolution with probabilistic tractography (CSD-PT) has provided superior quality results in clinical settings on adult subjects; however, it requires particular acquisition parameters and long sequences, which may limit clinical usage in the pediatric age group. The aim of this work was to compare the results of DTI with those of track density imaging (TDI) maps and CSD-PT on data from neonates and children, acquired with low angular resolution and low b-value diffusion sequences commonly used in pediatric clinical MRI examinations. MATERIALS AND METHODS: We analyzed DW-MRI studies of 50 children (eight neonates aged 3-28 days, 20 infants aged 1-8 months, and 22 children aged 2-17 years) acquired on a 1.5 T Philips scanner using 34 gradient directions and a b-value of 1,000 s/mm2. Other sequence parameters included 60 axial slices; acquisition matrix, 128 * 128; average scan time, 5:34 min; voxel size, 1.75 mm * 1.75 mm * 2 mm; one b = 0 image. For each subject, we computed principal eigenvector (EV) maps and directionally encoded color TDI maps (DEC-TDI maps) from whole-brain tractograms obtained with CSD-PT; the cerebellar-thalamic, corticopontocerebellar, and corticospinal tracts were reconstructed using both CSD-PT and DTI. Results were compared by two neuroradiologists using a 5-point qualitative score. RESULTS: The DEC-TDI maps obtained presented higher anatomical detail than EV maps, as assessed by visual inspection. In all subjects, white matter (WM) tracts were successfully reconstructed using both tractography methodologies. The mean qualitative scores of all tracts obtained with CSD-PT were significantly higher than those obtained with DTI (p-value < 0.05 for all comparisons). CONCLUSION: CSD-PT can be successfully applied to DW-MRI studies acquired at 1.5 T with acquisition parameters adapted for pediatric subjects, thus providing TDI maps with greater anatomical detail. This methodology yields satisfactory results for clinical purposes in the pediatric age group. PMID- 28913328 TI - Editorial: Oesophageal Atresia-Tracheoesophageal Fistula. PMID- 28913327 TI - In Vivo Evaluation of the Acute Pulmonary Response to Poractant Alfa and Bovactant Treatments in Lung-Lavaged Adult Rabbits and in Preterm Lambs with Respiratory Distress Syndrome. AB - BACKGROUND: Poractant alfa (Curosurf(r)) and Bovactant (Alveofact(r)) are two animal-derived pulmonary surfactants preparations approved for the treatment of neonatal respiratory distress syndrome (nRDS). They differ in their source, composition, pharmaceutical form, and clinical dose. How much these differences affect the acute pulmonary response to treatment is unknown. OBJECTIVES: Comparing these two surfactant preparations in two different animal models of respiratory distress focusing on the short-term response to treatment. METHODS: Poractant alfa and Bovactant were administered in a 50-200 mg/kg dose range to surfactant-depleted adult rabbits with acute respiratory distress syndrome induced by lavage and to preterm lambs (127-129 days gestational age) with nRDS induced by developmental immaturity. The acute impact of surfactant therapy on gas exchange and pulmonary mechanics was assessed for 1 h in surfactant-depleted rabbits and for 3 h in preterm lambs. RESULTS: Overall, treatment with Bovactant 50 mg/kg or Poractant alfa 50 mg/kg did not achieve full recovery of the rabbits' respiratory conditions, as indicated by significantly lower arterial oxygenation and carbon dioxide values. By contrast, the two approved doses for clinical use of Poractant alfa (100 and 200 mg/kg) achieved a rapid and sustained recovery in both animal models. The comparison of the ventilation indices of the licensed doses of Bovactant (50 mg/kg) and Poractant alfa (100 mg/kg) showed a superior performance of the latter preparation in both animal models. At equal phospholipid doses, Poractant alfa was superior to Bovactant in terms of arterial oxygenation in both animal models. In preterm lambs, surfactant replacement therapy with Poractant alfa at either 100 or 200 mg/kg was associated with significantly higher lung gas volumes compared to Bovactant treatment with 100 mg/kg. CONCLUSION: At the licensed doses, the acute pulmonary response to Poractant alfa was significantly better than the one observed after Bovactant treatment, either at 50 or at 100 mg/kg dose, in two animal models of pulmonary failure. PMID- 28913329 TI - Structured Transition Protocol for Children with Cystinosis. AB - The transition from pediatric to adult medical services has a greater impact on the care of adolescents or young adults with chronic diseases such as cystinosis. This transition period is a time of psychosocial development and new responsibilities placing these patients at increased risk of non-adherence. This can lead to serious adverse effects such as graft loss and progression of the disease. Our transition protocol will provide patients, families, physicians, and all those involved a structured guide to transitioning cystinosis patients. This structured protocol depends on four areas of competency: Recognition, Insight, Self-reliance, and Establishment of healthy habits (RISE). This protocol has not been tested and therefore challenges not realized. With a focus on medical, social, and educational/vocational aspects, we aim to improve transition for cystinosis patients in all aspects of their lives. PMID- 28913330 TI - Resurgence of Diphtheria in North Kerala, India, 2016: Laboratory Supported Case Based Surveillance Outcomes. AB - INTRODUCTION: As part of national program, laboratory supported vaccine preventable diseases surveillance was initiated in Kerala in 2015. Mechanisms have been strengthened for case investigation, reporting, and data management. Specimens collected and sent to state and reference laboratories for confirmation and molecular surveillance. The major objective of this study is to understand the epidemiological information generated through surveillance system and its utilization for action. METHODS: Surveillance data captured from reporting register, case investigation forms, and laboratory reports was analyzed. Cases were allotted unique ID and no personal identifying information was used for analysis. Throat swabs were collected from investigated cases as part of surveillance system. All Corynebacterium diphtheriae isolates were confirmed with standard biochemical tests, ELEK's test, and real-time PCR. Isolates were characterized using whole genome-based multi locus sequence typing method. Case investigation forms and laboratory results were recorded electronically. Public health response by government was also reviewed. RESULTS: A total of 533 cases were identified in 11 districts of Kerala in 2016, of which 92% occurred in 3 districts of north Kerala; Malappuram, Kozhikode, and Kannur. Almost 79% cases occurred in >10 years age group. In <18 years age group, 62% were male while in >=18 years, 69% were females. In <10 years age group, 31% children had received three doses of diphtheria vaccine, whereas in >=10 years, 3% cases had received all doses. Fifteen toxigenic C. diphtheriae isolates represented 6 novel sequence types (STs) (ST-405, ST-408, ST-466, ST-468, ST-469, and ST-470). Other STs observed are ST-50, ST-295, and ST-377. CONCLUSION: Diphtheria being an emerging pathogen, establishing quality surveillance for providing real-time information on disease occurrence and mortality is imperative. The epidemiological data thus generated was used for targeted interventions and to formulate vaccine policies. The data on molecular surveillance have given an insight on strain variation and transmission patterns. PMID- 28913331 TI - Health Effects and Public Health Concerns of Energy Drink Consumption in the United States: A Mini-Review. AB - As energy drink consumption continues to grow worldwide and within the United States, it is important to critically examine the nutritional content and effects on population health of these beverages. This mini-review summarizes the current scientific evidence on health consequences from energy drink consumption, presents relevant public health challenges, and proposes recommendations to mitigate these issues. Emerging evidence has linked energy drink consumption with a number of negative health consequences such as risk-seeking behaviors, poor mental health, adverse cardiovascular effects, and metabolic, renal, or dental conditions. Despite the consistency in evidence, most studies are of cross sectional design or focus almost exclusively on the effect of caffeine and sugar, failing to address potentially harmful effects of other ingredients. The negative health effects associated with energy drinks (ED) are compounded by a lack of regulatory oversight and aggressive marketing by the industry toward adolescents. Moreover, the rising trend of mixing ED with alcohol presents a new challenge that researchers and public health practitioners must address further. To curb this growing public health issue, policy makers should consider creating a separate regulatory category for ED, setting an evidence-based upper limit on caffeine, restricting sales of ED, and regulating existing ED marketing strategies, especially among children and adolescents. PMID- 28913332 TI - The Impact of Disclosure on Health and Related Outcomes in Human Immunodeficiency Virus-Infected Children: A Literature Review. AB - This review explores the association between pediatric human immunodeficiency virus (HIV) disclosure and health and related outcomes among children living with HIV. A multi-stage process was used to search for relevant articles on the ISI Web of Knowledge database. Fifteen articles met the inclusion criteria. Five major outcomes emerged from children's knowledge of their HIV-seropositive status: physical/physiological outcomes; adherence to antiretroviral therapy; psychosocial outcomes; sexual and reproductive health, including HIV prevention outcomes; and disclosure of status by the children. Disclosure of a child's HIV status to the child has value in terms of positive health outcomes for the child, such as better adherence and slower disease progression-albeit the different studies did not always reach the same conclusions, and some suggest negative health outcomes, such as increased psychiatric hospitalization. Yet, there does not seem to be a systematic or coherent system for child disclosure. One recommendation from this review, therefore, is for government and program policies and guidelines that will promote child HIV disclosure in order to address the current low rates of disclosure in sub-Saharan Africa (SSA). More rigorous and longitudinal studies on the outcomes of disclosure, with larger sample sizes, and in SSA, are also needed. PMID- 28913333 TI - Utilization of Parenteral Morphine by Application of ATC/DDD Methodology: Retrospective Study in the Referral Teaching Hospital. AB - BACKGROUND: Few studies analyzed the pattern of opioid analgesic utilization in hospital settings. The aim of this study was to determine the consumption pattern of parenteral morphine in patients hospitalized in the Serbian referral teaching hospital and to correlate it with utilization at the national and international level. METHODS: In retrospective study, the required data were extracted from medical records of surgical patients who received parenteral morphine in the 5 year period, from 2011 to 2015. We used the Anatomical Therapeutic Chemical Classification/Defined Daily Doses (DDD) international system for consumption evaluation. RESULTS: While the number of performed surgical procedures in our hospital steadily increased from 2011 to 2015, the number of inpatient bed-days decreased from 2012. However, the consumption of parenteral morphine varied and was not more than 0.867 DDD/100 bed-days in the observed period. CONCLUSION: Based on the available data, parenteral morphine consumption in our hospital was lower compared with international data. The low level of morphine use in the hospital was in accordance with national data, and compared with other countries, morphine consumption applied for medical indications in Serbia was low. Adequate legal provision to ensure the availability of opioids, better education and training of medical personnel, as well as multidisciplinary approach should enable more rational and individual pain management in the future, not only within the hospitals. PMID- 28913334 TI - Editorial: Signaling Pathways in Embryonic Development. PMID- 28913335 TI - Extracellular Vesicle Flow Cytometry Analysis and Standardization. AB - The term extracellular vesicles (EVs) describes membranous vesicles derived from cells, ranging in diameter from 30 to 1,000 nm with the majority thought to be in the region of 100-150 nm. Due to their small diameter and complex and variable composition, conventional techniques have struggled to accurately count and phenotype EVs. Currently, EV characterization using high-resolution flow cytometry is the most promising method when compared to other currently available techniques, due to it being a high-throughput, single particle, multi-parameter analysis technique capable of analyzing a large range of particle diameters. Whilst high resolution flow cytometry promises detection of the full EV diameter range, standardization of light scattering and fluorescence data between different flow cytometers remains an problem. In this mini review, we will discuss the advances in high-resolution flow cytometry development and future direction of EV scatter and fluorescence standardization. Standardization and therefore reproducibility between research groups and instrumentation is lacking, hindering the validation of EVs use as diagnostic biomarkers and therapeutics. PMID- 28913336 TI - Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma. AB - The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response). PMID- 28913337 TI - New Insights into the Pathogenesis of Celiac Disease. AB - Celiac disease (CD) is an autoimmune and multisystem gluten-related disorder that causes symptoms involving the gastrointestinal tract and other organs. Pathogenesis of CD is only partially known. It had been established that ingestion of gluten proteins present in wheat and other cereals are necessary for the disease and develops in individuals genetically predisposed carrying the DQ2 or DQ8 human leukocyte antigen haplotypes. In this review, we had pay specific attention on the last discoveries regarding the three cellular components mainly involved in the development and maintenance of CD: T-cells, B-cells, and microbioma. All of them had been showed critical for the interaction between inflammatory immune response and gluten peptides. Although the mechanisms of interaction among overall these components are not yet fully understood, recent proteomics and molecular studies had shed some lights in the pathogenic role of tissue transglutaminase 2 in CD and in the alteration of the intestinal barrier function induced by host microbiota. PMID- 28913338 TI - Clinical Validation of a Pixon-Based Reconstruction Method Allowing a Twofold Reduction in Planar Images Time of 111In-Pentetreotide Somatostatin Receptor Scintigraphy. AB - OBJECTIVE: The objective of this study was to evaluate the diagnostic efficacy of Pixon-based reconstruction method on planar somatostatin receptor scintigraphy (SRS). METHODS: All patients with neuroendocrine tumors (NETs) disease who were referred for SRS to our department during 1-year period from January to December 2015 were consecutively included. Three nuclear physicians independently reviewed all the data sets of images which included conventional images (CI; 15 min/view) and processed images (PI) obtained by reconstructing the first 450 s extracted data using Oncoflash(r) software package. Image analysis using a 3-point rating scale for abnormal uptake of 111 Indium-DTPA-Phe-octreotide in any lesion or organ was interpreted as positive, uncertain, or negative for the evidence of NET disease. A maximum grade uptake of the radiotracer in the lesion was assessed by the Krenning scale method. The results of image interpretation by the two methods were considered significantly discordant when the difference in organ involvement assessment was negative vs. positive or in lesion uptake was >=2 grades. Agreement between the results of two methods and by different scan observers was evaluated using Cohen kappa coefficients. RESULTS: There was no significant (p = 0.403) correlation between data acquisition protocol and quality image. The rates of significant discrepancies for exam interpretation and organs involvement assessment were 2.8 and 2.6%, respectively. Mean kappa values revealed a good agreement for concordance between CI and PI interpretation without difference of agreement for inter/intra-observer analysis. CONCLUSION: Our results suggest the feasibility to use a Pixon-based reconstruction method for SRS planar images allowing a twofold reduction of acquisition time and without significant alteration of image quality or on image interpretation. PMID- 28913339 TI - Ulcerative Gastritis and Esophagitis in Two Children with Sarcina ventriculi Infection. AB - Sarcina ventriculi is a Gram-positive, obligate anaerobic coccus, with a characteristic morphology. Only 22 cases of human infections by this microorganism, including 7 in children, have been reported in literature so far. Affected subjects usually present with abdominal pain, nausea, vomiting, and delayed gastric emptying. However, life-threatening complications, like emphysematous gastritis and gastric perforation have also been described. Gastroparesis and gastric outlet obstruction have been considered as a potential etiologic factor. All pediatric cases described thus far presented with concomitant gastrointestinal pathology, such as Helicobacter pylori gastritis, celiac disease, infection with Giardia lamblia or Candida spp. Here, we report two children with S. ventriculi infection, in whom the diagnosis was established by typical histological findings in mucosal biopsies. The first child presented with hematemesis due to ulcerative esophagitis and gastritis, the second child with a history of esophageal stricture had ulcerative gastritis. Confirmation of S. ventriculi infection is feasible by molecular microbiota detection methods, since this microorganism cannot be detected by classical culture techniques. Prompt treatment with antibiotics could prevent life-threatening complications. PMID- 28913340 TI - Caregiver Reports of Interactions between Children up to 6 Years and Their Family Dog-Implications for Dog Bite Prevention. AB - In children up to 6 years, interactions such as interfering with the dog's resources and also benign behaviors (e.g., petting) commonly precede a bite incident with the family dog. Therefore, the aim of the present study was to explore the development of everyday interactions between children up to 6 years and their family dogs and whether parents' attitudes to supervision are related to those interactions. Additionally, we investigated whether behavior of dogs that had lived in the family for longer than the child differed from those that grew up with children. A self-selected sample of caregivers living with a child up to 6 years and a family dog was surveyed via an online questionnaire (N = 402). Frequency of observed child behaviors directed toward the dog and dog behaviors directed toward the child were scored on a six-point scale (1-never and 6-very often). Data on characteristics of the caregiver, the child, and the dog were collected, and a section surveying attitudes to supervision of child-dog interactions was included. Additionally, we asked whether the dog already injured the child. Benign child behaviors toward dogs were most frequently reported (mean +/- SD: 4.1 +/- 1.2), increased with child age (rs = 0.38, p < 0.001), and reached high levels from 6 months on. Overall, resource-related interactions were relatively infrequent (2.1 +/- 1.1). Most common was the dog allowing the child to take objects from its mouth (4.1 +/- 1.7). This behavior was more common with older children (rs = 0.37, p < 0.001). Reported injuries during resource-related interactions occurred while feeding treats or taking objects from the dog during fetch play. Dogs that had lived in the family for longer than the child showed less affiliative behaviors toward the child (e.g., energetic affiliative: U = 7.171, p < 0.001) and more fear-related behaviors (U = -3.581, p < 0.001). Finally, the caregivers' attitudes to supervision were related to all child behaviors (e.g., allow unsafe behaviors-benign child behavior: rs = 0.47, p < 0.001). The results of this study underline the need for a dog bite prevention approach directed toward the caregivers very early in the child-dog relationship, taking into account the child's age and individual needs of the dog. PMID- 28913341 TI - Assessing the Risk of a Canine Rabies Incursion in Northern Australia. AB - Rabies is a globally distributed virus that causes approximately 60,00 human deaths annually with >99% of cases caused by dog bites. Australia is currently canine rabies free. However, the recent eastward spread of rabies in the Indonesian archipelago has increased the probability of rabies entry into northern Australian communities. In addition, many northern Australian communities have large populations of free-roaming dogs, capable of maintaining rabies should an incursion occur. A risk assessment of rabies entry and transmission into these communities is needed to target control and surveillance measures. Illegal transportation of rabies-infected dogs via boat landings is a high-risk entry pathway and was the focus of the current study. A quantitative, stochastic, risk assessment model was developed to evaluate the risk of rabies entry into north-west Cape York Peninsula, Australia, and rabies introduction to resident dogs in one of the communities via transport of rabies-infected dogs on illegal Indonesian fishing boats. Parameter distributions were derived from expert opinion, literature, and analysis of field studies. The estimated median probability of rabies entry into north-west Cape York Peninsula and into Seisia from individual fishing boats was 1.9 * 10-4/boat and 8.7 * 10-6/boat, respectively. The estimated annual probability that at least one rabies-infected dog enters north-west Cape York Peninsula and into Seisia was 5.5 * 10-3 and 3.5 * 10-4, respectively. The estimated median probability of rabies introduction into Seisia was 4.7 * 10-8/boat, and the estimated annual probability that at least one rabies-infected dog causes rabies transmission in a resident Seisia dog was 8.3 * 10-5. Sensitivity analysis using the Sobol method highlighted some parameters as influential, including but not limited to the prevalence of rabies in Indonesia, the probability of a dog on board an Indonesian fishing boat, and the probability of a Seisia dog being on the beach. Overall, the probabilities of rabies entry into north-west Cape York Peninsula and rabies introduction into Seisia are low. However, the potential devastating consequences of a rabies incursion in this region make this a non-negligible risk. PMID- 28913342 TI - Editorial: Towards Elimination of Dog Mediated Human Rabies. PMID- 28913344 TI - Farnesol inhibits translation to limit growth and filamentation in C. albicans and S. cerevisiae. AB - Candida albicans is a polymorphic yeast where the capacity to switch between yeast and filamentous growth is critical for pathogenicity. Farnesol is a quorum sensing sesquiterpene alcohol that, via regulation of specific signalling and transcription components, inhibits filamentous growth in Candida albicans. Here we show that farnesol also inhibits translation at the initiation step in both Candida albicans and S. cerevisiae. In contrast to fusel alcohols, that target the eukaryotic initiation factor 2B (eIF2B), farnesol affects the interaction of the mRNA with the small ribosomal subunit leading to reduced levels of the 48S preinitiation ribosomal complex in S. cerevisiae. Therefore, farnesol targets a different step in the translation pathway than fusel alcohols to elicit a completely opposite physiological outcome by negating filamentous growth. PMID- 28913345 TI - A yeast model for the mechanism of the Epstein-Barr virus immune evasion identifies a new therapeutic target to interfere with the virus stealthiness. AB - The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome replication and maintenance but also highly antigenic. Hence, EBV evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA at a minimal level to ensure its essential function thereby, at the same time, minimizing immune recognition. Defining intervention points where to interfere with EBNA1 immune evasion is an important step to trigger an immune response against EBV-carrying cancers. Thanks to a yeast-based assay that recapitulates all the aspects of EBNA1 self-limitation of expression, a recent study by Lista et al. [Nature Communications (2017) 7, 435 444] has uncovered the role of the host cell nucleolin (NCL) in this process via a direct interaction of this protein with G-quadruplexes (G4) formed in GAr encoding sequence of EBNA1 mRNA. In addition, the G4 ligand PhenDC3 prevents NCL binding on EBNA1 mRNA and reverses GAr-mediated repression of translation and antigen presentation. This shows that the NCL-EBNA1 mRNA interaction is a relevant therapeutic target to unveil EBV-carrying cancers to the immune system and that the yeast model can be successfully used for uncovering drugs and host factors that interfere with EBV stealthiness. PMID- 28913343 TI - Exacerbating and reversing lysosomal storage diseases: from yeast to humans. AB - Lysosomal storage diseases (LSDs) arise from monogenic deficiencies in lysosomal proteins and pathways and are characterized by a tissue-wide accumulation of a vast variety of macromolecules, normally specific to each genetic lesion. Strategies for treatment of LSDs commonly depend on reduction of the offending metabolite(s) by substrate depletion or enzyme replacement. However, at least 44 of the ~50 LSDs are currently recalcitrant to intervention. Murine models have provided significant insights into our understanding of many LSD mechanisms; however, these systems do not readily permit phenotypic screening of compound libraries, or the establishment of genetic or gene-environment interaction networks. Many of the genes causing LSDs are evolutionarily conserved, thus facilitating the application of models system to provide additional insight into LSDs. Here, we review the utility of yeast models of 3 LSDs: Batten disease, cystinosis, and Niemann-Pick type C disease. We will focus on the translation of research from yeast models into human patients suffering from these LSDs. We will also discuss the use of yeast models to investigate the penetrance of LSDs, such as Niemann-Pick type C disease, into more prevalent syndromes including viral infection and obesity. PMID- 28913346 TI - Live fast, die fast principle in a single cell of fission yeast. AB - Growth and death are both fundamental macroscopic properties for all living matters, and thus cell division and mortality rates are good parameters for characterizing cellular physiology in a given environment. While population growth rates in various conditions have been reported in literature, death rate is rarely measured, especially in favorable culture conditions where cells grow exponentially. In our recent study (Nakaoka and Wakamoto, 2017), we developed a microfluidics-based platform to track multiple single cell lineages until death. The system enabled us to monitor both cell growth and death in controlled steady environments, and we confirmed the absence of replicative aging in fission yeast old-pole cell lineages by showing remarkable constancy both in cell division and mortality rates. Furthermore, we revealed a growth-death trade-off relation in non-stressed conditions. The phenomenological law that constrains macroscopic physiological parameters could provide a new quantitative insight into possible balanced-growth states in various environments. PMID- 28913348 TI - The Use of Partial Least Square Regression and Spectral Data in UV-Visible Region for Quantification of Adulteration in Indonesian Palm Civet Coffee. AB - Asian palm civet coffee or kopi luwak (Indonesian words for coffee and palm civet) is well known as the world's priciest and rarest coffee. To protect the authenticity of luwak coffee and protect consumer from luwak coffee adulteration, it is very important to develop a robust and simple method for determining the adulteration of luwak coffee. In this research, the use of UV-Visible spectra combined with PLSR was evaluated to establish rapid and simple methods for quantification of adulteration in luwak-arabica coffee blend. Several preprocessing methods were tested and the results show that most of the preprocessing spectra were effective in improving the quality of calibration models with the best PLS calibration model selected for Savitzky-Golay smoothing spectra which had the lowest RMSECV (0.039) and highest RPDcal value (4.64). Using this PLS model, a prediction for quantification of luwak content was calculated and resulted in satisfactory prediction performance with high both RPD p and RER values. PMID- 28913347 TI - Haplotypes for Type, Degree, and Rate of Marbling in Cattle Are Syntenic with Human Muscular Dystrophy. AB - Traditional analyses of a QTL on Bota 19 implicate a surfeit of candidates, but each is of marginal significance in explaining the deposition of healthy, low melting temperature fat within marbled muscle of Wagyu cattle. As an alternative approach, we have used genomic, multigenerational segregation to identify 14 conserved, ancestral 20 Mb haplotypes. These determine the degree and rate of marbling in Wagyu and other breeds of cattle. The melting temperature of intramuscular fat is highly heritable and traceable by haplotyping. Fortunately, for the production of healthy beef, some of these haplotypes are sufficiently penetrant to be expressed in heterozygous crossbreds, thereby allowing selection of sires which will improve the healthiness of beef produced under even harsh climatic conditions. The region of Bota 19 is syntenic to a region of Hosa 17 known to be important in muscle metabolism and in determining susceptibility to a form of human muscular dystrophy. PMID- 28913349 TI - Brain-Computer Interface for Clinical Purposes: Cognitive Assessment and Rehabilitation. AB - Alongside the best-known applications of brain-computer interface (BCI) technology for restoring communication abilities and controlling external devices, we present the state of the art of BCI use for cognitive assessment and training purposes. We first describe some preliminary attempts to develop verbal motor free BCI-based tests for evaluating specific or multiple cognitive domains in patients with Amyotrophic Lateral Sclerosis, disorders of consciousness, and other neurological diseases. Then we present the more heterogeneous and advanced field of BCI-based cognitive training, which has its roots in the context of neurofeedback therapy and addresses patients with neurological developmental disorders (autism spectrum disorder and attention-deficit/hyperactivity disorder), stroke patients, and elderly subjects. We discuss some advantages of BCI for both assessment and training purposes, the former concerning the possibility of longitudinally and reliably evaluating cognitive functions in patients with severe motor disabilities, the latter regarding the possibility of enhancing patients' motivation and engagement for improving neural plasticity. Finally, we discuss some present and future challenges in the BCI use for the described purposes. PMID- 28913350 TI - Neuronal Regeneration after Electroacupuncture Treatment in Ischemia-Reperfusion Injured Cerebral Infarction Rats. AB - Adult neuronal cells which can regenerate have been reported. The present study investigated whether acupuncture enhances neuronal regeneration in ischemic stroke rats. We established an ischemic stroke rat model by occluding the cerebral blood flow of the right middle cerebral artery for 15 minutes and then allowing reperfusion in Sprague-Dawley rats. The results indicated that, in these rats, 2 Hz electroacupuncture (EA) at both Zusanli (ST36) and Shangjuxu (ST37) acupoints reduced the infarction/hemisphere ratio 8 days after reperfusion and reduced the modified neurological severity score (mNSS) and increased the rotarod test time 4 and 8 days after reperfusion, respectively. In addition, 2 Hz reduced nestin immunoreactive cells in the penumbra area and the ischemic core area; 2 Hz EA also reduced Ki67 immunoreactive cells and increased glial fibrillary acidic protein immunoreactive cells in the penumbra area. These findings suggest that 2 Hz EA at the ST36 and ST37 acupoints has a neuroprotective role. However, additional studies are needed to further investigate these preliminary results. PMID- 28913351 TI - Adequate Platelet Function Inhibition Confirmed by Two Inductive Agents Predicts Lower Recurrence of Ischemic Stroke/Transient Ischemic Attack. AB - BACKGROUND: The correlation between platelet function and recurrent ischemic stroke or TIA remains uncertain. OBJECTIVE: To investigate two inductive agents to detect platelet functions and assess associations with recurrent ischemic stroke/TIA. METHOD: The study included 738 ischemic stroke/TIA patients. On days 0, 3, and 9 after antiplatelet therapy, platelet function tests were determined by maximum aggregation rate (MAR) using a PL-11 platelet function analyzer and phase matching reagents. Two induction agents were used: arachidonic acid (AA) and adenosine diphosphate (ADP). At 3-month follow-up, recurrence of stroke/TIA was recorded. RESULT: Cut-off values of adequate platelet function inhibition were MARADP < 35% and MARAA < 35%. Data showed that antiplatelet therapy could reduce the maximum aggregation rate. More importantly, adequate platelet function inhibition of either MARADP or MARAA was not associated with the recurrence of stroke/TIA, but adequate platelet function inhibition of not only MARADP but also MARAA predicts lower recurrence (0/121 (0.00%) versus 18/459 (3.92%), P = 0.0188). CONCLUSION: The platelet function tested by PL-11 demonstrated that adequate inhibition of both MARADP and MARAA could predict lower risk of ischemic stroke/TIA recurrence. PMID- 28913353 TI - The Effects of Low-Intensity Ultrasound on Fat Reduction of Rat Model. AB - Nonfocused low-intensity ultrasound is generally believed to be less efficacious than High-Intensity Focused Ultrasound (HIFU) at body fat reduction; nevertheless, this technology has already been widely used clinically for body contouring purposes. This study aimed to evaluate the efficacy and safety of this new technology by applying 1 MHz nonfocused ultrasound at 3 W/cm2 to the outer thigh region of rat models. Ultrasonography measurement demonstrated an average reduction of 0.5 mm of subcutaneous fat thickness that persisted for at least three days after treatment. Biochemical analysis quantified a significant increase in lipid levels, specifically triglyceride, high-density lipoprotein, and total cholesterol. These two findings of subcutaneous fat reduction and plasma lipid increase showed a positive correlation. No evidence of adverse events or complications was observed after the treatment. This study validated nonfocused low-intensity ultrasound as an effective and safe method for body fat reduction, especially with repetitive treatment. However, the concurrent increase in plasma lipid level will require further investigation to determine this technology's long-term impact, if any, on health. PMID- 28913352 TI - New Roles of the Primary Cilium in Autophagy. AB - The primary cilium is a nonmotile organelle that emanates from the surface of multiple cell types and receives signals from the environment to regulate intracellular signaling pathways. The presence of cilia, as well as their length, is important for proper cell function; shortened, elongated, or absent cilia are associated with pathological conditions. Interestingly, it has recently been shown that the molecular machinery involved in autophagy, the process of recycling of intracellular material to maintain cellular and tissue homeostasis, participates in ciliogenesis. Cilium-dependent signaling is necessary for autophagosome formation and, conversely, autophagy regulates both ciliogenesis and cilium length by degrading specific ciliary proteins. Here, we will discuss the relationship that exists between the two processes at the cellular and molecular level, highlighting what is known about the effects of ciliary dysfunction in the control of energy homeostasis in some ciliopathies. PMID- 28913354 TI - Towards a Biohybrid Lung: Endothelial Cells Promote Oxygen Transfer through Gas Permeable Membranes. AB - In patients with respiratory failure, extracorporeal lung support can ensure the vital gas exchange via gas permeable membranes but its application is restricted by limited long-term stability and hemocompatibility of the gas permeable membranes, which are in contact with the blood. Endothelial cells lining these membranes promise physiological hemocompatibility and should enable prolonged application. However, the endothelial cells increase the diffusion barrier of the blood-gas interface and thus affect gas transfer. In this study, we evaluated how the endothelial cells affect the gas exchange to optimize performance while maintaining an integral cell layer. Human umbilical vein endothelial cells were seeded on gas permeable cell culture membranes and cultivated in a custom-made bioreactor. Oxygen transfer rates of blank and endothelialized membranes in endothelial culture medium were determined. Cell morphology was assessed by microscopy and immunohistochemistry. Both setups provided oxygenation of the test fluid featuring small standard deviations of the measurements. Throughout the measuring range, the endothelial cells seem to promote gas transfer to a certain extent exceeding the blank membranes gas transfer performance by up to 120%. Although the underlying principles hereof still need to be clarified, the results represent a significant step towards the development of a biohybrid lung. PMID- 28913355 TI - Evaluation of Mechanical Properties and Marginal Fit of Crowns Fabricated Using Commercially Pure Titanium and FUS-Invest. AB - This study investigated the mechanical properties and single crown accuracy of the tailor-made Fourth University Stomatology investment (FUS-invest) for casting titanium. Background. Current investment for casting titanium is not optimal for obtaining high-quality castings, and the commercially available titanium investment is costly. Methods. Titanium specimens were cast using the tailor-made FUS-invest. The mechanical properties were tested using a universal testing machine. Fractured castings were characterized by energy-dispersive spectroscopy. 19 titanium crowns were produced using FUS-invest and another 19 by Symbion. The accuracy of crowns was evaluated. Results. The mechanical properties of the titanium cast by FUS-invest were elastic modulus 125.6 +/- 8.8 GPa, yield strength 567.5 +/- 11.1 MPa, tensile strength 671.2 +/- 15.6 MPa, and elongation 4.6 +/- 0.2%. For marginal fit, no significant difference (P > 0.05) was found at four marker points of each group. For internal fit, no significant difference (P > 0.05) was found between two groups, whereas significant difference (P < 0.01) was found at different mark point of each group. Conclusions. The mechanical properties of titanium casted using FUS-invest fulfilled the ISO 9693 criteria. The marginal and internal fit of the titanium crowns using either the FUS-invest or Symbion were similar. PMID- 28913356 TI - Expression Profiling of Cellular MicroRNA in Asymptomatic HBsAg Carriers and Chronic Hepatitis B Patients. AB - BACKGROUND: MicroRNAs (miRNAs) may serve as potential molecular markers to predict liver injury resulting from chronic hepatitis B (CHB). In the present study, we want to study the expression profile and clinical significance of miRNAs at different stages of CHB virus infection. METHODS: Using miRNA microarray, we investigated the global expression profiles of cellular miRNA in asymptomatic hepatitis B antigen carriers (ASCs) and CHB patients, compared with healthy controls (HCs). RESULTS: We identified 79 and 203 differentially expressed miRNAs in the peripheral blood mononuclear cells of ASCs and CHB patients compared to HCs, respectively. Some of these miRNAs were common to ASCs and CHB patients, but another set of miRNAs that showed differential expression between ASCs and CHB patients was also identified. Gene ontology and pathway enrichment analysis showed that the target genes of the identified miRNAs played a role in important biological functions, such as learning or memory, cell-cell adherens junction, ion channel inhibitor activity, TGF-beta signaling pathway, and p53 signaling pathway. CONCLUSION: We identified some significant differentially expressed miRNA in different phases of HBV infection, which might serve as biomarkers or therapeutic targets in the future. PMID- 28913357 TI - The Association of Uric Acid Calculi with Obesity, Prediabetes, Type 2 Diabetes Mellitus, and Hypertension. AB - OBJECTIVES: To disclose the link between the composition of urolithiasis, especially that of uric acid calculi, and obesity, prediabetes, type 2 diabetes mellitus, and hypertension. MATERIALS AND METHODS: Patients who had urinary calculi and underwent surgical treatment were registered in the study. The composition of urinary calculi was analyzed and correlated with clinical features and biomedical profiles of the patients before surgical intervention. RESULTS: A total of 666 patients with urolithiasis who underwent surgical management were registered and analyzed. In those who had uric acid calculi, there was a significant association with prediabetic (OR: 20.11, 95% CI: 7.40-54.63, P < 0.001) and diabetic states (OR: 11.55, 95% CI: 4.41-29.97, P < 0.001). It also seemed that uric acid calculi were related to obesity but there was no statistical significance (OR: 2.45, 95% CI: 0.91-6.62, P = 0.078). There was no association of uric acid calculi with hypertension (OR: 1.08, 95% CI: 0.54-2.17, P = 0.822) and concurrent urinary tract infection (OR: 0.93, 95% CI: 0.44-1.96, P = 0.841). CONCLUSION: There was a remarkable association of uric acid calculi with prediabetic and diabetic states. The uric acid calculi were also seemingly associated with obesity in patients with urolithiasis undergoing surgical management. PMID- 28913358 TI - Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity. AB - Central nervous system (CNS) senses energy homeostasis by integrating both peripheral and autonomic signals and responding to them by neurotransmitters and neuropeptides release. Although it is previously considered an immunologically privileged organ, we now know that this is not so. Cells belonging to the immune system, such as B and T lymphocytes, can be recruited into the CNS to face damage or infection, in addition to possessing resident immunological cells, called microglia. In this way, positive energy balance during obesity promotes an inflammatory state in the CNS. Saturated fatty acids from the diet have been pointed out as powerful candidates to trigger immune response in peripheral system and in the CNS. However, how central immunity communicates to peripheral immune response remains to be clarified. Recently there has been a great interest in the neuropeptides, POMC derived peptides, ghrelin, and leptin, due to their capacity to suppress or induce inflammatory responses in the brain, respectively. These may be potential candidates to treat different pathologies associated with autoimmunity and inflammation. In this review, we will discuss the role of lipotoxicity associated with positive energy balance during obesity in proinflammatory response in microglia, B and T lymphocytes, and its modulation by neuropeptides. PMID- 28913359 TI - Nutraceutical, Anti-Inflammatory, and Immune Modulatory Effects of beta-Glucan Isolated from Yeast. AB - beta-Glucan is a dietary fibre, found in many natural sources, and controls chronic metabolic diseases effectively. However, beta-glucan from the yeast has rarely been investigated. Objectively, conditions were optimized to isolate beta glucan from the yeast (max. 66% yield); those optimized conditions included 1.0 M NaOH, pH 7.0, and 90 degrees C. The purity and identity of the isolated beta glucan were characterized through FT-IR, SEM, DSC, and physicofunctional properties. The obtained results from DSC revealed highly stable beta-glucan (m.p., 125 degrees C) with antioxidant activity (TAC value 0.240 +/- 0.0021 ug/mg, H2O2 scavenging 38%), which has promising bile acid binding 40.463% and glucose control (in vitro). In line with these results, we evaluated the in vivo anti-inflammatory potential, that is, myeloperoxidase activity and reduction in MDA and NO; protective effect on proteins and keeping viscosity within normal range exhibited improvement. Also, the in vivo cholesterol binding and reduction in the skin thickness by beta-glucan were highly encouraging. Finally, our results confirmed that yeast beta-glucan is effective against some of the inflammatory and oxidative stress markers studied in this investigation. In general, the effect of 4% beta-glucan was more noticeable versus 2% beta glucan. Therefore, our results support the utilization of beta-glucan as a novel, economically cheap, and functional food ingredient. PMID- 28913360 TI - Association between Sedentary Behaviour and Physical, Cognitive, and Psychosocial Status among Older Adults in Assisted Living. AB - OBJECTIVE: Identification of the factors that influence sedentary behaviour in older adults is important for the design of appropriate intervention strategies. In this study, we determined the prevalence of sedentary behaviour and its association with physical, cognitive, and psychosocial status among older adults residing in Assisted Living (AL). METHODS: Participants (n = 114, mean age = 86.7) from AL sites in British Columbia wore waist-mounted activity monitors for 7 consecutive days, after being assessed with the Timed Up and Go (TUG), Montreal Cognitive Assessment (MoCA), Short Geriatric Depression Scale (GDS), and Modified Fall Efficacy Scale (MFES). RESULTS: On average, participants spent 87% of their waking hours in sedentary behaviour, which accumulated in 52 bouts per day with each bout lasting an average of 13 minutes. Increased sedentary behaviour associated significantly with scores on the TUG (r = 0.373, p < 0.001) and MFES (r = -0.261, p = 0.005), but not with the MoCA or GDS. Sedentary behaviour also associated with male gender, use of mobility aid, and multiple regression with increased age. CONCLUSION: We found that sedentary behaviour among older adults in AL associated with TUG scores and falls-related self-efficacy, which are modifiable targets for interventions to decrease sedentary behaviour in this population. PMID- 28913361 TI - Insulin Resistance Predicts Atherogenic Lipoprotein Profile in Nondiabetic Subjects. AB - BACKGROUND: Atherogenic diabetes is associated with an increased cardiovascular risk and mortality in diabetic individuals; however, the impact of insulin resistance (IR) in lipid metabolism in preclinical stages is generally underreported. For that, we evaluated the capacity of IR to predict an atherogenic lipid subfraction profile. METHODS: Complete clinical evaluation and biochemical analysis (lipid, glucose profile, LDL, and HDL subfractions and LDL phenotype and size) were performed in 181 patients. The impact of IR as a predictor of atherogenic lipoproteins was tested by logistic regression analysis in raw and adjusted models. RESULTS: HDL-C and Apo AI were significantly lower in individuals with IR. Individuals with IR had a higher percentage of small HDL particles, lower percentage in the larger ones, and reduced frequency of phenotype A (IR = 62%; non-IR = 83%). IR individuals had reduced probability to have large HDL (OR = 0.213; CI = 0.999-0.457) and had twice more chances to show increased small HDL (OR = 2.486; CI = 1.341-7.051). IR was a significant predictor of small LDL (OR = 3.075; CI = 1.341-7.051) and atherogenic phenotype (OR = 3.176; CI = 1.469-6.867). CONCLUSION: IR, previously DM2 diagnosis, is a strong predictor of quantitative and qualitative features of lipoproteins directly associated with an increased atherogenic risk. PMID- 28913362 TI - Corrigendum to "Modeling and Measurement of Correlation between Blood and Interstitial Glucose Changes". AB - [This corrects the article DOI: 10.1155/2016/4596316.]. PMID- 28913363 TI - Associated Factors with Biochemical Hypoglycemia during an Oral Glucose Tolerance Test in a Chinese Population. AB - AIM: To find the association between biochemical hypoglycemia on a 2-hour screening oral glucose tolerance test (OGTT) and insulin resistance. METHOD: Subjects of this study were sampled from the China National Diabetes and Metabolic Disorders Study that was conducted during 2007 and 2008. Blood samples were drawn at 0, 30, and 120 minutes after the glucose load. Biochemical hypoglycemia was defined as 2-hour glucose < 3.0 mmol/l. RESULTS: In total, 26,606 participants were included, and 141 participants were diagnosed with biochemical hypoglycemia on a 2-hour OGTT. Compared to participants with normal glucose tolerance (NGT), participants with biochemical hypoglycemia presented with a younger age, lower BMI, lower levels of fasting glucose, and lower levels of 30-minute and 2-hour OGTT glucose. In terms of insulin resistance, participants with biochemical hypoglycemia showed higher levels of Matsuda ISI. In terms of beta-cell function, participants with biochemical hypoglycemia showed higher levels of Stumvoll early and late indexes. A multivariate regression analysis indicated that higher levels of Matsuda ISI and higher levels of Stumvoll early and late indexes were associated with biochemical hypoglycemia independently. CONCLUSION: This study indicated that biochemical hypoglycemia might be associated with lower levels of insulin resistance but higher levels of beta-cell function in a Chinese population. PMID- 28913365 TI - Frequency and Predictors of Self-Reported Hypoglycemia in Insulin-Treated Diabetes. AB - AIMS: Hypoglycemia is a limiting factor for achieving stringent glycemic control in diabetes. This study analyzes the frequency and predictors of hypoglycemia in insulin-treated diabetes in an ambulatory setting. METHODS: A retrospective chart review was performed to study self-monitored blood glucose (SMBG) data for 3 months prior to a patient's HbA1c test. RESULTS: Hypoglycemia occurred more frequently in type 1 than in type 2 diabetes; however, 19% of type 2 diabetes patients did experience at least one episode of severe hypoglycemia. For type 1 diabetes, hypoglycemia had a positive association with glycemic variability and duration of diabetes and a negative association with HbA1c and lowest blood glucose (BG). For type 2 diabetes, a positive association was noted with glycemic variability and a negative association with age and lowest BG. CONCLUSIONS: Delineating factors predisposing to hypoglycemia in type 2 diabetes is difficult. Lower HbA1c is a potential predictor of hypoglycemia in type 1 but not in type 2 diabetes. Longer duration of diabetes for type 1 and younger age for type 2 are associated with more hypoglycemia. Glycemic variability portends increased risk for hypoglycemia and should be a focus of further research. PMID- 28913364 TI - The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus. AB - Despite improvements in awareness and treatment of type II diabetes mellitus (TIIDM), this disease remains a major source of morbidity and mortality worldwide, and prevalence continues to rise. Oxidative damage caused by free radicals has long been known to contribute to the pathogenesis and progression of TIIDM and its complications. Only recently, however, has the role of the Nrf2/Keap1/ARE master antioxidant pathway in diabetic dysfunction begun to be elucidated. There is accumulating evidence that this pathway is implicated in diabetic damage to the pancreas, heart, and skin, among other cell types and tissues. Animal studies and clinical trials have shown promising results suggesting that activation of this pathway can delay or reverse some of these impairments in TIIDM. In this review, we outline the role of oxidative damage and the Nrf2/Keap1/ARE pathway in TIIDM, focusing on current and future efforts to utilize this relationship as a therapeutic target for prevention, prognosis, and treatment of TIID. PMID- 28913366 TI - The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers. AB - The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients' blood neutrophils (n = 108), DCs (mDC1 and pDC), and their costimulatory molecules (n = 30) were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC. PMID- 28913367 TI - Efficacy of Tumor-Infiltrating Lymphocytes Combined with IFN-alpha in Chinese Resected Stage III Malignant Melanoma. AB - BACKGROUND: This study aims to explore the efficacy of tumor-infiltrating lymphocytes (TIL) along with interferon-alpha (IFN-alpha) to treat stage III malignant melanoma (MM) patients in China. METHODS: Between May 2010 and October 2014, 77 patients of stage III MM who underwent surgery were collected in this study. These patients were divided into two groups: patients who received TIL + IFN-alpha +/- RetroNectin-activated cytokine-induced killer cells (R-CIK) in Arm 1 (n = 27) and IFN-alpha +/- R-CIK in Arm 2 (n = 50) as adjuvant therapy. The primary endpoints were disease-free survival (DFS) time and DFS rates measured at time points of 1, 2, and 3 years. The secondary endpoints were overall survival (OS) rates measured at time points of 1, 2, 3, and 5 years as well as OS as evaluated by Kaplan-Meier. RESULTS: Our results indicated that the median DFS and OS in Arm 1 were significantly better than those in Arm 2. The data also demonstrated that DFS rate and OS rates in Arm 1 were significantly better than those in Arm 2 at all measured time points. CONCLUSION: Patients who undergo surgical excision of stage III MM appear to enjoy prolonged DFS and OS when treated with TIL + IFN-alpha compared to IFN-alpha alone. PMID- 28913368 TI - Erratum to "Low Baseline Interleukin-17A Levels Are Associated with Better Treatment Response at 12 Weeks to Tocilizumab Therapy in Rheumatoid Arthritis Patients". AB - [This corrects the article DOI: 10.1155/2015/487230.]. PMID- 28913369 TI - Changes in the Width of the Tibiofibular Syndesmosis Related to Lower Extremity Joint Dynamics and Neuromuscular Coordination on Drop Landing During the Menstrual Cycle. AB - BACKGROUND: Many injuries of the lower extremities, especially the knee and ankle, occur during sports activity, and the incidence rate is higher in women than in men. HYPOTHESIS: The hypothesis was that phases of the menstrual cycle affect the width of the tibiofibular syndesmosis during drop landing in healthy young women and that such changes at the tibiofibular joint also affect the dynamics and neuromuscular coordination of the lower extremities. STUDY DESIGN: Descriptive laboratory study. METHODS: Participants included 28 healthy young women (mean age, 21.0 +/- 0.8 years). Blood samples were collected to determine plasma levels of estradiol and progesterone immediately before the performance of the task: drop landing on a single leg from a 30-cm platform. Using ultrasonography, the distance between the tibia and the distal end of the fibula, regarded as the width of the tibiofibular syndesmosis, was measured in an upright position without flexion of the ankle. The peak ground-reaction force (GRF) on landing was measured using a force platform. The time to peak GRF (Tp-GRF) was measured as the time from initial ground contact to the peak GRF. Hip, knee, and ankle joint angles during the single-leg landing were calculated using a 3 dimensional motion analysis system. Muscle activities of the lower extremities were measured using surface electromyography. RESULTS: The width of the tibiofibular syndesmosis was significantly greater in the luteal phase when compared with the menstrual, follicular, and ovulation phases (by 5%-8% of control). Also, during the luteal phase, the Tp-GRF was significantly shorter than in the follicular phase (by 6%); hip internal rotation and knee valgus were significantly greater than in the menstrual phase (by 43% and 34%, respectively); knee flexion was significantly less than in the menstrual and follicular phases (by 7%-9%); ankle dorsiflection was significantly less than in the follicular phase (by 11%); ankle adduction and eversion were significantly greater than in the menstrual and follicular phases (by 26%-46%, and 27%-33%, respectively); and activation of the gluteus maximus before landing was significantly lower than in the menstrual and follicular phases (by 20%-22%). CONCLUSION: The luteal phase appears to be associated with decreased strength and laxity of the ankle as well as lower extremity muscle activity in women. The changes presumably represent a greater risk for sports injuries. CLINICAL RELEVANCE: The results of this study suggest that the luteal phase may be related to the greater incidence of lower extremity injuries in women. PMID- 28913370 TI - Evaluating PROMIS Physical Function Measures in Older Adults at Risk for Alzheimer's Disease. AB - Activities of daily living can be affected by cognitive decline. Self-report measurement of functioning is attractive due to ease of data collection, low cost, and accessibility via technology-assisted means, and for understanding patient perspective. A concern is with reliability of such measurement as cognitive decline occurs. We compared a widely used, self-report "legacy" measure of functioning, Lawton and Brody's Instrumental Activities of Daily Living Scale (IADLS), with a subset of physical functioning items from the Patient-Reported Outcomes Measurement Information System (PROMIS). The study sample consisted of 304 individuals of varying cognitive status: normal, mild cognitive impairment (MCI), or early dementia. An expert consensus method was used to select PROMIS functional items most relevant to neurocognitive disorder and to identify major functional sub-domains. Selected PROMIS functional subscales and the IADLS were then evaluated with respect to cognitive status. Few PROMIS functional items were useful in identifying MCI, while we reaffirmed the utility of the IADLS. Also, even mild depression levels were found to have negative effects on functioning according to both PROMIS and IADLS. PMID- 28913371 TI - Comprehensive Gerontological Development: A Positive View on Aging. AB - Human aging can only be understood within its social and historical contexts. It is largely determined by the complex interrelation of biological, cultural, social, political, and economic factors. Furthermore, the phenomenon of population aging can be considered as a social and economic burden or as an invaluable social asset if understood within the perspective of the enormous potential of our aging populations. This article is based on the tenet that aging can be an enriching and productive stage marked by a lifelong process of personal growth and development. That is, in our perspective, ageing should become a process oriented toward the improvement and promotion of the individual's physical, psychological, and social potentialities to achieve the highest quality of life. The purpose of this article is to introduce the concept and practice of Comprehensive Gerontological Development that underlie current research at the Gerontological Research Unit of the Zaragoza Campus of the National Autonomous University of Mexico. PMID- 28913372 TI - Identifying Sociodemographic Characteristics Associated With Burden Among Caregivers of the Urban Homebound: The Importance of Racial and Relationship Differences. AB - Limited research has explored whether the burden associated with caring for homebound patients varies across racial groups or by relationship status. We examined these variations for this vulnerable population. Patients self identified informal caregivers and caregiver burden/depression were assessed using the Zarit Caregiver Burden Scale and the Center for Epidemiologic Studies Depression scale (CES-D). Forty-nine informal caregivers completed the interview. Mean age was 58 (SD = 14), 78% were female, 37% Black, 35% Hispanic, and 46% had completed high school. Over 60% of caregivers had moderate or severe caregiver burden and 30% had significant depression. White caregivers had greater burden than Black and Hispanic caregivers (p = .02). Mean caregiver burden was higher among spouse/partner caregivers, versus those who identified as children or other family or friends (p = .004). Additional research is needed to better understand the experience of racial and ethnic minorities and spouses in providing informal care to homebound adults. PMID- 28913375 TI - Important Lessons Learned From Nearly a Half-Century of Orthopedic Practice. PMID- 28913373 TI - Physical Activity Protects Men but Not Women for Sarcopenia Development. AB - Objective: Sarcopenia is among the most deleterious effects of aging. The objective of this study was to analyze the relationship between performance tests and muscular volume over the life span of male and female participants. Method: A correlation study was conducted with healthy individuals (50 males and 47 females) between the ages of 20 and 94; the study group included active older people, sedentary younger people, and young athletes. Muscular volume was determined by tomography and muscular performance (4-meter speed tests [4 MSTs], chair test, and handgrip test), and a correlation analysis between the groups was performed. Results: Sex-related differences were observed between the variables; in males, muscle volume and functional parameters were closely related with age and physical activity, whereas in females, they were not related at all. Conclusion: Male and female muscle volume and performance demonstrate strong differences, which should be considered during clinical evaluations of sarcopenia. PMID- 28913374 TI - Comparison of the Nutritional Values of Infant Formulas Available in Saudi Arabia. AB - Introduction. Optimum growth and development are best achieved by breastfeeding, which is the safest source for infant feeding. Mothers in Saudi Arabia start to breastfeed their infants but soon introduce formula brands. Objective. To assess the safety and nutritional adequacy of the oldest formula brands available in the Saudi market. Methods. An observational study has compared between 5 types of infant formula brands; they were chosen based on their international popularity. Also, they are considered as the oldest formula brands available in the Saudi market. The contents of all the included formulas were carefully collected from their containers. The collected data were compared with the global standard requirements for infant formulas according to the guidelines. Results. All the infant formula brands had their contents within the optimal range as stated by the ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) guidelines. Some formulas did not provide elements like fluoride and nucleotides. Moreover, the mandatory elements and the most dominant ingredient in each formula were documented. Discussion. According to the results of our study, all included formula brands are considered safe and nutritionally adequate. By assuming that the elements that were not found in some brands meant an abnormal value, Bebelac and Liptomil are the most suitable infant formulas available in the Saudi market. Conclusions. Adequate nutrition during infancy is essential in each health organization. The nutritional status of infants should be studied to achieve lifelong health and well-being. All formula brands in this study were found to be safe and nutritionally adequate. PMID- 28913376 TI - Joint Distraction in Advanced Osteoarthritis of the Ankle. AB - BACKGROUND: Ankle joint distraction (AJD) avoids the potential complications associated with ankle fusion or total ankle replacement (TAR) in patients with advanced ankle osteoarthritis (OA). AJD could a tenable option to ankle fusion or TAR. METHODS: A review has been performed on the role of AJD in advanced OA of the ankle. The exploration machine was MedLine. The keywords utilized were: joint distraction ankle. Three hundred and eleven articles were found. Of the above mentioned, only 14 were chosen and analyzed because they were rigorously focused on the issue and the question of this paper. RESULTS: The types of articles published until now have a poor level of evidence (levels III and IV). The overall number of patients managed until now by way of AJD is 249. The published mean follow-up is very variable, from 1 year to 12 years. CONCLUSION: The rate of good outcomes ranged between 73% and 91%. The percentage of failure (final ankle arthrodesis or TAR) ranged between 6.2% and 44%. A minimum of 5.8 mm of distraction gap must be achieved. Ankle function after AJD deteriorates over time. Putting together ankle movement and distraction will result in an early and maintained profitable influence on outcome. PMID- 28913377 TI - Early Versus Late Reverse Shoulder Arthroplasty for Proximal Humerus Fractures: Does It Matter? AB - BACKGROUND: This study compared the outcomes between patients with proximal humerus fractures (PHF) who underwent acute reverse total shoulder arthroplasty (RSA) to those who underwent an alternative initial treatment before requiring (secondary) RSA. METHODS: Patients who underwent RSA after suffering a PHF were identified. Two year clinical follow-up was required for inclusion. Patients were divided into an acute group (RSA <4 weeks of fracture) and a secondary group. The secondary RSA group was subdivided by initial treatment (non-operative, hemiarthroplasty, open reduction internal fixation (ORIF)). Clinical and radiographic outcomes were compared. RESULTS: Forty-seven patients met inclusion criteria with 15 in the acute RSA group and 32 in the secondary RSA group. The acute RSA group demonstrated better external rotation (28 degrees ) than the secondary RSA group (18 degrees , P=0.0495). The acute RSA group showed a trend towards better Single Assessment Numeric Evaluation (SANE) scores. Tuberosity healing rate was higher in the acute RSA group. CONCLUSION: While acute and secondary RSA can yield successful outcomes, acute RSA results in a higher tuberosity healing rate and improved external rotation. PMID- 28913378 TI - First Metatarsophalangeal Joint Arthrodesis: A Retrospective Comparison of Crossed-screws, Locking and Non-Locking Plate Fixation with Lag Screw. AB - BACKGROUND: Locking plate fixation is increasingly used for first metatarsophalangeal joint (MTP-I) arthrodesis. There are still few comparable clinical data regarding this procedure. In this study we aimed to compare the clinical and radiographical outcomes of crossed-screws, locking and non-locking plate fixation with lag screw for first metatarsophalangeal joint arthrodesis. METHODS: A total of 60 patients who had undergone arthrodesis of the MTP-I between January 2008 and June 2010 were retrospectively evaluated. Locking plate fixation with lag screw as well as arthrodesis with crossed-screws or with a non locking plate with lag screw was performed on three groups of 20 patients. RESULTS: There were four non-unions in patients with crossed-screws and one in non-locked plate group. All patients in locking plate group achieved union. 90% of the patients were completely or mildly satisfied in locking plate group, whereas this rate was 80% for patients in both crossed-screws and non-locking plate groups. CONCLUSION: Use of dorsal plating for arthrodesis of MTP-I joint, either locking or non-locking, were associated with high union rate and acceptable and comparable functional outcome. Although the rate of nonunion was higher with two crossed-screws, however, the functional outcome was not significantly different compared to dorsal plating. PMID- 28913379 TI - Is Spinal Anesthesia with Low Dose Lidocaine Better than Sevoflorane Anesthesia in Patients Undergoing Hip Fracture Surgery. AB - BACKGROUND: To evaluate general anesthesia with sevoflurane vs spinal anesthesia with low dose lidocaine 5% on hemodynamics changes in patients undergoing hip fracture surgery. METHODS: In this randomized double blind trial 100 patients (50 patients in each group) older than 60 years under hip surgery were randomized in general anesthesia with sevoflurane and spinal anesthesia with lidocaine 5%. Hemodynamic changes including mean arterial pressure (MAP) and heart rate, blood loss, pain severity, nausea and vomiting and opioids consumption were compared in two groups. RESULTS: During surgery, difference between two groups regarding changes in mean arterial pressure was not significant, but the changes in heart rate were significantly different. Mean arterial pressure changes during recovery between two groups were significantly different. But there was no significant difference in heart rate changes. Bleeding in the sevoflurane group was significantly more than spinal group (513.ml vs. 365 ml). Moreover, AS Score, opioid consumption, and the nausea and vomiting in spinal anesthesia group was significantly lower than the sevoflurane group. CONCLUSION: We showed that general anesthesia with sevoflurane and spinal anesthesia with low dose lidocaine 5% have comparable effects on hemodynamics changes in patients undergoing hip fracture surgery. However postoperative pain score, vomiting and morphine consumption in patients with spinal anesthesia were lower than general anesthesia. PMID- 28913380 TI - Questionable Word Choice in Scientific Writing in Orthopedic Surgery. AB - BACKGROUND: Given the strong influence of thoughts, emotions, and behaviors on musculoskeletal symptoms and limitations it's important that both scientific and lay writing use the most positive, hopeful, and adaptive words and concepts consistent with medical evidence. The use of words that might reinforce misconceptions about preference-sensitive conditions (particularly those associated with age) could increase symptoms and limitations and might also distract patients from the treatment preferences they would select when informed and at ease. METHODS: We reviewed 100 consecutive papers published in 2014 and 2015 in 6 orthopedic surgery scientific journals. We counted the number and proportion of journal articles with questionable use of one or more of the following words: tear, aggressive, required, and fail. For each word, we counted the rate of misuse per journal and the number of specific terms misused per article per journal. RESULTS: Eighty percent of all orthopedic scientific articles reviewed had questionable use of at least one term. Tear was most questionably used with respect to rotator cuff pathology. The words fail and require were the most common questionably used terms overall. CONCLUSION: The use of questionable words and concepts is common in scientific writing in orthopedic surgery. It's worth considering whether traditional ways or referring to musculoskeletal illness merit rephrasing. PMID- 28913381 TI - Is It "Fractured" or "Broken"? A Patient Survey Study to Assess Injury Comprehension after Orthopaedic Trauma. AB - BACKGROUND: Patients who sustain orthopaedic trauma in the form of fractures commonly ask treating providers whether the bone is "fractured" or "broken". While orthopaedic surgeons consider these terms synonymous, patients appear to comprehend the terms as having different meanings. Given the commonality of this frequently posed question, it may be important for providers to assess patients' level of understanding in order to provide optimal care. The purpose of this study is to evaluate patients' comprehension and understanding regarding the use of the terms fractured and broken. METHODS: A survey was administered as a patient-quality measure to patients, family members and/or other non-patients presenting to an orthopaedic outpatient clinic at an academic teaching hospital. RESULTS: 200 responders met inclusion criteria. Only 45% of responders understood the terms fractured and broken to be synonymous. Age, gender, nor ethnicity correlated with understanding of terminology. Responders described a "fractured" bone using synonyms of less severe characteristics for 55.7% of their answers and chose more severe characteristics 44.3% of the time, whereas responders chose synonyms to describe a "broken" bone with more severe characteristics as an answer in 62.1% of cases and chose less severe characteristics 37.9% of the time. The difference for each group was statistically significant (P=0.0458 and P <=0.00001, respectively). There was no correlation between level of education nor having a personal orthopaedic history of a previous fracture with understanding the terms fracture and broken as synonymous. Having an occupation in the medical field (i.e. physician or physical/occupational therapist) significantly improved understanding of terminology. CONCLUSION: The majority of people, regardless of the age, gender, race, education or history of previous fracture, may not understand that fractured and broken are synonymous terms. Providers need to be cognizant of the terminology they use when describing a patient's injury in order to optimize patient understanding and care. PMID- 28913382 TI - Psychometric Properties of the Persian Version of the Patient Rated Wris t Evaluation. AB - BACKGROUND: The patient-rated wrist evaluation (PRWE) score is one of the most common clinical instruments used as an outcome measurement tool for distal radius fractures and other upper extremity conditions. The purpose of this study was to translate the PRWE into its Persian version and to evaluate its validity and reliability in patients with upper extremity conditions. METHODS: One hundred and fourthly one adult patients with upper extremity conditions participated in this ethical board approved study from August 2015 to May 2016. After translating the original version of the PRWE into Persian, all patients filled out the PRWE in addition to the VAS (Visual analogue scale) and DASH questionnaires. For evaluating reliability, after three days the researchers called back some of the patients who did not receive treatment or any changes in symptoms and asked them to complete the PRWE retest (104 patients). RESULTS: Cronbach's alpha was calculated as high as 0.934, implying very reliable internal consistency. After each item deletion, the Cronbach's alpha was still constant (range: 0.926 to 0.936). Intraclass correlation coefficient was 0.952 and this showed excellent test-retest reliability. The correlation coefficient between the PRWE and DASH scores was strong. Multivariable analysis showed an association between the PRWE and years educated. CONCLUSION: Our study has shown that the Persian version of the PRWE is valid and reliable for patients with upper extremity conditions. PMID- 28913383 TI - The Effect of Sagittal Femoral Bowing on the Femoral Component Position in Total Knee Arthroplasty. AB - In the current study, we investigated that how sagittal femoral bowing can affect the sagittal alignment of the femoral component in total knee arthroplasty (TKA). There were 25 patients underwent TKA. Long leg radiography in lateral view was performed. The sagittal femoral bowing (SFB) and component alignment in relation to the sagittal mechanical axis and distal anterior cortical line (DACL) were measured. Finally, the correlation of component alignment and SFB was examined. Mean SFB was 7+/-2.7 degrees. The component was in flexion position in relation to mechanical axis and DACL as 8.4+/-2.9 degrees and 1.7+/-0.9 degrees, respectively. The flexion alignment of the component was significantly correlated with SFB. Mechanical alignment of the limb in both coronal and sagittal axes should be preserved in TKA. SFB can significantly increased the flexion alignment of the femoral component. PMID- 28913384 TI - Anatomical Repair of Stener-like Lesion of Medial Collateral Ligament: A case Series and Technical Note. AB - Medial collateral ligament tears usually will be treated through non-surgical methods, but, in some cases such as those with tears at the distal insertion where the reduction could be blocked by the pes anserine tendons (Stener-like lesion), surgery will be performed. Here, we present a surgical technique in such cases. In this retrospective case series, we describe six patients diagnosed with Stener-like lesion based on clinical evaluation and imaging results. In the one year follow-up visit, there was no complaining of pain or joint instability and full range of motion and negative valgus stress test were reported in all cases. The results showed this surgical technique is a useful and safe treatment approach in such cases. PMID- 28913385 TI - Closed Internal Degloving of the Flank. AB - Originally described in 1853 by Dr. Morel-Lavellee, closed internal degloving injuries represent an important, although uncommon, source of morbidity in trauma patients. These injuries are typically the result of a shearing or crushing force that traumatically separates the skin and subcutaneous tissue from the underlying fat. This results in disruption of perforating blood vessels and lymphatics, leading to hematoma/seroma formation. We describe two cases in which industrial crush injuries resulted in lumbar transverse process fracture. Both patients developed closed degloving injuries of the flank. To the author's knowledge, this is the first case series describing the occurrence of closed internal degloving injuries of the flank with transverse process fractures. We advise that a high level of suspicion for these lesions to occur with transverse spinal fractures should be maintained, as they may arise several years after initial injury. PMID- 28913386 TI - Persistent Medial Subluxation of the Ulna with Radiotrochlear Articulation. AB - Two patients-one with a terrible triad fracture dislocation and one with an anterior olecranon fracture dislocation-were treated for maltracking of the elbow (medial subluxation). The radial head articulated with the lateral trochlea while the ulnar trochlear notch was perched over the medial trochlea. The late revision surgery could not correct the subluxation because the joints were accustomed to the new alignment, however the overall function was reasonable. PMID- 28913387 TI - Personality traits and theory of mind: Performance data of a Spanish sample of university students. AB - This article allows consulting the performance data of 96 Spanish university students in two personality questionnaires and two theory of mind (ToM) tasks. Personality dimensions were evaluated through the OPERAS questionnaire (Vigil Colet et al., 2013) [1], which evaluates global personality through 5 scales: extraversion, agreeableness, conscientiousness, emotional stability, openness to experience, and the ESQUIZO-Q questionnaire (Fonseca-Pedrero et al., 2010) [2], which assesses schizotypy by means of 10 subscales: ideas of reference, magical thinking, unusual perceptual experiences, odd thinking and language, paranoid ideation, physical anhedonia, social anhedonia, odd behavior, lack of close friends, and excessive social anxiety. The ability to attribute/infer mental states, i.e. ToM, was measured through two computerized tasks: the revised Reading the Mind in the Eyes (Baron-Cohen et al., 1997, 2001) [3], [4], and the Director's task (Keysar et al., 2000, 2003; Dumontheil et al., 2010) [5-7]. PMID- 28913388 TI - Dataset representing the effect of indirect band gap region of Cd-free AlGaAs buffer layer in Cu(In,Ga)Se photovoltaic cell. AB - The dataset of physical properties for the proposed CIGS solar cell with Cd-free AlGaAs buffer layer has been depicted in this data article. The cell performance outcome due to different AlGaAs buffer layer band gap is reported along with optimum solar cell performance parameters for instance, open circuit voltage [Formula: see text], short circuit current density ([Formula: see text], fill factor [Formula: see text], efficiency [Formula: see text], as well as collection efficiency [Formula: see text]. PMID- 28913389 TI - Data set for extraction and transesterification of bio-oil from Stoechospermum marginatum, a brown marine algae. AB - The article presents the experimental data on the extraction and transesterification of bio-oil derived from Stoechospermum marginatum, a brown macro marine algae. The samples were collected from Mandapam region, Gulf of Mannar, Tamil Nadu, India. The bio-oil was extracted using Soxhlet technique with a lipid extraction efficiency of 24.4%. Single stage transesterification was adopted due to lower free fatty acid content. The yield of biodiesel was optimized by varying the process parameters. The obtained data showed the optimum process parameters as reaction time 90 min, reaction temperature 65 degrees C, catalyst concentration 0.50 g and 8:1 M ratio. Furthermore, the data pertaining to the physio-chemical properties of the derived algal biodiesel were also presented. PMID- 28913390 TI - Dataset on continuous passages of Trypanosoma brucei in different laboratory animals. AB - Scientist in developing countries maintain trypanosomes in laboratory animals for in vivo experiments. We generated data on the adaptation of Trypanosoma brucei (NITR201 strain) in balb/c mice (forty-five, 18-23 g), wistar rats (fifteen, 180 220 g) and New Zealand white and chinchilla rabbits (fifteen, 2.8-3.0 kg) in a controlled experimental system. The weight, haematological parameters, course of parasitaemia, temperature, mean survival time and survival proportions of laboratory animals in groups A-E were collected and analysed for differences in response to the same challenge of quantity, strain and species of T. brucei. Trypanosome pleomorphism of long, intermediate to short-stumpy forms were among the dataset counts for parasitaemia. Statistical data after analysis were summarised in the supplementary file to show the differences and corresponding reaction of multiple passages. PMID- 28913391 TI - Data on optical coherence tomography guidance for the management of angiographically intermediate left main bifurcation lesions. AB - The data presented in this article are related to the research article entitled "Optical coherence tomography guidance for the management of angiographically intermediate left main bifurcation lesions: early clinical experience" [1]. In this article we reports details about our clinical experience with frequency domain-optical coherence tomography (FD-OCT) guidance for the management of patients with left main (LM) bifurcation lesions of intermediate angiographic severity. LM patients were assessed by FD-OCT and, on the bases of the findings, managed by myocardial revascularization or conservative treatment (revascularization deferral). The observed outcomes support the feasibility of FD OCT guidance for LM bifurcated lesions and call for further clinical evaluations in appropriately designed prospective studies. PMID- 28913392 TI - Data on scaling up and in vivo human study of progesterone lipid nanoparticles. AB - Progesterone containing nanoparticles constituted of tristearin or tristearin in association with caprylic-capric triglyceride were produced in a lab scale by ultrasound homogenization and in a pilot scale by high pressure homogenization. A study was conducted to select the pressure to be used in order to obtain homogenously sized nanoparticles. The Dialysis method was performed to mimic subcutaneous administration of lipid nanoparticles. Mathematical analyses of the results were conducted to understand and compare the drug release mechanisms. A human in vivo study, based on tape stripping, was conducted to investigate the performance of nanoparticles as progesterone skin delivery systems. Tape stripped stratum corneum was analyzed by light microscopy. PMID- 28913393 TI - Data for automated, high-throughput microscopy analysis of intracellular bacterial colonies using spot detection. AB - Quantification of intracellular bacterial colonies is useful in strategies directed against bacterial attachment, subsequent cellular invasion and intracellular proliferation. An automated, high-throughput microscopy-method was established to quantify the number and size of intracellular bacterial colonies in infected host cells (Detection and quantification of intracellular bacterial colonies by automated, high-throughput microscopy, Ernstsen et al., 2017 [1]). The infected cells were imaged with a 10* objective and number of intracellular bacterial colonies, their size distribution and the number of cell nuclei were automatically quantified using a spot detection-tool. The spot detection-output was exported to Excel, where data analysis was performed. In this article, micrographs and spot detection data are made available to facilitate implementation of the method. PMID- 28913394 TI - The genesis of an idea: the International Committee of the American Association of Hip and Knee Surgeons. PMID- 28913395 TI - Simultaneous bilateral total hip arthroplasty in Morquio syndrome. AB - A 16-year-old girl who had Morquio syndrome presented with severe bilateral hip pain and limited mobility because of bilateral hip osteoarthritis and fixed flexion deformities. She was wheelchair bound for the previous 6 months. Cervical spine flexion-extension views showed mild subluxation (<3 mm), and there was thoracolumbar spine kyphosis. Magnetic resonance imaging of the cervical and thoracolumbar spine showed hypoplasia of the odontoid and vertebral bodies, but no spinal cord compression. Bilateral cemented total hip arthroplasty was performed through a posterior approach under general anesthesia with fiberoptic intubation. The femoral canals accepted a small-diameter stem, the right femoral head was used as a graft for superior right acetabular deficiency, and low profile all-polyethylene acetabular cups were implanted. Follow-up at 15 years after surgery showed that the patient was fully ambulatory without pain or supports, and radiographs showed no loosening. In summary, total hip arthroplasty at a young age may be necessary in patients who have Morquio syndrome because of severe arthritis and soft tissue contractures. Extensive preoperative evaluation that includes imaging of the entire spine is mandatory because of the risk of developing spinal cord compression. PMID- 28913396 TI - Severe heterotopic ossification and stiffness after revision knee surgery for a periprosthetic fracture. AB - Although heterotopic ossification (HO) after total hip arthroplasty has been very well described as a cause of disability, much less was written on clinical dysfunction of HO after total knee arthroplasty (TKA). To the extent of our knowledge, there has been no published case of complete bony ankylosis, secondary to severe generalized HO, after a TKA. We present the case of a 67-year-old female treated successfully, with surgical excision of ossification and TKA revision surgery, using a rotating hinge system. PMID- 28913397 TI - Cardiac transplant due to metal toxicity associated with hip arthroplasty. AB - Concerns regarding metal-on-metal (MoM) bearing couples in total hip arthroplasty are well documented in the literature with cobalt (Co) and chromium (Cr) toxicity causing a range of both local and systemic adverse reactions. We describe the case of a patient undergoing cardiac transplantation as a direct result of Co and Cr toxicity following a MoM hip replacement. Poor implant positioning led to catastrophic wear generating abundant wear particles leading to Co and Cr toxicity, metallosis, bony destruction, elevated metal ion levels, and adverse biological responses. Systemic symptoms continued for 3 years following cardiac transplantation with resolution only after revision hip arthroplasty. There was no realization in the initial cardiac assessment and subsequent transplant workup that the hip replacement was the likely cause of the cardiac failure, and the hip replacement was not recognized as the cause until years after the heart transplant. This case highlights the need for clinicians to be aware of systemic MoM complications as well as the importance of positioning when using these prostheses. PMID- 28913398 TI - Total femur arthroplasty for revision hip failure in osteogenesis imperfecta: limits of biology. AB - Osteogenesis imperfecta (OI) is a rare congenital disease characterized by alterations in bone quality, with susceptibility to fractures, instability, deformities, and osteoarthrosis. Prosthetic surgery in these patients is associated with an abnormally high rate of implant failures. On the other hand, abnormal bone fragility adds to the complexity of revision surgery in such individuals-thus representing a genuine challenge for the orthopaedic surgeon. We present a case of femoral reconstruction in a patient with OI and prosthetic loosening after reconstruction secondary to femoral septic pseudoarthrosis. Intramedullary total femoral reconstruction was carried out after exceeding the biological reconstruction limits. This is the first reported instance of the use of an intramedullary total femur arthroplasty as salvage technique in an OI patient. This technique should be considered when we have exceeded biological limits for femoral fixation. PMID- 28913399 TI - Reactive scoliosis: a challenging phenomenon in adolescent patients with hip arthritis. AB - Functional limb length discrepancy (LLD) in adolescents can result from soft tissue contracture following long-standing hip disease. We present a case of a 13 year-old girl with difficulty in ambulation due to right hip pain and LLD. Radiographs revealed severe arthritis of right hip with signs of avascular necrosis of the femoral head. The patient had developed reactive scoliosis of lumbar spine along with pelvic obliquity. After failing conservative management, total hip arthroplasty (THA) without attempting to equalize LLD was performed. At 6-month follow-up, patient was pain free with full range of motion and her functional LLD was completely resolved. In such adolescent patients, reactive scoliosis of spine is reversible, and with no evidence of true LLD, THA without correcting LLD should be the right choice. PMID- 28913400 TI - Novel cemented cup-holding technique while performing total hip arthroplasty with navigation system. AB - Recently, navigation systems have been more widely utilized in total hip arthroplasty. However, almost all of these systems have been developed for cementless cups. In the case of cemented total hip arthroplasty using a navigation system, a special-ordered cemented holder is needed. We propose a novel cemented cup-holding technique for navigation systems using readily available articles. We combine a cementless cup holder with an inverted cementless trial cup. The resulting apparatus is used as a cemented cup holder. The upside-down cup-holding technique is useful and permits cemented cup users to utilize a navigation system for placement of the acetabular component. PMID- 28913401 TI - Use of iPhone technology in improving acetabular component position in total hip arthroplasty. AB - Improper acetabular cup positioning is associated with high risk of complications after total hip arthroplasty. The aim of our study is to objectively compare 3 methods, namely (1) free hand, (2) alignment jig (Sputnik), and (3) iPhone application to identify an easy, reproducible, and accurate method in improving acetabular cup placement. We designed a simple setup and carried out a simple experiment (see Method section). Using statistical analysis, the difference in inclination angles using iPhone application compared with the freehand method was found to be statistically significant (F[2,51] = 4.17, P = .02) in the "untrained group". There is no statistical significance detected for the other groups. This suggests a potential role for iPhone applications in junior surgeons in overcoming the steep learning curve. PMID- 28913402 TI - Midterm analysis of the seleXys cup with ceramic inlay. AB - BACKGROUND: Ceramic-on-ceramic (CoC) articulations in total hip replacement (THR) has been accepted as giving reliable mid-term results; however recent studies have reported higher revision rates of some implants. This study analyses the nationwide results of the seleXys TPS cup and the Bionit2 liner (Mathys, Bettlach, Switzerland) with respect to implant survival, cause for revision and mortality rates compared to other CoC articulations using the same stem. METHODS: Utilising the New Zealand Joint Registry, we compared the seleXys TPS cup with Bionit2 liner used with an uncemented Twinsys femoral stem to every other uncemented CoC THR using the same stem. Multivariate analysis was used to determine the effects of patient age, gender, ASA score and implant head size on these rates. RESULTS: Between 2006 and 2013 a total of 1035 seleXys THRs were performed on 862 patients. The comparison group had 375 THRs on 280 patients. There were 77 revisions (1.4/100 component years) in the study group and two in the comparison group (0.12/100 component years). Overall hazards ratio for revision was 12.22 times higher and female gender was associated with an increased risk (hazards ratio 1.77). Causes for revision were disturbing noises (23.4%), acetabular loosening (20.8%), and fracture of the liner (18.2%). Mortality rates were not significantly different (P = .567). CONCLUSIONS: The seleXys TPS cup with the Bionit2 ceramic inlay coupling has an unacceptably high failure rate. We recommend avoiding this implant coupling and would advise that patients treated with this implant need close clinical and radiological follow up. PMID- 28913403 TI - Relative impact of hospital and surgeon procedure volumes on primary total hip arthroplasty revision: a nationwide cohort study in France. AB - BACKGROUND: Both surgeon and hospital procedure volumes have been found to be associated with total hip arthroplasty (THA) outcomes. However, little research has been conducted on the relative influence. We studied the association between THA survivorship and both hospital and surgeon procedure volumes, considering their relative impact. METHODS: A population-based cohort included all patients aged >=40 years having received a unilateral primary THA from 2010 to 2011, from the French National Health Insurance Database. Patients were followed up until the end of 2014. The outcome was THA revision. Exposures of interest were procedure volumes, divided into tertiles: <1.5, 1.5-4, >4 and <7, 7-15, >15 procedures per month defined as low, medium, and high volumes for surgeon and hospital, respectively. RESULTS: The cohort had 62,906 patients, with mean age 69 years and women 57%. Mean surgeon and hospital volumes were 8 and 23 procedures per month, respectively, and 5%, 72%, 22% and 7%, 28%, 65% of THAs were implanted by a low-, medium-, and high-volume surgeon or in a low-, medium-, and high volume hospital, respectively. Median follow-up was 45 months (range, 0-57 months). In multivariate analysis, adjusted for both surgeon and hospital volumes, for patient and THA characteristics, a lower surgeon volume was associated with poorer THA survivorship (adjusted hazard ratio [aHR] = 1.19; 95% confidence interval [CI], 1.07-1.34 and aHR = 1.70; 95% CI, 1.40-2.05, for medium and low-volume surgeon, respectively, compared with that of high volume), whereas hospital volume was not. CONCLUSIONS: This study brings evidence to support the notion that THAs performed by high-volume surgeons in French private hospitals have higher survivorship in the first 4 years. PMID- 28913404 TI - ESR and CRP are useful between stages of 2-stage revision for periprosthetic joint infection. AB - BACKGROUND: Serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are important tests in the initial diagnosis of periprosthetic joint infection. Many surgeons also use these tests to determine if infection has resolved between stages of a 2-stage procedure, but little data exist regarding this practice. METHODS: A retrospective review of our institutional total joint databases was conducted to determine sensitivity, specificity, and predictive values of elevated ESR and/or CRP to diagnose persistent infection between stages. RESULTS: Among 16 knees and 5 hips, sensitivity was 50% for CRP, 75% for ESR, and 100% when combined. The negative predictive value of persistent infection was 100% when neither test was elevated. CONCLUSIONS: Results of this study support the use of CRP and ESR as indicators of the resolution of periprosthetic joint infection between stages of 2-stage revision. PMID- 28913405 TI - Post-acute care disparities in total joint arthroplasty. AB - BACKGROUND: Understanding the socioeconomic factors that influence hospitalization and post-discharge metrics after joint replacement is important for identifying key areas of improvement in the delivery of orthopaedic care. METHODS: An institutional administrative data set of 2869 patients from an academic arthroplasty referral center was analyzed to quantify the relationship between socioeconomic factors and post-acute rehabilitation care received, length of stay, and cost of care. The study used International Classification of Disease, ninth edition coding in order to identify cohorts of patients who received joint arthroplasty of the knee and hip between January 2007 and May 2015. RESULTS: The study found that females (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.74-2.46), minorities (OR, 2.11; 95% CI, 1.78-2.51), and non-private insurance holders (OR, 1.56; 95% CI, 1.26-1.94) were more likely to be assigned to institutional care after discharge. The study also found that minorities (OR, 1.45; 95% CI, 1.24-1.70) and non-private insurance holders (OR, 1.43; 95% CI, 1.16-1.77) are more likely to exhibit longer length of stay. Mean charges were higher for males when compared to females ($80,010 vs $74,855; P < .001), as well as total costs ($19,910 vs $18,613; P = .001). CONCLUSIONS: Socioeconomic factors such as gender, race, and insurance status should be further explored with respect to healthcare policies seeking to influence quality of care and health outcomes. PMID- 28913406 TI - Long-term results of a porous tantalum monoblock tibia component: clinical and radiographic results at follow-up of 10 years. AB - BACKGROUND: The purpose of this study is to assess the long-term follow-up of cementless total knee arthroplasty with the trabecular metal (TM) monoblock tibial component at an average 10-year follow-up. This report is an extension of our previously reported series of 108 TM tibias reported in 2011 (Unger and Duggan, 2011). METHODS: Fifty-eight of the original 108 knees were available for review. Each follow-up patient was evaluated by radiologic and clinical Knee Society Scores. The average follow-up was 10.2 years. RESULTS: Our results indicate excellent long-term survivorship (96.5%) with 2 confirmed tibia revisions, and 1 femoral revision for periprosthetic fracture and 1 patella open reduction internal fixation. X-ray evaluation demonstrated one patient with 1 mm medial polyethylene wear and a nonprogressive 1 mm of radiolucency on the medial side. All the other tibial components showed full bone apposition and incorporation. Knee Society Scores were excellent in all the patients seen on follow-up. CONCLUSIONS: Long-term follow-up of TM monoblock tibia components confirm excellent survivorship and biologic implant fixation, with excellent outcomes and knee scores. PMID- 28913407 TI - Early intraprosthetic dislocation in dual-mobility implants: a systematic review. AB - BACKGROUND: Dual mobility implants are subject to a specific implant-related complication, intraprosthetic dislocation (IPD), in which the polyethylene liner dissociates from the femoral head. For older generation designs, IPD was attributable to late polyethylene wear and subsequent failure of the head capture mechanism. However, early IPDs have been reportedly affecting contemporary designs. METHODS: A systematic review of the literature according to the preferred reporting items for systematic reviews and meta-analyses guidelines was performed. A comprehensive search of PubMed, MEDLINE, Embase, and Google Scholar was conducted for English articles between January 1974 and August 2016 using various combinations of the keywords "intraprosthetic dislocation," "dual mobility," "dual-mobility," "tripolar," "double mobility," "double-mobility," "hip," "cup," "socket," and "dislocation." RESULTS: In all, 16 articles met our inclusion criteria. Fourteen were case reports and 2 were retrospective case series. These included a total of 19 total hip arthroplasties, which were divided into 2 groups: studies dealing with early IPD after attempted closed reduction and those dealing with early IPD with no history of previous attempted closed reduction. Early IPD was reported in 15 patients after a mean follow-up of 3.2 months (2.9 SD) in the first group and in 4 patients after a mean follow-up of 15.1 months (9.9 SD) in the second group. CONCLUSIONS: Based on the current data, most cases have been preceded by an attempted closed reduction in the setting of outer, large articulation dislocation, perhaps indicating an iatrogenic etiology for early IPD. Recognition of this possible failure mode is essential to its prevention and treatment. PMID- 28913409 TI - Nonepidemic Kaposi sarcoma: A recently proposed category. PMID- 28913408 TI - Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis. AB - BACKGROUND & AIMS: Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in LMNA, which encodes lamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is caused by primary hepatocyte defects or systemic alterations. METHODS: To address these questions, we generated mice carrying a hepatocyte-specific deletion of Lmna (knockout [KO] mice) and characterized the KO liver and primary hepatocyte phenotypes by immunoblotting, immunohistochemistry, microarray analysis, quantitative real-time polymerase chain reaction, and Oil Red O and Picrosirius red staining. RESULTS: KO hepatocytes manifested abnormal nuclear morphology, and KO mice showed reduced body mass. KO mice developed spontaneous male-selective hepatosteatosis with increased susceptibility to high-fat diet-induced steatohepatitis and fibrosis. The hepatosteatosis was associated with up regulated transcription of genes encoding lipid transporters, lipid biosynthetic enzymes, lipid droplet-associated proteins, and interferon-regulated genes. Hepatic Lmna deficiency led to enhanced signal transducer and activator of transcription 1 (Stat1) expression and blocked growth hormone-mediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signal-regulated kinase (Erk) signaling. CONCLUSIONS: Lamin A/C acts cell-autonomously to maintain hepatocyte homeostasis and nuclear shape and buffers against male-selective steatohepatitis by positively regulating growth hormone signaling and negatively regulating Stat1 expression. Lamins are potential genetic modifiers for predisposition to steatohepatitis and liver fibrosis. The microarray data can be found in the Gene Expression Omnibus repository (accession number: GSE93643). PMID- 28913410 TI - Contrast microsphere enhancement of the tricuspid regurgitant spectral Doppler signal - Is it still necessary with contemporary scanners? AB - BACKGROUND: Accurate evaluation of the tricuspid regurgitant (TR) spectral Doppler signal is important during transthoracic echocardiographic (TTE) evaluation for pulmonary hypertension (PHT). Contrast enhancement improves Doppler backscatter. However, its incremental benefit with contemporary scanners is less well established. The aim of this study was to assess whether the TR spectral Doppler signal using contemporary scanners was improved using a second generation contrast agent, Definity(r) (CE), compared to unenhanced TTE (UE). METHODS: Analysis of patients who underwent UE then CE TR interrogation was performed. TR signal was evaluated by an experienced reader and graded 1 (clear high level of confidence of interpretation and complete spectral Doppler envelope), 2 (suboptimal with medium-low level of confidence of interpretation and incomplete envelope), 3 (poor-absent and no measurable spectral Doppler signal). Maximal TR velocity (TRV) was defined as peak velocity that could be clearly identified. An inexperienced sonographer read 30 randomly selected studies. RESULTS: 176 TTE were performed in 173 patients (mean age 57 +/- 14.8 years). Wilcoxon signed rank test demonstrated significant improvement (p < 0.0001) in TR spectral Doppler signal quality with CE TTE. Mean score CE TTE vs. TTE = 2.32 +/- 0.85 vs. 2.56 +/- 0.75 respectively (p < 0.0001). Mean maximal TRV CE TTE vs. UE TTE = 2.61 +/- 0.44 m/s vs. 2.54 +/- 0.49 m/s respectively (p < 0.0001). The inexperienced reader had a greater improvement in scoring CE TTE signals vs. UE TTE (p < 0.0001). CONCLUSION: In the era of contemporary scanners, CE improved the ability to detect and measure TRV, except in those with clear unenhanced TR spectral Doppler signals or greater than mild tricuspid regurgitation. PMID- 28913411 TI - Difference of Success Rates of Mineral Trioxide Aggregate Pulpotomies Performed Both by Undergraduate Dental Students and by an Expert Operator: A Retrospective Study. AB - AIM: The aim of this retrospective study was to evaluate the clinical and radiographic success of pulpotomy on primary molars performed by dental students compared to that performed by an expert operator. METHODS: The study was conducted on 142 second primary molars in 102 children. The patients were randomly selected from the available records. The test group (treated by dental students) included 51 subjects (28 males and 23 females, mean age: 7.2 +/- 1) and the control group included 51 children (29 males and 22 females, mean age: 7.4 +/ 1.2 years). After pulpotomy, a clinical and radiographic evaluation after 12 months was performed. Chi-square test and odds ratio were calculated and significance level was set at p < 0.05. RESULTS: The success rate was significantly lower, 81.6% (p < 0.05), in the test group than in the control group (93%). The test group showed less clinical and radiographic success (86% and 80%, resp.) compared to the control group (97.2% for clinical success and 93% for radiographic success). CONCLUSIONS: Pulpotomy with MTA is an effective method that ensures a good percentage of success. The clinical experience of the operator is a contributing factor. PMID- 28913412 TI - Addition of Wollastonite Fibers to Calcium Phosphate Cement Increases Cell Viability and Stimulates Differentiation of Osteoblast-Like Cells. AB - Calcium phosphate cement (CPC) that is based on alpha-tricalcium phosphate (alpha TCP) is considered desirable for bone tissue engineering because of its relatively rapid degradation properties. However, such cement is relatively weak, restricting its use to areas of low mechanical stress. Wollastonite fibers (WF) have been used to improve the mechanical strength of biomaterials. However, the biological properties of WF remain poorly understood. Here, we tested the response of osteoblast-like cells to being cultured on CPC reinforced with 5% of WF (CPC-WF). We found that both types of cement studied achieved an ion balance for calcium and phosphate after 3 days of immersion in culture medium and this allowed subsequent long-term cell culture. CPC-WF increased cell viability and stimulated cell differentiation, compared to nonreinforced CPC. We hypothesize that late silicon release by CPC-WF induces increased cell proliferation and differentiation. Based on our findings, we propose that CPC-WF is a promising material for bone tissue engineering applications. PMID- 28913413 TI - Open versus Closed Kinetic Chain Exercises following an Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: There is no consensus on whether closed kinetic chain (CKC) or open kinetic chain (OKC) exercises should be the intervention of choice following an anterior cruciate ligament (ACL) injury or reconstruction. METHODS: A systematic search identified randomized controlled trials of OKC versus CKC exercise training in people who had undergone ACL reconstructive surgery. All published studies in this systematic review were comparisons between OKC and CKC groups. RESULTS: Seven studies were included. Lysholm knee scoring scale was not significantly different between OKC and CKC exercise patients: MD: -1.03%; CI: 13.02, 10.95; p value = 0.87 (Chi2 = 0.18, df = 1, and p value = 0.67). Hughston clinic questionnaire scores were not significantly different between OKC and CKC exercise patients: MD: -1.29% (-12.02, 9.43); p value = 0.81 (Chi2 = 0.01, df = 1, and p value = 0.93). CONCLUSIONS: While OKC and CKC may be beneficial during ACL surgical rehabilitation, there is insufficient evidence to suggest that either one is superior to the other. PMID- 28913414 TI - Diversity of Aerobic Bacteria Isolated from Oral and Cloacal Cavities from Free Living Snakes Species in Costa Rica Rainforest. AB - Costa Rica has a significant number of snakebites per year and bacterial infections are often complications in these animal bites. Hereby, this study aims to identify, characterize, and report the diversity of the bacterial community in the oral and cloacal cavities of venomous and nonvenomous snakes found in wildlife in Costa Rica. The snakes where captured by casual encounter search between August and November of 2014 in the Quebrada Gonzalez sector, in Braulio Carrillo National Park. A total of 120 swabs, oral and cloacal, were taken from 16 individuals of the Viperidae and Colubridae families. Samples were cultured on four different media at room temperature. Once isolated in pure culture, colonies were identified with the VITEK(r) 2C platform (bioMerieux). In order to test the identification provided on environmental isolates, molecular analyses were conducted on 27 isolates of different bacterial species. Specific 16S rDNA PCR mediated amplification for bacterial taxonomy was performed, then sequenced, and compared with sequences of Ribosomal Database Project (RDP). From 90 bacterial isolates, 40 different bacterial species were identified from both oral and cloacal swabs. These results indicate the diversity of opportunistic pathogens present and their potential to generate infections and zoonosis in humans. PMID- 28913415 TI - Forensic Pathology Education in Pathology Residency: A Survey of Current Practices, a Novel Curriculum, and Recommendations for the Future. AB - Forensic pathology is a fundamental part of anatomic pathology training during pathology residency. However, the lack of information on forensic teaching suggests the highly variable nature of forensic education. A survey of pathology residency program directors was performed to determine key aspects of their respective forensic rotations and curriculum. A total of 38.3% of programs from across the country responded, and the survey results show 5.6% don't require a forensic pathology rotation. In those that do, most forensic pathology rotations are 4 weeks long, are done at a medical examiner's office, and require set prerequisites. A total of 21.1% of responding programs have residents who are not receiving documented evaluations for this rotation. While 39.6% of programs have a defined forensics curriculum, as many as 15% do not. Furthermore, nearly 43% of programs place no limit on counting forensic autopsies when applying for pathology board examinations. Our survey confirmed the inconsistent nature of forensic pathology training in resident education. Additionally, our curriculum was reorganized to create a more robust educational experience. A pre- and post forensic lecture quiz and Resident In-Service Examination scores were analyzed to determine our curriculum's impact and effectiveness. Analysis of our pre- and post-lecture quiz showed an improved overall average as well as an increase in Resident In-Service Examination scores, indicating improved general forensic pathology knowledge. Using this knowledge, along with changes in our curriculum, we generated a number of recommendations for improving forensic pathology education in pathology residency. PMID- 28913416 TI - Using Focused Laboratory Management and Quality Improvement Projects to Enhance Resident Training and Foster Scholarship. AB - Training in patient safety, quality, and management is widely recognized as an important element of graduate medical education. These concepts have been intertwined in pathology graduate medical education for many years, although training programs face challenges in creating explicit learning opportunities in these fields. Tangibly involving pathology residents in management and quality improvement projects has the potential to teach and reinforce key concepts and further fulfill Accreditation Council for Graduate Medical Education goals for pursuing projects related to patient safety and quality improvement. In this report, we present our experience at a pathology residency program (University of Iowa) in engaging pathology residents in projects related to practical issues of laboratory management, process improvement, and informatics. In this program, at least 1 management/quality improvement project, typically performed during a clinical chemistry/management rotation, was required and ideally resulted in a journal publication. The residency program also initiated a monthly management/informatics series for pathology externs, residents, and fellows that covers a wide range of topics. Since 2010, all pathology residents at the University of Iowa have completed at least 1 management/quality improvement project. Many of the projects involved aspects of laboratory test utilization, with some projects focused on other areas such as human resources, informatics, or process improvement. Since 2012, 31 peer-reviewed journal articles involving effort from 26 residents have been published. Multiple projects resulted in changes in ongoing practice, particularly within the hospital electronic health record. Focused management/quality improvement projects involving pathology residents can result in both meaningful quality improvement and scholarly output. PMID- 28913417 TI - Parasite biodiversity faces extinction and redistribution in a changing climate. AB - Climate change is a well-documented driver of both wildlife extinction and disease emergence, but the negative impacts of climate change on parasite diversity are undocumented. We compiled the most comprehensive spatially explicit data set available for parasites, projected range shifts in a changing climate, and estimated extinction rates for eight major parasite clades. On the basis of 53,133 occurrences capturing the geographic ranges of 457 parasite species, conservative model projections suggest that 5 to 10% of these species are committed to extinction by 2070 from climate-driven habitat loss alone. We find no evidence that parasites with zoonotic potential have a significantly higher potential to gain range in a changing climate, but we do find that ectoparasites (especially ticks) fare disproportionately worse than endoparasites. Accounting for host-driven coextinctions, models predict that up to 30% of parasitic worms are committed to extinction, driven by a combination of direct and indirect pressures. Despite high local extinction rates, parasite richness could still increase by an order of magnitude in some places, because species successfully tracking climate change invade temperate ecosystems and replace native species with unpredictable ecological consequences. PMID- 28913418 TI - Unveiling the role and life strategies of viruses from the surface to the dark ocean. AB - Viruses are a key component of marine ecosystems, but the assessment of their global role in regulating microbial communities and the flux of carbon is precluded by a paucity of data, particularly in the deep ocean. We assessed patterns in viral abundance and production and the role of viral lysis as a driver of prokaryote mortality, from surface to bathypelagic layers, across the tropical and subtropical oceans. Viral abundance showed significant differences between oceans in the epipelagic and mesopelagic, but not in the bathypelagic, and decreased with depth, with an average power-law scaling exponent of -1.03 km 1 from an average of 7.76 * 106 viruses ml-1 in the epipelagic to 0.62 * 106 viruses ml-1 in the bathypelagic layer with an average integrated (0 to 4000 m) viral stock of about 0.004 to 0.044 g C m-2, half of which is found below 775 m. Lysogenic viral production was higher than lytic viral production in surface waters, whereas the opposite was found in the bathypelagic, where prokaryotic mortality due to viruses was estimated to be 60 times higher than grazing. Free viruses had turnover times of 0.1 days in the bathypelagic, revealing that viruses in the bathypelagic are highly dynamic. On the basis of the rates of lysed prokaryotic cells, we estimated that viruses release 145 Gt C year-1 in the global tropical and subtropical oceans. The active viral processes reported here demonstrate the importance of viruses in the production of dissolved organic carbon in the dark ocean, a major pathway in carbon cycling. PMID- 28913419 TI - Quantum coherence as a witness of vibronically hot energy transfer in bacterial reaction center. AB - Photosynthetic proteins have evolved over billions of years so as to undergo optimal energy transfer to the sites of charge separation. On the basis of spectroscopically detected quantum coherences, it has been suggested that this energy transfer is partially wavelike. This conclusion depends critically on the assignment of the coherences to the evolution of excitonic superpositions. We demonstrate that, for a bacterial reaction center protein, long-lived coherent spectroscopic oscillations, which bear canonical signatures of excitonic superpositions, are essentially vibrational excited-state coherences shifted to the ground state of the chromophores. We show that the appearance of these coherences arises from a release of electronic energy during energy transfer. Our results establish how energy migrates on vibrationally hot chromophores in the reaction center, and they call for a reexamination of claims of quantum energy transfer in photosynthesis. PMID- 28913420 TI - Ghost reefs: Nautical charts document large spatial scale of coral reef loss over 240 years. AB - Massive declines in population abundances of marine animals have been documented over century-long time scales. However, analogous loss of spatial extent of habitat-forming organisms is less well known because georeferenced data are rare over long time scales, particularly in subtidal, tropical marine regions. We use high-resolution historical nautical charts to quantify changes to benthic structure over 240 years in the Florida Keys, finding an overall loss of 52% (SE, 6.4%) of the area of the seafloor occupied by corals. We find a strong spatial dimension to this decline; the spatial extent of coral in Florida Bay and nearshore declined by 87.5% (SE, 7.2%) and 68.8% (SE, 7.5%), respectively, whereas that of offshore areas of coral remained largely intact. These estimates add to finer-scale loss in live coral cover exceeding 90% in some locations in recent decades. The near-complete elimination of the spatial coverage of nearshore coral represents an underappreciated spatial component of the shifting baseline syndrome, with important lessons for other species and ecosystems. That is, modern surveys are typically designed to assess change only within the species' known, extant range. For species ranging from corals to sea turtles, this approach may overlook spatial loss over longer time frames, resulting in both overly optimistic views of their current conservation status and underestimates of their restoration potential. PMID- 28913421 TI - Curvature and Rho activation differentially control the alignment of cells and stress fibers. AB - In vivo, cells respond to a host of physical cues ranging from substrate stiffness to the organization of micro- and nanoscale fibrous networks. We show that macroscale substrates with radii of curvature from tens to hundreds of micrometers influence cell alignment. In a model system of fibroblasts, isolated cells aligned strongly in the axial direction on cylinders with radii similar to the cell length and more weakly on cylinders of much larger radius. Isolated vascular smooth muscle cells did not align as effectively as fibroblasts. However, both cell types aligned robustly in weak curvature fields when in confluent monolayers. We identified two distinct populations of stress fibers in both cell types: long, apical stress fibers that aligned axially and short, basal stress fibers that aligned circumferentially. Circumferential alignment of the basal stress fibers is in apparent disagreement with a long-standing hypothesis that energetic penalties for bending enforce axial alignment on cylinders. To explore this phenomenon, we manipulated stress fibers by activating Rho, a small guanosine triphosphatase that regulates stress fiber assembly. In response, apical stress fibers disassembled, whereas basal stress fibers thickened and aligned more strongly in the circumferential direction. By activating Rho in confluent monolayers of vascular smooth muscle cells, we recapitulated the circumferential alignment pattern of F-actin within these cells that is observed in cylindrical vessels in vivo. In agreement with recent theory, these results suggest that stress fiber bending penalties are overcome when stress fiber contractility is enhanced and motivate deeper study of the mechanics of these distinct stress fiber populations. PMID- 28913422 TI - Ultratransparent and stretchable graphene electrodes. AB - Two-dimensional materials, such as graphene, are attractive for both conventional semiconductor applications and nascent applications in flexible electronics. However, the high tensile strength of graphene results in fracturing at low strain, making it challenging to take advantage of its extraordinary electronic properties in stretchable electronics. To enable excellent strain-dependent performance of transparent graphene conductors, we created graphene nanoscrolls in between stacked graphene layers, referred to as multilayer graphene/graphene scrolls (MGGs). Under strain, some scrolls bridged the fragmented domains of graphene to maintain a percolating network that enabled excellent conductivity at high strains. Trilayer MGGs supported on elastomers retained 65% of their original conductance at 100% strain, which is perpendicular to the direction of current flow, whereas trilayer films of graphene without nanoscrolls retained only 25% of their starting conductance. A stretchable all-carbon transistor fabricated using MGGs as electrodes exhibited a transmittance of >90% and retained 60% of its original current output at 120% strain (parallel to the direction of charge transport). These highly stretchable and transparent all carbon transistors could enable sophisticated stretchable optoelectronics. PMID- 28913424 TI - RecA filament maintains structural integrity using ATP-driven internal dynamics. AB - At the core of homologous DNA repair, RecA catalyzes the strand exchange reaction. This process is initiated by a RecA loading protein, which nucleates clusters of RecA proteins on single-stranded DNA. Each cluster grows to cover the single-stranded DNA but may leave 1- to 2-nucleotide (nt) gaps between the clusters due to three different structural phases of the nucleoprotein filaments. It remains to be revealed how RecA proteins eliminate the gaps to make a seamless kilobase-long filament. We develop a single-molecule fluorescence assay to observe the novel internal dynamics of the RecA filament. We directly observe the structural phases of individual RecA filaments and find that RecA proteins move their positions along the substrate DNA to change the phase of the filament. This reorganization process, which is a prerequisite step for interjoining of two adjacent clusters, requires adenosine triphosphate hydrolysis and is tightly regulated by the recombination hotspot, Chi. Furthermore, RecA proteins recognize and self-align to a 3-nt-period sequence pattern of TGG. This sequence-dependent phase bias may help the RecA filament to maintain structural integrity within the kilobase-long filament for accurate homology search and strand exchange reaction. PMID- 28913423 TI - Opto-thermophoretic assembly of colloidal matter. AB - Colloidal matter exhibits unique collective behaviors beyond what occurs at single-nanoparticle and atomic scales. Treating colloidal particles as building blocks, researchers are exploiting new strategies to rationally organize colloidal particles into complex structures for new functions and devices. Despite tremendous progress in directed assembly and self-assembly, a truly versatile assembly technique without specific functionalization of the colloidal particles remains elusive. We develop a new strategy to assemble colloidal matter under a light-controlled temperature field, which can solve challenges in the existing assembly techniques. By adding an anionic surfactant (that is, cetyltrimethylammonium chloride), which serves as a surface charge source, a macro ion, and a micellar depletant, we generate a light-controlled thermoelectric field to manipulate colloidal atoms and a depletion attraction force to assemble the colloidal atoms into two-dimensional (2D) colloidal matter. The general applicability of this opto-thermophoretic assembly (OTA) strategy allows us to build colloidal matter of diverse colloidal sizes (from subwavelength scale to micrometer scale) and materials (polymeric, dielectric, and metallic colloids) with versatile configurations and tunable bonding strengths and lengths. We further demonstrate that the incorporation of the thermoelectric field into the optical radiation force can achieve 3D reconfiguration of the colloidal matter. The OTA strategy releases the rigorous design rules required in the existing assembly techniques and enriches the structural complexity in colloidal matter, which will open a new window of opportunities for basic research on matter organization, advanced material design, and applications. PMID- 28913425 TI - Explaining opposition to refugee resettlement: The role of NIMBYism and perceived threats. AB - One week after President Donald Trump signed a controversial executive order to reduce the influx of refugees to the United States, we conducted a survey experiment to understand American citizens' attitudes toward refugee resettlement. Specifically, we evaluated whether citizens consider the geographic context of the resettlement program (that is, local versus national) and the degree to which they are swayed by media frames that increasingly associate refugees with terrorist threats. Our findings highlight a collective action problem: Participants are consistently less supportive of resettlement within their own communities than resettlement elsewhere in the country. This pattern holds across all measured demographic, political, and geographic subsamples within our data. Furthermore, our results demonstrate that threatening media frames significantly reduce support for both national and local resettlement. Conversely, media frames rebutting the threat posed by refugees have no significant effect. Finally, the results indicate that participants in refugee dense counties are less responsive to threatening frames, suggesting that proximity to previously settled refugees may reduce the impact of perceived security threats. PMID- 28913426 TI - Artificial solid electrolyte interphase for aqueous lithium energy storage systems. AB - Aqueous lithium energy storage systems address environmental sustainability and safety issues. However, significant capacity fading after repeated cycles of charge-discharge and during float charge limit their practical application compared to their nonaqueous counterparts. We introduce an artificial solid electrolyte interphase (SEI) to the aqueous systems and report the use of graphene films as an artificial SEI (G-SEI) that substantially enhance the overall performance of an aqueous lithium battery and a supercapacitor. The thickness (1 to 50 nm) and the surface area (1 cm2 to 1 m2) of the G-SEI are precisely controlled on the LiMn2O4-based cathode using the Langmuir trough-based techniques. The aqueous battery with a 10-nm-thick G-SEI exhibits a discharge capacity as high as 104 mA.hour g-1 after 600 cycles and a float charge current density as low as 1.03 mA g-1 after 1 day, 26% higher (74 mA.hour g-1) and 54% lower (1.88 mA g-1) than the battery without the G-SEI, respectively. We propose that the G-SEI on the cathode surface simultaneously suppress the structural distortion of the LiMn2O4 (the Jahn-Teller distortion) and the oxidation of conductive carbon through controlled diffusion of Li+ and restricted permeation of gases (O2 and CO x ), respectively. The G-SEI on both small (~1 cm2 in 1.15 mA.hour cell) and large (~9 cm2 in 7 mA.hour cell) cathodes exhibit similar property enhancement, demonstrating excellent potential for scale-up and manufacturing. PMID- 28913427 TI - Ultrastable atomic copper nanosheets for selective electrochemical reduction of carbon dioxide. AB - The electrochemical conversion of CO2 and H2O into syngas using renewably generated electricity is an attractive approach to simultaneously achieve chemical fixation of CO2 and storage of renewable energy. Developing cost effective catalysts for selective electroreduction of CO2 into CO is essential to the practical applications of the approach. We report a simple synthetic strategy for the preparation of ultrathin Cu/Ni(OH)2 nanosheets as an excellent cost effective catalyst for the electrochemical conversion of CO2 and H2O into tunable syngas under low overpotentials. These hybrid nanosheets with Cu(0)-enriched surface behave like noble metal nanocatalysts in both air stability and catalysis. Uniquely, Cu(0) within the nanosheets is stable against air oxidation for months because of the presence of formate on their surface. With the presence of atomically thick ultrastable Cu nanosheets, the hybrid Cu/Ni(OH)2 nanosheets display both excellent activity and selectivity in the electroreduction of CO2 to CO. At a low overpotential of 0.39 V, the nanosheets provide a current density of 4.3 mA/cm2 with a CO faradaic efficiency of 92%. No decay in the current is observed for more than 22 hours. The catalysts developed in this work are promising for building low-cost CO2 electrolyzers to produce CO. PMID- 28913428 TI - Rubbery electronics and sensors from intrinsically stretchable elastomeric composites of semiconductors and conductors. AB - A general strategy to impart mechanical stretchability to stretchable electronics involves engineering materials into special architectures to accommodate or eliminate the mechanical strain in nonstretchable electronic materials while stretched. We introduce an all solution-processed type of electronics and sensors that are rubbery and intrinsically stretchable as an outcome from all the elastomeric materials in percolated composite formats with P3HT-NFs [poly(3 hexylthiophene-2,5-diyl) nanofibrils] and AuNP-AgNW (Au nanoparticles with conformally coated silver nanowires) in PDMS (polydimethylsiloxane). The fabricated thin-film transistors retain their electrical performances by more than 55% upon 50% stretching and exhibit one of the highest P3HT-based field effect mobilities of 1.4 cm2/V?s, owing to crystallinity improvement. Rubbery sensors, which include strain, pressure, and temperature sensors, show reliable sensing capabilities and are exploited as smart skins that enable gesture translation for sign language alphabet and haptic sensing for robotics to illustrate one of the applications of the sensors. PMID- 28913430 TI - Time-of-day-dependent global distribution of lunar surficial water/hydroxyl. AB - A new set of time-of-day-dependent global maps of the lunar near-infrared water/hydroxyl (H2O/OH) absorption band strength near 2.8 to 3.0 MUm constructed on the basis of Moon Mineralogy Mapper (M3) data is presented. The analyzed absorption band near 2.8 to 3.0 MUm indicates the presence of surficial H2O/OH. To remove the thermal emission component from the M3 reflectance spectra, a reliable and physically realistic mapping method has been developed. Our maps show that lunar highlands at high latitudes show a stronger H2O/OH absorption band in the lunar morning and evening than at midday. The amplitude of these time of-day-dependent variations decreases with decreasing latitude of the highland regions, where below about 30 degrees , absorption strength becomes nearly constant during the lunar day at a similar level as in the high-latitude highlands at midday. The lunar maria exhibit weaker H2O/OH absorption than the highlands at all, but showing a smaller difference from highlands absorption levels in the morning and evening than at midday. The level around midday is generally higher for low-Ti than for high-Ti mare surfaces, where it reaches near zero values. Our observations contrast with previous studies that indicate a significant concentration of surficial H2O/OH at high latitudes only. Furthermore, although our results generally support the commonly accepted mechanism of H2O/OH formation by adsorption of solar wind protons, they suggest the presence of a more strongly bounded surficial H2O/OH component in the lunar highlands and parts of the mare regions, which is not removed by processes such as diffusion/thermal evaporation and photolysis in the course of the lunar day. PMID- 28913429 TI - Ultrahigh mobility and efficient charge injection in monolayer organic thin-film transistors on boron nitride. AB - Organic thin-film transistors (OTFTs) with high mobility and low contact resistance have been actively pursued as building blocks for low-cost organic electronics. In conventional solution-processed or vacuum-deposited OTFTs, due to interfacial defects and traps, the organic film has to reach a certain thickness for efficient charge transport. Using an ultimate monolayer of 2,7 dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) molecules as an OTFT channel, we demonstrate remarkable electrical characteristics, including intrinsic hole mobility over 30 cm2/Vs, Ohmic contact with 100 Omega . cm resistance, and band-like transport down to 150 K. Compared to conventional OTFTs, the main advantage of a monolayer channel is the direct, nondisruptive contact between the charge transport layer and metal leads, a feature that is vital for achieving low contact resistance and current saturation voltage. On the other hand, bilayer and thicker C8-BTBT OTFTs exhibit strong Schottky contact and much higher contact resistance but can be improved by inserting a doped graphene buffer layer. Our results suggest that highly crystalline molecular monolayers are promising form factors to build high-performance OTFTs and investigate device physics. They also allow us to precisely model how the molecular packing changes the transport and contact properties. PMID- 28913431 TI - Ultrahigh-current density anodes with interconnected Li metal reservoir through overlithiation of mesoporous AlF3 framework. AB - Lithium (Li) metal is the ultimate solution for next-generation high-energy density batteries but is plagued from commercialization by infinite relative volume change, low Coulombic efficiency due to side reactions, and safety issues caused by dendrite growth. These hazardous issues are further aggravated under high current densities needed by the increasing demand for fast charging/discharging. We report a one-step fabricated Li/Al4Li9-LiF nanocomposite (LAFN) through an "overlithiation" process of a mesoporous AlF3 framework, which can simultaneously mitigate the abovementioned problems. Reaction-produced Al4Li9 LiF nanoparticles serve as the ideal skeleton for Li metal infusion, helping to achieve a near-zero volume change during stripping/plating and suppressed dendrite growth. As a result, the LAFN electrode is capable of working properly under an ultrahigh current density of 20 mA cm-2 in symmetric cells and manifests highly improved rate capability with increased Coulombic efficiency in full cells. The simple fabrication process and its remarkable electrochemical performances enable LAFN to be a promising anode candidate for next-generation lithium metal batteries. PMID- 28913432 TI - Experimental phase diagram of zero-bias conductance peaks in superconductor/semiconductor nanowire devices. AB - Topological superconductivity is an exotic state of matter characterized by spinless p-wave Cooper pairing of electrons and by Majorana zero modes at the edges. The first signature of topological superconductivity is a robust zero-bias peak in tunneling conductance. We perform tunneling experiments on semiconductor nanowires (InSb) coupled to superconductors (NbTiN) and establish the zero-bias peak phase in the space of gate voltage and external magnetic field. Our findings are consistent with calculations for a finite-length topological nanowire and provide means for Majorana manipulation as required for braiding and topological quantum bits. PMID- 28913433 TI - Single-pixel computational ghost imaging with helicity-dependent metasurface hologram. AB - Different optical imaging techniques are based on different characteristics of light. By controlling the abrupt phase discontinuities with different polarized incident light, a metasurface can host a phase-only and helicity-dependent hologram. In contrast, ghost imaging (GI) is an indirect imaging modality to retrieve the object information from the correlation of the light intensity fluctuations. We report single-pixel computational GI with a high-efficiency reflective metasurface in both simulations and experiments. Playing a fascinating role in switching the GI target with different polarized light, the metasurface hologram generates helicity-dependent reconstructed ghost images and successfully introduces an additional security lock in a proposed optical encryption scheme based on the GI. The robustness of our encryption scheme is further verified with the vulnerability test. Building the first bridge between the metasurface hologram and the GI, our work paves the way to integrate their applications in the fields of optical communications, imaging technology, and security. PMID- 28913434 TI - Self-determined shapes and velocities of giant near-zero drag gas cavities. AB - Minimizing the retarding force on a solid moving in liquid is the canonical problem in the quest for energy saving by friction and drag reduction. For an ideal object that cannot sustain any shear stress on its surface, theory predicts that drag force will fall to zero as its speed becomes large. However, experimental verification of this prediction has been challenging. We report the construction of a class of self-determined streamlined structures with this free slip surface, made up of a teardrop-shaped giant gas cavity that completely encloses a metal sphere. This stable gas cavity is formed around the sphere as it plunges at a sufficiently high speed into the liquid in a deep tank, provided that the sphere is either heated initially to above the Leidenfrost temperature of the liquid or rendered superhydrophobic in water at room temperature. These sphere-in-cavity structures have residual drag coefficients that are typically less than [Formula: see text] those of solid objects of the same dimensions, which indicates that they experienced very small drag forces. The self-determined shapes of the gas cavities are shown to be consistent with the Bernoulli equation of potential flow applied on the cavity surface. The cavity fall velocity is not arbitrary but is uniquely predicted by the sphere density and cavity volume, so larger cavities have higher characteristic velocities. PMID- 28913436 TI - Our Journal in English. PMID- 28913437 TI - Biomarkers of sepsis, a never-ending story. PMID- 28913435 TI - IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy. AB - OBJECTIVE: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. METHODS: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL. RESULTS: We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and alpha-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system. CONCLUSIONS: Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities. PMID- 28913438 TI - Total Intravenous Anesthesia-Target Controlled Infusion for colorectal surgery. Remifentanil TCI vs sufentanil TCI. AB - : The aim of the study was to compare the effect of remifentanil and sufentanil administered for total intravenous anaesthesia (TIVA) using target-controlled infusion (TCI) on intraoperative hemodynamic response, tracheal intubation and extubation times in patients undergoing colorectal surgery. METHODS: Sixty patients undergoing open colorectal surgery for colorectal tumors or inflammatory diseases were randomized prospectively into one of two groups: remifentanil group R (n = 30) received TIVA-TCI with propofol and remifentanil and sufentanil group S (n = 30) received TIVA-TCI with propofol and sufentanil. Changes of mean arterial pressure (MAP) and heart rate (HR) were compared during induction and maintenance of anaesthesia. Response to tracheal intubation was assessed as episodes of hypertension, increased HR and bispectral index values, sweating, lacrimation, and coughing. The numbers of target plasma concentration (Cp) adjustments of opioids and propofol due to painful stimulation were recorded during surgery. Recovery time expressed as extubation time was also evaluated. RESULTS: MAP and HR, expressed as area under the curve (AUC), were not significantly different between groups during anesthesia and surgery. During induction of anesthesia, MAP values decrease from baseline, in both groups (p < 0.001). Intergroup comparison revealed that MAP decreased more in the remifentanil than sufentanil group (p = 0.027). HR decreased from baseline values only in the remifentanil group (p = 0.05). The number of target concentration adjustments for propofol and opioid was higher in the remifentanil group as compared with sufentanil group (p = 0.02 and p = 0.04). Hemodynamic responses to tracheal intubation and extubation times were not significantly different between the groups. CONCLUSION: Both remifentanil and sufentanil TCI produced stable hemodynamic conditions during open colorectal surgery but sufentanil TCI was associated with less decrease in blood pressure and heart rate, and required fewer dose adjustments during anesthesia induction. PMID- 28913439 TI - Predicting scores correlations in patients with septic shock - a cohort study. AB - BACKGROUND: ICU prognostic scores were developed to measure the severity of the disease and the patients' prognosis. The objective of this study was to assess the validity of the Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score II (SAPS II) scores in patients with septic shock. METHODS: The APACHE II, SOFA and SAPS II scores were determined prospectively, in the first 24 hours after admission, for all 56 patients with septic shock who were included in this study. Data were statistically evaluated; the discriminating power regarding survivors vs deceased patients was calculated based on the receiver operating characteristic curves (ROC). RESULTS: The overall mortality of the 56 patients with septic shock was 60.71% (34 deaths). The average APACHE II score was 25.36 +/- 7.477. The average SOFA score was 7.679 +/- 3.197. The average SAPS II score was 44.45 +/- 16.97. For the APACHE II and SOFA scores the differences when deceased and survivors were compared were not statistically significant (APACHE II: 26.76 +/- 6.742 vs 23.18 +/- 8.175 respectively for SOFA: 8.029 +/- 3.099 vs 7.136 +/- 3.342). For the SAPS II score the values are: 49.12 +/- 16.61 in deceased vs 37.23 +/- 15.20 in survivors, the difference being statistically significant (p = 0.0092). The areas under ROC for the three scores are 0.622 for APACHE II, 0.575 for SAPS II and 0.705 for SOFA. CONCLUSIONS: In our study the SAPS II score was superior to the other scores for predicting survival in patients with septic shock. PMID- 28913440 TI - The influence of the method of initial stabilization of traumatic femoral shaft fractures on postoperative morbidity and mortality - a retrospective study. AB - BACKGROUND: The last 20 years have been dedicated to extensive research regarding the pathophysiology of trauma and the consequences of interventions that follow. Several theories have been proposed in terms of what causative factors are associated with poor outcome in polytrauma patients. Once the "two event model" was accepted, it became clear that patients although initially resuscitated, but in a vulnerable condition, have a high risk that a secondary aggression (for example, surgical interventions) would precipitate a state of hyperinflammation and early multiple organ dysfunction syndrome (MODS). The aim of this retrospective study was the analysis of the "second hit" phenomenon, meaning the alterations that occur in patients having femoral shaft stabilization surgery after major trauma. METHODS: This is a retrospective study of severe polytrauma patients with femoral shaft fractures admitted to the intensive care unit of the Emergency clinical Hospital of Bucharest and treated from an orthopaedic point of view by either Damage Control Orthopaedics (DCO) or Early Total Care (ETC) principles. All patients had femoral shaft stabilization in the first 24 hours. Using patients files we recorded the following data: 30 day mortality, development of acute respiratory distress syndrome (ARDS) and MODS, local infectious complications (LIC), intensive care unit length of stay (ICU LOS), days of mechanical ventilation (MV), units of red blood cells units/48 h (RBC). We decided to analyze results in three groups - DCO group with shock on admission, DCO group without shock and ETC group. RESULTS: We observed significantly higher mortality in the DCO shock group (25%) compared with the other two groups (ETC - 9.4%; DCO without shock - 6.7%; p = 0.042/0.015). Similar results for: ICU LOS (16.29 +/- 6.7 versus 9.92 +/- 4.7 and 10 +/- 3.9; p = 0.001/0.002), days of MV (10.29 +/- 5.7 versus 6.83 +/- 4.7 and 6.8 +/- 3.4; p = 0.007/0.04), units of RBC/48 h (15.04 +/- 4.3 versus 8.08 +/- 4.3 and 7.33 +/- 1.5; p = 0.007/0.04). Although not statistically significant, MODS and ARDS incidences were higher in the DCO shock group: MODS (41.7% versus 22.6% and 20%; p = 0.08/0.17), ARDS (29.2% versus 17% and 20%; p = 0.22/0.53). These results correlate with a higher trauma score in these patients, more serious lesions requiring several damage control procedures. In the other two groups (DCO without shock and ETC) all outcomes were similar. Local septic complications were higher, as expected, in all patients with external fixation and we observed a very low incidence in the ETC group (8.3% - DCO shock group versus 1.9% - ETC group and 6.7% - DCO no shock group; p = 0.18/0.009). CONCLUSIONS: In patients who are not in a very severe condition (shock), the choice for femoral shaft stabilization by intramedullary nailing represents a safe option. We did not observe any differences in outcomes by comparing ETC and DCO types of procedures in these relatively stable patients. PMID- 28913441 TI - The interrelation between arterial lactate levels and postoperative outcome following liver transplantation. AB - BACKGROUND: The aim of this study was to determine whether arterial blood lactate concentration at the end of liver transplantation is associated with major postoperative complications, length of Intensive Care Unit (ICU) stay and mortality. METHODS: Arterial lactate concentration was recorded at the end of surgery in 48 patients (30 males and 18 females) who had underwent liver transplantation (LT) over a six month period between June 2013 and December 2013. Demographic data, laboratory results and postoperative outcome were recorded. RESULTS: The mean age in the study group was 51.14 years (16-62); all the patients had undergone deceased-donor liver transplantation. The etiology of liver disease was various: viral infections (HBV and HCV), alcoholic cirrhosis, hepatocarcinoma and other rare causes of cirrhosis (Wilson disease) were found. The mean duration of surgery was 407 minutes (240-580). Mean lactate was 2.77 mmol/L (0.8-7.9) and was increased above 1.5 mmol/L in 33 (68.75%) patients. ICU length of stay was longer in patients having lactate levels > 5 mmol/L (p = 0.05). Intraoperative blood loss was higher in patients with lactate > 3 mmol/L (p = 0.012). Major complications including acute kidney injury, need for emergency surgery during ICU stay or primary graft disfunction were observed only in patients with lactate levels > 1.5 mmol/L (18.2%). Sixty days mortality was 100% in the group with lactate > 5 mmol/L (4 patients) compared with 12.5% mortality in patients with lactate level < 5 mmol/L (p = 0.05). CONCLUSIONS: Arterial lactate concentrations at the end of liver transplantation correlates with increased intraoperative blood loss, longer ICU stay, and increased mortality. PMID- 28913442 TI - Cough, expiration and aspiration reflexes: possible anesthetic implications - a brief review. AB - Systematic study in animals indicated, that in addition to cough there are 2 distinct airway reflexes. The aspiration reflex (AspR) characterized by rapid and strong gasp-like inspiration provoked by stimulation of nasopharynx, nasal phyltrum or auricle of ear. The expiration reflex (ExpR) manifests by prompt expiration, induced by laryngeal stimulation. Both reflexes strongly activate the brainstem inspiratory or expiratory generators, respectively, and inhibit the opposite respiratory and various functional disorders. This paper indicates several functional disorders occurring during manipulation with airways in anaesthesiological practice, which can be influenced positively or negatively by application of these special reflexes (asphyxia, breath-holding, laryngospasm, bronchospasm, sleep apnoea episodes, arrhythmia, collapse, etc.). The AspR, ExpR and CR (cough reflex) have important clinical relevance in anaesthesia and emergency medicine applicable also in domestic therapy and in hardly accessible places particularly by application of ICT (Information & Communication Technologies) using a mobile connection of the patient with the remote hospital centre. PMID- 28913443 TI - Biomarkers in polytrauma induced systemic inflammatory response syndrome and sepsis - a narrative review. AB - Polytrauma still represents one of the leading causes of death in the first four decades of life. Septic complications represent the predominant causes of late death in polytrauma patients. Early diagnosis and treatment of infection is associated with an improved clinical outcome and reduced mortality. Several biomarkers have been evaluated for making early diagnosis of sepsis. Current evidence does not support the use of a single biomarker in diagnosing septic complications. Procalcitonin trend was found to be useful in early identification of post-traumatic sepsis. PMID- 28913445 TI - The i-gel as a conduit for the Aintree intubation catheter for subsequent fiberoptic intubation. AB - We report a clinical case of an 128 kg, 53 year old male, who was scheduled for sleeve gastrectomy surgery. Video laryngoscope (GlideScope - Verathron) assisted intubation was attempted. Despite repositioning of the head and neck and external laryngeal manipulations, two attempts to lift the epiglottis were unsuccessful. An i-gel (Intersurgical, Wokingham, Berkshire, United Kingdom) supraglottic device was successfully placed and normal oxygenation and ventilation was established with pressure controlled ventilation. An Aintree intubation catheter (AIC, Cook Medical, USA) pre-loaded onto a pediatric fiberoptic bronchoscope (FOB) was advanced through the i-gel. After fiber optic visualization of the vocal cords, the AIC and FOB were successfully placed into the patient's trachea. We conclude that the i-gel may not only serve as a substitute for failed tracheal intubation, but is also useful as a conduit for subsequent fiberoptic intubation. PMID- 28913444 TI - Oxidative stress and antioxidant therapy in traumatic spinal cord injuries. AB - Spinal cord injury (SCI) is often accompanied by motor, vegetative and sensitive dysfunctions that can significantly decrease the chance of the complete recovery of the patients. The pathophysiological implication of these dysfunctions is represented by the increased production of the reactive species that are extremely aggressive to the surrounding tissue. The combination of massive production of free radicals, low concentration of antioxidants and the hypermetabolism present in patients with SCI leads to enhancement of the oxidative stress. Current studies are focused on several biological active compounds that are able to reduce the effects of free radicals - tissue necrosis, inflammation, infection, apoptosis. In this paper, the mechanism of the action of several biological active compounds that are able to significantly reduce oxidative stress in critical patients with spinal cord injury is presented. PMID- 28913446 TI - Effects of a novel cytokine haemoadsorbtion system on inflammatory response in septic shock after cephalic pancreatectomy - a case report. AB - Severe sepsis and septic shock are associated with an inflammatory cascade that is primarily responsible for multiple organ dysfunction. To date, there are no specific treatments designed to modulate and rebalance inflammatory cytokines levels. We present a case of a 50 years old man with postoperative septic shock after undergoing cephalic pancreatectomy for a pancreatic cystic tumor. The use of a haemoadsorbtion device (CytoSorb(r)) in combination with continuous veno venous haemofiltration was associated with a decrease in TNFalpha, IL-1beta and IFNgamma and an increase in IL-10 levels measured before and after two consecutive procedures. The effect of CytoSorb(r) on inflammatory cytokines translated into a more stable haemodynamic profile with a stable cardiac output and normalization of systemic vascular resistance index and decreased vasopressor requirements. Further prospective large clinical trials are required in order to determine the indications for CytoSorb(r) and to evaluate the overall outcome. PMID- 28913447 TI - Dreaming with a broken heart: the importance of Takotsubo cardiomyopathy as a perioperative etiology of anesthetic-related cardiopulmonary dysfunction. PMID- 28913448 TI - What is hiding the compartment syndrome? PMID- 28913449 TI - Evaluation of O-POSSUM vs ASA and APACHE II scores in patients undergoing oesophageal surgery. AB - BACKGROUND AND AIMS: Risk and prognostic scores quantify the patient's risk of death or complication according to the severity of his illness. The aim of this study was to evaluate the predictive accuracy of O-POSSUM vs ASA and APACHE II models on patients undergoing oesophageal surgery. MATERIAL AND METHOD: In this observational retrospective study 55 patients were enrolled who had undergone surgical interventions of excision and reconstruction of the oesophagus for neoplastic oesophageal stenosis, in the Surgical Clinics (I and II) of the Clinical County Emergency Hospital Mures, between January 2011 and January 2014. By using patients file records after extracting the data we calculated the predictive mortality, according to the prognostic scores O-POSSUM, ASA and APACHE II and we analyzed its correlations with the postoperative evolution. We evaluated the discriminatory power of the three scores using the ROC (receiver operating characteristic) curves. According to the cut-off value corresponding to each score, we compared the Kaplan Meier survival curves during the hospitalization period. RESULTS: ROC curves analysis revealed that O-POSSUM had a better discriminatory power for mortality compared to the other two scores: AUC = 0.73 for O-POSSUM, AUC = 0.57 for APACHE II and AUC = 0.64 for ASA (p < 0.001). The cut-off value was statistically significant only in case of O-POSSUM, as it derives from the statistical analysis of the survival curves (p = 0.035). CONCLUSION: O-POSSUM predicts mortality more accurately compared to ASA or APACHE II in patients undergoing oesophageal surgery. PMID- 28913450 TI - Blood sampling as a cause of anemia in a general ICU - a pilot study. AB - OBJECTIVE: The objective of our pilot study was to evaluate the influence of daily phlebotomy on patients' haemoglobin levels from our general intensive care unit. METHODS: We prospectively enrolled 35 patients who did not present with acute haemorrhage or developed it during the study period. For each patient we recorded: the diagnosis, age, sex, haemoglobin, hematocrit, SOFA and APACHE II score, blood volume drawn in standardized vials, number of blood tests ordered per day, fluid balance per day, number of ICU days. The collected data were analyzed using the linear regression model, paired t-test, receiver operating characteristic curves, and descriptive analysis. Statistical analysis was performed with SPSS v.17 trial version (IBM, NY, USA). RESULTS: The mean volume of blood drawn per day was 18.1 (SD +/- 14.4) ml and the number of blood tests was 3.8 (SD +/- 1.75) per day. On univariate linear regression analysis both the blood volume drawn daily (p = 0.04) and the number of blood tests per day (p = 0.009) correlated with a drop in mean haemoglobin concentration. The difference in the mean value of haemoglobin at admission and discharge correlated with overall mortality (p = 0.03). The sensitivity of admission haemoglobin equal to 10.6 g/dL in predicting mortality was 82.4% with a specificity of 50%, (p = 0.019, AUC = 0.732). CONCLUSIONS: We evidenced the predictive power of blood sampling and number of blood tests done on haemoglobin concentration. Besides the main objective of the study we noticed that the difference in the mean value of haemoglobin at admission and discharge correlated with overall mortality. Considering that blood sampling contributes to anemia among ICU patients, we should limit the daily tests undertaken, to the tests absolutely necessary for guiding our therapy. PMID- 28913451 TI - Anaesthesia for carotid endarterectomy - general or loco-regional? AB - Carotid endarterectomy has been widely used for the surgical treatment of carotid stenosis, and may be performed under either general or loco-regional anaesthesia. The greatest risks of carotid endarterectomy are the neurologic complications and the myocardial infarction. Anaesthetic and surgical techniques are constantly under scrutiny to try to reduce the relatively high incidence of morbidity and mortality of an operation which in itself is only preventative. Loco-regional anaesthesia is an alternative to general anaesthesia which has attracted considerable attention amid claims of a reduction in operative morbidity and mortality. This review describes the problems and some solutions for providing loco-regional or general anaesthesia for carotid endarterectomy. PMID- 28913453 TI - Effectiveness versus efficiency in a medical skills laboratory. AB - Medical educators are facing the new challenge of using medical simulation for teaching purposes. The use of simulators seems attractive for trainers and for trainees, but prices of simulators may be prohibitive. In an era of limited resources it is mandatory when using such an expensive tool as simulation, to prove its benefits. Despite the fact that simulation provides opportunity for training, additional advantages are far from being established. The supposed benefits of using medical simulators in teaching and examination needs to be proven regarding two aspects: effectiveness and efficiency. PMID- 28913452 TI - Regional anaesthesia and postoperative analgesia techniques for spine surgery - a review. AB - The use of regional anaesthesia techniques for intra-operative anaesthesia and postoperative analgesia remains very controversial for patients scheduled to undergo spinal interventions. Spine surgeries, especially the most extensive types, are mostly performed under general anaesthesia. This has to be explained by the position required during surgery, the preference of the surgeon and/or anaesthesiologist and lack of sufficient literature supporting locoregional anaesthesia. In addition, there is an increasing trend to prefer general anaesthesia for spinal surgery. Nevertheless, with respect to spine surgeries more than 80% of the actual literature on neuraxial blocks is dated less than 12 years. The present overview was focused in the first place on the feasibility of (loco) regional techniques to be used intra-operatively. These techniques are also of interest for postoperative analgesia, either with a single bolus injection of local anaesthetics, opioids and adjuvants, alone or in combination, in continuous or intermittent administration and requiring the presence of foreign material in the neighborhood of the surgical field. As all techniques described offered variable success rates, future research is mandatory to determine their superiority over general intra-operative anaesthesia and conventional pain therapy with paracetamol, NSAIDs, opioids used alone or in combination. PMID- 28913454 TI - Current status of the EasyTube: a review of the literature. AB - EasyTube is an esophageal-tracheal double lumen airway device that combines the features of an endotracheal tube with a supraglottic airway device, enabling ventilation with either tracheal or esophageal insertion. EasyTube can be inserted blindly or by using a laryngoscope. Its main indication is for airway emergencies both in pre-and in-hospital areas. In this article we review the current knowledge on the use of the EasyTube. PMID- 28913455 TI - Postoperative Takotsubo cardiomyopathy triggered by intraoperative fluid overload and acute hypertensive crisis. AB - The Takotsubo cardiomyopathy is a rare haemodynamic dysfunction, only recently reported perioperatively. While the diagnostic criteria have been established and the outcome is known as favorable, the pathophysiological mechanisms are not entirely understood. Here we present the case of a patient scheduled for laparoscopic hysterectomy and adnexectomy, who early postoperatively developed a Takotsubo cardiomyopathy supposedly triggered by an acute hypertensive crisis due to intraoperative fluid overload. PMID- 28913456 TI - Acute compartment syndrome and regional anaesthesia - a case report. AB - We describe the case of an adult 19 year old male with a fractured right radius. The patient underwent a revision open reduction and internal fixation due to mal alignment under combined general anaesthesia and supraclavicular brachial plexus block. Postoperatively the patient developed disproportionately intense pain despite an otherwise fully functioning sensory and motor block. The limb was swollen, tender and there was loss of radial pulse. Upon re-exploration a large haematoma was evacuated, a bleeding vessel being the causative factor. There were no further sequellae. The hallmark of this case report is the presence of out-of proportion pain with an odd distribution in the forearm in the presence of a dense and fully established nerve block. Acute compartment syndrome was diagnosed based on classical signs and symptoms within two hours of block performance. Appropriate treatment lead to satisfactory outcome. PMID- 28913457 TI - Benefits of early haemofiltration during aorto-bifemural bypass with mesenteric revascularization - a case report. AB - The intraoperative vs postoperative initiation of haemofiltration procedures in patients submitted for major vascular surgery is a controversial issue and a subject of debate in recent literature. We report the case of a 50 yr old patient scheduled for aorto-bifemoral bypass with mesenteric revascularization in whom the haemofiltration procedure (Prismaflex with Onix filter) was installed intraoperatively. Known to have non-insulin-dependent type 2 diabetes, the patient was admitted for Leriche syndrome, abdominal aorta thrombosis, superior and inferior mesenteric artery occlusion, celiac trunk occlusion, bilateral critical limb ischemia and mild renal impairment. The filtration rate was 25 ml/kg/h, ultrafiltration rate of 50 ml/h and 2 h clampation time. Haemofiltration was continued postoperatively in the ICU for another 48 h. The patient had a favorable evolution with restoration of renal function and a significant improvement of the biochemical parameters. In conclusion the early haemofiltration applied in this case provided clear beneficial effects, probably preventing the evolution towards multiple organ dysfunction syndrome. PMID- 28913458 TI - Into the deep end: a look at the functional changes of neuronal pathways in the deeply anesthetized state. PMID- 28913459 TI - Benefits of antioxidant supplementation in multi-trauma patients. PMID- 28913460 TI - Less is more: lack of benefit of fentanyl addition to a bupivacaine-morphine spinal anesthetic for Cesarean section. PMID- 28913461 TI - Implementing the WHO Surgical Safety Checklist. PMID- 28913462 TI - Changes of cortical connectivity during deep anaesthesia. AB - BACKGROUND AND AIMS: The aim of this study was to evaluate the frontal intracortical connectivity during deep anaesthesia (burst-suppression). METHODS: Experiments were carried out on 5 adult Sprague Dawley rats. The anaesthesia was induced and maintained with isoflurane. Following the induction of anaesthesia, rats were placed in a stereotactic instrument. A hole was drilled in the skull over the frontal cortex and electrodes were inserted in order to record the local field potentials. Rats were maintained in deep level anaesthesia (burst suppression). The cortical connectivity was assessed by computing the coherence spectra. The frontal intracortical connectivity was calculated during burst, suppression (non-burst) and slow wave anaesthesia periods. RESULTS: The global cortical connectivity (0.5-100 Hz) was 0.61 +/- 0.078 during the burst periods compared to 0.55 +/- 0.032 (p < 0.05) during the suppression periods and 0.55 +/- 0.015 (p < 0.05) during slow wave anaesthesia. CONCLUSIONS: The global cortical connectivity increased during the burst periods compared to the suppression periods and slow wave anaesthesia. This increase in the cortical synchronization might be due to the subcortical origin of the bursts. PMID- 28913464 TI - Effects of fentanyl added to a mixture of intrathecal bupivacaine and morphine for spinal anaesthesia in elective caesearean section. AB - BACKGROUND: The use of either fentanyl or morphine intrathecally as adjuncts to bupivacaine for spinal anaesthesia in caesarean deliveries is commonplace. However, the use of fentanyl in combination with morphine and bupivacaine in elective caesarean section is debatable. We hypothesized that while the addition of intrathecal fentanyl to morphine and bupivacaine increases side effects, it does not improve the clinical quality of anaesthesia or analgesia in elective caesarean deliveries. METHODS: In this case-controlled, double-blinded study, women undergoing elective caesarean deliveries received intrathecal fentanyl plus morphine with bupivacaine (Group 1) or intrathecal morphine with bupivacaine alone (Group 2). Patients were assessed at 4 hours for pain at rest and on movement using the visual analog scale (VAS), time taken for sensory block to T6 and side effects. RESULTS: Fifty patients were randomized into Group 1 (n = 25) and Group 2 (n = 25). There was no difference in the mean VAS scores at rest or on movement between the two groups. At 4 hours, the mean (SD) VAS scores at rest were 13.2 (13.7) mm and 12.0 (11.5) mm in Group 1 and 2, respectively (P = 0.739). The mean (SD) VAS scores on movement in Group 1 were 38.0 (18.2) mm, and in Group 2 were 28.4 (12.4) mm (P = 0.349). Group 1 took 7.34 hours to the first request for postoperative opioid analgesia while Group 2 took 7.08 hours (P = 0.749). Correspondingly, patient satisfaction ratings were comparable for both groups, the mean (SD) rating in Group 1 at 84.4 (11.11) compared to Group 2 at 87.6 (9.02), (P = 0.269). Patients in both groups had similar onset of T6 block. The incidence of side effects was higher in Group 1 than Group 2. CONCLUSION: Our study found that the addition of intrathecal fentanyl to morphine and bupivacaine did not have an advantage for short-term postoperative analgesia, but increased the incidence of opioid-related side effects and thus cost of care in a maternal population attending for elective caesarean section. PMID- 28913463 TI - Influence of antioxidant therapy on the clinical status of multiple trauma patients. A retrospective single center study. AB - INTRODUCTION: The biochemical processes of bioproduction of free radicals (FR) are significantly increasing in polytrauma patients. Decreased plasma concentrations of antioxidants, correlated with a disturbance of the redox balance are responsible for the installation of the phenomenon called oxidative stress (OS). OS action is associated with a series of secondary complications with direct implications in reducing the rate of survival, as well as in increasing morbidity The objectives of this study were to reveal possible relations between antioxidant therapy and a number of serum biochemical variables (ALT, AST, APPT, LDH, urea, leukocytes, platelets), the length of mechanical ventilation, the time spent in the ICU, and the mortality rate in major trauma patients. MATERIALS AND METHODS: In this retrospective study from a single center, 64 medical files of polytrauma patients admitted to the ICU "Casa Austria" were analysed. The selection criteria were: the Injury Severity Score (ISS) > 16 and a systolic arterial pressure (SAP) < 89 mmHg. The selected patients (n = 34) were divided into two groups: Antiox group, 20 patients who benefited from antioxidant therapy and the Contr group, 14 patients who did not received antioxidant therapy and served as a control group. The antioxidant therapy consisted of the simultaneous administration of vitamin C (i.v.), vitamin B1 (i.v.) and N-acetylcysteine (i.v.). The clinical and the biological evaluation were performed repeatedly until discharge from the ICU or the death of the patient. RESULTS: No significant differences were highlighted concerning the demographic data, the magnitude or the trauma mechanism between the two groups. In comparison with patients from the Contr group, the patients submitted to antioxidant therapy showed lower values after the treatment for leukocytes (p = 0.0066), urea (p = 0.0076), LDH (p = 0.0238), AST (p = 0.0070) and ALT (p < 0.0001). No statistically significant differences were evidenced regarding the incidence of sepsis or the development of multiple organ dysfunction syndrome (MODS). The period of mechanical ventilation was longer in patients from the Contr group (p = 0.0498), with no differences concerning the ICU length of stay (p = 0.7313). The mortality rate was lower in the Contr group (p = 0.0475). CONCLUSION: In multiple trauma patients a prolonged antioxidant therapy improved the posttraumatic laboratory tests. PMID- 28913465 TI - Early post-anaesthesia recovery parameters - a prospective observational study. AB - STUDY OBJECTIVES: To evaluate the patients' baseline condition upon arrival in the PACU as a method of assessment of the quality of anaesthesia, and to establish a model for future comparisons. DESIGN: Prospective observational study. SETTING: Surgical PACU in an academic tertiary hospital. PATIENTS: All patients (n = 11,241) arriving in our hospital's recovery units after elective surgery. INTERVENTIONS: In this observational study, clinical data, vital signs and comfort parameters were collected from surgical patients who arrived in the PACU. For each parameter, its frequency distribution or percentage of occurrence was determined. MAIN RESULTS: The incidence of anaesthesia associated side effects such as hypoxemia, cold extremities, shivering and/or vomiting was 5%. The incidence of nausea, sore throat, headache and/or pruritus was 9%. Sore throat occurred in 4.8% of intubated patients, in 4% after laryngeal mask insertions and in 3.6% with no usage of any airway device. From all patients 48% had no pain at all (VAS = 0), 31% had low pain scores (VAS 1-3) and 16% had moderate (VAS 4-6) pain levels, while 5% indicated severe pain (VAS 7-10). 97.5% of patients were normothermic (35.0-37.3 degrees C), 77% had normal heart rate (60-100 beats per minute) and 74% had normal systolic blood pressure (90-140 mmHg). After use of neuromuscular relaxants, moderate clinical signs of residual curarisation (2 of 3 clinical criteria positive) were observed in 1% and slight clinical signs of residual curarisation (1 of 3 clinical criteria positive) were observed in 22.4% of patients. These findings were collected in all patients, independently whether they had reversal of neuromuscular relaxation. CONCLUSIONS: Compared with the figures published in the literature, we report a lower incidence and severity of anaesthesia related side effects, measured as baseline data, upon patients' arrival in the post anaesthesia care unit. The baseline data may serve as a model to trigger specific interventions aimed at improving the quality of anaesthetic care, which could be assessed in future investigations. PMID- 28913466 TI - A prospective observational assessment of Surgical Safety Checklist use in Brasov Children's Hospital, barriers to implementation and methods to improve compliance. AB - INTRODUCTION: The WHO surgical checklist is a universal tool which has been shown to reduce surgical morbidity and mortality and improve patient safety; however, simply implementing a checklist in a hospital may not lead to its utilisation. We aim to evaluate completion of this checklist, and to investigate problems in compliance and methods for improving these. METHODS: In July 2015 data was recorded regarding compliance with each of the components of the Surgical Safety Checklist (SSC) in a Children's Hospital in Brasov. 40 surgeries were observed over 10 days, information was gathered as regards to the surgical speciality, the number of surgeries per day, the number of theatre staff present and whether it was elective or emergency. At the end of the 10 days questionnaires were given to 15 staff members to ask their opinions regarding the surgical checklist. Data analysis was performed using a chi-squared with p < 0.05 determining statistical significance. RESULTS: None of the checklists in the patient files were filled in; however, components of the SSC were completed, with an average of 55% of the checklist being performed. The percentage of the SSC completed was not statistically significant with different numbers of staff, theatre numbers of the day, speciality and whether it was elective or emergency. CONCLUSION: The success of the Surgical Safety Checklist implementation is dependent on the training of staff to improve knowledge and compliance. It cannot be assumed that the introduction of a checklist will automatically lead to improved outcomes and communication with staff is essential in order to improve and ensure compliance. PMID- 28913467 TI - Duloxetine, an antidepressant with analgesic properties - a preliminary analysis. AB - Serotonin and norepinephrine reuptake inhibitors are second-line antidepressants largely used because of their good tolerance and their reduced side effects. Two of these drugs, duloxetine and venlafaxine, are used also in chronic pain management. In this review we present recent data regarding duloxetine's effects on the central nervous system, linked to acute pain management, and their efficiency in reducing postoperative chronic pain. The drug's efficacy results from its modulating effect on the descending inhibitory pain pathways and the inhibition of the nociceptive input. There are already several studies in favor of the analgesic properties of duloxetine. However, further and larger randomized studies are necessary in order to clarify duloxetine efficiency in acute postoperative settings, and thereafter on persistent chronic postoperative pain. PMID- 28913468 TI - Coronary fistula - an unexpected preanaesthetic finding. AB - Coronary artery fistulae are congenital vascular anomalies defined as aberrant communications between a coronary artery and a cardiac chamber, large vessel or another vascular structure. In the present case the preanaesthetic clinical assessment led to a fortuitous detection of a rare coronary artery anomaly, which changed the initial therapeutic option. A 21-year-old female patient was admitted for a right ankle fracture. She had a two years history of constrictive chest pain inconsistently generated by effort of medium intensity, which had not been investigated previously. Clinical examination identified a grade V systolic diastolic murmur audible on the entire anterior thorax, with no other abnormalities. The patient underwent cardiological evaluation including transthoracic (TTE) and transesophageal echocardiography (TEE). TTE and TEE revealed an important dilatation of the left main coronary artery (LM) and a dilated circumflex artery (CX), with a very turbulent flow and a fistulous traject drawing most probably in the right atrium. The TTE and TEE evaluation raised the suspicion of a coronaro-cavitary fistula between the CX and the right atrium. The patient underwent coronary catheterization which confirmed a coronary fistula connecting CX with a superior vena cava-right atrium junction, with a hemodynamic significant left- to-right shunt. Surgeons opted for a conservative orthopedic management of the fracture; the patient continued to present exertional chest pain and was scheduled for interventional fistula closure. Our case confirms the importance of the preanaesthetic clinical examination, as a gold standard, that was decisive in identifying this rare, but potentially lethal congenital anomaly, as it triggered a series of tests, which established the diagnosis. PMID- 28913469 TI - Management of accidental extubation during oral surgery by nasotracheal intubation using the King vision video laryngoscope and a gum elastic bougie - a case report. AB - Accidental extubation during intra operative period especially during oral surgery is challenging for any anaesthesiologist. Securing the definitive airway during this period is not only crucial and life saving but also challenging to the anaesthesia provider. Here we report a case which got extubated during hemimandibulectomy and was successfully reintubated using King Vision video laryngoscope. This videolaryngoscope proved to be a good rescue device in managing an accidental extubation during oral surgery and could represent a useful tool for the management of such unfamiliar situations. PMID- 28913470 TI - Propofol: to shake or not to shake. PMID- 28913471 TI - Propofol emulsion-free drug concentration is similar between batches and stable over time. AB - : Despite their widespread use for anesthesia and sedation, propofol emulsions have several unresolved issues, including pain on injection, stability concerns, and propensity to support bacterial growth. Pain accompanying a propofol injection has been attributed to the amount of free as opposed to emulsified propofol in the blood, which can differ with the formulation. Emulsions are inherently unstable and subject to several types of destabilization, but the actual mechanism may vary between formulations or batches. Free drug concentration and emulsion stability have not been widely studied between batches of propofol emulsions. Verifying whether batch-to-batch variability is a contributing factor to pain on injection or emulsion destabilization will help us better assess the causes and guide the design of future propofol formulations. METHODS: Several samples of generic 1% propofol emulsion from various batches were compared. Free drug concentration was measured using an equilibrium dialysis method. Emulsion stability was evaluated by visible observation and by measuring droplet size distribution and polydispersity during shelf storage for up to 21 months. RESULTS: Small differences in free drug concentration were observed between samples (10.6-16.7 MUg/mL), but these differences were not statistically significant (p > 0.05). Emulsion droplet size (235.4-221.1 nm) and polydispersity (0.115-0.095) did not differ statistically over 21 months of storage. All batches were resistant to creaming and other destabilization mechanisms. CONCLUSIONS: Batch-to-batch variability does not significantly alter the free drug concentration or stability of propofol formulations. If pain on injection of propofol is in fact related to the free propofol drug concentration, then it is unlikely that batch-to-batch variability causes any changes in pain on propofol injection. PMID- 28913472 TI - The efficacy of oblique subcostal transversus abdominis plane block in laparoscopic cholecystectomy - a prospective, placebo controlled study. AB - INTRODUCTION: Pain control after a laparoscopic cholecystectomy can represent a challenge, considering the side effects due to standard analgesia methods. Recently the transversus abdominis plane block (TAP Block) has been used as a part of multimodal analgesia with promising results. The subcostal approach (OSTAP Block), a variant on the TAP block, produces reliable unilateral supraumbilical analgesia. This study evaluated the efficacy of the OSTAP block with bupivacaine in laparoscopic cholecystectomy compared with the placebo OSTAP block. MATERIAL AND METHODS: Sixty ASA I/II adult patients listed for elective laparoscopic cholecystectomy were randomly allocated in one of two groups: Group A (OSTAP placebo) received preoperatively bilateral OSTAP block with sterile normal saline and Group B (OSTAP bupivacaine) received bilateral preoperatively OSTAP block with the same volumes of 0.25% bupivacaine. Twenty-four hours postoperative opioid consumption, the dose of opioid required during surgery, opioid dose in the recovery unit (PACU) and PACU length of stay were evaluated. The quality of analgesia was assessed by the Visual Analogue Scale (VAS) at specific interval hours during 24 h, at rest and with movement. RESULTS: The mean intraoperative opioid consumption showed a significant difference between the two groups, (385 +/- 72.52 mg in group A vs 173.67 +/- 48.60 mg in group B, p < 0.001). The mean 24 h opioid consumption showed a statistically significant difference between groups (32 +/- 26.05 mg vs 79 +/- 16.68 mg, p < 0.001). PACU length of stay was significantly lower for group B patients compared with group A patients (20.67 +/- 11.27 min vs 41.67 +/- 12.41 min, p < 0.001). The OSTAP bupivacaine group had a statistically significant lower pain score than the OSTAP placebo group at 0, 2, 4, 6, 12, 24 h, both at rest and with movement. No signs or symptoms of local anaesthetic systemic toxicity or other complications were detected. CONCLUSION: OSTAP block with bupivacaine 0.25% can provide effective analgesia up to 24 hours after laparoscopic cholecystectomy when combined with conventional multimodal analgesia regimen. PMID- 28913473 TI - The impact of donor liver graft quality on postoperative outcome in liver transplant recipients. A single centre experience. AB - INTRODUCTION: The Donor Risk Index (DRI) has become a universal score for organ allocation in liver transplantation (LT) worldwide. The aim of this study was to evaluate the impact of liver graft quality measured by DRI, CIT, WIT and donor age on intraoperative hemodynamics (reperfusion syndrome) and early postoperative outcome, defined as initial graft poor function (within 3 days of LT), of deceased donor liver transplant (DDLT) recipients. Secondary end-points were the assessment of the impact of graft quality on the intraoperative and postoperative day 1 hemostasis (evaluated using ROTEM assay). METHODS: We retrospectively analyzed 135 patients who underwent deceased-donor LT between January 2013 and December 2014. Patient demographic data (age, sex, cause of End-Stage Liver Disease), preoperative paraclinical data (total bilirubin, creatinine, serum sodium), severity of liver disease scores (Model for End-Stage Liver Disease - MELD and MELD-sodium), intraoperative blood loss and blood products transfusion, incidence of post reperfusion syndrome, postoperative biochemical data (including total bilirubin, hepatic transaminases, lactate levels) and outcome (initial graft poor function diagnosis) were noted. Donor characteristics including DRI, CIT, WIT and donor age were noted. Coagulation was assessed by rotational thromboelastometry (ROTEM) after reperfusion of the graft and on postoperative day 1 in order to determine the effects of liver graft quality on hemostasis. RESULTS: Donor age has significantly correlated with decreased derived ROTEM parameters time to the maximum velocity of clot formation - MaxVt (p = 0.000), area under the curve (AUC) (p = 0.008) and maximum clot elasticity (MCE) (p = 0.018) although no difference in transfusion requirements has been observed. A longer CIT was associated with an increase in AST and ALT observed during the early postoperative period: day 1 ALT (p = 0.032) and AST (p = 0.008), day 2 ALT (p = 0.001) and AST (p = 0.001) and day 3 AST (p = 0.010) and ALT (p = 0.001). Higher DRI correlated with higher bilirubin levels measured on postoperative day 1 (p = 0.027) and 2 (p = 0.001). Patients who developed initial graft poor function received liver grafts from older donors (p = 0.05) with a higher DRI (p = 0.002). CONCLUSION: Our results suggest a significant impact of donor age and DRI on perioperative coagulation kinetics that may be a result of initial graft poor function. Although CIT and DRI correlated with a more severe cholestasis and hepatocitolysis during the early postoperative period these seems to be short lived. PMID- 28913474 TI - Long-axis view for ultrasound-guided central venous catheter placement via the internal jugular vein. AB - BACKGROUND: In modern practice, real-time ultrasound guidance is commonly employed for the placement of internal jugular vein catheters. With a new tool, such as ultrasound, comes the opportunity to refine and further optimize the ultrasound view during jugular vein catheterization. We describe jugular vein access techniques and use the long-axis view as an alternative to the commonly employed short-axis cross-section view for internal jugular vein access and cannulation. CONCLUSION: The long-axis ultrasound-guided internal jugular vein approach for internal jugular vein cannulation is a useful alternative technique that can provide better needle tip and guidewire visualization than the more traditional short-axis ultrasound view. PMID- 28913475 TI - Anaesthesia in early childhood - is the development of the immature brain in danger? AB - Experimental studies performed on immature animal brains had demonstrated a neurotoxic effect following sedation and general anaesthetics administration. The same magnitude of neurotoxicity has been suggested but not been proven to neonates, infants and small children who have undergone anaesthesia. There is a justified and increasing inquiry regarding the administration of general anaesthesia to paediatric patients. PMID- 28913476 TI - Focused cardiac and lung ultrasonography: implications and applicability in the perioperative period. AB - Focused ultrasonography in anesthesia (FUSA) can be a procedural and diagnostic tool, as well as potentially a tool for monitoring, and can facilitate the perioperative management of surgical patients. Its utilization is proposed within the anesthesiologist and/or intensivist scope of practice. However, there are significant barriers to more generalized use, but evidence continues to evolve that might one day make this practice a standard of care in the perioperative period. Currently, the most widely used applications of FUSA include the guidance and characterization of perioperative shock (acute cor pulmonale, left ventricular dysfunction, cardiac tamponade, and hypovolemia) and acute respiratory failure (pneumothorax, acute pulmonary edema, large pleural effusion, major atelectasis, and consolidation). Increased diagnostic accuracy of all of these clinical conditions makes FUSA valuable in the perioperative period. Furthermore, FUSA can be applied to other anesthesiology fields, such as airway management and evaluation of gastric content in surgical emergencies. PMID- 28913478 TI - Utilization of paravertebral nerve blocks as part of a multimodal analgesic regimen in a patient with Bernard-Soulier syndrome undergoing a Nuss procedure. AB - We present a case of regional analgesia utilized in a 43-year-old woman with Bernard-Soulier syndrome (BSS) undergoing a Nuss procedure for the treatment of pectus excavatum. BSS is an extremely rare bleeding disorder (1:1,000,000) associated with prolonged bleeding times, giant platelets, and thrombocytopenia. Due to the rare incidence and heterogeneity in bleeding predisposition due to BSS, there is no clear consensus in management of such cases, and to our knowledge, utilization of regional analgesic techniques have not been described in the literature. The Nuss procedure is considered "minimally" invasive, and epidural analgesia is frequently utilized at our institution. Due to our patient's heterozygous presentation of BSS and mild history of bleeding, a modified perioperative multimodal analgesic plan was chosen which included bilateral single injection paravertebral nerve blocks (PVBs). Our report describes successful utilization of PVBs in a patient with BSS and our approach to this rare hereditary condition. PMID- 28913477 TI - Pulse waveform hemodynamic monitoring devices: recent advances and the place in goal-directed therapy in cardiac surgical patients. AB - Hemodynamic monitoring has evolved and improved greatly during the past decades as the medical approach has shifted from a static to a functional approach. The technological advances have led to innovating calibrated or not, but minimally invasive and noninvasive devices based on arterial pressure waveform (APW) analysis. This systematic clinical review outlines the physiologic rationale behind these recent technologies. We describe the strengths and the limitations of each method in terms of accuracy and precision of measuring the flow parameters (stroke volume, cardiac output) and dynamic parameters which predict the fluid responsiveness. We also analyzed the place of the APW monitoring devices in goal-directed therapy (GDT) protocols in cardiac surgical patients. According to the data from the three GDT-randomized control trials performed in cardiac surgery (using two types of APW techniques PiCCO and FloTrac/Vigileo), these devices did not demonstrate that they played a role in decreasing mortality, but only decreasing the ventilation time and the ICU and hospital length of stay. PMID- 28913479 TI - Acute mercury poisoning from occult ritual use. AB - Mercury exposure is a serious environmental issue that concerns people worldwide. Industrial emissions containing mercury, some pharmaceutical and cosmetic products represent exposure sources. In Romania, as in many other countries, a supplementary cause for mercury exposure is represented by various occult rituals where liquids containing mercury are supposed to be ingested. We present the case of a 28 year old female who was admitted to the hospital for oral paresthesia, nausea, vertigo and sialorrhoea, after ingesting 100 ml diluted liquid mercury during an occult ritual. After the gastrointestinal decontamination, including gastric lavage, activated charcoal and cathartics, the outcome was favourable and 48 hours after admission the patient was discharged. This case report emphasizes the importance of an early digestive decontamination in mercury poisoning and the danger of mercury ingestion during various occult rituals. PMID- 28913480 TI - Singularity now: using the ventricular assist device as a model for future human robotic physiology. AB - In our 21st century world, human-robotic interactions are far more complicated than Asimov predicted in 1942. The future of human-robotic interactions includes human-robotic machine hybrids with an integrated physiology, working together to achieve an enhanced level of baseline human physiological performance. This achievement can be described as a biological Singularity. I argue that this time of Singularity cannot be met by current biological technologies, and that human robotic physiology must be integrated for the Singularity to occur. In order to conquer the challenges we face regarding human-robotic physiology, we first need to identify a working model in today's world. Once identified, this model can form the basis for the study, creation, expansion, and optimization of human robotic hybrid physiology. In this paper, I present and defend the line of argument that currently this kind of model (proposed to be named "IshBot") can best be studied in ventricular assist devices - VAD. PMID- 28913481 TI - Management of the hopelessly ill patient: to stop or not to start? AB - The paper discusses the subject of futile treatment in the case of a hopelessly ill patient. The topic has many facets, among them the ethical precepts of preventing futile treatment, but also the economic and logistic impact of treating patients who do not have a fair chance of benefitting from managing their medical condition. A 75-year old patient, suffering from an advanced stage of Alzheimer's disease and a clinical picture of acute surgical abdomen, is presented and two approaches are discussed. The first scenario is the aggressive management, including immediate laparotomy and admission to an intensive care unit, a solution without a fair chance of saving the patient's life. The most favorable, but theoretical, output in this case would be the patient's return to his previous mental condition, without any connection with the reality and surroundings and in permanent need for help, supervision and assistance. The second option is letting the patient die in dignity, alleviating pain and surrounded by family. The role of the primary care physician and family is discussed and some ethical principles are presented in order to emphasize the importance of preventing futile treatment in a case of a terminally ill patient. PMID- 28913482 TI - Sleep disordered breathing and the anaesthetist. PMID- 28913483 TI - The prevalence of perioperative complications in patients with and without obstructive sleep apnoea: a prospective cohort study. AB - BACKGROUND AND AIMS: Patients with obstructive sleep apnoea (OSA) have a high risk of postoperative complications. The purpose of the study was to record the spectrum and frequency of postoperative complications in patients with OSA versus (vs.) without OSA depending on the type of surgery and type of anaesthesia in a large cohort of patients. METHODS: We conducted a prospective, descriptive study (n = 400). Ethics Committee approval was obtained and written informed consent was signed. The Berlin screening questionnaire was used for OSA screening (77.2% OSA [+]). Adverse events and complications were recorded postoperatively (AOS [+] vs. AOS [-]). Statistics: Chi square test. RESULTS: The highest rate of complications was found in patients who had underwent surgery in the abdominal cavity under general anaesthesia, AOS [+] vs. AOS [-]: cardiovascular [56.4%] vs. [7.5%], respiratory [17.6%] vs. [3.5%], stroke [0.7%] vs. [0.0% ], prolonged awakening from anaesthesia [2.5%] vs. [0.0%], postoperative fever [1.4%] vs. [0.3%], difficult orotracheal intubation [3.5%] vs. [0.3% ], unscheduled transfer to the intensive care unit [5.7%] vs. [0.0%]. CONCLUSIONS: OSA [+] patients who underwent abdominal surgery under general anaesthesia had a higher rate of complications compared to OSA [-] patients, and also compared to patients who had undergone peripheral limb surgery. Surgery on the musculoskeletal system is much better tolerated by patients with OSA, suffering a lower number and range of events and postoperative complications. Loco-regional anaesthesia should be considered a priority in patients with OSA. PMID- 28913484 TI - Identification of significant obstructive sleep apnoea in the obese patient: development of the novel DX-OSA score. AB - BACKGROUND AND OBJECTIVES: There is a high prevalence of undiagnosed obstructive sleep apnoea (OSA) in obese surgical patients. We investigated the extent to which anthropometric measurements can be used to identify the presence of significant OSA (Apnoea/Hypopnoea Index (AHI) >= 20) in adult patients. MATERIALS AND METHODS: We prospectively studied 1357 adult patients scheduled for elective laparoscopic bariatric surgery. Prior to surgery, body mass index (BMI), gender, neck circumference, STOP-Bang score, SpO2, neck and trunk fat (by dual X-ray absorptiometry) were recorded. All patients with a STOP-Bang score >= 5 underwent polysomnography. Auto-titrated Positive Airway Pressure (APAP) therapy was instituted when AHI >= 20/h. Predictors of OSA were identified and their cut-off values determined. RESULTS: In total, 1357 patients were screened; 345 patients underwent preoperative polysomnography; 190 had AHI >= 20/h and received APAP treatment. The novel Dual X-Ray-Obstructive Sleep Apnoea (DX-OSA) score was derived from the data. The score included 6 items: the STOP-Bang score, BMI, neck fat, trunk fat, baseline SpO2, and Expiratory Reserve Volume (ERV), and its sensitivity, specificity, positive-predictive values, negative-predictive values, likelihood ratios, and post-test probabilities determined. At a cut-off of 3, the DX-OSA score had the same sensitivity as the STOP-bang score, but better specificity. The lowest likelihood ratio was found for STOP-Bang and the highest for the DX-OSA score (OSA probability > 83%). CONCLUSION: The DX-OSA score may be useful for identifying obese patients with significant OSA who require CPAP (continuous positive airway pressure) treatment, and CPAP could be commenced without the need for polysomnography, therefore, without delaying surgery. PMID- 28913485 TI - An in vitro study of the release capacity of the local anaesthetics from siloxane matrices. AB - AIMS: In the field of anaesthesia and intensive care, the controlled release systems capable of delivering constantly local anaesthetics are of interest because of the advantages brought to pain management. In this paper we presented the release profiles by usage of siloxane matrices of two common local anaesthetics, lidocaine and bupivacaine, analysed in vitro. METHODS: The siloxane matrices were obtained in accordance with the methods described in the specialized literature, tetraethoxysilane (TEOS) and tetramethoxysilane (TMOS) were used as precursors. Lidocaine and bupivacaine were encapsulated in the synthesized gels. The controlled release was performed in vitro artificial systems in which temperature (30 degrees C, 36.5 degrees C, 40 degrees C) and pH (6, 7, 8) have varied. RESULTS: Following the analysis of the artificial systems similar profiles were highlighted for both local anaesthetics. Statistically significant differences were identified (p < 0.05) for systems where the release occurred at temperatures above 36.5 degrees C. There were no statistically significant differences regarding the influence of pH, the type of the entrapped anaesthetic or the type of the precursor used in the synthesis of siloxane matrices. CONCLUSIONS: According to this experimental study, the pH, the type of precursor or the type of anaesthetic does not statistically influence the release profile from the studied system. In conclusion, these systems are promising for obtaining pharmaceutical preparations which can be used in current clinical practice. Several studies on controlled release siloxane systems should be carried out both in vitro and in vivo in order to exclude possible toxicity and histopathological effects. PMID- 28913487 TI - Perioperative Surgical Home. Meeting tomorrow's challenges. AB - New healthcare models pose a variety of changes for anesthesiologists, ranging from the need to improve quality and to cost containment: as such, the concept of Perioperative Surgical Home (PSH) has been developed. Modelled after the UK's Enhanced Recovery After Surgery (ERAS), PSH takes a step further by coordinating care starting from the time a surgical decision is made for the patient to as many as 30 days postoperatively, taking a logical evidenced-based approach to judicious preoperative testing. Perioperative surgical home also relies heavily on engineering imported strategies such as the use of Lean Six Sigma methodologies, and involves active participation of all stakeholders. By comparison, ERAS is a series of well-defined clinical protocols that do not extend beyond the episode of surgical care. As an added aspect of its benefits, PSH also helps to control costs by decreasing unnecessary testing and cancellations, and allowing for more OR access by inpatients. PMID- 28913488 TI - Bilateral thoracic paravertebral nerve blocks for placement of percutaneous radiologic gastrostomy in patients with amyotrophic lateral sclerosis: a case series. AB - BACKGROUND AND AIMS: To assess the efficacy of bilateral thoracic paravertebral nerve blocks (PVB) in providing procedural anesthesia and post-procedural analgesia for placement of percutaneous radiologic gastrostomy tubes (PRG) in patients with amyotrophic lateral sclerosis (ALS). METHODS: We prospectively observed 10 patients with ALS scheduled for PRG placement that had bilateral thoracic PVBs at thoracic 7, 8, and 9 levels with administration of a mixture of 3 mL of 1% ropivacaine, 0.5 mg/mL dexamethasone, and 5 MUg/mL epinephrine at each level. The success of the block was assessed after 10 minutes. PRG placement was done in the interventional radiology suite without sedation. All patients were followed up via phone 24 hours after the procedure. RESULTS: All 10 patients had successful placement of PRG with PVBs as the primary anesthetic. Segmental anesthesia over the surgical site in all cases was successful with first attempt of the blocks. Three patients had significant hypotension after the block, requiring boluses of vasopressors and intravenous fluids. All patients reported high levels of satisfaction and sleep quality on the night of the procedure. CONCLUSIONS: Bilateral thoracic PVBs provided satisfactory procedural anesthesia and post-procedural analgesia, and thus, seem promising as a safe alternative to sedation in ALS patients having PRG placement. PMID- 28913486 TI - The switch from buprenorphine to tapentadol: is it worth? AB - Opioid analgesia continues to be the primary pharmacologic intervention for managing acute pain and malignant pain in both hospitalized and ambulatory patients. The increasing use of opioids in chronic nonmalignant pain is more problematic. Opioid treatment is complicated with the risks raised by adverse effects, especially cognitive disturbance, respiratory depression but also the risk of tolerance, opioid abuse and drug-disease interactions. Despite the growing number of available opioids within the last years, adequate trials of opioid rotation are lacking and most of the information is anecdotal. This article reviews the clinical evidence surrounding the switch from transdermal buprenorphine to tapentadol in malignant and non-malignant pain. Tapentadol acts on both the MU-opioid receptors (MOR) and on the neuronal reuptake of noradrenaline with a limited usefulness in acute pain management while buprenorphine is a mixed agonist-antagonist, and both present some advantages over other opioids. Both drugs show particular pharmacodynamic and pharmacokinetic properties which reduce the risks of development of tolerance, opioid abuse, diversion and determine fewer hormone changes than the "classical opioids" making these opioids more attractive than other opioids in long term opioid treatment. However, in the absence of powered clinical trials, the evidence to support the method used for transdermal buprenorphine rotation to tapentadol is weak. PMID- 28913489 TI - Cerebral salt wasting syndrome in patients with minor head trauma - two case reports. AB - We describe two polytrauma patients without severe head trauma who developed Cerebral Salt Wasting Syndrome (CSWS) during their stay in our ICU with natriuresis, hyponatremia and hypovolemia. Hyponatremia encountered in CSWS and the syndrome of inadequate antidiuretic hormone secretion (SIADH) is a common electrolyte finding in patients with severe head trauma, subarachnoid hemorrhage, malignancy and infections of the central nervous system. CSWS was an unexpected electrolyte finding in our patients with minor head trauma without neurological or neurosurgical problems. To rule out other causes of hyponatremia (SIADH, secondary adrenal dysfunction and thyroid dysfunction) a correct diagnosis is very important, as proper treatment of CSWS with fluid and salt replacement will decrease mortality and morbidity. In conclusion, CSWS should be suspected in any polytrauma patient with minor head trauma and hyponatremia. PMID- 28913490 TI - Early sepsis biomarkers and their relation to mortality. PMID- 28913491 TI - Medical simulation - a costly but essential teaching tool. PMID- 28913492 TI - Incorporating airway examination photography into the electronic record. AB - BACKGROUND: Photography of the airway has been used in research to validate preoperative airway assessment and the likelihood of identifying the difficult-to mask ventilate and/or intubate patient. Up till now, no study has demonstrated the perceived utility of incorporation of airway photographs into the anesthesia preassessment. METHODS: The University of Florida Health Presurgical Clinic routinely incorporates three photographs of all adult patients during their preanesthesia visit. The first is a head-on view of the patient opening the mouth widely as part of a Mallampati examination, and the second and third are side views of the patient prognathing and with the neck in maximal extension, respectively. After IRB approval, providers of anesthesia were surveyed regarding their opinions on the perceived value of the new process. Chi-square tests were used to determine if the responses to each question significantly differed from the distribution that would be predicted by chance. P < 0.05 was considered statistically significant. RESULTS: The survey was emailed to 180 individuals, with 145 responding. The responses significantly (P < 0.0001) indicated that the photographs helped the providers plan care for their patients and improved their satisfaction with the preoperative assessment. Technical and educational barriers were overcome using iterative Plan-Do-Study-Act cycles and coaching, respectively. CONCLUSIONS: Photographs of the airway assessment can successfully be taken and incorporated into an electronic medical record in a busy presurgical clinic. The pictures provide additional perceived value to the traditional written assessment of a patient's airway examination by someone else. PMID- 28913493 TI - An evaluation of operating room throughput in a stand-alone soft-tissue trauma operating theatre. AB - BACKGROUND: Operating room time is a limited, expensive commodity in acute hospitals. Strategies aimed at reduction of non-operative time improve operating room throughput and capacity. We conducted a prospective study to evaluate and augment operating room throughput and capacity using context-specific work practice changes. METHODS: Following institutional and ethical approval, an interdisciplinary group designed and introduced a series of work practice changes specific to a stand-alone soft tissue trauma theatre, comprising modifications to patient processing, staff behaviours and additional anaesthesiologist hours. Time intervals relating to each patient were measured during a 16 week period before and after implementing work practice changes. The primary outcome measure was non operative time, with daily caseload and cancellations amongst secondary outcome measures. RESULTS: 251 procedures were included over 58 working days (8 to 17 Monday to Friday). Non-operative time [55.6 (31.1) vs 52.3 (9.8) minutes, p = 0.48], daily caseload [4 [1-9] vs 4 [2-7], p = 0.56], and the number of daily cancellations [3 [0-11] vs 5 [0-8], p = 0.38], did not differ between baseline and study phases. Regional anaesthesia for upper limb surgery increased during the study phase [26/59 (44.0%) vs 10/63 (15.9%), p = 0.014] with resultant decrease in mean duration of recovery room stay [20.7 (17.7) vs 30 (20.5) minutes, p = 0.0001] and increased recovery room bypass [26/116 (22.4%) vs 6/135 (4.4%), p = 0.0002]. Avoidable delays accounted for 124.8 (72.2) minutes of theatre time lost each day. CONCLUSION: In conclusion, additional attending anaesthesiologist hours combined with work practice changes did not impact on measures of theatre throughput and capacity. The study identified important variables that contribute to avoidable delays, and points the way for future research. PMID- 28913494 TI - The public perception of the anaesthesiologist in Romania: a survey. AB - BACKGROUND: Previous studies have shown that the public perception of anaesthesiologists' duties regarding perioperative management lacks a good understanding. The aim of this study was to assess the public perception of the anaesthesiologist's role before, during and after surgery, in Romania. METHOD: The prospective cross-sectional study was undertaken between January 2015 and August 2016. A questionnaire that comprised 23 questions was uploaded on Google at https://docs.google.com/forms/d/1KxC8jSYydhEu3pn0Hr0LHEsuCEQLSEHQqUo_HzrHuw8/view orm. The link was forwarded on-line randomly (mail, social media). The questions were structured based on current literature. Inclusion criteria were people aged >15 years and not directly related to any medical activity. The answers were anonymously registered, in real time, in an Excel format, used later to process the statistics. RESULTS: 1153 people completed the questionnaire, 61% female and 39% male, 80.8% being from the urban area and 19.2% from the countryside. 62.7% were hospitalized in the past, and 49.8% had undergone at least one surgery. From the questioned group 65.2% had graduated university, and 64.3% were aged between 20 and 40 years. A majority of 1089 respondents (94.6%) knew that the anaesthesiologist was responsible for providing anaesthesia in the operating room. 26.6% considered that the surgeon and the anaesthesiologist played different roles in OR, but 54.4% understood that there is a collaboration between them during surgery. Only 36.2% were aware that the anaesthesiologist replaces blood losses and provides patients hemodynamic stability and proper oxygenation during surgery. 54.6% believe that the surgeon decides upon the postoperative pain management and only 32% know the anaesthesiologist is the physician in charge of intensive care patients. 79.5% of respondents are willing to receive from their anaesthesiologist detailed information, regarding anaesthesia and postoperative care, before surgery, and consider that more publicity should be made regarding this profession. CONCLUSION: The public perception of the anaesthesiologist's role in Romania is inaccurate in spite of the fact that a large group in our study comprised highly educated people living in urban areas. We consider that further strengthening of the anaesthesiologist/patient relationship and an increased media exposure of our specialty would help to improve its social perception. PMID- 28913495 TI - Improvement of recovery parameters using patient-controlled epidural analgesia after oncological surgery. A prospective, randomized single center study. AB - PURPOSE: The aim of this study was to compare patient-controlled epidural analgesia (PCEA) versus conventional opioid intravenous (IV) infusion after gastrointestinal cancer surgery regarding several post-surgery parameters of recovery. METHODS: One hundred and one patients were prospectively randomized to receive either thoracic/lumbar PCEA (PCEA group) or the standard analgesia technique used in our hospital, conventional IV infusion of morphine (IVMO group) after gastrointestinal cancer surgery. Pain intensity, time of mobilization and bowel function recovery were analyzed post-surgery. We also evaluated postoperative complications and length of Postoperative-Intermediate Intensive Care Unit (PI-ICU) stay and hospital stay. RESULTS: Pain intensity was significantly less in the PCEA group in comparison with the IVMO Group at awakening 2, 8, 24, 30 and 48 hours after surgery (p <0.001, p <0.001, p <0.001, p = 0.043, p = 0.036, and p = 0.029, respectively). The latency to bedside mobilization, walking, first postoperative flatus and apparition of first stool were significantly faster (1.74 versus 2.26 days, 3.06 versus 3.78 days, 2.1 versus 3.14 days and 3.73 versus 5.28 days, respectively) in the PCEA group than in the IVMO group (p <0.001, p <0.001, p <0.001, and p <0.001, respectively). The incidence of nausea/vomiting was significantly lower in the PCEA group in comparison with the IVMO group (p = 0.001). Surgical-associated complications were significantly lower in the IVMO Group than in the PCEA group (p = 0.023). Length of PI-ICU stay was similar in the two groups but length of hospital stay was significantly shorter in PCEA group (4 versus 5 days p = 0.2849, 9 versus 12 days; p <0.001). CONCLUSIONS: PCEA provides better postoperative pain control, improves postoperative recovery after gastrointestinal cancer surgery compared with conventional intravenous morphine infusion. Therefore, it is more acceptable than conventional pain management. PMID- 28913496 TI - Anaesthesiologists' simulation training during emergencies in obstetrics. AB - BACKGROUND AND AIMS: Methods of simulation training and quality assessment during obstetric emergencies are still ambiguous. The aim of this study was to evaluate the effectiveness of anaesthesiologists' simulation training for emergency situations in obstetrics. METHODS: We conducted a prospective, descriptive, and comparative study to evaluate the anaesthesiologists' simulation training effectiveness during obstetrical emergencies. Data of 109 obstetrical anaesthesiologists trained over two years for invasive procedures and cardiopulmonary resuscitation, high-fidelity scenarios and medical personnel teamwork included were analyzed. We used the two-sided t-test (p < 0.05 considered significant). RESULTS: We noted during the fifth training sessions, the anaesthesiologists had a significant manipulation time decrease for all skills compared to the ones assessed during their first training session (p < 0.01). The 100-grade scale scores for all invasive techniques significantly improved during the anaesthesiologists' training (p < 0.01). Cardiopulmonary resuscitation effectiveness and team work also improved significantly during the fifth session (p < 0.01). CONCLUSIONS: As a result of simulation training, significant improvement of speed and quality indicators, for invasive techniques in obstetrical emergency states treatment, was noted. For the fifth training sessions, there was a decrease in the practical skills execution time. The overall effectiveness and teamwork quality for cardiopulmonary resuscitation showed significant improvement. PMID- 28913497 TI - ECoG spectrum changes at different xenon-isoflurane anaesthesia depths. AB - BACKGROUND AND AIMS: The purpose of this study is to assess the frontal and parietal ECoG spectrum (gamma range) changes during isoflurane and combined xenon isoflurane anaesthesia in rats. METHODS: Experiments were carried out on four adult male Sprague-Dawley rats (250-300 g). The anaesthesia was induced with isoflurane and maintained with isoflurane and a xenon-isoflurane mixture. The rats were maintained at two different anaesthetic depths: light (isoflurane anaesthesia) and deep (isoflurane and xenon-isoflurane anaesthesia). The frontal and the parietal cortical activity was assessed by computing the median frequency, spectral edge frequency and functional connectivity between these two areas during light and deep anaesthesia. RESULTS: We noticed a decrease in cortical connectivity under deep isoflurane anaesthesia and an increase in connectivity under deep xenon-isoflurane anaesthesia. Moreover, during xenon isoflurane anaesthesia, a trend of regularity of electro-cortical activity was present compared with isoflurane anaesthesia. CONCLUSIONS: Xenon-isoflurane deep anaesthesia demonstrated a series of specific ECoG features regarding frontoparietal functional connectivity (gamma range connectivity increase) and regularity of the electrocortical activity compared with isoflurane anaesthesia. PMID- 28913498 TI - Quality trends in healthcare and their impact on anesthesiology. AB - The new approach of a patient-centred, appropriate and timely care that was at the heart of the Institute of Medicine (IOM) initiative is changing the face of the healthcare industry in general and, in particular, of anesthesiology as a speciality. The drivers of this change are better quality and decreased healthcare costs, since despite a large expenditure for healthcare, the quality of care has not changed tremendously. Metrics have been identified, derived from the cybernetic model first described by the quality "parent". Donabedian and each of those metrics have both advantages as well as disadvantages. Ultimately the outcome measures are the ones that CMS will hold hospitals accountable for financially as well as from a safety standpoint. The culture of safety and quality as well as methodologies to improve that culture will shape the future of quality of care and improve outcomes and patient satisfaction. PMID- 28913499 TI - Perioperative hyperoxia: perhaps a malady in disguise. AB - Oxygen is an element, which is used liberally during several medical procedures. The use of oxygen during perioperative care is a controversial issue. Anesthesiologists use oxygen to prevent hypoxemia during surgical procedures, but the effects of its liberal use can be harmful. Another argument for using high oxygen concentrations is to prevent surgical site infections by increasing oxygen levels at the incision site. Although inconclusive, literature concerning the use of high oxygen concentrations during anesthesia show that this approach may cause hemodynamic changes, altered microcirculation and increased oxidative stress. In intensive care it has been shown that high oxygen concentrations may be associated with increased mortality in certain patient populations such as post cardiac arrest patients. In this paper, a review of literature had been undertaken to warn anesthesiologists about the potential harmful effects of high oxygen concentrations. PMID- 28913500 TI - Neuroendocrine stress response: implications for cardiac surgery-associated acute kidney injury. AB - Surgical stress causes biochemical and physiologic perturbations of every homeostatic axis. These alterations include volume/baroreceptor regulation, sympathetic activation, parasympathetic suppression, neuroendocrine activation, acute phase response protein synthesis and secretion, immune response modulation and long-term behavioral adaptation. The kidney is central to the stress response because of its main role in the maintenance of water, electrolyte balance and hence, intracellular and extracellular compartments, including the intravascular volume. Acute kidney injury after cardiac surgery occurs as a result of numerous factors including ischemia-reperfusion, inflammation, oxidative stress, neurohormonal activation, metabolic factors, and nephrotoxicity or pigment nephropathy. The neuroendocrine stress response has a central role in initiating renal injury during cardiac surgery through an increased release of arginine vasopressin and activation of the sympathetic nervous system and the intrarenal and systemic renin-angiotensin-aldosterone system. The contribution of an exaggerated neuroendocrine stress response to cardiac surgery and cardiopulmonary bypass as key pathophysiologic mechanism for acute kidney injury after cardiac surgery represents an opportunity for scientific exploration. PMID- 28913501 TI - Acute poisoning due to ingestion of Datura stramonium - a case report. AB - Datura stramonium (DS) is a widespread annual plant, containing atropine, hyoscyamine, and scopolamine, which can produce poisoning with a severe anticholinergic syndrome. Teenagers ingest the roots, seeds or the entire plant to obtain its hallucinogenic and euphoric effects. We presented the case of a 22 year old male who was admitted to the Emergency Room in a coma after consuming Datura stramonium, 2 hours earlier. The patient presented with fever, tachycardia with right bundle branch block, and urinary retention. Rapid sequence induction and intubation was performed immediately, with sedation and assisted-control mechanical ventilation, after being transferred to the Intensive Care Unit. The patient received activated charcoal, in repeated doses, external and internal cooling was applied, and an infusion of neostigmine was started. The biological assessment revealed rhabdomyolysis and prevention of renal failure was initiated. After a proper neurological evaluation, 36 hours after using Datura stramonium, the patient was extubated and transferred to the Psychiatric ward for further assessment and care. PMID- 28913502 TI - Regional anesthesia for a total knee arthroplasty on an adult patient with spastic diplegia and an intrathecal baclofen pump. AB - We describe the clinical presentation of a patient with spastic diplegia, and its unique perioperative challenges. Opioids and antispasmodic medications are the primary therapy for managing pain and spasticity in the perioperative setting. However, such combination results in several side-effects and their sedative properties are synergistic. A 64-year-old woman with a history of spastic diplegia and an intrathecal baclofen pump for the treatment of her lower extremity spasticity was scheduled for a third elective left knee arthroplasty. She requested a regional anesthetic for the anticipated surgery and an opioid sparing postoperative analgesic regiment. We describe the successful use of a lumbar plexus and a sciatic nerve block as the primary anesthetic for the surgery and the use of a continuous lumbar plexus catheter for the postoperative course. Based on our patient's past anesthetic history, a regional anesthetic/analgesic technique is the ideal strategy in controlling perioperative pain and spasticity. PMID- 28913503 TI - Modern management of antimalarial usage and retinopathy. PMID- 28913504 TI - A review and meta-analysis of corneal cross-linking for post-laser vision correction ectasia. AB - PURPOSE: The aim of this study was to review the safety and stability of cornea cross-linking (CXL) for the treatment of keratectasia after Excimer Laser Refractive Surgery. METHODS: Eligible studies were identified by systematically searching PubMed, Embase, Web of Science and reference lists. Meta-analysis was performed using Stata 12.1 software. The primary outcome parameters included the changes of corrected distant visual acuity (CDVA), uncorrected visual acuity (UCVA), the maximum keratometry value (Kmax) and minimum keratometry value (Kmin), the surface regularity index (SRI), the surface asymmetry index (SAI), the keratoconus prediction index (KPI), corneal thickness, and endothelial cell count. Efficacy estimates were evaluated by weighted mean difference (WMD) and 95% confidence interval (CI) for absolute changes of the interested outcomes. RESULTS: Seven studies involving 118 patients treated with CXL for progressive ectasia after laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) (140 eyes; the follow-up time range from 12 to 62 months) were included in the meta-analysis. The pooled results showed that there were no significant differences in Kmax and Kmin values after CXL (WMD = 0.584; 95% CI: 0.289 to 1.458; P = 0.19; WMD = 0.466; 95% CI: -0.625 to 1.556; P = 0.403, respectively). The CDVA improved significantly after CXL (WMD = 0.045; 95% CI: 0.010 to 0.079; P = 0.011), whereas UCVA did not differ statistically (WMD = 0.011; 95% CI: -0.055 to 0.077; P = 0.746). The changes were not statistically significant in SRI, SAI, and KPI (WMD = 0.116; 95% CI: -0.090 to 0.322; P = 0.269; WMD = 0.240; 95% CI: -0.200 to 0.681; P = 0.285; WMD = 0.045; 95% CI: 0.001 to 0.090; P = 0.056, respectively). Endothelial cell count and corneal thickness did not deteriorate (WMD = 12.634; 95% CI: -29.460 to 54.729; P = 0.556; WMD = 0.657; 95% CI: -9.402 to 10.717; P = 0.898, respectively). CONCLUSION: The study showed that CXL is a promising treatment to stabilize the keratectasia after Excimer Laser Refractive Surgery. Further long-term follow-up studies are necessary to assess the persistence of the effect of the CXL. PMID- 28913506 TI - Comparison of the long-term outcomes of resident versus attending performed trabeculectomy. AB - PURPOSE: To compare the long-term outcomes obtained by residents and attending surgeons performing trabeculectomy. METHODS: After reviewing medical records of the patients, 41 residents performing trabeculectomy under supervision of attendings were compared to 41 attendings performing trabeculectomy. The primary outcome measure was the surgical success defined in terms of intraocular pressure (IOP) <= 21 mmHg (criterion A) and IOP <= 16 mmHg (criterion B), with at least 20% reduction in IOP, either with no medication (complete success) or with no more than 2 medications (qualified success). IOP, number of glaucoma medications, surgical complications, and visual acuity were analyzed as secondary outcome measures. RESULTS: Mean age of the patients was 59.5 +/- 8.6 years in the resident group and 59.6 +/- 12.31 years in the attending group (P = 0.96). Furthermore, mean duration of the follow-up was 62.34 +/- 5.51 months in the resident group and 64.80 +/- 7.80 months in the attending group (P = 0.10). The cumulative success according to criterion A was 87.8% in the resident group and 85.3% in the attending group (P = 0.50). Moreover, according to criterion B, it was 87.8% and 83% in the resident and attending groups, respectively (P = 0.62). Repeated glaucoma surgery was required in 12.2% and 2.4% of the patients in the resident and attending groups, respectively (P = 0.09). Rate of complications was 12.2% and 4.8% in the resident and attending groups, respectively (P = 0.23). CONCLUSION: There were comparable results with respect to success rates and complications between residents and attending surgeons performing trabeculectomy in the long-term follow-up. PMID- 28913507 TI - Keratoconus diagnosis using Corvis ST measured biomechanical parameters. AB - PURPOSE: To assess the diagnostic power of the Corneal Visualization Scheimpflug Technology (Corvis ST) provided corneal biomechanical parameters in keratoconic corneas. METHODS: The following biomechanical parameters of 48 keratoconic eyes were compared with the corresponding ones in 50 normal eyes: time of the first applanation and time from start to the second applanation [applanation-1 time (A1T) and applanation-2 time (A2T)], time of the highest corneal displacement [highest concavity time (HCT)], magnitude of the displacement [highest concavity deformation amplitude (HCDA)], the length of the flattened segment in the applanations [first applanation length (A1L) and second applanation length (A2L)], velocity of corneal movement during applanations [applanation-1 velocity (A1V) and applanation-2 velocity (A2V)], distance between bending points of the cornea at the highest concavity [highest concavity peak distance (HCPD)], central concave curvature at the highest concavity [highest concavity radius (HCR)]. To assess the change of parameters by disease severity, the keratoconus group was divided into two subgroups, and their biomechanical parameters were compared with each other and with normal group. The parameters' predictive ability was assessed by receiver operating characteristic (ROC) curves. To control the effect of central corneal thickness (CCT) difference between the two groups, two subgroups with similar CCT were selected, and the analyses were repeated. RESULTS: Of the 10 parameters compared, the means of the 8 were significantly different between groups (P < 0.05). Means of the parameters did not show significant difference between keratoconus subgroups (P > 0.05). ROC curve analyses showed excellent distinguishing ability for A1T and HCR [area under the curve (AUC) > 0.9], and good distinguishing ability for A2T, A2V, and HCDA (0.9 > AUC > 0.7). A1T reading was able to correctly identify at least 93% of eyes with keratoconus (cut-off point 7.03). In two CCT matched subgroups, A1T showed an excellent distinguishing ability again. CONCLUSIONS: The A1T seems a valuable parameter in the diagnosis of keratoconic eyes. It showed excellent diagnostic ability even when controlled for CCT. None of the parameters were reliable index for keratoconus staging. PMID- 28913505 TI - Periorbital facial rejuvenation; applied anatomy and pre-operative assessment. AB - PURPOSE: Since different subspecialties are currently performing a variety of upper facial rejuvenation procedures, and the level of knowledge on the ocular and periocular anatomy and physiology is different, this review aims to highlight the most important preoperative examinations and tests with special attention to the eye and periocular adnexal structures for general ophthalmologist and specialties other than oculo-facial surgeons in order to inform them about the fine and important points that should be considered before surgery to have both cosmetic and functional improvement. METHODS: English literature review was performed using PubMed with the different keywords of "periorbital rejuvenation", "blepharoptosis", "eyebrow ptosis", "blepharoplasty", "eyelid examination", "facial assessment", and "lifting". Initial screening was performed by the senior author to include the most pertinent articles. The full text of the selected articles was reviewed, and some articles were added based upon the references of the initial articles. Included articles were then reviewed with special attention to the preoperative assessment of the periorbital facial rejuvenation procedures. RESULTS: There were 254 articles in the initial screening from which 84 articles were found to be mostly related to the topic of this review. The number finally increased to 112 articles after adding the pertinent references of the initial articles. CONCLUSION: Static and dynamic aging changes of the periorbital area should be assessed as an eyelid-eyebrow unit paying more attention to the anthropometric landmarks. Assessing the facial asymmetry, performing comprehensive and detailed ocular examination, and asking about patients' expectation are three key elements in this regard. Furthermore, taking standard facial pictures, obtaining special consent form, and finally getting feedback are also indispensable tools toward a better outcome. PMID- 28913508 TI - Confocal biomicroscopic changes of the corneal layers following femtosecond laser assisted MyoRing implantation in keratoconus. AB - PURPOSE: To evaluate the effect of the femtosecond laser-assisted MyoRing implantation on the confocal biomicroscopic findings in different corneal layers of the patients with keratoconus. METHODS: Twelve eyes of 12 patients with mild to moderate keratoconus (keratometry between 48 and 52 diopters) and intolerance to hard contact lens entered the study. All the included patients underwent femtosecond laser-assisted MyoRing (Dioptex GmBH, Linz, Austria) implantation. The confocal biomicroscopy of the cornea was performed for all corneal layers in the center and periphery preoperatively and 3 and 6 months postoperatively. The cell counts and the qualitative findings in each layer of the cornea were compared between preoperative and 3 and 6 months postoperative images. RESULTS: Compared with preoperative values, the central epithelial and the central and peripheral midstromal cell counts were significantly decreased 6 months after MyoRing implantation (P = 0.015, P = 0.010 and 0.005, respectively). Furthermore, compared with preoperative values, the peripheral posterior stromal cell count was significantly decreased 3 months after MyoRing implantation (P = 0.033). In the qualitative analysis, highly reflective nuclei in the basal epithelium, transient disruption in the subepithelial nerve plexus, increase in the reflectivity of the stromal keratocyte, and normal endothelial cell morphology were seen. CONCLUSIONS: Our study demonstrated some findings similar to that reported in intrastromal corneal ring segments (ICRS): decreased central epithelial cell counts, highly reflective nuclei in the basal epithelium, transient disruption in the subepithelial nerve plexus, and normal endothelial cell count and morphology. In addition, a decrease in the central and peripheral midstromal, transient decrease in posterior stromal cell counts, and absence of amorphous depositions were in contrast with the findings reported in ICRS. PMID- 28913509 TI - Effects of single-segment Intacs implantation on visual acuity and corneal topographic indices of keratoconus. AB - PURPOSE: To assess the changes in visual acuity and topographic indices after implantation of single-segment Intacs. METHODS: Forty-two keratoconic eyes received Femtosecond-assisted single-segment Intacs. Uncorrected distance visual acuity (UDVA) and best spectacle corrected visual acuity (BSCVA), refractive error, keratometry (K1, K2, Km, and KMax.), and seven Pentacam measured topographical indices; index of surface variance (ISV), index of vertical asymmetry (IVA), keratoconus index (KI), central keratoconus index (CKI), index of height asymmetry (IHA), index of height decentration (IHD), and minimum radius of curvature (R Min) were assessed 4 months after surgery. Correlations between changes of visual acuity and topographical indices changes were evaluated. RESULTS: UDVA increased from 0.92 +/- 0.35 to 0.49 +/- 0.31 logMAR (P < 0.001), and BSCVA increased from 0.39 +/- 0.15 to 0.23 +/- 0.11 logMAR (P < 0.001). Subjective refraction spherical equivalent (SRSE) decreased from -3.92 +/- 1.66 diopters (D) to -2.00 +/- 1.51 D (P < 0.001). Mean central Keratometry decreased 2.16 +/- 1.09 D from the preoperative readings (P < 0.001). All Pentacam topographical indices except CKI significantly improved (for IHA P = 0.046, for five others P < 0.001). The correlation between improvement in topographical indices and visual acuity improvements was not week. CONCLUSION: Intacs implantation in keratoconic eyes increased visual acuity and made corneal shape less irregular. However, the improvements of visual acuity and corneal shape were not strongly correlated. PMID- 28913511 TI - Accuracy of formulae for secondary intraocular lens power calculations in pediatric aphakia. AB - PURPOSE: To compare the accuracy of axial length vergence formulas versus refractive vergence formulas for secondary intraocular lens (IOL) implantation in pediatric aphakia. METHODS: This retrospective comparative study, evaluated 31 eyes of 31 patients aged <=3.5 years, who had undergone secondary IOL implantation. The median absolute error (MedAE) was compared between axial length vergence formulas (Hoffer Q, Holladay I, SRK II, and SRK/T) and refractive vergence formulas (Lanchulev, Holladay R, Mackool, and Khan) as well as between formulas within the same vergence. RESULTS: There was a significant difference (P = 0.010) between MedAE for axial length vergence formulas [1.19 Diopter(D)] and MedAE for refractive vergence formulas (2.48 D). The MedAE of axial length vergence formulas were comparable as to Hoffer (1.59 D), Holladay (1.27 D), SRK/T (1.23 D), and SRK II (1.30 D). Among refractive vergence formulas, Lanchulev (5.00 D) and Holladay R (2.51 D) had significantly larger MedAE as compared to Khan (2.06 D) and Mackool (2.15 D). CONCLUSION: Axial length vergence formulas performed significantly better than refractive vergence formulas; however, axial length vergence formulas were comparable within the same vergence. PMID- 28913510 TI - The prevalence and determinants of pterygium in rural areas. AB - PURPOSE: To evaluate the prevalence of pterygium and its determinants in the underserved, rural population of Iran. METHODS: In this cross-sectional study of 3851 selected individuals, 86.5% participated in the study, and the prevalence of pterygium was evaluated in 3312 participants. A number of villages were selected from the north and south of Iran using multistage cluster sampling. Pterygium was diagnosed by the ophthalmologist using slit-lamp examination. RESULTS: The mean age of the study participants was 37.3 +/- 21.4 years (2-93 years), and 56.3% (n = 1865) of them were women. The prevalence of pterygium was 13.11% [95%confidence interval (CI):11.75-14.47]. The prevalence of pterygium was 14.99 (95%CI:12.79 17.19) in men and 12.07 (95%CI:10.3-13.84) in women. Pterygium was not seen in children below the age of 5 years. The prevalence of pterygium increased linearly with age; the lowest and highest prevalence of pterygium was observed in the age group 5-20 years (0.19%) and 61-70 years (28.57%). Evaluation of the relationship between pterygium with age, sex, educational level, and place of living using a multiple model showed that age, living in the south of Iran, and low educational level were correlated with pterygium. CONCLUSION: The prevalence of pterygium was significantly higher in Iranian villages when compared with the results of previous studies. This finding may represent the effect of a rural lifestyle and its risk factors. PMID- 28913512 TI - The distribution of negative and positive relative accommodation and their relationship with binocular and refractive indices in a young population. AB - PURPOSE: To determine the distribution of negative relative accommodation (NRA) and positive relative accommodation (PRA) and its relationship with binocular vision indices in a young population. METHODS: In this cross-sectional study conducted in a student population, samples were selected through multistage cluster sampling. All the samples underwent the measurement of uncorrected and corrected visual acuity and refraction. Then far and near cover tests were performed. The near point of convergence (NPC) and accommodation, accommodation facility, PRA and NRA were evaluated in all participants. RESULTS: The mean age of the 382 participants was 22.5 +/- 4.4 years (18-35 years). Mean NRA and PRA in the total sample was +2.08 +/- 0.33 diopter (D) and -2.92 +/- 0.76 D, respectively. Mean NRA was highest in hyperopic (P = 0.002) and mean PRA was highest in myopic (P = 0.003) participants. The multiple model showed that NRA had a direct relationship with accommodation facility and spherical refractive error, while PRA had a direct relationship with amplitude of accommodation (AA). CONCLUSION: This study provides the normal range of the NRA and PRA and their relationship with accommodation facility, spherical refractive error, and AA in a sample of the Iranian population. PMID- 28913513 TI - Choroidal thickness in non-ocular Behcet's disease - A spectral-domain OCT study. AB - PURPOSE: To evaluate choroidal thickness in patients with non-ocular Behcet's disease (BD) using spectral domain optical coherence tomography (SD-OCT) and to compare the results to normal eyes. METHODS: In this retrospective observational comparative study, we collected OCT and clinical data from the charts of 4 patients (7 eyes) with BD who had been referred for a screening eye exam and had a normal ocular examination. Data from 9 healthy volunteers (17 eyes) were collected as age-matched controls. The choroid was manually segmented from volume OCT scans using custom Doheny Image Reading Center OCT grading software (3D OCTOR). Main outcome measures were choroidal thickness and intensity were compared between eyes of patients with BD and those of healthy controls. RESULTS: Eyes of patients with non-ocular BD had significantly thinner mean central subfield choroidal thickness (227.5 +/- 56.93 versus 306.85 +/- 17.85, P = 0.04) and central subfield choroidal volume (0.18 +/- 0.04 vs 0.24 +/- 0.02, P = 0.005). There was no significant difference in mean choroidal thickness in the whole ETDRS grid or in mean choroidal intensity in the central subfield and the whole ETDRS grid between eyes of patients with non-ocular BD and those of controls. CONCLUSION: This study demonstrates that BD may have subclinical manifestations in the choroid, resulting in thinning of the choroid relative to normal eyes, even without overt signs of ocular involvement. PMID- 28913514 TI - The incidence of needle stick and sharp injuries and their associations with visual function among hospital nurses. AB - PURPOSE: To determine the one-year incidence of needle stick and sharp injuries (NSIs and SIs) and their associations with visual function among Iranian nurses. METHODS: In this cross-sectional study, 278 nurses working at one hospital were selected through stratified random sampling. After applying the exclusion criteria, the final analysis was performed on the data of 267 nurses. The data of occupational injuries were collected through a researcher-administered questionnaire. Visual function indices including distance and near best corrected visual acuities (BCVAs), color vision, stereoacuity, distance and near heterophorias, accommodative amplitude and facility, contrast sensitivity (CS) for high and low spatial frequencies (SFs), near point of convergence (NPC), saccadic and pursuit eye movements, distance and near convergence and divergence fusional reserves and peripheral vision were evaluated through optometric examinations using standard protocols. RESULTS: The one-year incidence of NSIs and SIs was 41.2% [95% Confidence interval (CI): 35.3-47.1] and 19.1% (95% CI: 14.4-23.8), respectively. Color vision deficiency, pursuit deficiency, abnormal near heterophoria, and decreased CS for high SF had a significant association with the increased incidence of NSIs with odds ratios of 3.26, 2.32, and 1.35, respectively. Moreover, saccadic deficiency, abnormal near heterophoria, and decreased near fusional divergence reserve were significantly associated with the increased incidence of SIs with odds ratios of 2.42, 2.40, and 1.27, respectively. CONCLUSIONS: Our findings showed a relatively high incidence of NSIs and SIs in Iranian nurses and their associations with some visual function indices. Therefore, pre-employment and periodic visual examinations are recommended to detect and remove the corresponding visual risk factors. Moreover, preventive strategies should be adopted to decrease the occurrence of the aforementioned injuries. PMID- 28913515 TI - Paradoxical head tilt in unilateral traumatic superior oblique palsy. AB - PURPOSE: We report a patient with abnormal head posture following ocular blunt trauma. METHODS: This is report of a case that despite findings compatible with diagnosis of left superior oblique (SO) palsy, the patient acquired an ipsilateral (left) head tilt. The interesting observation in our patient was reduction of left hypertropia and consequent less diplopia with ipsilateral head tilt. RESULTS: After blunt trauma, our patient adopted paradoxical left head tilt and consequently less diplopia despite acquired left SO palsy. Left inferior oblique myectomy resulted in significant improvement of patient's strabismus and abnormal head position. CONCLUSION: Traumatic SO palsy may present with paradoxical head tilt. PMID- 28913516 TI - A rare erosive orbital mass in a child: Case report of myofibroma. AB - PURPOSE: To present the clinical, histological, and radiographic findings of a case of orbital myofibroma in an unusual location. The literature is reviewed and the clinical relevance discussed. METHODS: A 5-year-old boy was examined with a 1.5-month history of progressive swelling in the left supraorbital region. RESULTS: Examination revealed a firm, painless mass in the supralateral region of the left orbit with slight reddish discoloration of the overlying skin. Computerized tomography (CT) scan images showed a well demarcated, homogenous, solid mass with extension to the lacrimal gland region and adjacent to frontal bone erosion. The mass was surgically excised and was confirmed to be myofibroma in diagnostic histological studies. There has been no evidence of recurrence in the first year after surgery. CONCLUSIONS: Clinical appearance and imaging findings are unspecific for this tumor, and histological examination still remains the definite method of diagnosis. Therefore, it is important to be able to differentiate myofibromas from other malignant tumors with a similar presentation in pediatric patients to avoid mismanagement. PMID- 28913517 TI - Intravitreal injection of ziv-aflibercept in the treatment of choroidal and retinal vascular diseases. AB - PURPOSE: To investigate the short-term outcomes after intravitreal injection of ziv-aflibercept in the treatment of choroidal and retinal vascular diseases. METHODS: Thirty-four eyes of 29 patients with age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion (RVO) received a single dose intravitreal injection of 0.05 ml ziv-aflibercept (1.25 mg). Visual acuity, spectral domain optical coherence tomography (SD-OCT) activity, and possible side effects were assessed before and at 1 week and 1 month after the intervention. RESULTS: At 1 month after treatment, mean central macular thickness (CMT) significantly decreased from 531.09 MUm to 339.5 MUm (P < 0.001), and no signs of side effects were observed in any subject. All patients responded to treatment in terms of reduction in CMT. The improvement in visual acuity was statistically non significant. CONCLUSION: Our findings suggest that a single dose intravitreal injection of ziv-aflibercept may have acceptable relative safety and efficacy in the treatment of patients with intraocular vascular disease. The trial was registered in the Iranian Registry of Clinical Trials (IRCT2015081723651N1). PMID- 28913518 TI - Naphthalene diimide-based non-fullerene acceptors flanked by open-ended and aromatizable acceptor functionalities. AB - Herein we present the design, synthesis and characterization of two novel, naphthalene diimide (NDI) core-based non-fullerene acceptors, N5 and N6, comprising respectively 2-methoxyethyl-2-cyanoacetate and cyanopyridone acceptor functionalities at the terminals. The influence of terminal units on optoelectronic and photovoltaic properties was studied. The target chromophore bearing cyanopyridone acceptor units (N6) afforded a power conversion efficiency of 6.10% when paired with the conventional donor polymer poly(3-hexylthiophene), a result that is the highest for the NDI core-based non-fullerene acceptors. PMID- 28913519 TI - Synergistic silver/scandium catalysis for divergent synthesis of skeletally diverse chromene derivatives. AB - The combination of AgTFA and Sc(OTf)3 enables the bimetallic synergistic catalysis of beta-alkynyl ketones and o-hydroxybenzyl alcohols, allowing divergent synthesis of three classes of skeletally diverse chromene derivatives with generally good yields and high diastereoselectivity through dehydroxylated bi- and tri-cyclization cascades. The selectivity of these cycloadditions was controlled by adjusting the catalyst loading and reaction temperatures. The mechanisms for forming these compounds were proposed. PMID- 28913520 TI - Evidential value of polymeric materials-chemometric tactics for spectral data compression combined with likelihood ratio approach. AB - Polymers have become a ubiquitous element of our culture. Therefore, these materials may play an important role in forensic investigations, serving as mute witnesses of occurrences such as car accidents. In this study, the possibilities provided by the likelihood ratio (LR) approach to estimate the evidential value of observed similarities and differences, and to discriminate among NIR spectral data originating from polypropylene automotive parts and household items, were investigated. Since the construction of LR models requires the introduction of only a few variables, the main objective was to reduce the dimensionality of registered spectra, which are characterised by over a thousand variables. The applied strategy was based on compression of NIR signals using discrete wavelet transform (DWT) followed by use of the SELECT algorithm for the selection and decorrelation of the most informative DWT coefficients. Selected features eventually served as an input for LR models. The performance of the developed models was assessed by measuring the rates of false positive and false negative answers as well as by applying an empirical cross entropy approach. Despite relatively small databases of polymeric objects, both univariate and multivariate LR models showed acceptable performances. The latter, however, gave the most satisfactory results, as it enabled successful discrimination of compared samples and delivered the lowest error rates. In addition, in order to verify the potential of NIR spectroscopy, the obtained results were compared with those obtained after application of the proposed tactics to the FTIR data, which is a well-established method in the forensic sphere. PMID- 28913521 TI - Solvation of Li+ by argon: how important are three-body forces? AB - A new analytical potential for Li+Ar2 including three-body interactions has been modeled by employing ab initio energies that were calculated within the CCSD(T) framework and a quadruple-zeta basis-set (i.e., cc-pVQZ for lithium and aug-cc pVQZ for argon) and, then, corrected for the basis-set superposition error (BSSE) with the counterpoise method. Departing from this function, we have constructed the potential energy surface for Li+Arn clusters by summing over all two-body and three-body terms. We have employed our evolutionary algorithm (EA) to perform a global geometry optimization that allows for the study of a Li+ ion microsolvated with argon atoms. For the smaller clusters, the putative global minimum geometry obtained for the analytical potential has been used as a starting point for an ab initio optimization at the MP2 level. For clusters up to n = 10, the energetics and structures from the analytical potential energy surface (PES) that includes three-body interactions show good agreement with the corresponding ones optimized at the ab initio level. Removing the three-body terms from the analytical PES leads to global minima that fail to represent the main energetic features and the structures become wrong in the case of the Li+Ar2, Li+Ar3 and Li+Ar10 clusters. For n > 10, the comparison between potentials with and without three-body forces shows significant structural and energetic differences for most of the cluster sizes. PMID- 28913522 TI - Single tube gene synthesis by phosphoramidate chemical ligation. AB - Templated chemical ligation of 5'-amino and 3'-phosphate oligonucleotides was used to synthesise a 762 base pair gene for green fluorescent protein. The phosphoramidate linkage can be read by DNA polymerase and transcribed to make RNA. We also show that phosphoramidate ligation and orthogonal CuAAC-mediated DNA ligation can be used simultaneously. PMID- 28913523 TI - The difficult search for organocerium(iv) compounds. AB - This Tutorial Review provides an overview of the historic and current development of the organometallic chemistry of cerium in its oxidation state 4+. Among the tetravalent lanthanide ions, only Ce4+ forms stable coordination compounds (e.g. (NH4)2[Ce(NO3)6]). Important fields of applications for cerium(iv) compounds include organic synthesis, bioinorganic chemistry, materials science, and industrial catalysis. In sharp contrast, organometallic cerium(iv) compounds are still exceedingly rare. The history of organocerium(iv) compounds is an exciting story of ups and downs. The so-called cerocene (= bis(eta8-cyclooctatetraenyl) cerium) has been known since 1976. Other early reports e.g. about Cp4Ce (Cp = eta5-cyclopentadienyl), were later disproven. However, significant progress in this field has been made in recent years through the use of carefully designed ligands and more sophisticated synthesis protocols. Taking the case of organocerium(iv) chemistry, this Tutorial Review also tries to exemplarily show how difficult synthetic and theoretical problems can eventually be solved through newly designed synthesis strategies (e.g. as accomplished for cyclopentadienyl and carbene derivatives) and a rewarding collaboration between synthetic and theoretical chemists (cf. the cerocene problem). PMID- 28913524 TI - Reassessing SERS enhancement factors: using thermodynamics to drive substrate design. AB - Over the past 40 years fundamental and application research into Surface-Enhanced Raman Scattering (SERS) has been explored by academia, industry, and government laboratories. To date however, SERS has achieved little commercial success as an analytical technique. Researchers are tackling a variety of paths to help break through the commercial barrier by addressing the reproducibility in both the SERS substrates and SERS signals as well as continuing to explore the underlying mechanisms. To this end, investigators use a variety of methodologies, typically studying strongly binding analytes such as aromatic thiols and azarenes, and report SERS enhancement factor calculations. However a drawback of the traditional SERS enhancement factor calculation is that it does not yield enough information to understand substrate reproducibility, application potential with another analyte, or the driving factors behind the molecule-metal interaction. Our work at the US Army Edgewood Chemical Biological Center has focused on these questions and we have shown that thermodynamic principles play a key role in the SERS response and are an essential factor in future designs of substrates and applications. This work will discuss the advantages and disadvantages of various experimental techniques used to report SERS enhancement with planar SERS substrates and present our alternative SERS enhancement value. We will report on three types of analysis scenarios that all yield different information concerning the effectiveness of the SERS substrate, practical application of the substrate, and finally the thermodynamic properties of the substrate. We believe that through this work a greater understanding for designing substrates will be achieved, one that is based on both thermodynamic and plasmonic properties as opposed to just plasmonic properties. This new understanding and potential change in substrate design will enable more applications for SERS based methodologies including targeting molecules that are traditionally not easily detected with SERS due to the perceived weak molecule-metal interaction of substrates. PMID- 28913525 TI - Formation of antireflection Zn/ZnO core-shell nano-pyramidal arrays by O2+ ion bombardment of Zn surfaces. AB - ZnO is probably one of the most studied oxides since ZnO nanostructures are a very rich family of nanomaterials with a broad variety of technological applications. Although several chemical techniques offer the possibility to obtain such ZnO nanostructures, here we show that the controlled modification of the zinc surface by low-energy O2+ bombardment leads to the formation of core shell Zn/ZnO nano-pyramidal arrays that suppress the reflection of light decreasing the reflectivity below 6% in the wavelength range of 300-900 nm. This controlled and scalable protocol opens the door to a broad range of possibilities for the use of ion bombardment to produce surface modifications for technological applications in the field of photoelectric devices and solar cells. PMID- 28913527 TI - Electron induced reactions in condensed mixtures of methane and ammonia. AB - We demonstrate the efficient formation of carbon-nitrogen bonds starting from CH4 and NH3 on a metal surface at cryogenic temperatures. Electrons in the energy range of 1-90 eV are used to initiate chemical reactions in mixed molecular films of CH4 and NH3 at ~15 K, and the products are detected by performing temperature programmed desorption (TPD). Extensive dehydrogenation occurs at all energies giving the products CH2NH and HCN in preference to CH3NH2. This is likely to do with the energetics of the reactions and the subsequent stability of these species in the condensed film. Thermal processing of the irradiated mixture favours dehydrogenation as indicated by the results of using different desorption rates. Electron impact excitation and subsequent dissociation into radicals is the reaction-initiating step rather than ionization of CH4 and NH3, as inferred from the yield of products as a function of electron energy. This could give insight into the important catalytic process of the industrial scale synthesis of HCN from CH4 and NH3 over Pt. This may also be a relevant pathway in the astrochemical environment where CN and HCN are abundant and low-energy electrons are found ubiquitously. PMID- 28913526 TI - New penta-saccharide-bearing tripod amphiphiles for membrane protein structure studies. AB - Integral membrane proteins either alone or as complexes carry out a range of key cellular functions. Detergents are indispensable tools in the isolation of membrane proteins from biological membranes for downstream studies. Although a large number of techniques and tools, including a wide variety of detergents, are available, purification and structural characterization of many membrane proteins remain challenging. In the current study, a new class of tripod amphiphiles bearing two different penta-saccharide head groups, designated TPSs, were developed and evaluated for their ability to extract and stabilize a range of diverse membrane proteins. Variations in the structures of the detergent head and tail groups allowed us to prepare three sets of the novel agents with distinctive structures. Some TPSs (TPS-A8 and TPS-E7) were efficient at extracting two proteins in a functional state while others (TPS-E8 and TPS-E10L) conferred marked stability to all membrane proteins (and membrane protein complexes) tested here compared to a conventional detergent. Use of TPS-E10L led to clear visualization of a receptor-Gs complex using electron microscopy, indicating profound potential in membrane protein research. PMID- 28913528 TI - DNA protection by ectoine from ionizing radiation: molecular mechanisms. AB - Ectoine, a compatible solute and osmolyte, is known to be an effective protectant of biomolecules and whole cells against heating, freezing and extreme salinity. Protection of cells (human keratinocytes) by ectoine against ultraviolet radiation has also been reported by various authors, although the underlying mechanism is not yet understood. We present the first electron irradiation of DNA in a fully aqueous environment in the presence of ectoine and at high salt concentrations. The results demonstrate effective protection of DNA by ectoine against the induction of single-strand breaks by ionizing radiation. The effect is explained by an increase in low-energy electron scattering at the enhanced free-vibrational density of states of water due to ectoine, as well as the use of ectoine as an OH-radical scavenger. This was demonstrated by Raman spectroscopy and electron paramagnetic resonance (EPR). PMID- 28913529 TI - A novel method to control carryover contamination in isothermal nucleic acid amplification. AB - We developed a novel method to control carryover contamination in loop-mediated isothermal amplification (LAMP) by primer engineering to carry recognition sites for a restriction endonuclease, providing a robust ability to eliminate carryover contaminants. PMID- 28913530 TI - Why microfluidics? Merits and trends in chemical synthesis. AB - The intrinsic limitations of conventional batch synthesis have hindered its applications in both solving classical problems and exploiting new frontiers. Microfluidic technology offers a new platform for chemical synthesis toward either molecules or materials, which has promoted the progress of diverse fields such as organic chemistry, materials science, and biomedicine. In this review, we focus on the improved performance of microreactors in handling various situations, and outline the trend of microfluidic synthesis (microsynthesis, MUSyn) from simple microreactors to integrated microsystems. Examples of synthesizing both chemical compounds and micro/nanomaterials show the flexible applications of this approach. We aim to provide strategic guidance for the rational design, fabrication, and integration of microdevices for synthetic use. We critically evaluate the existing challenges and future opportunities associated with this burgeoning field. PMID- 28913531 TI - Augmented pH-sensitivity absorbance of a ruthenium(ii) bis(bipyridine) complex with elongation of the conjugated ligands: an experimental and theoretical investigation. AB - An absorbance-based sensor employing ruthenium bipyridyl with a phenanthroline fused benzoylthiourea moiety formulated as [Ru(ii)(bpy)2(phen-nBT)](PF6)2 {bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, nBT = n-benzoylthiourea} has been synthesized and characterized by elemental analyses, mass spectrometry, and infrared, ultraviolet-visible, luminescence and nuclear magnetic resonance spectroscopy. The changes in the intensity of absorption and emission of the complex induced by functionalization of the benzoylthiourea ligands with amino and carbonyl in their protonated and deprotonated forms were studied experimentally. The absorption and emission properties of the complex exhibit a strong dependence on the pH (1-11) of the aqueous medium. This work highlights the pH-sensitivity augmentation of the absorption band by elongating the conjugation length in the structure of the ruthenium bipyridine complex. The principle of this work was to design the title compound to be capable of enhancing the differences in the absorption sensitivity responses towards pH between the protonated and deprotonated complexes in the absorption measurement. Along with significant and noticeable changes in the absorption spectra, subsequent theoretical investigations specifically on the electronic and absorbance properties of the title compound were carried out in this study. Protonation of the molecule significantly stabilized the lowest-unoccupied molecular orbital (LUMO), whereas the highest-occupied molecular orbital (HOMO) is greatly destabilized upon deprotonation. A time-dependent density functional theory (TDDFT) calculation in the linear-response (-LR) regime was performed to clarify the origin of the experimentally observed linear dependence of absorption intensity upon pH (1-11). The MLCT band exhibits hyperchromic shift at low pH as indicated by the large transition dipole moment and a wider distribution of the response charge of the molecule, which is induced by the stabilization of the electrostatic potential at the carbonyl moiety by protonation. This study provides the possibility of employing theoretical information to gain insight into the origin of the optical absorption obtained experimentally. The ruthenium complex was designed with an elongated ligand conjugation length and exhibited a tremendously large change in the absorption intensity of the protonated and deprotonated forms, which therefore demonstrates its feasibility as an indicator molecule especially for absorbance measurements. PMID- 28913532 TI - Stereodivergent hydrodefluorination of gem-difluoroalkenes: selective synthesis of (Z)- and (E)-monofluoroalkenes. AB - We have developed a novel approach for the stereodivergent hydrodefluorination of gem-difluoroalkenes using copper(i) catalysts to obtain stereodefined monofluoroalkenes. Both (Z)- and (E)-terminal monofluoroalkenes were obtained by the hydrodefluorination of gem-difluoroalkenes in the presence of copper(i) catalysts and diboron or hydrosilane, respectively, with high stereoselectivity. DFT calculations were conducted to elucidate the stereoselectivity. PMID- 28913533 TI - Synthesis and redox reactions of bis(verdazyl)palladium complexes. AB - The synthesis and ligand-centered redox chemistry of palladium complexes bearing two potentially bidentate verdazyl ligands is explored. Reaction of 1,5 diisopropyl-3-pyridin-2-yl-6-oxoverdazyl radical 1 with Pd(NCMe)4.2BF4 gives a complex containing two coordinated verdazyl radicals. The structure of this complex consists of one verdazyl bound to Pd in a bidentate mode and the second verdazyl bound in a monodentate fashion through the pyridine substituent; the fourth coordination site is occupied by a solvent molecule (acetonitrile (3) or dimethyl sulfoxide (4)). Two-electron reduction of this complex with decamethylferrocene affords a bis(verdazyl) palladium complex (5) in which both verdazyls have been reduced to their anionic state and are both bound to Pd in bidentate manner. Complex 5 can be independently synthesized by a redox reaction between 1 and Pd2(dba)3. Reduced complex 5 can be re-oxidized to 3 or 4 with AgBF4; in contrast, oxidation with PhICl2 leads to ligand dissociation, ultimately giving radical 1 and a mono(verdazyl)dichloropalladium complex 2. One electron oxidation using PhICl2 produces a formally "mixed valent" (in ligand) bis(verdazyl)chloropalladium complex (6) with one bidentate verdazyl anion ligand and one monodentate (pyridine-bound) verdazyl radical. Attempted protonation of the verdazyl ligands in complex 5 leads to complete ligand dissociation and protonation of both the tetrazine and pyridine moieties; deprotonation regenerates 5. Subsequent air oxidation of the tetrazane/pyridinium cation (formed as a tetrachloropalladate salt) leads to re-coordination of the verdazyl ligands to give 6 initially, but ultimately produces a combination of free radical 1 and 2. PMID- 28913534 TI - Shell isolated nanoparticles for enhanced Raman spectroscopy studies in lithium oxygen cells. AB - A critical and detailed assessment of using Shell Isolated Nanoparticles for Enhanced Raman Spectroscopy (SHINERS) on different electrode substrates was carried out, providing relative enhancement factors, as well as an evaluation of the distribution of shell-isolated nanoparticles upon the electrode surfaces. The chemical makeup of surface layers formed upon lithium metal electrodes and the mechanism of the oxygen reduction reaction on carbon substrates relevant to lithium-oxygen cells are studied with the employment of the SHINERS technique. SHINERS enhanced the Raman signal at these surfaces showing a predominant Li2O based layer on lithium metal in a variety of electrolytes. The formation of LiO2 and Li2O2, as well as degradation reactions forming Li2CO3, upon planar carbon electrode interfaces and upon composite carbon black electrodes were followed under potential control during the reduction of oxygen in a non-aqueous electrolyte based on dimethyl sulfoxide. PMID- 28913535 TI - Stepwise microhydration of aromatic amide cations: water solvation networks revealed by the infrared spectra of acetanilide+-(H2O)n clusters (n <= 3). AB - The structure and activity of peptides and proteins strongly rely on their charge state and the interaction with their hydration environment. Here, infrared photodissociation (IRPD) spectra of size-selected microhydrated clusters of cationic acetanilide (AA+, N-phenylacetamide), AA+-(H2O)n with n <= 3, are analysed by dispersion-corrected density functional theory calculations at the omegaB97X-D/aug-cc-pVTZ level to determine the stepwise microhydration process of this aromatic peptide model. The IRPD spectra are recorded in the informative X-H stretch (nuOH, nuNH, nuCH, amide A, 2800-3800 cm-1) and fingerprint (amide I-II, 1000-1900 cm-1) ranges to probe the preferred hydration motifs and the cluster growth. In the most stable AA+-(H2O)n structures, the H2O ligands solvate the acidic NH proton of the amide by forming a hydrogen-bonded solvent network, which strongly benefits from cooperative effects arising from the excess positive charge. Comparison with neutral AA-H2O reveals the strong impact of ionization on the acidity of the NH proton and the topology of the interaction potential. Comparison with related hydrated formanilide clusters demonstrates the influence of methylation of the amide group (H -> CH3) on the shape of the intermolecular potential and the structure of the hydration shell. PMID- 28913536 TI - Isoreticular expansion of polyMOFs achieves high surface area materials. AB - The concept of isoreticular chemistry has become a core principle in metal organic framework (MOF) materials. Isoreticular chemistry has shown that organic ligands of different sizes, but with a common geometry/symmetry can be used to generate MOFs of related topologies, but with expanded pore sizes and volumes. In this report, polymer-MOF hybrid materials (polyMOFs) with a UiO (UiO = University of Oslo) architecture are shown to adhere to the principle of isoreticular expansion, generating polyMOFs with large surface areas and enhanced stability. PMID- 28913537 TI - A metal-lustrous porphyrin foil. AB - A metal-lustrous self-standing film, named "porphyrin foil", was formed from a glass-forming polymeric porphyrin. The amorphous glass nature of the porphyrin foil played a key role in spontaneously producing a smooth surface. Its sharp contrast in intense absorption and specular reflection of light at each wavelength provided a brilliant metallic lustre. PMID- 28913538 TI - Differences in cisplatin distribution in sensitive and resistant ovarian cancer cells: a TEM/NanoSIMS study. AB - Cisplatin is a widely used anti-cancer drug, but its effect is often limited by acquired resistance to the compound during treatment. Here, we use a combination of transmission electron microscopy (TEM) and nanoscale-secondary ion mass spectrometry (NanoSIMS) to reveal differences between cisplatin uptake in human ovarian cancers cells, which are known to be susceptible to acquired resistance to cisplatin. Both cisplatin sensitive and resistant cell lines were studied, revealing markedly less cisplatin in the resistant cell line. In cisplatin sensitive cells, Pt was seen to distribute diffusely in the cells with hotspots in the nucleolus, mitochondria, and autophagosomes. Inductively coupled plasma mass spectrometry (ICP-MS) was used to validate the NanoSIMS results. PMID- 28913539 TI - Expression of Concern: Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats. PMID- 28913540 TI - Expression of Concern: Circulating ghrelin concentrations are lowered by intracerebroventricular insulin. PMID- 28913541 TI - Erratum to: The aberrant right subclavian artery: cadaveric study and literature review. PMID- 28913542 TI - Metal release profiles of orthodontic bands, brackets, and wires: an in vitro study. AB - AIM: The present study evaluated the temporal release of Co Cr, Mn, and Ni from the components of a typical orthodontic appliance during simulated orthodontic treatment. MATERIALS AND METHODS: Several commercially available types of bands, brackets, and wires were exposed to an artificial saliva solution for at least 44 days and the metals released were quantified in regular intervals using inductively coupled plasma quadrupole mass spectrometry (ICP-MS, Elan DRC+, Perkin Elmer, USA). Corrosion products encountered on some products were investigated by a scanning electron microscope equipped with an energy dispersive X-ray microanalyzer (EDX). RESULTS: Bands released the largest quantities of Co, Cr, Mn, and Ni, followed by brackets and wires. Three different temporal metal release profiles were observed: (1) constant, though not necessarily linear release, (2) saturation (metal release stopped after a certain time), and (3) an intermediate release profile that showed signs of saturation without reaching saturation. These temporal metal liberation profiles were found to be strongly dependent on the individual test pieces. The corrosion products which developed on some of the bands after a 6-month immersion in artificial saliva and the different metal release profiles of the investigated bands were traced back to different attachments welded onto the bands. CONCLUSION: The use of constant release rates will clearly underestimate metal intake by the patient during the first couple of days and overestimate exposure during the remainder of the treatment which is usually several months long. While our data are consistent with heavy metal release by orthodontic materials at levels well below typical dietary intake, we nevertheless recommend the use of titanium brackets and replacement of the band with a tube in cases of severe Ni or Cr allergy. PMID- 28913544 TI - What's new in PICU in resource limited settings? PMID- 28913543 TI - DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. AB - AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529. PMID- 28913546 TI - Economic Burden of Osteoporosis in South Korea: Claim Data of the National Health Insurance Service from 2008 to 2011. AB - The purpose of this study was to estimate the current economic burden of osteoporosis in South Korea using national claim data of the Korean National Health Insurance Service (KNHIS) from 2008 to 2011. Patients aged 50 years or older were identified from KNHIS nationwide database for all records of outpatient visits or hospital admissions. Healthcare costs for osteoporotic patients included direct medical costs for hospitalization, outpatient care, and prescription drugs for the year after discharge. Healthcare costs were estimated based on the perspective of KNHIS, and calculated using a bottom-up approach. Between 2008 and 2011, total healthcare costs for osteoporotic patients increased from 3976 million USD to 5126 million USD, with an annual increase of 9.2% which accounted for one-sixth (16.7%) of national healthcare expenditure. Healthcare cost for hospitalization was the highest ($1903 million, 40.0% of total healthcare cost), followed by cost for outpatient care ($1474 million, 31.0%) and cost for prescription drugs ($1379 million, 29.0%). Although total healthcare cost for osteoporotic men was 6 times lower than that for osteoporotic women, the cost per person was 1.5 times higher than that for women. Total healthcare cost for osteoporotic patients without fractures was higher than that for osteoporotic patients with fractures. However, cost per person was the opposite. Osteoporosis entails substantial epidemiologic and economic burden in South Korea. This study provides information about the total healthcare burden, which could be important when determining what attention and awareness osteoporosis should be given in the public health system. PMID- 28913545 TI - Periostin in vitreoretinal diseases. AB - Proliferative vitreoretinal diseases such as diabetic retinopathy, proliferative vitreoretinopathy (PVR), and age-related macular degeneration are a leading cause of decreased vision and blindness in developed countries. In these diseases, retinal fibro(vascular) membrane (FVM) formation above and beneath the retina plays an important role. Gene expression profiling of human FVMs revealed significant upregulation of periostin. Subsequent analyses demonstrated increased periostin expression in the vitreous of patients with both proliferative diabetic retinopathy and PVR. Immunohistochemical analysis showed co-localization of periostin with alpha-SMA and M2 macrophage markers in FVMs. In vitro, periostin blockade inhibited migration and adhesion induced by PVR vitreous and transforming growth factor-beta2 (TGF-beta2). In vivo, a novel single-stranded RNAi agent targeting periostin showed the inhibitory effect on experimental retinal and choroidal FVM formation without affecting the viability of retinal cells. These results indicated that periostin is a pivotal molecule for FVM formation and a promising therapeutic target for these proliferative vitreoretinal diseases. PMID- 28913547 TI - Probucol prevents the attenuation of beta2-adrenoceptor-mediated vasodilation of retinal arterioles in diabetic rats. AB - Probucol is an antihyperlipidemic drug with potent antioxidant properties. Oxidative stress plays an important role in the pathogenesis of diabetic retinopathy. In this study, we aimed to investigate the protective effects of probucol against diabetes-induced retinal vascular dysfunction in a rat model of diabetes. Diabetes was induced by a combination of streptozotocin treatment and D glucose feeding, and retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles. The vasodilator effect of salbutamol, a beta2 adrenoceptor agonist, on retinal arterioles was significantly diminished 2 weeks after the induction of diabetes. In non-diabetic rats, vasodilator responses to salbutamol were significantly reduced after an intravitreal injection of iberiotoxin, a blocker of large-conductance KCa (BKCa) channels. However, this effect was not observed in diabetic rats. Probucol had no significant effect on salbutamol-induced changes in diameter of retinal arterioles in non-diabetic rats, whereas it could prevent the attenuation of retinal vasodilator response to salbutamol in diabetic rats. These results suggest that the reduced function of BKCa channels is involved in the attenuation of beta2-adrenoceptor-mediated retinal vasodilation in diabetic rats. Probucol preserves the BKCa channel function in retinal arterioles under diabetic conditions; therefore, it may show beneficial effects on diabetic retinopathy by preventing or slowing the impairment of the retinal circulation in patients with diabetes mellitus. PMID- 28913548 TI - Changes in Histopathology, Enzyme Activities, and the Expression of Relevant Genes in Zebrafish (Danio rerio) Following Long-Term Exposure to Environmental Levels of Thallium. AB - Thallium is a rare-earth element, but widely distributed in water environments, posing a potential risk to our health. This study was designed to investigate the chronic effects of thallium based on physiological responses, gene expression, and changes in the activity of relevant enzymes in adult zebra fish exposed to thallium at low doses. The endpoints assessed include mRNA expression of metallothionein (MT)2 and heat shock protein HSP70; enzymatic activities of superoxide dismutase (SOD) and Na+/K+-ATPase; and the histopathology of gill, gonad, and liver tissues. The results showed significant increases in HSP70 mRNA expression following exposure to 100 ng/L thallium and in MT2 expression following exposure to 500 ng/L thallium. Significantly higher activities were observed for SOD in liver and Na+/K+-ATPase activity in gill in zebra fish exposed to thallium (20 and 100 ng/L, respectively) in comparison to control fish. Gill, liver, and gonad tissues displayed different degrees of damage. The overall results imply that thallium may cause toxicity to zebra fish at environmentally relevant aqueous concentrations. PMID- 28913549 TI - Multicenter phase II study of capecitabine plus cisplatin as first-line therapy for human epidermal growth factor receptor 2-negative advanced gastric cancer: Yokohama Clinical Oncology Group Study YCOG1107. AB - PURPOSE: S-1 plus cisplatin therapy is the recommended standard first-line regimen for human epidermal growth factor receptor 2 (HER-2)-negative advanced unresectable or recurrent gastric cancer (AGC) in the Japanese Gastric Cancer Treatment Guidelines. By contrast, capecitabine plus cisplatin (XP) therapy has been second-line therapy for these patients. This prospective study aimed to evaluate the efficacy and safety of XP as a first-line regimen for HER2-negative patients with AGC. METHODS: In this multicenter, open-label, phase II study, patients received cisplatin (80 mg/m2 i.v. day 1) plus capecitabine (1000 mg/m2 orally, twice daily, days 1-14) at 3 week intervals until disease progression or non-continuation for various reasons. The primary endpoint was overall response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profiles. RESULTS: Thirty-six patients with HER2 negative AGC were enrolled in this study. Of these, 16 patients with evaluable lesions were assessable for efficacy and 36 were assessable for toxicity. One patient achieved a complete response and five partial responses. The overall response rate was 37.5% [95% confidence interval (CI) 13.7-61.2%] calculated on an intention-to-treat basis. The median PFS and median OS were 5.2 months (95% CI 4.2-6.2 months) and 16.9 months (95% CI 5.8-27.9 months), respectively. Treatment related adverse events were generally mild; the most common grade 3/4 adverse event was neutropenia (27.8%), followed by anorexia (19.4%), leucopenia (16.7%), anemia (16.7%), and nausea (13.9%). CONCLUSION: XP as first-line therapy is effective and well tolerated by patients with HER2-negative AGC. PMID- 28913551 TI - Bladder cancer in the EMPA-REG OUTCOME trial. PMID- 28913550 TI - Oxidative Damage and Genetic Toxicity Induced by DBP in Earthworms (Eisenia fetida). AB - Di-n-butyl phthalate (DBP) is one of the most ubiquitous plasticizers used worldwide. However, it has negatives effects on the soil, water, atmosphere, and other environmental media and can cause serious pollution. According to the artificial soil test and previous studies, this study was conducted to evaluate the toxicity of earthworms induced by DBP at different concentrations (0, 0.1, 1.0, 10, and 50 mg kg-1) on the 7th, 14th, 21st, and 28th days of exposure. The variations in the antioxidant activities of enzymes, such as catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and glutathione-S-transferase (GST), in the amounts of malondialdehyde (MDA) and reactive oxygen species (ROS) and in the amount of DNA damage were measured to evaluate the toxic impact of DBP in earthworms. Upon exposure to DBP, the SOD, CAT, POD, and GST activities were significantly increased, with the exception of the 0.1 mg kg-1 treatment dose. High concentrations of DBP (10 and 50 mg kg-1) induced superfluous ROS to be produced and caused the MDA content to increase significantly. Therefore, we proposed that DBP led to DNA damage in earthworm coelomocytes in a dose-dependent manner, which means that DBP is a source of oxidative damage and genetic toxicity in earthworms. PMID- 28913552 TI - A Novel Scoring System for Diagnosing Acute Mesenteric Ischemia in the Emergency Ward: Methodological Issues. PMID- 28913553 TI - Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury. AB - Early reperfusion of ischemic cardiac tissue increases inflammatory cell infiltration which contributes to cardiomyocyte death and loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Neutrophil- and mast cell-derived proteases, cathepsin G (Cat.G) and chymase, are released early after IR, but their function is complicated by potentially redundant actions and targets. This study investigated whether a dual inhibition of Cat.G and chymase influences cardiomyocyte injury and wound healing after experimental IR in mice. Treatment with a dual Cat.G and chymase inhibitor (DCCI) immediately after reperfusion blocked cardiac Cat.G and chymase activity induced after IR, which resulted in decreased immune response in the infarcted heart. Mice treated with DCCI had less myocardial collagen deposition and showed preserved ventricular function at 1 and 7 days post-IR compared with vehicle-treated mice. DCCI treatment also significantly attenuated focal adhesion (FA) complex disruption and myocyte degeneration after IR. Treatment of isolated cardiomyocytes with Cat.G or chymase significantly promoted FA signaling downregulation, myofibril degeneration and myocyte apoptosis. Conversely, treatment of cardiac fibroblasts with Cat.G or chymase induced FA signaling activation and increased their migration and differentiation to myofibroblasts. These opposite responses in cardiomyocytes and fibroblasts were blocked by treatment with DCCI. These findings show that Cat.G and chymase are key mediators of myocyte apoptosis and fibroblast migration and differentiation that play a role in adverse cardiac remodeling and function post-IR. Thus, dual targeting of neutrophil- and mast cell-derived proteases could be used as a novel therapeutic strategy to reduce post-IR inflammation and improve cardiac remodeling. PMID- 28913554 TI - Reliability of size and echo intensity of abdominal skeletal muscles using extended field-of-view ultrasound imaging. AB - PURPOSE: This study aimed to examine the reliability of extended field-of-view (EFOV) ultrasound imaging to evaluate the cross-sectional area (CSA) and echo intensity of abdominal skeletal muscles. METHODS: Twenty-seven healthy young males (age 18.6 +/- 1.0 years, body mass index 20.9 +/- 2.8 kg/m2, waist circumference 75.0 +/- 7.9 cm, body fat 16.6 +/- 5.9%) visited the laboratory on 2 days. EFOV ultrasound images of the rectus abdominis, abdominal oblique, and erector spinae muscles were acquired at the height of the third lumbar vertebra with the subject lying on a bed. We then analyzed CSA and echo intensity using ImageJ software and calculated intra-class correlation coefficients (ICC) and the standard error of measurement (SEM). RESULTS: No significant differences (p = 0.149-0.679) were observed in CSA or echo intensity values for each skeletal muscle between days. ICC and SEM values in CSA for each skeletal muscle ranged between 0.944 and 0.958 and 4.9% and 7.3%, respectively. The corresponding values for echo intensity were 0.851-0.945 for ICC and 5.3-9.7% for SEM. CONCLUSIONS: The present results indicate that EFOV ultrasound imaging has high repeatability for measuring CSA and echo intensity of abdominal skeletal muscle groups in healthy college-aged males. PMID- 28913555 TI - Outcome of intrahepatic portosystemic shunt diagnosed prenatally. AB - : We analyzed the characteristics of the population with congenital portosystemic shunt diagnosed during the antenatal period and the organization of their perinatal care. This multicentric retrospective study included all the patients with a prenatal diagnosis of congenital portosystemic shunt. Between 1999 and 2015, 12 patients were included. Prenatal diagnosis was done at a median 26.5 weeks of gestation (21-34). All the patients presented intrahepatic CPSS, three of them had associated congenital cardiopathy, and one a Bannayan-Zonana syndrome. Ten patients had simple outcome on conservative treatment, eight of them having a spontaneous closure of their portosystemic shunt within the first 2 years of life. One patient had surgical treatment which failed and he developed a focal nodular hyperplasia. Another patient had radiological interventional closure of his shunt which was complicated by a venal portal thrombosis. CONCLUSION: Outcome of intrahepatic portosystemic shunt diagnosed prenatally is good in the majority of cases. What is known: * Multiples studies exist on congenital porto systemic shunt but when the diagnosis is done after birth. * The evolution, management, and complication are well known. What is new: * There is very few studies with only patients diagnosed in antenatal and it is a large series of cases. * Outcome of intrahepatic portosystemic shunt diagnosed prenatally is good in the majority of cases. PMID- 28913556 TI - High-dose vitamin D3 supplementation decreases the number of colonic CD103+ dendritic cells in healthy subjects. AB - PURPOSE: Vitamin D may induce tolerance in the intestinal immune system and has been shown to regulate the phenotype of tolerogenic intestinal dendritic cells (DCs) in vitro. It is unknown whether vitamin D supplementation affects human intestinal DCs in vivo, and we aimed to investigate the tolerability and effect on intestinal CD103+DCs of high-dose vitamin D3 treatment in healthy subjects. METHODS: Ten healthy subjects received a total of 480,000 IU oral vitamin D3 over 15 days and colonic biopsies were obtained before and after intervention by endoscopy. Lamina propria mononuclear cells (LPMCs) were isolated from the biopsies, stained with DC surface markers and analysed with flow cytometry. Snap frozen biopsies were analysed with qPCR for DC and regulatory T cell-related genes. RESULTS: No hypercalcemia or other adverse events occurred in the test subjects. Vitamin D decreased the number of CD103+ DCs among LPMCs (p = 0.006). Furthermore, vitamin D induced mRNA expression of TGF-beta (p = 0.048), TNF-alpha (p = 0.006) and PD-L1 (p = 0.02) and tended to induce IL-10 expression (p = 0.06). Multivariate factor analysis discriminated between pre- and post-vitamin D supplementation with a combined increased qPCR expression of PD1, PD-L1, TGF beta, IL-10, CD80, CD86, FOXP3, NFATc2 and cathelicidin. CONCLUSION: High-dose vitamin D supplementation is well tolerated by healthy subjects and has a direct effect on the CD103+ DCs, local cytokine and surface marker mRNA expression in the colonic mucosa, suggestive of a shift towards a more tolerogenic milieu. PMID- 28913557 TI - Improved joint-line restitution in unicompartmental knee arthroplasty using a robotic-assisted surgical technique. AB - PURPOSE: Joint-line restitution is one objective of unicompartmental knee arthroplasty (UKA). However, the joint line is often lowered when resurfacing femoral implants are used. The aim of this study was to compare the joint-line height in UKA performed by robotic-assisted and conventional techniques. METHODS: This retrospective case-control study compared two matched groups of patients receiving a resurfacing UKA between 2013 and 2016 by either a robotic-assisted (n = 40) or conventional (n = 40) technique. Each group comprised 27 women and 13 menm wuth a mean age of 69 and 68 years, respectively. Indications for surgery were osteoarthritis (n = 35) and condylar osteonecrosis (n = 5). Two validated radiologic measurement methods were used to assess joint-line height. RESULTS: Forty UKA (23 medial and 17 lateral) were analysed in each group. Restitution of joint-line height was significantly improved in the robotic-assisted group compared than the control group: +1.4 mm +/-2.6 vs +4.7 mm +/- 2.4 (p < 0.05) as assessed using method 1, and +1.5 mm +/-2.3 vs +4.6 mm +/-2.5 (p < 0.05) as assessed using method 2. CONCLUSIONS: Restitution of joint-line height in resurfacing UKA can be improved with robotic-assisted surgery. Improvement in clinical outcome measures must be demonstrated with long-term studies. PMID- 28913558 TI - Only SETBP1 hotspot mutations are associated with refractory disease in myeloid malignancies. AB - INTRODUCTION: SETBP1 mutations have been established as a diagnostic marker in myeloid malignancies and are associated with inferior survival. Since there is limited data on their clinical impact and stability during disease progression, we sought to investigate the relationship between SETBP1 mutations and disease evolution. METHODS: Bidirectional Sanger sequencing of the SETBP1 gene was performed for 442 unselected patients with World Health Organization (WHO) defined myeloid disorders. Follow-up analysis was performed on samples from 123/442 patients to investigate SETBP1 mutation dynamics. Targeted deep next generation sequencing for a panel of 30 leukemia-associated genes was established to study SETBP1 cooperating mutations. RESULTS: 10/442 patients (2.3%) had SETBP1 hotspot mutations (MDS/MPN, n = 7, sAML, n = 3), whereas four patients (1%) had SETBP1 non-hotspot mutations (MPN, n = 1; MDS, n = 2; sAML, n = 1). The median overall survival for patients with SETBP1 hotspot mutations, SETBP1 non-hotspot mutations, and SETBP1 wild type was 14 (range 0-31), 50 (range 0-71), and 47 months (range 0-402), respectively. In Kaplan-Meier analysis, SETBP1 hotspot mutations were significantly associated with reduced overall survival compared to SETBP1 non-hotspot mutations and the SETBP1 wild type (p < 0.001). All 10 patients with SETBP1 hotspot mutations died from relapse or disease progression. Three of four patients with SETBP1 non-hotspot mutations are alive with stable disease. Cooperating CSF3R and TET2 mutations were most frequently observed in patients with SETBP1 hotspot mutations. CONCLUSIONS: Patients with SETBP1 hotspot mutations suffered from aggressive disease with rapid evolution and inferior overall survival. Patients with SETBP1 non-hotspot mutations had less aggressive disease and a more favorable prognosis. Diagnostic screens for SETBP1 hotspot mutations may help identifying this dismal patient group and treat them in multicenter clinical studies. PMID- 28913559 TI - Risk factors for implant removal after spinal surgical site infection. AB - PURPOSE: Few studies have investigated the risk factors for implant removal after treatment for spinal surgical site infection (SSI). Therefore, there is no firmly established consensus for the management of implants. We aimed to investigate the incidence and risk factors for implant removal after SSI managed with instrumentation, and to examine potential strategies for avoiding implant removal. METHODS: Following a survey of seven spine centers, we retrospectively reviewed the records of 55 patients who developed SSI and were treated with reoperation, out of 3967 patients who had spinal instrumentation between 2003 and 2012. We examined implant survival rate and applied logistic regression analysis to assess the potential risk factors for implant removal. RESULTS: The overall rate of implant retention was 60% (33/55). A higher implant retention rate was observed for posterior cervical surgery than for posterior-thoracic/lumbar surgery (100 vs. 49%, P < 0.001). On univariate analysis, significant risk factors for implant removal included greater blood loss, delay of reoperation, and delay of intervention with effective antibiotics. Multivariate analysis revealed that a delay in administering effective antibiotics was an independent and significant risk factor for implant removal in posterior-thoracic/lumbar surgery (odds ratio 1.17; 95% confidence interval 1.02-1.35, P = 0.028). CONCLUSIONS: Patients with SSI who underwent posterior cervical surgery are likely to retain the implants. Immediate administration of effective antibiotics improves implant survival in SSI treatment. Our findings can be applied to identify SSI patients at higher risk for implant removal. PMID- 28913560 TI - Deregulation of obesity-relevant genes is associated with progression in BMI and the amount of adipose tissue in pigs. AB - The aim of this study was to elucidate the relative impact of three phenotypes often used to characterize obesity on perturbation of molecular pathways involved in obesity. The three obesity-related phenotypes are (1) body mass index (BMI), (2) amount of subcutaneous adipose tissue (SATa), and (3) amount of retroperitoneal adipose tissue (RPATa). Although it is generally accepted that increasing amount of RPATa is 'unhealthy', a direct comparison of the relative impact of the three obesity-related phenotypes on gene expression has, to our knowledge, not been performed previously. We have used multiple linear models to analyze altered gene expression of selected obesity-related genes in tissues collected from 19 female pigs phenotypically characterized with respect to the obesity-related phenotypes. Gene expression was assessed by high-throughput qPCR in RNA from liver, skeletal muscle and abdominal adipose tissue. The stringent statistical approach used in the study has increased the power of the analysis compared to the classical approach of analysis in divergent groups of individuals. Our approach led to the identification of key components of cellular pathways that are modulated in the three tissues in association with changes in the three obesity-relevant phenotypes (BMI, SATa and RPATa). The deregulated pathways are involved in biosynthesis and transcript regulation in adipocytes, in lipid transport, lipolysis and metabolism, and in inflammatory responses. Deregulation seemed more comprehensive in liver (23 genes) compared to abdominal adipose tissue (10 genes) and muscle (3 genes). Notably, the study supports the notion that excess amount of intra-abdominal adipose tissue is associated with a greater metabolic disease risk. Our results provide molecular support for this notion by demonstrating that increasing amount of RPATa has a higher impact on perturbation of cellular pathways influencing obesity and obesity-related metabolic traits compared to increase in BMI and amount of SATa. PMID- 28913561 TI - Conformational rearrangement of 1,2-d(GG) intrastrand cis-diammineplatinum crosslinked DNA is driven by counter-ion penetration within the minor groove of the modified site. AB - The major structural aberrations of DNA induced by a cis-diammineplatinum (II) 1,2-d(GG) intrastrand cross-link (CPT) have been known for decades. To gain deeper insights into the structural dynamics of the sequence-dependent DNA distortions adjacent to the CPT adduct, we employed molecular modeling and molecular dynamics (MD) simulations. The structural dynamics of native (N-DNA) and cisPt 1,2-d(GG) crosslinked (CPT-DNA) in the form of symmetric 36 nt d(G2T15G*G*T15G2)?C2A15CCA15C2) oligonucleotide duplexes is compared. The selected sequence context enabled tracking of the origin of the DNA axis curvature at the YpR flexible points (N-DNA), the enhancement of axis bending, and further distortions due to steric/electrostatic perturbations arising from the CPT-crosslink. In addition to the known structural distortions of CPT-DNA: helix bend towards the major groove; local helix unwinding; high roll angle between cross-linked guanine bases; and adoption of A-form DNA on the 5'-side of the CPT-crosslink (TpG junction); our results show the existence of a singular irreversible and reproducible conformational rearrangement, not previously observed, resulting in two stable CPT-DNA1 and CPT-DNA2 conformers. The CPT-DNA2 conformation presents an enhanced DNA axis bend and a wider and shallower minor grove with increased solvent accessibility within the modified site. It is concluded that the polymorphous (unstable) DNA environment near the cisPt 1,2 d(GG) unit in synergy with specific dynamic events, such as prolonged minor groove retention of particular Na+ ions and water redistribution within the d(TG*G*T) site, together with the formation of extra and more stable H-bonds between Pt(NH3)2 amines and neighboring nucleotides, are cooperatively responsible for the initiation of the conformational rearrangement leading to the CPT-DNA2 conformer, which, surprisingly, closely resembles the HMGB1-bound CPT DNA structure. Graphical abstract Superimposed averaged structures of normal (N DNA, green) and cisplatin intrastrand cross-linked (CPT-DNA, orange). Global DNA axes: N-DNA (blue beads); CPT-DNA (red beads); PT (yellow sphere); crosslinked dGs viewed from the minor groove (bold). PMID- 28913562 TI - Renal functional reserve: time to find a new bottle for the old wine? PMID- 28913563 TI - Dylan under the microscope: microbiology in Subterranean Homesick Blues. PMID- 28913564 TI - Moving Forward on Hypersexuality. PMID- 28913565 TI - A retrospective analysis of ramucirumab monotherapy in previously treated Japanese patients with advanced or metastatic gastric adenocarcinoma. AB - BACKGROUND: The REGARD trial demonstrated that ramucirumab monotherapy improved both overall survival (OS) and progression-free survival (PFS) compared with best supportive care plus placebo as second-line treatment for patients with advanced gastric cancer. However, the efficacy and safety of ramucirumab monotherapy for previously treated Japanese patients with advanced gastric cancer remains unknown. METHODS: Previously treated Japanese patients with advanced gastric cancer who received ramucirumab monotherapy between June 2015 and March 2016 at the Cancer Institute Hospital were enrolled in the study. OS, PFS, best overall response, and safety profiles were retrospectively evaluated. RESULTS: Nineteen patients were enrolled in this study. Ramucirumab monotherapy was generally administered as third-line therapy. After a median follow-up period of 7.4 months, the median PFS was 2.1 months (95% CI 1.0-3.5), and median OS was 12.9 months (95% CI 2.3, not reached). In 13 patients who had measurable lesions on radiologic examination, partial response was observed in one patient (7.7%) and stable disease was observed in five patients (38.5%). A total of 12 patients (63.2%) had adverse events (AEs). Common AEs included hypertension (8 patients, 42.1%), fatigue (6 patients, 31.6%), and bleeding (5 patients, 26.3%). Grade 3 AEs included gastrointestinal bleeding and aspiration pneumonia (1 patient each, 5.3%). CONCLUSIONS: Our data suggest that ramucirumab monotherapy in Japanese patients with previously treated advanced gastric cancer has comparable efficacy and safety profiles as reported in the REGARD trial. PMID- 28913567 TI - Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress. AB - PURPOSE: This study tests whether metformin or diet supplement BR-DIM-induced AMP activated protein kinase (AMPK) mediated effects on development are more pronounced in blastocysts or 2-cell mouse embryos. METHODS: Culture mouse zygotes to two-cell embryos and test effects after 0.5-1 h AMPK agonists' (e.g., Met, BR DIM) exposure on AMPK-dependent ACCser79P phosphorylation and/or Oct4 by immunofluorescence. Culture morulae to blastocysts and test for increased ACCser79P, decreased Oct4 and for AMPK dependence by coculture with AMPK inhibitor compound C (CC). Test whether Met or BR-DIM decrease growth rates of morulae cultured to blastocyst by counting cells. RESULT(S): Aspirin, metformin, and hyperosmotic sorbitol increased pACC ser79P ~ 20-fold, and BR-DIM caused a ~ 30-fold increase over two-cell embryos cultured for 1 h in KSOMaa but only 3- to 6-fold increase in blastocysts. We previously showed that these stimuli decreased Oct4 40-85% in two-cell embryos that was ~ 60-90% reversible by coculture with AMPK inhibitor CC. However, Oct4 decreased only 30-50% in blastocysts, although reversibility of loss by CC was similar at both embryo stages. Met and BR-DIM previously caused a near-complete cell proliferation arrest in two-cell embryos and here Met caused lower CC-reversible growth decrease and AMPK-independent BR DIM-induced blastocyst growth decrease. CONCLUSION: Inducing drug or diet supplements decreased anabolism, growth, and stemness have a greater impact on AMPK-dependent processes in two-cell embryos compared to blastocysts. PMID- 28913566 TI - ADAR RNA editing in human disease; more to it than meets the I. AB - We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutieres Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions. PMID- 28913568 TI - Piperlongumine induces G2/M phase arrest and apoptosis in cholangiocarcinoma cells through the ROS-JNK-ERK signaling pathway. AB - Cholangiocarcinoma (CCA) is an aggressive, metastatic bile duct cancer. CCA is difficult to diagnose, and responds poorly to current radio- and chemo-therapy. Piperlongumine (PL) is a naturally-occurring small molecule selectively toxic to cancer cells by targeting reactive oxygen species (ROS). In this study, we demonstrated the potential anticancer activity of PL in CCA. PL markedly induced death in CCA cell lines in a dose- and time-dependent manner through the activation of caspase-3 and PARP. PL also stimulated ROS accumulation in CCA. Co exposure of PL with the ROS scavenger N-acetyl-L-cysteine or GSH completely blocked PL-induced apoptosis in CCA cell lines. Increased p21 via the p53 independent pathway in PL-treated CCA cells led to G2/M phase arrest and cell apoptosis. In addition, the study showed that PL trigger CCA cell lines death through JNK-ERK activation. Furthermore, the different antioxidant capacity of CCA cell lines also indicates the susceptibility of the cells to PL treatment. Our findings reveal that PL exhibits anti-tumor activity and has potential to be used as a chemotherapeutic agent against CCA. PMID- 28913569 TI - Antegrade intramedullary Kirschner-wire fixation of displaced metacarpal shaft fractures. AB - PURPOSE: The objective of this study was to analyze complications and patient related functional outcome after antegrade intramedullary Kirschner-wire fixation of metacarpal shaft fractures. METHODS: All consecutive patients treated from January 2010 until December 2015 were retrospectively analyzed using patient logs and radiographic images. Indications for operative fixation were angulation > 40 degrees , shortening > 2 mm, or rotational deficit. Complications were registered from the patient logs. Functional outcome was assessed with the Patient-rated wrist/hand evaluation (PRWHE) and Disabilities of the Arm, Shoulder, and Hand score (DASH) questionnaire both ranging from 1 to 100 after a minimum follow-up of 6 months. RESULTS: During the study period, 34 fractures of 27 patients could be included. Mean outpatient follow-up was 11 weeks (range 4-24 weeks). The mean interval for functional assessment was 30 months (range 8-62 months) and 19 patients (70%) responded to the questionnaires. During outpatient follow-up, all fractures proceeded to union with no signs of secondary fracture dislocation or implant migration. One re-fracture after a new adequate trauma was seen and one patient underwent tenolysis due to persistent pain and impaired function. In 26 cases (81%), the K-wires were removed of which 23 (68%) were planned removals. Functional outcome was excellent with mean PRWHE and DASH scores of 7 and 5 points, respectively. CONCLUSIONS: If surgical treatment for metacarpal shaft fractures is considered, we recommend antegrade intramedullary K-wire fixation. This technique results in low complication rates and excellent functional outcome. PMID- 28913571 TI - ? AB - Cardiac rehabilitation is an evidence-based treatment to improve prognosis and quality of life in patients after a cardiac event. In general, cardiac rehabilitation programmes are offered in all European countries. Nevertheless a wide dispersion between countries exists in programme structure and design because of different national legislation and funding. The absence of international standards has a negative effect on programme quality and outcome. Most striking imbalance can be observed between patients eligible for cardiac rehabilitation and the real admission rate. Only three European countries report an admission rate of more than 50% of all eligible patients, and less than 25% are women. Thus, rehabilitation programmes in Europe are too heterogeneous. This needs measures for better standardization from "best evidence" to "best practice". The "Quality of Care Continuum" of cardiac rehabilitation could be helpful. PMID- 28913570 TI - Low physical activity is related to clustering of risk factors for fracture-a 2 year prospective study in children. AB - : The study investigates the effect of physical activity (PA) on a composite score for fracture risk in pre-pubertal children. Low PA in children is related to the composite score for fracture risk and the pre-pubertal years seem to be a period when PA positively affects the score. INTRODUCTION: This study evaluates if PA in children is related to clustering of risk factors for fracture. Research questions are the following: (i) What is the effect of physical activity (PA) on single traits and a composite score for fracture risk? (ii) Could this score be used to identify the level of PA needed to reach beneficial effects? METHODS: This prospective population-based study included 269 children, aged 7-9 years at baseline while 246 attended the 2-year follow-up. We estimated duration of PA by questionnaires and measured traits that independently predict fractures. We then calculated gender specific Z-scores for each variable. The mean Z-score of all traits was used as a composite score for fracture risk. We tested correlation between duration of PA, each trait, and the composite score and group differences between children in different quartiles of PA. RESULTS: At baseline, we found no correlation between duration of PA and any of the traits or the composite score. At follow-up, we found a correlation between PA and the composite score. Physical activity had an effect on composite score, and children in the lowest quartiles of PA had unbeneficial composite score compared to children in the other quartiles. CONCLUSION: Low PA in children is related to clustering of risk factors for fracture, and the pre-pubertal years seem to be a period when PA positively affects the composite score. PMID- 28913572 TI - Establishment of S100A8 Transgenic Rats to Understand Innate Property of S100A8 and Its Immunological Role. AB - The innate properties of S100A8 as a regulator in acute inflammation have not yet been elucidated in detail. Our aims are to newly establish S100A8 transgenic rats (Tg-S100A8) and to elucidate the immunological functions of S100A8. Following the treatment with 5% dextran sulfate sodium for 1 week, the body weight in Tg-S100A8 weakly decreased after the start; however, that in Japanese Wistar rats (WT) significantly decreased in the end. The serum level of CRP in Tg-S100A8 was significantly lower than that in WT, although the concentration of CRP apparently increased in both Tg-S100A8 and WT. The dynamic mobility of S100A8 and S100A9 in macrophages was microscopically observed using fluorescent immunological staining, in which the S100A9 was dominantly expressed in many macrophages in the rectal tissue of WT. As determined by PCR and real-time PCR, the levels of S100A8 messenger RNA (mRNA) in several organ tissues of the Tg-S100A8, such as heart and small intestine, were apparently higher than those of WT, respectively. The expression of IL-6 and TNF-alpha mRNAs was negatively regulated in main organ tissues of the large colon of Tg-S100A8 followed by down-regulation of IL-6 protein. An important result was that the expression of S100A8 mRNA was strongly induced in many macrophages of Tg-S100A8, whereas that of some inflammatory cytokine mRNAs described above were significantly reduced. Tg-S100A8 has potential as a useful experimental model rat not only for investigating the innate properties of S100A8 as a regulator, but also for clarifying its functional role in immune cells from a myeloid origin, particularly macrophages. PMID- 28913573 TI - Genetic analysis of Japanese and American specimens of Scirpus hattorianus suggests its introduction from North America. AB - Scirpus hattorianus is a possible alien species in Japan, and a clarification of its unclear taxonomy is required to reveal its origin. It is not known whether the plants initially described from Japan represent the same species distributed in North America. To clarify the origin of the species, we attempted to sequence old specimens collected about 80 years ago using newly designed primer pairs specific for short sequences, including the variable sites. Chloroplast sequences of ndhF were compared among Japanese and North American S. hattorianus, and the closely related species, S. atrovirens, S. flaccidifolius, and S. georgianus. We succeeded in sequencing all samples, and two haplotypes were detected in S. hattorianus: one was unique to the species and the other, detected from specimens potentially collected from the same population as the types, was shared by both North American S. hattorianus and two closely related species, S. atrovirens and S. flaccidifolius. Our results suggest that Japanese S. hattorianus is an alien species that was introduced from North America at least twice. PMID- 28913574 TI - The association between the lymphocyte-monocyte ratio and disease activity in rheumatoid arthritis. AB - The lymphocyte-monocyte ratio (LMR) is a systemic inflammatory marker for prediction of disease development, progress, and survival. Recently, a genome wide association study identified genetic variations in ITGA4 and HLA-DRB1 that affect the LMR levels and were widely believed to be susceptibility genes for autoimmune diseases, including rheumatoid arthritis (RA). However, the role of LMR in RA patients remains unclear. The LMR level and other laboratory data of 66 RA patients, 163 osteoarthritis (OA) patients, and 131 healthy controls (HC) were compared using binary logistic regression. The correlations between LMR and disease activity and other inflammatory markers were measured using the Spearman rank test. ROC curve analyses assessed the diagnostic accuracy of LMR in RA. The LMR and lymphocyte count were significantly lower in RA patients, whereas the monocyte count was significantly higher relative to the HC group/OA patients (p < 0.01). A decreased LMR has been associated with increased disease activity (p = 0.012). In addition, the DAS28 and traditional inflammatory markers, including ESR, CRP, RDW, PLR, and NLR, and immune-related factors, such as C4, IgA, and IgM, were inversely correlated with LMR, while hemoglobin and albumin were positively correlated with LMR. The ROC curve showed that the area under the curve of LMR was 0.705 (95%CI = 0.630-0.781). The corresponding specificity and sensitivity were 82.82 and 45.45%, respectively. The present study shows that the LMR is an important inflammatory marker which could be used to identify disease activity in RA patients and to distinguish RA from OA patients. PMID- 28913575 TI - Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2). AB - AIMS/HYPOTHESIS: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c. RESULTS: Day-to day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49). CONCLUSIONS/INTERPRETATION: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529. PMID- 28913576 TI - Interferon activates promoter of Nmi gene via interferon regulator factor-1. AB - N-Myc interactor (Nmi) is reported to participate in many activities, such as signaling transduction, transcription regulation, and antiviral responses. As Nmi may play important roles in interferon (IFN)-induced responses, we investigated the mechanism how Nmi protein is regulated. We identified and cloned the promoter of Nmi gene. Sequence analysis and luciferase assays shown that an IFN-stimulated response element (ISRE) and a GC box in the promoter were essential for the basal transcription activity of Nmi gene. We also found that interferon regulatory factor 1 (IRF-1) could activate transcription of Nmi by binding to the ISRE in the promoter. Knockdown of IRF-1 decreases IFN-induced Nmi transcription. These results revealed that IRF-1 is involved in the IFN-inducible expression of Nmi. PMID- 28913577 TI - A resequencing pathogen microarray method for high-throughput molecular diagnosis of multiple etiologies associated with central nervous system infection. AB - Central nervous system infection (CNSI) results in significant health and economic burdens worldwide, but the diversity of causative pathogens makes differential diagnosis very difficult. Although PCR and real-time fluorescent quantitative PCR (q-PCR) assays are widely applied for pathogen detection, they are generally optimized for the detection of a single or limited number of targets and are not suitable for the diagnosis of numerous CNSI agents. In this study, we describe the development of a resequencing pathogen microarray (RPM IVDC4) method for the simultaneous detection of viruses, bacteria, fungi and parasites that cause CNSI. The test panel of this assay included more than 100 microorganism species across 45 genera and 30 families. The analytical specificity and sensitivity were examined using a panel of positive reference strains, and the clinical performance was evaluated using 432 clinical samples by comparing the results with q-PCR assays. Our results demonstrated good performance of the RPM-IVDC4 assay in terms of sensitivity, specificity and detection range, suggesting that the platform can be further developed for high throughput CNSI diagnosis. PMID- 28913578 TI - Loci on chromosomes 1A and 2A affect resistance to tan (yellow) spot in wheat populations not segregating for tsn1. AB - KEY MESSAGE: QTL for tan spot resistance were mapped on wheat chromosomes 1A and 2A. Lines were developed with resistance alleles at these loci and at the tsn1 locus on chromosome 5B. These lines expressed significantly higher resistance than the parent with tsn1 only. Tan spot (syn. yellow spot and yellow leaf spot) caused by Pyrenophora tritici-repentis is an important foliar disease of wheat in Australia. Few resistance genes have been mapped in Australian germplasm and only one, known as tsn1 located on chromosome 5B, is known in Australian breeding programs. This gene confers insensitivity to the fungal effector ToxA. The main aim of this study was to map novel resistance loci in two populations: Calingiri/Wyalkatchem, which is fixed for the ToxA-insensitivity allele tsn1, and IGW2574/Annuello, which is fixed for the ToxA-sensitivity allele Tsn1. A second aim was to combine new loci with tsn1 to develop lines with improved resistance. Tan spot severity was evaluated at various growth stages and in multiple environments. Symptom severity traits exhibited quantitative variation. The most significant quantitative trait loci (QTL) were detected on chromosomes 2A and 1A. The QTL on 2A explained up to 29.2% of the genotypic variation in the Calingiri/Wyalkatchem population with the resistance allele contributed by Wyalkatchem. The QTL on 1A explained up to 28.1% of the genotypic variation in the IGW2574/Annuello population with the resistance allele contributed by Annuello. The resistance alleles at both QTL were successfully combined with tsn1 to develop lines that express significantly better resistance at both seedling and adult plant stages than Calingiri which has tsn1 only. PMID- 28913579 TI - Association between FTO gene polymorphisms and HDL cholesterol concentration may cause higher risk of cardiovascular disease in patients with acromegaly. AB - INTRODUCTION: Cardiovascular diseases are main cause of morbidity and mortality in acromegaly. Polymorphisms of FTO gene are associated with obesity and increased risk of CVD (independently of BMI). Aim of this study was to investigate the allele frequencies of two FTO gene polymorphisms: rs9939609 and rs9930506 in patients with acromegaly and to examine the association of FTO gene polymorphisms with BMI and selected metabolic parameters. MATERIALS AND METHODS: Identification of two single nucleotide polymorphisms of FTO gene was carried out in 51 patients with acromegaly using the minisequencing method. RESULTS: The risk allele frequencies of rs9939609 and rs9930506 polymorphisms were 0.471 and 0.529, respectively and they were higher than in general European population. There is no association of FTO gene polymorphisms with BMI, glucose, total cholesterol, LDL cholesterol and triglyceride. The risk alleles were associated with decreased HDL cholesterol concentration. Homozygotes for the rs9939609-risk allele had 1.25 fold lower HDL cholesterol concentration than carriers of the TT genotype (p = 0.0024). The estimated average decrease in HDL cholesterol concentration per risk allele for rs9930506 was 11.2%. Nevertheless, statistically significant differences were observed only between AG versus GG and AA versus GG genotypes. Homozygotes for the rs9930506-risk allele had 1.27-fold lower HDL cholesterol concentration than carriers of the AA genotype (p = 0.007). CONCLUSION: The risk allele frequencies of studied polymorphisms in acromegaly were higher than in general European population. There is an association between FTO gene polymorphisms and HDL cholesterol concentration, suggesting FTO gene polymorphisms may be associated with higher CVD risk in patients with acromegaly. PMID- 28913580 TI - In vitro tools for the toxicological evaluation of sediments and dredged materials: intra- and inter-laboratory comparisons of chemical and bioanalytical methods. AB - The implementation of in vitro bioassays for the screening of dioxin-like compounds (DLCs) into management guidelines of dredged material is of increasing interest to regulators and risk assessors. This study reports on an intra- and inter-laboratory comparison study between four independent laboratories. A bioassay battery consisting of RTL-W1 (7-ethoxy-resorufin-O-deethylase; EROD), H4IIE (micro-EROD), and H4IIE-luc cells was used to assess aryl hydrocarbon receptor-mediated effects of sediments from two major European rivers, differently contaminated with DLCs. Each assay was validated by characterization of its limit of detection (LOD) and quantification (LOQ), z-factor, reproducibility, and repeatability. DLC concentrations were measured using high resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) and compared to bioassay-specific responses via toxicity equivalents (TEQs) on intra- and inter-laboratory levels. The micro-EROD assay exhibited the best overall performance among the bioassays. It was ranked excellent (z-factor = 0.54), reached a repeatability > 75%, was highly comparable (r 2 = 0.87) and reproducible (83%) between two laboratories, and was well correlated (r 2 = 0.803) with TEQs. Its LOD and LOQ of 0.5 and 0.7 pM 2,3,7,8-TCDD, respectively, approached LOQs of HRGC/HRMS measurements. In contrast, cell lines RTL-W1 and H4IIE-luc produced LODs > 0.7 pM 2,3,7,8-TCDD, LOQs > 1.7 pM 2,3,7,8-TCDD, and repeatability < 70%. Based on the data obtained, the micro-EROD assay is the most favorable bioanalytical tool, and via a micro-EROD-based limit value, it would allow for the assessment of sediment DLC concentrations; thus, it could be considered for the implementation into testing and management guidelines for dredged materials. PMID- 28913581 TI - Investigation on the anaerobic co-digestion of food waste with sewage sludge. AB - In this laboratory-scale investigation on the applicability of the co-digestion of food waste with sewage sludge, evaluated were the effects of the single-stage versus two-stage operating modes at the hydraulic retention time (HRT) of 15 days, and the impact of HRTs: 15 days vs. 25 days, on the single-stage operation. An average volatile solid reduction (VSR) of 61% and methane yield of 314 ml/g-VS were achieved in the two-stage operation (HRT 15 days), while comparable VSR of 57% and the methane yield of 325 ml CH4/g-VS could only be detected at a longer HRT at 25 days in the single-stage operation. The difference in the operating modes showed much higher influence on shaping the overall bacterial structures than the two HRTs of the single-stage operation. The one operational taxonomic unit (OTU) annotatable at the family level of Thermotogaceae was most abundant (> 10%) in all the methanogenic co-digestion consortia, and its dominant role was recognized to be independent of other OTU lineages in the community. OTUs in the phylum Proteobacteria were much more common as the persistent OTUs in the single stage co-digestion consortia, while in the two-stage consortia, they were in the phylum Firmicutes. Annotation on the functional genes suggested that the phylum Firmicutes hosted the majority of pilus genes and hydrogenase genes that were reported to be essential for the syntrophic conversion of the high concentrations of alcohols and reduced fatty acids in the methanogenic reactor operated under the two-stage mode. PMID- 28913582 TI - Glyphosate (Ab)sorption by Shoots and Rhizomes of Native versus Hybrid Cattail (Typha). AB - Wetlands in the Prairie Pothole Region of North America are integrated with farmland and contain mixtures of herbicide contaminants. Passive nonfacilitated diffusion is how most herbicides can move across plant membranes, making this perhaps an important process by which herbicide contaminants are absorbed by wetland vegetation. Prairie wetlands are dominated by native cattail (Typha latifolia) and hybrid cattail (Typha x glauca). The objective of this batch equilibrium study was to compare glyphosate absorption by the shoots and rhizomes of native versus hybrid cattails. Although it has been previously reported for some pesticides that passive diffusion is greater for rhizome than shoot components, this is the first study to demonstrate that the absorption capacity of rhizomes is species dependent, with the glyphosate absorption being significantly greater for rhizomes than shoots in case of native cattails, but with no significant differences in glyphosate absorption between rhizomes and shoots in case of hybrid cattails. Most importantly, glyphosate absorption by native rhizomes far exceeded that of the absorption occurring for hybrid rhizomes, native shoots and hybrid shoots. Glyphosate has long been used to manage invasive hybrid cattails in wetlands in North America, but hybrid cattail expansions continue to occur. Since our results showed limited glyphosate absorption by hybrid shoots and rhizomes, this lack of sorption may partially explain the poorer ability of glyphosate to control hybrid cattails in wetlands. PMID- 28913583 TI - Economic assessment of conventional and conservation tillage practices in different wheat-based cropping systems of Punjab, Pakistan. AB - Wheat productivity and profitability is low under conventional tillage systems as they increase the production cost, soil compaction, and the weed infestation. Conservation tillage could be a pragmatic option to sustain the wheat productivity and enhance the profitability on long term basis. This study was aimed to evaluate the economics of different wheat-based cropping systems viz. fallow-wheat, rice-wheat, cotton-wheat, mung bean-wheat, and sorghum-wheat, with zero tillage, conventional tillage, deep tillage, bed sowing (60/30 cm beds and four rows), and bed sowing (90/45 cm beds and six rows). Results indicated that the bed sown wheat had the maximum production cost than other tillage systems. Although both bed sowing treatments incurred the highest production cost, they generated the highest net benefits and benefit: cost ratio (BCR). Rice-wheat cropping system with bed sown wheat (90/45 cm beds with six rows) had the highest net income (4129.7 US$ ha-1), BCR (2.87), and marginal rate of return compared with rest of the cropping systems. In contrast, fallow-wheat cropping system incurred the lowest input cost, but had the least economic return. In crux, rice wheat cropping system with bed sown wheat (90/45 cm beds with six rows) was the best option for getting the higher economic returns. Moreover, double cropping systems within a year are more profitable than sole planting of wheat under all tillage practices. PMID- 28913584 TI - Diffusivity changes in bevacizumab-responding and -refractory meningioma. PMID- 28913585 TI - On the Number of Non-equivalent Ancestral Configurations for Matching Gene Trees and Species Trees. AB - An ancestral configuration is one of the combinatorially distinct sets of gene lineages that, for a given gene tree, can reach a given node of a specified species tree. Ancestral configurations have appeared in recursive algebraic computations of the conditional probability that a gene tree topology is produced under the multispecies coalescent model for a given species tree. For matching gene trees and species trees, we study the number of ancestral configurations, considered up to an equivalence relation introduced by Wu (Evolution 66:763-775, 2012) to reduce the complexity of the recursive probability computation. We examine the largest number of non-equivalent ancestral configurations possible for a given tree size n. Whereas the smallest number of non-equivalent ancestral configurations increases polynomially with n, we show that the largest number increases with [Formula: see text], where k is a constant that satisfies [Formula: see text]. Under a uniform distribution on the set of binary labeled trees with a given size n, the mean number of non-equivalent ancestral configurations grows exponentially with n. The results refine an earlier analysis of the number of ancestral configurations considered without applying the equivalence relation, showing that use of the equivalence relation does not alter the exponential nature of the increase with tree size. PMID- 28913586 TI - Evolving Indications for Transcatheter Aortic Valve Interventions. AB - PURPOSE OF REVIEW: The purpose of this review was to summarize recent progress in the field of transcatheter aortic valve replacement (TAVR), discuss expansion of indications, and identify areas of future clinical applications. RECENT FINDINGS: Favorable clinical outcomes as well as continued refinement of transcatheter heart valve technology have prompted the continuous expansion of indications for TAVR. The results of randomized clinical trials comparing the safety and efficacy of TAVR relative to conventional surgical aortic valve replacement (SAVR) in lower- than high-risk patients have recently been published, and trials among lower-risk categories are ongoing. Furthermore, evidence of the feasibility and safety of TAVR in patients with other pathological conditions is accumulating. Large pivotal randomized studies support the extension of TAVR to intermediate risk patients. Moreover, TAVR is emerging as a valuable treatment option for other categories including patients with bicuspid aortic valve, those with pure native aortic regurgitation deemed inoperable, and those with degenerated surgical bioprosthetic valves. PMID- 28913587 TI - Isotopic effects of PCE induced by organohalide-respiring bacteria. AB - Reductive dechlorination performed by organohalide-respiring bacteria (OHRB) enables the complete detoxification of certain emerging groundwater pollutants such as perchloroethene (PCE). Environmental samples from a contaminated site incubated in a lab-scale microcosm (MC) study enable documentation of such reductive dechlorination processes. As compound-specific isotope analysis is used to monitor PCE degradation processes, nucleic acid analysis-like 16S-rDNA analysis-can be used to determine the key OHRB that are present. This study applied both methods to laboratory MCs prepared from environmental samples to investigate OHRB-specific isotope enrichment at PCE dechlorination. This method linkage can enhance the understanding of isotope enrichment patterns of distinct OHRB, which further contribute to more accurate evaluation, characterisation and prospection of natural attenuation processes. Results identified three known OHRB genera (Dehalogenimonas, Desulfuromonas, Geobacter) in diverse abundance within MCs. One species of Dehalogenimonas was potentially involved in complete reductive dechlorination of PCE to ethene. Furthermore, the isotopic effects of PCE degradation were clustered and two isotope enrichment factors (epsilon) (- 11.60/00, - 1.70/00) were obtained. Notably, epsilon values were independent of degradation rates and kinetics, but did reflect the genera of the dechlorinating OHRB. PMID- 28913588 TI - Efficacy of PDE5Is and SSRIs in men with premature ejaculation: a new systematic review and five meta-analyses. AB - PURPOSE: To clarify the efficacy of phosphodiesterase-5 inhibitors (PDE5Is) and selective serotonin reuptake inhibitors (SSRIs) in men with premature ejaculation (PE). METHODS: We searched the PubMed, Embase, and Cochrane Library databases to identify all randomized, controlled trials (RCTs) and compared the results, including intravaginal ejaculation latency time, satisfaction, intercourse per week and side effects after treatment with PDE5I or SSRIs versus placebo, combined use of PDE5I with SSRIs versus PDE5I or SSRIs alone, and PDE5I versus SSRIs for treating PE. RESULTS: The study inclusion criteria were met by 23 studies (ten RCTs with five crossover studies) involving 6145 patients. The data synthesized from these studies indicated that the efficacy of PDE5Is and SSRIs was better than that of placebo (p < 0.00001; p < 0.00001); however, more patients had side effects while taking PDE5Is and SSRIs (p < 0.00001; p < 0.00001). The efficacy of the combined treatment was significantly better than that of PDE5Is or SSRIs alone (p < 0.00001; p < 0.00001); however, more patients had side effects from the combined treatment than from SSRIs (p = 0.0002), with no significant difference in PDE5Is (p = 0.5). The efficacy of PDE5Is was better than that of SSRIs (p = 0.006), and no significant difference was observed in the frequency of side effects (p = 0.93). CONCLUSIONS: PDE5Is were significantly more effective than placebo or SSRIs for treating PE, while SSRIs were better than placebo. The combined treatment had better efficacy than PDE5Is or SSRIs alone. PMID- 28913589 TI - Estimating renal function in old people: an in-depth review. AB - Estimates of glomerular filtration rate (eGFR) should provide accurate measure of an individual's kidney function because important clinical decisions such as timing of renal replacement therapy and drug dosing may be dependent on eGFR. Formulae from which eGFR is derived are generally based on serum creatinine measurement, such as Cockcroft-Gault, MDRD and CKD-EPI. More recently, calculation of eGFR using other laboratory biomarkers such as cystatin C has emerged with apparent greater accuracy. In old people, there is age-related physiological change in the kidney, which could lead to reduced GFR. Likewise, physiological changes in body composition that occur with the ageing process impede the use of a single creatinine-based calculation of eGFR across all adult age groups. Studies have shown differences in the prevalence of CKD based on the type of equation used to estimate GFR. This review discusses the evolution of eGFR calculations and the relative accuracy of such equations in older population. PMID- 28913590 TI - Challenges of Anticoagulation Therapy in Pregnancy. AB - OPINION STATEMENT: Thrombotic complications in pregnancy represent a major cause of morbidity and mortality. Pregnancy is a primary hypercoagulable state due to enhanced production of clotting factors, a decrease in protein S activity, and inhibition of fibrinolysis. These physiologic changes will yield a collective rate of venous thromboembolism (VTE) of about 1-2 in 1000 pregnancies for the general obstetric population, which represents a five- to tenfold increased risk in pregnancy compared to age-matched non-pregnant peers. A select group of women, however, will carry a significantly higher rate of thrombosis due to primary thrombophilia, either inherited or acquired. This introduces a population of women who may benefit from prophylactic anticoagulation, either antepartum or postpartum. The coagulation changes that occur in preparation for the hemostatic challenges of delivery endure for several weeks postpartum. In fact, daily risk for pulmonary embolism (PE) is the highest postpartum. Use of anticoagulation in pregnancy introduces particular risk at the time of delivery, where bleeding and clotting risk collide. Altered metabolism rates of anticoagulants in pregnant women often necessitate closer monitoring than is required outside of pregnancy in order to ensure efficacy and safety. Heparin products are the mainstay of treating VTE in pregnancy, chiefly because they do not cross the placenta. In women with mechanical heart valves, the ideal anticoagulation regimen remains controversial as heparin use has shown inferior outcomes for preventing thromboembolic complications compared to warfarin, but warfarin carries risk for fetal embryopathy. Other populations where a heparin alternative is necessary include women with a history of heparin-associated thrombocytopenia (HIT) or other heparin intolerance. Further challenging the management of anticoagulation in pregnancy is the dearth of randomized clinical trials. The evidence governing treatment recommendations is largely based on expert guidelines, observational studies, or extrapolation from non-pregnant cohorts. A careful critique of a woman's history, as well as the available data, is essential for optimal management of anticoagulation in pregnancy. Such decisions should involve a multidisciplinary team involving obstetrics, hematology, cardiology, and anesthesia. PMID- 28913591 TI - Knowledge, attitudes and practices towards cystic echinococcosis in livestock among selected pastoral and agro-pastoral communities in Uganda. AB - A cross-sectional study was done from March 2013 to May 2014 to assess knowledge, attitudes, and practices towards cystic echinococcosis (CE) or hydatidosis among selected pastoral and agro-pastoral communities in Uganda. A structured questionnaire was administered to 381 respondents. Multivariate logistic regression analysis was done to find the relationship between knowledge about CE and factors such as age, sex, and level of education across all regions. The odds ratio and confidence interval were used to determine the difference in responses across regions. It was shown that age above 36 years was significantly (p < 0.001) associated with awareness about CE in livestock. Likewise, uneducated (p < 0.0001) and agro-pastoralists (p = 0.01) were significantly less knowledgeable than the educated and pastoralists across all regions. The overall knowledge towards CE in livestock was low 17.8% (95% CI = 14.0-21.6). Dog ownership was high and they never dewormed their freely roaming dogs. Dogs shared water with livestock. In conclusion, knowledge about CE in livestock was low across all regions. Therefore, public health education and formulation of policies towards its control by the relevant stakeholders should be done. Also, the true prevalence of CE in livestock needs to be done so that the magnitude and its public health significance are elucidated. PMID- 28913592 TI - Chronic Stress Causes Sex-Specific and Structure-Specific Alterations in Mitochondrial Respiratory Chain Activity in Rat Brain. AB - Chronic restraint stress (CRS) induces a variety of changes in brain function, some of which are mediated by glucocorticoids. The response to stress occurs in a sex-specific way, and may include mitochondrial and synaptic alterations. The synapse is highly dependent on mitochondrial energy supply, and when mitochondria become dysfunctional, they orchestrate cell death. This study aimed to investigate the CRS effects on mitochondrial respiratory chain activity, as well as mitochondrial potential and mass in cell body and synapses using hippocampus, cortex and striatum of male and female rats. Rats were divided into non-stressed (control) and stressed group (CRS during 40 days). Results showed that CRS increased complex I-III activity in hippocampus. We also observed an interaction between CRS and sex in the striatal complex II activity, since CRS induced a reduction in complex II activity in males, while in females this activity was increased. Also an interaction was observed between stress and sex in cortical complex IV activity, since CRS induced increased activity in females, while it was reduced in males. Glucocorticoid receptor (GR) content in cortex and hippocampus was sexually dimorphic, with female rats presenting higher levels compared to males. No changes were observed in GR content, mitochondrial potential or mass of animals submitted to CRS. It was concluded that CRS induced changes in respiratory chain complex activities, and some of these changes are sex-dependent: these activities are increased in the striatal mitochondria by CRS protocol mainly in females, while in males it is decreased. PMID- 28913594 TI - Developmental trajectory of the prefrontal cortex: a systematic review of diffusion tensor imaging studies. AB - Fluctuations in gray and white matter volumes in addition to the fibers' reorganization and refinement of synaptic connectivity apparently happen in a particular temporo-spatial sequence during the dynamic and prolonged process of cerebral maturation. These developmental events are associated with regional modifications of brain tissues and neural circuits, contributing to networks' specialization and enhanced cognitive processing. According to several studies, improvements in cognitive processes are possibly myelin-dependent and associated to white matter maturation. Of particular interest is the developmental pattern of the prefrontal cortex (PFC), more specifically the PFC white matter, due to its role in high-level executive processes such as attention, working memory and inhibitory control. A systematic review of the literature was conducted using the Web of Science, PubMed and Embase databases to analyze the development of PFC white matter using Diffusion Tensor Imaging (DTI), a widely used non-invasive technique to assess white matter maturation. Both the research and reporting of results were based on Cochrane's recommendations and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Information extracted from 27 published studies revealed an increased myelination, organization and integrity of frontal white matter with age, as revealed by DTI indexes (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD] and axial diffusivity [AD]). These patterns highlight the extended developmental course of the frontal structural connectivity, which parallels the improvements in higher-level cognitive functions observed between adolescence and early adulthood. PMID- 28913593 TI - Interaction of Arabidopsis TGA3 and WRKY53 transcription factors on Cestrum yellow leaf curling virus (CmYLCV) promoter mediates salicylic acid-dependent gene expression in planta. AB - MAIN CONCLUSION: This paper highlighted a salicylic acid-inducible Caulimoviral promoter fragment from Cestrum yellow leaf curling virus (CmYLCV). Interaction of Arabidopsis transcription factors TGA3 and WRKY53 on CmYLCV promoter resulted in the enhancement of the promoter activity via NPR1-dependent salicylic acid signaling. Several transcriptional promoters isolated from plant-infecting Caulimoviruses are being presently used worldwide as efficient tools for plant gene expression. The CmYLCV promoter has been isolated from the Cestrum yellow leaf curling virus (Caulimoviruses) and characterized more than 12 years ago; also we have earlier reported a near-constitutive, pathogen-inducible CmYLCV promoter fragment (-329 to +137 from transcription start site; TSS) that enhances stronger (3*) expression than the previously reported fragments; all these fragments are highly efficient in monocot and dicot plants (Sahoo et al. Planta 240: 855-875, 2014). Here, we have shown that the full-length CmYLCV promoter fragment (-729 to +137 from TSS) is salicylic acid (SA) inducible. In this context, we have performed an in-depth study to elucidate the factors responsible for SA-inducibility of the CmYLCV promoter. We found that the as-1 1 and W-box1 elements (located at -649 and -640 from the TSS) of the CmYLCV promoter are required for SA-induced activation by recruiting Arabidopsis TGA3 and WRKY53 transcription factors. Consequently, as a nascent observation, we established the physical interaction between TGA3 and WYKY53; also demonstrated that the N terminal domain of TGA3 is sufficient for the interaction with the full-length WRKY53. Such interaction synergistically activates the CmYLCV promoter activity in planta. Further, we found that activation of the CmYLCV promoter by SA through TGA3 and WRKY53 interaction depends on NPR1. Finally, the findings presented here provide strong support for the direct regulatory roles of TGA3 and WRKY53 in the SA and NPR1-dependent activation of a Caulimoviral promoter (CmYLCV). PMID- 28913595 TI - Health Professionals "Make Their Choice": Pharmaceutical Industry Leaders' Understandings of Conflict of Interest. AB - Conflicts of interest, stemming from relationships between health professionals and the pharmaceutical industry, remain a highly divisive and inflammatory issue in healthcare. Given that most jurisdictions rely on industry to self-regulate with respect to its interactions with health professionals, it is surprising that little research has explored industry leaders' understandings of conflicts of interest. Drawing from in-depth interviews with ten pharmaceutical industry leaders based in Australia, we explore the normalized and structural management of conflicts of interest within pharmaceutical companies. We contrast this with participants' unanimous belief that the antidote to conflicts of interest with health professionals were "informed consumers." It is, thus, unlikely that a self regulatory approach will be successful in ensuring ethical interactions with health professionals. However, the pharmaceutical industry's routine and accepted practices for disclosing and managing employees' conflicts of interest could, paradoxically, serve as an excellent model for healthcare. PMID- 28913596 TI - [Perioperative management of immunosuppressive treatment in patients undergoing joint surgery]. AB - The perioperative management of patients on immunosuppressive drugs is uncertain due to a lack of controlled studies. Continuation of medication without a pause may increase the risk of postoperative infections and wound healing disorders and when the pause is too long this can induce a flare of the underlying rheumatic disease. Additional factors, such as rheumatic disease activity, comorbidities, previous infections and the type of surgical procedure also modulate the risk. The highest risk of infection is associated with corticosteroids depending on the dose, so that a dosage as low as possible but stable in the perioperative period is recommended. Among the conventional disease-modifying antirheumatic drugs (DMARDs) only methotrexate has been sufficiently investigated and in this case a pause in treatment induces higher risks than continuation. Antimalarial agents and sulphasalazine should be continued due to the low risks, whereas leflunomide should be washed out before major surgical interventions. The perioperative risk of treatment with biologics is still far from clear; therefore, as a rule of thumb, withholding treatment for two serum half-lives before an intervention and restarting after completed wound healing are recommended. PMID- 28913597 TI - Trauma Leagues-A Novel Option to Attract Medical Students to a Surgical Career. AB - BACKGROUND: In Brazil, most medical schools do not offer trauma surgery in their undergraduate curriculum. The Trauma Leagues arose in Brazil as an important promoter of trauma education and stimulated activities related to surgical skills and practices. In recent decades, studies have demonstrated that the number of surgical residency applicants has decreased worldwide. Strategies to motivate medical students to choose surgery are needed. OBJECTIVE: To evaluate the impact of participation in the Unicamp Trauma League (UTL) during a 20-year period in the choice for a surgical career. METHODS: The study included 276 students in a Brazilian university hospital who were part of the Trauma League. Research of records in universities and medical societies about the specialties chosen during residency were evaluated. A Likert questionnaire was sent to participants to evaluate the impact of participating in the Trauma League in the student's professional career. RESULTS: The questionnaire was answered by 76% of the participants. Of those, 38.4% chose general surgery. About 55.1% did not know what medical career to choose when joined the league. Participation in the league had an influence on specialty choice in 79.1% of the students. Of those choosing surgery, 93.2% believed that participating in the league had positively influenced their career choice. Overall, 93.1% believed that participating in the league provided knowledge and information that the medical school curriculum was not able to provide. CONCLUSION: Participation in Trauma League has been an effective strategy to encourage medical students to choose a career in general surgery in Campinas, Brazil. PMID- 28913598 TI - Aqueous clay suspensions stabilized by alginate fluid gels for coal spontaneous combustion prevention and control. AB - We have developed aqueous clay suspensions stabilized by alginate fluid gels (AFG) for coal spontaneous combustion prevention and control. Specially, this study aimed to characterize the effect of AFG on the microstructure, static and dynamic stability, and coal fire inhibition performances of the prepared AFG stabilized clay suspensions. Compared with aqueous clay suspensions, the AFG stabilized clay suspensions manifest high static and dynamic stability, which can be ascribed to the formation of a robust three-dimensional gel network by AFG. The coal acceleration oxidation experimental results show that the prepared AFG stabilized clay suspensions can improve the coal thermal stability and effectively inhibit the coal spontaneous oxidation process by increasing crossing point temperature (CPT) and reducing CO emission. The prepared low-cost and nontoxic AFG-stabilized clay suspensions, exhibiting excellent coal fire extinguishing performances, indicate great application potentials in coal spontaneous combustion prevention and control. PMID- 28913601 TI - Emergency Neurological Life Support: Approach to the Patient with Coma. AB - Coma is an acute failure of neuronal systems governing arousal and awareness and represents a medical emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remediable causes, prevent ongoing neurologic injury, and determine a hierarchical plan for diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis. PMID- 28913599 TI - The mediating role of cortical thickness and gray matter volume on sleep slow wave activity during adolescence. AB - During the course of adolescence, reductions occur in cortical thickness and gray matter (GM) volume, along with a 65% reduction in slow-wave (delta) activity during sleep (SWA) but empirical data linking these structural brain and functional sleep differences, is lacking. Here, we investigated specifically whether age-related differences in cortical thickness and GM volume and cortical thickness accounted for the typical age-related difference in slow-wave (delta) activity (SWA) during sleep. 132 healthy participants (age 12-21 years) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study were included in this cross-sectional analysis of baseline polysomnographic, electroencephalographic, and magnetic resonance imaging data. By applying mediation models, we identified a large, direct effect of age on SWA in adolescents, which explained 45% of the variance in ultra-SWA (0.3-1 Hz) and 52% of the variance in delta-SWA (1 to <4 Hz), where SWA was lower in older adolescents, as has been reported previously. In addition, we provide evidence that the structure of several, predominantly frontal, and parietal brain regions, partially mediated this direct age effect, models including measures of brain structure explained an additional 3-9% of the variance in ultra-SWA and 4-5% of the variance in delta-SWA, with no differences between sexes. Replacing age with pubertal status in models produced similar results. As reductions in GM volume and cortical thickness likely indicate synaptic pruning and myelination, these results suggest that diminished SWA in older, more mature adolescents may largely be driven by such processes within a number of frontal and parietal brain regions. PMID- 28913600 TI - A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years. AB - PURPOSE: The increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions. METHODS: In this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness. RESULTS: A statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups. CONCLUSIONS: This study highlighted the safety and potential of a biomimetic implant. While no statistically significant differences were found compared to BMS for chondral lesions, this procedure can be considered a suitable option for the treatment of osteochondral lesions. LEVEL OF EVIDENCE: I. PMID- 28913602 TI - Devoting attention to glucose variability and hypoglycaemia in type 2 diabetes. AB - In the Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), insulin degludec was non-inferior to insulin glargine in terms of cardiovascular events and mortality. However, there were lower rates of severe hypoglycaemia with insulin degludec. DEVOTE investigators now extend these findings by presenting the results of two observational epidemiological analyses based on trial data. In the first of these analyses (DEVOTE 2), Zinman et al (Diabetologia DOI: 10.1007/s00125-017-4423-z ) demonstrate that, compared with individuals with lower day-to-day fasting glycaemic variability, those with higher day-to-day fasting glycaemic variability had a similar risk of major adverse cardiovascular events (MACE) but a higher risk of severe hypoglycaemia and all-cause mortality. In the second analysis (DEVOTE 3), Pieber et al (Diabetologia DOI: 10.1007/s00125-017-4422-0 ) found that individuals who experienced severe hypoglycaemia had a similar risk of MACE compared with those who never experienced severe hypoglycaemia, but had a more than twofold higher risk of subsequent total mortality and cardiovascular disease (CVD) mortality. The strengths of these studies relate to the availability of high-quality prospective data on adjudicated severe hypoglycaemia, MACE and mortality events in a large number of high-risk insulin-treated individuals with type 2 diabetes. Limitations include the observational nature of the data and thus residual confounding remains possible. Furthermore, the short duration of the trial resulted in limited statistical power for some analyses. Therefore, whilst DEVOTE 2 and DEVOTE 3 raise awareness of the mortality risks associated with glucose variability and severe hypoglycaemia in high-risk, insulin-treated patients with type 2 diabetes, they cannot clarify causal relationships. Preventing severe hypoglycaemia in those with type 2 diabetes should already be a priority in clinical practice. However, findings from future clinical trials are needed to guide physicians on whether it is beneficial to target glucose variability, and risk for severe hypoglycaemia, to reduce the risks for CVD events and mortality in these individuals. PMID- 28913603 TI - Influence of anthropometry, TMD, and sex on molar bite force in adolescents with and without orthodontic needs. AB - PURPOSE: Bite force has been studied as representative of functional indices of mastication and its value may have diagnostic significance in disorders of the musculoskeletal system of facial bones. This study aimed to evaluate bite force in adolescents with and without orthodontic needs considering presence of temporomandibular disorders (TMD) as well as anthropometry: craniofacial dimensions and body mass index (BMI). METHODS: A total of 80 subjects were screened (61 females, 19 males; 18 +/- 3 years old). Unilateral molar bite force was measured using a digital dynamometer with a fork thickness of 12 mm. Direct anthropometry was used to quantify craniofacial measurements. Dental Health Component of the Index of Orthodontic Treatment Need (IOTN-DHC) and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were used to classify samples according to malocclusion and to TMD, respectively. Data were analyzed using normality tests, Mann-Whitney U test, and multiple linear regression analyses with stepwise backward elimination, controlling for the presence of malocclusion and TMD (p <= 0.05). RESULTS: The cephalic index was greater in females with malocclusion and the longitudinal cranial diameter was reduced in females with malocclusion. BMI was not different between normal and malocclusion groups for either gender. Bite force was negatively related with vertical dimension of the face, and positively related with facial width and facial index. The model explained 32% of bite force variability, considering the sample size (coefficient of determination R 2 = 0.324). CONCLUSIONS: Even when orthodontic needs and TMD signs and symptoms are present, stronger bite force is still observed in males and in subjects with smaller anterior facial heights and wider facial widths. PMID- 28913604 TI - Differing Perceptions Concerning Research Integrity Between Universities and Industry: A Qualitative Study. AB - Despite the ever increasing collaboration between industry and universities, the previous empirical studies on research integrity and misconduct excluded participants of biomedical industry. Hence, there is a lack of empirical data on how research managers and biomedical researchers active in industry perceive the issues of research integrity and misconduct, and whether or not their perspectives differ from those of researchers and research managers active in universities. If various standards concerning research integrity and misconduct are upheld between industry and universities, this might undermine research collaborations. Therefore we performed a qualitative study by conducting 22 semi structured interviews in order to investigate and compare the perspectives and attitudes concerning the issues of research integrity and misconduct of research managers and biomedical researchers active in industry and universities. Our study showed clear discrepancies between both groups. Diverse strategies in order to manage research misconduct and to stimulate research integrity were observed. Different definitions of research misconduct were given, indicating that similar actions are judged heterogeneously. There were also differences at an individual level, whether the interviewees were active in industry or universities. Overall, the management of research integrity proves to be a difficult exercise, due to many diverse perspectives on several essential elements connected to research integrity and misconduct. A management policy that is not in line with the vision of the biomedical researchers and research managers is at risk of being inefficient. PMID- 28913605 TI - Emergency Neurological Life Support: Status Epilepticus. AB - Patients with prolonged or rapidly recurring convulsions lasting more than 5 min should be considered to be in status epilepticus (SE) and receive immediate resuscitation. Although there are few randomized clinical trials, available evidence and experience suggest that early and aggressive treatment of SE improves patient outcomes, for which reason this was chosen as an Emergency Neurological Life Support protocol. The current approach to the emergency treatment of SE emphasizes rapid initiation of adequate doses of first line therapy, as well as accelerated second line anticonvulsant drugs and induced coma when these fail, coupled with admission to a unit capable of neurological critical care and electroencephalography monitoring. This protocol will focus on the initial treatment of SE but also review subsequent steps in the protocol once the patient is hospitalized. PMID- 28913606 TI - Ranges of Injury Risk Associated with Impact from Unmanned Aircraft Systems. AB - Regulations have allowed for increased unmanned aircraft systems (UAS) operations over the last decade, yet operations over people are still not permitted. The objective of this study was to estimate the range of injury risks to humans due to UAS impact. Three commercially-available UAS models that varied in mass (1.2 11 kg) were evaluated to estimate the range of risk associated with UAS-human interaction. Live flight and falling impact tests were conducted using an instrumented Hybrid III test dummy. On average, live flight tests were observed to be less severe than falling impact tests. The maximum risk of AIS 3+ injury associated with live flight tests was 11.6%, while several falling impact tests estimated risks exceeding 50%. Risk of injury was observed to increase with increasing UAS mass, and the larger models tested are not safe for operations over people in their current form. However, there is likely a subset of smaller UAS models that are safe to operate over people. Further, designs which redirect the UAS away from the head or deform upon impact transfer less energy and generate lower risk. These data represent a necessary impact testing foundation for future UAS regulations on operations over people. PMID- 28913607 TI - Diabetes and the Esophagus. AB - OPINION STATEMENT: Chronic hyperglycemia is a well-known cause of gastrointestinal motility disorders extending from the esophagus to the anorectum. Even though little attention has been paid to esophageal disorders in the context of DM, its prevalence is higher compared to gastroparesis. Heartburn, as a typical symptom of gastroesophageal reflux disease (GERD), is the most prevalent symptom and has been found in 25 to 41% of patients with DM. Furthermore, DM has recently been established as possible independent factor for the development of Barrett's esophagus. The pathophysiology of esophageal disorders in patients with DM is complex and multifactorial, and the mechanisms described include the following: hyperglycemia, autonomic neuropathy, biomechanical and sensory alterations of the esophagus, presbyesophagus, and psychiatric comorbidity. Opportune detection, together with adequate glycemic control, can delay the onset of esophageal dysfunction and slow its progression in diabetic patients. There is limited evidence on patients with DM and esophageal dysfunction, with respect to medical treatment. Lifestyle modifications, prokinetics, and proton pump inhibitors should be indicated on an individual basis in patients that present with DM and esophageal disorders. A greater number of improved studies are needed to develop new therapeutic strategies. This chapter will review esophageal disorders associated with DM and the currently available treatment options. PMID- 28913609 TI - Modulation of the Emotional Response to Viewing Strabismic Children in Mothers Measured by fMRI. AB - PURPOSE: Strabismus influences not only the individual with nonparallel eyes but also the observer. It has previously been demonstrated by fMRI that adults viewing images of strabismic adults have a negative reaction to the images as demonstrated by limbic activation, especially activation of the left amygdala. The aim of this study was to see if mothers would have a similar reaction to viewing strabismic children and whether or not that reaction would be different in mothers of strabismic children. METHODS: Healthy mothers of children with strabismus (n = 10, Group I) and without strabismus (n = 15, Group II) voluntarily underwent fMRI at 3T. Blood oxygen level dependent signal responses to viewing images of strabismic and non-strabismic children were analyzed. RESULTS: Group II, while viewing images of strabismic children, showed significantly increased activation of the limbic network (p < 0.05) and bilateral amygdala activation. Group I showed considerably less limbic activation, compared to the group II, and had no amygdala activation. Both groups revealed statically significant activation in the FEF (frontal eye field) when they were viewing images of strabismic children as compared to when they were viewing children with parallel eyes. The activated FEF area for Group II was much larger than for group I. CONCLUSION: Mothers of non-strabismic children showed similar negative emotional fMRI patterns as adults did while viewing strabismic adults. Strabismus is an interpersonal organic issue for the observer, which also impacts the youngest members of our society. PMID- 28913608 TI - Efficacy of alpha-lipoic acid against cadmium toxicity on metal ion and oxidative imbalance, and expression of metallothionein and antioxidant genes in rabbit brain. AB - To explore the protective efficacy of alpha-lipoic acid (ALA) against Cd-prompted neurotoxicity, young male New Zealand rabbits (Oryctolagus cuniculus) were divided randomly into four groups. Group 1 (control) received demineralized water. Group 2 (Cd) administered cadmium chloride (CdCl2) 3 mg/kg bwt. Group 3 (ALA) administered ALA 100 mg/kg bwt. Group 4 (Cd + ALA) administered ALA 1 h after Cd. The treatments were administered orally for 30 consecutive days. Cd induced marked disturbances in neurochemical parameters were indicated by the reduction in micro- and macro-elements (Zn, Fe, Cu, P, and Ca), with the highest reduction in Cd-exposed rabbits, followed by Cd + ALA group and then ALA group. In the brain tissues, Cd has significantly augmented the lipid hydroperoxides (LPO) and reduced the glutathione (GSH) and total antioxidant capacity (TAC), and glutathione peroxidase and glutathione S-transferase enzyme activities but had an insignificant effect on the antioxidant redox enzymes. Administration of ALA effectively restored LPO and sustained GSH and TAC contents. Moreover, Cd downregulated the transcriptional levels of Nrf2, MT3, and SOD1 genes, and upregulated that of Keap1 gene. ALA treatment, shortly following Cd exposure, downregulated Keap1, and upregulated Nrf2 and GPx1, while maintained MT3 and SOD1 mRNA gene expression in the rabbits' brain. These data indicated the ALA effectiveness in protecting against Cd-induced oxidative stress and the depletion of cellular antioxidants in the brain of rabbits perhaps due to its antioxidant, free radical scavenging, and chelating properties. PMID- 28913610 TI - Eukaryotic Elongation Factor 2 (eEF2) is a Potential Biomarker of Prostate Cancer. AB - Eukaryotic elongation factor 2 (eEF2), a key regulator of protein synthesis, is involved in the progression of several types of cancer. This first study was to investigate the relationships between eEF2 protein and prostate cancer (PCa). Immunohistochemical staining was used to verify eEF2 protein in a set of 97 formalin-fixed, paraffin-embedded primary PCa tissues. Expression of eEF2 protein in positive cells was characterized by cytoplasmic staining. Correlations with clinicopathological factors were evaluated by Chi-square or Fisher's exact probability tests. eEF2 protein was found in 74 out of 97 (76.29%) patients. eEF2 positive had higher PSA and Gleason score than negative in all patients. In addition, the positive expression of eEF2 protein was significantly associated with PSA and Gleason score (P = 0.007 and 0.002). However, no significant correlations occurred between expression of eEF2 protein and TNM stage (P = 0.292). In those eEF2 protein-positive patients, we have found staining intensity of eEF2 protein was not only associated with PSA and Gleason score, but also associated with TNM stage (P = 0, 0.014 and 0.001, respectively). To conclude, our study indicates that expression of eEF2 protein is a potential biomarker for evaluating PCa. PMID- 28913611 TI - Prospective intraindividual comparison of gadoterate and gadobutrol for cervical and intracranial contrast-enhanced magnetic resonance angiography. AB - PURPOSE: Gadobutrol (GB) is reported to provide improved relaxivity and concentration compared to gadoterate (GT). This study was designed to intraindividually compare quantitative and qualitative enhancement characteristics of GB to GT in cervicocranial magnetic resonance angiography (MRA) of patients with cerebrovascular disease (CVD). METHODS: Patients (n = 54) with CVD underwent two identical contrast-enhanced magnetic resonance angiography (CE-MRA) examinations of the cervical and intracranial vasculature in randomized order, using GB and GT in equimolar dose. Signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) were obtained by two independent neuroradiologists, blinded to the applied contrast agents. Qualitative assessment was performed using a three-point scale with a focus on M1/M2 segments. RESULTS: One thousand and twenty-six vessel segments were analyzed. GB revealed a significantly higher SNR (p = 0.032) and CNR (p = 0.031) in all vessel segments. GB featured a significantly higher SNR and CNR in thoracic (p = 0.022; p = 0.016) and cervical vessels (p = 0.03; p = 0.038), as well as in the posterior circulation (p = 0.012; p = 0.005). In blinded qualitative assessment, overall preference was given to GB (p = 0.02), showing a significant better delineation of the M1/M2 segments (p = 0.041). CONCLUSION: Compared to GT, the use of GB results in a significantly higher SNR and CNR in cervical and cerebral CE-MRA, leading to a better delineation of the intracranial vasculature. Present results underline the potential of GB for improved CE-MRA assessment of vasculature in CVD patients. PMID- 28913612 TI - Finger tapping and pre-attentive sensorimotor timing in adults with ADHD. AB - Sensorimotor timing deficits are considered central to attention deficit/hyperactivity disorder (ADHD). However, the tasks establishing timing impairments often involve interconnected processes, including low-level sensorimotor timing and higher level executive processes such as attention. Thus, the source of timing deficits in ADHD remains unclear. Low-level sensorimotor timing can be isolated from higher level processes in a finger-tapping task that examines the motor response to unexpected shifts of metronome onsets. In this study, adults with ADHD and ADHD-like symptoms (n = 25) and controls (n = 26) performed two finger-tapping tasks. The first assessed tapping variability in a standard tapping task (metronome-paced and unpaced). In the other task, participants tapped along with a metronome that contained unexpected shifts (+/ 15, 50 ms); the timing adjustment on the tap following the shift captures pre attentive sensorimotor timing (i.e., phase correction) and thus should be free of potential higher order confounds (e.g., attention). In the standard tapping task, as expected, the ADHD group had higher timing variability in both paced and unpaced tappings. However, in the pre-attentive task, performance did not differ between the ADHD and control groups. Together, results suggest that low-level sensorimotor timing and phase correction are largely preserved in ADHD and that some timing impairments observed in ADHD may stem from higher level factors (such as sustained attention). PMID- 28913613 TI - Risk Factor Analysis Between Newly Screened and Established Hepatitis C in GI and Hepatology Clinics. AB - BACKGROUND: Several studies show inconsistencies in the rate of hepatitis C virus (HCV) detection among baby boomers (born 1945-1965). We conducted a cross sectional HCV screening followed by a case-controlled comparison of the newly screened population with established HCV subjects. METHOD: Enrollment was offered to subjects aged 40-75 at our gastroenterology and hepatology clinics. Demographic data and potential risk factors were obtained, and HCV antibody test was offered to those who had never been screened and compared with a group with established HCV. Logistic regression analysis and Fisher's exact test were performed. RESULTS: Six hundred and seventy-five patients were offered participation, of whom 128 declined while 50 consented to participate but did not perform the HCV antibody test. Of 497 enrolled subjects, 252 patients had HCV, while 245 subjects (188 patients among "baby boomer") underwent screening for HCV. There were more females (62.4 vs. 41.7%) and immigrants (34.7 vs. 22.2%) among the newly screened group. Among the screened population, five patients had HCV antibody (2.04%), and two of them had positive viral load (0.82%) of whom only one fell in the baby boomer category (0.53%). Compared to HCV group, screened group had significantly lower-risk factors, such as IV drug use (1.22 vs. 43.3%), intranasal cocaine use (14.3 vs. 49.6%), and blood transfusion (18.8 vs. 32.5%). CONCLUSION: We found a slightly lower but similar prevalence of HCV antibody when screening based on birth cohort as compared to larger baby boomer studies. Future studies evaluating addition of other screening strategies or possibly universal screening may be needed. PMID- 28913614 TI - Researchers must be aware of their roles at the interface of ecosystem services science and policy. AB - Scientists working on ecosystem service (ES) science are engaged in a mission driven discipline. They can contribute to science-policy interfaces where knowledge is co-produced and used. How scientists engage with the governance arena to mobilise their knowledge remains a matter of personal choice, influenced by individual values. ES science cannot be considered neutral and a discussion of the values that shape it forms an important part of the sustainability dialogue. We propose a simple decision tree to help ES scientists identify their role and the purpose of the knowledge they produce. We characterise six idealised scientific postures spanning possible roles at the science-policy interface (pure scientist, science arbiter-guarantor, issue advocate-guardian, officer, honest broker and stealth issue advocate) and illustrate them with feedbacks from interviews. We encourage ES scientists to conduct a reflexive exploration of their attitudes regarding knowledge production and use, with the intention of progressing toward a higher recognition of the political and ethical importance of ES assessments. PMID- 28913615 TI - Course of acute nonspecific mesenteric lymphadenitis: single-center experience. AB - : Available reports dealing with acute nonspecific mesenteric lymphadenitis do not address the total duration of symptoms. However, it is commonly assumed a time for recovery <= 4 weeks. The purpose of this report was to investigate the course of acute nonspecific mesenteric lymphadenitis in childhood. A review was made of the patients aged <= 16 years in whom the diagnosis of acute nonspecific mesenteric lymphadenitis was established between 2011 and 2015 at the Pediatric Emergency Unit. The records of the Pediatric Emergency Unit, those of the referring family doctors, and the results of a structured telephone interview with each family were used. Forty-four patients (25 girls and 19 boys) aged 2.5 to 16, median 8.2, years were included. A bimodal distribution in duration of symptoms was observed: symptoms persisted for <= 2 weeks in 22 patients and 3 to 10 weeks in 22. Clinical and laboratory characteristics were similar in children with symptoms persisting for 2 weeks or less 28 and in those with symptoms persisting for 3-10 weeks. CONCLUSION: In patients affected with acute nonspecific mesenteric lymphadenitis, it is advantageous to think of the time span for recovery in terms of >= 4 weeks. What is Known: * Mesenteric adenitis is a self-limiting inflammatory condition with well-characterized clinical presentation and imaging features. * A total duration of symptoms of <= 4 weeks is usually hypothesized. What is New: * Symptoms persist for 3 to 10 weeks in half of the patients. * At presentation, clinical and laboratory characteristics are similar in children with symptoms persisting for 2 weeks or less and in those with 45 symptoms persisting for 3-10 weeks. PMID- 28913616 TI - Bone Phenotype Assessed by HRpQCT and Associations with Fracture Risk in the GLOW Study. AB - The epidemiology and pathogenesis of fractures in postmenopausal women has previously been investigated in the Global Longitudinal study of Osteoporosis in Women (GLOW). To date, however, relationships between bone imaging outcomes and fracture have not been studied in this cohort. We examined relationships between high-resolution peripheral quantitative computed tomography (HRpQCT) parameters and fracture in the UK arm of GLOW, performing a cluster analysis to assess if our findings were similar to observations reported from older participants of the Hertfordshire Cohort Study (HCS), and extended the analysis to include tibial measurements. We recorded fracture events and performed HRpQCT of the distal radius and tibia and dual-energy X-ray absorptiometry (DXA) of the hip in 321 women, mean age 70.6 (SD 5.4) years, identifying four clusters at each site. We saw differing relationships at the radius and tibia. Two radial clusters (3 and 4) had a significantly lower hip areal bone mineral density (p < 0.001) compared to Cluster 1; only individuals in Cluster 4 had a significantly higher risk of fracture (p = 0.005). At the tibia, clusters 1, 3 and 4 had lower hip areal bone mineral density (p < 0.001) compared to Cluster 2; individuals in Cluster 3 had a significantly higher risk of fracture (p = 0.009). In GLOW our findings at the radius were very similar to those previously reported in the HCS, suggesting that combining variables derived from HRpQCT may give useful information regarding fracture risk in populations where this modality is available. Further data relating to tibial HRpQCT-phenotype and fractures are provided in this paper, and would benefit from validation in other studies. Differences observed may reflect age differences in the two cohorts. PMID- 28913618 TI - Estimating the potential of energy saving and carbon emission mitigation of cassava-based fuel ethanol using life cycle assessment coupled with a biogeochemical process model. AB - Global warming and increasing concentration of atmospheric greenhouse gas (GHG) have prompted considerable interest in the potential role of energy plant biomass. Cassava-based fuel ethanol is one of the most important bioenergy and has attracted much attention in both developed and developing countries. However, the development of cassava-based fuel ethanol is still faced with many uncertainties, including raw material supply, net energy potential, and carbon emission mitigation potential. Thus, an accurate estimation of these issues is urgently needed. This study provides an approach to estimate energy saving and carbon emission mitigation potentials of cassava-based fuel ethanol through LCA (life cycle assessment) coupled with a biogeochemical process model-GEPIC (GIS based environmental policy integrated climate) model. The results indicate that the total potential of cassava yield on marginal land in China is 52.51 million t; the energy ratio value varies from 0.07 to 1.44, and the net energy surplus of cassava-based fuel ethanol in China is 92,920.58 million MJ. The total carbon emission mitigation from cassava-based fuel ethanol in China is 4593.89 million kgC. Guangxi, Guangdong, and Fujian are identified as target regions for large scale development of cassava-based fuel ethanol industry. These results can provide an operational approach and fundamental data for scientific research and energy planning. PMID- 28913617 TI - Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV. AB - Fingolimod (FTY720), a structural analogue of sphingosine, targets sphingosine-1 phosphate receptor signaling and is currently an immunomodulatory therapy for multiple sclerosis. Fingolimod accesses the central nervous system (CNS) where its active metabolite, fingolimod phosphate (FTY720-P), has pleotropic neuroprotective effects in an inflammatory microenvironment. To investigate potential neuronal-specific mechanisms of fingolimod neuroprotection, we cultured the human neuronal progenitor cell line, hNP1, in differentiation medium supplemented with HIV- or Mock-infected supernatants, with or without FTY720-P. Gene expression was investigated using microarray and functional genomics. FTY720 P treatment increased differentially expressed (DE) neuronal genes by 33% in HIV exposed and 40% in Mock-exposed cultures. FTY720-P treatment broadened the functional profile of DE genes in HIV-exposed versus Mock-exposed neurons, including not only immune responses but also transcriptional regulation and cell differentiation, among others. FTY720-P treatment downregulated the gene for follistatin, the antagonist of activin signaling, in all culture conditions. FTY720-P treatment differentially affected both glycolysis-related and immune response genes in Mock- or HIV-exposed cultures, significantly upregulating 11 glycolysis-related genes in HIV-exposed neurons. FTY720-P treatment also differentially upregulated genes related to innate immune responses and antigen presentation in Mock-exposed and more so in HIV-exposed neurons. However, in HIV exposed neurons, FTY720-P depressed the magnitude of differential expression in almost half the genes, suggesting an anti-inflammatory potential. Moreover, in HIV-exposed neurons, FTY720-P reduced expression of the amyloid precursor protein (APP) gene, resulting in reduced expression of the APP protein. This study provides new evidence that fingolimod alters neuronal gene expression in inflammatory, viral-infected microenvironments, with the potential for neuroprotective effects. PMID- 28913619 TI - Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report. AB - Immune checkpoint inhibitors (ICIs) are becoming a standard therapy for non-small cell lung cancer in the advanced stage. As these ICIs become widely available in clinical practice, immune-related adverse effects will become more common. Here we report a patient with lung adenocarcinoma who was treated with nivolumab and developed obstruction because of biliary inflammation. A 63-year-old Japanese man having lung adenocarcinoma with pleural dissemination complained of epigastric pain on the fifth cycle of nivolumab. Computed tomography showed wall thickening at the lower part of the bile duct and cholecystitis. Endoscopic retrograde cholangiopancreatography was repeatedly performed for drainage and stenting of the bile duct. Biopsies did not show obvious malignancy. Laboratory data on day 85 demonstrated grade 3 elevation of serum alkaline phosphatase, transaminase, and amylase levels. We initiated high-dose oral prednisone, resulting in gradual improvement of symptoms and laboratory data. Follow-up magnetic resonance cholangiopancreatography demonstrated no progression of duct obstruction, which confirmed the absence of biliary malignancy. Combined with results from previous reports, nivolumab may cause extrahepatic cholangitis. PMID- 28913620 TI - A brief review on prognostic models of primary biliary cholangitis. AB - Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune liver disease characterized by progressive destruction of small intrahepatic bile ducts. If left untreated, PBC may eventually result in end stage liver disease. For better management of PBC and optimal allocation of medical resources, it is pivotal to accurately estimate the prognosis of patients with PBC. This article will briefly review the models that predict long-term outcome of PBC patients, with special focus on the applicability, strengths and limitations of the widely used models reported from 1983 to 2016. Among many, the Mayo score has been extensively validated and considered as the classic prognostic model for untreated PBC patients, whereas the well-validated Paris I and Paris II criteria are mainly used in ursodeoxycholic acid (UDCA)-treated patients with advanced PBC (stage III-IV) and early PBC (stege I-II), respectively. Based on multicenter studies with large sample sizes, the recently reported GLOBE score and UK-PBC score seem to be superior to previous models and can be applied in patients with different stages of PBC who are already on UDCA therapy, but further external validation may be justified. PMID- 28913621 TI - What Do We Mean by Physician Wellness? A Systematic Review of Its Definition and Measurement. AB - OBJECTIVE: Physician wellness (well-being) is recognized for its intrinsic importance and impact on patient care, but it is a construct that lacks conceptual clarity. The authors conducted a systematic review to characterize the conceptualization of physician wellness in the literature by synthesizing definitions and measures used to operationalize the construct. METHODS: A total of 3057 references identified from PubMed, Web of Science, and a manual reference check were reviewed for studies that quantitatively assessed the "wellness" or "well-being" of physicians. Definitions of physician wellness were thematically synthesized. Measures of physician wellness were classified based on their dimensional, contextual, and valence attributes, and changes in the operationalization of physician wellness were assessed over time (1989-2015). RESULTS: Only 14% of included papers (11/78) explicitly defined physician wellness. At least one measure of mental, social, physical, and integrated well being was present in 89, 50, 49, and 37% of papers, respectively. The number of papers operationalizing physician wellness using integrated, general-life well being measures (e.g., meaning in life) increased [X 2 = 5.08, p = 0.02] over time. Changes in measurement across mental, physical, and social domains remained stable over time. CONCLUSIONS: Conceptualizations of physician wellness varied widely, with greatest emphasis on negative moods/emotions (e.g., burnout). Clarity and consensus regarding the conceptual definition of physician wellness is needed to advance the development of valid and reliable physician wellness measures, improve the consistency by which the construct is operationalized, and increase comparability of findings across studies. To guide future physician wellness assessments and interventions, the authors propose a holistic definition. PMID- 28913622 TI - Comment on Singh et al.:A systematic review and meta-analysis of platelet-rich plasma versus corticosteroid injections for plantar fasciopathy. PMID- 28913623 TI - Updated strategies for the management, pathogenesis and molecular genetics of different forms of ichthyosis syndromes with prominent hair abnormalities. AB - Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment. PMID- 28913624 TI - Emergency Neurological Life Support: Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a neurological emergency because it may lead to sudden neurological decline and death and, depending on the cause, has treatment options that can return a patient to normal. Because there are interventions that can be life-saving in the first few hours after onset, SAH was chosen as an Emergency Neurological Life Support (ENLS) protocol. PMID- 28913625 TI - Calcium release-dependent inactivation precedes formation of the tubular system in developing rat cardiac myocytes. AB - Developing cardiac myocytes undergo substantial structural and functional changes transforming the mechanism of excitation-contraction coupling from the embryonic form, based on calcium influx through sarcolemmal DHPR calcium channels, to the adult form, relying on local calcium release through RYR calcium channels of sarcoplasmic reticulum stimulated by calcium influx. We characterized day-by-day the postnatal development of the structure of sarcolemma, using techniques of confocal fluorescence microscopy, and the development of the calcium current, measured by the whole-cell patch-clamp in isolated rat ventricular myocytes. We characterized the appearance and expansion of the t-tubule system and compared it with the appearance and progress of the calcium current inactivation induced by the release of calcium ions from sarcoplasmic reticulum as structural and functional measures of direct DHPR-RYR interaction. The release-dependent inactivation of calcium current preceded the development of the t-tubular system by several days, indicating formation of the first DHPR-RYR couplons at the surface sarcolemma and their later spreading close to contractile myofibrils with the growing t-tubules. Large variability of both of the measured parameters among individual myocytes indicates uneven maturation of myocytes within the growing myocardium. PMID- 28913626 TI - Role of 18F-FDG PET/CT in the diagnosis of cardiovascular implantable electronic device infections: A meta-analysis. AB - OBJECTIVE: We performed a meta-analysis evaluating the use of fluorine-18 fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in the diagnosis of cardiovascular implantable electronic device (CIED) infections. BACKGROUND: PET/CT may be helpful in the diagnosis of CIED infection, particularly in patients with the absence of localizing signs or definitive echocardiographic findings. METHODS: PubMed, Embase, Cochrane library, CINAHL, Web of Knowledge, and www.clinicaltrials.gov from January 1990 to April 2017 were searched for studies evaluating the accuracy of PET/CT in the diagnosis of CIED infections. RESULTS: Overall, 14 studies involving 492 patients were included in the meta-analysis. The pooled sensitivity of PET/CT for diagnosis of CIED infection was 83% (95% CI 78%-86%) and the pooled specificity was 89% (95% CI 84%-94%). PET/CT demonstrated a higher sensitivity of 96% (95% CI 86%-99%) and specificity of 97% (95% CI 86%-99%) for diagnosis of pocket infections. Diagnostic accuracy for lead infections or CIED-IE was lower with pooled sensitivity of 76% (95% CI 65%-85%) and specificity of 83% (95% CI 72%-90%). CONCLUSION: Use of PET/CT in the evaluation of CIED infection has both a high sensitivity (83%) and specificity (89%) and deserves consideration in the management of selected patients with suspected CIED infections. PMID- 28913627 TI - Everolimus-eluting bioresorbable vascular scaffold in daily clinical practice: A single-centre experience. AB - BACKGROUND: Recent evidence has raised concerns regarding the safety of the everolimus-eluting bioresorbable vascular scaffold (E-BVS) (Absorb, Abbott Vascular, Santa Clara, CA, USA). Following these data, the use of this device has diminished in the Netherlands; however, daily practice data are limited. Therefore we studied the incidence of safety and efficacy outcomes with this device in daily clinical practice in a single large tertiary centre in the Netherlands. METHODS: All E-BVS treated patients were included in this analysis. The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target vessel non-fatal myocardial infarction (TV-MI) and clinically driven target lesion revascularisation (TLR). The secondary endpoint was the incidence of definite scaffold thrombosis. RESULTS: Between October 2013 and January 2017, 105 patients were treated with 147 E-BVS. This population contained 42 (40%) patients with diabetes mellitus and 43 (40.9%) undergoing treatment for acute coronary syndrome, and thus represents a high-risk patient cohort. Mean follow-up was 19.8 months. Intravascular imaging guidance during scaffold implantation was used in 64/105 (43.5%) patients. The primary endpoint (TLF) occurred in 3 (2.9%) patients. All-cause mortality and cardiac mortality occurred in 2 (2%) and 0 (0%) patients respectively. TV-MI occurred in 2 patients (1.9%): both were periprocedural and not related to the BVS implantation. TLR occurred in 1 patient (1.0%) during follow-up. No definite scaffold thrombosis occurred during follow-up. CONCLUSION: This single-centre study examining the real-world experience of E-BVS implantation in a high-risk population shows excellent procedural safety and long-term clinical outcomes. PMID- 28913628 TI - Delayed Bronchocutaneous Fistula Without Pneumothorax Following a Microwave Ablation of a Recurrent Pulmonary Metastasis. AB - Percutaneous tumor ablations are rather safe and effective treatments in selected patients for non-operable non-small cell lung carcinomas or lung metastases. However, there are major complications such as bronchopleural or bronchocutaneous fistula, which it is important to know in order to manage them safely. We describe in this report a case of bronchocutaneous fistula without pneumothorax following a microwave ablation of a recurrent pulmonary metastasis and its management. PMID- 28913629 TI - Atherogenic index of plasma is positively associated with the risk of all-cause death in elderly women : A 10-year follow-up. AB - BACKGROUND: The blood concentrations of total cholesterol and low-density lipoprotein (LDL) do not predict survival in patients older than 60 years. The atherogenic index of plasma (AIP) is a logarithm of the triacylglycerol to high density lipoprotein (HDL) ratio and a surrogate for the concentration of small dense LDL. It might be a better reflection of the risk of all-cause death in elderly patients. METHODS: We conducted a prospective observational study of patients with arterial hypertension older than 60 years. The concentrations of total cholesterol, LDL, HDL and triacylglycerol were measured at the time of the recruitment and the patients were observed for 10 years. Cox regression analysis was performed to assess the effects of lipoproteins and AIP on survival. RESULTS: A total of 500 patients were recruited and 473 of them (226 men, 247 women) either died or successfully completed the 10-year follow-up and were included in the analysis. The AIP was positively associated, while HDL concentration was negatively associated with the risk of all-cause death adjusted for age, smoking habits, statin use, history of diabetes mellitus, myocardial infarction, stroke and peripheral artery occlusive disease (PAOD) in elderly women but not in men. The LDL, total cholesterol, triacylglycerol and non-HDL concentrations were not associated with the risk of death in both sexes. CONCLUSIONS: The AIP is positively associated with the risk of all-cause death in elderly women with arterial hypertension independent of age, smoking habits, statin therapy and comorbidities. PMID- 28913630 TI - Durability of treatment effects of the Sleep Position Trainer versus oral appliance therapy in positional OSA: 12-month follow-up of a randomized controlled trial. AB - PURPOSE: The Sleep Position Trainer (SPT) is a new option for treating patients with positional obstructive sleep apnea (POSA). This study investigated long-term efficacy, adherence, and quality of life during use of the SPT device compared with oral appliance therapy (OAT) in patients with POSA. METHODS: This prospective, multicenter trial randomized patients with mild to moderate POSA (apnea-hypopnea index [AHI] 5-30/h) to SPT or OAT. Polysomnography was performed at baseline and after 3 and 12 months' follow-up. The primary endpoint was OSA severity; adherence, quality of life, and adverse events were also assessed. RESULTS: Ninety-nine patients were randomized and 58 completed the study (29 in each group). Median AHI in the SPT group decreased from 13.2/h at baseline to 7.1/h after 12 months (P < 0.001); corresponding values in the OAT group were 13.4/h and 5.0/h (P < 0.001), with no significant between-group difference (P = 1.000). Improvements throughout the study were maintained at 12 months. Long-term median adherence was also similar in the two treatment groups; the proportion of patients who used their device for >= 4 h for 5 days in a week was 100% in the SPT group and 97.0% in the OAT group (P = 0.598). CONCLUSIONS: The efficacy of SPT therapy was maintained over 12 months and was comparable to that of OAT in patients with mild to moderate POSA. Adherence was relatively high, and similar in the two groups. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02045576). PMID- 28913631 TI - Comparative proteomic analysis and characterization of benzo(a)pyrene removal by Microbacterium sp. strain M.CSW3 under denitrifying conditions. AB - High-molecular-weight polycyclic aromatic hydrocarbons are persistent organic pollutants with great environmental and human health risks and the associated bioremediation activities have always been hampered by the lack of powerful bacterial species under redox conditions. A Microbacterium sp. strain capable of using benzo(a)pyrene as sole carbon and energy sources under denitrifying conditions was isolated. The difference in protein expression during BaP removal and removal characterization were investigated. A total of 146 proteins were differentially expressed, 44 proteins were significantly up-regulated and 102 proteins were markedly down-regulated. GO and COG analysis showed that BaP removal inhibited the expression of proteins related to glucose metabolism at different levels and activated other metabolic pathway. The proteins associated with catalytic activity and metabolic process were altered significantly. Furthermore, the BaP removal might be occurred in certain organelle of M.CSW3. The strain removed BaP with a speed of 0.0657-1.0072 mg/L/day over the concentrations range 2.5-100 mg/L. High removal rates (>70%) were obtained over the range of pH 7-11 in 14 days. Carbohydrates and organic acids which could be utilized by the strain, as well as heavy metal ions, reduced BaP removal efficiency. However, phenanthrene or pyrene addition enhanced the removal capability of M.CSW3. The strain was proved to have practical potential for bioremediation of PAHs-contaminated soil and this study provided a powerful platform for further application by improving production of associated proteins. PMID- 28913632 TI - [Withholding life-sustaining therapies-interdisciplinary responsibility]. PMID- 28913635 TI - Skin lipids of the striped plateau lizard (Sceloporus virgatus) correlate with female receptivity and reproductive quality alongside visual ornaments. AB - Sex pheromones can perform a variety of functions ranging from revealing the location of suitable mates to being honest signals of mate quality, and they are used in the mate selection process by many species of reptile. In this study, we determined whether the skin lipids of female striped plateau lizards (Sceloporus virgatus) can predict the reproductive quality of females, thereby having the potential to serve as pheromones. Using gas chromatography/mass spectrometry, we identified 17 compounds present in skin lipids of female lizards. Using principal component analysis to compare the skin lipid profile of receptive and non receptive females, we determined that an uncharacterized compound may allow for chemical identification of receptive mates. We also compared extracted principal components to measures of female fitness and reproductive qualities and found that the level of two 18 carbon fatty acids present in a female's skin lipids may indicate her clutch size. Finally, we compared the information content of the skin lipids to that of female-specific color ornaments to assess whether chemical and visual cues transmit different information or not. We found that the chroma of a female's orange throat patch is also related to her clutch size, suggesting that chemical signals may reinforce the information communicated by visual ornamentation in this species which would support the "backup signals" hypothesis for multiple signals. PMID- 28913634 TI - Emergency Neurological Life Support: Intracranial Hypertension and Herniation. AB - Sustained intracranial hypertension and acute brain herniation are "brain codes," signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, a brain code mandates the organized implementation of a stepwise management algorithm. The goal of this Emergency Neurological Life Support protocol is to implement an evidence-based, standardized approach to the evaluation and management of patients with intracranial hypertension and/or herniation. PMID- 28913633 TI - The function of endocytosis in Wnt signaling. AB - Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the beta-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/beta-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network. PMID- 28913636 TI - Gelidibacter flavus sp. nov., Isolated from Activated Sludge of Seawater Treatment System. AB - A Gram-stain-negative bacterial strain designated Con4T was isolated from activated sludge in a seawater treatment system. The strain was rod-shaped, motile, aerobic, and formed yellow-colored colonies on agar medium. Cells contained carotenoid pigments, but flexirubin-type pigments were absent. Based on 16S rRNA gene sequence analysis, the strain was assigned to the genus Gelidibacter. Optimum growth occurred at 20 degrees C, pH 7.0, and 1-2% (w/v) NaCl. Prominent fatty acid types were iso-C15:0, anteiso-C15:0, and iso-C16:0 3OH. Diphosphatidylglycerol and phosphatidylethanolamine were present as the major polar lipids. MK-6 was present as major menaquinone. Strain Con4T showed the highest sequence similarity with Gelidibacter mesophilus KCTC 12106T (96.5%), Gelidibacter gilvus IC158T (96.4%), and Gelidibacter algens ACAM 536T (95.8%). The G+C mol% contents of the strain Con4T were 37.7%. Distinct morphological, physiological, and genotypic differences from the previously described taxa support the classification of strain Con4T as a representative of a novel species in the genus Gelidibacter, for which the name Gelidibacter flavus sp. nov. is proposed. The type strain is Con4T (=KEMB 41-198T = JCM 31135T). PMID- 28913637 TI - Chemical characterization and identification of Pinaceae pollen by infrared microspectroscopy. AB - MAIN CONCLUSION: FTIR microspectroscopy, in combination with spectral averaging procedure, enables precise analysis of pollen grains for chemical characterization and identification studies of fresh and fossilised pollen in botany, ecology and palaeosciences. Infrared microspectroscopy (uFTIR) of Pinaceae pollen can provide valuable information on plant phenology, ecophysiology and paleoecology, but measurements are challenging, resulting in unreproducible spectra. The comparative analysis of uFTIR spectra belonging to morphologically different Pinaceae pollen, namely bisaccate Pinus and monosaccate Tsuga pollen, was conducted. The study shows that the main cause of spectral variability is non-radial symmetry of bisaccate pollen grains, while additional variation is caused by Mie scattering. Averaging over relatively small number of single pollen grain spectra (approx. 5-10) results with reproducible data on pollen chemical composition. The practical applicability of the uFTIR spectral averaging method has been demonstrated by the partial least-squares regression based differentiation of the two closely related Pinus species with morphologically indistinguishable pollen: Pinus mugo (mountain pine) and Pinus sylvestris (Scots pine). The study has demonstrated that the uFTIR approach can be used for identification, differentiation and chemical characterization of pollen with complex morphology. The methodology enables analysis of fresh pollen, as well as fossil pollen from sediment core samples, and can be used in botany, ecology and paleoecology for study of biotic and abiotic effects on plants. PMID- 28913638 TI - Psychosomatic medicine - viability of a discipline. PMID- 28913639 TI - Invited comment to the 'AbdoMAN': an artificial abdominal wall simulator for biomechanical studies on laparotomy closure techniques. L. F. Kroese, J. J. Harlaar, C. Ordrenneau, J. Verhelst, G. Guerin, F. Turquier, R. H. M. Goossens, G.-J. Kleinrensink, J. Jeekel, J. F. Lange. PMID- 28913640 TI - Case report of Kummell's disease with delayed onset myelopathy and the literature review. AB - INTRODUCTION: Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture. This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis. PURPOSES: The aim of this article is to carry out an international literature review regarding Kummell's disease, addressing its physiopathology, histopathology, clinical presentation, radiological characteristics and treatment modalities; at the same time, the literature is updated through the description of a new and interesting case, symbol of the pathology long-term potential complications, if not diagnosed and therefore not suitably treated. CASE REPORT: A patient with osteoporosis, following a slight spinal trauma, suffered a progressive necrosis of the D11 body; although the radiological exams showed a constant worsening of the thoracic-lumbar kyphosis and a restriction of the spinal canal, in another medical centre he was only treated with a corset and painkillers. A year after the injury, motor deficits concerning the lower limbs appeared. He was then sent to us and indication for posterior internal fixation was given. On the basis of both his medical history and radiological and histological findings, Kummell's disease was diagnosed. CONCLUSION: It is necessary to have a complete knowledge of the clinical, pathological and radiological characteristics of Kummell's disease, so as to follow a correct diagnostic course enabling to prepare the most suitable therapy. PMID- 28913641 TI - Periorbital edema from apixaban treatment. PMID- 28913642 TI - Small-Volume, Fast-Emptying Gastric Pouch Leads to Better Long-Term Weight Loss and Food Tolerance After Roux-en-Y Gastric Bypass. AB - INTRODUCTION: Anatomical and functional influences on gastric bypass (GBP) results are often poorly evaluated and not yet fully understood. PURPOSE: The purpose of this study is to evaluate the influence of the gastric pouch volume and its emptying rate on long-term weight loss and food tolerance after GBP. MATERIALS AND METHODS: Weight loss, food tolerance, pouch volumetry (V) by three dimensional reconstruction, and pouch emptying rate by 4 h scintigraphy were evaluated in 67 patients. Cutoffs were identified for V and retention percentage (%Ret) at 1 h (%Ret1). From these parameters, the sample was categorized, looking for associations between V, %Ret, weight loss, and food tolerance, assessed by a questionnaire for quick assessment of food tolerance (SS). RESULTS: PO median follow-up time was 47 months; median V was 28 mL; %Ret at 1, 2, and 4 h were 8, 2, and 1%, respectively. There were associations between V <= 40 mL and higher emptying rates up to 2 h (V <= 40 mL: %Ret1 = 6, %Ret2 = 2, p = 0.009; V > 40 mL: %Ret1 = 44, %Ret2 = 13.5, p = 0.045). An association was found between higher emptying speed in 1 h and higher late weight loss (WL), represented by lower percentage of excess weight loss (%EWL) regain (p = 0.036) and higher %EWL (p = 0.033) in the group with %Ret1 <= 12%, compared to the group %Ret1 >= 25%. Better food tolerance (SS > 24), was associated with lower %Ret1 (p = 0.003). CONCLUSION: Smaller pouch size is associated with a faster gastric emptying, greater WL maintenance, and better food tolerance. These data suggest that a small pouch with rapid emptying rate is an important technical parameter for good outcomes in GBP. PMID- 28913643 TI - Does oxytocin lead to emotional interference during a working memory paradigm? AB - BACKGROUND: Oxytocin administration may increase attention to emotional information. We hypothesized that this augmented emotional processing might in turn lead to interference on concurrent cognitive tasks. To test this hypothesis, we examined whether oxytocin administration would lead to heightened emotional interference during a working memory paradigm. Additionally, moderating effects of childhood maltreatment were explored. METHODS: Seventy-eight healthy males received 24 IU of intranasal oxytocin or placebo in a randomized placebo controlled double-blind between-subjects study. A working memory task was performed during which neutral, positive, and negative distractors were presented. RESULTS: The main outcome observed was that oxytocin did not enhance interference by emotional information during the working memory task. There was a non-significant trend for oxytocin to slow down performance irrespective of distractor valence, while accuracy was unaffected. Exploratory analyses showed that childhood maltreatment was related to lower overall accuracy, but in the placebo condition only. However, the maltreated group sample size was very small precluding any conclusions on its moderating effect. CONCLUSIONS: Despite oxytocin's previously proposed role in enhanced emotional processing, no proof was found that this would lead to reduced performance on a concurrent cognitive task. The routes by which oxytocin exerts its effects on cognitive and social emotional processes remain to be fully elucidated. PMID- 28913644 TI - Affective-associative two-process theory: a neurocomputational account of partial reinforcement extinction effects. AB - The partial reinforcement extinction effect (PREE) is an experimentally established phenomenon: behavioural response to a given stimulus is more persistent when previously inconsistently rewarded than when consistently rewarded. This phenomenon is, however, controversial in animal/human learning theory. Contradictory findings exist regarding when the PREE occurs. One body of research has found a within-subjects PREE, while another has found a within subjects reversed PREE (RPREE). These opposing findings constitute what is considered the most important problem of PREE for theoreticians to explain. Here, we provide a neurocomputational account of the PREE, which helps to reconcile these seemingly contradictory findings of within-subjects experimental conditions. The performance of our model demonstrates how omission expectancy, learned according to low probability reward, comes to control response choice following discontinuation of reward presentation (extinction). We find that a PREE will occur when multiple responses become controlled by omission expectation in extinction, but not when only one omission-mediated response is available. Our model exploits the affective states of reward acquisition and reward omission expectancy in order to differentially classify stimuli and differentially mediate response choice. We demonstrate that stimulus-response (retrospective) and stimulus-expectation-response (prospective) routes are required to provide a necessary and sufficient explanation of the PREE versus RPREE data and that Omission representation is key for explaining the nonlinear nature of extinction data. PMID- 28913645 TI - Local analgesia in paediatric dentistry: a systematic review of techniques and pharmacologic agents. AB - PURPOSE: To evaluate the evidence supporting effects and adverse effects of local analgesia using different pharmacological agents and injection techniques during dental treatment in children and adolescents aged 3-19 years. METHODS: A systematic literature search of databases including PubMed, Cochrane, and Scopus was conducted in November 2016. The PRISMA-statement was followed. Two review authors independently assessed the selected randomised control trials for risk of bias and quality. RESULTS: 725 scientific papers were identified. 89 papers were identified to be read in full text of which 80 were excluded. Finally, 9 papers were evaluated for quality and risk of bias. Many of the included papers had methodological shortcomings affecting the possibility to draw conclusions. Information about ethical clearance and consent were missing in some of the included papers. No alarming adverse effects were identified. One study was assessed as having low risk of bias. This reported inferior alveolar nerve block to be more effective than buccal infiltration for dental treatment of mandibular molars, while no differences were found regarding pharmacological agents. CONCLUSIONS: At present, there is insufficient evidence in support of any pharmacologic agent or injection technique as being superior compared to others. There is a need for more rigorous studies which also handle the ethical issues of including children in potentially painful studies. PMID- 28913646 TI - Computational investigation of the microstructural characteristics and physical properties of glycerol-based deep eutectic solvents. AB - Recently, there has been significant interest in the possibility of using deep eutectic solvents (DESs) as novel green media and alternatives to conventional solvents and ionic liquids (ILs) in many applications. Due to their attractive properties, such as their biodegradability, low cost, easy preparation, and nontoxicity, DESs appear to be very promising solvents for use in the field of green chemistry. This computational study investigated six glycerol-based DESs: DES1 (glycerol:methyl triphenyl phosphonium bromide), DES2 (glycerol:benzyl triphenyl phosphonium chloride), DES3 (glycerol:allyl triphenyl phosphonium bromide), DES4 (glycerol:choline chloride), DES5 (glycerol:N,N diethylethanolammonium chloride), and DES6 (glycerol:tetra-n-butylammonium bromide). The chemical structures and combination mechanisms as well as the sigma profiles and sigma potentials of the studied DESs were explored in detail. Moreover, density, viscosity, vapor pressure, and IR analytical data were predicted and compared with the corresponding experimental values reported in the literature for these DESs. To achieve these goals, the conductor-like screening model for realistic solvents (COSMO-RS) and the Amsterdam Density Functional (ADF) software package were used. The predicted results were found to be in good agreement with the corresponding experimental values reported in the literature. Further theoretical investigations are needed to confirm the experimental results regarding both properties and applications-reported for these DESs. PMID- 28913647 TI - Structure of the style and pollen tube pathway in the Ziziphoid and Rhamnoid clades of Rhamnaceae. AB - The ultrastructure of the style and pollen tube pathway before, during and after anthesis were studied in 13 species belonging to the tribes Pomaderreae, Paliureae, Colletieae and Gouanieae (Ziziphoid clade) and Rhamneae (Rhamnoid clade) using light microscopy and transmission electron microscopy. The aim of this study is to provide new morphological characters useful for phylogenetic analysis at suprageneric level in Rhamnaceae. The patterns of pollen tube growth and the ultrastructural changes undergone by cells of the style were also described. Species of Rhamneae (Scutia buxifolia and Condalia buxifolia) have a solid style, with the transmitting tissue forming three independent strands (S. buxifolia) or a central, single horseshoe-shaped strand as seen in transversal section (C. buxifolia) which could derive from the fusion of formerly independent strands. In contrast, Pomaderreae, Gouanieae and Paliureae showed semi-solid styles, while in Colletieae, as previously reported, the style is hollow with two or three stylar canals. The style anatomy and the ultrastructure of the pollen tube pathway show that there is a tendency towards a solid style with a single strand of transmitting tissue within the family. The three-canalled hollow style could be the plesiomorphic state of the character "type of style" in the family, the semi-solid style the synapomorphic state and the solid style with three strands of transmitting tissue the apomorphic state, with the solid style with a single strand of transmitting tissue as the most derived state. Therefore, Colletieae would be the most basal tribe of the Ziziphoid clade. PMID- 28913648 TI - Combined effect of the Saccharomyces cerevisiae lag phase and the non Saccharomyces consortium to enhance wine fruitiness and complexity. AB - Non-Saccharomyces (NS) species that are either naturally present in grape must or added in mixed fermentation with S. cerevisiae may impact the wine's chemical composition and sensory properties. NS yeasts are prevailing during prefermentation and early stages of alcoholic fermentation. However, obtaining the correct balance between S. cerevisiae and NS species is still a critical issue: if S. cerevisiae outcompetes the non-Saccharomyces, it may minimize their impact, while conversely if NS take over S. cerevisiae, it may result in stuck or sluggish fermentations. Here, we propose an original strategy to promote the non Saccharomyces consortium during the prefermentation stage while securing fermentation completion: the use of a long lag phase S. cerevisiae. Various fermentations in a Sauvignon Blanc with near isogenic S. cerevisiae displaying short or long lag phase were compared. Fermentations were performed with or without a consortium of five non-Saccharomyces yeasts (Hanseniaspora uvarum, Candida zemplinina, Metschnikowia spp., Torulaspora delbrueckii, and Pichia kluyveri), mimicking the composition of natural NS community in grape must. The sensorial analysis highlighted the positive impact of the long lag phase on the wine fruitiness and complexity. Surprisingly, the presence of NS modified only marginally the wine composition but significantly impacted the lag phase of S. cerevisiae. The underlying mechanisms are still unclear, but it is the first time that a study suggests that the wine composition can be affected by the lag phase duration per se. Further experiments should address the suitability of the use of long lag phase S. cerevisiae in winemaking. PMID- 28913649 TI - Improvement in diagnostic and therapeutic arthrocentesis via constant compression. AB - We hypothesized that constant compression of the knee would mobilize residual synovial fluid and promote successful arthrocentesis. Two hundred and ten knees with grade II-III osteoarthritis were included in this paired design study: (1) conventional arthrocentesis was performed with manual compression and success and volume (milliliters) determined; and (2) the intra-articular needle was left in place, and a circumferential elastomeric brace was tightened on the knee to provide constant compression. Arthrocentesis was attempted again and additional fluid volume was determined. Diagnostic procedural cost-effectiveness was determined using 2017 US Medicare costs. No serious adverse events were noted in 210 subjects. In the 158 noneffusive (dry) knees, sufficient synovial fluid for diagnostic purposes (>= 2 ml) was obtained in 5.0% (8/158) without compression and 22.8% (36/158) with compression (p = 0.0001, z for 95% CI = 1.96), and the absolute volume of arthrocentesis fluid obtained without compression was 0.28 +/- 0.79 versus 1.10 +/- 1.81 ml with compression (293% increase, p = 0.0001). In the 52 effusive knees, diagnostic synovial fluid (>= 2 ml) was obtained in 75% (39/52) without compression and 100% (52/52) with compression (p = 0.0001, z for 95% CI = 1.96), and the absolute volume of arthrocentesis without compression was 14.7 +/- 13.8 versus 25.3 +/- 15.5 ml with compression (72.1% increase, p = 0.0002). Diagnostic procedural cost-effectiveness was $655/sample without compression and $387/sample with compression. The new technique of constant compression via circumferential mechanical compression mobilizes residual synovial fluid beyond manual compression improving the success, cost effectiveness, and yield of diagnostic and therapeutic arthrocentesis in both the effusive and noneffusive knee. PMID- 28913650 TI - Does levonorgestrel-releasing intrauterine system increase breast cancer risk in peri-menopausal women? An HMO perspective. AB - PURPOSE: To evaluate the association between levonorgestrel-releasing intrauterine system (LNG-IUS) use and breast cancer (BC) risk. METHODS: A cohort of all Maccabi Healthcare Services (MHS) female members aged 40-50 years between 1/2003 and 12/2013 was used to identify LNG-IUS users as "cases," and 2 age matched non-users as "controls." Exclusion criteria included: prior BC diagnosis, prior (5 years pre-study) and subsequent treatment with other female hormones or prophylactic tamoxifen. Invasive tumors were characterized by treatments received (chemotherapy, hormonal therapy, trastuzumab, or combination thereof). RESULTS: The analysis included 13,354 LNG-IUS users and 27,324 controls (mean age: 44.1 +/ 2.6 vs. 44.9 +/- 2.8 years; p < 0.0001). No significant differences in 5-year Kaplan-Meier (KM) estimates for overall BC risk or ductal carcinoma in situ occurrence were observed between groups. There was a trend towards higher risk for invasive BC in LNG-IUS users (5-year KM-estimate: 1.06% vs. 0.93%; p = 0.051). This difference stemmed primarily from the younger women (40-45 years; 0.88% vs. 0.69%, p = 0.014), whereas in older women (46-50 years), it was non significant (1.44% vs. 1.21%; p = 0.26). Characterization of invasive BC by treatment demonstrated that LNG-IUS users had similar proportions of tumors treated with hormonal therapy, less tumors treated with trastuzumab, (7.5% vs. 14.5%) and more tumors treated with chemotherapy alone (25.8% vs. 14.9%; p = 0.041). CONCLUSIONS: In peri-menopausal women, LNG-IUS was not associated with an increased total risk of BC, although in the subgroup of women in their early 40's, it was associated with a slightly increased risk for invasive tumors. PMID- 28913651 TI - Outcomes of Percutaneous Portal Vein Intervention in a Single UK Paediatric Liver Transplantation Programme. AB - INTRODUCTION: Percutaneous transluminal angioplasty (PTA), with or without stent placement, has become the treatment of choice for portal vein complications (PVC) following liver transplantation. We aimed to assess long-term outcomes of intervention in paediatric transplant recipients, in a single institution. MATERIALS AND METHODS: 227 children received 255 transplants between November 2000 and September 2016. 30 patients developed PVC of whom 21 had percutaneous intervention. Retrospective clinical and procedural outcome data on these 21 patients were collected. RESULTS: 21 patients, with median age 1.7 years (range 0.4-16.2), underwent 42 procedures with PTA with or without stenting. 36 procedures were for PV stenosis and 6 for PV thrombosis. Treatment was with primary PTA, with stenting reserved for suboptimal PTA result or restenosis within 3 months. 28 procedures were performed with PTA and 13 with stenting. Technical success (>50% reduction in mean pressure gradient, absolute pressure gradient <=4 mmHg or venographic stenosis <30%) was achieved in 41 procedures. Failure to recanalise a thrombosed PV occurred in 1 procedure. There were no major procedural complications. Patients were followed-up with serial Doppler ultrasound surveillance. Kaplan-Meier estimated median primary patency was 9.9 months, with primary-assisted patency of 95% after median follow-up of 45.5 months (range 11.1-171.6). CONCLUSION: With regular surveillance, excellent patency rates can be achieved following percutaneous intervention for PVC post paediatric liver transplantation. PMID- 28913652 TI - Differences in bone structure and unloading-induced bone loss between C57BL/6N and C57BL/6J mice. AB - The C57BL/6 mouse, the most frequently utilized animal model in biomedical research, is in use as several substrains, all of which differ by a small array of genomic differences. Two of these substrains, C57BL/6J (B6J) and C57BL/6N (B6N), are commonly used but it is unclear how phenotypically similar or different they are. Here, we tested whether adolescent B6N mice have a bone phenotype and respond to the loss of weightbearing differently than B6J. At 9 weeks of age, normally ambulating B6N had lower trabecular bone volume fraction but greater bone formation rates and osteoblast surfaces than corresponding B6J. At 11 weeks of age, differences in trabecular indices persisted between the substrains but differences in cellular activity had ceased. Cortical bone indices were largely similar between the two substrains. Hindlimb unloading (HLU) induced similar degeneration of trabecular architecture and cellular activity in both substrains when comparing 11-week-old HLU mice to 11-week-old controls. However, unloaded B6N mice had smaller cortices than B6J. When comparing HLU to 9 weeks baseline control mice, deterioration in trabecular separation, osteoblast indices, and endocortical variables was significantly greater in B6N than B6J. These data indicate specific developmental differences in bone formation and morphology between B6N and B6J mice, giving rise to a differential response to mechanical unloading that may be modulated, in part, by the genes Herc2, Myo18b, and Acan. Our results emphasize that these substrains cannot be used interchangeably at least for investigations in which the phenotypic makeup and its response to extraneous stimuli are of interest. PMID- 28913653 TI - Soluble soil aluminum alters the relative uptake of mineral nitrogen forms by six mature temperate broadleaf tree species: possible implications for watershed nitrate retention. AB - Increased availability of monomeric aluminum (Al3+) in forest soils is an important adverse effect of acidic deposition that reduces root growth and inhibits nutrient uptake. There is evidence that Al3+ exposure interferes with NO3- uptake. If true for overstory trees, the reduction in stand demand for NO3- could increase NO3- discharge in stream water. These effects may also differ between species that tolerate different levels of soil acidity. To examine these ideas, we measured changes in relative uptake of NO3- and NH4+ by six tree species in situ under increased soil Al3+ using a 15N-labeling technique, and measured soluble soil Al levels in a separate whole-watershed acidification experiment in the Fernow Experimental Forest (WV). When exposed to added Al3+, the proportion of inorganic N acquired as NO3- dropped 14% across species, but we did not detect a reduction in overall N uptake, nor did tree species differ in this response. In the long-term acidification experiment, we found that soluble soil Al was mostly in the free Al3+ form, and the concentration of Al3+ was ~65 MUM higher (~250%) in the mineral soil of the acidified watershed vs. an untreated watershed. Thus, increased levels of soil Al3+ under acidic deposition cause a reduction in uptake of NO3- by mature trees. When our 15N uptake results were applied to the watershed acidification experiment, they suggest that increased Al3+ exposure could reduce tree uptake of NO3- by 7.73 kg N ha-1 year 1, and thus increase watershed NO3- discharge. PMID- 28913654 TI - Discriminating cirRNAs from other lncRNAs using a hierarchical extreme learning machine (H-ELM) algorithm with feature selection. AB - As non-coding RNAs, circular RNAs (cirRNAs) and long non-coding RNAs (lncRNAs) have attracted an increasing amount of attention. They have been confirmed to participate in many biological processes, including playing roles in transcriptional regulation, regulating protein-coding genes, and binding to RNA associated proteins. Until now, the differences between these two types of non coding RNAs have not been fully uncovered. It is still quite difficult to detect cirRNAs from other lncRNAs using simple techniques. In this study, we investigated these two types of non-coding RNAs using several computational methods. The purpose was to extract important factors that could distinguish cirRNAs from other lncRNAs and build an effective classification model to distinguish them. First, we collected cirRNAs, lncRNAs and their representations from a previous study, in which each cirRNA or lncRNA was represented by 188 features derived from its graph representation, sequence and conservation properties. Second, these features were analyzed by the minimum redundancy maximum relevance (mRMR) method. The obtained mRMR feature list, incremental feature selection method and hierarchical extreme learning machine algorithm were employed to build an optimal classification model with sensitivity of 0.703, specificity of 0.850, accuracy of 0.789 and a Matthews correlation coefficient of 0.561. Finally, we analyzed the 16 most important features. Of them, the sequences and structures of the RNA molecule were top ranking, implying they can be potential indicators of differences between cirRNAs and other lncRNAs. Meanwhile, other features of evolutionary conversation, sequence consecution were also important. PMID- 28913655 TI - Quantitative trait loci for resistance to stripe rust of wheat revealed using global field nurseries and opportunities for stacking resistance genes. AB - KEY MESSAGE: Quantitative trait loci controlling stripe rust resistance were identified in adapted Canadian spring wheat cultivars providing opportunity for breeders to stack loci using marker-assisted breeding. Stripe rust or yellow rust, caused by Puccinia striiformis Westend. f. sp. tritici Erikss., is a devastating disease of common wheat (Triticum aestivum L.) in many regions of the world. The objectives of this research were to identify and map quantitative trait loci (QTL) associated with stripe rust resistance in adapted Canadian spring wheat cultivars that are effective globally, and investigate opportunities for stacking resistance. Doubled haploid (DH) populations from the crosses Vesper/Lillian, Vesper/Stettler, Carberry/Vesper, Stettler/Red Fife and Carberry/AC Cadillac were phenotyped for stripe rust severity and infection response in field nurseries in Canada (Lethbridge and Swift Current), New Zealand (Lincoln), Mexico (Toluca) and Kenya (Njoro), and genotyped with SNP markers. Six QTL for stripe rust resistance in the population of Vesper/Lillian, five in Vesper/Stettler, seven in Stettler/Red Fife, four in Carberry/Vesper and nine in Carberry/AC Cadillac were identified. Lillian contributed stripe rust resistance QTL on chromosomes 4B, 5A, 6B and 7D, AC Cadillac on 2A, 2B, 3B and 5B, Carberry on 1A, 1B, 4A, 4B, 7A and 7D, Stettler on 1A, 2A, 3D, 4A, 5B and 6A, Red Fife on 2D, 3B and 4B, and Vesper on 1B, 2B and 7A. QTL on 1A, 1B, 2A, 2B, 3B, 4A, 4B, 5B, 7A and 7D were observed in multiple parents. The populations are compelling sources of recombination of many stripe rust resistance QTL for stacking disease resistance. Gene pyramiding should be possible with little chance of linkage drag of detrimental genes as the source parents were mostly adapted cultivars widely grown in Canada. PMID- 28913656 TI - New Insights into Cardiac Involvement in Juvenile Scleroderma: A Three Dimensional Echocardiographic Assessment Unveils Subclinical Ventricle Dysfunction. AB - Cardiac manifestations in juvenile scleroderma or systemic sclerosis (JSSc) have poor prognosis, begin in early stages of the disease, and remain clinically asymptomatic. New echocardiography modalities, such as 2D/3D speckle tracking (STE, strain analysis for regional and global ventricular functions), can detect cardiac involvement in early stages. We assessed 21 JSSc patients and 19 controls using 2D/3D STE. The left ventricular end diastolic volume, end systolic volume, and ejection fraction of the patient and control groups were significantly different (99.2 +/- 23.8 vs. 52 +/- 23.8, 40.6 +/- 16.0 vs. 20.2 +/- 17.4 and 59.2 +/- 7.5 vs. 65.6 +/- 5.2, respectively). Global longitudinal strain (GLS) and global circumferential strain (GCS) were lower in the patient group (18.4 +/- 4.7 vs. 22.4 +/- 3.7, 26.4 +/- 5.8 vs. 31.4 +/- 3.5), as were the peak systolic strain values of the right ventricular longitudinal strain (RVLS) septum and RVLS free wall (18.1 +/- 6.8 vs. 24.8 +/- 6.0 and 22.8 +/- 5.9 vs. 28.0 +/- 6.9, respectively). 3D measurements of RVEDV, RVESV, and RVSV were higher in the patient group (88.2 +/- 31.3 vs. 50.8 +/- 23.5, 43.1 +/- 17.6 vs. 19.0 +/- 12.2, and 45.0 +/- 16.2 vs. 31.7 +/- 12.6). RVLS freewall results were lower in the JSSc patients with interstitial lung fibrosis, arthritis, muscle weakness, weight loss, and anti-scl 70 antibodies than in the JSSc patients without these variables. We found that a GCS of <34.5% could identify patients for left ventricular (LV) dysfunction with a sensitivity of 93.3, specificity of 92.9, while an RVEF of <60.7% could identify patients for left ventricular (RV) dysfunction with a sensitivity of 92.9 and specificity of 21.4%. We highlighted key advantages of 3D STE for the tracking of early systolic dysfunction in patients with JSSc who would benefit from medical intervention for cardiac complications. PMID- 28913657 TI - Radical cystectomy for recurrent urothelial carcinoma after prior partial cystectomy: perioperative and oncologic outcomes. AB - PURPOSE: To evaluate perioperative and oncologic outcomes of patients undergoing radical cystectomy (RC) for recurrence of urothelial carcinoma (UC) after prior partial cystectomy (PC), and to compare these outcomes to patients undergoing primary RC. METHODS: Patients who underwent RC for recurrence of UC after prior PC were matched 1:3 to patients undergoing primary RC based on age, pathologic stage, and decade of surgery. Perioperative and oncologic outcomes were compared using Wilcoxon sign-rank test, McNemars test, the Kaplan-Meier method, and Cox proportional hazards regression analyses. RESULTS: Overall, the cohorts were well matched on clinical and pathological characteristics. No difference was noted in operative time (median 322 versus 303 min; p = 0.41), estimated blood loss (median 800 versus 700 cc, p = 0.10) or length of stay (median 9 versus 10 days; p = 0.09). Similarly, there were no differences in minor (51.7 versus 44.3%; p = 0.32) or major (10.3 versus 12.6%; p = 0.66) perioperative complications. Median follow-up after RC was 5.0 years (IQR 1.5, 13.1 years). Notably, CSS was significantly worse for patients who underwent RC after PC (10 year-46.8 versus 65.9%; p = 0.03). On multivariable analysis, prior PC remained independently associated with an increased risk of bladder cancer death (HR 2.28; 95% CI 1.17, 4.42). CONCLUSIONS: RC after PC is feasible, without significantly adverse perioperative outcomes compared to patients undergoing primary RC. However, the risk of death from bladder cancer may be higher, suggesting the need for careful patient counseling prior to PC and the consideration of such patients for adjuvant therapy after RC. PMID- 28913659 TI - Will Gay and Bisexual Men Taking Oral Pre-exposure Prophylaxis (PrEP) Switch to Long-Acting Injectable PrEP Should It Become Available? AB - Oral pre-exposure prophylaxis (PrEP) is highly effective at reducing HIV transmission risk and is CDC recommended for many gay, bisexual, and other men who have sex with men (GBM). We sought to investigate awareness of and preference for using long-acting injectable PrEP (LAI-PrEP) among GBM currently taking oral PrEP (n = 104), and identify their concerns. About half of GBM had heard of LAI PrEP, and 30.8% specifically preferred LAI-PrEP. GBM with more concerns about the level of protection and drug half-life of LAI-PrEP had lower odds of preferring LAI-PrEP. Given that daily pill adherence is a challenge for some on PrEP, it is important to investigate the degree to which those on PrEP might consider LAI PrEP as an alternative. PMID- 28913658 TI - Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice. AB - AIMS/HYPOTHESIS: The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Mice with global null mutation (Cc1 -/-) or with liver-specific inactivation (L-SACC1) of Cc1 (also known as Ceacam1) gene display hyperinsulinaemia resulting from impaired insulin clearance, insulin resistance, steatohepatitis and obesity. Because increased lipolysis contributes to the metabolic phenotype caused by transgenic inactivation of CEACAM1 in the liver, we aimed to further investigate the primary role of hepatic CEACAM1 dependent insulin clearance in insulin and lipid homeostasis. To this end, we examined whether transgenic reconstitution of CEACAM1 in the liver of global Cc1 /- mutant mice reverses their abnormal metabolic phenotype. METHODS: Insulin response was assessed by hyperinsulinaemic-euglycaemic clamp analysis and energy balance was analysed by indirect calorimetry. Mice were overnight-fasted and refed for 7 h to assess fatty acid synthase activity in the liver and the hypothalamus in response to insulin release during refeeding. RESULTS: Liver based rescuing of CEACAM1 restored insulin clearance, plasma insulin level, insulin sensitivity and steatohepatitis caused by global deletion of Cc1. It also reversed the gain in body weight and total fat mass observed with Cc1 deletion, in parallel to normalising energy balance. Mechanistically, reversal of hyperphagia appeared to result from reducing fatty acid synthase activity and restoring insulin signalling in the hypothalamus. CONCLUSIONS/INTERPRETATION: Despite the potential confounding effects of deleting Cc1 from extrahepatic tissues, liver-based rescuing of CEACAM1 resulted in full normalisation of the metabolic phenotype, underscoring the key role that CEACAM1-dependent hepatic insulin clearance pathways play in regulating systemic insulin sensitivity, lipid homeostasis and energy balance. PMID- 28913660 TI - Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else? AB - PURPOSE: This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET. METHODS: We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log binomial regression models were used to estimate relative risk for weight gain. RESULTS: The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03-1.52) and had Stage 3 BC (RR = 2.12, 1.59 2.82), mastectomy (RR = 1.49, 1.19-1.88), axillary node dissection (RR = 1.39, 1.11-1.73), and chemotherapy (RR = 1.80, 1.37-2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97-0.99, and RR = 0.99, 0.98 0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant. CONCLUSION: The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation. PMID- 28913662 TI - Effects of short-term exposure to sevoflurane on the survival, proliferation, apoptosis, and differentiation of neural precursor cells derived from human embryonic stem cells. AB - PURPOSE: Data from animal experiments suggest that exposure to general anesthetics in early life inhibits neurogenesis and causes long-term memory deficit. Considering short operating times and the popularity of sevoflurane in pediatric anesthesia, it is important to verify the effects of short-period exposure to sevoflurane on the developing brain. METHODS: We measured the effects of short-term exposure (2 h) to 3%, 6%, or 8% sevoflurane, the most commonly used anesthetic, on neural precursor cells derived from human embryonic stem cells, SNUhES32. Cell survival, proliferation, apoptosis, and differentiation on days 1, 3, 5, and 7 post treatment were analyzed. RESULTS: Treatment with 6% sevoflurane increased cell viability (P = 0.046) and decreased apoptosis (P = 0.014) on day 5, but the effect did not persist on day 7. Survival and apoptosis were not affected by 3% and 8% sevoflurane; there was no effect of proliferation at any of the tested concentrations. The differentiation of cells exposed to 6% or 8% sevoflurane decreased on day 1 (P = 0.033 and P = 0.036 for 6% and 8% sevoflurane, respectively) but was again normalized on days 3-7. CONCLUSION: Clinically relevant treatment with sevoflurane for 2 h induces no significant changes in the survival, proliferation, apoptosis, and differentiation of human neural precursor cells, although supraclinical doses of sevoflurane do alter human neurogenesis transiently. PMID- 28913661 TI - Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Abeta-induced mitochondrial dysfunction. AB - Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to beta amyloid (Abeta) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD). In this study, we generated an energy-based pharmacophore model by using the crystal structure of CypD-cyclosporine A (CsA) complex and performed virtual screening of ChemDiv database, which yielded forty-five potential hit compounds with novel scaffolds. We further tested those compounds using mitochondrial functional assays in neuronal cells and identified fifteen compounds with excellent protective effects against Abeta-induced mitochondrial dysfunction. To validate whether these effects derived from binding to CypD, we performed surface plasmon resonance (SPR)-based direct binding assays with selected compounds and discovered compound 29 was found to have the equilibrium dissociation constants (KD) value of 88.2 nM. This binding affinity value and biological activity correspond well with our predicted binding mode. We believe that this study offers new insights into the rational design of small molecule CypD inhibitors, and provides a promising lead for future therapeutic development. PMID- 28913663 TI - Effects of a Program to Promote High Quality Parenting by Divorced and Separated Fathers. AB - This paper reports on the effects on parenting and on children's mental health problems and competencies from a randomized trial of a parenting program for divorced and separated fathers. The program, New Beginnings Program-Dads (NBP Dads), includes ten group sessions (plus two phone sessions) which promote parenting skills to increase positive interactions with children, improve father child communication, use of effective discipline strategies, and skills to protect children from exposure to interparental conflict. The program was adapted from the New Beginnings Program, which has been tested in two randomized trials with divorced mothers and shown to strengthen mothers' parenting and improve long term outcomes for children (Wolchik et al. 2007). Fathers were randomly assigned to receive either NBP-Dads or a 2-session active comparison program. The sample consisted of 384 fathers (201 NBP-Dads, 183 comparisons) and their children. Assessments using father, youth, and teacher reports were conducted at pretest, posttest, and 10-month follow-up. Results indicated positive effects of NBP-Dads to strengthen parenting as reported by fathers and youth at posttest and 10-month follow-up. Program effects to reduce child internalizing problems and increase social competence were found at 10 months. Many of the program effects were moderated by baseline level of the variable, child age, gender, and father ethnicity. This is the first randomized trial to find significant effects to strengthen father parenting following divorce. In view of recent changes in family courts to allot fathers increasing amounts of parenting time following divorce, the results have significant implications for improving outcomes for children from divorced families. PMID- 28913664 TI - Supplementation of enzyme-treated soy protein saves dietary protein and promotes digestive and absorptive ability referring to TOR signaling in juvenile fish. AB - This study was conducted to evaluate the effect of enzyme-treated soy protein (ETSP) supplementation in the low-protein diet on growth performance, digestive and absorptive capacities, and related signaling molecules' gene expressions in juvenile Jian carp. The results showed that percent weight gain (PWG), specific growth rate (SGR), and feed intake (FI) were decreased by reducing dietary protein from 34 to 32% (P < 0.05). Supplying low-protein diet with optimal ETSP increased previously mentioned indices of juvenile Jian carp (P < 0.05), which also had no significant difference with the high-protein diet (34%CP) (P > 0.05). Compared with the low-protein diet, appropriate ETSP supplementation in the low protein diet increased (P < 0.05) (1) the trypsin, lipase, and amylase activities in the hepatopancreas; (2) cholecystokinin concentration in the proximal intestine; (3) the gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (AKP), and Na+/K+-ATPase activities in all intestinal segments; and (4) the messenger RNA (mRNA) levels of trypsin, lipase, and amylase in hepatopancreas and gamma-GT in the mid (MI) and distal (DI) intestine, alkaline phosphatase in MI, and Na+/K+-ATPase and target of rapamycin in all intestinal segments. At the same time, appropriate ETSP supplementation in the low-protein diet downregulated the mRNA levels of AKP in the DI and eIF4E-binding protein 2 in all intestinal segments (P < 0.05). In conclusion, adding 10 g ETSP/kg diet in the low-protein diet can restore the growth performance and digestive and absorptive abilities to the levels in group with 34% dietary protein. Supplementation of optimal ETSP in the low-protein diet enhanced the digestive and absorptive abilities and regulated the signaling molecules related to the TOR signaling pathway. PMID- 28913665 TI - Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases. AB - Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future. PMID- 28913666 TI - Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system. AB - The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we developed a quantitative mathematical model describing the intracellular trafficking. Dynamics of the prodrug and the model predictions were verified with experimental data using human cancer cells in vitro. The sensitivity analysis suggested that parameters related to extracellular concentration of released PTX, prodrug uptake, target engagement, and target abundance are critical in determining the combined killing efficacy of the prodrug. We found that released PTX cytotoxicity was most sensitive to the retention time of the drug in extracellular space. Modulating drug internalization and conjugating the agents targeted to abundant receptors may provide a new strategy for maximizing the killing capacity of the far-red light-activatable prodrug system. These results provide guidance for the design of the PDT combination study in vivo and have implications for other stimuli-responsive drug delivery systems. PMID- 28913667 TI - Microsurgical versus endoscopic transsphenoidal resection for acromegaly: a systematic review of outcomes and complications. AB - PURPOSE: The aim of this systematic review is to evaluate the long-term endocrine outcomes and postoperative complications following endoscopic vs. microscopic transsphenoidal resection (TSR) for the treatment of acromegaly. METHODS: A literature review was performed, and studies with at least five patients who underwent TSR for acromegaly, reporting biochemical remission criteria and long term remission outcomes were included. Data extracted from each study included surgical technique, perioperative complications, biochemical remission criteria, and long-term remission outcomes. RESULTS: Fifty-two case series from 1976 to 2016 met the inclusion criteria, comprising 4375 patients. Thirty-six reports were microsurgical (n = 3144) and 13 were endoscopic (n = 940). Three studies compared microsurgical (n = 111) to endoscopic TSR outcomes (n = 180). The overall initial and long-term remission rates were 58.2 vs. 57.4% and 69.2 vs. 70.2% for the microsurgical and endoscopic groups, respectively. For microadenomas, the initial and long-term remission rates were 77.6 vs. 82.2% and 76.9 vs. 73.5% for microsurgical and endoscopic approaches, respectively. For macroadenomas, the initial and long-term remission rates were 46.9 vs. 60.0% and 40.2 vs. 61.5% for microsurgical and endoscopic approaches, respectively. The rates of postoperative CSF leak were 3.0 vs. 2.3% for the microscopic and endoscopic groups, respectively. The rates of hypopituitarism and transient diabetes insipidus were 6.7 vs. 6.4% and 9.0 vs. 7.8% for the microscopic and endoscopic groups, respectively. CONCLUSIONS: Both endoscopic and microsurgical approaches for TSR of growth hormone-secreting adenomas are viable treatment options for patients with acromegaly, and yield similarly high rates of remission under the most current consensus criteria. PMID- 28913668 TI - Floral features of two species of Bulbophyllum section Lepidorhiza Schltr.: B. levanae Ames and B. nymphopolitanum Kraenzl. (Bulbophyllinae Schltr., Orchidaceae). AB - Two representatives of section Lepidorhiza, previously sometimes considered conspecific, Bulbophyllum levanae and Bulbophyllum nymphopolitanum, demonstrated both similarities and differences in floral features. There were significant differences in the length of sepals and micromorphological features of the labellum. In both species, osmophores are located on the extended apices of sepals and possibly on petals. An abundance of proteins in tepals is probably associated with the unpleasant scent of the flowers, whereas the thin wax layers on the epidermis are probably involved in the maintenance of the brilliance of floral tepals, which strongly attracts flies. In all tepals of both species, we noted the presence of dihydroxyphenolic globules in the cytoplasm after staining with FeCl3. Comparison with ultrastructure results revealed that they were associated with plastids containing plastoglobuli. The most remarkable feature was the presence of a prominent periplasmic space in the epidermal cells of both investigated species. Furthermore, in the labellum of B. levanae, the cuticle contained microchannels. The combination of periplasmic space and microchannels has not previously been recorded. PMID- 28913670 TI - Tension Gastrothorax and Hemodynamic Collapse due to Gastric Outlet Obstruction in a Paraesophageal Hernia. PMID- 28913669 TI - Resolving distinct molecular origins for copper effects on PAI-1. AB - Components of the fibrinolytic system are subjected to stringent control to maintain proper hemostasis. Central to this regulation is the serpin plasminogen activator inhibitor-1 (PAI-1), which is responsible for specific and rapid inhibition of fibrinolytic proteases. Active PAI-1 is inherently unstable and readily converts to a latent, inactive form. The binding of vitronectin and other ligands influences stability of active PAI-1. Our laboratory recently observed reciprocal effects on the stability of active PAI-1 in the presence of transition metals, such as copper, depending on the whether vitronectin was also present (Thompson et al. Protein Sci 20:353-365, 2011). To better understand the molecular basis for these copper effects on PAI-1, we have developed a gel-based copper sensitivity assay that can be used to assess the copper concentrations that accelerate the conversion of active PAI-1 to a latent form. The copper sensitivity of wild-type PAI-1 was compared with variants lacking N-terminal histidine residues hypothesized to be involved in copper binding. In these PAI-1 variants, we observed significant differences in copper sensitivity, and these data were corroborated by latency conversion kinetics and thermodynamics of copper binding by isothermal titration calorimetry. These studies identified a copper-binding site involving histidines at positions 2 and 3 that confers a remarkable stabilization of PAI-1 beyond what is observed with vitronectin alone. A second site, independent from the two histidines, binds metal and increases the rate of the latency conversion. PMID- 28913671 TI - The Effect of Educational Program Based on PRECEDE Model in Promoting Prostate Cancer Screening in a Sample of Iranian Men. AB - Prostate cancer is one of the most prevalent diseases among men. This study aimed to assess the effect of educational program based on Predisposing, Reinforcing, and Enabling Constructs in Educational/Environmental Diagnosis and Evaluation (PRECEDE) model in promoting prostate cancer screening in a sample of Iranian men. This is a quasi-experimental study carried out on 300 men aged 40 to 70 (the subjects 150 experimental and 150 control groups) in Shiraz City, Fars Province, Iran, in 2016. The participants of the intervention group attended training based on the PRECEDE model. The study compared mean scores of knowledge, attitude, enabling factors, perceived social support, quality of life, general health, self efficacy, and screening behaviors of the subjects before and 6 months after intervention in experimental and control groups. The mean age of experimental group was 56.45 +/- 8.65, and the mean age of the control group was 55.64 +/- 8.71 years (P = 0.521). The study showed that there was a significant increase in the mean score of knowledge, attitudes, perceived self-efficacy, enabling factors, perceived social support, quality of life, public health and screening behaviors of the experimental group; however, no significant change was observed in the mean score of knowledge, attitudes, self-efficacy, quality of life, general health, perceived social support, enabling factors, and screening behaviors of the control group. Our findings showed that the health education programs designed based on PRECEDE could positively affect prostate cancer screening behaviors of individuals by improving their knowledge level and attitude, enabling factors, perceived social support, quality of life, general health, and self-efficacy. PMID- 28913672 TI - Reversal of dabigatran-associated bleeding using idarucizumab: review of the current evidence. AB - Major bleeding occurs in about 4% of patients while on treatment with direct oral anticoagulants (DOACs). The case-fatality rate associated with these events is estimated to be about 5%. The specific roles of antidotes, when used with DOACs in reducing the case fatality or improving the overall clinical course of these events, are not thoroughly understood. To this regard, the US Food and Drug Administration as well as European Medicines Agency have recently licensed idarucizumab for the management of patients with life-threatening bleeding or the need for urgent surgery/procedures while on treatment with dabigatran. Specifically, idarucizumab is a humanized monoclonal antibody fragment that rapidly reverses the anticoagulant effect of dabigatran. Two other antidotes, andeXanet and ciraparantag are currently under evaluation for reversal of DOACs. Here, we report on the use of idarucizumab in two patients who experienced life threatening bleeding while on treatment with dabigatran for atrial fibrillation and provide a review highlighting the need for antidotes use with DOACs. PMID- 28913673 TI - Multiple non-catalytic ADAMs are novel integrin alpha4 ligands. AB - The ADAM (a disintegrin and metalloprotease) protein family uniquely exhibits both catalytic and adhesive properties. In the well-defined process of ectodomain shedding, ADAMs transform latent, cell-bound substrates into soluble, biologically active derivatives to regulate a spectrum of normal and pathological processes. In contrast, the integrin ligand properties of ADAMs are not fully understood. Emerging models posit that ADAM-integrin interactions regulate shedding activity by localizing or sequestering the ADAM sheddase. Interestingly, 8 of the 21 human ADAMs are predicted to be catalytically inactive. Unlike their catalytically active counterparts, integrin recognition of these "dead" enzymes has not been largely reported. The present study delineates the integrin ligand properties of a group of non-catalytic ADAMs. Here we report that human ADAM11, ADAM23, and ADAM29 selectively support integrin alpha4-dependent cell adhesion. This is the first demonstration that the disintegrin-like domains of multiple catalytically inactive ADAMs are ligands for a select subset of integrin receptors that also recognize catalytically active ADAMs. PMID- 28913675 TI - Diagnostic utility of 18FDG-PET/CT for ADPKD cyst infection. PMID- 28913674 TI - Prognostic significance of corticotroph staining in radiosurgery for non functioning pituitary adenomas: a multicenter study. AB - Silent corticotroph staining pituitary adenoma (SCA) represents an uncommon subset of Non-Functioning adenomas (NFAs), hypothesized to be more locally aggressive. In this retrospective multicenter study, we investigate the safety and effectiveness of Stereotactic Radiosurgery (SRS) in patients with SCA compared with other non-SCA NFA's. Eight centers participating in the International Gamma-Knife Research Foundation (IGKRF) contributed to this study. Outcomes of 50 patients with confirmed SCAs and 307 patients with confirmed non SCA NFA's treated with SRS were evaluated. Groups were matched. SCA was characterized by a lack of clinical evidence of Cushing disease, yet with positive immunostaining for corticotroph. Median age was 55.2 years (13.7-87). All patients underwent at least one trans-sphenoidal tumor resection prior to SRS. SRS parameters were comparable as well. Median follow-up 40 months (6-163). Overall tumor control rate (TCR) 91.2% (n = 280). In the SCA group, TCR were 82% (n = 41) versus 94.1% (n = 289) for the control-NFA (p = 0.0065). The SCA group showed a significantly higher incidence of new post-SRS visual deficit (p < 0.0001) assigned to tumor progression and growth, and post-SRS weakness and fatigue (p < 0.0001). In univariate and multivariate analysis, only the status of silent corticotroph staining (p = 0.005, p = 0.009 respectively) and margin dose (p < 0.0005, p = 0.0037 respectively) significantly influenced progression rate. A margin dose of >=17 Gy was noted to influence the adenoma progression rate in the entire cohort (p = 0.003). Silent corticotroph staining represents an independent factor for adenoma progression and hypopituitarism after SRS. A higher margin dose may convey a greater chance of TCR. PMID- 28913676 TI - The Cost of Being Cool: How Adolescent Pseudomature Behavior Maps onto Adult Adjustment. AB - During adolescence, one's status among peers is a major concern. Such status is often largely a function of popularity and establishing oneself as "cool." While there are conventional avenues to achieving status among adolescents, engaging in adult-like, or pseudomature, behaviors such as substance use or sexual activity is a frequent occurrence. Although past research has examined the consequences of adolescent delinquency, what remains unclear is the long-term fate of adolescents who are both popular and antisocial. Using data from a sample of African American males (N = 339) we employ latent class analysis to examine the adult consequences of achieving popularity during adolescence by engaging in pseudomature behavior. Our results identified four classes of adolescents: the conventionals, the pseudomatures, the delinquents, and the detached. The conventionals were low on popularity, pseudomature behavior, and affiliation with deviant peers but high on academic commitment. The pseudomatures were high on popularity, adult-like behavior, and academic commitment but low on affiliation with delinquent peers. The delinquents were low on popularity and school achievement but high on pseudomature behavior and affiliations with delinquent peers. Finally, the detached were low on school commitment, popularity and pseudomature behavior but they report high involvement with a delinquent peer group. By early adulthood, the costs of adolescent adult-like behavior were evident. Early popularity and academic commitment did not portend later social competence or college completion for the pseudomatures. Instead, they frequently experienced an early transition to parenthood, a likely consequence of precocious sexual activity. These findings suggest that interventions should not focus only on the most delinquent adolescents but also need to attend to the pseudomature students who are brimming with promise but are flirting with behaviors that may subvert realization of this potential. PMID- 28913677 TI - Thus Far and No Further: Should Diastolic Hypotension Limit Intensive Blood Pressure Lowering? AB - OPINION STATEMENT: Intensive blood pressure lowering to systolic blood pressure thresholds of less than 120 mmHg is making a slow comeback with the publication of trials supporting its benefit, especially in lowering stroke and congestive heart failure. At the same time, there is an increasing awareness of the prevalence and risk of diastolic hypotension, especially at levels of less than 60 mmHg, with support for the existence of a J-curve coming from post hoc analyses of trials and epidemiological data from large cohort studies. Hence, intensive lowering of systolic blood pressure should be done cautiously in those patients who have pre-existing coronary artery disease, and a diastolic blood pressure between 60 and 70 mmHg. Among those with diastolic blood pressure already below 60 mmHg, but whose systolic blood pressure is not at target, we recommend shared decision-making with an explicit discussion of the risks and benefits, and taking patient preferences into account. Further research with biomarkers and risk models exploring heterogeneity of outcomes might allow for more precise targeting of intensive blood pressure lowering in individuals most likely to benefit, with avoiding those most likely to harm. PMID- 28913678 TI - Comparison of point-source pollutant loadings to soil and groundwater for 72 chemical substances. AB - Fate and transport of 72 chemicals in soil and groundwater were assessed by using a multiphase compositional model (CompFlow Bio) because some of the chemicals are non-aqueous phase liquids or solids in the original form. One metric ton of chemicals were assumed to leak in a stylized facility. Scenarios of both surface spills and subsurface leaks were considered. Simulation results showed that the fate and transport of chemicals above the water table affected the fate and transport of chemicals below the water table, and vice versa. Surface spill scenarios caused much less concentrations than subsurface leak scenarios because leaching amounts into the subsurface environment were small (at most 6% of the 1 t spill for methylamine). Then, simulation results were applied to assess point source pollutant loadings to soil and groundwater above and below the water table, respectively, by multiplying concentrations, impact areas, and durations. These three components correspond to the intensity of contamination, mobility, and persistency in the assessment of pollutant loading, respectively. Assessment results showed that the pollutant loadings in soil and groundwater were linearly related (r 2 = 0.64). The pollutant loadings were negatively related with zero order and first-order decay rates in both soil (r = - 0.5 and - 0.6, respectively) and groundwater (- 1.0 and - 0.8, respectively). In addition, this study scientifically defended that the soil partitioning coefficient (K d) significantly affected the pollutant loadings in soil (r = 0.6) and the maximum masses in groundwater (r = - 0.9). However, K d was not a representative factor for chemical transportability unlike the expectation in chemical ranking systems of soil and groundwater pollutants. The pollutant loadings estimated using a physics-based hydrogeological model provided a more rational ranking for exposure assessment, compared to the summation of persistency and transportability scores in the chemical ranking systems. In the surface spill scenario, the pollutant loadings were zeros for all chemicals, except methylamine to soil whose pollutant loading was smaller than that in the subsurface leak scenario by 4 orders of magnitude. The maximum mass and the average mass multiplied by duration in soil greatly depended on leaching fluxes (r = 1.0 and 0.9, respectively), while the effect of leaching fluxes diminished below the water table. The contribution of this work is that a physics-based numerical model was used to quantitatively compare the subsurface pollutant loading in a chemical accident for 72 chemical substances, which can scientifically defend a simpler and more qualitative assessment of pollutant loadings. Besides, this study assessed pollutant loadings to soil (unsaturated zone) and groundwater (saturated zone) all together and discussed their interactions. PMID- 28913679 TI - Erratum to: Towards Robot-Assisted Echocardiographic Monitoring in Catheterization Laboratories : Usability-Centered Manipulator for Transesophageal Echocardiography. PMID- 28913680 TI - UV-C as an efficient means to combat biofilm formation in show caves: evidence from the La Glaciere Cave (France) and laboratory experiments. AB - Ultra-violet C (UV-C) treatment is commonly used in sterilization processes in industry, laboratories, and hospitals, showing its efficacy against microorganisms such as bacteria, algae, or fungi. In this study, we have eradicated for the first time all proliferating biofilms present in a show cave (the La Glaciere Cave, Chaux-les-Passavant, France). Colorimetric measurements of irradiated biofilms were then monitored for 21 months. To understand the importance of exposition of algae to light just after UV radiation, similar tests were carried out in laboratory conditions. Since UV-C can be deleterious for biofilm support, especially parietal painting, we investigated their effects on prehistoric pigment. Results showed complete eradication of cave biofilms with no algae proliferation observed after 21 months. Moreover, quantum yield results showed a decrease directly after UV-C treatment, indicating inhibition of algae photosynthesis. Furthermore, no changes in pigment color nor in chemical and crystalline properties has been demonstrated. The present findings demonstrate that the UV-C method can be considered environmentally friendly and the best alternative to chemicals. This inexpensive and easily implemented method is advantageous for cave owners and managers. PMID- 28913681 TI - Calculation of intercepted runoff depth based on stormwater quality and environmental capacity of receiving waters for initial stormwater pollution management. AB - While point source pollutions have gradually been controlled in recent years, the non-point source pollution problem has become increasingly prominent. The receiving waters are frequently polluted by the initial stormwater from the separate stormwater system and the wastewater from sewage pipes through stormwater pipes. Consequently, calculating the intercepted runoff depth has become a problem that must be resolved immediately for initial stormwater pollution management. The accurate calculation of intercepted runoff depth provides a solid foundation for selecting the appropriate size of intercepting facilities in drainage and interception projects. This study establishes a separate stormwater system for the Yishan Building watershed of Fuzhou City using the InfoWorks Integrated Catchment Management (InfoWorks ICM), which can predict the stormwater flow velocity and the flow of discharge outlet after each rainfall. The intercepted runoff depth is calculated from the stormwater quality and environmental capacity of the receiving waters. The average intercepted runoff depth from six rainfall events is calculated as 4.1 mm based on stormwater quality. The average intercepted runoff depth from six rainfall events is calculated as 4.4 mm based on the environmental capacity of the receiving waters. The intercepted runoff depth differs when calculated from various aspects. The selection of the intercepted runoff depth depends on the goal of water quality control, the self-purification capacity of the water bodies, and other factors of the region. PMID- 28913682 TI - [Therapeutic options in hyperlipidemia]. AB - Treatment of lipid disorders (dyslipidemia) is the cornerstone of atherosclerosis prevention and reduction of progression. Lifestyle modification is the first step to improve the plasma lipid profile. Statins play a central role in the reduction of LDL cholesterol. Whether and to what extent other lipids such as triglycerides or lipoprotein(a) should also be treated depends on the extent of atherosclerotic disease and its progression over time. Especially in residential cardiac rehabilitation we have the opportunity to encourage adherence and adapt medication as necessary due to a face to face contact over 4 weeks. Moreover, the prescription for a PCSK9-inhibitor could be resolved or the indication for a lipoprotein apheresis could be considered. PMID- 28913684 TI - [Telemedicine in stroke care]. AB - Telemedicine is already widely used in many telestroke networks and ensures stroke treatment close to the patient's home in rural and medically underserved areas. This is particularly effective when telemedicine is integrated into a stroke unit concept. While telemedically based thrombolysis therapy has become routine practice for many years, practical implementation of comprehensive mechanical thrombectomy and the related processes remains challenging. The main tasks for the future further include development of a structured stroke aftercare system in neurologically underserved areas and permanent assurance of high quality stroke care in telemedically connected sites. PMID- 28913685 TI - [Ramp lesions : Tips and tricks in diagnostics and therapy]. AB - There is an increasing biomechanical and anatomical understanding of the different types of meniscal lesions. Lesions of the posterior part of the medial meniscus in the meniscosynovial area have recently received increased attention. They generally occur in association with anterior cruciate ligament (ACL) injuries. They are often missed ("hidden lesions") due to the fact that they cannot be seen by routine anterior arthroscopic inspection. Furthermore, meniscosynovial lesions play a role in anteroposterior knee laxity and, as such, they may be a cause of failure of ACL reconstruction or of postoperative persistent laxity. Little information is available regarding their cause with respect to injury mechanism, natural history, biomechanical implications, healing potential and treatment options. This article presents an overview of the currently available knowledge of these ramp lesions, their possible pathomechanism, classification, biomechanical relevance as well as repair techniques. PMID- 28913688 TI - The Effects of Condom Availability on College Women's Sexual Discounting. AB - College students commonly engage in risky sexual behaviors, such as casual sexual encounters and inconsistent condom use. Discounting paradigms that examine how individuals devalue rewards due to their delay or uncertainty have been used to improve our understanding of behavioral problems, including sexual risk. The current study assessed relations between college women's sexual partners discounting and risky sexual behavior. In this study, college women (N = 42) completed two sexual partners delay discounting tasks that assessed how choices among hypothetical sexual partners changed across a parametric range of delays in two conditions: condom availability and condom unavailability. Participants also completed two sexual partners probability discounting tasks that assessed partner choices across a parametric range of probabilities in condom availability and unavailability conditions. Additionally, participants reported risky sexual behavior on the Sexual Risk Survey (SRS). Participants discounted delayed partners more steeply in the condom availability condition, but those differences were significant only for those women with three or fewer lifetime sexual partners. There were no consistent differences in discounting rate across condom availability conditions for probability discounting. Sexual partners discounting measures correlated with risky sexual behaviors as measured by the SRS, but a greater number of significant relations were observed with the condoms unavailable delay discounting task. These findings suggest the importance of examining the interaction of inconsistent condom use and multiple partners in examinations of sexual decision-making. PMID- 28913686 TI - Pretreatment quality of life in patients with rectal cancer is associated with intrusive thoughts and sense of coherence. AB - PURPOSE: Quality of life may predict survival. In addition to clinical variables, it may be influenced by psychological factors, some of which may be accessible for intervention. The primary objective of this study was to investigate the association of intrusive thoughts and the patients' sense of coherence with pretreatment quality of life in patients with newly diagnosed rectal cancer. METHODS: Patients were prospectively included in 16 hospitals in Sweden and Denmark. They answered an extensive questionnaire after receiving their treatment plan. Clinical data were retrieved from national quality registries for rectal cancer. RESULTS: Of 1248 included patients, a total of 1085 were evaluable. Pretreatment global health-related and overall quality of life was lower in patients planned for palliative compared with curative treatment (median 53 vs. 80 on the EuroQoL visual analogue scale, p < 0.001 and odds ratio 0.56, 95% confidence interval 0.36-0.88, respectively). Quality of life was associated with intrusive thoughts (odds ratio 0.33, 95% confidence interval 0.24-0.45) and sense of coherence (odds ratio 0.44, 95% confidence interval 0.37-0.52) irrespective of the treatment plan. CONCLUSIONS: Pretreatment quality of life was influenced by the intent of treatment as well as by intrusive thoughts and the patients' sense of coherence. Interventions could modify these psychological factors, and future studies should focus on initiatives to improve quality of life for this group of patients. PMID- 28913687 TI - Non-Atherosclerotic Vascular Disease in Women. AB - OPINION STATEMENT: Takayasu arteritis, fibromuscular dysplasia (FMD), spontaneous arterial dissection, Raynaud's phenomenon, and chilblains are vascular conditions that are associated with an increased predisposition in women and are often underdiagnosed. Takayasu arteritis has an incidence rate of 2.6 cases per million individuals per year in the USA and predominantly affects women of childbearing age. HLA-B5 genetic locus is linked with Takayasu arteritis susceptibility. Methods to determine active disease are limiting; currently utilized clinical and imaging findings and laboratory tests are of limited value for this purpose. Pregnancy poses risks for maternal and fetal complications, and these patients need additional monitoring and care before and after conception. Controlling hypertension and immunosuppression using steroids, biological and non-biological immunosuppressants, are key components of managing patients with this arteritis. FMD commonly affects middle-aged, white females. Its true prevalence is unknown. Renal and cerebrovascular beds are the most frequently involved vascular beds. Its clinical presentation varies from no symptoms to catastrophic events. Controlling vascular risk factors, periodic surveillance, and revascularization when indicated are important factors in FMD management. Spontaneous arterial dissections are less common, but are an important cause of morbidity and mortality in specific populations. Cervicocephalic dissection causes 10-20% of the strokes in young adults, and coronary artery dissection is the culprit in almost one fourth of young women presenting with acute myocardial infarction. Early diagnosis is key to improving prognosis in these patients, as the majority of patients have spontaneous resolution of the dissection with conservative management alone. Increased clinician awareness of the presentation features and angiographic findings are imperative for early diagnosis. Raynaud's phenomenon and chilblains are cold- or stress-induced cutaneous lesions, commonly involving distal extremities. Secondary causes such as connective tissue diseases and malignancies must be thoroughly excluded during evaluation of these conditions. Cold avoidance, systemic and local warming, and oral vasodilator therapy are the mainstays of therapy. PMID- 28913689 TI - The evaluation of protective effect of lycopene against genotoxic influence of X irradiation in human blood lymphocytes. AB - Many studies suggest that exogenous antioxidants may protect cells against DNA damage caused with ionizing radiation. One of the most powerful antioxidants is lycopene (LYC), a carotenoid derived from tomatoes. The aim of this study was to investigate, using the comet assay, whether LYC can act as protectors/modifiers and prevent DNA damage induced in human blood lymphocytes, as well as to mitigate the effects of radiation exposure. In this project, LYC, dissolved in DMSO at a concentration of 10, 20 or 40 MUM/ml of cell suspension, was added to the isolated lymphocytes from human blood at appropriate intervals before or after the X-irradiation at doses of 0.5, 1 and 2 Gy. Cell viability in all groups was maintained at above 70%. The results showed the decrease of DNA damage in cells treated with various concentrations of LYC directly and 1 h before exposure to X rays compared to the control group exposed to irradiation alone. Contrary results were observed in cells exposed to LYC immediately after exposure to ionizing radiation. The studies confirmed the protective effect of LYC against DNA damage induced by ionizing radiation, but after irradiation the carotenoid did not stimulate of DNA repair and cannot act as modifier. However, supplementation with LYC, especially at lower doses, may be useful in protection from radiation induced oxidative damage. PMID- 28913690 TI - Natural manganese ore catalyst for low-temperature selective catalytic reduction of NO with NH3 in coke-oven flue gas. AB - Different types of manganese ore raw materials were prepared for use as catalysts, and the effects of different manganese ore raw materials and calcination temperature on the NO conversion were analyzed. The catalysts were characterized by XRF, XRD, BET, XPS, H2-TPR, NH3-TPD, and SEM techniques. The results showed that the NO conversion of calcined manganese ore with a Mn:Fe:Al:Si ratio of 1.51:1.26:0.34:1 at 450 degrees C reached 80% at 120 degrees C and 98% at 180~240 degrees C. The suitable proportions and better dispersibility of active ingredients, larger BET surface area, good reductibility, a lot of acid sites, contents of Mn4+ and Fe3+, and surface adsorbed oxygen played important roles in improving the NO conversion. PMID- 28913683 TI - An Evidence Map of the Women Veterans' Health Research Literature (2008-2015). AB - BACKGROUND: Women comprise a growing proportion of Veterans seeking care at Veterans Affairs (VA) healthcare facilities. VA initiatives have accelerated changes in services for female Veterans, yet the corresponding literature has not been systematically reviewed since 2008. In 2015, VA Women's Health Services and the VA Women's Health Research Network requested an updated literature review to facilitate policy and research planning. METHODS: The Minneapolis VA Evidence based Synthesis Program performed a systematic search of research related to female Veterans' health published from 2008 through 2015. We extracted study characteristics including healthcare topic, design, sample size and proportion female, research setting, and funding source. We created an evidence map by organizing and presenting results within and across healthcare topics, and describing patterns, strengths, and gaps. RESULTS: We identified 2276 abstracts and assessed each for relevance. We excluded 1092 abstracts and reviewed 1184 full-text articles; 750 were excluded. Of 440 included articles, 208 (47%) were related to mental health, particularly post-traumatic stress disorder (71 articles), military sexual trauma (37 articles), and substance abuse (20 articles). The number of articles addressing VA priority topic areas increased over time, including reproductive health, healthcare organization and delivery, access and utilization, and post-deployment health. Three or fewer articles addressed each of the common chronic diseases: diabetes, hypertension, depression, or anxiety. Nearly 400 articles (90%) used an observational design. Eight articles (2%) described randomized trials. CONCLUSIONS: Our evidence map summarizes patterns, progress, and growth in the female Veterans' health and healthcare literature. Observational studies in mental health make up the majority of research. A focus on primary care delivery over clinical topics in primary care and a lack of sex-specific results for studies that include men and women have contributed to research gaps in addressing common chronic diseases. Interventional research using randomized trials is needed. PMID- 28913691 TI - Intestinal Mechanomorphological Remodeling Induced by Long-Term Low-Fiber Diet in Rabbits. AB - Short-term feeding with low-fiber diet remodels the mechanomorphological properties in the rabbit small intestine. The aims were to study the effect of feeding low-fiber diet for 5 months on mechanomorphological properties including the collagen fraction in the rabbit intestines. Fifteen rabbits were divided into an Intervention group (IG, n = 10) fed a low-fiber diet and a Control group (CG, n = 5) fed a normal diet for 5 months. Five months later, four 10-cm-long segments obtained from the duodenum, jejunum, ileum and large intestine were used for histological and mechanical analysis, respectively. The wall thickness, wall area, mucosa and muscle layer thickness decreased whereas the submucosa layer thickness increased in the IG (p < 0.05). The collagen fraction decreased in all layers and segments in the IG (p < 0.05). The opening angle increased in the large intestine and decreased in the ileum in the IG (p < 0.05). The intestinal stress-strain curves for IG shifted to the right, indicating softening. The creep did not change in the four segments. The wall stiffness was associated with wall thickness and collagen fraction in the submucosa layer. Long-term low-fiber diet in rabbits induced histomorphometric and biomechanical remodelling of the intestines. PMID- 28913692 TI - Nanotechnology and water purification: Indian know-how and challenges. AB - Water contamination being ubiquitous problem across the world. A significant strata of population worldwide are still struggling to get drinkable water. This demand to develop technologies to provide clean water at affordable price is unveiling the need of rigorous research in this area. There are several technologies available for removal of persistent as well as emerging pollutants from water. Nanotechnology-based technology are providing the promising solution because of its extraordinary characteristics like large surface area, low cost maintenance and reuse, etc. During the past decade, there is an advancement in the field of nanotechnology and diligent efforts of researchers in achieving milestones in developing nanosorbents, nanostructured catalytic membranes, efficient photo catalysts, bioactive nanoparticles and new filtration regime. This article gives an overview of nanotechnology applications in water purification in India with an attempt to ponder indigenous technologies for implementation. A bibliometric approach is applied to bring the indigenous technologies available. In addition, we discuss some challenges associated with the development of convincing material and building water processing plants for purification of the wastewater. PMID- 28913693 TI - Human papillomavirus genotype distribution in cervical samples among vaccine naive Barbados women. AB - PURPOSE: This study was undertaken to provide baseline HPV genotype distribution among women in Barbados before HPV immunization was introduced. This information would then be used as a denominator for post-vaccine surveillance and is expected to aid in understanding the effect of vaccination on cervical disease in Barbados. METHODS: Liquid-based cytology specimens were collected from 413 women (age range 18-65 years) attending three clinics, in a pre-vaccination, population based study. After consent was obtained, sexual behavior and socio-demographic information were acquired from self-administered questionnaires. HPV types were detected using Luminex-based HPV PCR genotyping methodology. RESULTS: HPV was detected in 33% (135/413) of the subjects overall (95% CI 32.7, 33.37), of which 70% (95/135) were high-risk types, with 35 different types being detected in this population. Single and multiple high-risk HPV types were detected in 14% (13/95) and 31% (29/95) of the subjects, respectively. The most common high-risk HPV types detected were 45(n = 22, 23%), 16 (n = 17, 18%), 52 (n = 16, 17%), and 58 (n = 10, 11%). Persons with the highest level of infection by age were 21-25 (n = 25/135;19%; 95% CI 18.8, 19.3); 26-30 (n = 22/135;16%; 95% CI 15.9, 16.2); 31-35 (n = 19/135;14%; 95% CI 13.9, 14.2); 36-40 (n = 17/135;13%; 95% CI 12.2, 13.2), and 18-21 (n = 15/135;11%; 95% CI 10.9, 11.2). 91/413 (22%) persons had a normal cytology result. CONCLUSION: A high prevalence of HPV type 45 was found in the screening population of women in Barbados. The results of cytological examinations and HPV positivity suggest that both tests should be used for greater reliable diagnosis of HPV infection. PMID- 28913695 TI - Comparison of helminth community of Apodemus agrarius and Apodemus flavicollis between urban and suburban populations of mice. AB - The growing human population and the development of urban areas have led to fragmentation and destruction of many natural habitats but have also created new urban habitats. These environmental changes have had a negative impact on many species of plants and animals, including parasite communities. The aim of present study was to compare the helminth communities of Apodemus flavicollis and Apodemus agrarius in natural and urban habitats. Helminth burdens were assessed in 124 mice, 48 A. flavicollis, and 76 A. agrarius from two managed forests close to the city boundaries and two city parks within Warsaw, Central Poland. In total, eight species of helminths, Nematoda (n = 3), Digenea (n = 2), and Cestoda (n = 3), were identified. Helminth community structure and prevalence/abundance of individual helminth species differed significantly between the two Apodemus species. Overall, prevalence and abundance of helminth species were significantly higher in A. agrarius compared to A. flavicollis. For A. flavicollis, higher prevalence and abundance of helminths were detected in individuals from managed forest habitats in comparison to city parks. In striped field mice, much higher prevalence and mean abundance were recorded in rodents trapped in city parks than in managed forests. This phenomenon may be explained by better adaptation of A. agrarius, compared to A. flavicollis, to city habitats, resulting in high local densities of mice and the full range of parasite species affecting this host species. Our data confirm also that the established routes of infection exist for selected helminth species in the urban environment. PMID- 28913694 TI - Emergency Neurological Life Support: Traumatic Spine Injury. AB - Traumatic spine injuries (TSIs) carry significantly high risks of morbidity, mortality, and exorbitant health care costs from associated medical needs following injury. For these reasons, TSI was chosen as an ENLS protocol. This article offers a comprehensive review on the management of spinal column injuries using the best available evidence. Though the review focuses primarily on cervical spinal column injuries, thoracolumbar injuries are briefly discussed as well. The initial emergency department (ED) clinical evaluation of possible spinal fractures and cord injuries, along with the definitive early management of confirmed injuries, are also covered. PMID- 28913696 TI - Clinicopathological Risk Factors for Distant Metastasis in Differentiated Thyroid Carcinoma: A Meta-analysis. AB - INTRODUCTION: Distant metastasis (DM) is not a frequent event in differentiated thyroid carcinoma (DTC) but has an adverse impact on mortality of patients with DTC. In the current study, we aimed to conduct a comprehensive systematic review and meta-analysis to investigate the risk factors for DM in DTCs and for each histological subtype. METHODS: Five electronic databases were searched from inception to December 2016 for relevant articles. Pooled odd ratios and 95% confidence interval were calculated using random-effect model. RESULTS: Thirty four articles with 73,219 patients were included for meta-analyses. In DTCs, male gender, age >=45 years, tumor size >=4 cm, multifocality, vascular invasion (VI), extrathyroidal extension (ETE), lymph node metastasis (LNM), and lateral LNM were demonstrated to be associated with significant risks for DM. In addition, several clinicopathological factors such as age >=45 years, VI, ETE, and LNM were shown to be significant risk factors for DM in both PTC and FTC subgroups. CONCLUSION: Our study demonstrated the promising value of several clinicopathological factors such as male gender, older age, VI, ETE, and LNM in predicting DM in PTCs and FTCs. Our study affirms the value of the selected clinicopathological factors for tumor risk stratification and assessment of patients' prognosis. PMID- 28913697 TI - Developing a post-treatment survivorship care plan to help breast cancer survivors understand their fertility. AB - PURPOSE: Reproductive-aged breast cancer survivors (BCS) who have completed initial cancer treatment frequently want to know about their future fertility potential. The purpose of this qualitative study was to assess if the fertility related content presented in the survivorship care plan prototype met the informational needs of post-treatment BCS and to provide an opportunity for the target audience to review and react to the proposed content and design. METHODS: We conducted and analyzed transcripts from seven focus groups with BCS to evaluate their reactions to the survivorship care plan prototype. We independently coded transcripts for consistent themes and sub-themes and used a consensus-building approach to agree on interpretation of results. RESULTS: We identified five themes that describe the post-treatment BCS' responses to the prototype survivorship care plan in the context of their informational needs and experiences: (1) the prototype's fertility-related information is relevant; (2) desire for clinical parameters to help survivors understand their infertility risk; (3) fertility-related information is important throughout survivorship; (4) evidence-based content from a neutral source is trustworthy; and (5) the recommendation to see a fertility specialist is helpful, but cost is a barrier. CONCLUSIONS: BCS have concerns and needs related to their fertility potential after initial breast cancer treatment. The evidence-based information offered in our prototype survivorship care plan was acceptable to BCS and has significant potential to address these needs. Additional primary data that identify post cancer treatment indicators of fertility would advance this effort. PMID- 28913698 TI - Reduced Value-Driven Attentional Capture Among Children with ADHD Compared to Typically Developing Controls. AB - The current study examined whether children with ADHD were more distracted by a stimulus previously associated with reward, but currently goal-irrelevant, than their typically-developing peers. In addition, we also probed the associated cognitive and motivational mechanisms by examining correlations with other behavioral tasks. Participants included 8-12 year-old children with ADHD (n = 30) and typically developing controls (n = 26). Children were instructed to visually search for color-defined targets and received monetary rewards for accurate responses. In a subsequent search task in which color was explicitly irrelevant, we manipulated whether a distractor item appeared in a previously reward associated color. We examined whether children responded more slowly on trials with the previously-rewarded distractor present compared to trials without this distractor, a phenomenon referred to as value-driven attentional capture (VDAC), and whether children with and without ADHD differed in the extent to which they displayed VDAC. Correlations among working memory performance, immediate reward preference (delay discounting) and attentional capture were also examined. Children with ADHD were significantly less affected by the presence of the previously rewarded distractor than were control participants. Within the ADHD group, greater value-driven attentional capture was associated with poorer working memory. Although both ADHD and control participants were initially distracted by previously reward-associated stimuli, the magnitude of distraction was larger and persisted longer among control participants. PMID- 28913699 TI - Morphological analysis of the filamentous fungus Penicillium chrysogenum using flow cytometry-the fast alternative to microscopic image analysis. AB - An important parameter in filamentous bioreactor cultivations is the morphology of the fungi, due to its interlink to productivity and its dependency on process conditions. Filamentous fungi show a large variety of morphological forms in submerged cultures. These range from dispersed hyphae, to interwoven mycelial aggregates, to denser hyphal aggregates, the so-called pellets. Depending on the objective function of the bioprocess, different characteristics of the morphology are favorable and need to be quantified accurately. The most common method to quantitatively characterize morphology is image analysis based on microscopy. This method is work intensive and time consuming. Therefore, we developed a faster, at-line applicable, alternative method based on flow cytometry. Within this contribution, this novel method is compared to microscopy for a penicillin production process. Both methods yielded in comparable distinction of morphological sub-populations and described their morphology in more detail. In addition to the appropriate quantification of size parameters and the description of the hyphal region around pellets, the flow cytometry method even revealed a novel compactness parameter for fungal pellets which is not accessible via light microscopy. Hence, the here presented flow cytometry method for morphological analysis is a fast and reliable alternative to common tools with some new insights in the pellet morphology, enabling at-line use in production environments. PMID- 28913700 TI - Mobility and dissipation of chlorpyriphos and quinalphos in sandy clay loam in an agroecosystem-a laboratory-based soil column study. AB - Leaching potential of pesticides, apart from climatological factors, depends on soil physical properties, soil-pesticide interaction and chemical nature of the molecule. Recent investigations have revealed the presence of various organophosphate pesticides in various agroecosystems. The present study investigated the soil transport mechanism of commonly used organophosphate pesticides in acidic sandy clay loam soils of Kerala State, India. Packed soil column experiment was undertaken under laboratory condition for 30 days. Unsaturated flow was carried out using distilled water/0.01 M CaCl2 solution after applying chlorpyriphos and quinalphos at the rate of 0.04% a.i.ha-1 and 0.025% a.i.ha-1, respectively. The study revealed the retention of residues of chlorpyriphos and quinalphos in the top 5-cm layer. Irrespective of the applied concentration of chlorpyriphos and quinalphos, the relative concentration of the pesticides in soil was similar. About 56% of the applied chemicals were dissipated in 30 days of unsaturated flow. A new dissipation compound iron, tricarbonyl [N-(phenyl-2-pyridinylmethyene) benzenamine-N, N'], was detected in GCMS analysis of soil extract from distilled water percolated soil. The dissipation of chlorpyriphos and quinalphos was faster in 0.01 M CaCl2-treated soil column. Among the pesticides analysed, the residue of quinalphos was detected in leachate. PMID- 28913701 TI - Complete heart block during ultrasound-guided central venous catheterization. PMID- 28913702 TI - Impaired fertility and motor function in a zebrafish model for classic galactosemia. AB - Classic galactosemia is a genetic disorder of galactose metabolism, caused by severe deficiency of galactose-1-phosphate uridylyltransferase (GALT) enzyme activity due to mutations of the GALT gene. Its pathogenesis is still not fully elucidated, and a therapy that prevents chronic impairments is lacking. In order to move research forward, there is a high need for a novel animal model, which allows organ studies throughout development and high-throughput screening of pharmacologic compounds. Here, we describe the generation of a galt knockout zebrafish model and present its phenotypical characterization. Using a TALEN approach, a galt knockout line was successfully created. Accordingly, biochemical assays confirm essentially undetectable galt enzyme activity in homozygotes. Analogous to humans, galt knockout fish accumulate galactose-1-phosphate upon exposure to exogenous galactose. Furthermore, without prior exposure to exogenous galactose, they exhibit reduced motor activity and impaired fertility (lower egg quantity per mating, higher number of unsuccessful crossings), resembling the human phenotype(s) of neurological sequelae and subfertility. In conclusion, our galt knockout zebrafish model for classic galactosemia mimics the human phenotype(s) at biochemical and clinical levels. Future studies in our model will contribute to improved understanding and management of this disorder. PMID- 28913703 TI - Using Technology and Assessment to Personalize Instruction: Preventing Reading Problems. AB - Children who fail to learn to read proficiently are at serious risk of referral to special education, grade retention, dropping out of high school, and entering the juvenile justice system. Accumulating research suggests that instruction regimes that rely on assessment to inform instruction are effective in improving the implementation of personalized instruction and, in turn, student learning. However, teachers find it difficult to interpret assessment results in a way that optimizes learning opportunities for all of the students in their classrooms. This article focuses on the use of language, decoding, and comprehension assessments to develop personalized plans of literacy instruction for students from kindergarten through third grade, and A2i technology designed to support teachers' use of assessment to guide instruction. Results of seven randomized controlled trials demonstrate that personalized literacy instruction is more effective than traditional instruction, and that sustained implementation of personalized literacy instruction first through third grade may prevent the development of serious reading problems. We found effect sizes from .2 to .4 per school year, which translates into about a 2-month advantage. These effects accumulated from first through third grade with a large effect size (d = .7) equivalent to a full grade-equivalent advantage on standardize tests of literacy. These results demonstrate the efficacy of technology-supported personalized data driven literacy instruction to prevent serious reading difficulties. Implications for translational prevention research in education and healthcare are discussed. PMID- 28913704 TI - Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit. AB - BACKGROUND: Hyponatremia can unmask hypopituitarism and secondary adrenal insufficiency. This is important, since the need to screen for steroid deficiency, in patients with hyponatremia is often neglected. PATIENTS AND METHODS: In a retrospective study, twenty-five patients (13f/12m, age 58.9 +/- 18.6 years) with hyponatremia (119.7 +/- 10.5 mmol/L) were identified among 260 in-patients treated for hypopituitarism in our specialized endocrine unit, over the last decade. We analyzed clinical characteristics, etiology, and severity of hypopituitarism in patients who presented with hyponatremia. RESULTS: Hyponatremia was recorded in 9.6% of our patients with hypopituitarism. In 80.7% it was the key to diagnosis of hypopituitarism. All patients with hyponatremia were steroid deficient with complete hypopituitarism compared to 75% (steroid deficient) and 60% (complete hypopituitarism) of the patients in the cohort. The most common etiology of hypopituitarism was non-functioning pituitary macro adenoma (NFPA) (n = 128, 49.2%). Patients with hyponatremia were divided into two groups, based on the etiology of hypopituitarism: Group 1. with NFPA n = 15 (5F/10M), mean age 71.47 +/- 4.8 years, who were significantly older compared to patients with hyponatremia from other rare causes of hypopituitarism in Group 2. n = 10 (8F/2M), mean age 40.2 +/- 15.3 years (p < 0.01), such as: congenital hypopituitarism(n = 2), Sheehan's syndrome (n = 2), intracranial aneurysm (n = 2), lymphocytic hypophysitis (n = 1), traumatic brain injury (n = 1), surgery and radiotherapy for astrocytoma (n = 1), pituitary metastasis from bronchial carcinoma (n = 1). Hyponatremia was more severe in Group 2. compared to Group 1. (113.5 +/- 10.9 mmol/L vs. 124.3 +/- 8.1 mmol/L, p < 0.01). Older age (p = 0.0001) and number of endocrine deficiencies (p < 0.05) were identified as predictive factors for hyponatremia by multivariate analysis in patients with hypopituitarism. CONCLUSION: Hyponatremia is an important presenting feature of pituitary disease and a strong indicator of life-threatening steroid deficiency. Old age and severity of hypopituitarism are major risk factors for hyponatremia. In older patients NFPA is the most common etiology, while other rare causes of hypopituitarism are more prevalent in younger patients with hyponatremia. PMID- 28913705 TI - Variable PARK2 Mutations Cause Early-Onset Parkinson's Disease in a Small Restricted Population. AB - Early-onset Parkinson's disease (EOPD) is less common than the typical adult onset PD and may be associated with a genetic etiology. Mutations in several genes are known to cause autosomal recessive (AR) PD. This study aimed to detect the etiology of EOPD in consanguineous families or families living in a specific small geographic region in Israel. Six families with EOPD affecting more than a single individual were recruited. Homozygous mapping analysis using a single nucleotide polymorphism-based array was performed in all families, followed by Sanger sequencing of related genes based on the mapping results. In addition, all families underwent PARK2 sequencing and testing for large deletions and duplications in PD-associated genes. Different truncating mutations were detected in the PARK2 gene among affected individuals of three families: c.996C>A (p.Cys332X) and c.101delA in either homozygous or compound heterozygous fashion. Exon 4 deletion was detected in a heterozygous manner in a late-onset PD and in homozygous state in early-onset disease in the same family. No disease-causing mutations were detected in any other tested genes. In total, mutations in the PARK2 gene were detected in four of the six tested families with a history of EOPD. These results further demonstrate the role of PARK2 in AR PD. We recommend genetic analysis for the PARK2 gene when AR PD is suspected. PMID- 28913706 TI - Novel pericatheter retrograde urethrogram technique is a viable method for postoperative urethroplasty imaging. AB - PURPOSE: The purpose of this study is to describe our technique for pericatheter retrograde urethrogram (pcRUG) and to evaluate the utility of a pcRUG to detect a clinically significant leak after urethral reconstruction. METHODS: We retrospectively reviewed our prospective IRB-approved database of patients undergoing urethral reconstruction. pcRUG was performed at 3-4 weeks after surgery, in standardized fashion. Patients were placed in oblique position, and with the penis stretched, diluted contrast was instilled via an angiocatheter alongside the indwelling urethral catheter under dynamic fluoroscopy. The image was then evaluated for the presence of any contrast extravasation. Patient with and without extravasation seen on initial pcRUG were compared. RESULTS: From September 2012 through February 2017, 144 pericatheter retrograde urethrograms were performed on 130 patients. 115 patients (88.5%) had no extravasation on pcRUG. Fifteen patients (11.5%) demonstrated extravasation, with 13 of those patients (10%) undergoing a repeat pcRUG. Patients with extravasation seen on initial pcRUG were more likely to have strictures that were panurethral (36 vs. 9%, p = 0.029) and >=10 cm (43 vs. 11%, p = 0.016). One patient (0.8%) presented with urinary leak and scrotal abscess after a urethra was assessed as sufficiently healed at the initial pcRUG and the catheter removed. There were otherwise no infectious or procedural complications related to pericatheter retrograde urethrogram. CONCLUSIONS: Our pericatheter retrograde urethrogram technique is a safe and reproducible technique to effectively assess urethral healing after urethroplasty and determine timing of catheter removal. The pcRUG is minimally invasive and is comparable in accuracy and sensitivity to voiding cystourethrography and retrograde urethrography that have traditionally been used to assess healing after urethroplasty. PMID- 28913707 TI - Endocytic pathways involved in PLGA nanoparticle uptake by grapevine cells and role of cell wall and membrane in size selection. AB - KEY MESSAGE: PLGA NPs' cell uptake involves different endocytic pathways. Clathrin-independent endocytosis is the main internalization route. The cell wall plays a more prominent role than the plasma membrane in NPs' size selection. In the last years, many studies on absorption and cell uptake of nanoparticles by plants have been conducted, but the understanding of the internalization mechanisms is still largely unknown. In this study, polydispersed and monodispersed poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs) were synthesized, and a strategy combining the use of transmission electron microscopy (TEM), confocal analysis, fluorescently labeled PLGA NPs, a probe for endocytic vesicles (FM4-64), and endocytosis inhibitors (i.e., wortmannin, ikarugamycin, and salicylic acid) was employed to shed light on PLGA NP cell uptake in grapevine cultured cells and to assess the role of the cell wall and plasma membrane in size selection of PLGA NPs. The ability of PLGA NPs to cross the cell wall and membrane was confirmed by TEM and fluorescence microscopy. A strong adhesion of PLGA NPs to the outer side of the cell wall was observed, presumably due to electrostatic interactions. Confocal microscopy and treatment with endocytosis inhibitors suggested the involvement of both clathrin-dependent and clathrin-independent endocytosis in cell uptake of PLGA NPs and the latter appeared to be the main internalization pathway. Experiments on grapevine protoplasts revealed that the cell wall plays a more prominent role than the plasma membrane in size selection of PLGA NPs. While the cell wall prevents the uptake of PLGA NPs with diameters over 50 nm, the plasma membrane can be crossed by PLGA NPs with a diameter of 500-600 nm. PMID- 28913708 TI - Emergency Neurological Life Support: Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is a subset of stroke due to spontaneous bleeding within the parenchyma of the brain. It is potentially lethal, and survival depends on ensuring an adequate airway, proper diagnosis, and early management of several specific issues such as blood pressure, coagulopathy reversal, and surgical hematoma evacuation for appropriate patients. ICH was chosen as an Emergency Neurological Life Support (ENLS) protocol because intervention within the first hours may improve outcome, and it is critical to have site-specific protocols to drive care quickly and efficiently. PMID- 28913709 TI - Unprecedented anticancer activities of organorhenium sulfonato and carboxylato complexes against hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells. AB - Cisplatin and other metal-based drugs often display side effects and tumor resistance after prolonged use. Because rhenium-based anticancer complexes are often less toxic, a novel series of organorhenium complexes were synthesized of the types: XRe(CO)3Z (X = alpha-diimines and Z = p-toluenesulfonate, 1 naphthalenesulfonate, 2-naphthalenesulfonate, picolinate, nicotinate, aspirinate, naproxenate, flufenamate, ibuprofenate, mefenamate, tolfenamate, N-acetyl tryptophanate), and their biological properties were examined. Specifically, in hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells, the p-toluenesulfonato, 1-naphthalenesulfonato, 2 naphthalenesulfonato, picolinato, nicotinato, acetylsalicylato, flufenamato, ibuprofenato, mefenamato, and N-acetyl-tryptophanato complexes were found to be far more potent than conventional drug cisplatin. DNA-binding studies were performed in each case via UV-Vis titrations, cyclic voltammetry, gel electrophoresis, and viscosity, which suggest DNA partial intercalation interaction, and the structure-activity relationship studies suggest that the anticancer activities increase with the increasing lipophilicities of the compounds, roughly consistent with their DNA-binding activities. PMID- 28913710 TI - Performance of multiple docking and refinement methods in the pose prediction D3R prospective Grand Challenge 2016. AB - We describe the performance of multiple pose prediction methods for the D3R 2016 Grand Challenge. The pose prediction challenge includes 36 ligands, which represent 4 chemotypes and some miscellaneous structures against the FXR ligand binding domain. In this study we use a mix of fully automated methods as well as human-guided methods with considerations of both the challenge data and publicly available data. The methods include ensemble docking, colony entropy pose prediction, target selection by molecular similarity, molecular dynamics guided pose refinement, and pose selection by visual inspection. We evaluated the success of our predictions by method, chemotype, and relevance of publicly available data. For the overall data set, ensemble docking, visual inspection, and molecular dynamics guided pose prediction performed the best with overall mean RMSDs of 2.4, 2.2, and 2.2 A respectively. For several individual challenge molecules, the best performing method is evaluated in light of that particular ligand. We also describe the protein, ligand, and public information data preparations that are typical of our binding mode prediction workflow. PMID- 28913711 TI - Emergency Neurological Life Support: Resuscitation Following Cardiac Arrest. AB - Cardiac arrest is the most common cause of death in North America. An organized bundle of neurocritical care interventions can improve chances of survival and neurological recovery in patients who are successfully resuscitated from cardiac arrest. Therefore, resuscitation following cardiac arrest was chosen as an Emergency Neurological Life Support protocol. Key aspects of successful early post-arrest management include: prevention of secondary brain injury; identification of treatable causes of arrest in need of emergent intervention; and, delayed neurological prognostication. Secondary brain injury can be attenuated through targeted temperature management (TTM), avoidance of hypoxia and hypotension, avoidance of hyperoxia, hyperventilation or hypoventilation, and treatment of seizures. Most patients remaining comatose after resuscitation from cardiac arrest should undergo TTM. Treatable precipitants of arrest that require emergent intervention include, but are not limited to, acute coronary syndrome, intracranial hemorrhage, pulmonary embolism and major trauma. Accurate neurological prognostication is generally not appropriate for several days after cardiac arrest, so early aggressive care should never be limited based on perceived poor neurological prognosis. PMID- 28913712 TI - Surgical Site Infection Is Associated with Tumor Recurrence in Patients with Extrahepatic Biliary Malignancies. AB - BACKGROUND: Surgical site infections (SSI) are one of the most common complications after hepato-pancreato-biliary surgery. Infectious complications may lead to an associated immune-modulatory effect that inhibits the body's response to cancer surveillance. We sought to define the impact of SSI on long term prognosis of patients undergoing surgical resection of extrahepatic biliary malignancies (EHBM). METHODS: Patients undergoing surgery for EHBM between 2000 and 2014 were identified using a large, multi-center, national cohort dataset. Recurrence free survival (RFS) was calculated and a multivariable Cox proportional hazards model was utilized to identify potential risk factors for RFS including SSI. RESULTS: Seven hundred twenty-eight patients included in the analytic cohort; 236 (32.4%) patients had perihilar cholangiocarcinoma, 241 (33.1%) gallbladder cancer, and 251 (34.5%) distal cholangiocarcinoma. A major resection, liver resection, was performed in 205 (28.3%) patients, while 110 (15.2%) patients had a pancreaticoduodenectomy. The overall incidence of morbidity was 55.8%; among the 397 patients who experienced a complication, 161 patients specifically had an SSI. The SSI occurred as an infection of the surgical site (n = 70, 9.6%) or formation of an abscess in the operative bed (n = 91, 12.5%). SSI was associated with long-term survival as patients who experienced an SSI had a median RFS of 19.5 months compared with 30.5 months for those patients who did not have an SSI (HR 1.40, 95% CI 1.08-1.80; p = 0.01). Among 279 patients who had EHBM that had no associated lymph node metastases, well-to-moderate tumor differentiation, as well as an R0 resection margin, SSI remained associated with worse RFS (HR 1.84, 95% CI 1.03-3.29; p = 0.038), as well as overall survival (HR 1.87, 95% CI 1.18-2.97; p = 0.008). CONCLUSION: SSI was a relatively common occurrence following surgery for EHBM as 1 in 10 patients experienced an SSI. In addition to standard tumor-specific factors, the occurrence of postoperative SSI was adversely associated with long-term survival. PMID- 28913713 TI - Ethnic Groups Differ in How Poor Self-Rated Mental Health Reflects Psychiatric Disorders. AB - AIM: This study aimed to explore cross-ethnic variation in the pattern of the associations between psychiatric disorders and self-rated mental health (SRMH) in the USA. METHODS: This cross-sectional study used data from the Collaborative Psychiatric Epidemiology Surveys (CPES), 2001-2003, a national household probability sample. The study enrolled 18,237 individuals who were either Non Hispanic White (n = 7587), African American (n = 4746), Mexican (n = 1442), Cuban (n = 577), Puerto Rican (n = 495), Other Hispanic (n = 1106), Vietnamese (n = 520), Filipino (n = 508), Chinese (n = 600) or Other Asian (n = 656). SRMH was the outcome. Independent variables were psychiatric disorders including major depressive disorder [MDD], general anxiety disorder [GAD], social phobia, alcohol abuse, binge eating disorders, panic disorder, and post-traumatic stress disorder [PTSD], measured by the Composite International Diagnostic Interview (CIDI). Demographic (age and gender) and socioeconomic (education and income) factors were covariates. RESULTS: The only psychiatric disorder which was universally associated with SRMH across all ethnic groups was MDD. More psychiatric disorders were associated with poor SRMH in Non-Hispanic Whites than any other ethnic groups. Among African Americans, demographic and socioeconomic factors could fully explain the associations between psychiatric disorders and SRMH. Among Mexican and Other Hispanics, demographic and socioeconomic factors could only explain the association between some but not all psychiatric disorders and SRMH. In all other ethnic groups, demographic and socioeconomic factors did not explain the link between psychiatric disorders and SRMH. CONCLUSION: Although SRMH is a useful tool for estimation of mental health needs of populations, poor SRMH may not have universal meanings across ethnically diverse populations. Ethnic groups differ in how their poor SRMH reflects psychiatric conditions and the role of demographic and socioeconomic factors in explaining such links. These ethnic differences may be a source of measurement bias in cross-ethnic health comparisons. PMID- 28913714 TI - High transient colonization by Pneumocystis jirovecii between mothers and newborn. AB - : The aim of the study was to explore the frequency and dynamics of acquisition and colonization of Pneumocystis jirovecii among neonates, as well as the epidemiological and genotypic characteristics in mother-child binomial. In a prospective enrolled cohort of women in their third trimester of pregnancy, nasopharyngeal swabs (NPS) and clinical and epidemiological data were collected at four different times: 17 days, 2nd, 4th, and 6th month of life of the newborn. P. jirovecii was detected by nested-PCR for the mtLSU-rRNA gene in each NPS; the genotypes were determined amplifying four genes. Forty-three pairs and 301 NPS were included. During the third trimester, 16.3% of pregnant women were colonized. The rate of colonization in mothers at delivery was 16, 6, 16, and 5% and in their children 28, 43, 42, and 25%, respectively. Within pregnant women, 53% remained negative throughout follow-up, and among these, 91% of their children were positive in at least one of their samples. In both, mothers and children, the most frequent genotype of P. jirovecii was 1. CONCLUSION: The frequency of colonization by P. jirovecii was higher in newborns than in their respective progenitors. Colonization of both mothers and children is transitory; however, the mother of the newborn is not necessarily the source of primary infection. What is Known: * We did not find studies comparing P. jirovecii colonization between mothers and children simultaneously, yet the frequency of colonization by serologic and molecular methods in pregnant women has been reported. What is New: * According to our findings, 3/4 of the children had transient colonization during the first 6 months of life, in only half in the mothers, without proof of mother-to-child transmission or vice versa. PMID- 28913715 TI - Oxidized low-density lipoprotein (oxLDL) affects load-free cell shortening of cardiomyocytes in a proprotein convertase subtilisin/kexin 9 (PCSK9)-dependent way. AB - Recent studies have documented that oxidized low-density lipoprotein cholesterol (oxLDL) levels directly impact myocardial structure and function. However, the molecular mechanisms by which oxLDL affects cardiac myocytes are not well established. We addressed the question whether oxLDL modifies load-free cell shortening, a standardized readout of cardiac cellular function, and investigated whether proprotein convertase subtilisin/kexin-9 (PCSK9) is involved on oxLDL dependent processes. Adult rat ventricular cardiomyocytes were isolated and incubated for 24 h with oxLDL. PCSK9 was silenced by administration of siRNA. Load-free cell shortening was analyzed via a line camera at a beating frequency of 2 Hz. RT-PCR and immunoblots were used to identify molecular pathways. We observed a concentration-dependent reduction of load-free cell shortening that was independent of cell damage (apoptosis, necrosis). The effect of oxLDL was attenuated by silencing of oxLDL receptors (LOX-1), blockade of p38 MAP kinase activation, and silencing of PCSK9. oxLDL increased the expression of PCSK9 and caused oxidative modification of tropomyosin. In conclusion, we found that oxLDL significantly impaired contractile function via induction of PCSK9. This is the first report about the expression of PCSK9 in adult terminal differentiated ventricular cardiomyocytes. The data are important in the light of recent development of PCSK9 inhibitory strategies. PMID- 28913716 TI - A case of a mucin-producing bile duct tumor diagnosed over the course of 6 years. AB - We report a case of a mucin-producing intraductal papillary neoplasm of the intrahepatic bile duct (M-IPNB) diagnosed over a period of 6 years. A 64-year-old man underwent follow-up evaluations for an abdominal aortic aneurysm at our hospital. In 2009, a computed tomography (CT) scan revealed a simple hepatic cyst in segment 3 of the liver. Annual CT scans initially showed almost no change in the size or shape of the cyst. The cystic lesion, which measured 5 cm in 2014, had increased to 11 cm by 2015, and a solid component was detected within the cyst. A biliary cystic tumor was suspected and we performed a left lateral hepatectomy. Pathological examination showed that the papillary lesion in the cyst included adenocarcinoma and adenoma components. We diagnosed M-IPNB in 2015. Identification of the solid component of the cyst, as well as an increase in cyst diameter in the image analyses, was critical for diagnosis of M-IPNB. PMID- 28913717 TI - After Deployment, Adaptive Parenting Tools: 1-Year Outcomes of an Evidence-Based Parenting Program for Military Families Following Deployment. AB - Despite significant stressors facing military families over the past 15 years of wars in Iraq and Afghanistan, no parenting programs adapted or developed for military families with school-aged children have been rigorously tested. We present outcome data from the first randomized controlled trial of a behavioral parent training program for families with a parent deployed to Iraq or Afghanistan. In the present study, 336 primarily National Guard and Reserve families with 4-12-year-old children were recruited from a Midwestern state. At least one parent in each family had deployed to the recent conflicts: Operations Iraqi or Enduring Freedom, or New Dawn (OIF/OEF/OND). Families were randomized to a group-based parenting program (After Deployment, Adaptive Parenting Tools (ADAPT)) or web and print resources-as-usual. Using a social interaction learning framework, we hypothesized an indirect effects model: that the intervention would improve parenting, which, in turn, would be associated with improvements in child outcomes. Applying intent-to-treat analyses, we examined the program's effect on observed parenting, and children's adjustment at 12-months post baseline. Controlling for demographic (marital status, length, child gender), deployment variables (number of deployments), and baseline values, families randomized to the ADAPT intervention showed significantly improved observed parenting compared to those in the comparison group. Observed parenting, in turn, was associated with significant improvements in child adjustment. These findings present the first evidence for the effectiveness of a parenting program for deployed military families with school-aged children. PMID- 28913718 TI - Identify a shared neural circuit linking multiple neuropsychiatric symptoms with Alzheimer's pathology. AB - Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28 AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions' functional connectivity classified symptomatic subjects across individual NPS at 69.46-81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration. PMID- 28913719 TI - Green garden snail, Cantareus apertus, as biomonitor and sentinel for integrative metal pollution assessment in roadside soils. AB - The present investigation was conceived to study, in a small scale field study, the potential of the green garden snail, Cantareus apertus, as biomonitor and sentinel for integrative metal pollution assessment in soils. For this purpose, we investigated the association between the trace metal (Cd, Pb, As, Fe, Cr, Cu, Ni, and Zn) concentrations in soil, plants (Trifolium repens), and C. apertus depending on the distance (20, 150, and 700 m) from a main roadside in Tunisia as well as between metal concentrations and biomarkers of oxidative stress, oxidative damage, and neurotoxicity in C. apertus. Results revealed a clear association between the concentration of metals such as Ni, Cu, and Zn in snail digestive gland, both amongst them and with oxidative stress and neurotoxicity biomarkers recorded in the same organ. Interestingly, Ni, Pb, and Zn occurred at the highest concentration in soil, plant, and snails and the association appeared related to the immediacy of the roadside and the concentration of these three metals tended to decrease with distance from the roadside in the soil-plant-snail system. Conversely, Cd and Cu were bioaccumulated in plants and snails but their concentrations in soil were not high and did not show a decline in concentration with distance from the roadside. After PCA analysis, PC-01 (56% of the variance) represented metal bioaccumulation and associated toxic effects in snails in the presence of high levels of metal pollution (nearby the roadside) while PC-02 (35% of the variance) represented stress induced by moderate levels of metal pollution (at intermediate distances from the roadside). The four studied sites were clearly discriminated one from each other, depending on how they are affected by traffic pollution. In summary, this field study reveals that (a) C. apertus can be used as biomonitor for metal pollution in roadside soils and as sentinel for pollution effects assessment based on biochemical biomarkers; and (b) that oxidative stress and neurotoxicity biomarkers endow with a powerful biological tool for metal pollution biomonitoring in soils, especially in combination with chemical analysis of the soil-plant-snail transfer system. Moreover, this study provides some baseline data for future impact assessments concerning trace metal pollution in Tunisia. PMID- 28913720 TI - Emergency Neurological Life Support: Acute Ischemic Stroke. AB - Acute ischemic stroke is a neurological emergency that can be treated with time sensitive interventions, including both intravenous thrombolysis and endovascular approaches to thrombus removal. Extensive study has demonstrated that rapid, protocolized, assessment and treatment is essential to improving neurological outcome. For this reason, acute ischemic stroke was chosen as an emergency neurological life support protocol. The protocol focuses on the first hour of medical care following the acute onset of a neurological deficit. PMID- 28913722 TI - Nonlinear data assimilation for the regional modeling of maximum ozone values. AB - We present a new method of data assimilation with the aim of correcting the forecast of the maximum values of ozone in regional photo-chemical models for areas over complex terrain using multilayer perceptron artificial neural networks. Up until now, these types of models have been used as a single model for one location when forecasting concentrations of air pollutants. We propose a method for constructing a more ambitious model: a single model, which can be used at several locations because the model is spatially transferable and is valid for the whole 2D domain. To achieve this goal, we introduce three novel ideas. The new method improves correlation at measurement station locations by 10% on average and improves by approximately 5% elsewhere. PMID- 28913721 TI - Intraperitoneal antibiotic administration for prevention of postoperative peritoneal catheter-related infections. AB - BACKGROUND: It is recommended that systemic prophylactic antibiotics be given immediately prior to peritoneal catheter insertion. This administration requires intravenous access and could be inconvenient in dynamic and unpredictable operation room schedule. Intraperitoneal antibiotics could be an alternative simple way for prevention of postoperative peritoneal catheter infections. METHODS: Medical records from 109 patients undergoing permanent PD catheter placement procedures were reviewed retrospectively. Group I patients (66 patients) received intraperitoneal cefazolin through the inserted Tenckhoff catheter in operation room. Group II (43 patients) received intravenous cefazolin 2 h prior to the surgery. The effect of prophylactic antibiotics on the occurrence of peritonitis and exit site infection in the 14 days following surgical peritoneal dialysis catheter placement was evaluated. RESULTS: During the follow-up period, one patients from group II (2.3%) and none from group I developed peritonitis (P = 0.3945). One patient from each group developed exit site infection (P = 1.000). CONCLUSION: It was found that intraperitoneal antibiotics have the similar efficacy compared with intravenous antibiotics for postoperative peritoneal catheter-related infections' prevention. It does not require intravenous access and overcome the issue of unpredictable operation room schedule. PMID- 28913724 TI - Use of phytoproductivity data in the choice of native plant species to restore a degraded coal mining site amended with a stabilized industrial organic sludge. AB - Coal mining-related activities result in a degraded landscape and sites associated with large amounts of dumped waste material. The arid soil resulting from acid mine drainage affects terrestrial and aquatic ecosystems, and thus, site remediation programs must be implemented to mitigate this sequential deleterious processes. A low-cost alternative material to counterbalance the affected physico-chemical-microbiological aspects of the degraded soil is the amendment with low contaminated and stabilized industrial organic sludge. The content of nutrients P and N, together with stabilized organic matter, makes this material an excellent fertilizer and soil conditioner, fostering biota colonization and succession in the degraded site. However, choice of native plant species to restore a degraded site must be guided by some minimal criteria, such as plant survival/adaptation and plant biomass productivity. Thus, in this 3 month study under environmental conditions, phytoproductivity tests with five native plant species (Surinam cherry Eugenia uniflora L., C. myrianthum Citharexylum myrianthum, Inga-Inga spp., Brazilian peppertree Schinus terebinthifolius, and Sour cherry Prunus cerasus) were performed to assess these criteria, and additional biochemical parameters were measured in plant tissues (i.e., protein content and peroxidase activity) exposed to different soil/sludge mixture proportions. The results show that three native plants were more adequate to restore vegetation on degraded sites: Surinam cherry, C. myrianthum, and Brazilian peppertree. Thus, this study demonstrates that phytoproductivity tests associated with biochemical endpoint measurements can help in the choice of native plant species, as well as aiding in the choice of the most appropriate soil/stabilized sludge proportion in order to optimize biomass production. PMID- 28913723 TI - Therapeutic Implications of the Molecular and Immune Landscape of Triple-Negative Breast Cancer. AB - Treatment and management of breast cancer imposes a heavy burden on public health care, and incidence rates continue to increase. Breast cancer is the most common female neoplasia and primary cause of death among women worldwide. The recognition of breast cancer as a complex and heterogeneous disease, comprising different molecular entities, was a landmark in our understanding of this malignancy. Valuing the impact of the molecular characteristics on tumor behavior enabled a better assessment of a patient's prognosis and increased the predictive power to therapeutic response and clinical outcome. Molecular heterogeneity is also prominent in the triple-negative breast cancer subtype, and is reflected by the distinct prognostic and patient's sensitivity to treatment, being chemotherapy the only systemic treatment currently available. From a therapeutic perspective, gene expression profiling of triple-negative tumors has notably contributed to the exploration of new druggable targets and brought to light the need to align these patients to the various therapies according to their triple negative subtype. Additionally, the higher amount of tumor infiltrating lymphocytes, and the prevalence of an increased expression of PD-1 receptor and its ligand, PD-L1, in triple-negative tumors, created a new treatment opportunity with immune checkpoint inhibitors. This manuscript addresses the current knowledge on the molecular and immune profiles of breast cancer, and its impact on the development of targeted therapies, with a particular emphasis on the triple-negative subtype. PMID- 28913725 TI - Exercise and Competitive Sport: Physiology, Adaptations, and Uncertain Long-Term Risks. AB - OPINION STATEMENT: The benefits of regular and moderate exercise training on cardiovascular outcomes have been well established. In addition, strenuous exercise training leads to corollary cardiac structural and functional adaptations that are sport-specific and facilitate athletic performance. In this review, the normal physiologic and hemodynamic changes that occur during exercise and the subsequent differential exercise-induced cardiac remodeling patterns that develop will be discussed. Paradoxically, recent data have raised concern about the long-term impact of higher doses of physical activity and exercise on mortality and cardiovascular health outcomes. We will discuss important aspects of these controversial data and review the supporting evidence as well as the limitations of prior research. Specifically, we will address the association between high levels of exercise and relative reductions in overall mortality, increased risk of atrial fibrillation, arrhythmogenic cardiac remodeling, and accelerated coronary artery calcifications. For the practitioner, this review aims to detail these contemporary sports cardiology controversies and highlights the critical need to incorporate shared decision making with the athlete in dealing with the uncertainties that exist. Finally, we will discuss key "athlete specific" variables that should be considered in the design of future important research in this arena. PMID- 28913726 TI - Diagnosis and Treatment of Progressive Multifocal Leukoencephalopathy Associated with Multiple Sclerosis Therapies. AB - Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system-typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied. PMID- 28913728 TI - Shoulder strengthening exercises adapted to specific shoulder pathologies can be selected using new simulation techniques: a pilot study. AB - PURPOSE: Shoulder strength training exercises represent a major component of rehabilitation protocols designed for conservative or postsurgical management of shoulder pathologies. Numerous methods are described for exercising each shoulder muscle or muscle group. Limited information is available to assess potential deleterious effects of individual methods with respect to specific shoulder pathologies. Thus, the goal of this pilot study was to use a patient-specific 3D measurement technique coupling medical imaging and optical motion capture for evaluation of a set of shoulder strength training exercises regarding glenohumeral, labral and subacromial compression, as well as elongation of the rotator cuff muscles. METHODS: One volunteer underwent magnetic resonance imaging (MRI) and motion capture of the shoulder. Motion data from the volunteer were recorded during three passive rehabilitation exercises and twenty-nine strengthening exercises targeting eleven of the most frequently trained shoulder muscles or muscle groups and using four different techniques when available. For each exercise, glenohumeral and labral compression, subacromial space height and rotator cuff muscles elongation were measured on the entire range of motion. RESULTS: Significant differences in glenohumeral, subacromial and labral compressions were observed between sets of exercises targeting individual shoulder muscles. Muscle lengths computed by simulation compared to MRI measurements showed differences of 0-5%. CONCLUSIONS: This study represents the first screening of shoulder strengthening exercises to identify potential deleterious effects on the shoulder joint. Motion capture combined with medical imaging allows for reliable assessment of glenohumeral, labral and subacromial compression, as well as muscle-tendon elongation during shoulder strength training exercises. PMID- 28913727 TI - Sleep-amount differentially affects fear-processing neural circuitry in pediatric anxiety: A preliminary fMRI investigation. AB - Insufficient sleep, as well as the incidence of anxiety disorders, both peak during adolescence. While both conditions present perturbations in fear processing-related neurocircuitry, it is unknown whether these neurofunctional alterations directly link anxiety and compromised sleep in adolescents. Fourteen anxious adolescents (AAs) and 19 healthy adolescents (HAs) were compared on a measure of sleep amount and neural responses to negatively valenced faces during fMRI. Group differences in neural response to negative faces emerged in the dorsal anterior cingulate cortex (dACC) and the hippocampus. In both regions, correlation of sleep amount with BOLD activation was positive in AAs, but negative in HAs. Follow-up psychophysiological interaction (PPI) analyses indicated positive connectivity between dACC and dorsomedial prefrontal cortex, and between hippocampus and insula. This connectivity was correlated negatively with sleep amount in AAs, but positively in HAs. In conclusion, the presence of clinical anxiety modulated the effects of sleep-amount on neural reactivity to negative faces differently among this group of adolescents, which may contribute to different clinical significance and outcomes of sleep disturbances in healthy adolescents and patients with anxiety disorders. PMID- 28913729 TI - Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients. AB - PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial beta oxidation and ATP production (P = 4.16 * 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 * 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 * 10-4, 95% CI 2.83 28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC. PMID- 28913731 TI - Inter- and intra-observer reproducibility of quantitative analysis for FP-CIT SPECT in patients with DLB. AB - BACKGROUND: Dopamine transporter single photon emission CT (DAT-SPECT) is useful in the evaluation of dementia with Lewy bodies (DLB). The specific binding ratio (SBR) is an index to measure DAT density. However, poorly reproducible cases are occasionally experienced in clinical practice. We hypothesized that distance weighted histogram (DWH) may be useful to improve the reproducibility of SBR. The purpose of this study was to investigate inter- and intra-observer reproducibility of SBR with conventional and DWH methods, and to visually evaluate the precision in reference voxel of interest (VOI) definition using these methods. METHODS: This study included 50 adult patients with probable DLB. They underwent brain MRI, DAT-SPECT, and cerebral blood flow SPECT with N isopropyl-p-[123I]iodoamphetamine (I-123 IMP). SBR of the striatum was calculated using conventional and DWH method. For inter-observer reproducibility validation, conventional and DWH SBR were independently evaluated by experienced nuclear medicine physicians; these measurements were repeated by the nuclear medicine physician to investigate intra-observer reproducibility. RESULTS: Proper reference VOI definition was achieved in 60.0% using conventional SBR and in 98.0% with DWH SBR. Both conventional and DWH SBR demonstrated good inter- and intra-observer reproducibility, however, there were statistically significant inter- and intra-observer variations with conventional SBR measurements. Average inter- and intra-observer errors of conventional SBR were 7.9 and 6.1%, respectively. Conversely, DWH SBR errors were not observed in all patients. Moreover, average inter- and intra-observer errors were significantly higher in conventional SBR with improper reference VOI definition than in that with proper reference VOI definition. CONCLUSIONS: Although the reproducibility of conventional and DWH SBR was good, inter- and intra-observer bias could not be ignored in conventional SBR, particularly with improper reference VOI definition. Thus, DWH may be useful to improve inter- and intra-observer reproducibility of SBR. PMID- 28913730 TI - Current Treatment Strategies for Tricuspid Regurgitation. AB - PURPOSE OF REVIEW: Tricuspid regurgitation is common; however, recognition and diagnosis, clinical outcomes, and management strategies are poorly defined. Here, we will describe the etiology and natural history of tricuspid regurgitation (TR), evaluate existing surgical outcomes data, and review the evolving field of percutaneous interventions to treat TR. RECENT FINDINGS: Previously, the only definitive corrective therapy for TR was surgical valve repair or replacement which is associated with significant operative mortality. Advances in percutaneous valve repair techniques are now being translated to the tricuspid valve. These novel interventions may offer a lower-risk alternative treatment in patients at increased surgical risk. Significant TR adversely impacts survival. Surgery remains the only proven therapy for treatment of TR and may be underutilized due to mixed outcomes data. Early experience with percutaneous interventions is promising, but large clinical experience is lacking. Further study will be required before these therapies are introduced into broader clinical practice. PMID- 28913732 TI - Patient and provider perceptions of Internet-delivered cognitive behavior therapy for recent cancer survivors. AB - PURPOSE: Although most cancer survivors adjust well, a subset experiences clinical levels of anxiety and depression following cancer treatment. Internet delivered cognitive behavior therapy (iCBT) is a promising intervention for symptoms of anxiety and depression among survivors; however, patient and provider perceptions of iCBT have not been examined. METHODS: We employed an exploratory qualitative method and conducted semi-structured interviews with 13 cancer survivors and 10 providers to examine iCBT strengths and weaknesses, areas for improvement, and perceived barriers to program completion. A thematic content analysis approach was used to analyze the data. RESULTS: The majority of survivors liked the flexible, convenient, and private nature of the program. Many viewed the program as helping them feel less alone following cancer treatment. Areas of improvement included suggestions of additional information regarding cancer treatment side effects. Barriers to completing the program were identified by a minority of survivors and included finding time to complete the program and current symptoms. Providers liked the program's accessibility and its ability to provide support to patients after cancer treatment. All providers perceived the program as useful in their current work with survivors. Concerns around the fit of the program (e.g., for particular patients) were expressed by a minority of providers. CONCLUSIONS: Results provide additional evidence for the acceptability of an iCBT program among recent cancer survivors and providers in oncology settings. The current study highlights the value of research exploring iCBT for cancer survivors and provides insights for other groups considering Internet delivered care for survivors. PMID- 28913733 TI - A prospective feasibility trial of a novel intravascular catheter system with retractable coiled tip guidewire placed in difficult intravascular access (DIVA) patients in the Emergency Department. AB - The primary study objective was to evaluate insertion success rates. Secondary objectives included patient satisfaction, procedure time, complication rates, completion of therapy and dwell time of the novel AccuCath(r) 2.25" Blood Control (BC) Catheter System (FDA approved) placed in difficult-access patients. This was a single-arm feasibility trial evaluating the AccuCath(r) 2.25" BC Catheter System in a convenience sample of DIVA patients defined as at least two failed initial attempts or a history of difficult access plus the inability to directly visualize or palpate a target vein. All enrolled patients were 18 years of age or older. A total of 120 patients were enrolled. These patients had an average of 3.7 and median of 3 prior attempts at vascular access prior to AccuCath placement. Successful access was gained in 100% of the patients, 77% on the first attempt and all within three attempts; 88.5% of patients completed therapy, with the remaining 12.5% experiencing minor complications that required discontinuation of the catheter. The average patient satisfaction score on a 5 point Likert scale was highly positive at 4.6. Preliminary results show that the AccuCath(r) 2.25" BC Catheter System has excellent success rates in gaining vascular access in an extremely difficult patient population. The device did not lead to any significant complications. Patients were also very satisfied with the procedure. PMID- 28913734 TI - Molecular profile of atypical hyperplasia of the breast. AB - PURPOSE: Atypical ductal and atypical lobular hyperplasia (AH) of the breast are important proliferative lesions which are associated with a significantly increased risk for breast cancer. The breast cancer which develops in association with AH may occur synchronously, representing local progression, or metachronously at a later date in either the ipsilateral or contralateral breast. These high-risk characteristics of AH suggest they contain significant genomic changes. METHODS: To define the genomic changes in AH, a comprehensive review of the literature was conducted to identify the numerical chromosomal and structural chromosomal changes, DNA methylation, and gene expression abnormalities in atypical ductal and atypical lobular hyperplasia. RESULTS: AHs are characterized by advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangements such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences between AH and surrounding normal breast tissue including significant estrogen receptor expression. Many of these changes are shared by an associated synchronous breast cancer, consistent with an important precursor role for AH. At the same time, many of the genomic changes of AHs are also shared by common sporadic breast cancer, consistent with a high risk for future development of metachronous breast cancer. CONCLUSIONS: This molecular profile should help clarify the genomic characteristics and malignant predisposition of AH, and aid in the identification of new targets for the prevention of breast cancer. PMID- 28913735 TI - Efficacy and Safety of Tazarotene 0.1% Plus Clindamycin 1% Gel Versus Adapalene 0.1% Plus Clindamycin 1% Gel in Facial Acne Vulgaris: A Randomized, Controlled Clinical Trial. AB - BACKGROUND: Acne vulgaris is a multifactorial disorder which is ideally treated with combination therapy with topical retinoids and antibiotics. OBJECTIVES: The present study was conducted to compare the efficacy and safety of tazarotene plus clindamycin against adapalene plus clindamycin in facial acne vulgaris. METHODS: This study is a randomized, open-label, parallel design clinical trial conducted on 60 patients with facial acne at the outpatient dermatology department in a tertiary healthcare center. The main outcome measures were change in the acne lesion count, Investigator's Static Global Assessment (ISGA) score, Global Acne Grading System (GAGS) score, and Acne-Specific Quality of Life Questionnaire (Acne-QoL) at the end of 4 weeks of therapy. After randomization one group (n = 30) received tazarotene 0.1% plus clindamycin 1% gel and another group (n = 30) received adapalene 0.1% plus clindamycin 1% gel for 1 month. At follow-up, all the parameter were reassessed. RESULT: In both treatment regimens the total number of facial acne lesions decreased significantly. The difference in the change in the total count between the two combination regimens was also significant [6.51, 95% confidence interval (CI) 1.91-11.09, p = 0.007]. A >=50% reduction in the total lesion count from the baseline levels was achieved by 71% of patients in the tazarotene plus clindamycin group and 22% of patients in the adapalene plus clindamycin group (p = 0.0012). The difference in the change of inflammatory (p = 0.017) and non-inflammatory (p = 0.039) lesion counts in the tazarotene plus clindamycin group were significantly higher than the adapalene plus clindamycin group. The difference in change of the GAGS score was also significantly higher in the tazarotene plus clindamycin group (p = 0.003). The ISGA score improved in 17 patients in the tazarotene plus clindamycin group versusnine patients in the adapalene plus clindamycin group (p = 0.04). The change of total quality-of-life score was found to be significantly (p = 0.027) higher in the tazarotene plus clindamycin group. CONCLUSIONS: Both treatment regimens were efficacious, but tazarotene plus clindamycin was found to be superior to adapalene plus clindamycin. The tolerability profile of both regimens was comparable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02721173. PMID- 28913736 TI - PTFE-coated non-stick cookware and toxicity concerns: a perspective. AB - PTFE is used as an inner coating material in non-stick cookware. This unique polymer coating prevents food from sticking in the pans during the cooking process. Such cookware is also easy to wash. At normal cooking temperatures, PTFE coated cookware releases various gases and chemicals that present mild to severe toxicity. Only few studies describe the toxicity of PTFE but without solid conclusions. The toxicity and fate of ingested PTFE coatings are also not understood. Moreover, the emerging, persistent, and well-known toxic environmental pollutant PFOA is also used in the synthesis of PTFA. There are some reports where PFOA was detected in the gas phase released from the cooking utensils under normal cooking temperatures. Due to toxicity concerns, PFOA has been replaced with other chemicals such as GenX, but these new alternatives are also suspected to have similar toxicity. Therefore, more extensive and systematic research efforts are required to respond the prevailing dogma about human exposure and toxic effects to PTFE, PFOA, and GenX and other alternatives. PMID- 28913737 TI - Minimally invasive endoscopic thyroid surgery using a collar access: experience in 246 cases with the CEViTS technique. AB - BACKGROUND: The arguments for applying minimally invasive techniques are, besides cosmetic results, reduced access trauma and less postoperative pain. In thyroid surgery, cosmetic aspects are gaining importance. Whether minimally invasive endoscopic thyroid surgery is less painful has not been shown yet. METHOD: In this study, we analyse the outcome of 246 patients who underwent cervical endoscopic video-assisted thyroid surgery (CEViTS) regarding the surgery itself, their postoperative pain and satisfaction with the procedure. RESULTS: CEViTS is routinely performed in our hospital. In this study, no postoperative bleedings that would have made a reoperation necessary occurred. All lobectomies could be completed endoscopically. In two cases, conversions (enlargement of the 5-mm incision to 25 mm) were necessary. Transient nerve palsy was registered in three patients (1.22%). One patient (0.41%) had a permanent palsy of the recurrent laryngeal nerve. In comparison to open surgery (n = 173 patients), the 246 CEViTS patients had a significantly lower pain level (p = 0.047). CONCLUSIONS: Cervical endoscopic video-assisted thyroid surgery (CEViTS) can be considered a safe, less traumatizing and useful minimally invasive procedure in endoscopic thyroid surgery. PMID- 28913739 TI - The Wurzburg MIH concept: the MIH treatment need index (MIH TNI) : A new index to assess and plan treatment in patients with molar incisior hypomineralisation (MIH). AB - AIM: This was to create a new easy-to-use index for the treatment of MIH. METHODS: An international MIH working group developed a new MIH index as an epidemiological screening procedure for assessing MIH treatment needs (MIH-TNI), and also for the screening and monitoring of individuals by dental practitioners. RESULTS: The MIH TNI assesses in particular the extent of the destruction of tooth structure in combination with any hypersensitivity occurring in MIH. The MIH-TNI is suggested as a basis for individual dental examinations covering all MIH typical problems or treatment planning. In addition, this index shall be the basis for decision-making in any MIH therapy studies already planned. CONCLUSION: After the validation of the MIH TNI it may be possible to create a standardised approach for dental treatment for MIH. PMID- 28913738 TI - Comparison of the efficiency of bacterial and fungal laccases in delignification and detoxification of steam-pretreated lignocellulosic biomass for bioethanol production. AB - This study evaluates the potential of a bacterial laccase from Streptomyces ipomoeae (SilA) for delignification and detoxification of steam-exploded wheat straw, in comparison with a commercial fungal laccase from Trametes villosa. When alkali extraction followed by SilA laccase treatment was applied to the water insoluble solids fraction, a slight reduction in lignin content was detected, and after a saccharification step, an increase in both glucose and xylose production (16 and 6%, respectively) was observed. These effects were not produced with T. villosa laccase. Concerning to the fermentation process, the treatment of the steam-exploded whole slurry with both laccases produced a decrease in the phenol content by up to 35 and 71% with bacterial and fungal laccases, respectively. The phenols reduction resulted in an improved performance of Saccharomyces cerevisiae during a simultaneous saccharification and fermentation (SSF) process, improving ethanol production rate. This enhancement was more marked with a presaccharification step prior to the SSF process. PMID- 28913740 TI - Temporary Mechanical Circulatory Support for Cardiogenic Shock. AB - OPINION STATEMENT: Cardiogenic shock is a life-threatening presentation of severe heart failure with high morbidity and mortality. Given the modest increased in cardiac output and neutral/negative survival benefits with today's available inotropes (namely, dobutamine and milrinone), the use of mechanical circulatory support (MCS) has increased dramatically over the past 2 decades. In this review article, we discuss the physiologic concept, clinical evidence of benefit, and current use and indications/potential complications of the four most commonly used devices for MCS: intra-aortic balloon pump, Impella percutaneous ventricular assist device, TandemHeart, and extracorporeal membrane oxygenation (ECMO). We also compare these devices in terms of complexity of implantation and hemodynamic effects. PMID- 28913742 TI - Automated Morphological and Morphometric Analysis of Mass Spectrometry Imaging Data: Application to Biomarker Discovery. AB - Mass spectrometry imaging datasets are mostly analyzed in terms of average intensity in regions of interest. However, biological tissues have different morphologies with several sizes, shapes, and structures. The important biological information, contained in this highly heterogeneous cellular organization, could be hidden by analyzing the average intensities. Finding an analytical process of morphology would help to find such information, describe tissue model, and support identification of biomarkers. This study describes an informatics approach for the extraction and identification of mass spectrometry image features and its application to sample analysis and modeling. For the proof of concept, two different tissue types (healthy kidney and CT-26 xenograft tumor tissues) were imaged and analyzed. A mouse kidney model and tumor model were generated using morphometric - number of objects and total surface - information. The morphometric information was used to identify m/z that have a heterogeneous distribution. It seems to be a worthwhile pursuit as clonal heterogeneity in a tumor is of clinical relevance. This study provides a new approach to find biomarker or support tissue classification with more information. Graphical Abstract ?. PMID- 28913741 TI - Pressure dependence of side chain 13C chemical shifts in model peptides Ac-Gly Gly-Xxx-Ala-NH2. AB - For evaluating the pressure responses of folded as well as intrinsically unfolded proteins detectable by NMR spectroscopy the availability of data from well defined model systems is indispensable. In this work we report the pressure dependence of 13C chemical shifts of the side chain atoms in the protected tetrapeptides Ac-Gly-Gly-Xxx-Ala-NH2 (Xxx, one of the 20 canonical amino acids). Contrary to expectation the chemical shifts of a number of nuclei have a nonlinear dependence on pressure in the range from 0.1 to 200 MPa. The size of the polynomial pressure coefficients B 1 and B 2 is dependent on the type of atom and amino acid studied. For HN, N and Calpha the first order pressure coefficient B 1 is also correlated to the chemical shift at atmospheric pressure. The first and second order pressure coefficients of a given type of carbon atom show significant linear correlations suggesting that the NMR observable pressure effects in the different amino acids have at least partly the same physical cause. In line with this observation the magnitude of the second order coefficients of nuclei being direct neighbors in the chemical structure also are weakly correlated. The downfield shifts of the methyl resonances suggest that gauche conformers of the side chains are not preferred with pressure. The valine and leucine methyl groups in the model peptides were assigned using stereospecifically 13C enriched amino acids with the pro-R carbons downfield shifted relative to the pro-S carbons. PMID- 28913743 TI - Predicting the affinity of Farnesoid X Receptor ligands through a hierarchical ranking protocol: a D3R Grand Challenge 2 case study. AB - The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4.2 and manual edition of available structures for binding poses generation using SeeSAR, (2) the use of HYDE scoring for pose selection, and (3) a hierarchical ranking using HYDE and MM/GBSA. In this report, we detail our pose generation and ligands ranking protocols and provide guidelines to be used in a prospective computer aided drug design program. PMID- 28913744 TI - Eight-Year Latent Class Trajectories of Academic and Social Functioning in Children with Attention-Deficit/Hyperactivity Disorder. AB - We examined trajectories of academic and social functioning in children with attention-deficit/hyperactivity disorder (ADHD) to identify those who might be at risk for especially severe levels of academic and social impairment over time. We estimated a series of growth mixture models using data from two subsamples of children participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) including those with at least baseline and 96 month data for reading and mathematics achievement (n = 392; 77.3% male; M age = 7.7; SD = 0.8) or social skills ratings from teachers (n = 259; 74.9% male; M age = 7.6; SD = 0.8). We compared latent trajectories for children with ADHD to mean observed trajectories obtained from a local normative (i.e., non-ADHD) comparison group (n = 289; 80.6% male; M age = 9.9; SD = 1.1). Results indicated six latent trajectory classes for reading and mathematics and four classes for teacher social skills ratings. There was not only a relationship between trajectories of inattention symptoms and academic impairment, but also a similarly strong association between trajectory classes of hyperactive-impulsive symptoms and achievement. Trajectory class membership correlated with socio-demographic and diagnostic characteristics, inattention and hyperactive-impulsive symptom trajectories, externalizing behavior in school, and treatment receipt and dosage. Although children with ADHD display substantial heterogeneity in their reading, math, and social skills growth trajectories, those with behavioral and socio demographic disadvantages are especially likely to display severe levels of academic and social impairment over time. Evidence-based early screening and intervention that directly address academic and social impairments in elementary school-aged children with ADHD are warranted. The ClinicalTrials.gov identifier is NCT00000388. PMID- 28913746 TI - Leptomeningeal Carcinomatosis Associated with Gall Bladder Carcinoma: a Case Report and Review of Literature. PMID- 28913745 TI - Management of Type 1 Diabetes in the Hospital Setting. AB - PURPOSE OF REVIEW: The purpose of this article was to review recent guideline recommendations on glycemic target, glucose monitoring, and therapeutic strategies, while providing practical recommendations for the management of medical and surgical patients with type 1 diabetes (T1D) admitted to critical and non-critical care settings. RECENT FINDINGS: Studies evaluating safety and efficacy of insulin pump therapy, continuous glucose monitoring, electronic glucose management systems, and closed loop systems for the inpatient management of hyperglycemia are described. Due to the increased prevalence and life expectancy of patients with type 1 diabetes, a growing number of these patients require hospitalization every year. Inpatient diabetes management is complex and is best provided by a multidisciplinary diabetes team. In the absence of such resource, providers and health care staff must become familiar with the features of this condition to avoid complications such as severe hyperglycemia, ketoacidosis, hypoglycemia, or glycemic variability. We reviewed most recent guidelines and relevant literature in the topic to provide practical recommendations for the inpatient management of patients with T1D. PMID- 28913747 TI - Primary Sjogren's syndrome: Extraglandular manifestations and hydroxychloroquine therapy. AB - The use of hydroxychloroquine (HCQ) in Primary Sjogren's Syndrome (pSS) has been assessed in different studies over the last years, with conflicting results regarding its efficacy in sicca syndrome and extraglandular manifestations (EGM). The goal of this study was to compare the incidence rate of EGM in pSS patients with and without HCQ therapy.We performed a multicenter retrospective study, including patients with pSS (European classification criteria) with at least 1 year of follow-up. Subjects with concomitant fibromyalgia, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis were excluded. Demographics and pSS characteristics were recorded. The EGM were defined by EULAR SS disease activity index (ESSDAI). Patients were divided into two groups according to their use or not of HCQ therapy. We evaluated the use of HCQ and its relationship to EGM. HCQ therapy was defined as the continuous use of the drug for at least 3 months. A descriptive analysis of demographics and pSS characteristics was performed. We compared the incidence of EGM between groups defined by HCQ therapy using chi2 test or Fisher's exact test. A total of 221 patients were included (97.3% women), mean age, 55.7 years (SD 14). Mean age at diagnosis, 48.8 years (SD 15); median disease duration, 60 months (IQR 35-84). One hundred and seventy patients (77%) received HCQ. About half of the patients had at least one EGM during the course of the disease, 20% of them developed an EGM before the onset of the sicca syndrome and 26% simultaneously with dryness symptom. Overall, EGM were less frequent in those on HCQ therapy (36.5% vs 63.5%, p < 0.001). Considering each EGM individually, the following manifestations were more frequent in the non-treated group: arthritis (p < 0.001), fatigue (p < 0.001), purpura (p = 0.01), Raynaud phenomenon (p = 0.003), and hypergammaglobulinemia (p = 0.006). Immunosuppressive treatment was indicated on 28 patients (12.7%), 13 of which were receiving also HCQ. The first reason for those treatments was the presence of arthritis in 12/28 patients (42.8%), and the drug used in all the cases was methotrexate. Only three patients required immunosuppressive therapy with cyclophosphamide, due to the presence of glomerulonephritis, vasculitis, and interstitial lung disease. None of the patients received biologic therapy. The lower incidence of EGM was observed in patients on HCQ therapy supports its efficacy in pSS. However, further large scale prospective studies are needed to confirm these findings. PMID- 28913749 TI - Erratum to: Potential lung carcinogenicity induced by chronic exposure to PM2.5 in the rat. PMID- 28913748 TI - Religious Affiliation Influences on the Health Status and Behaviours of Students Attending Seventh-Day Adventist Schools in Australia. AB - Students attending Seventh-day Adventist (Adventist) schools in Australia have been shown to have better health status and behaviours compared to secular norms, yet these schools cater for a high percentage of non-Adventist students. The purpose of this study was to investigate the influence of religious affiliation (Adventist/non-Adventist) on the health status and behaviours of students attending Adventist secondary schools in Australia. The sample included 1734 students who responded to a health and lifestyle survey that captured demographic details, self-reported height and weight, self-reported health status, mental health and select health behaviours. Students who identified themselves as Adventist reported significantly better health behaviours than the non-Adventist students in several behavioural domains, especially among the male students. However, this did not translate to a difference in health status. Further research is needed to understand the causal mechanisms responsible for the potential health advantage of Adventist students, which may include family or church religious influences. PMID- 28913750 TI - Selective and Sensitive Fluorescein-Benzothiazole Based Fluorescent Sensor for Zn2+ Ion in Aqueous Media. AB - An efficient fluorescent sensor based on fluorescein-benzothiazole (FB) for Zn2+ ion was synthesized and characterized systematically. FB exhibited selective and sensitive recognition toward Zn2+ in MeCN-H2O (v/v = 2/1) over other cations due to the spirolactam ring-opening power of Zn2+. The complexation property of FB with Zn2+ ion was examined by 1H NMR, 13C NMR and FTIR experiments. The stoichiometric ratio of the FB-Zn2+ complex was determined from a Job plot to be 1:1. The binding constant (K a) of Zn2+ binding to FB was found to be 4.22 * 104 M- 1, with a detection limit of 5.64 MUM. In addition, the practical utility of FB was explored in the form of test strips. Graphical Abstract. PMID- 28913752 TI - The first-generation ABSORB BVS: awaiting dissolving outcomes. PMID- 28913753 TI - Herbivorous snails can increase water clarity by stimulating growth of benthic algae. AB - Eutrophication in shallow lakes is characterized by a switch from benthic to pelagic dominance of primary productivity that leads to turbid water, while benthification is characterized by a shift in primary production from the pelagic zone to the benthos associated with clear water. A 12-week mesocosm experiment tested the hypothesis that the herbivorous snail Bellamya aeruginosa stimulates the growth of pelagic algae through grazing on benthic algae and through accelerating nutrient release from sediment. A tube-microcosm experiment using 32P-PO4 as a tracer tested the effects of the snails on the release of sediment phosphorus (P). The mesocosm experiment recorded greater total nitrogen (TN) concentrations and a higher ratio of TN:TP in the overlying water, and a higher light intensity and biomass of benthic algae as measured by chlorophyll a (Chl a) in the snail treatment than in the control. Concentrations of total phosphorus (TP), total suspended solids (TSSs), and inorganic suspended solids (ISSs) in the overlying water were lower in the snail treatment than in the control, though no significant difference in Chl a of pelagic algae between the snail treatment and control was observed. In the microcosm experiment, 32P activity in the overlying water was higher in the snail treatment than in the control, indicating that snails accelerated P release from the sediment. Our interpretation of these results is that snails enhanced growth of benthic algae and thereby improved water clarity despite grazing on the benthic algae and enhancing P release from the sediment. The rehabilitation of native snail populations may therefore enhance the recovery of eutrophic shallow lakes to a clear water state by stimulating growth of benthic algae. PMID- 28913751 TI - Emergency Neurological Life Support: Airway, Ventilation, and Sedation. AB - Airway management and ventilation are central to the resuscitation of the neurologically ill. These patients often have evolving processes that threaten the airway and adequate ventilation. Furthermore, intubation, ventilation, and sedative choices directly affect brain perfusion. Therefore, Airway, Ventilation, and Sedation was chosen as an Emergency Neurological Life Support protocol. Topics include airway management, when and how to intubate with special attention to hemodynamics and preservation of cerebral blood flow, mechanical ventilation settings and the use of sedative agents based on the patient's neurological status. PMID- 28913754 TI - Emergency Neurological Life Support: Severe Traumatic Brain Injury. AB - Severe traumatic brain injury (TBI) causes substantial morbidity and mortality, and is a leading cause of death in both the developed and developing world. The need for a systematic evidence-based approach to the care of severe TBI patients within the emergency setting has led to its inclusion as an Emergency Neurological Life Support topic. This protocol was designed to enumerate the practice steps that should be considered within the first critical hours of neurological injury from severe TBI. PMID- 28913755 TI - Management and clinical outcome of stable coronary artery disease in Austria : Results from 5 years of the CLARIFY registry. AB - BACKGROUND: The population of patients with established coronary artery disease (CAD) is growing because of an improvement in outcomes and survival from acute disease episodes. Nevertheless, these patients remain at high risk of cardiovascular events. Thus, CAD management is important in prevention of disease progression. The objective of this analysis was to describe disease management and clinical outcome of Austrian outpatients with stable CAD over 5 years by using data from the international CLARIFY registry. METHODS: CLARIFY was an international prospective observational registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization (CABG or PCI), coronary stenosis of more than 50% by coronary angiography or chest pain with myocardial ischemia. We analyzed demographic characteristics, risk factors, treatments and clinical outcomes of 424 Austrian outpatients with established CAD who were enrolled between November 2009 and July 2010 and observed until September 2015. RESULTS: The primary risk factors in Austrian outpatients with stable CAD were smoking (current smokers: 13.2%), overweight (77.1%), hypertension (78.5%), raised low-density lipoprotein (LDL) cholesterol plasma levels (81.4% >= 0.7 g/l or 1.8 mmol/l), elevated heart rate (>=70 bpm: 60.9% in patients with anginal symptoms) and poor physical activity (none or light activity: 63.4%). Patients received lipid-lowering drugs (predominantly statins), aspirin, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors according to current recommendations. After 5 years a systolic blood pressure (SBP) < 140 mm Hg and diastolic blood pressure (DBP) < 90 mm Hg was reached in 58.5% of patients. Of the patients 70.4% had LDL cholesterol plasma levels below 1.0 g/l (2.6 mmol/l), 42.1% of smokers had stopped smoking, 42.9% of patients with anginal symptoms had a heart rate <=60 bpm and 26.0% of diabetic patients had brought their HbA1c levels below 6.5%. Cardiovascular death, myocardial infarction or stroke occurred in 30 patients (7.1%), all-cause death in 25 cases (5.9%) and cardiovascular death in 15 cases (3.5%). Myocardial infarction was reported in 14 patients (fatal and non-fatal: 3.3%) and stroke in 8 patients (fatal and non-fatal: 1.9%), 39 patients (9.2%) underwent myocardial revascularization and 124 patients (29.2%) experienced cardiovascular hospitalization. CONCLUSION: Characteristics of Austrian outpatients with stable CAD corresponded to those of patients with CAD in other developed countries. Medical treatments following the recommendations of the European guidelines were prescribed in the majority of patients; however, recommended goals of life style interventions including a heart rate less than 60 bpm and general risk factor management were not achieved by a high proportion of patients. Heart rate control and life style changes remain unmet needs of cardiovascular care in Austria. PMID- 28913756 TI - Spatial analysis and health risk assessment of heavy metals concentration in drinking water resources. AB - The heavy metals available in drinking water can be considered as a threat to human health. Oncogenic risk of such metals is proven in several studies. Present study aimed to investigate concentration of the heavy metals including As, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, and Zn in 39 water supply wells and 5 water reservoirs within the cities Ardakan, Meibod, Abarkouh, Bafgh, and Bahabad. The spatial distribution of the concentration was carried out by the software ArcGIS. Such simulations as non-carcinogenic hazard and lifetime cancer risk were conducted for lead and nickel using Monte Carlo technique. The sensitivity analysis was carried out to find the most important and effective parameters on risk assessment. The results indicated that concentration of all metals in 39 wells (except iron in 3 cases) reached the levels mentioned in EPA, World Health Organization, and Pollution Control Department standards. Based on the spatial distribution results at all studied regions, the highest concentrations of metals were derived, respectively, for iron and zinc. Calculated HQ values for non carcinogenic hazard indicated a reasonable risk. Average lifetime cancer risks for the lead in Ardakan and nickel in Meibod and Bahabad were shown to be 1.09 * 10-3, 1.67 * 10-1, and 2 * 10-1, respectively, demonstrating high carcinogenic risk compared to similar standards and studies. The sensitivity analysis suggests high impact of concentration and BW in carcinogenic risk. PMID- 28913757 TI - Mycobacterium shimoidei-cavitary pulmonary disease with favorable outcome. AB - We report a case of cavitary pulmonary disease caused by Mycobacterium shimoidei in 67-year-old female with history of asthma. Even though susceptibility testing was not available, choice of treatment regimen (streptomycin, rifampicin, ethambutol, and clarithromycin), based on a few cases with favorable outcome reported in the literature, resulted with an excellent clinical, microbiological, and radiological response. This is the first report of pulmonary disease caused by M. shimoidei, but also the first ever isolation of M. shimoidei in Croatia. PMID- 28913758 TI - A Review of Hydrogen Production by Photosynthetic Organisms Using Whole-Cell and Cell-Free Systems. AB - Molecular hydrogen is a promising currency in the future energy economy due to the uncertain availability of finite fossil fuel resources and environmental effects from their combustion. It also has important uses in the production of fertilizers and platform chemicals as well as in upgrading conventional fuels. Conventional methods for producing molecular hydrogen from natural gas produce carbon dioxide and use a finite resource as feedstock. However, these issues can be overcome by using light energy from the Sun combined with microorganisms and their molecular machinery capable of photosynthesis. In the presence of light, the proteins involved in photosynthesis coupled with appropriate catalysts in higher plants, algae, and cyanobacteria can produce molecular hydrogen, and optimization via genetic modifications and biomolecular engineering further improves production rates. In this review, we will discuss techniques that have been utilized to improve rates of hydrogen production in biological systems based on the protein machinery of photosynthesis coupled with appropriate catalysts. We will also suggest areas for improvement and future directions for work in the field. PMID- 28913759 TI - Biofuel consumption, biodiversity, and the environmental Kuznets curve: trivariate analysis in a panel of biofuel consuming countries. AB - This study examined the relationship between biofuel consumption, forest biodiversity, and a set of national scale indicators of per capita income, foreign direct investment (FDI) inflows, trade openness, and population density with a panel data of 12 biofuels consuming countries for a period of 2000 to 2013. The study used Global Environmental Facility (GEF) biodiversity benefits index and forest biodiversity index in an environmental Kuznets curve (EKC) framework. The results confirmed an inverted U-shaped relationship between GEF biodiversity index and per capita income, while there is flat/no relationship between carbon emissions and economic growth, and between forest biodiversity and economic growth models. FDI inflows and trade openness both reduce carbon emissions while population density and biofuel consumption increase carbon emissions and decrease GEF biodiversity index. Trade openness supports to increases GEF biodiversity index while it decreases forest biodiversity index and biofuel consumption in a region. PMID- 28913761 TI - Radioactive Seed Localization Versus Wire-Guided Localization for Nonpalpable Breast Cancer: A Cost and Operating Room Efficiency Analysis. AB - BACKGROUND: This study aimed to compare the cost and resource use between our first-year experience using breast-conserving surgery (BCS) with radioactive seed localization (RSL) and the previous-year standard practice of BCS with wire guided localization (WGL) for patients with nonpalpable breast cancer at a large Canadian tertiary center. METHODS: For this retrospective cohort study, data for BCS cases with RSL was collected from 1 April 2015 to 31 March 2016 and for BCS cases with WGL from 1 April 2014 to 31 March 2015. RESULTS: The study compared 153 WGL patients with 194 RSL patients. The two groups had no significant demographic differences. The average cost per patient for RSL, including opportunity costs, was $250.90 versus $1130.41 for WGL. Dedicated allocated radiology appointments to RSL increased (9 per day), and fewer radiologists were required for these procedures per day. Patients were transported to the operating room more quickly for RSL procedures (120 vs. 254 min; p < 0.001). Fewer vasovagal reactions occurred after insertion of RSL versus WGL (p = 0.05). No significant differences were observed in terms of surgical time, specimen volume, positive margins, or margin reexcision rates. No significant differences in postoperative complication rates were observed. CONCLUSIONS: In this study, RSL had lower costs than WGL, allowed for more efficient use of radiology scheduling and resources, and had shorter wait times for patients on their day of surgery. In addition, RSL led to fewer vasovagal reactions at insertion. Therefore, RSL should be used instead of WGL given the reduced cost, decreased need of human resources, improved efficiency, and potential benefits to the patient experience. PMID- 28913762 TI - The role of computed tomography (CT) in predicting diplopia in orbital blowout fractures (BOFs). AB - PURPOSE: The management of orbital blowout fractures (BOFs) is controversial: the evaluation of diplopia is the most important criterion for planning whether to undertake surgery. Our aim was to determine CT findings that may suggest the presence of diplopia when patients with BOFs cannot be adequately examined to plan an orbital repair. METHOD AND MATERIALS: We retrospectively evaluated CT of all patients presented to our Emergency Department for blunt craniofacial trauma (N = 3334) from January 2014 to March 2016, selecting patients with CT demonstrated BOFs. The following CT variables were assessed: fracture location, fracture multifocality, bone fragments displacement, extraocular muscles (EOM) thickening, EOM entrapment, EOM displacement, EOM hooking, intraconal and extraconal emphysema, intraconal and extraconal hematoma, and fat herniation. All patients underwent Hess-Lancaster test, to establish the presence of diplopia. After performing group comparison with Pearson chi2 test, we derived our prediction model by using logistic regression, with diplopia as the prediction and CT variables as predictors. RESULTS: We observed 299 patients with BOFs, 46 (15.4%) with a Hess Lancaster test-proven diplopia. The CT variables with statistically significant difference between the group with diplopia and the group without diplopia were as follows: floor fracture (p = .014), bone fragments displacement (p = .001), multifocality (p = .005), EOM thickening (p = .001), EOM entrapment (p < .001), EOM displacement (p < .001), fat herniation (p = .003). The CT variables with significance as predictors of diplopia at multivariate analysis were as follows: orbital floor fracture (p value 0.015; odds ratio 2.871, 95% confidence interval of odds ratio 0.223-6.738), EOM displacement (p value 0.001; odds ratio 10.693, 95% confidence interval of odds ratio 3.761 30.401), EOM entrapment (p value 0.001; odds ratio 11.510, 95% confidence interval of odds ratio 3.059-43.306). CONCLUSION: The presence of diplopia can be suggested on the basis of CT findings after an orbital trauma. PMID- 28913760 TI - Impact of histopathology, tumor-infiltrating lymphocytes, and adjuvant chemotherapy on prognosis of triple-negative breast cancer. AB - BACKGROUND: Given its high recurrence risk, guidelines recommend systemic therapy for most patients with early-stage triple-negative breast cancer (TNBC). While some clinicopathologic factors and tumor-infiltrating lymphocytes (TILs) are known to be prognostic in patients receiving chemotherapy, their prognostic implications in systemically untreated patients remain unknown. METHODS: From a cohort of 9982 women with surgically treated non-metastatic breast cancer, all patients with clinically reported ER-negative/borderline (<=10%) disease were selected for central assessment of ER/PR/HER2, histopathology, Ki-67, and TILs. The impact of these parameters on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. RESULTS: Six hundred five patients met the criteria for TNBC (ER/PR < 1% and HER2 negative). Most were T1-2 (95%), N0-1 (86%), grade 3 (88%), and had a Ki-67 >15% (75%). Histologically, 70% were invasive carcinoma of no special type, 16% medullary, 8% metaplastic, and 6% apocrine. The median stromal TIL content was 20%. Four hundred twenty-three (70%) patients received adjuvant chemotherapy. Median OS follow-up was 10.6 years. On multivariate analysis, only higher nodal stage, lower TILs, and the absence of adjuvant chemotherapy were associated with worse IDFS and OS. Among systemically untreated patients (n = 182), the 5-year IDFS was 69.9% (95% CI 60.7-80.5) [T1a: 82.5% (95% CI 62.8-100), T1b: 67.5% (95% CI 51.9-87.8) and T1c: 67.3% (95% CI 54.9-82.6)], compared to 77.8% (95% CI 68.3 83.6) for systemically treated T1N0. Nodal stage and TILs remained strongly associated with outcomes. CONCLUSIONS: In early-stage TNBC, nodal involvement, TILs, and receipt of adjuvant chemotherapy were independently associated with IDFS and OS. In systemically untreated TNBC, TILs remained prognostic and the risk of recurrence or death was substantial, even for T1N0 disease. PMID- 28913763 TI - A Patient-Specific Three-Dimensional Hemodynamic Model of the Circle of Willis. AB - Circle of Willis (CoW) is one of the most important cerebral arteries in the human body and various attempts have been made to study the hemodynamic of blood flow in this vital part of the brain. In the present study, blood flow in a patient specific CoW is numerically modeled to predict disease-prone regions of the CoW. Medical images and computer aided design software are used to construct a realistic three-dimensional model of the CoW for this particular case. The arteries are considered as elastic conduits and the interactions between arterial walls and the blood flow are taken into account. Mooney-Rivlin hyperelastic model is used to describe the behavior of arterial walls and blood is considered as a non-Newtonian fluid obeying the Carreau model. An available experimental-based pulsatile velocity profile is used at the entrance of the CoW. The finite element based commercial software, ADINA, is used to solve the governing equations. Blood pressure and velocity and arterial wall shear stress are calculated in different regions of the CoW. A simplified form of the model is also compared with the available published data. Results affirmed that the proposed computational model has the potential to capture the hemodynamic characteristics of the CoW. The computational results can be used to determine disease-prone locations for a given CoW. PMID- 28913764 TI - Drivers, challenges and opportunities of forage technology adoption by smallholder cattle households in Cambodia. AB - Forage technology has been successfully introduced into smallholder cattle systems in Cambodia as an alternative feed source to the traditional rice straw and native pastures, improving animal nutrition and reducing labour requirements of feeding cattle. Previous research has highlighted the positive impacts of forage technology including improved growth rates of cattle and household time savings. However, further research is required to understand the drivers, challenges and opportunities of forage technology for smallholder cattle households in Cambodia to facilitate widespread adoption and identify areas for further improvement. A survey of forage-growing households (n = 40) in July September 2016 examined forage technology adoption experiences, including reasons for forage establishment, use of inputs and labour requirements of forage plot maintenance and use of forages (feeding, fattening, sale of grass or seedlings and silage). Time savings was reported as the main driver of forage adoption with household members spending approximately 1 h per day maintaining forages and feeding it to cattle. Water availability was reported as the main challenge to this activity. A small number of households also reported lack of labour, lack of fencing, competition from natural grasses, cost of irrigation and lack of experience as challenges to forage growing. Cattle fattening and sale of cut forage grass and seedlings was not found to be a widespread activity by interviewed households, with 25 and 10% of households reporting use of forages for these activities, respectively. Currently, opportunities exist for these households to better utilise forages through expansion of forage plots and cattle activities, although assistance is required to support these households in addressing current constraints, particularly availability of water, if the sustainability of this feed technology for smallholder cattle household is to be established in Cambodia. PMID- 28913765 TI - Treatment of Theiler's virus-induced demyelinating disease with teriflunomide. AB - Teriflunomide is an oral therapy approved for the treatment of relapsing remitting multiple sclerosis (MS), showing both anti-inflammatory and antiviral properties. Currently, it is uncertain whether one or both of these properties may explain teriflunomide's beneficial effect in MS. Thus, to learn more about its mechanisms of action, we evaluated the effect of teriflunomide in the Theiler's encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model, which is both a viral infection and an excellent model of the progressive disability of MS. We assessed the effects of the treatment on central nervous system (CNS) viral load, intrathecal immune response, and progressive neurological disability in mice intracranially infected with TMEV. In the TMEV IDD model, we showed that teriflunomide has both anti-inflammatory and antiviral properties, but there seemed to be no impact on disability progression and intrathecal antibody production. Notably, benefits in TMEV-IDD were mostly mediated by effects on various cytokines produced in the CNS. Perhaps the most interesting result of the study has been teriflunomide's antiviral activity in the CNS, indicating it may have a role as an antiviral prophylactic and therapeutic compound for CNS viral infections. PMID- 28913766 TI - Computational Modeling and Treatment Identification in the Myelodysplastic Syndromes. AB - PURPOSE OF REVIEW: This review discusses the need for computational modeling in myelodysplastic syndromes (MDS) and early test results. RECENT FINDINGS: As our evolving understanding of MDS reveals a molecularly complicated disease, the need for sophisticated computer analytics is required to keep track of the number and complex interplay among the molecular abnormalities. Computational modeling and digital drug simulations using whole exome sequencing data input have produced early results showing high accuracy in predicting treatment response to standard of care drugs. Furthermore, the computational MDS models serve as clinically relevant MDS cell lines for pre-clinical assays of investigational agents. MDS is an ideal disease for computational modeling and digital drug simulations. Current research is focused on establishing the prediction value of computational modeling. Future research will test the clinical advantage of computer-informed therapy in MDS. PMID- 28913767 TI - Management of Atypical Renal Cell Carcinomas. AB - OPINION STATEMENT: Non-clear cell renal cell carcinoma (RCC) encompasses a diverse group of diseases, with research yielding different histologic findings and genetic profiles with each distinct subgroup. Simply mirroring the management techniques of clear cell RCC and borrowing from its growing armamentarium of therapeutic agents, while somewhat productive at first, but will ultimately be limiting. Further investigation into the molecular pathogenesis of disease, similarities and differences between specific subtypes, and mechanisms of resistance to therapeutics will help identify new targets, stimulate development of novel agents, and improve clinical trial offerings for non-clear cell RCC (nccRCC). As nccRCC has been largely excluded from past trials, there will be a need for future trials to be designed either to evaluate nccRCC specifically, or to include nccRCC as a prespecified subgroup. Multi-center collaborative trials should be supported, as many of the nccRCC subtypes are rare and remain underrepresented even within the construct of trials that only enroll nccRCC. Given the absence of clear molecular targets at present, patients with metastatic nccRCC should be offered and encouraged enrollment on clinical studies whenever possible. PMID- 28913768 TI - Ionic effects on the temperature-force phase diagram of DNA. AB - Double-stranded DNA (dsDNA) undergoes a structural transition to single-stranded DNA (ssDNA) in many biologically important processes such as replication and transcription. This strand separation arises in response either to thermal fluctuations or to external forces. The roles of ions are twofold, shortening the range of the interstrand potential and renormalizing the DNA elastic modulus. The dsDNA-to-ssDNA transition is studied on the basis that dsDNA is regarded as a bound state while ssDNA is regarded as an unbound state. The ground state energy of DNA is obtained by mapping the statistical mechanics problem to the imaginary time quantum mechanics problem. In the temperature-force phase diagram the critical force F c (T) increases logarithmically with the Na+ concentration in the range from 32 to 110 mM. Discussing this logarithmic dependence of F c (T) within the framework of polyelectrolyte theory, it inevitably suggests a constraint on the difference between the interstrand separation and the length per unit charge during the dsDNA-to-ssDNA transition. PMID- 28913769 TI - Plantactinospora solaniradicis sp. nov., a novel actinomycete isolated from the root of a tomato plant (Solanum lycopersicum L.). AB - A Gram-positive, non-motile actinomycete, designated strain NEAU-FJL1T, was isolated from tomato root (Solanum lycopersicum L.) collected from Harbin, Heilongjiang province, north China. The strain formed single spores with smooth surfaces from substrate mycelia. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NEAU-FJL1T should be affiliated with the genus Plantactinospora and forms a distinct branch with its close neighbour Plantactinospora soyae NEAU-gxj3T (99.2% sequence similarity). The cell wall was found to contain meso-diaminopimelic acid and the whole cell sugars were identified as xylose, glucose, arabinose and galactose. The predominant menaquinones were identified as MK-10(H6) and MK-10(H4). The phospholipid profile was found to consist of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. The major fatty acids were identified as C15:0, iso-C16:0, anteiso-C17:0, C17:0 and iso-C15:0. With reference to phenotypic characteristics, phylogenetic data and DNA-DNA hybridization results, strain NEAU-FJL1T can be distinguished from its most closely related strain and classified as a new species, for which the name Plantactinospora solaniradicis sp. nov. is proposed. The type strain is NEAU-FJL1T (= DSM 100596T = CGMCC 4.7284T). PMID- 28913770 TI - Sleep Deprived and Overwhelmed: Sleep Behaviors of Medical Students in the USA. PMID- 28913771 TI - Criminal Prohibition of Wrongful Re-identification: Legal Solution or Minefield for Big Data? AB - The collapse of confidence in anonymization (sometimes also known as de identification) as a robust approach for preserving the privacy of personal data has incited an outpouring of new approaches that aim to fill the resulting trifecta of technical, organizational, and regulatory privacy gaps left in its wake. In the latter category, and in large part due to the growth of Big Data driven biomedical research, falls a growing chorus of calls for criminal and penal offences to sanction wrongful re-identification of "anonymized" data. This chorus cuts across the fault lines of polarized privacy law scholarship that at times seems to advocate privacy protection at the expense of Big Data research or vice versa. Focusing on Big Data in the context of biomedicine, this article surveys the approaches that criminal or penal law might take toward wrongful re identification of health data. It contextualizes the strategies within their respective legal regimes as well as in relation to emerging privacy debates focusing on personal data use and data linkage and assesses the relative merit of criminalization. We conclude that this approach suffers from several flaws and that alternative social and legal strategies to deter wrongful re-identification may be preferable. PMID- 28913772 TI - Weight gain after subthalamic nucleus deep brain stimulation in Parkinson's disease is influenced by dyskinesias' reduction and electrodes' position. AB - Parkinson's disease is a common neurodegenerative disease that can be treated with pharmacological or surgical therapy. Subthalamic nucleus (STN) deep brain stimulation is a commonly used surgical option. A reported side effect of STN-DBS is weight gain: the aim of our study was to find those factors that determine weight gain, through one year-long observation of 32 patients that underwent surgery in our centre. During the follow-up, we considered: anthropometric features, hormonal levels, motor outcome, neuropsychological and quality of life outcomes, therapeutic parameters and electrodes position. The majority (84%) of our patients gained weight (6.7 kg in 12 months); more than a half of the cohort became overweight. At 12th month, weight gain showed a correlation with dyskinesias reduction, electrodes voltage and distance on the lateral axis. In the multivariate regression analysis, the determinants of weight gain were dyskinesias reduction and electrodes position. In this study, we identified dyskinesias reduction and distance between the active electrodes and the third ventricle as determining factors of weight gain after STN-DBS implantation in PD patients. The first finding could be linked to a decrease in energy consumption, while the second one could be due to a lower stimulation of the lateral hypothalamic area, known for its important role in metabolism and body weight control. Weight gain is a common finding after STN-DBS implantation, and it should be carefully monitored given the potential harmful consequences of overweight. PMID- 28913773 TI - Food nitrogen footprint reductions related to a balanced Japanese diet. AB - Dietary choices largely affect human-induced reactive nitrogen accumulation in the environment and resultant environmental problems. A nitrogen footprint (NF) is an indicator of how an individual's consumption patterns impact nitrogen pollution. Here, we examined the impact of changes in the Japanese diet from 1961 to 2011 and the effect of alternative diets (the recommended protein diet, a pescetarian diet, a low-NF food diet, and a balanced Japanese diet) on the food NF. The annual per capita Japanese food NF has increased by 55% as a result of dietary changes since 1961. The 1975 Japanese diet, a balanced omnivorous diet that reportedly delays senescence, with a protein content similar to the current level, reduced the current food NF (15.2 kg N) to 12.6 kg N, which is comparable to the level in the recommended protein diet (12.3 kg N). These findings will help consumers make dietary choices to reduce their impacts on nitrogen pollution. PMID- 28913774 TI - Is Integration Always most Adaptive? The Role of Cultural Identity in Academic Achievement and in Psychological Adaptation of Immigrant Students in Germany. AB - Immigrant adaptation research views identification with the mainstream context as particularly beneficial for sociocultural adaptation, including academic achievement, and identification with the ethnic context as particularly beneficial for psychological adaptation. A strong identification with both contexts is considered most beneficial for both outcomes (integration hypothesis). However, it is unclear whether the integration hypothesis applies in assimilative contexts, across different outcomes, and across different immigrant groups. This study investigates the association of cultural identity with several indicators of academic achievement and psychological adaptation in immigrant adolescents (N = 3894, 51% female, M age= 16.24, SD age = 0.71) in Germany. Analyses support the integration hypothesis for aspects of psychological adaptation but not for academic achievement. Moreover, for some outcomes, findings vary across immigrant groups from Turkey (n = 809), the former Soviet Union (n = 712), and heterogeneous other countries (n = 2373). The results indicate that the adaptive potential of identity integration is limited in assimilative contexts, such as Germany, and that it may vary across different outcomes and groups. As each identification is positively associated with at least one outcome, however, both identification dimensions seem to be important for the adaptation of immigrant adolescents. PMID- 28913775 TI - Complete mitochondrial genome of Taharana fasciana (Insecta, Hemiptera: Cicadellidae) and comparison with other Cicadellidae insects. AB - Here, we describe the first complete mitochondrial genome (mitogenome) sequence of the leafhopper Taharana fasciana (Coelidiinae). The mitogenome sequence contains 15,161 bp with an A + T content of 77.9%. It includes 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one non-coding (A + T rich) region; in addition, a repeat region is also present (GenBank accession no. KY886913). These genes/regions are in the same order as in the inferred insect ancestral mitogenome. All protein-coding genes have ATN as the start codon, and TAA or single T as the stop codons, except the gene ND3, which ends with TAG. Furthermore, we predicted the secondary structures of the rRNAs in T. fasciana. Six domains (domain III is absent in arthropods) and 41 helices were predicted for 16S rRNA, and 12S rRNA comprised three structural domains and 24 helices. Phylogenetic tree analysis confirmed that T. fasciana and other members of the Cicadellidae are clustered into a clade, and it identified the relationships among the subfamilies Deltocephalinae, Coelidiinae, Idiocerinae, Cicadellinae, and Typhlocybinae. PMID- 28913776 TI - Interactions of antisera to different Chlamydia and Chlamydophila species with the ribosomal protein RPS27a correlate with impaired protein synthesis in a human choroid plexus papilloma cell line. AB - Chlamydia trachomatis (CT) and the Chlamydophila species (CS) Chlamydophila pneumoniae (CPn), and Chlamydophila psittaci (CPs) are suggested to induce autoantibodies causative of several human autoimmune disorders like rheumatoid arthritis and systemic lupus erythematosus (SLE). The aim of the present study was therefore to identify cellular protein interaction partners with antisera to CT (alpha-CT) or CS (alpha-CS) and to identify functional consequences of such interaction in vitro. As detected with a commercial first trimester human prenatal brain multiprotein array (hEXselect, Engine, Germany), the most frequent interaction partner with both alpha-CT and alpha-CS was the ribosomal small subunit protein RPS27a. This could be confirmed by Western blot analysis with a recombinant RPS27a sample. In addition, immunocytochemistry with both antisera in the human choroid plexus papilloma cell line HIBCPP revealed a granular cytoplasmic staining, and Western blot analysis with whole-cell protein samples of HIBCPP cells revealed both antisera to label protein bands of different molecular weights and intensity. By 2D Western blot analysis and mass spectrometry, one of the protein spots interacting with alpha-CT could be identified as the RPS27a. Finally, two different methods for the detection of protein synthesis activity, the SUnSET technique and an HPG fluorescence assay revealed both antisera to cause reduced translational activity in HIBCPP cells. Together with previous findings of RPS27a as an autoimmune target in a mouse model of systemic lupus erythematosus (SLE), these results suggest that infections with CT and/or CS could induce SLE-associated immune modifications. However, direct evidence for a pathogenic role of these interactions for SLE demands further investigations. PMID- 28913778 TI - Neural Basis of Early Somatosensory Change Detection: A Magnetoencephalography Study. AB - The mismatch negativity (MMN) reflects the early detection of changes in sensory stimuli at the cortical level. The mechanisms underlying its genesis remain debated. This magnetoencephalography study investigates the spatio-temporal dynamics and the neural mechanisms of the magnetic somatosensory MMN. Somatosensory evoked magnetic fields elicited by tactile stimulation of the right fingertip (Single), tactile stimulation of the right middle phalanx and fingertip (Double) or omissions (Omitted) of tactile stimuli were studied in different paradigms: in oddballs where Double/Omitted followed a sequence of four Single, in sequences of two stimuli where Double occurred after one Single, and in random presentation of Double only. The predictability of Double occurrence in oddballs was also manipulated. Cortical sources of evoked responses were identified using equivalent current dipole modeling. Evoked responses elicited by Double were significantly different from those elicited by Single at the contralateral secondary somatosensory (cSII) cortex. Double elicited higher cSII cortex responses than Single when preceded by a sequence of four Single, compared to when they were preceded by one Single. Double elicited higher cSII cortex response when presented alone compared to when Double were preceded by one or a sequence of Single. Omitted elicited similar cSII cortex response than Single. Double in oddballs led to higher cSII cortex responses when less predictable. These data suggest that early tactile change detection involves mainly cSII cortex. The predictive coding framework probably accounts for the SII cortex response features observed in the different tactile paradigms. PMID- 28913779 TI - Effects of sublethal Abamectin exposure on some hormonal profiles and testicular histopathology in male albino rats and the possible ameliorative role of Eruca sativa. AB - The ameliorative role of Eruca sativa on some hormonal profile and testicular histopathology in male albino rats exposed to a sublethal dose of 1 mg/kg body weight (b.wt). Abamectin (Crater 3.37% EC) was evaluated. Eighteen male albino rats were divided into three groups: control group, Abamectin-treated group, and Abamectin + E. sativa-treated group. Rats of the second group were orally administrated 1 mg/kg b.wt. of Abamectin, the third group received a mixture of sublethal oral dose of Abamectin (1 mg/kg b.wt.) and E. sativa suspension (5 g/kg b.wt.) every 48 h for 28 days. At the end of the study, blood samples were collected from all groups to measure some hormonal parameters; also, rats were dissected and tissue sections from the testes were prepared and stained with hematoxylin and eosin for examination under light microscope. The results of the present study revealed a disturbance in the hormonal parameters and some testicular histopathological changes. In addition, administration of E. sativa might have a promising effect against Abamectin toxicity-induced disorders of thyroid hormones and impaired testicular functions, which were correlated with histopathological changes in the testes of male rats. PMID- 28913777 TI - Diabetes and the Small Intestine. AB - OPINION STATEMENT: Diabetes mellitus (DM) and its associated complications are becoming increasingly prevalent. Gastrointestinal symptoms associated with diabetes is known as diabetic enteropathy (DE) and may manifest as either diarrhea, fecal incontinence, constipation, dyspepsia, nausea, and vomiting or a combination of symptoms. The long-held belief that vagal autonomic neuropathy is the primary cause of DE has recently been challenged by newer theories of disease development. Specifically, hyperglycemia and the resulting oxidative stress on neural networks, including the nitrergic neurons and interstitial cells of Cajal (ICC), are now believed to play a central role in the development of DE. DE occurs in the majority of patients with diabetes; however, tools for early diagnosis and targeted therapy to counter the detrimental and potentially irreversible effects on the small bowel are lacking. Delay in diagnosis is further compounded by the fact that DE symptoms overlap with those of gastroparesis or can be confused with side effects from diabetes medications. Still, early recognition of the presence of DE is essential to mitigating symptoms and preventing further progression of complications including dysmotility and malabsorption. Current diagnostic modalities include manometry, wireless motility capsule (SmartPillTM), and scintigraphy; however, these are not regularly utilized in clinical practice due to limited availability. Several medications are available for symptom relief in DE patients including rifaximin for small intestinal bacterial overgrowth (SIBO) and somatostatin analogues for diarrhea. While rodent models on stem cell therapy and alteration of the microbiome are promising, there is still a great need for further research on the pathologic underpinnings and development of novel treatment modalities for DE. PMID- 28913780 TI - Anxiolytic-like effects of alpha-asarone in a mouse model of chronic pain. AB - alpha-asarone (ASR) is a major bioactive compound isolated from the rhizome of Acorus tatarinowii Schott and it has extensive biological effects. Clinically, anxiety disorder is a common comorbidity of chronic pain. However, limited information is available regarding the effects of ASR on chronic pain-related anxiety. This study aims to evaluate the anxiolytic effects of ASR in chronic pain mice. Chronic inflammatory pain was induced by hind-paw injection of complete Freund's adjuvant (CFA). Behavioral tests, western-blot analysis and whole-cell patch recordings were performed to evaluate the subsequent events. We found that ASR induced anxiolytic activities in CFA-injected mice but did not affect the nociceptive threshold. ASR administration reversed the up-regulation of GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, NR2A-containing N-methyl-D-aspartate (NMDA) receptors and down regulation of gamma-aminobutyric acid A (GABAA) receptors in the basolateral amygdala (BLA) of CFA-injected mice. Electrophysiological data revealed that ASR treatment restored the balance between excitatory and inhibitory neurotransmissions, which was disturbed in the BLA of CFA-injected mice. Moreover, ASR prevented the hyper-excitability of pyramidal neurons in the BLA of chronic pain mice. Our results suggested that the anxiolytic effects of ASR were partially due to maintaining the balance between excitatory/inhibitory transmissions and attenuating neuronal hyper-excitability of excitatory neurons in the BLA. PMID- 28913781 TI - Effects of Fluoride and/or Sulfur Dioxide on Morphology and DNA Integrity in Rats' Hepatic Tissue. AB - This study was aimed to evaluate the toxic effects of fluoride (F) and/or sulfur dioxide (SO2) on morphology and DNA integrity in liver of male rats. For this, 96 Wistar rats (12-week-old) were randomly divided into four groups after 1-week adaptive breeding: the control group, treated with deionized water; the NaF group, administered high F (100 mg NaF/L in the drinking water); the SO2 group, with sulfur dioxide in ambient air (15 ppm SO2, 4 h/day); and NaF + SO2 group, treated with high F and sulfur dioxide together for 8 consecutive weeks. The body weight, liver organ coefficient, morphology, and DNA damage in the liver of rats were examined. The results showed that the body weight and liver organ coefficient were not significantly changed; however, significant pathological changes of liver tissues were observed in the NaF + SO2 group compared with the individual treated groups and control group. Furthermore, comet assay indicated that DNA damage in liver was significantly increased in the F and/or SO2 treatment groups at 2, 4, 6, and 8 weeks, especially at 4 weeks. These results indicate that the liver morphology and DNA integrity of rats are adversely affected by F and/or SO2 exposure. PMID- 28913782 TI - Docking of small molecules to farnesoid X receptors using AutoDock Vina with the Convex-PL potential: lessons learned from D3R Grand Challenge 2. AB - The 2016 D3R Grand Challenge 2 provided an opportunity to test multiple protein ligand docking protocols on a set of ligands bound to farnesoid X receptor that has many available experimental structures. We participated in the Stage 1 of the Challenge devoted to the docking pose predictions, with the mean RMSD value of our submission poses of 2.9 A. Here we present a thorough analysis of our docking predictions made with AutoDock Vina and the Convex-PL rescoring potential by reproducing our submission protocol and running a series of additional molecular docking experiments. We conclude that a correct receptor structure, or more precisely, the structure of the binding pocket, plays the crucial role in the success of our docking studies. We have also noticed the important role of a local ligand geometry, which seems to be not well discussed in literature. We succeed to improve our results up to the mean RMSD value of 2.15-2.33 A dependent on the models of the ligands, if docking these to all available homologous receptors. Overall, for docking of ligands of diverse chemical series we suggest to perform docking of each of the ligands to a set of multiple receptors that are homologous to the target. PMID- 28913783 TI - State of the art: the evolving role of RT in combined modality therapy for GBM. PMID- 28913784 TI - Managing wastes as green resources: cigarette butt-synthesized pesticides are highly toxic to malaria vectors with little impact on predatory copepods. AB - The development of novel mosquito control tools is a key prerequisite to build effective and reliable Integrated Vector Management strategies. Here, we proposed a novel method using cigarette butts for the synthesis of Ag nanostructures toxic to young instars of the malaria vector Anopheles stephensi, chloroquine (CQ) resistant malaria parasites Plasmodium falciparum and microbial pathogens. The non-target impact of these nanomaterials in the aquatic environment was evaluated testing them at sub-lethal doses on the predatory copepod Mesocyclops aspericornis. Cigarette butt-synthesized Ag nanostructures were characterized by UV-vis and FTIR spectroscopy, as well as by EDX, SEM and XRD analyses. Low doses of cigarette butt extracts (with and without tobacco) showed larvicidal and pupicidal toxicity on An. stephensi. The LC50 of cigarette butt-synthesized Ag nanostructures ranged from 4.505 ppm (I instar larvae) to 8.070 ppm (pupae) using smoked cigarette butts with tobacco, and from 3.571 (I instar larvae) to 6.143 ppm (pupae) using unsmoked cigarette butts without tobacco. Smoke toxicity experiments conducted against adults showed that unsmoked cigarette butts-based coils led to mortality comparable to permethrin-based positive control (84.2 and 91.2%, respectively). A single treatment with cigarette butts extracts and Ag nanostructures significantly reduced egg hatchability of An. stephensi. Furthermore, the antiplasmodial activity of cigarette butt extracts (with and without tobacco) and synthesized Ag nanostructures was evaluated against CQ resistant (CQ-r) and CQ-sensitive (CQ-s) strains of P. falciparum. The lowest IC50 values were achieved by cigarette butt extracts without tobacco, they were 54.63 MUg/ml (CQ-s) and 63.26 MUg/ml (CQ-r); while Ag nanostructure IC50 values were 72.13 MUg/ml (CQ-s) and 77.33 MUg/ml (CQ-r). In MIC assays, low doses of the Ag nanostructures inhibited the growth of Bacillus subtilis, Klebsiella pneumoniae and Salmonella typhi. Finally, the predation efficiency of copepod M. aspericornis towards larvae of An. stephensi did not decrease in a nanoparticle contaminated environment, if compared to control predation assays. Overall, the present research would suggest that an abundant hazardous waste, such as cigarette butts, can be turned to an important resource for nanosynthesis of highly effective antiplasmodials and insecticides. PMID- 28913785 TI - Evolution of Patient-Reported Outcomes and Their Role in Multiple Sclerosis Clinical Trials. AB - Patient-reported outcomes (PROs) are playing an increasing role in multiple sclerosis (MS) research and practice, and are essential for understanding the effects that MS and MS treatments have on patients' lives. PROs are captured directly from patients and include symptoms, function, health status, and health related quality of life. In this article, we review different categories (e.g., generic, targeted, preference-based) of PRO measures and considerations in selecting a measure. The PROs included in MS clinical research have evolved over time, as have the measures used to assess them. We describe findings from recent MS clinical trials that included PROs when evaluating Food and Drug Administration-approved disease-modifying therapies (e.g., daclizumab, teriflunomide). Variation in the measures used in these trials makes it difficult to draw any conclusions from the data. We therefore suggest a standardized approach to PRO assessment in MS research and describe 2 generic, National Institutes of Health-supported measurement systems [Neuro-QoL and the Patient Reported Outcomes Measurement Information System (PROMIS)] that would facilitate such an approach. The use of PROs in MS care and research is expanding beyond clinical trials, as is demonstrated by examples from comparative effectiveness and other patient-centered research. The importance of PRO assessment is expected to continue to grow in the future. PMID- 28913786 TI - The lipid droplet: A conserved cellular organelle. AB - The lipid droplet (LD) is a unique multi-functional organelle that contains a neutral lipid core covered with a phospholipid monolayer membrane. The LDs have been found in almost all organisms from bacteria to humans with similar shape. Several conserved functions of LDs have been revealed by recent studies, including lipid metabolism and trafficking, as well as nucleic acid binding and protection. We summarized these findings and proposed a hypothesis that the LD is a conserved organelle. PMID- 28913787 TI - Mortality rates and risk factors for emergent open repair of abdominal aortic aneurysms in the endovascular era. AB - The background of this paper is to report the mortality at 30 and 90 days and at mean follow-up after open abdominal aortic aneurysms (AAA) emergent repair and to identify predictive risk factors for 30- and 90-day mortality. Between 1997 and 2002, 104 patients underwent emergent AAA open surgery. Symptomatic and ruptured AAAs were observed, respectively, in 21 and 79% of cases. Mean patient age was 70 (SD 9.2) years. Mean aneurysm maximal diameter was 7.4 (SD 1.6) cm. Primary endpoints were 30- and 90-day mortality. Significant mortality-related risk factor identification was the secondary endpoint. Open repair trend and its related perioperative mortality with a per-year analysis and a correlation subanalysis to identify predictive mortality factor were performed. Mean follow up time was 23 (SD 23) months. Overall, 30-day mortality was 30%. Significant mortality-related risk factors were the use of computed tomography (CT) as a preoperative diagnostic tool, AAA rupture, preoperative shock, intraoperative cardiopulmonary resuscitation (CPR), use of aortic balloon occlusion, intraoperative massive blood transfusion (MBT), and development of abdominal compartment syndrome (ACS). Previous abdominal surgery was identified as a protective risk factor. The mortality rate at 90 days was 44%. Significant mortality-related risk factors were AAA rupture, aortocaval fistula, peripheral artery disease (PAD), preoperative shock, CPR, MBT, and ACS. The mortality rate at follow-up was 45%. Correlation analysis showed that MBT, shock, and ACS are the most relevant predictive mortality factor at 30 and 90 days. During the transition period from open to endovascular repair, open repair mortality outcomes remained comparable with other contemporary data despite a selection bias for higher risk patients. MBT, shock, and ACS are the most pronounced predictive mortality risk factors. PMID- 28913788 TI - Suboptimal use of statins for secondary cardiovascular prevention: a "planetary" issue. PMID- 28913789 TI - Cardiac sarcoidosis after glucocorticoid therapy evaluated by 18F fluorodeoxyglucose PET/MRI. PMID- 28913791 TI - Enabling Molecular Technologies for Trait Improvement in Wheat. AB - Wheat is the major staple food crop and a source of calories for humans worldwide. A steady increase in the wheat production is essential to meet the demands of an ever-increasing global population and to achieve food security. The large size and structurally intricate genome of polyploid wheat had hindered the genomic analysis. However, with the advent of new genomic technologies such as next generation sequencing has led to genome drafts for bread wheat and its progenitors and has paved the way to design new strategies for crop improvement. Here we provide an overview of the advancements made in wheat genomics together with the available "omics approaches" and bioinformatics resources developed for wheat research. Advances in genomic, transcriptomic, and metabolomic technologies are highlighted as options to circumvent existing bottlenecks in the phenotypic and genomic selection and gene transfer. The contemporary reverse genetics approaches, including the novel genome editing techniques to inform targeted manipulation of a single/multiple genes and strategies for generating marker-free transgenic wheat plants, emphasize potential to revolutionize wheat improvement shortly. PMID- 28913792 TI - What Will Be the Benefits of Biotech Wheat for European Agriculture? AB - In European countries, wheat occupies the largest crop area with high yielding production. France, a major producer and exporter in Europe, ranks the fifth producer worldwide. Biotic stresses are European farmers' major challenges (fungal and viral diseases, and insect pests) followed by abiotic ones such as drought and grain protein composition. During the last 40 years, 1136 scientific articles on biotech wheat were published by USA followed by China, Australia, Canada, and European Union with the UK. European research focuses on pests and diseases resistances using widely marker-assisted selection (MAS). Transgenesis is used in basic research to develop resistance against some fungi (Fusarium head blight) while RNA interference (RNAi) silencing is used against some fungi and virus. Transgenic plants were also transformed with genes from various species for drought tolerance. The UK (mostly with transgenesis and site-specific nucleases) and France (with no transgenic tools but with MAS and site-specific nucleases) are the main countries carrying out research programs for both biotic stress and drought tolerance. Thus, few European countries used transgenesis for gluten protein composition and RNAi-mediated silencing in celiac disease. Because of vandalism field trials of transgenics dropped since 2000. No transgenic wheat is cultivated in Europe for political reasons. PMID- 28913790 TI - Delivery of HSP90 Inhibitor Using Water Soluble Polymeric Conjugates with High Drug Payload. AB - PURPOSE: HSP90 (Heat shock protein 90kD) has been validated as a therapeutic target in Castrate Resistant Prostate Cancer. Unfortunately, HSP90 inhibitors suffer from dose-limiting toxicities that hinder their clinical applications. Previously developed polymeric delivery systems for HSP90 inhibitors had either low drug content or low biological activity suggesting the need for better delivery system for HSP90 inhibitors. METHODS: We developed a simplified synthetic strategy to prepare polyethylene glycol based water-soluble polymeric system for model HSP90 inhibitor geldanamycin (GDM). We then investigated the effect of cathepsin B degradable linker and drug content in polymeric conjugates on their growth inhibitory property using DU145 (androgen independent) and LNCaP (androgen dependent) cell lines. RESULTS: Water-soluble polymeric conjugates were synthesized with GDM content ranging from 9 to 30% wt/wt. We demonstrated the importance of cathepsin B degradable linker from the context of drug content and different prostate cancer cell lines. The most active conjugate against DU145 cells exhibited IC50 value of 2.9 MUM. This was similar to the IC50 (2.1 MUM) of small molecular drug aminohexane geldanamycin. CONCLUSION: Water-soluble polymeric conjugate with high drug content was synthesized that exhibited in vitro growth inhibitory activity similar to small molecular weight HSP90 inhibitor. Graphical Abstract Water soluble degradable polymeric conjugate for the delivery of Geldanamycin. PMID- 28913793 TI - Overview of the Wheat Genetic Transformation and Breeding Status in China. AB - In the past two decades, Chinese scientists have achieved significant progress on three aspects of wheat genetic transformation. First, the wheat transformation platform has been established and optimized to improve the transformation efficiency, shorten the time required from starting of transformation procedure to the fertile transgenic wheat plants obtained as well as to overcome the problem of genotype-dependent for wheat genetic transformation in wide range of wheat elite varieties. Second, with the help of many emerging techniques such as CRISPR/cas9 function of over 100 wheat genes has been investigated. Finally, modern technology has been combined with the traditional breeding technique such as crossing to accelerate the application of wheat transformation. Overall, the wheat end-use quality and the characteristics of wheat stress tolerance have been improved by wheat genetic engineering technique. So far, wheat transgenic lines integrated with quality-improved genes and stress tolerant genes have been on the way of Production Test stage in the field. The debates and the future studies on wheat transformation have been discussed, and the brief summary of Chinese wheat breeding research history has also been provided in this review. PMID- 28913794 TI - Wheat Improvement in India: Present and Future. AB - Wheat (Triticum aestivum L.) contributes substantially to global food and nutritional security. With the growing demands under the constraints of depleting natural resources, environmental fluctuation, and increased risk of epidemic outbreaks, the task of increasing wheat production has become daunting. The factors responsible for first green revolution seem to be exhausting rapidly, and there is an immediate need to develop the technologies which can not only increase the wheat production but also sustain the same at a higher level without adversely affecting the natural resources. Understanding abiotic stress factors such as temperature, drought tolerance, and biotic stress tolerance traits such as insect pest and pathogen resistance in combination with high yield in plants is of paramount importance to counter climate change related adverse effects on the productivity of wheat crops. Thus, an important goal of wheat breeding is to develop high-yielding varieties with better nutritional quality and resistance to major diseases. Therefore, in this chapter, we present a judicious mixture of basic as well as applied research outlooks. We trust that the information covered in this chapter would bridge the much-researched area of stress in plants with the information to breed climate-ready crop cultivars to ensure food security in the future. PMID- 28913795 TI - Overview of Methods for Assessing Salinity and Drought Tolerance of Transgenic Wheat Lines. AB - Salinity and drought are interconnected, causing phenotypic, physiological, biochemical, and molecular changes in a cell. These stresses are the major factors adversely affecting growth and productivity in cereals. Genetic engineering methods have advanced to enable development of genotypes with improved salinity and drought tolerance. The resulting transgenic plant produces a group of progenies which includes moderate to high-stress tolerant transgenic lines. Development of reproducible screening methods to identify high-stress tolerant germplasm under laboratory, greenhouse, or field conditions is must. Further, field level demonstration of improved phenotypes and yield under salinity and drought stress conditions is both challenging and expensive. Fast and efficient screening techniques that could be used to screen transgenic lines under greenhouse conditions, for salt and drought stress tolerance, may contribute toward the identification of promising lines for field conditions. This chapter provides information on various approaches which can be developed during different stages of plant development for selecting salinity and drought tolerant plants in cereals, especially wheat. PMID- 28913797 TI - Agribusiness Perspectives on Transgenic Wheat. AB - Declining yields of the major human food crops, looming growth in global population and rise of populism, and ill-founded bans on agricultural and horticultural crops and foodstuffs which are genetically modified have potentially serious implications. It makes the chance less than otherwise would be the case that agribusiness value chains in the future will meet the growing demand around the world for more and different foods from more and wealthier people. In the agribusiness value chain, transgenic wheat, meeting a consumer "trigger need" also must meet the "experience" and "credence," risk-related criteria of well-informed consumers. Public policy that rejects science-based evidence about the reductions in costs of production and price of genetically modified agricultural products and the science about the safety of genetically modified foods, including transgenic wheat, has imposed significant costs on producers and consumers. If the science-based evidence is accepted, transgenic wheat has potential to improve significantly the well-being of grain growers and consumers all over the world. PMID- 28913796 TI - Allergenicity Assessment of Transgenic Wheat Lines In Silico. AB - Agriculture biotechnology is a promising tool for developing varieties with enhanced quality and quantity. Transgenic proteins expressed by genetically modified (GM) food crops improve crop characteristics like nutritional value, taste, and texture, and endow plants with resistance against fungus, pests, and insects. Despite such potential benefits, there are concerns regarding possible adverse effects of GM crops on human health, animals and the environment. Among the proposed guidelines for GM food safety testing-the weight-of-evidence approach proposed by the Codex Alimentarius Commission (ALINORM 03/34A) is the most recent. Till date, several transgenic wheat lines have been developed and research is underway for further improvement. However, GM wheat is not being grown or consumed in any part of the world. In the present study, in silico tools were employed for safety testing of eight transgenes used for the development of transgenic wheat lines. Among the genes studied, none of them shared sequence homology with the reported allergens and may be safe for use in genetic engineering. In conclusion, gene selection for developing transgenic wheat lines should be done with utmost care to ensure its safety for feed and fodder. PMID- 28913798 TI - Agrobacterium-Mediated Transformation of Wheat Using Immature Embryos. AB - Methods of the Agrobacterium-mediated transformation of bread wheat (Triticum aestivum L.) have been improved in recent years so that genetic engineering can be routinely used for functional genomics as well as for wheat breeding. In the protocol described here, immature embryos of the spring-type model genotype Bobwhite SH 98 26 have been used. Preculture and temperature pretreatment of these explants have led to the reproducible generation of transgenic plants at efficiencies between 5 and 15%. Whereas primary transgenic plants regenerated in vitro commonly show reduced fitness and fertility, no apparent variations with regard to morphology and grain set in their transgenic progeny as compared to wild-type counterparts were observed. PMID- 28913799 TI - Biolistic Transformation of Wheat. AB - The wheat genome encodes some 100,000 genes. To understand how the expression of these genes is regulated it will be necessary to carry out many genetic transformation experiments. Robust protocols that allow scientists to transform a wide range of wheat genotypes are therefore required. In this chapter, we describe a protocol for biolistic transformation of wheat that uses immature embryos and small quantities of DNA cassettes. An original method for DNA cassette purification is also described. This protocol can be used to transform a wide range of wheat genotypes and other related species. PMID- 28913800 TI - Wheat Genetic Transformation Using Mature Embryos as Explants. AB - Feeding the growing population utilizing the limited agricultural resources remains a great challenge. Plant biotechnology plays a vital role in crop improvement by incorporating desired quality traits, tolerance to abiotic stresses and resistance to biotic stresses, which are otherwise tough to achieve by conventional plant breeding methodologies. Genetic engineering is a powerful tool to develop desired traits in selected crops to make the crops suitable for future demand and environment. For genetic engineering of crops like wheat, the development of efficient transformation and regeneration systems has always been a prime requirement. Immature embryo cultures have been used largely for genetic engineering purposes in wheat, but the availability of healthy immature embryos as explant throughout the year is difficult. In contrast, mature embryos are readily available throughout the year. Therefore, it is essential to develop an efficient transformation and regeneration system employing mature embryos as explant. Here, we summarize the recent developments in wheat tissue culture using mature embryos as explants and its use in genetic transformation. PMID- 28913801 TI - Targeted Mutagenesis in Hexaploid Bread Wheat Using the TALEN and CRISPR/Cas Systems. AB - The use of sequence-specific transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeats associated system (CRISPR/Cas9) have provided powerful reverse genetic approaches to the targeted modification of genomes in numerous organisms. Both systems have been employed to generate loss-of-function alleles in bread wheat, by targeting multiple and single copies of genes. Here we present protocols for modifying the wheat genome using the two systems. The protocols include the design of TALEN and CRISPR/Cas9 target sites and their construction, evaluation of their activities in protoplasts, transformation of plants, and mutation screening. PMID- 28913802 TI - Design and Assembly of CRISPR/Cas9 Reagents for Gene Knockout, Targeted Insertion, and Replacement in Wheat. AB - Advances in cereal transformation along with the completion of the wheat genome sequence assembly have increased the demand for tools that perform targeted and specific modifications in this crop plant. This protocol demonstrates the construction of reagents using a comprehensive genome engineering kit to create single and multiple gene "knockouts," site-specific chromosome deletions and gene replacement or "knockins" including the use of geminivirus replicons (GVRs). The reagents allow for both easy construction of simple genome engineering vectors, and "mix and match" swapping of components such as the Cas9, guide RNA and donor template cassettes for gene targeting. In addition, a web-based tool greatly streamlines vector selection, primer design, and vector construction. PMID- 28913803 TI - Doubled Haploid Transgenic Wheat Lines by Microspore Transformation. AB - Microspores are preferred explant choice for genetic transformation, as their use shortens the duration of obtaining homozygous transformants. All established gene delivery methods of particle bombardment, electroporation, and cocultivation with Agrobacterium tumefaciens were optimized on androgenic microspores or derived tissues. In the biolistic gene delivery method 35-40 days old haploid microspore embryoids were used for genetic transformation, whereas freshly isolated androgenic microspores were used for genetic transformation in the electroporation and Agrobacterium cocultivation-based methods. The genetic transformation methods of biolistic gene-delivery and electroporation gave rise to the chimeric plants, whereas the method involving cocultivation with Agrobacterium yielded homozygous transformants. These methods were tested on a large number of cultivars belonging to different market classes of wheat, and found to be fairly independent of the explant genotype. Other benefits of using microspores or derived tissues for transformation are: (1) a few explant donors are required to obtain desired transformants and (2) the time required for obtaining homozygous transformants is about 8 months in case of spring wheat genotypes and about a year in case of winter wheat genotypes. PMID- 28913804 TI - Doubled Haploid Laboratory Protocol for Wheat Using Wheat-Maize Wide Hybridization. AB - In traditional wheat breeding, the uniformity of lines derived from a breeding population is obtained by repeated selfing from the F1 which takes several generations to reach homozygosity in loci controlling traits of interest. Using doubled haploid technology, however, it is possible to attain 100% homozygosity at all loci in a single generation and completely homogeneous breeding lines can be obtained in 1-2 years. Thus, doubled haploid technology may significantly reduce cultivar development time. Two major methods for producing wheat doubled haploids are androgenesis (anther culture and microspore culture) and embryo culture using wheat-maize wide hybridization, the latter being the most effective and widely used method. The method of wide hybridization between wheat and maize is laborious but is widely successful for rapidly obtaining homozygous lines. This technique includes six major steps: emasculation of the wheat flower; pollination of the emasculated flower with maize pollen; hormone treatment; embryo rescue; haploid plant regeneration in tissue culture medium; and chromosome doubling. It has been observed that the efficiency of doubled haploid production depends on both maize and wheat genotypes, good plant health and proper greenhouse conditions (without disease, insects, or drought stress), and proper conduct of all procedures. Therefore, the procedures may need minor modification in order to produce higher numbers of embryos, haploid green plants, and doubled haploid plants. PMID- 28913805 TI - Real-Time PCR for the Detection of Precise Transgene Copy Number in Wheat. AB - Despite the unceasing advances in genetic transformation techniques, the success of common delivery methods still lies on the behavior of the integrated transgenes in the host genome. Stability and expression of the introduced genes are influenced by several factors such as chromosomal location, transgene copy number and interaction with the host genotype. Such factors are traditionally characterized by Southern blot analysis, which can be time-consuming, laborious, and often unable to detect the exact copy number of rearranged transgenes. Recent research in crop field suggests real-time PCR as an effective and reliable tool for the precise quantification and characterization of transgene loci. This technique overcomes most problems linked to phenotypic segregation analysis and can analyze hundreds of samples in a day, making it an efficient method for estimating a gene copy number integrated in a transgenic line. This protocol describes the use of real-time PCR for the detection of transgene copy number in durum wheat transgenic lines by means of two different chemistries (SYBR(r) Green I dye and TaqMan(r) probes). PMID- 28913806 TI - Endogenous Reference Genes and Their Quantitative Real-Time PCR Assays for Genetically Modified Bread Wheat (Triticum aestivum L.) Detection. AB - Endogenous reference genes (ERG) and their derivate analytical methods are standard requirements for analysis of genetically modified organisms (GMOs). Development and validation of suitable ERGs is the primary step for establishing assays that monitoring the genetically modified (GM) contents in food/feed samples. Herein, we give a review of the ERGs currently used for GM wheat analysis, such as ACC1, PKABA1, ALMT1, and Waxy-D1, as well as their performances in GM wheat analysis. Also, we discussed one model for developing and validating one ideal RG for one plant species based on our previous research work. PMID- 28913807 TI - Phenotypic Characterization of Transgenic Wheat Lines Against Fungal Pathogens Puccinia triticina and Fusarium graminearum. AB - Leaf rust (LR) and Fusarium head blight (FHB) caused by Puccinia triticina and Fusarium graminearum, respectively, are among the most damaging fungal diseases challenging wheat production worldwide. Genetic resistance in combination with fungicide application has been the most widely employed approach to combat these fungal pathogens. Alternative approaches that could augment current practices are needed for the control of these devastating pathogens. To that end, we have recently shown that the extracellular expression of antifungal defensin MtDEF4.2 from Medicago truncatula confers resistance to LR. Additionally, we show that expression of this defensin also provides Type II resistance to FHB under controlled growth chamber conditions. These findings have practical applications for control of these important fungal diseases in wheat. Here, we provide details on conducting LR and FHB bioassays of transgenic wheat lines in the growth chamber. PMID- 28913808 TI - Databases for Wheat Genomics and Crop Improvement. AB - The genomics revolution brought on by advances in high-throughput sequencing has led to the production of vast amounts of data. Databases play an essential role in storing and managing this information to make it available to researchers and crop breeders. This chapter provides an outline of how to use databases and tools for wheat genome research. PMID- 28913809 TI - High-Density SNP Genotyping Array for Hexaploid Wheat and Its Relatives. AB - A lack of genetic diversity between wheat breeding lines has been recognized as a significant block to future yield increases. Wheat breeding and prebreeding strategies are increasingly using material from wheat ancestors or wild relatives to reintroduce diversity. Where molecular markers are polymorphic between the host and introgressed material, they may be used to track the size and location of the introgressed material through generations of backcrossing. To generate markers for this purpose, sequence capture targeted resequencing was carried out for a range of wheat varieties, wheat relatives, and wheat progenitors. From these sequences, putative SNPs were identified and used to generate the Axiom(r) Wheat HD array. A selection of varieties representing a selection of elite wheat breeding material, progenitor species, and wild relatives were used to validate the array. The procedures used are described here in detail. PMID- 28913810 TI - Effect of nanoscale zero-valent iron confined in mesostructure on Escherichia coli. AB - Nanoscale zero-valent iron particles (NZVIs) confined in the mesochannels of SBA 15 have superabilities in the remediation of contaminated groundwater. As a new kind of remediation nanomaterials, it is necessary to investigate the ecotoxicity of NZVIs/SBA-15 composites during their applications. In this study, we evaluated the toxicity of NZVIs/SBA-15 on Escherichia coli and proposed a possible mechanism. Compared with the bare NZVIs and SBA-15 surface-supported NZVIs at the same equivalent concentration of NZVIs (0.42 or 0.84 g/L), NZVIs/SBA-15 composites had a minimal cytotoxicity on E. coli, though they had the smallest iron nanoparticle size, the largest zeta potential, and the best stability in water. The mechanism may be attributed to the protection of the mesochannels and the electrostatic hindrance resulting from the silica host that could keep NZVIs from directly contacting with the cell. Thus, NZVIs confined in the mesostructures can be safely used in the remediation of contaminated natural water. PMID- 28913811 TI - Emergency Neurological Life Support: Third Edition, Updates in the Approach to Early Management of a Neurological Emergency. AB - Emergency Neurologic Life Support (ENLS) is an educational program designed to provide users advisory instructions regarding management for the first few hours of a neurologic emergency. The content of the course is divided into 14 modules, each addressing a distinct category of neurological injury. The course is appropriate for practitioners and providers from various backgrounds who work in environments of variable medical complexity. The focus of ENLS is centered on a standardized treatment algorithm, checklists, to guide early patient care, and a structured format for communication of findings and concerns to other healthcare professionals. Certification and training in ENLS is hosted by the Neurocritical Care Society. This document introduces the concept of ENLS and describes revisions that constitute the third version. PMID- 28913812 TI - Theory of liquid crystal elastomers and polymer networks : Connection between neoclassical theory and differential geometry. AB - In liquid crystal elastomers and polymer networks, the orientational order of liquid crystals is coupled with elastic distortions of crosslinked polymers. Previous theoretical research has described these materials through two different approaches: a neoclassical theory based on the liquid crystal director and the deformation gradient tensor, and a geometric elasticity theory based on the difference between the actual metric tensor and a reference metric. Here, we connect those two approaches using a formalism based on differential geometry. Through this connection, we determine how both the director and the geometry respond to a change of temperature. PMID- 28913813 TI - Pharmacotherapy Pearls for Emergency Neurological Life Support. AB - The appropriate use of medications during Emergency Neurological Life Support (ENLS) is essential to optimize patient care. Important considerations when choosing the appropriate agent include the patient's organ function and medication allergies, potential adverse drug effects, drug interactions and critical illness and aging pathophysiologic changes. Critical medications used during ENLS include hyperosmolar therapy, anticonvulsants, antithrombotics, anticoagulant reversal and hemostatic agents, anti-shivering agents, neuromuscular blockers, antihypertensive agents, sedatives, vasopressors and inotropes, and antimicrobials. This article focuses on the important pharmacokinetic and pharmacodynamics characteristics, advantages and disadvantages and clinical pearls of these therapies, providing practitioners with essential drug information to optimize pharmacotherapy in acutely ill neurocritical care patients. PMID- 28913814 TI - Child with Abdominal Pain. AB - Abdominal pain is one of the common symptoms reported by children in urgent care clinics. While most children tend to have self-limiting conditions, the treating pediatrician should watch out for underlying serious causes like intestinal obstruction and perforation peritonitis, which require immediate referral to an emergency department (ED). Abdominal pain may be secondary to surgical or non surgical causes, and will differ as per the age of the child. The common etiologies for abdominal pain presenting to an urgent care clinic are acute gastro-enteritis, constipation and functional abdominal pain; however, a variety of extra-abdominal conditions may also present as abdominal pain. Meticulous history taking and physical examination are the best tools for diagnosis, while investigations have a limited role in treating benign etiologies. PMID- 28913815 TI - Pharmacokinetic-Pharmacodynamic Analysis of Cisplatin with Hydration and Mannitol Diuresis: The Contribution of Urine Cisplatin Concentration to Nephrotoxicity. AB - BACKGROUND AND OBJECTIVES: Forced diuresis, high-volume hydration with diuresis, is widely used as a prophylactic treatment against cisplatin nephrotoxicity. However, the details of the underlying mechanisms and the optimal protocol of forced diuresis remain unclear. The present study investigated the alterations in pharmacokinetics and pharmacodynamics (nephrotoxicity) of cisplatin with forced diuresis treatment. METHODS: Cisplatin (5 mg/kg) was intravenously injected to rats (5 rats/group, except for control group in pharmacodynamic study, n = 13) treated with or without forced diuresis 2-h pre- and post-hydration with 10% mannitol at different infusion rates (0.3, 1.0, and 3.0 mL/h). The unbound cisplatin concentrations in plasma and urine, and the platinum amount in the kidney were monitored in the pharmacokinetic studies. The plasma creatinine concentration was evaluated as an index of nephrotoxicity in the pharmacodynamic studies. RESULTS: Forced diuresis treatment did not significantly alter the plasma cisplatin pharmacokinetics but dramatically decreased the urine concentration of unbound cisplatin and its accumulation into the kidneys in a dose-dependent manner, and correspondingly, nephrotoxicity was dose-dependently attenuated by forced diuresis. The pharmacokinetic-pharmacodynamic analysis suggested that the urine cisplatin concentration has a comparable impact on the cisplatin-induced nephrotoxicity to that in plasma, probably owing to the reabsorption of cisplatin from urine, which can be attenuated by forced diuresis. CONCLUSIONS: These results indicated that the nephroprotective effect of forced diuresis is a pharmacokinetic-based drug-drug interaction possibly due to the inhibition of cisplatin reabsorption from urine. Monitoring of urine cisplatin concentration may lead to the optimization of a forced diuresis protocol with mannitol. PMID- 28913817 TI - Return-to-Play in 2017 and the Role of Shared Decision-Making in Patients with Inherited and Acquired Channelopathies and Cardiomyopathies. AB - OPINION STATEMENT: Shared decision-making is based upon a physician-patient encounter in which there is adequate education using aids if needed, a mutual discussion of how to assist the patient in weighing risks and benefits, and a supportive environment that allows the patient to deliberate on the clinical decision and make their own choice. This decision-making paradigm centers on the principles of autonomy and self-determination. Physical activity is a critical part of healthy lifestyle choices that helps lower risk of cardiovascular disease or the progression of it. Exercise is also a significant contributor to quality of life in many patients in additional to the health benefits. In patients with inherited or acquired cardiovascular disease, exercise may increase risk of electrical and hemodynamic instability. There is a paucity of data to guide physicians and committees that create guidelines regarding athletic and fitness participation in these patients, particularly when the patient wants to participate in those activities that are considered moderate-severe in intensity. As a consequence, the principles of shared decision-making are critical for physicians to use to help patients with cardiovascular disease make the best decision regarding fitness participation that will minimize their risk of new disease or progression of their disease and enhance their quality of life. PMID- 28913816 TI - Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases. AB - PURPOSE OF REVIEW: The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism. RECENT FINDINGS: Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system. Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities. Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance). PMID- 28913818 TI - A Spectroscopic Study of Interaction of Auricyanide with n-Acetylcysteine. AB - Interaction of auricyanide, an important metabolite of anti-arthritic gold-based drug auranofin, was studied in vitro with a pharmacologically active ligand n acetylcysteine with a view to understand reactivity of gold in vivo. Formation of reduction product aurocyanide occurred through mono- and di-n-acetylcysteine substituted intermediates. The product and intermediates were identified and monitored spectrophotometrically and by electrospray ionization mass spectrometry. This study suggests successive substitution with n-acetylcysteine through trans effect. At equimolar concentrations of auricyanide and n acetylcysteine, only mono-substituted mixed-ligand complex was formed. Substitution of the data obtained to various kinetic models suggested that the reaction orders are 0.6 in terms of n-acetylcysteine, 1.5 in terms of auricyanide, and 2 overall. The intermediates detected in this work may help to synthesize more effective and less toxic gold drugs. PMID- 28913819 TI - Emergency Neurologic Life Support: Spinal Cord Compression. AB - There are many causes of acute myelopathy including multiple sclerosis, systemic disease, and acute spinal cord compression (SCC). SCC should be among the first potential causes considered given the significant permanent loss of neurologic function commonly associated with SCC. This impairment can occur over a short period of time, and may be avoided through rapid and acute surgical intervention. Patients with SCC typically present with a combination of motor and sensory dysfunction that has a distribution referable to a spinal level. Bowel and bladder dysfunction and neck or back pain may also be part of the clinical presentation, but are not uniformly present. Because interventions are critically time-sensitive, the recognition and treatment of SCC was chosen as an ENLS protocol. PMID- 28913820 TI - Is Ribavirin Teratogenic in Humans? No Evidence So Far. PMID- 28913821 TI - Erratum to: Foreword to the special issue "Electroporation for biomedical applications". PMID- 28913822 TI - Improved Glycemic Control in a Patient Group Performing 7-Point Profile Self Monitoring of Blood Glucose and Intensive Data Documentation: An Open-Label, Multicenter, Observational Study. AB - INTRODUCTION: Regular self-monitoring of blood glucose (SMBG) is recommended as an integral part of therapy for all patients with diabetes treated with insulin. In the current study, the effects on glycemic control of taking 7-point SMBG profiles and using a diabetes management system (DMA) on a smartphone were investigated. METHODS: In a 12-week, open-label, multicenter, observational study, 51 patients [26 with type 1 diabetes mellitus (T1DM) and 25 with type 2 diabetes mellitus (T2DM)] were instructed to perform SMBG at least seven times a day using DMA combined with the iBGStar (r) SMBG system. HbA1c was measured at regular visits to the study sites. Patients reviewed and managed their data as well as their treatment on their own and there were no further assistance or treatment recommendations. Adverse events (AEs) were recorded throughout. RESULTS: Overall, mean (SD) change from baseline in HbA1c at week 12 was -0.46 (0.57)% [-5 (6) mmol/mol (p < 0.0001)]. The change in HbA1c was observed in patients with T1DM [-0.27 (0.45)% (-3 [5] mmol/mol; p = 0.0063)] and T2DM [-0.65 (0.62)% (-7 [7] mmol/mol; p < 0.0001)]. The change in HbA1c was not correlated with an increased number of hypoglycemic events (blood glucose less than 55 mg/dL). The majority of AEs were symptomatic hypoglycemic events (42 events; nine patients). CONCLUSIONS: Glycemic control can be improved, without receiving any recommendations or advice on insulin dose, by performing daily 7-point SMBG profiles and using electronic documentation with a smartphone app. These results must be confirmed in a larger controlled trial, but they already strengthen the importance of structured SMBG in diabetes therapy. FUNDING: Sanofi. PMID- 28913823 TI - Dietary patterns as a red flag for higher risk of eating disorders among female teenagers with and without type I diabetes mellitus : Adolescents with type I diabetes mellitus are a risk factor for eating disorders: a case-control study. AB - BACKGROUND: Female adolescents with type I diabetes mellitus (TIDM) have an increased risk of developing eating disorders (ED) due to the dietary recommendations. OBJECTIVE: Investigate the association between dietary intake and increased risk of ED. METHODS: Case-control study with 50 T1DM female adolescents (11-16 years) and 100 healthy peers (CG). Measures included food frequency questionnaire (FFQ-PP), Child-EDE.12, economic and anthropometric data. RESULTS: Comparing female adolescents with T1DM vs CG, the first had higher intake of: bread, cereal, rice, and pasta (29.7 vs 23.8%, p = 0.001), vegetables (6.5 vs 2.8%, p < 0.001), milk yogurt and cheese (9.9 vs 7.6%, p = 0.032), fat, and oils (8.2 vs 5.9%, p = 0.003), besides higher fiber intake (19.2 vs 14.7%, p = 0.006) and lower consumption of sweets (13.6 vs 30.7%, p < 0.001). No differences on ED psychopathology (Child-EDE subscales and global score) were found between groups. In unadjusted association between the ED psychopathology and dietary intake, a diet rich in fiber was significantly associated with both the global and eating concern scores. Among CG, increased intake of meat, poultry, fish, and eggs and decreased bread, cereal, rice, and pasta consumption were significantly associated with higher ED psychopathology. When BMI and age are adjusted, the association between fiber intake and ED psychopathology is no longer significant among diabetic participants; however, in the CG, this association remains. CONCLUSIONS: The study suggests that an association between dietary intake and ED psychopathology might exist in female adolescents with and without TIDM and that careful evaluation of the dietary profile and risk of developing an ED should be considered in clinical practice. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 28913824 TI - A randomised controlled trial of consumption of dark chocolate in pregnancy to reduce pre-eclampsia: Difficulties in recruitment, allocation and adherence. AB - In 2013-2014 we undertook a randomised controlled trial (RCT) to determine whether the daily ingestion of dark chocolate during pregnancy could reduce the incidence of pre-eclampsia in primigravidae. However, after two years we had not succeeded in recruiting more than 3.5% of the number of participants required to answer the research question, and the trial was halted. We also reviewed the literature on this topic and found it to be limited. We report here our findings and discuss the difficulties facing researchers in this area. PMID- 28913825 TI - A Nursing Intervention Increases Quality of Life and Self-Efficacy in Migraine: A 1-Year Prospective Controlled Trial. AB - OBJECTIVES: To compare the impact of a combined nursing and medical approach to a medical follow-up only on headache outcomes, quality of life, and self-efficacy in a cohort of migraineurs. BACKGROUND: Interdisciplinary approaches have been proposed for migraine management. A nursing intervention could improve patient outcomes. METHODS: We prospectively studied new patients referred to our tertiary headache center for migraine. The control group was followed by a physician; the active group was also followed by a nurse with a personalized intervention including adaptation of the lifestyle. RESULTS: Two hundred patients (176 women and 24 men, mean age 40 years old) were included and classified according to headache frequency. Each group was followed for 12 months with daily headache diaries. One hundred and sixty-two completed the study. There were no significant differences between groups for the decrease in headache days, the percent of chronic patients reverting to episodic status or the cessation of medication overuse. Patients in the control group were more likely to find a successful prophylaxis (55.6 vs 27.7%, P = .002). Despite this, the mean decrease in HIT-6 scores at month 8 was 5.23 +/- 9.18 for the active group compared with a decrease of 2.10 +/- 9.27 for the control group (P = .030, clinically significant difference of 3.13). Headache Management Self-Efficacy Scale (HMSE) scores, representing the feeling of self-efficacy, increased by 14.35 +/- 18.41 for the active group vs 4.69 +/- 21.22 in the control group (P = .002). CONCLUSION: A nursing intervention can lower the impact of migraines on the patient's life. The improvement in the HIT-6 score in this study was correlated with improvements in self-efficacy. PMID- 28913826 TI - Modeling Tolerance Development for the Effect on Heart Rate of the Selective S1P1 Receptor Modulator Ponesimod. AB - Ponesimod is a selective sphingosine-1-phosphate-1 (S1P1 ) receptor modulator currently under investigation for the treatment of multiple sclerosis. S1P receptor modulators reduce heart rate following treatment initiation. This effect disappears with repeated dosing, enabling development of innovative uptitration regimens to optimize patient safety. There are currently no published pharmacokinetic/pharmacodynamic models describing the heart rate reduction of S1P receptor modulators in humans. The model developed here provides quantification of this effect for ponesimod. A direct-effect Imax model with estimated maximum reduction of 45%, tolerance development, and circadian variation best described this effect. The pooled data from nine clinical studies enabled characterization of interindividual variability. The model was used to simulate different treatment regimens to compare the effect of high initial doses vs. gradual uptitration with respect to the occurrence of bradycardia. The results indicate a better safety profile when using gradual uptitration. The model allows studying dosing regimens not clinically tested in silico. PMID- 28913827 TI - When More Is Less: An Exploratory Study of the Precautionary Reporting Bias and Its Impact on Safety Signal Detection. AB - Concerns have been expressed that large numbers of nonvalue-added reports have been accumulating in adverse drug reaction (ADR) databases, for example, via patient support programs. We performed an assessment of the impact of such reports, which we refer to as "precautionary reports," on safety signal detection in the Netherlands. The case narratives of ADR reports of three case products were screened with text-mining algorithms to identify those reports that lack a causal relationship with the suspected medicinal product. We demonstrate that precautionary reports impede the optimal use of the pharmacovigilance system by, on the one hand, masking safety signals and, on the other hand, creating spurious signals. The precautionary reporting bias and its suppressing effect on statistical signal detection results in an altered adverse event safety profile. The findings from this study highlight the need for a better alignment between regulatory authorities and marketing authorization holders regarding pharmacovigilance guidelines. PMID- 28913828 TI - Diet and body shape changes of paroko Kelloggella disalvoi (Gobiidae) from intertidal pools of Easter Island. AB - This study assesses seasonal variation in the morphology and diet of juveniles and adults of the Easter Island endemic goby Kelloggella disalvoi from intertidal pools during September-October 2015 (spring) and June-July 2016 (winter), utilizing geometric morphometric and gut-content analyses. A set of 16 landmarks was digitized in 128 individuals. Shape changes related to size changes (i.e. allometry) were low (18.6%) and were seasonally similar. Body shape changes were mainly dorsoventral (44.2% of variance) and comprised posteroventral displacement of the premaxilla and bending of the body. The latter included vertical displacement of the anterior portion of the first and second dorsal fins and the entire base of the caudal fin. Diets mainly comprised developmental stages of harpacticoid copepods (from eggs to adults), ostracods, isopods, gastropods and bivalves. Also, trophic niche breadth remained constant throughout development and did not vary between seasons. Nonetheless, significant dietary differences were detected in specimens collected during spring (main prey items: harpacticoid copepods and copepod eggs) and winter (harpacticoid copepods and copepod nauplii). Finally, there was weak but significant covariation between diet and morphology: molluscivores were characterized by having an inferior mouth gape, whereas planktivores had an anteriorly directed premaxilla. PMID- 28913829 TI - A Retrospective Examination of Child Protection Involvement Among Young Adults Accessing Homelessness Services. AB - Childhood maltreatment is associated with a variety of young adult adversities including homelessness. This study used linked administrative records to develop a population-level, epidemiological characterization of the child protection histories of young adults accessing homelessness services. The records of all 17- to 24-year-olds receiving homeless services between 2011 and 2014 in San Francisco County, California (n = 2241) were probabilistically linked to statewide child protective service (CPS) records. Findings document that 50.0% of young adults had been reported for maltreatment at least once during childhood, yet the prevalence of past CPS involvement varied across demographic and child welfare characteristics. Homeless female youth were significantly more likely to have a CPS history than male youth (58.1% vs. 41.5%). Nearly twice as many Black clients accessing homelessness services had a CPS history as did White clients (59.8% vs. 31.8%). Roughly half (47.3%) of those with a childhood history of reported maltreatment had been last reported for maltreatment in another California county. Targeting services that address past trauma and instability among homeless young adults may be justified given the prevalence of CPS history in this population. PMID- 28913830 TI - Ontogenesis of opercular deformities in gilthead sea bream Sparus aurata: a histological description. AB - The aim of this study was to characterize histological changes during opercular osteogenesis in farmed gilthead sea bream Sparus aurata larvae from 7 to 69 days post hatching (dph) and compare normal osteogenesis with that of deformed opercles. Mild opercular deformities were first detected in 19 dph larvae by folding of the opercle's distal edge into the gill chamber. Here, the variation in the phenotype and the irregular bone structure at the curled part of the opercles is described and compared with the histology of normal opercles. Results indicated that deformed opercles still undergo bone growth with the addition of new matrix by osteoblasts at the opercular surface, especially at its edges. No significant difference was found in bone thickness between deformed and normal opercles. In addition to differences in bone architecture, differences in collagen fibre thickness between normal and deformed opercles were also found. PMID- 28913832 TI - Corrigendum: Rapid and visual Chlamydia trachomatis detection using loop-mediated isothermal amplification and hydroxynaphthol blue. PMID- 28913831 TI - Asymmetry between ON and OFF alpha ganglion cells of mouse retina: integration of signal and noise from synaptic inputs. AB - KEY POINTS: Bipolar and amacrine cells presynaptic to the ON sustained alpha cell of mouse retina provide currents with a higher signal-to-noise power ratio (SNR) than those presynaptic to the OFF sustained alpha cell. Yet the ON cell loses proportionately more SNR from synaptic inputs to spike output than the OFF cell does. The higher SNR of ON bipolar cells at the beginning of the ON pathway compensates for losses incurred by the ON ganglion cell, and improves the processing of positive contrasts. ABSTRACT: ON and OFF pathways in the retina include functional pairs of neurons that, at first glance, appear to have symmetrically similar responses to brightening and darkening, respectively. Upon careful examination, however, functional pairs exhibit asymmetries in receptive field size and response kinetics. Until now, descriptions of how light-adapted retinal circuitry maintains a preponderance of signal over the noise have not distinguished between ON and OFF pathways. Here I present evidence of marked asymmetries between members of a functional pair of sustained alpha ganglion cells in the mouse retina. The ON cell exhibited a proportionately greater loss of signal-to-noise power ratio (SNR) from its presynaptic arrays to its postsynaptic currents. Thus the ON cell combines signal and noise from its presynaptic arrays of bipolar and amacrine cells less efficiently than the OFF cell does. Yet the inefficiency of the ON cell is compensated by its presynaptic arrays providing a higher SNR than the arrays presynaptic to the OFF cell, apparently to improve visual processing of positive contrasts. Dynamic clamp experiments were performed that introduced synaptic conductances into ON and OFF cells. When the amacrine-modulated conductance was removed, the ON cell's spike train exhibited an increase in SNR. The OFF cell, however, showed the opposite effect of removing amacrine input, which was a decrease in SNR. Thus ON and OFF cells have different modes of synaptic integration with direct effects on the SNR of the spike output. PMID- 28913833 TI - Symptom trajectories throughout two family therapy treatments for adolescent anorexia nervosa. AB - OBJECTIVE: This study aimed to examine the trajectory of symptom remission and affective functioning throughout the course of two family-based treatments for adolescent anorexia nervosa (AN): conjoint family-based treatment (FBT) and parent-focused treatment (PFT). METHOD: Participants were 107 adolescents (Mage = 15.5 years, SD = 1.5) with a primary diagnosis of AN who participated in a randomized clinical trial comparing FBT (N = 55) and PFT (N = 51). Patient weight and self-reported assessments of dietary restraint and positive and negative affect were recorded at regular intervals throughout treatment. RESULTS: Multilevel models revealed increases in weight (beta = 0.33, p < .001) and positive affect (beta = 0.03, p < .001), and decreases in dietary restraint (beta = -0.03, p < .001) and negative affect (beta = -0.04, p < .001) over the course of treatment. No significant effects emerged by treatment type. DISCUSSION: These findings suggest that PFT may bring about comparable trajectories of weight gain and reduced dietary restraint as conjoint FBT, despite adolescents not being directly involved in treatment. These findings also highlight that the exclusively behavioral focus throughout both PFT and FBT is associated with significant increments in positive affect and significant reductions in negative affect. PMID- 28913834 TI - Which children and young people are excluded from school? Findings from a large British birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). AB - BACKGROUND: Exclusion from school is increasingly recognized as pertinent to child health. National educational data reveal that boys, children who are looked after, living in poverty, have special educational needs, or from certain ethnic minorities, are disproportionately excluded from school. As population-based data on the wider characteristics of excluded children are scarce, we aimed to describe predictors of school exclusion in the Avon Longitudinal Study of Parents and Children. METHOD: Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based birth cohort study, collected parent reports of permanent school exclusions by 8 years and parent and self-reports of permanent and fixed-term exclusions in the preceding 12 months at 16 years. Potential risk factors were examined for associations with exclusion using logistic regression, with a focus on child mental health and neurodevelopment. RESULTS: Analyses were based on all available data on 53/8,245 (0.6%) pupils excluded from school by 8 years and 390/4,482 (8.7%) at 16 years. Key factors associated with exclusion at both time points included male gender, lower socio-economic status, maternal psychopathology, mental health and behavioural difficulties, psychiatric disorder, social communication difficulties, language difficulties, antisocial activities, bullying/being bulled, lower parental engagement with education, low school engagement, poor relationship with teacher, low educational attainment, and special educational needs (all p < .05). CONCLUSION: Exclusion from school was associated with child, family and school-related factors identifiable at, or prior to, primary school age. Child health professionals have an important role in the holistic, multidisciplinary assessment of children who are at risk of exclusion from school. Mental health and neurodevelopmental difficulties should be recognized and supported, to improve the health and educational outcomes among this vulnerable group. PMID- 28913835 TI - Retributive justifications for jail diversion of individuals with mental disorder. AB - Jail diversion programs have proliferated across the United States as a means to decrease the incarceration of individuals with mental illnesses. These programs include pre-adjudication initiatives, such as crisis intervention teams, as well as post-adjudication programs, such as mental health courts and specialized probationary services. Post-adjudication programs often operate at the point of sentencing, so their comportment with criminal justice norms is crucial. This article investigates whether and under what circumstances post-adjudication diversion for offenders with serious mental illnesses may cohere with principles of retributive justice. Key tenets of retributive theory are that punishments must not be inhumane and that their severity must be proportionate to an offender's desert. Three retributive rationales could justify jail diversion for offenders with serious mental illnesses: reduced culpability, the avoidance of inhumane punishment, and the achievement of punishment of equal impact with similarly situated offenders. This article explores current proposals to effectuate these rationales, their manifestations in law, and how these considerations may impact decisions to divert individuals with serious mental illnesses from jail to punishment in the community. PMID- 28913836 TI - Female reproductive system morphology of crab-eating fox (Cerdocyon thous) and cryopreservation of genetic material for animal germplasm bank enrichment. AB - The sprawl of the urbanization and road network process without building ecological corridors contributes to the high mortality rates and a threat to the population decline of wild species such as the crab-eating fox. A strategy for the ex situ conservation is the study of the reproductive biology of the species and cryopreservation of their genetic heritage through the formation of an animal germplasm bank. This research is in accordance with the principles adopted by Brazilian College of Animal Experimentation. Reproductive systems of Cerdocyon thous females (n = 7) were examined macroscopically and microscopically by histological techniques and scanning electron microscopy. Gross features showed the shape of the ovaries was similar to a bean, and the elongated oviducts lengths were between 5 and 8 cm, with body of the uterus (3 cm) with long and narrow uterine horns (9-11 cm). The cervix was as a single annular conformation carrying out communication between the uterus and the vagina. The vagina has lengthened and circular muscle and the vulva with dense anatomical conformation with a quite pronounced clitoris. In addition, with regard to the establishment of a cell line (fibroblasts) for the gene bank enrichment, cells showed a low clonogenic capacity, especially when compared to domestic dogs, which can be explained by "in vitro" environment, age and diet of the animal. However, it was possible to create a bank of limited cell number. This study had morphological and preservationist character and aimed to help at long term in the conservation of wild animal's genetic resources. PMID- 28913837 TI - Practical recommendations for reporting Fine-Gray model analyses for competing risk data. AB - In survival analysis, a competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. Outcomes in medical research are frequently subject to competing risks. In survival analysis, there are 2 key questions that can be addressed using competing risk regression models: first, which covariates affect the rate at which events occur, and second, which covariates affect the probability of an event occurring over time. The cause specific hazard model estimates the effect of covariates on the rate at which events occur in subjects who are currently event-free. Subdistribution hazard ratios obtained from the Fine-Gray model describe the relative effect of covariates on the subdistribution hazard function. Hence, the covariates in this model can also be interpreted as having an effect on the cumulative incidence function or on the probability of events occurring over time. We conducted a review of the use and interpretation of the Fine-Gray subdistribution hazard model in articles published in the medical literature in 2015. We found that many authors provided an unclear or incorrect interpretation of the regression coefficients associated with this model. An incorrect and inconsistent interpretation of regression coefficients may lead to confusion when comparing results across different studies. Furthermore, an incorrect interpretation of estimated regression coefficients can result in an incorrect understanding about the magnitude of the association between exposure and the incidence of the outcome. The objective of this article is to clarify how these regression coefficients should be reported and to propose suggestions for interpreting these coefficients. PMID- 28913838 TI - Simultaneous acquisition of perfusion image and dynamic MR angiography using time encoded pseudo-continuous ASL. AB - PURPOSE: Both dynamic magnetic resonance angiography (4D-MRA) and perfusion imaging can be acquired by using arterial spin labeling (ASL). While 4D-MRA highlights large vessel pathology, such as stenosis or collateral blood flow patterns, perfusion imaging provides information on the microvascular status. Therefore, a complete picture of the cerebral hemodynamic condition could be obtained by combining the two techniques. Here, we propose a novel technique for simultaneous acquisition of 4D-MRA and perfusion imaging using time-encoded pseudo-continuous arterial spin labeling. METHODS: The time-encoded pseudo continuous arterial spin labeling module consisted of a first subbolus that was optimized for perfusion imaging by using a labeling duration of 1800 ms, whereas the other six subboli of 130 ms were used for encoding the passage of the labeled spins through the arterial system for 4D-MRA acquisition. After the entire labeling module, a multishot 3D turbo-field echo-planar-imaging readout was executed for the 4D-MRA acquisition, immediately followed by a single-shot, multislice echo-planar-imaging readout for perfusion imaging. The optimal excitation flip angle for the 3D turbo-field echo-planar-imaging readout was investigated by evaluating the image quality of the 4D-MRA and perfusion images as well as the accuracy of the estimated cerebral blood flow values. RESULTS: When using 36 excitation radiofrequency pulses with flip angles of 5 or 7.5 degrees , the saturation effects of the 3D turbo-field echo-planar-imaging readout on the perfusion images were relatively moderate and after correction, there were no statistically significant differences between the obtained cerebral blood flow values and those from traditional time-encoded pseudo-continuous arterial spin labeling. CONCLUSIONS: This study demonstrated that simultaneous acquisition of 4D-MRA and perfusion images can be achieved by using time-encoded pseudo-continuous arterial spin labeling. Magn Reson Med 79:2676-2684, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28913839 TI - Long-term Stability of a Compounded Suspension of Torsemide (5 mg/mL) for Oral Administration. AB - BACKGROUND: Torsemide use for congestive heart failure (CHF) has been reported, but prescription frequency is unknown. Commercially available tablet sizes in North America limit dosing precision, indicating a need to evaluate its strength and stability in suspension. OBJECTIVES: To determine the frequency of torsemide prescriptions and to determine a beyond use date (BUD) of a compounded suspension of torsemide for oral administration stored under 2 temperature conditions for 90 days. ANIMALS: No animals used. METHODS: Pharmacy records were retrospectively reviewed for torsemide and furosemide prescriptions from 2008 to 2015 at 2 veterinary referral centers. After preliminary strength testing, compounded torsemide suspension (5 mg/mL) for oral administration was prepared using torsemide tablets suspended in OraPlus:OraSweet 1:1, buffered to a pH of 8.3 and stored at refrigeration (2-8 degrees C) and room temperature (20-25 degrees C) in 2 oz amber plastic bottles. Samples were analyzed by reverse phase high performance liquid chromatography (RP-HPLC) on days 0, 14, 30, 60, and 90. RESULTS: Prescriptions for torsemide increased from 2008 to 2015. Analysis of the torsemide 5 mg/mL suspension for oral administration at each time point met United States Pharmacopeia (USP) requirements for torsemide content of 90-110% of label claim. The average strength at 90 days decreased to 92 +/- 3% at 2-8 degrees C and 95 +/- 2% at 20-25 degrees C. Stability testing did not detect unknown impurities. CONCLUSIONS: Increasing torsemide use warrants availability of a validated and stable compounded formulation. Our results support the assignment of a 90-day BUD for torsemide 5 mg/mL suspension for oral administration compounded in OraPlus:Sweet 1:1 buffered to a pH of 8.3. PMID- 28913840 TI - Loss of regulatory characteristics in CD4+ CD25+/hi T cells induced by impaired transforming growth factor beta secretion in pneumoconiosis. AB - Pneumoconiosis is caused by the accumulation of airborne dust in the lung, which stimulates a progressive inflammatory response that ultimately results in lung fibrosis and respiratory failure. It is possible that regulatory cells in the immune system could function to suppress inflammation and possibly slow or reverse disease progression. However, results in this study suggest that in pneumoconiosis patients, the regulatory T cells (Tregs) and B cells are functionally impaired. First, we found that pneumoconiosis patients presented an upregulation of CD4+ CD25+ T cells compared to controls, whereas the CD4+ CD25+ and CD4+ CD25hi T cells were enriched with Th1- and Th17-like cells but not Foxp3 expressing Treg cells and evidenced by significantly higher T-bet, interferon (IFN)-gamma, and interleukin (IL)-17 expression but lower Foxp3 and transforming growth factor (TGF)-beta expression. Regarding the CD4+ CD25hi T-cell subset, the frequency of this cell type in pneumoconiosis patients was significantly reduced compared to controls, together with a reduction in Foxp3 and TGF-beta and an enrichment in T-bet, RORgammat, IFN-gamma, and IL-17. This skewing toward Th1 and Th17 types of inflammation could be driven by monocytes and B cells, since after depleting CD14+ monocytes and CD19+ B cells, the levels of IFN-gamma and IL-17 were significantly decreased. Whole peripheral blood mononuclear cells and isolated monocytes and B cells in pneumoconiosis patients also presented reduced capacity of TGF-beta secretion. Furthermore, monocytes and B cells from pneumoconiosis patients presented reduced capacity in inducing Foxp3 upregulation, a function that could be rescued by exogenous TGF-beta. Together, these data indicated a potential pathway for the progression of pneumoconiosis through a loss of Foxp3+ Treg cells associated with impaired TGF-beta secretion. PMID- 28913841 TI - Diversion at re-entry using criminogenic CBT: Review and prototypical program development. AB - Society and the criminal justice system prioritize the reduction of reoffending risk as part of any criminal justice intervention. The Sequential Intercept Model identifies five points of interception at which justice-involved individuals can be diverted into a more rehabilitative alternative: (1) law enforcement/emergency services; (2) booking/initial court hearings; (3) jails/courts; (4) re-entry; and (5) community corrections/community support. The present article focuses on diversion as part of Intercept 5 - re-entry planning and specialized services in the community. We describe the challenges associated with diversion at this stage, and review the relevant research. Next, we describe a "criminogenic cognitive behavioral therapy" project that has been developed and implemented as part of a federal re-entry court. Finally, we discuss the implications of the challenges of intervention at this stage, and the recently developed "Re-entry Project," for research, policy, and practice. PMID- 28913842 TI - The updated grading system of prostate carcinoma: an inter-observer agreement study among general pathologists in an academic practice. AB - In 2016, the grading criteria for Gleason scoring (GS) have been updated in the WHO classification of tumors of the prostate, and a new set of grade groups (GG) was introduced. As the inter-observer discordance is a well-known concern in Gleason grading before the update and no reproducibility study testing the grade groups exists, we planned to evaluate the inter-observer agreement of the most updated grading system. Four pathologists assessed 126 cores of prostatic carcinoma, and Kappa (k) test was calculated. The agreements for both GS and GG were substantial (k = 0.753 and 0.752; respectively). Discerning GG 2 from 3 also attained reasonable outcome (k = 0.675). Based on our results, the updated grading system seems to be reproducible, with satisfactory inter-observer concordance rate. PMID- 28913843 TI - Food and functional dyspepsia: a systematic review. AB - BACKGROUND: Functional dyspepsia (FD) is a debilitating functional gastrointestinal disorder characterised by early satiety, post-prandial fullness or epigastric pain related to meals, which affects up to 20% of western populations. A high dietary fat intake has been linked to FD and duodenal eosinophilia has been noted in FD. We hypothesised that an allergen such as wheat is a risk factor for FD and that withdrawal will improve symptoms of FD. We aimed to investigate the relationship between food and functional dyspepsia. METHODS: Sixteen out of 6451 studies identified in a database search of six databases met the inclusion criteria of studies examining the effect of nutrients, foods and food components in adults with FD or FD symptoms. RESULTS: Wheat-containing foods were implicated in FD symptom induction in six studies, four of which were not specifically investigating gluten and two that were gluten-specific, with the implementation of a gluten-free diet demonstrating a reduction in symptoms. Dietary fat was associated with FD in all three studies that specifically measured this association. Specific foods reported as inducing symptoms were high in either natural food chemicals, high in fermentable carbohydrates or high in wheat/gluten. Caffeine was associated with FD in four studies, although any association with alcohol was uncertain. CONCLUSIONS: Wheat and dietary fats may play key roles in the generation of FD symptoms and reduction or withdrawal eased symptoms. Randomised trials investigating the roles of gluten, FODMAPs (fermentable oligosaccharide, disaccharide, monosaccharide and polyols) and high fat ingestion and naturally occurring food chemicals in the generation of functional dyspepsia symptoms are warranted and further investigation of the mechanisms is now required. PMID- 28913844 TI - Synergetic Metals on Carbocatalyst Shungite. AB - The naturally occurring Palaeoproterozoic carbon mineral shungite is a complex raw carbon microporous matrix, loaded with a wide range of elements. Shungite exhibits a disordered and amorphous structure with highly irregular building blocks. Shungite incorporates metals in its structure; typically catalytic elements such Fe and Ni are present, as well as the toxic elements Pb and As at mg g-1 levels. We show here that incorporation of the metals in the carbon matrix of shungite leads into synergistic catalytic effect. We investigate the application of shungite in energy related electrochemical catalytic reactions, such as the hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR). All elements have a synergetic effect, thus contributing for shungite's interesting catalytic performance towards a different range of electrochemical reactions, outperforming other tested carbon allotropes, such as carbon black, metal loaded carbon nanotubes, fullerene, and glassy carbon. These findings have profound impact on the application of the natural carbon materials for catalysis. PMID- 28913845 TI - Urinary WT1-positive cells as a non-invasive biomarker of crescent formation. AB - OBJECTIVE: The purpose of this study was to assess the relationship between urinary WT1-positive cells (podocytes and active parietal epithelial cells) and WT1-positive cells in renal biopsy to investigate whether urinary WT1-positive cells are useful for detection of crescent formation. METHODS: Fifty-two patients with kidney disease were investigated (15 cases with crescentic lesions and 37 cases with non-crescentic lesions) for immunoenzyme staining using anti-WT1 antibody for urine cytology and renal biopsy. Numbers of WT1-positive cells in urine and renal biopsy were counted. RESULTS: There was no correlation between urinary WT1-positive cells and WT1-positive cells in renal biopsy. However, the number of urinary WT1-positive cells in patients with crescentic lesions was significantly higher than in patients with non-crescentic lesions. In addition, the best cut-off value to detect patients with crescentic lesions using urinary was 5 cells/10-mL (area under the concentration-time curve=0.735). CONCLUSIONS: The results of our study suggest urinary WT1-positive cells can be used to detect patients with crescent formation using 5 cells/10-mL cutoff value. WT1-positive glomerular podocytes and parietal epithelial cells may be shed into urine in active glomerular disease. This study, investigating the relationship between WT1 positive cells in urine and in the renal biopsy found no correlation; however, the results do suggest that, using a cutoff value of 5 cells/10 mL, WT1 positive urinary cells can be used to detect patients with crescent formation. PMID- 28913846 TI - Cardioprotective Effects of Pomegranate (Punica granatum) Juice in Patients with Ischemic Heart Disease. AB - Ischemic heart disease is the leading cause of mortality worldwide. The purpose of this study was to evaluate the cardioprotective effects of pomegranate juice in patients with ischemic heart disease. One hundred patients, diagnosed with unstable angina or myocardial infarction, were randomly assigned to the test and the control groups (n = 50, each). During 5 days of hospitalization, in addition to the conventional medical therapies, the test groups received 220 mL pomegranate juice, daily. During the hospitalization period, the blood pressure, heart rate, as well as the intensity, occurrence, and duration of the angina were evaluated on a regular basis. At the end of the hospitalization period, the serum levels of malondialdehyde, interleukin-6, and tumor necrosis factor alpha were measured in all patients. The levels of serum troponin and high-sensitive C reactive protein levels were also assayed in patients diagnosed with myocardial infarction. Pomegranate juice caused significant reductions in the intensity, occurrence, and duration of angina pectoris in patients with unstable angina. Consistently, the test patients had significantly lower levels of serum troponin and malondialdehyde. Other studied parameters did not change significantly. The results of this study suggest protective effects of pomegranate juice against myocardial ischemia and reperfusion injury. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28913847 TI - Incidence, malignancy rates of diagnoses and cyto-histological correlations in the new Italian Reporting System for Thyroid Cytology: An institutional experience. AB - OBJECTIVE: FNA biopsy is considered as the most accurate method for the selection of patients with thyroid nodules that need for surgery or for the wait and see management. The aim of the present study is to clarify the risk of malignancy for the cytological data classified according to the 2014 Italian reporting system. METHODS: We report a retrospective analysis of 4043 patients in our institution's experience during the period April 2014 through December 2016 with the Italian reporting system for thyroid cytology. RESULTS: The diagnostic incidences of the 4043 cases were as follows: 9.8% TIR1; 1.3% TIR1C; 70% TIR2; 6.6% TIR3A; 4.5% TIR3B; 2.4% TIR4; 5.2% TIR5. A repeated aspiration was carried out in 68 out of 269 cases (25%) classified as TIR3A. A total of 407 cases with cytology underwent surgical resection. A malignant neoplasm was detected in 261 out of 407 (64%) cases. Regarding TIR3B, surgical excision was undertaken in 109 cases, which included 42 high-risk lesions and 67 Hurthle cell neoplasms. The risk of malignancy was significantly higher in the former compared to the latter (50% vs 9%; P<.05). CONCLUSIONS: This investigation emphasises the reliability of the 2014 Italian Reporting System concerning the mutual frequency of the diagnostic categories. The risk of malignancy is perfectly within the range of the estimated values. PMID- 28913848 TI - Effect of the duration of hospice and palliative care on the quality of dying and death in patients with terminal cancer: A nationwide multicentre study. AB - Early referral to hospice and palliative care (HPC) has significant benefits, but little is known about the appropriate time for referral. The purpose of this study of terminal cancer patients was to identify the most appropriate time for referral to HPC. Cross-sectional correlation study design was used. Participants were the bereaved relatives, who were the adult primary caregivers of the 1,829 terminal cancer patients who died 2-6 months previously in nationwide centres that provide HPC in Korea. A post-bereavement survey (Good Death Inventory, GDI) of family caregivers was used to assess patients' quality of dying and death. Relative to patients who were in HPC for 3-7 days and HPC for 8-21 days, those in HPC for 22-84 days had significantly higher quality of dying. Propensity score matched comparison between the group hospitalised for 22-84 days (n = 65) and the group hospitalised for 85 days or longer (n = 65) showed no significant differences in all the items on quality of dying and death. Our results suggest that terminal cancer patients who stay in HPC at least for 22 days have improved quality of dying and death. PMID- 28913849 TI - Ethnic disparities in renal cell carcinoma: An analysis of Hispanic patients in a single-payer healthcare system. AB - OBJECTIVE: To investigate differences between Hispanics and non-Hispanic whites diagnosed with and treated for renal cell carcinoma in an equal access healthcare system. METHODS: We carried out a retrospective cohort study within the Kaiser Permanente healthcare system using records from renal cell carcinoma cases. Ethnicity was identified as Hispanic or non-Hispanic whites. Patient characteristics, comorbidities, tumor characteristics and treatment were compared. Overall and disease-specific survival was calculated, and a Cox proportion hazard model estimated the association of ethnicity and survival. RESULTS: A total of 2577 patients (2152 non-Hispanic whites, 425 Hispanic) were evaluated. Hispanics were diagnosed at a younger age (59.6 years vs 65.3 years). Clear cell renal cell carcinoma was more prevalent, whereas papillary renal cell carcinoma was less common among Hispanics. Hispanics had a lower American Joint Committee on Cancer stage (I/II vs III/IV) than non-Hispanic whites (67.4% vs 62.2%). Hispanics were found to have a greater frequency of comorbidities, such as chronic kidney disease and diabetes, but were more likely to receive surgery. The presence of metastases, nodal involvement, increased tumor size, non-surgical management, increasing age and Hispanic ethnicity were independent predictors of worse cancer-specific outcome. CONCLUSIONS: Within an equal access healthcare system, Hispanics seem to be diagnosed at younger ages, to have greater comorbidities and to present more frequently with clear cell renal cell carcinoma compared with non-Hispanic white patients. Despite lower stage and greater receipt of surgery, Hispanic ethnicity seems to be an independent predictor of mortality. Further work is necessary to confirm these findings. PMID- 28913850 TI - Hyphenation of proton transfer reaction mass spectrometry with thermal analysis for monitoring the thermal degradation of retinyl acetate. AB - RATIONALE: The processing of retinyl acetate, a vitamin and biomarker, at high temperatures causes significant decomposition of the compound and thus loss of its activity. The rate of mass loss can be conveniently studied by thermogravimetry (TG). However, this technique generally fails to reveal which compounds have evolved from the compound. In this work we propose a new hyphenation approach to continuously monitor the thermal decomposition of retinyl acetate and follow the evolution of specific volatile organic compounds (VOCs). METHODS: Thermal degradation of retinyl acetate was followed by TG coupled to a direct injection mass spectrometer based on proton transfer reaction mass spectrometry (PTR-MS) to follow continuously the thermal decomposition of retinyl acetate. The results were also compared with those obtained by a second evolved gas analysis system based on the coupling of TG with FTIR. RESULTS: The TG results showed two main mass losses, at 180 degrees C and 350 degrees C. When the PTR-MS instrument was connected to the outlet of the TG instrument, specific fragment ions (m/z 43, 61, 75, 85 and 97) showed characteristic evolution profiles. The first mass loss was mainly associated with the release of acetic acid (m/z 43 and 61), whereas the second mass loss was connected with the degradation of the molecule backbone (m/z 43, 61, 75, 85 and 97). These results were substantially correlated with those achieved by TG coupled with FTIR, although PTR-MS showed superior performance in terms of the qualitative identification of specific fragments and better sensitivity toward complex organic VOCs. CONCLUSIONS: The proposed TG-PTR-MS technique shows a great potential for following in real time the thermal degradation of ingredients such as retinyl acetate and identifying compounds evolved at specific temperatures. PMID- 28913851 TI - Pathways to Housing Policy: Translating Research to Policy to Achieve Impact on Well Being. AB - Policy emerges from the legislative, agency, and practice levels and from several pathways, including litigation; high profile or tragic events; community-based service provision and practice innovations; and research evidence. This commentary places an emphasis throughout on discussions of the articles included in this issue. It explores pathways that influenced the development of housing policy targeting child and family well being and provides examples to illustrate each pathway. The article further highlights how research on housing and child well being has influenced policy and practice and notes gaps for further research. It concludes with suggestions for structuring research to more effectively assist policymakers to make informed decisions that achieve positive change for children, youth, and families. PMID- 28913852 TI - Testing support for the northern and southern dispersal routes out of Africa: an analysis of Levantine and southern Arabian populations. AB - OBJECTIVES: The Northern Dispersal Route (NDR) and Southern Dispersal Route (SDR) are hypothesized to have been used by modern humans in the dispersal out of Africa. The NDR follows the Nile into Northeast Africa and crosses the Red Sea into the Levant. The SDR emerges from the Horn of Africa and crosses the Bab el Mandeb into southern Arabia. In this study, we analyze genetic data from populations living along the NDR and SDR to test support for each dispersal route. MATERIALS AND METHODS: We genotyped 90 Yemeni samples on the Affymetrix Human Origins array. We analyzed these data with published data from Levantine and other southern Arabian populations as well as 157 comparative populations for a total sample size of >550,000 genetic variants from >2,000 individuals in >160 populations. We calculated outgroup f3 statistics to test how Levantine and southern Arabian populations relate to African populations living along the NDR and SDR and to other non-African populations. RESULTS: We find that Levantine and southern Arabian populations bear similar genetic relationships to both African and non-African populations, thus providing no support for the use of one dispersal route over the other. DISCUSSION: Our results are consistent with a history of gene flow between the Levant and southern Arabia. Consideration of genetic, archaeological, and paleoclimate data provide a slight edge for the SDR but, ultimately, more data are needed to definitively identify which dispersal route out of Africa was used. PMID- 28913853 TI - Dose Rationalization of Pembrolizumab and Nivolumab Using Pharmacokinetic Modeling and Simulation and Cost Analysis. AB - Pembrolizumab and nivolumab are highly selective anti-programmed cell death 1 (PD 1) antibodies approved for the treatment of advanced malignancies. Variable exposure and significant wastage have been associated with body size dosing of monoclonal antibodies (mAbs). The following dosing strategies were evaluated using simulations: body weight, dose banding, fixed dose, and pharmacokinetic (PK)-based methods. The relative cost to body weight dosing for band, fixed 150 mg and 200 mg, and PK-derived strategies were -15%, -25%, + 7%, and -16% for pembrolizumab and -8%, -6%, and -10% for band, fixed, and PK-derived strategies for nivolumab, respectively. Relative to mg/kg doses, the median exposures were 1.0%, -4.6%, + 27.1%, and +3.0% for band, fixed 150 mg, fixed 200 mg, and PK derived strategies, respectively, for pembrolizumab and -3.1%, + 1.9%, and +1.4% for band, fixed 240 mg, and PK-derived strategies, respectively, for nivolumab. Significant wastage can be reduced by alternative dosing strategies without compromising exposure and efficacy. PMID- 28913854 TI - Preoperative ultraviolet B inflammation in skin: Modelling individual differences in acute postoperative pain and neuro-immune interactions. AB - BACKGROUND: Neuroimmune interactions play a vital role in many of the most common pain conditions, such as arthritis. There have been many attempts to derive clinically predictive information from an individual's inflammatory response in order to gauge subsequent pain perception. OBJECTIVES: Here, we wanted to test whether this effort could be enhanced and complemented by the use of a model system which takes into account the function of not just circulating, but also tissue-resident immune cells: ultraviolet B (UVB) irradiation of the skin. METHODS: We conducted psychophysical and transcriptional analysis of hyperalgesia arising as a result of UVB-induced inflammation in patients before total knee arthroplasty (TKA, n = 23). Levels of acute postoperative pain were assessed and correlated with preoperative data. RESULTS: Cytokine and chemokine responses after UVB irradiation were found to be inversely correlated with the level of pain experienced after surgery (Spearman's rho = -0.498). CONCLUSION: It may be possible to use this simple model to study and predict the nature of neuro-immune responses at more remote, clinically relevant sites. SIGNIFICANCE: A simple model of UVB inflammation in the skin might predict the degree of a patient's neuro immune response and the extent of their postoperative pain after total knee arthroplasty. PMID- 28913855 TI - Effect of Simulated Mastication on the Retention of Locator Attachments for Implant-Supported Overdentures: An In Vitro Pilot Study. AB - PURPOSE: Limited information is currently available relative to the effect of masticatory loads on the retentive properties of Locator attachments. The aims of this in vitro study were to assess and compare the effect of simulated mastication on the retention of white, pink, and blue Locator inserts for overdentures retained by 2 implants. MATERIALS AND METHODS: Thirty specimens simulating a nonanatomic edentulous flat ridge with two implants and an overdenture were divided into 3 groups according to the color of the fitted insert: transparent clear group (n = 10), pink group (n = 10), and blue group (n = 10). Retention forces were measured in an axial direction initially and after 100,000 cycles of simulated masticatory loads. One-way ANOVA followed by Tukey's post hoc tests were used to compare retention values and percentage retention loss between the 3 groups with significance set at p = 0.05. RESULTS: The 3 groups presented significant differences in retention at baseline (9.95 +/- 1.91 N, 15.43 +/- 4.08 N, and 41.73 +/- 9.29 N for the blue, pink, and clear groups, respectively) and after simulated mastication (6.37 +/- 2.64 N, 14.00 +/- 3.89 N, 38.20 +/- 5.11 N for the blue, pink, and clear groups, respectively). Within the same group, cyclic loading did not significantly affect retention in the clear and pink groups, while the blue inserts showed a significant retention loss ( 37%) after loading. CONCLUSIONS: The results suggest that short-term simulated mastication affects the extra-light blue inserts but not the more-retentive inserts. PMID- 28913857 TI - Dynamic Molecular Invasion into a Multiply Interlocked Catenane. AB - A multiply interlocked catenane with a novel molecular topology was synthesized; a phthalocyanine bearing four peripheral crown ethers was quadruply interlocked with a cofacial porphyrin dimer bridged with four alkylammonium chains. The supramolecular conjugate has two nanospaces surrounded by a porphyrin, a phthalocyanine, and four alkyl chains to accommodate guest molecules. Because the phthalocyanine can move along the alkyl chains, it acts as an adjustable wall, thus permitting the invasion of large molecules into the nanospaces without spoiling the affinity of the association. The dynamic molecular invasion allowed the intercalation of dianionic porphyrins into both nanospaces with high affinity. A photometric titration experiment revealed the two-step inclusion phenomenon. The multiply interlocked catenane complexed with three Cu2+ ions, and the spin-spin interaction was switched off by the intercalation of dianionic porphyrins. PMID- 28913856 TI - Multiplate and TEG platelet mapping in a population of severely injured trauma patients. AB - OBJECTIVES: The objectives of this study were to compare thromboelastography platelet mapping (TEG PM) with impedance aggregometry (Multiplate, MP) in a single trauma population and relate their results clinically. BACKGROUND: Platelet function as measured by thromboelastography and impedance aggregometry demonstrates significant reductions that persist for days following traumatic injury. However, no study compares these devices and the correlation between them is not known. METHODS: In level 1 trauma patients, TEG PM and MP were conducted at their initial presentation to the emergency department. Within-device repeatability and between-device association were determined using correlation analyses. Demographic variables, Injury Severity Score, blood product transfusion, laboratory test results and mortality rate were recorded. RESULTS: Ninety-two patients were enrolled. Within-device repeatability was high for TEG PM and MP for arachidonic acid (AA) and adenosine diphosphate (ADP) activation pathways. When comparing TEG PM with MP, results correlated poorly in the ADP pathway (Spearman's rho = 0.11, P = 0.44) and moderately in the AA pathway (Spearman's rho = 0.56, P < 0.0001). TEG PM was predictive of blood product transfusion and correlated with increased base deficit, whereas MP was only predictive of mortality. CONCLUSIONS: Intra-device variability was low for TEG PM and MP, but the two point-of-care devices measuring platelet function correlate poorly with each other in injured trauma patients. Each device also had different clinical associations. PMID- 28913858 TI - Relationships between mineral concentrations and physicochemical characteristics in the Longissimus thoracis muscle of Japanese Black cattle. AB - The relationship between mineral concentrations, and the relationship of mineral concentrations with physicochemical characteristics in muscles were investigated using the Longissimus thoracis (LT) muscle of 44 Japanese Black steers. We determined moisture content, fat content, meat color, fatty acid composition and mineral concentrations in the LT muscle. Magnesium (Mg), potassium (K) and zinc (Zn) concentrations had negative correlations with fat content, but sodium (Na), manganese (Mn), copper (Cu) and molybdenum (Mo) concentrations were not correlated with fat content. The concentrations of Mg, Mn, Fe, Cu and Zn largely and positively contributed to the first principal component of mineral concentrations. Because the red muscle was rich in these minerals compared to the white muscle, the variation of these minerals probably results from the abundance of red fibers in the LT muscle. The concentration of K was positively correlated with moisture content but Na concentration was not related to moisture content, suggesting that the intracellular fluid volume can largely affect moisture content. The results of the present experiment suggest that mineral concentrations reflect some traits such as not only fat content but also the composition of myofiber type and the intracellular fluid volume in the LT muscle of Japanese Black cattle. PMID- 28913859 TI - Changes in frontal and posterior cortical activity underlie the early emergence of executive function. AB - Executive function (EF) is a key cognitive process that emerges in early childhood and facilitates children's ability to control their own behavior. Individual differences in EF skills early in life are predictive of quality-of life outcomes 30 years later (Moffitt et al., 2011). What changes in the brain give rise to this critical cognitive ability? Traditionally, frontal cortex growth is thought to underlie changes in cognitive control (Bunge & Zelazo, 2006; Moriguchi & Hiraki, 2009). However, more recent data highlight the importance of long-range cortical interactions between frontal and posterior brain regions. Here, we test the hypothesis that developmental changes in EF skills reflect changes in how posterior and frontal brain regions work together. Results show that children who fail a "hard" version of an EF task and who are thought to have an immature frontal cortex, show robust frontal activity in an "easy" version of the task. We show how this effect can arise via posterior brain regions that provide on-the-job training for the frontal cortex, effectively teaching the frontal cortex adaptive patterns of brain activity on "easy" EF tasks. In this case, frontal cortex activation can be seen as both the cause and the consequence of rule switching. Results also show that older children have differential posterior cortical activation on "easy" and "hard" tasks that reflects continued refinement of brain networks even in skilled children. These data set the stage for new training programs to foster the development of EF skills in at-risk children. PMID- 28913861 TI - Food as medicine: the nutrition seminar series. PMID- 28913860 TI - Connectivity-based parcellation of the anterior limb of the internal capsule. AB - The anterior limb of the internal capsule (ALIC) is an important locus of frontal subcortical fiber tracts involved in cognitive and limbic feedback loops. However, the structural organization of its component fiber tracts remains unclear. Therefore, although the ALIC is a promising target for various neurosurgical procedures for psychiatric disorders, more precise understanding of its organization is required to optimize target localization. Using diffusion tensor imaging (DTI) collected on healthy subjects by the Human Connectome Project (HCP), we generated parcellations of the ALIC by dividing it according to structural connectivity to various frontal regions. We then compared individuals' parcellations to evaluate the ALIC's structural consistency. All 40 included subjects demonstrated a posterior-superior to anterior-inferior axis of tract organization in the ALIC. Nonetheless, subdivisions of the ALIC were found to vary substantially, as voxels in the average parcellation were accurately assigned for a mean of only 66.2% of subjects. There were, however, some loci of consistency, most notably in the region maximally connected to orbitofrontal cortex. These findings clarify the highly variable organization of the ALIC and may represent a tool for patient-specific targeting of neuromodulation. Hum Brain Mapp 38:6107-6117, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28913862 TI - The effect of neuromuscular blockade on the efficiency of facemask ventilation in patients difficult to facemask ventilate: a prospective trial. AB - Facemask ventilation of the lungs can be an important rescue intervention in a 'cannot intubate' scenario. We assessed the effect of neuromuscular blockade on expiratory tidal volumes in patients with expected difficulty in mask ventilation. The lungs of patients with at least three predictors of difficulty in mask ventilation were ventilated using a facemask held with two hands, with mechanical ventilation set in a pressure-controlled mode. Tidal volumes were recorded before and after the establishment of complete neuromuscular block. In 113 patients, median (IQR [range]) tidal volume increased from 350 (260-492 [80 850]) ml initially, by 48% to 517 (373-667 [100-1250]) ml 30 s after rocuronium administration, (p < 0.001). After the onset of the complete neuromuscular block, a median tidal volume of 600 (433-750 [250-1303]) ml was observed, corresponding to an increase of 71% from baseline values (p < 0.001), and 16% from values obtained 30 s after rocuronium administration, respectively; p = 0.003). No decrease in the tidal volume during the measurements was observed. We conclude that the administration of rocuronium at a dose of 0.6 mg.kg-1 was able to improve facemask ventilation in all cases with a potentially clinically relevant increase in tidal volume. The early use of a neuromuscular blocking agent can be considered as a therapeutic option in case of difficulty with mask ventilation. PMID- 28913863 TI - Neighborhood Predictors of Intimate Partner Violence: A Theory-Informed Analysis Using Hierarchical Linear Modeling. AB - Due to high prevalence rates and deleterious effects on individuals, families, and communities, intimate partner violence (IPV) is a significant public health problem. Because IPV occurs in the context of communities and neighborhoods, research must examine the broader environment in addition to individual-level factors to successfully facilitate behavior change. Drawing from the Social Determinants of Health framework and Social Disorganization Theory, neighborhood predictors of IPV were tested using hierarchical linear modeling. Results indicated that concentrated disadvantage and female-to-male partner violence were robust predictors of women's IPV victimization. Implications for theory, practice, and policy, and future research are discussed. PMID- 28913864 TI - Strand Displacement in Coiled-Coil Structures: Controlled Induction and Reversal of Proximity. AB - Coiled-coil peptides are frequently used to create new function upon the self assembly of supramolecular complexes. A multitude of coil peptide sequences provides control over the specificity and stability of coiled-coil complexes. However, comparably little attention has been paid to the development of methods that allow the reversal of complex formation under non-denaturing conditions. Herein, we present a reversible two-state switching system. The process involves two peptide molecules for the formation of a size-mismatched coiled-coil duplex and a third, disruptor peptide that targets an overhanging end. A real-time fluorescence assay revealed that the proximity between two chromophores can be switched on and off, repetitively if desired. Showcasing the advantages provided by non-denaturing conditions, the method permitted control over the bivalent interactions of the tSH2 domain of Syk kinase with a phosphopeptide ligand. PMID- 28913865 TI - Transcriptome characterization of HPG axis from Chinese sea perch Lateolabrax maculatus. AB - Here the transcriptome and differential gene expression in the adult brain and gonads of the Chinese sea perch Lateolabrax maculatus were reported. A total of 78 256 909 clean reads were generated from the adult brain, ovary and testis by using the Illumina HiSeq2000 platform and assembled into 274 909 contigs. A total of 31 683 unigenes were annotated based on sequence similarity and 20 702 unigenes were found to exhibit 8237 gene ontology terms and 3888 signal pathways. Transcripts of 26 623 unigenes were present in all of the tissues, whereas pairwise comparisons revealed that 671/367, 496/315 and 1668/580 unigenes were up down regulated by at least two-fold between the brain and ovary, ovary and testis and brain and testis, respectively. Homology search led to the identification of reproduction-associated genes of the brain-gonad axis, including those involved in sex differentiation and maintenance. The data provided an integrated and comprehensive transcriptome resource for L. maculatus, which could be used for further research on hypothalamus-pituitary-gonad axis gene function, reproduction regulation and sex-biased gene expression. PMID- 28913866 TI - Conversion of array-based single nucleotide polymorphic markers for use in targeted genotyping by sequencing in hexaploid wheat (Triticum aestivum). AB - Wheat breeders and academics alike use single nucleotide polymorphisms (SNPs) as molecular markers to characterize regions of interest within the hexaploid wheat genome. A number of SNP-based genotyping platforms are available, and their utility depends upon factors such as the available technologies, number of data points required, budgets and the technical expertise required. Unfortunately, markers can rarely be exchanged between existing and newly developed platforms, meaning that previously generated data cannot be compared, or combined, with more recently generated data sets. We predict that genotyping by sequencing will become the predominant genotyping technology within the next 5-10 years. With this in mind, to ensure that data generated from current genotyping platforms continues to be of use, we have designed and utilized SNP-based capture probes from several thousand existing and publicly available probes from Axiom(r) and KASPTM genotyping platforms. We have validated our capture probes in a targeted genotyping by sequencing protocol using 31 previously genotyped UK elite hexaploid wheat accessions. Data comparisons between targeted genotyping by sequencing, Axiom(r) array genotyping and KASPTM genotyping assays, identified a set of 3256 probes which reliably bring together targeted genotyping by sequencing data with the previously available marker data set. As such, these probes are likely to be of considerable value to the wheat community. The probe details, full probe sequences and a custom built analysis pipeline may be freely downloaded from the CerealsDB website (http://www.cerealsdb.uk.net/cerealgenomics/CerealsDB/sequence_capture.php). PMID- 28913867 TI - Effects of FCGRIIIa-158V/F polymorphism on antibody-dependent cellular cytotoxicity activity of adalimumab. AB - The associations between the efficacy of IgG reagents and the FCGRIIIa-158V/F polymorphism (rs396991) have been investigated. Although the genotype frequencies in healthy Japanese have been reported, those have varied, as one study reported that the proportions of V/V, V/F, and F/F were 59.1%, 38.6%, and 2.3%, respectively, while another study found that they were 4%, 44%, and 52%, respectively. However, there are no known investigations of the association between the antibody-dependent cellular cytotoxicity (ADCC) activity of adalimumab (ADA), an IgG reagent, in combination with FcgammaRIIIa and the polymorphism. In this study, we analyzed healthy Japanese to clarify genotype frequency using a direct sequence method. In addition, we examined the association between the ADA-mediated ADCC activity and the polymorphism. Our results showed that the frequencies of the V/V, V/F, and F/F genotypes in healthy Japanese were 9.2%, 39.8%, and 51.0%, respectively. The average activity of ADA mediated ADCC was 25.0%, 19.0%, and 13.3% in the V/V, V/F, and F/F genotypes, respectively. Then, the ADCC activity of V/V was significantly higher than that of F/F (p < 0.05) in therapeutic concentration. The differences in therapeutic effect of ADA among individuals can be explained, in part, by ADCC activity via the FCGRIIIa-158V/F polymorphism. PMID- 28913869 TI - Fast-growing oysters show reduced capacity to provide a thermal refuge to intertidal biodiversity at high temperatures. AB - Ecosystem engineers that modify the thermal environment experienced by associated organisms might assist in the climate change adaptation of species. This depends on the ability of ecosystem engineers to persist and continue to ameliorate thermal stress under changing climatic conditions-traits that may display significant intraspecific variation. In the physically stressful intertidal, the complex three-dimensional structure of oysters provides shading and traps moisture during aerial exposure at low tide. We assessed variation in the capacity of a faster- and slower-growing population of the Sydney Rock Oyster, Saccostrea glomerata, to persist, form three-dimensional structure and provide a cool microhabitat to invertebrates under warmer conditions. The two populations of oysters were exposed to a temperature gradient in the field by attaching them to passively warmed white, grey and black stone pavers and their growth, survivorship and colonisation by invertebrates was monitored over a 12-month period. Oysters displayed a trade-off between fast growth and thermal tolerance. The growth advantage of the fast-growing population diminished with increasing substrate temperature, and at higher temperatures, the faster-growing oysters suffered greater mortality, formed less habitat, and were consequently less effective at ameliorating low-tide air temperature extremes than slower-growing oysters. The greater survivorship of slower-growing oysters, in turn, produced a cooler microclimate which fed back to further bolster oyster survivorship. Invertebrate recruitment increased with habitat cover and was greater among the slower than the faster-growing population. Our results show that the capacity of ecosystem engineers to serve as microhabitat refugia to associated organisms in a warming climate displays marked intraspecific variation. Our study also adds to growing evidence that fast growth may come at the expense of thermal tolerance. PMID- 28913870 TI - Mimicry in butterflies: co-option and a bag of magnificent developmental genetic tricks. AB - Butterfly wing patterns are key adaptations that are controlled by remarkable developmental and genetic mechanisms that facilitate rapid evolutionary change. With swift advancements in the fields of genomics and genetic manipulations, identifying the regulators of wing development and mimetic wing patterns has become feasible even in nonmodel organisms such as butterflies. Recent mapping and gene expression studies have identified single switch loci of major effects such as transcription factors and supergenes as the main drivers of adaptive evolution of mimetic and polymorphic butterfly wing patterns. We highlight several of these examples, with emphasis on doublesex, optix, WntA and other dynamic, yet essential, master regulators that control critical color variation and sex-specific traits. Co-option emerges as a predominant theme, where typically embryonic and other early-stage developmental genes and networks have been rewired to regulate polymorphic and sex-limited mimetic wing patterns in iconic butterfly adaptations. Drawing comparisons from our knowledge of wing development in Drosophila, we illustrate the functional space of genes that have been recruited to regulate butterfly wing patterns. We also propose a developmental pathway that potentially results in dorsoventral mismatch in butterfly wing patterns. Such dorsoventrally mismatched color patterns modulate signal components of butterfly wings that are used in intra- and inter-specific communication. Recent advances-fuelled by RNAi-mediated knockdowns and CRISPR/Cas9-based genomic edits-in the developmental genetics of butterfly wing patterns, and the underlying biological diversity and complexity of wing coloration, are pushing butterflies as an emerging model system in ecological genetics and evolutionary developmental biology. WIREs Dev Biol 2018, 7:e291. doi: 10.1002/wdev.291 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Comparative Development and Evolution > Regulation of Organ Diversity Comparative Development and Evolution > Evolutionary Novelties. PMID- 28913868 TI - Alterations of c-di-GMP turnover proteins modulate semi-constitutive rdar biofilm formation in commensal and uropathogenic Escherichia coli. AB - Agar plate-based biofilm of enterobacteria like Escherichia coli is characterized by expression of the extracellular matrix components amyloid curli and cellulose exopolysaccharide, which can be visually enhanced upon addition of the dye Congo Red, resulting in a red, dry, and rough (rdar) colony morphology. Expression of the rdar morphotype depends on the transcriptional regulator CsgD and occurs predominantly at ambient temperature in model strains. In contrast, commensal and pathogenic isolates frequently express the csgD-dependent rdar morphotype semi constitutively, also at human host body temperature. To unravel the molecular basis of temperature-independent rdar morphotype expression, biofilm components and c-di-GMP turnover proteins of seven commensal and uropathogenic E. coli isolates were analyzed. A diversity within the c-di-GMP signaling network was uncovered which suggests alteration of activity of the trigger phosphodiesterase YciR to contribute to (up)regulation of csgD expression and consequently semi constitutive rdar morphotype development. PMID- 28913871 TI - Experimental asbestos studies in the UK: 1912-1950. AB - The asbestos industry originated in the UK in the 1870s. By 1898, asbestos had many applications and was reported to be one of the four leading causes of severe occupational disease. In 1912, the UK government sponsored an experimental study that reported that exposure to asbestos produced no more than a modicum of pulmonary fibrosis in guinea pigs. In the 1930s, the newly established Medical Research Council, with assistance from industry, sponsored a study of the effects of exposing animals to asbestos by injection (intratracheal and subcutaneous) and by inhalation in the factory environment. Government reports, publications, and contemporary records obtained by legal discovery have been reviewed in the context of the stage of scientific development and the history of the times. Experimenters were engaged in a learning process during the 1912-1950 period, and their reports of the effects of asbestos were inconsistent. Pathologists who studied the effects of asbestos experimentally, at whole animal, tissue and cellular levels, advanced experimental methodology and mechanistic knowledge. In the hands of public relations experts, however, research was exploited to preserve an industry and perpetuate preventable diseases, a practice that continues to this day. PMID- 28913872 TI - High primary antibiotic resistance of Helicobacter Pylori strains isolated from dyspeptic patients: A prevalence cross-sectional study in Spain. AB - BACKGROUND: The rate of H. pylori resistance to different antibiotics is increasing and determines the selection of eradication therapy. The aim of this study was to determine the resistance patterns of H. pylori strains in our area. METHODS: Biopsies from gastric corpus for microbiological culture and antibiotic resistance were obtained in patients undergoing upper gastrointestinal endoscopy for dyspepsia. Selective Agar Pylori for isolation of the bacteria and Agar Mueller-Hinton supplemented with blood to test the sensitivity to antibiotics were used. Presence of H. pylori was confirmed using direct observation with phase-contrast microscopy and/or smears stained with acridine orange. In vitro bacterial susceptibility to amoxicillin, clarithromycin, rifampicin, tetracycline, metronidazole, and levofloxacin was tested using diffusion MIC test strips. Minimum inhibitory concentration values were determined based on the 6th version of the EUCAST (European Committee on Antimicrobial Susceptibility Testing) Clinical Breakpoint (2016). RESULTS: Two hundred and seventeen patients were included (58.1% female, median age 64 years, range 25-92). H. pylori was identified in 108 patients (49.8%); culture and antibiogram were completed in 77 of them (71.3% of H. pylori-positive patients). The resistance rates were as follows: levofloxacin 38.7%, rifampicin 33.3%, metronidazole 27% and clarithromycin 22.4%. No case of amoxicillin or tetracycline resistance was identified. Dual clarithromycin-metronidazole resistance was observed in 10% of strains, whereas multiple drug-resistant was observed in 14.2%. CONCLUSIONS: Resistance rate of H. pylori to antibiotics is high in the northwest of Spain. The high resistance to levofloxacin and clarithromycin advises against their wide empirical use of these antibiotics in eradication regimens. PMID- 28913873 TI - Improvement of Decellularization Efficiency of Porcine Aorta Using Dimethyl Sulfoxide as a Penetration Enhancer. AB - Decellularization of tissues and organs enables researchers to obtain extracellular matrix (ECM) with the natural conformation and chemical composition of specific tissues. However, drawbacks exist such as the structural alteration of ECM or loss of some important components in ECM due to overexposure to chemicals during the decellularization process. In this study, porcine aorta was decellularized by sodium dodecyl sulfate (SDS). Dimethyl sulfoxide (DMSO) was used as a penetration enhancer in the decellularization process to enhance the penetration of SDS, consequently reducing the exposure time of SDS to treated tissues. It is revealed that by addition of DMSO to the decellularization process 64.4% more DNA was removed when compared with just SDS exposure within a 3 h reaction. Cross-validation by DAPI staining showed that, in the presence of DMSO, the penetration of SDS was improved and almost all cells were removed from the aorta within the 3 h exposure time. Collagen staining revealed that just SDS treatment showed less polarized collagen fibers, while the DMSO addition groups revealed denser and organized collagen fibers. Moreover 77% glycosaminoglycan content was preserved by addition of DMSO in resultant tissues. Scanning electron microscopy analysis of decellularized aortic matrix showed that ECM components remained in the adventitia layer with the addition of DMSO treatment, while the layer was removed with just SDS treatment. Biocompatibility assays proved that after washing the decellularized samples with media supplemented with 3% antibiotic and antimycotic solution for 2 days there was no cytotoxic effect related to the SDS + DMSO decellularization protocol. This study demonstrates that the new decellularization protocol not only improves the removal efficiency of cellular components but also protects the crucial ECM components. PMID- 28913874 TI - An algorithmic approach to diagnose haematolymphoid neoplasms in effusion by combining morphology, immunohistochemistry and molecular cytogenetics. AB - OBJECTIVE: There are limited studies of cytology diagnosis of haematopoietic and lymphoid tumours in serosal effusion except for occasional case reports. We would like to demonstrate an algorithmic approach for accurate diagnosis, especially in patients without previous history. METHODS: We reviewed 36 cases of lymphoma diagnosed in serosal effusion following an algorithmic approach. Suspected tumour cells were classified into small, intermediate and large sizes and two characteristic forms of plasmacytoid and Reed Sternberg-like on smears (step 1), followed by utilising panels of immunohistochemical markers and Epstein-Barr encoding region in situ hybridisation on cell blocks (step 2). A panel of CD3, CD20 and Ki-67 formed the basic workup, followed by pertinent batteries of immunostaining. Molecular tests were applied in 22 selected cases by fluorescence in situ hybridisation (step 3). RESULTS: There were 15 diffuse large B-cell lymphomas; 12 plasma cell myelomas; two mantle cell lymphomas; one anaplastic large cell lymphoma ALK +; one small lymphocytic lymphoma; one plasmablastic lymphoma; one peripheral T-cell lymphoma, not otherwise specified, one extranodal NK/T-cell lymphoma, nasal type and two T-cell lymphoblastic lymphomas. 14 cases with previous history had complete concordance in immunophenotype between cytology and histology. Another 14 cases were primarily diagnosed in patients with initial symptom of effusion based on immunophenotyping and cytogenetic test in selected cases. Eight cases were diagnosed based on morphology alone. CONCLUSION: An algorithmic approach based on morphology and immunohistochemistry is the key to making an accurate diagnosis of haematopoietic and lymphoid tumours in effusion. A molecular test is also important for confirmation and prognostic prediction. We reviewed 36 haematolymphoid neoplasms diagnosed in effusion including 14 cases primarily diagnosed in patients without previous history following an algorithmic approach by combining morphology, immunohistochemistry and molecular cytogenetics. PMID- 28913876 TI - An Assessment of Participant-Described Interprofessional Oral Health Referral Systems Across Rurality. AB - PURPOSE: As a means to identify and quantify oral health interprofessional collaborative practice (IPP), we examined participant-described medical-to-dental (M2D) referral networks and how they function across rurality. METHODS: We conducted a cross-sectional survey on the appraisal of IPP referral systems in 2016. Secondarily, we examined if rural health clinics (RHCs) have different experiences with M2D referrals compared to other practice types. Independent variables included geographic and organizational indicators, referral system attributes, and respondent characteristics. Data were coded by Census region and state Medicaid expansion status. Bivariable and multivariable analyses were conducted using SAS. FINDINGS: A convenience cohort (n = 559) from 44 states was examined. Nearly, half (48.7%) reported dependable M2D referral systems. In bivariate analysis, all independent variables were significant except for state Medicaid expansion status. In multivariable analysis, Census region retained significance (P = .0093). Organization type and practice issues with no shows/missed appointments continued to have significance (P < .001 and .002, respectively). Accountable care organizations were over 5 times (5.72, P = .001) more likely than RHCs to report dependable M2D referral systems. Federally qualified health clinics were slightly over 3 times more likely than RHCs to report dependable M2D referral (3.04, P < .001). No differences between RHCs and other private practices were observed. CONCLUSIONS: The importance of IPP continues to be promoted in the current health care environment. Our study demonstrates that, in this motivated study population, M2D referrals can work well, even in rural areas. Organization type, directionality of referral, broken appointment rates, and electronic health information management were all found to significantly impact the respondents' rating on the dependability of an M2D referral process. PMID- 28913875 TI - Alterations in the alpha2 delta ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies. AB - OBJECTIVES: Thrombospondins, which are known to interact with the alpha2 delta subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). METHODS: We measured the transcripts of thrombospondin-1 and alpha2 delta subunit, and protein levels of alpha2 delta, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS CoGIE Consortium. RESULTS: Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. SIGNIFICANCE: These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs. PMID- 28913877 TI - Minimal important difference of target lobar volume reduction after endobronchial valve treatment for emphysema. AB - BACKGROUND AND OBJECTIVE: Target lobar volume reduction (TLVR) is an important efficacy outcome measure for bronchoscopic lung volume reduction (BLVR) treatment using one-way endobronchial valves (EBV) in patients with severe emphysema. The commonly used cut-off value for TLVR that expresses a perceivable clinical benefit is -350 mL. However, a scientifically determined minimal important difference (MID) for TLVR never has been published. The objective of the present study was to determine the MID for TLVR on HRCT in patients who were treated with EBV. METHODS: A total of 318 patients with severe emphysema from two BLVR trials were analysed. Anchor-based methods were used to define the TLVR MID at 6 months follow-up. Forced expiratory volume in 1 s (FEV1 ), residual volume (RV) and St. George's Respiratory Questionnaire (SGRQ) were used as anchors. RESULTS: The calculated TLVR MID with each anchor was: FEV1 -587 mL, RV -534 mL and SGRQ -560 mL. The combined MID (average of the three anchor-based MIDs) was -563 mL. CONCLUSION: Using the anchor-based method, we established a TLVR MID of -563 mL in patients with severe emphysema at 6 months follow-up after EBV treatment. This value can be useful for both interpreting the results from trials and clinical practice, as well as for designing future studies on lung volume reduction. PMID- 28913879 TI - Short T2 imaging using a 3D double adiabatic inversion recovery prepared ultrashort echo time cones (3D DIR-UTE-Cones) sequence. AB - PURPOSE: To investigate high contrast imaging of short T2 tissues with a three dimensional double adiabatic inversion recovery prepared ultrashort echo time Cones (3D DIR-UTE-Cones) sequence. METHODS: The sequence used two sequential adiabatic inversion pulses to suppress signals from long T2 tissues, followed by multispoke UTE acquisition to detect signals from short T2 tissues. The two adiabatic inversion pulses are identical with a center frequency located at the water peak, but the spectral width is broad enough to cover both water and fat frequencies. The feasibility of this technique was demonstrated through numerical simulation and phantom studies. Finally, DIR-UTE-Cones was applied to three healthy volunteers to image cortical bone, patellar tendon, and Achilles tendon. T2* was also measured via single-component exponential fitting. RESULTS: Numerical simulation suggests that the DIR technique provides perfect nulling of muscle and fat as well as efficient suppression of other long T2 tissues with T1 values between fat and water or those above water. Excellent image contrast can be achieved with DIR-UTE-Cones for the short T2 tissues, with fitted T2* values of 0.28-0.38 ms for cortical bone, 0.56 +/- 0.07 ms for the patella tendon, and 0.45 +/- 0.06 ms for the Achilles tendon, respectively. CONCLUSION: The 3D DIR UTE-Cones sequence provides robust suppression of long T2 tissues and allows selective imaging as well as T2* measurement of short T2 tissues such as cortical bone, patellar tendon, and the Achilles tendon. Magn Reson Med 79:2555-2563, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28913880 TI - Contraction of pi-Conjugated Rings upon Oxidation from Cyclooctatetraene to Benzene via the Tropylium Cation. AB - We have serendipitously discovered a unique transformation of a cyclooctatetraene derivative 1 into a cycloheptatriene spirolactone 3 upon oxidation, which is the first such transformation reported in 60 years. Product 3 could be reversibly interconverted into the aromatic tropylium cation 3H+ by acid/base treatment, which was accompanied by drastic spectroscopic changes. The resultant cycloheptatriene could be further converted into benzene upon oxidation. We characterized all the key structures by X-ray studies. Eventually, the pi conjugated ring size shrinks from 8 to 7, then finally to 6 upon oxidation, in the direction of the stronger aromatization. PMID- 28913878 TI - Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation. AB - Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 * 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 * 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. PMID- 28913881 TI - Effect of negative dietary cation-anion differences on carcass characteristics and beef tenderness of Japanese Black steers. AB - Lowering dietary cation-anion differences (DCAD) can enhance responsiveness to Ca homeostatic hormones and increase Ca availability, which might have potential to activate a Ca-dependent protease, calpain, and to enhance postmortem myofibrillar proteolysis. In this study, we investigated the effects of DCAD manipulation on calpain activity and beef tenderness in Japanese Black cattle which are characterized by their high marbling. Thirty-six Japanese Black steers were allotted to one of two treatments: (i) control (CON; DCAD +6.09 mEq/100 g of dry matter (DM)) or (ii) negative DCAD (NEGD; DCAD -8.27 mEq/100 g DM) for 70 days before slaughter. Lowering DCAD decreased DM and energy intake (P < 0.01) even though it did not negatively affect the growth performance or carcass characteristics. In NEGD, urine pH was decreased by acidification caused by the negative DCAD (P < 0.01). Calpain activities tended to be improved in NEGD (P = 0.09), but Warner-Bratzler shear force values were not affected by treatment. Although calpain activities tended to improve, lowering DCAD to -8.27 for 70 days before slaughter was insufficient to enhance beef tenderness in Japanese Black steers. PMID- 28913882 TI - Reducing Disparities in Cancer Screening and Prevention through Community-Based Participatory Research Partnerships with Local Libraries: A Comprehensive Dynamic Trial. AB - Reduction of cancer-related disparities requires strategies that link medically underserved communities to preventive care. In this community-based participatory research project, a public library system brought together stakeholders to plan and undertake programs to address cancer screening and risk behavior. This study was implemented over 48 months in 20 large urban neighborhoods, selected to reach diverse communities disconnected from care. In each neighborhood, Cancer Action Councils were organized to conduct a comprehensive dynamic trial, an iterative process of program planning, implementation and evaluation. This process was phased into neighborhoods in random, stepped-wedge sequence. Population-level outcomes included self-reported screening adherence and smoking cessation, based on street intercept interviews. Event-history regressions (n = 9374) demonstrated that adherence outcomes were associated with program implementation, as were mediators such as awareness of screening programs and cancer information seeking. Findings varied by ethnicity, and were strongest among respondents born outside the U.S. or least engaged in care. This intervention impacted health behavior in diverse, underserved and vulnerable neighborhoods. It has been sustained as a routine library system program for several years after conclusion of grant support. In sum, participatory research with the public library system offers a flexible, scalable approach to reduce cancer health disparities. PMID- 28913883 TI - Interactions between erythromycin, flunixin meglumine, levamisole and plant secondary metabolites towards bovine gastrointestinal motility-in vitro study. AB - Continued ingestion of plant secondary metabolites by ruminants can provoke pharmacological interactions with pharmaceutical agents used in animals. As some drugs and phytocompounds affect smooth muscle activity, the aim of this study was to verify the possible interaction between selected pharmaceutical agents and plant secondary metabolites towards bovine gastrointestinal motility. The interactions between phytocompounds-apigenin, quercetin, hederagenin, medicagenic acid-and medicines-erythromycin, flunixin meglumine and levamisole-were evaluated on bovine isolated abomasal and duodenal specimens obtained from routinely slaughtered cows. The obtained results confirmed the contractile effect of all three drugs used solely. Hederagenin and medicagenic acid (0.001 MUM) enhanced the contractile effect of levamisole. Hederagenin additionally increased the impact of erythromycin. Both saponins (100 MUM) showed synergistic effects with all tested pharmaceuticals. Apigenin and quercetin (0.001 MUM) intensified the contractile response induced by erythromycin and levamisole. Moreover, both flavonoids (100 MUM) showed an antagonistic interaction with all tested drugs which in that situation were devoid of the prokinetic effect. To conclude, plant metabolic metabolites such as saponins and flavonoids are potent modifiers of the effect of drugs towards gut motility. The synergy observed between phytocompounds and selected medicines can be beneficial in the treatment of cows with hypomotility disorders. PMID- 28913884 TI - Syntheses and Properties of Tin-Containing Conjugated Heterocycles. AB - Heterocycles that contain tin atoms can be aromatic in a similar sense to well known aromatic compounds such as benzene or thiophene, but such examples are rare. However, due to the low-lying sigma*-orbitals of the tin-substituent bond in stannoles, they are capable of sigma*-pi* conjugation in a way that is exclusive to heavier element containing heterocycles. This makes stannoles very interesting alternatives for purely organic heterocycles in material applications, in which optoelectronic properties are of interest. This Concept article will highlight the synthesis, reactivity and physical properties of stannoles and related fluorenostannoles. At first, a brief introduction to different types of tin-containing heterocycles is presented, followed by a discussion on different approaches to prepare stannoles, their reactivity and their physical properties. In addition, the first stannole-containing polymer will be reviewed. PMID- 28913885 TI - Development and evaluation of high-density Axiom(r) CicerSNP Array for high resolution genetic mapping and breeding applications in chickpea. AB - To accelerate genomics research and molecular breeding applications in chickpea, a high-throughput SNP genotyping platform 'Axiom(r) CicerSNP Array' has been designed, developed and validated. Screening of whole-genome resequencing data from 429 chickpea lines identified 4.9 million SNPs, from which a subset of 70 463 high-quality nonredundant SNPs was selected using different stringent filter criteria. This was further narrowed down to 61 174 SNPs based on p-convert score >=0.3, of which 50 590 SNPs could be tiled on array. Among these tiled SNPs, a total of 11 245 SNPs (22.23%) were from the coding regions of 3673 different genes. The developed Axiom(r) CicerSNP Array was used for genotyping two recombinant inbred line populations, namely ICCRIL03 (ICC 4958 * ICC 1882) and ICCRIL04 (ICC 283 * ICC 8261). Genotyping data reflected high success and polymorphic rate, with 15 140 (29.93%; ICCRIL03) and 20 018 (39.57%; ICCRIL04) polymorphic SNPs. High-density genetic maps comprising 13 679 SNPs spanning 1033.67 cM and 7769 SNPs spanning 1076.35 cM were developed for ICCRIL03 and ICCRIL04 populations, respectively. QTL analysis using multilocation, multiseason phenotyping data on these RILs identified 70 (ICCRIL03) and 120 (ICCRIL04) main effect QTLs on genetic map. Higher precision and potential of this array is expected to advance chickpea genetics and breeding applications. PMID- 28913886 TI - What's parenting got to do with it: emotional autonomy and brain and behavioral responses to emotional conflict in children and adolescents. AB - Healthy parenting may be protective against the development of emotional psychopathology, particularly for children reared in stressful environments. Little is known, however, about the brain and behavioral mechanisms underlying this association, particularly during childhood and adolescence, when emotional disorders frequently emerge. Here, we demonstrate that psychological control, a parenting strategy known to limit socioemotional development in children, is associated with altered brain and behavioral responses to emotional conflict in 27 at-risk (urban, lower income) youth, ages 9-16. In particular, youth reporting higher parental psychological control demonstrated lower activity in the left anterior insula, a brain area involved in emotion conflict processing, and submitted faster but less accurate behavioral responses-possibly reflecting an avoidant pattern. Effects were not replicated for parental care, and did not generalize to an analogous nonemotional conflict task. We also find evidence that behavioral responses to emotional conflict bridge the previously reported link between parental overcontrol and anxiety in children. Effects of psychological control may reflect a parenting style that limits opportunities to practice self regulation when faced with emotionally charged situations. Results support the notion that parenting strategies that facilitate appropriate amounts of socioemotional competence and autonomy in children may be protective against social and emotional difficulties. PMID- 28913887 TI - The equity of access to primary dental care in Sao Paulo, Brazil: A geospatial analysis. AB - OBJECTIVES: Brazil is one of the largest countries in the world, in terms of geography and population. Most Brazilians reside in the south and south-eastern regions, with notable numbers in the regions' megacities, such as Sao Paulo city. Healthcare provision in such a complex environment is difficult. Thus, a clear understanding of the distribution - or rather, the maldistribution - of these services is fundamental for optimising the allocation of human and financial resources to areas of greatest privation. The present study aimed to determine the distribution of primary dental clinics in Sao Paulo city. METHODS: A total of 4,101 primary dental clinics in Sao Paulo city were identified and geocoded. Clinic locations were integrated with the city's 19,128 constituent census tracts - each containing sociodemographic data for the 11,252,204 residents - using Geographic Information Systems (GIS). RESULTS: Approximately two-thirds (64.8%) of the population resided within 0.5 km of a primary dental clinic, and a further 23.9% were within 1 km. Populations more than 1 km out were typically characterised as sociodemographically disadvantaged. Primary dental clinics were also more sparsely distributed in the city's peripheral census tracts than central census tracts. CONCLUSION: Primary dental clinics are maldistributed in Sao Paulo city, with disadvantaged populations having less spatial access than their advantaged counterparts. PMID- 28913888 TI - Viral upper respiratory infection at pediatric liver transplantation is associated with hepatic artery thrombosis. PMID- 28913890 TI - Interfacial Fracture Toughness of Adhesive Resin Cement-Lithium-Disilicate/Resin Composite Blocks. AB - PURPOSE: Resin composite blocks (RCB) are advocated as alternative to ceramic blocks (CB). Prior to use, adherence to these materials should characterized. This study aimed to test the null hypothesis (H0 ) that material and surface treatment combinations do not influence interfacial fracture toughness (KIC ) of a self-cured adhesive resin cement [RelyX Ultimate (RXU)] to RCB or CB, under nonaged and aged conditions. MATERIALS AND METHODS: Two RCB, Lava Ultimate (LU) and Enamic (EN), and one CB, IPS e.max Press (EMP) were used. Half-size [(6 * 6 * 6 * 6 mm)] specimens were prepared for EMP (n = 30), EN (n = 30), and LU (n = 60). RCB specimens were prepared by wet cutting/grinding, while CB specimens were pressed. Surfaces of EMP and EN were preconditioned with hydrofluoric acid (5%); surfaces of LU were sandblasted with either 27 MUm alumina (LUS) or 30 MUm silica modified alumina Rocatec soft (LUR). All specimens were bonded with Scotchbond Universal adhesive and RXU. Additionally, twenty (4 * 4 * 4 * 8 mm) RXU specimens were prepared. All specimens were stored in water at 37 degrees C and tested after 1 and 60 days. Interfacial KIC was determined with the notchless triangular prism specimen KIC test. Results were analyzed with two-way ANOVA and Scheffe multiple means comparisons (alpha = 0.05). Preconditioned and selected fractured surfaces were characterized with scanning electron microscopy. RESULTS: At 24 hours, LUS-RXU and LUR-RXU had significantly higher interfacial KIC than EN-RXU and EMP-RXU and were not different from KIC of RXU. Aging lead to a significant decrease in KIC of RXU and interfacial KIC of LUS-RXU, LUR-RXU, and EMP-RXU; interfacial KIC of EN-RXU was not affected. Based on the results, H0 was rejected. CONCLUSION: Under the conditions of this study, at 24 hours, interfacial KIC of LUS-RXU and LUR-RXU was superior to EMP-RXU and EN-RXU. Aging in water at 37 degrees C did not affect interfacial KIC of EN-RXU but adversely affected KIC of RXU and the other interfacial KIC . CLINICAL IMPLICATIONS: The results suggest that RXU and its adherence to LU and EMP deteriorates upon exposure to water at 37 degrees C. In making clinical decisions related to material selection, practitioners should consider in vitro results. PMID- 28913891 TI - Venous thromboembolism and risk of cancer in patients with rheumatoid arthritis. AB - : Essentials Can venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients be marker of cancer? RA patients with VTE and comparison cohorts from population-based registries were compared. Increased risk of cancer in RA patients with VTE during the first year of VTE was observed. Risk of cancer in RA patients was increased also during the longer period following VTE. SUMMARY: Background It is unknown whether venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients can be a marker of occult cancer. Objectives To examine risk of cancer subsequent to VTE among RA patients compared with risk of cancer in an RA cohort without VTE and in a general population without RA and without VTE. Patients/Methods All RA patients with a first-time diagnosis of VTE (index date) during 1978-2013 and comparison cohorts were identified from population based registries in Denmark. Results We identified three cohorts: 2497 RA patients with VTE, 11 672 RA patients without VTE and 12 730 persons from the general population. The cumulative incidence of cancer within the first year of the index date was 3.2% among RA with VTE, 2.2% among RA without VTE, and 2.0% in the general population cohort. Incidence rate ratios (IRRs) were 1.79 (95% confidence interval [CI], 1.37-2.33) for RA patients with VTE vs. RA patients without VTE and 2.12 (95% CI, 1.63-2.76) for RA patients with VTE vs. the general population. The IRR of cancer at > 1 to 36 years from the index date among RA patients with VTE was 1.16 (95% CI, 1.00-1.34) compared with the RA patients without VTE and 1.33 (95% CI, 1.15-1.53) compared with the general population. Conclusions We found an increased risk of cancer in RA patients with VTE during the first year following VTE and also during the longer follow-up period. Thus, VTE may not only be a result of inflammation and immunological dysfunctions associated with RA, but may also be a marker for occult cancer. PMID- 28913892 TI - Implementation of a simulation-based telemedicine curriculum. PMID- 28913889 TI - Prevalence and Contributors to Low-grade Inflammation in Three U.S. Populations of Reproductive Age Women. AB - BACKGROUND: Inflammation, measured by high-sensitivity C-reactive protein (hsCRP), is linked to adverse reproductive outcomes. However, prevalence and predictors of low-grade inflammation are poorly understood among reproductive age women. Therefore, the current aim was to characterize: (i) the prevalence of elevated hsCRP and (ii) whether the association of various demographic, anthropometric, life style, and metabolic characteristics with higher hsCRP varies across populations of reproductive age women with varying risk profiles for adverse reproductive outcomes. METHODS: Bivariate analysis of characteristics among women ages 18-40 having hsCRP <2.0 vs. >=2.0 mg/L in the BioCycle Study (N = 259), the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR) (N = 1228), and the National Health and Nutrition Examination Survey (NHANES; N = 2173) were conducted. Multivariable regression analysis estimated the association of all characteristics to hsCRP within each cohort. RESULTS: Prevalence of hsCRP>=2 mg/L ranged from 20 to 40%. Age, BMI, waist circumference, blood pressure, lipids, glucose, and insulin were frequently higher in women with hsCRP >=2 mg/L. In multivariable models, however, only adiposity (BMI, waist circumference) was independently associated with hsCRP within all three cohorts. Some variables showed cohort-specific associations with higher hsCRP: white race (EAGeR), higher fasting glucose (BioCycle), and lesser education and employment (NHANES). The total characteristics explained 28-46% of the variation in hsCRP across the three cohorts. CONCLUSIONS: Low-grade inflammation was common, including among predominantly non-obese women, affecting from 20 to 40% of reproductive age women. Given the potential to reduce inflammation through inexpensive, widely available therapies, examination of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed. PMID- 28913893 TI - Gonial Angle Measured by Orthopantomography as a Predictor of Maximum Occlusal Force. AB - PURPOSE: To establish the accuracy of measuring the gonial angle on an orthopantomogram (GAO), as defined by the anatomic relationship between the inferior and posterior borders of the mandible. Furthermore, to examine the relationship between GAO and maximum occlusal force (MOF) in the premolar and molar regions of healthy young adults. MATERIALS AND METHODS: Orthopantomograms of dry mandibles were obtained in three orientations in the sagittal plane, to represent variation in image acquisition in clinical settings. The GAO was measured using image-processing software, and reliability was analyzed using the intraclass correlation coefficient. Then, GAO, MOF, gender, and body mass index (BMI) were measured in a cohort of healthy young adult volunteers. MOF was measured using an Occlusal Force Meter GM 10 device. The relationships between GAO, MOF, sex, and BMI were examined using the Pearson correlation coefficient and multiple regression analysis. RESULTS: In five dry mandibles, there was a high correlation between the GAOs measured in the different orientations (p < 0.001). In 58 healthy volunteers (31 women and 27 men, mean age 24.6 years), the mean GAO was 123.3 degrees +/- 7.5 degrees . The mean MOFs at the first premolar, second premolar, and first molar teeth were 256.4 N +/- 128.3 N, 319.0 N +/- 171.7 N, and 487.5 N +/- 227.2 N, respectively. Men had significantly greater MOF than women at all teeth. The GAO was significantly inversely correlated with MOF at the second premolar (r = -0.376, p = 0.005) and first molar teeth (r = -0.479, p < 0.001). Multiple regression analysis showed that GAO was a significant explanatory factor for MOF at the second premolar and first molar teeth (p = 0.012 and 0.001, respectively). CONCLUSIONS: GAOs were measured accurately on the orthopantomograms taken in this study and were a reliable predictor of MOF between the second premolar and first molar teeth. A smaller GAO was associated with a greater MOF at the second premolar and first molar teeth. PMID- 28913894 TI - Veteran treatment courts: A promising solution. AB - The high prevalence of substance use, traumatic brain injury, post-traumatic stress disorder, and other mental illness in the veteran population presents unique public health and social justice challenges. Veteran involvement in the justice system has been identified as a national concern. Criminal justice involvement compounds pre-existing socioeconomic stressors and further strains support systems. The point of contact with the criminal justice system, however, presents an opportunity to establish mental health treatment. This is consistent with the concept of the sequential intercept model that seeks to divert offenders with mental illness from the criminal justice system into treatment. In recent years, many jurisdictions have established veterans treatment courts (VTCs), a type of problem-solving court serving this diversion function for military veterans. This article presents an overview of the problem, the ethical basis for their development, a brief history of the courts, and their potential for success. The Harris County Veterans Court is presented as an example. PMID- 28913895 TI - NRAMP2, a trans-Golgi network-localized manganese transporter, is required for Arabidopsis root growth under manganese deficiency. AB - To cope with manganese (Mn) deficiency, plants have evolved an efficient transport system to uptake and redistribute Mn. However, the underlying molecular mechanisms remain to be demonstrated. We carried out a forward genetic screen in a root high-affinity Mn transporter nramp1 mutant background in Arabidopsis thaliana and identified an uncharacterized Mn transport NRAMP2. We investigated the effect of nramp2 mutation on root growth and reactive oxygen species (ROS) accumulation and we also examined the NRAMP2 expression pattern, and the subcellular localization and transport activity of NRAMP2. Mutation of NRAMP2 impaired plant growth, while overexpression of NRAMP2 improved plant growth under low Mn conditions. In the nramp2-1nramp1 double mutant, Mn deficiency inhibited root cell elongation and root hair development, which was associated with increased hydrogen peroxide (H2 O2 ) accumulation. NRAMP2 is preferentially localized to the trans-Golgi network. NRAMP2 has Mn influx transport activity in yeast, and mutation of NRAMP2 led to greater Mn retention in roots. Our results suggest that under Mn-deficient conditions, increased accumulation of H2 O2 is partially responsible for the root growth inhibition and NRAMP2 is involved in remobilization of Mn in Golgi for root growth. PMID- 28913896 TI - A novel non-azole topical treatment reduces Malassezia numbers and associated dermatitis: a short term prospective, randomized, blinded and placebo-controlled trial in naturally infected dogs. AB - BACKGROUND: Malassezia yeast overgrowth on the skin is a common and often recurrent cause of dermatitis in dogs; it can be an exacerbating factor of atopic dermatitis. Anti-fungal drugs have been a standard treatment, but there is some concern that resistance may be evolving in a spectrum of Malassezia species. Safe, efficient and easy-to-use alternatives are needed. OBJECTIVES: To assess if a commercially available topical non-azole solution applied to paws affected by Malassezia-associated dermatitis (MAD), could ameliorate Malassezia numbers and associated signs over a short term (14 day) trial. ANIMALS: Eighteen dogs with MAD affecting at least two paws. METHODS: The study design was prospective, randomized, blinded and placebo-controlled, using a split-body protocol. Dogs were treated once daily with the test solution on one paw and placebo on the other. Dogs were examined at days 0 and 14 +/- 3. The primary end-point was Malassezia numbers assessed cytologically. Secondary end-points were clinical scores for lesion severity and pruritus as assessed by a pruritus Visual Analog Scale (PVAS). Owner compliance and adverse effects were assessed. RESULTS: There was a statistically significant reduction in Malassezia numbers and clinical scores for paws treated with the test solution versus placebo. No statistical difference in PVAS was found. CONCLUSION: Daily topical application of the test solution was effective in reducing the Malassezia burden, as well as improving clinical scores in dogs with MAD of the paws. No adverse effects were reported and owners described the product as either "easy" or "very easy" to use. PMID- 28913897 TI - Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta. AB - Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Abeta) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Abeta toxicity influencing cognitive outcomes (Adas-cog). Preventive Abeta targeted therapies were simulated to minimize the Abeta difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Abeta, a 15% decrease in Abeta (using an imaging biomarker) is related to 15-20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Abeta continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design. PMID- 28913898 TI - Structural basis for binding and transfer of heme in bacterial heme-acquisition systems. AB - Periplasmic heme-binding proteins (PBPs) in Gram-negative bacteria are components of the heme acquisition system. These proteins shuttle heme across the periplasmic space from outer membrane receptors to ATP-binding cassette (ABC) heme importers located in the inner-membrane. In the present study, we characterized the structures of PBPs found in the pathogen Burkholderia cenocepacia (BhuT) and in the thermophile Roseiflexus sp. RS-1 (RhuT) in the heme free and heme-bound forms. The conserved motif, in which a well-conserved Tyr interacts with the nearby Arg coordinates on heme iron, was observed in both PBPs. The heme was recognized by its surroundings in a variety of manners including hydrophobic interactions and hydrogen bonds, which was confirmed by isothermal titration calorimetry. Furthermore, this study of 3 forms of BhuT allowed the first structural comparison and showed that the heme-binding cleft of BhuT adopts an "open" state in the heme-free and 2-heme-bound forms, and a "closed" state in the one-heme-bound form with unique conformational changes. Such a conformational change might adjust the interaction of the heme(s) with the residues in PBP and facilitate the transfer of the heme into the translocation channel of the importer. PMID- 28913900 TI - An applied distance-based course on health equity for physicians in training. PMID- 28913899 TI - Genotyping-by-sequencing through transcriptomics: implementation in a range of crop species with varying reproductive habits and ploidy levels. AB - The application of genomics in crops has the ability to significantly improve genetic gain for agriculture. Many marker-dense tools have been developed, but few have seen broad adoption in plant genomics due to issues of significant variations of genome size, levels of ploidy, single nucleotide polymorphism (SNP) frequency and reproductive habit. When combined with limited breeding activities, small research communities and scant sequence resources, the suitability of popular systems is often suboptimal and routinely fails to effectively balance cost-effectiveness and sample throughput. Genotyping-by-sequencing (GBS) encompasses a range of protocols including resequencing of the transcriptome. This study describes a skim GBS-transcriptomics (GBS-t) approach developed to be broadly applicable, cost-effective and high-throughput while still assaying a significant number of SNP loci. A range of crop species with differing levels of ploidy and degree of inbreeding/outbreeding were chosen, including perennial ryegrass, a diploid outbreeding forage grass; phalaris, a putative segmental allotetraploid outbreeding forage grass; lentil, a diploid inbreeding grain legume; and canola, an allotetraploid partially outbreeding oilseed. GBS-t was validated as a simple and largely automated, cost-effective method which generates sufficient SNPs (from 89 738 to 231 977) with acceptable levels of missing data and even genome coverage from c. 3 million sequence reads per sample. GBS-t is therefore a broadly applicable system suitable for many crops, offering advantages over other systems. The correct choice of subsequent sequence analysis software is important, and the bioinformatics process should be iterative and tailored to the specific challenges posed by ploidy variation and extent of heterozygosity. PMID- 28913901 TI - Real-time continuous monitoring of injection pressure at the needle tip for peripheral nerve blocks: description of a new method. AB - The measurement of injection pressure during the performance of peripheral nerve blocks can be pivotal to detect intraneural placement of the needle tip and thus avoid intrafascicular injection. However, injection pressure can only be measured along the injection line (tubing), which is influenced by several factors. The primary aim of this feasibility study was to describe and validate the principle of a novel nerve-block needle conceived for real-time continuous monitoring of injection pressures at the needle tip. Our secondary aim was to provide measurements and compare injection pressure values at the needle tip and in the injection line. Four porcine lower limb anatomic models were prepared and extraneural injections were performed with fractioned boluses of 2 ml saline at a controlled infusion rate of 10 ml.min-1 (0.16 ml.s-1 ). Injection pressure at the needle tip was monitored and compared with the pressure in the injection line. The system proved to be reliable. Thirty injections were successfully performed without technical failures. The mean (95%CI) difference between pressures at the needle tip and the injection line varied substantially from 14.33 (12.58-16.08) kPa at 0.5 ml injected volume to 41.56 (39.66-43.45) kPa at the end of the injection. This study demonstrates that the described system allows for real-time continuous monitoring of injection pressure at the needle tip. Moreover, this study shows that injection pressure values measured in the injection line cannot be assumed to be a reliable indicator of the injection pressure at the needle tip. PMID- 28913903 TI - Acinetobacter baumannii isolated from hospital-acquired infection: biofilm production and drug susceptibility. AB - Acinetobacter baumannii cause opportunistic nosocomial infections and is often multidrug resistant. It has ability to form biofilm. The possession of drug resistance mechanism and ability of biofilm formation seems to be the different way to enhancement of viability in stressful environment. In this study, we evaluate relation between these two factors. The biofilm formation was investigated in M63 medium with casein in microtiter plates, and the drug susceptibility was performed by disk diffusion methods. We found that 80-98% strains formed a biofilm. Strains showing sensitivity to amikacin and tobramycin from ICU produced more biofilm than strains showing resistance to these antibiotics. Ceftazidime-sensitive strains formed a smaller biofilm than resistant. The logistic regression shows association between drug resistance and strains originating from ICU. In case of ceftazidime, strong biofilm formation and descending from ICU reduced the likelihood of drug sensitivity. For other drugs such as aminoglycosides, fluoroquinolones, trimethoprim/sulfamethoxazole, and tetracycline, we found opposite relation (but it was not statistically significance). However, generally it seems that strong biofilm producers from ICUs are often more susceptible to antibiotics. This situation can be explained by the fact that bacteria protected in biofilm do not need mechanisms responsible for resistance of planktonic cells. PMID- 28913902 TI - Analysis of cancer gene expression data with an assisted robust marker identification approach. AB - Gene expression (GE) studies have been playing a critical role in cancer research. Despite tremendous effort, the analysis results are still often unsatisfactory, because of the weak signals and high data dimensionality. Analysis is often further challenged by the long-tailed distributions of the outcome variables. In recent multidimensional studies, data have been collected on GEs as well as their regulators (e.g., copy number alterations (CNAs), methylation, and microRNAs), which can provide additional information on the associations between GEs and cancer outcomes. In this study, we develop an ARMI (assisted robust marker identification) approach for analyzing cancer studies with measurements on GEs as well as regulators. The proposed approach borrows information from regulators and can be more effective than analyzing GE data alone. A robust objective function is adopted to accommodate long-tailed distributions. Marker identification is effectively realized using penalization. The proposed approach has an intuitive formulation and is computationally much affordable. Simulation shows its satisfactory performance under a variety of settings. TCGA (The Cancer Genome Atlas) data on melanoma and lung cancer are analyzed, which leads to biologically plausible marker identification and superior prediction. PMID- 28913904 TI - Re-emergence of rabies virus maintained by canid populations in Paraguay. AB - Paraguay has registered no human cases of rabies since 2004, and the last case in dogs, reported in 2009, was due to a variant maintained in the common vampire bat "Desmodus rotundus". In 2014, a dog was diagnosed as positive for rabies with aggression towards a boy and all required measures of control were successfully adopted. Epidemiological investigation revealed that the dog was not vaccinated and had been attacked by a crab-eating fox, "zorro" (Cerdocyon thous). The sample was diagnosed by the Official Veterinary Service of the Country and sent to the Center on Rabies Research from the University of Sao Paulo, Brazil, for antigenic and genetic characterization. A second sample from a dog positive for rabies in the same region in 2015 and 11 samples from a rabies outbreak from Asuncion in 1996 were also characterized. The antigenic profile of the samples, AgV2, was compatible with one of the variants maintained by dogs in Latin America. In genetic characterization, the samples segregated in the canine (domestic and wild species)-related group in an independent subgroup that also included samples from Argentina. These results and the epidemiology of the case indicate that even with the control of rabies in domestic animals, the virus can still circulate in wildlife and may be transmitted to domestic animals and humans, demonstrating the importance of continuous and improved surveillance and control of rabies, including in wild species, to prevent outbreaks in controlled areas. PMID- 28913905 TI - Clinicopathological study of lip cancer: a retrospective hospital-based study in Taiwan. AB - To evaluate the clinicopathological characteristics, high-risk lifestyle factors (HRLF: chronic exposure to sun, betel quid, alcohol, and tobacco), and prognostic factors of lip cancer. The hospital records of patients with pathologically confirmed lip squamous cell carcinoma (LSCC, n = 112) and lip basal cell carcinoma (LBCC, n = 21) were reviewed. Differences in clinicopathological characteristics between LSCC and LBCC, upper and lower lip, and status of second primary tumors were compared by chi-square test and logistic regression. The prognostic factors for LSCC were analyzed by Cox regression. Compared with LBCC patients, LSCC patients were men-predominant (p < 0.001), had younger ages at onset (p < 0.001), and higher rates of lower lips involvement (p < 0.001) and HRLFs. Patients with second primary tumors were highly associated with lower lip cancer involvement (adjusted odds ratio = 2.91, p = 0.03). Patients with lower lip cancer had more HRLFs with an increasing linear trend (p = 0.004). The poorer prognostic factors of LSCC for disease-specific survival were advanced stage III/IV [crude hazard ratio (CHR) = 11.16, p < 0.001], tumor dimension >4 cm (CHR = 8.19, p = 0.006), lymph node involvement (CHR = 11.48, p < 0.001), and recurrence (CHR = 3.96, p = 0.01); whereas for disease-free survival were moderately to poorly differentiated LSCC (CHR = 4.97, p = 0.002) and alcohol consumption (CHR = 3.13, p = 0.04). LSCC and lower lip cancer were highly associated with HRLFs. PMID- 28913906 TI - Semiautomatic extraction of cortical thickness and diaphyseal curvature from CT scans. AB - The understanding of locomotor patterns, activity schemes, and biological variations has been enhanced by the study of the geometrical properties and cortical bone thickness of the long bones measured using CT scan cross-sections. With the development of scanning procedures, the internal architecture of the long bones can be explored along the entire diaphysis. Recently, several methods that map cortical thickness along the whole femoral diaphysis have been developed. Precise homology is vital for statistical examination of the data; however, the repeatability of these methods is unknown and some do not account for the curvature of the bones. We have designed a semiautomatic workflow that improves the morphometric analysis of cortical thickness, including robust data acquisition with minimal user interaction and considering the bone curvature. The proposed algorithm also performs automatic landmark refinement and rigid registration on the extracted morphometric maps of the cortical thickness. Because our algorithm automatically reslices the diaphysis into 100 cross sections along the medial axis and uses an adaptive thresholding method, it is usable on CT scans that contain soft tissues as well as on bones that have not been oriented specifically prior to scanning. Our approach exhibits considerable robustness to error in user-supplied landmarks, suppresses distortion caused by the curvature of the bones, and calculates the curvature of the medial axis. PMID- 28913907 TI - Primate diversification inferred from phylogenies and fossils. AB - Biodiversity arises from the balance between speciation and extinction. Fossils record the origins and disappearance of organisms, and the branching patterns of molecular phylogenies allow estimation of speciation and extinction rates, but the patterns of diversification are frequently incongruent between these two data sources. I tested two hypotheses about the diversification of primates based on ~600 fossil species and 90% complete phylogenies of living species: (1) diversification rates increased through time; (2) a significant extinction event occurred in the Oligocene. Consistent with the first hypothesis, analyses of phylogenies supported increasing speciation rates and negligible extinction rates. In contrast, fossils showed that while speciation rates increased, speciation and extinction rates tended to be nearly equal, resulting in zero net diversification. Partially supporting the second hypothesis, the fossil data recorded a clear pattern of diversity decline in the Oligocene, although diversification rates were near zero. The phylogeny supported increased extinction ~34 Ma, but also elevated extinction ~10 Ma, coinciding with diversity declines in some fossil clades. The results demonstrated that estimates of speciation and extinction ignoring fossils are insufficient to infer diversification and information on extinct lineages should be incorporated into phylogenetic analyses. PMID- 28913908 TI - Provision of cellular blood components to CMV-seronegative patients undergoing allogeneic stem cell transplantation in the UK: survey of UK transplant centres. AB - OBJECTIVES: To identify current UK practice with regards to provision of blood components for cytomegalovirus (CMV)-seronegative, potential, allogeneic stem cell recipients of seronegative grafts. BACKGROUND: Infection with CMV remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (aSCT). CMV transmission has been a risk associated with the transfusion of blood components from previously exposed donors, but leucocyte reduction has been demonstrated to minimise this risk. In 2012, the UK Advisory Committee for the Safety of Tissues and Organs (SaBTO) recommended that CMV-unselected components could be safely transfused without increased risk of CMV transmission. METHODS: We surveyed UK aSCT centres to establish current practice. RESULTS: Fifteen adult and seven paediatric centres (75%) responded; 22.7% continue to provide components from CMV-seronegative donors. Reasons cited include the continued perceived risk of CMV transmission by blood transfusion, its associated morbidity and concerns regarding potential for ambiguous CMV serostatus in seronegative potential transplant recipients due to passive antibody transfer from CMV seropositive blood donors, leading to erroneous donor/recipient CMV matching at transplant. CONCLUSIONS: The survey demonstrated a surprisingly high rate (22.7%) of centres continuing to provide blood components from CMV-seronegative donors despite SaBTO guidance. PMID- 28913909 TI - Local delivery of strontium ranelate promotes regeneration of critical size bone defects filled with collagen sponge. AB - The effect of local delivery of strontium ranelate (SR) on bone regeneration of critical size bone defects filled with collagen sponge was evaluated. Bone defects of 5 mm diameter created in rat calvaria were filled with collagen sponge (C); collagen sponge with 5 mM Sr2+ SR (C5SR) or collagen sponge with 50 mM Sr2+ SR (C50SR). After 2, 4, and 6 weeks, bone volume (BV), bone surface (BS), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) were evaluated by computed microtomography. At 6 weeks, histological analysis was performed. Intragroup comparisons were made by the Friedman test, while comparisons between groups were made by Kruskal-Wallis test (alpha = 5%). All groups showed increased BV, BS, Tb.Th, and Tb.N over time, but only C50SR promoted the reduction of Tb.Sp (p < 0.05). No significant differences between groups were detected at weeks 2 and 4. However, C50SR showed the highest values of BV, BS, and Tb.Th at 6 weeks (p < 0.05). Histological analysis revealed connective tissue in C and C5SR and immature bone tissue in C50SR. Local delivery of SR 50 mM Sr2+ associated with collagen sponge increased and accelerated bone regeneration in critical bone defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 333-341, 2018. PMID- 28913910 TI - Rapid and high-resolution stable isotopic measurement of biogenic accretionary carbonate using an online CO2 laser ablation system: Standardization of the analytical protocol. AB - RATIONALE: The elaborate sampling and analytical protocol associated with conventional dual-inlet isotope ratio mass spectrometry has long hindered high resolution climate studies from biogenic accretionary carbonates. Laser-based on line systems, in comparison, produce rapid data, but suffer from unresolvable matrix effects. It is, therefore, necessary to resolve these matrix effects to take advantage of the automated laser-based method. METHODS: Two marine bivalve shells (one aragonite and one calcite) and one fish otolith (aragonite) were first analysed using a CO2 laser ablation system attached to a continuous flow isotope ratio mass spectrometer under different experimental conditions (different laser power, sample untreated vs vacuum roasted). The shells and the otolith were then micro-drilled and the isotopic compositions of the powders were measured in a dual-inlet isotope ratio mass spectrometer following the conventional acid digestion method. RESULTS: The vacuum-roasted samples (both aragonite and calcite) produced mean isotopic ratios (with a reproducibility of +/-0.2 0/00 for both delta18 O and delta13 C values) almost identical to the values obtained using the conventional acid digestion method. As the isotopic ratio of the acid digested samples fall within the analytical precision (+/-0.2 0/00) of the laser ablation system, this suggests the usefulness of the method for studying the biogenic accretionary carbonate matrix. CONCLUSIONS: When using laser-based continuous flow isotope ratio mass spectrometry for the high resolution isotopic measurements of biogenic carbonates, the employment of a vacuum-roasting step will reduce the matrix effect. This method will be of immense help to geologists and sclerochronologists in exploring short-term changes in climatic parameters (e.g. seasonality) in geological times. PMID- 28913911 TI - Older Adults' Awareness of Deprescribing: A Population-Based Survey. AB - OBJECTIVES: To determine older adults' awareness of the concept of medication induced harm and their familiarity with the term "deprescribing." Secondary objectives were to ascertain determinants of self-initiated deprescribing conversations and to identify how older adults seek information on medication harms. DESIGN: Cross-sectional population-based household telephone survey using random-digit dialling. SETTING: Canada. PARTICIPANTS: Community-dwelling adults aged 65 and older (N = 2,665; n = 898 men, n = 1,767 women, mean age 74.9 +/- 7.2, range 65-100). MEASUREMENTS: Information was gathered on age; sex; awareness of the term "deprescribing"; knowledge and information-seeking behaviors related to medication harms; and previous initiation of a deprescribing conversation with a healthcare professional. Three targeted classes of potentially inappropriate prescriptions were asked about: sedative-hypnotics, glyburide, and proton pump inhibitors. Descriptive statistics and regression analyses were used to quantify associations. RESULTS: Two-thirds (65.2%, 95% confidence interval (CI) = 63.4 67.0%) of participants were familiar with the concept of medication-induced harms. Only 6.9% (95% CI = 5.9-7.8%) recognized the term deprescribing; 48% (95% CI = 46-50%) had researched medication-related harms. Older adults most commonly sought information from the Internet (35.5%, 95% CI = 33.4-37.6%), and from health care professionals (32.2%, 95% CI = 30.1-34.3%). Patient-initiated deprescribing conversations were associated with awareness of medication harms (odds ratio (OR) = 1.74, 95% CI = 1.46-2.07), familiarity with the term deprescribing (OR = 1.55, 95% CI = 1.13-2.12), and information-seeking behaviors (OR = 4.57, 95% CI = 3.84-5.45), independent of age and sex. CONCLUSION: Healthcare providers can facilitate patient-initiated deprescribing conversations by providing information on medication harms and using the term "deprescribing." PMID- 28913912 TI - Streptococcus pneumoniae colonization of the nasopharynx is associated with increased severity during respiratory syncytial virus infection in young children. AB - BACKGROUND AND OBJECTIVE: Respiratory syncytial virus (RSV) is the most significant cause of acute respiratory infection (ARI) in early life. RSV and other respiratory viruses are known to stimulate substantial outgrowth of potentially pathogenic bacteria in the upper airways of young children. However, the clinical significance of interactions between viruses and bacteria is currently unclear. The present study aimed to clarify the effect of viral and bacterial co-detections on disease severity during paediatric ARI. METHODS: Nasopharyngeal aspirates from children under 2 years of age presenting with ARI to the emergency department were screened by quantitative PCR for 17 respiratory viruses and the bacterial pathogens Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Associations between pathogen detection and clinical measures of disease severity were investigated. RESULTS: RSV was the most common virus detected, present in 29 of 58 samples from children with ARI (50%). Detection of S. pneumoniae was significantly more frequent during RSV infections compared to other respiratory viruses (adjusted effect size: 1.8, P: 0.03), and co-detection of both pathogens was associated with higher clinical disease severity scores (adjusted effect size: 1.2, P: 0.03). CONCLUSION: Co detection of RSV and S. pneumoniae in the nasopharynx was associated with more severe ARI, suggesting that S. pneumoniae colonization plays a pathogenic role in young children. PMID- 28913913 TI - Development of the cancer-related loneliness assessment tool: Using the findings of a qualitative analysis to generate questionnaire items. AB - The aim of this research was to develop a tool to identify and assess the qualities of cancer-related loneliness in adult cancer survivors who have completed treatment. In addition to reporting the development of the tool, we explicate the process of using the findings of a qualitative analysis to generate questionnaire items, as currently little guidance exists on this topic. The findings of our qualitative research exploring the experience of loneliness in adult cancer survivors who had completed treatment, together with the findings of our concept analysis of loneliness, were used to develop an assessment tool for cancer-related loneliness following treatment completion. Cognitive testing was undertaken to assess fidelity of comprehension and feasibility in administration. The Cancer-Related Loneliness Assessment Tool is a 10-item self-report questionnaire capturing the essential elements of cancer-related loneliness following treatment completion. Experts believed the questionnaire to be face valid and usable in clinical practice, and preliminary cognitive testing indicated that the items generate the information intended and individuals have little trouble completing the tool. Following further development work, the tool could be employed to identify cancer-related loneliness following treatment completion. It could also aid with the development/adaptation and evaluation of person-centred interventions to address such loneliness. PMID- 28913914 TI - New onset of asthma and job status change among world trade center responders and workers. AB - BACKGROUND: Despite the high rates, the consequences of new onset asthma among the World Trade Center (WTC) responders in terms of the change in job status have not been studied. METHODS: This study consists of a cohort of 8132 WTC responders out of the total 25 787 responders who held a full-time job at the baseline visit, and participated in at least one follow-up visit. RESULTS: Overall, 34% of the study cohort changed their job status from full-time at a follow-up visit. Multivariable models showed that asthmatics were respectively 27% and 47% more likely to have any job status change and get retired, and twice as likely to become disabled as compared to non-asthmatics. CONCLUSIONS: With asthma incidence from WTC exposure, negative job status change should be considered as a potential long-term consequence of WTC exposure. PMID- 28913915 TI - Home Use, Remotely Supervised, and Remotely Controlled Transcranial Direct Current Stimulation: A Systematic Review of the Available Evidence. AB - OBJECTIVES: Transcranial direct current stimulation (tDCS) is gaining growing importance in the treatment of neurological and psychiatric disorders and is currently investigated for home-based and remotely supervised applications. METHODS: Here, we systematically review the available evidence from a database search (PubMed, ICTRP, clinicaltrials.gov) from January 2000 to May 2017. RESULTS: We detected 22 original research papers, trial protocols or trial registrations dealing with tDCS as an add-on intervention to cognitive or physiotherapeutic intervention. Overall, study samples are small; many studies are single-blinded and focus on feasibility and safety. There are two guideline papers setting basic requirements for clinical trials. CONCLUSIONS: Further research needs to focus on home-based treatment from different viewpoints, that is, safety, technical monitoring, reproducibility of repeated applications, feasibility of combined interventions and systematic assessment of efficacy, and safety in large randomized controlled clinical trials (RCTs). However, remotely controlled and supervised tDCS for home use represents a promising approach for widespread use of noninvasive brain stimulation (NIBS) in clinical care. PMID- 28913916 TI - Red and processed meat intake and cancer risk: Results from the prospective NutriNet-Sante cohort study. AB - The International Agency for Research on Cancer (WHO-IARC) classified red meat and processed meat as probably carcinogenic and carcinogenic for humans, respectively. These conclusions were mainly based on studies concerning colorectal cancer, but scientific evidence is still limited for other cancer locations. In this study, we investigated the prospective associations between red and processed meat intakes and overall, breast, and prostate cancer risk. This prospective study included 61,476 men and women of the French NutriNet-Sante cohort (2009-2015) aged >=35 y and who completed at least three 24 hrs dietary records during the first year of follow-up. The risk of developing cancer was compared across sex-specific quintiles of red and processed meat intakes by multivariable Cox models. 1,609 first primary incident cancer cases were diagnosed during follow-up, among which 544 breast cancers and 222 prostate cancers. Red meat intake was associated with increased risk of overall cancers [HRQ5vs.Q1 =1.31 (1.10-1.55), ptrend = 0.01) and breast cancer (HRQ5vs.Q1 = 1.83 (1.33-2.51), ptrend = 0.002]. The latter association was observed in both premenopausal [HRQ5vs.Q1 =2.04 (1.03-4.06)] and postmenopausal women [HRQ5vs.Q1 =1.79 (1.26-2.55)]. No association was observed between red meat intake and prostate cancer risk. Processed meat intake was relatively low in this study (cut offs for the 5th quintile = 46 g/d in men and 29 g/d in women) and was not associated with overall, breast or prostate cancer risk. This large cohort study suggested that red meat may be involved carcinogenesis at several cancer locations (other than colon-rectum), in particular breast cancer. These results are consistent with mechanistic evidence from experimental studies. PMID- 28913917 TI - Merging [2+2] Cycloaddition with Radical 1,4-Addition: Metal-Free Access to Functionalized Cyclobuta[a]naphthalen-4-ols. AB - A metal-free [2+2] cycloaddition and 1,4-addition sequence induced by S-centered radicals has been achieved by treating benzene-linked allene-ynes with aryldiazonium tetrafluoroborates and DABCO-bis(sulfur dioxide) in a one-pot procedure. The reaction provides a greener and more practical access to functionalized cyclobuta[a]naphthalen-4-ols with valuable applications. More than 50 examples are demonstrated with excellent diastereoselectivity and chemical yields. The reaction pathway is proposed to proceed by the following steps:[2+2] cycloaddition, insertion of SO2 , 1,4-addition, diazotization, and tautomerization. PMID- 28913918 TI - Clopidogrel in Critically Ill Patients. AB - Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ~30 fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ~5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors. PMID- 28913919 TI - Technical Note: On the use of cylindrical ionization chambers for electron beam reference dosimetry. AB - PURPOSE: To investigate the use of cylindrical chambers for electron beam dosimetry independent of energy by studying the variability of relative ion chamber perturbation corrections, one of the main concerns for electron beam dosimetry with cylindrical chambers. METHODS: Measurements are made with sets of cylindrical and plane-parallel reference-class chambers as a function of depth in water in 8 MeV and 18 MeV electron beams. The ratio of chamber readings for similar chambers is normalized in a high-energy electron beam and can be thought of as relative perturbation corrections. Data are plotted as a function of mean electron energy at depth for a range of depths close to the phantom surface to R80 , the depth at which the ionization falls to 80% of its maximum value. Additional, similar measurements are made in a Virtual Water(r) phantom with cylindrical chambers at the reference depth in a 4 MeV electron beam. RESULTS: The variability of relative ion chamber perturbation corrections for nominally identical cylindrical Farmer-type chambers is found to be less than 0.4%, no worse than plane-parallel chambers with similar specifications. CONCLUSIONS: This work discusses several issues related to the use of plane-parallel ion chambers and suggests that reference-class cylindrical chambers may be appropriate for reference dosimetry of all electron beams. This would simplify the reference dosimetry procedure and improve accuracy of beam calibration. PMID- 28913920 TI - Dramatic pretend play games uniquely improve emotional control in young children. AB - Pretense is a naturally occurring, apparently universal activity for typically developing children. Yet its function and effects remain unclear. One theorized possibility is that pretense activities, such as dramatic pretend play games, are a possible causal path to improve children's emotional development. Social and emotional skills, particularly emotional control, are critically important for social development, as well as academic performance and later life success. However, the study of such approaches has been criticized for potential bias and lack of rigor, precluding the ability to make strong causal claims. We conducted a randomized, component control (dismantling) trial of dramatic pretend play games with a low-SES group of 4-year-old children (N = 97) to test whether such practice yields generalized improvements in multiple social and emotional outcomes. We found specific effects of dramatic play games only on emotional self control. Results suggest that dramatic pretend play games involving physicalizing emotional states and traits, pretending to be animals and human characters, and engaging in pretend scenarios in a small group may improve children's emotional control. These findings have implications for the function of pretense and design of interventions to improve emotional control in typical and atypical populations. Further, they provide support for the unique role of dramatic pretend play games for young children, particularly those from low-income backgrounds. A video abstract of this article can be viewed at: https://youtu.be/2GVNcWKRHPk. PMID- 28913921 TI - Analgesic efficacy of local infiltration analgesia vs. femoral nerve block after anterior cruciate ligament reconstruction: a systematic review and meta-analysis. AB - Many published reports consider blockade of the femoral nerve distribution the best available analgesic treatment after anterior cruciate ligament reconstruction. However, some argue that an alternative approach of infiltrating local anaesthetic into the surgical site has similar efficacy. The objectives of this meta-analysis were to compare the analgesic and functional outcomes of both treatments following anterior ligament reconstruction. The primary outcomes were pain scores at rest (analogue scale, 0-10) in the early (0-2 postoperative hours), intermediate (3-12 hours) and late postoperative periods (13-24 hours). Secondary outcomes included range of motion, quadriceps muscle strength and complication rates (neurological problems, cardiovascular events, falls and knee infections). Eleven trials, including 628 patients, were identified. Pain scores in the early, intermediate and late postoperative periods were significantly lower in patients who received a femoral nerve block, with mean differences (95%CI) of 1.6 (0.2-2.9), p = 0.02; 1.2 (0.4-1.5), p = 0.002; and 0.7 (0.1-1.4), p = 0.03 respectively. The quality of evidence for our primary outcomes was moderate to high. Regarding functional outcomes, only one trial reported a similar range of motion between groups at 48 postoperative hours. No trial sought to record complications. In conclusion, femoral nerve block provides superior postoperative analgesia after anterior cruciate ligament reconstruction to local infiltration analgesia. The impact of improved analgesia on function remains unclear due to the lack of reporting of functional outcomes in the existing literature. PMID- 28913922 TI - A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy. AB - Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were <=20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 * 106 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%. PMID- 28913924 TI - Nurse managers and the sandwich support model. AB - AIM: To explore the interplay between the work of nurse managers and the support they receive and provide. BACKGROUND: Support is the cornerstone of management practices and is pivotal in employees feeling committed to an organisation. Support for nurse managers is integral to effective health sector management; its characteristics merit more attention. METHODS: The experiences of 15 nurse managers in rural health institutions in South Australia were explored using structured interviews, observation and document review. RESULTS: Effective decision making requires adequate support, which influences the perceptions and performance of nurse managers, creating an environment in which they feel appreciated and valued. An ideal support system is proposed, the "sandwich support model," to promote effective functioning and desirable patient outcomes via support "from above" and "from below." IMPLICATIONS FOR NURSING MANAGEMENT: The need to support nurse managers effectively is crucial to how they function. The sandwich support model can improve management practices, more effectively assisting nurse managers. Organisations should revisit and strengthen support processes for nurse managers to maximize efficiencies. CONCLUSION: This paper contributes to understanding the importance of supporting nurse managers, identifying the processes used and the type of support offered. It highlights challenges and issues affecting support practices within the health sector. PMID- 28913925 TI - A cascade of destabilizations: Combining Wolbachia and Allee effects to eradicate insect pests. AB - The management of insect pests has long been dominated by the use of chemical insecticides, with the aim of instantaneously killing enough individuals to limit their damage. To minimize unwanted consequences, environmentally friendly approaches have been proposed that utilize biological control and take advantage of intrinsic demographic processes to reduce pest populations. We address the feasibility of a novel pest management strategy based on the release of insects infected with Wolbachia, which causes cytoplasmic incompatibilities in its host population, into a population with a pre-existing Allee effect. We hypothesize that the transient decline in population size caused by a successful invasion of Wolbachia can bring the population below its Allee threshold and, consequently, trigger extinction. We develop a stochastic population model that accounts for Wolbachia-induced cytoplasmic incompatibilities in addition to an Allee effect arising from mating failures at low population densities. Using our model, we identify conditions under which cytoplasmic incompatibilities and Allee effects successfully interact to drive insect pest populations towards extinction. Based on our results, we delineate control strategies based on introductions of Wolbachia-infected insects. We extend this analysis to evaluate control strategies that implement successive introductions of two incompatible Wolbachia strains. Additionally, we consider methods that combine Wolbachia invasion with mating disruption tactics to enhance the pre-existing Allee effect. We demonstrate that Wolbachia-induced cytoplasmic incompatibility and the Allee effect act independently from one another: the Allee effect does not modify the Wolbachia invasion threshold, and cytoplasmic incompatibilities only have a marginal effect on the Allee threshold. However, the interaction of these two processes can drive even large populations to extinction. The success of this method can be amplified by the introduction of multiple Wolbachia cytotypes as well as the addition of mating disruption. Our study extends the existing literature by proposing the use of Wolbachia introductions to capitalize on pre existing Allee effects and consequently eradicate insect pests. More generally, it highlights the importance of transient dynamics, and the relevance of manipulating a cascade of destabilizatons for pest management. PMID- 28913923 TI - An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure. AB - Age-related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease; however, these do not exist for the dry form. Complement factor H polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, RPE damage, and visual decline. We have derived and characterized induced pluripotent stem cell (iPSC) lines from two subjects without AMD and low-risk genotype and two patients with advanced AMD and high-risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H, factor I, and factor H-like protein 1. The iPSC RPE cells derived from high-risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy, and deposition of "drusen"-like deposits. The low- and high-risk RPE cells respond differently to intermittent exposure to UV light, which leads to an improvement in cellular and functional phenotype only in the high-risk AMD-RPE cells. Taken together, our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing. Stem Cells 2017;35:2305-2320. PMID- 28913926 TI - Dangers on the road: A longitudinal examination of passenger-initiated violence against bus drivers. AB - This study examined the impact of workplace violence against 109 bus drivers over a 1-year span. Workplace violence is related to both psychological and work related consequences. Our findings showed that bus drivers experienced a wide range of violence at work and the psychological consequences were devastating: Half of the participants met the diagnostic criteria for acute stress disorder within the first month following the index event. Majority of them experienced at least moderate levels of post-traumatic stress disorder (PTSD) problems over the 1-year span. About 9.3% of participants showed a delayed onset of PTSD 6 months after. Furthermore, counter-supportive behaviours and reexposure to violence played important roles in the maintenance of PTSD symptoms over time. Even though PTSD symptoms per se did not relate to bus driver's confidence in coping with aggressive passengers, the immediate post-traumatic reaction-symptoms of acute stress disorder-showed a significant long-term negative effect on bus drivers' confidence in dealing with aggressive passengers 12 months after. This study provided empirical evidence of the changing nature of PTSD symptoms over time among bus drivers. PMID- 28913927 TI - The efficacy and safety of a monophasic hyaluronic acid filler in the correction of nasolabial folds: A randomized, multicenter, single blinded, split-face study. AB - BACKGROUND: The different rheological properties of hyaluronic acid (HA) filler reflect their specific manufacturing processes and resultant physicochemical characteristics. However, there are few researches about the relationship between product differences and clinical outcome when HA fillers are used for nasolabial folds (NLFs). AIMS: This study sought to compare the rheological properties, efficacy and safety of a monophasic HA filler, and a well-studied biphasic HA filler, in the treatment of NLFs. PATIENTS/METHODS: A total of 72 Korean subjects with moderate to severe NLFs were randomized to receive injections with monophasic HA or biphasic HA on the left or right side of the face. Efficacy was evaluated by the change in the Wrinkle Severity Rating Scale (WSRS) at 2, 10, 18, 26, and 52 weeks. Safety was assessed on the basis of all abnormal reactions during the clinical test period. To compare the rheological characteristics of two cross-linked HA fillers, viscoelastic analysis was performed. RESULTS: At week 26, the mean WSRS was 2.26+/-0.56 for the monophasic HA side and 2.24+/-0.54 for the biphasic HA side. Both treatments were well tolerated. The adverse reactions were mild and transient. Monophasic HA filler had lower elasticity and higher viscosity than biphasic HA filler. CONCLUSION: Despite a number of different rheological properties, monophasic HA is noninferior to biphasic HA in the treatment of moderate to severe NLFs for 52 weeks. Therefore, monophasic HA provides an alternative option for NLFs correction. PMID- 28913928 TI - A new complementary approach for oral health and diabetes management: health coaching. AB - BACKGROUND: Health coaching (HC) is based on 'partnering with clients in a thought-provoking and creative process that inspires them to maximise their personal and professional potential' to adopt healthy lifestyles through 'building awareness and empowerment'. This study's objective is to assess, for the first time to our knowledge, the effectiveness of HC compared with health education (HE) using clinical and subjective measures among type 2 diabetes (DM2) patients in Turkey and Denmark. METHODS: This stratified random prospective study selected type 2 diabetes patients in Turkey (n = 186) (TR) (2010-2012) and in Denmark (n = 116) (DK) (2012-2014). Participants were assigned to HC or HE groups. Selected outcomes were HbA1c, periodontal treatment need index (CPI), health behaviours and anthropometric measures. The study duration was 12 months (6 months initiation-maintenance, 6 months follow-up). RESULTS: At baseline, there were no statistically significant differences between the HC and HE groups. Post-intervention, a reduction of HbA1c in the HC groups was observed (TR: 0.8%; DK: 0.4%, P < 0.01) but not in the HE groups. The HC patients had a higher reduction in CPI than the HE group (P < 0.01). Principal component analysis showed that HbA1c, CPI and 'behaviour change' compose one cluster in the HCTR and HETR groups. Three clusters were formed for the HCDK; respectively HbA1c and CPI, lean mass and body fat percentage, 'behaviour change'. CONCLUSIONS: The results indicate that HC has a greater impact on DM management and health outcomes. There is a need for common health promotion strategies with behavioural interventions such as health coaching for the management of type 2 diabetes that focus on multidisciplinary approaches including oral health. PMID- 28913929 TI - High nutrition risk is associated with higher risk of dysphagia in advanced age adults newly admitted to hospital. AB - AIM: To establish the prevalence of nutrition risk and associated risk factors among adults of advanced age newly admitted to hospital. METHODS: A cross sectional study was undertaken in adults aged over 85 years admitted to one of two hospital wards in Auckland within the previous 5 days. An interviewer administered questionnaire was used to establish participant's socio-demographic and health characteristics. Markers of body composition and muscle strength were collected. Nutrition risk was assessed using the Mini Nutritional Assessment Short Form (MNA-SF), dysphagia risk using the 10-Item Eating Assessment Tool (EAT 10) and level of cognition using the Montreal Cognitive Assessment. RESULTS: A total of 88 participants with a mean age of 90.0 +/- 3.7 years completed the assessments. A third (28.4%) of the participants were categorised by the MNA-SF as malnourished and 43.2% were classified at risk of malnutrition. A third (29.5%) were at risk of dysphagia as assessed by EAT-10. Malnourished participants were more likely to be at risk of dysphagia (P = 0.015). The MNA-SF score was positively correlated with body mass index (r = 0.484, P < 0.001) and grip strength (r = 0.250, P = 0.026) and negatively correlated with risk of dysphagia (r = -0.383, P < 0.001). CONCLUSIONS: Among newly hospitalised adults of advanced age, over two thirds were malnourished or at risk of malnutrition, and a third were at risk of dysphagia. Nutrition risk was positively correlated with low BMI and grip strength and negatively correlated with dysphagia risk. Findings highlight the importance of screening for dysphagia risk, especially in those identified to be malnourished or at nutrition risk. PMID- 28913931 TI - Automatic structure prediction of oligomeric assemblies using Robetta in CASP12. AB - Many naturally occurring protein systems function primarily as symmetric assemblies. Prediction of the quaternary structure of these assemblies is an important biological problem. This article describes automated tools we have developed for predicting the structures of symmetric protein assemblies in the Robetta structure prediction server. We assess the performance of this pipeline on a set of targets from the recent CASP12/CAPRI blind quaternary structure prediction experiment. Our approach successfully predicted 5 of 7 symmetric assemblies in this challenge, and was assessed as the best participating server group, and 1 of only 2 groups (human or server) with 2 predictions judged as high quality by the assessors. We also assess the method on a broader set of 22 natively symmetric CASP12 targets, where we show that oligomeric modeling can improve the accuracy of monomeric structure determination, particularly in highly intertwined oligomers. PMID- 28913930 TI - Accuracy, repeatability, and interplatform reproducibility of T1 quantification methods used for DCE-MRI: Results from a multicenter phantom study. AB - PURPOSE: To determine the in vitro accuracy, test-retest repeatability, and interplatform reproducibility of T1 quantification protocols used for dynamic contrast-enhanced MRI at 1.5 and 3 T. METHODS: A T1 phantom with 14 samples was imaged at eight centers with a common inversion-recovery spin-echo (IR-SE) protocol and a variable flip angle (VFA) protocol using seven flip angles, as well as site-specific protocols (VFA with different flip angles, variable repetition time, proton density, and Look-Locker inversion recovery). Factors influencing the accuracy (deviation from reference NMR T1 measurements) and repeatability were assessed using general linear mixed models. Interplatform reproducibility was assessed using coefficients of variation. RESULTS: For the common IR-SE protocol, accuracy (median error across platforms = 1.4-5.5%) was influenced predominantly by T1 sample (P < 10-6 ), whereas test-retest repeatability (median error = 0.2-8.3%) was influenced by the scanner (P < 10-6 ). For the common VFA protocol, accuracy (median error = 5.7-32.2%) was influenced by field strength (P = 0.006), whereas repeatability (median error = 0.7-25.8%) was influenced by the scanner (P < 0.0001). Interplatform reproducibility with the common VFA was lower at 3 T than 1.5 T (P = 0.004), and lower than that of the common IR-SE protocol (coefficient of variation 1.5T: VFA/IR-SE = 11.13%/8.21%, P = 0.028; 3 T: VFA/IR-SE = 22.87%/5.46%, P = 0.001). Among the site-specific protocols, Look-Locker inversion recovery and VFA (2-3 flip angles) protocols showed the best accuracy and repeatability (errors < 15%). CONCLUSIONS: The VFA protocols with 2 to 3 flip angles optimized for different applications achieved acceptable balance of extensive spatial coverage, accuracy, and repeatability in T1 quantification (errors < 15%). Further optimization in terms of flip-angle choice for each tissue application, and the use of B1 correction, are needed to improve the robustness of VFA protocols for T1 mapping. Magn Reson Med 79:2564-2575, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28913932 TI - Hox D genes and the fin-to-limb transition: Insights from fish studies. AB - Genes in the 5' extremity of the HoxD cluster encode DNA-binding transcription factors essential for development of the autopod and digits, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Comparative studies focused on their expression and regulation have led to the idea that evolution of a bimodal regulation of the HoxD cluster, mainly due to the activation of cis-regulatory units in the centromeric side of the cluster, was a fundamental mechanism that potentiated the fin-to-limb transition in vertebrates. In addition, functional assays demonstrated that increased levels of 5'HoxD genes stimulate the production of additional endochondral bone, while repressing the formation of dermal skeleton distally. Other data have come to light in recent years suggesting that these genes may interfere directly with the production of dermal skeleton components in fish and with the activity of cis regulatory units involved in the formation of autopod and digits. Finally, increasing evidences suggest that the role of HoxD genes in fin evolution may relate to their ability to change the fate of distal mesenchymal cells conducting them to differentiate into endochondral bone rather than in dermal skeleton. Here, we trace the history of the research concerning the involvement of HoxD genes in the fin-to-limb transition in vertebrates. To this end, we discuss three interconnected topics that have benefited from profound advances in recent years due to comparative analyses and functional assays performed using fish species: (a) comparative HoxD genes expression; (b) comparative HoxD gene transcriptional regulation; and (c) functional characterization of 5'HoxD genes. PMID- 28913933 TI - Diagnostic accuracy of FNAC and cyto-histopathological correlation in testicular and paratesticular mass lesions. AB - OBJECTIVE: FNAC has a definitive role and has proved extremely useful in diagnosis of testicular and paratesticular mass lesions. In view of the dearth of literature of studies involving large cohorts of patients, the present study describes at length the detailed cytological evaluation of testicular and paratesticular mass lesions. METHODS: Our study consisted of 85 cases in 5-year retrospective and 1-year prospective analyses carried out in the Department of Pathology, Government Medical College, Jammu. The study depicts cytomorphological findings of testicular and paratesticular mass lesions. We evaluate the concordance rate of cytological diagnosis with the histological diagnosis as a percentage and assess the diagnostic accuracy of FNAC by calculating sensitivity and specificity. RESULTS: Out of 85 cases, inflammatory lesions comprised the largest group comprising 47 cases (55.29%) followed by 20 cases (23.5%) of cystic lesions. In addition, there were 10 cases (11.76%) of malignant tumours and three cases (3.5%) of benign tumours. Overall, acute orchitis was the most common inflammatory lesions (12.94%) followed by tubercular epididymitis (9.4%). The most common cystic lesion was benign epididymal cyst (10.5%) and the most common malignant tumours were seminoma and embryonal carcinoma. Cytohistological correlation was available for 16 (18.82%) cases only and cytological diagnosis was concordant with the histological diagnosis in all these cases. Sensitivity and specificity of FNAC was 100% in our study. CONCLUSION: FNAC is a useful diagnostic modality for testicular and paratesticular mass lesions due to its high sensitivity and specificity in discriminating between different types of lesions and high concordance rates with histopathological diagnosis. PMID- 28913935 TI - Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. AB - : Hepatocellular carcinomas (HCC) contain a subpopulation of cancer stem cells (CSCs), which exhibit stem cell-like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular-level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem-cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic-cell reprogramming. Here, we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly differentiated tumor phenotypes. Using HCC cell lines, we found that short hairpin RNA-mediated macroH2A1 knockdown induces acquisition of CSC-like features, including the growth of significantly larger and less differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxic responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes and drove hyperactivation of the nuclear factor kappa B p65 pathway. Blocking phosphorylation of nuclear factor kappa B p65 on Ser536 inhibited the emergence of CSC-like features in HCC cells knocked down for macroH2A1. CONCLUSION: The absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC. (Hepatology 2017). PMID- 28913934 TI - The incidence of sarcopenia among hospitalized older patients: results from the Glisten study. AB - BACKGROUND: New evidence is emerging on the importance of lean body mass during periods of illness and recovery. The preservation of lean body mass during such periods of intense stress impacts both patient and treatment outcomes. However, data concerning the incidence of sarcopenia among older people during hospitalization are scarce. The objective of this study was to evaluate the development of sarcopenia in a sample of hospitalized older subjects. METHODS: We used data of 394 participants from the multicentre Italian Study conducted by the Gruppo Lavoro Italiano Sarcopenia-Trattamento e Nutrizione (GLISTEN) in 12 Acute Care Wards (Internal Medicine and Geriatrics) of University Hospitals across Italy. This study was designed to determine the prevalence of sarcopenia at hospital admission and the change in muscle mass and strength during hospitalization. Sarcopenia was defined as low skeletal mass index (kg/m2 ) along with either low handgrip strength or slow walking speed [European Working Groups on Sarcopenia in Older People (EWGSOP) criteria]. Estimation of skeletal muscle mass was performed by bioelectrical impedance analysis (BIA). RESULTS: The mean age of the 394 enrolled patients (including 211 females who accounted for 53% of the sample) was 79.6 +/- 6.4 years. Among those without sarcopenia at hospital admission, 14.7% of the study sample met the EWGSOP sarcopenia diagnostic criteria at discharge. The incidence of sarcopenia during hospitalization was significantly associated with the number of days spent in bed but was not correlated with the total length of hospital stay. In particular, patients who developed sarcopenia spent an average of 5.1 days in bed compared with 3.2 days for those with no sarcopenia at discharge (P = 0.02). Patients with sarcopenia showed a significantly lower body mass index compared with non-sarcopenic peers (25.0 +/- 3.8 kg/m2 vs. 27.6 +/- 4.9 kg/m2 , respectively; P < 0.001). Similarly, the skeletal mass index at admission was significantly lower among patients who developed sarcopenia during hospital stay. CONCLUSIONS: Incident sarcopenia during hospital stay is relatively common and is associated with nutritional status and the number of days of bed rest. PMID- 28913937 TI - Healthcare professionals' perceptions of neglect of older people in Mexico: A qualitative secondary analysis. AB - AIMS AND OBJECTIVES: To describe healthcare professionals' perceptions of neglect of older people in Mexico. BACKGROUND: Mistreatment of older people, particularly neglect, has emerged as a significant public health concern worldwide. However, few studies have been conducted to examine neglect of older people in low- and middle-income countries. Most research has focused on estimating the prevalence of neglect in older populations with little emphasis on the perceptions of healthcare professionals and their role in addressing neglect of older people. DESIGN: Qualitative secondary analysis. METHODS: The parent study consisted of nine focus groups conducted with healthcare professionals at five public hospitals in Mexico. The purpose of the parent study was to perform a needs assessment to determine the feasibility of adapting the Nurses Improving Care for Healthsystem Elders programme to Mexico. A qualitative secondary analysis with directed content analysis approach was used to extract data related to neglect of older people. RESULTS: A total of 89 participants representing healthcare professionals from several disciplines were interviewed. Three themes emerged: (i) The main point is not here; (ii) We feel hopeless; and (iii) We need preparation. Participants reported distress and hopelessness related to neglect of older people. Lack of community-based resources was noted as contributing to neglect. Increased education regarding care of older people for both caregivers and healthcare professionals and greater interdisciplinary collaboration were identified as potential solutions to combat neglect. CONCLUSIONS: Community-based services and resource allocation need to be re-evaluated to improve the care of older Mexicans. Interdisciplinary models of care should be developed to address concerns related to neglect of older people. IMPLICATIONS FOR PRACTICE: Neglect negatively impacts healthcare professionals' ability to adequately care for older patients. There is a need to invest in community-based services and models of care to address these concerns. PMID- 28913936 TI - Detection of Bovine Coronavirus in Healthy and Diarrheic Dairy Calves. AB - BACKGROUND: BCoV is identified in both healthy and diarrheic calves, complicating its assessment as a primary pathogen. OBJECTIVES: To investigate the detection rates of bovine coronavirus (BCoV) in feces of healthy and diarrheic calves and to describe the usefulness of a pancoronavirus reverse transcriptase (RT) PCR (PanCoV-RT-PCR) assay to identify BCoV in samples of diarrheic calves. ANIMALS: Two hundred and eighty-six calves <21 days. Calves with liquid or semiliquid feces, temperature >39.5 degrees C, and inappetence were considered as cases, and those that had pasty or firm feces and normal physical examination were designated as controls. METHODS: Prospective case-control study. A specific BCoV RT-PCR assay was used to detect BCoV in fecal samples. Association between BCoV and health status was evaluated by exact and random effect logistic regression. Fecal (n = 28) and nasal (n = 8) samples from diarrheic calves were tested for the presence of BCoV by both the PanCoV-RT-PCR and a specific BCoV-RT-PCR assays. A Kappa coefficient test was used to assess the level of agreement of both assays. RESULTS: BCoV was detected in 55% (157/286) of calves; 46% (66/143), and 64% (91/143) of healthy and diarrheic calves, respectively. Diarrheic calves had higher odds of BCoV presence than healthy calves (OR: 2.16, 95% CI: 1.26 to 3.83, P = 0.004). A good agreement between PanCoV-RT-PCR and BCoV-RT-PCR to detect BCoV was identified (kappa = 0.68, 95% CI: 0.392 to 0.967; P < 0.001). CONCLUSIONS AND CLINICAL IMPORTANCE: BCoV was more likely to be detected in diarrheic than healthy calves. The PanCoV-RT-PCR assay can be a useful tool to detect CoV samples from diarrheic calves. PMID- 28913938 TI - Application of CRAFT (complete reduction to amplitude frequency table) in nonuniformly sampled (NUS) 2D NMR data processing. AB - The recently published CRAFT (complete reduction to amplitude frequency table) technique converts the raw FID data (i.e., time domain data) into a table of frequencies, amplitudes, decay rate constants, and phases. It offers an alternate approach to decimate time-domain data, with minimal preprocessing step. It has been shown that application of CRAFT technique to process the t1 dimension of the 2D data significantly improved the detectable resolution by its ability to analyze without the use of ubiquitous apodization of extensively zero-filled data. It was noted earlier that CRAFT did not resolve sinusoids that were not already resolvable in time-domain (i.e., t1 max dependent resolution). We present a combined NUS-IST-CRAFT approach wherein the NUS acquisition technique (sparse sampling technique) increases the intrinsic resolution in time-domain (by increasing t1 max), IST fills the gap in the sparse sampling, and CRAFT processing extracts the information without loss due to any severe apodization. NUS and CRAFT are thus complementary techniques to improve intrinsic and usable resolution. We show that significant improvement can be achieved with this combination over conventional NUS-IST processing. With reasonable sensitivity, the models can be extended to significantly higher t1 max to generate an indirect DEPT spectrum that rivals the direct observe counterpart. PMID- 28913939 TI - Elderly living donor kidney transplantation allows worthwhile outcomes: The Japan Academic Consortium of Kidney Transplantation study. AB - OBJECTIVE: To compare transplant outcomes among elderly (aged >=60 years) and non elderly recipients, and to evaluate the acceptability of elderly living donor kidney transplantation in practice after consideration of living donor type. METHODS: We included 830 adult patients with living donor kidney transplantation between 2000 and 2011 in this retrospective cohort study. We compared death censored graft survival, patient survival, biopsy-proven rejection, complications, and renal function in elderly (n = 119) and non-elderly recipients (n = 278). RESULTS: There was no significant difference in 10-year death-censored graft survival (P = 0.980). Corresponding patient survival rates in the elderly and non-elderly groups were 84.1% and 98.1%, respectively (hazard ratio 6.15, 95% confidence interval 2.12-17.82, P < 0.001). Elderly patients had more complications and chronic T-cell-mediated rejection. Factors associated with death in elderly recipients with functioning grafts were residual advanced recipient age (hazard ratio 1.39), decreased hemoglobin (hazard ratio 4.10), hepatitis B virus (hazard ratio 7.89), hepatitis C virus (hazard ratio 13.12) and elevated alanine aminotransferase (hazard ratio 1.13). CONCLUSIONS: Elderly living donor kidney transplantation seems to provide adequate acceptable outcomes. However, physicians should be cautious when evaluating elderly patients with hepatitis, and further studies are required to improve long-term outcomes. PMID- 28913940 TI - Caesarean Birth is Associated with Both Maternal and Paternal Origin in Immigrants in Sweden: a Population-Based Study. AB - BACKGROUND: To investigate the association between maternal country of birth and father's origin and unplanned and planned caesarean birth in Sweden. METHODS: Population-based register study including all singleton births in Sweden between 1999 and 2012 (n = 1 311 885). Multinomial regression was conducted to estimate odds ratios (OR) for unplanned and planned caesarean with 95% confidence intervals for migrant compared with Swedish-born women. Analyses were stratified by parity. RESULTS: Women from Ethiopia, India, South Korea, Chile, Thailand, Iran, and Finland had statistically significantly higher odds of experiencing unplanned (primiparous OR 1.10-2.19; multiparous OR 1.13-2.02) and planned caesarean (primiparous OR 1.18-2.25; multiparous OR 1.13-2.46). Only women from Syria, the former Yugoslavia and Germany had consistently lower risk than Swedish born mothers (unplanned: primiparous OR 0.76-0.86; multiparous OR 0.74-0.86. Planned; primiparous OR 0.75-0.82; multiparous OR 0.60-0.94). Women from Iraq and Turkey had higher odds of an unplanned caesarean but lower odds of a planned one (among multiparous). In most cases, these results remained after adjustment for available social characteristics, maternal health factors, and pregnancy complications. Both parents being foreign-born increased the odds of unplanned and planned caesarean in primiparous and multiparous women. CONCLUSIONS: Unplanned and planned caesarean birth varied by women's country of birth, with both higher and lower rates compared with Swedish-born women, and the father's origin was also of importance. These variations were not explained by a wide range of social, health, or pregnancy factors. PMID- 28913941 TI - Effects of hybrid and bacterial inoculation on fermentation quality and fatty acid profile of barley silage. AB - This study estimated the effects of hybrid and bacterial inoculant on fermentation quality and fatty acid profile of barley silages. Yuyeon (Silkless) and Youngyang (Silking) barley hybrids were harvested at 24.9 and 27.1% dry matter, respectively, and chopped to 10 cm lengths. Each hybrid was treated with or without an inoculant (2 * 104 colony-forming units/g of Lactobacillus plantarum). A total of 48 silos were prepared in an experiment with a 2 * 2 (hybrid * inoculant) treatment arrangement with four replications and three ensiling durations (2, 7 and 100 days). After 100 days of ensiling, Yuyeon silage had higher (P < 0.05) in vitro dry matter digestibility and C18:3n-3 than Youngyang silage. Youngyang silage had higher (P < 0.05) acetic acid and C18:2n-6 than Yuyeon silage. Inoculation reduced the C18:3n-3 concentration of both hybrids and increased (P < 0.05) the C18:2n-6 of Youngyang. However, fermentation quality was not improved by the inoculant. These results indicate that Yuyeon hybrid might have better potential benefits on animal performances due to its smooth awn and silkless nature, and higher in vitro dry matter digestibility. Its higher C18:3n-3 would be better for improving fatty acid profile of meat or milk than Youngyang hybrid. PMID- 28913942 TI - The Journal of Rural Health Reviewers, July 2016 - June 2017. PMID- 28913943 TI - Bimetallic Co-Mn Perovskite Fluorides as Highly-Stable Electrode Materials for Supercapacitors. AB - Bimetallic Co-Mn perovskite fluorides (KCox Mn1-x F3 , denoted as K-Co-Mn-F) with various Co/Mn ratios (1:0, 12:1, 6:1, 3:1, 1:1, 1:3, 0:1) were prepared through a one-pot solvothermal strategy and further used as electrode materials for supercapacitors. The optimal K-Co-Mn-F candidate (Co/Mn=6:1) showed a size range of 0.1-1 MUm and uniform elemental distribution; exhibiting small changes in XRD peaks and XPS binding energy in comparison to the bare K-Co-F and K-Mn-F, due to the structural/electronic effects. Owing to the stronger synergistic effect of Co/Mn redox species, the K-Co-Mn-F (Co/Mn=6:1) electrode exhibited superior specific capacity and rate behavior (113-100 C g-1 at 1-16 Ag-1 ) together with excellent cycling stability (118 % for 5000 cycles at 8 Ag-1 ), and the activated carbon (AC)//K-Co-Mn-F (Co/Mn=6:1) asymmetric capacitor showed superior energy and power densities (8.0-2.4 Wh kg-1 at 0.14-8.7 kW kg-1 ) along with high cycling stability (90 % for 10 000 cycles at 5 Ag-1 ). PMID- 28913944 TI - The more you test, the more you find: The smallest P-values become increasingly enriched with real findings as more tests are conducted. AB - The increasing accessibility of data to researchers makes it possible to conduct massive amounts of statistical testing. Rather than follow specific scientific hypotheses with statistical analysis, researchers can now test many possible relationships and let statistics generate hypotheses for them. The field of genetic epidemiology is an illustrative case, where testing of candidate genetic variants for association with an outcome has been replaced by agnostic screening of the entire genome. Poor replication rates of candidate gene studies have improved dramatically with the increase in genomic coverage, due to factors such as adoption of better statistical practices and availability of larger sample sizes. Here, we suggest that another important factor behind the improved replicability of genome-wide scans is an increase in the amount of statistical testing itself. We show that an increase in the number of tested hypotheses increases the proportion of true associations among the variants with the smallest P-values. We develop statistical theory to quantify how the expected proportion of genuine signals (EPGS) among top hits depends on the number of tests. This enrichment of top hits by real findings holds regardless of whether genome-wide statistical significance has been reached in a study. Moreover, if we consider only those "failed" studies that produce no statistically significant results, the same enrichment phenomenon takes place: the proportion of true associations among top hits grows with the number of tests. The enrichment occurs even if the true signals are encountered at the logarithmically decreasing rate with the additional testing. PMID- 28913946 TI - Facial emotion recognition in schizophrenia: An exploratory study on the role of comorbid alcohol and substance use disorders and COMT Val158Met. AB - OBJECTIVES: To explore whether facial emotion recognition (FER), impaired in both schizophrenia and alcohol and substance use disorders (AUDs/SUDs), is additionally compromised among comorbid subjects, also considering the role of catechol-O-methyltransferase (COMT) Val158Met. METHODS: We conducted a cross sectional study, randomly recruiting 67 subjects with a DSM-IV-TR diagnosis of schizophrenia, and rigorously assessing AUDs/SUDs and COMT Val158Met polymorphism. FER was assessed using the Ekman 60 Faces Test- EK-60F. RESULTS: As a whole, the sample scored significantly lower than normative data on EK-60F. However, subjects with comorbid AUDs/SUDs did not perform worse on EK-60F than those without, who had a better performance on EK-60F if they carried the COMT Val/Met variant. CONCLUSIONS: This study is the first to date examining the impact of AUDs/SUDs and COMT variants on FER in an epidemiologically representative sample of subjects with schizophrenia. Our findings do not suggest an additional impairment from comorbid AUDs/SUDs on FER among subjects with schizophrenia, whilst COMT Val158Met, though based on a limited sample, might have a role just among those without AUDs/SUDs. Based on our results, additional research is needed also exploring differential roles of various substances. PMID- 28913947 TI - Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study. AB - Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell-to-cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN-17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN-17 and clinical outcome after surgical and nonsurgical treatment. CIN-17 was detected in 45.4% (158/348) and extreme CIN-17 in 28.4% (99/348). Extreme CIN-17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN-17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263-0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN 17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively. PMID- 28913949 TI - Relationship of Number of Missing Teeth to Hip Fracture in Elderly Patients: A Cohort Pilot Study. AB - PURPOSE: To determine the relationship between the number of missing natural teeth or remaining natural teeth and osteoporotic hip fracture in elderly patients and to determine the relationship between the number of missing teeth or remaining teeth and osteoporotic fracture risk assessment (FRAX) probability. MATERIALS AND METHODS: Number of missing teeth was determined by clinical oral exam on a total of 100 subjects, 50 with hip fractures and 50 without. Ten-year fracture risk and hip fracture risk probabilities were calculated using the FRAX tool. Statistical analyses were performed to determine strength of associations between number of missing natural teeth and likelihood of experiencing a fracture. Degree of correlation between number of missing natural teeth and FRAX probabilities were calculated. RESULTS: There appears to be an association between the number of missing natural teeth and hip fractures. For every 5-tooth increase in the number of missing teeth, the likelihood of being a subject in the hip fracture group increased by 26%. Number of missing natural teeth was positively correlated with FRAX overall fracture and hip fracture probability. CONCLUSIONS: Number of missing natural teeth may be a valuable tool to assist members of medical and dental teams in identifying patients with higher FRAX scores and higher likelihood of experiencing a hip fracture. Additional research is necessary to validate these findings. PMID- 28913948 TI - Synthesis of Size-Tunable Hollow Polypyrrole Nanostructures and Their Assembly into Folate-Targeting and pH-Responsive Anticancer Drug-Delivery Agents. AB - Chemotherapeutic drugs currently used in clinical settings have high toxicity, low specificity, and short half-lives. Herein, polypyrrole-based anticancer drug nanocapsules were prepared by tailoring the size of the nanoparticles with a template method, controlling drug release by means of an aromatic imine, increasing nanoparticle stability through PEGylation, and improving tumor-cell selectivity by folate mediation. The nanoparticles were characterized by TEM and dynamic light scattering. alpha-Folate receptor expression levelsof tumor cells and normal cells were investigated by western blot and quantitative polymerase chain reaction analyses. Flow cytometry and fluorescence imaging were used to verify the cell uptake of the different-sized nanoparticles. From the different sized polypyrrole nanoparticles, the optimally functionalized nanoparticles of 180 nm hydrodynamic diameter were chosen and further usedfor in vitroandin vivotests. The nanoparticles showed excellent biocompatibility and the drug loaded nanoparticles exhibited effective inhibition of tumor cell growth in vitro. Moreover, the drug-loaded nanoparticles showed substantially enhanced accumulation in tumor regions and effectively inhibitedin vivotumor growth. Furthermore, the nanoparticles showed reduced doxorubicin-induced toxicity andno significant side effects in normal organs of tumor-bearing mice, as measured by body-weight shifts and evaluationof drug distribution. Overall, the functionalized nanoparticles are promising nanocarriers for tumor-targeting drug delivery. PMID- 28913950 TI - Do transgender children (gender) stereotype less than their peers and siblings? AB - In the present work, we ask whether socially transitioned, transgender children differ from other children in their endorsement of gender stereotypes and response to others' gender nonconformity. We compare transgender children (N = 56) to a group of siblings of transgender children (N = 37), and a group of unrelated control participants (N = 56) during middle childhood (ages 6-8 years old). Our results indicate that transgender children and the siblings of transgender children endorse gender stereotypes less than the control group. Further, transgender children see violations of gender stereotypes as more acceptable, and they are more willing to indicate a desire to befriend and attend school with someone who violates gender stereotypes than the control participants. These results held after statistically controlling for demographic differences between families with and without transgender children. We discuss several possible reasons that can explain these differences. PMID- 28913951 TI - Rapid response team patients triaged to remain on ward despite deranged vital signs: missed opportunities? AB - BACKGROUND: Rapid response teams (RRTs) triage most patients to stay on ward, even though some of them have deranged vital signs according to RRTs themselves. We investigated the prevalence and outcome of this RRT patient cohort. METHODS: A prospective observational study was conducted in a Finnish tertiary referral centre, Tampere University Hospital. Data on RRT activations were collected between 1 May 2012 and 30 April 2015. Vital signs of patients triaged to stay on ward without treatment limitations were classified according to objective RRT trigger criteria observed during the reviews. RESULTS: During the study period, 860 patients had their first RRT review and were triaged to stay on ward. Of these, 564 (66%) had deranged vital signs, while 296 (34%) did not. RRT patients with deranged vital signs were of comparable age and comorbidity index as stable patients. Even though the patients with deranged vital signs had received RRT interventions, such as fluids and medications, more often than the stable patients, they required new RRT reviews more often and had higher in-hospital and 30-day mortality. Moreover, the former group had substantially higher 1-year mortality than the latter (37% vs. 29%, P = 0.014). In a multivariate regression analysis, deranged vital signs during RRT review was found to be independently associated with 30-day mortality (OR 1.74; 95% CI 1.12-2.70). CONCLUSION: Patients triaged to stay on ward despite deranged vital signs are high-risk patients who could benefit from routine follow-up by RRT nurses before they deteriorate beyond salvation. PMID- 28913952 TI - New-age ideas about age-old sex: separating meiosis from mating could solve a century-old conundrum. AB - Ever since Darwin first addressed it, sexual reproduction reigns as the 'queen' of evolutionary questions. Multiple theories tried to explain how this apparently costly and cumbersome method has become the universal mode of eukaryote reproduction. Most theories stress the adaptive advantages of sex by generating variation, they fail however to explain the ubiquitous persistence of sexual reproduction also where adaptation is not an issue. I argue that the obstacle for comprehending the role of sex stems from the conceptual entanglement of two distinct processes - gamete production by meiosis and gamete fusion by mating (mixis). Meiosis is an ancient, highly rigid and evolutionary conserved process identical and ubiquitous in all eukaryotes. Mating, by contrast, shows tremendous evolutionary variability even in closely related clades and exhibits wonderful ecological adaptability. To appreciate the respective roles of these two processes, which are normally linked and alternating, we require cases where one takes place without the other. Such cases are rather common. The heteromorphic sex chromosomes Y and W, that do not undergo meiotic recombination are an evolutionary test case for demonstrating the role of meiosis. Substantial recent genomic evidence highlights the accelerated rates of change and attrition these chromosomes undergo in comparison to those of recombining autosomes. I thus propose that the most basic role of meiosis is conserving integrity of the genome. A reciprocal case of meiosis without bi-parental mating, is presented by self-fertilization, which is fairly common in flowering plants, as well as most types of apomixis. I argue that deconstructing sex into these two distinct processes - meiosis and mating - will greatly facilitate their analysis and promote our understanding of sexual reproduction. PMID- 28913953 TI - Marine depth use of sea trout Salmo trutta in fjord areas of central Norway. AB - The vertical behaviour of 44 veteran sea trout Salmo trutta (275-580 mm) in different marine fjord habitats (estuary, pelagic, near shore with and without steep cliffs) was documented during May-February by acoustic telemetry. The swimming depth of S. trutta was influenced by habitat, time of day (day v. night), season, seawater temperature and the body length at the time of tagging. Mean swimming depth during May-September was 1.7 m (individual means ranged from 0.4 to 6.4 m). Hence, S. trutta were generally surface oriented, but performed dives down to 24 m. Mean swimming depth in May-September was deeper in the near shore habitats with or without steep cliffs (2.0 m and 2.5 m, respectively) than in the pelagic areas (1.2 m). May-September mean swimming depth in all habitats was slightly deeper during day (1.9 m) than at night (1.2 m), confirming that S. trutta conducted small-scale diel vertical movements. During summer, S. trutta residing in near-shore habitat progressively moved deeper over the period May (mean 1.1 m) to August (mean 4.0 m) and then reoccupied shallower areas (mean 2.3 m) during September. In winter (November and February), individuals residing in the innermost part of the fjords were found at similar average depths as they occupied during the summer (mean 1.3 m). The swimming depths of S. trutta coincide with the previously known surface orientation of salmon lice Lepeophtheirus salmonis. Combined with previous studies on horizontal use of S. trutta, this study illustrates how S. trutta utilize marine water bodies commonly influenced by anthropogenic factors such as aquaculture, harbours and marine constructions, marine renewable energy production or other human activity. This suggests that the marine behaviour of S. trutta and its susceptibility to coastal anthropogenic factors should be considered in marine planning processes. PMID- 28913954 TI - The relationship between pain, fatigue, sleep disorders and quality of life in adult patients with acute leukaemia: During the first year after diagnosis. AB - The aim of this study was to investigate the relationship between pain, fatigue, sleep disorders and quality of life and assess the most powerful predictor of quality of life in patients with acute leukaemia. In this cross-sectional multicentre study, 406 patients were recruited. Data were collected using the Iranian Short-Form 36-item Health Survey, the Pittsburgh Sleep Quality Index, and the Numeric Rating Scale for Pain and Fatigue Intensity. It was found that pain and fatigue had direct relationship with sleep disorders. Statistically significant relationships were reported between pain, fatigue, sleep disorders and QoL. Also, a statistically significant relationship was found between pain and QoL (p < .001). Pain, fatigue and sleep disorders in total had the predictive power for quality of life (R2 = 36%). The most powerful predictor of quality of life was pain. It is suggested that healthcare professionals note the importance of patients' symptoms in clinical investigations and take appropriate measures for their management. The assessment of pain as the most powerful predictor of quality of life can be considered a basis for the improvement of quality of life, fatigue and sleep quality in patients with acute leukaemia. PMID- 28913955 TI - Controlled JAGGED1 delivery induces human embryonic palate mesenchymal cells to form osteoblasts. AB - Osteoblast commitment and differentiation are controlled by multiple growth factors including members of the Notch signaling pathway. JAGGED1 is a cell surface ligand of the Notch pathway that is necessary for murine bone formation. The delivery of JAGGED1 to induce bone formation is complicated by its need to be presented in a bound form to allow for proper Notch receptor signaling. In this study, we investigate whether the sustained release of JAGGED1 stimulates human mesenchymal cells to commit to osteoblast cell fate using polyethylene glycol malemeide (PEG-MAL) hydrogel delivery system. Our data demonstrated that PEG-MAL hydrogel constructs are stable in culture for at least three weeks and maintain human mesenchymal cell viability with little cytotoxicity in vitro. JAGGED1 loaded on PEG-MAL hydrogel (JAGGED1-PEG-MAL) showed continuous release from the gel for up to three weeks, with induction of Notch signaling using a CHO cell line with a Notch1 reporter construct, and qPCR gene expression analysis in vitro. Importantly, JAGGED1-PEG-MAL hydrogel induced mesenchymal cells towards osteogenic differentiation based on increased Alkaline phosphatase activity and osteoblast genes expression including RUNX2, ALP, COL1, and BSP. These results thus indicated that JAGGED1 delivery in vitro using PEG-MAL hydrogel induced osteoblast commitment, suggesting that this may be a viable in vivo approach to bone regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 552-560, 2018. PMID- 28913956 TI - Regioselective Intermolecular Allylic C-H Amination of Disubstituted Olefins via Rhodium/pi-Allyl Intermediates. AB - A method for catalytic intermolecular allylic C-H amination of trans disubstituted olefins is reported. The reaction is efficient for a range of common nitrogen nucleophiles bearing one electron-withdrawing group, and proceeds under mild reaction conditions. Good levels of regioselectivity are observed for a wide range of electronically diverse trans-beta-alkyl styrene substrates. PMID- 28913957 TI - Autologous peripheral blood stem cell transplantation and the role of lenalidomide in patients affected by poems syndrome. AB - POEMS syndrome is a rare paraneoplastic condition, with a poorly understood pathogenesis. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been reported to be an effective therapeutic option for patients with good performance status. Here, we review the role of ASCT for POEMS syndrome and discuss indications together with advantages and disadvantages, and related issues such lenalidomide given before or after ASCT, VEGF levels as a marker of disease, and different regimens for stem cell mobilization. PMID- 28913958 TI - Preoperative nutritional management of bariatric patients in Australia: The current practice of dietitians. AB - AIM: The aim of this observational study was to investigate the reported practices of Australian dietitians managing bariatric surgery patients in the preoperative stage. METHODS: An online survey of dietitians providing nutritional care to bariatric patients was developed for the purpose of this investigation. The survey questions were guided by the Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic and Nonsurgical Support of the Bariatric Surgery Patient guidelines and current literature. RESULTS: Ninety-nine dietitians completed the survey. Most participants recommended one to two different medical nutrition therapy strategies for preoperative weight loss (n = 69, 74%), with a very-low-energy diet exclusively from liquid meal replacements being the most frequently prescribed (n = 62, 69%). A significantly higher proportion of dietitians working privately reported the involvement of a bariatric surgeon in the multidisciplinary team (P = 0.002). More private practitioners also reported providing education on the nutritional consequences of the different types of bariatric procedures (P = 0.005) and postoperative vitamin and mineral supplementation (P = 0.013), as well as the use of the guidelines to guide their practice (P = 0.014), compared to dietitians who worked in the public sector. A higher proportion of dietitians working in metropolitan areas reported that screening occurred more frequently for vitamin D (P = 0.008), fasting blood lipids (P = 0.03) and glycated haemoglobin (P = 0.003) compared to those in regional/rural/remote areas. CONCLUSIONS: Reported preoperative screening practices were not consistent with the recommendations from the literature and current American guidelines. Further investigation into the difference in the nutritional management strategies and work environments is warranted. PMID- 28913959 TI - Quantification through TLC-densitometric analysis, repellency and anticholinesterase activity of the homemade extract of Indian cloves. AB - The rise of the mosquitoes-transmitted diseases, like dengue, zika and chikungunya in Brazil in the last years has increased concerns on protection against mosquitoes bites. However, the prohibitive prices of the commercially available repellents for the majority of the Brazilian population has provoked a search for cheaper solutions, like the use of the homemade ethanolic extract of Indian clove (Syzygium aromaticum L.) as repellent, which has been reported as quite efficient by the local press. In order to verify this, we performed here the quantification of the main components of this extract through high performance thin-layer chromatography (HPTLC)-densitometry and evaluated its efficiency as a repellent and its acetylcholinesterase (AChE) inhibition capacity. Our results have proved HPTLC-densitometry as an efficient and appropriate method for this quantification and confirmed the repellency activity, as well as its capacity of AChE inhibition. PMID- 28913960 TI - Psychosocial barriers associated with organ donation in Mexico. AB - INTRODUCTION: There is a severe shortage of organs for transplantation worldwide, and Mexico has one of the lowest organ donation rates. In this study, we explored the psychosocial barriers that prevent posthumous organ donation by Mexicans. METHOD: We asked 218 adults who were not willing to be donors to complete the sentence "I don't want to donate my organs after death because organ donation is..." The data were analyzed using the Natural Semantic Networks Technique. RESULTS: The most important answers given by the participants were related to mistrust. Older participants and those with limited education gave more answers that reflect misconceptions about organ donation. Many participants acknowledged its benefits, even though they did not want to be donors, especially the youngest and those with a higher education. CONCLUSIONS: Mistrust and poor education are problems that urgently need to be addressed in order to increase acceptance of organ donation and transplantation. PMID- 28913961 TI - Generalized Pustular Psoriasis With IL-36 Receptor Antagonist Mutation Successfully Treated With Granulocyte and Monocyte Adsorption Apheresis Accompanied by Reduced Serum IL-6 Level. PMID- 28913962 TI - Refining estimates of prescription durations by using observed covariates in pharmacoepidemiologic databases: Necessary refinements to stimulate alternative approaches. PMID- 28913964 TI - Post-marketing surveillance in Japan: Potential best way forward. PMID- 28913965 TI - Guidance to reinforce the credibility of health care database studies and ensure their appropriate impact. PMID- 28913963 TI - Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0. AB - PURPOSE: Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. METHODS: We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. CONCLUSION: Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases. PMID- 28913967 TI - The variation in quality and content of patient-focused health information on the Internet for otitis media. AB - BACKGROUND: When symptoms of otitis media appear, parents and patients often access the Internet for health information. We study the content and quality of health information in parent-patient-focused websites for otitis media. METHODS: We searched the 3 search engines (Google, Yahoo, and Bing) using "otitis media" and "middle ear infection" then reviewed the top 30 hits for each search. We included sites that were focused on providing patient-patient information about otitis media. A variety of instruments were used to assess website content and quality. RESULTS: In 35 included websites, there was considerable variation in content, with the average site having 11 out of 15 informational items potentially useful to parents and patients on otitis media (range 4-15). Across included websites, the mean DISCERN score was 47 out of 80 (low to medium quality), 16 (46%) were HONcode certified, and 8 (23%) fulfilled all the JAMA benchmark criteria. The average website was written at a 9th/10th-grade reading level. CONCLUSION: The content and quality of health information for otitis media in parent-and-patient-focused websites is highly variable. Although easy-to-read, high-quality websites with complete content are available, the average website sites is difficult to read without a high school education and is difficult to use. Consideration should be given to adopting a standard approach for presenting disease-specific information to parents and patients. PMID- 28913966 TI - Good practices for real-world data studies of treatment and/or comparative effectiveness: Recommendations from the joint ISPOR-ISPE Special Task Force on real-world evidence in health care decision making. AB - PURPOSE: Real-world evidence (RWE) includes data from retrospective or prospective observational studies and observational registries and provides insights beyond those addressed by randomized controlled trials. RWE studies aim to improve health care decision making. METHODS: The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) created a task force to make recommendations regarding good procedural practices that would enhance decision makers' confidence in evidence derived from RWD studies. Peer review by ISPOR/ISPE members and task force participants provided a consensus-building iterative process for the topics and framing of recommendations. RESULTS: The ISPOR/ISPE Task Force recommendations cover seven topics such as study registration, replicability, and stakeholder involvement in RWE studies. These recommendations, in concert with earlier recommendations about study methodology, provide a trustworthy foundation for the expanded use of RWE in health care decision making. CONCLUSION: The focus of these recommendations is good procedural practices for studies that test a specific hypothesis in a specific population. We recognize that some of the recommendations in this report may not be widely adopted without appropriate incentives from decision makers, journal editors, and other key stakeholders. PMID- 28913969 TI - Spray-inlet microwave plasma torch ionization tandem mass spectrometry for the direct detection of drug samples in liquid solutions. AB - RATIONALE: Drug abuse or dependence results in a series of social problems, including crime and traffic accidents. Spray-inlet microwave plasma torch tandem mass spectrometry (MPT-MS/MS) was developed and used for the direct detection of such drugs in liquid solutions. METHODS: Drug sample solutions were directly sprayed into the flame of an MPT by a sampling pump and the ions produced by Penning ionization and ion-molecule reactions were guided into a quadrupole time of-flight (QTOF) tandem mass spectrometer for mass analysis. The MPT was operated at 40 W and 2.45 GHz in a 700 mL/min argon flow both for the inner and middle plasma. RESULTS: Intact quasi-molecular and molecular ions of various drugs were successfully characterized by spray-inlet MPT-MS/MS. The analysis of one sample was finished within 30 s. Furthermore, the method exhibited excellent efficiency, precision and sensitivity, and the limits of detection and limits of quantification of the samples in methanol were in the range of 5.25-60.0 and 17.5 200 ng g-1 , respectively. Excellent linearities with coefficients of determination (R2 ) of 0.9627-0.9980 were verified in the range 0.05-50 MUg g-1 . Four different beverages purchased locally were also analyzed with spray-inlet MPT-MS/MS, and caffeine was directly determined in two of the beverages. By adding six standard drug samples to sport drinks (each drug was 1 MUg g-1 ) and Chinese spirit (each drug was 0.1 MUg g-1 ), all the drugs except for caffeine were detected successfully. CONCLUSIONS: This study indicates that spay-inlet MPT MS/MS is an effective method for direct and rapid identification of drug solutions, and it has substantial potential for fast and sensitive drug residue detection. PMID- 28913970 TI - Human neutrophils show decreased survival upon long-term exposure to clozapine. AB - OBJECTIVE: Clozapine is an atypical antipsychotic prescribed for treatment resistant schizophrenic patients, but treatment with clozapine is strictly limited because it can induce lethal-hematologic side effects. We investigated the effects of short- and long-term exposure of human neutrophils derived from healthy subjects to clozapine and compared them with the effects of reactive metabolite of clozapine, olanzapine, and doxorubicin. METHODS: Neutrophils were exposed to clozapine and olanzapine (1, 10, 50, or 100 MUM), reactive metabolite of clozapine (50 or 100 MUM), or doxorubicin (0.2 MUM) and cultured for a short (2 hr) or long (24 or 48 hr) duration, and then the survival rate of neutrophils was calculated. RESULTS: Decreased human neutrophil survival was observed in short-term exposure to clozapine (100 MUM) and long-term exposure to clozapine even at a lower concentration (50 MUM). A similar phenomenon was observed in reactive metabolite of clozapine and long-term exposure to doxorubicin (0.2 MUM), but not to olanzapine (1-100 MUM). CONCLUSIONS: The effect of long-term exposure to clozapine on neutrophil survival is plausibly associated with delayed onset of agranulocytosis after initial exposure. Our results suggest that human neutrophils are vulnerable to clozapine and its reactive metabolite in a concentration- and time-dependent manner. PMID- 28913972 TI - Significance of histone methyltransferase SETDB1 expression in colon adenocarcinoma. AB - This study investigated the clinical implications of SETDB1 (also known as KMT1E) in human colon adenocarcinoma. Expression levels of SETDB1 proteins were analyzed by immunohistochemistry staining, and tissue microarrays were used to examine expression profiles in human patients. Our results revealed that SETDB1 protein expression was significantly higher in tumor tissue than in normal tissue for the breast, colon, liver, and lung (p < 0.05). Moreover, an analysis with SurvExpress software suggested that elevated expression of SETDB1 mRNA was significantly associated with the overall survival of colon adenocarcinoma patients (p < 0.05); and additional analysis involving 90 paired samples of colon adenocarcinoma tissue and normal tissue revealed that SETDB1 protein expression was 82% higher in cancerous cells (p < 0.001). High SETDB1 expression was also found to be significantly correlated with histological grade (p = 0.005), TNM stage (p = 0.003), T-class/primary tumor (p = 0.001), and N-class/regional lymph nodes (p = 0.017); and Kaplan-Meier survival curves indicated that SETDB1 protein expression was significantly associated with poor survival. Finally, univariate analysis demonstrated that SETDB1 protein expression was related to TNM stage (p = 0.004) and SETDB1 score (p = 0.001), whereas multivariate analysis showed that the influence of SETDB1 on overall colon adenocarcinoma survival was independent from other risk factors. Taken together, our results suggest that the SETDB1 protein could serve as a clinical prognostic indicator for colon adenocarcinoma. PMID- 28913973 TI - Bone Marrow Stem Cells Do Not Contribute to Endometrial Cell Lineages in Chimeric Mouse Models. AB - Studies from five independent laboratories conclude that bone marrow stem cells transdifferentiate into endometrial stroma, epithelium, and endothelium. We investigated the nature of bone marrow-derived cells in the mouse endometrium by reconstituting irradiated wild type recipients with bone marrow containing transgenic mTert-green fluorescent protein (GFP) or chicken beta-actin (Ch beta actin)-GFP reporters. mTert-GFP is a telomerase marker identifying hematopoietic stem cells and subpopulations of epithelial, endothelial, and immune cells in the endometrium. Ch beta-actin-GFP is a ubiquitous reporter previously used to identify bone marrow-derived cells in the endometrium. Confocal fluorescence microscopy for GFP and markers of endometrial and immune cells were used to characterize bone marrow-derived cells in the endometrium of transplant recipients. No evidence of GFP+ bone marrow-derived stroma, epithelium, or endothelium was observed in the endometrium of mTert-GFP or Ch beta-actin-GFP recipients. All GFP+ cells detected in the endometrium were immune cells expressing the pan leukocyte marker CD45, including CD3+ T cells and F4/80+ macrophages. Further examination of the Ch beta-actin-GFP transplant model revealed that bone marrow-derived F4/80+ macrophages immunostained weakly for CD45. These macrophages were abundant in the stroma, infiltrated the epithelial and vascular compartments, and could easily be mistaken for bone marrow-derived endometrial cells. We conclude that it is unlikely that bone marrow cells are able to transdifferentiate into endometrial stroma, epithelium, and endothelium. This result has important therapeutic implications, as the expectation that bone marrow stem cells contribute directly to endometrial regeneration is shaping strategies designed to regenerate endometrium in Asherman's syndrome and to control aberrant endometrial growth in endometriosis. Stem Cells 2018;36:91-102. PMID- 28913976 TI - High-performance liquid chromatography/high-resolution mass spectrometry for the characterization of transformation products of ionic liquids. AB - RATIONALE: Ionic liquids (ILs) are a subject of active research in the field of alternative solvents. We studied the behaviour of a piperidine IL, 1-butyl-1 methylpiperidinium tetrafluoroborate (BMPA), through the elucidation of its transformation products (TPs) in water. METHODS: The transformation pathways of BMPA were investigated using high-performance liquid chromatography (HPLC) combined with a hybrid LTQ-Orbitrap instrument on the basis of mass defect filtering. TPs of BMPA were identified by fragmentation patterns and accurate mass measurements. RESULTS: The separation and identification of 32 TPs was achieved. BMPA can be oxidized at different positions in the alkyl chains. The ultimate products corresponds to N-methyl-piperidinium and some byproducts involving ring-opening. Tests of acute toxicity, evaluated with Vibrio Fischeri bacteria, show that BMPA transformation proceeds through the formation of slightly harmful compounds. CONCLUSIONS: Results showed that the main transformation pathways of BMPA were alkyl chain hydroxylation/shortening and de alkylation, and that HPLC/LTQ-Orbitrap can serve as an important analytical platform to gather the unknown TPs of ILs. PMID- 28913974 TI - Impact of ladder-related falls on the emergency department and recommendations for ladder safety. AB - OBJECTIVES: To describe the characteristics of patients who presented to the ED from a ladder-related fall and their injuries, highlight the impact of ladder related falls on the ED, identify contributing factors of ladder falls and draw recommendations to improve ladder safety. METHODS: A prospective observational study was conducted in two EDs. Patients' demographics and ED services used were obtained from medical records. A 53-item questionnaire was used to gather information about the type of ladder used, ladder activity, circumstances of the fall, contributing factors and future recommendations. RESULTS: A total of 177 patients were recruited for this study. The typical patient was male, over the age of 50 and using a domestic ladder. The ED length of stay was between 30 min and 16 h, and was longer if patients were transferred to the short stay unit. Services most utilised in the ED included diagnostic tests, procedures and referrals to other healthcare teams. Most falls occurred because of ladder movement and slips or misstep. The major contributing factors identified were a combination of user features and flaws in ladder setup. CONCLUSIONS: Ladder related falls carry a considerable burden to the ED. Recommendations include ladder safety interventions that target ladder users most at risk of falls: men, >=50 years old and performing domestic tasks. Safety interventions should emphasise task avoidance, education and training, utilisation of safety equipment and appropriate ladder setup. PMID- 28913971 TI - Nanobodies: Chemical Functionalization Strategies and Intracellular Applications. AB - Nanobodies can be seen as next-generation tools for the recognition and modulation of antigens that are inaccessible to conventional antibodies. Due to their compact structure and high stability, nanobodies see frequent usage in basic research, and their chemical functionalization opens the way towards promising diagnostic and therapeutic applications. In this Review, central aspects of nanobody functionalization are presented, together with selected applications. While early conjugation strategies relied on the random modification of natural amino acids, more recent studies have focused on the site specific attachment of functional moieties. Such techniques include chemoenzymatic approaches, expressed protein ligation, and amber suppression in combination with bioorthogonal modification strategies. Recent applications range from sophisticated imaging and mass spectrometry to the delivery of nanobodies into living cells for the visualization and manipulation of intracellular antigens. PMID- 28913977 TI - The effect of diet or exercise on ectopic adiposity in children and adolescents with obesity: a systematic review and meta-analysis. AB - OBJECTIVE: Ectopic fat depostion in youth with obesity is associated with an increased cardiovascular disease risk. The aim of this meta-analysis was to summarize the evidence for the use of diet and/or exercise on ectopic adiposity in this population. METHODS: A systematic literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta analysis statement. Clinical trials that assessed ectopic fat deposition and included study arms with diet and/or exercise were searched in PubMed, PEDro and the Cochrane database. RESULTS: Hepatic fat content and intramyocellular lipid content were described in nine studies and three studies, respectively. Most studies included teenagers, and study duration ranged between 3 and 12 months without follow-up. Using random-effects weights, the standardized mean difference of the change in hepatic adiposity (totalling 320 subjects) was -0.54 Hedges' g (95% confidence interval: -0.69 to -0.38 with p < 0.0001). By re-expressing this effect size, it is seen that diet and/or exercise results in an absolute reduction of intrahepatic lipid with 2%, which accords with a relative reduction up to 70%. Although there were significant ameliorations of insulin sensitivity, no significant changes in intramyocellular lipid were observed. CONCLUSIONS: This meta-analysis showed that diet and/or exercise is effective to reduce hepatic adiposity in youth with obesity. PMID- 28913978 TI - A temperature sensor implant for active implantable medical devices for in vivo subacute heating tests under MRI. AB - PURPOSE: To introduce a temperature sensor implant (TSI) that mimics an active implantable medical device (AIMD) for animal testing of MRI heating. Computer simulations and phantom experiments poorly represent potential temperature increases. Animal experiments could be a better model, but heating experiments conducted immediately after the surgery suffer from alterations of the thermoregulatory and tissue properties during acute testing conditions. Therefore, the aim of this study was to introduce a temperature sensor implant that mimics an AIMD and capable of measuring the electrode temperature after implantation of the device without any further intervention at any time after the surgery in an animal model. METHODS: A battery-operated TSI, which resembled an AIMD, was used to measure the lead temperature and impedance and the case temperature. The measured values were transmitted to an external computer via a low-power Bluetooth communication protocol. In addition to validation experiments on the phantom, a sheep experiment was conducted to test the feasibility of the system in subacute conditions. RESULTS: The measurements had a maximum of 0.5 degrees C difference compared to fiber-optic temperature probes. In vivo animal experiments demonstrated feasibility of the system. CONCLUSION: An active implant, which can measure its own temperature, was proposed to investigate implant heating during MRI examinations. Magn Reson Med 79:2824-2832, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28913979 TI - Physical pain increases interpersonal trust in females. AB - BACKGROUND: People behave and interact with others differently when experiencing physical pain. Pain has dramatic effects on one's emotional responses, cognitive functions and social interaction. However, little has been known about whether and how physical pain influences interpersonal trust in social interaction. In the present study, we examined the influence of physical pain on trusting behaviour. METHODS: A total of 112 healthy participants were recruited and assigned to physical pain condition (induced by Capsaicin) and control condition (with hand cream), respectively. Thirty minutes after pain induction, three decision-making tasks were conducted to measure behaviours in social interaction, including trust and trustworthiness (trust game), non-social risk-taking (risk game) and altruism (dictator game). RESULTS: Results showed that physical pain increased interpersonal trust among females, but not among males. Pain did not influence non-social risk-taking, altruism or trustworthiness, as evaluated by monetary transfers in those tasks. Moreover, the effect of physical pain on interpersonal trust was fully mediated by expectation of monetary profit. CONCLUSIONS: These findings demonstrate an effect of pain on interpersonal trust and suggest a reciprocity mechanism that the effect may be driven by self interest rather than altruistic motivation. The pain effect on trust was evident only in females, implying distinct pain coping strategies used by both genders. SIGNIFICANCE: The present work highlights the social component of pain and extends our understanding of mutual interactions between pain and social cognition. PMID- 28913980 TI - Identifying the Elusive Framework Niobium in NbS-1 Zeolite by UV Resonance Raman Spectroscopy. AB - It was found that bands at 739, 963, and 1107 cm-1 in the resonant Raman spectra are characteristics of framework penta-coordinated NbV -OH species, and that a band at 1336 cm-1 in the UV Raman spectrum with excitation line at 320 nm is a sensitive detector for identifying extra-framework niobium species. The change of framework penta-coordinated NbV -OH species into Nb+ and NbO- species due to dehydration was definitively confirmed based on UV resonance Raman and UV/Vis results. PMID- 28913981 TI - Age-dependent expression of Nav1.9 channels in medial prefrontal cortex pyramidal neurons in rats. AB - Developmental changes that occur in the prefrontal cortex during adolescence alter behavior. These behavioral alterations likely stem from changes in prefrontal cortex neuronal activity, which may depend on the properties and expression of ion channels. Nav1.9 sodium channels conduct a Na+ current that is TTX resistant with a low threshold and noninactivating over time. The purpose of this study was to assess the presence of Nav1.9 channels in medial prefrontal cortex (mPFC) layer II and V pyramidal neurons in young (20-day old), late adolescent (60-day old), and adult (6- to 7-month old) rats. First, we demonstrated that layer II and V mPFC pyramidal neurons in slices obtained from young rats exhibited a TTX-resistant, low-threshold, noninactivating, and voltage dependent Na+ current. The mRNA expression of the SCN11a gene (which encodes the Nav1.9 channel) in mPFC tissue was significantly higher in young rats than in late adolescent and adult rats. Nav1.9 protein was immunofluorescently labeled in mPFC cells in slices and analyzed via confocal microscopy. Nav1.9 immunolabeling was present in layer II and V mPFC pyramidal neurons and was more prominent in the neurons of young rats than in the neurons of late adolescent and adult rats. We conclude that Nav1.9 channels are expressed in layer II and V mPFC pyramidal neurons and that Nav1.9 protein expression in the mPFC pyramidal neurons of late adolescent and adult rats is lower than that in the neurons of young rats. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1371-1384, 2017. PMID- 28913982 TI - Validation of the American Joint Commission on Cancer (8th edition) changes for patients with stage III gastric cancer: survival analysis of a large series from a Specialized Eastern Center. AB - The 8th edition of the TNM was released in 2016 and included major revisions, especially for stage III. We aimed to compare the prognostic value of the 7th and 8th editions of the AJCC TNM classification for stage III gastric cancer. Clinical data from 1557 patients operated on for stage III gastric cancer according to the 7th edition between 2007 and 2014 were analyzed and compared using the 7th and 8th TNM classifications. A proposed staging system was established, and the three systems were compared in terms of prognostic performance. The stage shifted for 669 (42.96%) patients. It shifted from IIIA to IIIB (one patient, 0.06%), IIIB to IIIA (230 patients, 14.8%), IIIB to IIIC (94 patients, 6.0%), and IIIC to IIIB (344 patients, 22.1%). However, the new AJCC subgroupings did not prove distinctive for survival levels between T3N3aM0 (stage IIIB) and T3N3bM0 (stage IIIC) or between T4aN3aM0 (stage IIIB) and T4aN3bM0 (stage IIIC) when <30 lymph nodes (LNs) were resected. The performance of the 8th edition (c-index, 0.614; 95% confidence interval [CI], 0.596-0.633) revealed no relevant improvement compared to the 7th edition (c-index, 0.624; 95% CI, 0.605 0.643). The proposed staging system generated the best prognostic stratification. The 8th TNM edition may not provide better accuracy in predicting the prognosis of stage III gastric cancer. The proposed staging system, comprised of a combination of the number of LNs harvested and the 7th and 8th AJCC classifications, may improve predictive capacities for stage III gastric cancer. PMID- 28913984 TI - Effective Strategies for Managing Asthma Exacerbations for Precision Medicine. PMID- 28913983 TI - The impact of ischemic time on early rejection after pediatric heart transplant. AB - Prolonged graft ischemia may be a risk factor for early rejection post-HTx, but this has not been well studied in children. Furthermore, factors moderating the association between IT and early rejection have not been investigated. From 2004 to 2012, pediatric HTx recipients (n = 2381) were identified from the UNOS database. A ROC curve determined the optimal IT discriminating patients by the presence of early rejection. Separate univariate analyses identified factors associated with: (i) early (prior to hospital discharge) rejection, and (ii) IT. A multivariable logistic regression assessed independent risk factors for early rejection. We included interaction terms to evaluate whether IT's independent risk effect on early rejection is moderated via interaction with associated factors found in univariate analysis. Longer IT was associated with an increased risk of early rejection. In multivariable analysis, IT > 3.1 hours was an independent risk factor for early rejection (AOR 1.44, P = .01). No interaction terms between IT and any associated factors were significant. Longer IT is an independent risk for early rejection in pediatric HTx recipients. Better understanding the association between IT and early rejection may identify interventions to mitigate this risk. PMID- 28913986 TI - Chronic Spontaneous Urticaria: Pathogenesis and Treatment Considerations. AB - The treatment of chronic spontaneous urticaria begins with antihistamines; however, the dose required typically exceeds that recommended for allergic rhinitis. Second-generation, relatively non-sedating H1-receptor blockers are typically employed up to 4 times a day. First-generation antihistamines, such as hydroxyzine or diphenhydramine (Atarax or Benadryl), were employed similarly in the past. Should high-dose antihistamines fail to control symptoms (at least 50%), omalizumab at 300 mg/month is the next step. This is effective in 70% of antihistamine-refractory patients. H2-receptor blockers and leukotriene antagonists are no longer recommended; they add little and the literature does not support significant efficacy. For those patients who are unresponsive to both antihistamines and omalizumab, cyclosporine is recommended next. This is similarly effective in 65%-70% of patients; however, care is needed regarding possible side-effects on blood pressure and renal function. Corticosteroids should not be employed chronically due to cumulative toxicity that is dose and time dependent. Brief courses of steroid e.g., 3-10 days can be employed for severe exacerbations, but should be an infrequent occurrence. Finally, other agents, such as dapsone or sulfasalazine, can be tried for those patients unresponsive to antihistamines, omalizumab, and cyclosporine. PMID- 28913985 TI - Asthma Biomarkers: Do They Bring Precision Medicine Closer to the Clinic? AB - Measurement of biomarkers has been incorporated within clinical research of asthma to characterize the population and to associate the disease with environmental and therapeutic effects. Regrettably, at present, there are no specific biomarkers, none is validated or qualified, and endotype-driven choices overlap. Biomarkers have not yet reached clinical practice and are not included in current asthma guidelines. Last but not least, the choice of the outcome upholding the value of the biomarkers is extremely difficult, since it has to reflect the mechanistic intervention while being relevant to both the disease and the particular person. On the verge of a new age of asthma healthcare standard, we must embrace and adapt to the key drivers of change. Disease endotypes, biomarkers, and precision medicine represent an emerging model of patient care building on large-scale biologic databases, omics and diverse cellular assays, health information technology, and computational tools for analyzing sizable sets of data. A profound transformation of clinical and research pattern from population to individual risk and from investigator-imposed subjective disease clustering (hypothesis driven) to unbiased, data-driven models is facilitated by the endotype/biomarker-driven approach. PMID- 28913987 TI - Clinical Characteristics of Exacerbation-Prone Adult Asthmatics Identified by Cluster Analysis. AB - PURPOSE: Asthma is a heterogeneous disease characterized by various types of airway inflammation and obstruction. Therefore, it is classified into several subphenotypes, such as early-onset atopic, obese non-eosinophilic, benign, and eosinophilic asthma, using cluster analysis. A number of asthmatics frequently experience exacerbation over a long-term follow-up period, but the exacerbation prone subphenotype has rarely been evaluated by cluster analysis. This prompted us to identify clusters reflecting asthma exacerbation. METHODS: A uniform cluster analysis method was applied to 259 adult asthmatics who were regularly followed-up for over 1 year using 12 variables, selected on the basis of their contribution to asthma phenotypes. After clustering, clinical profiles and exacerbation rates during follow-up were compared among the clusters. RESULTS: Four subphenotypes were identified: cluster 1 was comprised of patients with early-onset atopic asthma with preserved lung function, cluster 2 late-onset non atopic asthma with impaired lung function, cluster 3 early-onset atopic asthma with severely impaired lung function, and cluster 4 late-onset non-atopic asthma with well-preserved lung function. The patients in clusters 2 and 3 were identified as exacerbation-prone asthmatics, showing a higher risk of asthma exacerbation. CONCLUSIONS: Two different phenotypes of exacerbation-prone asthma were identified among Korean asthmatics using cluster analysis; both were characterized by impaired lung function, but the age at asthma onset and atopic status were different between the two. PMID- 28913988 TI - Prevalence of Respiratory Viral Infections in Korean Adult Asthmatics With Acute Exacerbations: Comparison With Those With Stable State. AB - PURPOSE: Viral infections are involved in ~50% of exacerbations among Caucasian adult asthmatics. However, there have been few reports on the causative virus of exacerbations in Korean adult asthmatics. Thus, we compared frequencies and types of viruses between lower respiratory tract illnesses (LRTIs) with exacerbations (exacerbated LRTIs) and those without exacerbations (stable LRTIs) to evaluate contribution of respiratory viruses to exacerbations. METHODS: Viral RNA was extracted from sputum using the Viral Gene-spinTM Kit. Reverse transcription polymerase chain reaction (RT-PCR) was performed to detect adenovirus (ADV), metapneumovirus (MPV), parainfluenza virus (PIV) 1/2/3, influenza virus (IFV) A, IFV B, respiratory syncytial virus (RSV) A/B, and rhinovirus (RV) A. RESULTS: Among the 259 patients, 210 underwent a single sputum examination, and the remaining 49 underwent 2 to 4 sputum examinations. Virus was detected in 68 of the 259 exacerbated episodes and in 11 of the 64 stable episodes. Among the exacerbated episodes, RV was the most frequently detected virus, followed by influenza A, parainfluenza, RSV A/B, and ADV. Among the 11 stable episodes, RV was most frequently detected. Detection rates of these viruses did not differ between the 2 groups (P>0.05). Thirty-five patients underwent the virus examination at 2 episodes of exacerbation, while 14 patients underwent at each time of exacerbated and stable episodes. Virus detection rate at the second examination was significantly higher in cases with 2 exacerbation episodes than in those with initial exacerbation and sequential stable episodes (P=0.003). A seasonal pattern was noted in the detection rates of RV (September to December), IFV (January to April), PIV (May to September), and RSV A/B (September to April). CONCLUSIONS: Respiratory viruses were identified in approximately 20% of LRTI irrespective of the presence of asthma exacerbation. RV and IFV A/B were most frequently detected. A group of patients experienced frequent viral infections followed by asthma exacerbations. PMID- 28913989 TI - Patterns of Inhalant Allergen Sensitization and Geographical Variation in Korean Adults: A Multicenter Retrospective Study. AB - PURPOSE: Inhalant allergen sensitization is one of the major factors involved in the pathogenesis of allergic respiratory diseases. However, the sensitization is determined by interactions between genetic and environmental factors. Thus, testing panels of inhalant allergens may differ among geographical areas. Here we aimed to determine 10 common inhalant allergens in Korean adult patients with suspected respiratory allergies and to examine the variation between different geographical locations. METHODS: A total of 28,954 patient records were retrieved for retrospective analysis, from 12 referral allergy clinics located in 9 different areas. Inclusion criteria were Korean adults (>=18 years old) who underwent the inhalant allergen skin prick test for suspected history of respiratory allergy. The primary outcome was inhalant allergen skin prick response. Demographic and clinical information were also collected. Positive skin prick responses to allergens were defined as allergen-to-histamine wheal ratio >=1. Based on skin test results, the most prevalent aeroallergens were determined. RESULTS: The overall prevalence of allergic sensitization was 45.3%. Dermatophagoides farinae and Dermatophagoides pteronyssinus were the most commonly sensitized allergens. Other common inhalant allergens were cat epithelium (8.1%), birch (7.7%), mugwort (6.9%), alder (6.7%), hazel (6.7%), beech (6.7%), oak (6.6%), and Tyrophagus putres (6.2%), in decreasing order frequency. These 10 inhalant allergens explained 90% of inhalant allergen sensitization in the study participants. However, distinct patterns of the 10 inhalant sensitization were observed in patients living in Chungnam and Jeju. American cockroach, Gernam cockroach, and Trichophyton metagrophytes were unique in Chungnam. Orchard, Japanese cedar, and Velvet were unique in Jeju. CONCLUSIONS: The present analysis suggests a panel of 10 most common inhalant allergens in Korean adult patients with suspected respiratory allergies, which explained 90% of inhalant allergen sensitization. This panel can be utilized as a practical and convenient tool for primary practice and epidemiological surveys of respiratory allergic diseases. PMID- 28913990 TI - Association Between Sensitization to Mold and Impaired Pulmonary Function in Children With Asthma. AB - PURPOSE: Recent data indicate that sensitization to mold contributes to the severity and persistence of asthma. In this study, we investigated the relationships between sensitization to mold and lung function parameters in children with asthma. METHODS: We retrospectively reviewed clinical data from 551 asthmatic subjects. We selected subjects who met clinical diagnostic criteria of asthma. Their spirometry, methacholine challenge tests, and measurements of blood eosinophils, serum IgE, eosinophil cationic protein (ECP) and fractional exhaled nitric oxide (FeNO) results were included. Skin prick testing (SPT) results with 13 common aeroallergens in Korea including house dust mites, animal dander, pollen, cockroach and mold were reviewed. Subjects were divided into 3 groups according to their SPT results. Subjects who showed no positive result to any aeroallergen were designated as group 1 (non-sensitized). Group 2 represented subjects who were sensitized to aeroallergens other than mold (other allergen sensitized) and group 3 included subjects who were sensitized to mold allergens (mold-sensitized). RESULTS: Among the 551 asthmatic subjects, 67 (12.2%) were sensitized to mold and 366 (66.4%) were sensitized to other aeroallergens. The log mean IgE levels were higher in groups 2 (5.96+/-1.14 IU/mL) and 3 (5.81+/ 0.97 IU/mL) compared to group 1 (3.88+/-1.68 IU/mL). Blood eosinophils, ECP and FeNO concentrations were significantly higher in groups 2 and 3, but no significant difference was found between the 2 groups. The mean FEV1 value was significantly lower in group 3 (86.9+/-12.1%pred) than in groups 2 (92.0+/ 14.8%pred) and 1 (93.4+/-15.4%pred). The log mean methacholine PC20 was significantly lower in group 3 (0.08+/-1.91 mg/mL) than in groups 2 (1.31+/-1.69 mg/mL) and 1 (2.29+/-1.66 mg/mL). CONCLUSIONS: We observed a differential association between mold and other aeroallergen sensitization, and severity of asthma. Sensitization to mold is associated with lower lung function and increased airway hyper-responsiveness in children with asthma. Mold sensitization could be an important factor determining asthma severity particularly airflow limitation in children. PMID- 28913991 TI - Seasonal Cycle and Relationship of Seasonal Rhino- and Influenza Virus Epidemics With Episodes of Asthma Exacerbation in Different Age Groups. AB - PURPOSE: Seasonal variations in asthma exacerbation (AE) are associated with respiratory virus outbreaks and the return of children to school after vacation. This study aims to elucidate the period, phase, and amplitude of seasonal cycles of AE in 5 different age groups with regard to rhino- and influenza virus epidemics in Korea. METHODS: The number of daily emergency department (ED) visits for AE in all age groups of Korea and the nationwide weekly incidence of rhino- and influenza virus, were obtained for 2008-2012. Fourier regression was used to model rhythmicity, and the Cosinor method was used to determine the amplitude and phase of the cycles in each age group. The cross-correlation function (CCF) between AE and the rhino- and influenza virus epidemics was also calculated. RESULTS: There were 157,559 events of AE (0.62 events/1,000 individuals/year) during the study period. There were spring and fall peaks of AE in children and adults, but only 1 winter peak in the elderly. The amplitude of the AE peak in infants was higher in spring than in fall (9.16 vs 3.04, P<0.010), and the fall peak was approximately 1 month later in infants than in school children (October 11 vs November 13, P<0.010). The association between AE and rhinovirus was greatest in school children (rho=0.331), and the association between AE and influenza virus was greatest in those aged >=60 years (rho=0.682). CONCLUSIONS: The rhythmicity, amplitude, and phase of the annual cycle of AE differed among different age groups. The patterns of AE were related to the annual rhino- and influenza virus epidemics. PMID- 28913993 TI - A Retrospective Study of Korean Adults With Food Allergy: Differences in Phenotypes and Causes. AB - PURPOSE: Increasing in prevalence, food allergy (FA) is becoming an important public health concern. In Korean adults, however, clinical phenotypes and causes of FA have not been studied. We aimed to study common causative allergens and clinical manifestations of FA in Korean adults. METHODS: This study was conducted as a retrospective review of medical records for 95 patients (>=19 years old) diagnosed with FA from September 2014 to August 2015 at a single university hospital. RESULTS: In the 95 patients, 181 FA events were recorded. The mean age of first onset of FA symptoms was 34.7+/-15.8 years. The most frequent causative food was seafood (34.8%); shrimp and crab allergies ranked highest, regardless of age and sex. Among all FA events, there were 47 (26.0%) cases of anaphylaxis and 26 (14.4%) cases of oral allergy syndrome (OAS). Seafood (51.1%) was the most frequent cause of anaphylaxis, followed by grains (14.9%). Most OAS cases were associated with fruits (95.7%). The frequency of fruit-induced FA was significantly higher in males than in females (23.0% vs 8.4%, P=0.011). While no cases of vegetables-induced FA were noted in younger individuals (19 to 30 years), vegetables accounted for 20.5% of FA symptoms in older subjects (>=51 years, P<0.001). Allergic rhinitis (44.2%) and drug allergy (20.0%) were major comorbidities associated with FA. Overall, 29 FA events had cofactors, of which 10 were combined with exercise. CONCLUSIONS: The major causes of FA in Korean adults were crustacean, fruits, and grains. Interestingly, the clinical manifestations of FA and demographics varied according to type of food allergen. PMID- 28913992 TI - Effects of Immunoglobulin Replacement on Asthma Exacerbation in Adult Asthmatics with IgG Subclass Deficiency. AB - PURPOSE: Recurrent respiratory tract infection is a common manifestation of primary immunodeficiency disease, and respiratory viruses or bacteria are important triggers of asthma exacerbations. Asthma often coexists with humoral immunodeficiency in adults, and some asthmatics with immunoglobulin (Ig) G subclass deficiency (IgGSCD) suffer from recurrent exacerbations. Although some studies suggest a benefit from Ig replacement, others have failed to support its use. This study aimed to assess the effect of Ig replacement on asthma exacerbation caused by respiratory infection as well as the asthma control status of adult asthmatics with IgGSCD. METHODS: This is a multi-center, open-label study of adult asthmatics with IgGSCD. All patients received monthly intravenous immunoglobulin (IVIG) for 6 months and were evaluated regarding asthma exacerbation related to infection, asthma control status, quality of life, and lung function before and after IVIG infusion. RESULTS: A total of 30 patients were enrolled, and 24 completed the study. Most of the patients had a moderate degree of asthma severity with partly (52%) or uncontrolled (41%) status at baseline. IVIG significantly reduced the proportion of patients with asthma exacerbations, lowered the number of respiratory infections, and improved asthma control status, compared to the baseline values (P<0.001). The mean asthma specific quality of life and asthma control test scores were improved significantly (P=0.009 and P=0.053, respectively); however, there were no significant changes in lung function. CONCLUSIONS: IVIG reduced the frequency of asthma exacerbations and improved asthma control status in adult asthmatics with IgGSCD, suggesting that IVIG could be an effective treatment option in this population. PMID- 28913994 TI - Mouse Model of IL-17-Dominant Rhinitis Using Polyinosinic-Polycytidylic Acid. AB - Interleukin (IL)-17 plays an important role in rhinitis and the level thereof correlates with the severity of disease. However, no mouse model for IL-17 dominant rhinitis has yet been developed. Our objective was to establish a mouse model of IL-17-dominant rhinitis via intranasal application of polyinosinic polycytidylic acid (abbreviated as Poly(I:C)). Mice were divided into 6 groups (n=8 for each group); 1) 1 negative control group, 2) 1 positive control group (OVA/alum model), 3) 2 Poly(I:C) groups (10 or 100 MUg), and 4) 2 OVA/Poly(I:C) groups (10 or 100 MUg). The positive control group was treated with the conventional OVA/alum protocol. In the Poly(I:C) and OVA/Poly(I:C) groups, phosphate-buffered saline or an OVA solution plus Poly(I:C) were administered. The OVA/Poly(I:C) groups exhibited significantly greater neutrophil infiltration and increased IL-17/interferon gamma expression compared with the other groups. However, the levels of total immunoglobulin E (IgE), OVA-specific IgE, eosinophil infiltration, IL-4, IL-5, IL-6, and IL-10 were significantly lower in the OVA/Poly(I:C) groups than in mice subjected to conventional Th2-dominant OVA/alum treatment (the positive control group). IL-17 and neutrophil measurement, chemokine (C-X-C motif) ligand 1 immunohistochemistry, and confocal microscopy revealed increased numbers of IL-17-secreting cells in the nasal mucosa of the OVA/Poly(I:C) groups, which included natural killer cells, CD4 T cells, and neutrophils. In conclusion, we developed a mouse model of IL-17-dominant rhinitis using OVA together with Poly(I:C). This model will be useful in research on neutrophil- or IL-17-dominant rhinitis. PMID- 28913968 TI - Risk factors for unfavourable postoperative outcome in patients with Crohn's disease undergoing right hemicolectomy or ileocaecal resection An international audit by ESCP and S-ECCO. AB - BACKGROUND: Patient and disease-related factors, as well as operation technique all have the potential to impact on postoperative outcome in Crohn's disease. The available evidence is based on small series and often displays conflicting results. AIM: To investigate the effect of pre- and intra-operative risk factors on 30-day postoperative outcome in patients undergoing surgery for Crohn's disease. METHOD: International prospective snapshot audit including consecutive patients undergoing right hemicolectomy or ileocaecal resection. This study analysed a subset of patients who underwent surgery for Crohn's disease. The primary outcome measure was the overall Clavien-Dindo postoperative complication rate. The key secondary outcomes were anastomotic leak, re-operation, surgical site infection and length of stay at hospital. Multivariable binary logistic regression analyses were used to produce odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Three hundred and seventy five resections in 375 patients were included. The median age was 37 and 57.1% were female. In multivariate analyses, postoperative complications were associated with preoperative parenteral nutrition (OR 2.36 95% CI 1.10-4.97)], urgent/expedited surgical intervention (OR 2.00, 95% CI 1.13-3.55) and unplanned intraoperative adverse events (OR 2.30, 95% CI 1.20-4.45). The postoperative length of stay in hospital was prolonged in patients who received preoperative parenteral nutrition (OR 31, CI [1.08-1.61]) and those who had urgent/expedited operations (OR 1.21, CI [1.07-1.37]). CONCLUSION: Preoperative parenteral nutritional support, urgent/expedited operation and unplanned intraoperative adverse events were associated with unfavourable postoperative outcome. Enhanced preoperative optimization and improved planning of operation pathways and timings may improve outcomes for patients. This article is protected by copyright. All rights reserved. PMID- 28913995 TI - Intraoperatively Observed Lacrimal Obstructive Features and Surgical Outcomes in External Dacryocystorhinostomy. AB - PURPOSE: To analyze the features of lacrimal drainage system obstruction confirmed during external dacryocystorhinostomy surgeries and report the surgical outcomes. METHODS: We reviewed the medical records of a total of 769 cases who underwent external dacryocystorhinostomy for primary lacrimal drainage obstruction between 2005 and 2014. Data about detailed location and extent of obstruction were collected intraoperatively. The sites of obstruction were classified into nasolacrimal duct obstruction (NLDO), common canalicular obstruction (CCO), and canalicular obstruction. Lacrimal sac mucosa and lumen were grossly inspected, and the frequency of lacrimal sac changes, such as significant inflammation or fibrosis, was analyzed in cases of CCO or canalicular obstruction. The surgical success rate was also evaluated including effect of lacrimal sac status in the CCO and canalicular obstruction groups. RESULTS: Of 769 cases, primary NLDO with patent canaliculi was diagnosed intraoperatively in 432 cases (56.2%), CCO in 253 (32.9%), and canalicular obstruction in 84 (10.9%). Of 253 cases with CCO, 122 (48.2%) showed clear lacrimal sac lumen, and the other 131 (51.8%) showed significant inflammation or fibrosis of the lacrimal sac. In cases with canalicular obstruction, 35 of 84 (41.7%) showed a clear lacrimal sac, and the other 49 cases (58.3%) cases revealed mucosal changes of the lacrimal sac. The functional success rate was 87.5% for primary NLDO, 75.5% for CCO, and 72.6% for canalicular obstruction. In the CCO group, the functional success rate was lower in cases with significant lacrimal sac change (p = 0.044). CONCLUSIONS: Even in patients with CCO or canalicular obstruction, a large number of cases have lacrimal sac changes, and those changes were associated with lower functional success rate. PMID- 28913996 TI - Intraocular Lens Power Calculation after Refractive Surgery: A Comparative Analysis of Accuracy and Predictability. AB - PURPOSE: To compare the accuracy of intraocular lens (IOL) power calculation using conventional regression formulae or the American Society of Cataract and Refractive Surgery (ASCRS) IOL power calculator for previous corneal refractive surgery. METHODS: We retrospectively reviewed 96 eyes from 68 patients that had undergone cataract surgery after keratorefractive surgeries. We calculated the formula with two approaches: IOL powers using the ASCRS IOL power calculator and IOL powers using conventional formulae with previous refractive data (Camellin, Jarade, Savini, and clinical history method) or without prior data (0, 2 and, 4 mm total mean power in topography, Wang-Koch-Maloney, Shammas, Seitz, and Maloney). Two conventional IOL formulae (the SRK/T and the Hoffer Q) were calculated with the single K and double K methods. Mean arithmetic refractive error and mean absolute error were calculated at the first postoperative month. RESULTS: In conventional formulae, the Jarade method or the Seitz method, applied in the Hoffer Q formula with the single K or double K method, have the lowest prediction errors. The least prediction error was found in the Shammas-PL method in the ASCRS group. There was no statistically significant difference between the 10 lowest mean absolute error conventional methods, the Shammas-PL method and the Barrett True-K method calculated with using the ASCRS calculator, without using preoperative data. CONCLUSIONS: The Shammas-PL formula and the Barrett True-K formula, calculated with the ASCRS calculator, without using history, were methods comparable to the 10 most accurate conventional formulae. Other methods using the ASCRS calculator show a myopic tendency. PMID- 28913999 TI - Five-year Outcomes of Ranibizumab in Neovascular Age-related Macular Degeneration: Real Life Clinical Experience. AB - PURPOSE: To evaluate the outcomes of 5-year ranibizumab treatment in neovascular age-related macular degeneration (nAMD) in a single center and real life clinical setting. METHODS: The records of nAMD patients who were treated with ranibizumab between January 2010 and June 2011 were retrospectively reviewed. Patients who completed 5 years of follow-up were included. Main outcome measures were change in best-corrected visual acuity, central retinal thickness, and visit and injection numbers. RESULTS: Forty-four eyes of 37 patients were included. Mean best-corrected visual acuity decreased from 0.82 +/- 0.69 to 1.11 +/- 0.65 logarithm of minimal angle of resolution after 5 years. Twenty-four eyes (54.5%) had visual acuity loss >=3 lines, and 20 eyes (45.5%) had stable or improved vision (loss <3 lines, remained stable, or gained >=1 line) at month 60. The mean total number of visits was 25.3 +/- 5.8 (range, 14 to 42), and the mean total number of injections was 12.6 +/- 6.4 (range, 3 to 26) at month 60. CONCLUSIONS: Half of the ranibizumab-treated nAMD patients maintained their vision during the 5 years of follow-up. Visit and injection numbers were found to be lower than in prospective studies, reflecting a real world clinical practice. PMID- 28913998 TI - Depressive Symptoms and Quality of Life in Age-related Macular Degeneration Based on Korea National Health and Nutrition Examination Survey (KNHANES). AB - PURPOSE: This study was conducted to investigate the depressive symptoms and quality of life (QOL) in patients with age-related macular degeneration (AMD) using data obtained from the Korea National Health and Nutritional Examination Survey V-2 (KNHANES V-2) conducted in 2011. METHODS: This was a population-based, cross-sectional study that selected 329 participants from the fifth KNHANES (2011) who were diagnosed with AMD by an ophthalmologist based on fundus photography. The prevalence of depressive symptoms and the health-related QOL (using EuroQol indices) in this cohort were also estimated. Factors associated with depressive symptoms, including socioeconomic status, QOL indices, and associated chronic diseases, were investigated using multivariate regression models. RESULTS: Depressive symptoms were observed more frequently in AMD patients than in non-AMD controls (p = 0.013). Among the total 329 AMD participants, 65 (19.8%) had depressive symptoms. There were 16 males (24.6%) and 49 females (75.4%). Upon multivariate analysis, significant factors found to be associated with depressive symptoms were female gender (odds ratio [OR], 2.082; 95% confidence interval [CI], 1.001 to 4.330), being in the "dependent" group for activities of daily living (OR, 4.638; 95% CI, 2.061 to 10.435), and having "some problems" in the "anxiety-depression" dimension of the EQ-5D (OR, 7.704; 95% CI, 1.890 to 31.408). CONCLUSIONS: Female gender and being dependent on others for activities of daily living increased the association of depressive symptoms in this cohort of AMD participants. Screening for depressive symptoms in East Asian AMD patients with these characteristics should be an important component of their care. PMID- 28913997 TI - Additive Effect of Oral Steroid with Topical Nonsteroidal Anti-inflammatory Drug for Preventing Cystoid Macular Edema after Cataract Surgery in Patients with Epiretinal Membrane. AB - PURPOSE: To investigate the additive effect of oral steroid with topical nonsteroidal anti-inflammatory drug (NSAID) on cystoid macular edema (CME) in patients with epiretinal membrane (ERM) after cataract surgery. METHODS: Medical records of subjects who underwent uneventful cataract surgery (n = 1,349) were retrospectively reviewed; among these patients, those with pre-existing ERM (n = 81) were included. Patients were divided into two groups: one group had postoperative administration of oral steroid for 1 week (n = 45) and the other group did not have oral steroid administration (n = 36). Changes in macular thickness and incidence of CME were compared in both groups. Topical NSAIDs were administered in both groups for 1 month postoperatively. Definite CME and probable CME were defined by changes in retinal contour with or without cystoid changes. Change in central macular thickness of more than three standard deviations (>=90.17 MUm) was defined as possible CME. Macular thickness was measured at 1 month after the operation by optical coherence tomography. RESULTS: The incidence of definite, probable, and possible CME were 2.22%, 4.44%, and 8.89% with the use of steroid and 2.78%, 5.56%, and 8.33% without steroid, respectively (p = 0.694, p = 0.603, and p = 0.625), and regardless of treatment group, the incidences in these patients were higher compared to incidences in whole subjects (1.26%, 2.30%, and 4.32%; p = 0.048, p = 0.032, and p = 0.038, respectively). The differences in macular thickness were not statistically different between the two groups. Average changes of central foveal thickness in 3 mm and 6 mm zone were 29.29 MUm, 35.93 MUm, and 38.02 MUm with the use of steroid and 32.25 MUm, 44.08 MUm, and 45.39 MUm without steroid (p = 0.747, p = 0.148, and p = 0.077, respectively). CONCLUSIONS: This study suggests that administration of oral steroid may not have a synergistic effect in reduction of CME and retinal thickness in patients with pre-existing ERM after cataract surgery, when topical NSAIDs are applied. PMID- 28914000 TI - Trends of Pars Plana Vitrectomy Rates in South Korea: A Nationwide Cohort Study. AB - PURPOSE: To assess the trends in pars plana vitrectomy surgery rates and factors affecting rate change between 2002 and 2013 in South Korea. METHODS: Data from National Health Insurance Service-National Sample Cohort 2002-2013, which represents 1,025,340 samples with a sampling rate of 2.2% from the total eligible Korean population, was analyzed. RESULTS: A total of 3,816 vitrectomy procedures were performed (male, 2,010; female, 1,806) from 2002 to 2013. Annual rates of vitrectomy increased from 15.1 (in 2002) to 49.4 (in 2013) per 100,000 individuals, and this trend was prominent in those aged 60 years or older. As for the anesthetic method, vitrectomy under local anesthesia increased more prominently than vitrectomy under general anesthesia. The most common diagnoses associated with vitrectomy were diabetic retinopathy, retinal detachment, epiretinal membrane, and macular hole. CONCLUSIONS: The average annual rate of vitrectomy surgery was 31.5 per 100,000 between 2002 and 2013, and the rate has steadily increased. PMID- 28914001 TI - Comparative Study of the Effects of Trabecular Meshwork Outflow Drugs on the Permeability and Nitric Oxide Production in Trabecular Meshwork Cells. AB - PURPOSE: To compare the effects of the barrier function in human trabecular meshwork (TM) cells monolayer and the production of nitric oxide (NO) between trabecular outflow drugs, Rho-associated kinase (ROCK) inhibitors, adenosine, and statin. METHODS: Primary cultured TM cells were exposed to 10 or 25 MUM Y-27632, 0.1 or 1 MUM N6-cyclohexyladenosine (CHA), or 15 or 30 MUM simvastatin for 24 hours. NO production and expression of endothelial nitric oxide synthase mRNA were measured by Griess assay and reverse transcription polymerase chain reaction, respectively. Barrier functions of the TM cell monolayer were measured by carboxyfluorescein and trans-endothelial electrical resistance. The expression of matrix metalloproteinase-2 mRNA was assessed with reverse transcription polymerase chain reaction. RESULTS: In TM cells, treatment with each drug increased endothelial nitric oxide synthase mRNA expression. Treatment with 25 MUM Y-27632 and 1.0 MUM CHA increased NO production significantly (p = 0.035 and p = 0.043, respectively). Treatment with each drug increased the permeability (all p = 0.001) and decreased the trans-endothelial electron resistance of the TM cell monolayer. Treatment with 0.1 MUM and 1.0 MUM CHA significantly increased matrix metalloproteinase-2 mRNA expression, but simvastatin inhibited its expression. CONCLUSIONS: Since treatment with ROCK inhibitor more greatly increased NO production and permeability than did adenosine or statin, ROCK inhibitor seems to be more effective for lowering intraocular pressure. PMID- 28914002 TI - A Case of Rothia mucilaginosa Keratitis in South Korea. PMID- 28914003 TI - Visual Fatigue Induced by Viewing a Tablet Computer with a High-resolution Display. AB - PURPOSE: In the present study, the visual discomfort induced by smart mobile devices was assessed in normal and healthy adults. METHODS: Fifty-nine volunteers (age, 38.16 +/- 10.23 years; male : female = 19 : 40) were exposed to tablet computer screen stimuli (iPad Air, Apple Inc.) for 1 hour. Participants watched a movie or played a computer game on the tablet computer. Visual fatigue and discomfort were assessed using an asthenopia questionnaire, tear film break-up time, and total ocular wavefront aberration before and after viewing smart mobile devices. RESULTS: Based on the questionnaire, viewing smart mobile devices for 1 hour significantly increased mean total asthenopia score from 19.59 +/- 8.58 to 22.68 +/- 9.39 (p < 0.001). Specifically, the scores for five items (tired eyes, sore/aching eyes, irritated eyes, watery eyes, and hot/burning eye) were significantly increased by viewing smart mobile devices. Tear film break-up time significantly decreased from 5.09 +/- 1.52 seconds to 4.63 +/- 1.34 seconds (p = 0.003). However, total ocular wavefront aberration was unchanged. CONCLUSIONS: Visual fatigue and discomfort were significantly induced by viewing smart mobile devices, even though the devices were equipped with state-of-the-art display technology. PMID- 28914004 TI - Mislocation of Boundary of Localized Retinal Nerve Fiber Layer Defect in Red-free Photography of Three Glaucoma Patients. PMID- 28914005 TI - Delayed Absorption of Subretinal Fluid after Retinal Reattachment Surgery and Associated Choroidal Features. AB - PURPOSE: The aim of this study was to investigate the incidence and associated clinical factors of delayed absorption of subretinal fluid (SRF) after surgery for rhegmatogenous retinal detachment. METHODS: This study involved 36 eyes of 36 consecutive patients who underwent successful surgery for rhegmatogenous retinal detachment. A complete ophthalmologic evaluation, including clinical fundus examination, optical coherence tomography, and indocyanine green angiography, was conducted before and after surgery. Delayed absorption was defined as the presence of residual concave SRF or an SRF bleb at 6 months after surgery. Clinical factors and choroidal features on indocyanine green angiography were compared according to the presence and absence of delayed absorption. RESULTS: Eighteen of 36 eyes (50%) showed delayed absorption. Macular involvement and worse preoperative visual acuity were significantly related to the presence of delayed absorption (p = 0.001 and p = 0.034, respectively). On indocyanine green angiography, preoperative choroidal vascular hyperpermeability was noted in 70% of eyes with delayed absorption and in 14% of eyes without it (p = 0.010). CONCLUSIONS: Delayed absorption of SRF after retinal reattachment surgery was not rare, with a 50% of incidence in this study. Macula-off status was significantly related to the incidence of delayed SRF absorption, and choroidal features such as choroidal vascular hyperpermeability might be responsible in part, possibly through the resultant exudative property of choroid. PMID- 28914006 TI - Acute Angle Closure Glaucoma in a Patient with Pseudoxanthoma Elasticum. PMID- 28914007 TI - Approximate P3 solution for the semi-infinite medium: steady state and time domain. AB - The steady-state solution of the Green's function obtained by the P3 equation in a semi-infinite medium is presented, the proposed solution is a diffusion-based model. Two time-domain solutions are established: one is the solution under extrapolation boundary condition, which we call the optical parameter method, and the other corresponds to the diffusion equation, which we call the double diffusion coefficient method. The spatial-resolved reflectance and the time resolved reflectance are calculated. The Monte Carlo simulation is used to verify the P3 equation. The results show that the P3 steady-state equation and the two time-domain equations are in good agreement with the Monte Carlo simulation. In the steady state, when the distance between the detector and the light source is less than several free paths, the P3 equation is more accurate than the diffusion equation. In other cases, the P3 model and the diffusion model have similar results. However, when the absorption coefficient is large, P3 is more accurate. In the time domain, the optical parameter method is more accurate, and the double diffusion coefficient method is more consistent with the diffusion equation. PMID- 28914008 TI - Linearly chirped fiber Bragg grating response to thermal gradient: from bench tests to the real-time assessment during in vivo laser ablations of biological tissue. AB - The response of a fiber optic sensor [linearly chirped fiber Bragg grating (LCFBG)] to a linear thermal gradient applied on its sensing length (i.e., 1.5 cm) has been investigated. After these bench tests, we assessed their feasibility for temperature monitoring during thermal tumor treatment. In particular, we performed experiments during ex vivo laser ablation (LA) in pig liver and in vivo thermal ablation in animal models (pigs). We investigated the following: (i) the relationship between the full width at half maximum of the LCFBG spectrum and the temperature difference among the extremities of the LCFBG and (ii) the relationship between the mean spectrum wavelength and the mean temperature acting on the LCFBG sensing area. These relationships showed a linear trend during both bench tests and LA in animal models. Thermal sensitivity was significant although different values were found with regards to bench tests and animal experiments. The linear trend and significant sensitivity allow hypothesizing a future use of this kind of sensor to monitor both temperature gradient and mean temperature within a tissue undergoing thermal treatment. PMID- 28914009 TI - Luminescent diagnostics of skin defects in the near-infrared range. AB - Photodynamic therapy becomes a widely spread method due to cancer growth in the world. However, to detect tumors at early stages, it is necessary to carry out diagnostic measures in a timely manner. Our aim was to test the developed pharmaceutical composition, which can be used for external application in early fluorescent diagnostics even in the absence of visual changes, as well as for therapy effectiveness control. Pharmacokinetic studies on laboratory animals and volunteers were carried out. The results have shown that the dipotassium salt of Yb3+-dimethoxyhematoporphyrin IX, which is highly soluble in water and stable in storage, is a promising marker for earlier diagnostics of tumors and can be used in dermatology, dentistry, gynecology, cosmetology, ear, nose, and throat diseases, veterinary, and in other areas of medicine. PMID- 28914010 TI - FRET-based method for evaluation of the efficiency of reversible and irreversible sonoporation. AB - It is widely known that not all of the treated cells survive after introduction of exogenous molecules via any physical method. Therefore, it is important to develop methods that would allow simultaneous evaluation of both molecular delivery efficiency and cell viability. This study presents Forster resonance energy transfer (FRET)-based method that allows molecular transfer and cell viability evaluation in a single measurement by employing two common fluorescent dyes, namely, ethidium bromide and trypan blue. The method has been validated using cell sonoporation. The FRET-based method allows the efficiency evaluation of both reversible and irreversible sonoporation in a single experiment. Therefore, this method could be used to reduce time, labor, and material cost while improving the accuracy of evaluations. PMID- 28914011 TI - [Combinations in Fangji of Chinese medicine: holistic view]. AB - The modernization research on Fangji is not only an important approach to the improvement on the clinical effects of Chinese medicine, but also a representative field on the inheritance and innovation of Chinese medicine in this new historical period. For the rule of the combintions in Fangji, we proposed a hypothesis of "the holistic harmonious pharmacological effect", which is defined as the different efficacies of different combinations in Fangji deriving from the harmoniousness on the diversity of pharmacological effects like antagonism, complementarity, regulation, etc. In our paper, by analyzing the different pharmacological mechanisms in the differential genes and pathways for the additive effect on the combinations of gardenoside and baicalin as well as the synergy effect on the combinations of gardenoside and cholic acid, we introduced a developed analytical technique for the principle of comprehensive pharmacological effects, pointed out the encountered dilemma in the researches on the combinations in Fangji and at last proposed three transformations to the further researches in this fields. PMID- 28914012 TI - [Advance in molecular biology of Dendrobium (Orchidaceae)]. AB - With the development of molecular biology, the process in molecular biology research of Dendrobium is going fast. Not only did it provide new ways to identify Dendrobium quickly, reveal the genetic diversity and relationship of Dendrobium, but also lay the vital foundation for explaining the mechanism of Dendrobium growth and metabolism. The present paper reviews the recent process in molecular biology research of Dendrobium from three aspects, including molecular identification, genetic diversity and functional genes. And this review will facilitate the development of this research area and Dendrobium. PMID- 28914013 TI - [Disease of root-knot nematode and control strategy in medicinal plants]. AB - Root-knot nematode (Meloidogyne spp.) is one of the important disease of medicinal plant cultivation and seriously hinders the sustainable development of traditional Chinese medicine industry. We introduced the main species, identification methods and control strategies of root-knot nematode diseases in the medicinal plants in this study. Identifications of morphology and molecular were the main tools for the distinction of root-knot nematodes at present. This study stated that integrated system was established for root-knot nematode control, including that integrated control technique was the first step, disease resistant varieties with high yield were the basis, and normalized patterns of cultivation and management were the measure. These strategies would improve the sustainable development of medicinal plants and environmental protection. PMID- 28914014 TI - [Application and prospect of "couplet medicine" techniques in preservation of Chinese medicinal materials]. AB - Chinese medicinal materials (CMMs) are easily to be contaminated by all kinds of molds to produce various mycotoxins due to their internal factors and the external environmental conditions during the growth, harvesting, processing, and especially storage processes. This will not only affect the quality of CMMs, resulting in enormous financial loss, but also influence the safety and effectiveness of CMMs, posing potential threats to human health. With the increase in awareness of "traditional Chinese medicine health" idea, more and more attention has been paid on how to prevent and control these CMMs from being mouldy to guarantee their safety. Some physical and chemical techniques have been restricted for protecting CMMs due to their own disadvantages. As a green, safe and economic strategy for the preservation of CMMs, "couplet medicine" technique based on the principle of "protecting CMM with another CMM" has been developed: two kinds of CMMs are stored together and fight against each other to prevent mildew metamorphism, exhibiting no obvious changes in color, smell and quality. Nowadays, certain application results have been obtained for the "antagonistic storage" method based on the above mode and principle. In this paper, we would review and discuss the mechanism, practical application and the problems of "couplet medicine" technique, and provide scientific evidences for developing safe and effective tools to protect CMMs from being mouldy. PMID- 28914015 TI - [Relationship between hepatic drug-metabolizing enzymes CYP450 and traditional Chinese medicine-induced hepatotoxicity]. AB - In recent years, with the emergence of new methods and technologies in traditional Chinese medicines metabolism, the relationship between medicine metabolism and cytochrome P450 has gradually been revealed. The research on P450 drug metabolizing enzymes can be used to predict the side effects of traditional Chinese medicines and explore the relationship between compatibility of medicines and toxicity reducing and efficacy enhancing. This paper aims to summarize the progress of CYP450 research, the mechanism of hepatic drug-metabolizing enzymes in the process of drug-metabolism and the relationship between CYP450 and medicine hepatotoxicity. Furthermore, we set out the regulation effects of typical traditional Chinese medicines on CYP450 to provide a reliable basis for the rational use of Chinese medicines. PMID- 28914016 TI - [Analysis and evaluation of resourceful chemical compositions in different parts of Zanthoxylum bungeanum fruit and its seed oil]. AB - The study aims of this study is to analyze and evaluate the resourceful chemical compositions in different parts of mature fruit of Zanthoxylum bungeanum, and provide a scientific basis for the comprehensive utilization of this medicinal plant resources. GC-MS method was used to analyze the volatile oils and the fatty acids, and HPLC method was used to determine the flavonoids and phenolic acids in the pericarp, seed and seed oil of Z.bungeanum. There were 26, 19 and 11 kinds of volatile components detected in the pericarp, seed and seed oil, respectively, in which terpenoids and their oxy-derivatives were the main components, and the contents of linalool and its esters in pericarp were relatively high. The contents of total fatty acids in the pericarp, seed and seed oil were 108.42, 331.63, 966.04 mg*g-1, respectively.Oleic acid, linoleic acid andalpha-linolenic acid were abundantin all samples. The pericarp contains relatively high content of flavonoids, such as hyperoside, quercitrin, rutin, isoquercitrin, while the above components were not detected in the seed and seed oil. These results confirmed that the fruit of Z.bungeanum contains high contents of the resourceful chemical compositions, and their composition and contents were differed among organs, which provide a scientific basis for the utilization of Z.bungeanumfruit. PMID- 28914017 TI - [Study on correlation of oxygen consumption rate and suffocation point of Whitmania pigra and Bellamya purificata and optimum way of feeding Whitmania pigra]. AB - The oxygen consumption, oxygen consumption rate and suffocation point of different quality Whitmania pigra and Bellamya purificata were determined by hydrostatic breathing room method. The effects of feeding modes on growth of W.pigra were determined by biomass. The results showed that the oxygen consumption correlated positively with the weight of W.pigra and B. purificata(P<0.05), suffocation point increased with the increases of the weight(P<0.05).Oxygen consumption correlated negatively with the weight of W. pigra, the oxygen consumption rate of B.purificata first increased and then decreased with the increasing of the weight. Feeding modes had no significant effects on the finial weight, SGR, WGR, death rates of W. pigra. Feeding modes had significant effects on eating ratio. It suggested that the optimum feeding frequency of W. pigra was once every three days. Scientific and reasonable feeding amount of B. purificata should be calculated based on oxygen consumption and suffocation point of W.pigra and B.purificata at every period. Meanwhile, stocking density, water area and water exchanging frequency should be taken into consideration. PMID- 28914018 TI - [Effects of exogenous MeJA, SA and two kinds of endophytic fungi on physiology and total phenols content of seedlings of Bletilla striata]. AB - Tissue culture seedlings of Bletilla striata were treated with MeJA, SA and two kinds of endophytic fungi in order to study the effects of those treatments on the physiology and total phenols content. The method of tissue culture was used to culture seeds into seedlings, and then different treatments were applied on them to observe and measure the changes of physiology and total phenols content. We find that the growth of seedlings treated with SA was poor, which treated with 40 MUmol*L-1 MeJA, 50 mL*L-1 Hypocrea koningii and 10 mL*L-1 Trichoderma koningiopsis showed better. The activity of SOD, POD and CAT was at a high level under SA treatment of each concentration. The activity of SOD and POD increased as the rise of MeJA concentration, while CAT was highest at 80 MUmol*L-1. The activity of SOD and POD increased with the increasing of the concentration of H. koningii treatment, while CAT reached the highest at 1 mL*L-1. The activity of SOD, POD and CAT increased first and then declined with the concentration of T. koningiopsis increasing, and the highest activity was at 10 mL*L-1. The contents of MDA, soluble protein and proline were increased more or less under the four treatments. The content of polysaccharide was at a high level under 60 MUmol*L-1 of MeJA. The total phenols content was at a high level under 40 MUmol*L-1 of MeJA, 60 MUmol*L-1 of SA, 1 mL*L-1 of H. koningii and 10 mL*L-1 of T. koningiopsis. The results indicated that the addition of exogenous MeJA, SA and endophytic fungi under certain concentrations could improve the resistance of B. striata and increase the content of total phenols at some degree and the trearment of MeJA, H. koningii and T. koningiopsis could promote the growth of seedlings under certain concentrations. PMID- 28914019 TI - [Correlation between Andrographis Herba preparation's fingerprint, pharmacological activity and preparation process]. AB - Process design grants the quality connotation to products. This paper was to investigate the correlation between changes of chemical fingerprints of Andrographis Herba preparation and its pharmacological activity, and set up the bridge between key process and quality attributes. By referring to the preparation process of Andrographis Herba. preparation (extracting-concentrating drying-granulation), HPLC fingerprints were employed to determine the difference of the effective materials of the intermediate micro components. Cluster analysis results indicated that the extraction link had great influence on quality connotation variation of Andrographis Herba preparation. The pharmacological activity of various intermediates was continuously decreased in the models of DPPH antioxidant activity and LPS-induced anti-inflammatory activity in mice peritoneal macrophages. Traditional high temperature treatment process was detrimental to its clinical effect from the curve equation between the key process parameters and pharmacodynamic activity. Partial least square (PLS) was used to construct spectrum-efficiency model equation, and it was verified that this equation could accurately predict the relationship between fingerprints and pharmacological activity, which would facilitate the subsequent evaluation of quality attributes and provide scientific basis for further quality control of the whole process. PMID- 28914020 TI - [Preparation of borneol loaded hollow mesoporous silica nanoparticles and effect on borneol volatility]. AB - The hollow mesoporous silica nanoparticles (HMSNs) were prepared by hard template method, with a size of 300 nm and shell thickness of 25 nm. Borneol was loaded with solvent impregnation method in order to solve the stability problem of borneol in pharmaceutics, and the BET, TEM and FT-IR were used to characterize the HMSNs and the borneol-HMSNs drug delivery system. The optimal drug loading time, maximum drug loading capacity and the volatility of borneol were investigated. The results showed that HMSNs which were prepared at room temperature and neutral conditions had good sphericity, achieved high drug loading of borneol in a short time, and the drug loading was up to 74.04% within 6 hours; meanwhile, volatility of borneol in the system was greatly improved. This novel drug delivery system provides a new idea for wide application of borneol in the traditional Chinese medicine. PMID- 28914021 TI - [Application of time domain reflectometry for determination of wate content in Xiangsha Yangwei pills]. AB - Xiangsha Yangwei pill was selected as a model drug in this research, and time domain reflectometry (TDR) was used to determine the water content in the pill. The effects of five factors including the number of pill layers, pill packing density, atmospheric moisture, ambient temperature and the ratio of pill formula were investigated on water content. The results showed that the number of pill layers and ambient temperature had significant effects on water content of pills, while the pill packing density, atmospheric moisture and pill formula ratio had little effect on the determination of water content in pills. The reflection value was stable when 6 layers of pills were used. Under the condition of 25 C and 45% relative humidity, the water content of pills ranged from 4.01% to 22.38%, showing good linear relationship between water content and reflection value, and the model equation was as follows: Y=0.279X-21.670 (R2=0.997 0). Verification experiment was used to explain the feasibility of this prediction model. The precision of the method complied with the methodology standard. It is concluded that TDR can be used in determination of water content in Xiangsha Yangwei pills. Additionally, TDR, as a new way to quickly and efficiently determine the water content, has a prospect application in the processing of traditional Chinese medicine pharmacy, especially for concentrated pill. PMID- 28914022 TI - [Effect of Astragali Radix with different sulfur fumigation technologies on immune function in mice]. AB - To investigate the effect of Astragali Radix with different sulfur fumigation technologies on immune function in mice, and observe the effect of different Astragali Radix samples on carbon clearance in cyclophosphamide induced immunosuppressed mice, on immune organ weight in immunosuppressed mice and on delayed type hypersensitivity response (DTH) induced by 2,4 dinitrochlorobenzene. Carbon clearance index, phagocytic index, organ index and ear swelling rate were taken as the indexes. The results showed that, all of the Astragali Radix with different sulfur fumigation technologies markedly increased the carbon clearance index K, phagocytic index alpha, immune organ weight and improved the ability of DTH response in immunosuppressed mice. As compared with the model group, combined hot air-microwave group had the most significant difference, but when other groups were compared with and combined hot air-microwave group, only carbon clearance test had significant difference. From the perspective of pharmacodynamics, the effect of Astragali Radix with different sulfur fumigationon technologies on the immune function of mice was investigated, which provided a reference for the selection of appropriate alternative technology, and also provided guidance for clinical medication. PMID- 28914023 TI - [Stability of cantharidin and cantharidic acid in Mylabris aqueous solution]. AB - To investigate the stability and the conversion rules of cantharidin and cantharidic acid contained in the Mylabris aqueous solution under different conditions. The contents of cantharidin and cantharidic acid under different conditions (pH, temperature and light) were determined by HPLC-TQ-MS. The results showed that the content of cantharidin was gradually decreased with the rising of pH value, while on the contrary, the content of cantharidic acid was increased gradually; after Mylabris aqueous solution with different pH values were placed at 25, 40 C and 25 C respectively for lighting for 90 days, the samples were collected for analysis. The results showed the contents of cantharidin and cantharidic acid were changed greatly in the first 10 days, mainly including the decrease of cantharidic acid and increase of cantharidin when the solution was acidic, and the increase of cantharidic acid and decrease of cantharidin when the solution was alkaline. After that, the contents of the above two components basically remained stable. This study revealed that pH was the main factor to affect the contents of cantharidin and cantharidic acid, and they could be converted into each other with the changes of pH value. High temperature and light can accelerate the speed of achieving such balance. The study can provide certain reference for the quality control of the medicines using the Mylabris as raw material. PMID- 28914024 TI - [A new flavonoid with an aryl moiety from Selaginella uncinata]. AB - The present study is to investigate the chemical constituents of the whole plants of Selaginella uncinata. A new flavonoid was isolated from the 75% ethanol extract of Selaginella uncinata by column chromatographies over macroporous resin, silica gel, Sephadex LH-20 and prep-HPLC. The structure was elucidated as 8-[4-(carboxyl)phenoxy]-5,4'-dihydroxy-7-methoxyflavanone (1) and named unciflacone G. PMID- 28914025 TI - [Sesquiterpenoids from aerial parts of Artemisia myriantha]. AB - The present study is to investigate the chemical constituents from the aerial parts of Artemisia myriantha. The chemical constituents were isolated by column chromatographies over silica gel, Sephadex LH-20, ODS and Semi-prep HPLC, and the structures were identified by NMR and MS data. Thirteen known compounds were isolated and identified as: blumenol A (1),(+)-dehydrovomifoliol (2),(+)-3 hydroxy-beta-ionone (3),(3R, 6R, 7E)-3-hydroxy-4, 7-megastigmadien-9-one (4),(-) 10-oxo-isodauc-3-en-15-oic acid (5),isoerivanin (6),eudesmafraglaucolide (7), artanomalide A (8),13-acetoxy-3beta-hydroxy-germacra-1(10) E,4E,7(11)-trien 12,6alpha-olide (9),13-acetoxy-3beta-tigloyl-germacra-1(10) E, 4E, 7(11)-trien 12, 6alpha-olide (10),13-acetoxy-3beta-(3-methylbutanoyl)-germacra-1(10)E, 4E, 7(11)-trien-12, 6alpha-olide (11),3,9-diacetoxy-13-hydroxy-1(10), 4, 7(11) germacratrien-12,6alpha-olide (12), and 8alpha-angeloyloxycostunolide (13). Compounds 1-6 and 13 were obtained from the genus Artemisia for the first time, and 7-9 and 12 were isolated from this plant for the first time. Compound 8 exhibited selective cytotoxicity against human colon cancer (HCT-8) and human gastric cancer (BGC-823) with IC50 values of 2.33 and 4.53 MUmol*L -1, respectively. PMID- 28914026 TI - [Studies on alkaloids from Fissistigma oldhamii]. AB - 14 alkaloids were obtained from stems and leaves of Fissistigma oldhamii, by silica gel, ODS, Sephadex LH-20 column chromatographies, and semi-preparative HPLC. Using physicochemical and spectral methods, the isolated alkaloids were identified as norcepharadione B(1), asimilobine(2), lanuginosine(3), laurotanine(4), isocorydine(5), anolobine(6), xylopine(7), N-methylbuxifoline(8), aristolactam AIIIa(9), piperumbellactam A(10), goniopedaline(11), aristololactam BIII(12), liriodenine(13), and salutaridine(14), respectively. Compounds 3-5, 8, 10, 11 and 14 were isolated from the genus Fissistigma for the first time. PMID- 28914027 TI - [Integrative research of QAMS model used in assay of flavonoids in Epimedii Folium, its processed products and finished Chinese medicines]. AB - Through a series of methodology investigations, we established a new method for simultaneous analysis of epimedins A, B, C, icariin and baohuoside I in Epimedii Folium by using high performance liquid chromatography (HPLC). Meanwhile, using Icariin as an internal reference substance to establish the relative correct factors and relative retention values of Epimedins A, B, C and Baohuoside I to Icariin, then using the quantitative analysis of multi-components by single marker (QAMS) model, the five analytes can be quantitatively determined in Epimedii Folium and its processed products as well as Kanggu Zengsheng capsule only by measuring the content of icariin in the corresponding samples. All these analysis are completed in the same chromatorgraphic conditions. This paper played the part of demonstration role in the popularization and application of QAMS method established in a single herb to the proprietary Chinese medicines containing this herb. PMID- 28914028 TI - [A new method on investigate chemical constituents which have anti-thrombin effect by HPLC]. AB - An in vitro anti-thrombin bioassay was developed to investigate the chemical constituents which have anti-thrombin effect from the water soluble components of Salvia miltiorrhiza. Using Chromozym TH as a probe combined with ethyl acetate Semi-micro extraction was applied to measure p-nitroaniline by HPLC. According to the results, the inactivationrate of thrombin by sodium danshensu, salvianolic acid A and salvianolic acid B under a given set of conditions were 3.06%, 77.77% and 2.35%, respectively. In the water-soluble components, salvianolic acid A has a direct inhibition of thrombin, while sodium danshensu and salvianolic acid B have no significant effect on thrombin. The method is sensitive and low consumption. It can eliminate the interference absorbed for the sample itself which can be used for screening single or multiple direct antithrombin active ingredient of herbal extract. PMID- 28914029 TI - [Polymorphism of shikimic acid]. AB - This study was performed to systematically investigate the polymorphism of shikimic acid. Through optimizing the recrystallization solvent, solvent volume, recrystallization temperature, time and pressure, three crystal forms were discovered and prepared. The differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (PXRD) and infrared spectrometry (IR) were used to characterize these solid states. Furthermore, the influencing factor experiments were used to explore the stability of these polymorphisms and the transformation among them. Three new polymorphisms were prepared and identified. The results indicated that only PXRD could identify different polymorphisms and there was no solvent in all three crystal forms. The composition, thermodynamic property and transformation of these crystal forms were described in this work. Furthermore, an effective method for qualitative analysis of these crystal forms was established. PMID- 28914030 TI - [Preliminary investigation on mechanism of Naoxintong capsule's preventive treatment of cardio-cerebrovascular disease based on serum proteomics]. AB - Naoxintong capsule has beneficial effects for activating blood circulation, dispersing blood stasis and dredging collateral. It is widely used in the treatment of coronary heart disease, angina pectoris, stroke and cardiovascular disease. However, the pharmacodynamic basis and possible mechanism of its preventive effects are not clear. In this study, 10 male and 10 female C57BL/6 mice were used, and were randomly divided into the control group (saline) and Naoxintong group. Adaptively fed for 7 days in common conditions, mice were given Naoxintong capsule or saline for 3 days via intragastric administration. Serum was collected from 6 mice in each group 1 h after the last administration. Serum proteins were prepared to do two-dimensional gel electrophoresis. Then image analysis and mass spectrometry detection were carried out to screen and identify the differentially expressed proteins and make bioinformatics analysis. It was found that 24 differentially expressed proteins between Naoxintong group and control group. Compared with the control group, 12 proteins were increased, and 12 were decreased. The proteins were involved in apoptosis signal pathway and vascular endothelial growth factor signal transduction pathway, in which vasohibin-1 is a negative feedback regulation factor in angiogenesis. Western blot showed that the expression of vasohibin-1 in Naoxintong group was reduced, which is consistent with the result in two-dimensional electrophoresis. Serum proteins expression is different between Naoxintong and control groups. The targets of these differentially expressed proteins include endothelial cells, inflammatory cells and platelets. The changes on proteins showed that Naoxintong capsule may ameliorate coronary heart disease and ischemic cerebrovascular disease, and provide potential biological markers to prevent ischemic disease. PMID- 28914031 TI - [Oxymatrine alleviates oxidative stress in fat-induced insulin resistance mice by suppressing p38MAPK pathway]. AB - This paper was aimed to investigate the effect of oxymatrine on fat-induced insulin resistance mice(IR), and to explore the effects of oxymatrine on oxidative stress and on p38 mitogen activated protein kinase (p38MAPK) pathway. ApoE-/- mice with high fat diet for 16 weeks were selected as IR animal model and randomly divided into the model group, oxymatrine 25, 50, 100 mg*kg-1 group. C57BL/6J mice were selected as the normal control group. Mice were gavage for 8 weeks. Fasting blood glucose (FBG), cholesterol (TC), triglyceride (TG), fatty acid (FFA) and serum insulin (FINS) in the plasma were detected. Activity of superoxide dismutase (SOD), glutathione peroxidase, glutathione peroxidase (GSH Px) and content of malondialdehyde (MDA) in liver were detected. Reactive oxygen species (ROS) content in liver cells were detected by Flow cytometry. The expression of heme oxygenase-1(HO-1), gamma-glutamyl cysteine synthetase (gamma GCS) of liver was examined by Real time PCR and Western blot. The protein expression of p38MAPK, p-p38MAPK was examined by Western blot. In the study, the authors found that oxymatrine reduced the levels of FBG, TC, TG and FFA, increased SOD and GSH-Px contents, decreased MDA and ROS content. Compared with model group, HO-1, gamma-GCS mRNA and protein expression significantly increased in 50, 100 mg*kg-1 oxymatrine group. The expression of p-p38MAPK decreased in oxymatrine group. The results showed that oxymatrine alleviate oxidative stress in hepatic by inhibiting the phosphorylation of p38MAPK, to ameliorate fat induced insulin resistance mice. PMID- 28914032 TI - [Effect of hyperforin on learning and memory abilities and Abeta1-42, betaAPP and BACE1 protein expressions in hippocampus of Alzheimer's disease model mice]. AB - To investigate the effect of the hyperforin (HF) on learning and memory function and Abeta1-42, betaAPP and BACE1 protein expressions in hippocampus of five-month old APP/PS1 double transgenic mice, and discuss the underlying mechanism of HF. The five-month-old APP/PS1 double transgenic mice were randomly divided into the model group, rosiglitazone group (12 mg*kg-1*d-1) and HF high dose, middle dose and low dose groups (600, 300 and 150 mg*kg-1*d-1) in each group; in addition, 15C57BL/6J mice with the same months and background were selected as normal group. Drugs were diluted in the same volume before using, and then administrated by ig for 7 months, 1 time a day; the mice in normal group and model group received the same volume of distilled water. The learning and memory ability was tested by Morris water maze; Abeta1-42, betaAPP and BACE1proteinexpressionlevelswere tested by immunohistochemistry and Western blot. The Morris water maze results showed that as compared with the normal group, the learning and memory ability was significantly impaired in mice of model group (P<0.01); as compared with the model group, the learning and memory ability was improved in mice of rosiglitazone group and HF high, middle and low dose groups(P<0.01 or P<0.05). Immunohistochemistry and western blot results showed thatas compared with the normal group, the Abeta1-42, betaAPP and BACE1 protein expression levels in hippocampus were significantly increased in mice of model group (P<0.01);as compared with the model group, Abeta1-42, betaAPP and BACE1 protein expression levels in hippocampus were decreased in mice of rosiglitazone group and HF high, middle and low dose groups (P<0.01 or P<0.05). HF may improve the learning and memory ability of AD model mice via inhibition of betaAPP and BACE1 protein expressions, thus reduced the generation of Abeta1-42 proteins and amyloid plaque deposits in the brain. PMID- 28914033 TI - [Effect of turmeric volatile oil on proliferation and apoptosis of human skin SCC A431 cells]. AB - To investigate the effect of turmeric volatile oil (TVO) on the apoptosis and proliferation of human skin SCC A431 cells, A431 cells were incubated with different concentrations (5-80 mg*L-1) of TVO in vitro.The proliferation and cell cycle were assessed by CCK8 assay. The change of morphology was observed with inverted microscope. Apoptosis was evaluated with AO/EB double staining and flow cytometry (FCM); cell cycle was analyzed with FCM .Western blot method was used to detect caspase-3 and caspase-9 protein expression. Results indicated that TVO has significant inhibitory effects on the growth of A431 cells in a dose dependent relationship, the difference between groups has statistically significant (P<0.05). TVO group compared with control group, concentrations in cells shrivel and broken phenomenon, cell apoptosis rate increased, and a dose dependent and increased the expression of caspase-3 and caspase-9. The experiment results suggested that TVO could restrain skin squamous carcinoma A431 cells proliferation, and induce its apoptosis. The mechanism may be related to increase the expression of caspase-3 and caspase-9. PMID- 28914034 TI - [Effects of serums containing Buzhong Yiqi decoction with Astragalus Radix or Hedysari Radix on anti-immunosenescence in spleen lymphocytes of SAMP8 mice]. AB - This paper was aimed to compare the effect of Buzhong Yiqi decoction containing Hedysari Radix or Astragali Radix on anti-immunosenescence effects in spleen lymphocytes of senescence accelerated mouse 8 (SAMP8). The effect of the serums on the proliferation of spleen T lymphocytes in SAMP8 mice induced by ConA was tested by MTT. The effect of the serums on the T lymphocytes subsets of SAMP8 mice was measured by flow cytometry. ELISA was used to detect the level of IL-2 and IFN-gamma in the culture supernatants of spleen lymphocytes. The effect of the serums on the expression of CD28 mRNA in spleen T lymphocytes was detected by fluorescent quantitative PCR. Western blot was used to detect the expression of CD28 protein in spleen T lymphocytes of SAMP8 mice. Both the serums of Buzhong Yiqi decoctions containing Hedysari Radix or Astragali Radix improved the proliferation of T lymphocytes in SAMP8 mice. Both the serums had no obvious effect on the differentiation of spleen T lymphocytes'subsets in SAMP8 mice. Both the serums increased the content of IL-2 and INF-gamma in the culture supernatants of spleen lymphocytes. And for the content of IL-2, the serum of Buzhong Yiqi decoction with Hedysari Radix was better(P<0.05). Both the serums improved the expression of CD28 mRNA in spleen T lymphocytes of SAMP8 mice. And the effect of Hedysari Radix group was better than that of Astragalus Radix group(P<0.05). Both the serums improved the expression of CD28 protein in spleen T lymphocytes of SAMP8 mice. The role of the serums containing Buzhong Yiqi decoction with Astragalus Radix and the decoction with Hedysari Radix in anti immunosenescence was through the effect of the CD28. And the effect of Hedysari Radix group was better than that of Astragalus Radix group on improved the expression of CD28 mRNA in T lymphocytes of SAMP8 mice. Astragalus Radix and Hedysari Radix could swap in the aspect of anti-immunosenescence. PMID- 28914035 TI - [Effects of extractionfrom raspberry on hippocampus proteomics of mice suffered from ovariectomized-induced AD]. AB - This paper was aimed to investigate the impact of the extraction from raspberry on the Alzheimer disease model protein expression. According to weight, the ovariectomized mice were randomly divided into shame operation group, model group, estrogen positive control group(0.1 g*L-1) and ethyl acetate extraction part control group(in dose of 18 g*kg-1). Each mouse in positive control group was subcutaneous injected of estradiol with 0.2 mL every two days. Raspberry effective parts group were given 0.01 mL*g-1 raspberry ethylacetate extracts, model group and control group were given 0.01 mL*g-1 saline once a day. The drug administration lasted for 32 days. Proteins from mice's hippocampus were extracted, then Nanol-ESI liquid-mass spectrometry system was used for detection and ProteinDiscovery software was used for identification to qualitative analysis different groups of hippocampal proteins by using the software of SIEVE. The results showed that model group compared with the mice of ethyl acetate extraction part control group have 66 differentially expressed proteins including heat shock protein, microtubule protein, protein involved in energy metabolism and protein of brain protection related proteins associated with AD. Those differences protein may be the target that Raspberry prevention and treatment of AD. PMID- 28914036 TI - [Chinmedomics strategy to discover effective constituents and elucidate action mechanism of Nanshi capsule against kidney-yang deficiency syndrome]. AB - The chinmedomics method was used to explore the effect of Nanshi capsule on endogenous metabolites of rats with kidney-yang deficiency syndrome, investigate the metabolites and metabolic pathways closely related to kidney-yang deficiency syndrome (KYDS)and identify the therapeutic basis of Nanshi capsule(NPC)as well as its action mechanism for KYDS. The routine biochemical indexes of serum were detected and histomorphology was observed. Based on the chinmedomics technology platform, discriminatory analysis in multivariate modes was conducted for rat blood and urine, thus to investigate the biomarkers of KYDS and the therapeutic effect of NPC against KYDS. Meanwhile, the main constituents of NPC in rat serum were also detected to analyze its correlation between the constituents in vivo and the biomarkers of KYDS, and determine the potential effective compounds for therapeutic effect. Eleven biomarkers of KYDS were identified in the rat models, involving steroid hormone biosynthesis, tryptophan metabolism and tyrosine metabolism. It was found that NPC could regulate steroid hormone biosynthesis, tryptophan metabolism and tyrosine metabolism; PCMS analysis showed that caffeic acid, 2-hydroxy-1-methoxy-anthraquinone, 1-hydroxy-2-methoxyanthraquinone, ferulic acid glucuronide conjugation, deacetylasperulosidic acid, cynaroside, betaine and umbelliferone were the main effective compounds of NPC for KYDS. In this study, cynaroside, betaine, umbelliferone and other compounds in NPC could integrally regulate the disturbance of metabolic profile in KYDS by improving the hormone synthesis, hormone synthesis pathway, hormone synthesis and release pathway in tyrosine metabolism and linoleic acid synthesis pathway in linoleic acid metabolism. These results indicated that the NPC had the characteristics of multi-pathway, multi-target and overall regulation in the treatment of KYDS. Chinmedomics approach can provide methodology support to discover innovative drug from traditional Chinese medicine. PMID- 28914037 TI - [Preliminary study on effective components of Tripterygium wilfordii for liver toxicity based on spectrum-effect correlation analysis]. AB - In this paper, the spectrum-effect correlation analysis method was used to explore the main effective components of Tripterygium wilfordii for liver toxicity, and provide reference for promoting the quality control of T. wilfordii. Chinese medicine T.wilfordii was taken as the study object, and LC-Q TOF-MS was used to characterize the chemical components in T. wilfordii samples from different areas, and their main components were initially identified after referring to the literature. With the normal human hepatocytes (LO2 cell line)as the carrier, acetaminophen as positive medicine, and cell inhibition rate as testing index, the simple correlation analysis and multivariate linear correlation analysis methods were used to screen the main components of T. wilfordii for liver toxicity. As a result, 10 kinds of main components were identified, and the spectrum-effect correlation analysis showed that triptolide may be the toxic component, which was consistent with previous results of traditional literature. Meanwhile it was found that tripterine and demethylzeylasteral may greatly contribute to liver toxicity in multivariate linear correlation analysis. T. wilfordii samples of different varieties or different origins showed large difference in quality, and the T. wilfordii from southwest China showed lower liver toxicity, while those from Hunan and Anhui province showed higher liver toxicity. This study will provide data support for further rational use of T. wilfordii and research on its liver toxicity ingredients. PMID- 28914038 TI - [Absorption mechanism of neobavaisoflavone in Caco-2 cell monolayer mode]. AB - Neobavaisoflavone is one of flavonoids of traditional Chinese medicine Psoralea corylifolial. It has numerous biological properties such as antibacterial, anti inflammatory, anti-cancer, and anti-osteoporosis effects. This paper aimed to investigate the absorption mechanism of neobavaisoflavone in Caco-2 cell monolayer model. The analyte and osalmide were separated on Thermo Syncronis C18 column with methanol-0.1% formic acid solution (90?10) as the mobile phase, at a flow rate of 0.2 mL*min-1. The concentration of neobavaisoflavone was determined in eletrospray ionization(ESI) positive ion mode with osalmide as an the internal standard. The effects of time, concentration, P-gp inhibitor verapamil, MRP-2 inhibitor MK-571 and BCRP inhibitor Ko143 on the absorption of neobavaisoflavone were investigated. According to the results, neobavaisoflavone showed a good linearity within the concentration of 10-2 000 MUg*L-1, and the results of its specificity, matrix effect, extraction recovery, precision, accuracy and stability all met the requirements. In the Caco-2 cell monolayer model, the transport volume of neobavaisoflavone was correlated positively with the time and concentration. The ER values of 15, 30, 50 MUmol*L-1 neobavaisoflavone were 1.64, 1.94,0.99, respectively. As compared with the control group, all of verapamil hyduochloride, MK-571 and Ko143 could promote the transportation of neobavaisoflavone, and the effect was more obvious in verapamil hyduochloride and Ko143. The absorption of neobavaisoflavone may be mainly of active transport in Caco-2 cell monolayer model, and also involve passive transport. Excretion mechanism of intestinal transport protein may be also involved. PMID- 28914039 TI - [Research on application status of Chinese herbal decoction pieces based on clinical survey]. AB - Chinese herbal decoction pieces are the basic approaches for clinical traditional Chinese medicine (TCM), reflecting the features and advantages of TCM. In order to investigate the clinical application status and features of Chinese herbal decoction pieces, the questionnaire on application of commonly used Chinese herbal decoction pieces was designed in this study for analysis of the application situations of Chinese herbal decoction pieces from 56 medical institutions in 10 provinces. The results showed 549 varieties of Chinese herbs and 801 varieties of decoction pieces were used on clinic. They can be classified into 19 categories according to their effects. The varieties of Gancao (Glycyrrhizae Radix et Rhizoma), Huangqi (Astragali Radix), Dihuang (Rehmanniae Radix), Chuanxiong (Chuanxiong Rhizoma), Baizhu (Atractylodis Macrocephale Rhizima), Huangqin (Scutellariae Radix), Danggui (Angelicae Sinenses Radix), Baishao (Paeoniae Radix Alba) and Maidong (Ophiopogonis Radix) were most common ones; the application of Chinese herbal decoction pieces from different medical institutions was differentiated from areas to areas. The survey results reflected the general situation about application of decoction pieces, providing the basic data for recording and completing Chinese herbal decoction pieces in essential drug system, with certain reference significance for the production of Chinese medicinal materials and the allocation of the varieties of Chinese herbal decoction pieces. PMID- 28914040 TI - [Prescription rules of preparations containing Crataegi Fructus in Chinese patent drug]. AB - To analyze the prescription rules of preparations containing Crataegi Fructus in the drug standards of the People's Republic of China Ministry of Public Health Chinese Patent Drug(hereinafter referred to as Chinese patent drug), and provide some references for clinical application and the research and development of new medicines. Based on TCMISS(V2.5), the prescriptions containing Crataegi Fructus in Chinese patent drug were collected to build the database; association rules, frequency statistics and other data mining methods were used to analyze the disease syndrome, common drug compatibility and prescription rules. There were a total of 308 prescriptions containing Crataegi Fructus, involving 499 kinds of Chinese medicines, 34 commonly used drug combinations, and mainly for 18 kinds of diseases. Drug combination analysis was done with "Crataegi Fructus-Citri Reticulatae Pericarpium" and "Crataegi Fructus-Poria" as the high-frequency herb pairs and with "stagnation" and "diarrhea" as the high-frequency diseases. The results indicated that the Crataegi Fructus in different herb pairs had a roughly same function, and its therapy effect was different in different diseases. The prescriptions containing Crataegi Fructus in Chinese patent drug had the effect of digestion, and they were widely used in clinical application, often used together with spleen-strengthening medicines to achieve different treatment effects; the prescription rules reflected the prescription characteristics of Crataegi Fructus for different diseases, providing a basis for its clinically scientific application and the research and development of new medicines. PMID- 28914041 TI - [Research on problem of exogenous pollution of Chinese medicine resources from perspective of circular economy]. AB - Based on the in-depth analysis of the current situation of the exogenous pollution of Chinese medicine resources, this research mainly discusses the intrinsic link and practical significance between the development of circular economy in Chinese medicine resources and the control of the problem of the exogenous pollution from the perspective of circular economy, and proposes some suggestions to develop the recycling economy of Chinese medicine resources from the establishment of legal system, mechanism of development, production norms, industry standards and regulatory system of the recycling of Chinese medicine resources. PMID- 28914042 TI - Meeting of the International Task Force for Disease Eradication, June 2017. PMID- 28914043 TI - Decrease in size and activity of parathyroid adenoma after ultrasound guided biopsy. PMID- 28914044 TI - How many patients with TIR3 FNA really have a thyroid neoplasm? PMID- 28914045 TI - Electron Transfer from Bi-Isonicotinic Acid Emerges upon Photodegradation of N3 Sensitized TiO2 Electrodes. AB - The long-term stability of dye-sensitized solar cells (DSSCs) is determined to a large extent by the photodegradation of their sensitizers. Understanding the mechanism of light-induced decomposition of dyes sensitizing a mesoporous oxide matrix may therefore contribute to solutions to increase the life span of DSSCs. Here, we investigate, using ultrafast terahertz photoconductivity measurements, the evolution of interfacial electron-transfer (ET) dynamics in Ru(4,4' dicarboxylic acid-2,2'-bipyridine)2(NCS)2 (N3) dye-sensitized mesoporous TiO2 electrodes upon dye photodegradation. Under inert environment, interfacial ET dynamics do not change over time, indicating that the dye is stable and photodegradation is absent; the associated ET dynamics are characterized by a sub 100 fs rise of the photoconductivity, followed by long-lived (?1 ns) electrons in the oxide electrode. When the N3-TiO2 sample is exposed to air under identical illumination conditions, dye photodegradation is evident from the disappearance of the optical absorption associated with the dye. Remarkably, approximately half of the sub-100 fs ET is observed to still occur but is followed by very rapid (~10 ps) electron-hole recombination. Laser desorption/ionization mass spectrometry, attenuated total reflection-Fourier transform infrared, and terahertz photoconductivity analyses reveal that the photodegraded ET signal originates from the N3 dye photodegradation product as bi-isonicotinic acid (4,4' dicarboxylic acid-2,2'-bipyridine), which remains bonded to the TiO2 surface via either bidentate chelation or bridging-type geometry. PMID- 28914046 TI - Synergistic Effect of Polypyrrole-Intercalated Graphene for Enhanced Corrosion Protection of Aqueous Coating in 3.5% NaCl Solution. AB - Dispersion of graphene in water and its incorporation into waterborne resin have been rarely researched and hardly achieved owing to its hydrophobicity. Furthermore, it has largely been reported that graphene with impermeability contributed to the improved anticorrosion property. Here, we show that highly concentrated graphene aqueous solution up to 5 mg/mL can be obtained by synthesizing hydrophilic polypyrrole (PPy) nanocolloids as intercalators and ultrasonic vibration. On the basis of pi-pi interaction between PPy and graphene, stacked graphene sheets are exfoliated to the thickness of three to five layers without increasing defects. The corrosion performance of coatings without and with PPy and graphene is obtained by potential and impedance measurements, Tafel curves, and fitted pore resistance by immersing in a 3.5 wt % NaCl solution. It turns out that composite coating with 0.5 wt % graphene additive exhibits superior anticorrosive ability. The mechanism of intercalated graphene-based coating is interpreted as the synergistic protection of impermeable graphene sheets and self-healing PPy and proved by the identification of corrosion products and the scanning vibrating electrode technique. PMID- 28914047 TI - Light-Triggered CO2 Breathing Foam via Nonsurfactant High Internal Phase Emulsion. AB - Solid materials for CO2 capture and storage have attracted enormous attention for gaseous separation, environmental protection, and climate governance. However, their preparation and recovery meet the problems of high energy and financial cost. Herein, a controllable CO2 capture and storage process is accomplished in an emulsion-templated polymer foam, in which CO2 is breathed-in under dark and breathed-out under light illumination. Such a process is likely to become a relay of natural CO2 capture by plants that on the contrary breathe out CO2 at night. Recyclable CO2 capture at room temperature and release under light irradiation guarantee its convenient and cost-effective regeneration in industry. Furthermore, CO2 mixed with CH4 is successfully separated through this reversible breathing in and out system, which offers great promise for CO2 enrichment and practical methane purification. PMID- 28914048 TI - Impacts of Pb and SO2 Poisoning on CeO2-WO3/TiO2-SiO2 SCR Catalyst. AB - A CeO2-WO3/TiO2-SiO2 catalyst was employed to investigate the poisoning mechanisms of Pb and SO2 during selective catalytic reduction (SCR). The introduction of Pb and SO2 suppressed the catalytic performance by decreasing the numbers of surface acid and redox sites. Specifically, Pb preferentially bonded with amorphous WO3 species rather than with CeO2, decreasing the numbers of both Lewis and Bronsted acid sites but exerting less influence on the reducibility. SO2 preferentially bonded with CeO2 as sulfate species rather than with WO3, leading to a significant decrease in reducibility and the loss of surface active oxygen groups. Although SO2 provided additional Bronsted acid sites via the interaction of SO42- and CeO2, it had little positive effect on catalytic activity. A synergistic deactivation effect of Pb and SO42- on CeO2 was found. Pb covered portions of the weakly bonded catalyst sites poisoned by SO42-, which increased the decomposition temperature of the sulfate species on the catalyst. PMID- 28914049 TI - Polarization-Dependent Photoinduced Bias-Stress Effect in Single-Crystal Organic Field-Effect Transistors. AB - Photoinduced charge transfer between semiconductors and gate dielectrics can occur in organic field-effect transistors (OFETs) operating under illumination, leading to a pronounced bias-stress effect in devices that are normally stable while operating in the dark. Here, we report an observation of a polarization dependent photoinduced bias-stress effect in two prototypical single-crystal OFETs, based on rubrene and tetraphenylbis(indolo{1,2-a})quinolin. We find that the decay rate of the source-drain current in these OFETs under illumination is a periodic function of the polarization angle of incident photoexcitation with respect to the crystal axes, with a periodicity of pi. The angular positions of maxima and minima of the bias-stress rate match those of the optical absorption coefficient of the corresponding crystals. The analysis of the effect shows that it stems from a charge transfer of "hot" holes, photogenerated in the crystal within a very short thermalization length (?MUm) from the semiconductor dielectric interface. The observed phenomenon is a type of intrinsic structure property relationship, revealing how molecular packing affects parameter drift in organic transistors under illumination. We also demonstrate that a photoinduced charge transfer in OFETs can be used for recording rewritable accumulation channels with an optically defined geometry and resolution, which can be used in a number of potential applications. PMID- 28914050 TI - Boric Acid as an Efficient Agent for the Control of Polydopamine Self-Assembly and Surface Properties. AB - The deposition of polydopamine (PDA) films on surfaces, a versatile deposition method with respect to the nature of the used substrate, is unfortunately accompanied by deposition of insoluble precipitates in solution after a prolonged oxidation time of dopamine solutions. Therefore, there is evident interest to find methods able to stop the deposition of PDA on surfaces and to simultaneously control the self-assembly of PDA in solution to get stable colloidal aggregates. In addition to proposed methods relying on the use of polymers like poly(vinyl alcohol) and proteins like human serum albumin, we show herein that boric acid is an efficient adjuvant that is simultaneously able to stop the self-assembly of PDA in solution as well as on surfaces and to change the adhesive properties of the resulting PDA coatings. PMID- 28914051 TI - Chromosome-Centric Human Proteome Project Allies with Developmental Biology: A Case Study of the Role of Y Chromosome Genes in Organ Development. AB - One of the main goals of Chromosome-Centric Human Proteome Project is to identify protein evidence for missing proteins (MPs). Here, we present a case study of the role of Y chromosome genes in organ development and how to overcome the challenges facing MPs identification by employing human pluripotent stem cell differentiation into cells of different organs yielding unprecedented biological insight into adult silenced proteins. Y chromosome is a male-specific sex chromosome which escapes meiotic recombination. From an evolutionary perspective, Y chromosome has preserved 3% of ancestral genes compared to 98% preservation of the X chromosome based on Ohno's law. Male specific region of Y chromosome (MSY) contains genes that contribute to central dogma and govern the expression of various targets throughout the genome. One of the most well-known functions of MSY genes is to decide the male-specific characteristics including sex, testis formation, and spermatogenesis, which are majorly formed by ampliconic gene families. Beyond its role in sex-specific gonad development, MSY genes in coexpression with their X counterparts, as single copy and broadly expressed genes, inhibit haplolethality and play a key role in embryogenesis. The role of X Y related gene mutations in the development of hereditary syndromes suggests an essential contribution of sex chromosome genes to development. MSY genes, solely and independent of their X counterparts and/or in association with sex hormones, have a considerable impact on organ development. In this Review, we present major recent findings on the contribution of MSY genes to gonad formation, spermatogenesis, and the brain, heart, and kidney development and discuss how Y chromosome proteome project may exploit developmental biology to find missing proteins. PMID- 28914052 TI - CO2 Plasma-Treated TiO2 Film as an Effective Electron Transport Layer for High Performance Planar Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) have received great attention because of their excellent photovoltaic properties especially for the comparable efficiency to silicon solar cells. The electron transport layer (ETL) is regarded as a crucial medium in transporting electrons and blocking holes for PSCs. In this study, CO2 plasma generated by plasma-enhanced chemical vapor deposition (PECVD) was introduced to modify the TiO2 ETL. The results indicated that the CO2 plasma treated compact TiO2 layer exhibited better surface hydrophilicity, higher conductivity, and lower bulk defect state density in comparison with the pristine TiO2 film. The quality of the stoichiometric TiO2 structure was improved, and the concentration of oxygen-deficiency-induced defect sites was reduced significantly after CO2 plasma treatment for 90 s. The PSCs with the TiO2 film treated by CO2 plasma for 90 s exhibited simultaneously improved short-circuit current (JSC) and fill factor. As a result, the PSC-based TiO2 ETL with CO2 plasma treatment affords a power conversion efficiency of 15.39%, outperforming that based on pristine TiO2 (13.54%). These results indicate that the plasma treatment by the PECVD method is an effective approach to modify the ETL for high-performance planar PSCs. PMID- 28914053 TI - Construction of Functional Coatings with Durable and Broad-Spectrum Antibacterial Potential Based on Mussel-Inspired Dendritic Polyglycerol and in Situ-Formed Copper Nanoparticles. AB - A novel surface coating with durable broad-spectrum antibacterial ability was prepared based on mussel-inspired dendritic polyglycerol (MI-dPG) embedded with copper nanoparticles (Cu NPs). The functional surface coating is fabricated via a facile dip-coating process followed by in situ reduction of copper ions with a MI dPG coating to introduce Cu NPs into the coating matrix. This coating has been demonstrated to possess efficient long-term antibacterial properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and kanamycin resistant E. coli through an "attract-kill-release" strategy. The synergistic antibacterial activity of the coating was shown by the combination of two functions of the contact killing, reactive oxygen species production and Cu ions released from the coating. Furthermore, this coating inhibited biofilm formation and showed good compatibility to eukaryotic cells. Thus, this newly developed Cu NP-incorporated MI-dPG surface coating may find potential application in the design of antimicrobial coating, such as implantable devices. PMID- 28914054 TI - Total Synthesis of Glycinocins A-C. AB - The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics structurally related to the clinically approved daptomycin. Herein, we describe a divergent total synthesis of glycinocins A-C, which differ in the structure of a branched alpha,beta-unsaturated fatty acyl moiety. The three natural products exhibited calcium-dependent antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MICs ranging from 5.5 to 17 MUM. PMID- 28914055 TI - Two-Dimensional Graphene-Gold Interfaces Serve as Robust Templates for Dielectric Capacitors. AB - The electronic structures of novel heterostructures, namely, graphene-Au van der Waals (vdW) interfaces, have been studied using density functional theory. Dispersion-corrected PBE-D2 functionals are used to describe the phonon spectrum and binding energies. Ab initio molecular dynamics simulations reveal that the vdW framework is preserved till 1200 K. Beyond T = 1200 K, a transition of the quasiplanar Au into the three-dimensional cluster-like structure is observed. A dielectric capacitor is designed by placing 1-4 hexagonal boron nitride (h-BN) monolayers between graphene and Au conductive plates. Charge separation between the Au and graphene plates is carried out under the effect of an external field normal to the graphene-h-BN-Au interface. The gravimetric capacitances are computed as C1 = 7.6 MUF/g and C2 = 3.2 MUF/g for h-BN bilayers with the Au graphene heterostructures. The capacitive behavior shows strong deviations from the classical charging models and exemplifies the importance of quantum phenomenon at short contacts, which eventually nullifies at large interelectrode distances. The graphene-Au interface is predicted to be an exciting vdW heterostructure with a potential application as a dielectric capacitor. PMID- 28914056 TI - Effect of the Composition and Structure of Excipient Emulsion on the Bioaccessibility of Pesticide Residue in Agricultural Products. AB - The influence of co-ingestion of food emulsions with tomatoes on the bioaccessibility of a model pesticide (chlorpyrifos) was studied. Emulsions were fabricated with different oil contents (0-8%), lipid compositions (medium chain triglyceride (MCT) and corn oil), and particle diameters (d32 = 0.17 and 10 MUm). The emulsions were then mixed with chlorpyrifos-contaminated tomato puree, and the mixtures were subjected to a simulated gastrointestinal tract (GIT) consisting of mouth, stomach, and small intestine. The particle size, surface charge, and microstructure of the emulsions was measured as they passed through the GIT, and chlorpyrifos bioaccessibility was determined after digestion. The composition and structure of the emulsions had a significant impact on chlorpyrifos bioaccessibility. Bioaccessibility increased with increasing oil content and was higher for corn oil than MCT, but did not strongly depend on oil droplet size. These results suggest that co-ingestion of emulsions with fruits or vegetables could increase pesticide bioaccessibility. PMID- 28914057 TI - Tight-Binding Quantum Chemical Molecular Dynamics Study on the Friction and Wear Processes of Diamond-Like Carbon Coatings: Effect of Tensile Stress. AB - Diamond-like carbon (DLC) coatings have attracted much attention as an excellent solid lubricant due to their low-friction properties. However, wear is still a problem for the durability of DLC coatings. Tensile stress on the surface of DLC coatings has an important effect on the wear behavior during friction. To improve the tribological properties of DLC coatings, we investigate the friction process and wear mechanism under various tensile stresses by using our tight-binding quantum chemical molecular dynamics method. We observe the formation of C-C bonds between two DLC substrates under high tensile stress during friction, leading to a high friction coefficient. Furthermore, under high tensile stress, C-C bond dissociation in the DLC substrates is observed during friction, indicating the atomic-level wear. These dissociations of C-C bonds are caused by the transfer of surface hydrogen atoms during friction. This work provides atomic-scale insights into the friction process and the wear mechanism of DLC coatings during friction under tensile stress. PMID- 28914058 TI - Delayed Triplet-State Formation through Hybrid Charge Transfer Exciton at Copper Phthalocyanine/GaAs Heterojunction. AB - Light absorption in organic molecules on an inorganic substrate and subsequent electron transfer to the substrate create so-called hybrid charge transfer exciton (HCTE). The relaxation process of the HCTE states largely determines charge separation efficiency or optoelectronic device performance. Here, the study on energy and time-dispersive behavior of photoelectrons at the hybrid interface of copper phthalocyanine (CuPc)/p-GaAs(001) upon light excitation of GaAs reveals a clear pathway for HCTE relaxation and delayed triplet-state formation. According to the ground-state energy level alignment at the interface, CuPc/p-GaAs(001) shows initially fast hole injection from GaAs to CuPc. Thus, the electrons in GaAs and holes in CuPc form an unusual HCTE state manifold. Subsequent electron transfer from GaAs to CuPc generates the formation of the triplet state in CuPc with a few picoseconds delay. Such two-step charge transfer causes delayed triplet-state formation without singlet excitation and subsequent intersystem crossing within the CuPc molecules. PMID- 28914059 TI - Physiochemical Characteristics and Molecular Structures for Digestible Carbohydrates of Silages. AB - The main objectives of this study were (1) to assess the magnitude of differences among new barley silage varieties (BS) selected for varying rates of in vitro neutral detergent fiber (NDF) digestibility (ivNDFD; Cowboy BS with higher ivNDFD, Copeland BS with intermediate ivNDFD, and Xena BS with lower ivNDFD) with regard to their carbohydrate (CHO) molecular makeup, CHO chemical fractions, and rumen degradability in dairy cows in comparison with a new corn silage hybrid (Pioneer 7213R) and (2) to quantify the strength and pattern of association between the molecular structures and digestibility of carbohydrates. The carbohydrate-related molecular structure spectral data was measured using advanced vibrational molecular spectroscopy (FT/IR). In comparison to BS, corn silage showed a significantly (P < 0.05) higher level of starch and energy content and higher degradation of dry matter (DM). Cowboy BS had lower feeding value (higher indigestible fiber content and lower starch content) and lower DM degradation in the rumen compared to other BS varieties (P < 0.05). The spectral intensities of carbohydrates were significantly (P < 0.05) correlated with digestible carbohydrate content of the silages. In conclusion, the univariate approach with only one-factor consideration (ivNDFD) might not be a satisfactory method for evaluating and ranking BS quality. FT/IR molecular spectroscopy can be used to evaluate silage quality rapidly, particularly the digestible fiber content. PMID- 28914060 TI - Nuclear Spin Symmetry Conservation in 1H216O Investigated by Direct Absorption FTIR Spectroscopy of Water Vapor Cooled Down in Supersonic Expansion. AB - We report the results of an experimental study related to the relaxation of the nuclear spin isomers of the water molecule in a supersonic expansion. Rovibrational lines of both ortho and para spin isomers were recorded in the spectral range of H2O stretching vibrations at around 3700 cm-1 using FTIR direct absorption. Water vapor seeded in argon, helium, or oxygen or in a mixture of oxygen and argon was expanded into vacuum through a slit nozzle. The water vapor partial pressure in the mixture varied over a wide range from 1.5 to 102.7 hPa, corresponding to a water molar fraction varying between 0.2 and 6.5%. Depending on expansion conditions, the effect of water vapor clustering was clearly seen in some of our measured spectra. The Boltzmann plot of the line intensities allowed the H2O rotational temperatures in the isentropic core and in the lateral shear layer probed zones of the planar expansion to be determined. The study of the OPR, i.e., the ratio of the ortho to para absorption line intensities as a function of Trot, did not reveal any signs of the OPR being relaxed to the sample temperature. In contrast, the OPR was always conserved according to the stagnation reservoir equilibrium temperature. The conservation of the OPR was found irrespective of whether water molecule clustering was pronounced or not. Also, no effect of the paramagnetic oxygen admixture enhancing OPR relaxation was observed. PMID- 28914061 TI - Mobile applications as good intervention tools for individuals with depression. AB - At present mental disorders affect approximately 450 million people around the world. Depressive disorder is probably one of the most serious disorders and as a type of chronic disease, it represents a global threat and burdens economic and social systems of both individuals and governments worldwide. One of these most recent non-pharmacological approaches is also the so-called mHealth (mobile health), the use of mobile devices for the practice of medicine and public health, which proves to be effective particularly in the early stages of depression. The purpose of this article is to explore the most recent randomized controlled trial studies which indicate efficacy of the use of mobile applications in the detection, diagnostics or treatment of depression. The methods used in this study include a method of literature search of the studies focused on the impacts of individual applications for people with depression and on the specification of criteria evaluating quality of these applications. The findings of the randomized controlled trials (RCT) show that there is a big potential of mobile applications in the detection, diagnostics, and treatment of depression, particularly in mild and moderate stages of the disease. They seem to be especially relevant for self-monitoring of depressive symptoms in the early stages of depression. There is an urgent need of more longitudinal RCT in this field in order to prove conclusive efficacy of these mobile applications in the treatment of depression. The authors list the main strengths and weaknesses of mobile applications in the detection, diagnostics, and treatment of depression.Key words: mobile applications depression treatment. PMID- 28914062 TI - [Separation of phenylalanine and methionine enantiomers by HPLC method: a comparison of stationary phase types]. AB - The paper deals with enantioselective separation of amino acids by the high performance liquid chromatography method. Separations of enantiomeric forms were tested on the chiral stationary phases based on beta-cyclodextrine, isopropyl carbamate cyclofructan 6, and the macrocyclic antibiotic teicoplanin. The best enantioseparation was obtained on the teicoplanin-based chiral stationary phase in the reversed-phase mode. UV spectrophotometric detection at 210 nm was used for detection of amino acids. The method was validated with respect to linearity, precision, limit of detection, limit of quantitation, and recovery. Limits of quantitation for phenylalanine and methionine enantiomers were 0.3 and 0.2 ug.ml 1, respectively. The HPLC method with teicoplanin-based chiral stationary phase was applied for analysis of dietary supplements.Key words: separation of enantiomers HPLC phenylalanine methionine. PMID- 28914063 TI - Identifying the interprofessional agreement between community pharmacists and general practitioners views on collaborative practice in Slovakia. AB - BACKGROUND: The collaboration of community pharmacists (CPs) and general practitioners (GPs) has a positive effect on healthcare outcomes. There are still many countries, where no efforts have been made to enhance this type of teamwork. There is no evidence of how GPs and CPs collaborate in Slovakia. The objective of this study is to identify the current level of GPs and CPs teamwork in Slovakia and to identify the key factors, where these professions agree. METHODS: Two parallel electronic surveys were prepared and sent out by e-mail to CPs and GPs in Slovakia. The questions in the multi-choice questionnaires were divided into 6 sections: teamwork experience, attitudes to collaborative practice, preferred method of communication, preferred tasks done by CPs, anticipated areas of future collaboration and perceived barriers to collaborative practice. The results were analyzed separately by the proportion of agreements within each group. RESULTS: From the total of 670 questionnaires, which were sent out (434 to GPs and 236 to CPs) 347 were completed and returned by GPs (79.95%) and 181 by CPs (76.7%). The overall response rate was 78.33%. The perfect match of agreements between the CPs and the GPs answers was identified in: their preference to collaborate face-to face (p = 0.0001) perception of the role of the community pharmacist (p < 0.0001) barriers to collaboration (p < 0.0001) areas for future collaboration (p = 0.0468) The majority of respondents confirmed (without proportional agreement) that their collaboration improves patient outcomes (71.3% of CPs, 60.5% of GPs), however, only 15.5% CPs and 17.6% GPs indicated, that they would consider team working in the future. CONCLUSION: The responding health professionals agreed about the current role of CPs in Slovakia. Both professions reported their willingness to collaborate in the following areas: 1. patient counselling and 2. patient adherence improvement. Face-to-face communication was preferred by both groups of respondents, as a potential key factor to improve their relationships (general trust). However, in order to create a sustainable collaborative environment, the identified barriers need to be taken into account.Key words: agreement barriers collaboration community pharmacist general practitioner. PMID- 28914064 TI - [Targeted drug delivery system: potential application to resveratrol]. AB - Drug delivery system (DDS) is intended to increasing effectiveness of drugs through targeted distribution and to reducing of unwanted effects. In this mini review, the basic principles of nanotechnology that were developed for DDS were reported including sections on the present research in key areas that are important for future investigations. Attention is paid on resveratrol as a model phytochemical with interesting pharmacologic profile which was demonstrated in great numbers of studies and for its wide use as supplemental therapy. Due to complicated pharmacokinetic profile of resveratrol that is characterized by very low bioavailability in spite of high oral absorption, the effects of resveratrol is being studied in new nanotechnology preparations of pharmaceutical formulation. Herein we report on results of present in vitro and in vivo investigations with resveratrol in new types of drug formulations using different nanoparticles as liposomes, solid lipid particles, cyclodextrins and micelles.Key words: targeted drug delivery nanotechnology resveratrol. PMID- 28914065 TI - [The image of a good pharmacist in the works of Saladin di Ascoli and Valerius Cordus]. AB - Separation of pharmacy from medicine induced the requirements formulation for an ideal pharmacist. Two prominent authors did so, Saladin di Ascoli (the first half of the XVth century) in the work Compendium aromatariorum (1488) and Valerius Cordus (1515-1544) in the work Dispensatorium pharmacopolarum (1546). Both of them formulate similar postulates of both professional and ethical nature, namely a knowledge of Latin, good education, experience, good character traits, need of satisfied marriage; both say that the pharmacist is required to be a good Christian, they condemn alcohol, relationships with women, poisons and abortifacients, remember right relationship to money. In addition, Cordus adds a good financial situation. Their considerations had a great impact on further development of pharmacy across Europe.Key words: Saladin di Ascoli Valerius Cordus ideal pharmacist. PMID- 28914066 TI - [Herpes simplex virus infection: an overview of the problem, pharmacologic therapy and dietary measures]. AB - Treatment of infectious diseases remains one of the principal research target for many researchers and healthcare providers worldwide. Herpes simplex virus 1 (HSV 1) and herpes simplex virus 2 (HSV-2) are common human pathogens with an estimated 60-95% of the adult population infected by at least one of them. The worldwide disease burden of HSV is substantial, and acyclovir and related nucleoside analogues (viral DNA polymerase inhibitors) as therapies have led to significantly increased treatment efficacy of HSV infections. Although the treatment of HSV infection has greatly advanced through the use of nucleoside analogues therapy, the treatment efficacy has decreased significantly. This is due to the extensive use of nucleoside analogues drugs, which has created drug resistance, associated with other adverse effects as well. In this review, we aim to shed light on the HSV infection, the current pharmacologic treatment, and the use of dietary measures as alternative therapy option.Key words: HSV infection dietary measures antiviral drugs nucleoside analogues natural compounds. PMID- 28914067 TI - [Drugs and dosage forms as risk factors for dental caries]. AB - Dental caries is a multifactorial disease which, despite a series of preventive measures, remains the most common infectious disease worldwide. Susceptibility or resistance to caries may be a result of the presence of risk or protective factors, genetic predisposition, inappropriate lifestyle associated with education, behavioural and socioeconomic factors. The aim of this review is to highlight the risks associated with the use of some drugs and dosage forms in relation to the formation and development of dental caries. Drugs are classified by the mechanism of their action in this process, into those that 1. influence the tooth development, especially enamel, 2. directly or indirectly damage the tooth structure and/or 3. disrupt the protective function of saliva, causing oral microflora dysbiosis. The review article assesses the current possibilities in the treatment and prevention of dental caries using drugs, dietary supplements and supporting measures. The conclusion of the study deals with recommendations for prevention of adverse effects of drug therapy in the oral cavity, through preventive measures and/or by considering the duration of the treatment to achieve an optimal balance between benefits and risks. Since the topic of the study is of an interdisciplinary character, information on prevention within the oral health improvement in the population can be used not only by pharmacists, who should primarily warn patients about the risks associated with pharmacotherapy, but also dentists, paediatricians/general practitioners and the public.Key words: dental caries prevention drug dosage form adverse effect. PMID- 28914068 TI - [The extent of the burnout syndrome among pharmacists: partial study]. AB - The paper deals with the possibilities of investigating the susceptibility to burnout syndrome in pharmacists and pharmaceutical assistants working in pharmacies. By using the Maslach Burnout Inventory, between November 2015 and January 2016, 53 healthcare professionals were contacted in 11 pharmacies (Brno, Vyskov). The results of the research show that with an increasing length of practice the average EE factor (emotional exhaustion) increases. The DP (depersonalization) factor does not increase significantly with the increase in the length of practice. Respondents with the longest experience are at high risk of burnout syndrome presented by the factor PA (personal satisfaction from work). It has also been shown that with an increasing age the factor EE slightly increases, the DP factor is in the low range, and the PA factor is significantly reduced in the "oldest" age category, it is high in the band.Key words: stress burnout syndrome pharmacists research. PMID- 28914069 TI - The role of a hospital pharmacist in the management of asthma in Great Britain. AB - The role of the pharmacist in the asthma management is well established. However, there is still a considerable number of patients with suboptimal asthma control affecting patients quality of life and resulting in poor outcomes, morbidity and mortality. The aim was to identify patients factors, explore the hospital pharmacists role in the asthma management and identify any areas for improvement in Great Britain. Qualitative data collection was selected. Patients case studies and semi-structured open interviews with the hospital multi-disciplinary team (MDT) were applied. Data were analysed and grouped into themes. Patients case studies showed a variety in the patients understanding of the pharmacists role in their asthma management and similarly of the pharmacy services available to them. From the MDT interviews it emerged that communication across the secondary/primary care is lacking at times, and as a result new communication systems are being implemented. More research is needed into the asthma-patients needs and expectations of pharmacy service. The hospital pharmacists are well placed to recognise asthma patients requiring pharmaceutical interventions and to provide medicines optimisation, across the primary/ secondary care settings. It was observed that the level of patients involvement in their asthma was dependent on their interest in utilising asthma information and pharmacy services.Key words: asthma asthma management hospital pharmacist secondary care case studies qualitative research. PMID- 28914070 TI - Effect of the vaginal pessaries Melanizol(r) and Klimedeks(r) on the glycogen level in the vaginal tissue of rats on the background of experimental vaginitis. AB - The experimental studies of the new vaginal pessaries Melanizol(r) and Klimedeks(r) have been carried out on the model of experimental vaginitis induced in rats by a mixture of terebenthine oil and dimethyl sulfoxide. The obtained experimental data indicate that the vaginal pessaries Melanizol(r) and Klimedeks(r) on the background of experimental vaginitis have a therapeutic effect on the 5th and 8th days of the experiment, significantly surpassing the group of animals of control pathology and placebo in its ability to restore physiological functions and accumulate glycogen by the vaginal epithelium. Melanizol(r) and Klimedeks(r) have significantly surpassed the reference drugs, the pessaries Gravagin(r) and Hippophaes oleum, but have been less efficient in the activity to the reference drug, the vaginal tablets Micogynax(r) on this criterion.Key words: glycogen vaginal pessaries vaginitis rats. PMID- 28914071 TI - A qualitative study of the service experiences of women with autism spectrum disorder. AB - It is recognized that the experiences of women with autism spectrum disorder are often underrepresented in the literature. In this study, 20 women with autism spectrum disorder participated in five focus groups with discussions centered on their service use, unmet service needs, and barriers to care. Overall, women emphasized high unmet service needs, particularly with respect to mental health concerns, residential supports, and vocational and employment services. Participants also perceived many service providers as disregarding or misunderstanding women's service needs. Findings of the current exploratory study are discussed in relation to areas of future research required to ensure effective care for this understudied population. PMID- 28914073 TI - Problems managed and medications prescribed during encounters with people with autism spectrum disorder in Australian general practice. AB - Autism spectrum disorder is associated with high rates of co-occurring health conditions. While elevated prescription rates of psychotropic medications have been reported in the United Kingdom and the United States, there is a paucity of research investigating clinical and prescribing practices in Australia. This study describes the problems managed and medications prescribed by general practitioners in Australia during encounters where an autism spectrum disorder was recorded. Information was collected from 2000 to 2014 as part of the Bettering the Evaluation and Care of Health programme. Encounters where patients were aged less than 25 years and autism spectrum disorder was recorded as one of the reasons for encounter and/or problems managed ( n = 579) were compared to all other Bettering the Evaluation and Care of Health programme encounters with patients aged less than 25 years ( n = 281,473). At 'autism spectrum disorder' encounters, there was a significantly higher management rate of psychological problems, and significantly lower management rates of skin, respiratory and general/unspecified problems, than at 'non-autism spectrum disorder' encounters. The rate of psychological medication prescription was significantly higher at 'autism spectrum disorder' encounters than at 'non-autism spectrum disorder' encounters. The most common medications prescribed at 'autism spectrum disorder' encounters were antipsychotics and antidepressants. Primary healthcare providers need adequate support and training to identify and manage physical and mental health concerns among individuals with autism spectrum disorder. PMID- 28914072 TI - Social media addiction: What is the role of content in YouTube? AB - Background YouTube, the online video creation and sharing site, supports both video content viewing and content creation activities. For a minority of people, the time spent engaging with YouTube can be excessive and potentially problematic. Method This study analyzed the relationship between content viewing, content creation, and YouTube addiction in a survey of 410 Indian-student YouTube users. It also examined the influence of content, social, technology, and process gratifications on user inclination toward YouTube content viewing and content creation. Results The results demonstrated that content creation in YouTube had a closer relationship with YouTube addiction than content viewing. Furthermore, social gratification was found to have a significant influence on both types of YouTube activities, whereas technology gratification did not significantly influence them. Among all perceived gratifications, content gratification had the highest relationship coefficient value with YouTube content creation inclination. The model fit and variance extracted by the endogenous constructs were good, which further validated the results of the analysis. Conclusion The study facilitates new ways to explore user gratification in using YouTube and how the channel responds to it. PMID- 28914074 TI - Impact of Test Conditions on ADP-Induced Platelet Function Results With the Multiplate Assay: Is Further Standardization Required? AB - BACKGROUND: Platelet function testing was suggested to help tailor P2Y12 inhibitor therapy; however, the lack of proper standardization is still a limitation. METHODS: In a prospective study, we enrolled clopidogrel-treated and P2Y12-inhibitor naive patients to investigate the influence of (1) time from blood collection, (2) stability of the stored Adenosine diphosphate (ADP) reagent, and (3) the use of enoxaparin on results of the Multiplate assay. Measurements were performed from samples kept for 0, 30, 60, 120, and 240 minutes at room temperature before processing. To determine the impact of the reagent stability, freshly thawed ADP was compared with ADP kept for 3 to 5 or 8 to 13 days at 2 degrees C to 8 degrees C. Finally, samples containing enoxaparin at therapeutic or prophylactic doses were compared with enoxaparin-free blood. RESULTS: A total of 180 measurements were performed. ADP-stimulated platelet reactivity values decreased significantly over time (67 +/- 40 U to 68 +/- 37 U to 58 +/- 37 U to 45 +/- 33 U to 35 +/- 33 U; P < .0001). Consequently, a dramatic reduction was observed in the proportion of patients with high platelet reactivity ( P < .0001). A significant drop in platelet reactivity was observed with ADP stored for 8 to 13 days as compared to freshly thawed ADP ( P = .011). Enoxaparin triggered a slight, concentration-dependent increase in platelet reactivity ( P < .05). CONCLUSION: Test conditions may have profound impacts on the obtained results with the Multiplate assay. Our findings highlight the large influence of the time from sample collection until testing, suggesting that measurements should be performed within an hour of blood collection. PMID- 28914075 TI - The temperature of storage of a batch of wheat distillers dried grains with solubles samples on their nutritive value for broilers. AB - 1. A batch of wheat distillers dried grains with solubles (DDGS) was obtained immediately after production and was separated into 5 equal parts and placed in woven polypropylene sacks. The samples were stored under 5 different temperature conditions for 1 year as follows: kept at a constant -20 degrees C; kept at -20 degrees C for 24 h period and after that kept at a constant +4 degrees C; kept at a constant +4 degrees C only; kept at a constant +15 degrees C; stored at ambient temperature (range of weekly mean temperatures was from +4 to +22 degrees C). 2. Each of the 5 wheat DDGS samples was included (200 g/kg) in a nutritionally complete diet and fed to broiler chickens from 7 to 21 d of age. The chemical composition of the DDGS samples was determined at the beginning and at the end of the 1-year storage period. 3. The nitrogen corrected apparent metabolisable energy (AMEn) and the nutrient availability of each sample was measured using a total collection technique. The growth performance of birds was also determined. 4. The DDGS samples kept at a constant -20 degrees C had higher dry matter, lower oxidation value and lower antioxidant contents. The DDGS sample that was stored at ambient temperatures had a higher AMEn than the rest of the DDGS samples. 5. The results of this experiment have shown that there can be changes in the AMEn of wheat DDGS during storage at ambient temperatures. In general, there were no serious effects of storage of DDGS on its feeding value to broiler chickens. PMID- 28914076 TI - Integrative Review of the Literature on Hispanics and Hospice. AB - The provision of optimal end-of-life care to Hispanics receiving hospice care requires familiarity with hospice-specific variables. For example, a preference for nondisclosure of terminal prognosis in some Hispanics is incongruous with traditional hospice practice. In addition, the Spanish word for hospice, "hospicio," has negative connotations about abandonment of loved ones. Added to cultural considerations are socioeconomic considerations. Many marginalized Hispanic individuals may experience distinct challenges when enrolling in hospice due to socioeconomic hardships relating to poverty, citizenship, and lack of insurance. This systematic integrative review examines the research literature on Hispanics and hospice to report on the state of the science for this topic. Reviewed articles were identified systematically using computer research databases and inclusion and exclusion criteria. Of the 21 reviewed articles, many are survey and low-inference qualitative designs with limited validity and trustworthiness. Most survey instruments were not validated for Spanish language or Hispanic culture. None of the qualitative studies included theoretical sampling or follow-up interviews. Few study designs considered heterogeneity within the Hispanic population. Interpreting results cautiously, there is evidence that some Hispanics find some satisfaction with hospice care in spite of cultural incongruities and socioeconomic challenges. Future research calls for intervention studies and high-inference qualitative designs to gain insight into hospice experiences and what constitutes quality hospice care from the perspectives of Hispanic subgroups. Assessing quality and designing interventions for these end-of-life cultural and socioeconomic issues will improve end-of-life care and facilitate the hospice philosophy of promoting emotional growth at end of life. PMID- 28914077 TI - Decision Algorithms for Direct Oral Anticoagulant Use in Patients With Nonvalvular Atrial Fibrillation: A Practical Guide for Neurologists. AB - Direct oral anticoagulants (DOACs) are valid alternative options to vitamin K antagonists due to their limited interactions with drugs or food and the fact that they do not require regular coagulation monitoring. To this regard, recent practice guidelines recommend that DOACs should be considered as first-line anticoagulant therapy for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). This review (1) outlines current international guidelines for the management of DOACs to prevent stroke in patients with NVAF, (2) outlines indications for elderly patients as well as specific settings including acute coronary syndromes and intracranial hemorrhage, and (3) offers a practical guide for the use of DOACs in neurological settings. PMID- 28914078 TI - Evaluation of Expression Level of Apolipoprotein M as a Diagnostic Marker for Primary Venous Thromboembolism. AB - Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE. A total of 357 patients with suspected first episode of VTE were recruited prospectively in the SCORE study. Plasma samples from 307 patients were available for quantifying the plasma levels of ApoM in patients with VTE using sandwich enzyme-linked immunosorbent assay method. Among the whole population, plasma levels (mean [standard deviation]) of ApoM were not significantly different between patients with VTE (0.72 [0.20]) and non-VTE patients (0.72 [0.16]), P = .99. Similarly, in regression analyses, no significant association of ApoM plasma levels with the risk of VTE was found on univariate (odds ratio [OR] =1.0, 95% confidence interval [CI] 0.21-4.84, P = .99) and multivariate analysis (OR = 1.25, 95% CI = 0.19-8.34, P = .819) after adjusting for age, body mass index, and smoking. Moreover, results did not differ significantly after stratification of data according to sex ( P > .05). In this study, our results do not suggest a diagnostic role for ApoM plasma levels in patients with primary VTE. Moreover, the current study suggests that role of ApoM as a risk factor may differ for primary VTE and recurrent VTE in male patients. PMID- 28914079 TI - Co-infection of human herpesvirus type 2 (HHV-2) and human immunodeficiency virus (HIV) among pregnant women in Rio de Janeiro, Brazil. AB - Pregnant women who are infected with the Human Immunodeficiency Virus (HIV) are particularly vulnerable to severe and recurrent infections with Human Herpesvirus 2 (HHV-2). Neonatal transmission of HHV-2 has been associated with malformations and neurological sequelae in infants, which makes it very important to perform antenatal monitoring for genital herpes. In the study, 134 pregnant women infected with HIV were tested for HHV-2 IgM and IgG using an enzyme-linked immunosorbent assay (ELISA) and had HHV-2 DNA analyzed by Real Time Polymerase Chain Reaction (qPCR). Fisher's exact test was applied to analyze the epidemiological dates (p < 0.05). A total of 59.7% of the pregnant women infected with HIV had HHV-2 IgG and 3.75% of them showed HHV-2 viremia. HHV-2 IgM was found in 6% of the pregnant women and 25% of them had HHV-2 viremia. The risk factors associated with HHV-2 seropositive were age under 20 and a CD4/CD8 ratio > 1. Our study found high HHV-2/HIV coinfection prevalence and HHV-2 viremia among patients with recurrent and primary genital infection, reinforcing the need of prevention and control of HHV-2 infection in order to avoid this virus transmission. PMID- 28914080 TI - Gender identity and sexual orientation in autism spectrum disorder. AB - Clinical impressions indicate that there is an overrepresentation of gender dysphoria within the autism spectrum disorder. However, little is presently known about the demographics of gender-identity issues in autism spectrum disorder. Based upon what little is known, we hypothesized that there would be an increased prevalence of gender-dysphoria among those with autism spectrum disorder compared to a typically developing population. We surveyed gender-dysphoria with the Gender-Identity/Gender-Dysphoria Questionnaire among 90 males and 219 females with autism spectrum disorder and compared these rates to those of 103 males and 158 females without autism spectrum disorder. When compared to typically developing individuals, autistic individuals reported a higher number of gender dysphoric traits. Rates of gender-dysphoria in the group with autism spectrum disorder were significantly higher than reported in the wider population. Mediation analysis found that the relationship between autistic traits and sexual orientation was mediated by gender-dysphoric traits. Results suggest that autism spectrum disorder presents a unique experience to the formation and consolidation of gender identity, and for some autistic individuals, their sexual orientation relates to their gender experience. It is important that clinicians working with autism spectrum disorder are aware of the gender-diversity in this population so that the necessary support for healthy socio-sexual functioning and mental well being is provided. PMID- 28914081 TI - C-reactive Protein Is Associated With Prevalence of the Metabolic Syndrome, Hypertension, and Diabetes Mellitus in US Adults. AB - The prevalence of metabolic syndrome (MetS) has increased globally and is associated with an increased risk of cardiovascular diseases that may be related to its association with inflammation. We have assessed whether the prevalence of the MetS correlates with a serum high-sensitivity C-reactive protein (hsCRP) concentration in a population-based sample of US men and women. Participants were selected from the US National Health and Nutrition Examination Survey from 2005 to 2010. Of the 17 689 participants analyzed, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample (between men and women P = .047). The prevalence of MetS, diabetes mellitus, and hypertension increased across quartiles for hsCRP (all P < .001). Moreover, we found that for the age-, race-, sex-, and smoking-adjusted logistic regression, with increasing hsCRP, the risk of having MetS increased with an odds ratio of 5.20 (95% confidence interval, 4.54-5.93, P < .001) when comparing the highest quartile of serum hsCRP with the lowest. This study provides further evidence for an association between MetS and subclinical inflammation. PMID- 28914082 TI - Characterizing psychiatric comorbidity in children with autism spectrum disorder receiving publicly funded mental health services. AB - Publicly funded mental health programs play a significant role in serving children with autism spectrum disorder. Understanding patterns of psychiatric comorbidity for this population within mental health settings is important to implement appropriately tailored interventions. This study (1) describes patterns of psychiatric comorbidity in children with autism spectrum disorder who present to mental health services with challenging behaviors and (2) identifies child characteristics associated with comorbid conditions. Data are drawn from baseline assessments from 201 children with autism spectrum disorder who participated in a community effectiveness trial across 29 publicly funded mental health programs. Non-autism spectrum disorder diagnoses were assessed using an adapted Mini International Neuropsychiatric Interview, parent version. Approximately 92% of children met criteria for at least one non-autism spectrum disorder diagnosis (78% attention deficit hyperactivity disorder, 58% oppositional defiant disorder, 56% anxiety, 30% mood). Logistic regression indicated that child gender and clinical characteristics were differentially associated with meeting criteria for attention deficit hyperactivity disorder, oppositional defiant disorder, an anxiety, or a mood disorder. Exploratory analyses supported a link between challenging behaviors and mood disorder symptoms and revealed high prevalence of these symptoms in this autism spectrum disorder population. Findings provide direction for tailoring intervention to address a broad range of clinical issues for youth with autism spectrum disorder served in mental health settings. PMID- 28914083 TI - The importance of context in early autism intervention: A qualitative South African study. AB - The majority of individuals with autism spectrum disorder live in low- and middle income countries and receive little or no services from health or social care systems. The development and validation of autism spectrum disorder interventions has almost exclusively occurred in high-income countries, leaving many unanswered questions regarding what contextual factors would need to be considered to ensure the effectiveness of interventions in low- and middle-income countries. This study qualitatively explored contextual factors relevant to the adaptation of a caregiver-mediated early autism spectrum disorder intervention in a low-resource South African setting. We conducted four focus groups and four in-depth interviews with 28 caregivers of young children with autism spectrum disorder and used thematic analysis to identify key themes. Eight contextual factors including culture, language, location of treatment, cost of treatment, type of service provider, support, parenting practices, and stigma emerged as important. Caregivers reported a preference for an affordable, in-home, individualized early autism spectrum disorder intervention, where they have an active voice in shaping treatment goals. Distrust of community-based health workers and challenges associated with autism spectrum disorder-related stigma were identified. Recommendations that integrate caregiver preferences with the development of a low-cost and scalable caregiver-mediated early autism spectrum disorder intervention are included. PMID- 28914084 TI - LC-MS determination of fentanyl in human serum and application to a fentanyl transdermal delivery pharmacokinetic study. AB - AIM: Fentanyl is an opioid agonist used for acute and chronic pain management. In this report, a highly sensitive and simple LC-MS/MS method using Hydrophilic Interaction Chromatography (HILIC) column was validated and used for fentanyl quantification in human serum. RESULTS: The isocratic mobile phase was composed of acetonitrile: 10 mM ammonium formate buffer (pH = 3.2; 90:10, v/v). The assay was linear over a concentration range of 10-10,000 pg/ml. The accuracy of the validation method ranged from 93.2 to 107%, and the precision was within 6.4%. Fentanyl was stable during short- and long-term storage. CONCLUSION: The assay has been successfully applied to serum samples obtained from healthy subjects of a fentanyl transdermal pharmacokinetic study. PMID- 28914085 TI - Development of a patient-centered conceptual model of the impact of living with autism spectrum disorder. AB - The aim of this study was to generate a patient-centered conceptual model of the impact of living with autism spectrum disorder, which can be used to support the selection of outcome measures for clinical trials. Following an initial literature review to identify preliminary concepts and inform an interview guide, in-depth face-to-face interviews were conducted with adolescents and adults with autism spectrum disorder (IQ ? 70) (n = 10), as well as parents of children, adolescents, and adults with autism spectrum disorder (IQ ? 70) (n = 26). Data were analyzed using established qualitative research methods. The resultant conceptual model contains three interrelated domains reflecting core symptoms of autism spectrum disorder (communication deficits, socialization deficits, and restrictive, repetitive patterns of behavior), three domains reflecting associated symptoms of autism spectrum disorder (physical, cognitive, and emotional/behavioral), and three domains representing the impacts of living with autism spectrum disorder (impacts on activities of daily living, school/work, and social life). Interview respondents also cited social communication deficits as priority targets for new treatments. The conceptual model provides a patient centered perspective of relevant concepts of autism spectrum disorder from the perspectives of people with autism spectrum disorder and their parents and offers a valuable tool for identifying valid patient-centered outcome measures for future clinical trials. PMID- 28914086 TI - Preliminary efficacy of a daily living skills intervention for adolescents with high-functioning autism spectrum disorder. AB - Daily living skills deficits are strongly associated with poor adult outcomes for individuals with high-functioning autism spectrum disorder, and yet, there are no group interventions targeting daily living skills. Seven adolescents with autism spectrum disorder and their parents participated in a feasibility pilot of a 12 week manualized group treatment targeting specific daily living skills (i.e. morning routine, cooking, laundry, and money management). Outcomes included the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) age equivalence scores and four goal attainment scaling scores. Adolescents demonstrated significant improvement on two Vineland-II subdomains and on all goal attainment scaling scores at post-treatment and 6-month follow-up. The intervention has promise for improving critical daily living skills' deficits that affect independent living and employment. Limitations and implications for future studies are discussed. PMID- 28914088 TI - Multi-morbidity: A patient perspective on navigating the health care system and everyday life. AB - OBJECTIVE: The importance of everyday life when managing the burden of treatment is rarely studied. This article explores the burden of treatment among people with multi-morbidity by investigating the tension between everyday life and the health care system. METHOD: This was an ethnographic study using individual interviews and participant-observations. An inductive analytical approach was applied, moving from observations and results to broader generalisations. RESULTS: People with multi-morbidity experience dilemmas related to their individual priorities in everyday life and the management of their treatment burdens. Dilemmas were identified within three domains: family and social life; work life; agendas and set goals in appointments with health professionals. Individual resources and priorities in everyday life play a dominant role in resolving dilemmas and navigating the tension between everyday life and the health care system. DISCUSSION: People with multi-morbidity are seldom supported by health professionals in resolving the dilemmas they must face. This study suggests an increased focus on patient-centredness and argues in favour of planning health care through cooperation between health professionals and people with multi-morbidity in a way that integrates both health and everyday life priorities. PMID- 28914087 TI - Effect of myofascial techniques for treatment of persistent arm pain after breast cancer treatment: randomized controlled trial. AB - OBJECTIVE: To investigate the effect of myofascial therapy in addition to a standard physical therapy program for treatment of persistent arm pain after finishing breast cancer treatment. DESIGN: Double-blinded (patient and assessor) randomized controlled trial. SETTING: University Hospitals Leuven, Belgium. PATIENTS: A total of 50 patients with persistent arm pain and myofascial dysfunctions after breast cancer treatment. INTERVENTION: Over three months, all patients received a standard physical therapy program. The intervention group received in addition 12 sessions of myofascial therapy, and the control group received 12 sessions of placebo therapy. MAIN MEASUREMENTS: Main outcome parameters were pain intensity (primary outcome) (maximum visual analogue scale (VAS) (0-100)), prevalence rate of arm pain, pressure hypersensitivity (pressure pain thresholds (kg/cm2) and pain quality (McGill Pain Questionnaire). Measures were taken before and after the intervention and at long term (6 and 12 months follow-up). RESULTS: Patients in the intervention group had a significantly greater decrease in pain intensity compared to the control group (VAS -44/100 vs. -24/100, P = 0.046) with a mean difference in change after three months between groups of 20/100 (95% confidence interval, 0.4 to 39.7). After the intervention, 44% versus 64% of patients still experienced pain in the intervention and control group, respectively ( P = 0.246). No significant differences were found for the other outcomes. CONCLUSION: Myofascial therapy is an effective physical therapy modality to decrease pain intensity at the arm in breast cancer survivors at three months, but no other benefits at that time were found. There were no long term effects at 12 months either. PMID- 28914089 TI - Art museum-based intervention to promote emotional well-being and improve quality of life in people with dementia: The ARTEMIS project. AB - ARTEMIS (ART Encounters: Museum Intervention Study) is an art-based intervention designed especially for people with dementia and their care partners that involves a combination of museum visits and artistic activity. This paper reports the results of a randomized wait-list controlled study on the influence of the ARTEMIS intervention on the emotional state, well-being, and quality of life of dementia patients. People with mild-to-moderate dementia (n = 44) and their care partners (n = 44) visited the Frankfurt Stadel Museum once a week on six pre arranged occasions. The intervention consisted of six different guided art tours (60 minutes), followed by art-making in the studio (60 minutes). Independent museum visits served as a control condition. A mixed-methods design was used to assess several outcomes including cognitive status, emotional well-being, self rated aspects of quality of life, and subjective evaluations by informal caregivers. In a pre-post-assessment, we found significant improvements in participants' self-rated quality of life (t = -3.15, p < .05). In a situational assessment of emotional well-being immediately before and after each of the museum sessions, we were able to demonstrate statistically significant positive changes with medium effect sizes (dcorr = .74-.77). Furthermore, the total Neuropsychiatric Inventory score as well as the affective (depressed mood and anxiety) and apathy subscales were significantly lower after the ARTEMIS intervention (tNPI total = 2.43; tNPI affective = 2.24; tNPI apathy = 2.52; p < .05). The results show that art museum-based art interventions are able to improve the subjective well-being, mood, and quality of life in people with dementia. This promising psychosocial approach deserves further attention in future studies and consideration in community-based dementia care programs. PMID- 28914090 TI - Exploring the theoretical foundations of visual art programmes for people living with dementia. AB - Despite the growing international innovations for visual arts interventions in dementia care, limited attention has been paid to their theoretical basis. In response, this paper explores how and why visual art interventions in dementia care influence changes in outcomes. The theory building process consists of a realist review of primary research on visual art programmes. This aims to uncover what works, for whom, how, why and in what circumstances. We undertook a qualitative exploration of stakeholder perspectives of art programmes, and then synthesised these two pieces of work alongside broader theory to produce a conceptual framework for intervention development, further research and practice. This suggests effective programmes are realised through essential attributes of two key conditions (provocative and stimulating aesthetic experience; dynamic and responsive artistic practice). These conditions are important for cognitive, social and individual responses, leading to benefits for people with early to more advanced dementia. This work represents a starting point at identifying theories of change for arts interventions, and for further research to critically examine, refine and strengthen the evidence base for the arts in dementia care. Understanding the theoretical basis of interventions is important for service development, evaluation and implementation. PMID- 28914091 TI - Short-term carbon dynamics in a temperate grassland and heathland ecosystem exposed to 104 days of drought followed by irrigation. AB - Temperate ecosystems are susceptible to drought events. The effect of a severe drought (104 days) followed by irrigation on the plant C uptake, its assimilation and input of C in soil were examined using a triple 13CO2 pulse-chase labelling experiment in model grassland and heathland ecosystems. First 13CO2 pulse at day 0 of the experiment revealed much higher 13C tracer uptake for shoots, roots and soil compared to the second pulse (day 44), where all plants showed significantly lower 13C tracer uptake. After the third 13CO2 pulse (day 70), very low 13C uptake in shoots led to a negligible allocation of 13C into roots and soil. During irrigation after the severe drought, the 13C tracer that was allocated in plant tissues during the second and third pulse labelling was re-allocated in roots and soil, as soon as the irrigation started. This re-allocation was higher and longer lasting in heathland compared to grassland ecosystems. PMID- 28914092 TI - Mental Health Professionals' Suicide Risk Assessment and Management Practices. AB - BACKGROUND: Approximately 20% of suicide decedents have had contact with a mental health professional within 1 month prior to their death, and the majority of mental health professionals have treated suicidal individuals. Despite limited evidence-based training, mental health professionals make important clinical decisions related to suicide risk assessment and management. AIMS: The current study aimed to determine the frequency of suicide risk assessment and management practices and the association between fear of suicide-related outcomes or comfort working with suicidal individuals and adequacy of suicide risk management decisions among mental health professionals. METHOD: Mental health professionals completed self-report assessments of fear, comfort, and suicide risk assessment and management practices. RESULTS: Approximately one third of mental health professionals did not ask every patient about current or previous suicidal thoughts or behaviors. Further, comfort, but not fear, was positively associated with greater odds of conducting evidence-based suicide risk assessments at first appointments and adequacy of suicide risk management practices with patients reporting suicide ideation and a recent suicide attempt. LIMITATIONS: The study utilized a cross-sectional design and self-report questionnaires. CONCLUSION: Although the majority of mental health professionals report using evidenced-based practices, there appears to be variability in utilization of evidence-based practices. PMID- 28914093 TI - Problematizing Men's Suicide, Mental Health, and Well-Being. AB - BACKGROUND: The Province of Quebec, Canada (PQ), witnessed a drastic rise in suicide among adult men between 1990 and 2000, followed by a continuous drop since then. At the end of the 1990s, men's suicide became recognized as a social issue, leading to implementation of gender-responsive strategies focusing on positive aspects of masculinity. Many of these strategies received positive assessments. AIMS: This article offers a critical overview of the evolution of social responses to men's suicide in PQ. METHOD: We highlight elements of success with examples of interventions targeting men directly, professionals who work with men, and natural support networks of men. RESULTS: Results and discussion suggest the benefits to shift towards salutogenic, gender-transformative approach to men's suicide prevention. CONCLUSION: Closing remarks question the current gaps and upcoming challenges in suicide prevention among men. PMID- 28914094 TI - Quality Assessment of Economic Evaluations of Suicide and Self-Harm Interventions. AB - BACKGROUND: Death following self-harm constitutes a major global public health challenge and there is an urgent need for governments to implement cost effective, national suicide prevention strategies. AIM: To conduct a systematic review and quality appraisal of the economic evaluations of interventions aimed at preventing suicidal behavior. METHOD: A systematic literature search was performed in several literature databases to identify relevant articles published from 2003 to 2016. Drummond's 10-item appraisal tool was used to assess the methodological quality of the included studies. RESULTS: In total, 25 documents encompassing 30 economic evaluations were included in the review. Of the identified evaluations, 10 studies were found to be of poor quality, 14 were of average quality, and six studies were considered of good quality. The majority of evaluations found the interventions to be cost-effective. LIMITATIONS: Several limitations were identified and discussed in the article. CONCLUSION: A notable few economic evaluations were identified. The studies were diverse, primarily set in high-income countries, and often based on modeling, emphasizing the need for more primary research into the topic. The discussion of suicide and self-harm prevention should be as nuanced as possible, including health economics along with cultural, social, and political aspects. PMID- 28914095 TI - Depressed Multiple-Suicide-Attempters - A High-Risk Phenotype. AB - BACKGROUND: There is compelling evidence that suicide attempts are among the strongest predictors of suicide and future suicide attempts. AIM: This study aimed to examine psychopathology in multiple-suicide attempters. METHOD: We compared the demographic and clinical features of three groups: depressed patients without a history of suicide attempts (non-attempters), depressed patients with a history of one to three suicide attempts (attempters), and depressed patients with a history of four or more suicide attempts (multiple attempters). RESULTS: We found that attempters and multiple attempters had higher levels of depression, hopelessness, aggression, hostility, and impulsivity and were more likely to have borderline personality disorder and family history of major depression or alcohol use disorder compared with non-attempters, but did not differ between each other on these measures. Multiple attempters had greater suicidal ideation at study entry and were more likely to have family history of suicide attempt compared with attempters. Importantly, multiple attempters had greater suicide intent at the time of the most medically serious suicide attempt and more serious medical consequences during their most medically serious suicide attempt compared with attempters. LIMITATIONS: The cross-sectional design of the study. CONCLUSION: Our data suggest that multiple-suicide attempters require careful evaluation as their behavior can have serious medical consequences. PMID- 28914097 TI - Advanced glycation end products interfere in luteinizing hormone and follicle stimulating hormone signaling in human granulosa KGN cells. AB - Advanced glycation end products accumulate in the ovarian granulosa-cell layer of women with polycystic ovarian syndrome. Taken that the MAPK/ERK-pathway is a key regulator of oocyte maturation and function, consisting the main pathway used by the gonadotrophic hormones (luteinizing hormone, follicle stimulating hormone) to control ovulation, the present study aims to assess advanced glycation end products' interference into luteinizing hormone-and follicle stimulating hormone signaling via the MAPK/ERK-pathway in the human granulosa KGN cell line. KGN cells were treated with luteinizing hormone or follicle stimulating hormone in the absence or presence of human glycated albumin. The specific activation of the main components of the MAPK/ERK1/2-pathway (namely c-Raf, MEK and ERK1/2) was assessed. Treatment of KGN cells with an MEK1/2-inhibitor or a blocking anti-RAGE antibody was also performed to shed further light on the mechanism of the involvement of advanced glycation end products in luteinizing hormone and/or follicle stimulating hormone-related signaling pathways. Luteinizing hormone treatment increased p-ERK1/2 levels in human granulosa cells, while the combined treatment of luteinizing hormone and human glycated albumin provoked a decrease of p-ERK1/2 levels. A similar reducing effect was also observed for the upstream molecule phospho-cRaf upon combined treatment, while treatment with an MEK inhibitor confirmed that the phenomenon is MAPK/ERK-pathway-dependent. Similarly, follicle stimulating hormone treatment increased p-ERK1/2 and p-MEK1/2 levels, while the combined treatment of follicle stimulating hormone and human glycated albumin downregulated their levels. Advanced glycation end products reduce the luteinizing hormone- and follicle stimulating hormone-induced ERK1/2 activation that is critical for granulosa cell mitogenesis and proliferation. Inappropriate activation of ERK1/2 in granulosa cells may block the granulosa cell differentiation pathway and/or impair follicular responses to hormones, potentially leading to ovulation failure that characterizes polycystic ovarian syndrome. PMID- 28914096 TI - MicroRNAs as biomarkers for clinical studies. AB - The development of better diagnostic and prognostic non-invasive biomarkers holds an enormous potential to improve the ability to diagnose and individualize treatment of a great number of human diseases and substantially reduce health care cost. The discovery of a fundamental role of microRNAs in the disease pathogenesis and their presence and stability in biological fluids has led to extensive investigation of the role of microRNAs as potential non-invasive biomarkers for disease diagnosis and prognosis. The result of this research has suggested that alterations of microRNAs may be sensitive indicators of various pathologies; however, despite the indisputable progress in this field, the diagnostic promise of microRNAs has remained a work in progress, and circulating microRNAs have not entered the field of clinical medicine yet. Commonly reported microRNAs as disease biomarkers are largely not disease-specific and the results are often contradicting in independent studies. This review summarizes the current knowledge on the role of microRNAs as disease indicators and emphasizes the current gaps, challenges, and questions that need to be addressed in future well-designed and well-controlled studies for a successful translation of microRNA profiling into clinically meaningful tests. Impact statement This review summarizes the current knowledge on the role of circulating miRNAs as clinical diagnostic biomarkers and highlights the challenges that need to be addressed in future studies for a successful translation of circulating miRNAs into a novel diagnostic tool. PMID- 28914098 TI - The antimicrobial effects of three phenolic extracts from Rosmarinus officinalis L., Vitis vinifera L. and Polygonum cuspidatum L. on food pathogens. AB - In this study three phenolic extracts were examined, without volatile fraction, against common food pathogens. The samples, all suitable for food application, were from the leaves of Rosmarinus officinalis L., Vitis vinifera L., and the root of Polygonum cuspidatum L. The microorganisms tested were Escherichia coli O157:H7, Salmonella Enteritidis, Salmonella Typhi, Yersinia enterocolitica and Listeria monocytogenes, well-known as important food pathogens. The results demonstrated a microbicidal activity of all the tested compounds at different concentrations; the rosemary extract showed greater efficacy than the other compounds against the tested microorganisms. In particular, the best results were obtained with rosemary extract against E. coli O157:H7 and L. monocytogenes with values of 200 and 270 MUg/mL, respectively. Our results show that rosemary extract, often present as a natural antioxidant in food, can also be proposed as a natural disinfectant in the food field. PMID- 28914099 TI - Integrating social class and privilege in the community medicine curriculum. AB - Social class and privilege are hidden variables that impact the physician-patient relationship and health outcomes. This article presents a sample of activities from three programs utilized in the community health curriculum to teach resident physicians about patients within context, including how social class and privilege impact physician-patient relationships and patient health. These activities address resident physicians' resistance to discussion of privilege, social class, and race by emphasizing direct experience and active learning rather than traditional didactic sessions. The group format of these activities fosters flexible discussion and personal engagement that provide opportunities for reflection. Each activity affords opportunities to develop a vocabulary for discussing social class and privilege with compassion and to adopt therapeutic approaches that are more likely to meet patients where they are. PMID- 28914100 TI - Acute myeloid leukemia and the infectious diseases consultant. AB - Infectious complications following treatment of acute myeloid leukemia (AML) are important causes of morbidity and mortality. The spectrum and complexity of these infections is reflected by the severe net state of immunosuppression of AML patients, that is dynamic and continuously changing, the polypharmacy, including the widespread use of anti-infectives and the complex epidemiology of severe and frequently resistant pathogens afflicting these patients. Infectious diseases (ID) consultants having a critical mass of expertise and intimate knowledge of the intricacies of leukemia care, add considerable value in improving outcomes of patients with AML who develop infections. Furthermore, pharmaco-economic considerations such as length of stay, choice of cost-effective anti-infective program, infection control and antibiotic stewardship strategies create a delicate interplay of the ID consultant and the ecosystem of care of AML patients. This is an increasingly recognized area of cross collaboration and a productive direction for future collaborative practice models and research. PMID- 28914101 TI - Pelvic incidence and hip disorders. AB - Background and purpose - The role of pelvic incidence in hip disorders is unclear. Therefore, we undertook a literature review to evaluate the evidence on that role. Methods - A search was carried out on MEDLINE, SCOPUS, CENTRAL, and CINAHL databases. Quantitative analysis was based on comparison with a reference population of asymptomatic subjects. Results - The search resulted in 326 records: 15 studies were analyzed qualitatively and 13 quantitatively. The estimates of pelvic incidence varied more than 10 degrees from 47 (SD 3.7) to 59 (SD 14). 2 studies concluded that higher pelvic incidence might contribute to the development of coxarthrosis while 1 study reported the opposite findings. In 2 studies, lower pelvic incidence was associated with a mixed type of femoroacetabular impingement. We formed a reference population from asymptomatic groups used or cited in the selected studies. The reference comprised 777 persons with pooled average pelvic incidence of 53 (SD 10) degrees. The estimate showed a relatively narrow 95% CI of 52 to 54 degrees. The 95% CIs of only 4 studies did not overlap the CIs of reference: 2 studies on coxarthrosis, 1 on mixed femoroacetabular impingement, and 1 on ankylosing spondylitis Interpretation - We found no strong evidence that pelvic incidence plays any substantial role in hip disorders. Lower pelvic incidence may be associated with the mixed type of femoroacetabular impingement and hip problems amongst patients with ankylosing spondylitis. The evidence on association between pelvic incidence and coxarthrosis remained inconclusive. PMID- 28914102 TI - 5-HTTLPR-brain-derived neurotrophic factor (BDNF) gene interactions and early adverse life events effect on impulsivity in suicide attempters. AB - OBJECTIVES: An expanding body of research suggests that childhood adverse experiences can lead to different negative health outcomes, including attempted suicide. Serotonergic genes such as the promoter region of the serotonin transporter gene (5-HTTLPR) have been associated both with impulsivity in suicide attempts and reactivity to environmental stress exposure. BDNF gene may play an epigenetic role. METHODS: We studied the influence of childhood stressful events and 5-HTTLPR genotype on impulsivity measured by Barratt Impulsivity Scale (BIS 10) in a multicentre sample of 1,655 suicide attempters (69.4% women, 30.6% men; mean age 40.13 years). A co-dominant additive genetic model was used for the statistical analyses. Interaction between 5-HTTLPR genotype and early trauma exposure was tested using moderated and multiple regression techniques. Interaction plots were used to explore BDNF genotype modulation. RESULTS: Mildly higher impulsivity scores were found in men with SS compared with SL or LL genotypes, and men with childhood emotional and physical abuse. Interaction analyses showed that combination of 5-HTTLPR-SS genotype and early trauma exposure increase impulsivity scores independently. Impulsivity scores were not affected by the modulation of BDNF genes. CONCLUSIONS: Childhood trauma and 5 HTTLPR genotype seem to be independently involved in suicide attempts, sharing a common pathway of increasing impulsivity. PMID- 28914103 TI - The first 6 weeks of recovery after primary total hip arthroplasty with fast track. PMID- 28914104 TI - Influence of previous body mass index and sex on regional fat changes in a weight loss intervention. AB - OBJECTIVES: Men and women may lose weight in a different fashion. This study compares the changes in different anatomical regions after a well-controlled weight loss program by sex and initial BMI. METHODS: A total of 180 subjects (48 overweight women, 36 overweight men, and 48 obese women and 48 obese men) were recruited to participate in a 22-week weight loss programme (diet + exercise). RESULTS: Regarding percentage body weight change from baseline, there was no triple interaction (BMI, sex and anatomical region), but there was interaction between BMI and anatomical region (F2,840 = 34.5; p < 0.001), and between sex and anatomical region (F2,840 = 98.8; p < 0.001). Usually, the arms and legs are the regions that lose more weight in obese participants, but men lose the highest percentage of mass from the trunk. There were differences between men and women for the areas of left trunk mass (750g), right trunk mass (700g), total mass of the trunk (1400g), android mass (350g), and finally in the total mass in overweight participants (1300g), with higher values for men than for women. The region that loses more weight and fat is the trunk, followed by the legs, and then the arms, when the loss is observed in function of the total weight or fat lost. CONCLUSION: Both BMI and sex exert a definite influence fat loss, especially in some anatomical regions. PMID- 28914105 TI - Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients. AB - Background and purpose - The incidence of orthopedic methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. Vancomycin may therefore play an increasingly important role in orthopedic perioperative antimicrobial prophylaxis. Studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. We assessed single-dose plasma, subcutaneous adipose tissue (SCT) and bone concentrations of vancomycin using microdialysis in male patients undergoing total knee replacement. Methods - 1,000 mg of vancomycin was administered postoperatively intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, SCT, cancellous, and cortical bone were measured over the following 8 hours. Microdialysis was applied for sampling in solid tissues. Results - For all solid tissues, tissue penetration of vancomycin was significantly impaired. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L was 3, 36, 27, and 110 min for plasma, SCT, cancellous, and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L could not be reached in cortical bone. The area under the concentration-time curve from 0 to the last measured value and peak drug concentrations (Cmax) for SCT, cancellous, and cortical bone was lower than that of free plasma. The time to Cmax was higher for all tissues compared with free plasma. Interpretation - Postoperative penetration of vancomycin to bone and SCT was impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached using standard prophylactic dosage. PMID- 28914106 TI - Concomitant diseases and their effect on disease prognosis in Meniere's disease: diabetes mellitus identified as a negative prognostic factor. AB - OBJECTIVE: To study comorbidities and their effect on the disease progression in Meniere's disease (MD). METHODS: Retrospective study on 350 definite MD patients diagnosed according to AAO-HNS 1995 criteria using hospital records and postal questionnaire. RESULTS: The prevalence of migraine, hypothyroidism, allergies, coronary heart disease and autoimmune diseases was more common in MD patients than reported in the general population of Finland. Diabetes mellitus was associated with both more severe hearing impairment (p = .033) and more frequent vertigo (p = .028) in MD patients. The number of concomitant diseases was associated with more frequent vertigo (p = .021). CONCLUSIONS: A patient's concomitant diseases, especially diabetes, should be treated effectively because they might affect the progression of MD. Further studies on the effects of concomitant diseases on MD prognosis are needed. PMID- 28914107 TI - Using beta-lactam/beta-lactamase inhibitors for infections due to extended spectrum beta-lactamase-producing Enterobacteriaceae to slow the emergence of carbapenem-resistant Enterobacteriaceae. PMID- 28914108 TI - Does particle disease really exist? PMID- 28914109 TI - Stem cell therapy for the systemic right ventricle. AB - INTRODUCTION: In specific forms of congenital heart defects and pulmonary hypertension, the right ventricle (RV) is exposed to systemic levels of pressure overload. The RV is prone to failure in these patients because of its vulnerability to chronic pressure overload. As patients with a systemic RV reach adulthood, an emerging epidemic of RV failure has become evident. Medical therapies proven for LV failure are ineffective in treating RV failure. Areas covered: In this review, the pathophysiology of the failing RV under pressure overload is discussed, with specific emphasis on the pivotal roles of angiogenesis and oxidative stress. Studies investigating the ability of stem cell therapy to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload are then reviewed. Finally, clinical trials utilizing stem cell therapy to prevent RV failure under pressure overload in congenital heart disease will be discussed. Expert commentary: Although considerable hurdles remain before their mainstream clinical implementation, stem cell therapy possesses revolutionary potential in the treatment of patients with failing systemic RVs who currently have very limited long-term treatment options. Rigorous clinical trials of stem cell therapy for RV failure that target well-defined mechanisms will ensure success adoption of this therapeutic strategy. PMID- 28914110 TI - Evaluation of dual target-specific real-time PCR for the detection of Kingella kingae in a Danish paediatric population. AB - BACKGROUND: We aimed to evaluate the relevance of dual target real-time polymerase chain (PCR) assays targeting the rtxA and cpn60 genes of the paediatric pathogen Kingella kingae. We also studied for the first time the clinical and epidemiological features of K. kingae infections in a Danish population. METHOD: Children with K. kingae-positive cultures were identified from 11,477 children and 86 children younger than 16 years old from whom blood cultures and joint fluid cultures were obtained between January 2010 and November 2016. Results were then compared to microbiological results obtained from 29 joint fluids (28 children) tested by dual target K. kingae real-time PCR from September 2014 to November 2016. Epidemiological data of all children with microbiologically confirmed K. kingae infections were collected. RESULTS: From 2010 to 2016, we diagnosed 17 children with microbiological-proven K. kingae infections. During this period, blood cultures from five children and joint fluid cultures from a single child yielded K. kingae. Dual target K. kingae real-time PCR allowed us to increase the diagnostic yield of K. kingae infections by detecting the organism in 12 of 29 (41.4%) specimens. Notably, the 12 real-time PCR-positive specimens were rtxA-positive whereas only 10 (83.3%) were cpn60 positive. PCR-positive children were significantly younger than PCR-negative children (p-value: .01). A significant seasonal variation was found for patients with proven K. kingae infection (p-value: <.001), with a peak in autumn. CONCLUSION: Dual target-specific real-time PCR markedly improved the detection of K. kingae in clinical specimens when compared to culture methods. PMID- 28914111 TI - Analyzing How Discursive Practices Affect Physicians' Decision-Making Processes: A Phenomenological-Based Qualitative Study in Critical Care Contexts. AB - An intensive care unit (ICU) is a demanding environment, defined by significant complexity, in which physicians must make decisions in situations characterized by high levels of uncertainty. This study used a phenomenological approach to investigate the decision-making (DM) processes among ICU physicians' team with the aim of understanding what happens when ICU physicians must reach a decision about the infectious status of a patient. The focus was put on the identification of how the discursive practices influence physicians' DM processes and on how different ICU environments make different discursive profiles emerge, particularly when a key issue is at the center of the physicians' discussion. A naturalistic approach used in this study is particularly suitable for investigating health care practices because it can best illuminate the essential meaning of the "lived experiences" of the participants. The findings revealed a common framework of elements that provide insight into DM processes in ICUs and how these are affected by discursive practices. PMID- 28914113 TI - Erratum. PMID- 28914112 TI - Socioeconomic differences in childhood vaccination in developed countries: a systematic review of quantitative studies. AB - INTRODUCTION: The reasons for vaccine hesitancy and its relation to individual socioeconomic status (SES) must be better understood. Areas covered: This review focused on developed countries with programs addressing major financial barriers to vaccination access. We systematically reviewed differences by SES in uptake of publicly funded childhood vaccines and in cognitive determinants (beliefs, attitudes) of parental decisions about vaccinating their children. Using the PRISMA statement to guide this review, we searched three electronic databases from January 2000 through April 2016. We retained 43 articles; 34 analyzed SES differences in childhood vaccine uptake, 7 examined differences in its cognitive determinants, and 2 both outcomes. Expert commentary: Results suggest that barriers to vaccination access persist among low-SES children in several settings. Vaccination programs could be improved to provide all mandatory and recommended vaccines 100% free of charge, in both public organizations and private practices, and to reimburse vaccine administration. Multicomponent interventions adapted to the context could also be effective in reducing these inequalities. For specific vaccines (notably for measles, mumps, and rubella), in UK and Germany, uptake was lowest among the most affluent. Interventions carefully tailored to respond to specific concerns of vaccine-hesitant parents, without reinforcing hesitancy, are needed. PMID- 28914114 TI - Shining dead bone-cause for cautious interpretation of [18F]NaF PET scans. AB - Background and purpose - [18F]Fluoride ([18F]NaF) PET scan is frequently used for estimation of bone healing rate and extent in cases of bone allografting and fracture healing. Some authors claim that [18F]NaF uptake is a measure of osteoblastic activity, calcium metabolism, or bone turnover. Based on the known affinity of fluoride to hydroxyapatite, we challenged this view. Methods - 10 male rats received crushed, frozen allogeneic cortical bone fragments in a pouch in the abdominal wall on the right side, and hydroxyapatite granules on left side. [18F]NaF was injected intravenously after 7 days. 60 minutes later, the rats were killed and [18F]NaF uptake was visualized in a PET/CT scanner. Specimens were retrieved for micro CT and histology. Results - MicroCT and histology showed no signs of new bone at the implant sites. Still, the implants showed a very high [18F]NaF uptake, on a par with the most actively growing and remodeling sites around the knee joint. Interpretation - [18F]NaF binds with high affinity to dead bone and calcium phosphate materials. Hence, an [18F]NaF PET/CT scan does not allow for sound conclusions about new bone ingrowth into bone allograft, healing activity in long bone shaft fractures with necrotic fragments, or remodeling around calcium phosphate coated prostheses. PMID- 28914115 TI - Knowledge, attitudes and perspective on adverse drug reaction reporting in a public sector hospital in South Africa: baseline analysis. AB - OBJECTIVE: Adverse drug reactions (ADRs) can cause significant harm in patients; however, ADRs are under-reported in many countries, including South Africa, where evidence of a pharmacovigilance (PV) system to monitor and manage ADRs is a requirement for compliance with norms and standards for quality healthcare delivery. We conducted an analysis amongst health care professionals (HCPs) at Sebokeng Hospital to assess the situation there and make recommendations. METHODS: Data were collected using a structured self-administered questionnaire, targeting all medical practitioners, nurses, pharmacists and pharmacist assistants in the hospital. Current procedures for reporting of ADRs were documented. Records were reviewed to determine the number of ADR reports submitted for the 18-month period prior to the study. Data were analysed with SAS. Ethical clearance was obtained. RESULTS: The questionnaire was completed by 132 HCPs (nurses: 58.3%; medical practitioners: 23.5%; pharmacist assistants: 11.4%; pharmacists: 6.8%). The vast majority indicated ADR reporting is necessary (96.2%) and their professional obligation (89.4%). Only 18.9% were aware of an existing PV system in the hospital, 15.2% had an ADR form available and 18.9% knew to whom the form should be submitted. The vast majority had never reported an ADR, had never received training in PV, but wanted training on ADR reporting. Factors discouraging ADR reporting included not knowing how to report them (53.8%), lack of time (37.1%), additional work load (22.0%), uncertainty about the outcome of reporting (32.6%), and lack of confidence to discuss ADRs with colleagues (22.0%). Only 2.3% knew how many ADRs were reported, that ADRs are discussed by a committee (6.1%) and that internal feedback is received on reported ADRs (6.1%). CONCLUSION: There is an extensive need in Sebokeng Hospital for training on ADR reporting and implementation of systems to facilitate relevant processes; a need which may also exist in other public hospitals in South Africa. PMID- 28914116 TI - Defining a core outcome set for adolescent and young adult patients with a spinal deformity. AB - Background and purpose - Routine outcome measurement has been shown to improve performance in several fields of healthcare. National spine surgery registries have been initiated in 5 Nordic countries. However, there is no agreement on which outcomes are essential to measure for adolescent and young adult patients with a spinal deformity. The aim of this study was to develop a core outcome set (COS) that will facilitate benchmarking within and between the 5 countries of the Nordic Spinal Deformity Society (NSDS) and other registries worldwide. Material and methods - From August 2015 to September 2016, 7 representatives (panelists) of the national spinal surgery registries from each of the NSDS countries participated in a modified Delphi study. With a systematic literature review as a basis and the International Classification of Functioning, Disability and Health framework as guidance, 4 consensus rounds were held. Consensus was defined as agreement between at least 5 of the 7 representatives. Data were analyzed qualitatively and quantitatively. Results - Consensus was reached on the inclusion of 13 core outcome domains: "satisfaction with overall outcome of surgery", "satisfaction with cosmetic result of surgery", "pain interference", physical functioning", "health-related quality of life", "recreation and leisure", "pulmonary fatigue", "change in deformity", "self-image", "pain intensity", "physical function", "complications", and "re-operation". Panelists agreed that the SRS-22r, EQ-5D, and a pulmonary fatigue questionnaire (yet to be developed) are the most appropriate set of patient-reported measurement instruments that cover these outcome domains. Interpretation - We have identified a COS for a large subgroup of spinal deformity patients for implementation and validation in the NSDS countries. This is the first study to further develop a COS in a global perspective. PMID- 28914117 TI - Making the case for innovative reentry employment programs: previously incarcerated women as birth doulas - a case study. AB - Purpose The purpose of this paper is to make a case for novel and innovative reentry programs focused on women of color and to describe policy recommendations that are necessary to support the sustainability of these programs and in turn the success of the women who participate in them. Design/methodology/approach A review and analysis of the literature that described job-training opportunities specifically targeted to women exiting jail and the impact on recidivism provided limited information. The authors developed, implemented, and evaluated doula training program for low-income and women of color to determine if birth work could provide stable income and decrease recidivism. Findings Training low-income formerly incarcerated women to become birth doulas is an innovative strategy to solve employment barriers faced by women reentering communities from jail. Realigning women within communities via birth support to other women also provides culturally relevant and appropriate members of the healthcare team for traditionally vulnerable populations. Doulas are important members of the healthcare workforce and can improve birth outcomes. The authors' work testing doula training, as a reentry vocational program has been successful in producing 16 culturally relevant and appropriate doulas of color that experienced no re arrests and to date no program participant has experienced recidivism. Originality/value To be successful, the intersections of race, gender, and poverty, for women of color should be considered in the design of reentry programs for individuals exiting jail. The authors' work provided formerly incarcerated and low-income women of color with vocational skills that provide consistent income, serve as a gateway to the health professions, and increase the numbers of well-trained people of color who serve as providers of care. PMID- 28914118 TI - Universal opt-out screening for hepatitis C virus (HCV) within correctional facilities is an effective intervention to improve public health. AB - Purpose Worldwide efforts to identify individuals infected with the hepatitis C virus (HCV) focus almost exclusively on community healthcare systems, thereby failing to reach high-risk populations and those with poor access to primary care. In the USA, community-based HCV testing policies and guidelines overlook correctional facilities, where HCV rates are believed to be as high as 40 percent. This is a missed opportunity: more than ten million Americans move through correctional facilities each year. Herein, the purpose of this paper is to examine HCV testing practices in the US correctional system, California and describe how universal opt-out HCV testing could expand early HCV detection, improve public health in correctional facilities and communities, and prove cost effective over time. Design/methodology/approach A commentary on the value of standardizing screening programs across facilities by mandating all facilities (universal) to implement opt-out testing policies for all prisoners upon entry to the correctional facilities. Findings Current variability in facility-level testing programs results in inconsistent testing levels across correctional facilities, and therefore makes estimating the actual number of HCV-infected adults in the USA difficult. The authors argue that universal opt-out testing policies ensure earlier diagnosis of HCV among a population most affected by the disease and is more cost-effective than selective testing policies. Originality/value The commentary explores the current limitations of selective testing policies in correctional systems and provides recommendations and implications for public health and correctional organizations. PMID- 28914119 TI - Building on mental health training for law enforcement: strengthening community partnerships. AB - Purpose The purpose of this paper is to describe the current state of law enforcement training related to the high number of interactions with persons with mental illness, and to recommend next steps in preparing law enforcement to effectively meet this challenge. Design/methodology/approach The authors reviewed the current literature on relevant law enforcement training programs, focusing primarily on crisis intervention team (CIT) training, and used the case example of California to identify opportunities to improve and enhance law enforcement preparedness for the challenge of responding to persons with mental illness. Findings Broad-based community partnerships working together to develop programs that meet the local needs of both those with mental illness and law enforcement, the availability of mental health treatment centers with no-refusal policies, and a coordinating person or agency to effectively liaise among stakeholders are critical enhancements to CIT training. Originality/value As increasing attention is paid to adverse interactions between police and vulnerable populations, this paper identifies policies that would build on existing training programs to improve police responses to persons with mental illness. PMID- 28914120 TI - The furthest left behind: the urgent need to scale up harm reduction in prisons. AB - Purpose Raise awareness about the disproportionate impact of HIV and hepatitis C (HCV) on prisoners worldwide and the need for key harm reduction services such as needle and syringe programmes and opioid substitution therapy in prisons offer practical recommendations to assist policy makers in implementing or scaling up these services. The paper aims to discuss these issues. Design/methodology/approach This study is a desk review of existing data and evidence on HIV, HCV and harm reduction in prisons, analysis of political barriers and formulation of key policy recommendations. Findings Harm reduction works, yet service provision in prisons remains extremely limited. There is an urgent need for governments to enhance political leadership and funding for harm reduction in prisons. Authorities must also work to remove obstacles to the implementation of harm reduction services in prisons, enhance the monitoring and evaluation of laws, policies and programmes relating to HIV, HCV and drugs in prison settings, and recognise access to harm reduction in prisons as a fundamental human right. Until these obstacles are addressed, the world will not meet the Sustainable Development Goal of eradicating HIV and HCV by 2030. Originality/value More than just a desk review, this policy brief provides a political analysis of the harm reduction crisis in prisons and offers clear-cut recommendations for policy makers. PMID- 28914121 TI - Evidence-based recommendations to improve reproductive healthcare for incarcerated women. AB - Purpose The purpose of this paper is to describe standards for evidence-based reproductive healthcare for incarcerated women. Design/methodology/approach The literature on reproductive healthcare in the US criminal justice system and recommendations from professional organizations were reviewed and critical areas of concern were identified. Within these areas, studies and expert opinion were synthesized and policy recommendations were formulated through an iterative process of group discussion and document revision. This brief specifically addresses women's incarceration in the USA, but the recommendations are grounded in a human rights framework with global relevance. Findings Women who are incarcerated have health needs that are distinct from those of men, and there is a clear need for gender-responsive reproductive healthcare within the criminal justice system. This brief identifies five core domains of reproductive healthcare: routine screening, menstruation-related concerns, prenatal and postpartum care, contraception and abortion, and sexually transmitted infections. The recommendations emphasize the continuity between the criminal justice system and the community, as well as the dignity and self-determination of incarcerated women. Originality/value This brief provides a unique synthesis of the available evidence with concrete recommendations for improving the reproductive healthcare for incarcerated women. PMID- 28914122 TI - Improving health in prisons - from evidence to policy to implementation - experiences from the UK. AB - Purpose The purpose of this paper is to understand the components of a high quality prison healthcare system and the impact, ten-years on, of the transfer of accountability in England, from a justice ministry to a health ministry. Design/methodology/approach A rapid the evidence review was undertaken, which included a review of 82 papers and qualitative interviews with key informants. The concepts and themes identified were summarised and analysed through a framework analysis, designed to improve population outcomes and address health inequalities. The use of a rapid evidence assessment, rather than a systematic review methodology, the use of abstracts (rather than full-text articles) to extract the data, and limiting the search strategy to articles published in the English language only might mean that some relevant research papers and themes were not identified. The need for the evidence to be produced within a limited time frame and with limited resources determined these pragmatic approaches. Findings The review found that English prison healthcare has undergone "transformation" during this period, leading to increased quality of care through organisational engagement, professionalisation of the healthcare workforce, transparency, use of evidence-based guidance and responsiveness of services. The review also highlighted that there is still room for improvement, for example, relating to the prison regime and the lack of focus on early/preventive interventions, as well as specific challenges from limited resources. Research limitations/implications Time and resource constraints meant a rapid evidence review of papers in the English language was undertaken, rather than a systematic review. This might mean relevant papers have been missed. The review also only covered small number of countries, which may limit the transferability of findings. The lack of qualitative data necessitated the use of quantitative data gathered from key informants. However, this enabled a good understanding of current practice. Practical implications The review findings support the World Health Organisation position on the value of integrated prison and public health systems in improving quality of healthcare. It also recommends future policy needs to take account of the "whole prison approach" recognising that healthcare in prisons cannot operate in isolation from the prison regime or the community. Originality/value This is unique research which has great value in supporting prison reform in England. It will also be of interest internationally due to the paucity of data in the published peer-reviewed literature on the impact of commissioning models on healthcare or health outcomes. PMID- 28914123 TI - Advancing evidence-based interventions at the intersection of criminal justice and health. PMID- 28914124 TI - Case management helps prevent criminal justice recidivism for people with serious mental illness. AB - Purpose The purpose of this paper is to discuss how case management can decrease recidivism for people with serious mental illness (SMI) because people with SMI are at high risk for incarceration and recidivism. Design/methodology/approach Examples of successful case management models for formerly incarcerated individuals with SMI found through a secondary analysis of qualitative data and an analysis of the literature are presented. Findings Currently, no international, national, or statewide guidelines exist to ensure that formerly incarcerated individuals with SMI receive case management upon community reentry despite evidence that such services can prevent further criminal justice involvement. Recommendations include establishment of and evaluation of best practices for case management. In addition, the authors recommend additional funding for case management with the goal of greatly increasing the number of individuals with SMI leaving the criminal justice system in their ability to access adequate case management. Originality/value Providing effective case management tailored to the needs of formerly incarcerated people with SMI improves their quality of life and reduces their involvement in the criminal justice system with clear positive outcomes for public safety and public health. PMID- 28914125 TI - Mobilizing cross-sector community partnerships to address the needs of criminal justice-involved older adults: a framework for action. AB - Purpose The rapidly increasing number of older adults cycling through local criminal justice systems (jails, probation, and parole) suggests a need for greater collaboration among a diverse group of local stakeholders including professionals from healthcare delivery, public health, and criminal justice and directly affected individuals, their families, and advocates. The purpose of this paper is to develop a framework that local communities can use to understand and begin to address the needs of criminal justice-involved older adults. Design/methodology/approach The framework included solicit input from community stakeholders to identify pressing challenges facing criminal justice-involved older adults, conduct needs assessments of criminal justice-involved older adults and professionals working with them; implement quick-response interventions based on needs assessments; share findings with community stakeholders and generate public feedback; engage interdisciplinary group to develop an action plan to optimize services. Findings A five-step framework for creating an interdisciplinary community response is an effective approach to action planning and broad stakeholder engagement on behalf of older adults cycling through the criminal justice system. Originality/value This study proposes the Criminal Justice Involved Older Adults in Need of Treatment Initiative Framework for establishing an interdisciplinary community response to the growing population of medically and socially vulnerable criminal justice-involved older adults. PMID- 28914126 TI - Patient navigators effectively support HIV-infected individuals returning to the community from jail settings. AB - Purpose Patient navigation is an evidence-based approach for enhancing medical and support service co-ordination and ensuring linkage to medical care for people living with HIV released from jail. The paper aims to discuss this issue. Design/methodology/approach This brief describes the benefits of patient navigation and issues to consider when implementing a navigator program. The authors use process data to describe the type and amount of navigation services delivered as part of a randomized study, the "The San Francisco Navigator Project." Findings Navigation programs are able to accommodate a range of service needs; most clients required multiple types of services, particularly during the first two months after release. Originality/value Navigation programs should be prioritized because they provide unique and essential support for people leaving jail during the particularly vulnerable time immediately after release navigation plays a crucial role in retaining individuals in care and preventing onward transmission of HIV. PMID- 28914127 TI - Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry. AB - OBJECTIVES: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. METHODS: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. RESULTS: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5 67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2 69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of >=1 neurological manifestation at enrolment. CONCLUSIONS: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C. PMID- 28914128 TI - Risk factors associated with acute kidney injury in a cohort of 20,575 arthroplasty patients. PMID- 28914129 TI - Maternal high-fat diet programs cerebrovascular remodeling in adult rat offspring. AB - Maternal environmental factors such as diet have consequences on later health of the offspring. We found that maternal high-fat diet (HFD) exposure renders adult offspring brain more susceptible to ischemic injury. The present study was further to investigate whether HFD consumption during rat pregnancy and lactation influences the cerebral vasculature in adult male offspring. Besides the endothelial damage observed in the transmission electron microscopy, the MCAs of offspring from fat-fed dams fed with control diet (HFD/C) also displayed increased wall thickness and media/lumen ratio, suggesting that cerebrovascular hypertrophy or hyperplasia occurs. Moreover, smaller lumen diameter and elevated myogenic tone of the MCAs over a range of intralumenal pressures indicate inward cerebrovascular remodeling in HFD/C rats, with a concomitant increase in vessel stiffness. More importantly, both wire and pressure myography demonstrated that maternal HFD intake also enhanced the MCAs contractility to ET-1, accompanied by increases in ET types A receptor (ETAR) but not B (ETBR) density in the arteries. Furthermore, ETAR antagonism but not ETBR antagonism restored maternal HFD induced cerebrovascular dysfunction in adult offspring. Taken together, maternal diet can substantially influence adult offspring cerebrovascular health, through remodeling of both structure and function, at least partially in an ET-1 manner. PMID- 28914130 TI - High failure rate after internal fixation and beneficial outcome after arthroplasty in treatment of displaced femoral neck fractures in patients between 55 and 70 years. AB - Background and purpose - The treatment of patients between 55 and 70 years with displaced intracapsular femoral neck fracture remains controversial. We compared internal fixation (IF), bipolar hemiarthroplasty (HA) and total hip arthroplasty (THA) in terms of mortality, reoperations and patient-reported outcome by using data from the Norwegian Hip Fracture Register. Patients and methods - We included 2,713 patients treated between 2005 and 2012. 1,111 patients were treated with IF, 1,030 with HA and 572 patients with THA. Major reoperations (defined as re osteosynthesis, secondary arthroplasty, exchange, or removal of prosthesis components and Girdlestone procedure), patient-reported outcome measures (satisfaction, pain, and health-related quality of life (EQ5D) after 4 and 12 months), 1-year mortality, and change in treatment methods over the study period were investigated. Results - Major reoperations occurred in 27% after IF, 3.8% after HA and 2.8% after THA. 549 patients (20% of total study population) answered both questionnaires. Compared with IF, patients treated with THA were more satisfied after 4 and 12 months, reported less pain after 4 months and 12 months, had a higher EQ5D-index score after 4 months and 12 months, and EQ-VAS score after 4 months. Compared with IF, patients treated with HA were more satisfied and reported less pain after 4 months. EQ5D-index and EQ-VAS were similar. Patients treated with HA had higher 1-year mortality and had more comorbidities than both the THA and IF group. All these differences were statistically and clinically significant. Interpretation - This study showed high reoperation rate after IF and better patient-reported outcome after both THA and HA with medium follow-up. Patients selected for HA represented a frailer group than patients treated with THA or IF. PMID- 28914131 TI - Safety and Efficacy of Repeat Open-Label AbobotulinumtoxinA Treatment in Pediatric Cerebral Palsy. AB - This was a prospective, repeat-treatment, open-label study (NCT01251380) of abobotulinumtoxinA for the management of lower limb spasticity in children who had completed a double-blind study. Children (2-17 years) received injections into the gastrocnemius-soleus complex, and other distal and proximal muscles as required (maximum total dose per injection cycle: 30 U/kg or 1000U). A total of 216 of the 241 double-blind patients entered the extension study and 207 received >=1 open label injection into the gastrocnemius-soleus; 17-24% of patients also had injections into the hamstrings. The most frequent adverse events were related to common childhood infections and the most frequent treatment-related adverse event was injection site pain (n = 10). There was no evidence of a cumulative effect on adverse events. Sustained significant clinical improvements in muscle tone (Modified Ashworth Scale), spasticity (Tardieu Scale), overall clinical benefit (Physicians Global Assessment), and goal attainment (Goal Attainment Scale) were also observed across treatment cycles. PMID- 28914133 TI - Age of donor of human mesenchymal stem cells affects structural and functional recovery after cell therapy following ischaemic stroke. AB - Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion. PMID- 28914134 TI - Blunted cerebrovascular response is associated with elevated beta-amyloid. AB - The goal of this study was to explore the association of beta-amyloid accumulation and cerebrovascular response (CVR) in cognitively normal older adults. Beta-amyloid accumulation was characterized with [18F] Florbetapir positron emission tomography scans. CVR was calculated as middle cerebral artery blood flow velocity change from rest to moderate intensity exercise. We found that individuals with elevated beta-amyloid aggregation had a blunted CVR ( n = 25, age 70.1 +/- 4.8; 3.3 +/- 3.7 cm/s) compared to non-elevated individuals ( n = 45, age 72.0 +/- 4.9; 7.2 +/- 5.0 cm/s, p < 0.001). Further, greater beta amyloid burden was linearly associated with less CVR across all participants (b = -11.7, p < 0.001). Greater CVR and less beta-amyloid burden were associated with processing speed ( p < 0.05). This study is the first to show that CVR from rest to exercise is blunted across increased global beta-amyloid burden. PMID- 28914132 TI - Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury. AB - Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+. We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme's flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process. PMID- 28914135 TI - Hemodynamic and Anatomic Predictors of Renovisceral Stent-Graft Occlusion Following Chimney Endovascular Repair of Juxtarenal Aortic Aneurysms. AB - PURPOSE: To identify anatomic and hemodynamic changes associated with impending visceral chimney stent-graft occlusion after endovascular aneurysm repair (EVAR) with the chimney technique (chEVAR). METHODS: A retrospective evaluation was performed of computed tomography scans from 41 patients who underwent juxtarenal chEVAR from 2008 to 2012 to identify stent-grafts demonstrating conformational changes following initial placement. Six subjects (mean age 74 years; 3 men) were selected for detailed reconstruction and computational hemodynamic analysis; 4 had at least 1 occluded chimney stent-graft. This subset of repairs was systematically analyzed to define the anatomic and hemodynamic impact of these changes and identify signature patterns associated with impending renovisceral stent-graft occlusion. Spatial and temporal analyses of cross-sectional area, centerline angle, intraluminal pressure, and wall shear stress (WSS) were performed within the superior mesenteric and renal artery chimney grafts used for repair. RESULTS: Conformational changes in the chimney stent-grafts and associated perturbations, in both local WSS and pressure, were responsible for the 5 occlusions in the 13 stented branches. Anatomic and hemodynamic signatures leading to occlusion were identified within 1 month postoperatively, with a lumen area <14 mm2 (p=0.04), systolic pressure gradient >25 Pa/mm (p=0.03), and systolic WSS >45 Pa (p=0.03) associated with future chimney stent-graft occlusion. CONCLUSION: Chimney stent-grafts at increased risk for occlusion demonstrated anatomic and hemodynamic signatures within 1 month of juxtarenal chEVAR. Analysis of these parameters in the early postoperative period may be useful for identifying and remediating these high-risk stent-grafts. PMID- 28914136 TI - Protecting the Innocence of Youth: Moral Sanctity Values Underlie Censorship From Young Children. AB - Three studies examined the relationship between people's moral values (drawing on moral foundations theory) and their willingness to censor immoral acts from children. Results revealed that diverse moral values did not predict censorship judgments. It was not the case that participants who valued loyalty and authority, respectively, sought to censor depictions of disloyal and disobedient acts. Rather, censorship intentions were predicted by a single moral value sanctity. The more people valued sanctity, the more willing they were to censor from children, regardless of the types of violations depicted (impurity, disloyalty, disobedience, etc.). Furthermore, people who valued sanctity objected to indecent exposure only to apparently innocent and pure children-those who were relatively young and who had not been previously exposed to immoral acts. These data suggest that sanctity, purity, and the preservation of innocence underlie intentions to censor from young children. PMID- 28914137 TI - Comparing phoneme frequency, age of acquisition, and loss in aphasia: Implications for phonological universals. AB - Phonological complexity may be central to the nature of human language. It may shape the distribution of phonemes and phoneme sequences within languages, but also determine age of acquisition and susceptibility to loss in aphasia. We evaluated this claim using frequency statistics derived from a corpus of phonologically transcribed Italian words (phonitalia, available at phonitalia,org), rankings of phoneme age of acquisition (AoA) and rate of phoneme errors in patients with apraxia of speech (AoS) as an indication of articulatory complexity. These measures were related to cross-linguistically derived markedness rankings. We found strong correspondences. AoA, however, was predicted by both apraxic errors and frequency, suggesting independent contributions of these variables. Our results support the reality of universal principles of complexity. In addition they suggest that these complexity principles have articulatory underpinnings since they modulate the production of patients with AoS, but not the production of patients with more central phonological difficulties. PMID- 28914138 TI - The Role of Conscious Attention in How Weight Serves as an Embodiment of Importance. AB - Inconsistency among findings in the embodied cognition literature suggests a need for theoretical boundary conditions. The current research proposes that conscious attention of a bodily state can moderate its influence on social judgment. Three studies tested this possibility in the case of the demonstrated effect of weight sensations on judgments of an abstract idea's importance. Studies 1 and 2 showed that participants rated a topic as more important when holding a moderately heavy, compared with light, clipboard. However, when the clipboard was very heavy, participants rated the survey topic as less important compared with when the clipboard was moderately heavy. The differences in importance ratings were not caused by derogation of the topic or the activation of a different metaphor. In Study 3, the importance rating difference between light and moderately heavy clipboards was eliminated by explicitly drawing perceiver's attention to the clipboard's weight. Implications and future directions are discussed. PMID- 28914139 TI - The influence of geometric design variables on the kinematic performance of a surface-guided total knee replacement. AB - OBJECTIVE: Tibiofemoral geometries in a total knee replacement (TKR) affect the performance of an implant during activities of daily living. The specially shaped components of a surface-guided TKR aim to control the tibiofemoral motion, such that a normal pattern of motion is achieved, even at high flexion angles. The purpose of this study was to assess the influence of the design parameters on the kinematic behavior of such an implant. A combination of design variables was determined that resulted in the least deviation from the design kinematic target. METHODS: Six major design variables were considered to generate customized surface-guided TKR candidates. The contribution of these variables was evaluated by principal component analysis considering the input design variables and the results of the kinematic performance from a virtual simulation of deep squatting. The tibial internal-external rotation and the anterior-posterior translation of the medial and lateral femoral condyles were recorded for each design candidate. A quantified objective function of the kinematic behavior was used to define the design with a maximum agreement with the target pattern of motion. RESULTS: The location and orientation of the flexion-extension axis and the tibial slope were the most contributing parameters on the modes of variation. On the other hand, the conformity between the lateral guiding arcs had the least contribution. CONCLUSION: Virtual simulation showed that the current TKR reached deep flexion angles under squat load, while the tibia pivoted around the medial center. The tibial rotation was within the expected range of the IE rotation from healthy joints. PMID- 28914140 TI - The Faces of Group Members Share Physical Resemblance. AB - Perceivers form strong inferences of disposition from others' facial appearance, and these inferences guide a wide variety of important behaviors. The current research examines the possibility that similar-looking individuals are more likely to form groups with one another. We do so by testing a necessary downstream consequence of this process, examining whether the faces of individuals within groups more physically resemble one another than those in other groups. Across six studies, we demonstrate that individuals' group membership can be accurately classified both from ratings of members' faces, and from direct measurement of members' faces. Results provide insight into how affiliative groups initially form and maintain membership over time, as well as the perception of homogeneity of groups. PMID- 28914141 TI - Higher USA State Resident Neuroticism Is Associated With Lower State Volunteering Rates. AB - Highly neurotic persons have dispositional characteristics that tend to precipitate social anxiety that discourages formal volunteering. With the 50 American states as analytical units, Study 1 found that state resident neuroticism correlated highly ( r = -.55) with state volunteering rates and accounted for another 26.8% of the volunteering rate variance with selected state demographics controlled. Study 2 replicated Study 1 during another period and extended the association to college student, senior, secular, and religious volunteering rates. Study 3 showed state resident percentages engaged in other social behaviors involving more familiarity and fewer demands than formal volunteering related to state volunteering rates but not to neuroticism. In Study 4, state resident neuroticism largely accounted statistically for relations between state volunteering rates and state population density, collectivism, social capital, Republican preference, and well-being. This research is the first to show that state resident neuroticism is a potent predictor of state volunteering rates. PMID- 28914142 TI - Theorizing and Measuring Religiosity Across Cultures. AB - For almost 50 years, psychologists have been theorizing about and measuring religiosity essentially the way Gordon Allport did, when he distinguished between intrinsic and extrinsic religiosity. However, there is a historical debate regarding what this scale actually measures, which items should be included, and how many factors or subscales exist. To provide more definitive answers, we estimated a series of confirmatory factor analysis models comparing four competing theories for how to score Gorsuch and McPherson's commonly used measure of intrinsic and extrinsic religiosity. We then formally investigated measurement invariance across U.S. Protestants, Irish Catholics, and Turkish Muslims and across U.S. Protestants, Catholics, and Muslims. We provide evidence that a five item version of intrinsic religiosity is invariant across the U.S. samples and predicts less warmth toward atheists and gay men/lesbians, validating the scale. Our results suggest that a variation of Gorsuch and McPherson's measure may be appropriate for some but not all uses in cross-cultural research. PMID- 28914143 TI - In Harm's Way: On Preferential Response to Threatening Stimuli. AB - Given the evolutionary significance of survival, the mind might be particularly sensitive (in terms of strength and speed of reaction) to stimuli that pose an immediate threat to physical harm. To rectify limitations in past research, we pilot-tested stimuli to obtain images that are threatening, nonthreatening negative, positive, or neutral. Three studies revealed that participants (a) were faster to detect a threatening than nonthreatening-negative image when each was embedded among positive or neutral images, (b) oriented their initial gaze more frequently toward threatening than nonthreatening-negative, positive, or neutral images, and (c) evidenced larger startle-eyeblinks to threatening than to nonthreatening-negative, positive, or neutral images. Social-psychological implications for the mind's sensitivity to threat are discussed. PMID- 28914144 TI - Impaired disengagement of attention and its relationship to emotional distress in infants at high-risk for autism spectrum disorder. AB - INTRODUCTION: We provide data on visual orienting and emotional distress in infants at high and low risk for autism spectrum disorder (ASD). METHOD: Participants included 83 high-risk (HR) infants with an older sibling with ASD and 53 low-risk (LR) control infants with no family history of ASD. Infants were assessed on the gap-overlap task and a parent-completed temperament questionnaire at 6 and 12 months of age. At 36 months of age, an independent, gold standard diagnostic assessment for ASD was conducted. RESULTS: HR infants subsequently diagnosed with ASD were distinguished at 12 months by an asymmetric disengage impairment (for left- vs. right-sided stimuli) that was associated with an increase in latencies between 6 and 12 months. Across groups, prolonged left directed disengage latencies at 12 months were associated with emotional distress (high irritability and difficult to soothe). CONCLUSIONS: The asymmetry in our findings raises the question of whether the disengage problem in ASD is at base one of orienting or alerting attention. Our findings also raise the question of whether attention training might be a critical ingredient in the early treatment of ASD. PMID- 28914145 TI - Did You Reject Me for Someone Else? Rejections That Are Comparative Feel Worse. AB - Rejections differ. For those who are rejected, one important difference is whether they are rejected for someone else (comparative rejection) or no one at all (noncomparative rejection). We examined the effect of this distinction on emotional reactions to a rejection in four studies ( N = 608), one of which was fully preregistered. Our results show that comparative rejections feel worse than noncomparative rejections and that this may be because such rejections lead to an increased sense of exclusion and decreased belonging. Furthermore, we found evidence that, by default, people react to a rejection as though it were comparative-that is, in the absence of any information about whether they have been rejected for someone or no one, they react as negatively as if they were rejected for someone. Our discussion focuses on the implications of these findings, including why people often seek out information in the wake of a rejection. PMID- 28914146 TI - Effects of age and type of picture on visuospatial working memory assessed with a computerized jigsaw-puzzle task. AB - We investigated the effect of age and color in a computerized version of the jigsaw-puzzle task. In Experiment 1, young and older adults were presented with puzzles in color and black-and-white line drawings, varying in difficulty from 4 to 9 pieces. Older adults performed the task better with the black-and-white stimuli and younger adults performed better with the color ones. In Experiment 2, new older and young adults identified the same fragmented pictures as fast and accurately as possible. The older group identified the black-and-white stimuli faster than those presented in color, while the younger adults identified both similarly. In Experiment 3A, new older and young groups performed the puzzle task with the same color pictures and their monochrome versions. In Experiment 3B, participants performed a speeded identification task with the two sets. The findings of these experiments showed that older adults have a memory not a perceptual difficulty. PMID- 28914147 TI - Attitudes Toward Euthanasia Among Turkish University Students. AB - This study aims to examine perceptions and attitudes toward euthanasia among university students who are pursuing bachelor's degrees. Although the legalization and application of euthanasia are discussed commonly by health-care professionals and partially by lawyers, the ideas of other segments of society, especially university students, are taken place very rarely. The research was conducted descriptively to determine the ideas of 1,170 students at Kastamonu University from six different departments: arts and sciences, theology, tourism, nursing, school of physical education, and sports with using a questionnaire. Findings demonstrated that 73.2% of the students do not approve euthanasia. Also, it was found that there are significant differences depending on age, gender, department of study, income level, place of living, and the loss of kinsmen. This study serves as a resource for future research to understand the effects of sociodemographic characteristics on the decision of euthanasia. PMID- 28914148 TI - DNA methylation in candidate genes for handedness predicts handedness direction. AB - Handedness is a complex trait influenced by both genetic and non-genetic factors. Asymmetries of DNA methylation and gene expression in the developing foetus are thought to underlie its development. However, its molecular epigenetics are not well understood. We collected buccal cells from adult left- and right-handers (n = 60) to investigate whether epigenetic biomarkers of handedness can be identified in non-neuronal tissue. We associated DNA methylation in promoter regions of candidate genes with handedness direction. Results indicate that DNA methylation of genes asymmetrically expressed in the foetal brain or spinal cord might play a role within such a multifactorial model. Moreover, we provide tentative evidence that birth stress might be a factor that affects DNA methylation in NEUROD6, a gene that is asymmetrically expressed in foetal brains. PMID- 28914149 TI - Identifying the nature of impairments in executive functioning and working memory of children with severe difficulties in arithmetic. AB - An age-matched achievement-matched design was used to examine whether the executive functioning and working memory impairments exhibited by children with severe difficulties in arithmetic (SDA) are better viewed as developmental lags or as cognitive deficits. Three groups of children were included: 20 SDA children, 20 typically achieving children (CM) matched in chronological age with the SDA children, and 20 younger typically achieving children (AM) matched in achievement with the SDA group. While children with SDA did not exhibit impairments in color-word inhibition and verbal working memory, they did demonstrate impairments in shifting, quantity-digits inhibition, and visuospatial working memory. As children with SDA did not perform more poorly than their AM counterparts on any of these tasks, impairments in specific areas of executive functioning and working memory appear to reflect developmental lags rather than cognitive deficits. PMID- 28914150 TI - A computerized test for the assessment of mild cognitive impairment subtypes in sentence processing. AB - This study examines thesentence processing ability of mild cognitive impairment (MCI) subtypes. In addition to standard MCI neuropsychological tests, an experimental approach was applied to assess language. 133 people (93 MCI/40 controls) participated in novel computerized sentence processing tasks. Results presented statistically significant differences between MCI/controls andMCI subtypes (ANOVA):(a) duration F(2,92) = 19.259,p < .001) in sentence construction; (b) correct answers (F(2, 89) = 8.560,p < .001) and duration (F2,89) = 15.525,p < .001)in text comprehension; (c) correct answers (F(2, 92) = 8.975,p < .001) andduration (F(2, 92) = 4.360,p = .016) in metaphoric sentences comprehension; (d) correct answers (F(2, 92) = 12.836,p < .001) andduration (F(2, 92) = 10.974,p < .001) in verb form generation. Subtle changes in MCIsubtypes could affect sentence processing and provide useful information for cognitive decline risk estimation and screening purposes. PMID- 28914151 TI - Defining Social Class Across Time and Between Groups. AB - We examined changes over four decades and between ethnic groups in how people define their social class. Changes included the increasing importance of income, decreasing importance of occupational prestige, and the demise of the "Victorian bargain," in which poor people who subscribed to conservative sexual and religious norms could think of themselves as middle class. The period also saw changes (among Whites) and continuity (among Black Americans) in subjective status perceptions. For Whites (and particularly poor Whites), their perceptions of enhanced social class were greatly reduced. Poor Whites now view their social class as slightly but significantly lower than their poor Black and Latino counterparts. For Black respondents, a caste-like understanding of social class persisted, as they continued to view their class standing as relatively independent of their achieved education, income, and occupation. Such achievement indicators, however, predicted Black respondents' self-esteem more than they predicted self-esteem for any other group. PMID- 28914152 TI - Half a Gift Is Not Half-Hearted: A Giver-Receiver Asymmetry in the Thoughtfulness of Partial Gifts. AB - Four studies document an asymmetry in givers' and receivers' evaluations of gifts: Givers underestimate the extent to which receivers perceive partial (but more desirable) gifts to be thoughtful, valuable, and worthy of appreciation. Study 1 documents this asymmetry and suggests that givers underestimate the extent to which partial gifts signal thoughtfulness to receivers. Study 2 replicates this asymmetry in the context of a real gift exchange among friends. Study 3 shows that this asymmetry arises because givers believe that purchasing partial gifts is a greater violation of gift-giving norms than do receivers, leading givers to expect that partial gifts will damage receivers' perceptions of a gift's value. Study 4 offers an intervention that induces givers to select the (partial) gifts that receivers prefer more than givers expect: framing a gift's separate components as complete units. PMID- 28914153 TI - Cardiotoxicity with carfilzomib at doses greater than 27 mg/m2: A case series. AB - Carfilzomib is a second-generation proteasome inhibitor that irreversibly inhibits chymotrypsin-like (CT-L) activities of the proteasome, and is indicated for relapsed or refractory multiple myeloma. Cardiotoxicity is a well-established adverse effect of carfilzomib. The extent of cardiac toxicity in the literature spans anywhere from palpitations to cardiac arrest, with the most commonly reported manifestation being new-onset or worsening heart failure. A pre-clinical study of the pharmacokinetics and pharmacodynamics of carfilzomib given via intravenous bolus or 30-minute infusion in rats showed that carfilzomib can strongly induce apoptosis and potently damage cardiac myocytes at clinically relevant concentrations. Moreover, the mortality rate with the bolus administration was 44% whereas the same dose administered as a 30-minute infusion did not result in mortality. There remains limited clinical data regarding the safety of carfilzomib at doses of 27-56 mg/m2 based on infusion times as these doses have not been well studied. This retrospective review was conducted to evaluate the safety of carfilzomib at doses >27 mg/m2 at all infusion times. PMID- 28914154 TI - The Failure of Null Hypothesis Significance Testing When Studying Incremental Changes, and What to Do About It. AB - A standard mode of inference in social and behavioral science is to establish stylized facts using statistical significance in quantitative studies. However, in a world in which measurements are noisy and effects are small, this will not work: selection on statistical significance leads to effect sizes which are overestimated and often in the wrong direction. After a brief discussion of two examples, one in economics and one in social psychology, we consider the procedural solution of open postpublication review, the design solution of devoting more effort to accurate measurements and within-person comparisons, and the statistical analysis solution of multilevel modeling and reporting all results rather than selection on significance. We argue that the current replication crisis in science arises in part from the ill effects of null hypothesis significance testing being used to study small effects with noisy data. In such settings, apparent success comes easy but truly replicable results require a more serious connection between theory, measurement, and data. PMID- 28914155 TI - Psychological Foundations of Xenophilia: Understanding and Measuring the Motivational Functions of Exploratory Cross-Cultural Contact. AB - Two multipart studies (total N = 1,638) were conducted to introduce and test a functional perspective on exploratory cross-cultural contact. Studies 1a and 1b addressed the lack of standardized measures and developed a psychometrically valid inventory of six individual motivational functions: knowledge and understanding, value expression, professional advancement, social development, personal-, and group-image concerns. Studies 2a and 2b produced experimental evidence that different environments offer differing "fulfillment opportunities" such that the motivating potential of a distinct contact function results from a function by environment fit. First, participants were more persuaded by and wanted to visit a cultural center more when it matched their motivational functions (Study 2a). Second, participants showed a preference to choose an intercultural interaction partner with a higher potential over a partner with a lower potential to fulfill their primary cross-cultural contact motivation (Study 2b, preregistered). Theoretical and practical implications of this perspective are discussed. PMID- 28914156 TI - Lexical decision performance in developmental surface dysgraphia: Evidence for a unitary orthographic system that is used in both reading and spelling. AB - The relationship between spelling, written word recognition, and picture naming is investigated in a study of seven bilingual adults who have developmental surface dysgraphia in both Greek (their first language) and English (their second language). Four of the cases also performed poorly at orthographic lexical decision in both languages. This finding is consistent with similar results in Italian that have been taken as evidence of a developmental impairment to a single orthographic system that is used for both reading and spelling. The remaining three participants performed well at orthographic lexical decision. At first sight, preserved lexical decision in surface dysgraphia is less easy to explain in terms of a shared orthographic system. However, the results of subsequent experiments showed clear parallels between the nature of the reading and spelling difficulties that these three individuals experienced, consistent with the existence of a single orthographic system. The different patterns that were observed were consistent with the claims of Friedmann and Lukov (2008. Developmental surface dyslexias. Cortex, 44, 1146-1160) that several distinct sub types of developmental surface dyslexia exist. We show that individual differences in spelling in surface dysgraphia are also consistent with these sub types; there are different developmental deficits that can give rise, in an individual, to a combination of surface dyslexia and dysgraphia. Finally, we compare the theoretical framework used by Friedmann and her colleagues that is based upon the architecture of the DRC model with an account that relies instead upon the Triangle model of reading]. PMID- 28914157 TI - Keeping Minorities Happy: Hierarchy Maintenance and Whites' Decreased Support for Highly Identified White Politicians. AB - We test the hypothesis that, to avoid provoking minorities, Whites will withhold their support for White political candidates who are highly identified with their race. In Study 1, we found that White Republicans were less supportive of White candidates the higher the perceived White identity of the candidate due to beliefs that such candidates would provoke racial minorities. In Study 2, we replicated this effect with a manipulation of candidates' White identity. Study 3 found that Whites reported less support for high-identity candidates when they were led to believe that the hierarchy was unstable rather than stable. Consistent with our hypothesis that those who have the most to lose are most likely to avoid provoking minorities, in Study 4, we found that Whites with high subjective socioeconomic status (SES) varied their support for provocative White candidates as a function of hierarchy stability, whereas those with low subjective SES did not. PMID- 28914158 TI - Studying Positive and Negative Direct and Extended Contact: Complementing Self Reports With Social Network Analysis. AB - Traditionally, studies of intergroup contact have primarily relied on self reports, which constitute a valid method for studying intergroup contact, but has limitations, especially if researchers are interested in negative or extended contact. In three studies, we apply social network analyses to generate alternative contact parameters. Studies 1 and 2 examine self-reported and network based parameters of positive and negative contact using cross-sectional datasets ( N = 291, N = 258), indicating that both methods help explain intergroup relations. Study 3 examines positive and negative direct and extended contact using the previously validated network-based contact parameters in a large-scale, international, and longitudinal dataset ( N = 12,988), demonstrating that positive and negative direct and extended contact all uniquely predict intergroup relations (i.e., intergroup attitudes and future outgroup contact). Findings highlight the value of social network analysis for examining the full complexity of contact including positive and negative forms of direct and extended contact. PMID- 28914159 TI - Positive Stereotype Validation: The Bolstering Effects of Activating Positive Stereotypes After Intellectual Performance. AB - Past research has found that members of stigmatized groups may feel more certain of poor performance when negative stereotypes are made accessible after finishing a task (i.e., stereotype validation). However, no research to date has identified the potential effects of activating positive stereotypes after performance. Based on past research and theory, we hypothesized that such positive stereotype validation may serve to bolster-rather than hinder-important beliefs related to one's abilities and future task performance. Across three studies, the accessibility of positive group stereotypes was manipulated after participants completed an initial test on a topic. Consistent with predictions, the activation of positive, self-relevant stereotypes after the initial test was found to increase how certain participants were that they performed well on it. Furthermore, these increases in evaluative certainty predicted more positive ability beliefs, higher expectations for future performance, and better performance on a follow-up test that participants completed. PMID- 28914160 TI - Making Boundaries Great Again: Essentialism and Support for Boundary-Enhancing Initiatives. AB - Psychological essentialism entails a focus on category boundaries (e.g., categorizing people as men or women) and an increase in the conceptual distance between those boundaries (e.g., accentuating the differences between men and women). Across eight studies, we demonstrate that essentialism additionally entails an increase in support for boundary-enhancing legislation, policies, and social services, and that it does so under conditions that disadvantage social groups, as well as conditions that benefit them. First, individual differences in essentialism were associated with support for legislation mandating that transgender people use restrooms corresponding with their biological sex, and with support for the boundary-enhancing policies of the 2016 then-presumptive Republican presidential nominee (i.e., Donald Trump). Second, essentialism was associated with support for same-gender classrooms designed to promote student learning, as well as support for services designed to benefit LGBTQ (lesbian, gay, bisexual, transgender, queer) individuals. These findings demonstrate the boundary-enhancing implications of essentialism and their social significance. PMID- 28914161 TI - A Net of Friends: Investigating Friendship by Integrating Attachment Theory and Social Network Analysis. AB - The current article focuses on attachment style-an individual difference widely studied in the field of close relationships-and its application to the study of social networks. Specifically, we investigated whether attachment style predicts perception and management of social networks. In Study 1, we examined the associations of attachment style with perceptions of network tie strength and multiplexity. In Studies 2a and 2b, we investigated the association between attachment style and network management skills (initiating, maintaining, and dissolving ties) and whether network management skills mediated the associations of attachment style with network tie strength and multiplexity. In Study 3, experimentally enhancing attachment security made people more likely to initiate and less likely to dissolve social ties (for the latter, especially among those high on avoidance or anxiety). As for maintenance, security priming also increased maintenance; however, mainly among people high on attachment anxiety or low on attachment avoidance. PMID- 28914162 TI - Mere Gifting: Liking a Gift More Because It Is Shared. AB - We investigated a type of mere similarity that describes owning the same item as someone else. Moreover, we examined this mere similarity in a gift-giving context, whereby givers gift something that they also buy for themselves (a behavior we call "companionizing"). Using a Heiderian account of balancing unit sentiment relations, we tested whether gift recipients like gifts more when gifts are companionized. Akin to mere ownership, which describes people liking their possessions more merely because they own them, we tested a complementary prediction: whether people like their possessions more merely because others own them too. Thus, in a departure from previous work, we examined a type of similarity based on two people sharing the same material item. We find that this type of sharing causes gift recipients to like their gifts more, and feel closer to gift givers. PMID- 28914163 TI - Truth or Punishment: Secrecy and Punishing the Self. AB - We live in a world that values justice; when a crime is committed, just punishment is expected to follow. Keeping one's misdeed secret therefore appears to be a strategic way to avoid (just) consequences. Yet, people may engage in self-punishment to right their own wrongs to balance their personal sense of justice. Thus, those who seek an escape from justice by keeping secrets may in fact end up serving that same justice on themselves (through self-punishment). Six studies demonstrate that thinking about secret (vs. confessed) misdeeds leads to increased self-punishment (increased denial of pleasure and seeking of pain). These effects were mediated by the feeling one deserved to be punished, moderated by the significance of the secret, and were observed for both self-reported and behavioral measures of self-punishment. PMID- 28914164 TI - The Danish National Youth Study 2014: Study design, population characteristics and non-response analysis. AB - AIMS: This paper aims to give a description of the Danish National Youth Study 2014 in terms of study design, study population and questionnaire content. The differences between participants and non-participants regarding socioeconomic characteristics are also described. METHODS: The Danish National Youth Study 2014 was a web-based survey with data collected through self-completion questionnaires administered in the classroom. There were two questionnaires: one for students, with >250 core questions; and one for school leaders on the school environment. Data collection took place at 119 high schools and 10 vocational schools. RESULTS: A total of 75,853 students participated (70,674 high school students and 5179 vocational school students). In the participating schools, 85% of high school students and 69% of vocational school students took part in the survey. A total of 166 school leaders responded. Among the high school students, 61% were girls, and among vocational school students, 24% were girls. The average age was 17.9 years for high school students and 20.9 years for vocational school students. Participants were more likely than non-participants to be of Danish origin and to have parents with higher educational levels and a higher disposable income. CONCLUSIONS: The Danish National Youth Study 2014 contributes to knowledge on adolescent health behaviour, health and well-being. It is unique in its size, diversity of questionnaire content, high participation rate and possibility of linkage to various national registers through the Danish Civil Registration System. The study offers great opportunities for health planning and a wide range of future research projects. PMID- 28914165 TI - Mobile instant messaging for rural community health workers: a case from Malawi. AB - BACKGROUND: Mobile instant messaging (MIM) tools, such as WhatsApp, have transformed global communication practice. In the field of global health, MIM is an increasingly used, but little understood, phenomenon. OBJECTIVES: It remains unclear how MIM can be used by rural community health workers (CHWs) and their facilitators, and what are the associated benefits and constraints. To address this gap, WhatsApp groups were implemented and researched in a rural setting in Malawi. METHODS: The multi-site case study research triangulated interviews and focus groups of CHWs and facilitators with the thematic qualitative analysis of the actual conversations on WhatsApp. A survey with open questions and the quantitative analysis of WhatsApp conversations were used as supplementary triangulation sources. RESULTS: The use of MIM was differentiated according to instrumental (e.g. mobilising health resources) and participatory purposes (e.g. the enactment of emphatic ties). The identified benefits were centred on the enhanced ease and quality of communication of a geographically distributed health workforce, and the heightened connectedness of a professionally isolated health workforce. Alongside minor technical and connectivity issues, the main challenge for the CHWs was to negotiate divergent expectations regarding the social versus the instrumental use of the space. CONCLUSIONS: Despite some challenges and constraints, the implementation of WhatsApp was received positively by the CHWs and it was found to be a useful tool to support distributed rural health work. PMID- 28914166 TI - Repeated Iron-Soot Exposure and Nose-to-brain Transport of Inhaled Ultrafine Particles. AB - Particulate exposure has been implicated in the development of a number of neurological maladies such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, and idiopathic Parkinson's disease. Only a few studies have focused on the olfactory pathway as a portal through which combustion-generated particles may enter the brain. The primary objective of this study was to define the deposition, uptake, and transport of inhaled ultrafine iron-soot particles in the nasal cavities of mice to determine whether combustion-generated nanoparticles reach the olfactory bulb via the olfactory epithelium and nerve fascicles. Adult female C57B6 mice were exposed to iron-soot combustion particles at a concentration of 200 MUg/m3, which included 40 MUg/m3 of iron oxide nanoparticles. Mice were exposed for 6 hr/day, 5 days/week for 5 consecutive weeks (25 total exposure days). Our findings visually demonstrate that inhaled ultrafine iron-soot reached the brain via the olfactory nerves and was associated with indicators of neural inflammation. PMID- 28914167 TI - Nephrotic syndrome in infants and children: pathophysiology and management. AB - Nephrotic syndrome is defined by nephrotic-range proteinuria (>=40 mg/m2/hour or urine protein/creatinine ratio >=200 mg/mL or 3+ protein on urine dipstick), hypoalbuminaemia (<25 g/L) and oedema. This review focuses on the classification, epidemiology, pathophysiology, management strategies and prognosis of idiopathic nephrotic syndrome of childhood, and includes a brief overview of the congenital forms. PMID- 28914168 TI - Synthesis of Cr3+-doped TiO2 nanoparticles: characterization and evaluation of their visible photocatalytic performance and stability. AB - Cr3+-doped TiO2 nanoparticles (Ti-Cr) were synthesized by microwave-assisted sol gel method. The Ti-Cr catalyst was characterized by X-ray diffraction, ultraviolet-visible diffuse reflectance spectroscopy, N2 adsorption-desorption analysis, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy (XPS) and zetametry. The anatase mesoporous Ti-Cr material exhibited a specific surface area of 54.5 m2/g. XPS analysis confirmed the proper substitution of Ti4+ cations by Cr3+ cations in the TiO2 matrix. The particle size was of average size of 17 nm for the undoped TiO2 but only 9.5 nm for Ti-Cr. The Cr atoms promoted the formation of hydroxyl radicals and modified the surface adsorptive properties of TiO2 due to the increase in surface acidity of the material. The photocatalytic evaluation demonstrated that the Ti-Cr catalyst completely degraded (4-chloro-2-methylphenoxy) acetic acid under visible light irradiation, while undoped TiO2 and P25 allowed 45.7% and 31.1%, respectively. The rate of degradation remained 52% after three cycles of catalyst reuse. The higher visible light photocatalytic activity of Ti-Cr was attributed to the beneficial effect of Cr3+ ions on the TiO2 surface creating defects within the TiO2 crystal lattice, which can act as charge-trapping sites, reducing the electron-hole recombination process. PMID- 28914169 TI - Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care. AB - BACKGROUND: Early identification of virological failure (VF) limits occurrence and spread of drug-resistant viruses in patients receiving antiretroviral treatment (ART). Viral load (VL) monitoring is therefore recommended, but capacities to comply with this are insufficient in many low-income countries. Clinical algorithms might identify persons at higher likelihood of VF to allocate VL resources. OBJECTIVES: We aimed to construct a VF algorithm (the Viral Load Testing Criteria; VLTC) and compare its performance to the 2013 WHO treatment failure criteria. METHODS: Subjects with VL results available 1 year after ART start (n = 494) were identified from a cohort of ART-naive adults (n = 812), prospectively recruited and followed 2011-2015 at Ethiopian health centres. VF was defined as VL>=1000 copies/mL. Variables recorded at the time of sampling, with potential association with VF, were used to construct the algorithm based on multivariate logistic regression. RESULTS: Fifty-seven individuals (12%) had VF, which was independently associated with CD4 count <350 cells/mm3, previous ART interruption, and short mid-upper arm circumference (<24cm and <23cm, for men and women, respectively). These variables were included in the VLTC. In derivation, the VLTC identified 52/57 with VF; sensitivity 91%, specificity 43%, positive predictive value (PPV) 17%, negative predictive value (NPV) 97%. In comparison, the WHO criteria identified 38/57 with VF (sensitivity 67%, specificity 74%, PPV 25%, NPV 94%). CONCLUSIONS: The VLTC identified subjects at greater likelihood of VF, with higher sensitivity and NPV than the WHO criteria. If external validation confirms this performance, these criteria could be used to allocate limited VL resources. Due to its limited specificity, it cannot be used to determine treatment failure in the absence of a confirmatory viral load. PMID- 28914170 TI - The investigation of the effects of topiramate on the hypothalamic levels of fat mass/obesity-associated protein and neuropeptide Y in obese female rats. AB - OBJECTIVE: The aim of the present study is to investigate the effects of topiramate on the fat mass/obesity-associated protein (FTO) and on the neuropeptide Y (NPY) level in the hypothalamus depending on the recently increased prevalence of obesity. METHOD: In this study, twenty-four female rats were divided into four equal groups: Non-obese control, obese control, non-obese topiramate, and obese topiramate. Obese groups were fed with a 40% high-fat diet. At the end of the 9th week, the drug treatment started and the subjects were treated with topiramate once a day for 6 weeks. All animals underwent cardiac perfusion under high-dose anesthesia on the 15th week. Tissues were analyzed using biochemical, histological, and stereological methods. RESULTS: In terms of neuron number in the arcuate nucleus area, a significant difference was observed among all groups (P < 0.01). The neuron number of the non-obese topiramate group was found to be significantly higher than that of the non-obese control group (P < 0.01). In the examination of the ventromedial nucleus of the entire group, it was observed that the neuron number of the non-obese control group was significantly lower than those of the other groups (P < 0.01). A significant increase in the NPY levels of the obese groups compared to the groups treated with topiramate was observed. Furthermore, the amount of the FTO protein increased in obese rats, while FTO and NPY levels decreased in the groups treated with topiramate. DISCUSSION: In conclusion, the mechanism of the effect of topiramate to create a state of obesity is thought to involve the decrease in the levels of NPY and FTO. PMID- 28914171 TI - Exploring the effects of high temperature on mortality in four cities in the Philippines using various heat wave definitions in different mortality subgroups. AB - BACKGROUND: Sustained high temperatures, specifically heat waves (HW), increase the risk of dying, especially among risk populations, which are highly vulnerable to its additional effect. In developing countries, there are only a few studies which focused on the magnitude of the risks attributed to HWs. OBJECTIVES: This study explored the HW effects using 15 HW definitions through the combination of duration (> 2, > 4, and > 7 consecutive days) and intensity (at the >= 90th, >= 95th, >= 97th, >= 98th, and >= 99th temperature percentiles). METHODS: Daily mortality count data from 2006-2010 were obtained from the four tropical cities of the Philippines, and were further stratified by mortality sub-groups, such as cause of death, sex, and age. The same period of daily maximum temperature and relative humidity were also collected. We used a distributed lag non-linear model to determine the risks associated with the main temperature effects, as well as the added HW effects. RESULTS: It has been observed that the main temperature effects comprise a substantial portion of the risks compared to the HW effects, even across the mortality sub-groups. Further stratification by the sub-groups showed significant HW effects among the young and male populations. CONCLUSIONS: Results of this study can be of use to improve (1) candidate HW definition identification/selection, and (2) risk population-specific strategies, taking into consideration the risk attributions. PMID- 28914172 TI - Effects of pharmacological inhibition of plasminogen binding on liver regeneration in rats. AB - The fibrinolysis system is thought to play an important role in liver regeneration. We previously found that plasminogen (Plg) is localized to the cell surface of regenerating liver tissue as well as proliferating hepatocytes in vitro. Here, we investigated the significance of Plg binding to the cell surface during liver regeneration. Pre-administration of tranexamic acid (TXA), which is a competitive inhibitor of Plg binding, to hepatectomized rats mildly delayed restoration of liver weight in vivo. Although binding of Plg to the cell membrane decreased following TXA administration, TXA showed little effect on hepatocyte proliferation in rats. We also discovered that Plg treatment did not stimulate proliferation of primary rat hepatocytes in vitro. These results suggest that Plg/plasmin potentiates liver regeneration via a pathway distinct from those through which hepatocyte proliferation is stimulated. PMID- 28914173 TI - Flow cytometric analysis of patients with hereditary spherocytosis - an Indian scenario. AB - OBJECTIVES: Flow cytometry osmotic fragility test (FC-OFT) was a recently introduced screening test for hereditary spherocytosis (HS). This study was conducted to evaluate the utility of FC-OFT in all newly diagnosed cases of HS, to compare its diagnostic value with conventional OFT and to correlate with clinical disease severity. METHODS: In this study, the percentage of residual red cells (%RRC) was measured using flow cytometer after creating a red cell suspension. Subsequently, this was spiked with deionized water for FC-OFT in all cases of HS (n = 40), healthy subjects (n = 40) and beta-thalassemia traits (BTT) (n = 20). RESULTS: The receiver operator curve analysis defined the optimal cut offs for FC-OFT-derived indices, such as %RRC value (<=16.29%) and %RRC ratio (>1.72), for HS cases when compared with healthy subjects and BTT (p < 0.05). The FC-OFT (96%) achieved higher test efficiency than the conventional OF test (68.9%). A significant positive and a negative correlation were found between number of spherocytes/hpf and %RRC ratio (p = 0.001) and %RRC values (p = 0.0486). No significant correlation was observed between %RRC value (p = 0.8934), %RRC ratio (p = 0.6348) and HS disease severity score. CONCLUSION: Our results suggest that FC-OFT could be the better screening test for HS cases in developing countries if flow cytometer is available. PMID- 28914174 TI - (Dis)entangling Barad: Materialisms and ethics. AB - In the wake of the widespread uptake of and debate surrounding the work of Karen Barad, this article revisits her core conceptual contributions. We offer descriptions, elaborations, problematizations and provocations for those intrigued by or invested in this body of work. We examine Barad's use of quantum physics, which underpins her conception of the material world. We discuss the political strengths of this position but also note tensions associated with applying quantum physics to phenomena at macro-scales. We identify both frictions and unacknowledged affinities with science and technology studies in Barad's critique of reflexivity and her concept of diffraction. We flesh out Barad's overarching position of 'agential realism', which contains a revised understanding of scientific apparatuses. Building upon these discussions, we argue that inherent in agential realism is both an ethics of inclusion and an ethics of exclusion. Existing research has, however, frequently emphasized entanglement and inclusion to the detriment of foreclosure and exclusion. Nonetheless, we contend that it is in the potential for an ethics of exclusion that Barad's work could be of greatest utility within science and technology studies and beyond. PMID- 28914175 TI - Menstruation experiences of South African women belonging to the ama-Xhosa ethnic group. AB - A growing body of research has emphasised the salience of cultural beliefs and traditional practices to women's experiences of menstruation. Relatively less research has, however, been undertaken in South Africa. This study explored the experience of menstruation among women from the ama-Xhosa ethnic group, one of the largest ethnic groups in the country. Among the ama-Xhosa, there are distinct cultural practices associated with menstruation, including the female rite of passage (intonjane) and virginity testing (inkciyo). However, few studies have explored the experience of menstruation for women from this cultural group. This study involved the synthesis of data from individual interviews and focus group discussions conducted among a sample of ama-Xhosa women. The data were analysed using thematic analysis. Distinctive findings included women's participation in traditional cultural practices of intonjane and inkciyo and the presence of cultural taboos associated with menstruation. Women's narratives revealed strong ambivalence regarding these practices. On the one hand, they wanted to adhere to traditional practices but experienced these customs as evoking discomfort and shame. The study confirmed the prevalence of negative constructions of menstruation. Positive appraisals of menstruation as evoking joy and happiness were also encountered. PMID- 28914176 TI - Intraoperative Gutter Leaks That Merit Our Attention. AB - INTRODUCTION: The natural history and potential morbidity of gutter endoleaks are unclear. We present our experience with intraoperative gutter endoleaks and strategies to determine which of these require intervention. METHODS: This is a retrospective review of all patients treated with parallel stent grafts from January 2010 to September 2015. We reviewed all operative records and intraoperative angiograms as well as all postoperative imaging and secondary interventions. All gutter leaks were classified as low-flow/nonsac-enhancing gutter endoleaks or high-flow/sac-enhancing gutter endoleaks. Adjunctive interventions to manage the gutter leaks were noted, as were all subsequent interventions for gutter leak and endoleak management. RESULTS: Seventy-eight patients had 144 parallel stents placed over a 5-year period with an average of 1.8 stents per patient. Twenty-eight patients (36%) had gutter endoleaks diagnosed intraoperatively. Seventeen patients had adjunctive procedures to reduce gutter leaks prior to leaving the operating room (OR). Patients selected for treatment had gutters filling early during completion angiography and/or contrast enhancement of the aneurysm sac. Twenty-two patients (28%) left the OR with low-flow/delayed/nonsac-enhancing gutter endoleaks. At 30 days, a total of 6 persistent gutter endoleaks were diagnosed on computed tomographic angiography. This gives a 73% rate of resolution for low-flow/nonaneurysm sac-enhancing endoleaks. There were 2 de novo endoleaks not detected at the index procedure diagnosed at 6-month follow-up. Of the 8 total postoperative endoleaks, 5 required additional intervention with a 100% success rate. Multivariate analysis revealed that the only significant predictor of having a postoperative endoleak is leaving the OR with an endoleak. CONCLUSIONS: Intraoperative treatment of gutter endoleaks has an acceptable rate of resolution. It does have a high rate of converting high-flow endoleaks to low-flow endoleaks. Low-flow/nonsac enhancing gutter endoleaks have a high rate of spontaneous resolution. Intraoperative gutter endoleaks are not predictive of future aneurysm sac growth. PMID- 28914177 TI - Sedentariness and weight status related to SES and family characteristics in Italian adults: exploring geographic variability through multilevel models. AB - AIM: In this study, our aim was to assess the prevalence of sedentariness and overweight/obesity, two modifiable risk factors for non-communicable diseases (NCDs), and to investigate the geographic variability in their association with socio-economic status (SES) and family characteristics in Italian adults. METHODS: The Multipurpose Survey on Health Conditions and the Recourse to Health Services (MSHC), 2012/2013 edition, conducted by the National Institute of Statistics was used as data source. The sample for this study included 99,479 interviewed people aged 18 and over, which are representative of about 50 million persons. For the scope of this analysis, data were considered as individuals nested within families within regions and analysed through multilevel models. RESULTS: It was estimated that 39.8% of Italian adults are sedentary, 38.1% are partially active and 22.1% are physically active; 11.3% of Italian adults are obese and the 34.5% are overweight. There was evidence of inverse socio-economic gradient for both sedentariness and body mass index (BMI). There was higher risk of sedentariness for one-parent (odds ratio (OR) = 1.10; 95% confidence interval (CI) = (1.02; 1.20)) and other family types (OR = 1.34; 95% CI = (1.20; 1.48 )) compared with couples with children. Also, the relative variation of BMI was statistically significant for one-parent, one-person and other families ( p < 0.05). An increasing north-south gradient was suggested for BMI, but not for sedentariness. CONCLUSIONS: Policy interventions could be addressed to reduce BMI levels in the southern area and to encourage physical activity in regions with high sedentariness. The Italian family is the key driver to promote virtuous healthy behaviours. PMID- 28914178 TI - 'You just have to learn to keep moving on': young women's experiences with unplanned pregnancy in the Cook Islands. AB - The Cook Islands is one of several countries in the Pacific region that has high rates of teenage pregnancy and birth. While the social determinants of pregnancy and early motherhood are well established in the global context, little is known about how Cook Islands young women who become pregnant before age 20 make sense of their experiences. Drawing on individual interviews with a purposive sample of 10 young mothers, this paper examines the phenomenology of early pregnancy from their perspectives. Structural, cultural and individual factors emerged as salient themes in participants' accounts. Qualitative analysis revealed that nearly all the pregnancies were unplanned and every participant reacted negatively when she learned she was pregnant. While some participants wanted to terminate their pregnancies, lack of access to safe, legal and affordable abortion care limited their options. Ultimately, while nearly all participants wished they had been able to delay motherhood, they expressed happiness and pride about their new-found status as mothers. These findings allow for a fuller understanding of factors shaping young women's experiences of pregnancy in the Cook Islands, which have policy implications for reproductive health and rights. PMID- 28914179 TI - Neutralization of acidic drainage by Cryptococcus sp. T1 immobilized in alginate beads. AB - We isolated Cryptococcus sp. T1 from Lake Tazawa's acidic water in Japan. Cryptococcus sp. T1 neutralized an acidic casamino acid solution (pH 3.0) and released ammonia from the casamino acids to aid the neutralization. The neutralization volume was estimated to be approximately 0.4 mL/h. The casamino acids' amino acids decreased (1.24->0.15 mM); ammonia increased (0.22->0.99 mM). We neutralized acidic drainage water (1 L) from a Tamagawa River neutralization plant, which was run through the column with the T1-immobilized alginate beads at a flow rate of 0.5 mL/min, and observed that the viscosity, particle size and amounts of the alginate beads affected the acidic drainage neutralization with an increase of the pH value from 5.26 to 6.61 in the last fraction. An increase in the Al concentration decreased Cryptococcus sp. T1's neutralization ability. After 48 h, the pH of acidic water with 50 mg/L Al was apparently lower than that without Al. Almost no pH increase was observed at 75 mg/L. PMID- 28914181 TI - Remediation approach for organic compounds and arsenic co-contaminated soil using the pressurized hot water extraction process. AB - Successful remediation of soil with co-existing organics contaminants and arsenic (As) is a challenge as the chemical and remediation technologies are different for each group of pollutants. In this study, the treatment effectiveness of the pressurized hot water (PHW) extraction process was investigated for remediation of soil co-contaminated with phenol, crude oil, polycyclic aromatic hydrocarbons (PAHs), and As. An elimination percentage of about 99% was achieved for phenol, and in the range of 63-100% was observed for the PAHs at 260 degrees C for 90 min operation. The performance of PHW extraction in the removal of total petroleum hydrocarbons was found to be 86%. Of the 87 mg/kg of As in untreated soil, 67% of which was eliminated after treatment. The removal of organic contaminants was mainly via desorption, dissolution and degradation in subcritical water, while As was eliminated probably by oxidation and dissolution of arsenic-bearing minerals. According to the experimental results, the PHW extraction process can be suggested as an alternative cleaning technology, instead of using any organic solvents for remediation of such co-contaminated soil. PMID- 28914180 TI - Symptoms-Based Phenotypes Among Women With Dysmenorrhea: A Latent Class Analysis. AB - Dysmenorrhea is highly prevalent and may increase women's risk for developing other chronic pain conditions. Although it is highly variable, symptom-based dysmenorrhea phenotypes have not been identified. The aims of the study were to identify symptom-based dysmenorrhea phenotypes and examine their relationships with demographic and clinical characteristics. In a cross-sectional study, 762 women with dysmenorrhea rated severity of 14 dysmenorrhea-related symptoms. Using latent class analysis, we identified three distinctive phenotypes. Women in the "mild localized pain" phenotype ( n = 202, 26.51%) had mild abdominal cramps and dull abdominal pain/discomfort. Women in the "severe localized pain" phenotype ( n = 412, 54.07%) had severe abdominal cramps. Women in the "multiple severe symptoms" phenotype ( n = 148, 19.42%) had severe pain at multiple locations and multiple gastrointestinal symptoms. Race, ethnicity, age, and comorbid chronic pain conditions were significantly associated with phenotypes. Identification of these symptom-based phenotypes provides a foundation for research examining genotype-phenotype associations, etiologic mechanisms, and/or variability in treatment responses. PMID- 28914182 TI - Energy Drink Adverse Effects: What Is Being Done to Protect Public Health? PMID- 28914183 TI - Enhancing mercury removal across air pollution control devices for coal-fired power plants by desulfurization wastewater evaporation. AB - Desulfurization wastewater evaporation technology is used to enhance the removal of gaseous mercury (Hg) in conventional air pollution control devices (APCDs) for coal-fired power plants. Studies have affirmed that gaseous Hg is oxidized and removed by selective catalytic reduction (SCR), an electrostatic precipitator (ESP) and wet flue gas desulfurization (WFGD) in a coal-fired thermal experiment platform with WFGD wastewater evaporation. Effects of desulfurization wastewater evaporation position, evaporation temperature and chlorine ion concentration on Hg oxidation were studied as well. The Hg0 oxidation efficiency was increased ranging from 30% to 60%, and the gaseous Hg removal efficiency was 62.16% in APCDs when wastewater evaporated before SCR. However, the Hg0 oxidation efficiency was 18.99% and the gaseous Hg removal efficiency was 40.19% in APCDs when wastewater evaporated before ESP. The results show that WFGD wastewater evaporation before SCR is beneficial to improve the efficiency of Hg oxidized and removed in APCDs. Because Hg2+ can be easily removed in ACPDs and WFGD wastewater in power plants is enriched with chlorine ions, this method realizes WFGD wastewater zero discharge and simultaneously enhances Hg removal in APCDs. PMID- 28914184 TI - Elements of effective community engagement: lessons from a targeted malaria elimination study in Lao PDR (Laos). AB - BACKGROUND: Mass drug (antimalarial) administration (MDA) is currently under study in Southeast Asia as part of a package of interventions referred to as targeted malaria elimination (TME). This intervention relies on effective community engagement that promotes uptake and adherence in target communities (above 80%). OBJECTIVE: Based on the experienced of designing and implementing the community engagement for TME in Laos, in this article we aim to present the elements of effective community engagement for mass antimalarial administration. METHODS: The design and implementation of community engagement, which took place from September 2015 to August 2016 was recorded as field notes, meeting minutes and photographs. These data underwent qualitative content analysis. RESULTS: The community engagement strategy that accompanied TME in Laos was successful in terms of contributing to high levels of participation in mass anti-malarial administration (above 85%). Based on the experience of designing and implementing the community engagement, five key elements were identified: (1) stakeholder and authority engagement, which proceeded from national level, to regional/district and local level; (2) local human resources, particularly the recruitment of local volunteers who were integral to the design and implementation of activities in the study villages; (3) formative research, to rapidly gain insight into the local social and economic context; (4) responsiveness whereby the approach was adapted according to the needs of the community and their responses to the various study components; and (5) sharing control/leadership with the community in terms of decisions on the organization of TME activities. CONCLUSIONS: The community engagement that accompanied TME in Laos had to deal with challenges of implementing a complex study in remote and linguistically isolated villages. Despite these challenges, the study recorded high population coverage. Lessons learnt from this experience are useful for studies and intervention programs in diverse contexts. PMID- 28914186 TI - Viral and parasitic pathogen burden and the association with stroke in a population-based cohort. AB - Background Higher cumulative burden of viral and bacterial pathogens may increase the risk of stroke, but the contribution of parasitic infections in relation to cumulative pathogen burden and risk of stroke has rarely been examined. Aim To estimate the association of multiple persistent viral and parasitic infections with stroke in a representative sample of adults in the United States. Methods Serological evidence of prior infection was categorized as positive for 0-1, 2, 3, or 4-5 infections based on immunoglobulin G seropositivity to cytomegalovirus, hepatitis A virus, hepatitis B virus, Toxoplasma gondii, and Toxocara spp. in 13,904 respondents from the National Health and Nutrition Examination Survey III. Regression analysis was used to estimate the cross-sectional association between serological evidence of prior infection and history of stroke adjusting for demographic risk factors, and potential mediators of stroke. Results Age-adjusted models that included serological evidence of prior infection to cytomegalovirus, hepatitis A virus, hepatitis B virus, Toxoplasma gondii, and Toxocara spp. showed that adults in the highest serological evidence of prior infection category (4-5 infections) had a higher prevalence of stroke (5.50%, 95% confidence interval 2.44-10.46%) than those in the lowest serological evidence of prior infection categories (1.49%, 95% confidence interval 1.01-2.11%), and a trend test suggested a graded association between serological evidence of prior infection and stroke ( p = 0.02). In multivariable logistic regression models, the positive association of serological evidence of prior infection with stroke prevalence remained significant after adjustment for other significant risk factors (odds ratio = 1.4, p = 0.01) but was only significant among those aged 20-59 (odds ratio = 2.0, p = 0.005) and not among those aged 60-69 ( p = 0.78) or 70 and older ( p = 0.43). Conclusion We found support for a connection between serological evidence of prior infection to cytomegalovirus, hepatitis A virus, hepatitis B virus, Toxoplasma gondii, and Toxocara spp. and stroke among those aged 20-59. There may be a need to consider common parasitic infections in addition to viral and bacterial pathogens when calculating serological evidence of prior infection in relation to cerebrovascular disease. PMID- 28914187 TI - Improving quality and outcomes of stroke care in hospitals: Protocol and statistical analysis plan for the Stroke123 implementation study. AB - : Rationale The effectiveness of clinician-focused interventions to improve stroke care is uncertain. Aims To determine whether an organizational intervention can improve the quality of stroke care over usual care. Sample size estimates To detect an absolute 10% difference in overall performance (composite outcome), a minimum of 21 hospitals and 843 patients per group was determined. Methods and design Before and after controlled design in hospitals in Queensland, Australia. Intervention Externally facilitated program (StrokeLink) using outreach workshops incorporating clinical performance feedback, patient outcomes (survival, quality of life at 90-180 days), local barrier assessments to best practice care, action planning, and ongoing support. Descriptive and multivariable analyses adjusted for patient correlations by hospital (intention to-treat method). Context Concurrent implementation of financial incentives to increase stroke unit access and use of the Australian Stroke Clinical Registry for performance monitoring. Study outcome(s) Primary outcome: net change in composite score (i.e. total number of process indicators achieved divided by the sum of eligible indicators for each cohort). SECONDARY OUTCOMES: change in individual indicators, change in composite score comparing hospitals that did or did not develop action plans (per-protocol analysis), impact on 90-180-day health outcomes. Sensitivity analyses: hospital self-rated status, alternate cross sectional audit data (Stroke Foundation). To account for temporal effects, comparison of Queensland hospital performance relative to other Australian hospitals will also be undertaken. Discussion Twenty-one hospitals were recruited; however, one was unable to participate within the study time frame. Workshops were held between 11 March 2014 and 7 November 2014. Data are ready for analysis. PMID- 28914188 TI - A Retrospect Study on Thiazole Derivatives as the Potential Antidiabetic Agents in Drug Discovery and Developments. AB - BACKGROUND: Heterocycles containing thiazole, a moiety with sulfur and nitrogen is a core structure which is found in a number of biologically active compounds. The thiazole ring is notable as a component of the certain natural products, such as vitamin B1 (thiamine) and penicillins. Thiazole is also known as wonder nucleus and has uses in different biological fields. A number of new compounds contain heterocycle thiazole moieties, thus it is one of the important areas of research. METHODS: We searched the scientific database using relevant keywords. Among the searched literature only peer-reviewed papers were collected which addresses our questions. The retrieved quality research articles were screened and analyzed critically. The key findings of these studies were included along with their importance. RESULTS: The quality research articles included in this review were selected for the lifethreatening diseases i.e. diabetes, which is one of the serious issues all over the globe with an estimated worldwide prevalence in 2016 of 422 million people, which is expected to rise double to by 2030. Since 1995, there has been an explosion of the introduction of new classes of pharmacological agents having thiazole moieties. However, most of the drugs can cause noncompliance, hypoglycemia, and obesity. Thus, new antidiabetic drugs with thiazole moieties came up with improved compliance and reduced side effects such as pioglitazone (Actos), rosiglitazone (Avandia), netoglitazone, DRF-2189, PHT46, PMT13, DRF-2519. With such a great importance, research in thiazole is part of many academic and industrial laboratories worldwide. CONCLUSION: The present review describes the importance of thiazole nucleus and its derivatives as antidiabetic agents with an emphasis on the past as well as recent developments. PMID- 28914185 TI - Power, potential, and pitfalls in global health academic partnerships: review and reflections on an approach in Nepal. AB - BACKGROUND: Global health academic partnerships are centered around a core tension: they often mirror or reproduce the very cross-national inequities they seek to alleviate. On the one hand, they risk worsening power dynamics that perpetuate health disparities; on the other, they form an essential response to the need for healthcare resources to reach marginalized populations across the globe. OBJECTIVES: This study characterizes the broader landscape of global health academic partnerships, including challenges to developing ethical, equitable, and sustainable models. It then lays out guiding principles of the specific partnership approach, and considers how lessons learned might be applied in other resource-limited settings. METHODS: The experience of a partnership between the Ministry of Health in Nepal, the non-profit healthcare provider Possible, and the Health Equity Action and Leadership Initiative at the University of California, San Francisco School of Medicine was reviewed. The quality and effectiveness of the partnership was assessed using the Tropical Health and Education Trust Principles of Partnership framework. RESULTS: Various strategies can be taken by partnerships to better align the perspectives of patients and public sector providers with those of expatriate physicians. Actions can also be taken to bring greater equity to the wealth and power gaps inherent within global health academic partnerships. CONCLUSIONS: This study provides recommendations gleaned from the analysis, with an aim towards both future refinement of the partnership and broader applications of its lessons and principles. It specifically highlights the importance of targeted engagements with academic medical centers and the need for efficient organizational work-flow practices. It considers how to both prioritize national and host institution goals, and meet the career development needs of global health clinicians. PMID- 28914189 TI - A Hopeful Prospect of Riociguat as a Soluble Guanylate Cyclase Stimulator for Management of Pressure Ulcers. AB - BACKGROUND: Pressure ulcer remains as a common problem, especially developed in disabled patients and hence, subjected to continuous pressure for prolonged periods of time. Most of the studies investigating the preventive and therapeutic approaches have focused on wound cleansing, dressing and supportive strategies, as well as pharmacological therapy including zinc sulphate, vitamin A or phenytoin. Despite such efforts, pressure ulcer continues to impair the life quality and expectancy. Thus involving in the paradigm shift in biomedical studies, the recent ones focus on biological signaling pathways involving nitric oxide (NO)- soluble guanylatecyclase (sGC)- cyclic guanosine monophosphate (cGMP) contributing in vasodilation, reperfusion and oxygen delivery. METHODS: Literatures review focusing on NO/sGC/cGMP pathway was performed as well as seeking themolecular biology aspects inKyoto Encyclopedia of genes and genomes (KEGG). RESULTS: NO is an important signaling molecule activating sGC and cGMP production, which is a mediator of vasodilation and platelet inhibition. Considering the subject, it could be hypothesized that the application of sGC stimulators and activators is a very curious strategy for pressure ulcer healing. It is well known that pressure and shear forces usually produce the blood vessel obstruction, inducing ischemia and tissue necrosis and in pathologic states, damaged endothelium leads to a reduced synthesis of NO and inadequate oxygen supply contributing to delayed wound healing. Riociguat is the first FDA approved agent of new class of sGC stimulators, involving in activation of sGC both in presence and absence of NO. CONCLUSION: The findings of this review confirm that Riociguat could start a new therapeutic approach for pressure ulcer treatment even with dysfunctional endothelium. PMID- 28914190 TI - Perioperative Considerations of Herbal Medications. AB - BACKGROUND: A considerable portion of the US population uses herbal supplements on a daily basis for their various proposed beneficial effects. However, the over the-counter nature of these medications and lack of knowledge of adverse effect profiles can have unexpected serious impact on the perioperative course. The growing list of supplements presents a pharmacologic conundrum to the anesthesiologist. OBJECTIVE: The study aimed to compile a comprehensive list of vitamins, herbals, and supplements used commonly by patients, describe the risks associated with them, and identify recommendations for perioperative management. METHOD: The current literature on PubMed and Medline was reviewed for the years 2000 through 2016. The reference lists of each selected article were also reviewed for additional sources of information. RESULTS: The review identified 23 herbals and supplements that are commonly used and their perioperative considerations. CONCLUSION: The management of herbals and supplements is an issue for the anesthesiologist. Although it would be prudent to stop the use of most substances a week or more preoperatively, the perioperative physician must be wary of the potential for withdrawal. PMID- 28914191 TI - Neoisoliquiritigenin Inhibits Tumor Progression by Targeting GRP78-beta- catenin Signaling in Breast Cancer. AB - BACKGROUND: Breast cancer mortality has been stable or decreasing in the world, its incidence and recurrence rates have sharply risen worldwide in the recent years. OBJECTIVE: To investigate the clinicopathological significance and potential function of GRP78 in the development and progression of breast cancer. To explore the effects of neoisoliquiritigenin (NISL) in breast cancer and the underlying mechanism. METHOD: GRP78 was detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs), and the association between GRP78 levels and clinicopathological factors and prognosis was analyzed. The functional effects of GRP78 on breast cancer were validated by an MTT assay, foci formation assay, Matrigel invasion assay and mouse xenograft assay. The effects of NISL were tested by an MTT assay, apoptosis assay and mouse xenograft assay. A LigandFit algorithm, ATPase activity assay, western blot and IHC assay were used to discover the underlying mechanism of the effects of NSIL. RESULTS: GRP78 was highly expressed in breast cancer cell lines and tissues. In addition, high expression of GRP78 was correlated to poor outcomes and distant metastasis. Functional experiments showed that GRP78 promoted breast cancer proliferation and invasion in vitro and in vivo. NISL inhibited cell proliferation and induced cell apoptosis in breast cancer by directly binding to GRP78 to regulate the beta catenin pathway. CONCLUSION: Taken together, these results highlighted the significance of GRP78 in breast cancer development and suggested NISL as a natural candidate to inhibit breast cancer by targeting GRP78 and beta-catenin signaling. PMID- 28914192 TI - Current Trends in Cancer Biomarker Discovery Using Urinary Metabolomics: Achievements and New Challenges. AB - : The development of effective screening methods for early cancer detection is one of the foremost challenges facing modern cancer research. Urinary metabolomics has recently emerged as a potentially transformative approach to cancer biomarker discovery owing to its noninvasive sampling characteristics and robust analytical feasibility. OBJECTIVE: To provide an overview of new developments in urinary metabolomics, cover the most promising aspects of hyphenated techniques in untargeted and targeted metabolomics, and to discuss technical and clinical limitations in addition to the emerging challenges in the field of urinary metabolomics and its application to cancer biomarker discovery. METHOD: A systematic review of research conducted in the past five years on the application of urinary metabolomics to cancer biomarker discovery was performed. Given the breadth of this topic, our review focused on the five most widely studied cancers employing urinary metabolomics approaches, including lung, breast, bladder, prostate, and ovarian cancers. RESULTS: As an extension of conventional metabolomics, urinary metabolomics has benefitted from recent technological developments in nuclear magnetic resonance, mass spectrometry, gas and liquid chromatography, and capillary electrophoresis that have improved urine metabolome coverage and analytical reproducibility. Extensive metabolic profiling in urine has revealed a significant number of altered metabolic pathways and putative biomarkers, including pteridines, modified nucleosides, and acylcarnitines, that have been associated with cancer development and progression. CONCLUSION: Urinary metabolomics presents a transformative new approach toward cancer biomarker discovery with high translational capacity to early cancer screening. PMID- 28914193 TI - Chalcone Derivatives: Anti-inflammatory Potential and Molecular Targets Perspectives. AB - Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-kappaB (NF- kappaB), Intracellular Cell Adhesion Molecule-1 (ICAM 1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein 1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted. PMID- 28914194 TI - Diabetic Retinopathy: Recent Updates on Different Biomarkers and Some Therapeutic Agents. AB - BACKGROUND: Diabetic Retinopathy is a leading cause of sight-threatening complication, which occurs due to a number of physiological and metabolic abnormalities during later stages of diabetes. Many of these abnormal changes are consistent with altered oxidative stress, inflammation, genetic set up, advanced glycation end products, and hematological changes. So the altered levels of different biomolecules related to these changes serve as important biomarkers to assess better evaluation and early treatment of this disease. Some treatments like laser therapy may be fast and specific but are more expensive, limited and can result in severe contraindications. Several other novel treatment strategies have been evolved recently besides classical approaches like control over hyperglycemia, hypertension, lipid profile to control diabetic retinopathy. These precise treatments are based on targeting the elevated biomarkers in retina. Such treatments include use of anti-VEGF therapy, intravitreal corticosteroids, gamigliptin and flavonoids. CONCLUSION: The present review discusses the latest updates on diabetic retinopathy, common etiology, different biomarkers and current treatments. In conclusion, perfection and proper supervision of diabetes and early treatment of diabetic retinopathy are crucial in controlling the occurrence and severity of this disease. PMID- 28914195 TI - Polymorphism rs9939609 of Fat Mass and Obesity-associated Gene Correlation with Leptin Level of Obese Women Suffered from Type 2 Diabetes. AB - BACKGROUND: Recent studies reported that Fat Mass and Obesity-associated gene (FTO) single nucleotides polymorphisms (SNPs), especially rs9939609, have association with obesity and type 2 diabetes mellitus. On the other hand, many researches confirmed that leptin, an adipocytokine, is related to the obesity and Body Mass Index (BMI) in patients who suffered from Type 2 Diabetes (T2DM). OBJECTIVE: In this study, the correlation of FTO rs9939609 polymorphism and leptin level was investigated in the obese women who suffered from T2DM. METHODS: In case-control study, metabolic and anthropometric parameters, and leptin level of 38 obese diabetic and 38 non-diabetic women were investigated. Genotyping of rs9939609 FTO gene was completed by sequencing of PCR amplicons for all cases. RESULTS: According to the results, FBS, age, HbA1c, insulin level, HOMA index and leptin level showed statistically significant difference between diabetic and non diabetic women (P < 0.05). Based on the adjusting of FTO rs9939609 SNP with anthropometric and metabolic parameters, no significant difference was found between the three genotypes (AA, TA and TT) in non-diabetic women (P > 0.05). But, in the diabetic group, only TC had significant difference and mean of TC was higher in mutant genotypes (AA and TA) than wild genotype (TT). Also, BMI, insulin, LDL and HDL showed negative correlation with leptin level in both groups but these correlations were not statistically significant. CONCLUSION: The results of our study (with little sample size) showed that the mean of leptin level in diabetic women was lower than non-diabetic women (significant difference). However, the level of leptin was not statistically significant between three genotypes, and odds ratio of rs9939609 was higher in diabetic women in comparison with non-diabetic women. PMID- 28914196 TI - Ethnic Disparity and Increased Prevalence of Type 2 Diabetes Among South Asians: Aetiology and Future Implications for Diabetes Prevention and Management. AB - BACKGROUND: Type 2 Diabetes Mellitus (T2DM) is turning out to be a global health crisis. Currently available literature clearly indicates an increased risk of type 2 diabetes amongst South Asian population. OBJECTIVE: The objective of this narrative review is to explore the non-modifiable and modifiable risk factors of T2DM in South Asian population, including their beliefs, attitudes, socio economic and cultural barriers and also to explore the possible implications in designing culture specific diabetes prevention and management programs. METHODS: This narrative review is based upon the data from individual studies and review article known to the authors. Additional relevant studies were identified through PubMed search on Englishlanguage papers published in 2000-2017 using the relevant keywords. Where appropriate, the reference lists of key papers were reviewed to identify additional studies of interest. RESULTS: Many genetic and environmental risk factors such as diet, physical inactivity, and sleep contribute to the increased prevalence of diabetes in the ethnic group. Providing mere knowledge about diabetes and these risk factors might not be sufficient in this particular ethnic group. It is essential to address their beliefs, attitudes and the cultural barriers faced. CONCLUSION: To overcome the health disparity in the South Asian ethnic group, various risk factors associated with diabetes, and the challenges faced are to be considered while designing future diabetes prevention and management strategies. PMID- 28914197 TI - Characterization of Inherent Particles and Mechanism of Thermal Stress Induced Particle Formation in HSV-2 Viral Vaccine Candidate. AB - BACKGROUND: Vaccine formulations may contain visible and/or subvisible particles, which can vary in both size and morphology. Extrinsic particles, which are particles not part of the product such as foreign contaminants, are generally considered undesirable and should be eliminated or controlled in injectable products. However, biological products, in particular vaccines, may also contain particles that are inherent to the product. Here we focus on the characterization of visible and subvisible particles in a live, replication-deficient viral vaccine candidate against HSV genital herpes in an early developmental stage. METHOD: HSV-2 viral vaccine was characterized using a panel of analytical methods, including Fourier transform infrared spectroscopy (FTIR), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, liquid chromatography-mass spectrometry (LC-MS), light microscopy, transmission electron microscopy (TEM), micro-flow imaging (MFI), dynamic light scattering (DLS), right angle light scattering (RALS), and intrinsic fluorescence. RESULTS: Particles in HSV-2 vaccine typically ranged from hundreds of nanometers to hundreds of micrometers in size and were determined to be inherent to the product. The infectious titer did not correlate with any trend in subvisible particle concentration and size distribution as shown by DLS, MFI, and TEM under stressed conditions. This suggested that particle changes in the submicron range were related to HSV-2 virion structure and had direct impact on biological activity. It was also observed that subvisible and visible particles could induce aggregation in the viral product. The temperature induced aggregation was observed by RALS, intrinsic fluorescence, and DLS. The increase of subvisible particle size with temperature could be fitted to a two-step thermokinetic model. CONCLUSION: Visible and subvisible particles were found to be inherent to the HSV 2 viral vaccine product. The mechanism of protein aggregation was discussed and a two-step thermokinetic aggregation profile was proposed. The approaches reported in this study may be applied to a variety of vaccines and other biological products, as a way to assess the consistency of the manufacturing process and identify key product quality attributes. PMID- 28914198 TI - PeMtb: A Database of MHC Antigenic Peptide of Mycobacterium tuberculosis. AB - BACKGROUND: For design of a subunit vaccine for tuberculosis, identification of antigenic Tcell epitope is of utmost importance. Several MHC prediction server are available that can accurately predict antigenic peptide of variable lengths. However, peptides predicted from one server not necessarily are predicted form another server, thus creating a confusing situation for scientists to choose a best epitope. METHOD: Keeping the above problem in mind, we developed a comprehensive database of peptides of Mycobacterial proteins. Each protein was taken from PubMed and was run through different MHC prediction servers, with the results being compiled into one database. RESULTS: For each protein, PeMtb generates a set of three different mers of variable lengths (12 mer or 13-mer) based on their ranking; with each mer being predicted for a plethora of MHC alleles. Researcher can choose the peptide (mers) that gives best binding affinity from most of the servers. CONCLUSION: The database relieves the investigators of the painstaking task of searching various MHC prediction servers for the right epitope (T-cell epitope) for a particular Mycobacterial antigen. We trust and anticipate that PeMtb will be a practical platform for trial and computational analyses of antigenic peptides for Mycobacterium tuberculosis. All the resources and information can be accessed by PeMtb home page www.pemtb amu.org. PMID- 28914199 TI - Clinical Applications of Intravenous Immunoglobulins in Child Neurology. AB - BACKGROUND: While there are guidelines for the use of intravenous immunoglobulins in children with Guillain-Barre syndrome and myasthenia gravis based on high level evidence studies, data are scarce for the majority of neurologic disorders in this age group. Neuronal antibodies are detected in children with seizures of autoimmune etiology. Intravenous immunoglobulins with their broad immunomodulatory mechanism of action could be ideally effective in different forms of immunedysregulated intractable epilepsies such as autoimmune epilepsy and autoimmune Rasmussen encephalitis. We conducted a systematic review of the literature for evidence of the use of intravenous immunoglobulins in a variety of neurologic diseases in childhood. METHOD: A comprehensive literature search was conducted using Pubmed as the medical database source without date range. Prospective studies in pediatric groups including objective measures of clinical outcomes were systematically selected. RESULTS: A total of 11 prospective studies were identified in the literature demonstrating a favorable effect of this therapeutic option in children with drug-resistant epilepsy and in cases of encephalitis. No serious adverse effects were reported. No prospective studies about the use of intravenous immunoglobulins in children with demyelinating disorders or neurologic paraneoplasmatic syndromes were found. CONCLUSION: In this review, we summarize the recent advances in the field of intravenous immunoglobulins used in pediatric neurological diseases. Literature data supports a beneficial effect in this age group. Whilst awaiting the results of large scale studies, administration of intravenous immunoglobulins could be justified in refractory child epilepsy. Otherwise, its use should be guided by the individual needs of each child, depending on the underlying neurological disease. PMID- 28914201 TI - The Transport Mechanism of Extracellular Vesicles at the Blood-Brain Barrier. AB - Recently, extracellular vesicles (EVs), like exosomes and microvesicles, have attracted attention as potent carriers of intercellular communication throughout the body, including the brain. They transmit biological signals from donor cells to recipient cells, and recent evidence suggests that they may even carry such signals to distant destinations through peripheral circulation. In the central nervous system (CNS), EVs contribute to maintaining normal neuronal function, as well as to the pathological development of neurodegenerative diseases. Although some evidence has suggested that EVs can cross the blood-brain barrier (BBB), moving from the peripheral circulation to the CNS, the mechanisms by which EVs facilitate communication between peripheral tissues and the CNS are not well understood. The BBB is a dynamic interface that regulates molecular trafficking between the peripheral circulation and the CNS. However, there is limited mechanistic understanding of how bloodborne EVs cross the BBB under physiological and pathological conditions. In this review, we focus on current knowledge of trafficking of EVs between the peripheral circulation and the brain. Moreover, we describe hypothetical transport routes by which EVs may cross the BBB based on previous reports. Further investigation is needed to understand the precise mechanisms by which EVs are transported across the BBB. PMID- 28914202 TI - Statins and contrast-induced nephropathy: a systematic review and meta-analysis. AB - Contrast-induced nephropathy (CIN) is a type of acute kidney injury associated with intravascular administration of iodinated contrast, usually reversible. Contrast agents are an essential component of invasive and noninvasive coronary angiography. These agents have been modified over time to enhance patient safety and tolerability, but adverse reactions still occur. CIN has been variably defined, as a rise in serum creatinine of 0.5 mg/dl, or a 25% increase in serum creatinine above baseline within 24-72 hours after the procedure. The incidence of CIN varies based on the definition used and risk profile of the patients. CIN is rare among patients with normal renal function at baseline. In low-risk patients, CIN occurs in 1-5%, whereas in higher-risk populations, the incidence can be as high as 30%. CIN is also associated with a 5- to 20-fold increased risk of other early adverse events including in-hospital myocardial infarction, target vessel occlusion, and early mortality. The main prevention strategies are adequate intravenous hydration before, during and after the procedure as well as restriction of contrast load with maximum volume approximately no more than three times the serum creatinine clearance. Recent observational and small prospective randomized trials demonstrate the reduction of CIN incidence with HMG-CoA enzyme inhibitors. In this systematic review and meta-analysis we explore the effects of statin administration in prevention of CIN. PMID- 28914203 TI - Phytomedicines are Efficient Complementary Therapies for the Treatment of Atopic Dermatitis: A Review of Mechanistic Insight and Recent Updates. AB - BACKGROUND: Phytomedicines have been well-accepted alternative complementary therapies for the treatment of a wide range of acute and chronic skin inflammatory diseases including chronic herpes, prurigo, psoriasis, and atopic dermatitis (AD). A plethora of in vitro and in vivo studies have evidenced the therapeutic viability of phytomedicines, polyherbal formulations, plant-based materials and their decoctions for the treatment of mild-to-severe AD. OBJECTIVE: This review was aimed to summarize and critically discuss the convincing evidence for the therapeutic effectiveness of phytomedicines for the treatment of AD and explore their anti-AD efficacy. RESULTS: The critical analysis of a wide algorithm of herbal medicines revealed that their remarkable anti-AD efficacy is attributed to their potential of reducing erythema intensity, oedema, inflammation, transepidermal water loss (TEWL) and a remarkable suppression of mRNA expression of ADassociated inflammatory biomarkers including histamine, immunoglobulin (Ig)-E, prostaglandins, mast cells infiltration and production of cytokines and chemokines in the serum and skin biopsies. CONCLUSION: In conclusion, herbal medicines hold great promise as complementary and alternative therapies for the treatment of mild-to-moderate AD when used as monotherapy and for the treatment of moderate-to-severe AD when used in conjunction with other pharmacological agents. PMID- 28914204 TI - A Review on the Effects of Testosterone Supplementation in Hypogonadal Men with Cognitive Impairment. AB - Cognitive function and testosterone level of men decline concurrently with age. Low testosterone levels are associated with higher risk of Alzheimer's disease and mild cognitive impairment in men. There are continuous debates on whether this relationship is casual. This paper aims to summarize the current evidence on the association between testosterone level and cognitive function in elderly men. The presence of testosterone, androgen receptor and its responsive genes indicates that testosterone has biological functions in the central nervous system. The ability of the body to convert testosterone into estrogen suggests that part of the actions of testosterone could be mediated by estrogen. Observational studies generally showed that low endogenous testosterone levels were associated with poor cognitive performance in healthy elderly men. Testosterone substitution exerted positive effects on certain cognitive domains in normal and hypogonadal elderly men. In conclusion, testosterone may influence cognitive function in elderly men and its substitution may be considered in men with cognitive impairment and testosterone deficiency. PMID- 28914200 TI - Development of Peptide Vaccines in Dengue. AB - Dengue is one of the most important arboviral infections worldwide, infecting up to 390 million people and causing 25,000 deaths annually. Although a licensed dengue vaccine is available, it is not efficacious against dengue serotypes that infect people living in South East Asia, where dengue is an endemic disease. Hence, there is an urgent need to develop an efficient dengue vaccine for this region. Data from different clinical trials indicate that a successful dengue vaccine must elicit both neutralizing antibodies and cell mediated immunity. This can be achieved by designing a multi-epitope peptide vaccine comprising B, CD8+ and CD4+ T cell epitopes. As recognition of T cell epitopes are restricted by human leukocyte antigens (HLA), T cell epitopes which are able to recognize several major HLAs will be preferentially included in the vaccine design. While peptide vaccines are safe, biocompatible and cost-effective, it is poorly immunogenic. Strategies to improve its immunogenicity by the use of long peptides, adjuvants and nanoparticle delivery mechanisms are discussed. PMID- 28914205 TI - Vitamin D and Depression: The Evidence from an Indirect Clue to Treatment Strategy. AB - Depression is a common psychiatric disorder that decreases the quality of life and increases the mortality of patients. It incurs significant healthcare costs if left untreated. Even though intervention with antidepressants can reduce depressive symptoms, side effects are often an issue and relapse is very common. Vitamin D, commonly known as the sunshine vitamin, is an essential fat-soluble vitamin for the absorption of calcium to prevent rickets (children) and osteomalacia (adults). Evidence on a possible relationship between vitamin D deficiency and depression is growing. In this review, the authors summarized the evidence on the association between vitamin D status and depression in human observational studies, followed by clinical trials to evaluate the effects of vitamin D supplementation in treating depression. In conclusion, vitamin D deficiency may be associated with an increased risk or severity of depression. Supplementation of vitamin D may confer protection for depressed patients. PMID- 28914206 TI - Mesenchymal Stem Cell as a Potential Therapeutic for Inflammatory Bowel Disease- Myth or Reality? AB - BACKGROUND: Inflammatory bowel diseases (IBD), which include Crohn's disease and Ulcerative Colitis, are inflammatory autoimmune diseases which severely affect the quality of life. Till date, no long-lasting cure has been found for the disease and all the current treatment strategies are mainly focused on dampening the symptomatic inflammatory process that has certain side effects. In addition, a large number of patients remain refractory to conventional therapies. Mesenchymal stem cells (MSCs) can be looked upon as a biodrug to treat IBD owing to their immune-suppressive and regenerative capabilities. MSCs provide an advantage over the other widely used adult stem cells- hematopoietic stem cells in the aspects of lower side effects and enhanced tolerability. MSCs have had reasonable success thus far in clinical trials to treat IBD via systemic delivery as well as in local delivery (perianal Crohn's disease). OBJECTIVE: In order to optimize and standardize, MSC based therapy for IBD, a better understanding of cellular and molecular mechanisms of the therapeutic activities of MSCs, is extremely mandatory. There has been a plethora of publications in the last decade which elucidates the biologic rationale that makes MSC a promising therapeutic tool for IBD. Recent studies have witnessed a replacement of hypotheses regarding the mechanism of MSCs in curing IBD. The present review summarizes all these discussions, the results of the trials carried out to date and the future prospects in this field. CONCLUSION: Based on the current development of MSC based clinical trials and the ever-increasing rate of in-vitro studies, with a purpose to unveil the mechanism of curative approach of these cells, MSC based therapy for IBD can be expected to achieve clinical relevance in the near future. PMID- 28914207 TI - A Systematic Review And Meta-Analysis of Clinical Trials of Mesenchymal Stem Cell Therapy for Cartilage Repair. AB - BACKGROUND: Osteoarthritis (OA) is a major global burden creating significant morbidity worldwide. Current curative therapies are expensive, challenging to access and have significant risks, making them infeasible and difficult in many cases. Mesenchymal stem cells (MSCs) can be applied to joints and may regenerate the cartilage damaged in OA, this therapy may be advantageous to existing treatments. OBJECTIVE: We systematically reviewed clinical trials of MSCs for cartilage repair and provide an overview of the literature in this area here. MEDLINE, Embase, CENTRAL, clinicaltrials.gov and Open- Grey were searched for controlled trials and case series with >5 patents involving MSC therapy for cartilage repair. The controlled trials were meta-analysed and the primary outcome measure was improvement in pain over the control group. A narrative synthesis was composed for the case series. RESULTS: A significant reduction in pain was found with the use of MSCs over controls: Standardised mean difference= 1.27 (95% Confidence intervals -1.95 to -0.58). However, the data was extremely heterogeneous with I2=95%, this may be attributed to differing therapies, clinical indication for treatment and joints treated amongst others. Case series showed improvements in treated patients with a variety of differing treatments and by many outcomes. There were no severe adverse outcomes found across all studies that could be attributed to MSCs, implying their safety. CONCLUSION: We conclude that MSCs have significant potential for the treatment of OA, however, larger, more consistent trials are needed for conclusive analysis. PMID- 28914208 TI - A Systematic Review of Clinical Studies Investigating Mesenchymal Stem Cells for Fracture Non-Union and Bone Defects. AB - BACKGROUND: Fracture non-union is a significant problem with a wide range demographic and massive socioeconomic elements, as well as the clinical difficulties it presents. Conventional treatments with autograft and allograft bone grafting pose serious difficulties, thus, it is necessary to develop novel techniques with our ever increasing knowledge of bioengineering using natural materials. OBJECTIVE: To search for current evidence regarding the treatment of fracture non-union or bone defects using mesenchymal stem cells (MSCs). RESULTS: The results presented in this review show that the use of mesenchymal stem cells for the treatment of non-union and bone defects is optimistic. Several papers had positive outcomes to report. There is a need for higher level evidence. CONCLUSION: A strong need of clinical results is required to further progress in cell therapy. Launched trials will hopefully provide this information in the near future. If clinical trials are positive, further development of complex tissue engineering techniques may be developed to treat large bone defects. PMID- 28914209 TI - Knee Ligament Injury and the Clinical Application of Tissue Engineering Techniques: A Systematic Review. AB - BACKGROUND: The incidence of knee ligament injury is increasing and represents a significant cost to healthcare providers. Current interventions include tissue grafts, suture repair and non-surgical management. These techniques have demonstrated good patient outcomes but have been associated graft rejection, infection, long term immobilization and reduced joint function. The limitations of traditional management strategies have prompted research into tissue engineering of knee ligaments. OBJECTIVE: This paper aims to evaluate whether tissue engineering of knee ligaments offers a viable alternative in the clinical management of knee ligament injuries. A search of existing literature was performed using OVID Medline, Embase, AMED, PubMed and Google Scholar, and a manual review of citations identified within these papers. RESULTS: Silk, polymer and extracellular matrix based scaffolds can all improve graft healing and collagen production. Fibroblasts and stem cells demonstrate compatibility with scaffolds, and have been shown to increase organized collagen production. These effects can be augmented using growth factors and extracellular matrix derivatives. Animal studies have shown tissue engineered ligaments can provide the biomechanical characteristics required for effective treatment of knee ligament injuries. CONCLUSION: There is a growing clinical demand for a tissue engineered alternative to traditional management strategies. Currently, there is limited consensus regarding material selection for use in tissue engineered ligaments. Further research is required to optimize tissue engineered ligament production before clinical application. Controlled clinical trials comparing the use of tissue engineered ligaments and traditional management in patients with knee ligament injury could determine whether they can provide a cost-effective alternative. PMID- 28914210 TI - [Sepsis: new insights, new definition]. AB - - Incidence of sepsis is increasing, partly due to an ageing population, increased use of immunosuppressants, and antibiotic resistance. Sepsis survival has improved substantially, in part because of continuously improving intensive care and implementation of evidence-based guidelines.- Sepsis is defined as 'life threatening organ dysfunction due to a dysregulated host response to infection'. The Sequential Organ Failure Assessment (SOFA) score can be used to estimate organ dysfunction severity.- In this article, we discuss the new sepsis definitions - including reactions to these definitions, an overview of current insights in sepsis pathogenesis, and the new treatment guidelines.- Prevention of sepsis, faster pathogen detection, new lung and kidney function-preserving treatment strategies, further individualisation of patient care and attention to long-term consequences of sepsis will determine the research agenda for the coming years. PMID- 28914211 TI - [A toddler with a vaginal mass and blood loss; the rhabdomyosarcoma]. AB - BACKGROUND: The differential diagnosis of vaginal blood loss in childhood is broad, and includes irritation of the mucous membranes, trauma, tumours, foreign bodies and sexual abuse. Physical and additional examination is often initially difficult; however, prompt detection of a rhabdomyosarcoma, a soft-tissue tumour principally diagnosed in childhood, is vitally important. CASE DESCRIPTION: A 3 year-old girl with a history of vaginal blood loss and an introital mass was referred to the gynaecologist. Treatment with oestriol and triamcinolone cream did not lead to healing. Pathological examination of a biopsy taken under general anaesthetic indicated an embryonic rhabdomyosarcoma. Chemotherapy, surgical resection and brachytherapy lead to persistent remission of the tumour. CONCLUSION: Because rhabdomyosarcoma is rare and can present atypically, diagnosis can be delayed. Early recognition is, however, essential and this condition should be placed high in the differential diagnosis by vaginal blood loss or vaginal abnormality in childhood. PMID- 28914212 TI - [From being a child to being ill; changes in thinking about Alzheimer's disease]. AB - In 1984 the public consciousness about Alzheimer's disease radically changed. Suddenly, especially in the media, a tremendous interest in the phenomenon arose. In the years before, there was hardly any public knowledge about 'Alzheimer's disease'. Mental deterioration was seen as a natural and inevitable part of a human being's course of life. Starting in 1984 however, this deterioration was seen as the most dreaded disease that could struck a person. The disease seemed to rob a person from its most essential abilities: the ability to think, to communicate and to be an individual. This new disease concept had clear advantages for many parties: scientists could develop new knowledge; healthy elderly were protected against stereotypes about their age; and the elderly who actually deteriorated seriously, could blame this on a disease, something they could do nothing about. In the year 1984, the foundation of this Alzheimer revolution was laid. PMID- 28914213 TI - [Medical treatment of people with dementia requires dealing with uncertainty]. AB - Here we report on a number of medical dilemmas during the final 6 years of life of a 78-year-old woman with dementia. Questions concerning both diagnostic procedures and treatment options are discussed. The first dilemma concerns mild symptoms leading to the diagnosis of paroxysmal atrial fibrillation and the requirement for anticoagulation; the second dilemma concerns vague symptoms of tiredness with anaemia leading to the diagnosis of colon cancer and the requirement for surgery. The conclusion is that there are no protocols that can be used to solve questions of this nature, and we need careful reflection with colleagues, the patient and important people in the patient's life in order to make decisions in the best interest of the quality of life as experienced by the patient. This is a complicated task for any doctor who has to deal with medical uncertainties and an incapacitated patient. PMID- 28914214 TI - [What if a patient with dementia asks for help]. AB - Imagine that a patient with mild or moderate cognitive problems comes to your surgery - usually with a carer - or presents at the Emergency Department or an outpatient clinic. As a physician, what should you do or not do? How do you make contact? How do you explain things? What are the pitfalls in communication that you should avoid? This article provides you with eight practical tips for dealing with this situation. PMID- 28914215 TI - [Treatment of sepsis in perspective: what have 25 years of sepsis definition brought us?] AB - The first official definition of sepsis was published in 1992. Last year, in 2016, the third version was published. In this article we discuss the various definitions, the evolving insights into pathophysiology and several of the treatments that have been implemented over the last 25 years. PMID- 28914216 TI - [Driving with Alzheimer's disease]. AB - OBJECTIVE: To summarise the available literature on driving with Alzheimer's disease (AD) and to investigate the relationship between driving and cognitive functioning. DESIGN: Literature review. METHOD: A systematic search of the electronic databases PubMed/MEDLINE was conducted to select the relevant literature on the driving competence of patients with Alzheimer's disease. RESULTS: A total of 31 studies were selected that investigated driving competence in AD using either an on-road driving assessment or a driving simulator. The driving competence of patients with AD was less accurate compared with controls. The most commonly made errors included errors in staying in lane, lane changing, slower reaction times, and more fluctuations in speed. Cognitive functioning was more predictive of driving competence than a diagnosis of AD alone. CONCLUSION: Based on the available literature it is difficult to determine when patients with AD should be restricted in their driving. In addition, there is currently no consensus on which neuropsychological tests are useful in clinical practice to predict driving competence. Specific practical guidelines that can be implemented in daily practice are still lacking. PMID- 28914217 TI - [Unexplained behaviour and dementia]. AB - Behavioural changes, often resulting in negative or challenging behaviour, are highly prevalent in patients with dementia. Here we describe two patients in whom challenging behaviour was the first sign of an evolving dementia process. We discuss the relevance of a multifactorial approach in analysis and treatment, starting from a biopsychosocial model of behaviour in dementia. One pitfall is underestimating the contribution of physical co-morbidity to challenging behaviour in these patients; a further pitfall is the 'attribution phenomenon', i.e. the tendency to attribute new behavioural symptoms to conditions that are already known, such as chronic psychiatric illness. Guidelines for the assessment and management of challenging behaviour in patients who have already been diagnosed with dementia are also useful in cases where the physician is confronted with unexplained behavioural changes and challenging behaviour in older adults who have not yet been diagnosed with this condition. PMID- 28914218 TI - [Apathetic geriatric patient benefits from methylphenidate]. AB - Two independent, home-dwelling geriatric patients presented with apathy at a general practice in the Netherlands and were seen by an elderly care physician after (non-)medical interventions had failed. Both patients were treated with low dose methylphenidate. During treatment, apathy symptoms decreased and the patients became more active. Apathy is a frequent symptom of several neuropsychiatric diseases, depression and somatic conditions. Its incidence varies from 1.3% in healthy elderly people to more than 50% in the elderly with depression or dementia. In this clinical lesson we present these two cases and discuss considerations for treatment of apathy with methylphenidate. PMID- 28914219 TI - [Euthanasia and advanced dementia]. AB - Somewhere around 1975 there was a shift in our perception of suffering that is soon followed by death: it seemed a good idea to skip this unhappy stage of life. A complicated national debate arose, and continues to this day, about whether a life may be prematurely terminated in cases of insoluble misery. Legislation came into effect 2002, after 30 years of deliberation, and the rest of the world looked on in horror. England, in particular, liked to point out that the Dutch were on a very slippery slope. PMID- 28914220 TI - [Leading cause of death in young Dutch people: the cigarette]. AB - OBJECTIVE: To investigate the impact of smoking on premature death in the Netherlands and the difference between causes of death for smokers and non smokers. DESIGN: Observational cohort study. METHOD: Data on smoking behaviour were obtained from 40,000 people who participated in the CBS (Statistics Netherlands) health survey between 2001-2006. These data were linked to data on death and cause of death for the 10 years following this questionnaire. Hazard ratios were calculated for premature deaths among smokers, classified into smoking intensity, and ex-smokers as compared with those who had never smoked. These data were used to estimate cumulative death of smokers versus non-smokers. RESULTS: The hazard ratio for premature death was 3.8 (95% CI: 3.2-4.5) for heavy smokers, 2.6 (95% CI: 2.2-3.0) for moderate smokers and 1.7 (95% CI: 1.3-2.3) for light smokers. Lifelong heavy smokers had a chance of 23% of dying before the age of 65. For moderate and light smokers and for non-smokers, the chance was respectively 16, 11 and 7%. For half of all people who died relatively young, cancer was the underlying cause of death. This was mainly lung cancer for smokers. Heavy smokers are estimated to have lost 13 years of life, moderate smokers 9 and light smokers 5. Smoking cessation at any age still benefited health. Ex-smokers who had quit before an approximate age of 35 had the same life expectancy as lifelong non-smokers. CONCLUSION: An estimated four in ten premature deaths can be attributed to smoking in the Netherlands. Cancer is the predominant cause of death amongst smokers. Smoking cessation increases life expectancy. Therefore, the earlier a smoker stops, the better. PMID- 28914221 TI - [The default setting of memory is 'forgetting']. AB - From the age of about 60, many people begin to experience difficulties with tasks that require the use of prospective memory and begin to have trouble finding words and names. Worried that these symptoms may be indicative of the onset of Alzheimer's disease, many of them fill in online self-tests or consult their family doctor. In the vast majority of cases, symptoms like these indicate completely natural age-related forgetfulness. Physicians should encourage a socially active lifestyle to slow down further decline. In cases of mild cognitive impairment (MCI), the physician should be aware of patients who deny or trivialise memory problems, especially if these problems have repercussions for performance in professions such as that of airline pilots or medical practitioners. In the absence of formal annual performance checks, ageing physicians should keep a close watch on themselves and on their colleagues. PMID- 28914222 TI - Process measures or patient reported experience measures (PREMs) for comparing performance across providers? A study of measures related to access and continuity in Swedish primary care. AB - : Aim To study (a) the covariation between patient reported experience measures (PREMs) and registered process measures of access and continuity when ranking providers in a primary care setting, and (b) whether registered process measures or PREMs provided more or less information about potential linkages between levels of access and continuity and explaining variables. BACKGROUND: Access and continuity are important objectives in primary care. They can be measured through registered process measures or PREMs. These measures do not necessarily converge in terms of outcomes. Patient views are affected by factors not necessarily reflecting quality of services. Results from surveys are often uncertain due to low response rates, particularly in vulnerable groups. The quality of process measures, on the other hand, may be influenced by registration practices and are often more easy to manipulate. With increased transparency and use of quality measures for management and governance purposes, knowledge about the pros and cons of using different measures to assess the performance across providers are important. METHODS: Four regression models were developed with registered process measures and PREMs of access and continuity as dependent variables. Independent variables were characteristics of providers as well as geographical location and degree of competition facing providers. Data were taken from two large Swedish county councils. Findings Although ranking of providers is sensitive to the measure used, the results suggest that providers performing well with respect to one measure also tended to perform well with respect to the other. As process measures are easier and quicker to collect they may be looked upon as the preferred option. PREMs were better than process measures when exploring factors that contributed to variation in performance across providers in our study; however, if the purpose of comparison is continuous learning and development of services, a combination of PREMs and registered measures may be the preferred option. Above all, our findings points towards the importance of a pre-analysis of the measures in use; to explore the pros and cons if measures are used for different purposes before they are put into practice. PMID- 28914223 TI - Educator Readiness to Improve Gerontological Curricula in Health and Social Service Education. AB - This study investigated the state of gerontology content in health and social service education programs in Ontario, and readiness indicators for change among administrators and faculty. We conducted a survey of teaching faculty (n = 100) and deans or directors (n = 56) of 89 education programs, which revealed mixed evidence on readiness for change. Most respondents thought their programs were adequate but needed enhancement. However, they were unaware of published gerontological competencies with which to evaluate their curricula. Beliefs about capacity for change varied, with half the participants indicating that their programs had sufficient faculty expertise in gerontology and geriatrics. Factors influencing readiness for change include lack of gerontological expertise; need for institutional and management support; need for additional teaching resources; and recognizing the need for change. There is an opportunity, by committing resources and time, to capitalize on the faculty and administrators who thought their programs should improve. PMID- 28914224 TI - Rapid Risk Assessment Report for Schistosomiasis Epidemic in Jianli County Caused by the Sunk "Oriental Star" Cruise Ship. AB - BACKGROUND: At 9:28 pm on June 1, 2015, the cruise ship "Oriental Star" sank into Yangtze River in Jianli County, with 422 people killed. When the accident occurred, the Chinese government took immediate action and dispatched more than 9000 rescuers. The risk for outbreak of schistosomiasis was increased because of the shipwreck. Obviously it is critical to carry out risk assessment as soon as possible. METHODS: By means of the Delphi method, the situation was analyzed so that the government could fathom the severity of the accident. Then, through matrix and sigma-plotting (3-dimensional graphics) methods, related authorities performed risk assessment after site investigation. RESULTS: The latest news reported that more than 9000 people were involved in the rescue. The affected river was analyzed and mapped using SigmaPlot software, according to which the possibility, harmfulness, and controllability of the accident were determined to be medium (6), medium (6), and poor (7), respectively. CONCLUSION: The site of the accident where the cruise ship sank and rescue operations were carried out is a schistosomiasis epidemic area with high mortality and morbidity. The chance of an outbreak of the schistosomiasis epidemic in Jianli County is quite high. To protect people in this county from the epidemic, relevant logistic services should be arranged and all remains should be cleared up carefully. (Disaster Med Public Health Preparedness. 2018;12:147-153). PMID- 28914225 TI - New Directions for Care Management Journals. PMID- 28914226 TI - Comprehensive Care. AB - Illness is a combination of pathophysiology and associated thoughts, emotions, and behaviors. Given the large number of treatments that are discretionary and preference sensitive, one goal is accurate diagnosis of patient preferences. Reliance on biomedical treatments (e.g., medication and procedures) may overlook important opportunities for improved health such as amelioration of stress and distress and training in more effective coping strategies. PMID- 28914227 TI - A System Analysis of Delay in Outpatient Respiratory Equipment Delivery. AB - OBJECTIVES: To systematically assess barriers delaying home respiratory equipment requisition and to evaluate for temporal correlation between delays and emergency room or hospitalization episodes. BACKGROUND: Initiation of home respiratory treatments is delayed because of delays in delivery of durable medical equipment (DME). This study assesses root causes of such delays from a system perspective. We also describe clinical consequences by measuring emergency room visits and hospitalization days for temporal correlations. METHODS: We conducted a retrospective review of DME ordering records from April 2011 to March of 2012. SETTINGS: Outpatient DME records in Pediatric Pulmonary Division. RESULTS: Of 164 available orders studied, deliveries were made as followed: 31 (19%) within 24 hr: 18 (59%) oxygen orders and 10 (32%) nebulizer orders 50 (30%) within 1 week: 25 (50%) nebulizer orders and 10 (20%) oxygen orders Delays: 45 (27%) delivered > 1 month: Bilevel positive airway pressure (BPAP) = 16 (36%) Oxygen = 12 (26%) Cough assist device = 7 (16%) Nebulizer = 5 (11%) Miscellaneous devices = 5 (11%) Analysis of barriers includes (a) type of insurance, (b) human error, (c) communication barrier, (d) deficit in training or knowledge, (e) no clear policy, (f) differences in clinical policy/ standard, (g) no DME benefit, (h) no clinical justification, and (i) error in communication/record keeping. Six patients with 7 emergency department (ED) visits and 4 inpatient admissions, totaling 24 hospital days, were temporally associated with delays in delivery of equipment over 30 days. CONCLUSION: One half of commonly used DMEs were delivered within the first week. One quarter of more expensive required more steps for approval. Twenty-nine ED/hospital days with respiratory morbidities were temporally associated with delays. PMID- 28914228 TI - An Integrated Case Management Model to Assist Pacific Youth Offenders and Their Families in Australia. AB - Pasifika Support Services (PSS) was a program managed by a nongovernment organization, Mission Australia, and funded by the New South Wales Premiers Office to meet the needs of young offenders from a Pacific background. PSS ran from June 2005 to June 2009 and implemented a cost-effective integrated case management model with the New South Wales Police Force adapted to address social risk factors specific to Pacific youth offenders and family support networks. Sixty young people were reviewed regarding the outcomes achieved through their participation, further supported by an evaluation carried out by an external evaluator who found that 65% of participants did not reoffend after 18 months of completing the program. An importance of developing a shared approach to employing a holistic and intensive model of case management that affects individual, community, and organizational change through culturally relevant processes and practices, paired with a cross institutional commitment underpins the various outcomes discussed. PMID- 28914229 TI - Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation. AB - BACKGROUND: At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-beta) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost effectiveness. OBJECTIVES: To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-beta and GA in relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. REVIEW METHODS: Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost effectiveness analysis used published literature, findings from the Department of Health's risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. RESULTS: In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was L31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of L33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was L34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of L12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-beta-1 (125 ug) was the most cost-effective option of the individual DMTs compared with BSC (ICER L7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER L16,500 per QALY gained). LIMITATIONS: Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. CONCLUSIONS: DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow up and systematic review and meta-synthesis of qualitative studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016043278. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28914231 TI - Plasmonic resonances in hybrid systems of aluminum nanostructured arrays and few layer graphene within the UV-IR spectral range. AB - The size-controllable and ordered Al nanocavities and nanodomes arrays were synthesized by electrochemical anodization of aluminum using phosphoric acid, citric acid and mixture both acids. Few layer graphene (FLG) was transferred directly on top of Al nanostructures and their morphology were evaluated by scanning electron microscopy. The interaction between FLG and the plasmonic properties of Al nanostructures arrays were investigated based on specular reflectivity in the ultraviolet-visible-infrared range and Raman spectroscopy. We found that their optical reflectivity was dramatically reduced as compared with unstructured Al. At the same time pronounced reflectivity dips were detectable in the 200-896 nm wavelength range, which were ascribed to plasmonic resonances. The plasmonic properties of these nanostructures do not exhibit evident changes by the presence of FLG in the UV-vis range of the electromagnetic spectrum. By contrast, the surface-enhanced Raman spectroscopy of FLG was observed in nanocavities and nanodomes structures that result in an intensity increase of the characteristic G and 2D bands of FLG induced by the plasmonic properties of Al nanostructures. PMID- 28914230 TI - Prefrontal cortical responses in children with prenatal alcohol-related neurodevelopmental impairment: A functional near-infrared spectroscopy study. AB - OBJECTIVE: Disruption in the neural activation of the prefrontal cortex (PFC) in modulating arousal was explored in children with heavy prenatal alcohol exposure (PAE), who have known neurobehavioral impairment. METHODS: During a task that elicits frustration, functional near-infrared spectroscopy (fNIRS) was used to measure PFC activation, specifically levels of oxygenated (HBO) and deoxygenated (HBR) hemoglobin, in children with PAE (n=18) relative to typically developing Controls (n=12) and a Clinical Contrast group with other neurodevelopmental or behavioral problems (n=14). RESULTS: Children with PAE had less activation during conditions with positive emotional arousal, as indicated by lower levels of HBO in the medial areas of the PFC and higher levels of HBR in all areas of the PFC sampled relative to both other groups. Children in the Control group demonstrated greater differentiation of PFC activity than did children with PAE. Children in the Clinical Contrast group demonstrated the greatest differences in PFC activity between valences of task conditions. CONCLUSIONS: Specific patterns of PFC activation differentiated children with PAE from typically developing children and children with other clinical problems. SIGNIFICANCE: FNIRS assessments of PFC activity provide new insights regarding the mechanisms of commonly seen neurobehavioral dysfunction in children with PAE. PMID- 28914232 TI - Combined rTMS and virtual reality brain-computer interface training for motor recovery after stroke. AB - OBJECTIVE: Combining repetitive transcranial magnetic stimulation (rTMS) with brain-computer interface (BCI) training can address motor impairment after stroke by down-regulating exaggerated inhibition from the contralesional hemisphere and encouraging ipsilesional activation. The objective was to evaluate the efficacy of combined rTMS + BCI, compared to sham rTMS + BCI, on motor recovery after stroke in subjects with lasting motor paresis. APPROACH: Three stroke subjects approximately one year post-stroke participated in three weeks of combined rTMS (real or sham) and BCI, followed by three weeks of BCI alone. Behavioral and electrophysiological differences were evaluated at baseline, after three weeks, and after six weeks of treatment. MAIN RESULTS: Motor improvements were observed in both real rTMS + BCI and sham groups, but only the former showed significant alterations in inter-hemispheric inhibition in the desired direction and increased relative ipsilesional cortical activation from fMRI. In addition, significant improvements in BCI performance over time and adequate control of the virtual reality BCI paradigm were observed only in the former group. SIGNIFICANCE: When combined, the results highlight the feasibility and efficacy of combined rTMS + BCI for motor recovery, demonstrated by increased ipsilesional motor activity and improvements in behavioral function for the real rTMS + BCI condition in particular. Our findings also demonstrate the utility of BCI training alone, as shown by behavioral improvements for the sham rTMS + BCI condition. This study is the first to evaluate combined rTMS and BCI training for motor rehabilitation and provides a foundation for continued work to evaluate the potential of both rTMS and virtual reality BCI training for motor recovery after stroke. PMID- 28914233 TI - Lessons from two cases of radiation induced skin injuries in fluoroscopic procedures in Bulgaria. AB - BACKGROUND: Radiation-induced injuries to patient skin as a result of fluoroscopy guided interventional procedures are infrequently reported, often misdiagnosed and there is a need to learn lessons from every injury. METHODS: This paper describes two cases of radiation induced skin injuries that are, to the best of our knowledge, the first ever reported cases from Bulgaria and possibly from Eastern Europe, and would thus have educational value. RESULTS: The important messages from the skin injuries reported here are: lack of awareness among part of the interventional specialists about the potential for radiation induced skin injury, misdiagnosis after injury happened because of lack of awareness and knowledge among general physicians, dermatologists and surgeons who followed up cases of skin injuries; the lack of system to monitor patients with relatively high exposure; the important role played by the medical physicist in diagnosing the injury and overall in initiating actions; the role of training and informational material displayed in interventional facilities. CONCLUSIONS: For avoidance of skin injuries from interventional procedures it is of utmost importance to implement a system that includes (a) regular monitoring of radiation dose parameters of the procedure; (b) established trigger values for reporting; PMID- 28914234 TI - Selective hierarchical patterning of silicon nanostructures via soft nanostencil lithography. AB - It is challenging to hierarchically pattern high-aspect-ratio nanostructures on microstructures using conventional lithographic techniques, where photoresist (PR) film is not able to uniformly cover on the microstructures as the aspect ratio increases. Such non-uniformity causes poor definition of nanopatterns over the microstructures. Nanostencil lithography can provide an alternative means to hierarchically construct nanostructures on microstructures via direct deposition or plasma etching through a free-standing nanoporous membrane. In this work, we demonstrate the multiscale hierarchical fabrication of high-aspect-ratio nanostructures on microstructures of silicon using a free-standing nanostencil, which is a nanoporous membrane consisting of metal (Cr), PR, and anti-reflective coating. The nanostencil membrane is used as a deposition mask to define Cr nanodot patterns on the predefined silicon microstructures. Then, deep reactive ion etching is used to hierarchically create nanostructures on the microstructures using the Cr nanodots as an etch mask. With simple modification of the main fabrication processes, high-aspect-ratio nanopillars are selectively defined only on top of the microstructures, on bottom, or on both top and bottom. PMID- 28914235 TI - Jump stabilization and landing control by wing-spreading of a locust-inspired jumper. AB - Bio-inspired robotics is a promising design strategy for mobile robots. Jumping is an energy efficient locomotion gait for traversing difficult terrain. Inspired by the jumping and flying behavior of the desert locust, we have recently developed a miniature jumping robot that can jump over 3.5 m high. However, much like the non-adult locust, it rotates while in the air and lands uncontrollably. Inspired by the winged adult locust, we have added spreading wings and a tail to the jumper. After the robot leaps, at the apex of the trajectory, the wings unfold and it glides to the ground. The advantages of this maneuver are the stabilization of the robot when airborne, the reduction of velocity at landing, the control of the landing angle and the potential to change the robot's orientation and control its flight trajectory. The new upgraded robot is capable of jumping to a still impressive height of 1.7 m eliminating airborne rotation and reducing landing velocity. Here, we analyze the dynamic and aerodynamic models of the robot, discuss the robot's design, and validate its ability to perform a jump-glide in a stable trajectory, land safely and change its orientation while in the air. PMID- 28914236 TI - The Krummel (Germany) Childhood Leukaemia Cluster: a review and update. AB - The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krummel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krummel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krummel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krummel site shows that the incidence rates are now comparable to the average rate in Germany. PMID- 28914237 TI - Thrust areas for pedodontic research: The way ahead! PMID- 28914238 TI - Assessment of dental caries, oral hygiene status, traumatic dental injuries and provision of basic oral health care among visually impaired children of Eastern Odisha. AB - CONTEXT: The magnitude and severity of oral health problems in visually impaired population are worse than in general population, and they tend to have more untreated dental diseases and more problems accessing dental care. AIMS: The aim of this study is to assess dentition status and treatment needs, oral hygiene status, and traumatic dental injuries among institutionalized children attending special schools for the visually impaired in eastern Odisha. SETTINGS AND DESIGN: A descriptive, cross-sectional study was conducted using a universal sampling protocol. SUBJECTS AND METHODS: American Dental Association Type III clinical examination was carried out using plane mouth mirrors and community periodontal index probes under adequate natural illumination by a single examiner assisted by a trained recording assistant. After completion of the study, all participants were provided with basic oral health care through outreach programs. STATISTICAL ANALYSIS: Comparisons were done using Student's t-test, analysis of variance, and Chi-square test. RESULTS: Caries prevalence for primary and permanent dentition was 15% and 46%, respectively. Mean oral hygiene index-simplified (OHI-S) was 2.43 +/- 1.03. The prevalence of traumatic dental injuries was 11%. A statistically significant difference in mean decayed, missing, and filled teeth (DMFT/dmft) was observed in children consuming liquid sugar as compared to solid and those consuming sticky sugars as compared to nonsticky. A statistically significant difference in mean OHI-S scores was observed when compared with frequency of changing toothbrush. CONCLUSIONS: This sample of visually impaired children has a high prevalence of dental caries, traumatic dental injuries, and poor oral hygiene. Unmet needs for dental caries were found to be high indicating very poor accessibility and availability of oral health care. PMID- 28914239 TI - Road blocks perceived by the dentists toward the treatment of early childhood caries in Chennai city - A cross-sectional study. AB - BACKGROUND: The problem of early childhood caries remains a worldwide public concern, as most of the caries remains untreated. Despite advances in dental care, most children fail to benefit from oral health-care services not only due to differences in attitudes in parents but also in oral health-care providers. OBJECTIVES: The objective of the study is to determine the road blocks perceived by the dentist in Chennai, toward the treatment of early childhood caries. METHODS: Following a simple random sampling technique, a cross-sectional questionnaire study was conducted among general dentists (n = 50) and pediatric dentists (n = 50) in Chennai city. Each selected dentist was asked to complete the Barriers to Childhood Caries Treatment (BaCCT) questionnaire: a 29-item measure considering child, parent, dentist, and healthcare system factors. RESULTS: The mean BaCCT score was found to be significantly higher among general dentists 2.68 +/- 0.36 when compared to pediatric dentists 2.36 +/- 0.45 (P = 0.0001). Similarly, mean BaCCT score was found to be significantly higher among general dentists in Domain-I (child coping abilities), Domain-II (dentist attitudes toward offering restorative treatment), and Domain-III (dentist attitudes toward restoring primary teeth) when compared to the pediatric dentists (P < 0.001). CONCLUSIONS: The general dentists exhibited inherent barriers in providing treatment for early childhood caries compared to pediatric dentists. Training in the field of pediatric dentistry enhances their ability to handle early child caries better. PMID- 28914240 TI - Comparison of Candida species isolated from children with and without early childhood caries: A descriptive cross-sectional study. AB - BACKGROUND: Early childhood caries (ECC) is characterized by the presence of one or more decayed, missing (due to caries), or filled teeth surfaces in any primary tooth, in a child below 6 years of age. Although ECC is primarily associated with high levels of maternal Streptococcus mutans, there has been an increased interest in finding the relationship between oral fungal flora and dental caries. OBJECTIVE: The aim of the study is to identify and characterize the Candida species and to compare the candidal isolates in children with ECC and without ECC. MATERIALS AND METHODS: The study was conducted on children below 6 years of age, who were categorized into ECC and non-ECC groups of fifty children each. Samples were collected using sterile cotton swabs and were inoculated on Sabouraud's Dextrose Agar and incubated at 37 degrees C for 24 h. Candidal colonies were isolated, species identified and virulence factors tested for both ECC and non-ECC groups. RESULTS: The candidal carriage among the ECC children was found to be 84%, which was significantly higher than the non-ECC group of 24%. Candida albicans and non-albicans Candida (NAC) were isolated in both ECC and non ECC groups. Phospholipase production was significantly high in ECC group whereas hemolysin production and germ tube formation showed no significant difference between the two groups. CONCLUSION: A significant correlation was found between the presence of Candida and ECC. NAC also plays an important role in the development of ECC. The virulence factors such as phospholipase may be responsible for the pathogenicity of Candida in the development of ECC. PMID- 28914241 TI - Validation of different diagnostic aids in detection of occlusal caries in primary molars: An in vitro study. AB - AIM AND OBJECTIVE: To estimate the accuracy and assess the sensitivity and specificity of direct visual examination (DVE), computerized radiograph (VISTA SCAN mini), and DIAGNOdent (DD) for caries diagnosis in primary molars as compared to histological examination of the teeth. MATERIALS AND METHODS: An in vitro comparative study was carried out on 40 freshly extracted primary molars with questionable pit and fissures that yielded 89 examination sites. These samples were mounted on plaster and were subjected to examination methods for caries detection on the occlusal surface by two trained and calibrated examiners. The examination methods used in this study were DVE, computerized radiographic (CR) examination, laser fluorescence examination using DD followed by histological examination which is a gold standard; later, these samples were examined under microscope for caries extent. The scoring criteria given by Nytun et al. were used in this study for scoring the extent of caries. RESULTS: The sensitivity for caries in enamel were 66.10%, 52.86%, and 54.17% for DVE, CR, and DD, respectively, while the specificity for DVE, CR, and DD were found to be 86.67%, 68.42%, and 76.47%, respectively. For dentinal caries, sensitivity for DVE, CR, and DD were 86.67%, 92.86%, and 81.25%, respectively, while the specificity were 66.10%, 56%, and 54.79%, respectively. The accuracy were 73.03%, 61.80%, and 59.55%, respectively, suggesting that the DVE showed highest sensitivity, specificity, and accuracy for enamel caries, whereas for dentinal caries, CR showed highest sensitivity and DVE showed highest specificity and accuracy. CONCLUSION: The DD exhibited better specificity than sensitivity for enamel lesions and better sensitivity than specificity for lesions into dentin. DD may prove useful as a predictive clinical tool and should only be used in addition to other diagnostic methods such as visual inspection and dental radiographs to avoid false-positive diagnoses. PMID- 28914242 TI - Assessment of plaque regrowth with a probiotic toothpaste containing Lactobacillus paracasei: A spectrophotometric study. AB - BACKGROUND: Probiotics are live microorganisms which when administered in adequate amounts confer health benefits on the host. Commonly, most of the organisms ascribed as having probiotic properties belong to the genera Lactobacillus and Bifidobacterium and milk is the most commonly used vehicle. OBJECTIVES: The study was aimed at analyzing the biofilm formation by plaque regrowth method upon the usage of a probiotic toothpaste containing Lactobacillus paracasei by measuring the optical density using a spectrophotometer. MATERIALS AND METHODS: A commercially available probiotic toothpaste, PerioBiotic (spearmint flavored) from the company Designs for Health, has been tested. The toothpaste contains the strain L. paracasei, which has been found to co-aggregate with Streptococcus mutans (MS). The Plaque Glycolysis and Regrowth Method (PGRM) was used for the evaluation of the antimicrobial effects on plaque metabolism in vivo. PGRM is based on the observation that natural fasted dental plaque, sampled from different quadrants of the dentition, exhibits similar metabolic and regrowth properties when suspended at equal "biomass" in standardized media. CONCLUSION: The results suggest that L. paracasei-based toothpaste, PerioBiotic, is effective in the reduction of MSmonospecies biofilm, but the activity appears short lived when high sucrose exposure is administered. PMID- 28914243 TI - An in vitro comparison of casein phosphopeptide-amorphous calcium phosphate paste, casein phosphopeptide-amorphous calcium phosphate paste with fluoride and casein phosphopeptide-amorphous calcium phosphate varnish on the inhibition of demineralization and promotion of remineralization of enamel. AB - AIM: This study aims to determine and compare the extent of inhibition of demineralization and promotion of remineralization of permanent molar enamel with and without application of three remineralizing agents. MATERIALS AND METHODS: Forty extracted permanent molars were randomly divided into two groups 1 and 2, longitudinally sectioned into four and divided into subgroups A, B, C, and D. The sections were coated with nail varnish leaving a window of 3 mm * 3 mm. All sections of Group 1 were treated with their respective subgroup-specific agent: Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste for subgroup A, CPP-amorphous calcium phosphate fluoride (ACPF) paste for subgroup B, CPP-ACPF varnish for subgroup C and subgroup D served as a control. The sections were then subjected to demineralization for 12 days following which lesional depth was measured under the stereomicroscope. All the sections of Group 2 were subjected to demineralization for 12 days, examined for lesional depth, then treated with their respective subgroup specific agents and immersed in artificial saliva for 7 days. The sections were then examined again under the stereomicroscope to measure the lesional depth. RESULTS: CPP-ACPF varnish caused significant inhibition of demineralization. All three agents showed significant remineralization of previously demineralized lesions. However, CPP-ACPF varnish showed the greatest remineralization, followed by CPP-ACPF paste and then CPP-ACP paste. CONCLUSION: This study shows that CPP-ACPF varnish is effective in preventing demineralization as well as promoting remineralization of enamel. Thus, it can be used as an effective preventive measure for pediatric patients where compliance with the use of tooth mousse may be questionable. PMID- 28914244 TI - Comparative evaluation of salt water rinse with chlorhexidine against oral microbes: A school-based randomized controlled trial. AB - BACKGROUND: Mouth rinse that is natural, safe, cost-effective, readily available and culturally acceptable is required as an adjunct to routine tooth brushing to combat dental diseases. The aim of present study was to compare the effectiveness of salt water rinse with chlorhexidine mouth rinse in reducing dental plaque and oral microbial count. MATERIALS AND METHODS: The Minimum Inhibitory Concentration (MIC) of salt water against S. mutans, L.acidophilus, A. actinomycetemcomitans and P. gingivalis was determined by Macrobroth Dilution method. Thirty participants were randomly allocated into study group (salt water rinse) and control group (chlorhexidine rinse). Baseline DMFS, defs and plaque scores were recorded. Baseline unstimulated saliva samples were collected by spitting method. Oral prophylaxis was done after baseline sample collection. The participants were advised to rinse the allocated mouthrinse for 5 days under the supervision of co- investigator. Pre- rinse (after oral prophylaxis) and Post -rinse (5th day of mouthrinsing) plaque examination and salivary microbial analysis was done. The collected salivary samples were immediately transported and streaked on the respective media for microbial count. RESULT: MIC of salt water was 0.7 M for S. mutans, A. actinomycetemcomitans and P. gingivalis and 0.8M for L. acidophilus. There was statistically significant reduction in the plaque scores, salivary S. mutans, L. acidophilus, A. actinomycetemcomitans and P. gingivalis count from baseline, pre-rinse to post-rinse in the study group (p=0.001) and control group (p=0.001). Salt water was as effective as chlorhexidine in reducing dental plaque (p = 0.19) and A. actinomycetemcomitans (p = 0.35) count and while chlorhexidine was superior against S. mutans (p = 0.001), L. acidophilus (p = 0.001) and P. gingivalis (p =0.001). CONCLUSION: Salt water rinse can be used as adjunct to routine mechanical plaque control for prevention of oral diseases. PMID- 28914245 TI - A comparative evaluation of clinical and radiographic success rate of pulpotomy in primary molars using antioxidant mix and mineral trioxide aggregate: An in vivo 1-year follow-up study. AB - INTRODUCTION: Pulpotomy technique is most widely accepted clinical procedure for treating primary teeth with coronal pulp inflammation caused by caries with no involvement of the radicular pulp. AIM AND OBJECTIVE: The aim of the study was to evaluate the success and efficacy of mineral trioxide aggregate (MTA) and antioxidant mix as pulpotomy agents both clinically and radiographically. MATERIALS AND METHODS: A total of forty primary molars in children aged between 6 and 9 years, requiring for pulpotomy procedures, were selected. Random samples distribution was done, antioxidant mix (n = 20) and MTA (n = 20) both were used as pulpotomy agent. Under rubber dam isolation, pulpotomy procedure was performed in all samples followed by restoration with stainless steel crowns. Later, the patients were recalled after 6 and 12 months for clinical and radiographic evaluation. The data were evaluated using Fisher's exact test. RESULTS: Statistically analysis shows no significant difference between the two groups (P > 0.05) with respect to clinical and radiographic success rate, but antioxidant mix showed more efficient result than MTA. CONCLUSION: Antioxidant mix pulpotomy is more biocompatible and cost effective than any other commercially available medicament. PMID- 28914246 TI - Comparative evaluation of the effects of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and xylitol-containing chewing gum on salivary flow rate, pH and buffering capacity in children: An in vivo study. AB - AIM: This study aimed to compare and evaluate the changes in the salivary flow rate, pH, and buffering capacity before and after chewing casein phosphopeptide amorphous calcium phosphate (CPP-ACP) and xylitol-containing chewing gums in children. MATERIALS AND METHODS: Sixty children aged between 8 and 12 years were selected for the study. They were randomly divided into Group 1 (CPP-ACP chewing gum) and Group 2 (xylitol-containing chewing gum) comprising thirty children each. Unstimulated and stimulated saliva samples at 15 and 30 min interval were collected from all children. All the saliva samples were estimated for salivary flow rate, pH, and buffering capacity. RESULTS: Significant increase in salivary flow rate, pH, and buffering capacity from baseline to immediately after spitting the chewing gum was found in both the study groups. No significant difference was found between the two study groups with respect to salivary flow rate and pH. Intergroup comparison indicated a significant increase in salivary buffer capacity in Group 1 when compared to Group 2. CONCLUSION: Chewing gums containing CPP-ACP and xylitol can significantly increase the physiochemical properties of saliva. These physiochemical properties of saliva have a definite relation with caries activity in children. PMID- 28914247 TI - Assessment of hypoxia, sedation level, and adverse events occurring during inhalation sedation using preadjusted mix of 30% nitrous oxide + 70%oxygen. AB - PURPOSE: To assess the efficacy of nitrous oxide (N2O)-oxygen (O2) inhalation sedation by rapid induction technique using preadjusted mix of 30% N2O and 70% O2 in children. MATERIALS AND METHODS: Sixty children with a treatment plan which included pulp therapy were recruited for the study. Children categorized 3 and 4 of Frankl behavior rating scale and American Society of Anesthesiologists health status I and II were included for the study. Children were distributed into study group (Group-I) and control group (Group-II) by fishbowl randomization. Children in Group-I were induced inhalation sedation using a preadjusted mix of 30% N2O and 70% O2 through rapid induction technique, and children in Group-II were exposed to inhalation sedation by conventional slow induction technique. Parameters such as least oxygen saturation, sedation levels by Richmond Agitation Sedation Scale, time taken to achieve ideal sedation, maximum N2O concentrations used, and adverse events were recorded and evaluated for each procedure. Data were analyzed using independent sample t-test and Chi-square tests. RESULTS: Analysis of data showed statistically significant difference between both groups in time taken to achieve ideal sedation (P < 0.001). No significant difference was seen in incidence of hypoxia (P < 0.512), maximum N2O concentrations used (P < 0.118), and occurrence of any adverse events. CONCLUSION: None of the children from both groups exhibited hypoxia. Sense of detachment was seen in one child each from both groups. Rapid induction by preadjusted mix resulted in ideal sedation in 57% children of the Group-I; rest had achieved these levels at 40% N2O. There was a significant difference in the time taken to achieve ideal sedation by rapid induction which was almost half the time taken with slow induction. PMID- 28914248 TI - Comparative evaluation of clinical and radiological success of zinc oxide ozonated oil, modified 3mix-mp antibiotic paste, and vitapex as treatment options in primary molars requiring pulpectomy: An in vivo study. AB - OBJECTIVES: The aim of this study was to evaluate the clinical and radiographic success of zinc oxide-ozonated oil (ZnO-OO), modified 3Mix antibiotic paste, and Vitapex in treatment of primary molars requiring pulpectomy. METHODS: Sixty-four primary molars of forty three children aged between 4 and 8 years with pulpally involved primary molars requiring root canal procedures were treated with ZnO-OO, modified 3Mix-MP paste, and Vitapex. The subjects were followed up clinically at 1, 6, and 12 months whereas radiographically at 6 and 12 months, respectively. RESULTS: The results showed that the clinical and radiographic success rates of ZnO-OO and Vitapex over 12 months period of observation were 100% whereas, for modified 3Mix-MP paste, the results were 95.8% and 79.2%, respectively. CONCLUSION: On the basis of the overall success rates of all the three medicaments, following order of performance can be inferred clinical success and radiographical success:- ZnO-OO = Vitapex > modified 3MIX-MP paste. PMID- 28914249 TI - Visual pedagogy and probiotics for hearing impaired children: A pilot study. AB - CONTEXT: Oral health care for children with special needs remains largely unmet. It is important that we should focus on preventive strategies for special children to help curtail and prevent oral diseases. AIM: This study aimed to assess the effect of visual pedagogy and probiotic mouth rinse on the periodontal health of hearing impaired children. MATERIALS AND METHODOLOGY: The study cohort consisted of twenty children with hearing impairment (HI) and 20 age-matched healthy children. The gingival index (GI), plaque index (PI), and salivary pH for all children were assessed at baseline, 15 days after oral hygiene training using visual pedagogy, 15 days after probiotic mouth rinse introduction, and at the end of the test period, i.e., 2 months after discontinuing probiotics. STATISTICAL ANALYSIS: Comparison of means was carried out using the Student's t-test. Intragroup parameters were assessed using the one-way ANOVA, followed by the post hoc Scheffe test. Value for statistical significance was fixed at 0.05. RESULTS: The GI and PI scores did not improve significantly after oral hygiene training in either of the two groups. The use of probiotic mouth rinse significantly reduced GI scores (<0.01) and PI scores (<0.01) and increased salivary pH above the critical pH in both groups. CONCLUSION: The use of visual pedagogy coupled with probiotic mouth rinsing may improve the periodontal status of children with HI and should be explored as a preventive procedure for children with special health care needs. PMID- 28914250 TI - A comparative evaluation of retention of pit and fissure sealant bonded using sixth-, seventh-, and eighth-generation adhesives: An in vivo study. AB - INTRODUCTION: Dental caries is one of the most common preventable childhood infections. a number of measures are available to prevent occlusal caries; pit and fissure sealants are one of the various methods currently available to cost effectively reduce dental caries. AIM: To evaluate the retention of pit and fissure sealant bonded using sixth (Adper promt), seventh (Optibond) and eighth (Futurabond Dual Cure) generations of adhesives. SETTINGS AND DESIGN: A total of 37 healthy children who fulfilled the inclusion were randomly selected. A total of 148 teeth (4 in each subject) were used as samples for the study. METHODS AND MATERIAL: The teeth to be sealed were then isolated using rubber dam. The placement of adhesives was done using split mouth design. The first permanent molars were randomly divided into four groups on the basis of sealant placed without and with using 6th, 7th and 8th generation bonding agents as follows: GROUP A (N=37):- Pit and fissure sealant placed without bonding agent. GROUP B (N=37):- Pit and fissure sealant placed following sixth generation bonding agent (ADPER PROMT). GROUP C (N=37):- Pit and fissure sealant placed following seventh generation bonding agent. (OPTIBOND). GROUP D (N=37):- Pit and fissure sealant placed following eighth generation bonding agent. (FUTURA BOND DUAL CURE). The integrity of the sealant placed was assessed immediately after completion of the procedure, 3 months and 6 months after placement. The post-operative evaluation for retention was done using Simonsen criteria. A score of 0 was given for complete retention, 1 for partial retention and 2 for no retention. STATISTICAL ANALYSIS USED: The statistical analysis was done using SPSS (Statistical Package for Social Sciences) software version 21. RESULTS: It was found that there was no statistically significant difference between the groups after 3 and 6 months as the value obtained (0.133) was much greater than the p-value (0.05). CONCLUSIONS: This study concluded that the use of bonding agent prior to application of pit and fissure sealant does not necessarily aid in retention of sealant as compared to pit and fissure sealant placed without bonding agent, Sealants effectiveness is directly related to its retention and it dependent on application procedures. The failure of retention of pit and fissure sealants can attribute to moisture contamination, improper curing methods, inadequate adhesion, improper application procedure or early age placement. PMID- 28914251 TI - Clinical and radiographic comparison of platelet-rich fibrin and mineral trioxide aggregate as pulpotomy agents in primary molars. AB - AIM: This study aimed to evaluate and compare the Platelet-rich fibrin (PRF) and Mineral trioxide aggregate (MTA) as a pulpotomy agent in primary molars. MATERIAL AND METHODS: In this study, 50 primary molars from 50 healthy children aged 5-9 years requiring pulpotomy were randomly allocated into two groups. In PRF group, after coronal pulp removal and hemostasis, remaining pulp tissue was covered with PRF preparation. In the MTA group, the pulp stumps were covered with MTA (Pro Root MTA-Root Canal Repair Material, Dentsply International Inc.) paste obtained by mixing MTA powder with sterile water at a 3:1 powder to water ratio. All teeth were restored with reinforced zinc oxide eugenol base and glass - ionomer cement. Stainless steel crowns were given in both groups 24 h after treatment. Clinical evaluation was undertaken at 1, 3, and 6 months intervals whereas radiographic evaluation of the treated teeth was carried out at the interval of 6 months. RESULTS: By the end of 6 months, the overall success rate was 90% in PRF group and 92% in MTA Group. A statistically significant difference was observed between the groups at 6 months of follow-up (P < 0.05). The results were statistically nonsignificant between the groups (P > 0.05). CONCLUSION: Radiographic and clinical outcome in PRF group could suggest it as an acceptable alternative in pulpotomy of primary teeth. PRF holds a promising future in the area of primary tooth vital pulp therapy. PMID- 28914252 TI - Unilateral fourth, fifth, sixth, and seventh molar in a nonsyndromic patient: A rare and unusual case report. AB - Multiple supernumerary teeth are rare developmental anomalies which are often associated with syndromes. Only few examples of nonsyndromic supernumerary teeth have been reported with fourth, fifth, sixth, and seventh molar rarest of all. The cause, frequency, complications, and surgical operation of supernumerary teeth are always interesting subjects for study and research. Literature reports increased occurrence of the supernumeraries in the maxilla, but here, a unique and unusual case report of 12-year-old female patient with unilateral multiple impacted supernumerary teeth in the mandible in otherwise healthy individual has been presented. PMID- 28914253 TI - Mineral trioxide aggregate-induced apical closure in nonvital immature permanent maxillary incisor. AB - Treatment of nonvital immature permanent teeth with calcium hydroxide is associated with few difficulties such as weakened tooth root, root canal reinfection, and long treatment time. Mineral trioxide aggregate (MTA) apical plug method is an alternative treatment method for open apices and has gained popularity in the recent times. This case report describes the management of a late-referral case of periapically involved, traumatized immature permanent incisor by endodontic treatment and the use of MTA apical plug. After preparing the access cavity, the working length was determined. The root canals were irrigated with 3% sodium hypochlorite and disinfected with metapex for 2 weeks. MTA was then placed in the apical 3 mm of the root canal. The remaining part of the root canal was filled with thermoplastic gutta-percha, and the coronal restoration was finished with composite resin. After 1-year follow-up, radiograph showed successful healing of periradicular radiolucency. PMID- 28914254 TI - Homeopathic therapy for sleep bruxism in a child: Findings of a 2-year case report. AB - Bruxism is a sleep disorder characterized by grinding and biting teeth with multifactorial etiology, resulting in deleterious effects on teeth, periodontium, and temporomandibular joint. There is a lack of scientific evidence evaluating the effectiveness of medicines in treating this parafunction. The present case report was drafted under the rules of CARE checklist. An 8-year-old male patient with sleep bruxism and associated symptoms received a combined homeopathic therapy of Phytolacca decandra 12c and Melissa officinalis 12c for 2 months. After this period of combined homeopathic therapy, the bruxism and associated symptoms completely disappeared. After 2 years of clinical follow-ups, the patient had no recurrences. The use of homeopathic therapy was successful and should be seen as an alternative to treat sleep bruxism and its associated symptoms in children. PMID- 28914255 TI - Microabrasion-remineralization (MAb-Re): An innovative approach for dental fluorosis. AB - Enamel microabrasion is a noninvasive method that removes intrinsic and superficial defects from teeth aimed to improve dental esthetic with minimal loss of dental tissue. This case presentation describes the attempt for teeth color correction utilizing that conservative technique in a young girl whose maxillary anterior teeth presented an opaque white/brown stain. Along with microabrasion, an innovative approach of application of casein phosphopeptide-amorphous calcium phosphate creme on the tooth, and remineralization was carried out thereby reducing postoperative sensitivity of the treated tooth. Based on the results of this case report, it can be concluded that this technique is efficient and can be considered a minimally invasive procedure. PMID- 28914257 TI - Corrigendum: Detecting sulphate aerosol geoengineering with different methods. AB - This corrects the article DOI: 10.1038/srep39169. PMID- 28914258 TI - Corrigendum: Obstructive Sleep Apnea and the Subsequent Risk of Chronic Rhinosinusitis: A Population-Based Study. AB - This corrects the article DOI: 10.1038/srep20786. PMID- 28914256 TI - Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis. AB - Spermatogenesis is a differentiation process during which diploid spermatogonial stem cells (SSCs) produce haploid spermatozoa. This highly specialized process is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine (m6A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactivation of the m6A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Combined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The spermatids from double mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermiogenesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis. PMID- 28914259 TI - Epigenetic targeting of Notch1-driven transcription using the HDACi panobinostat is a potential therapy against T-cell acute lymphoblastic leukemia. PMID- 28914260 TI - High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. AB - High-dose methotrexate (Hd-MTX) therapy has recently been applied to the treatment of adult acute lymphoblastic leukemia (ALL) based on pediatric protocols; however, its effectiveness for adult ALL has not yet been confirmed in a rigorous manner. We herein conducted a randomized phase III trial comparing Hd MTX therapy with intermediate-dose (Id)-MTX therapy. This study was registered at UMIN-CTR (ID: C000000063). Philadelphia chromosome (Ph)-negative ALL patients aged between 25 and 64 years of age were enrolled. Patients who achieved complete remission (CR) were randomly assigned to receive therapy containing Hd-MTX (3 g/m2) or Id-MTX (0.5 g/m2). A total of 360 patients were enrolled. The CR rate was 86%. A total of 115 and 114 patients were assigned to the Hd-MTX and Id-MTX groups, respectively. The estimated 5-year disease-free survival rate of the Hd MTX group was 58%, which was significantly better than that of the Id-MTX group at 32% (P=0.0218). The frequencies of severe adverse events were not significantly different. We herein demonstrated the effectiveness and safety of Hd-MTX therapy for adult Ph-negative ALL. Our results provide a strong rationale for protocols containing Hd-MTX therapy being applied to the treatment of adult ALL. PMID- 28914261 TI - RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia. AB - Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML. PMID- 28914262 TI - Transmembrane TNF-alpha Density, but not Soluble TNF-alpha Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease. AB - OBJECTIVES: Anti-tumor necrosis factor (TNF)-alpha agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF alpha (tmTNF-alpha) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders. METHODS: A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-alpha (sTNF-alpha), percentage of circulating TNF-alpha positive cells, mean fluorescence intensity (MFI) of tmTNF-alpha, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders. RESULTS: Mean sTNF-alpha was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-alpha bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-alpha in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002). CONCLUSIONS: The percentage of tmTNF-alpha bearing lymphocytes and monocytes and the intensity of tmTNF-alpha in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due-as assessed by the apoptosis rate-to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients. PMID- 28914263 TI - Coexistent genetic alterations involving ALK, RET, ROS1 or MET in 15 cases of lung adenocarcinoma. AB - In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients. PMID- 28914264 TI - Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases. AB - PurposeWe sought to determine the analytical sensitivity of several extended exome variation analysis approaches in terms of their contribution to diagnostic yield and their clinical feasibility.MethodsWe retrospectively analyzed the results of genetic testing in 1,059 distinct cases referred for exome sequencing to our institution. In these, we routinely employed extended exome analysis approaches in addition to basic variant analysis, including (i) copy-number variation (CNV) detection, (ii) nonconsensus splice defect detection, (ii) genomic breakpoint detection, (iv) homozygosity mapping, and (v) mitochondrial variant analysis.ResultsExtended exome analysis approaches assisted in identification of causative genetic variant in 44 cases, which represented a 4.2% increase in diagnostic yield. The greatest contribution was associated with CNV analysis (1.8%) and splice variant prediction (1.2%), and the remaining approaches contributed an additional 1.2%. Analysis of workload has shown that on average nine additional variants per case had to be interpreted in the extended analysis.ConclusionWe show that extended exome analysis approaches improve the diagnostic yield of heterogeneous genetic disorders and result in considerable increase of diagnostic yield of exome sequencing with a minor increase of interpretative workload. PMID- 28914265 TI - Fragile X testing as a second-tier test. PMID- 28914266 TI - Medical genetics and genomics education and its impact on genomic literacy of the clinical workforce. PMID- 28914267 TI - Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group. AB - PurposeImplementation research provides a structure for evaluating the clinical integration of genomic medicine interventions. This paper describes the Implementing Genomics in Practice (IGNITE) Network's efforts to promote (i) a broader understanding of genomic medicine implementation research and (ii) the sharing of knowledge generated in the network.MethodsTo facilitate this goal, the IGNITE Network Common Measures Working Group (CMG) members adopted the Consolidated Framework for Implementation Research (CFIR) to guide its approach to identifying constructs and measures relevant to evaluating genomic medicine as a whole, standardizing data collection across projects, and combining data in a centralized resource for cross-network analyses.ResultsCMG identified 10 high priority CFIR constructs as important for genomic medicine. Of those, eight did not have standardized measurement instruments. Therefore, we developed four survey tools to address this gap. In addition, we identified seven high-priority constructs related to patients, families, and communities that did not map to CFIR constructs. Both sets of constructs were combined to create a draft genomic medicine implementation model.ConclusionWe developed processes to identify constructs deemed valuable for genomic medicine implementation and codified them in a model. These resources are freely available to facilitate knowledge generation and sharing across the field. PMID- 28914268 TI - Impact of HIPAA's minimum necessary standard on genomic data sharing. AB - This article provides a brief introduction to the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule's minimum necessary standard, which applies to sharing of genomic data, particularly clinical data, following 2013 Privacy Rule revisions. This research used the Thomson Reuters Westlaw database and law library resources in its legal analysis of the HIPAA privacy tiers and the impact of the minimum necessary standard on genomic data sharing. We considered relevant example cases of genomic data-sharing needs. In a climate of stepped-up HIPAA enforcement, this standard is of concern to laboratories that generate, use, and share genomic information. How data-sharing activities are characterized-whether for research, public health, or clinical interpretation and medical practice support-affects how the minimum necessary standard applies and its overall impact on data access and use. There is no clear regulatory guidance on how to apply HIPAA's minimum necessary standard when considering the sharing of information in the data-rich environment of genomic testing. Laboratories that perform genomic testing should engage with policy makers to foster sound, well informed policies and appropriate characterization of data-sharing activities to minimize adverse impacts on day-to-day workflows. PMID- 28914270 TI - Transplantation: CXCL10 linked to poor outcomes. PMID- 28914271 TI - Surgery: Postprandial hypoglycaemia following bariatric surgery. PMID- 28914272 TI - A Randomized Controlled Trial of a CPR Decision Support Video for Patients Admitted to the General Medicine Service. AB - BACKGROUND: Patient preferences regarding cardiopulmonary resuscitation (CPR) are important, especially during hospitalization when a patient's health is changing. Yet many patients are not adequately informed or involved in the decision-making process. OBJECTIVE: We examined the effect of an informational video about CPR on hospitalized patients' code status choices. DESIGN: This was a prospective, randomized trial conducted at the Minneapolis Veterans Affairs Health Care System in Minnesota. PARTICIPANTS: We enrolled 119 patients, hospitalized on the general medicine service, and at least 65 years old. The majority were men (97%) with a mean age of 75. INTERVENTION: A video described code status choices: full code (CPR and intubation if required), do not resuscitate (DNR), and do not resuscitate/do not intubate (DNR/DNI). Participants were randomized to watch the video (n = 59) or usual care (n = 60). MEASUREMENTS: The primary outcome was participants' code status preferences. Secondary outcomes included a questionnaire designed to evaluate participants' trust in their healthcare team and knowledge and perceptions about CPR. RESULTS: Participants who viewed the video were less likely to choose full code (37%) compared to participants in the usual care group (71%) and more likely to choose DNR/DNI (56% in the video group vs. 17% in the control group) (?? < 0.00001). We did not see a difference in trust in their healthcare team or knowledge and perceptions about CPR as assessed by our questionnaire. CONCLUSIONS: Hospitalized patients who watched a video about CPR and code status choices were less likely to choose full code and more likely to choose DNR/DNI. PMID- 28914273 TI - Patterns and Appropriateness of Thrombophilia Testing in an Academic Medical Center. AB - BACKGROUND: Clinical guidelines recommend against routine use of thrombophilia testing in patients with acute thromboembolism. Thrombophilia testing rarely changes acute management of a thrombotic event. OBJECTIVE: To determine appropriateness of thrombophilia testing in a teaching hospital. DESIGN: Retrospective cohort study. SETTING: One academic medical center in Utah. PARTICIPANTS: All patients who received thrombophilia testing between July 1, 2014, and December 31, 2014. MAIN MEASUREMENTS: Proportion of thrombophilia tests occurring in situations associated with minimal clinical utility, defined as tests meeting at least 1 of the following criteria: discharged before results available; test type not recommended; testing in situations associated with decreased accuracy; duplicate testing; and testing following a provoked thrombotic event. RESULTS: Overall, 163 patients received a total of 1451 thrombophilia tests for stroke (50% of tests; 35% of patients), venous thromboembolism (21% of tests; 21% of patients), and pregnancy-related conditions (15% of tests; 25% of patients). Of the 39 different test types performed, the most common were cardiolipin IgG and IgM antibodies (9% each), lupus anticoagulant (9%), and beta2-glycoprotein 1 IgG and IgM antibodies (8% each). In total, 911 tests (63%) were performed in situations associated with minimal clinical utility, with 126 patients (77%) receiving at least one such test. Only 2 patients (1%) had clear documentation of being offered genetic consultation. CONCLUSIONS: Thrombophilia testing in this single-center study was often associated with minimal clinical utility. Strategies to improve testing practices (eg, hematology specialty consult prior to inpatient testing, improved order panels) might help minimize inappropriate testing and promote value-driven care. PMID- 28914274 TI - Influenza Season Hospitalization Trends in Israel: A Multi-Year Comparative Analysis 2005/2006 Through 2012/2013. AB - BACKGROUND: Influenza-related morbidity impacts healthcare systems, including hospitals. OBJECTIVE: To obtain a quantitative assessment of hospitalization burden in pediatric and internal medicine departments during influenza seasons compared with the summer months in Israel. METHODS: Data on pediatric and internal medicine hospitalized patients in general hospitals in Israel during the influenza seasons between 2005 and 2013 were analyzed for rate of hospitalizations, rate of hospitalization days, hospital length of stay (LOS), and bed occupancy and compared with the summer months. Data were analyzed for hospitalizations for all diagnoses, diagnoses of respiratory or cardiovascular disease (ICD9 390-519), and influenza or pneumonia (ICD9480-487), with data stratified by age. The 2009-2010 pandemic influenza season was excluded. RESULTS: Rates of monthly hospitalizations and hospitalization days for all diagnoses were 4.8% and 8% higher, respectively, during influenza seasons as compared with the summers. The mean LOS per hospitalization for all diagnoses demonstrated a small increase during influenza seasons as compared with summer seasons. The excess hospitalizations and hospitalization days were especially noticed for the age groups under 1 year, 1-4 years, and 85 years and older. The differences were severalfold higher for patients with a diagnosis of respiratory or cardiovascular disease and influenza or pneumonia. Bed occupancy was higher during influenza seasons compared with the summer, particularly in pediatric departments. CONCLUSIONS: Hospital burden in pediatric and internal medicine departments during influenza seasons in Israel was associated with age and diagnosis. These results are important for optimal preparedness for influenza seasons. PMID- 28914275 TI - National Trends (2007-2013) of Clostridium difficile Infection in Patients with Septic Shock: Impact on Outcome. AB - BACKGROUND: Clostridium difficile is the most common infectious cause of healthcare-associated diarrhea and is associated with worse outcomes and higher cost. Patients with septic shock (SS) are at increased risk of acquiring C. difficile infections (CDIs) during hospitalization, but little data are available on CDI complicating SS. OBJECTIVE: Prevalence of CDI in SS between 2007-2013 and impact of CDI on outcomes in SS. METHODS: Outcomes were prevalence of CDI in SS, effect on mortality, length of stay (LOS), and 30-day readmission. RESULTS: There were 2,031,739 hospitalizations with SS (2007-2013). CDI was present in 8.2% of SS. The in-hospital mortality of SS with and without CDI were comparable (37.1% vs 37.0%; ?? = 0.48). Median LOS was longer for SS with CDI (13 days vs 9 days; ?? < 0.001). LOS >75th percentile (>17 days) was 36.9% in SS with CDI vs 22.7% without CDI (?? < 0.001). Similarly, LOS > 90th percentile (> 29 days) was 17.5% vs 9.1%, ?? < 0.001. Odds of LOS >75% and >90% in SS were greater with CDI (odds ratio [OR] 2.11; 95% confidence interval [CI], 2.06-2.15; ?? < 0.001 and OR 2.25; 95% CI, 2.22-2.28; ?? < 0.001, respectively). Hospital readmission of SS with CDI was increased, adjusted OR 1.26 (95% CI, 1.22-1.31; ?? < 0.001). CONCLUSIONS: CDI complicating SS is common and is associated with increased hospital LOS and 30 day hospital readmission. This represents a population in which a focus on prevention and treatment may improve clinical outcomes. PMID- 28914269 TI - Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases. AB - PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses. PMID- 28914276 TI - Appropriate Reconciliation of Cardiovascular Medications After Elective Surgery and Postdischarge Acute Hospital and Ambulatory Visits. AB - OBJECTIVE: To describe appropriate discharge reconciliation of cardiovascular medications and assess associations with postdischarge healthcare utilization in surgical patients. DESIGN: Retrospective cohort study from January 2007 to December 2011. SETTING: An academic medical center. PATIENTS: Seven hundred and fifty-two adults undergoing elective noncardiac surgery and taking antiplatelet agents, beta-blockers, renin-angiotensin system inhibitors, or statin lipid lowering agents before surgery. MEASUREMENTS: Primary predictor: appropriate discharge reconciliation of preoperative cardiovascular medications (continuation without documented contraindications). Primary outcomes: acute hospital visits (emergency department visits or hospitalizations) and unplanned ambulatory visits (primary care or surgical) at 30 days after surgery. RESULTS: Preoperative medications were appropriately reconciled in 436 (58.0%) patients. For individual medications, appropriate discharge reconciliation occurred for 156 of the 327 patients on antiplatelet agents (47.7%), 507 of the 624 patients on beta-blockers (81.3%), 259 of the 361 patients on renin-angiotensin system inhibitors (71.8%), and 302 of the 406 patients on statins (74.4%). In multivariable analyses, appropriate reconciliation of all preoperative medications was not associated with acute hospital (adjusted odds ratio [AOR], 0.94; 95% confidence interval [CI], 0.63-1.41) or unplanned ambulatory visits (AOR, 1.48; 95% CI, 0.94-2.35). Appropriate reconciliation of statin therapy was associated with lower odds of acute hospital visits (AOR, 0.47; 95% CI, 0.26-0.85). There were no other statistically significant associations between appropriate reconciliation of individual medications and either outcome. CONCLUSIONS: Although large gaps in appropriate discharge reconciliation of chronic cardiovascular medications were common in patients undergoing elective surgery, these gaps were not consistently associated with postdischarge acute hospital or ambulatory visits. PMID- 28914277 TI - Antidepressant Use and Depressive Symptoms in Intensive Care Unit Survivors. AB - Nearly 30% of intensive care unit (ICU) survivors have depressive symptoms 2-12 months after hospital discharge. We examined the prevalence of depressive symptoms and risk factors for depressive symptoms in 204 patients at their initial evaluation in the Critical Care Recovery Center (CCRC), an ICU survivor clinic based at Eskenazi Hospital in Indianapolis, Indiana. Thirty-two percent (N = 65) of patients had depressive symptoms on initial CCRC visit. For patients who are not on an antidepressant at their initial CCRC visit (N = 135), younger age and lower education level were associated with a higher likelihood of having depressive symptoms. For patients on an antidepressant at their initial CCRC visit (N = 69), younger age and being African American race were associated with a higher likelihood of having depressive symptoms. Future studies will need to confirm these findings and examine new approaches to increase access to depression treatment and test new antidepressant regimens for post-ICU depression. PMID- 28914278 TI - Magnitude of Potentially Inappropriate Thrombophilia Testing in the Inpatient Hospital Setting. AB - Laboratory costs of thrombophilia testing exceed an estimated $650 million (in US dollars) annually. Quantifying the prevalence and financial impact of potentially inappropriate testing in the inpatient hospital setting represents an integral component of the effort to reduce healthcare expenditures. We conducted a retrospective analysis of our electronic medical record to evaluate 2 years' worth of inpatient thrombophilia testing measured against preformulated appropriateness criteria. Cost data were obtained from the Centers for Medicare and Medicaid Services 2016 Clinical Laboratory Fee Schedule. Of the 1817 orders analyzed, 777 (42.7%) were potentially inappropriate, with an associated cost of $40,422. The tests most frequently inappropriately ordered were Factor V Leiden, prothrombin gene mutation, protein C and S activity levels, antithrombin activity levels, and the lupus anticoagulant. Potentially inappropriate thrombophilia testing is common and costly. These data demonstrate a need for institution-wide changes in order to reduce unnecessary expenditures and improve patient care. PMID- 28914279 TI - Blood Products Provided to Patients Receiving Futile Critical Care. AB - The number of hospitalized patients receiving treatment perceived to be futile is not insignificant. Blood products are valuable resources that are donated to help others in need. We aimed to quantify the amount of blood transfused into patients who were receiving treatment that the critical care physician treating them perceived to be futile. During a 3-month period, critical care physicians in 5 adult intensive care units completed a daily questionnaire to identify patients perceived as receiving futile treatment. Of 1136 critically ill patients, physicians assessed 123 patients (11%) as receiving futile treatment. Fifty-nine (48%) of the 123 patients received blood products after they were assessed to be receiving futile treatment: 242 units of packed red blood cells (PRBCs) (7.6% of all PRBC units transfused into critical care patients during the 3-month study period); 161 (9.9%) units of plasma, 137 (12.1%) units of platelets, and 21 (10.5%) units of cryoprecipitate. Explicit guidelines on the use of blood products should be developed to ensure that the use of this precious resource achieves meaningful goals. PMID- 28914280 TI - Internal Medicine Resident Engagement with a Laboratory Utilization Dashboard: Mixed Methods Study. AB - The objective of this study was to measure internal medicine resident engagement with an electronic medical record-based dashboard providing feedback on their use of routine laboratory tests relative to service averages. From January 2016 to June 2016, residents were e-mailed a snapshot of their personalized dashboard, a link to the online dashboard, and text summarizing the resident and service utilization averages. We measured resident engagement using e-mail read-receipts and web-based tracking. We also conducted 3 hour-long focus groups with residents. Using grounded theory approach, the transcripts were analyzed for common themes focusing on barriers and facilitators of dashboard use. Among 80 residents, 74% opened the e-mail containing a link to the dashboard and 21% accessed the dashboard itself. We did not observe a statistically significant difference in routine laboratory ordering by dashboard use, although residents who opened the link to the dashboard ordered 0.26 fewer labs per doctor-patient day than those who did not (95% confidence interval, -0.77 to 0.25; ?? = 0 .31). While they raised several concerns, focus group participants had positive attitudes toward receiving individualized feedback delivered in real time. PMID- 28914281 TI - Two-Unit Red Cell Transfusions in Stable Anemic Patients. PMID- 28914282 TI - Mass Confusion. PMID- 28914283 TI - Morbo Serpentino. PMID- 28914284 TI - The Weekend Effect in Hospitalized Patients: A Meta-Analysis. AB - BACKGROUND: The presence of a "weekend effect" (increased mortality rate during Saturday and/or Sunday admissions) for hospitalized inpatients is uncertain. PURPOSE: We performed a systematic review to examine the presence of a weekend effect on hospital inpatient mortality. DATA SOURCES: PubMed, EMBASE, SCOPUS, and Cochrane databases (January 1966-April 2013) were utilized for our search. STUDY SELECTION: We examined the mortality rate for hospital inpatients admitted during the weekend compared with those admitted during the workweek. To be included, the study had to provide discrete mortality data around the weekends (including holidays) versus weekdays, include patients who were admitted as inpatients over the weekend, and be published in English. DATA EXTRACTION: The primary outcome was all-cause weekend versus weekday mortality with subgroup analysis by personnel staffing levels, rates and times to procedures rates and delays, or illness severity. DATA SYNTHESIS: A total of 97 studies (N = 51,114,109 patients) were examined. Patients admitted on the weekends had a significantly higher overall mortality (relative risk, 1.19; 95% confidence interval, 1.14-1.23). With regard to the subgroup analyses, patients admitted on the weekends consistently had higher mortality than those admitted during the week, regardless of the levels of weekend/weekday differences in staffing, procedure rates and delays, and illness severity. CONCLUSIONS: Hospital inpatients admitted during weekends may have a higher mortality rate compared with inpatients admitted during the weekdays. PMID- 28914285 TI - Hospital Medicine Point of Care Ultrasound Credentialing: An Example Protocol. AB - Though the use of point-of-care ultrasound (POCUS) has increased over the last decade, formal hospital credentialing for POCUS may still be a challenge for hospitalists. This document details the Hospital Medicine Department Ultrasound Credentialing Policy from Regions Hospital, which is part of the HealthPartners organization in Saint Paul, Minnesota. National organizations from internal medicine and hospital medicine (HM) have not published recommended guidelines for POCUS credentialing. Revised guidelines for POCUS have been published by the American College of Emergency Physicians, though these are not likely intended to guide hospitalists when working with credentialing committees and medical boards. This document describes the scope of ultrasound in HM and our training, credentialing, and quality assurance program. This report is intended to be used as a guide for hospitalists as they work with their own credentialing committees and will require modification for each institution. However, the overall process described here should assist in the establishment of POCUS at various institutions. PMID- 28914286 TI - A Video Is Worth a Thousand Words. PMID- 28914287 TI - Certification of Point-of-Care Ultrasound Competency. PMID- 28914288 TI - Inpatient Thrombophilia Testing: At What Expense? PMID- 28914289 TI - Does the Week-End Justify the Means? PMID- 28914290 TI - Reducing Routine Labs-Teaching Residents Restraint. PMID- 28914291 TI - White light induced covalent modification of graphene using a phenazine dye. AB - Herein, we report a novel strategy for a covalent modification of graphene nanoplatelets with photoactive dyes. The functionalization of the graphene surface was carried out using white light to photochemically generate phenazine radicals and the reaction progress was followed up spectrophotometrically. The characterization of the modified material was carried out using FTIR, XRD, UV-vis absorption, fluorescence, Raman spectroscopy and SEM imaging. The hybrid material has improved solubility, shows an optical band gap of 1.95 eV and is highly emissive in the visible wavelength region. PMID- 28914292 TI - pH and redox dual-sensitive polysaccharide nanoparticles for the efficient delivery of doxorubicin. AB - A pH and redox dual-sensitive biodegradable polysaccharide, succinic acid decorated dextran-g-phenylalanine ethyl ester-g-cysteine ethyl ester (Dex-SA-l Phe-l-Cys), was synthesized to load doxorubicin hydrochloride (DOX.HCl). The DOX loaded nanoparticles, which were prepared in aqueous solution and free of organic solvent, could spontaneously self-assemble into uniform sizes. When loading DOX.HCl, mercapto Dex-SA-l-Phe-l-Cys was oxidized into a crosslinked disulfide linkage to form pH and redox dual-sensitive nanoparticles (DOX-S-NPs). The amphiphilic polymer loaded DOX.HCl into the core through electrostatic and hydrophobic interactions, meanwhile the crosslinked disulfide bond could stabilize the drug loaded nanoparticles. As a control with similar polymer structure, succinic acid decorated dextran-g-phenylalanine ethyl ester (Dex-SA-l Phe) was prepared to obtain pH-sensitive DOX-loaded micelles (DOX-N-NPs). The controlled pH and redox-dependent release profiles of the DOX-S-NPs in vitro were certified in different releasing mediums. Furthermore, the cellular uptake of the DOX-S-NPs was comparable with that of free DOX.HCl, determined by confocal laser scanning microscopy (CLSM) and flow cytometry. Cytotoxicity assay in vitro showed that the DOX-S-NPs and free DOX.HCl were similar in inhibiting the proliferation of non-small cell lung carcinoma A549 and breast cancer MCF-7 cell lines. DOX-S NPs displayed similar antitumor efficiency compared with free DOX.HCl, but lower toxicity by body weight. These dual-sensitive DOX-S-NPs provide a useful strategy for anti-tumor therapy. PMID- 28914293 TI - The first lead cobalt phosphite, PbCo2(HPO3)3. AB - Single crystals of a new lead cobalt phosphite, PbCo2(HPO3)3, have been synthesized using mild hydrothermal techniques and characterized by X-ray diffraction analysis, SQUID magnetic measurements, IR spectroscopy, UV/vis spectroscopy, thermogravimetric analysis, and scanning electron microscopy. PbCo2(HPO3)3 crystallizes in the non-centrosymmetric (NCS) R3m space group, a = 5.3145(15) A, c = 25.494(7) A, V = 623.6(4) A3. The crystal structure of PbCo2(HPO3)3 is based upon 2D heteropolyhedral blocks built up from Co2O9 octahedral dimers and HPO3 pseudo-tetrahedra. Lead cations reside in the interlayer space of the structure. Here, the NCS character results reasonably from the cooperative Pb2+ lone electron pair arrangements, by analogy to the centrosymmetric compound (NH4)2Co2(HPO3)3 with similar but disordered blocks. A local twisting of specific HPO3 groups arises due to unreasonably short HH contacts between two phosphite oxoanions. In terms of the magnetic behavior, the new PbCo2(HPO3)3 phase demonstrates weak antiferromagnetic interactions inside the Co2O9 dimers between cobalt ions as expected from the phosphite MU-O bridges. PMID- 28914294 TI - Facile synthesis of CdS/Bi4V2O11 photocatalysts with enhanced visible-light photocatalytic activity for degradation of organic pollutants in water. AB - The development of Z-scheme heterojunction photocatalytic systems is a promising strategy to produce hydrogen and for pollutant degradation. In this study, the direct Z-scheme CdS/Bi4V2O11 photocatalysts were synthesized via a two-step solvothermal method. The photocatalytic properties of the samples were measured by ciprofloxacin (CIP), tetracycline (TC) and rhodamine B (RhB) degradation under visible light (lambda > 420 nm). In addition, a probable reaction mechanism for organic pollutants over CdS/Bi4V2O11 photocatalysts was also proposed based on the analysis of electron spin resonance (ESR) and active species capture experiments. The enhanced photocatalytic activity of CdS/Bi4V2O11 photocatalysts was ascribed to the efficient electron transfer of direct Z-scheme CdS/Bi4V2O11 photocatalysts. PMID- 28914295 TI - A novel photo-active Cd:1,4-benzene dicarboxylate metal organic framework templated using [Ru(ii)(2,2'-bipyridine)3]2+: synthesis and photophysics of RWLC 5. AB - The development of photoactive porous materials is of significant importance for applications ranging from sustainable energy to pharmaceutical development and catalysis. A particularly attractive class of photo-active materials is the metal organic framework (MOF)-based platform in which the photo-active elements are components of the framework itself or photo-active guests encapsulated within the MOF cavities. It has now been demonstrated that the photo-active [Ru(2,2' bipyridine)3]2+ (RuBpy) complex can template the formation of MOFs with varying three dimensional structures. Here we report the synthesis and structural and photo-physical characterization of a new RuBpy-templated MOF composed of Cd2+ ions with 1,4-benzenedicarboxylate ligands (RWLC-5) that contains crystallographically resolved RuBpy complexes. The new material displays a biphasic emission decay (130 ns and 1180 ns, T = 20 degrees C) and a bathochromically shifted emission maximum, relative to RuBpy in solution (603 nm for RuBpy in ethanol vs. 630 nm for RWLC-5). The emission lifetimes also do not display temperature-dependent decays which are characteristic of RuBpy type complexes as well as other RuBpy templated MOFs. The lack of temperature dependence is consistent with the complete deactivation of the 3LF state of the encapsulated RuBpy complex due to a constrained environment. The fast phase decay is attributed to a water molecule hydrogen bonded to a bipyridine ligand associated with ~38% of the encapsulated RuBpy complexes resulting in the nonradiative deactivation of the 3MLCT state. PMID- 28914296 TI - Correction: Observation of crystalline changes of titanium dioxide during lithium insertion by visible spectrum analysis. AB - Correction for 'Observation of crystalline changes of titanium dioxide during lithium insertion by visible spectrum analysis' by Inho Nam et al., Phys. Chem. Chem. Phys., 2017, 19, 13140-13146. PMID- 28914297 TI - Dispersion of Ni2+ ions via acetate precursor in the preparation of NaNiPO4 nanoparticles: effect of acetate vs. nitrate on the capacitive energy storage properties. AB - The influence of the precursors on the dispersion of Ni2+ ions and the presence of several other functional groups was investigated in the preparation of sodium nickel phosphate (NaNiPO4) cathode for a supercapacitor study. The dispersion of nickel phases, in the form of nanosheets, is influenced by the type of precursors used in the synthesis. XPS based spectroscopic information on the surface functional groups on NaNiPO4 show differences between the precursors (i.e.) acetate- and nitrate-derived materials. The benefits of using acetate as an alternative to nitrate are explored by using the NaNiPO4 nanoparticles as a cathode for supercapacitor applications. The acetate-derived material exhibits improved electrochemical properties possessing both redox behaviour and double layer capacitance. The results indicate that the metal acetates are homogenously distributed. Acetate functionalization resulted in an improved capacitance of 90 F g-1 compared with that obtained from the nitrate precursor derived material (58 F g-1). Capacitance retention and high rate capability were also a feature of the acetate-derived material. The sodium nickel phosphate cathode material has provided useful insights on the precursor chemistry in storing renewable energy have been reported for the first time. PMID- 28914298 TI - Folic acid on iron oxide nanoparticles: platform with high potential for simultaneous targeting, MRI detection and hyperthermia treatment of lymph node metastases of prostate cancer. AB - The overexpression of the folate receptor in most cancers has been widely exploited to specifically deliver folic acid (FA) coupled nanomedicines to tumors. However, complex coupling chemistry is often used to bind FA to the nanoparticles. Furthermore, very little has been reported for the targeting of nanomedicines to lymph node metastases (LNMs) of prostate cancer. We here report the simple and aqueous coating of iron oxide nanoparticles (IONPs) with FA for theranostics of LNMs of prostate cancer. FA was directly bound to the IONPs' surface without the use of any linker, simultaneously playing the role of the coating molecule and targeting agent. We measured for FA-IONPs a hydrodynamic diameter around 100 nm and a negative surface charge, what is needed to access and to be retained in the lymphatic system for the LNMs targeting. We also show that FA-IONPs are specifically uptaken by prostate cancer cells expressing the prostate specific membrane antigen, including LNMs cells. FA-IONPs also displayed both high relaxivity for MRI detection and high specific absorption rate needed for hyperthermia treatment of tumors. Our study provides a theranostic platform for targeting LNMs of prostate cancer with high potential for their detection by MRI and treatment by hyperthermia. PMID- 28914299 TI - A dinuclear copper(i) thiodiacetate complex as an efficient and reusable 'click' catalyst for the synthesis of glycoconjugates. AB - We report herein the facile synthesis and structural characterization of a highly stable dinuclear Cu(i) complex, [(PPh3)2Cu(MU-tda)Cu(PPh3)2].6H2O 1 (tda = thiodiacetate anion), in which the Cu-Cu distance is 7.197 A. This "pre-formed" complex serves as an extremely efficient and recyclable homogeneous catalyst (2 mol%, 30 min) for CuAAC in dichloromethane solvent. The synthesis of a variety of glycoconjugates under ambient conditions is successfully achieved using 1 as a catalyst. The products are obtained in high yields and very short reaction times while complying with the "click protocols". A simpler procedure solely involving the mixing of substrates with 1 (i.e. base free and solvent free) gave the corresponding glycoconjugate in 10 min using 2 mol% of the catalyst. PMID- 28914300 TI - Highly efficient electrocatalytic oxidation of urea on a Mn-incorporated Ni(OH)2/carbon fiber cloth for energy-saving rechargeable Zn-air batteries. AB - A Mn-incorporated Ni(OH)2/carbon fiber cloth (Mn-Ni(OH)2/CFC) fabricated via a room-temperature solution route exhibited superior electrocatalytic activities of the oxygen reduction and urea oxidation reactions, delivering 12-21% energy saving in the charging process of Mn-Ni(OH)2/CFC assembled Zn-air batteries in the presence of 0.5 M urea compared to the battery without urea. PMID- 28914301 TI - Addressing the distribution of proteins spotted on MUPADs. AB - Adsorption is the most common approach to immobilize biorecognition elements on the surface of paper-based devices. Adsorption is also the route selected to coat the substrate with albumin, therefore minimizing the interaction of other proteins. While similar in nature, the structure of the selected proteins as well as the conditions selected from the immobilization have a significant effect on the amount and distribution of the resulting composites. To illustrate these differences and provide general guidelines to efficiently prepare these devices, this article explores the interaction (adsorption and desorption) of BSA with 3MM chromatography paper. The experimental conditions investigated were the protein concentration, the interaction time, the number of times the protein was spotted, the pH of buffer solution, and the ionic strength of the buffer solution. The proposed approach mimics the steps involved in the fabrication (adsorption) and use (rinsing induced by the sample) of paper-based microfluidic devices. To identify the protein location following the rinsing step, the protein was fixed by dehydration in a convection oven and then stained using Coomassie Blue. The color intensity, which was found to be proportional to the amount of protein immobilized, was determined using a desktop scanner. To highlight the importance of understanding the adsorption process to the rational development of MUPADs, results were complemented by experiments performed with lysozyme and immunoglobulin G. PMID- 28914302 TI - Li3Co1.06(1)TeO6: synthesis, single-crystal structure and physical properties of a new tellurate compound with CoII/CoIII mixed valence and orthogonally oriented Li-ion channels. AB - A tellurate compound with CoII/CoIII mixed valence states and lithium ions within orthogonally oriented channels was realized in Li3Co1.06(1)TeO6. The single crystal structure determination revealed two independent and interpenetrating Li/O and (Co,Te)/O substructures with octahedral oxygen coordination of the metal atoms. In contrast to other mixed oxides, a honeycomb-like ordering of CoO6 and TeO6 octahedra was not observed. Li3Co1.06(1)TeO6 crystallizes orthorhombically with the following unit cell parameters and refinement results: Fddd, a = 588.6(2), b = 856.7(2), c = 1781.5(4) pm, R1 = 0.0174, wR2 = 0.0462, 608 F2 values, and 33 variables. Additional electron density in tetrahedral voids in combination with neighboring face-linked and under-occupied octahedral lithium sites offers an excellent possible diffusion pathway for lithium ions. According to the symmetry of the crystal structure the diffusion pathways in Li3Co1.06(1)TeO6 were found in two orthogonal orientations. The CoII/CoIII mixed valence was investigated via X-ray photoelectron spectroscopy (XPS), revealing a composition comparable to that derived from single-crystal X-ray diffractometry. Magnetic susceptibility measurements underlined the coexistence of CoII and CoIII, the title compound, however, showed no magnetic ordering down to low temperatures. The ionic conductivity of Li3Co1.06(1)TeO6 was determined via alternating current (AC) electrochemical impedance spectroscopy and was found to be in the range of 1.6 * 10-6 S cm-1 at 573 K. PMID- 28914303 TI - Structure dependence of intramolecular electron transfer reactions of simple dyads of a zinc(ii) porphyrin complex bearing a peripheral bipyridine moiety. AB - New dyad systems based on a zinc(ii) porphyrin complex and a 2,2'-bipyridine moiety linked by amide bridges having various bridging groups were synthesized. The photochemical behavior was investigated using fluorescence spectroscopy and a time-resolved absorption technique. The singlet excited state of the porphyrin complex was found to be partially quenched by Cu2+ in methanol, and a photoinduced electron transfer from the excited state of the porphyrin moiety to the Cu(ii)-bipyridine moiety was observed using a transient absorption technique. The relatively long lifetime of the charge-separated state was ascribed to the slow electron-transfer reaction of the Cu(ii)/Cu(i) couple bound to the bipyridine moiety. The lifetime of the charge-separated state of dyads becomes longer with the increase of the distance between the porphyrin and bipyridine moieties, and these findings are discussed using an empirical formula for the relationship between the reactivity and molecular structure of dyads. PMID- 28914304 TI - High-accuracy and high-sensitivity spectroscopic measurement of dinitrogen pentoxide (N2O5) in an atmospheric simulation chamber using a quantum cascade laser. AB - A spectroscopic instrument based on a mid-infrared external cavity quantum cascade laser (EC-QCL) was developed for high-accuracy measurements of dinitrogen pentoxide (N2O5) at the ppbv-level. A specific concentration retrieval algorithm was developed to remove, from the broadband absorption spectrum of N2O5, both etalon fringes resulting from the EC-QCL intrinsic structure and spectral interference lines of H2O vapour absorption, which led to a significant improvement in measurement accuracy and detection sensitivity (by a factor of 10), compared to using a traditional algorithm for gas concentration retrieval. The developed EC-QCL-based N2O5 sensing platform was evaluated by real-time tracking N2O5 concentration in its most important nocturnal tropospheric chemical reaction of NO3 + NO2 <-> N2O5 in an atmospheric simulation chamber. Based on an optical absorption path-length of Leff = 70 m, a minimum detection limit of 15 ppbv was achieved with a 25 s integration time and it was down to 3 ppbv in 400 s. The equilibrium rate constant Keq involved in the above chemical reaction was determined with direct concentration measurements using the developed EC-QCL sensing platform, which was in good agreement with the theoretical value deduced from a referenced empirical formula under well controlled experimental conditions. The present work demonstrates the potential and the unique advantage of the use of a modern external cavity quantum cascade laser for applications in direct quantitative measurement of broadband absorption of key molecular species involved in chemical kinetic and climate-change related tropospheric chemistry. PMID- 28914305 TI - Two-step crystallization of a phase-pure Ln2(OH)5NO3.nH2O layered compound for the smallest Ln ions of Tm, Yb and Lu, anion exchange, and exfoliation. AB - Crystallization of the Ln2(OH)5NO3.nH2O layered hydroxide (LLnH) is the most difficult for the three smallest lanthanide ions of Tm, Yb and Lu. By applying a novel two-step crystallization technique, which involves chemical precipitation at a freezing-temperature of ~4 degrees C and subsequent Ostwald ripening at 50 degrees C for Tm and Yb and 65 degrees C for Lu, the three compounds have been obtained in a phase-pure form without the use of any mineralizer. The resulting LTmH and LYbH (n ~ 1.5) were shown to accommodate free NO3- anions in the interlayer gallery, which are readily exchangeable by DS- (C12H25OSO3-). Delamination of the DS- derivatives in formamide produced micron-sized nanosheets of ~1.7 nm thick. A similar anion exchange was found to hardly proceed for LLuH even at 65 degrees C, owing to the direct coordination of the interlayer NO3- with the Lu3+ center. PMID- 28914306 TI - Enhanced intermediate-temperature CO2 splitting using nonstoichiometric ceria and ceria-zirconia. AB - CO2 splitting via thermo-chemical or reactive redox has emerged as a novel and promising carbon-neutral energy solution. Its performance depends critically on the properties of the oxygen carriers (OC). Ceria is recognized as one of the most promising OC candidates, because of its fast chemistry, high ionic diffusivity, and large oxygen storage capacity. The fundamental surface ion incorporation pathways, along with the role of surface defects and the adsorbates remain largely unknown. This study presents a detailed kinetics study of CO2 splitting using CeO2 and Ce0.5Zr0.5O2 (CZO) in the temperature range 600-900 degrees C. Given our interest in fuel-assisted reduction, we limit our study to relatively lower temperatures to avoid excessive sintering and the need for high temperature heat. Compared to what has been reported previously, we observe higher splitting kinetics, resulting from the utilization of fine particles and well-controlled experiments which ensure a surface-limited-process. The peak rates with CZO are 85.9 MUmole g-1 s-1 at 900 degrees C and 61.2 MUmole g-1 s-1 at 700 degrees C, and those of CeO2 are 70.6 MUmole g-1 s-1 and 28.9 MUmole g-1 s-1. Kinetic models are developed to describe the ion incorporation dynamics, with consideration of CO2 activation and the charge transfer reactions. CO2 activation energy is found to be -120 kJ mole-1 for CZO, half of that for CeO2, while CO desorption energetics is analogous between the two samples with a value of ~160 kJ mole-1. The charge-transfer process is found to be the rate-limiting step for CO2 splitting. The evolution of CO32- with surface Ce3+ is examined based on the modeled kinetics. We show that the concentration of CO32- varies with Ce3+ in a linear-flattened-decay pattern, resulting from a mismatch between the kinetics of the two reactions. Our study provides new insights into the significant role of surface defects and adsorbates in determining the splitting kinetics. PMID- 28914307 TI - Revealing the distinct thermal transition behavior between PEGA-based linear polymers and their disulfide cross-linked nanogels. AB - The distinct thermal transition behavior of thermoresponsive block polymers based on poly(ethylene glycol)methyl ether acrylate (PEGA) and their corresponding disulfide-cross-linked nanogels was studied by using FTIR measurements in combination with two-dimensional correlation spectroscopy (2Dcos). Spectral analysis clearly reveals that the sharp thermal transition of the precursor polymer is accompanied by a forced hydration process induced by the formation of hydrogen bonds between the entrapped water molecules and the C[double bond, length as m-dash]O groups, while the nanogel with a relatively continuous thermal transition is related to the existence of various dehydrating states of the C[double bond, length as m-dash]O groups. The C-H groups in the pyridyl disulfide (PDS) units exhibit a distinct change in the thermoresponsive profile of the precursor and the nanogel to show the effect of the polymer architecture on the thermal transition behavior. Additionally, a portion of the poly(N,N dimethylacrylamide) (PDMA) segments is entrapped in the nanogel core, indicating that the thiol-disulfide exchange reaction occurs rapidly within the nanogels. PMID- 28914308 TI - Multicomponent ionic liquid CMC prediction. AB - We created a model to predict CMC of ILs based on 704 experimental values published in 43 publications since 2000. Our model was able to predict CMC of variety of ILs in binary or ternary system in a presence of salt or alcohol. The molecular volume of IL (Vm), solvent-accessible surface (S), solvation enthalpy (DeltasolvGinfinity), concentration of salt (Cs) or alcohol (Ca) and their molecular volumes (Vms and Vma, respectively) were chosen as descriptors, and Kernel Support Vector Machine (KSVM) and Evolutionary Algorithm (EA) as regression methodologies to create the models. Data was split into training and validation set (80/20) and subjected to bootstrap aggregation. KSVM provided better fit with average R2 of 0.843, and MSE of 0.608, whereas EA resulted in R2 of 0.794 and MSE of 0.973. From the sensitivity analysis it was shown that Vm and S have the highest impact on ILs micellization in both binary and ternary systems, however surprisingly in the presence of alcohol the Vm becomes insignificant/irrelevant. Micelle stabilizing or destabilizing influence of the descriptors depends upon the additives. Previous attempts at modelling the CMC of ILs was generally limited to small number of ILs in simplified (binary) systems. We however showed successful prediction of the CMC over a range of different systems (binary and ternary). PMID- 28914309 TI - Tetragonal phase of cylinders self-assembled from binary blends of AB diblock and (A'B)n star copolymers. AB - The phase behavior of binary blends composed of AB diblock and (A'B)n star copolymers is studied using the polymeric self-consistent field theory, focusing on the formation and stability of the stable tetragonal phase of cylinders. In general, cylindrical domains self-assembled from AB-type block copolymers are packed into a hexagonal array, although a tetragonal array of cylinders could be more favourable for lithography applications in microelectronics. The polymer blends are designed such that there is an attractive interaction between the A and A' blocks, which increases the compatibility between the two copolymers and thus suppresses the macroscopic phase separation of the blends. With an appropriate choice of system parameters, a considerable stability window for the targeted tetragonal phase is identified in the blends. Importantly, the transition mechanism between the hexagonal and tetragonal phases is elucidated by examining the distribution of the two types of copolymers in the unit cell of the structure. The results reveal that the short (A'B)n star copolymers are preferentially located in the bonding area connecting two neighboring domains in order to reduce extra stretching, whereas the long AB diblock copolymers are extended to further space of the unit cell. PMID- 28914310 TI - Plasmonic enhancement of SERS measured on molecules in carbon nanotubes. AB - We isolated the plasmonic contribution to surface-enhanced Raman scattering (SERS) and found it to be much stronger than expected. Organic dyes encapsulated in single-walled carbon nanotubes are ideal probes for quantifying plasmonic enhancement in a Raman experiment. The molecules are chemically protected through the nanotube wall and spatially isolated from the metal, which prevents enhancement by chemical means and through surface roughness. The tubes carry molecules into SERS hotspots, thereby defining molecular position and making it accessible for structural characterization with atomic-force and electron microscopy. We measured a SERS enhancement factor of 106 on alpha-sexithiophene (6T) molecules in the gap of a plasmonic nanodimer. This is two orders of magnitude stronger than predicted by the electromagnetic enhancement theory (104). We discuss various phenomena that may explain the discrepancy (including hybridization, static and dynamic charge transfer, surface roughness, uncertainties in molecular position and orientation), but found all of them lacking in enhancement for our probe system. We suggest that plasmonic enhancement in SERS is, in fact, much stronger than currently anticipated. We discuss novel approaches for treating SERS quantum mechanically that appear promising for predicting correct enhancement factors. Our findings have important consequences on the understanding of SERS as well as for designing and optimizing plasmonic substrates. PMID- 28914312 TI - Plasmon induced polymerization using a TERS approach: a platform for nanostructured 2D/1D material production. AB - Plasmon-induced chemical reactions have recently attracted great attention as a promising method for high efficiency light-energy conversion and proved to be useful in a wealth of different domains of chemistry and physics. One of the interesting and, so far, less explored avenues of such reactions is their potential for efficient, highly localized and controlled polymer production. Here, we present the first example of a localized, directed plasmon catalyzed polymerization process of a self-assembled monolayer on both silver and gold surfaces monitored by surface- and tip-enhanced Raman spectroscopy (SERS and TERS). As a proof-of-concept, a bi-functionalized dibenzo(1,2)dithiine-3,8 diamine (D3ATP) molecule that undergoes a well-known plasmon-induced coupling via the amino group into an azo group has been used. Initial dimerization is demonstrated using established marker bands associated with the formation of the azo group. A subsequent indicator for a polymerization reaction, the appearance of a new characteristic band, is monitored by time-dependent SERS and TERS experiments. We demonstrate that the dimerization reaction and hence, the subsequent polymerization, can be induced by a plasmonic feature, e.g. a TERS tip, at specific nanoscale locations and, at a much larger micron scale, by continuously scanning the plasmonic probe. The presented results provide the basis for designing further plasmonic catalysis experiments in general, and offer a new platform for producing ultra-thin polymer films with a defined structural dimension. PMID- 28914311 TI - Comparing Caenorhabditis elegans gentle and harsh touch response behavior using a multiplexed hydraulic microfluidic device. AB - The roundworm Caenorhabditis elegans is an important model system for understanding the genetics and physiology of touch. Classical assays for C. elegans touch, which involve manually touching the animal with a probe and observing its response, are limited by their low throughput and qualitative nature. We developed a microfluidic device in which several dozen animals are subject to spatially localized mechanical stimuli with variable amplitude. The device contains 64 sinusoidal channels through which worms crawl, and hydraulic valves that deliver touch stimuli to the worms. We used this assay to characterize the behavioral responses to gentle touch stimuli and the less well studied harsh (nociceptive) touch stimuli. First, we measured the relative response thresholds of gentle and harsh touch. Next, we quantified differences in the receptive fields between wild type worms and a mutant with non-functioning posterior touch receptor neurons. We showed that under gentle touch the receptive field of the anterior touch receptor neurons extends into the posterior half of the body. Finally, we found that the behavioral response to gentle touch does not depend on the locomotion of the animal immediately prior to the stimulus, but does depend on the location of the previous touch. Responses to harsh touch, on the other hand, did not depend on either previous velocity or stimulus location. Differences in gentle and harsh touch response characteristics may reflect the different innervation of the respective mechanosensory cells. Our assay will facilitate studies of mechanosensation, sensory adaptation, and nociception. PMID- 28914313 TI - Cohesiveness and flowability of particulated solid and semi-solid food systems. AB - Cohesiveness and flowability of particulated food systems is of particular interest in the oral processing and swallowing of food products, especially for people suffering from dysphagia. Although cohesiveness of a bolus is an essential parameter in swallowing, a robust technique for objective measurement of cohesiveness of particulated semi- or soft-solids is still lacking. In our approach the ring shear tester is used to measure the cohesiveness and flowability of a model particulated food system based on fresh green pea powders and pastes with controlled moisture content. The focus is on how the cohesiveness and flowability of dry pea particles change as they absorb moisture, swell and soften, while continuously agglomerating until a paste like bolus is achieved. Differently hydrated pea powders start to granulate with increasing moisture content resulting in decreasing flowability and increasing cohesiveness until a critical moisture content of approximately 73 wt% is reached. Above the critical moisture content, cohesiveness starts to decrease and flowability increases, i.e. indicating the transition into the rheological domain of concentrated suspension flow. Besides moisture content we also show that water adsorption capacity i.e. hydration properties and resulting degree of particle softness tremendously influences the flowability factor and cohesiveness of powder systems. Thus ring shear tester can be used to provide guidelines for food paste formulation with controlled cohesiveness. PMID- 28914314 TI - The impact of extrusion on the nutritional composition, dietary fiber and in vitro digestibility of gluten-free snacks based on rice, pea and carob flour blends. AB - Consumers and the food industry are demanding healthier products. Expanded snacks with a high nutritional value were developed from different rice, pea and carob flour blends. The proximate composition, starch (total and resistant), amylose and amylopectin, dietary fiber (soluble and insoluble) contents, and the in vitro protein digestibility of different rice-legume formulations, were evaluated before and after the extrusion process. Compared with the corresponding non extruded blends (control), the extrusion treatment did not change the total protein content, however, it reduced the soluble protein (61-86%), the fat (69 92%) and the resistant starch contents (100%). The total starch content of all studied blends increased (2-19%) after extrusion. The processing increased the in vitro protein digestibility, reaching values around 88-95% after extrusion. Total dietary fiber was reduced around 30%, and the insoluble fraction was affected to a larger extent than the soluble fraction by the extrusion process. Because of its balanced nutritional composition, high dietary fiber content, as well as low energy density, these novel gluten-free snack-like foods could be considered as functional foods and a healthier alternative to commercially available gluten containing or gluten-free and low nutritional value snacks. PMID- 28914315 TI - Tyr25, Tyr58 and Trp133 of Escherichia coli bacterioferritin transfer electrons between iron in the central cavity and the ferroxidase centre. AB - Ferritins are 24meric proteins that overcome problems of toxicity, insolubility and poor bioavailability of iron in all types of cells by storing it in the form of a ferric mineral within their central cavities. In the bacterioferritin (BFR) from Escherichia coli iron mineralization kinetics have been shown to be dependent on an intra-subunit catalytic diiron cofactor site (the ferroxidase centre), three closely located aromatic residues and an inner surface iron site. One of the aromatic residues, Tyr25, is the site of formation of a transient radical, but the roles of the other two residues, Tyr58 and Trp133, are unknown. Here we show that these residues are important for the rates of formation and decay of the Tyr25 radical and decay of a secondary radical observed during Tyr25 radical decay. The data support a mechanism in which these aromatic residues function in electron transfer from the inner surface site to the ferroxidase centre. PMID- 28914316 TI - Negative Gaussian curvature induces significant suppression of thermal conduction in carbon crystals. AB - From the mathematic category of surface Gaussian curvature, carbon allotropes can be classified into three types: zero curvature, positive curvature, and negative curvature. By performing Green-Kubo equilibrium molecular dynamics simulations, we found that surface curvature has a significant impact on the phonon vibration and thermal conductivity (kappa) of carbon crystals. When curving from zero curvature to negative or positive curvature structures, kappa is reduced by several orders of magnitude. Interestingly, we found that kappa of negatively curved carbon crystals exhibits a monotonic dependence on curvature. Through phonon mode analysis, we show that curvature induces remarkable phonon softening in phonon dispersion, which results in the reduction of phonon group velocity and flattening of phonon band structure. Furthermore, the curvature was found to induce phonon mode hybridization, leading to the suppression of phonon relaxation time. Our study provides physical insight into thermal transport in curvature materials, and will be valuable in the modulation of phonon activity through surface curvature. PMID- 28914317 TI - A bifunctional nanomodulator for boosting CpG-mediated cancer immunotherapy. AB - Unmethylated cytosine-phosphate-guanine (CpG) oligonucleotides (ODNs) possess high immunostimulatory activity and represent attractive tools for cancer treatment. However, their success in eliminating large solid tumors was hampered by the immunosuppressive tumor microenvironment. Herein, we report that the design of a novel MnO2-CpG-silver nanoclusters (AgNCs)-doxorubicin (DOX) conjugate for enhanced cancer immunotherapy, in which MnO2 nanosheets function as unique supports to integrate the chemotherapy drug DOX and the immunotherapeutic agent CpG-AgNCs. Importantly, DOX could be conjugated with MnO2 nanosheets through pi-pi interactions to serve as a bifunctional modulator of the tumor microenvironment to activate a tumor-specific immune response by inducing immunogenic cell death, and reverse the immunosuppressive tumor microenvironment via abrogating the immune-suppressive activity of regulatory T cells, both of which would greatly improve the immune response of CpG-AgNCs. In this way, the T cell immune responses of CpG-AgNCs which are linked to MnO2 nanosheets were significantly enhanced and could exhibit remarkable antitumor activity against large solid tumors. Our study may guide the rational design of immunotherapeutic boosters for improving cancer treatment. PMID- 28914318 TI - Analytical, numerical, and experimental studies of viscoelastic effects on the performance of soft piezoelectric nanocomposites. AB - Piezoelectric composite (p-NC) made of a polymeric matrix and piezoelectric nanoparticles with conductive additives is an attractive material for many applications. As the matrix of p-NC is made of viscoelastic materials, both elastic and viscous characteristics of the matrix are expected to contribute to the piezoelectric response of p-NC. However, there is limited understanding of how viscoelasticity influences the piezoelectric performance of p-NC. Here we combined analytical and numerical analyses with experimental studies to investigate effects of viscoelasticity on piezoelectric performance of p-NC. The viscoelastic properties of synthesized p-NCs were controlled by changing the ratio between monomer and cross-linker of the polymer matrix. We found good agreement between our analytical models and experimental results for both quasi static and dynamic loadings. It is found that, under quasi-static loading conditions, the piezoelectric coefficients (d33) of the specimen with the lowest Young's modulus (~0.45 MPa at 5% strain) were ~120 pC N-1, while the one with the highest Young's modulus (~1.3 MPa at 5% strain) were ~62 pC N-1. The results suggest that softer matrices enhance the energy harvesting performance because they can result in larger deformation for a given load. Moreover, from our theoretical analysis and experiments under dynamic loading conditions, we found the viscous modulus of a matrix is also important for piezoelectric performance. For instance, at 40 Hz and 50 Hz the storage moduli of the softest specimen were ~0.625 MPa and ~0.485 MPa, while the loss moduli were ~0.108 MPa and ~0.151 MPa, respectively. As piezocomposites with less viscous loss can transfer mechanical energy to piezoelectric particles more efficiently, the dynamic piezoelectric coefficient (d'33) measured at 40 Hz (~53 pC N-1) was larger than that at 50 Hz (~47 pC N-1) though it has a larger storage modulus. As an application of our findings, we fabricated 3D piezo-shells with different viscoelastic properties and compared the charging time. The results showed a good agreement with the predicted trend that the composition with the smallest elastic and viscous moduli showed the fastest charging rate. Our findings can open new opportunities for optimizing the performance of polymer-based multifunctional materials by harnessing viscoelasticity. PMID- 28914319 TI - Femtosecond laser induced robust periodic nanoripple structured mesh for highly efficient oil-water separation. AB - Marine oil spills have induced severe water pollution and threatened sea ecosystems, which also result in a loss of energy resources. To deal with this problem, much work has been done for using superhydrophobic or superhydrophilic mesh for oil-water separation. Nevertheless, there are still great challenges in the rapid fabrication of extremely durable mesh with superwetting properties, particularly considering the highly efficient oil-water separation. In this study, we present a simple, efficient method to fabricate superhydrophilic and underwater superoleophobic stainless steel mesh surfaces with one-step femtosecond laser induced periodic nanoripple structures. The as-prepared mesh shows high separation efficiency, which is higher than 99% for various oil-water mixtures. More importantly, the wettability and the separation efficiency of the fabricated mesh show no obvious change after the abrasion tests and corrosion tests, indicating that the as-prepared samples possess robust stability. This study provides an efficient route for constructing durable and highly efficient separation mesh, which can be applied in the cleanup of large-scale oil spills in the near future. PMID- 28914320 TI - Fabrication of metalosomes (metal containing cationic liposomes) using single chain surfactants as a precursor via formation of inorganic organic hybrids. AB - Among the self-assembled forms of surfactants, vesicles/liposomes are a highly promising and interesting feature of surfactants, which are usually formed from water insoluble surfactants. Herein, we demonstrate the formation of liposomes from single-chain cationic surfactants with the help of metals as a part of the counter ion, and these metal embedded liposomes are termed as metalosomes. It is a noteworthy advancement in the area of self-assembled molecular structures since we report the preparation of metal embedded liposomes (metalosomes) from a water soluble single chain cationic surfactant, which is otherwise a property or an arrangement made by double tailed surfactants, or more precisely lipids that are poorly water soluble. We can use this method for various cationic surfactants and metal combinations and the studies are still in process. However, this preliminary report on manganese-based surfactants depicts the successful formation of cationic metalosomes (with/without cholesterol), and the formation, structure and size has been verified using TEM, FE-SEM, DLS XRD and SAXS. The comparison of metalosomes with reverse vesicles in different solvents further gave an insight of microstructure and solvent environment effects on the self assembly of metallosurfactants. In addition, we have also evaluated the encapsulation ability of metalosomes for fluorescein dye. High encapsulation efficiency of Mn-somes makes them promising candidates for several applications, particularly because of its water solubility. PMID- 28914321 TI - Photoredox catalysis enabled alkylation of alkenyl carboxylic acids with N (acyloxy)phthalimide via dual decarboxylation. AB - A ruthenium based photoredox catalyst in combination with a substoichiometric amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) efficiently catalyzed dual decarboxylative couplings between alkenyl carboxylic acids and N (acyloxy)phthalimides derived from aliphatic carboxylic acids, delivering alkylated styrene derivatives in a high regio- and stereo-selective manner under mild reaction conditions. Various types of secondary, tertiary, and quaternary aliphatic carboxylic acids as well as alpha-amino acids can be used as suitable substrates. Mechanistic analysis suggested that the reaction proceeds through a radical mechanism mediated by a Ru(i)/Ru(ii) catalytic cycle with DABCO acting both as the base and the co-catalyst for single electron transfer. PMID- 28914322 TI - Harnessing sunlight without a photosensitizer for highly efficient consecutive [3+2]/[4+2] annulation to synthesize fused benzobicyclic skeletons. AB - A photosensitizer-free, highly efficient sunlight-promoted tandem [3+2]/[4+2] annulation of unsaturated alpha-bromocarbonyls with o-alkynylanilines was developed, and allowed for convenient synthesis of fused benzobicyclic skeletons. The reaction was clean and practical in mild conditions and showed excellent functional group compatibility. PMID- 28914323 TI - The spectroscopic impact of interactions with the four Gouterman orbitals from peripheral decoration of porphyrins with simple electron withdrawing and donating groups. AB - Tetrapyrroles are of great interest for solar cell and photodynamic therapy applications due to their structural analogy with chlorophyll, a natural photosensitizer. Unsubstituted symmetric porphyrins exhibit weak absorption in the red region which makes them unsuitable for these applications. The push-pull peripheral decoration modifies the energies of the frontier molecular orbitals, which in turn influences the tetrapyrrole's spectroscopic properties. The absorption, magnetic circular dichroism, and emission spectra were measured for four zinc tetratolylporphyrin compounds substituted peripherally with a fused dimethoxybenzo group as an electron withdrawing group (EWG) on one pyrrole and on the opposite pyrrole, a single acetamido (1), a nitro (2), a proton (3), or a benzoylamino (4) substituent. Unusually, the magnetic circular dichroism spectrum of 2 exhibited a negative A term for the lowest energy absorption band (the Q band) and its emission spectrum was also unlike those of 1, 3, and 4. A complete computational analysis was carried out to obtain the energies and electron distribution, shown by electron density surfaces, of the four Gouterman MOs. TD DFT calculations showed that for 2, DeltaLUMO was greater than DeltaHOMO, which accounted for the observed negative A term. The trend in the estimated MCD A term magnitudes, normalized to the absorbance as [A/(dipole strength) BM], provides experimental confirmation of the computationally determined ratio of DeltaLUMO/DeltaHOMO data. The value of DeltaHOMO was confirmed by the trend in oscillator strengths. A series of fictive porphyrins (F1-F5) incorporating simple push-pull substituents were designed and their electronic structures were investigated using TD-DFT calculations. The substituents in the five fictive molecules illustrate the differential effect of the donor and acceptor groups in the beta-position of the pyrroles on the relative stabilities of the four Gouterman orbitals. NO2 groups result in the greatest splitting of the LUMO pair. We show that on using strong EWGs, opposite electron donating groups result in a DeltaLUMO > 0, which red-shifts the Q band and introduces a strong dipole. With the nitro and formyl EWGs, DeltaLUMO becomes greater than DeltaHOMO, resulting in a complex electronic structure of the Q band, recognizable by a negative A term suggesting a design objective for future photosensitizers. PMID- 28914324 TI - Multiple particle tracking study of thermally-gelling nanoemulsions. AB - We perform multiple particle tracking (MPT) on a thermally-gelling oil-in-water nanoemulsion system. Carboxylated and plain polystyrene probes are used to investigate the role of colloidal probe size and surface chemistry on MPT in the nanoemulsion system. As temperature increases, hydrophobic groups of PEG-based gelators (PEGDA) partition into the oil/water interface and bridge droplets. This intercolloidal attraction generates a wide variety of microstructures consisting of droplet-rich and droplet-poor phases. By tailoring the MPT colloidal probe surface chemistry, we can control the residence of probes in each domain, thus allowing us to independently probe each phase. Our results show stark differences in probe dynamics in each domain. For certain conditions, the mean squared displacement (MSD) can differ by over four orders of magnitude for the same probe size but different surface chemistry. Carboxylated probe surface chemistries result in "slippery" probes while plain polystyrene probes appear to tether to the nanoemulsion gel network. We also observe probe hopping between pores in the gel for carboxylated probes. Our approach demonstrates that probes with different surface chemistries are useful in probing the local regions of a colloidal gel and allows the measurement of local properties within structurally heterogeneous hydrogels. PMID- 28914325 TI - Night work, long work weeks, and risk of accidental injuries. A register-based study. AB - Objectives The aims of this study were to (i) investigate the association between night work or long work weeks and the risk of accidental injuries and (ii) test if the association is affected by age, sex or socioeconomic status. Methods The study population was drawn from the Danish version of the European Labour Force Survey from 1999-2013. The current study was based on 150 438 participants (53% men and 47% women). Data on accidental injuries were obtained at individual level from national health registers. We included all 20-59-year-old employees working >=32 hours a week at the time of the interview. We used Poisson regression to estimate the relative rates (RR) of accidental injuries as a function of night work or long work weeks (>40 hours per week) adjusted for year of interview, sex, age, socioeconomic status (SES), industry, and weekly working hours or night work. Age, sex and SES were included as two-way interactions. Results We observed 23 495 cases of accidental injuries based on 273 700 person years at risk. Exposure to night work was statistically significantly associated with accidental injuries (RR 1.11, 99% CI 1.06-1.17) compared to participants with no recent night work. No associations were found between long work weeks (>40 hours) and accidental injuries. Conclusion We found a modest increased risk of accidental injuries when reporting night work. No associations between long work weeks and risk of accidental injuries were observed. Age, sex and SES showed no trends when included as two-way interactions. PMID- 28914326 TI - Negative attitudes related to violence against women: gender and ethnic differences among youth living in Serbia. AB - OBJECTIVES: This study aimed to identify to what extent negative attitudes towards intimate partner violence against women are present among young women and men living in Serbia, in Roma and non-Roma settlements. METHODS: We used the data from the 2010 Multiple Indicator Cluster Survey conducted in Serbia, for the respondents who were 15-24 years old. Regression analyses were used to examine the association between judgmental attitudes, socio-demographic factors and life satisfaction. RESULTS: In Roma settlements, 34.8% of men and 23.6% of women believed that under certain circumstances men are justified to be violent towards wives, while among non-Roma it was 5.6 and 4.0%, respectively. These negative attitudes were significantly associated with lower educational level, lower socio economic status and being married. In multivariate model, in both Roma and non Roma population women who were not married were less judgmental, while the richest Roma men were least judgmental (OR 0.40, 95% CI 0.18-0.87). CONCLUSIONS: Violence prevention activities have to be focused on promoting gender equality among youth in vulnerable population groups such as Roma, especially through social support, strengthening their education and employment. PMID- 28914328 TI - Erratum to: Improving isopropanol tolerance and production of Clostridium beijerinckii DSM 6423 by random mutagenesis and genome shuffling. PMID- 28914327 TI - Repeated 2% sevoflurane administration in 7- and 60-day-old rats : Neurotoxicity and neurocognitive dysfunction. AB - BACKGROUND: Sevoflurane is one of the most widely used inhalation anesthetics in pediatric anesthesia. A large number of studies have demonstrated that repeated treatment with high concentrations or long durations of sevoflurane anesthesia during the neonatal period can induce neuroapoptosis and long-term learning disability. In clinical practice, we observed that a subset of patients underwent minor surgery under sevoflurane anesthesia more than once from birth to adolescence. Therefore, this research was conducted to investigate whether a 2% concentration of sevoflurane (clinically relevant usage of sevoflurane) for 1 h (a short duration) can induce neuroapoptosis and neurocognitive dysfunction in adolescent rats that received sevoflurane (2% for 1 h) during the neonatal period. MATERIAL AND METHODS: Group I: neonatal rats at postnatal day 7 (PND-7) were treated with oxygen under controlled conditions and then raised to PND-60. Group II: PND-7 rats were treated with 2% sevoflurane for 1 h and then raised to PND-60. Group III: the PND-60 rats were treated with 2% sevoflurane for 1 h and in group IV the PND-7 rats were treated with 2% sevoflurane for 1 h and then anesthetized with 2% sevoflurane for 1 h at PND-60 again. The expression of caspase-3, Bax and Bcl-2 in the hippocampal dentate gyrus (DG) were measured by Western blot analysis. Neuroapoptosis in the hippocampal DG was assessed using NeuN/caspase-3 double-immunofluorescence staining. Spatial reference memory was tested by the Morris water maze test. RESULTS: The present data showed that sevoflurane (2% for 1 h) did not induce obvious hippocampal neuroapoptosis in the PND-7 rats and PND-60 rats; their performance in hippocampal-dependent spatial memory was not significantly impaired; however, the rats in group IV showed poor performance in the Morris water maze test and the neuroapoptosis in group IV was significantly increased. CONCLUSION: Our findings suggested that sevoflurane can induce neuroapoptosis and cognitive dysfunction in adolescent rats that received repeated sevoflurane (2% for 1 h) during the postnatal period. These findings will promote further studies to investigate the effects of repeated sevoflurane exposure on the development of the central nervous system and function of learning and memory, as well as the underlying mechanisms in vitro and in vivo. PMID- 28914329 TI - ? PMID- 28914330 TI - ? PMID- 28914331 TI - [The IDEALE-handover]. PMID- 28914332 TI - [Comment on: ketamine for prevention of postoperative delirium and pain]. PMID- 28914333 TI - [Acute skin infections and their imitators in children : A photo quiz]. AB - BACKGROUND: Skin infections account for 40% of emergency visits in pediatric dermatology. It is important to promptly recognize skin infections with potential complications and initiate treatment. However some characteristic skin findings may imitate skin infections and are often misdiagnosed. OBJECTIVES: To illustrate frequent pediatric skin infections and pitfalls in view of imitators and differential diagnoses. MATERIALS AND METHODS: A photo quiz is presented with the discussion of a selection of acute pediatric skin infections in comparison to their infectious or noninfectious differential diagnoses. RESULTS: The following infectious skin conditions and imitators are described and clinical clues for differentiation highlighted: eczema herpeticum and bacterial superinfection of atopic dermatitis; exanthematous hand, foot and mouth disease and varicella infection; erythema chronicum multilocularis and anular urticaria; Gianotti Crosti syndrome and Gianotti-Crosti-like reaction; bacterial folliculitis of the scalp and kerion celsi and eosinophilic pustular folliculitis of the scalp; cutaneous Leishmaniasis and idiopathic facial aseptic granuloma; allergic and bacterial lymphangitis; bullous impetigo contagiosa and nonaccidental scalding. CONCLUSIONS: Careful anamnesis and skin examination with attention to the here illustrated differential diagnoses are essential to avoid pitfalls in the evaluation of acute pediatric skin infections. PMID- 28914335 TI - Regulatory experience of TOPS: an internet-based system to prevent healthy subjects from over-volunteering for UK clinical trials. AB - PURPOSE: The aim was to review the use of The Over-volunteering Prevention System (TOPS) since the HRA began hosting it in 2013, and the Medicines and Healthcare products Regulatory Agency (MHRA) experience of monitoring its use by UK clinical research units. METHODS: The HRA searched the TOPS database for the number, type and location of units and the number of entries. The MHRA inspectors reviewed their findings from routine inspections. RESULTS: Twenty-two additional UK units registered to use TOPS during 2013-2016, making a total of 84 units since TOPS was established in 2002. Use of TOPS is now a condition of research ethics committee approval of a phase 1 study and fulfils MHRA accreditation requirements for preventing over-volunteering. The total number of entries by all active units during 2013-2016 was 89,335, of which 84% were UK citizens and 16% non-UK citizens. The total number of entries during 2002-2016 was 249,612. Only 15 of 24,531 subjects (1/1600) and 18 of 18,745 subjects (1/1040) entered in 2015 and 2016, respectively, were deemed potential over-volunteers. CONCLUSIONS: The findings continue to support the concept that TOPS not only helps to prevent over volunteering, but also deters subjects from trying to do so. Regulation of TOPS by the HRA and MHRA has enhanced its effectiveness, benefited all users and helped to improve the safety of volunteers who participate in non-therapeutic trials in the UK. The UK is still the only country with a national database to prevent over-volunteering that has published data on its widespread use and effectiveness. PMID- 28914334 TI - The clinical and radiological results of individualized surgical treatment depending on pathologic abnormalities in recurrent patellar dislocation: low recurrence rate, but unintended patella baja. AB - PURPOSE: To evaluate the clinical and radiological outcomes and chondral lesion change using individualized surgery for recurrent patellar dislocation. METHODS: A total of 31 knees with recurrent patellar dislocation underwent surgery depending on individual pathologic abnormalities. Pathologic abnormalities including medial laxity, lateral tightness, increased tibial tuberosity (TT)-to trochlear groove distance (>20 mm), and patella alta (Caton-Deschamps ratio >1.2) were evaluated in each patient. The abnormalities were corrected through medial patellofemoral ligament reconstruction, TT distalization, TT anteromedialization, and lateral retinacula release. The mean follow-up period was 33 months. RESULTS: There was one recurrent case (3.2%), requiring additional surgery. The mean Kujala scores were significantly (P = 0.002) improved from 75.8 (SD 12.4) to 84.6 (SD 13.1). Tegner scores were significantly improved from 3.7 (range 1-9) to 5.4 (range 2-9) (P < 0.001), as were and visual analogue scale pain scores from 4.7 (SD 2.5) to 2.6 (SD 2.2) (P = 0.001). Caton-Deschamps ratio was significantly decreased from 1.1 (SD 0.2) to 0.9 (SD 0.1) (P < 0.001), regardless of TT distalization. Chondral lesions of the patella and trochlear groove were improved or maintained in 57.1 and 71.4% of patients, respectively. CONCLUSION: Individualized surgery in recurrent patellar dislocation was effective and safe with a low recurrence rate. However, the possibility of unintended patella baja, which might be related to post-operative anterior knee pain, should be considered. LEVEL OF EVIDENCE: IV. PMID- 28914337 TI - Obesity: how much does it matter for female pelvic organ prolapse? AB - INTRODUCTION AND HYPOTHESIS: The objective was to determine the association between body mass index (BMI) and symptoms and signs of female pelvic organ prolapse (POP). METHODS: An observational cross-sectional study of 964 archived datasets of women seen for symptoms and signs of lower urinary tract and pelvic organ dysfunction between September 2011 and February 2014 at a tertiary urogynaecology centre in Australia was carried out. An in-house standardised interview, the International Continence Society Pelvic Organ Prolapse Quantification (ICS POP-Q) and 4-D translabial ultrasound, followed by analysis of ultrasound volumes for pelvic organ descent and hiatal area on Valsalva, were performed, blinded against other data. RESULTS: There is a positive association between BMI and posterior compartment prolapse on clinical examination and ultrasound imaging, but not for the anterior and central compartments. There was no association with prolapse symptom bother and a negative association with symptoms of prolapse. CONCLUSIONS: In this observational study, we found a strong association between all tested measures of posterior compartment descent and BMI, both clinical and on imaging. PMID- 28914336 TI - Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy. AB - AIMS/HYPOTHESIS: The determinants and mechanisms of the development of diabetic sensorimotor polyneuropathy as a painful (DSPN+p) or painless (DSPN-p) entity remain unclear. We examined the degree of cutaneous nerve fibre loss and regeneration in individuals with type 2 diabetes with DSPN+p or DSPN-p compared with individuals with recent-onset type 2 diabetes and corresponding healthy volunteers. METHODS: In this cross-sectional study, skin biopsies taken from the distal lateral calf were obtained from individuals with recent-onset type 2 diabetes (n = 32) from the German Diabetes Study, with DSPN+p (n = 34) and DSPN-p (n = 32) from the PROPANE study, and volunteers with normal glucose tolerance (n = 50). Double immunofluorescence staining for protein gene product 9.5 (PGP9.5) (pan-neuronal marker) and growth-associated protein 43 (GAP-43) (nerve regeneration marker) was applied to assess intraepidermal nerve fibre density (IENFD) and length (IENFL) and dermal nerve fibre length (DNFL). DSPN was diagnosed using the modified Toronto Consensus (2011) criteria, while neuropathic pain was assessed using an 11-point Numerical Rating Scale. RESULTS: After adjustment for age, sex, BMI and HbA1c, IENFD and IENFL were reduced for both markers in individuals with recent-onset diabetes and both DSPN groups compared with control participants (all p < 0.05), but did not differ between the DSPN groups. The DNFL GAP-43/PGP9.5 ratio was higher in the DSPN+p and DSPN-p groups compared with control participants (1.18 +/- 0.28 and 1.07 +/- 0.10 vs 1.02 +/- 0.10; p <= 0.05) and in the DSPN + p group compared with DSPN-p (p < 0.05). Correlation analyses showed distinct inverse associations between the DNFL GAP 43/PGP9.5 ratio and PGP9.5 positive IENFD as well as DNFL (IENFD: beta = -0.569, DNFL: beta = -0.639; both p < 0.0001) in individuals with type 2 diabetes, but not in the control group. A similar pattern was found for correlations between the DNFL GAP-43/PGP9.5 ratio and peripheral nerve function tests. CONCLUSIONS/INTERPRETATION: Dermal nerve fibre regeneration is enhanced in DSPN, particularly in DSPN+p, and increases with advancing intraepidermal nerve fibre loss. These data suggest that, despite progressive epidermal fibre loss, dermal nerve repair is preserved, particularly in DSPN+p, but fails to adequately counteract epidermal neurodegenerative processes. PMID- 28914338 TI - The UK National Prolapse Survey: 10 years on. AB - INTRODUCTION AND HYPOTHESIS: To assess trends in the surgical management of pelvic organ prolapse (POP) amongst UK practitioners and changes in practice since a previous similar survey. METHODS: An online questionnaire survey (Typeform Pro) was emailed to British Society of Urogynaecology (BSUG) members. They included urogynaecologists working in tertiary centres, gynaecologists with a designated special interest in urogynaecology and general gynaecologists. The questionnaire included case scenarios encompassing contentious issues in the surgical management of POP and was a revised version of the questionnaire used in the previous surveys. The revised questionnaire included additional questions relating to the use of vaginal mesh and laparoscopic urogynaecology procedures. RESULTS: Of 516 BSUG members emailed, 212 provided completed responses.. For anterior vaginal wall prolapse the procedure of choice was anterior colporrhaphy (92% of respondents). For uterovaginal prolapse the procedure of choice was still vaginal hysterectomy and repair (75%). For posterior vaginal wall prolapse the procedure of choice was posterior colporrhaphy with midline fascial plication (97%). For vault prolapse the procedure of choice was sacrocolpopexy (54%) followed by vaginal wall repair and sacrospinous fixation (41%). The laparoscopic route was preferred for sacrocolpopexy (62% versus 38% for the open procedure). For primary prolapse, vaginal mesh was used by only 1% of respondents in the anterior compartment and by 3% in the posterior compartment. CONCLUSION: Basic trends in the use of native tissue prolapse surgery remain unchanged. There has been a significant decrease in the use of vaginal mesh for both primary and recurrent prolapse, with increasing use of laparoscopic procedures for prolapse. PMID- 28914339 TI - Do we need randomized clinical trials in extracorporeal respiratory support? Yes. AB - Extracorporeal respiratory support, also known as extracorporeal gas exchange, may be used to rescue the most severe forms of acute hypoxemic respiratory failure with high blood flow venovenous extracorporeal membrane oxygenation. Alternatively, lower flow extracorporeal carbon dioxide removal might be applied to reduce the intensity of mechanical ventilation in patients with less severe forms of the disease. However, critical reading of the results of the randomized trials and case series published to date reveals major methodological biases. Older trials are not relevant anymore since the ECMO circuitry was not heparin coated leading to severe hemorrhagic complications due to high levels of anticoagulation, and because extracorporeal membrane oxygenation (ECMO) and control group patients did not receive lung-protective ventilation. Alternatively, in the more recent CESAR trial, many patients randomized to the ECMO arm did not receive ECMO and no standardized protocol for lung-protective mechanical ventilation existed in the control group. Since these techniques are costly and associated with potentially serious adverse events, there is an urgent need for high-quality data, for which the cornerstone remains randomized controlled trials. PMID- 28914340 TI - Interpreting signal-intensity ratios without visible T1 hyperintensities in clinical gadolinium retention studies. PMID- 28914341 TI - Knee joint preservation: a call for daily practice revival of realignment surgery and osteotomies around the knee. PMID- 28914342 TI - Quantification of the Intracellular Life Time of Water Molecules to Measure Transport Rates of Human Aquaglyceroporins. AB - Orthodox aquaporins are transmembrane channel proteins that facilitate rapid diffusion of water, while aquaglyceroporins facilitate the diffusion of small uncharged molecules such as glycerol and arsenic trioxide. Aquaglyceroporins play important roles in human physiology, in particular for glycerol metabolism and arsenic detoxification. We have developed a unique system applying the strain of the yeast Pichia pastoris, where the endogenous aquaporins/aquaglyceroporins have been removed and human aquaglyceroporins AQP3, AQP7, and AQP9 are recombinantly expressed enabling comparative permeability measurements between the expressed proteins. Using a newly established Nuclear Magnetic Resonance approach based on measurement of the intracellular life time of water, we propose that human aquaglyceroporins are poor facilitators of water and that the water transport efficiency is similar to that of passive diffusion across native cell membranes. This is distinctly different from glycerol and arsenic trioxide, where high glycerol transport efficiency was recorded. PMID- 28914343 TI - Image-guided percutaneous removal of ballistic foreign bodies secondary to air gun injuries. AB - BACKGROUND: Ballistic injuries with retained foreign bodies from air guns is a relatively common problem, particularly in children and adolescents. If not removed in a timely fashion, the foreign bodies can result in complications, including pain and infection. Diagnostic methods to identify the presence of the foreign body run the entire gamut of radiology, particularly radiography, ultrasound (US) and computed tomography (CT). Removal of the foreign bodies can be performed by primary care, emergency, surgical, and radiologic clinicians, with or without imaging guidance. OBJECTIVE: To evaluate the modalities of radiologic detection and the experience of image-guided ballistic foreign body removal related to air gun injuries within the interventional radiology department of a large pediatric hospital. MATERIALS AND METHODS: A database of more than 1,000 foreign bodies that were removed with imaging guidance by the interventional radiologists at our institution was searched for ballistic foreign bodies from air guns. The location, dimensions, diagnostic modality, duration, complications and imaging modality used for removal were recorded. In addition, the use of sedation and anesthesia required for the procedures was also recorded. RESULTS: Sixty-one patients with ballistic foreign bodies were identified. All foreign bodies were metallic BBs or pellets. The age of the patients ranged from 5 to 20 years. The initial diagnostic modality to detect the foreign bodies was primarily radiography. The primary modality to assist in removal was US, closely followed by fluoroscopy. For the procedure, 32.7% of the patients required some level of sedation. Only two patients had an active infection at the time of the removal. The foreign bodies were primarily in the soft tissues; however, successful removal was also performed from intraosseous, intraglandular and intratendinous locations. All cases resulted in successful removal without complications. CONCLUSION: Image-guided removal of ballistic foreign bodies secondary to air guns is a very effective procedure that can obviate the need for open surgical procedures in children. PMID- 28914344 TI - Influence of genetic co-factors on the population pharmacokinetic model for clopidogrel and its active thiol metabolite. AB - PURPOSE: A high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4). METHODS: The study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7.3 software, and first-order conditional estimation method with interaction was applied. Also, the influence of covariates was evaluated (age, weight, body mass index (BMI), obesity defined as BMI >= 30 kg/m2, sex, diabetes mellitus, co-administration of PPI or statins, presence of CYP2C19*2, CYP2C19*17, CYP3A4*1G alleles, and ABCB1 3435 TT genotype). RESULTS: It was found that the only significant covariate was the presence of CYP2C19*2 allele, which had an impact on lower conversion of clopidogrel to H4. As a result, predicted area under the time-concentration curve values was lower in carriers of this allele, with median 5.94 ng h/ml (interquartile range 3.92-12.51 [ng?h/ml]) vs. 12.70 ng h/ml in non-carriers (interquartile range, 7.00-19.39 [ng?h/ml]), respectively (p = 0.004). CONCLUSIONS: Developed model predicts that the only significant covariate influencing the observed concentrations and therefore the exposure to the active H4 metabolite is the presence of CYP2C19*2 allele. PMID- 28914346 TI - Is the obesity a risk factor for delayed colonic post-polypectomy bleeding? PMID- 28914347 TI - Intermetatarsal bursa primary synovial chondromatosis: case report and review of the literature. AB - Primary synovial chondromatosis is a benign neoplastic process, occurring mostly in large joints, more rarely in tendon sheaths, and extremely uncommonly in bursae. We describe a patient with primary synovial chondromatosis arising in the fourth intermetatarsal bursa. Knowledge of the bursal anatomy of the forefoot, and of characteristic imaging findings and the pathogenesis of synovial chondromatosis, is essential in including this uncommon entity in the differential when occurring in unusual locations. PMID- 28914345 TI - Comparison of clinical outcomes between open and thoracoscopic repair for esophageal atresia with tracheoesophageal fistula: a systematic review and meta analysis. AB - OBJECTIVE: A meta-analysis was performed for a comparison of outcomes between open repair (OR) and thoracoscopic repair (TR) for esophageal atresia with tracheoesophageal fistula (EA with TEF). METHODS: Electronic databases, including PubMed, Cochrane Library, and Medline, were searched systematically for the literatures aimed mainly at comparing the therapeutic effects for EA with TEF administrated by OR and TR. Corresponding data sets were extracted and two reviewers independently assessed the methodological quality. Meta-analysis was performed with Stata 12.0. RESULTS: Ten studies meeting the inclusion criteria were included, involving 447 subjects in total. It was observed that OR entailed a shorter operative time with significant statistical differences (SMD 0.604; 95% CI 0.344-0.864, P = 0). While TR was superior in two aspects: shorter length of hospital stay (SMD 0.584; 95% CI 0.214-0.953; P = 0.002) and shorter first oral feeding time (SMD 0.652; 95% CI 0.27-1.035; P = 0.001). However, meta-analyses of occurrence rate of leaks (OR, 1.747; 95% CI 0.817-3.737; P = 0.15), strictures (OR, 0.937; 95% CI 0.5-1.757; P = 0.839), pulmonary complications (OR, 1.08; 95% CI 0.21-5.44; P = 0.897), fundoplication rate of Gastroesophageal Reflux Disease (GERD) (OR, 1.642; 95% CI 0.855-3.153; P = 0.601), and blood loss (SMD 0.048; 95% CI -1.292 to 1.388; P = 0.944) showed no significant differences between OR and TR. Meta-analysis of ventilation time showed similar outcome between OR and TR (SMD 0.474; 95% CI 0.02-0.968; P = 0.06), but the result remained controversial due to estimated result changing after sensitivity analysis (SMD 0.61; 95% CI 0.16-1.07; P = 0). CONCLUSIONS: Compared with OR, a longer operative time was associated within TR group, although the TR procedure could possibly reduce the length of hospital stay and first oral feeding time. Meanwhile, the occurrence rate for leaks, strictures, pulmonary complications, and the fundoplication rate of GERD, and blood loss were similar between the OR and TR groups. Estimated result of ventilation time between the two groups remained ambiguous. PMID- 28914348 TI - Immunogenicity and antimicrobial effectiveness of Pseudomonas aeruginosa specific bacteriophage in a human lung in vitro model. AB - The rise of antibiotic resistant bacteria is posing a serious threat to human health. For example, resistant strains of Pseudomonas aeruginosa have resulted in untreatable and potentially lethal infections in both cystic fibrosis and immunocompromised patients. Due to the growing need for alternative treatment options, bacteriophage, or phage, therapy is gaining considerable attention. While previous studies have demonstrated the effectiveness of phage in combating persistent bacterial infections, there is currently a lack of knowledge regarding the host immunological response following phage exposure. In the present study, the bioresponses of an enhanced in vitro model were characterized following exposure to either DMS3 or PEV2, P. aeruginosa targeting phages. Results demonstrated a PEV2-dependent increase in IL-6 and TNF-alpha production, but no changes associated with DMS3 exposure. Additionally, following the establishment of an in vitro infection model, DMS3 was found to successfully protect mammalian lung cells from P. aeruginosa. Taken together, the biocompatibility and antibacterial effectiveness distinguish DMS3 bacteriophage as a strong candidate for phage therapy. However, as DMS3 is pilin dependent and bacterial receptor expression varies significantly, this work highlights the necessity of generating phage cocktails. PMID- 28914349 TI - Reverse total shoulder arthroplasty for type I fracture sequelae after internal fixation of proximal humerus fractures. AB - INTRODUCTION: Complications after internal fixation of proximal humerus fracture are common and may require surgical revision. Reverse total shoulder arthroplasty (RTSA) is frequently performed in such cases. The aim of the present study was to evaluate the functional results and complications after RTSA for the treatment of type I fracture sequelae after internal fixation of proximal humerus fractures. MATERIALS AND METHODS: 26 patients (18 female, 8 male) underwent surgical revision of type I fracture sequelae of the proximal humerus after locking plate (n = 22) or intramedullary nail (n = 4) fixation. The mean age of the patients at the time of the revision was 75 years (range 65-89). After a mean follow-up of 36 months (range 18-58), clinical examination was performed and the age- and gender related Constant-Murley Score (CMS) and the Oxford Shoulder Score (OSS) were obtained from all patients and compared to the pre-revision values. RESULTS: The mean age- and gender-related CMS of the affected shoulder increased from 44% (range 17-65) to 73% (range 44-97). This difference was statistically significant (p < 0.001). The CMS of the unaffected shoulder was 93% (range 72-98). This relates to a ratio in the CMS of 78% between the affected and the contralateral shoulder. The mean OSS was 28 points (range 12-54) for the operated shoulder and 43 points (range 34-48) for the unaffected side, resulting in 66% ratio. Again, the OSS improved significantly when compared with the preoperative values (p < 0.001). A total of five complications including two periprosthetic fractures were observed and required surgical revision. CONCLUSION: Satisfying results can be obtained with RTSA as a salvage procedure for type I fracture sequelae after previous internal fixation of proximal humerus fractures. PMID- 28914350 TI - A stochastic model for speciation by mating preferences. AB - Mechanisms leading to speciation are a major focus in evolutionary biology. In this paper, we present and study a stochastic model of population where individuals, with type a or A, are equivalent from ecological, demographical and spatial points of view, and differ only by their mating preference: two individuals with the same genotype have a higher probability to mate and produce a viable offspring. The population is subdivided in several patches and individuals may migrate between them. We show that mating preferences by themselves, even if they are very small, are enough to entail reproductive isolation between patches, and we provide the time needed for this isolation to occur as a function of the carrying capacity. Our results rely on a fine study of the stochastic process and of its deterministic limit in large population, which is given by a system of coupled nonlinear differential equations. Besides, we propose several generalisations of our model, and prove that our findings are robust for those generalisations. PMID- 28914351 TI - Subfascial fat herniation: sonographic features of back mice. AB - Three adult patients are described with sonographic features of subfascial fat hernation. Each patient presented to the musculoskeletal ultrasound department at our institution for the evaluation of a palpable mass of the low back. Subfascial fat hernation, also known as back mice and fibro-fatty nodule, are an uncommon cause of a palpable mass in the low back or low back pain. They are small mobile subcutaneous nodules in a characteristic location near the posterior superior iliac spine. This entity has not been described in the radiology literature. These cases are presented in order to demonstrate the sonographic findings of back mice and to describe key anatomic features. PMID- 28914352 TI - Impact of Physical Activity on Reporting of Childhood Asthma Symptoms. AB - This study aims to determine the impact of physical activity on asthma symptom reporting among children living in an inner city. Among 147 children aged 5-12 years with physician-diagnosed asthma, we assessed asthma symptoms using twice daily diaries and physical activity using the physical activity questionnaire for children during three 8-day periods (baseline, 3 and 6 months). Linear, logistic, and quasi-poisson regression models were used to determine the association between physical activity and asthma symptoms; adjusting for age, sex, race, BMI, caregiver's education, asthma severity, medication use, and season. A 1-unit increase in PAQ score was significantly associated with reporting more nocturnal symptoms [risk ratio (RR): 1.03; 95% CI 1.00-1.06], daytime symptoms (RR: 1.04; 95% CI 1.00-1.09), being bothered by asthma (RR: 1.05; 95% CI 1.00-1.09), and trouble breathing (RR: 1.05; 95% CI 1.00-1.10). Level of physical activity should be taken into account in clinical management of asthma and epidemiological studies of asthma symptom burden. PMID- 28914353 TI - Optic neuritis in patients with anti-MOG antibodies spectrum disorder: MRI and clinical features from a large multicentric cohort in France. PMID- 28914355 TI - Nasal injury and comfort with jet versus bubble continuous positive airway pressure delivery systems in preterm infants with respiratory distress. AB - : Nasal injuries with use of nasal continuous positive airway pressure (CPAP) range from blanching of nasal tip to septal necrosis and septal drop. This analysis was done in preterm neonates of < 34-week gestation, who received nasal CPAP as primary support as part of a randomized trial comparing Jet device with Bubble device for delivery of CPAP, both through nasal prongs of different structure, make and fixation methods. Nasal injury was assessed using a validated nasal injury score. Out of 170 neonates enrolled, 103 (61%) had nasal injuries; moderate and severe injuries were observed in 18 (11%) and 8 (5%) infants, respectively. Septum was the most common site injured. The incidence and severity of nasal injury were significantly lesser in Jet group compared to Bubble group [RR 0.6 (95% C.I. 0.5-0.8); p < 0.001]. Similarly, neonates in Jet group had lesser average [median (IQR): 3 (3,4) vs. 4 [8, 14]; p = 0.04] as well as peak N PASS pain scores [median (IQR): 4 [8, 14] vs. 5 [13, 16]; p = 0.01] in comparison to Bubble group. However, Jet group neonates had significantly more common prong displacements. CONCLUSION: Bubble CPAP device with its nasal interface had higher and more serious incidence of nasal injuries in comparison to Jet CPAP device. What is known: * Nasal injuries are becoming increasingly common with use of nasal CPAP low gestational age, low birth weight, longer use of CPAP and longer NICU stay are risk factors for such injuries * Validated nasal injury scores have been created for assessment of nasal trauma in neonates What is new: * Bubble device with its interface had higher and more serious incidence of nasal injuries in comparison to Jet device * Even though pain assessed by N-PASS was less with Jet device, prong displacements were more frequent with its system. PMID- 28914354 TI - Comorbidity of dementia with amyotrophic lateral sclerosis (ALS): insights from a large multicenter Italian cohort. AB - To assess the association, at diagnosis, between amyotrophic lateral sclerosis (ALS) and dementia in a large cohort of well-characterized Italian patients. We investigated the phenotypic profile of 1638 incident patients with definite, probable or laboratory-supported probable ALS, diagnosed from January 2009 to December 2013 in 13 Italian Referral Centers, located in 10 Italian Regions, and classified in two independent subsamples accounting for presence or not of dementia. The collected ALS features, including survival and other follow-up data, were compared between the two subgroups using a one-way analysis of variance and Chi-square test, as appropriate, logistic regression models and Kaplan-Meier survival analysis. Between-subgroup comparisons showed an older age at clinical observation (p = .006), at onset and at diagnosis (p = .002) in demented versus non demented ALS patients. After adjustment for these variables, diagnosis of dementia was significantly associated with higher odds of family history of ALS (p = .001) and frontotemporal dementia (p = .003) and of bulbar onset (p = .004), and lower odds of flail leg phenotype (p = .019) and spinal onset (p = .008). The median survival time was shorter in demented versus non demented patients, especially in case of classical, bulbar and flail limb phenotypes and both bulbar and spinal onset. Our multicenter study emphasized the importance of an early diagnosis of comorbid dementia in ALS patients, which may have clinical impact and prognostic relevance. Moreover, our results may give further inputs to validation of ALS-specific tools for the screening of cognitive impairment in clinical practice. PMID- 28914357 TI - Erratum to: Density-dependent effects of larval dispersal mediated by host plant quality on populations of an invasive insect. AB - There was a coding error in the original paper resulting in incorrect model parameter estimates and in some cases incorrect model conclusions. The error was the specification of logistic models (using the glm and glmer functions) in R as cbind (survived, total) instead of cbind (survived, dead). The differences between the originally published and correct models of those affected are detailed. PMID- 28914356 TI - In vivo treatment with nitazoxanide induces anaerobic metabolism in experimental intraperitoneal cysticercosis. AB - Taenia crassiceps cysticerci are used as experimental model to study the host parasite relationship and treatment of cysticercosis. One of the described mode of actions of nitazoxanide (NTZ) is to block the pyruvate ferredoxine oxidoreductase (PFOR) enzyme which is an essential enzyme to the parasite metabolism. The aim of this study was to determine the in vivo influence of one dosage of NTZ on the energetic metabolism of T. crassiceps cysticerci. Thirty days after the intraperitoneal inoculation of T. crassiceps cysticerci, BALB/c mice were orally treated with 7.5 mg/kg of NTZ. The control group was treated with physiologic solution (NaCl 0.9%). After 24 h, the animals were euthanized and the cysticerci were removed, washed, and processed for biochemical analysis. The organic acids detection occurred through high-performance liquid chromatographic and spectrophotometric analysis. While there was no difference in the glucose dosages, it was possible to observe a significant increase in the lactate concentrations and a decrease in the pyruvate concentrations of the NTZ treated groups when compared to the control group. Also, there was a decrease in the urea and alpha-ketoglutarate concentrations. This probably occurred due to the impairment of the parasite's PFOR and nitroreductases leading an impairment of the mitochondrial aerobic pathways. In conclusion, the in vivo NTZ treatment leads to an increase in the lactic fermentation and to a decrease in the protein catabolism in T. crassiceps cysticerci. PMID- 28914358 TI - Dynamic foraging of a top predator in a seasonal polar marine environment. AB - The seasonal movement of animals at broad spatial scales provides insight into life-history, ecology and conservation. By combining high-resolution satellite tagged data with hierarchical Bayesian movement models, we can associate spatial patterns of movement with marine animal behavior. We used a multi-state mixture model to describe humpback whale traveling and area-restricted search states as they forage along the West Antarctic Peninsula. We estimated the change in the geography, composition and characteristics of these behavioral states through time. We show that whales later in the austral fall spent more time in movements associated with foraging, traveled at lower speeds between foraging areas, and shifted their distribution northward and inshore. Seasonal changes in movement are likely due to a combination of sea ice advance and regional shifts in the primary prey source. Our study is a step towards dynamic movement models in the marine environment at broad scales. PMID- 28914359 TI - Changes in acid-base and ion balance during exercise in normoxia and normobaric hypoxia. AB - PURPOSE: Both exercise and hypoxia cause complex changes in acid-base homeostasis. The aim of the present study was to investigate whether during intense physical exercise in normoxia and hypoxia, the modified physicochemical approach offers a better understanding of the changes in acid-base homeostasis than the traditional Henderson-Hasselbalch approach. METHODS: In this prospective, randomized, crossover trial, 19 healthy males completed an exercise test until voluntary fatigue on a bicycle ergometer on two different study days, once during normoxia and once during normobaric hypoxia (12% oxygen, equivalent to an altitude of 4500 m). Arterial blood gases were sampled during and after the exercise test and analysed according to the modified physicochemical and Henderson-Hasselbalch approach, respectively. RESULTS: Peak power output decreased from 287 +/- 9 Watts in normoxia to 213 +/- 6 Watts in hypoxia (-26%, P < 0.001). Exercise decreased arterial pH to 7.21 +/- 0.01 and 7.27 +/- 0.02 (P < 0.001) during normoxia and hypoxia, respectively, and increased plasma lactate to 16.8 +/- 0.8 and 17.5 +/- 0.9 mmol/l (P < 0.001). While the Henderson-Hasselbalch approach identified lactate as main factor responsible for the non-respiratory acidosis, the modified physicochemical approach additionally identified strong ions (i.e. plasma electrolytes, organic acid ions) and non-volatile weak acids (i.e. albumin, phosphate ion species) as important contributors. CONCLUSIONS: The Henderson-Hasselbalch approach might serve as basis for screening acid-base disturbances, but the modified physicochemical approach offers more detailed insights into the complex changes in acid-base status during exercise in normoxia and hypoxia, respectively. PMID- 28914360 TI - Adaptive variation in vein placement underpins diversity in a major Neotropical plant radiation. AB - Vein placement has been hypothesised to control leaf hydraulic properties, but the ecophysiological significance of variation in vein placement in the angiosperms has remained poorly understood. The highly diverse Neotropical Bromeliaceae offers an excellent system for exploring understudied relationships between leaf vein placement, physiological functions, and species ecology. To test key hypotheses regarding the links between vein placement, functional type divergences, and ecological diversity in the Bromeliaceae, I characterised the ratio of interveinal distance (IVD) to vein-epidermis distance (VED) in 376 species, representing all major functional types and 10% of the species diversity in the family, as well as bioclimatic properties and key leaf traits for subsets of species. There were significant differences in vein placement parameters in species of contrasting functional type, habitat association, and bioclimatic distribution. In many C3 tank-epiphytes, a greater ratio between interveinal distance and the depth of veins within the mesophyll reflects optimisation for resource foraging in shady, humid habitats. In succulent terrestrials, overinvestment in veins probably facilitates rapid recharge of water storage tissue, as well as restricting water loss. These results highlight how divergences in vein placement relate to distinctive ecophysiological strategies between and within bromeliad functional types, and provide timely insights into how structural-functional innovation has impacted the evolution of ecological diversity in a major radiation of tropical herbaceous angiosperms. PMID- 28914361 TI - In reply: Sevoflurane in patients at risk of ventricular dysrhythmias. PMID- 28914362 TI - Shared decision-making in palliative care: desires and facts. PMID- 28914363 TI - Additional new insights into biometeorology. PMID- 28914364 TI - Unhealthy lifestyle habits and diabetes-specific health-related quality of life in youths with type 1 diabetes. AB - AIMS: Management of type 1 diabetes mellitus (T1DM) influences several aspects of life, such as adherence to healthy lifestyle habits and health-related quality of life (HRQoL). Our aim was to evaluate the association between unhealthy lifestyle habits and HRQoL in adolescents and young adults with T1DM. METHODS: Two hundred and forty-two Caucasian patients (13-19 years) consecutively enrolled over a 12 month period in three Regional Pediatric Diabetes Centers in Italy. Demographics, clinical, and laboratory parameters, adherence to lifestyle habits (Mediterranean Diet assessed by KIDMED, Physical Activity levels and sedentary behavior by questionnaire) considered either separately or in cluster, and HRQoL by Pediatric Quality of Life Inventory Diabetes Module (PedsQL 3.0 DM) were collected. Metabolic control was determined by HbA1cmean of previous year. RESULTS: Only 15 (6.2%) patients fulfilled the cluster of three healthy lifestyle habits without gender differences (p = 0.353); 62 (25.6%) had 1 unhealthy lifestyle habit, and 165 (68.2%) had >=2. Adolescents meeting physical activity recommendations had better PedsQL scores than those who did not meet. PedsQL total score and specific sub-scales decreased in patients with unhealthy lifestyle habits. High PedsQL was significantly associated with being male, living in South Italy, having lower HbA1c mean levels, and reporting lower adherence to unhealthy lifestyle habits. CONCLUSIONS: The clustering of unhealthy lifestyle habits is associated with reduced HRQoL in adolescents and young adults with T1DM. Promoting multiple behavior changes may be a useful approach to improve the health status and the HRQoL in youths with T1DM. PMID- 28914365 TI - Effect of swallowing maneuver on fentanyl-induced coughing. PMID- 28914366 TI - Geriatric assessment with management intervention in older adults with cancer: a randomized pilot study. AB - BACKGROUND: Older adults receiving cancer therapy have heightened risk for treatment-related toxicity. Geriatric assessment (GA) can identify impairments, which may contribute to vulnerability and adverse outcomes. GA management interventions can address these impairments and have the potential to improve outcomes when implemented. METHODS: We conducted a randomized pilot study comparing GA with management interventions versus usual care in patients with stage III/IV solid tumor malignancies (N = 71). In all patients, a trained coordinator conducted and scored a baseline GA with pre-determined cutoffs for impairment. For patients randomized to the intervention arm, an algorithm was used to identify GA management recommendations based upon identified impairments. Recommendations were relayed to the primary oncologist for implementation. GA was repeated at 3 months. The primary outcome was grade 3-5 chemotherapy toxicity. Secondary outcomes included feasibility, hospitalizations, dose reductions, dose delays, and early treatment discontinuation. RESULTS: The mean participant age was 76 (70-89). The total number of GA management recommendations relayed was 409, of which 35.4% were implemented by the primary oncologist. Incidence of grade 3-5 chemotherapy toxicity did not differ between the two groups. Prevalence of hospitalization, dose reductions, dose delays, and early treatment discontinuation also did not differ between the two groups. CONCLUSIONS: An algorithm can be used to guide GA management recommendations in older adults with cancer. However, reliance upon the primary oncologist for execution resulted in a low prevalence of implementation. Future work should aim to understand barriers to implementation and explore alternate models of implementing geriatric-focused care for older adults with cancer. PMID- 28914367 TI - No association of single nucleotide polymorphisms within H19 and HOX transcript antisense RNA (HOTAIR) with genetic susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and primary Sjogren's syndrome in a Chinese Han population. AB - The H19 (rs2839698, rs3741219) and HOTAIR (rs920778) polymorphisms were related to many kinds of cancers. However, these polymorphisms have been scarcely explored in different autoimmune diseases. Here, we aimed to examine the association of the polymorphisms with susceptibility to or protection against systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren's syndrome (pSS) among Chinese Han patients. We conducted a case-control study including 800 patients (300 with SLE, 350 with RA, and 150 with pSS) and 350 healthy control individuals. The polymorphisms were specified from genomic DNA using TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. H19 rs2839698 was not associated with SLE susceptibility and was not associated with RA and pSS, respectively (P > 0.05). Similarly, we did not find significant differences of allele or genotype frequencies between SLE, RA, and pSS patients and healthy controls for H19 gene rs3741219 polymorphism (P > 0.05). In addition, no significant evidence was detected for the relationship of HOTAIR rs920778 polymorphism with risk of these diseases. Our results suggested that H19 rs2839698, rs3741219, and HOTAIR rs920778 polymorphisms may not be involved in the genetic background of SLE, RA, and pSS in Chinese. PMID- 28914368 TI - Macrophage activation syndrome in Still's disease: analysis of clinical characteristics and survival in paediatric and adult patients. AB - Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, complicating Still's disease, both in paediatric and adult patients. In this work, we aimed to investigate clinical picture and outcome of Still's disease patients developing MAS. We performed a retrospective analysis of patients, both paediatrics and adults, affected by Still's disease attending our department. During the follow-up, each patient was investigated for MAS occurrence and possible predictors, clinical and laboratory factors, were analysed. We evaluated 50 patients affected by Still's disease, 21 paediatric and 29 adult patients. Ten patients experienced MAS (five adult and five paediatric patients) and its development significantly reduced the survival rate when compared with patients without this complication (p < 0.0001). The analysis of possible predictors showed that high-value systemic score (p = 0.03) and high levels of serum ferritin (p = 0.002) were independently associated with an increased likelihood of MAS. MAS occurrence significantly reduced survival rate in both paediatric and adult patients affected by Still's disease. The high levels of serum ferritin and an elevated systemic score, at the time of diagnosis, were significantly associated with MAS. PMID- 28914369 TI - Joint involvement in Mexican patients with ulcerative colitis: a hospital-based retrospective study. AB - The most frequent extra-intestinal manifestation in ulcerative colitis (UC) around the world is joint involvement. There are no previous data in Latin America that is about this aspect of disease; hence, the aim of this study was to determine the frequency and factors associated to joint involvement in Mexican patients with UC. A total of 295 patients with histological diagnosis of UC were studied, divided into two groups: (1) 154 cases with at least one joint affection (arthralgia, peripheral, or axial arthropathy (sacroilitis (SI) or ankylosing spondylitis (AS))) and (2) 141 controls that had never presented any joint involvement during the clinical course of UC. Demographic, clinical, and laboratory variables were collected from the clinical records, at the time of presentation of the joint involvement for the cases and with the last information available for controls. A total of 52.2% of the patients had joint involvement, which was also the most frequent extra-intestinal manifestation (EIM). The frequency of peripheral arthralgia was 46.8% and of axial arthropathy was 5.4% (2.7% AS, 2.4% SI, and 0.3% both). The female gender (P = 0.01, OR = 3.061 95% CI: 1.311-7.15), elevated erythrocyte sedimentation rate (ESR) (P = 0.07, OR = 8.04 95% CI: 1.759-36.764), and moderate disease activity by Truelove and Witts criteria (P = 0.024, OR = 4.37 95% CI: 1.211-15.78) were factors associated at the time of presentation of the joint affection. Joint involvement is the most frequent EIM in Mexican patients with UC. The female gender, elevated ESR, and disease activity are factors associated with its presentation. PMID- 28914370 TI - Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes. AB - We aimed to investigate the possible effects of thioredoxin 1 (Trx1) on the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and elucidate the possible mechanisms involved. We investigated the distribution and expression of Trx1 in synovial tissues from RA and osteoarthritis (OA) patients by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analyses. RA-FLSs were isolated and cultured under normoxic (21% oxygen) or hypoxic (3% oxygen) concentrations. Transfection of Trx1 siRNAs and a Trx1 overexpression construct was conducted to manipulate the expression of Trx1. Protein expression was detected by Western blot. Doxorubicin (Adriamycin, ADR) was used to induce apoptosis. LY-294002 was used for the inhibition of PI3K-Akt. Cell proliferation and apoptosis were determined by MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium, inner salt) assay and flow cytometry, respectively. The mRNA and protein expression of Trx1 in RA tissues was higher than that in OA tissues. The expression levels of Trx1 and cell proliferation in RA-FLSs were increased under hypoxia in comparison to those under normoxia. In hypoxia, downregulation of Trx1 significantly suppressed FLS proliferation, and the expression of PI3Kp85, phospho-Akt, and Bcl-2, while notably increased FLS apoptosis and the expression of active Caspase3 and Bax. In normoxia, Trx1 overexpression promoted the FLS proliferation and the expression of PI3Kp85, phospho-Akt, and Bcl-2, but inhibited FLS apoptosis and the expression of active Caspase3 and Bax in FLSs. Such effects were partially repressed by LY-294002 treatment. Trx1 may play an important role in regulating the proliferation and apoptosis of RA-FLSs by modulating PI3K-Akt activation. PMID- 28914371 TI - Serum cystatin C is associated with kidney function but not with cardiovascular risk factors or subclinical atherosclerosis in patients with Systemic Lupus Erythematosus. AB - Cystatin C (CysC) is a protein considered as an excellent marker of renal function, and it has been suggested as an independent predictor of cardiovascular (CV) risk. We evaluated the association of serum CysC with renal function, CV risk factors, inflammation, and subclinical atherosclerosis in Systemic Lupus Erythematosus (SLE) patients. Sixty-one SLE female patients were selected according to estimated glomerular filtration rate (GFR) > 60 ml/min/1.73m2. Renal function parameters, SLE specific factors, CV risk factors, and inflammatory markers were assessed. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry. Serum CysC concentration was measured using a particle-enhanced immunonephelometric assay that established 0.59-1.01 mg/l as reference values. Patients with high CysC showed significantly altered creatinine, microalbuminuria, and GFR in addition to a significant higher presence of traditional CV risk factors such as arterial hypertension (p < 0.001), metabolic syndrome (p < 0.001), hypertrigliceridemia (p < 0.001), tobacco habit (p < 0.05), and a strong association with arterial stiffness (p = 0.017). Positive correlation between CysC, homocysteine (r = 0.511; p < 0.001) and fibrinogen levels (r = 0.304; p < 0.02) were also observed. A significantly higher SLICC/ACR score was related to high CysC level (p = 0.011), together with higher endothelin-1 and lower TNF serum concentration (p < 0.005). Considering only patients without any renal impairment (microalbumin/creatinine <30 mg/g), no association between CysC level and CV risk factors, arterial stiffness, or SLE-related factors was found. Serum CysC is a good marker of renal function in SLE patients, but it is not independently associated with cardiovascular risk factor or subclinical atherosclerosis. PMID- 28914372 TI - The role of gut microbiota in the pathogenesis of rheumatic diseases. AB - Rheumatic diseases refer to many diseases with a loss of immune self-tolerance, leading to a chronic inflammation, degeneration, or metabolic derangement in multiple organs or tissues. The cause of rheumatic diseases remains to be elucidated, though both environmental and genetic factors are required for the development of rheumatic diseases. Over the past decades, emerging studies suggested that alteration of intestinal microbiota, known as gut dysbiosis, contributed to the occurrence or development of a range of rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, and Sjogren's syndrome, through profoundly affecting the balance between pro- and anti-inflammatory immune responses. In this article, we discussed the role of gut microbiota in the pathogenesis of rheumatic diseases based on a large number of experimental and clinical materials, thereby providing a new insight for microbiota-targeted therapies to prevent or cure rheumatic diseases. PMID- 28914374 TI - Bacterial penetration into filled root canals exposed to different pressures and to the oral environment-in vivo analysis. AB - OBJECTIVES: The study aims to correlate the depth of bacterial penetration into filled root canals with the time of exposure to the oral environment and different pressures. MATERIALS AND METHODS: One-hundred and twenty-two root canals of male Beagle dog teeth were prepared and filled. The root canals were distributed into three groups, according to the pressure applied: (A) no pressure, (B) 30 kPa, and (C) 60 kPa. Then, the root canals were exposed to the oral environment, establishing sub-groups considering the time intervals of exposure: (1) 45 days and (2) 120 days (n = 17). Sub-groups had positive and negative controls (n = 5). The animals were sacrificed, and the specimens were prepared for histological analysis. RESULTS: There was no significant difference in the bacterial penetration among groups A, B, and C at 45 days (P = 0.903) and 120 days (P = 0.211). No statistically significant difference was found (P = 0.608) between the exposure time intervals. Most of the specimens from experimental groups exposed for 120 days presented moderate inflammatory infiltrate. CONCLUSIONS: Pressures of 30 and 60 kPa did not affect sealing ability of root canal filling. The time of exposure did not influence bacterial penetration, which was limited to the first 4 mm of the root canals exposed for 120 days. CLINICAL RELEVANCE: This animal study demonstrated that disinfection of the first millimeters of root canals could be considered before retreatment of their entire length. However, clinical studies in humans should be conducted before validation of this protocol. PMID- 28914375 TI - Central nervous system involvement in patients with granulomatosis with polyangiitis: a single-center retrospective study. AB - The aims of this study were to estimate the frequency of central nervous system (CNS) involvement in Greek patients with granulomatosis with polyangiitis (GPA) and describe the related clinical characteristics and long-term outcomes of these patients. Medical charts of all ANCA-associated vasculitis patients were retrospectively reviewed, and GPA patients with CNS involvement were identified. Demographics, serological, and clinical features throughout the disease course were recorded. Comparisons of disease characteristics and long-term outcomes were performed between GPA patients with and without CNS involvement. Seventy-seven GPA patients were studied. Of these, 9 (11.7%) developed CNS manifestations. At the time of CNS involvement, all patients had increased acute phase reactants, and all but one had vasculitic manifestations in multiple systems and increased ANCA titers. CNS manifestations included the following: sensor/sensorimotor symptomatology (33.3%), severe headache and hearing loss (33.3%), delirium/seizures (22.2%), diplopia (11.1%), and cerebellar symptoms (11.1%). At initial GPA diagnosis, patients with CNS involvement, compared to those without, had ENT involvement more frequently (77.8 versus 25.4%, p = 0.004) along with a lower disease activity (BVAS) while during the overall disease course, they experienced lung vasculitis less frequently (44.4 vs. 79.4%, p = 0.02). Comparisons between the two groups did not reveal any differences regarding the long-term outcomes, including relapse rate, treatment-related adverse events, and patient survival. CNS involvement was recorded in 11.7% of our GPA patients. At disease onset, ENT involvement and lower BVAS scores were more common in GPA patients with CNS manifestations. Based on our results, CNS involvement did not affect the long-term outcomes of GPA patients. PMID- 28914373 TI - The therapeutic effect of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of randomized control trials. AB - Rheumatoid arthritis is an autoimmune disease in which probiotics appears to have an immune modulating action along with decreased inflammatory process. Therefore, we aim to investigate the efficacy of probiotics as an adjuvant therapy for rheumatoid arthritis. A comprehensive literature search was performed using nine databases including PubMed and Web of Science. Interesting data was extracted and meta-analyzed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD 42016036769). We found nine studies involving 361 patients who met our eligibility criteria. Our meta-analysis indicated that pro-inflammatory cytokine IL-6 was significantly lower in the probiotics compared with the placebo group (standardized mean difference = - 0.708; 95% confidence interval (CI) - 1.370 to 0.047, P = 0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P = 0.940). Probiotics lowered pro inflammatory cytokines IL-6 in RA; however, its clinical effect is still unclear. Hence, many high-quality randomized controlled trials (RCTs) are still needed to prove this effect. PMID- 28914376 TI - Cubic membrane formation supports cell survival of amoeba Chaos under starvation induced stress. AB - Cubic membranes (CM) are highly organized membrane structures found in biological systems. They are mathematically well defined and reveal a three-dimensional nano periodic structure with cubic symmetry. These membrane arrangements are frequently induced in cells under stress, disease conditions, or upon viral infection. In this study, we investigated CM formation in the mitochondria of amoeba Chaos carolinense and observed a striking correlation between the organism's ability to generate CM and the cell survival under starvation. Since starvation also induces autophagy, rapamycin was used to pharmacologically induce autophagy, and interestingly, CM formation was observed in parallel. Conversely, inhibition of autophagy reverted the cubic mitochondrial inner membrane morphology to tubular structure. In starved Chaos cells, mitochondria and autophagosomes did not co-localize and ATP production was sustained. CM transition in the mitochondria during starvation or upon induction of autophagy might prevent their sequestration by autophagosomes, thus slowing their rate of degradation. Such sustained mitochondrial activity may allow amoeba Chaos cells to survive for a longer period upon starvation. PMID- 28914377 TI - The permeability enhancing mechanism of menthol on skin lipids: a molecular dynamics simulation study. AB - The stratum corneum (SC), the outermost layer of skin, represents the primary barrier to molecules penetrating the skin. Menthol is widely used in clinical medicine as a penetration enhancer due to its high efficiency and relative safety. In this study, molecular dynamics simulations have been performed to investigate the effect of menthol molecules on the structural and permeability of both single component and ternary mixed bilayers. The lipid matrix is modeled as pure ceramide (CER2) or as a 2:2:1 mixture of CER2, cholesterol (CHOL), and free fatty acid (FFA). The effect of menthol on the SC bilayer was investigated at various concentrations of menthol. For both models, the area per lipid decreases and the membrane thickness increases with increased menthol concentration, which may be due to the fact that menthol molecules penetrate into the bilayer and aggregate at the bilayer center. As for ternary mixed bilayer at high concentration, the lipids rearranged, and one more layer formed inside the former two leaflets. Our simulation results are consistent with the experimental evidence that high concentrations of menthol fluidize the SC lipids and enhance permeability. The penetration enhancement of menthol may take place through direct interactions with lipids rather than by forming water pores. Graphical abstract The effect of menthol on the structural and permeability of skin lipids was investigated using a molecular dynamics simulation method. Increased menthol concentration makes the area per lipid decrease and the membrane thickness increase. Our results show that the penetration enhancement of menthol may take place through direct interactions with lipids. PMID- 28914378 TI - The spectrum of psoriatic arthritis in a South African cohort. AB - The aim of this study was to describe the clinical features of patients with psoriatic arthritis (PsA) in a South African cohort. This is a retrospective analysis of patients contributing to development of the international classification criteria for PsA, ClASsification criteria for Psoriatic ARthritis (CASPAR). Patients were all seen at the arthritis clinics at Groote Schuur Hospital, Cape Town. Demographic, clinical, laboratory and radiographic information was collected. This study describes the relevant findings relating to the clinical profile of the patients seen at our centre as well as the effect of family history and/or dactylitis in determining the severity of psoriatic arthritis. There were 45 patients with a male to female ratio of 1:1.25. The mean age of psoriasis onset was 38.34 years (SD 15.54), whilst that of arthritis onset was 43.86 years (SD 13.4). Polyarthritis was the commonest pattern and sacro iliitis was uncommon. Dactylitis was present in 26%. The presence of family history or of dactylitis did not predict more severe disease. There was a significant correlation between tender and swollen joints. The mean Health Assessment Questionnaire (HAQ) score was 1.05. Eighty-three percent showed evidence of radiological changes, and distal interphalangeal (DIP) erosions were found in 54%. Arthritis mutilans was present in 31%. There were no black subjects in the cohort. The clinical patterns of PsA in our cohort are similar to those reported elsewhere. The paucity of blacks amongst this cohort requires further study. PsA-specific measures of disease activity need to be developed. PsA causes significant joint damage and disability. PMID- 28914379 TI - Sudomotor function in diabetic peripheral artery disease: a role for diabetic neuropathy? PMID- 28914380 TI - Secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis. AB - The goals of this study were to determine if secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis (RA) compared to control subjects and to examine the relationships of S-SMase activity with functional status, quality of life, and RA disease activity measurements. We collected data on 33 patients who were diagnosed with RA and 17 non-RA controls who were comparable in terms of age, sex, and race. Demographic, clinical data and self-reported measures of fatigue, pain, and physical function were obtained directly from patients and controls. RA patients also completed quantitative joint assessment using a 28-joint count and functional status and quality of life assessment using the Modified Health Assessment Questionnaire (MHAQ). Archived serum samples were used to analyze retrospectively serum S-SMase activity in patients and controls. The mean serum S-SMase activity was 1.4-fold higher in patients with RA (RA 2.8 +/- 1.0 nmol/ml/h vs. controls 2.0 +/- 0.8 nmol/ml/h; p = 0.014). Spearman's rho correlations between S-SMase activity and oxidant activity, markers of inflammation and endothelial activation with the exception of P-selectin (rho = 0.40, p = 0.034), measures of disease activity, functional status, and quality of life were not statistically significant in patients with RA. We confirmed that S-SMase activity is higher among RA patients compared to controls, as in other acute and chronic inflammatory diseases. Future studies can build on the present findings to understand more fully the biologic role(s) of S SMase activity in RA. PMID- 28914381 TI - Response to the letter to the editor of Nicolas Nicastro et al. PMID- 28914383 TI - Central pontine myelinolysis and poorly controlled diabetes: MRI's hints for pathogenesis. PMID- 28914384 TI - Gonorrhea resistance: don't forget the old chaps. PMID- 28914382 TI - Clinical high risk for psychosis in children and adolescents: a systematic review. AB - The concept of being at risk for psychosis has been introduced both for adults and children and adolescents, but fewer studies have been conducted in the latter population. The aim of this study is to systematically review the articles associated with clinical description, interventions, outcome and other areas in children and adolescents at risk for psychosis. We searched in MEDLINE/PubMed and PsycINFO databases for articles published up to 30/06/16. Reviewed articles were prospective studies; written in English; original articles with Clinical High Risk (CHR) for psychosis samples; and mean age of samples younger than 18 years. From 103 studies initially selected, 48 met inclusion criteria and were systematically reviewed. Studies show that CHR children and adolescents present several clinical characteristics at baseline, with most attenuated positive symptom inclusion criteria observed, reporting mostly perceptual abnormalities and suspiciousness, and presenting comorbid conditions such as depressive and anxiety disorders. CHR children and adolescents show lower general intelligence and no structural brain changes compared with controls. Original articles reviewed show rates of conversion to psychosis between 17 and 20% at 1 year follow-up and between 7 and 21% at 2 years. While 36% of patients recovered from their CHR status at 6-year follow-up, 40% still met CHR criteria. Studies in children and adolescents with CHR were conducted with different methodologies, assessments tools and small samples. It is important to conduct studies on psychopharmacological and psychological treatment, as well as replication of the few studies found. PMID- 28914386 TI - Concomitant neurosyphilis and herpes simplex encephalitis in an immunocompetent patient: a case report. PMID- 28914385 TI - Multiple sclerosis and rehabilitation: an overview of the different rehabilitation settings. AB - To date, a lack of accurate information about how the different rehabilitation settings are actually delivered to people with multiple sclerosis (PwMS) is still present. Here, we described how PwMS use the different rehabilitation settings in Italy. An observational retrospective study was designed and data collected through an anonymous questionnaire distributed attending MS clinical centers, rehabilitation units, or among PwMS affiliated to the Italian MS Society. We considered as settings: out-patient ambulatory therapy (OUT), hospitalized therapy (HOSP, in-patient and out-patient hospitalized therapy), and home-based therapy (HOME). One thousand six hundred eighty-six subjects at all disability levels were included in the analysis. A high number (53%, n = 890) did not receive rehabilitation care in the last 3 months before the interview. Main causes were probably due to organizational aspects and poor transports and road networks especially in Center and the Islands. The rehabilitation setting profile of the 796 subjects obtaining rehabilitation care consisted in 58.3% (n = 464) receiving only OUT setting, 9.4% (n = 75) only HOSP setting, and 21.7% (n = 173) only HOME setting. We observed a percentage of overlap among different rehabilitation settings: 3.9% (n = 31) OUT-HOME, 3.6% (n = 29) OUT-HOSP, 2.6% (n = 21) HOSP-HOME, and 0.4% (n = 3) OUT-HOME-HOSP. The physiotherapy was the treatment more common among different rehabilitation settings. Only in the in patient hospitalized therapy setting, the patient received more frequently diversified treatment. Considering the results, the admission to rehabilitation care in Italy is still far from the standards outlined by the recent guidelines that hypothesize a multidisciplinary evaluation and a more individualized rehabilitation plan. PMID- 28914387 TI - Joint stimulus control in a temporal discrimination task. AB - The ability to identify stimuli that signal important events is fundamental for an organism to adapt to its environment. In the present paper, we investigated how more than one stimulus could be used jointly to learn a temporal discrimination task. Ten pigeons were exposed to a symbolic matching-to-sample procedure with three durations as samples (2, 6, and 18 s of keylight) and two colors as comparisons (red and green hues). A 30-s intertrial interval (ITI), illuminated with a houselight, separated the trials. Both the houselight and the sample keylight could control responding, so two tests were run to assess how these stimuli influenced choice. In the no-sample test, the keylight was not presented; in the dark-ITI test, the houselight was not illuminated. Results suggest that both houselight and keylight controlled choice, and with the exception of one animal, the more a pigeon relied on one of these stimuli, the less it appeared to rely on the other. PMID- 28914388 TI - Diet has independent effects on the pace and shape of aging in Drosophila melanogaster. AB - Studies examining how diet affects mortality risk over age typically characterise mortality using parameters such as aging rates, which condense how much and how quickly the risk of dying changes over time into a single measure. Demographers have suggested that decoupling the tempo and the magnitude of changing mortality risk may facilitate comparative analyses of mortality trajectories, but it is unclear what biologically meaningful information this approach offers. Here, we determine how the amount and ratio of protein and carbohydrate ingested by female Drosophila melanogaster affects how much mortality risk increases over a time standardised life-course (the shape of aging) and the tempo at which animals live and die (the pace of aging). We find that pace values increased as flies consumed more carbohydrate but declined with increasing protein consumption. Shape values were independent of protein intake but were lowest in flies consuming ~90 MUg of carbohydrate daily. As protein intake only affected the pace of aging, varying protein intake rescaled mortality trajectories (i.e. stretched or compressed survival curves), while varying carbohydrate consumption caused deviation from temporal rescaling (i.e. changed the topography of time-standardised survival curves), by affecting pace and shape. Clearly, the pace and shape of aging may vary independently in response to dietary manipulation. This suggests that there is the potential for pace and shape to evolve independently of one another and respond to different physiological processes. Understanding the mechanisms responsible for independent variation in pace and shape, may offer insight into the factors underlying diverse mortality trajectories. PMID- 28914390 TI - Germline mutations in lung cancer and personalized medicine. PMID- 28914389 TI - State-of-the-art review: stress T1 mapping-technical considerations, pitfalls and emerging clinical applications. AB - In vivo mapping of the myocardial T1 relaxation time has recently attained wide clinical validation of its potential utility. In this review, we address the basic principles of the T1 mapping techniques, with particular attention to the emerging application of vasodilatory stress agents to interrogate the myocardial microvascular compartment, and differences between commonly used T1 mapping methods when applied in clinical practice. PMID- 28914391 TI - Sedimentation and erosion in Lake Diefenbaker, Canada: solutions for shoreline retreat monitoring. AB - This study looks into sedimentation and erosion rates in Lake Diefenbaker, a prairie reservoir, in Saskatchewan, Canada, which has been in operation since 1968. First, we looked at the historical data in all different formats over the last 70 years, which includes data from more than 20 years before the formation of the lake. The field observations indicate high rates of shoreline erosion, especially in the upstream portion as a potential region for shoreline retreat. Because of the great importance of this waterbody to the province, monitoring sedimentation and erosion rates is necessary for maintaining the quality of water especially after severe floods which are more common due to climate change effects. Second, we used Google Maps Elevation API, a new tool from Google that provides elevation data for cross sections drawn between two points, by drawing 24 cross sections in the upstream area extending 250 m from each bank. This feature from Google can be used as an easy and fast monitoring tool, is free of charge, and provides excellent control capabilities for monitoring changes in cross-sectional profiles. PMID- 28914393 TI - Costunolide induces micronuclei formation, chromosomal aberrations, cytostasis, and mitochondrial-mediated apoptosis in Chinese hamster ovary cells. AB - Costunolide (CE) is a sesquiterpene lactone well-known for its antihepatotoxic, antiulcer, and anticancer activities. The present study focused on the evaluation of the cytogenetic toxicity and cellular death-inducing potential of CE in CHO cells, an epithelial cell line derived from normal ovary cells of Chinese hamster. The cytotoxic effect denoting MTT assay has shown an IC50 value of 7.56 MUM CE, where 50% proliferation inhibition occurs. The oxidative stress caused by CE was confirmed based on GSH depletion induced cell death, conspicuously absent in N-acetylcysteine (GSH precursor) pretreated cells. The evaluation of genotoxic effects of CE using cytokinesis block micronucleus assay and chromosomal aberration test has shown prominent induction of binucleated micronucleated cells and aberrant metaphases bearing chromatid and chromosomal breaks, indicating CE's clastogenic and aneugenic potential. The apoptotic death in CE treated cells was confirmed by an increase in the number of cells in subG1 phase, exhibiting chromatin condensation and membranous phosphatidylserine translocation. The apoptosis induction follows mitochondrial mediation, evident from an increase in the BAX/Bcl-2 ratio, caspase-3/7 activity, and mitochondrial membrane permeability. CE also induces cytostasis in addition to apoptosis, substantiated by the reduced cytokinetic (replicative indices) and mitotic (mitotic indices and histone H3 Ser-10 phosphorylation) activities. Overall, the cellular GSH depletion and potential genotoxic effects by CE led the CHO cells to commit apoptosis and lowered cell division. The observed sensitivity of CHO cells doubts unintended adverse effects of CE on normal healthy cells, suggesting higher essentiality of further studies in order to establish its safety efficacy in therapeutic explorations. PMID- 28914392 TI - Alginate/hyaluronic acid hydrogel delivery system characteristics regulate the differentiation of periodontal ligament stem cells toward chondrogenic lineage. AB - Cartilage tissue regeneration often presents a challenging clinical situation. Recently, it has been shown that Periodontal Ligament Stem Cells (PDLSCs) possess high chondrogenic differentiation capacity. In this study, we developed a stem cell delivery system based on alginate/hyaluronic acid (HA) loaded with TGF-beta1 ligand, encapsulating PDLSCs; and investigated the chondrogenic differentiation of encapsulated cells in alginate/HA hydrogel microspheres in vitro and in vivo. The results showed that PDLSCs, as well as human bone marrow mesenchymal stem cells (hBMMSCs), as the positive control, were stained positive for both toluidine blue and alcian blue staining, while exhibiting high levels of gene expression related to chondrogenesis (Col II, Aggrecan and Sox-9), as assessed via qPCR. The quantitative PCR analyses exhibited that the chondrogenic differentiation of encapsulated MSCs can be regulated by the modulus of elasticity of hydrogel delivery system, confirming the vital role of the microenvironment, and the presence of inductive signals for viability and differentiation of MSCs. In vivo, histological and immunofluorescence staining for chondrogenic specific protein markers confirmed ectopic cartilage-like tissue regeneration inside transplanted hydrogels. PDLSCs presented significantly greater capability for chondrogenic differentiation than hBMMSCs (P < 0.05). Altogether, our findings confirmed that alginate/HA hydrogels encapsulating PDLSCs are a promising candidate for cartilage regeneration. PMID- 28914394 TI - Bioinformatics-Based Identification of Methylated-Differentially Expressed Genes and Related Pathways in Gastric Cancer. AB - BACKGROUND AND AIMS: The aim of the study was to identify methylated differentially expressed genes (MDEGs) in gastric cancer and investigate their potential pathways. METHODS: Expression profiling (GSE13911 and GSE29272) and methylation profiling (GSE25869 and GSE30601) data were obtained from GEO DataSets. Differentially expressed genes and differentially methylated genes were identified using GEO2R. Gene ontology and pathway enrichment analyses were performed for the MDEGs. Protein-protein interaction (PPI) networks were established by STRING and Cytoscape. Analysis of modules in the PPI networks was performed using MCODE. Further, the hub genes derived from the PPI networks were verified by The Cancer Genome Atlas (TCGA) database and human tissues, with methylation-specific PCR for genes methylation and real-time qPCR for genes expression. RESULTS: A total of 445 genes were identified as hypermethylated, lowly expressed genes (Hyper-LGs), which were enriched in the regulation of system process and channel activity. A total of 129 genes were identified as hypomethylated, highly expressed genes (Hypo-HGs), which were involved in cell adhesion, cell proliferation, and protein binding. Pathway analysis showed that Hyper-LGs were associated with neuroactive ligand-receptor interaction and calcium signaling pathway, while Hypo-HGs were enriched in pathways in cancer. In the PPI networks, after verification by TCGA analysis and human tissue detection, CASR, CXCL12, and SST were identified as significantly different hub genes. CONCLUSIONS: MDEG analysis helps to understand the epigenetic regulation mechanisms involved in the development and progression of gastric cancer. The hub genes have predictive and prognostic value as methylation-based biomarkers for the precise diagnosis and treatment of gastric cancer. PMID- 28914395 TI - Repetitive on-demand drug release from polymeric matrices containing a macroscopic spherical iron core. AB - : A system for multiple on-demand drug release has been prepared that can be activated with an alternating magnetic field as external trigger. The core/shell samples have been developed based on a macroscopic spherical iron core coated with a thermoresponsive polymer, poly(styrene-stat-butyl methacrylate), containing ibuprofen as a model drug. During exposure of the samples to the magnetic field (ON state), the release rate of ibuprofen is significantly increased, up to 35 times the release rate without the magnetic field (OFF state). Using one sample or two samples in line with the magnetic field does not influence the ON/OFF ratio of the system, showing the possibility of using multiple samples to increase and tune the drug dose. Increasing the concentration of ibuprofen in the polymer layer is shown to increase the release rate in both the ON and OFF states. Increasing the size of the iron core and, consequently, decreasing the polymer thickness, was found to only increase the release rate during exposure resulting in higher ON/OFF ratios. The developed on demand drug delivery systems represents a promising development towards on demand drug delivery implants. REFLECTIONS ON CAREER GOALS: During my chemical engineering studies, it was only during my master thesis work that I decided to continue with PhD research as I really enjoyed doing original research. When coming to the end of my PhD research under supervision of Prof. Ulrich S. Schubert, I developed the ambition to pursue an academic career. Fortunately, I got the opportunity to stay with Prof. Schubert as project leader for the Dutch Polymer Institute (DPI). Within this position, I supervised ten researchers and was able to start developing my independent research lines. Despite that I now advise students to not stay in the same laboratory, this first position allowed me to gain some initial independence and to publish a large number of papers that has been a great benefit in my further career. After two and a half years I needed a new challenge that I found by taking up a part-time position at a start-up company in Eindhoven, Dolphys Medical BV, while I also continued as part-time group leader for the DPI. As senior product developer, I was in charge of the research and learned to focus on the application rather than scientific curiosity. This experience made me realize that I prefer the freedom to do academic blue sky research and decided to fully go for an academic position. After personal discussions with some prominent professors in the Netherlands, I applied for a postdoc fellowship in the Netherlands with Prof. Roeland Nolte as well as a Humboldt fellowship in Germany with Prof. Martin Moller, which I both got. As a result, I went one year 'abroad' to Aachen and returned to Nijmegen where I intended to start my independent career. However, another opportunity came along. Via my personal network I was informed that I would make a good chance if I applied for a new professor scheme in Ghent. So I applied and the rest is history. Picture of the Supramolecular Chemistry Group (2017). PMID- 28914396 TI - The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA mutation carriers, by age at mastectomy. AB - PURPOSE: Preventive breast surgery is offered to unaffected BRCA mutation carriers to prevent breast cancer incidence and mortality. The clinical benefit of preventive mastectomy can be measured in several ways, including extension of life expectancy (mean years of life gained) and by estimating the probability of surviving until age 80. We sought to estimate the expected benefit of a preventive mastectomy at various ages, using these indices of mortality, by simulating hypothetical cohorts of women. METHODS: The age-specific annual risks of developing breast cancer were used to estimate the actuarial risk of developing breast cancer by age 80 for women with a BRCA1 or BRCA2 mutation. The probability of developing breast cancer before age 80 was then modified to include competing causes of death, including from ovarian cancer. The mortality rate from breast cancer after a diagnosis of breast cancer was set at 2% annually for the first 10 years and then 1% annually for years ten to twenty. The incidence rate and mortality rate from ovarian cancer were based on published literature. We assumed that preventive mastectomy was associated with complete protection against subsequent breast cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) until age 80, according to the age at mastectomy. RESULTS: The actuarial risk of developing breast cancer until age 80 was estimated to be 70.8%. The actual risk (incorporating competing risks) was 64.0%. The probability of being alive at age 80 by having a mastectomy at age 25 increased by 8.7% (from 42.7 to 51.3%). The estimated benefit declined with age at mastectomy; for surgery done at age 50 the improvement in survival to age 80 was much more modest (2.8% at age 80, from 42.7 to 45.5%). CONCLUSIONS: Among BRCA mutation carriers, the mortality benefit of preventive mastectomy at age 25 is substantial, but the expected benefit declines rapidly with increasing age at surgery. PMID- 28914397 TI - Influence of acid treatment on surface properties and in vivo performance of Ti6Al4V alloy for biomedical applications. AB - The purpose of this work was to investigate the influence of acid treatment on the surface properties and in vivo performance of titanium grade 5 (Ti6Al4V) alloy. Mini-implants with surface treatment were inserted into New Zealand rabbit tibia for 1, 4 and 8 weeks. SEM analysis showed intercommunicated micropores in acid treated samples. AFM showed micron and sub-micron roughness. The thickness of the titanium oxide layer increased with surface treatment, with a significant reduction of Al and V concentration. Acid treated implant removal torque was larger than without treatment. The implants/bone interface of acid treated implants showed dense adhered Ca/P particles with spreading osteoblasts after 4 weeks and newly formed bone trabeculae after 8 weeks. Analysis of rabbit blood that received treated implant showed lower Al and V contents at all times. Acid treatment improved surface morphology and mechanical stability, which allowed initial events of osseointegration, while Al-V ion release was reduced. GRAPHICAL ABTSRACT. PMID- 28914398 TI - Characteristics and prognosis of breast cancer after liver or kidney transplantation. AB - PURPOSE: Immunoediting is crucial in cancer development and progression. This study compared the characteristics and prognosis of post-transplant breast cancer (PTBC) patients receiving immunosuppressants and general breast cancer patients. METHODS: Data from the Asan Medical Center Breast Cancer (AMCBC), kidney transplantation, and liver transplantation databases recorded during 1989-2013 were retrospectively analyzed. Four controls of AMCBC cohort per one case of PTBC cohort were selected based on tumor size, lymph node metastasis, and age. RESULTS: After a median of 61 and 90.8 months after liver and kidney transplantation, respectively, 8 and 16 patients were diagnosed with breast cancer, respectively (p = 0.178). Mean age at breast cancer diagnosis was 51.9 (+/-8.7) and 45.2 (+/-4.5) years in liver and kidney transplantation patients, respectively. Age at diagnosis was significantly younger in kidney transplantation patients than in general breast cancer patients (45.2 +/- 4.5 vs. 48.5 +/- 10.1 years; p = 0.008). Cancer was detected via asymptomatic screening in 41.7% of the PTBC cohort but 30.6% of the control cohort (p = 0.241). In the PTBC cohort, 7 (29.2%) patients had stage 0 breast cancer compared with 1704 (9.7%) in the control cohort (p = 0.022); 22 (91.7%) patients had lymph node negative cancer compared with 11,704 (66.8%) in the control cohort (p = 0.01). Estrogen receptor, progesterone receptor, and HER2 positivity did not differ between cohorts. Immunosuppressant use was not a poor prognostic factor for breast cancer patients. CONCLUSIONS: Age at breast cancer diagnosis was younger in patients who received kidney transplants; the subtype and prognosis of breast cancer were comparable with that in the general cohort. Immunosuppressants do not adversely affect breast cancer prognosis. PMID- 28914399 TI - Surgery for Duodenal Gastrointestinal Stromal Tumors: A Single-Center Experience. AB - BACKGROUND: The duodenal gastrointestinal stromal tumors (GISTs) are an extremely rare subset of GISTs. The optimal surgical procedure remains not well defined. AIMS: We assessed the surgical approach and long-term outcomes of patients with duodenal GISTs who underwent limited resection (LR) versus pancreaticoduodenectomy (PD). METHODS: From November 2005 to January 2016, 64 consecutive patients with duodenal GISTs in a single center were retrospectively analyzed. Overall survival (OS), recurrence-free survival (RFS), and perioperative outcomes were analyzed according to the different surgical type. RESULTS: A total of 41 patients (64.1%) underwent LR, while 23 patients (35.9%) underwent PD. All patients had negative surgical margins (R0). Median tumor size was larger for PD (6 cm) versus LR (4 cm) (P = 0.041). PD also had more complications than LR (PD, 69.6 vs. LR, 31.7%) (P = 0.002). The 3-year and 5-year RFS was 62.9 and 44.3%, respectively. The 3-year and 5-year OS was 85.7 and 59.5%, respectively. The multivariate analysis demonstrated the only unfavorable predictive factor was tumor size >5 cm for RFS and OS. Although the complication rate in the PD group was higher than in the LR group, OS and RFS were not affected by the complication (P = 0.492 for OS, P = 0.512 for RFS). PD versus LR was not associated with RFS and OS. Adjuvant imatinib mesylate (IM) did not improve the survival of the patients after operation. CONCLUSIONS: Survival of duodenal GISTs is mainly dependent on tumor biology rather than surgical procedure. LR should be the surgical procedure of choice for duodenal GISTs when technically feasible and no anatomical constrains. LR shows comparable survival and lower risk of postoperative complications compared by PD. The administration of IM both as adjuvant and neoadjuvant therapy for duodenal GISTs needs large population and prospective study to evaluate its effect. PMID- 28914400 TI - An in vivo study on endothelialized vascular grafts produced by autologous biotubes and adipose stem cells (ADSCs). AB - Currently, commercial synthetic vascular grafts made from Dacron and ePTFE for small-diameter, vascular applications (<6 mm) show limited reendothelization and are less compliant, often resulting in thrombosis and intimal hyperplasia. Although good blood compatibility can be achieved in autologous arteries and veins, the number of high quality harvest sites is limited, and the grafts are size-mismatched for use in the fistula or cardiovascular bypass surgery; thus, alternative small graft substitutes must be developed. A biotube is an in vivo, tissue-engineered approach for the growth of autologous grafts through the subcutaneous implantation of an inert rod through the inflammation process. In the present study, we embedded silicone rods with a diameter of 2 mm into the dorsal subcutaneous tissue of rabbits for 4 weeks to grow biotubes. The formation of functional endothelium cells aligned on the inner wall surface was achieved by seeding with adipose stem cells (ADSCs). The ADSCs-seeded biotubes were implanted into the carotid artery of rabbits for more than 1 month, and the patency rates and remodeling of endothelial cells were observed by angiography and fluorescence staining, respectively. Finally, the mechanical properties of the biotube were also evaluated. The fluorescence staining results showed that the ADSCs differentiated not only into endothelia cells but also into smooth muscle cells. Moreover, the patency of the ADSCs-seeded biotube remained high for at least 5 months. These small-sized ADSCs-seeded vascular biotubes may decrease the rate of intimal hyperplasia during longer implantation times and have potential clinical applications in the future. PMID- 28914402 TI - Analytical modeling of the mechanics of early invasion of a merozoite into a human erythrocyte. AB - In this study, we used a continuum model based on contact mechanics to understand the mechanics of merozoite invasion into human erythrocytes. This model allows us to evaluate the indentation force and work as well as the contact pressure between the merozoite and erythrocyte for an early stage of invasion (gamma = 10%). The model predicted an indentation force of 1.3e -11N and an indentation work of 1e -18J. The present analytical model can be considered as a useful tool not only for investigations in mechanobiology and biomechanics but also to explore novel therapeutic targets for malaria and other parasite infections. PMID- 28914403 TI - Self-Transformation at the Boundary of Religious Conversion and Psychosis. AB - The relationship between religious conversion, as a form of spiritual emergency, and psychosis is one of the fundamental issues at the meeting point of theology and clinical psychology. In the present study, we assessed 53 individuals referred to a psychiatry center with the initial diagnosis of a psychotic episode by focusing on the clinical diagnosis (psychosis vs. spiritual emergency), subjective experiences (basic symptoms), and neuropsychological functions. Twenty nine individuals meet the diagnosis of schizophrenia-spectrum disorders, but 24 persons experienced only religious and spiritual problems (religious conversion). Both groups reported similar levels of perplexity (e.g., ambivalence, inability to discriminate between own feelings, and hyperreflectivity) and self-disorder (e.g., depersonalization, impression of a change in one's mirror image, and experience of discontinuity in own action). Diminished affectivity, disturbed contact, and perceptual/cognitive disorders were pronounced in psychosis, whereas anxiety and depressive symptoms were more severe in people with spiritual and religious problems. These results indicate that perplexity, self-disorder, and emotional turmoil are common features of turbulent religious conversion and psychosis, but a broader emergence of anomalous subjective experiences and cognitive deficits are detectable only in psychosis. PMID- 28914404 TI - Development and characterization of hybrid tubular structure of PLCL porous scaffold with hMSCs/ECs cell sheet. AB - Tissue engineering offers an alternate approach to providing vascular graft with potential to grow similar with native tissue by seeding autologous cells into biodegradable scaffold. In this study, we developed a combining technique by layering a sheet of cells onto a porous tubular scaffold. The cell sheet prepared from co-culturing human mesenchymal stem cells (hMSCs) and endothelial cells (ECs) were able to infiltrate through porous structure of the tubular poly (lactide-co-caprolactone) (PLCL) scaffold and further proliferated on luminal wall within a week of culture. Moreover, the co-culture cell sheet within the tubular scaffold has demonstrated a faster proliferation rate than the monoculture cell sheet composed of MSCs only. We also found that the co-culture cell sheet expressed a strong angiogenic marker, including vascular endothelial growth factor (VEGF) and its receptor (VEGFR), as compared with the monoculture cell sheet within 2 weeks of culture, indicating that the co-culture system could induce differentiation into endothelial cell lineage. This combined technique would provide cellularization and maturation of vascular construct in relatively short period with a strong expression of angiogenic properties. PMID- 28914406 TI - Manganese-Induced Neurotoxicity and Alterations in Gene Expression in Human Neuroblastoma SH-SY5Y Cells. AB - Manganese (Mn) is an essential trace element required for many physiological functions including proper biochemical and cellular functioning of the central nervous system (CNS). However, exposure to excess level of Mn through occupational settings or from environmental sources has been associated with neurotoxicity. The cellular and molecular mechanism of Mn-induced neurotoxicity remains unclear. In the current study, we investigated the effects of 30-day exposure to a sub-lethal concentration of Mn (100 MUM) in human neuroblastoma cells (SH-SY5Y) using transcriptomic approach. Microarray analysis revealed differential expression of 1057 transcripts in Mn-exposed SH-SY5Y cells as compared to control cells. Gene functional annotation cluster analysis exhibited that the differentially expressed genes were associated with several biological pathways. Specifically, genes involved in neuronal pathways including neuron differentiation and development, regulation of neurogenesis, synaptic transmission, and neuronal cell death (apoptosis) were found to be significantly altered. KEGG pathway analysis showed upregulation of p53 signaling pathways and neuroactive ligand-receptor interaction pathways, and downregulation of neurotrophin signaling pathway. On the basis of the gene expression profile, possible molecular mechanisms underlying Mn-induced neuronal toxicity were predicted. PMID- 28914405 TI - Managing Asthma in Low-Income, Underrepresented Minority, and Other Disadvantaged Pediatric Populations: Closing the Gap. AB - PURPOSE OF REVIEW: In this article, we review current understanding of the epidemiology and etiology of disparities in asthma. We also highlight current and emerging literature on solutions to tackle disparities while underscoring gaps and pressing future directions. RECENT FINDINGS: Tailored, multicomponent approaches including the home, school, and clinician-based interventions show great promise. Managing asthma in disadvantaged populations can be challenging as they tend to have disproportionately worse outcomes due to a multitude of factors. However, multifaceted, innovative interventions that are sustainable and scalable are key to improving outcomes. PMID- 28914408 TI - 3D Volumetry and its Correlation Between Postoperative Gastric Volume and Excess Weight Loss After Sleeve Gastrectomy. AB - BACKGROUND: The volume of the postoperative gastric remnant is a key factor in excess weight loss (EWL) after sleeve gastrectomy (SG). Traditional methods to estimate gastric volume (GV) after bariatric procedures are often inaccurate; usually conventional biplanar contrast studies are used. METHODS: Thirty patients who underwent SG were followed prospectively and evaluated at 6 months after the surgical procedure, performing 3D CT reconstruction and gastric volumetry, to establish its relationship with EWL. The gastric remnant was distended with effervescent sodium bicarbonate given orally. Helical CT images were acquired and reconstructed; GV was estimated with the software of the CT device. The relationship between GV and EWL was analyzed. RESULTS: The study allowed estimating the GV in all patients. A dispersion diagram showed an inverse relationship between GV and %EWL. 55.5% of patients with GV <= 100 ml had %EWL 25 75% and 38.8% had an %EWL above 75% and patients with GV >= 100 ml had an %EWL under 25% (50% of patients) or between 25 and 75% (50% of this group). The Pearson's correlation coefficient was R = 6.62, with bilateral significance (p <= .01). The Chi-square result correlating GV and EWL showed a significance of .005 (p <= .01). The 3D reconstructions showed accurately the shape and anatomic details of the gastric remnant. CONCLUSIONS: 3D volumetry CT scans accurately estimate GV after SG. A significant relationship between GV and EWL 6 months after SG was established, seeming that GV >= 100 ml at 6 months of SG is associated with poor EWL. PMID- 28914409 TI - Evaluation of contactless human-machine interface for robotic surgical training. AB - PURPOSE: Teleoperated robotic systems are nowadays routinely used for specific interventions. Benefits of robotic training courses have already been acknowledged by the community since manipulation of such systems requires dedicated training. However, robotic surgical simulators remain expensive and require a dedicated human-machine interface. METHODS: We present a low-cost contactless optical sensor, the Leap Motion, as a novel control device to manipulate the RAVEN-II robot. We compare peg manipulations during a training task with a contact-based device, the electro-mechanical Sigma.7. We perform two complementary analyses to quantitatively assess the performance of each control method: a metric-based comparison and a novel unsupervised spatiotemporal trajectory clustering. RESULTS: We show that contactless control does not offer as good manipulability as the contact-based. Where part of the metric-based evaluation presents the mechanical control better than the contactless one, the unsupervised spatiotemporal trajectory clustering from the surgical tool motions highlights specific signature inferred by the human-machine interfaces. CONCLUSIONS: Even if the current implementation of contactless control does not overtake manipulation with high-standard mechanical interface, we demonstrate that using the optical sensor complete control of the surgical instruments is feasible. The proposed method allows fine tracking of the trainee's hands in order to execute dexterous laparoscopic training gestures. This work is promising for development of future human-machine interfaces dedicated to robotic surgical training systems. PMID- 28914407 TI - Association of fetuin B with markers of liver fibrosis in nonalcoholic fatty liver disease. AB - OBJECTIVE: The liver-derived plasma protein fetuin B is associated with nonalcoholic fatty liver disease (NAFLD) and impaired glucose homeostasis in mice. However, its association with non-invasive ultrasound- and magnetic resonance (MR)-based markers of liver fibrosis and steatosis, the enhanced liver fibrosis (ELF) score, liver biopsy, as well as rs738409 in PNPLA3, has not been elucidated in NAFLD, so far. DESIGN AND METHODS: The association of circulating fetuin B and transient elastography (TE), controlled attenuation parameter (CAP), 1H-MR-spectroscopy, the ELF score, liver biopsy, as well as risk alleles in rs738409 in PNPLA3, was studied in 101 NAFLD patients as compared to 15 healthy controls. RESULTS: Serum fetuin B levels did not differ between NAFLD patients and controls (p = 0.863). Fetuin B was independently and negatively associated with transient elastography liver stiffness measurement (LSM) (p = 0.002), but not with the steatosis markers CAP or 1H-MR-spectroscopy. Fetuin B serum concentrations were significantly lower in individuals with LSM > 7.0 kPa as compared to patients with LSM < 7.0 kPa (p = 0.024). Furthermore, the ELF score and histologically proven fibrosis were independent and negative predictors of circulating fetuin B. Moreover, serum fetuin B significantly depended on number of rs738409 risk alleles (p = 0.026). CONCLUSIONS: Fetuin B is independently and negatively associated with non-invasive markers of liver fibrosis and PNPLA3 status in NAFLD patients but does not show a correlation with the hepatic lipid content. Future studies need to elucidate the pathophysiological significance of fetuin B in NAFLD and its potential value as predictor for disease severity. PMID- 28914410 TI - C21 steroid derivatives from the Dai herbal medicine Dai-Bai-Jie, the dried roots of Marsdenia tenacissima, and their screening for anti-HIV activity. AB - Twenty-three new C21 steroidal glycosides, marstenacissides C1-C10 (1-10), D1-D7 (11-17) and E1-E6 (18-23), and four new C21 steroids, 11alpha,12beta-O-ditigloyl tenacigenin C (24), 11alpha-O-benzoyl-12beta-O-tigloyl-tenacigenin C (25), 11alpha-O-tigloyl-12beta-O-benzoyl-tenacigenin C (26) and 11alpha-O-tigloyl 12beta-O-benzoyl-marsdenin (27), were isolated from the Dai herbal medicine Dai Bai-Jie, derived from the roots of Marsdenia tenacissima. The chemical structures of all compounds were established by spectroscopic techniques, including high resolution mass spectrometry and NMR spectroscopy, as well as by comparison with reported spectral data. The anti-HIV activities of these compounds were screened, and the compounds obtained displayed inhibitory effects against HIV-1 with inhibition rates of 36.4-81.3% at 30 MUM. PMID- 28914411 TI - Body farms. PMID- 28914412 TI - Body farms. PMID- 28914413 TI - Study of the mechanism of remediation of Cd-contaminated soil by novel biochars. AB - This article used novel non-magnetized and magnetized biochars prepared under a CO2 atmosphere returned to Cd-contaminated soil and compared these to the effects of conventional biochars prepared under a N2 atmosphere with regard to Cd contaminated soil remediation. A pot experiment with lettuce (Lactuca sativa) was conducted to investigate the relative soil remediation effects of these biochars. The soil used for the pot experiment was spiked with 20 mg kg-1 Cd and amended with 5% of a biochar before sowing. Through these research works, some important results were obtained as follows: (1) applying biochar treated by pyrolysis under a CO2 atmosphere can obtain the best remediation effect of Cd-contaminated soil that the content of cadmium in the lettuce roots, stems, and leaves was reduced 67, 62, and 63%, respectively; (2) the magnetic biochar aggregation for the soil is weak, so the heavy metal cadmium in the soil could not be immobilized well by the magnetic biochar; (3) The remediation mechanism of novel biochars is that biochar includes a large number of organic functional groups (-C-OH, -C=O, COO-) that can act in a complexing reaction with heavy metal Cd(II) and the inorganic salt ions (Si, S, Cl, etc.) that can combine with cadmium and generate a stable combination. PMID- 28914414 TI - Novel insights in biopurification system for dissipation of a pesticide mixture in repeated applications. AB - A biopurification system based on the adsorption and degradation capacity of a biomixture to degrade a mixture of pesticides (atrazine, chlorpyrifos, iprodione; 50 mg kg-1 each) in repeated applications (0, 30, and 60 days) was evaluated. Tanks of 1 m3 packed with a biomixture (rho 0.29 g mL-1) with and without vegetal cover were used. The biomixture contained soil, peat, and wheat straw in a proportion 1:1:2 by volume, respectively. Pesticide concentrations, biological activities (urease, phenoloxidase, and dehydrogenase), and microbial community changes (DGGE and qPCR) were evaluated periodically. Pesticide dissipation was higher in tanks with vegetal cover (> 95%) and no variation was observed after the three applications; contrarily, pesticide dissipation decreased in the tank without vegetal cover after each application. The presence of vegetal cover decreased the half-life of pesticides by at least twice. Biological activities were in general not affected by the application and reapplication of pesticides in the same treatment; however, they exhibited some differences between tanks containing and lacking the vegetal cover. High similarity between microbial groups (actinobacteria, bacteria, and fungi) was observed, suggesting no influence ascribable to the successive pesticide applications. The number of copies of bacteria and actinobacteria remained almost constant during the assay. However, the number of copies of fungi was significantly higher in the uncontaminated tank without vegetal cover. PMID- 28914415 TI - A randomized trial of restarting warfarin at maintenance versus loading doses following an elective procedure. AB - Guidelines suggest restarting warfarin at known maintenance doses, although this may result in a delay to achieving therapeutic anticoagulation. As such, we compared the time to achieve an INR >= 2.0 between those restarting warfarin maintenance vs loading doses after transient interruption, and the impact on protein C, S and factor II levels. Patients requiring interruption of warfarin for elective procedures without hospitalization were randomized 1:1 to receive warfarin maintenance or loading doses (1.5 times the maintenance dose for 3 days followed by pre-procedural warfarin maintenance dosing). Protein C, S and Factor II were drawn at baseline (prior to warfarin interruption), 7 and 14 days after restarting warfarin. Among 19 patients randomized to maintenance and 20 to loading doses, nearly half in each group had mechanical heart valves with gastrointestinal endoscopic procedures most commonly performed (41%). The median number of days to reach an INR >= 2.0 was 7.8 days in the loading and 9.0 in the maintenance group (difference between medians 1.2 days, 95% CI -3.1 to 4.9; P = 0.19). Although levels of protein C, S and factor II were lower in the loading vs maintenance dose group, all remained above that of baseline. Warfarin resumption with loading doses shortened the time to achieve a therapeutic INR by a median of 1.2 days. Prompt warfarin dose escalation should be done in response to the INR. Protein C and S remained above pre-warfarin interruption levels, implying a lack of depletion with restarting warfarin. PMID- 28914401 TI - 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary. PMID- 28914416 TI - Heterogeneity analysis of diffusion-weighted MRI for prediction and assessment of microstructural changes early after one cycle of induction chemotherapy in nasopharyngeal cancer patients. AB - PURPOSE: To evaluate whether the pretreatment apparent diffusion coefficient (ADC) heterogeneity parameters and their alterations, after one cycle of induction chemotherapy, can be used as reliable markers of treatment response to induction chemotherapy in patients with nasopharyngeal cancer. MATERIALS AND METHODS: Ten patients were recruited and received induction chemotherapy (IC). Diffusion-weighted imaging was performed prior to, during, and after IC. The first-order ADC histogram parameters at the intra-treatment time-point were compared to the baseline time-point in the metastatic lymph nodes (LNs). Some ADC pretreatment parameters were combined with each other, employing discriminant analysis to achieve a feasible model to separate the complete response (CR) from the partial response (PR) groups. RESULTS: For ten patients, significant rise in Mean and Txt1Mean (p = 0.048 and 0.015, respectively) was observed in the metastatic nodes following one cycle of IC. Txt5Energy significantly decreased (p = 0.002). Discriminant analysis on pretreatment parameters illustrated that Txt5Energypre was the best parameter to use to correctly classify CR and PR patients. This was followed by Txt9Percentile75pre, Txt1Meanpre, and Txt2Standard Deviationpre. CONCLUSIONS: Our results suggest that heterogeneity metrics extracted from ADC-maps in metastatic lymph nodes, before and after IC, can be used as supplementary IC response indicators. PMID- 28914418 TI - Spermidine rescues proximal tubular cells from oxidative stress and necrosis after ischemic acute kidney injury. AB - Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative stress and necrosis; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated increases in plasma creatinine concentration and tubular injury score after IRI. In addition, exogenous spermidine potently inhibited oxidative stress, especially lipid peroxidation after IRI in kidneys and exposure to hydrogen peroxide in kidney proximal tubular cells, suppressing plasma membrane disruption and necrosis. Consistent with spermidine supplementation, upregulation of ornithine decarboxylase (ODC) in human kidney proximal tubular cells significantly diminished lipid peroxidation and necrosis induced by hydrogen peroxide-induced injury. Conversely, ODC deficiency significantly enhanced lipid peroxidation and necrosis after exposure to hydrogen peroxide. Finally, small interfering RNA-mediated ODC inhibition induced functional and histological damage in kidneys as well as it increased lipid hydroperoxide levels after IRI. In conclusion, these data suggest that spermidine level determines kidney proximal tubular damage through oxidative stress and necrosis induced by IRI, and this finding provides a novel target for prevention of tubular damage induced by IRI. PMID- 28914417 TI - Early decrease of oxidative stress by non-invasive ventilation in patients with acute respiratory failure. AB - Oxidative stress plays an important role in chronic respiratory diseases where the use of non-invasive ventilation seems to reduce the oxidative damage. Data on acute respiratory failure are still lacking. The aim of the study is to investigate the interplay between oxidative stress and acute respiratory failure, and the role of non-invasive ventilation in this setting. We enrolled 60 patients suffering from acute respiratory failure (PaO2/FiO2 ratio <300): 30 consecutive patients treated with non-invasive ventilation and 30 consecutive patients treated with conventional oxygen therapy. Serum levels of soluble Nox2-derived peptide (sNOX2-dp), a marker of NADPH-oxidase activation, and 8-iso-PGF2alpha and H2O2, markers of oxidative stress, were evaluated at baseline and after 3 h of treatment. At baseline, higher values of sNOX2-dp, 8-iso-PGF2alpha and H2O2 are associated with lower values of PaO2/FiO2 ratio (p < 0.001). After 3 h, serum levels of sNOX2-dp, H2O2, and 8-iso-PGF2alpha significantly decrease in patients treated with non-invasive ventilation, but not in patients treated with conventional oxygen therapy. Delta changes of oxidative stress parameters correlate inversely with the delta changes of PaO2/FiO2 (R = -0.623, p < 0.001 for sNOX2-dp; R = -0.428, p < 0.001 for H2O2; R = -0.548, p < 0.001 for 8-iso PGF2alpha). In the acute respiratory failure setting, treatment with non-invasive ventilation reduces the levels of oxidative stress in the first hours. This reduction is associated with an improvement of PaO2/FiO2 ratio as well as in a reduction of NADPH-oxidase activity. PMID- 28914419 TI - Social Isolation During Adolescence Induces Anxiety Behaviors and Enhances Firing Activity in BLA Pyramidal Neurons via mGluR5 Upregulation. AB - Social isolation during the vulnerable period of adolescence contributes to the occurrence of psychiatric disorders and profoundly affects brain development and adult behavior. Although the impact of social isolation during adolescence on anxiety behaviors has been well studied, much less is known about the onset and underlying mechanisms of these behaviors. We observed that following 2 weeks, but not 1 week, of social isolation, adolescent mice exhibited anxiety behaviors. Strikingly, the mGluR5 protein levels in the amygdala increased concomitantly with anxiety behaviors, and both intraperitoneal administration and intra basolateral amygdala (BLA) infusion of MPEP, a metabotropic glutamate receptor 5 antagonist, normalized anxiety behaviors. Furthermore, electrophysiological studies showed that 2 weeks of social isolation during adolescence facilitated pyramidal neuronal excitability in the BLA, which could be normalized by MPEP. Together, these results reveal a critical period in adolescence during which social isolation can induce anxiety behaviors and facilitate BLA pyramidal neuronal excitability, both of which are mediated by mGluR5, thus providing mechanistic insights into the onset of anxiety behaviors after social isolation during adolescence. PMID- 28914420 TI - Labdane-type diterpenoids from Vitex limonifolia and their antivirus activities. AB - Phytochemical investigation of the methanol extract of Vitex limonifolia leaves led to the isolation of three new labdane-type diterpenoids, vitexlimolides A-C (1-3) and eight known compounds, 5,4'-dihydroxy-3,7-dimethoxyflavone (4), vitecetin (5), 5,4'-dihydroxy-7,3'-dimethoxyflavone (6), verrucosin (7), 2alpha, 3alpha-dihydroxy-urs-12-en-28-oic acid (8), euscaphlic acid (9), 18,19-seco, 2alpha, 3alpha-dihydroxy-19-oxo-urs-11,13(18)-dien-28-oic acid (10), and maslinic acid (11). Their chemical structures were elucidated by physical and chemical methods. All compounds were evaluated for antiviral activities against CVB3, HRV1B, and EV71 viruses. As a result, compounds 4 and 6 showed potent antiviral activity against CVB3 infection with IC50 values of 0.12 +/- 0.06 and 1.86 +/- 0.18 (uM), respectively. PMID- 28914422 TI - Normative Data for IVC Diameter and its Correlation with the Somatic Parameters in Healthy Indian Children. AB - OBJECTIVE: To determine the normative data for inferior vena cava (IVC) diameter in children and its correlation with various somatic parameters like height, weight and body surface area in Indian children. Readily available baseline data of IVC diameter in normal children shall be of great help in rapid assessment of variations in sick children. METHODS: Total 475 healthy children aged one month to 12 y visiting out patient clinics (OPD's) were enrolled in this study. Weight, height and body surface area were calculated at the time of examination. The maximum and minimum diameters of IVC were measured during the expiratory and inspiratory phase of the respiratory cycle respectively using M mode ultrasonography. Collapsibility Index was also calculated for each subject by measuring difference between the maximum (expiratory) and minimum (inspiratory) IVC diameters divided by the maximum diameter. RESULTS: The mean age of study subjects was 4.72 +/- 3.72 y. Out of 475 subjects, 285 (60%) were boys and 190 (40%) were girls. Mean weight for age (%) of subjects was 89.18 +/- 13.26%. Correlation was studied between physical parameters and IVC diameter which revealed a positive correlation of age, height and weight with both maximum and minimum IVC diameter. Regression analysis was also performed to derive the equations for maximum and minimum diameters of children from 1 y to 12 y. CONCLUSIONS: This study provides reference values of IVC diameters for Indian children of different age groups. PMID- 28914421 TI - Acid-base safety during the course of a very low-calorie-ketogenic diet. AB - BACKGROUND AND AIMS: Very low-calorie ketogenic (VLCK) diets have been consistently shown to be an effective obesity treatment, but the current evidence for its acid-base safety is limited. The aim of the current work was to evaluate the acid-base status of obese patients during the course of a VLCK diet. METHOD: Twenty obese participants undertook a VLCK diet for 4 months. Anthropometric and biochemical parameters, and venous blood gases were obtained on four subsequent visits: visit C-1 (baseline); visit C-2, (1-2 months); maximum ketosis; visit C-3 (2-3 months), ketosis declining; and visit C-4 at 4 months, no ketosis. Results were compared with 51 patients that had an episode of diabetic ketoacidosis as well as with a group that underwent a similar VLCK diet in real life conditions of treatment. RESULTS: Visit C1 blood pH (7.37 +/- 0.03); plasma bicarbonate (24.7 +/- 2.5 mmol/l); plasma glucose (96.0 +/- 11.7 mg/l) as well as anion gap or osmolarity were not statistically modified at four months after a total weight reduction of 20.7 kg in average and were within the normal range throughout the study. Even at the point of maximum ketosis all variables measured were always far from the cut-off points established to diabetic ketoacidosis. CONCLUSION: During the course of a VLCK diet there were no clinically or statistically significant changes in glucose, blood pH, anion gap and plasma bicarbonate. Hence the VLCK diet can be considered as a safe nutritional intervention for the treatment of obesity in terms of acid-base equilibrium. PMID- 28914423 TI - Influences of nitrogen fertilization and energy supplementation for growth perfomance of beef cattle on Alexander grass. AB - This study evaluated the influences of nitrogen fertilizer and energy supplementation cattle on the growth performance of beef cattle. This study was conducted at the Federal University of Technology of Parana, Dois Vizinhos through continuous grazing on 6.3 ha, divided into nine paddocks. The treatments were: Alexander grass +100 kg ha-1 of N (N100); Alexander grass + 100 kg ha-1 of N + 0.5 kg per 100 kg of weight live supplementation of wheat bran (N100S); and Alexander grass +200 kg ha-1 of N (N200), with an average herbage allowance of 10% for all treatments. Crossbred and non-castrated steers with an average weight of 276 +/- 41 kg were used for 107 days. The crude protein from entire plant differed (P < 0.05) between treatments, with the greater value (14.8%) occurring in the N200, and the lesser value (13.3%) occurring in the N100S. The herbage accumulation rate was greater (P < 0.05) in the N200 (55.7 DM ha-1 d-1) than that in the N100S and N100 (40.0 and 39.7 kg DM ha-1 d-1, respectively). The N100S produced greater (P < 0.05) average daily weight gains (0.815 kg animal day 1) than did the N200 (0.685 kg animal day-1) and N100 treatments (0.727 kg animal day-1). PMID- 28914425 TI - Platelet factor 4 increases bone marrow B cell development and differentiation. AB - Platelet factor 4 (PF4) is a megakaryocyte-/platelet-derived chemokine with diverse functions as a regulator of vascular and immune biology. PF4 has a central role in vessel injury responses, innate immune cell responses, and T helper cell differentiation. We have now discovered that PF4 has a direct role in B cell differentiation in the bone marrow. Mice lacking PF4 (PF4-/- mice) had fewer developing B cells in the bone marrow beginning after the pre-pro-B cell stage of differentiation. In vitro, PF4 increased the differentiation of hematopoietic progenitors to B cell lineage cells, indicating that PF4 has a direct effect on B cell differentiation. STAT5 activation is essential in early B cell development and PF4 increased the phosphorylation of STAT5. Taken together, these data demonstrate that PF4 has an important role in increasing B cell differentiation in the bone marrow environment. PMID- 28914424 TI - New perspectives in nanotherapeutics for chronic respiratory diseases. AB - According to the World Health Organization (WHO), hundreds of millions of people of all ages and in all countries suffer from chronic respiratory diseases, with particular negative consequences such as poor health-related quality of life, impaired work productivity, and limitations in the activities of daily living. Chronic obstructive pulmonary disease, asthma, occupational lung diseases (such as silicosis), cystic fibrosis, and pulmonary arterial hypertension are the most common of these diseases, and none of them are curable with current therapies. The advent of nanotechnology holds great therapeutic promise for respiratory conditions, because non-viral vectors are able to overcome the mucus and lung remodeling barriers, increasing pharmacologic and therapeutic potency. It has been demonstrated that the extent of pulmonary nanoparticle uptake depends not only on the physical and chemical features of nanoparticles themselves, but also on the health status of the organism; thus, the huge diversity in nanotechnology could revolutionize medicine, but safety assessment is a challenging task. Within this context, the present review discusses some of the major new perspectives in nanotherapeutics for lung disease and highlights some of the most recent studies in the field. PMID- 28914426 TI - Resistance training status modifies inflammatory response to explosive and hypertrophic resistance exercise bouts. AB - The purpose of the present study was to examine the immediate and prolonged immune response in circulating cytokine and adipocytokine concentrations after two different resistance exercise bouts: hypertrophic (HYP1, 5 * 10, 80% of 1RM) and maximal explosive (POW1, 10 * 5, 60% of 1RM) resistance exercise bouts and how 12 weeks of resistance training (RT) modifies these responses (HYP2, POW2). Eight men completed the study. RE-induced interleukin-6 (IL-6), interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1ra), monocyte-chemoattractant protein-1 (MCP-1), leptin, resistin, and adiponectin were measured before (PRE) and immediately (POST0), 24 (POST24) and 48 (POST48) hours after RE bouts before and after RT. In the untrained state, IL-6 increased immediately after RE in HYP1 (p = 0.002) and in POW1 (p = 0.003) whereas no changes were observed after RT. Similar results were observed in IL-1beta, whereas conversely, IL-1ra increased only after RT in HYP2 and POW2 (p < 0.05). Resistin increased before RT in HYP1 and in POW1 (p = 0.011 and p = 0.003, respectively), but after RT, significant responses were not observed. Interestingly, in HYP2, MCP-1 increased significantly at POST24 (p = 0.009) and at POST48 (p = 0.032) only following RT. The present study shows that RT modifies RE-induced cytokine responses towards an anti-inflammatory direction. PMID- 28914427 TI - The clinical and genetic Spectrum of Maroteaux-Lamy syndrome (Mucopolysaccharidosis VI) in the Eastern Province of Saudi Arabia. AB - Mucopolysaccharidosis (MPS VI) or Maroteaux-Lamy syndrome is an autosomal recessive lysosomal storage disease caused by deficiency of the enzyme N acetylgalactosamine 4-sulfatase or arylsulfatase B. It is involved in the degradation of glycosaminoglycans and characterized by a wide spectrum of clinical and genetic heterogeneity. So far, more than 150 mutations have been reported in the ARSB gene. Most of these mutations are either novel, private, or compound heterozygous making phenotype-genotype correlation as well as population screening difficult. The aim of our study is to determine the genotypes and phenotypes of MPS VI among the Saudi population at the Eastern Province of Saudi Arabia. The clinical data of all the patients seen and diagnosed with MPS VI (Maroteaux-Lamy syndrome) at the main hospital from January 1, 1983, to December 31, 2016, were reviewed. A total of 18 patients from 6 unrelated consanguineous families (first-cousin parents) were diagnosed with MPS VI during the defined 33 years. All of the affected patients displayed the severe phenotype of MPS VI. Only one genotype (c.753C > Gp.Y251X) was identified among five of the studied families. All of those families were inhabitants of Al-Hofuf area, but they descended from different clans. A second genotype (c270_274del5bp pc.91Afs*34) was detected in a single family who had originated from Abha area (the southern west region of the country). This report demonstrated the homogeneity for both phenotype and genotype of our studied patients with MPS VI. This may eventually make selective asymptomatic carrier test and newborn screening highly feasible in this region of country. PMID- 28914430 TI - Position paper: recommendations for a digital mammography quality assurance program V4.0. AB - In 2001 the ACPSEM published a position paper on quality assurance in screen film mammography which was subsequently adopted as a basis for the quality assurance programs of both the Royal Australian and New Zealand College of Radiologists (RANZCR) and of BreastScreen Australia. Since then the clinical implementation of digital mammography has been realised and it has become evident that existing screen-film protocols were not appropriate to assure the required image quality needed for reliable diagnosis or to address the new dose implications resulting from digital technology. In addition, the advantages and responsibilities inherent in teleradiology are most critical in mammography and also need to be addressed. The current document is the result of a review of current overseas practice and local experience in these areas. At this time the technology of digital imaging is undergoing significant development and there is still a lack of full international consensus about some of the detailed quality control (QC) tests that should be included in quality assurance (QA) programs. This document describes the current status in digital mammography QA and recommends test procedures that may be suitable in the Australasian environment. For completeness, this document also includes a review of the QA programs required for the various types of digital biopsy units used in mammography. In the future, international harmonisation of digital quality assurance in mammography and changes in the technology may require a review of this document. Version 2.0 represented the first of these updates and key changes related to image quality evaluation, ghost image evaluation and interpretation of signal to noise ratio measurements. In Version 3.0 some significant changes, made in light of further experience gained in testing digital mammography equipment were introduced. In Version 4.0, further changes have been made, most notably digital breast tomosynthesis (DBT) testing and QC have been addressed. Some additional testing for conventional projection imaging has been added in order that sites may have the capability to undertake dose surveys to confirm compliance with diagnostic reference levels (DRLs) that may be established at the National or State level. A key recommendation is that dosimetry calculations are now to be undertaken using the methodology of Dance et al. Some minor changes to existing facility QC tests have been made to ensure the suggested procedures align with those most recently adopted by the Royal Australian and New Zealand College of Radiologists and BreastScreen Australia. Future updates of this document may be provided as deemed necessary in electronic format on the ACPSEM's website ( https://www.acpsem.org.au/whatacpsemdoes/standards-position-papers and see also http://www.ranzcr.edu.au/quality-a-safety/radiology/practice-quality activities/mqap ). PMID- 28914429 TI - A Systematic Review of Patient and Caregiver Experiences with a Tracheostomy. AB - BACKGROUND: A tracheostomy is a surgically created opening through the anterior neck tissues and the trachea, into which a tube is inserted. Despite its influence on basic human needs such as respiration, communication and nutrition, little is known about the impact of tracheostomy on patients and their caregivers or what could be done to enable better care and quality of life (QoL) for these individuals. OBJECTIVE: The aim of this review was to better understand the current knowledge related to the experience and QoL of adults living with a tracheostomy and their caregivers so as to be able to improve these experiences. METHOD: A systematic review of the English-language, peer-reviewed literature was conducted in PubMed, Scopus, PsychINFO, Google Scholar, and CINAHL databases. Articles were eligible if they included adult patient or lay caregiver-reported experiences of tracheostomy. RESULTS: Overall, 1080 articles were identified and 17 eligible for inclusion. Fourteen articles reported on experiences of tracheostomy patients, while three focused on those of their caregivers. Studies were conducted in the home setting (n = 5), on a hospital ward (n = 4), in an intensive care unit (n = 3), in an outpatient clinic (n = 3), in a rehab facility (n = 1), and online (n = 1). Patients and their caregivers reported a range of mostly negative experiences related to the care, support, and management of a tracheostomy, speech and communication, wellbeing and QoL, disfigurement and body image, and stigma and social withdrawal. CONCLUSION: Few studies have published data on the patient and caregiver experiences with tracheostomy, especially in the community setting. There is a need to better understand these experiences in order to be able to formulate strategies and provide resources to improve the quality of care and overall QoL of patients with a tracheostomy and their caregivers in-hospital and in the community. PMID- 28914431 TI - A rare disorder or not? How a child with jaundice changed a nationwide regimen in the Netherlands. AB - Due to global migration, there is an increased frequency of diseases, which used to be rare in Western countries. Here, we describe a striking case in order to create awareness for diseases that are known for decades but sometimes "forgotten" in Western countries, including glucose-6-phosphate dehydrogenase deficiency. We will discuss how everyday practice can lead to serious medical problems and present general recommendations to support. PMID- 28914428 TI - Anhydroecgonine Methyl Ester (AEME), a Product of Cocaine Pyrolysis, Impairs Spatial Working Memory and Induces Striatal Oxidative Stress in Rats. AB - When burning crack cocaine, the pyrolysis of cocaine generates anhydroecgonine methyl ester (AEME). AEME has been shown to be highly neurotoxic but its effects on cognitive function and oxidative stress are still unknown. Thus, this study investigated the effects of AEME on spatial working memory and on parameters of oxidative stress in the prefrontal cortex, hippocampus, and striatum. First, 18 well-trained rats in 8-arm radial maze (8-RM) procedures received acute intracerebroventricular (icv) administration of AEME at doses of 10, 32, or 100 MUg or saline (SAL) in a counterbalanced order and were tested 5 min later in 1-h delayed tasks in the 8-RM. Secondly, separated animals received acute icv administration of AEME at doses of 10 (n = 5), 32 (n = 5), or 100 MUg (n = 5) or SAL (n = 5) for analysis of advanced oxidation protein products, thiobarbituric acid, catalase, glutathione peroxidase, and superoxide dismutase. A higher number of errors were seen in the 1-h post-delay performance after AEME 32 MUg and AEME 100 MUg when compared to SAL. In the striatum, animals receiving AEME 100 MUg icv showed increased advanced oxidation protein products levels when compared to 10 MUg, and also showed increased activity of glutathione peroxidase enzyme when compared to SAL but also comparing to AEME 32 MUg and AEME 10 MUg. These results showed that AEME impairs long-term spatial working memory and also induces greater protein oxidation and increased levels of antioxidant enzymes in the striatum. PMID- 28914432 TI - Relationship between the peroxidation of leukocytes index ratio and a functional mathematical index including uric acid levels and health-related habits: a pilot study. PMID- 28914433 TI - Platelet transfusion refractoriness after T-cell-replete haploidentical transplantation is associated with inferior clinical outcomes. AB - Haploidentical stem cell transplantation (haplo-SCT) has been an alternative source of bone marrow for patients without human leukocyte antigen (HLA)-matched donors. The aim of this study was to investigate the relationships between platelet transfusion refractoriness (PTR) and clinical outcomes in the setting of haplo-SCT. Between May 2012 and March 2014, 345 patients who underwent unmanipulated haplo-SCT were retrospectively enrolled. PTR occurred in 20.6% of all patients. Patients in the PTR group experienced higher transplant-related mortality (TRM, 43.7% vs. 13.5%, P<0.001), lower overall survival (OS, 47.9% vs. 76.3%, P<0.001) and lower leukemia-free survival (LFS, 47.9% vs. 72.3%, P<0.001) compared to patients in the non-PTR group. The multivariate analysis showed that PTR was associated with TRM (P=0.002), LFS (P<0.001), and OS (P<0.001). The cumulative incidences of PTR in patients receiving >12 platelet (PLT) transfusions (third quartile of PLT transfusions) were higher than in patients receiving either >6 (second quartile) or >3 (first quartile) PLT transfusions (56.1% vs. 41.6% vs. 28.2%, respectively; P<0.001). The multivariate analysis also showed that PTR was associated with the number of PLT transfusions (P<0.001). PTR could predict poor transplant outcomes in patients who underwent haploidentical SCT. PMID- 28914434 TI - Human infection with a further evolved avian H9N2 influenza A virus in Sichuan, China. PMID- 28914435 TI - Combination Therapy of Tacrolimus and Chinese Herb Medicated Bath in Children with Inverse Psoriasis. PMID- 28914436 TI - Chinese and Indian women's experience with alternative medications for menopause related symptoms: A qualitative analysis. AB - OBJECTIVE: To explore women's rationalization for using alternative medications, their experience and view on safety of long-term use. METHODS: Two focus group discussions, involving 5 participants each for Chinese and Indian groups, were conducted separately. Participant's personal information was collected anonymously. The discussion covered 5 areas: determinants for taking medications; reason for choosing alternative medications rather than hormone replacement therapy (HRT); how these medications help them; their view on cost-effectiveness and concerns over long-term use. The discussions were audio-taped, transcribed and analyzed. RESULTS: Chinese participants took supplements for controlling symptoms while Indian participants used herbs as a preventive measure during menopause according to their tradition. Women of both groups mentioned that they did not take HRT because of fear of side effects. Chinese group mentioned that medications remarkably improved their symptoms whereas Indian participants appreciated their herbals more for improvement in general wellbeing than for specific symptoms. All members agreed that using alternative medication was cost effective. Both Chinese and Indian participants were quite confident in saying that long-term use will not be associated with any side effects. However, Indian group emphasized that proper preparation of herbal compound using different types of leaves, is essential in order to avoid untoward effects. CONCLUSIONS: Chinese and Indian women used alternative medicine in prevention and treatment of menopause-related problems even as they were avoiding HRT because of the fear of side effects. They believed that their supplements were effective, safe and cost beneficial even with long-term use. PMID- 28914437 TI - Salutary potential of ethanolic extract of avocado fruit on anomalous carbohydrate metabolic key enzymes in hepatic and renal tissues of hyperglycaemic albino rats. AB - OBJECTIVE: To assess the beneficial potential of ethanolic extract of avocado fruit on abnormal carbohydrate metabolic key enzymes in hepatic and renal tissues in streptozotocin (STZ) induced hyperglycemic albino rats. METHODS: Twenty-four male albino rats were randomly divided into four groups with six in each group by simple random sampling method. Group 1 as control rats; Group 2 as STZ induced diabetic rats; Group 3 as diabetic rats treated with avocado fruit extract (AFE), 300 mg/kg as aqueous suspension orally for 30 days; Group 4 as diabetic rats treated with gliclazide (5 mg/kg) in aqueous solution orally for 30 days. The rats were fasted overnight and sacrificed by cervical dislocation and the blood was collected for various biochemical analysis and excision of hepatic and kidney were done for histological analysis. Levels of fasting blood glucose, plasma insulin and glycosylated hemoglobin were estimated. The activities of key enzymes in carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6- phosphatase, fructose-1, 6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase were assayed by standard methods described in the methodology. RESULTS: Oral administration of AFE significantly improved the altered levels of blood glucose, plasma insulin, glycosylated hemoglobin, and modulated the activities of carbohydrate metabolizing enzymes (P<0.05, respectively). The glycogen content in hepatic tissues was significantly increased in diabetic rats treated with AFE (P<0.05, respectively). CONCLUSION: AFE plays a pivotal role to maintain normoglycemia in diabetes by modulating the activities of carbohydrate metabolic enzymes. PMID- 28914438 TI - Antihypercholesterolemic, antioxidant and renal protective effects of Mengkudu (Rubiaceae) fruit in nephropathy-induced albino rats. AB - OBJECTIVE: To assess the modulatory impact of alcoholic extract of fruit of Mengkudu (AEFM, Morinda citrifolia L., Rubiaceae) on renal oxido-lipidemic stress in hypercholesterolemic albino rats. METHODS: Twenty-four male albino rats were randomly divided into four groups with six rats in each group: group I as control, group II fed with hypercholesterolemic diet (HCD) for 45 days (4% cholesterol and 1% cholic acid), Group III rats fed with HCD for 45 days + AEFM (300 mg/kg body weight/day orally) for last 30 days and group IV normal rats fed AEFM alone. The blood was collected using ethylenediamine tetraacetic acid (EDTA) as an anticoagulant for various biochemical analysis, and excision of kidney was done for histological analysis. RESULTS: The levels of total cholesterol (TC), triacylglycerol (TG), phospholipids (PLs), renal functional parameters and lipid peroxidation products were markedly mitigated in AEFM treated hypercholesterolemic rats (group III) compared to group I (P<0.01). Activities of both enzymic and non-enzymic free radical scavenging factors were significantly increased in group III compared to group I (P<0.01). In group III the mRNA levels of interstitial endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) genes were obviously up-regulated (P<0.01) and down regulated in (P<0.05) compared with group I. Histomorphological observations also exhibited similar as in group III AEFM commendably protects the renal tissues compared with group I (P<0.01). CONCLUSION: AEFM can act as nephroprotective agent by attenuating the renal oxidative stress, lipid levels as well as regulating NOS level and by this means protects the kidney in hypercholesterolemic induced nephropathy experimental rats. PMID- 28914439 TI - Dampness-Heat Accelerates DMBA-Induced Mammary Tumors in Rats. AB - OBJECTIVE: To investigate the impact of dampness-heat (DH) on the development of mammary tumors in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rats. METHODS: Forty rats were randomly divided into 3 groups in a randomized block design, including the control group (n=13), DMBA group (n=14), and DMBA plus DH group (n=13). Rats in the DMBA group and DMBA plus DH group were intragastrically administrated with DMBA (100 mg/kg) for twice, once per week, while rats in the control group were treated with equivalent volumes of sesame oil. After DMBA administration, rats in the DMBA plus DH group were exposed to a simulated climate chamber with ambient temperature (33.0+/-0.5 degrees C) and humidity (90%+/-5%) for 8 weeks, 8 h per day. The body weight, time of tumor formation, and number of tumors were measured weekly to calculate tumor incidence, average latency period, average number of tumors, and average tumor weight. At the end of the experiment, the levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) in serum, and the contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta in serum and tumor tissue were measured, respectively. Some tumor tissues were processed for hematoxylin-eosin staining to determine the histopathological changes. RESULTS: Compared with DMBA, DMBA plus DH significantly increased the average number of tumors, average tumor weight, levels of serum MMP-9, TIMP-1, TNF-alpha and IL 1beta, and contents of tumor tissue TNF-alpha and IL-1beta (P<0.05 or P<0.01). CONCLUSION: DH could accelerate the development of mammary tumors through increasing the expressions of MMP-9, TIMP-1, TNF-alpha and IL-1beta in DMBA induced rats. PMID- 28914440 TI - Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Care Excellence Single Technology Appraisal. AB - The manufacturer of olaratumab (Lartruvo(r)), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were L46,076 and L47,127 per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of L50,000 per QALY gained, applicable to end-of-life treatments, was 0.54. The respective ICERs from the ERG's analysis were approximately L60,000/QALY gained, and the probability of the treatment being cost effective was 0.21. In August 2017, the NICE Appraisal Committee recommended olaratumab in combination with doxorubicin for this indication for use via the UK Cancer Drugs Fund under the agreed CAA until further evidence being collected in the ongoing phase III trial-ANNOUNCE becomes available in December 2020. PMID- 28914441 TI - Do children grow into cerebral palsy? PMID- 28914442 TI - Evaluating treatment options for spasticity. PMID- 28914443 TI - Indirect effects of larval dispersal following mass mortality events. PMID- 28914444 TI - Studies on cyanobacterial protein PipY shed light on structure, potential functions, and vitamin B6 -dependent epilepsy. AB - The Synechococcus elongatus COG0325 gene pipY functionally interacts with the nitrogen regulatory gene pipX. As a first step toward a molecular understanding of such interactions, we characterized PipY. This 221-residue protein is monomeric and hosts pyridoxal phosphate (PLP), binding it with limited affinity and losing it upon incubation with D-cycloserine. PipY crystal structures with and without PLP reveal a single-domain monomer folded as the TIM barrel of type III fold PLP enzymes, with PLP highly exposed, fitting a role for PipY in PLP homeostasis. The mobile PLP phosphate-anchoring C-terminal helix might act as a trigger for PLP exchange. Exploiting the universality of COG0325 functions, we used PipY in site-directed mutagenesis studies to shed light on disease causation by epilepsy-associated mutations in the human COG0325 gene PROSC. PMID- 28914445 TI - The prevalence of mental health disorders and symptoms in children and adolescents with cerebral palsy: a systematic review and meta-analysis. AB - AIM: Mental health conditions and problems are often reported in children and adolescents with cerebral palsy (CP). A systematic review was undertaken to describe their prevalence. METHOD: MEDLINE and PsycINFO databases from 1996 to 2016 were searched and reference lists of selected studies were reviewed. Studies were included if they reported point prevalence of mental health diagnoses or symptoms in a general population of children and/or adolescents with CP. Pooled prevalence for mental health symptoms was determined using a random effects meta analysis. RESULTS: Of the 3158 studies identified, eight met the inclusion criteria. Mental health disorders were diagnosed by psychiatric interview in one study, giving a prevalence of 57% (32 out of 56 children). The remaining seven studies (n=1715 children) used parent-report mental health screening tools. The pooled prevalence for mental health symptoms using the Strengths and Difficulties Questionnaire (n=5 studies) was 35% (95% confidence interval [CI] 20-61) and using the Child Behavior Checklist (n=2 studies) was 28% (95% CI 22-36). Evidence was characterized by a moderate level of bias. INTERPRETATION: More studies are needed to ascertain the prevalence of mental health disorders. Mental health symptoms are common and mental health evaluations should be incorporated into multidisciplinary assessments for these children. WHAT THIS PAPER ADDS: Children with cerebral palsy and intellectual disability have a higher risk of mental health symptoms. The prevalence of mental health symptoms for age and severity groups is unclear. PMID- 28914447 TI - Are brown trout Salmo trutta fario and rainbow trout Oncorhynchus mykiss two of a kind? A comparative study of salmonids to temperature-influenced Tetracapsuloides bryosalmonae infection. AB - Proliferative kidney disease (PKD) of salmonids caused by Tetracapsuloides bryosalmonae causes high mortalities of wild brown trout (Salmo trutta fario) and farmed rainbow trout (Oncorhynchus mykiss) at elevated water temperatures. Here the aim was to compare the temperature-dependent modulation of T. bryosalmonae in the two salmonid host species, which display different temperature optima. We used a novel experimental set-up in which we exposed brown trout and rainbow trout to an identical quantified low concentration of T. bryosalmonae for a short time period (1 hr). We followed the development of the parasite in the fish hosts for 70 days. PKD prevalence and parasite kinetics were assessed using qPCR. Exposures were performed at temperatures (12 degrees C and 15 degrees C) that reflect an environmental scenario that may occur in the natural habitat of salmonids. T. bryosalmonae infection was confirmed earliest in brown trout kept at 15 degrees C (day 7 post-exposure) while, in all other groups, T. bryosalmonae was not confirmed until day 15 post-exposure. Moreover, significantly greater infection prevalence and a faster increase of parasite intensity were observed in brown trout kept at 15 degrees C than in all other groups. These results indicate that PKD is differentially modulated by water temperature in related host species. PMID- 28914446 TI - Risk factors for thiopurine-induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype. AB - BACKGROUND: Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases. AIM: To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections. METHODS: Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 * 109 /L and infections were classified according to the Common Terminology Criteria for Adverse Events. RESULTS: Sixty hundred and ninety-five patients (90.6%) included in the TOPIC trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P < .01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P < .01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P = .01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P = .02]). CONCLUSIONS: Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant. PMID- 28914448 TI - Significant burden of nonalcoholic fatty liver disease with advanced fibrosis in the US: a cross-sectional analysis of 2011-2014 National Health and Nutrition Examination Survey. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in the US. Understanding the epidemiology of NAFLD, with specific focus on individuals with hepatic fibrosis is important to guide healthcare resource planning. AIM: To evaluate prevalence and predictors of hepatic fibrosis among US adults with NAFLD. METHODS: We performed a cross sectional study using data from the updated 2011-2014 National Health and Nutrition Examination Survey, a national, stratified, multistage sampling survey of non-institutionalised US adults age >= 20. METAVIR F2 or greater fibrosis among individuals with NAFLD was assessed using AST to Platelet Ratio Index (APRI) score > 0.7. METAVIR F3 or greater fibrosis was assessed using NAFLD fibrosis score (NFS) > 0.676 and FIB-4 score > 3.25. Multivariate logistic regression models evaluated for predictors of fibrosis among individuals with NAFLD. RESULTS: Overall prevalence of NAFLD among US adults was 21.9% (95% CI 20.6-23.3), representing 51.6 million adults. Among individuals with NAFLD, we observed a 23.8% prevalence of >=F2 fibrosis, representing 12.2 million individuals, and we observed a 2.3%-9.7% prevalence of >=F3 fibrosis, representing as many as 5.0 million adults. On multivariate regression analyses, increasing age, obesity and concurrent diabetes mellitus were associated with increased risk of >=F3 fibrosis. CONCLUSIONS: NAFLD represents a major healthcare burden among US adults with as many as 5 million adults estimated to have NAFLD with >=F3 fibrosis. Age and the components of the metabolic syndrome are independently associated with higher risk of fibrosis. PMID- 28914449 TI - Insights on the stilbenes in Raboso Piave grape (Vitis vinifera L.) as a consequence of postharvest vs on-vine dehydration. AB - BACKGROUND: Grape withering is a process used to produce reinforced wines and raisins. Dehydration is usually carried out postharvest by keeping ripe grapes in special warehouses in controlled conditions of temperature, relative humidity (RH) and air flow. Alternatively, grape clusters can be left on the vines after the canes have been pruned. In general, dehydration increases stilbenes in grape, but there are few studies on the effects of on-vine withering. The stilbene profiles of Raboso Piave grape during postharvest and on-vine dehydration were studied here. RESULTS: High-resolution mass spectrometry (MS) was used to identify 19 stilbenes, including resveratrol monomers, dimers (viniferins), oligomers and glucoside derivatives. The two dehydration methods generally had different effects on the above nutraceuticals in grape. The samples kept in warehouses revealed significant increases in Z-omega-viniferin, E-epsilon viniferin, delta-viniferin and another resveratrol dimer which were not observed in the plants. Trans-Resveratrol increased significantly only in samples dehydrated in the warehouse at 21 degrees C and 60-70% RH. CONCLUSION: The findings increase knowledge of stilbene composition in grapes subjected to withering on-vine. The choice of dehydration method affects the contents of these nutraceuticals in the grape and consequently in wines. Reasonably, it could also affect other secondary metabolites important for wine quality. (c) 2017 Society of Chemical Industry. PMID- 28914450 TI - Changes in composition and content of food-derived peptide in human blood after daily ingestion of collagen hydrolysate for 4 weeks. AB - BACKGROUND: Daily ingestion of collagen hydrolysate for a long period improves skin and joint conditions. It has been speculated that the beneficial effects are exerted by food-derived hydroxyproline (Hyp) peptides, which are detected in human blood after single ingestions. In the present study, to investigate the effect of long-term ingestion of collagen hydrolysate on Hyp peptides profile in blood, the concentrations of Hyp-peptides in human blood before and after daily ingestion for a long period were examined. RESULTS: Hyp-peptides increased to a maximum level at 1 h after ingestion and reverted to their initial levels within 24 h during experimental period. Pro-Gly and Hyp-peptides such as Pro-Hyp-Gly, Pro-Hyp, Ile-Hyp, Leu-Hyp, Hyp-Gly, Glu-Hyp and Ala-Hyp were identified in the blood after ingestion of collagen hydrolysate at 4.5 g day-1 for 4 weeks. For the whole period, Pro-Hyp was the leading compound. The compositional rate of Hyp-Gly showed a tendency to increase, while that of Pro-Hyp tended to decrease after daily ingestion. CONCLUSION: The present results indicate that daily ingestion of collagen hydrolysate for a long period can change compositional rate of Hyp peptides in human blood. This fact suggests that long-term ingestion of collagen hydrolysate might change exo- or endo-type protease activity in the digestive tract, which may consequently promote beneficial effects. (c) 2017 Society of Chemical Industry. PMID- 28914451 TI - Pilomatrix carcinoma: 12-year experience and review of the literature. AB - Pilomatrix carcinoma is a rare, locally aggressive tumor with a tendency to recur. Distant metastases have been reported, with pulmonary lesions being the most frequent manifestation. Similar to pilomatrixoma, pilomatrix carcinoma typically presents as a nontender, firm dermal swelling and is found most commonly in the head and neck region. Although pilomatrixomas and pilomatrix carcinoma are well-recognized lesions, clinically they are frequently misdiagnosed as other skin conditions. By reviewing the literature over the past 10 years, the aims of this review are to analyze the cause, clinical presentation, histopathologic features, management and outcomes of pilomatrix carcinoma amongst children and adults. PMID- 28914452 TI - Comparative evaluation of MCP gene in worldwide strains of Megalocytivirus (Iridoviridae family) for early diagnostic marker. AB - Members of the Iridoviridae family have been considered as aetiological agents of iridovirus diseases, causing fish mortalities and economic losses all over the world. Virus identification based on candidate gene sequencing is faster, more accurate and more reliable than other traditional phenotype methodologies. Iridoviridae viruses are covered by a protein shell (capsid) encoded by the important candidate gene, major capsid protein (MCP). In this study, we investigated the potential of the MCP gene for use in the diagnosis and identification of infections caused Megalocytivirus of the Iridoviridae family. We selected data of 66 Iridoviridae family isolates (53 strains of Megalocytivirus, eight strains of iridoviruses and five strains of Ranavirus) infecting various species of fish distributed all over the world. A total of 53 strains of Megalocytivirus were used for designing the complete primer sets for identifying the most hypervariable region of the MCP gene. Further, our in silico analysis of 102 sequences of related and unrelated viruses reconfirms that primer sets could identify strains more specifically and offers a useful and fast alternative for routine clinical laboratory testing. Our findings suggest that phenotype observation along with diagnosis using universal primer sets can help detect infection or carriers at an early stage. PMID- 28914453 TI - Potential effectiveness of visible and near infrared spectroscopy coupled with wavelength selection for real time grapevine leaf water status measurement. AB - BACKGROUND: Increasing attention is being paid to non-destructive methods for water status real time monitoring as a potential solution to replace the tedious conventional techniques which are time consuming and not easy to perform directly in the field. The objective of this study was to test the potential effectiveness of two portable optical devices (visible/near infrared (vis/NIR) and near infrared (NIR) spectrophotometers) for the rapid and non-destructive evaluation of the water status of grapevine leaves. Moreover, a variable selection methodology was proposed to determine a set of candidate variables for the prediction of water potential (Psi, MPa) related to leaf water status in view of a simplified optical device. RESULTS: The statistics of the partial least square (PLS) models showed in validation R2 between 0.67 and 0.77 for models arising from vis/NIR spectra, and R2 ranged from 0.77 to 0.85 for the NIR region. The overall performance of the multiple linear regression (MLR) models from selected wavelengths was slightly worse than that of the PLS models. Regarding the NIR range, acceptable MLR models were obtained only using 14 effective variables (R2 range 0.63-0.69). CONCLUSION: To address the market demand for portable optical devices and heading towards the trend of miniaturization and low cost of the devices, individual wavelengths could be useful for the design of a simplified and low-cost handheld system providing useful information for better irrigation scheduling. (c) 2017 Society of Chemical Industry. PMID- 28914454 TI - Optimization of protein recovery from bovine lung by pH shift process using response surface methodology. AB - BACKGROUND: Response surface methodology (RSM) was used in a sequential manner to optimize solubilization and precipitation conditions in the recovery of protein from bovine lung using pH shift. RESULTS: Separate D-optimal designs were employed for protein solubilization and precipitation. Independent variables investigated for protein solubilization were time (10-120 min), temperature (4-20 degrees C), pH (8.0-11.0) and solvent/sample ratio (2.5-10). Variables for protein precipitation were time (0-60 min) and pH (4.25-6.00). Soluble protein yields ranged from 323 to 649 g kg-1 and the quadratic model for protein solubilization revealed a coefficient of determination R2 of 0.9958. Optimal conditions for maximum protein solubility were extraction time 140 min, temperature 19 degrees C, pH 10.8 and solvent/sample ratio 13.02. Protein precipitation yields varied from 407 to 667 g kg-1 , giving a coefficient of determination R2 of 0.9335. Optimal conditions for maximum protein precipitation were pH 5.03 and 60 min. Based on the RSM model, solubilization conditions were manipulated to maximize protein solubilization under reduced water and alkaline usage. These conditions were also validated. CONCLUSION: Models for solubilization and precipitation using bovine and porcine lung were validated; predicted and actual yields were in good agreement, showing cross-species applicability of the results. (c) 2017 Society of Chemical Industry. PMID- 28914455 TI - Using probiotics to prevent necrotising enterocolitis. PMID- 28914456 TI - Ovarian structure and oogenesis of the extremophile viviparous teleost Poecilia mexicana (Poeciliidae) from an active sulfur spring cave in Southern Mexico. AB - The structure of the ovary and oogenesis of Poecilia mexicana from an active sulfur spring cave is documented. Poecilia mexicana is the only poeciliid adapted to a subterranean environment with high hydrogen sulfide levels and extreme hypoxic conditions. Twenty females were captured throughout one year at Cueva del Azufre, located in the State of Tabasco in Southern Mexico. Ovaries were processed with histological techniques. P. mexicana has a single, ovoid ovary with ovigerous lamella that project to the ovarian lumen. The ovarian wall presents abundant loose connective tissue, numerous melanomacrophage centers and large blood vessels, possibly associated with hypoxic conditions. The germinal epithelium bordering the ovarian lumen contains somatic and germ cells forming cell nests projecting into the stroma. P. mexicana stores sperm in ovarian folds associated with follicles at different developmental phases. Oogenesis in P. mexicana consisted of the following stages: (i) oogonial proliferation, (ii) chromatin nucleolus, (iii) primary growth, subdivided into: (a) one nucleolus, (b) multiple nucleoli, (c) droplet oils-cortical alveoli steps; (iv) secondary growth, subdivided in: (a) early secondary growth, (b) late secondary growth, and (c) full grown. Follicular atresia was present in all stages of follicular development; it was characterized by oocyte degeneration, where follicle cells hypertrophy and differentiate in phagocytes. The ovary and oogenesis are similar to these seen in other poeciliids, but we found frequent atretic follicles, melanomacrophage centers, reduced fecundity and increased of offspring size. PMID- 28914457 TI - Gross brain morphology of the armoured catfish Rineloricaria heteroptera, Isbrucker and Nijssen (1976), (Siluriformes: Loricariidae: Loricariinae): A descriptive and quantitative approach. AB - The gross morphology of the brain of Rineloricaria heteroptera and its relation to the sensory/behavioural ecology of the species is described and discussed. The sexual and ontogenetic intraspecific variation in the whole brain length and mass, as well as within/between the eight different brain subdivisions volumes, is also examined and discussed. Negative allometry for the whole brain length/mass and relative growth of the telencephalon and optic tecta was observed. Positive allometry was observed for the relative growth of the olfactory bulbs and medulla oblongata. Univariate and multivariate statistical analyses did not reveal significant differences in the brain subdivision growth rates among sexes and/or developmental stages, except for the optic tectum and some portions of the medulla oblongata, with juveniles and males showing more developed optic tecta and medullary subdivisions, respectively. The growth rates for each brain subdivision were relatively constant, and the slopes of the growth equations were almost parallel, except for those of the olfactory bulbs and medulla oblongata subdivisions, suggesting some degree of tachyauxesis of subdivisions against the entire brain. The corpus cerebelli was the more voluminous brain subdivision in most specimens (principally adults), followed by the optic tectum (the more voluminous subdivision in juveniles), hypothalamus, and telencephalon, in that order. Differences in the number of lamellae and relative size of the olfactory organ were also detected among developmental stages, which were more numerous and larger in adults. Based on these results, it is possible to infer an ontogenetic shift in the habitat/resource use and behaviour of R. heteroptera. Vision, primarily routed through the optic tectum, could be fundamental in early stages, whereas in adults, olfaction and taste, primarily routed through the olfactory bulbs and medulla oblongata, play more important roles. PMID- 28914458 TI - Are men monkeys? Why are child healthcare professionals reluctant to include fathers in parenting support interventions? PMID- 28914459 TI - Testing a biopsychosocial model of the basic birth beliefs. AB - BACKGROUND: Women perceive what birth is even before they are pregnant for the first time. Part of this conceptualization is the basic belief about birth as a medical and natural process. These two separate beliefs are pivotal in the decision-making process about labor and birth. Adapting Engel's biopsychosocial framework, we explored the importance of a wide range of factors which may contribute to these beliefs among first-time mothers. METHOD: This observational study included 413 primiparae >=24 weeks' gestation, recruited in medical centers and in natural birth communities in Israel. The women completed a questionnaire which included the Birth Beliefs Scale and a variety of biopsychosocial characteristics such as obstetric history, birth environment, optimism, health related anxiety, and maternal expectations. RESULTS: Psychological dispositions were more related to the birth beliefs than the social or biomedical factors. Sociodemographic characteristics and birth environment were only marginally related to the birth beliefs. The basic belief that birth is a natural process was positively related to optimism and to conceiving spontaneously. Beliefs that birth is a medical process were related to pessimism, health-related anxiety, and to expectations that an infant's behavior reflects mothering. Expectations about motherhood as being naturally fulfilling were positively related to both beliefs. CONCLUSION: Psychological factors seem to be most influential in the conceptualization of the beliefs. It is important to recognize how women interpret the messages they receive about birth which, together with their obstetric experience, shape their beliefs. Future studies are recommended to understand the evolution of these beliefs, especially within diverse cultures. PMID- 28914460 TI - Structure of supporting elements in the dorsal fin of percid fishes. AB - The dorsal fin is one of the most varied swimming structures in Acanthomorpha, the spiny-finned fishes. This fin can be present as a single contiguous structure supported by bony spines and soft lepidotrichia, or it may be divided into an anterior, spiny dorsal fin and a posterior, soft dorsal fin. The freshwater fish family Percidae exhibits especially great variation in dorsal fin spacing, including fishes with separated fins of varying gap length and fishes with contiguous fins. We hypothesized that fishes with separated dorsal fins, especially those with large gaps between fins, would have stiffened fin elements at the leading edge of the soft dorsal fin to resist hydrodynamic loading during locomotion. For 10 percid species, we measured the spacing between dorsal fins and calculated the second moment of area of selected spines and lepidotrichia from museum specimens. There was no significant relationship between the spacing between dorsal fins and the second moment of area of the leading edge of the soft dorsal fin. PMID- 28914461 TI - From Five to Seven: Ring Expansion of Monoazadiene Titanium Complexes by Insertion of Aldehydes, Ketones and Nitriles. AB - The ring enlargement reactions at ambient temperatures of non C-terminus substituted monoazabutadiene (eta4 -RN=CHCH=CH2 ) titanium complexes 2 are investigated. The insertion of aldehydes/ketones (five examples) and nitriles (four examples) into the Ti-C bonds result in expansion of the five-membered rings to uncommon seven-membered titanacycles 3 and 4 in good yields. These new compounds are fully characterized by NMR spectroscopy and single-crystal X-ray diffraction. In subsequent reactions, the seven-membered ring systems are protolyzed and the released organic fragments are isolated. Whereas the aldehyde/ketone insertion products 3 form substituted delta-amino alcohols 5 after reduction with NaBH3 CN, the nitrile insertion products 4 form substituted pyrroles 6 via cyclization. PMID- 28914462 TI - Specimen mammography distorts margin status in patients undergoing breast conserving surgery for early-stage breast cancer. PMID- 28914463 TI - Burrowing with a kinetic snout in a snake (Elapidae: Aspidelaps scutatus). AB - Of the few elongate, fossorial vertebrates that have been examined for their burrowing mechanics, all were found to use an akinetic, reinforced skull to push into the soil, powered mostly by trunk muscles. Reinforced skulls were considered essential for head-first burrowing. In contrast, I found that the skull of the fossorial shield-nosed cobra (Aspidelaps scutatus) is not reinforced and retains the kinetic potential typical of many non-fossorial snakes. Aspidelaps scutatus burrows using a greatly enlarged rostral scale that is attached to a kinetic snout that is independently mobile with respect to the rest of the skull. Two mechanisms of burrowing are used: (1) anteriorly directed head thrusts from a loosely bent body that is anchored against the walls of the tunnel by friction, and (2) side-to-side shovelling using the head and rostral scale. The premaxilla, to which the rostral scale is attached, lacks any direct muscle attachments. Rostral scale movements are powered by, first, retractions of the palato pterygoid bar, mediated by a ligament that connects the anterior end of the palatine to the transverse process of the premaxilla and, second, by contraction of a previously undescribed muscle slip of the m. retractor pterygoidei that inserts on the skin at the edge of the rostral scale. In derived snakes, palatomaxillary movements are highly conserved and power prey capture and transport behaviors. Aspidelaps scutatus has co-opted those mechanisms for the unrelated function of burrowing without compromising the original feeding functions, showing the potential for evolution of functional innovations in highly conserved systems. PMID- 28914465 TI - Exploring avenues for best use of cytotechnologists in non-gynaecological cytology: Double screening or independent sign-out. AB - OBJECTIVE: Cytotechnologist (CT) screening workload has been decreasing due to the falling number of Papanicolaou tests. This continuing trend has prompted exploration of ways to best employ the CT skillset. One potential way of more effective use is by having two CTs double screen non-gynaecological (NGC) cases to assess whether this improves screening quality and concordance with pathologists. Another is evaluating the CT's performance on low-complexity negative NGC cases for a potential independent CT sign-out without pathologist review. METHODS: In total, 1119 NGC cases were reviewed; 577 screened by two CTs and 542 screened by one CT. All cases were signed out by a pathologist and all CT interpretations were compared to the pathologist final diagnoses. The disagreements were classified based on degree of discrepancy. The extra workload by adding the second screener was assessed. RESULTS: The agreement rate between the CT's screening interpretation and pathologist's interpretation did not improve by adding a second CT compared to a single screener (91.5% vs 92.9%, respectively). CT to pathologist concordance was very high on low complexity NGC cases (voided urine, fluid, sputum) whether screened and interpreted as negative by one CT (97.3%) or two CTs (99.3%). CONCLUSION: Double screening of NGC cases by two cytotechnologists prior to pathologist sign-out does not improve screening quality and is not cost-effective. The high concordance between the CTs and pathologists in this limited group of low complexity negative cases suggests that such cases could be signed out independently by cytotechnologists. PMID- 28914464 TI - Expression of caveolin-1 in the interfollicular but not the follicle-associated epithelial cells in the bursa of fabricius of chickens. AB - The surface epithelium of the bursa of Fabricius consists of interfollicular (IFE) and follicle-associated epithelium (FAE). The IFE comprises (i) cylindrical shaped secretory cells (SC) and (ii) cuboidal basal cells (BCs). The FAE provides histological and two-way functional connections between the bursal lumen and medulla of the follicle. We used a carbon solution and anti-caveolin-1 (Cav-1) to study the endocytic activity of FAE. Carbon particles entered the intercellular space of FAE, but the carbon particles were not internalized by the FAE cells. Cav-1 was not detectable in the FAE cells or the medulla of the bursal follicle. The absence of Cav-1 indicates that no caveolin-mediated endocytosis occurs in the FAE cells, B cells, bursal secretory dendritic cells (BSDC), or reticular epithelial cells. Surprisingly, a significant number of Cav-1 positive cells can be found among the SC, which are designated SC II. Cav-1 negative cell are called SC I, and they produce mucin for lubricating the bursal lumen and duct. Occasionally, BCs also express Cav-1, which suggests that BC is a precursor of a SC. Transmission electron microscopy confirmed the existence of type I and II SC. The SC II are highly polarized and have an extensive trans-Golgi network that is rich in different granules and vesicles. Western blot analysis of bursa lysates revealed a 21-23 kDa compound (caveolin) and Filipin fluorescence histochemistry provided evidence for intracellular cholesterol. High amount of cholesterol in the feces shows the cholesterol efflux from SC II. The presence of Cav-1 and cholesterol in SC II indicates, that the bursa is a complex organ in addition to possessing immunological function contributes to the cholesterol homeostasis in the chickens. PMID- 28914466 TI - Supramolecular Hydro- and Ionogels: A Study of Their Properties and Antibacterial Activity. AB - Diimidazolium-based organic salts, bearing peptides or amino acids as anions have been synthesised and tested for their gelling ability in biocompatible solvents. These low molecular weight salts were successfully used as gelators in phosphate buffered saline (PBS) solution and ionic liquids. Then, the properties of the obtained soft materials were analysed in terms of melting temperature and gel strength as accounted for by rheological investigations. The gel-phase formation was studied by using UV/Vis and resonance light scattering measurements, whereas the morphology of the soft materials was analysed by using polarised optical microscopy and scanning electron microscopy. To get information about the organisation of the gelator in the gelatinous matrix, X-ray diffraction measurements were performed both on the neat gelators and their gels. The results collected show that the properties of the gel phases, like the thermal stability, the self-repairing ability, the resistance to flow as well as the morphology, are dependent on the nature of the anion. Furthermore, bioassays revealed that the obtained diimidazolium organic salts possessed antimicrobial activity, against gram-negative and gram-positive tester strains. In particular and noteworthy, the diimidazolium organic salts exert a bactericidal capability, which was retained even if they are included in the gel phase. Thus, a novel kind of bioactive soft material was obtained that could be fruitfully employed as a non-covalent coating exerting antibacterial capability. PMID- 28914467 TI - Cloning, expression pattern analysis, and subcellular localization of Capra hircus SCD1 gene with production of transgenic mice. AB - This study aimed to clone the Stearoyl-CoA desaturase 1 (SCD1) gene derived from Xuhuai goat (Capra hircus), and analyze the sub-cellular localization in cells and tissues. The cDNA was cloned by reverse transcription polymerase chain reaction (RT-PCR). pEGFP-SCD1 vector was constructed to detect sub-cellular localization and tissue distribution. pEGFP-SCD1 was transfected into NIH-3T3 cells using polyethylene imine (PEI) and observed under fluorescence inversion microscope system 48 h after transfection. The expression level of SCD1 was detected by RT-PCR. Testicular injection was used to produce transgenic mice with goat SCD1 gene. DNA and protein were extracted from the tail tissue of F1 mice. The expression of exogenous gene in the F1 generation was detected in both DNA and protein. The results showed that the coding sequence (CDS) fragments of C. hircus SCD1 gene was 1074 bp and encodes 360 amino acids. RT-PCR results showed that SCD1 could be expressed successfully in NIH-3T3 cells in vitro. Sub-cellular localization analysis showed that pEGFP-SCD1 fusion protein located in the cytoplasm. It can be concluded that transgenic mice with goat SCD1 expressed in sperm and tail tissue was successfully produced in the F1 mice generation. PMID- 28914468 TI - The toxic alpha-gliadin peptide 31-43 enters cells without a surface membrane receptor. AB - Alpha-gliadin peptide 31-43 is considered to be the main peptide responsible for the innate immune response in celiac disease patients. Recent evidence indicates that peptide 31-43 rapidly enters cells and interacts with the early endocytic vesicular compartment. However, the mechanism of its uptake is not completely understood. Our aim is to characterize, isolate and identify possible cell surface proteins involved in peptide 31-43 internalization by Caco-2 cells. In this study, we used a chemical cross-linker to block peptide 31-43 on cell surface proteins, and pulled-down peptide-proteins complexes using antibodies raised against peptide 31-43. Through this experimental approach, we did not observe any specific complex between cell proteins and peptide 31-43 in Coomassie stained denaturating gels or by Western blotting. We also found that type 2 transglutaminase was not necessary for peptide 31-43 internalization, even though it had a regulatory role in the process. Finally, we demonstrated that peptide 31 43 did not behave as a classical ligand, indeed the labeled peptide did not displace the unlabeled peptide in a competitive binding assay. On the basis of these findings and of previous evidence demonstrating that peptide 31-43 is able to interact with a membrane-like environment in vitro, we conclude that membrane composition and organization, rather than a specific receptor protein, may have a major role in peptide 31-43 internalization by cells. PMID- 28914469 TI - Morphology and Spelling in French: A Comparison of At-Risk Readers and Typically Developing Children. AB - We present two studies that examine the role of morphology in French spelling. In Study 1, we examined the concurrent and longitudinal relationships between inflectional awareness and derivational awareness and spelling within a sample of 77 children in a French immersion programme in Canada. Children completed a non verbal reasoning measure and French measures of phonological awareness, word reading, vocabulary, morphological awareness, and spelling. Results showed that inflectional morphological awareness in Grade 3 was a predictor of spelling in the same grade. Inflectional awareness in Grade 2 predicted Grade 3 spelling, controlling for reading-related skills and spelling at Grade 2. These analyses support the role of inflectional morphological awareness in the development of spelling of children of a range of reading and spelling abilities. In contrast, derivational awareness in Grades 2 and 3 did not predict spelling concurrently in both grades respectively. Study 2 contrasted the morphological errors in the spellings of six children at risk for reading difficulties with those of six chronological age-matched and six reading level-matched children. Analyses showed that at-risk children exhibited more difficulties with spelling roots and suffixes in words as compared with their age-matched peers, although they performed similarly to children matched on reading level. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28914470 TI - Selective Electrochemical Reduction of Carbon Dioxide to Ethanol on a Boron- and Nitrogen-Co-doped Nanodiamond. AB - Electrochemical reduction of CO2 to ethanol, a clean and renewable liquid fuel with high heating value, is an attractive strategy for global warming mitigation and resource utilization. However, converting CO2 to ethanol remains great challenge due to the low activity, poor product selectivity and stability of electrocatalysts. Here, the B- and N-co-doped nanodiamond (BND) was reported as an efficient and stable electrode for selective reduction of CO2 to ethanol. Good ethanol selectivity was achieved on the BND with high Faradaic efficiency of 93.2 % (-1.0 V vs. RHE), which overcame the limitation of low selectivity for multicarbon or high heating value fuels. Its superior performance was mainly originated from the synergistic effect of B and N co-doping, high N content and overpotential for hydrogen evolution. The possible pathway for CO2 reduction revealed by DFT computation was CO2 ->*COOH->*CO->*COCO->*COCH2 OH->*CH2 OCH2 OH >CH3 CH2 OH. PMID- 28914471 TI - WASH overexpression enhances cancer stem cell properties and correlates with poor prognosis of esophageal carcinoma. AB - There is increasing evidence that cytoskeleton remodeling is involved in cancer progression. Wiskott-Aldrich syndrome protein (WASP) family represents a key regulator of actin cytoskeleton remodeling. However, the underlying mechanism of the WASP family in cancer progression remains elusive. Here, we studied the role of WASP and SCAR Homolog (WASH), a recently identified WASP family member, in human esophageal squamous cell carcinoma (ESCC). Using three human ESCC cell lines, we found that WASH expression was significantly elevated in cancer stem like cells enriched by sphere formation assay. WASH knockdown decreased the sphere-forming capacity of esophageal cancer cells whereas WASH over-expression exhibited the opposite effect. Mechanistically, we identified interleukin-8 (IL 8) as a key downstream target of WASH. IL-8 knockdown completely attenuated tumor sphere formation induced by WASH overexpression. WASH knockdown also delayed the growth of human ESCC xenografts in BALB/c nude mice. Importantly, high WASH levels were associated with poor clinical prognosis in a total of 145 human ESCC tissues. Collectively, our results suggest an essential role of the WASH/IL-8 pathway in human ESCC by maintaining the stemness of cancer cells. Hence, targeting this pathway might represent a promising strategy to control human esophageal carcinoma. PMID- 28914472 TI - Imitation, Inspiration, and Creation: Cognitive Process of Creative Drawing by Copying Others' Artworks. AB - To investigate the cognitive processes underlying creative inspiration, we tested the extent to which viewing or copying prior examples impacted creative output in art. In Experiment 1, undergraduates made drawings under three conditions: (a) copying an artist's drawing, then producing an original drawing; (b) producing an original drawing without having seen another's work; and (c) copying another artist's work, then reproducing that artist's style independently. We discovered that through copying unfamiliar abstract drawings, participants were able to produce creative drawings qualitatively different from the model drawings. Process analyses suggested that participants' cognitive constraints became relaxed, and new perspectives were formed from copying another's artwork. Experiment 2 showed that exposure to styles of artwork considered unfamiliar facilitated creativity in drawing, while styles considered familiar did not do so. Experiment 3 showed that both copying and thoroughly viewing artwork executed using an unfamiliar style facilitated creativity in drawing, whereas merely thinking about alternative styles of artistic representation did not do so. These experiments revealed that deep encounters with unfamiliar artworks-whether through copying or prolonged observation-change people's cognitive representations of the act of drawing to produce novel artwork. PMID- 28914473 TI - Ethers on Si(001): A Prime Example for the Common Ground between Surface Science and Molecular Organic Chemistry. AB - By using computational chemistry it has been shown that the adsorption of ether molecules on Si(001) under ultrahigh vacuum conditions can be understood with classical concepts of organic chemistry. Detailed analysis of the two-step reaction mechanism-1) formation of a dative bond between the ether oxygen atom and a Lewis acidic surface atom and 2) nucleophilic attack of a nearby Lewis basic surface atom-shows that it mirrors acid-catalyzed ether cleavage in solution. The O-Si dative bond is the strongest of its kind, and the reactivity in step 2 defies the Bell-Evans-Polanyi principle. Electron rearrangement during C-O bond cleavage has been visualized with a newly developed method for analyzing bonding, which shows that the mechanism of nucleophilic substitutions on semiconductor surfaces is identical to molecular SN 2 reactions. Our findings illustrate how surface science and molecular chemistry can mutually benefit from each other and unexpected insight can be gained. PMID- 28914474 TI - Determination of net energy content of soybean oil fed to growing pigs using indirect calorimetry. AB - The objectives of this experiment were: (i) to determine the net energy (NE) of soybean oil (SBO) fed to growing pigs using indirect calorimetry (IC); and (ii) to evaluate the effects of inclusion rate of SBO on heat production, oxidative status and nutrient digestibility in growing pigs. Eighteen growing barrows were allotted to three diets based on completely randomized design with six replicate pigs (period) per diet. Diets included a corn-soybean meal basal diet and two test diets containing 5% or 10% SBO at the expense of corn and soybean meal. During each period, pigs were individually housed in metabolism crates for 14 days, including 7 days to adapt to feed, metabolism crate and environmental conditions. On day 8, pigs were transferred to the open-circuit respiration chambers for measurement of daily O2 consumption and CO2 and CH4 production. During this time, pigs were fed one of the three diets at 2.4 MJ metabolizable energy/kg body weight (BW)0.6 /day. Total feces and urine were collected and daily total heat production (THP) was measured from days 9 to 13 and fasted on day 14 to evaluate their fasting heat production (FHP). The results show that trends of decreased apparent total tract digestibility of neutral detergent fiber (linear, P = 0.09) and acid detergent fiber (linear, P = 0.07) were observed as the content of dietary lipids increased. The average THP for the three diets were 1326, 1208 and 1193 kJ/kg BW0.6 /day, respectively. The FHP of pigs averaged 843 kJ/kg BW0.6 /day and was not affected by diet characteristics. A reduction of the respiratory quotients in the fed state as the inclusion level of SBO increased was observed. In conclusion, the NE values of SBO we determined by indirect calorimetry were 33.45 and 34.05 MJ/kg dry matter under two inclusion levels. THP could be largely reduced when SBO is added in the feed, but the THP of SBO included at 5% in a corn-soybean meal diet is not different from the THP of SBO included at 10%. PMID- 28914475 TI - The Predicament of the Probably Benign Breast MRI: Should We Rely on Intuition? PMID- 28914476 TI - Corrigendum: Digital Quantification of DNA Replication and Chromosome Segregation Enables Determination of Antimicrobial Susceptibility after only 15 Minutes of Antibiotic Exposure. PMID- 28914477 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 39/2017. PMID- 28914478 TI - Mechanistic Insights into Cyclic Peptide Generation by DnaE Split-Inteins through Quantitative and Structural Investigation. AB - Inteins carry out protein-splicing reactions, which are used in protein chemistry, protein engineering and biotechnological applications. Rearrangement of the order of the domains in split-inteins results in head-to-tail cyclisation of the target sequence, which can be used for genetic encoding and expression of libraries of cyclic peptides (CPs). The efficiency of the splicing reaction depends on the target sequence. Here we used mass spectrometry to assess in vivo cyclic peptide formation from different hexameric target sequences by the DnaE split-inteins from Synechocystis sp. and Nostoc punctiforme, revealing a strong impact of the target sequence and of the intein on the intracellular peptide concentration. Furthermore, we determined the crystal structures of their pre splicing complexes, which allowed us to identify F-block Asp17 as crucial for the DnaE-mediated splicing reaction. PMID- 28914479 TI - A Freestanding Selenium Disulfide Cathode Based on Cobalt Disulfide-Decorated Multichannel Carbon Fibers with Enhanced Lithium Storage Performance. AB - SeS2 shows attractive advantages beyond bare S and Se as a cathode material for lithium storage. Here, a freestanding lotus root-like carbon fiber network decorated with CoS2 nanoparticles (denoted as CoS2 @LRC) has been designed and prepared as the SeS2 host for enhancing the lithium storage performance. The integrated electrode is constructed by three-dimensional interconnected multichannel carbon fibers, which can not only accommodate high content of SeS2 (70 wt %), but also promise excellent electron and ion transport for achieving high capacity utilization of 1015 mAh g-1 at 0.2 A g-1 . What is more, there are numerous CoS2 nanoparticles decorated all over the inner walls and surfaces of the carbon fibers, providing efficient sulfiphilic sites for restricting the dissolution of polysulfides and polyselenides during the electrochemical processes, thus successfully suppressing the shuttle effect and maintaining excellent cycling stability over 400 cycles at 0.5 A g-1 . PMID- 28914480 TI - Wireless Electrochemical Actuation of Conducting Polymers. AB - Electrochemical actuation of conducting polymers usually requires a direct connection to an electric power supply. In this contribution, we suggest to overcome this issue by using the concept of bipolar electrochemistry. This allows changing the oxidation state of the polymer in a gradual and wireless way. Free standing polypyrrole films were synthesized with an intrinsic morphological asymmetry of their two faces in order to form a bilayer structure. Immersing such objects in an electrolyte solution and exposing them to a potential gradient leads to the asymmetric oxidation/reduction of the polymer, resulting in differential shrinking and swelling along the main axis. This additional asymmetry is responsible for a structural deformation. Optimization allowed highly efficient bending, which is expected to open up completely new directions in the field of actuation due to the wireless mode of action. PMID- 28914481 TI - Boron and nitrogen co-doped carbon dots as a sensitive fluorescent probe for the detection of curcumin. AB - In this present study, a fluorescent probe was developed to detect curcumin, which is derived from the rhizomes of the turmeric. We used a simple and economical way to synthesize boron and nitrogen co-doped carbon dots (BNCDs) by microwave heating. The maximum emission wavelength of the BNCDs was 450 nm at an excitation wavelength of 360 nm. The as-prepared BNCDs were characterized by multiple analytical techniques such as transmission electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and infrared spectroscopy. The synthesized carbon nanoparticles had an average particle diameter of 4.23 nm. The BNCDs exhibited high sensitivity to the detection of curcumin at ambient conditions. The changes of BNCDs fluorescent intensity show a good linear relationship with the curcumin concentrations in the range 0.2-12.5 MUM. This proposed method has been successfully applied to detect the curcumin in urine samples with the recoveries of 96.5-105.5%. PMID- 28914483 TI - The Thermodynamic Basis of the Fuzzy Interaction of an Intrinsically Disordered Protein. AB - Many intrinsically disordered proteins (IDP) that fold upon binding retain conformational heterogeneity in IDP-target complexes. The thermodynamics of such fuzzy interactions is poorly understood. Herein we introduce a thermodynamic framework, based on analysis of ITC and CD spectroscopy data, that provides experimental descriptions of IDP association in terms of folding and binding contributions which can be predicted using sequence folding propensities and molecular modeling. We show how IDP can modulate the entropy and enthalpy by adapting their bound-state structural ensemble to achieve optimal binding. This is explained in terms of a free-energy landscape that provides the relationship between free-energy, sequence folding propensity, and disorder. The observed "fuzzy" behavior is possible because of IDP flexibility and also because backbone and side-chain interactions are, to some extent, energetically decoupled allowing IDP to minimize energetically unfavorable folding. PMID- 28914484 TI - Fluorine Effects on Group Migration via a Rhodium(V) Nitrenoid Intermediate. AB - An unprecedented rhodium(III)-catalyzed hydroarylation of alpha,alpha difluoromethylene alkynes with N-pivaloxyl aroylamides through sequential C-H activation and aryl migration is detailed herein. A large array of alpha,alpha difluoromethylene alkynes and N-pivaloxyl aryl amides were amenable to this transformation, thus providing a novel synthetic protocol for the construction of difluorinated 2-alkenyl aniline derivatives in high yields and with excellent regioselectivity. Notably, unique fluorine effects were found to underlie the thus unconventional reaction manifold. PMID- 28914485 TI - Match of psychosocial risk and psychosocial care in families of a child with cancer. AB - OBJECTIVE: The Psychosocial Assessment Tool (PAT) was developed to screen for psychosocial risk, aimed to be supportive in directing psychosocial care to families of a child with cancer. This study aimed to determine (i) the match between PAT risk score and provided psychosocial care with healthcare professionals blind to outcome of PAT assessment, and (ii) the match between PAT risk score and team risk estimation. METHODS: Eighty-three families of children with cancer from four pediatric oncology centers in the Netherlands participated (59% response rate). The PAT and team risk estimation was assessed at diagnosis (M = 40.2 days, SD = 14.1 days), and the content of provided psychosocial care in the 5-month period thereafter resulting in basic or specialized care. RESULTS: According to the PAT, 65% of families were defined as having low (universal), 30% medium (targeted), and 5% high (clinical) risk for developing psychosocial problems. Thirty percent of patients from universal group got basic psychosocial care, 63% got specialized care, and 7% did not get any care. Fourteen percent of the families at risk got basic care, 86% got specialized care. Team risk estimations and PAT risk scores matched with 58% of the families. CONCLUSIONS: This study showed that families at risk, based on standardized risk assessment with the PAT, received more specialized care than families without risk. However, still 14% of the families with high risks only received basic care, and 63% of the families with standard risk got specialized care. Standardized risk assessment can be used as part of comprehensive care delivery, complementing the team. PMID- 28914486 TI - A Systematic Structure-Activity Study of a New Type of Small Peptidic Transfection Vector Reveals the Importance of a Special Oxo-Anion-Binding Motif for Gene Delivery. AB - We discovered a new class of artificial peptidic transfection vectors based on an artificial anion-binding motif, the guanidiniocarbonylpyrrole (GCP) cation. This new type of vector is surprisingly smaller than traditional systems, and our previous work suggested that the GCP group was important for promoting critical endosomal escape. We now present here a systematic comparison of similar DNA ligands featuring our GCP oxo-anion-binding motif with DNA ligands only consisting of naturally occurring amino acids. Structure-activity studies showed that the artificial binding motif clearly outperformed natural amino acids such as histidine, lysine, and arginine. It improved the ability to shuttle foreign genetic material into cells, yet successfully mediated endosomal escape. Also, plasmids that were complexed by our artificial ligands were stabilized against cytosolic degradation to some extent. This resulted in the successful expression of plasmid information (comparable to gold standards such as polyethyleneimine). Hence, our study clearly demonstrates the importance of the tailor-made GCP anion binding site for efficient gene transfection. PMID- 28914487 TI - Illness Perceptions Explain the Variance in Functional Disability, but Not Habitual Physical Activity, in Patients With Chronic Low Back Pain: A Cross Sectional Study. AB - INTRODUCTION: Although the importance of psychosocial factors has been highlighted in many studies in patients with chronic low back pain (CLBP), there is a lack of research examining the role of illness perceptions in explaining functional disability and physical activity in patients with CLBP. AIM: The aim of the study was to explore the value of illness perceptions in explaining functional disability and physical activity in patients with CLBP. METHODS: Eighty-four participants with CLBP (of > 3 months' duration) completed a battery of questionnaires investigating psychosocial factors (Pain Catastrophizing Scale [PCS], Illness Perceptions Questionnaire Revised [IPQ-R], and 36-Item Short Form mental health scale [SF-36_MH]) and perceived pain intensity (visual analog scale [VAS]), as well as the Oswestry Disability Index (ODI) and Baecke questionnaire. The latter 2 were entered separately as dependent variables in a regression analysis. RESULTS: The combined variables (VAS, PCS, SF-36_MH, IPQ-R) accounted for 62% of the variance in functional disability (ODI). Adding the results of the IPQ-R to the scores of the other 3 variables (VAS, PCS, SF-36_MH) significantly increased the explained variance of ODI scores in CLBP patients, yielding 18% additional information (P < 0.01). Only 5% of the variance in the Baecke questionnaire was explained by combining the 4 variables. None of the single variables alone made a significant contribution to R2. CONCLUSIONS: Illness perceptions are an important factor for explaining functional disability, but not for explaining habitual physical activity in CLBP patients. PMID- 28914488 TI - A Hebrew adaptation of the tinnitus functional index. PMID- 28914489 TI - Responses of microbial decomposers to drought in streams may depend on the environmental context. AB - A consequence of drought in streams is the emersion of decomposing leaf litter, which may alter organic matter recycling. We assessed the effects of emersion on decomposition of black poplar leaves and associated microbes (microbial biomass, extracellular enzyme activities and microbial diversity) in two streams with distinct characteristics, in particular nutrients, temperature and oxygen levels. Leaf decomposition rates, fungal biomass and extracellular enzyme activities were lower in the most impacted stream (high nutrients and temperature, low oxygen). Also, the structure of fungal and bacterial communities differed between streams. Emersion strongly affected all microbial functional measures. Leaf decomposition, fungal biomass and extracellular enzyme activities were more sensitive at the most pristine site, while fungal reproduction and bacterial biomass production were more affected by emersion at the most impacted stream. Microbial community structure was strongly altered after emersion. Although similar effects on leaf associated microbes were found in both streams, functional responses to emersion differed probably as a consequence of different initial microbial communities with different sensitivity to the drying stress. Our study highlights the need of understanding the effects of drought in streams suffering from different environmental perturbations, since responses to emersion appear to depend on the environmental context. PMID- 28914490 TI - A Catalytic Microwave Process for Superfast Preparation of High-Quality Reduced Graphene Oxide. AB - Herein we report that a small amount of graphite can unexpectedly act as the catalyst to greatly promote the microwave exfoliation and reduction of graphite oxide in ambient air. The reaction can be finished in a few seconds in contrast to more than ten minutes without catalyst. The catalytic microwave exfoliated graphite oxide (CMEGO) is of higher quality than the traditional microwave exfoliated graphite oxide, including a much higher exfoliation degree with thinner graphene sheets and higher specific surface area (886 m2 g-1 vs. 466 m2 g-1 ), a much larger C/O ratio (19.4 vs. 6.3) and a higher lattice crystallinity, as well as significantly improved electrical conductivity (53180 S m-1 vs. 5140 S m-1 ). The CMEGO is used as anode for lithium-ion battery (LIB) and sodium-ion battery (SIB), and delivers ultrahigh reversible capacities, remarkable rate capabilities, and superior cycling stabilities in both LIB and SIB. PMID- 28914491 TI - nirS-type denitrifying bacterial assemblages respond to environmental conditions of a shallow estuary. AB - Molecular analysis of dissimilatory nitrite reductase genes (nirS) was conducted using a customized microarray containing 165 nirS probes (archetypes) to identify members of sedimentary denitrifying communities. The goal of this study was to examine denitrifying community responses to changing environmental variables over spatial and temporal scales in the New River Estuary (NRE), NC, USA. Multivariate statistical analyses revealed three denitrifier assemblages and uncovered 'generalist' and 'specialist' archetypes based on the distribution of archetypes within these assemblages. Generalists, archetypes detected in all samples during at least one season, were commonly world-wide found in estuarine and marine ecosystems, comprised 8%-29% of the abundant NRE archetypes. Archetypes found in a particular site, 'specialists', were found to co-vary based on site specific conditions. Archetypes specific to the lower estuary in winter were designated Cluster I and significantly correlated by sediment Chl a and porewater Fe2+ . A combination of specialist and more widely distributed archetypes formed Clusters II and III, which separated based on salinity and porewater H2 S respectively. The co-occurrence of archetypes correlated with different environmental conditions highlights the importance of habitat type and niche differentiation among nirS-type denitrifying communities and supports the essential role of individual community members in overall ecosystem function. PMID- 28914492 TI - Bacterial aetiology of recalcitrant acute otitis media in 62 children-high risk of pathogen colonisation after treatment. PMID- 28914493 TI - Rethinking ethnicity, fetal growth and customised charts. PMID- 28914494 TI - Sketching Biological Phenomena and Mechanisms. AB - In many fields of biology, both the phenomena to be explained and the mechanisms proposed to explain them are commonly presented in diagrams. Our interest is in how scientists construct such diagrams. Researchers begin with evidence, typically developed experimentally and presented in data graphs. To arrive at a robust diagram of the phenomenon or the mechanism, they must integrate a variety of data to construct a single, coherent representation. This process often begins as the researchers create a first sketch, and it continues over an extended period as they revise the sketch until they arrive at a diagram they find acceptable. We illustrate this process by examining the sketches developed in the course of two research projects directed at understanding the generation of circadian rhythms in cyanobacteria. One identified a new aspect of the phenomenon itself, whereas the other aimed to develop a new mechanistic account. In both cases, the research resulted in a paper in which the conclusion was presented in a diagram that the authors deemed adequate to convey it. These diagrams violate some of the normative "cognitive design principles" advanced by cognitive scientists as constraints on successful visual communication. We suggest that scientists' sketching is instead governed by norms of success that are broadly explanatory: conveying the phenomenon or mechanism. PMID- 28914495 TI - Acculturation-based family conflict: A validation of Asian American Family Conflict Scale among Chinese Americans. AB - Acculturation-based family conflicts can influence parent-child relationships and children's development among immigrant families. The Asian American Family Conflict Scale (AAFCS) was developed to measure conflicting practices and values between parents and children in the context of acculturation. Given that considerable cultural and institutional changes have taken place in original countries for the Chinese immigrant population, it is important to investigate whether the factor structure of the AAFCS is appropriate for measuring the attitudes and practices of acculturation among the current Chinese immigrant population. A sample of Chinese American immigrant parents (n = 269) from the Survey of Asian American Families was employed to conduct exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The principal-axis factoring method of EFA was used to determine the factor structure of the AAFCS, followed by the weighted least squares means and variance estimation in CFA to assess the fitness of the measurement model. A nine-item one-factor model (without the first item regarding decision making) was suggested by EFA with all factor loadings greater than .45. CFA results indicated a good fit of the nine item one-factor model: chi2 (27, 296) = 40.24, p < .05, root-mean-square error of approximation = .04, 90% CI [.00, .07], comparative fit index = .99, Tucker-Lewis index = .99. The validation of the AAFCS is useful for practitioners and researchers to better assess the outcomes of acculturation conflicts among Chinese immigrants who are adjusting to living in the United States. This study can inform social work practitioners in regards to cultural sensitivity and cultural competency when working with Chinese immigrants and their U.S.-born children. PMID- 28914496 TI - Silver Thiolate Nano-sized Molecular Clusters and Their Supramolecular Covalent Frameworks: An Approach Toward Pre-templated Synthesis. AB - A series of seven new complexes including silver-thiolate molecular clusters and their covalent supramolecular frameworks have been assembled from the silver carbide precursor Ag2 C2 using a C22- pre-templated approach. Herein, two prototype clusters Ag14 (SR)6 and CO3 @Agm (SR)10 (R=isopropyl, cyclohexyl or tert-butyl; m=18 or 20) are employed to construct cluster-based metal-organic frameworks of different dimensions. In particular, both new ellipsoidal tetradecanuclear molecular cluster compounds, namely, Ag14 (S-iPr)6 (CO2 CF3 )8 ?(DMSO)6 (two polymorphic forms 1, 2) and [Ag14 (S-Cy)6 (CO2 CF3 )8 (DMSO)4 ]?(DMSO)3 (3), and a cluster-based metal-organic framework {Ag3 [Ag14 (S-iPr)6 (CO2 CF3 )11 (H2 O)3 CH3 OH]?(H2 O)2.5 }n (4) have been isolated and structurally characterized. Furthermore, increased acidity of the reaction mixture afforded three carboxylate-templated cluster based frameworks: a chain-like compound {[HN(CH3 )2 CO]?[CO3 @Ag18 (S-tBu)10 (NO3 )7 (DMF)4 ]?DMF}n (5), as well as two layer-type compounds, namely, {Ag[CO3 @Ag20 (S-iPr)10 (CO2 CF3 )9 (CO2 HCF3 )(CH3 OH)2 ]}n (6) and {Ag2 [CO3 @Ag20 (S-Cy)10 (CO2 CF3 )10 (CO2 HCF3 )2 (H2 O)2 ]?(H2 O)3 ?(CH3 OH)3 }n (7) exhibiting sql-net characteristics. It is demonstrated that the C=C2- pre-template, which draws several Ag+ ions together to form the C2 @Agn entity, plays an indispensable role in the syntheses of these compounds. Furthermore, covalent linkage of these nano-sized silver thiolate clusters from one- to three-dimensions revealed enormous potential for the future development of silver cluster-based frameworks. PMID- 28914497 TI - Fuel Production from Seawater and Fuel Cells Using Seawater. AB - Seawater is the most abundant resource on our planet and fuel production from seawater has the notable advantage that it would not compete with growing demands for pure water. This Review focuses on the production of fuels from seawater and their direct use in fuel cells. Electrolysis of seawater under appropriate conditions affords hydrogen and dioxygen with 100 % faradaic efficiency without oxidation of chloride. Photoelectrocatalytic production of hydrogen from seawater provides a promising way to produce hydrogen with low cost and high efficiency. Microbial solar cells (MSCs) that use biofilms produced in seawater can generate electricity from sunlight without additional fuel because the products of photosynthesis can be utilized as electrode reactants, whereas the electrode products can be utilized as photosynthetic reactants. Another important source for hydrogen is hydrogen sulfide, which is abundantly found in Black Sea deep water. Hydrogen produced by electrolysis of Black Sea deep water can also be used in hydrogen fuel cells. Production of a fuel and its direct use in a fuel cell has been made possible for the first time by a combination of photocatalytic production of hydrogen peroxide from seawater and dioxygen in the air and its direct use in one-compartment hydrogen peroxide fuel cells to obtain electric power. PMID- 28914498 TI - Shared temptations: An fMRI study of dishonest profit maximization. AB - A single case of a tempting-decision task involving financial gain is reported. The subject showed a prosocial Social Value Orientation and applied a profit maximizing strategy. Differential brain activation patterns for self-serving and other-serving decisions were observed. Results provide new insight into the design of paradigms on bounded ethicality and self- and group-serving behavior. PMID- 28914499 TI - Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism. AB - Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs. PMID- 28914501 TI - Andrology of male-to-female transsexuals: influence of cross-sex hormone therapy on testicular function. AB - Patients with gender dysphoria are offered cross-sex hormone therapy and sex reassignment surgery to achieve the transition between the sex assigned at birth and gender identity. According to international guidelines, cross-sex hormone therapy in trans-women should lead to a psychologically and physiologically healthy body with feminized serum hormone levels, resulting in suppression of spermatogenesis. However, in a recently published multi-center study, we discovered a high proportion of patients with male serum hormone levels and qualitatively intact spermatogenesis on the day of sex reassignment surgery. The objective of this study was to review the content of 11 publications that focus on the influence of cross-sex hormone therapy on testicular morphology. These publications were identified based on a PubMed search for the key words transgender/transsexual/gender dysphoria in male-to-female persons, cross-sex hormone therapy, and testicular tissues. Whereas three publications described a marked reduction of the spermatogenic level in all patients examined, eight publications reported inconsistent results. Histological analyses showed highly variable outcomes from qualitatively normal spermatogenesis and undisturbed Leydig/Sertoli cell morphology to full testicular regression with severe cellular damage and hyalinization. Explanations for these heterogeneous findings include insufficient cross-sex hormone therapy regarding dosage or duration. As complete spermatogenesis is associated with virilized serum hormone levels, these patients may face challenges especially after sex reassignment surgery in adjusting to the abruptly established hypogonadal state following removal of the testes. These findings also suggest that contraception should be discussed, and fertility preservation should be offered during/prior to cross-sex hormone therapy. There is a need for more individualized and better-controlled cross-sex hormone therapy and post-treatment regimens. Evidence-based guidelines for attending clinicians need to be established in order to deliver the most appropriate care. PMID- 28914502 TI - Probiotics to improve testicular function (Andrology 5:439-444, 2017) - a comment on mechanism of action and therapeutic potential of probiotics beyond reproduction. PMID- 28914500 TI - Comprehensive proteomics analysis of exosomes derived from human seminal plasma. AB - Exosomes are membranous nanovesicles of endocytic origin that carry and transfer regulatory bioactive molecules and mediate intercellular communication between cells and tissues. Although seminal exosomes have been identified in human seminal plasma, their exact composition and possible physiologic function remain unknown. The objective of this study was to perform a comprehensive proteomics analysis of exosomes derived from human seminal plasma. Seminal exosomes were isolated and purified from 12 healthy donors using a 30% sucrose cushion-based exosome-isolation protocol, followed by characterization by western blot, transmission electron microscopy, and nanoparticle tracking analysis before performing extensive liquid chromatography tandem mass spectrometry proteomics analysis. The identified proteins were analyzed by bioinformatics analysis, and seminal exosomes-associated proteins were selectively validated by western blot. A total of 1474 proteins were identified in all seminal exosomes samples, with Gene Ontology analysis demonstrating that these identified seminal exosomes associated proteins were mostly linked to 'exosomes,' 'cytoplasm,' and 'cytosol.' Bioinformatics analysis indicated that these proteins were mainly involved in biologic processes, including metabolism, energy pathways, protein metabolism, cell growth and maintenance, and transport. Of these identified proteins, PHGDH, LGALS3BP, SEMG1, ACTB, GAPDH, and the exosomal-marker protein ALIX were validated by western blot. This study provided a more comprehensive description of the seminal exosomes proteome and could also be a resource for further screening of biomarkers and comparative proteomics studies, including those associated with male infertility and prostate cancer. PMID- 28914503 TI - Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial. AB - The purpose of the study was to evaluate whether testosterone replacement therapy improves muscle mechanical and physical function in addition to increasing lean leg mass and total lean body mass in aging men with type 2 diabetes and lowered bio-available testosterone (BioT) levels. Thirty-nine men aged 50-70 years with type 2 diabetes and BioT levels <7.3 nmol/L were included from an academic tertiary-care medical center. Patients were randomized to testosterone gel (testosterone replacement therapy, n = 20) or placebo (n = 19) for 24 weeks, applying a double-blinded design. Muscle mechanical function was assessed by Nottingham Leg Rig (leg extension power) and isokinetic dynamometry (knee extensor maximal isometric contraction, rate of force development (RFD100), maximal dynamic contraction (Dyn180)). Physical function was assessed by gait speed. Body composition was assessed by whole body dual-energy X-ray absorptiometry (total lean body mass, lean leg mass, total fat mass, leg fat mass). Levels of total testosterone (TotalT), BioT, free testosterone (FreeT), and sex hormone-binding globulin were measured from fasting blood samples. Coefficients (b) represent the placebo-controlled mean effect of intervention. Maximal isometric contraction (b = 18.4 Nm, p = 0.039), RFD100 (b = 195.0 Nm/s, p = 0.017) and Dyn180 (b = 10.2 Nm, p = 0.019) increased during testosterone replacement therapy compared with placebo. No changes were observed in leg power or gait speed. Total lean body mass (b = 1.9 kg, p = 0.001) and lean leg mass (b = 0.5 kg, p < 0.001) increased, while total fat mass (b = -1.3 kg, p = 0.009) and leg fat mass (b = -0.7 kg, p = 0.025) decreased during testosterone replacement therapy compared with placebo. Total T (b = 14.5 nmol/L, p = 0.056), BioT (b = 7.6 nmol/L, p = 0.046), and FreeT (b = 0.32 nmol/L, p = 0.046) increased during testosterone replacement therapy compared with placebo, while sex hormone-binding globulin (n = -2 nmol/L, p = 0.030) decreased. Knee extensor muscle mechanical function was preserved, and body composition improved substantially during testosterone replacement therapy for 24 weeks compared with placebo, whereas physical function (gait speed) was unchanged in aging men with type 2 diabetes and lowered BioT levels. PMID- 28914519 TI - Inadequate hand-off communication. PMID- 28914520 TI - Where Have All the Babies Gone? PMID- 28914521 TI - Health Care In and Out of Prison. PMID- 28914522 TI - Nanozyme-Mediated Dual Immunoassay Integrated with Smartphone for Use in Simultaneous Detection of Pathogens. AB - Nanozymes are an excellent class of optical reporters for the development of sensitive biosensors for widespread applications. In this study, mesoporous core shell palladium@platinum (Pd@Pt) nanoparticles were synthesized and then applied as signal amplifier in a dual lateral flow immunoassay (LFIA) and integrated with a smartphone-based device for use in simultaneous detection of Salmonella Enteritidis and Escherichia coli O157:H7. After optimization, the limit of detections were calculated to be ~20 cfu/mL for S. Enteritidis and ~34 cfu/mL for E. coli O157:H7, respectively. The greatly improved sensitivity was contributed by the peroxidase-like catalytic activity of the Pd@Pt nanoparticles for signal enhancement and the parallel design of dual detection for eliminating the cross interference. The estimated recoveries of the dual LFIA range from 91.44 to 117.00%, which indicated that the developed method is capable of detecting live bacteria in food samples. This approach provides an attractive platform for S. Enteritidis and E. coli O157:H7 detection using a smartphone-based device as the sole piece of equipment, indicating great promise for foodborne pathogen analysis or in-field food safety tracking. PMID- 28914523 TI - Aqueous Processing of Na0.44MnO2 Cathode Material for the Development of Greener Na-Ion Batteries. AB - The implementation of aqueous electrode processing of cathode materials is a key for the development of greener Na-ion batteries. Herein, the development and optimization of the aqueous electrode processing for the ecofriendly Na0.44MnO2 (NMO) cathode material, employing carboxymethyl cellulose (CMC) as binder, are reported for the first time. The characterization of such an electrode reveals that the performances are strongly affected by the employed electrolyte solution, especially, the sodium salt and the use of electrolyte's additives. In particular, the best results are obtained using the 1 M solution of NaPF6 in EC/DEC (ethylene carbonate/diethyl carbonate) 3:7 (v/v) + 2 wt % FEC (fluoroethylene carbonate). With this electrolyte, the outstanding capacity of 99.7 mA h g-1 is delivered by the CMC-NMO cathode after 800 cycles at a 1C charge/discharge rate. On the basis of this excellent long-term performance, a full sodium cell, composed of a CMC-based NMO cathode and hard carbon from biowaste (corn cob), has been assembled and tested. The cell delivers excellent performances in terms of specific capacity, capacity retention, and long-term cycling stability. After 75 cycles at a C/5 rate, the capacity of the NMO in the full-cell approaches 109 mA h g-1 with a Coulombic efficiency of 99.9%. PMID- 28914524 TI - Templated and Catalytic Fabrication of N-Doped Hierarchical Porous Carbon-Carbon Nanotube Hybrids as Host for Lithium-Sulfur Batteries. AB - Nitrogen-doped hierarchical porous carbon and carbon nanotube hybrids (N-HPC CNTs) are fabricated by simple pyrolysis of the N-rich raw material melamine formaldehyde (MF) resin in the presence of nano-CaCO3 and a bimetallic combination of Fe-Co catalyst. During carbonization, nano-CaCO3 acts as a template for creating a hierarchical porous carbon, and the N atoms originated from MF resin are in situ doped into the carbon matrix simultaneously. Meanwhile, volatile gases generated by the thermal decomposition of MF resin could serve as carbon and nitrogen sources to grow nitrogen-doped CNTs on HPC. The growth mechanism is the same as that for conventional chemical vapor deposition (CVD) growth of CNTs on the metal catalysts, but the technological requirements are obviously not as harsh as those for the CVD method. Low-cost raw materials and simple equipment are sufficient for the growth. Moreover, the density and length of the CNTs are tunable, which can be simply adjusted via applying different amounts of Fe-Co catalysts. Such an N-doped hybrid structured carbon with mesopores can not only effectively prompt the physical and chemical adsorption of polysulfides but also ensures a fast electron transfer because of the incorporation of CNTs, which provides sufficient conducting pathways and effective connections between the CNTs and HPC. Furthermore, CNTs grown on HPC can act as physical barriers to block the large pores on HPC, thereby reducing the polysulfide loss. Benefiting from the advantages, the N-HPC-CNT hybrids are a desirable host prospect for Li-S batteries. PMID- 28914525 TI - Two Distinct Polymorphic Folding States of Self-Assembly of the Non-amyloid-beta Component Differ in the Arrangement of the Residues. AB - Parkinson's disease is a degenerative disorder of the central nervous system. It is characterized by presence of Lewy bodies (LBs), in which the main components of the LBs are alpha-synuclein (AS) aggregates. The central domain of AS, known as the "non-amyloid-beta component" (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-beta structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains is crucial in order to understand the molecular mechanisms of AS aggregation. This is a first study that illustrates two distinct polymorphic folding states of NAC that differ in the arrangement of the residues along the sequence. One of the polymorphic folding states reveals a conformational change that is similar to the other polymorphic folding state in the backbone shape but differs in the arrangement of the residues along the backbone. This work provides insight into the molecular mechanisms through which AS can self-assembled in two different pathways yielding a conformational change between the two polymorphic folding states. PMID- 28914526 TI - g-C3N4/TiO2 Mesocrystals Composite for H2 Evolution under Visible-Light Irradiation and Its Charge Carrier Dynamics. AB - The photocatalytic performance of graphitic carbon nitride (g-C3N4) has been limited to low efficiency due to fast charge recombination. Here, we constructed g-C3N4 nanosheets/TiO2 mesocrystals metal-free composite (g-C3N4 NS/TMC) to promote the efficiency of charge separation. The photocatalytic H2 evolution experiments indicate that coupling g-C3N4 NS with TMC increases photogenerated charge carriers in g-C3N4 NS/TMC composite due to efficient charge separation. g C3N4 NS (31 wt %)/TMC shows the highest photocatalytic activity and the corresponding H2 evolution rate is 3.6 MU mol h-1. This value is 20 times larger than that of g-C3N4 NS without any noble metal cocatalyst under visible-light irradiation (lambda > 420 nm). The photocatalytic activity of g-C3N4 NS/TMC (3.6 MUmol h-1) is 7 times higher than that of g-C3N4 NS/P25 (0.5 MU mol h-1), confirming the importance of strong interface interaction between two-dimensional g-C3N4 NS and plate-shape TMC. Femtosecond time-resolved diffuse reflectance (fs TDR) was employed to study the fundamental photophysical processes of bulk g C3N4, g-C3N4 NS, and g-C3N4/TMC composite which are essential to explain the photocatalytic activity. Using fs-TDR, we demonstrate that the photocatalytic activity depends on the increased driving force for photoinduced electron transfer and a higher percentage of photogenerated charges. PMID- 28914527 TI - Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment. AB - Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the "browning" at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type 2 diabetes in vivo in a diet-induced obesity mouse model. PMID- 28914528 TI - Inhibition of Human and Rat Sucrase and Maltase Activities To Assess Antiglycemic Potential: Optimization of the Assay Using Acarbose and Polyphenols. AB - : We optimized the assays used to measure inhibition of rat and human alpha glucosidases (sucrase and maltase activities), intestinal enzymes which catalyze the final steps of carbohydrate digestion. Cell-free extracts from fully differentiated intestinal Caco-2/TC7 monolayers were shown to be a suitable source of sucrase-isomaltase, with the same sequence as human small intestine, and were compared to a rat intestinal extract. The kinetic conditions of the assay were optimized, including comparison of enzymatic and chromatographic methods to detect the monosaccharide products. Human sucrase activity was more susceptible than the rat enzyme to inhibition by acarbose (IC50 (concentration required for 50% inhibition) = 2.5 +/- 0.5 and 12.3 +/- 0.6 MUM, respectively), by a polyphenol-rich green tea extract, and by pure (-)-epigallocatechin gallate (EGCG) (IC50 = 657 +/- 150 and 950 +/- 86 MUM respectively). In contrast, the reverse was observed when assessing maltase activity (e.g. , EGCG: IC50 = 677 +/- 241 and 14.0 +/- 2.0 MUM for human and rat maltase, respectively). 5 Caffeoylquinic acid did not significantly inhibit maltase and was only a very weak inhibitor of sucrase. The data show that for sucrase and maltase activities, inhibition patterns of rat and human enzymes are generally qualitatively similar but can be quantitatively different. PMID- 28914529 TI - Well-Hidden Grain Boundary in the Monolayer MoS2 Formed by a Two-Dimensional Core Shell Growth Mode. AB - Guided by the hexagonal lattice symmetry, triangles and hexagons are the most basic morphological units for two-dimensional (2D) transition metal dichalcogenides (TMDs) synthesized by chemical vapor deposition (CVD). Also, it is widely acknowledged that these units start from the single nucleation site and then grow epitaxially. Accordingly, the triangular monolayer (ML) samples are generally considered as single crystals. Here, we report a 2D core-shell growth mode in the CVD process for ML-MoS2, which leads to one kind of "pseudo" single crystal triangles containing triangular outline grain boundaries (TO-GBs). It is difficult to be optically distinguished from the "true" single-crystal triangles. The weakening of Raman peaks and the remarkable enhancement of photoluminescence (PL) are found at the built-in TO-GBs, which could be useful for high-performance optoelectronics. In addition, the electrical measurements indicate that the TO GBs are conductive. Furthermore, TO-GBs and the common grain boundaries (CO-GBs) can coexist in a single flake, whereas their optical visibility and optical modifications (Raman and PL) are quite different. This work is helpful in further understanding the growth mechanism of 2D TMD materials and may also play a significant role in related nanodevices. PMID- 28914530 TI - Emergence of the Reactivity Continuum of Organic Matter from Kinetics of a Multitude of Individual Molecular Constituents. AB - The reactivity continuum (RC) model is a powerful statistical approach for describing the apparent kinetics of bulk organic matter (OM) decomposition. Here, we used ultrahigh resolution mass spectrometry data to evaluate the main premise of the RC model, namely that there is a continuous spectrum of reactivity within bulk OM, where each individual reactive type undergoes exponential decay. We performed a 120 day OM decomposition experiment on lake water, with an untreated control and a treatment preexposed to UV light, and described the loss of bulk dissolved organic carbon with RC modeling. The behavior of individual molecular formulas was described by fitting the single exponential model to the change in peak intensities over time. The range of the empirically derived apparent exponential decay coefficients (kexp) was indeed continuous. The character of the corresponding distribution, however, differed from the conceptual expectations, due to the effects of intrinsic averaging, overlaps in formula-specific loss and formation rates, and the limitation of the RC model to include apparently accumulating compounds in the analysis. Despite these limitations, both the RC model-simulated and empirical (mass spectrometry-derived) distributions of kexp captured the effects of preexposure to UV light. Overall, we present experimental evidence that the reactivity continuum within bulk OM emerges from a range of reactivity of numerous individual components. This constitutes direct empirical support for the major assumption behind the RC model of the natural OM decomposition. PMID- 28914531 TI - Systems-Level Annotation of a Metabolomics Data Set Reduces 25 000 Features to Fewer than 1000 Unique Metabolites. AB - When using liquid chromatography/mass spectrometry (LC/MS) to perform untargeted metabolomics, it is now routine to detect tens of thousands of features from biological samples. Poor understanding of the data, however, has complicated interpretation and masked the number of unique metabolites actually being measured in an experiment. Here we place an upper bound on the number of unique metabolites detected in Escherichia coli samples analyzed with one untargeted metabolomics method. We first group multiple features arising from the same analyte, which we call "degenerate features", using a context-driven annotation approach. Surprisingly, this analysis revealed thousands of previously unreported degeneracies that reduced the number of unique analytes to ~2961. We then applied an orthogonal approach to remove nonbiological features from the data using the 13C-based credentialing technology. This further reduced the number of unique analytes to less than 1000. Our 90% reduction in data is 5-fold greater than previously published studies. On the basis of the results, we propose an alternative approach to untargeted metabolomics that relies on thoroughly annotated reference data sets. To this end, we introduce the creDBle database ( http://creDBle.wustl.edu ), which contains accurate mass, retention time, and MS/MS fragmentation data as well as annotations of all credentialed features. PMID- 28914532 TI - Aggregation-Induced Electrochemiluminescence of Platinum(II) Complexes. AB - We report the electrochemiluminescence properties of square-planar Pt(II) complexes that result from the formation of supramolecular nanostructures. We define this new phenomenon as aggregation-induced electrochemiluminescence (AIECL). In this system, self-assembly changes the HOMO and LUMO energies, making their population accessible via ECL pathways and leading to the generation of the luminescent excited state. Significantly, the emission from the self-assembled system is the first example of electrochemiluminescence (ECL) of Pt(II) complexes in aqueous solution having higher efficiency than the standard, Ru(bpy)32+.The finding can lead to a new generation of bright emitters that can be used as ECL labels. PMID- 28914533 TI - Mossbauer Spectroscopic Characterization of Iron(III)-Polysaccharide Coordination Complexes: Photochemistry, Biological, and Photoresponsive Materials Implications. AB - While polycarboxylates and hydroxyl-acid complexes have long been known to be photoactive, simple carboxylate complexes which lack a significant LMCT band are not typically strongly photoactive. Hence, it was somewhat surprising that a series of reports demonstrated that materials synthesized from iron(III) and polysaccharides such as alginate (poly[guluronan-co-mannuronan]) or pectate (poly[galacturonan]) formed photoresponsive materials that convert from hydrogels to sols under the influence of visible light. These materials have numerous potential applications in areas such as photopatternable materials, materials for controlled drug delivery, and tissue engineering. Despite the near-identity of the functional units in the polysaccharide ligands, the reactivity of iron(III) hydrogels can depend on the configuration of some chiral centers in the sugar units and in the case of alginate the guluronate to mannuronate block composition, as well as pH. Here, using temperature- and field-dependent transmission Mossbauer spectroscopy, we show that the dominant iron compound detected for both the alginate and pectate gels displays features typical of a polymeric (Fe3+O6) system. The Mossbauer spectra of such systems are strongly dependent on temperature, field, size, and crystallinity, indicative of superparamagnetic relaxation of magnetically ordered nanoparticles. Pectate and alginate hydrogels differ in the size distribution of the iron oxyhydroxy nanoparticles, suggesting that in general smaller nanoparticles are more reactive. Potential biological implications of these results are also discussed. PMID- 28914534 TI - Stochastic Formulation of the Resolution of Identity: Application to Second Order Moller-Plesset Perturbation Theory. AB - A stochastic orbital approach to the resolution of identity (RI) approximation for 4-index electron repulsion integrals (ERIs) is presented. The stochastic RI ERIs are then applied to second order Moller-Plesset perturbation theory (MP2) utilizing a multiple stochastic orbital approach. The introduction of multiple stochastic orbitals results in an O(NAO3) scaling for both the stochastic RI-ERIs and stochastic RI-MP2, NAO being the number of basis functions. For a range of water clusters we demonstrate that this method exhibits a small prefactor and observed scalings of O(Ne2.4) for total energies and O(Ne3.1) for forces (Ne being the number of correlated electrons), outperforming MP2 for clusters with as few as 21 water molecules. PMID- 28914535 TI - Small Molecule Near-Infrared Boron Dipyrromethene Donors for Organic Tandem Solar Cells. AB - Three furan fused boron dipyrromethenes (BODIPYs) with a CF3 group on the meso carbon are synthesized as near-infrared absorbing materials for vacuum processable organic solar cells. The best single junction device reaches a short circuit current (jsc) of 13.3 mA cm-2 and a power conversion efficiency (PCE) of 6.1%. These values are highly promising for an electron donor material with an absorption onset beyond 900 nm. In a tandem solar cell comprising a NIR BODIPY subcell and a matching "green" absorber subcell, complementary absorption is achieved, resulting in PCE of ~10%. PMID- 28914536 TI - Determination of the True Lateral Grain Size in Organic-Inorganic Halide Perovskite Thin Films. AB - In this letter, methylammonium lead iodide (MAPbI3) thin films were examined via piezoresponse force microscopy (PFM) and nanoindentation (NI) to determine if long-range atomic order existed across the full width and depth of the apparent grains. From the PFM, the piezoelectric response of the films was strongly correlated with low-index planes of the crystal structure and ferroelastic domains in macroscale solution-grown MAPbI3 crystals, which implied long-range order near the top surface. From the NI, it was found that the induced cracks were straight and extended across the full width of the apparent grains, which indicated that the long-range order was not limited to the near-surface region, but extended through the film thickness. Interestingly, the two MAPbI3 processes examined resulted in subtle differences in the extracted electro-mechanical and fracture properties, but exhibited similar power conversion efficiencies of >17% in completed devices. PMID- 28914537 TI - Coupling Bioflocculation of Dehalococcoides mccartyi to High-Rate Reductive Dehalogenation of Chlorinated Ethenes. AB - Continuous bioreactors operated at low hydraulic retention times have rarely been explored for reductive dehalogenation of chlorinated ethenes. The inability to consistently develop such bioreactors affects the way growth approaches for Dehalococcoides mccartyi bioaugmentation cultures are envisioned. It also affects interpretation of results from in situ continuous treatment processes. We report bioreactor performance and dehalogenation kinetics of a D. mccartyi-containing consortium in an upflow bioreactor. When fed synthetic groundwater at 11-3.6 h HRT, the upflow bioreactor removed >99.7% of the influent trichloroethene (1.5 2.8 mM) and produced ethene as the main product. A trichloroethene removal rate of 98.51 +/- 0.05 me- equiv L-1 d-1 was achieved at 3.6 h HRT. D. mccartyi cell densities were 1013 and 1012 16S rRNA gene copies L-1 in the bioflocs and planktonic culture, respectively. When challenged with a feed of natural groundwater containing various competing electron acceptors and 0.3-0.4 mM trichloroethene, trichloroethene removal was sustained at >99.6%. Electron micrographs revealed that D. mccartyi were abundant within the bioflocs, not only in multispecies structures, but also as self-aggregated microcolonies. This study provides fundamental evidence toward the feasibility of upflow bioreactors containing D. mccartyi as high-density culture production tools or as a high rate, real-time remediation biotechnology. PMID- 28914538 TI - Interface-Confined FeOx Adlayers Induced by Metal Support Interaction in Pt/FeOx Catalysts. AB - Active oxide nanolayers can be stabilized on noble metal surfaces through interface confinement effect in oxide/metal inverse catalysts. Here, using normal metal/oxide catalysts we show that Fe oxide nanolayers can be confined on Pt nanoparticles (NPs) when treating a Pt/FeOx catalyst in Ar or H2/O2 atmospheres at elevated temperatures. Pt NPs partially covered with Fe oxide nanopatches are more active in CO oxidation than bare Pt NPs, while those with fully encapsulated Fe oxide shells in strong metal-support interaction (SMSI) state show much lower activity. Characterization results indicate that three steps play an important role in the formation of Fe oxide overlayers: Pt-aided reduction of interfacial Fe oxide, Pt alloying of interfacial Fe atoms, and surface segregation of alloyed Fe atoms onto surface of Pt NPs. Active surface oxides in so-called support-metal interface confinement (SMIC) state and fully encapsulated oxide layers in the SMSI state can be sequentially produced which depend on the treatment conditions. PMID- 28914539 TI - Phonon-Assisted Ultrafast Charge Transfer at van der Waals Heterostructure Interface. AB - The van der Waals (vdW) interfaces of two-dimensional (2D) semiconductor are central to new device concepts and emerging technologies in light-electricity transduction where the efficient charge separation is a key factor. Contrary to general expectation, efficient electron-hole separation can occur in vertically stacked transition-metal dichalcogenide heterostructure bilayers through ultrafast charge transfer between the neighboring layers despite their weak vdW bonding. In this report, we show by ab initio nonadiabatic molecular dynamics calculations, that instead of direct tunneling, the ultrafast interlayer hole transfer is strongly promoted by an adiabatic mechanism through phonon excitation occurring on 20 fs, which is in good agreement with the experiment. The atomic level picture of the phonon-assisted ultrafast mechanism revealed in our study is valuable both for the fundamental understanding of ultrafast charge carrier dynamics at vdW heterointerfaces as well as for the design of novel quasi-2D devices for optoelectronic and photovoltaic applications. PMID- 28914540 TI - Adhesion and Separation of Nanoparticles on Polymer-Grafted Porous Substrates. AB - This work explores interactions of functionalized nanoparticles (NP) with polymer brushes (PB) in a binary mixture of good and poor solvents. NP-PB systems are used in multiple applications, and we are particularly interested in the problem of chromatographic separation of NPs on polymer-grafted porous columns. This process involves NP flow through the pore channels with walls covered by PBs. NP PB adhesion is governed by adsorption of polymer chains to NP surface and entropic repulsion caused by the polymer chain confinement between NP and the channel wall. Both factors depend on the solvent composition, variation of which causes contraction or expansion of PB. Using dissipative particle dynamics simulations in conjunction with the ghost tweezers free energy calculation technique, we examine the free energy landscapes of functionalized NPs within PB grafted channels depending on the solvent composition at different PB grafting densities and polymer-solvent affinities. The free energy landscape determines the probability of NP location at a given distance to the surface, positions of equilibrium adhesion states, and the Henry constant that characterizes adsorption equilibrium and NP partitioning between the stationary phase of PB and mobile phase of flowing solvent. We analyze NP transport through a polymer-grafted channel and calculate the mean velocity and retention time of NP depending on the NP size and solvent composition. We find that, with the increase of the bad (poor) solvent fraction and respective PB contraction, NP separation exhibits a transition from the hydrodynamic size exclusion regime with larger NPs having shorter retention time to the adsorption regime with smaller NPs having shorter retention time. The observed reversal of the sequence of elution is reminiscent of the critical condition in polymer chromatography at which the retention time is molecular weight independent. This finding suggests the possibility of the existence of an analogous special regime in nanoparticle chromatography at which NPs with like surface properties elute together regardless of their size. The latter has important practical implications: NPs can be separated by surface chemistry rather than by their size employing the gradient mode of elution with controlled variation of solvent composition. PMID- 28914541 TI - Ullmann-Type Intramolecular C-O Reaction Toward Thieno[3,2-b]furan Derivatives with up to Six Fused Rings. AB - A new strategy for the efficient synthesis of thieno[3,2-b]benzofuran derivatives (15 examples) was achieved on the basis of successive regioselective intermolecular Suzuki and newly developed intramolecular Ullmann C-O reactions in up to a 70% overall yield. The fast intramolecular C-O reaction can be realized by an efficient catalytic combination of CuI/1,10-phenanthroline in up to a 97% yield. This method is suitable for the construction of highly fused thieno[3,2 b]furan-containing heterocycles including DTBDF and TTDBF. The pi-pi and hydrogen bonding interactions observed for the C8-DTBDF single crystal suggest its great potential for OFET applications in the near future. PMID- 28914542 TI - Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to Synthesize Chiral Acetal-Containing Polycyclic Derivatives from Cyclic Hemiacetals and Enones. AB - We have developed an efficient one-pot, two-step sequential process to synthesize biologically and synthetically important chiral acetal-containing polycyclic derivatives. This novel protocol had been proved to proceed via Michael lactolization-oxocarbenium ion ring-closing sequence, which was initiated by a key reactive enamine intermediate and interrupted the previously established reaction pathway of two different enones used in this work, and generated the corresponding cycloadducts with excellent stereoselectivity bearing up to seven continuous stereocenters. Both chiral and racemic starting cyclic hemiacetals worked well in this strategy. The synthetic applications of the obtained polycyclic products have also been demonstrated. PMID- 28914543 TI - Modified Conducting Polymer Hole Injection Layer for High-Efficiency Perovskite Light-Emitting Devices: Enhanced Hole Injection and Reduced Luminescence Quenching. AB - Modification of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with sodium-poly(styrenesulfonate) leads to a ca. 0.3 eV increase in the work function and 15 times enhancement in the photoluminescence intensity of the overlying perovskite layer, which is closely correlated with the formation of a highly PSS-enriched top layer. As a direct result, the hybrid halide perovskite light-emitting devices with a modified PEDOT:PSS layer show the maximum external quantum efficiency of 7.2% and power efficiency of 19.0 lm W-1, which are 14-20 times those of the analogous devices using a pristine PEDOT:PSS layer and among the best reported values for the light-emitting devices using a neat perovskite emission layer. Our results illustrate that insufficient hole injection and luminescence quenching at the PEDOT:PSS anode are among the most important factors limiting the external quantum efficiencies of inverted perovskite light emitting devices. PMID- 28914544 TI - Fabrication of Hollow Silica Microspheres with Orderly Hemispherical Protrusions and Capability for Heat-Induced Controlled Cracking. AB - Hollow silica microspheres with orderly protrusions on their outer and inner surfaces were fabricated in three simple steps: (1) suspension polymerization of a polymerizable monomer containing silica nanoparticles to obtain polymeric microspheres with a layered shell of silica particles; (2) sol-gel reaction of tetraethoxysilane (TEOS) on the surface of the microspheres to connect the silica nanoparticles; (3) removal of polymer core by calcination. The shell composed of silica-connected silica nanoparticles remained spherical even after calcination, and the characteristic surface morphology with protrusions were obtained on both inner and outer surfaces. Measurements of the mechanical strength revealed that the compression modulus of the hollow microspheres increased with increasing thickness of the silica layer, which could be controlled by changing the concentration of TEOS in the sol-gel reaction. Rapid heating of the hollow silica microspheres with the thin silica-connected layer led to silica shell cracking, and the cracks were mostly observed in the connecting layer between the silica nanoparticles. The stress was probably concentrated in the connecting layer because of its lower thickness than the nanoparticles. Such characteristic of the hollow microspheres is useful for a capsule with capability for heat-induced controlled cracking caused by internal pressure changes. PMID- 28914545 TI - Spin-Multiplet Components and Energy Splittings by Multistate Density Functional Theory. AB - Kohn-Sham density functional theory has been tremendously successful in chemistry and physics. Yet, it is unable to describe the energy degeneracy of spin multiplet components with any approximate functional. This work features two contributions. (1) We present a multistate density functional theory (MSDFT) to represent spin-multiplet components and to determine multiplet energies. MSDFT is a hybrid approach, taking advantage of both wave function theory and density functional theory. Thus, the wave functions, electron densities and energy density-functionals for ground and excited states and for different components are treated on the same footing. The method is illustrated on valence excitations of atoms and molecules. (2) Importantly, a key result is that for cases in which the high-spin components can be determined separately by Kohn-Sham density functional theory, the transition density functional in MSDFT (which describes electronic coupling) can be defined rigorously. The numerical results may be explored to design and optimize transition density functionals for configuration coupling in multiconfigurational DFT. PMID- 28914546 TI - Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome. AB - OBJECTIVE: To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. DATA SOURCES: A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: English language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. DATA SYNTHESIS: Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. CONCLUSIONS: Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness. PMID- 28914547 TI - Challenges and resilience related to aging in the United States among older Chinese immigrants. AB - OBJECTIVES: This study sought to identify challenges and protective factors for resilience related to the process of aging among older Chinese immigrants in the United States. METHODS: This study used qualitative methods and involved 24 in depth interviews with Chinese immigrants aged 65 or older in Los Angeles. Content analysis was employed to analyze qualitative data. RESULTS: Three major themes emerged regarding challenges older Chinese immigrants encountered in aging in the United States: language barriers, loneliness and social isolation, and insufficient use of social services. Four themes were identified regarding resilience protective factors: acceptance and optimism; independence and autonomy; informal social support; and use of the formal social welfare system. CONCLUSION: This study provides several implications for future human services to build relational and societal resilience and enhance Chinese older immigrants' personal resilience. Cultural strengths should be taken into consideration by practitioners and policy makers. PMID- 28914548 TI - Neurohormonal modulation for treatment of cardiac involvement in dystrophinopathies and mitochondrial disease. PMID- 28914549 TI - Age groups related glioblastoma study based on radiomics approach. AB - Glioblastoma is the most aggressive malignant brain tumor with poor prognosis. Radiomics is a newly emerging and promising technique to reveal the complex relationships between high-throughput medical image features and deep information of disease including pathology, biomarkers and genomics. An approach was developed to investigate the internal relationship between magnetic resonance imaging (MRI) features and the age-related origins of glioblastomas based on a quantitative radiomics method. A fully automatic image segmentation method was applied to segment the tumor regions from three dimensional MRI images. 555 features were then extracted from the image data. By analyzing large numbers of quantitative image features, some predictive and prognostic information could be obtained by the radiomics approach. 96 patients diagnosed with glioblastoma pathologically have been divided into two age groups (<45 and >=45 years old). As expected, there are 101 features showing the consistency with the age groups (T test, p < .05), and unsupervised clustering results of those features also show coherence with the age difference (T test, p= .006). In conclusion, glioblastoma in different age groups present different radiomics-feature patterns with statistical significance, which indicates that glioblastoma in different age groups should have different pathologic, protein, or genic origins. PMID- 28914550 TI - SOCS3 participates in cholinergic pathway regulation of synovitis in rheumatoid arthritis. AB - Stimulation of the cholinergic inflammatory pathway can attenuate collagen induced arthritis (CIA) and inhibit synovitis by Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 signaling. Suppressor of cytokine signaling (SOCS) protein can also regulate the inflammatory processes and activate JAK/STAT signal transduction, but its involvement in rheumatoid arthritis (RA) has not been demonstrated. This study investigated the effect of SOCS on cholinergic pathway regulation of synovitis in the fibroblast-like synoviocytes (FLSs) of RA and CIA mice. The effects of nicotine on SOCS1 and SOCS3 protein expression in FLSs were assayed by western blotting before and after transfection with a small interfering RNA oligonucleotide (SOCS3-siRNA or control-siRNA). Interleukin-6 was measured by enzyme-linked immunosorbent assay of SOCS3-siRNA and control-siRNA transfected FLS culture supernatants. Histopathological evaluation and immunohistochemical staining of SOCS3 were performed in joint tissue sections of control, CIA model, vagotomy, and nicotine treated DBA/1 mice. Nicotine increased SOCS3 expression in the FLSs of RA. The inhibitory effect of nicotine on inflammatory factors was abolished by siRNA knockdown of SOCS3 protein expression. Nicotine increased the expression of SOCS3 protein in the synovium and reduced synovitis and bone erosion in CIA mice. PMID- 28914551 TI - Screening after hypertensive pregnancy disorders: She can do best. PMID- 28914552 TI - Myelodysplastic syndromes (MDS) in regular care in Germany - the oldest patients come to the fore. PMID- 28914553 TI - Nanomaterials as nanocarriers: a critical assessment why these are multi-chore vanquisher in breast cancer treatment. AB - Breast cancer is a group of diseases with various subtypes and leads to high mortality throughout the globe. Various conventional techniques are in practice to cure breast cancer but these techniques are linked with various shortcomings. Mostly these treatments are not site directed and cause toxicity towards normal cells. In order to overcome these issues, we need smart system that can deliver anticancer drugs to specific sites. Targeted drug delivery can be achieved via passive or active drug delivery using nanocarriers. This mode of drug delivery is more effective against breast cancer and may help in the reduction of mortality rate. Potentially used nanocarriers for targeted drug delivery belong to organic and inorganic molecules. Various FDA approved nano products are in use to cure breast cancer. However, body's defense system is main limitation for potential use of nano systems. However, this can be overcome by surface modification of nanocarriers. In this review, breast cancer and its types, targeted drug delivery and nanocarriers used to cure breast cancer are discussed. By progressing nanotechnology, we will be able to fight against this life threatening issue and serve the humanity, which is the basic aim of scientific knowledge. PMID- 28914554 TI - When cooperation goes wrong: brain and behavioural correlates of ineffective joint strategies in dyads. AB - PURPOSE: Human life is connoted by sophisticated interactions that involve not only single individuals, but larger social groups composed by members interacting each other. Cooperation secures a benefit to all the people engaged as well as important behaviors like helping, sharing, and acting prosocially. But what happens when the joint actions are not effective? MATERIALS AND METHOD: In the present study, we asked 24 participants paired in 12 dyads to cooperate during an attentional task in a way to synchronize their responses and obtain better outcomes. In addition we tested inter-brain and cognitive strategy similarities between subjects. Then, we frustrated their strategies by providing false feedbacks signalling the incapacity to create a synergy, which was reinforced by a general negative evaluation halfway through the task. The effects of the feedback inmodulating subjects behavioural performance and brain responsiveness were explored by means of functional near-infrared spectroscopy (fNIRS). RESULTS: Results showed a worsen performance after the negative feedback in the form of longer reaction times and a specifc pattern of brain activation involving th dorsolateral prefrontal cortex (DLPFC) and the superior frontal gyrus. The DLPFC showed increased O2Hb (oxy-haemoglobin) level after the feedback, compatible with the need for higher cognitive effort. In addition, fNIRS measures revealed a decreased inter-brain synchronicity in post-feedback condition for the dyad. Also, the representation of negative emotions in response to failing interactions was signalled by a right-lateralized effect. CONCLUSIONS: Results were interpreted at light of available knowledge on perceived self-efficacy and the implementation of common goals and strategies. PMID- 28914555 TI - Evaluation of the quality of care of elderly patients with chronic and breakthrough pain treated with opioids: SAND study. AB - OBJECTIVE: The objective of this study was to evaluate the quality of care of elderly patients with treatment for chronic pain (CP) and breakthrough pain (BTP). METHODS: A cross-sectional observational study was conducted in 20 pain units, selecting patients aged 70 years or older with baseline controlled CP in treatment with opioids and a diagnosis of BTP. Patients were classified as first episode of BTP or patient in follow-up. The patients completed the SF-12 quality of life questionnaire, Brief Pain Inventory, Lattinen Index, and Edmonton Symptoms Assessment Scale. The patient's satisfaction with the treatment was evaluated through a visual analogue scale (VAS). RESULTS: A total of 199 patients were included with 67.7% women (132). There were 28.5% (55) attending the first visit for BTP and 71.5% (138) were on follow-up visits. On the physical component of the SF-12, 95% had a score below the mean for the Spanish general population and 44% had a score below the mean on the mental component. Worse scores were observed for women in the bodily pain dimension (p = .032) and in the overall physical component (p = .045). There were 62.9% (112) patients satisfied with the treatment for BTP. In the multivariate analysis, SF-12 physical component scores (p = .017) and patient's satisfaction with BTP treatment was better in follow-up visits (p = .031). CONCLUSIONS: All clinical parameters compared between first visit for the treatment of BTP and follow-up visits were improved, so the quality of care was also considered improved. Elderly women and non-oncologic patients were observed to be the population with worse symptom control. PMID- 28914556 TI - Acute lymphoblastic leukemia during the third trimester of pregnancy. PMID- 28914557 TI - An analysis of the types of recently published research in the field of cachexia. AB - Introduction Cachexia is a common complication of many and varied chronic disease processes, yet it has received very little attention as an area of clinical research effort until recently. We sought to survey the contemporary literature on published research into cachexia to define where it is being published and the proportion of output classified into the main types of research output. Methods I searched the PubMed listings under the topic research term "cachexia" and related terms for articles published in the calendar years of 2015 and 2016, regardless of language. Searches were conducted and relevant papers extracted by two observers, and disagreements were resolved by consensus. Results There were 954 publications, 370 of which were review articles or commentaries, 254 clinical observations or non-randomised trials, 246 original basic science reports and only 26 were randomised controlled trials. These articles were published in 478 separate journals but with 36% of them being published in a core set of 23 journals. The H-index of these papers was 25 and there were 147 papers with 10 or more citations. Of the top 100 cited papers, 25% were published in five journals. Of the top cited papers, 48% were review articles, 18% were original basic science, and 7% were randomised clinical trials. Discussion This analysis shows a steady but modest increase in publications concerning cachexia with a strong pipeline of basic science research but still a relative lack of randomised clinical trials, with none exceeding 1000 patients. Research in cachexia is still in its infancy, but the solid basic science effort offers hope that translation into randomised controlled clinical trials may eventually lead to effective therapies for this troubling and complex clinical disease process. PMID- 28914558 TI - Robotics in percutaneous cardiovascular interventions. AB - INTRODUCTION: The fundamental technique of performing percutaneous cardiovascular (CV) interventions has remained unchanged and requires operators to wear heavy lead aprons to minimize exposure to ionizing radiation. Robotic technology is now being utilized in interventional cardiology partially as a direct result of the increasing appreciation of the long-term occupational hazards of the field. This review was undertaken to report the clinical outcomes of percutaneous robotic coronary and peripheral vascular interventions. Areas covered: A systematic literature review of percutaneous robotic CV interventions was undertaken. The safety and feasibility of percutaneous robotically-assisted CV interventions has been validated in simple to complex coronary disease, and iliofemoral disease. Studies have shown that robotically-assisted PCI significantly reduces operator exposure to harmful ionizing radiation without compromising procedural success or clinical efficacy. In addition to the operator benefits, robotically-assisted intervention has the potential for patient advantages by allowing more accurate lesion length measurement, precise stent placement and lower patient radiation exposure. However, further investigation is required to fully elucidate these potential benefits. Expert commentary: Incremental improvement in robotic technology and telecommunications would enable treatment of an even broader patient population, and potentially provide remote robotic PCI. PMID- 28914559 TI - Bilateral Posterior Scleritis Associated with Giant Cell Arteritis: A Case Report. AB - AIM: To report a case of bilateral posterior scleritis associated with giant cell arteritis Case Report: A 62-year-old female patient presented with bilateral progressive vision loss was diagnosed with bilateral posterior scleritis. According to clinical signs and symptoms and laboratory testing, Giant cell arteritis was also diagnosed. Within 8 weeks of the corticosteroid treatment, the serous retinal detachments completely resolved and choroidal thickness decreased in both eyes. Visual acuity increased, and the symtoms related to Giant cell arteritis improved. CONCLUSION: Posterior scleritis is an inflammatory disease that may be associated with many autoimmune systemic diseases. GCA should be thought of particularly in patients over the age of 50 with bilateral involvement, and a relevant detailed history should be obtained for early and correct diagnosis and treatment. PMID- 28914560 TI - Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine. AB - BACKGROUND: Azathioprine is frequently used in severe eczema. It is converted in the liver into active metabolites, including 6-thioguanine nucleotide (6-TGN) and methylated 6-methylmercaptopurine (6-MMP). In the past, the therapeutic potential of azathioprine may have not been fully utilized. Recent investigations on inflammatory bowel disease have led to a better understanding of azathioprine metabolism and optimizing treatment. OBJECTIVE: To investigate whether measuring thiopurine metabolites in circulation can improve the effectiveness and safety of azathioprine treatment in patients with atopic dermatitis and/or chronic hand/foot eczema. METHODS: Azathioprine metabolite levels were measured in eczema patients during maintenance treatment (Part I) and dose escalation (Part II). Clinical effectiveness, hepatotoxicity, and bone marrow suppression were analyzed and TPMT genotype was assessed. RESULTS: A wide variation in metabolite levels in all dose groups was observed. In Part I (32 patients), there were no significant differences in 6-TGN levels between clinical responders and non-responders (p = .806). No hepatoxicity or myelotoxicity was observed. In Part II, all 6-TGN and 6 MMP levels increased during dose escalation. Hypermethylation was observed in 2/8 patients. CONCLUSION: For individual eczema patients treated with azathioprine, routinely measuring 6-TGN and 6-MMP can be helpful in optimizing azathioprine dose, improving clinical effectiveness, and preventing side effects. PMID- 28914561 TI - Oral and depot progestin therapy for endometriosis: towards a personalized medicine. AB - INTRODUCTION: Endometriosis is an estrogen-dependent chronic inflammatory disorder that requires a life-long management plan. Long-term adherence to treatment is pivotal to ensure an effective clinical management. In this optic, one of the cornerstone of endometriosis medical treatment is represented by progestins. Areas covered: This narrative review examines the clinical efficacy, safety and tolerability of oral and depot progestins used in the treatment of endometriosis. The material included in the current manuscript was obtained with a MEDLINE search through PubMed from inception until February 2017. Expert opinion: Progestins are effective in controlling pain symptoms in the majority of women with endometriosis, and their effect seems not inferior to that achieved with other compounds used to treat the disease, such as gonadotropin-releasing hormone agonist. Available progestins include a broad range of both oral and depot compounds, and represent, in most cases, an inexpensive treatment option. In addition, progestins do not increase significantly thrombotic risk and could be adopted in those women with metabolic or cardiovascular contraindication to estrogen-progestins. The choice between the different available compounds should be tailored for every woman with preference to the most cost-effective treatment, depending on the most complained symptom and disease location. PMID- 28914562 TI - The effect of regular aquatic exercise on blood pressure: A meta-analysis of randomized controlled trials. AB - Background No meta-analysis has examined the effect of regular aquatic exercise on blood pressure. The purpose of this study was to perform a meta-analysis to evaluate the effects of regular aquatic exercise on blood pressure. Design A meta analysis of randomized controlled trials. Methods Databases were searched for literature published up to April 2017. The randomized controlled trials analysed involved healthy adults, an intervention group that only performed aquatic exercise and a control group that did not exercise, no other intervention, and trials indicated mean systolic blood pressure or diastolic blood pressure. The net change in blood pressure was calculated from each trial, and the changes in blood pressure were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis of subjects with hypertension, subjects who performed endurance exercise (or not), and subjects who only swam (or not) was performed, and the net changes in blood pressure were pooled. Results The meta-analysis examined 14 trials involving 452 subjects. Pooled net changes in blood pressure improved significantly (systolic blood pressure -8.4 mmHg; diastolic blood pressure -3.3 mmHg) and the changes in systolic blood pressure contained significant heterogeneity. When subjects were limited to those with hypertension, those who performed endurance exercise and subjects who did not swim, pooled net changes in systolic and diastolic blood pressure decreased significantly, but the heterogeneity of systolic blood pressure did not improve. Conclusion Like exercise on land, aquatic exercise should have a beneficial effect by lowering blood pressure. In addition, aquatic exercise should lower the blood pressure of subjects with hypertension, and other forms of aquatic exercise besides swimming should also lower blood pressure. PMID- 28914563 TI - Patients with psychological ICPC codes in primary care; a case-control study investigating the decade before presenting with problems. AB - BACKGROUND: Recognizing patients with psychological problems can be difficult for general practitioners (GPs). Use of information collected in electronic medical records (EMR) could facilitate recognition. OBJECTIVES: To assess relevant EMR parameters in the decade before patients present with psychological problems. METHODS: Exploratory case-control study assessing EMR parameters of 58 228 patients recorded between 2013 and 2015 by 54 GPs. We compared EMR parameters recorded before 2014 of patients who presented with psychological problems in 2014 with those who did not. RESULTS: In 2014, 2406 patients presented with psychological problems. Logistic regression analyses indicated that having registrations of the following statistically significant parameters increased the chances of presenting with psychological problems in 2014: prior administration of a depression severity questionnaire (odds ratio (OR): 3.3); fatigue/sleeping (OR: 1.6), neurological (OR: 1.5), rheumatic (OR: 1.5) and substance abuse problems (OR: 1.5); prescriptions of opioids (OR: 1.3), antimigraine preparations (OR: 1.5), antipsychotics (OR: 1.7), anxiolytics (OR: 1.4), hypnotics and sedatives (OR: 1.4), antidepressants (OR: 1.7), and antidementia drugs (OR: 2.1); treatment with minimal interventions (OR: 2.2) and physical exercise (OR: 3.3), referrals to psychology (OR: 1.5), psychiatry (OR: 1.6), and psychosocial care (OR: 2.1); double consultations (OR: 1.2), telephone consultations (OR: 1.1), and home visits (OR: 1.1). CONCLUSION: This study demonstrates that possible indications of psychological problems can be identified in EMR. Many EMR parameters of patients presenting with psychological problems were different compared with patients who did not. PMID- 28914564 TI - Neurohumoral treatment for cardiac disease in dystrophinopathies and mitochondrial disorders. PMID- 28914565 TI - Reducing overdiagnosis in primary care is needed. PMID- 28914567 TI - Chemotherapy-free, triple combination of obinutuzumab, venetoclax and idasanutlin: antitumor activity in xenograft models of non-Hodgkin lymphoma. PMID- 28914566 TI - A novel ETFDH mutation in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. AB - AIM OF THE STUDY: To report a novel mutation in the electron transfer flavoprotein dehydrogenase (ETFDH) gene in an adult patient with late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. MATERIALS AND METHODS: The genomic DNAs from a patient whose main clinical presentations are muscles weakness and hypoglycemia was analysed. RESULTS: The patient was identified to carry compound heterozygous mutations in ETFDH gene. Two missense mutations c.814 G > A and c.389 A > T were found. CONCLUSION: This is the first report of c.814G > A mutation in ETFDH in adult patient with MADD. PMID- 28914568 TI - Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Decrease the Development of Severe Experimental Autoimmune Uveitis in B10.RIII Mice. AB - PURPOSE: We investigated the effect of exogenously administered human embryonic stem cell-derived mesenchymal stromal cells (hESC-MSCs) in experimental autoimmune uveitis (EAU) in B10.RIII mice, a murine model of severe uveitis. METHODS: B10.RIII mice were immunized with an uveitogenic peptide, and intraperitoneal injections of 5 million hESC-MSCs per animal were given on the same day. Behavioral light sensitivity assays, histological evaluation, cytokine production, and regulatory T cells were analyzed at the peak of the disease. RESULTS: Histological and behavioral evidence demonstrated that early systemic treatment with hESC-MSCs decreases the development of severe EAU in B10.RIII mice. hESC-MSCs suppress Th17 and upregulate Th1 and Th2 responses as well as IL 2 and GM-CSF in splenocytes from hESC-MSC-treated mice. CONCLUSIONS: MSCs that originate from hESC decrease the development of severe EAU in B10.RIII mice, likely through systemic immune modulation. Further investigation is needed to determine any potential effect on active EAU. PMID- 28914569 TI - Mutations in myeloproliferative neoplasms - their significance and clinical use. AB - INTRODUCTION: Clonal hematologic diseases of the blood such as polycythemia vera, essential thrombocythemia and primary myelofibrosis belong to the BCR-ABL negative Myeloproliferative Neoplasms (MPN). These diseases are characterized by clonal expansion of hematopoietic precursor cells followed by increased production of differentiated cells of the myeloid lineage. Initiation of clonal hematopoiesis, formation of a clinical phenotype as well as disease progression form part of MPN disease evolution. The disease is driven by acquired somatic mutations in critical pathways such as cytokine signaling, epigenetic regulation, RNA splicing, and transcription factor signaling. Areas covered: The following review aims to provide an overview of the mutational landscape of MPN, the impact of these mutations in MPN pathogenesis as well as their prognostic value. Finally, a summary of how these mutations are being used or could potentially be used for the treatment of MPN patients is presented. Expert commentary: The genetic landscape of MPN patients has been successfully dissected within the past years with the advent of new sequencing technologies. Integrating the genetic information within a clinical setting is already benefitting patients in terms of disease monitoring and prognostic information of disease progression but will be further intensified within the next years. PMID- 28914570 TI - Inflammasome Deficiency Makes Pro-resolving Lipid Mediators Great Again. PMID- 28914571 TI - High-Frequency Oscillation in Acute Respiratory Distress Syndrome. The End of the Story? PMID- 28914572 TI - Bleeding and Thrombosis in Pediatric Extracorporeal Membrane Oxygenation. Can We Improve Anticoagulation Strategies? PMID- 28914573 TI - The Tobacco Industry Targets Youth. PMID- 28914574 TI - One of us: the story of Anders Breivik and the massacre in Norway. PMID- 28914575 TI - Clinician's guide to psychological assessment and testing: with forms and templates for effective practice. PMID- 28914576 TI - Behavioral health care and technology: using science-based innovations to transform practice. PMID- 28914577 TI - Unbalanced Vitreous Levels of Osteoprotegerin, RANKL, RANK, and TRAIL in Proliferative Diabetic Retinopathy. AB - PURPOSE: We investigated the expression of the proinflammatory and proangiogenic factor osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor-kappaB ligand (RANKL), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and the receptor RANK in proliferative diabetic retinopathy (PDR). MATERIALS AND METHODS: Vitreous samples from PDR and nondiabetic control patients and epiretinal membranes from PDR patients were studied by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis. RESULTS: Vascular endothelial growth factor, OPG, and soluble RANK levels in vitreous samples from PDR patients were significantly higher than that in nondiabetic controls. Soluble TRAIL levels were significantly lower in PDR patients than that in nondiabetic control, whereas soluble RANKL levels did not differ significantly. RANKL, RANK, and TRAIL were expressed in vascular endothelial cells, myofibroblasts, and CD45-expressing leukocytes in PDR epiretinal membranes. CONCLUSIONS: Dysregulated expression of OPG/RANKL/RANK pathway and TRAIL might be related to inflammation and angiogenesis in PDR. PMID- 28914578 TI - The Choroidal Vascularity Index Decreases and Choroidal Thickness Increases in Vogt-Koyanagi-Harada Disease Patients During a Recurrent Anterior Uveitis Attack. AB - PURPOSE: To measure changes in the choroidal vascularity index (CVI) in chronic Vogt-Koyanagi-Harada (VKH) disease during a recurrent anterior uveitis attack. METHODS: Forty VKH patients and 40 normal controls were included in this study. Choroidal images were recorded before and during a recurrent anterior uveitis attack, as well as after appropriate treatment. CVI was measured by the binarization technique using ImageJ software (Bethesda, MD). RESULTS: The CVI was 0.75 +/- 0.09 in quiescent VKH patients, which was significantly higher compared to healthy controls (0.70 +/- 0.05, p < 0.0001). The CVI significantly decreased to 0.72 +/- 0.09 when granulomatous anterior uveitis appeared in these patients. However, it returned to 0.75 +/- 0.08 after uveitis resolved. CONCLUSIONS: A significant decrease of the CVI occurred during recurrent anterior uveitis in chronic VKH. CVI may provide a novel parameter to guide the treatment of VKH disease. PMID- 28914579 TI - A polymicrobial view of disease potential in Crohn's-associated adherent-invasive E. coli. AB - The human gut is home to trillions of bacteria and provides the scaffold for one of the most complex microbial ecosystems in nature. Inflammatory bowel diseases, such as Crohn's disease, involve a compositional shift in the microbial constituents of this ecosystem with a marked expansion of Enterobacteriaceae, particularly Escherichia coli. Adherent-invasive E. coli (AIEC) strains are frequently isolated from the biopsies of Crohn's patients, where their ability to elicit inflammation suggests a possible role in Crohn's pathology. Here, we consider the origins of the AIEC pathovar and discuss how risk factors associated with Crohn's disease might influence AIEC colonization dynamics within the host to alter the overall disease potential of the microbial community. PMID- 28914580 TI - IF2 and unique features of initiator tRNAfMet help establish the translational reading frame. AB - Translation begins at AUG, GUG, or UUG codons in bacteria. Start codon recognition occurs in the P site, which may help explain this first-position degeneracy. However, the molecular basis of start codon specificity remains unclear. In this study, we measured the codon dependence of 30S*mRNA*tRNAfMet and 30S*mRNA*tRNAMet complex formation. We found that complex stability varies over a large range with initiator tRNAfMet, following the same trend as reported previously for initiation rate in vivo (AUG > GUG, UUG > CUG, AUC, AUA > ACG). With elongator tRNAMet, the codon dependence of binding differs qualitatively, with virtually no discrimination between GUG and CUG. A unique feature of initiator tRNAfMet is a series of three G-C basepairs in the anticodon stem, which are known to be important for efficient initiation in vivo. A mutation targeting the central of these G-C basepairs causes the mRNA binding specificity pattern to change in a way reminiscent of elongator tRNAMet. Unexpectedly, for certain complexes containing fMet-tRNAfMet, we observed mispositioning of mRNA, such that codon 2 is no longer programmed in the A site. This mRNA mispositioning is exacerbated by the anticodon stem mutation and suppressed by IF2. These findings suggest that both IF2 and the unique anticodon stem of fMet-tRNAfMet help constrain mRNA positioning to set the correct reading frame during initiation. PMID- 28914581 TI - Circulating lymphocyte levels and relationship with infection status in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta. AB - BACKGROUND:: Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing-remitting multiple sclerosis. OBJECTIVE:: To analyse total and differential lymphocyte levels and relationship with infection status. METHODS:: In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- ( n = 919) or intramuscular interferon beta-1a treated ( n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4+/CD8+ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme ( n = 2236). RESULTS:: Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4+ and CD8+ T-cell counts decreased <10% (7.1% vs 1.6%, 9.7% vs 2.0%, 9.3% vs 5.9%: daclizumab beta vs interferon beta-1a, respectively); shifts to ALC below lower limit of normal occurred in 13% versus 15%, respectively. Grade 3 lymphopenia was uncommon (TSP: <1%) and transient. Lymphocyte changes generally occurred within 24 weeks after treatment initiation and were reversible within 12 weeks of discontinuation. In DECIDE, mean CD4+/CD8+ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE. CONCLUSION:: When observed, ALC and CD4+/CD8+ T-cell count decreases in daclizumab beta-treated patients were generally mild-to modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections. PMID- 28914582 TI - A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib. AB - A 52-year-old man with a past medical history of chronic myeloid leukemia (CML) in remission developed progressive shortness of breath over a two-month period. He was initially treated with dasatinib for four years, until developing pulmonary arterial hypertension (PAH) with pleural effusions. His symptoms improved after stopping dasatinib. He was then switched to bosutinib for approximately one year, which was then stopped before admission due to worsening shortness of breath. His initial workup showed bilateral pleural effusions with severe PAH and cor pulmonale. He had symptomatic improvement with PAH-specific therapy following discontinuation of the bosutinib. The life expectancy of CML patients has increased in the era of the tyrosine kinase inhibitors (TKIs), and managing adverse events (AEs) of the TKIs and improving quality of life are becoming more important. Pulmonary hypertension (PH) and pleural effusions are rarely reported AEs of bosutinib. More reports with PH and pleural effusions arising after bosutinib use in patients previously treated with dasatinib is furthermore concerning. In this era with novel chemotherapeutic agents, physicians ought to be weary of the significant morbidity implicated by these agents in the lives of patients. PMID- 28914583 TI - The DEKA hand: A multifunction prosthetic terminal device-patterns of grip usage at home. AB - BACKGROUND: Research is needed to understand how upper limb prosthesis users take advantage of multiple grip options. OBJECTIVES: To quantify usage of DEKA hand grip patterns during home use and compare patterns of usage at home to test sessions. STUDY DESIGN: Observational study design. METHODS: Data were collected from 21 subjects. Engineering data on grip were downloaded at various intervals. Proportion of time in each grip was calculated for the first 4 weeks of home use, later months, and test sessions (testing use) and compared statistically across intervals. Exploratory analyses compared grip proportion by DEKA Arm level and prior prosthesis use. RESULTS: Three most commonly used grips during home use were power, pinch open, and lateral pinch. There were no significant differences between grip use during the first month and later months. Power grip was used 55% of the time at home and 23% of the time in testing use. Pinch closed, lateral, and chuck grip were used less at home than in tests. Comparisons were by configuration level and prosthetic use and no significant differences were found. CONCLUSION: Patterns of DEKA hand grip usage differed between home and test environments, suggesting that users relied on fewer grip patterns at home. Clinical relevance These findings have implications for prosthetic training with multi-articulating terminal devices. PMID- 28914584 TI - Circumferential Ciliary Body Cysts Presenting as Acute Pigment Dispersion and Ocular Hypertension. AB - PURPOSE: To report a case of circumferential neuroepithelial cyst of the ciliary body presenting with pigment dispersion (PD) and ocular hypertension. CASE REPORT: 48-year-old female patient presented with a complaint of pain in the left eye. On examination, visual acuity of the left eye was 0.9, and the intraocular pressure was 48 mmHg. Biomicroscopic anterior segment examination of the left eye revealed 4+ pigmented cells in the anterior chamber. Active PD from the pupillary region at 11 o'clock was noticed at the time of the examination. Ultrasound biomicroscopy demonstrated 360o cystic lesions of the ciliary body in the left eye. The patient was diagnosed as neuroepithelial cyst of the ciliary body. CONCLUSION: Our case is unique as it is the first case of circumferential neuroepithelial ciliary body cyst presenting with acute PD and ocular hypertension. PMID- 28914585 TI - Planning future care services: Analyses of investments in Norwegian municipalities. AB - AIMS: To analyse whether the Norwegian Central Government's goal of subsidizing 12,000 places in nursing homes or sheltered housing using an earmarked grant was reached and to determine towards which group of users the planned investments were targeted. METHODS: Data from the investment plans at municipal level were provided by the Norwegian Housing Bank and linked to variables describing the municipalities' financial situation as well as variables describing the local needs for services provided by Statistics Norway. Using regression analyses we estimated the associations between municipal characteristics and planned investments in total and by type of care place. RESULTS: The Norwegian Central Government reached its goal of giving subsidies to 12,000 new or rebuilt places in nursing homes and sheltered housing. A total of 54% of the subsidies (6878 places) were given to places in nursing homes. About 7500 places were available by the end of the planning period and the rest were under construction. About 50% of the places were planned for user groups aged <67 years and 23% of the places for users aged <25 years. One-third of the places were planned for users with intellectual disabilities. Investments in nursing homes were correlated with the share of the population older than 80 years and investments in sheltered houses were correlated with the share of users with intellectual disabilities. CONCLUSIONS: Earmarked grants to municipalities can be adequate measures to affect local resource allocation and thereby stimulate investments in future care. With the current institutional setup the municipalities adapt investments to local needs. PMID- 28914586 TI - Presenilins at the crossroad of a functional interplay between PARK2/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases. AB - Autophagic and mitophagic defects are consistently observed in Alzheimer's disease-affected brains. However, the mechanistic defects underlying these anatomical lesions remained unexplained. We have delineated a molecular cascade by which PSEN1 and PSEN2 (presenilins 1 and 2) control PINK1 transcription and function by an AICD-mediated FOXO3a-dependent mechanism. Further, we establish that PARK2 (parkin) acts upstream to PINK1 and regulates its function by a PSEN dependent mechanism. Our study thus demonstrates a functional interplay between PSEN and PINK1 and establishes a feedback process by which PARK2 and PINK1 could control mitochondrial dysfunction and autophagic processes in various neurodegenerative pathologies including Alzheimer's and Parkinson's diseases. PMID- 28914587 TI - Self-rated health and social capital in Iraqi immigrants to Sweden: The MEDIM population-based study. AB - OBJECTIVES: Poor self-rated health is an estimator of quality of life and a predictor of mortality seldom studied in immigrant populations. This work aimed to study self-rated health in relation to social capital, socioeconomic status, lifestyle and comorbidity in immigrants from Iraq - one of the largest non European immigrant group in Sweden today - and to compare it with the self-rated health of native Swedes. DESIGN: The study was a cross-sectional population-based study conducted from 2010 to 2012 among citizens of Malmo, Sweden, aged 30-65 years and born in Iraq or Sweden. All participants underwent a health examination and answered questionnaires on self-rated health, social capital, comorbidity, lifestyle and socioeconomic status. RESULTS: In total, 1348 Iraqis and 677 Swedes participated. Poor self-rated health was identified in 43.9% of Iraqis and 21.9% of native Swedes ( p<0.001), with the highest prevalence (55.5%) among Iraqi women. Low social capital was highly prevalent in the immigrants. Female gender showed higher odds of poor self-rated health in Iraqis than in Swedes (OR 1.8, 95% CI 1.4-2.5, pinteraction=0.024), independent of other risk factors connected to social capital, socioeconomic status, lifestyle or comorbidity. CONCLUSIONS: Although public health initiatives promoting social capital, socioeconomic status and comorbidity in immigrants are crucial, the excess risk of poor self-rated health in Iraqi women is not fully attributed to known risk factors for self rated health, but remains to be further explored. PMID- 28914588 TI - Interstitial telomeric repeats-associated DNA breaks. AB - During a cell's lifespan, DNA break formation is a common event, associated with many processes, from replication to apoptosis. Most of DNA breaks are readily repaired, but some are meant to persist in time, such as the chromosome ends, protected by telomeres. Besides them, eukaryotic genomes comprise shorter stretches of interstitial telomeric repeats. We assumed that the latter may also be associated with the formation of DNA breaks meant to persist in time. In zebrafish and mouse embryos, cells containing numerous breakage foci were identified. These breaks were not associated with apoptosis or replication, nor did they seem to activate DNA damage response machinery. Unlike short-living, accidental sparse breaks, the ones we found seem to be closely associated, forming discrete break foci. A PCR-based method was developed, allowing specific amplification of DNA regions located between inverted telomeric repeats associated with breaks. The cloning and sequencing of such DNA fragments were found to denote some specificity in their distribution for different tissue types and development stages. PMID- 28914589 TI - HPLC-DAD method development and validation for the quantification of hydroxymethylfurfural in corn chips by means of response surface optimisation. AB - In recent years, there has been an increased concern about the presence of toxic compounds derived from the Maillard reaction produced during food cooking at high temperatures. The main toxic compounds derived from this reaction are acrylamide and hydroxymethylfurfural (HMF). The majority of analytical methods require sample treatments using solvents which are highly polluting for the environment. The difficulty of quantifying HMF in complex fried food matrices encourages the development of new analytical methods. This paper provides a rapid, sensitive and environmentally-friendly analytical method for the quantification of HMF in corn chips using HPLC-DAD. Chromatographic separation resulted in a baseline separation for HMF in 3.7 min. Sample treatment for corn chip samples first involved a leaching process using water and afterwards a solid-phase extraction (SPE) using HLB-Oasis polymeric cartridges. Sample treatment optimisation was carried out by means of Box-Behnken fractional factorial design and Response Surface Methodolog y to examine the effects of four variables (sample weight, pH, sonication time and elution volume) on HMF extraction from corn chips. The SPE HPLC-DAD method was validated. The limits of detection and quantification were 0.82 and 2.20 mg kg-1, respectively. Method precision was evaluated in terms of repeatability and reproducibility as relative standard deviations (RSDs) using three concentration levels. For repeatability, RSD values were 6.9, 3.6 and 2.0%; and for reproducibility 18.8, 7.9 and 2.9%. For a ruggedness study the Yuden test was applied and the result demonstrated the method as robust. The method was successfully applied to different corn chip samples. PMID- 28914590 TI - Canine Salivary Glands: Analysis of Rab and SNARE Protein Expression and SNARE Complex Formation With Diverse Tissue Properties. AB - The comparative structure and expression of salivary components and vesicular transport proteins in the canine major salivary glands were investigated. Histochemical analysis revealed that the morphology of the five major salivary glands-parotid, submandibular, polystomatic sublingual, monostomatic sublingual, and zygomatic glands-was greatly diverse. Immunoblot analysis revealed that expression levels of alpha-amylase and antimicrobial proteins, such as lysozyme, lactoperoxidase, and lactoferrin, differed among the different glands. Similarly, Rab proteins (Rab3d, Rab11a, Rab11b, Rab27a, and Rab27b) and soluble N ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) proteins VAMP4, VAMP8, syntaxin-2, syntaxin-3, syntaxin-4, and syntaxin-6 were expressed at various levels in individual glands. mmunohistochemistry of Rab3d, Rab11b, Rab27b, VAMP4, VAMP8, syntaxin-4, and syntaxin-6 revealed their predominant expression in serous acinar cells, demilunes, and ductal cells. The VAMP4/syntaxin-6 SNARE complex, which is thought to be involved in the maturation of secretory granules in the Golgi field, was found more predominantly in the monostomatic sublingual gland than in the parotid gland. These results suggest that protein expression profiles in canine salivary glands differ among individual glands and reflect the properties of their specialized functions. PMID- 28914592 TI - Effect of Topically-Applied Hyaluronic-Acid on Pain and Palatal Epithelial Wound Healing: An Examiner-Blind, Randomized, Controlled Clinical Trial. AB - BACKGROUND: This study aimed to evaluate the effects of two different concentrations of topical hyaluronic-acid on post-operative patient discomfort and wound healing of palatal donor sites following free gingival graft (FGG) surgery. METHODS: Thirty-six patients requiring FGG were randomly assigned into three groups in an examiner-blind, randomized-controlled clinical trial. After harvesting palatal grafts, 0.2% and 0.8% hyaluronic-acid gels were used in the test-1 and -2 groups, respectively. Gels were applied on donor sites and protected with periodontal dressing in the test groups whereas the wound was covered only with periodontal dressing in the control group. On days 3-7-14 and 21, pain and burning sensation were recorded by using visual analog scale (VAS) as well as other parameters such as complete epithelization (CE) and color match on days 3-7-14-21-42. RESULTS: Test groups experienced less pain than the control group on days 3 and 7 (P<0.001 and P<0.001, respectively). The mean VAS score for burning sensation was higher in the control group on day 3 compared to the test-1 and -2 groups (P=0.033 and P=0.020, respectively). CE in all patients was achieved on day 21 in both test groups while it was achieved on day 42 in the control group. The test groups showed higher color match scores than the control group on days 21 (P<0.001 and P<0.001, respectively) and 42 (P=0.004 and P=0.002, respectively). CONCLUSION: Topical application of hyaluronic-acid exhibits positive impact on post-operative pain, burning sensation and accelerates palatal wound healing in terms of epithelization and color match. PMID- 28914591 TI - Mucosa-associated microbiota dysbiosis in colitis associated cancer. AB - Gut microbiota dysbiosis has been associated with inflammatory bowel diseases (IBD). In colorectal cancer, the gut microbiota has also been recognized as potentially involved in aggravating or favoring the tumor development. However, very little is known on the structure and role of the microbiota in colitis associated cancer (CAC), an important complication of IBD in human. Here we analyzed the bacterial and fungal composition of the mucosa associated microbiota of patients suffering CAC, sporadic cancer (SC) and of healthy subjects (HS) by barcode sequences analysis on the following cohort: 7 CAC patients, 10 SC patients and 10 HS using 16S (MiSeq) and ITS2 (pyrosequencing) sequencing, for bacteria and fungi respectively. Mucosa-associated bacterial microbiota in CAC was significantly different from the ones in SC or in HS, while the fungal showed no differences. Comparison between mucosa-associated microbiota on the tumor site or in normal mucosa near the tumor showed very similar patterns. The global mucosa-associated bacterial microbiota in cancer patients was characterized by a restriction in biodiversity but no change for the fungal community. Compared to SC, CAC was characterized by an increase of Enterobacteriacae family and Sphingomonas genus and a decrease of Fusobacterium and Ruminococcus genus. Our study confirms the alteration of the mucosa-associated bacterial microbiota in IBD and SC. Although the cohort is limited in number, this is the first evidence of the existence of an altered bacterial microbiota in CAC clearly different from the one in SC patients. PMID- 28914593 TI - Effects of Local Administration of Tiludronic Acid on Experimental Periodontitis in Diabetic Rats. AB - BACKGROUND: Tiludronic acid (TIL) presents antiresorptive and anti-inflammatory properties and it has not been evaluated in the association periodontitis diabetes mellitus (DM) to date. This study evaluated the effects of local administration of TIL on experimental periodontitis (EP) in rats with streptozotocin-induced DM. METHODS: Thirty-two animals (Rattus norvegicus, albinus, Wistar) were divided into groups DM/C (Control), DM/EP, DM/EP/TIL1 and DM/EP/TIL3. In groups EP, a ligature was placed around mandibular molars (MM). In groups DM/EP/TIL1 and DM/EP/TIL3, TIL solutions (1 and 3 mg/kg, respectively) were injected into the gingival tissue of MM every other day during 10 days, until euthanasia. Periodontal tissues were analyzed by microcomputed tomography, histomorphometry, immunohistochemistry (TRAP, RANKL, OPG, cleaved caspase 3) and qRT-PCR (IL-1beta, VEGF). RESULTS: In microtomographic analyses, groups DM/EP/TIL1 and DM/EP/TIL3 presented reduced alveolar bone resorption (p<0.05). Group DM/EP/TIL3 presented decreased attachment loss (p<0.05). The amount of TRAP positive multinucleated cells was decreased in TIL groups (p<0.05). Group DM/EP/TIL3 presented lower immunolabeling pattern for RANKL (p<0.05). TIL treatment decreased the genic expression of IL-1beta and, in group DM/EP/TIL3, the expression of VEGF was increased (p<0.05). CONCLUSIONS: Local administration of TIL promoted a protective effect against tissue destruction in EP in diabetic rats, and the dosage of 3 mg/kg of TIL promoted the best results regarding its antiresorptive and anti-inflammatory effects. PMID- 28914594 TI - Salivary Neuropeptides, Stress and Periodontitis. AB - BACKGROUND: Scientific evidence for psychological stress as a risk factor for periodontitis is fragmentary relying mostly on either questionnaire-based or biomarker studies. The aim of this study was to investigate Brain Derived Neurotrophic Factor, Substance P, Vasoactive Intestinal Peptide (VIP), Neuropeptide Y (NPY), Calcitonin Gene Related Peptide and Adrenomedullin as well as cortisol in saliva and serum in periodontal health and disease combined with different aspects of stress and possible associations with clinical parameters. METHODS: In total, 56 patients with aggressive and chronic periodontitis and 44 healthy controls were screened by ELISA and mass spectrometry for the presence of neuropeptides and cortisol in saliva and serum. Psychological stress was evaluated by validated questionnaires. All substances were explored for a possible relationship to periodontitis, clinical parameters and stress. RESULTS: VIP and NPY showed significantly higher levels in the saliva but not in the serum of patients with periodontitis. These neuropeptides correlated with the extent, severity and bleeding on probing scores in periodontitis patients. Females had significantly lower salivary VIP levels. There were no differences among the participants regarding psychological stress. CONCLUSIONS: VIP and NPY in saliva could be potential gender-specific salivary biomarkers for periodontitis regardless of psychological stress. PMID- 28914595 TI - Evaluation of gingival crevicular fluid and peri-implant sulcus fluid levels of periostin: A preliminary report. AB - BACKGROUND: Periostin is a protein present in alveolar bone and periodontal ligament whose function is related to response to external forces. The aims of this study are to detect levels of periostin in peri-implant sulcular fluid (PISF) and gingival crevicular fluid (GCF) and to evaluate the relationship between periostin, pyridinoline cross-linked carboxyterminal telopeptide of Type I collagen (ICTP), and C-terminal cross-linked telopeptide of Type I collagen (CTX) levels and clinical inflammatory symptoms and duration of functional loading. METHODS: The study population comprised nine women and four men with mean age 43.23 +/- 12.48. Twenty "bone-level designed" dental implants (DIs) placed in molar or premolar sites, without any signs of peri-implant bone loss and with a restoration in function for at least 12 months, were included in the study with 20 contralateral natural teeth (NT) as controls. Clinical parameters and restoration dates of the implants were recorded. PISF, GCF, ICTP, CTX, and periostin levels were evaluated using enzyme-linked immunosorbent assay. RESULTS: ICTP, CTX, and periostin levels were similar between DI and NT groups. There were no statistically significant differences between PISF and GCF values. When implants were grouped as healthy (gingival index [GI] = 0) and inflamed (GI >=0), ICTP levels and PISF volume were lower in healthy implants compared with the inflamed group. Both periostin and CTX levels were negatively correlated with functioning time, suggesting less bone remodeling around DIs at later stages of functioning. CONCLUSION: Findings of this study suggest collagen breakdown products may be used as markers to evaluate peri-implant metabolism. PMID- 28914596 TI - Obesity and periodontitis: An experimental study to evaluate periodontal and systemic effects of comorbidity. AB - BACKGROUND: Obesity and overweight have been associated with periodontitis. This study aims to evaluate periodontal and systemic effects of this association in a validated experimental model. METHODS: Twenty-eight male Wistar rats were randomly divided into four groups: 1) control group (Con) (fed with standard diet); 2) high-fat diet group (HFD) (fed with a diet containing 35.2% fat); 3) control group with induced periodontitis (Con-Perio); and 4) HFD group with induced periodontitis (HFD-Perio). To induce periodontitis, oral gavages with Porphyromonas gingivalis ATCC W83K1 and Fusobacterium nucleatum DMSZ 20482 were used. Periodontal outcomes were evaluated by inflammatory parameters, periodontal probing depth (PD), and modified gingival index (MGI). Systemic effects were evaluated by measuring levels of inflammatory cytokines, insulin, adiponectin, and leptin using multiplex immunoassays and levels of visfatin, resistin, lipid profiles, transaminases, and plasma endotoxin using colorimetric tests and the glucose tolerance test. RESULTS: Clinical parameters (PD and MGI) were significantly increased (P < 0.05) in the induced periodontitis groups compared with controls. The HFD-Perio group demonstrated significantly higher PD compared with Con-Perio group. Lipid profiles, cytokines, and adipocytokines showed significantly elevated levels in the HFD-Perio group compared with the other groups. Similarly, glucose levels in the HFD-Perio group were significantly higher (P < 0.05) than in the HFD group, and hepatic damage parameters demonstrated a tendency toward higher levels in the HFD-Perio group. CONCLUSION: Obesity and periodontitis demonstrated a comorbidity effect on both systemic inflammatory and metabolic dysregulation biomarkers, with increased glucose, dyslipidemia and hepatic damage. PMID- 28914597 TI - Combination of Ultrasonic Decontamination, Soft Tissue Curettage and Submucosal Air Polishing With Povidone-Iodine Application for Non-Surgical Therapy of Peri Implantitis: 12 Months Clinical Outcomes. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcomes of a concept for non-surgical peri-implantitis combining stepwise mechanical debridement measures with adjuvant Povidone-iodine application with and without systemic antibiotics. METHODS: 45 patients with chronic periodontitis comprising 164 screw-typed implants with peri-implantitis were included. Peri-implantitis was defined as radiographic bone loss of >2 mm, probing pocket depth (PD) >=5 mm with bleeding on probing (BOP). Stepwise treatment of implants was performed with ultrasonic debridement, soft tissue curettage (STC), glycine powder air polishing (GPAP) and a repeated submucosal application of Povidone-iodine. Teeth with PD >4mm were treated simultaneously according to the same concept except STC. In cases with severe periodontitis (N = 24), amoxicillin and metronidazole (AM) were prescribed for 7 days. RESULTS: After 12 months, implants treated without AM showed significant reductions (p<0.05) of mean PD (1.4 +/- 0.7 mm), CAL (1.3 +/- 0.8 mm) and BOP (33.4 +/- 17.2%). In deep pockets (PD >6mm) changes of mean PD (2.3 +/- 1.3 mm), CAL (2.0 +/- 1.6 mm) and BOP (44.0 +/- 41.7%) were more pronounced. Intake of AM did not significantly influence the changes of these parameters. However, the reduction of implant sites with PD >4 mm and BOP was significantly higher in patients with AM than in those without AM (31.8 +/- 12.6% vs. 20.8 +/- 14.7%; p<0.05). CONCLUSIONS: The combination of ultrasonic debridement, STC and GPAP with adjuvant Povidone-iodine led to significant clinical improvements at implants. Systemic antibiotics had limited effects on the reduction of persisting implant sites with treatment need. PMID- 28914598 TI - Ovarian Cancer: Prevalence in Incidental Simple Adnexal Cysts Initially Identified in CT Examinations of the Abdomen and Pelvis. AB - Purpose To evaluate the rate of malignancy in incidentally detected simple adnexal cysts at computed tomography (CT) to determine if simple-appearing cysts require follow-up. Materials and Methods In this HIPAA-compliant, institutional review board-approved retrospective cohort study, an institutional database was searched for abdominal and pelvic CT studies performed between June 2003 and December 2010 in women reported to have adnexal cysts. Adnexal cyst characterization was determined by prospective report description as well as image review by a research fellow and by a fellowship-trained abdominal radiologist for examinations with disagreement between the original report and the research fellow's assessment. Patients with known ovarian cysts or ovarian cancer at time of the index CT examination were excluded. Clinical outcome was assessed by using follow-up imaging studies, medical records, and the state cancer registry. Benign outcome was determined by benign findings at surgery, a decrease in size or resolution of a simple-appearing cyst at follow-up imaging, or stability of the cyst for at least 1 year. Descriptive statistics and 95% confidence intervals (CIs) were calculated. Results Among 42 111 women who underwent abdominal and pelvic CT examinations in the study period, 2763 (6.6%; 95% CI: 6.3%, 6.8%) (mean age, 48.1 years +/- 18.1; range, 15-102 years) had a newly detected finding of ovarian cyst described in the body or impression section of the report. Median cyst size was 3.1 cm (range, 0.8-20.0 cm). Eighteen (0.7%; 95% CI: 0.4%, 1.0%) of 2763 patients were found to have ovarian cancer after an average follow-up of 5.1 years +/- 3.8 (range, 0-12.8 years). None (95% CI: 0%, 0.4%) of 1031 women with simple-appearing cysts were given a diagnosis of ovarian cancer. This included none (95% CI: 0%, 0.4%) of 904 women with simple appearing cysts with an adequate reference standard for benign outcome. Conclusion The prevalence of previously unknown adnexal cysts at CT was 6.6%, with an ovarian cancer rate of 0.7% (95% CI: 0.4%, 1.0%). All simple-appearing cysts were benign (95% CI: 99.6%, 100%). (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28914599 TI - Ductal Carcinoma in Situ: Quantitative Preoperative Breast MR Imaging Features Associated with Recurrence after Treatment. AB - Purpose To investigate whether specific imaging features on breast magnetic resonance (MR) images are associated with ductal carcinoma in situ (DCIS) recurrence risk after definitive treatment. Materials and Methods Patients with DCIS who underwent preoperative dynamic contrast material-enhanced (DCE) MR imaging between 2004 and 2014 with ipsilateral recurrence more than 6 months after definitive surgical treatment were retrospectively identified. For each patient, a control subject with DCIS that did not recur was identified and matched on the basis of clinical, histopathologic, and treatment features known to affect recurrence risk. On DCE MR images, lesion characteristics (longest diameter, functional tumor volume [FTV], peak percentage enhancement [PE], peak signal enhancement ratio [SER], and washout fraction) and normal tissue features (background parenchymal enhancement [BPE] volume, mean BPE) were quantitatively measured. MR imaging features were compared between patients and control subjects by using the Wilcoxon signed-rank test, with adjustment for multiple comparisons. Results Of 415 subjects with DCIS who underwent preoperative MR imaging, 14 experienced recurrence and 11 had an identifiable matching control subject (final cohort, 11 patients and 11 control subjects). Median time to recurrence was 14 months, and median follow-up for control subjects was 102 months. When compared with matched control subjects, patients with DCIS recurrence exhibited significantly greater FTV (median, 9.3 cm3 vs 1.3 cm3, P = .01), lesion peak SER (median, 1.7 vs 1.2; P = .03), and mean BPE (median, 58.3% vs 41.1%; P = .02). Conclusion Quantitative lesion and normal breast tissue characteristics at preoperative MR imaging in women with newly diagnosed DCIS show promise for association with breast cancer recurrence after treatment. (c) RSNA, 2017. PMID- 28914600 TI - Reduction of 18F-FDG Dose in Clinical PET/MR Imaging by Using Silicon Photomultiplier Detectors. AB - Purpose To determine the level of clinically acceptable reduction in injected fluorine 18 (18F) fluorodeoxyglucose (FDG) dose in time-of-flight (TOF)-positron emission tomography(PET)/magnetic resonance (MR) imaging by using silicon photomultiplier (SiPM) detectors compared with TOF-PET/computed tomography (CT) using Lu1.8Y0.2SiO5(Ce), or LYSO, detectors in patients with different body mass indexes (BMIs). Materials and Methods Patients were enrolled in this study as part of a larger prospective study with a different purpose than evaluated in this study (NCT02316431). All patients gave written informed consent prior to inclusion into the study. In this study, 74 patients with different malignant diseases underwent sequential whole-body TOF-PET/CT and TOF-PET/MR imaging. PET images with simulated reduction of injected 18F-FDG doses were generated by unlisting the list-mode data from PET/MR imaging. Two readers rated the image quality of whole-body data sets, as well as the image quality in each body compartment, and evaluated the conspicuity of malignant lesions. Results The image quality with 70% or 60% of the injected dose of 18F-FDG at PET/MR imaging was comparable to that at PET/CT. With 50% of the injected dose, comparable image quality was maintained among patients with a BMI of less than 25 kg/m2. PET images without TOF reconstruction showed higher artifact scores and deteriorated sharpness than those with TOF reconstruction. Conclusion Sixty percent of the usually injected 18F-FDG dose (reduction of up to 40%) in patients with a BMI of more than 25 kg/m2 results in clinically adequate PET image quality in TOF-PET/MR imaging performed by using SiPM detectors. Additionally, in patients with a BMI of less than 25 kg/m2, 50% of the injected dose may safely be used. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28914601 TI - Left Ventricular Long-Axis Function Assessed with Cardiac Cine MR Imaging Is an Independent Predictor of All-Cause Mortality in Patients with Reduced Ejection Fraction: A Multicenter Study. AB - Purpose To evaluate the prognostic value of a simple index of left ventricular (LV) long-axis function-lateral mitral annular plane systolic excursion (MAPSE) in a large multicenter population of patients with reduced ejection fraction (EF) who were undergoing cardiac magnetic resonance (MR) imaging. Materials and Methods This retrospective study included 1040 consecutive patients (mean age, 59.5 years +/- 15.8) at four U.S. medical centers who were undergoing cardiac MR imaging for assessment of LV dysfunction with EF less than 50%. Lateral MAPSE was measured in the four-chamber cine view. The primary end point was all-cause death. Cox proportional hazards regression modeling was used to examine the independent association between lateral MAPSE and death. The incremental prognostic value of lateral MAPSE was assessed in nested models. Results During a median follow-up of 4.4 years, 132 patients died. With Kaplan-Meier analysis, the risk of death increased significantly with decreasing tertiles of lateral MAPSE (log-rank P = .0001). Patients with relatively preserved lateral MAPSE (>9 mm) had very few deaths, regardless of whether their EF was above or below 35%. Patients with late gadolinium enhancement (LGE) and low lateral MAPSE had significantly reduced survival compared to those with LGE and high lateral MAPSE (log-rank P < .0001). Lateral MAPSE was independently associated with risk of death after adjustment for clinical and imaging risk factors, which were univariate predictors (age, body mass index, diabetes, LV end-diastolic volume index, LGE, EF) (hazard ratio = 2.051 per mm decrease; 95% confidence interval [CI]: 1.520, 2.768; P < .001). Inclusion of lateral MAPSE in this model resulted in significant improvement in model fit (likelihood ratio test P < .0001) and C statistic (increasing from 0.675 to 0.844; P < .0001). Continuous net reclassification improvement was 1.036 (95% CI: 0.878, 1.194). Conclusion Lateral MAPSE measured during routine cine cardiac MR imaging is a significant independent predictor of mortality in patients with LV dysfunction, incremental to common clinical and cardiac MR risk factors-including EF and LGE. (c) RSNA, 2017. PMID- 28914602 TI - Initial Clinical Experience with a Modulated Holmium Laser Pulse-Moses Technology: Does It Enhance Laser Lithotripsy Efficacy? AB - OBJECTIVE: The Lumenis(r) High-power Holmium Laser (120H) has a unique modulated pulse mode, MosesTM technology. Moses technology modulates the laser pulse to separate the water (vapor bubble), then deliver the remaining energy through the bubble. Proprietary laser fibers were designed for the Moses technology. Our aim was to compare stone lithotripsy with and without the Moses technology. METHODS: We designed a questionnaire for the urologist to fill immediately after each ureteroscopy in which the Lumenis 120H was used. We compared procedures with (n=23) and without (n=11) the use of Moses technology. Surgeons ranked the Moses technology in 23 procedures, in comparison to regular lithotripsy (worse, equivalent, better, much better). Laser working time and energy use were collected from the Lumenis 120H log. RESULTS: During 4 months, five urologists used the Lumenis 120H in 34 ureteroscopy procedures (19 kidney stones, 15 ureteral stones; 22 procedures with a flexible ureteroscope, and 12 with a semi rigid ureteroscope). Three urologists ranked Moses technology as much better or better in 17 procedures. In 2 cases, it was ranked equivalent, and in 4 cases ranking was not done. Overall, laser lithotripsy with Moses technology utilized laser energy in less time to achieve a satisfying stone fragmentation rate of 95.8 mm3/min versus 58.1 mm3/min, P=0.19. However, this did not reach statistical significance. CONCLUSION: The new Moses laser technology demonstrated good stone fragmentation capabilities when used in everyday clinical practice. PMID- 28914603 TI - Synaptic up-scaling preserves motor circuit output after chronic, natural inactivity. AB - Neural systems use homeostatic plasticity to maintain normal brain functions and to prevent abnormal activity. Surprisingly, homeostatic mechanisms that regulate circuit output have mainly been demonstrated during artificial and/or pathological perturbations. Natural, physiological scenarios that activate these stabilizing mechanisms in neural networks of mature animals remain elusive. To establish the extent to which a naturally inactive circuit engages mechanisms of homeostatic plasticity, we utilized the respiratory motor circuit in bullfrogs that normally remains inactive for several months during the winter. We found that inactive respiratory motoneurons exhibit a classic form of homeostatic plasticity, up-scaling of AMPA-glutamate receptors. Up-scaling increased the synaptic strength of respiratory motoneurons and acted to boost motor amplitude from the respiratory network following months of inactivity. Our results show that synaptic scaling sustains strength of the respiratory motor output following months of inactivity, thereby supporting a major neuroscience hypothesis in a normal context for an adult animal. PMID- 28914604 TI - Scc2/Nipbl hops between chromosomal cohesin rings after loading. AB - The cohesin complex mediates DNA-DNA interactions both between (sister chromatid cohesion) and within chromosomes (DNA looping). It has been suggested that intra chromosome loops are generated by extrusion of DNAs through the lumen of cohesin's ring. Scc2 (Nipbl) stimulates cohesin's ABC-like ATPase and is essential for loading cohesin onto chromosomes. However, it is possible that the stimulation of cohesin's ATPase by Scc2 also has a post-loading function, for example driving loop extrusion. Using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking in human cells, we show that Scc2 binds dynamically to chromatin, principally through an association with cohesin. Scc2's movement within chromatin is consistent with a 'stop-and-go' or 'hopping' motion. We suggest that a low diffusion coefficient, a low stoichiometry relative to cohesin, and a high affinity for chromosomal cohesin enables Scc2 to move rapidly from one chromosomal cohesin complex to another, performing a function distinct from loading. PMID- 28914605 TI - A causal role for right frontopolar cortex in directed, but not random, exploration. AB - The explore-exploit dilemma occurs anytime we must choose between exploring unknown options for information and exploiting known resources for reward. Previous work suggests that people use two different strategies to solve the explore-exploit dilemma: directed exploration, driven by information seeking, and random exploration, driven by decision noise. Here, we show that these two strategies rely on different neural systems. Using transcranial magnetic stimulation to inhibit the right frontopolar cortex, we were able to selectively inhibit directed exploration while leaving random exploration intact. This suggests a causal role for right frontopolar cortex in directed, but not random, exploration and that directed and random exploration rely on (at least partially) dissociable neural systems. PMID- 28914608 TI - Models and materials for generalized Kitaev magnetism. AB - The exactly solvable Kitaev model on the honeycomb lattice has recently received enormous attention linked to the hope of achieving novel spin-liquid states with fractionalized Majorana-like excitations. In this review, we analyze the mechanism proposed by Jackeli and Khaliullin to identify Kitaev materials based on spin-orbital dependent bond interactions and provide a comprehensive overview of its implications in real materials. We set the focus on experimental results and current theoretical understanding of planar honeycomb systems (Na2IrO3, alpha Li2IrO3, and alpha-RuCl3), three-dimensional Kitaev materials (beta- and gamma Li2IrO3), and other potential candidates, completing the review with the list of open questions awaiting new insights. PMID- 28914606 TI - Nanoscale architecture of the Schizosaccharomyces pombe contractile ring. AB - The contractile ring is a complex molecular apparatus which physically divides many eukaryotic cells. Despite knowledge of its protein composition, the molecular architecture of the ring is not known. Here we have applied super resolution microscopy and FRET to determine the nanoscale spatial organization of Schizosaccharomyces pombe contractile ring components relative to the plasma membrane. Similar to other membrane-tethered actin structures, we find proteins localize in specific layers relative to the membrane. The most membrane-proximal layer (0-80 nm) is composed of membrane-binding scaffolds, formin, and the tail of the essential myosin-II. An intermediate layer (80-160 nm) consists of a network of cytokinesis accessory proteins as well as multiple signaling components which influence cell division. Farthest from the membrane (160-350 nm) we find F-actin, the motor domains of myosins, and a major F-actin crosslinker. Circumferentially within the ring, multiple proteins proximal to the membrane form clusters of different sizes, while components farther from the membrane are uniformly distributed. This comprehensive organizational map provides a framework for understanding contractile ring function. PMID- 28914609 TI - Effect of multiple perfusion components on pseudo-diffusion coefficient in intravoxel incoherent motion imaging. AB - The aim of this work was to investigate the effect of multiple perfusion components on the pseudo-diffusion coefficient D * in the bi-exponential intravoxel incoherent motion (IVIM) model. Simulations were first performed to examine how the presence of multiple perfusion components influences D *. The real data of livers (n = 31), spleens (n = 31) and kidneys (n = 31) of 31 volunteers was then acquired using DWI for in vivo study and the number of perfusion components in these tissues was determined together with their perfusion fraction and D *, using an adaptive multi-exponential IVIM model. Finally, the bi-exponential model was applied to the real data and the mean, standard variance and coefficient of variation of D * as well as the fitting residual were calculated over the 31 volunteers for each of the three tissues and compared between them. The results of both the simulations and the in vivo study showed that, for the bi-exponential IVIM model, both the variance of D * and the fitting residual tended to increase when the number of perfusion components was increased or when the difference between perfusion components became large. In addition, it was found that the kidney presented the fewest perfusion components among the three tissues. The present study demonstrated that multi-component perfusion is a main factor that causes high variance of D * and the bi exponential model should be used only when the tissues under investigation have few perfusion components, for example the kidney. PMID- 28914610 TI - Fluorescent J-aggregates of cyanine dyes: basic research and applications review. AB - J-aggregates are fascinating fluorescent nanomaterials formed by highly ordered assembly of organic dyes with the spectroscopic properties dramatically different from that of single or disorderly assembled dye molecules. They demonstrate very narrow red-shifted absorption and emission bands, strongly increased absorbance together with the decrease of radiative lifetime, highly polarized emission and other valuable features. The mechanisms of their electronic transitions are understood by formation of delocalized excitons already on the level of several coupled monomers. Cyanine dyes are unique in forming J-aggregates over the broad spectral range, from blue to near-IR. With the aim to inspire further developments, this review is focused on the optical characteristics of J aggregates in connection with the dye structures and on their diverse already realized and emerging applications. PMID- 28914607 TI - Cortex-wide BOLD fMRI activity reflects locally-recorded slow oscillation associated calcium waves. AB - Spontaneous slow oscillation-associated slow wave activity represents an internally generated state which is characterized by alternations of network quiescence and stereotypical episodes of neuronal activity - slow wave events. However, it remains unclear which macroscopic signal is related to these active periods of the slow wave rhythm. We used optic fiber-based calcium recordings of local neural populations in cortex and thalamus to detect neurophysiologically defined slow calcium waves in isoflurane anesthetized rats. The individual slow wave events were used for an event-related analysis of simultaneously acquired whole-brain BOLD fMRI. We identified BOLD responses directly related to onsets of slow calcium waves, revealing a cortex-wide BOLD correlate: the entire cortex was engaged in this specific type of slow wave activity. These findings demonstrate a direct relation of defined neurophysiological events to a specific BOLD activity pattern and were confirmed for ongoing slow wave activity by independent component and seed-based analyses. PMID- 28914611 TI - Deep convolutional neural network with transfer learning for rectum toxicity prediction in cervical cancer radiotherapy: a feasibility study. AB - Better understanding of the dose-toxicity relationship is critical for safe dose escalation to improve local control in late-stage cervical cancer radiotherapy. In this study, we introduced a convolutional neural network (CNN) model to analyze rectum dose distribution and predict rectum toxicity. Forty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively collected, including twelve toxicity patients and thirty non-toxicity patients. We adopted a transfer learning strategy to overcome the limited patient data issue. A 16-layers CNN developed by the visual geometry group (VGG-16) of the University of Oxford was pre-trained on a large-scale natural image database, ImageNet, and fine-tuned with patient rectum surface dose maps (RSDMs), which were accumulated EBRT + BT doses on the unfolded rectum surface. We used the adaptive synthetic sampling approach and the data augmentation method to address the two challenges, data imbalance and data scarcity. The gradient-weighted class activation maps (Grad-CAM) were also generated to highlight the discriminative regions on the RSDM along with the prediction model. We compare different CNN coefficients fine-tuning strategies, and compare the predictive performance using the traditional dose volume parameters, e.g. D 0.1/1/2cc, and the texture features extracted from the RSDM. Satisfactory prediction performance was achieved with the proposed scheme, and we found that the mean Grad-CAM over the toxicity patient group has geometric consistence of distribution with the statistical analysis result, which indicates possible rectum toxicity location. The evaluation results have demonstrated the feasibility of building a CNN-based rectum dose-toxicity prediction model with transfer learning for cervical cancer radiotherapy. PMID- 28914612 TI - BNC NanoShells a Novel Structure for Atomic Storage. AB - Quantum molecular dynamics (QMD) and density functional theory (DFT) are employed in this work in order to study the structural and electronics properties of carbon, Boron Nitride or hybrid BNC nanoshells (BNCNSs). The studied nanoshells can be formed by stacking two zigzag graphene nanoribbons (zGNRs), two zigzag Boron Nitride nanoribbons (zBNNRs) or one zigzag graphene nanoribbon on a Boron Nitride nanoribbon. In all cases only one of the edges of the ribbon is passivated, while the other one is left unpassivated. Our QMD results show that these nanoribbons collapse just a few femtoseconds after the beginning of the simulation, forming a coalesced structure in the shape of a shell. Our band structure calculations revealed that this structures may be metallic or semiconductor, depending on its stoichiometry. Furthermore, a spin splitting for energies near the Fermi level is predicted for both the pure carbon and the hybrid BNC-nanoshell systems. We further show that when a transverse electric field is applied to these systems, the nanoshell structure tends to open up. This effect can lead to the application of these nanoshells for molecular storage. As a proof of concept, we investigate this storage effect for the H2 molecule. PMID- 28914613 TI - A novel system for commissioning brachytherapy applicators: example of a ring applicator. AB - A novel system was developed to improve commissioning and quality assurance of brachytherapy applicators used in high dose rate (HDR). It employs an imaging panel to create reference images and to measure dwell times and dwell positions. As an example: two ring applicators of the same model were evaluated. An applicator was placed on the surface of an imaging panel and a HDR 192Ir source was positioned in an imaging channel above the panel to generate an image of the applicator, using the gamma photons of the brachytherapy source. The applicator projection image was overlaid with the images acquired by capturing the gamma photons emitted by the source dwelling inside the applicator. We verified 0.1, 0.2, 0.5 and 1.0 cm interdwell distances for different offsets, applicator inclinations and transfer tube curvatures. The data analysis was performed using in-house developed software capable of processing the data in real time, defining catheters and creating movies recording the irradiation procedure. One applicator showed up to 0.3 cm difference from the expected position for a specific dwell position. The problem appeared intermittently. The standard deviations of the remaining dwell positions (40 measurements) were less than 0.05 cm. The second ring applicator had a similar reproducibility with absolute coordinate differences from expected values ranging from -0.10 up to 0.18 cm. The curvature of the transfer tube can lead to differences larger than 0.1 cm whilst the inclination of the applicator showed a negligible effect. The proposed method allows the verification of all steps of the irradiation, providing accurate information about dwell positions and dwell times. It allows the verification of small interdwell positions (?0.1 cm) and reduces measurement time. In addition, no additional radiation source is necessary since the HDR 192Ir source is used to generate an image of the applicator. PMID- 28914614 TI - Structural Control in Porous/Compact Multilayer Systems Grown by Magnetron Sputtering. AB - In this work we analyze a phenomenon that takes place when growing magnetron sputtered porous/compact multilayer systems by alternating the oblique angle and the classical configuration geometries. We show that the compact layers develop numerous fissures rooted in the porous structures of the film below, in a phenomenon that amplifies when increasing the number of stacked layers. We demonstrate that these fissures emerge during growth due to the high roughness of the porous layers and the coarsening of a discontinuous interfacial region. To minimize this phenomenon, we have grown thin interlayers between porous and compact films under the impingement of energetic plasma ions, responsible for smoothing out the interfaces and inhibiting the formation of structural fissures. This method has been tested in practical situations for compact TiO2/porous SiO2 multilayer systems, although it can be extrapolated to other materials and conditions. PMID- 28914616 TI - Effect of Full-Length Carbon Fiber Insoles on Lower Limb Kinetics in Patients With Midfoot Osteoarthritis: A Pilot Study. AB - OBJECTIVES: We investigated the effects of full-length carbon fiber (FCF) insoles on gait, muscle activity, kinetics, and pain in patients with midfoot osteoarthritis (OA). DESIGN: We enrolled 13 patients with unilateral midfoot OA (mild: Visual Analog Scale [VAS] range, 1-3; moderate, VAS range, 4-7) and healthy controls. All participants were asked to walk under two conditions: with and without FCF insole. The outcome measures were ground reaction force, quantitative gait parameters, electromyography activities and pain severity (VAS). RESULTS: In the patients with moderate midfoot OA, significantly longer gait cycle and higher muscle activity of lower limb during loading-response phase were observed while walking without FCF insoles. In the mild midfoot OA group, there was no significant difference in VAS score (without, 2.0 +/- 1.0 vs. with, 2.0 +/- 0.5) with FCF insole use. However, significantly reduced VAS score (without, 5.5 +/- 1.4 vs. with, 2.0 +/- 0.5) and muscle activity of the tibialis anterior and increased muscle activity of gastrocnemius were observed in the moderate midfoot OA group by using an FCF insole (P < 0.05). CONCLUSIONS: Full length carbon fiber insoles can improve pain in individuals with moderate midfoot OA, which might be associated with changes in the kinetics and muscle activities of the lower limb. Taken together, the results of the present study suggest that FCF insoles may be used as a helpful option for midfoot OA. PMID- 28914615 TI - Apoptosis generates mechanical forces that close the lens vesicle in the chick embryo. AB - During the initial stages of eye development, optic vesicles grow laterally outward from both sides of the forebrain and come into contact with the surrounding surface ectoderm (SE). Within the region of contact, these layers then thicken locally to create placodes and invaginate to form the optic cup (primitive retina) and lens vesicle (LV), respectively. This paper examines the biophysical mechanisms involved in LV formation, which consists of three phases: (1) lens placode formation; (2) invagination to create the lens pit (LP); and (3) closure to form a complete ellipsoidally shaped LV. Previous studies have suggested that extracellular matrix deposited between the SE and optic vesicle causes the lens placode to form by locally constraining expansion of the SE as it grows, while actomyosin contraction causes this structure to invaginate. Here, using computational modeling and experiments on chick embryos, we confirm that these mechanisms for Phases 1 and 2 are physically plausible. Our results also suggest, however, that they are not sufficient to close the LP during Phase 3. We postulate that apoptosis provides an additional mechanism by removing cells near the LP opening, thereby decreasing its circumference and generating tension that closes the LP. This hypothesis is supported by staining that shows a ring of cell death located around the LP opening during closure. Inhibiting apoptosis in cultured embryos using caspase inhibitors significantly reduced LP closure, and results from a finite-element model indicate that closure driven by cell death is plausible. Taken together, our results suggest an important mechanical role for apoptosis in lens development. PMID- 28914617 TI - Distribution Patterns of the Vulnerable Vessels Around Cervical Nerve Roots: A Computed Tomography-Based Study. AB - OBJECTIVE: The aim of the study was to evaluate the prevalence of vulnerable vessels around the target of cervical transforaminal epidural steroid injection at the C3-C7 cervical nerve root levels in a clinical setting. DESIGN: Retrospective, cross-sectional study was conducted. PARTICIPANTS: Patients complaining of neck or arm pain with no previous surgical history and who had undergone both precontrast and contrast-enhanced neck computed tomography were included retrospectively. RESULTS: In 26 (21.0%) of 124 patients, none of the vulnerable vessels around the target of cervical transforaminal epidural steroid injection around both sides of the C3-C7 nerve roots were observed. Of 248 cervical root levels, the C3 level had 103 vessels (41.5%), the C4 level had 110 vessels (44.4%), the C5 level had 98 vessels (39.5%), the C6 level had 59 vessels (23.8%), and the C7 level had 34 vessels (13.7%) close to each target nerve root. In addition, variations of the vertebral artery at the C4-C7 level were observed in 11 (8.9%) of 124 patients. CONCLUSIONS: To prevent unexpected critical complications involving injury to vulnerable vessels during cervical transforaminal epidural steroid injection, it is recommended to routinely evaluate the vulnerable vessels around the cervical nerve root with computed tomography or Doppler ultrasound before cervical transforaminal epidural steroid injection, especially for the upper cervical nerve root level. PMID- 28914618 TI - Hereditary Breast and Ovarian Cancer Syndrome: Moving Beyond BRCA1 and BRCA2. AB - The recent implementation of next generation sequencing and multigene platforms has expanded the spectrum of hereditary breast and ovarian cancer syndrome, beyond the traditional genes BRCA1 and BRCA2. A large number of other moderate penetrance genes have now been uncovered, which also play critical roles in repairing double stranded DNA breaks through the homologous recombination pathway. This review discusses the landmark discoveries of BRCA1 and BRCA2, the homologous repair pathway and new genes discovered in hereditary breast and ovarian cancer syndrome, as well as their clinicopathologic significance and implications for genetic testing. It also highlights the new role of PARP inhibitors in the context of synthetic lethality and prophylactic surgical options. PMID- 28914619 TI - There Are No Magic Bullets in Hematopathology: Even Immunostains for CD20 and CD3 Can Get You Into Trouble. AB - Immunohistochemistry is a powerful tool for the diagnosis and subclassification of hematolymphoid neoplasms. However, the expression of certain markers is not always as expected, and unusual patterns of staining can lead to misdiagnosis. CD20 and CD3 are our most commonly used markers for identification of B cells and T cells, respectively, and they almost always yield reliable, specific staining. This discussion focuses on diagnostic pitfalls related to the use of immunohistochemistry for CD20 and CD3 in hematopathology, and specifically on diagnostic challenges that arise when (1) CD20 is not expressed in B-cell lymphomas, when (2) CD20 is expressed in plasma cell neoplasms and T-cell lymphomas, and when (3) CD3 is expressed in B-cell lymphomas and Hodgkin lymphoma. PMID- 28914620 TI - New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis. AB - Pancreatic cancer is an aggressive disease with a dismal prognosis in dire need of novel diagnostic and therapeutic approaches. The past decade has witnessed an explosion of data on the genetic alterations that occur in pancreatic cancer, as comprehensive next-generation sequencing analyses have been performed on samples from large cohorts of patients. These studies have defined the genomic landscape of this disease and identified novel candidates whose mutations contribute to pancreatic tumorigenesis. They have also clarified the genetic alterations that underlie multistep tumorigenesis in precursor lesions and provided insights into clonal evolution in pancreatic neoplasia. In addition to these important insights into pancreatic cancer biology, these large scale genomic studies have also provided a foundation for the development of novel early detection strategies and targeted therapies. In this review, we discuss the results of these comprehensive sequencing studies of pancreatic neoplasms, with a particular focus on how their results will impact the clinical care of patients with pancreatic cancer. PMID- 28914621 TI - CE: Original Research: Exploring How Nursing Schools Handle Student Errors and Near Misses. AB - : : Background: Little attention has been paid to how nursing students learn about quality and safety, and to the tools and policies that guide nursing schools in helping students respond to errors and near misses. PURPOSE: This study sought to determine whether prelicensure nursing programs have a policy for reporting and following up on student clinical errors and near misses, a tool for such reporting, a tool or process (or both) for identifying trends, strategies for follow-up with students after errors and near misses, and strategies for follow-up with clinical agencies and individual faculty members. METHODS: A national electronic survey of 1,667 schools of nursing with a prelicensure registered nursing program was conducted. Data from 494 responding schools (30%) were analyzed. RESULTS: Of the responding schools, 245 (50%) reported having no policy for managing students following a clinical error or near miss, and 272 (55%) reported having no tool for reporting student errors or near misses. CONCLUSIONS: Significant work is needed if the principles of a fair and just culture are to shape the response to nursing student errors and near misses. For nursing schools, some essential first steps are to understand the tools and policies a school has in place; the school's philosophy regarding errors and near misses; the resources needed to establish a fair and just culture; and how faculty can work together to create learning environments that eliminate or minimize the negative consequences of errors and near misses for patients, students, and faculty. PMID- 28914622 TI - CE: Assessing Patients During Septic Shock Resuscitation. AB - : In 2015, the Surviving Sepsis Campaign six-hour bundle was updated. The revised version now recommends documenting the reassessment of volume status and tissue perfusion after initial fluid resuscitation through a repeated focused examination. This article addresses the practice and interpretation of two components of this examination in adults: capillary refill time and skin mottling score. It further discusses how to best integrate these noninvasive parameters into the care of patients undergoing resuscitation for septic shock. PMID- 28914623 TI - Prevalence and Prognosis Impact of Patient-Ventilator Asynchrony in Early Phase of Weaning according to Two Detection Methods. AB - BACKGROUND: Patient-ventilator asynchrony is associated with a poorer outcome. The prevalence and severity of asynchrony during the early phase of weaning has never been specifically described. The authors' first aim was to evaluate the prognosis impact and the factors associated with asynchrony. Their second aim was to compare the prevalence of asynchrony according to two methods of detection: a visual inspection of signals and a computerized method integrating electromyographic activity of the diaphragm. METHODS: This was an ancillary study of a multicenter, randomized controlled trial comparing neurally adjusted ventilatory assist to pressure support ventilation. Asynchrony was quantified at 12, 24, 36, and 48 h after switching from controlled ventilation to a partial mode of ventilatory assistance according to the two methods. An asynchrony index greater than or equal to 10% defined severe asynchrony. RESULTS: A total of 103 patients ventilated for a median duration of 5 days (interquartile range, 3 to 9 days) were included. Whatever the method used for quantification, severe patient ventilator asynchrony was not associated with an alteration of the outcome. No factor was associated with severe asynchrony. The prevalence of asynchrony was significantly lower when the quantification was based on flow and pressure than when it was based on the electromyographic activity of the diaphragm at 0.3 min (interquartile range, 0.2 to 0.8 min) and 4.7 min (interquartile range, 3.2 to 7.7 min; P < 0.0001), respectively. CONCLUSIONS: During the early phase of weaning in patients receiving a partial ventilatory mode, severe patient ventilator asynchrony was not associated with adverse clinical outcome, although the prevalence of patient-ventilator asynchrony varies according to the definitions and methods used for detection. PMID- 28914624 TI - Management of Type I and Type II laryngeal clefts: controversies and evidence. AB - PURPOSE OF REVIEW: To summarize the pediatric Type I and Type II laryngeal cleft literature, paying special attention to recent trends, including evolution of surgical techniques, standardization of outcome assessments, and utilization of management algorithms. RECENT FINDINGS: There are a variety of options to choose from whenever considering Type I and Type II cleft repair, including endoscopic repair, transoral robotic surgery, and injection laryngoplasty. Conservative management including feeding therapy and treatment of comorbid medical conditions is recommended prior to repair. Validated outcome measures have arisen for swallow study interpretation and timing, as well as caregiver quality-of-life assessment. In addition, a series of medical algorithms have been proposed, which provide specific recommendations for diagnosis, treatment, and follow-up. SUMMARY: For clefts that fail conservative management, endoscopic repair has become the gold standard. In addition, injection laryngoplasty appears to provide both a diagnostic and therapeutic option in the management of these patients. Transoral robotic-assisted endoscopic repair appears well tolerated and feasible, although broader implementation of this technology remains limited. The development and refinement of best practice algorithms can help standardize management and improve decision-making. Furthermore, incorporating validated outcome measures, recorded and followed over time, will improve both patient care and research efforts moving forward. PMID- 28914625 TI - Editorial. PMID- 28914626 TI - Secondary Traumatic Stress in NICU Nurses: A Mixed-Methods Study. AB - BACKGROUND: Secondary traumatic stress is an occupational hazard for healthcare providers who care for patients who have been traumatized. This type of stress has been reported in various specialties of nursing, but no study to date had specifically focused on neonatal intensive care unit (NICU) nurses. PURPOSE: (1) To determine the prevalence and severity of secondary traumatic stress in NICU nurses and (2) to explore those quantitative findings in more depth through nurses' qualitative descriptions of their traumatic experiences caring for critically ill infants in the NICU. METHODS: Members of NANN were sent e-mails with a link to the electronic survey. In this mixed-methods study, a convergent parallel design was used. Neonatal nurses completed the Secondary Traumatic Stress Scale (STSS) and then described their traumatic experiences caring for critically ill infants in the NICU. SPSS version 24 and content analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: In this sample of 175 NICU nurses, 49% of the nurses' scores on the STSS indicated moderate to severe secondary traumatic stress. Analysis of the qualitative data revealed 5 themes that described NICU nurses' traumatic experiences caring for critically ill infants. IMPLICATIONS FOR PRACTICE: NICU nurses need to know the signs of secondary traumatic stress that they may experience caring for their critically ill infants. Avenues for dealing with the stress should be provided. IMPLICATIONS FOR RESEARCH: Future research with a higher response rate to increase the external validity of the findings to the population of neonatal nurses is needed. PMID- 28914627 TI - Antinociceptive effects of JWH015 in female and male rats. AB - Despite greater chronic pain prevalence in females compared with males, and the analgesic potential of cannabinoid receptor type 2 (CB2) agonists, CB2 agonists have rarely been tested in females. The aim of the present study was to compare the antinociceptive effects of a CB2-preferring agonist, (2-methyl-1-propyl-1H indol-3-yl)-1-naphthalenylmethanone (JWH015), in female and male rats against acute pain and persistent inflammatory pain. JWH015 (5-20 mg/kg, intraperitoneally) produced dose-dependent and time-dependent increases in latency to respond on the tail withdrawal and paw pressure tests that did not differ statistically between the sexes. JWH015 dose-dependently decreased locomotor activity in both sexes, but was more potent in females than males. JWH015 produced little catalepsy in either sex. In females, the antinociceptive effects of JWH015 against acute pain were blocked by rimonabant and SR144528, whereas locomotor suppression was antagonized by rimonabant. When administered 3 days after intraplantar injection of complete Freund's adjuvant, JWH015 produced a significantly greater antiallodynic effect in females at the highest dose tested (10 mg/kg, intraperitoneally). Antiallodynic effects of JWH015 were antagonized by rimonabant and SR144528 in both sexes. These studies indicate that systemically administered JWH015 produced antinociception that was both CB1 and CB2 receptor-mediated in both sexes. Unlike [INCREMENT]-9-tetrahydrocannabinol and other nonselective cannabinoid agonists, the CB2-preferring agonist JWH015 may produce more equivalent antinociception in females and males. PMID- 28914628 TI - Wanted: Effective Followers in Surgery. AB - BRIEF DESCRIPTION: This SURGICAL PERSPECTIVE paper brings to our readers the general topic of "followership." Leadership has received a lot of attention in the administrative education domain; however, there is a history of academic research on the role and importance of the effective follower. We review some of the critical articles in this field, and present a possible approach for incorporating the notion of effective followership in a surgical context. PMID- 28914629 TI - Association between ambulatory blood pressure values and central aortic pressure in a large population of normotensive and hypertensive patients. AB - OBJECTIVE: Our aim was to examine the association of ambulatory blood pressure monitoring (ABPM) and central blood pressure (CBP) data in a large set of normotensive and hypertensive patients and its relation with pulse wave velocity (PWV). PATIENTS AND METHODS: This cross-sectional study was carried out in a single centre and included 2864 individuals who carried out an ABPM, measurement of CBP from the aortic waveform (SphygmoCor) and carotid-femoral PWV (Complior). RESULTS: In our study, 26.6% of the normotensive individuals and 32.5% of controlled hypertensive patients had abnormal values of at least one or of both ABPM and CBP values, compared with 96.6% of uncontrolled hypertensive patients. In the overall population, normal ABPM and CBP occurred in 25.3% (group 1), abnormal ABPM and CBP occurred in 44.4% (group 4), abnormal ABPM and normal CBP occurred in 10.5% (group 3) and normal ABPM and abnormal CBP occurred in 19.8% (group 2). PWV was significantly superior in group 4 versus group 3; group 4 versus group 1 and group 3 versus group 2 and group 2 versus group 1 (Mann Whitney U-test; P<0.001). CONCLUSION: At least 26-32% of patients classified as normotensive or controlled hypertensive patients have abnormal ABPM or CBP associated with target organ damages. When abnormal values of ABPM and CBP coexist, target organ damage (aortic stiffness) is greater than that occurring when only one abnormal ABPM or CBP is present in the absence of the other. Isolated central hypertension entails greater organ damage than both normal ABPM and CBP. These patients may be at higher risk of further target organ damage because of unawareness of their central hypertension. PMID- 28914630 TI - Strategies for the use of nonstatin therapies. AB - PURPOSE OF REVIEW: Dyslipidaemias are a major risk factor for cardiovascular disease (CVD); in particular, high levels of low-density lipoprotein cholesterol (LDL-C) have been associated to a higher cardiovascular risk. Reducing LDL-C levels decreases the risk of coronary heart disease (CHD), and the greater the LDL-C reduction, the greater the decrease in cardiovascular risk. Although statins represent the first line lipid-lowering therapy, many patients do not reach the recommended goals or exhibit adverse side effects leading to therapy discontinuation; in addition, a significant percentage of statin-treated patients continue to experience cardiovascular events even in the presence of well controlled LDL-C levels, because of alterations in other lipid/lipoprotein classes, including triglycerides and high-density lipoprotein cholesterol. RECENT FINDINGS: These conditions require further therapeutic interventions to achieve the recommended lipid goals. Several drugs have been developed to address these needs. Recent studies have shown that the association of ezetimibe with rosuvastatin or atorvastatin results in a better hypolipidaemic effect; in addition to this, PCSK9 inhibitors significantly reduce LDL-C levels and cardiovascular events. SUMMARY: For patients who are intolerant to statins or not able to reach the recommended LDL-C levels, despite maximal tolerated dose of statin, or exhibiting additional lipid alterations, several drugs are available that can be used either in monotherapy or on top of the maximally tolerated dose of statins. PMID- 28914631 TI - Evaluation of Buccal Bone Concavity in the Esthetic Zone: A Cadaver Study. AB - PURPOSE: The primary aim of this study was to evaluate the buccal bone concavity position and depth in the anterior maxilla. The accuracy of cone beam computed tomography (CBCT) to measure the buccal bone concavity was also investigated. MATERIAL AND METHODS: Eleven fresh cadaver heads were used in this study. CBCT images were first acquired, on which the location and depth of the buccal bone concavity were measured in maxillary incisors and canines. After full-thickness mucoperiosteal flap reflection, the corresponding measurements were made directly on cadavers. The accuracy and correlations between direct and image-derived measurements were analyzed statistically. RESULTS: A total of 53 sites were measured. The mean depths were 2.88 +/- 1.37 mm and 2.40 +/- 1.29 mm (with direct and CBCT measurement, respectively). The deepest concavities were found in the lateral incisors sites (3.15 +/- 1.32 mm). There was a statistically significant underestimation of the depth of concavity (0.2 to 0.6 mm) by CBCT. Nevertheless, there is a high statistical correlation (r = 0.8) between the direct and CBCT measurements. CONCLUSIONS: Within the limitations of this study, it can be concluded that buccal bone concavity is the most prominent at the lateral incisor sites. The CBCT readings were highly correlated but underestimated to the direct measurements. PMID- 28914632 TI - Stepwise Guided Photorefractive Keratectomy in Treatment of Irregular Astigmatism After Penetrating Keratoplasty and Deep Anterior Lamellar Keratoplasty. AB - PURPOSE: To report the outcome of stepwise ablation using topography-guided photorefractive keratectomy to treat irregular astigmatism after either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK). METHODS: This is a retrospective, interventional analysis including patients with irregular astigmatism after either PKP or DALK, who underwent topography-guided photorefractive keratectomy. The entire cohort was analyzed, as well as the PKP and DALK groups separately. Analysis of factors associated with a better outcome was also performed. RESULTS: Thirty-four eyes of 34 patients (20 PKP patients and 14 DALK patients) aged 47.4 +/- 15.9 years were included. Twenty-one patients underwent more than 1 ablation. Refractive stability and a minimal period of 5 months were required before repeat ablation. The average follow-up duration was 17.0 +/- 6.0 months. Corrected distance visual acuity (CDVA) improved significantly from 0.22 +/- 0.14 logarithm of the minimum angle of resolution (logMAR) to 0.14 +/- 0.12 logMAR at final follow-up (P = 0.035). Uncorrected distance visual acuity (UDVA) improved significantly from 0.90 +/- 0.54 logMAR to 0.57 +/- 0.40 logMAR at final follow-up (P = 0.004). CDVA and UDVA improved by >=1 Snellen lines in 54.2% and 70.8% of the eyes, respectively, and by >=3 Snellen lines in 16.7% and 54.2% of the eyes, respectively. Statistically significant improvement was seen in optical aberrometry indices (total root mean square, higher-order aberration root mean square, defocus, coma, trefoil, and spherical aberration). The difference between PKP and DALK in either CDVA (P = 0.562) or UDVA (P = 0.384) improvement was nonsignificant. CONCLUSIONS: The stepwise topography-guided photorefractive keratectomy approach in cases of irregular astigmatism after PKP or DALK can help improve visual acuity outcomes. Patients should be appropriately counseled that more than 1 treatment will likely be needed. PMID- 28914633 TI - Gaps in Current Knowledge and Priorities for Future Research in Dry Eye. AB - PURPOSE: Dry eye, a common yet underrecognized and evolving field, has few recommended treatment algorithms, mostly based on expert consensus rather than robust research evidence. There are high costs associated with managing dry eye and conducting research to identify effective and safe long-term treatments. To support evidence-based management of dry eye, our purpose was to identify and prioritize important clinical research questions for future clinical research. METHODS: We translated recommendations from the American Academy of Ophthalmology's 2013 Preferred Practice Patterns for dry eye into answerable clinical research questions about treatment effectiveness. Clinicians around the world who manage patients with dry eye rated each question's importance from 0 (not important) to 10 (very important) using a 2-round online Delphi survey. We considered questions as "important" if >=75% of respondents assigned a rating of 6 or more in round 2. We mapped the identified important clinical research questions to reliable systematic reviews published up to March 2016. RESULTS: Seventy-five clinicians from at least 21 countries completed both Delphi rounds. Among the 58 questions, 24 met our definition of "important": 9/24 and 7/24 addressed topical and systemic treatments, respectively. All 4 questions with the highest 25th percentiles addressed topical treatments. Although 6/24 "important" questions were associated with 4 existing reliable systematic reviews, none of these reviews came to a definitive conclusion about treatment effectiveness. CONCLUSIONS: We identified gaps pertaining to treatment options for dry eye. Future clinical research on the management of dry eye should strongly consider these prioritized questions. PMID- 28914634 TI - Cellular Therapy With Human Autologous Adipose-Derived Adult Stem Cells for Advanced Keratoconus. PMID- 28914636 TI - Dietary intervention for preventing food allergy in children. AB - PURPOSE OF REVIEW: In the past decade, food allergy has been increasingly recognized as an important public health issue. The role of maternal and infant diet in the development of food allergy has been a major focus of research throughout this period. Recently, research in this area has moved from observational studies to intervention trials, and the findings from these trials have started to influence infant feeding guidelines. In this article, we review recent studies of dietary interventions for preventing food allergy, summarize current knowledge and discuss future research directions. RECENT FINDINGS: The latest result from an intervention trial shows that introduction of peanut in the first year of life reduces the risk of peanut allergy in high-risk infants. A systematic review and meta-analysis of intervention trials also suggests a protective effect of egg introduction from around 4 to 6 months of age for reducing the risk of egg allergy, with most studies conducted in high-risk infants. Despite several intervention trials involving modifications to the maternal diet, the effect of maternal diet during pregnancy and lactation in preventing food allergy remains unclear. SUMMARY: Earlier introduction of allergenic foods is a promising intervention to reduce the risk of some food allergies in high-risk infants. Further work is needed to improve knowledge of how to prevent food allergy in the general population. PMID- 28914635 TI - Clinical genetics of craniosynostosis. AB - PURPOSE OF REVIEW: When providing accurate clinical diagnosis and genetic counseling in craniosynostosis, the challenge is heightened by knowledge that etiology in any individual case may be entirely genetic, entirely environmental, or anything in between. This review will scope out how recent genetic discoveries from next-generation sequencing have impacted on the clinical genetic evaluation of craniosynostosis. RECENT FINDINGS: Survey of a 13-year birth cohort of patients treated at a single craniofacial unit demonstrates that a genetic cause of craniosynostosis can be identified in one quarter of cases. The substantial contributions of mutations in two genes, TCF12 and ERF, is confirmed. Important recent discoveries are mutations of CDC45 and SMO in specific craniosynostosis syndromes, and of SMAD6 in nonsyndromic midline synostosis. The added value of exome or whole genome sequencing in the diagnosis of difficult cases is highlighted. SUMMARY: Strategies to optimize clinical genetic diagnostic pathways by combining both targeted and next-generation sequencing are discussed. In addition to improved genetic counseling, recent discoveries spotlight the important roles of signaling through the bone morphogenetic protein and hedgehog pathways in cranial suture biogenesis, as well as a key requirement for adequate cell division in suture maintenance. PMID- 28914637 TI - Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders. AB - PURPOSE OF REVIEW: To describe primary immunodeficiencies caused by gain-of function (GOF) mutations of signal transducer and activator of transcription (STAT) genes, a group of genetically determined disorders characterized by susceptibility to infections and, in many cases, autoimmune manifestations. RECENT FINDINGS: GOF mutations affecting STAT1 result in increased STAT tyrosine phosphorylation and secondarily increased response to STAT1-signaling cytokines, such as interferons. In contrast, STAT3 hyperactivity is not usually related to hyperphosphorylation but rather to increased STAT3-mediated transcriptional activity. In both cases, heterozygous STAT1 and STAT3 GOF mutations trigger a distinct set of genes in target cells that lead to abnormal functioning of antimicrobial response and/or autoimmunity and result in autosomal dominant diseases. SUMMARY: Clinical manifestations of patients with STAT1 GOF are characterized by mucocutaneous candidiasis and recurrent lower tract respiratory infections. In addition, many patients have thyroiditis, type 1 diabetes mellitus, autoimmune cytopenias, cancer or aneurysms. Patients with germline STAT3 GOF mutations have an increased frequency of early-onset multiorgan autoimmunity (i.e. autoimmune enteropathy, type 1 diabetes mellitus, autoimmune interstitial lung disease and autoimmune cytopenias), lymphoproliferation, short stature and, less frequently, severe recurrent infections. Treatment options range from antimicrobial therapy, intravenous or subcutaneous immunoglobulin and immunosuppressive drugs. Some patients with STAT1 GOF disorder have undergone hematopoietic stem cell transplantation, although these have been difficult because of the underlying proinflammatory milieu from the mutation. PMID- 28914638 TI - Long-term risk and predictors of cardiovascular death in stable coronary artery disease: the CORONOR study. AB - BACKGROUND: There is limited knowledge on the residual risk of cardiovascular death (CVD) in patients with stable coronary artery disease (CAD) who receive modern secondary prevention. Our aim was to analyze the causes of death and to determine predictors of CVD in the 5-year CORONOR registry. METHODS: We studied 4184 consecutive CAD outpatients who were free from any myocardial infarction (MI) or coronary revascularization for more than 1 year at inclusion. Antithrombotics were prescribed in 99%, statins in 92%, inhibitors of renin angiotensin system in 82%, and beta-blockers in 79%; 86% had prior coronary revascularization. Follow-up was performed at 5 years with adjudication of the causes of death. RESULTS: There were 677 deaths during follow-up. The cause of death was cardiovascular in 269 patients (1.3%/year), with 99 deaths from heart failure (HF), 91 sudden deaths, and 65 vascular deaths (stroke, MI, limb or mesenteric ischemia, aortic aneurysm). Predictors of CVD were age [subhazard ratio (SHR)=1.06 (1.04-1.07) per year increase], previous hospitalization for decompensated HF [SHR=3.10 (2.19-4.40)], left ventricular ejection fraction [SHR=0.97 (0.96-0.98) per percentage increase], prior aortic or peripheral intervention [SHR=1.61 (1.12-2.13)], and estimated glomerular filtration rate [SHR=0.99 (0.98-1.00)] per ml/min/1.73m increase]. In analyses stratified on age, prior HF, and left ventricular ejection fraction, the estimated 5-year cardiovascular mortality rates varied from less than 2% to more than 50%. CONCLUSION: In stable CAD patients widely treated by secondary prevention medications, the main causes of CVD are death from HF and sudden death. The risk of CVD can be predicted by simple baseline variables. New therapeutic strategies are needed for the high-risk patients. PMID- 28914639 TI - Correlation Between Squamous Cell Carcinoma Antigen Level and the Clinicopathological Features of Early-Stage Cervical Squamous Cell Carcinoma and the Predictive Value of Squamous Cell Carcinoma Antigen Combined With Computed Tomography Scan for Lymph Node Metastasis. AB - OBJECTIVE: The aim of this study was to analyze the relationship between serum squamous cell carcinoma antigen (SCC-Ag) and the clinicopathological features of cervical squamous cell carcinoma. The value of SCC-Ag and computed tomography (CT) for predicting lymph node metastasis (LNM) was evaluated. METHODS: A total of 197 patients with International Federation of Gynecology and Obstetrics stages IB to IIA cervical squamous cell carcinoma who underwent radical surgery were enrolled in this study. The SCC-Ag was measured, and CT scans were used for the preoperative assessment of lymph node status. RESULTS: Increased preoperative SCC Ag levels were associated with International Federation of Gynecology and Obstetrics stage (P = 0.001), tumor diameter of greater than 4 cm (P < 0.001), lymphovascular invasion (P = 0.001), LNM (P < 0.001), and greater than one half stromal infiltration (P < 0.001). Multivariate analysis identified LNM (P < 0.001, odds ratio [OR] = 4.399), tumor diameter of greater than >4 cm (P = 0.001, OR = 4.019), and greater than one half stromal infiltration (P = 0.002, OR = 3.680) as independent factors affecting SCC-Ag greater than or equal to 2.35 ng/mL. In the analysis of LNM, SCC-Ag greater than or equal to 2.35 ng/mL (P < 0.001, OR = 4.825) was an independent factor for LNM. The area under the receiver operator characteristic curve (AUC) of SCC-Ag was 0.763 for all patients, and 0.805 and 0.530 for IB1 + IIA1 and IB2 + IIA2 patients, respectively; 2.35 ng/mL was the optimum cutoff for predicting LNM. The combination of CT and SCC-Ag showed a sensitivity and specificity of 82.9% and 66% in parallel tests, and 29.8% and 93.3% in serial tests, respectively. CONCLUSIONS: The increase of SCC Ag level in the preoperative phase means that there may be a pathological risk factor for postoperative outcomes. The SCC-Ag (>=2.35 ng/mL) may be a useful marker for predicting LNM of cervical cancer, especially in stages IB1 and IIA1, and the combination of SCC-Ag and CT may help identify patients with LNM to provide them with the most appropriate therapeutic approach. PMID- 28914640 TI - Machine learning: novel bioinformatics approaches for combating antimicrobial resistance. AB - PURPOSE OF REVIEW: Antimicrobial resistance (AMR) is a threat to global health and new approaches to combating AMR are needed. Use of machine learning in addressing AMR is in its infancy but has made promising steps. We reviewed the current literature on the use of machine learning for studying bacterial AMR. RECENT FINDINGS: The advent of large-scale data sets provided by next-generation sequencing and electronic health records make applying machine learning to the study and treatment of AMR possible. To date, it has been used for antimicrobial susceptibility genotype/phenotype prediction, development of AMR clinical decision rules, novel antimicrobial agent discovery and antimicrobial therapy optimization. SUMMARY: Application of machine learning to studying AMR is feasible but remains limited. Implementation of machine learning in clinical settings faces barriers to uptake with concerns regarding model interpretability and data quality.Future applications of machine learning to AMR are likely to be laboratory-based, such as antimicrobial susceptibility phenotype prediction. PMID- 28914641 TI - Elderly recipients of liver transplantation: impact of age and psychosocial variables on outcome. AB - PURPOSE OF REVIEW: With expanding experience and success of liver transplantation, increasing numbers of elderly candidates await and undergo liver transplantation. There is accumulating evidence that graft survival and mortality does not appear to differ significantly between the young and carefully selected elderly liver transplantation recipients. Although existing evidence suggests that psychosocial factors impact outcomes after liver transplantation in general, no such information is available specifically for elderly (age >=65 years) liver transplantation recipients. We conducted a broad medical literature review of outcome studies of elderly liver transplantation recipients. In this review article, we summarize the findings and comment on psychosocial variables included in these studies. RECENT FINDINGS: Ten outcome studies have reported on the impact of age on the liver transplantation outcomes. There is increasing evidence of favorable outcomes in elderly liver transplantation recipients. Few of these studies include measures of quality of life, functional improvement and other psychosocial variables. SUMMARY: Very limited information is available about the impact of psychosocial factors on outcomes in elderly liver transplantation recipients. This dearth of information represents a critical gap in our knowledge and has implications for optimal candidate selection and outcomes after liver transplantation. PMID- 28914642 TI - Implications of weight loss for cancer patients receiving radiotherapy. AB - PURPOSE OF REVIEW: Cancer-associated weight loss is a common comorbid condition best described among patients with advanced malignancy receiving systemic therapy, but its relationship to patients undergoing radiation treatment is less well described. We review the interaction between cancer-associated weight loss and radiation treatment as well as its prognostic significance. RECENT FINDINGS: Multiple studies demonstrate a consistent detrimental effect of cancer-associated weight loss either existing prior to treatment or developing during radiotherapy. Emerging data suggest cancer-associated weight loss independently contributes to an aggressive malignant phenotype rather than simply reflecting a consequence of disease. Novel therapies are urgently needed to address the unmet burden of cancer-associated weight loss. SUMMARY: Consideration of cancer-associated weight loss is important among patients receiving radiotherapy. Further study will further characterize the relationship and identify targetable biologic mechanisms of cancer cachexia. PMID- 28914643 TI - Cancer-associated weight loss: releasing its firm grip on negative clinical outcomes. PMID- 28914644 TI - Systemic therapy in advanced melanoma: integrating targeted therapy and immunotherapy into clinical practice. AB - PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable. Data from subgroup analyses of large clinical trials, as well as patient-centred factors, help guide clinicians in their choice of first-line therapy. SUMMARY: Immune checkpoint inhibitors and MAP kinase pathway-targeted therapies have revolutionized the management of advanced melanoma, and significantly prolong the overall survival of patients with this disease. The median overall survival is over 2 years for both anti-PD-1-based therapy and combined BRAF and MEK inhibition. Without head-to-head comparison data for either therapy, choice of first-line drug treatment is difficult. PMID- 28914645 TI - Notch inhibitors and their role in the treatment of triple negative breast cancer: promises and failures. AB - PURPOSE OF REVIEW: Notch signaling is a highly evolutionarily conserved cell-to cell communication system that is involved in a number of pivotal cellular processes, such as development, stem cell maintenance, cell fate specification, differentiation, proliferation, and death. Much progress has been made in understanding Notch signaling. This review will focus on the role of canonical Notch signaling pathway in breast cancer cause and progressing. RECENT FINDINGS: In this review, we will discuss the results of the studies using drugs, which target the Notch pathway. SUMMARY: Notch sustains a proliferative signaling and protects from apoptosis, favors the angiogenic switch, the chemoresistance and radioresistance, controls the cancer stemness, and induces a prometastatic phenotype. Therefore, Notch-signaling represented an interesting target in the strategy against cancer growth. PMID- 28914646 TI - In Response: Comment on "Assessing the Utility of Fluoroscopy for Epidural Catheter Placement: What End Points Are Important?" PMID- 28914647 TI - Effect of an Intravenous Dexamethasone Added to Caudal Local Anesthetics to Improve Postoperative Pain: A Systematic Review and Meta-analysis With Trial Sequential Analysis. AB - BACKGROUND: Caudal anesthesia has been used for postoperative pain control in pediatric surgical patients, but the duration of the analgesic effect is occasionally unsatisfactory. Intravenous steroids have been shown to be effective for postsurgical pain management after certain surgeries. The aim of this meta analysis with trial sequential analysis (TSA) was to evaluate the analgesic effect of steroids in patients administered with caudal anesthesia. METHODS: This study was a systematic review and meta-analysis. A search of published literature was conducted in the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases and in trial registration sites. Randomized controlled trials that compared intravenous steroids with a placebo in pediatric patients who had received caudal anesthesia for surgery were included in the study. The primary outcomes from the present meta-analysis were the analgesic duration and the number of patients who required rescue analgesics. The analgesic duration and incidence of rescue use were summarized using mean difference or risk ratio with a 97.5% confidence interval (CI), respectively. If the 97.5% CI of the mean difference or risk ratio included a value of 0 or 1, respectively, we considered the difference not to be significant. We used the random effects model to combine the results. Heterogeneity was quantified with the I statistic. The quality of the trials was evaluated using the Cochrane methodology. Moreover, a TSA with a risk of type 1 error of 2.5% and power of 90% was performed. We established the minimum clinically meaningful difference of analgesic duration as 3 hours. The target sample size for meta-analysis was also calculated in the TSA. We also assessed adverse events. RESULTS: Six trials with 424 patients were included; 211 patients received intravenous steroids. All trials compared dexamethasone of at least 0.5 mg/kg dose with a placebo. Dexamethasone prolonged the duration of caudal analgesia (mean difference, 244 minutes; 97.5% CI, 188-300). Heterogeneity was considerable with an I value of 94.8%. Quality of evidence was very low. The TSA suggested that only 17.0% of the target sample size had been reached, but the cumulative Z score crossed the trial sequential monitoring boundary to indicate a benefit. Rescue use was reported in 4 studies with 260 patients. Rescue use was not significantly reduced in the dexamethasone group (risk ratio, 0.53; 97.5% CI, 0.09-3.30; I, 98.7%). No increase in adverse events was reported. CONCLUSIONS: Intravenous dexamethasone prolongs the analgesic duration of caudal anesthesia. Trials to investigate the effectiveness of a lower dose of the dexamethasone in prolonging analgesic effects would be of interest. Further trials with a low risk of bias are necessary. PMID- 28914648 TI - Dexmedetomidine Maintains Its Direct Cardioprotective Effect Against Ischemia/Reperfusion Injury in Hypertensive Hypertrophied Myocardium. AB - BACKGROUND: Dexmedetomidine (DEX) has a direct cardioprotective effect against ischemia/reperfusion injury through endothelial nitric oxide synthase (eNOS) phosphorylation via alpha2-adrenoreceptor (alpha2-AR). By using spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat models, the cardioprotective effect of DEX in hypertrophied myocardium and the differential characteristics of cardiac alpha2-AR and the I1 imidazoline receptor (I1R) were examined. METHODS: Langendorff-perfused rat hearts underwent 40 minutes of global ischemia followed by 120 minutes of reperfusion in the presence or absence of DEX before ischemia. Infarct size was measured, and eNOS phosphorylation was assessed by Western blotting. The presence and expression of the receptors were assessed by immunohistochemistry, real-time reverse transcriptase polymerase chain reaction, and Western blotting. RESULTS: In WKY, DEX significantly decreased infarct size and increased phosphorylated-eNOS/eNOS. These effects were counteracted by yohimbine (alpha2-AR antagonist) and efaroxan (alpha2-AR and I1R antagonist). In SHR, DEX significantly decreased infarct size, and the effect was counteracted by efaroxan but not yohimbine. DEX did not alter phosphorylated-eNOS/eNOS in SHR. alpha2-AR and I1R were observed in WKY and SHR hearts. Although alpha2A-AR and alpha2B-AR messenger RNA and protein levels were upregulated in SHR, I1R expression was comparable between the 2 species. CONCLUSIONS: In the hypertrophied heart, DEX maintains its direct cardioprotective effect against ischemia/reperfusion injury via I1R in an eNOS-nondependent manner despite upregulation of alpha2-AR. PMID- 28914650 TI - Assessing the Utility of Fluoroscopy for Epidural Catheter Placement: What End Points Are Important? PMID- 28914651 TI - Sedation After Cardiac Surgery With Propofol or Dexmedetomidine: Between Scylla and Charybdis? PMID- 28914652 TI - In Response: Sedation After Cardiac Surgery With Propofol or Dexmedetomidine: Between Scylla and Charybdis? PMID- 28914654 TI - Accuracy of tests used to detect infection with Chlamydia trachomatis in asymptomatic pregnant women: a systematic review. AB - PURPOSE OF REVIEW: Infection with Chlamydia trachomatis in pregnancy is linked to increased risk of miscarriage, stillbirth, and preterm birth. Currently, PCR or DNA-based tests are the gold standard when detecting the infection; however, they are costly and require access to specialist equipment. The aim of this systematic review was to assess the accuracy of available tests to detect infection in an asymptomatic pregnant population. RECENT FINDINGS: There was evidence of the superior accuracy of nucleic acid amplification tests to cell culture in nonpregnant asymptomatic women; however, there are multiple commercial nucleic acid amplification tests with varying sensitivities and specificities. There is a gap in current literature on accuracy studies in an asymptomatic pregnant population, particularly within routine antenatal settings. SUMMARY: There is a need for a point-of-care test for Chlamydia in pregnancy. Future test accuracy studies for this population should aim to use a universally established reference standard. Further research should provide relevant evidence to guide practice. PMID- 28914655 TI - Percutaneous Nucleoplasty for the Treatment of a Contained Cervical Disk Herniation. AB - Cervical radiculopathy is characterized by compression of the roots of the nerve. When conservative treatment fails and symptoms persist or increase in severity, surgical treatment is considered. Anterior cervical discectomy with or without fusion is regarded as the standard treatment for cervical disk herniation. Recently, there is an evolving trend in spinal surgery towards less invasive techniques. Nucleoplasty is a minimally invasive technique in which radiofrequency technology is used for percutaneous decompression. During the last years nucleoplasty has been proven to be a safe and effective treatment to alleviate radiculopathy, caused by a contained disk herniation. Nucleoplasty is usually performed on an outpatient basis and is associated with a fast recovery time. This paper will describe the preoperative and postoperative management of cervical nucleoplasty as well as the surgical technique, accompanied by a video. PMID- 28914657 TI - Hearing Protective Devices Should Be Used by Recipients of Repetitive Transcranial Magnetic Stimulation. PMID- 28914656 TI - Charcot-Marie-Tooth Disease Type 1A: Influence of Body Mass Index on Nerve Conduction Studies and on the Charcot-Marie-Tooth Examination Score. AB - PURPOSE: Charcot-Marie-Tooth Disease type 1A (CMT1A) is caused by a duplication of the peripheral myelin protein gene 22 at chromosome 17p11.2-12. There is limited data regarding whether body mass index (BMI) affects electrophysiological or clinical data in those with CMT1A. METHODS: Electrophysiological data, the Charcot-Marie-Tooth examination score (CMTES) and BMI from 101 patients with known CMT1A were obtained and analyzed. RESULTS: When controlling for age, a higher BMI does not affect ulnar motor nerve conduction studies in those with CMT1A, but rather components of the CMTES (loss of pinprick and motor strength in the lower extremities). CONCLUSIONS: BMI and clinical components of the CMTES are correlated, but it is uncertain which came first-whether the loss of lower extremity pinprick sensation and motor strength results in a higher BMI or if higher BMI results in these signs. PMID- 28914658 TI - Are the Sensory Fibers of the Ulnar Nerve Affected in Carpal Tunnel Syndrome? AB - PURPOSE: Distribution of paresthesia throughout the skin area without median nerve innervation is frequently seen in carpal tunnel syndrome (CTS). However, its pathophysiologic mechanisms are still unclear. We aimed to research whether a dysfunction in sensory fibers of the ulnar nerve (UN) was present or not in hands with CTS. METHODS: Totally, upper extremity nerve conduction study recordings of 508 patients were considered. After exclusions, 331 upper extremity recordings of 277 patients were included. We compared the results of sensory conduction studies of median nerve and UN between normal hands and hands with CTS. RESULTS: The mean distal sensory latency of the median nerve was longer, the mean conduction velocity was slower, and mean nerve action potential amplitude was higher in the hands with CTS than in normal hands (P < 0.001 for all comparisons). There was no statistically significant difference on any sensory conduction parameters of UN recorded on digit IV or digit V between the disease and control groups (P > 0.05 for all comparisons). The rates of conduction abnormalities of the UN sensory fibers were also similar in hands with CTS and in normal hands (P > 0.05 for all comparisons). CONCLUSIONS: The hands with CTS do not have an increased rate of conduction abnormalities of UN sensory fibers compared with the normal hands in our study population. Therefore, our study did not confirm the distortion of UN sensory fibers as a mechanism underlying the spread of paresthesia throughout the skin area without median nerve innervation in CTS. PMID- 28914659 TI - Relationship Between Alpha Rhythm and the Default Mode Network: An EEG-fMRI Study. AB - PURPOSE: Reports of the relationship between the default mode network (DMN) and alpha power are conflicting. Our goal was to assess this relationship by analyzing concurrently obtained EEG/functional MRI data using hypothesis independent methods. METHODS: We collected functional MRI and EEG data during eyes-closed rest in 20 participants aged 19 to 37 (10 females) and performed independent component analysis on the functional MRI data and a Hamming-windowed fast Fourier transform on the EEG data. We correlated functional MRI fluctuations in the DMN with alpha power. RESULTS: Of the six independent components found to have significant relationships with alpha, four contained DMN-associated regions: One independent component was positively correlated with alpha power, whereas all others were negatively correlated. Furthermore, two independent components with opposite relationships with alpha had overlapping voxels in the medial prefrontal cortex and posterior cingulate cortex, suggesting that subpopulations of neurons within these classic nodes within the DMN may have different relationships to alpha power. CONCLUSIONS: Different parts of the DMN exhibit divergent relationships to alpha power. Our results highlight the relationship between DMN activity and alpha power, indicating that networks, such as the DMN, may have subcomponents that exhibit different behaviors. PMID- 28914660 TI - Mediterranean diet impact on cardiovascular diseases: a narrative review. AB - : Cardiovascular disease (CVD) accounts for more than 17 million deaths per year worldwide. It has been estimated that the influence of lifestyle on CVD mortality amounts to 13.7% for smoking, 13.2% for poor diet, and 12% for inactive lifestyle. These results deeply impact both the healthy status of individuals and their skills in working. The impact of CVD on productivity loss accounts for the 24% in total costs for CVD management.Mediterranean diet (MedD) can positively impact on natural history of CVD. It is characterized by a relatively high consumption of inexpensive and genuine food such as cereals, vegetables, legumes, nuts, fish, fresh fruits, and olive oil as the principal source of fat, low meat consumption and low-to-moderate consumption of milk, dairy products, and wine.Its effects on cardiovascular health are related to the significant improvements in arterial stiffness. Peripheral artery disease, coronary artery disease, and chronic heart failure are all positively influenced by the MedD. Furthermore, MedD lowers the risk of sudden cardiac death due to arrhythmias.The present narrative review aims to analyze the effects of MedD on CVD. PMID- 28914661 TI - Percutaneous aortic leak closure in a small and frail annulus after double heart valve replacement. AB - : Paravalvular leak (PVL) is an uncommon but serious complication associated with the implantation of prosthetic valves. Following aortic valve replacement, up to 5% of patients affected by PVL develop clinical symptoms of heart failure, hemolysis or both. Percutaneous treatment of PVL has emerged instead of conventional surgery, as a well tolerated and less invasive procedure but remains a challenge. We present the case of a young woman with mechanical aortic and mitral prostheses, who presented surgical aortic PVL caused by a serious frailty of native annulus, became symptomatic after 5 months and was successfully percutaneously treated with an Amplatzer Duct Occluder device. PMID- 28914662 TI - A concealed case of takotsubo syndrome as consequence of ab ingestis episode in a revascularized patient. PMID- 28914664 TI - Three-dimensional MRI analyses of prereduced femoral head sphericity in patients with developmental dysplasia of the hip after Pavlik harness failure. AB - We used three-dimensional (3D) MRI to assess the sphericity of the cartilaginous femoral head in developmental dysplasia of the hip. We assessed 21 children using 3D-MRI. The smallest sphere including the femoral head cartilage was drawn, the diameter was measured, and the center of the sphere was defined. We compared the diameters of the femoral heads between unaffected and diseased sides. The diameter of the affected side was smaller, with flattening at the posteromedial area and proximoposterior areas. 3D-MRI showed that the shape of the dislocated femoral head was aspherical with focal growth failure. PMID- 28914663 TI - Physicians' Decision-making When Implementing Buprenorphine With New Patients: Conjoint Analyses of Data From a Cohort of Current Prescribers. AB - OBJECTIVES: Few studies have considered how providers make decisions to prescribe buprenorphine to new patients with opioid use disorder. This study examined the relative importance of patients' clinical, financial, and social characteristics on physicians' decision-making related to willingness to prescribe buprenorphine to new patients and the number of weeks of medication that they are willing to initially prescribe after induction. METHODS: A national sample of 1174 current prescribers was surveyed. Respondents rated willingness to prescribe on a 0 to 10 scale and indicated the number of weeks of medication (ranging from none to >4 weeks) for 20 hypothetical patients. Conjoint analysis estimated relative importance scores and part-worth utilities for these 2 outcome ratings. RESULTS: The mean rating for willingness to prescribe was 5.52 (SD 2.47), indicating a moderate willingness to implement buprenorphine treatment. The mean prescription length was 2.06 (SD 1.34), which corresponds to 1 week of medication. For both ratings, the largest importance scores were for other risky substance use, method of payment, and spousal involvement in treatment. Illicit benzodiazepine use, having Medicaid insurance to pay for the office visit, and having an opioid-using spouse were negatively associated with these outcome ratings, whereas a history of no risky alcohol or benzodiazepine use, cash payment, and having an abstinent spouse were positively associated with both ratings. CONCLUSIONS: Reticence to prescribe to individuals using an illicit benzodiazepine and individuals with a drug-using spouse aligns with practice guidelines. However, reluctance to prescribe to patients with Medicaid may hamper efforts to expand access to treatment. PMID- 28914665 TI - Role of a tendon transfer as a dynamic checkrein reducing recurrence of equinus following distal tibial dorsiflexion osteotomy. AB - Tibial dorsiflexion osteotomy for recalcitrant equinus in clubfeet is reported to have a high recurrence rate with growth. We present the results of closing wedge tibial dorsiflexion osteotomy and tendon transfers in 15 feet and 11 patients. The mean age at presentation was 7 (range: 3.98-12.38) years. At a mean follow-up of 4.16 (range: 2.09-6.87) years, 11 of the 15 feet remained corrected. Mean correction of the dorsiflexion was 24.5 degrees and mean correction of anterior distal tibial angle was 10.9 degrees at final review. Muscle rebalancing appears to influence bone remodeling and reduce recurrence of equinus. PMID- 28914666 TI - The regulation and importance of monocyte chemoattractant protein-1. AB - PURPOSE OF REVIEW: Monocyte chemoattractant protein (MCP)-1, a chemokine regulating monocyte chemotaxis and T-lymphocyte differentiation by binding to the CC chemokine receptor 2 (CCR2), plays a crucial role in the pathogenesis of inflammatory diseases, atherosclerosis and cancer. This review summarizes the current knowledge on the regulation and importance of the MCP-1/CCR2 axis, focusing on the therapeutic potential of its inhibition. RECENT FINDINGS: Differential modulation of MCP-1 and CCR2 lead to downstream activation pathways, pathogenetic to differing disease conditions characterized by dysregulated monocyte/macrophage tissue recruitment. Pharmacological targeting of the MCP 1/CCR2 axis has led to selective MCP-1/CCR2 antagonists that have now entered phase I/II clinical trials for the treatment of inflammatory diseases, atherosclerosis and cancer. The pleiotropic nonselective MCP-1/CCR2 inhibition by current pharmacological agents is thought to contribute to their anti inflammatory and antiatherosclerotic effects that is also seen for nutraceutical compounds such as curcumin. SUMMARY: MCP-1 has a critical role in regulating chemotaxis both in health and disease, with increasing interest in its pharmacological inhibition. However, the therapeutic efficacy and safety of targeting the MCP-1/CCR2 axis is still in evolution. PMID- 28914667 TI - Metabolic regulation of macrophages in tumor microenvironment. AB - PURPOSE OF REVIEW: Insight into the metabolic changes in cancer has become so important that cancer is regarded as a disease entity full of metabolic implications. We summarize the recent findings pertaining to cancer cell-derived metabolic changes that regulate the function of macrophages to favor cancer cell survival, and the reported approaches to reverse these changes. RECENT FINDINGS: Since the observation and dramatic revitalization of the Warburg effect, metabolic changes were thought to be confined in cancer cells. However, the Warburg effect has recently been proven to exist in various types of immune cells in tumor tissue. A growing number of publications now indicate that cancer cells interact with other cells in the tumor microenvironment, not only through traditional inflammatory mediators, but also through oncometabolites, and that metabolic changes in immune cells by oncometabolites are the key factors favoring the survival of cancer cells and pro-tumoral function of immune cells. Notably, these metabolic changes do not occur uniformly in tumor progression. SUMMARY: Understanding of the complex metabolic interactions in the tumor microenvironment can not only set a new paradigm for tumor progression, but also provide new breakthroughs to control cancer by modulation of function in tumor-associated macrophages. PMID- 28914668 TI - Minimally Invasive Palmaris Longus Abductorplasty for Severe Carpal Tunnel Syndrome. AB - Camitz abductorplasty is the most commonly used tendon transfer in patients with severe carpal tunnel syndrome with significant muscle wasting and loss of opposition. This procedure requires a long incision in the palm to harvest a strip of palmar aponeurosis to lengthen the palmaris longus tendon, allowing it to reach the abductor pollicis brevis insertion. Several complications have been attributed to this extensive dissection in the palm. We describe a minimally invasive palmaris longus abductorplasty using a strip of free flexor carpi radialis tendon graft to achieve the necessary length. This can be done together with carpal tunnel release in patients with severe carpal tunnel syndrome. PMID- 28914670 TI - Endometrial Stromal Neoplasm in the Placenta: Report of a Case and Review of the Literature. AB - Placental neoplasms involving the fetal membranes are exceptionally rare. In leiomyomas and endometrial stromal neoplasms, a uterine origin for nodules in the membranes is also a possibility. We present a case of an incidental endometrial stromal nodule found in the decidua of the free membranes and review the literature. PMID- 28914669 TI - Infection Staging and Incidence Surveillance Applications of High Dynamic Range Diagnostic Immuno-Assay Platforms. AB - BACKGROUND: Custom HIV staging assays, including the Sedia HIV-1 Limiting Antigen (LAg) Avidity EIA and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify "recent" infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and long-standing infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications. METHODS: We tested a panel of 2500 well-characterized specimens with estimable duration of HIV infection with the 3 assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRIs), context-specific false-recent rates (FRRs) and correlation between diagnostic signal intensity and LAg measurements. Hypothetical epidemiological scenarios were constructed to evaluate utility in surveillance applications. RESULTS: Over a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR ~ 0.5% and 1.5%, respectively at MDRI ~ 200 days), and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (relative SE ~ 17.5% and 15%, respectively at MDRI ~ 200 days). ARCHITECT S/CO measurements were highly correlated with LAg optical density measurements (r = 0.80), and values below 200 are strongly predictive of LAg recency and duration of infection less than 1 year. CONCLUSIONS: Low quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing, and its use is feasible in clinical staging and incidence surveillance applications. PMID- 28914671 TI - Endometrial Polyps and Benign Endometrial Hyperplasia Have Increased Prevalence of DNA Fragmentation Factors 40 and 45 (DFF40 and DFF45) Together With the Antiapoptotic B-Cell Lymphoma (Bcl-2) Protein Compared With Normal Human Endometria. AB - DNA fragmentation factor 40 (DFF40) is a key executor of apoptosis. It localizes to the nucleus together with DNA fragmentation factor 45 (DFF45), which acts as a DFF40 inhibitor and chaperone. B-cell lymphoma (Bcl-2) protein is a proven antiapoptotic factor present in the cytoplasm. In this study, we aimed to investigate DFF40, DFF45, and Bcl-2 immunoexpression in endometrial polyps (EPs) and benign endometrial hyperplasia (BEH) tissue compared with that in normal proliferative endometrium (NPE) and normal secretory endometrium (NSE) as well as normal post menopausal endometrium (NAE). This study used archived samples from 65 and 62 cases of EPs and BEH, respectively. The control group consisted of 52 NPE, 54 NSE, and 54 NAE specimens. Immunohistochemistry was used to detect DFF40, DFF45, and Bcl-2. DFF40, DFF45, and Bcl-2 were more highly expressed in the glandular layer of EPs and BEH compared with the stroma, and this was not influenced by menopausal status. Both glandular and stromal expression of DFF40, DFF45, and Bcl-2 were significantly higher in EPs compared with NPE, NSE, and NAE. Glandular BEH tissue showed significantly higher DFF40, DFF45, and Bcl-2 expression than in NPE, NSE, and NAE. No differences in the glandular expression of DFF40, DFF45, and Bcl-2 were observed between EP and BEH tissues, while Bcl-2 stromal expression in BEH was significantly lower than in EPs. Glandular, menopause-independent DFF40, DFF45, and Bcl-2 overexpression may play an important role in the pathogenesis of EPs and BEH. PMID- 28914672 TI - Endometrial Changes in Surgical Specimens of Perimenopausal Patients Treated With Ulipristal Acetate for Uterine Leiomyomas. AB - Ulipristal acetate (UPA) is used to treat leiomyomas, and its effect on the endometrium has been studied in biopsy material. Reversible histologic modifications were found, named progesterone receptor modulators-associated endometrial changes (PAEC). However, hysterectomies from patients treated with UPA have not been analyzed. For the first time, we examined surgical specimens from 100 leiomyoma-treated patients for UPA-related endometrial changes. We analyzed the distribution of lesions, involution after treatment, and the relationship between type and extent of lesions and dosage. Clinically, 72 patients were treated with 1 cycle of UPA; 23 patients with 2 cycles, and 5 with 3 cycles. A total of 66 patients underwent surgery in the first 4 wk after treatment, 24 were operated between 5 and 12 wk after discontinuation of UPA, and 10 after more than 12 wk after the last cycle, up to a maximum of 32 wk. Histologically normal endometria were found in 41 cases and PAEC in 59 cases. PAEC consisted of irregular, cystic glands showing a flattened secretory-like epithelium with vacuolation, coexisting mitoses and apoptosis, and were found focally within cyclic endometria in 51 cases. Only in 8 cases did diffuse PAEC involve the whole endometrium, transforming it into a thick spongy cushion. PAEC also occurred in adenomyosis. There was no relationship between dosage and type and extent of lesions. Diffuse PAEC, which usually presents differential diagnoses with hyperplasia, occurred in only 8 cases, being only present during the first 4 wk after discontinuation of treatment and was independent of the number of cycles administered. PMID- 28914673 TI - Nodular Hyperplasia of the Bartholin Gland, A Benign Mimicker of Aggressive Angiomyxoma: A Case Series and Literature Review. AB - Nodular hyperplasia (NH) of the Bartholin gland is an exceedingly rare benign solid lesion of the female genital tract that can mimic the Bartholin gland cyst clinically. The histologic criteria for NH were established in 1998 by Koenig and Tavassoli. In this case series, we describe 4 cases of NH from Women and Infants Hospital in Rhode Island. All cases have microscopic features of lobular proliferation of acini and inspissated mucin. One case especially has extensive mucin extravasation mimicking an aggressive angiomyxoma. In this case series, we call attention to NH as another entity to consider in the differential diagnosis of an enlarged Bartholin gland. We also discuss ways to distinguish it from other benign and malignant solid lesions of the vulvar vestibule. PMID- 28914674 TI - Frequent PD-L1 Expression in Malignant Melanomas of the Vulva. AB - Blockade of immune checkpoint pathways such as the programmed cell death protein 1 pathway (PD-1/PD-L1) is an emerging approach in the treatment of solid tumors. In malignant melanoma, the efficiacy of antibodies against PD-L1 has been shown to be associated with PD-L1 protein expression. To evaluate whether this approach may be of use in the rare cases of primary melanoma of the vulva, we have evaluated a series of 13 cases for PD-L1 expression as well as additional molecular alterations of KIT, NRAS, KRAS, and BRAF. PD-L1 expression was detected in 69% of cases and was not associated with any other molecular alteration, tumor stage or morphology. In conclusion, targeting PD-L1 by selective antibodies may be of benefit in the treatment of these uncommon tumors. PMID- 28914675 TI - Ganglioneuroblastoma Arising in an Ovarian Dermoid Cyst: First Report in the Literature. AB - The development of a somatic neoplasm within an ovarian dermoid cyst (mature cystic teratoma) is a rare, but well described, phenomenon which occurs in approximately 1% of all cases. Any of the tissue components of a dermoid cyst has the potential to undergo neoplastic transformation with carcinoid tumors and squamous cell carcinomas being among the most common neoplasms. We report a case of a ganglioneuroblastoma arising within an ovarian dermoid cyst, an association which, as far as we are aware, has not been described previously. PMID- 28914676 TI - Is Dexmedetomidine a Miracle Drug for Sedation in Patients With Neuroacanthocytosis With Involuntary Movements? PMID- 28914677 TI - Survival of the Fittest, Part 2: The Emergence of Super Fungi. PMID- 28914678 TI - Update: Topical Antimicrobial Agents for Chronic Wounds. AB - GENERAL PURPOSE: To provide information on the use of topical antimicrobial agents for the treatment of chronic wounds. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Examine features of wounds and wound healing as well as the purpose of specific antimicrobial agents.2. Identify potential therapeutic and adverse effects of specific topical antimicrobial agents for the treatment of chronic wounds. ABSTRACT: Bacteria can delay or prevent healing in the surface compartment of a chronic wound or invade the deep and surrounding structures. This article focuses on the superficial compartment and the appropriate use of topical antimicrobial therapies. The authors have reviewed the published evidence for the last 5 years (2012-2017) and extrapolated findings to clinical practice with critical appraisal and synthesis of the recent literature with expert opinion, patient-centered concerns, and healthcare systems perspectives. Summary evidence tables for commonly used topical antimicrobials are included. PMID- 28914679 TI - Reliability of a Skin Diagnostic Device in Assessing Hydration and Erythema. AB - OBJECTIVE: To examine the reliability of a skin diagnostic device, the SD202 (Courage+Khazaka GmBH, Cologne, Germany), in assessing hydration and erythema of periwound skin and pressure injury-prone areas. DESIGN: Intrarater reliabilities from 3 cross-sectional and prospective studies are reported. SETTING AND PARTICIPANTS: Patients attending an outpatient, nurse-led wound dressing clinic (n = 16), a podiatrist-led high-risk foot clinic (n = 17), and residents (n = 38) at a single residential aged-care facility. MAIN OUTCOME MEASURE: Skin hydration and erythema levels assessed using the SD202. MAIN RESULTS: High internal consistency was maintained for consecutive skin hydration and erythema measures at a single point on the venous leg ulcer periwound (alpha > .996 and alpha > .970 for hydration and erythema, respectively) and for the pressure-prone areas of the sacrum (alpha > .916), right (alpha > .994) and left (alpha > .967) ischium, right (alpha > .989) and left (alpha > .916) trochanter, right (alpha > .985) and left (alpha > .992) calcaneus, and right (alpha > .991) and left (alpha > .990) lateral malleolus. High consistency was also found for the measures obtained at 4 different locations around the periwound for the venous leg ulcer (alpha > .935 and alpha > .870 for hydration and erythema, respectively). In diabetic foot ulcer assessment, acceptable internal consistency of hydration measures around the periwound was observed (alpha > .634). Internal consistency of erythema measures was variable, ranging from low to high reliability, particularly among predebridement measures. CONCLUSIONS: Using the protocols outlined in this study, the SD202 demonstrates high reliability for assessing skin hydration and erythema levels. It is possible that the SD202 can be used in clinical practice as an appropriate tool for skin hydration and erythema assessment. PMID- 28914680 TI - Outcomes in Patients Treated with a Novel, Simple Method for Hemostasis of Dermal Avulsion Injuries. AB - OBJECTIVE: A recently described technique proposes a simple method to achieve permanent hemostasis of distal fingertip dermal avulsion injuries. It is simple to learn and easy to perform with readily available materials found in most emergency departments. However, long-term outcomes for patients treated with this technique have not yet been evaluated. A primary objective of the current article is to provide safety data for the technique using an off-label product indication. SETTING: Emergency department of Kaiser Permanente Medical Center, San Francisco, California. MATERIALS AND METHODS: Six patients were treated in the emergency department for fingertip dermal avulsion injuries using a tourniquet and tissue adhesive glue (Dermabond by Ethicon, Somerville, New Jersey). Patients were subsequently contacted to assess healing and satisfaction with cosmetic outcome through interview and photographs of their wounds at 9 months following the date of injury. RESULTS: All 6 patients were satisfied with the cosmetic outcome of treatment, and none received a diagnosis of serious complications. CONCLUSIONS: This series demonstrates cosmetic outcomes for injuries treated with the technique, highlights potential problems that may be perceived by patients during their clinical course, and creates the groundwork for a larger clinical study examining the use of the technique. PMID- 28914681 TI - Randomized Controlled Trial Comparing Collagen/Oxidized Regenerated Cellulose/Silver to Standard of Care in the Management of Venous Leg Ulcers. AB - OBJECTIVE: To assess healing outcomes in venous leg ulcers (VLUs) treated with a combination of collagen, oxidized regenerated cellulose, and silver in conjunction with standard of care (SOC; intervention group) compared with SOC alone (control group). Standard of care included ADAPTIC nonadhering dressing (Acelity, San Antonio, Texas) and compression. DESIGN AND SETTING: Randomized controlled trial that followed patients in 3 US facilities for 12 weeks or until complete healing. PATIENTS AND INTERVENTION: Forty-nine patients with VLUs were randomized to either the intervention group (n = 22) or the control group (n = 27). MAIN OUTCOME MEASURE: Wound healing over 12 weeks. MAIN RESULTS: Intent-to treat analysis showed a mean percentage wound area reduction at 12 weeks of 85.6% (SD, 28.6%) for the intervention group and 72.5% (SD, 77.8%) for the control group. There was a higher healing rate in the intervention group compared with patients who received SOC only at both week 4 (23% vs 11%) and week 12 (64% vs 59%). There were no adverse events related to the study therapy. CONCLUSIONS: Although the results were not significant, there was a trend toward faster healing in the intervention group. The results of this study indicate that collagen/oxidized regenerated cellulose/silver is a suitable and safe adjunctive intervention for use with SOC to manage VLUs. PMID- 28914682 TI - Refractory Ulcerated Necrobiosis Lipoidica: Closure of a Difficult Wound with Topical Tacrolimus. AB - OBJECTIVE: To report a case of refractory ulcerated necrobiosis lipoidica (NL) with significant response to treatment with topical tacrolimus. SUBJECT: A 55 year-old woman without diabetes and with a previous history of NL presented to the Helen L. and Martin S. Kimmel Hyperbaric and Advanced Wound Healing Center of NYU Langone Medical Center, New York, with bilateral lower-leg ulcerations resistant to wound healing techniques at other institutions. MATERIALS AND METHODS: Repeat biopsy performed at the author's institution confirmed the diagnosis of NL. Initial therapy was based on reports of other successful treatment methods, which included collagen wound grafts and collagen-based dressings coupled with compression. These methods initially showed promising results; however, the wounds reulcerated, and any gains in wound healing were lost. Alternative options were initiated, including topical clobetasol and narrowband ultraviolet B; however, no significant improvement was observed. The patient's lower-extremity wounds began to deteriorate. The patient also refused systemic therapy. Treatment was changed to topical 0.1% tacrolimus ointment and was applied daily for 10 months with multilayer compression wraps. RESULTS: Both lower-extremity ulcerations began to show significant improvement, with the ulcers progressing toward closure except for 1 very small area on the left lower extremity. CONCLUSIONS: Topical tacrolimus seems to be an effective treatment option for patients with refractory chronic ulcerated NL who do not want systemic oral therapy. The authors found that successful wound closure may require a multimodal approach, which promotes wound healing, but also concurrently addresses the underlying disease process. PMID- 28914683 TI - Primum Non Nocere and the 5 Rights. AB - Overutilization of hyperbaric oxygen therapy (HBOT) is commonplace and primarily associated with outpatient wound care. While the number of hospitals providing HBOT is at an all-time high, the number of those willing to treat patients in immediate need is at an all-time low. Huge areas of the country, including major population areas, are now completely devoid of 24/7 HBOT availability and inpatient access. Purchasers of healthcare, including the Centers for Medicare and Medicaid Services, have become increasingly concerned to the point that several strategies have been introduced to constructively deal with this issue. This commentary serves as a counterpoint to concerns that one such approach, prior authorization of elective indications, adversely delays medically necessary care. The historical evolution of HBOT practice will be described to underscore how this problem has become so widespread and, to date, largely unchecked. It will also address the paradoxical national crisis of access for emergencies. PMID- 28914685 TI - Update: Topical Antimicrobial Agents for Chronic Wounds. PMID- 28914684 TI - Merit-Based Incentive Payment System Audit Checklist for 2017. PMID- 28914686 TI - Rhenium-188 as a therapeutic radionuclide in low-income and middle-income countries. PMID- 28914687 TI - Prevention of macular edema after cataract surgery. AB - PURPOSE OF REVIEW: Although cataract surgery can effectively restore visual function in many patients with cataract, PCME remains an important cause of suboptimal visual acuity. The present review provides an overview of the current literature on the prevention and treatment of PCME. RECENT FINDINGS: Optimal prevention of PCME starts preoperatively with a personalized risk assessment. Diabetes mellitus, retinal vein occlusion, epiretinal membrane, macular hole, and uveitis are the most important risk factors for developing cystoid macular edema after cataract surgery. Topical NSAIDs either in addition to, or instead of, topical corticosteroids reduce the risk of developing PCME. Additional intravitreal corticosteroid and antivascular endothelial growth factor injections have been studied in patients with diabetes. Timely diagnosis and treatment of PCME is essential. Topical NSAIDs solely, or in addition to corticosteroids, improve visual acuity in patients with PCME. Oral acetazolamide and intravitreal dexamethasone implants have been used in refractory cases. SUMMARY: Topical NSAIDs can be used solely, or in combination with topical corticosteroids, to prevent and treat PCME. Further research is needed to compare the efficacy of various NSAIDs, and to investigate the cost-effectiveness and long-term benefit of anti-inflammatory treatments on visual acuity, contrast sensitivity, and quality of life. PMID- 28914688 TI - Femtosecond laser-assisted versus phacoemulsification for cataract extraction and intraocular lens implantation: clinical outcomes review. AB - PURPOSE OF REVIEW: Femtosecond laser-assisted cataract surgery (FLACS) has gained popularity in recent years with the new technology suggesting potential improvements in clinical and safety outcomes over conventional phacoemulsification cataract surgery (PCS). A decade since the advent of FLACS has given time and experience for laser technology to develop in maturity, and better quality evidence to become available. This review evaluates current evidence on the clinical and safety outcomes for FLACS in comparison to PCS. RECENT FINDINGS: FLACS technology continues to improve and with it our confidence in tackling more complex patient indications. Concurrently other new technologies such as precision pulse capsulotomy also look to deliver the biomechanically ideal 5.2 mm capsulotomy, particularly as there remain suggestions from large studies and meta-analyses of raised capsular complications with FLACS compared with PCS and IOL technology responding to advantages of a consistent capsulotomy. Visual benefits of FLACS over and above PCS also remain to be conclusively demonstrated, with equivalence but not superiority. Economic modelling continues to indicate that FLACS remains 'not' cost-effective. SUMMARY: FLACS can be considered non-inferior to conventional PCS in term of safety and clinical outcomes. However, FLACS has yet to demonstrate an overall cost-benefit to the patient. PMID- 28914689 TI - The European Journal of Cancer Prevention special issue on 'Joining forces for better cancer registration in Europe': achievements and perspectives. PMID- 28914690 TI - Incidence trends and survival of skin melanoma and squamous cell carcinoma in Cluj County, Romania. AB - The aim of this study was to determine the incidence trends of cutaneous melanoma (CM) and squamous cell carcinoma (SCC) in Cluj County, from 1998 to 2011, and the 5-year net survival between 2006 and 2010. Data on all cases of CM and SCC between 1998 and 2011 were obtained from Cluj Cancer Registry. Incidence rates were age standardized by the direct method Age Standardized Incidence Rate (ASIR), using the world standard population. Trends and annual percentage change (APC) of incidence rates were calculated by joinpoint regression analysis. The Pohar-Perme estimator was used to examine the 5-year net survival of cases diagnosed during 2006-2010 and followed up until December 2015. A total of 580 cases of CM and 397 cases of SCC were reported. During 1998-2011, the ASIR of CM increased significantly by 7.8% APC in male patients and by 7.42% APC in female patients, and the ASIR for SCC increased by 9.40% APC in male patients. In female patients, the incidence of SCC increased by 12.65% APC during 2002-2011. The 5 year net survival during 2006-2010 was 0.64 in men and 0.75 in women for CM and 0.86 and 1.00, respectively, for SCC. Survival rates showed an improving trend during 2006-2010, and were generally lower in men. Survival from both entities decreased with age and was lower in rural areas and in advanced stages in both sexes. This study reveals a rising incidence of cutaneous cancers in concordance with international trends. These data support the important role of primary and secondary prevention of skin cancers, focusing not only on melanoma, due to its lower survival, but also on SCC, in order to reduce their burden. PMID- 28914691 TI - Time trends and spatial patterns in the mesothelioma incidence in Slovenia, 1961 2014. AB - We aimed to explore the temporal and spatial variations in mesothelioma incidence in Slovenia for the last 50 years and, among these, to evaluate the consequences of asbestos usage. The incidence data from the population-based Cancer Registry of Republic of Slovenia for the period 1961-2014 were analysed. The data of asbestos imported to Slovenia were used as a proxy for asbestos exposure in manufacturing areas. Log-linear joinpoint regression and age-period-cohort Poisson models were used in the time-trend analysis. The mesothelioma maps were produced according to the method of local standardized incidence ratio estimates and are presented together with the map of Slovenian major asbestos-exposed locations. The maximum value of the asbestos import curve corresponds to the peak of mesothelioma curve exactly 30 years later. Both increases before the peak are comparable in time interval and steepness. The highest mesothelioma risk was detected for the cohort born between 1940 and 1944. In maps, the mesothelioma clusters manifest around known asbestos sources predominantly in the years 1980 1990, but in the last few years, the geographical distribution is more dispersed. The data from our long-existing population-based cancer registry provide a good insight into the on-going mesothelioma epidemic in Slovenia. Our results imply that the mesothelioma peak has already been reached in Slovenia. In the future, new cases will emerge more randomly throughout the country. PMID- 28914692 TI - Increasing suicide risk among cancer patients in Lithuania from 1993 to 2012: a cancer registry-based study. AB - Certain groups of individuals seem to have an increased risk of committing suicide, and a number of studies have reported an increased risk of suicide among cancer patients. In this study, we aim to estimate the risk of suicide among cancer patients in Lithuania over the period 1993-2012. The records of patients diagnosed with primary cancer were extracted from the population-based Lithuanian Cancer Registry and 273 511 cases of first cancer were included in the analysis. Sex, age and calendar period-standardized mortality ratios (SMRs) were calculated by dividing the observed numbers of suicides among cancer patients by the expected number using national rates. An increased suicide risk was found for both sexes combined [SMR=1.31, 95% confidence interval (CI): 1.21-1.41] compared with the general population. For all cancer sites except melanoma and skin, and breast and thyroid cancers, the relative suicide risk was elevated. The suicide risk was almost three-fold higher for advanced-stage patients compared with the general population (SMR=2.89, 95% CI: 2.24-3.73). The highest suicide risk observed in our study was during the first 3 months following cancer diagnosis (SMR=2.43, 95% CI: 1.96-3.01), indicating a critical period shortly after diagnosis. Despite ongoing increases in survival among cancer patients and decreases in suicide mortality in the general Lithuanian population during our study period, the increasing risk for suicide indicates that cancer patients' clinical and psychosocial needs remain unsatisfied. The major clinical implication of these data suggests the importance of multidisciplinary preventive interventions. PMID- 28914693 TI - Care patterns and changes in treatment for nonmetastatic breast cancer in 2013 2014 versus 2005: a population-based high-resolution study. AB - Studies on recent trends in patterns of care for breast cancer patients are scarce. This study aims to examine the patterns and trends in the treatment of women with nonmetastatic breast cancer according to major recommended treatment options. A population-based study was carried out in Navarra, Spain, including all women with a primary invasive nonmetastasized breast cancer, diagnosed in 2005 and in 2013-2014. We compared patients' characteristics and treatment patterns between periods. Factors associated with receipt of recommended treatment were examined by multivariate logistic regression. Of the 719 patients included, 90% received guideline-adherent locoregional treatment. Over the two periods, there was an increasing use of sentinel lymph node biopsy as opposed to axillary lymph node dissection as the first axillary procedure. Among women with oestrogen receptor-positive tumours, 96% received endocrine therapy. The proportion of high-risk patients who were treated with chemotherapy increased between the two periods from 65 to 74% (P=0.079) and, among patients with human epidermal growth factor receptor 2-positive tumours, the receipt of targeted treatment increased from 37 to 72% (P<0.001). The main factors associated independently with a lower probability of receiving recommended treatment were age 70 years or older for all treatment modalities and comorbidity for locoregional treatment and chemotherapy. The proportion of women with breast cancer who received treatment according to recent European guidelines in Navarra has increased from 2005 to 2013-2014, resulting in a high level of adherence to standard care. Most failures in adherence to these standards are related to older age or comorbidities. PMID- 28914695 TI - Autoimmune acute liver failure and seronegative autoimmune liver disease in children: Are they different from classical disease? AB - OBJECTIVES: Presentation as autoimmune acute liver failure (AI-ALF) and seronegative autoimmune liver disease (SN-AILD) represents two uncommon variants of AILD. We compared the clinical profile and outcome of AI-ALF with autoimmune non-acute liver failure (AI-non-ALF) and also SN-AILD with seropositive autoimmune liver disease (SP-AILD). MATERIALS AND METHODS: Children managed as AI ALF and AI-non-ALF including SN-AILD and SP-AILD were enrolled and compared. AI non-ALF was diagnosed by simplified diagnostic criteria and AI-ALF by Pediatric Acute Liver Failure Study Group criteria with positive autoantibody, exclusion of other etiologies, elevated immunoglobulin G and histology when available. RESULTS: Seventy children [AI-ALF=15 and AI-non-ALF=55 (SN-AILD=11, SP-AILD=44)] were evaluated. Age at presentation [7 (1.2-16) vs. 9 (2-17) years] percentage of female patients (67 vs. 62%), and AILD type (type II, 53 vs. 31%) were similar in AI-ALF and AI-non-ALF patients], respectively. 8/15 AI-ALF cases were treated with steroids (improved-4, liver transplant-1, and death-3) and 7/15 died before initiation of therapy. Hepatic encephalopathy (100 vs. 16.3%; P<0.001), massive hepatic necrosis (60 vs. 0%; P<0.001), and higher pediatric end-stage liver disease [n=53, 29.9 (13.1-56.9) vs. 9.8 (-10-28.7) P<0.001], model for end-stage liver disease [n=17, 38.5 (24-46) vs. 18 (6-24); P=0.005], and Child-Turcotte Pugh [n=70, 13 (8-13) vs. 9 (5-13); P<0.001] scores were features of AI-ALF. Poorer response to immunosuppression (4/8 vs. 48/55; P=0.02) and higher mortality (11/15 vs. 4/55; P=0.0001) were seen in AI-ALF than in AI-non-ALF patients. Clinicolaboratory profile, therapeutic response, and outcome were similar in SN AILD and SP-AILD. CONCLUSION: AI-ALF is characterized by poorer liver function, lower response to immunosuppression, and higher mortality compared with SP or SN AI-non-ALF, which are similar. PMID- 28914694 TI - The association of nonalcoholic steatohepatitis and obstructive sleep apnea. AB - BACKGROUND AND AIM: The association between obstructive sleep apnea (OSA) and abnormal liver enzymes has been reported in multiple studies. The existing literature regarding the relationship between OSA and nonalcoholic steatohepatitis (NASH) is conflicting. Thus we aimed to determine the relationship between OSA and NASH from a large database. PATIENTS AND METHODS: A cross-sectional study was performed using the 2012 Nationwide Inpatient Sample. We identified adult patients (18-90 years) who had a diagnosis of OSA using the International Classification of Diseases 9th version codes. The control group was comprised of adult individuals with no discharge records of OSA. NASH diagnosis was also identified using the International Classification of Diseases 9th version codes. The association between OSA and NASH was calculated using univariable and multivariable logistic regression. RESULTS: A total of 30 712 524 hospitalizations were included. The OSA group included 1 490 150 patients versus 29 222 374 in the control non-OSA group. The OSA group average age was 61.8+/ 0.07 years (44.2% females) compared with 57.0+/-0.11 years (60.1% females) in the non-OSA group. NASH prevalence was significantly higher in the OSA group compared with the non-OSA group [2% (95% confidence interval (CI): 1.9, 2.1) vs. 0.65% (95% CI: 0.63, 0.66), P<0.001]. After adjusting for obesity, diabetes, hypertension, dyslipidemia, the metabolic syndrome and Charlson comorbidity index, OSA patients were three times more likely to have NASH [adjusted odds ratio: 3.1 (95% CI: 3.0-3.3), P<0.001]. CONCLUSION: Patients with OSA are three times more likely to have NASH compared with patients without OSA after controlling for other confounders. These data indicate that OSA should be considered as an independent risk factor for developing NASH. PMID- 28914696 TI - The overlap of gastroesophageal reflux disease and functional constipation in children: the efficacy of constipation treatment. AB - OBJECTIVES: This study was designed to investigate the frequency of gastroesophageal reflux disease (GERD) in children with functional constipation (FC). It was structured to assess the improvement level in reflux symptoms by measuring the acid reflux in these patients after they had received FC treatment. METHODS: Ninety-four children who suffered from constipation were evaluated prospectively. Data forms were completed to assess the GERD symptoms in all the cases. Twenty-four-hour pH meter monitoring was performed in 55 of the patients with GERD symptoms. The cases with abnormal acid reflux were treated by conventional therapy for FC. These cases were re-evaluated for GERD symptoms and weekly defecation frequency, and 24-h pH meter monitoring was performed at the end of a 3-month period. RESULTS: An abnormal level of acid reflux was determined in 23 of the 55 cases. After the constipation treatment, a significant improvement was achieved in the acid reflux index and GERD symptoms, whereas the weekly defecation frequency increased. CONCLUSION: GERD is a frequent problem in children with FC. Treatment of the constipation can improve the reflux symptoms and abnormal acid reflux in these cases. Physicians should bear in mind the co occurrence of these two prevalent problems for better disease management. PMID- 28914697 TI - Are we ready to treat hepatitis C virus in individuals with opioid use disorder: assessment of readiness in European countries on the basis of an expert-generated model. AB - Individuals with a history of injecting drugs have a high prevalence of chronic hepatitis C (HCV) infection. Many have a history of opioid use disorder (OUD). Despite novel treatments with improved efficacy and tolerability, treatment is limited in the group. A faculty of experts shared insights from clinical practice to develop an HCV care-readiness model. Evidence and expert knowledge was collected. Ten experts developed a model of three factors (with measures): 'healthcare engagement', 'guidance' and 'place'. Overall, 40-90% of individuals with OUD engage with drug treatment services. Ten of 12 HCV guidelines provided specific advice for the OUD population. Ten of 12 OUD care guidelines provided useful HCV care advice. In 11 of 12 cases, location of HCV/drug treatment care was in different places. This readiness assessment shows that there are important limitations to successful HCV care in OUD. Specific actions should be taken: maintain/increase access to OUD treatment services/opioid agonist therapy, updating HCV guidance, locate care in the same place and allow wider prescribing of anti HCV medicines. PMID- 28914698 TI - Male hepatitis C patients' sexual functioning and its determinants. AB - OBJECTIVE: The aim of the study was to detect sexual impairment in male hepatitis C virus patients and determine its associations. PATIENTS AND METHODS: A total of 61 male hepatitis C virus patients were enrolled in this cross-sectional study. Sexual functioning was assessed using the International Index of Erectile Function. Health-related quality of life (HRQOL) was evaluated using the Greek version of the Short Form 36 Health Survey, and the presence and severity of anxiety and depression were assessed using the Greek version of the Hospital Anxiety and Depression Scale. RESULTS: Noncirrhotic patients showed clinically significant dysfunction, mainly in intercourse (59.6%) and overall satisfaction (57.4%). Erectile functioning and desire were correlated with depression (r= 0.520, P=0.000 and r=-0.473, P=0.000), anxiety (r=-0.443, P=0.000 and r=-0.428, P=0.001), physical (r=0.427, P=0.001 and r=0.329, P=0.012), and mental (r=0.379, P=0.003 and r=0.432, P=0.001) HRQOL, platelet count (r=-0.357, P=0.012 and r=0.366, P=0.010), and international normalized ratio (INR) levels (r=-0.373, P=0.013 and r=-0.440, P=0.003). Erection was also correlated with albumin levels (r=0.310, P=0.032). Orgasmic functioning was associated significantly with platelet count (r=0.322, P=0.024) and INR levels (r=-0.425, P=0.004). Intercourse satisfaction was significantly related to depression (r=-0.435, P=0.001) and anxiety (r=-0.335, P=0.008) levels, physical (r=0.374, P=0.004) and mental (r=0.300, P=0.022) HRQOL, platelet count (r=0.333, P=0.020), and INR levels (r= 0.373, P=0.013), and overall satisfaction was significantly correlated with depressive (r=-0.435, P=0.001) and anxiety (r=-0.278, P=0.033) symptoms, mental HRQOL (r=0.340, P=0.010), platelet count (r=0.316, P=0.029), and INR levels (r= 0.332, P=0.030). CONCLUSION: Hepatitis C is accompanied by poor sexual functioning even in the absence of cirrhosis and different correlations emerge for distinct subdomains of male sexuality. PMID- 28914699 TI - Ergonomics in Surgery: A Review. AB - OBJECTIVE: Work-related musculoskeletal disorders (WMSDs) are prevalent among surgeons and may result in practice modification. We aimed to perform a comprehensive review of the English-language literature regarding ergonomic risk, prevalence of WMSDs, and unique ergonomic considerations by route of surgery. METHODS: Multiple searches were performed of PubMed and University library resources to access English-language publications related to surgeon ergonomics. Combinations of keywords were used for each mode of surgery, including the following: "ergonomics," "guidelines," "injury," "operating room," "safety," "surgeon," and "work-related musculoskeletal disorders." Each citation was read in detail, and references were reviewed. RESULTS: Surgeon WMSDs are prevalent, with rates ranging from 66% to 94% for open surgery, 73% to 100% for conventional laparoscopy, 54% to 87% for vaginal surgery, and 23% to 80% for robotic-assisted surgery. Risk factors for injury in open surgery include use of loupes, headlamps, and microscopes. Unique risks in laparoscopic surgery include table and monitor position, long-shafted instruments, and poor instrument handle design. In vaginal surgery, improper table height and twisted trunk position create injury risk. Although robotic surgery offers some advantages, it remains associated with trunk, wrist, and finger strain. Surgeon WMSDs often result in disability but are under-reported to institutions. Additionally, existing research tools face limitations in the operating room environment. CONCLUSIONS: Work-related musculoskeletal disorders are prevalent among surgeons but have received little attention owing to under-reporting of injury and logistical constraints of studying surgical ergonomics. Future research must aim to develop objective surgical ergonomics instruments and guidelines and to correlate ergonomics assessments with pain and tissue-level damage in surgeons with WMSDs. Ergonomics training should be developed to protect surgeons from preventable, potentially career-altering injuries. PMID- 28914700 TI - Use of Ketorolac After Outpatient Urogynecologic Surgery: A Randomized Control Trial. AB - OBJECTIVE: Patient surveys highlight a prevalence of moderate to severe pain in the postanesthesia care unit. Multimodal analgesia has been promoted to improve this with fewer opioid-induced adverse effects. The aim of this study was to evaluate the opioid sparing and analgesic effect of postoperative intravenous (IV) ketorolac after outpatient transvaginal surgery. METHODS: Forty patients were enrolled in this institutional review board-approved, randomized, double blind, placebo-controlled study, to receive either 30 mg of IV ketorolac or IV saline placebo postoperatively. Pain was assessed by visual analog scale at timed intervals. Narcotic pain medication was provided upon request. Narcotic use was reassessed by telephone 5 to 7 days postoperatively. Categorical characteristics were compared by chi. Continuous variables were evaluated by Mann-Whitney U test. RESULTS: Twenty patients were randomized to each group. Groups were similar in age, health, and operative factors. There was no significant difference in mean pain scores at any interval. The ketorolac group had a total morphine equivalent consumption median of 7.5 mg versus 4.0 mg for placebo, which was not significant (P = 0.17). Total use of narcotic pills postoperatively was equivalent (median, 5). There was no difference in postoperative nausea. One Dindo grade II complication was reported in the ketorolac group of a postoperative pelvic hematoma requiring transfusion. DISCUSSION: Intravenous ketorolac administered after outpatient transvaginal surgery did not result in a reduction of pain scores or total morphine consumption. There was one Dindo grade II complication in the ketorolac group. Larger randomized control trials are needed to validate these findings. PMID- 28914701 TI - Elevated Postvoid Residual Urine Volume: Identifying Risk Factors and Predicting Resolution in Women With Pelvic Organ Prolapse. AB - OBJECTIVES: This study aims to identify risk factors for elevated preoperative postvoid residual (PVR) and persistently elevated postoperative PVR and to evaluate the resolution rate of elevated PVR urine volume in patients undergoing reconstructive surgery for pelvic organ prolapse (POP). METHODS: This was a retrospective cohort study comparing 50 women with elevated preoperative PVR (>=100 mL) and 50 women with normal PVR (<100 mL). Preoperative demographic, physical examination, urodynamic data, type of surgery performed, and postoperative trial of void data were collected. Variables were evaluated for association with elevated PVR using Student t test or Mann-Whitney U test, and chi or Fisher exact test. RESULTS: The elevated PVR cohort was older (65.5 +/- 13.3 vs 60.6 +/- 10.1 years, P = 0.04). The cohorts did not differ by body mass index, parity, number of cesarean deliveries, prior hysterectomy, incontinence, prolapse surgery, menopausal status, hormone replacement therapy, history of recurrent urinary tract infections, diabetes mellitus, or maximum bladder capacity. Most patients had preoperative anterior prolapse stage 2 or 3. Complaints of incontinence, incomplete bladder emptying, and overactive bladder did not differ between groups. Performed Surgical procedures, cystoscopy findings, and rate of postoperative trial of void failures did not differ between groups. One patient per cohort learned clean intermittent self-catheterization for persistently elevated PVR. CONCLUSIONS: All women undergoing surgery for POP had postoperative resolution of elevated PVR. Patients with nonneurogenic elevated PVR can be reassured that bladder emptying will improve after surgical repair of POP. PMID- 28914702 TI - Digitation to Void: What Is the Significance of This Symptom? AB - OBJECTIVE: Digitation to void is defined as the need to apply manual pressure on the perineum or the vagina to assist with voiding. It has been associated with prolapse; however, there is little objective data concerning this symptom. Our aim was to determine the correlation between digitation to void, symptoms and signs of pelvic organ prolapse (POP), and urodynamic data. METHODS: This was a retrospective study that included a total of 1174 patients seen at a tertiary urogynecological unit. A standardized history was obtained from all patients followed by multichannel urodynamic testing, Pelvic Organ Prolapse Quantification scoring and 3-D/4-D translabial ultrasound. Stored 4-D translabial ultrasound volumes were obtained and analyzed at a later date. RESULTS: Digitation to void was present in 7% (n = 83) of our population. It is associated with primary symptoms of POP (odds ratio [OR], 25.75; confidence interval [CI], 8.08-82.05), clinically significant POP (OR, 5.62; CI, 2.25-14.02), and POP on ultrasound (OR, 5.39; CI, 2.67-10.88). Cystocele presented the strongest association, clinically (OR, 3.45; CI, 1.98-6.03) and on ultrasound (OR, 4.04; CI, 2.46-6.64). Digitation to void was also associated with symptoms of voiding dysfunction (OR, 6.38 [3.83 10.64]) and slower maximum urine flow rate centile (18.4 vs 24.9, P = 0.017). CONCLUSIONS: Digitation to void is strongly associated with primary symptoms of prolapse and of voiding dysfunction, clinically significant POP, and pelvic organ descent on ultrasound. It is also associated with objective voiding dysfunction. The strongest associations were found with cystocele, both clinically and on imaging. PMID- 28914703 TI - Length of Catheter Use After Hysterectomy as a Risk Factor for Urinary Tract Infection. AB - OBJECTIVES: The aims of this study were to determine the effect of length of postoperative catheterization on risk of urinary tract infection (UTI) and to identify risk factors for postoperative UTI. METHODS: This was a retrospective case-control study. Demographic and perioperative data, including duration of indwelling catheter use and postoperative occurrence of UTI within 30 days of surgery, were analyzed for hysterectomies using the Michigan Surgical Quality Collaborative database. Catheter exposure was categorized as low-no catheter placed/catheter removed the day of surgery, intermediate-catheter removed postoperative day 1, high-catheter removal on postoperative day 2 or later, or highest-patient discharged home with catheter. A multivariable logistic regression model was developed to identify factors associated with UTI. An interaction term was included in the final model. RESULTS: Overall, UTI prevalence was 2.3% and increased with duration of catheter exposure (low: 1.3% vs intermediate: 2.1% vs high: 4.1% vs highest: 6.5%, P < 0.0001). High (odds ratio [OR] = 2.54 [1.51-4.27]) and highest (OR = 3.39 [1.86-6.17]) catheter exposure, operative time (OR = 1.15 [1.03-1.29]), and dependent functional status (OR = 4.62 [1.90-11.20]) were independently associated with UTI. Women who had a vaginal hysterectomy with sling/pelvic organ prolapse repair were more likely to have a UTI than those who had a vaginal hysterectomy alone (OR = 2.58 [1.10 6.07]) and more likely to have a UTI than women having an abdominal or laparoscopic hysterectomy with a sling/pelvic organ prolapse repair (OR = 2.13 [1.12-4.04]). CONCLUSIONS: Length of catheterization and operative time are modifiable risk factors for UTI after hysterectomy. An interaction between vaginal hysterectomy and concomitant pelvic reconstruction increases the odds of UTI. PMID- 28914704 TI - Rectoneovaginal Fistula in a Transgender Woman Successfully Repaired Using a Buccal Mucosa Graft. AB - BACKGROUND: Rectoneovaginal fistulae (RnVFs) are abnormal connections between the rectum and a surgically created neovagina. Although very uncommon, they confer significant morbidity in patients and may require a multidisciplinary team approach to the repair. Risk factors for RnVF include rectal injury at the time of neovaginoplasty, malignancy in the neovagina, trauma (iatrogenic or otherwise), radiation, and neovaginal revision surgery. CASE DESCRIPTION: The patient is a 64-year-old transgender woman with recurrent RnVF following penile skin inversion neovaginoplasty, which was complicated by an intraoperative rectal injury. After failing an initial attempt at repair, the fistula was successfully repaired with a buccal mucosa graft. CONCLUSIONS: In some cases, RnVFs following vaginoplasty surgery for gender affirmation may be repaired successfully with a buccal mucosa graft. PMID- 28914705 TI - Increasing Anteroposterior Genital Hiatus Widening Does Not Limit Apical Descent for Prolapse Staging During Valsalva's Maneuver: Effect on Symptom Severity and Surgical Decision Making. AB - OBJECTIVE: Determine if anteroposterior genital hiatus (GH) widening obscures rather than facilitates signs and symptoms, inadvertently altering management decisions for women with pelvic organ prolapse (POP) during Valsalva's Maneuver, at a given total vaginal length (TVL). METHODS: We performed a retrospective cohort with nested cross-sectional study of patients who underwent POP surgery. Data from obstetric and gynecologic history, preoperative and postoperative physical examinations, and 20-item Pelvic Floor Distress Inventory (PFDI-20) and 7-item Pelvic Floor Impact Questionnaire (PFIQ-7) scores were extracted. Study participants were compared in 2 groups: anteroposterior widened (>3 cm) and not widened (<=3 cm) GH, for baseline leading edge and POP stage, while controlling for TVL. Baseline PFDI-20 and PFIQ-7 scores were evaluated within GH groups. Delta GH, PFDI-20, and PFIQ-7 scores after apical suspension with and without posterior colporrhaphy were compared to assess the clinical value of the procedure. RESULTS: Study participants with anteroposterior GH widening during Valsalva maneuver had greater baseline leading edge descent and higher POP stage compared with those without anteroposterior GH widening after controlling for TVL. Baseline PFDI-20 and PFIQ-7 scores were similar within both GH categories controlling for prolapse severity. Adding posterior colporrhaphy to apical suspension resulted in a greater anteroposterior GH reduction without improving delta PFDI-20 or PFIQ-7 scores. CONCLUSIONS: Facilitation through herniation rather than obscuration from anteroposterior GH widening explains why patients will not be undertreated based on signs and symptoms of disease. Adding posterior colporrhaphy to apical suspension more effectively reduces anteroposterior GH widening without differential improvement in symptoms rendering the operation to no more than a cosmetic procedure. PMID- 28914706 TI - Long-Term Sexual Function After Obstetric Anal Sphincter Injuries. AB - OBJECTIVES: Obstetric anal sphincter injuries (OASIS) are associated with severe short and long-term morbidities, although little is known about the long-term sexual function or satisfaction of women and partners of women with history of OASIS. The objective of this study was to describe the long-term sexual function and satisfaction of women who previously sustained OASIS and to assess sexual satisfaction among their male partners. METHODS: This was a follow-up study of participants enrolled in the For Optimal Recovery: Care After Severe Tears (FORCAST) prospective cohort study of women with a history of OASIS after delivery of a full-term singleton infant between 2011 and 2013. A total of 47 women and 25 male partners at a mean of 45 months +/- 8 months after incident delivery completed online validated questionnaires assessing current sexual functioning and satisfaction. The Female Sexual Functioning Index (FSFI) was completed by female participants, whereas the Golombok-Rust Inventory of Sexual Satisfaction (GRISS) was completed by both female participants and their male partners. RESULTS: Nearly half (47%) of women met the criteria for female sexual dysfunction according to the Female Sexual Functioning Index. One-third of women (34%) had an overall GRISS score of 5 or greater, indicating sexual dysfunction. Sixty-two percent of women had a subsequent delivery. Seven male partners (28%) met the criteria for sexual dysfunction according to the GRISS. The most problematic GRISS subscale reported by both men and women was that of infrequency of intercourse. CONCLUSIONS: Even 3 years after sustaining OASIS, up to half of women and many male partners meet the criteria for sexual dysfunction. Future studies including women without history of OASIS are needed to further investigate the role OASIS may play in the development of long-term sexual dysfunction. PMID- 28914707 TI - Prospective Randomized Feasibility Study Assessing the Effect of Cyclic Sacral Neuromodulation on Urinary Urge Incontinence in Women. AB - OBJECTIVES: The aim of this prospective, randomized, multicenter, single-blind, 4 * 4 crossover study was to estimate the effect of 4 InterStim cycling settings (continuous, 16 seconds on/8 seconds off, 10 minutes on/10 minutes off, and 30 minutes on/23.5 hours off) on efficacy, Global Response Assessment, and safety. METHODS: Eligible women implanted for at least 3 months for urgency urinary incontinence (UI) were enrolled, and daily diaries were collected. General linear mixed models were used to estimate the cycling effect on efficacy. Quality of life measured by Global Response Assessment (subjects' perception of effectiveness) and safety were summarized. RESULTS: Primary efficacy analysis was based on the first 24 subjects who completed unique randomization sequences. Mean age was 64 years, and mean implant duration was 2.8 years. Results showed no significant cycling (P = 0.3773) or period (P = 0.0800) effect on UI. There was a statistically significant interaction between cycling and period (P = 0.0032). In the first period, subjects on 10 minutes on/10 minutes off had significantly fewer UI episodes compared with subjects on 16 seconds on/8 seconds off (P = 0.0026); this difference was not observed in any other period or sensitivity analyses. No cycling effect was found on urgency or pad usage. When programmed to 10 minutes on/10 minutes off, 54% of subjects felt their incontinence symptoms improved compared with when they entered the study, followed by 42% on 30 minutes on/23.5 hours off, 38% on 16 seconds on/8 seconds off, and 29% on continuous. Safety was similar across cycling settings. CONCLUSIONS: The results suggest that patients with overactive bladder who have been implanted with sacral neuromodulation devices and are receiving substantial benefit may perceive further optimization by switching to cycling settings. PMID- 28914708 TI - Efficacy of FemiScan Pelvic Floor Therapy for the Treatment of Anal Incontinence. AB - OBJECTIVES: Pelvic floor muscle training can be effective in alleviating anal incontinence; however, women need instruction, motivation, and feedback to gain optimal benefit. The FemiScan Pelvic Floor Therapy System is approved in the United States and European Union for the treatment of urinary incontinence. It uses office electromyography and an in-home programmable device. This study was undertaken to document the effect of FemiScan on anal incontinence symptoms of women who completed a physician-supervised program. METHODS: Women referred for treatment of urinary symptoms who also reported anal incontinence symptoms were included in the analysis. We collected patient demographics, electromyographic measurements, and responses to subjective questions about the status of their anal incontinence. RESULTS: Forty eight (55%) of 88 patients who started treatment completed the 8-visit protocol. No adverse events were reported. Mean age was 54.8 +/- 12.0 years. There was a statistically significant increase in the mean maximal response comparing the first and final electromyographic measurements obtained during the first and last office visits: left side, 13.7 +/ 9.3 MUV versus 23.2 +/- 13.5 MUV, P < 0.001 and right side, 14.6 +/- 2.4 MUV versus 22.7 +/- 10.6 MUV, P < 0.001 were analyzed separately. Fifty six percent reported that they were 100% free of symptoms, and 77% considered their symptoms at least 80% improved. Colorectal Anal Distress Inventory results demonstrated a statistically significant improvement when comparing the first and last visit (28.9 +/- 17.9 vs 2.1 +/- 7.8, P < 0.001). CONCLUSIONS: FemiScan appears to be a safe and effective treatment for anal incontinence with concomitant increased pelvic floor electromyographic activity. PMID- 28914709 TI - Outcomes of Vaginal Hysterectomy With and Without Perceived Contraindications to Vaginal Surgery. AB - OBJECTIVE: The aim of this study was to compare outcomes of vaginal hysterectomy between patients with and without the following perceived contraindications to vaginal surgery: uterine weight greater than 280 g, prior cesarean delivery, no vaginal parity, and obesity. METHODS: Retrospective cohort of benign vaginal hysterectomies between 2009 and 2013 was obtained. Outcomes included uterine debulking, transfusion, intraoperative complications, length of stay, and Accordion grade 2+ postoperative complications. For each outcome, the association between the presence of each contraindication and the outcome was evaluated using univariate and multivariate logistic regression models. RESULTS: Among 692 vaginal hysterectomies, 11% (76/691) had a uterine weight greater than 280 g, 11.3% (78/690) had no vaginal parity, 14.9% (103/690) had a history of cesarean delivery, and 37.7% (248/657) had a body mass index of 30 kg/m or greater; 110 (15.9%) had 2 or more contraindications. Uterine debulking occurred in 146 women (21.1%), and both uterine weight greater 280 g (adjusted odds ratio, 39.2; 95% confidence interval, 18.4-83.5) and prior cesarean delivery (adjusted odds ratio, 2.1; 95% confidence interval, 1.2-3.7) were significantly associated with an increased likelihood of uterine debulking after adjusting for age, hematologic disease, and preoperative diagnosis. None of the contraindications were significantly associated with need for a blood transfusion, presence of an intraoperative complication, length of stay greater than 2 days, or presence of an Accordion grade 2+ postoperative complication, which occurred in 2.7%, 2.5%, 14.0%, and 6.9% of all women, respectively. CONCLUSIONS: Vaginal hysterectomy can be safely performed with favorable outcomes, even in women with a uterus greater than 280 g, prior cesarean delivery, no vaginal parity, and obesity. Our findings challenge several perceived contraindications to vaginal hysterectomy. PMID- 28914710 TI - Effect of Time to Operative Intervention on Motility Outcomes Following Orbital Floor Fracture Repair in Children. AB - PURPOSE: To evaluate the relationship between time to surgical intervention and extraocular motility outcomes in children following repair of an orbital floor fracture with inferior rectus entrapment. METHODS: After institution review board's approval, a retrospective, consecutive case series of 28 children with unilateral orbital floor fractures entrapping the inferior rectus muscle was conducted. Clinical examinations and CT images were performed on all children. The main outcomes measures were postoperative motility measurements. RESULTS: Eleven patients underwent surgery within 24 hours of reported injury, while 17 patients underwent surgery after 24 hours. There was no statistically significant difference in average age at the time of surgery (p = 0.47) or average preoperative motility scores (p = 1.0) between the 2 groups. Patients who underwent surgery within 24 hours of reported injury had an improved likelihood of recovery (log hazard ratio = 0.469; 95% confidence interval, -0.42 to 1.36). CONCLUSIONS: Our exploratory study suggests that surgical reduction of inferior rectus entrapment in pediatric orbital floor fractures within 24 hours from the time of injury shows an improved, but nonstatistically significant, likelihood of recovery in motility deficits with earlier surgical intervention. PMID- 28914712 TI - Quality, Reliability, Repeatability - What about Excellence? PMID- 28914711 TI - Change in Eyelid Position Following Muller's Muscle Conjunctival Resection With a Standard Versus Variable Resection Length. AB - PURPOSE: This study compares the use of a standard 7 mm resection length to a variable 4:1 ratio of resection length to desired elevation nomogram when performing Muller's muscle conjunctival resection surgery. METHODS: In this cross sectional case control study, 2 groups were defined. The first underwent Muller's muscle conjunctival resection surgery with a standard 7 mm resection length and the second underwent the same surgery with a variable resection length determined by a 4:1 ratio of resection length to desired elevation nomogram. Groups were matched for age (within 5 years) and sex. Pre- and postoperative photographs were measured digitally. Change in upper marginal reflex distance 1 (MRD1) and final MRD1 were the primary outcome measures. The study was powered to detect a 1 mm difference in MRD1 to a beta error of 0.95. RESULTS: No significant preoperative differences between the groups were noted. No significant difference in final MRD1 (0.1 mm; p = 0.74) or change in MRD1 (0.2 mm; p = 0.52) was noted. Mean resection length to elevation ratios were 3.9:1 for standard group and 4.3:1 for the variable group (p = 0.54). CONCLUSION: The authors were not able to detect a significant difference in final MRD1 or change in MRD1 for patients undergoing Muller's muscle conjunctival resection surgery with standard or variable resection lengths. These results tend to argue against a purely mechanical mechanism for Muller's muscle conjunctival resection surgery. PMID- 28914713 TI - The hyperfibrinolytic phenotype is the most lethal and resource intense presentation of fibrinolysis in massive transfusion patients. AB - BACKGROUND: Among bleeding patients, we hypothesized that the hyperfibrinolytic (HF) phenotype would be associated with the highest mortality, whereas shutdown (SD) patients would have the greatest complication burden. METHODS: Severely injured patients predicted to receive a massive transfusion at 12 Level I trauma centers were randomized to one of two transfusion ratios as described in the Pragmatic, Randomized, Optimal Platelet and Plasma Ratio trial. Fibrinolysis phenotypes were determined based on admission clot lysis at 30 minutes (LY30): SD <=0.8%, physiologic (PHYS) 0.9-2.9%, and HF >=3%. Univariate and multivariate analysis was performed. Logistic regression was used to adjust for age, gender, arrival physiology, shock, injury severity, center effect, and treatment arm. RESULTS: Among the 680 patients randomized, 547(80%) had admission thrombelastography (TEG) values available to determine fibrinolytic phenotypes. Compared to SD and PHYS, HF patients had higher Injury Severity Score (25 vs. 25 vs. 34), greater base deficit (-8 vs. -6 vs. -12) and were more uniformly hypocoagulable on admission by PT, PTT, and TEG values; all p <0.001. HF patients also received more red blood cells, plasma, and platelets (at 3, 6, and 24 hours); had fewer ICU-, ventilator-, and hospital-free days; and had higher 24 hour and 30-day mortality. There were no differences in complications between the three phenotypes. Multivariate logistic regression demonstrated that HF on admission was associated with a threefold higher mortality (OR 3.06, 95% CI 1.57 5.95, p = 0.001). CONCLUSIONS: Previous data have shown that both the SD and HF phenotypes are associated with increased mortality and complications in the general trauma population. However, in a large cohort of bleeding patients, HF was confirmed to be a much more lethal and resource-intense phenotype. These data suggest that further research into the understanding of SD and HF is warranted to improve outcomes in this patient population. LEVEL OF EVIDENCE: Prognostic, level II. PMID- 28914714 TI - Radiologically Undetected Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation: An Immunohistochemical Correlation With LI-RADS Score. AB - Orthotopic liver transplantation is the best option for patients with carefully selected unresectable disease because of underlying liver dysfunction. The 5-year survival rate after orthotopic liver transplantation for early detected hepatocellular carcinoma (HCC) is high, and a similar or even higher rate is reported in those with radiologically undetected HCC. This study evaluated and compared the histologic features of pretransplant radiologically undetected (14 patients, 25 tumors) versus detected (36 patients, 45 tumors) HCCs. Tumor size, tumor differentiation, number of unpaired arteries, mitotic count per 10 high power fields, CD34 immunostain to assess microvessel density, and Ki67 immunostain were compared with the Liver Imaging Reporting and Data System score, which was retrospectively assigned to each tumor in both groups. The Liver Imaging Reporting and Data System score was significantly higher in the HCC detected group (P<0.001). The vast majority of the undetected HCCs (88%) was <2 cm in size. Only 12% of the undetected HCCs were >=2 cm, whereas 51% of the detected HCCs were >=2 cm in size. Higher rate of moderate to poor tumor differentiation was noted in the detected HCCs compared with the undetected group (89% vs. 60%; P=0.004). No statistically significant difference in the number and distribution of unpaired arteries, or mitotic count was observed in 2 groups (although fewer unpaired arteries were identified in the undetected group). The detected HCCs had a higher rate of 2+ CD34 staining compared with the undetected HCCs (68% vs. 27%; P=0.002), whereas the opposite was observed for 1+ CD34 staining (59% undetected HCCs vs. 17% detected HCCs; P=0.002). Ki67 proliferative index was not statistically different between the 2 groups (120.8/1000 cells detected HCCs vs. 81.8/1000 cells undetected HCCs; P=0.36). The factors associated with failing to detect HCCs pretransplant by radiologic studies include small tumor size (<2 cm), low-grade histologic differentiation, and low microvessel density (low CD34 staining). A significant association between the number and distribution of unpaired arteries and HCC detection has not been established by our study. PMID- 28914716 TI - Diagnostic Utility of SATB2 in Metastatic Krukenberg Tumors of the Ovary: An Immunohistochemical Study of 70 Cases With Comparison to CDX2, CK7, CK20, Chromogranin, and Synaptophysin. AB - SATB2 is a sensitive marker for colorectal adenocarcinomas. No study has investigated its diagnostic utility in metastatic Krukenberg tumors (MKTs) of the ovary. Here we performed immunohistochemical staining SATB2 in 70 MKTs of various origins (stomach 27, colorectum 13, appendix 20 including 19 metastatic adenocarcinomas ex goblet cell carcinoids [AdexGCC] and 1 conventional poorly differentiated carcinoma with signet ring cells, breast 5, bladder 3, lung 2) to assess its diagnostic utility. We also compared SATB2 with CDX2, CK7, CK20, chromogranin, and synaptophysin in MKTs of gastric origin (MKTs-stomach), those of colorectal origin (MKTs-colorectum) and those due to appendiceal AdexGCCs (MKT AdexGCCs) for their sensitivity and specificity to distinguish these tumors. SATB2 staining was seen in 1/27 (4%) MKTs-stomach (40% cells), 7/13 (54%) MKTs colorectum (mean: 17% cells, median: 7%, range: 2% to 60%), and 19/19 (100%) of MKT-AdexGCCs (mean: 97% cells, median: 100%, range: 80% to 100%) (P<0.01 between any two). SATB2 staining was seen in 1/1 metastatic appendiceal poorly differentiated carcinoma with signet ring cells (5% cells), 1/3 MKTs of bladder origin (60% cells), 0/2 MKTs of pulmonary origin, and 1/5 MKTs of breast origin (10% cells). SATB2 staining was diffuse strong in MKT-AdexGCCs whereas in other MKTs it was focal and weak in the signet ring and nonsignet ring nonglandular cells and from focal weak to diffuse strong in well-formed glands. MKTs-stomach, MKTs-colorectum, and MKT-AdexGCCs showed no significant staining difference in CDX2 (100%, 100%, 100% cases, respectively; P=1.0), CK20 (96%, 100%, 100%, respectively; P=1.0), chromogranin (59%, 31%, 63%, respectively; P>0.05) or synaptophysin (59%, 63%, 84%, respectively; P>0.05) but they had significant difference in CK7 staining (93%, 8%, 42%, respectively; P<0.05). Among these 6 markers, SATB2 is the best one to distinguish MKT-AdexGCCs from MKTs-stomach (100% sensitivity, 96% specificity) and MKTs-colorectum (100% sensitivity and 100% specificity if staining more than 75% tumor cells as the cutoff). In distinguishing MKTs-stomach from MKTs-colorectum, SATB2 is not as good as CK7 which is the best marker. Our results indicate that SATB2 is a highly sensitive marker (100% sensitivity) for metastatic MKT-AdexGCCs with high specificity (100% specificity when showing strong staining in at least 75% cells) among MKTs. SATB2 is a useful marker for determining the primary sites of MKTs of the ovary. PMID- 28914715 TI - Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma. AB - NOTCH1 is frequently mutated in adenoid cystic carcinoma (ACC). To test the idea that immunohistochemical (IHC) staining can identify ACCs with NOTCH1 mutations, we performed IHC for activated NOTCH1 (NICD1) in 197 cases diagnosed as ACC from 173 patients. NICD1 staining was positive in 194 cases (98%) in 2 major patterns: subset positivity, which correlated with tubular/cribriform histology; and diffuse positivity, which correlated with a solid histology. To determine the relationship between NICD1 staining and NOTCH1 mutational status, targeted exome sequencing data were obtained on 14 diffusely NICD1-positive ACC specimens from 11 patients and 15 subset NICD1-positive ACC specimens from 15 patients. This revealed NOTCH1 gain-of-function mutations in 11 of 14 diffusely NICD1-positive ACC specimens, whereas all subset-positive tumors had wild-type NOTCH1 alleles. Notably, tumors with diffuse NICD1 positivity were associated with significantly worse outcomes (P=0.003). To determine whether NOTCH1 activation is unique among tumors included in the differential diagnosis with ACC, we performed NICD1 IHC on a cohort of diverse salivary gland and head and neck tumors. High fractions of each of these tumor types were positive for NICD1 in a subset of cells, particularly in basaloid squamous cell carcinomas; however, sequencing of basaloid squamous cell carcinomas failed to identify NOTCH1 mutations. These findings indicate that diffuse NICD1 positivity in ACC correlates with solid growth pattern, the presence of NOTCH1 gain-of-function mutations, and unfavorable outcome, and suggest that staining for NICD1 can be helpful in distinguishing ACC with solid growth patterns from other salivary gland and head and neck tumors. PMID- 28914717 TI - The Relationship Between Mismatch Repair Deficiency and PD-L1 Expression in Breast Carcinoma. AB - Mismatch repair (MMR) deficiency in solid tumors has recently been linked to susceptibility to immunotherapies targeting the programmed cell death-1 (PD 1)/programmed cell death-1 ligand (PD-L1) axis. Loss of MMR proteins has been shown to correlate with tumoral PD-L1 expression in colorectal and endometrial carcinomas, but the association between expression of MMR proteins and PD-L1 has not previously been studied in breast carcinoma, where MMR deficiency is less common. We assessed the relationship between PD-L1 and MMR protein expression by immunohistochemistry in 245 primary and 40 metastatic breast carcinomas. Tumoral staining for PD-L1 was positive in 12% of all cases, including 32% of triple negative cancers. MMR deficiency was observed in 0.04% of breast cancers; the single MMR-deficient case was a high-grade, triple-negative ductal carcinoma which showed dual loss of MLH1 and PMS2 proteins and expressed PD-L1. Two ER carcinomas initially were scored with MMR protein loss in tissue microarray format but were subsequently shown to be MMR-intact on whole sections. Analysis of MMR gene mutation in The Cancer Genome Atlas corroborates low frequency of MMR deficiency for invasive breast cancer. MMR protein expression is therefore unlikely to show utility as a screen for immunotherapeutic vulnerability in this tumor type, and may provoke unwarranted genetic testing in patients unlikely to have a heritable cancer syndrome. PD-L1 may be a more clinically relevant biomarker for anti-PD-1/PD-L1 therapies in this setting. PMID- 28914718 TI - Balance Evaluation of Prefrail and Frail Community-Dwelling Older Adults. AB - BACKGROUND AND PURPOSE: With the increase in the percentage of the population in older adulthood, issues such as frailty syndrome need to be considered. The aim of the present study was to evaluate the ability of the Balance Evaluation Systems Test (BESTest) and center of pressure (COP) in their ability to discriminate between nonfrail, prefrail, and frail older adults. The proposed hypothesis is that frail older adults would show poorer performance in BESTest tasks and higher oscillation of COP on a force platform. METHODS: Sixty older adults 65 years or older were divided into 3 groups of 20: group 1, nonfrail; group 2, prefrail; and group 3, frail. The prefrail and frail identifications were made by Fried's 5 frailty phenotype criteria. Balance was assessed using the BESTest and a force platform in 6 positions: (1) fixed platform with eyes open; (2) fixed platform with eyes closed; (3) unstable platform with foam, with eyes open; (4) unstable platform, with eyes closed; (5) semitandem with eyes open; and (6) semitandem with eyes closed. RESULTS: Frail older adults had lower scores in all sections and in the total score of the BESTest, indicating worse performance in the tasks. However, on the force platform, the frail older adults did not show higher oscillations, having similar mean values when compared with the prefrail and nonfrail older adults, indicating similar behavior of COP. CONCLUSION: The BESTest seems to be more appropriate than a force plate for assessing postural control impairment and discriminating balance performance among frail, prefrail, and nonfrail older adults, providing information about different components of postural control rather than the force plate, which evaluates sensory orientation. PMID- 28914719 TI - Physical Therapy Management of Patients With Chronic Low Back Pain and Hip Abductor Weakness. AB - BACKGROUND AND PURPOSE: Hip abductor dysfunction is common in individuals with chronic low back pain (CLBP). Previous research investigating abductor strengthening in the heterogeneous CLBP population is sparse and has failed to target those patients most likely to benefit. The aim of the current case series was to describe the physical therapy management and outcomes of 3 patients with CLBP matching a previously identified subgroup characterized by substantial hip abductor weakness. CASE DESCRIPTION: Three nonconsecutive patients with CLBP-a 77 year-old man, a 78-year-old woman, and an 85-year-old woman-were treated in an outpatient physical therapy clinic. All 3 patients matched a previously identified CLBP subgroup characterized by substantial hip abductor weakness. INTERVENTION: Patients were treated using a targeted exercise approach consisting mostly of hip abductor strengthening for 11 to 17 visits over 8 to 10 weeks. Patients received additional treatments including heel lift and pain neuroscience education when indicated. OUTCOMES: By discharge, all patients had made clinically important improvements in pain (3- to 7-point reduction on the Numeric Pain Rating Scale), function (10- to 16-point change on the Modified Oswestry Disability Index), and perceived improvement (6-7 on Global Rating of Change Scale). Lumbar range of motion was painless, and hip abductor strength was improved from 2+/5 to 3+/5 in all 3 patients. These gains were maintained at 3 month follow-up. DISCUSSION: The current case series describes the use of a targeted exercise approach consisting mostly of hip abductor strengthening in a group of patients with CLBP and hip abductor weakness. The results indicated that this approach may be effective in reducing pain and improving function, particularly for older patients. PMID- 28914720 TI - Effects of Corrective Exercise for Thoracic Hyperkyphosis on Posture, Balance, and Well-Being in Older Women: A Double-Blind, Group-Matched Design. AB - BACKGROUND AND PURPOSE: The purpose of this study was to identify the effects of a corrective exercise for thoracic hyperkyphosis on posture, balance, and well being in Korean community-dwelling older women. METHODS: Fifty women 65 years of age and older, recruited from 2 senior centers, participated in this study. Participants were assigned to either the experimental group (EG) or the control group (CG) on the basis of convenience of location, and 22 in each were analyzed. Participants in the EG underwent a thoracic corrective exercise program 1 hour each session, twice per week for 8 weeks (a total of 16 sessions), which consisted of specific exercises to enhance breathing, thoracic mobility and stability, and awareness of thoracic alignment. The CG received education on the same thoracic corrective exercise program and a booklet of the exercises. Outcome measures included the extent of postural abnormality (angle of thoracic kyphosis, kyphosis index calculated both in relaxed- and best posture using flexicurve, the ratio of the kyphosis index calculated best posture/relaxed posture, craniovertebral angle, and tragus-to-wall distance), balance (Short Physical Performance Battery and limit of stability), and well-being (Geriatric Depression Scale Short Form and the 36-Item Short Form Health Survey [SF-36]). All data were collected by 6 blinded assessors at baseline, at 8 weeks after the completion of intervention, and at 16 weeks for follow-up. RESULTS AND DISCUSSION: For participants of the EG, means of all parameters showed significant improvements over time (P < .05), with improved values both in comparison of baseline to postintervention and baseline to follow-up. Means of CG parameters were significantly improved in only the angle of thoracic kyphosis and the tragus-to wall distance (P < .05). Furthermore, in all parameters, percent change between baseline and postintervention data was significantly (P < .05) higher for the EG than that for the CG, except for the limit of stability and SF-36 which improved but not significantly. All parameters between baseline and follow-up data were significantly (P < .05) higher for the EG than those for the CG, except for the limit of stability. CONCLUSIONS: The findings of this study suggest that a well designed exercise program may be beneficial to improve spinal posture, balance, and well-being in older women with thoracic hyperkyphosis. We recommend the use of the therapeutic strategies utilized in this study to enhance thoracic posture, balance, and well-being of older women with thoracic hyperkyphosis. Future research is needed to apply this exercise protocol on a larger and more diverse population. PMID- 28914721 TI - Sepsis in Children: Global Implications of the World Health Assembly Resolution on Sepsis. AB - BACKGROUND: Sepsis, worldwide the leading cause of death in children, has now been recognized as the global health emergency it is. On May 26, 2017, the World Health Assembly, the decision-making body of the World Health Organization, adopted a resolution proposed by the Global Sepsis Alliance to improve the prevention, diagnosis, and management of sepsis. OBJECTIVE: To discuss the implications of this resolution for children worldwide. CONCLUSIONS: The resolution highlights sepsis as a global threat and urges the 194 United Nations member states to take specific actions and implement appropriate measures to reduce its human and health economic burden. The resolution is a major step toward achieving the targets outlined by the Sustainable Developmental Goals for decreasing mortality in infants and children, but implementing it will require a concerted global effort. PMID- 28914722 TI - Factors Associated With Pediatric Ventilator-Associated Conditions in Six U.S. Hospitals: A Nested Case-Control Study. AB - OBJECTIVES: A newly proposed surveillance definition for ventilator-associated conditions among neonatal and pediatric patients has been associated with increased morbidity and mortality among ventilated patients in cardiac ICU, neonatal ICU, and PICU. This study aimed to identify potential risk factors associated with pediatric ventilator-associated conditions. DESIGN: Retrospective cohort. SETTING: Six U.S. hospitals PATIENTS:: Children less than or equal to 18 years old ventilated for greater than or equal to 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified children with pediatric ventilator associated conditions and matched them to children without ventilator-associated conditions. Medical records were reviewed for comorbidities and acute care factors. We used bivariate and multivariate conditional logistic regression models to identify factors associated with ventilator-associated conditions. We studied 192 pairs of ventilator-associated conditions cases and matched controls (113 in the PICU and cardiac ICU combined; 79 in the neonatal ICU). In the PICU/cardiac ICU, potential risk factors for ventilator-associated conditions included neuromuscular blockade (odds ratio, 2.29; 95% CI, 1.08-4.87), positive fluid balance (highest quartile compared with the lowest, odds ratio, 7.76; 95% CI, 2.10-28.6), and blood product use (odds ratio, 1.52; 95% CI, 0.70-3.28). Weaning from sedation (i.e., decreasing sedation) or interruption of sedation may be protective (odds ratio, 0.44; 95% CI, 0.18-1.11). In the neonatal ICU, potential risk factors included blood product use (odds ratio, 2.99; 95% CI, 1.02 8.78), neuromuscular blockade use (odds ratio, 3.96; 95% CI, 0.93-16.9), and recent surgical procedures (odds ratio, 2.19; 95% CI, 0.77-6.28). Weaning or interrupting sedation was protective (odds ratio, 0.07; 95% CI, 0.01-0.79). CONCLUSIONS: In mechanically ventilated neonates and children, we identified several possible risk factors associated with ventilator-associated conditions. Next steps include studying propensity-matched cohorts and prospectively testing whether changes in sedation management, transfusion thresholds, and fluid management can decrease pediatric ventilator-associated conditions rates and improve patient outcomes. PMID- 28914723 TI - Inducing Somatic Symptoms in Functional Syndrome Patients: Effects of Manipulating State Negative Affect. AB - OBJECTIVE: Induction of negative affective states can enhance bodily symptoms in high habitual symptom reporters among healthy persons and in patients with irritable bowel syndrome. The aims of this study were to replicate this effect in patients with fibromyalgia and chronic fatigue syndrome and to investigate the role of moderators, focusing on alexithymia, negative affectivity, and absorption. METHODS: Patients with fibromyalgia and/or chronic fatigue syndrome (n = 81) and HCs (n = 41) viewed series of neutral, positive, and negative affective pictures. After every picture series, participants filled out a somatic symptom checklist and rated emotions experienced during the picture series on valence, arousal, and perceived control. RESULTS: Patients reported more somatic symptoms after viewing negative pictures (least square mean [LSM] = 19.40, standard error (SE) = 0.50) compared with neutral (LSM = 17.59, SE = 0.42, p < .001) or positive (LSM = 17.04, SE = 0.41, p < .001) pictures, whereas somatic symptom ratings of HCs after viewing negative picture series (LSM = 12.07, SE = 0.71) did not differ from ratings after viewing neutral (LSM = 11.07, SE = 0.59, p = .065) or positive (LSM = 11.10, SE = 0.58, p = .93) pictures. Negative affectivity did not moderate the symptom-enhancing effect of negative affective pictures, whereas the alexithymia factor "difficulty identifying feelings" and absorption did (p = .016 and p = .006, respectively). CONCLUSION: Negative affective states elicit elevated somatic symptom reports in patients experiencing fibromyalgia and/or chronic fatigue syndrome. This symptom-enhancing effect is greater in patients having higher difficulty to identify feelings and higher absorption scores. The results are discussed in a predictive coding framework of symptom perception. PMID- 28914724 TI - Role of Brain Structure in Predicting Adherence to a Physical Activity Regimen. AB - OBJECTIVE: Physical activity (PA) is important for maintaining health throughout the lifespan. However, adherence to PA regimens is poor with approximately 50% of older adults terminating activity intervention programs within 6 months. In this study, we tested whether gray matter volume and white matter microstructural integrity before the initiation of a PA intervention predicts PA adherence. METHODS: One hundred fifty-nine adults aged 60 to 80 years were randomly assigned to a moderate-intensity aerobic walking condition or a nonaerobic stretching and toning condition. Participants engaged in supervised exercise 3 times per week for 12 months. Data were collected for a period of 1 year. Voxel-based morphometry and tract-based spatial statistics protocols were used to process neuroimaging data, and ordinary least squares regression models with bootstrapping were used to analyze voxelwise neural predictors of PA adherence. RESULTS: Greater volume in several regions predicted greater PA adherence, including prefrontal, motor, somatosensory, temporal, and parietal regions (p < .01). We also found that higher fractional anisotropy in several white matter tracts predicted greater PA adherence (pFDR-corrected < .05), including the superior longitudinal fasciculus, anterior thalamic radiation, forceps minor, and body of the corpus callosum. CONCLUSIONS: These findings provide preliminary support for macro- and microstructural neural predictors of PA adherence and may translate to other health behaviors and behavioral goal pursuit more broadly. PMID- 28914725 TI - Sleep Duration and Quality as Related to Left Ventricular Structure and Function. AB - OBJECTIVE: Inadequate sleep is associated with increased risk of cardiovascular events; however, the associations between sleep duration or quality and cardiac function or structure are not well understood. This cross-sectional study was conducted to investigate to what extent sleep duration and quality are associated with left ventricular (LV) diastolic dysfunction or structural deterioration. METHODS: A total of 31,598 healthy Korean adults who received echocardiography and completed the Pittsburg Sleep Quality Index were enrolled in this study. Participants were stratified into three groups by self-reported sleep duration (i.e., <7, 7-9, >9 hours) and into two groups by subjective sleep quality. Sleep duration was also assessed as a continuous variable. The odds ratios for impaired LV diastolic function, increased relative wall thickness, and LV hypertrophy (LVH) were compared between groups using multivariable logistic regression analyses. RESULTS: After adjustment for confounding variables (e.g., age, smoking, body mass index), there was a statistically significant association between short sleep duration (<7 hours) and greater LVH (fully adjusted odds ratio = 1.32 [95% confidence interval {CI} = 1.02-1.73]). Short sleep duration was also significantly associated with greater LVH (0.87 per hour [95% CI = 0.78 0.98]) and increased relative wall thickness (0.92 [95% CI = 0.86-0.99]), but there was no significant association between sleep and LV diastolic function. Among individuals with normal sleep duration, poor quality of sleep was not associated with adverse cardiac measures. CONCLUSIONS: These results indicate that short sleep duration (<7 hours) is associated with unfavorable LV structural characteristics. The association of insufficient sleep with adverse cardiovascular health outcomes may be mediated in part by adverse changes in cardiac structure and function. PMID- 28914726 TI - Proinflammatory Cytokines, Mood, and Sleep in Interepisode Bipolar Disorder and Insomnia: A Pilot Study With Implications for Psychosocial Interventions. AB - OBJECTIVE: Proinflammatory cytokines are associated with bipolar disorder (BD), but less is known about how cytokines function during the interepisode period. This study examined cytokines, mood symptoms, and sleep in individuals with interepisode BD with complaints of insomnia. We also investigated the effects of a BD-specific modification of cognitive behavior therapy for insomnia (CBTI-BP) on cytokine levels. METHODS: Twenty-two adults with interepisode BD type I and insomnia were drawn from a subset of a National Institute of Mental Health funded study. Participants were randomly allocated to CBTI-BP (n = 11) or psychoeducation (n = 11). Participants completed a sleep diary, rated self-report measures of mania and depression, and provided samples assayed for interleukin (IL)-6 and tumor necrosis factor soluble receptor 2 (sTNF-R2). RESULTS: IL-6 was associated with mania symptoms (rs = 0.44, p = .041) and total sleep time (rs = 0.49, p = .026). IL-6 was related to depression symptoms at the trend level (rs = 0.43, p = .052). sTNF-R2 was not significantly related to mood or sleep measures. From pretreatment to posttreatment, CBTI-BP compared with psychoeducation was associated with a nonsignificant, large effect size decrease in IL-6 (z = -1.61, p = .13, d = -0.78) and a nonsignificant, small-medium effect size decrease in sTNF-R2 (z = -0.79, p = .44, d = -0.38). CONCLUSIONS: These findings provide preliminary evidence that IL-6 is related to mania symptoms and shorter total sleep time in interepisode BD. A treatment that targets sleep in BD could potentially decrease IL-6 although replication is warranted. PMID- 28914728 TI - Reason for Referral Predicts Utilization and Perceived Impact of Early Intervention Services. AB - OBJECTIVE: Children participating in early intervention (EI) vary in their medical needs and degree of delay, and previous studies have shown significant differences in EI enrollment based on the reason for referral. The effect of reason for referral on service provision and family satisfaction is largely unknown. METHODS: We used data from the National Early Intervention Longitudinal Study for our secondary data analysis. The main predictor was the reason for referral: a diagnosed condition, documented developmental delay, or other risk factors. Outcomes included unmet service needs, program dropout, and family satisfaction with services. RESULTS: The 2966 participants were mostly white (51.9%), male (60.3%), and had an annual household income at or below $50,000 (77.0%). There were 1924 referred due to diagnosis, 691 due to delay, and 351 due to other risks. Compared with the diagnosis group, children with delays were more likely (adjusted odds ratio [aOR] 1.38, 95% confidence interval [CI], 1.02-1.87) to have unmet service needs and to drop out of EI programs (aOR 1.44, 95% CI, 1.07-1.96); their families were less likely to report that services were highly individualized (aOR 0.80, 95% CI, 0.65-0.98) or had an impact on their children's development (aOR 0.77, 95% CI, 0.62-0.96). CONCLUSION: Children participating in EI because of developmental delays are more likely to have unmet service needs, drop out of services because of a reason other than ineligibility (family or child-related reason), and have lower caregiver satisfaction than those participating because of diagnosed conditions. It is important to determine reasons for these differences and their impact on developmental outcomes. PMID- 28914727 TI - Summer Healthy-Lifestyle Intervention Program for Young Children Who Are Overweight: Results from a Nonrandomized Pilot Trial. AB - OBJECTIVE: To examine initial outcomes of an 8-week Healthy-Lifestyle Intervention Program (HIP) which included children's participation in a daily summer camp along with parents' participation in a parenting program focused on overweight/obesity. METHODS: Using a nonrandomized pilot trial design, 16 children (M child age = 6.42 yr; 81% male; 100% Latino) classified as overweight/obese and their mothers completed 3 assessments (baseline, posttreatment, and 6-8 mo follow-up). RESULTS: Children who completed HIP experienced significant decreases in their body mass index z-scores (primary outcome) from baseline to posttreatment (d = -1.11) with such decreases being moderately maintained at follow-up (d = -0.64). In terms of secondary outcomes, HIP was effective in improving and maintaining healthy habits in both children and mothers and children's nutritional knowledge and fitness. Objective food data showed that children's dietary intake during HIP improved. High attendance and satisfaction were reported for families who completed HIP. CONCLUSION: This pilot treatment development study shows that a family lifestyle intervention conducted in a summer camp setting that targets both children and parents is a promising option for addressing pediatric obesity in young children. PMID- 28914729 TI - Mental Health Service Use Among Youth with Autism Spectrum Disorder. AB - OBJECTIVE: Although youth with autism have elevated rates of mental health problems compared to typically developing youth, little is known about the mental health services that they receive. The current study examines predisposing, enabling, and clinical need factors as they relate to mental health service use in youth with autism. METHODS: The current study surveyed parents of 2337 children and adolescents with autism, compared their access to behavioral management and mental health treatment (MHT), and isolated the correlates of such receipt. RESULTS: Children used behavioral management more than adolescents, whereas the opposite was true for MHT. Mental health treatment receipt was associated with caregiver-related and mental health problems in both age groups, with routine health service use in children and with behavioral problems in adolescents. Behavioral management was correlated with caregiver-related services and behavioral problems in both age groups, and with sex and intellectual disability in adolescents. CONCLUSION: Clinical needs and caregiver service use are consistently associated with mental health care across ages, whereas the role of youth characteristics is particularly relevant when considering service use for adolescents. PMID- 28914730 TI - Family and Environmental Influences on Child Behavioral Health: The Role of Neighborhood Disorder and Adverse Childhood Experiences. AB - OBJECTIVE: The Adverse Childhood Experiences study suggests childhood adversity is a "root" origin for health and human development. Newer research is examining the more immediate impact of adverse childhood experiences (ACEs) on child development and the impact of neighborhood environment on the likelihood of and prevention ACEs. The extent to which all of these aspects of the child context fit together remains unclear. The current study seeks to fill this gap examining the precursors for ACEs and the multitude of ways in which a child's home life can impact his or her development. METHODS: Using data from 3001 mothers of children in the Fragile Families and Child Wellbeing Study, this study investigates the relationship between neighborhood disorder, ACEs, and child behavioral health. Using a path analysis, the direct and indirect relations between neighborhood disorder and child behavioral health are estimated, with ACEs as the key mediator. RESULTS: The most common ACE in our study was intimate partner violence (IPV), followed by child emotional abuse. Neighborhood disorder is associated with higher levels of ACEs and is both directly and indirectly (through its relation with ACEs) negatively related to child behavioral health. CONCLUSION: Screening for ACEs for children living in disordered neighborhoods may help reduce those experiences and their impacts in this high-risk population. Preventive interventions related to IPV and child emotional abuse may be especially helpful. PMID- 28914731 TI - Academic Developmental-Behavioral Pediatric Faculty at Developmental-Behavioral Pediatric Research Network Sites: Changing Composition and Interests. AB - OBJECTIVE: To obtain and review workforce data, given the critical demand for developmental pediatricians (DPs). METHODS: Survey of demographics and professional activities of DP physician faculty at Developmental-Behavioral Pediatric (DBP) Research Network fellowship training sites. RESULTS: Of the eligible providers at 12 centers, 76% (n = 50) completed surveys. They were on average 50 years old and mostly female (86%), white (82%), and working full time (74%). Full timers reported a mean 50.2-hour week made up of clinical work (23.2 hours), supervision (5.9 hours), research (8.8 hours), administration (5.2 hours), teaching (1.5 hours), advocacy (1.1 hours), and other (4.3 hours). Compared with those >10 years out of training, the 20 physicians (40%) <=10 years out of fellowship were more likely to be nonwhite (p = .003). Overall faculty interest/expertise (I/E) was highest in autism (90%) and attention deficit hyperactivity disorder (ADHD; 86%). Those <=10 years out of fellowship had more I/E in autism (p = .05) and less in chronic illness (p = .06) and parenting (p = .06). DPs practiced most frequently in a General DBP Clinic (74%), followed by clinics specific for: Autism (36%), Toddlers (22%), ADHD (20%), Infants (18%) and Preschoolers (16%). Common clinics were Autism (9), syndrome specific (9), ADHD (6), and School-Aged (5). CONCLUSION: Developmental pediatrician faculty in DBP training sites feed the pipeline of much needed DP physicians. This survey provides baseline information on the professional activities of DP faculty and found changing demographics and I/E as well as a wide variety of clinic types. PMID- 28914732 TI - Predictors of Weight-Related Quality of Life in Adolescents Who Are Overweight or Obese. AB - OBJECTIVE: Weight-related quality of life (WRQOL) is a type of health-related QOL that may serve as a patient-reported outcome of the potential burden of overweight. The present study uses structural equation modeling path analysis methods to examine body mass index (BMI) and other potential predictors of WRQOL components among adolescents who were overweight/obese from predominantly low income, urban households. METHODS: Baseline data were obtained from 360 participants (10-13 year olds; 57.8% female; 76.7% black; average BMI of 27.12) and their parents/legal guardians from a randomized, controlled, treatment trial. Youth completed measures of WRQOL, depressive symptoms, and family/friend social support for healthy eating. Parents completed measures of demographics and child social problems. RESULTS: The initial model included BMI, gender, parent education, family/friend social support for healthy eating, child social problems, body esteem and social life WRQOL, and depressive symptoms. The final model fit the data well (chi = 27.738; df = 16; p = .034). Higher BMI was indirectly related to lower social life and body esteem WRQOL through greater social problems. Physical comfort and family relations WRQOL were unrelated to BMI and were not included. Lower social life and body esteem related to more depressive symptoms. Family/friend discouragement for healthy eating was associated with lower body esteem; also, family discouragement was related to lower social life. CONCLUSION: Body mass index may not directly relate to WRQOL but may be associated through other factors, including child social problems. Interventions should screen for and treat mood and social problems and address family/friend support for healthy eating. PMID- 28914733 TI - Metabolic connectivity: methods and applications. AB - PURPOSE OF REVIEW: Metabolic connectivity modelling aims to detect functionally interacting brain regions based on PET recordings with the glucose analogue [F]fluorodeoxyglucose (FDG). Here, we outline the most popular metabolic connectivity methods and summarize recent applications in clinical and basic neuroscience. RECENT FINDINGS: Metabolic connectivity is modelled by various methods including a seed correlation, sparse inverse covariance estimation, independent component analysis and graph theory. Given its multivariate nature, metabolic connectivity possess added value relative to conventional univariate analyses of FDG-PET data. As such, metabolic connectivity provides valuable insights into pathophysiology and diagnosis of dementing, movement disorders, and epilepsy. Metabolic connectivity can also identify resting state networks resembling patterns of functional connectivity as derived from functional MRI data. SUMMARY: Metabolic connectivity is a valuable concept in the fast developing field of brain connectivity, at least as reasonable as functional connectivity of functional MRI. So far, the value of metabolic connectivity is best established in neurodegenerative disorders, but studies in other brain diseases as well as in the healthy state are emerging. Growing evidence indicates that metabolic connectivity may serve a marker of normal and pathological cognitive function. A relationship of metabolic connectivity with structural and functional connectivity is yet to be established. PMID- 28914734 TI - Revisiting the concept of amyotrophic lateral sclerosis as a multisystems disorder of limited phenotypic expression. AB - PURPOSE OF REVIEW: The current review will examine the contemporary evidence that amyotrophic lateral sclerosis (ALS) is a syndrome in which the unifying feature is a progressive loss of upper and lower motor neuron function. RECENT FINDINGS: Although ALS is traditionally viewed as a neurodegenerative disorder affecting the motor neurons, there is considerable phenotypic heterogeneity and widespread involvement of the central nervous system. A broad range of both causative and disease modifying genetic variants are associated with both sporadic and familial forms of ALS. A significant proportion of ALS patients have an associated frontotemporal dysfunction which can be a harbinger of a significantly shorter survival and for which there is increasing evidence of a fundamental disruption of tau metabolism in those affected individuals. Although the traditional neuropathology of the degenerating motor neurons in ALS is that of neuronal cytoplasmic inclusions composed neuronal intermediate filaments, the presence of neuronal cytoplasmic inclusions composed of RNA binding proteins suggests a key role for RNA dysmetabolism in the pathogenesis of ALS. SUMMARY: ALS is a complex multisystem neurodegenerative syndrome with marked heterogeneity at not only the level of clinical expression, but also etiologically. PMID- 28914735 TI - Palliative care in neuromuscular diseases. AB - PURPOSE OF REVIEW: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating physical disabilities. Most NMDs are not amenable to curative treatment and would thus qualify for palliative care. Amyotrophic lateral sclerosis is a relentlessly progressive disease, which leads to death about 2 years after onset due to respiratory muscle weakness. Increasingly, neurologists caring for these patients learn to apply the principles of palliative care. However, this does not yet apply to other well known and frequently occurring NMDs. RECENT FINDINGS: There is sparse literature on palliative care in NMDs such as Duchenne muscular dystrophy, spinal muscular atrophy, muscular dystrophies, some congenital myopathies, Pompe's disease and myotonic dystrophy type 1. These NMDs are often associated with imminent respiratory insufficiency and/or heart failure leading to a reduced life expectancy. Reasons for underutilization may include misconceptions about palliative care amongst patients, family carers and healthcare professionals or lack of awareness of the usefulness of this approach in these severely affected patients and the possibilities of integration of palliative principles into care for children and adults with NMDs. SUMMARY: There is an urgent need for increased attention to the development of palliative care in chronic progressive neuromuscular diseases associated with increasing functional incapacities and premature death. This will require education and training of the healthcare professionals, involvement of patient associations and funding to perform research. PMID- 28914736 TI - Update on tauopathies. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on the role of tau beyond the stabilization of microtubules and on the clinical, pathological, diagnostic and therapeutic aspects of tauopathies. RECENT FINDINGS: Beyond its function as a microtubule-associated tau protein, tau is also involved in gene regulation, signal transduction and metabolism. Experimental models allow for the development of new diagnostic and therapeutic tools. Tauopathies encompass different disorders that may manifest with various clinical syndromes. Differential diagnosis with other proteinopathies is still challenging. Cerebrospinal fluid biomarkers and radiotracers were extensively studied in the last year. Although diagnostic accuracy remains deceiving in non-Alzheimer's disease tauopathies, positron emission tomography tau tracers could be used to monitor disease progression. SUMMARY: Despite the advent of novel therapeutic approaches and the increasing number of clinical trials in tauopathies, accurate clinical diagnosis is still an unmet need and better tau biomarkers are still desperately needed. Although primary taupathies are rare and heterogeneous disorders, their combined prevalence and the importance of tau disorder in Alzheimer's disease and secondary tauopathies makes research on tauopathy a priority - because it could benefit many patients. PMID- 28914737 TI - Evidence of semantic processing impairments in behavioural variant frontotemporal dementia and Parkinson's disease. AB - PURPOSE OF REVIEW: Category-specific impairments caused by brain damage can provide important insights into how semantic concepts are organized in the brain. Recent research has demonstrated that disease to sensory and motor cortices can impair perceptual feature knowledge important to the representation of semantic concepts. This evidence supports the grounded cognition theory of semantics, the view that lexical knowledge is partially grounded in perceptual experience and that sensory and motor regions support semantic representations. Less well understood, however, is how heteromodal semantic hubs work to integrate and process semantic information. RECENT FINDINGS: Although the majority of semantic research to date has focused on how sensory cortical areas are important for the representation of semantic features, new research explores how semantic memory is affected by neurodegeneration in regions important for semantic processing. Here, we review studies that demonstrate impairments to abstract noun knowledge in behavioural variant frontotemporal degeneration (bvFTD) and to action verb knowledge in Parkinson's disease, and discuss how these deficits relate to disease of the semantic selection network. SUMMARY: Findings demonstrate that semantic selection processes are supported by the left inferior frontal gyrus (LIFG) and basal ganglia, and that disease to these regions in bvFTD and Parkinson's disease can lead to categorical impairments for abstract nouns and action verbs, respectively. PMID- 28914738 TI - Age-related resting-state functional connectivity in the olfactory and trigeminal networks. AB - Brain networks for intranasal chemosensation have been shown to be intrinsically organized in humans . However, little is known about how changes in the intrinsic functional connectivity (FC) in chemosensory networks are related to aging. We, therefore, investigated the impact of age on resting-state FC in the olfactory and trigeminal networks (ON and TN) by combining two freely available resting state fMRI data sets (obtained from the NITRC.org; Atlanta and New York) with data collected in our lab to generate a large sample size (N=103; 51 women) spanning the age range of 20-61 years. Seed regions were defined using Montreal Neurological Institute's coordinates that anchor ON and TN in activation studies and meta-analyses. The ON included the piriform cortex and the oribtofrontal cortex. The TN included the anterior insula and the cingulate cortex. Scanner site, sex, and age were used as covariates in group-level analyses. The FC between the ON and the parahippocampal gyrus was correlated negatively with age. The FC between the TN and the parahippocampal gyrus, however, was positively correlated. Similarly, age was correlated positively with the ON FC to the ventral striatum and the TN FC to the default mode network. These results reflect divergent age-related alterations in the intrinsic FC of the human chemosensory system. PMID- 28914739 TI - Hypothermic neuroprotections in the brain of an echolocation bat, Hipposideros terasensis. AB - The present study aimed to investigate how bats protect their brain in a hypothermic situation. Formosan leaf-nosed bats (Hipposideros terasensis) were used in this study and treated under three conditions: room temperature (25+/-1 degrees C), low temperature (4+/-1 degrees C), and hibernation. The reactive oxygen species (ROS) levels in the blood and apoptosis-related proteins in the brain tissue were assessed and then compared among those bats under three conditions. Our results showed that the blood ROS levels of bats treated under conditions of low temperature and hibernation were significantly reduced compared with bats treated under the condition of room temperature. Both immunohistochemistry and immunoblotting expressions of hypoxia, inflammation, and apoptosis-related proteins in the brain tissue of bats treated under the condition of hibernation were significantly reduced compared with those bats treated under conditions of room temperature and low temperature. Thus, we suggested that bats can protect the brain in cold environment by reducing blood ROS levels and decreasing expressions of hypoxia, inflammation, and apoptosis related proteins in the brain. Possible protection mechanisms involved in hypothermic adaptations need to be further clarified. PMID- 28914741 TI - Eosinophilic Bronchiolitis. PMID- 28914740 TI - The role of precisely matching fascicles in the quick recovery of nerve function in long peripheral nerve defects. AB - Peripheral nerve injury therapy in the clinic remains less than satisfactory. The gold standard of treatment for long peripheral nerve defects is autologous nerve grafts; however, numerous clinical complications are associated with this treatment. As tissue engineering has developed, tissue-engineered nerve grafts (TENGs) have shown potential applications as alternatives to autologous nerve grafts. To verify the important role of the biomimetic pathway of fascicle design in TENGs, we designed an animal model to study the role of the precise matching of fascicles in the effectiveness of nerve function recovery. 24 Sprague-Dawley rats were divided randomly into three groups (eight/group) that corresponded to 100% fascicle matching (100%FM), 50%FM and 0%FM. We selected Sprague-Dawley rat long-gap (15 mm) sciatic nerve defects. In the 6 weeks after surgery, we found that the 100%FM group showed the most effective functional recovery among the three groups. The 100%FM group showed better functional recovery on the basis of the sciatic functional index than the 50%FM and 0%FM groups. According to histological evaluation, the 100%FM group showed more regenerating nerve fibres. Moreover, in terms of the prevention of muscle atrophy, the 100%FM group showed excellent physiological outcomes. The 100%FM as tissue-engineered scaffolds can enhance nerve regeneration and effective functional recovery after the repair of large nerve defects. The results of this study provide a theoretical basis for future TENG designs including biomimetic fascicle pathways for repairing long nerve defects. PMID- 28914742 TI - Mature Cystic Teratoma With an Element of Hepatocellular Carcinoma in Anterior Mediastinum: Magnetic Resonance-Pathologic Correlation. PMID- 28914744 TI - Cardiac Computed Tomography: Before and After Cardiac Surgery. AB - Cardiac computed tomography angiography (CCTA) is a noninvasive imaging technique that has been rapidly adopted into clinical practice. Over the past decade, technological advances have improved CCTA accuracy, and there is an increasing amount of data supporting its prognostic value in the assessment of coronary artery disease. Recently, "appropriate use criteria" has been used as a tool to minimize inappropriate testing and reduce patient exposure to unnecessary risk and inconclusive studies. This review will summarize the appropriate uses of CCTA in patients before and after cardiac surgery. Although the most common indication for CCTA is assessment of patency of native coronary arteries, other potential perioperative uses (eg, assessment of congenital heart disease, valvular heart disease, pericardial disease, myocardial disease, cardiac anatomy, bypass grafts, aortic disease, and cardiac masses) will be reviewed. PMID- 28914743 TI - Effectiveness of Bone Suppression Imaging in the Detection of Lung Nodules on Chest Radiographs: Relevance to Anatomic Location and Observer's Experience. AB - OBJECTIVE: To evaluate the effectiveness of bone suppression imaging (BSI) software in lung-nodule detection on chest radiographs (CXRs) in relation to nodule location and observer's experience. MATERIALS AND METHODS: The CXRs of 80 patients, of which 40 had a lung nodule (8 to 30 mm in diameter) and 40 did not have any nodules, were interpreted by 20 observers comprising of 7 pulmonologists with >10 years of experience and 13 pulmonology residents. Each patient's image was sequentially read, first using the standard CXR and thereafter with the BSI software. The nodule location and confidence level with regard to the presence of a lung nodule were recorded. Receiver operating characteristic analysis was used to evaluate observer performance. RESULTS: The average area under the curve (AUC) for the observers' receiver operating characteristic significantly improved from 0.867 to 0.900 (P=0.004) with the use of the BSI software. The average AUC for experienced pulmonologists improved from 0.877 to 0.924 (P=0.017) for lung nodules located in the apical and peripheral areas but not for those in the inner area. The average AUC for residents improved regardless of nodule location. CONCLUSION: The use of BSI software improved the performance in lung-nodule detection on CXRs regardless of observer's experience and was more effective for observers with limited experience. PMID- 28914745 TI - Is Digital Tomosynthesis on Par With Computed Tomography for the Detection and Measurement of Pulmonary Nodules? AB - Chest digital tomosynthesis (DT) has potential advantages compared to computed tomography (CT) such as radiation dose reduction. However, the role of DT in pulmonary nodule management remains investigative. We compared DT against CT for pulmonary nodule detection and size measurement. A clinical population comprising 54 nodules from 30 patients and a screening population comprising 42 nodules from 52 patients were included. Scans were independently read by two radiologists. Agreement in nodule measurements between readers and between modalities was assessed by Bland-Altman analysis using a 95% level of significance. The DT true positive fraction for the two readers was 0.44 and 0.39 in the clinical population, and 0.10 and 0.05 in the screening population. No significant inter modality bias was observed between DT and CT measurements of nodule size, but the range of variation between modalities was approximately 30%. Inter-reader DT measurements also showed no significant bias, with a range of variation of approximately 15%. We conclude that DT has poor nodule detection sensitivity compared to CT. However, DT showed good measurement reproducibility and may be useful for monitoring growth of existing pulmonary nodules. PMID- 28914746 TI - Thin-section Computed Tomographic Findings of Multicentric Castleman Disease Changing Over 10 Years. PMID- 28914747 TI - Appropriate Use Criteria for Cardiac Computed Tomography: Does Computed Tomography Have Incremental Value in All Appropriate Use Criteria Categories? AB - PURPOSE: Cardiac imaging expenditures have come under scrutiny, and a focus on appropriate use criteria (AUC) has arisen to ensure cost-effective resource utilization. Although AUC has been developed by clinical experts, it has not undergone rigorous quality assurance testing to ensure that inappropriate indications for testing yield little clinical benefit. The objective of the study was to evaluate the potential incremental prognostic value of coronary computed tomographic angiography (CCTA) in the different AUC categories. MATERIALS AND METHODS: Consecutive patients enrolled into a cardiac CT Registry were collated. Patient indications were reviewed and based on the 2010 AUC (appropriate, uncertain, and inappropriate). Patients were followed-up for death, myocardial infarction (MI), and late revascularization, with the primary composite endpoint being cardiac death, nonfatal MI, and late revascularization. The prognostic value of CCTA over clinical variables in each of the AUC categories was assessed. RESULTS: Indications for CCTA were appropriate, uncertain, and inappropriate in 1284 (66.5%), 312 (16.2%), and 334 (17.3%) patients, respectively. Rates of all cause of death, cardiac death, nonfatal MI, and late revascularization were similar across patients with appropriate, uncertain, and inappropriate indications for CCTA. Moreover, in each AUC category, CCTA had incremental prognostic value over a routine clinical risk score (National Cholesterol Education Program) with hazard ratios of 9.98, 7.39, and 5.61. CONCLUSIONS: CCTA has incremental prognostic value in all AUC categories, even when the reason for the study was deemed "inappropriate." This suggests that CCTA may still have clinical value in "inappropriate" indications and that further quality assurance AUC studies are needed. PMID- 28914748 TI - Klebsiella pneumoniae: Virulence, Biofilm and Antimicrobial Resistance. PMID- 28914749 TI - Raised Frequency of Microcephaly Related to Zika Virus Infection in Two Birth Defects Surveillance Systems in Bogota and Cali, Colombia. AB - Zika virus infection during pregnancy is now known to cause congenital microcephaly and severe brain defects. In 2016, rates of microcephaly appeared to start increasing around May, peaking in July, and declining through December. The occurrence of microcephaly appears to have increased nearly 4-fold in 2 large cities in Colombia, concurrently with the reported Zika virus epidemic in the country. PMID- 28914750 TI - Live Attenuated Influenza Vaccination Before 3 Years of Age and Subsequent Development of Asthma: A 14-year Follow-up Study. AB - BACKGROUND: Live-attenuated influenza vaccines (LAIVs) are not licensed in children younger than 2 years of age because of a wheezing safety signal that has not been fully elucidated. In 2000, the Kaiser Permanente Vaccine Study Center conducted a placebo-controlled randomized clinical trial (RCT) of LAIV in children. As many of these children were still enrolled in Kaiser Permanente in 2014, we could assess the possible long-term association between LAIV and subsequent asthma diagnosis. METHODS: We identified all children who were originally enrolled into the LAIV RCT at younger than 3 years of age. We followed up subjects until disenrollment from the health plan, a first diagnosis of asthma, or through the end of the study period in 2014. Asthma was defined by a first International Classification of Diseases, 9th revision, Clinical Modification code (493.*) assigned at an outpatient or emergency department encounter. We performed a survival analysis of time to first asthma diagnosis among children receiving LAIV or placebo with a Cox proportional hazards model. RESULTS: We identified 1151 children in the original RCT who were 12 through 35 months of age at the time of enrollment and who had received 2 doses of LAIV or placebo. A total of 767 (66.7%) RCT participants were still Kaiser Permanente Northern California members in 2014. There was no evidence of differential dropout by treatment group. The hazard ratio for new-onset asthma for LAIV recipients compared with placebo was 1.1 (95% confidence interval: 0.88-1.41; P = 0.38). CONCLUSIONS: We found no evidence of increased risk of subsequent asthma diagnosis among children younger than 3 years of age who received LAIV compared with placebo. PMID- 28914751 TI - Magnetic Resonance Imaging-Based Prostate-Specific Antigen Density for Prediction of Gleason Score Upgrade in Patients With Low-Risk Prostate Cancer on Initial Biopsy. AB - OBJECTIVE: The aim of this study was to assess the utility of prostate-specific antigen density (PSAD) calculated using magnetic resonance imaging for predicting Gleason score (GS) upgrade in patients with low-risk prostate cancer on biopsy. METHODS: Seventy-three patients were divided into 2 groups according to the concordance between biopsy and prostatectomy GS: group 1 (6/6) and group 2 (6/>=7). Magnetic resonance imaging-based PSAD, prostate volume, prostate specific antigen (PSA), and age were compared between the 2 groups. Logistic regression and receiver operating characteristic curve analysis were performed. RESULTS: Gleason score was upgraded in 40 patients. Patients in group 2 had significantly higher PSAD and PSA values and smaller prostate volume than did those in group 1. Prostate-specific antigen density of 0.26 ng/mL per cm or higher, PSA of 7.63 ng/mL or higher, and prostate volume of 25.1 cm or less were related to GS upgrade, with area-under-the-curve values of 0.765, 0.721, and 0.639, respectively. CONCLUSIONS: Magnetic resonance imaging-based PSAD could help in predicting postoperative GS upgrade in patients with low-risk prostate cancer. PMID- 28914752 TI - CT Attenuation of Pericoronary Adipose Tissue in Normal Versus Atherosclerotic Coronary Segments as Defined by Intravascular Ultrasound. AB - BACKGROUND: The factors influencing genesis of atherosclerosis at specific regions within the coronary arterial system are currently uncertain. Local mechanical factors such as shear stress as well as metabolic factors, including inflammatory mediators released from epicardial fat, have been proposed. We analyzed computed tomographic (CT) attenuation of pericoronary adipose tissue in normal versus atherosclerotic coronary segments as defined by intravascular ultrasound (IVUS). PATIENTS AND METHODS: We evaluated the data sets of 29 patients who were referred for invasive coronary angiography and in whom IVUS of 1 coronary vessel was performed for clinical reasons. Coronary CT angiography was performed within 24 hours from invasive coronary angiography. Computed tomographic angiography was performed using dual-source CT (Siemens Healthcare; Forchheim, Germany). A contrast-enhanced volume data set was acquired (120 kV, 400 mA/rot, collimation 2 * 64 * 0.6 mm, 60-80 mL intravenous contrast agent). Intravascular ultrasound was performed using a 40-MHz IVUS catheter (Atlantis; Boston Scientific Corporation, Natick, Mass) and motorized pullback at 0.5 mm/s. Sixty corresponding coronary artery segments within the coronary artery system were identified in both dual source computed tomography and IVUS using bifurcation points as fiducial markers. In dual source computed tomography data sets, 8 serial parallel cross sections (2-mm slice thickness) were rendered orthogonal to the center line of the coronary artery for each segment. For each cross section, pericoronary adipose tissue within a radius of 3 mm from the coronary artery and enclosed within the epicardium (excluding coronary veins and myocardium) was manually traced and mean CT attenuation values were obtained. Intravascular ultrasound was used to define coronary segments as follows: presence of predominantly fibrous atherosclerotic plaque (hyperechoic), presence of predominantly lipid-rich atherosclerotic plaque (hypoechoic), and absence of atherosclerotic plaque. RESULTS: In IVUS, 20 coronary segments with fibrous plaque, 20 segments with lipid-rich plaque, and 20 coronary segments without plaque were identified. The mean CT attenuation of pericoronary adipose tissue for segments with any coronary atherosclerotic plaque was -34 +/- 14 Hounsfield units (HU), as compared with -56 +/- 16 HU for segments without plaque (P = 0.005). The density of pericoronary fat in segments with fibrous versus lipid rich plaque as defined by IVUS was not significantly different (-35 +/- 19 HU vs 36 +/- 16 HU, P = 0.8). CONCLUSIONS: Mean CT attenuation of pericoronary adipose tissue is significantly lower for normal versus atherosclerotic coronary segments. This supports a hypothesis of different types of pericoronary adipose tissue, the more metabolically active of which might exert local effects on the coronary vessels, thus contributing to atherogenesis. PMID- 28914753 TI - On Optimal Cooperative Sensing with Energy Detection in Cognitive Radio. AB - In this paper, we propose an optimal cooperative sensing technique for cognitive radio to maximize sensing performance based on energy detection. In most spectrum sensing research, many cooperation methods have been proposed to overcome the sensitivity of energy detection so that both primary and secondary users are better off in terms of spectral efficiency. However, without assigning a proper sensing threshold to each sensing node, cooperation may not be effective unless the received average primary user signal-to-noise ratio (SNR) is identical. We show that equal threshold energy detection severely degrades sensing performance when cooperative sensing nodes experience diverse average SNRs, and it is not unusual for even single-node sensing to be better than cooperative sensing. To this end, based on the Neyman-Pearson criterion we formulate an optimization problem to maximize sensing performance by using optimized thresholds. Since this is a non-convex optimization problem, we provide a condition that convexifies the problem and thus serves as a sufficient optimality condition. We find that, perhaps surprisingly, in all practical cases one may consider this condition satisfied, and thus optimal sensing performance can be obtained. Through extensive simulations, we demonstrate that the proposed technique achieves a globally optimal solution, i.e., it maximizes the probability of detection under practical operating parameters such as the target probability of false alarm, different SNRs, and the number of cooperative sensing nodes. PMID- 28914754 TI - Investigation of Antimicrobial Peptide Genes Associated with Fungus and Insect Resistance in Maize. AB - Antimicrobial peptides (AMPs) are small defense proteins present in various organisms. Major groups of AMPs include beta-barrelin, hevein, knottin, lipid transfer protein (LTP), thionin, defensin, snakin, and cyclotide. Most plant AMPs involve host plant resistance to pathogens such as fungi, viruses, and bacteria, whereas a few plant AMPs from the cyclotide family carry insecticidal functions. In this research, a genome-wide investigation on antimicrobial peptide genes in maize genome was conducted. AMPs previously identified from various plant species were used as query sequences for maize genome data mining. Thirty-nine new maize AMPs were identified in addition to seven known maize AMPs. Protein sequence analysis revealed 10 distinguishable maize AMP groups. Analysis of mRNA expression of maize AMP genes by quantitative real-time polymerase chain reaction (qRT-PCR) revealed different expression patterns in a panel of 10 maize inbred lines. Five maize AMP genes were found significantly associated with insect or fungus resistance. Identification of maize antimicrobial peptide genes will facilitate the breeding of host plant resistance and improve maize production. PMID- 28914756 TI - An Anti-Electromagnetic Attack PUF Based on a Configurable Ring Oscillator for Wireless Sensor Networks. AB - Wireless sensor networks (WSNs) are an emerging technology employed in some crucial applications. However, limited resources and physical exposure to attackers make security a challenging issue for a WSN. Ring oscillator-based physical unclonable function (RO PUF) is a potential option to protect the security of sensor nodes because it is able to generate random responses efficiently for a key extraction mechanism, which prevents the non-volatile memory from storing secret keys. In order to deploy RO PUF in a WSN, hardware efficiency, randomness, uniqueness, and reliability should be taken into account. Besides, the resistance to electromagnetic (EM) analysis attack is important to guarantee the security of RO PUF itself. In this paper, we propose a novel architecture of configurable RO PUF based on exclusive-or (XOR) gates. First, it dramatically increases the hardware efficiency compared with other types of RO PUFs. Second, it mitigates the vulnerability to EM analysis attack by placing the adjacent RO arrays in accordance with the cosine wave and sine wave so that the frequency of each RO cannot be detected. We implement our proposal in XINLINX A-7 field programmable gate arrays (FPGAs) and conduct a set of experiments to evaluate the quality of the responses. The results show that responses pass the National Institute of Standards and Technology (NIST) statistical test and have good uniqueness and reliability under different environments. Therefore, the proposed configurable RO PUF is suitable to establish a key extraction mechanism in a WSN. PMID- 28914755 TI - Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia. AB - Mitochondrial oxidative stress is thought to be a key contributor towards the development of diabetic cardiomyopathy. Thioredoxin 2 (Trx2) is a mitochondrial antioxidant that, along with Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), scavenges H2O2 and offers protection against oxidative stress. Our previous study showed that TrxR inhibitors resulted in Trx2 oxidation and increased ROS emission from mitochondria. In the present study, we observed that TrxR inhibition also impaired the contractile function of isolated heart. Our studies showed a decrease in the expression of Trx2 in the high glucose-treated H9c2 cardiac cells and myocardium of streptozotocin (STZ)-induced diabetic rats. Overexpression of Trx2 could significantly diminish high glucose-induced mitochondrial oxidative damage and improved ATP production in cultured H9c2 cells. Notably, Trx2 overexpression could suppress high glucose-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. Our studies suggest that high glucose-induced mitochondrial oxidative damage can be prevented by elevating Trx2 levels, thereby providing extensive protection to the diabetic heart. PMID- 28914757 TI - PIG's Speed Estimated with Pressure Transducers and Hall Effect Sensor: An Industrial Application of Sensors to Validate a Testing Laboratory. AB - The pipeline inspection using a device called Pipeline Inspection Gauge (PIG) is safe and reliable when the PIG is at low speeds during inspection. We built a Testing Laboratory, containing a testing loop and supervisory system to study speed control techniques for PIGs. The objective of this work is to present and validate the Testing Laboratory, which will allow development of a speed controller for PIGs and solve an existing problem in the oil industry. The experimental methodology used throughout the project is also presented. We installed pressure transducers on pipeline outer walls to detect the PIG's movement and, with data from supervisory, calculated an average speed of 0.43 m/s. At the same time, the electronic board inside the PIG received data from odometer and calculated an average speed of 0.45 m/s. We found an error of 4.44%, which is experimentally acceptable. The results showed that it is possible to successfully build a Testing Laboratory to detect the PIG's passage and estimate its speed. The validation of the Testing Laboratory using data from the odometer and its auxiliary electronic was very successful. Lastly, we hope to develop more research in the oil industry area using this Testing Laboratory. PMID- 28914758 TI - Up-Regulation of HSFA2c and HSPs by ABA Contributing to Improved Heat Tolerance in Tall Fescue and Arabidopsis. AB - Abscisic acid (ABA) is known to play roles in regulating plant tolerance to various abiotic stresses, but whether ABA's effects on heat tolerance are associated with its regulation of heat stress transcription factors (HSFs) and heat shock proteins (HSPs) is not well documented. The objective of this study was to determine whether improved heat tolerance of tall fescue (Festuca arundinacea Schreb.) by ABA was through the regulation of HSFs and HSPs. ABA responsive transcriptional factors, ABA-responsive element binding protein 3 (FaAREB3) and dehydration-responsive element binding protein 2A (FaDREB2A) of tall fescue, were able to bind to the cis-elements in the promoter of tall fescue heat stress transcription factor A2c (FaHSFA2c). Exogenous ABA (5 MUM) application enhanced heat tolerance of tall fescue, as manifested by increased leaf photochemical efficiency and membrane stability under heat stress (37/32 degrees C, day/night). The expression levels of FaHSFA2c, several tall fescue HSPs (FaHSPs), and ABA-responsive transcriptional factors were up-regulated in plants treated with ABA. Deficiency of Arabidopsis heat stress transcription factor A2 (AtHSFA2) suppressed ABA-induction of AtHSPs expression and ABA improved heat tolerance in Arabidopsis. These results suggested that HSFA2 plays an important role in ABA-mediated plant heat tolerance, and FaAREB3 and FaDREB2A may function as upstream trans-acting factors and regulate transcriptional activity of FaHSFA2c and the downstream FaHSPs, leading to improved heat tolerance. PMID- 28914759 TI - Isoform Sequencing Provides a More Comprehensive View of the Panax ginseng Transcriptome. AB - Korean ginseng (Panax ginseng C.A. Meyer) has been widely used for medicinal purposes and contains potent plant secondary metabolites, including ginsenosides. To obtain transcriptomic data that offers a more comprehensive view of functional genomics in P. ginseng, we generated genome-wide transcriptome data from four different P. ginseng tissues using PacBio isoform sequencing (Iso-Seq) technology. A total of 135,317 assembled transcripts were generated with an average length of 3.2 kb and high assembly completeness. Of those unigenes, 67.5% were predicted to be complete full-length (FL) open reading frames (ORFs) and exhibited a high gene annotation rate. Furthermore, we successfully identified unique full-length genes involved in triterpenoid saponin synthesis and plant hormonal signaling pathways, including auxin and cytokinin. Studies on the functional genomics of P. ginseng seedlings have confirmed the rapid upregulation of negative feed-back loops by auxin and cytokinin signaling cues. The conserved evolutionary mechanisms in the auxin and cytokinin canonical signaling pathways of P. ginseng are more complex than those in Arabidopsis thaliana. Our analysis also revealed a more detailed view of transcriptome-wide alternative isoforms for 88 genes. Finally, transposable elements (TEs) were also identified, suggesting transcriptional activity of TEs in P. ginseng. In conclusion, our results suggest that long-read, full-length or partial-unigene data with high-quality assemblies are invaluable resources as transcriptomic references in P. ginseng and can be used for comparative analyses in closely related medicinal plants. PMID- 28914760 TI - GNSS Receiver Identification Using Clock-Derived Metrics. AB - Falsifying Global Navigation Satellite System (GNSS) data with a simulator or with a fake receiver can have a significant economic or safety impact in many transportation applications where Position, Velocity and Time (PVT) are used to enforce a regulation. In this context, the authentication of the source of the PVT data (i.e., the GNSS receiver) is a requirement since data faking can become a serious threat. Receiver fingerprinting techniques represent possible countermeasures to verify the authenticity of a GNSS receiver and of its data. Herein, the potential of clock-derived metrics for GNSS receiver fingerprinting is investigated, and a filter approach is implemented for feature selection. Novel experimental results show that three intrinsic features are sufficient to identify a receiver. Moreover, the adopted technique is time effective as data blocks of about 40 min are sufficient to produce stable features for fingerprinting. PMID- 28914761 TI - Flavonolignans Inhibit IL1-beta-Induced Cross-Talk between Blood Platelets and Leukocytes. AB - Interleukin-1 beta (IL-1beta)-the most potent pro-inflammatory is responsible for a broad spectrum of immune and inflammatory responses, it induces T-cell and B cell activation and consequently the synthesis of other pro-inflammatory cytokines (such as IFN-gamma and TNF). IL-1beta induces the formation of blood platelet-leukocyte aggregates (PLAs), which suggests that IL-1beta significantly affects the cross-talk between blood platelets and the immune response system, leading to coronary thrombosis. The aim of our study is to investigate the effect of flavonolignans (silybin, silychristin and silydianin) on the IL-1beta-induced interaction between platelets and leukocytes, as well as on the expression and the secretion of pro-inflammatory factors. Whole blood samples were pre-incubated with commercially available flavonolignans (silybin, silychristin and silydianin) in a concentration range of 10-100 uM (30 min, 37 degrees C). Next, samples were activated by IL-1beta for 1 h. Blood platelet-leukocyte aggregates were detected by using the double-labeled flow cytometry (CD61/CD45). The level of produced cytokines was estimated via the ELISA immunoenzymatic method. IFN-gamma and TNF gene expression was evaluated using Real Time PCR with TaqMan arrays. We observed that in a dose-dependent manner, silybin and silychristin inhibit the IL-1beta induced formation of blood platelet-leukocyte aggregates in whole blood samples, as well as the production of pro-inflammatory cytokines-IL-2, TNF, INF-alpha, and INF-gamma. Additionally, these two flavonolignans abolished the IL-1beta-induced expression of mRNA for IFN-gamma and TNF. Our current results demonstrate that flavonolignans can be novel compounds used in the prevention of cardiovascular diseases with dual-use action as antiplatelet and anti-inflammatory agents. PMID- 28914762 TI - The 1-Week and 8-Month Effects of a Ketogenic Diet or Ketone Salt Supplementation on Multi-Organ Markers of Oxidative Stress and Mitochondrial Function in Rats. AB - We determined the short- and long-term effects of a ketogenic diet (KD) or ketone salt (KS) supplementation on multi-organ oxidative stress and mitochondrial markers. For short-term feedings, 4 month-old male rats were provided isocaloric amounts of KD (n = 10), standard chow (SC) (n = 10) or SC + KS (~1.2 g/day, n = 10). For long-term feedings, 4 month-old male rats were provided KD (n = 8), SC (n = 7) or SC + KS (n = 7) for 8 months and rotarod tested every 2 months. Blood, brain (whole cortex), liver and gastrocnemius muscle were harvested from all rats for biochemical analyses. Additionally, mitochondria from the brain, muscle and liver tissue of long-term-fed rats were analyzed for mitochondrial quantity (maximal citrate synthase activity), quality (state 3 and 4 respiration) and reactive oxygen species (ROS) assays. Liver antioxidant capacity trended higher in short-term KD- and SC + KS-fed versus SC-fed rats, and short-term KD-fed rats exhibited significantly greater serum ketones compared to SC + KS-fed rats indicating that the diet (not KS supplementation) induced ketonemia. In long term fed rats: (a) serum ketones were significantly greater in KD- versus SC- and SC + KS-fed rats; (b) liver antioxidant capacity and glutathione peroxidase protein was significantly greater in KD- versus SC-fed rats, respectively, while liver protein carbonyls were lowest in KD-fed rats; and (c) gastrocnemius mitochondrial ROS production was significantly greater in KD-fed rats versus other groups, and this paralleled lower mitochondrial glutathione levels. Additionally, the gastrocnemius pyruvate-malate mitochondrial respiratory control ratio was significantly impaired in long-term KD-fed rats, and gastrocnemius mitochondrial quantity was lowest in these animals. Rotarod performance was greatest in KD-fed rats versus all other groups at 2, 4 and 8 months, although there was a significant age-related decline in performance existed in KD-fed rats which was not evident in the other two groups. In conclusion, short- and long-term KD improves select markers of liver oxidative stress compared to SC feeding, although long-term KD feeding may negatively affect skeletal muscle mitochondrial physiology. PMID- 28914763 TI - Emerging Estrogenic Pollutants in the Aquatic Environment and Breast Cancer. AB - The number and amount of man-made chemicals present in the aquatic environment has increased considerably over the past 50 years. Among these contaminants, endocrine-disrupting chemicals (EDCs) represent a significant proportion. This family of compounds interferes with normal hormonal processes through multiple molecular pathways. They represent a potential risk for human and wildlife as they are suspected to be involved in the development of diseases including, but not limited to, reprotoxicity, metabolic disorders, and cancers. More precisely, several studies have suggested that the increase of breast cancers in industrialized countries is linked to exposure to EDCs, particularly estrogen like compounds. Estrogen receptors alpha (ERalpha) and beta (ERbeta) are the two main transducers of estrogen action and therefore important targets for these estrogen-like endocrine disrupters. More than 70% of human breast cancers are ERalpha-positive and estrogen-dependent, and their development and growth are not only influenced by endogenous estrogens but also likely by environmental estrogen like endocrine disrupters. It is, therefore, of major importance to characterize the potential estrogenic activity from contaminated surface water and identify the molecules responsible for the hormonal effects. This information will help us understand how environmental contaminants can potentially impact the development of breast cancer and allow us to fix a maximal limit to the concentration of estrogen-like compounds that should be found in the environment. The aim of this review is to provide an overview of emerging estrogen-like compounds in the environment, sum up studies demonstrating their direct or indirect interactions with ERs, and link their presence to the development of breast cancer. Finally, we emphasize the use of in vitro and in vivo methods based on the zebrafish model to identify and characterize environmental estrogens. PMID- 28914764 TI - Antioxidant Activity of Spices and Their Impact on Human Health: A Review. AB - Antioxidants are substances that prevent oxidation of other compounds or neutralize free radicals. Spices and herbs are rich sources of antioxidants. They have been used in food and beverages to enhance flavor, aroma and color. Due to their excellent antioxidant activity, spices and herbs have also been used to treat some diseases. In this review article, the chemical composition and antioxidant activity of spices and culinary herbs are presented. The content of flavonoids and total polyphenols in different spices and herbs are summarized. The applications of spices and their impacts on human health are briefly described. The extraction and analytical methods for determination of antioxidant capacity are concisely reviewed. PMID- 28914766 TI - Development of a Sensitive Electrochemical Enzymatic Reaction-Based Cholesterol Biosensor Using Nano-Sized Carbon Interdigitated Electrodes Decorated with Gold Nanoparticles. AB - We developed a versatile and highly sensitive biosensor platform. The platform is based on electrochemical-enzymatic redox cycling induced by selective enzyme immobilization on nano-sized carbon interdigitated electrodes (IDEs) decorated with gold nanoparticles (AuNPs). Without resorting to sophisticated nanofabrication technologies, we used batch wafer-level carbon microelectromechanical systems (C-MEMS) processes to fabricate 3D carbon IDEs reproducibly, simply, and cost effectively. In addition, AuNPs were selectively electrodeposited on specific carbon nanoelectrodes; the high surface-to-volume ratio and fast electron transfer ability of AuNPs enhanced the electrochemical signal across these carbon IDEs. Gold nanoparticle characteristics such as size and morphology were reproducibly controlled by modulating the step-potential and time period in the electrodeposition processes. To detect cholesterol selectively using AuNP/carbon IDEs, cholesterol oxidase (ChOx) was selectively immobilized via the electrochemical reduction of the diazonium cation. The sensitivity of the AuNP/carbon IDE-based biosensor was ensured by efficient amplification of the redox mediators, ferricyanide and ferrocyanide, between selectively immobilized enzyme sites and both of the combs of AuNP/carbon IDEs. The presented AuNP/carbon IDE-based cholesterol biosensor exhibited a wide sensing range (0.005-10 mM) and high sensitivity (~993.91 uA mM-1 cm-2; limit of detection (LOD) ~1.28 uM). In addition, the proposed cholesterol biosensor was found to be highly selective for the cholesterol detection. PMID- 28914765 TI - Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines. AB - Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP+/NADPH relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates. PMID- 28914767 TI - Feasibility of Equivalent Dipole Models for Electroencephalogram-Based Brain Computer Interfaces. AB - This article examines the localization errors of equivalent dipolar sources inverted from the surface electroencephalogram in order to determine the feasibility of using their location as classification parameters for non-invasive brain computer interfaces. Inverse localization errors are examined for two head models: a model represented by four concentric spheres and a realistic model based on medical imagery. It is shown that the spherical model results in localization ambiguity such that a number of dipolar sources, with different azimuths and varying orientations, provide a near match to the electroencephalogram of the best equivalent source. No such ambiguity exists for the elevation of inverted sources, indicating that for spherical head models, only the elevation of inverted sources (and not the azimuth) can be expected to provide meaningful classification parameters for brain-computer interfaces. In a realistic head model, all three parameters of the inverted source location are found to be reliable, providing a more robust set of parameters. In both cases, the residual error hypersurfaces demonstrate local minima, indicating that a search for the best-matching sources should be global. Source localization error vs. signal-to-noise ratio is also demonstrated for both head models. PMID- 28914768 TI - Tilted Fiber Bragg Grating Sensor with Graphene Oxide Coating for Humidity Sensing. AB - In this study, we propose a tilted fiber Bragg grating (TFBG) humidity sensor fabricated using the phase mask method to produce a TFBG that was then etched with five different diameters of 20, 35, 50, 55 and 60 MUm, after which piezoelectric inkjet technology was used to coat the grating with graphene oxide. According to the experimental results, the diameter of 20 MUm yielded the best sensitivity. In addition, the experimental results showed that the wavelength sensitivity was -0.01 nm/%RH and the linearity was 0.996. Furthermore, the measurement results showed that when the relative humidity was increased, the refractive index of the sensor was decreased, meaning that the TFBG cladding mode spectrum wavelength was shifted. Therefore, the proposed graphene oxide film TFBG humidity sensor has good potential to be an effective relative humidity monitor. PMID- 28914769 TI - Multifunctional Nanotechnology-Enabled Sensors for Rapid Capture and Detection of Pathogens. AB - Nanomaterial-based sensing approaches that incorporate different types of nanoparticles (NPs) and nanostructures in conjunction with natural or synthetic receptors as molecular recognition elements provide opportunities for the design of sensitive and selective assays for rapid detection of contaminants. This review summarizes recent advancements over the past ten years in the development of nanotechnology-enabled sensors and systems for capture and detection of pathogens. The most common types of nanostructures and NPs, their modification with receptor molecules and integration to produce viable sensing systems with biorecognition, amplification and signal readout are discussed. Examples of all in-one systems that combine multifunctional properties for capture, separation, inactivation and detection are also provided. Current trends in the development of low-cost instrumentation for rapid assessment of food contamination are discussed as well as challenges for practical implementation and directions for future research. PMID- 28914770 TI - Silicon and Nitrate Differentially Modulate the Symbiotic Performances of Healthy and Virus-Infected Bradyrhizobium-nodulated Cowpea (Vigna unguiculata), Yardlong Bean (V. unguiculata subsp. sesquipedalis) and Mung Bean (V. radiata). AB - The effects of 2 mM silicon (Si) and 10 mM KNO3 (N)-prime signals for plant resistance to pathogens-were analyzed in healthy and Cowpea chlorotic mottle virus (CCMV) or Cowpea mild mottle virus (CMMV)-infected Bradyrhizobium-nodulated cowpea, yardlong bean and mung bean plants. In healthy plants of the three Vigna taxa, nodulation and growth were promoted in the order of Si + N > N > Si > controls. In the case of healthy cowpea and yardlong bean, the addition of Si and N decreased ureide and alpha-amino acids (AA) contents in the nodules and leaves in the order of Si + N> N > Si > controls. On the other hand, the addition of N arrested the deleterious effects of CCMV or CMMV infections on growth and nodulation in the three Vigna taxa. However, the addition of Si or Si + N hindered growth and nodulation in the CCMV- or CMMV-infected cowpea and yardlong bean, causing a massive accumulation of ureides in the leaves and nodules. Nevertheless, the AA content in leaves and nodules of CCMV- or CMMV-infected cowpea and yardlong bean was promoted by Si but reduced to minimum by Si + N. These results contrasted to the counteracting effects of Si or Si + N in the CCMV and CMMV-infected mung bean via enhanced growth, nodulation and levels of ureide and AA in the leaves and nodules. Together, these observations suggest the fertilization with Si + N exclusively in virus-free cowpea and yardlong bean crops. However, Si + N fertilization must be encouraged in virus-endangered mung bean crops to enhance growth, nodulation and N-metabolism. It is noteworthy to see the enhanced nodulation of the three Vigna taxa in the presence of 10 mM KNO3. PMID- 28914772 TI - The Heat-Stable Enterotoxin Receptor, Guanylyl Cyclase C, as a Pharmacological Target in Colorectal Cancer Immunotherapy: A Bench-to-Bedside Current Report. AB - Cancer immunotherapy is becoming a routine treatment modality in the oncology clinic, in spite of the fact that it is a relatively nascent field. The challenge in developing effective immunotherapeutics is the identification of target molecules that promote anti-tumor efficacy across the patient population while sparing healthy tissue from damaging autoimmunity. The intestinally restricted receptor guanylyl cyclase C (GUCY2C) is a target that has been investigated for the treatment of colorectal cancer and numerous animal, and clinical studies have demonstrated both efficacy and safety. Here, we describe the current state of GUCY2C-directed cancer immunotherapy and the future directions of this work. PMID- 28914771 TI - Geminiviruses and Plant Hosts: A Closer Examination of the Molecular Arms Race. AB - Geminiviruses are plant-infecting viruses characterized by a single-stranded DNA (ssDNA) genome. Geminivirus-derived proteins are multifunctional and effective regulators in modulating the host cellular processes resulting in successful infection. Virus-host interactions result in changes in host gene expression patterns, reprogram plant signaling controls, disrupt central cellular metabolic pathways, impair plant's defense system, and effectively evade RNA silencing response leading to host susceptibility. This review summarizes what is known about the cellular processes in the continuing tug of war between geminiviruses and their plant hosts at the molecular level. In addition, implications for engineered resistance to geminivirus infection in the context of a greater understanding of the molecular processes are also discussed. Finally, the prospect of employing geminivirus-based vectors in plant genome engineering and the emergence of powerful genome editing tools to confer geminivirus resistance are highlighted to complete the perspective on geminivirus-plant molecular interactions. PMID- 28914773 TI - Vitamin D Nutritional Status and its Related Factors for Chinese Children and Adolescents in 2010-2012. AB - Vitamin D plays a critical role in calcium and phosphate metabolism and helps maintain skeletal integrity in childhood, yet vitamin D status in Chinese children and adolescents is not well documented. The aim of this study was to assess the vitamin D status and analyze the risk factors for vitamin D deficiency in Chinese children and adolescents aged 6-17 years. Serum 25 hydroxyvitamin D (25(OH)D) was measured with a radioimmunoassay kit in 15,000 children and adolescent participants in the Chinese national nutrition and health survey (CNNHS) 2010-2012. Age, gender, region type, ethnicity, outdoor time, and vitamin D supplementation were recorded in unified design questionnaires. The season was recorded by the date of blood taken; location was divided into north and south by China's Qinling Mountains and Huaihe River; and ambient ultraviolet B (UVB) radiation level was classified according to the corresponding dose of each participant living area from National Aeronautics and Space Administration data. 14,473 participants from the cross-sectional study of CNNHS 2010-2012 were included in this study. The median serum 25(OH)D concentration was 48.2 (35.4 63.4) nmol/L, and the concentration for males was 50.0 (36.5-65.7) nmol/L, which was statistically higher than that of females (46.7 (34.4-60.9) nmol/L) (P < 0.001). The general prevalence of vitamin D deficiency was 53.2%; 50.0% for males and 56.5% for females at the cut-off 50 nmol/L. According to the results of the log-binomial regression analysis, vitamin D deficiency in Chinese children and adolescents was specifically related to female gender (P < 0.0001), to ages 12-14 years (P < 0.0001) and 15-17 years (P < 0.0001), living in large cities (P < 0.0001) or ordinary rural areas (P < 0.0001), low ambient UVB levels (P < 0.0001) and medium ambient UVB levels (P < 0.0001), spring (P < 0.0001), autumn (P < 0.0001) and winter seasons (P < 0.0001). The data showed that vitamin D deficiency was very common among children and adolescents aged 6-17 years in China. Effective sun exposure should be encouraged in both genders aged 6-17 years, dietary vitamin D and vitamin D supplements are also recommended, especially in the seasons of spring and winter. PMID- 28914775 TI - New Methods to Address Old Challenges: The Use of Administrative Data for Longitudinal Replication Studies of Child Maltreatment. AB - Administrative data are crucial to the "big data" revolution of social science and have played an important role in the development of child maltreatment research. These data are also of value to administrators, policy makers, and clinicians. The focus of this paper is the use of administrative data to produce and replicate longitudinal studies of child maltreatment. Child protection administrative data have several advantages. They are often population-based, and allow longitudinal examination of child maltreatment and complex multi-level analyses. They also allow comparison across subgroups and minority groups, remove burden from individuals to disclose traumatic experiences, and can be less biased than retrospective recall. Finally, they can be linked to data from other agencies to explore comorbidity and outcomes, and are comparatively cost and time effective. The benefits and challenges associated with the use of administrative data for longitudinal child maltreatment research become magnified when these data are used to produce replications. Techniques to address challenges and support future replication efforts include developing a biographical understanding of the systems from which the data are drawn, using multiple data sources to contextualize the data and research results, recognizing and adopting various approaches to replication, and documenting all data coding and manipulation processes. These techniques are illustrated in this paper via a case study of previous replication work. PMID- 28914776 TI - Worldwide Occurrence and Investigations of Contamination of Herbal Medicines by Tropane Alkaloids. AB - Tropane alkaloids occur mainly in Solanaceae plants. In the present review, the main objective is to describe the worldwide occurrence and investigations of anticholinergic poisoning due to the contamination of herbal teas and herbs by tropane alkaloids. Tropane alkaloid poisoning can occur after consumption of any medicinal plant if Solanaceae plants or plant parts are present as contaminants. Globally, almost all reports in 1978-2014 involve herbal teas and one of the prescribed herbs in composite formulae. Contamination most likely occurs during harvest or processing. As for prescribed herbs, on-site inspection is necessary to exclude cross-contamination and accidental mix-up at the retail level. The diagnosis is confirmed by screening for the presence of Solanaceae species and tropane alkaloids. Herbal teas and herbs contaminated by tropane alkaloids can pose a serious health hazard because these relatively heat-stable alkaloids may exist in large quantities. The WHO repeatedly emphasises the importance of good agricultural and collection practices for medicinal plants. DNA barcoding is increasingly used to exclude the presence of contaminants (particularly toxic species) and product substitution. All suspected cases should be reported to health authorities so that investigations along the supply chain and early intervention measures to protect the public can be initiated. PMID- 28914777 TI - The Usefulness of Contrast-Enhanced Ultrasound in the Assessment of Early Kidney Transplant Function and Complications. AB - OBJECTIVES: The routine diagnostic method for assessment of renal graft dysfunction is Doppler ultrasound. However, contrast-enhanced ultrasound (CEUS) may provide more information about parenchymal flow and vascular status of kidney allografts. The aim of the study was to assess the effectiveness of CEUS in the immediate post-transplant period, focusing on acute vascular complications. A brief review of available literature and a report of our initial experience is made. MATERIAL AND METHODS: 15 kidney transplant (KT) cases with clinical suspicion of acute surgical complication were assessed with CEUS and conventional Doppler ultrasound (US). In addition, bibliographic review was conducted through PubMed, Embase, and ClinicalKey databases. RESULTS: 10% of KT underwent CEUS, useful for detecting vascular complication or cortical necrosis in 4 (26%) and exclude them in 74%. Grafts with acute vascular complications have a delayed contrast-enhancement with peak intensity lower than normal kidneys. Perfusion defects can be clearly observed and the imaging of cortical necrosis is pathognomonic. CONCLUSIONS: CEUS is a useful tool in the characterization of renal graft dysfunction with special interest on acute vascular complications after renal transplant. It is a feasible technique for quantitative analysis of kidney perfusion, which provides information on renal tissue microcirculation and regional parenchymal flow. Exploration could be done by a urologist at the patient's bedside while avoiding iodinated contrast. PMID- 28914778 TI - Screening for Autochthonous Phytoextractors in a Heavy Metal Contaminated Coal Mining Area. AB - In order to protect public health and crops from soil heavy metal (HM) contamination at a coal mining area in Henan, central China, HM pollution investigation and screening of autochthonous HM phytoextractors were conducted. The concentrations of cadmium (Cd), lead (Pb), copper (Cu) and zinc (Zn) in surface soils exceeded the corresponding local background values and the China National Standard (CNS). The maximum potential ecological risk (RI) was 627.30, indicating very high ecological risk. The monomial risk of Cd contributed the most to the RI, varying from 85.48% to 96.48%. The plant community structure in the study area was simple, and was composed of 24 families, 37 genera and 40 species. B. pilosa, A. roxburghiana, A. argyi, A. hispidus were found to be the most dominant species at considerable risk sites. Based on the comprehensive analysis of Cd concentration, bioconcentration factor, translocation factor and adaptability factor, B. pilosa and A. argyi had potential for phytoextraction at considerable risk sites. A. roxburghiana had potential for Cd phytoextraction at moderately risk sites and A. hispidus seemed suitable for phytostabilization. The results could contribute to the phytoremediation of the similar sites. PMID- 28914779 TI - Simultaneous Recognition and Relative Pose Estimation of 3D Objects Using 4D Orthonormal Moments. AB - Both three-dimensional (3D) object recognition and pose estimation are open topics in the research community. These tasks are required for a wide range of applications, sometimes separately, sometimes concurrently. Many different algorithms have been presented in the literature to solve these problems separately, and some to solve them jointly. In this paper, an algorithm to solve them simultaneously is introduced. It is based on the definition of a four dimensional (4D) tensor that gathers and organizes the projections of a 3D object from different points of view. This 4D tensor is then represented by a set of 4D orthonormal moments. Once these moments are arranged in a matrix that can be computed off-line, recognition and pose estimation is reduced to the solution of a linear least squares problem, involving that matrix and the 2D moments of the observed projection of an unknown object. The abilities of this method for 3D object recognition and pose estimation is analytically proved, demonstrating that it does not rely on experimental work to apply a generic technique to these problems. An additional strength of the algorithm is that the required projection is textureless and defined at a very low resolution. This method is computationally simple and shows very good performance in both tasks, allowing its use in applications where real-time constraints have to be fulfilled. Three different kinds of experiments have been conducted in order to perform a thorough validation of the proposed approach: recognition and pose estimation under z axis (yaw) rotations, the same estimation but with the addition of y axis rotations (pitch), and estimation of the pose of objects in real images downloaded from the Internet. In all these cases, results are encouraging, at a similar level to those of state-of-the art algorithms. PMID- 28914774 TI - Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. AB - Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail. PMID- 28914780 TI - Public Health Network Structure and Collaboration Effectiveness during the 2015 MERS Outbreak in South Korea: An Institutional Collective Action Framework. AB - Following the 2015 Middle East Respiratory Syndrome (MERS) outbreak in South Korea, this research aims to examine the structural effect of public health network explaining collaboration effectiveness, which is defined as joint efforts to improve quality of service provision, cost savings, and coordination. We tested the bonding and bridging effects on collaboration effectiveness during the MERS outbreak response by utilizing an institutional collective action framework. The analysis results of 114 organizations responding during the crisis show a significant association between the bonding effect and the effectiveness of collaboration, as well as a positive association between risk communication in disseminating public health information and the effectiveness of collaboration. PMID- 28914781 TI - Response to Elwood, M. et al., Comment on: Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring. Int. J. Environ. Res. Public Health 2017, 14, 27. AB - Dear Editor, Thank you for inviting us to reply to a "Comment" paper to our published paper "Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring" (Authors: Elodie Haraux, Karine Braun, Philippe Buisson, Erwan Stephan Blanchard, Jannick Ricard, Camille Devauchelle, Bernard Boudailliez, Pierre Tourneux, Richard Gouron, Karen Chardon).[...]. PMID- 28914783 TI - Smoothed Temporal Atlases of Age-Gender All-Cause Mortality in South Africa. AB - Most mortality maps in South Africa and most contried of the sub-Saharan region are static, showing aggregated count data over years or at specific years. Lack of space and temporral dynamanics in these maps may adversely impact on their use and application for vigorous public health policy decisions and interventions. This study aims at describing and modeling sub-national distributions of age gender specific all-cause mortality and their temporal evolutions from 1997 to 2013 in South Africa. Mortality information that included year, age, gender, and municipality administrative division were obtained from Statistics South Africa for the period. Individual mortality level data were grouped by three ages groups (0-14, 15-64, and 65 and over) and gender (male, female) and aggregated at each of the 234 municipalities in the country. The six age-gender all-cause mortality rates may be related due to shared common social deprivation, health and demographic risk factors. We undertake a joint analysis of the spatial-temporal variation of the six age-gender mortality risks. This is done within a shared component spatial model construction where age-gender common and specific spatial and temporal trends are estiamted using a hierarchical Bayesian spatial model. The results show municipal and temporal differentials in mortality risk profiles between age and gender groupings. High rates were seen in 2005, especially for the 15-64 years age group for both males and females. The dynamic geographical and time distributions of subnational age-gender all-cause mortality contribute to a better understanding of the temporal evolvement and geographical variations in the relationship between demographic composition and burden of diseases in South Africa. This provides useful information for effective monitoring and evaluation of public health policies and programmes targeting mortality reduction across time and sub-populations in the country. PMID- 28914784 TI - Antiallodynic Effects of Bee Venom in an Animal Model of Complex Regional Pain Syndrome Type 1 (CRPS-I). AB - Neuropathic pain in a chronic post-ischaemic pain (CPIP) model mimics the symptoms of complex regional pain syndrome type I (CRPS I). The administration of bee venom (BV) has been utilized in Eastern medicine to treat chronic inflammatory diseases accompanying pain. However, the analgesic effect of BV in a CPIP model remains unknown. The application of a tight-fitting O-ring around the left ankle for a period of 3 h generated CPIP in C57/Bl6 male adult mice. BV (1 mg/kg ; 1, 2, and 3 times) was administered into the SC layer of the hind paw, and the antiallodynic effects were investigated using the von Frey test and by measuring the expression of neurokinin type 1 (NK-1) receptors in dorsal root ganglia (DRG). The administration of BV dose-dependently reduced the pain withdrawal threshold to mechanical stimuli compared with the pre-administration value and with that of the control group. After the development of the CPIP model, the expression of NK-1 receptors in DRG increased and then decreased following the administration of BV. SC administration of BV results in the attenuation of allodynia in a mouse model of CPIP. The antiallodynic effect was objectively proven through a reduction in the increased expression of NK-1 receptors in DRG. PMID- 28914782 TI - The Future Challenge of Reactive Oxygen Species (ROS) in Hypertension: From Bench to Bed Side. AB - Reactive oxygen species (ROS) act as signaling molecules that control physiological processes, including cell adaptation to stress. Redox signaling via ROS has quite recently become the focus of much attention in numerous pathological contexts, including neurodegenerative diseases, kidney and cardiovascular disease. Imbalance in ROS formation and degradation has also been implicated in essential hypertension. Essential hypertension is characterized by multiple genetic and environmental factors which do not completely explain its associated risk factors. Thereby, even if advances in therapy have led to a significant reduction in hypertension-associated complications, to interfere with the unbalance of redox signals might represent an additional therapeutic challenge. The decrease of nitric oxide (NO) levels, the antioxidant activity commonly found in preclinical models of hypertension and the ability of antioxidant approaches to reduce ROS levels have spurred clinicians to investigate the contribution of ROS in humans. Indeed, particular effort has recently been devoted to understanding how redox signaling may contribute to vascular pathobiology in human hypertension. However, although biomarkers of oxidative stress have been found to positively correlate with blood pressure in preclinical model of hypertension, human data are less convincing. We herein provide an overview of the most relevant mechanisms via which oxidative stress might contribute to the pathophysiology of essential hypertension. Moreover, alternative approaches, which are directed towards improving antioxidant machinery and/or interfering with ROS production, are also discussed. PMID- 28914785 TI - Hsp90alpha Mediates BMI1 Expression in Breast Cancer Stem/Progenitor Cells through Facilitating Nuclear Translocation of c-Myc and EZH2. AB - Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the correct folding and functionality of its client protein. Numerous Hsp90-client proteins are involved in cancer development. Thus, Hsp90 inhibitors have potential applications as anti-cancer drugs. We previously discovered that Hsp90alpha expression increased in breast cancer stem cells (BCSCs), which can initiate tumorigenesis and metastasis and resist treatment. In the present study, we further demonstrated that 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90, could suppress the self-renewal of BCSCs by downregulating B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a polycomb family member with oncogenic activity in breast cancer. Through immunoprecipitation analysis, we found that BMI1 did not interact with Hsp90alpha and that the downregulation of BMI1 by 17-DMAG was mediated by the inhibition of c-Myc and enhancement of zeste homolog 2 (EZH2) expression. The transcriptional and BMI1 promoter-binding activities of c-Myc in BCSCs were inhibited by 17-DMAG treatment. The overexpression of EZH2 attenuated the inhibitory effect of 17-DMAG on BMI1 and c-Myc expression. Furthermore, Hsp90alpha could be co immunoprecipitated with c-Myc and EZH2 and bind to the BMI1 promoter. Treatment with 17-DMAG decreased the nuclear expression of EZH2 and c-Myc but not that of Hsp90alpha. In conclusion, our data suggested that Hsp90alpha could positively regulate the self-renewal of BCSCs by facilitating the nuclear translocation of c Myc and EZH2 to maintain BMI1 expression. PMID- 28914786 TI - Baseline and Estimated Trends of Sodium Availability and Food Sources in the Costa Rican Population during 2004-2005 and 2012-2013. AB - In 2012, Costa Rica launched a program to reduce salt and sodium consumption to prevent cardiovascular disease and associated risk factors, but little was known about the level of sodium consumption or its sources. Our aim was to estimate the magnitude and time trends of sodium consumption (based on food and beverage acquisitions) in Costa Rica. Data from the National Household Income and Expenditure Surveys carried out in 2004-2005 (n = 4231) and 2012-2013 (n = 5705) were used. Records of food purchases for household consumption were converted into sodium and energy using food composition tables. Mean sodium availability (per person/per day and adjusted for a 2000-kcal energy intake) and the contribution of food groups to this availability were estimated for each year. Sodium availability increased in the period from 3.9 to 4.6 g/person/day (p < 0.001). The income level was inversely related to sodium availability. The main sources of sodium in the diet were domestic salt (60%) in addition to processed foods and condiments (with added sodium) (27.4%). Dietary sources of sodium varied within surveys (p < 0.05). Sodium available for consumption in Costa Rican households largely exceeds the World Health Organization-recommended intake levels (<2 g sodium/person/day). These results are essential for the design and implementation of effective policies and interventions. PMID- 28914787 TI - A Sparse Dictionary Learning-Based Adaptive Patch Inpainting Method for Thick Clouds Removal from High-Spatial Resolution Remote Sensing Imagery. AB - Cloud cover is inevitable in optical remote sensing (RS) imagery on account of the influence of observation conditions, which limits the availability of RS data. Therefore, it is of great significance to be able to reconstruct the cloud contaminated ground information. This paper presents a sparse dictionary learning based image inpainting method for adaptively recovering the missing information corrupted by thick clouds patch-by-patch. A feature dictionary was learned from exemplars in the cloud-free regions, which was later utilized to infer the missing patches via sparse representation. To maintain the coherence of structures, structure sparsity was brought in to encourage first filling-in of missing patches on image structures. The optimization model of patch inpainting was formulated under the adaptive neighborhood-consistency constraint, which was solved by a modified orthogonal matching pursuit (OMP) algorithm. In light of these ideas, the thick-cloud removal scheme was designed and applied to images with simulated and true clouds. Comparisons and experiments show that our method can not only keep structures and textures consistent with the surrounding ground information, but also yield rare smoothing effect and block effect, which is more suitable for the removal of clouds from high-spatial resolution RS imagery with salient structures and abundant textured features. PMID- 28914788 TI - A Decrease of Incidence Cases of Fumonisins in South Korean Feedstuff between 2011 and 2016. AB - Several plant pathogen Fusarium species produce fumonisins (FUMs); which can end up in food and feed and; when ingested; can exhibit harmful effects on humans and livestock. Mycotoxin intoxication by fumonisin B1 (FB1) and fumonisin B2 (FB2) can cause porcine pulmonary edema; leukoencephalomalacia in equines; esophageal cancer and birth defects by natural contamination. Herein; the occurrence of FB1 and FB2 in feedstuff (compound feed and feed ingredients) was investigated between 2011 and 2016 in South Korea. A total of 535 animal feed samples (425 compound feed samples and 110 feed ingredients) produced domestically were sampled four times between 2011 and 2016 (2011; 2012; 2014 and 2016) from feed factories in South Korea. The limit of detection (LOD) for FB1 and FB2 was 20 MUg/kg and 25 MUg/kg; respectively; and the limit of quantitation (LOQ) was 30 MUg/kg and 35 MUg/kg; respectively. The recovery range (%) was between 86.4% and 108.8%; and the relative standard deviation (RSD) (%) was 4.7-12.1%. Seven (swine feed samples) out of the 425 feed samples exceeded the European Union (EU) and South Korea commission regulations over the six-year test period; and no feed ingredients exceeded the guidelines. PMID- 28914789 TI - Phytochemical Constituents, Health Benefits, and Industrial Applications of Grape Seeds: A Mini-Review. AB - Grapes are one of the most widely grown fruits and have been used for winemaking since the ancient Greek and Roman civilizations. Grape seeds are rich in proanthocyanidins which have been shown to possess potent free radical scavenging activity. Grape seeds are a complex matrix containing 40% fiber, 16% oil, 11% proteins, and 7% complex phenols such as tannins. Grape seeds are rich sources of flavonoids and contain monomers, dimers, trimers, oligomers, and polymers. The monomeric compounds includes (+)-catechins, (-)-epicatechin, and (-)-epicatechin 3-O-gallate. Studies have reported that grape seeds exhibit a broad spectrum of pharmacological properties against oxidative stress. Their potential health benefits include protection against oxidative damage, and anti-diabetic, anti cholesterol, and anti-platelet functions. Recognition of such health benefits of proanthocyanidins has led to the use of grape seeds as a dietary supplement by the consumers. This paper summarizes the studies of the phytochemical compounds, pharmacological properties, and industrial applications of grape seeds. PMID- 28914790 TI - Ancient Living Organisms Escaping from, or Imprisoned in, the Vents? AB - We have recently criticised the natural pH gradient hypothesis which purports to explain how the difference in pH between fluid issuing from ancient alkali vents and the more acidic Hadean ocean could have driven molecular machines that catalyse reactions that are useful in prebiotic and autotrophic chemistry. In this article, we temporarily suspend our earlier criticism while we consider difficulties for primitive organisms to have managed their energy supply and to have left the vents and become free-living. We point out that it may have been impossible for organisms to have acquired membrane-located proton (or sodium ion) pumps to replace the natural pH gradient, and independently to have driven essential molecular machines such as the ATP synthase. The volumes of the ocean and of the vent fluids were too large for a membrane-located pump to have generated a significant ion concentration gradient. Our arguments apply to three of the four concurrent models employed by the proponents of the natural pH gradient hypothesis. A fourth model is exempt from these arguments but has other intrinsic difficulties that we briefly consider. We conclude that ancient organisms utilising a natural pH gradient would have been imprisoned in the vents, unable to escape and become free-living. PMID- 28914791 TI - Quercetin Attenuates Manganese-Induced Neuroinflammation by Alleviating Oxidative Stress through Regulation of Apoptosis, iNOS/NF-kappaB and HO-1/Nrf2 Pathways. AB - Manganese (Mn) is an essential trace element required for the development of human body and acts as an enzyme co-factor or activator for various reactions of metabolism. While essential in trace amounts, excessive Mn exposure can result in toxic accumulations in human brain tissue and resulting extrapyramidal symptoms called manganism similar to idiopathic Parkinson's disease (PD). Quercetin (QCT) has been demonstrated to play an important role in altering the progression of neurodegenerative diseases by protecting against oxidative stress. This study aimed to investigate the protective effect of QCT on Mn-induced neurotoxicity and the underlying mechanism in SK-N-MC human neuroblastoma cell line and Sprague Dawley (SD) male rat brain. The results showed that Mn treatment significantly decreased the cell viability of SK-N-MC cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by QCT pretreatment at 10 and 20 ug/mL. Compared to the Mn alone group, QCT pretreatment significantly attenuated Mn induced oxidative stress, mitochondrial dysfunction and apoptosis. Meanwhile, QCT pretreatment markedly downregulated the NF-kappaB but upregulated the heme oxygenase-1 (HO-1) and Nrf2 proteins, compared to the Mn alone group. Our result showed the beneficial effect of QCT on hematological parameters against Mn in rat brain. QCT decrease reactive oxygen species (ROS) and protein carbonyl levels and increased Cu/Zn-superoxide dismutase (SOD) activity induced in Mn-treated rats. QCT administration caused a significant reduction in the Mn-induced neuroinflammation by inhibiting the expression of inflammatory markers such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). QCT lowered the Mn elevated levels of various downstream apoptotic markers, including Bax, cytochrome c, cleaved caspase-3 and polymerase-1 (PARP 1), while QCT treatment upregulated anti-apoptotic Bcl-2 proteins and prevented Mn-induced neurodegeneration. Furthermore, administration of QCT (25 and 50 mg/kg) to Mn-exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of QCT to Mn-exposed rats showed significant reduction of 8-hydroxy-2'-deoxyguanosine (8-OHdG), Bax, activated caspase-3 and PARP-1 immunoreactivity. These results indicate that QCT could effectively inhibit Mn induced apoptosis and inflammatory response in SK-N MC cells and SD rats, which may involve the activation of HO-1/Nrf2 and inhibition of NF-kappaB pathway. PMID- 28914792 TI - Impact of Source and Manufacturing of Collagen Matrices on Fibroblast Cell Growth and Platelet Aggregation. AB - Collagen is a main component of the extracellular matrix. It is often used in medical applications to support tissue regeneration, hemostasis, or wound healing. Due to different sources of collagen, the properties and performance of available products can vary significantly. In this in vitro study, a comparison of seven different collagen matrices derived from bovine, equine, and porcine sources was performed. As performance indicators, the scaffold function for fibroblasts and platelet aggregation were used. We found strong variation in platelet aggregation and fibroblast growth on the different collagen materials. The observed variations could not be attributed to species differences alone, but were highly dependent on differences in the manufacturing process. PMID- 28914793 TI - Multi-Aperture Shower Design for the Improvement of the Transverse Uniformity of MOCVD-Derived GdYBCO Films. AB - A multi-aperture shower design is reported to improve the transverse uniformity of GdYBCO superconducting films on the template of sputtered-LaMnO3/epitaxial MgO/IBAD-MgO/solution deposition planarization (SDP)-Y2O3-buffered Hastelloy tapes. The GdYBCO films were prepared by the metal organic chemical vapor deposition (MOCVD) process. The transverse uniformities of structure, morphology, thickness, and performance were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), step profiler, and the standard four-probe method using the criteria of 1 MUV/cm, respectively. Through adopting the multi aperture shower instead of the slit shower, measurement by step profiler revealed that the thickness difference between the middle and the edges based on the slit shower design was well eliminated. Characterization by SEM showed that a GdYBCO film with a smooth surface was successfully prepared. Moreover, the transport critical current density (Jc) of its middle and edge positions at 77 K and self field were found to be over 5 MA/cm2 through adopting the micro-bridge four-probe method. PMID- 28914795 TI - Synthesis, In Vitro alpha-Glucosidase Inhibitory Activity and Molecular Docking Studies of Novel Benzothiazole-Triazole Derivatives. AB - Benzothiazole-triazole derivatives 6a-6s have been synthesized and characterized by 1HNMR and 13C-NMR. All synthetic compounds were screened for their in vitro alpha-glucosidase inhibitory activity by using Baker's yeast alpha-glucosidase enzyme. The majority of compounds exhibited a varying degree of alpha-glucosidase inhibitory activity with IC50 values between 20.7 and 61.1 MUM when compared with standard acarbose (IC50 = 817.38 MUM). Among the series, compound 6s (IC50 = 20.7 MUM) bearing a chlorine group at the 5-position of the benzothiazole ring and a tertbutyl group at the para position of the phenyl ring, was found to be the most active compound. Preliminary structure-activity relationships were established. Molecular docking studies were performed to predict the binding interaction of the compounds in the binding pocket of the enzyme. PMID- 28914796 TI - Enhanced Interface Structure and Properties of Titanium Carbonitride-Based Cermets with the Extra Solid Phase Reaction. AB - In this paper, the influence of the extra solid phase reaction on the interface structure and mechanical properties of titanium carbonitride-based cermets were investigated. The extra solid phase reaction in the preparation process of cermets could induce the formation of a core/rim/binder interface with the coherent structure and reinforce the interface bonding strength in cermets. The existence of a coherent structure interface can inhibit crack spread and improve the toughness and abrasion resistance of titanium carbonitride-based cermets significantly. Cermets can exhibit the high hardness Rockwell Hardness A (HRA) 92.3, fracture toughness of 11.6 MPa.m1/2, and transverse rupture strength of 2810 MPa. PMID- 28914797 TI - Dynamic Recrystallization of the Constituent gamma Phase and Mechanical Properties of Ti-43Al-9V-0.2Y Alloy Sheet. AB - A crack-free Ti-43Al-9V-0.2Y alloy sheet was successfully fabricated via hot-pack rolling at 1200 degrees C. After hot-rolling, the beta/gamma lamellar microstructure of the as-forged TiAl alloy was completely converted into a homogeneous duplex microstructure with an average gamma grain size of 10.5 MUm. The dynamic recrystallization (DRX) of the gamma phase was systematically investigated. A recrystallization fraction of 62.5% was obtained for the gamma phase in the TiAl alloy sheet, when a threshold value of 0.8 degrees was applied to the distribution of grain orientation spread (GOS) values. The high strain rate and high stress associated with hot-rolling are conducive for discontinuous dynamic recrystallization (DDRX) and continuous dynamic recrystallization (CDRX), respectively. A certain high-angle boundary (HAGB: theta = 89 degrees +/- 3 degrees <100>), which is associated with DDRX, occurs in both the recrystallized and deformed gamma grains. The twin boundaries play an important role in the DDRX of the gamma phase. Additionally, the sub-structures and sub-boundaries originating from low-angle boundaries in the deformed grains also indicate that CDRX occurs. The mechanical properties of the alloy sheet were determined at both room and elevated temperatures. At 750 degrees C, the alloy sheet exhibited excellent elongation (53%), corresponding to a failure strength of 467 MPa. PMID- 28914794 TI - Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. AB - The human gastrointestinal tract is colonised by a complex ecosystem of microorganisms. Intestinal bacteria are not only commensal, but they also undergo a synbiotic co-evolution along with their host. Beneficial intestinal bacteria have numerous and important functions, e.g., they produce various nutrients for their host, prevent infections caused by intestinal pathogens, and modulate a normal immunological response. Therefore, modification of the intestinal microbiota in order to achieve, restore, and maintain favourable balance in the ecosystem, and the activity of microorganisms present in the gastrointestinal tract is necessary for the improved health condition of the host. The introduction of probiotics, prebiotics, or synbiotics into human diet is favourable for the intestinal microbiota. They may be consumed in the form of raw vegetables and fruit, fermented pickles, or dairy products. Another source may be pharmaceutical formulas and functional food. This paper provides a review of available information and summarises the current knowledge on the effects of probiotics, prebiotics, and synbiotics on human health. The mechanism of beneficial action of those substances is discussed, and verified study results proving their efficacy in human nutrition are presented. PMID- 28914798 TI - Genome Instability and gammaH2AX. AB - gammaH2AX has emerged in the last 20 years as a central player in the DDR (DNA damage response), with specificity for DSBs (double-strand breaks). Upon the generation of DSBs, gamma-phosphorylation extends along megabase-long domains in chromatin, both sides of the damage. The significance of this mechanism is of great importance; it depicts a biological amplification mechanism where one DSB induces the gamma-phosphorylation of thousands of H2AX molecules along megabaselong domains of chromatin, that are adjusted to the sites of DSBs. A sequential recruitment of signal transduction factors that interact to each other and become activated to further amplify the signal that will travel to the cytoplasm take place on the gamma-phosphorylated chromatin. gamma-phosphorylation is an early event in the DSB damage response, induced in all phases of the cell cycle, and participates in both DSB repair pathways, the HR (homologous recombination) and NHEJ (non-homologous end joining). Today, numerous studies support the notion that gammaH2AX functions as a guardian of the genome by preventing misrepaired DSB that increase the mutation load of the cells and may further lead to genome instability and carcinogenesis. PMID- 28914799 TI - Resonance Frequency Readout Circuit for a 900 MHz SAW Device. AB - A monolithic resonance frequency readout circuit with high resolution and short measurement time is presented for a 900 MHz RF surface acoustic wave (SAW) sensor. The readout circuit is composed of a fractional-N phase-locked loop (PLL) as the stimulus source to the SAW device and a phase-based resonance frequency detecting circuit using successive approximation (SAR). A new resonance frequency searching strategy has been proposed based on the fact that the SAW device phase frequency response crosses zero monotonically around the resonance frequency. A dedicated instant phase difference detecting circuit is adopted to facilitate the fast SAR operation for resonance frequency searching. The readout circuit has been implemented in 180 nm CMOS technology with a core area of 3.24 mm2. In the experiment, it works with a 900 MHz SAW resonator with a quality factor of Q = 130. Experimental results show that the readout circuit consumes 7 mW power from 1.6 V supply. The frequency resolution is 733 Hz, and the relative accuracy is 0.82 ppm, and it takes 0.48 ms to complete one measurement. Compared to the previous results in the literature, this work has achieved the shortest measurement time with a trade-off between measurement accuracy and measurement time. PMID- 28914800 TI - Effect of Clotting Duration and Temperature on BDNF Measurement in Human Serum. AB - Brain-derived neurothrophic factor (BDNF) is a neurotrophin expressed in different tissues and cells, including neurons, endothelial cells, leukocytes, megakaryocytes and platelets. Modifications of BDNF in plasma and/or in serum are associated with neurodegenerative and psychiatric disorders, cardiovascular diseases, metabolic syndrome and with mortality risk. Indeed, changes in blood levels of BDNF may reflect those of its tissue of origin and/or promote pathological dysfunctions. The measurement of BDNF amount in plasma or in serum has been characterized with particular attention in the impact of different anti coagulants, clotting duration, temperature (<=21 degrees C) and delay in blood sample centrifugation as well as in stability of storage. However, the influences of normothermic conditions (37 degrees C) and of clotting duration on BDNF levels in human serum have not been investigated yet. Here, we showed that time and temperature during serum preparation could be taken into consideration to assess the association and/or impact of BDNF levels in the occurrence of pathological conditions. PMID- 28914801 TI - Gender Differences in Problematic Alcohol Consumption in University Professors. AB - The role of job satisfaction and other psychosocial variables in problematic alcohol consumption within professional settings remains understudied. The aim of this study is to assess the level of problematic alcohol consumption among male and female university professors and associated psychosocial variables. A total of 360 professors (183 men and 177 women) of a large private university in Ecuador were surveyed using standardized instruments for the following psychosocial measures: alcohol consumption, job satisfaction, psychological stress, psychological flexibility, social support and resilience. Problematic alcohol consumption was found in 13.1% of participants, although this was significantly higher (chi2 = 15.6; d.f. = 2, p < 0.001) in men (19.1%) than women (6.8%). Problematic alcohol consumption was reported in men with higher perceived stress and job satisfaction. However, 83.3% of women with problematic alcohol use reported lower job satisfaction and higher psychological inflexibility. Results suggest that job satisfaction itself did not prevent problematic alcohol consumption in men; stress was associated with problematic consumption in men and psychological inflexibility in women. Findings from this study support the need to assess aspects of alcohol consumption and problematic behavior differently among men and women. Intervention strategies aimed at preventing or reducing problematic alcohol consumption in university professors must be different for men and women. PMID- 28914803 TI - Achieving Congestion Mitigation Using Distributed Power Control for Spectrum Sensor Nodes in Sensor Network-Aided Cognitive Radio Ad Hoc Networks. AB - The data sequence of spectrum sensing results injected from dedicated spectrum sensor nodes (SSNs) and the data traffic from upstream secondary users (SUs) lead to unpredictable data loads in a sensor network-aided cognitive radio ad hoc network (SN-CRN). As a result, network congestion may occur at a SU acting as fusion center when the offered data load exceeds its available capacity, which degrades network performance. In this paper, we present an effective approach to mitigate congestion of bottlenecked SUs via a proposed distributed power control framework for SSNs over a rectangular grid based SN-CRN, aiming to balance resource load and avoid excessive congestion. To achieve this goal, a distributed power control framework for SSNs from interior tier (IT) and middle tier (MT) is proposed to achieve the tradeoff between channel capacity and energy consumption. In particular, we firstly devise two pricing factors by considering stability of local spectrum sensing and spectrum sensing quality for SSNs. By the aid of pricing factors, the utility function of this power control problem is formulated by jointly taking into account the revenue of power reduction and the cost of energy consumption for IT or MT SSN. By bearing in mind the utility function maximization and linear differential equation constraint of energy consumption, we further formulate the power control problem as a differential game model under a cooperation or noncooperation scenario, and rigorously obtain the optimal solutions to this game model by employing dynamic programming. Then the congestion mitigation for bottlenecked SUs is derived by alleviating the buffer load over their internal buffers. Simulation results are presented to show the effectiveness of the proposed approach under the rectangular grid based SN-CRN scenario. PMID- 28914802 TI - Phylogenetic Analysis and Antimicrobial Profiles of Cultured Emerging Opportunistic Pathogens (Phyla Actinobacteria and Proteobacteria) Identified in Hot Springs. AB - Hot spring water may harbour emerging waterborne opportunistic pathogens that can cause infections in humans. We have investigated the diversity and antimicrobial resistance of culturable emerging and opportunistic bacterial pathogens, in water and sediment of hot springs located in Limpopo, South Africa. Aerobic bacteria were cultured and identified using 16S ribosomal DNA (rDNA) gene sequencing. The presence of Legionella spp. was investigated using real-time polymerase chain reaction. Isolates were tested for resistance to ten antibiotics representing six different classes: beta-lactam (carbenicillin), aminoglycosides (gentamycin, kanamycin, streptomycin), tetracycline, amphenicols (chloramphenicol, ceftriaxone), sulphonamides (co-trimoxazole) and quinolones (nalidixic acid, norfloxacin). Gram-positive Kocuria sp. and Arthrobacter sp. and gram-negative Cupriavidus sp., Ralstonia sp., Cronobacter sp., Tepidimonas sp., Hafnia sp. and Sphingomonas sp. were isolated, all recognised as emerging food-borne pathogens. Legionella spp. was not detected throughout the study. Isolates of Kocuria, Arthrobacter and Hafnia and an unknown species of the class Gammaproteobacteria were resistant to two antibiotics in different combinations of carbenicillin, ceftriaxone, nalidixic acid and chloramphenicol. Cronobacter sp. was sensitive to all ten antibiotics. This study suggests that hot springs are potential reservoirs for emerging opportunistic pathogens, including multiple antibiotic resistant strains, and highlights the presence of unknown populations of emerging and potential waterborne opportunistic pathogens in the environment. PMID- 28914804 TI - The Role of ERK Signaling in Experimental Autoimmune Encephalomyelitis. AB - Extracellular signal-regulated kinase (ERK) signaling plays a crucial role in regulating immune cell function and has been implicated in autoimmune disorders. To date, all commercially available inhibitors of ERK target upstream components, such as mitogen-activated protein (MAP) kinase/ERK kinase (MEKs), but not ERK itself. Here, we directly inhibit nuclear ERK translocation by a novel pharmacological approach (Glu-Pro-Glu (EPE) peptide), leading to an increase in cytosolic ERK phosphorylation during T helper (Th)17 cell differentiation. This was accompanied by diminished secretion of granulocyte-macrophage colony stimulating factor (GM-CSF), a cytokine influencing the encephalitogenicity of Th17 cells. Neither the production of the cytokine interleukin (IL)-17 nor the proliferation rate of T cells was affected by the EPE peptide. The in vivo effects of ERK inhibition were challenged in two independent variants of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Overall, ERK inhibition had only a very minor impact on the clinical disease course of EAE. This indicates that while ERK translocation might promote encephalitogenicity in T cells in vitro by facilitating GM-CSF production, this effect is overcome in more complex in vivo animal models of central nervous system (CNS) autoimmunity. PMID- 28914806 TI - Comparison of Ti-Based Coatings on Silicon Nanowires for Phosphopeptide Enrichment and Their Laser Assisted Desorption/Ionization Mass Spectrometry Detection. AB - We created different TiO2-based coatings on silicon nanowires (SiNWs) by using either thermal metallization or atomic layer deposition (ALD). The fabricated surfaces were characterized by X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectroscopy (EDX), and reflectivity measurements. Surfaces with different TiO2 based coating thicknesses were then used for phosphopeptide enrichment and subsequent detection by laser desorption/ionization mass spectrometry (LDI-MS). Results showed that the best enrichment and LDI-MS detection were obtained using the silicon nanowires covered with 10 nm of oxidized Ti deposited by means of thermal evaporation. This sample was also able to perform phosphopeptide enrichment and MS detection from serum. PMID- 28914805 TI - A Recombinant HAV Expressing a Neutralization Epitope of HEV Induces Immune Response against HAV and HEV in Mice. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) are causative agents of acute viral hepatitis transmitted via the fecal-oral route. Both viruses place a heavy burden on the public health and economy of developing countries. To test the possibility that HAV could be used as an expression vector for the development of a combination vaccine against hepatitis A and E infections, recombinant HAV HEp148 was created as a vector to express an HEV neutralization epitope (HEp148) located at aa 459-606 of the HEV capsid protein. The recombinant virus expressed the HEp148 protein in a partially dimerized state in HAV-susceptible cells. Immunization with the HAV-HEp148 virus induced a strong HAV- and HEV-specific immune response in mice. Thus, the present study demonstrates a novel approach to the development of a combined hepatitis A and E vaccine. PMID- 28914807 TI - Development, Optimization and In Vitro/In Vivo Characterization of Collagen Dextran Spongious Wound Dressings Loaded with Flufenamic Acid. AB - The aim of this study was the development and optimization of some topical collagen-dextran sponges with flufenamic acid, designed to be potential dressings for burn wounds healing. The sponges were obtained by lyophilization of hydrogels based on type I fibrillar collagen gel extracted from calf hide, dextran and flufenamic acid, crosslinked and un-crosslinked, and designed according to a 3 factor, 3-level Box-Behnken experimental design. The sponges showed good fluid uptake ability quantified by a high swelling ratio. The flufenamic acid release profiles from sponges presented two stages-burst effect resulting in a rapid inflammation reduction, and gradual delivery ensuring the anti-inflammatory effect over a longer burn healing period. The resistance to enzymatic degradation was monitored through a weight loss parameter. The optimization of the sponge formulations was performed based on an experimental design technique combined with response surface methodology, followed by the Taguchi approach to select those formulations that are the least affected by the noise factors. The treatment of experimentally induced burns on animals with selected sponges accelerated the wound healing process and promoted a faster regeneration of the affected epithelial tissues compared to the control group. The results generated by the complex sponge characterization indicate that these formulations could be successfully used for burn dressing applications. PMID- 28914808 TI - Structural and Dynamics Perspectives on the Binding of Substrate and Inhibitors in Mycobacterium tuberculosis DHFR. AB - Dihydrofolate reductase (DHFR), an essential enzyme in the folate pathway, is a potential target for new anti-tuberculosis drugs. Fifteen crystal structures of Mycobacterium tuberculosis DHFR complexed with NADPH and various inhibitors are available in the RCSB Protein Data Bank, but none of them is a substrate binding structure. Therefore, we performed molecular dynamics simulations on ternary complexes of M. tuberculosis DHFR:NADPH with a substrate (dihydrofolate) and each of three competitive inhibitors the in 2,4-diaminopyrimidine series (P1, P157, and P169), in order to gain insight into the inhibition-mechanism of DHFR in the folate pathway. The binding energy and thermodynamics values of each system were calculated by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method. The dynamics of the enzyme and the motion of each amino acid residue at the active site were examined. The key factors that promote the binding of P157 and P169 on M. tuberculosis DHFR (mtbDHFR) reveal opportunities for using these compounds as novel anti-tuberculosis drugs. PMID- 28914809 TI - Perception of Radiation Risk as a Predictor of Mid-Term Mental Health after a Nuclear Disaster: The Fukushima Health Management Survey. AB - Predictive factors including risk perception for mid-term mental health after a nuclear disaster remain unknown. The purpose of this study was to examine the association between perceived radiation risk and other factors at baseline and mid-term mental health after the Fukushima Daiichi nuclear disaster of 2011 in Japan. A mail-based questionnaire survey was conducted in January 2012 and January 2013. Mental health status was assessed using the K6 scale. Psychological distress over the 2-year period was categorized into the following four groups: chronic, recovered, resistant, or worsened. Most participants (80.3%) were resistant to the disaster. A positive association was found between the radiation risk perception regarding immediate effects and the worsened group in women. Baseline post-traumatic stress disorder (PTSD) or a history of psychiatric disease predicted being in the chronic or worsened group in mid-term course. These results suggest that evacuees who believed that their health was substantially affected by the nuclear disaster were at an increased risk of having poor mid-term mental health in women. Careful assessment of risk perception after a nuclear disaster, including the presence of PTSD or a history of psychiatric disease, is needed for appropriate interventions. PMID- 28914810 TI - An NMR-Based Metabolomic Approach to Unravel the Preventive Effect of Water Soluble Extract from Dendrobium officinale Kimura & Migo on Streptozotocin Induced Diabetes in Mice. AB - Dendrobium officinale Kimura & Migo (D. officinale) is a precious herbal medicine. In this study, we investigated metabolic mechanism underlying the effect of D. officinale water extract (DOWE) on diabetes prevention in mice after streptozotocin (STZ) exposure using NMR-based metabolomics. Interestingly, we found a decrease in blood glucose and an increase in liver glycogen in mice pretreated with DOWE after STZ exposure. The DOWE pretreatment significantly increased citrate and glutamine in the serum as well as creatine, alanine, leucine, isoleucine, valine, glutamine, glutathione and taurine in the liver of STZ-treated mice. Furthermore, serum glucose was significantly negatively correlated with citrate, pyruvate, alanine, isoleucine, histidine and glutamine in the serum as well as alanine and taurine in the liver. These findings suggest that the effect of DOWE on diabetes prevention may be linked to increases in liver glycogen and taurine as well as the up-regulation of energy and amino acid metabolism. PMID- 28914811 TI - Leptolide Improves Insulin Resistance in Diet-Induced Obese Mice. AB - Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in mice. Considering the beneficial effects of leptolide in diabetic mice, in this study, we aimed to address the capability of leptolide to improve insulin resistance associated with the pathology of obesity. To this end, we tested the hypothesis that leptolide should protect against fatty acid-induced insulin resistance in hepatocytes. In a time-dependent manner, leptolide (0.1 uM) augmented insulin-stimulated phosphorylation of protein kinase B (PKB) by two-fold above vehicle-treated HepG2 cells. In addition, leptolide (0.1 uM) counteracted palmitate-induced insulin resistance by augmenting by four fold insulin-stimulated phosphorylation of PKB in HepG2 cells. In vivo, acute intraperitoneal administration of leptolide (0.1 mg/kg and 1 mg/kg) improved glucose tolerance and insulin sensitivity in lean mice. Likewise, prolonged leptolide treatment (0.1 mg/kg) in diet-induced obese mice improved insulin sensitivity. These effects were paralleled with an ~50% increased of insulin stimulated phosphorylation of PKB in liver and skeletal muscle and reduced circulating pro-inflammatory cytokines in obese mice. We concluded that leptolide significantly improves insulin sensitivity in vitro and in obese mice, suggesting that leptolide may be another potential treatment for T2DM. PMID- 28914812 TI - Probing Gas Adsorption in Zeolites by Variable-Temperature IR Spectroscopy: An Overview of Current Research. AB - The current state of the art in the application of variable-temperature IR (VTIR) spectroscopy to the study of (i) adsorption sites in zeolites, including dual cation sites; (ii) the structure of adsorption complexes and (iii) gas-solid interaction energy is reviewed. The main focus is placed on the potential use of zeolites for gas separation, purification and transport, but possible extension to the field of heterogeneous catalysis is also envisaged. A critical comparison with classical IR spectroscopy and adsorption calorimetry shows that the main merits of VTIR spectroscopy are (i) its ability to provide simultaneously the spectroscopic signature of the adsorption complex and the standard enthalpy change involved in the adsorption process; and (ii) the enhanced potential of VTIR to be site specific in favorable cases. PMID- 28914815 TI - A Systematic Review: Family Support Integrated with Diabetes Self-Management among Uncontrolled Type II Diabetes Mellitus Patients. AB - The rate of type-2 diabetes mellitus (T2D) is dramatically increasing worldwide. Continuing diabetes mellitus (DM) care needs effective self-management education and support for both patients and family members. This study aimed to review and describe the impacts of diabetes mellitus self-management education (DSME) that involve family members on patient outcomes related to patient health behaviors and perceived self-efficacy on self-management such as medication adherence, blood glucose monitoring, diet and exercise changes, health outcomes including psychological well-being and self-efficacy, and physiological markers including body mass index, level of blood pressure, cholesterol level and glycemic control. Three databases, PubMed, CINAHL, and Scopus were reviewed for relevant articles. The search terms were "type 2 diabetes," "self-management," "diabetes self management education (DSME)," "family support," "social support," and "uncontrolled glycaemia." Joanna Briggs Institute (JBI) guidelines were used to determine which studies to include in the review. Details of the family support components of DSME intervention and the impacts of these interventions had on improving the health outcomes patients with uncontrolled glycaemia patients. A total of 22 intervention studies were identified. These studies involved different DSME strategies, different components of family support provided, and different health outcomes to be measured among T2D patients. Overall, family support had a positive impact on healthy diet, increased perceived support, higher self-efficacy, improved psychological well-being and better glycemic control. This systematic review found evidence that DSME with family support improved self-management behaviors and health outcomes among uncontrolled glycaemia T2D patients. The findings suggest DSME models that include family engagement can be a useful direction for improving diabetes care. PMID- 28914816 TI - Energy-Saving Traffic Scheduling in Hybrid Software Defined Wireless Rechargeable Sensor Networks. AB - Software Defined Wireless Rechargeable Sensor Networks (SDWRSNs) are an inexorable trend for Wireless Sensor Networks (WSNs), including Wireless Rechargeable Sensor Network (WRSNs). However, the traditional network devices cannot be completely substituted in the short term. Hybrid SDWRSNs, where software defined devices and traditional devices coexist, will last for a long time. Hybrid SDWRSNs bring new challenges as well as opportunities for energy saving issues, which is still a key problem considering that the wireless chargers are also exhaustible, especially in some rigid environment out of the main supply. Numerous energy saving schemes for WSNs, or even some works for WRSNs, are no longer suitable for the new features of hybrid SDWRSNs. To solve this problem, this paper puts forward an Energy-saving Traffic Scheduling (ETS) algorithm. The ETS algorithm adequately considers the new characters in hybrid SDWRSNs, and takes advantage of the Software Defined Networking (SDN) controller's direct control ability on SDN nodes and indirect control ability on normal nodes. The simulation results show that, comparing with traditional Minimum Transmission Energy (MTE) protocol, ETS can substantially improve the energy efficiency in hybrid SDWRSNs for up to 20-40% while ensuring feasible data delay. PMID- 28914814 TI - Zearalenone (ZEN) and Its Influence on Regulation of Gene Expression in Carp (Cyprinus carpio L.) Liver Tissue. AB - Zearalenone (ZEN) is a frequently-occurring mycotoxin in both animal and fish feeds. In order to characterize its effects on carp, three groups of fish were fed for 28 days with feeds contaminated with three different levels of ZEN (low: 332 ug kg-1, medium: 621 ug kg-1, and high: 797 ug kg-1 feed). The reversibility of the effects of ZEN was assessed by feeding all of the groups with uncontaminated feed for a further 14 days. Gene expression of immune genes in the liver tissue of the fish was analysed, revealing reduced expressions of immune, antioxidative, and estrogen-related genes after the fish had been exposed to ZEN. However, the expression of vacuole-type H+ ATPase increased substantially with ZEN exposure, thus supporting the previously-reported sensitivity of lysosomal functions to ZEN. Feeding the fish with a ZEN-free diet for a further two weeks changed the effects of ZEN on the expression of some genes, including the expressions of the cytokines IL-1beta, IL-8, IL-10, and arginase 2, which were not influenced after four weeks of treatment, but showed lower values after the recovery phase in fish previously treated with ZEN compared with the control group. In summary, this study confirmed the broad effects of ZEN on different essential functions in carp and suggests that the current maximum allowable levels in compound feed are too high to prevent damage to fish. PMID- 28914813 TI - Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis. AB - Human lactoferrin (hLf), an iron-binding multifunctional cationic glycoprotein secreted by exocrine glands and by neutrophils, is a key element of host defenses. HLf and bovine Lf (bLf), possessing high sequence homology and identical functions, inhibit bacterial growth and biofilm dependently from iron binding ability while, independently, bacterial adhesion to and the entry into cells. In infected/inflamed host cells, bLf exerts an anti-inflammatory activity against interleukin-6 (IL-6), thus up-regulating ferroportin (Fpn) and transferrin receptor 1 (TfR1) and down-regulating ferritin (Ftn), pivotal actors of iron and inflammatory homeostasis (IIH). Consequently, bLf inhibits intracellular iron overload, an unsafe condition enhancing in vivo susceptibility to infections, as well as anemia of inflammation (AI), re-establishing IIH. In pregnant women, affected by AI, bLf oral administration decreases IL-6 and increases hematological parameters. This surprising effect is unrelated to iron supplementation by bLf (80 MUg instead of 1-2 mg/day), but to its role on IIH. AI is unrelated to the lack of iron, but to iron delocalization: cellular/tissue overload and blood deficiency. BLf cures AI by restoring iron from cells to blood through Fpn up-expression. Indeed, anti-inflammatory activity of oral and intravaginal bLf prevents preterm delivery. Promising bLf treatments can prevent/cure transitory inflammation/anemia/oral pathologies in athletes. PMID- 28914818 TI - Optimal Energy Efficiency Fairness of Nodes in Wireless Powered Communication Networks. AB - In wireless powered communication networks (WPCNs), it is essential to research energy efficiency fairness in order to evaluate the balance of nodes for receiving information and harvesting energy. In this paper, we propose an efficient iterative algorithm for optimal energy efficiency proportional fairness in WPCN. The main idea is to use stochastic geometry to derive the mean proportionally fairness utility function with respect to user association probability and receive threshold. Subsequently, we prove that the relaxed proportionally fairness utility function is a concave function for user association probability and receive threshold, respectively. At the same time, a sub-optimal algorithm by exploiting alternating optimization approach is proposed. Through numerical simulations, we demonstrate that our sub-optimal algorithm can obtain a result close to optimal energy efficiency proportional fairness with significant reduction of computational complexity. PMID- 28914817 TI - LEDGF/p75 Deficiency Increases Deletions at the HIV-1 cDNA Ends. AB - Processing of unintegrated linear HIV-1 cDNA by the host DNA repair system results in its degradation and/or circularization. As a consequence, deficient viral cDNA integration generally leads to an increase in the levels of HIV-1 cDNA circles containing one or two long terminal repeats (LTRs). Intriguingly, impaired HIV-1 integration in LEDGF/p75-deficient cells does not result in a correspondent increase in viral cDNA circles. We postulate that increased degradation of unintegrated linear viral cDNA in cells lacking the lens epithelium-derived growth factor (LEDGF/p75) account for this inconsistency. To evaluate this hypothesis, we characterized the nucleotide sequence spanning 2-LTR junctions isolated from LEDGF/p75-deficient and control cells. LEDGF/p75 deficiency resulted in a significant increase in the frequency of 2-LTRs harboring large deletions. Of note, these deletions were dependent on the 3' processing activity of integrase and were not originated by aberrant reverse transcription. Our findings suggest a novel role of LEDGF/p75 in protecting the unintegrated 3' processed linear HIV-1 cDNA from exonucleolytic degradation. PMID- 28914819 TI - Construction of Hierarchical CuO/Cu2O@NiCo2S4 Nanowire Arrays on Copper Foam for High Performance Supercapacitor Electrodes. AB - Hierarchical copper oxide @ ternary nickel cobalt sulfide (CuO/Cu2O@NiCo2S4) core shell nanowire arrays on Cu foam have been successfully constructed by a facile two-step strategy. Vertically aligned CuO/Cu2O nanowire arrays are firstly grown on Cu foam by one-step thermal oxidation of Cu foam, followed by electrodeposition of NiCo2S4 nanosheets on the surface of CuO/Cu2O nanowires to form the CuO/Cu2O@NiCo2S4 core-shell nanostructures. Structural and morphological characterizations indicate that the average thickness of the NiCo2S4 nanosheets is ~20 nm and the diameter of CuO/Cu2O core is ~50 nm. Electrochemical properties of the hierarchical composites as integrated binder-free electrodes for supercapacitor were evaluated by various electrochemical methods. The hierarchical composite electrodes could achieve ultrahigh specific capacitance of 3.186 F cm-2 at 10 mA cm-2, good rate capability (82.06% capacitance retention at the current density from 2 to 50 mA cm-2) and excellent cycling stability, with capacitance retention of 96.73% after 2000 cycles at 10 mA cm-2. These results demonstrate the significance of optimized design and fabrication of electrode materials with more sufficient electrolyte-electrode interface, robust structural integrity and fast ion/electron transfer. PMID- 28914820 TI - Indoor Positioning System Based on a PSD Detector, Precise Positioning of Agents in Motion Using AoA Techniques. AB - Here, we present an indoor positioning system (IPS) for detecting mobile agents based on a single Position Sensitive Device sensor (PSD) sited in the environment and InfraRed Emitter Diode (IRED) located on mobile agents. The main goal of the work is to develop an alternative IPS to other sensing technologies, cheaper, easier to install and with a low computational load to obtain a high rate of measurements per second. The proposed IPS has the capacity to accurately determine 3D position from the angle of arrival (AoA) of the signal received at the PSD sensor. In this first approach to the method, the agents are considered to move along a plane. We propose two alternatives for determining position: in one, tones are emitted on a frequency unique to each transmitter, while in the other, sequences are emitted.The paper proposes and set up a very simple and easy to deploy system capable of performing 3D positioning with a single analog sensor, obtaining a high accurate positioning and a reduced execution time for the signal processing. The low computational load of the IPS makes it possible to obtain a very high position update rate (more than 100 times per second), yielding millimetric accuracies. PMID- 28914821 TI - Biocompatibility of Titania Nanotube Coatings Enriched with Silver Nanograins by Chemical Vapor Deposition. AB - Bioactivity investigations of titania nanotube (TNT) coatings enriched with silver nanograins (TNT/Ag) have been carried out. TNT/Ag nanocomposite materials were produced by combining the electrochemical anodization and chemical vapor deposition methods. Fabricated coatings were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. The release effect of silver ions from TNT/Ag composites immersed in bodily fluids, has been studied using inductively coupled plasma mass spectrometry (ICP MS). The metabolic activity assay (MTT) was applied to determine the L929 murine fibroblasts adhesion and proliferation on the surface of TNT/Ag coatings. Moreover, the results of immunoassays (using peripheral blood mononuclear cells PBMCs isolated from rats) allowed the estimation of the immunological activity of TNT/Ag surface materials. Antibacterial activity of TNT/Ag coatings with different morphological and structural features was estimated against two Staphylococcus aureus strains (ATCC 29213 and H9). The TNT/Ag nanocomposite layers produced revealed a good biocompatibility promoting the fibroblast adhesion and proliferation. A desirable anti-biofilm activity against the S. aureus reference strain was mainly noticed for these TiO2 nanotube coatings, which contain dispersed Ag nanograins deposited on their surface. PMID- 28914822 TI - Cytotoxic Evaluation of (2S)-5,7-Dihydroxy-6-prenylflavanone Derivatives Loaded PLGA Nanoparticles against MiaPaCa-2 Cells. AB - The search for new alternatives for the prevention and treatment of cancer is extremely important to minimize human mortality. Natural products are an alternative to chemical drugs, since they are a source of many potential compounds with anticancer properties. In the present study, the (2S)-5,7 dihydroxy-6-prenylflavanone (semi-systematic name), also called (2S)-5,7 dihydroxy-6-(3-methyl-2-buten-1-yl)-2-phenyl-2,3-dihydro-4H-1-Benzopyran-4-one (CAS Name registered) (1) was isolated from Eysenhardtia platycarpa leaves. This flavanone 1 was considered as the lead compound to generate new cytotoxic derivatives 1a, 1b, 1c and 1d. These compounds 1, 1a, 1b, 1c, and 1d were then loaded in nanosized drug delivery systems such as polymeric nanoparticles (NPs). Small homogeneous spherical shaped NPs were obtained. Cytotoxic activity of free compounds 1, 1a, 1b, 1c, and 1d and encapsulated in polymeric NPs (NPs1, NPs1a, NPs1b, NPs1c and NPs1d) were evaluated against the pancreatic cancer cell line MiaPaCa-2. The obtained results demonstrated that NPs1a and NPs1b exhibited optimal cytotoxicity, and an even higher improvement of the cytotoxic efficacy was exhibited with the encapsulation of 1a. Based on these results, NPs1a were proposed as promising anticancer agent candidates. PMID- 28914823 TI - Hole-Transporting Materials for Printable Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) represent undoubtedly the most significant breakthrough in photovoltaic technology since the 1970s, with an increase in their power conversion efficiency from less than 5% to over 22% in just a few years. Hole-transporting materials (HTMs) are an essential building block of PSC architectures. Currently, 2,2',7,7'-tetrakis-(N,N'-di-p-methoxyphenylamine)-9,9' spirobifluorene), better known as spiro-OMeTAD, is the most widely-used HTM to obtain high-efficiency devices. However, it is a tremendously expensive material with mediocre hole carrier mobility. To ensure wide-scale application of PSC based technologies, alternative HTMs are being proposed. Solution-processable HTMs are crucial to develop inexpensive, high-throughput and printable large-area PSCs. In this review, we present the most recent advances in the design and development of different types of HTMs, with a particular focus on mesoscopic PSCs. Finally, we outline possible future research directions for further optimization of the HTMs to achieve low-cost, stable and large-area PSCs. PMID- 28914825 TI - Effects of Pulse Parameters on Weld Microstructure and Mechanical Properties of Extra Pulse Current Aided Laser Welded 2219 Aluminum Alloy Joints. AB - In order to expand the application range of laser welding and improve weld quality, an extra pulse current was used to aid laser-welded 2219 aluminum alloy, and the effects of pulse current parameters on the weld microstructure and mechanical properties were investigated. The effect mechanisms of the pulse current interactions with the weld pool were evaluated. The results indicated that the coarse dendritic structure in the weld zone changed to a fine equiaxed structure using an extra pulse current, and the pulse parameters, including medium peak current, relatively high pulse frequency, and low pulse duty ratio benefited to improving the weld structure. The effect mechanisms of the pulse current were mainly ascribed to the magnetic pinch effect, thermal effect, and electromigration effect caused by the pulse current. The effect of the pulse parameters on the mechanical properties of welded joints were consistent with that of the weld microstructure. The tensile strength and elongation of the optimal pulse current-aided laser-welded joint increased by 16.4% and 105%, respectively, compared with autogenous laser welding. PMID- 28914824 TI - Use of Principal Components Analysis and Kriging to Predict Groundwater-Sourced Rural Drinking Water Quality in Saskatchewan. AB - Groundwater drinking water supply surveillance data were accessed to summarize water quality delivered as public and private water supplies in southern Saskatchewan as part of an exposure assessment for epidemiologic analyses of associations between water quality and type 2 diabetes or cardiovascular disease. Arsenic in drinking water has been linked to a variety of chronic diseases and previous studies have identified multiple wells with arsenic above the drinking water standard of 0.01 mg/L; therefore, arsenic concentrations were of specific interest. Principal components analysis was applied to obtain principal component (PC) scores to summarize mixtures of correlated parameters identified as health standards and those identified as aesthetic objectives in the Saskatchewan Drinking Water Quality Standards and Objective. Ordinary, universal, and empirical Bayesian kriging were used to interpolate arsenic concentrations and PC scores in southern Saskatchewan, and the results were compared. Empirical Bayesian kriging performed best across all analyses, based on having the greatest number of variables for which the root mean square error was lowest. While all of the kriging methods appeared to underestimate high values of arsenic and PC scores, empirical Bayesian kriging was chosen to summarize large scale geographic trends in groundwater-sourced drinking water quality and assess exposure to mixtures of trace metals and ions. PMID- 28914826 TI - Pulmonary alveolar proteinosis: a case report. AB - INTRODUCTION: Pulmonary alveolar proteinosis is a rare, diffuse interstitial lung disease, characterized by alveolar obstruction due to the accumulation of pulmonary surfactant. CLINICAL PRESENTATION: A 30-year-old male with progressively worsening dyspnea and non-productive cough for one year. He was a sugar cane plantation worker and had prior recurrent respiratory infections. Physical exam revealed cyanosis, and bilateral coarse and fine rales. Chest computed tomography showed diffuse crazy paving pattern. Bronchoscopy with bronchoalveolar lavage yielded a foamy, thick whitish material. Cytology revealed lymphocytes and acellular proteinaceous eosinophilic material. Transbronchial biopsy confirmed the diagnosis of pulmonary alveolar proteinosis. Patient met criteria for whole lung lavage, responding favorably to this therapy. CONCLUSION: Pulmonary alveolar proteinosis is a rare lung disease and important to consider due to the diagnostic and therapeutic challenge it represents. PMID- 28914827 TI - [Endovascular surgery for critical ischemia of lower extremities with suppurative necrotic lesion of the feet]. AB - AIM: To improve treatment of patients with grade IV chronic ischemia of lower extremities via endovascular angioplasty combined with surgical methods for suppurative-necrotic lesions of the feet. MATERIAL AND METHODS: 51 patients with grade IV chronic ischemia of lower extremities underwent endovascular interventions (balloon angioplasty, stenting). A total of 23 stents were deployed in 16 patients including 12 stents in superficial and common femoral arteries, 5 in popliteal artery, 6 in iliac artery. There were no stents in crural arteries. The most perspective artery for wound healing was preferred in case of revascularization below popliteal segment. Necrectomy was performed along with angioplasty in patients with suppurative-necrotic lesion of the feet followed by delayed reconstructive operations if it was necessary. RESULTS: Endovascular surgery for grade IV chronic ischemia of lower extremities was associated with good immediate results in most cases due to revascularization and organ-sparing interventions for suppurative lesions of the feet. Current endovascular methods allow to perform successful re-operations to restore blood flow in previously repaired arteries and implanted stents with restenosis or thrombosis. PMID- 28914828 TI - [The results of profundoplasty in patients with critical ischemia of lower extremities]. PMID- 28914829 TI - [Circular tracheal resection for cicatrical stenosis and functioning tracheostomy]. AB - AIM: To analyze the results of tracheal resection for cicatricial stenosis depending on the presence of tracheostomy. MATERIAL AND METHODS: 1128 patients with tracheal cicatricial stenosis were treated for the period 1963-2015. The first group consisted of 297 patients for the period 1963-2000, the second group 831 patients for the period 2001-2015. Most of them 684 (60.6%) were young and able-bodied (age from 21 to 50 years). In the first group 139 (46.8%) out of 297 patients had functioning tracheostomy. For the period 2001-2015 tracheostomy was made in 430 (51.7%) out of 831 patients with cicatricial stenosis. Time of cannulation varied from a few weeks to 21 years. RESULTS: Re-tracheostomy within various terms after decanulation was performed in 68 (15.8%) patients. Tracheal resection with anastomosis was performed in 59 and 330 in both groups respectively. At present time these operations are performed more often in view of their standard fashion in everyday practice. In the second group tracheal resection followed by anastomosis was observed in 110 (25.6%) out of 430 patients with tracheostomy that is 4.4 times more often than in previous years. In total 2 patients died after 330 circular tracheal resections within 2001-2015 including one patient with and one patient without tracheostomy. Mortality was 0.6%. Moreover, this value was slightly higher in patients operated with a functioning tracheostomy compared with those without it - 0.9 vs. 0.5% respectively. The causes of death were bleeding into tracheobronchial lumen and pulmonary embolism. The source of bleeding after tracheal resection was innominate artery. Overall incidence of postoperative complications was 2 times higher in tracheostomy patients compared with those without it - 22 (20%) vs. 26 (11.8%) cases respectively. Convalescence may be achieved in 89.8% patients after circular tracheal resection. Adverse long-term results are associated with postoperative complications. So their prevention and treatment will improve the outcomes. PMID- 28914830 TI - [Combined forecasting system of peritonitis outcome]. AB - AIM: To create a reliable system for assessing of severity and prediction of the outcome of peritonitis. MATERIAL AND METHODS: Critical analysis of the systems for peritonitis severity assessment is presented. The study included outcomes of 347 patients who admitted at the Department of Faculty Surgery of Peoples' Friendship University of Russia in 2015-2016. The cause of peritonitis were destructive forms of acute appendicitis, cholecystitis, perforated gastroduodenal ulcer, various perforation of small and large intestines (including tumor). RESULTS: Combined forecasting system for peritonitis severity assessment is created. The system includes clinical, laboratory data, assessment of systemic inflammatory response (SIRS) and severity of organ failure (qSOFA). The authors focused on easily identifiable parameters which are available in virtually any surgical hospital. Threshold value (lethal outcome probability over 50%) is 8 scores in this system. Sensitivity, specificity and accuracy were 93.3, 99.7 and 98.9%, respectively according to ROC-curve that exceeds those parameters of MPI and APACHE II. PMID- 28914831 TI - [Technical features of laparoscopic cholecystectomy in patients with overweight and obesity]. AB - AIM: To improve surgical treatment of patients with cholelithiasis and obesity by using of different technologies of laparoscopic cholecystectomy. MATERIAL AND METHODS: There were 88 (16.4%) patients with overweight and obesity among 538 patients who underwent laparoscopic cholecystectomy. Conventional laparoscopic cholecystectomy was performed in 33 (6.1%) cases, cholecystectomy through single laparoscopic access - in 12 (2.3%), cholecystectomy via single laparoscopic access with trocar support - in 43 (8.0%) patients with body mass index 25-52.3 kg/m2. The article describes the technical features of laparoscopic cholecystectomy. RESULTS: Complications were absent in 83 (94.3%) of 88 cases after laparoscopic cholecystectomy. The lowest pain severity in early postoperative period was noted in case of single laparoscopic access (p<0.05). CONCLUSION: Conventional and single-port laparoscopic cholecystectomy is advisable in patients with calculous cholecystitis, overweight and obesity. PMID- 28914832 TI - [Enteroenterostomy in surgical treatment of malignant colonic obstruction]. AB - AIM: To consider surgical tactics and to study the immediate results of primary enteroenterostomy in surgical treatment of malignant colonic obstruction. MATERIAL AND METHODS: Radical surgery was performed in 170 (63.9%) out of 266 patients with malignant obstructive colonic obstruction. Colonic resection followed by anastomosis was performed in 68 patients. Conventional hemicolectomy (9 patients) and various original techniques of Y-shaped ileotransversanastomoses (27 patients) were used for right-sided tumor process. In case of left-sided tumor we used intraoperative colonic irrigation with enterosorption (20 operations), Y-shaped anastomoses (9 operations) and subtotal colectomy (3 operations). RESULTS: There was significantly increased mortality in patients with sub- and decompensated stages of malignant colonic obstruction. Postoperative mortality after radical surgery was 10.6%, after palliative interventions - 21.9%. There was similar postoperative mortality after various types of radical interventions with/without enteroenterostomy (8.8% and 11.8%, respectively). CONCLUSION: In favorable clinical situation radical surgery with tumor removal at the first emergency stage should be preferred for malignant colonic obstruction. At the specialized hospital segmental colonic resection with primary anastomosis is possible after comprehensive assessment of surgical risk, intraoperative colonic irrigation is obligatory for left-sided tumor. This approach increases surgical effectiveness and provides early rehabilitation. PMID- 28914833 TI - [Endoscopic interventions in patients with colorectal cancer: the effect of comorbidities]. AB - AIM: To evaluate endoscopic technologies in treatment of patients with colorectal cancer and severe comorbidities. MATERIAL AND METHODS: Two groups of patients after endoscopic (group 1, n = 58) and open (group 2, n = 40) surgery were assessed. RESULTS: Comorbidities were observed in 90.7% patients in group 1 and 83.3% patients in group 2 (p > 0.05). Mean comorbidity index was 6.9+/-0.3 (2-14) and 7.1+/-0.7 (2-18) in both groups respectively. Comorbidities ASA grade 3-4 were observed in 88.2% patients of group 1 had and in 71.4% patients of group 2 (p > 0.05). One patient of group 1 with intra-abdominal bleeding required conversion of surgical approach. In another case the conversion was due to technical difficulties during intestinal resection. Postoperative complications were noted in 2 patients (3.4%). There were no intraoperative complications in group 2. Postoperative complications were observed in two cases (5.0%). CONCLUSION: Severe comorbidities do not impose serious restrictions on the choice of endoscopic approach in colorectal cancer patients. PMID- 28914834 TI - [Plasma management in complex treatment of late inflammatory complications after injection contour plasty with polyacrylamide gel]. AB - AIM: To improve the results of treatment of late inflammatory complications after injection contour plasty with polyacrylamide gel. MATERIAL AND METHODS: The authors analyze treatment of 21 patients with late septic complications of body contour plasty with polyacrylamide gel (PAGE) for the period 2010-2015. Mean age of women was 47.4 years. Time after primary intervention was 10-22 years. The depth of soft tissue lesion corresponded to II-III grade by D. Ahrenholz classification (1991), length - from 67 to 180 cm2. Mammary glands were the most common area of augmentation (18 cases). Besides antibiotic therapy and surgery complex treatment included exposure with plasma flows in various modes. RESULTS: Plasma technology significantly accelerated regenerative processes and provided stable microbial decontamination in 100% patients. High-energy vaporization was associated with maximum possible removal of PAGE from the tissues that was confirmed by histological examination. PMID- 28914835 TI - [Surgical treatment of pain syndrome in lumbar spine in patients with obesity]. AB - AIM: To analyze the reduction of pain severity, time of surgery, intraoperative blood loss, incidence of unintentional lesion of dura mater, infectious complications and hospital-stay after lumbar microdiscectomy. MATERIAL AND METHODS: The study included 104 patients aged 24-58 years (37 men and 67 women, mean age 45 years) who underwent lumbar microdiscectomy within January 2015 - June 2016. The main and control groups consisted of 48 and 56 patients with and without obesity respectively. In all cases lumbar microdiscectomy was made. Pain syndrome was assessed by visual analogue scale and Oswestry questionnaire. RESULTS: In 6 weeks, 6 and 12 months after surgery significant improvement of both lumbar and leg pain was observed. Significantly reduced pain was stable and similar in both groups within follow-up although there was a tendency to increased pain in long-term period in group 1. Blood loss and infections were slightly higher in obese group while surgery time and hospital-stay were significantly higher in these patients. CONCLUSION: Features of patients with excessive body weight should be considered prior to elective surgery. Probably, implants are advisable to stabilize spinal motion segment and improve the outcomes among patients with excessive body weight. PMID- 28914836 TI - [Preclinical tests of additive materials for personified endoprostheses of hand joints]. AB - AIM: To evaluate the biocompatibility of additive materials for personified endoprostheses of hand joints in vivo. MATERIAL AND METHODS: We tested a material based on titanium that was implanted into muscles and bone tissue in experiment on rabbits. Follow-up was 30 and 90 days. RESULTS: Implantation into muscle tissue is accompanied by reaction against foreign body followed by fibrosis without concomitant inflammation. Induction of osteogenesis and trabecular structures remodeling were detected after implantation into bone tissue. CONCLUSION: Biocompatibility of tested titanium-based material was confirmed. PMID- 28914838 TI - [Native collagen application in clinical practice for chronic wounds treatment]. PMID- 28914837 TI - [Our experience in treating children with acute destructive pancreatitis]. PMID- 28914839 TI - [Off-pump left ventricular reconstruction for giant aneurysm in patient with low myocardial capacity]. PMID- 28914841 TI - [Surgical treatment of patient with intra-abdominal malignant schwannoma]. PMID- 28914840 TI - [Transanal total mesorectumectomy with D3-lymphodissection through a single laparoscopic approach]. PMID- 28914842 TI - [Chronic duodenal obstruction due to high fixation of duodenojejunal transition and adhesive peritoneal disease]. PMID- 28914843 TI - [Colonic malformations as a cause of acute intestinal obstruction]. PMID- 28914844 TI - [Molecular genetic predictors of resistance to anti-Helicobacter pylori therapy]. AB - In current clinical practice, there is no optimal empirical therapy for Helicobacter pylori (H. pylori) infection and there is a progressive decrease in the efficiency of classical eradication therapy (ET) regimens. The variability in the efficiency of ET in a specific patient is largely due to the heterogeneous molecular genetic mechanisms underlying the resistance of the microorganism to the components of the treatment regimens. The basis of the mechanisms for antibiotic resistance in H. pylori is mainly the point mutations in some genes, which determine alterations in the mechanisms of action of drugs, such as clarithromycin (domain V of 23S rRNA), metronidazole (rdxA, frxA), amoxicillin (pbp1A), tetracycline (16S rRNA), and levofloxacin (gyrA). The predictors of resistance to ET are also the CagA-negative status of the microorganism and the presence of the vacA s2 allele. There are a number of host genetic determinants (the CYP2C19 genotype (*1/*1, *1/*17, *17/*17) and the MDR1 3435 T/T genotype (in an Asian population)) that reduce the efficiency of ET, by altering the pharmacokinetics of proton pump inhibitors. In addition, the IL-1beta-511 C/C polymorphism that affects gastric acid secretion is a predictor of the inefficiency of ET. PMID- 28914845 TI - [Allergic bronchopulmonary aspergillosis in patients with asthma: Results of a prospective study]. AB - AIM: To estimate the frequency of fungal sensitization and the incidence of allergic bronchopulmonary aspergillosis (ABPA) in asthmatic patients. SUBJECTS AND METHODS: A total of 140 asthmatic patients were examined. They underwent allergologic (skin tests for fungal allergens, estimation of total and fungal allergen-specific IgE levels) and mycological (microscopy and inoculation of respiratory biosubstrates) examinations. Chest computed tomography, when indicated, was done. A group of patients with ABPA and that of patients with severe asthma and fungal sensitization were identified. RESULTS: The frequency of fungal sensitization in asthmatic patients was 36%; the main allergenic fungi were Aspergillus and Alternaria. The incidence of ABPA was as high as 4% in the patients with asthma and 11% in those with severe asthma and fungal sensitization. CONCLUSION: The given current diagnostic criteria will assist practitioners to identify ABPA, to prevent its progression, and to initiate specific anti-inflammatory and antifungal therapy in due time. PMID- 28914846 TI - [Analysis of the efficiency of antimicrobial treatment for community-acquired pneumonia in clinical practice]. AB - AIM: To analyze actual drug consumption based on the defined daily dose (DDD analysis) and to analyze the utilization of drugs based on their proportion of the total defined daily doses (DU90% analysis) for the antimicrobial therapy of community-acquired pneumonia (CAP) in clinical practice at a hospital in Russia. MATERIAL AND METHODS: The investigation materials were the data of 117 case histories of male (51.3%) and female (48.7%) patients hospitalized with CAP at Nizhny Novgorod City Clinical Hospital Five in 2015. The investigation enrolled all the patients admitted to the hospital over the analyzed period. DDD analysis and DU90% analysis were used as study methods. RESULTS: DDD analysis and DU90% analysis of antimicrobial therapy for CAP were carried out at the hospital in clinical practice during a year. The annual number of defined daily doses (NDDD) for antimicrobial drugs, the number of defined daily doses per 100 bed-days (NDDD/100 bed-days), and a drug load (g) per 1000 CAP patients per day and per CAP patient per year were determined. The largest NDDD/year for CAP treatment with ceftriaxone was 376 g, or 43.43 NDDD/100 bed-days, which is much higher than that with other antimicrobial agents. The daily drug load of ceftriaxone per 1,000 CAP patients was 8.8 g, which exceeds that of moxifloxacin by 18.7 times, azithromycin and levofloxacin by 5 times, and ampicillin/sulbactam by 2.3 times. The daily drug load of ceftriaxone per CAP patient was 3.2 g, which exceeds that of of ampicillin/sulbactam by 2.3 times, levofloxacin and azithromycin by 5 times, and moxifloxacin by 19 times. CONCLUSION: It may be recommended that the proportion of cephalosporins as drugs that promote the rise of resistance in microbes and their production of extended-spectrum beta-lactamases should be further limited, the proportion of penicillins be extended, and the administered ampicillin/sulbactam be added, for example, by amoxicillin/clavulanate. Penicillins contribute to the rise of resistance to a lesser degree, and the use of two different penicillin molecules specified in the guidelines for the treatment of CAP will be able to slow the process further. By the same reasoning, it is also advisable to use cefuroxime (second-generation cephalosporins) along with ceftriaxone in patients in stable condition, without impairing vital functions. PMID- 28914847 TI - [Efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders]. AB - AIM: To evaluate the efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders (DD). MATERIAL AND METHODS: 153 patients with uncontrolled hypertension were examined, of whom 82 patients were diagnosed with mild and moderate DD. A combination of perindopril 10 mg/day, indapamide SR 1.5 mg/day, and amlodipine at an initial dose of 5 mg/day was given to patients with hypertension and DD. After 4 weeks of treatment, if target blood pressure (BP) levels could not be achieved, the dose of amlodipine was increased up to 10 mg/day. General clinical examination and 24 hour BP monitoring (BPM) were performed in all the patients at baseline and in the patients with DD also after 24 weeks of therapy. The traditional measures of the diurnal BP profile, as well as the parameters characterizing arterial stiffness and central aortic pressure (CAP) were estimated. RESULTS: After 8 weeks of therapy, target BP levels were recorded in 63 (76.8%) patients. After 24 weeks of treatment, the hypertensive patients with DD showed significant positive changes in all the investigated 24-hour BPM parameters and normalization of the diurnal BP profile in 65.1% of cases. During the treatment, there were significant decreases in pulse wave velocity, brachial arterial and aortic augmentation indices, aortic systolic and diastolic pressures, and mean aortic BP and an increase in the velocity of the reflected wave. CONCLUSION: Triple therapy, including perindopril, indapamide SR, and amlodipine, contributed to the achievement of target BP levels in the majority of hypertensive patients with DD, with significant positive changes in all 24-hour BPM parameters, optimization of the diurnal BP profile in most patients, clinically significant improvement of the parameters that characterize arterial stiffness and CAP. PMID- 28914848 TI - [Effect of a fixed-dose combination of perindopril arginine/amlodipine on the level and variability of blood pressure according to its office visit-to-visit measurements and self-measurements at home: A subanalysis of the PREVOSHODSTVO (SUPERIORITY) program]. AB - AIM: To study the effect of a fixed-dose combination of perindopril arginine/amlodipine (prestans) on the goal levels and variability of blood pressure (BP) according to its office visit-to-visit measurements and self measurement (OVVM and SM) in a subgroup of 483 people from the population of the Russian observational SUPERIORITY program, most cases of whom are given the combination replacing the previously ineffective mono- and combination antihypertensive therapy (AHT). SUBJECTS AND METHODS: The subanalysis included data on 483 patients (34% men) aged 57.9+/-10.8 years with uncontrolled hypertension, who were both untreated and treated with antihypertensive mono- or combination therapy using a free or fixed-dose combination of 2-3 antihypertensive drugs and in whom the physicians decided to use prestans to correct AHT. The follow-up period was 24 weeks. RESULTS: At the end of the investigation, the patients received prestans in the following doses: 5/5 mg (34% of the patients), 10/5 mg (39.5%), 5/10 mg (3.9%), and 10/10 mg (22%). In the analyzed patient group, the baseline BP was 160.8+/-8.8/92.6+/-7.4 mm Hg and dropped to 125.9+/-7.9/77.8+/-5.0 mm Hg at 24 weeks (p<0.001). According to SM, the morning BP significantly decreased from 147.0+/-13.3/85.6+/-7.2 to 127.5+/ 8.3/78,9+/-5.6 mm Hg at 24 weeks (p<0.001). The evening BP readings showed the similar trends. Target BP was achieved in 93 and 78% of the patients, as shown by OVVM and SM, respectively. According to SCM, the day-to-day variability of BP significantly decreased from 5.1+/-3.2/3.4+/-2.3 Hg mm at Visit 2 to 2.7+/ 2/0/2,3+/-1/5 mm Hg at Visit 5 (p<0.001). CONCLUSION: The use of the fixed-dose combination of perindopril arginine/amlodipine in hypertensive patients just at the beginning of treatment, by switching from insufficiently effective mono- or combination AHT to the fixed-dose combination of perindopril arginine/amlodipine, is an effective way to optimize AHT in clinical practice, which lowers the BP level and variability, as evidenced by both OVVM and SM. PMID- 28914849 TI - [Analysis of the clinical efficiency of eradication therapy in patients with coronary heart disease associated with gastroduodenal pathology]. AB - AIM: To comparatively analyze the clinical efficiency of eradiation therapy (ET) in patients with coronary heart disease (CHD) concurrent with gastroduodenal pathology (GDP). SUBJECTS AND METHODS: The study was conducted in three steps. In Step 1, 1588 patients with chronic CHD were examined. In Step 2, the characteristics of the course of CHD concurrent with Helicobacter pylori associated GDP in 147 patients with these conditions compared to the same number of CHD patients without GDP. In Step 3, the impact of a GDP treatment option on the efficiency of treatment was investigated in the patients with CHD. Group 1 received ET + basic therapy (BT); Group 2 used antisecretory therapy + BT; Group 3 consisted of CHD patients without concomitant GDP who received BT only. The time course of changes in clinical and quality-of-life (QOL) indicators was assessed. RESULTS: The patients with CHD concurrent with GDP have a more severe course of the disease as manifested by deterioration in clinical status and QOL. After ET, anginal attack rates were decreased by 62.6% in Group 1, by 30.7% in Group 2 (during antisecretory therapy), and by 29.5% in Group 3. The level of physical QOL increased by 23.7% in Group 1, which was not observed in Groups 2 and 3. CONCLUSION: Inclusion of ET in an algorithm for treating CHD patients with GDP promotes the angina stability and normalizes QOL in the patients. PMID- 28914850 TI - [Correction of small bowel function as a new direction for treating patients with metabolic syndrome]. AB - AIM: To provide a rationale for and to evaluate the therapeutic efficiency of the combined use of pancreatic enzymes and actovegin in the combination therapy of patients with metabolic syndrome (MS) on the basis of comprehensive clinical and functional studies of the small bowel (SB). SUBJECTS AND METHODS: In the course of treatment, 120 patients with MS (verified using the diagnostic criteria elaborated by the All-Russian Research Society of Cardiology (2009)) underwent a comprehensive study of SB function: an isolated study of resorptive processes; evaluation of parietal and cavitary digestion, motor-evacuation function. The peripheral blood levels of gastrin, insulin, cortisol, thyroxine and thyrotropin were determined. RESULTS: The combined use of pancreatic enzymes and actovegin has a positive impact on the clinical and functional state of SB, which was manifested as restoration of its hydrolysis and absorption, as well as motor evacuation function in the patients with MS. The treatment resulted in reductions in the levels of triglycerides from 2.85+/-0.34 to 1.53+/-0.18 mmol/l (p<0.01), total cholesterol from 6.08+/-0.16 to 5.19+/-0.21 mmol/l (p<0.05), and atherogenic factor from 5.21+/-0.28 to 2.93+/-0.34 (p<0.05). Posttreatment HOMA IR decreased from 4.22+/-0.8 to 2.12+/-0.8. There were no substantial changes in insulin levels and insulin resistance index in the patients on standard therapy. CONCLUSION: The combined use of pancreatic enzymes and actovegin is pathogenetically sound in correcting SB dysfunctions and may be one of the most effective directions for the treatment of patients with MS. PMID- 28914851 TI - [Oxidative stress in women with insomnia in different stages of menopause]. AB - AIM: To investigate of a lipid peroxidation (LPO) process and the antioxidant defense system (ADS) in peri- and postmenopausal women with insomnia. SUBJECTS AND METHODS: 47 perimenopausal women and 71 postmenopausal ones were examined. Each group was divided into 2 subgroups: 1) individuals with insomnia and 2) controls. LPO-ADS spectrophotometric studies were used in the investigation. RESULTS: There was an increase in the serum levels of ketodienes and conjugated trienes and a decrease in those of alpha-tocopherol and retinol in postmenopause versus in perimenopause. In insomnia, there was a rise in the level of ketodienes and conjugated trienes in perimenopause; LPO substrates with conjugated double bonds, diene conjugates, and thiobarbituric acid-active products in postmenopause. The indicators of ADS do not differ from those in the controls. The integral indicator of oxidative stress assessment suggests that there is a LPO-ADS imbalance in the menopausal women with insomnia, which is most pronounced in postmenopause. CONCLUSION: The findings suggest that the patients with insomnia develop oxidative stress that is more marked in postmenopause. PMID- 28914852 TI - [Efficiency of immunosuppressive therapy in virus-negative and virus-positive patients with morphologically verified lymphocytic myocarditis]. AB - AIM: To evaluate the efficiency of immunosuppressive therapy (IST) in virus negative (V-) and virus-positive (V+) patients with lymphocytic myocarditis (LM). SUBJECTS AND METHODS: 60 patients (45 males) (mean age 46.7+/-11.8 years) with dilated cardiomyopathy (mean left ventricular (LV) end diastolic size (EDS) 6.7+/ 0.7 cm; ejection fraction (EF) 26.2+/-9.1%) were examined. The diagnosis of active/borderline LM was verified by right ventricular endomyocardial biopsy in 38 patients, by intraoperative LV biopsy in 10, in the study of explanted hearts from 3 patients and at autopsy in 9. The investigators determined the genomes of parvovirus B19, herpes viruses types 1, 2 and 6, Epstein-Barr (EBV), zoster, and cytomegalovirus in the blood and myocardium and, if antibodies were present in the blood, hepatitis B and C viruses, as well as antibodies against antigens in the endothelium, cardiomyocytes and their nuclei, smooth muscles, fibers of the conducting system. IST was used in terms of histological, immune, and viral activities. IST was performed in 22 V+ patients (Group 1) and in 24 V- patients (Group 2); this was not done in 10 V+ patients (Group 3) and V- patients (Group 4). IST comprised methylprednisolone at a mean dose of 24 mg/day (n=40), hydroxychloroquine 200 mg/day (n=20), azathioprine at a mean dose of 150 mg/day (n=21); antiviral therapy included acyclovir, ganciclovir, intravenous immunoglobulin (n=24). The follow-up period was 19 (7.3-40.3) months. RESULTS: The viral genome was detected in the myocardium of 32 patients who made up a V+ group. The degree of histological activity did not differ in relation to the presence of viral genome in the myocardium. The degree of immune activity (anticardiolipin antibody titers) in the V+ patients was as high as that in V- ones. At baseline, the V+ patients had a significantly higher LV EDS and a lower EF than the V- patients. Overall, IST only could lead to a significant increase in EF (from 26.5+/-0.9 to 36.0+/-10.8%; p<0.001) and reductions in NYHA functional class from III to II (p<0.001), LV EDS (from 6.7+/-0.7 to 6.4+/-0.8 cm; p<0.01), pulmonary artery systolic pressure (from 48.9+/-15.5 to 39.4+/-11.5 mm Hg (p<0.01); the IST group had significantly lower mortality rates than the non-IST group (23.9 and 64.3%; p<0.01). At the same time, a significant trend was seen in both V- and V+ patients. The mortality rate in the V+ patients, as a whole, was higher (46.9 and 17.9%; p<0.05). CONCLUSION: IST leads to a significant improvement of functional indices and it is associated with lower mortality rates in both myocardial V- and V+ patients with LM. A more than 10% EF increase in the first 2 months is associated with a good prognosis. The presence of viral genome in the myocardium (primarily herpesviruses rather than parvovirus 19) is accompanied by more severe initial dysfunction, a less pronounced effect of IST, and higher mortality rates. However, the positive effect of IST also persists in V+ patients. No positive changes (a decrease in EF was observed) were absent only in IST-naive V+ patients. PMID- 28914853 TI - [Uromodulin gene polymorphisms in patients with cast nephropathy in multiple myeloma]. AB - AIM: To investigate the nature of mutations in exons 4 and 5 of the uromodulin (UM) gene, including in the area encoding the domain of 8 cysteines (D8C), in patients with multiple myeloma (MM) with the secretion of monoclonal light chains (LC) in cast nephropathy (CN) and without kidney injury. SUBJECTS AND METHODS: The investigation enrolled 24 patients in MM remission, who were observed to have monoclonal LC secretion at onset. Group 1 included 14 patients with CN; Group 2 consisted of 10 patients with normal renal function (a comparison group). The compared groups did not differ in the number of serum and urinary monoclonal LCs. Genomic DNA was extracted from the peripheral blood samples of patients. The nucleotide sequence of exons 4 and 5 of the UM gene was determined by the Sanger method. RESULTS: No differences were found in the frequency of polymorphisms depending on the severity of kidney injury. The missense mutation p.142R>R/Q in the UM gene, which had not been previously described, was discovered. CONCLUSION: The patients with MM were not found to have statistically significant differences in the frequency and nature of polymorphisms of exons 4 and 5 in the UM gene, including in the area encoding D8C, in CN without kidney injury. PMID- 28914854 TI - [Giant cell arteritis: Genetic and epigenetic aspects]. AB - The paper describes clinical cases in 2 patients (brothers) with giant cell arteritis. It analyzes the genetic and epigenetic aspects of the disease. The data available in the Russian and foreign literature are given. PMID- 28914855 TI - [Late-onset rheumatoid arthritis in a patient with successfully treated IgA nephropathy]. AB - The paper describes a rare clinical case of rheumatoid arthritis (RA) that developed in a patient 9 years after diagnosing IgA nephropathy. Kidney disease was characterized by a stable course with moderate urinary syndrome, hypertension, and reduced renal function. Immunosuppressive therapy using glucocorticosteroids and then mycophenolic acid led to remission of nephritis and recovery of renal function. However, the absence of nephritis activity and discontinuation of immunosuppressants was responsible for articular syndrome. The diagnosis of RA is based on its characteristic radiological patterns and immunological characteristics after ruling out a number of systemic diseases and infections. The common pathogenetic components of IgA nephropathy and RA, including the role of rheumatoid factor IgA, are discussed. PMID- 28914856 TI - [The Russian consensus on the diagnosis and treatment of chronic pancreatitis: Enzyme replacement therapy]. AB - Pancreatology Club Professional Medical Community, 1A.S. Loginov Moscow Clinical Research and Practical Center, Moscow Healthcare Department, Moscow; 2A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow; 3Kazan State Medical University, Ministry of Health of Russia, Kazan; 4Kazan (Volga) Federal University, Kazan; 5Far Eastern State Medical University, Ministry of Health of Russia, Khabarovsk; 6Morozov City Children's Clinical Hospital, Moscow Healthcare Department, Moscow; 7I.I. Mechnikov North Western State Medical University, Ministry of Health of Russia, Saint Petersburg; 8Siberian State Medical University, Ministry of Health of Russia, Tomsk; 9M.F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow; 10Maimonides State Classical Academy, Moscow; 11V.I. Razumovsky State Medical University, Ministry of Health of Russia, Saratov; 12I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow; 13S.M. Kirov Military Medical Academy, Ministry of Defense of Russia, Saint Petersburg; 14Surgut State Medical University, Ministry of Health of Russia, Surgut; 15City Clinical Hospital Five, Moscow Healthcare Department, Moscow; 16Nizhny Novgorod Medical Academy, Ministry of Health of Russia, Nizhny Novgorod; 17Territorial Clinical Hospital Two, Ministry of Health of the Krasnodar Territory, Krasnodar; 18Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, Saint Petersburg; 19Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don; 20Omsk Medical University, Ministry of Health of Russia, Omsk; 21Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia, Moscow; 22Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk; 23Stavropol State Medical University, Ministry of Health of Russia, Stavropol; 24Kemerovo State Medical University, Ministry of Health of Russia, Kemerovo; 25N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow; 26A.M. Nikiforov All-Russian Center of Emergency and Radiation Medicine, Russian Ministry for Civil Defense, Emergencies and Elimination of Consequences of Natural Disasters, Saint Petersburg; 27Research Institute for Medical Problems of the North, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk; 28S.P. Botkin City Clinical Hospital, Moscow Healthcare Department, Moscow; 29Tver State Medical University, Ministry of Health of Russia, Tver The Russian consensus on the diagnosis and treatment of chronic pancreatitis has been prepared on the initiative of the Russian Pancreatology Club to clarify and consolidate the opinions of Russian specialists (gastroenterologists, surgeons, and pediatricians) on the most significant problems of diagnosis and treatment of chronic pancreatitis. This article continues a series of publications explaining the most significant interdisciplinary consensus statements and deals with enzyme replacement therapy. PMID- 28914857 TI - [Characteristics of lipid metabolism and the cardiovascular system in glycogenosis types I and III]. AB - Glycogen storage disease (GSD) is an inherited metabolic disorder characterized by early childhood lipid metabolic disturbances with potentially proatherogenic effects. The review outlines the characteristics of impaired lipid composition and other changes in the cardiovascular system in GSD types I and III. It analyzes the factors enabling and inhibiting the development of atherosclerosis in patients with GSD. The review describes the paradox of vascular resistance to the development of early atherosclerosis despite the proatherogenic composition of lipids in the patients of this group. PMID- 28914858 TI - [Bosentan use in pulmonary arterial hypertension: Russian and foreign experience]. AB - The results of evaluating the efficacy and safety of bosentan in patients with pulmonary arterial hypertension (PAH), as shown by the data of foreign randomized controlled trials and the authors' own experience, convincingly demonstrate that the introduction of the drug into clinical practice has led to a significant improvement of the possibilities of drug therapy in patients with this serious illness. Bosentan substantially improves physical activity in patients, reduces the severity of clinical symptoms, slows down the rates of disease progression, and prolongs survival in patients with different forms of PAH. PMID- 28914859 TI - [Depression, anxiety, and stress in patients with coronary heart disease]. AB - The analytical paper summarized the results of recent studies of an association of depression, anxiety, and stress with coronary heart disease (CHD). Mental disorders are shown to be associated with increased risk of CHD and to worsen the course of coronary disease. Antidepressants and psychotherapy improve the control of mental disorders, quality of life, and, in some cases, have a positive impact on the course of coronary disease. PMID- 28914860 TI - [New opportunities for inhaled therapy for inflammatory diseases of the respiratory system]. AB - The paper considers current approaches to mucoregulatory therapy for various inflammatory diseases of the respiratory system. It gives the advantages and disadvantages of common drugs used in their treatment. Emphasis is laid on the use of inhaled hypertonic saline of NaCl in combination with hyaluronic acid (Hyaneb). Clinical examples of its use in chronic obstructive pulmonary disease, acute and chronic bronchitis, and severe asthma are considered. PMID- 28914861 TI - [Kagocel in the therapy of influenza and acute respiratory viral infections: Data analysis and systematization from the results of preclinical and clinical trials]. AB - The article provides the summarized data of clinical trials evaluating the efficacy and safety of kagocel used to prevent and treat influenza and acute respiratory viral infections of different etiologies. The results of numerous preclinical and clinical trials suggest that the kagocel substance is highly safe and that it is appropriate to use the drug for the treatment and prevention of influenza and acute respiratory viral infections of another etiology. PMID- 28914862 TI - [Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation]. AB - The paper gives an update on the role of the gut microbiome (GM) in the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver cirrhosis (LC), and its complications, such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), and discusses the possibilities of its correction with prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The pathophysiology of the liver diseases in question demonstrates some common features that are characterized by pathogenic changes in the composition of the gastrointestinal tract microflora, by intestinal barrier impairments, by development of endotoxemia, by increased liver expression of proinflammatory factors, and by development of liver inflammation. In progressive liver disease, the above changes are more pronounced, which contributes to the development of LC, HE, and HCC. GM modulation using prebiotics, probiotics, synbiotics, antibiotics, and FMT diminishes dysbacteriosis, strengthens the intestinal mucosal barrier, reduces endotoxemia and liver damage, and positively affects the clinical manifestations of HE. Further investigations are needed, especially in humans, firstly, to assess a relationship of GM to the development of liver diseases in more detail and, secondly, to obtain evidence indicating the therapeutic efficacy of GM modulating agents in large-scale, well-designed, randomized, controlled, multicenter studies. PMID- 28914863 TI - [Chronic gastritis: Instructions for use of medications]. AB - The paper highlights the features of drug use in the legal aspect. It analyzes instructions for medical use of proton pump inhibitors (PPIs) and gastric protective agents. Taking into account the characteristics of indications registered in the instruction, the authors discuss the possibility of using various PPIs. The instruction for medical application is an official document approved by the Ministry of Health, the basis of which is the data of trials carried out by a manufacturer, and it should be a key or fundamental source for a physician in choosing a medication. The use of a drug with no indications given in the manual (the so-called 'off-label' use in foreign practice), is a clinical trial of a sort conducted by a physician individually, by taking upon himself/herself a legal liability. If arguments break out over the correct choice of this or that drug in treating the specific patient, the instruction containing the indications for use of specific medications to treat a specific disease is one of the proofs that the physician has correctly chosen the drug or a criterion for skilled medical care. The inclusion of chronic gastritis as a primary and only diagnosis into the primary documentation substantially limits the possibilities of using PPIs. When a PPI is indicated for therapy of erosive gastritis, a formal rationale is contained only in the instruction for use of Controloc. There are no registered indications for PPI use to treat chronic non erosive gastritis; the gastric protective agent Rebagit is indicated. PMID- 28914864 TI - [Hyponatremia: A clinical approach]. AB - Hyponatremia is the most common electrolyte metabolic abnormality in clinical practice. The unfavorable course of many diseases is associated with hyponatremia. Acute severe hyponatremia is life-threatening because cerebral edema may develop. Less obvious chronic hyponatremia increases the risk of balance problems, falls and fractures, especially in elderly patients. In any occasion, hyponatremia should not be now regarded only as a laboratory phenomenon in critically ill patients, but it necessitates a thorough clinical analysis of each individual case and appropriate therapy. The paper presents approaches to diagnosing and treating hyponatremia in various clinical situations. PMID- 28914865 TI - [Main results of the World Congress of Internal Medicine (Bali, 2016)]. PMID- 28914866 TI - [Extended endoscopic endonasal posterior (transclival) approach to tumors of the clival region and ventral posterior cranial fossa. Part 1. Topographic and anatomical features of the clivus and adjacent structures]. AB - OBJECTIVE: to describe the main topographic and anatomical features of the clival region and its adjacent structures for improvement and optimization of the extended endoscopic endonasal posterior (transclival) approach for resection of tumors of the clival region and ventral posterior cranial fossa. MATERIAL AND METHODS: We performed a craniometric study of 125 human skulls and a topographic anatomical study of heads of 25 cadavers, the arterial and venous bed of which was stained with colored silicone (the staining technique was developed by the authors) to visualize bed features and individual variability. Currently, we have clinical material from more than 120 surgical patients with various skull base tumors of the clival region and ventral posterior cranial fossa (chordomas, pituitary adenomas, meningiomas, cholesteatomas, etc.) who were operated on using the endoscopic transclival approach. RESULTS: We present the main anatomical landmarks and parameters of some anatomical structures that are required for performing the endoscopic endonasal posterior approach. The anatomical landmarks, such as the intradural openings of the abducens and glossopharyngeal nerves, may be used to arbitrarily divide the clival region into the superior, middle, and inferior thirds. The anatomical landmarks important for the surgeon, which are detected during a topographic anatomical study of the skull base, facilitate identification of the boundaries between the different clival portions and the C1 segments of the internal carotid arteries. The superior, middle, and inferior transclival approaches provide an access to the ventral surface of the upper, middle, and lower neurovascular complexes in the posterior cranial fossa. CONCLUSION: The endoscopic transclival approach may be used to access midline tumors of the posterior cranial fossa. The approach is an alternative to transcranial approaches in surgical treatment of clival region lesions. This approach provides results comparable (and sometimes better) to those of the transcranial and transfacial approaches. PMID- 28914867 TI - [On the classification of large and giant paraclinoid internal carotid artery aneurysms]. AB - Large and giant intradural ICA aneurysms or the so-called paraclinoid aneurysms are a surgical challenge requiring high qualification of the neurosurgeon. Despite numerous publications on this topic, there is still no generally accepted classification of paraclinoid aneurysms. In this paper, we analyzed the definitions and classifications of paraclinoid aneurysms, which were available in the medical literature. The paper presents our own surgical classification of paraclinoid ICA aneurysms, which has been developed by Prof. Sh.Sh. Eliava and co authors at the Burdenko Neurosurgical Institute. The classification is based on the aneurysm neck position relative to the ICA wall, aneurysm dome direction, and type of aneurysm clipping. PMID- 28914868 TI - [Combination treatment of cerebral arteriovenous malformations using endovascular and microsurgical techniques]. AB - MATERIAL AND METHODS: The study included 40 patients with cerebral AVMs. In the study group, 14 (35%) patients underwent microsurgical resection without preliminary embolization (1st group), and 26 (65%) patients underwent combined treatment (endovascular embolization and microsurgical intervention, 2nd group). The first group included patients with S&M grade I-III AVMs, and the second group included patients with S&M grade II-V AVMs. Treatment outcomes were evaluated with allowance for completeness of AVM resection, operative blood loss, duration of surgery, changes in clinical and neurological impairments according to the modified Rankin scale, and rate of neurological and surgical complications. RESULTS: According to postoperative findings, AVMs were totally resected in all patients. Persistent focal neurological symptoms developed in 2 (7.7%) cases in the second group; neurological complications occurred in 1 (7.1%) patient in the first group. The mean blood loss during resection of AVMs without preliminary embolization and embolized AVMs in patients with S&M grade I-III AVMs was 271.4 mL and 149.1 mL, respectively. The duration of surgery and blood loss did not differ significantly in microsurgery and combination treatment groups. CONCLUSION: Combination treatment, including microsurgical intervention after endovascular embolization, is an effective treatment for AVMs, in particular for high grade (S&M grade III-V) AVMs. Teamwork and coordination among the surgeon, endovascular surgeon, and radiologist in treatment of AVMs is a prerequisite for a good outcome. PMID- 28914869 TI - [Spinal dural arteriovenous fistulas. A series of clinical cases and an analysis of the literature data]. AB - : Spinal dural arteriovenous fistulas (SDAVFs) are the most common vascular malformation of the spinal cord, causing segmental lesions of the spinal cord due to venous ischemia. Functional outcomes of treatment in SDAVF patients are favorable, but the rate of improvement varies from 25 to 100%, which complicates prediction of the treatment outcome. AIM: the study aim was to identify a relationship between fistula localization and clinical manifestations and evaluate the effect of disease duration and severity of neurological impairments on immediate and long-term treatment outcomes, based on analysis of the literature and own data. MATERIAL AND METHODS: In September 2016, we performed a PubMed search for publications using keywords 'spinal arteriovenous fistula', 'treatment', and 'outcome'. We selected publications containing information on the patient's age, fistula location, disease duration, and evaluation of symptom severity (Aminoff-Logue scale) preoperatively, postoperatively, and at least 3 months after surgery. The analysis also included data on patients operated on at the clinic. A total of 187 patients were included in the analysis. RESULTS: The fistula was most often located at the T6, T7, and T9 level, with motor disorders being more severe for fistulas located at or below the T9 vertebra. Surgical isolation of the fistula improved the functional state of patients, with patients under the age of 60 years having a better prognosis for recovery of impaired functions. Motor disorders significantly regressed in the early postoperative period in all patients, but in the long-term period, there was worsening of motor disorders in patients with a better baseline functional state. PMID- 28914870 TI - [Shunt-induced craniosynostosis: topicality of the problem, choice of the approach, and features of surgical treatment]. AB - RATIONALE: Shunt-induced craniosynostosis is one of the late complications of CSF shunting surgery, which affects the patient's condition, clinical picture, and treatment approach. OBJECTIVE: to evaluate the prevalence rate and clinical significance of this disease, define the indications for surgery, and choose the optimal surgical approach. MATERIAL AND METHODS: The study included 59 children with shunt system dysfunction, aged 1 to 14 years, who were treated at the Department in the period from 2014 to 2016. The inclusion criteria were as follows: 1) age at the time of examination is older than 1 year; 2) implantation of a shunt system in the first 12 months of life. The state of cranial sutures was assessed using three-dimensional reconstruction of patient's computerized tomography images. Images obtained before or in the first months after primary implantation of a shunt system were used to exclude cases of primary craniosynostosis. RESULTS: Premature synostosis of the cranial sutures was detected in 27 (46%) cases. Of these, 3 (11%) patients with clinical symptoms of increased intracranial pressure and radiographic signs of craniocerebral disproportion underwent cranial vault remodeling surgery: two biparietal craniotomies and one fronto-parieto-occipital reconstruction. In two cases, simultaneous replacement of a valve with a programmable one was performed. There were no complications after reconstructive surgery. CONCLUSION: Shunt-associated craniosynostosis is one of the late complications of CSF shunting surgery. However, its presence is not an indication for surgery and should not be a reason for surgical aggression. Surgery for increasing the intracranial volume is indicated only for secondary craniosynostosis combined with signs of craniocerebral disproportion. In these cases, reconstructive surgery is an effective treatment option for improving the patient's condition. PMID- 28914871 TI - [Intramedullary spinal cord tumors and hydrocephalus: an analysis of the results of surgical treatment in 541 patients]. AB - : The article addresses the problem of intramedullary tumors (IMTs) combined with hydrocephalus (HC). PURPOSE: The study purpose was to explore, based on large clinical material, the occurrence of hydrocephalus combined with intramedullary tumors, possible pathogenetic mechanisms of its development, effect of tumor resection on the course of hydrocephalus, and need and timing of shunting surgery. MATERIAL AND METHODS: We present and analyze the data of the largest individual series of patients of all age groups operated on for IMTs of the spinal cord: 541 patients; 586 operations; age from 2 months to 72 years. RESULTS AND CONCLUSION: Our findings confirm a potential pathogenetic relationship between IMT and HC. The overall occurrence rate of HC in IMT patients was 6.3%. In patients with benign tumors (WHO Grade 1-2; 449 patients), HC developed in 25 (5.6%) cases; in patients with malignant tumors (WHO Grade 3-4; 84 patients), HC developed in 7 (8.3%) cases. A statistically significant prevalence of cervico medullary tumors was found in HC patients: 19 (59.4%) cases. According to our data, dissemination of the tumor process is a potential factor of HC development. PMID- 28914872 TI - [The efficacy of desmopressin in the treatment of central diabetes insipidus after resection of chiasmo-sellar region tumors]. AB - : Central diabetes insipidus (CDI) is a neuroendocrine disease, the pathogenesis of which is associated with abnormal secretion of the antidiuretic hormone. One of the specific causes of CDI is neurosurgical resection of chiasmatic-sellar region tumors. AIM: to study the efficacy and safety of desmopressin in CDI patients after resection of chiasmatic-sellar region (CSR) tumors. MATERIAL AND METHODS: Examination and treatment of patients were performed at a hospital for 7 14 days after surgery and then were continued after discharge. During treatment, the following tests were performed: a daily fluid intake and excretion volume, serum levels of sodium, potassium, and glucose twice a day, morning urine specific gravity, and Zimnitsky's test. RESULTS: Twenty-three patients with CSR tumors (11 craniopharyngiomas, 10 pituitary adenomas, 1 skull base chordoma, and 1 CSR meningioma) and CDI after neurosurgical treatment received desmopressin. On treatment, a thirst decrease, a reduced rate of diuresis, a reduced amount of excreted urine, and normalization of the sodium level were observed in all patients. In 12 patients (with pituitary adenoma, skull base chordoma, and meningioma) with transient CDI, desmopressin therapy was discontinued upon regression of symptoms 7-30 days after surgery. Eleven patients with permanent CDI continued to receive the drug at a dose of 1 to 4 doses per day. All patients well tolerated the drug without significant adverse effects. CONCLUSION: Therapy with desmopressin in the form of a nasal spray (vazomirin) in patients with transient and permanent CDI after resection CSR tumors of various histological nature (craniopharyngiomas, pituitary adenomas, meningiomas, and chordomas) was effective and safe in the early postoperative and long-term postoperative periods. PMID- 28914873 TI - [The extended endoscopic endonasal transsphenoidal approach in surgery for epidermoid cysts of the chiasmatic region]. AB - : Surgical treatment for epidermoid cysts of the chiasmatic region is a challenge because of the tendency to a massive spread of epidermoid masses through the cerebrospinal fluid pathways and a significant lesion deviation from the midline. PURPOSE: To analyze capabilities of the extended endoscopic endonasal transsphenoidal approach in surgery for epidermoid cysts. MATERIAL AND METHODS: The study included 6 patients with epidermoid cysts of the chiasmatic region who were operated on using the extended anterior endoscopic endonasal transsphenoidal approach at the Burdenko Neurosurgical Institute in the past 5 years. RESULTS: Epidermoid masses were completely removed in 5 patients; in none of the cases, complete removal of the epidermoid cyst capsule was achieved. There were no cases of vision deterioration and the development of new focal neurological symptoms. One female patient developed hypopituitary disorders in the postoperative period. There was no recurrence of epidermoid cysts during follow-up. CONCLUSION: Removal of epidermoid cysts of the chiasmatic region using the extended anterior endoscopic transsphenoidal approach may be an alternative to transcranial microsurgery. PMID- 28914874 TI - [Craniofacial tumors blood supply]. AB - : Because of the spread to different anatomical regions, craniofacial tumors (CFTs) usually receive blood supply from several arterial systems, and CFT removal is often accompanied by abundant blood loss. PURPOSE: The study purpose was to develop an algorithm of diagnostic angiography for planning surgical treatment of CFT patients. MATERIAL AND METHODS: Complex preoperative angiography was performed in 72 patients with craniofacial tumors, aged 10 to 78 years (mean age, 45.5 years), who underwent surgical treatment at the Burdenko Neurosurgical Institute in the period from 2012 to 2015. At the first stage, blood supply to tumors was quantified using SCT perfusion. Then, depending on an assessed degree of tumor vascularization, direct angiography or modern minimally invasive angiographic techniques (3D TOF HR MR angiography, SCT angiography) were applied. RESULTS: In 12 cases of hypervascular tumors, accessible afferents were preoperatively embolized through the external carotid artery, which was accompanied by an increase in the blood supply to tumors via alternative routes of the external and internal carotid arteries. The obtained data were used to plan the surgical approach. A comparative analysis of the SCT perfusion data and the expression level of endothelial markers in histological specimens revealed no significant correlation. CONCLUSION: The study demonstrated the importance of a comprehensive assessment of the blood supply to CFTs in planning of the surgical treatment and enabled the development of algorithms for preoperative angiographic diagnosis, depending on the baseline clinical and radiological data. PMID- 28914875 TI - [A malignant peripheral nerve sheath tumor developed from the auditory nerve: a case report and a literature review]. AB - We present a rare clinical case of a patient with a malignant peripheral nerve sheath tumor developed from the auditory nerve as well as a literature review, including 30 reported cases of this disease. PMID- 28914876 TI - [An aneurysm of the medial posterior choroidal artery: a case report and a literature review]. AB - INTRODUCTION: Aneurysms of the medial posterior choroidal artery are very rare. To date, only 5 cases have been reported. The article presents a case of successful surgical treatment of an aneurysm of the medial posterior choroidal artery and a literature review. CLINICAL CASE: A 57-year-old male was admitted to the Center 1 month after a massive subarachnoid hemorrhage. CT angiography revealed an aneurysm of the right posterior medial choroidal artery in the perimesencephalic cistern and resolved hemorrhage. TREATMENT: The paramedian supracerebellar transtentorial approach to the lateral surface of the midbrain was used. The posterior cerebral artery was identified in the perimesencephalic cistern, and the medial posterior choroidal artery aneurysm was isolated and successfully clipped, with the parent artery being preserved. Postoperative CT and MRI scans revealed a small asymptomatic ischemic lesion in the tectal region on the right. The patient was discharged without any neurological symptoms 10 days after surgery. CONCLUSION: Medial posterior choroidal artery aneurysms can be clipped using the paramedian supracerebellar transtentorial approach. PMID- 28914877 TI - [Expansive suboccipital cranioplasty in Chiari 1 malformation (a case report and technical notes)]. AB - In this case report, we describe the use of expansive suboccipital cranioplasty in Chiari-1 malformation. The technique improves the efficacy and safety of treatment for Chiari-1 malformation. The technique can be used as an adjunct treatment together with any variant of posterior fossa decompression, including duroplasty and extradural decompression. PMID- 28914878 TI - [Pineal cyst]. AB - : A pineal cyst (PC) is a benign neoplasm in the pineal region, or more precisely in the pineal body. Most cysts are incidental findings and are not associated with symptoms typical of patients seeking medical advice. Symptomatic cysts are discovered less often and, depending on the clinical picture, require different treatment approaches. MATERIAL AND METHODS: We analyzed the literature data about the clinical picture, diagnosis, and treatment of PCs for more than a century (1914-2016). CONCLUSION: To date, there is no single approach for managing PC patients. The indications for surgical treatment of symptomatic PCs are still not fully defined. It remains unclear which PC cases should be followed-up, and how often control examinations should be performed. More research of PCs is needed to develop new approaches to treatment of PC patients. PMID- 28914879 TI - Metabolite toxicity slows local diversity loss during expansion of a microbial cross-feeding community. AB - Metabolic interactions between populations can influence patterns of spatial organization and diversity within microbial communities. Cross-feeding is one type of metabolic interaction that is pervasive within microbial communities, where one genotype consumes a resource into a metabolite while another genotype then consumes the metabolite. A typical feature of cross-feeding is that the metabolite may impose toxicity if it accumulates to sufficient concentrations. However, little is known about the effect of metabolite toxicity on spatial organization and local diversity within microbial communities. We addressed this knowledge gap by experimentally varying the toxicity of a single cross-fed metabolite and measuring the consequences on a synthetic microbial cross-feeding community. Our results demonstrate that metabolite toxicity slows demixing and thus slows local diversity loss of the metabolite-producing population. Using mathematical modeling, we show that this is because toxicity slows growth, which enables more cells to emigrate from the founding region and contribute towards population expansion. Our results show that metabolite toxicity is an important factor affecting local diversity within microbial communities and that spatial organization can be affected by non-intuitive mechanisms. PMID- 28914880 TI - Tremblaya phenacola PPER: an evolutionary beta-gammaproteobacterium collage. AB - Many insects rely on bacterial endosymbionts to obtain nutrients that are scarce in their highly specialized diets. The most surprising example corresponds to the endosymbiotic system found in mealybugs from subfamily Pseudococcinae in which two bacteria, the betaproteobacterium 'Candidatus Tremblaya princeps' and a gammaproteobacterium, maintain a nested endosymbiotic consortium. In the sister subfamily Phenacoccinae, however, a single beta-endosymbiont, 'Candidatus Tremblaya phenacola', has been described. In a previous study, we detected a trpB gene of gammaproteobacterial origin in 'Ca. Tremblaya phenacola' from two Phenacoccus species, apparently indicating an unusual case of horizontal gene transfer (HGT) in a bacterial endosymbiont. What we found by sequencing the genome of 'Ca. Tremblaya phenacola' PPER, single endosymbiont of Phenacoccus peruvianus, goes beyond a HGT phenomenon. It rather represents a genome fusion between a beta and a gammaproteobacterium, followed by massive rearrangements and loss of redundant genes, leading to an unprecedented evolutionary collage. Mediated by the presence of several repeated sequences, there are many possible genome arrangements, and different subgenomic sequences might coexist within the same population. PMID- 28914881 TI - MicroRNA-200c impairs uterine receptivity formation by targeting FUT4 and alpha1,3-fucosylation. AB - Successful embryo implantation requires the establishment of a receptive endometrium. Poor endometrial receptivity has generally been considered as a major cause of infertility. Protein glycosylation is associated with many physiological and pathological processes. The fucosylation is catalyzed by the specific fucosyltransferases. Fucosyltransferase IV (FUT4) is the key enzyme for the biosynthesis of alpha1,3-fucosylated glycans carried by glycoproteins, and the previous studies showed FUT4 expression changed dynamically during perimplantation. MicroRNAs (miRNAs) are known to regulate specific gene expression. However, the relationship between specific miRNA and FUT4, as well as the role of miRNA/FUT4 in the establishment of uterine receptivity remains elusive. In the current study, we reported that the levels of miR-200 family members were significantly increased in serum from infertility and abortion patients relative to healthy non-pregnancy and early-pregnancy women. Among these, miR-200c was the most sensitive diagnostic criterion for infertility by receiver operating characteristic curve analysis. FUT4 was lower in the serum from infertility and abortion patients compared with the healthy non-pregnancy and early-pregnancy women. Using endometrial cell lines and a mouse model, we demonstrated that miR-200c targeted and inhibited FUT4 expression, leading to the dysfunction of uterine receptivity. Our results also revealed that miR-200c decreased alpha1.3-fucosylation on glycoprotein CD44, which further inactivated Wnt/beta-catenin signaling pathway. Taken together, miR-200c hampers uterine receptivity formation by targeting FUT4 and alpha1.3-fucosylation on CD44. miR 200c and FUT4 may be applied together as the potential markers for endometrial receptivity, and useful diagnostic and therapeutic targets for infertility. PMID- 28914882 TI - SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress. AB - Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by increased ATP production and decreased mitochondrial stress. Inhibition of mitochondrial activity or an increase in mitochondrial superoxide production significantly suppressed osteoblast differentiation. During differentiation, SOD2 was specifically induced to eliminate excess mitochondrial superoxide and protein oxidation, whereas SIRT3 expression was increased to enhance SOD2 activity through deacetylation of K68. Both SOD2 and SIRT3 knockdown resulted in suppression of differentiation. Meanwhile, mice deficient in SIRT3 exhibited obvious osteopenia accompanied by osteoblast dysfunction, whereas overexpression of SOD2 or SIRT3 improved the differentiation capability of primary osteoblasts derived from SIRT3-deficient mice. These results suggest that SIRT3/SOD2 is required for regulating mitochondrial stress and plays a vital role in osteoblast differentiation and bone formation. PMID- 28914884 TI - Parkinson disease: CSMD1 gene mutations can lead to familial Parkinson disease. PMID- 28914883 TI - CIDP and other inflammatory neuropathies in diabetes - diagnosis and management. AB - Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes. PMID- 28914885 TI - Multiple sclerosis: Intrathecal inflammation mediates mood in relapsing-remitting multiple sclerosis. PMID- 28914886 TI - Multiple sclerosis: Concussion during adolescence linked to increased risk of MS. PMID- 28914887 TI - Neural repair and rehabilitation: Prolonged neural stem cell maturation restores motor function in spinal cord-lesioned rats. PMID- 28914888 TI - Parkinson disease: Asthma drug could protect against PD. PMID- 28914889 TI - Two-color walking Peregrine solitary waves. AB - We study the extreme localization of light, evolving upon a non-zero background, in two-color parametric wave interaction in nonlinear quadratic media. We report the existence of quadratic Peregrine solitary waves, in the presence of significant group-velocity mismatch between the waves (or Poynting vector beam walk-off), in the regime of cascading second-harmonic generation. This finding opens a novel path for the experimental demonstration of extreme rogue waves in ultrafast quadratic nonlinear optics. PMID- 28914890 TI - High-energy and efficient Raman soliton generation tunable from 1.98 to 2.29 um in an all-silica-fiber thulium laser system. AB - We demonstrate a compact, all-fiber-integrated laser system that delivers Raman solitons with a duration of ~100 fs and pulse energy of up to 13.3 nJ, continuously wavelength tunable from 1.98 to 2.29 um via Raman-induced soliton self-frequency shift (SSFS) in a thulium-doped fiber amplifier. We realize a >90% efficiency of Raman conversion, the highest reported value from SSFS-based sources, to the best of our knowledge. This enables us to achieve >10 nJ soliton energy from a 2.16 to 2.29 um range, the highest energy demonstrated above 2.22 um from an SSFS-assisted, all-fiber tunable single-soliton-pulse source, to the best of our knowledge. Our simple and compact all-fiber tunable laser could serve as an efficient ~2 um femtosecond source for a wide range of mid-infrared applications. PMID- 28914891 TI - Optimization of primary Kerr optical frequency combs for tunable microwave generation. AB - We analyze the condition under which Kerr combs generate the highest microwave output power after photodetection. These optimal comb states correspond to configurations in which the sidemode-to-pump ratio is the highest possible. For the case of primary combs, we show how the interplay between the power and frequency of the pump laser critically influences this ratio, which has a direct influence on the phase noise performance of the generated microwaves. We also experimentally demonstrate primary combs with a sidemode-to-pump ratio as high as -2 dB, thereby leading to efficient energy conversion from the lightwave to the microwave frequency range. PMID- 28914892 TI - Linearly polarized cascaded Raman fiber laser with random distributed feedback operating beyond 1.5 MUm. AB - We report on, to the best of our knowledge, the first demonstration of a linearly polarized cascaded Raman fiber laser based on a simple half-open cavity with a broadband composite reflector and random distributed feedback in a polarization maintaining phosphosilicate fiber with a zero dispersion wavelength at ~1400 nm. Pumped by a 1080 nm Yb-doped fiber laser, the random laser delivers more than 8 W at 1262 nm and 9 W at 1515 nm with a polarization extinction ratio of 27 dB. The generation linewidths amount to about 1 and 3 nm, respectively, being almost independent of power, in correspondence with the theory of a cascaded random fiber lasing. PMID- 28914894 TI - 2.3 MUm Tm3+:YLF mode-locked laser. AB - A passively mode-locked Tm:YLF laser emitting at 2.3 MUm is reported for the first time, to the best of our knowledge. The continuous-wave stable mode-locking operation is obtained with a semiconductor saturable absorber mirror at a repetition rate of 100 MHz. The average output power is 165 mW for a pulse duration of 94 ps. PMID- 28914893 TI - High-contrast 10 fs OPCPA-based front end for multi-PW laser chains. AB - Applications using multi-PW lasers necessitate high temporal pulse quality with a tremendous contrast ratio (CR). The first crucial prerequisite to achieve multi PW peak power is the generation of ultrashort pulses with good spectral phase quality. Second, to avoid any deleterious pre-ionization effect on targets, nanosecond contrast better than 1012 is also targeted. In the framework of the Apollon 10 PW French laser program, we present a high-contrast 10 fs front-end design study to inject highly energetic Ti:sapphire PW lasers. The CR has been measured and analyzed in different time ranges highlighting the different major contributions for each scale. PMID- 28914895 TI - Experimental generation of discrete ultraviolet wavelength by cascaded intermodal four-wave mixing in a multimode photonic crystal fiber. AB - In this Letter, we demonstrate experimentally for the first time, to the best of our knowledge, discrete ultraviolet (UV) wavelength generation by cascaded intermodal FWM when femtosecond pump pulses at 800 nm are launched into the deeply normal dispersion region of the fundamental guided mode of a multimode photonic crystal fiber (MPCF). For pump pulses at average input powers of Pav=450, 550, and 650 mW, the first anti-Stokes waves are generated at the visible wavelength of 538.1 nm through intermodal phase matching between the fundamental and second-order guided mode of the MPCF. The first anti-Stokes waves generated then serve as the secondary pump for the next intermodal FWM process. The second anti-Stokes waves in the form of the third-order guided mode are generated at the UV wavelength of 375.8 nm. The maximum output power is above 10 mW for Pav=650 mW. We also confirm that the influences of fiber bending and intermodal walk-offs on the cascaded intermodal FWM-based frequency conversion process are negligible. PMID- 28914896 TI - Rapid measurement of transversal flow velocity vector with high spatial resolution using speckle decorrelation optical coherence tomography. AB - We propose and demonstrate a novel method that uses only three sets of B-scans to accurately determine both the direction and the speed of a transversal flow using speckle decorrelation optical coherence tomography. Our tri-scan method has the advantages of high measurement speed, high spatial resolution, and insensitivity to the flow speed. By introducing error maps, we show that the flow angle inaccuracy can be minimized by choosing the measurement result with a lesser error between results obtained from the x- and y-scans. Finally, we demonstrate that the flow angle measurement accuracy can be further improved for the high speed flows by increasing the speed of the x- and y-scans. PMID- 28914897 TI - Dual-frequency Doppler lidar for wind detection with a superconducting nanowire single-photon detector. AB - A dual-frequency direct detection Doppler lidar is demonstrated using a superconducting nanowire single-photon detector (SNSPD) at 1.5 MUm. The so-called double-edge technique is implemented by using a dual-frequency laser pulse, rather than using a double-channel Fabry-Perot interferometer. Such a modification to the reported lidars enhances the frequency stability in the system level. Using the time-division multiplexing method, only one piece of SNSPD is used in the optical receiver, making the system simplified and robust. The SNSPD is adopted to enhance the temporal resolution since it offers merits of high quantum efficiency, low dark count noise, no after-pulsing probability, and a high maximum count rate. Two telescopes that point westward and northward at a zenith angle of 30 degrees are used to detect the line-of-sight wind components, which are used to synthesize the horizontal wind profile. Horizontal wind profiles up to an altitude of about 2.7 km are calculated with vertical spatial/temporal resolution of 10 m/10 s. Wind dynamic evolution and vertical wind shears are observed clearly. PMID- 28914898 TI - Highly sensitive temperature sensor based on an ultra-compact Mach-Zehnder interferometer with side-opened channels. AB - We demonstrated an ultra-compact and highly sensitive temperature sensor by using an in-fiber Mach-Zehnder interferometer (MZI) with side-opened channels. The MZI was constructed by off-center splicing a thin piece of microstructured optical fiber (MOF) between two single-mode fibers. Then, two side-opened channels were drilled through the MOF along the transverse direction by using a femtosecond laser to let the liquid with a high thermo-optic coefficient enter into the air cavity of the MZI. Due to the large effective refractive index (RI) difference between the core mode and the cavity mode excited by the offset splicing point, the scale of the MOF-based MZI can be reduced to several hundred micrometers. Experimental results show that the MOF-based MZI infiltrated with isopropanol has a temperature sensitivity up to 3.8 nm/ degrees C with small strain cross sensitivity of 0.0001 degrees C/MUepsilon in the temperature range of 22 degrees C-34 degrees C, which makes it a competitive fiber sensor in highly sensitive temperature sensing applications, including healthcare and consumer electronics. PMID- 28914899 TI - Tapered polysilicon core fibers for nonlinear photonics: erratum. AB - We correct an error of the nonlinear refractive index used in our original paper. PMID- 28914900 TI - Cycle-slip-less low-complexity phase recovery algorithm for coherent optical receivers. AB - We propose and experimentally validate a blind phase recovery algorithm based on tracking low-frequency components of the phase noise, which we call "filtered carrier-phase estimation (F-CPE)." Tracking only the low-frequency components allows F-CPE to reduce the computational complexity by using a frequency-domain equalizer and to simplify the partitioning of a 16 quadrature amplitude modulation (16QAM) constellation. Further, this approach eliminates cycle slips by suppressing the impact of amplified spontaneous emission on phase noise estimation. The experimental results demonstrate cycle-slip-free operation for 15 and 32 GBd 16QAM signals. Additionally, the proposed method showed similar or better sensitivity compared with the blind-phase-search algorithm, near standard forward error correction thresholds of modern wavelength division multiplexing systems. PMID- 28914901 TI - Interaction of surface plasmon polaritons and acoustic waves inside an acoustic cavity. AB - In this Letter, we introduce an approach for manipulation of active plasmon polaritons via acoustic waves at sub-terahertz frequency range. The acoustic structures considered are designed as phononic Fabry-Perot microresonators where mirrors are presented with an acoustic superlattice and the structure's surface, and a plasmonic grating is placed on top of the acoustic cavity so formed. It provides phonon localization in the vicinity of the plasmonic grating at frequencies within the phononic stop band enhancing phonon-light interaction. We consider phonon excitation by shining a femtosecond laser pulse on the plasmonic grating. Appropriate theoretical model was used to describe the acoustic process caused by the pump laser pulse in the GaAs/AlAs-based acoustic cavity with a gold grating on top. Strongest modulation is achieved upon excitation of propagating surface plasmon polaritons and hybridization of propagating and localized plasmons. The relative changes in the optical reflectivity of the structure are more than an order of magnitude higher than for the structure without the plasmonic film. PMID- 28914902 TI - Development of an atmospheric polarization Scheimpflug lidar system based on a time-division multiplexing scheme. AB - A polarization Scheimpflug lidar system based on the Scheimpflug principle has been developed by employing two linearly polarized 808 nm laser diodes and a complementary metal-oxide-semiconductor (CMOS) image sensor. The polarization of one laser diode is rotated 90 degrees by a half-wave plate. The two laser beams with orthogonal polarizations are combined by a polarization beam splitter and transmitted into the atmosphere. The corresponding parallel- and perpendicular polarized backscattering echoes are detected by the 45 degrees tilted CMOS sensor using a time-division multiplexing scheme. A 24 h continuous atmospheric vertical profiling of the depolarization ratio has been performed by using the polarization Scheimpflug lidar system. The promising results successfully demonstrated that the present lidar system has potential for the polarization studies of atmospheric aerosols. PMID- 28914903 TI - Experimental demonstration of an apodized-imaging chip-fiber grating coupler for Si3N4 waveguides. AB - A silicon nitride waveguide is a promising platform for integrated photonics, particularly due to its low propagation loss compared to other complementary metal-oxide-semiconductor compatible waveguides, including silicon-on-insulator. Input/output coupling in such thin optical waveguides is a key issue for practical implementations. Fiber-to-chip grating couplers in silicon nitride usually exhibit low coupling efficiency because the moderate index contrast leads to weak radiation strengths and poor directionality. Here, we present the first, to the best of our knowledge, experimental demonstration of a recently proposed apodized-imaging fiber-to-chip grating coupler in silicon nitride that images an in-plane waveguide mode to an optical fiber placed at a specific distance above the chip. By employing amplitude and phase apodization, the diffracted optical field of the grating is matched to the fiber mode. High grating directionality is achieved by using staircase grating teeth, which produce a blazing effect. Experimental results demonstrate an apodized-imaging grating coupler with a record coupling efficiency of -1.5 dB and a 3 dB bandwidth of 60 nm in the C band. PMID- 28914904 TI - Probing the degenerate states of V-point singularities. AB - V-points are polarization singularities in spatially varying linearly polarized optical fields and are characterized by the Poincare-Hopf index eta. Each V-point singularity is a superposition of two oppositely signed orbital angular momentum states in two orthogonal spin angular momentum states. Hence, a V-point singularity has zero net angular momentum. V-points with given |eta| have the same (amplitude) intensity distribution but have four degenerate polarization distributions. Each of these four degenerate states also produce identical diffraction patterns. Hence to distinguish these degenerate states experimentally, we present in this Letter a method involving a combination of polarization transformation and diffraction. This method also shows the possibility of using polarization singularities in place of phase singularities in optical communication and quantum information processing. PMID- 28914905 TI - High-repetition-rate, multi-pulse all-normal-dispersion fiber laser. AB - In this Letter, a fiber laser that exploits the dissipative Faraday instability as a pulse-generating mechanism is presented, and its dynamics are studied numerically. The proposed laser operates in the all-normal-dispersion regime and produces a train of quasi-parabolic pulses, with a repetition rate that can be controlled depending on the cavity dispersion and nonlinearity, ranging from 10 to 50 GHz. It exploits a lumped amplification scheme, which can be potentially realized with rare-earth gain media. The issues concerning the stability of the pulses are discussed, and the differences with similar pulsed lasers are highlighted. In particular, the transition from the ordered multi-pulse regime proposed here to the random pulse operation mode already studied in the literature is discussed. PMID- 28914906 TI - Modal birefringence-free lithium niobate waveguides. AB - We investigate polarization-insensitive waveguide designs afforded by the interplay of material and waveguide birefringence in LiNbO3-on-insulator photonic wires. Fundamental mode birefringence-free operation in the 0.8-1.8 MUm spectral range is predicted for a suitable choice of waveguide widths in the 375-600 nm range. Optimized buried waveguide designs yield broadband (1350-1625 nm) index matching between TE00 and TM00 modes. Furthermore, simultaneous phase- and group velocity matching at infrared wavelengths appears feasible for pulse durations as short as 100 fs. PMID- 28914907 TI - Fast electroholographic wavelength selective switching implemented in a slab waveguide. AB - We present wavelength selective switching with a rise time of 25 ns implemented in a slab waveguide constructed in a KLTN:Cu crystal. The waveguide was fabricated by implantations of alpha particles at 2.1 MeV which produced a 0.5 MUm thick cladding layer with reduced refractive index at 4.5 MUm underneath the crystal surface. This demonstrates the feasibility of implementing electroholography in waveguides maintaining the performance obtained in bulk crystals, providing in potential the basis for constructing integrated photonic circuits which incorporate interconnected electroholographic wavelength selective switches and electrical wavelength tuning devices for employing wavelength addressing routing schemes in computer networks, in particular for relieving the bandwidth bottlenecks in data center networks. PMID- 28914908 TI - Phase-matched nonlinear optics via patterning layered materials. AB - The ease of integration and a large second-order nonlinear coefficient of atomically thin layered two-dimensional (2D) materials presents a unique opportunity to realize second-order nonlinearity in a silicon compatible integrated photonic system. However, the phase-matching requirement for second order nonlinear optical processes makes the nanophotonic design difficult. We show that by nano-patterning the 2D material, quasi-phase-matching can be achieved. Such patterning-based quasi-phase-matching could potentially compensate for inevitable fabrication errors and significantly simplify the design process of the nonlinear nanophotonic devices. PMID- 28914909 TI - Pump-degenerate phase-sensitive amplification in amorphous silicon waveguides. AB - We demonstrate phase-sensitive amplification in hydrogenated amorphous silicon photonic waveguides based on pump-degenerate four-wave mixing at continuous-wave (CW) operation, as well as at repetition rates of both 90 MHz and 10 GHz. At 90 MHz pulsed operation, an 11.7 dB phase-sensitive extinction ratio (ER) is achieved with a peak pump power of 1.6 W. At 10 GHz pulsed operation, a 6.6 dB phase-sensitive ER is achieved with a peak pump power of 0.5 W. At CW operation, a 1.6 dB ER is achieved with a pump power of 38 mW. PMID- 28914910 TI - Large-bandwidth, low-loss, efficient mode mixing using long-period mechanical gratings. AB - We propose a new architecture for using long-period fiber gratings (LPGs) to induce strong mode mixing with low loss for space-division multiplexing. In this architecture, LPGs are installed in step-index (SI) few-mode fibers that support more modes than the transmission fiber. Such a design could significantly reduce losses due to coupling from the highest-order mode group to cladding modes. In our experiment, efficient mixing of three spatial modes over a broad bandwidth was achieved by a mechanical long-period grating on a SI fiber that supports eight spatial modes. The insertion loss, including two splice losses, is less than 0.5 dB, and the coupling matrix and mode-dependent loss (MDL) are characterized experimentally for the first time, to the best of our knowledge. Strong mixing between LP01 and LP11 for a whole C band is demonstrated, and MDL introduced to the system is negligible. PMID- 28914911 TI - Iridescence-free and narrowband perfect light absorption in critically coupled metal high-index dielectric cavities. AB - Perfect light absorption in the visible and near-infrared (NIR) was demonstrated using metamaterials, plasmonic nanostructures, and thin films. Thin film absorbers offer a simple and low-cost design as they can be produced on large areas and without lithography. Light is strongly absorbed in thin film metal dielectric-metal (MDM) cavities at their resonance frequencies. However, a major drawback of MDM absorbers is their strong resonance iridescence, i.e., angle dependence. Here, we solve the iridescence problem by achieving angle-insensitive narrowband perfect and near-perfect light absorption. In particular, we show analytically that using a high-index dielectric in MDM cavities is sufficient to achieve angle-insensitive cavity resonance. We demonstrate experimentally angle insensitive perfect and near-perfect absorbers in the NIR and visible regimes up to +/-60 degrees . By overcoming the iridescence problem, we open the door for practical applications of MDM absorbers at optical frequencies. PMID- 28914912 TI - Quasiperiodic one-dimensional photonic crystals with adjustable multiple photonic bandgaps. AB - We propose an elegant approach to produce photonic bandgap (PBG) structures with multiple photonic bandgaps by constructing quasiperiodic photonic crystals (QPPCs) composed of a superposition of photonic lattices with different periods. Generally, QPPC structures exhibit both aperiodicity and multiple PBGs due to their long-range order. They are described by a simple analytical expression, instead of quasiperiodic tiling approaches based on substitution rules. Here we describe the optical properties of QPPCs exhibiting two PBGs that can be tuned independently. PBG interband spacing and its depth can be varied by choosing appropriate reciprocal lattice vectors and their amplitudes. These effects are confirmed by the proof-of-concept measurements made for the porous silicon-based QPPC of the appropriate design. PMID- 28914913 TI - High-repetition-rate, deep-infrared, picosecond optical parametric oscillator based on CdSiP2. AB - We report a high-repetition-rate picosecond optical parametric oscillator (OPO) based on CdSiP2 (CSP) that is synchronously pumped by an Yb-fiber laser at 1064 nm and provides high average power in the deep-infrared (deep-IR) at 79.5 MHz. The OPO is tunable across 6205-6710 nm in the idler, providing as much as 105 mW of average power at 6205 nm and >55 mW over nearly the entire tuning range. The deep-IR idler output exhibits passive power stability better than 2.3% rms over 12 h in good beam quality. The near-IR signal pulses from the OPO have a Gaussian pulse duration of ~19 ps, measured at 1284 nm. We have investigated the temperature tuning characteristics of the OPO and compared the data with the theoretical calculations using the most recent Sellmeier equations and thermo optic coefficients for the crystal. To the best of our knowledge, this is the first picosecond OPO based on CSP operating at MHz repetition rates. PMID- 28914914 TI - Regularized Huygens' plasmonic wave field synthesis using a metal-clad plasmonic waveguide array. AB - Huygens' principle states that point sources are the basis of optical wave field generation, and an array of point sources with complex amplitudes that are separated by subwavelength distances can generate a desired optical field distribution. In field synthesis based on the Huygens' principle, the construction of ideal point sources has been overlooked when compared to other elements in optical field synthesis engineering, such as complex modulation. However, the construction of ideal point sources should be considered an important goal because the use of non-ideal point sources generates considerable optical noise in the background of the synthesized field distribution. In this Letter, we investigate Huygens' plasmonic wave field synthesis and its regularization by analyzing the noise features that arise during wave field synthesis based on non-ideal point sources and proposing a novel structure for regularized point source construction. It is shown that the quality of plasmonic wave field synthesis based on the Huygens' principle is greatly improved with the proposed design of a structure that generates a unit point source. Practical field synthesis examples involving plasmonic focusing and Airy beams are presented in support of the proposed design. PMID- 28914915 TI - Long-wavelength infrared solitons in air. AB - Dispersion and optical nonlinearity of atmospheric air in the long-wavelength infrared (LWIR) range are shown to enable unique soliton dynamics in freely propagating laser beams. Analysis of spatiotemporal LWIR waveform evolution in air reveals soliton self-compression scenarios whereby ultrashort LWIR subterawatt pulses can be compressed to single-cycle terawatt field waveforms. PMID- 28914916 TI - Continuous-wave optically pumped green perovskite vertical-cavity surface emitter. AB - We report an optically pumped green perovskite vertical-cavity surface-emitter operating in continuous-wave (CW) with a power density threshold of ~89 kW/cm2. The device has an active region of CH3NH3PbBr3 embedded in a dielectric microcavity; this feat was achieved with a combination of optimal spectral alignment of the optical cavity modes with the perovskite optical gain, an adequate Q-factor of the microcavity, adequate thermal stability, and improved material quality with a smooth, passivated, and annealed thin active layer. Our results signify a way towards efficient CW perovskite emitter operation and electrical injection using low-cost fabrication methods for addressing monolithic optoelectronic integration and lasing in the green gap. PMID- 28914917 TI - Compact single-shot radial shearing interferometer with random phase shift. AB - We propose a compact phase-shifting radial shearing interferometer based on a pixelated micro-retarder array (MRA). The MRA is made of a thin birefringence plate, and is composed of identical units that have pixels of four different thicknesses. We demonstrate that pixelated phase delay between two shearing beams can be introduced by applying the fast axis of birefringence plate in the horizontal or vertical orientation. We also present an approach to extract the wavefront under test with random phase shift, which dramatically reduces the machining difficulty of the MRA. The feasibility and accuracy of the proposed method are further validated through our numerical analysis. With the advantages of vibration immunity, simultaneous phase stepping, and broad spectral range, the presented interferometer is expected to be of potential use in a variety of applications, such as the detection of moving objects and dynamic processes. PMID- 28914918 TI - Cascading second-order nonlinear processes in a lithium niobate-on-insulator microdisk. AB - Whispering-gallery-mode (WGM) microcavities are very important in both fundamental science and practical applications, among which on-chip second-order nonlinear microresonators play an important role in integrated photonic functionalities. Here we demonstrate resonant second-harmonic generation (SHG) and cascaded third-harmonic generation (THG) in a lithium niobate-on-insulator (LNOI) microdisk resonator. Efficient SHG in the visible range was obtained with only several mW input powers at telecom wavelengths. THG was also observed through a cascading process, which reveals simultaneous phase matching and strong mode coupling in the resonator. Cascading of second-order nonlinear processes gives rise to an effectively large third-order nonlinearity, which makes on-chip second-order nonlinear microresonators a promising frequency converter for integrated nonlinear photonics. PMID- 28914919 TI - Highly sensitive optical sensor for precision measurement of electrical charges based on optomechanically induced difference-sideband generation. AB - Difference-sideband generation in an optomechanical system coupled to a charged object is investigated beyond the conventional linearized description of optomechanical interactions. An exponential decay law for difference-sideband generation in the presence of electric interaction is identified which exhibits more sensitivity to electrical charges than the conventional linearized effects. Using the exact same parameters with previous work based on the linearized dynamics of the optomechanical interactions, we show that optomechanically induced difference-sideband generation may enable an all-optical sensor for precision measurement of electrical charges with higher precision and lower power. The proposed mechanism is especially suited for on-chip optomechanical devices, where nonlinear optomechanical interaction in the weak coupling regime is within current experimental reach. PMID- 28914920 TI - Spectral focusing dual-comb coherent anti-Stokes Raman spectroscopic imaging. AB - Coherent Raman microscopy provides label-free imaging by interrogating the intrinsic vibration of molecules. Here, we present a concept in a 100 MHz dual comb scheme to facilitate high-speed and broadband coherent anti-Stokes Raman spectroscopic imaging based on down-converted, automatically varying delay-time in spectral focusing excitation. A rapid measurement of vibrational microspectroscopy on submicrosecond scale over a spectral span ~700 cm-1 with a refresh rate of 1.2 kHz provides access to well-resolved molecular signatures within the fingerprint region. We demonstrate hyperspectral images of a mixture of spatially inhomogeneous distributions of chemical substances. PMID- 28914922 TI - Effect of nitrogen doping on the photoluminescence intensity of graphene quantum dots. AB - We have developed a facile, fast, and one-step synthetic method to prepare graphene quantum dots (GQDs) simultaneously with nitrogen (N) doping via pulsed laser ablation. The N-doped GQDs (N-GQDs) with an average size around 3 nm and an N/C atomic ratio of 33% have been obtained. The N-GQDs emit blue photoluminescence (PL), where the PL intensity enhances as the N doping increases. The PL enhancement for the N-GQDs with a factor as high as 25 has been achieved as compared to GQDs. The origin of the PL enhancement in GQDs after N doping is attributed to the increased densities of pyridinic and graphitic N. PMID- 28914921 TI - Truly unentangled photon pairs without spectral filtering. AB - We demonstrate that an integrated silicon microring resonator is capable of efficiently producing photon pairs that are completely unentangled; such pairs are a key component of heralded single-photon sources. A dual-channel interferometric coupling scheme can be used to independently tune the quality factors associated with the pump and signal and idler modes, yielding a biphoton wavefunction with a Schmidt number arbitrarily close to unity. This will permit the generation of heralded single-photon states with unit purity. PMID- 28914923 TI - Gigabit free-space multi-level signal transmission with a mid-infrared quantum cascade laser operating at room temperature. AB - Gigabit free-space transmissions are experimentally demonstrated with a quantum cascaded laser (QCL) emitting at mid-wavelength infrared of 4.65 MUm, and a commercial infrared photovoltaic detector. The QCL operating at room temperature is directly modulated using on-off keying and, for the first time, to the best of our knowledge, four- and eight-level pulse amplitude modulations (PAM-4, PAM-8). By applying pre- and post-digital equalizations, we achieve up to 3 Gbit/s line data rate in all three modulation configurations with a bit error rate performance of below the 7% overhead hard decision forward error correction limit of 3.8*10-3. The proposed transmission link also shows a stable operational performance in the lab environment. PMID- 28914924 TI - Additivity of the coefficient of thermal expansion in silicate optical fibers. AB - A model that predicts the material additivity of the thermal expansion coefficient in the binary silicate glasses most commonly used for present (GeO2 SiO2, P2O5-SiO2, B2O3-SiO2, and Al2O3-SiO2) and emerging (BaO-SiO2) optical fibers is proposed. This model is based on a derivation of the expression for the coefficient of thermal expansion in isotropic solids, and gives direct insight on the parameters that govern its additivity in silicate glasses. Furthermore, a consideration of the local structural environment of the glass system is necessary to fully describe its additivity behavior in the investigated systems. This Letter is important for better characterizing and understanding of the impact of temperature and internal stresses on the behavior of optical fibers. PMID- 28914925 TI - Application of polarization information to a light-controlling-light technique. AB - Nonlinear effects of photo-induced waveguides based on isomerization photochemistry are investigated. It is found that polarization information of the controlling light can be used to control the propagation of the signal light in all-optical waveguides, and an accurate and convenient light-controlling-light scheme is proposed, that is, controlling propagation of the signal light by synergic use of the intensity information and polarization information of the controlling light. The polarization dependence of optical nonlinearity is expected to enrich the connotation of the optical nonlinear effects and has theoretical significance and practical value. PMID- 28914926 TI - Single-polarization fiber-pigtailed high-finesse silica waveguide ring resonator for a resonant micro-optic gyroscope. AB - A new record for high-finesse silica waveguide ring resonators (WRRs), to the best of our knowledge, is demonstrated experimentally. The achieved finesse and resonant depths of the silica WRR with a length of 7.9 cm and a diameter of 2.5 cm are 196.7% and 98%, respectively. In addition, the silica WRR chip is coupled with single-polarization fiber to improve the polarization extinction ratio (PER) and, thus, to reduce the polarization error. With the application of this high finesse and high-PER WRR to the resonant micro-optic gyroscope (RMOG), a bias stability of 0.004 degrees /s is observed over a 1 h timeframe. To the best of our knowledge, this is the first RMOG reported in the open literature that can sense the earth's rotation rate (15 degrees /h). PMID- 28914927 TI - Secure communications of CAP-4 and OOK signals over MMF based on electro-optic chaos. AB - Chaos-based secure communication can provide a high level of privacy in data transmission. Here, we experimentally demonstrate secure signal transmission over two kinds of multimode fiber (MMF) based on electro-optic intensity chaos. High quality synchronization is achieved in an electro-optic feedback configuration. Both 5 Gbit/s carrier-less amplitude/phase (CAP-4) modulation and 10 Gbit/s on off key (OOK) signals are recovered efficiently in electro-optic chaos-based communication systems. Degradations of chaos synchronization and communication system due to mismatch of various hardware keys are also discussed. PMID- 28914928 TI - Multi-resonant Lugiato-Lefever model. AB - We introduce a new model that extends the Lugiato-Lefever equation to the description of multiple resonances in Kerr optical cavities. It perfectly agrees quantitatively (in both stationary and dynamical regimes) with the exact Ikeda map, even when using a small number of resonances. Our model predicts the onset of complex phenomena such as the recently observed super-cavity solitons and the coexistence of multiple nonlinear states. It will be of crucial importance for the analytical understanding of new nonlinear phenomena in Kerr cavities when the intensities or nonlinearities are high enough to be able to excite more than one cavity resonance. PMID- 28914929 TI - Full-vectorial propagation model and modified effective mode area of four-wave mixing in straight waveguides. AB - We derive from Maxwell's equations full-vectorial nonlinear propagation equations of four-wave mixing valid in straight semiconductor-on-insulator waveguides. Special attention is given to the resulting effective mode area, which takes a convenient form known from studies in photonic crystal fibers, but has not been introduced in the context of integrated waveguides. We show that the difference between our full-vectorial effective mode area and the scalar equivalent often referred to in the literature may lead to mistakes when evaluating the nonlinear refractive index and optimizing designs of new waveguides. We verify the results of our derivation by comparing it to experimental measurements in a silicon-on insulator waveguide, taking tolerances on fabrication parameters into account. PMID- 28914930 TI - Continuous-wave, singly resonant parametric oscillator-based mid-infrared optical vortex source. AB - We report on a high-power, continuous-wave source of optical vortices tunable in the mid-infrared (mid-IR) wavelength range. Using the orbital angular momentum (OAM) conservation of the parametric processes and the threshold conditions of the cavity modes of the singly resonant optical parametric oscillator (SRO), we have transferred the OAM of the pump beam at the near-infrared wavelength to the idler beam tunable in the mid-IR. Pumped with a vortex beam of order lp=1 at 1064 nm, the SRO, configured in a four curved mirror-based ring cavity with a 50 mm long MgO-doped periodically poled LiNbO3 crystal, produces an idler beam with an output power in excess of 2 W in a vortex spatial profile with the order li=1, tunable across 2217-3574 nm and corresponding signal beam in Gaussian intensity distribution across 1515-2046 nm. For pump vortices of the order lp=1 and 2, and a power of 22 W, the SRO produces idler vortices of the same order as that of the pump beam with a maximum power of 5.23 and 2.3 W, corresponding to near-IR to mid IR vortex conversion efficiency of 23.8% and 10.4%, respectively. The idler vortex beam has a spectral width, and a passive rms power stability of 101 MHz and 4.9% over 2 h, respectively. PMID- 28914931 TI - High-speed 2D Raman imaging at elevated pressures. AB - Two-dimensional (2D) Raman scattering at 10 kHz in non-reacting flow mixtures is demonstrated by employing a burst-mode laser with a long-duration pulse of about 70 ns and pulse energy of about 750 mJ at 532 nm. To avoid optical breakdown, the pulse width of the laser was varied in the range of 10-1000 ns. The effects of pulse shape, pulse energy, and harmonic conversion on 2D measurements are also studied. The applications of high-speed, single-shot, 2D imaging of CH4 and H2 jets in N2 at elevated pressures are demonstrated. In addition, the scalar dissipation rate of CH4 in N2 at 20 bar is determined, and multi-dimensional, multi-species, high-speed imaging of flows at elevated pressures is demonstrated. PMID- 28914932 TI - Observation of 7pP23/2->7dD2 optical transitions in 209 and 210 francium isotopes. AB - We report on the direct experimental observation of the 7pP23/2->7dD2 optical transitions in 209 and 210 francium isotopes. By continuously monitoring the fluorescence emitted by the isotopes collected in a magneto-optical trap (MOT), the electric dipole transitions 7pP23/2->7dD25/2 of Fr209, not yet experimentally observed, and 7pP23/2->7dD25/2, 7pP23/2->7dD25/2 of Fr210 were detected as sub Doppler depletion dips of the cold atom population. This approach allowed unambiguous identification of the excited state hyperfine structures, even in the absence of a large stable vapor. Our findings demonstrate the effectiveness and the flexibility of fluorescence monitoring of trap depletion upon laser excitation, and broaden the experimental knowledge of francium isotopes and their electronic and nuclear properties. These results will have a relevant impact on ongoing researches for low-energy testing of fundamental symmetries with francium, from atomic parity non-conservation to the electron dipole moment. PMID- 28914933 TI - Broadband high-order mode pass filter based on mode conversion. AB - We report a unique concept to implement a high-order mode pass filter using mode converters. Our proposed design method implements a high-order mode pass filter of any order, uses different mode converters available, and applies to a variety of planar lightwave circuit material platforms. We fabricate a broadband fundamental mode filter device using a Mach-Zehnder interferometer and Y junctions to demonstrate our idea. The performance of the fabricated device is demonstrated experimentally in the wavelength range of 1.530-1.565 MUm (C-band). This filter exhibits a simulated extinction ratio of 37 dB with an excess loss of 0.52 dB for the first-order mode transmission. PMID- 28914934 TI - Extended Yeh's method for optically active anisotropic layered media. AB - We extend the original method of Yeh [J. Opt. Soc. Am.69, 742 (1979)JOSAAH0030 394110.1364/JOSA.69.000742] for calculating the reflection and transmission from anisotropic layered structures to media exhibiting not only dielectric, but also magnetic anisotropy, as well as optical activity. We likewise establish the relationship between the optical activity and gyration tensors from the two most used constitutive relations for optically active media and illustrate the extended Yeh's method on a practically important example. PMID- 28914935 TI - Optical parametric generation in orientation-patterned gallium phosphide. AB - We report an optical parametric generator (OPG) based on the new nonlinear material, orientation-patterned gallium phosphide (OP-GaP). Pumped by a Q switched nanosecond Nd:YAG laser at 1064 nm with 25 kHz pulse repetition rate, the OPG can be tuned across 1721-1850 nm in the signal and 2504-2787 nm in the idler. Using a 40-mm-long crystal in single-pass configuration, we have generated a total average output power of up to ~18 mW, with ~5 mW of idler power at 2670 nm, for 2 W of input pump power. The OPG exhibits a passive stability in total output power better than 0.87% rms over 1 h, at a crystal temperature of 120 degrees C, compared to 0.14% rms for the input pump. The output signal pulses, recorded at 1769 nm, have duration of 5.9 ns for input pump pulses of 9 ns. Temperature-dependent loss measurements for the pump polarization along the [100] axis in the OP-GaP crystal have also been performed, for the first time, indicating a drop in transmission from 28.8% at 50 degrees C to 19.4% at 160 degrees C. PMID- 28914936 TI - Study of middle infrared difference frequency generation using a femtosecond laser source in LGT. AB - We demonstrate phase-matched difference frequency generation in the emerging nonlinear crystal La3Ga5.5Ta0.5O14. Tunable wavelengths between 1.4 and 4.7 MUm are generated by using femtosecond sources. We also report on the measurements of the optical damage threshold in the femtosecond regime and on the nonlinear refractive index n2. PMID- 28914937 TI - Efficient spot size converter for higher-order mode fiber-chip coupling. AB - We propose and demonstrate a silicon-based spot size converter (SSC), composed of two identical tapered channel waveguides and a Y-junction. The SSC is designed for first-order mode fiber-to-chip coupling on the basis of mode petal separation and the recombination method. Compared with a traditional on-chip SSC, this method is superior with reduced coupling loss when dealing with a higher-order mode. To the best of our knowledge, we present the first experimental observations of a higher-order SSC which is fully compatible with a standard fabrication process. Average coupling losses of 3 and 5.5 dB are predicted by simulation and demonstrated experimentally. A fully covered 3 dB bandwidth over a 1515-1585 nm wavelength range is experimentally observed. PMID- 28914938 TI - Full color waveguide liquid crystal display. AB - We developed a waveguide liquid crystal display from a liquid crystal (LC)/polymer composite. It does not need polarizers or color filters. It is illuminated by color LEDs installed on its edge. The light produced by the edge LEDs is coupled into the display and then waveguided through the display. When the LC is in the transparent state, the incident light is waveguided through and no light comes out of the viewing side of the display. When the LC is in the scattering state, the incident light is scattered and comes out of the display. It can be used either for transparent display or for direct view display. The composite has a submillisecond response time, and a field sequential scheme can be used to display full color images. Because the display does not need polarizers or color filters, its energy efficiency is much higher than current liquid crystal displays. PMID- 28914939 TI - Multicore fiber-Bragg-grating-based directional curvature sensor interrogated by a broadband source with a sinusoidal spectrum. AB - A simple, spectral-drift-insensitive interrogation scheme for a multicore fiber Bragg grating (FBG)-based directional curvature sensor is proposed. The basic principle is to transform the wavelength shift of FBGs into the reflected power variation, which is accomplished by utilizing a broadband source with a sinusoidal spectrum. The closed-form expression of the relationship between the reflected power of the FBG and the corresponding peak wavelength is derived for the first time, to the best of our knowledge; therefore, the peak wavelength of the FBG can be precisely interrogated by using a single photodiode. The experimental results show that, with respect to conventional wavelength measurement by an optical spectrum analyzer, the demodulated wavelength error by our proposed interrogation scheme is within +/-20 pm. The proposed scheme is further extended to interrogate the direction and curvature using a multicore FBG based curvature sensor; the interrogated curvature with an error less than 8% is achieved. PMID- 28914940 TI - Asymmetric dual-loop feedback to suppress spurious tones and reduce timing jitter in self-mode-locked quantum-dash lasers emitting at 1.55 MUm. AB - We demonstrate an asymmetric dual-loop feedback method to suppress external cavity side-modes induced in self-mode-locked quantum-dash lasers with conventional single- and dual-loop feedback. In this Letter, we report optimal suppression of spurious tones by optimizing the delay in the second loop. We observed that asymmetric dual-loop feedback, with large (~8*) disparity in loop lengths, gives significant suppression in external-cavity side-modes and produces flat radio frequency (RF) spectra close to the main peak with a low timing jitter, compared to single-loop feedback. Significant reduction in RF linewidth and timing jitter was produced by optimizing the delay time in the second feedback loop. Experimental results based on this feedback configuration validate predictions of recently published numerical simulations. This asymmetric dual loop feedback scheme provides simple, efficient, and cost-effective stabilization of optoelectronic oscillators based on mode-locked lasers. PMID- 28914941 TI - Mid-infrared fiber-optic photothermal interferometry. AB - We demonstrate mid-infrared photothermal interferometry (PTI) in a hollow-core fiber (HCF) for trace gas detection. Compared with free-space PTI, the optical intensity could be increased by orders of magnitude by confining the pump and probe lights in the hollow core. We coupled the pump light at 4.46 MUm from a quantum cascade laser and the 1555.14 nm probe light into the HCF with a bore size of 200 MUm. The HCF was filled with nitrous oxide (N2O) which has strong absorption at the pump wavelength. The probe light detects the N2O absorption induced phase change in the HCF via a fiber-optic Mach-Zehnder interferometer. With a 25 cm fiber length and 6 mW of pump power, we have achieved a minimum detection limit of 0.8 ppm for N2O, corresponding to a normalized noise equivalent absorption coefficient of 4.9*10-7 cm-1 WHz-1/2. PMID- 28914942 TI - A room temperature reversible phase transition containing dielectric switching of a host-guest supramolecular metal-halide compound. AB - Following our recent findings on dielectric materials, we synthesized a new host guest supramolecular metal-halide compound, [(2-AMPD)(18-crown-6)]CuCl4 (1, 2 AMPD = 2-aminomethylpiperidinium). Systematic characterization techniques such as variable-temperature crystal structure analyses, differential scanning calorimetry (DSC) measurements, temperature-dependent dielectric measurements and powder X-ray diffraction (PXRD) measurements demonstrate that 1 undergoes a reversible phase transition at room temperature, accompanied by switchable dielectric responses and remarkable anisotropy along three different crystallographic axes. The structural phase transition mechanism is triggered by the order-disorder transition of the 18-crown-6 molecules. We believe that these findings might further promote the application of a host-guest inclusion compound in the field of switchable dielectric materials. PMID- 28914943 TI - Mammalian cell defence mechanisms against the cytotoxicity of NaYF4:(Er,Yb,Gd) nanoparticles. AB - Water-soluble upconversion nanoparticles (UCNPs), based on polyvinylpyrrolidone (PVP)-coated NaYF4:Er3+,Yb3+,Gd3+, with various concentrations of Gd3+ ions and relatively high upconversion efficiencies, were synthesized. The internalization and cytotoxicity of the thus obtained UCNPs were evaluated in three cell lines (HeLa, HEK293 and astrocytes). No cytotoxicity was observed even at concentrations of UCNPs up to 50 MUg ml-1. The fate of the UCNPs within the cells was studied by examining their upconversion emission spectra with confocal microscopy and confirming these observations with transmission electron microscopy. It was found that the cellular uptake of the UCNPs occurred primarily by clathrin-mediated endocytosis, whereas they were secreted from the cells via lysosomal exocytosis. The results of this study, focused on the mechanisms of the cellular uptake, localization and secretion of UCNPs, demonstrate, for the first time, the co-localization of UCNPs within discrete cell organelles. PMID- 28914944 TI - First-principles studies on the effects of halogen adsorption on monolayer antimony. AB - Using first-principles calculations, we carry out systematic studies on the electronic, magnetic and structural properties of halogenated beta-phase antimonene. We consider two different levels of halogen adatom coverage i.e. Theta = 1/8 and Theta = 1/18. It is found that F, Cl and Br adatoms act as acceptors whereas the I adatom acts as a donor. For a high coverage of Theta = 1/8, halogenated beta-phase antimonene exhibits metallic characteristics. With a lower coverage of Theta = 1/18, through the adsorption of F, Cl and Br the semiconducting unstrained antimonene becomes metallic. In contrast, I-adsorbed antimonene remains semiconducting but exhibits magnetic behavior. We further investigate the effects of bi-axial strain on the halogenated beta-phase antimonene. It is found that bi-axial strain can only induce ferromagnetism on the halogenated antimonene at Theta = 1/18. However, the ferromagnetism is suppressed when the applied strain is high. We uncover that the emergence of strain-dependent magnetism is attributed to the presence of localized states in the bandgap resulting from collective effects of bi-axial strain and the adsorption of halogen atoms. PMID- 28914945 TI - Amorphous/crystalline hybrid MoO2 nanosheets for high-energy lithium-ion capacitors. AB - A carbon-free MoO2 nanosheet with amorphous/crystalline hybrid domain was synthesized, and demonstrated to be an efficient host material for lithium-ion capacitors. Discrepant crystallinity in MoO2 shows unique boundaries, which can improve Li-ion diffusion through the electrode. Improved rate capacities and cycling stability open the door to design of high-performance lithium ion capacitor bridging batteries and supercapacitors. PMID- 28914946 TI - The role of metal oxide interactions: revisiting Pt growth on the TiO2 surface in the process of impregnation method. AB - First-principles calculations and experiments with PtOx on TiO2 surfaces were performed together to understand the interactions of metal oxides during the calcination process and their influence on the growth pattern of Pt on the TiO2 surface. Our calculations indicate that PtOx with a high concentration of oxygen binds more strongly to rutile than to anatase, indicating the formation of stronger interactions between Pt oxide and the rutile surface compared with anatase during the calcination stage under an oxidative atmosphere. X-ray photoelectron spectra quantification analysis illustrates that higher amounts of Pt oxide are obtained when impregnation is performed with a rutile support after calcination in comparison with that of anatase. After reduction, the stronger interaction between PtOx and rutile leads to a larger amount of partially charged and highly dispersed Pt nanoclusters on the surface, while the weaker interaction between PtOx and anatase illustrates the dispersion and sintering of higher amounts of metal nanoparticles on the anatase surface. Furthermore, the photocatalytic oxygen evolution test highlights the importance of understanding the interaction between the metal oxide and anatase/rutile for targeted synthesis of the supported catalyst. PMID- 28914947 TI - Singlet oxygen-mediated one-pot chemoselective peptide-peptide ligation. AB - We here describe a furan oxidation based site-specific chemical ligation approach using unprotected peptide segments. This approach involves two steps: after photooxidation of a furan-containing peptide, ligation is achieved by reaction of the unmasked keto-enal with C- or N-terminal alpha-nucleophilic moieties of the second peptide such as hydrazine or hydrazide to form a pyridazinium or pyrrolidinone linkage respectively. PMID- 28914948 TI - Nanotopography mediated osteogenic differentiation of human dental pulp derived stem cells. AB - Advanced medical devices, treatments and therapies demand an understanding of the role of interfacial properties on the cellular response. This is particularly important in the emerging fields of cell therapies and tissue regeneration. In this study, we evaluate the role of surface nanotopography on the fate of human dental pulp derived stem cells (hDPSC). These stem cells have attracted interest because of their capacity to differentiate to a range of useful lineages but are relatively easy to isolate. We generated and utilized density gradients of gold nanoparticles which allowed us to examine, on a single substrate, the influence of nanofeature density and size on stem cell behavior. We found that hDPSC adhered in greater numbers and proliferated faster on the sections of the gradients with higher density of nanotopography features. Furthermore, greater surface nanotopography density directed the differentiation of hDPSC to osteogenic lineages. This study demonstrates that carefully tuned surface nanotopography can be used to manipulate and guide the proliferation and differentiation of these cells. The outcomes of this study can be important in the rational design of culture substrates and vehicles for cell therapies, tissue engineering constructs and the next generation of biomedical devices where control over the growth of different tissues is required. PMID- 28914949 TI - Influence of flavonol-rich excipient food (onion peel and Dendropanax morbifera) on the bioavailability of green tea epicatechins in vitro and in vivo. AB - The impacts of onion peel (OP) and Dendropanax morbifera (DM), as excipient foods rich in flavonols, on the digestive recovery, intestinal absorption, and pharmacokinetics of GT epicatechins were studied via an in vitro digestion model system with Caco-2 cells and an in vivo study. The digestive stability of total epicatechins recovered from GT upon the addition of 2% DM was up to 1.12 times higher than that observed with OP. The combined effects of OP and DM, which were observed with 2% OP + DM in a ratio of 1 : 4 (w : w), significantly increased (by a factor of 1.31) the digestive recovery of total epicatechins (p < 0.05). Remarkable cellular uptakes of EC (185.36%) and ECG (188.08%) were found with 4% OP + DM (4 : 1, w : w), and those of EGC (112.30%) and EGCG (136.27%) were obtained with 2% OP + DM (4 : 1, w : w) and 1% OP + DM (1 : 1, w : w), respectively. The peak plasma concentrations of total epicatechins from GT, GT + 5% OP, GT + 5% DM, and GT + 2% OP + 2% DM were 1044.78 +/- 609.10, 2267.18 +/- 3734.38, 1270.35 +/- 547.59, and 714.53 +/- 499.27 ng mL-1, respectively. The Cmax value of total epicatechins in rats orally administrated with GT with 5% OP was found to be approximately twice of that obtained with GT alone. The co ingestion of GT with flavonol-rich excipient foods possibly enhances the absorption of epicatechins because flavonols act as not only enhancers of digestive stability but also modulators of the biotransformation of epicatechins. The results obtained from the current study suggest that the absorption of GT catechins can vary depending upon the kinds and doses of excipient foods co ingested. PMID- 28914950 TI - Enhanced luminescence of delaminated layered europium hydroxide (LEuH) composites with sensitizer anions of coumarin-3-carboxylic acid. AB - The organic compound of coumarin-3-carboxylic acid (CCA), deprotonated beforehand by NaOH, and the 1-octane sulfonic acid anion (OS) were co-intercalated into the gallery of the layered europium hydroxide (LEuH) via an ion exchange method. Different molar ratios of CCA/OS and NaOH/CCA gave rise to the composites of CCA1 xOSx-LEuH (x = 0.8-1.0) showing different emission intensities. In formamide (FM), all composites were delaminated and the formed colloidal suspensions exhibited enhanced red luminescence of Eu3+ in comparison with the OS-LEuH without CCA. Also, the red emissions of the composites were different from the violet emission (421 nm) of free CCA- and blue emission (471 nm) of CCA2- anions in different deprotonation states. The energy levels of CCA and Eu3+ were analyzed to explain the sensitization effect for Eu3+ luminescence. The fluorescence lifetimes of CCA0.2OS0.8-LEuH-1 : 1, CCA0.02OS0.98-LEuH-1 : 1, CCA0.2OS0.8-LEuH-1 : 2, and CCA0.02OS0.98-LEuH-1 : 2 were determined to be 0.705, 0.704, 0.699 and 0.638 ms, respectively, indicating significantly longer lifetimes. The PL quantum yields of ~10% demonstrate the excellent luminescence properties of the as-prepared CCA1-xOSx-LEuH composites. This is the first report on the sensitized luminescence properties of layer Eu3+ ions in LRH composites in the delaminated state. The intriguing red luminescence of delaminated LEuH composites offers a promising approach to achieve efficient luminescent film materials. PMID- 28914951 TI - Plasmonic color metasurfaces fabricated by a high speed roll-to-roll method. AB - Lab-scale plasmonic color printing using nano-structured and subsequently metallized surfaces have been demonstrated to provide vivid colors. However, upscaling these structures for large area manufacturing is extremely challenging due to the requirement of nanometer precision of metal thickness. In this study, we have investigated a plasmonic color meta-surface design that can be easily upscaled. We have demonstrated the feasibility of fabrication of these plasmonic color surfaces by a high-speed roll-to-roll method, comprising roll-to-roll extrusion coating at 10 m min-1 creating a polymer foil having 100 nm deep pits of varying sub-wavelength diameter and pitch length. Subsequently this polymer foil was metallized and coated also by high-speed roll-to-roll methods. The perceived colors have high tolerance towards the thickness of the metal layer, when this thickness exceeds the depths of the pits, which enables the robust high speed fabrication. This finding can pave the way for plasmonic meta-surfaces to be implemented in a broader range of applications such as printing, memory, surface enhanced Raman scattering (SERS), biosensors, flexible displays, photovoltaics, security, and product branding. PMID- 28914952 TI - Nanocarriers for TRAIL delivery: driving TRAIL back on track for cancer therapy. AB - Since its initial identification, tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) has been shown to be capable of selectively inducing apoptosis in cancer cells. However, translation of the encouraging preclinical studies of this cytokine into the clinic has been restricted by its extremely short half-life, the presence of resistant cancer cell populations, and its inefficient in vivo delivery. Recently, there has been exceptional progress in developing novel formulations to increase the circulatory half-life of TRAIL and new combinations to treat cancers that are resistant to TRAIL. In particular, TRAIL-based nanotherapies offer the potential to improve the stability of TRAIL and prolong its half-life in plasma, to specifically deliver TRAIL to a particular target site, and to overcome resistance to TRAIL. The aim of this review is to provide an overview of the state-of-the art drug delivery systems that are currently being tested or developed to improve the biological attributes of TRAIL-based therapies. PMID- 28914953 TI - Grafting of a Eu3+-tfac complex on to a Tb3+-metal organic framework for use as a ratiometric thermometer. AB - Microrods of [Tb2(bpydc)3(H2O)3].nDMF (TbMOF) were employed as a platform for grafting a beta-diketonate complex of Eu3+ for the purpose of obtaining ratiometric luminescence thermometer materials. A straightforward post-synthetic functionalization is employed to obtain the TbMOF@Eu_tfac (tfac = trifluoroacetylacetonate) compounds. The emission color of the TbMOF@Eu compounds can be slightly tuned by varying the percentage of the grafted beta-diketonate complex of Eu3+. Also, as shown, the thermometric properties of the material can be tuned by the percentage of grafted beta-diketonate complex of Eu3+. The TbMOF@3%Eu_tfac and TbMOF@7.3%Eu_tfac compounds were investigated in detail for their use as luminescent ratiometric thermometers. For the TbMOF@3%Eu_tfac compound an absolute sensitivity Sa of 0.069 K-1 (225 K) and relative sensitivity Sr of 2.59%K-1 (225 K) were obtained showing its good sensing capability. For the TbMOF@7.3%Eu_tfac compound a Sa of 0.012 K-1 (275 K) and relative sensitivity Sr of 1.33%K-1 (325 K) were obtained showing that the TbMOF@3%Eu_tfac compound is superior for temperature sensor applications. We also show that the emission color of the parent TbMOF material itself can be tuned by varying the excitation wavelength from 250-380 nm. It can be tuned from light-green to blue by simply changing the excitation wavelength. PMID- 28914954 TI - Resident Rounds Part III: Case Report: Metastatic Cutaneous Squamous Cell Carcinoma in an African American Female. AB - Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer diagnosed in African Americans.1 Twenty to forty percent of cSCCs reported in African Americans are related to chronic scarring processes or areas of in ammation.2 Risk factors for developing cSCCs in patients of color include chronic scars resulting from burns, skin ulcers, and radiation sites; and chronic inflammatory diseases such as discoid lupus and hidradenitis suppuritiva.1 Although skin cancer only accounts for 1% to 2% of cancers diagnosed within African Americans, it is associated with increased morbidity and mortality in this population.1,3 Significant delays in diagnosis and treatment are largely thought to be responsible for this prognostic incongruity. The rate of metastasis in patients of color is 31%, compared with only 4% in Caucasians.4,5 Early recognition by physicians and increased awareness resulting in preventative measures by patients may decrease this noted disparity. J Drugs Dermatol. 2016;16(1):81-84.. PMID- 28914956 TI - Ischemic femoral head osteonecrosis in a piglet model causes three dimensional decrease in acetabular coverage. AB - Legg-Calve-Perthes disease (LCPD) is a childhood form of ischemic osteonecrosis marked by development of severe femoral head deformity and premature osteoarthritis. The pathogenesis of femoral head deformity has been studied extensively using a piglet model of ischemic osteonecrosis, however, accompanying acetabular changes have not been investigated. The purpose of this study was to determine if acetabular changes accompany femoral head deformity in a well established piglet model of LCPD and to define the acetabular changes using three dimensional computed tomography (3-D CT) and modeling. Twenty-four piglets were surgically induced with ischemic osteonecrosis on the right side. The contralateral hip was used as control. At 8 weeks postoperative, pelvi were retrieved and imaged with CT. Custom software was used to measure acetabular morphologic parameters on 3-D CT images. Moderate to severe femoral head deformities were present in all animals. Acetabula with accompanying femoral head deformity had a significant decrease in acetabular version and tilt (p < 0.001) and in coverage angle in the superior, posterior, and inferior quadrants (p < 0.05). These findings indicate that the development of femoral head deformity following ischemic osteonecrosis produces specific and predictable changes to the shape of the acetabulum. Acetabular changes described in patients with LCPD were observed in the piglet model. This model may serve as a valuable tool to elucidate the relationship between femoral head and acetabular deformities. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1173-1177, 2018. PMID- 28914955 TI - Alcohol-Related Mortality in Patients With Psoriasis: A Population-Based Cohort Study. AB - Importance: People diagnosed with psoriasis have an increased risk of premature mortality, but the underlying reasons for this mortality gap are unclear. Objective: To investigate whether patients with psoriasis have an elevated risk of alcohol-related mortality. Design, Setting, and Participants: An incident cohort of patients with psoriasis aged 18 years and older was delineated for 1998 through 2014 using the Clinical Practice Research Datalink (CPRD) and linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records. Patients with psoriasis were matched with up to 20 comparison patients without psoriasis on age, sex, and general practice. Main Outcomes and Measures: Alcohol-related deaths were ascertained via the Office for National Statistics mortality records. A stratified Cox proportional hazard model was used to estimate the cause-specific hazard ratio for alcohol-related death, with adjustment for socioeconomic status. Results: The cohort included 55 537 with psoriasis and 854 314 patients without psoriasis. Median (interquartile) age at index date was 47 (27) years; 408 230 of total patients (44.9%) were men. During a median (IQR) of 4.4 (6.2) years of follow-up, the alcohol-related mortality rate was 4.8 per 10 000 person-years (95% CI, 4.1-5.6; n = 152) for the psoriasis cohort, vs 2.5 per 10 000 (95% CI, 2.4- 2.7; n = 1118) for the comparison cohort. The hazard ratio for alcohol-related death in patients with psoriasis was 1.58 (95% CI, 1.31-1.91), and the predominant causes of alcohol-related deaths were alcoholic liver disease (65.1%), fibrosis and cirrhosis of the liver (23.7%), and mental and behavioral disorders due to alcohol (7.9%). Conclusions and Relevance: People with psoriasis have approximately a 60% greater risk of dying due to alcohol-related causes compared with peers of the same age and sex in the general population. This appears to be a key contributor to the premature mortality gap. These findings call for routine screening, identification and treatment, using the Alcohol Use Disorders Identification Test (AUDIT-C) in both primary and secondary care to detect alcohol consumption and misuse among people diagnosed with psoriasis. PMID- 28914957 TI - Hepatitis B virus core-related antigen levels predict progression to liver cirrhosis in hepatitis B carriers. AB - BACKGROUND AND AIM: Several hepatitis B virus (HBV) markers have been identified as risk factors for progression to liver cirrhosis in patients with chronic HBV infection. The predictive impact of HBV markers on progression to cirrhosis in HBV carriers was clarified. METHODS: A total of 529 hepatitis B e antigen seroconverters with fibrosis-4 (FIB-4) index <= 3.6 not on nucleos(t)ide analogue therapy were included. Univariate and multivariate analyses of associations between HBV markers and progression to cirrhosis were performed. In addition, the hazard ratio (HR) spline curves for continuous HBV markers were compared. RESULTS: Eighty-four patients progressed to cirrhosis (FIB-4 index > 3.6) during the follow-up period. Hepatitis B surface antigen (HBsAg), HBV DNA, HBV core related antigen (HBcrAg), and basal core promoter status, but not genotype and precore status, were significantly associated with progression to cirrhosis in univariate Cox proportional hazards models. Multivariate Cox proportional hazards models adjusted for HBV genotype, HBsAg, HBV DNA, HBcrAg, precore status, and basal core promoter status indicated that HBsAg >= 3.0 log IU/mL (HR, 0.53; 95% confidence interval [CI], 0.30-0.94) and HBcrAg >= 3.7 log U/mL (HR, 3.28; 95% CI, 1.60-6.75) are independently associated with progression to cirrhosis. In the HR spline curve analysis, HR and 95% CI gradually increased as HBcrAg levels increased. Conversely, HRs and 95% CIs for HBsAg and HBV DNA did not show this tendency as their levels increased. CONCLUSIONS: Elevated HBcrAg levels in HBV carriers increases the risk for progression to cirrhosis. HBcrAg is an excellent predictor of the development of cirrhosis. PMID- 28914958 TI - Assessment of histopathological features of maculopapular viral exanthem and drug induced exanthem. AB - BACKGROUND: Viral infections and drug reactions are the commonest causes of exanthems in clinical practice. Clinically, their overlapping features may pose a diagnostic challenge. Hematologic, in vitro, and drug provocation tests are either unreliable or impractical. METHODS: This was a descriptive, prospective study to assess and compare histopathological features of maculopapular viral and drug exanthem. Subjects fulfilling case definition of exanthems were included. Serum C-reactive protein (CRP) and absolute eosinophil count (AEC) were also studied. RESULTS: Skin biopsy slides of 48 cases were evaluated and AEC and CRP were performed. Both median AEC and CRP were lower in viral exanthem compared with drug exanthem. On histopathological evaluation, features such as lymphocytic exocytosis, and dermal infiltrate of eosinophils, lymphocytes and histiocytes were seen in a significantly greater number of drug exanthems. Other findings such as focal spongiosis, acanthosis, keratinocyte necrosis, basal cell damage, papillary dermal edema and atypical lymphocytes in the dermis were also observed in higher though not statistically significant number of drug exanthem biopsies. CONCLUSIONS: Certain histopathological features can help to differentiate between the two exanthems and this modality may be used in situations when there is clinical overlap and when drug rechallenge cannot be undertaken. PMID- 28914960 TI - Hidradenitis suppurativa is associated with myocardial infarction, but not stroke or peripheral arterial disease of the lower extremities. PMID- 28914959 TI - Nocturia is Associated with Poor Sleep Quality Among Older Women in the Study of Osteoporotic Fractures. AB - OBJECTIVES: (1) To examine relationships between frequency of nocturia and self reported sleep quality and objective sleep measures in older women, and (2) to estimate the amount of variation in sleep measures that is specifically attributable to frequency of nocturia. DESIGN AND SETTING: Secondary, cross sectional analysis of the multicenter prospective cohort Study of Osteoporotic Fractures (SOF). PARTICIPANTS: Community-dwelling women aged >=80 years. MEASUREMENTS: Frequency of nocturia in the previous 12 months, Pittsburgh Sleep Quality Index sleep quality subscale, and actigraphy-measured wake after sleep onset (WASO) and total sleep time (TST). RESULTS: Of 1,520 participants, 25% (n = 392) reported their nocturia frequency was 3-4 times/night and an additional 60% (n = 917) reported their nocturia frequency was 1-2 times/night. More frequent nocturia was associated with poor sleep quality (3-4/night: 26.8% reported fairly bad or very bad sleep quality; 1-2/night: 14.7%; 0/night: 7.7%; P < .001) and longer WASO (3-4/night: 89.8 minutes; 1-2/night: 70.6; 0/night: 55.5; P < .001). In nested regression models, a nocturia frequency of 3-4/night quadrupled the odds of poor sleep quality (odds ratio: 4.26 [95% CI 1.65, 11.01]; P = .003) and was associated with a 37-minute worsening in WASO (95% CI 26.0, 49.0; P < .001). Frequency of nocturia explained an additional 6% variation in WASO, above and beyond demographic, medical/psychiatric conditions, and medication factors (?R2 = 0.06). CONCLUSIONS: Nocturia is common among octogenarian and nonagenarian women and is independently associated with poor sleep quality and longer wake time at night. Interventions that improve nocturia may be useful in improving sleep quality and wake time at night. PMID- 28914961 TI - A semiparametric likelihood-based method for regression analysis of mixed panel count data. AB - Panel-count data arise when each study subject is observed only at discrete time points in a recurrent event study, and only the numbers of the event of interest between observation time points are recorded (Sun and Zhao, 2013). However, sometimes the exact number of events between some observation times is unknown and what we know is only whether the event of interest has occurred. In this article, we will refer this type of data to as mixed panel-count data and propose a likelihood-based semiparametric regression method for their analysis by using the nonhomogeneous Poisson process assumption. However, we establish the asymptotic properties of the resulting estimator by employing the empirical process theory and without using the Poisson assumption. Also, we conduct an extensive simulation study, which suggests that the proposed method works well in practice. Finally, the method is applied to a Childhood Cancer Survivor Study that motivated this study. PMID- 28914962 TI - Impaired Phosphate Tolerance Revealed With an Acute Oral Challenge. AB - Elevated serum phosphate is consistently linked with cardiovascular disease (CVD) events and mortality in the setting of normal and impaired kidney function. However, serum phosphate does not often exceed the upper limit of normal until glomerular filtration rate (GFR) falls below 30 mL/min/m2 . It was hypothesized that the response to an oral, bioavailable phosphate load will unmask impaired phosphate tolerance, a maladaptation not revealed by baseline serum phosphate concentrations. In this study, rats with varying kidney function as well as normo phosphatemic human subjects, with inulin-measured GFR (13.2 to 128.3mL/min), received an oral phosphate load. Hormonal and urinary responses were evaluated over 2 hours. Results revealed that the more rapid elevation of serum phosphate was associated with subjects and rats with higher levels of kidney function, greater responsiveness to acute changes in parathyroid hormone (PTH), and significantly more urinary phosphate at 2 hours. In humans, increases in urinary phosphate to creatinine ratio did not correlate with baseline serum phosphate concentrations but did correlate strongly to early increase of serum phosphate. The blunted rise in serum phosphate in rats with CKD was not the result of altered absorption. This result suggests acute tissue deposition may be altered in the setting of kidney function impairment. Early recognition of impaired phosphate tolerance could translate to important interventions, such as dietary phosphate restriction or phosphate binders, being initiated at much higher levels of kidney function than is current practice. (c) 2017 American Society for Bone and Mineral Research. PMID- 28914963 TI - Class categories and the subjective dimension of class: the case of Denmark. AB - Class relations have been proven to affect various aspects of social life, even in modern individualized societies. However, following claims on individualization and the so-called 'death of class' thesis, studying the subjective dimension of class - that is, the way individuals perceive of class relations and their own position within them - has gone out of style. We argue that even in equalized societies, subjective class perceptions may still influence attitudes and behaviour as they evolve to fit modern class relations. To explore the existence as well as structure and content of perceived social classes, this article investigates how people describe society and social groups in focus group discussions. We find that groups in different positions in terms of education and economy all tend to apply hierarchical class categories to describe Danish society, which is normally seen as one of the most equal societies and political systems in the world. In addition, we find that economic resources serve as a baseline for the hierarchical ordering, often supplemented with notions of education, lifestyle and/or occupational profile. Even though people are somewhat uncomfortable with the notion of class, their descriptions of Danish society and classes are surprisingly similar within and across groups. We conclude that not only do class relations matter; people are also highly aware of the existing classes and able to position themselves and others according to their notion of classes. PMID- 28914964 TI - Clinicopathological and molecular implications of aberrant thyroid transcription factor-1 expression in colorectal carcinomas: an immunohistochemical analysis of 1319 cases using three different antibody clones. AB - AIMS: The precise profile of aberrant expression of thyroid transcription factor 1 (TTF-1) according to antibody clones in colorectal carcinomas (CRCs) has been controversial. Moreover, the detailed clinicopathological and molecular features of CRCs with TTF-1 expression have rarely been investigated. The aim of this study was to evaluate TTF-1 expression status in a large series of CRC cases by using three different antibody clones. METHODS AND RESULTS: Immunohistochemistry for TTF-1 with clones 8G7G3/1, SPT24 and SP141 was performed on tumour tissues of 1319 primary CRCs and 98 corresponding metastatic lesions. Among the 1319 CRCs, TTF-1 expression was detected in 68 cases by both clone SPT24 and clone SP141. TTF-1 expression was not detected in any of the cases when clone 8G7G3/1 was used. The 68 CRCs with TTF-1 expression detected by both clone SPT24 and clone SP141 were considered to be TTF-1-positive in this study. TTF-1 positivity was significantly associated with distal tumour location, non-mucinous histology, intact CDX2 expression and a low frequency of KRAS mutations in CRCs. Nearly all TTF-1-positive CRCs showed microsatellite-stable and CpG island methylator phenotype-negative statuses. TTF-1 positivity was also found in all metastatic lesions of the five TTF-1-positive primary CRCs. TTF-1 negativity was maintained in all metastatic lesions of the 93 TTF-1-negative primary CRCs. CONCLUSIONS: Our study confirmed that the frequency and characteristics of aberrant TTF-1 expression in CRCs vary according to the antibody clone. Aberrant TTF-1 expression detected by clone SPT24 or SP141 may be encountered preferentially in distally located, conventional pathway-type CRCs. PMID- 28914966 TI - Monte Carlo methods for nonparametric regression with heteroscedastic measurement error. AB - Nonparametric regression is a fundamental problem in statistics but challenging when the independent variable is measured with error. Among the first approaches was an extension of deconvoluting kernel density estimators for homescedastic measurement error. The main contribution of this article is to propose a new simulation-based nonparametric regression estimator for the heteroscedastic measurement error case. Similar to some earlier proposals, our estimator is built on principles underlying deconvoluting kernel density estimators. However, the proposed estimation procedure uses Monte Carlo methods for estimating nonlinear functions of a normal mean, which is different than any previous estimator. We show that the estimator has desirable operating characteristics in both large and small samples and apply the method to a study of benzene exposure in Chinese factory workers. PMID- 28914968 TI - Neighborhood Characteristics and Adolescent Suicidal Behavior: Evidence from a Population-based Study. AB - Research on the relationship between neighborhood characteristics and adolescents' risk of nonfatal suicidal behavior is scarce. We used California survey data to examine associations between measures of objective neighborhood quality (levels of violent crime, property crime, and socioeconomic disadvantage) and subjective neighborhood quality (perceptions of neighborhood safety and social cohesion) and adolescents' self-reported suicidal ideation and suicide attempt. Objective measures of neighborhood quality were unrelated to adolescents' risk of suicidal behavior. However, adolescents who perceived their neighborhoods to be less safe and less cohesive were 20%-45% more likely than nonsuicidal peers to report suicidal ideation and attempt. PMID- 28914967 TI - The chemotherapy response score is a useful histological predictor of prognosis in high-grade serous carcinoma. AB - AIMS: High-grade serous carcinoma (HGSC) is the most common tubal/ovarian malignant tumour, and usually presents at an advanced stage. Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) is being increasingly used for the management of these patients. The chemotherapy response score (CRS) has been proposed for grading the response of tubo-ovarian HGSC to NACT on the basis of examination of IDS specimens. Our aims were to evaluate the CRS in post-NACT cases, assess the interobserver agreement, and correlate it with overall and progression-free survival. METHODS AND RESULTS: The CRS was applied by two independent pathologists on omental and adnexal tumour tissue sections from post NACT patients with HGSC who had undergone IDS. The assigned primary site of tumour origin was documented. The interobserver agreement and prognostic significance of the CRS were evaluated. There were 103 cases, and in 61.1% of cases a fallopian tubal origin was confirmed. There were 26, 35 and 42 cases with CRSs of 1, 2, and 3, respectively. The interobserver variability for CRS was low (kappa = 0.806). The CRS showed a significant correlation with progression-free survival (CRS 1 and 2 versus 3: median survival 16 months versus 18 months; P = 0.004); however, after controlling for debulking status, this association was not significant. The CRS applied to adnexal sections did not show any prognostic significance for either progression-free or overall survival. CONCLUSION: The CRS is an easy and reproducible method for predicting the prognosis in post-NACT HGSC patients. PMID- 28914969 TI - Autocrine and Paracrine Regulation of the Murine Skeleton by Osteocyte-Derived Parathyroid Hormone-Related Protein. AB - Parathyroid hormone-related protein (PTHrP) and parathyroid hormone (PTH) have N terminal domains that bind a common receptor, PTHR1. N-terminal PTH (teriparatide) and now a modified N-terminal PTHrP (abaloparatide) are US Food and Drug Administration (FDA)-approved therapies for osteoporosis. In physiology, PTHrP does not normally circulate at significant levels, but acts locally, and osteocytes, cells residing within the bone matrix, express both PTHrP and the PTHR1. Because PTHR1 in osteocytes is required for normal bone resorption, we determined how osteocyte-derived PTHrP influences the skeleton. We observed that adult mice with low PTHrP in osteocytes (targeted with the Dmp1(10kb)-Cre) have low trabecular bone volume and osteoblast numbers, but osteoclast numbers were unaffected. In addition, bone size was normal, but cortical bone strength was impaired. Osteocyte-derived PTHrP therefore stimulates bone formation and bone matrix strength, but is not required for normal osteoclastogenesis. PTHrP knockdown and overexpression studies in cultured osteocytes indicate that osteocyte-secreted PTHrP regulates their expression of genes involved in matrix mineralization. We determined that osteocytes secrete full-length PTHrP with no evidence for secretion of lower molecular weight forms containing the N-terminus. We conclude that osteocyte-derived full-length PTHrP acts through both PTHR1 receptor-mediated and receptor-independent actions in a paracrine/autocrine manner to stimulate bone formation and to modify adult cortical bone strength. (c) 2017 American Society for Bone and Mineral Research. PMID- 28914970 TI - MicroRNA-410 is involved in mitophagy after cardiac ischemia/reperfusion injury by targeting high-mobility group box 1 protein. AB - Mitochondrial dysfunction has emerged as a critical pathophysiological factor of myocardial ischemia/reperfusion (I/R) injury. A thorough understanding of mitochondrial dysfunction during I/R at the molecular level is urgently needed. One prominent microRNA, miR-410, was previously reported to be dynamically regulated in diverse cardiomyopathies, but its mechanism is unclear. In the present study, in a cardiac I/R injury mice model, the expression of miR-410 was significantly upregulated, accompanied with decreased mitochondrial function and mitophagy deficit. After an unbiased search for downstream messenger RNA targets of miR-410, effects of the target gene in mitochondrial dysfunction during I/R injury and the underlying mechanism were further explored in cultured human adult cardiac myocytes (HACMs). The results showed that MitoTracker Red-labeled HACMs mitochondria overlapped with GFP-LC3-labeled autophagosomes, suggesting the presence of mitophagy. MiR-410 expression was significantly increased in hypoxia/reoxygenation (H/R)-stimulated HACMs. MiR-410 overexpression further inhibited cell viability, ATP production, mitochondrial membrane potential and mitophagy level, and increased caspase-3 activity, Bax expression and cytochrome c release. Conversely, inhibition of miR-410 attenuated these effects. We found that miR-410 directly interacted with the 3'-untranslated region of the suppressor of high-mobility group box 1 protein (HMGB1) by Dual-Luciferase assay. Moreover, pcDNA3.1-HMGB1 pretreatment effectively reduced the inhibition effects of cell viability and mitophagy brought by H/R, while all those effects can be attenuated by pretreatment with HSPB1 siRNA transfection. Taken together, our results suggest that miR-410 may inhibit mitophagy after cardiac I/R injury by modulating HSPB1 activity via directly targeting HMGB1. PMID- 28914971 TI - Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts. AB - Hydrological models are often set up to provide specific forecasts of interest. Owing to the inherent uncertainty in data used to derive model structure and used to constrain parameter variations, the model forecasts will be uncertain. Additional data collection is often performed to minimize this forecast uncertainty. Given our common financial restrictions, it is critical that we identify data with maximal information content with respect to forecast of interest. In practice, this often devolves to qualitative decisions based on expert opinion. However, there is no assurance that this will lead to optimal design, especially for complex hydrogeological problems. Specifically, these complexities include considerations of multiple forecasts, shared information among potential observations, information content of existing data, and the assumptions and simplifications underlying model construction. In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when selecting future measurement sets. PMID- 28914972 TI - Seasonal patterns of acute and recurrent idiopathic pericarditis. AB - BACKGROUND: Idiopathic pericarditis is presumed to result from viral infection. The incidence rates of some viral infections have typical seasonal patterns. The data in the literature on a possible seasonal pattern of acute pericarditis are very limited. The mechanism and possible seasonality of recurrent episodes are not well established . HYPOTHESIS: The incidence of acute idiopathic pericarditis has a seasonal pattern. METHODS: The computerized database of a tertiary, university-affiliated hospital was searched for all patients admitted with a first episode of acute idiopathic pericarditis between January 1, 2010 and December 31, 2015. Patients for whom a nonviral etiology for the pericarditis was identified were excluded. RESULTS: The final cohort included 175 patients (75% male) ages 19 to 86 years (median = 50.0 +/- 18.2 years). The incidence of the disease was twice as high during the colder half of the year (October-March) than the warmer half, peaking in the first quarter (January-March, P = 0.001). This first-quarter peak was observed in each of the 6 years examined. Comparison of the patients who acquired pericarditis during peak and nonpeak quarters yielded no differences in baseline characteristics, peak body temperature, white blood cell count, C-reactive protein level, or frequency of myocardial involvement or liver enzyme elevation. No seasonal pattern was identified for recurrent episodes of pericarditis (n = 57). CONCLUSIONS: Acute idiopathic pericarditis appears to have a seasonal pattern with a distinct late winter peak. No seasonal pattern was identified for recurrent episodes. PMID- 28914973 TI - Comparison of mid- to long-term clinical outcomes between anatomical testing and usual care in patients with suspected coronary artery disease: A meta-analysis of randomized trials. AB - BACKGROUND: Controversies remain regarding clinical outcomes following initial strategies of coronary computed tomography angiography (CCTA) vs usual care with functional testing in patients with suspected coronary artery disease (CAD). HYPOTHESIS: CCTA as initial diagnostic strategy results in better mid- to long term outcomes than usual care in patients with suspected CAD. METHODS: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials comparing clinical outcomes during >=6 months' follow-up between initial anatomical testing by CCTA vs usual care with functional testing in patients with suspected CAD. Occurrence of all-cause mortality, nonfatal myocardial infarction (MI), and major adverse cardiovascular events (MACE), and use of invasive coronary angiography and coronary revascularization, were compared between the 2 diagnostic strategies. RESULTS: Twelve trials were included (20 014 patients; mean follow-up, 20.5 months). Patients undergoing CCTA as initial noninvasive testing had lower risk of nonfatal MI compared with those treated with usual care (risk ratio [RR]: 0.70, 95% confidence interval [CI]: 0.52-0.94, P = 0.02). There was a tendency for reduced MACE following initial CCTA strategy, but not for risk of all-cause mortality. Compared with functional testing, the CCTA strategy increased use of invasive coronary angiography (RR: 1.53, 95% CI: 1.12-2.09, P = 0.007) and coronary revascularization (RR: 1.49, 95% CI: 1.11-2.00, P = 0.007). CONCLUSIONS: Anatomical testing with CCTA as the initial noninvasive diagnostic modality in patients with suspected CAD resulted in lower risk of nonfatal MI than usual care with functional testing, at the expense of more frequent use of invasive procedures. PMID- 28914974 TI - Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-keratin 5-specific transgenic mice. AB - BACKGROUND: Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. METHODS: Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. RESULTS: We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. CONCLUSION: Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation. PMID- 28914975 TI - Seroepidemiology of hepatitis E virus infection in pigs in Durango State, Mexico. AB - No information about hepatitis E virus (HEV) infection in pigs in the northern Mexican state of Durango exists. We determined the seroprevalence and correlates of anti-HEV IgG antibodies in pigs in Durango, Mexico. Through a cross-sectional study, we studied 427 pigs raised in backyards (n = 328), or slaughtered (n = 99) in Durango. Sera of pigs were analyzed for anti-HEV IgG antibodies using a commercially available enzyme-linked immunoassay. Antibodies to HEV were found in 193 (45.2%) of the 427 pigs studied. A significantly higher seroprevalence was observed in slaughtered pigs (79.8%) than in backyard pigs (34.8%). Bivariate analysis showed that HEV seropositivity was associated with age, sex, breed, climate, altitude, mean annual temperature, mean annual rainfall, and farm raising. Logistic regression analysis showed that HEV seropositivity was associated with the origin (Sonora State) of pigs (OR=6.51; 95%CI: 3.74-11.32; P < 0.001), and mean annual rainfall (<=600 mm) (OR=1.78; 95%CI: 1.01-3.15; P = 0.04). A high seroprevalence of HEV infection in pigs slaughtered for human consumption in Durango City was found. This is the first report of an association between HEV seropositivity in pigs and climatic factors. Infection factors found may help for the optimal planning of preventive measures against HEV infection. PMID- 28914976 TI - Haloperidol Versus 5-HT3 Receptor Antagonists for Postoperative Vomiting and QTc Prolongation: A Noninferiority Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials. AB - Haloperidol is an antipsychotic with well-known antiemetic potential. It is underutilized for postoperative nausea vomiting due to reported corrected QT interval (QTc) prolongation. This meta-analysis evaluates its safety and efficacy as an antiemetic in the perioperative period. Trials comparing haloperidol to 5 HT3 -receptor antagonists (5-HT3 -RA) for 24 postoperative vomiting incidences published up to May 2017 were searched in the medical database. Comparisons were made for antiemetic efficiency variables (vomiting incidence, rescue antiemetic need, and patients with complete response) during early (until 6 hours) and late postoperative phases. Eight randomized controlled double-blinded trials were included in the final analysis. Twenty-four-hour vomiting incidence was similar in groups (fixed effects, P = 0.52, I2 = 0%). Trial-sequential analysis confirmed noninferiority of haloperidol over 5-HT3 -RAs (alpha = 5%, beta = 20%, delta = 10%), with "information size" being 859 (required > 812). Pooled results did not demonstrate superiority/inferiority of 5-HT3 -RAs over haloperidol in all other antiemetic efficacy variables (early and delayed). Negligible heterogeneity was found in all the comparisons made. Pooled Mantel Haenszel odds ratio for QTc prolongation was equivalent in both groups (fixed effects, P = 0.23, I2 = 0%). The mean dose of haloperidol used was 1.34 mg, and no trial reported extrapyramidal side effects. Trial-sequential analysis showed statistical equivalence (alpha = 5%, beta = 20%, delta = 10%), with information size being 745 (required > 591). Publication bias was unlikely (Egger test, X-intercept = 2.07, P = 0.10). We conclude that haloperidol is equivalent to the well established 5-HT3 -RAs in preventing vomiting during the first day after surgery. The incidence of QTc prolongation with haloperidol is statistically equivalent to 5-HT3 -RAs and thus should not be the factor that discourages its use for treatment/prophylaxis of postoperative nausea vomiting. PMID- 28914977 TI - Autism, theory of mind, and the reactive attitudes. AB - Whether to treat autism as exculpatory in any given circumstance appears to be influenced both by models of autism and by theories of moral responsibility. This article looks at one particular combination of theories: autism as theory of mind challenges and moral responsibility as requiring appropriate experience of the reactive attitudes. In pursuing this particular combination of ideas, we do not intend to endorse them. Our goal is, instead, to explore the implications of this combination of especially prominent ideas about autism and about moral responsibility. These implications can be quite serious and practical for autists and those who interact directly with autists, as well as for broader communities as they attend to the fair, compassionate, and respectful treatment of increasing numbers of autistic adults. We find that these theories point to a limited range of situations in which autists should not be blamed for transgressive actions for which neurotypical individuals should be blamed. We build on what others have written on these issues by bringing in a recent cognitive model of the role theory of mind plays in empathy, by discussing the social implications of the theoretical findings, and by raising questions about the compatibility of reactive attitude theories of moral responsibility with the neurodiversity approach to autism. PMID- 28914978 TI - Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children. AB - Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children. Accordingly, a semimechanistic pharmacokinetic-enzyme turnover model was developed in a step-wise approach: (1) a population pharmacokinetic model for adults was developed; (2) the adult model was scaled to children using allometry and physiology-based scaling; and (3) the scaled model was externally qualified, updated with clinical data, and optimal doses were projected. A 2-compartment model accounting for saturable clearance and GSTZ1 enzyme turnover successfully characterized the DCA PK in adults and children. DCA-induced inactivation of GSTZ1 resulted in phenoconversion of all subjects into slow metabolizers after repeated dosing. However, rate and extent of inactivation was 2-fold higher in subjects without the wild-type EGT allelic variant of GSTZ1, resulting in further phenoconversion into ultraslow metabolizers after repeated DCA administration. Furthermore, DCA-induced GSTZ1 inactivation rate and extent was found to be 25- to 30-fold lower in children than in adults, potentially accounting for the observed age-dependent changes in PK. Finally, a 12.5 and 10.6 mg/kg twice-daily DCA dose was optimal in achieving the target steady-state trough concentrations (5-25 mg/L) for EGT carrier and EGT noncarrier children, respectively. PMID- 28914979 TI - Systemic Evaluation of Vascular Dysfunction by High-Resolution Sonography in an Nomega -Nitro-l-Arginine Methyl Ester Hydrochloride-Induced Mouse Model of Preeclampsia-Like Symptoms. AB - OBJECTIVES: The purpose of this study was to evaluate vascular function, including arterial resistance and endothelial function, by high-resolution sonography in an Nomega -nitro-l-arginine methyl ester hydrochloride (l-NAME) induced mouse model of preeclampsia-like symptoms. METHODS: Pregnant mice were subcutaneously injected with a saline solution (control; n = 10) or l-NAME (n = 10) between the 7th and 18th days of gestation. The resistive index and pulsatility index (RI and PI, indicators of arterial resistance) of the uteroplacental, umbilical, femoral, and common carotid arteries and the flow mediated dilatation (index of endothelial function) of the femoral artery were measured by high-frequency sonography in both groups. RESULTS: We noted significant increases in the RI and PI of the uteroplacental and umbilical arteries and a decrease in the flow-mediated dilatation of the femoral artery in the l-NAME group compared with the control group. We also found that the RI and PI of the uteroplacental and umbilical arteries were negatively correlated with fetal weight and crown-rump length. The results of the multivariate analysis using a logistic regression model indicated that the flow-mediated dilatation at 120 seconds was an independent diagnostic criterion for the l-NAME-induced preeclampsia-like model. A receiver operating characteristic analysis showed that flow-mediated dilatation at 120 seconds had the greatest area under the curve of 0.934, with an optimal cutoff point of 11.1%, yielding sensitivity of 100% and specificity of 84.6%. CONCLUSIONS: The PI and RI of the fetomaternal vasculature can identify fetuses in "high-risk" pregnancies, and flow-mediated dilatation is a reliable indicator for predicting preeclampsia. Assessment of vascular function by high-resolution sonography provides a useful platform for preeclampsia-related basic research with high reproducibility. PMID- 28914980 TI - Co3 O4 @Co/NCNT Nanostructure Derived from a Dicyanamide-Based Metal-Organic Framework as an Efficient Bi-functional Electrocatalyst for Oxygen Reduction and Evolution Reactions. AB - There has been growing interest in the synthesis of efficient reversible oxygen electrodes for both the oxygen reduction reaction (ORR) and the oxygen evolution reactions (OER), for their potential use in a variety of renewable energy technologies, such as regenerative fuel cells and metal-air batteries. Here, a bi functional electrocatalyst, derived from a novel dicyanamide based nitrogen rich MOF {[Co(bpe)2 (N(CN)2 )]?(N(CN)2 )?(5 H2 O)}n [Co-MOF-1, bpe=1,2-bis(4 pyridyl)ethane, N(CN)2- =dicyanamide] under different pyrolysis conditions is reported. Pyrolysis of the Co-MOF-1 under Ar atmosphere (at 800 degrees C) yielded a Co nanoparticle-embedded N-doped carbon nanotube matrix (Co/NCNT-Ar) while pyrolysis under a reductive H2 /Ar atmosphere (at 800 degrees C) and further mild calcination yielded Co3 O4 @Co core-shell nanoparticle-encapsulated N-doped carbon nanotubes (Co3 O4 @Co/NCNT). Both catalysts show bi-functional activity towards ORR and OER, however, the core-shell Co3 O4 @Co/NCNT nanostructure exhibited superior electrocatalytic activity for both the ORR with a potential of 0.88 V at a current density of -1 mA cm-2 and the OER with a potential of 1.61 V at 10 mA cm-2 , which is competitive with the most active bi functional catalysts reported previously. PMID- 28914981 TI - FNA cytology of solitary fibrous tumors and the diagnostic value of STAT6 immunocytochemistry. AB - BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors commonly located in the pleura, soft tissues, or meninges and are characterized by the NGFI-A-binding protein 2 (NAB2)-signal transducer and activator of transcription 6 (STAT6) fusion gene. Recent studies have indicated that nuclear STAT6 immunohistochemistry is a specific marker for SFTs. METHODS: The authors reviewed fine-needle aspiration (FNA) specimens from extracranial SFTs diagnosed at their institution between 1993 and 2017. Histologic blocks and available formalin-fixed smears of FNA specimens from SFTs were investigated for STAT6 immunoreactivity using a monoclonal antibody. STAT6 immunocytochemistry was also investigated in schwannomas and spindle cell lipomas. Cytopathologic and clinical characteristics were described. RESULTS: Nineteen benign and 9 malignant SFTs were identified. Both benign and malignant SFTs had a female predominance (female-to-male ratio, 2.8:1 and 1.25, respectively). Localization varied, and approximately one-half of the extrapleural tumors were located in the extremities and frequently were intramuscular. Benign and malignant primary tumors had limited differences in cytologic presentation, the most notable feature being nuclear pleomorphism. Cytomorphologic features included low-to-moderate cellularity of mixed oval, elongated, round, and stellate cells with pink collagenous stroma and hypercellular clusters with infrequent atypia. In metastatic SFTs, the cytopathology was suggestive of sarcoma. Immunohistochemistry revealed nuclear STAT6 immunoreactivity in SFTs (n = 5) with cytoplasmic reactivity in cytologic mimickers. CONCLUSIONS: Benign and malignant SFTs have common cytopathologic features, and the ability to distinguish between them is limited. Nuclear STAT6 immunoreactivity is a valuable cytologic marker for SFTs. Cancer Cytopathol 2018;126:36-43. (c) 2017 American Cancer Society. PMID- 28914982 TI - Production of accurate skeletal models of domestic animals using three dimensional scanning and printing technology. AB - Access to adequate anatomical specimens can be an important aspect in learning the anatomy of domestic animals. In this study, the authors utilized a structured light scanner and fused deposition modeling (FDM) printer to produce highly accurate animal skeletal models. First, various components of the bovine skeleton, including the femur, the fifth rib, and the sixth cervical (C6) vertebra were used to produce digital models. These were then used to produce 1:1 scale physical models with the FDM printer. The anatomical features of the digital models and three-dimensional (3D) printed models were then compared with those of the original skeletal specimens. The results of this study demonstrated that both digital and physical scale models of animal skeletal components could be rapidly produced using 3D printing technology. In terms of accuracy between models and original specimens, the standard deviations of the femur and the fifth rib measurements were 0.0351 and 0.0572, respectively. All of the features except the nutrient foramina on the original bone specimens could be identified in the digital and 3D printed models. Moreover, the 3D printed models could serve as a viable alternative to original bone specimens when used in anatomy education, as determined from student surveys. This study demonstrated an important example of reproducing bone models to be used in anatomy education and veterinary clinical training. Anat Sci Educ 11: 73-80. (c) 2017 American Association of Anatomists. PMID- 28914983 TI - Suggesting the cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A retrospective analysis of atypical and suspicious nodules. AB - BACKGROUND: The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) has replaced a subset of follicular variant of papillary thyroid carcinoma due to the indolent behavior of such tumors. NIFTPs are most often classified in an "indeterminate" diagnostic category. In the current study, the authors sought to identify cytologic features helpful in distinguishing NIFTP from other entities in these categories, particularly benign nodules. METHODS: The authors retrospectively evaluated a consecutive cohort of 130 thyroid fine-needle aspiration (FNA) specimens with an indeterminate diagnosis and available histopathologic follow-up. All FNA specimens were evaluated using the ThinPrep method. Each FNA was blindly reviewed by 2 board certified cytopathologists, who assessed overall cellularity; architectural parameters; and nuclear features, including nuclear pallor and fine chromatin, distinct nucleoli, and irregular nuclear membranes. Each case received a score of 0 to 3, based on the presence or absence of these 3 nuclear features. RESULTS: Nuclear but not architectural features appeared to distinguish NIFTP from benign nodules. Ninety-one percent of the NIFTPs (32 of 35 NIFTPs) received a score of >=2, compared with 35% of benign nodules (23 of 66 benign nodules) (P<.0001). In contrast, NIFTP could not be differentiated from the invasive/infiltrative follicular variant of papillary thyroid carcinoma using these criteria (P = 1.000). Nuclear scoring was found to be especially useful in atypia of undetermined significance/follicular lesion of undetermined significance (AUS); a score >=2 enriched for NIFTP (39% vs 3% of AUS cases with a score <2), whereas a score <2 was more likely benign (85% vs 50% of AUS cases with a score >=2). CONCLUSIONS: In indeterminate FNA specimens, the distinction of a possible NIFTP from a benign thyroid nodule can be suggested using a simple nuclear scoring system that is most valuable in AUS aspirates. Cancer Cytopathol 2018;126:86-93. (c) 2017 American Cancer Society. PMID- 28914986 TI - Linkages of Nursing Diagnoses, Outcomes, and Interventions Performed by Nurses Caring for Medical and Surgical Patients Using a Decision Support System. PMID- 28914985 TI - Cherubism Mice Also Deficient in c-Fos Exhibit Inflammatory Bone Destruction Executed by Macrophages That Express MMP14 Despite the Absence of TRAP+ Osteoclasts. AB - Currently, it is believed that osteoclasts positive for tartrate-resistant acid phosphatase (TRAP+) are the exclusive bone-resorbing cells responsible for focal bone destruction in inflammatory arthritis. Recently, a mouse model of cherubism (Sh3bp2KI/KI ) with a homozygous gain-of-function mutation in the SH3-domain binding protein 2 (SH3BP2) was shown to develop auto-inflammatory joint destruction. Here, we demonstrate that Sh3bp2KI/KI mice also deficient in the FBJ osteosarcoma oncogene (c-Fos) still exhibit noticeable bone erosion at the distal tibia even in the absence of osteoclasts at 12 weeks old. Levels of serum collagen I C-terminal telopeptide (ICTP), a marker of bone resorption generated by matrix metalloproteinases (MMPs), were elevated, whereas levels of serum cross linked C-telopeptide (CTX), another resorption marker produced by cathepsin K, were not increased. Collagenolytic MMP levels were increased in the inflamed joints of the Sh3bp2KI/KI mice deficient in c-Fos. Resorption pits contained a large number of F4/80+ macrophages and genetic depletion of macrophages rescued these erosive changes. Importantly, administration of NSC405020, an MMP14 inhibitor targeted to the hemopexin (PEX) domain, suppressed bone erosion in c Fos-deficient Sh3bp2KI/KI mice. After activation of the NF-kappaB pathway, macrophage colony-stimulating factor (M-CSF)-dependent macrophages from c-Fos deficient Sh3bp2KI/KI mice expressed increased amounts of MMP14 compared with wild-type macrophages. Interestingly, receptor activator of NF-kappaB ligand (RANKL)-deficient Sh3bp2KI/KI mice failed to show notable bone erosion, whereas c Fos deletion did restore bone erosion to the RANKL-deficient Sh3bp2KI/KI mice, suggesting that osteolytic transformation of macrophages requires both loss-of function of c-Fos and gain-of-function of SH3BP2 in this model. These data provide the first genetic evidence that cells other than osteoclasts can cause focal bone destruction in inflammatory bone disease and suggest that MMP14 is a key mediator conferring pathological bone-resorbing capacity on c-Fos-deficient Sh3bp2KI/KI macrophages. In summary, the paradigm that osteoclasts are the exclusive cells executing inflammatory bone destruction may need to be reevaluated based on our findings with c-Fos-deficient cherubism mice lacking osteoclasts. (c) 2017 American Society for Bone and Mineral Research. PMID- 28914987 TI - European Society of Cardiology 2017. AB - Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians. PMID- 28914984 TI - Hypercalcemic Disorders in Children. AB - Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. (c) 2017 American Society for Bone and Mineral Research. PMID- 28914988 TI - Metallacrowns as Templates for Diabolo-like {LnCu8 } Complexes with Nearly Perfect Square Antiprismatic Geometry. AB - A series of diabolo-like nonanuclear {LnIII CuII8 } (Ln=Tb, Dy, Ho, Er, Tm, Yb, and Y) clusters were prepared in which the LnIII ion is capped by two 8-MC-4 metallacrown ligands to form a nearly ideal square antiprismatic (SAP) coordination geometry with D4d symmetry. Despite the lack of crystallographic symmetry, these molecules engender the lanthanide ions with highly axial mJ states. The axial/equatorial nature of the crystal field in environments close to ideal SAP geometry is very subtle and influenced by the nature of the ligand lone pairs. Slow magnetic relaxation behaviour was observed for the DyIII , ErIII , TmIII , and YbIII analogues, and the obtained effective energy barriers are not consistent with excitations on the LnIII ion, suggesting a more nuanced situation. PMID- 28914990 TI - Simulating the multi-disciplinary care team approach: Enhancing student understanding of anatomy through an ultrasound-anchored interprofessional session. AB - Quality of healthcare delivery is dependent on collaboration between professional disciplines. Integrating opportunities for interprofessional learning in health science education programs prepares future clinicians to function as effective members of a multi-disciplinary care team. This study aimed to create a modified team-based learning (TBL) environment utilizing ultrasound technology during an interprofessional learning activity to enhance musculoskeletal anatomy knowledge of first year medical (MD) and physical therapy (PT) students. An ultrasound demonstration of structures of the upper limb was incorporated into the gross anatomy courses for first-year MD (n = 53) and PT (n = 28) students. Immediately before the learning experience, all students took an individual readiness assurance test (iRAT) based on clinical concepts regarding the assigned study material. Students observed while a physical medicine and rehabilitation physician demonstrated the use of ultrasound as a diagnostic and procedural tool for the shoulder and elbow. Following the demonstration, students worked within interprofessional teams (n = 14 teams, 5-6 students per team) to review the related anatomy on dissected specimens. At the end of the session, students worked within interprofessional teams to complete a collaborative clinical case based multiple choice post-test. Team scores were compared to the mean individual score within each team with the Wilcoxon signed-rank test. Students scored higher on the collaborative post-test (95.2 +/-10.2%) than on the iRAT (66.1 +/- 13.9% for MD students and 76.2 +/-14.2% for PT students, P < 0.0001). Results suggest that this interprofessional team activity facilitated an improved understanding and clinical application of anatomy. Anat Sci Educ 11: 94-99. (c) 2017 American Association of Anatomists. PMID- 28914989 TI - Encapsulating Active Pharmaceutical Ingredients in Self-Assembling Adamantanes with Short DNA Zippers. AB - Formulating pharmaceutically active ingredients for drug delivery is a challenge. There is a need for new drug delivery systems that take up therapeutic molecules and release them into biological systems. We propose a novel mode of encapsulation that involves matrices formed through co-assembly of drugs with adamantane hybrids that feature four CG dimers as sticky ends. Such adamantanes are accessible via inexpensive solution-phase syntheses, and the resulting materials show attractive properties for controlled release. This is demonstrated for two different hybrids and a series of drugs, including anticancer drugs, antibiotics, and cyclosporin. Up to 20 molar equivalents of active pharmaceutical ingredients (APIs) are encapsulated in hybrid materials. Encapsulation is demonstrated for DNA-binding and several non-DNA binding compounds. Nanoparticles were detected that range in size from 114-835 nm average diameter, and zeta potentials were found to be between -29 and +28 mV. Release of doxorubicin into serum at near-constant rates for 10 days was shown, demonstrating the potential for slow release. The encapsulation and release in self-assembling matrices of dinucleotide-bearing adamantanes appears to be broadly applicable and may thus lead to new drug delivery systems for APIs. PMID- 28914991 TI - Resistiveness to Care as Experienced by Family Caregivers Providing Care for Someone With Dementia. AB - PURPOSE: This research explored family caregivers' lived experiences of resistiveness to care when they provided care for people with dementia. The goal was to identify a general meaning of family caregivers' lived experiences to target potential areas for future nursing interventions to help family caregivers manage their caregiving role and provide a base for future research surrounding resistiveness to care. DESIGN: Descriptive phenomenology was used to provide descriptions of eight family caregivers who provided care for someone with dementia and experienced resistiveness to care. Family caregivers were recruited from Alzheimer's support groups from June to November 2014. METHOD: Caregiver interviews were transcribed verbatim and analyzed using scientific phenomenology to identify essential constituents of the experience. FINDINGS: The identified general meaning structure contained five essential constituents. These included self-questioning of abilities; signal for increased future caregiver responsibilities; changed perception of personal self; unexpected emotional responses; and seeing a changed person, not the disease. CONCLUSIONS: Study findings represent family caregivers' lived perceptions of resistiveness to care, which are different from current research findings regarding nurses' perceptions of resistiveness to care. The identified meaning structure indicates focus areas for future research and for nursing interventions to help family caregivers manage their distress when experiencing resistiveness to care. CLINICAL RELEVANCE: Identification of the meaning caregivers ascribe to their lived experience of resistiveness to care (five essential constituents) provides nurses with opportunities to help family caregivers (coproviders of care) holistically. Supporting caregivers in their caregiving role can decrease caregiver distress when resistiveness to care occurs. PMID- 28914992 TI - An effective thermal therapy against cancer using an E-jet 3D-printing method to prepare implantable magnetocaloric mats. AB - Magnetic hyperthermia has been rapidly developed as a potential cancer treatment in recent years. Artificially induced hyperthermia close to a tumor can raise the temperature to 45 degrees C causing tumor cell death. Herein, we introduce a novel method for rapid preparation of anti-cancer magnetocaloric PCL/Fe3 O4 mats capable of high-performance hyperthermia using E-jet 3D printing technology. Our 3D printed mats not only maintained the heating efficiency of traditional techniques for magnetic hyperthermia but also prolonged the effective therapy in vivo. When Fe3 O4 nanoparticles (NPs) were used in mats at a concentration of 6 mmol/L, 0.07 g PCL/Fe3 O4 mats were able to increase the temperature peripherally to 45 degrees C under an alternating magnetic field (AMF) within 45 min. Moreover, the reproducibility experiment indicated that the maximum temperature was achieved following repeated heating and cooling cycles. Cell toxicity tests showed a high cell death rate during one treatment cycle. In vivo experiments indicated clear signs of tumor growth inhibitory and prolonged survival time of tumor-bearing mice after 4 weeks of treatment. The present magnetic mats may be a potential candidate for a novel heat-generating substrate for localized hyperthermia cancer therapy. Furthermore, the main advantage of such implantable magnetic mats is the local and precise delivery of Fe3 O4 NPs, ideal for the hyperthermia treatment of easily accessible tumors. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1827-1841, 2018. PMID- 28914993 TI - Hyaluronan incorporation into model contact lens hydrogels as a built-in lubricant: Effect of hydrogel composition and proteoglycan 4 as a lubricant in solution. AB - Contact lens friction significantly correlates with subjective comfort. Hyaluronan (HA) and proteoglycan 4 (PRG4) are natural boundary lubricants present in the body. The objective of this study was to assess the effect of crosslinked HA into the bulk of model contact lens materials pHEMA, pHEMA/TRIS, and DMAA/TRIS on surface wettability, protein sorption, and boundary lubricating properties at a material-cornea biointerface, both alone and synergistically with PRG4 in solution. Surface wettability was assessed by water contact angle measurement, protein sorption by lysozyme sorption assay, and boundary lubricating properties using an in vitro friction test method. HA incorporation (HAinc ) increased the surface wettability of all materials, and reduced protein sorption for pHEMA and DMAA/TRIS. HAinc increased friction for pHEMA, and DMAA/TRIS, whereas a decrease was observed for pHEMA/TRIS. A combination of HAinc and PRG4sol had a synergistic effect of reducing friction only for pHEMA/TRIS. This combination had similar friction reduction compared with PRG4sol alone for DMAA/TRIS. These results indicate HA incorporation could be an effective internal wetting agent, antiadhesive, and boundary lubricant for pHEMA/TRIS silicone hydrogels. In conclusion, HA incorporation can reduce friction of hydrogels alone and in combination with PRG4 in solution, though in a hydrogel composition-dependent (e.g., TRIS) manner. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1818-1826, 2018. PMID- 28914994 TI - Hessian-based quantitative image analysis of host-pathogen confrontation assays. AB - Host-fungus interactions have gained a lot of interest in the past few decades, mainly due to an increasing number of fungal infections that are often associated with a high mortality rate in the absence of effective therapies. These interactions can be studied at the genetic level or at the functional level via imaging. Here, we introduce a new image processing method that quantifies the interaction between host cells and fungal invaders, for example, alveolar macrophages and the conidia of Aspergillus fumigatus. The new technique relies on the information content of transmitted light bright field microscopy images, utilizing the Hessian matrix eigenvalues to distinguish between unstained macrophages and the background, as well as between macrophages and fungal conidia. The performance of the new algorithm was measured by comparing the results of our method with that of an alternative approach that was based on fluorescence images from the same dataset. The comparison shows that the new algorithm performs very similarly to the fluorescence-based version. Consequently, the new algorithm is able to segment and characterize unlabeled cells, thus reducing the time and expense that would be spent on the fluorescent labeling in preparation for phagocytosis assays. By extending the proposed method to the label-free segmentation of fungal conidia, we will be able to reduce the need for fluorescence-based imaging even further. Our approach should thus help to minimize the possible side effects of fluorescence labeling on biological functions. (c) 2017 International Society for Advancement of Cytometry. PMID- 28914995 TI - Silencing HMGN5 suppresses cell growth and promotes chemosensitivity in esophageal squamous cell carcinoma. AB - Previous study has demonstrated that high mobility group nucleosome-binding domain 5 (HMGN5) is involved in tumorigenesis and the development of multidrug resistance in several human cancers. However, the role of HMGN5 in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we showed that HMGN5 was significantly upregulated in ESCC cells. Knockdown of HMGN5 significantly inhibited cell growth and induced cell apoptosis of ESCC cells. Moreover, knockdown of HMGN5 increased the sensitivity of ESCC cells towards cisplatin. By contrast, overexpression of HMGN5 showed the opposite effects. Further experiments demonstrated that HMGN5 regulated the expression of multidrug resistance 1, cyclin B1, and Bcl-2. Overall, our results reveal that HMGN5 promotes tumor progression of ESCC and is also an important regulator of chemoresistance. Our study suggests that inhibition of HMGN5 may be a potential strategy for improving effectiveness of ESCC treatment. PMID- 28914996 TI - Enzymatic Synthesis, Amplification, and Application of DNA with a Functionalized Backbone. AB - The ability to amplify DNA along with its unprecedented sequence control has led to its use for different applications, but all are limited by the properties available to natural nucleotides. We previously reported the evolution of polymerase SFM4-3, which better tolerates 2'-modified substrates. To explore the utility of SFM4-3, we now report the characterization of its recognition of substrates with 2'-azido, 2'-chloro, 2'-amino, or arabinose sugars. We find that SFM4-3 can efficiently synthesize polymers composed of these nucleotides, and most interestingly, that SFM4-3 can also PCR amplify these modified oligonucleotides. When combined with post-amplification modification, the latter allows for the exponential amplification of polymers that may be functionalized with desired moieties arrayed in a controlled fashion, the utility of which we demonstrate with extensive small molecule functionalization and the production and initial characterization of a novel DNA hydrogel. PMID- 28914997 TI - Synergistic effect of l-ascorbic acid and hyaluronic acid on the expressions of matrix metalloproteinase-3 and -9 in human chondrocytes. AB - Proinflammatory cytokines and reactive oxygen species (ROS) are known to be involved in the initiation and progression of osteoarthritis (OA). New evidence clarifying the correlation between ROS and inflammation has indicated that oxidative stress can up-regulate inflammatory cytokines. l-Ascorbic acid (AA), an antioxidant, has been shown to have anti-inflammatory effects and improve matrix deposition in chondrocytes. The purpose of this study was to examine the effects of hyaluronic acid (HA; 100 MUg/mL) supplemented with AA (50 MUg/mL) on human normal and interleukin-1 beta-stimulated (IL-1beta, 10 ng/mL) chondrocytes. HA, AA, and HA + AA treatment did not change cell morphology, viability, proliferation, and glycosaminoglycan production in normal chondrocytes. HA, AA, and HA + AA, by contrast, partially restored viability and morphology of hypertrophic chondrocytes, and HA and HA + AA further decreased the cytotoxicity of IL-1beta. Real-time PCR revealed that AA and HA + AA had no substantial effects on unstimulated chondrocytes, except for down-regulation of matrix metalloproteinase (MMP)-9 mRNA levels. For IL-1beta-stimulated chondrocytes, significant down-regulation of IL-1beta, tumor necrosis factor-alpha (TNF-alpha), MMP-3, and MMP-9 mRNA expression was found when cells were cultured in HA supplemented media. Moreover, HA + AA supplementation further significantly decreased MMP-3 and MMP-9 mRNA expression. The protein production of MMP-3 was decreased, with a significant difference between the HA + AA group and HA group. The antioxidant capacity and superoxide dismutases activity were also partially restored in stimulated chondrocytes. HA supplemented with AA modulates MMPs expression and antioxidant fuction in chondrocytes. AA may enhance the anticatabolic effects of HA on OA chondrocytes. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1809-1817, 2018. PMID- 28914998 TI - Clinicopathological characteristics of distant metastases of adenocarcinoma, squamous cell carcinoma and urothelial carcinoma: An autopsy study of older Japanese patients. AB - AIM: We aimed to clarify the characteristics of malignancies in older adults focusing on distant metastasis in the whole body. METHODS: We retrospectively evaluated 7710 cases of autopsies (4011 men, 3699 women, median age of 80 years), and analyzed the characteristics of metastasis of adenocarcinoma, squamous cell carcinoma and urothelial carcinoma in each organ. RESULTS: The total number of cases with adenocarcinoma, squamous cell carcinoma or urothelial carcinoma was 2856, and most of them were adenocarcinomas. Among them, 1604 had metastatic lesions, and patients with metastasis were younger than those without metastasis. The major primary organs of adenocarcinoma were the stomach, colon, lung, prostate, gallbladder and pancreas, whereas those for squamous cell carcinoma were the lung, esophagus and uterus. Urothelial carcinoma cases were found in the urinary bladder, kidney and ureter. Metastatic adenocarcinomas mainly originated from the stomach, colon, lung, pancreas and gallbladder. Metastatic squamous cell carcinomas were from the lung, esophagus and uterus, whereas the kidney, bladder and ureter were the primary origins of metastatic urothelial carcinomas. Squamous cell carcinoma showed the highest incidence of metastasis, suggestive of it being of an aggressive phenotype. Furthermore, metastatic ability and the preferred metastatic sites varied among primary organs. CONCLUSIONS: We revealed an accurate incidence and the characteristics of metastatic cancer in a large-scale autopsy study of older Japanese patients from one institution. Identifying these features might prompt screening for malignancies, and consequently improve quality of life for older adults. Geriatr Gerontol Int 2018; 18: 211-215. PMID- 28914999 TI - The art of caring: In health care settings, the arts and creative arts therapies help patients and their caregivers express themselves and find relief from pain, anxiety, and depression. PMID- 28915000 TI - Ductile Glass of Polyrotaxane Toughened by Stretch-Induced Intramolecular Phase Separation. AB - A new class of ductile glasses is created from a thermoplastic polyrotaxane. The hard glass, which has a Young's modulus of 1 GPa, shows crazing, necking, and strain hardening with a total elongation of 330%. Stress concentration is prevented through a unique stretch-induced intramolecular phase separation of the cyclic components and the exposed backbone. In situ synchrotron X-ray scattering studies indicate that the backbone polymer chains slip through the cyclic components in the regions where the stress is concentrated. PMID- 28915001 TI - Design of Donor Polymers with Strong Temperature-Dependent Aggregation Property for Efficient Organic Photovoltaics. AB - Bulk heterojunction (BHJ) organic solar cells (OSCs) have attracted intensive research attention over the past two decades owing to their unique advantages including mechanical flexibility, light weight, large area, and low-cost fabrications. To date, OSC devices have achieved power conversion efficiencies (PCEs) exceeding 12%. Much of the progress was enabled by the development of high performance donor polymers with favorable morphological, electronic, and optical properties. A key problem in morphology control of OSCs is the trade-off between achieving small domain size and high polymer crystallinity, which is especially important for the realization of efficient thick-film devices with high fill factors. For example, the thickness of OSC blends containing state-of-the-art PTB7 family donor polymers are restricted to ~100 nm due to their relatively low hole mobility and impure polymer domains. To further improve the device performance and promote commercialization of OSCs, there is a strong demand for the design of new donor polymers that can achieve an optimal blend morphology containing highly crystalline yet reasonably small domains. In this Account, we highlight recent progress on a new family of conjugated polymers with strong temperature-dependent aggregation (TDA) property. These polymers are mostly disaggregated and can be easily dissolved in solution at high temperatures, yet they can strongly aggregate when the solution is cooled to room temperature. This unique aggregation property allows us to control the disorder-order transition of the polymer during solution processing. By preheating the solution to high temperature (~100 degrees C), the polymer chains are mostly disaggregated before spin coating; as the temperature of the solution drops during the spin coating process, the polymer can strongly aggregate and form crystalline domains yet that are not excessivelylarge. The overall blend morphology can be optimized by various processing conditions (e.g., temperature, spin-rates, concentration, etc.). This well-controlled and near-optimal BHJ morphology produced over a dozen cases of efficient OSCs with an active layer nearly 300 nm thick that can still achieve high FFs (70-77%) and efficiencies (10-11.7%). By studying the structure property relationships of the donor polymers, we show that the second position branched alkyl chains and the fluorination on the polymer backbone are two key structural features that enable the strong TDA property. Our comparative studies also show that the TDA polymer family can be used to match with non-fullerene acceptors yielding OSCs with low voltage losses. The key difference between the empirical matching rules for fullerene and non-fullerene OSCs is that TDA polymers with slightly reduced crystallinity appear to match better with small molecular acceptors and yield higher OSC performances. PMID- 28915002 TI - MicroRNA-Catalyzed Cancer Therapeutics Based on DNA-Programmed Nanoparticle Complex. AB - The use of cancer-relevant microRNA molecules as endogenous drug release stimuli is promising for personalized cancer treatment yet remains a great challenge because of their low abundance. Herein, we report a new type of microRNA catalyzed drug release system based on DNA-programmed gold nanoparticle (GNP) quantum dot (QD) complex. We show that a trace amount of miRNA-21 molecules could specifically catalyze the disassembly of doxorubicin (Dox)-loaded GNP-QDs complex through entropy driven process, during which the Dox-intercalating sites are destructed for drug release. This catalytic reaction could proceed both in fixed cells and live cells with miRNA-21 overexpression. Dox molecules could be efficiently released in the cells and translocate to cell nuclei. QD photoluminescence is simultaneously activated during catalytic disassembly process, thus providing a reliable feedback for microRNA-triggered drug release. The GNP-QDs-Dox complex exhibits much higher drug potency than free Dox molecules, and therefore represents a promising platform for accurate and effective cancer cell treatment. PMID- 28915003 TI - The Evolution of DNA-Templated Synthesis as a Tool for Materials Discovery. AB - Precise control over reactivity and molecular structure is a fundamental goal of the chemical sciences. Billions of years of evolution by natural selection have resulted in chemical systems capable of information storage, self-replication, catalysis, capture and production of light, and even cognition. In all these cases, control over molecular structure is required to achieve a particular function: without structural control, function may be impaired, unpredictable, or impossible. The search for molecules with a desired function is often achieved by synthesizing a combinatorial library, which contains many or all possible combinations of a set of chemical building blocks (BBs), and then screening this library to identify "successful" structures. The largest libraries made by conventional synthesis are currently of the order of 108 distinct molecules. To put this in context, there are 1013 ways of arranging the 21 proteinogenic amino acids in chains up to 10 units long. Given that we know that a number of these compounds have potent biological activity, it would be highly desirable to be able to search them all to identify leads for new drug molecules. Large libraries of oligonucleotides can be synthesized combinatorially and translated into peptides using systems based on biological replication such as mRNA display, with selected molecules identified by DNA sequencing; but these methods are limited to BBs that are compatible with cellular machinery. In order to search the vast tracts of chemical space beyond nucleic acids and natural peptides, an alternative approach is required. DNA-templated synthesis (DTS) could enable us to meet this challenge. DTS controls chemical product formation by using the specificity of DNA hybridization to bring selected reactants into close proximity, and is capable of the programmed synthesis of many distinct products in the same reaction vessel. By making use of dynamic, programmable DNA processes, it is possible to engineer a system that can translate instructions coded as a sequence of DNA bases into a chemical structure-a process analogous to the action of the ribosome in living organisms but with the potential to create a much more chemically diverse set of products. It is also possible to ensure that each product molecule is tagged with its identifying DNA sequence. Compound libraries synthesized in this way can be exposed to selection against suitable targets, enriching successful molecules. The encoding DNA can then be amplified using the polymerase chain reaction and decoded by DNA sequencing. More importantly, the DNA instruction sequences can be mutated and reused during multiple rounds of amplification, translation, and selection. In other words, DTS could be used as the foundation for a system of synthetic molecular evolution, which could allow us to efficiently search a vast chemical space. This has huge potential to revolutionize materials discovery-imagine being able to evolve molecules for light harvesting, or catalysts for CO2 fixation. The field of DTS has developed to the point where a wide variety of reactions can be performed on a DNA template. Complex architectures and autonomous "DNA robots" have been implemented for the controlled assembly of BBs, and these mechanisms have in turn enabled the one-pot synthesis of large combinatorial libraries. Indeed, DTS libraries are being exploited by pharmaceutical companies and have already found their way into drug lead discovery programs. This Account explores the processes involved in DTS and highlights the challenges that remain in creating a general system for molecular discovery by evolution. PMID- 28915004 TI - Calcium-Induced Morphological Transitions in Peptide Amphiphiles Detected by 19F Magnetic Resonance Imaging. AB - Misregulation of extracellular Ca2+ can indicate bone-related pathologies. New, noninvasive tools are required to image Ca2+ fluxes and fluorine magnetic resonance imaging (19F-MRI) is uniquely suited to this challenge. Here, we present three, highly fluorinated peptide amphiphiles that self-assemble into nanoribbons in buffered saline and demonstrate these nanostructures can be programmed to change 19F-NMR signal intensity as a function of Ca2+ concentration. We determined these nanostructures show significant reduction in 19F-NMR signal as nanoribbon width increases in response to Ca2+, corresponding to 19F-MR image intensity reduction. Thus, these peptide amphiphiles can be used to quantitatively image biologically relevant Ca2+ concentrations. PMID- 28915005 TI - A Novel Type of Aqueous Dispersible Ultrathin-Layered Double Hydroxide Nanosheets for in Vivo Bioimaging and Drug Delivery. AB - Layered double hydroxide (LDH) nanoparticles have been widely used for various biomedical applications. However, because of the difficulty of surface functionalization of LDH nanoparticles, the systemic administration of these nanomaterials for in vivo therapy remains a bottleneck. In this work, we develop a novel type of aqueous dispersible two-dimensional ultrathin LDH nanosheets with a size of about 50 nm and a thickness of about 1.4 to 4 nm. We are able to covalently attach positively charged rhodamine B fluorescent molecules to the nanosheets, and the nanohybrid retains strong fluorescence in liquid and even dry powder form. Therefore, it is available for bioimaging. Beyond this, it is convenient to modify the nanosheets with neutral poly(ethylene glycol) (PEG), so the nanohybrid is suitable for drug delivery through systemic administration. Indeed, in the test of using these nanostructures for delivery of a negatively charged anticancer drug, methotrexate (MTX), in a mouse model, dramatically improved therapeutic efficacy is achieved, indicated by the effective inhibition of tumor growth. Furthermore, our systematic in vivo safety investigation including measuring body weight, determining biodistribution in major organs, hematology analysis, blood biochemical assay, and hematoxylin and eosin stain demonstrates that the new material is biocompatible. Overall, this work represents a major development in the path of modifying functional LDH nanomaterials for clinical applications. PMID- 28915006 TI - Chemical and Electronic Repair Mechanism of Defects in MoS2 Monolayers. AB - Using ab initio density functional theory calculations, we characterize changes in the electronic structure of MoS2 monolayers introduced by missing or additional adsorbed sulfur atoms. We furthermore identify the chemical and electronic function of substances that have been reported to reduce the adverse effect of sulfur vacancies in quenching photoluminescence and reducing electronic conductance. We find that thiol-group-containing molecules adsorbed at vacancy sites may reinsert missing sulfur atoms. In the presence of additional adsorbed sulfur atoms, thiols may form disulfides on the MoS2 surface to mitigate the adverse effect of defects. PMID- 28915007 TI - Synthesis and Properties of 2D Carbon-Graphdiyne. AB - Graphdiyne (GDY) is a flat material comprising sp2- and sp-hybridized carbon atoms with high degrees of pi conjugation that features uniformly distributed pores. It is interesting not only from a structural point of view but also from the perspective of its electronic, chemical, mechanical, and magnetic properties. We have developed an in situ homocoupling reaction of hexaethynylbenzene on Cu foil for the fabrication of large-area ordered films of graphdiyne. These films are uniform and composed of graphdiyne multilayers. The conductivity of graphdiyne films, calculated at 2.52 * 10-4 S m-1, is comparable to that of Si, suggesting excellent semiconducting properties. Through morphology-controlled syntheses, we have prepared several well-defined graphdiyne structures (e.g., nanotubes, nanowires, and nanowalls) having distinct properties. The graphdiyne nanotube arrays and graphdiyne nanowalls exhibited excellent field emission performance, higher than that of some other semiconductors such as graphite and carbon nanotubes. These structures have several promising applications, for example, as energy storage materials and as anode materials in batteries. The unique atomic arrangement and electronic structure of graphdiyne also inspired us to use it to develop highly efficient catalysts; indeed, its low reduction potential and highly conjugated electronic structure allow graphdiyne to be used as a reducing agent and stabilizer for the electroless deposition of highly dispersed and surfactant-free Pd clusters. GDY-based three-dimensional (3D) nanoarchitectures featuring well-defined porous network structures can function as highly active cathodes for H2 evolution. Heteroatom-doped GDY structures are excellent metal-free electrocatalysts for the oxygen reduction reaction (ORR). Its excellent electrocatalytic activity and inexpensive, convenient, and scalable preparation make GDY a promising candidate for practical and efficient energy applications; indeed, we have explored the application of GDY as a highly efficient lithium storage material and have elucidated the method through which lithium storage occurs in multilayer GDY. Lithium-ion batteries featuring GDY based electrodes display excellent electrochemical performance, including high specific capacity, outstanding rate performance, and long cycle life. We have also explored the application of GDY in energy conversion and found that it exhibits excellent conductivity. In this Account, we summarize the relationships between the functions of graphdiyne and its well-defined nanostructures. Our results suggest that GDY is a novel 2D carbon material possessing many attractive properties. It can be designed into new nanostructures and materials across a range of compositions, sizes, shapes, and functionalities and can be applied in the fields of electronics, optics, energy, and optoelectronics. PMID- 28915008 TI - H2S Activated Drug Release from Protein Cages. AB - We took advantage of gasotransmitter H2S as a chemical reaction-based trigger for controlled release of doxorubicin which is precoordinated by copper ions and enclosed in horse spleen apoferritin. The nanocomposite is stable at physiological pH and temperature before H2S activation. The drug release process avoids disassembly of protein shells and is controllable by the strong affinity of sulfide with copper ions. The in vitro cytotoxicity assay indicates the antitumor effect of doxorubicin toward tumor cells could be achievable by H2S activation. PMID- 28915009 TI - Electron Stability and Negative-Tetron Luminescence in Free-Standing Colloidal n Type CdSe/CdS Quantum Dots. AB - We examine the effects of CdS shell growth on photochemical reduction of colloidal CdSe quantum dots (QDs) and describe the spectroscopic properties of the resulting n-type CdSe/CdS QDs. CdS shell growth greatly slows electron trapping. Because of this improvement, complete two-electron occupancy of the 1Se conduction-band orbital is achieved in CdSe/CdS QDs and found to be much more stable than in past experiments. Simultaneous photoluminescence at two different energies is now observed from QDs possessing two excess conduction-band electrons, reflecting competing recombination of discretized 1Se and 1Pe conduction-band electrons within photogenerated four-carrier negative tetrons (three electrons and one hole). Stable occupancy of the 1Pe level is not achievable under these conditions, and possible reasons are discussed. The stability and accessibility of these multielectron configurations, and the facile spectroscopic detection of negative tetrons, both make photodoped core/shell QDs attractive for exploring the physical properties of free-standing heavily n-doped colloidal CdSe-based QDs. PMID- 28915010 TI - Molecular Engineering for Enhanced Charge Transfer in Thin-Film Photoanode. AB - We developed three types of dithieno[3,2-b;2',3'-d]thiophene (DTT)-based organic sensitizers for high-performance thin photoactive TiO2 films and investigated the simple but powerful molecular engineering of different types of bonding between the triarylamine electron donor and the conjugated DTT pi-bridge by the introduction of single, double, and triple bonds. As a result, with only 1.3 MUm transparent and 2.5-MUm TiO2 scattering layers, the triple-bond sensitizer (T DAHTDTT) shows the highest power conversion efficiency (eta = 8.4%; VOC = 0.73 V, JSC = 15.4 mA.cm-2, and FF = 0.75) in an iodine electrolyte system under one solar illumination (AM 1.5, 1000 W.m-2), followed by the single-bond sensitizer (S-DAHTDTT) (eta = 7.6%) and the double-bond sensitizer (D-DAHTDTT) (eta = 6.4%). We suggest that the superior performance of T-DAHTDTT comes from enhanced intramolecular charge transfer (ICT) induced by the triple bond. Consequently, T DAHTDTT exhibits the most active photoelectron injection and charge transport on a TiO2 film during operation, which leads to the highest photocurrent density among the systems studied. We analyzed these correlations mainly in terms of charge injection efficiency, level of photocharge storage, and charge-transport kinetics. This study suggests that the molecular engineering of a triple bond between the electron donor and the pi-bridge of a sensitizer increases the performance of dye-sensitized solar cell (DSC) with a thin photoactive film by enhancing not only JSC through improved ICT but also VOC through the evenly distributed sensitizer surface coverage. PMID- 28915011 TI - Highly Controllable and Efficient Synthesis of Mixed-Halide CsPbX3 (X = Cl, Br, I) Perovskite QDs toward the Tunability of Entire Visible Light. AB - CsPbX3 (X = Cl, Br, I) perovskite quantum dots (PQDs) have been intensively investigated on photoelectric devices due to their superior optical properties. To date, the stability of CsPbX3 PQDs is still an open challenge. The previous mixed-halide CsPbX3 PQDs were generally obtained via the anion-exchange method at 40 degrees C. Here, the single- and mixed-halide CsPbX3 PQDs are synthesized at high temperature via the hot injection technique. The surface ligands could thus be strongly coordinated onto the surface of the PQDs, which dramatically improve the optical properties of the PQDs. The resulting CsPbX3 PQDs have high quantum yield (QY, 40-95%), narrow full width at half-maximum (FWHM) (the narrowest FWHM <10 nm), tunable band gap (408-694 nm), and highly strong photostability. The variation of their emission peaks upon anion atoms is well-supported by the theoretical band gaps calculated by the density functional theory calculations with the alloy formula correction. Hence, these PQDs show great potential as good candidates for photoelectric devices. PMID- 28915012 TI - Managing the SOS Response for Enhanced CRISPR-Cas-Based Recombineering in E. coli through Transient Inhibition of Host RecA Activity. AB - Phage-derived "recombineering" methods are utilized for bacterial genome editing. Recombineering results in a heterogeneous population of modified and unmodified chromosomes, and therefore selection methods, such as CRISPR-Cas9, are required to select for edited clones. Cells can evade CRISPR-Cas-induced cell death through recA-mediated induction of the SOS response. The SOS response increases RecA dependent repair as well as mutation rates through induction of the umuDC error prone polymerase. As a result, CRISPR-Cas selection is more efficient in recA mutants. We report an approach to inhibiting the SOS response and RecA activity through the expression of a mutant dominant negative form of RecA, which incorporates into wild type RecA filaments and inhibits activity. Using a plasmid based system in which Cas9 and recA mutants are coexpressed, we can achieve increased efficiency and consistency of CRISPR-Cas9-mediated selection and recombineering in E. coli, while reducing the induction of the SOS response. To date, this approach has been shown to be independent of recA genotype and host strain lineage. Using this system, we demonstrate increased CRISPR-Cas selection efficacy with over 10 000 guides covering the E. coli chromosome. The use of dominant negative RecA or homologues may be of broad use in bacterial CRISPR-Cas based genome editing where the SOS pathways are present. PMID- 28915013 TI - A Polyoxovanadate-Resorcin[4]arene-Based Porous Metal-Organic Framework as an Efficient Multifunctional Catalyst for the Cycloaddition of CO2 with Epoxides and the Selective Oxidation of Sulfides. AB - In this work, we report a new polyoxovanadate-resorcin[4]arene-based metal organic framework (PMOF), [Co2L0.5V4O12].3DMF.5H2O (1), assembled with a newly functionalized wheel-like resorcin[4]arene ligand (L). 1 features an elegant porous motif and represents a rare example of PMOFs composed of both a resorcin[4]arene ligand and polyoxovanadate. Remarkably, 1 shows open V sites in the channel, which makes 1 an efficient heterogeneous Lewis acid catalyst for the cycloaddition of carbon dioxide to epoxides with high conversion and selectivity. Strikingly, 1 also exhibits high catalytic activity for the heterogeneous oxidative desulfurization of sulfides. Particularly, the heterogeneous catalyst 1 can be easily separated and reused with good catalytic activity. PMID- 28915014 TI - A Bispidol Chelator with a Phosphonate Pendant Arm: Synthesis, Cu(II) Complexation, and 64Cu Labeling. AB - Here we present the synthesis and characterization of a new bispidine (3,7 diazabicyclo[3.3.1]nonane) ligand with N-methanephosphonate substituents (L2). Its physicochemical properties in water, as well as those of the corresponding Cu(II) and Zn(II) complexes, have been evaluated by using UV-visible absorption spectroscopy, potentiometry, 1H and 31P NMR, and cyclic voltammetry. Radiolabeling experiments with 64CuII have been carried out, showing excellent radiolabeling properties. Quantitative complexation was achieved within 60 min under stoichiometric conditions, at room temperature and in the nanomolar concentration range. It was also demonstrated that the complexation occurred below pH 2. Properties have been compared to those of the analogue bispidol bearing a N-methanecarboxylate substituent (L1). Although both systems meet the required criteria to be used as new chelator for 64/67Cu in terms of the kinetics of formation, thermodynamic stability, selectivity for Cu(II), and kinetic inertness regarding redox- or acid-assisted decomplexation processes, substitution of the carboxylic acid function by the phosphonic moiety is responsible for a significant increase in the thermodynamic stability of the Cu(II) complex (+2 log units for pCu) and also leads to an increase in the radiochemical yields with 64CuII which is quantitative for L2. PMID- 28915015 TI - Small-Scale Metal-Based Syntheses of Lanthanide Iodide, Amide, and Cyclopentadienyl Complexes as Analogues for Transuranic Reactions. AB - Small-scale reactions of the Pu analogues La, Ce, and Nd have been explored in order to optimize reaction conditions for milligram scale reactions of radioactive plutonium starting from the metal. Oxidation of these lanthanide metals with iodine in ether and pyridine has been studied, and LnI3(Et2O)x (1-Ln; x = 0.75-1.9) and LnI3(py)4 (2-Ln; py = pyridine, NC5H5) have been synthesized on scales ranging from 15 mg to 2 g. The THF adducts LnI3(THF)4 (3-Ln) were synthesized by dissolving 1-Ln in THF. The viability of these small-scale samples as starting materials for amide and cyclopentadienyl f-element complexes was tested by reacting KN(SiMe3)2, KCp' (Cp' = C5H4SiMe3), KCp'' (Cp'' = C5H3(SiMe3)2 1,3), and KC5Me4H with 1-Ln generated in situ. These reactions produced Ln[N(SiMe3)2]3 (4-Ln), Cp'3Ln (5-Ln), Cp"3Ln (6-Ln), and (C5Me4H)3Ln (7-Ln), respectively. Small-scale samples of Cp'3Ce (5-Ce) and Cp'3Nd (5-Nd) were reduced with potassium graphite (KC8) in the presence of 2.2.2-cryptand to check the viability of generating the crystallographically characterizable Ln2+ complexes [K(2.2.2-cryptand)][Cp'3Ln] (8-Ln; Ln = Ce, Nd). PMID- 28915016 TI - Cell-Free Protein Synthesis Enhancement from Real-Time NMR Metabolite Kinetics: Redirecting Energy Fluxes in Hybrid RRL Systems. AB - A counterintuitive cell-free protein synthesis (CFPS) strategy, based on reducing the ribosomal fraction in rabbit reticulocyte lysate (RRL), triggers the development of hybrid systems composed of RRL ribosome-free supernatant complemented with ribosomes from different mammalian cell-types. Hybrid RRL systems maintain translational properties of the original ribosome cell types, and deliver protein expression levels similar to RRL. Here, we show that persistent ribosome-associated metabolic activity consuming ATP is a major obstacle for maximal protein yield. We provide a detailed picture of hybrid CFPS systems energetic metabolism based on real-time nuclear magnetic resonance (NMR) investigation of metabolites kinetics. We demonstrate that protein synthesis capacity has an upper limit at native ribosome concentration and that lower amounts of the ribosomal fraction optimize energy fluxes toward protein translation, consequently increasing CFPS yield. These results provide a rationalized strategy for further mammalian CFPS developments and reveal the potential of real-time NMR metabolism phenotyping for optimization of cell-free protein expression systems. PMID- 28915017 TI - Cationic and Anionic Disorder in CZTSSe Kesterite Compounds: A Chemical Crystallography Study. AB - The cationic and anionic disorder in the Cu2ZnSnSe4-Cu2ZnSnS4 (CZTSe-CZTS) system has been investigated through a chemical crystallography approach including X-ray diffraction (in conventional and resonant setup), 119Sn and 77Se NMR spectroscopy, and high-resolution transmission electron microscopy (HRTEM) techniques. Single-crystal XRD analysis demonstrates that the studied compounds behave as a solid solution with the kesterite crystal structure in the whole S/(S + Se) composition range. As previously reported for pure sulfide and pure selenide compounds, the 119Sn NMR spectroscopy study gives clear evidence that the level of Cu/Zn disorder in mixed S/Se compounds depends on the thermal history of the samples (slow cooled or quenched). This conclusion is also supported by the investigation of the 77Se NMR spectra. The resonant single crystal XRD technique shows that regardless of the duration of annealing step below the order-disorder critical temperature the ordering is not a long-range phenomenon. Finally, for the very first time, HREM images of pure selenide and mixed S/Se crystals clearly show that these compounds have different microstructures. Indeed, only the mixed S/Se compound exhibits a mosaic-type contrast which could be the sign of short-range anionic order. Calculated images corroborate that HRTEM contrast is highly dependent on the nature of the anion as well as on the local anionic order. PMID- 28915018 TI - Recent Advances in the Chemical Synthesis of C-Glycosides. AB - Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C-C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg-Backlund rearrangement, and 1,2-Wittig rearrangement, which usually involve concerted pathways, constitute another category of C glycosylations. An alternative to the C-glycosylations is the formation of pyranoside/furanoside rings after construction of the predetermined glycosidic C C bonds, which might involve cyclization of acyclic precursors or D-A cycloadditions. Throughout, the stereoselectivity in the formation of the resultant C-glycosidic linkages is highlighted. PMID- 28915019 TI - Correction to "Oxidative Substitution of Boranephosphonate Diesters as a Route to Post-synthetically Modified DNA". PMID- 28915020 TI - Rotating Magnetocaloric Effect in an Anisotropic Two-Dimensional CuII[WV(CN)8]3- Molecular Magnet with Topological Phase Transition: Experiment and Theory. AB - Conventional (MCE) and rotating (RMCE) magnetocaloric effects have been explored in the two-dimensional (2D) coordination polymer {(tetren)H5)0.8CuII4[WV(CN)8]4.7.2H2O}n (WCu-t; tetren = tetraethylenepentamine). The unusual magnetostructural properties were exploited, including the bilayered Prussian Blue like coordination skeleton and the XY easy-plane magnetic anisotropy based on the in-plane correlation between WV and CuII spins of 1/2, underlying the Berezinskii-Kosterlitz-Thouless (BKT) topological phase transition to the long-range-ordered state at TC = 33 K. The magnetic properties were studied on single crystals along the H?ac easy plane and H?b hard axis. The maximal entropy change for MCE for easy-plane geometry at 38.0 K and the magnetic field change MU0DeltaH = 7.0 T reached ~4.01 J K-1 kg-1. The strong magnetic anisotropy was used to study the RMCE in which the maximal entropy change was observed at 35.5 K for 7.0 T, attaining 1.81 J K-1 kg-1. Moreover, easy-plane anisotropy introduces the inverse magnetocaloric effect for H?b, which enhances the RMCE by up to 47%. This observation was confirmed by a theoretical investigation considering the XY model using a molecular field and cluster variational method in the pair approximation approach, dedicated to the bilayered systems with the adequate nearest neighbor number z = 5 and spin S = 1/2. PMID- 28915021 TI - Novel Approach for in Situ Recovery of Lithium Carbonate from Spent Lithium Ion Batteries Using Vacuum Metallurgy. AB - Lithium is a rare metal because of geographical scarcity and technical barrier. Recycling lithium resource from spent lithium ion batteries (LIBs) is significant for lithium deficiency and environmental protection. A novel approach for recycling lithium element as Li2CO3 from spent LIBs is proposed. First, the electrode materials preobtained by mechanical separation are pyrolyzed under enclosed vacuum condition. During this process the Li is released as Li2CO3 from the crystal structure of lithium transition metal oxides due to the collapse of the oxygen framework. An optimal Li recovery rate of 81.90% is achieved at 973 K for 30 min with a solid-to-liquid ratio of 25 g L-1, and the purity rate of Li2CO3 is 99.7%. The collapsed mechanism is then presented to explain the release of lithium element during the vacuum pyrolysis. Three types of spent LIBs including LiMn2O4, LiCoO2, and LiCoxMnyNizO2 are processed to prove the validity of in situ recycling Li2CO3 from spent LIBs under enclosed vacuum condition. Finally, an economic assessment is taken to prove that this recycling process is positive. PMID- 28915022 TI - Cobalt(II) Ions Connecting [CoII4] Helicates into a 2-D Coordination Polymer Showing Slow Relaxation of the Magnetization. AB - The reactions of cobalt(II) perchlorate with a diazine tetratopic helicand, H4L, in the presence of sodium carbonate afford two coordination polymers constructed from tetranuclear anionic helicates as building blocks: infinity3[Co4L3Na4(H2O)4].4H2O (1) and infinity2[Co5L3Na2(H2O)9].2.7H2O.DMF (2). The tetranuclear triple-stranded helicates, {CoII4L3}4-, are connected in 1 by sodium(I) ions and in 2 by sodium(I) and cobalt(II) ions (H4L results from the condensation reaction between 3-formylsalicylic acid and hydrazine). The crystal structures of the two compounds have been solved. In both compounds the anionic helicates interact with the assembling cations through the carboxylato oxygen atoms. Compound 2 features chains resulting from connecting the tetranuclear helicates through cobalt(II) ions. The analysis of the magnetic properties of compounds 1 and 2 evidenced a dominant antiferromagnetic coupling for 1, resulting in a diamagnetic ground state. In contrast, the magnetic behavior of 2 is dominated at low temperature by the CoII ion which connects the antiferromagnetically coupled {CoII4} helical moieties. The ac magnetic measurements for 2 reveal the occurrence of slow relaxation of the magnetization that is due to the single, uncorrelated cobalt(II) ions, which are diluted in an essentially diamagnetic matrix of {CoII4} moieties (DeltaEeff = 26.7 +/- 0.3 cm-1 with tau0 = (2.3 +/- 0.2) * 10-6 s). PMID- 28915023 TI - Detecting Activity at Different Length Scales: From Subdiffraction to Whole Animal Activity. PMID- 28915024 TI - Synthesis and Crystal Structure of Suboxide Solid Solutions, Ti12-deltaGaxBi3 xO10. AB - Single crystals of suboxide solid solutions Ti12-deltaGaxBi3-xO10 (x = 1.42-1.74; delta = 0.77-0.62) were prepared at 900 degrees C with a Bi flux. Crystal structure analysis by X-ray diffraction (XRD) revealed that the solid solutions are isostructural with Ti12-deltaSn3O10 (cubic, space group Fm3m). The cell parameter a decreases from 13.5616(3) to 13.5402(5) A with increasing Ga content, x, while the total valence electron number of Ti12-deltaGaxBi3-xO10 is maintained at 117.1 by decreasing Ti defects, delta. Stella octangula is formed by sharing of the edges of four supertetrahedra composed of O-centered Ti tetrahedra and trigonal bipyramids (oxide part). Another superpolyhedron is formed by sharing of the pyramidal planes of Ga/Bi-centered, Ti-monocapped square antiprisms (intermetallic part). These two parts are incorporated in the structure. A polycrystalline bulk of a solid solution with x = 2.01 and delta = 0.67 [a = 13.53772(13) A] was synthesized by reaction sintering at 950 degrees C from a mixture of Ti, TiO2, Bi2O3, and Ga2O3. The resistivities measured for the bulk were (2.2-2.4) * 10-5 Omega m in the temperature range from 10 to 300 K. PMID- 28915026 TI - Supercubes, Supersquares, and Superrods of Face-Centered Cubes (FCC): Atomic and Electronic Requirements of [Mm(SR)l(PR'3)8]q Nanoclusters (M = Coinage Metals) and Their Implications with Respect to Nucleation and Growth of FCC Metals. AB - Understanding the nucleation and growth pathways of nanocrystallites allows precise control of the size and shape of functional crystalline nanomaterials of importance in nanoscience and nanotechnology. This paper provides a detailed analysis of the stereochemical and electronic requirements of three series of nanoclusters based on face-centered cubes (fcc) as the basic building blocks, namely, 1-, 2-, and 3-D assemblages of fcc to form superrods (n), supersquares (n2), and supercubes (n3). The generating functions for calculating the numbers (and arrangements) of surface and interior metal atoms, as well as the number and dispositions of the ligands, for these particular sequences of fcc metal clusters of the general formula [Mm(SR)l(PR'3)8]q (where M = coinage metals; SR = thiolates (or group XI ligands), and PR'3 = phosphines) are presented. An electron-counting scheme based on the jelliumatic shell nodel, a variant of the jellium model, predicts the electron requirements and hence the chemical compositions that are critical in the design and synthesis of the next generation of giant nanoclusters in the nanorealm. The ligand binding specificities, which are keys to effective surface ligand control of the size and shape of these nanoclusters, are defined. Finally, a connection is made with regard to the growth of fcc metals, n3, from fcc supercubes (n < 10) to fcc nanocrystallites/particles (10 < n < 102) and to fcc bulk phase (n > 102). PMID- 28915025 TI - Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase. AB - Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocatalyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism-inspired ligand. The structure supports two key features of the NCS "dopamine-first" mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance. The catalytically vital residue Glu-110 occupies a previously unobserved ligand-bound conformation that may be catalytically significant. The potential roles of inhibitory binding and alternative amino acid conformations in the mechanism have also been revealed. This work significantly advances our understanding of the NCS mechanism and will aid future efforts to engineer the substrate scope and catalytic properties of this useful biocatalyst. PMID- 28915027 TI - Structure and Dynamics of Membrane Proteins and Membrane Associated Proteins with Native Bicelles from Eukaryotic Tissues. AB - In vitro studies of protein structure, function, and dynamics typically preclude the complex range of molecular interactions found in living tissues. In vivo studies elucidate these complex relationships, yet they are typically incompatible with the extensive and controlled biophysical experiments available in vitro. We present an alternative approach by extracting membranes from eukaryotic tissues to produce native bicelles to capture the rich and complex molecular environment of in vivo studies while retaining the advantages of in vitro experiments. Native bicelles derived from chicken egg or mouse cerebrum tissues contain a rich composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (PA), lysolipids, cholesterol, ceramides (CM), and sphingomyelin (SM). The bicelles also contain source-specific lipids such as triacylglycerides (TAGs) and sulfatides from egg and brain tissues, respectively. With the influenza hemagglutinin fusion peptide (HAfp) and the C-terminal Src homology domain of lymphocyte-specific protein-tyrosine kinase (lck-cSH2), we show that membrane proteins and membrane associated proteins reconstituted in native bicelles produce high-resolution NMR data and probe native protein-lipid interactions. PMID- 28915028 TI - Acid Rock Drainage Treatment Using Membrane Distillation: Impacts of Chemical Free Pretreatment on Scale Formation, Pore Wetting, and Product Water Quality. AB - Acid rock drainage (ARD) is a metal-rich wastewater that forms upon oxidation of sulfidic minerals. Although ARD impacts >12,000 miles of rivers in the U.S. and has an estimated cleanup cost of $32-$72 billion, the low pH and high metal concentrations in ARD make rapid, high volume treatment without chemical addition difficult. This research focuses on a novel method of ARD treatment, membrane distillation (MD). In MD, heated ARD is separated from a cooled distillate by a hydrophobic, water-excluding membrane. Because water only passes through the membrane in the vapor phase, nonvolatile sulfate and heavy metals are retained in the concentrate stream. A preliminary in silico analysis using an electrolyte thermodynamic model indicated that MD of 10 different mine wastes yields product water containing no contaminants at concentrations >0.2 ppm. MD tests of synthetic ARD used a ~34 degrees C temperature difference, operated at 80% recovery, and produced an initial flux of 38.4 +/- 1.1 L.m-2.h-1. This flux decreased slightly after scaling by iron oxyhydroxide; however, membranes maintained >99% dissolved solids rejection. Both flux decline and membrane scale formation decreased after a chemical-free, thermal precipitation pretreatment. These results indicate that MD can purify contaminated, acidic wastewater using low-grade heat sources, such as geothermal energy, without chemical addition. PMID- 28915029 TI - Rapid One-Pot Solvothermal Batch Synthesis of Porous Nanocrystal Assemblies Composed of Multiple Transition-Metal Elements. AB - The ability of a rapid-heating solvothermal process to synthesize porous nanocrystal assemblies composed of the multiple transition metals was demonstrated. The rapid heating facilitated the quick formation of nascent nanocrystals to generate homogeneous mixed transition-metal oxides. Systematic studies of the synthesis of mixed-metal oxides under various experimental conditions indicated that the present simple method is suitable to develop a wide variety of binary and ternary transition-metal systems such as Co/Mn, Ni/Mn, and Co/Mn/Fe mixed-metal oxides. The products obtained from the rapid heating process were hierarchically assembled porous nanospheres composed of sub-10 nm nanocrystals, which had an extraordinarily high surface area and nano/mesopores. Electrochemical tests revealed the high catalytic ability of the porous nanocrystal assemblies in water oxidation. PMID- 28915030 TI - Radical-Enhanced Acidity: Why Bicarbonate, Carboxyl, Hydroperoxyl, and Related Radicals Are So Acidic. AB - Comparison of accepted pKa values of bicarbonate, carboxyl, and hydroperoxyl radicals, with those of models having the unpaired electron replaced by H atoms, implied the acidity of the radicals was greatly increased. A Density Functional Theory computational method of estimating pKas was developed and applied to a set of radicals designed to probe the phenomenon of radical-enhanced deprotonation (RED-shift) and its underlying causes. Comparison of the computed pKa values of 12 acid radicals to those of the corresponding model acids confirmed the intensified acidity of the title radicals and also pin-pointed the carboxy ethynyl (HO2CC=C*) and the carboxy-aminyl (HO2CNH*) radicals as having enhanced acidity. The underlying cause was found to be extensive charge distribution away from the anionic O atoms of the conjugate radical anions, coupled with spin density displaced toward these O atoms. Ethyne spacers, between the radical and carboxylate centers, transmitted the effect extremely efficiently such that measurable enhancement was detectable up to at least six alkyne units. The bicyclo[1.1.1]pent-1-yl-3-carboxylic acid radical also displayed enhanced acidity, but additional cage units drastically attenuated the effect. Nitroxide radicals with suitably situated carboxylic acid substituents also exhibited enhanced acidity. Several families of potentially persistent radicals with enhanced acidity were identified. PMID- 28915031 TI - Unexpectedly Large Spin Coherence Effects in the Recombination Fluorescence from Irradiated Highly Polar Solutions on a Nanosecond Time Scale. AB - Spin correlation effects in the geminate recombination of radical ion pairs in irradiated highly polar liquids are typically believed to be negligible due to a high escape probability for the ions. This report presents the results of an exploratory study of organic polar solvents aimed at the searching for, and estimating the magnitude of, the time-resolved magnetic field effects (TR MFEs) in the delayed radiation-induced fluorescence from diluted solutions of a luminophore. It has been found that upon the high-energy irradiation of the solutions in polar liquids, such as dichloroethane (epsilon ~ 10), methanol (epsilon ~ 33), acetonitrile (epsilon ~ 37), dimethylformamide (epsilon ~ 37), dimethyl sulfoxide (epsilon ~ 47), ethylene carbonate (epsilon ~ 89), substantial spin coherence effects in the delayed fluorescence can be observed within a time range up to ~100 ns. In most of the cases studied, magnetic resonance characteristics of primary or very early solvent-related radical ions were evaluated from the TR MFE curves. This approach can, therefore, be widely used to complement results obtained by the pulse radiolysis technique with structural and kinetic data extracted from the magnetic resonance characteristics of the short lived radical ions formed in irradiated media. PMID- 28915032 TI - Ion Pair Formation between Tertiary Aliphatic Amines and Perchlorate in the Biphasic Water/Dichloromethane System. AB - The ability of aliphatic amines (AAs), namely, tripropylamine (TPrA), trisobutylamine (TisoBuA), and tributylamine (TBuA), to form ion pairs with perchlorate anion (ClO4-) in biphasic aqueous/dichloromethane (CH2Cl2) mixtures containing ClO4- 0.1 M has been demonstrated by GC with flame ionization (FID) and mass detectors (MS) and by NMR measurements. The extraction efficiency of the AAs to the organic phase was modeled by equations that were used to fit the experimental GC data, allowing us to determine values for KP (partition constant of the free AA), KIP (formation constant of the ion pair), and KPIP (partition constant of the ion pair) for TPrA, TisoBuA, and TBuA at 25 degrees C. Ion pairs were shown to form in CH2Cl2 also when ClO4- is replaced by other inorganic anions, like NO3-, ClO3-, Cl-, H2PO4-, and IO3-. No ion pairs formed when CH2Cl2 was replaced by n-hexane, suggesting that aliphatic amine ion pairs can form in polar organic solvents but not in nonpolar ones. PMID- 28915033 TI - Stereoselective Synthesis of Nitrogen-Containing Compounds from Enamines. AB - The domino reaction of enamines, electrophiles (N-sulfonylimines, N tosylisocyanate, or diethyl azodicarboxylate), and trichlorosilane provided trans amines (trans/cis = > 99:1 to 96:4). Meanwhile, the sequential imino ene-type reaction of enamines and electrophiles/NaBH3CN reduction afforded cis-amines (trans/cis = 1:>99 to 15:85). The reversal of selectivity is discussed on the basis of diastereofacial selection of the plausible iminium ion intermediates. For the domino reaction of cyclic enamines and cyclic imines, high enantioselectivity (er = 95.7:4.3 to 99.9:0.1) was achieved by utilizing chiral Lewis base catalysts. PMID- 28915034 TI - Affinity-Guided Oxime Chemistry for Selective Protein Acylation in Live Tissue Systems. AB - Catalyst-mediated protein modification is a powerful approach for the imaging and engineering of natural proteins. We have previously developed affinity-guided 4 dimethylaminopyridine (AGD) chemistry as an efficient protein modification method using a catalytic acyl transfer reaction. However, because of the high electrophilicity of the thioester acyl donor molecule, AGD chemistry suffers from nonspecific reactions to proteins other than the target protein in crude biological environments, such as cell lysates, live cells, and tissue samples. To overcome this shortcoming, we here report a new acyl donor/organocatalyst system that allows more specific and efficient protein modification. In this method, a highly nucleophilic pyridinium oxime (PyOx) catalyst is conjugated to a ligand specific to the target protein. The ligand-tethered PyOx selectively binds to the target protein and facilitates the acyl transfer reaction of a mild electrophilic N-acyl-N-alkylsulfonamide acyl donor on the protein surface. We demonstrated that the new catalytic system, called AGOX (affinity-guided oxime) chemistry, can modify target proteins, both in test tubes and cell lysates, more selectively and efficiently than AGD chemistry. Low-background fluorescence labeling of the endogenous cell-membrane proteins, carbonic anhydrase XII and the folate receptor, in live cells allowed for the precise quantification of diffusion coefficients in the protein's native environment. Furthermore, the excellent biocompatibility and bioorthogonality of AGOX chemistry were demonstrated by the selective labeling of an endogenous neurotransmitter receptor in mouse brain slices, which are highly complicated tissue samples. PMID- 28915035 TI - Photoelectrochemistry of Photosystem II in Vitro vs in Vivo. AB - Factors governing the photoelectrochemical output of photosynthetic microorganisms are poorly understood, and energy loss may occur due to inefficient electron transfer (ET) processes. Here, we systematically compare the photoelectrochemistry of photosystem II (PSII) protein-films to cyanobacteria biofilms to derive: (i) the losses in light-to-charge conversion efficiencies, (ii) gains in photocatalytic longevity, and (iii) insights into the ET mechanism at the biofilm interface. This study was enabled by the use of hierarchically structured electrodes, which could be tailored for high/stable loadings of PSII core complexes and Synechocystis sp. PCC 6803 cells. The mediated photocurrent densities generated by the biofilm were 2 orders of magnitude lower than those of the protein-film. This was partly attributed to a lower photocatalyst loading as the rate of mediated electron extraction from PSII in vitro is only double that of PSII in vivo. On the other hand, the biofilm exhibited much greater longevity (>5 days) than the protein-film (<6 h), with turnover numbers surpassing those of the protein-film after 2 days. The mechanism of biofilm electrogenesis is suggested to involve an intracellular redox mediator, which is released during light irradiation. PMID- 28915036 TI - Collagen Peptides from Crucian Skin Improve Calcium Bioavailability and Structural Characterization by HPLC-ESI-MS/MS. AB - The effects of collagen peptides (CPs), which are derived from crucian skin, were investigated in a retinoic acid-induced bone loss model. The level of serum bone alkaline phosphatase (BALP) in the model group (117.65 +/- 4.66 units/L) was significantly higher than those of the other three groups (P < 0.05). After treatment with 600 and 1200 mg of CPs/kg, the level of BALP decreased to 85.26 +/ 7.35 and 97.03 +/- 7.21 units/L, respectively. After treatment with 600 mg of CPs/kg, the bone calcium content significantly increased by 22% (femur) and 12.38% (tibia) compared to those of the model group. In addition, the bone mineral density in the 600 mg of CPs/kg group was significantly higher (femur, 0.37 +/- 0.02 g/cm2; tibia, 0.33 +/- 0.02 g/cm2) than in the model group (femur, 0.26 +/- 0.01 g/cm2; tibia, 0.23 +/- 0.02 g/cm2). The morphology results indicated bone structure improved after the treatment with CPs. Structural characterization demonstrated that Glu, Lys, and Arg play important roles in binding calcium and promoting calcium uptake. Our results indicated that CPs could promote calcium uptake and regulate bone formation. PMID- 28915037 TI - Reactivity of a FeS Surface under Room Temperature Exposure to Nitrogen and H2S. AB - The reactivity of an iron monosulfide surface exposed at room temperature to molecular nitrogen and hydrogen sulfide has been investigated using X-ray photoemission spectroscopy (XPS) and thermal desorption spectroscopy (TDS). We have observed adsorption of nitrogen at room temperature that depends on the surface nanostructure and on the electronic state of nitrogen. The subsequent reaction of this adsorbed nitrogen with hydrogen sulfide results in depletion of the nitrogen surface content which can be interpreted in terms of ammonia formation. The XPS nitrogen N 1s core level line shape shows different components one of which seems to be the most reactive one in the ensuing H2S reaction. PMID- 28915038 TI - Frustrated Lewis Pair Polymers as Responsive Self-Healing Gels. AB - Steric bulk prevents the formation of strong bonds between Lewis acids and bases in frustrated Lewis pairs (FLPs), where latent reactivity makes these reagents transformative in small molecule activations and metal-free catalysis. However, their use as a platform for developing materials chemistry is unexplored. Here we report a fully macromolecular FLP, built from linear copolymers that containing either a sterically encumbered Lewis base or Lewis acid as a pendant functional group. The target functional copolymers were prepared by a controlled radical copolymerization of styrene with designer boron or phosphorus containing monomers. Mixtures of the B- and P-functionalized polystyrenes do not react, with the steric bulk of the functional monomers preventing the favorable Lewis acid base interaction. Addition of a small molecule (diethyl azodicarboxylate) promotes rapid network formation, cross-linking the reactive polymer chains. The resulting gel is dynamic, can self-heal, is heat responsive, and can be reshaped by postgelation processing. PMID- 28915039 TI - A First-Principles Molecular Dynamics Study of the Solvation Shell Structure, Vibrational Spectra, Polarity, and Dynamics around a Nitrate Ion in Aqueous Solution. AB - A first-principles molecular dynamics study is presented for the structural, dynamical, vibrational, and dipolar properties of the solvation shell of a nitrate ion in deuterated water. A detailed description of the anisotropic structure of the solvation shell is presented through calculations of various structural distributions in different conical shells around the perpendicular axis of the ion. The nitrate ion-water dimer potential energies are also calculated for many different orientations of water. The average vibrational stretch frequency of OD modes in the solvation shell is found to be higher than that of other OD modes in the bulk, which signifies a weakening of hydrogen bonds in the hydration shell. A splitting of the NO stretch frequencies and an associated fast spectral diffusion of the solute are also observed in the current study. The dynamics of rotation and hydrogen bond relaxation are found to be faster in the hydration shell than that in the bulk water. The residence time of water in the hydration shell is, however, found to be rather long. The nitrate ion is found to have a dipole moment of 0.9 D in water which can be attributed to its fluctuating interactions with the surrounding water. PMID- 28915041 TI - Preorganized Cyclic alpha,alpha-Disubstituted alpha-Amino Acids Bearing Functionalized Side Chains That Act as Peptide-Helix Inducers. AB - Preorganized cyclic alpha,alpha-disubstituted alpha-amino acids (dAA) bearing functionalized side chains that acted as peptide-helix inducers, which could be used for solid-phase peptide synthesis, were designed and synthesized. Furthermore, a helical octapeptide with the following amino acid sequence was prepared, and its preferred conformation was analyzed based on its CD spectra: Ac X1EYSAX2KA-NH2 (11: X1 = ApiC4N3, X2 = Ac6c). The side-chain azido functional group of peptide 11 was efficiently converted to various 1,2,3-triazole groups via Huisgen 1,3-dipolar cycloaddition reactions involving different types of alkynes. The new cyclic dAA derivatives, which combine the advantages of conformational preorganization and side-chain functional groups, should prove to be a useful tool for the further development of biologically active peptides. PMID- 28915040 TI - Elucidating the Interdependence of Drug Resistance from Combinations of Mutations. AB - HIV-1 protease is responsible for the cleavage of 12 nonhomologous sites within the Gag and Gag-Pro-Pol polyproteins in the viral genome. Under the selective pressure of protease inhibition, the virus evolves mutations within (primary) and outside of (secondary) the active site, allowing the protease to process substrates while simultaneously countering inhibition. The primary protease mutations impede inhibitor binding directly, while the secondary mutations are considered accessory mutations that compensate for a loss in fitness. However, the role of secondary mutations in conferring drug resistance remains a largely unresolved topic. We have shown previously that mutations distal to the active site are able to perturb binding of darunavir (DRV) via the protein's internal hydrogen-bonding network. In this study, we show that mutations distal to the active site, regardless of context, can play an interdependent role in drug resistance. Applying eigenvalue decomposition to collections of hydrogen bonding and van der Waals interactions from a series of molecular dynamics simulations of 15 diverse HIV-1 protease variants, we identify sites in the protease where amino acid substitutions lead to perturbations in nonbonded interactions with DRV and/or the hydrogen-bonding network of the protease itself. While primary mutations are known to drive resistance in HIV-1 protease, these findings delineate the significant contributions of accessory mutations to resistance. Identifying the variable positions in the protease that have the greatest impact on drug resistance may aid in future structure-based design of inhibitors. PMID- 28915042 TI - Mode of PEG Coverage on Carbon Nanotubes Affects Binding of Innate Immune Protein C1q. AB - Surface modification of nanoparticles with poly(ethylene glycol) (PEG) is used in biomedicine to increase the circulation time of the particles after intravenous injection. Here, we study the interaction of PEG-covered carbon nanotubes (CNTs) with the serum complement protein C1q. Besides being the target-recognizing unit of the initiating complex for the classical pathway of complement in our innate immune system, C1q is involved in a range of important physiological processes. We modified the surface of multiwalled CNTs with covalently grafted PEG and physically adsorbed PEG. Transmission electron microscopy revealed the interaction of these PEG-coated CNTs with C1q. We found abundant C1q coverage on the PEG-grafted CNTs but not on the CNTs with adsorbed PEG. We tested the ability of these CNTs to activate the complement system using in vitro complement activation assays. None of the CNTs studied activated the C1q-dependent classical complement pathway. These findings are pertinent to the safe design and novel biomedical applications of PEGylated CNTs. PMID- 28915043 TI - Proton Network Flexibility Enables Robustness and Large Electric Fields in the Ketosteroid Isomerase Active Site. AB - Hydrogen-bond networks play vital roles in biological functions ranging from protein folding to enzyme catalysis. Here we combine electronic structure calculations and ab initio path integral molecular dynamics simulations, which incorporate both nuclear and electronic quantum effects, to show why the network of short hydrogen bonds in the active site of ketosteroid isomerase is remarkably robust to mutations along the network and how this gives rise to large local electric fields. We demonstrate that these properties arise from the network's ability to respond to a perturbation by shifting proton positions and redistributing electronic charge density. This flexibility leads to small changes in properties such as the partial ionization of residues and pKa isotope effects upon mutation of the residues, consistent with recent experiments. This proton flexibility is further enhanced when an extended hydrogen-bond network forms in the presence of an intermediate analogue, which allows us to explain the chemical origins of the large electric fields in the enzyme's active site observed in recent experiments. PMID- 28915044 TI - Real-Space Bonding Indicator Analysis of the Donor-Acceptor Complexes X3BNY3, X3AlNY3, X3BPY3, and X3AlPY3 (X, Y = H, Me, Cl). AB - Calculations of real-space bonding indicators (RSBI) derived from Atoms-In Molecules (AIM), Electron Localizability Indicator (ELI-D), Non-Covalent Interactions index (NCI), and Density Overlap Regions Indicator (DORI) toolkits for a set of 36 donor-acceptor complexes X3BNY3 (1, 1a-1h), X3AlNY3 (2, 2a-2h), X3BPY3 (3, 3a-3h), and X3AlPY3 (4, 4a-4h) reveal that the donor-acceptor bonds comprise covalent and ionic interactions in varying extents (X = Y = H for 1-4; X = H, Y = Me for 1a-4a; X = H, Y = Cl for 1b-4b; X = Me, Y = H for 1c-4c; X, Y = Me for 1d-4d; X = Me, Y = Cl for 1e-4e; X = Cl, Y = H for 1f-4f; X = Cl, Y = Me for 1g-4g; X, Y = Cl for 1h-4h). The phosphinoboranes X3BPY3 (3, 3a-3h) in general and Cl3BPMe3 (3f) in particular show the largest covalent contributions and the least ionic contributions. The aminoalanes X3AlNY3 (2, 2a-2h) in general and Me3AlNCl3 (2e) in particular show the least covalent contributions and the largest ionic contributions. The aminoboranes X3BNY3 (1, 1a-1h) and the phosphinoalanes X3AlPY3 (4, 4a-4h) are midway between phosphinoboranes and aminoalanes. The degree of covalency and ionicity correlates with the electronegativity difference BP (DeltaEN = 0.15) < AlP (DeltaEN = 0.58) < BN (DeltaEN = 1.00) < AlN (DeltaEN = 1.43) and a previously published energy decomposition analysis (EDA). To illustrate the importance of both contributions in Lewis formula representations, two resonance formulas should be given for all compounds, namely, the canonical form with formal charges denoting covalency and the arrow notation pointing from the donor to the acceptor atom to emphasis ionicity. If the Lewis formula mainly serves to show the atomic connectivity, the most significant should be shown. Thus, it is legitimate to present aminoalanes using arrows; however, for phosphinoboranes the canonical form with formal charges is more appropriate. PMID- 28915045 TI - Identification and Validation of Reaction Coordinates Describing Protein Functional Motion: Hierarchical Dynamics of T4 Lysozyme. AB - While adequately chosen reaction coordinates are expected to reveal the mechanism of a dynamical process, it proves to be notoriously difficult to model the complex structural rearrangements of a macromolecule by a low-dimensional collective coordinate. Adopting the hinge-bending motion of T4 lysozyme (T4L) as a prominent example and performing a 50 MUs long unbiased molecular dynamics (MD) simulation of T4L, a general strategy to identify reaction coordinates of protein functional dynamics is developed. As a systematic method to reduce the dimensionality of the dynamics, first various types of principal component analyses are employed, and it is shown that the applicability and outcome of the approach crucially depends on the type of input coordinates used. In a second step, prospective candidates for a reaction coordinate are tested by studying the molecule's response to external pulling along the coordinate, using targeted MD simulations. While trying to directly enforce the open-closed transition does not recover the two-state behavior of T4L, this transition is triggered by a locking mechanism, by which the side chain of Phe4 changes from a solvent-exposed to a hydrophobically buried state. The mechanism is found to stabilize the open and closed states of T4L and thereby causes their relatively long lifetime of ~10 MUs. In extension of the usual two-state picture, a four-state model of the functional motion of T4L is proposed, which describes a hierarchical coupling of the fast nanosecond opening-closing motion and the slow microsecond locking transition. PMID- 28915046 TI - Factors Affecting the Bioaccessibility and Intestinal Transport of Difenoconazole, Hexaconazole, and Spirodiclofen in Human Caco-2 Cells Following in Vitro Digestion. AB - This study examined how gastrointestinal conditions affect pesticide bioaccessibility and intestinal transepithelial transport of pesticides (difenoconazole, hexaconazole, and spirodiclofen) in humans. We used an in vitro model combining human gastric and intestinal digestion, followed with Caco-2 cell model for human intestinal absorption. Bioaccessibility of three tested pesticides ranged from 25.2 to 76.3% and 10.6 to 79.63% in the gastric and intestinal phases, respectively. A marked trend similar to the normal distribution was observed between bioaccessibility and pH, with highest values observed at pH 2.12 in gastric juice. No significant differences were observed with increasing digestion time; however, a significant negative correlation was observed with the solid-liquid (S/L) ratio, following a logarithmic equation. R2 ranged from 0.9198 to 0.9848 and 0.9526 to 0.9951 in the simulated gastric and intestinal juices, respectively, suggesting that the S/L ratio is also a major factor affecting bioaccessibility. Moreover, significant dose- and time-response effects were subsequently observed for intestinal membrane permeability of difenoconazole, but not for hexaconazole or spirodiclofen. This is the first study to demonstrate the uptake of pesticides by human intestinal cells, aiding quantification of the likely effects on human health and highlighting the importance of considering bioaccessibility in studies of dietary exposure to pesticide residues. PMID- 28915047 TI - Two-Photon Absorption in Pentacene Dimers: The Importance of the Spacer Using Upconversion as an Indirect Route to Singlet Fission. AB - In this proof of concept study, we show that intramolecular singlet fission (iSF) can be initiated from a singlet excited state accessed by two-photon absorption, rather than through a traditional route of direct one-photon excitation (OPE). Thus, iSF in pentacene dimers 2 and 3 is enabled through NIR irradiation at 775 nm, a wavelength where neither dimer exhibits linear absorption of light. The adamantyl and meta-phenylene spacers 2 and 3, respectively, are designed to feature superimposable geometries, which establishes that the electronic coupling between the two pentacenes is the significant structural feature that dictates iSF efficiency. PMID- 28915048 TI - X-ray Free Electron Laser Radiation Damage through the S-State Cycle of the Oxygen-Evolving Complex of Photosystem II. AB - The oxygen-evolving complex (OEC) catalyzes water-splitting through a reaction mechanism that cycles the OEC through the "S-state" intermediates. Understanding structure/function relationsships of the S-states is crucial for elucidating the water-oxidation mechanism. Serial femtosecond X-ray crystallography has been used to obtain radiation damage-free structures. However, it remains to be established whether "diffraction-before-destruction" is actually accomplished or if significant changes are produced by the high-intensity X-ray pulses during the femtosecond scattering measurement. Here, we use ab initio molecular dynamics simulations to estimate the extent of structural changes induced on the femtosecond time scale. We found that the radiation damage is dependent on the bonding and charge of each atom in the OEC, in a manner that may provide lessons for XFEL studies of other metalloproteins. The maximum displacement of Mn and oxygen centers is 0.25 and 0.39 A, respectively, during the 50 fs pulse, which is significantly smaller than the uncertainty given the 1.9 A resolution of the current PSII crystal structures. However, these structural changes might be detectable when comparing isomorphous Fourier differences of electron density maps of the different S-states. One conclusion is that pulses shorter than 15 fs should be used to avoid significant radiation damage. PMID- 28915049 TI - Ruthenium-Catalyzed ortho/meta-Selective Dual C-H Bonds Functionalizations of Arenes. AB - The first example of transition-metal-catalyzed ortho/meta-selective dual C-H functionalizations of arenes in one reaction is described. In this transformation, ortho-C-H chlorination and meta-C-H sulfonation of 2 phenoxypyri(mi)dines were achieved simultaneously under catalysis by [Ru(p cymene)Cl2]2. The other reactant, namely, an arylsulfonyl chloride, played the role of both a sulfonation and chlorination reagent. More importantly, the arylsulfonyl chloride was also an oxidant in the process. Mechanistic studies indicated that six-membered ruthenacycles were the key intermediate in the reaction. PMID- 28915050 TI - One-Pot Synthesis of 1,2-Disubstituted 4-, 5-, 6-, and 7-Azaindoles from Amino-o halopyridines via N-Arylation/Sonogashira/Cyclization Reaction. AB - A direct synthesis of several 1,2-disubstituted 4-, 5-, 6-, and 7-azaindoles from available amino-o-halopyridines is described. This procedure involves a palladium catalyzed N-arylation followed by a Sonogashira reaction and subsequent cyclization in a one-pot manner, exhibiting a wide scope and compatibility with electron-withdrawing and electron-donating groups. The strategy represents an advancement in azaindole chemistry with a straightforward approach toward 1,2 disubstituted azaindoles, while avoiding complex N-arylations of hindered 2 substituted azaindoles and difficult purification steps of intermediates. PMID- 28915051 TI - Reconfigurable Positioning of Vertically-Oriented Nanowires Around Topographical Features in an AC Electric Field. AB - We report the effect of topographical features on gold nanowire assemblies in a vertically applied AC electric field. Nanowires 300 nm in diameter *2.5 MUm long, and coated with ~30 nm silica shell, were assembled in aqueous solution between top and bottom electrodes, where the bottom electrode was patterned with cylindrical dielectric posts. Assemblies were monitored in real time using optical microscopy. Dielectrophoretic and electrohydrodynamic forces were manipulated through frequency and voltage variation, organizing nanowires parallel to the field lines, i.e., standing perpendicular to the substrate surface. Field gradients around the posts were simulated and assembly behavior was experimentally evaluated as a function of patterned feature diameter and spacing. The electric field gradient was highest around these topographic features, which resulted in accumulation of vertically oriented nanowires around the post perimeters when dielectrophoresis dominated (high AC frequency) or between the posts when electrohydrodynamics dominated (low AC frequency). This general type of reconfigurable assembly, coupled with judicious choice of nanowire and post materials/dimensions, could ultimately enable new types of optical materials capable of switching between two functional states by changing the applied field conditions. PMID- 28915052 TI - Mass Spectrometric Analysis of SOX11-Binding Proteins in Head and Neck Cancer Cells Demonstrates the Interaction of SOX11 and HSP90alpha. AB - Deregulated expression of SOX11 has been shown to be involved in the progression of various types of cancer. However, the role of SOX11 in head and neck cancer remains largely unknown. In this study, coimmunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were performed to identify the proteins that bind to SOX11 at significantly higher levels in head and neck cancer cells than in normal human oral keratinocytes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that many potential SOX11-binding partners were associated with protein synthesis, cell metabolism, and cell-cell adhesion. One of the identified proteins, heat shock protein 90 alpha (HSP90alpha), was selected for further investigation. The binding of HSP90alpha with SOX11 in head and neck cancer cells was validated by Co-IP with western blotting. In addition, HSP90alpha was found to be remarkably overexpressed in head and neck cancer cell lines when compared to its level in normal human oral keratinocytes, and knockdown of HSP90alpha inhibited the proliferation and invasion capacity of these cancer cells. On the basis of The Cancer Genome Atlas (TCGA) data analysis, HSP90AA1 gene was overexpressed in head and neck cancer tissues compared to normal controls and increased HSP90AA1 gene expression was positively associated with extracapsular spread and clinical stage. Head and neck cancer patients with higher HSP90AA1 expression had significantly poorer long-term overall and disease-free survival rates than those with lower HSP90AA1 expression. Collectively, our studies indicate that SOX11 binds to HSP90alpha, a highly overexpressed protein that may promote invasion and progression of head and neck cancer cells. PMID- 28915053 TI - Heterogeneous Nucleation of Colloidal Crystals on a Glass Substrate with Depletion Attraction. AB - The heterogeneous nucleation of colloidal crystals with attractive interactions has been investigated via in situ observations. We have found two types of nucleation processes: a cluster that overcomes the critical size for nucleation with a monolayer, and a method that occurs with two layers. The Gibbs free energy changes (DeltaG) for these two types of nucleation processes are evaluated by taking into account the effect of various interfacial energies. In contrast to homogeneous nucleation, the change in interfacial free energy, Deltasigma, is generated for colloidal nucleation on a foreign substrate such as a cover glass in the present study. The Deltasigma and step free energy of the first layer, gamma1, are obtained experimentally based on the equation deduced from classical nucleation theory (CNT). It is concluded that the DeltaG of q-2D nuclei is smaller than of monolayer nuclei, provided that the same number of particles are used, which explains the experimental result that the critical size in q-2D nuclei is smaller than that in monolayer nuclei. PMID- 28915054 TI - Rapid Removal and Mineralization of Bisphenol A by Heterosupramolecular Plasmonic Photocatalyst Consisting of Gold Nanoparticle-Loaded Titanium(IV) Oxide and Surfactant Admicelle. AB - The establishment of technology for rapid and complete removal and mineralization of harmful phenolic compounds from water is of great importance for environmental conservation. Visible-light irradiation (lambda > 430 nm, light intensity integrated from 420 to 485 nm = 6.0 mW cm-2) of Au nanoparticle (NP)-loaded TiO2 (Au/TiO2) in dilute aqueous solutions of bisphenol A (BPA) and p-cresol (PC) causes degradation of the phenols. The addition of trimethylstearylammonium chloride (C18TAC) enhances the adsorption of BPA on Au/TiO2 to greatly increase the rate of reaction. Consequently, 10 MUM phenols are completely removed from the solutions within 2.5 h irradiation, and prolonging irradiation time to 24 h quantitatively oxidizes BPA to CO2. Dynamic light scattering zeta-potential measurements indicate that a C18TAC bilayer or admicelle is formed on the Au/TiO2 particle surface at C18TAC concentration >50 MUM. The action spectrum for reaction shows that this reaction is driven by the Au NP localized surface plasmon resonance excitation-induced interfacial electron transfer from Au to TiO2. We propose a possible reaction scheme on the basis of the experimental results including intermediate analysis. PMID- 28915055 TI - Efficient Method of Designing Stable Layered Cathode Material for Sodium Ion Batteries Using Aluminum Doping. AB - Despite their high specific capacity, sodium layered oxides suffer from severe capacity fading when cycled at higher voltages. This key issue must be addressed in order to develop high-performance cathodes for sodium ion batteries (SIBs). Herein, we present a comprehensive study on the influence of Al doping of Mn sites on the structural and electrochemical properties of a P2-Na0.5Mn0.5 xAlxCo0.5O2 (x = 0, 0.02, or 0.05) cathode for SIBs. Detailed structural, morphological, and electrochemical investigations were carried out using X-ray diffraction, cyclic voltammetry, and galvanostatic charge-discharge measurements, and some new insights are proposed. Rietveld refinement confirmed that Al doping caused TMO6 octahedra (TM = transition metal) shrinkage, resulting in wider interlayer spacing. After optimizing the aluminum concentration, the cathode exhibited remarkable electrochemical performance, with better stability and improved rate performance. Electrochemical impedance spectroscopy (EIS) measurements were performed at various states of charge to probe the surface and bulk effects of Al doping. The material presented here exhibits exceptional stability over 100 cycles within a 1.5-4.3 V window and outperforms several other Mn-Co-based cathodes for SIBs. This study presents a facile method for designing structurally stable cathodes for SIBs. PMID- 28915056 TI - Gigahertz Optomechanical Modulation by Split-Ring-Resonator Nanophotonic Meta Atom Arrays. AB - Using polarization-resolved transient reflection spectroscopy, we investigate a metasurface consisting of coherently vibrating nanophotonic U-shaped split-ring meta-atoms that exhibit colocalized optical and mechanical resonances. With an array of these resonators formed of gold on glass, essentially miniature tuning forks, we monitor the visible-pump induced gigahertz oscillations in reflected infrared light intensity to probe the multimodal vibrational response. Numerical simulations of the associated transient deformations and strain fields elucidate the complex nanomechanical dynamics contributing to the ultrafast optical modulation and point to the role of acousto-plasmonic interactions through the opening and closing motion of the SRR gaps as the dominant effect. Applications include ultrafast acoustooptic modulator design and sensing. PMID- 28915057 TI - Highly Efficient Flavin-Adenine Dinucleotide Glucose Dehydrogenase Fused to a Minimal Cytochrome C Domain. AB - Flavin-adenine dinucleotide (FAD) dependent glucose dehydrogenase (GDH) is a thermostable, oxygen insensitive redox enzyme used in bioelectrochemical applications. The FAD cofactor of the enzyme is buried within the proteinaceous matrix of the enzyme, which makes it almost unreachable for a direct communication with an electrode. In this study, FAD dependent glucose dehydrogenase was fused to a natural minimal cytochrome domain in its c-terminus to achieve direct electron transfer. We introduce a fusion enzyme that can communicate with an electrode directly, without the use of a mediator molecule. The new fusion enzyme, with its direct electron transfer abilities displays superior activity to that of the native enzyme, with a kcat that is ca. 3 times higher than that of the native enzyme, a kcat/KM that is more than 3 times higher than that of GDH and 5 to 7 times higher catalytic currents with an onset potential of ca. (-) 0.15 V vs Ag/AgCl, affording higher glucose sensing selectivity. Taking these parameters into consideration, the fusion enzyme presented can serve as a good candidate for blood glucose monitoring and for other glucose based bioelectrochemical systems. PMID- 28915058 TI - Valorization of Unconventional Lipids from Microalgae or Tall Oil via a Selective Dual Catalysis One-Pot Approach. AB - A dual catalysis approach enables selective functionalization of unconventional feedstocks composed of complex fatty acid mixtures with highly unsaturated portions like eicosapentaenoate (20:5) along with monounsaturated compounds. The degree of unsaturation is unified by selective heterogeneous hydrogenation on Pd/gamma-Al2O3, complemented by effective activation to a homogeneous carbonylation catalyst [(dtbpx)PdH(L)]+ by addition of diprotonated diphosphine (dtbpxH2)(OTf)2. By this one-pot approach, neat 20:5 as a model substrate is hydrogenated to up to 80% to the monounsaturated analogue (20:1), this is functionalized to the desired C21 alpha,omega-diester building block with a linear selectivity of over 90%. This catalytic approach is demonstrated to be suitable for crude microalgae oil from Phaeodactylum tricornutum genetically engineered for this purpose, as well as tall oil, an abundant waste material. Both substrates were fully converted with an overall selectivity to the linear alpha,omega-diester of up to 75%. PMID- 28915059 TI - Difluoromethylation of Carboxylic Acids via the Addition of Difluorinated Phosphorus Ylide to Acyl Chlorides. AB - A one-step protocol for the difluoromethylation of carboxylic acids is described. The reaction involves the interaction of intermediate acyl chlorides with in situ generated difluorinated phosphorus ylide Ph3P?CF2. Aromatic acids can be selectively transformed within one step either to bis-difluoromethylated alcohols or to difluorinated ketones depending on the particular reaction conditions. For bulky alpha-branched carboxylic acids, only ketones are produced. PMID- 28915060 TI - The Long Noncoding RNA LnRPT Is Regulated by PDGF-BB and Modulates the Proliferation of Pulmonary Artery Smooth Muscle Cells. AB - Pulmonary artery hypertension (PAH) is a rare and fatal disorder that involves extensive remodeling of the pulmonary arteries mediated by hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Aberrant platelet-derived growth factor (PDGF) activity can lead to hyperproliferation of PASMCs; however, little is known about the role of long noncoding RNA (lncRNA) in this process. Using RNA sequencing, we identified 725 lncRNAs in rat PASMCs, 95 of which were expressed differentially in response to PDGF-BB treatment. Depletion of four lncRNAs affected the proliferation of rat PASMCs as measured by 5-ethynyl-2'-deoxyuridine incorporation assay. Among these, one lncRNA, named LnRPT (lncRNA regulated by PDGF and transforming growth factor beta), was found to be the most potent in promoting the proliferation of PASMCs when knocked down. In contrast, proliferation of PASMCs was repressed when LnRPT was overexpressed. Mechanistically, LnRPT inhibited the expression of two genes involved in the Notch signaling pathway (notch3 and jag1) as well as the cell-cycle-regulating gene ccna2. In addition, downregulation of LnRPT induced by PDGF-BB was abrogated when phosphatidylinositol 3'-kinase activity was inhibited with pictilisib. Downregulation of LnRPT was also observed in the pulmonary arteries of rats with monocrotaline-induced PAH. This study provides novel insights into the effects of PDGF-BB on lncRNA expression in PASMCs, and identifies one lncRNA, LnRPT, that plays a role in PAH development as a regulator of PASMC proliferation by mediating the Notch signaling pathway and cell cycle. PMID- 28915061 TI - Prevalence of Complementary and Alternative Medicine and Herbal Remedy Use in Hispanic and Non-Hispanic White Women: Results from the Study of Women's Health Across the Nation. AB - OBJECTIVES: To investigate the prevalence of complementary and alternative medicine (CAM) use, including botanical/herbal remedies, among Hispanic and non Hispanic white women from the Study of Women's Health Across the Nation (SWAN), New Jersey site. We also examined whether attitudes toward CAM and communication of its use to providers differed for Hispanic and non-Hispanic women. STUDY DESIGN: SWAN is a community-based, multiethnic cohort study of midlife women. At the 13th SWAN follow-up, women at the New Jersey site completed both a general CAM questionnaire and a culturally sensitive CAM questionnaire designed to capture herbal products commonly used in Hispanic/Latina communities. Prevalence of and attitudes toward CAM use were compared by race/ethnicity and demographic characteristics. RESULTS: Among 171 women (average age 61.8 years), the overall prevalence of herbal remedy use was high in both Hispanic and non-Hispanic white women (88.8% Hispanic and 81.3% non-Hispanic white), and prayer and herbal teas were the most common modalities used. Women reported the use of multiple herbal modalities (mean 6.6 for Hispanic and 4.0 for non-Hispanic white women; p = 0.001). Hispanic women were less likely to consider herbal treatment drugs (16% vs. 37.5%; p = 0.005) and were less likely to report sharing the use of herbal remedies with their doctors (14.4% Hispanic vs. 34% non-Hispanic white; p = 0.001). The number of modalities used was similar regardless of the number of prescription medications used. CONCLUSIONS: High prevalence of herbal CAM use was observed for both Hispanic and non-Hispanic white women. Results highlight the need for healthcare providers to query women regarding CAM use to identify potential interactions with traditional treatments and to determine whether CAM is used in lieu of traditional medications. PMID- 28915062 TI - A Recombinant Fragment of Human Surfactant Protein D Suppresses Basophil Activation and T-Helper Type 2 and B-Cell Responses in Grass Pollen-induced Allergic Inflammation. AB - RATIONALE: Recombinant fragment of human surfactant protein D (rfhSP-D) has been shown to suppress house dust mite- and Aspergillus fumigatus-induced allergic inflammation in murine models. OBJECTIVES: We sought to elucidate the effect of rfhSP-D on high-affinity IgE receptor- and CD23-mediated, grass pollen-induced allergic inflammatory responses. METHODS: rfhSP-D, containing homotrimeric neck and lectin domains, was expressed in Escherichia coli BL21(lambdaDE3)pLysS cells. Peripheral blood mononuclear cells and sera were obtained from individuals with grass pollen allergy (n = 27). The effect of rfhSP-D on basophil activation and histamine release was measured by flow cytometry. IgE-facilitated allergen binding and presentation were assessed by flow cytometry. T-helper cell type 2 (Th2) cytokines were measured in cell culture supernatants. The effect of rfhSP-D on IgE production by B cells when stimulated with CD40L, IL-4, and IL-21 was also determined. MEASUREMENTS AND MAIN RESULTS: rfhSP-D bound to Phleum pratense in a dose- and calcium-dependent manner. Allergen-induced basophil responsiveness and histamine release were inhibited in the presence of rfhSP-D, as measured by CD63, CD203c (P = 0.0086, P = 0.04205), and intracellularly labeled diamine oxidase (P = 0.0003, P = 0.0148). The binding of allergen-IgE complexes to B cells was reduced by 51% (P = 0.002) in the presence of rfhSP-D. This decrease was concomitant with reduction in CD23 expression on B cells (P < 0.001). rfhSP-D suppressed allergen-driven CD27-CD4+CRTh2+ T-cell proliferation (P < 0.01), IL-4, and IL-5 levels (all P < 0.01). Moreover, rfhSP-D inhibited CD40L/IL-4- and IL-21 mediated IgE production (77.12%; P = 0.02) by B cells. CONCLUSIONS: For the first time, to our knowledge, we show that rfhSP-D inhibited allergen-induced basophil responses at a single-cell level and suppressed CD23-mediated facilitated allergen presentation and Th2 cytokine production. In addition, rfhSP-D inhibited IgE synthesis by B cells, which is also a novel observation. PMID- 28915063 TI - Twist1 in Hypoxia-induced Pulmonary Hypertension through Transforming Growth Factor-beta-Smad Signaling. AB - Pulmonary hypertension (PH) is a devastating pulmonary vascular disease characterized by aberrant muscularization of the normally nonmuscularized distal pulmonary arterioles. The expression of the transcription factor, Twist1, increases in the lungs of patients with pulmonary arterial hypertension. However, the mechanisms by which Twist1 controls the pathogenesis of PH remain unclear. It is becoming clear that endothelial-to-mesenchymal transition (EndMT) contributes to various vascular pathologies, including PH; Twist1 is known to mediate EndMT. In this report, we demonstrate that Twist1 overexpression increases transforming growth factor (TGF) beta receptor2 (TGF-betaR2) expression and Smad2 phosphorylation, and induces EndMT in cultured human pulmonary arterial endothelial (HPAE) cells, whereas a mutant construct of Twist1 at the serine 42 residue (Twist1S42A) fails to induce EndMT. We also implanted fibrin gel supplemented with HPAE cells on the mouse lung, and found that these HPAE cells form vascular structures and that Twist1-overexpressing HPAE cells undergo EndMT in the gel, whereas Twist1S42A-overexpressing cells do not. Furthermore, hypoxia induced EndMT is inhibited in endothelial cells overexpressing Twist1S42A mutant construct in vitro. Hypoxia-induced accumulation of alpha-smooth muscle actin positive cells in the pulmonary arterioles is attenuated in Tie2-specific Twist1 conditional knockout mice in vivo. These findings suggest that Twist1 serine 42 phosphorylation plays a key role in EndMT through TGF-beta signaling and that modulation of Twist1 phosphorylation could be an effective strategy for managing PH. PMID- 28915064 TI - The Immunopathologic Effects of Mycoplasma pneumoniae and Community-acquired Respiratory Distress Syndrome Toxin. A Primate Model. AB - Mycoplasma pneumoniae infection has been linked to poor asthma outcomes. M. pneumoniae produces an ADP-ribosylating and vacuolating toxin called community acquired respiratory distress syndrome (CARDS) toxin that has a major role in inflammation and airway dysfunction. The objective was to evaluate the immunopathological effects in primates exposed to M. pneumoniae or CARDS toxin. A total of 13 baboons were exposed to M. pneumoniae or CARDS toxin. At Days 7 and 14, BAL fluid was collected and analyzed for cell count, percent of each type of cell, CARDS toxin by PCR, CARDS toxin by antigen capture, eosinophilic cationic protein, and cytokine profiles. Serum IgM, IgG, and IgE responses to CARDS toxin were measured. All animals had a necropsy for analysis of the histopathological changes on lungs. No animal developed signs of infection. The serological responses to CARDS toxin were variable. At Day 14, four of seven animals exposed to M. pneumoniae and all four animals exposed to CARDS toxin developed histological "asthma-like" changes. T cell intracellular cytokine analysis revealed an increasing ratio of IL-4/IFN-gamma over time. Both M. pneumoniae and CARDS toxin exposure resulted in similar histopathological pulmonary changes, suggesting that CARDS toxin plays a major role in the inflammatory response. PMID- 28915066 TI - A Quantitative Assessment of the Reporting Quality of Herbal Medicine Research: The Road to Improvement. AB - OBJECTIVES: To quantify different aspects of the quality of reporting of herbal medicine clinical trials, to determine how that quality is affecting the conclusions of meta-analyses, and to target areas for improvement in future herbal medicine research reporting. STUDY DESIGN: The Electronic databases PubMed, Academic Search Premier, ScienceDirect, and Alt HealthWatch were searched for meta-analyses of herbal medicines in refereed journals and Cochrane Reviews in the years 2000-2004 and 2010-2014. The search was limited to meta-analyses of randomized controlled trials involving humans and published in English. Judgments and descriptions within the meta-analyses were used to report on risks of bias in the included clinical trials and the meta-analyses themselves. RESULTS: Out of 3264 citations, 9 journal-published meta-analyses were selected from 2000 to 2004, 116 from 2010 to 2014, and 44 Cochrane Reviews from 2010 to 2014. Across both time frames and categories of publication, <42% of the trials included in the meta-analyses described adequate randomization; <19% described concealment methods; <26% described double blinding; <29% described outcome assessment blinding, <=53% discussed incomplete data, and <36% were nonselective in their reporting. Less than 54% of trials reported on adverse events and 64% of meta analyses did not include a single trial with a low risk of bias. Taxonomic verification and chemical characterization of test products were infrequent in trials. Only 40% of meta-analyses considered publication bias and, of those that did, 90% found evidence for it. Cochrane Reviews were more likely than other sources to make negative conclusions of efficacy or to defer conclusions because of the absence of high quality trials. CONCLUSIONS: Meta-analyses of herbal medicines include a significant number of clinical trials that do not meet the recommended standards for clinical trial reporting. This quantitative assessment identified significant publication bias and other bias risks that may be due to inadequate trial design or incomplete reporting of outcomes. Suggested improvements to herbal medicine clinical trial reporting are discussed. PMID- 28915067 TI - Reverse Message-Framing Effects on Accelerometer-Assessed Physical Activity Among Older Outpatients With Type 2 Diabetes. AB - It has been suggested that gain-framed messages are more effective than loss framed messages in promoting low-risk health behaviors such as physical activity. Because of a heightened health concern and possible medical complications, older adults with type 2 diabetes (T2D) may consider physical activity to be risky. This study examined whether a reverse message-framing effect would be found among older adults with T2D. The participants included 211 sedentary and older adults with T2D recruited from an outpatient clinic. The participants were randomly assigned to receive either gain-framed or loss-framed messages and wore an accelerometer to monitor their physical activity for 2 weeks. The participants who received loss-framed messages were more physically active than those who received gain-framed messages (beta = 0.13, p = .033). This loss-frame advantage might be attributable to the heightened perceived risks among older outpatients with T2D and the temporarily activated prevention-focused orientation in a clinical setting. PMID- 28915065 TI - Targeting Hypoxia-Inducible Factor-1alpha/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis. AB - Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-beta-induced myofibroblast differentiation through HIF-1alpha, whereas overexpression of the critical HIF-1alpha-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1alpha. Inhibition of the HIF 1alpha/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1alpha/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis. PMID- 28915068 TI - Prevalence and Transmission of Antimicrobial Resistance in a Vertically Integrated Veal Calf Production System. AB - Transmission of antimicrobial resistance (AMR) from animal production systems to humans through the food supply is a public health concern. Currently, little is known about the prevalence of AMR among veal calves in the United States. Therefore, the objective of this prospective cohort study was to estimate the prevalence of AMR and multidrug resistance (MDR) among Escherichia coli within a vertically integrated production system. In addition, this study aimed to identify genes associated with phenotypic resistance to third- and fourth generation cephalosporins (3GC and 4GC). Calves from four veal cohorts were randomly sampled resulting in a total of 166 farm fecal samples, 159 harvest fecal swabs, 164 preevisceration swabs, and 122 final carcass swabs. The prevalence of MDR among random-pick E. coli isolates recovered from the respective samples was 97% (161/166), 35% (55/159), 61% (51/84), and 24% (5/21). A selective isolation protocol found cefotaxime (a 3GC)-resistant isolates in 91% (127/140) of farm fecal samples, 34% (55/164) of preevisceration swabs, and 19% (23/122) of final carcass swabs tested. Isolates resistant to cefepime, a 4GC, were found among 24% (33/140), 6.7% (11/164), and 0.8% (1/122) of the same, respective samples. Isolates resistant to ciprofloxacin, a fluoroquinolone, were recovered from 75% (73/98) of farm fecal samples, 23% (38/164) of preevisceration swabs, and 6.6% (8/122) of final carcass swabs. The blaCMY-2 and blaCTX-M resistance genes were found in 89% (93/105) and 100% (42/42) of tested subsets of 3GC- and 4GC-resistant isolates, respectively. Pulsed-field gel electrophoresis (PFGE) analysis conducted on 3GC- and fluoroquinolone-resistant isolates showed three indistinguishable PFGE patterns from cefotaxime-resistant isolates recovered at farm and from two preevisceration carcass swabs. Although the prevalence of resistance declined between initial farm fecal samples and final carcass swabs, resistant bacteria recovered from carcasses illustrate the potential transmission of AMR to the human food supply. PMID- 28915069 TI - Facilitators and Barriers to Positive Airway Pressure Adherence for Adolescents. A Qualitative Study. AB - RATIONALE: Low adherence to positive airway pressure (PAP) treatment for adolescents with obstructive sleep apnea (OSA) can have long-term cardiometabolic and developmental impact. OBJECTIVES: To explore the facilitators and barriers to PAP use in adolescents with OSA. METHODS: We conducted a qualitative study using a descriptive thematic analysis approach. A total of 21 interviews were conducted in the clinical setting with adolescents prescribed PAP to treat OSA within the previous 12 months. Interview audio recordings were transcribed verbatim for analysis. Transcripts were reviewed, and data were categorized using a coding framework developed by the research team. Codes were structured into themes related to the barriers and facilitators to using PAP. RESULTS: Participants described numerous challenges with the physical design of the PAP machine, including the restriction of the tubing, the discomfort of the mask, and concerns with its size and weight. A period of adjustment to wearing and preparing the PAP machine was described whereby participants had to develop their own strategies to improve comfort. After initiating the therapy, the challenges experienced by participants were cited more often than the perceived benefits, particularly for those who were less adherent. Finally, the unique needs of adolescents were highlighted, which impacted the amount of family support desired in using PAP. CONCLUSIONS: This study identifies factors affecting PAP adherence when prescribed in adolescence and highlights the need for ongoing dialogue between adolescents and their clinical team with respect to challenges encountered, troubleshooting, adherence strategies, and parental engagement. PMID- 28915070 TI - Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non diagnostic ciliary ultrastructure. AB - Primary ciliary dyskinesia (PCD) is a genetic disorder causing chronic oto-sino pulmonary disease. No single diagnostic test will detect all PCD cases. Transmission electron microscopy (TEM) of respiratory cilia was previously considered the gold standard diagnostic test for PCD, but 30% of all PCD cases have either normal ciliary ultrastructure or subtle changes which are non diagnostic. These cases are identified through alternate diagnostic tests, including nasal nitric oxide measurement, high-speed videomicroscopy analysis, immunofluorescent staining of axonemal proteins, and/or mutation analysis of various PCD causing genes. Autosomal recessive mutations in DNAH11 and HYDIN produce normal TEM ciliary ultrastructure, while mutations in genes encoding for radial spoke head proteins result in some cross-sections with non-diagnostic alterations in the central apparatus interspersed with normal ciliary cross sections. Mutations in nexin link and dynein regulatory complex genes lead to a collection of different ciliary ultrastructures; mutations in CCDC65, CCDC164, and GAS8 produce normal ciliary ultrastructure, while mutations in CCDC39 and CCDC40 cause absent inner dynein arms and microtubule disorganization in some ciliary cross-sections. Mutations in CCNO and MCIDAS cause near complete absence of respiratory cilia due to defects in generation of multiple cellular basal bodies; however, the scant cilia generated may have normal ultrastructure. Lastly, a syndromic form of PCD with retinal degeneration results in normal ciliary ultrastructure through mutations in the RPGR gene. Clinicians must be aware of these genetic causes of PCD resulting in non-diagnostic TEM ciliary ultrastructure and refrain from using TEM of respiratory cilia as a test to rule out PCD. PMID- 28915072 TI - Parent-Driven Campaign Videos: An Analysis of the Motivation and Affect of Videos Created by Parents of Children With Complex Healthcare Needs. AB - Caring for a child with complex health care needs places additional stress and time demands on parents. Parents often turn to their peers to share their experiences, gain support, and lobby for change; increasingly this is done through social media. The WellChild #notanurse_but is a parent-driven campaign that states its aim is to "shine a light" on the care parents, who are not nurses, have to undertake for their child with complex health care needs and to raise decision-makers' awareness of the gaps in service provision and support. This article reports on a study that analyzed the #notanurse_but parent-driven campaign videos. The purpose of the study was to consider the videos in terms of the range, content, context, perspectivity (motivation), and affect (sense of being there) in order to inform the future direction of the campaign. Analysis involved repeated viewing of a subset of 30 purposively selected videos and documenting our analysis on a specifically designed data extraction sheet. Each video was analyzed by a minimum of 2 researchers. All but 2 of the 30 videos were filmed inside the home. A variety of filming techniques were used. Mothers were the main narrators in all but 1 set of videos. The sense of perspectivity was clearly linked to the campaign with the narration pressing home the reality, complexity, and need for vigilance in caring for a child with complex health care needs. Different clinical tasks and routines undertaken as part of the child's care were depicted. Videos also reported on a sense of feeling different than "normal families"; the affect varied among the researchers, ranging from strong to weaker emotional responses. PMID- 28915071 TI - Transcriptional Response of Respiratory Epithelium to Nontuberculous Mycobacteria. AB - The incidence of pulmonary nontuberculous mycobacteria (NTM) disease is increasing, but host responses in respiratory epithelium infected with NTM are not fully understood. In this work, we aimed to identify infection-relevant gene expression signatures of NTM infection of the respiratory epithelium. We infected air-liquid interface (ALI) primary respiratory epithelial cell cultures with Mycobacterium avium subsp. avium (MAC) or Mycobacterium abscessus subsp. abscessus (MAB). We used cells from four different donors to obtain generalizable data. Differentiated respiratory epithelial cells at the ALI were infected with MAC or MAB at a multiplicity of infection of 100:1 or 1,000:1, and RNA sequencing was performed at Days 1 and 3 after infection. In response to infection, we found down-regulation of ciliary genes but upregulation of genes associated with cytokines/chemokines, such as IL-32, and cholesterol biosynthesis. Inflammatory response genes tended to be more upregulated by MAB than by MAC infection. Primary respiratory epithelial cell infection with NTM at the ALI identified ciliary function, cholesterol biosynthesis, and cytokine/chemokine production as major host responses to infection. Some of these pathways may be amenable to therapeutic manipulation. PMID- 28915073 TI - Internalized Homonegativity and Substance Use Among U.S. Men Who Have Sex with Men Only (MSMO) and Men Who Have Sex with Men and Women (MSMW). AB - BACKGROUND: Internalized homonegativity may promote substance use among U.S. men who have sex with men only (MSMO) and men who have sex with men and women (MSMW). However, studies have produced mixed findings, used non-representative samples, and not adequately examined MSMW. OBJECTIVES: We investigated (1) internalized homonegativity in relation to substance use and (2) the extent of temporal change in internalized homonegativity among MSMO and MSMW. METHODS: Using merged 2002, 2006-2010, and 2011-2013 cycles of the National Survey of Family Growth-a nationally representative U.S. sample of persons aged 15-44 years-we acquired subsamples of MSMO (n = 419) and MSMW (n = 195). Rao-Scott chi-square tests examined internalized homonegativity in relation to past-month binge drinking and use of marijuana. These tests examined past-year use of any illicit substance, cocaine, crack, injection drugs, and methamphetamine. Multivariable logistic regression models controlled for covariates. Rao-Scott chi-square tests examined temporal changes in internalized homonegativity. RESULTS: Among MSMO, internalized homonegativity was associated with increased odds of using any illicit substance, cocaine, and methamphetamine. Among MSMW, however, internalized homonegativity was associated with decreased odds of using any illicit substance, cocaine, crack, injection drugs, and methamphetamine. The proportion of MSMO and MSMW who expressed internalized homonegativity did not significantly change during 2002-2013. Conclusions/Importance: Internalized homonegativity may be positively associated with substance use among MSMO, but negatively associated with substance use among MSMW. Future studies should seek to better understand internalized homonegativity and other determinants of substance use among MSMO and MSMW. PMID- 28915074 TI - Palliative Care Units Are Really Cost Effective Compared With Usual Care. PMID- 28915075 TI - Responding to Patient Requests for Hastened Death: Physician Aid in Dying and the Clinical Oncologist. AB - Physician aid in dying (PAD) or assisted suicide is becoming legal in more US jurisdictions. Meanwhile, the needs of terminally ill patients with cancer are receiving greater attention, including the integration of palliative care into oncology practice. This article highlights a case vignette of a patient with advanced cancer who requests PAD from her oncologist, as a backdrop to help the practicing oncologist examine his or her moral stance regarding participation in aid in dying. The article concludes by offering a framework within which the practicing oncologist can receive and process a patient's request for PAD. PMID- 28915076 TI - Reply to S.R. Isenberg et al. PMID- 28915077 TI - Patient-Clinician Communication: American Society of Clinical Oncology Consensus Guideline Summary. PMID- 28915078 TI - Pediatric-Specific End-of-Life Care Quality Measures: An Unmet Need of a Vulnerable Population. AB - We must ensure that the 20,000 US children (age 0 to 19 years) who die as a result of serious illness annually receive high-quality end-of-life care. Ensuring high-quality end-of-life care requires recognition that pediatric end-of life care is conceptually and operationally different than that for adults. For example, in-hospital adult death is considered an outcome to be avoided, whereas many pediatric families may prefer hospital death. Because pediatric deaths are comparatively rare, not all centers offer pediatric-focused palliative care and hospice services. The unique psychosocial issues facing families who are losing a child include challenges for parent decision makers and young siblings. Furthermore, the focus on advance directive documentation in adult care may be less relevant in pediatrics because parental decision makers are available. Health care quality measures provide a framework for tracking the care provided and aid in agency and provider accountability, reimbursement, and educated patient choice for location of care. The National Quality Forum, Joint Commission, and other groups have developed several end-of-life measures. However, none of the current quality measures focus on the unique needs of dying pediatric patients and their caregivers. To evolve the existing infrastructure to better measure and report quality pediatric end-of-life care, we propose two changes. First, we outline how existing adult quality measures may be modified to better address pediatric end-of-life care. Second, we suggest the formation of a pediatric quality measure end-of-life task force. These are the next steps to evolving end-of-life quality measures to better fit the needs of seriously ill children. PMID- 28915080 TI - Weight-adjusted Intravenous Reslizumab in Severe Asthma with Inadequate Response to Fixed-Dose Subcutaneous Mepolizumab. AB - RATIONALE: Clinical benefits of fixed-dose 100-mg subcutaneous (SC) mepolizumab in prednisone-dependent patients are modest when sputum eosinophilia is not adequately controlled. OBJECTIVES: This study compared treatment response of weight-adjusted intravenous (IV) reslizumab in patients previously treated with 100-mg SC mepolizumab. METHODS: Ten prednisone-dependent patients with asthma (sputum eosinophils >3% and blood eosinophils >300 cells/MUl), who had previously received mepolizumab (100 mg SC dosed every 4 wk [Q4W]) for at least 1 year, received two infusions of placebo (Q4W) followed by four infusions of 3.0 mg/kg reslizumab Q4W in a single-blind, placebo-controlled sequential trial. Primary outcomes were reduction of eosinophils in sputum and blood. Additional outcomes included FEV1, asthma control questionnaire, eosinophil peroxidase, IL-5, sputum and blood innate lymphoid cells group 2, eosinophil progenitor cells, and autoimmune responses. MEASUREMENTS AND MAIN RESULTS: IV reslizumab attenuated sputum eosinophils by 91.2% (P = 0.002), blood eosinophil counts by 87.4% (P = 0.004), and sputum eosinophil peroxidase levels by 65.5% (P = 0.03) compared with placebo. Attenuation of both local and systemic eosinophilia was associated with statistically significant improvements in FEV1 (P = 0.004) and asthma control questionnaire five-question instrument scores (P = 0.006). Decrease in percent sputum eosinophil was greater with reslizumab (by 42.7%) compared with mepolizumab (by 5.0%) and this was associated with greater improvement in asthma control questionnaire (P = 0.01; analysis of covariance of Delta between before and after treatment, mepolizumab vs. reslizumab, adjusted for baseline prednisone). Changes in sputum IL-5 and anti-eosinophil peroxidase IgG after anti IL-5 therapy were predictors of response. CONCLUSIONS: Weight-adjusted IV reslizumab was superior to fixed-dose SC mepolizumab in attenuating airway eosinophilia in prednisone-dependent patients with asthma, with associated improvement in asthma control. Clinical trial registered with www.clinicaltrials.gov (NCT 02559791). PMID- 28915081 TI - The Story of RNA Interference as a New Therapeutic Paradigm from Nobel Laureate Craig Mello. PMID- 28915082 TI - A Combined Study of SLC6A15 Gene Polymorphism and the Resting-State Functional Magnetic Resonance Imaging in First-Episode Drug-Naive Major Depressive Disorder. AB - AIMS: The SLC6A15 gene has been identified as a novel candidate gene for major depressive disorder (MDD). However, the mechanism underlying the effects of how the SLC6A15 gene affects functional brain activity of patients with MDD remains unknown. METHODS: In the present study, we investigated the effect of the SLC6A15 gene polymorphism, rs1545843, on resting-state brain function in MDD with the imaging genomic technology and the regional homogeneity (ReHo) method. Sixty seven MDD patients and 44 healthy controls underwent functional magnetic resonance imaging scans and genotyping. The differences in ReHo between genotypes were initially tested using the student's t test. We then performed a 2 * 2 (genotypes * disease status) analysis of variance to identify the main effects of genotypes, disease status, and their interactions in MDD. RESULTS: MDD patients with A+ genotypes showed decreased ReHo in the medial cingulum compared with MDD patients with the GG genotype. This was in contrast to normal controls with A+ genotypes who showed increased ReHo in the posterior cingulum and the frontal, temporal, and parietal lobes and decreased ReHo in the left corpus callosum, compared with controls with the GG genotypes. The main effect of disease was found in the frontal, parietal, and temporal lobes. The main effect of genotypes was found in the left corpus callosum and the frontal lobe. There was no interaction between rs1545843 genotypes and disease status. We found that the left corpus callosum ReHo was positively correlated with total scores of the Hamilton Depression Scale (HAMD) (p = 0.021), so as was the left inferior parietal gyrus ReHo with cognitive disorder (p = 0.02). In addition, the right middle temporal gyrus had a negative correlation with retardation (p = 0.049). CONCLUSION: We observed an association between the SLC6A15 rs1545843 and resting state brain function of the corpus callosum, cingulum and the frontal, parietal, and temporal lobes in MDD patients, which may be involved in the pathogenesis of MDD. PMID- 28915083 TI - Research for the People by the People. PMID- 28915086 TI - Effective Physical Activity Promotion to Survivors of Cancer Is Likely to Be Home Based and to Require Oncologist Participation. PMID- 28915085 TI - Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. AB - Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks * 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar. PMID- 28915087 TI - Feasibility of Detecting Bioorganic Compounds in Enceladus Plumes with the Enceladus Organic Analyzer. AB - Enceladus presents an excellent opportunity to detect organic molecules that are relevant for habitability as well as bioorganic molecules that provide evidence for extraterrestrial life because Enceladus' plume is composed of material from the subsurface ocean that has a high habitability potential and significant organic content. A primary challenge is to send instruments to Enceladus that can efficiently sample organic molecules in the plume and analyze for the most relevant molecules with the necessary detection limits. To this end, we present the scientific feasibility and engineering design of the Enceladus Organic Analyzer (EOA) that uses a microfluidic capillary electrophoresis system to provide sensitive detection of a wide range of relevant organic molecules, including amines, amino acids, and carboxylic acids, with ppm plume-detection limits (100 pM limits of detection). Importantly, the design of a capture plate that effectively gathers plume ice particles at encounter velocities from 200 m/s to 5 km/s is described, and the ice particle impact is modeled to demonstrate that material will be efficiently captured without organic decomposition. While the EOA can also operate on a landed mission, the relative technical ease of a fly-by mission to Enceladus, the possibility to nondestructively capture pristine samples from deep within the Enceladus ocean, plus the high sensitivity of the EOA instrument for molecules of bioorganic relevance for life detection argue for the inclusion of EOA on Enceladus missions. Key Words: Lab-on-a-chip-Organic biomarkers-Life detection-Planetary exploration. Astrobiology 17, 902-912. PMID- 28915088 TI - Abiotic and Biotic Formation of Amino Acids in the Enceladus Ocean. AB - The active plume at Enceladus' south pole makes the indirect sampling of its global ocean possible. The partially resolved chemistry of the plume, which points to conditions that are seemingly compatible with life, has made orbital sampling missions a priority. We present a conceptual model of energy flux, hydrothermal H2 production, and both abiotic and biotic production of amino acids. Based on the energy flux observed at the south pole and the inferred internal hydrothermal activity, we estimate an H2 production of 0.6-34 mol/s from serpentinization, sufficient to sustain abiotic and biotic amino acid synthesis of 1.6-87 and 1-44 g/s, respectively. Two-dimensional (2D) numerical simulations of the hydrothermal vent suggest that the vent fluids could reach the ice-water boundary in less than 11-55 days for a 50 km deep ocean diluted by ambient ocean water 10 to 1. Concentrations of glycine, alanine, alpha-amino isobutyric acid, and glutamic acid in the plume and in the ambient ocean could all be above 0.01 MUM just due to abiotic production. Biological synthesis, if occurring, could produce a maximum of 90 MUM concentrations of amino acids based on a methanogenic ecosystem consuming H2 and CO2. Racemization timescales in the ocean are short compared with production timescales. Thus, no enantiomeric excess is expected in the ambient ocean, and if biology is present, enantiomeric excess at the vent fluids is expected to be less than 10% in the plume. From vent H2 concentrations of 7.8 mM (e.g., Lost City) and assuming complete H2 use and conversion to chemical energy by methanogens, cell production is estimated. Annual biomass production in the methanogenic-based biology model is 4 * 104-2 * 106 kg/year. This corresponds to cell concentrations ~109 cells/cm3 in the vents and ~108 cells/cm3 in the plume, and when diluted into the ambient ocean, we predict cell concentrations of 80-4250 cells/cm3. Key Words: Abiotic organic synthesis Enceladus-Extraterrestrial life. Astrobiology 17, 862-875. PMID- 28915089 TI - Transgender Teachers: The Personal, Pedagogical, and Political. AB - This empirical research study examines the experiences of three male-to-female transgender teachers who transitioned genders, in three different decades (1980s, 1990s, 2000s) while actively teaching within Canadian K-12 public schools. I utilize poststructural storylines to explore how these transgender teachers navigated the personal, pedagogical, and political and the survival and transition strategies they developed to become intelligible within their schools. Their storylines illustrate how they developed counternarratives to challenge traditional discourses of trans invisibility, silence, shame, and fear. PMID- 28915090 TI - Evaluating the consistency of scales used in adult attention deficit hyperactivity disorder assessment of college-aged adults. AB - OBJECTIVE: Neurocognitive evaluations are commonly integrated with clinical assessment to evaluate adult Attention Deficit Hyperactivity Disorder (ADHD). Study goal is to identify measures most strongly related to ADHD diagnosis and to determine their utility in screening processes. PARTICIPANTS: 230 students who were evaluated at the Vanderbilt University Psychological and Counseling Center between July 2013 and October 2015. METHODS: We retrospectively examined charts, including clinical diagnosis, family history, childhood parental reported and current self-reported ADHD symptoms, psychiatric comorbidities, and continuous performance test (CPT). RESULT: Positive report of childhood and current ADHD symptoms, and lack of comorbid psychiatric symptoms were strongly associated with clinical diagnosis. CPT results were not associated with an ADHD diagnosis. The absence of reported childhood and current ADHD symptoms may serve as a contradictory marker for ADHD diagnosis. CONCLUSION: Clinical assessment of ADHD symptoms and ADHD childhood history, but not CPT, contributes to an accurate diagnosis of ADHD in college-aged adults. PMID- 28915091 TI - Working with the Complexity and Refusing to Simplify: Undocuqueer Meaning Making at the Intersection of LGBTQ and Immigrant Rights Discourses. AB - This study brings gender, sexuality, and immigration status, and their conceptual margins, to the center of analysis via the narratives of 31 self-identified undocuqueer immigrants. Undocuqueer immigrants ascribe meaning to their experiences by producing alternate subjectivities and subject positions that resist multiple axes of oppression. These subjectivities problematize the exclusionary repercussions of single-axis identity categorization that mostly benefit those who already have some structural privileges. Undocuqueer as a form of resistance to essentialized identity discourses was evidenced in participants' opposition to heteronormative, homonormative, and DREAMer discourses. This study has implications for further understanding the way that queer politics and identity interact with various axes of inequality. PMID- 28915092 TI - Sexual Orientation in State Hate Crime Laws: Exploring Social Construction and Criminal Law. AB - Several studies have described and analyzed the development and diffusion of hate crime laws in the United States, but none specifically examined state-level differences in protected categories. Forty-five of the 50 states have a hate crime statute, but only 30 of those include sexual orientation. In this study the social construction framework is applied to the hate crime policy domain in order to determine whether or not variations in the social and political status of gays and lesbians are associated with the inclusion of sexual orientation in state hate crime laws. Content analysis of daily newspapers in six states revealed that a positive social construction is associated with groups seeking hate crime law protections, and that political influence may also be a key factor. PMID- 28915093 TI - Sport Skill-Specific Expertise Biases Sensory Integration for Spatial Referencing and Postural Control. AB - The authors asked how sport expertise modulates visual field dependence and sensory reweighting for controlling posture. Experienced soccer athletes, ballet dancers, and nonathletes performed (a) a Rod and Frame test and (b) a 100-s bipedal stance task during which vision and proprioception were successively or concurrently disrupted in 20-s blocks. Postural adaptation was assessed in the mean center of pressure displacement, root mean square of center of pressure velocity and ankle muscles integrated electromyography activity. Soccer athletes were more field dependent than were nonathletes. During standing, dancers were more destabilized by vibration and required more time to reweigh sensory information compared with the other 2 groups. These findings reveal a sport skill specific bias in the reweighing of sensory inputs for spatial orientation and postural control. PMID- 28915094 TI - Surgical Site Infections after Tissue Flaps Performed in Low- and Middle-Human Development Index Countries: A Systematic Review. AB - BACKGROUND: Surgical site infections (SSIs) affect the safety of surgical care and are particularly problematic and prevalent in low and middle Human Development Index Countries (LMHDICs). METHODS: We performed a systematic review of the existing literature on SSIs after tissue flap procedures in LMHDICs through the PubMed, Ovid, and Web of Science databases. Of the 405 abstracts identified, 79 were selected for full text review, and 30 studies met inclusion criteria for analysis. RESULTS: In the pooled analysis, the SSI rate was 5.8 infections per 100 flap procedures (95% confidence interval [CI] 2%-10%, range: 0 40%). The most common indication for tissue flap was pilonidal sinus repair, which had a pooled SSI rate of 5.6 infections per 100 flap procedures (95% CI 2% 10%, range: 0-15%). No fatalities from an infection were noted. The reporting of infection epidemiology, prevention, and treatment was poor, with few studies reporting antibiotic agent use (37%), responsible pathogens (13%), infection comorbidities (13%), or time to infection (7%); none reported cost. CONCLUSIONS: Our review highlights the need for more work to develop standardized hospital based reporting for surgical outcomes and complications, as well as future studies by large, multi-national groups to establish baseline incidence rates for SSIs and best practice guidelines to monitor SSI rates. PMID- 28915095 TI - Ethical Considerations For Social Workers Working with Muslim Refugees. AB - In 2016 almost 39,000 Muslim refugees entered the United States, representing a record of admissions during a time of elevated anti-Muslim political rhetoric and public sentiment. Anti-Muslim attitudes and policies can affect refugees' ability to successfully resettle and contribute to decreased health status. Given the current social and political moment there is an ethical imperative for social workers to engage in resistance to anti-Muslim sentiment and the encoding of Islamophobia in resettlement policy. In this article, the authors explore constraints on resettlement social workers' engagement with advocacy and make suggestions for ethical practice that promotes social and emotional well-being. PMID- 28915096 TI - Dietary supplement use, perceptions, and associated lifestyle behaviors in undergraduate college students, student-athletes, and ROTC cadets. AB - OBJECTIVE: To identify the prevalence of dietary supplement (DS) use, perceptions of DS efficacy, and lifestyle behaviors of DS users and non-users. PARTICIPANTS: Undergraduate students, student-athletes, and ROTC cadets at a Midwestern University between September 2014 and January 2015. METHODS: A cross-sectional online survey was administered. Analysis included descriptive statistics, chi square, and independent sample t-tests. RESULTS: At least 50% of respondents from each group reported DS use. Users generally reported favorable perceptions of efficacy. Undergraduate student DS users reported more exercise and more healthful dietary habits compared to non-users; however, nearly 72% of undergraduates who reported tobacco use also reported DS use. Less significant differences were observed in the student-athlete and cadet samples. CONCLUSIONS: DS use is common on college campuses, and many DS users report favorable perceptions of efficacy. With the exception of tobacco use, collegiate DS users generally report lifestyles that are as healthy or healthier than non-users. PMID- 28915098 TI - Balance, Proprioception, and Gross Motor Development of Chinese Children Aged 3 to 6 Years. AB - The authors' aim was to find the features of balance, proprioception, and gross motor development of Chinese children 3-6 years old and their correlations, provide theoretical support for promoting children's motor development, and enrich the world theoretical system of motor development. This study used a Tekscan foot pressure measurement instrument (Tekscan, Inc., Boston, MA), walking on a balance beam, Xsens 3-dimensional positional measuring system (Xsens Technologies, Enschede, the Netherlands), and Test of Gross Motor Development-2 to assess static balance, dynamic balance, knee proprioception, and levels of gross motor development (GMD) of 3- to 6-year-old children (n = 60) in Beijing. The results are as follows: children had significant age differences in static balance, dynamic balance, proprioception, and levels of GMD; children had significant gender differences in static balance, proprioception, and levels of GMD; children's static balance, dynamic balance, and proprioception had a very significant positive correlation with GMD (p < .01), but no significant correlation with body mass index. PMID- 28915097 TI - Synergies and Motor Equivalence in Voluntary Sway Tasks: The Effects of Visual and Mechanical Constraints. AB - The authors used two analyses developed within the framework of the uncontrolled manifold hypothesis to quantify multimuscle synergies during voluntary body sway: analysis of intertrial variance and analysis of motor equivalence with respect to the center of pressure (COP) trajectory. Participants performed voluntary sway tasks in the anteroposterior direction at 0.33 and 0.66 Hz. Muscle groups were identified in the space of muscle activations and used as elemental variables in the synergy analyses. Changing mechanical and vision feedback-based constraints led to significant changes in indices of sway performance such as COP deviations in the uninstructed, mediolateral direction and indices of spontaneous postural sway. In contrast, there were no significant effects on synergy indices. These findings show that the neural control of performance and of its stability may involve different control variables and neurophysiological structures. There were strong correlations between the indices of motor equivalence and those computed using the intercycle variance analysis. This result is potentially important for studies of patients with movement disorders who may be unable to perform multiple trials (cycles) at any given task, making analysis of motor equivalence of single trials a viable alternative to explore changes in stability of actions. PMID- 28915099 TI - Examining Readmissions through the Zone of Tolerance Theory. AB - The relationship between readmissions and customer service expectations is examined through the lens of the Zone of Tolerance (ZoT) theory. ZoT theory is expanded to consider the potential conflicting expectations and nature of the payer and patent customer dichotomy of the healthcare industry. The paper will suggest opportunities to influence patient expectations and understanding. It will also present empirical methods for understanding and responding to payer service expectations. PMID- 28915101 TI - These Unprecedented Times. PMID- 28915100 TI - Promotion of Immunizations for Health Professionals in Europe: A Qualitative Study in Seven European Member States. AB - Health Care Workers (HCWs) are a high-risk group for contracting Vaccine Preventable Diseases who, despite legislation and guidance, remain undervaccinated. In order to understand their barriers and needs, focus groups were formed with 278 physicians, nurses, infection-control personnel, and policy makers in 7 EU MS. Several implications for the development of promotional initiatives were identified including the need to overcome organizational barriers, to sensitize HCWs about the importance of immunization and to provide specific up-to-date information about vaccinations covering prevalence of diseases, protection years, side effects, administration times, antibody examinations, costs and immunization settings. PMID- 28915102 TI - Acceleration-selective Arterial Spin-labeling MR Angiography Used to Visualize Distal Cerebral Arteries and Collateral Vessels in Moyamoya Disease. AB - Purpose To evaluate and compare the performance of acceleration-selective arterial spin labeling (AccASL) magnetic resonance (MR) angiography in the visualization of cerebral arteries and collateral vessels in patients with Moyamoya disease with that of time-of-flight (TOF) MR angiography, with digital subtraction angiography (DSA) as the reference standard. Materials and Methods Thirty-six cerebral hemispheres from 22 patients with Moyamoya disease underwent TOF and AccASL MR angiography and DSA. Qualitative evaluations included imaging of the terminal internal carotid artery (ICA), distal middle cerebral arteries (MCAs), Moyamoya vessels, and leptomeningeal anastomosis (LMA) collaterals with reference to DSA. Quantitative evaluations included assessment of contrast-to noise ratio (CNR) and number of vessels in MCA branches. The linear mixed-effect model was used to compare the two methods. Results Mean scores for qualitative evaluation were significantly higher with AccASL angiography than with TOF angiography for imaging distal MCAs (3.9 +/- 0.3 [standard deviation] vs 2.9 +/- 1.1; P < .001), Moyamoya vessels (3.6 +/- 0.6 vs 2.7 +/- 0.9, P < .001), and LMA collaterals (3.8 +/- 0.6 vs 1.8 +/- 0.7, P < .001). Scores for steno-occlusive degree around the terminal ICAs were better with TOF angiography than with AccASL angiography (2.6 +/- 0.5 vs 2.4 +/- 0.6, P = .023). CNRs in the M4 segment were significantly higher with AccASL angiography (11.9 +/- 12.9, P < .001) than with TOF angiography (4.1 +/- 7.9). The number of vessels was significantly higher with AccASL angiography (18.3 +/- 5.0, P < .001) than with TOF angiography (8.9 +/- 4.9). The increase in the number of vessels from TOF angiography to AccASL angiography was greater in patients with severe ICA steno-occlusion (late ICA stage group, 11.4 +/- 4.5; early ICA stage group, 6.8 +/- 4.0; P = .007) and well developed leptomeningeal anastomosis (mildly developed LMA group, 7.1 +/- 4.3; well-developed LMA group, 11.3 +/- 4.5; P = .011). Conclusion AccASL MR angiography enables better visualization of distal cerebral arteries and collateral vessels in patients with Moyamoya disease than does TOF MR angiography, while TOF MR angiography enables better visualization of stenosis of proximal arteries. Both methods work in a mutually beneficial manner in the assessment of cerebral arteries. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28915103 TI - MR Spectroscopy-derived Proton Density Fat Fraction Is Superior to Controlled Attenuation Parameter for Detecting and Grading Hepatic Steatosis. AB - Purpose To prospectively compare the diagnostic accuracy of controlled attenuation parameter (CAP) obtained with transient elastography and proton density fat fraction (PDFF) obtained with proton magnetic resonance (MR) spectroscopy with results of liver biopsy in a cohort of adult patients suspected of having nonalcoholic fatty liver disease (NAFLD). Materials and Methods The institutional review board approved this study. Informed consent was obtained from all patients. The authors evaluated 55 patients suspected of having NAFLD (40 men, 15 women). Patients had a median age of 52.3 years (interquartile range [IQR], 43.7-57.6 years) and a median body mass index of 27.8 kg/m2 (IQR, 26.0 33.1 kg/m2). CAP and PDFF measurements were obtained on the same day, within 27 days of biopsy (IQR, 7-44 days). CAP and PDFF were compared between steatosis grades by using the Jonckheere-Terpstra test. Diagnostic accuracies of CAP and PDFF for grading steatosis were assessed with receiver operating characteristic (ROC) analysis. Within-weeks reproducibility (CAP and PDFF) and within-session repeatability were assessed with linear regression analyses, intraclass correlation coefficients, and coefficients of variation. Results Steatosis grades at liver biopsy were distributed as follows: S0, five patients; S1, 24 patients; S2, 17 patients; and S3, nine patients. Both PDFF and CAP helped detect histologically proven steatosis (>=S1), but PDFF showed better diagnostic accuracy than CAP in terms of the area under the ROC curve (0.99 vs 0.77, respectively; P = .0334). PDFF, but not CAP, enabled the grading of steatosis (P < .0001). For within-weeks reproducibility, the intraclass correlation coefficient with PDFF was higher than that with CAP (0.95 vs 0.65, respectively; P = .0015); coefficients of variation were similar (19% vs 11%, P = .55). Within session repeatability of CAP was good, with a coefficient of variation of 4.5%. Conclusion MR spectroscopy-derived PDFF is superior to CAP in detecting and grading liver steatosis in human NAFLD. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28915105 TI - Variations of ankle-foot orthosis-constrained movements increase ankle range of movement while maintaining power output of recumbent cycling. AB - Previous research investigated recumbent cycle power output (PO) from the perspective of knee and hip joint biomechanics. However, ankle-foot biomechanics and, in particular, the effect of ankle-foot orthosis (AFO)-constrained movements on cycle PO has not been widely explored. Therefore, the purpose of this study was to determine whether AFOs of a fixed position (FP) and in dorsi plantarflexion (DPF)-, dorsiflexion (DF)- and plantarflexion (PF)-constrained movements might influence PO during voluntary recumbent cycling exercises. Twenty five healthy individuals participated in this study. All underwent 1-min cycling at a fixed cadence for each of the AFOs. The peak and average PO of each condition were analyzed. The peak and average PO were 27.2+/-12.0 W (range 6-60) and 17.2+/-9.0 W (range 2-36), respectively, during voluntary cycling. There were no significant differences in the peak PO generated by the AFOs (p=0.083). There were also no significant differences in the average PO generated using different AFOs (p=0.063). There were no significant differences in the changes of the hip and knee joint angles with different AFOs (p=0.974 and p=1.00, respectively). However, there was a significant difference in the changes of the ankle joint angle (p<0.00). The present study observed that AFO-constrained movements did not have an influence in altering PO during voluntary recumbent cycling in healthy individuals. This finding might serve as a reference for future rehabilitative cycling protocols. PMID- 28915104 TI - Rift Valley fever phlebovirus NSs protein core domain structure suggests molecular basis for nuclear filaments. AB - Rift Valley fever phlebovirus (RVFV) is a clinically and economically important pathogen increasingly likely to cause widespread epidemics. RVFV virulence depends on the interferon antagonist non-structural protein (NSs), which remains poorly characterized. We identified a stable core domain of RVFV NSs (residues 83 248), and solved its crystal structure, a novel all-helical fold organized into highly ordered fibrils. A hallmark of RVFV pathology is NSs filament formation in infected cell nuclei. Recombinant virus encoding the NSs core domain induced intranuclear filaments, suggesting it contains all essential determinants for nuclear translocation and filament formation. Mutations of key crystal fibril interface residues in viruses encoding full-length NSs completely abrogated intranuclear filament formation in infected cells. We propose the fibrillar arrangement of the NSs core domain in crystals reveals the molecular basis of assembly of this key virulence factor in cell nuclei. Our findings have important implications for fundamental understanding of RVFV virulence. PMID- 28915106 TI - Making sense of a haemolysis monitoring and reporting system: a nationwide longitudinal multimethod study of 68 Australian laboratory participant organisations. AB - BACKGROUND: The key incident monitoring and management systems (KIMMS) quality assurance program monitors incidents in the pre- and postanalytical phases of testing in medical laboratories. Haemolysed specimens have been found to be the most frequent preanalytical error and have major implications for patient care. The aims of this study were to assess the suitability of KIMMS for quality reporting of haemolysis and to devise a meaningful method for reporting and monitoring haemolysis. METHODS: A structured survey of 68 Australian KIMMS laboratory participant organisations was undertaken. Quarterly haemolysis reports (2011-2014) were analysed. RESULTS: Among 110 million accessions reported, haemolysis rates varied according to the reporting methods that participants used for assigning accessions (16% of participants reported haemolysis by specimen and 83% reported by episode) and counting haemolysis rejections (61% by specimen, 35% by episode and 3% by test). More than half of the participants (56%) assigned accessions by episode and counted rejections by specimen. For this group, the average haemolysis rate per 100,000 episodes was 177 rejected specimens with the average rate varying from 100 to 233 over time. The majority of participants (91%) determined rejections using the haemolysis index. Two thirds of participants (66%) recorded the haemolysis manually in laboratory information systems. CONCLUSIONS: KIMMS maintains the largest longitudinal haemolysis database in the world. However, as a means of advancing improvements in the quality of the preanalytical laboratory process, there is a need to standardise reporting methods to enable robust comparison of haemolysis rejection rates across participant laboratories. PMID- 28915107 TI - Selective changes in cholesterol metabolite levels in plasma of breast cancer patients after tumor removal. PMID- 28915108 TI - Development of an internally controlled quantitative PCR to measure total cell associated HIV-1 DNA in blood. PMID- 28915109 TI - Factors affecting utilization of youth friendly health services in Lagos State, Nigeria. AB - Background Youth friendly health services (YFHS) are services that attract, respond to the needs of and retain young people for continuing care. This study was conducted to determine the factors affecting utilization of government (GYFF) and non-governmental youth friendly facilities (NGYFF) in Lagos state, Nigeria. Methods A descriptive cross-sectional study was conducted. A total of 543 adolescents aged 15-24 years, between August 1, 2014 and October 31, 2014 were consecutively recruited from 10 (five government and five non-governmental) youth friendly health facilities that had been in operation for at least 6 months prior to the study. Logistic regression was used to determine predictors of utilization of youth friendly health facilities. Results Overall, the mean age of respondents was 17.9 +/- 2.8. However, the mean age of respondents at GYFF (18.5 +/- 3.0) was significantly higher than those at NGYFF (17.1 +/- 2.5) (p < 0.001). Of the 567 youths enrolled, 196 (34.6%) had good utilization of youth friendly facilities (YFF) (34% from the GYFF and 35.2% from the NGYFF). Marital status, school attendance, having a baby, satisfaction with visit, perception that information shared was kept confidential and accessibility of the youth friendly services were associated with utilization of YFF (p < 0.05). Confidentiality and access to facilities were predictors of utilization of YFF. Conclusion There is poor utilization of both government and non-governmental youth friendly services in Lagos, Nigeria. There is a need for both the government and private sector to harmonize resources aimed at encouraging utilization of YFF in Lagos, Nigeria. PMID- 28915110 TI - Diet quality of adolescents with eating disorders. AB - Purpose To compare the nutritional intake of adolescents with eating disorders (EDs) to recommended Daily Values of macronutrients and micronutrients, using the Nutrition Data Systems for Research (NDSR); to determine if nutritional content varied among the different sub-types of EDs; and to use the Healthy Eating Index 2010 (HEI-2010) as a measurement of diet quality in this population. Methods Forty-six adolescents referred to an ED Program were recruited for inclusion in this study. A detailed 24-h dietary recall from each participant was obtained and a detailed nutritional analysis was generated, allowing for calculation of the HEI-2010. Descriptive statistics were calculated to determine baseline characteristics of the study population and to determine associations and differences between ED subtypes. Results Average daily caloric intake was below recommended values in the study population. Despite this, the distribution of macronutrients was within the ranges recommended for older children and adolescents by the Dietary Guidelines for Americans, 2010. Micronutrient content varied considerably. The study population had a mean HEI-2010 score of 60.1, falling within the "needs improvement" category. A majority of the participants had insufficient caloric intake for the HEI to be applicable. Conclusion Results suggest that adolescents with EDs have a surprisingly normal distribution of macronutrient intake. Although using a diet quality assessment tool such as the HEI-2010 has been helpful in analyzing overall diet quality in the general population, the restrictive caloric intake which characterizes the ED population prevents the utility of such a guide for most patients with EDs. PMID- 28915111 TI - The effect of group counseling based on self-awareness skill on sexual risk taking among girl students in Gorgan, Iran: a randomized trial. AB - Background Sexual puberty in adolescents occurs before their mental and emotional maturity and exposes them to high-risk sexual behaviors. Because sexual risk taking occurs before adolescents become involved in a sexual relationship, this study was conducted to identify the effect of group counseling based on self awareness skill on sexual risk-taking among female high school students in Gorgan in order to suggest some preventative measures. Methods The present parallel study is a randomized field trial conducted on 96 girl students who were studying in grades 10, 11 and 12 of high school with an age range of 14-18 years old. Sampling was done based on a multi-stage process. In the first stage, through the randomized clustering approach, four centers among six health centers were selected. In the second stage, 96 samples were collected through consecutive sampling. Finally, the samples were divided into two intervention and control groups (each one having 48 subjects) through the simple randomized approach. It has to be noted that no blinding was done in the present study. The data were collected using a demographic specifications form and the Iranian Adolescents Risk-Taking Scale (IARS). The consultation sessions based on self-awareness skill were explained to an intervention group through 60-min sessions over 7 weeks. The pretest was conducted for both groups and the posttest was completed 1 week and 1 month after the intervention by the intervention and control groups. Finally, after the loss of follow-up/drop out, a total of 80 subjects remained in the study; 42 subjects in the intervention group and 38 subjects in the control group. Data analyses were done using SPSS v.16 along with the Freidman non parametric test and the Mann-Whitney and Wilcoxon tests. Results The results showed that the sexual risk-taking mean scores in the intervention group (10.54 +/- 15.64) were reduced by applying 1-week (8.03 +/- 12.82) and 1-month (4.91 +/- 10.10) follow-ups after the intervention. This reduction was statistically significant (p = 14%). However, no statistically significant difference was observed in the control group. Conclusion Group counseling based on self awareness skill decreased the sexual risk-taking in girl students of the high school. As prevention is prior to treatment, this method could be proposed as the prevention of high-risk sexual behavior to healthcare centers and educational environments and non-government organizations (NGOs) interacting with adolescents. PMID- 28915112 TI - Raising awareness on cyber safety: adolescents' experience of a primary healthcare professional-led, school-based, multi-center intervention. AB - Purpose Although safe Internet use is an emerging public health issue, there is a scarcity of published work describing relevant school-based interventions. The objective of this study was to explore the impact of a health professional-led, school-based intervention in raising awareness on cyber-safety in adolescents, Therefore, the aim of this study was to investigate adolescents' evaluation of this school-based intervention, 6 months after its implementation, as well as the impact of adolescents' school class and gender on their evaluation. Methods A student sample was selected using a multistage stratified random sampling technique, according to the location and school grade level (middle, high school). The students - aged from 12 to 18 years old experienced an interactive presentation in their classrooms on the amount of time spent online, the use of social networks and the available support services. An evaluation tool was completed anonymously and voluntarily 6 months after the intervention. Results Four hundred and sixty-two students (response rate 90.7%, 246 middle, 216 high school) completed the evaluation tool. Younger students, especially the ones in the first year of middle school, scored significantly higher in all six parameters used in the evaluation of this intervention compared with all the older participants: (a) they had kept the presented information on Safeline and Saferinternet websites and the helpline Ypostirizo (70.2% vs. 33.7%, p < 0.001) (b) they had already used it (32.5% vs. 12.3%, p < 0.001), (c) they had learned new information on cyber safety (66.4% vs. 34%, p < 0.001), (d) they rated the intervention as more interesting (median 8 vs. 7, p < 0.05), (e) they had reconsidered the way they use Internet (median 7 vs. 6, p < 0.05) and (f) they had changed their cyber behavior (median 7 vs. 5, p < 0.05). Conclusion The active involvement of students in a discussion on cyber-safety based on their experiences was highly evaluated. The impact of the intervention on the youngest students underlines the need for raising awareness on cyber-safety and support services, earlier in the students' life. PMID- 28915113 TI - Causative factors for sexual and reproductive health status of pregnant adolescent girls in urban communities of Lagos, Nigeria. AB - Background The overall goal of this study was to determine the causative factors for pregnancy status in adolescent girls in two communities in the Lagos Island local government area. Methods A mixed methods (quantitative and qualitative) study reviewing routine health facility antenatal care (ANC) records and conducting focus group discussions among 46 pregnant adolescents, exploring their views about sex, contraception, pregnancy and sexual and reproductive health (SRH) services, was carried out. Key informant interviews were also carried out among healthcare workers and community members to assess their perceptions of adolescents' SRH problems. Results Five percent of those accessing ANC services were adolescents. Pregnant adolescents were found to access health services at later stages of their pregnancies due to the shame and stigma associated with their condition. The presence of morbidity in the form of anaemia (33%) and HIV (2.4%) was also found in this population. Social factors such as peer pressure and the desire to develop or maintain a relationship were found to be the major reasons for initiation of sexual activity by the adolescents. There was generally poor knowledge and utilisation of contraceptives, leading to unprotected sex and, thus, unintended pregnancies. Conclusion SRH information and services should be made readily available to adolescents at all levels of care. PMID- 28915114 TI - Association between sleep quality and quality of life among students: a cross sectional study. AB - Background Lack of sleep and on going sleep disorder can affect family health and interpersonal relationships. Objective The aim of study was to investigate the association between sleep quality and the probable determinants of quality of life among students of a public health faculty at Shahid Beheshti University of Medical Sciences (SBMU) in the 2015 academic year. Methods The data from a cross sectional study of 275 students that randomly stratified sampling between different classes of college students of a public health faculty of Shahid Beheshti University of Medical Sciences were used in this study. The data were collected using a structured questionnaire consisted of modules on socio demographic characteristics, the Petersburg Standardized Sleep Quality Questionnaire(PSQL) and the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF). Data analysis was done with descriptive and logistic regression. All analyses were carried out using SPSS software V.19. Results A total of 275 students participated in this study. The mean age +/- standard deviation (SD) was 22.1 +/- 3.6 years. In the univariable model, students that were living in their own homes had the odds of 2.18 times more than the others to have a higher quality of life level [95% confidence interval (CI): 1.07-4.45]. Moreover, sleep disorder was negatively associated with the quality of life [odds ratio (OR) = 0.23; 95% CI: 0.12-0.46]. Conclusion These results will help university administrators and policy makers to identify factors associated with poor sleep and provide approaches to enhance sleep hygiene and relevant knowledge in university students. Living in a dormitoy while also suffering from sleep problems could significantly reduce the quality of life. PMID- 28915115 TI - Anti-arthritic and gastroprotective activities of Ardisia crispa root partially mediated via its antioxidant effect. AB - Background Ardisia crispa Thunb A.DC (Myrsinaceae), commonly known as "hen's eyes", has been traditionally used in treating various inflammatory diseases. The present study evaluated anti-arthritic, gastroprotective and antioxidant activities of Ardisia crispa root hexane extract (ACRH) in various animal models. Methods Anti-arthritic activity was evaluated in complete Freund adjuvant (CFA) induced adjuvant arthritis and gastroprotective effect was studied in the ethanol induced ulcer model in rats. ACRH was further isolated to yield quinone-rich fraction (QRF) and both were analyzed for their total phenolic content, total flavonoid content and antioxidant activities in various antioxidant assays. Both ACRH and QRF were also analyzed for the quinone composition via gas chromatography analysis. Results ACRH exerted significant reduction of IL-1beta and TNF-alpha at a lower dose range in CFA-induced arthritis, as well as exhibited its cytoprotective effect against ethanol-induced ulcer lesion via involvement of mucosal nonprotein sulfhydryl (NP-SH) groups. ACRH also showed higher phenolic and flavonoid contents, as well as better antioxidant activities than QRF. Conclusions These findings demonstrated the plant as a potential anti inflammatory agent, with ACRH succeeded in inhibiting both arthritic and ulcerogenic effect, possibly mediated via its antioxidant effect. PMID- 28915116 TI - A review of Tunisian medicinal plants with anticancer activity. AB - Cancer is a major public health problem in the world. The use of the medicinal plants in cancer prevention and management is frequent in Africa, especially in Tunisia, and it is transmitted from generation to generation within cultures. Many previous studies showed that a wide range of Tunisian medicinal plants exerted cytotoxic and anticancer activity. A comprehensive review was conducted to collect information from scientific journal articles, including indigenous knowledge researches, about Tunisian medicinal plants used for the prevention and management of cancer. The aim of this review article is to provide the reader with information concerning the importance of Tunisian medicinal plants in the prevention and management of cancer and to open the door for the health professionals and scientists working in the field of pharmacology and therapeutics to produce new drug formulations to treat different types of cancer. PMID- 28915117 TI - Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism. AB - BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH. METHODS: We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing. RESULTS: We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation in ANOS1 (X-linked recessive); three and four having a mutation in FGFR1 and CHD7, respectively (autosomal dominant); and one having two TACR3 mutations (autosomal recessive). Among four patients with KS carrying a CHD7 mutation, one had perceptive deafness and two had a cleft lip/palate. CONCLUSIONS: The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort. PMID- 28915118 TI - Delayed diagnosis of proopiomelanocortin (POMC) deficiency with type 1 diabetes in a 9-year-old girl and her infant sibling. AB - BACKGROUND: Proopiomelanocortin (POMC) protein, encoded by the POMC gene, is the precursor of adrenocorticotropic hormone (ACTH) that is released from the anterior pituitary gland. Homozygous mutations in the POMC gene is associated with hyperphagia, severe and early-onset obesity, adrenal insufficiency, hypopigmentation of the skin and red hair. CASE PRESENTATION: A 9-year-old girl from a consanguineous family of Iraqi origin was diagnosed with type 1 diabetes. She also had a tall stature. Her laboratory assessment showed low cortisol and ACTH concentrations, normal renin and poor response to ACTH stimulation. Genetic testing revealed a novel biallelic mutation in the POMC gene. Her sibling who had severe obesity and central adrenal insufficiency was found to be a carrier of the same mutation. Both siblings had alabaster-colored skin and brown hair. CONCLUSIONS: POMC deficiency results in significant morbidity due to obesity, and it is also a potentially life threatening disease because of adrenal insufficiency. Therefore any suggestive symptom or sign of POMC deficiency warrants detailed investigations. PMID- 28915119 TI - Cytogenetic analysis in fetuses with late onset abnormal sonographic findings. AB - OBJECTIVE: To determine the rate of chromosomal cytogenetic abnormalities in fetuses with late onset abnormal sonographic findings. DESIGN: Retrospective cohort of women who underwent amniocentesis at or beyond 23 weeks of gestation, for fetal karyotype and chromosomal microarray analysis, indicated due to late onset abnormal sonographic findings. RESULTS: All 103 fetuses had a normal karyotype. Ninety-five women also had chromosomal microarray analysis (CMA) performed. The detection rate of abnormal CMA (5/95, 5.3%) was similar to that of women who underwent amniocentesis due to abnormal early onset ultrasound findings detected at routine prenatal screening tests during the first or early second trimester (7.3%, P=0.46) and significantly higher than that for women who underwent amniocentesis and CMA upon request, without a medical indication for CMA (0.99%, P<0.0001). CONCLUSIONS: Late onset sonographic findings are an indication for amniocentesis, and if performed, CMA should be applied to evaluate fetuses with late onset abnormal sonographic findings. PMID- 28915120 TI - Ultrasound study of fetal movements in singleton and twin pregnancies at 12-19 weeks. AB - Objective To evaluate fetal behavioral differences between singleton and twin fetuses before 20 weeks of gestation using four-dimensional (4D) ultrasound. Methods 4D ultrasound was used to examine fetal movements in 58 singleton and 48 twin normal fetuses at 12-19 weeks. The frequencies of eight fetal movements were assessed through 15-min recordings. The fetuses were divided into two gestational age groups (12-13 and 14-19 weeks) to evaluate the changes with advancing gestation in twin versus singleton fetuses. Results Arm and general movements were the most frequent movements in singleton fetuses, whereas only general movement was significantly more frequent than the other seven fetal movements in twin fetuses at 12-13 weeks. At 14-19 weeks, frequencies of arm and leg movements were significantly higher than those of the other six movements in singleton fetuses, while only arm movement was significantly more frequent than the other fetal movements in twin fetuses. Comparisons of fetal movements between singleton and twin fetuses revealed that only arm movement showed a significant difference at 12-13 weeks, while the frequencies of all movements in singleton fetuses were significantly higher than those in twin fetuses at 14-19 weeks. Conclusion Our results suggest that the limitation of available space and crowding of twin fetuses with advancing gestation may have a marked impact on twin fetal movements compared with singleton fetuses, even in the first half of pregnancy. Further studies are needed to assess whether decreased fetal movements in twin pregnancy can affect fetal and neonatal development and maturation before and after birth. PMID- 28915121 TI - An observation of umbilical coiling index in a low risk population in Nigeria. AB - OBJECTIVES: The umbilical coiling index (UCI) is one of cord parameters for foetal assessment with limited studies in our environment. With recent advances in its evaluation, its significance, pattern, abnormalities and correlates need to be defined in our parturients. METHODS: The umbilical cords of 436 neonates were examined. Gross examination was done within 5 min of delivery. The UCI was defined as the number of complete coils per centimetre of cord. Normal UCI was defined as values between the 10th and 90th percentiles of the study population. RESULTS: The mean umbilical cord length was 52.7+/-11.5 cm, mean number of coils was 10.8+/-5.1 and mean UCI was 0.21+/-0.099. The range was between 0.0 and 1.0. UCI values of 0.13 and 0.30 were 10th and 90th percentiles, respectively. Normal UCI was observed in 351 (80.5%) neonates, 44 (10.4%) and 41 (9.1%) had hypo- and hypercoiled cords, respectively. Congenital abnormalities occurred in the normocoiled and hypercoiled groups but was not demonstrated in the hypocoiled group. The mean value of UCI in neonates with congenital abnormalities was 0.29+/ 0.12 (P=0.011). There was no significant statistical relationship between foetal outcome and degree of UCI. CONCLUSION: The UCI was not associated with adverse perinatal outcome in this study. PMID- 28915122 TI - Understanding fetal factors that contribute to preterm birth: Sjogren-Larsson syndrome as a model. AB - AIM: Preterm birth is the world's leading cause of neonatal death. Unfortunately, the pathophysiology of preterm birth remains poorly understood. Sjogren-Larsson syndrome is a rare, neurometabolic disorder caused by a fatty aldehyde dehydrogenase deficiency. A majority of patients with Sjogren-Larsson syndrome is born preterm. METHODS: Data of all known Dutch patients with Sjogren-Larsson syndrome and all cases reported in literature were analyzed to learn from preterm birth in context of this rare disease. RESULTS: Exact gestational age was known in 33 Dutch patients; 24 (73%) of them were born preterm, with a median gestational age of 36 weeks. The literature search confirmed our findings: 13 (59%) of 22 cases was born preterm. CONCLUSIONS: Preterm birth is a hallmark of Sjogren-Larsson syndrome, presumably caused by the abnormal lipid metabolism of the fetus. At least five additional rare genetic disorders (namely Ehlers-Danlos syndrome, ichthyosis prematurity syndrome, congenital analbuminemia, osteogenesis imperfecta type II and restrictive dermopathy) were found in literature that lead to preterm birth of the affected fetus. These disorders are in fact "experiments of nature" and as such they shed new lights on the mechanisms causing preterm birth. PMID- 28915123 TI - Placental examination in nonmacerated stillbirth versus neonatal mortality. AB - AIM: To retrospectively statistically compare clinical and placental phenotypes of nonmacerated fetuses and live-born perinatal deaths in 3rd trimester pregnancies. METHODS: Twenty-five clinical and 47 placental phenotypes were statistically compared among 93 cases of nonmacerated (intrapartum, or recent antepartum death) 3rd trimester fetal deaths (Group 1), 118 3rd trimester neonatal deaths (Group 2) and 4285 cases without perinatal mortality (Group 3). RESULTS: Sixteen clinical and placental phenotypes were statistically significantly different between Group 3 and the two groups of perinatal deaths, which included eight placental phenotypes of fetal vascular malperfusion and eight other placental phenotypes of various etiology (amnion nodosum, 2-vessel umbilical cord, villous edema, increased extracellular matrix of chorionic villi, erythroblasts in fetal blood and trophoblastic lesions of shallow placentation). Statistically significant differences between Groups 1 and 2 were scant (oligohydramnios, fetal malformations, cesarean sections, hypercoiled umbilical cord and amnion nodosum being more common in the latter, and retroplacental hematoma more common in the former). CONCLUSION: Placental examination in neonatal mortality shows thrombotic pathology related to umbilical cord compromise and features of shallow placental implantation that are similar to those in nonmacerated stillbirth; however, the features of placental abruption were more common in recent antepartum death, as were the features related to neonatal congenital malformations in neonatal deaths. PMID- 28915124 TI - Effect of female genital cutting performed by health care professionals on labor complications in Egyptian women: methodological concerns. PMID- 28915125 TI - Air pollution, aeroallergens and suicidality: a review of the effects of air pollution and aeroallergens on suicidal behavior and an exploration of possible mechanisms. AB - OBJECTIVE: Risk factors for suicide can be broadly categorized as sociodemographic, clinical and treatment. There is interest in environmental risk and protection factors for suicide. Emerging evidence suggests a link between environmental factors in the form of air pollution and aeroallergens in relation to suicidality. METHODS: Herein, we conducted a systematic review of 15 articles which have met inclusion criteria on the aforementioned effects. RESULTS: The majority of the reviewed articles reported an increased suicide risk alongside increased air pollutants or aeroallergens (i.e. pollen) increase; however, not all environmental factors were explored equally. In specific, studies that were delimited to evaluating particulate matter (PM) reported a consistent association with suicidality. We also provide a brief description of putative mechanisms (e.g. inflammation and neurotransmitter dysregulation) that may mediate the association between air pollution, aeroallergens and suicidality. CONCLUSION: Available evidence suggests that exposure to harmful air quality may be associated with suicidality. There are significant public health implications which are amplified in regions and countries with greater levels of air pollution and aeroallergens. In addition, those with atopic sensitivity may represent a specific subgroup that is at risk. PMID- 28915126 TI - Toxicological profile of organochlorines aldrin and dieldrin: an Indian perspective. AB - Several epidemiological studies have suggested various environmental factors as a possible cause for increased incidence of various abnormalities. Of the various environmental contaminants, the most prevalent and the most discussed are the endocrine disrupting chemicals. Contact of such disruptors with humans has become inevitable today. They are cosmopolitan and present from agriculture to industrial sectors, even in day-to-day consumer products. Aldrin and dieldrin belong to one such class of substances which are known to have a toxic effect on various physiological systems of the human body. Despite an imposed ban on their manufacture and commercial use, these pesticides could still be detected in probable areas of consumption like agriculture. The present review discusses the known possible toxic effects of aldrin and dieldrin and their current existence in the ecosystem across India. PMID- 28915127 TI - One-dimensional quantum matter: gold-induced nanowires on semiconductor surfaces. AB - Interacting electrons confined to only one spatial dimension display a wide range of unusual many-body quantum phenomena, ranging from Peierls instabilities to the breakdown of the canonical Fermi liquid paradigm to even unusual spin phenomena. The underlying physics is not only of tremendous fundamental interest, but may also have bearing on device functionality in future micro- and nanoelectronics with lateral extensions reaching the atomic limit. Metallic adatoms deposited on semiconductor surfaces may form self-assembled atomic nanowires, thus representing highly interesting and well-controlled solid-state realizations of such 1D quantum systems. Here we review experimental and theoretical investigations on a few selected prototypical nanowire surface systems, specifically Ge(0 0 1)-Au and Si(hhk)-Au, and the search for 1D quantum states in them. We summarize the current state of research and identify open questions and issues. PMID- 28915128 TI - Polyphenols: dietary assessment and role in the prevention of cancers. AB - PURPOSE OF REVIEW: Polyphenols are a large and diverse family of phytochemicals widely consumed by humans. Here we summarize the latest epidemiological evidence for associations between cancer risk and polyphenol intake, taking into account difficulties in the accurate estimation of exposure. RECENT FINDINGS: Flavonoids are the most studied subgroup of polyphenols with regard to cancer risk. In recent epidemiological studies, total flavonoid intake has rarely been associated with a reduction in cancer risk. However, isoflavones, whose main dietary source is soy foods, plausibly reduce the risk of colorectal, breast, and prostate cancers, especially in Asian countries. Findings depend heavily upon the assessment of polyphenol intake, which is usually measured by food frequency questionnaires coupled to databases of food polyphenol composition. To a lesser extent, nutritional biomarkers have been used whenever estimating associations of polyphenol intake with cancer. SUMMARY: Polyphenol intake may mitigate cancer risk but this depends on cancer site, the subgroup of compounds under study, and accurate assessment of dietary exposure. Further work must better characterize the effects of intake of different flavonoid subclasses and begin to investigate the role of phenolic acids and other minor polyphenol classes. PMID- 28915129 TI - Atypical Exit Wound in High-Voltage Electrocution. AB - Electrocution fatality cases are difficult to investigate. High-voltage electrocution burns resemble burns caused by other sources, especially if the person survives for few days. In that case, circumstantial evidence if correlated with the autopsy findings helps in determining the cause and manner of death. In addition, the crime scene findings also help to explain the pattern of injuries observed at autopsy. A farmer came in contact with a high-voltage transmission wire and sustained superficial to deep burns over his body. A charred and deeply scorched area was seen over the face, which was suggestive of the electric entry wound. The exit wound was present over both feet and lower leg and was atypical in the form of a burnt area of peeled blistered skin, charring, and deep scorching. The injuries were correlated with crime scene findings, and the circumstances that lead to his electrocution are discussed here. PMID- 28915130 TI - Dolichoectasia of Vertebrobasilar Arteries as a Cause of Hydrocephalus and Ischemic Cerebral Stroke. AB - INTRODUCTION: Dolichoectasia of vertebrobasilar artery is a rare vasculopathy, which is characterized by ectasia, elongation, and tortuosity of the basilar artery. CASE DESCRIPTION: A 85-year-old man was referred to the Clinic of Neurology with sudden-onset coma. A brain computed tomography scan showed remarkable fusiform dilatation with elongation of basilar artery, with compressive effect on brain stem. Autopsy confirmed existence of vertebrobasilar dolichoectasia, with organized old thrombus and partially with recent occlusive thrombosis. The histology and immunohistochemical staining were showing a loss of the elastic tissue with significant fibrosis in the tunica media and small groups of foam macrophages and cholesterol crystals in atherosclerotic plaque. CONCLUSIONS: We presented a case of dolichoectasia of vertebrobasilar artery with an obstructive hydrocephalus, due to direct compression on pons and midbrain, which is an extremely rare entity. This case had been analyzed during the patient's life through clinical, laboratory, and radiology examinations and after he died through autopsy. PMID- 28915131 TI - Body Mass Index and Saltwater Drowning. AB - Comparison of body mass index (BMI) was undertaken between 30 cases of salt water drowning and 30 age- and sex-matched controls randomly selected from the autopsy files of Forensic Science SA, Adelaide, Australia, during the period 2000 to 2017. The age range of drowning cases and controls was 18 to 80 (average, 49) years, with a male to female ratio of 19:11. The BMIs of the drowning cases ranged from 15.5 to 37.5 (average, 25.4; median, 23). The control cases had higher BMIs ranging from 22.9 to 44.3 (average, 29.2; median, 25). The number of obese (BMI, >=30) decedents in the drowning group was 5 (17%) and in the controls was 9 (30%). Individuals who drown in the sea may regularly swim, and thus be fitter and therefore slimmer than more sedentary controls. However, it is also possible that greater amounts of adipose tissue may be protective against drowning, as increased fat stores could improve buoyancy. Thinner individuals with denser body mass may have to struggle more to avoid submersion. It could be that a low BMI is an underappreciated finding that may increase the risk of lethal immersion along with alcohol intoxication and poor swimming skills. PMID- 28915132 TI - Clinical update regarding general anesthesia-associated neurotoxicity in infants and children. AB - PURPOSE OF REVIEW: The U.S. Federal Drug Administration (FDA) recently released a warning stating that 'repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains' (www.fda.gov/ucm582356.htm). The goal of this article is to review the most recent clinical studies which provide evidence that these concerns may be overstated for the majority of healthy young children who require surgery and anesthesia. RECENT FINDINGS: Three large retrospective matched cohort studies published within the past year provide data on a total of 59 814 children exposed to general anesthesia before age 4 (including 30 021 <2 years and 9814 multiple exposure). All three studies independently conclude that neither exposure to anesthesia in children under 2 years of age nor multiple exposures are associated with adverse neurodevelopmental consequences in the patient populations studied. Biological, environmental, and social factors were found to be of far greater import. SUMMARY: These findings suggest that anesthetic neurotoxicity is not a major contributory pathway for adverse neurodevelopmental outcomes in the majority of healthy children who require surgery before 3 years of age. Future work should focus on the particular vulnerabilities of the fetus, premature infant, and children with developmental disabilities, major congenital, cardiac or neurological abnormalities not specifically addressed by these studies. PMID- 28915133 TI - Complications and unplanned admissions in nonoperating room procedures. AB - PURPOSE OF REVIEW: The purpose of this article is to review complications and unplanned hospital admissions in patients presenting for ambulatory procedures requiring anesthesia care in the gastrointestinal endoscopy, bronchoscopy, and radiology suites. RECENT FINDINGS: The range of ambulatory diagnostic and therapeutic procedures being undertaken in the gastrointestinal endoscopy, bronchoscopy, and radiology suites is expanding rapidly. Recent observational studies in gastrointestinal endoscopy confirm low incidences of complications and unplanned admissions. Deep propofol-based sedation is associated with more complications than lighter sedation. Older patients suffer more complications but obstructive sleep apnea does not appear to increase risk. Sedation improves patient comfort during bronchoscopy. Propofol-based sedation is associated with fewer complications than benzodiazepine-based sedation, but all combinations are associated with high patient satisfaction. Obesity and obstructive sleep apnea are not associated with worse outcomes in bronchoscopy patients. Sedation is increasingly required for interventions in the radiology suite. When patients are involved in choosing sedation depth, there is a trend to lighter sedation and high patient satisfaction. SUMMARY: Sedation and anesthesia are required for the increasing number of increasingly complex procedures being undertaken outside the operating suite. Large randomized trials are required to define the optimum sedation drugs, sedation depth and sedation provider. PMID- 28915134 TI - Vitamin D in obesity. AB - PURPOSE OF REVIEW: Vitamin D is essential for bone health, and may also have important functions in immunity and other systems. Vitamin D deficiency is common, and testing and supplementation is increasing. Serum vitamin D is lower in obese people; it is important to understand the mechanism of this effect and whether it indicates clinically significant deficiency. RECENT FINDINGS: Vitamin D is fat soluble, and distributed into fat, muscle, liver, and serum. All of these compartments are increased in volume in obesity, so the lower vitamin D likely reflects a volumetric dilution effect and whole body stores of vitamin D may be adequate. Despite lower serum vitamin D, obese adults do not have higher bone turnover or lower bone mineral density. Patients undergoing bariatric surgery do have bone loss, and ensuring vitamin D sufficiency in these patients may help to attenuate bone loss. SUMMARY: Lower vitamin D in obese people is a consistent finding across age, ethnicity, and geography. This may not always reflect a clinical problem. Obese people need higher loading doses of vitamin D to achieve the same serum 25-hydroxyvitamin D as normal weight. PMID- 28915135 TI - Otolaryngologic management of Down syndrome patients: what is new? AB - PURPOSE OF REVIEW: The management of children with Down syndrome as it pertains to the otolaryngologist continues to evolve. Obstructive sleep apnea (OSA) has dominated the recent literature, but other topics including hearing loss, swallowing, and perioperative considerations are also reported. RECENT FINDINGS: The prevalence of OSA in children with Down syndrome ranges from 57 to 73% in certain cohorts, and, whereas adentonsillectomy can decrease Apnea-Hypopnea Index, up to 80% may have persistent OSA. Surgical techniques involving reduction of the base of tongue are effective for those who fail adenotonsillectomy, and it is expected that drug-induced sleep endoscopy may improve outcomes. New technology is also on the horizon that can assist with diagnosis and treatment including computational modelling and upper airway stimulation. Children with Down syndrome may not respond to medical management of eustachian tube dysfunction as well as normally developing children. In addition, there is a high prevalence of inner ear anomalies, increasing the risk for sensorineural hearing loss. SUMMARY: Questions remain pertinent to the otolaryngologist regarding the ideal management of children with Down syndrome. Additional studies are necessary, to optimize understanding and treatment of this complex population, in particular as opportunities develop with technological advances. PMID- 28915136 TI - Laparoscopic Mesh-Less Cervicosacropexy for Uterovaginal Prolapse. AB - OBJECTIVES: This study aimed to evaluate surgical and clinical outcomes of laparoscopic mesh-less cervicosacropexy for the treatment of uterovaginal prolapse. METHODS: This single institutional review board-approved prospective cohort study enrolled 46 consecutive, sexually active symptomatic women requiring surgical correction of uterovaginal prolapse, from July 2013 to March 2016. After supracervical laparoscopic hysterectomy, the cervix was suspended to the anterior longitudinal ligament of the sacral promontory through a continuous suture with plication and shortening of the right uterosacral ligament. Pelvic organs' function was evaluated through validated questionnaires during preoperative and postoperative follow-up evaluations. The anatomical recurrences of genital prolapse with a Pelvic Organ Prolapse Quantitative stage 2 or higher, in particular of central compartment (Pelvic Organ Prolapse Quantitative score C >= 1), were recorded. RESULTS: Mean +/- SD age was 55.5 +/- 10.9 years. Mean +/- SD operating time was 97.4 +/- 25.6 (range, 60-180) minutes. Mean +/- SD hospitalization length was 3.6 +/- 0.9 (range, 2-6) days. No intraoperative complications were recorded. Median length of follow-up was 24 (range, 12-38) months. During the follow-up period, the objective success rates for central compartment prolapse and for all compartments were 93.5% and 89.1%, respectively. No woman presented dyspareunia at follow-up. Thirty-nine women (84.8%) reported very high satisfaction related to surgery and 6 (13%) a moderate satisfaction. Overall Female Sexual Function Index, Knowles-Eccersley-Scott Symptom, and Bristol Female Lower Urinary Tract scores improved significantly after surgery, except for incontinence score domain. CONCLUSIONS: Laparoscopic mesh-less cervicosacropexy represents an effective and feasible option for the surgical treatment of uterovaginal prolapse in sexually active women, avoiding postoperative complications due to the mesh use. PMID- 28915137 TI - Xenoislets: porcine pancreatic islets for the treatment of type I diabetes. AB - PURPOSE OF REVIEW: Porcine islets are being extensively investigated as alternative sources of insulin-secreting cells for transplantation in insulin dependent diabetic patients. The present review focuses on recent advances in porcine islet transplantation with particular emphasis on new transgenic pig models, islet encapsulation, and biosafety considerations. RECENT FINDINGS: Genetic modifications aimed to reduce islet cell immunogenicity, to prolong their survival, and to improve their secretory function have been reported. Micro- and macroencapsulation of porcine islets should allow their use in the clinic with no or minimal immunosuppression. The risk of porcine endogenous retrovirus transmission is being re-evaluated since no evidence for infection was found in several clinical and preclinical studies. SUMMARY: Pig islet xenotransplantation is still a serious contestant in the race for novel treatments for type I diabetes. Adequate pathogen screening, animal selection, and the establishment of microbiological, genetic, and potency release quality controls should increase safety and efficacy of future porcine islets transplantation clinical trials. PMID- 28915138 TI - The Dosimetric Demise of 97MNB. AB - Radionuclide differences between ICRP Publication 38 and its succeeding work, ICPR Publication 107, are reviewed. The specific example of the isomer Nb is discussed, examining how dose reporting for this nuclide can be an issue. PMID- 28915139 TI - Left and right ventricular morphology, function and late gadolinium enhancement extent and localization change with different clinical presentation of acute myocarditis Data from the ITAlian multicenter study on MYocarditis (ITAMY). AB - AIMS: Poor data exist about cardiac magnetic resonance (CMR) findings in a large sample of acute myocarditis with different clinical presentations (heart failure, arrhythmias, and infarct-like presentation). METHODS: Five hundred and forty three in-patients with a clinical suspected of acute myocarditis confirmed by CMR were enrolled. The clinical indications to perform CMR were chest pain and/or dyspnea and/or palpitations, or effort intolerance/malaise in the last month; elevated troponin and/or new ventricular dysfunction, and/or new ECG abnormalities; and suspected inflammatory cause. CMR examination has permitted to identify epicardial and mid-layer distribution of late gadolinium enhancement (LGE) and to quantify left ventricular (LV) and right ventricular (RV) volumes, and ejection fraction. RESULTS: According to the main clinical pattern of presentation, three groups were categorized: heart failure (heart failure group; 35 patients, 6.4%), arrhythmias (arrhythmias group; 24 patients, 4.4%), and infarct-like (infarct-like group, 484 patients, 89.2%).Heart failure group and arrhythmias group had significantly higher LV volumes and number of LGE segments and lower LV and RV ejection fraction than the infarct-like group.Epicardial LGE in the LV inferolateral wall was the most frequent LGE location in each group. Mid-layer LV septal LGE showed a greater prevalence in the heart failure (52%) and arrhythmias (47%) groups than in the infarct-like group (27%, P < 0.0001). CONCLUSION: In patients with CMR-detected acute myocarditis, heart failure, and arrhythmias have both a higher prevalence of LV and RV dysfunction, segments with LGE, and septal LGE with respect to the infarct-like group. PMID- 28915140 TI - Life-Threatening Massive Hemoptysis After Cryoablation for Atrial Fibrillation. AB - A 59-year-old man developed massive hemoptysis, 1 month after undergoing cryoablation procedure for atrial fibrillation. He underwent emergent bronchoscopy that revealed massive, active bleeding with clots requiring repeated suctioning, epinephrine, and cold saline injection. The source of bleeding was identified in a follow-up bronchoscopy performed few days later-a 2*3 cm area of ulceration of the left main stem bronchus which was missed in the initial bronchoscopy owing to blood obscuring the field of vision. Considering the timeline, the ulcer most likely resulted from cryoablation-induced bronchial injury. Patient remained asymptomatic after stabilization and 2 months following discharge, another bronchoscopy was performed which showed the ulcer to be healing. Hemoptysis following cryoablation is quite rare with a reported incidence <2%. The cases of hemoptysis reported thus far have all been mild and self-limiting and manifesting within hours to days following the procedure. To our knowledge, this is the first reported case of massive hemoptysis associated with cryoballoon ablation, presenting 1 month after procedure. PMID- 28915141 TI - Clinical Success Stenting Distal Bronchi for "Lobar Salvage" in Bronchial Stenosis. AB - BACKGROUND: Airway stents are traditionally used in central airway obstructions to maintain airway patency. Historically, distal bronchial stenting within lobar and segmental bronchi has not been amenable to stenting. In addition, there are questionable benefits to stenting small airways. The Atrium iCast stent is a polytetrafluoroethylene covered stainless steel balloon deployed stent which can be deployed through a flexible bronchoscope under direct visualization. The purpose of this study was to assess the feasibility, complications, and long-term impact of using this stent in patients with lobar bronchial stenosis either secondary to malignancy or benign etiologies. METHODS: All records of patients who had the placement of an iCast stent were reviewed over 3.5 years. For each patient the age, sex, location, histology, stent size, duration of stent placement, radiographic improvement, and complications were collected. RESULTS: A total of 122 iCast stents were deployed in 38 patients with lobar bronchial stenosis. The average age was 58 years with 50% male. The etiology included 45% malignant and 55% due to benign conditions. In total, 18.5% patients had stents placed in >1 segment. There was an average of 4 procedures per patient with a mean time to stent revision or removal of 85 days. All patients had symptomatic or radiographic improvement. Common complications included migration (10%), granulation tissue formation (5%), deployment malfunction (2%), stent dislodgement immediately after deployment (2%), mucous plugging (1%), and tumor occlusion (1%). CONCLUSION: Stenting small airways with lobar salvage is feasible and improves symptoms and radiographic outcomes. PMID- 28915142 TI - Probe-based Confocal Laser Endomicroscopy in Metastatic Pulmonary Calcification. AB - We report a case of metastatic pulmonary calcification in a patient with chronic renal failure on hemodialysis and secondary hyperparathyroidism. The diagnosis was made by using a probe-based confocal endomicroscopy which showed specific structures in the lung tissue and was proven by a transbronchial lung biopsy. To the best of our knowledge, this is the first reported case of the confocal endomicroscopy findings in a patient with metastatic pulmonary calcification. PMID- 28915143 TI - Evaluating Cultural Competency Concepts Using Program Theory-Driven Evaluation Framework. AB - Research has shown that there is no consistent method of teaching cultural competence or incorporating it into nursing curricula. Thus, nursing programs are at risk for misinterpretation or not meeting required program outcomes or accreditation standards. Although considered social research, program theory driven evaluation has been cited as an acceptable evaluation method for nursing programs. This research looks at program inputs and program outputs to establish congruency with accreditation standards and to ensure validity and reliability of future research on cultural competency levels of nursing graduates. PMID- 28915144 TI - The Development of a Clinical Peer Review Tool. AB - Faculty evaluation for the purpose of promotion and tenure frequently includes peer review as a part of the process. Faculty review by a peer may provide an assessment of teaching effectiveness and information related to the faculty member's professional development activities. This article presents an innovative, evidence-based approach using selected National League for Nursing core competencies and International Nursing Association for Clinical Simulation and Learning clinical simulation standards in the development of a faculty peer review tool to gather data on clinical teaching to be used during the promotion and tenure process. PMID- 28915145 TI - Posttraumatic Stress Disorder Symptoms Among Trauma-Exposed Inpatient Adolescents: The Role of Emotional Nonacceptance and Anxiety Symptom Severity. AB - The present investigation examined the role of anxiety symptom severity in the relation between emotional nonacceptance and posttraumatic stress disorder (PTSD) symptoms in a diverse sample of trauma-exposed adolescents admitted for acute psychiatric care at an inpatient state hospital (N = 50; 52.0% women; 44% white; mean [SD] age, 15.1 [0.51] years; range, 12-17 years). Anxiety symptom severity partially accounted for the association between emotional nonacceptance and PTSD total symptoms, and fully accounted for the association between emotional nonacceptance and PTSD symptom cluster severity, even after controlling for covariates. Reverse model testing provided confidence in the direction of hypothesized effects. These findings add to a body of literature underscoring the detrimental effect of nonaccepting reactions to negative emotions in the context of PTSD and provide preliminary support for a possible underlying role of anxiety symptom severity in the association between emotional nonacceptance and PTSD symptoms. PMID- 28915146 TI - Engendered Responses to, and Interventions for, Shame in Dissociative Disorders: A Survey and Experimental Investigation. AB - This study examined shame and responses to it in adult dissociative disorder (DD; n = 24) and comparison psychiatric (n = 14) samples. To investigate how helpful different therapeutic responses are after shame disclosures in therapy, participants heard two vignettes from "mock" patients disclosing a) shame and b) surprise. Participants rated the helpfulness of five potential responses. Interventions covered withdrawing from the affect (withdrawal focused) to feeling it (feeling focused), with other interventions on cognitions (cognitive focused), management strategies (management focused), and previous experiences (history focused). The DD sample reported higher characterological and bodily shame, and more shame avoidance and withdrawal. There was no difference across groups for intervention ratings. For shame, interventions focused on feelings, cognitions, or previous shame experiences were deemed most helpful, but this was qualified by experiencing dissociation while hearing the script, where the history intervention was reported less helpful. Exposure to shame while monitoring dissociation should accompany therapy for DDs. PMID- 28915147 TI - Measuring thrombin activity in frozen brain tissue. AB - Thrombin is a coagulation factor implicated in various pathological and physiological processes in the brain, exerting beneficial and deleterious effects in a concentration-dependent manner. Measurement of thrombin activity levels in pathological animal models is needed and in some cases, because of technical considerations, only frozen samples are available. In the current study, we used a quantitative method to evaluate thrombin activity in fresh and frozen brain sections of 43 male and female adult healthy mice. We stratified data per brain section, brain hemisphere, and mouse sex. We found lower thrombin activity in frozen sections compared with fresh sections, falling within levels considered central nervous system protective in previous studies. The results suggest that fresh section thrombin activity levels in healthy mice can be extrapolated from frozen brain sections. In addition, we found varying thrombin activity across the brain sections, with maximal activity in the olfactory system and hippocampus containing sections. Thrombin activity did not vary between males and females, or between the right and the left hemispheres, in a statistically significantly manner. PMID- 28915148 TI - Adult Fmr1 knockout mice present with deficiencies in hippocampal interleukin-6 and tumor necrosis factor-alpha expression. AB - Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a single genetic mutation in the FMR1 gene. Mutations in the FMR1 gene are the largest monogenic cause of autism spectrum disorder (ASD), and thus both disorders share many of the same cognitive and behavioral impairments. There is increasing evidence suggesting that dysregulated immune responses play a role in the pathophysiology of ASD; however, the association between FXS and altered immunity requires further investigation. This study examined whether Fmr1 knockout (KO) and wild-type mice on a FVB/NJ background strain had altered cytokine expression at baseline levels in the hippocampus. Results showed Fmr1 KO mice to have decreased proinflammatory cytokine hippocampal mRNA expression, specifically interleukin (IL)-6 and tumor necrosis factor-alpha, compared with wild-type mice. However, no differences were detected in the expression levels of IL-1beta, MCP 1, interferon-gamma, or IL-10. Despite the high comorbidity between FXS and ASD, these results suggest that the Fmr1 KO mouse does not mimic the increased proinflammatory cytokine expression commonly found in ASD mouse models and patients. Further investigation of the immune profile of the Fmr1 KO mouse is critical to understand whether this deficiency of cytokines in the hippocampus is indicative of a broader immunologic deficit associated with FXS. PMID- 28915149 TI - Bulleyaconitine A preferably reduces tetrodotoxin-sensitive sodium current in uninjured dorsal root ganglion neurons of neuropathic rats probably via inhibition of protein kinase C. AB - Oral Bulleyaconitine A (BLA) is effective for treating neuropathic pain in human patients, but the underlying mechanism is poorly understood. Here, we tested whether BLA blocked voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons. Compelling evidence shows that voltage-gated sodium channels are upregulated in uninjured DRG neurons but downregulated in injured ones following peripheral nerve injury. We found that BLA preferably inhibited Na currents in uninjured DRG neurons in neuropathic rats. Compared to sham rats, IC50 values for resting and inactivated Na currents were 113 and 74 times lower in injured and uninjured neurons of L4-6 DRGs in spared nerve injury (SNI) rats (4.55 and 0.56 nM) and were 688 and 518 times lower in the uninjured L4 and L6 DRG neurons of L5 spinal nerve ligation (L5-SNL) rats. The use-dependent blockage of BLA on Na currents was more potent in neuropathic rats compared to sham rats. Bulleyaconitine A facilitated the inactivation of Na channels in each group. IC50 values for resting and inactivated tetrodotoxin-sensitive (TTX-S) channels were 1855 and 1843 times lower than those for TTX-resistant channels in the uninjured neurons of L5 spinal nerve ligation rats. The upregulation of protein kinase C was associated with the preferable effect of BLA on TTX-S Na channels in the uninjured DRG neurons. Local application of BLA onto L4-6 DRGs at 0.1 to 10 nM dose-dependently alleviated the mechanical allodynia and thermal hyperalgesia in L5 spinal nerve ligation model. Thus, preferable blockage of TTX-S Na channels in uninjured DRG neurons may contribute to BLA's antineuropathic pain effect. PMID- 28915150 TI - Tics and Tourette: a clinical, pathophysiological and etiological review. AB - PURPOSE OF REVIEW: Describe developments in the etiological understanding of Tourette syndrome. RECENT FINDINGS: Tourette syndrome is a complex heterogenous clinical syndrome, which is not a unitary entity. Pathophysiological models describe gamma-aminobutyric acid-ergic-associated disinhibition of cortico-basal ganglia motor, sensory and limbic loops. MRI studies support basal ganglia volume loss, with additional white matter and cerebellar changes. Tourette syndrome cause likely involves multiple vulnerability genes and environmental factors. Only recently have some vulnerability gene findings been replicated, including histidine decarboxylase and neurexin 1, yet these rare variants only explain a small proportion of patients. Planned large genetic studies will improve genetic understanding. The role of inflammation as a contributor to disease expression is now supported by large epidemiological studies showing an association with maternal autoimmunity and childhood infection. Investigation of blood cytokines, blood mRNA and brain mRNA expression support the role of a persistent immune activation, and there are similarities with the immune literature of autistic spectrum disorder. Current treatment is symptomatic, although there is a better appreciation of factors that influence treatment response. SUMMARY: At present, therapeutics is focused on symptom-based treatments, yet with improved etiological understanding, we will move toward disease-modifying therapies in the future. PMID- 28915151 TI - Analgesic Effects of Locally Administered Ketorolac-based Analgesics After Breast Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: Reducing postoperative pain following breast surgery is crucial for rapid recovery and shortening hospital stay. Ketorolac, a nonsteroidal anti inflammatory drug, has been used as a postoperative analgesic in many surgical procedures. We conducted a systemic review and meta-analysis on the efficacy of locally administered ketorolac-based analgesics in managing pain after breast surgery. METHODS: We searched the PubMed, Embase, Cochrane Library, Scopus, and ClinicalTrials.gov registry for randomized control trials (RCTs) published up to September 2016. The primary outcome was pain level assessed using a visual analog scale (VAS) at 1 and 6 hours following breast surgery. RESULTS: We reviewed 4 RCTs with 255 patients. For meta-analysis, VAS at 1 and 6 hours of 3 similar RCTs were compared. At 1 hour, VAS scores were significantly lower in patients administered a ketorolac solution [weighted mean difference (WMD)=-2.04; 95% confidence interval (CI): -3.08 to -1.00] or ketorolac-bupivacaine solution (WMD= 2.30; 95% CI, -4.07 to -0.54) than in controls. At 6 hours, the ketorolac bupivacaine solution reduced VAS scores significantly (WMD=-1.40; 95% CI, -2.48 to -0.32) compared with controls. However, at 1 hour, the ketorolac solution was significantly more effective than the bupivacaine solution was (WMD=-1.70; 95% CI, -2.81 to -0.59). DISCUSSION: The effects of ketorolac-based analgesics vary as per the surgery and disease type. Locally administered ketorolac-based analgesics decreased postoperative pain in breast surgery patients, and the effect of local ketorolac was better than local bupivacaine. Therefore, ketorolac based analgesics demonstrate considerable local infiltration during pain management after breast surgery. PMID- 28915152 TI - Predictors of Adherence to Psychological Treatment for Insomnia and Pain: Analysis from a Randomized Trial. AB - OBJECTIVES: Poor adherence to psychological treatment for insomnia is common and limits treatment gains. Very little is known about predictors of adherence among patients with chronic pain, although adherence is theorized to be more critical and more challenging for these patients. This secondary data analysis examines predictors of drop-out and therapy nonattendance in an osteoarthritis population receiving psychological treatment for insomnia and pain. METHODS: Data were analyzed from the "Lifestyles" trial, a randomized controlled trial of a 6-week group cognitive behavioral pain coping skills intervention (CBT-P), group cognitive-behavioral therapy for pain and insomnia (CBT-PI), and an education only attention control group (EOC). The current analysis focuses on 122 participants randomized to CBT-PI from 6 primary care clinics. Measures of treatment acceptability, demographics, and symptoms were collected at baseline. Factor analysis was used to clarify the boundaries of these domains, and hierarchical regression was used to examine the incremental predictive power of these patient characteristics on therapy attendance. RESULTS: Ratings of treatment acceptability were distinct from demographic and medical variables and baseline symptoms. Treatment acceptability was significantly related to session attendance and drop-out (rs ranging from 0.24 to 0.32) and was also one of the strongest predictors of session attendance (beta=0.20; P<0.05). DISCUSSION: Perceptions of treatment acceptability early in treatment represent a potentially modifiable target to enhance adherence to psychological treatment for insomnia and pain among patients with chronic pain. This work represents an important step towards understanding how to best maximize sleep treatments for this patient population. PMID- 28915153 TI - Associations of Early Opioid Use With Patient-reported Outcomes and Health Care Utilization Among Older Adults With Low Back Pain. AB - OBJECTIVES: The objective of this study was to compare outcomes and health care utilization of older patients who did versus did not fill opioid prescriptions within 90 days of initiating care for low back pain. MATERIALS AND METHODS: For patients >=65 years with new back pain visits, we used propensity scores to match those who filled no opioid prescriptions to those who filled >=2 opioid prescriptions within 90 days (and the first opioid prescription within 30 d) of the index visit. Over 24 months, we examined patient-reported outcomes, health care utilization, and subsequent opioid prescription fills. RESULTS: Among 1954 patients eligible for matching, 238 (12%) filled >=2 opioid prescriptions within 90 days; 200 of these were matched to controls. Patients with versus without early opioid prescriptions had similar patient-reported outcomes but were more likely to have filled >=1 opioid prescription 18 to 24 months after the index visit (odds ratio [95% confidence interval]=2.4 [1.5-3.9]) and to have had >=1 visit to the emergency department in the subsequent 24 months (OR, 1.6; 95% confidence interval, 1.0-2.5). DISCUSSION: Among older patients with new back pain visits, filling >=2 opioid prescriptions within 90 days of the visit was associated with similar back pain-related outcomes but increased likelihood of filling opioid prescriptions 18 to 24 months later compared with matched patients who did not fill early opioid prescriptions. PMID- 28915154 TI - Risk Factors for Low Back Pain in Childhood and Adolescence: A Systematic Review. AB - OBJECTIVES: To identify factors associated with low back pain (LBP) in children and adolescents. MATERIALS AND METHODS: A systematic review was conducted (Prospero CRD42016038186). Observational studies analyzing LBP risk factors among participants aged between 9 and 16 were searched for in 13 electronic databases and 8 specialized journals until March 31, 2016, with no language restrictions. In addition, references in the identified studies were manually tracked. All identified studies that included >=50 participants aged 9 to 16, were reviewed. Their methodological quality was assessed by 2 reviewers separately, using validated tools, which scored, from worst to best, 0 to 100 for cross-sectional and 0 to 12 for cohort studies. A sensitivity analysis only included studies that had adjusted for confounders, had >=500 participants, and had a methodological score of >=50%. RESULTS: A total of 5142 citations were screened and 61 studies, including 137,877 participants from 5 continents, were reviewed. Their mean (range) methodological scores were 74.56 (50 to 100) for cross-sectional studies and 7.36 (5 to 9) for cohort studies. The studies had assessed 35 demographic, clinical, biological, family, psychological, ergonomic, and lifestyle risk factors. The mean (range) prevalence of LBP ranged between 15.25% (3.20 to 57.00) for point prevalence and 38.98% (11.60 to 85.56) for lifetime prevalence. Results on the association between LBP and risk factors were inconsistent. In the sensitivity analysis, "older age" and "participation in competitive sports" showed a consistent association with LBP. DISCUSSION: Future studies should focus on muscle characteristics, the relationship between body and backpack weights, duration of carrying the backpack, characteristics of sport practice, and which are the factors associated with specifically chronic pain. PMID- 28915155 TI - Social Support and Pain Outcomes After Trauma Exposure Among Older Adults: A Multicenter Longitudinal Study. AB - OBJECTIVES: Certain forms of social support have been shown to improve pain coping behaviors and pain outcomes in older adults with chronic pain, but little is known about the effect of social support on pain outcomes in older adults following trauma exposure. METHODS: We analyzed data from a prospective longitudinal study of adults aged 65 years and older presenting to an emergency department after a motor vehicle collision (MVC) to characterize the relationship between perceived social support and MVC-related pain after trauma overall and by subgroups based on sex, depressive symptoms, and marital status. RESULTS: In our sample (N=176), patients with low perceived social support had higher pain severity 6 weeks after MVC than patients with high perceived social support after adjustment for age, sex, race, and education (4.2 vs. 3.2, P=0.04). The protective effect of social support on pain severity at 6 weeks was more pronounced in men and in married individuals. Patients with low social support were less likely to receive an opioid prescription in the emergency department (15% vs. 32%, P=0.03), but there was no difference in opioid use at 6 weeks (22% vs. 20%, P=0.75). DISCUSSION: Among older adults experiencing trauma, low perceived social support was associated with higher levels of pain at 6 weeks. PMID- 28915156 TI - A Risk Calculator Using Preoperative Opioids for Prediction of Total Knee Revision Arthroplasty. AB - OBJECTIVES: Total knee arthroplasty (TKA) is a procedure to improve quality of life. However, some patients require early total knee revision (TKR). Chronic opioid use before TKA is associated with TKR. No risk calculator including opioid use or other risk factors is currently available for predicting TKR. MATERIALS AND METHODS: We retrospectively analyzed medical records of Veterans Affairs patients who underwent TKA from January 1, 2006 to January 1, 2012. Patients were followed until January 1, 2013. Chronic opioid use was defined as opioid use for >=3 months preoperatively. A cross-validated Cox proportional hazards model was created to predict TKR before initial TKA. Model performance was evaluated by the mean absolute error at 1 and 5 years. RESULTS: Totally, 32,297 patients were included. A risk calculator was generated with a mean absolute error of 0.1% at 1 year and 3.6% at 5 years. Chronic opioid use was a significant predictor of TKR (hazard ratio [HR], 1.27; 95% confidence interval, 1.13-1.43; P<0.001). Other model variables were age (HR, 0.95; P<0.001), female sex (HR, 0.77; P=0.020), body mass index (HR, 0.99; P=0.022), diabetes (HR, 1.20; P=0.001), chronic kidney disease (HR, 1.48; P<0.001), and nonchronic opioid use (HR, 1.07; P=0.313). DISCUSSION: Preoperative chronic opioid use is a predictor of TKR. Using this association and others, a TKA revision risk calculator was generated at http://www.bit.do/tka. PMID- 28915157 TI - Abortion in the media. AB - PURPOSE OF REVIEW: To review updates in how abortion care is depicted and analysed though various media outlets: news, television, film, and social media. RECENT FINDINGS: A surge in recent media-related abortion research has recognized several notable and emerging themes: abortion in the news media is often inappropriately sourced and politically motivated; abortion portrayal in US film and television is frequently misrepresented; and social media has a new and significant role in abortion advocacy. SUMMARY: The portrayal of abortion onscreen, in the news, and online through social media has a significant impact on cultural, personal, and political beliefs in the United States. This is an emerging field of research with wide spread potential impact across several arenas: medicine, policy, public health. PMID- 28915158 TI - Simulation training for family planning procedures. AB - PURPOSE OF REVIEW: To review the current evidence for use of simulation in family planning procedural training. RECENT FINDINGS: A variety of simulation models exist for abortion, contraception, and sterilization procedures, ranging from low to high fidelity. Most models for abortion and contraception are low fidelity, inexpensive, and provide opportunities for acquisition and practice of procedural skills. Hysteroscopic and laparoscopic simulation models for sterilization procedures are generally higher fidelity, and their use has been shown to increase knowledge, skill performance, and procedural comfort. SUMMARY: Existing evaluation of family planning simulation education shows consistently positive results related to improved procedural knowledge and comfort. Although some studies have shown increased provision of family planning services following simulation-training interventions, further evaluation is needed to determine the impact on clinical outcomes. PMID- 28915159 TI - Contraception in US servicewomen: emerging knowledge, considerations, and needs. AB - PURPOSE OF REVIEW: We describe current literature regarding contraceptive use among women serving in the military. We explore the state of contraceptive use by female servicewomen, gaps in knowledge, special considerations, and evidence of unmet needs. RECENT FINDINGS: Recent data on US servicewomen show that overall rates of contraceptive use remain low. Data highlight disparities and suggest barriers to contraceptive uptake persist, with contraceptive use being lower around the time of deployment. Methods that do not require daily use or prescription refills, such as long-acting reversible contraception (LARC) - intrauterine devices and contraceptive implants - may be distinctly well suited for service and deployment. Two contemporary studies document growing popularity of LARC methods among female members of the military, possibly driven by a surge in contraceptive implant use. Nonetheless, LARC appears to remain underutilized. SUMMARY: Despite no-cost provision, the importance of preventing unplanned pregnancy, and the potential benefits of cycle control during service, emerging data about the US military suggest barriers to and underutilization of contraception, particularly LARC. Research is needed to explore preferences and tailor contraceptive counseling to servicewomen. Existing and future work can inform efforts to standardize military provider training and ensure all servicewomen are appropriately counseled and have timely access to any method they may choose. PMID- 28915160 TI - Current insights in obstetric antiphospholipid syndrome. AB - PURPOSE OF REVIEW: Antiphospholipid syndrome (APS) is defined as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). In this review, we will highlight the most important clinical presentations of APS with a focus on the obstetric morbidity, the current management strategies and the outlook for the future. RECENT FINDINGS: The use of aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS have a successful pregnancy outcome. Unfortunately, the current standard of care does not prevent all pregnancy complications as the current treatment fails in 20-30% of APS pregnancies. This therefore highlights the need for alternative treatments to improve obstetrical outcome. Other treatment options are currently explored and retrospective studies show that pravastatin for example is beneficial in women with aPL-related early preeclampsia. Moreover, the immunmodulator hydroxychloroquine may play a beneficial role in the prevention of aPL-related pregnancy complications. SUMMARY: APS is among the most frequent acquired risk factors for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischaemic placental dysfunction, such as fetal growth restriction, preeclampsia, premature birth and intrauterine death. Current treatment is mainly based on aspirin and heparin. Studies to inform on alternative treatment options are urgently needed. PMID- 28915161 TI - Unenhanced Dual-Energy Computed Tomography: Visualization of Brain Edema. AB - PURPOSE: The aim of this study was to determine whether dual-energy computed tomography (DECT) imaging is superior to conventional noncontrast computed tomography (CT) imaging for the detection of acute ischemic stroke. MATERIALS AND METHODS: This was a retrospective, single-center study of 40 patients who presented to the emergency department (ED) of a major, acute care, teaching center with signs and symptoms of acute stroke. Only those patients who presented to the ED within 4 hours of symptom onset were included in this study. All 40 patients received a noncontrast DECT of the head at the time of presentation. Each patient also received standard noncontrast CT of the head 24 hours after their initial presentation to the ED. "Brain edema" images were then reconstructed using 3-material decomposition with parameters adjusted to suppress gray/white matter contrast while preserving edema and increasing its conspicuity. The initial unenhanced, mixed images, brain edema, and 24-hour follow-up true noncontrast (TNC) images were reviewed and assigned Alberta Stroke Program Early CT scores. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Of the 40 patients, 28 (70%) were diagnosed with an acute infarction. Brain edema reconstructions were better able to predict end infarction volume, with Alberta Stroke Program Early CT scores similar to the 24-hour follow-up TNC CT (7.75 vs 7.7; P > 0.05), whereas the mixed images routinely underestimated the extent of infarction (8.975 vs 7.7; P < 0.001). Initial TNC images had a sensitivity, specificity, PPV, and NPV of 80% (95% confidence interval [CI], 51.9%-95.7%), 72.7% (95% CI, 39%-94%), 80% (95% CI, 51.9%-95.7%), and 72.73% (95% CI, 51.91%-95.67%), respectively. The DECT brain edema images provided a sensitivity, specificity, PPV, and NPV of 93.33% (95% CI, 68.05%-99.83%), 100% (95% CI, 71.51%-100%), 100% (95% CI, 76.84% 100%), and 91.67% (95% CI, 61.52%-99.79%), respectively. There was very good interrater reliability across all 3 imaging techniques. CONCLUSION: Brain edema reconstructions are able to more accurately detect edema and end-infarct volume as compared with initial TNC images. This provides a better assessment of the degree and extent of infarction and may serve to better guide therapy in the future. PMID- 28915162 TI - The Effect of Perinatal Gadolinium-Based Contrast Agents on Adult Mice Behavior. AB - OBJECTIVES: The aim of this study was to examine the effects of perinatal exposure to gadolinium (Gd)-based contrast agents (GBCAs) on the behavior of adulthood offspring. MATERIALS AND METHODS: Pregnant Balb/C mice (n = 5 per group) were intravenously injected with gadoterate meglumine (Magnescope, macrocyclic GBCA), gadodiamide (Omniscan, linear GBCA), or vehicle from pregnancy day 15 to 19, corresponding to embryonic day 15 to 19 of the fetus, at 2 mmol/kg body weight per day. Brain samples from dams and pups were collected on postpartum day 28. The total Gd concentration was quantified by inductively coupled plasma-mass spectrometry (dams, n = 3; gadoterate meglumine-treated pups group, n = 9; and gadodiamide-treated pups group, n = 10). Behavioral testing of offspring was started on postpartum day 70 (control group, n = 22; gadoterate meglumine-treated group, n = 23; and gadodiamide-treated group, n = 20). RESULTS: Higher levels of Gd retention were observed in dams and pups in the gadodiamide treated group. Perinatal exposure to GBCAs caused anxiety-like behavior, disrupted motor coordination, impaired memory function, stimulated tactile sensitivity, and decreased muscle strength, particularly in the gadodiamide treated group. CONCLUSIONS: In the present study, we showed that Gd was transferred to pups and was retained in their brain during postnatal development. Gadolinium retention may lead to impaired brain development. These findings indicate that the use of GBCAs in pregnant women should be avoided because it may have adverse effects on the fetus, particularly on brain development. PMID- 28915163 TI - Do prehospital providers and emergency nurses agree on triage assignment?: an efficacy study. AB - OBJECTIVES: The aim of this study was to investigate the agreement on triage level between prehospital providers and emergency department (ED) nurses in clinical practice when using the same triage system. The objectives were as follows: (a) What is the agreement of triage between prehospital providers and ED nurses, when using Danish Emergency Process Triage (DEPT) correctly? (b) Which part of the triage process yields the highest agreement regarding the final triage? METHODS: The study was a prospective and observational efficacy study. Patients transported to the ED by ambulances were included. They were triaged by prehospital providers while being transported by ambulance to the ED, and by ED nurses upon arrival. Triage was done using the DEPT - a five-level triage system based on vital signs and a presenting complaint algorithm. An agreement analysis was performed. RESULTS: DEPT was used correctly by both professions in 292 patients. In 182 (62%) patients the prehospital providers and the ED nurses agreed on the same triage level. This equals to kappa=0.47 [95% confidence interval (CI): 0.41-0.56]. When considering the triage based on vital signs the agreement was 72% (kappa=0.46; 95% CI: 0.41-0.47), and based on presenting complaint the agreement was 46% (kappa=0.41; 95% CI: 0.37-0.44). CONCLUSION: There was a moderate interrater agreement on triage assignment between ED nurses and prehospital providers. They agreed on final triage more often if they agreed on triage based on vital signs rather than presenting complaints. PMID- 28915164 TI - Organizational and Environmental Factors Influencing Hospital Community Orientation. AB - BACKGROUND: Community orientation refers to hospitals' efforts to assess and meet the health needs of the local population. Variations in the number of community orientation-related activities offered by hospitals may be attributed to differences in organizational and environmental characteristics. Therefore, hospitals have to strategically respond to these internal and external constraints to improve community health. Understanding the facilitators and barriers of hospital community orientation is important to health care managers facing pressure from the external environment to meet the expectations of the community as well as Affordable Care Act guidelines. PURPOSE: The purpose of this study was to examine the organizational and environmental factors that promote or impede hospital community orientation. METHODOLOGY: A multivariate regression with random effects was conducted using data from the American Hospital Association Annual Survey from 2007 to 2010 and county level data from the Area Health Resource Files. FINDINGS: Not-for-profit, system-affiliated, network affiliated, and larger hospitals have a higher degree of community orientation. In addition, the percentage of the county residents under the age of 65 years with health insurance and hospitals in states with certificate-of-need laws were also positively related to the degree of community orientation. During the study period, it appears that organizational factors mattered more in determining the degree of community orientation. PRACTICE IMPLICATIONS: Overall, a better understanding of the factors that influence community orientation can assist hospital administrators and policymakers in stimulating the hospital's role in improving population health and its responsiveness to community health needs. These efforts may occur by building interorganizational relationships or by incentivizing those hospitals that are least likely to be community oriented. PMID- 28915165 TI - Employee organizational commitment and hospital performance. AB - BACKGROUND: There is widespread evidence of the purported benefits of employee organizational commitment (EOC) and its impact on both individual and organizational performance. This study contributes to this literature by providing a unique insight into this relationship, focusing on the interrelationship between EOC with hospital performance and the role of the provision of adequate facilities in eliciting EOC. PURPOSE: The aim of this study was to introduce and empirically examine a new theoretical model in which it is argued that the performance of hospitals with regard to the provision of adequate facilities (medical facilities, support facilities, and staff resources) influences the level of EOC, which in turn influences hospital performance with regard to patient care and operational effectiveness. METHODOLOGY/APPROACH: To examine the interrelationships between the provision of adequate facilities, EOC, and hospital performance, the study utilizes a survey of hospital managers. RESULTS: The findings support the theoretical model, with the provision of support facilities and staff resources positively indirectly associated with both patient care and operational effectiveness through their impact on EOC. CONCLUSION: The findings highlight the importance of providing adequate facilities and EOC within hospitals and suggest that CEOs and general managers should try to enhance the provision of such resources in an attempt to elicit EOC within their hospitals. PRACTICE IMPLICATIONS: The findings suggest that managers should try to enhance their provision of adequate facilities in order to elicit EOC and enhance hospital performance. With regard to medical facilities, they should consider and incorporate the latest technology and up-to-date equipment. They should also provide adequate staff resources, including appropriate numbers of beds, nurses, and doctors, to prevent "fatigue" (West, 2001, p. 41) and provide adequate support facilities. PMID- 28915166 TI - Factors associated with hospital participation in Centers for Medicare and Medicaid Services' Accountable Care Organization programs. AB - BACKGROUND: In 2012, the Centers for Medicare and Medicaid Services (CMS) initiated the Medicare Shared Savings Program (MSSP) and Pioneer Accountable Care Organization (ACO) programs. Organizations in the MSSP model shared cost savings they generated with CMS, and those in the Pioneer program shared both savings and losses. It is largely unknown what hospital and environmental characteristics are associated with the development of CMS ACOs with one- or two-sided risk models. PURPOSE: The aim of this study was to assess the organizational and environmental characteristics associated with hospital participation in the MSSP and Pioneer ACOs. METHODOLOGY: Hospitals participating in CMS ACO programs were identified using primary and secondary data. The ACO hospital sample was linked with the American Hospital Association, Health Information and Management System Society, and other data sets. Multinomial probit models were estimated that distinguished organizational and environmental factors associated with hospital participation in the MSSP and Pioneer ACOs. RESULTS: Hospital participation in both CMS ACO programs was associated with prior experience with risk-based payments and care management programs, advanced health information technology, and location in higher-income and more competitive areas. Whereas various health system types were associated with hospital participation in the MSSP, centralized health systems, higher numbers of physicians in tightly integrated physician organizational arrangements, and location in areas with greater supply of primary care physicians were associated with Pioneer ACOs. Favorable hospital characteristics were, in the aggregate, more important than favorable environmental factors for MSSP participation. CONCLUSION: MSSP ACOs may look for broader organizational capabilities from participating hospitals that may be reflective of a wide range of providers participating in diverse markets. Pioneer ACOs may rely on specific hospital and environmental characteristics to achieve quality and spending targets set for two-sided contracts. PRACTICE IMPLICATIONS: Hospital and ACO leaders can use our results to identify hospitals with certain characteristics favorable to their participation in either one- or two-sided ACOs. PMID- 28915167 TI - The Promise of Traditional Chinese Medicine After Cardiac Arrest: An Untapped Resource? PMID- 28915168 TI - Fluid Management in Sepsis-Is There a Golden Hour (or Two)? PMID- 28915169 TI - Group Therapy in the ICU. PMID- 28915170 TI - Life on MARS? PMID- 28915171 TI - Determinants of Care-When Is Prolonged Mechanical Ventilation No Longer Appropriate and Who Decides? PMID- 28915172 TI - No Luck With Preadmission Anti-Inflammatory Drugs to Prevent Postcritical Illness Psychiatric Morbidity. PMID- 28915173 TI - Intracranial Hemorrhage and Extracorporeal Membrane Oxygenation: Chicken or the Egg? PMID- 28915174 TI - The Importance of Clinical Context on Assessing Outcomes in Sepsis. PMID- 28915175 TI - When the Letter "F" Meets the Letter "D": Beneficial Impact of Open Visiting and Family Presence on Incidence of Delirium Among ICU Patients. PMID- 28915176 TI - Prognostication of Critically Ill Patients With Cancer: A Long Road Ahead. PMID- 28915177 TI - Bad Response or Bad Luck? A New Versus Recrudescent Sepsis Readmission. PMID- 28915178 TI - Expanding the Donor Pool: Organ Donation After Brain Death for Extracorporeal Membrane Oxygenation Patients. PMID- 28915179 TI - Evaluating Cognitive Deficits in Childhood After Neonatal Critical Illness With MRI. PMID- 28915180 TI - Central Venous Catheter Insertion and Bedside Ultrasound: Building a New Standard of Care? PMID- 28915181 TI - Sedating Children on Extracorporeal Membrane Oxygenation: Achieving More With Less. PMID- 28915183 TI - Autonomous Resuscitation on the Horizon? PMID- 28915182 TI - Hyperoxia in Septic Shock: Crafty Therapeutic Weapon or Double-Edged Sword? PMID- 28915184 TI - Wide Disagreement Between Alternative Assessments of Premorbid Physical Activity: Subjective Patient and Surrogate Reports and Objective Smartphone Data. AB - OBJECTIVES: Surrogate-decision maker and patient self-reported estimates of the distances walked prior to acute illness are subjective and may be imprecise. It may be possible to extract objective data from a patient's smartphone, specifically, step and global position system data, to quantify physical activity. The objectives were to 1) assess the agreement between surrogate decision maker and patient self-reported estimates of distance and time walked prior to resting and daily step-count and 2) determine the feasibility of extracting premorbid physical activity (step and global position system) data from critically ill patients. DESIGN: Prospective cohort study. SETTING: Quaternary ICU. PATIENTS: Fifty consecutively admitted adult patients who owned a smartphone, who were ambulatory at baseline, and who remained in ICU for more than 48 hours participated. MEASURMENTS AND MAIN RESULTS: There was no agreement between patients and surrogates for all premorbid walking metrics (mean bias 108% [99% lower to 8,700% higher], 83% [97% to 2,100%], and 71% [96% to 1,080%], for distance, time, and steps, respectively). Step and/or global position system data were successfully extracted from 24 of 50 phones (48%; 95% CI, 35-62%). Surrogate decision makers, but not patient self-reported, estimates of steps taken per day correlated with smartphone data (surrogates: n = 13, rho = 0.56, p < 0.05; patients: n = 13, rho = 0.30, p = 0.317). CONCLUSION: There was a lack of agreement between surrogate-decision maker and patient self-reported subjective estimates of distance walked. Obtaining premorbid physical activity data from the current-generation smartphones was feasible in approximately 50% of patients. PMID- 28915185 TI - Updating Evidence for Using Therapeutic Hypothermia in Pediatric Severe Traumatic Brain Injury. PMID- 28915186 TI - The authors reply. PMID- 28915187 TI - Early Electroencephalography Dynamics After Cardiac Arrest. PMID- 28915188 TI - The authors reply. PMID- 28915189 TI - Interpreting Immune Mediator Dysbalance in Sepsis. PMID- 28915190 TI - The authors reply. PMID- 28915191 TI - Primary Outcomes in Acute Respiratory Distress Syndrome Research. PMID- 28915192 TI - The authors reply. PMID- 28915193 TI - Procalcitonin Clearance and Prognosis in Sepsis: Are There Really an Optimal Cutoff and Time Interval? PMID- 28915194 TI - The authors reply. PMID- 28915195 TI - Hyperchloremia Is Associated With Acute Kidney Injury in Patients With Aneurysmal Subarachnoid Hemorrhage: Not Sure. PMID- 28915196 TI - The authors reply. PMID- 28915197 TI - Beneficial Effects of Noninvasive Ventilation in Acute Hypoxemic Respiratory Failure: Caution With Findings From Meta-Analyses. PMID- 28915199 TI - The Overlap Between Burnout and Depression in ICU Staff. PMID- 28915198 TI - The authors reply. PMID- 28915200 TI - Optimal Sampling Frequency of Serum Cortisol Concentrations After Cardiac Surgery. PMID- 28915201 TI - Letter to the Editor on "Effects of Antigravity Treadmill Training on Gait, Balance, and Fall Risk in Children With Diplegic Cerebral Palsy". PMID- 28915202 TI - Objectively Measured Physical Activity and Falls in Well-Functioning Older Adults: Findings From the Baltimore Longitudinal Study of Aging. AB - OBJECTIVE: Previous work demonstrates the consequences of falling in older adults and the potential of physical activity (PA) to reduce falls, but few studies have used accelerometer-measured PA to compare overall and time-of-day activity patterns of nonfallers, fallers, or subgroups of fallers. METHODS: In 840 participants (mean age, 66.7; s = 13.2; range, 26-97) of the Baltimore Longitudinal Study of Aging between 2007 and 2014, PA was measured objectively with Actiheart accelerometers and falling status (faller/nonfaller) was assessed during an in-person interview. Differences in daily PA and PA by time-of-day were assessed using multiple linear regression. Differences in PA (multiple linear regression), and functional status (chi) were further examined in subgroups of "risky" or "normal" fallers. RESULTS: Overall, fallers and nonfallers exhibited similar daily (beta = 22.6, P = 0.48) and time-specific PA; however, those who fell doing risky activities were more active overall (beta = 243.8, P = 0.002), during the morning (beta = 77.3, P = 0.004), afternoon (beta = 78.4, P = 0.001), and late afternoon/evening (beta = 56.3, P = 0.006) than those who fell doing normal activities. Risky fallers were significantly higher functioning than normal fallers. CONCLUSIONS: Persons who fell while engaging in normal activities exhibited lower PA overall and throughout most of the day, and were of lower functional status than persons who fell while engaging in risky or unusual activities, suggesting that engagement in risky or unusual PA is associated with higher functional ability and lower falls risk in older persons. PMID- 28915203 TI - Treatment of Zenker's Diverticulum With Endoscopic Stapled Esophago divertisculostomy (ESD): Analysis of Long-term Outcome. AB - BACKGROUND: Endoscopic Zenker diverticulum (ZD) treatment has become quite common because of the low complication rates, reduced procedure time, and shorter hospital stay. Many endoscopic treatments are available including the endoscopic stapled esophago-diverticulostomy (ESD). Many data regarding ESD are available on the short-term outcomes, but few on the long-term ones. MATERIALS AND METHODS: From March 1998 to July 2016, 126 patients with ZD were candidate for ESD. Since 2009, 2 stay sutures were routinely positioned at the lateral edges of the septum using Medtronic Endostitch 10 mm suturing device. Demographic and perioperative data, symptoms, and surgical outcomes were recorded. Long-term ESD results were analyzed. An extra-analysis on the surgical outcome was performed comparing patients treated with or without stay sutures. RESULTS: In total, 117 patients successfully underwent ESD. The mean age was 69.9 years with a male predominance. Intraoperative complications occurred in 6.8% of cases. Only 2.6% of the patients reported postoperative complications. For the long-term analysis, we were able to contact 92 patients for a mean period follow-up of 65.3 months. At 6-month outpatient visit 77.68% of patients were completely asymptomatic. In total, 22.3% of the patients needed an extratreatment due to incomplete section of the septum, reaching a success rate of 95.5%. The long-term resolution rate remained high (91.3%). The use of stay sutures did not statistically influence the operative time (22.8 vs. 26.7 min, P=0.070), nor intraoperative and postoperative complication rate, but a statistically significant higher complete resolution rate of symptoms with a single session of ESD was observed respect those treated without (87.3% vs. 65.3%, respectively). CONCLUSIONS: ESD is a safe and effective treatment of ZD and it can control symptoms even in a long-term follow-up. In our experience, the use of stay sutures placed with Endostitch increases short and long-term results reducing the need for further treatments. PMID- 28915204 TI - Laparoscopy for Trauma and the Changes in its Use From 1990 to 2016: A Current Systematic Review and Meta-Analysis. AB - BACKGROUND: The role of laparoscopy in the diagnosis and treatment of stable abdominal trauma patients is still a matter of serious debate and only incomplete data are available. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of the literature between January 1990 and August 2016. RESULTS: Overall, 9817 laparoscopies were performed for abdominal trauma; only 26.2% of the cases were converted to a laparotomy. The incidence of therapeutic laparotomies showed a reduction from 69% to 47.5%, whereas the incidence of therapeutic laparoscopies increased from 7.2% to 22.7%.The overall perioperative mortality rate was significantly lower in the laparoscopy group [odds ratio (M-H, random); 95% confidence interval, 0.35 (0.26-0.48)]. The same group showed shorter length of hospital stay [odds ratio (M-H, random); 95% confidence interval, -3.48 (-8.91 to 1.96)]. CONCLUSIONS: This systematic review shows a significant decrease in the use of laparoscopy in trauma patients. Most likely the widespread use of imaging techniques allows a more accurate selection of patients for diagnostic laparoscopy. Infact, a reduction in incidence of nontherapeutic laparotomies is evident in these selected patients undergoing diagnostic laparoscopy. Moreover, the literature reported an increasing trend of therapeutic laparoscopy, demonstrating that it is safe and effective. The small number and poor quality of the studies identified, the retrospective observational nature of the studies (low level of evidence), the high risk of bias, and the high heterogeneity of some outcomes make the applicability of the results of this meta-analysis unclear. PMID- 28915205 TI - Postoperative Pain After Laparoscopic Repair of Primary Umbilical Hernia: Titanium Tacks Versus Absorbable Tacks: A Prospective Comparative Cohort Analysis of 80 Patients With a Long-term Follow-up. AB - We investigated if a novel fixation device with absorbable tacks (Securestrap) causes less early and chronic postoperative pain after laparoscopic repair with a double-crown mesh fixation of ventral abdominal wall hernia when compared with the standard fixation device with nonabsorbable titanium tacks (Protack). The primary outcome measure was early postoperative pain at 2, 6, and 12 weeks postoperatively. The secondary outcome measure was chronic postoperative pain measured >=18 months after surgery. Pain levels were assessed using a visual analog scale ranging from 0 (no pain) to 100 mm (excruciating pain). Early postoperative pain was significantly lower in group 2 (absorbable tacks) at 6 (2 vs. 5; P=0.008) and 12 weeks (1 vs. 2; P=0.008) but not at follow-up (6 vs. 11; P=0.21). Given the very low visual analog scale scores in both groups, the clinical significance of these finding remains open to discussion. PMID- 28915206 TI - Laparoscopic Colorectal Surgery in Patients With Previous Abdominal Surgery: A Single-center Experience and Literature Review. AB - To present the outcomes of laparoscopic colorectal surgery in colorectal cancer patients with a previous history of abdominal surgery. Data of a total of 121 patients with primary colorectal cancer who underwent laparoscopic surgery were retrospectively analyzed. The patients were divided into 2 groups as those with previous abdominal surgery (PAS, n=34) and those without (non-PAS, n=87). Gastric and colonic surgeries were the most common procedures in the major PAS group, whereas gynecologic and obstetric surgeries and appendectomy were the most common procedures in the minor PAS group. However, there were statistically significant differences in the overall complication rates, wound complications, and anastomotic leaks, although there were no significant differences in the rates of postoperative ileus, pneumonia, port site herniation, and postoperative bleeding between the groups. Our study results suggest that laparoscopic colorectal surgery can be safely performed in patients with colorectal cancer who underwent abdominal surgery previously. PMID- 28915207 TI - Risk Factors and Oncologic Outcomes of Anastomosis Leakage After Laparoscopic Right Colectomy. AB - PURPOSE: We estimated the incidence of anastomosis leakage and explore possible risk factors and oncologic outcomes following laparoscopic right-side colon resection among colon cancer patients. MATERIALS AND METHODS: We retrospectively analyzed 423 patients who were diagnosed with appendiceal, cecal, ascending, or hepatic flexure colon cancer who underwent laparoscopic colonic resection and anastomosis between September 2006 and July 2014. We compared short-term and long term outcomes between no-leakage and leakage groups. RESULTS: There were 16 cases of right-side anastomosis leakage in a total 423 colon cancer cases (3.78%). The risk of leakage was increased in smokers (odds ratio=6.592, P=0.007) and with a longer operating time (odds ratio=1.024, P<0.001). There were no significant differences between the groups in local recurrence (P=0.106), overall survival (P=0.055), or cancer-specific survival (P=0.235). CONCLUSIONS: Smoking and long operating time are risk factors for right-side colon anastomosis. There were no significant differences in oncologic outcomes. PMID- 28915208 TI - Appropriate Use Criteria for Cardiac Computed Tomography: Impact on Diagnostic Utility. AB - BACKGROUND: Appropriate Use Criteria (AUC) guidelines for cardiac computed tomography (CCT) were developed to limit testing to reasonable clinical settings. However, significant testing is still done for inappropriate indications. This study investigates the impact of AUC on evaluability of CCT to determine if inappropriate tests result in a greater proportion of nondiagnostic results. METHODS: Investigators reviewed the medical records of 2417 consecutive patients who underwent CCT at the University of Ottawa Heart Institute. We applied the 2010 AUC and classified them as appropriate, inappropriate, or uncertain. Unclassifiable tests, as well as those with uncertain appropriateness, were excluded from the final analysis. Cardiac computed tomography results were classified as diagnostic if (1) all coronary segments were visualized, evaluable, and without obstructive stenosis; or (2) obstructive coronary artery disease with greater than 50% diameter stenosis in at least 1 coronary artery. All other test results were considered nondiagnostic. RESULTS: Of the 1984 patients included in the final analysis, 1522 patients (76.7%) had indications that were appropriate, whereas the remaining 462 (23.3%) were inappropriate. Inappropriate tests resulted in a higher rate of nondiagnostic results compared with appropriate CCT (9.0% vs 6.2%, P = 0.034). Inappropriate tests also had significantly more studies with nonevaluable segments than appropriate tests (24.5% vs 16.4%, P < 0.001) and were more likely to reveal obstructive coronary disease than appropriate CCT (50.5% vs 32.7%, P < 0.001). CONCLUSIONS: Cardiac computed tomography done for inappropriate indications may be associated with lower diagnostic yield and could impact future downstream resource utilization and health care costs. PMID- 28915209 TI - The Expanded Use of Autoaugmentation Techniques in Oncoplastic Breast Surgery. AB - BACKGROUND: Autoaugmentation techniques have been applied to oncoplastic reductions to assist with filling larger, more remote defects, and to women with smaller breasts. The purpose of this report is to describe the use of autoaugmentation techniques in oncoplastic reduction and compare the results with those of traditional oncoplastic reduction. METHODS: The authors queried a prospectively maintained database of all women who underwent partial mastectomy and oncoplastic reduction between 1994 and October of 2015. The autoaugmentation techniques were defined as (1) extended primary nipple autoaugmentation pedicle, and (2) primary nipple pedicle and secondary autoaugmentation pedicle. Comparisons were made to a control oncoplastic group. RESULTS: There were a total of 333 patients, 222 patients (67.7 percent) without autoaugmentation and 111 patients (33 percent) with autoaugmentation (51 patients with an extended autoaugmentation pedicle, and 60 patients with a secondary autoaugmentation pedicle). Biopsy weight was smallest in the extended pedicle group (136 g) and largest in the regular oncoplastic group (235 g; p = 0.017). Superomedial was the most common extended pedicle, and lateral was the most common location. Inferolateral was the most common secondary pedicle for lateral and upper outer defects. There were no significant differences in the overall complication rate: 15.5 percent in the regular oncoplastic group, 19.6 percent in the extended pedicle group, and 20 percent in the secondary pedicle group. CONCLUSIONS: Autoaugmentation techniques have evolved to manage complex defects not amenable to standard oncoplastic reduction methods. They are often required for lateral defects, especially in smaller breasts. Autoaugmentation can be performed safely without an increased risk of complications, broadening the indications for breast conservation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28915210 TI - Septum-Based Nasal Tip Plasty: A Comparative Study between Septal Extension Graft and Double-Layered Conchal Cartilage Extension Graft. AB - BACKGROUND: The septal extension graft is currently the most commonly used primary and secondary rhinoplasty technique in Asia because it provides maximal tip projection and rotational controllability. The authors compared the tip projection amount and rotational controllability of the tip support between the septal extension graft based on the L-strut septum and double-layer conchal cartilage graft based on the full septum at the nasal tip. METHODS: Twenty-seven consecutive patients who underwent nasal tip plasty with the septal extension graft or double-layer conchal cartilage graft for purely aesthetic reasons between March of 2014 and July of 2016 were included. The nasal tip projection and columellar labial angle preoperatively (time 0), immediately postoperatively (time 1, an average of 2 weeks after the operation), and postoperatively (time 2, an average of 7 months after the operation) were analyzed with clinical photography. RESULTS: Fourteen patients (group A) underwent septal extension graft surgery and 13 (group B) underwent double-layer conchal cartilage graft surgery. Changes of 61 and 74 percent in tip projection ratio were immediately achieved and were maintained after surgery for groups A and B, respectively (time 2 versus time 0 dividing time 1 versus time 0; p = 0.722 for groups A and B). Therefore, the relapse ratio of this technique was 39 and 26 percent for groups A and B, respectively. CONCLUSIONS: This comparative study between the septal extension graft and double-layer conchal cartilage graft showed that both nasal tip plasties are similar in terms of stability. Considering the fact that the double-layer conchal cartilage graft could preserve septal support, this technique could become an effective and safe alternative option for rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28915211 TI - Minimally Invasive Laparoscopically Dissected Deep Inferior Epigastric Artery Perforator Flap: An Anatomical Feasibility Study and a First Clinical Case. AB - The deep inferior epigastric perforator (DIEP) flap is a workhorse of breast reconstruction. Risks of herniation derive from violation of the rectus abdominis muscle anterior rectus sheath and might be reduced by minimally invasive laparoscopic dissection ("MILD") of the deep inferior epigastric vessels. The authors performed a feasibility study on five anatomical subjects and performed a secondary right breast reconstruction on a 67-year-old woman. A 30-degree laparoscope was used with laparoscopy ports inset to preserve the flap. Blunt preperitoneal dissection followed by carbon dioxide insufflation allowed the deep inferior epigastric pedicle to be dissected and clip-sectioned. The anterior rectus sheath was opened around the perforating vessels, and the flap was anastomosed on the internal mammary vessels. The length of incision in the anterior rectus sheath was compared between laparoscopic and conventional approaches. The mean incision length in the anterior rectus sheath was 3 cm versus 12 cm in the classic approach. Average duration of laparoscopic flap harvest was 50 minutes, including a mean of 30 minutes for deep inferior epigastric dissection. Adhesions led to a 1-cm peritoneal laceration in our first anatomical subject. There were no preoperative or postoperative complications in the clinical case. The clinical procedure duration was 8 hours 15 minutes, with the anterior rectus sheath incision reduced from the conventional 12 cm to 5 cm. Flap ischemia lasted 50 minutes. The patient was discharged on postoperative day 5. This anatomical study and first successful laparoscope-assisted DIEP flap harvest prove that reduced trauma to the anterior rectus sheath is feasible and promising. PMID- 28915212 TI - 22 Cases of BIA-ALCL: Awareness and Outcome Tracking from the Italian Ministry of Health. AB - BACKGROUND: To date, 359 cases of anaplastic large cell lymphoma in women with breast implants (BIA-ALCL) worldwide have been reported out of more than 10 million implanted patients but Health Care Authorities suspect this is a possible underestimation and the limited number of cases makes it difficult to clarify its etiology. The General Directorate of Medical Devices and Pharmaceutical Services of the Italian Ministry of Health (IMoH) has examined and studied the Italian BIA ALCL cases, and the aim of this study is to report on the knowledge and experience gained on this new emerging disease. PATIENTS AND METHODS: An official document has been diffused by the IMoH to all the Italian medical associations, aiming at encouraging all physicians to notify each BIA-ALCL case through the compilation of a specific on-line form. A retrospective study has been performed on the notified BIA-ALCL cases collected in the IMoH's database named DISPOVIGILANCE. RESULTS: Research on DISPOVIGILANCE gives back a list of 22 Italian BIA-ALCL cases. The patients' mean age was 49.6 years (range 30 -71). The average time to the onset of the symptoms was 6.8 years (range 1-22). The average time to the diagnosis was 7.8 years (range 4 -22). The estimated incidence of the Italian BIA-ALCL cases related to 2015 is 2.8 per 100.000 patients. CONCLUSIONS: The BIA-ALCL pathogenesis remains unknown. The Italian Ministry of Health, together with scientific associations and other Competent Authorities worldwide, is working on the BIA-ALCL issue to increase awareness and knowledge of this disease by healthcare professionals. PMID- 28915213 TI - What's New in SHOCK October 2017? PMID- 28915214 TI - Non-Hemodynamic Effects of Catecholamines. AB - Circulatory shock is defined as an imbalance between tissue oxygen supply and demand, and mostly results from a loss of blood volume, cardiac pump failure, and/or reduction of vasomotor tone. The clinical hallmarks of circulatory shock are arterial hypotension and lactate acidosis. Since the degree and duration of hypotension are major determinants of outcome, vasopressor administration represents a cornerstone therapy to treat these patients. Current guidelines recommend the use of catecholamines as the drug of first choice. However, apart from their hemodynamic effects, which depend on the different receptor profile, receptor affinity, receptor density, and the relative potency of the individual molecule, catecholamines have numerous other biological effects as a result of the ubiquitous presence of their receptors. In shock states, catecholamines aggravate hypermetabolism by promoting hyperglycemia and hyperlactatemia, and further increase oxygen demands, which can contribute to further organ damage. In the mitochondria, catecholamines may promote mitochondrial uncoupling, and aggravate oxidative stress, thereby contributing to the progression of mitochondrial dysfunction. Immunological side effects have also gained specific attention. Although both pro- and anti-inflammatory effects have been described, current evidence strongly indicates an immunosuppressive effect, thereby making patients potentially vulnerable to secondary infections. Catecholamines may not only decrease splanchnic perfusion due to their vasoconstrictor properties, but can also directly impair gastrointestinal motility. This article reviews the non hemodynamic effects of different catecholamines, both under physiologic and pathophysiologic conditions, with a special focus on energy metabolism, mitochondrial function, immune response, and the gastrointestinal system. PMID- 28915215 TI - Mechanisms Involved in Secondary Cardiac Dysfunction in Animal Models of Trauma and Hemorrhagic Shock. AB - Clinical evidence reveals the existence of a trauma-induced secondary cardiac injury (TISCI) that is associated with poor patient outcomes. The mechanisms leading to TISCI in injured patients are uncertain. Conversely, animal models of trauma hemorrhage have repeatedly demonstrated significant cardiac dysfunction following injury, and highlighted mechanisms through which this might occur. The aim of this review was to provide an overview of the animal studies describing TISCI and its pathophysiology.Basic science models of trauma show evidence of innate immune system activation via Toll-like receptors, the exact protagonists of which remain unclear. Shortly following trauma and hemorrhage, cardiomyocytes upregulate gene regulatory protein and inflammatory molecule expression including nuclear factor kappa beta, tumor necrosis factor alpha, and interleukin-6. This is associated with expression of membrane bound adhesion molecules and chemokines leading to marked myocardial leukocyte infiltration. This cell activation and infiltration is linked to a rise in enzymes that cause oxidative and nitrative stress and subsequent protein misfolding within cardiomyocytes. Such protein damage may lead to reduced contractility and myocyte apoptosis. Other molecules have been identified as cardioprotective following injury. These include p38 mitogen-activated protein kinases and heat shock proteins.The balance between increasing damaging mediators and a reduction in cardio-protective molecules appears to define myocardial function following trauma. Exogenous therapeutics have been trialled in rodents with promising abilities to favorably alter this balance, and subsequently lead to improved cardiac function. PMID- 28915216 TI - Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked in vivo Using Molecular Imaging. AB - Inhaled hydrogen gas (H2) provides protection in rat models of human acute lung injury (ALI). We previously reported that biomarker imaging can detect oxidative stress and endothelial cell death in vivo in a rat model of ALI. Our objective was to evaluate the ability of Tc-hexamethylpropyleneamineoxime (HMPAO) and Tc duramycin to track the effectiveness of H2 therapy in vivo in the hyperoxia rat model of ALI. Rats were exposed to room air (normoxia), 98% O2 + 2% N2 (hyperoxia) or 98% O2 + 2% H2 (hyperoxia+H2) for up to 60 h. In vivo scintigraphy images were acquired following injection of Tc-HMPAO or Tc-duramycin. For hyperoxia rats, Tc-HMPAO and Tc-duramycin lung uptake increased in a time dependent manner, reaching a maximum increase of 270% and 150% at 60 h, respectively. These increases were reduced to 120% and 70%, respectively, in hyperoxia+H2 rats. Hyperoxia exposure increased glutathione content in lung homogenate (36%) more than hyperoxia+H2 (21%), consistent with increases measured in Tc-HMPAO lung uptake. In 60-h hyperoxia rats, pleural effusion, which was undetectable in normoxia rats, averaged 9.3 gram/rat, and lung tissue 3 nitrotyrosine expression increased by 790%. Increases were reduced by 69% and 59%, respectively, in 60-h hyperoxia+H2 rats. This study detects and tracks the anti-oxidant and anti-apoptotic properties of H2 therapy in vivo after as early as 24 h of hyperoxia exposure. The results suggest the potential utility of these SPECT biomarkers for in vivo assessment of key cellular pathways in the pathogenesis of ALI and for monitoring responses to therapies. PMID- 28915217 TI - Estradiol Modulates Local Gut Injury Induced by Intestinal Ischemia-Reperfusion in Male Rats. AB - Intestinal ischemia and reperfusion (I/R) triggers a systemic inflammatory response characterized by leukocyte mobilization from the bone marrow, release of cytokines to the circulation, and increased microvascular permeability, leading to high mortality. Females have shown attenuated inflammatory response to trauma when compared with males, indicating a role for female sex hormones in this process. Here, we have evaluated the effect of estradiol on the local gut injury induced by I/R in male rats. I/R was induced by the clamping of the superior mesenteric artery for 45 min, followed by 2 h of reperfusion. A group received 17beta-estradiol (280 MUg/kg, i.v., single dose) at 30 min of ischemia. Morphometric analysis of the gut showed I/R induced a reduction of villous height that was prevented by estradiol. White blood cells, notably granulocytes, were mobilized from the circulation to the intestine by I/R, which was also prevented by estradiol treatment. Groups had the intestine wrapped in a plastic bag to collect intestinal fluid, where leukocytes count, TNF-alpha, and IL-10 levels were increased by I/R. Serum chemokines (CINC-1, MIP-1alpha, MIP-2), ICAM-1 expression in the mesenteric tissue, and neutrophils spontaneous migration measured in vitro were also increased after I/R. Estradiol treatment reduced leukocytes numbers and TNF-alpha on intestinal fluid, serum chemokine release and also downregulated MIP-1alpha, MIP-2 gene expression, and spontaneous in vitro neutrophil migration. In conclusion, estradiol blunts intestinal injury induced by I/R by modulating chemokines release and leukocyte trafficking. PMID- 28915218 TI - Endotoxemia Results in Trapping of Transfused Red Blood Cells in Lungs with Associated Lung Injury. AB - BACKGROUND: Red blood cell (RBC) transfusion is associated with organ failure, in particular in the critically ill. We hypothesized that endotoxemia contributes to increased trapping of RBCs in organs. Furthermore, we hypothesized that this effect is more pronounced following transfusion of stored RBCs compared with fresh RBCs. METHODS: Adult male Sprague-Dawley rats were randomized to receive injection with lipopolysaccharide from E coli or vehicle and transfusion with fresh or stored biotinylated RBCs. After 24 h, the amount of biotinylated RBCs in organs was measured by flow cytometry, as well as the 24-h post-transfusion recovery. Markers of organ injury and histopathology of organs were assessed. RESULTS: Endotoxemia resulted in systemic inflammation and organ injury. Following RBC transfusion, donor RBCs were recovered from the lung and kidney of endotoxemic recipients (1.2 [0.8-1.6]% and 2.2 [0.4-4.4]% of donor RBCs respectively), but not from organs of healthy recipients. Trapping of donor RBCs in the lung was associated with increased lung injury, but not with kidney injury. Stored RBCs induced organ injury in the spleen and yielded a lower 24-h post-transfusion recovery, but other effects of storage time were limited. CONCLUSION: Endotoxemia results in an increased percentage of donor RBCs recovered from the lung and kidney, which is associated with lung injury following transfusion. PMID- 28915219 TI - Intrabronchial Catheter Resuscitation for Respiratory and Cardiorespiratory Arrest. AB - INTRODUCTION: We sought to determine whether intrabronchial oxygenation would provide adequate gas exchange during both anesthesia induced apneic and cardiopulmonary arrest and cardiac massage (CPR). METHODS: Ten pigs underwent general anesthesia with mechanical ventilation. Blood gases were measured in each animal at 4 min intervals for up to 28 min. An intrabronchial catheter (4 L/min O2) was inserted through an endotracheal tube after respirator cessation. Group A animals (6) were resuscitated with the catheter but without CPR. Group B animals (4) were rendered apneic and cardioplegic and resuscitated by CPR for 28 min using the intrabronchial device. RESULTS: All group A animals were resuscitated and survived after 24 min of apnea. Mean pO2 decreased from 378 mmHg (95% confidence interval [CI], 288-468) to 292 mmHg (95% CI, 246-339), P = 0.009; pCO2 increased from 52 mmHg (95% CI, 43-61) to 137 mmHg (95% CI, 116-158), P < 0.0001; and pH decreased from 7.32 (7.29-7.36) to 6.98 (6.92-7.03), P < 0.0001. In a control animal bronchial catheter oxygen flow ceased at baseline and pO2 decreased from 268 to 30 mmHg by 20 min. In group B animals mean pO2 decreased from 426 mmHg (95% CI, 273-579) to 130 mmHg (95% CI, 92-168) after 28 min, P < 0.0001; pCO2 increased from 49 mmHg (95% CI, 41-58) to 73 mmHg (95% CI, 61-86), P = 0.03; and pH decreased from 7.34 (7.33-7.35) to 7.07 (6.98-7.16), P < 0.0001. In the control receiving intratracheal oxygen pO2 decreased from 324 to 88 mmHg after 16 minu of CPR. CONCLUSIONS: Intrabronchial oxygenation provides sustained hyperoxemia during complete apnea and cardiac arrest with CPR. PMID- 28915220 TI - Predicting the Severity of Acute Pancreatitis With Red Cell Distribution Width at Early Admission Stage. AB - Red cell distribution width (RDW) has been proposed as an early prognosis marker with increased mortality in variety of pathophysiological conditions. We hypothesized that elevated RDW could be used in judging the severity of acute pancreatitis (AP). We retrospectively and prospectively studied 545 and 72 AP patients, who were admitted to the Shanghai Tenth People's Hospital of Tongji University, respectively. Compared with mild acute pancreatitis, significantly higher RDW was observed in patients with moderately severe acute pancreatitis and sever acute pancreatitis (14.03 +/- 1.74% vs. 13.23 +/- 1.23%, P < 0.000). RDW values were also found positively correlated with the patient's blood urea nitrogen (r = 0.120, P = 0.026), creatinine (r = 0.182, P = 0.000), age (r = 0.099, P = 0.028), and bedside index of severity in acute pancreatitis scoring system (r = 0.147, P = 0.001), and were negatively correlated with the serum albumin (r = -0.244, P = 0.000). The area under the receiver-operating characteristics was as follows-RDW: 0.677 (95% confidence interval [CI], 0.619 0.735, P < 0.000); combination of RDW and albumin: 0.693 (95% CI, 0.625-0.761, P < 0.000); and the optimal cutoff value for RDW to predict whether patients with AP should be in intensive care unit (ICU) was 13.55 with a sensitivity of 54.5% and a specificity of 73.6%. In the validation study, AP with RDW >= 13.55% had significantly higher ICU admission ratio than those with RDW < 13.55% (44.4% vs. 9.8%, P < 0.000). In conclusion, RDW is positively associated with AP severity, and is likely a useful predictive parameter of AP severity. PMID- 28915221 TI - Metformin Exerts Beneficial Effects in Hemorrhagic Shock in An AMPKalpha1 Independent Manner. AB - Despite therapeutic advances in hemorrhagic shock, mortality from multiple organ failure remains high. AMP-activated protein kinase (AMPK) is involved in cellular energy homeostasis. Two catalytic subunits, alpha1 and alpha2, have been identified, with alpha1 subunit largely expressed in major organs. Here, we hypothesized that genetic deficiency of AMPKalpha1 worsens hemorrhage-induced multiple organ failure. We also investigated whether treatment with metformin, a clinically used drug for metabolic homeostasis, affords beneficial effects. AMPKalpha1 wild-type (WT) and knock-out mice (KO) were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with shed blood and Lactated Ringer's solution and treatment with vehicle or metformin. Mice were sacrificed at 3 h after resuscitation. Compared with vehicle-treated WT animals, KO animals exhibited a more severe hypotension, higher lung and liver injury and neutrophil infiltration, and higher levels of plasma inflammatory cytokines. Metformin treatment ameliorated organ injury and mean arterial blood pressure in both WT and KO mice, without affecting systemic cytokine levels. Furthermore, metformin treatment reduced liver lipid peroxidation and increased levels of complex II cosubstrate FAD and levels of ATP in WT and KO mice. Beneficial effects of metformin were associated with organ-specific nuclear-cytoplasmic shuttling and activation of liver kinase B1 and AMPKalpha2. Thus, our data suggest that AMPKalpha1 is an important regulator of hemodynamic stability and organ metabolic recovery during hemorrhagic shock. Our data also suggest that metformin affords beneficial effects, at least in part, independently of AMPKalpha1 and secondary to AMPKalpha2 activation, increase of Complex II function and reduction of oxidative stress. PMID- 28915222 TI - Effect of Goal Setting Using a Visual Display on Patient Quality of Life and Self efficacy. PMID- 28915223 TI - Quality Measures: A Stakeholder Analysis. AB - For quality measures, confusion and discontentment have increased, as availability of electronic data and data collection tools has expanded. We examined current issues with quality measures across 4 stakeholder groups: developers, regulators/endorsers, data collectors, and consumer advocates. There are missing quality measures, issues with data quality and purpose, questionable usability of electronic health records, and an increased measurement burden and cost. Policymakers, administrators, health care professionals, and consumers need to collaborate on measure development and selection. PMID- 28915224 TI - Systolic and Diastolic Left Ventricular Mechanics during and after Resistance Exercise. AB - PURPOSE: To improve the current understanding of the impact of resistance exercise on the heart, by examining the acute responses of left ventricular (LV) strain, twist, and untwisting rate ("LV mechanics"). METHODS: LV echocardiographic images were recorded in systole and diastole before, during and immediately after (7-12 s) double-leg press exercise at two intensities (30% and 60% of maximum strength, one-repetition maximum). Speckle tracking analysis generated LV strain, twist, and untwisting rate data. Additionally, beat-by-beat blood pressure was recorded and systemic vascular resistance (SVR) and LV wall stress were calculated. RESULTS: Responses in both exercise trials were statistically similar (P > 0.05). During effort, stroke volume decreased, whereas SVR and LV wall stress increased (P < 0.05). Immediately after effort, stroke volume returned to baseline, whereas SVR and wall stress decreased (P < 0.05). Similarly, acute exercise was accompanied by a significant decrease in systolic parameters of LV muscle mechanics (P < 0.05). However, diastolic parameters, including LV untwisting rate, were statistically unaltered (P > 0.05). Immediately after exercise, systolic LV mechanics returned to baseline levels (P < 0.05) but LV untwisting rate increased significantly (P < 0.05). CONCLUSIONS: A single, acute bout of double-leg press resistance exercise transiently reduces systolic LV mechanics, but increases diastolic mechanics after exercise, suggesting that resistance exercise has a differential impact on systolic and diastolic heart muscle function. The findings may explain why acute resistance exercise has been associated with reduced stroke volume but chronic exercise training may result in increased LV volumes. PMID- 28915225 TI - Physical Activity, Not Sedentary Time, Predicts Dual-Energy X-ray Absorptiometry measured Adiposity Age 5 to 19 Years. AB - PURPOSE: To examine the associations among physical activity (PA), sedentary time (SED), and TV viewing (TV) with fat mass (FAT) and visceral adipose tissue mass (VAT) from childhood through adolescence (5-19 yr). METHODS: Participants in the Iowa Bone Development Study (n = 230 males and 233 females) were examined at ages 5, 8, 11, 13, 15, 17, and 19 yr. Accelerometers measured moderate- or vigorous intensity PA (MVPA; min.d), light-intensity PA (LPA; min.d), and SED (h.d). Parent-proxy report (5 and 8 yr) and child-report (11, 13, 15, 17, and 19 yr) measured TV (h.d). X-ray absorptiometry scans measured FAT (kg) and VAT (g). Sex specific growth models were used to create FAT and VAT growth curves for individual participants (level 1), and to test the effect of MVPA, LPA, SED, and TV (level 2) after adjusting for weight, height, linear age, nonlinear age, and maturity. RESULTS: Growth models indicated that low levels of MVPA were associated with high levels of FAT and VAT for males and high levels of FAT for females. TV viewing was positively associated with FAT and VAT for males and females. LPA was positively associated with FAT in males. Sedentary time was not associated with FAT or VAT for males or females (P > 0.05). CONCLUSIONS: This study supports current PA guidelines focusing on MVPA rather than SED. The contribution of high TV, but not high SED, to high levels of adiposity suggests that TV's contribution to obesity is not just a function of low energy expenditure. PMID- 28915227 TI - Dietary sodium intake among US adults with hypertension, 1999-2012. AB - OBJECTIVE: Excess sodium consumption has strong links with hypertension and cardiovascular disease with Food and Drug Association calling to limit sodium intake. However, little is known regarding the trends of sodium intake among hypertensive patients in the United States. METHODS: Data from The National Health and Nutrition Examination Survey (1999-2012) were used to identify adults older than 20 years with self-reported hypertension. Sodium intake was measured through 24-h dietary recall. Linear regression was used to assess the time trends of sodium intake. RESULTS: Between the years of 1999 and 2012, sodium consumption increased 14.2% among all adults with hypertension (P = 0.012). The increase was seen in both sexes (by 13.3%, P = 0.023 for male, and by 12.1%, P = 0.015 for female). A significant increase was seen in the amount of sodium consumption among Hispanic (by 26.2%, P = 0.021) and African-American (by 20%, P = 0.031) participants, but not among non-Hispanic whites (by 2%, P = 0.096) during the study period. Participants with higher level of education (3487 +/- 1678 vs. 3230 +/- 1785 mg, P = 0.002) and household income (3527 +/- 1770 vs. 3301 +/- 1726 mg, P = 0.009) were found to consume more sodium, which remained significant after adjustment for age. CONCLUSION: Sodium intake has increased over the last two decades among individuals with hypertension. The increase was especially marked for Hispanics and African-Americans. Improved population-based interventions, including more effective strategies and aggressive approaches to reduce the sodium consumption among hypertensive adults, are needed. PMID- 28915226 TI - Pulmonary Vascular Function and Aerobic Exercise Capacity at Moderate Altitude. AB - PURPOSE: There has been suggestion that a greater "pulmonary vascular reserve" defined by a low pulmonary vascular resistance (PVR) and a high lung diffusing capacity (DL) allow for a superior aerobic exercise capacity. How pulmonary vascular reserve might affect exercise capacity at moderate altitude is not known. METHODS: Thirty-eight healthy subjects underwent an exercise stress echocardiography of the pulmonary circulation, combined with measurements of DL for nitric oxide (NO) and carbon monoxide (CO) and a cardiopulmonary exercise test at sea level and at an altitude of 2250 m. RESULTS: At rest, moderate altitude decreased arterial oxygen content (CaO2) from 19.1 +/- 1.6 to 18.4 +/- 1.7 mL.dL, P < 0.001, and slightly increased PVR, DLNO, and DLCO. Exercise at moderate altitude was associated with decreases in maximum O2 uptake (VO2max), from 51 +/- 9 to 43 +/- 8 mL.kg?min, P < 0.001, and CaO2 to 16.5 +/- 1.7 mL.dL, P < 0.001, but no different cardiac output, PVR, and pulmonary vascular distensibility. DLNO was inversely correlated to the ventilatory equivalent of CO2 (VE/VCO2) at sea level and at moderate altitude. Independent determinants of VO2max as determined by a multivariable analysis were the slope of mean pulmonary artery pressure-cardiac output relationship, resting stroke volume, and resting DLNO at sea level as well as at moderate altitude. The magnitude of the decrease in VO2max at moderate altitude was independently predicted by more pronounced exercise-induced decrease in CaO2 at moderate altitude. CONCLUSION: Aerobic exercise capacity is similarly modulated by pulmonary vascular reserve at moderate altitude and at sea level. Decreased aerobic exercise capacity at moderate altitude is mainly explained by exercise-induced decrease in arterial oxygenation. PMID- 28915228 TI - Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. AB - BACKGROUND: The study aimed to analyze genes involved in Mendelian forms of low renin hypertension in Chinese early-onset hypertensive patients. METHODS: A panel of nine genes, namely SCNN1B, SCNN1G, WNK1, WNK4, KLHL3, CUL3, nuclear receptor subfamily 3, group C (NR3C)1, NR3C2, and HSD11B2 were screened by targeted resequencing in 260 Chinese early-onset hypertensive patients. Additionally, exon 13 of both SCNN1B and SCNN1G was sequenced in an independent cohort of 506 Chinese early-onset hypertensive patients. RESULTS: About 81 nonrare and 41 rare variants were, respectively, detected in 221 (85.0%) and 39 (15.0%) patients from the cohort of 260. Of the total 766 patients, those with rare variants in exon 13 of either SCNN1B or SCNN1G had a significantly earlier onset of hypertension (24.7 +/- 7.5 vs. 29.0 +/- 7.7 years, P = 0.015) and lower serum potassium (3.57 +/- 0.59 vs. 3.96 +/- 0.41 mmol/l, P = 0.007) than those without rare variants. However, other identified rare variants had no effects on clinical expression. Seven patients (0.91%) were diagnosed with Liddle's syndrome, and the Liddle's syndrome prevalence was 1.72% among the 407 patients with hypertension diagnosed before the age of 30. Genetic screening of the probands' relatives identified 10 additional Liddle's syndrome patients. Treatment of Liddle's syndrome patients with amiloride resulted in normalization of both blood pressure and serum potassium. CONCLUSION: Liddle's syndrome appears to be the most common low-renin Mendelian hypertension in young Chinese hypertensive patients. Sequencing exon 13 of both SCNN1B and SCNN1G is highly advisable in patients with early-onset and low-renin hypertension. PMID- 28915229 TI - The optimal night-time home blood pressure monitoring schedule: agreement with ambulatory blood pressure and association with organ damage. AB - OBJECTIVE: Night-time home blood pressure (HBP) monitoring has emerged as a feasible, reliable and low-cost alternative to ambulatory blood pressure (ABP) monitoring. This study evaluated the optimal schedule of night-time HBP monitoring in terms of agreement with night-time ABP and association with preclinical target-organ damage. METHODS: Untreated hypertensive adults were evaluated with ABP (24-h) and HBP monitoring (daytime: six days, duplicate morning and evening measurements; night-time: three nights, three-hourly automated measurements/night), and determination of left ventricular mass index, common carotid intima-media thickness and urinary albumin excretion. RESULTS: A total of 94 patients with all nine night-time HBP measurements were analysed [mean age 51.8 +/- 11.1 (SD) years, men 57%). By averaging an increasing number of night-time systolic HBP readings, there was a consistent trend towards stronger association of night-time HBP with night-time ABP (correlation coefficients r increased from 0.69 to 0.81), and with target-organ damage indices (for left ventricular mass index r increased from 0.13 to 0.22, carotid intima media thickness 0.12-0.25, urinary albumin excretion 0.33-0.41). However, no further improvement in the association was observed by averaging more than four to six night-time readings. The diagnostic agreement between HBP and ABP in detecting nondippers was improved by averaging more readings, with a plateau at four readings (single reading: agreement 81%, kappa 0.37; four readings: 88%, 0.49; nine readings: 84%, 0.40). CONCLUSION: A two-night HBP schedule (six readings) appears to be the minimum requirement for a reliable assessment of night-time HBP, which gives reasonable agreement with ABP and association with preclinical organ damage. PMID- 28915230 TI - Albuminuria and Endothelial Dysfunction in Patients with Non-Diabetic Chronic Kidney Disease. AB - BACKGROUND Albuminuria has been associated with cardiovascular events, but whether such an association can be explained by endothelial dysfunction is not fully understood. In this study, we examined the relationship between the urine albumin-to-creatinine ratio (UACR) and biomarkers of endothelial function in patients with chronic kidney disease (CKD). MATERIAL AND METHODS The cross sectional associations of renal dysfunction and UACR with procoagulant and inflammatory factors were evaluated for 151 consecutive CKD (stage 3-5) patients. Subjects were grouped by UACR (<=300 mg/g or >300 mg/g) and estimated glomerular filtration rate (eGFR) (30<= eGFR <60, 15<= eGFR <30, or eGFR <15 ml/min per 1.73 m2). RESULTS A higher UACR level was associated with an increase in von Willebrand factor antigen (vWF: Ag) levels, vWF activity, factor VIII, interleukin-2, and log (interleukin-6), even after adjustment for risk factors. Linear regression analysis indicated that for every 88.5 mg/g increase in UACR, the vWF activity and factor VIII were elevated by 8.3% and 6.3%, respectively. The factorial design ANOVA data showed no statistically significant interaction between UACR and CKD stage with procoagulant and inflammatory factors. CONCLUSIONS Our study shows an eGFR-independent association of higher UACR with elevations in markers of endothelial dysfunction and inflammatory factors in CKD patients. PMID- 28915231 TI - Postnatal polyunsaturated fatty acids associated with larger preterm brain tissue volumes and better outcomes. AB - BackgroundHuman studies investigating the link between postnatal polyunsaturated fatty acids and preterm brain growth are limited, despite emerging evidence of potential effects on outcomes.MethodsSixty preterm neonates <32 weeks gestational age with magnetic resonance imaging (MRI) scanning at near-birth and near-term age were assessed for brain tissue volumes, including cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and ventricular cerebrospinal fluid. Red blood cell fatty acid content was evaluated within 1 week of each MRI scan. Neurodevelopmental outcome at 30-36 months corrected age was assessed.ResultsAdjusting for potential confounders, higher near-birth docosahexaenoic acid levels are associated with larger cortical gray matter, deep gray matter, and brainstem volumes and higher near-term levels with larger deep gray matter, cerebellar, and brainstem volumes at near-term age; lower near-birth linoleic acid levels are correlated with larger white matter volume at near-term age. By 30-36 months corrected age, larger cortical and deep gray matter, cerebellar, and brainstem volumes by term age are associated with improved language scores and larger cerebellar and brainstem volumes with improved motor scores.ConclusionSpecific polyunsaturated fatty acid levels have differential and time-dependent associations with brain region growth. Larger brain volumes are associated with improved outcomes at preschool age. PMID- 28915232 TI - Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns. AB - BackgroundThis study aimed to investigate the effect of nutrition and growth during the first 4 weeks after birth on cerebral volumes and white matter maturation at term equivalent age (TEA) and on neurodevelopmental outcome at 2 years' corrected age (CA), in preterm infants.MethodsOne hundred thirty-one infants born at a gestational age (GA) <31 weeks with magnetic resonance imaging (MRI) at TEA were studied. Cortical gray matter (CGM) volumes, basal ganglia and thalami (BGT) volumes, cerebellar volumes, and total brain volume (TBV) were computed. Fractional anisotropy (FA) in the posterior limb of internal capsule (PLIC) was obtained. Cognitive and motor scores were assessed at 2 years' CA.ResultsCumulative fat and enteral intakes were positively related to larger cerebellar and BGT volumes. Weight gain was associated with larger cerebellar, BGT, and CGM volume. Cumulative fat and caloric intake, and enteral intakes were positively associated with FA in the PLIC. Cumulative protein intake was positively associated with higher cognitive and motor scores (all P<0.05).ConclusionOur study demonstrated a positive association between nutrition, weight gain, and brain volumes. Moreover, we found a positive relationship between nutrition, white matter maturation at TEA, and neurodevelopment in infancy. These findings emphasize the importance of growth and nutrition with a balanced protein, fat, and caloric content for brain development. PMID- 28915233 TI - The utility of stem cells in pediatric urinary bladder regeneration. AB - Pediatric patients with a neurogenic urinary bladder, caused by developmental abnormalities including spina bifida, exhibit chronic urological problems. Surgical management in the form of enterocystoplasty is used to enlarge the bladder, but is associated with significant clinical complications. Thus, alternative methods to enterocystoplasty have been explored through the incorporation of stem cells with tissue engineering strategies. Within the context of this review, we will examine the use of bone marrow stem cells and induced pluripotent stem cells (iPSCs), as they relate to bladder regeneration at the anatomic and molecular levels. The use of bone marrow stem cells has demonstrated significant advances in bladder tissue regeneration as multiple aspects of bladder tissue have been recapitulated including the urothelium, bladder smooth muscle, vasculature, and peripheral nerves. iPSCs, on the other hand, have been well characterized and used in multiple tissue-regenerative settings, yet iPSC research is still in its infancy with regards to bladder tissue regeneration with recent studies describing the differentiation of iPSCs to the bladder urothelium. Finally, we examine the role of the Sonic Hedgehog signaling cascade that mediates the proliferative response during regeneration between bladder smooth muscle and urothelium. Taken together, this review provides a current, comprehensive perspective on bladder regeneration. PMID- 28915234 TI - Tissue regeneration using endothelial colony-forming cells: promising cells for vascular repair. AB - Repairing and rebuilding damaged tissue in diseased human subjects remains a daunting challenge for clinical medicine. Proper vascular formation that serves to deliver blood-borne nutrients and adequate levels of oxygen and to remove wastes is critical for successful tissue regeneration. Endothelial colony-forming cells (ECFC) represent a promising cell source for revascularization of damaged tissue. ECFCs are identified by displaying a hierarchy of clonal proliferative potential and by pronounced postnatal vascularization ability in vivo. In this review, we provide a brief overview of human ECFC isolation and characterization, a survey of a number of animal models of human disease in which ECFCs have been shown to have prominent roles in tissue repair, and a summary of current challenges that must be overcome before moving ECFC into human subjects as a cell therapy. PMID- 28915235 TI - Transamniotic stem cell therapy: a novel strategy for the prenatal management of congenital anomalies. AB - Transamniotic stem cell therapy, or TRASCET, is an emerging therapeutic concept for the management of congenital anomalies based on the augmentation of the biological role of select populations of stem cells that already occur in the amniotic fluid, for targeted therapeutic benefit. Amniotic fluid-derived mesenchymal stem cells (afMSCs) have a central role in the enhanced ability of the fetus to repair tissue damage. This germane recent finding constitutes the biological foundation for the use of afMSCs in TRASCET. It has been shown experimentally that simple intra-amniotic delivery of afMSCs in large numbers can either elicit the repair, or significantly mitigate the effects associated with major congenital anomalies by boosting the activity that these cells normally have. For example, TRASCET can induce partial or complete coverage of experimental spina bifida by promoting the local formation of host-derived skin, thus protecting the spinal cord from further damage. In another example, it can significantly alleviate the bowel damage associated with gastroschisis, one of the most common major abdominal wall defects. Other applications involving different congenital anomalies and/or other stem cells present in the amniotic fluid in diseased pregnancies are currently under investigation in this freshly evolving facet of fetal stem cell therapy. PMID- 28915236 TI - Modeling antibiotic treatment in hospitals: A systematic approach shows benefits of combination therapy over cycling, mixing, and mono-drug therapies. AB - Multiple treatment strategies are available for empiric antibiotic therapy in hospitals, but neither clinical studies nor theoretical investigations have yielded a clear picture when which strategy is optimal and why. Extending earlier work of others and us, we present a mathematical model capturing treatment strategies using two drugs, i.e the multi-drug therapies referred to as cycling, mixing, and combination therapy, as well as monotherapy with either drug. We randomly sample a large parameter space to determine the conditions determining success or failure of these strategies. We find that combination therapy tends to outperform the other treatment strategies. By using linear discriminant analysis and particle swarm optimization, we find that the most important parameters determining success or failure of combination therapy relative to the other treatment strategies are the de novo rate of emergence of double resistance in patients infected with sensitive bacteria and the fitness costs associated with double resistance. The rate at which double resistance is imported into the hospital via patients admitted from the outside community has little influence, as all treatment strategies are affected equally. The parameter sets for which combination therapy fails tend to fall into areas with low biological plausibility as they are characterised by very high rates of de novo emergence of resistance to both drugs compared to a single drug, and the cost of double resistance is considerably smaller than the sum of the costs of single resistance. PMID- 28915237 TI - DNA replication stress restricts ribosomal DNA copy number. AB - Ribosomal RNAs (rRNAs) in budding yeast are encoded by ~100-200 repeats of a 9.1kb sequence arranged in tandem on chromosome XII, the ribosomal DNA (rDNA) locus. Copy number of rDNA repeat units in eukaryotic cells is maintained far in excess of the requirement for ribosome biogenesis. Despite the importance of the repeats for both ribosomal and non-ribosomal functions, it is currently not known how "normal" copy number is determined or maintained. To identify essential genes involved in the maintenance of rDNA copy number, we developed a droplet digital PCR based assay to measure rDNA copy number in yeast and used it to screen a yeast conditional temperature-sensitive mutant collection of essential genes. Our screen revealed that low rDNA copy number is associated with compromised DNA replication. Further, subculturing yeast under two separate conditions of DNA replication stress selected for a contraction of the rDNA array independent of the replication fork blocking protein, Fob1. Interestingly, cells with a contracted array grew better than their counterparts with normal copy number under conditions of DNA replication stress. Our data indicate that DNA replication stresses select for a smaller rDNA array. We speculate that this liberates scarce replication factors for use by the rest of the genome, which in turn helps cells complete DNA replication and continue to propagate. Interestingly, tumors from mini chromosome maintenance 2 (MCM2)-deficient mice also show a loss of rDNA repeats. Our data suggest that a reduction in rDNA copy number may indicate a history of DNA replication stress, and that rDNA array size could serve as a diagnostic marker for replication stress. Taken together, these data begin to suggest the selective pressures that combine to yield a "normal" rDNA copy number. PMID- 28915239 TI - Structural basis for the high specificity of a Trypanosoma congolense immunoassay targeting glycosomal aldolase. AB - BACKGROUND: Animal African trypanosomosis (AAT) is a neglected tropical disease which imposes a heavy burden on the livestock industry in Sub-Saharan Africa. Its causative agents are Trypanosoma parasites, with T. congolense and T. vivax being responsible for the majority of the cases. Recently, we identified a Nanobody (Nb474) that was employed to develop a homologous sandwich ELISA targeting T. congolense fructose-1,6-bisphosphate aldolase (TcoALD). Despite the high sequence identity between trypanosomatid aldolases, the Nb474-based immunoassay is highly specific for T. congolense detection. The results presented in this paper yield insights into the molecular principles underlying the assay's high specificity. METHODOLOGY/PRINCIPAL FINDINGS: The structure of the Nb474-TcoALD complex was determined via X-ray crystallography. Together with analytical gel filtration, the structure reveals that a single TcoALD tetramer contains four binding sites for Nb474. Through a comparison with the crystal structures of two other trypanosomatid aldolases, TcoALD residues Ala77 and Leu106 were identified as hot spots for specificity. Via ELISA and surface plasmon resonance (SPR), we demonstrate that mutation of these residues does not abolish TcoALD recognition by Nb474, but does lead to a lack of detection in the Nb474-based homologous sandwich immunoassay. CONCLUSIONS/SIGNIFICANCE: The results show that the high specificity of the Nb474-based immunoassay is not determined by the initial recognition event between Nb474 and TcoALD, but rather by its homologous sandwich design. This (i) provides insights into the optimal set-up of the assay, (ii) may be of great significance for field applications as it could explain the potential detection escape of certain T. congolense strains, and (iii) may be of general interest to those developing similar assays. PMID- 28915238 TI - A high resolution atlas of gene expression in the domestic sheep (Ovis aries). AB - Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of 'guilt by association' was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages. PMID- 28915240 TI - Improved reliability of serological tools for the diagnosis of West Nile fever in horses within Europe. AB - West Nile Fever is a zoonotic disease caused by a mosquito-borne flavivirus, WNV. By its clinical sensitivity to the disease, the horse is a useful sentinel of infection. Because of the virus' low-level, short-term viraemia in horses, the primary tools used to diagnose WNV are serological tests. Inter-laboratory proficiency tests (ILPTs) were held in 2010 and 2013 to evaluate WNV serological diagnostic tools suited for the European network of National Reference Laboratories (NRLs) for equine diseases. These ILPTs were designed to evaluate the laboratories' and methods' performances in detecting WNV infection in horses through serology. The detection of WNV immunoglobulin G (IgG) antibodies by ELISA is widely used in Europe, with 17 NRLs in 2010 and 20 NRLs in 2013 using IgG WNV assays. Thanks to the development of new commercial IgM capture kits, WNV IgM capture ELISAs were rapidly implemented in NRLs between 2010 (4 NRLs) and 2013 (13 NRLs). The use of kits allowed the quick standardisation of WNV IgG and IgM detection assays in NRLs with more than 95% (20/21) and 100% (13/13) of satisfactory results respectively in 2013. Conversely, virus neutralisation tests (VNTs) were implemented in 33% (7/21) of NRLs in 2013 and their low sensitivity was evidenced in 29% (2/7) of NRLs during this ILPT. A comparison of serological diagnostic methods highlighted the higher sensitivity of IgG ELISAs compared to WNV VNTs. They also revealed that the low specificity of IgG ELISA kits meant that it could detect animals infected with other flaviviruses. In contrast VNT and IgM ELISA assays were highly specific and did not detect antibodies against related flaviviruses. These results argue in favour of the need for and development of new, specific serological diagnostic assays that could be easily transferred to partner laboratories. PMID- 28915241 TI - The relative contribution of DNA methylation and genetic variants on protein biomarkers for human diseases. AB - Associations between epigenetic alterations and disease status have been identified for many diseases. However, there is no strong evidence that epigenetic alterations are directly causal for disease pathogenesis. In this study, we combined SNP and DNA methylation data with measurements of protein biomarkers for cancer, inflammation or cardiovascular disease, to investigate the relative contribution of genetic and epigenetic variation on biomarker levels. A total of 121 protein biomarkers were measured and analyzed in relation to DNA methylation at 470,000 genomic positions and to over 10 million SNPs. We performed epigenome-wide association study (EWAS) and genome-wide association study (GWAS) analyses, and integrated biomarker, DNA methylation and SNP data using between 698 and 1033 samples depending on data availability for the different analyses. We identified 124 and 45 loci (Bonferroni adjusted P < 0.05) with effect sizes up to 0.22 standard units' change per 1% change in DNA methylation levels and up to four standard units' change per copy of the effective allele in the EWAS and GWAS respectively. Most GWAS loci were cis regulatory whereas most EWAS loci were located in trans. Eleven EWAS loci were associated with multiple biomarkers, including one in NLRC5 associated with CXCL11, CXCL9, IL-12, and IL-18 levels. All EWAS signals that overlapped with a GWAS locus were driven by underlying genetic variants and three EWAS signals were confounded by smoking. While some cis-regulatory SNPs for biomarkers appeared to have an effect also on DNA methylation levels, cis-regulatory SNPs for DNA methylation were not observed to affect biomarker levels. We present associations between protein biomarker and DNA methylation levels at numerous loci in the genome. The associations are likely to reflect the underlying pattern of genetic variants, specific environmental exposures, or represent secondary effects to the pathogenesis of disease. PMID- 28915242 TI - A retrospective cost-analysis of additional homeopathic treatment in Germany: Long-term economic outcomes. AB - OBJECTIVES: This study aimed to provide a long-term cost comparison of patients using additional homeopathic treatment (homeopathy group) with patients using usual care (control group) over an observation period of 33 months. METHODS: Health claims data from a large statutory health insurance company were analysed from both the societal perspective (primary outcome) and from the statutory health insurance perspective (secondary outcome). To compare costs between patient groups, homeopathy and control patients were matched in a 1:1 ratio using propensity scores. Predictor variables for the propensity scores included health care costs and both medical and demographic variables. Health care costs were analysed using an analysis of covariance, adjusted for baseline costs, between groups both across diagnoses and for specific diagnoses over a period of 33 months. Specific diagnoses included depression, migraine, allergic rhinitis, asthma, atopic dermatitis, and headache. RESULTS: Data from 21,939 patients in the homeopathy group (67.4% females) and 21,861 patients in the control group (67.2% females) were analysed. Health care costs over the 33 months were 12,414 EUR [95% CI 12,022-12,805] in the homeopathy group and 10,428 EUR [95% CI 10,036 10,820] in the control group (p<0.0001). The largest cost differences were attributed to productivity losses (homeopathy: EUR 6,289 [6,118-6,460]; control: EUR 5,498 [5,326-5,670], p<0.0001) and outpatient costs (homeopathy: EUR 1,794 [1,770-1,818]; control: EUR 1,438 [1,414-1,462], p<0.0001). Although the costs of the two groups converged over time, cost differences remained over the full 33 months. For all diagnoses, homeopathy patients generated higher costs than control patients. CONCLUSION: The analysis showed that even when following-up over 33 months, there were still cost differences between groups, with higher costs in the homeopathy group. PMID- 28915243 TI - Rapid, actionable diagnosis of urban epidemic leptospirosis using a pathogenic Leptospira lipL32-based real-time PCR assay. AB - BACKGROUND: With a conservatively estimated 1 million cases of leptospirosis worldwide and a 5-10% fatality rate, the rapid diagnosis of leptospirosis leading to effective clinical and public health decision making is of high importance, and yet remains a challenge. METHODOLOGY: Based on parallel, population-based studies in two leptospirosis-endemic regions in Brazil, a real-time PCR assay which detects lipL32, a gene specifically present in pathogenic Leptospira, was assessed for the diagnostic effectiveness and accuracy. Patients identified by active hospital-based surveillance in Salvador and Curitiba during large urban leptospirosis epidemics were tested. Real-time PCR reactions were performed with DNA-extracted samples obtained from 127 confirmed and 23 unconfirmed cases suspected of leptospirosis, 122 patients with an acute febrile illness other than leptospirosis, and 60 healthy blood donors. PRINCIPAL FINDINGS: The PCR assay had a limit of detection of 280 Leptospira genomic equivalents/mL. Sensitivity for confirmed cases was 61% for whole blood and 29% for serum samples. Sensitivity was higher (86%) for samples collected within the first 6 days after onset of illness compared to those collected after 7 days (34%). The real-time PCR assay was able to detect leptospiral DNA in blood from 56% of serological non-confirmed cases. The overall specificity of the assay was 99%. CONCLUSIONS: These findings indicate that real-time PCR may be a reliable tool for early diagnosis of leptospirosis, which is decisive for clinical management of severe and life threatening cases and for public health decision making. PMID- 28915244 TI - Metacognitive monitoring and control in visual change detection: Implications for situation awareness and cognitive control. AB - Metacognitive monitoring and control of situation awareness (SA) are important for a range of safety-critical roles (e.g., air traffic control, military command and control). We examined the factors affecting these processes using a visual change detection task that included representative tactical displays. SA was assessed by asking novice observers to detect changes to a tactical display. Metacognitive monitoring was assessed by asking observers to estimate the probability that they would correctly detect a change, either after study of the display and before the change (judgement of learning; JOL) or after the change and detection response (judgement of performance; JOP). In Experiment 1, observers failed to detect some changes to the display, indicating imperfect SA, but JOPs were reasonably well calibrated to objective performance. Experiment 2 examined JOLs and JOPs in two task contexts: with study-time limits imposed by the task or with self-pacing to meet specified performance targets. JOPs were well calibrated in both conditions as were JOLs for high performance targets. In summary, observers had limited SA, but good insight about their performance and learning for high performance targets and allocated study time appropriately. PMID- 28915245 TI - Effects of GnRH vaccination in wild and captive African Elephant bulls (Loxodonta africana) on reproductive organs and semen quality. AB - OBJECTIVES: Although the African elephant (Loxodonta africana) is classified as endangered by the International Union for Conservation of Nature (IUCN), in some isolated habitats in southern Africa, contraception is of major interest due to local overpopulation. GnRH vaccination has been promoted as a non-invasive contraceptive measure for population management of overabundant wildlife. We tested the efficacy of this treatment for fertility control in elephant bulls. METHODS: In total, 17 male African elephants that were treated with a GnRH vaccine were examined in two groups. In the prospective study group 1 (n = 11 bulls, ages: 8-36 years), semen quality, the testes, seminal vesicles, ampullae and prostate, which were all measured by means of transrectal ultrasound, and faecal androgen metabolite concentrations were monitored over a three-year period. Each bull in the prospective study received 5 ml of Improvac(r) (1000 MUg GnRH conjugate) intramuscularly after the first examination, followed by a booster six weeks later and thereafter every 5-7 months. In a retrospective study group (group 2, n = 6, ages: 19-33 years), one examination was performed on bulls which had been treated with GnRH vaccine for 5-11 years. RESULTS: In all bulls of group 1, testicular and accessory sex gland sizes decreased significantly after the third vaccination. In six males examined prior to vaccination and again after more than five vaccinations, the testis size was reduced by 57.5%. Mean testicular height and length decreased from 13.3 +/- 2.6 cm x 15.2 +/- 2.8 cm at the beginning to 7.6 +/- 2.1 cm x 10.2 +/- 1.8 cm at the end of the study. Post pubertal bulls (>9 years, n = 6) examined prior to vaccination produced ejaculates with viable spermatozoa (volume: 8-175 ml, sperm concentration: 410 4000x106/ml, total motility: 0-90%), while after 5-8 injections, only 50% of these bulls produced ejaculates with a small number of immotile spermatozoa. The ejaculates of group 2 bulls (vaccinated >8 times) were devoid of spermatozoa. Faecal androgen metabolite concentrations measured in captive males decreased significantly after the fourth vaccination. None of the males entered musth during the treatment period. CONCLUSIONS: Our results showed a marked decrease in semen quality, testicle and secondary sex gland sizes following repeated GnRH vaccinations. After 2-4 years of continuous treatment every 5-7 months, the effects were similar to surgical castration. PMID- 28915247 TI - Trends and correlates of cystic echinococcosis in Chile: 2001-2012. AB - Echinococcosis is a neglected zoonotic disease affecting over 1 million people worldwide at any given time. It is the leading cause of hospital admissions for parasitic diseases in Chile. We conducted a retrospective investigation of hospitalized cases to describe the epidemiological trends of echinococcosis in Chile. We also examined the potential environmental risk factors for echinococcosis hospitalization rates. Through nation-wide hospital discharge data, a total of 11,516 hospitalized patients with cystic echinococcosis were identified between January 2001 and December 2012. The mean age of hospitalization was 40 years, with notable gender difference in pediatric patients. The hospitalization rate was found to be overall steadily decreasing from 2001 (7.02 per 100,000) to 2012 (4.53 per 100,000) with a 5% decrease per year (rate ratio = 0.95 [95% CI: 0.94, 0.96]). The hospitalization rate was higher in the south of Chile compared to the north. Goat density and intermediate precipitation were found to be significantly positively associated with the hospitalization rate while annual average temperature was found to be significantly negatively associated with the hospitalization rate. Findings of this study indicate that echinococcosis is still an important public health burden in Chile related to interaction with livestock and climate. Efforts should be placed on targeted prevention measures for farmers and raising awareness of echinococcosis among health care workers. PMID- 28915248 TI - Invasion strategy and abiotic activity triggers for non-native gobiids of the River Rhine. AB - The 24 hour activity patterns of three non-native gobiids (round goby Neogobius melanostomus, Western tubenose goby Proterorhinus semilunaris and bighead goby Ponticola kessleri) were assessed over 46 consecutive months between 2011 and 2014 from their occurrence in the cooling water intake of a nuclear power plant on the River Rhine, Germany. In total, 117717 gobiids were identified and classified. The occurrence of all three species varied strongly between sampling years, and species-specific activity triggers were identified. The activity of juveniles of all three gobiids species was positively temperature dependent while adult tubenose goby activity appeared to be negatively temperature dependent. Increasing fluvial discharge in the adjoining main river stimulated the activity of juvenile round goby but inhibited activity of adult tubenose goby. Except for adult bighead goby, activity was also structured by time of day, but with no uniform mean. Meteorological factors such as precipitation, air pressure and duration of sunshine hours had little or no influence on gobiid activity. On selected rare occasions, mainly at night, all three species exhibited pulsed swarming behaviour, with thousands of individuals recorded in the intake water. Round goby swarms exhibited both the highest intensity and the largest swarming individuals, suggesting a potential competitive advantage over tubenose and bighead goby. Electric fishing surveys in natural river stretches corroborated this observation. Negative effects on the native fish fauna were apparent only for the bullhead, Cottus gobio. The activity triggers identified offer a unique insight into the invasion mechanisms of these ecosystem-changing non-native gobiids. PMID- 28915246 TI - Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance. AB - Tumor Necrosis Factor alpha (TNF-alpha) has been shown to be released by tumor cells in response to docetaxel, and lipopolysaccharides (LPS), the latter through activation of toll-like receptor 4 (TLR4). However, it is unclear whether the former involves TLR4 receptor activation through direct binding of the drug to TLR4 at the cell surface. The current study was intended to better understand drug-induced TNF-alpha production in tumor cells, whether from short-term drug exposure or in cells selected for drug resistance. ELISAs were employed to measure cytokine release from breast and ovarian tumor cells in response to several structurally distinct chemotherapy agents and/or TLR4 agonists or antagonists. Drug uptake and drug sensitivity studies were also performed. We observed that several drugs induced TNF-alpharelease from multiple tumor cell lines. Docetaxel-induced cytokine production was distinct from that of LPS in both MyD88-positive (MCF-7) and MyD88-deficient (A2780) cells. The acquisition of docetaxel resistance was accompanied by increased constitutive production of TNF alphaand CXCL1, which waned at higher levels of resistance. In docetaxel resistant MCF-7 and A2780 cell lines, the production of TNF-alpha could not be significantly augmented by docetaxel without the inhibition of P-gp, a transporter protein that promotes drug efflux from tumor cells. Pretreatment of tumor cells with LPS sensitized MyD88-positive cells (but not MyD88-deficient) to docetaxel cytotoxicity in both drug-naive and drug-resistant cells. Our findings suggest that taxane-induced inflammatory cytokine production from tumor cells depends on the duration of exposure, requires cellular drug-accumulation, and is distinct from the LPS response seen in breast tumor cells. Also, stimulation of the LPS-induced pathway may be an attractive target for treatment of drug resistant disease. PMID- 28915249 TI - Effect of treatment with angiopoietin-2 and vascular endothelial growth factor on the quality of xenografted bovine ovarian tissue in mice. AB - Cryopreservation and transplantation of ovarian tissue (OT) represents a method for fertility preservation. However, as the transplantation is performed without vessel anastomosis, unavoidable ischemic damage occurs. To reduce this ischemic damage and improve outcomes after transplantation, we used two kind of angiogenic factors, angiopoietin-2 (ang-2) and vascular endothelial growth factor (VEGF). Fresh or vitrified-warmed bovine OTs were prepared for xenotransplantation (XT). Fresh OTs were immediately xenografted into nude mice (XT-Fresh). Vitrified warmed OTs were xenografted into four subgroups of mice, which were injected intraperitoneally before XT with saline (XT-Vitri), Ang-2 (XT-Ang-2), VEGF (XT VEGF), and a combination of Ang-2 and VEGF (XT-Combined). Seven or 28 days post grafting, grafted OTs and blood samples were collected for evaluation. Follicle normality was higher in the angiogenic factor-treated groups than in the XT-Vitri group. The XT-VEGF and the XT-Combined showed higher (P<0.05) follicular density than the XT-Vitri group. The highest apoptotic follicle ratio was observed in the XT-Vitri group on day 7; this was decreased (P<0.05) in the XT-Combined group. Microvessel densities were higher in the angiogenic factor-treated groups than in the XT-Vitri group. The largest fibrotic area was showed in the XT-Vitri group on day 28, and it was decreased (P<0.05) in the XT-combined group. Based on these results, administration of Ang-2 and VEGF to recipients prior to XT appeared to alleviate ischemic damage by enhancing angiogenesis, which resulted in the maintenance of follicle integrity and density, and reduced follicle apoptosis and OT fibrosis. PMID- 28915250 TI - Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype. AB - Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1) mutations. PTCH1 is a hedgehog (Hh) receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU) or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over *30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome. PMID- 28915251 TI - Computational analysis of network activity and spatial reach of sharp wave ripples. AB - Network oscillations of different frequencies, durations and amplitudes are hypothesized to coordinate information processing and transfer across brain areas. Among these oscillations, hippocampal sharp wave-ripple complexes (SPW-Rs) are one of the most prominent. SPW-Rs occurring in the hippocampus are suggested to play essential roles in memory consolidation as well as information transfer to the neocortex. To-date, most of the knowledge about SPW-Rs comes from experimental studies averaging responses from neuronal populations monitored by conventional microelectrodes. In this work, we investigate spatiotemporal characteristics of SPW-Rs and how microelectrode size and distance influence SPW R recordings using a biophysical model of hippocampus. We also explore contributions from neuronal spikes and synaptic potentials to SPW-Rs based on two different types of network activity. Our study suggests that neuronal spikes from pyramidal cells contribute significantly to ripples while high amplitude sharp waves mainly arise from synaptic activity. Our simulations on spatial reach of SPW-Rs show that the amplitudes of sharp waves and ripples exhibit a steep decrease with distance from the network and this effect is more prominent for smaller area electrodes. Furthermore, the amplitude of the signal decreases strongly with increasing electrode surface area as a result of averaging. The relative decrease is more pronounced when the recording electrode is closer to the source of the activity. Through simulations of field potentials across a high density microelectrode array, we demonstrate the importance of finding the ideal spatial resolution for capturing SPW-Rs with great sensitivity. Our work provides insights on contributions from spikes and synaptic potentials to SPW-Rs and describes the effect of measurement configuration on LFPs to guide experimental studies towards improved SPW-R recordings. PMID- 28915252 TI - Expression and regulation of the neutral amino acid transporter B0AT1 in rat small intestine. AB - Absorption of neutral amino acids across the luminal membrane of intestinal enterocytes is mediated by the broad neutral amino acid transporter B0AT1 (SLC6A19). Its intestinal expression depends on co-expression of the membrane anchored peptidase angiotensin converting enzyme 2 (ACE2) and is additionally enhanced by aminopeptidase N (CD13). We investigated in this study the expression of B0AT1 and its auxiliary peptidases as well as its transport function along the rat small intestine. Additionally, we tested its possible short- and long-term regulation by dietary proteins and amino acids. We showed by immunofluorescence that B0AT1, ACE2 and CD13 co-localize on the luminal membrane of small intestinal villi and by Western blotting that their protein expression increases in distal direction. Furthermore, we observed an elevated transport activity of the neutral amino acid L-isoleucine during the nocturnal active phase compared to the inactive one. Gastric emptying was delayed by intragastric application of an amino acid cocktail but we observed no acute dietary regulation of B0AT1 protein expression and L-isoleucine transport. Investigation of the chronic dietary regulation of B0AT1, ACE2 and CD13 by different diets revealed an increased B0AT1 protein expression under amino acid-supplemented diet in the proximal section but not in the distal one and for ACE2 protein expression a reverse localization of the effect. Dietary regulation for CD13 protein expression was not as distinct as for the two other proteins. Ring uptake experiments showed a tendency for increased L-isoleucine uptake under amino acid-supplemented diet and in vivo L isoleucine absorption was more efficient under high protein and amino acid supplemented diet. Additionally, plasma levels of branched-chain amino acids were elevated under high protein and amino acid diet. Taken together, our experiments did not reveal an acute amino acid-induced regulation of B0AT1 but revealed a chronic dietary adaptation mainly restricted to the proximal segment of the small intestine. PMID- 28915253 TI - Persistence of marine fish environmental DNA and the influence of sunlight. AB - Harnessing information encoded in environmental DNA (eDNA) in marine waters has the potential to revolutionize marine biomonitoring. Whether using organism specific quantitative PCR assays or metabarcoding in conjunction with amplicon sequencing, scientists have illustrated that realistic organism censuses can be inferred from eDNA. The next step is establishing ways to link information obtained from eDNA analyses to actual organism abundance. This is only possible by understanding the processes that control eDNA concentrations. The present study uses mesocosm experiments to study the persistence of eDNA in marine waters and explore the role of sunlight in modulating eDNA persistence. We seeded solute permeable dialysis bags with water containing indigenous eDNA and suspended them in a large tank containing seawater. Bags were subjected to two treatments: half the bags were suspended near the water surface where they received high doses of sunlight, and half at depth where they received lower doses of sunlight. Bags were destructively sampled over the course of 87 hours. eDNA was extracted from water samples and used as template for a Scomber japonicus qPCR assay and a marine fish-specific 12S rRNA PCR assay. The latter was subsequently sequenced using a metabarcoding approach. S. japonicus eDNA, as measured by qPCR, exhibited first order decay with a rate constant ~0.01 hr -1 with no difference in decay rate constants between the two experimental treatments. eDNA metabarcoding identified 190 organizational taxonomic units (OTUs) assigned to varying taxonomic ranks. There was no difference in marine fish communities as measured by eDNA metabarcoding between the two experimental treatments, but there was an effect of time. Given the differences in UVA and UVB fluence received by the two experimental treatments, we conclude that sunlight is not the main driver of fish eDNA decay in the experiments. However, there are clearly temporal effects that need to be considered when interpreting information obtained using eDNA approaches. PMID- 28915254 TI - Mirror-normal difference in the late phase of mental rotation: An ERP study. AB - Mirror-normal letter discriminations are thought to require mental rotation in order to transform the rotated alphanumeric character into its canonical orientation. Moreover, out-of-plane rotation is likely to occur after in-plane rotation to fully normalize the mirror version before the final mirror-normal judgment. The so-called rotation-related negativity, which varies with orientation, is found in both ERPonset (averaged with respect to stimulus onset) and ERPRT (averaged with respect to response time), representing the involvement of mental rotation in both time windows. Additionally, the mean amplitude of ERPRT correlates with individual performance. We performed a comprehensive analysis of the mirror-normal differences in the early and late phases of mental rotation and deduced that out-of-plane rotation is more likely to occur in the late phase and interacts with both in-plane rotation and the decision-making process, as indicated by both behavioral and electrophysiological findings. PMID- 28915255 TI - Scrambled eggs: A highly sensitive molecular diagnostic workflow for Fasciola species specific detection from faecal samples. AB - BACKGROUND: Fasciolosis, due to Fasciola hepatica and Fasciola gigantica, is a re emerging zoonotic parasitic disease of worldwide importance. Human and animal infections are commonly diagnosed by the traditional sedimentation and faecal egg counting technique. However, this technique is time-consuming and prone to sensitivity errors when a large number of samples must be processed or if the operator lacks sufficient experience. Additionally, diagnosis can only be made once the 12-week pre-patent period has passed. Recently, a commercially available coprological antigen ELISA has enabled detection of F. hepatica prior to the completion of the pre-patent period, providing earlier diagnosis and increased throughput, although species differentiation is not possible in areas of parasite sympatry. Real-time PCR offers the combined benefits of highly sensitive species differentiation for medium to large sample sizes. However, no molecular diagnostic workflow currently exists for the identification of Fasciola spp. in faecal samples. METHODOLOGY/PRINCIPAL FINDINGS: A new molecular diagnostic workflow for the highly-sensitive detection and quantification of Fasciola spp. in faecal samples was developed. The technique involves sedimenting and pelleting the samples prior to DNA isolation in order to concentrate the eggs, followed by disruption by bead-beating in a benchtop homogeniser to ensure access to DNA. Although both the new molecular workflow and the traditional sedimentation technique were sensitive and specific, the new molecular workflow enabled faster sample throughput in medium to large epidemiological studies, and provided the additional benefit of speciation. Further, good correlation (R2 = 0.74-0.76) was observed between the real-time PCR values and the faecal egg count (FEC) using the new molecular workflow for all herds and sampling periods. Finally, no effect of storage in 70% ethanol was detected on sedimentation and DNA isolation outcomes; enabling transport of samples from endemic to non-endemic countries without the requirement of a complete cold chain. The commercially-available ELISA displayed poorer sensitivity, even after adjustment of the positive threshold (65-88%), compared to the sensitivity (91-100%) of the new molecular diagnostic workflow. CONCLUSIONS/SIGNIFICANCE: Species-specific assays for sensitive detection of Fasciola spp. enable ante-mortem diagnosis in both human and animal settings. This includes Southeast Asia where there are potentially many undocumented human cases and where post-mortem examination of production animals can be difficult. The new molecular workflow provides a sensitive and quantitative diagnostic approach for the rapid testing of medium to large sample sizes, potentially superseding the traditional sedimentation and FEC technique and enabling surveillance programs in locations where animal and human health funding is limited. PMID- 28915256 TI - Optical coherence tomography angiography of the peripapillary capillaries in primary open-angle and normal-tension glaucoma. AB - OBJECTIVES: To evaluate the vascular architecture of the radial peripapillary capillaries (RPCs) and its relation with visual function in patients with open angle glaucoma (OAG) and normal-tension glaucoma using spectral-domain optical coherence tomography (SD-OCT) angiography. SUBJECTS AND METHODS: Clear OCT angiography images of blood vessels in the optic disc and peripapillary retina were obtained from 52 patients (52 eyes) aged 55.42+/-10.64 (range 28-72) years with primary OAG. The mean spherical equivalent was -3.19+/-2.31 diopters, and the mean deviation (MD) of the central 24/30-2 threshold test using the Humphrey Field Analyzer (HFA) was -10.47+/-7.99 dB. The correlations between the disappearance angle of the RPCs on OTC images, flow density (FD) and the circumpapillary retinal nerve fiber layer (cpRNFL) thickness, the angle of retinal nerve fiber layer (RNFL) defect, the MD and pattern standard deviation (PSD) values of the HFA central 24/30-2 threshold test using the Swedish interactive thresholding algorithm, the sensitivity threshold, age, corneal thickness, and refractive value were analyzed. In addition, the correlation between FD and the cpRNFL thickness was analyzed at FD measurement points. RESULTS: FD was significantly correlated with cpRNFL thickness, PSD value, MD value, and sensitivity threshold, whereas the disappearance angle of the RPCs was significantly correlated with the angle of the RNFL defect (P<0.001), MD value (P<0.01), and sensitivity threshold (P<0.01). There was a negative correlation between FD and age (P<0.05). The Pearson correlation coefficient of FD and cpRNFL thickness in the area surrounding the optic disc revealed the most significant correlation in the inferior visual field (r = 0.851, P<0.001), followed by the superior visual field (r = 0.803, P<0.001) and then the temporal visual field (r = 0.653, P<0.001). CONCLUSION: SD-OCT angiography enabled thorough observation of the RPCs. FD and the disappearance angle of the RPCs were significantly and independently correlated with glaucoma-related functional and morphological changes in the optic nerve, suggesting that these two factors are novel functional and morphological indicators of visual defects due to glaucoma. PMID- 28915257 TI - Outbreaks of epidemic keratoconjunctivitis caused by human adenovirus type 8 in the Tibet Autonomous Region of China in 2016. AB - From April to November 2016, two outbreaks of epidemic keratoconjunctivitis (EKC) occurred successively at primary and middle schools in the Tibet Autonomous Region of China, and a total of 197 clinically diagnosed cases were reported. Real-time PCR analyses confirmed that human adenovirus (HAdV) infection was related to these outbreaks. Further studies involving sequence determination and phylogenetic analysis based on the penton base, hexon, and fiber genes indicated that human adenovirus type 8 (HAdV-8), belonging to species D, was responsible for the outbreaks. This is the first report of a HAdV-8 associated EKC outbreak in mainland of China, and the results of this study are expected to provide support for future research into HAdV-8 in China. PMID- 28915258 TI - Rapid Emergency Medicine Score: A novel prognostic tool for predicting the outcomes of adult patients with hepatic portal venous gas in the emergency department. AB - OBJECTIVE: This study aims to evaluate the performance of Rapid Emergency Medicine Score (REMS), Rapid Acute Physiology Score (RAPS), and Modified Early Warning Score (MEWS) in ascertaining the severity of illness and predicting the mortality of adult hepatic portal venous gas (HPVG) patients presenting to the emergency department (ED). This will assist emergency physicians (EPs) in risk stratification. METHODS: Data for 66 adult HPVG patients who visited the EDs of 2 research hospitals between October 1999 and April 2016 were analyzed. REMS, RAPS, and MEWS were calculated based on data in the ED, and probability of death was calculated for each patient based on these scores. The ability of REMS, RAPS, and MEWS to predict group mortality was assessed by using receiver operating characteristic (ROC) curve analysis and calibration analysis. RESULTS: The sensitivity, specificity, and accuracy for each scoring system were 92.1%, 89.3%, and 90.9% for REMS, 86.8%, 82.1%, and 84.8% for RAPS, and 78.9%, 89.3%, and 83.3% for MEWS respectively. In the ROC curve analysis, the areas under the curve for REMS, RAPS, and MEWS were 0.929, 0.877, and 0.856 respectively. CONCLUSION: Our study is the largest series performed in a population of adult HPVG patients in the ED. The results from this study demonstrate that REMS is superior in predicting the mortality of these patients compared to RAPS and MEWS. We therefore recommend that REMS be used for outcome prediction and risk stratification of adult HPVG in the ED. PMID- 28915259 TI - A novel mechanism of antibody-mediated enhancement of flavivirus infection. AB - Antibody-dependent enhancement of viral infection is a well-described phenomenon that is based on the cellular uptake of infectious virus-antibody complexes following their interaction with Fcgamma receptors expressed on myeloid cells. Here we describe a novel mechanism of antibody-mediated enhancement of infection by a flavivirus (tick-borne encephalitis virus) in transformed and primary human cells, which is independent of the presence of Fcgamma receptors. Using chemical cross-linking and immunoassays, we demonstrate that the monoclonal antibody (mab) A5, recognizing an epitope at the interface of the dimeric envelope protein E, causes dimer dissociation and leads to the exposure of the fusion loop (FL). Under normal conditions of infection, this process is triggered only after virus uptake by the acidic pH in endosomes, resulting in the initiation of membrane fusion through the interaction of the FL with the endosomal membrane. Analysis of virus binding and cellular infection, together with inhibition by the FL-specific mab 4G2, indicated that the FL, exposed after mab A5- induced dimer-dissociation, mediated attachment of the virus to the plasma membrane also at neutral pH, thereby increasing viral infectivity. Since antibody-induced enhancement of binding was not only observed with cells but also with liposomes, it is likely that increased infection was due to FL-lipid interactions and not to interactions with cellular plasma membrane proteins. The novel mechanism of antibody-induced infection enhancement adds a new facet to the complexity of antibody interactions with flaviviruses and may have implications for yet unresolved effects of polyclonal antibody responses on biological properties of these viruses. PMID- 28915260 TI - Obesity is not associated with recurrent venous thromboembolism in elderly patients: Results from the prospective SWITCO65+ cohort study. AB - BACKGROUND: Whether obesity is associated with recurrent venous thromboembolism (VTE) in elderly patients is unknown. OBJECTIVES: To examine the association between two obesity measures, the body mass index (BMI) and the waist circumference (WC), and recurrent VTE in elderly patients. PATIENTS/METHODS: We studied 986 patients aged >=65 years with an acute VTE from a prospective multicenter cohort study (09/2009-12/2013). The BMI was determined and categorized as <25, 25 to <30, or >=30 kg/m2. The WC was categorized as <80 cm in women (w)/<94 cm in men (m), 80 to <88 cm (w)/94 to <102 cm (m), or >=88 cm (w)/>=102 cm (m). We examined the association between the BMI and the WC and the time to a first symptomatic recurrent VTE using competing risk regression, adjusting for known risk factors of VTE recurrence and periods of anticoagulation. RESULTS: The mean follow-up was 28 months. The 3-year cumulative incidence of recurrent VTE did not vary by BMI and was 17.6% for a BMI <25 kg/m2, 11.5% for a BMI 25 to <30 kg/m2, and 16.9% for a BMI >=30 kg/m2 (P = 0.09). The 3 year cumulative incidence of recurrent VTE did not vary by WC. After adjustment, neither the BMI (sub-hazard ratio [SHR] 1.02, 95% confidence interval [CI 0.98 1.05]) nor the WC (SHR 1.01, 95% CI 0.99-1.02) was associated with recurrent VTE. CONCLUSIONS: Measures of body weight were not associated with recurrent VTE in our cohort. Obesity does not appear to be a predictor of recurrent VTE in the elderly. PMID- 28915261 TI - Simultaneous determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in dried blood spots: Second-tier LC-MS/MS assay for newborn screening of propionic acidemia, methylmalonic acidemias and combined remethylation disorders. AB - BACKGROUND AND AIMS: Increased propionylcarnitine levels in newborn screening are indicative for a group of potentially severe disorders including propionic acidemia (PA), methylmalonic acidemias and combined remethylation disorders (MMACBL). This alteration is relatively non-specific, resulting in the necessity of confirmation and differential diagnosis in subsequent tests. Thus, we aimed to develop a multiplex approach for concurrent determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid from the same dried blood spot (DBS) as in primary screening (second-tier test). We also set out to validate the method using newborn and follow-up samples of patients with confirmed PA or MMACBL. METHODS: The assay was developed using liquid chromatography-tandem mass spectrometry and clinically validated with retrospective analysis of DBS samples from PA or MMACBL patients. RESULTS: Reliable determination of all three analytes in DBSs was achieved following simple and fast (<20 min) sample preparation without laborious derivatization or any additional pipetting steps. The method clearly distinguished the pathological and normal samples and differentiated between PA and MMACBL in all stored newborn specimens. Methylcitric acid was elevated in all PA samples; 3-hydroxypropionic acid was also high in most cases. Methylmalonic acid was increased in all MMACBL specimens; mostly together with methylcitric acid. CONCLUSIONS: A liquid chromatography-tandem mass spectrometry assay allowing simultaneous determination of the biomarkers 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in DBSs has been developed. The assay can use the same specimen as in primary screening (second-tier test) which may reduce the need for repeated blood sampling. The presented preliminary findings suggest that this method can reliably differentiate patients with PA and MMACBL in newborn screening. The validated assay is being evaluated prospectively in a pilot project for extension of the German newborn screening panel ("Newborn screening 2020"; Newborn Screening Center, University Hospital Heidelberg). PMID- 28915262 TI - Associations between body mass index and mortality or cardiovascular events in a general Korean population. AB - BACKGROUND/OBJECTIVES: The relationship between body mass index (BMI) and mortality remains controversial. Furthermore, the association between BMI and cardiovascular events (CVE) is not conclusive and may differ by ethnicity. We aimed to estimate the associations between the BMI and mortality or cardiovascular disease in a general Korean population. SUBJECTS/METHODS: This study was based on a sample cohort database released by the Korean National Health Insurance Service. We analyzed a total of 415,796 adults older than 30 years of age who had undergone a national health examination at least once from 2002 to 2012. Hazard ratios for death and cardiovascular events were calculated using Cox proportional hazards models. RESULTS: For both men and women, BMI and overall mortality showed a U-shaped association, with the lowest mortality rate among those with a BMI of 25-27.4 kg/m2. Compared with them, subjects with a BMI >= 30kg/m2, men with a BMI < 25 kg/m2, and women with a BMI < 22.5 kg/m2 showed significantly higher overall mortality. Additionally, men with a BMI < 22.5 kg/m2 and women with a BMI < 20 kg/m2 displayed an increased risk of cardiovascular mortality. Unlike the mortality trend, the CVD events trend showed a linearly positive association. The risk of a CVE was the lowest in men with a BMI ranging from 20 to 22.4 kg/m2 and in women with a BMI < 20 kg/m2. CONCLUSIONS: The BMI showed a U-shaped association with overall mortality, where slightly obese subjects showed the lowest rate of mortality. The CVE exhibited a linear association with the BMI, where the lowest risk was observed for normal weight subjects in a general Korean population. PMID- 28915263 TI - Universal representations of evaporation modes in sessile droplets. AB - In this work, we provide a simple method to represent the contact line dynamics of an evaporating sessile droplet. As a droplet evaporates, two distinct contact line dynamics are observed. They are collectively known as modes of evaporation, namely Constant Contact Radius (CCR) and Constant Contact Angle (CCA). Another intermediate mode-Stick-Slide (SS) or mixed mode is also commonly observed. In this article, we are able to provide a graphical representation to these modes (named as MOE plot), which is visually more comprehensive especially for comparative studies. In addition, the method facilitates quantitative estimation for mode of evaporation (named as MOE fraction or MOEf), which doesn't exist in literature. Thus, various substrates can now be compared based on mode of evaporation (or contact line dynamics), which are governed by fluid property and surface characteristics. PMID- 28915264 TI - Inhibition of infection spread by co-transmitted defective interfering particles. AB - Although virus release from host cells and tissues propels the spread of many infectious diseases, most virus particles are not infectious; many are defective, lacking essential genetic information needed for replication. When defective and viable particles enter the same cell, the defective particles can multiply while interfering with viable particle production. Defective interfering particles (DIPs) occur in nature, but their role in disease pathogenesis and spread is not known. Here, we engineered an RNA virus and its DIPs to express different fluorescent reporters, and we observed how DIPs impact viral gene expression and infection spread. Across thousands of host cells, co-infected with infectious virus and DIPs, gene expression was highly variable, but average levels of viral reporter expression fell at higher DIP doses. In cell populations spatial patterns of infection spread provided the first direct evidence for the co transmission of DIPs with infectious virus. Patterns of spread were highly sensitive to the behavior of initial or early co-infected cells, with slower overall spread stemming from higher early DIP doses. Under such conditions striking patterns of patchy gene expression reflected localized regions of DIP or virus enrichment. From a broader perspective, these results suggest DIPs contribute to the ecological and evolutionary persistence of viruses in nature. PMID- 28915265 TI - The accessory parotid gland and facial process of the parotid gland on computed tomography. AB - The purpose of this study was to determine the incidence of an anterior extension of the parotid gland, such as an accessory parotid gland (APG) or facial process (FP) and to evaluate its characteristics on computed tomography (CT) scans. We reviewed CT scans of 1,600 parotid glands from 800 patients. An APG on CT was defined as a soft-tissue mass of the same density as the main parotid gland, located at the anterior part of the main parotid gland, and completely separate from the main parotid gland. An FP was defined as a lobe of the parotid gland protruding anteriorly over the anterior edge of the ramus of the mandible on CT and showing continuity with the main gland. The overall incidence rates and characteristics of APGs and FPs were evaluated according to age, sex, and side. The incidence rates of APGs and FPs were 10.2% (163/1,600) and 28.3% (452/1,600), respectively. The mean size of an APG was 15.8 mm * 5.0 mm and the mean distance from the main parotid gland was 10.5 mm. The FP reached anteriorly between the anterior edge of the mandibular ramus and the anterior border of the masseter muscle in 405 (89.6%) cases, while it extended over the anterior border of the masseter muscle in 47 (10.4%) cases. The incidence rates of APGs and FPs decreased and increased, respectively, with increasing age, showing significant linear correlations. However, the incidence of an anterior extension of the parotid gland (either an APG or an FP) was similar across all age groups. The present study showed that CT might be helpful in identifying anterior extensions of the parotid gland including APGs and FPs. The anatomical information gained from this study contributes to a better understanding of APGs and FPs and how their incidence changes with age. PMID- 28915266 TI - Evaluation of a conceptual framework for predicting navigation performance in virtual reality. AB - Previous research in spatial cognition has often relied on simple spatial tasks in static environments in order to draw inferences regarding navigation performance. These tasks are typically divided into categories (e.g., egocentric or allocentric) that reflect different two-systems theories. Unfortunately, this two-systems approach has been insufficient for reliably predicting navigation performance in virtual reality (VR). In the present experiment, participants were asked to learn and navigate towards goal locations in a virtual city and then perform eight simple spatial tasks in a separate environment. These eight tasks were organised along four orthogonal dimensions (static/dynamic, perceived/remembered, egocentric/allocentric, and distance/direction). We employed confirmatory and exploratory analyses in order to assess the relationship between navigation performance and performances on these simple tasks. We provide evidence that a dynamic task (i.e., intercepting a moving object) is capable of predicting navigation performance in a familiar virtual environment better than several categories of static tasks. These results have important implications for studies on navigation in VR that tend to over emphasise the role of spatial memory. Given that our dynamic tasks required efficient interaction with the human interface device (HID), they were more closely aligned with the perceptuomotor processes associated with locomotion than wayfinding. In the future, researchers should consider training participants on HIDs using a dynamic task prior to conducting a navigation experiment. Performances on dynamic tasks should also be assessed in order to avoid confounding skill with an HID and spatial knowledge acquisition. PMID- 28915267 TI - Cooling induces phase separation in membranes derived from isolated CNS myelin. AB - Purified myelin membranes (PMMs) are the starting material for biochemical analyses such as the isolation of detergent-insoluble glycosphingolipid-rich domains (DIGs), which are believed to be representatives of functional lipid rafts. The normal DIGs isolation protocol involves the extraction of lipids under moderate cooling. Here, we thus address the influence of cooling on the structure of PMMs and its sub-fractions. Thermodynamic and structural aspects of periodic, multilamellar PMMs are examined between 4 degrees C and 45 degrees C and in various biologically relevant aqueous solutions. The phase behavior is investigated by small-angle X-ray scattering (SAXS) and differential scanning calorimetry (DSC). Complementary neutron diffraction (ND) experiments with solid supported myelin multilayers confirm that the phase behavior is unaffected by planar confinement. SAXS and ND consistently show that multilamellar PMMs in pure water become heterogeneous when cooled by more than 10-15 degrees C below physiological temperature, as during the DIGs isolation procedure. The heterogeneous state of PMMs is stabilized in physiological solution, where phase coexistence persists up to near the physiological temperature. This result supports the general view that membranes under physiological conditions are close to critical points for phase separation. In presence of elevated Ca2+ concentrations (> 10 mM), phase coexistence is found even far above physiological temperatures. The relative fractions of the two phases, and thus presumably also their compositions, are found to vary with temperature. Depending on the conditions, an "expanded" phase with larger lamellar period or a "compacted" phase with smaller lamellar period coexists with the native phase. Both expanded and compacted periods are also observed in DIGs under the respective conditions. The observed subtle temperature-dependence of the phase behavior of PMMs suggests that the composition of DIGs is sensitive to the details of the isolation protocol. PMID- 28915268 TI - Large-scale cross-species chemogenomic platform proposes a new drug discovery strategy of veterinary drug from herbal medicines. AB - Veterinary Herbal Medicine (VHM) is a comprehensive, current, and informative discipline on the utilization of herbs in veterinary practice. Driven by chemistry but progressively directed by pharmacology and the clinical sciences, drug research has contributed more to address the needs for innovative veterinary medicine for curing animal diseases. However, research into veterinary medicine of vegetal origin in the pharmaceutical industry has reduced, owing to questions such as the short of compatibility of traditional natural-product extract libraries with high-throughput screening. Here, we present a cross-species chemogenomic screening platform to dissect the genetic basis of multifactorial diseases and to determine the most suitable points of attack for future veterinary medicines, thereby increasing the number of treatment options. First, based on critically examined pharmacology and text mining, we build a cross species drug-likeness evaluation approach to screen the lead compounds in veterinary medicines. Second, a specific cross-species target prediction model is developed to infer drug-target connections, with the purpose of understanding how drugs work on the specific targets. Third, we focus on exploring the multiple targets interference effects of veterinary medicines by heterogeneous network convergence and modularization analysis. Finally, we manually integrate a disease pathway to test whether the cross-species chemogenomic platform could uncover the active mechanism of veterinary medicine, which is exemplified by a specific network module. We believe the proposed cross-species chemogenomic platform allows for the systematization of current and traditional knowledge of veterinary medicine and, importantly, for the application of this emerging body of knowledge to the development of new drugs for animal diseases. PMID- 28915269 TI - The biometric antecedents to happiness. AB - It has been suggested that biological markers are associated with human happiness. We contribute to the empirical literature by examining the independent association between various aspects of biometric wellbeing measured in childhood and happiness in adulthood. Using Young Finns Study data (n = 1905) and nationally representative linked data we examine whether eight biomarkers measured in childhood (1980) are associated with happiness in adulthood (2001). Using linked data we account for a very rich set of confounders including age, sex, body size, family background, nutritional intake, physical activity, income, education and labour market experiences. We find that there is a negative relationship between triglycerides and subjective well-being but it is both gender- and age-specific and the relationship does not prevail using the later measurements (1983/1986) on triglycerides. In summary, we conclude that none of the eight biomarkers measured in childhood predict happiness robustly in adulthood. PMID- 28915271 TI - Extending topological surgery to natural processes and dynamical systems. AB - Topological surgery is a mathematical technique used for creating new manifolds out of known ones. We observe that it occurs in natural phenomena where a sphere of dimension 0 or 1 is selected, forces are applied and the manifold in which they occur changes type. For example, 1-dimensional surgery happens during chromosomal crossover, DNA recombination and when cosmic magnetic lines reconnect, while 2-dimensional surgery happens in the formation of tornadoes, in the phenomenon of Falaco solitons, in drop coalescence and in the cell mitosis. Inspired by such phenomena, we introduce new theoretical concepts which enhance topological surgery with the observed forces and dynamics. To do this, we first extend the formal definition to a continuous process caused by local forces. Next, for modeling phenomena which do not happen on arcs or surfaces but are 2 dimensional or 3-dimensional, we fill in the interior space by defining the notion of solid topological surgery. We further introduce the notion of embedded surgery in S3 for modeling phenomena which involve more intrinsically the ambient space, such as the appearance of knotting in DNA and phenomena where the causes and effect of the process lies beyond the initial manifold, such as the formation of black holes. Finally, we connect these new theoretical concepts with a dynamical system and we present it as a model for both 2-dimensional 0-surgery and natural phenomena exhibiting a 'hole drilling' behavior. We hope that through this study, topology and dynamics of many natural phenomena, as well as topological surgery itself, will be better understood. PMID- 28915270 TI - The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target. AB - BACKGROUND: Giardiasis is an intestinal infection correlated with poverty and poor drinking water quality, and treatment options are limited. According to the Center for Disease Control and Prevention, Giardia infections afflict nearly 33% of people in developing countries, and 2% of the adult population in the developed world. This study describes the single cyclic nucleotide-specific phosphodiesterase (PDE) of G. lamblia and assesses PDE inhibitors as a new generation of anti-giardial drugs. METHODS: An extensive search of the Giardia genome database identified a single gene coding for a class I PDE, GlPDE. The predicted protein sequence was analyzed in-silico to characterize its domain structure and catalytic domain. Enzymatic activity of GlPDE was established by complementation of a PDE-deficient Saccharomyces cerevisiae strain, and enzyme kinetics were characterized in soluble yeast lysates. The potency of known PDE inhibitors was tested against the activity of recombinant GlPDE expressed in yeast and against proliferating Giardia trophozoites. Finally, the localization of epitope-tagged and ectopically expressed GlPDE in Giardia cells was investigated. RESULTS: Giardia encodes a class I PDE. Catalytically important residues are fully conserved between GlPDE and human PDEs, but sequence differences between their catalytic domains suggest that designing Giardia specific inhibitors is feasible. Recombinant GlPDE hydrolyzes cAMP with a Km of 408 MUM, and cGMP is not accepted as a substrate. A number of drugs exhibit a high degree of correlation between their potency against the recombinant enzyme and their inhibition of trophozoite proliferation in culture. Epitope-tagged GlPDE localizes as dots in a pattern reminiscent of mitosomes and to the perinuclear region in Giardia. CONCLUSIONS: Our data strongly suggest that inhibition of G. lamblia PDE activity leads to a profound inhibition of parasite proliferation and that GlPDE is a promising target for developing novel anti giardial drugs. PMID- 28915272 TI - Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle. AB - Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant multisystemic disorders caused by expansion of microsatellite repeats. In both forms, the mutant transcripts accumulate in nuclear foci altering the function of alternative splicing regulators which are necessary for the physiological mRNA processing. Missplicing of insulin receptor (IR) gene (INSR) has been associated with insulin resistance, however, it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature in DM. We have analysed the insulin pathway in skeletal muscle biopsies and in myotube cultures from DM patients to assess whether downstream metabolism might be dysregulated and to better characterize the mechanism inducing insulin resistance. DM skeletal muscle exhibits alterations of basal phosphorylation levels of Akt/PKB, p70S6K, GSK3beta and ERK1/2, suggesting that these changes might be accompanied by a lack of further insulin stimulation. Alterations of insulin pathway have been confirmed on control and DM myotubes expressing fetal INSR isoform (INSR-A). The results indicate that insulin action appears to be lower in DM than in control myotubes in terms of protein activation and glucose uptake. Our data indicate that post-receptor signalling abnormalities might contribute to DM insulin resistance regardless the alteration of INSR splicing. PMID- 28915273 TI - Longitudinal co-variations between inflammatory cytokines, lung function and patient reported outcomes in patients with asthma. AB - BACKGROUND: Asthma is a chronic inflammatory respiratory disorder associated with reduced lung function and poor quality of life. The condition is also associated with poor self-rated health, a major predictor of objective health trajectories. Of biological correlates to self-rated health, evidence suggests a role for inflammatory cytokines and related sickness behaviours. However, this is mainly based on cross-sectional data, and the relation has not been investigated in patients with chronic inflammatory conditions. OBJECTIVE: To investigate inflammatory cytokines, lung function, sickness behaviour and asthma-related quality of life as determinants of self-rated health in patients with asthma, and to investigate if these variables co-vary over time. METHODS: Plasma cytokines (IL-5, IL-6), lung function (FEV1), sickness behaviour, asthma-related quality of life and self-rated health were assessed in 181 patients with allergic asthma aged 18-64 years in a one-year longitudinal study. Mixed effect regression models and Spearman's correlation were performed to analyse the associations between repeated measurements. RESULTS: More sickness behaviour and poorer asthma-related quality of life were associated with poorer self-rated health (p's<0.001). In men, both low and high levels of interleukin (IL)-6 and poorer lung function were related with poorer self-rated health (p's<0.05). Over the year, improved asthma related quality of life was associated with better self-rated health (Spearman's rho = -0.34 women,-0.36 men, p's<0.01). Further, if sickness behaviour decreased, self-rated health improved, but only in women (Rho = -0.21, p<0.05). Increased FEV1 in men was associated with an increase in IL-6 (Rho = 0.24, p<0.05) as well as improved self-rated health (Rho = -0.21, p<0.05) and asthma-related quality of life (Rho = 0.29, p<0.01) over the year. CONCLUSION: The study highlights the importance of subjectively perceived sickness behaviour and asthma-related quality of life together with lung function as determinants of self-rated health in asthmatic patients. The importance of inflammatory activation for patient reported outcomes in chronic inflammatory conditions need further investigation. PMID- 28915274 TI - Prevalence of mind and body exercises (MBE) in relation to demographics, self rated health, and purchases of prescribed psychotropic drugs and analgesics. AB - : This study aims to identify any differences regarding gender, age, socioeconomic status (SES), self-rated health, perceived stress and the purchase of prescribed drugs among people who practice mind and body exercises (MBE) extensively compared to people who do not. METHODS: The study includes 3,913 men and 4,803 women aged 20-72 who participated in the Swedish Longitudinal Occupational Survey of Health (SLOSH). The respondents were divided into three groups depending on frequency of MBE practice (never/seldom/often). Measures regarding MBE practice, health behaviors, self-rated health, and illnesses were drawn from the SLOSH questionnaire, while more objective measures of socioeconomic status and education were derived from registry data. In addition, data on purchases of prescription drugs for all respondents were included in the study. These data were obtained from the Swedish Prescribed Drug Register, which contains information about prescription drugs dispensed at Swedish pharmacies. Separate analyses were performed for mental MBE (mindfulness, meditation, relaxation techniques) and physical MBE (yoga, Tai Chi, Qi Gong), respectively. RESULTS: A high intensity MBE practice is cross-sectionally related to poor self assessed health (sleeping problems, pain, depressive symptoms, mental disorders), high levels of stress, and high levels of purchases of psychotropic drugs and analgesics. These cross-sectional relationships are generally stronger for mental MBE than for bodily-directed MBE. More women than men are practicing MBE on a regular basis, and physically active people participate to a greater extent in MBE compared with the physically inactive. CONCLUSION: Overall, the study shows that frequent participation in mind and body exercises is associated with high levels of purchases of psychotropic drugs and analgesics as well as with poor self-assessed health and high levels of stress. However, since this is a cross sectional study, it is impossible to establish cause and effect, and to further investigate the associations found; longitudinal studies that can account for temporality between covariates and MBE use are needed. PMID- 28915276 TI - Relationship between rectus abdominis muscle thickness and metabolic syndrome in middle-aged men. AB - BACKGROUND AND OBJECTIVE: Skeletal muscle has been suggested as an important factor in the pathophysiology of metabolic syndrome. During the aging process, muscle mass is lost in specific body parts. However, few studies have investigated the relationship between site-specific muscle loss assessed using computed tomography (CT) and metabolic syndrome. This study was conducted to investigate the association between metabolic syndrome and rectus abdominis muscle thickness at the umbilicus level (RAM), which reflects site-specific muscle loss of the abdomen using CT image. METHODS: This cross-sectional study was conducted on 725 middle-aged Korean men. Anthropometric evaluation and biochemical tests were performed. The RAMs of the subjects were measured from CT images taken at the umbilicus level. RESULTS: The mean RAM (mean +/-SD) of subjects with metabolic syndrome was 2.46 +/-0.01, which was thinner than that of subjects without metabolic syndrome (2.52 +/-0.01, p<0.01). Moreover, RAM decreased as the number of metabolic syndrome components increased (p-value for trend<0.01). RAM was positively correlated with body mass index (r = 0.21, p<0.01), skeletal muscle index (r = 0.26, p<0.01), and creatinine (r = 0.12, p<0.01), while RAM was negatively correlated with age(r = -0.11, p<0.01), abdominal circumference(r = -0.22, p<0.01), fasting glucose (r = -0.10, p<0.01), and triglycerides(r = -0.15, p<0.01). Using a stepwise multiple logistic regression analysis, we found that RAM was an independent factor associated with metabolic syndrome (OR: 0.861, 95%CI, 0.779-0.951, p<0.01). The result was not different in the statistical analysis including the components of MS (OR: 0.860, 95% CI, 0.767-0.965, p = 0.01). CONCLUSION: RAM was associated with metabolic syndrome in middle-aged men. Moreover, site-specific muscle loss at the abdomen, as evaluated by RAM, also may be a predictor of metabolic syndrome like SMI. PMID- 28915275 TI - Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients. AB - OBJECTIVES: To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4 related disease (IgG4-RD) patients. METHODS: Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. RESULTS: Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 +/-21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 +/-11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia <=5 g/l in 3 patients. CONCLUSION: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy. PMID- 28915278 TI - Differential Diagnosis of Seborrheic Keratosis: Clinical and Dermoscopic Features. AB -

Seborrheic keratosis (SK) is a benign epidermal keratinocytic tumor that is extremely common, particularly in individuals over the age of 50. Most individuals with SK will have more than one lesion and the presence of over 10 lesions in the same person is not uncommon. Although the clinical morphology of most SK with their stuck-on, symmetric, keratotic, and waxy appearance makes them easy to identify, many manifest a morphology resembling melanoma or squamous cell carcinoma. One can argue that such cases will ultimately not prove to be problematic since a simple biopsy will easily reveal their benign nature and eliminate any concerns. However, the cost and morbidity associated with the biopsy of benign lesions should not be underestimated. Methods to improve our in vivo ability to correctly identify SK will prove beneficial not only to the health care system in general but to the individual patient specifically. The issue of greater concern resides with skin cancers that mimic SK or when skin cancers arise in association with SK. Needless to say, in vivo methods to help identify malignancy and differentiate them from benign lesions would be welcomed by all. Fortunately, we do now have in vivo imaging methods such as dermoscopy that can improve the clinician's diagnostic accuracy. In this article, we summarize the current knowledge regarding the clinical and dermoscopic features of SK, and provide clues to aid in their diagnosis.

J Drugs Dermatol. 2017;16(9):835-842.

. PMID- 28915277 TI - A portable bioelectronic sensing system (BESSY) for environmental deployment incorporating differential microbial sensing in miniaturized reactors. AB - Current technologies are lacking in the area of deployable, in situ monitoring of complex chemicals in environmental applications. Microorganisms metabolize various chemical compounds and can be engineered to be analyte-specific making them naturally suited for robust chemical sensing. However, current electrochemical microbial biosensors use large and expensive electrochemistry equipment not suitable for on-site, real-time environmental analysis. Here we demonstrate a miniaturized, autonomous bioelectronic sensing system (BESSY) suitable for deployment for instantaneous and continuous sensing applications. We developed a 2x2 cm footprint, low power, two-channel, three-electrode electrochemical potentiostat which wirelessly transmits data for on-site microbial sensing. Furthermore, we designed a new way of fabricating self contained, submersible, miniaturized reactors (m-reactors) to encapsulate the bacteria, working, and counter electrodes. We have validated the BESSY's ability to specifically detect a chemical amongst environmental perturbations using differential current measurements. This work paves the way for in situ microbial sensing outside of a controlled laboratory environment. PMID- 28915279 TI - First Consensus on Primary Prevention and Early Intervention in Aesthetic Medicine. AB - BACKGROUND: Facial aging is a complex interplay of extrinsic and intrinsic factors leading to progressive changes in the skin, subcutaneous tissue, and bone. Clinical experience suggests that early aesthetic intervention may slow the signs of aging, but treatment in the absence of symptoms or with minimal signs of aging has not yet been properly addressed. OBJECTIVES: To provide treatment recommendations for primary prevention and early intervention in individuals with no or minimal signs of aging. METHODS: Fourteen specialists in aesthetic medicine convened over a full-day meeting under the guidance of a certified moderator. RESULTS: Tailored treatment recommendations have been provided for prevention and early intervention of fine wrinkles, static lines and folds, irregular pigmentation, laxity, and subcutaneous volume loss by protecting the epidermis, stimulating neocollagenesis, reducing hyperkinetic musculature, and reinforcing supporting structures. CONCLUSION: Preventive measures and early therapeutic interventions that may alter the course of facial aging were defined. Further studies are needed to support these recommendations with the best possible evidence.

J Drugs Dermatol. 2017;16(9):846-854.

. PMID- 28915280 TI - Communication Concepts for Prevention and Early Intervention in Aesthetic Medicine: Consensus and Literature Review. AB - BACKGROUND: Communication concepts relating to prevention and early intervention (P&E) within aesthetic medicine are poorly understood and highly underexplored. However, effective communication is a key criterion for successful outcomes. OBJECTIVES: To introduce the framework for P&E communication strategies within a younger population and explore the barriers that may be encountered. METHODS: A literature review on P&E communication strategies in aesthetic medicine and related topics of interest was conducted and used to construct a working framework that may be applied in clinical practice. RESULTS: Examination of existing literature revealed a need for a more structured communication framework for P&E encompassing up-to-date evidence-based learning and educational marketing that is tailored to individual needs and target populations. Message framing-the way in which a message is presented-is an important consideration in the dissemination of information to promote changes in health behaviour. A structured consultation is key to optimising patient engagement and ensures a tailored approach to understanding and catering to the specific needs of each patient. CONCLUSION: This is the first paper to discuss the communication concepts behind P&E within aesthetic medicine and paves the way for further research and focus in this significant field.

J Drugs Dermatol. 2017;16(9):859-864.

. PMID- 28915281 TI - Precision in Dermal Filling: A Comparison Between Needle and Cannula When Using Soft Tissue Fillers. AB - BACKGROUND: Precise implantation of soft tissue fillers to treat the signs of aging is crucial for patient safety and the best aesthetic outcome. Injections are performed commonly with either needles or cannulas, but quantitative comparative data on precise implantation are still elusive. METHODS: Ten fresh frozen cephalic foreheads (9 male, 1 female) were injected with radiopaque material using both needles and cannulas. Needle injection relied on a perpendicular transcutaneous approach, whereas cannulas were moved in the supra periosteal plane until reaching the same location as the needle. Two-dimensional distribution of the material in the horizontal and in the vertical axes was quantified using fluoroscopic imaging. Additional CT and MR imaging was performed to confirm results. RESULTS: The two-dimensional extent of injected material in the horizontal plane was 25.6 mm+/-10.5 mm vs 13.5 mm +/- 6.5 mm (cannula vs needle; P=0.006) and 3.0 mm +/- 0.90 mm vs 3.99 mm +/- 0.97 mm (cannula vs needle; P=0.028) in the vertical plane. In 60% of injections using a needle, the implanted material changed its plane; this was not observed when using the cannula (0%; P=0.003). Retrograde backflow, however, was greater with a cannula (90.2%) compared to a needle (33.3%). CONCLUSIONS: If precision in filler injection is defined as the filler material remaining in the plane of intended implantation, then using cannulas resulted in a more precise injection of material as compared to needles. Applications with needles resulted in the distribution of material into more superficial layers, which was not noted for cannulas.

J Drugs Dermatol. 2017;16(9):866-872.

. PMID- 28915282 TI - Factors Affecting the Rheological Measurement of Hyaluronic Acid Gel Fillers. AB - BACKGROUND: With the number of available dermal fillers increasing, so is the demand for scientifically based comparisons, often with rheological properties in focus. Since analytical results are always influenced by instrument settings, consensus on settings is essential to make comparison of results from different investigators more useful. OBJECTIVE: Preferred measurement settings for rheological analysis of hyaluronic acid (HA) fillers are suggested, and the reasoning behind the choices is presented by demonstrating the effect of different measurement settings on select commercial HA fillers. MATERIALS AND METHODS: Rheological properties of 8 HA fillers were measured in a frequency sweep from 10 to 0.01 Hz at 0.1% strain, using an Anton Paar MCR 301, a PP-25 measuring system with a gap of 1 mm at 25 degrees C. A 30-min period was used for relaxation of the sample between loading and measuring. RESULTS: The data presented here, together with previously published data, demonstrate differences in G' from 1.6 to 7.4 times for the same product. CONCLUSION: A large part of the differences were concluded to be due to differences in rheometry measurement settings. The confusion from the many parameters involved in rheometry can be avoided by simply using the elastic modulus (G') to differentiate products.

J Drugs Dermatol. 2017;16(9):876-882.

. PMID- 28915283 TI - Clinical Evaluation of a Multi-Modal Facial Serum That Addresses Hyaluronic Acid Levels in Skin. AB - BACKGROUND: Hyaluronic acid (HA), the major glycosaminoglycan present in the human skin, is a key contributor to water retention and mechanical support in skin. The level, size, and functionality of cutaneous HA are known to diminish with age. Topical treatments designed to increase the HA content of skin have been met with limited success. The purpose of this study was to evaluate the tolerance and efficacy of a multi-modal facial serum containing HA, Proxylane (C Xyloside), purple rice extract, and dipotassium glycyrrhizate in addressing HA levels in skin. METHODS: A 12-week, single center, clinical study was conducted on 59 women with mild to moderate photodamage. Clinical grading to assess the efficacy and tolerability was conducted on the face at baseline and at weeks 4, 8, and 12. Bioinstrumentation measurements were taken, including corneometer, tewameter, ultrasound, and standardized digital imaging. A randomized subset of 20 subjects from the study population had 3 mm punch biopsies collected for quantitative RT-PCR analysis from 2 sites on the face at baseline and week 12. Additionally, a 4-week, single center, clinical study was conducted on the photodamaged forearms of 12 subjects. At both baseline and week 4, a 4 mm punch biopsy was obtained from the subjects' randomized forearms. Biopsy samples were subjected to immunohistochemical staining and analysis of HA content. RESULTS: Statistically-significant improvements in all facial skin attributes (weeks 4, 8, and 12), stratum corneum hydration (week 12), and transepidermal water loss (week 12) were observed. Tolerability was excellent, with no increases in irritation parameters noted. A significant increase of HA content in skin after 4 weeks of treatment was observed. By PCR analysis, there was a significant increase in hyaluronan synthase 2, as well as a significant increase in collagen type 1a1 after 12 weeks of application. CONCLUSION: The findings suggest that this novel topical facial serum is capable of stimulating HA and skin extracellular matrix components, as well as improving skin hydration and skin quality in women with mild to moderate photodamage.

J Drugs Dermatol. 2017;16(9):884 890.

. PMID- 28915284 TI - Long-term Comparison of a Large Spot Vacuum Assisted Handpiece vs the Small Spot Size Traditional Handpiece of the 800 nm Diode Laser. AB - : BACKGROUND The 800 nm long-pulsed diode laser machine is safe and effective for permanent hair reduction. Traditionally, most long-pulsed diode lasers used for hair removal had a relatively small spot size. Recently, a long-pulsed diode laser with a large spot size and vacuum assisted suction handpiece was introduced. The treatment parameters of each type of handpiece differ. Short and long-term clinical efficacy, treatment associated pain, and patient satisfaction are important factors to be considered. OBJECTIVE: This study aims to conduct a direct head to head comparison of both handpieces of the 800nm long-pulsed diode laser by evaluating long term hair reduction, treatment associated pain and patient satisfaction. METHODS: Thirteen subjects were enrolled in this prospective, self-controlled, single-center study of axillary laser hair removal. The study involved 4 treatments using a long pulsed diode laser with a large spot size HS handpiece (single pass), HS handpiece (double pass), and a small spot size ET handpiece according to a randomized choice. The treatment sessions were done at 4-8 week intervals with follow up visits taken at 6 and 12 months after the last treatment session. Hair clearance and thickness analysis were assessed using macro hair count photographs taken at baseline visit, at each treatment session visit and at follow up visits. Other factors including pain, treatment duration, and patients' preference were secondary study endpoints. RESULTS: At 6 months follow up visits after receiving four laser treatments, there was statistically significant hair clearance in the three treatment arms with 66.1 % mean percentage hair reduction with the ET handpiece, 43.6% with the HSS (single pass) and 64.1 % with the HSD (double). However, at one year follow up, the results significantly varied from the 6 months follow up. The mean percentage hair reduction was 57.8% with the ET handpiece treated axillas (n=9), 16.5% with the HSS (single pass) handpiece treated axillas (n=7), and 46.9% with the HSD (double pass) handpiece treated axillas (n=6). Thus, at one year follow up, there was a significant hair reduction that was similar in both the ET and HSD treated axillae (57.8% and 46.9 %), but only minimal hair reduction (16.5%)was observed in the HSS treated axillae. CONCLUSIONS: This is the first study that compared the long-term efficacy of the ET and HS handpieces after four treatment sessions with up to 12 months follow up after the last treatment session. It is also the first study that provided head to head comparison between HS (double pass), HS (single pass), and ET handpiece taking into consideration the end hair reduction result, the time consumed, the pain score experienced, and the overall patient satisfaction. HSD had better hair clearance and patient satisfaction when compared to ET and HSS. The long term follow up results showed that ET was superior to HSS (P less than .05), but was not superior to HSD (P greater than 0.05). However, HSD treated patients had lower pain scores with HSD than with ET. We conclude that ET handpiece is almost as efficacious as HSD handpiece, and the desired end results could be achieved with HDD with better patient satisfaction, less treatment duration and less pain.

J Drugs Dermatol. 2017;16(9):893 898.

. PMID- 28915285 TI - Diluted Calcium Hydroxylapatite for Skin Tightening of the Upper Arms and Abdomen. AB - BACKGROUND: The collagen-stimulating properties of Radiesse(r) (calcium hydroxylapatite, CaHA) can be used for skin-tightening procedures by hyper diluting the product with lidocaine or saline. OBJECTIVE: To evaluate the effectiveness and safety of diluted CaHA for skin tightening in two case series of women with skin laxity in the upper arms or abdomen. METHODS: For each case series, 10 female subjects were enrolled. In the upper arms, CaHA diluted 1:2 with normal saline solution and 2% lidocaine was injected subdermally using a short, linear-threading technique. Skin elasticity was assessed at baseline and Months 1 and 3 using a cutometer. In the abdominal wall, CaHA diluted 1:4 with saline solution was injected subdermally using a linear-threading technique. Subjects underwent pre- and post-treatment (70 days) ultrasound scans to determine dermal thickness around the umbilicus and sides of the abdomen. Subjects and physicians assessed treatment outcomes using the 5-point Global Aesthetic Improvement Scale (GAIS). Adverse events and tolerability were recorded. RESULTS: Cutometry results for upper arm skin showed an increase in skin elasticity from 72 U at baseline to 82 U at Month 3 (P<=0.05). Ultrasound measures of the abdominal wall demonstrated statistically significant increases in dermal thickness after injection of diluted CaHA of 0.7 mm (umbilicus) and 0.4 mm (sides of abdomen). Diluted CaHA resulted in an overall increase in dermal thickness of 26.7% (P<=0.05). In both case series, 90% of subjects and physicians rated treatment outcomes on GAIS as much or very much improved. Treatment was well tolerated. CONCLUSIONS: Diluted CaHA improved skin elasticity and increased dermal thickness in the upper arms and abdomen after only a single treatment. The procedures were well tolerated, and subject and investigator satisfaction with treatment results was very high. Injection of diluted CaHA is an effective procedure for skin tightening in the upper arms and abdomen.

J Drugs Dermatol. 2017;16(9):900-906.

. PMID- 28915286 TI - Treatment of Rosacea With Concomitant Use of Topical Ivermectin 1% Cream and Brimonidine 0.33% Gel: A Randomized, Vehicle-controlled Study. AB - BACKGROUND: There is currently a lack of data on the simultaneous treatment of different features of rosacea. Individually, ivermectin 1% (IVM) cream and brimonidine 0.33% (BR) gel have demonstrated efficacy on inflammatory lesions and persistent erythema, respectively. OBJECTIVE: To evaluate the efficacy, safety, patient satisfaction, and optimal timing of administration of IVM associated with BR (IVM+BR) versus their vehicles in rosacea (investigator global assessment [IGA] >=3). METHODS: Multicenter, randomized, double-blind study including subjects with rosacea characterized by moderate to severe persistent erythema and inflammatory lesions. The active treatment group included the IVM+BR/12 weeks subgroup (once-daily BR and once-daily IVM for 12 weeks), and the IVM+BR/8 weeks subgroup (once-daily BR vehicle for 4 weeks followed by once-daily BR for the remaining 8 weeks and once-daily IVM for 12 weeks). The vehicle group received once-daily BR vehicle and once-daily IVM vehicle for 12 weeks. RESULTS: The association showed superior efficacy (IGA success [clear/almost clear]) for erythema and inflammatory lesions in the total active group (combined active subgroups) compared to vehicle (55.8% vs. 36.8%, P=0.007) at week 12. The success rate increased from 32.7% to 61.2% at hour 0 and hour 3, respectively, in the IVM+BR/12 weeks subgroup, and from 28.3% to 50% in the IVM+BR/8 weeks subgroup. Reductions in erythema and inflammatory lesion counts confirmed the additive effect of BR to IVM treatment. Subjects reported greater improvement in the active subgroups than in the vehicle group, and similar rates for facial appearance satisfaction after the first 4 weeks of treatment in both active subgroups. All groups showed similar tolerability profiles. CONCLUSION: Concomitant administration of IVM cream with BR gel demonstrated good efficacy and safety, endorsing the comprehensive approach to this complex disease. Early introduction of BR, along with a complete daily skin care regimen may accelerate treatment success without impairing tolerability.

J Drugs Dermatol. 2017;16(9):909-916.

. PMID- 28915287 TI - Efficacy and Safety of Desoximetasone 0.25% Spray in Adult Atopic Dermatitis Subjects: Pilot Study. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disorder. One of the most disturbing symptoms of AD is pruritus. The first line treatment for AD is topical corticosteroids, topical immunomodulators, topical barrier creams, oral antihistamines, and systemic treatments. Desoximetasone 0.25% spray is a superpotent topical corticosteroid delivered in a novel way and it may be a suitable option for the treatment of pruritus in adult atopic dermatitis patients. STUDY DESIGN: A single-center, open labeled pilot study was conducted to investigate the efficacy and safety of desoximetasone 0.25% spray for pruritus in adult atopic dermatitis patients. RESULTS: Twice daily application of desoximetasone 0.25% spray to affected areas resulted in a significant reduction in all outcomes (IGA, pruritus, VAS assessment of pruritus) within 1 week of initiation of treatment. The reductions exhibited were sustained throughout the study period of 4 weeks. Significant improvements in quality of life, as measured by the DLQI, were observed. No adverse events were reported. CONCLUSION: Desoximetasone 0.25% spray is effective for treating pruritic symptoms of AD. Given its efficacy and convenience as a spray, desoximetasone 0.25% spray should continue to be evaluated as a treatment for AD in larger trials.

J Drugs Dermatol. 2017;16(9):919-922.

. PMID- 28915288 TI - Successful Treatment of Keloid With Fractionated Carbon Dioxide (CO2) Laser and Laser-Assisted Drug Delivery of Triamcinolone Acetonide Ointment in an African American Man. AB - Keloids are fibrous growths that occur as a result of abnormal response to dermal injury. Keloids are cosmetically disfiguring and may impair function, often resulting in decreased patient quality-of-life. Treatment of keloids remains challenging, and rate of recurrence is high. We present a case of a 39-year-old African-American man (Fitzpatrick VI) with a 10-year history of keloid, who was successfully treated with eight sessions of fractionated carbon dioxide (CO2) laser immediately followed by laser-assisted drug delivery (LADD) of topical triamcinolone acetonide (TAC) ointment and review the medical literature on fractionated CO2 laser treatment of keloids. To the best of our knowledge, this is the first report of successful treatment of a keloid using combination therapy of fractionated CO2 laser and LADD with topical TAC ointment in an African American man (Fitzpatrick VI) with excellent cosmetic results sustained at 22 months post-treatment. We believe that this combination treatment modality may be safe and efficacious for keloids in skin of color (Fitzpatrick IV-VI) and other patients. This case highlights the ability of laser surgeons to safely use fractionated CO2 lasers in patients of all skin colors.

J Drugs Dermatol. 2017;16(9):925-927.

. PMID- 28915289 TI - Mild to Moderate Dysphagia Following Very Low-dose Abobotulinumtoxin A for Platysmal Bands. AB - Onabotulinumtoxin A (Botox) can be a safe and successful off-label treatment of vertical platysma bands of various severities. Due to risk of the botulinum toxin diffusing to the underlying anatomic structures such as the deglutition muscles, the larynx, and the neck flexors, a maximal dose of 100 units has been suggested and there have been no known reports of untoward effects with doses less than 60 units. We present a case of mild to moderate dysphagia in a patient after very low doses of Abobutulinumtoxin (60 units, equivalent to 20 units of Onabotulinumtoxin using a 3:1 conversion ratio). We speculate that the adverse effects noted may be due to several possibilities, such as diffusion, injection technique, or intravascular injection. Thus, although botulinum toxin-A is generally considered a safe off-label treatment for vertical platysma bands, readers should still be aware of the possible side-effects even with low dose use, as supported by our case report of mild to moderate dysphagia with relatively conservative doses of Abobotulinumtoxin A.

J Drugs Dermatol. 2017;16(9):929-930.

. PMID- 28915290 TI - Lifting the Lower Face With an Absorbable Polydioxanone (PDO) Thread. AB - Traditional rejuvenation techniques include chemical peels, rhytidectomy of the skin, laser resurfacing, injection of dermal fillers and neurotoxins, and invasive surgical procedures. Patients with brow ptosis, jowl formation, and deepening nasolabial folds currently seek antiaging procedures with no incisions and minimal downtime such as thread-lifting with barbed sutures. The present report describes a case in which polydioxanone threads were used to lift the lower third of a patient's face. Fillers were used to supplement the results achieved by the thread lift because often, when tissue has been lifted, volume deficits are revealed, which can be corrected with dermal fillers. The procedure was performed in less than 30 minutes and was well tolerated. Mild swelling at the insertion points and general treatment area resolved within 7 days without intervention. Bruising was not observed. The patient showed remarkable improvement 7 months after the procedure.

J Drugs Dermatol. 2017;16(9):932 934.

. PMID- 28915291 TI - Cosmetic Practitioners Take Huge Risks Purchasing and Administering Illegal Botulinum Toxin Drug Products. AB - In their article "Importing Injectables" in the September 2014 issue of the Journal of Drugs in Dermatology, Dr. Kenneth Beer and Karen Rothschild highlighted the possible harm to patients and practitioners from the use of unapproved botulinum toxin products - eg, Botox, Dysport, Xeomin, and Myobloc - and other cosmetic prescription drug products purchased from foreign or unlicensed suppliers.1 In the intervening years, the accuracy of their critique has been repeatedly demonstrated, as the dangers to patients' health, as well as to cosmetic practitioners' liberty, has only increased. PMID- 28915292 TI - NEWS, VIEWS, AND REVIEWS: A Tool for My Laser Practice I Simply Can't Do Without: Shining a Light on My Favorite Light (Source). AB - With laser surgery, what you see is what you get. Visualizing the target for treatment, be it a port-wine stain, a cluster of spider veins, a tattoo or freckles, or simply photodamaged skin requires seeing through surface reflections, dry skin, and often quite dark laser goggles. The tool that has been indispensable to me in my practice is the Syris v900L polarizing and magnifying headlamp. This indispensable tool makes laser treatment more precise, effective, and easier by truly shining a light on the subject of a laser treatment. Future uses of this dynamic, yet simple invention, should be found in all of dermatology and beyond, anywhere that seeing what you are looking at more clearly is important.

J Drugs Dermatol. 2017;16(9):939-944.

. PMID- 28915293 TI - Children's Health Must Remain a Focus in the Recovery From Hurricane Harvey. PMID- 28915294 TI - Estimating Nonorganic Hearing Thresholds Using Binaural Auditory Stimuli. AB - Purpose: Minimum contralateral interference levels (MCILs) are used to estimate true hearing thresholds in individuals with unilateral nonorganic hearing loss. In this study, we determined MCILs and examined the correspondence of MCILs to true hearing thresholds to quantify the accuracy of this procedure. Method: Sixteen adults with normal hearing participated. Subjects were asked to feign a unilateral hearing loss at 1.0, 2.0, and 4.0 kHz. MCILs were determined. Subjects also made lateralization judgments for simultaneously presented tones with varying interaural intensity differences. Results: The 90% confidence intervals, calculated for the distributions, indicate that the MCIL in 90% of cases would be expected to be very close to threshold to approximately 17-19 dB poorer than the true hearing threshold. How close the MCIL is to true threshold appears to be based on the individual's response criterion. Conclusions: Response bias influences the MCIL and how close an MCIL is to true hearing threshold. The clinician can never know a client's response bias and therefore should use a 90% confidence interval to predict the range for the expected true threshold. On the basis of this approach, a clinician may assume that true threshold is at or as much as 19 dB better than MCIL. PMID- 28915295 TI - Error Type and Lexical Frequency Effects: Error Detection in Swedish Children With Language Impairment. AB - Purpose: The first aim of this study was to investigate if Swedish-speaking school-age children with language impairment (LI) show specific morphosyntactic vulnerabilities in error detection. The second aim was to investigate the effects of lexical frequency on error detection, an overlooked aspect of previous error detection studies. Method: Error sensitivity for grammatical structures vulnerable in Swedish-speaking preschool children with LI (omission of the indefinite article in a noun phrase with a neuter/common noun, and use of the infinitive instead of past-tense regular and irregular verbs) was compared to a control error (singular noun instead of plural). Target structures involved a high-frequency (HF) or a low-frequency (LF) noun/verb. Grammatical and ungrammatical sentences were presented in headphones, and responses were collected through button presses. Results: Children with LI had similar sensitivity to the plural control error as peers with typical language development, but lower sensitivity to past-tense errors and noun phrase errors. All children showed lexical frequency effects for errors involving verbs (HF > LF), and noun gender effects for noun phrase errors (common > neuter). Conclusions: School-age children with LI may have subtle difficulties with morphosyntactic processing that mirror expressive difficulties in preschool children with LI. Lexical frequency may affect morphosyntactic processing, which has clinical implications for assessment of grammatical knowledge. PMID- 28915296 TI - Investigating the Role of Salivary Cortisol on Vocal Symptoms. AB - Purpose: We investigated whether participants who reported more often occurring vocal symptoms showed higher salivary cortisol levels and if such possible associations were different for men and women. Method: The participants (N = 170; men n = 49, women n = 121) consisted of a population-based sample of Finnish twins born between 1961 and 1989. The participants submitted saliva samples for hormone analysis and completed a web questionnaire including questions regarding the occurrence of 6 vocal symptoms during the past 12 months. The data were analyzed using the generalized estimated equations method. Results: A composite variable of the vocal symptoms showed a significant positive association with salivary cortisol levels (p < .001). Three of the 6 vocal symptoms were significantly associated with the level of cortisol when analyzed separately (p values less than .05). The results showed no gender difference regarding the effect of salivary cortisol on vocal symptoms. Conclusions: There was a positive association between the occurrence of vocal symptoms and salivary cortisol levels. Participants with higher cortisol levels reported more often occurring vocal symptoms. This could have a connection to the influence of stress on vocal symptoms because stress is a known risk factor of vocal symptoms and salivary cortisol can be seen as a biomarker for stress. PMID- 28915297 TI - Language Sample Analysis and Elicitation Technique Effects in Bilingual Children With and Without Language Impairment. AB - Purpose: This study examined whether the language sample elicitation technique (i.e., storytelling and story-retelling tasks with pictorial support) affects lexical diversity (D), grammaticality (grammatical errors per communication unit [GE/CU]), sentence length (mean length of utterance in words [MLUw]), and sentence complexity (subordination index [SI]), which are commonly used indices for diagnosing primary language impairment in Spanish-English-speaking children in the United States. Method: Twenty bilingual Spanish-English-speaking children with typical language development and 20 with primary language impairment participated in the study. Four analyses of variance were conducted to evaluate the effect of language elicitation technique and group on D, GE/CU, MLUw, and SI. Also, 2 discriminant analyses were conducted to assess which indices were more effective for story retelling and storytelling and their classification accuracy across elicitation techniques. Results: D, MLUw, and SI were influenced by the type of elicitation technique, but GE/CU was not. The classification accuracy of language sample analysis was greater in story retelling than in storytelling, with GE/CU and D being useful indicators of language abilities in story retelling and GE/CU and SI in storytelling. Conclusion: Two indices in language sample analysis may be sufficient for diagnosis in 4- to 5-year-old bilingual Spanish English-speaking children. PMID- 28915298 TI - The Effect of Stimulus Variability on Learning and Generalization of Reading in a Novel Script. AB - Purpose: The benefit of stimulus variability for generalization of acquired skills and knowledge has been shown in motor, perceptual, and language learning but has rarely been studied in reading. We studied the effect of variable training in a novel language on reading trained and untrained words. Method: Sixty typical adults received 2 sessions of training in reading an artificial script. Participants were assigned to 1 of 3 groups: a variable training group practicing a large set of 24 words, and 2 nonvariable training groups practicing a smaller set of 12 words, with twice the number of repetitions per word. Results: Variable training resulted in higher accuracy for both trained and untrained items composed of the same graphemes, compared to the nonvariable training. Moreover, performance on untrained items was correlated with phonemic awareness only for the nonvariable training groups. Conclusions: High stimulus variability increases the reliance on small unit decoding in adults reading in a novel script, which is beneficial for both familiar and novel words. These results show that the statistical properties of the input during reading acquisition influence the type of acquired knowledge and have theoretical and practical implications for planning efficient reading instruction methods. Supplemental Material: https://doi.org/10.23641/asha.5302195. PMID- 28915299 TI - Home and Community Language Proficiency in Spanish-English Early Bilingual University Students. AB - Purpose: This study assessed home and community language proficiency in Spanish English bilingual university students to investigate whether the vocabulary gap reported in studies of bilingual children persists into adulthood. Method: Sixty five early bilinguals (mean age = 21 years) were assessed in English and Spanish vocabulary and verbal reasoning ability using subtests of the Woodcock-Munoz Language Survey-Revised (Schrank & Woodcock, 2009). Their English scores were compared to 74 monolinguals matched in age and level of education. Participants also completed a background questionnaire. Results: Bilinguals scored below the monolingual control group on both subtests, and the difference was larger for vocabulary compared to verbal reasoning. However, bilinguals were close to the population mean for verbal reasoning. Spanish scores were on average lower than English scores, but participants differed widely in their degree of balance. Participants with an earlier age of acquisition of English and more current exposure to English tended to be more dominant in English. Conclusions: Vocabulary tests in the home or community language may underestimate bilingual university students' true verbal ability and should be interpreted with caution in high-stakes situations. Verbal reasoning ability may be more indicative of a bilingual's verbal ability. PMID- 28915300 TI - Inflammation in Osteoarthritis. AB - Advances in the understanding of chondrocytes and the synovial membrane as targets of and participants in the inflammatory process in articular joints have provided insights into the role of inflammation in cartilage and subchondral bone injury in rheumatic diseases. Reports that describe the inflammatory cellular infiltration of synovial membranes in patients with osteoarthritis, studies that associate cartilage structural injury with synovial membrane inflammatory status, the development of new imaging modalities that quantitatively measure synovial membrane inflammation and basic science advances that explore inflammatory pathways in the synovial cavity all suggest that inflammation plays an important role in cartilage injury in osteoarthritis. As a result there is a shift in the notion that osteoarthritis is a disease caused merely by mechanical forces that increase joint loading. In response to this change in the current paradigm, innovative treatments involving the use of medications that modify the body's immune response (i.e., biologic and disease- modifying agents) are being studied. Implications for the population of Puerto Rico are discussed herein. PMID- 28915301 TI - The Work of US Public Health Service Officers in Puerto Rico, 1898-1919. AB - The history of the US Public Health Service (PHS) is usually presented in terms of diseases or discoveries; this article examines twenty years' activity in one location. When the United States invaded Puerto Rico in 1898, the Marine Hospital Service (now PHS) took responsibility for foreign quarantine, inspection of immigrants, and medical care for merchant seamen. Its officers evaluated the sanitary conditions of port cities, helped reorganize local disease surveillance and control, and investigated endemic diseases (e.g., hookworm-related anemia) and epidemics (e.g., bubonic plague). After World War I and pandemic influenza, and the greater self-government allowed Puerto Rico by Congress in 1917, PHS officers withdrew from routine local sanitary actions. A narrow geographic focus (Puerto Rico), to examine PHS activity over time (1898 to 1919) provides a richer picture of the agency's impact, and reveals how the sum of disease control activities affected the development of an area's health status and institutions. The duties and, importantly, the personal initiatives of PHS officers in Puerto Rico, such as WW King, produced lasting impact on scientific institutions and administrative, professional, and health care practices. PMID- 28915302 TI - Prevalence of Gingivitis in a Group of 35- to 70-Year-Olds Residing in Puerto Rico. AB - OBJECTIVE: Gingivitis, an inflammation of the gingival tissues, typically progresses to periodontitis. The objective of this study is to estimate the prevalence of gingivitis in 35- to 70-year-olds residing in San Juan, Puerto Rico, and assess the differences in gingivitis distribution between age and gender groups. METHODS: A cross-sectional epidemiological study was conducted with a sample of patients from a private practice and patients/employees of the Puerto Rico Medical Center. Participants completed a medical history questionnaire and received soft/hard tissue and gingival assessments based on a modified Loe-Silness index. Descriptive statistics were employed to estimate the overall gingivitis prevalence, severity (mild, moderate, severe), and mean gingival index (GI). Bleeding on probing (BOP) prevalence and the mean percentage of BOP sites were calculated by gender and age. Multinomial logistic regression was used to evaluate the associations between age, gender, and severity in 3 categories; multivariate logistic regression was used for having >=40% sites with BOP (vs. having <40% sites with BOP as reference). Odds ratios were also estimated. RESULTS: All 300 participants (52% women; 48% men) had gingivitis. The mean GI was 1.38. Moderate gingivitis was detected in 83% of the participants, mild in 7.3%, and severe in 9.3%. BOP was observed in 99% of the subjects (mean % BOP sites = 34%). After adjusting for age, men had significantly higher odds of moderate (OR = 4.66) and severe gingivitis (OR =10.06), compared to women, as well as 1.76 times higher odds of having 40% or more sites with BOP. CONCLUSION: Gingivitis was observed in all participants. Men had significantly higher GI, compared to women. The prevalence of gingivitis was higher in Puerto Rico than in the US. PMID- 28915303 TI - Prevalence of Functional Dentition in a Group of Mexican Adult Males. AB - OBJECTIVE: To determine the prevalence of functional dentition and associated periodontal variables in a sample of Mexican adult males. METHODS: A cross sectional study of 161 policemen in Campeche, Mexico, was carried out. A clinical examination using an electronic probe was used to collect variables (dental plaque, periodontal pockets, gingival recession, suppuration, and bleeding on probing) on 6 periodontal sites (a maximum of 168 sites, excluding third molars). Sociodemographic, socioeconomic, and behavioral variables were collected through a self-administered survey. Functional dentition was defined as having 21 or more natural teeth. Data were analyzed with STATA 11.0, using logistic regression models. RESULTS: Mean age was 38.3 (+/-10.9) years. The prevalence of having a functional dentition was 83.8% in the sample. The odds of having a functional dentition declined with age (odds ratio [OR] = 0.93), having diabetes (OR = 0.27) and with having a high percentage of sites with plaque (OR = 0.77), with bleeding on probing (OR = 0.97), and with gingival recession (OR = 0.82). CONCLUSION: While a large proportion of subjects had a functional dentition in this community dwelling sample of adult Mexican males, the likelihood of their having a functional dentition decreased with age, with their having been diagnosed with diabetes, and with assorted negative indicators of periodontal/gingival status. PMID- 28915304 TI - Trends in HPV Vaccine Initiation and Completion among Girls in Texas: Behavioral Risk Factor Surveillance System Data, 2008-2010. AB - OBJECTIVE: The objective of this study was to evaluate the trend of HPV vaccine initiation and completion among girls in Texas from 2008 to 2010. METHODS: Data were obtained from the Behavioral Risk Factors Surveillance System (BRFSS) over 3 years (2008-2010). The information regarding HPV vaccination was gathered from the parents of 9- to 17-year-old daughters (choosing only 1 per household) in randomly selected households in the sample area. RESULTS: The highest prevalence of vaccine initiation and completion were detected in 2010 (20.9% and 9.7%, respectively). Over the study period, HPV vaccine initiation statistically significantly increased (2008, 14.9%; 2009, 20.7%; 2010, 24.3%; p = 0.002), corresponding to an annual increase in coverage of 33.5% (odds ratio [OR] = 1.33; 95% confidence interval [CI]: 1.11-1.60). Similarly, HPV vaccination completion increased (2008, 6.3%; 2009, 9.6%; 2010, 11.6%; p = 0.021), corresponding to an annual increase in coverage of 37.1% (OR = 1.37; 95% CI: 1.05-1.79). Increasing trends in HPV vaccination initiation and completion were observed in mothers, white, non-Hispanic parents, parents who had attended some college or were college graduates, parents who were married/partnered, and parents who lived in urban areas. CONCLUSION: Although HPV vaccination coverage in Texas is lower than recommended, there have been increases in the trends of vaccine initiation and completion. The campaigns promoting HPV vaccination should target specific population groups in which HPV immunization rates did not increase over time. PMID- 28915305 TI - Trauma Epidemiology of Women in Puerto Rico, 2002-2011. AB - OBJECTIVE: Recent literature has suggested that trauma is heterogenic and that physiological response to it differs between sexes. The study represented in this manuscript aimed to describe gender differences in the mortality rates of trauma patients at the Puerto Rico Trauma Hospital (PRTH). MATERIALS AND METHODS: This was a cross-sectional study performed at PRTH. A total of 14,874 injured patients admitted to the hospital from 2002 to 2011 were included in the sample and divided into 2 groups, based on sex. Pearson's chi-square test was employed for categorical variables and the Mann-Whitney U test for continuous ones. A logistic regression model was undertaken to estimate the association between gender and study outcomes, after adjusting for confounders. A p-value lower than 0.05 was an indication of statistical significance. IRB approval was received. RESULTS: The most common injury areas for women were the chest (32.50%), followed by the extremities (25.83%) and the head/neck (21.51%). Road traffic collisions (RTCs) (45.08%), falls (19.62%), and pedestrian accidents (16.08%) were the most common injury mechanisms for women. The highest frequency of RTC injuries (57.52%) among females occurred in patients who were from 18 to 39 years old. Females 65 years old and older exhibited the highest frequency of falls (39.78%) and pedestrian injuries (25.14%). Males 17 years and under were more likely to have an Injury Severity Score (ISS) of 15 or greater (AOR = 1.56; 95% CI: 1.19-2.03) than were their female counterparts; and, overall, males were more likely to have a Glasgow coma score (GCS) under 9 (AOR = 1.30; 95% CI: 1.11-1.53) than females were. Despite these results, there were no differences between gender mortality rates (AOR = 1.04; 95% CI: 0.86-1.25). CONCLUSION: Our results suggest that there is no sex dimorphism conferring protection on females. Future studies should be conducted to assess this issue. PMID- 28915306 TI - Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico. AB - OBJECTIVE: To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. METHODS: A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. RESULTS: According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. CONCLUSION: Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility. PMID- 28915307 TI - The Use of Bone Morphogenetic Protein in Spinal Transforaminal Lumbar Interbody Fusion: Our Experience. AB - OBJECTIVE: Since its introduction and FDA approval, rhBMP-2 has been adopted by spine surgeons as a substitute for ICBG in numerous spinal fusion techniques. As broad clinical use increased, reports on potential complications associated with rhBMP-2 also increased. We provide our experience with TLIF using rhBMP-2 or ICBG in an entirely Hispanic population. METHODS: This was a 2-year retrospective study of 67 patients, with 26 in the rhBMP-2 group and 41 in the ICBG group, who underwent TLIF. Pertinent information was obtained through review of the medical records documenting complications, intraoperative times, and EBL, among other things. RESULTS: There were 28 post-operative complications with 15 (53.6%) in the ICBG group and 13 (46.4%) in the rhBMP-2 group. The average EBL was 572.3 mL (SD: 411.8) in the ICBG group and 397.9 mL (SD: 312.2) in the rhBMP-2 group. The average intraoperative time was 243.1 minutes (SD: 79.5) in the ICBG group and 226.5 minutes (SD: 64.7) in the rhBMP-2 group. Fifty-two patients underwent open TLIF and 15 patients underwent MI TLIF. The average EBL was 571.2 mL (SD: 375.3) in the open TLIF group and 228.3 mL (SD: 299.3) in the MI-TLIF group. The average intraoperative time was 241.0 minutes (SD: 76.0) for patients in the open TLIF group and 218.8 minutes (SD: 65.0) for those in the MI-TLIF group. There were no new cancer events at any of the 2-year follow-up visits. RESULTS: Our results suggest that the safety profile of rhBMP-2 may be inferior to that of ICBG, rejecting the possibility of ICBG being replaced by rhBMP-2 as the gold standard for spinal fusion. PMID- 28915308 TI - Mutilating Purpura Fulminans in an Adult with Meningococcal Sepsis. AB - We report a dramatic case of meningococcal sepsis manifesting as purpura fulminans in an elderly diabetic woman. Hemodynamic instability and severe bilateral cutaneous lesions involving her hands and feet developed rapidly. Specific antibiotic therapy and the administration of inotropic and vasopressor drugs were initiated. The severity and extension of the cutaneous lesions (attributed to purpura fulminans) worsened because of the need for vasoconstrictors for the treatment of septic shock. Bilateral transmetatarsal and metacarpal amputations were required to stabilize the patient. PMID- 28915309 TI - Genital Aphthous Ulcers and a Case of Suspected Chikungunya: A Short Clinical Case. AB - Genital aphthous ulcers can result from multiple conditions including febrile syndromes. Chikungunya infection manifests mainly as fever accompanied by polyarthralgia and pruritic rash. Nevertheless, healthcare providers should be alert to additional presentations. This is the case of a young woman presenting with painful genital ulcers after a three day prodome of fever and polyarthralgia. As a suspected case of Chikungunya infection and a clinical diagnosis of aphthae, treatment with oral prednisone for two weeks produced complete resolution of ulcers with no scarring. It is important to recognize that genital aphthous ulcers can develop in a febrile presentation such as that with Chikungunya. Although sexually transmitted diseases should be ruled out as a more common diagnosis in cases of genital lesions, knowledge about this unusual dermatological presentation would represent not only adequate prompt treatment but will minimize equivocal diagnosis as a sexually transmitted disease. PMID- 28915310 TI - Modelling the effects of lactic acid, sodium benzoate and temperature on the growth of Candida maltosa. AB - : The growth of the oxidatively imperfect yeast Candida maltosa Komagata, Nakase et Katsuya was studied experimentally and modelled mathematically in relation to sodium benzoate and lactic acid concentrations at different temperatures. Application of gamma models for the growth rate resulted in determination of cardinal temperature parameters for the growth environment containing lactic acid or sodium benzoate (Tmin = 0.7/1.3 degrees C, Tmax = 45.3/45.0 degrees C, Topt = 36.1/37.0 degrees C, MUopt = 0.88/0.96 h-1 ) as well as the maximal lactic acid concentration for growth (1.9%) or sodium benzoate (1397 mg kg-1 ). Based on the model, the times to reach the density of C. maltosa at the level of 105 CFU per ml can be determined at each combination of storage temperature and preservative concentration. The approach used in this study can broaden knowledge of the microbiological quality of fermented milk products during storage as well as the preservation efficacy of mayonnaise dressing for storage and consumption. SIGNIFICANCE AND IMPACT OF THE STUDY: The strain of Candida maltosaYP1 was originally isolated from air filters that ensured clean air overpressure in yoghurt fermentation tanks. Its growth in contaminated yoghurts manifested outwardly through surface growth, assimilation lactic acid and slight production of carbon dioxide. This was the opportunity to model the effects of lactic acid and sodium benzoate on growth and predict its behaviour in foods. The approach used in this study provides knowledge about microbiological quality development during storage of the fermented milk products as well as some preserved foods for storage and consumption. PMID- 28915311 TI - Can increased spatial resolution solve the crossing fiber problem for diffusion MRI? AB - It is now widely recognized that voxels with crossing fibers or complex geometrical configurations present a challenge for diffusion MRI (dMRI) reconstruction and fiber tracking, as well as microstructural modeling of brain tissues. This "crossing fiber" problem has been estimated to affect anywhere from 30% to as many as 90% of white matter voxels, and it is often assumed that increasing spatial resolution will decrease the prevalence of voxels containing multiple fiber populations. The aim of this study is to estimate the extent of the crossing fiber problem as we progressively increase the spatial resolution, with the goal of determining whether it is possible to mitigate this problem with higher resolution spatial sampling. This is accomplished using ex vivo MRI data of the macaque brain, followed by histological analysis of the same specimen to validate these measurements, as well as to extend this analysis to resolutions not yet achievable in practice with MRI. In both dMRI and histology, we find unexpected results: the prevalence of crossing fibers increases as we increase spatial resolution. The problem of crossing fibers appears to be a fundamental limitation of dMRI associated with the complexity of brain tissue, rather than a technical problem that can be overcome with advances such as higher fields and stronger gradients. PMID- 28915312 TI - DCE- and DW-MRI as early imaging biomarkers of treatment response in a preclinical model of triple negative breast cancer. AB - This work evaluates quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) parameters as early biomarkers of response in a preclinical model of triple negative breast cancer (TNBC). The standard Tofts' model of DCE-MRI returns estimates of the volume transfer constant (Ktrans ) and the extravascular extracellular volume fraction (ve ). DW-MRI returns estimates of the apparent diffusion coefficient (ADC). Mice (n = 38) were injected subcutaneously with MDA-MB-231. Tumors were grown to approximately 275 mm3 and sorted into the following groups: saline controls, low dose Abraxane (15 mg/kg) and high-dose Abraxane (25 mg/kg). Animals were imaged at days zero, one and three. On day three, tumors were extracted for immunohistochemistry. The positive percentage change in ADC on day one was significantly higher in both treatment groups relative to the control group (p < 0.05). In addition, the positive percentage change in Ktrans was significantly higher than controls (p < 0.05) on day one for the high-dose group and on days one and three for the low-dose group. The percentage change in tumor volume was significantly different between the high-dose and control groups on day three (p = 0.006). Histology confirmed differences at day three through reduced numbers of proliferating cells (Ki67 staining) in the high-dose group (p = 0.03) and low dose group (p = 0.052) compared with the control group. Co-immunofluorescent staining of vascular maturity [using von Willebrand Factor (vWF) and alpha-smooth muscle actin (alpha-SMA)] indicated significantly higher vascular maturation in the low-dose group compared with the controls on day three (p = 0.03), and trending towards significance in the high-dose group compared with controls on day three (p = 0.052). These results from quantitative imaging with histological validation indicate that ADC and Ktrans have the potential to serve as early biomarkers of treatment response in murine studies of TNBC. PMID- 28915313 TI - A Metabolomic Approach Applied to a Liquid Chromatography Coupled to High Resolution Tandem Mass Spectrometry Method (HPLC-ESI-HRMS/MS): Towards the Comprehensive Evaluation of the Chemical Composition of Cannabis Medicinal Extracts. AB - INTRODUCTION: Cannabis sativa L. is a powerful medicinal plant and its use has recently increased for the treatment of several pathologies. Nonetheless, side effects, like dizziness and hallucinations, and long-term effects concerning memory and cognition, can occur. Most alarming is the lack of a standardised procedure to extract medicinal cannabis. Indeed, each galenical preparation has an unknown chemical composition in terms of cannabinoids and other active principles that depends on the extraction procedure. OBJECTIVE: This study aims to highlight the main differences in the chemical composition of Bediol(r) extracts when the extraction is carried out with either ethyl alcohol or olive oil for various times (0, 60, 120 and 180 min for ethyl alcohol, and 0, 60, 90 and 120 min for olive oil). METHODOLOGY: Cannabis medicinal extracts (CMEs) were analysed by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) using an untargeted metabolomics approach. The data sets were processed by unsupervised multivariate analysis. RESULTS: Our results suggested that the main difference lies in the ratio of acid to decarboxylated cannabinoids, which dramatically influences the pharmacological activity of CMEs. Minor cannabinoids, alkaloids, and amino acids contributing to this difference are also discussed. The main cannabinoids were quantified in each extract applying a recently validated LC-MS and LC-UV method. CONCLUSIONS: Notwithstanding the use of a standardised starting plant material, great changes are caused by different extraction procedures. The metabolomics approach is a useful tool for the evaluation of the chemical composition of cannabis extracts. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28915314 TI - 1 H-MRS processing parameters affect metabolite quantification: The urgent need for uniform and transparent standardization. AB - Proton magnetic resonance spectroscopy (1 H-MRS) can be used to quantify in vivo metabolite levels, such as lactate, gamma-aminobutyric acid (GABA) and glutamate (Glu). However, there are considerable analysis choices which can alter the accuracy or precision of 1 H-MRS metabolite quantification. It is currently unknown to what extent variations in the analysis pipeline used to quantify 1 H MRS data affect outcomes. The purpose of this study was to evaluate whether the quantification of identical 1 H-MRS scans across independent and experienced research groups would yield comparable results. We investigated the influence of model parameters and spectral quantification software on fitted metabolite concentration values. Sixty spectra in 30 individuals (repeated measures) were acquired using a 7-T MRI scanner. Data were processed by four independent research groups with the freedom to choose their own individualized and optimal parameter settings using LCModel software. Data were processed a second time in one group using an independent software package (NMRWizard) for an additional comparison with a different post-processing platform. Correlations across research groups of the ratio between the highest and, arguably, the most relevant resonances for neurotransmission [N-acetyl aspartate (NAA), N-acetyl aspartyl glutamate (NAAG) and Glu] over the total creatine [creatine (Cr) + phosphocreatine (PCr)] concentration, using Pearson's product-moment correlation coefficient (r), were calculated. Mean inter-group correlations using LCModel software were 0.87, 0.88 and 0.77 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. The mean correlations when comparing NMRWizard results with LCModel fitting results at University Medical Center Utrecht (UMCU) were 0.87, 0.89 and 0.71 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. Metabolite quantification using identical 1 H-MRS data was influenced by processing parameters, basis sets and software choice. Locally preferred processing choices affected metabolite quantification, even when using identical software. Our results reinforce the notion that standard practices should be established to regularize outcomes of 1 H-MRS studies, and that basis sets used for processing should be made available to the scientific community. PMID- 28915315 TI - On the causes of trends in the seasonal amplitude of atmospheric CO2. AB - No consensus has yet been reached on the major factors driving the observed increase in the seasonal amplitude of atmospheric CO2 in the northern latitudes. In this study, we used atmospheric CO2 records from 26 northern hemisphere stations with a temporal coverage longer than 15 years, and an atmospheric transport model prescribed with net biome productivity (NBP) from an ensemble of nine terrestrial ecosystem models, to attribute change in the seasonal amplitude of atmospheric CO2 . We found significant (p < .05) increases in seasonal peak-to trough CO2 amplitude (AMPP-T ) at nine stations, and in trough-to-peak amplitude (AMPT-P ) at eight stations over the last three decades. Most of the stations that recorded increasing amplitudes are in Arctic and boreal regions (>50 degrees N), consistent with previous observations that the amplitude increased faster at Barrow (Arctic) than at Mauna Loa (subtropics). The multi-model ensemble mean (MMEM) shows that the response of ecosystem carbon cycling to rising CO2 concentration (eCO2 ) and climate change are dominant drivers of the increase in AMPP-T and AMPT-P in the high latitudes. At the Barrow station, the observed increase of AMPP-T and AMPT-P over the last 33 years is explained by eCO2 (39% and 42%) almost equally than by climate change (32% and 35%). The increased carbon losses during the months with a net carbon release in response to eCO2 are associated with higher ecosystem respiration due to the increase in carbon storage caused by eCO2 during carbon uptake period. Air-sea CO2 fluxes (10% for AMPP-T and 11% for AMPT-P ) and the impacts of land-use change (marginally significant 3% for AMPP-T and 4% for AMPT-P ) also contributed to the CO2 measured at Barrow, highlighting the role of these factors in regulating seasonal changes in the global carbon cycle. PMID- 28915316 TI - Plate pattern clarification of the marine dinophyte Heterocapsa triquetra sensu Stein (Dinophyceae) collected at the Kiel Fjord (Germany). AB - One of the most common marine dinophytes is a species known as Heterocapsa triquetra. When Stein introduced the taxon Heterocapsa, he formally based the type species H. triquetra on the basionym Glenodinium triquetrum. The latter was described by Ehrenberg and is most likely a species of Kryptoperidinium. In addition to that currently unresolved nomenclatural situation, the thecal plate composition of H. triquetra sensu Stein (1883) was controversial in the past. To clarify the debate, we collected material and established the strain UTKG7 from the Baltic Sea off Kiel (Germany, the same locality as Stein had studied), which was investigated using light and electron microscopy, and whose systematic position was inferred using molecular phylogenetics. The small motile cells (18 26 MUm in length) had a biconical through fusiform shape and typically were characterized by a short asymmetrically shaped, horn-like protuberance at the antapex. A large spherical nucleus was located in the episome, whereas a single pyrenoid laid in the lower cingular plane. The predominant plate pattern was identified as apical pore complex (Po, cp?, X), 4', 2a, 6'', 6c, 5s, 5''', 2''''. The triradiate body scales were 254-306 nm in diameter, had 6 ridges radiating from a central spine, 9 peripheral and 3 radiating spines, and 12 peripheral bars as well as a central depression in the basal plate. Our work provides a clarification of morphological characters and a new, validly published name for this important but yet formally undescribed species of Heterocapsa: H. steinii sp. nov. PMID- 28915317 TI - The theoretical reliability of PCR-based fish viral diagnostic methods is critically affected when they are applied to fish populations with low prevalence and virus loads. AB - AIMS: The reliability of polymerase chain reaction (PCR) techniques is an important issue in viral diagnosis, and it is even crucial when they must be applied for detection of viruses in asymptomatic carriers. The problems will arise when the aim is to study wild fish populations, where the viral loads and prevalence values are extremely low. We have evaluated several PCR procedures employed by two laboratories for monitoring fish captured in several oceanographic campaigns performed in the Gulf of Cadiz. METHODS AND RESULTS: To evaluate the reliability of different diagnostics test used, we have re-analysed fish samples that had been previously subjected to diagnosis for a surveillance of viruses performed in 2010-2011 in wild fish populations. The following parameters were employed: the clinical sensitivity (Ss), the clinical specificity (Sp), the predictive positive value, the predictive negative value, and the positive and negative likelihood ratio (LR+ and LR- ). For viral nervous necrosis virus, a RT-PCR procedure supplemented by nested PCR showed the highest values (100%) for all the parameters. For viral haemorrhagic septicaemia virus, the highest values were provided by RT-PCR supplemented by dot-blot hybridization. In the case of infectious pancreatic necrosis virus, none of the procedures yielded 100% for any parameter. CONCLUSIONS: The results obtained for viral prevalence indicate: (i) that the conservation of the samples at -80 degrees C did not affect to the capacity of detection of the virus in the tissues, and (ii) that the reproducibility of the diagnosis can be affected by factors including the staff experience and/or the materials employed. Finally, the use of a combination of procedures in advised to ensure the maximum reliability of the diagnosis when it is applied to asymptomatic fish populations. SIGNIFICANCE AND IMPACT OF THE STUDY: This paper describes a strategy of combining diagnostic tests for the surveillance and monitoring of wild fish populations to reduce underestimation of the prevalence of viruses this type of populations. PMID- 28915319 TI - An improved model for prostate diffusion incorporating the results of Monte Carlo simulations of diffusion in the cellular compartment. AB - The purpose of this work was to refine a previously published model of prostate diffusion by incorporating improved estimates of cellular diffusivity obtained by Monte Carlo simulation. Stromal and epithelial cell size and intracellular volume fraction in different grades of cancer were determined from histological images. Diffusion in different mixtures of cells, corresponding to different tumor grades, was simulated and cellular apparent diffusion coefficient and kurtosis values determined. These values were incorporated into the previously published model of prostate diffusion and model predictions compared with values found in the literature. Stromal cell radius and intracellular volume fraction were 3.74 +/- 0.96 MUm and 13 +/- 3% respectively in normal peripheral zone (PZ), and were similar in all grades of cancer. Epithelial cell radius and intracellular volume fraction were 3.40 +/- 0.15 MUm and 45 +/- 5% respectively in normal PZ, rising to 4.75 +/- 0.20 MUm and 70 +/- 8% in high grade cancer. Cellular apparent diffusion coefficient and kurtosis were 1.02 MUm2 ms-1 and 0.58 respectively in normal PZ, and 0.61 MUm2 ms-1 and 1.15 in high grade cancer (variation in simulation values are less than 0.1%). Agreement between model predictions and measurements were good, with a mean square error of 0.22 MUm2 ms-1 . Incorporation of cellular diffusion coefficient and kurtosis values obtained by Monte Carlo simulation into a model of prostate diffusion gives good agreement with published results. PMID- 28915318 TI - Applications of high-resolution magic angle spinning MRS in biomedical studies II Human diseases. AB - High-resolution magic angle spinning (HRMAS) MRS is a powerful method for gaining insight into the physiological and pathological processes of cellular metabolism. Given its ability to obtain high-resolution spectra of non-liquid biological samples, while preserving tissue architecture for subsequent histopathological analysis, the technique has become invaluable for biochemical and biomedical studies. Using HRMAS MRS, alterations in measured metabolites, metabolic ratios, and metabolomic profiles present the possibility to improve identification and prognostication of various diseases and decipher the metabolomic impact of drug therapies. In this review, we evaluate HRMAS MRS results on human tissue specimens from malignancies and non-localized diseases reported in the literature since the inception of the technique in 1996. We present the diverse applications of the technique in understanding pathological processes of different anatomical origins, correlations with in vivo imaging, effectiveness of therapies, and progress in the HRMAS methodology. PMID- 28915321 TI - Regulation and Functions of the Renin-Angiotensin System in White and Brown Adipose Tissue. AB - The renin angiotensin system (RAS) is a major regulator of blood pressure, fluid, and electrolyte homeostasis. RAS precursor angiotensinogen (Agt) is cleaved into angiotensin I (Ang I) and II (Ang II) by renin and angiotensin converting enzyme (ACE), respectively. Major effects of Ang II, the main bioactive peptide of this system, is mediated by G protein coupled receptors, Angiotensin Type 1 (AGTR1, AT1R) and Type 2 (AGTR2, AT2R) receptors. Further, the discovery of additional RAS peptides such as Ang 1-7 generated by the action of another enzyme ACE2 identified novel functions of this complex system. In addition to the systemic RAS, several local RAS exist in organs such as the brain, kidney, pancreas, and adipose tissue. The expression and regulation of various components of RAS in adipose tissue prompted extensive research into the role of adipose RAS in metabolic diseases. Indeed, animal studies have shown that adipose-derived Agt contributes to circulating RAS, kidney, and blood pressure regulation. Further, mice overexpressing Agt have high blood pressure and increased adiposity characterized by inflammation, adipocyte hypertrophy, and insulin resistance, which can be reversed at least in part by RAS inhibition. These findings highlight the importance of this system in energy homeostasis, especially in the context of obesity. This overview article discusses the depot-specific functions of adipose RAS, genetic and pharmacological manipulations of RAS, and its applications to adipogenesis, thermogenesis, and overall energy homeostasis. (c) 2017 American Physiological Society. Compr Physiol 7:1137-1150, 2017. PMID- 28915322 TI - Hormonal Regulation of Adipogenesis. AB - Adipose tissue includes multiple anatomical depots that serve as an energy reserve that can expand or contract to maintain metabolic homeostasis. During normal growth and in response to overnutrition, adipose tissue expands by increasing the volume of preexisting adipocytes (hypertrophy) and/or by generating new adipocytes (hyperplasia) via recruitment and differentiation of adipose progenitors. This so-called healthy expansion through hyperplasia is thought to be beneficial in that it protects against obesity associated metabolic disorders by allowing for the "safe" storage of excess energy. Remodeling adipose tissue to replace dysfunctional adipocytes that accumulate with obesity and age also requires new fat cell formation and is necessary to maintain metabolic health. Adipogenesis is the process by which adipose progenitors become committed to an adipogenic lineage and differentiate into mature adipocytes. This transition is regulated by complex array of transcriptional factors and numerous autocrine, paracrine, and endocrine signals. We will focus on hormonal factors that regulate adipocyte differentiation and their molecular mechanisms of actions on adipogenesis as studied in vitro and in vivo. Accumulating evidence indicates that adipose progenitors isolated from different adipose tissues exhibit intrinsic differences in adipogenic potential that may contribute to the depot and sex differences in adipose expansion and remodeling capacity. We will put special emphasis on the hormonal factors that are known to depot-dependently affect body fat accumulation and adipocyte development. (c) 2017 American Physiological Society. Compr Physiol 7:1151-1195, 2017. PMID- 28915324 TI - Facioscapulohumeral Muscular Dystrophy. AB - Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression of the array, and possibly the surrounding 4q35 region, allowing misexpression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. The less common form of the disease, FSHD2, results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele, also leading to the derepression of DUX4, further supporting a central role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a major focus of current investigation. Misexpression of other genes at the 4q35 locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also been implicated as disease modifiers, leading to several competing disease models. In this review, we describe recent advances in understanding the pathophysiology of FSHD, including the application of MRI as a research and diagnostic tool, the genetic and epigenetic disruptions associated with the disease, and the molecular basis of FSHD. We discuss how these advances are leading to the emergence of new approaches to enable development of FSHD therapeutics. (c) 2017 American Physiological Society. Compr Physiol 7:1229-1279, 2017. PMID- 28915320 TI - Adipose Tissue as a Site of Toxin Accumulation. AB - We examine the role of adipose tissue, typically considered an energy storage site, as a potential site of toxicant accumulation. Although the production of most persistent organic pollutants (POPs) was banned years ago, these toxicants persist in the environment due to their resistance to biodegradation and widespread distribution in various environmental forms (e.g., vapor, sediment, and water). As a result, human exposure to these toxicants is inevitable. Largely due to their lipophilicity, POPs bioaccumulate in adipose tissue, resulting in greater body burdens of these environmental toxicants with obesity. POPs of major concern include polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p dioxins and furans (PCDDs/PCDFs), and polybrominated biphenyls and diphenyl ethers (PBBs/PBDEs), among other organic compounds. In this review, we (i) highlight the physical characteristics of toxicants that enable them to partition into and remain stored in adipose tissue, (ii) discuss the specific mechanisms of action by which these toxicants act to influence adipocyte function, and (iii) review associations between POP exposures and the development of obesity and diabetes. An area of controversy relates to the relative potential beneficial versus hazardous health effects of toxicant sequestration in adipose tissue. (c) 2017 American Physiological Society. Compr Physiol 7:1085-1135, 2017. PMID- 28915323 TI - Hair Cell Transduction, Tuning, and Synaptic Transmission in the Mammalian Cochlea. AB - Sound pressure fluctuations striking the ear are conveyed to the cochlea, where they vibrate the basilar membrane on which sit hair cells, the mechanoreceptors of the inner ear. Recordings of hair cell electrical responses have shown that they transduce sound via submicrometer deflections of their hair bundles, which are arrays of interconnected stereocilia containing the mechanoelectrical transducer (MET) channels. MET channels are activated by tension in extracellular tip links bridging adjacent stereocilia, and they can respond within microseconds to nanometer displacements of the bundle, facilitated by multiple processes of Ca2+-dependent adaptation. Studies of mouse mutants have produced much detail about the molecular organization of the stereocilia, the tip links and their attachment sites, and the MET channels localized to the lower end of each tip link. The mammalian cochlea contains two categories of hair cells. Inner hair cells relay acoustic information via multiple ribbon synapses that transmit rapidly without rundown. Outer hair cells are important for amplifying sound evoked vibrations. The amplification mechanism primarily involves contractions of the outer hair cells, which are driven by changes in membrane potential and mediated by prestin, a motor protein in the outer hair cell lateral membrane. Different sound frequencies are separated along the cochlea, with each hair cell being tuned to a narrow frequency range; amplification sharpens the frequency resolution and augments sensitivity 100-fold around the cell's characteristic frequency. Genetic mutations and environmental factors such as acoustic overstimulation cause hearing loss through irreversible damage to the hair cells or degeneration of inner hair cell synapses. (c) 2017 American Physiological Society. Compr Physiol 7:1197-1227, 2017. PMID- 28915326 TI - Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. AB - Adipose tissue (AT) is the primary energy reservoir organ, and thereby plays a critical role in energy homeostasis and regulation of metabolism. AT expands in response to chronic overnutrition or aging and becomes a major source of inflammation that has marked influence on systemic metabolism. The chronic, sterile inflammation that occurs in the AT during the development of obesity or in aging contributes to onset of devastating diseases such as insulin resistance, diabetes, and cardiovascular pathologies. Numerous studies have shown that inflammation in the visceral AT of humans and animals is a critical trigger for the development of metabolic syndrome. This work underscores the well-supported conclusion that the inflammatory immune response and metabolic pathways in the AT are tightly interwoven by multiple layers of relatively conserved mechanisms. During the development of diet-induced obesity or age-associated adiposity, cells of the innate and the adaptive immune systems infiltrate and proliferate in the AT. Macrophages, which dominate AT-associated immune cells in mouse models of obesity, but are less dominant in obese people, have been studied extensively. However, cells of the adaptive immune system, including T cells and B cells, contribute significantly to AT inflammation, perhaps more in humans than in mice. Lymphocytes regulate recruitment of innate immune cells into AT, and produce cytokines that influence the helpful-to-harmful inflammatory balance that, in turn, regulates organismal metabolism. This review describes inflammation, or more precisely, metabolic inflammation (metaflammation) with an eye toward the AT and the roles lymphocytes play in regulation of systemic metabolism during obesity and aging. (c) 2017 American Physiological Society. Compr Physiol 7:1307 1337, 2017. PMID- 28915328 TI - CNS Targets of Adipokines. AB - Our understanding of adipose tissue as an endocrine organ has been transformed over the last 20 years. During this time, a number of adipocyte-derived factors or adipokines have been identified. This article will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted. (c) 2017 American Physiological Society. Compr Physiol 7:1359-1406, 2017. PMID- 28915329 TI - Mitophagy as a Protective Mechanism against Myocardial Stress. AB - Mitochondria are dynamic organelles that can undergo fusion, fission, biogenesis, and autophagic elimination to maintain mitochondrial quality control. Since the heart is in constant need of high amounts of energy, mitochondria, as a central energy supply source, play a crucial role in maintaining optimal cardiac performance. Therefore, it is reasonable to assume that mitochondrial dysfunction is associated with the pathophysiology of heart diseases. In non-dividing, post mitotic cells such as cardiomyocytes, elimination of dysfunctional organelles is essential to maintaining cellular function because non-dividing cells cannot dilute dysfunctional organelles through cell division. In this review, we discuss the recent findings regarding the physiological role of mitophagy in the heart and cardiomyocytes. Moreover, we discuss the functional role of mitophagy in the progression of cardiovascular diseases, including myocardial ischemic injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. (c) 2017 American Physiological Society. Compr Physiol 7:1407-1424, 2017. PMID- 28915330 TI - Impact of Adrenal Steroids on Regulation of Adipose Tissue. AB - Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11beta-HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. (c) 2017 American Physiological Society. Compr Physiol 7:1425-1447, 2017. PMID- 28915331 TI - Dual Specificity Phosphatase 5-Substrate Interaction: A Mechanistic Perspective. AB - The mammalian genome contains approximately 200 phosphatases that are responsible for catalytically removing phosphate groups from proteins. In this review, we discuss dual specificity phosphatase 5 (DUSP5). DUSP5 belongs to the dual specificity phosphatase (DUSP) family, so named after the family members' abilities to remove phosphate groups from serine/threonine and tyrosine residues. We provide a comparison of DUSP5's structure to other DUSPs and, using molecular modeling studies, provide an explanation for DUSP5's mechanistic interaction and specificity toward phospho-extracellular regulated kinase, its only known substrate. We also discuss new insights from molecular modeling studies that will influence our current thinking of mitogen-activated protein kinase signaling. Finally, we discuss the lessons learned from identifying small molecules that target DUSP5, which might benefit targeting efforts for other phosphatases. (c) 2017 American Physiological Society. Compr Physiol 7:1449-1461, 2017. PMID- 28915325 TI - Brown and Beige Adipose Tissues in Health and Disease. AB - Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRalpha+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRalpha+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases. (c) 2017 American Physiological Society. Compr Physiol 7:1281-1306, 2017. PMID- 28915327 TI - Adipose Tissue in HIV Infection. AB - HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-gamma and other regulatory gene expression, and increased proinflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. (c) 2017 American Physiological Society. Compr Physiol 7:1339-1357, 2017. PMID- 28915333 TI - Air Pollution and Other Environmental Modulators of Cardiac Function. AB - Cardiovascular disease (CVD) is the leading cause of death in developed regions and a worldwide health concern. Multiple external causes of CVD are well known, including obesity, diabetes, hyperlipidemia, age, and sedentary behavior. Air pollution has been linked with the development of CVD for decades, though the mechanistic characterization remains unknown. In this comprehensive review, we detail the background and epidemiology of the effects of air pollution and other environmental modulators on the heart, including both short- and long-term consequences. Then, we provide the experimental data and current hypotheses of how pollution is able to cause the CVD, and how exposure to pollutants is exacerbated in sensitive states. Published 2017. Compr Physiol 7:1479-1495, 2017. PMID- 28915332 TI - Obesity and Cardiometabolic Defects in Heart Failure Pathology. AB - Obesity is a major global epidemic that sets the stage for diverse multiple pathologies, including cardiovascular disease. The obesity-related low-grade chronic inflamed milieu is more pronounced in aging and responsive to cardiac dysfunction in heart failure pathology. Metabolic dysregulation of obesity integrates with immune reservoir in spleen and kidney network. Therefore, an integrative systems biology approach is necessary to delay progressive cardiac alternations. The purpose of this comprehensive review is to largely discuss the impact of obesity on the cardiovascular pathobiology in the context of problems and challenges, with major emphasis on the diversified models, and to study cardiac remodeling in obesity. The information in this article is immensely helpful in teaching advanced undergraduate, graduate, and medical students about the advancement and impact of obesity on cardiovascular health. (c) 2017 American Physiological Society. Compr Physiol 7:1463-1477, 2017. PMID- 28915334 TI - Epithelial Organization: The Gut and Beyond. AB - Epithelial cells are essential to the survival and homeostasis of complex organisms. These cells cover the surfaces of all mucosae, the skin, and other compartmentalized structures essential to physiological function. In addition to maintenance of barriers that separate internal and external compartments, epithelia display a variety of organ-specific differentiated functions. Function is reflected in overall epithelial structure and organization, shape of individual cells, and proteins expressed by these cells. More than one epithelial cell type is often present within a single organ and, in many cases, individual cells differentiate to change their functional behaviors as part of normal development or in response to extracellular stimuli. This article discusses the diversity of epithelial structure and function in general terms and explores representative tissues in greater depth to highlight organ specific functions and their contributions to physiology and disease. (c) 2017 American Physiological Society. Compr Physiol 7:1497-1518, 2017. PMID- 28915335 TI - ECM-Related Myopathies and Muscular Dystrophies: Pros and Cons of Protein Therapies. AB - Extracellular matrix (ECM) myopathies and muscular dystrophies are a group of genetic diseases caused by mutations in genes encoding proteins that provide critical links between muscle cells and the extracellular matrix. These include structural proteins of the ECM, muscle cell receptors, enzymes, and intracellular proteins. Loss of adhesion within the myomatrix results in progressive muscle weakness. For many ECM muscular dystrophies, symptoms can occur any time after birth and often result in reduced life expectancy. There are no cures for the ECM related muscular dystrophies and treatment options are limited to palliative care. Several therapeutic approaches have been explored to treat muscular dystrophies including gene therapy, gene editing, exon skipping, embryonic, and adult stem cell therapy, targeting genetic modifiers, modulating inflammatory responses, or preventing muscle degeneration. Recently, protein therapies that replace components of the defective myomatrix or enhance muscle and/or extracellular matrix integrity and function have been explored. Preclinical studies for many of these biologics have been promising in animal models of these muscle diseases. This review aims to summarize the ECM muscular dystrophies for which protein therapies are being developed and discuss the exciting potential and possible limitations of this approach for treating this family of devastating genetic muscle diseases. (c) 2017 American Physiological Society. Compr Physiol 7:1519-1536, 2017. PMID- 28915336 TI - The microbiome associated with two Synechococcus ribotypes at different levels of ecological interaction. AB - Planktonic cyanobacteria belonging to the genus Synechococcus are ubiquitously distributed in marine and fresh waters, substantially contributing to total carbon fixation on a global scale. While their ecological relevance is acknowledged, increasing resolution in molecular techniques allows disentangling cyanobacteria's role at the micro-scale, where complex microbial interactions may drive the overall community assembly. The interplay between phylogenetically different Synechococcus clades and their associated bacterial communities can affect their ecological fate and susceptibility to protistan predation. In this study, we experimentally promoted different levels of ecological interaction by mixing two Synechococcus ribotypes (MW101C3 and LL) and their associated bacteria, with and without a nanoflagellate grazer (Poterioochromonas sp.) in laboratory cultures. The beta-diversity of the Synechococcus-associated microbiome in laboratory cultures indicated that the presence of the LL ribotype was the main factor determining community composition changes (41% of total variance), and prevailed over the effect of protistan predation (18% of total variance). Our outcomes also showed that species coexistence and predation may promote microbial diversity, thus highlighting the underrated ecological relevance of such micro-scale factors. PMID- 28915337 TI - The cost and cost-effectiveness of childhood cancer treatment in El Salvador, Central America: A report from the Childhood Cancer 2030 Network. AB - BACKGROUND: Although previous studies have examined the cost of treating individual childhood cancers in low-income and middle-income countries, to the authors' knowledge none has examined the overall cost and cost-effectiveness of operating a childhood cancer treatment center. Herein, the authors examined the cost and sources of financing of a pediatric cancer unit in Hospital Nacional de Ninos Benjamin Bloom in El Salvador, and make estimates of cost-effectiveness. METHODS: Administrative data regarding costs and volumes of inputs were obtained for 2016 for the pediatric cancer unit. Similar cost and volume data were obtained for shared medical services provided centrally (eg, blood bank). Costs of central nonmedical support services (eg, utilities) were obtained from hospital data and attributed by inpatient share. Administrative data also were used for sources of financing. Cost-effectiveness was estimated based on the number of new patients diagnosed annually and survival rates. RESULTS: The pediatric cancer unit cost $5.2 million to operate in 2016 (treating 90 outpatients per day and experiencing 1385 inpatient stays per year). Approximately three-quarters of the cost (74.7%) was attributed to 4 items: personnel (21.6%), pathological diagnosis (11.5%), pharmacy (chemotherapy, supportive care medications, and nutrition; 31.8%), and blood products (9.8%). Funding sources included government (52.5%), charitable foundations (44.2%), and a social security contribution scheme (3.4%). Based on 181 new patients per year and a 5-year survival rate of 48.5%, the cost per disability-adjusted life-year averted was $1624, which is under the threshold considered to be very cost effective. CONCLUSIONS: Treating childhood cancer in a specialized unit in low income and middle-income countries can be done cost-effectively. Strong support from charitable foundations aids with affordability. Cancer 2018;124:391-7. (c) 2017 American Cancer Society. PMID- 28915338 TI - Neurocognitive, psychosocial, and quality-of-life outcomes in adult survivors of childhood non-Hodgkin lymphoma. AB - BACKGROUND: Children with non-Hodgkin lymphoma (NHL) undergo treatment with central nervous system-directed therapy, the potentially neurotoxic effects of which have not been reported in NHL survivors. METHODS: NHL survivors (n = 187) participating in the St. Jude Lifetime Cohort who were 10 or more years from their diagnosis and were 18 years old or older underwent neurocognitive, emotional distress (Brief Symptom Inventory 18), and health-related quality of life (HRQOL) assessments (36-Item Short Form Health Survey). Age-adjusted z scores were compared with community controls (n = 181) and normative data. Treatment exposures were abstracted from medical records. Models adjusted for the age, sex, and time from diagnosis were used to calculate the risk of impairment. RESULTS: The mean ages at evaluation were similar for the survivors and the controls (35.7 +/- 8.9 vs 35.5 +/- 11.0 years; P = .86). Survivors were 25.2 +/- 8.8 years from their diagnosis: 43 (23%) received cranial radiation, 70 (37%) received high-dose methotrexate, 40 (21%) received high-dose cytarabine, and 151 (81%) received intrathecal chemotherapy. Survivors' intelligence and attention were within normal limits; however, their memory, executive function, processing speed, and academics were impaired in comparison with both population norms and community controls (P values < .05). Treatment-related exposures were not associated with neurocognitive function; however, neurocognitive impairment was associated with lower educational attainment, unemployment, and occupational status (P values < .03). Slower processing speed and worse self-reported executive function were associated with symptoms of depression (P values <= .003) and poorer HRQOL (P values < .05). CONCLUSIONS: Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor HRQOL. Early-detection and intervention strategies are recommended. Cancer 2017. (c) 2017 American Cancer Society. PMID- 28915339 TI - A vapour phase assay for evaluating the antimicrobial activities of essential oils against bovine respiratory bacterial pathogens. AB - : The objectives of this study were to develop a new assay for the evaluation of the antimicrobial activities of essential oils (EOs) in vapour phase and to demonstrate the antimicrobial activities of commercial EOs against BRPs. To achieve the first objective, a microtube cap containing 100 MUl of EO was embedded in an agar plate. An agar plug (diameter 13 mm) inoculated with a bacterial suspension containing108 CFU per ml was then placed over the cap and incubated at 37 degrees C for 24 h. Subsequently, bacteria were recovered from the agar plug by immersion in 5 ml of broth for 10 min, followed by vortexing for 30 s, and the broths were then plated for enumeration. To demonstrate the usefulness of the assay, nine commercial EOs derived from the following specific plants: ajowan, carrot seed, cinnamon leaf, citronella, fennel, ginger grass, lavender, rosemary and thyme were first evaluated for their vapour phase antimicrobial activities against Mannheimia haemolytica serotype 1. Selected EOs were further tested against Pasteurella multocida and Histophilus somni. The EOs of ajowan, thyme and cinnamon leaf completely or partially inhibited BRPs growth. This new assay provided reproducible results on the vapour phase antimicrobial activities of EOs against BRPs. These results support further study of EOs as a potential mitigation strategy against BRPs. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we present a new vapour phase assay for evaluating the antimicrobial activities of essential oils (EO) against bovine respiratory pathogens (BRPs). Using this assay, we identified EOs, such as ajowan, thyme and cinnamon leaf, that can effectively inhibit growth of the BRPs Mannheimia haemolytica serotype 1, Pasteurella multocida and Histophilus somni. This is the first study to demonstrate the vapour phase antimicrobial activity of EOs against BRPs. PMID- 28915340 TI - Metabolic profile of visual cortex in diabetic rats measured with in vivo proton MRS. AB - The purpose of the present study was to characterize the metabolic profile of the visual cortex in streptozotocin-induced Type 1 diabetic rats by means of in vivo proton MRS. Several metabolite concentration ratios in the visual cortex were calculated. In addition, postmortem histologic analyses for retinal ganglion cell (RGC) loss, optic nerve injury and visual cortex alterations were monitored. The results showed that diabetes induced several changes in visual cortex metabolites, such as reduced N-acetylaspartate, glutamate, gamma-aminobutyric acid, taurine and choline-containing compound levels. Nevertheless, myo-inositol levels increased significantly as compared with controls. Remarkable RGC loss and optic nerve degeneration were observed by morphological analysis. Moreover, the results showed significant neuronal loss and glial activation in the visual cortex. These findings indicated that, besides vascular abnormalities, neuronal loss and degeneration in the visual pathway were induced due to disrupted glucose homeostasis in diabetes. Metabolic or functional abnormalities were induced in cerebral neurons of the visual cortex by diabetes. PMID- 28915342 TI - Transplantation of solid organ recipients shedding Epstein-Barr virus DNA pre transplant: A prospective study. AB - Epstein-Barr virus (EBV) poses a significant threat to patient and graft survival post-transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post-transplant. To test this hypothesis, we conducted a 5-year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre-transplant samples were available from 98 subjects. EBV DNA was detected pre-transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre-transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post-transplant EBV viremia-free survival (P = .8). There were no cases of EBV-related disease or post-transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre-transplant. In conclusion, detectable EBV DNA pre-transplant was not associated with differences in patient/graft survival, post-transplant EBV viremia, or EBV-related diseases including PTLD. PMID- 28915341 TI - 31 P magnetic resonance fingerprinting for rapid quantification of creatine kinase reaction rate in vivo. AB - The purpose of this work was to develop a 31 P spectroscopic magnetic resonance fingerprinting (MRF) method for fast quantification of the chemical exchange rate between phosphocreatine (PCr) and adenosine triphosphate (ATP) via creatine kinase (CK). A 31 P MRF sequence (CK-MRF) was developed to quantify the forward rate constant of ATP synthesis via CK ( kfCK), the T1 relaxation time of PCr ( T1PCr), and the PCr-to-ATP concentration ratio ( MRPCr). The CK-MRF sequence used a balanced steady-state free precession (bSSFP)-type excitation with ramped flip angles and a unique saturation scheme sensitive to the exchange between PCr and gammaATP. Parameter estimation was accomplished by matching the acquired signals to a dictionary generated using the Bloch-McConnell equation. Simulation studies were performed to examine the susceptibility of the CK-MRF method to several potential error sources. The accuracy of nonlocalized CK-MRF measurements before and after an ischemia-reperfusion (IR) protocol was compared with the magnetization transfer (MT-MRS) method in rat hindlimb at 9.4 T (n = 14). The reproducibility of CK-MRF was also assessed by comparing CK-MRF measurements with both MT-MRS (n = 17) and four angle saturation transfer (FAST) (n = 7). Simulation results showed that CK-MRF quantification of kfCK was robust, with less than 5% error in the presence of model inaccuracies including dictionary resolution, metabolite T2 values, inorganic phosphate metabolism, and B1 miscalibration. Estimation of kfCK by CK-MRF (0.38 +/- 0.02 s-1 at baseline and 0.42 +/- 0.03 s-1 post-IR) showed strong agreement with MT-MRS (0.39 +/- 0.03 s-1 at baseline and 0.44 +/- 0.04 s-1 post-IR). kfCK estimation was also similar between CK-MRF and FAST (0.38 +/- 0.02 s-1 for CK-MRF and 0.38 +/- 0.11 s-1 for FAST). The coefficient of variation from 20 s CK-MRF quantification of kfCK was 42% of that by 150 s MT-MRS acquisition and was 12% of that by 20 s FAST acquisition. This study demonstrates the potential of a 31 P spectroscopic MRF framework for rapid, accurate and reproducible quantification of chemical exchange rate of CK in vivo. PMID- 28915344 TI - Seeking the views of service users: From impossibility to necessity. PMID- 28915343 TI - Identifying preferred format and source of exercise information in persons with multiple sclerosis that can be delivered by health-care providers. AB - BACKGROUND: There is increasing recognition of the benefits of exercise in individuals with multiple sclerosis (MS), yet the MS population does not engage in sufficient amounts of exercise to accrue health benefits. There has been little qualitative inquiry to establish the preferred format and source for receiving exercise information from health-care providers among persons with MS. OBJECTIVE: We sought to identify the desired and preferred format and source of exercise information for persons with MS that can be delivered through health care providers. SETTING AND PARTICIPANTS: Participants were adults with MS who had mild or moderate disability and participated in a range of exercise levels. All participants lived in the Midwest of the United States. METHODS: Fifty semi structured interviews were conducted and analysed using thematic analysis. RESULTS: Two themes emerged, (i) approach for receiving exercise promotion and (ii) ideal person for promoting exercise. Persons with MS want to receive exercise information through in-person consultations with health-care providers, print media and electronic media. Persons with MS want to receive exercise promotion from health-care providers with expertise in MS (ie neurologists) and with expertise in exercise (eg physical therapists). CONCLUSIONS: These data support the importance of understanding how to provide exercise information to persons with MS and identifying that health-care providers including neurologists and physical therapists should be involved in exercise promotion. PMID- 28915345 TI - Chemoselective and Catalyst-Free O-Borylation of Silanols: A Facile Access to Borasiloxanes. AB - This paper demonstrates the first highly chemoselective syntheses of various borasiloxanes from hydroboranes and silanols, achieved through catalyst-free dehydrogenative coupling at room temperature. This green protocol, which uses easily accessible reagents, allows for the obtaining of borasiloxanes under air atmosphere and solvent-free conditions. PMID- 28915347 TI - Re: SAEM Annual Meeting Abstracts. PMID- 28915346 TI - A review of chemical 'spot' tests: A presumptive illicit drug identification technique. AB - Chemical 'spot' tests are a presumptive illicit drug identification technique commonly used by law enforcement, border security personnel, and forensic laboratories. The simplicity, low cost, and rapid results afforded by these tests make them particularly attractive for presumptive identification globally. In this paper, we review the development of these long-established methods and discuss color test recommendations and guidelines. A search of the scientific literature revealed the chemical reactions occurring in many color tests are either not actively investigated or reported as unknown. Today, color tests face many challenges, from the appearance of new psychoactive substances to concerns regarding selectivity, sensitivity, and safety. Advances in technology have seen color test reagents used in digital image color analysis, solid sensors, and microfluidic devices for illicit drug detection. This summarizes current research and suggests the future of presumptive color testing. PMID- 28915349 TI - Watery Saliva Secreted by the Grain Aphid Sitobion avenae Stimulates Aphid Resistance in Wheat. AB - Infestation with Sitobion avenae induces localized defense responses in wheat; in this study, the role of S. avenae watery saliva in resistance induction was examined by infiltrating aphid saliva into wheat leaves. After feeding S. avenae on an artificial diet for 48 h, we first collected watery saliva from them and then separated the salivary proteins using one-dimensional gel electrophoresis. Gene expression studies showed that infiltration of S. avenae watery saliva in wheat leaves induced a strong salicylic acid-responsive defense but moderate jasmonic acid-dependent defense. Feeding on wheat leaves infiltrated with aphid saliva, compared with untreated leaves, significantly decreased the number of nymphs produced per day and the intrinsic rate of increase of the population of S. avenae. In a choice test against untreated wheat, saliva-infiltrated wheat had repellent effects on aphids. Additionally, electrical penetration graph results showed that the feeding behavior of S. avenae on saliva-treated wheat was negatively affected compared with that on untreated wheat. These findings provided direct evidence that salivary components of S. avenae are involved in the induction of wheat resistance against aphids and further demonstrated the important roles of watery saliva in aphid-plant interactions. PMID- 28915348 TI - Activation of factor XIII is accompanied by a change in oligomerization state. AB - : Factor XIII A (FXIIIA) is a member of the transglutaminase enzyme family that cross-links both intra- and extracellular protein substrates. To prevent undesired cross-linking, FXIIIA is expressed as an inactive zymogen and exists intracellularly as an A2 homodimer. In plasma, FXIII A2 is complexed with two protective factor XIII B subunits (A2 B2 ) that dissociate upon activation of the zymogen. Based on limited experimental data, activated FXIII was considered a dimer of two catalytically active A subunits. However, accumulating but indirect evidence has suggested activation may lead to a monomeric state instead. In the present study, we employed analytical ultracentrifugation (AUC) to directly explore the oligomerization state of zymogen as well as active FXIIIA in solution. We first confirmed that the zymogen was a FXIIIA2 dimer. When we activated FXIIIA nonproteolytically (by high mm Ca2+ ), the protein dissociated to monomers. More importantly, FXIIIA incubation with its physiological partner, the protease thrombin, led to a monomeric state as well. AUC studies of partially cleaved FXIIIA further suggested that thrombin cleavage of a single activation peptide in a zymogen dimer is sufficient to weaken intersubunit interactions, initiating the transition to monomer. The enzymatic activity of the thrombin cleaved species was higher than nonproteolytically activated enzyme, suggesting that displacement of the activation peptide renders the FXIIIA more accessible to substrates. Thus, results provide evidence that FXIII undergoes a change in oligomerization state as part of the activation process, and emphasize the role of the activation peptide in preventing FXIIIA catalytic activity. ENZYMES: Factor XIIIA (EC2.3.2.13). PMID- 28915350 TI - Zeta Potential of Poly(methyl methacrylate) (PMMA) in Contact with Aqueous Electrolyte-Surfactant Solutions. AB - The addition of surfactants can considerably impact the electrical characteristics of an interface, and the zeta potential measurement is the standard method for its characterization. In this article, a comprehensive study of the zeta potential of poly(methyl methacrylate) (PMMA) in contact with aqueous solutions containing an anionic, a cationic, or a zwitterionic surfactant at different pH and ionic strength values is conducted. Electrophoretic mobilities are inferred from electrophoretic light scattering measurements of the particulate PMMA. These values can be converted into zeta potentials using permittivity and viscosity measurements of the continuous phase. Different behaviors are observed for each surfactant type, which can be explained with the various adsorption mechanisms on PMMA. For the anionic surfactant, the absolute zeta potential value below the critical micelle concentration (CMC) increases with the concentration, while it becomes rather constant around the CMC. At concentrations above the CMC, the absolute zeta potential increases again. We propose that hydrophobic-based adsorption and, at higher concentrations, the competing micellization process drive this behavior. The addition of cationic surfactant results in an isoelectric point below the CMC where the negative surface charge is neutralized by a layer of adsorbed cationic surfactant. At concentrations near the CMC, the positive zeta potential is rather constant. In this case, we propose that electrostatic interactions combined with hydrophobic adsorption are responsible for the observed behavior. The zeta potential in the presence of zwitterionic surfactant is influenced by the adsorption, because of hydrophobic interactions between the surfactant tail and the PMMA surface. However, there is less influence, compared to the ionic surfactants. For all three surfactant types, the zeta potential changes to more-negative or less positive values for alkaline pH values, because of hydroxide adsorption. An increase of the ionic strength decreases the absolute value of the zeta potential, because of the shielding effects. PMID- 28915351 TI - Relaxation Dynamics vs Crystallization Kinetics in the Amorphous State: The Case of Stiripentol. AB - With the aim of finding a correlation between the crystallization kinetics and the molecular dynamics of a substance that would allow prediction of its crystallization time as a function of temperature for a given alpha relaxation time, we have studied stiripentol, an anticonvulsant drug. Stiripentol has been characterized in its supercooled liquid, amorphous (glass), and crystalline states by the concurrent use of broadband dielectric spectroscopy (BDS), differential scanning calorimetry, X-ray diffraction, and optical microscopy. BDS was employed to study both the dipolar molecular dynamics and the kinetics of crystallization from the melt. Three different molecular relaxation dynamics were identified: an alpha relaxation corresponding to the collective reorientation of the molecules and associated with the glass transition (Tg = 246.2 +/- 0.5 K), a Johari Goldstein beta relaxation that can be associated with the single-molecule precursor of the alpha process, and a gamma relaxation arising from intramolecular motions. Isothermal crystallization of Stiripentol was studied by means of BDS well above the glass transition (between 273 and 293 K), and it was observed under optical microscope at ambient conditions. Stiripentol did not exhibit any sign of polymorphism at ambient pressure, and it recrystallized from the melt into its stable crystalline form. The crystallization kinetics did not obey the Avrami law. Stiripentol displayed a very low nucleation rate, and drops of liquid stiripentol were observed to crystallize completely from a single nucleus before the appearance of new nuclei, so that the crystallite grew according to the morphology of the liquid domains, a fact that might explain the lack of validity of the Avrami law. Possible correlations between the crystallization kinetics and the molecular dynamics have been analyzed, finding that the crystallization time has a sublinear dependence on the cooperative relaxation time, as is the case in other substances reported in the scientific literature. This could suggest a general correlation of these parameters, at least at temperatures above Tg. The low nucleation rate is an interesting feature in the quest of possible mechanisms that allow enhancing the physical stability of amorphous drugs. PMID- 28915352 TI - All-Atom Simulations Reveal Protein Charge Decoration in the Folded and Unfolded Ensemble Is Key in Thermophilic Adaptation. AB - Thermophilic proteins denature at much higher temperature compared to their mesophilic homologues, in spite of high structural and sequential similarity. Computational approaches to understand this puzzle face three major challenges: (i) unfolded ensembles are usually neglected, (ii) simulation studies of the folded states are often too short, and (iii) the majority of investigations focus on a few protein pairs, obscuring the prevalence of different strategies across multiple protein systems. We address these concerns by carrying out all-atom simulations to characterize physicochemical properties of both the folded and the disordered ensemble in multiple (12) thermophilic-mesophilic homologous protein pairs. We notice two clear trends in most pairs (10 out of 12). First, specific distribution of charges in the native basin-sampled from multimicrosecond long Molecular Dynamics (MD) simulation trajectories-leads to more favorable electrostatic interaction energy in thermophiles compared to mesophiles. Next, thermophilic proteins have lowered electrostatic interaction in their unfolded state-generated using Monte Carlo (MC) simulation-compared to their mesophilic counterparts. The net contribution of interaction energy to folding stability, however, remains more favorable in thermophiles compared to mesophiles. The overall contribution of electrostatics quantified by combining the net interaction energy and the solvation penalty of folding-due to differential charge burial in the folded and the unfolded ensemble-is also mostly favorable in thermophilic proteins compared to mesophiles. The systems that deviate from this trend provide interesting test cases to learn more about alternate design strategies when modification of charges is not viable due to functional reasons. The unequal contribution of the unfolded state to the stability in thermophiles and mesophiles highlights the importance of modeling the disordered ensemble to understand thermophilic adaptation as well as protein stability, in general. Our integrated approach-combining finite element analysis with MC and MD-can be useful in designing charge mutations to alter protein stability. PMID- 28915353 TI - Detection of CuAuPd Phase Boundaries Using Core Level Shifts. AB - A high throughput study has been conducted of the Cu 2p3/2, Au 4f7/2, and Pd 3d3/2 X-ray photoemission spectra obtained from a continuous distribution of CuxAuyPd1-x-y alloy samples prepared as a single composition spread alloy film (CSAF). All three elements exhibit shifts of their core level binding energies with respect to their pure states when diluted into the alloy. The Cu 2p3/2 core level shift (CLS) exhibits additional shifts over the composition ranges at which the CuxAuyPd1-x-y alloy transitions between FCC and B2 phases. This discontinuous CLS has been used to map the extent of the B2 phase across the ternary CuxAuyPd1 x-y alloy composition space. The sensitivity of core level binding energies to the alloy phase offers an opportunity to use XPS to study phases in alloy nanoparticles, ultrathin films, and other morphologies that are not amenable to structure determination by diffraction based methods. PMID- 28915354 TI - Rose Essential Oil Delayed Alzheimer's Disease-Like Symptoms by SKN-1 Pathway in C. elegans. AB - There are no effective medications for delaying the progress of Alzheimer's disease (AD), the most common neurodegenerative disease in the world. In this study, our results with C. elegans showed that rose essential oil (REO) significantly inhibited AD-like symptoms of worm paralysis and hypersensivity to exogenous 5-HT in a dose-dependent manner. Its main components of beta citronellol and geraniol acted less effectively than the oil itself. REO significantly suppressed Abeta deposits and reduced the Abeta oligomers to alleviate the toxicity induced by Abeta overexpression. Additionally, the inhibitory effects of REO on worm paralysis phenotype were abrogated only after skn-1 RNAi but not daf-16 and hsf-1 RNAi. REO markedly activated the expression of gst-4 gene, which further supported SKN-1 signaling pathway was involved in the therapeutic effect of REO on AD C. elegans. Our results provided direct evidence on REO for treating AD on an organism level and relative theoretical foundation for reshaping medicinal products of REO in the future. PMID- 28915355 TI - Thiamin deficiency on fetal brain development with and without prenatal alcohol exposure. AB - Adequate thiamin levels are crucial for optimal health through maintenance of homeostasis and viability of metabolic enzymes, which require thiamine as a co factor. Thiamin deficiency occurs during pregnancy when the dietary intake is inadequate or excessive alcohol is consumed. Thiamin deficiency leads to brain dysfunction because thiamin is involved in the synthesis of myelin and neurotransmitters (e.g., acetylcholine, gamma-aminobutyric acid, glutamate), and its deficiency increases oxidative stress by decreasing the production of reducing agents. Thiamin deficiency also leads to neural membrane dysfunction, because thiamin is a structural component of mitochondrial and synaptosomal membranes. Similarly, in-utero exposure to alcohol leads to fetal brain dysfunction, resulting in negative effects such as fetal alcohol spectrum disorder (FASD). Thiamin deficiency and prenatal exposure to alcohol could act synergistically to produce negative effects on fetal development; however, this area of research is currently under-studied. This minireview summarizes the evidence for the potential role of thiamin deficiency in fetal brain development, with or without prenatal exposure to alcohol. Such evidence may influence the development of new nutritional strategies for preventing or mitigating the symptoms of FASD. PMID- 28915356 TI - Real-Time Apoptosis and Viability High-Throughput Screening of 3D Multicellular Tumor Spheroids Using the Celigo Image Cytometer. AB - Three-dimensional tumor spheroid models have been increasingly used to investigate and characterize cancer drug compounds. Previously, the Celigo image cytometer has demonstrated its utility in a high-throughput screening manner for evaluating potential drug candidates in a 3D multicellular tumor spheroid (MCTS) primary screen. In addition, we have developed real-time kinetic caspase 3/7 apoptosis and propidium iodide viability 3D MCTS assays, both of which can be used in a secondary screen to better characterize the hit compounds. In this work, we monitored the kinetic apoptotic and cytotoxic effects of 14 compounds in 3D MCTS produced from the glioblastoma cell line U87MG in 384-well plates for 9 days. The kinetic results allowed the categorization of the effects from 14 drug compounds into early and late cytotoxic, apoptotic, cytostatic, and no effects. The real-time apoptosis and viability screening method can serve as an improved secondary screen to better understand the mechanism of action of these potential drug candidates identified from the primary screen, allowing one to identify a more qualified drug candidate and streamline the drug discovery process of research and development. PMID- 28915357 TI - A yigP mutant strain is a small colony variant of E. coli and shows pleiotropic antibiotic resistance. AB - Small colony variants (SCVs) are a commonly observed subpopulation of bacteria that have a small colony size and distinctive biochemical characteristics. SCVs are more resistant than the wild type to some antibiotics and usually cause persistent infections in the clinic. SCV studies have been very active during the past 2 decades, especially Staphylococcus aureus SCVs. However, fewer studies on Escherichia coli SCVs exist, so we studied an E. coli SCV during an experiment involving the deletion of the yigP locus. PCR and DNA sequencing revealed that the SCV was attributable to a defect in the yigP function. Furthermore, we investigated the antibiotic resistance profile of the E. coli SCV and it showed increased erythromycin, kanamycin, and d-cycloserine resistance, but collateral sensitivity to ampicillin, polymyxin, chloramphenicol, tetracycline, rifampin, and nalidixic acid. We tried to determine the association between yigP and the pleiotropic antibiotic resistance of the SCV by analyzing biofilm formation, cellular morphology, and coenzyme Q (Q8) production. Our results indicated that impaired Q8 biosynthesis was the primary factor that contributed to the increased resistance and collateral sensitivity of the SCV. This study offers a novel genetic basis for E. coli SCVs and an insight into the development of alternative antimicrobial strategies for clinical therapy. PMID- 28915358 TI - Remote myocardial injury: the protective role of fluoxetine. AB - Aortic cross-clamping-induced ischemia-reperfusion (IR) is an important factor in the development of postoperative acute cardiac injury following abdominal aortic surgery. We investigated the possible anti-oxidant/anti-inflammatory effects of fluoxetine (FLX), which is used widely as a preoperative anxiolytic on cardiac injury induced by IR of the infrarenal abdominal aorta. FLX was administered to IR-performed (60 min of ischemia and 120 min of reperfusion) rats for 3 days, once daily at 20 mg/kg i.p. dosage. Results were compared to control and non-FLX treated IR-performed rats. Serum creatine kinase (CK) and CK-MB levels, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti oxidant balance levels in the IR group were significantly higher whereas superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels were lower than for the control. IR also increased myeloperoxidase activity, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 and decreased interleukin-10 levels. FLX decreased CK, CK-MB, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti-oxidant balance levels while increasing superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels. FLX also decreased myeloperoxidase activity, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 levels and increased interleukin-10 levels compared to IR. FLX attenuated the morphological changes associated with cardiac injury. Our study clearly demonstrates that FLX confers protection against aortic IR-induced cardiac injury, tissue leucocyte infiltration, and cellular integrity via its anti-oxidant/anti-inflammatory effects. PMID- 28915359 TI - Presence of beta-Lactamase Encoding Genes in Burkholderia cepacia Complex Isolated from Soil. AB - Burkholderia cepacia complex has emerged as an important opportunistic bacteria group for immunocompromised patients, and it has a high level of intrinsic resistance for different antibiotic classes. Hydrolysis of beta-lactam antibiotics by beta-lactamases is the most common resistance mechanism in Gram negative bacteria, and the presence of such enzymes complicates the selection of appropriate therapy. This study aimed at investigating the antimicrobial resistance profile and the presence of beta-lactamase encoding genes in B. cepacia complex isolated from Brazilian soils. High-level ceftazidime resistance and several beta-lactamase encoding genes were found, including the first report of blaKPC genes in bacteria isolated from soil. PMID- 28915360 TI - Risk Factors for Reoperation and Performance-Based Outcomes After Operative Fixation of Foot Fractures in the Professional Athlete: A Cross-Sport Analysis. AB - BACKGROUND: Professional athletes are predisposed to fractures of the foot due to large stresses placed on the lower extremity. These players are concerned with efficiently returning to play at a high level. Return-to-play rates after operative treatment have been previously reported, yet performance outcomes after such treatment are generally unknown in this population. HYPOTHESIS: Overall, professional athletes sustaining a foot fracture would return to play at high rates with little impact on postoperative performance or league participation. However, National Football League (NFL) athletes would have a significantly greater decline in performance due to the high-impact nature of the sport. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: Level 4. METHODS: Athletes in the National Basketball League (NBA), NFL, Major League Baseball (MLB), and National Hockey League (NHL) undergoing operative fixation of a foot fracture were identified through a well-established protocol confirmed by multiple sources of the public record. Return-to-play rate and time to return were collected for each sport. League participation and game performance data were collected before and after surgery. Statistical analysis was performed, with significance accepted as P <= 0.05. RESULTS: A total of 77 players undergoing 84 procedures met the inclusion criteria. Overall, 98.7% (76/77) of players were able to return to play, with a median time to return across all sports of 137 days. Players returned to preoperative performance levels within 1 season of surgery. Six players (7.8%) sustained refracture requiring reoperation, all of whom were in the NBA. Percentage of games started during the season after primary operative treatment was a predictive factor for reinjury (99% vs 40%, P = 0.001). CONCLUSION: Athletes returned to play at a high rate after foot fracture fixation, with excellent postoperative performance levels, regardless of sport and fracture location. NBA athletes sustaining fifth metatarsal and navicular fractures are at greater risk of reinjury compared with other athletes. Returning to high levels of athletic participation soon after surgery may predispose athletes to refracture and subsequent reoperation. CLINICAL RELEVANCE: Players, coaches, and team physicians should be aware of the impact of foot fractures on career performance and longevity to best guide therapy. PMID- 28915361 TI - Cultural Change: The How and the Why. AB - More than half a century of cross-cultural research has demonstrated group-level differences in psychological and behavioral phenomena, from values to attention to neural responses. However, cultures are not static, with several specific changes documented for cultural products, practices, and values. How and why do societies change? Here we juxtapose theory and insights from cultural evolution and social ecology. Evolutionary approaches enable an understanding of the how of cultural change, suggesting transmission mechanisms by which the contents of culture may change. Ecological approaches provide insights into the why of cultural change: They identify specific environmental pressures, which evoke shifts in psychology and thereby enable greater precision in predictions of specific cultural changes based on changes in ecological conditions. Complementary insights from the ecological and cultural evolutionary approaches can jointly clarify the process by which cultures change. We end by discussing the relevance of cultural change research for the contemporary societal shifts and by highlighting several critical challenges and future directions for the emerging field of cross-temporal research on culture and psychology. PMID- 28915362 TI - Efficacy of hyperthermia in human colon adenocarcinoma cells is improved by auraptene. AB - Colon adenocarcinoma is one of the most common cancers worldwide, and resistance to current therapeutic modalities is a serious drawback in its treatment. Auraptene is a natural coumarin with considerable anticancer effects. The goal of this study was to introduce a novel combinatorial approach for treatment against colon adenocarcinoma cells. To do so, HT29 cells were pretreated with nontoxic auraptene and then hyperthermia was induced. Afterwards, the viability of the cells was assessed, changes induced in the cell cycle were analyzed, and the expression patterns of candidate genes were studied. Results from the MTT assay demonstrated significant (p < 0.01) decreases in cell viability when 20 MUg/mL auraptene was used for 72 h, heat shock was induced, and cells were allowed to recover for 24 h. Flow cytometry analysis also indicated considerable changes in the distribution of cells between the sub-G1/G1 and G2/M phases of cell cycle after the combinatorial treatment. Real-time RT-PCR studies revealed significant (p < 0.01) up-regulation of P21 in the cells pretreated with auraptene after heat shock, whereas no significant change was observed in HSP27 expression. Our findings not only indicate, for the first time, that the efficacy of hyperthermia was improved by auraptene pretreatment, but also suggest that this coumarin could be used in the future to achieve more effective therapeutic outcomes. PMID- 28915363 TI - Sample Identification Capacity of 20 Single Nucleotide Polymorphisms in Blood Derived Genomic DNA Samples of Korean Individuals. PMID- 28915364 TI - Nosocomial, Multidrug-Resistant Klebsiella pneumoniae Strains Isolated from Mexico City Produce Robust Biofilms on Abiotic Surfaces but Not on Human Lung Cells. AB - BACKGROUND: Klebsiella pneumoniae (Kpn) strains are a leading cause of hospital acquired infections, including ventilator-associated pneumonia. Resistance to antibiotics, biofilm formation, and the production of certain fimbriae play an important role in the pathogenesis. AIM: We investigated the genetic relatedness, antibiotic resistance, virulence potential, and ability to form biofilms of Kpn strains isolated from hospital-acquired infections (n = 76). Strains were isolated at three major hospitals serving the largest metropolitan urban area in Mexico City, Mexico. RESULTS: Enterobacterial repetitive intergenic consensus (ERIC)-PCR demonstrated that clonal groups predominate in each hospital. Selected strains chosen from clonal groups (n = 47) were multidrug resistant (MDR, 83%), although the majority (~70%) were susceptible to carbapenems. All strains produced robust biofilms on abiotic surfaces, and ~90% harbored adhesin genes fimH, mrkA, and ecpA. The ultrastructure of biofilms was further studied by high resolution confocal microscopy. The average height of Kpn biofilms on abiotic surfaces was ~40 MUm. We then assessed formation of biofilms on human lung cells, as a surrogate of lung infection. While Kpn strains formed robust biofilms on abiotic surfaces, studies on lung cells revealed attachment to human cells but scarce formation of biofilms. Gene expression studies revealed a differential temporal expression of an adhesin (ecpA) and a capsule (galF) gene when biofilms were formed on different substrates. CONCLUSIONS: Kpn strains isolated from nosocomial infections in Mexico City are MDR, although the majority are still susceptible to carbapenems and form more robust biofilms on polystyrene in comparison to those formed on human cells. PMID- 28915366 TI - Structural encoding processes contribute to individual differences in face and object cognition: Inferences from psychometric test performance and event-related brain potentials. AB - The enhanced N1 component in event-related potentials (ERP) to face stimuli, termed N170, is considered to indicate the structural encoding of faces. Previously, individual differences in the latency of the N170 have been related to face and object cognition abilities. By orthogonally manipulating content domain (faces vs objects) and task demands (easy/speed vs difficult/accuracy) in both psychometric and EEG tasks, we investigated the uniqueness of the processes underlying face cognition as compared with object cognition and the extent to which the N1/N170 component can explain individual differences in face and object cognition abilities. Data were recorded from N = 198 healthy young adults. Structural equation modeling (SEM) confirmed that the accuracies of face perception (FP) and memory are specific abilities above general object cognition; in contrast, the speed of face processing was not differentiable from the speed of object cognition. Although there was considerable domain-general variance in the N170 shared with the N1, there was significant face-specific variance in the N170. The brain-behavior relationship showed that faster face-specific processes for structural encoding of faces are associated with higher accuracy in both perceiving and memorizing faces. Moreover, in difficult task conditions, qualitatively different processes are additionally needed for recognizing face and object stimuli as compared with easy tasks. The difficulty-dependent variance components in the N170 amplitude were related with both face and object memory (OM) performance. We discuss implications for understanding individual differences in face cognition. PMID- 28915368 TI - A Chromatin-Based Mechanism for Limiting Divergent Noncoding Transcription. PMID- 28915369 TI - Subunit Architecture and Functional Modular Rearrangements of the Transcriptional Mediator Complex. PMID- 28915367 TI - Breathlessness and the body: Neuroimaging clues for the inferential leap. AB - Breathlessness debilitates millions of people with chronic illness. Mismatch between breathlessness severity and objective disease markers is common and poorly understood. Traditionally, sensory perception was conceptualised as a stimulus-response relationship, although this cannot explain how conditioned symptoms may occur in the absence of physiological signals from the lungs or airways. A Bayesian model is now proposed, in which the brain generates sensations based on expectations learnt from past experiences (priors), which are then checked against incoming afferent signals. In this model, psychological factors may act as moderators. They may alter priors, change the relative attention towards incoming sensory information, or alter comparisons between priors and sensations, leading to more variable interpretation of an equivalent afferent input. In the present study we conducted a supplementary analysis of previously published data (Hayen et al., 2017). We hypothesised that individual differences in psychological traits (anxiety, depression, anxiety sensitivity) would correlate with the variability of subjective perceptions of equivalent breathlessness challenges. To better understand the resulting inferential leap in the brain, we explored where these behavioural measures correlated with functional brain activity across subjects. Behaviourally, anxiety sensitivity was found to positively correlate with each subject's variability of intensity and unpleasantness during mild breathlessness, and with variability of unpleasantness during strong breathlessness. In the brain, anxiety sensitivity was found to negatively correlate with precuneus activity during anticipation, positively correlate with anterior insula activity during mild breathlessness, and negatively correlate with parietal sensorimotor areas during strong breathlessness. Our findings suggest that anxiety sensitivity may reduce the robustness of this Bayesian sensory perception system, increasing the variability of breathlessness perception and possibly susceptibility to symptom misinterpretation. These preliminary findings in healthy individuals demonstrate how differences in psychological function influence the way we experience bodily sensations, which might direct us towards better understanding of symptom mismatch in clinical populations. PMID- 28915370 TI - A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage. PMID- 28915371 TI - An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses. PMID- 28915372 TI - Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors. PMID- 28915373 TI - Bioaccumulation of metals in juvenile rainbow trout (oncorhynchus mykiss) via dietary exposure to blue mussels. AB - The potential for metals to bioaccumulate in aquatic species, such as fish, via trophic level transfer was investigated. An in vivo experiment was set up in a flow-through system in which juvenile rainbow trout were fed blue mussels collected from a Class A pristine site and an effluent-impacted river estuary, over a period of 28 days. Selected elements (As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Mo, Ni, Se, Sn, V, Zn) were determined in the mussels and fish tissues (muscle and skin) collected at 0, 14 and 28 days. This study reveals the occurrence of metals in mussels sampled in the Irish marine environment and highlights the bioaccumulation potential of metals in fish tissues via trophic transfer. All 14 monitored metals were determined in the mussels collected from both sites and mussels collected from the effluent-impacted site contained three times more Co, Mo, Sn and V than the mussels collected from the Class A site. Following a 28-day dietary exposure, concentrations of As and Se (fish muscle), and Pb, Se and Zn (fish skin), were significantly greater in fish feeding on contaminated mussels compared to those with a regular fish feed diet. The significance of metal detection and bioaccumulation in the mussel and fish tissues, highlights the potential for metal exposure to humans through the food chain. As fish are recommended as a healthy and nutritious food source, it is important to fully understand metal bioaccumulation in commercially important aquatic species and ensure the safety of human consumers. PMID- 28915374 TI - Enhanced degradation of chloramphenicol at alkaline conditions by S(-II) assisted heterogeneous Fenton-like reactions using pyrite. AB - The Fenton-like reactions catalyzed by pyrite can efficiently degrade organic contaminants by oxidation process. When chloramphenicol (CAP) was exposed to the pyrite-H2O2 system, the CAP removal rate rapidly reached 100% however slowed to a halt at alkaline conditions. Results indicated that by adding S(-II) in pyrite H2O2 system improved the oxidation efficiency of CAP at alkaline conditions. The transformation of S22- and Sn2- observed by X-ray photoelectron spectroscopy (XPS), confirmed that amorphous iron polysulfide (FeSn) was freshly generated on the pyrite surface. The availability of S(-II) promoted the generation of FeSn. Besides, S(-II) played a role in accelerating the Fe(III)/Fe(II) cycles. The potential of S(-II) activating H2O2 to generate hydroxyl radicals (OH), which was confirmed by electron spin resonance (ESR) spectroscopy, quenching experiments, and trapping experiments, have supported the proposed mechanisms. This study came up with an efficient way of enhancing Fenton-like reactions by pyrite catalyzed at alkaline conditions, by adding S(-II) in the system. The new findings have implications for sulfide minerals, their interactions with pollutants, and the transformation products of sulfur in systems where Fe species are also present. PMID- 28915375 TI - The presence of mercury and other trace metals in surface soils in the Norwegian Arctic. AB - Svalbard is an important study area for investigating the long-range transport of mercury (Hg) and other trace elements to the Arctic. Few studies have focused on their concentrations in Arctic soils. With ongoing climate change leading to thawing permafrost ground the soil compartment is of increasing importance in the Arctic. In this study, elemental composition and soil organic matter (SOM) content of surface and mineral soils in Svalbard are presented. The aim is to provide new data on soils in the Arctic and to gain more knowledge about the role of the soil in the biogeochemical cycle of mercury (Hg). Concentrations are reported for Al, As, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, S and Zn. Samples were taken in Adventdalen and in the area near Ny-Alesund. We obtained a mean Hg concentration of 0.111 +/- 0.036 MUg/g in surface soils (range 0.041-0.254 MUg/g). Hg levels in mineral soils (mean: 0.025 +/- 0.013 MUg/g; range: 0.004 0.060 MUg/g) were substantially lower than in the corresponding surface soils. Hg strongly accumulates in the surface soil layer (upper 3 cm) and is associated with SOM (surface soil: 59 +/- 14%). Hg concentrations in the surface soil were slightly lower than those in the humus layer in mainland Norway and were comparable to levels in soils elsewhere in the Arctic. An inverse association of Hg was found with elements attributed to the mineral soil, indicating that Hg is predominantly derived from atmospheric deposition. PMID- 28915376 TI - Psychometric properties of the Postpartum Bonding Questionnaire and correlates of mother-infant bonding impairment in Italian new mothers. AB - OBJECTIVE: impaired maternal bonding is a risk factor for problems with infant well-being and development. The investigation of perinatal variables related to disorders of the mother-infant relationship as well as the administration of reliable and valid screening tools to new mothers in the postpartum can help identify early signs of a disturbed mother-child relationship. The Postpartum Bonding Questionnaire (PBQ) has been shown to be a valid screening instrument, but its dimensional structure is still controversial. An analysis of the literature demonstrated the need for research into the perinatal correlates of the quality of mother-newborn bonding as measured by the PBQ, and for information about the reliability and validity of the Italian version of the questionnaire. AIM: to (a) carry out preliminary analysis of the psychometric properties of an Italian version of the PBQ and (b) explore how mother-infant disturbances are related to relevant perinatal psychological variables. DESIGN: the research design consisted of a prenatal and a postnatal phase. SETTING: prenatal education classes delivered in public and private institutions. PARTICIPANTS: 123 pregnant Italian women were recruited from prenatal education classes. MEASUREMENTS: in the prenatal period participants completed a questionnaire measuring maternal fetal attachment; at the postnatal assessment (3 months postpartum) participants completed the Italian PBQ together with measures of mother-infant attachment, the couple's adjustment and maternal psychological well-being. Exploratory factor analysis was used to investigate the factor structure of the PBQ. Internal consistencies were evaluated using Cronbach's alpha. Nomological validity was assessed via Pearson correlations. FINDINGS: a three-factor model provided the most meaningful representation of the PBQ data, with one factor reflecting annoyance and anger towards the infant, another reflecting detachment and rejection and the third reflecting anxiety about infant care. Internal consistencies were good. Impaired mother-infant bonding was negatively correlated with prenatal and postnatal mother-infant attachment and couple adjustment, as well as being positively correlated with maternal depressive symptoms. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the Italian PBQ is a reliable, valid screening instrument and can be used for research, including transcultural comparisons in perinatal psychiatry. It can also be used clinically to detect signs of a disordered mother-child relationship. Knowledge of the variables generally associated with mother-infant bonding problems combined with data from postpartum administration of the PBQ could be used in midwifery to develop preventive programmes based on the specific needs of new mothers. PMID- 28915377 TI - Midwives' experiences of caring for pregnant women admitted to Ebola centres in Sierra Leone. AB - OBJECTIVE: to explore and describe midwives' experiences of caring for pregnant women admitted to Ebola centres in Sierra Leone. DESIGN: a qualitative interview study with an exploratory and descriptive approach. SETTING: individual semi structured interviews with midwives who provided care for pregnant woman in eight different Ebola centres in Sierra Leone during the Ebola outbreak in 2014-16. PARTICIPANTS: 11 midwives, Sierra Leoneans and expatriates, who worked for three different humanitarian organisations in Sierra Leone during the Ebola outbreak in 2014-2016. FINDINGS: three themes emerged as a result of the analysis. The first theme described how personal and public fears of Ebola infection affected the midwives' professional and personal lives. Secondly, motivation and support influenced the midwives' ability to cope with challenging midwifery care and finally competency, creativity and courage was described as essential for improving clinical guidelines and learn for the future. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwives who worked in Ebola centres in Sierra Leone have a wide range of experiences in caring for pregnant women affected by Ebola. Their views should therefore be sought and considered when new guidelines are being developed on how best to provide care for pregnant women during an outbreak of Ebola virus disease, or any comparable infectious disease. Balanced information, sufficient training, adequate equipment and access to support by colleagues and peers would assist the midwives in coping with the challenges they face. PMID- 28915378 TI - Revisiting murine models for atopic dermatitis and psoriasis with multipolar cytokine axes. AB - Atopic dermatitis (AD) and psoriasis are one of the common skin diseases. Animal models are a powerful tool to analyze these diseases, which are complicated by multiple cytokine pathways. However, many discrepancies between the human diseases and murine models have been noticed. Therefore, investigators should be aware of the differences between the murine AD models and human AD when translating murine data to human skin diseases. This review highlights the differences between the inflammatory profiles between murine models and human diseases focusing on AD and psoriasis. PMID- 28915379 TI - Study on the oxygen reduction reaction catalyzed by a cold-tolerant marine strain phylogenetically related to Erythrobacter citreus. AB - As the development of marine economy, the submarine battery with the seawater electrolyte has obtained more and more attentions. Owing to the conventional electrochemical catalysts of the cathodes in seawater battery are expensive, it is to seek the new biological catalysts to improve the electrochemical performance of the cathode and reduce the cost of seawater battery. A novel marine bacterial strain (Strain SQ-32) phylogenetically related to the Erythrobactercitreus strain has been isolated from the sea-bed sludge in the Yellow Sea of China successfully. The electrochemical measurements, which include the cyclic voltammetry, potentiostatic polarization, and electrochemical impedance spectroscopy, have been conducted in synthetic seawater. The electrochemical testing results show that the Strain SQ-32 is a cold-tolerant bacterium, which may exhibit a catalytic activity for the ORR in synthetic seawater at a freezing temperature. The SEM photo demonstrates that the Strain SQ 32 displays a rod-shaped characteristic, which has a diameter of 0.4MUm and a length of about 1-2.5MUm. By the testing of Gram staining, the Strain SQ-32 has been identified as a Gram-negative bacterium. The chemical analytical result reveals that the bacterium cell of Strain SQ-32 contains 1.92mgg-1 (DCW) of coenzyme Q10, which is a possible impact factor on the electro-catalytic effect on the Strain SQ-32. The exploitation of Strain SQ-32 may boost the development of the biocathode of seawater battery at a low temperature. PMID- 28915380 TI - Oxytocin receptor gene polymorphisms exert a modulating effect on the onset age in patients with obsessive-compulsive disorder. AB - The oxytocin receptor (OXTR) is a potential candidate in the pathophysiology of obsessive-compulsive disorder (OCD). The present study investigated the association between common single-nucleotide polymorphism (SNPs) of the OXTR gene and the affected status of OCD or distinct clinical subtypes of OCD including the age at onset and symptom dimensions. Ten SNPs of OXTR were examined in 615 patients with OCD and 581 healthy controls. Single-marker and haplotype-based association analyses were conducted. While OXTR variants were not associated with the affected status of OCD or its clinical symptom dimensions, rs2268493 (p=0.00185) and rs13316193 (p=0.00461) of the OXTR gene were associated with the age at onset in patients with OCD. In addition, in haplotype-based association analyses, there was a significant association between the OXTR gene and the onset age in patients with OCD. In particular, the G-C-G haplotype of rs2268493 rs2254298-rs11316193 and the T-G-A haplotype of rs237887-rs2268490-rs4686301 were positively associated with late-onset OCD. Our results suggest that common variants of OXTR may exert a modulating effect on the onset age in OCD pathophysiology. The potential involvement of the oxytocin system in the development and expression of OCD warrants further longitudinal research. PMID- 28915381 TI - Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice. AB - Vitamin D deficiency is prevalent in adults throughout the world. Epidemiological studies have shown significant associations between vitamin D deficiency and an increased risk of various neuropsychiatric and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's disease and cognitive impairment. However, studies based on observational epidemiology cannot address questions of causality; they cannot determine if vitamin D deficiency is a causal factor leading to the adverse health outcome. The main aim of this study was to determine if AVD deficiency would exacerbate the effects of a secondary exposure, in this case social stress, in BALB/c mice and in the more resilient C57BL/6 mice. Ten-week old male BALB/c and C57BL/6 mice were fed a control or vitamin D deficient diet for 10 weeks, and the mice were further separated into one of two groups for social treatment, either Separated (SEP) or Social Defeat (DEF). SEP mice were placed two per cage with a perforated Plexiglas divider, whereas the DEF mice underwent 10days of social defeat prior to behavioural testing. We found that AVD-deficient mice were more vulnerable to the effects of social stress using a social avoidance test, and this was dependent on strain. These results support the hypothesis that vitamin D deficiency may exacerbate behavioural outcomes in mice vulnerable to stress, a finding that can help guide future studies. Importantly, these discoveries support the epidemiological link between vitamin D deficiency and neuropsychiatric and neurodegenerative disorders; and has provided clues that can guide future studies related to unravelling the mechanisms of action linking adult vitamin D deficiency and adverse brain related outcomes. PMID- 28915382 TI - Oxytocin modulates human communication by enhancing cognitive exploration. AB - Oxytocin is a neuropeptide known to influence how humans share material resources. Here we explore whether oxytocin influences how we share knowledge. We focus on two distinguishing features of human communication, namely the ability to select communicative signals that disambiguate the many-to-many mappings that exist between a signal's form and meaning, and adjustments of those signals to the presumed cognitive characteristics of the addressee ("audience design"). Fifty-five males participated in a randomized, double-blind, placebo controlled experiment involving the intranasal administration of oxytocin. The participants produced novel non-verbal communicative signals towards two different addressees, an adult or a child, in an experimentally-controlled live interactive setting. We found that oxytocin administration drives participants to generate signals of higher referential quality, i.e. signals that disambiguate more communicative problems; and to rapidly adjust those communicative signals to what the addressee understands. The combined effects of oxytocin on referential quality and audience design fit with the notion that oxytocin administration leads participants to explore more pervasively behaviors that can convey their intention, and diverse models of the addressees. These findings suggest that, besides affecting prosocial drive and salience of social cues, oxytocin influences how we share knowledge by promoting cognitive exploration. PMID- 28915383 TI - Force-activatable biosensor enables single platelet force mapping directly by fluorescence imaging. AB - Integrin-transmitted cellular forces are critical for platelet adhesion, activation, aggregation and contraction during hemostasis and thrombosis. Measuring and mapping single platelet forces are desired in both research and clinical applications. Conventional force-to-strain based cell traction force microscopies have low resolution which is not ideal for cellular force mapping in small platelets. To enable platelet force mapping with submicron resolution, we developed a force-activatable biosensor named integrative tension sensor (ITS) which directly converts molecular tensions to fluorescent signals, therefore enabling cellular force mapping directly by fluorescence imaging. With ITS, we mapped cellular forces in single platelets at 0.4um resolution. We found that platelet force distribution has strong polarization which is sensitive to treatment with the anti-platelet drug tirofiban, suggesting that the ITS force map can report anti-platelet drug efficacy. The ITS also calibrated integrin molecular tensions in platelets and revealed two distinct tension levels: 12-54 piconewton (nominal values) tensions generated during platelet adhesion and tensions above 54 piconewton generated during platelet contraction. Overall, the ITS is a powerful biosensor for the study of platelet mechanobiology, and holds great potential in antithrombotic drug development and assessing platelet activity in health and disease. PMID- 28915384 TI - Supramolecular nano-sniffers for ultrasensitive detection of formaldehyde. AB - Supramolecular nanoparticle hybrids for biosensing of analytes have been a major focus due to their tunable optical and surface properties. Quantum dots-Gold nanoparticle (QDs-GNP) based FRET probes involving turn on/off principles have gained immense interest due to their specificity and sensitivity. Recent focus is on applying these supramolecular hybrids for enzyme operated biosensors that can specifically turn-on fluorescence induced by co-factor or product formed from enzymatic reaction. The present study focuses on locking and unlocking the interaction between QD-GNP pair leading to differential fluorescent properties. Cationic GNPs efficiently quenched the anionic QD fluorescence by forming nanoparticle hybrid. Quenching interaction between QD-GNP pair was unlocked by NADH leading to QD fluorescence turn-on. This phenomenon was applied for the successful detection of formaldehyde using NAD+ dependent formaldehyde dehydrogenase. The proposed nano-sniffer could successfully detect formaldehyde from 0.001 to 100000ng/mL (R2 = 0.9339) by the turn off-turn on principle. It could also detect formaldehyde in fruit juice and wine samples indicating its stability and sensitivity in real samples. The proposed nanoprobe can have wide applications in developing enzyme biosensors in future. PMID- 28915385 TI - Photoluminescent lateral flow based on non-radiative energy transfer for protein detection in human serum. AB - A new paper-based lateral flow immunoassay configuration was engineered and investigated. The assay is intended for the detection of a model protein in human serum, that is, human immunoglobulin G, with the aim to demonstrate a virtually universal protein detection platform. Once the sample is added in the strip, the analyte is selectively captured by antibody-decorated silica beads (Ab-SiO2) onto the conjugate pad and the sample flows by capillarity throughout the strip until reaching the test line, where a sandwich-like immunocomplex takes place due to the presence of antibody-functionalized QDs (Ab-QDs) onto the test line. Eventually, GO is added as a revealing agent and the photoluminescence of those sites protected by the complex Ab-SiO2/Antigen/Ab-QDs will not be quenched, whereas those photoluminescent sites directly exposed are expected to be quenched by GO, including the control line, made of bare QDs, reporting that the assay occurred successfully. Hence, the photoluminescence of the test line is modulated by the formation of sandwich-like immunocomplexes. The proposed device achieves a limit of detection (LOD) of 1.35ngmL-1 in standard buffer, which is lower when compared with conventional lateral flow technology reported by gold nanoparticles, including other amplification strategies. Moreover, the resulting device was proven useful in human serum analysis, achieving a LOD of 6.30ngmL-1 in this complex matrix. This low-cost disposable and easy-to-use device will prove valuable for portable and automated diagnostics applications, and can be easily transferred to other analytes such as clinically relevant protein biomarkers. PMID- 28915386 TI - The role of growth hormone receptor in beta cell function. AB - Growth hormone (GH) exerts numerous effects on tissues through binding to its receptor, GHR, which resides on cell membranes in many different organs and tissues. Endocrine pancreatic beta cells are the only source of insulin secretion in response to metabolic demand, thereby regulating blood glucose and maintaining metabolic homeostasis. beta cell dysfunction is the main composition of diabetes mellitus. Numerous studies have provided strong evidence that GHR signaling plays an independent role in beta cell function. In this review, we focus on the role of GHR signaling in beta cell actions and the underlying molecular mechanisms. PMID- 28915387 TI - Can circular inference relate the neuropathological and behavioral aspects of schizophrenia? AB - Schizophrenia is a complex and heterogeneous mental disorder, and researchers have only recently begun to understand its neuropathology. However, since the time of Kraepelin and Bleuler, much information has been accumulated regarding the behavioral abnormalities usually encountered in patients suffering from schizophrenia. Despite recent progress, how the latter are caused by the former is still debated. Here, we argue that circular inference, a computational framework proposed as a potential explanation for various schizophrenia symptoms, could help end this debate. Based on Marr's three levels of analysis, we discuss how impairments in local and more global neural circuits could generate aberrant beliefs, with far-ranging consequences from probabilistic decision making to high level visual perception in conditions of ambiguity. Interestingly, the circular inference framework appears to be compatible with a variety of pathophysiological theories of schizophrenia while simulating the behavioral symptoms. PMID- 28915388 TI - EPA and DHA, but not ALA, have antidepressant effects with 17beta-estradiol injection via regulation of a neurobiological system in ovariectomized rats. AB - Our previous studies found that n-3 polyunsaturated fatty acids (PUFAs) and estrogen had synergistic antidepressant-like effects. The purpose of the present study was to investigate the hypothesis that three major n-3 PUFAs, alpha linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), individually had antidepressant effects combined with 17beta-estradiol-3-benzoate (E) through a neurobiological pathway in ovariectomized rats. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFAs and 1% ALA, EPA and DHA relative to total energy intake for 12 weeks and were injected with corn oil or E every 4 days during the last 3 weeks. Supplementation of EPA, DHA and E increased serum concentrations of serotonin and climbing behavior, and decreased immobility during a forced swimming test. Supplementation with EPA, DHA and E also decreased hippocampal expressions of interleukin-6 and tumor necrosis factor-alpha, and increased cAMP response element binding protein, brain-derived neurotrophic factor (BDNF) and estrogen receptor-alpha. Immunofluorescence staining consistently showed elevated expressions of BDNF. Magnetic resonance spectroscopy showed that E increased glucose and decreased glutamate, glutamine and myo-inositol concentrations regardless of n-3 PUFA supplementation. In addition, supplementation with EPA, DHA and E decreased levels of nitrite and nitrate. However, ALA had no antidepressant effect. The present study suggested that the antidepressant-like effects of EPA and DHA supplementation and E injection could be due to the regulation of serotonergic neurotransmission and inflammatory cytokines rather than due to the antioxidative system. Supplementation with n-3 PUFA and E had the additional function of modulating neurometabolites in the hippocampus. PMID- 28915390 TI - Navy and black bean supplementation primes the colonic mucosal microenvironment to improve gut health. AB - Common beans (Phaseolus vulgaris L.) are enriched in non-digestible fermentable carbohydrates and phenolic compounds that can modulate the colonic microenvironment (microbiota and host epithelial barrier) to improve gut health. In a comprehensive assessment of the impact of two commonly consumed bean varieties (differing in levels and types of phenolic compounds) within the colonic microenvironment, C57Bl/6 mice were fed diets supplemented with 20% cooked navy bean (NB) or black bean (BB) flours or an isocaloric basal diet control (BD) for 3 weeks. NB and BB similarly altered the fecal microbiota community structure (16S rRNA sequencing) notably by increasing the abundance of carbohydrate fermenting bacteria such as Prevotella, S24-7 and Ruminococcus flavefaciens, which coincided with enhanced short chain fatty acid (SCFA) production (microbial-derived carbohydrate fermentation products) and colonic expression of the SCFA receptors GPR-41/-43/-109a. Both NB and BB enhanced multiple aspects of mucus and epithelial barrier integrity vs. BD including: (i) goblet cell number, crypt mucus content and mucin mRNA expression, (ii) anti microbial defenses (Reg3gamma), (iii) crypt length and epithelial cell proliferation, (iv) apical junctional complex components (occludin, JAM-A, ZO-1 and E-cadherin) mRNA expression and (v) reduced serum endotoxin concentrations. Interestingly, biomarkers of colon barrier integrity (crypt height, mucus content, cell proliferation and goblet cell number) were enhanced in BB vs. NB fed mice, suggesting added benefits attributable to unique BB components (e.g., phenolics). Overall, NB and BB improved baseline colonic microenvironment function by altering the microbial community structure and activity and promoting colon barrier integrity and function; effects which may prove beneficial in attenuating gut-associated diseases. PMID- 28915389 TI - Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity. AB - Maternal obesity increases placental transport of macronutrients, resulting in fetal overgrowth and obesity later in life. Choline participates in fatty acid metabolism, serves as a methyl donor and influences growth signaling, which may modify placental macronutrient homeostasis and affect fetal growth. Using a mouse model of maternal obesity, we assessed the effect of maternal choline supplementation on preventing fetal overgrowth and restoring placental macronutrient homeostasis. C57BL/6J mice were fed either a high-fat (HF, 60% kcal from fat) diet or a normal (NF, 10% kcal from fat) diet with a drinking supply of either 25 mM choline chloride or control purified water, respectively, beginning 4 weeks prior to mating until gestational day 12.5. Fetal and placental weight, metabolites and gene expression were measured. HF feeding significantly (P<.05) increased placental and fetal weight in the HF-control (HFCO) versus NF-control (NFCO) animals, whereas the HF choline-supplemented (HFCS) group effectively normalized placental and fetal weight to the levels of the NFCO group. Compared to HFCO, the HFCS group had lower (P<.05) glucose transporter 1 and fatty acid transport protein 1 expression as well as lower accumulation of glycogen in the placenta. The HFCS group also had lower (P<.05) placental 4E-binding protein 1 and ribosomal protein s6 phosphorylation, which are indicators of mechanistic target of rapamycin complex 1 activation favoring macronutrient anabolism. In summary, our results suggest that maternal choline supplementation prevented fetal overgrowth in obese mice at midgestation and improved biomarkers of placental macronutrient homeostasis. PMID- 28915391 TI - Hepatitis B surface antigen incorporated in dissolvable microneedle array patch is antigenic and thermostable. AB - Alternatives to syringe-based administration are considered for vaccines. Intradermal vaccination with dissolvable microneedle arrays (MNA) appears promising in this respect, as an easy-to-use and painless method. In this work, we have developed an MNA patch (MNAP) made of hydroxyethyl starch (HES) and chondroitin sulphate (CS). In swines, hepatitis B surface antigen (HBsAg) formulated with the saponin QS-21 as adjuvant, both incorporated in HES-based MNAP, demonstrated the same level of immunogenicity as a commercially available aluminum-adjuvanted HBsAg vaccine, after two immunizations 28 days apart. MNAP application was associated with transient skin reactions (erythema, lump, scab), particularly evident when the antigen was delivered with the adjuvant. The thermostability of the adjuvanted antigen when incorporated in the HES-based matrix was also assessed by storing MNAP at 37, 45 or 50 degrees C for up to 6 months. We could demonstrate that antigenicity was retained at 37 and 45 degrees C and only a 10% loss was observed after 6 months at 50 degrees C. Our results are supportive of MNAP as an attractive alternative to classical syringe-based vaccination. PMID- 28915392 TI - Impact of antibiotic therapy in severe community-acquired pneumonia: Data from the Infauci study. AB - Antibiotic therapy (AT) is the cornerstone of the management of severe community acquired pneumonia (CAP). However, the best treatment strategy is far from being established. To evaluate the impact of different aspects of AT on the outcome of critically ill patients with CAP, we performed a post hoc analysis of all CAP patients enrolled in a prospective, observational, multicentre study. Of the 502 patients included, 76% received combination therapy, mainly a beta-lactam with a macrolide (80%). AT was inappropriate in 16% of all microbiologically documented CAP (n=177). Hospital and 6months mortality were 34% and 35%. In adjusted multivariate logistic regression analysis, combination AT with a macrolide was independently associated with a reduction in hospital (OR 0.17, 95%CI 0.06-0.51) and 6months (OR 0.21, 95%CI 0.07-0.57) mortality. Prolonged AT (>7days) was associated with a longer ICU (14 vs. 7days; p<0.001) and hospital length of stay (LOS) (25 vs. 17days; p<0.001). Combination AT with a macrolide may be the most suitable AT strategy to improve both short and long term outcome of severe CAP patients. AT >7days had no survival benefit and was associated with a longer LOS. PMID- 28915393 TI - The comparative effectiveness of noninvasive and invasive ventilation in patients with pneumonia. AB - PURPOSE: To compare the outcomes of patients hospitalized with pneumonia treated with noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV). MATERIALS AND METHODS: Using the HealthFacts multihospital electronic medical record database, we included patients hospitalized with a diagnosis of pneumonia and treated with NIV or IMV. We developed a propensity model for receipt of initial NIV and assessed the outcomes in a propensity-matched cohort, and in a covariate adjusted and propensity score weighted models. RESULTS: Among 3971 ventilated patients, 1109 (27.9%) were initially treated with NIV. Patients treated with NIV were older, had lower acuity of illness score, and were more likely to have congestive heart failure and chronic pulmonary disease. Mortality was 15.8%, 29.8% and 25.9.0% among patients treated with initial NIV, initial IMV and among those with NIV failure. In the propensity matched analysis, the risk of death was lower in patients treated with NIV (relative risk: 0.71, 95% CI: 0.59 0.85). Subgroup analysis showed that NIV was beneficial among patients with cardiopulmonary comorbidities (relative risk 0.59, 95% CI: 0.47-0.75) but not in those without (relative risk 0.96, 95% CI: 0.74-0.1.25)NIV failure was significantly (p=0.002) more common in patients without cardiopulmonary conditions (21.3%) compared to those with these conditions (13.8%). CONCLUSIONS: Initial NIV was associated with better survival among the subgroup of patients hospitalized with pneumonia who had COPD or heart failure. Patients who failed NIV had high in-hospital mortality, emphasizing the importance of careful patient selection monitoring when managing severe pneumonia with NIV. PMID- 28915394 TI - Overcoming the Warburg Effect: Is it the key to survival in sepsis? AB - Sepsis is a leading cause of mortality in the U.S. and Europe. Sepsis and septic shock are the results of severe metabolic abnormalities following infection. Aerobic glycolysis (the Warburg Effect) is as much a hallmark of sepsis as it is of cancer. Warburg observed that cancer cells generated energy through glycolysis (generation of ATP through degradation of glucose, usually associated with anaerobic conditions) rather than through oxidative phosphorylation (generation of ATP through the mitochondrial inner membrane via the tricarboxylic acid cycle, usually associated with aerobic conditions). Although the initial pathways of cancer and sepsis may be different, the mechanisms which allow aerobic glycolysis to occur, even in the presence of oxygen, are similar. This review provides some evidence that reversing these steps reverses the Warburg Effect in model systems and some pathological consequences of this effect. Therefore, this implies that these steps might be modifiable in sepsis to reverse the Warburg Effect and possibly lead to better outcomes. PMID- 28915395 TI - Effects of polymyxin B hemoperfusion on hemodynamics and prognosis in septic shock patients. AB - PURPOSE: We designed this study to examine the clinical effects of polymyxin B hemoperfusion (PMX-HP) in septic shock patients. MATERIAL AND METHODS: We retrospectively examined the effects of PMX-HP in septic shock patients with intra-abdominal or gram-negative bacterial infection during October 2013-May 2016. A one-to-one matching between the PMX-HP and conventional groups was performed, and 28-day mortality, and change in inotropic score, Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score at 24h in the two groups were compared. In addition, multivariable regression analysis and Cox proportional hazards regression model were applied in all eligible patients. RESULTS: Sixty-nine patients were eligible, of whom fifty patients were enrolled for matched cohort analysis. In matched cohort analysis, change in inotropic score after 24h (-24.8 [19.7] vs. -6.4 [20.0], p=0.002) differed significantly between the PMX-HP and conventional groups. Multivariable regression analysis revealed that PMX-HP was associated with lower 28-day mortality (odds ratio 0.18, 95% CI 0.04-0.92, p=0.039) and greater improvement in inotropic and APACHE II scores. CONCLUSIONS: PMX-HP may have potential benefits for hemodynamic and prognostic outcomes in septic shock patients with intra-abdominal or gram-negative bacterial infection. PMID- 28915396 TI - A novel biodegradation pathway of the endocrine-disruptor di(2-ethyl hexyl) phthalate by Pleurotus ostreatus based on quantum chemical investigation. AB - Di(2-ethyl hexyl) phthalate (DEHP) is a plasticizer that interfere with endocrine systems in mammals. Growth parameters for Pleurotus ostreatus grown on media containing glucose and different concentrations of DEHP (0, 500 and 1000mg/L) were evaluated. The highest biomass production was observed in medium supplemented with 1000mg of DEHP/L. Half-life of DEHP biodegradation, biodegradation constant of DEHP, and percentage of removal efficiency (%E) were also determined. P. ostreatus degraded 100% of DEHP after 504h. %E was 99.3% and 98.4% for 500 and 1000mg of DEHP/L, respectively. Intermediate compounds of biodegraded DEHP were identified by GC-MS and a DEHP biodegradation pathway was proposed using quantum chemical investigation. DEHP might be metabolized through three pathways; a de-esterification pathway, an oxidation pathway and an oxidation-hydrolysis pathway, forming phthalic acid, acetic acid and butanediol, respectively. P. ostreatus degrades and uses (as carbon and energy source) high concentrations of DEHP. PMID- 28915397 TI - Alleviation of cadmium toxicity in Lemna minor by exogenous salicylic acid. AB - Cadmium (Cd) is a significant environmental pollutant in the aquatic environment. Salicylic acid (SA) is a ubiquitous phenolic compound. The goal of this study was to assess the morphological, physiological and biochemical changes in duckweed (L. minor) upon exposure to 10MUM CdCl2, 10MUM CdCl2 plus 50MUM SA, or 50MUM SA for 7 days. Reversing the effects of Cd, SA decreased Cd accumulation in plants, improved accumulation of minerals (Ca, Mg, Fe, B, Mo) absorption, increased endogenous SA concentration, and phenylalanine ammonialyase (PAL) activity. Chlorosis-associated symptoms, the reduction in chlorophyll content, and the overproduction of reactive oxygen species induced by Cd exposure were largely reversed by SA. SA significantly decreased the toxic effects of Cd on the activities of the superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, and glutathione reductase in the fronds of L. minor. Furthermore, SA reversed the detrimental effects of Cd on total ascorbate, glutathione, the ascorbic acid/oxidized dehydroascorbate and glutathione/glutathione disulphide ratios, lipid peroxidation, malondialdehyde concentration, lipoxygenase activity, and the accumulation of proline. SA induced the up-regulation of heat shock proteins (Hsp70) and attenuated the adverse effects of Cd on cell viability. These results suggest that SA confers tolerance to Cd stress in L. minor through different mechanisms. PMID- 28915398 TI - Masculinization and reproductive effects in western mosquitofish (Gambusia affinis) after long-term exposure to androstenedione. AB - Androstenedione (AED) is a naturally occurring steroid hormone. It is metabolized to potent androgens, which may induce androgenic effects in fish. However, little is known whether and how the androgens interfere with the fish gonadal development and reproduction. This study aimed at demonstrating the effects of long-term AED exposure on reproduction and development in mosquitofish (Gambusia affinis). The growth, development and several morphological endpoints, including the segment number and length of anal fin, histological changes of gonads and liver, were evaluated in mosquitofish during development from fertilized embryo to adulthood (180 days) after exposure of AED at environmentally relevant concentrations. We found that the growth (length, body weight and condition factor) of fish was negatively correlated with AED concentration in females, but not in males. The significant elongation of the ray and increment of segment numbers in the anal fin, were detected in all mosquitofish after exposure. Moreover, AED exposure (0.4gu/L) caused damages in gonads and reduced the number of pregnant females. These findings indicate that AED has adverse effects on the growth and development of the western mosquitofish after long-term exposure (180d). Long-term exposure (180d) to AED, including environmentally relevant concentration (0.4ug/L and 4ug/L), induced masculinization in female mosquitofish under the experimental conditions. PMID- 28915399 TI - Climate change impact of livestock CH4 emission in India: Global temperature change potential (GTP) and surface temperature response. AB - Two climate metrics, Global surface Temperature Change Potential (GTP) and the Absolute GTP (AGTP) are used for studying the global surface temperature impact of CH4 emission from livestock in India. The impact on global surface temperature is estimated for 20 and 100 year time frames due to CH4 emission. The results show that the CH4 emission from livestock, worked out to 15.3 Tg in 2012. In terms of climate metrics GTP of livestock-related CH4 emission in India in 2012 were 1030 Tg CO2e (GTP20) and 62 Tg CO2e (GTP100) at the 20 and 100 year time horizon, respectively. The study also illustrates that livestock-related CH4 emissions in India can cause a surface temperature increase of up to 0.7mK and 0.036mK over the 20 and 100 year time periods, respectively. The surface temperature response to a year of Indian livestock emission peaks at 0.9mK in the year 2021 (9 years after the time of emission). The AGTP gives important information in terms of temperature change due to annual CH4 emissions, which is useful when comparing policies that address multiple gases. PMID- 28915400 TI - Recent advances in understanding physical health problems in personality disorders. AB - Personality disorders are associated with a range of adverse health outcomes, contributing to the high healthcare utilization seen in patients with these disorders. A growing literature supports a robust association of personality disorders and health problems. The primary aim of this article is to summarize the most recent research documenting the associations between personality disorders and health conditions. Extending past reviews, we discuss the association of personality disorders with chronic physical illnesses, sleep disturbances, pain conditions, and obesity. We provide recommendations for future research in this area. PMID- 28915401 TI - The modified ketogenic diet for adults with refractory epilepsy: An evaluation of a set up service. AB - PURPOSE: The ketogenic diet (KD) has been proven to be effective in children with refractory epilepsy and is recommended by the National Institute of Health and Care Excellence (NICE). There is no randomised control trial (RCT) evidence for the clinical or cost effectiveness of KD in adults, for whom the KD is not currently recommended. We assessed the feasibility of the modified ketogenic diet (MKD) in adults with refractory epilepsy along with the willingness of patients to participate in a future RCT. METHODS: The service evaluation was undertaken in two parts; questionnaire and diet evaluation. RESULTS: 102 patients completed a questionnaire, of which 51 patients were willing to try the MKD for 3 months to assess effect on seizures. Forty three patients were willing to participate in a clinical trial to investigate deliverability, efficacy and tolerability. Thirty seven of which would still be willing to participate if the trial were randomised. Of the 17 patients who commenced the diet, 9 completed the 12 week period, 7 of which stayed on the diet for the longer term. Constipation (n=6) and loose stools (n=3) were the only reported adverse effects. CONCLUSION: Our results indicate that there is demand for a ketogenic diet service in adults. The MKD is well tolerated, feasible and financially viable to deliver to adults with epilepsy in the NHS. There is also interest in and willingness to participate in a UK based RCT that would ultimately inform decisions about commissioning appropriate services. PMID- 28915402 TI - Complete immunization coverage and its determinants among children in Malaysia: findings from the National Health and Morbidity Survey (NHMS) 2016. AB - OBJECTIVES: The success of the Expanded Program on Immunization among children will greatly reduce the burden of illness and disability from vaccine preventable diseases. The aim of the study was to evaluate the complete immunization coverage and its determinants among children aged 12-23 months in Malaysia. STUDY DESIGN: Cross-sectional study. METHODS: Data on immunization were extracted from the 2016 National Health and Morbidity Survey. Complete immunization coverage was classified as received all recommended primary vaccine doses by the age of 12 months and verified by vaccination cards, and incompletely immunized if they received partially recommended vaccine dose or not received any recommended vaccine dose or had no vaccination card. The multiple logistic regression analyses were conducted to determine the sociodemographic factors associated with complete immunization coverage. RESULTS: The overall complete immunization coverage among children (verified by cards) was 86.4% (n = 8920, 95% confidence interval: 85.4-87.4). Multivariable logistic regression analyses model revealed that factors significantly associated with complete immunization coverage were ethnicity, occupation of the mother, head of household's education level, and head of household's occupation. While sex, citizenship, household income, mother's age, and marital status were not significantly associated with complete immunization coverage. CONCLUSIONS: According to the World Health Organization criteria, the present study demonstrated that the immunization coverage of 86.4% is still unsatisfactory. Thus, the current intervention program should be enhanced in order to achieve the 95% coverage for all antigens in the national vaccination program. PMID- 28915403 TI - Highs and lows: Naturalistic changes in mood and everyday hassles over school and vacation periods in adolescents. AB - This study investigated changes in adolescents' mood and everyday hassles across school-terms and vacation periods. 146 (52.7% female) community-dwelling adolescents aged 16.2 +/- 1.0 years (M+/-SD) completed self-report measures on depression, anxiety, and everyday hassles at four time points: during a school vacation, and the start, middle, and end of school-terms. Latent growth modeling showed that the end of a school-term was associated with significantly higher symptoms of depression, anxiety, and hassles; these measures were lower during the vacation. Hassles were strongly associated with more negative mood at all times. Our findings suggest significant fluctuations in adolescent mood and everyday hassles across school-vacation cycles. These findings call for careful consideration and reporting of timing in mood and stress assessment in adolescent research, as school-vacation cycles may have strong influence on both. Naturalistic changes in mood over school-vacation cycles reported are also clinically informative for designing and delivering adolescent wellbeing programs. PMID- 28915404 TI - Dynamic phosphorylation of Ebola virus VP30 in NP-induced inclusion bodies. AB - Zaire Ebolavirus (EBOV) causes a severe feverish disease with high case fatality rates. Transcription of EBOV is dependent on the activity of the nucleocapsid protein VP30 which represents an essential viral transcription factor. Activity of VP30 is regulated via phosphorylation at six N-terminal serine residues. Recent data demonstrated that dynamic phosphorylation and dephosphorylation of serine residue 29 is essential for transcriptional support activity of VP30. To analyze the spatio/temporal dynamics of VP30 phosphorylation, we generated a peptide antibody recognizing specifically VP30 phosphorylated at serine 29. Using this antibody we could demonstrate that (i) the majority of VP30 molecules in EBOV-infected cells is dephosphorylated at the crucial position serine 29, (ii) both, VP30 phosphorylation and dephosphorylation take place in viral inclusion bodies that are induced by the nucleoprotein NP and (iii) NP influences the phosphorylation state of VP30. PMID- 28915405 TI - Hepatic immunopathology during occult hepacivirus re-infection. AB - Despite drug advances for Hepatitis C virus (HCV), re-infections remain prevalent in high-risk populations. Unfortunately, the role of preexisting viral immunity and how it modulates re-infection is unclear. GBV-B infection of common marmosets is a useful model to study tissue immune responses in hepacivirus infections, and in this study we re-challenged 4 animals after clearance of primary viremia. Although only low-to-absent viremia was observed following re-challenge, GBV-B viral RNA was detectable in liver, confirming re-infection. Microscopic hepatic lesions indicated severe-to-mild lymphocyte infiltration and fibrosis in 3 out of 4 animals. Further, GBV-B-specific T cells were elevated in animals with moderate to-severe hepatopathology, and up to 3-fold increases in myeloid dendritic and activated natural killer cells were observed after infection. Our data indicate that occult hepacivirus re-infections occur and that new liver pathology is possible even in the presence of anti-hepacivirus T cells and in the absence of high viremia. PMID- 28915406 TI - Autographa californica multiple nucleopolyhedrovirus PK1 is a factor that regulates high-level expression of very late genes in viral infection. AB - The remarkable ability of baculovirus is to hyperexpress very late genes, but the mechanisms remain unclear. Here we report the effect of PK1, a baculovirus encoded serine/threonine kinase, on very late gene hyperexpression. PK1 knockout does not completely disrupt very late gene expression, but down regulates the hyperexpression. Those truncated PK1s that exhibit kinase activity in vitro rescue the decline of very late hyperexpression, while other truncated PK1s and a point mutant PK1 (D137A) without kinase activity fail to rescue the decline of very late hyperexpression, suggesting that PK1 regulates very late gene expression by its kinase activity. In addition, those PK1 mutants that can rescue the hyperexpression are able to interact with very late promoter containing 5' UTR. Based on the above data, we hypothesize that PK1 binds to very late promoter containing 5' UTR to regulate the hyperexpression of very late genes by its kinase activity. PMID- 28915407 TI - Differentiation and sarcomere formation in skeletal myocytes directly prepared from human induced pluripotent stem cells using a sphere-based culture. AB - Human induced-pluripotent stem cells (iPSCs) are a promising resource for propagation of myogenic progenitors. Our group recently reported a unique protocol for the derivation of myogenic progenitors directly (without genetic modification) from human pluripotent cells using free-floating spherical culture. Here we expand our previous efforts and attempt to determine how differentiation duration, culture surface coatings, and nutrient supplements in the medium influence progenitor differentiation and formation of skeletal myotubes containing sarcomeric structures. A long differentiation period (over 6 weeks) promoted the differentiation of iPSC-derived myogenic progenitors and subsequent myotube formation. These iPSC-derived myotubes contained representative sarcomeric structures, consisting of organized myosin and actin filaments, and could spontaneously contract. We also found that a bioengineering approach using three-dimensional (3D) artificial muscle constructs could facilitate the formation of elongated myotubes. Lastly, we determined how culture surface coating matrices and different supplements would influence terminal differentiation. While both Matrigel and laminin coatings showed comparable effects on muscle differentiation, B27 serum-free supplement in the differentiation medium significantly enhanced myogenesis compared to horse serum. Our findings support the possibility to create an in vitro model of contractile sarcomeric myofibrils for disease modeling and drug screening to study neuromuscular diseases. PMID- 28915408 TI - Transarterial chemoembolisation for breast cancer with liver metastasis: A systematic review. AB - BACKGROUND: There is limited data on the impact of transarterial chemoembolisation (TACE) on survival in patients of breast cancer with liver metastasis (BCLM). METHODS: A systematic review was conducted to assess TACE effect on BCLM patients. A search for clinical studies published since 1/1/2000 to 1/1/2017 was performed. Survival data from all studies were extracted to evaluate the efficacy of TACE, including overall survival, disease free survival and response rate. Toxic side effects data were also extracted to assess the safety of TACE. RESULTS: A total of 10 studies with 519 BCLM patients were identified. 78.0% patients were treated with TACE, 9.9% were treated with TACE plus systematic chemotherapy and 12.1% were treated with systematic chemotherapy alone. Pooled median overall survival of patients who received TACE ranged from 7.3 to 47.0 months, median disease free survival ranged from 2.9 to 17.0 months and response rates ranged from 7.0 to 73.5%. Pooled Grade 3 and 4 side effects (blood toxicities, liver toxicity and post-embolization syndrome) ranged from 0.0 to 17.4%. CONCLUSIONS: TACE is one of an effective treatment for BCLM and whether a specific patient is appropriate to receive TACE depends on a multiple disciplinary team discussion. PMID- 28915409 TI - Androgen receptor cytosine, adenine, and guanine trinucleotide repeat polymorphism in Korean patients with endometriosis: A case-control study. AB - STUDY OBJECTIVE: To investigate the association between the androgen receptor (AR) cytosine, adenine, and guanine (CAG) repeat polymorphisms and endometriosis. STUDY DESIGN: A prospective case-control, genetic association study was performed on women with surgically proven endometriosis (n=421) and controls free of endometriosis (n=349). AR CAG repeat lengths were determined from peripheral blood samples. The difference in the frequency of each alleles were compared in patients with endometriosis and controls using Chi-square test. MAIN RESULTS: No significant difference in biallelic length mean between patients and controls was observed. Alleles containing 24 CAG repeats were significantly more frequent in stage I-II (mild) endometriosis than in the control samples (19.8% and 13.3%, respectively; OR 1.60, 95% CI 1.04-2.47). Additionally, a higher frequency of both alleles with 24 or more CAG repeats was observed in individuals with mild endometriosis, in comparison with the controls (25.6% and 15.2%, respectively; OR 1.92, 95% CI 1.09-3.38). CONCLUSIONS: AR gene CAG repeat polymorphisms are associated with the increased risk of mild endometriosis. PMID- 28915410 TI - AIEgens for biological process monitoring and disease theranostics. AB - Biological processes are of great significance for the normal physiological functions of living organisms and closely related to the health. Monitoring of biological processes and diagnosis of diseases based on fluorescent techniques would provide comprehensive insight into mechanism of life and pathogenesis of diseases, precisely guiding therapeutic effect in theranostics. It largely relied on fluorophores with the properties of excellent photostability, large Stokes shift, high signal-to-noise ratio and free of aggregation-caused quenching (ACQ) effect. Luminogens with aggregation-induced emission characteristic (AIEgens) could serve as superior agents for biological process monitoring and disease theranostics. Herein, we review the recent results in the aspects of monitoring biological processes such as autophagy, mitophagy, mitochondrion-related dynamics, cell mitotic, long-term cellular tracing and apoptosis as well as the diagnosis of related diseases based on AIEgens in real time. As part of AIEgens and AIEgen-based nanoparticles with the functionalities of drugs, photosensitizers and adjuvants accompanied with imaging, they exhibit huge potential in theranostic systems for image-guided chemotherapy, photodynamic therapy, radiotherapy and so on. Collectively, these examples show the potentials of AIEgens for understanding disease pathogenesis, for drug development and evaluation, and for clinical disease diagnosis and therapy. Future research efforts focused on developing long-wavelength excitable and phosphorescence emissive AIEgens with improved depth-penetration and minimized background interference for fluorescence and photoacoustic imaging, will extend the potential applications of AIEgens in in vivo. PMID- 28915411 TI - Uncontrolled variables in standardized psychiatric patient methodology. PMID- 28915412 TI - Aspergillus section Flavi community structure in Zambia influences aflatoxin contamination of maize and groundnut. AB - Aflatoxins are cancer-causing, immuno-suppressive mycotoxins that frequently contaminate important staples in Zambia including maize and groundnut. Several species within Aspergillus section Flavi have been implicated as causal agents of aflatoxin contamination in Africa. However, Aspergillus populations associated with aflatoxin contamination in Zambia have not been adequately detailed. Most of Zambia's arable land is non-cultivated and Aspergillus communities in crops may originate in non-cultivated soil. However, relationships between Aspergillus populations on crops and those resident in non-cultivated soils have not been explored. Because characterization of similar fungal populations outside of Zambia have resulted in strategies to prevent aflatoxins, the current study sought to improve understanding of fungal communities in cultivated and non cultivated soils and in crops. Crops (n=412) and soils from cultivated (n=160) and non-cultivated land (n=60) were assayed for Aspergillus section Flavi from 2012 to 2016. The L-strain morphotype of Aspergillus flavus and A. parasiticus were dominant on maize and groundnut (60% and 42% of Aspergillus section Flavi, respectively). Incidences of A. flavus L-morphotype were negatively correlated with aflatoxin in groundnut (log y=2.4990935-0.09966x, R2=0.79, P=0.001) but not in maize. Incidences of A. parasiticus partially explained groundnut aflatoxin concentrations in all agroecologies and maize aflatoxin in agroecology III (log y=0.1956034+0.510379x, R2=0.57, P<0.001) supporting A. parasiticus as the dominant etiologic agent of aflatoxin contamination in Zambia. Communities in both non-cultivated and cultivated soils were dominated by A. parasiticus (69% and 58%, respectively). Aspergillus parasiticus from cultivated and non cultivated land produced statistically similar concentrations of aflatoxins. Aflatoxin-producers causing contamination of crops in Zambia may be native and, originate from non-cultivated areas, and not be introduced with non-native crops such as maize and groundnut. Non-cultivated land may be an important reservoir from which aflatoxin-producers are repeatedly introduced to cultivated areas. The potential of atoxigenic members of the A. flavus-L morphotype for management of aflatoxin in Zambia is also suggested. Characterization of the causal agents of aflatoxin contamination in agroecologies across Zambia gives support for modifying fungal community structure to reduce the aflatoxin-producing potential. PMID- 28915413 TI - Transmission electron microscopy studies and modeling of 3D reciprocal space of omega forming alloy. AB - Initial stage of omega phase formation and associated anomalous features that appear in diffraction patterns of a metastable beta transition metal alloy have been investigated in this study with the aid of transmission electron microscopy, simulation and modeling. The paper explores discrete features that emerge in selected area diffraction patterns of quenched Ti-15wt%Mo alloy and analyzes the correlation between omega reflections and diffuse arcs by considering all variants of omega phase as per the formation kinetics of omega phase in beta matrix while quenching. Superimposed simulated diffraction patterns have been compared with experimental counterparts and it is deduced that there is lack of congruence between omega reflections and diffuse arcs even after considering trigonal omega with varying degrees of displacement. Direct lattice imaging of trigonal omega in beta matrix has been demonstrated by phase contrast microscopy coupled with Fourier filtering techniques. By investigating the nature of omega reflections and diffuse arcs with the aid of electron diffraction pattern calculations and phase contrast microscopy, it is shown that, existing model of three-dimensional (3D) reciprocal space of omega forming alloy at quenched stage is not complete. A new model incorporating a patterned intensity distribution is fitted at the octahedral sites of an fcc reciprocal lattice whose planar intersections with Ewald's sphere show a better fit with the observed experimental diffraction patterns. PMID- 28915414 TI - Evaluation of surgical decision making and resulting outcome in patients with highly eloquent glioblastoma: Results of a multicenter assessment. AB - INTRODUCTION: Treatment of glioblastoma(GB) patients amenable only for a subtotal resection(STR) is controversial. Since outcome of patients is affected by surgical management, our aim was to assess surgical decision making and resulting outcome in patients with highly eloquent GBs. PATIENTS AND METHODS: We retrospectively assessed GB patients with intended sub-total resection (STR) or stereotactic biopsy (STX) of 3 neurooncological centers operated between 2008 and 2013. A volumetric assessment of overall extent of resection(oEoR), presence of complications, new permanent neurological deficits(nPNDs) was performed. A central reviewer reassessed all cases blinded and gave recommendation on surgical management and on a potential EoR(pEoR) based on imaging data. We compared outcome data using Mann-Whitney-U-test and Sign-Rank-Test. Survival was assessed based on Kaplan-Meier-estimates. RESULTS: 97 patients were included. In 17 patients received STX, 70 patients a STR and 10 patients a near total resection (NTR, EoR>95%). Median OS was significantly different from STX patients only if NTR was reached (16 vs. 7 months, p=0.042). The central reviewer recommended a more aggressive strategy(NTR or STR resp.) in 41 patients and a less aggressive strategy in 13 patients. Overall, management recommendation was significantly different to clinical treatment (p<0.001). Mean pEoR was significantly higher than oEoR (85.7% vs. 71.3%, p=0.001). Regarding the different OR subgroups, no significant differences were found in the NTR group(12/13 ties, p=1) and in STX group (14/17 ties, p=0.125). In STR group, a significant difference was found (p=0.001). In 38/69 patients a NTR and in 13/77 patients a STX was recommended. CONCLUSION: Surgery in GB patients with intended STR requires precise preoperative planning since potential EoR is mainly underestimated. Especially, patients with lesions amenable for a NTR should not be missed. PMID- 28915415 TI - Transcriptomic analysis of the hepatopancreas induced by eyestalk ablation in shrimp, Litopenaeus vannamei. AB - Although eyestalk ablation (ESA) is currently considered the most effective method to facilitate molting and maturation, its physiological responses are still not clearly explained in decapod crustaceans. In this study, we analyzed the hepatopancreatic transcriptomes of Litopenaeus vannamei after ESA using the Illumina Miseq platform. After screening 53,029 contigs with high cutoff values (fold change>|10|; P-value<0.05; RPKM>1), we were able to identify 105 differentially expressed genes (DEGs), of which 100 were up-regulated and five were down-regulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that many DEGs were involved in the synthetic pathways for glycerol and trehalose, which are known to function as the major protectants under conditions of low temperature and osmotic stress in arthropods. Additional analysis of the other DEGs enabled us to classify them in four categories: immunity; cellular trafficking; transcriptional regulation; molting and maturation. Many DEGs were involved in immunity and stress responses, in particular the proPO activation system, which is the major immune and wound healing system in arthropods. In addition to immunity and stress responses, we were also able to identify DEGs involved in molting and maturation processes (e.g., group I chitinase), as well as those involved in hormone metabolism and trafficking. Collectively, based on the transcriptomic analysis, ESA causes not only stress and immune responses, but also molting and maturation in L. vannamei. The DEGs identified in this study could be useful markers to understand the physiological responses that ESA induces in shrimp, such as molting, maturation, and immunity. PMID- 28915416 TI - Methodological approaches in analysing observational data: A practical example on how to address clustering and selection bias. AB - BACKGROUND: Because not every scientific question on effectiveness can be answered with randomised controlled trials, research methods that minimise bias in observational studies are required. Two major concerns influence the internal validity of effect estimates: selection bias and clustering. Hence, to reduce the bias of the effect estimates, more sophisticated statistical methods are needed. AIM: To introduce statistical approaches such as propensity score matching and mixed models into representative real-world analysis and to conduct the implementation in statistical software R to reproduce the results. Additionally, the implementation in R is presented to allow the results to be reproduced. METHOD: We perform a two-level analytic strategy to address the problems of bias and clustering: (i) generalised models with different abilities to adjust for dependencies are used to analyse binary data and (ii) the genetic matching and covariate adjustment methods are used to adjust for selection bias. Hence, we analyse the data from two population samples, the sample produced by the matching method and the full sample. RESULTS: The different analysis methods in this article present different results but still point in the same direction. In our example, the estimate of the probability of receiving a case conference is higher in the treatment group than in the control group. Both strategies, genetic matching and covariate adjustment, have their limitations but complement each other to provide the whole picture. CONCLUSION: The statistical approaches were feasible for reducing bias but were nevertheless limited by the sample used. For each study and obtained sample, the pros and cons of the different methods have to be weighted. PMID- 28915417 TI - LC-MS/MS quantification of 7alpha-hydroxy-4-cholesten-3-one (C4) in rat and monkey plasma. AB - 7alpha-hydroxy-4-cholesten-3-one (C4) is an oxidative enzymatic product of cholesterol metabolism via cholesterol 7alpha-hydroxylase, an enzyme also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1). C4 is a stable intermediate in the rate limiting pathway of bile acid biosynthesis. Previous studies showed that plasma C4 levels correlated with CYP7A1 enzymatic activity and could serve as a biomarker for bile acid synthesis. Here we developed and qualified a simple and robust high-throughput method using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to quantify C4 in rat and monkey plasma. As C4 being an endogenous compound, this method used calibration standards in 50/50: acetonitrile/water (v/v). In order to mimic the incurred samples, quality control samples were prepared in the authentic plasma. Stable isotope labeled C4 (C4-d7) was used as the internal standard. The sample volume for analysis was 20MUL and the sample preparation method was protein precipitation with acetonitrile. The average endogenous C4 concentrations, from 10 different lots of rat and monkey plasma, were 53.0+/-16.5ng/mL and 6.8+/ 5.6ng/mL, respectively. Based on these observed endogenous C4 levels, the calibration curve ranges were established at 1-200ng/mL and 0.5-100ng/mL for rat assay and monkey assay, respectively. The method was qualified with acceptable accuracy, precision, linearity, and specificity. Matrix effect, recovery, and plasma stability of bench-top, freeze-thaw, and long-term frozen storage were also evaluated. The method has been successfully applied to pre-clinical studies. PMID- 28915418 TI - Purification, identification and molecular mechanism of two dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from Antarctic krill (Euphausia superba) protein hydrolysate. AB - Dipeptidyl peptidase IV (DPP-IV) played an important role in blood glucose regulation. Inhibition of DPP-IV may improve glycemic control in diabetics by preventing the rapid breakdown of incretin hormones and prolonging their physiological action. In this study, Antarctic krill (Euphausia superba) protein was hydrolyzed using animal proteolytic enzymes. The hydrolysate was purified sequentially by ultrafiltration, gel filtration chromatography and reversed phase high-performance liquid chromatography (RP-HPLC). DPP-IV inhibitory activity of the fractions achieved from Antarctic krill protein was determined by DPP-IV screening reagent kit. Two purified peptides were identified by Xevo G2-XS QTof mass spectrometer (QTOF-MS). One peptide purified was Ala-Pro (AP) with IC50 values of 0.0530mg/mL, the other Ile-Pro-Ala (IPA) with IC50 values of 0.0370mg/mL. They both exhibited strong DPP-IV inhibitory activity. The molecular docking analysis revealed that DPP-IV inhibition by AP and IPA was mainly due to formation of a strong interaction surface force with the 91-96 and 101-105 amino acids of the DPP-IV. Our results suggested that the protein hydrolysate from Antarctic krill can be considered as a promising natural source of DPP-IV inhibitory peptides in the management of diabetes. PMID- 28915419 TI - Sensitivity improvement of the LC-MS/MS quantification of carbidopa in human plasma and urine by derivatization with 2,4-pentanedione. AB - The reliable quantification of carbidopa in biological samples at low concentrations is challenging because of the polar and highly unstable nature of the compound. In this paper, LC-MS/MS methods are described for the determination of carbidopa in 50MUL of human plasma and 25MUL of human urine in the concentration ranges 1-1,000ng/mL and 100-50,000ng/mL, respectively. After a simple protein precipitation (plasma) or dilution (urine) step, carbidopa is derivatized at its hydrazine moiety by reaction for one hour with 2,4 pentanedione under acidic conditions and at 40 degrees C. The product is a relatively non-polar molecule that is suitable for reversed-phase liquid chromatography (3.5min run time) with detection by tandem mass spectrometry with electrospray ionization. A stable-isotope labeled internal standard is used for response normalization. Precision, accuracy and selectivity of the methods meet the criteria of international guidelines for bioanalytical method validation. Acidification of urine to pH 1.5 and the addition of two anti-oxidants (5mg/mL sodium metabisulfite and 1mg/mL butylated hydroxytoluene) to plasma, in combination with sampling and analysis on ice and under yellow light, ensure sufficient stability of carbidopa. The methods were successfully used to determine plasma pharmacokinetics and urinary excretion of carbidopa in healthy volunteers after a single 37.5mg oral dose. PMID- 28915420 TI - Determination of eight quinolones in milk using immunoaffinity microextraction in a packed syringe and liquid chromatography with fluorescence detection. AB - We have established a new, highly selective, and sensitive method for the determination of eight quinolones (QNs) in milk: danofloxacin, enrofloxacin, orbifloxacin, norfloxacin, ofloxacin, lomefloxacin, fleroxacin, and ciprofloxacin. The method uses immunoaffinity microextraction in a packed syringe and liquid chromatography with fluorescence detection (IA-MEPS-LC-FLD). Traditionally, QN residues are determined by liquid-liquid extraction (LLE) and solid phase extraction (SPE) sample preparation techniques; however, these methods are time-consuming and require large quantities of organic solvents. We thus developed a novel immunoaffinity adsorbent combined with MEPS for QN residue analysis. The syringe was filled with 0.2g of microbeads bound with a QN monoclonal antibody using glutaraldehyde. The relevant parameters of the IA-MEPS method were optimized and discussed herein. Milk samples were extracted at a flow rate of 3.5mL/min, 600MUL of methanol-and phosphate-buffered saline (9:1, v/v) was used for elution, and 200MUL of mobile phase was used for reconstitution after the sample was dried with nitrogen. Then, the sample was detected by LC FLD. For the eight QNs, the limit of detection ranged from 0.05 to 0.1ng/g, the limit of quantification ranged from 0.15 to 0.3ng/g, and the intra- and inter-day precision were 3.2%-14.6% and 9.1%-15.8%, respectively. The advantages of the IA MEPS method includ simple operation, low cost and reduced organic solvent use. Moreover, the sample pretreatment is environmentally friendly because of the reduced solvent volume requirements. PMID- 28915421 TI - Determination of chlormequat and mepiquat residues and their dissipation rates in tomato cultivation matrices by ultra-performance liquid chromatography-tandem mass spectrometry. AB - This study described the development and validation of a simple, rapid, specific and sensitive method for detecting chlormequat chloride (CQ) and mepiquat chloride (MQ) residues in tomato cultivation matrices covering soil, water, seedling samples. The dissipation rates of CQ and MQ in tomato cultivation matrices were also determined in this study. A Hydrophilic Interaction Liquid Chromatography (HILIC) column was used for chromatographic separation. A triple quadrupole mass spectrometer equipped with an electrospray ionisation source in positive ion mode by multiple reaction monitoring was used for detection. Soil samples were extracted with accelerated solvent extraction (ASE) and cleaned up with WCX phase extraction column; water samples were extracted with WCX phase extraction column; seedling samples were extracted with methanol-ammonium acetate solution. LODs and LOQs of CQ and MQ were 0.02MUg/kg and 0.1MUg/kg in soil samples, 0.005ng/mL and 0.02ng/mL in water samples, and 0.05MUg/kg and 1.0MUg/kg in seedling samples, respectively. The mean recovery rate of CQ in soil, water and seedling samples ranged from 76.98% to 111.60%. While the mean recovery rate of MQ in soil, water and seedling samples ranged from 96.90% to 105.40%. The fastest to the slowest metabolising rates of CQ and MQ were as follows: soil samples>seedling samples>water samples. In conclusion, this study provided a new potential method for detecting CQ and MQ in tomato cultivation matrices using ultra-performance liquid chromatography-tandem mass spectrometry. PMID- 28915422 TI - Determination of hydroxyurea in human plasma by HPLC-UV using derivatization with xanthydrol. AB - A simple and rapid high performance liquid chromatography (HPLC) method using ultraviolet (UV) detection was developed to determine hydroxyurea (HU) concentration in plasma sample after derivatization with xanthydrol. Two hundred microliters samples were spiked with methylurea (MeU) as internal standard and proteins were precipitated by adding methanol. Derivatization of HU and MeU was immediately performed by adding 0.02M xanthydrol and 1.5M HCl in order to obtain xanthyl-derivatives of HU and MeU that can be further separated using HPLC and quantified using UV detection at 240nm. Separation was achieved using a C18 column with a mobile phase composed of 20mM ammonium acetate and acetonitrile in gradient elution mode at a flow rate of 1mL/min. The total analysis time did not exceed 18min. The method was found linear from 5 to 400MUM and all validation parameters fulfilled the international requirements. Between- and within-run accuracy error ranged from -4.7% to 3.2% and precision was lower than 12.8%. This simple method requires small volume samples and can be easily implemented in most clinical laboratories to develop pharmacokinetics studies of HU and to promote its therapeutic monitoring. PMID- 28915423 TI - Premature psychotherapy termination in an outpatient treatment program for personality disorders: a survival analysis. AB - OBJECTIVE: Psychological treatment for patients with personality disorders (PD) is plagued with a high proportion of early dropouts, and attempts to identify risk factors for attrition have generated very few conclusive results. The purpose of the present study is to identify significant predictors of early treatment termination in a long-term psychotherapy program for PD. METHODS: Data was retrospectively retrieved from 174 files of patients who began long-term psychotherapy in an outpatient treatment program in Quebec City, Canada. Socio demographic, initial disturbance, and diagnostic variables were considered for prediction, along with a measure specifically designed to identify PD patients at risk of dropping out early from psychotherapy, the Treatment Attrition-Retention Scale for Personality Disorders (TARS-PD). Survival analysis using Cox proportional hazard regression was performed to identify significant predictors. RESULTS: Results using univariate Cox proportional hazards regressions revealed that unemployment, Global Assessment of Functioning scores, and recent hetero aggressive behavior were significant predictors of early dropout in the first six months of therapy. Adjusting for these three confounders, four of the factor scores from the TARS-PD (Narcissism, Secondary gains, Low distress, and Cluster A features) were significantly associated with dropout in univariate Cox proportional hazards regressions. Secondary gains and Narcissism remained significant predictors after entering all five TARS-PD factors in a multivariate Cox proportional hazards regression adjusting for confounders. CONCLUSIONS: Taking into consideration specific treatment prognosis variables, such as those measured by the TARS-PD, might be more useful for dropout prediction in PD patients in comparison with more general demographic and diagnostic variables. PMID- 28915424 TI - Emergency surgery in a newborn patient with severe congenital hypothyrodism. PMID- 28915425 TI - Substance abuse in the anesthesia block room by a patient. PMID- 28915426 TI - Intravenous dexamethasone as an adjunct to improve labor analgesia: A randomized, double-blinded, placebo controlled clinical trial. AB - OBJECTIVE: To study the role of intravenous (i.v.) dexamethasone as an analgesic adjunct in labor analgesia. DESIGN: Double-blinded randomized controlled trial. SETTING: Labor analgesia in a tertiary-care teaching hospital. PATIENTS: Eighty consenting ASA I-II parturients, age>18year, nulliparous, single gestation, cephalic presentation at >=36 wk. of gestation, in early spontaneous labor (cervical dilatation<=5cm) requesting epidural analgesia. INTERVENTIONS: The patients were randomized to two groups. The Dexa group received 8mg of dexamethasone i.v. in 50ml normal saline approximately 45min before the procedure. Placebo group patients received 50ml normal saline only. All patients underwent epidural labor analgesia per hospital protocol. After an initial bolus, they received continuous background infusion of 5ml/h of 0.1% of levobupivacaine with 2MUg/ml of fentanyl, with the provision of patient controlled boluses of 5ml of the same drug combination with a lockout interval of 12min if needed. MEASUREMENTS: Primary outcome measure: hourly average consumption of neuraxially administered levobupivacaine-fentanyl combination. Secondary outcomes and observations: pain score, maternal satisfaction, sensory and motor block characteristics, hemodynamic parameters of mother, fetal heart rate, duration of second stage of labor, mode of delivery, Apgar scores at 1 and 5min, and adverse effects. MAIN RESULTS: Average hourly drug consumption was significantly lower in Dexa group as compared to Placebo group (10.34+/-1.79ml/h vs. 11.34+/-1.83ml/h; mean difference 1.007, 95% CI 0.199-1.815; P=0.015). The median number of bolus doses was 4 (interquartile-range [IQR] 3-5.75) and 5 (IQR 3-6) in the Dexa and Placebo groups, respectively (P=0.162). There was no significant difference between groups with regard to pain scores, maternal satisfaction and hemodynamics, mode of delivery, and adverse effects. CONCLUSIONS: I.v. dexamethasone significantly decreased hourly average drug consumption of levobupivacaine-fentanyl combination through the epidural route, demonstrating the epidural drug dose sparing effect during labor analgesia. PMID- 28915427 TI - Breast lymphoma in a patient with B-cell Non Hodgkin Lymphoma: A case report study. AB - INTRODUCTION: Breast involvement in Non Hodgkin Lymphoma is a rare entity as it accounts for 2.2% of all extranodal lymphomas. PRESENTATION OF CASE: A 59-year old woman was referred to our Breast Unit because of two nodules of the right breast newly discovered during her annual mammography. Moreover, during the physical examination, a red-brown itchy lump of the scalp was discovered. The punch biopsies of the scalp lesion and ultrasound-guided core biopsies of both nodules of the right breast, revealed the presence of diffuse large B-cell Non Hodgkin Lymphoma in all tissue specimen sites. DISCUSSION: Breast lymphomas represent an uncommon form of localized extranodal lymphomas that can be classified as Primary (PBL) or Secondary (SBL) breast lymphomas. CONCLUSION: The value of preoperative diagnosis should be underlined as the patient avoids unnecessary surgical intervention and has earlier initiation of chemotherapy. PMID- 28915428 TI - Compression neuropathy of the common peroneal nerve caused by an intraosseous ganglion cyst of fibula. AB - We present a case of a compression neuropathy of the common peroneal nerve caused by an intraosseous Ganglion cyst of fibula. PMID- 28915429 TI - Neuroendocrine tumor of the extrahepatic bile duct: A case report. AB - INTRODUCTION: Neuroendocrine tumors (NETs) of the extrahepatic bile ducts are extremely rare neoplasms arising from endocrine cells and have variable malignant potential. They most commonly occur in young females and usually present with painless jaundice. PRESENTATION OF CASE: Here we present the case of an asymptomatic 57-year-old woman with NET of the common bile duct that was incidentally discovered on abdominal ultrasound during a medical examination. She was admitted to our hospital with a diagnosis of hepatic hilar tumor. Computed tomography revealed the tumor surrounding the hepatic hilum and duodenum. Magnetic resonance cholangiopancreatography revealed a filling defect of the common bile duct with morphology suggestive of external compression. Endoscopic ultrasound confirmed a submucosal tumor of the duodenal bulb measuring 30*20mm in size. The patient qualified for surgery with a preoperative diagnosis of submucosal tumor of the duodenal bulb. Intraoperative examination revealed that the tumor location involved the common bile duct and/or cystic duct with no signs of invasion to other organs or metastatic lymph nodes. Excision of the biliary ducts and tumor was followed by Roux-en-Y anastomosis. Histological results showed NET grade 1. DISCUSSION: Preoperative diagnosis of NETs is difficult because of their rarity. A definitive diagnosis is usually established intraoperatively or after histopathological evaluation. CONCLUSION: For these tumors, surgical resection is currently the only treatment modality for achieving a potentially curative effect and prolonged disease-free survival. PMID- 28915430 TI - Care interrupted: Poverty, in-migration, and primary care in rural resource towns. AB - Internationally, rural people have poorer health outcomes relative to their urban counterparts, and primary care providers face particular challenges in rural and remote regions. Drawing on ethnographic fieldnotes and 14 open-ended qualitative interviews with care providers and chronic pain patients in two remote resource communities in Northern Ontario, Canada, this article examines the challenges involved in providing and receiving primary care for complex chronic conditions in these communities. Both towns struggle with high unemployment in the aftermath of industry closure, and are characterized by an abundance of affordable housing. Many of the challenges that care providers face and that patients experience are well-documented in Canadian and international literature on rural and remote health, and health care in resource towns (e.g. lack of specialized care, difficulty with recruitment and retention of care providers, heavy workload for existing care providers). However, our study also documents the recent in migration of low-income, largely working-age people with complex chronic conditions who are drawn to the region by the low cost of housing. We discuss the ways in which the needs of these in-migrants compound existing challenges to rural primary care provision. To our knowledge, our study is the first to document both this migration trend, and the implications of this for primary care. In the interest of patient health and care provider well-being, existing health and social services will likely need to be expanded to meet the needs of these in-migrants. PMID- 28915431 TI - Ethical implications of location and accelerometer measurement in health research studies with mobile sensing devices. AB - Quantification of individual behaviours using mobile sensing devices, including physical activity and spatial location, is a rapidly growing field in both academic research and the corporate world. In this case study, we summarize the literature examining the ethical aspects of mobile sensing and argue that a robust discussion about the ethical implications of mobile sensing for research purposes has not occurred sufficiently in the literature. Based on our literature summary and guided by basic ethical principles set out in Canadian, US, and International Ethics documents we propose four areas where further discussion should occur: consent, privacy and confidentiality, mitigating risk, and consideration of vulnerable populations. We argue that ongoing consent is crucial for participants to be aware of the precision and volume of data that is collected with mobile sensing devices. Related to privacy we discuss that participants may not agree that anonymized data is sufficient for privacy and confidentiality when mobile sensing data are collected. There has been some discussion about mitigating risk in the literature. We highlight that the researchers' obligations toward mitigating risks that are not directly related to the study purpose are unclear and require considerable discussion. Finally, using mobile sensing devices to study vulnerable populations requires careful consideration, particularly with respect to balancing research needs with participant burden. Based on our discussion, we identify a broad set of unanswered questions about the ethics of mobile sensing that should be addressed by the research community. PMID- 28915432 TI - New uses for old complexes: The very first report on the trypanocidal activity of symmetric trinuclear ruthenium complexes. AB - This work reports on the trypanocidal activity of a series of symmetric triruthenium complexes combined with azanaphthalene ligands of general formula [Ru3O(CH3COO)6(L)3]PF6 (L=(1) quinazoline (qui), (2) 5-nitroisoquinoline (5 nitroiq), (3) 5-bromoisoquinoline (5-briq), (4) isoquinoline (iq), (5) 5 aminoisoquinoline (5-amiq), and (6) 5,6,7,8-tetrahydroisoquinoline (thiq)). All complexes within the series presented in vitro trypanocidal activity against both the trypomastigote and amastigote forms of T. cruzi. The IC50 values obtained for complexes 1-6 ranged from 1.39 to 165.9MUM for the trypomastigote form and from 1.06 to 53.16MUM for the amastigote form. These values were lower than the values observed for the metallic core [Ru3O(CH3COO)6(CH3OH)3]+ itself and for the free ligands in all cases. Remarkably, complex 6 displayed lower IC50 values than the reference drug (benznidazole) for the acute (trypomastigote form) and chronic (amastigote form) phases of Chagas disease. These findings, combined with the low toxicity against healthy cells (LLK-MK2 strain) and a high SI value (Selectivity Index >10) make complex 6 an excellent candidate for in vivo tests. PMID- 28915433 TI - Trans-Golgi network/early endosome: a central sorting station for cargo proteins in plant immunity. AB - In plants, the trans-Golgi network (TGN) functionally overlaps with the early endosome (EE), serving as a central sorting hub to direct newly synthesized and endocytosed cargo to the cell surface or vacuole. Here, we focus on the emerging role of the TGN/EE in sorting of immune cargo proteins for effective plant immunity against pathogenic bacteria and fungi. Specific vesicle coat and regulatory components at the TGN/EE ensure that immune cargoes are correctly sorted and transported to the location of their cellular functions. Our understanding of the identity of immune cargoes and the underlying cellular mechanisms regulating their sorting are still rudimentary, but this knowledge is essential to understanding the physiological contribution of the TGN/EE to effective immune responses. PMID- 28915434 TI - Neutralization of viral infectivity by zebrafish c-reactive protein isoforms. AB - This work explores the unexpected in vivo and in vitro anti-viral functions of the seven c-reactive protein (crp1-7) genes of zebrafish (Danio rerio). First results showed heterogeneous crp1-7 transcript levels in healthy wild-type zebrafish tissues and organs and how those levels heterogeneously changed not only after bacterial but also after viral infections, including those in adaptive immunity-deficient rag1-/- mutants. As shown by microarray hybridization and proteomic techniques, crp2/CRP2 and crp5/CRP5 transcripts/proteins were among the most modulated during in vivo viral infection situations including the highest responses in the absence of adaptive immunity. In contrast crp1/CRP1/and crp7/CRP7 very often remained unmodulated. All evidences suggested that zebrafish crp2-6/CRP2-6 may have in vivo anti-viral activities in addition to their well known anti-bacterial and/or physiological functions in mammalians. Confirming those expectations, in vitro neutralization and in vivo protection against spring viremia carp virus (SVCV) infections were demonstrated by crp2-6/CRP2-6 using crp1-7 transfected and/or CRP1-7-enriched supernatant-treated fish cells and crp2 5-injected one-cell stage embryo eggs, respectively. All these findings discovered a crp1-7/CRP1-7 primitive anti-viral functional diversity.These findings may help to study similar functions on the one-gene-coded human CRP, which is widely used as a clinical biomarker for bacterial infections, tissue inflammation and coronary heart diseases. PMID- 28915435 TI - An overview of systematic reviews on the public health consequences of social isolation and loneliness. AB - OBJECTIVES: Social isolation and loneliness have been associated with ill health and are common in the developed world. A clear understanding of their implications for morbidity and mortality is needed to gauge the extent of the associated public health challenge and the potential benefit of intervention. STUDY DESIGN: A systematic review of systematic reviews (systematic overview) was undertaken to determine the wider consequences of social isolation and loneliness, identify any differences between the two, determine differences from findings of non-systematic reviews and to clarify the direction of causality. METHODS: Eight databases were searched from 1950 to 2016 for English language reviews covering social isolation and loneliness but not solely social support. Suitability for inclusion was determined by two or more reviewers, the methodological quality of included systematic reviews assessed using the a measurement tool to assess systematic reviews (AMSTAR) checklist and the quality of evidence within these reviews using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Non-systematic reviews were sought for a comparison of findings but not included in the primary narrative synthesis. RESULTS: Forty systematic reviews of mainly observational studies were identified, largely from the developed world. Meta-analyses have identified a significant association between social isolation and loneliness with increased all-cause mortality and social isolation with cardiovascular disease. Narrative systematic reviews suggest associations with poorer mental health outcomes, with less strong evidence for behavioural and other physical health outcomes. No reviews were identified for wider socio-economic or developmental outcomes. CONCLUSIONS: This systematic overview highlights that there is consistent evidence linking social isolation and loneliness to worse cardiovascular and mental health outcomes. The role of social isolation and loneliness in other conditions and their socio-economic consequences is less clear. More research is needed on associations with cancer, health behaviours, and the impact across the life course and wider socio-economic consequences. Policy makers and health and local government commissioners should consider social isolation and loneliness as important upstream factors impacting on morbidity and mortality due to their effects on cardiovascular and mental health. Prevention strategies should therefore be developed across the public and voluntary sectors, using an asset-based approach. PMID- 28915436 TI - Radiation hazards and lifetime risk assessment of tap water using liquid scintillation counting and high-resolution gamma spectrometry. AB - In this work, two complementary techniques, viz. liquid scintillation counting and high-resolution gamma spectrometry are utilized to analyze radionuclides concentrations in tap water of Irbid governorate, Jordan, and study their correlation. Gross alpha and gross beta concentrations, in the tap water samples collected from the nine districts of Irbid governorate, ranged from <82 to 484 mBq/L with a mean of 295 mBq/L and from <216 to 984 mBq/L with a mean of 611 mBq/L, respectively. Furthermore, gamma spectrometry analysis, for the tap water samples, shows that the activity concentrations of 226Ra, 232Th, and 40K ranged between <19 and 302 mBq/L, 24 to 119 mBq/L, and <101 to 342 mBq/L, respectively. There was a weak or even no correlation among the identified natural radionuclides with no trace of artificial radioactivity. In addition, the results of both techniques show that storing tap water in drilled wells leads to higher levels of radioactivity concentrations beyond the international permissible limits. Furthermore, the average lifetime risk and annual effective dose received by age-grouped inhabitants due to direct and indirect tap water consumption are evaluated, where most of the received dose is attributed to 226Ra. PMID- 28915437 TI - Temporal characterization of the non-structural Adenovirus type 2 proteome and phosphoproteome using high-resolving mass spectrometry. AB - The proteome and phosphoproteome of non-structural proteins of Adenovirus type 2 (Ad2) were time resolved using a developed mass spectrometry approach. These proteins are expressed by the viral genome and important for the infection process, but not part of the virus particle. We unambiguously confirm the existence of 95% of the viral proteins predicted to be encoded by the viral genome. Most non-structural proteins peaked in expression at late time post infection. We identified 27 non-redundant sites of phosphorylation on seven different non-structural proteins. The most heavily phosphorylated protein was the DNA binding protein (DBP) with 15 different sites. The phosphorylation occupancy rate could be calculated and monitored with time post infection for 15 phosphorylated sites on various proteins. In the DBP, phosphorylations with time dependent relation were observed. The findings show the complexity of the Ad2 non structural proteins and opens up a discussion for potential new drug targets. PMID- 28915438 TI - Cell wall biomechanics: a tractable challenge in manipulating plant cell walls 'fit for purpose'! AB - The complexity and recalcitrance of plant cell walls has contributed to the success of plants colonising land. Conversely, these attributes have also impeded progress in understanding the roles of walls in controlling and directing developmental processes during plant growth and also in unlocking their potential for biotechnological innovation. Recent technological advances have enabled the probing of how primary wall structures and molecular interactions of polysaccharides define their biomechanical (and hence functional) properties. The outputs have led to a new paradigm that places greater emphasis on understanding how the wall, as a biomechanical construct and cell surface sensor, modulates both plant growth and material properties. Armed with this knowledge, we are gaining the capacity to design walls 'fit for (biotechnological) purpose'! PMID- 28915439 TI - Alpha-Mangostin suppresses interleukin-1beta-induced apoptosis in rat chondrocytes by inhibiting the NF-kappaB signaling pathway and delays the progression of osteoarthritis in a rat model. AB - Osteoarthritis (OA) is a chronic degenerative joint disease that is characterized by progressive joint dysfunction and pain. Apoptosis and catabolism in chondrocytes play critical roles in the development of OA. Alpha-Mangostin (alpha MG), one of the main components of the mangosteen, has been reported to have anti apoptotic, anti-inflammatory and antioxidant effects. We investigated the therapeutic effects of alpha-MG on OA through experiments on rat chondrocytes in vitro and in a rat model of OA induced by destabilization of the medial meniscus (DMM). In vitro, we provided experimental evidence that alpha-MG inhibits the expression of MMP-13 and ADAMTs-5, and promotes the expression of SOX-9 in rat chondrocytes stimulated with interleukin-1beta (IL-1beta). In addition, we also found that alpha-MG can inhibit the expression of pro-apoptotic proteins such as Bax, Cyto-c, and C-caspase3, and increase the expression of the anti-apoptotic protein Bcl-2. These changes may be related to an alpha-MG induced inhibition of the IL-1beta-induced activation of the NF-kB signaling pathway. In vivo, we also found that alpha-MG can limit the development of OA in rat models. The above results show that alpha-MG has a potential therapeutic effect on OA, and that this effect may be achieved by inhibiting the mitochondrial apoptosis of chondrocytes induced by an activation of the NF-kB pathway. PMID- 28915440 TI - Multiple beam ptychography for large field-of-view, high throughput, quantitative phase contrast imaging. AB - The ability to record large field-of-view images without a loss in spatial resolution is of crucial importance for imaging science. For most imaging techniques however, an increase in field-of-view comes at the cost of decreased resolution. Here we present a novel extension to ptychographic coherent diffractive imaging that permits simultaneous full-field imaging of multiple locations by illuminating the sample with spatially separated, interfering probes. This technique allows for large field-of-view imaging in amplitude and phase while maintaining diffraction-limited resolution, without an increase in collected data i.e. diffraction patterns acquired. PMID- 28915441 TI - Femtosecond mega-electron-volt electron microdiffraction. AB - To understand and control the basic functions of physical, chemical and biological processes from micron to nano-meter scale, an instrument capable of visualizing transient structural changes of inhomogeneous materials with atomic spatial and temporal resolutions, is required. One such technique is femtosecond electron microdiffraction, in which a short electron pulse with femtosecond-scale duration is focused into a micron-scale spot and used to obtain diffraction images to resolve ultrafast structural dynamics over a localized crystalline domain. In this letter, we report the experimental demonstration of time-resolved mega-electron-volt electron microdiffraction which achieves a 5 MUm root-mean square (rms) beam size on the sample and a 110 fs rms temporal resolution. Using pulses of 10k electrons at 4.2 MeV energy with a normalized emittance 3 nm-rad, we obtained high quality diffraction from a single 10 MUm paraffin (C44H90) crystal. The phonon softening mode in optical-pumped polycrystalline Bi was also time-resolved, demonstrating the temporal resolution limits of the instrument. This new characterization capability will open many research opportunities in material and biological sciences. PMID- 28915442 TI - Electron cryo-tomography captures macromolecular complexes in native environments. AB - Transmission electron microscopy has a long history in cellular biology. Fixed and stained samples have been used for cellular imaging for over 50 years, but suffer from sample preparation induced artifacts. Electron cryo-tomography (cryoET) instead uses frozen-hydrated samples, without chemical modification, to determine the structure of macromolecular complexes in their native environment. Recent developments in electron microscopes and associated technologies have greatly expanded our ability to visualize cellular features and determine the structures of macromolecular complexes in situ. This review highlights the technological improvements and the new areas of biology these advances have made accessible. We discuss the potential of cryoET to reveal novel and significant biological information on the nanometer or subnanometer scale, and directions for further work. PMID- 28915443 TI - Cerebral white matter hyperintensity is associated with intracranial atherosclerosis in a healthy population. AB - BACKGROUND AND AIMS: Cerebral white matter hyperintensity (WMH) is commonly found in ischemic stroke patients, especially when accompanied by intracranial atherosclerosis (ICAS). However, the relationship between WMH and ICAS in a healthy population has not been evaluated. METHODS: A total of 3159 healthy subjects who underwent health checkups, including brain magnetic resonance imaging and angiography, were enrolled. ICAS was defined as an occlusion or more than 50% stenosis of intracranial vessels on magnetic resonance angiography. Volumes of WMH were quantitatively rated. RESULTS: Eighty-two (2.6%) subjects had ICAS. The mean age of the cohort was 56 years, and the median volume of WMH was 1.02 [0.20-2.60] mL. In a multivariate analysis, ICAS [beta = 0.331, 95% confidence interval (CI) = 0.086 to 0.576, p = 0.008] was significantly associated with WMH volumes after adjusting confounders. Age (beta = 0.046, 95% CI = 0.042 to 0.050, p < 0.001), hypertension (beta = 0.113, 95% CI = 0.017 to 0.210, p = 0.021), and diabetes (beta = 0.154, 95% CI = 0.043 to 0.265, p = 0.006) were also significant, independently of ICAS. The ICAS (+) group had more frequent vascular risk factors including hypertension, diabetes, and statin use, than the ICAS (-) group, and these tendencies increased when WMH was accompanied by ICAS. CONCLUSIONS: ICAS is associated with larger WMH volume in a healthy population. Close observation of this group and strict control of vascular risk factors are needed. PMID- 28915444 TI - Age and composite end-point events in medium follow-up of patients with carotid artery total occlusion using drug therapy. AB - BACKGROUND AND AIMS: The outcome of carotid artery total occlusion (CATO) is unclear. The aim of this study is to report the medium incidence of composite end point events and risk factors (especially age), in patients with CATO, treated medically. METHODS: This was a single center retrospective study. Composite end point events included death, ischemic stroke, transient ischemic attack, hemorrhagic stroke, myocardial infarction, or angina. Logistic regression analysis was used to analyze risk factors of composite end-point events. RESULTS: A total of 94 patients with CATO were included in the study. The mean follow-up duration was 30 +/- 16 months. There were 16 cases who experienced composite end point events (17.0%); among them, there were 15 cases of death (16.0%), 8 cases of ischemic stroke (7 cases of fatal stroke and 1 case of non-fatal stroke) (8.5%), and 1 case of angina pectoris (1%) (the patient later developed ischemic stroke). With increased age, the incidence of composite end-point events was significantly increased (p = 0.002). Multivariate logistic regression analysis showed that only age was a risk factor (OR = 3.051 (1.351-6.890), p = 0.007). CONCLUSIONS: The incidence of composite end-point events in patients with CATO was as high as 17.0% at approximately 3 years after drug therapy alone. For every 10 years of age increase, the risk increase of composite end-point events doubles. PMID- 28915445 TI - Exploring the association of rs10490924 polymorphism with age-related macular degeneration: An in silico approach. AB - The polymorphism rs10490924 (A69S) in the age-related maculopathy susceptibility 2 (ARMS2) gene is highly associated with age-related macular degeneration, which is the leading cause of blindness among the elderly population. The ARMS2 gene encodes a putative small (11kDa) protein, which the function and localization of the ARMS2 protein remain under debate. For a better understanding of functional impacts of the A69S mutation, we performed a detailed analysis of the ARMS2 sequence with a broad set of bioinformatics tools. In silico analysis was followed to predict the tertiary structure, putative binding site regions, and binding site residues. Also, the effects of this mutation on protein stability, aggregation propensity, and homodimerization were analyzed. Next, a molecular dynamic simulation was carried out to understand the dynamic behavior of wild type, A69S, and phosphorylated A69S structures. The results showed alterations in the putative post-translational modification sites on the ARMS2 protein, due to the mutation. Furthermore, the stability of protein and putative homodimer conformations were affected by the mutation. Molecular dynamic simulation results revealed that the A69S mutation enhances the rigidity of the ARMS2 structure and residue serine at position 69 is buried and may not be phosphorylated; however, phosphorylated serine enhances the flexibility of the ARMS2 structure. In conclusion, our study provides new insights into the deleterious effects of the A69S mutation on the ARMS2 structure. PMID- 28915446 TI - Embracing chemical and structural diversity with UCONGA: A universal conformer generation and analysis program. AB - Molecular properties depend on molecular structure, so the first step in any computational chemistry investigation is to generate all thermally accessible conformers. Typically it is necessary to make a trade-off between the number of conformers to be explored and the accuracy of the method used to calculate their energies. Ab initio potential energy surface scans can, in principle, be applied to any molecule, but their conformational cost scales poorly with both molecular size and dimensionality of the search space. Specialized conformer generation techniques rely on parameterized force fields and may also use knowledge-based rules for generating conformers, and are typically only available for drug-like organic molecules. Neither approach is well-suited to generating or identifying chemically sensible conformers for larger non-organic molecules. The Universal CONformer Generation and Analysis (UCONGA) program package fills this niche. It requires no parameters other than built-in atomic van der Waals radii to generate comprehensive ensembles of sterically-allowed conformers, for molecules of arbitrary composition and connectivity. Analysis scripts are provided to identify representative structures from clusters of similar conformers, which may be further refined by subsequent geometry optimization. This approach is particularly useful for molecules not described by parameterized force fields, as it minimizes the number of computationally intensive ab initio calculations required to characterize the conformer ensemble. We anticipate that UCONGA will be particularly useful for computational and structural chemists studying flexible non-drug-like molecules. PMID- 28915447 TI - Oxidative stress induced modulation of platelet integrin alpha2bbeta3 expression and shedding may predict the risk of major bleeding in heart failure patients supported by continuous flow left ventricular assist devices. AB - INTRODUCTION: Oxidative stress and platelet integrin alpha2bbeta3 plays important role in the process of hemostasis and thrombosis. We hypothesized that device induced patient specific oxidative stress and integrin alpha2bbeta3 shedding may be linked to major bleeding complication (MBC) in heart failure (HF) patients supported by continuous flow left ventricular assist devices (CF-LVADs). MATERIALS AND METHODS: We recruited 47patients implanted with CF-LVADs and 15 healthy volunteers. Fourteen patients developed MBC (bleeder group) within one month after implantation while others were considered non-bleeder group (n=33). Oxidative stresses were evaluated by measuring reactive oxygen species (ROS) in platelets, superoxide dismutase (SOD) activity, total antioxidant capacity (TAC) and oxidized low density lipoprotein (oxLDL). Assessments of alpha2bbeta3 were carried out using flow cytometry and ELISA. RESULTS: Biomarkers of oxidative stress and alpha2bbeta3 shedding (decreased surface expression and higher plasma levels) were found to be preexisting condition in all HF patients prior to CF LVAD implantation compared to the healthy volunteers. Significantly elevated levels of ROS and oxLDL; concomitant depletion of SOD and TAC; and alpha2bbeta3 shedding were observed in the bleeder group temporarily in comparison to the non bleeder group after CF-LVAD implantation. A significantly strong association between alpha2bbeta3 shedding and biomarkers of oxidative stress was observed; suggesting a potential role of oxidative stress in platelet integrin shedding leading to MBC after CF-LVAD implantation. Moreover, a receiver operating characteristic (ROC) analysis indicated that the likelihood of MBC data from Integrin alpha2bbeta3 shedding had a predictive power of MBC in CF-LVAD patients. CONCLUSIONS: Oxidative stress might play a potential role in accelerating alpha2bbeta3 shedding and platelet dysfunction, resulting in MBC in CF-LVAD patients. Integrin alpha2bbeta3 shedding may be used to refine bleeding risk stratification in CF-LVAD patients. PMID- 28915449 TI - Increased expression of NLRP3 inflammasome in placentas from pregnant women with severe preeclampsia. AB - Preeclampsia is a pregnancy disorder characterized by imbalance between pro- and anti-inflammatory cytokines associated with high plasma levels of uric acid and Interleukin-1 beta (IL-1beta). The inflammasome is a protein complex that mediates innate immune responses via caspase-1 activation promoting secretion of IL-1beta and IL-18 in their active forms, and also release of the high-mobility group box 1 protein (HMGB1). As the placenta seems to play an important role in the pathogenesis of PE, the present study investigated the expression of genes and proteins related to the inflammasome in placentas from pregnant women with severe preeclampsia. Placental tissue was collected from 20 normotensive pregnant women and 20 preeclamptic women, and inflammasome components, NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3), caspase-1, IL-1beta and IL 18, as well as tumor necrosis factor-alpha (TNF-alpha) and HMGB1 were evaluated by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and also quantified by reverse transcription-qPCR (RT-qPCR). Compared with normotensive pregnant women, placenta from women with PE showed a significant increase in NLRP3, caspase-1, IL-1beta, TNF-alpha and HMGB1 mRNA. Immunohistochemical staining of NLRP3, caspase-1, IL-1beta and TNF-alpha in placental villi, as well as the levels of caspase-1, IL-1beta, TNF-alpha and HMGB1 in placental homogenate were significantly higher in the preeclamptic group than in the normotensive group. However, mRNA expression of IL-18 and its protein concentrations were lower in placentas from preeclamptic women. The results suggest that placentas from pregnant women with preeclampsia show higher expression of NLRP3 inflammasome, which may be involved in the exaggerated inflammatory state in preeclampsia. PMID- 28915448 TI - The composition of the vaginal microbiome in first trimester pregnant women influences the level of autophagy and stress in vaginal epithelial cells. AB - Epithelial cells lining the vagina are major components of genital tract immunity. The influence of the vaginal microbiome on properties of host epithelial cells is largely unexplored. We evaluated whether differences in the most abundant lactobacilli species or bacterial genera in the vagina of first trimester pregnant women were associated with variations in the extent of stress and autophagy in vaginal epithelial cells. Vaginal swabs from 154 first trimester pregnant women were analyzed for bacterial composition by amplification and sequencing of the V1-V3 region of bacterial 16S rRNA genes. Vaginal epithelial cells were lysed and autophagy quantitated by measurement of p62. Intracellular levels of the inducible 70kDa heat shock protein (hsp70), an indicator of cell stress and an autophagy inhibitor, were determined. When Lactobacillus crispatus was the most abundant member of the vaginal microbiota, epithelial p62 and hsp70 levels were lowest as compared to when other bacterial taxa were most abundant. The highest concentrations of p62 and hsp70 were associated with Streptococcus and Bifidobacterium abundance. The p62 level associated with Gardnerella abundance was lower than that observed when lactobacilli other than L. crispatus were most abundant. In conclusion, in the first trimester of pregnancy the abundance of different bacterial taxa is associated with variations in autophagy and magnitude of the stress response in vaginal epithelial cells. PMID- 28915450 TI - Molecular signature and functional analysis of uterine ILCs in mouse pregnancy. AB - In addition to natural killer cells, other innate lymphoid cells have recently been identified in the mouse and human uterus, but their roles in successful pregnancy remain poorly defined. In this study, we examined the dynamic changes of uterine innate lymphoid cells throughout pregnancy in mice. We found that the total number of uterine innate lymphoid cells markedly increased at early gestation. Among the three groups of uterine innate lymphoid cells, the number of the group 2 uterine innate lymphoid cells increased the most during pregnancy. We also determined that the depletion of uterine innate lymphoid cells in Rag1-/- mice resulted in impaired uterine spiral artery remodeling. These results suggest that uterine innate lymphoid cells may play an important role in mouse reproduction. PMID- 28915451 TI - Rotavirus genotype shifts among Swedish children and adults-Application of a real time PCR genotyping. AB - BACKGROUND: It is well known that human rotavirus group A is the most important cause of severe diarrhoea in infants and young children. Less is known about rotavirus infections in other age groups, and about how rotavirus genotypes change over time in different age groups. OBJECTIVES: Develop a real-time PCR to easily genotype rotavirus strains in order to monitor the pattern of circulating genotypes. STUDY DESIGN: In this study, rotavirus strains in clinical samples from children and adults in Western Sweden during 2010-2014 were retrospectively genotyped by using specific amplification of VP 4 and VP 7 genes with a new developed real-rime PCR. RESULTS: A genotype was identified in 97% of 775 rotavirus strains. G1P[8] was the most common genotype representing 34.9%, followed by G2P[4] (28.3%), G9P[8] (11.5%), G3P[8] (8.1%), and G4P[8] (7.9%) The genotype distribution changed over time, from predominance of G1P[8] in 2010-2012 to predominance of G2P[4] in 2013-2014. There were also age-related differences, with G1P[8] being the most common genotype in children under 2 years (47.6%), and G2P[4] the most common in those over 70 years of age (46.1%.). The shift to G2P[4] in 2013-2014 was associated with a change in the age distribution, with a greater number of rotavirus positive cases in elderly than in children. CONCLUSIONS: By using a new real-time PCR method for genotyping we found that genotype distribution was age related and changed over time with a decreasing proportion of G1P[8]. PMID- 28915452 TI - BK virus replication in renal transplant recipients: Analysis of potential risk factors may contribute in reactivation. AB - BACKGROUND: Considering the increasing problem of BK virus infection during post renal transplant surveillance, it is necessary to distinguish the main risk factors leading to reactivation of latent BK virus. Up to now, some probable risk factors have been investigated in some studies, but the results have been confusing and contradictory. OBJECTIVES: The goal of the present study was to determine the frequency and potential risk factors that may play a role in BK polyomavirus reactivation and nephropathy. STUDY DESIGN: In this cross-sectional study, 110 patients, who underwent consecutive transplantation between 2010 and 2013, were enrolled without preliminary screening. Urine and blood samples were taken, and quantitative Real-time PCR assay was used to detect and measure the viral load. Demographic and clinical characteristics of the patients who had BK viremia and/or viruria were documented. RESULTS: Among 110 cases of renal transplant recipients, BK viruria and viremia were found in 54 (49%) and 22 people (20%) respectively. The pre-transplant durations of dialysis among patients with BK viruia were found longer in comparison to BK negative patients. Treatment with Tacrolimus (p=0.03) was found to be a risk factor for development of BK viruria. In patients with viruria and viremia the median creatinine levels were 1.45mg/dl and 1.35mg/dl respectively, which were higher than those in the patients with negative results for BK viruria (p=0.002) and viremia (p=0.02). Also, treatment with Cyclosporine could significantly increase the incidence of BK virus shedding in both urine and blood among patients who received it (p=0.01). Significant relation between reactivation of BK virus and other factors such as age, sex, acute rejection and diabetes was not found. CONCLUSION: Based on our findings, the main potential risk factors for shedding of BK virus into urine in renal transplant recipients were prolonged pre-transplant dialysis and Tacrolimus regimen. Cyclosporine regimens could be considered as risk factor for both BK viruria and viremia. A significant correlation between BK virus replication and elevated creatinine level was seen among our patients. PMID- 28915453 TI - Soil organic matter in podzol horizons of the Amazon region: Humification, recalcitrance, and dating. AB - Characteristics of soil organic matter (SOM) are important, especially in the Amazon region, which represents one of the world's most relevant carbon reservoirs. In this work, the concentrations of carbon and differences in its composition (humification indexes) were evaluated and compared for several horizons (0 to 390cm) of three typical Amazonian podzol profiles. Fluorescence spectroscopy was used to investigate the humic acid (HA) fractions of SOM isolated from the different samples. Simple and labile carbon structures appeared to be accumulated in surface horizons, while more complex humified compounds were leached and accumulated in intermediate and deeper Bh horizons. The results suggested that the humic acids originated from lignin and its derivatives, and that lignin could accumulate in some Bh horizons. The HA present in deeper Bh horizons appeared to originate from different formation pathways, since these horizons showed different compositions. There were significant compositional changes of HA with depth, with four types of organic matter: recalcitrant, humified, and old dating; labile and young dating; humified and young dating; and little humified and old dating. Therefore, the humification process had no direct relation with the age of the organic matter in the Amazonian podzols. PMID- 28915454 TI - Assessing the potential contributions of additional retention processes to PFAS retardation in the subsurface. AB - A comprehensive understanding of the transport and fate of per- and poly fluoroalkyl substances (PFAS) in the subsurface is critical for accurate risk assessments and design of effective remedial actions. A multi-process retention model is proposed to account for potential additional sources of retardation for PFAS transport in source zones. These include partitioning to the soil atmosphere, adsorption at air-water interfaces, partitioning to trapped organic liquids (NAPL), and adsorption at NAPL-water interfaces. An initial assessment of the relative magnitudes and significance of these retention processes was conducted for two PFAS of primary concern, perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), and an example precursor (fluorotelomer alcohol, FTOH). The illustrative evaluation was conducted using measured porous medium properties representative of a sandy vadose-zone soil. Data collected from the literature were used to determine measured or estimated values for the relevant distribution coefficients, which were in turn used to calculate retardation factors for the model system. The results showed that adsorption at the air-water interface was a primary source of retention for both PFOA and PFOS, contributing approximately 50% of total retention for the conditions employed. Adsorption to NAPL-water interfaces and partitioning to bulk NAPL were also shown to be significant sources of retention. NAPL partitioning was the predominant source of retention for FTOH, contributing ~98% of total retention. These results indicate that these additional processes may be, in some cases, significant sources of retention for subsurface transport of PFAS. The specific magnitudes and significance of the individual retention processes will depend upon the properties and conditions of the specific system of interest (e.g., PFAS constituent and concentration, porous medium, aqueous chemistry, fluid saturations, co-contaminants). In cases wherein these additional retention processes are significant, retardation of PFAS in source areas would likely be greater than what is typically estimated based on the standard assumption of solid-phase adsorption as the sole retention mechanism. This has significant ramifications for accurate determination of the migration potential and magnitude of mass flux to groundwater, as well as for calculations of contaminant mass residing in source zones. Both of which have critical implications for human health risk assessments. PMID- 28915455 TI - Estimation of water consumption for ecosystems based on Vegetation Interfaces Processes Model: A case study of the Aksu River Basin, Northwest China. AB - Based on the Moderate Resolution Imaging Spectroradiometer (MODIS) - Normalized Difference Vegetation Index (NDVI), the Vegetation Interfaces Processes (VIP) model simulated the spatio-temporal patterns of actual evapotranspiration (ET) and the water consumption of different ecosystems in the Aksu River Basin, Northwest China between 2000 and 2015. The results revealed that: (1) the applicability of the VIP model was confirmed, with good agreement (R2=0.79, P<0.05) between the VIP-ET and water balance model (WB)-ET in the Aksu River Basin; (2)arable land showed the highest annual actual ET per unit pixel (362.4mm/pixel), followed by forest (159.6mm/pixel), and grass land (142.8mm/pixel); (3) water consumption for arable, forest, and grass land were determined as 19.45*108, 1.94*108, and 28*108m3/a, respectively; and (4) there was a significant trend (P<0.05) of increasing water consumption of 0.379*108m3/a in the artificial ecosystem, but there was no significant trend in the time series of the natural ecosystem. Overall, the study demonstrated that the VIP model is able to supply important information for water resource management at the catchment-scale. PMID- 28915456 TI - Carbon and nitrogen elemental and isotopic ratios of filter-feeding bivalves along the French coasts: An assessment of specific, geographic, seasonal and multi-decadal variations. AB - Primary consumers play a key role in coastal ecosystems by transferring organic matter from primary producers to predators. Among them, suspension-feeders, like bivalve molluscs are widely used in trophic web studies. The main goal of this study was to investigate variations of C and N elemental and isotopic ratios in common bivalves (M. edulis, M. galloprovincialis, and C. gigas) at large spatial (i.e. among three coastal regions) and different temporal (i.e. from seasonal to multi-decadal) scales in France, in order to identify potential general or specific patterns and speculate on their drivers. The observed spatial variability was related to the trophic status of the coastal regions (oligotrophic Mediterranean Sea versus meso- to eutrophic English Channel and Atlantic ocean), but not to ecosystem typology (estuaries, versus lagoons versus bays versus littoral systems). Furthermore, it highlighted local specificities in terms of the origin of the POM assimilated by bivalves (e.g., mainly continental POM vs. marine phytoplankton vs. microphytobenthic algae). Likewise, seasonal variability was related both to the reproduction cycle for C/N ratios of Mytilus spp. and to changes in trophic resources for delta13C of species located close to river mouth. Multi-decadal evolution exhibited shifts and trends for part of the 30-year series with decreases in delta13C and delta15N. Specifically, shifts appeared in the early 2000's, likely linking bivalve isotopic ratios to a cascade of processes affected by local drivers. PMID- 28915457 TI - Tracking oil and gas wastewater-derived organic matter in a hybrid biofilter membrane treatment system: A multi-analytical approach. AB - Dissolved organic matter (DOM) present in oil and gas (O&G) produced water and fracturing flowback was characterized and quantified by multiple analytical techniques throughout a hybrid biological-physical treatment process. Quantitative and qualitative analysis of DOM by liquid chromatography - organic carbon detection (LC-OCD), liquid chromatography-high-resolution mass spectrometry (LC-HRMS), gas chromatography-mass spectrometry (GC-MS), and 3D fluorescence spectroscopy, demonstrated increasing removal of all groups of DOM throughout the treatment train, with most removal occurring during biological pretreatment and some subsequent removal achieved during membrane treatment. Parallel factor analysis (PARAFAC) further validated these results and identified five fluorescent components, including DOM described as humic acids, fulvic acids, proteins, and aromatics. Tryptophan-like compounds bound by complexation to humics/fulvics were most difficult to remove biologically, while aromatics (particularly low molecular weight neutrals) were more challenging to remove with membranes. Strong correlation among PARAFAC, LC-OCD, LC-HRMS, and GC-MS suggests that PARAFAC can be a quick, affordable, and accurate tool for evaluating the presence or removal of specific DOM groups in O&G wastewater. PMID- 28915459 TI - Relationships of CO2 assimilation rates with exposure- and flux-based O3 metrics in three urban tree species. AB - The relationships of CO2 assimilation under saturated-light conditions (Asat) with exposure- (AOTX, Accumulated Ozone exposure over a hourly Threshold of X ppb) and flux-based (PODY, Phytotoxic Ozone Dose over a hourly threshold Y nmol.m 2.s-1) O3 metrics was studied on three common urban trees, Fraxinus chinensis (FC), Platanus orientalis (PO) and Robinia pseudoacacia (RP). Parameterizations for a stomatal multiplicative model were proposed for the three species. RP was the species showing lower species-specific maximum stomatal conductance (gmax) and experiencing lower cumulative O3 uptake along the experiment, but in contrast it was the most sensitive to O3. PODY was slightly better than AOTX metric at estimating relative Asat (R-Asat)for PO and RB but not for FC. The best fittings obtained for the regressions between R-Asat and AOTX for FC, PO and RP were 0.904, 0.868, and 0.876, when the thresholds of X were 60ppb, 55ppb and 30ppb, respectively. However, AOT40 performed also well for all of them, with R2 always >0.83. For PODY, the highest R2 values for FC, PO and RB were 0.863, 0.897 and 0.911 at thresholds Y=7, 5 and 1nmolO3m-2s-1, respectively. Given the potentially higher O3 removal capacity of FC and PO by stomatal uptake and their lower sensitivity to this pollutant than RP, the former two species would be appropriate for urban gardens and areas where O3 levels are high. Parameterization and modeling of stomatal conductance for the main urban tree species may provide reliable estimations of the stomatal uptake of O3 and other gaseous pollutants by vegetation, which may support decision making on the most suitable species for green urban planning in polluted areas. PMID- 28915460 TI - Persistent and widespread long-term phosphorus declines in Boreal lakes in Sweden. AB - We present an analysis of long-term (1988-2013; 26years) total phosphorus (TP) concentration trends in 81 Swedish boreal lakes subject to minimal anthropogenic disturbance. Near universal increases in dissolved organic carbon (DOC) concentrations and a widespread but hitherto unexplained decline in TP were observed. Over 50% of the lakes (n=42) had significant declining TP trends over the past quarter century (Sen's slope=2.5%y-1). These declines were linked to catchment processes related to changes in climate, recovery from acidification, and catchment soil properties, but were unrelated to trends in P deposition. Increasing DOC concentrations appear to be masking in-lake TP declines. When the effect of increasing DOC was removed, the small number of positive TP trends (N=5) turned negative and the average decline in TP increased to 3.9%y-1. The greatest relative TP declines occurred in already nutrient poor, oligotrophic systems and TP concentrations have reached the analytical detection limit (1MUgL 1) in some lakes. In addition, ongoing oligotrophication may be exacerbated by increased reliance on renewable energy from forest biomass and hydropower. It is a cause of significant concern that potential impairments to lake ecosystem functioning associated with oligotrophication are not well handled by a management paradigm focused exclusively on the negative consequences of increasing phosphorus concentrations. PMID- 28915458 TI - Physical water scarcity metrics for monitoring progress towards SDG target 6.4: An evaluation of indicator 6.4.2 "Level of water stress". AB - Target 6.4 of the recently adopted Sustainable Development Goals (SDGs) deals with the reduction of water scarcity. To monitor progress towards this target, two indicators are used: Indicator 6.4.1 measuring water use efficiency and 6.4.2 measuring the level of water stress (WS). This paper aims to identify whether the currently proposed indicator 6.4.2 considers the different elements that need to be accounted for in a WS indicator. WS indicators compare water use with water availability. We identify seven essential elements: 1) both gross and net water abstraction (or withdrawal) provide important information to understand WS; 2) WS indicators need to incorporate environmental flow requirements (EFR); 3) temporal and 4) spatial disaggregation is required in a WS assessment; 5) both renewable surface water and groundwater resources, including their interaction, need to be accounted for as renewable water availability; 6) alternative available water resources need to be accounted for as well, like fossil groundwater and desalinated water; 7) WS indicators need to account for water storage in reservoirs, water recycling and managed aquifer recharge. Indicator 6.4.2 considers many of these elements, but there is need for improvement. It is recommended that WS is measured based on net abstraction as well, in addition to currently only measuring WS based on gross abstraction. It does incorporate EFR. Temporal and spatial disaggregation is indeed defined as a goal in more advanced monitoring levels, in which it is also called for a differentiation between surface and groundwater resources. However, regarding element 6 and 7 there are some shortcomings for which we provide recommendations. In addition, indicator 6.4.2 is only one indicator, which monitors blue WS, but does not give information on green or green-blue water scarcity or on water quality. Within the SDG indicator framework, some of these topics are covered with other indicators. PMID- 28915461 TI - Forecasting wheat and barley crop production in arid and semi-arid regions using remotely sensed primary productivity and crop phenology: A case study in Iraq. AB - Crop production and yield estimation using remotely sensed data have been studied widely, but such information is generally scarce in arid and semi-arid regions. In these regions, inter-annual variation in climatic factors (such as rainfall) combined with anthropogenic factors (such as civil war) pose major risks to food security. Thus, an operational crop production estimation and forecasting system is required to help decision-makers to make early estimates of potential food availability. Data from NASA's MODIS with official crop statistics were combined to develop an empirical regression-based model to forecast winter wheat and barley production in Iraq. The study explores remotely sensed indices representing crop productivity over the crop growing season to find the optimal correlation with crop production. The potential of three different remotely sensed indices, and information related to the phenology of crops, for forecasting crop production at the governorate level was tested and their results were validated using the leave-one-year-out approach. Despite testing several methodological approaches, and extensive spatio-temporal analysis, this paper depicts the difficulty in estimating crop yield on an annual base using current satellite low-resolution data. However, more precise estimates of crop production were possible. The result of the current research implies that the date of the maximum vegetation index (VI) offered the most accurate forecast of crop production with an average R2=0.70 compared to the date of MODIS EVI (Avg R2=0.68) and a NPP (Avg R2=0.66). When winter wheat and barley production were forecasted using NDVI, EVI and NPP and compared to official statistics, the relative error ranged from -20 to 20%, -45 to 28% and -48 to 22%, respectively. The research indicated that remotely sensed indices could characterize and forecast crop production more accurately than simple cropping area, which was treated as a null model against which to evaluate the proposed approach. PMID- 28915462 TI - Abundance of large old trees in wood-pastures of Transylvania (Romania). AB - Wood-pastures are special types of agroforestry systems that integrate trees with livestock grazing. Wood pastures can be hotspots for large old tree abundance and have exceptional natural values; but they are declining all over Europe. While presence of large old trees in wood-pastures can provide arguments for their maintenance, actual data on their distribution and abundance are sparse. Our study is the first to survey large old trees in Eastern Europe over such a large area. We surveyed 97 wood-pastures in Transylvania (Romania) in order to (i) provide a descriptive overview of the large old tree abundance; and (ii) to explore the environmental determinants of the abundance and persistence of large old trees in wood-pastures. We identified 2520 large old trees belonging to 16 taxonomic groups. Oak was present in 66% of the wood-pastures, followed by beech (33%), hornbeam (24%) and pear (22%). For each of these four species we constructed a generalized linear model with quasi-Poisson error distribution to explain individual tree abundance. Oak trees were most abundant in large wood pastures and in wood-pastures from the Saxon cultural region of Transylvania. Beech abundance related positively to elevation and to proximity of human settlements. Abundance of hornbeam was highest in large wood-pastures, in wood pastures from the Saxon cultural region, and in places with high cover of adjacent forest and a low human population density. Large old pear trees were most abundant in large wood-pastures that were close to paved roads. The maintenance of large old trees in production landscapes is a challenge for science, policy and local people, but it also can serve as an impetus for integrating economic, ecological and social goals within a landscape. PMID- 28915463 TI - Freshwater vulnerability under high end climate change. A pan-European assessment. AB - As freshwater availability is crucial for securing a sustainable, lower-carbon future, there is a critical connection between water management and climate policies. Under a rapidly changing climate, it is more important than ever to estimate the degree of future water security. This is a challenging task as it depends on many different variables: the degree of warming and its consequent effects on hydrological resources, the water demand by different sectors, and the possible ameliorations or deteriorations of the effects due to climate change adaptation and mitigation strategies. A simple and transparent conceptual framework has been developed to assess the European vulnerability to freshwater stress under the present hydro-climatic and socioeconomic conditions, in comparison to projections of future vulnerability for different degrees of global warming (1.5 degrees C, 2 degrees C and 4 degrees C), under the high-rate warming scenario (RCP8.5). Different levels of adaptation to climate change are considered in the framework, by employing various relevant pathways of socioeconomic development. A spatially detailed pan-European map of vulnerability to freshwater shortage has been developed at the local administrative level, making this approach extremely useful for supporting regional level policymaking and implementation and strategic planning against future freshwater stress. PMID- 28915464 TI - SAR studies of some acetophenone phenylhydrazone based pyrazole derivatives as anticathepsin agents. AB - Cathepsins have emerged as promising molecular targets in a number of diseases such as Alzeimer's, inflammation and cancer. Elevated cathepsin's levels and decreased cellular inhibitor concentrations have emphasized the search for novel inhibitors of cathepsins. The present work is focused on the design and synthesis of some acetophenone phenylhydrazone based pyrazole derivatives as novel non peptidyl inhibitors of cathepsins B, H and L. The synthesized compounds after characterization have been explored for their inhibitory potency against cathepsins B, H and L. The results show that some of the synthesized compounds exhibit anti-catheptic activity with Ki value of the order of 10-10M. Differential inhibitory effects have been observed for cathepsins B, H and L. Cathepsin L is inhibited more pronounced than cathepsin B and cathepsin H in that order. PMID- 28915465 TI - Traditional Chinese medicinal herbs as potential AChE inhibitors for anti Alzheimer's disease: A review. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting 25 million people worldwide, and cholinergic hypothesis is considered as an important hypotheses in the processes of improving cognitive function and recognition skills in recent years. For the long-term treatment of AD, traditional Chinese medicine are particularly suitable for drug discovery. In this review, we sum up six traditional Chinese medicinal herbs concerned with development of AChEIs, including Herba Epimedii, Coptis Chinensis Franch, Rhizoma Curcumae Longae, Green tea, Ganoderma, Panax Ginseng. The listed compounds based on these herbs are belonging to six classes Flavonoids, Alkaloids, Ketones, Polyphenols, Terpenoid and Saponins, respectively. These compounds could be very promising agents in the search for potent anti-Alzheimer's drugs. PMID- 28915466 TI - Synthesis and characterization of bright green terbium coordination complex derived from 1,4-bis(carbonylmethyl)terephthalate: Structure and luminescence properties. AB - A photoluminescent terbium (Tb) complex involving a novel benzoic-acid compound with a unique coordinated structure, namely 1,4-bis(carbonylmethyl)terephthalate (BCMT), has been designed and synthesized. The new coordinate structure and energy-transfer mechanism between the ligand and Tb(III) ions were investigated in detail. The results demonstrated that the BCMT-Tb(III) complex shows strong fluorescence intensity (4*106a.u.) and long fluorescence lifetime (1.302ms), owing to the favorable degree of energy matching between the triplet excited level of the ligand and the resonant level of Tb(III) ions. Based on the analysis of three-dimensional luminescence spectra, the as-prepared Tb(III) complex can be effectively excited in the range of 250-310nm, and it shows high color purity, with a bright green appearance. PMID- 28915467 TI - The broad emission at 785nm in YAG:Ce3+,Cr3+ phosphor. AB - Luminescence of defects and/or impurities is important for phosphors. One broad emission band centered at 785nm was observed in (Y0.97Ce0.03)3(Al1-xCrx)5O12 (x=0.005, 0.01, 0.03, 0.06, 0.09), (YAG:Ce,Cr) nano-particles synthesized by polymer-assisted sol-gel method in this work. In order to study the source of this wide emission band, the crystalline phase structure of the phosphors was examined by X-ray diffraction (XRD). No obvious diffraction peaks due to impurity phase were observed even though the calcining temperature of the samples arrived at 1400 degrees C. The anti-site defects were excluded. No detectable signals of impurities were obtained by X-ray Photoelectron Spectroscopy (XPS) or inductively coupled plasma mass spectrometry (ICP-MS). Based on the photo-luminescence results of YAG:Ce,Cr, YAG:Ce and YAG:Fe phosphors, the wide emission band is attributed to the 4T1(4G)->6A1(6S) transition from the trace impurity of Fe3+. The excitation band at 280nm is assigned to Fe3+-O2- charge transfer band. PMID- 28915468 TI - Spectral and computational features of the binding between riparins and human serum albumin. AB - The green Brazilian bay leaf, a spice much prized in local cuisine (Aniba riparia, Lauraceae), contains chemical compounds presenting benzoyl-derivatives named riparins, which have anti-inflammatory, antimicrobial and anxiolytic properties. However, it is unclear what kind of interaction riparins perform with any molecular target. As a profitable target, human serum albumin (HSA) is one of the principal extracellular proteins, with an exceptional capacity to interact with several molecules, and it also plays a crucial role in the transport, distribution, and metabolism of a wide variety of endogenous and exogenous ligands. To outline the HSA-riparin interaction mechanism, spectroscopy and computational methods were synergistically applied. An evaluation through fluorescence spectroscopy showed that the emission, attributed to Trp 214, at 346 nm decreased with titrations of riparins. A static quenching mechanism was observed in the binding of riparins to HSA. Fluorescence experiments performed at 298, 308 and 318 K made it possible to conduct thermodynamic analysis indicating a spontaneous reaction in the complex formation (DeltaG<0). The enthalpy-entropy balance experiment with a molecular modeling calculation revealed that hydrophobic, hydrogen bond and non-specific interactions are present for riparin I-III with HSA. The set of results from fractional fluorescence changes obtained through Schatchard was inconclusive in establishing what kind of cooperativity is present in the interaction. To shed light upon the HSA-riparins complex, Hill's approach was utilized to distinguish the index of affinity and the binding constant. A correspondence between the molecular structures of riparins, due to the presence of the hydroxyl group in the B-ring, with thermodynamic parameters and index of affinity were observed. Riparin III performs an intramolecular hydrogen bond, which affects the Hill coefficient and the binding constant. Therefore, the presence of hydroxyl groups is capable of modulating the interaction between riparins and HSA. Site marker competitive experiments indicated Site I as being the most suitable, and the molecular modeling tools reinforced the experimental results detailing the participation of residues. PMID- 28915469 TI - Synthesis of water-soluble curcumin derivatives and their inhibition on lysozyme amyloid fibrillation. AB - The potential application of curcumin was heavily limited in biomedicine because of its poor solubility in pure water. To circumvent the detracting feature, two novel water-soluble amino acid modified curcumin derivatives (MLC and DLC) have been synthesized through the condensation reaction between curcumin and Nalpha Fmoc-Nepsilon-Boc-l-lysine. Benefiting from the enhanced solubility of 3.32*10 2g/mL for MLC and 4.66*10-2g/mL for DLC, the inhibition effects of the as prepared derivatives on the amyloid fibrillation of lysozyme (HEWL) were investigated detaily in water solution. The obtained results showed that the amyloid fibrillation of HEWL was inhibited to a great extent when the concentrations of MLC and DLC reach to 20.139mM and 49.622mM, respectively. The fluorescence quenching upon the addition of curcumin to HEWL provide a support for static and dynamic recombination quenching process. The binding driving force was assigned to classical hydrophobic interaction between curcumin derivatives and HEWL. In addition, UV-Vis absorption and circular dichroism (CD) spectra confirmed the change of the conformation of HEWL. PMID- 28915470 TI - Emotional and behavioural problems in children with Developmental Coordination Disorder: Exploring parent and teacher reports. AB - BACKGROUND: Although characterised by motor impairments, children with Developmental Coordination Disorder (DCD) also show high rates of psychopathology (anxiety, depression, low self-esteem). Such findings have led to calls for the screening of mental health problems in this group. AIMS: To investigate patterns and profiles of emotional and behavioural problems in children with and without DCD, using the Strengths and Difficulties Questionnaire (SDQ). METHODS AND PROCEDURES: Teachers and parents completed SDQs for 30 children with DCD (7-10 years). Teacher ratings on the SDQ were also obtained from two typically developing (TD) groups: 35 children matched for chronological age, and 29 younger children (4-7 years) matched by motor ability. OUTCOMES AND RESULTS: Group and individual analyses compared parent and teacher SDQ scores for children with DCD. Teacher reports showed that children with DCD displayed higher rates of emotional and behavioural problems (overall, and on each subscale of the SDQ) relative to their TD peers. No differences were observed between the two TD groups. Inspection of individual data points highlighted variability in the SDQ scores of the DCD group (across both teacher and parent ratings), with suggestions of elevated hyperactivity but comparably lower levels of conduct problems across this sample. Modest agreement was found between teacher and parent ratings of children with DCD on the SDQ. CONCLUSIONS AND IMPLICATIONS: There is a need to monitor levels of emotional and behavioural problems in children with DCD, from multiple informants. PMID- 28915471 TI - Characterization of mechanical properties of pericardium tissue using planar biaxial tension and flexural deformation. AB - Flexure is an important mode of deformation for native and bioprosthetic heart valves. However, mechanical characterization of bioprosthetic leaflet materials has been done primarily through planar tensile testing. In this study, an integrated experimental and computational cantilever beam bending test was performed to characterize the flexural properties of glutaraldehyde-treated bovine and porcine pericardium of different thicknesses. A strain-invariant based structural constitutive model was used to model the pericardial mechanical behavior quantified through the bending tests of this study and the planar biaxial tests previously performed. The model parameters were optimized through an inverse finite element (FE) procedure in order to describe both sets of experimental data. The optimized material properties were implemented in FE simulations of transcatheter aortic valve (TAV) deformation. It was observed that porcine pericardium TAV leaflets experienced significantly more flexure than bovine when subjected to opening pressurization, and that the flexure may be overestimated using a constitutive model derived from purely planar tensile experimental data. Thus, modeling of a combination of flexural and biaxial tensile testing data may be necessary to more accurately describe the mechanical properties of pericardium, and to computationally investigate bioprosthetic leaflet function and design. PMID- 28915472 TI - "Assessing the methodological quality of systematic reviews in radiation oncology: A systematic review". AB - OBJECTIVE: The objective of our study was to evaluate the methodological quality of systematic reviews and meta-analyses in Radiation Oncology. METHODS: A systematic literature search was conducted for all eligible systematic reviews and meta-analyses in Radiation Oncology from 1966 to 2015. Methodological characteristics were abstracted from all works that satisfied the inclusion criteria and quality was assessed using the critical appraisal tool, AMSTAR. Regression analyses were performed to determine factors associated with a higher score of quality. RESULTS: Following exclusion based on a priori criteria, 410 studies (157 systematic reviews and 253 meta-analyses) satisfied the inclusion criteria. Meta-analyses were found to be of fair to good quality while systematic reviews were found to be of less than fair quality. Factors associated with higher scores of quality in the multivariable analysis were including primary studies consisting of randomized control trials, performing a meta-analysis, and applying a recommended guideline related to establishing a systematic review protocol and/or reporting. CONCLUSIONS: Systematic reviews and meta-analyses may introduce a high risk of bias if applied to inform decision-making based on AMSTAR. We recommend that decision-makers in Radiation Oncology scrutinize the methodological quality of systematic reviews and meta-analyses prior to assessing their utility to inform evidence-based medicine and researchers adhere to methodological standards outlined in validated guidelines when embarking on a systematic review. PMID- 28915473 TI - Endocrine disrupting compounds in streams in Israel and the Palestinian West Bank: Implications for transboundary basin management. AB - Endocrine disrupting compounds (EDCs) frequently enter surface waters via discharges from wastewater treatment plants (WWTPs), as well as from industrial and agricultural activities, creating environmental and health concerns. In this study, selected EDCs were measured in water and sediments along two transboundary streams flowing from the Palestinian Authority (PA) into Israel (the Zomar Alexander and Hebron-Beer Sheva Streams). We assessed how the complicated conflict situation between Israel and the PA and the absence of a coordinated strategy and joint stream management commission influence effective EDC control. Both streams receive raw Palestinian wastewater in their headwaters, which flows through rural areas and is treated via sediment settling facilities after crossing the 1949 Armistice Agreement Line. Four sampling campaigns were conducted over two years, with concentrations of selected EDCs measured in both the water and the sediments. Results show asymmetrical pollution profiles due to socio-economic differences and contrasting treatment capacities. No in-stream attenuation was observed along the stream and in the sediments within the Palestinian region. After sediment settling in treatment facilities at the Israeli border, however, significant reductions in the EDC concentrations were measured both in the sediments and in the water. Differences in sedimentation technologies had a substantial effect on EDC removal at the treatment location, positively affecting the streams' ability to further remove EDCs downstream. The prevailing approach to addressing the Israeli-Palestinian transboundary wastewater contamination reveals a narrow perspective among water managers who on occasion only take local interests into consideration, with interventions focused solely on improving stream water quality in isolated segments. Application of the "proximity principle" through the establishment of WWTPs at contamination sources constitutes a preferable strategy for reducing contamination by EDCs and other pollutants to ensure minimization of public health risks due to the pollution of streams and underlying potable groundwater. PMID- 28915474 TI - Simultaneous removal of cadmium, zinc and manganese using electrocoagulation: Influence of operating parameters and electrolyte nature. AB - In the present study, the influence of operating parameters and electrolyte nature on the simultaneous removal of toxic metals (cadmium, zinc and manganese) from synthetic smelting wastewater by batch electrocoagulation was investigated. This wastewater contained high concentrations of anion-cation electrolytes. Results indicated that the efficiency of heavy metals removal can be enhanced by increasing the solution pH and current density. The Fe-Fe electrode combination is more effective than the other combinations (Al-Al, Al-Fe and Fe-Al). The interaction of heavy metal ions showed that the increase of initial Zn2+ concentration adversely affects on Cd2+ removal. In addition, the single chloride system exhibits the optimum removal efficiency on Mn2+. Single sulfate and binary anion systems exert a more positive effect on Cd2+ and Zn2+ removal because of the stronger charge neutralization and destabilization of iron hydroxide flocs. Increases of Ca2+ and Mg2+ ions exert a significant negative effect on metal removal. However, the addition of a small amount of sodium chloride into a high sulfate and hardness solution can accelerate the removal of heavy metals. Finally, the sludge samples generated from electrocoagulation were characterized by XRD and SEM-EDS analyses. PMID- 28915475 TI - Survival of European plaice discarded from coastal otter trawl fisheries in the English Channel. AB - Species that have a high likelihood of surviving the discarding process have become great concern since the European Union reformed the Common Fisheries Policy and enacted a landing obligation prohibiting the discarding any individuals of species under quota. Among species presenting an elevated survival potential, plaice (Pleuronectes platessa) is one of the most discarded in the coastal otter trawl fishery in the English Channel. The objective of this study is to provide the most reliable estimates of plaice survival after release in commercial conditions, and to identify the factors that influence survival rates. A captivity experiment was conducted in January-February in the English fishery to assess the survival of discarded plaice as a function of a semi-quantitative index of fish vitality, which has been demonstrated to be a good proxy of fish survival in comparable fishing and environmental conditions. This study examined the potential of this index to estimate discard survival in three trials from the English and French fisheries and at three different seasons. The vitality index was then used to analyse the influence of several factors (fishing practices, environmental conditions and fish biological characteristics) on the discard survival. The survival rates for plaice were accurately estimated at 62.8% in January-February, 66.6% in November and 45.2% in July. While these rates remained substantial whatever the fishing, environmental or fish biological conditions, the time fish spent on the deck, the bottom and air temperatures, the tow depth and the fish length had a significant influence on plaice survival. In practice, plaice survival could be enhanced by releasing the fish early during catch sorting and avoiding exposure to extreme air temperatures. PMID- 28915476 TI - Microbial remediation of fluoride-contaminated water via a novel bacterium Providencia vermicola (KX926492). AB - The present study emphasizes on the isolation, identification and characterization of a fluoride-resistant bacteria from contaminated groundwater of a severely affected rural area. The isolate was investigated for its possible role towards bioremediation of fluoride. Bacterial growth was determined by various carbon and nitrogen sources. Influence of parameters like initial fluoride concentration (5-25 mg L-1), pH (3-9) and temperature (15-42 degrees C) on fluoride removal by Providencia sp. KX926492 were also examined. SEM, EDX and FTIR were performed to analyse the surface texture, elemental composition and functional groups of the bacterium involved in the uptake of fluoride ions. 16S rRNA sequencing was performed to identify the isolate. Plackett-Burman design was employed to optimize the various parametric conditions of fluoride removal. Maximum removal of 82% was achieved when the initial fluoride concentration was 20 mgL-1 at pH 7 and 37 degrees C temperature with dextrose and nitrogen concentrations of 5 and 4 g per 50 mL respectively. Results suggested that Providencia vermicola (KX926492) could be a potential bacterium in removal of fluoride from contaminated water. PMID- 28915477 TI - Combined Homogeneous Surface Diffusion Model - Design of experiments approach to optimize dye adsorption considering both equilibrium and kinetic aspects. AB - Adsorption, a popular technique for removing azo dyes from aqueous streams, is influenced by several factors such as pH, initial dye concentration, temperature and adsorbent dosage. Any strategy that seeks to identify optimal conditions involving these factors, should take into account both kinetic and equilibrium aspects since they influence rate and extent of removal by adsorption. Hence rigorous kinetics and accurate equilibrium models are required. In this work, the experimental investigations pertaining to adsorption of acid orange 10 dye (AO10) on activated carbon were carried out using Central Composite Design (CCD) strategy. The significant factors that affected adsorption were identified to be solution temperature, solution pH, adsorbent dosage and initial solution concentration. Thermodynamic analysis showed the endothermic nature of the dye adsorption process. The kinetics of adsorption has been rigorously modeled using the Homogeneous Surface Diffusion Model (HSDM) after incorporating the non-linear Freundlich adsorption isotherm. Optimization was performed for kinetic parameters (color removal time and surface diffusion coefficient) as well as the equilibrium affected response viz. percentage removal. Finally, the optimum conditions predicted were experimentally validated. PMID- 28915479 TI - Effect of design and operational conditions on the performance of subsurface flow treatment wetlands: Emerging organic contaminants as indicators. AB - Six pilot-scale subsurface flow treatment wetlands loaded with primary treated municipal wastewater were monitored over one year for classical wastewater parameters and a set of emerging organic compounds (EOCs) serving as process indicators for biodegradation: caffeine, ibuprofen, naproxen, benzotriazole, diclofenac, acesulfame, and carbamazepine. The wetland technologies investigated included conventional horizontal flow, unsaturated vertical flow (single and two stage), horizontal flow with aeration, vertical flow with aeration, and reciprocating. Treatment efficiency for classical wastewater parameters and EOCs generally increased with increasing design complexity and dissolved oxygen concentrations. The two aerated wetlands and the two-stage vertical flow system showed the highest EOC removal, and the best performance in warm season and most robust performance in the cold season. These three systems performed better than the adjacent conventional WWTP with respect to EOC removal. Acesulfame was observed to be removed (>90%) by intensified wetland systems and with use of a tertiary treatment sand filter during the warm season. Elevated temperature and high oxygen content (aerobic conditions) proved beneficial for EOC removal. For EOCs of moderate to low biodegradability, the co-occurrence of aerobic conditions and low content of readily available carbon appears essential for efficient removal. Such conditions occurred in the aerated systems and with use of a tertiary treatment sand filter. PMID- 28915478 TI - Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes. AB - BACKGROUND: Tobacco products containing menthol are widely used by youth. We used e-cigarettes to conduct an experimental evaluation of the independent and interactive effects of menthol and nicotine among youth. PROCEDURES: Pilot chemosensory experiments with fourteen e-cigarette users identified low (barely perceptible, 0.5%) and high (similar to commercial e-liquid, 3.5%) menthol concentrations. Sixty e-cigarette users were randomized to a nicotine concentration (0mg/ml, 6mg/ml, 12mg/ml) and participated in 3 laboratory sessions. During each session, they received their assigned nicotine concentration, along with one of three menthol concentrations in random counterbalanced order across sessions (0, 0.5%, 3.5%), and participated in three fixed-dose, and an ad-lib, puffing period. Urinary menthol glucuronide and salivary nicotine levels validated menthol and nicotine exposure. We examined changes in e-cigarette liking/wanting and taste, coolness, stimulant effects, nicotine withdrawal and ad-lib use. RESULTS: Overall, the high concentration of menthol (3.5%) significantly increased e-cigarette liking/wanting relative to no menthol (p<0.001); there was marginal evidence of nicotine* menthol interactions (p=0.06), with an increase in liking/wanting when 3.5% menthol was combined with 12mg/ml nicotine, but not 6mg/ml nicotine. Importantly, both 0.5% and 3.5% menthol concentrations significantly improved taste and increased coolness. We did not observe nicotine or menthol-related changes in stimulant effects, nicotine withdrawal symptoms or ad-lib use. CONCLUSIONS: Menthol, even at very low doses, alters the appeal of e-cigarettes among youth. Further, menthol enhances positive rewarding effects of high nicotine-containing e-cigarettes among youth. PMID- 28915480 TI - Facile fabrication of mediator-free Z-scheme photocatalyst of phosphorous-doped ultrathin graphitic carbon nitride nanosheets and bismuth vanadate composites with enhanced tetracycline degradation under visible light. AB - To realize the sustainable employment of solar energy in contaminant degradation and environmental recovery, design and development of an efficient photocatalyst is urgently needed. Herein, a novel direct Z-scheme composite photocatalysts consist of phosphorous-doped ultrathin g-C3N4 nanosheets (PCNS) and bismuth vanadate (BiVO4) are developed via a one-pot impregnated precipitation method. The as-prepared hybrid nanocomposite was utilized for the degradation tetracycline (TC) under visible light irradiation. Among the composites with various PCNS/BiVO4 ratios, the prepared PCNS/BVO-400 photocatalyst presents the best performance, showing a TC (10mg/L) removal efficiency of 96.95% within 60min, more than double that of pristine BiVO4 (41.45%) and higher than that of pure PCNS (71.78%) under the same conditions. The effects of initial TC concentration, catalyst dosage, pH value and different water sources have been studied in detail. The improved photocatalytic performance of the as-prepared PCNS/BiVO4 nanocomposites could be attributed to the promoted separation efficiency of the photogenerated electrons and the enhanced charge carrier lifetime (1.65ns) owing to the synergistic effect between the PCNS and BiVO4. The degradation intermediates and decomposition pathway of TC were also analyzed and proposed. Additionally, radical trapping experiments and ESR measurement indicated that the photogenerated holes (h+), superoxide radical (O2-) and hydroxyl radical (OH) all participated in the TC removal procedure in the reaction system. The high performance of PCNS/BVO-400 in real wastewater indicated the potential of the prepared composite in practical application. This work provides an efficient and promising approach for the formation of high performance Z-scheme photocatalyst and study the possibility for real wastewater treatment. PMID- 28915481 TI - General synthesis of hierarchical C/MOx@MnO2 (M=Mn, Cu, Co) composite nanofibers for high-performance supercapacitor electrodes. AB - Improving the conductivity and specific surface area of electrospun carbon nanofibers (CNFs) is beneficial to a rapid realization of their applications in energy storage field. Here, a series of one-dimensional C/MOx (M=Mn, Cu, Co) nanostructures are first prepared by a simple two-step process consisting of electrospinning and thermal treatment. The presence of low-valence MOx enhances the porosity and conductivity of nanocomposites to some extent through expanding graphitic domains or mixing metallic Cu into the CNF substrates. Next, the C/MOx frameworks are coated with MnO2 nanosheets/nanowhiskers (C/MOx@MnO2), during which process the low-valence MOx can partly reduce KMnO4 so as to mitigate the consumption of CNFs. When used as active materials for supercapacitor electrodes, the obtained C/MOx@MnO2 exhibit excellent electrochemical performances in comparison with the common CNFs@MnO2 (CM) core-shell electrode due to the combination of desired functions of the individual components and the introduction of extra synergistic effect. It is believed that these results will provide an alternative way to further increase the capacitive properties of CNFs- or metal oxide-based nanomaterials and potentially stimulate the investigation on other kinds of C/MOx composite nanostructures for various applications. PMID- 28915482 TI - Nickel nanoparticles encapsulated in porous carbon and carbon nanotube hybrids from bimetallic metal-organic-frameworks for highly efficient adsorption of dyes. AB - Nickel nanoparticles encapsulated in porous carbon/carbon nanotube hybrids (Ni/PC CNT) were successfully prepared by a facile carbonization process using Ni/Zn-MOF as the precursor. Distinct from previous studies, Ni/Zn-MOF precursors were prepared via a direct precipitation method at room temperature for only 5min. After the carbonization, magnetic Ni nanoparticles were well embedded in the porous carbon and carbon nanotube. The obtained Ni/PC-CNT composites had a high surface area (999m2 g-1), large pore volume (0.86cm3 g-1) and well-developed graphitized wall. The Ni/PC-CNT composites showed excellent adsorption capacity for removal of malachite green (MG), congo red (CR), rhodamine B (Rh B), methylene blue (MB) and methyl orange (MO) from aqueous solution. The maximum adsorption capacity of Ni/PC-CNT composites were about 898, 818, 395, 312 and 271mg/g for MG, CR, RB, MB and MO dyes, respectively, which were much higher than most of the previously reported adsorbents. Moreover, the Ni/PC-CNT composites could be easily regenerated by washing it with ethanol and easy magnetic separation. PMID- 28915483 TI - Sulphur and nitrogen dual-doped mesoporous carbon hybrid coupling with graphite coated cobalt and cobalt sulfide nanoparticles: Rational synthesis and advanced multifunctional electrochemical properties. AB - Doping-type carbon matrixes not only play a vital role on their electrochemical properties, but also are capable of suppressing the crush and aggregation phenomenon in the electrode reaction process for pristine metallic compound. Herein, graphite coated cobalt and cobalt sulfide nanoparticles decorating on sulphur and nitrogen dual-doped mesoporous carbon (Co@Co9S8/S-N-C) was fabricated by a combined hydrothermal reaction with pyrolysis method. Benefited from g-C3N4 template and original synthetic route, as-obtained Co@Co9S8/S-N-C possessed high specific surface area (751.7m2g-1), large pore volume (1.304cm3g-1), S and N dual doped component and relative integrated graphite skeleton, as results it was developed as decent oxygen reduction electro-catalyst and ultra-long-life Li-ion battery anode. Surprisingly, compared with commercial Pt/C, it displayed a higher half-wave potential (0.015V positive) and lower Tafel slop (66mVs-1), indicating its superior ORR activities. Moreover, the ultra-long-life cyclic performances were revealed for lithium ion battery, exhibiting the retention capacities of 652.1mAhg-1 after 610 cycles at 0.2Ag-1, 432.1 and 405.7mAhg-1 at 5 and 10Ag-1 after 1000 cycles, respectively. We propose that the synergistic effect of structure and chemical component superiorities should be responsible for the remarkable electrochemical behaviors of the Co@Co9S8/S-N-C. PMID- 28915484 TI - Spontaneous vesicle formation and vesicle-to-micelle transition of sodium 2 ketooctanate in water. AB - Single-tailed short-chain alkyl keto-acids/salts, a class of fatty acid/salt derivatives, such as sodium 2-ketooctanate (KOCOONa), are a kind of weakly acid/salt type amphiphiles and plausible prebiotic molecules, and the current understanding of their aggregation behavior in aqueous solutions is still limited. Herein, the aggregation behavior of KOCOONa in aqueous solution was studied by changing its concentration (C), using equilibrium surface tension, conductivity, and fluorescence measurements. The aggregates formed were characterized using freeze-fracture and cryogenic transmission electron microscopy, dynamic light scattering, atomic force microscopy, and confocal laser scanning microscopy. A concentration-driven stepwise aggregation was identified in the KOCOONa solution. Vesicles can spontaneously form from the single component aqueous solution, with a critical vesicle concentration (CVC) of ~15mM, which is obviously lower than that of octanoic acid/salt (120-200mM). With increasing C, a vesicle-to-micelle transition can occur, showing a critical micelle concentration (CMC) of ~80mM. In addition, the membrane permeability of the KOCOONa vesicles was examined using small-size Calcein and large-size FITC BSA as fluorescence probes, showing a size-selective permeability, similar to short-chain (C8-C11) fatty acid vesicles. For the first time, the aggregation behavior of single-tailed keto-acid salt surfactant is reported. PMID- 28915485 TI - Long-acting and broad-spectrum antimicrobial electrospun poly (epsilon caprolactone)/gelatin micro/nanofibers for wound dressing. AB - Trimethoxysilylpropyl octadecyldimethyl ammonium chloride (QAS), which forms facile bonds with hydroxyl groups, acts asa cationic antibacterial agent. In this work, QAS was introduced into a polycaprolactone (PCL)/gelatin hybrid in increasing concentrations to fabricate a long-acting and broad-spectrum antimicrobial micro/nanofiber membrane as a novel wound dressing. The physical interactions and chemical bonding between QAS/PCL and QAS/gelatin were demonstrated by infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS. Measured water contact angle between the PCL-gelatin/QAS (PG-Q) nanofiber membranes suggested a hydrophobic surface, which has been shown to aid in removal of wound dressings. The mechanical strength of the membranes was sufficient to meet the clinical requirements. Furthermore, the 15% QAS (PG-Q15) and 20% QAS (PG Q20) formulated nanofiber membranes showed a considerable increase in their bacteriostatic activity towards Staphylococcus aureus (gram-positive) and Pseudomonas aeruginosa (gram-negative) bacteria, suggesting a broad-spectrum bactericidal effect by the PG-Q membranes. The PG-Q membranes with various QAS formulations demonstrated little cytotoxicity. Therefore, the long-acting and broad-spectrum antimicrobial electrospun PG-Q micro/nanofibers membrane demonstrate potential efficacy asan antibacterial wound dressing. PMID- 28915486 TI - Ultrathin Beta-Nickel hydroxide nanosheets grown along multi-walled carbon nanotubes: A novel nanohybrid for enhancing flame retardancy and smoke toxicity suppression of unsaturated polyester resin. AB - Novel nanohybrid (beta-Ni(OH)2-CNTs) obtained by ultrathin Beta-Nickel hydroxide (beta-Ni(OH)2) nanosheets grown along multi-walled carbon nanotubes (CNTs) was successfully synthesized and then incorporated into UPR to prepare UPR/beta Ni(OH)2-CNTs nanocomposites. Structure of beta-Ni(OH)2-CNTs nanohybrid was confirmed by X-ray diffraction, scanning electron microscopy measurements. Compared with single CNTs or beta-Ni(OH)2, the dispersion of beta-Ni(OH)2-CNTs in UPR was improved greatly. And the UPR/beta-Ni(OH)2-CNTs nanocomposites exhibited significant improvements in flame retardancy, smoke suppression, and mechanical properties, including decreased peak heat release rate by 39.79%, decreased total heat release by 44.87%, decreased smoke release rate by 29.86%, and increased tensile strength by 12.1%. Moreover, the amount of toxic volatile from UPR nanocomposites decomposition was dramatically reduced, and smoke generation was effectively inhibited during combustion. The dramatical reduction of fire hazards can be ascribed to the good dispersion, the catalytic charring effect of beta Ni(OH)2 nanosheets and physical barrier effect of stable network structure consisted of beta-Ni(OH)2 and CNTs. PMID- 28915487 TI - Genetic backgrounds and hidden trait complexity in natural populations. AB - Dissecting the genetic basis of natural phenotypic variation is a major goal in biology. We know that most traits are strongly heritable. However, their genetic architecture is a long-standing question, which is unfortunately confounded by the lack of complete knowledge of the genetic components as well as their phenotypic effect in a specific genetic background. Many genetic variants are known to affect phenotypes but the same functional variant can have a different effect on the phenotype in different individuals of the same species. Understanding the impact of genetic background on the expressivity of a given phenotype is essential because this effect complicates our ability to predict phenotype from genotype. Here, we briefly review recent progress on the exploration of the effect of genetic background and we discuss how a deeper characterization of the inheritance, expressivity and genetic interactions hidden behind the phenotypic landscape of natural variation could provide a better understanding of the relationship between genotype and phenotype. PMID- 28915488 TI - Plant mating systems: self-incompatibility and evolutionary transitions to self fertility in the mustard family. AB - Flowering plants have evolved diverse mechanisms that promote outcrossing. The most widespread of these outbreeding devices are self-incompatibility systems, the highly selective prefertilization mating barriers that prevent self fertilization by disrupting pollen-pistil interactions. Despite the advantages of outcrossing, loss of self-incompatibility has occurred repeatedly in many plant families. In the mustard family, the highly polymorphic receptors and ligands that mediate the recognition and inhibition of self-pollen in self incompatibility have been characterized and the 3D structure of the receptor ligand complex has been solved. Sequence analyses and empirical studies in self incompatible and self-compatible species are elucidating the genetic basis of switches from the outcrossing to selfing modes of mating and beginning to provide clues to the diversification of the self recognition repertoire. PMID- 28915489 TI - Clinical features and surgical procedures of congenital vaginal atresia-A retrospective study of 67 patients. AB - OBJECTIVE: To explore the characteristics of congenital vaginal atresia, further improve its classification, and therefore help the clinical diagnosis and treatment of congenital vaginal atresia. METHODS: This was a retrospective study of 67 patients with congenital vaginal atresia (from March 1984 to March 2015). Clinical and surgical characteristics were analyzed. RESULTS: For lower vaginal atresia, 25 patients successfully underwent vaginoplasty at the lower portion of the vagina. For complete vagina atresia, 25 patients with type i cervical atresia were treated with artificial vaginoplasty+tracheloplasty, and all showed no dysmenorrhea within six months after surgery. Four patients with type ii cervical atresia and two patients with type iii cervical atresia successfully underwent hysterectomy+artificialvaginoplasty. Two patients with type iv cervical atresia underwent combined abdominoperineal artificial vaginoplasty+tracheloplasty. One patient with upper vaginal atresia successfully underwent hysterectomy via the narrow segment of the cervix. Three patients with top vaginal atresia had no dysmenorrhea after transvaginaltracheloplasty. CONCLUSION: This study suggests two new categories of vaginal atresia (upper vaginal atresia and top vaginal atresia), which could be used as a reference for treatment of this condition. Appropriate treatments were performed using a personalized approach and satisfactory results were achieved. PMID- 28915490 TI - Bioremoval of zinc and manganese by bacterial biofilm: A bioreactor-based approach. AB - Industrialization has led to the disposal of a massive amount of heavy metals every year, showing perilous effects on humans, marine life and agricultural products. There are numerous chemical and biological approaches available but their implementation is limited due to high cost and low efficiency. Therefore, the present study was focused on the biofilm- based bioremoval of heavy metals (zinc and manganese) using indigenous bacteria isolated from the tannery sludge obtained from Ranipet, Tamil Nadu. The effective isolate was capable of tolerating up to 2000mg/L of zinc and manganese and was further used for development of biofilm on the peels of Cucumis sativus. The isolate was found to be a close neighbour of Pseudomonas beteli by 16S rRNA gene sequencing. The uptake efficiency of the biofilm formed on the substrate was estimated to be 69.9% for zinc and 78.4% for manganese by atomic absorption spectroscopy. The scanning electron microscopy showed the biofilm formation on the substrate and also revealed the presence of heavy metal ions adsorbed on the biofilm. The adsorption kinetics of the substrate followed a heterogeneous mode of adsorption of the heavy metals as it showed a higher R2 value for the Freundlich isotherm kinetics as compared to that of Langmuir. Thus, the peels of Cucumis sativus was assessed to be effective for the bioremoval of zinc and manganese. PMID- 28915491 TI - Green synthesis of carbon dots originated from Lycii Fructus for effective fluorescent sensing of ferric ion and multicolor cell imaging. AB - Green, economical and effective method was developed for synthesis of fluorescent carbon dots (CDs), using one-pot hydrothermal treatment of Lycii Fructus. Optical and structural properties of the CDs have been extensively studied by UV-visible and fluorescence spectroscopic, x-ray diffraction (XRD) techniques, transmission electron microscopy (TEM) and high resolution TEM (HRTEM). Surface functionality and composition of CDs has been illustrated by Fourier transform infrared spectroscopy (FTIR), x-ray photoelectron spectroscopy (XPS) spectra and elemental analysis. The fabricated CDs possess stable fluorescent properties. The fluorescent quantum yield of the CDs can reach 17.2%. The prepared CDs emitted a broad fluorescence between 415 and 545nm and their fluorescence was tuned by changing excitation wavelength. Meanwhile, the fluorescence intensity of the CDs could be significantly quenched by Fe3+ (turn-off). The CDs exhibit captivating sensitivity and selectivity toward Fe3+ with a linear range from 0 to 30MUM and a detection limit of 21nM. The prepared CDs were successfully applied to the determination of Fe3+ in the urine samples, the water samples from the from the Yellow River and living HeLa (Henrietta Lacks) cells. Moreover, the low-toxicity and excellent biocompatibility of the CDs were evaluated through MTT assay on HeLa cells. The CDs were also employed as fluorescent probes for multicolor imaging of HeLa cells successfully. PMID- 28915492 TI - Enhancement of 5-aminolevulinic acid phototoxicity by encapsulation in polysaccharides based nanocomplexes for photodynamic therapy application. AB - Polysaccharides based nanocomplexes have been developed for encapsulation, controlled delivery and to enhance the phototoxicity of the photosensitizer 5 aminolevulinic acid for application in photodynamic therapy. The nanocomplexes were prepared by coacervation in a solvent free environment using chitosan as polycation while alginic and polygalacturonic acid as polyanions. The complexes showed average dimension in the range 90-120nm, good stability in simulated physiological media and high drug encapsulation efficiency, up to 800MUg per mg of carrier. Release studies demonstrate the possibility to tune the overall release rate and the intensity of the initial burst by changing the external pH. Cytotoxicity and photocytotoxicity tests confirmed the not toxicity of the used polysaccharides. Cell viability results confirmed the improvement of 5 aminolevulinic acid phototoxicity when loaded into the carrier compared to the free form. No effect of the irradiation on the nanocomplexes structure and on the release kinetics of the drug was observed. The results demonstrate that the prepared formulations have suitable properties for future application in photodynamic therapy and to ameliorate the therapeutic efficacy and overcome the side-effects related to the use of the photosensitizer 5-aminolevulinic acid. PMID- 28915493 TI - In situ spectral response of the Arabian Gulf and Sea of Oman coastal waters to bio-optical properties. AB - Mapping of Chlorophyll-a (Chl-a) over the coastal waters of the Arabian Gulf and the Sea of Oman using the satellite-based observations, such as MODIS (Moderate Resolution Imaging Spectro-radiometer), has shown inferior performance (Chl-a overestimation) than that of deep waters. Studies in the region have shown that this poor performance is due to three reasons: (i) water turbidity (sediments re suspension), and the presence of colored dissolved organic matter (CDOM), (ii) bottom reflectance and (iii) incapability of the existing atmospheric correction models to reduce the effect of the aerosols from the water leaving radiance. Therefore, this work focuses on investigating the sensitivity of the in situ spectral signatures of these coastal waters to the algal (chlorophyll: Chl-a), non-algal (sediments and CDOM) and the bottom reflectance properties, in absence of contributions from the atmosphere. Consequently, the collected in situ spectral signatures will improve our understanding of Arabian Gulf and Sea of Oman water properties. For this purpose, comprehensive field measurements were carried out between 2013 and 2016, over Abu-Dhabi (Arabian Gulf) and Fujairah (Sea of Oman) where unique water quality data were collected. Based on the in situ water spectral analysis, the bottom reflectance (water depth<20m) are found to degrade the performance of the conventional ocean color algorithms more than the sediment-laden waters where these waters increase the Rrsat the blue and red ranges. The increasing presence of CDOM markedly decreases the Rrsin the blue range, which is conflicting with the effect of Chl-a. Given the inadequate performance of the widely used ocean-color algorithms (OC3: ocean color 3, OC2: ocean color 2) in retrieving Chl-a in these very shallow coastal waters, therefore, a new algorithm is proposed here based on a 3-bands ratio approach using [Rrs (656) -1-Rrs (506) -1]*Rrs (661). The selected optimum bands (656nm, 506nm, and 661nm) from this approach can be used to retrieve the Chl-a more accurately in these coastal Case II (turbid) waters which are close to the bands of the current missions such as Sentinel-3 OLCI (Ocean and Land Colour Instrument), MODIS, VIIRS (Visible Infrared Imaging Radiometer Suite) and LandSat 8. However, more uniformly distributed data over the Arabian Gulf is required to have a highly accurate regional model for Chl-a retrieval. PMID- 28915494 TI - Social class shapes the form and function of relationships and selves. AB - Social class shapes relational realities, which in turn situate and structure different selves and their associated psychological tendencies. We first briefly review how higher class contexts tend to foster independent models of self and lower class contexts tend to foster interdependent models of self. We then consider how these independent and interdependent models of self are situated in and adapted to different social class-driven relational realities. We review research demonstrating that in lower social class contexts, social networks tend to be small, dense, homogenous and strongly connected. Ties in these networks provide the bonding capital that is key for survival and that promotes the interdependence between self and other(s). In higher social class contexts, social networks tend to be large, far-reaching, diverse and loosely connected. Ties in these networks provide the bridging capital that is key for achieving personal goals and that promotes an independence of self from other. We conclude that understanding and addressing issues tied to social class and inequality requires understanding the form and function of relationships across class contexts. PMID- 28915495 TI - Impact of chemotherapy on metabolic reprogramming: Characterization of the metabolic profile of breast cancer MDA-MB-231 cells using 1H HR-MAS NMR spectroscopy. AB - Doxorubicin, cisplatin, and tamoxifen are part of many chemotherapeutic regimens. However, studies investigating the effect of chemotherapy on the metabolism of breast cancer cells are still limited. We used 1H high-resolution magic angle spinning (HR-MAS) NMR spectroscopy to study the metabolic profile of human breast cancer MDA-MB-231 cells either untreated (control) or treated with tamoxifen, cisplatin, and doxorubicin. 1H HR-MAS NMR single pulse spectra evidenced signals from all mobile cell compounds, including fatty acids (membranes), water-soluble proteins, and metabolites. NMR spectra showed that phosphocholine (i.e., a biomarker of breast cancer malignant transformation) signals were stronger in control than in treated cells, but significantly decreased upon treatment with tamoxifen/cisplatin. NMR spectra acquired with Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence were interpreted only qualitatively because signal areas were attenuated according to their transverse relaxation times (T2). The CPMG method was used to identify soluble metabolites such as organic acids, amino acids, choline and derivatives, taurine, guanidine acetate, tyrosine, and phenylalanine. The fatty acid variations observed by single pulse as well as the lactate, acetate, glycine, and phosphocholine variations observed through CPMG 1H HR-MAS NMR have potential to characterize both responder and non-responder tumors in a molecular level. Additionally, we emphasized that comparable tumors (i.e., with the same origin, in this case breast cancer) may respond totally differently to chemotherapy. Our observations reinforce the theory that alterations in cellular metabolism may contribute to the development of a malignant phenotype and cell resistance. PMID- 28915496 TI - Solid-phase microextraction coupled to gas chromatography-mass spectrometry followed by multivariate data analysis for the identification of volatile organic compounds as possible biomarkers in lung cancer tissues. AB - Solid-phase microextraction and gas chromatography-mass spectrometry followed by multivariate data analysis were used to analyze lung tissues from both healthy and carcinogenic patients. A total of 78 volatile compounds belonging to different chemical classes were identified, seven of which were able to discriminate between the two groups. Discriminant analysis allowed to correctly classify 98.3% of the cases. By using the leave-one-method, 100% of the cross validated samples belonging to the "tumor" group was correctly classified, whereas 2 cross-validated healthy samples out of 48 were erroneously allocated in the "tumor" group. Achieved results suggest the need of further investigation to assess the role of the seven identified compounds as lung cancer biomarkers in breath analysis, thus allowing the development of low-cost diagnostic devices. PMID- 28915497 TI - PEGylated polydopamine-coated magnetic nanoparticles for combined targeted chemotherapy and photothermal ablation of tumour cells. AB - The integration of multifunctional therapeutic capabilities into a single nanosystem has attracted much attention for use as an efficient cancer therapy. However, developing biocompatible therapeutic nano-agents with desirable safety, efficiency, targeting, and synergistic effects remains challenging. Herein, we designed a class of multifunctional PEGylated magnetic nanoparticles (NPs) with a core-shell structure and polydopamine (PDA) coating, which were loaded with the anticancer drug doxorubicin (DOX) for simultaneous targeted chemotherapy and photothermal ablation of tumour cells. This nanosystem showed strong near infrared absorption due to the polydopamine layer and was capable of magnetic field-guided drug delivery due to the superparamagnetism of the carrier. The resultant product exhibited excellent stability and biocompatibility in vitro due to the PEGylation of dopamine. Notably, the combination of chemotherapy and photothermal therapy had an evident synergistic effect on the ablation of tumour cells. This multifunctional nanoplatform has promising potential as an efficient therapeutic agent for multimodal cancer treatment. PMID- 28915498 TI - Tantalum-coated pedicle screws enhance implant integration. AB - Because titanium alloy (Ti) has the natural advantage of a low elastic modulus, it has become the most commonly used material for the manufacturing of pedicle screws. However, its poor shear strength and osteogenic ability are undesirable properties. The superior osteoinductivity demonstrated by tantalum (Ta) in oral and maxillofacial surgery and joint surgery leads us to assume that the tantalum coated pedicle screws may have better osteogenic properties and bone anchoring strength. To verify this hypothesis, MC3T3-E1 cells and human mesenchymal stem cells (hBMSCs) were seeded on the surface of Ta and Ti disks to compare the effects of two different metals on cell adhesion, proliferation, and differentiation. At the same time, we observed the inhibitory effect of Ta on osteoclasts. As an in vivo study, conventional Ti pedicle screws and Ta-coated screws were implanted in bilateral pedicles of Bama pigs. The results showed that compared to titanium, tantalum promoted greater cell adhesion and proliferation and improved the level of hBMSC mineralization, and Ta-coated screws exerted an inhibitory effect on osteoclasts. More importantly, we found that the effect of tantalum on osteogenic differentiation was mediated through the Wnt/beta-catenin and TGF-beta/smad signaling pathways. Ta-coated screws significantly promoted trabecular bone growth compared with Ti as evidenced by micro-CT, histology and biomechanical examination. Our study clearly indicated that tantalum was a superior promoter of osteogenesis and proved that tantalum coating is an effective improvement for titanium alloy implants. PMID- 28915499 TI - Linkage, charge state and layer of L-Cysteine on copper surfaces. AB - The control of linkage and charge state between biomolecules and metals represents a key issue for the architect of bioactive systems. In this paper, the linkage, charge state and layer of L-Cysteine (L-Cys) self-assembled films were handled on copper surfaces at pH=6.86. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were performed to measure the film quality and the details of self-assembled progress. X-ray photoelectron spectroscopy (XPS) and quantum chemical calculations of density functional theory (DFT) were used to characterize the linkage, charge state and layer of the L-Cys molecules on copper surfaces. The results indicate that, from 0s to 24h, the self assembled process can be classified as three steps, fast adsorption at the beginning, and then rearrangement to form a monolayer, and then the formation of double layer. And L-Cys molecules link to the copper surface through CuS bond, not CuN bond. The thickness of monolayer is 10.5A. Then the L-Cys molecules of second layer recline on the first layer. Finally, by the interaction of amine group and carboxylic acid group between the two layers, the second self-assembled film stands uprightly, and the -S- group of the second layer point outward. The thickness of the double layer is 19.7A. All the Cu/L-Cys films have negative charges because the pH (6.86) of the self-assembled solution is more than the isoelectric point of the L-Cys (5.05). PMID- 28915500 TI - Motives for simultaneous alcohol and marijuana use among young adults. AB - The majority of young adults who use alcohol and marijuana sometimes use the two substances simultaneously. Understanding why young adults engage in simultaneous alcohol and marijuana (SAM) use may inform interventions and help offset negative consequences. To date, research has not yet examined motives for SAM use. The current study tested a 26-item measure of motives for SAM use in a community sample of young adults to identify the factor structure and to evaluate associations of subscales of SAM motives with alcohol and marijuana motives and substance use. Young adults from the Seattle metropolitan area (N=286; 58% female, 67% White/Caucasian) were asked about their motives for using alcohol, marijuana, and SAM as well as their use of alcohol and marijuana and related consequences in the past month. Exploratory factor analysis with promax rotation identified four factors to characterize motives for SAM use: (1) conformity (8 items, alpha=0.87, e.g., "to fit in with a group I like," "pressure from others"), (2) positive effects (6 items, alpha=0.88, e.g., "cross-faded effects are better," "to get a better high") (3) calm/coping (3 items, alpha=0.77, e.g., "to calm me down," "to cope with anxiety"), and (4) social (5 items, alpha=0.78, e.g., "because it is customary on special occasions," "as a way to celebrate"). Results revealed that alcohol, marijuana, and SAM motives were moderately correlated. Even after controlling for alcohol or marijuana motives, SAM motives were associated with SAM use and marijuana use/consequences (but not alcohol use/consequences). PMID- 28915501 TI - Is there an observational effect? An exploratory study into speed cameras and self-reported offending behaviour. AB - Fixed and mobile speed cameras are an important element of enforcement initiatives designed to create a strong deterrent effect and improve road safety. Despite the widespread use of the technology and the need to create a strong deterrent effect, research has yet to determine if there is a relationship between levels of exposure to the devices and subsequent self-reported deterrent effects. As a result, licensed motorists (N=536; 51% female) in Queensland (Australia) were recruited to complete a questionnaire that measured exposure to speed cameras and associated offending behaviours. Data were analyzed utilising descriptive, bivariate and multivariate statistics. The key findings that emerged were: the sample reported a higher level of exposure to fixed cameras (even though there are more operational mobile cameras), younger males were most likely to speed and be observant of speed cameras and that perceived certainty of apprehension was the largest reported deterrent force. However, a positive (rather than negative) relationship was found between perceived camera exposure levels and speeding behaviours, which indicates a range of additional factors (both legal and non-legal factors as well as driving exposure levels) influence speed limit non-compliance. Furthermore, multivariate analysis revealed that higher levels of perceptual certainty were associated with general speed compliance and perceptions of the severity and swiftness of sanctions, rather than levels of self-reported camera exposure. This paper is the first to reveal that while motorists prone to speed may be more cognisant of speed camera operations, this in itself does not ensure appropriate behaviour modification. PMID- 28915502 TI - To stop or not to stop: Contrasting compliant and non-compliant driver behaviour at rural rail level crossings. AB - Many rail level crossings (RLXs) have only passive protection, such as static signs instructing road users to stop, yield, or look for trains. Stop signs have been suggested as a low-cost option to improve safety at passive RLXs, as requiring drivers to stop should encourage safe behaviour. However, field observations have noted high rates of non-compliance at stop-controlled RLXs. To explore this further, we conducted an on-road study to identify factors that influence compliance at stop-controlled RLXs. Twenty-two drivers drove a 30.5km route in rural Australia, encompassing three stop-controlled RLXs. In over half of all cases (59%) drivers stopped completely at the RLX; on 27% of crossings drivers executed a rolling stop, and on 14% of crossings drivers violated the stop controls. Rolling stops were defined as a continuous deceleration to <10km/h, but remaining above 0km/h, before accelerating to >10km/h. Behavioural patterns, including visual checks and decision-making, were similar when comparing drivers who made complete versus rolling stops. Non-compliant drivers did not differ from compliant drivers in approach speeds, but spent less time visually checking for trains. Post-drive interviews revealed some drivers wilfully disregarded the stop sign, whereas others did not notice the stop sign. Those who intentionally violated noted trains were infrequent and suggested sight distance was good enough (even though all crossings had been formally assessed as having inadequate sight distance). Overall the results suggest most drivers exhibit safe behaviour at passive RLXs, but a notable minority disregard or fail to notice signs. Potential avenues for redesigning passive RLXs to improve safety are discussed. PMID- 28915503 TI - Availability and consistency of health and non-health data for road traffic fatality: Analysis of data from 195 countries, 1985-2013. AB - High-quality data are critical for validly monitoring progress toward global initiatives related to road traffic crash prevention. We assessed the availability and consistency of road traffic mortality data from health and non health departments in national governments, plus changes in data consistency over time from 1985 to 2013. Using freely accessible data, we systematically assessed availability and consistency of health and non-health data from 1985 to 2013 in 195 countries. Data availability was reflected by the presence of data on motor vehicle mortality rates in that country at any points between 1985 and 2013. The ratio of 'health data divided by non-health data' was calculated to measure the consistency of the two types of data sources. We found that 77 of the 195 countries in the world (39%) had both health and non-health data sources available from 1985 to 2013. None of the 34 low-income countries had both kinds of data sources simultaneously available, while 41 of 55 high-income countries had both kinds of data sources. Of the 71 countries having both kinds of data for five years or more, 33 countries demonstrated high consistency between data sources, 25 countries showed moderate data consistency, and 13 countries displayed low consistency. Jamaica, Mexico, and China had the largest data inconsistencies. 26 of the 71 countries witnessed improved data consistency between 1985 and 2013, but nine experienced decreasing data consistency, in a few cases to a large degree. Efforts are needed to identify reasons leading to data quality changes, and to develop approaches to improve data quality in those nations where it is inadequate. PMID- 28915504 TI - In situ optical properties of foliar flavonoids: Implication for non-destructive estimation of flavonoid content. AB - Flavonoids are a ubiquitous multifunctional group of phenolics of paramount importance for the terrestrial plants involved in protection from biotic and abiotic stresses, color and chemical signaling and other functions. Deciphering of in situ absorption of foliar Flv is important but was thought to be impossible due to a strong overlap with other pigments, complex in situ chemistry of Flv and sophisticated leaf optics. We deduced in situ absorbance of foliar Flv and introduced a concept of specific absorbance spectrum indicative of each pigment group contribution to light absorption and provided a rationale for the choice of spectral bands for non-destructive assessment of Flv in leaves with variable content of other pigments including anthocyanins. Only a narrow band 400-430nm was suitable for Flv assessment, however the effect of other pigments remained substantial, so subtraction of their contribution was necessary. The devised leaf absorbance-based algorithm allowed estimating Flv with error below 21%. Absorption by Flv in plant tissues might extend into the blue and can be commensurate to that of chlorophylls and carotenoids. The potential capacity of Flv to shield the cell in situ from the visible light might be essential for assessments of high light stress tolerance of plants. PMID- 28915505 TI - Hypertension risk and clinical care in patients with bipolar disorder or schizophrenia; a systematic review and meta-analysis. AB - BACKGROUND: A higher cardiovascular morbidity and mortality has been observed in patients with bipolar disorder (BPD) or schizophrenia, partly due to an increased risk of hypertension (HTN), or a less effective care of it. This systematic review and meta-analysis, presents a critical appraisal and summary of the studies addressing the risk of HTN, or the differences in its care, for those with schizophrenia or BPD. METHODS: Prospective studies were searched in PubMed, Embase, PsycINFO, Scopus, and the Web of Science, from database inception to June 2017. A meta-analysis was undertaken to obtain pooled estimates of the risk of HTN. RESULTS: Five studies reporting the risk of HTN, and five studies presenting differences in its clinical care, were identified. An increased risk of HTN was observed for BPD patients, with an overall Incidence Rate Ratio 1.27(1.15-1.40). The pooled Incidence Rate Ratio of HTN for those with schizophrenia was 0.94 (0.75 - 1.14). A poorer care of HTN (lower rates of screening, prescription, and adherence) was reported in four studies of schizophrenia, and two of BPD patients, compared to people without these conditions. LIMITATIONS: reduced number of studies on risk and care of HTN on patients with BPD or schizophrenia. CONCLUSIONS: Limited evidence suggests that patients with BPD have a higher risk of HTN. Patients with schizophrenia and BPD receive poor care of HTN. Understanding the risk of HTN, and the differences in its care, is essential for clinicians to reduce the cardiovascular morbidity and overall mortality of these patients. PMID- 28915506 TI - Maternal diethylhexyl phthalate exposure affects adiposity and insulin tolerance in offspring in a PCNA-dependent manner. AB - The ubiquitous plasticizer, diethylhexyl phthalate (DEHP), is a known endocrine disruptor. However, DEHP exposure effects are not well understood. Changes in industrial and agricultural practices have resulted in increased prevalence of DEHP exposure and has coincided with the heightened occurrence of metabolic syndrome and obesity. DEHP and its metabolites are detected in the umbilical cord blood of newborns; however, the prenatal and perinatal effects of DEHP exposure have not been intensively studied. Previously, we discovered that phosphorylation (p) of proliferating cell nuclear antigen (PCNA) at tyrosine 114 (Y114) is required for adipogenesis and diet-induced obesity in mice. Here, we show the unique ability of DEHP to induce p-Y114 in PCNA in vitro. We also show that while DEHP promotes adipogenesis of wild type (WT) murine embryonic fibroblasts, mutation of Y114 to phenylalanine (Y114F) in PCNA blocked adipocyte differentiation. Given the induction of p-Y114 in PCNA by DEHP and the relationship to obesity, WT and Y114F PCNA mice were exposed to DEHP during gestation or lactation, followed by high fat diet feeding. Paradoxically, in utero exposure of Y114F PCNA females to DEHP led to a significant increase in body mass and was associated with augmented expression of PPARgamma, a critical regulator of obesity, compared to WT controls. In utero exposure of WT mice to DEHP led to insulin sensitivity while Y114F mutation ablated this phenotype, indicating that PCNA is an important regulator of early DEHP exposure and ensuing metabolic phenotypes. PMID- 28915507 TI - Ambient fine particulate matters induce cell death and inflammatory response by influencing mitochondria function in human corneal epithelial cells. AB - Ambient fine particulate matter (AFP) is a main risk factor for the cornea as ultraviolet light. However, the mechanism of corneal damage following exposure to AFP has been poorly understood. In this study, we first confirmed that AFP can penetrate the cornea of mice, considering that two-dimensional cell culture systems are limited in reflecting the situation in vivo. Then, we investigated the toxic mechanism using human corneal epithelial (HCET) cells. At 24h after exposure, AFP located within the autophagosome-like vacuoles, and cell proliferation was clearly inhibited in all the tested concentration. Production of ROS and NO and secretion of pro-inflammatory cytokines were elevated in a dose dependent manner. Additionally, conversion of LC3B from I-type to II-type and activation of caspase cascade which show autophagic- and apoptotic cell death, respectively, were observed in cells exposed to AFP. Furthermore, AFP decreased mitochondrial volume, inhibited ATP production, and altered the expression of metabolism-related genes. Taken together, we suggest that AFP induces cell death and inflammatory response by influencing mitochondrial function in HCET cells. In addition, we recommend that stringent air quality regulations are needed for eye health. PMID- 28915508 TI - Preoperative Intraaortic Balloon Pump Improves Early Outcomes Following High-Risk Coronary Artery Bypass Graft Surgery: A Meta-Analysis of Randomized Trials and Prospective Study Design. AB - BACKGROUND: Despite widespread use, evidence to support preemptive intraaortic balloon pump (IABP) insertion for patients undergoing high-risk coronary artery bypass graft (CABG) surgery remains sparse, and in need of a well-defined clinical trial. To inform the design of a prospective trial, we sought to review outcomes in randomized controlled trials (RCTs) of anticipatory IABP use vs control in patients undergoing high-risk CABG through meta-analysis. The primary endpoint was all-cause mortality within 30 days of surgery. The secondary endpoint was major adverse cardiac and cerebrovascular event (MACCE), a composite of death, myocardial infarction, stroke, or repeat revascularization. METHODS: Using Ovid MEDLINE, we systematically reviewed all RCTs comparing preoperative IABP with control in patients undergoing high-risk CABG, defined as: left ventricular ejection fraction (LVEF) <=40%, left main stenosis >=70%, unstable angina, recent myocardial infarction, or prior myocardial revascularization undergoing elective or emergent CABG on or off pump. RESULTS: Of 950 articles assessed for eligibility, 10 RCTs of 1261 subjects (mean age, 65.0 years; 21.8% women; mean LVEF, 35%) were included. Mortality was significantly lower in patients receiving IABP compared with control (relative risk [RR], 0.48; 95% confidence interval [CI], 0.30-0.76; P<.01). The risk of MACCE was also lower with IABP (RR, 0.67; 95% CI, 0.54-0.84; P<.001). No significant differences in major bleeding events (RR, 1.27; 95% CI, 0.44-3.72) or vascular complications (RR, 1.13; 95% CI, 0.42-3.06) were detected. CONCLUSIONS: A strategy of routine prophylactic IABP use may reduce short-term mortality and MACCE in high-risk CABG patients. A definitive, adequately powered, prospective, randomized trial is warranted to confirm these results. PMID- 28915509 TI - Device Motion Indication: A Novel Image-Based Tool to Measure Relative Device Motion During Coronary Intervention. AB - BACKGROUND: Movement of the stent delivery system in the coronary bed as a result of the cardiac cycle is a well-known clinical observation that usually is either underestimated or ignored. This effect may potentially jeopardize precise stent deployment. We used a novel technology to objectively measure the relative intracoronary device motion in the different coronary segments throughout the cardiac cycle. METHODS: A total of 193 patients undergoing coronary angiography were enrolled and their studies were analyzed for device movement using the SyncVision System (Philips Volcano). The SyncVision System is an add-on image processing system with unique enhancement and stabilization capabilities. A new feature, the device-motion indication, can precisely display the predeployment device movement measurement (DMM). The device movements within the three segments of each coronary artery were recorded. RESULTS: We identified 218 branch point sites. Median axial displacement was 2.97 mm at the right coronary artery (RCA), 2.22 mm at the left circumflex, and 1.84 mm at the left anterior descending segments. The most movable segments were mid and distal RCA (P<.05). Both heart rate and cardiac contractility significantly affected DMM. CONCLUSIONS: The study demonstrates an innovative feature of the SyncVision System as a tool to precisely measure relative device displacement. We claim that the relative device movement is an important quality metric to consider for achieving an effective stent implantation process. PMID- 28915510 TI - Drug-Eluting vs Bare-Metal Stents in Patients With Chronic Kidney Disease and Coronary Artery Disease: Insights From a Systematic Review and Meta-Analysis. AB - BACKGROUND: Most drug-eluting stent (DES) trials have excluded patients with chronic kidney disease (CKD). The efficacy of DES implantation in patients with CKD is therefore not known. OBJECTIVES: To evaluate the outcomes with DES vs bare metal stent (BMS) implantation in patients with CKD. METHODS AND RESULTS: MEDLINE, EMBASE, and CENTRAL were searched for studies including at least 100 patients with CKD (estimated glomerular filtration rate <=60 mL/min/1.73 m2 or on dialysis) treated with DES or BMS and followed for at least 1 month and reporting outcomes of all-cause mortality, cardiovascular (CV) mortality, myocardial infarction (MI), target-vessel revascularization (TVR), and stent thrombosis (ST). Thirty-one studies (5 randomized) with 91,817 participants (49,081 DES and 42,736 BMS) fulfilled the inclusion criteria. DES was associated with lower all cause mortality (relative risk [RR], 0.77; 95% confidence interval [CI], 0.71 0.84), CV mortality (RR, 0.51; 95% CI, 0.38-0.70), MI (RR, 0.90; 95% CI, 0.86 0.95), TVR (RR, 0.61; 95% CI, 0.47-0.80), and numerically lower ST (RR, 0.75; 95% CI, 0.55-1.01) when compared with BMS. Analysis by study type (RCTs vs non-RCTs) showed similar results for most outcomes (Pinteraction>.05) except all-cause mortality, where there was no difference between DES vs BMS in RCTs (Pinteraction=.04). The effects were greater with 2nd-generation DES vs BMS (for example, ST: RR, 0.38; 95% CI, 0.20-0.72). CONCLUSIONS: In patients with CKD, the available evidence, largely from observational studies, suggests significantly fewer events with DES vs BMS with even a lower ST rate with 2nd-generation DES. These findings should be tested in large, randomized trials. PMID- 28915511 TI - Children's Comprehension of Object Relative Sentences: It's Extant Language Knowledge That Matters, Not Domain-General Working Memory. AB - Purpose: The aim of this study was to determine whether extant language (lexical) knowledge or domain-general working memory is the better predictor of comprehension of object relative sentences for children with typical development. We hypothesized that extant language knowledge, not domain-general working memory, is the better predictor. Method: Fifty-three children (ages 9-11 years) completed a word-level verbal working-memory task, indexing extant language (lexical) knowledge; an analog nonverbal working-memory task, representing domain general working memory; and a hybrid sentence comprehension task incorporating elements of both agent selection and cross-modal picture-priming paradigms. Images of the agent and patient were displayed at the syntactic gap in the object relative sentences, and the children were asked to select the agent of the sentence. Results: Results of general linear modeling revealed that extant language knowledge accounted for a unique 21.3% of variance in the children's object relative sentence comprehension over and above age (8.3%). Domain-general working memory accounted for a nonsignificant 1.6% of variance. Conclusions: We interpret the results to suggest that extant language knowledge and not domain general working memory is a critically important contributor to children's object relative sentence comprehension. Results support a connectionist view of the association between working memory and object relative sentence comprehension. Supplemental Materials: https://doi.org/10.23641/asha.5404573. PMID- 28915512 TI - A Systematic Review and Meta-Analysis of Predictors of Expressive-Language Outcomes Among Late Talkers. AB - Purpose: The purpose of this study was to explore the literature on predictors of outcomes among late talkers using systematic review and meta-analysis methods. We sought to answer the question: What factors predict preschool-age expressive language outcomes among late-talking toddlers? Method: We entered carefully selected search terms into the following electronic databases: Communication & Mass Media Complete, ERIC, Medline, PsycEXTRA, Psychological and Behavioral Sciences, and PsycINFO. We conducted a separate, random-effects model meta analysis for each individual predictor that was used in a minimum of 5 studies. We also tested potential moderators of the relationship between predictors and outcomes using metaregression and subgroup analysis. Last, we conducted publication-bias and sensitivity analyses. Results: We identified 20 samples, comprising 2,134 children, in a systematic review. According to the results of the meta-analyses, significant predictors of expressive-language outcomes included toddlerhood expressive-vocabulary size, receptive language, and socioeconomic status. Nonsignificant predictors included phrase speech, gender, and family history. Conclusions: To our knowledge this is the first synthesis of the literature on predictors of outcomes among late talkers using meta-analysis. Our findings clarify the contributions of several constructs to outcomes and highlight the importance of early receptive language to expressive-language development. Supplemental Materials: https://doi.org/10.23641/asha.5313454. PMID- 28915513 TI - The Influence of Executive Functions on Phonemic Processing in Children Who Do and Do Not Stutter. AB - Purpose: The aim of the present study was to investigate dual-task performance in children who stutter (CWS) and those who do not to investigate if the groups differed in the ability to attend and allocate cognitive resources effectively during task performance. Method: Participants were 24 children (12 CWS) in both groups matched for age and sex. For the primary task, participants performed a phoneme monitoring in a picture-written word interference task. For the secondary task, participants made pitch judgments on tones presented at varying (short, long) stimulus onset asynchrony (SOA) from the onset of the picture. Results: The CWS were comparable to the children who do not stutter in performing the monitoring task although the SOA-based performance differences in this task were more variable in the CWS. The CWS were also significantly slower in making tone decisions at the short SOA and showed a trend for making more errors in this task. Conclusions: The findings are interpreted to suggest higher dual-task cost effects in CWS. A potential explanation for this finding requiring further testing and confirmation is that the CWS show reduced efficiency in attending to the tone stimuli while simultaneously prioritizing attention to the phoneme monitoring task. PMID- 28915514 TI - Developmental Stuttering in Children Who Are Hard of Hearing. AB - Purpose: A number of studies with large sample sizes have reported lower prevalence of stuttering in children with significant hearing loss compared to children without hearing loss. This study used a parent questionnaire to investigate the characteristics of stuttering (e.g., incidence, prevalence, and age of onset) in children who are hard of hearing (CHH). Method: Three hundred three parents of CHH who participated in the Outcomes of Children With Hearing Loss study (Moeller & Tomblin, 2015) were sent questionnaires asking about their child's history of stuttering. Results: One hundred ninety-four parents of CHH responded to the survey. Thirty-three CHH were reported to have stuttered at one point in time (an incidence of 17.01%), and 10 children were still stuttering at the time of survey submission (a prevalence of 5.15%). Compared to estimates in the general population, this sample displayed a significantly higher incidence and prevalence. The age of onset, recovery rate, and other characteristics were similar to hearing children. Conclusions: Based on this sample, mild to moderately severe hearing loss does not appear to be a protective factor for stuttering in the preschool years. In fact, the incidence and prevalence of stuttering may be higher in this population compared to the general population. Despite the significant speech and language needs that children with mild to moderately severe hearing loss may have, speech-language pathologists should appropriately prioritize stuttering treatment as they would in the hearing population. Supplemental Material: https://doi.org/10.23641/asha.5397154. PMID- 28915516 TI - MOG Antibodies in Pediatric Neurology. PMID- 28915515 TI - The Association of Decision-to-Incision Time for Cesarean Delivery with Maternal and Neonatal Outcomes. AB - OBJECTIVE: The objective of this study was to estimate whether the decision-to incision (DTI) time for cesarean delivery (CD) is associated with differences in maternal and neonatal outcomes. METHODS: This analysis is of data from women at 25 U.S. medical centers with a term, singleton, cephalic nonanomalous gestation and no prior CD, who underwent an intrapartum CD. Perinatal and maternal outcomes associated with DTI intervals of <= 15, 16 to 30, and > 30 minutes were compared. RESULTS: Among 3,482 eligible women, median DTI times were 46 and 27 minutes for arrest and fetal indications for CD, respectively (p < 0.01). Women with a fetal indication whose DTI interval was > 30 minutes had similar odds to the referent group (DTI of 16-30 minutes) for the adverse neonatal and maternal composites (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.40-1.71 and OR: 0.89, 95% CI: 0.63-1.27). For arrest disorders, the odds of the adverse neonatal composite were lower among women with a DTI of > 30 minutes (OR: 0.25, 95% CI: 0.08-0.77), and the adverse maternal composite was no different (OR: 1.15, 95% CI: 0.81 1.63). CONCLUSION: In this analysis, DTI times longer than 30 minutes were not associated with worse maternal or neonatal outcomes. PMID- 28915517 TI - Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2 Related Epilepsy. AB - Recently, heterozygous de novo mutations in SCL1A2 have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in SCL1A2 (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism. PMID- 28915519 TI - [E-Cigarettes on Everyone's Lips - Current Representative Data on Use Among Adolescents and Adults]. AB - Background International data suggest an increase in e-cigarette use. However, there are still significant deficits in the reporting of its current prevalence. The present study reports representative data on e-cigarette use that make it possible to differentiate users both by the nicotine content of the e-cigarette liquids being used and by their smoking status. Methods and material The underlying data are taken from the National Cancer Aid Monitoring (NCAM). In its first wave, 3000 persons aged between 14 and 45 were interviewed by telephone. Point estimates, confidence intervals and determinants of use will be presented. Results Overall, 20 % of respondents had used an e-cigarette before, of which 80 % used liquids containing nicotine. Men, younger persons, persons with a migrant background and persons with a lower education level were more likely to have used an e-cigarette before than their respective reference groups. Half of all ever users of e-cigarettes also smoked tobacco cigarettes, while roughly one third had never used tobacco products before. Conclusions For the first time, a representative study was conducted combining questions on the use of e-cigarettes with questions on smoking tobacco cigarettes and the nicotine content of the liquids being used. Target groups for future prevention measures are adolescents, as they had the highest prevalence of e-cigarette use, as well as non-smokers, since one third of e-cigarette users had never used a tobacco product before. Both groups also seem to be relevant target groups for which the introduction to e-cigarettes should be prevented. PMID- 28915518 TI - [Primary Care in Germany - Equal Access for Everyone?] AB - BACKGROUND: Access to primary care plays an important role in medical care provision in Germany. Therefore, current health care planning aims at providing equal access for every patient in Germany no matter where they live. OBJECTIVE: This study examined accessibility of primary care and compared the result with current primary care planning data. MATERIALS AND METHODS: Spatial accessibility to primary care was measured by the integrated Floating Catchment Area method ("accessibility index") using a geographical information system at the level of square kilometers cells (hectare grid cells for major urban areas). RESULTS: The analysis of 649 million generated records showed considerable geographical variations of accessibility: 4.7 % of the total population lived in areas with significantly lower primary care accessibility (z-score = -3.4), whereas 48.0 % of the population lived in areas with significantly higher primary care accessibility (z-score = 9.7). The average accessibility index was 0.14 (SD = 0.15) and increased the more urban (r = 0.64; p < 0.001) and the less deprived (r = -0.37; p < 0.001) the area was. Within health care planning regions, the accessibility index varied by an average of Delta = 0.23 (SD = 0.19) and was not correlated with the degree of care provision (r = -0.04; p = 0.28). CONCLUSION: With regard to primary care, there are urban-rural disparities and regional social inequalities in Germany. Therefore, health care planning should take greater account of spatial accessibility in the future. PMID- 28915520 TI - [Effect of the Disease Management Program on HbA1c Value in Type 2 Diabetes Mellitus Patients: A Retrospective Comparison between Disease Management Programs and Standard Care]. AB - Background This retrospective study aims to measure the effect of the disease management program (DMP) for type 2 diabetes mellitus (T2DM) patients on HbA1c value within Germany. Methods This study is based on patient data from the Disease Analyzer panel (IMS Health). An adequate control group was created using 2:1 propensity score matching. After matching, the analysis included 14 759 patients. Of these, 5875 participated in a DMP while 8884 received standard care. The DMP effect was estimated on the basis of the matched data, using an unpaired t-test. In addition, subgroups were considered from the perspective of personalized medicine. Results The reduction in HbA1c values in the DMP group amounted to an average of 1.0 percentage point (baseline HbA1c = 8.1 vs. final HbA1c = 7.1), while the SC group was able to achieve an average reduction in HbA1c values of 0.9 percentage point (baseline HbA1c = 8.1 vs. final HbA1c = 7.2). The DMP group thus achieved an average reduction in HbA1c values that exceeded that of the SC group by only 0.1 percentage point (95 % CI: 0.04 - 0.16). Descriptively, it also became apparent that patients from the DMP group received a greater average number of annual prescriptions and had more HbA1c measurements. The subgroup analysis identified groups of patients who benefit more from DMPs than others. Thus, young patients or patients who are being treated by diabetologists are able to benefit most from a DMP. Furthermore, the baseline HbA1c value has an influence on the DMP effect. Conclusion T2DM patients in the DMP exhibit a significantly higher reduction in HbA1c value. However, it is questionable whether this effect is clinically relevant. Certain groups of patients benefit more from DMPs than others. Nevertheless, further studies are needed in order to better understand the impact of the DMP on HbA1c value and the reasons for the subgroup effects. Such studies should be carried out using a randomized controlled design. PMID- 28915521 TI - Comparative Analysis of Gene Expression between Cartilage and Menisci in Early Phase Osteoarthritis of the Knee-An Animal Model Study. AB - Cartilage degeneration is believed to be the primary event in the development of osteoarthritis (OA). On the other hand, meniscal degeneration is observed with high prevalence, and some researchers have pointed out that pathological changes in menisci precede that of cartilage. The purpose of the present study is to investigate comprehensive gene expression pattern of cartilage and menisci in the initial phase of surgically induced OA and to compare them. Secondary OA was surgically induced in 10-week-old male Wistar rats by anterior cruciate ligament transection (ACLT). Articular cartilage and menisci were separately dissected from six ACLT- and six sham-operated rats. Each specimen was analyzed by microarray, histological, and immunohistochemical analysis 3 weeks after surgery. Of the 36,685 transcripts detectable by microarray, the number of upregulated transcripts in ACLT menisci was >2.5-fold compared with that in ACLT menisci in any given threshold. Cluster analysis using the Database for Annotation Visualization and Integrated Discovery (DAVID) showed genes related to OA, such as response to stimulus, angiogenesis, and apoptosis, which were predominantly found in menisci in ACLT rats. Representative proteases including Adamts2, 4, Mmp2, 12, 13, 14, 16, extracellular matrix genes including versican (Vcan), lumican (Lum), syndecan1 (Sdc1), and Prostaglandin endoperoxide synthase2 (Ptgs2) were up-regulated in menisci, but were not up-regulated in cartilage. Our results indicated that the molecular changes that occurred in menisci preceded those occurred in cartilage in the very early phase of surgically induced OA models. PMID- 28915522 TI - Comparison of Platelet-Rich Plasma, Stromal Vascular Fraction (SVF), or SVF with an Injectable PLGA Nanofiber Scaffold for the Treatment of Osteochondral Injury in Dogs. AB - Stromal vascular fraction (SVF) contains a small number of mesenchymal stem cells and has been used as a treatment for osteoarthritis and cartilage injury. Due to limited evidence of successful cartilage regeneration with injected stem cell therapies, there is interest in combining cellular therapies with injectable scaffolding materials to increase intra-articular residence times of stem cells and improve tissue regeneration. However, the safety of intra-articular injection of SVF combined with injectable scaffolds is unestablished. Also, it is unclear if SVF therapy is superior to more easily prepared biologics, such as platelet rich plasma (PRP). The purpose of this study was to assess the safety of SVF when combined with an injectable poly(L-lactide-co-glycolide) nanofiber scaffold and to provide a comparison of SVF therapy to PRP. A total of 12 Beagles had osteochondral defects created in both medial femoral condyles and 4 dogs each were allocated to treatment groups of SVF (n = 4), SVF plus PLGA scaffolding (n = 4), or leukoreduced PRP (n = 4). One knee in each dog received treatment, and the contralateral knee was sham treated with saline. Dogs were assessed over a 6 month period, and outcome measures included functional, radiographic, biochemical, and histological assessments. PRP treatment resulted in improvements in lameness scores and objective kinetic assessments of function. There were no statistically significant improvements in function, cartilage biochemical composition, or histology for SVF-treated knees. The combination of SVF and the injectable PLGA scaffold had worse outcomes than other groups including sham treatment based upon functional, biochemical, and histological assessments, raising concerns over the safety of this scaffold for intra-articular injection. PMID- 28915523 TI - [Biologic Reconstruction of Full Sized Cartilage Defects of the Hip: A Guideline from the DGOU Group "Clinical Tissue Regeneration" and the Hip Committee of the AGA]. AB - Background Symptomatic pre-arthritic deformities such as femoroacetabular impingement (FAI) or hip dysplasia often lead to localised cartilage defects and subsequently to osteoarthritis. The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) and the hip committee of the AGA (German speaking Society for Arthroscopy and Joint Surgery) provides an overview of current knowledge of the diagnosis and surgical treatment of cartilage defects, in order to infer appropriate therapy recommendations for the hip. Methods Review of FAI and resultant cartilage damage in the hip as reported in published study findings in the literature and discussion of the advantages and disadvantages of different surgical procedures to preserve the joint. Results Most published studies on the surgical treatment of cartilage damage in the hip report defects caused by cam-type FAI at the acetabulum. Development of these defects can be prevented by timely elimination of the relevant deformities. At present, current full-thickness cartilage defects are mostly treated with bone marrow-stimulating techniques such as microfracture (MFx), with or without a biomaterial, and matrix-assisted autologous chondrocyte transplantation (MACT). Osteochondral autologous transplantation (OAT) is not the treatment of choice for isolated full-thickness chondral defects at the hip, because of the unfavourable risk-benefit profile. Due to the relatively short history of cartilage repair surgery on the hip, the studies available on these procedures have low levels of evidence. However, it is already becoming obvious that the experience gained with the same procedures on the knee can be applied to the hip as well. For example, limited healing and regeneration of chondral defects after MFx can also be observed at the hip joint. Conclusions The cartilage surface of the acetabulum, where FAI-related chondral lesions appear, is considerably smaller than the weight-bearing cartilage surface of the knee joint. However, as in the knee joint, MACT is the therapy of choice for full thickness cartilage defects of more than 1.5 - 2 cm2. Minimally invasive types of MACT (e.g. injectable chondrocyte implants) should be preferred in the hip joint. In cases where a single-stage procedure is indicated or there are other compelling reasons for not performing a MACT, a bone marrow-stimulating technique in combination with a biomaterial covering is preferable to standard MFx. For treatment of lesions smaller than 1.5 - 2 cm2 the indication for a single-stage procedure is wider. As with defects in the knee, it is not possible to determine a definite upper age limit for joint-preserving surgery or MACT in the hip, as the chronological age of patients does not necessarily correlate with their biological age or the condition of their joints. Advanced osteoarthritis of the hip is a contraindication for any kind of hip-preserving surgery. Long-term observations and prospective randomised studies like those carried out for other joints are necessary. PMID- 28915525 TI - Infiltrating Mammary Duct Adenocarcinoma in the Right Labia Majora Along the Milk Line. AB - Introduction Breast tissue rarely arises from the vulva and malignancy might develop in it. Case Thirty-eight-year-old woman presented with a suspicious ulcer in the right labia majora discovered accidently and removed by wide local excision. Histopathology revealed infiltrating mammary duct adenocarcinoma along the milk line. Immunohistochemistry was positive for estrogen and progesterone receptors and equivocal overexpression for HER2 protein with a score of 2+. Metastatic work-up was clear. Inguinal lymph nodes were enlarged and lymphadenectomy done which showed positive lymph nodes on the right side and none on the left. She is receiving adjuvant therapy. Conclusion Mammary duct carcinoma along the nipple line is rare but should be considered when dealing with suspicious vulvar lesions. PMID- 28915524 TI - Risk of colorectal cancer after a negative colonoscopy in low-to-moderate risk individuals: impact of a 10-year colonoscopy. AB - Background and study aims National societies recommend colorectal cancer (CRC) screening 10 years after a normal ("negative") colonoscopy in low-risk individuals. We studied the impact of a 10-year repeat colonoscopy on the risk of early incident CRC. Patients and methods We used health administrative data from Ontario, Canada, to conduct a population-based retrospective cohort study in 50 - 74-year-old individuals at low-to-moderate risk of CRC who had a negative colonoscopy between 1996 and 2001. We approximated exposure to repeat colonoscopy using an 8 - 12-year window. We excluded individuals who underwent lower endoscopy or colectomy, developed CRC, or were lost to follow-up between the baseline and repeat colonoscopies. We matched exposed individuals 1:1 to individuals who did not undergo lower endoscopy within 12 years for age, sex, and calendar year of baseline colonoscopy, and followed matched pairs for incident CRC. The primary analysis was multivariable hazards regression, adjusting for competing risks. Results A total of 13 350 matched pairs were observed for a median of 4.5 years (interquartile range 3.2 - 5.9 years). The cumulative probability of CRC following the matching date was 0.70 % (95 % confidence interval [CI] 0.42 % - 1.11 %) in individuals who underwent repeat colonoscopy and 0.77 % (95 %CI 0.48 % - 1.2 %) in individuals who did not undergo repeat colonoscopy. The adjusted hazard ratio for CRC was 0.91 (95 %CI 0.68 - 1.22). Conclusions We did not find an association between a second colonoscopy performed 10 years after a negative colonoscopy and early incident CRC. Our findings support the need for further studies on the utility of 10-year re-screening with colonoscopy in this setting. PMID- 28915526 TI - [EXIT - A Possible Intervention for New- and Earlyborn Babies with Severe Hydrops Fetalis and Hydrothoraces on Both Sides]. AB - The EXIT (ex utero intrapartum treatment) procedure is an established method of respiratory protection, originally used in the delivery of fetuses with congenital obstructive airway diseases (tumors in the throat area, hygromas, so called congenital high airway obstruction syndrome (CHAOS)). Meanwhile, the procedure is also carried out in large perinatal centers for pronounced diaphragmatic hernia or other special indications (EXIT to ECMO, congenital lung airway malformations (CCAM), pulmonary atresia). We present our experience with adapted EXIT procedures in 5 preterm infants with secondary generalized hydrops fetalis and pronounced bilateral hydrothoraces. PMID- 28915527 TI - Palliative Therapies for Congenital Heart Disease with Ductus Dependent Pulmonary Circulation. AB - In neonates, the management of ductus dependent pulmonary circulation is challenging. There have been three palliative therapies for this lesion: the modified Blalock-Taussig shunt, ductal stenting and prostaglandin E infusions, for maintaining the ductal patency before definite operations. Debates remain with regard to the indications and disadvantages of three palliative therapies. The aim of this article is to give a brief review of these three palliative therapies. PMID- 28915528 TI - [Antenatal Steroid Therapy in Threatened Premature Birth - State of the Art]. AB - The aim of this work is to provide an overview of the recommendations in the current literature for the induction of lung maturation therapy. In particular, special attention is focused on specific situations, such as chorioamnionitis, intrauterine growth retardation and preeclampsia, which often lead to premature birth. Additionally, some aspects of antenatal steroid therapy, despite its widespread use, still require clarification. Among them is the repetitive administration of steroid therapy. On the basis of the Cochrane analysis of 2015, advantages and disadvantages for children and pregnant women are explained. Furthermore, the data on the use of antenatal steroid therapy in multiple pregnancies remain insufficient. PMID- 28915529 TI - Centralized Pediatric Surgery in the Nordic Countries: A Role Model for Europe? PMID- 28915530 TI - French Connection between Specialized and Routine Pediatric Surgical Care. PMID- 28915531 TI - Subclinical Hyperthyroidism and the Cardiovascular Disease. AB - Thyroid hormone excess has complex metabolic effects, particularly on the cardiovascular system. Treatment of these conditions is universally suggested by international guidelines. Subclinical hyperthyroidism, defined by reduced or suppressed TSH levels in the presence of normal free thyroxine and free triiodothyronine values, is common in the general population and progressively increases with aging, being as high as 15.4% in subjects more than 75 years old and more frequent in subjects with nodular goiter. Subclinical hyperthyroidism is often asymptomatic and the diagnosis is incidentally made during screening exams. However, this form of thyroid disorder has gained attention in the last years for its association with cardiovascular disease, in particular with atrial fibrillation. Less clear are the effects of subclinical hyperthyroidism on blood pressure, stroke, or heart failure. The decision to treat subclinical hyperthyroidism is made on the clinical judge, particularly in elderly patients and/or in the presence of comorbidities. PMID- 28915532 TI - Formation mechanism of human serum albumin monolayers on positively charged polymer microparticles. AB - Human serum albumin (HSA) adsorption on positively and negatively charged polystyrene microparticles was studied at various pHs and NaCl concentrations. Thorough electrophoretic mobility measurements were carried out that enabled to monitor in situ the progress of protein adsorption. The maximum coverage of irreversibly adsorbed HSA on microparticles was determined by different concentration depletion methods, one of them involving AFM imaging of residual molecules. An anomalous adsorption of HSA on the positive microparticles was observed at pH 3.5 where the maximum coverage attained 1.0mgm-2 for NaCl concentrations of 0.05M despite that the molecules were on average positively charged. For comparison, the maximum coverage of HSA on negatively charged microparticles was equal to 1.3mgm-2 at this pH and NaCl concentration. At pH 7.4 the maximum coverage on positive microparticles was equal to 2.1mgm-2 for 0.05M NaCl concentration. On the other hand, for negative microparticles, negligible adsorption of HSA was observed at pH 7.4 and 9.7. These experimental data were adequately interpreted in terms of the random sequential adsorption approach exploiting the bead model of the HSA molecule. Different orientations of adsorbed molecules, inert alia, the edge-on orientation prevailing for positively charged microparticles at pH 7.4, were confirmed. This was explained in terms of a heterogeneous charge distribution over the HSA molecule prevailing for a wide range of pHs. PMID- 28915533 TI - Long non-coding RNA MALAT1 promotes proliferation and invasion via targeting miR 129-5p in triple-negative breast cancer. AB - BACKGROUND: Long non-coding RNA Metastasis associated lung adenocarcinoma transcript 1(lncRNA MALAT1) play important roles in tumor progression. In the present study, we determined the regulatory function of MALAT1 in triple-negative breast cancer (TNBC). METHODS: A total of 43 cases of TNBC tissues and paired adjacent non-tumor tissues were collected for the research. MALAT1 expression was explored by qRT-PCR. In vitro functional validation experiments were used to determine the effect of MALAT1 on TNBC progression. We further identified the downstream target miRNAs for MALAT1. RESULTS: Relative expression of MALAT1 was increased in TNBC tissues and cell lines. High MALAT1 expression was closely correlated to advance clinical features and poor overall survival in TNBC patients. Function assay showed that MALAT1 silencing significantly decreased cell proliferation, migration, and invasion. Flow cytometry assay revealed that MALAT1 inhibition significantly induced cell cycle arrest in the G0/G1 phase. In addition, we showed that the roles of MALAT1 on TNBC cells progression was mediated by miR-129-5p. CONCLUSION: Our results demonstrated that the "MALAT1-miR 129-5p" axis might play an important role in the progression of TNBC, thereby might provide a potential therapeutic strategy for the treatment of TNBC. PMID- 28915534 TI - Revealing anti-inflammation mechanism of water-extract and oil of forsythiae fructus on carrageenan-Induced edema rats by serum metabolomics. AB - Forsythiae Fructus is an important Chinese medicine which shows a significant effect against inflammation. This study aimed to investigate the preventive anti inflammation mechanism of Forsythiae Fructus by serum metabolomics strategy and compare the difference of the metabolism pathways between Forsythia extract and Forsythia oil in rat. Four groups (control group, model group, Forsythia extract group and Forsythia oil group) were orally administered 10mL/kg 0.5% Tween 80 solution, 10mL/kg 0.5% Tween 80 solution, 5g/kg Forsythia extract and 0.48mL/kg Forsythia oil respectively. 30min after drug administration, rat acute inflammation was induced by subcutaneous injection of carrageenan in the right paw in model group, Forsythia extract group and Forsythia oil group. After being administered Forsythia extract and Forsythia oil, the percentage of rat paw edema was significantly decreased (P<0.05) compared with model group. Metabolomics based on UPLC-Q-TOF-MS/MS was used to analyze the collected serum sample. Multivariate analysis was established for metabolomics analysis. According to Principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) results, four groups were clearly separated. And thirteen alterative biomarkers were identified in the serum, namely PC (19:0/0:0), LysoPC (20:0), LysoPC (20:1), LysoPC (17:0), Sphingosine, Linoleic acid, 3R-hydroxy butanoic acid (3-HB), 2-hydroxyhexadecanoic acid, Lactic acid, L-Threonine, L Leucine, Maleic acid, Adipic acid. The change of biomarkers suggested that Forsythia extract affected Linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, Sphingolipid metabolism and Glycerophospholipid metabolism. Forsythia oil affected Sphingolipid metabolism and Glycerophospholipid metabolism. It indicated that Forsythia extract and Forsythia oil both showed significant preventive anti-inflammatory effect through acting on different metabolism pathways. Moreover, efficacy mechanism of Forsythiae Fructus could recover metabolites disturb in the body through affecting particular drug targets associated with the inflammatory pathway. PMID- 28915535 TI - Isoquercetin ameliorated hypoxia/reoxygenation-induced H9C2 cardiomyocyte apoptosis via a mitochondrial-dependent pathway. AB - Isoquercetin exerts multiple pharmacological effects against various diseases. The present research sought to further investigate the role of isoquercetin in hypoxia/reoxygenation (H/R)-treated cardiomyocytes and its potential mechanism involved. The H/R model in H9C2 cells was established to mimic myocardial I/R injury in vitro. Cell proliferation and apoptosis were tested using MTT assay and Annexin V FITC-PI staining assay, respectively. We found that isoquercetin protected H9C2 cells from H/R-induced injury as the evidences that isoquercetin administration attenuated the effects of H/R treatment on H9C2 cell viability, cell apoptosis and ROS generation after H/R treatment. More importantly, isoquercetin protects mitochondrial function and prevents cytochrome c release in H9C2 cells after I/R injury. In conclusion, these results revealed the potential cardiovascular protective effects of isoquercetin in the treatment of I/R-related myocardial injury. PMID- 28915536 TI - Protective effect of the standardized extract of ginkgo biloba (EGb761) against hypertension with hypercholesterolemia-induced renal injury in rats: Insights in the underlying mechanisms. AB - The potential protective role of the standardized leaf extract of ginkgo biloba (EGb761) on hypertension with hypercholesterolemia-induced renal injury was investigated in rats. Hypertension was induced by L-N(G)-nitroarginine methyl ester (L-NAME) and hypercholesterolemia was induced by feeding rats with a diet containing 1% cholesterol. In these animals repeated treatment with EGb761 produced a progressive reduction in the systolic, diastolic and mean arterial blood pressure (BP). EGb761 increased the progressive reduction in the systolic, diastolic and mean arterial BP induced by repeated administration of losartan with simvastatin. EGb761 corrected the compromised serum lipid profile and enhanced the effect of losartan with simvastatin on lipid profile. EGb761 protected against hypertension with hypercholesterolemia-induced renal injury as assessed by measurement of serum renal function markers and by histopathological examination. EGb761 enhanced the renoprotective effect of losartan with simvastatin in these rats. Concomitantly, hypertension with hypercholesterolemia induced elevation of renal tissue malondialdehyde (MDA) and nitrite levels and reduction of intracellular reduced glutathione (GSH) level were inhibited by repeated treatment with EGb761. In addition, hypertension with hypercholesterolemia-induced increases in tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) levels in renal tissues were inhibited by treatment with EGb761. Also, EGb761 inhibited hypertension with hypercholesterolemia-induced decrease in endothelial nitric oxide synthase (eNOS) protein expression and increase in the protein expressions of inducible NO synthase (iNOS), TNF-alpha, IL-6 and IL-1beta in the kidney tissues. Losartan with simvastatin produced similar effects on renal tissues oxidative stress, nitrite and inflammatory markers levels and on protein expressions of eNOS, iNOS, TNF-alpha, IL-6 and IL-1beta. EGb761 enhanced losartan with simvastatin effects. These results indicate that EGb761 has the ability to protect against hypertension with hypercholesterolemia-induced renal injury. The ability of EGb761 to provide this renoprotective effect may positively correlate, besides its antihypertensive and antihypercholesterolemic effects, to its ability to suppress renal oxidative stress, nitrosative stress and inflammation. PMID- 28915537 TI - MTA1 expression in human cancers - Clinical and pharmacological significance. AB - Remarkably, majority of the cancer deaths are due to metastasis, not because of primary tumors. Metastasis is one of the important hallmarks of cancer. During metastasis invasion of primary tumor cells from the site of origin to a new organ occurs. Metastasis associated proteins (MTAs) are a small family of transcriptional coregulators that are closely associated with tumor metastasis. These proteins are integral components of nuclear remodeling and deacetylation complex (NuRD). By virtue of being integral components of NuRD, these proteins regulate the gene expression by altering the epigenetic changes such as acetylation and methylation on the target gene chromatin. Among the MTA proteins, MTA1 expression is very closely correlated with the aggressiveness of several cancers that includes breast, liver, colon, pancreas, prostate, blood, esophageal, gastro-intestinal etc. Considering its close association with aggressiveness in human cancers, MTA1 may be considered as a potential therapeutic target for cancer treatment. The recent developments in its crystal structure further strengthened the idea of developing small molecule inhibitors for MTA1. In this review, we discuss the recent trends on the diverse functions of MTA1 and its role in various cancers, with the focus to consider MTA1 as a 'druggable' target in the control of human cancers. PMID- 28915538 TI - Long-term T3 and T4 treatment as an alternative to aerobic exercise training in improving cardiac function post-myocardial infarction. AB - Here we aimed to compare the beneficial effects of T3 and T4 hormone treatment to those provided by aerobic exercise training in Wistar rats post-myocardial infarction (MI). Rats in one group were SHAM-operated and in the other group were subjected to MI surgery. One week after surgery, the MI group animals either received T3 and T4 hormones by gavage or underwent a low intensity aerobic exercise training protocol on a treadmill, and both treatments lasted until 10 weeks after MI. Untreated SHAM-operated and MI groups were also followed for the same duration. The cardiac function was assessed by echocardiography and catheterization, followed by blood collection (to measure T3, T4, and TSH hormones), and euthanasia. The lung, liver, heart, and tibia were collected (to assess hypertrophy and congestion indices). The left ventricle homogenate (without a scar) was used for the analyses of calcium handling proteins. Results showed that enhanced cardiac function was promoted by both interventions, with infarct size reduction, increased ejection fraction, and diastolic posterior wall thickness, but no alterations in heart rate, cardiac output, or T3, T4, and TSH levels. There was a positive force-frequency relationship accompanied by increased alpha-MHC, as well as decreased HSP70 protein expression. In conclusion, the effects of T3 and T4 hormone treatments were similar, and in some parameters superior, to those provided by the aerobic exercise training. Thus, lower doses of thyroid hormones could be more suitable as a coadjuvant treatment after MI, as a plausible alternative for patients who are intolerant to aerobic exercise training. PMID- 28915539 TI - Astaxanthin alleviated acute lung injury by inhibiting oxidative/nitrative stress and the inflammatory response in mice. AB - The purpose of the present study was to assess the effect of astaxanthin (ASX) treatment on the acute lung injury (ALI) induced by cecal ligation and puncture (CLP) in mice. Mice were randomly allocated into the following groups: (1) the saline control group, in which mice were given saline before sham operation; (2) the ASX control group, in which mice received ASX before sham operation; (3) the ALI group, in which mice were given saline before CLP operation; and (4) the ALI+ASX group, in which mice received ASX before CLP operation. ASX was dissolved in olive oil and administrated by oral gavage for 14days consecutively before the CLP or sham operation. In experiment 1, Kaplan-Meier survival analysis was conducted for 72h after CLP. In experiment 2, blood, bronchoalveolar lavage fluid (BALF) and lung tissues were collected at 24h after the CLP or sham operation to determine the severity of lung injury. The results showed that ASX treatment could significantly decrease the CLP-induced mortality rate in mice. Meanwhile, ASX treatment significantly attenuated CLP-induced lung histopathological injury, inflammatory infiltration, total protein and albumin concentration, and total cell and neutrophil counts in the BALF. Furthermore, ASX treatment alleviated oxidative/nitrative stress, inflammation levels and pulmonary apoptosis in lung tissues. In addition, ASX treatment markedly down-regulated the expression of inducible nitric oxide synthase (i-NOS), nitrotyrosine (NT) and nuclear factor kappa B (NF-Kappab) P65 in the lung tissues compared with that in the ALI group. Astaxanthin treatment had markedly protective effect against ALI in mice, and the potential mechanism is associated with its ability to inhibit the inflammatory response, oxidative/nitrative stress, and pulmonary apoptosis, as well as down regulate NF-kappaB P65 expression. PMID- 28915540 TI - Impact of partial fuel switch on household air pollutants in sub-Sahara Africa. AB - Over 700 million people in Sub-Saharan Africa depend on solid biomass fuel and use simple cookstoves in poorly ventilated kitchens, which results in high indoor concentrations of household air pollutants. Switching from biomass to biogas as a cooking fuel can reduce airborne emissions of fine particulate matter (PM2.5) and carbon monoxide (CO), but households often only partially convert to biogas, continuing to use solid biomass fuels for part of their daily cooking needs. There is little evidence of the benefits of partial switching to biogas. This study monitored real-time PM2.5 and CO concentrations in 35 households in Cameroon and Uganda where biogas and firewood (or charcoal) were used. The 24 h mean PM2.5 concentrations in households that used: (1) firewood and charcoal; (2) both firewood (mean 54% cooking time) and biogas (mean 46% cooking time); and (3) only biogas, were 449 MUg m-3, 173 MUg m-3 and 18 MUg m-3 respectively. The corresponding 24 h mean CO concentrations were 14.2 ppm, 2.7 ppm and 0.5 ppm. Concentrations of both PM2.5 and CO were high and exceeded the World Health Organisation guidelines when firewood and charcoal were used. Partially switching to biogas reduced CO exposure to below the World Health Organisation guidelines, but PM2.5 concentrations were only below the 24 h recommended limits when households fully converted to biogas fuel. These results indicate that partial switching from solid fuels to biogas is not sufficient and continues to produce concentrations of household air pollution that are likely to harm the health of those exposed. Programmes introducing biogas should aim to ensure that household energy needs can be fully achieved using biogas with no requirement to continue using solid fuels. PMID- 28915541 TI - Temporal variability in aerosol characteristics and its radiative properties over Patiala, northwestern part of India: Impact of agricultural biomass burning emissions. AB - A comprehensive measurements of aerosol optical depth (AOD), particulate matter (PM) and black carbon (BC) mass concentrations have been carried out over Patiala, a semi-urban site in northwest India during October 2008 to September 2010. The measured aerosol data was incorporated in an aerosol optical model to estimate various aerosol optical parameters, which were subsequently used for radiative forcing estimation. The measured AOD at 500 nm (AOD500) shows a significant seasonal variability, with maximum value of 0.81 during post-monsoon (PoM) and minimum of 0.56 during winter season. The Angstrom exponent (alpha) has higher values (i.e. more fine-mode fraction) during the PoM/winter periods, and lower (i.e. more coarse-mode fraction) during pre-monsoon (PrM). In contrast, turbidity coefficient (beta) exhibits an opposite trend to alpha during the study period. BC mass concentration varies from 2.8 to 13.9 MUg m-3 (mean: 6.5 +/- 3.2 MUg m-3) during the entire study period, with higher concentrations during PoM/winter and lower during PrM/monsoon seasons. The average single scattering albedo (SSA at 500 nm) values are 0.70, 0.72, 0.82 and 0.75 during PoM, winter, PrM and monsoon seasons, respectively. However, inter-seasonal and inter-annual variability in measured aerosol parameters are statistically insignificant at Patiala. These results suggest strong changes in emission sources, aerosol composition, meteorological parameters as well as transport of aerosols over the station. Higher values of AOD, alpha and BC, along with lower SSA during PoM season are attributed to agriculture biomass burning emissions over and around the station. The estimated aerosol radiative forcing within the atmosphere is positive (i.e. warming) during all the seasons with higher values (~60 Wm-2) during PoM-08/PoM-09 and lower (~40 Wm-2) during winter-09/PrM-10. The present study highlights the role of BC aerosols from agricultural biomass burning emissions during post-monsoon season for atmospheric warming at Patiala. PMID- 28915542 TI - Comparative susceptibility of two Neotropical predators, Eriopis connexa and Chrysoperla externa, to acetamiprid and pyriproxyfen: Short and long-term effects after egg exposure. AB - Compatibility assessments between selective insecticides and the natural enemies of pests are essential for integrated-pest-management programs. Chrysoperla externa and Eriopis connexa are two principal Neotropical predators of agricultural pests whose conservation in agroecosystems requires a toxicity evaluation of pesticides to minimize the impact on those beneficial insects on the environment. The objective of this work was to evaluate the toxicity of the insecticides pyriproxyfen and acetamiprid on C. externa and E. connexa eggs exposed to the maximum recommended field concentrations of each along with three successive dilutions. The survival and the immature developmental time were assessed daily until adulthood and the mean survival time calculated over a 10 day period. The cumulative survival of E. connexa was reduced at all concentrations of both insecticides, while that of C. externa was significantly decreased by >=50 mg L-1 of acetamiprid and >=37.6 mg L-1 of pyriproxyfen. In both species, the reductions occurred principally on the eggs and first larval instar. Survival curves, in general, differed from those of the controls, with the mean survival time of E. connexa being significantly shorter in insecticides treatments than that of the controls. Certain concentrations of each of the insecticide lengthened the egg and first-larval-instar developmental periods of E. connexa and C. externa, respectively. Also, pyriproxyfen reduced the first larval-instar period and lengthened the fourth of E. connexa. Acetamiprid was more toxic to E. connexa than to C. externa at the two highest concentrations. Conversely, at those same concentrations of pyriproxyfen, the relative toxicity to the two species was reversed. The present work represents the first investigation on the comparative susceptibility of two relevant Neotropical biological control agents to acetamiprid and pyriproxyfen. Also, it highlights the necessity of assessing long-term effects in the compatibility studies between natural enemies of agricultural pests and insecticides. PMID- 28915543 TI - Effects of diisononyl phthalate on Danio rerio reproduction. AB - Di-isononyl phthalate (DiNP) is a high molecular weight phthalate commonly used as a plasticizer. It was introduced as a replacement for bis (2-ethylhexyl) phthalate (DEHP) which is used in the production of plasticized polyvinyl chloride (PVC). The purpose of this study was to investigate for the first time the effect of DiNP on female reproductive physiology in Danio rerio. Fish were exposed to five different doses of DiNP plus control (0 MUg/L; 0.42 MUg/L; 4.2 MUg/L; 42 MUg/L; 420 MUg/L; 4200 MUg/L) for a period of 21 days. We evaluated fish fecundity, oocyte growth, autophagic and apoptotic processes, as well as changes in morphological and biochemical composition of oocytes, using, qPCR analysis, histology and Fourier transform infrared imaging. The results demonstrate a non-monotonic dose response to DiNP. Greater differences were observed at the lowest (0.42 MUg/L) and higher concentrations (420 MUg/L; 4200 MUg/L) of DiNP. The findings provide evidence that exposure to DiNP adversely affect oocytes growth and maturation, leading to abnormal gonadal development and reproduction in zebrafish. PMID- 28915544 TI - Mobilisation of toxic trace elements under various beach nourishments. AB - To enhance protection and maintain wide beaches for recreation, beaches are replenished with sand: so-called beach nourishments. We compared four sites: two traditional beach nourishments, a mega beach nourishment and a reference without beach nourishment. Two sites contain calcareous-rich sand, whereas the other two sites have calcareous-poor sand. We aimed to understand hydrogeochemical processes to indicate factors critical for the mobility of trace elements at nourishments. We therefore analysed the chemical characteristics of sediment and pore water to ascertain the main drivers that mobilise toxic trace elements. With Dutch Quality Standards for soil and groundwater, the characteristics of sediment and pore water were compared to Target Values (the values at which there is a sustainable soil quality) and Intervention Values (the threshold above which the soil's functions are at risk). The pore water characteristics revealed that Target Values were regularly exceeded, especially for the nourishment sites and mainly for Mo (78%), Ni (24%), Cr (55%), and As (21%); Intervention Values for shallow groundwater were occasionally exceeded for As (2%), Cr (2%) and Zn (2%). The sediment characteristics did not exceed the Target Values and showed that trace elements were mainly present in the fine fraction of <150 MUm. The oxidation of sulphide minerals such as pyrite resulted into the elevated concentration for all nourishment sites, especially when an unsaturated zone was present and influence of rainwater was apparent. To prevent trace metal mobility at a mega beach nourishment it is important to retain seawater influences and limit oxidation processes. In this respect, a shoreface nourishment is recommended rather than a mega beach nourishment with a thick unsaturated zone. Consequently, we conclude that whether a site is carbonate-rich or carbonate-poor is unimportant, as the influence of seawater will prevent decalcification, creating a low risk of mobilisation of trace elements. PMID- 28915545 TI - Air pollution at Rochester, NY: Long-term trends and multivariate analysis of upwind SO2 source impacts. AB - There have been many changes in the air pollutant sources in the northeastern United States since 2001. To assess the effect of these changes, trend analyses of the monthly average values were performed on PM2.5 and its components including major ions, elemental carbon (EC), organic carbon (OC), and gaseous pollutant concentrations measured between 2001 (in some cases 1999) and 2015 at the NYS Department of Environmental Conservation sites in Rochester, NY. Mann Kendall regression with Sen's slope was applied to estimate the trends and seasonality. Using piecewise regression, significant reductions in the air pollution of Rochester area were observed between 2008 and 2010 when a 260MW coal fired power plant was decommissioned, new heavy-duty diesel trucks had to be equipped with catalytic regenerator traps, and the economic recession that began in 2008 reduced traffic and other activities. The monthly average PM2.5 mass showed a downward trend (-5MUg/m3; -41%) in Rochester between 2001 and 2015. This change is largely due to reductions in particulate sulfate that showed a 65% decrease. The sulfate concentrations were compared to changes in SO2 emissions in seventeen upwind source domains, and other systematic changes by multivariate linear regression. Selectivity ratio obtained from target projection discriminated the most important source domains that are SO2 emissions from Georgia for winter, North Carolina for transition (spring and fall) and Ohio along with other influences for summer. North Carolina and Michigan were identified as the main sources for entire period. These observations suggest that any further reductions in the specified regional SO2 emissions would result in a proportional decrease in sulfate in Rochester. PMID- 28915546 TI - Emergent contaminants: Endocrine disruptors and their laccase-assisted degradation - A review. AB - Herein, an effort has been made to highlight the trends of the state-of-the-art of laccase-assisted degradation of emerging contaminants at large and endocrine disruptors in particular. Since first described in the 19th century, laccase has received particular interest for inter- and multidisciplinary investigations due to its uniqueness and remarkable biotechnological applicability. There has always been a paramount concern over the widespread occurrences of various pollutant types, around the globe. Therefore, pollution free processes are gaining ground all over the world. With ever increasing scientific knowledge, socioeconomic awareness, human health-related issues and ecological apprehensions, people are more concerned about the widespread environmental pollutants. In this context, the occurrences of newly identified pollutants so-called "emerging contaminants - ECs" in our main water bodies is of continued and burning concern worldwide. Undoubtedly, various efforts have already been made to tackle this challenging ECs concern though using different approaches including physical and chemical, however, each has considerable limitations. In this review, we present information on how laccase-assisted approach can change this limited tendency of physical and chemical based approaches. A special focus has been given to the laccase-assisted systems including pristine laccase, laccase-mediator catalyzed system and immobilized-laccase catalyzed system that promotes the endocrine disruptors removal. Towards the end, a list of outstanding questions and research gaps are given that can pave the way for future studies. PMID- 28915547 TI - Persistence, mobility and bioavailability of emerging organic contaminants discharged from sewage treatment plants. AB - Little is known about the impact of emissions of micropollutants from small and large-scale sewage treatment plants (STPs) on drinking water source areas. We investigated a populated catchment that drains into Lake Malaren, which is the drinking water source for around 2 million people including the inhabitants of Stockholm, Sweden. To assess the persistence, mobility, bioavailability and bioaccumulation of 32 structurally diverse emerging organic contaminants, sediment, integrated passive and grab water samples were collected along the catchment of the River Fyris, Sweden. The samples were complemented with STP effluent and fish samples from one sampling event. Contaminants identified as persistent, mobile, and bioavailable were 4,6,6,7,8,8-hexamethyl-1,3,4,7 tetrahydrocyclopenta[g]isochromene (galaxolide), 2,4,7,9-tetramethyl-5-decyn-4,7 diol, tris(2-chloro-ethyl) phosphate, tris(1,3-dichloro-2-propyl) phosphate, and tris(1-chloro-2-propyl) phosphate. Galaxolide and 2,4,7,9-tetramethyl-5-decyn-4,7 diol were additionally found to be bioaccumulative, whereas n butylbenzenesulfonamide was found to be only persistent and mobile. The total median mass flux of the persistent and mobile target analytes from Lake Ekoln into the drinking water source area of Lake Malaren was estimated to be 27kg per year. Additionally, 10 contaminants were tentatively identified by non-target screening using NIST library searches and manual review. Two of those were confirmed by reference standards and further two contaminants, propylene glycol and rose acetate, were discharged from STPs and travelled far from the source. Attenuation of mass fluxes was highest in the summer and autumn seasons, suggesting the importance of biological degradation and photodegradation for the persistence of the studied compounds. PMID- 28915548 TI - A spatio-temporal statistical model of maximum daily river temperatures to inform the management of Scotland's Atlantic salmon rivers under climate change. AB - The thermal suitability of riverine habitats for cold water adapted species may be reduced under climate change. Riparian tree planting is a practical climate change mitigation measure, but it is often unclear where to focus effort for maximum benefit. Recent developments in data collection, monitoring and statistical methods have facilitated the development of increasingly sophisticated river temperature models capable of predicting spatial variability at large scales appropriate to management. In parallel, improvements in temporal river temperature models have increased the accuracy of temperature predictions at individual sites. This study developed a novel large scale spatio-temporal model of maximum daily river temperature (Twmax) for Scotland that predicts variability in both river temperature and climate sensitivity. Twmax was modelled as a linear function of maximum daily air temperature (Tamax), with the slope and intercept allowed to vary as a smooth function of day of the year (DoY) and further modified by landscape covariates including elevation, channel orientation and riparian woodland. Spatial correlation in Twmax was modelled at two scales; (1) river network (2) regional. Temporal correlation was addressed through an autoregressive (AR1) error structure for observations within sites. Additional site level variability was modelled with random effects. The resulting model was used to map (1) spatial variability in predicted Twmax under current (but extreme) climate conditions (2) the sensitivity of rivers to climate variability and (3) the effects of riparian tree planting. These visualisations provide innovative tools for informing fisheries and land-use management under current and future climate. PMID- 28915549 TI - PRRT2, a network stability gene. PMID- 28915550 TI - Transglutaminase in neurological disease. PMID- 28915551 TI - Cancer's new Achilles' heel? PMID- 28915552 TI - Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2. AB - Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA biogenesis. Here, we found that DICER was downregulated in tumor samples of colorectal cancer (CRC) patients at both mRNA and protein levels. Importantly, intestinal epithelial cell (IEC)-specific deletion of Dicer mice got more tumors after azoxymethane and dextran sulfate sodium (DSS) administration. Interestingly, IEC specific deletion of Dicer led to severe chronic inflammation and epithelium layer remodeling in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines showed that miR-324-5p was one of the most significantly decreased miRNAs. In the intestinal epithelium of IEC-specific deletion of Dicer mice, miR-324-5p was also found to be markedly reduced. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMG-box containing 3 (HMGXB3) and WAS protein family member 2 (WASF-2), two key proteins participated in cell motility and cytoskeleton remodeling, to suppress their expressions. Intraperitoneal injection of miR-324-5p AgomiR (an agonist of miR-324-5p) curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in IEC-specific deletion of Dicer mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in tumorigenesis of CRC by regulation of cytoskeleton remodeling and maintaining integrity of intestinal barriers. PMID- 28915553 TI - Identification of a novel p53 target, COL17A1, that inhibits breast cancer cell migration and invasion. AB - p53 mutation is a marker of poor prognosis in breast cancers. To identify downstream targets of p53, we screened two transcriptome datasets, including cDNA microarrays of MCF10A breast epithelial cells with wild-type p53 or p53-null background, and RNA sequence analysis of breast invasive carcinoma. Here, we unveil ten novel p53 target candidates that are up-regulated after the induction of p53 in wild-type cells. Their expressions are also high in breast invasive carcinoma tissues with wild-type p53. The GO analysis identified epidermis development and ectoderm development, which COL17A1 participates, as significantly up-regulated by wild-type p53. The COL17A1 expressions increased in a p53-dependent manner in human breast cells and mouse mammary tissues. Reporter assay and ChIP assay identified intronic p53-binding sequences in the COL17A1 gene. The MDA-MB-231 cells that genetically over-express COL17A1 gene product exhibited reduced migration and invasion in vitro. Similarly, COL17A1 expression was decreased in metastatic tumors compared to primary tumors and normal tissues, even from the same patients. Moreover, high COL17A1 expression was associated with longer survival of patients with invasive breast carcinoma. In conclusion, we revealed that COL17A1 is a novel p53 transcriptional target in breast tissues that inhibits cell migration and invasion and is associated with better prognosis. PMID- 28915554 TI - Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells. AB - PURPOSE: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. EXPERIMENTAL DESIGN: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured. Tumor-bearing mice were treated with MDSC depletion and CTLA-4 checkpoint blockade. Immune signatures within the human HNSCC datasets from The Cancer Genome Atlas (TCGA) were analyzed and differentially expressed genes from sorted human peripheral MDSCs were examined. RESULTS: gMDSCs accumulated with tumor progression and correlated with depletion of effector immune cells. Selective depletion of gMDSC restored tumor and draining lymph node antigen-specific T lymphocyte responses lost with tumor progression. A subset of T-cell inflamed tumors responded to CTLA-4 mAb alone, but the addition of gMDSC depletion induced CD8 T-lymphocyte-dependent rejection of established tumors in all treated mice that resulted in immunologic memory. MDSCs differentially expressed chemokine receptors. Analysis of the head and neck cancer TCGA cohort revealed high CTLA-4 and MDSC-related chemokine and an MDSC-rich gene expression profile with a T-cell inflamed phenotype in > 60% of patients. CXCR2 and CSF1R expression was validated on sorted peripheral blood MDSCs from HNSCC patients. CONCLUSIONS: MDSCs are a major contributor to local immunosuppression that limits responses to checkpoint inhibition in head and neck cancer. Limitation of MDSC recruitment or function represents a rational strategy to enhance responses to CTLA-4-based checkpoint inhibition in these patients. PMID- 28915555 TI - Identification of a p53-repressed gene module in breast cancer cells. AB - The p53 protein is a sophisticated transcription factor that regulates dozens of target genes simultaneously in accordance with the cellular circumstances. Although considerable efforts have been made to elucidate the functions of p53 induced genes, a holistic understanding of the orchestrated signaling network repressed by p53 remains elusive. Here, we performed a systematic analysis to identify simultaneously regulated p53-repressed genes in breast cancer cells. Consequently, 28 genes were designated as the p53-repressed gene module, whose gene components were simultaneously suppressed in breast cancer cells treated with Adriamycin. A ChIP-seq database showed that p53 does not preferably bind to the region around the transcription start site of the p53-repressed gene module elements compared with that of p53-induced genes. Furthermore, we demonstrated that p21/CDKN1A plays a pivotal role in the suppression of the p53-repressed gene module in breast cancer cells. Finally, we showed that appropriate suppression of some genes belonging to the p53-repressed gene module contributed to a better prognosis of breast cancer patients. Taken together, these findings disentangle the gene regulatory network underlying the built-in p53-mediated tumor suppression system. PMID- 28915556 TI - Critical roles of SMYD2-mediated beta-catenin methylation for nuclear translocation and activation of Wnt signaling. AB - Accumulation of beta-catenin in the nucleus is a hallmark of activation of the Wnt/beta-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of beta-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of beta-catenin on its nuclear translocation. Knockdown of SMYD2 attenuates the nuclear localization of beta-catenin protein in human cancer cells. Consequently, transcriptional levels of well-known Wnt-signaling molecules, cMYC and CCND1, are significantly reduced. Substitution of lysine 133 to alanine in beta-catenin almost completely abolishes its nuclear localization. We also demonstrate the K133 methylation is critical for the interaction of beta-catenin with FOXM1. Furthermore, after treatment with a SMYD2 inhibitor, significant reduction of nuclear beta-catenin and subsequent induction of cancer cell death are observed. Accordingly, our results imply that beta-catenin methylation by SMYD2 promotes its nuclear translocation and activation of Wnt signaling. PMID- 28915557 TI - Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb independent pathway. AB - The tumor suppressor p16INK4A (p16) inhibits cell cycle progression through the CDK4/Rb pathway. We have previously shown that p16 regulates cellular oxidative stress, independent of its role in cell cycle control. We investigated whether loss of p16 had a direct impact on the mitochondria. We found that p16-null primary mouse fibroblasts (PMFs) displayed increased mitochondrial mass and expression of mitochondrial respiratory subunit proteins compared to wild-type (WT) PMFs. These findings in p16-null PMFs were associated with increased expression of the mitochondrial biogenesis transcription factors PRC and TFAM. On the other hand, p16-deficient PMFs demonstrated reduced mitochondrial respiration capacity consistent with electron microscopy findings showing that mitochondria in p16-deficient PMFs have abnormal morphology. Consistent with increased mitochondrial mass and reduced respiratory capacity, p16-deficient PMFs generated increased mitochondrial superoxide. One biological consequence of elevated ROS in p16-deficient PMFs was enhanced migration, which was reduced by the ROS scavenger N-acetylcysteine. Finally, p16-deficient PMFs displayed increased mitochondrial membrane potential, which was also required for their enhanced migration. The mitochondrial and migration phenotype was restored in p16-deficient PMFs by forced expression of p16. Similarly, over-expression of p16 in human melanocytes and A375 melanoma cells led to decreased expression of some mitochondrial respiratory proteins, enhanced respiration, and decreased migration. Inhibition of Rb phosphorylation in melanocytes and melanoma cells, either by addition of chemical CDK4 inhibitors or RNAi-mediated knockdown of CDK4, did not mimic the effects of p16 loss. These results suggest that p16 regulates mitochondrial biogenesis and function, which is independent of the canonical CDK4/Rb pathway. PMID- 28915558 TI - Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85alpha and p85beta. AB - Our understanding of isoform-specific activities of phosphatidylinositol 3-kinase (PI3K) is still rudimentary, and yet, deep knowledge of these non-redundant functions in the PI3K family is essential for effective and safe control of PI3K in disease. The two major isoforms of the regulatory subunits of PI3K are p85alpha and p85beta, encoded by the genes PIK3R1 and PIK3R2, respectively. These isoforms show distinct functional differences that affect and control cellular PI3K activity and signaling [1-4]. In this study, we have further explored the differences between p85alpha and p85beta by genetic truncations and substitutions. We have discovered unexpected activities of the mutant proteins that reflect regulatory functions of distinct p85 domains. These results can be summarized as follows: Deletion of the SH3 domain increases oncogenic and PI3K signaling activity. Deletion of the combined SH3-RhoGAP domains abolishes these activities. In p85beta, deletion of the cSH2 domain reduces oncogenic and signaling activities. In p85alpha, such a deletion has an activating effect. The deletions of the combined cSH2 and iSH2 domains and also the deletion of the cSH2, iSH2 and nSH2 domains yield results that go in the same direction, generally activating in p85alpha and reducing activity in p85beta. The contrasting functions of the cSH2 domains are verified by domain exchanges with the cSH2 domain of p85beta exerting an activating effect and the cSH2 domain of p85alpha an inactivating effect, even in the heterologous isoform. In the cell systems studied, protein stability was not correlated with oncogenic and signaling activity. These observations significantly expand our knowledge of the isoform-specific activities of p85alpha and p85beta and of the functional significance of specific domains for regulating the catalytic subunits of class IA PI3K. PMID- 28915559 TI - Zbtb1 controls NKp46+ ROR-gamma-T+ innate lymphoid cell (ILC3) development. AB - Innate lymphoid cells (ILCs) play a central role conferring protection at the mucosal frontier. In this study, we have identified a requirement of the transcription factor Zbtb1 for the development of RORgammat+ ILCs (ILC3s). Zbtb1 deficient mice lacked NKp46+ ILC3 cells in the lamina propria of the small and large intestine. This requirement of Zbtb1 was cell intrinsic, as NKp46+ ILC3s were not generated from Zbtb1-deficient progenitors in bone marrow chimeras and Zbtb1-deficient RORgammat+ CCR6-NKp46- ILC3s didn't generate NKp46+ ILC3s in co cultures with OP9-DL1 stroma. In correlation with this impairment, Zbtb1 deficient ILC3 cells failed to upregulate T-bet expression, and to acquire IFN gamma production characteristic of NKp46+ cells. Finally, absence of NKp46+ILC3 cells combined with the absence of T-cells in Zbtb1-deficient mice, led to a transient susceptibility to C. rodentium infections. Altogether, these results establish that Zbtb1 is essential for the development of NKp46+ ILC3 cells. PMID- 28915560 TI - Pharynx mitochondrial [Ca2+] dynamics in live C. elegans worms during aging. AB - Progressive decline in mitochondrial function is generally considered one of the hallmarks of aging. We have expressed a Ca2+ sensor in the mitochondrial matrix of C. elegans pharynx cells and we have measured for the first time mitochondrial [Ca2+] ([Ca2+]M) dynamics in the pharynx of live C. elegans worms during aging. Our results show that worms stimulated with serotonin display a pharynx [Ca2+]M oscillatory kinetics that includes both high frequency oscillations (up to about 1Hz) and very prolonged "square-wave" [Ca2+]M increases, indicative of energy depletion of the pharynx cells. Mitochondrial [Ca2+] is therefore able to follow "beat-to-beat" the fast oscillations of cytosolic [Ca2+]. The fast [Ca2+]M oscillations kept steady frequency values during the whole worm life, from 2 to 12 days old, but the height and width of the peaks was progressively reduced. [Ca2+]M oscillations were also present with similar kinetics in respiratory chain complex I nuo-6 mutant worms, although with smaller height and frequency than in the controls, and larger width. In summary, Ca2+ fluxes in and out of the mitochondria are relatively well preserved during the C. elegans life, but there is a clear progressive decrease in their magnitude during aging. Moreover, mitochondrial Ca2+ fluxes were smaller in nuo-6 mutants with respect to the controls at every age and decreased similarly during aging. PMID- 28915561 TI - Differentially expressed lncRNAs and miRNAs with associated ceRNA networks in aged mice with postoperative cognitive dysfunction. AB - Postoperative cognitive dysfunction (POCD) is a common postoperative complication observed in elderly patients. Using microarray analyses, we comprehensively compared long non-coding RNA (lncRNA), messenger RNA (mRNA), and microRNA (miRNA) expression profiles in hippocampal tissues from a mouse model of POCD and control mice. A total of 175 lncRNAs, 117 mRNAs, and 26 miRNAs were differentially expressed between POCD and control mice. Gene ontology (GO) and KEGG pathway enrichment analyses were performed to explore the principal functions of dysregulated genes. Correlated coding-noncoding co-expression (CNC) and competing endogenous RNA (ceRNA) expression networks were constructed using bioinformatics methods. lncRNA NONMMUT000708 correlated positively with expression of the inflammation-related gene Hif3a. lncRNAs NONMMUT043249 and NONMMUT028705 mediated gene expression by binding the transcription factor cAMP response element-binding protein (CREB). The constructed ceRNA network suggested lncRNA NONMMUT055714 binds competitively with miR-7684-5p, increasing expression of its target gene, Sorl1. Finally, eight dysregulated lncRNAs, four miRNAs, and ten mRNAs were confirmed via quantitative real-time polymerase chain reaction (PCR) in 10 POCD healthy mouse paired samples. These results suggest that lncRNAs and miRNAs are involved in POCD pathogenesis and progression. Our ceRNA network will improve understanding of lncRNA-mediated ceRNA regulatory mechanisms operating during the pathogenesis of POCD. PMID- 28915562 TI - Detecting the genetic link between Alzheimer's disease and obesity using bioinformatics analysis of GWAS data. AB - Alzheimer's disease (AD) represents the major form of dementia in the elderly. In recent years, accumulating evidence indicate that obesity may act as a risk factor for AD, while the genetic link between the two conditions remains unclear. This bioinformatics analysis aimed to detect the genetic link between AD and obesity on single nucleotide polymorphisms (SNPs), gene, and pathway levels based on genome-wide association studies data. A total of 31 SNPs were found to be shared by AD and obesity, which were linked to 7 genes. These genes included PSMC3, CELF1, MYBPC3, SPI1, APOE, MTCH2 and RAPSN. Further functional enrichment analysis of these genes revealed the following biological pathways, including proteasome, osteoclast differentiation, hypertrophic cardiomyopathy, dilated cardiomyopathy, Epstein-Barr virus and TLV-I infection, as well as several cancer associated pathways, to be common among AD and obesity. The findings deepened our understanding on the genetic basis linking obesity and AD and may help shape possible prevention and treatment strategies. PMID- 28915563 TI - NiaoDuQing granules relieve chronic kidney disease symptoms by decreasing renal fibrosis and anemia. AB - NiaoDuQing (NDQ) granules, a traditional Chinese medicine, has been clinically used in China for over fourteen years to treat chronic kidney disease (CKD). To elucidate the mechanisms underlying the therapeutic benefits of NDQ, we designed an approach incorporating chemoinformatics, bioinformatics, network biology methods, and cellular and molecular biology experiments. A total of 182 active compounds were identified in NDQ granules, and 397 putative targets associated with different diseases were derived through ADME modelling and target prediction tools. Protein-protein interaction networks of CKD-related and putative NDQ targets were constructed, and 219 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to the TGF-beta, the p38MAPK, and the erythropoietin (EPO) receptor signaling pathways, which are known contributors to renal fibrosis and/or renal anemia. A rat model of CKD was established to validate the drug target mechanisms predicted by the systems pharmacology analysis. Experimental results confirmed that NDQ granules exerted therapeutic effects on CKD and its comorbidities, including renal anemia, mainly by modulating the TGF-beta and EPO signaling pathways. Thus, the pharmacological actions of NDQ on CKD symptoms correlated well with in silico predictions. PMID- 28915564 TI - Classical swine fever virus Shimen infection increases p53 signaling to promote cell cycle arrest in porcine alveolar macrophages. AB - Classical swine fever virus (CSFV) replicates in macrophages and causes persistent infection. Despite its role in disastrous economic losses in swine industries, the molecular mechanisms underlying its pathogenesis are poorly understood. The virus evades the neutralizing immune response, subverting the immune system to ensure its own survival and persistence. Our genome-wide analysis of porcine alveolar macrophage transcriptional responses to CSFV Shimen infection using the Solexa/Illumina digital gene expression system revealed that p53 pathway components and cell cycle molecules were differentially regulated during infection compared to controls. Further, we investigated the molecular changes in macrophages infected with CSFV Shimen, focusing on the genes involved in the p53 pathway. CSFV Shimen infection led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, CSFV Shimen infection upregulated cyclin-dependent kinase inhibitor 1A (p21) mRNA and protein. In addition, CSFV Shimen infection induced cell cycle arrest at the G1 phase, as well as downregulation of cyclin E1 and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-alpha during CSFV Shimen infection. Our data suggest that CSFV Shimen infection increases expression of host p53 and p21, and inhibits expression of cyclin E1 and CDK2, leading to cell cycle arrest at the G1 phase. CSFV may utilize this strategy to subvert the innate immune response and proliferate in host cells. PMID- 28915565 TI - PKCtheta utility in diagnosing c-KIT/DOG-1 double negative gastrointestinal stromal tumors. AB - BACKGROUND: The aim of this study was to evaluate the diagnosis value of an immunohistochemical (IHC) panel of three antibodies for the diagnosis of gastrointestinal stromal tumors (GISTs). MATERIAL AND METHODS: In 80 consecutive GISTs without lymph node metastases, the IHC examinations were performed using the antibodies CD117 (c-KIT), DOG-1 and c-theta (PKCtheta) protein. The diagnostic value of PKCtheta in c-KIT/DOG-1 negative GISTs has been explored in fewer than 10 Medline-indexed papers. RESULTS: The c-KIT, PKCtheta and DOG-1 positivity was noted in 92.50% (n = 74), 90% (n = 72) and 76.25% (n = 61) of the cases, respectively. All of the C-KIT negative cases (n = 6) were also DOG-1 negative but displayed PKCtheta positivity. All of the DOG-1 positive cases (n = 61) also expressed c-KIT. No correlation between the examined markers and clinicopathological parameters was noted. CONCLUSIONS: The PKCtheta sensitivity is similar to c-KIT and superior to DOG-1 sensitivity. All of the c-KIT/DOG-1 negative GISTs seem to express PKCtheta. For a proper diagnosis of GIST, the c KIT/DOG-1/PKCtheta panel should be used, with possible therapeutic but not prognostic value. PMID- 28915566 TI - Synergistic antibiotic effect of looped antimicrobial peptide CLP-19 with bactericidal and bacteriostatic agents. AB - The treatment of drug-resistant infections is complicated and the alarming rise in infectious diseases poses a unique challenge for development of effective therapeutic strategies. Antibiotic-induced liberation of the bacterial endotoxin lipopolysaccharide (LPS) may have immediate adverse effects promoting septic shock in patients. In the present study, we first confirmed our previous finding that looped antimicrobial peptide CLP-19 exerts non-specific direct antibacterial activity with no toxic to mammalian cells and second revealed that CLP-19 has synergistic effect to enhance the antibacterial activities of other conventional bactericidal (ampicillin and ceftazidime) and bacteriostatic (erythromycin and levofloxacin) agents. Third, the underlying mechanism of antibiotic effect was likely associated with stimulation of hydroxyl radical generation. Lastly, CLP-19 was shown to effectively reduce the antibiotic-induced liberation of LPS, through direct neutralization of the LPS. Thus, CLP-19 is a potential therapeutic agent for combinatorial antibiotic therapy. PMID- 28915567 TI - Melatonin inhibits Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes to attenuate osteoarthritis. AB - Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage degradation. Interleukin-1beta (IL-1beta) contributes to OA pathogenesis by enhancing oxidative stress and inflammation. Melatonin reportedly elicits potent protection against OA. However, the role of melatonin and underlying mechanism in IL-1beta-stimulated chondrocytes remain largely unclear. In this study, we found that melatonin inhibited IL-1beta-induced toxicity and sirtuin 1 (Sirt1) enhancement in human chondrocytes. Melatonin reduced the IL 1beta-increased nicotinamide phosphoribosyltransferase (NAMPT) expression and the NAD+ level in chondrocytes in a Sirt1-dependent manner. In turn, the inhibitory effect of melatonin on Sirt1 was mediated by NAMPT. Moreover, melatonin suppressed IL-1beta-induced Sirt1-mediated matrix metalloproteinase (MMP)-3 and MMP-13 production. Melatonin also decreased the Sirt1-steered nuclear factor of activated T cells 5 (NFAT5) expression in IL-1beta-challenged chondrocytes. NFAT5 depletion mimicked the suppressive effects of melatonin on IL-1beta-elevated production of inflammatory mediators, including tumor necrosis factor-alpha (TNF alpha), IL-1beta, prostaglandin E2 (PGE2), and nitric oxide (NO) in chondrocytes. TNF-alpha, IL-1beta, PGE2, or NO decrease caused the similar reduction of MMP-3 and MMP-13 by melatonin in IL-1beta-insulted chondrocytes. Highly consistent with in vitro findings, in vivo results demonstrated that melatonin repressed the expression of relevant genes in rat OA pathogenesis in anterior cruciate ligament transection model. Overall, these results indicate that melatonin effectively reduced IL-1beta-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes, suggesting melatonin as a potential therapeutic alternative for chondroprotection of OA patients. PMID- 28915568 TI - Hyperosmotic stress stimulates autophagy via polycystin-2. AB - Various intracellular mechanisms are activated in response to stress, leading to adaptation or death. Autophagy, an intracellular process that promotes lysosomal degradation of proteins, is an adaptive response to several types of stress. Osmotic stress occurs under both physiological and pathological conditions, provoking mechanical stress and activating various osmoadaptive mechanisms. Polycystin-2 (PC2), a membrane protein of the polycystin family, is a mechanical sensor capable of activating the cell signaling pathways required for cell adaptation and survival. Here we show that hyperosmotic stress provoked by treatment with hyperosmolar concentrations of sorbitol or mannitol induces autophagy in HeLa and HCT116 cell lines. In addition, we show that mTOR and AMPK, two stress sensor proteins involved modulating autophagy, are downregulated and upregulated, respectively, when cells are subjected to hyperosmotic stress. Finally, our findings show that PC2 is required to promote hyperosmotic stress induced autophagy. Downregulation of PC2 prevents inhibition of hyperosmotic stress-induced mTOR pathway activation. In conclusion, our data provide new insight into the role of PC2 as a mechanosensor that modulates autophagy under hyperosmotic stress conditions. PMID- 28915569 TI - GABARAPL1 tumor suppressive function is independent of its conjugation to autophagosomes in MCF-7 breast cancer cells. AB - The GABARAPL1 protein belongs to the ATG8 family whose members are involved in autophagy. Our laboratory previously demonstrated that GABARAPL1 associates with autophagic vesicles, regulates autophagic flux and acts as a tumor suppressor protein in breast cancer. In this study, we aimed to determine whether GABARAPL1 conjugation to autophagosomes is necessary for its tumor suppressive functions using the MCF-7 breast cancer cell line overexpressing GABARAPL1 or a G116A mutant, which is unable to be lipidated and associated to autophagosomes. We show that the G116A mutation impaired GABARAPL1 function in autophagosome/lysosome fusion and inhibited lysosome activity but did not alter MTOR and ULK1 activities or tumor growth in vivo. Our results demonstrate for the first time that GABARAPL1 plays different regulatory functions during early and late stages of autophagy, independently or not of its conjugation to autophagosomes, but its tumor suppressive function appeared to be independent of its conjugation to autophagic vesicles. PMID- 28915570 TI - IL1 genes polymorphism and the risk of renal cell carcinoma in Chinese Han population. AB - Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. However, with the lack of diagnostic screening biomarkers, early diagnosis of RCC is challenging. Our study was investigated the association of IL1 gene polymorphisms and RCC risk. We conducted a case-control study of 291 RCC cases and 463 controls to evaluation the IL1RN of single nucleotide polymorphisms (SNPs) on RCC risk. We selection of 16 SNPs in IL1RN, IL1A, IL1B genes were analyzed. Using the chi squared (chi2) test and genetic model analysis, we found an association with RCC risk for five SNPs [rs3783550 (IL1A), rs3783546 (IL1A), rs1609682 (IL1A), rs3783521 (IL1A), and rs1143623 (IL1B)] and increased the risk of RCC. Stratified analyses show that smoking, not drinking and age>55 populations relative to nonsmoking, drinking and age<55 more susceptible. Our study suggested that IL1B and IL1A may involve in the development of RCC in Chinese Han population. PMID- 28915571 TI - P62 plasmid can alleviate diet-induced obesity and metabolic dysfunctions. AB - A high-calorie diet (HCD) induces two mutually exacerbating effects contributing to diet-induced obesity (DIO): impaired glucose metabolism and increased food consumption. A link between the metabolic and behavioral manifestations is not well understood yet. We hypothesized that chronic inflammation induced by HCD plays a key role in linking together the two components of diet-induced pathology. Based on this hypothesis, we tested if a plasmid (DNA vaccine) encoding p62 (SQSTM1) would alleviate DIO including its metabolic and/or food consumption abnormalities. Previously we reported that injections of the p62 plasmid reduce chronic inflammation during ovariectomy-induced osteoporosis. Here we found that the p62 plasmid reduced levels of pro-inflammatory cytokines IL 1beta, IL-12, and INFgamma and increased levels of anti-inflammatory cytokines IL 4, IL-10 and TGFbeta in HCD-fed animals. Due to this anti-inflammatory response, we further tested whether the plasmid can alleviate HCD-induced obesity and associated metabolic and feeding impairments. Indeed, p62 plasmid significantly reversed effects of HCD on the body mass index (BMI), levels of glucose, insulin and glycosylated hemoglobin (HbA1c). Furthermore, p62 plasmid partially restored levels of the satiety hormone, serotonin, and tryptophan, simultaneously reducing activity of monoamine oxidase (MAO) in the brain affected by the HCD. Finally, the plasmid partially reversed increased food consumption caused by HCD. Therefore, the administering of p62 plasmid alleviates both metabolic and behavioral components of HCD-induced obesity. PMID- 28915572 TI - Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance. AB - The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a liver specific functional receptor for the hepatitis B virus (HBV). Previous studies indicated that the expression of NTCP may be associated with the proliferation status of hepatocytes. However, the involvement of NTCP in hepatocellular carcinoma (HCC) cells proliferation remains unclear. In this study, we confirmed that NTCP was down-regulated in HCC tumor tissues compared with that in the adjacent non-tumor tissues (P < 0.0001). Clinically, lower expression of NTCP was correlated with poor post-surgery survival rate (P = 0.0009) and larger tumor tissue mass (P = 0.003) of HCC patients. This was supported by the finding that ectopic expression of NTCP in both HepG2 and Huh-7 cells could significantly suppress hepatocytes growth by arresting cells in G0/G1 phase. We also discovered that cyclin D1 could transcriptionally suppress NTCP expression by inhibiting the activity of NTCP promoter, while arresting HCC cells in G0/G1 phase by serum starvation could upregulate NTCP mRNA levels. This is the first study to report that the transcriptional inhibition of NTCP expression during cell cycle progression was mediated by cyclin D1. The down-regulated NTCP expression was associated with poor prognosis and lower HBV cccDNA level in HCC patients. Therefore, NTCP expression levels might serve as a novel prognostic predictive marker for post-surgery survival rate of HCC patients. PMID- 28915573 TI - Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade. AB - Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting. PMID- 28915574 TI - Comparative study of whole genome amplification and next generation sequencing performance of single cancer cells. AB - BACKGROUND: Whole genome amplification (WGA) is required for single cell genotyping. Effectiveness of currently available WGA technologies in combination with next generation sequencing (NGS) and material preservation is still elusive. RESULTS: In respect to the accuracy of SNP/mutation, indel, and copy number aberrations (CNA) calling, the HiSeq2000 platform outperformed IonProton in all aspects. Furthermore, more accurate SNP/mutation and indel calling was demonstrated using single tumor cells obtained from EDTA-collected blood in respect to CellSave-preserved blood, whereas CNA analysis in our study was not detectably affected by fixation. Although MDA-based WGA yielded the highest DNA amount, DNA quality was not adequate for downstream analysis. PCR-based WGA demonstrates superiority over MDA-PCR combining technique for SNP and indel analysis in single cells. However, SNP calling performance of MDA-PCR WGA improves with increasing amount of input DNA, whereas CNA analysis does not. The performance of PCR-based WGA did not significantly improve with increase of input material. CNA profiles of single cells, amplified with MDA-PCR technique and sequenced on both HiSeq2000 and IonProton platforms, resembled unamplified DNA the most. MATERIALS AND METHODS: We analyzed the performance of PCR-based, multiple-displacement amplification (MDA)-based, and MDA-PCR combining WGA techniques (WGA kits Ampli1, REPLI-g, and PicoPlex, respectively) on single and pooled tumor cells obtained from EDTA- and CellSave-preserved blood and archival material. Amplified DNA underwent exome-Seq with the Illumina HiSeq2000 and ThermoFisher IonProton platforms. CONCLUSION: We demonstrate the feasibility of single cell genotyping of differently preserved material, nevertheless, WGA and NGS approaches have to be chosen carefully depending on the study aims. PMID- 28915575 TI - Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a KRAS-driven cancer with a high incidence of metastasis and an overall poor prognosis. Previous work in a genetically engineered mouse model of PDAC showed glucose metabolism to be important for maintaining tumor growth. Multiple glycolytic enzymes, including hexokinase 2 (HK2), were upregulated in primary PDAC patient tumors, supporting a role for glycolysis in promoting human disease. HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Pharmacologic inhibition of lactate production reduced the HK2-driven increase in invasion while addition of extracellular lactate enhanced invasion, together providing a link between glycolytic activity and metastatic potential. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic. PMID- 28915576 TI - Hepatic B cell leukemia-3 suppresses chemically-induced hepatocarcinogenesis in mice through altered MAPK and NF-kappaB activation. AB - The transcriptional nuclear factor kappa B (NF-kappaB)-coactivator B cell leukemia-3 (Bcl-3) is a molecular regulator of cell death and proliferation. Bcl 3 has been shown to be widely expressed in different cancer types including hepatocellular carcinoma (HCC). Its influence on hepatocarcinogenesis is still undetermined. To examine the role of Bcl-3 in hepatocarcinogenesis mice with hepatocyte-specific overexpression of Bcl-3 (Bcl-3Hep) were exposed to diethylnitrosamine (DEN) and phenobarbital (PB). Hepatic Bcl-3 overexpression attenuated DEN/PB-induced hepatocarcinogenesis. Bcl-3Hep mice exhibited a lower number and smaller tumor nodules in response to DEN/PB at 40 weeks of age. Reduced HCC formation was accompanied by a lower rate of cell proliferation and a distinct expression pattern of growth and differentiation-related genes. Activation of c-Jun N-terminal kinase (JNK) and especially extracellular-signal regulated kinase (ERK) was reduced in tumor and tumor-surrounding liver tissue of Bcl-3Hep mice, while p38 and NF-kappaB p65 were phosphorylated to a higher extent compared to the wild type. In parallel, the absolute number of intrahepatic macrophages, CD8+ T cells and activated B cells was reduced in DEN/PB-treated Bcl 3Hep mice mirroring a reduction of tumor-associated inflammation. Interestingly, at the early time point of 7 weeks following tumor initiation, a higher rate of apoptotic cell death was observed in Bcl-3Hep mice. In summary, hepatocyte restricted Bcl-3 overexpression reduced hepatocarcinogenesis related to prolonged liver injury early after tumor initiation likely due to decreased survival of DEN/PB-damaged, premalignant cells. Therefore, Bcl-3 could become a novel player in the development of therapeutic and diagnostic tools for HCC. PMID- 28915577 TI - Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha. AB - Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-alpha expression, absent HIF-alpha association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic. PMID- 28915578 TI - Targeting hypoxic cancer stem cells (CSCs) with Doxycycline: Implications for optimizing anti-angiogenic therapy. AB - Here, we report new mechanistic insight into how chronic hypoxia increases 'stemness' in cancer cells. Using chemical inhibitors, we provide direct experimental evidence that ROS production and mitochondrial biogenesis are both required for the hypoxia-induced propagation of CSCs. More specifically, we show that hypoxic CSCs can be effectively targeted with i) simple mitochondrial anti oxidants (Mito-TEMPO) and/or ii) inhibitors of mitochondrial biogenesis (Doxycycline). In this context, we discuss the idea that mitochondrial biogenesis itself may be a primary driver of "stemness" in hypoxic cancer cells, with metabolic links to fatty acid oxidation (FAO). As Doxycycline is an FDA-approved drug, we propose that it could be re-purposed to target hypoxic CSCs, either alone or in combination with chemotherapy, i.e., Paclitaxel. For example, we demonstrate that Doxycycline effectively targets the sub-population of hypoxia induced CSCs that are Paclitaxel-resistant, overcoming hypoxia-induced drug resistance. Finally, anti-angiogenic therapy often induces tumor hypoxia, allowing CSCs to survive and propagate, ultimately driving tumor progression. Therefore, we suggest that Doxycycline could be used in combination with anti angiogenic agents, to actively prevent or minimize hypoxia-induced treatment failure. In direct support of this assertion, Paclitaxel is already known to behave as an angiogenesis inhibitor. PMID- 28915580 TI - Molecular and functional characterization of a new 3' end KIT juxtamembrane deletion in a duodenal GIST treated with neoadjuvant Imatinib. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express the receptor tyrosine kinase KIT, and the majority of GISTs present KIT gain-of-function mutations that cluster in the 5' end of the receptor juxtamembrane domain. On the other hand, little information is known about GISTs carrying mutations in the 3' end of the KIT juxtamembrane domain. Here we report and discuss a clinical case of localized duodenal GIST whose molecular characterization revealed the presence of a new 21 nucleotide/7 amino acid deletion in the 3' end of KIT juxtamembrane domain (Delta574-580). The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well as the original tumor mass reduced, ultimately allowing conservative surgery. In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Delta574-580 mutation displays constitutive phosphorylation, which can be switched-off upon Imatinib treatment. In addition, results from this study showed that a clinical useful procedure, neoadjuvant treatment, can occasionally be of value for the understanding of the molecular pathogenesis of GIST. PMID- 28915579 TI - MicroRNA profiling associated with non-small cell lung cancer: next generation sequencing detection, experimental validation, and prognostic value. AB - BACKGROUND: The average five-year survival for non-small cell lung cancer (NSCLC) patients is approximately 15%. Emerging evidence indicates that microRNAs (miRNAs) constitute a new class of gene regulators in humans that may play an important role in tumorigenesis. Hence, there is growing interest in studying their role as possible new biomarkers whose expression is aberrant in cancer. Therefore, in this study we identified dysregulated miRNAs by next generation sequencing (NGS) and analyzed their prognostic value. METHODS: Sequencing by oligo ligation detection technology was used to identify dysregulated miRNAs in a training cohort comprising paired tumor/normal tissue samples (N = 32). We validated 22 randomly selected differentially-expressed miRNAs by quantitative real time PCR in tumor and adjacent normal tissue samples (N = 178). Kaplan-Meier survival analysis and Cox regression were used in multivariate analysis to identify independent prognostic biomarkers. RESULTS: NGS analysis revealed that 39 miRNAs were dysregulated in NSCLC: 28 were upregulated and 11 were downregulated. Twenty-two miRNAs were validated in an independent cohort. Interestingly, the group of patients with high expression of both miRNAs (miR 21high and miR-188high) showed shorter relapse-free survival (RFS) and overall survival (OS) times. Multivariate analysis confirmed that this combined signature is an independent prognostic marker for RFS and OS (p = 0.001 and p < 0.0001, respectively). CONCLUSIONS: NGS technology can specifically identify dysregulated miRNA profiles in resectable NSCLC samples. MiR-21 or miR-188 overexpression correlated with a negative prognosis, and their combined signature may represent a new independent prognostic biomarker for RFS and OS. PMID- 28915581 TI - Up-regulation of LINC00161 correlates with tumor migration and invasion and poor prognosis of patients with hepatocellular carcinoma. AB - Accumulating evidence suggested that long non-coding RNAs (lncRNAs) play essential roles in various biological processes, including tumorigenesis. Aberrant expression of LINC00161 has been reported in some cancer types, however, the association of LINC00161 and hepatocellular carcinoma (HCC) has not been evaluated. Here, we measured the expression of LINC00161 in HCC tissues and corresponding normal liver tissues using real-time PCR. The result showed that the expression level of LINC00161 was significantly higher in HCC tissues. Further analysis indicated that HCC patients with higher LINC00161 expression have shorter survival. Multivariate Cox regression analysis showed that LINC00161 expression was an independent prognostic factor for the overall survival. Furthermore, our result indicated that knock-down of LINC00161 can significantly inhibit liver cancer cell migration and invasion. The present work indicated that LINC00161 might serve as an oncogenic gene and play a pivotal role in promoting tumor migration and invasion in HCC. Our work implicates the promising effect of LINC00161 on the prognosis of HCC. PMID- 28915582 TI - MicroRNA-610 suppresses osteosarcoma oncogenicity via targeting TWIST1 expression. AB - Osteosarcoma is the most frequent primary bone tumor affects adolescents and young adults. Recently, microRNAs (miRNAs) are short, non-coding and endogenous RNAs that played as important roles in the initiation and progression of tumors. In this study, we try to explore the biological function and expression of miR 610 in the osteosarcoma. We showed that miR-610 expression was downregulated in the osteosarcoma tissues and cell lines. Elevated expression of miR-610 suppressed the osteosarcoma cell proliferation, cell cycle, invasion and EMT program. Moreover, overexpression of miR-610 increased sensitivity of MG-63 and U2OS cells to cisplatin. Twist1 was identified as a direct target gene of miR-610 in the osteosarcoma cell. Furthermore, we demonstrated that Twist1 was upregulated in the osteosarcoma tissues and cell lines. The expression of Twist1 was negatively associated with the expression of miR-610 expression in the osteosarcoma tissues. Ectopic expression of Twist1 inhibited the sensitivity of miR-610-overexpressing MG-63 cells to cisplatin. We also showed that overexpression of Twist1 increased the proliferation and invasion of miR-610 overexpressing MG-63 cells. These data indicated that ectopic expression of miR 610 suppressed the osteosarcoma cell proliferation, cell cylce, invasion and increased the sensitivity of osteosarcoma cells to cisplatin through targeting the Twist1 expression. PMID- 28915583 TI - N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F FDG PET imaging. AB - Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2 accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2 accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4. PMID- 28915584 TI - A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors. AB - Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose limiting toxicities pose limitations to treatment. Abexinostat, an oral pan histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade >=3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade >=3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions. PMID- 28915585 TI - Time dependent modulation of tumor radiosensitivity by a pan HDAC inhibitor: abexinostat. AB - Despite prominent role of radiotherapy in lung cancer management, there is an urgent need for strategies increasing therapeutic efficacy. Reversible epigenetic changes are promising targets for combination strategies using HDAC inhibitors (HDACi). Here we evaluated on two NSCLC cell lines, the antitumor effect of abexinostat, a novel pan HDACi combined with irradiation in vitro in normoxia and hypoxia, by clonogenic assays, demonstrating that abexinostat enhances radiosensitivity in a time dependent way with mean SER10 between 1.6 and 2.5 for A549 and H460. We found, by immunofluorescence staining, flow cytometry assays and western blotting, in abexinostat treated cells, increasing radio-induced caspase dependent apoptosis and persistent DNA double-strand breaks associated with decreased DNA damage signalling and repair. Interestingly, we demonstrated on nude mice xenografts that abexinostat potentiates tumor growth delay in combined modality treatments associating not only abexinostat and irradiation but also when adding cisplatin. Altogether, our data demonstrate in vitro and in vivo anti-tumor effect potentiation by abexinostat combined with irradiation in NSCLC. Moreover, our work suggests for the first time to our knowledge promising triple combination opportunities with HDACi, irradiation and cisplatin which deserves further investigations and could be of major interest in the treatment of NSCLC. PMID- 28915587 TI - Expression and release of glucose-regulated protein-78 (GRP78) in multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses. RESULTS: GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM. In bone marrow plasma, the amount of released GRP78 protein was not significantly increased between MGUS-, NDMM- and RRMM patients. MM cells of the three cell lines release GRP78 as full-length protein under apoptotic, but not under acidotic or ER-stress conditions. In necrosis, only proteolytic fragments of GRP78 were detected in supernatants of MM cells. MATERIALS AND METHODS: GRP78 protein expression and plasma levels were quantified in bone marrow aspirates of patients with monoclonal gammopathy of undetermined significance (MGUS, n = 29), newly diagnosed MM (NDMM, n = 29) and with relapsed/refractory MM (RRMM, n = 15) by immunohistochemistry and sandwich ELISA. The human MM cell lines U266, NCI-H929 and OPM-2 were used for functional GRP78 release- and processing studies after induction of acidosis, ER stress, apoptosis and necrosis. CONCLUSIONS: Ectopic expression of GRP78 on cell membrane or its release in the microenvironment is not a suitable marker to distinguish MGUS from NDMM and RRMM. PMID- 28915586 TI - Hepatitis C virus core protein targets 4E-BP1 expression and phosphorylation and potentiates Myc-induced liver carcinogenesis in transgenic mice. AB - Hepatitis C virus (HCV) is a leading cause of liver diseases including the development of hepatocellular carcinoma (HCC). Particularly, core protein has been involved in HCV-related liver pathologies. However, the impact of HCV core on signaling pathways supporting the genesis of HCC remains largely elusive. To decipher the host cell signaling pathways involved in the oncogenic potential of HCV core, a global quantitative phosphoproteomic approach was carried out. This study shed light on novel differentially phosphorylated proteins, in particular several components involved in translation. Among the eukaryotic initiation factors that govern the translational machinery, 4E-BP1 represents a master regulator of protein synthesis that is associated with the development and progression of cancers due to its ability to increase protein expression of oncogenic pathways. Enhanced levels of 4E-BP1 in non-modified and phosphorylated forms were validated in human hepatoma cells and in mouse primary hepatocytes expressing HCV core, in the livers of HCV core transgenic mice as well as in HCV infected human primary hepatocytes. The contribution of HCV core in carcinogenesis and the status of 4E-BP1 expression and phosphorylation were studied in HCV core/Myc double transgenic mice. HCV core increased the levels of 4E-BP1 expression and phosphorylation and significantly accelerated the onset of Myc-induced tumorigenesis in these double transgenic mice. These results reveal a novel function of HCV core in liver carcinogenesis potentiation. They position 4E BP1 as a tumor-specific target of HCV core and support the involvement of the 4E BP1/eIF4E axis in hepatocarcinogenesis. PMID- 28915588 TI - FoxR2 promotes glioma proliferation by suppression of the p27 pathway. AB - FoxR2 plays an important role in the development of many human tumors. However, the effects of FoxR2 on tumorigenicity of human glioma remain unclear. In this study, we investigated the roles of FoxR2 in cell proliferation and invasion of glioma. We found that overexpression of FoxR2 promoted the proliferation, migration and invasion of glioma cells. Knockout of FoxR2 induced G1 arrest by decreasing the expression levels of cyclin D1, cyclin E and p-Rb. Mechanistically, upregulation of FoxR2 increased the level and activity of MMP-2 and decreased the expression of p27. Furthermore, overexpression of FoxR2 decreased the nuclear accumulation of p27. Taken together, these results indicate that upregulation of FoxR2 may confer enhanced tumorigenicity in glioma cells. PMID- 28915589 TI - Casticin attenuates liver fibrosis and hepatic stellate cell activation by blocking TGF-beta/Smad signaling pathway. AB - Although many advances have been made in understanding the pathogenesis of liver fibrosis, few options are available for treatment. Casticin, one of the major flavonoids in Fructus Viticis extracts, has shown hepatoprotective potential, but its effects on liver fibrosis are not clear. In this study, we investigated the antifibrotic activity of casticin and its underlying mechanism in vivo and in vitro. Male mice were injected intraperitoneally with carbon tetrachloride (CCl4) or underwent bile duct ligation (BDL) to induce liver fibrosis, followed by treatment with casticin or vehicle. In addition, transforming growth factor beta1(TGF-beta1)-activated LX-2 cells were used. In vivo experiments showed that treatment with casticin alone had no toxic effect while significantly attenuating CCl4-or BDL-induced liver fibrosis, as indicated by reductions in the density of fibrosis, hydroxyproline content, expression of alpha-SMA and collagen alpha1(I) mRNA. Moreover, casticin inhibited LX2 proliferation, induced apoptosis in a time and dose-dependent manner in vitro. The underlying molecular mechanisms for the effect of casticin involved inhibition of hepatic stellate cell (HSC) activation and reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 resulting from blocking TGF beta1/Smad signaling, as well as increased the apoptosis of HSCs. The results suggest that casticin has potential benefits in the attenuation and treatment of liver fibrosis. PMID- 28915590 TI - Combination of DESI2 and IP10 gene therapy significantly improves therapeutic efficacy against murine carcinoma. AB - DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex. We found that, in vitro, the combination of DESI2 and IP10 more efficiently inhibited proliferation of CT26, LL2, SKOV3 and A549 cancer cells via apoptosis. In vivo, the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice. Mechanistically, the augmented antitumor activity in vivo was associated with induction of apoptosis and inhibition of angiogenesis. The anti-angiogenesis was further mimicked by inhibiting proliferation of immortalized HUVEC cells in vitro. Meanwhile, the infiltration of lymphocytes also contributed to the enhanced antitumor effects. Depletion of CD8+ T lymphocytes significantly abrogated the antitumor activity, whereas depletion of CD4+ T cells or NK cells showed partial abrogation. Our data suggest that the combined gene therapy of DESI2 and IP10 can significantly enhance the antitumor activity as apoptosis inducer, angiogenesis inhibitor and immune response initiator. The present study may provide a novel and effective method for treating cancer. PMID- 28915591 TI - Eugenol alleviated breast precancerous lesions through HER2/PI3K-AKT pathway induced cell apoptosis and S-phase arrest. AB - Eugenol can be separated from the oil extract of clove bud, and has many pharmacological functions such as anticancer and transdermal absorption. HER2/PI3K-AKT is a key signaling pathway in the development of breast cancer. In this study, 80 MUM eugenol could significantly inhibit the proliferation of HER-2 positive MCF-10AT cells and the inhibition rate was up to 32.8%, but had no obvious inhibitory effect on MCF-7 and MCF-10A cells with HER2 weak expression. Eugenol also significantly induced human breast precancerous lesion MCF-10AT cell apoptosis and cell cycle S-phase arrest, but the biological effects nearly disappeared after HER2 over-expression through transfecting pcDNA3.1-HER2. In MCF 10AT cells treated by 180 MUM eugenol, the protein expressions of HER2, AKT, PDK1, p85, Bcl2, NF-kappaB, Bad and Cyclin D1 were decreased and the decreased rates were respectively 63.0%, 60.0%, 52.9%, 62.9%, 37.1%, 47.2%, 61.7%, 59.1%, while the p21, p27 and Bax expression were increased by 4.48-, 4.76- and 2.57 fold respectively. In the rat models of breast precancerous lesion, 1 mg eugenol for external use significantly inhibited the progress of breast precancerous lesion and the occurrence rate of breast precancerous lesions and invasive carcinomas was decreased by about 30.5%. Furthermore eugenol for external (1 mg) markedly decreased the protein expressions of HER2 (62.9%), AKT (58.6%), PDK1 (56.4%), p85 (54.3%), Bcl2 (59.3%), NF-kappaB (65.7%), Bad (64.0%), Cyclin D1 (43.0%), while p21, p27 and Bax protein expressions were respectively increased 1.83-, 2.52- and 2.51-fold. The results showed eugenol could significantly inhibit the development of breast precancerous lesions by blocking HER2/PI3K-AKT signaling network. So eugenol may be a promising external drug for breast precancerous lesions. PMID- 28915592 TI - Targeted alpha therapy using a novel CD70 targeted thorium-227 conjugate in in vitro and in vivo models of renal cell carcinoma. AB - The cell surface receptor CD70 has been previously reported as a promising target for B-cell lymphomas and several solid cancers including renal cell carcinoma. We describe herein the characterization and efficacy of a novel CD70 targeted thorium-227 conjugate (CD70-TTC) comprising the combination of the three components, a CD70 targeting antibody, a chelator moiety and the short-range, high-energy alpha-emitting radionuclide thorium-227 (227Th). In vitro analysis demonstrated that the CD70-TTC retained binding affinity to its target and displayed potent and specific cytotoxicity compared to an isotype control-TTC. A biodistribution study in subcutaneous tumor-bearing nude mice using the human renal cell carcinoma cell line 786-O demonstrated significant uptake and retention with 122 +/- 42% of the injected dose of 227Th per gram (% ID/g) remaining in the tumor seven days post dose administration compared to only 3% ID/g for the isotype control-TTC. Tumor accumulation correlated with a dose dependent and statistically significant inhibition in tumor growth compared to vehicle and isotype control-TTC groups at radioactivity doses as low as 50 kBq/kg. The CD70-TTC was well tolerated as evidenced by only modest changes in hematology and normal gain in body weight of the mice. To our knowledge, this is the first report describing molecular targeting of CD70 expressing tumors using a targeted alpha-therapy (TAT). PMID- 28915593 TI - A novel EGFR-TKI inhibitor (cAMP-H3BO3complex) combined with thermal therapy is a promising strategy to improve lung cancer treatment outcomes. AB - PURPOSE: Although EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) induce favorable responses as first-line non-small cell lung cancer treatments, drug resistance remains a serious problem. Meanwhile, thermal therapy also shows promise as a cancer therapy strategy. Here we combine a novel EGFR-TKI treatment with thermal therapy to improve lung cancer treatment outcomes. RESULTS: The results suggest that the cAMP-H3BO3 complex effectively inhibits EGFR auto-phosphorylation, while inducing apoptosis and cell cycle arrest in vitro. Compared to the negative control, tumor growth was significantly suppressed in mice treated with oxidative phosphorylation uncoupler thyroxine sodium and either cAMP-H3BO3 complex or cAMP-H3BO3 complex (P < 0.05). Moreover, the body temperature increase induced by treatment with thyroxine sodium inhibited tumor growth. Immunohistochemical analyses showed that A549 cell apoptosis was significantly higher in the cAMP-H3BO3 complex plus thyroxine sodium treatment group than in the other groups. Moreover,Ca2+ content analysis showed that the Ca2+ content of tumor tissue was significantly higher in the cAMP H3BO3 complex plus thyroxine sodium treatment group than in other groups. MATERIALS AND METHODS: Inhibition of EGFR auto-phosphorylation by cAMP and cAMP H3BO3 complex was studied using autoradiography and western blot. The antitumor activity of the novel EGFR inhibitor (cAMP-H3BO3 complex) with or without an oxidative phosphorylation uncoupler (thyroxine sodium) was investigated in vitro and in a nude mouse xenograft lung cancer model incorporating human A549 cells. CONCLUSIONS: cAMP-H3BO3 complex is a novel EGFR-TKI. Combination therapy using cAMP-H3BO3 with thyroxine sodium-induced thermal therapy may improve lung cancer treatment outcomes. PMID- 28915594 TI - Identification of precision treatment strategies for relapsed/refractory multiple myeloma by functional drug sensitivity testing. AB - Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4;14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM. PMID- 28915595 TI - Baicalein inhibits pancreatic cancer cell proliferation and invasion via suppression of NEDD9 expression and its downstream Akt and ERK signaling pathways. AB - Baicalein, a flavone ingredient of Scutellaria baicalensis Georgi, is a promising anti-cancer agent. However, its potential anti-pancreatic cancer effects and the underlying mechanisms are still unclear. In this study, we showed that Baicalein not only induced apoptosis, but also suppressed proliferation, migration and invasion of two pancreatic cancer cell lines BxPC-3 and PANC-1 in a dose- and time-dependent manner. Notably, Baicalein exhibited low toxicity to normal human liver or kidney cells. We further discovered that Baicalein suppressed BxPC-3 and PANC-1 cell proliferation and invasion through targeting the expression of NEDD9, a Cas scaffolding protein, to decrease Akt and ERK activities. Especially, Baicalein decreased Akt phosphorylation at T-308 via lowering NEDD9-dependent PDK1 expression. Overexpression of NEDD9 effectively rescued proliferation and invasion of BxPC-3 and PANC-1 cells dampened by Baicalein. Taken together, our findings suggest that Baicalein is a potent remedy applied to pancreatic cancer treatment in the future. PMID- 28915596 TI - Androgen receptor expression identifies patient with favorable outcome in operable triple negative breast cancer. AB - In this study we sought to investigate the prevalence and prognostic value of androgen receptor (AR) status in operable triple-negative breast cancer (TNBC) patients. We collected the clinical data of 360 patients with TNBC, and found a positivity AR expression of 31.4% with a cut-off value of 10%. Tumors expressing the negative CK5/6 (P=0.013) and low Ki-67 (P=0.007) are more likely to have positive AR. In multivariate survival analysis, AR expression is correlated with increased DFS (HR=0.467, 95%CI 0.271-0.805; P=0.006) and OS (HR=0.488, 95%CI 0.267-0.894, P=0.020) independently. In addition, patients with AR+ tumors are more likely to have favorable outcome in patients with young, pre-menopausal, large tumor size, more node involvement (4+), high stage, high grade, vascular invasion+, P53+, CK5/6-, and higher Ki-67. Our study has indicated that the absence of AR might help to identify patients with relatively higher risk of disease relapse and death, and further clinical studies of anti-androgen agents are warranted to enrich the therapeutic strategy options for AR+ TNBCs. PMID- 28915597 TI - IL-8 promotes inflammatory mediators and stimulates activation of p38 MAPK/ERK-NF kappaB pathway and reduction of JNK in HNSCC. AB - This investigation identifies interleukin 8 (IL-8) as the main inflammatory mediator in head and neck squamous cell carcinoma (HNSCC). The expressions of chemokines of IL-8, IL-1beta and IL-6 and the cytokines of tumor necrosis factor alpha (TNF-alpha) were higher in HNSCC patient tissues than in non-cancerous matched tissues (NCMT) whereas the expression of IL-10 was lower. IL-8 is most highly expressed in the tissues of patients with HNSCC. Treatment of HNSCC cells with IL-8 increased the secretion of IL-1beta, IL-6 and TNF-alpha and reduced IL 10 expression; the increase in the expression of IL-1beta was particularly considerable. IL-8 silencing by siRNA reduced IL-1beta expression in HNSCC cells, suggesting that IL-8 as a main inflammatory mediator improved IL-1beta expression in HNSCC. The expressions of p-p38 mitogen-activated protein kinases (MAPK) and p extracellular signal regulated kinase (p-ERK) were higher and that of p-c-Jun-NH2 terminal kinase (p-JNK) was lower in HNSCC patient tissues than in NCMT. IL-8 treatment induced p-p38 MAPK and p-ERK expression, but reduced p-JNK expressions in HNSCC cells. IL-8 siRNA suppressed p38 MAPK and ERK but increased JNK expression in HNSCC cells. Exposure of SCC25 cells to IL-8, increased the expressions of p-IkappaB-alpha and nuclear factor (NF)-kappaB, suggesting that IL 8 regulates inflammatory response by modulating the MAPK and NF-kappaB pathway in HNSCC cells. IL-8 promotes the migration of SCC25 cells and increases matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. These results reveal that IL-8 is the major stimulus of inflammatory mediation in HNSCC progression and migration by activating the p38 MAPK/ERK-NF-kappaB pathway and reducing JNK. PMID- 28915598 TI - Urine miR-21-5p as a potential non-invasive biomarker for gastric cancer. AB - Many reports have implicated that microRNAs involve in cancer development and progression, such as miR-155 in breast cancers and miR-196 in gastric cancers. Furthermore, microRNAs are more stable than typical protein-coding gene mRNAs in varieties of clinical samples including body fluids. This suggests that they are potentially valuable biomarkers for cancer monitoring. In this study, we have used urine samples of gastric cancer patients to demonstrate the feasibility of urine microRNAs for gastric cancer detection. Urine samples of gastric cancer patients were extracted for total RNA, which were examined for the expression of miR-21-5p using quantitative stem-loop PCR. Our results demonstrated that miR-21 5p could be detected in small amounts of urine samples with good stability, and the expression levels of miR-21-5p were reduced following surgical removal of gastric cancer tissues. These results implicate that urine miR-21-5p could be utilized as a novel non-invasive biomarker of gastric cancer detection and monitoring. PMID- 28915599 TI - Copy number variations of circulating, cell-free DNA in urothelial carcinoma of the bladder patients treated with radical cystectomy: a prospective study. AB - The aim of the present study was to establish a rapid profiling method using multiplex ligation-dependent probe amplification (MLPA) and characterize copy number variations (CNV) in circulating, cell-free DNA (cfDNA) in 85 urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MLPA was tested for the use of cfDNA extracted from serum and plasma by various commercial extraction kits. Eighteen probes served as reference to control denaturation, ligation and amplification efficiency. MLPA was exclusively suitable for cfDNA extracted from serum. Serum from 72 patients (84.7%) could be analyzed. Thirty-five patients (48.6%) had presence of CNV in cfDNA. The median CNV count in patients with presence of CNV was 2. Predominantly, CNV were located in the genes CDH1, ZFHX3, RIPK2 and PTEN in 15 patients (20.8%), 12 patients (16.7%), 9 patients (12.5%) and 7 patients (9.7%), respectively. CNV in TSG1, RAD21, KIAA0196, ANXA7 and TMPRSS2 were associated with presence of variant UCB histology (p = 0.029, 0.029, 0.029, 0.029, 0.043, respectively). Furthermore, CNV in miR-15a, CDH1 and ZFHX3 were associated with presence of incidental prostate cancer (p = 0.023, 0.003, 0.025, respectively). Patients with CNV in KLF5, ZFHX3 and CDH1 had reduced cancer-specific survival, compared to patients without CNV in these genes (pairwise p = 0.028, 0.026, 0.044, respectively). MLPA represents an efficient method for the detection of CNV among numerous genes on various chromosomal regions. CNV in specific genes seem to be associated with aggressive UCB biologic features and presence of incidental prostate cancer, and may have a negative impact on cancer-specific survival. PMID- 28915600 TI - Tumor vasculogenic mimicry formation as an unfavorable prognostic indicator in patients with breast cancer. AB - Vasculogenic mimicry (VM), a newly defined pattern of tumor blood perfusion, describes the functional plasticity of aggressive tumor cells forming de novo vascular networks and is associated with the cancer progression and metastasis. However, the VM-positive rate and the impact of VM status on breast cancer patients' clinicopathological parameters and prognosis remain unclear. Thus, we performed a meta-analysis by incorporating all available evidence to clarify these issues. Eight studies that involved 1,238 breast cancer patients were eligible for inclusion in our study. We found the VM-positive rate was 24% (pooled proportion was 0.24, 95% CI= 0.13-0.34), and VM was significantly associated with larger tumor size (>2 cm) (OR=0.49, 95% CI=0.26-0.90, P=0.02) and lymph node metastasis (OR=0.27, 95% CI=0.13-0.57, P=0.0005). A boardline correlation was also identified between VM and poorer differentiation (Grade II III) (OR=0.07, 95% CI=0.00-1.24, P=0.07). Nevertheless, no statistically significant associations were observed between VM and hormone receptor and human epidermal growth factor receptor 2 status. Moreover, the results showed that breast cancer patients with VM-positive have a shorter overall survival than those with VM-negative (HR=0.23, 95% CI=0.08-0.38,P=0.003). In summary, VM was associated with more aggressive tumor phenotype and poor prognosis in patients with breast cancer. Developing strategies against the VM formation would be a promising therapeutic approach to breast cancer. PMID- 28915601 TI - MiR-148a impairs Ras/ERK signaling in B lymphocytes by targeting SOS proteins. AB - Although microRNAs have been recognized as central cellular regulators, there is an evident lack of knowledge about their targets. Here, we analyzed potential target genes for miR-148a functioning in Ras signaling in B cells, including SOS1 and SOS2. A dual-luciferase reporter assay showed significantly decreased luciferase activity upon ectopic overexpression of miR-148a in HEK-293T cells that were co-transfected with the 3'UTR of either SOS1 or SOS2. Each of the 3'UTRs of SOS1 and SOS2 contained two binding sites for miR-148a both of which were necessary for the decreased luciferase activity. MiR-148a overexpression in HEK-293T lead to significantly reduced levels of both endogenous SOS1 and SOS2 proteins. Likewise, reduced levels of SOS proteins were found in two B cell lines that were transfected with miR-148a. The level of ERK1/2 phosphorylation as one of the most relevant downstream members of the Ras/ERK signaling pathway was also reduced in cells with miR-148a overexpression. The data show that miR-148a impairs the Ras/ERK signaling pathway via SOS1 and SOS2 proteins in B cells. PMID- 28915602 TI - Increased expression of calponin 2 is a positive prognostic factor in pancreatic ductal adenocarcinoma. AB - Calponin 2 plays an important role in regulating actin cytoskeleton, which is critical for cell division and migration. Previous studies have demonstrated that calponin 2 inhibits prostate cancer cell proliferation and metastasis. However, the role of calponin 2 in pancreatic tumor growth, metastasis and patient survival remains unclear. Here, we demonstrate that the level of calponin 2 is a positive prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC). Patients with high calponin 2 expression in the tumor presented less lymph node metastasis and longer survival. Knockdown of calponin 2 facilitated pancreatic cancer cell proliferation and metastasis. Further experiments suggested that PI3K/AKT, NF-kappaB, Vimentin, Fibronectin, Snail and Slug were upregulated and E-cadherin was downregulated after calponin 2 was knocked down, implicating altered functions in PDAC proliferation and metastasis. In addition, we verified that calponin 2 functioned through inhibiting PI3K/AKT and NF-kappaB pathways. Our study suggests that the upregulation of calponin 2 in PDAC correlates to lower malignancy and presents a novel target for the development of new treatment. PMID- 28915603 TI - Estrogen promotes tumor metastasis via estrogen receptor beta-mediated regulation of matrix-metalloproteinase-2 in non-small cell lung cancer. AB - In non-small cell lung cancer (NSCLC), estrogen significantly promotes NSCLC cell growth via estrogen receptor beta (ERbeta). However, the effects by which ERbeta contributes to metastasis in NSCLC have not been previously reported. This study aims at defining whether the stimulation of ERbeta promotes NSCLC metastasis in vitro and in vivo. Here, Our results showed that estrogen and ERbeta agonist enhanced aggressiveness of two lung cancer cell lines (A549 and H1793) and promoted murine lung metastasis formation. ER-inhibitor Fulvestrant treatment or ERbeta-knockdown significantly suppressed the migration, invasion and nodule formation of NSCLC cells. The expression level of ERbeta protein was analyzed in matched samples of metastatic lymph node and primary tumor tissues from the same individuals, and we found significantly higher levels of ERbeta were expressed in lymph node compared to primary tumor tissues. Moreover, Studies on both surgical biopsies and on lung cancer cells revealed that the expression level of ERbeta and matrix-metalloproteinase-2 (MMP-2) were associated. Furthermore, inhibition of ERbeta resulted in down-regulation of MMP-2 expression. Taken together, our results demonstrate that activation of ERbeta in lung cancer cells promotes tumor metastasis through increasing expression of invasiveness-associated MMP-2. These results also highlight the therapeutic potential of inhibition of ERbetain the treatment of advanced NSCLC. PMID- 28915604 TI - Overexpression of a functional calcium-sensing receptor dramatically increases osteolytic potential of MDA-MB-231 cells in a mouse model of bone metastasis through epiregulin-mediated osteoprotegerin downregulation. AB - INTRODUCTION AND AIMS: Osteolytic bone metastases are observed in advanced cases of breast cancer. In vitro data suggest that the activity of the calcium-sensing receptor (CaSR) expressed by metastatic cells could potentiate their osteolytic potential. This study aimed to demonstrate in vivo the involvement of the CaSR in breast cancer cells osteolytic potential and to identify potential targets linked to CaSR activity. METHODS AND RESULTS: MDA-MB-231 stably transfected with plasmids containing either a full-length wild-type CaSR (CaSR-WT), or a functionally inactive dominant negative mutant (CaSR-DN) or an empty vector (EV) were intratibially injected into Balb/c-Nude mice. X-ray analysis performed 19 days after injection showed a dramatic increase of osteolytic lesions in mice injected with CaSR-WT-transfected cells as compared to mice injected with EV- or CaSR-DN-transfected cells. This was associated with decreased BV/TV ratio and increased tumor burden. Epiregulin, an EGF-like ligand, was identified by a DNA microarray as a possible candidate involved in CaSR-mediated osteolysis. Indeed, in vitro, CaSR overexpression increased both epiregulin expression and secretion as compared to EV- or CaSR-DN-transfected cells. Increased epiregulin expression was also detected in osteolytic bone lesions from mice injected with CaSR-WT transfected MDA-MB-231. In vitro, exposure of osteoblastic cells (HOB and SaOS2) to exogenous epiregulin significantly decreased OPG mRNA expression. Exposure of osteoblastic cells to conditioned media prepared from CaSR-WT-transfected cells also decreased OPG expression. This effect was partially blocked after addition of an anti-epiregulin antibody. CONCLUSIONS: Overexpression of a functional CaSR in metastatic breast cancer cells dramatically amplifies their osteolytic potential through epiregulin-mediated OPG downregulation. PMID- 28915605 TI - HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance. AB - Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17 demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities. PMID- 28915606 TI - Proteolytic cleavages in the extracellular domain of receptor tyrosine kinases by membrane-associated serine proteases. AB - The epithelial extracellular membrane-associated serine proteases matriptase, hepsin, and prostasin are proteolytic modifying enzymes of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR). Matriptase also cleaves the ECD of the vascular endothelial growth factor receptor 2 (VEGFR2) and the angiopoietin receptor Tie2. In this study we tested the hypothesis that these serine proteases may cleave the ECD of additional receptor tyrosine kinases (RTKs). We co-expressed the proteases in an epithelial cell line with Her2, Her3, Her4, insulin receptor (INSR), insulin-like growth factor I receptor (IGF-1R), the platelet-derived growth factor receptors (PDGFRs) alpha and beta, or nerve growth factor receptor A (TrkA). Western blot analysis was performed to detect the carboxyl-terminal fragments (CTFs) of the RTKs. Matriptase and hepsin were found to cleave the ECD of all RTKs tested, while TMPRSS6/matriptase-2 cleaves the ECD of Her4, INSR, and PDGFR alpha and beta. Prostasin was able to cleave the ECD of Her3 and PDGFRalpha. Matriptase cleaves phosphorylated Her2 at Arg558 and Arg599 and the Arg599 cleavage produces a CTF not recognized by the monoclonal antibody trastuzumab/Herceptin. Her2 cleavages by matriptase can be inhibited by the hepatocyte growth factor activator inhibitor 1 (HAI-1) in the MDA-MB-231 human breast cancer cells. Matriptase silencing in the Her2, matriptase, and HAI 1 triple-positive SKBR3 human breast cancer cells enhanced Her2 protein down regulation induced by a sustained exposure to phorbol 12-myristate 13-acetate (PMA), which down-regulated matriptase protein. The novel Her2 cleavage and expression regulation mechanisms mediated by matriptase may have potential impacts in Her2-targeting therapies. PMID- 28915607 TI - Coal tar pitch extract could induce chromosomal instability of human bronchial epithelial cells mediated by spindle checkpoint-related proteins. AB - Coal tar pitch (CTP) is a byproduct of coal tar distillation. The workers working with coal tar or in aluminum smelters, potrooms and carbon plants have the opportunities of exposing to coal tar pitch volatiles. Coal tar pitches from which polycyclic aromatic hydrocarbons (PAHs) originate have been shown to exhibit lung carcinogenicity in humans. Chromosomal instability (CIN) is a mechanism in carcinogenesis, however, whether CIN is involved in coal tar pitch induced lung cancer remains elusive. In this present study, human bronchial epithelial cells (BEAS-2B) were first exposed to coal tar pitch extracts (CTPE) to induce a malignant transformation model. Then, the occurrence of severe chromosomal changes detected using G band, R band and multiplex fluorescence in situ hybridization (M-FISH) staining were examined. It was shown that more clones of transformed BEAS-2B cells at passage 30 following stimulation with CTPE were formed in the soft agar compared with the vehicle control. Moreover, the expression of the spindle checkpoint-related proteins, mitotic arrest defective 2 (Mad2), budding uninhibited in benzimidazole 1 (Bub1), and anaphase-promoting complex (APC), indicators of abnormal chromosomes and carcinogenesis, reduced in CTPE-treated BEAS-2B cells at Passage 30 compared with the vehicle control using real-time PCR and immunohistochemistry. In summary, exposure of BEAS-2B cells to CTPE may induce chromosomal instability through spindle checkpoint-related proteins. PMID- 28915608 TI - A genome-wide microRNA profiling indicates miR-424-5p and miR-503-5p as regulators of ALK expression in neuroblastoma. AB - The discovery of missense mutations of ALK gene identified this receptor tyrosine kinase as a therapeutic target in neuroblastoma (NB). Moreover, a high level of ALK protein has been associated with metastatic NB cases and with a worse prognosis, suggesting that also ALK overexpression is involved in NB tumorigenesis. Since miRNAs play key roles in the regulation of gene expression we aimed at identifying those miRNAs that can regulate ALK in NB. We therefore analyzed the genome-wide expression profile of miRNAs in two sample sets of 16 NB cell lines and 22 NB samples by using miRNA microarrays. Both sample sets were then divided into two subgroups showing high (ALK+) or low/absent (ALK-) expression of ALK. Results showed a down-regulation of 30 and 23 miRNAs (p-value <0.05) in the ALK+ group in NB cell lines and samples, respectively. Validation analysis indicated that miR-424-5p and miR-503-5p, belonging to the same cluster, were differentially expressed in both NB cell lines and tumor samples. Although only miR-424-5p showed a direct binding to ALK 3'-UTR, both miRNAs led to a remarkable decreasing of ALK protein as well as to the inhibition of cell viability in ALK+ NB cell lines. In conclusion, our data indicate that both miR 424-5p and miR-503-5p are involved in regulating ALK expression in NB, either by directly targeting ALK receptor or indirectly, and may thus serve as potential therapeutic tools in ALK dependent NBs. PMID- 28915609 TI - Polymorphisms of pri-miR-219-1 are associated with the susceptibility and prognosis of non-small cell lung cancer in a Northeast Chinese population. AB - Occurrence and development of non-small cell lung cancer (NSCLC) is a complex process affected both by gene and environment. Single nucleotide polymorphisms (SNPs) in microRNAs' (miRNAs) biogenesis influenced the expression of mature miRNAs, further had an impact on risk of NSCLC. Our study focused on the correlation between rs213210, rs421446 or rs107822 polymorphisms in pri-miR-219-1 and susceptibility or prognosis of NSCLC in Chinese. A case-control study of 405 new-diagnosis patients and 405 controls was performed. Ten ml venous blood from each subject was collected for genotype test via using TaqMan allelic discrimination methodology and SPSS was performed for statistical analyses. We found that CC genotype in rs213210 (OR=3.462, 95%CI=2.222-5.394, P<0.001) compared with TT genotype and GG genotype in rs107822 (OR=3.553, 95%CI=2.329 5.419, P<0.001) compared with AA genotype showed significantly increased risk of NSCLC. Haplotype analysis showed that pri-miR-219-1 haplotype Crs213210Crs421446Grs107822 was a dangerous haplotype for lung cancer. And polymorphisms in pri-miR-219-1 have showed no relationship with overall survival of NSCLC. Overall, these findings firstly showed that rs213210 and rs107822 could be meaningful as genetic markers for lung cancer risk. PMID- 28915610 TI - MiR-451 as a new tumor marker for gastric cancer. AB - Gastric cancer is the second most common malignancy in China. However, the prognosis for gastric cancer patients remains poor. The purpose of this study was to investigate whether miR-451 was a potential prognostic biomarker for gastric cancer. Fresh tissues were immediately frozen in liquid nitrogen until use. The plasma was extracted and quantitative real-time polymerase chain reaction was performed to detect miR-451 expression. The Student's t test analysis and multivariate Cox regression analysis were performed to analyze expression of miR 451. The analysis results showed that the expression level of miR-451 was decreased expression in gastric cancer tissue. The down-regulation of miR-451 tended to be positively correlated with tumor stage, lymphatic metastasis and shorter overall survival of patients. MiR-451 may be a potential biomarker and a potential therapeutic target for the diagnoses and prognosis of gastric cancer. PMID- 28915611 TI - Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. AB - Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian , and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5 Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-kB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells. PMID- 28915612 TI - The roles of ING5 in gliomas: a good marker for tumorigenesis and a potential target for gene therapy. AB - To elucidate the anti-tumor effects and molecular mechanisms of ING5 on glioma cells, we overexpressed it in U87 cells, and examined the phenotypes and their relevant molecules. It was found that ING5 overexpression suppressed proliferation, energy metabolism, migration, invasion, and induced G2/M arrest, apoptosis, dedifferentiation, senescence, mesenchymal- epithelial transition and chemoresistance to cisplatin, MG132, paclitaxel and SAHA in U87 cells. There appeared a lower expression of N-cadherin, Twist, Slug, Zeb1, Zeb2, Snail, Ac-H3, Ac-H4, Cdc2, Cdk4 and XIAP, but a higher expression of Claudin 1, Histones 3 and 4, p21, p53, Bax, beta-catenin, PI3K, Akt, and p-Akt in ING5 transfectants. ING5 overexpression suppressed tumor growth of U87 cells in nude mice by inhibiting proliferation and inducing apoptosis. Down-regulated ING5 expression was closely linked to the tumorigenesis and histogenesis of glioma. These data indicated that ING5 expression might be considered as a good marker for the tumorigenesis and histogenesis of gliomas. It might be employed as a potential target for gene therapy of glioma. PI3K/Akt or beta-catenin/TCF-4 activation might be positively linked to chemotherapeutic resistance, mediated by ING5. PMID- 28915613 TI - Alternative promotion and suppression of metastasis by JNK2 governed by its phosphorylation. AB - Fos-related antigen 1 (Fra1) has been proposed as a gatekeeper of the mesenchymal epithelial transition to epithelial-mesenchymal transition. Here, we showed that de-phosphorylated JNK2 increased the expression of Fra1 by promoting the expression of c-Jun and Jun-B. Conversely, phosphorylated JNK2 suppressed its expression via enhancing the ubiquitination of c-Jun and Jun-B. These data provided insights into the regulatory mechanism of JNK2 on the expression of Fra1. Our study thus demonstrated that the conversion of JNK2 from its phosphorylation to de-phosphorylation status promoted the switch of breast cancer cells from mesenchymal-epithelial transition to epithelial-mesenchymal transition. PMID- 28915614 TI - Mitochondrial protein 18 (MTP18) plays a pro-apoptotic role in chemotherapy induced gastric cancer cell apoptosis. AB - One of the severe limitations of chemotherapy is the development of drug resistance. However, the mechanisms underlying chemotherapy resistance remain to be elucidated. Mitochondrial mediated apoptosis is a form of cell death induced by chemotherapy. Several chemotherapeutic agents have been shown to induce mitochondrial fission, and finally activate the apoptosis cascade in various cancer cells. Here, we report that the mitochondrial membrane protein 18 (MTP18) induced mitochondrial fragmentation in gastric cancer cells under doxorubicin (DOX) exposure. Upon over-expression of MTP18, a sub-cytotoxic dose of DOX could sensitize a significant number of cells to undergo mitochondrial fission and subsequent apoptosis. These findings suggest that MTP18 can enhance the sensitivity of gastric cancer cells to DOX. Mechanistically, we found that MTP18 enriched dynamic-related protein 1 (DRP1) accumulation in mitochondria and it was responsible for mediating DOX-induced signaling required for mitochondrial fission. Intriguingly, MTP18 expression was downregulated during DOX treatment. Thus, down-regulation of MTP18 expression could be one of the resistance factors interfering with DOX-induced apoptosis in gastric cancer cells. PMID- 28915615 TI - Expression of CD38 in myeloma bone niche: A rational basis for the use of anti CD38 immunotherapy to inhibit osteoclast formation. AB - It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies. Results indicate that only plasma cells expressed CD38 at high level within the bone niche. In addition, the flow cytometry analysis shows that CD38 was also expressed by monocytes and early osteoclast progenitors but not by osteoblasts and mature osteoclasts. Indeed, CD38 was lost during in vitro osteoclastogenesis. Consistently, we found that Daratumumab reacted with CD38 expressed on monocytes and its binding inhibited in vitro osteoclastogenesis and bone resorption activity from bone marrow total mononuclear cells of MM patients, targeting early osteoclast progenitors. The inhibitory effect was not observed from purified CD14+ cells, suggesting an indirect inhibitory effect of Daratumumab. Interestingly, all-trans retinoic acid treatment increased the inhibitory effect of Daratumumab on osteoclast formation. These observations provide a rationale for the use of an anti-CD38 antibody-based approach as treatment for multiple myeloma-induced osteoclastogenesis. PMID- 28915616 TI - TDP-43/HDAC6 axis promoted tumor progression and regulated nutrient deprivation induced autophagy in glioblastoma. AB - Glioblastoma Multiforme (GBM) is a lethal primary brain tumor with poor survival lifespan and dismal outcome. Surgical resection of GBM is greatly limited due to the biological significance of brain, giving rise to tumor relapse in GBM patients. Transactive response DNA binding protein-43 (TDP-43) is a DNA/RNA binding protein known for causing neurodegenerative diseases through post translational modification; but little is known about its involvement in cancer development. In this study, we found that nutrient deprivation in GBM cell lines elevated TDP-43 expression by a mechanism of evasion from ubiquitin-dependent proteolytic pathway, and subsequently activated the autophagy process. Exogenous overexpression of TDP-43 consistently activated autophagy and suppressed stress induced apoptosis. The inhibition of autophagy in TDP-43-overexpressing cells effectively increased the apoptotic population under nutrition shortage. Furthermore, we demonstrated that HDAC6 was involved in the activation of autophagy in TDP-43-overexpressing GBM cell lines. The treatment with SAHA, a universal HDAC inhibitor, significantly reduced TDP-43-mediated anti-apoptotic effect. Additionally, the results of immunohistochemistry showed that TDP-43 and HDAC6 collaborated in GBM-tumor lesions and negatively correlated with the relapse-free survival of GBM patients. Taken together, our results suggest that the TDP-43-HDAC6 signaling axis functions as a stress responsive pathway in GBM tumorigenesis and combats nutrient deprivation stress via activating autophagy, while inhibition of HDAC6 overpowers the pathway and provides a novel therapeutic strategy against GBM. PMID- 28915617 TI - Predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab. AB - OBJECTIVE: This study was performed to investigate the proportion as well as the predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH). RESULTS: The pCR rate in the breast, axilla and both was 44.3% (39/88), 47.7% (42/88) and 34.1% (30/88), respectively. Patients with and without pCR were similar in term of age, BMI, menstrual status, family history, treatment cycles and tumor characteristics (laterality and size of tumor). Multivariate logistic regression demonstrated that pCR was significantly associated with HR negativity (HR = 5.587, 95% CI 2.25-3.889, p < 0.001), high Ki67 index (HR = 4.130, 95% CI 1.607-10.610, p = 0.003). Further investigation found that patients with HR-negative/high Ki67 index had higher pCR rate, compared to other patients (HR = 7.583, 95% CI 2.503-22.974, p < 0.001). MATERIALS AND METHODS: 88 consecutive Chinese HER2-positive/axillary lymph node positive breast cancer patients with neodjuvant therapy regimen containing paclitaxel, carboplatin and trastuzumab were divided into two groups: pathological complete response (pCR) or non-pCR group. Clinico-pathological characteristics were compared and analyzed, and univariate and multivariate analyses were performed to detect the predictive factors of pCR. CONCLUSIONS: Preoperative PCH regimen was an effective neoadjuvant therapy in HER2 positive and axillary lymph node positive patients, and patients coexisting with HR negative and high Ki67 index may benefit more from this regimen. PMID- 28915618 TI - Suppression of miR-16 promotes tumor growth and metastasis through reversely regulating YAP1 in human cholangiocarcinoma. AB - BACKGROUND & AIMS: Aberrant expression of microRNAs is associated with many cancers progression. Many studies have shown that miR-16 is down-regulated in many cancers. However, its role in cholangiocarcinoma (CCA) is unknown. METHODS: Quantitative real-time PCR (qRT-PCR) was developed to measure miR-16 expression in CCA tissues and cell lines. CCK-8, colony formation and transwell assays were used to reveal the role of miR-16 in CCA cell proliferation and malignant transformation in vitro. The loss-and-gain function was further validated by subcutaneous xenotransplantation and tail vein injection xenotransplantation model in vivo. Dual-luciferase reporter assay was performed to validate the relationship of miR-16 with YAP1. RESULTS: MiR-16 was notably downregulated in CCA tissues, which was associated with tumor size, metastasis, and TNM stage. Both in vitro and in vivo studies demonstrated that miR-16 could suppress proliferation, invasion and metastasis throughout the progression of CCA. We further identified YAP1 as a direct target gene of miR-16 and found that miR-16 could regulate CCA cell growth and invasion in a YAP1-dependent manner. In addition, YAP1 was markedly upregulated in CCA tissues, which was reversely correlated with miR-16 level in tissue samples. Besides, Down-regulation of miR 16 was remarkably associated with tumor progression and poor survival in CCA patients through a Kaplan-Meier survival analysis. CONCLUSIONS: miR-16, as a novel tumor suppressor in CCA through directly targeting YAP1, might be a promising therapeutic target or prognosis biomarker for CCA. PMID- 28915619 TI - Autosomal InDel polymorphisms for population genetic structure and differentiation analysis of Chinese Kazak ethnic group. AB - In the present study, we assessed the genetic diversities of the Chinese Kazak ethnic group on the basis of 30 well-chosen autosomal insertion and deletion loci and explored the genetic relationships between Kazak and 23 reference groups. We detected the level of the expected heterozygosity ranging from 0.3605 at HLD39 locus to 0.5000 at HLD136 locus and the observed heterozygosity ranging from 0.3548 at HLD39 locus to 0.5283 at HLD136 locus. The combined power of discrimination and the combined power of exclusion for all 30 loci in the studied Kazak group were 0.999999999999128 and 0.9945, respectively. The dataset generated in this study indicated the panel of 30 InDels was highly efficient in forensic individual identifcation but may not have enough power in paternity cases. The results of the interpopulation differentiations, PCA plots, phylogenetic trees and STRUCTURE analyses showed a close genetic affiliation between the Kazak and Uigur group. PMID- 28915620 TI - PRPF overexpression induces drug resistance through actin cytoskeleton rearrangement and epithelial-mesenchymal transition. AB - Pre-mRNA processing factor (PRPF) 4B kinase belongs to the CDK-like kinase family, and is involved in pre-mRNA splicing, and in signal transduction. In this study, we observed that PRPF overexpression decreased the intracellular levels of reactive oxygen species, and inhibited resveratrol-induced apoptosis by activating the cell survival signaling proteins NFkappaB, ERK, and c-MYC in HCT116 human colon cancer cells. PRPF overexpression altered cellular morphology, and rearranged the actin cytoskeleton, by regulating the activity of Rho family proteins. Moreover, it decreased the activity of RhoA, but increased the expression of Rac1. In addition, PRPF triggered the epithelial-mesenchymal transition (EMT), and decreased the invasiveness of HCT116, PC3 human prostate, and B16-F10 melanoma cells. The loss of E-cadherin, a hallmark of EMT, was observed in HCT116 cells overexpressing PRPF. Taken together, these results indicate that PRPF blocks the apoptotic effects of resveratrol by activating cell survival signaling pathways, rearranging the actin cytoskeleton, and inducing EMT. The elucidation of the mechanisms that underlie anticancer drug resistance and the anti-apoptosis effect of PRPF may provide a therapeutic basis for inhibiting tumor growth and preventing metastasis in various cancers. PMID- 28915621 TI - Wip1 is associated with tumorigenity and metastasis through MMP-2 in human intrahepatic cholangiocarcinoma. AB - Wip1 has been shown to correlate with the metastasis/invasion of several tumors. This study was designed to investigate the clinical significance and biological function of Wip1 in intrahepatic cholangiocarcinoma (ICC). The expression of Wip1 was investigated in sixty human ICC biopsy samples by immunohistochemistry. Transient and stable knockdown of Wip1 in two human ICC cells (ICC-9810 and SSP25) were established using short hairpin RNA expression vector. Immunohistochemistry revealed that Wip1 was up-regulated in human ICC tissues (47/60, 78.3%). High levels of Wip1 in human ICC correlated with metastasis to the lymph metastasis (P=0.022). Genetic depletion of Wip1 in ICC cells resulted in significantly inhibited proliferation and invasion compared with controls. Most importantly, Wip1 down-regulation impaired tumor migration capacity of ICC cells in vivo. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) is an important target of Wip1. Consistently, in human ICC tissues, Wip1 level was positively correlated with MMP-2 expression. Taken together, our founding indicates that Wip1 may be a crucial regulator in the tumorigenicity and invasion of human ICC, Wip1 exerts its pro-invasion function at least in part through the MMP-2 signaling pathway, suggesting Wip1 as a potential therapeutic target for ICC. PMID- 28915622 TI - Genomic analysis-integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway. AB - Neuroblastoma (NB) is a childhood solid malignant tumor originating from precursor cells of the peripheral nervous system. We have previously established a risk classification system based on DNA copy number profiles. To further explore the pathogenesis of NBs in distinct risk groups, we performed whole-exome sequencing analysis of 57 primary and 7 recurrent/metastatic tumors with unique chromosomal aberration profiles as categorized by our genomic sub-grouping system. Overall, a low frequency of somatic mutations was found. Besides ALK (4/64, 6.3%), SEMA6C, SLIT1 and NRAS, genes involved in the axon guidance pathway, were identified as recurrently mutated in 6 of 64 tumors (9.4%). Pathway enrichment analysis revealed enrichment of 25 mutated genes in the mitogen activated protein kinase (MAPK) pathway, 13 genes in the Wnt pathway, and 12 genes in the axon guidance pathway. Genomic analyses demonstrated that primary and matched recurrent or metastatic tumors obtained from sporadic and monozygotic twin NBs were clonally related with variable extents of genetic heterogeneity. Monozygotic twin NBs displayed different evolutionary trajectories. These results indicate the involvement of the axon guidance, MAPK and Wnt pathways in NB and demonstrate genomic diversity with NB progression. PMID- 28915623 TI - Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. AB - The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells. In contrast, when the AKT inhibitor AZD7328 was applied to patient-derived prostate cultures that retained expression of PTEN, activation of a compensatory Ras/MEK/ERK pathway was observed. Moreover, whilst autophagy was induced following treatment with AZD7328, cell viability was less affected in the patient-derived cultures than in cell lines. Surprisingly, treatment with a combination of both AZD7328 and two separate MEK1/2 inhibitors further enhanced phosphorylation of ERK1/2 in primary prostate cultures. However, it also induced irreversible growth arrest and senescence. Ex vivo treatment of a patient-derived xenograft (PDX) of prostate cancer with a combination of AZD7328 and the mTOR inhibitor KU-0063794, significantly reduced tumour frequency upon re engraftment of tumour cells. The results demonstrate that single agent targeting of the PI3K/AKT/mTOR pathway triggers activation of the Ras/MEK/ERK compensatory pathway in near-patient samples. Therefore, blockade of one pathway is insufficient to treat prostate cancer in man. PMID- 28915624 TI - Microwave ablation combined with EGFR-TKIs versus only EGFR-TKIs in advanced NSCLC patients with EGFR-sensitive mutations. AB - We conducted this retrospective study to investigate whether microwave ablation (MWA) of primary tumor sites plus epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) could improve survival in advanced non small cell lung cancer (NSCLC) with EGFR mutations. MWA was conducted at the primary tumor sites, followed by EGFR-TKIs in the MWA plus EGFR-TKIs group. EGFR-TKIs were administered until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS) and objective response rate (ORR). A total of 58 patients were recruited, including 34 in the MWA plus EGFR-TKIs group and 24 in the EGFR-TKIs group. No significant difference in ORR was observed with MWA treatment (61.8% vs. 45.8%, p = 0.230). Patients treated with MWA plus EGFR-TKIs failed to show superior survival in either PFS (13.2 months vs. 11.6 months, p = 0.640) or OS (39.8 months vs. 20.4 months, p = 0.288). MWA was not an independent prognostic factor for PFS or OS. MWA of primary tumor sites plus EGFR-TKIs demonstrated no survival advantage compared with EGFR-TKIs alone in advanced NSCLC patients with EGFR sensitive mutations. MWA should not be recommended for unselected patients with EGFR-sensitive mutations. PMID- 28915625 TI - Long-term cigarette smoke exposure inhibits histone deacetylase 2 expression and enhances the nuclear factor-kappaB activation in skeletal muscle of mice. AB - Long-term cigarette smoke induces lung inflammatory injury and chronic obstructive pulmonary disease (COPD), associated with skeletal muscle inflammation. This study aimed at investigating how cigarette smoke promotes skeletal muscle inflammation and its molecular pathogenesis. Mice were exposed to air or cigarette smoke for 12 or 24 weeks, and C2C12 cells were stimulated with cigarette smoke extract (CSE). The mass and function, myotube formation, inflammatory cytokine production, histone deacetylase 2 (HDAC2) and nuclear factor-kappaB (NF-kappaB) p65 expression were detected in the gastrocnemius muscles of mice and C2C12 cells. In comparison with the control mice, cigarette smoke significantly damaged the lung and reduced the gastrocnemius muscle mass and body weights in mice. Cigarette smoke significantly down-regulated myosin heavy chain (MHC)-IIbeta and HDAC2 expression, but enhanced NF-kappaBp65, keratinocyte chemoattractant (KC) and tumor necrosis factor (TNF)-alpha expression in the gastrocnemius muscles. CSE stimulation significantly inhibited the myotube formation, MyoD and HDAC2 expression, but enhanced NF-kappaBp65 expression, KC and TNF-alpha production in C2C12 cells, which were enhanced by HDAC2 knockdown and abrogated by a NF-kappaB inhibitor. CSE significantly inhibited the interaction of HDAC2 with NF-kappaBp65, and increased the levels of acetyl-NF-kappaBp65 in C2C12 cells. These data indicated that cigarette smoke inhibited HDAC2 expression and its interaction with NF-kappaBp65 to stimulate inflammation, contributing to the pathogenesis of COPD-related skeletal muscle atrophy in mice. PMID- 28915626 TI - HDL-cholesterol concentration in pregnant Chinese Han women of late second trimester associated with genetic variants in CETP, ABCA1, APOC3, and GALNT2. AB - OBJECTIVE: To investigate whether HDL-C level in pregnant Chinese Han women of late second trimester correlated with loci in high-density lipoprotein cholesterol (HDL-C)-related genes found in genome-wide association studies (GWAS). METHODS: Seven single-nucleotide polymorphisms (rs3764261 in CETP, rs1532085 in LIPC, rs7241918 in LIPG, rs1883025 in ABCA1, rs4225 in APOC3, rs1059611 in LPL, and rs16851339 in GALNT2) were genotyped using the Sequenom MassArray system for 1,884 pregnant women. RESULTS: The following polymorphisms were statistically associated with HDL-C level after adjusting for age, gestational week, pre-pregnancy BMI and state of GDM or HOMAIR: (i) rs3764261 (b = -0.055 mmol/L, 95% CI -0.101 to -0.008, p = 0.021), (ii) rs1883025 (b = -0.054 mmol/L, 95% CI -0.097 to -0.012, p = 0.013), (iii) rs4225 (b = -0.071 mmol/L, 95% CI -0.116 to -0.027, p = 1.79E-3) and (iv) rs16851339 (b = -0.064 mmol/L, 95% CI 0.120 to -0.008, p = 0.025). The more risk alleles the pregnant women have, the lower the plasma HDL-C levels of the subjects are. CONCLUSIONS: Several risk alleles found to be related to HDL-C in GWAS are also associated with HDL-C levels in pregnant Chinese Han women and these risk loci contribute additively to low HDL-C levels. PMID- 28915627 TI - Panobinostat, a histone deacetylase inhibitor, suppresses leptomeningeal seeding in a medulloblastoma animal model. AB - Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding. Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased. Panobinostat effectively down-regulated protein expression of CCND1 and ID3 which has been associated with leptomeningeal seeding of MB. After panobinostat treatment, neurophil-like cellular processes developed and expression of synaptophysin and NeuroD1 was increased, indicating neuronal differentiation. In MB leptomeningeal seeding in vivo model, the panobinostat-treated group showed significantly decreased spinal leptomeningeal seeding and a survival benefit. The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation. An HDAC inhibitor might be a potent treatment option for the treatment of MB patients with leptomeningeal seeding. PMID- 28915628 TI - Clinicopathological and prognostic significance of c-Met overexpression in breast cancer. AB - BACKGROUND: c-Met has been shown to promote organ development and cancer progression in many cancers. However, clinicopathological and prognostic value of c-Met in breast cancer remains elusive. METHODS: PubMed and EMBASE databases were searched for eligible studies. Correlation of c-Met overexpression with survival data and clinicopathological features was analyzed by using hazard ratio (HR) or odds ratio (OR) and fixed-effect or random-effect model according to heterogeneity. All statistical tests were two-sided. RESULTS: 32 studies with 8281 patients were analyzed in total. The c-Met overexpression was related to poor OS (overall survival) (HR=1.65 (1.328, 2.051)) of 18 studies with 4751 patients and poor RFS/DFS (relapse/disease free survival) (HR=1.53 (1.20, 1.95)) of 12 studies with 3598 patients. Subgroup analysis according to data source/methods/ethnicity showed c-Met overexpression was related to worse OS and RFS/DFS in Given by author group, all methods group and non-Asian group respectively. Besides, c-Met overexpression was associated with large tumor size, high histologic grade and metastasis. CONCLUSIONS: Our results showed that c-Met overexpression was connected with poor survival rates and malignant activities of cancer, including proliferation, migration and invasion, which highlighted the potential of c-Met as significant candidate biomarker to identify patients with breast cancer at high risk of tumor death. PMID- 28915629 TI - IER3IP1 deficiency leads to increased beta-cell death and decreased beta-cell proliferation. AB - Mutations in the gene for Immediate Early Response 3 Interacting Protein 1 (IER3IP1) cause permanent neonatal diabetes mellitus in human. The mechanisms involved have not been determined and the role of IER3IP1 in beta-cell survival has not been characterized. In order to determine if there is a molecular link between IER3IP1 deficiency and beta-cell survival and proliferation, we knocked down Ier3ip1 gene expression in mouse MIN6 insulinoma cells. IER3IP1 suppression induced apoptotic cell death which was associated with an increase in Bim and a decrease in Bcl-xL. Knockdown of Bim reduced apoptotic cell death in MIN6 cells induced by IER3IP1 suppression. Overexpression of the anti-apoptotic molecule Bcl xL prevents cell death induced by IER3IP1 suppression. Moreover, IER3IP1 also regulates activation of the unfolded protein response (UPR). IER3IP1 suppression impairs the Inositol Requiring 1 (IRE1) and PKR-like ER kinase (PERK) arms of UPR. The cell proliferation of MIN6 cells was also decreased in IER3IP1 deficient cells. These results suggest that IER3IP1 suppression induces an increase in cell death and a decrease in cell proliferation in MIN6 cells, which may be the mechanism that mutations in IER3IP1 lead to diabetes. PMID- 28915630 TI - CASP8 -652 6N insertion/deletion polymorphism and overall cancer risk: evidence from 49 studies. AB - : The CASP8 -652 6N insertion/deletion (I/D) polymorphism reduces expression of caspase 8. We conducted a meta-analysis to clarify the relationship between this polymorphism and cancer risk. Eligible articles were retrieved from PubMed, EMBASE, CNKI, and WANFANG databases through February 2017. A total of 33 articles with 49 studies, including 33,494 cases and 36,397 controls, were analyzed. We found that the CASP8 -652 6N ins/del polymorphism was associated with decreased overall cancer risk in five genetic models [DD vs. II: odds ratio (OR)=0.76, 95% confidence interval (CI)=0.69-0.84, ID vs. II: OR=0.87, 95% CI=0.83-0.92, DD vs. ID/II: OR=0.82, 95% CI=0.75-0.89, ID/DD vs. II: OR=0.85, 95% CI=0.80-0.90, and D vs. I: OR=0.87, 95% CI=0.83-0.91]. Stratified analyses showed that the polymorphism was associated with decreased risk of colorectal, breast, esophageal, renal cell, lung, cervical, bladder, gastric, and other cancers. Overall cancer risk was reduced in Asian and Caucasian patients, both hospital- and population-based studies, and both high and low quality studies. Our results highlight the role of the CASP8 -652 6N ins/del polymorphism in decreasing cancer risk. Further studies with large-cohort populations, especially for specific cancer types and ethnic groups, are needed to confirm our findings. PMID- 28915631 TI - In vivo autophagy and biogenesis of autophagosomes within male haploid cells during spermiogenesis. AB - Autophagy is a unique catabolic pathway that is linked to several physiological processes. However, its role in the process of spermiogenesis is largely unknown. The aim of the current study was to determine the in vivo role of autophagy and the origin of autophagosome membrane biogenesis within male haploid cells. Our immunohistochemistry results demonstrated that LC3 and ATG7 localization were increased dramatically in round to elongated spermatids (haploid cells) towards the lumen of seminiferous tubules, however, poorly expressed in the early stages of germ cells near the basal membrane. Moreover, transmission electron microscopy revealed that the numbers of lysosomes and autophagosomes increased in the elongated spermatids as spermiogenesis progressed. However, no evidence was found for the presence of autophagosomes in the Sertoli cells, spermatogonia or early primary spermatocytes (diploid cells). Furthermore, TEM showed that many endoplasmic reticula were transformed into a "chrysanthemum flower center," from which a double-layered isolation membrane appeared to develop into an autophagosome. This study provides novel evidence about the formation of autophagosomes through the chrysanthemum flower center from the endoplasmic reticulum, and suggests that autophagy may have an important role in the removal of extra cytoplasm within male haploid cells during spermiogenesis. PMID- 28915632 TI - Decitabine inhibits T cell proliferation via a novel TET2-dependent mechanism and exerts potent protective effect in mouse auto- and allo-immunity models. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by the dysregulated immune response including innate and adaptive immune responses. Increasing evidence has proven the importance of epigenetic modification in the progression of MS. Recent studies revealed that low-dose decitabine (Dec, 5-Aza 2'-deoxycytidine), which incorporates into replicating DNA and inhibits DNA methylation, could prevent experimental autoimmune encephalomyelitis (EAE) development by increasing the number of regulatory T cells (Tregs). Here, we showed that higher-dose decitabine relative to previous studies could also distinctly protect mice from EAE and allogeneic cardiac transplantation. Mechanistic studies revealed decitabine suppressed innate responses in EAE mice through inhibiting the activation of microglia and monocyte-derived macrophages that contributed to reduce the severity of EAE. Furthermore, differentiation of naive CD4+ T cells into Th1 and Th17 cells was significantly suppressed by decitabine in vivo and in vitro. Though in vitro studies showed decitabine could induce Treg differentiation, there was no obvious change in the percentage of Tregs in Dec-treated EAE mice. Most importantly, we found that T cell proliferation was potently inhibited in vivo and in vitro by higher-dose decitabine through increased gene expression of the DNA dioxygenase TET2 which facilitated the expression of several cell cycle inhibitors. Collectively, our study provides novel mechanistic insights of using the epigenetic modifying agents in the management of both allo- and auto-immune responses. PMID- 28915633 TI - Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma. AB - Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin alphavbeta6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin alphavbeta6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P<0.001, respectively) and CP (P=0.003 and P<0.001, respectively). Avbeta6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, alphavbeta6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC. PMID- 28915634 TI - DNA methylation signature of long noncoding RNA genes during human pre implantation embryonic development. AB - DNA methylation have crucial roles in regulating the expression of developmental genes during mammalian pre-implantation embryonic development (PED). However, the DNA methylation dynamic pattern of long noncoding RNA (lncRNA) genes, one type of epigenetic regulators, in human PED have not yet been demonstrated. Here, we performed a comprehensive analysis of lncRNA genes in human PED based on public reduced representation bisulphite sequencing (RRBS) data. We observed that both lncRNA and protein-coding genes complete the major demethylation wave at the 2 cell stage, whereas the promoters of lncRNA genes show higher methylation level than protein-coding genes during PED. Similar methylation distribution was observed across the transcription start sites (TSS) of lncRNA and protein-coding genes, contrary to previous observations in tissues. Besides, not only the gamete specific differentially methylated regions (G-DMRs) but also the embryonic developmental-specific DMRs (D-DMRs) showed more paternal bias, especially in promoter regions in lncRNA genes. Moreover, coding-non-coding gene co-expression network analysis of genes containing D-DMRs suggested that lncRNA genes involved in PED are associated with gene expression regulation through several means, such as mRNA splicing, translational regulation and mRNA catabolic. This firstly provides study provides the methylation profiles of lncRNA genes in human PED and improves the understanding of lncRNA genes involvement in human PED. PMID- 28915635 TI - Dysregulation of an X-linked primate-specific epididymal microRNA cluster in unexplained asthenozoospermia. AB - Asthenoszoopermia, characterized by reduced sperm motility, is one of the primary forms of male infertility. Whereas most cases were diagnosed into unexplained asthenozoospermia (UA) because the etiology cannot be identified. In animal models, epigenetic dysregulation in epididymis can impair sperm maturation and result in asthenozoospermia. However, researches of epididymal epigenetic regulation on humans are impeded by the difficulty in obtaining epididymal tissues. We previously identified cell-free seminal microRNAs predominately derived from epididymis in human ejaculate. In the present study, these microRNAs were used to screen and validate the microRNA dysregulation in men with UA, which were divided into screening set and validation set. The expression of five miRNAs (miR-891b, miR-892b, miR-892a, miR-888 and miR-890) was found and confirmed to be dysregulated in men with UA. Interestingly, these five miRNAs belong to a primate specific miRNA cluster located on the X chromosome with epididymis specific expression. Moreover, obvious coherent dysregulation of these miRNAs were observed in 13% men with UA. Regression analysis demonstrated that levels of these miRNAs were significantly correlated with progressive sperm motility. Functions and pathways of predicted target genes of this cluster suggested its role in sperm maturation. Dysregulation of this miRNA cluster might be an epigenetic basis for some patients with UA. We also showed a noninvasive and feasible approach to get epigenetic information of human epididymis. PMID- 28915636 TI - Role of glucose metabolism related gene GLUT1 in the occurrence and prognosis of colorectal cancer. AB - Colorectal cancer (CRC) ranks the third most commonly diagnosed cancer in males and the second in females worldwide. However, the functional and causal SNPs for CRC remain to be mined. Glucose transporter 1 (GLUT1), a pivotal rate-limiting element in the transport of glucose in malignancy cells, has been identified to be associated with many cancers. Here, we aim to explore the role of GLUT1 in the occurrence and prognosis of colorectal cancer in a Chinese population. We found that GLUT1 expression levels in CRC tumor tissues were significantly higher than those in the corresponding adjacent normal tissues, and Cox multivariate analysis demonstrated that the GLUT1 expression was an independent prognostic factor for CRC (HR = 2.11, 95% CI = 1.33-3.34, P=0.001). For a functional polymorphism of GLUT1 (rs710218), we found that individuals with TT genotype (OR = 1.68, 95% CI = 1.02-2.75, P = 0.041) or AT genotype (OR = 1.47, 95% CI = 1.09-1.99, P = 0.012) of rs710218 had a significantly increased risk of CRC compared to those with AA homozygote. These findings strongly suggest that glucose metabolism related gene GLUT1, and its functional SNP, rs710218 might contribute to CRC susceptibility and prognosis, and the exact biological mechanism awaits further research. PMID- 28915637 TI - BTK suppresses myeloma cellular senescence through activating AKT/P27/Rb signaling. AB - We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts. Knockdown BTK expression by shRNA induced MM cellular senescence using beta galactosidase (SA-b-gal) staining, cell growth arrest by cell cycle staining and decreased clonogenicity while forcing BTK expression in MM cells abrogated these characteristics. We also validated this feature in mouse embryonic fibroblast cells (MEFs), which showed that elevated BTK expression was resistant to MEF senescence after serial cultivation in vitro. Further mechanism study revealed that BTK activated AKT signaling leading to down-regulation of P27 expression and hindered RB activity while AKT inhibitor, LY294002, overcame BTK-overexpression induced cellular senescence resistance. Eventually we demonstrated that BTK inhibitor, CGI-1746, induced MM cellular senescence, colony reduction and tumorigenecity inhibition in vivo. Summarily, we designate a novel mechanism of BTK in mediating MM growth, and BTK inhibitor is of great potential in vivo and in vitro suggesting BTK is a promising therapeutic target for MM. PMID- 28915638 TI - Oleoylethanolamide inhibits alpha-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells. AB - The present study aimed to examine the potential inhibitory activity of oleoylethanolamide (OEA) on alpha-melanocyte stimulating hormone (alpha-MSH) stimulated melanogenesis and the molecular mechanism(s) involved in the process in B16 mouse melanoma cells. Our data demonstrated that OEA markedly inhibited melanin synthesis and tyrosinase activity in alpha-MSH-stimulated B16 cells. In addition, the expression of melanogenesis-related proteins, such as melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and tyrosinase, was suppressed in a concentration-dependent manner by OEA. In addition, OEA may suppress melanogenesis through a peroxisome proliferator-activated receptor alpha (PPARalpha)-independent pathway. Moreover, OEA activated ERK, Akt, p38 pathways and inhibits CREB pathway in alpha-MSH-stimulated B16 cells. The specific ERK inhibitor PD98059 partly blocked OEA-inhibited melanin synthesis and tyrosinase activity and partly abrogated the OEA-suppressed expression of melanogenic proteins. Furthermore, OEA presented remarkable inhibition on the body pigmentation in the zebrafish model system. Our findings demonstrated that OEA is an effective inhibitor of hyperpigmentation through activation of ERK, Akt and p38 pathways, inhibition of the CREB pathway, and subsequent down-regulation of MITF, TRP-1 and tyrosinase production. PMID- 28915639 TI - Heptamethine carbocyanine DZ-1 dye for near-infrared fluorescence imaging of hepatocellular carcinoma. AB - Near-infrared fluorescence (NIRF) dyes have recently emerged as promising tools for non-invasive imaging of different types of cancers. Here, we explored the potential utility of a NIRF DZ-1 dye, with dual imaging and tumour targeting functions, in hepatocellular carcinoma (HCC). We showed the preferential uptake of DZ-1 by HCC cells in vitro and in derived subcutaneous/orthotopic tumour xenografts, accompanied by a minimal effect on normal cells. DZ-1 simplified tumour growth profiling as well, since we were able to correlate NIRF signals with tumour volume and/or tumour-emitting luminescence in mice. Using both orthotopic tumour transplantation and cirrhosis models in parallel, we demonstrated the ability of DZ-1 to differentiate liver tumour from cirrhosis. DZ 1 showed superiority in HCC imaging over indocyanine green by demonstrating significantly enhanced tumour-targeting specificity. At the cellular level, DZ-1 was mainly retained in mitochondria and lysosomes. Additionally, DZ-1 fluorescence spectroscopy has been used for the intraoperative navigation of rabbit liver cancer, to determine surgical margins. We showed that tumor hypoxia and select organic anion-transporting polypeptide genes mediate NIRF dye uptake in HCC, which was supported by clinical evidence. All these findings represent the first evidence that DZ-1 is an effective molecular probe for tumour-specific imaging in HCC, and provide insights into the development of a new generation of imaging agents for intraoperative guidance of cancer surgery. PMID- 28915640 TI - Marsdenia tenacissima extract overcomes Axl- and Met-mediated erlotinib and gefitinib cross-resistance in non-small cell lung cancer cells. AB - Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance. PMID- 28915641 TI - Reevaluation of ATR signaling in primary resting chronic lymphocytic leukemia cells: evidence for pro-survival or pro-apoptotic function. AB - ATM, primarily activated by DNA double-strand breaks, and ATR, activated by single-stranded DNA, are master regulators of the cellular response to DNA damage. In primary chronic lymphocytic leukemia (CLL) cells, ATR signaling is considered to be switched off due to ATR downregulation. Here, we hypothesized that ATR, though expressed at low protein level, could play a role in primary resting CLL cells after genotoxic stress. By investigating the response of CLL cells to UV-C irradiation, a prototypical activator of ATR, we could detect phosphorylation of ATR at Thr-1989, a marker for ATR activation, and also observed that selective ATR inhibitors markedly decreased UV-C-induced phosphorylation of ATR targets, including H2AX and p53. Similar results were obtained with the purine analogs fludarabine and cladribine that were also shown to activate ATR and induce ATR-dependent phosphorylation of H2AX and p53. In addition, ATR inhibition was found to sensitize primary CLL cells to UV-C by decreasing DNA repair synthesis. Conversely, ATR inhibition rescued CLL cells against purine analogs by reducing expression of the pro-apoptotic genes PUMA and BAX. Collectively, our study indicates that ATR signaling can be activated in resting CLL cells and play a pro-survival or pro-apoptotic role, depending on the genotoxic context. PMID- 28915643 TI - Relationship between the TERT, TNIP1 and OBFC1 genetic polymorphisms and susceptibility to colorectal cancer in Chinese Han population. AB - Colorectal cancer (CRC) is one of the most common diseases worldwide, and telomere length has been reported correlate with CRC. This study aimed to investigate whether polymorphisms of telomere length related genes are associated with susceptibility to CRC in Chinese Han population. 11 SNPs from TERT, TNIP1 and OBFC1 genes were selected and genotyped, in addition odds ratio (OR) and 95% confidence intervals (CI) were used to evaluate association between the SNPs and CRC risk in 247 patients clinically and 300 controls in a Chinese Han population. Our results showed that minor allele "G" of rs7708392 and minor allele "C" of rs10036748 in TNIP1 gene were significantly associated with an increased the CRC risk in genotype model, dominant model and additive model after Bonferroni's multiple adjusted (P<0.0011). Moreover, the two SNPs rs7708392 and rs10036748 were in strong linkage disequilibrium. We observed that the haplotype "G-C" was more frequent among CRC patients and associated with a 1.58-fold increased CRC risk (95%CI=1.17-2.13, P=0.003). Contrarily, haplotype "C-T" was associated with a 0.63-fold reduced CRC risk (95%CI=0.47-0.86, P=0.003). Additionally, SNPs in this study except rs7708392 and rs10036748 were found a modest connection with CRC risk. In conclusion, our study firstly provides evidence for a novel association between polymorphisms of telomere length related TNIP1 gene and CRC susceptibility in Chinese Han population, and the results need a further identification in a large sample size and other populations. PMID- 28915642 TI - A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience. AB - We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naive patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naive (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naive patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order. PMID- 28915644 TI - Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death. AB - Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N-acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD 35-induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death. PMID- 28915645 TI - SOCS1 gene promoter methylation status is associated with in-stent restenosis after percutaneous coronary intervention. AB - BACKGROUND: Inflammation is involved in the development of In-stent restenosis (ISR) after percutaneous coronary intervention. We aimed to investigate the association between of suppressor of cytokine signaling-1 (SOCS1), a major negative regulator for inflammation, and the occurrence of ISR in Chinese patients. METHODS: We enrolled patients with coronary artery disease who underwent PCI with stenting. PCI procedures were performed successfully and a follow-up angiography was repeated 1 year later to determine ISR presence. Real time quantitative reverse transcription polymerase chain reaction and methylation specific polymerase chain reaction (MSP) was used for SOCS1 methylation status determination. RESULTS: There are a total of 187 patients had SOCS1 methylation while there are 275 had no methylated SOCS1. Patients with SOCS1 methylation have a higher inflammatory status. Of note, patients with SOCS1 methylation had a significantly lower SOCS1 mRNA levels compared to those without. Patients with ISR tend to have a significantly higher percentage of SOCS1 gene methylation (P<0.001). We next conducted the Binary logistic regression analyses to determine the correlation of SOCS1 with ISR, using demographic and clinical characteristics. Our data show that SOCS1 methylation is the only factors which are closely associated with ISR incidence. Patients with SOCS1 methylation are 5 times more likely to have ISR after successful PCI as opposed to those without SOCS1 methylation (P<0.001). CONCLUSION: Our data suggest that blood SOCS1 gene promoter methylation status is closely associated with ISR occurrence, thus may be used as a marker to predict ISR. PMID- 28915646 TI - Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an ex vivo autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC. PMID- 28915647 TI - Necroptosis as a potential therapeutic target in multiple organ dysfunction syndrome. AB - PURPOSE: To investigate how necroptosisis, i.e. programmed necrosis, is involved in MODS, and to examine whether Nec-1, a specific necroptosis inhibitor, ameliorates multiorgan injury in MODS. EXPERIMENTAL DESIGN: A model of MODS was established in six-week old SD rats using fracture trauma followed by hemorrhage. Control animals received sham surgery. Cell death form and necrosome formation were measured by fluorescence-activated cell sorting and western blotting. MODS rats were randomly assigned to receive Nec-1 or saline with pretreatment and once daily. The first end-point was 72 hours survival. Organ injury and dysfunction, inflammatory cytokine levels, and necroptotic execution protein expression were also recorded. RESULTS: Organ injury and dysfunction were significantly more severe in the MODS group than the sham group (all p<0.01). Furthermore, MODS induced liver, lung and kidney tissue injury was characterized by necroptosis rather than apoptosis, and accompanied by necrosome formation. Compared to MODS group, Nec-1 administration significantly improved 72 hours survival (p<0.01). Nec-1 administration significantly reduced necroptosis-induced liver, lung and kidney injury and dysfunction, inhibited inflammatory cytokines production, inhibited release of necroptotic execution proteins such as high-mobility group box 1 and mixed-lineage kinase domain-like protein pseudokinase in MODS rats (all p<0.01). CONCLUSIONS: These results suggest that necroptosis is involved the pathology of MODS. Further, a necroptotic inhibitor Nec-1 may be considered as an adjunct treatment for MODS. PMID- 28915648 TI - Synergistic suppression of t(8;21)-positive leukemia cell growth by combining oridonin and MAPK1/ERK2 inhibitors. AB - One of the most common chromosomal translocations in acute myeloid leukemia is t(8;21)(q22;q22), which results in the appearance of abnormal transcripts encoding for the fusion protein RUNX1-ETO. Therefore, this oncoprotein is considered to be a pertinent and promising target for treating t(8;21) leukemia. Previously, we have shown that downregulation of RUNX1-ETO leads to activation of intracellular signaling pathways enhancing cell survival and determined that the protein ERK2 can mediate activation of most of these pathways. Here we used a combination of oridonin (natural tetracycline diterpenoid), which has been shown to exhibit anti-RUNX1-ETO activity, and ERK2 kinase inhibitors. We found that treatment of leukemic t(8;21)-positive Kasumi-1 cells with oridonin cause decrease of phosphorylated ERK1/2. Treatment of these cells with ERK2 inhibitors makes them more sensitive to RUNX1-ETO inhibition with oridonin. Therefore we postulate that simultaneous inhibition of RUNX1-ETO and ERK2 cause synergistic effect on survival of leukemic cells. PMID- 28915649 TI - Digoxin-induced anemia among patients with atrial fibrillation and heart failure: clinical data analysis and drug-gene interaction network. AB - Digoxin is widely used to treat various heart conditions. In order to clarify the association between digoxin and anemia adverse reaction, we inspected case reports submitted to the FDA Adverse Event Reporting System (FAERS) between January 2004 and December 2015. These reports involved 75618 atrial fibrillation patients and 15699 heart failure patients. Compared to other therapies, digoxin treatment was significantly more likely to be concurrent with anemia adverse reaction among both atrial fibrillation patients (pooled OR = 1.38, 95% CI 1.14 1.68, P-value = 0.001) and heart failure patients (pooled OR =1.50, 95% CI 1.33 1.59-, P =4.27*10-5). We further explored previously published evidences and found 821 human genes directly or indirectly interacting with digoxin. Functional analysis indicated that these genes were significantly enriched in the biological processes of iron transport, which are closely related to iron deficiency anemia. Taken together, our retrospective analysis demonstrated the significant association between digoxin treatment and anemia adverse reaction, which should be seriously considered in clinical practice. Functional enrichment analysis on digoxin-related genes warranted subsequent research on the underlying toxicological mechanisms. PMID- 28915650 TI - MicroRNA-107-5p suppresses non-small cell lung cancer by directly targeting oncogene epidermal growth factor receptor. AB - MicroRNAs (miRNAs) are dysregulated in cancers, including human non-small cell lung cancer (NSCLC). The function of MicroRNA-107-5p (miR-107-5p) in NSCLC is not fully elucidated. Epidermal growth factor receptor (EGFR) is a cancer-driven gene in tumorigenesis. In this study, we found that miR-107-5p was significantly decreased in NSCLC tissues and NSCLC cell lines. Moreover, our results indicated that miR-107-5p could suppress cell proliferation, inhibit metastasis, impede cell cycle, and promote apoptosis via directly targeting EGFR. We also investigated roles of miR-107-5p in vivo. The results showed that it could inhibit tumor growth. Therefore, our study demonstrated that miR-107-5p not only suppressed the progression in NSCLC cells by inhibiting the expression of EGFR, but also could be a promising and a new potential therapeutic target for lung cancer. PMID- 28915652 TI - PLD1 overexpression promotes invasion and migration and function as a risk factor for Chinese glioma patients. AB - Glioma is a lethal disease with few effective therapeutic options. Recently, insights into cancer biology had suggested that abnormal lipid metabolism was a risk factor for various human malignancies, including glioma. As a key enzyme implicated in lipid metabolism, PLD1 was overexpression in multiple human cancers, and it was stated to be responsible for aggressive phenotypes, such as angiogenesis and chemoresistance. However, there was still much to know about its expression and function in glioma. In the present study, we showed that PLD1 was overexpression in clinical samples of glioma. In addition, the correlation assay revealed that PLD1 overexpression was correlated with poor differentiation (p = 0.04), and it was responsible for a poor prognosis for the patients (p = 0.009). Furthermore, we showed in COX regression assay that PLD1 was a risk factor for glioma (p = 0.018, HR = 0.461, 95% CI = 0.243-0.887). Consistently, we found that PLD1 was overexpression in glioma cell lines, and it could facilitate the proliferation and migration. Taken together, our study suggested that PLD1 was pro-tumoral in glioma, and that further studies were urgently needed so as to define whether it was a novel therapeutic target for the disease. PMID- 28915651 TI - Programmed differentiated natural killer cells kill leukemia cells by engaging SLAM family receptors. AB - Natural killer (NK) cells are important innate immune cells that can directly kill transformed or virus-infected cells. The adoptive transfer of NK cells has been used to treat hematological malignancies; however, the limited sources and quantities of NK cells have restricted their clinical application. Here, we acquired sufficient quantities of functional NK cells from CD34+ cells treated with a cytokine cocktail. Microarray analysis of the cultured cells revealed a two-stage pattern of programmed differentiation during NK cell development. Different transcription factors were enriched during these two stages, suggesting that preparation of progenitors committed to the NK cell lineage occurs in program 1, while NK cell transformation and maturation occur in program 2. Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SFR ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs. Moreover, the binding between SFRs on NK cells and their ligands on leukemia cells suggests a new basis for NK cell therapy for treatment of leukemia. PMID- 28915653 TI - Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma. AB - Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma. PMID- 28915654 TI - Daurinol blocks breast and lung cancer metastasis and development by inhibition of focal adhesion kinase (FAK). AB - FAK overexpression has been reported in diverse primary and metastatic tumor tissues, supporting its pro-tumorigenic and pro-metastatic roles. Therefore, we have developed a neo-treatment strategy using daurinol to effectively treat cancer metastasis. Daurinol blocked cancer cell migration and invasion in vitro and exhibited anti-metastatic activity in an experimental metastasis model of breast and lung cancer. Daurinol selectively inhibited phosphorylation of FAK at Tyr925, Tyr576/577, and Tyr397 sites in a dose- and time-dependent manner. Daurinol effectively suppressed migration and invasion of MDA-MB-231 and A549 cancer cells. These data were associated with inhibition of expression and secretion of invasion factors, including matrix metalloproteinase (MMP) 2, MMP9, and urokinase plasminogen activator (uPA). Consistent with these in vitro results, daurinol (10 mg/kg; Oral gavage) effectively inhibited breast and lung cancer metastasis in a mouse model. In addition, daurinol showed strong suppressive activity of cell survival as revealed by colony formation assays. Analysis of cellular phenotypes revealed that inhibition of FAK phosphorylation in cancer cells limited colony formation, cell migration, and invasion, thereby reducing the cell proliferation rate. Furthermore, daurinol significantly reduced tumor development in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Our results suggest that daurinol suppresses lung metastasis through inhibition of migration and survival via blockade of FAK activity. PMID- 28915655 TI - Notch system is differentially expressed and activated in pituitary adenomas of distinct histotype, tumor cell lines and normal pituitaries. AB - Pituitary adenomas are among the most frequent intracranial neoplasms and treatment depends on tumor subtype and clinical features. Unfortunately, non responder cases occur, then new molecular targets are needed. Notch system component expression and activation data are scarce in pituitary tumorigenesis, we therefore aimed to characterize Notch system in pituitary tumors of different histotype. In human pituitary adenomas we showed NOTCH1-4 receptors, JAGGED1 ligand and HES1 target gene expression with positive correlations between NOTCH1,2,4 and HES1, and NOTCH3 and JAGGED1 denoting Notch system activation in a subset of tumors. Importantly, NOTCH3 positive cells were higher in corticotropinomas and somatotropinomas compared to non functioning adenomas. In accordance, Notch activation was evidenced in AtT20 tumor corticotropes, with higher levels of NOTCH1-3 active domains, Jagged1 and Hes1 compared to normal pituitary. In the prolactinoma cell lines GH3 and MMQ, in vivo GH3 tumors and normal glands, Notch system activation was lower than in corticotropes. In MMQ cells only the NOTCH2 active domain was increased, whereas NOTCH1 active domain was higher in GH3 tumors. High levels of Jagged1 and Dll1 were found solely in GH3 cells, and Hes1, Hey1 and Hey2 were expressed in a model dependent pattern. Prolactinomas harbored by lacDrd2KO mice expressed high levels of NOTCH1 active domain and reduced Hes1. We show a differential expression of Notch system components in tumoral and normal pituitaries and specific Notch system involvement depending on adenoma histotype, with higher activation in corticotropinomas. These data suggest that targeting Notch pathway may benefit non responder pituitary adenomas. PMID- 28915656 TI - Patterns and clinical significance of cervical lymph node metastasis in papillary thyroid cancer patients with Delphian lymph node metastasis. AB - Although the roles of Delphian lymph node (DLN) metastasis in papillary thyroid cancer (PTC) have been previously reported, there are still limited data on correlations of clinicopathologic factors with DLN metastasis and unique patterns of cervical node subsite metastasis in PTC patients with DLN metastasis. We retrospectively reviewed medical records of 320 patients with a diagnosis of PTC who underwent primary surgery. Clinicopathologic features and DLN metastasis patterns were analyzed for predicting extensive cervical lymph node metastasis. Both univariate and multivariate Cox regression analyses were used to identify independent factors for cervical lymph node metastasis. DLN metastasis was significantly associated with multifocality, tumor size > 1 cm, extrathyroid extension, BRAFV600E mutation, central neck node metastasis (CNNM), and lateral neck nodes metastases. Patients with DLN metastasis had more lymph node metastases in the central compartment. CNNM number and tumor size > 1 cm were independent risk factors for DLN metastasis. DLN metastasis was highly predictive of lateral lymph node metastasis with moderate sensitivity and high specificity. DLN metastasis is associated with several poor prognostic factors, including extensive cervical lymph node metastasis, and can serve as a predictor of advanced PTC. The presence of DLN metastasis should prompt surgeons to perform an aggressive surgery approach. PMID- 28915657 TI - The prevalence, subtypes and associated factors of hyperuricemia in lupus nephritis patients at chronic kidney disease stages 1-3. AB - There is a high prevalence of hyperuricemia (HUA) in the chronic kidney disease (CKD) population. However, there's a dearth of research on HUA's prevalence, subtypes, early detection, and treatment strategies of HUA in lupus nephritis (LN) patients. The aim of this study is to address these knowledge gaps. LN patients presenting to the Department of Nephrology at Shanghai Rui Jin Hospital from January 2011 to January 2016 were recruited. The effective sample size was derived using the power analysis. The demographic, clinical and laboratory characteristics of the LN patients with HUA were compared with those of patients without HUA. Two statistical models for analyzing HUA were built and compared using the receiver operating characteristic (ROC) curve analysis. The total prevalence of HUA in the cohort was 40.11%. The subtypes of HUA included urate underexcretion-type, overproduction-type and combined-type, which proportion being 67.7%, 9.7% and 22.6% respectively. The CKD stage was closely associated with the prevalence of HUA in patients with LN. The other significant associated factors were hypertension, triglycerides, serum creatinine, serum albumin, hemoglobin, parathyroid hormone, phosphorus, calcium, etc. The statistical algorithm successfully identified LN patients at risk of HUA. In conclusion, there was a high prevalence of HUA in LN patients at CKD stages 1-3, and renal underexcretion hyperuricemia was the most prevalent subtype. The occurrence of HUA in LN may be related to renal insufficiency, metabolic disorder and lupus itself. Early care coordination programs can employ risk models to improve HUA prevention and target interventions in LN patients. PMID- 28915658 TI - Oxidative stress mediates an increased formation of vascular endothelial growth factor in human hepatocarcinoma cells exposed to erlotinib. AB - The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC). Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed. We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1.2, HCC-3). Cyp3A4 and Cyp1A2, microarray gene expression, cell viability, LDH release, DHFC fluorescence were assessed. VEGF expression was analysed by real-time RT-PCR and ELISA. Higher cumulative expression of erlotinib metabolizing enzymes was observed in HCC-1.2 and HCC-3 cells. Gene expression microarray analysis showed upregulation of VEGF signalling by erlotinib. VEGF was increased up to 134 +/- 14% (n = 5, p = 0.002) in HCC-1.2, HCC-3 and Huh7 cells. Interventions by Cyp1A2 and Mek2siRNA, MEK inhibitor UO126, diphenylene iodonium, as well as a combination of N-acetylcysteine with selenium all inhibited VEGF upregulation caused by erlotinib. Thus, erlotinib increases VEGF production by mechanisms involving Cyp1A2, oxidative stress and MEK1/2. VEGF may favour angiogenesis and growth of early HCC tumours limiting the therapeutic and chemopreventive effects of erlotinib. PMID- 28915659 TI - Data-driven analysis of immune infiltrate in a large cohort of breast cancer and its association with disease progression, ER activity, and genomic complexity. AB - The tumor microenvironment is now widely recognized for its role in tumor progression, treatment response, and clinical outcome. The intratumoral immunological landscape, in particular, has been shown to exert both pro tumorigenic and anti-tumorigenic effects. Identifying immunologically active or silent tumors may be an important indication for administration of therapy, and detecting early infiltration patterns may uncover factors that contribute to early risk. Thus far, direct detailed studies of the cell composition of tumor infiltration have been limited; with some studies giving approximate quantifications using immunohistochemistry and other small studies obtaining detailed measurements by isolating cells from excised tumors and sorting them using flow cytometry. Herein we utilize a machine learning based approach to identify lymphocyte markers with which we can quantify the presence of B cells, cytotoxic T-lymphocytes, T-helper 1, and T-helper 2 cells in any gene expression data set and apply it to studies of breast tissue. By leveraging over 2,100 samples from existing large scale studies, we are able to find an inherent cell heterogeneity in clinically characterized immune infiltrates, a strong link between estrogen receptor activity and infiltration in normal and tumor tissues, changes with genomic complexity, and identify characteristic differences in lymphocyte expression among molecular groupings. With our extendable methodology for capturing cell type specific signal we systematically studied immune infiltration in breast cancer, finding an inverse correlation between beneficial lymphocyte infiltration and estrogen receptor activity in normal breast tissue and reduced infiltration in estrogen receptor negative tumors with high genomic complexity. PMID- 28915660 TI - Mass spectrometry-based assay for the molecular diagnosis of glioma: concomitant detection of chromosome 1p/19q codeletion, and IDH1, IDH2, and TERT mutation status. AB - The World Health Organization recently revised the diagnosis of glioma, to integrate molecular parameters, including IDH mutations and codeletion (loss of heterozygosity; LOH) of chromosome arms 1p/19q, into the definitions of adult glioma histological subtypes. Mutations in the TERT promoter may also be useful for glioma diagnosis and prognosis. The integration of molecular markers into routine diagnosis requires their rapid and reliable assessment. We propose a MassARRAY (MS)-based test that can identify 1p/19q codeletion using quantitative SNP genotyping and, simultaneously, characterize hotspot mutations in the IDH1, IDH2, and TERT genes in tumor DNA. We determined the reliability of the MS approach testing 50 gliomas and comparing the MS results with those obtained by standard methods, such as short tandem repeat genotyping, array comparative genomic hybridization (array-CGH) and Fluorescence In Situ Hybridization (FISH) for 1p/19q codeletion and Sanger sequencing for hotspots mutations. The results indicate that MS is suitable for the accurate, rapid, and cost-effective evaluation of chromosome deletions combined with hotspot mutation detection. This MS approach could be similarly exploited in evaluation of LOH in other situations of clinical and/or research importance. PMID- 28915662 TI - Cbl-b predicts postoperative survival in patients with resectable pancreatic ductal adenocarcinoma. AB - Casitas B-lineage lymphoma b (Cbl-b) is a ubiquitin-protein ligase and a signal transducing adaptor protein involved in immune regulation, and it may be involved in the development and progression of cancer. We investigated the association between Cbl-b expression and prognosis in patients with resectable pancreatic ductal adenocarcinoma (PDAC). The clinicopathological characteristics and survival data of 134 patients with surgery for PDAC between January 2009 and February 2012 were retrospectively evaluated, and Cbl-b expression was assayed by immunohistochemical staining. The association of Cbl-b expression with clinicopathological features and postoperative prognosis was analyzed. Cbl-b expression was strongly associated with the pathological primary tumor (pT) category (P = 0.005) and pathological TNM (pTNM) stage (P = 0.035), but not with other clinicopathological characteristics (all P > 0.05). In addition to current markers including pathological regional lymph nodes (pN) category, CA19-9, and histological differentiation, univariate and multivariate analysis found that Cbl b was independently associated with overall survival (OS) of patients with resectable PDAC. Cbl-b was predictive of OS in a subgroup of patients with serum CA19-9 >= 37 U/mL. Cbl-b expression combined with pN, histological differentiation, and CA19-9 level could be used as a novel clinical model predictive of OS for patients with resectable PDAC. In conclusion, Cbl-b in resectable PDAC was an independent predictor of adverse prognosis. Cbl-b expression together with pN, histological differentiation, and CA19-9 level might lead to improved risk stratification and prognosis for patients with resectable PDAC. PMID- 28915661 TI - Small molecular floribundiquinone B derived from medicinal plants inhibits acetylcholinesterase activity. AB - Being a neurodegenerative disorder, Alzheimer's disease (AD) is the one of the most terrible diseases. And acetylcholinesterase (AChE) is considered as an important target for treating AD. Acetylcholinesterase inhibitors (AChEI) are considered to be one of the effective drugs for the treatment of AD. The aim of this study is to find a novel potential AChEI as a drug for the treatment of AD. In this study, instead of using the synthetic compounds, we used those extracted from plants to investigate the interaction between floribundiquinone B (FB) and AChE by means of both the experimental approach such as fluorescence spectra, ultraviolet-visible (UV-vis) absorption spectrometry, circular dichroism (CD) and the theoretical approaches such as molecular docking. The findings reported here have provided many useful clues and hints for designing more effective and less toxic drugs against Alzheimer's disease. PMID- 28915663 TI - MiR-223-3p inhibits angiogenesis and promotes resistance to cetuximab in head and neck squamous cell carcinoma. AB - MicroRNAs (miRs) participate in tumor growth and dissemination by regulating expression of various target genes. MiR-223-3p is suspected of being involved in head and neck squamous cell carcinoma (HNSCC) growth although its precise role has not been elucidated. In this study, we showed that miR-223-3p is present in biopsies of HNSCC patients and that its presence is correlated with high neutrophil infiltrate. We found that overexpression of miR-223-3p slightly increased proliferation of the CAL27 squamous carcinoma cell line both in vitro and in vivo. Moreover, miR-223-3p induced CAL27 apoptosis in an orthotopic xenograft mouse model, counteracting the proliferative effect and resulting in no impact on overall tumor growth. We analyzed the effect of miR-223-3p overexpression on signaling pathways and showed that it induced pERK2, pAKT and AKT, consistent with an increase in cell proliferation. In addition, we found that miR-223-3p reduced the STAT3 level correlating with increased cell apoptosis and inhibited vasculature formation. In HNSCC tissues, miR-223-3p expression was inversely correlated to CD31, highlighting the relationship between miR-223 and vessel formation. Finally, we studied the effect of miR-223-3p on response to selected anticancer agents and showed that cells expressing miR-223-3p are more resistant to drugs, notably cetuximab. In conclusion, our study is the first to show the antiangiogenic properties of miR-223-3p in HNSCC patients and to question whether expression levels of miR-223-3p can be evaluated as an indicator of eligibility for non-treatment of HNSCC patients with cetuximab. PMID- 28915664 TI - Morusin inhibits cell proliferation and tumor growth by down-regulating c-Myc in human gastric cancer. AB - Morusin is a pure extract from the root bark of Morus australis (Moraceae). In recent years, morusin has been reported to exhibit anti-tumor biological activity in some types of human cancers through different mechanisms. Here, we attempted to investigate the inhibitory effect and mechanism of morusin on gastric cancer. Morusin markedly inhibited gastric cancer cell proliferation by down-regulating CDKs and Cyclins, such as CDK2, CDK4, Cyclin D1 and Cyclin E1. Additionally, morusin suppressed tumor growth in vitro and in vivo. Up-regulation of CDKs and Cyclins in gastric cancer cells was induced by c-Myc binding at the E-Box regions of CDKs and the Cyclin promoter. In addition, compared with the control group, the morusin-treated group showed reduced expression of c-Myc and c-Myc protein binding at the E-Box regions. Based on these results, we overexpressed c-Myc in gastric cancer cells and found that overexpressing c-Myc rescued morusin-induced inhibition of cell proliferation and tumor growth. These results suggest that morusin inhibits cell proliferation and tumor growth by down-regulating c-Myc in human gastric cancer. PMID- 28915665 TI - The ketogenic diet is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer's syndrome. AB - The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFalpha) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFalpha, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction. PMID- 28915666 TI - ARD1-mediated aurora kinase A acetylation promotes cell proliferation and migration. AB - Aurora kinase A (AuA) is a prerequisite for centrosome maturation, separation, and mitotic spindle assembly, thus, it is essential for cell cycle regulation. Overexpression of AuA is implicated in poor prognosis of many types of cancer. However, the regulatory mechanisms underlying the functions of AuA are still not fully understood. Here, we report that AuA colocalizes with arrest defective protein 1 (ARD1) acetyltransferase during cell division and cell migration. Additionally, AuA is acetylated by ARD1 at lysine residues at positions 75 and 125. The double mutations at K75/K125 abolished the kinase activity of AuA. Moreover, the double mutant AuA exhibited diminished ability to promote cell proliferation and cell migration. Mechanistic studies revealed that AuA acetylation at K75/K125 promoted cell proliferation via activation of cyclin E/CDK2 and cyclin B1. In addition, AuA acetylation stimulated cell migration by activating the p38/AKT/MMP-2 pathway. Our findings indicate that ARD1-mediated acetylation of AuA enhances cell proliferation and migration, and probably contributes to cancer development. PMID- 28915667 TI - Assessment of near-infrared fluorophores to study the biodistribution and tumor targeting of an IL13 receptor alpha2 antibody by fluorescence molecular tomography. AB - Non-invasive imaging using radiolabels is a common technique used to study the biodistribution of biologics. Due to the limited shelf-life of radiolabels and the requirements of specialized labs, non-invasive optical imaging is an attractive alternative for preclinical studies. Previously, we demonstrated the utility of fluorescence molecular tomography (FMT) an optical imaging modality in evaluating the biodistribution of antibody-drug conjugates. As FMT is a relatively new technology, few fluorophores have been validated for in vivo imaging. The goal of this study was to characterize and determine the utility of near-infrared (NIR) fluorophores for biodistribution studies using interleukin-13 receptor subunit alpha-2 antibody (IL13Ralpha2-Ab). Eight fluorophores (ex/em: 630/800 nm) with an N-hydroxysuccinimide (NHS) linker were evaluated for Ab conjugation. The resulting antibody-fluorophore (Ab-F) conjugates were evaluated in vitro for degree of conjugation, stability and target-binding, followed by in vivo/ex vivo FMT imaging to determine biodistribution in a xenograft model. The Ab-F conjugates (except Ab-DyLight800) showed good in vitro stability and antigen binding. All Ab-F conjugates (except for Ab-BOD630) resulted in a quantifiable signal in vivo and had similar biodistribution profiles, with peak tumor accumulation between 6 and 24 h post-injection. In vivo/ex vivo FMT imaging showed 17-34% ID/g Ab uptake by the tumor at 96 h. Overall, this is the first study to characterize the biodistribution of an Ab using eight NIR fluorophores. Our results show that 3-dimensional optical imaging is a valuable technology to understand biodistribution and targeting, but a careful selection of the fluorophore for each Ab is warranted. PMID- 28915669 TI - Folate metabolism genetic polymorphisms and meningioma and glioma susceptibility in adults. AB - Polymorphic variants of genes involved in folate metabolism are implicated in the susceptibility to meningioma and glioma, but the results from published articles are controversial and inconclusive. Therefore, we performed this meta-analysis including all studies available to evaluate the relationship between folate metabolism genetic polymorphisms and the susceptibility to meningioma and glioma in adults. We searched the literature in PubMed, EMBASE and Cochrane Central Library for relevant articles published up to August 2016. The odds ratios (ORs) and the corresponding 95% confidence intervals (95%Cls) were used to evaluate the associations of two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) with the risk of meningioma and glioma in adults. We found significant association of MTHFR A1298C (rs1801131) variant genotypes with increased incidence of meningioma and glioma in this study population (CA vs. AA: OR=1.22, P<0.001; CA+CC vs. AA: OR=1.18, P=0.002). Moreover, we found that MTRR A66G (rs1801394) variant genotypes was associated with increased risk of meningioma and glioma (G vs. A: OR=1.11, P=0.020; GG vs. AA+AG: OR=1.17, P=0.043; GG vs. AA: OR=1.22, P=0.023). In conclusion, our meta-analysis suggests that two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) contribute to genetic susceptibility to meningioma and glioma in adults. PMID- 28915668 TI - NSC30049 inhibits Chk1 pathway in 5-FU-resistant CRC bulk and stem cell populations. AB - The 5-fluorouracil (5-FU) treatment induces DNA damage and stalling of DNA replication forks. These stalled replication forks then collapse to form one sided double-strand breaks, leading to apoptosis. However, colorectal cancer (CRC) stem cells rapidly repair the stalled/collapsed replication forks and overcome treatment effects. Recent evidence suggests a critical role of checkpoint kinase 1 (Chk1) in preventing the replicative stress. Therefore, Chk1 kinase has been a target for developing mono or combination therapeutic agents. In the present study, we have identified a novel orphan molecule NSC30049 (NSC49L) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk and FOLFOX-resistant cell lines in culture with minimal effect on normal colonic epithelial cells. It also inhibits the sphere forming activity of CRC stem cells, and decreases the expression levels of mRNAs of CRC stem cell marker genes. Results showed that NSC49L induces 5-FU-mediated S-phase cell cycle arrest due to increased load of DNA damage and increased gamma-H2AX staining as a mechanism of cytotoxicity. The pharmacokinetic analysis showed a higher bioavailability of this compound, however, with a short plasma half-life. The drug is highly tolerated by animals with no pathological aberrations. Furthermore, NSC49L showed very potent activity in a HDTX model of CRC stem cell tumors either alone or in combination with 5-FU. Thus, NSC49L as a single agent or combined with 5-FU can be developed as a therapeutic agent by targeting the Chk1 pathway in 5-FU-resistant CRC heterogeneous bulk and CRC stem cell populations. PMID- 28915670 TI - Prostate cancer diagnosis using epigenetic biomarkers, 3D high-content imaging and probabilistic cell-by-cell classifiers. AB - BACKGROUND: Prostate cancer (PCa) management can benefit from novel concepts/biomarkers for reducing the current 20-30% chance of false-negative diagnosis with standard histopathology of biopsied tissue. METHOD: We explored the potential of selected epigenetic markers in combination with validated histopathological markers, 3D high-content imaging, cell-by-cell analysis, and probabilistic classification in generating novel detailed maps of biomarker heterogeneity in patient tissues, and PCa diagnosis. We used consecutive biopsies/radical prostatectomies from five patients for building a database of ~140,000 analyzed cells across all tissue compartments and for model development; and from five patients and the two well-characterized HPrEpiC primary and LNCaP cancer cell types for model validation. RESULTS: Principal component analysis presented highest covariability for the four biomarkers 4',6-diamidino-2 phenylindole, 5-methylcytosine, 5-hydroxymethylcytosine, and alpha-methylacyl-CoA racemase in the epithelial tissue compartment. The panel also showed best performance in discriminating between normal and cancer-like cells in prostate tissues with a sensitivity and specificity of 85%, correctly classified 87% of HPrEpiC as healthy and 99% of LNCaP cells as cancer-like, identified a majority of aberrant cells within histopathologically benign tissues at baseline diagnosis of patients that were later diagnosed with adenocarcinoma. Using k-nearest neighbor classifier with cells from an initial patient biopsy, the biomarkers were able to predict cancer stage and grade of prostatic tissue that occurred at later prostatectomy with 79% accuracy. CONCLUSION: Our approach showed favorable diagnostic values to identify the portion and pathological category of aberrant cells in a small subset of sampled tissue cells, correlating with the degree of malignancy beyond baseline. PMID- 28915671 TI - Integration of ALV into CTDSPL and CTDSPL2 genes in B-cell lymphomas promotes cell immortalization, migration and survival. AB - Avian leukosis virus induces tumors in chickens by integrating into the genome and altering expression of nearby genes. Thus, ALV can be used as an insertional mutagenesis tool to identify novel genes involved in tumorigenesis. Deep sequencing analysis of viral integration sites has identified CTDSPL and CTDSPL2 as common integration sites in ALV-induced B-cell lymphomas, suggesting a potential role in driving oncogenesis. We show that in tumors with integrations in these genes, the viral promoter is driving the expression of a truncated fusion transcript. Overexpression in cultured chick embryo fibroblasts reveals that CTDSPL and CTDSPL2 have oncogenic properties, including promoting cell migration. We also show that CTDSPL2 has a previously uncharacterized role in protecting cells from apoptosis induced by oxidative stress. Further, the truncated viral fusion transcripts of both CTDSPL and CTDSPL2 promote immortalization in primary cell culture. PMID- 28915672 TI - An updated meta-analysis of amantadine for treating dyskinesia in Parkinson's disease. AB - In recent years, a few of randomized controlled trials (RCTs) about amantadine for treating dyskinesia in Parkinson's disease (PD) were completed. Here, we conducted a systematic literature review about the clinical research to provide the updated evidence for treating dyskinesia. Electronic search of Medline, PubMed, Cochrane Library, and other databases up to May 2016 for relevant studies was performed. We selected the Unified Parkinson's Disease Rating Scale IV (UPDRS IV) and Dyskinesia Rating Scales (DRS) as efficacy outcomes of amantadine on dyskinesia. Pooled data from included studies was then used to carry out meta analysis. A total of eleven eligible RCTs that involved 356 PD patients with existing dyskinesia were included in the present study. The results of meta analysis showed that amantadine significantly improved UPDRS IV (P < 0.0001) and DRS (P < 0.00001). Meanwhile, there was a mild reduction in Unified Parkinson's Disease Rating Scale III after amantadine treatment in advanced PD patients with dyskinesia (P = 0.01) compared with placebo. High dosage of amantadine obviously improved existing dyskinesia in PD, yet at the expense of the increased adverse events. It was necessary to detect the optimal therapeutic efficacy to balance the incidence of adverse events when we used amantadine to treat existing dyskinesia in PD patients. PMID- 28915673 TI - Prognositic value of CD73-adenosinergic pathway in solid tumor: A meta-analysis and systematic review. AB - CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that is encoded by NT5E gene, plays multiple roles in tumor processes. Previous studies have presented a potential value of CD73 served as a detectable biomarker for prognosis of several solid tumors, but the results were more controversially. A comprehensive meta-analysis was conducted to precisely evaluate the prognostic role of CD73 in solid tumors. The included studies were searched in PubMed, Web of Science and EBSCO from Jan 1990 to Jan 2016. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for overall survival (OS), disease free survival (DFS) were carried out using a fixed or random effects model. Totally, 13 studies about 12,533 patients were included. CD73-high expression was correlating with poor OS (pooled HR = 1.28, 95% CI = 1.19-1.37). In addition, CD73 expression had borderline association with worse DFS (pooled HR = 1.28, 95% CI = 1.01-1.62). Egger's tests indicated that there was no evidence of significant publication bias. CD73 is an efficient prognostic biomarker in solid tumors, and over-expression of CD73 is associated with inverse OS or DFS. But this predictive value and target therapy for clinical practice yet needs advanced research. PMID- 28915674 TI - Bevacizumab combined with chemotherapy for glioblastoma: a meta-analysis of randomized controlled trials. AB - Bevacizumab, as antibodies, were applied to inhibit tumor angiogenesis by preventing activation of vascular endothelial growth factor receptor. We analyzed four clinical trials, including 607 patients, to investigate the efficacy and safety of bevacizumab when combined with chemotherapy for the treatment of glioblastomas. Results demonstrated that bevacizumab when combined with chemotherapy improved progression-free survival (HR = 0.66; 95% CI 0.56-0.78; p < 0.00001) compared with bevacizumab or chemotherapy alone. Furthermore, overall survival showed insignificant difference between two arms (HR 0.99; 95% CI 0.8 1.21; p = 0.92). However, we found that patients treated with bevacizumab containing therapy reported increased objective response rate (OR 1.85, 95% CI 1.17-2.93; p = 0.009), but more treatment-related adverse events (OR 1.75; 95% CI 1.09-2.83; p = 0.02). PMID- 28915675 TI - Association of apelin and apelin receptor with the risk of coronary artery disease: a meta-analysis of observational studies. AB - It is well established that apelin-APLNR (apelin receptor) pathway plays a central role in cardiovascular system. In this meta-analysis, we summarized published results on circulating apelin concentration in association with coronary artery disease (CAD), apelin and APLNR genetic polymorphism(s) in predisposition to CAD risk and circulating apelin changes after surgical treatment for CAD. The results from 15 articles were pooled. Two authors independently took charge of literature search, article selection and information collection. Overall, circulating apelin concentration was significantly lower in CAD patients (N=1021) than in controls (N=654) (weighted mean difference [WMD]: 1.285 ng/mL, 95% confidence interval [CI]: -1.790 to -0.780, P<0001), with significant heterogeneity (I2=99.3%) but without publication bias. For the association of APLNR gene rs9943582 polymorphism with CAD (patients/controls: 5975/4717), the mutant T allele was associated with a 5.2% increased risk relative to the wild C allele (odds ratio: 1.052, 95% CI: 0.990 to 1.117, P=0.100), without heterogeneity (I2=0.0%) or publication bias. Circulating apelin was increased significantly after surgical treatment for CAD (N=202) (WMD: 2.011 ng/mL, 95% CI: 0.541 to 3.481, P=0.007), with significant heterogeneity (I2=98.0%). Stratified analyses showed that circulating apelin was significantly reduced in studies with age- and sex-matched patients and controls (WMD: -1.881 ng/mL, 95% CI: -2.457 to -1.304, P<0.001) and with total sample size >=125 (WMD: 1.657 ng/mL, 95% CI: -2.378 to -0.936, P<0.001), relative to studies without matching reports and with total sample size <125. In brief, our results suggested that circulating apelin was a prominent athero-protective marker against the development of CAD. PMID- 28915676 TI - Clinical outcomes of WBRT plus EGFR-TKIs versus WBRT or TKIs alone for the treatment of cerebral metastatic NSCLC patients: a meta-analysis. AB - Whether WBRT plus EGFR-TKIs has a greater survival benefit than EGFR-TKIs alone or WBRT alone remains controversial in NSCLC patients with multiple brain metastases. To rectify this, we conducted a systematic meta-analysis based on 9 retrospective studies and 1 randomized controlled study published between 2012 and 2016, comprising 1041 patients. Five studies were included in the comparison of WBRT plus EGFR-TKIs and EGFR-TKIs alone. The combined HR for OS of patients with EGFR mutation was 1.25 [95% CI 0.98-2.15; P = 0.08] and for intracranial PFS was 1.30 [95% CI 1.03-1.65; P = 0.03], which revealed that EGFR-TKIs alone produced a superior intracranial PFS than WBRT plus EGFR-TKIs. Five studies were included in the comparison of WBRT plus EGFR-TKIs and WBRT alone. The combined HR for OS, intracranial PFS and extracranial PFS were 0.52 [95% CI 0.37-0.75; P = 0.0004], 0.36 [95% CI 0.24-0.53; P < 0.001] and 0.52 [95% CI 0.38-0.71; P < 0.001], respectively, which revealed a significant benefit of WBRT plus EGFR-TKIs compared with WBRT alone. The results indicated that EGFR-TKIs alone should be the first option for the treatment of NSCLC patients with multiple BM, especially with EGFR mutation, since it provides similar OS and extracranial PFS but superior intracranial PFS compared with WBRT plus EGFR-TKIs. PMID- 28915677 TI - Docetaxel versus docetaxel plus cisplatin for non-small-cell lung cancer: a meta analysis of randomized clinical trials. AB - OBJECTIVE: To compare the activity, efficacy and toxicity of docetaxel versus docetaxel plus cisplatin in patients with non-small-cell lung cancer. METHODS: A literature search was performed in the EMBASE, Medline, Cochrane Library, Web of Science, China National Knowledge Internet, Wan-fang databases. The trials that were found were then evaluated for eligibility. The Cochrane Collaboration's Review Manager software was used to perform the meta-analyses. RESULTS: Nine clinical trials including 1257 patients were included. The docetaxel plus cisplatin regimens had higher overall response rates compared with the docetaxel regimen (RR = 0.70; 95% CI, 0.61 to 0.80; P < 0.00001). No statistically significant difference was observed between the two regimens with respect to the one-year survival rate (RR = 1.04; 95% CI, 0.90 to 1.19; P = 0.62). Patients treated with the DP regimen were more likely to experience anemia, thrombocytopenia, nausea/vomiting, nephrotoxicity, hyponatremia, mucositis and treatment-related deaths compared with patients treated with docetaxel alone. No significant difference was observed between the two regimens with respect to the occurrence of neurotoxicity, diarrhea, fatigue, pneumonitis, neutropenia and leucopenia. CONCLUSIONS: The docetaxel plus cisplatin combination regimen resulted in a high response rate and a high adverse effect rate compared with docetaxel monochemotherapy for non-small-cell lung cancer. PMID- 28915678 TI - Meta-analysis of the incidence and risks of interstitial lung disease and QTc prolongation in non-small-cell lung cancer patients treated with ALK inhibitors. AB - BACKGROUND: To conduct a systematic review and meta-analysis to assess the overall incidence and risk of interstitial lung disease (ILD) and QTc prolongation associated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) in non-small-cell lung cancer (NSCLC) patients. RESULTS: A total of 1,770 patients from 8 clinical trials were included. The incidences of high-grade ILD and QTc prolongation was 2.5% (95% CI 1.7-3.6%), and 2.8% (95% CI 1.8-4.3%), respectively. Meta-analysis demonstrated that the use of ALK-TKIs in NSCLC patients significantly increased the risk of developing high-grade ILD (Peto OR, 3.27, 95%CI: 1.18-9.08, p = 0.023) and QTc prolongation (Peto OR 7.51, 95% CI, 2.16-26.15; p = 0.002) in comparison with chemotherapy alone. MATERIALS AND METHODS: A systematic literature search was performed to identify related citations up to January 31, 2017. Data were extracted, and summary incidence rates, Peto odds ratios (Peto ORs), and 95% confidence intervals (CIs) were calculated. CONCLUSIONS: The use of ALK-TKIs significantly increases the risk of developing high-grade ILD and QTc prolongation in lung cancer patients. Clinicians should pay attention to the risks of severe ILD and QTc prolongation with the administration of these drugs. PMID- 28915679 TI - Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta analysis. AB - BACKGROUND: In patients with gastric cancer, the prognostic value of tumor infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer. MATERIALS AND METHODS: We identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity. RESULTS: A total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43-0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients' survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04-2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60-0.96; P = 0.022). CONCLUSIONS: This meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer. PMID- 28915680 TI - Combination therapy versus pharmacotherapy, endoscopic variceal ligation, or the transjugular intrahepatic portosystemic shunt alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized controlled trials. AB - Patients with liver cirrhosis and variceal hemorrhage are at increased risk of rebleeding. We performed a meta-analysis toassess the clinical efficacy of combination therapy (pharmacotherapy and endoscopic variceal ligation (EVL)) compared with pharmacotherapy, EVL, or transjugular intrahepatic portosystemic shunt (TIPS) alone in the prevention of rebleeding and mortality. A literature search of MEDLINE, EMBASE, and the Cochrane Controlled Trials Register, up until November 2016, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0. Regarding overall mortality, combination therapy was as effective as EVL, pharmacotherapy, and TIPS (relative risk (RR) = 0.62, 95% confidence interval (CI): 0.36-1.08, RR=1.05, 95% CI: 0.68-1.63, and RR=1.39, 95% CI: 0.92-2.09, respectively). Combination therapy was as effective as EVL and pharmacotherapy alone in reducing blood-related mortality (RR=0.43, 95% CI: 0.15 1.25, and RR=0.42, 95% CI: 0.17-1.06), whereas TIPS was more effective than combination therapy (RR=5.66, 95% CI: 1.02-31.40). This was also the case for rebleeding; combination therapy was more effective than EVL and pharmacotherapy alone (RR=0.57, 95% CI: 0.41-0.79, and RR=0.65, 95% CI: 0.48-0.88), whereas TIPS was more effective than combination therapy (RR=9.42, 95% CI: 2.99-29.65). Finally, regarding rebleeding from esophageal varices, combination therapy was as effective as EVL alone (RR=0.59, 95% CI: 0.33-1.06) and was more effective than pharmacotherapy alone (RR=0.58, 95% CI: 0.40-0.85), although was less effective than TIPS (RR=2.20, 95% CI: 1.22-3.99). TIPS was recommended as the first choice of therapy in the secondary prevention of esophageal variceal bleeding. PMID- 28915681 TI - Association of P73 polymorphisms with susceptibilities of cervical carcinoma: a meta-analysis. AB - OBJECTIVE: The relation between P73 gene polymorphism and cervical cancer has not been determined. At present, we utilized a meta-analysis method to elucidate the association between P73 and cervical cancer. RESULTS: The present study included 635 patients with cervical cancer and 998 cancer-free control subjects. Using meta-analysis, we found a significant association of P73 genetic polymorphism with cervical cancer in a recessive model [OR = 0.91, 95% CI: 0.84-0.98; P = 0.02.]. However, this association was not find in a dominant model [OR = 0.76, 95% CI (0.45-1.27); P = 0.29], in a co-dominant model [OR = 1.01; 95% CI: 0.98 1.04, P = 0.56] or in an allelic model [OR = 0.97, 95% CI: 0.93-1.00; P = 0.09]. MATERIALS AND METHODS: To further evaluate the relation between the P73 gene polymorphism and cervical cancer, we selected 5 case-control studies related to P73 gene polymorphism and cervical cancer by searching CNKI, VIP, WanFang, PubMed and EMbase database. We utilized Q-test and I2 test to test the heterogeneity between each study. The fixed effects model was utilized to calculate the odds ratio (OR) and its 95% confidence interval. CONCLUSIONS: Our results suggest that P73 gene polymorphism was associated with the risk of cervical cancer. However, our conclusion still requires large sample size of case-control studies or cohort studies to further confirm this result. PMID- 28915682 TI - Systematic review and meta-analysis of the efficacy of breast conservation therapy followed by radiotherapy in four breast cancer subtypes. AB - The different molecular subtypes of breast cancer are associated with distinct outcomes. We assessed the efficacy of breast conservation therapy (BCT) followed by radiotherapy for patients with different breast cancer subtypes. We searched the MEDLINE, EMBASE, and Cochrane Library databases to identify studies published prior to April 30, 2016 that assessed the efficacy of BCT followed by radiotherapy in breast cancer patients with different molecular subtypes. A meta analysis of seven studies that included 3,798 luminal A, 770 luminal B, 344 human epidermal growth factor receptor 2 (Her-2), and 767 triple-negative breast cancer (TNBC) patients was performed. The pooled odds ratio [OR] for local relapse-free survival in luminal A compared to Her-2 patients was 0.1960 (95% confidence interval [CI]: 0.0440-0.8728, p = 0.0325) at 5 years and 0.2592 (95% CI: 0.1301 0.5167, p = 0.0001) at 10 years. The pooled OR for local-regional relapse-free survival in luminal A compared to TNBC patients was 0.1381 (95% CI: 0.0565 0.3374, p = 0.0000) at 5 years and 0.1221 (95% CI: 0.0182-0.8192, p = 0.0304) at 10 years. Thus, the rate of local-regional control is higher in luminal A patients than in Her-2 or TNBC patients. PMID- 28915683 TI - Association between 8q24 rs6983267 polymorphism and cancer susceptibility: a meta analysis involving 170,737 subjects. AB - Published data on the association between 8q24 rs6983267 polymorphism and cancer risk are inconsistent. Thus, we conducted a meta-analysis to evaluate the relationship between rs6983267 polymorphism and cancer risk. We searched on PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) up to November 1, 2016 for relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of this association. We included 78 case-control studies with a total of 73,996 cases and 96,741 controls in this meta-analysis. The pooled results showed that rs6983267 polymorphism was significantly associated with increased risk of overall cancer in all genetic models (dominant model: OR = 1.19, 95% CI = 1.13-1.26; recessive model: OR = 1.19, 95% CI = 1.14-1.25; homozygous model: OR= 1.31, 95% CI = 1.23-1.40; heterozygous model: OR = 1.14, 95% CI = 1.10-1.19; allelic model: OR = 1.14, 95% CI = 1.11-1.18). Stratified analyses indicated that rs6983267 significantly increased the risk of colorectal cancer in Caucasians, prostate cancer in Caucasians and Asians, thyroid cancer in Caucasians and lung cancer in Asians. When studies were stratified by study quality, source of controls and genotyping method, significant associations were especially found in the high quality studies, the publication-based studies, the hospital-based studies, and the PCR RFLP studies. Additional well-designed studies with large samples should be performed to validate our results. PMID- 28915684 TI - Lack of association between NAT2 polymorphism and prostate cancer risk: a meta analysis and trial sequential analysis. AB - Previous studies have investigated the association between NAT2 polymorphism and the risk of prostate cancer (PCa). However, the findings from these studies remained inconsistent. Hence, we performed a meta-analysis to provide a more reliable conclusion about such associations. In the present meta-analysis, 13 independent case-control studies were included with a total of 14,469 PCa patients and 10,689 controls. All relevant studies published were searched in the databates PubMed, EMBASE, and Web of Science, till March 1st, 2017. We used the pooled odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association between NAT2*4 allele and susceptibility to PCa. Subgroup analysis was carried out by ethnicity, source of controls and genotyping method. What's more, we also performed trial sequential analysis (TSA) to reduce the risk of type I error and evaluate whether the evidence of the results was firm. Firstly, our results indicated that NAT2*4 allele was not associated with PCa susceptibility (OR = 1.00, 95% CI= 0.95-1.05; P = 0.100). However, after excluding two studies for its heterogeneity and publication bias, no significant relationship was also detected between NAT2*4 allele and the increased risk of PCa, in fixed-effect model (OR = 0.99, 95% CI= 0.94-1.04; P = 0.451). Meanwhile, no significant increased risk of PCa was found in the subgroup analyses by ethnicity, source of controls and genotyping method. Moreover, TSA demonstrated that such association was confirmed in the present study. Therefore, this meta analysis suggested that no significant association between NAT2 polymorphism and the risk of PCa was found. PMID- 28915685 TI - Prognostic significance of neutrophil-to-lymphocyte ratio in patients with malignant pleural mesothelioma: a meta-analysis. AB - Systemic inflammation responses can be reflected by peripheral blood count and combine index like the neutrophil-to-lymphocyte (NLR). The NLR has been reported to be a poor prognostic indicator in cancer recently. However, the prognostic effect of the NLR in patients with malignant pleural mesothelioma (MPM) still unclear yet. We conducted this meta-analysis aiming to evaluate the pooled value of NLR in prognosis as well as clinical characteristics in malignant pleural mesothelioma. A total of 11 studies with 1533 patients were included in this meta analysis, in which 10 studies investigated the prognosis role of NLR using hazard ratio (HR) and 95% confidence intervals (95% CI). The elevated NLR was detected to be associated with a poor overall survival (OS)(HR=1.48, 95%CI=1.16-1.89, P < 0.001). The significant prognostic roles of NLR were also indicated in subgroup analyses. NLR level was also associated with histology instead of gender, stage or performance status (PS) score. These findings suggested that the elevated NLR could be a potential prognostic factor for malignant pleural mesothelioma patients and might be associated with histology as an efficient clinical index to stratify patients. PMID- 28915686 TI - Evaluation on efficacy and safety of the addition of X-knife therapy to gefitinib in NSCLC patients with symptomatic brain metastases. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a widely used therapy for brain metastases(BMs) in Non-small cell lung cancer(NSCLC). However, its role in symptomatic patients with EGFR mutation remains unclear. We have retrospectively reviewed the clinical data of patients with symptomatic BMs whom received SRS as a salvage approach and concurrent gifitinib therapy. METHODS: Seven patients with primary NSCLC, symptomatic BMs, and EGFR mutation were identified in a retrospective review of patients treated with SRS using X-knife at Guangdong 999 Brain Hospital between 1 January 2012 and 31 August 2014. The median follow-up of these patients was 16 months. Image fusion technique was used to determine cumulative doses to targeted lesions, whole brain, and critical brain structures. Toxicities and complications were identified by clinical records. RESULTS: SRS(X knife) was selected to be performed on seven patients (two males and five females) diagnosed with NSCLC and EGFR mutation due to the presence of encephaledema, compression of ventricles, or other complications. Neurological symptoms (such as paresis, aphasia, sensory and visual disturbances) were not present in any patients before or after SRS treatment, and the postoperative Karnofsky performance status(KPS) was improved in all patients. Median overall survival(OS) was 16 months and median progression free survival(PFS) was 10 months. CONCLUSIONS: The improvement of KPS and survival were reliable by SRS(X knife) with concurrent gifitinib therapy in NSCLC patients with symptomatic BMs, and EGFR mutation. Given the small sample size, further prospective studies with a greater number of patients are warranted to confirm our results. PMID- 28915688 TI - Neutrophil-to-lymphocyte ratio and neurological deterioration following acute cerebral hemorrhage. AB - Immunity plays key roles in pathophysiology of intracerebral hemorrhage (ICH). The aim of the study was to determine whether the peripheral leukocyte count and neutrophil-to-lymphocyte ratio (NLR) predicted neurological deterioration (ND) after ICH. We identified consecutive patients with ICH who had blood sampling performed within 24 hours from symptom's onset. Total white blood cells (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were retrieved, and the NLR computed as the ratio of the ANC to ALC values. The study endpoint was the occurrence of neurological deterioration (ND) within 7 days after ICH. One hundred ninety-two subjects were enrolled, whose 54 (28.1%) presented ND. At multivariate analysis, the WBC (adjusted odd ratio [adjOR] for 1,000 leukocytes increase 1.29, 95% confidence interval [CI] 1.11-1.50), ANC (adjOR for 1,000 neutrophils increase 1.61, 95% CI 1.30-1.99), ALC (adjOR for 1,000 lymphocytes increase 0.21, 95% CI 0.09-0.49) and NLR (adjOR for 1-point increase 1.65, 95% CI 1.36-2.00) were independently associated with ND (p<=0.001). The NLR resulted the best discriminating variable for the occurrence of the adverse outcome (area under the curve 0.888, 95% CI 0.832-0.945; p < 0.001). The NLR predicted ND after acute ICH and can aid in the risk stratification of patients. PMID- 28915687 TI - Features and risk factors of carotid atherosclerosis in a population with high stroke incidence in China. AB - Epidemiological studies have reported associations between traditional cardiovascular risk factors and carotid intima-media thickness (CIMT) or carotid plaque. However, definite risk factors at different phases of carotid atherosclerosis remain controversial. We aimed to explore risk factors and characteristics of carotid atherosclerosis at different stages in a low-income population with a high incidence of stroke in China. Between April 2014 and January 2015, we recruited 3789 stroke-free and cardiovascular disease-free residents aged >= 45 years. B-mode ultrasonography was performed to measure CIMT and the presence of carotid plaque. Traditional risk factors were compared between the increased CIMT group and normal CIMT group, and between those with and without carotid plaque. A total of 3789 participants were assessed in this study, with a mean age (standard deviation) of 59.92 (9.70) years. The prevalence of increased CIMT and carotid plaque increased with older age and higher education levels. Age, hypertension, diabetes, and high low-density lipoprotein cholesterol levels were risk factors for increased CIMT and carotid plaque. Furthermore, compared to never smoking, passive smoking was positively associated with increased CIMT, with an odds ratio (95% confidence interval) of 1.26 (1.05, 1.53; P = 0.016); high body mass index was an obvious protective factor against carotid plaque, with an odds ratio (95% confidence interval) of 0.97 (0.95, 0.99; P = 0.004). It is important to identify factors associated with atherosclerosis to prevent cardiovascular disease and stroke and reduce the burden of stroke in this high-risk population. PMID- 28915689 TI - Different long-term oncologic outcomes after radical surgical resection for neuroendocrine carcinoma and adenocarcinoma of the stomach. AB - PURPOSE: To explore differences in long-term outcomes between gastric neuroendocrine carcinoma (GNEC) and gastric adenocarcinoma (GAC). METHODS: One hundred GNEC patients and 3089 GAC patients were enrolled. Differences in long term outcomes between the groups were analyzed by 1:2 propensity score matching. RESULTS: Statistically significant differences between the groups were noted in terms of gender, American Society of Anesthesiologists score, tumor size, T stage, N stage, TNM stage and surgical approach. However, differences were not significant after matching. The 3-year and 5-year overall survival rates for the GNEC group were reduced compared with those for the GAC group, though disease free survival rates and mean recurrence times were similar. Notably, the mean post-recurrence survival of the GNEC group was significantly worse than that of the GAC group (5.2 vs. 14.8 months, p<0.001). A strong negative correlation was found between a high Ki-67 labeling index and overall survival time. Cox regression analysis indicated the Ki-67 labeling index to be an independent factor influencing patient post-recurrence survival. CONCLUSIONS: The long-term oncologic outcome of GNEC was worse than that of GAC, which may be relative to its reduced post-recurrence survival. A high Ki-67 labeling index was an independent factor influencing patient post-recurrence survival. PMID- 28915690 TI - Efficacy and safety of a reduced calcineurin inhibitor dose combined with mycophenolate mofetil in liver transplant patients with chronic renal dysfunction. AB - Calcineurin inhibitors (CNIs) are frequently given at a reduced dose in combination with mycophenolate mofetil (MMF) to avoid nephrotoxicity, but the optimal reduction in CNI dose has not been established. In this prospective, open label, multicenter study, liver transplant recipients with chronic renal dysfunction who were administered a CNI-based immunosuppressive regimen were included in the intent-to-treat (ITT) population. The primary endpoint was declination in renal function, which was defined as a >= 20% decrease in the glomerular filtration rate during the year following regimen adjustment. In the ITT population, renal function declined after regimen adjustment in three patients (7%) in the MMF plus 50% CNI reduction group. Additionally, three of 40 patients (7.5%) in the MMF plus 75% CNI reduction group experienced at least one clinically suspected or biopsy-proven acute rejection. There were no differences between the two groups. The corrected mean improvement in creatinine clearance at week 52 was 6.551 mL/min in the MMF plus 50% CNI reduction group and 6.442 mL/min in the MMF plus at least 75% CNI reduction group. Thus, a regimen of MMF combined with a 50% or at least 70% reduction in CNI dose could improve renal function and was both tolerable and safe. PMID- 28915691 TI - Preoperative monocyte-lymphocyte and neutrophil-lymphocyte but not platelet lymphocyte ratios are predictive of clinical outcomes in resected patients with non-metastatic Siewert type II/III adenocarcinoma of esophagogastric junction: a prospective cohort study (the AMONP corhort). AB - AIMS: To propectively reveal the clinicopathological and prognostic significances of monocyte-lymphocyte ratio (MLR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in resected patients with non-metastatic Siewert type II/III adenocarcinoma of esophagogastric junction (AEG). METHODS: A total of 611 patients diagnosed with Siewert type II/III AEG and undergoing surgery between 2006 and 2011 were prospectively followed-up until April 2016. Associations between preoperative peripheral MLR, NLR, and PLR and clinicopathological parameters were quantified using the multivariate Logistic regression model with adjustment. The correlation between the 3 ratios and cancer specific survival (CSS) was investigated using the univariate and adjusted multivariate Cox regression models with stratifications. The periodical survival rates for the low- and high-level arms were obtained using the Kaplan-Meier method. RESULTS: We set the medians (0.223, 2.22, and 124.4) as the cut-off values of preoperative MLR, NLR, and PLR, respectively. MLR was higher in male patients and those > 63 years; PLR was higher in patients with type II tumors. The (marginally-)significantly inverse ratio-CSS association was detected in male patients, those <= 63 years, those with type III tumors, and those with pTNM stage III tumors for MLR, and in female patients, those > 63 years, those with type III tumors, those with vessel invasion, and those with stage III tumors for NLR, but was generally negative concerning PLR. The association majorly existed in type III and pTNM stage III tumors. CONCLUSION: MLR and NLR might be prognostic factors for patients with non-metastatic Siewert type II/III AEG, while PLR had limited significance. PMID- 28915693 TI - The application of IS6110-baced loop-mediated isothermal amplification (LAMP) in the early diagnosis of tuberculous meningitis. AB - Here, we evaluated the potential activity of rapid Mycobacterium tuberculosis detection with loop-mediated isothermal amplification (LAMP), for the early diagnosis of tuberculous meningitis (TBM). Patients with suspected TBM from January 2014 to December 2015 were reviewed retrospectively. The cerebrospinalfluid(CSF) was collected. Acid-fast bacillus (AFB) staining, MGIT 960 culture, real-time fluorescent quantitative polymerase chain reaction (RTFQ PCR) and LAMP were performed. A total of 200 patients were included in the study. Of which, 172 of them were diagnosed with TBM (86.00%). The sensitivities of AFB staining, MGIT 960 culture, LAMP and RTFQ PCR for TBM diagnosis were 2.91% (5/172), 12.79% (22/172), 43.02% (74/172), and 34.30% (59/172), respectively. The sensitivity of LAMP for TBM was significantly higher than those of AFB staining and MGIT960 culture (chi2 = 75.11, P < 0.001; chi2 = 43.88, P = 0.002). LAMP's sensitivity was however comparable to RTFQ PCR assay (chi2 = 2.08, P = 0.130). The specificity, positive predictive value and negative predictive value of LAMP in the diagnosis of TBM were 92.86% (26/28), 97.37% (74/76) and 20.97 % (26/124), respectively. The overall consistency between LAMP and RTFQ PCR in the diagnosis of TBM was 88.5% (177/200), with Kappa value of 0.870. The consistency between LAMP and MGIT960 culture was 71% (142/200), with Kappa value of 0.730. Among all the methods, LAMP had high sensitivity, specificity and positive predictive value, showing high consistency with MGIT960 culture and RTFQ PCR. PMID- 28915692 TI - Biomarker analysis of the phase 3 TORCH trial for first line erlotinib versus chemotherapy in advanced non-small cell lung cancer patients. AB - BACKGROUND: The TORCH phase III trial compared the efficacy of first-line erlotinib followed by chemotherapy at progression (experimental arm) with the reverse sequence (standard arm) in unselected advanced non-small cell lung cancer (NSCLC) patients. Here we report biomarker analyses. METHODS: EGFR and KRAS mutation, expression of EGFR family members and of cMET and PTEN and EGFR and ABCG2 germline polymorphisms were tested on tumor tissue or blood samples to either confirm previously proposed predictive role or describe it in an explorative setting. Progression-free survival (PFS) was the primary end-point, overall survival, response rate and side effects (diarrhoea and skin toxicity) were secondary end-points. Interactions between biomarkers and treatment were studied with multivariable models (either Cox model or logistic regression). Statistical analyses accounted for multiple comparisons. RESULTS: At least one biomarker was assessed in 324 out of 760 patients in the TORCH study. EGFR mutation was more common in female (P = 0.0001), East Asians (P < 0.0001) and never smoker (P < 0.0001) patients; low MET protein expression by IHC (H-score <200) was more frequent in squamous (P < 0.00009) and ABCG2 C/A or A/A polymorphism was more frequent among East-Asian patients (P = 0.0003). A significant interaction was found for EGFR mutation in PFS and response rate analyses while no predictive effect on OS was found for any biomarker. No biomarker tested was prognostic for PFS and OS. No polymorphism was significantly associated with skin toxicity or diarrhea. CONCLUSION: In the present study, beyond the known role of EGFR mutation, no other biomarker has predictive or prognostic role. PMID- 28915694 TI - Association of pre-operative depressive and anxiety symptoms with five-year survival of glioma and meningioma patients: a prospective cohort study. AB - BACKGROUND: Mental symptoms are common and associated with worse health status of brain tumor patients. We evaluated the association of pre-operative depressive and anxiety symptoms with 5-year mortality of glioma and meningioma patients. METHODS: One-hundred and fifty-two patients (mean age 56.9+/-14.7 years, 69% women) were evaluated for functional status (Barthel index), and depressive and anxiety symptom severity (Hospital Anxiety and Depression scale or HADS). Patients were categorized as having mild, moderate or severe depressive/anxiety symptoms if they scored <=7, 8-10 or >=11 on the HADS, respectively. Information pertaining to histological diagnosis, extent of resection and adjuvant therapies were obtained from medical records. Follow-up continued through November, 2015. RESULTS: Forty-three patients were diagnosed with high-grade glioma, 20 with low grade glioma and 89 with meningioma. Moderate to severe depressive and anxiety symptoms were diagnosed in 28% and 36% of patients, respectively. In meningioma patients, survival was the shortest in patients with severe depressive symptoms (40.32+/-7.92 months) followed by patients with moderate (46.66+/-6.05 months) and mild (55.68+/-1.77 months) depressive symptoms (Log-Rank = 6.211, p = 0.045). After adjusting for patients' age, gender, functional status, extent of resection, history of depression, and tumor location, laterality and grade, severe depressive symptoms were associated with increased 5-year mortality risk of meningioma patients (HR = 7.083 [95%CI: 1.755-28.588], p = 0.006). Depressive and anxiety symptoms were not associated with mortality of glioma patients. CONCLUSIONS: Depressive and anxiety symptoms are common in glioma and meningioma patients. Pre-operative depressive symptoms are associated with shorter survival of meningioma patients independently from clinical prognostic indicators. PMID- 28915695 TI - Evaluation of intracavitary administration of curcumin for the treatment of sarcomatoid mesothelioma. AB - A rat model of sarcomatoid mesothelioma, mimicking some of the worst clinical conditions encountered, was established to evaluate the therapeutic potential of intracavitary curcumin administration. The M5-T1 cell line, selected from a collection established from F344 rats induced with asbestos, produces tumors within three weeks, with extended metastasis in normal tissues, after intraperitoneal inoculation in syngeneic rats. The optimal concentration/time conditions for killing M5-T1 cells with curcumin were first determined in vitro. Secondly, the potential of intraperitoneal curcumin administration to kill tumor cells in vivo was evaluated in tumor-bearing rats, in comparison with a reference epigenetic drug, SAHA. Both agents administered at days 21 and 26 after tumor challenge produced necrosis within the solid tumors at day 28. However, tumor tissue necrosis induced with curcumin was much more extensive than with SAHA, and was characterized by infiltration with mononuclear phagocytic cells. In contrast, tumor tissue treated with SAHA contained foci of resistant cells and was infiltrated by many isolated CD8+ cells. The treatment of tumor-bearing rats with 1.5 mg/kg curcumin on days 7, 9, 11 and 14 after tumor challenge dramatically reduced the mean total tumor mass at day 16. Clusters of CD8+ T lymphocytes were observed at the periphery of small residual tumor masses in the peritoneal cavity, which presented a significant reduction in mitotic index, IL6 and vimentin expression compared with tumors in untreated rats. These data open up interesting new prospects for the therapy of sarcomatoid mesothelioma with curcumin and its derivatives. PMID- 28915696 TI - TOP2A, GGH, and PECAM1 are associated with hematogenous, lymph node, and peritoneal recurrence in stage II/III gastric cancer patients enrolled in the ACTS-GC study. AB - BACKGROUND: To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS 1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. PATIENTS AND METHODS: Surgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR. Gene expression normalized to reference genes was categorized as lower or higher than the median, and association with relapse sites was analyzed based on 5-year relapse-free survival. RESULTS: Hematogenous, lymph node, and peritoneal recurrence developed in 72, 105, and 138 of the 829 patients, respectively; hazard ratios were 0.79 (95% confidential interval: 0.54-1.16), 0.51 (0.31-0.82), and 0.60 (0.42-0.84), respectively. Expression of platelet/endothelial cell adhesion molecule 1 (PECAM1) and topoisomerase II alpha (TOP2A) was strongly correlated with hematogenous recurrence and peritoneal recurrence, respectively (false discovery rate = 7.7*10-5 and 0.002, respectively). Gamma-glutamyl hydrolase (GGH) expression was moderately correlated with lymph node recurrence (false discovery rate = 0.34). Relapse-free survival was worse in patients expressing high levels of PECAM1 (hazard ratio = 2.37, 1.65-3.41), TOP2A (hazard ratio = 2.35, 1.55 3.57), or GGH (hazard ratio = 1.87, 1.13-3.08), respectively. A multivariate analysis revealed that these were stronger independent risk factors than tumor histological type. CONCLUSION: In patients with stage II/III gastric cancer, TOP2A, GGH, and PECAM1 levels in primary tumors are linked to high risk of hematogenous, lymph node, and peritoneal recurrence, respectively. PMID- 28915697 TI - Preoperative assessment of mitral valve abnormalities in left atrial myxoma patients using cardiac CT. AB - BACKGROUND: To retrospectively evaluate mitral valve abnormality in left atrial myxoma patients by using cardiac computed tomography (CT). MATERIAL AND METHODS: Cardiac CT was performed in 56 patients with left atrial myxoma and 50 controls. Tumor and mitral valve characteristics were analyzed. The mitral valve parameters differences were compared between patients with myxoma and controls, myxoma with or without mitral valve obstruction, different obstruction degrees, respectively. Receiver operating characteristic analysis was performed to determine the cut-off values of abnormal mitral valve parameters for myxoma patients. Multiple linear regression, logistic regression models and cox regression analysis were used to determine factors associated with mitral valve abnormalities, mitral obstruction, mitral regurgitation and postoperative recovery, respectively. RESULTS: Myxoma induced the dilation of mitral valve, with different results among different degrees of obstruction (p<0.001). Mitral valve parameters had relationship with myxoma parameters. The cut-off values for discriminating mitral valve abnormalities in myxoma patients were found. Some significant predictors for mitral obstruction were tumor pedicle-tumor volume and patient age (HR, 0.886 30.811; p = 0.011-0.043). Moreover, the predictor for mitral regurgitation was mitral annulus diameter in diastolic phase (HR, 20.862; 95%CI,1.331-327.100; p = 0.031). Some predictors associated with postoperative recovery of mitral regurgitation were age, mitral annulus area, mitral annulus diameter and mitral valve diameter cutoff value for diastolic phase (HR, 0.001-119.160; p = 0.012 0.028). CONCLUSION: Cardiac CT is capable of quantitatively assessing myxoma characteristic and mitral valve abnormality induced by myxoma, thus providing guidance of operative management and postoperative evaluation. PMID- 28915698 TI - Risk of aortic aneurysm and dissection in patients with autosomal-dominant polycystic kidney disease: a nationwide population-based cohort study. AB - Although cardiovascular complications are the most common cause of death in patients with autosomal-dominant polycystic kidney disease (ADPKD), the incidence and risk of aortic aneurysm and dissection (AAD) in ADPKD remains unclear due to limited data and insufficient cases. We utilized the data from Taiwan National Health Insurance Research Database (NHIRD) to do a population-based cohort study (1997-2008). After excluding those patients with age <18 years old and initially concomitant diagnoses of end-stage renal disease and AAD, a total of 2076 ADPKD patients were selected from 1,000,000 of general population. Additionally, the non-ADPKD group was set up as comparison group in 1:10 ratio after matching with age, gender, income and urbanization (n=20760). The result showed that ADPKD group had higher frequency of comorbidities than non-ADPKD group. The frequency of AAD in ADPKD was significantly higher than in general population (0.92% v.s. 0.11%, p<0.0001). Of them, 58% of AAD were acute aortic dissection. In addition, Kaplan-Meier analysis demonstrated that cumulative incidence of AAD was remarkably higher in the ADPKD than non-ADPKD group (p<0.001). The mean time period from ADPKD diagnosis to AAD occurrence was 4.02+/-3.16 years. After adjusting for age, gender and comorbidities, the ADPKD patients had up to 5.49 fold greater risk for AAD occurrence as compared to non-ADPKD counterparts (95% CI 2.86-10.52, p<0.0001). Particularly, those patients with co-existing ADPKD and hypertension had very high risk for future development of AAD. In conclusion, the risk of AAD significantly increases in patients with ADPKD as compared with those of general population. PMID- 28915699 TI - Biological effects and epidemiological consequences of arsenic exposure, and reagents that can ameliorate arsenic damage in vivo. AB - Through contaminated diet, water, and other forms of environmental exposure, arsenic affects human health. There are many U.S. and worldwide "hot spots" where the arsenic level in public water exceeds the maximum exposure limit. The biological effects of chronic arsenic exposure include generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage, epigenetic DNA modification, induction of genomic instability, and inflammation and immunomodulation, all of which can initiate carcinogenesis. High arsenic exposure is epidemiologically associated with skin, lung, bladder, liver, kidney and pancreatic cancer, and cardiovascular, neuronal, and other diseases. This review briefly summarizes the biological effects of arsenic exposure and epidemiological cancer studies worldwide, and provides an overview for emerging rodent-based studies of reagents that can ameliorate the effects of arsenic exposure in vivo. These reagents may be translated to human populations for disease prevention. We propose the importance of developing a biomarker-based precision prevention approach for the health issues associated with arsenic exposure that affects millions of people worldwide. PMID- 28915701 TI - Comparison among fertility-sparing therapies for well differentiated early-stage endometrial carcinoma and complex atypical hyperplasia. AB - OBJECTIVE: To compare fertility-sparing therapies including oral progestogens, hysteroscopic resection (HR), and the levonorgestrel- releasing intrauterine system (LNG-IUS) in achieving disease regression, recurrence and live birth rate in well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia(CAH). STUDY DESIGN: This was a meta-analysis of previous studies focus on the fertility-sparing therapy for well differentiate early-stage endometrial carcinoma (eEC) and complex atypical hyperplasia (CAH). DATE SOURCES: Medline, the Cochrane Library and Embase was searched with the terms and Synonyms: words similar to eEC and CAH with therapies associated with fertility sparing. MAIN OUTCOME MEASURES: The number of all patients accepted fertility sparing therapies, patients got regressed, relapsed and delivered were extracted from each study, and the regression, recurrence, and live birth rate of each study were calculated. The regression, recurrence and live birth rates between each two interventions were compared with the aid of meta-regression in packages of "meta" and "meta for" written in R. RESULTS: Fifty-four studies reported fertility sparing therapies in young women with eEC and CAH were included. Meta analysis showed that HR followed by progestogens achieved a higher pooled regression (98.06% vs 77.20% P < 0.0001) and live birth rate (52.57% vs 33.38%, P = 0.0944) and a lower recurrence rate compared with oral progestogens alone (4.79% vs 32.17% P = 0.0004). At the same time, the pooled live birth rate (52.57% vs 18.09% P =0.0399) of HR followed by progestogens are significantly higher than the LNG-IUS alone. Which no statistical difference in regression (98.06% vs 94.24%; P = 0.4098) and recurrence rates (4.79% vs 3.90% P = 0.8561) was seen. CONCLUSIONS: Of the available fertility-sparing therapeutic options, HR followed by progestogens may be a more effective one. PMID- 28915700 TI - The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance. AB - Growing evidence has raised the important roles of adipocytes as an active player in the tumor microenvironment. In many tumors adipocytes are in close contact with cancer cells. They secrete various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Moreover, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, has been established as a risk factor for cancer incidence and cancer-related mortality. In this review, we summarize the mechanisms of the adipocyte-cancer cell crosstalk in both obese and lean conditions as well as its impact on cancer cell growth, local invasion, metastatic spread and resistance to treatments. Better characterization of cancer associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and suggest efficient therapeutic opportunities. PMID- 28915702 TI - Targeted therapies for gastric cancer: failures and hopes from clinical trials. AB - Gastric cancer is the third leading cause of cancer mortality worldwide. As surgery is the only curative treatment strategy and conventional chemotherapy has shown limited efficacy -with a median overall survival of 10 months- new treatments are urgently needed. Trastuzumab and Ramucirumab (targeting HER2 and VEGFR2, respectively) are the only targeted therapies approved so far. Indeed, most Phase III clinical trials evaluating molecular drugs in gastric cancer failed. This review will retrace the relevant clinical trials with molecular therapies performed in gastric cancer patients, discussing the possible reasons for their failure and indicating new perspective for a real improvement of the treatment of this disease. PMID- 28915703 TI - Treatments of traumatic neuropathic pain: a systematic review. AB - Traumatic neuropathic pain caused by traumatic neuroma has long been bothering both doctors and patients, the mechanisms of traumatic neuropathic pain are widely discussed by researchers and the treatment is challenging. Clinical treatment of painful neuroma is unclear. Numerous treatment modalities have been introduced by experts in this field. However, there is still no single standard recognized treatment. Different forms of treatments have been tested in animals and humans, but pharmacotherapies (antidepressants, antiepileptics) remain the basis of traumatic neuropathic pain management. For intractable cases, nerve stump transpositions into a muscle, vein or bone are seen as traditional surgical procedures which provide a certain degree of efficacy. Novel surgical techniques have emerged in recent years, such as tube guided nerve capping, electrical stimulation and adipose autograft have substantially enriched the abundance of the treatment for traumatic neuropathic pain. Several treatments show advantages over the others in terms of pain relief and prevention of neuroma formation, making it difficult to pick out a single modality as the reference. An effective and standardized treatment for traumatic neuropathic pain would provide better choice for researchers and clinical workers. In this review, we summarized current knowledge on the treatment of traumatic neuropathic pain, and found a therapeutic strategy for this intractable pain. We tried to provide a useful guideline for choosing the right modality in management of traumatic neuropathic pain. PMID- 28915704 TI - Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies. AB - Lung cancer is one of the most common causes of cancer-related death in the world. The large number of lung cancer cases is non-small cell lung cancer (NSCLC), which approximately accounting for 75% of lung cancer. Over the past years, our comprehensive knowledge about the molecular biology of NSCLC has been rapidly enriching, which has promoted the discovery of driver genes in NSCLC and directed FDA-approved targeted therapies. Of course, the targeted therapies based on driver genes provide a more exact option for advanced non-small cell lung cancer, improving the survival rate of patients. Now, we will review the landscape of driver genes in NSCLC including the characteristics, detection methods, the application of target therapy and challenges. PMID- 28915705 TI - Promising landscape for regulating macrophage polarization: epigenetic viewpoint. AB - Macrophages are critical myeloid cells with the hallmark of phenotypic heterogeneity and functional plasticity. Macrophages phenotypes are commonly described as classically-activated M1 and alternatively-activated M2 macrophages which play an essential role in the tissues homeostasis and diseases pathogenesis. Alternations of macrophage polarization and function states require precise regulation of target-gene expression. Emerging data demonstrate that epigenetic mechanisms and transcriptional factors are becoming increasingly appreciated in the orchestration of macrophage polarization in response to local environmental signals. This review is to focus on the advanced concepts of epigenetics changes involved with the macrophage polarization, including microRNAs, DNA methylation and histone modification, which are responsible for the altered cellular signaling and signature genes expression during M1 or M2 polarization. Eventually, the persistent investigation and understanding of epigenetic mechanisms in tissue macrophage polarization and function will enhance the potential to develop novel therapeutic targets for various diseases. PMID- 28915707 TI - Augmented expression of polo-like kinase 1 indicates poor clinical outcome for breast patients: a systematic review and meta-analysis. AB - Polo-like kinases 1 (PLK1), a key regulator of mitosis, plays an essential role in maintaining genomic stability. Up-regulation of PLK1 was found in tumorigenesis and tumor progression of diverse cancers. However, the clinicopathological and prognostic implications of PLK1 in breast cancer (BC) have yet to be unveiled. Therefore, using PubMed, Web of Science, Embase, and Chinese databases, we conducted a meta-analysis to define the potential clinical value of PLK1 in BC. Eleven eligible articles with 2481 patients enrolled were included in the present meta-analysis, of which eight studies reported on the relationship between PLK1 expression and clinicopathological features, and nine studies provided survival data in BC patients. Furthermore, the results revealed that high PLK1 levels were significantly associated with larger tumor size (OR=1.703, 95%CIs: 1.315-2.205, P<0.001), higher pathological grading (OR=6.028, 95%CIs: 2.639-13.772, P<0.001), and lymph node metastasis (OR= 1.524, 95%CIs: 1.192-1.950, P=0.001). Moreover, PLK1 was found to be a valuable factor for distinguishing lobular BC from ductal BC with the pooled OR=0.215(95%CIs: 0.083 0.557, P=0.002). Analysis of included data showed that high PLK1 expression significantly indicated worse overall survival for BC patients (HR= 3.438, 95%CIs: 2.293-5.154, P<0.001), as well as worse cancer specific survival and disease-free survival (HR=2.414, 95%CIs: 1.633-3.567, P<0.001 and HR= 2.261, 95%CIs: 1.796-2.951, P<0.001, respectively). This quantitative meta-analysis suggests that high PLK1 expression is a credible indicator for the progression of BC and confirms a higher risk of a worse survival rate in patients with BC. PMID- 28915706 TI - The role of autophagy in hepatocellular carcinoma: friend or foe. AB - Autophagy is an evolutionarily conserved lysosome-dependent catabolic process which degrades cell's components in order to recycle substrates to exert optimally and adapt to tough circumstances. It is a critical cellular homeostatic mechanism with stress resistance, immunity, antiaging, and pro-tumor or anti tumor effects. Among these, the role of autophagy in cancer is the most eye catching that is not immutable but dynamic and highly complex. Basal autophagy acts as a tumor suppressor by maintaining genomic stability in normal cells. However, once a tumor is established, unbalanced autophagy will contribute to carcinoma cell survival under tumor microenvironment and in turn promote tumor growth and development. The dynamic role of autophagy can also apply on hepatocellular carcinoma (HCC). HCC is a highly malignant cancer with high morbidity and poor survival rate. Decline or overexpression of autophagic essential genes such as ATG7, ATG5 or Beclin 1 plays a key role in the occurrence and development of HCC but the exact mechanisms are still highly controversial. Signaling pathways or molecules involving in autophagy, for example PI3K/AKT/mTOR pathway, ERK/MAPK pathway, PERK pathway, p53, LncRNA PTENP1 (Long non-coding RNA PTENP1), microRNA-375 and so on, occupy an important position in the complex role of autophagy in HCC. Here, we discuss the dynamic role, the signaling pathways and the potential prognostic and therapy value of autophagy in HCC. PMID- 28915708 TI - Targeting metabolism and AMP-activated kinase with metformin to sensitize non small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials. AB - Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept. PMID- 28915709 TI - The prognostic value of long noncoding RNAs in prostate cancer: a systematic review and meta-analysis. AB - The abnormally expressed LncRNAs played irreplaceable roles in the prognosis of prostate cancer (PCa). Therefore, we conducted this systematic review and meta analysis to summarize the association between the expression of LncRNAs, prognosis and clinicopathology of PCa. 18 eligible studies were recruited into our analysis, including 18 on prognosis and 9 on clinicopathological features. Results indicated that aberrant expression of LncRNAs was significantly associated with biochemical recurrence-free survival (BCR-FS) (HR = 1.55, 95%CI: 1.01-2.37, P < 0.05), recurrence free survival (RSF) (HR = 3.07, 95%CI: 1.07 8.86, P < 0.05) and progression free survival (PFS) (HR = 2.34, 95%CI: 1.94-2.83, P < 0.001) in PCa patients. LncRNAs expression level was correlated with several vital clinical features, like tumor size (HR = 0.52, 95%CI: 0.28-0.95, P = 0.03), distance metastasis (HR = 4.55, 95%CI: 2.26-9.15, P < 0.0001) and histological grade (HR = 6.23, 95% CI: 3.29-11.82, P < 0.00001). Besides, down-regulation of PCAT14 was associated with the prognosis of PCa [over survival (HR = 0.77, 95%CI: 0.63-0.95, P = 0.01), BCR-FS (HR = 0.61, 95%CI: 0.48-0.79, P = 0.0001), prostate cancer-specific survival (HR = 0.64, 95%CI: 0.48-0.85, P = 0.002) and metastasis free survival (HR = 0.61, 95%CI: 0.50-0.74, P < 0.00001)]. And, the increased SChLAP1 expression could imply the worse BCR-FS (HR = 2.54, 95%CI: 1.82-3.56, P < 0.00001) and correlate with Gleason score (< 7 vs >= 7) (OR = 4.11, 95% CI: 1.94 8.70, P = 0.0002). Conclusively, our present work demonstrated that LncRNAs transcription level might be potential prognostic markers in PCa. PMID- 28915710 TI - Insights from animal models of bladder cancer: recent advances, challenges, and opportunities. AB - Bladder cancer (urothelial cancer of the bladder) is the most common malignancy affecting the urinary system with increasing incidence and mortality. Treatment of bladder cancer has not advanced in the past 30 years. Therefore, there is a crucial unmet need for novel therapies, especially for high grade/stage disease that can only be achieved by preclinical model systems that faithfully recapitulate the human disease. Animal models are essential elements in bladder cancer research to comprehensively study the multistep cascades of carcinogenesis, progression and metastasis. They allow for the investigation of premalignant phases of the disease that are not clinically encountered. They can be useful for identification of diagnostic and prognostic biomarkers for disease progression and for preclinical identification and validation of therapeutic targets/candidates, advancing translation of basic research to clinic. This review summarizes the latest advances in the currently available bladder cancer animal models, their translational potential, merits and demerits, and the prevalent tumor evaluation modalities. Thereby, findings from these model systems would provide valuable information that can help researchers and clinicians utilize the model that best answers their research questions. PMID- 28915712 TI - Formation, function, and exhaustion of notochordal cytoplasmic vacuoles within intervertebral disc: current understanding and speculation. AB - Notochord nucleus pulposus cells are characteristic of containing abundant and giant cytoplasmic vacuoles. This review explores the embryonic formation, biological function, and postnatal exhaustion of notochord vacuoles, aiming to characterize the signal network transforming the vacuolated nucleus pulposus cells into the vacuole-less chondrocytic cells. Embryonically, the cytoplasmic vacuoles within vertebrate notochord originate from an evolutionarily conserved vacuolation process during neurulation, which may continue to provide mechanical and signal support in constructing a mammalian intervertebral disc. For full vacuolation, a vacuolating specification from dorsal organizer cells, synchronized convergent extension, well-structured notochord sheath, and sufficient post-Golgi trafficking in notochord cells are required. Postnatally, age-related and species-specific exhaustion of vacuolated nucleus pulposus cells could be potentiated by Fas- and Fas ligand-induced apoptosis, intolerance to mechanical stress and nutrient deficiency, vacuole-mediated proliferation check, and gradual de-vacuolation within the avascular and compression-loaded intervertebral disc. These results suggest that the notochord vacuoles are active and versatile organelles for both embryonic notochord and postnatal nucleus pulposus, and may provide novel information on intervertebral disc degeneration to guide cell-based regeneration. PMID- 28915714 TI - The efficacy of anti-PD-1/PD-L1 therapy and its comparison with EGFR-TKIs for advanced non-small-cell lung cancer. AB - PURPOSE: To better understand the efficacy and safety of anti-PD-1/PD-L1 therapy (atezolizumab, pembrolizumab, nivolumab) in patients with previously treated advanced non-small-cell lung cancer (NSCLC). METHODS: The Cochrane Controlled Trial Register, Embase, Medline, and the Science Citation Index were searched for prospective published reports of atezolizumab, pembrolizumab, nivolumab in previously treated patients with advanced NSCLC. RESULTS: Finally, we identified 14 prospective published reports including four trials of atezolizumab covering 542 subjects, three trials of pembrolizumab covering 1566 subjects, seven trials of nivolumab covering 1678 subjects. When compared to docetaxel, anti-PD-1/PD-L1 therapy could significantly improve overall survival (hazard ratio [HR] 0.67, P<0.001) and progression-free survival (HR 0.83, P=0.002) for previously treated patients with advanced NSCLC. Anti-PD-1/PD-L1 therapy produced an overall response rate of 19% in the 2374 evaluable patients. When using docetaxel as the common comparator, indirect comparison of anti-PD-1/PD-L1 therapy versus EGFR TKIs showed progression-free survival benefit (HR 0.62, P<0.001) and overall survival benefit (HR 0.60, P<0.001) for those patients with EGFR wild-type. Meanwhile, for those EGFR mutant patients, indirect comparison indicated that anti-PD-1/PD-L1 therapy was inferior to EGFR-TKIs therapy in terms of progression free survival (HR 3.20, P<0.001), but no survival difference (HR 1.30, P=0.18). CONCLUSION: Anti-PD-1/PD-L1 therapy could produce progression-free survival and overall survival improvement over docetaxel for patients with previously treated NSCLC. For EGFR wild-type patients, anti-PD-1/PD-L1 therapy seemed to prolong progression-free survival and overall survival when compared to EGFR-TKIs. Meanwhile, for these EGFR mutant patients, anti-PD-1/PD-L1 therapy was inferior to EGFR-TKIs therapy in terms of progression-free survival. PMID- 28915711 TI - Vitamin K and its analogs: Potential avenues for prostate cancer management. AB - Epidemiological studies have demonstrated a relationship between cancer incidence and dietary habits. Especially intake of certain essential nutrients like vitamins has been shown to be beneficial in experimental studies and some clinical trials. Vitamin K (VK) is an essential nutrient involved in the blood clotting cascade, and there are considerable experimental data demonstrating its potential anticancer activity in several cancer types including prostate cancer. Previous in vitro and in vivo studies have focused mainly on anti-oxidative effects as the underlying anticancer mechanism of VK. However, recent studies reveal that VK inhibits the growth of cancer cells through other mechanisms, including apoptosis, cell cycle arrest, autophagy, and modulation of various transcription factors such as Myc and Fos. In the present review, we focus on the anticancer effect of dietary VK and its analogs on prostate cancer, with an emphasis on the signaling pathways that are activated following exposure to these compounds. This review also highlights the potential of VK and its derivatives as an adjuvant treatment in combination with other vitamins or with chemotherapeutic drugs. Based on our recent results and a review of the existing literature, we present evidence that VK and its derivatives can potentially be explored as cancer therapy, especially for prostate cancer. PMID- 28915713 TI - The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy. AB - Although survival outcomes of cancer patients have been improved dramatically via conventional chemotherapy and targeted therapy over the last decades, there are still some tough clinical challenges that badly needs to be overcome, such as anticancer drug resistance, inevitable recurrences, cancer progression and metastasis. Simultaneously, accumulated evidence demonstrates that aberrant glucose metabolism termed 'the Warburg effect' in cancer cell is closely associated with malignant phenotypes. In 2009, a novel 'two-compartment metabolic coupling' model, also named 'the reverse Warburg effect', was proposed and attracted lots of attention. Based on this new model, we consider whether this new viewpoint can be exploited for improving the existent anti-cancer therapeutic strategies. Our review focuses on the paradigm shift from 'the Warburg effect' to 'the reverse Warburg effect', the features and molecular mechanisms of 'the reverse Warburg effect', and then we discuss its significance in fundamental researches and clinical practice. PMID- 28915715 TI - Epigenetic regulation during the differentiation of stem cells to germ cells. AB - Gametogenesis is an essential process to ensure the transfer of genetic information from one generation to the next. It also provides a mechanism by which genetic evolution can take place. Although the genome of primordial germ cells (PGCs) is exactly the same with somatic cells within an organism, there are significant differences between their developments. For example, PGCs eventually undergo meiosis to become functional haploid gametes, and prior to that they undergo epigenetic imprinting which greatly alter their genetic regulation. Epigenetic imprinting of PGCs involves the erasure of DNA methylation and the reestablishment of them during sperm and oocyte formation. These processes are necessary and important during gametogenesis. Also, histone modification and X chromosome inactivation have important roles during germ cell development. Recently, several studies have reported that functional sperm or oocytes can be derived from stem cells in vivo or in vitro. To produce functional germ cells, induction of germ cells from stem cells must recapitulate these processes similar to endogenous germ cells, such as epigenetic modifications. This review focuses on the epigenetic regulation during the process of germ cell development and discusses their importance during the differentiation from stem cells to germ cells. PMID- 28915716 TI - Implementation and utilization of the molecular tumor board to guide precision medicine. AB - BACKGROUND: With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. MATERIALS AND METHODS: Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place. Because profiling of stage IV lung cancer, colon cancer, and melanoma cancers were standard of care, these cancer types were excluded from this process. We subsequently analyzed the types of cases referred for testing and approved with regards to their results. RESULTS: 191 cases were discussed at the MTB and 132 cases were approved for testing. Forty-six cases (34.8%) had driver mutations that were associated with an active targeted therapeutic agent, including BRAF, PIK3CA, IDH1, KRAS, and BRCA1. An additional 56 cases (42.4%) had driver mutations previously reported in some type of cancer. Twenty-two cases (16.7%) did not have any clinically significant mutations. Eight cases did not yield adequate DNA. 15 cases were considered for targeted therapy, 13 of which received targeted therapy. One patient experienced a near complete response. Seven of 13 had stable disease or a partial response. CONCLUSIONS: MTB at University of Alabama-Birmingham is unique because it reviews the appropriateness of NGS testing for patients with recurrent cancer and serves as a forum to educate our physicians about the pathways of precision medicine. Our results suggest that our detection of actionable mutations may be higher due to our careful selection. The application of precision medicine and molecular genetic testing for cancer patients remains a continuous educational process for physicians. PMID- 28915717 TI - p53, p63 and p73 in the wonderland of S. cerevisiae. AB - Since its discovery in 1979, p53 has been on the forefront of cancer research. It is considered a master gene of cancer suppression and is found mutated in around 50% of all human tumors. In addition, the progressive identification of p53 related transcription factors p63 and p73 as well as their multiple isoforms have added further layers of complexity to an already dense network. Among the numerous models used to unravel the p53 family mysteries, S. cerevisiae has been particularly useful. This seemingly naive model allows the expression of a functional human p53 and thus the assessment of p53 intrinsic transcriptional activity. The aim of this article is to review the various contributions that the budding yeast has made to the understanding of p53, p63 and p73 biology and to envision new possible directions for yeast-based assays in the field of cancer as well as other p53-family-related diseases. PMID- 28915719 TI - Genomic analysis of exceptional responder to regorafenib in treatment-refractory metastatic rectal cancer: a case report and review of the literature. AB - We present the case of a 53-year-old male with metastatic rectal cancer who was treatment resistant to FOLFOX and FOLFOXIRI. Due to a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, regorafenib was given in the third line setting. Surprisingly, the patient had a prolonged partial response that lasted 27 months. Mutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for this unusual event. A poorly characterized but nontransforming mutation in Fms-like tyrosine kinase 4 (FLT4) was present in the tumor. Prior to and at the time of clinical progression, we found amplification of fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR), loss of the FLT4 mutation, and gain of KIT proto-oncogene receptor tyrosine kinase (KIT) G961S suggesting potential roles in acquired resistance. PMID- 28915718 TI - The PI3K/Akt pathway: a critical player in intervertebral disc degeneration. AB - Intervertebral disc degeneration (IDD) is thought to be the primary cause of low back pain, a severe public health problem worldwide. Current therapy for IDD aims to alleviate the symptoms and does not target the underlying pathological alternations within the disc. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway protects against IDD, which is attributed to increase of ECM content, prevention of cell apoptosis, facilitation of cell proliferation, induction or prevention of cell autophagy, alleviation of oxidative damage, and adaptation of hypoxic microenvironment. In the current review, we summarize recent progression on activation and negative regulation of the PI3K/Akt signaling pathway, and highlight its impact on IDD. Targeting this pathway could become an attractive therapeutic strategy for IDD in the near future. PMID- 28915720 TI - Pseudoprogression in microsatellite instability-high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review. AB - Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden. Tumor regression was subsequently observed and patient has remained in stable disease. Despite the substantial radiological progression, the symptomatic improvement reported by the patient led us to the decision of treatment continuation based on the suspicion of pseudoprogression, illustrating the importance of clinical evaluation in medical decision making while managing patients on immunotherapy. Additionally, the patient's MSI-high status contributes to his good, maintained response to PD-L1 blockade. Our case provides a frame of reference for fluctuation in tumor burden associated with pseudoprogression. Here we also evaluate the incidence and scale of pseudoprogression across solid tumor types. PMID- 28915721 TI - Dramatic response of CTNNB1 and VEGFR-2 mutant temporal bone squamous cell carcinoma to bevacizumab in combination with pemetrexed. AB - High recurrence rates and poor survival rates for late stage/advanced temporal bone squamous cell carcinoma with the standard treatments continues to be a significant challenge to otolaryngologists. Targeted therapy for temporal bone squamous cell carcinoma after relapse has not been reported. Here we present a 58 year-old man who was diagnosed with recurrent temporal bone squamous cell carcinoma and treated with a regimen developed using whole exome sequencing. Somatic mutations in genes encoding catenin beta 1 and vascular endothelial growth factor receptor 2 were identified in the patient's tumor sample compared to the normal tissue. The patient was then treated with Bevacizumab in combination with pemetrexed. After two weeks of treatment, tumor volume was reduced by 95% measured by MRI, and the Visual Analogue Scale headache scores went down from 10/10 to 2/10. Our results reveal novel gene mutations of temporal bone squamous cell carcinoma and demonstrate, for the first time, an effective targeted therapy for temporal bone squamous cell carcinoma. The successful treatment regimen of bevacizumab and pemetrexed may provide a new treatment option for treating recurrent temporal bone squamous cell carcinoma that fails to respond to conventional tumor resection, radiotherapy, and/or chemotherapy. PMID- 28915722 TI - Correction: A novel highly potent trivalent TGF-beta receptor trap inhibits early stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands. AB - [This corrects the article DOI: 10.18632/oncotarget.13343.]. PMID- 28915723 TI - Correction: Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis. AB - [This corrects the article DOI: 10.18632/oncotarget.14331.]. PMID- 28915724 TI - C1orf64 is a novel androgen receptor target gene and coregulator that interacts with 14-3-3 protein in breast cancer. AB - This study investigated the network of genes that are co-expressed with androgen receptor (AR) to discover novel AR targets in breast cancer. Bioinformatics analysis of two datasets from breast cancer cell lines resulted in the identification of an AR-gene signature constituted of 98 genes that highly correlated with AR expression. Notably, C1orf64 showed the highest positive correlation with AR across the datasets with a correlation coefficient (CC) of 0.737. In addition, C1orf64 closely correlated with AR expression in primary and metastatic breast tumors and C1orf64 expression was relatively higher in breast tumors with a lower grade and lobular histology. Furthermore, there is a functional interplay between AR and C1orf64 in breast cancer. In this process, AR activation directly represses C1orf64 transcription and C1orf64, in turn, interacts with AR as a corepressor and negatively regulates the AR-mediated induction of prolactin-induced protein (PIP) and AR reporter activity. Moreover, the corepressor effect of C1orf64 results in a reduction of AR binding to PIP promoter. The other aspect of this interplay involves a cross-talk between AR and estrogen receptor (ER) signaling in which C1orf64 silencing intensifies the AR mediated down-regulation of ER target gene, progesterone receptor. Therefore, the repression of C1orf64 by AR provides an underlying mechanism for the AR inhibitory effects on ER signaling. To elucidate the biochemical mechanisms of C1orf64 function, this study demonstrates that C1orf64 is a phosphothreonine protein that interacts with the chaperone protein 14-3-3. In summary, C1orf64 is a novel AR coregulator and a 14-3-3 binding partner in breast cancer. PMID- 28915726 TI - Thermodynamic Route to Efficient Prediction of Gas Diffusivity in Nanoporous Materials. AB - We report an efficient computational procedure for rapid and accurate prediction of the self-diffusivity of gas molecules in nanoporous materials by implementing the transition state theory for intercage hopping at infinite dilution with the string method in conjunction with the excess-entropy scaling for predicting gas diffusion coefficients at finite loadings. The theoretical procedure has been calibrated with molecular dynamics simulations for the diffusion coefficients of methane and hydrogen gases in representative nanoporous materials including metal organic frameworks and zeolites. Combined with the classical density functional theory for calculating the excess entropy of gas molecules in micropores, the theoretical procedure enables efficient computation of both thermodynamic and transport properties important for design and screening of nanostructured materials for gas storage and separation. PMID- 28915725 TI - Distribution of Rotavirus Genotypes Ccirculating in Ahvaz, Iran in 2016 AB - Background: Group A rotavirus (RVA) mainly causes acute gastroenteritis, exclusively in young children in developing countries. The prevalence and determination of the molecular epidemiology of rotavirus genotypes will determine the dominant rotavirus genotypes in the region and provide a strategy for the development of appropriate vaccines. Methods: A total of 100 fecal samples were collected from children below five years with acute gastroenteritis who referred to Aboozar Children's Hospital of Ahvaz city during October 2015 to March 2016. All samples were screened by latex agglutination for the presence of rotavirus antigen. Rotavirus-positive samples were further analyzed by the semi-multiplex RT-PCR, and the sequencing was performed for G/P genotyping. Results: Findings showed that 32% of the specimens were RVA-positive. Among the 32 VP7 genotyped strains, the predominant G genotype was G9 (37.5%), followed by G2 (21.9%), G1 (12.5%), G12 (9.4%), G4 (9.4%), G2G9 (6.3%), and G3 (3.1%). Among the 31 VP4 genotyped strains, P[8] genotype was the dominant (62.5%), followed by P[4] (31.3%) and P[4] P[8] (3.1%). The genotypes for G and P were identified for 31 rotaviruses (96.87%), but only one strain, G9, remained non-typeable for the P genotype. The most prevalent G/P combination was G9P[8] (28.5%), followed by G2P[4] (18.8%), G1P[8] (9.4%), G12P[8] (9.4%), G4P[8] (9.4%), G2G9P[4] (6.3%), G9P[4] P[8] (3.1%), G3P[8] (3.1%), G9P[4] (3.1%), G2P[8] (3.1%), and G9P[non typeable] (3.1%). Conclusion: A novel rotavirus strain, G12, was detected, for the first time, in patients from the southwest of Iran. Comprehensive investigations are required to evaluate the emergence of this strain. PMID- 28915728 TI - Atomic-Level Simulation Study of n-Hexane Pyrolysis on Silicon Carbide Surfaces. AB - Ethylene production plays a key role in the petrochemical industry. The severe operation conditions of ethylene thermal cracking, such as high-temperature and coke-formation, pose challenges for the development of new corrosion-resistant and coking-resistant materials for ethylene reactor radiant coils tubes (RCTs). We investigated the performance of ceramic materials such as silicon carbide (SiC) in severe pyrolysis conditions by using reactive force field molecular dynamics (ReaxFF MD) simulation method. Our results indicate that beta-SiC surface remains fully stable at 1500 K, whereas increased temperature results in melted interface. At 2500 K, fully grown cross-linked-graphene-like polycyclic aromatic hydrocarbon coking structure on SiC surfaces was observed. Such coking was particularly severe in the carbon-side of the surface slab. The coking structures were mainly derived from surface atoms at the initial 3.0 ns, as a result of the loss of interfacial hydroxyl layer and further hydrothermal corrosion. The SiC substrate surface enhances the ethylene cracking rate and also leads to different intermediate-state compounds. Our fundamental research will have significant and broad impact on both petrochemical industry and academic research in materials science, petrochemistry, and combustion chemistry. PMID- 28915727 TI - The Protein and Energy Metabolic Response of Skeletal Muscle to the Low-Protein Diets in Growing Pigs. AB - This study was conducted to determine the effect of low-protein diets on protein and energy metabolism in skeletal muscle, and to elucidate the underlying mechanism. A total of 18 growing pigs (average initial body weight = 36.47 kg) were individually penned and assigned to three treatments; each treatment was fed one of three diets containing either 18%, 15%, or 12% CP. The results showed that reducing dietary CP contents decreased (P < 0.05) the weight of half Longissimus dorsi (LD) muscle and serum concentration of insulin-like growth factor 1 (IGF 1). Compared with the 18% and 15% CP treatments, the 12% CP treatment suppressed (P < 0.05) the components of mammalian target of rapamycin complex 1 (mTORC1) pathway, but upregulated (P < 0.05) the mRNA levels for proteolysis-related genes, and concomitantly caused an increase (P < 0.05) in the percentage of apoptotic cells in LD muscle. Along with lower (P < 0.05) AMP/ATP ratio and greater (P < 0.05) energy charge value in LD muscle of the 12% CP treatment, there was a concurrent decrease (P < 0.05) in the proteins for AMP-activated protein kinase alpha (AMPKalpha) pathway. Likewise, these results were also observed in the Biceps femoris muscle with slightly different degree of impacts. These results indicate that the retardation effect of low-protein supply on muscle growth of growing pigs could be likely regulated by inhibiting IGF 1/mTORC1 protein synthesis cascade, along with strong alterations in energy status and AMPKalpha pathway. PMID- 28915729 TI - Thermal Diffusion in Binary Mixtures: Transient Behavior and Transport Coefficients from Equilibrium and Nonequilibrium Molecular Dynamics. AB - Equilibrium and nonequilibrium molecular dynamics simulations are combined to compute the full set of coefficients that appear in the phenomenological equations describing thermal transport in a binary mixture subject to a constant thermal gradient. The Dynamical Non-Equilibrium Molecular Dynamics approach (D NEMD) is employed to obtain the microscopic time evolution of the density and temperature fields, together with that of the mass and energy fluxes. D-NEMD enables one to study not only the steady state, but also the evolution of the fields during the transient that follows the onset of the thermal gradient, up to the establishment of the steady state. This makes it possible to ensure that the system has indeed reached a stationary condition, and to analyze the transient mechanisms and time scales of the mass and energy transport. A local time averaging procedure is applied to each trajectory contributing to the calculation to improve the signal-to-noise ratio in the estimation of the fluxes and to obtain a clear signal with the, relatively limited, statistics available. PMID- 28915730 TI - Adsorption and Diffusion of Fluids in Defective Carbon Nanotubes: Insights from Molecular Simulations. AB - Single-walled carbon nanotubes (SWNTs) have been shown from both simulations and experiments to have remarkably low resistance to gas and liquid transport. This has been attributed to the remarkably smooth interior surface of pristine SWNTs. However, real SWNTs are known to have various defects that depend on the synthesis method and procedure used to activate the SWNTs. In this paper, we study adsorption and transport properties of atomic and molecular fluids in SWNTs having vacancy point defects. We construct models of defective nanotubes that have either unrelaxed defects, where the overall structure of the SWNT is not changed, or reconstructed defects, where the bonding topology and therefore the shape of the SWNT is allowed to change. Furthermore, we include partial atomic charges on the SWNT carbon atoms due to the reconstructed defects. We consider adsorption and diffusion of Ar atoms and CO2 and H2O molecules as examples of a noble gas, a linear quadrupolar fluid, and a polar fluid. Adsorption isotherms were found to be fairly insensitive to the defects, even for the case of water in the charged, reconstructed SWNT. We have computed both the self-diffusivities and corrected diffusivities (which are directly related to the transport diffusivities) for each of these fluids. In general, we found that at zero loading that defects can dramatically reduce the self- and corrected diffusivities. However, at high, liquidlike loadings, the self-diffusion coefficients for pristine and defective nanotubes are very similar, indicating that fluid-fluid collisions dominate the dynamics over the fluid-SWNT collisions. In contrast, the corrected diffusion coefficients can be more than an order of magnitude lower for water in defective SWNTs. This dramatic decrease in the transport diffusion is due to the formation of an ordered structure of water, which forms around a local defect site. It is therefore important to properly characterize the level and types of defects when accurate transport diffusivities are needed. PMID- 28915731 TI - Investigating Alkylsilane Monolayer Tribology at a Single-Asperity Contact with Molecular Dynamics Simulation. AB - Chemisorbed monolayer films are known to possess favorable characteristics for nanoscale lubrication of micro- and nanoelectromechanical systems (MEMS/NEMS). Prior studies have shown that the friction observed for monolayer-coated surfaces features a strong dependence on the geometry of contact. Specifically, tip-like geometries have been shown to penetrate into monolayer films, inducing defects in the monolayer chains and leading to plowing mechanisms during shear, which result in higher coefficients of friction (COF) than those observed for planar geometries. In this work, we use molecular dynamics simulations to examine the tribology of model silica single-asperity contacts under shear with monolayer coated substrates featuring various film densities. It is observed that lower monolayer densities lead to reduced COFs, in contrast to results for planar systems where COF is found to be nearly independent of monolayer density. This is attributed to a liquid-like response to shear, whereby fewer defects are imparted in monolayer chains from the asperity, and chains are easily displaced by the tip as a result of the higher free volume. This transition in the mechanism of molecular plowing suggests that liquid-like films should provide favorable lubrication at single-asperity contacts. PMID- 28915732 TI - Virial Coefficients and Equations of State for Hard Polyhedron Fluids. AB - Hard polyhedra are a natural extension of the hard sphere model for simple fluids, but there is no general scheme for predicting the effect of shape on thermodynamic properties, even in moderate-density fluids. Only the second virial coefficient is known analytically for general convex shapes, so higher-order equations of state have been elusive. Here we investigate high-precision state functions in the fluid phase of 14 representative polyhedra with different assembly behaviors. We discuss historic efforts in analytically approximating virial coefficients up to B4 and numerically evaluating them to B8. Using virial coefficients as inputs, we show the convergence properties for four equations of state for hard convex bodies. In particular, the exponential approximant of Barlow et al. (J. Chem. Phys. 2012, 137, 204102) is found to be useful up to the first ordering transition for most polyhedra. The convergence behavior we explore can guide choices in expending additional resources for improved estimates. Fluids of arbitrary hard convex bodies are too complicated to be described in a general way at high densities, so the high-precision state data we provide can serve as a reference for future work in calculating state data or as a basis for thermodynamic integration. PMID- 28915733 TI - Ab Initio Studies of the Diffusion of Intrinsic Defects and Silicon Dopants in Bulk InAs. AB - We expose the predominant diffusional pathways for In and As in InAs, as well as dopant Si atoms in InAs, using Nudged Elastic Band calculations in conjunction with accurate Density Functional Theory calculations of the energy of defective systems. Our results show that As is a very fast diffuser compared to In and Si for both vacancy-assisted and interstitially mediated mechanisms. Larger indium atoms, on the other hand, are very slow diffusers and strongly prefer to remain on the In sublattice. Silicon also prefers to stay in substitutional sites in the In sublattice, in agreement with the fact that Si is used to create n-doped InAs. We find that the mechanism by which Si diffuses within the InAs lattice is very unlikely to proceed via vacancy-assisted jumps, since these routes encounter energy barriers above 2 eV. In contrast, silicon can readily make interstitial jumps since they occur with energy barriers as small as 0.23 eV. This suggests that an interstitial diffusion mechanism is strongly preferred for Si diffusion in InAs which challenges the common presumption made for another similar III-V compound, namely GaAs, that Si diffusion takes place via a vacancy-assisted mechanism. PMID- 28915734 TI - Ce in the +4 oxidation state: Anion photoelectron spectroscopy and photodissociation of small CexOyHz- molecules. AB - The anion photoelectron (PE) spectra of a range of small mono-cerium molecular species, along with the Ce2O4- and Ce3O6- stoichiometric clusters, are presented and analyzed with the support of density functional theory calculations. A common attribute of all of the neutral species is that the Ce centers in both the molecules and clusters are in the +4 oxidation state. In bulk ceria (CeO2), an unoccupied, narrow 4f band lies between the conventional valence (predominantly O 2p) and conduction (Ce 5d) bands. Within the CeO2-, CeO3H2-, and Ce(OH)4- series, the PE spectra and computational results suggest that the Ce 6s-based molecular orbital is the singly occupied HOMO in CeO2- but becomes destabilized as the Ce 4f-local orbital becomes stabilized with increasing coordination. CeO3-, a hyperoxide, undergoes photodissociation with 3.49 eV photon energy to form the stoichiometric neutral CeO2 and O-. In the CeO2-, Ce2O4- ,and Ce3O6- stoichiometric cluster series, the 6s destabilization with 4f stabilization is associated with increasing cluster size, suggesting that a bulk-like band structure may be realized with fairly small cluster sizes. The destabilization of the 6s-based molecular orbitals can be rationalized by their diffuse size relative to Ce-O bond lengths in a crystal structure, suggesting that 6s bands in the bulk may be relegated to the surface. PMID- 28915735 TI - The effect of finite pore length on ion structure and charging. AB - Nanoporous supercapacitors play an important role in modern energy storage systems, and their modeling is essential to predict and optimize the charging behaviour. Two classes of models have been developed that consist of finite and infinitely long pores. Here, we show that although both types of models predict qualitatively consistent results, there are important differences emerging due to the finite pore length. In particular, we find that the ion density inside a finite pore is not constant, but increases linearly from the pore entrance to the pore end, where the ions form a strongly layered structure. This hinders a direct quantitative comparison between the two models. In addition, we show that although the ion density between the electrodes changes appreciably with the applied potential, this change has a minor effect on charging. Our simulations also reveal a complex charging behaviour, which is adsorption-driven at high voltages, but it is dominated either by co-ion desorption or by adsorption of both types of ions at low voltages, depending on the ion concentration. PMID- 28915736 TI - Communication: A method to compute the transport coefficient of pure fluids diffusing through planar interfaces from equilibrium molecular dynamics simulations. AB - The computation of diffusion coefficients in molecular systems ranks among the most useful applications of equilibrium molecular dynamics simulations. However, when dealing with the problem of fluid diffusion through vanishingly thin interfaces, classical techniques are not applicable. This is because the volume of space in which molecules diffuse is ill-defined. In such conditions, non equilibrium techniques allow for the computation of transport coefficients per unit interface width, but their weak point lies in their inability to isolate the contribution of the different physical mechanisms prone to impact the flux of permeating molecules. In this work, we propose a simple and accurate method to compute the diffusional transport coefficient of a pure fluid through a planar interface from equilibrium molecular dynamics simulations, in the form of a diffusion coefficient per unit interface width. In order to demonstrate its validity and accuracy, we apply our method to the case study of a dilute gas diffusing through a smoothly repulsive single-layer porous solid. We believe this complementary technique can benefit to the interpretation of the results obtained on single-layer membranes by means of complex non-equilibrium methods. PMID- 28915737 TI - Periodic layers of a dodecagonal quasicrystal and a floating hexagonal crystal in sedimentation-diffusion equilibria of colloids. AB - We investigate the behaviour of a system of colloidal particles interacting with a hard-core and a repulsive square shoulder potential under the influence of a gravitational field using event-driven Brownian dynamics simulations. We use a fixed square shoulder diameter equal to 1.4 times the hard-core diameter of the colloids, for which we have previously calculated the equilibrium phase diagram considering two-dimensional disks [H. Pattabhiraman et al., J. Chem. Phys. 143, 164905 (2015) and H. Pattabhiraman and M. Dijkstra, J. Phys.: Condens. Matter 20, 094003 (2017)]. The parameters in the simulations are chosen such that the pressure at the bottom of the sediment facilitates the formation of phases in accordance with the calculated phase diagram of the two-dimensional system. It is surprising that we observe the formation of layers with dodecagonal, square, and hexagonal symmetries at the relevant pressures in the three-dimensional sedimentation column. In addition, we also observe a re-entrant behaviour exhibited by the colloidal fluid phase, engulfing a hexagonal crystal phase, in the sedimentation column. In other words, a floating crystal is formed between the colloidal fluid regions. PMID- 28915738 TI - Re-examination of the Cs2 ground singlet X1Sigmag+ and triplet a3Sigmau+ states. AB - This paper clarifies the disagreement in the depth of the potential energy curve of the cesium dimer singlet ground state which has lasted for nearly a decade. We point out that the origin of this disagreement must be a technical misprint in the values of the three binding energies reported by Danzl et al. [Science 321, 1062 (2008)], while the X1Sigmag+ state potential reported by Coxon and Hajigeorgiou [J. Chem. Phys. 132, 094105 (2010)], based on experimental data by Amiot and Dulieu [J. Chem. Phys. 117, 5155 (2002)], is quite correct. We have recalculated the potential energy function of the triplet ground state a3Sigmau+ by using the available experimental data spanning both the attractive and the repulsive branches so that the potential energy function complies asymptotically with the singlet ground state X1Sigmag+ potential energy function by Coxon and Hajigeorgiou. This is important for the simulation of the near dissociation properties such as Feshbach resonances, which are typically observed in modern experiments with ultracold atoms and molecules. PMID- 28915739 TI - Many-body expansion of the Fock matrix in the fragment molecular orbital method. AB - A many-body expansion of the Fock matrix in the fragment molecular orbital method is derived up to three-body terms for restricted Hartree-Fock and density functional theory in the atomic orbital basis and compared to the expansion in the basis of fragment molecular orbitals (MOs). The physical nature of many-body corrections is revealed in terms of charge transfer terms. An improvement of the fragment MO expansion is proposed by adding exchange to the embedding. The accuracy of all developed methods is demonstrated in comparison to unfragmented results for polyalanines, a water cluster, Trp-cage (PDB: 1L2Y) and crambin (PDB: 1CRN) proteins, a zeolite cluster, a Si nano-wire, and a boron nitride ribbon. The physical nature of metallicity is discussed, and it is shown what kinds of metallic systems can be treated by fragment-based methods. The density of states is calculated for a fully closed and a partially open nano-ring of boron nitride with a diameter of 105 nm. PMID- 28915740 TI - Charge compensation at the interface between the polar NaCl(111) surface and a NaCl aqueous solution. AB - Periodic supercell models of electric double layers formed at the interface between a charged surface and an electrolyte are subject to serious finite size errors and require certain adjustments in the treatment of the long-range electrostatic interactions. In a previous publication Zhang and Sprik [Phys. Rev. B 94, 245309 (2016)], we have shown how this can be achieved using finite field methods. The test system was the familiar simple point charge model of a NaCl aqueous solution confined between two oppositely charged walls. Here this method is extended to the interface between the (111) polar surface of a NaCl crystal and a high concentration NaCl aqueous solution. The crystal is kept completely rigid and the compensating charge screening the polarization can only be provided by the electrolyte. We verify that the excess electrolyte ionic charge at the interface conforms to the Tasker 1/2 rule for compensating charge in the theory of polar rock salt (111) surfaces. The interface can be viewed as an electric double layer with a net charge. We define a generalized Helmholtz capacitance CH which can be computed by varying the applied electric field. We find CH=8.23 MUF cm-2, which should be compared to the 4.23 MUF cm-2 for the (100) non-polar surface of the same NaCl crystal. This is rationalized by the observation that compensating ions shed their first solvation shell adsorbing as contact ions pairs on the polar surface. PMID- 28915741 TI - Variation of ionic conductivity in a plastic-crystalline mixture. AB - Ionically conducting plastic crystals (PCs) are possible candidates for solid state electrolytes in energy-storage devices. Interestingly, the admixture of larger molecules to the most prominent molecular PC electrolyte, succinonitrile, was shown to drastically enhance its ionic conductivity. Therefore, binary mixtures seem to be a promising way to tune the conductivity of such solid-state electrolytes. However, to elucidate the general mechanisms of ionic charge transport in plastic crystals and the influence of mixing, a much broader database is needed. In the present work, we investigate mixtures of two well known plastic-crystalline systems, cyclohexanol and cyclooctanol, to which 1 mol. % of Li ions were added. Applying differential scanning calorimetry and dielectric spectroscopy, we present a thorough investigation of the phase behavior and the ionic and dipolar dynamics of this system. All mixtures reveal plastic-crystalline phases with corresponding orientational glass-transitions. Moreover, their conductivity seems to be dominated by the "revolving-door" mechanism, implying a close coupling between the ionic translational and the molecular reorientational dynamics of the surrounding plastic-crystalline matrix. In contrast to succinonitrile-based mixtures, there is no strong variation of this coupling with the mixing ratio. PMID- 28915742 TI - The Gibbs free energy of homogeneous nucleation: From atomistic nuclei to the planar limit. AB - In this paper we discuss how the information contained in atomistic simulations of homogeneous nucleation should be used when fitting the parameters in macroscopic nucleation models. We show how the number of solid and liquid atoms in such simulations can be determined unambiguously by using a Gibbs dividing surface and how the free energy as a function of the number of solid atoms in the nucleus can thus be extracted. We then show that the parameters (the chemical potential, the interfacial free energy, and a Tolman correction) of a model based on classical nucleation theory can be fitted using the information contained in these free-energy profiles but that the parameters in such models are highly correlated. This correlation is unfortunate as it ensures that small errors in the computed free energy surface can give rise to large errors in the extrapolated properties of the fitted model. To resolve this problem we thus propose a method for fitting macroscopic nucleation models that uses simulations of planar interfaces and simulations of three-dimensional nuclei in tandem. We show that when the chemical potentials and the interface energy are pinned to their planar-interface values, more precise estimates for the Tolman length are obtained. Extrapolating the free energy profile obtained from small simulation boxes to larger nuclei is thus more reliable. PMID- 28915743 TI - Electronic orbital response of regular extended and infinite periodic systems to magnetic fields. I. Theoretical foundations for static case. AB - A theoretical treatment for the orbital response of an infinite, periodic system to a static, homogeneous, magnetic field is presented. It is assumed that the system of interest has an energy gap separating occupied and unoccupied orbitals and a zero Chern number. In contrast to earlier studies, we do not utilize a perturbation expansion, although we do assume the field is sufficiently weak that the occurrence of Landau levels can be ignored. The theory is developed by analyzing results for large, finite systems and also by comparing with the analogous treatment of an electrostatic field. The resulting many-electron Hamilton operator is forced to be hermitian, but hermiticity is not preserved, in general, for the subsequently derived single-particle operators that determine the electronic orbitals. However, we demonstrate that when focusing on the canonical solutions to the single-particle equations, hermiticity is preserved. The issue of gauge-origin dependence of approximate solutions is addressed. Our approach is compared with several previously proposed treatments, whereby limitations in some of the latter are identified. PMID- 28915744 TI - Communication: Charge transfer dominates over proton transfer in the reaction of nitric acid with gas-phase hydrated electrons. AB - The reaction of HNO3 with hydrated electrons (H2O)n- (n = 35-65) in the gas phase was studied using Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry and ab initio molecular dynamics simulations. Kinetic analysis of the experimental data shows that OH-(H2O)m is formed primarily via a reaction of the hydrated electron with HNO3 inside the cluster, while proton transfer is not observed and NO3-(H2O)m is just a secondary product. The reaction enthalpy was determined using nanocalorimetry, revealing a quite exothermic charge transfer with -241 +/- 69 kJ mol-1. Ab initio molecular dynamics simulations indicate that proton transfer is an allowed reaction pathway, but the overall thermochemistry favors charge transfer. PMID- 28915745 TI - Non-local effects of point mutations on the stability of a protein module. AB - We combine experimental and theoretical methods to assess the effect of a set of point mutations on c7A, a highly mechanostable type I cohesin module from scaffoldin CipA from Clostridium thermocellum. We propose a novel robust and computationally expedient theoretical method to determine the effects of point mutations on protein structure and stability. We use all-atom simulations to predict structural shifts with respect to the native protein and then analyze the mutants using a coarse-grained model. We examine transitions in contacts between residues and find that changes in the contact map usually involve a non-local component that can extend up to 50 A. We have identified mutations that may lead to a substantial increase in mechanical and thermodynamic stabilities by making systematic substitutions into alanine and phenylalanine in c7A. Experimental measurements of the mechanical stability and circular dichroism data agree qualitatively with the predictions provided the thermal stability is calculated using only the contacts within the secondary structures. PMID- 28915746 TI - Single, double, and triple Auger decays from 1s shake-up states of the oxygen molecule. AB - The single, double, and triple Auger decays from the 1s shake-up states of O2 have been studied using a multi-electron coincidence method. Efficient populations of two-hole final states are observed in single Auger decays of the pi-pi* shake-up states, which is understood as a characteristic property of the Auger transitions from shake-up states of an open-shell molecule. The O23+ populations formed by double Auger decays show similar profiles for both the O1s 1 and shake-up states, which is due to the contributions from cascade double Auger processes. While the cascade contributions to the double Auger decays increase with the initial shake-up energy, the probability of direct double Auger processes remains unchanged between the O1s-1 and shake-up states, which implies a weak influence of the excited electron on the double Auger emission that originates from the electron correlation effect. PMID- 28915747 TI - Mechanisms and rates of nucleation of amyloid fibrils. AB - The classical nucleation theory finds the rate of nucleation proportional to the monomer concentration raised to the power, which is the "critical nucleus size," nc. The implicit assumption, that amyloids nucleate in the same way, has been recently challenged by an alternative two-step mechanism, when the soluble monomers first form a metastable aggregate (micelle) and then undergo conversion into the conformation rich in beta-strands that are able to form a stable growing nucleus for the protofilament. Here we put together the elements of extensive knowledge about aggregation and nucleation kinetics, using a specific case of Abeta1-42 amyloidogenic peptide for illustration, to find theoretical expressions for the effective rate of amyloid nucleation. We find that at low monomer concentrations in solution and also at low interaction energy between two peptide conformations in the micelle, the nucleation occurs via the classical route. At higher monomer concentrations, and a range of other interaction parameters between peptides, the two-step "aggregation-conversion" mechanism of nucleation takes over. In this regime, the effective rate of the process can be interpreted as a power of monomer concentration in a certain range of parameters; however, the exponent is determined by a complicated interplay of interaction parameters and is not related to the minimum size of the growing nucleus (which we find to be ~7-8 for Abeta1-42). PMID- 28915748 TI - Magnetic two-dimensional organic topological insulator: Au-1,3,5 triethynylbenzene framework. AB - Based on first-principles calculations, we demonstrate that the recently synthesized 2D organometallic framework consisting of Au atoms and 1,3,5 triethynylbenzene (Au-TEB) is a magnetic 2D organic topological insulator (OTI). The charge transfer and covalent bonding character lead to ferromagnetism and half-metallicity in the framework, and the weak spin-orbit coupling (SOC) of C pz orbitals mediated by Au d orbitals opens modest bandgaps in the vicinity of the Fermi level. Moreover, using tight-binding model simulations, we further characterize the nonzero Chern number and edge states of Au-TEB to confirm its topological nontriviality that remains intact when the framework is supported on an insulating substrate, and applying an external strain can increase the magnitude of SOC gaps, leading to an enhanced topological nontriviality. Our results suggest that the Au-TEB organometallic framework is promising for the potential applications in quantum spintronics with the merits of low cost and easy synthesis. PMID- 28915749 TI - Note: Effect of a small surface defect on the Smoluchowski rate constant and capacitance of a spherical capacitor. PMID- 28915750 TI - Near-infrared spectroscopy and anharmonic theory of the H2O+Ar1,2 cation complexes. AB - Weakly bound complexes of the water radical cation with argon (H2O+Arn, n = 1,2) were generated by an electrical discharge/supersonic expansion and probed with mid- and near-infrared photodissociation spectroscopy in the 2050-4550 and 4850 7350 cm-1 regions. To elucidate these spectra, these complexes were studied computationally at the CCSD(T) level including anharmonicity with the VPT2 method. The comparison between experiment and predicted spectra demonstrates that the VPT2 method is adequate to capture most of the vibrational band positions and their intensities. In addition to the fundamentals, overtones of the symmetric and the asymmetric water stretches and their combination were detected. Additional bands were assigned to combinations of the overtone of the bound O-H stretch with multiple excitation levels of the intermolecular Ar-H stretch. H2O+Ar2 could not be dissociated in the higher frequency region (4850-7350 cm-1). PMID- 28915751 TI - Photobleaching of randomly rotating fluorescently decorated particles. AB - Randomly rotating particles that have been isotropically labeled with rigidly linked fluorophores will undergo non-isotropic (patchy) photobleaching under illumination due to the dipole coupling of fluorophores with light. For a rotational diffusion rate D of the particle and a photobleaching time scale tau of the fluorophores, the dynamics of this process are characterized by the dimensionless combination Dtau. We find significant interparticle fluctuations at intermediate Dtau. These fluctuations vanish at both large and small Dtau or at small or large elapsed times t. Associated with these fluctuations between particles, we also observe transient non-monotonicities of the brightness of individual particles. These non-monotonicities can be as much as 20% of the original brightness. We show that these novel photobleach-fluctuations dominate over variability of single-fluorophore orientation when there are at least 103 fluorophores on individual particles. PMID- 28915752 TI - A new insight into diffusional escape from a biased cylindrical trap. AB - Recent experiments with single biological nanopores, as well as single-molecule fluorescence spectroscopy and pulling studies of protein and nucleic acid folding raised a number of questions that stimulated theoretical and computational investigations of barrier crossing dynamics. The present paper addresses a closely related problem focusing on trajectories of Brownian particles that escape from a cylindrical trap in the presence of a force F parallel to the cylinder axis. To gain new insights into the escape dynamics, we analyze the "fine structure" of these trajectories. Specifically, we divide trajectories into two segments: a looping segment, when a particle unsuccessfully tries to escape returning to the trap bottom again and again, and a direct-transit segment, when it finally escapes moving without touching the bottom. Analytical expressions are derived for the Laplace transforms of the probability densities of the durations of the two segments. These expressions are used to find the mean looping and direct-transit times as functions of the biasing force F. It turns out that the force-dependences of the two mean times are qualitatively different. The mean looping time monotonically increases as F decreases, approaching exponential F dependence at large negative forces pushing the particle towards the trap bottom. In contrast to this intuitively appealing behavior, the mean direct-transit time shows rather counterintuitive behavior: it decreases as the force magnitude, |F|, increases independently of whether the force pushes the particles to the trap bottom or to the exit from the trap, having a maximum at F = 0. PMID- 28915753 TI - Non-renewal statistics for electron transport in a molecular junction with electron-vibration interaction. AB - Quantum transport of electrons through a molecule is a series of individual electron tunneling events separated by stochastic waiting time intervals. We study the emergence of temporal correlations between successive waiting times for the electron transport in a vibrating molecular junction. Using the master equation approach, we compute the joint probability distribution for waiting times of two successive tunneling events. We show that the probability distribution is completely reset after each tunneling event if molecular vibrations are thermally equilibrated. If we treat vibrational dynamics exactly without imposing the equilibration constraint, the statistics of electron tunneling events become non-renewal. Non-renewal statistics between two waiting times tau1 and tau2 means that the density matrix of the molecule is not fully renewed after time tau1 and the probability of observing waiting time tau2 for the second electron transfer depends on the previous electron waiting time tau1. The strong electron-vibration coupling is required for the emergence of the non renewal statistics. We show that in the Franck-Condon blockade regime, extremely rare tunneling events become positively correlated. PMID- 28915755 TI - Defects and oxidation of group-III monochalcogenide monolayers. AB - Among various two-dimensional (2D) materials, monolayer group-III monochalcogenides (GaS, GaSe, InS, and InSe) stand out owing to their potential applications in microelectronics and optoelectronics. Devices made of these novel 2D materials are sensitive to environmental gases, especially O2 molecules. To address this critical issue, here we systematically investigate the oxidization behaviors of perfect and defective group-III monochalcogenide monolayers by first principles calculations. The perfect monolayers show superior oxidation resistance with large barriers of 3.02-3.20 eV for the dissociation and chemisorption of O2 molecules. In contrast, the defective monolayers with single chalcogen vacancy are vulnerable to O2, showing small barriers of only 0.26-0.36 eV for the chemisorption of an O2 molecule. Interestingly, filling an O2 molecule to the chalcogen vacancy of group-III monochalcogenide monolayers could preserve the electronic band structure of the perfect system-the bandgaps are almost intact and the carrier effective masses are only moderately disturbed. On the other hand, the defective monolayers with single vacancies of group-III atoms carry local magnetic moments of 1-2 MUB. These results help experimental design and synthesis of group-III monochalcogenides based 2D devices with high performance and stability. PMID- 28915756 TI - A thermally driven differential mutation approach for the structural optimization of large atomic systems. AB - A computational method is presented which is capable to obtain low lying energy structures of topological amorphous systems. The method merges a differential mutation genetic algorithm with simulated annealing. This is done by incorporating a thermal selection criterion, which makes it possible to reliably obtain low lying minima with just a small population size and is suitable for multimodal structural optimization. The method is tested on the structural optimization of amorphous graphene from unbiased atomic starting configurations. With just a population size of six systems, energetically very low structures are obtained. While each of the structures represents a distinctly different arrangement of the atoms, their properties, such as energy, distribution of rings, radial distribution function, coordination number, and distribution of bond angles, are very similar. PMID- 28915754 TI - Modeling the mechanism of CLN025 beta-hairpin formation. AB - Beta-hairpins are substructures found in proteins that can lend insight into more complex systems. Furthermore, the folding of beta-hairpins is a valuable test case for benchmarking experimental and theoretical methods. Here, we simulate the folding of CLN025, a miniprotein with a beta-hairpin structure, at its experimental melting temperature using a range of state-of-the-art protein force fields. We construct Markov state models in order to examine the thermodynamics, kinetics, mechanism, and rate-determining step of folding. Mechanistically, we find the folding process is rate-limited by the formation of the turn region hydrogen bonds, which occurs following the downhill hydrophobic collapse of the extended denatured protein. These results are presented in the context of established and contradictory theories of the beta-hairpin folding process. Furthermore, our analysis suggests that the AMBER-FB15 force field, at this temperature, best describes the characteristics of the full experimental CLN025 conformational ensemble, while the AMBER ff99SB-ILDN and CHARMM22* force fields display a tendency to overstabilize the native state. PMID- 28915757 TI - Liquid bridging of cylindrical colloids in near-critical solvents. AB - Within mean field theory, we investigate the bridging transition between a pair of parallel cylindrical colloids immersed in a binary liquid mixture as a solvent that is close to its critical consolute point Tc. We determine the universal scaling functions of the effective potential and of the force between the colloids. For a solvent that is at the critical concentration and close to Tc, we find that the critical Casimir force is the dominant interaction at close separations. This agrees very well with the corresponding Derjaguin approximation for the effective interaction between the two cylinders, while capillary forces originating from the extension of the liquid bridge turn out to be more important at large separations. In addition, we are able to infer from the wetting characteristics of the individual colloids the first-order transition of the liquid bridge connecting two colloidal particles to the ruptured state. While specific to cylindrical colloids, the results presented here also provide an outline for identifying critical Casimir forces acting on bridged colloidal particles as such and for analyzing the bridging transition between them. PMID- 28915758 TI - Co-adsorption of water and oxygen on GaN: Effects of charge transfer and formation of electron depletion layer. AB - Species from ambient atmosphere such as water and oxygen are known to affect electronic and optical properties of GaN, but the underlying mechanism is not clearly known. In this work, we show through careful measurement of electrical resistivity and photoluminescence intensity under various adsorbates that the presence of oxygen or water vapor alone is not sufficient to induce electron transfer to these species. Rather, the presence of both water and oxygen is necessary to induce electron transfer from GaN that leads to the formation of an electron depletion region on the surface. Exposure to acidic gases decreases n type conductivity due to increased electron transfer from GaN, while basic gases increase n-type conductivity and PL intensity due to reduced charge transfer from GaN. These changes in the electrical and optical properties, as explained using a new electrochemical framework based on the phenomenon of surface transfer doping, suggest that gases interact with the semiconductor surface through electrochemical reactions occurring in an adsorbed water layer present on the surface. PMID- 28915759 TI - An ab initio study of hydroxylated graphane. AB - Graphene-based derivatives with covalent functionalization and well-defined stoichiometry are highly desirable in view of their application as functional surfaces. Here, we have evaluated by ab initio calculations the energy of formation and the phase diagram of hydroxylated graphane structures, i.e., fully functionalized graphene derivatives coordinated with -H and -OH groups. We compared these structures to different hydrogenated and non-hydrogenated graphene oxide derivatives, with high level of epoxide and hydroxyl groups functionalization. Based on our calculations, stable phases of hydroxylated graphane with low and high contents of hydrogen are demonstrated for high oxygen and hydrogen partial pressure, respectively. Stable phases of graphene oxide with a mixed carbon hybridization are also found. Notably, the synthesis of hydroxylated graphane has been recently reported in the literature. PMID- 28915760 TI - Molybdenum disulfide and water interaction parameters. AB - Understanding the interaction between water and molybdenum disulfide (MoS2) is of crucial importance to investigate the physics of various applications involving MoS2 and water interfaces. An accurate force field is required to describe water and MoS2 interactions. In this work, water-MoS2 force field parameters are derived using the high-accuracy random phase approximation (RPA) method and validated by comparing to experiments. The parameters obtained from the RPA method result in water-MoS2 interface properties (solid-liquid work of adhesion) in good comparison to the experimental measurements. An accurate description of MoS2-water interaction will facilitate the study of MoS2 in applications such as DNA sequencing, sea water desalination, and power generation. PMID- 28915761 TI - A potential model for sodium chloride solutions based on the TIP4P/2005 water model. AB - Despite considerable efforts over more than two decades, our knowledge of the interactions in electrolyte solutions is not yet satisfactory. Not even one of the most simple and important aqueous solutions, NaCl(aq), escapes this assertion. A requisite for the development of a force field for any water solution is the availability of a good model for water. Despite the fact that TIP4P/2005 seems to fulfill the requirement, little work has been devoted to build a force field based on TIP4P/2005. In this work, we try to fill this gap for NaCl(aq). After unsuccessful attempts to produce accurate predictions for a wide range of properties using unity ionic charges, we decided to follow recent suggestions indicating that the charges should be scaled in the ionic solution. In this way, we have been able to develop a satisfactory non-polarizable force field for NaCl(aq). We evaluate a number of thermodynamic properties of the solution (equation of state, maximum in density, enthalpies of solution, activity coefficients, radial distribution functions, solubility, surface tension, diffusion coefficients, and viscosity). Overall the results for the solution are very good. An important achievement of our model is that it also accounts for the dynamical properties of the solution, a test for which the force fields so far proposed failed. The same is true for the solubility and for the maximum in density where the model describes the experimental results almost quantitatively. The price to pay is that the model is not so good at describing NaCl in the solid phase, although the results for several properties (density and melting temperature) are still acceptable. We conclude that the scaling of the charges improves the overall description of NaCl aqueous solutions when the polarization is not included. PMID- 28915762 TI - On the relationship between the local segmental dynamics and the tagged monomer dynamics in lamellar phases of diblock copolymers. AB - In this brief article, we present results from coarse-grained molecular dynamics simulations which probed the relationship between the local segmental dynamics and the tagged monomer dynamics in lamellar phases of diblock copolymers. Our results demonstrate that monomer relaxation times do not provide directly a quantitatively accurate measure of the spatial variations in segmental dynamics. However, a convolution of the monomer density distributions with their corresponding relaxation times is shown to provide an approximate, but accurate, quantitative characterization of the average local segmental dynamics. PMID- 28915763 TI - Extended screened exchange functional derived from transcorrelated density functional theory. AB - We propose a new formulation of the correlation energy functional derived from the transcorrelated method in use in density functional theory (TC-DFT). An effective Hamiltonian, HTC, is introduced by a similarity transformation of a many-body Hamiltonian, H, with respect to a complex function F: HTC=1FHF. It is proved that an expectation value of HTC for a normalized single Slater determinant, Dn, corresponds to the total energy: E[n] = ?Psin|H|Psin?/?Psin|Psin? = ?Dn|HTC|Dn? under the two assumptions: (1) The electron density nr associated with a trial wave function Psin = DnF is v representable and (2) Psin and Dn give rise to the same electron density nr. This formulation, therefore, provides an alternative expression of the total energy that is useful for the development of novel correlation energy functionals. By substituting a specific function for F, we successfully derived a model correlation energy functional, which resembles the functional form of the screened exchange method. The proposed functional, named the extended screened exchange (ESX) functional, is described within two-body integrals and is parametrized for a numerically exact correlation energy of the homogeneous electron gas. The ESX functional does not contain any ingredients of (semi-)local functionals and thus is totally free from self-interactions. The computational cost for solving the self-consistent-field equation is comparable to that of the Hartree-Fock method. We apply the ESX functional to electronic structure calculations for a solid silicon, H- ion, and small atoms. The results demonstrate that the TC-DFT formulation is promising for the systematic improvement of the correlation energy functional. PMID- 28915764 TI - Sequence dependent aggregation of peptides and fibril formation. AB - Deciphering the links between amino acid sequence and amyloid fibril formation is key for understanding protein misfolding diseases. Here we use Monte Carlo simulations to study the aggregation of short peptides in a coarse-grained model with hydrophobic-polar (HP) amino acid sequences and correlated side chain orientations for hydrophobic contacts. A significant heterogeneity is observed in the aggregate structures and in the thermodynamics of aggregation for systems of different HP sequences and different numbers of peptides. Fibril-like ordered aggregates are found for several sequences that contain the common HPH pattern, while other sequences may form helix bundles or disordered aggregates. A wide variation of the aggregation transition temperatures among sequences, even among those of the same hydrophobic fraction, indicates that not all sequences undergo aggregation at a presumable physiological temperature. The transition is found to be the most cooperative for sequences forming fibril-like structures. For a fibril-prone sequence, it is shown that fibril formation follows the nucleation and growth mechanism. Interestingly, a binary mixture of peptides of an aggregation-prone and a non-aggregation-prone sequence shows the association and conversion of the latter to the fibrillar structure. Our study highlights the role of a sequence in selecting fibril-like aggregates and also the impact of a structural template on fibril formation by peptides of unrelated sequences. PMID- 28915765 TI - The parameter uncertainty inflation fallacy. AB - Statistical estimation of the prediction uncertainty of physical models is typically hindered by the inadequacy of these models due to various approximations they are built upon. The prediction errors caused by model inadequacy can be handled either by correcting the model's results or by adapting the model's parameter uncertainty to generate prediction uncertainties representative, in a way to be defined, of model inadequacy errors. The main advantage of the latter approach (thereafter called PUI, for Parameter Uncertainty Inflation) is its transferability to the prediction of other quantities of interest based on the same parameters. A critical review of implementations of PUI in several areas of computational chemistry shows that it is biased, in the sense that it does not produce prediction uncertainty bands conforming to model inadequacy errors. PMID- 28915766 TI - Should an LDL-Cholesterol Target-Based Approach Be Readopted? AB - OBJECTIVE: To review clinical trials driving the evolution of hyperlipidemic guidelines, discuss whether low-density lipoprotein (LDL) targets and adjunctive therapy on top of statins should be used, and summarize the pharmacist's role in helping achieve LDL goals. DATA SOURCES: MEDLINE search (1/1980-5/2017) using terms including LDL, lipid, and statin, with forward and backward citation tracking. STUDY SELECTION AND DATA EXTRACTION: English-language studies and guidelines assessing LDL-lowering therapy were included. DATA SYNTHESIS: In 2013, the American Heart Association and American College of Cardiology (AHA/ACC) hyperlipidemic guideline stepped back from LDL goals opting for statin monotherapy with an intensity of dosing predicated on baseline risk. This was driven by abundant clinical trial evidence for the statins, with adjunctive therapy on top of statins failing to show substantial benefit. However, recent evidence suggests that returning to LDL goals is warranted and adjuvant ezetimibe or PCSK9 inhibitor therapy may further reduce cardiovascular events. This is reflected in some society guidelines but not from the AHA/ACC. Pharmacists are well positioned to help achieve LDL goals, as they have positively affected LDL goal attainment across a multitude of settings. CONCLUSIONS: Statins are the mainstay of therapy but patients should have LDL targets, and if patients on maximally tolerated statin doses are not at goal, adjunctive therapy with ezetimibe and PCSK9 inhibitors may improve outcomes. In the emerging LDL goal paradigm, the pharmacist has a critical role to play. PMID- 28915767 TI - Sick leave among people in paid work after age 65: A Swedish population-based study covering 1995, 2000, 2005 and 2010. AB - AIMS: Extending working life into older age groups is discussed in many countries. However, there is no knowledge about how this affects rates of sick leave. The aim of this work was to investigate rates of sick leave among people in paid work after retirement age and if such rates have changed over time. METHODS: Swedish nationwide register data on people aged >65 years and living in Sweden in 1995, 2000, 2005 and 2010 were analysed. All people with a sufficiently high work income to be eligible for public sick leave benefits were included. The proportions in paid work and compensated rates of sick leave for people aged 66 70 and >=71 were analysed by sex, educational level, country of birth, living area, and employment type and sector. RESULTS: The percentage of people in paid work at ages 66-70 years increased from <10% in 1995 to 24% in 2010 and among those aged >=71 years from 2.7% in 1995 to 3.5% in 2010. The rates of sick leave among working people aged 66-70 years were 3.3% in 1995 and 2.4% in 2010 and for people aged >=71 years the rates of sick leave were 2.2% in 1995 and 0.2% in 2010. Women had higher rates of sick leave than men in 2005 and 2010, but lower in 1995 and 2000. In 2010, the rates of sick leave were similar between employees and the self-employed, and higher among employees in the public sector than among employees in the private sector. CONCLUSIONS: Rates of sick leave among workers aged >65 years were lower in 2010 than in 1995, despite much higher rates of labour market participation in 2010. PMID- 28915768 TI - Isotopic composition of bottled water in Saudi Arabia. AB - The 18O/16O and 2H/1H ratios of 18 water brands representing the most popular bottled water brands in the Saudi market were measured using a system based on the latest advancements in tunable off-axis integrated cavity output diode laser spectroscopy (OA-ICOS) in the near-infrared spectral region. Utilizing delta18O and the delta2H values of locally produced water samples, a meteoric water line (delta2H = 7.84 delta18O + 2.11) was extracted and found to be consistent with the slope of the global meteoric water line (GMWL) and the geographic location of Saudi Arabia. PMID- 28915769 TI - Robotic lymphadenectomy of an internal mammary lymph node metastasis. AB - A 58-year-old woman was diagnosed with a left-sided lone internal mammary swollen lymph node on a routine follow-up computer tomography, 42 months after a left mastectomy in the context of a ductal carcinoma grade III. The suspected metastasis was successfully removed in toto using a 3-port-da Vinci robotic procedure and the patient was discharged home without any complication on the third postoperative day. Robotically assisted oncological lymph node removal is safe, easily performed and economically affordable. PMID- 28915770 TI - Helmet-induced headache among Danish military personnel. AB - AIMS: External compression headache is defined as a headache caused by an external physical compression applied on the head. It affects about 4% of the general population; however, certain populations (e.g. construction workers and military personnel) with particular needs of headwear or helmet are at higher risk of developing this type of headache. External compression headache is poorly studied in relation to specific populations. This study aimed to investigate the prevalence and pattern of helmet-induced external compression headache among Danish military personnel of the Northern Jutland region in Denmark. METHODS: Data acquisition was based on a custom-made questionnaire delivered to volunteers who used helmets in the Danish military service and who agreed to participate in this study. The military of the Northern Jutland region of Denmark facilitated recruitment of the participants. The questionnaires were delivered on paper and the collected (anonymous) answers (total 279) were used for further analysis. RESULTS: About 30% of the study participants reported headache in relation to wearing a military helmet. Headache was defined as a pressing pain predominantly in the front of the head with an average intensity of 4 on a visual analogue scale of 0 (no pain) to 10 (worst pain imaginable). It was also found that helmets with different designs influenced both the occurrence of headache and its characteristics. CONCLUSIONS: This study is the first to demonstrate the prevalence and pattern of compression headache among military personnel in North Jutland, Denmark. The findings of this study call for further attention to helmet induced external compression headache and strategies to minimize the burden. PMID- 28915771 TI - Low Back Pain With Impact at 17 Years of Age Is Predicted by Early Adolescent Risk Factors From Multiple Domains: Analysis of the Western Australian Pregnancy Cohort (Raine) Study. AB - Study Design Prospective cohort study of the Western Australian Pregnancy Cohort (Raine) Study. Background Low back pain (LBP) commonly develops in adolescence and is a significant risk factor for adult LBP. A broad range of factors have been associated with the development of adolescent LBP, but prior literature has limitations related to characterization of LBP and the scope of risk factors considered. Objective This study aimed to identify potential factors contributing to the development of LBP, with and without impact, at 17 years of age, utilizing a broad range of exposures at 14 years of age. Methods Data from 1088 participants (52.1% female) with "no LBP," "LBP with minimal impact," and "LBP with impact" at 17 years of age and a range of measures from multiple domains, including spinal pain, physical, psychological, social, and lifestyle, at 14 years of age were collected for the study. Multivariable multinomial logistic regression was used to estimate the association of potential mechanistic factors at 14 years of age with LBP at 17 years of age. Results Female sex and back pain at 14 years of age were strongly associated with LBP at 17 years of age. Potential mechanistic factors for LBP outcomes at 17 years of age included exposures from the pain (neck/shoulder pain) and physical domains (standing posture subgroup membership, back muscle endurance, throwing distance), psychological domain (somatic complaints, aggressive behavior), social domain (socioeconomic area), and lifestyle domain (exercise out of school). Conclusion The findings support the multidimensional nature of adolescent LBP and highlight the challenge this presents for epidemiological research, clinical practice, and prevention initiatives in the general population. Level of Evidence Prognosis, level 1b. J Orthop Sports Phys Ther 2017;47(10):752-762. doi:10.2519/jospt.2017.7464. PMID- 28915772 TI - Hypermobility in Adolescent Athletes: Pain, Functional Ability, Quality of Life, and Musculoskeletal Injuries. AB - Study Design Cross-sectional. Background Generalized joint hypermobility (GJH) may increase pain and likelihood of injuries and also decrease function and health-related quality of life (HRQoL) in elite-level adolescent athletes. Objective To assess the prevalence of GJH in elite-level adolescent athletes, and to study the association of GJH with pain, function, HRQoL, and musculoskeletal injuries. Methods A total of 132 elite-level adolescent athletes (36 adolescent boys, 96 adolescent girls; mean +/- SD age, 14.0 +/- 0.9 years), including ballet dancers (n = 22), TeamGym gymnasts (n = 57), and team handball players (n = 53), participated in the study. Generalized joint hypermobility was classified by Beighton score as GJH4 (4/9 or greater), GJH5 (5/9 or greater), and GJH6 (6/9 or greater). Function of the lower extremity, musculoskeletal injuries, and HRQoL were assessed with self-reported questionnaires, and part of physical performance was assessed by 4 postural-sway tests and 2 single-legged hop-for-distance tests. Results Overall prevalence rates for GJH4, GJH5, and GJH6 were 27.3%, 15.9%, and 6.8%, respectively, with a higher prevalence of GJH4 in ballet dancers (68.2%) and TeamGym gymnasts (24.6%) than in team handball players (13.2%). There was no significant difference in lower extremity function, injury prevalence and related factors (exacerbation, recurrence, and absence from training), HRQoL, or lengths of hop tests for those with and without GJH. However, the GJH group had significantly larger center-of-pressure path length across sway tests. Conclusion For ballet dancers and TeamGym gymnasts, the prevalence of GJH4 was higher than that of team handball players. For ballet dancers, the prevalence of GJH5 and GJH6 was higher than that of team handball players and the general adolescent population. The GJH group demonstrated larger sway in the balance tests, which, in the current cross-sectional study, did not have an association with injuries or HRQoL. However, the risk of having (ankle) injuries due to larger sway for the GJH group must be studied in future longitudinal studies. J Orthop Sports Phys Ther 2017;47(10):792-800. doi:10.2519/jospt.2017.7682. PMID- 28915773 TI - Does Motor Development in Infancy Predict Spinal Pain in Later Childhood? A Cohort Study. AB - Study Design Longitudinal cohort study. Background Spinal pain is responsible for a huge personal and societal burden, but its etiology remains unclear. Deficits in motor control have been associated with spinal pain in adults, and delayed motor development is associated with a range of health problems and risks in children. Objective To assess whether there is an independent relationship between the age at which infants first sit and walk without support and spinal pain at 11 years of age. Methods Data from the Danish National Birth Cohort were analyzed, using the age at which children first sat and first walked without support as predictors. Parents reported the predictors when the children were 6 months and 18 months of age, and also provided information in response to a comprehensive list of covariates, including child sex, birth weight, and cognitive development; socioeconomic indicators; and parental health variables. Outcomes were measured at 11 years of age using the Young Spine Questionnaire, which assesses the presence and intensity of spinal pain. Data were analyzed using multivariable logistic regression models to estimate determinants of neck, thoracic, lumbar, and multisite pain. Results The analyses included data from approximately 23 000 children and their parents. There were no consistent independent associations between the age at first sitting or walking and spinal pain at the age of 11. Odds ratios were between 0.95 and 1.00 for the various pain sites. Conclusion The age at which a child first sits or walks without support does not influence the likelihood that he or she will experience spinal pain in later childhood. Level of Evidence Prognosis, level 4. J Orthop Sports Phys Ther 2017;47(10):763-768. doi:10.2519/jospt.2017.7484. PMID- 28915774 TI - Pyoderma Gangrenosum: A Current Problem as Much as an Unknown One. AB - Pyoderma gangrenosum (PG) is a rare neutrophilic inflammatory skin disease, characterized by recurrent skin ulcers, which in almost 50% of cases are associated with systemic autoimmune disorders, including rheumatoid arthritis, chronic hepatitis, inflammatory bowel disease, paraproteinemias and hematological malignancies. A systematic search of literature for PG was carried out using the PubMed, Embase, and Google Scholar databases for the purpose of this review and 2780 articles were retrieved up to February 2017. Inflammation represents the predominant aspect of the disease, but its pathophysiological mechanisms are not completely clear yet, since there are many studies showing only one or more isolated findings of the disease. The goal of PG treatment is to reduce inflammation in order to promote ulcer healing by minimizing side effects of therapy. Several systemic and local treatments are available, but the lack of large randomized double-blind studies results in an absence of a uniform therapeutic standard: thus, more clinical studies are required in order to make head-to-head comparisons between combination and single-drug therapies and to identify specific combination therapies for distinctive clinical patterns of PG. PMID- 28915775 TI - Wound Healing and Anti-inflammatory Effects of Topical Hyaluronic Acid Injection in Surgical-Site Infection Caused by Staphylococcus aureus. AB - Surgical-site infection (SSI) is a common postoperative complication, primarily caused by Staphylococcus aureus. S aureus produces hyaluronidase which degrades hyaluronic acid (HA). HA prevents bacterial proliferation and has anti inflammatory effects to promote wound healing. We evaluated the effect of HA injection with systemic antibiotics for prevention and treatment of SSIs caused by S aureus. An open wound was created on the dorsum of 40 rats. The wound bed was sutured with S aureus inoculated thread. The test group was injected with HA (HA group), and the control group received a subcutaneous injection of normal saline (NS group). All groups were then treated with intraperitoneal cefazolin injection. The sutures were removed 2 days after the procedure. Gross pathology, bacterial count, and wound histology were assessed at days 2, 4, 6, and 8 postprocedure. The HA group showed a significant reduction in the wound area compared with the control group on gross pathology (at days 8 postprocedure, 36.54% +/- 6.12% vs 50.59% +/- 5.50%, P < .001). The HA group showed significantly better wound healing than the control group on histological analysis, including assessment of abscess, neutrophilic infiltration, and necrosis (4.2 +/- 1.2 vs 11.5 +/- 2.1, P < .001). The HA group showed a lower bacterial count compared with the NS group, but the result was not significant statistically (at days 6 postprocedure, 5.11 +/- 0.31 vs 5.91 +/- 0.35 logCFU/mL, P = .706). In conclusion, immediate local injection of HA in wounds can reduce SSI occurrence and promote wound healing in an animal model. PMID- 28915776 TI - Sharing the Vision-Innovation, Integration, and New Horizons: Report of the Third Transatlantic Wound Science and Podiatric Medicine Conference 2017. PMID- 28915777 TI - Unmet Needs in Wound Healing. PMID- 28915778 TI - Prosodic Variation and Segmental Reduction and Their Roles in Cuing Turn Transition in Swedish. AB - Prosody has often been identified alongside syntax as a cue to turn hold or turn transition in conversational interaction. However, evidence for which prosodic cues are most relevant, and how strong those cues are, has been somewhat scattered. The current study addresses prosodic cues to turn transition in Swedish. A perception study looking closely at turn changes and holds in cases where the syntax does not lead inevitably to a particular outcome shows that Swedish listeners are sensitive to duration variations, even in the very short space of the final unstressed syllable of a turn, and that they may use pitch cues to a lesser extent. An investigation of production data indicates that duration, and to some extent segmental reduction, demonstrate consistent variation in relation to the types of turn boundaries they accompany, while fundamental frequency and glottalization do not. Taken together, these data suggest that duration may be the primary cue to turn transition in Swedish conversation, rather than fundamental frequency, as some other studies have suggested. PMID- 28915779 TI - Relative Salience of Speech Rhythm and Speech Rate on Perceived Foreign Accent in a Second Language. AB - We investigated the independent contribution of speech rate and speech rhythm to perceived foreign accent. To address this issue we used a resynthesis technique that allows neutralizing segmental and tonal idiosyncrasies between identical sentences produced by French learners of English at different proficiency levels and maintaining the idiosyncrasies pertaining to prosodic timing patterns. We created stimuli that (1) preserved the idiosyncrasies in speech rhythm while controlling for the differences in speech rate between the utterances; (2) preserved the idiosyncrasies in speech rate while controlling for the differences in speech rhythm between the utterances; and (3) preserved the idiosyncrasies both in speech rate and speech rhythm. All the stimuli were created in intoned (with imposed intonational contour) and flat (with monotonized, constant F0) conditions. The original and the resynthesized sentences were rated by native speakers of English for degree of foreign accent. We found that both speech rate and speech rhythm influence the degree of perceived foreign accent, but the effect of speech rhythm is larger than that of speech rate. We also found that intonation enhances the perception of fine differences in rhythmic patterns but reduces the perceptual salience of fine differences in speech rate. PMID- 28915780 TI - Cognitive Load Reduces Perceived Linguistic Convergence Between Dyads. AB - Speech convergence is the tendency of talkers to become more similar to someone they are listening or talking to, whether that person is a conversational partner or merely a voice heard repeating words. To elucidate the nature of the mechanisms underlying convergence, this study uses different levels of task difficulty on speech convergence within dyads collaborating on a task. Dyad members had to build identical LEGO(r) constructions without being able to see each other's construction, and with each member having half of the instructions required to complete the construction. Three levels of task difficulty were created, with five dyads at each level (30 participants total). Task difficulty was also measured using completion time and error rate. Listeners who heard pairs of utterances from each dyad judged convergence to be occurring in the Easy condition and to a lesser extent in the Medium condition, but not in the Hard condition. Amplitude envelope acoustic similarity analyses of the same utterance pairs showed that convergence occurred in dyads with shorter completion times and lower error rates. Together, these results suggest that while speech convergence is a highly variable behavior, it may occur more in contexts of low cognitive load. The relevance of these results for the current automatic and socially driven models of convergence is discussed. PMID- 28915781 TI - F2 slope as a Perceptual Cue for the Front-Back Contrast in Standard Southern British English. AB - Acoustic studies of several languages indicate that second-formant (F2) slopes in high vowels have opposing directions (independent of consonantal context): front [i?]-like vowels are produced with a rising F2 slope, whereas back [u?]-like vowels are produced with a falling F2 slope. The present study first reports acoustic measurements that confirm this pattern for the English variety of Standard Southern British English (SSBE), where /u?/ has shifted from the back to the front area of the vowel space and is now realized with higher midpoint F2 values than several decades ago. Subsequently, we test whether the direction of F2 slope also serves as a reliable cue to the /i?/-/u?/ contrast in perception. The findings show that F2 slope direction is used as a cue (additional to midpoint formant values) to distinguish /i?/ from /u?/ by both young and older Standard Southern British English listeners: an otherwise ambiguous token is identified as /i?/ if it has a rising F2 slope and as /u?/ if it has a falling F2 slope. Furthermore, our results indicate that listeners generalize their reliance on F2 slope to other contrasts, namely /E/-/alpha/ and /ae/-/alpha/, even though F2 slope is not employed to differentiate these vowels in production. This suggests that in Standard Southern British English, a rising F2 seems to be perceptually associated with an abstract feature such as [+front], whereas a falling F2 with an abstract feature such as [-front]. PMID- 28915782 TI - Voicing Assimilation in Czech and Slovak Speakers of English: Interactions of Segmental Context, Language and Strength of Foreign Accent. AB - This study focuses on voicing assimilation across word boundaries in the speech of second language (L2) users. We compare native speakers of British English to speakers of two West Slavic languages, Czech and Slovak, which, despite their many similarities, differ with respect to voicing assimilation rules. Word-final voicing was analysed in 30 speakers, using the static value of voicing percentage and the voicing profile method. The results of linear mixed-effects modelling suggest an effect of first language (L1) transfer in all L2 English speaker groups, with the tendency to assimilate being correlated with the strength of foreign accent. Importantly, the two language groups differed in assimilation strategies before sonorant consonants, as a clear effect of L1-based phonetic influence. PMID- 28915783 TI - Prediction of Agreement and Phonetic Overlap Shape Sublexical Identification. AB - The mapping between the physical speech signal and our internal representations is rarely straightforward. When faced with uncertainty, higher-order information is used to parse the signal and because of this, the lexicon and some aspects of sentential context have been shown to modulate the identification of ambiguous phonetic segments. Here, using a phoneme identification task (i.e., participants judged whether they heard [o] or [a] at the end of an adjective in a noun adjective sequence), we asked whether grammatical gender cues influence phonetic identification and if this influence is shaped by the phonetic properties of the agreeing elements. In three experiments, we show that phrase-level gender agreement in Spanish affects the identification of ambiguous adjective-final vowels. Moreover, this effect is strongest when the phonetic characteristics of the element triggering agreement and the phonetic form of the agreeing element are identical. Our data are consistent with models wherein listeners generate specific predictions based on the interplay of underlying morphosyntactic knowledge and surface phonetic cues. PMID- 28915784 TI - The Role of Fundamental Frequency and Temporal Envelope in Processing Sentences with Temporary Syntactic Ambiguities. AB - Previous experiments have demonstrated the impact of speech prosody on syntactic processing. The present study was designed to examine how listeners use specific acoustic properties of prosody for grammatical interpretation. We investigated the independent contributions of two acoustic properties associated with the pitch and rhythmic properties of speech; the fundamental frequency and temporal envelope, respectively. The effect of degrading these prosodic components was examined by testing listeners' ability to parse early-closure garden-path sentences. A second aim was to investigate how effects of prosody interact with semantic effects of sentence plausibility. Using a task that required both a comprehension and a production response, we were able to determine that degradation of the speech envelope more consistently affects syntactic processing than degradation of the fundamental frequency. These effects are exacerbated in sentences with plausible misinterpretations, showing that prosodic degradation interacts with contextual cues to sentence interpretation. PMID- 28915785 TI - Seed maturation associated transcriptional programs and regulatory networks underlying genotypic difference in seed dormancy and size/weight in wheat (Triticum aestivum L.). AB - BACKGROUND: Maturation forms one of the critical seed developmental phases and it is characterized mainly by programmed cell death, dormancy and desiccation, however, the transcriptional programs and regulatory networks underlying acquisition of dormancy and deposition of storage reserves during the maturation phase of seed development are poorly understood in wheat. The present study performed comparative spatiotemporal transcriptomic analysis of seed maturation in two wheat genotypes with contrasting seed weight/size and dormancy phenotype. RESULTS: The embryo and endosperm tissues of maturing seeds appeared to exhibit genotype-specific temporal shifts in gene expression profile that might contribute to the seed phenotypic variations. Functional annotations of gene clusters suggest that the two tissues exhibit distinct but genotypically overlapping molecular functions. Motif enrichment predicts genotypically distinct abscisic acid (ABA) and gibberellin (GA) regulated transcriptional networks contribute to the contrasting seed weight/size and dormancy phenotypes between the two genotypes. While other ABA responsive element (ABRE) motifs are enriched in both genotypes, the prevalence of G-box-like motif specifically in tissues of the dormant genotype suggests distinct ABA mediated transcriptional mechanisms control the establishment of dormancy during seed maturation. In agreement with this, the bZIP transcription factors that co-express with ABRE enriched embryonic genes differ with genotype. The enrichment of SITEIIATCYTC motif specifically in embryo clusters of maturing seeds irrespective of genotype predicts a tissue specific role for the respective TCP transcription factors with no or minimal contribution to the variations in seed dormancy. CONCLUSION: The results of this study advance our understanding of the seed maturation associated molecular mechanisms underlying variation in dormancy and weight/size in wheat seeds, which is a critical step towards the designing of molecular strategies for enhancing seed yield and quality. PMID- 28915786 TI - Nutrition in primary and secondary prevention of cardiovascular risk in the continental and Mediterranean regions of Croatia. AB - BACKGROUND: The aim of this observational study was to evaluate the effect of Mediterranean and continental nutrition on cardiovascular risk in patients with acute and chronic coronary heart disease in Croatia. METHODS: The study included 1284 patients who were hospitalized in a 28-month period due to acute or chronic ischaemic heart disease in hospitals across Croatia. An individual questionnaire was prepared which enabled recording of various cardiovascular risk factors. RESULTS: Patients with chronic coronary artery disease have a better index of healthy diet than patients with acute coronary disease. Women have a better index of diet than men in both Croatian regions. When the prevalence of risk factors (impaired glucose tolerance, diabetes mellitus types I and II, hypercholesterolaemia, hypertriglyceridaemia and hypertension) in patients with Mediterranean and continental nutrition is compared, a trend is seen for patients who have risk factors to consume healthier food. CONCLUSION: The Mediterranean diet is associated with reduced risk of developing cardiovascular disease. This effect is more evident in patients with known cardiovascular disease. PMID- 28915787 TI - mmquant: how to count multi-mapping reads? AB - BACKGROUND: RNA-Seq is currently used routinely, and it provides accurate information on gene transcription. However, the method cannot accurately estimate duplicated genes expression. Several strategies have been previously used (drop duplicated genes, distribute uniformly the reads, or estimate expression), but all of them provide biased results. RESULTS: We provide here a tool, called mmquant, for computing gene expression, included duplicated genes. If a read maps at different positions, the tool detects that the corresponding genes are duplicated; it merges the genes and creates a merged gene. The counts of ambiguous reads is then based on the input genes and the merged genes. CONCLUSION: mmquant is a drop-in replacement of the widely used tools htseq-count and featureCounts that handles multi-mapping reads in an unabiased way. PMID- 28915788 TI - Morphogenesis along the animal-vegetal axis: fates of primary quartet micromere daughters in the gastropod Crepidula fornicata. AB - BACKGROUND: The Spiralia are a large, morphologically diverse group of protostomes (e.g. molluscs, annelids, nemerteans) that share a homologous mode of early development called spiral cleavage. One of the most highly-conserved features of spiralian development is the contribution of the primary quartet cells, 1a-1d, to the anterior region of the embryo (including the brain, eyes, and the anterior ciliary band, called the prototroch). Yet, very few studies have analyzed the ultimate fates of primary quartet sub-lineages, or examined the morphogenetic events that take place in the anterior region of the embryo. RESULTS: This study focuses on the caenogastropod slipper snail, Crepidula fornicata, a model for molluscan developmental biology. Through direct lineage tracing of primary quartet daughter cells, and examination of these cells during gastrulation and organogenesis stages, we uncovered behaviors never described before in a spiralian. For the first time, we show that the 1a2-1d2 cells do not contribute to the prototroch (as they do in other species) and are ultimately lost before hatching. During gastrulation and anterior-posterior axial elongation stages, these cells cleavage-arrest and spread dramatically, contributing to a thin provisional epidermis on the dorsal side of the embryo. This spreading is coupled with the displacement of the animal pole, and other pretrochal cells, closer to the ventrally-positioned mouth, and the vegetal pole. CONCLUSIONS: This is the first study to document the behavior and fate of primary quartet sub lineages among molluscs. We speculate that the function of 1a2-1d2 cells (in addition to two cells derived from 1d12, and the 2b lineage) is to serve as a provisional epithelium that allows for anterior displacement of the other progeny of the primary quartet towards the anterior-ventral side of the embryo. These data support a new and novel mechanism for axial bending, distinct from canonical models in which axial bending is suggested to be driven primarily by differential proliferation of posterior dorsal cells. These data suggest also that examining sub-lineages in other spiralians will reveal greater variation than previously assumed. PMID- 28915789 TI - Rapid transcriptional and metabolic regulation of the deacclimation process in cold acclimated Arabidopsis thaliana. AB - BACKGROUND: During low temperature exposure, temperate plant species increase their freezing tolerance in a process termed cold acclimation. This is accompanied by dampened oscillations of circadian clock genes and disrupted oscillations of output genes and metabolites. During deacclimation in response to warm temperatures, cold acclimated plants lose freezing tolerance and resume growth and development. While considerable effort has been directed toward understanding the molecular and metabolic basis of cold acclimation, much less information is available about the regulation of deacclimation. RESULTS: We report metabolic (gas chromatography-mass spectrometry) and transcriptional (microarrays, quantitative RT-PCR) responses underlying deacclimation during the first 24 h after a shift of Arabidopsis thaliana (Columbia-0) plants cold acclimated at 4 degrees C back to warm temperature (20 degrees C). The data reveal a faster response of the transcriptome than of the metabolome and provide evidence for tightly regulated temporal responses at both levels. Metabolically, deacclimation is associated with decreasing contents of sugars, amino acids, glycolytic and TCA cycle intermediates, indicating an increased need for carbon sources and respiratory energy production for the activation of growth. The early phase of deacclimation also involves extensive down-regulation of protein synthesis and changes in the metabolism of lipids and cell wall components. Hormonal regulation appears particularly important during deacclimation, with extensive changes in the expression of genes related to auxin, gibberellin, brassinosteroid, jasmonate and ethylene metabolism. Members of several transcription factor families that control fundamental aspects of morphogenesis and development are significantly regulated during deacclimation, emphasizing that loss of freezing tolerance and growth resumption are transcriptionally highly interrelated processes. Expression patterns of some clock oscillator components resembled those under warm conditions, indicating at least partial re activation of the circadian clock during deacclimation. CONCLUSIONS: This study provides the first combined metabolomic and transcriptomic analysis of the regulation of deacclimation in cold acclimated plants. The data indicate cascades of rapidly regulated genes and metabolites that underlie the developmental switch resulting in reduced freezing tolerance and the resumption of growth. They constitute a large-scale dataset of genes, metabolites and pathways that are crucial during the initial phase of deacclimation. The data will be an important reference for further analyses of this and other important but under-researched stress deacclimation processes. PMID- 28915790 TI - The process-related dynamics of microbial community during a simulated fermentation of Chinese strong-flavored liquor. AB - BACKGROUND: Famous Chinese strong-flavored liquor (CSFL) is brewed by microbial consortia in a special fermentation pit (FT). However, the fermentation process was not fully understood owing to the complicate community structure and metabolism. In this study, the process-related dynamics of microbial communities and main flavor compounds during the 70-day fermentation process were investigated in a simulated fermentation system. RESULTS: A three-phase model was proposed to characterize the process of the CSFL fermentation. (i) In the early fermentation period (1-23 days), glucose was produced from macromolecular carbohydrates (e.g., starch). The prokaryotic diversity decreased significantly. The Lactobacillaceae gradually predominated in the prokaryotic community. In contrast, the eukaryotic diversity rose remarkably in this stage. Thermoascus, Aspergillus, Rhizopus and unidentified Saccharomycetales were dominant eukaryotic members. (ii) In the middle fermentation period (23-48 days), glucose concentration decreased while lactate acid and ethanol increased significantly. Prokaryotic community was almost dominated by the Lactobacillus, while eukaryotic community was mainly comprised of Thermoascus, Emericella and Aspergillus. (iii) In the later fermentation period (48-70 days), the concentrations of ethyl esters, especially ethyl caproate, increased remarkably. CONCLUSIONS: The CSFL fermentation could undergo three stages: saccharification, glycolysis and esterification. Saccharomycetales, Monascus, and Rhizopus were positively correlated to glucose concentration (P < 0.05), highlighting their important roles in the starch saccharification. The Lactobacillaceae, Bacilli, Botryotinia, Aspergillus, unidentified Pleosporales and Capnodiales contributed to the glycolysis and esterification, because they were positively correlated to most organic acids and ethyl esters (P < 0.05). Additionally, four genera, including Emericella, Suillus, Mortierella and Botryotinia, that likely played key roles in fermentation, were observed firstly. This study observed comprehensive dynamics of microbial communities during the CSFL fermentation, and it further revealed the correlations between some crucial microorganisms and flavoring chemicals (FCs). The results from this study help to design effective strategies to manipulate microbial consortia for fermentation process optimization in the CSFL brew practice. PMID- 28915791 TI - Segmentation and classification of two-channel C. elegans nucleus-labeled fluorescence images. AB - BACKGROUND: Aging is characterized by a gradual breakdown of cellular structures. Nuclear abnormality is a hallmark of progeria in human. Analysis of age-dependent nuclear morphological changes in Caenorhabditis elegans is of great value to aging research, and this calls for an automatic image processing method that is suitable for both normal and abnormal structures. RESULTS: Our image processing method consists of nuclear segmentation, feature extraction and classification. First, taking up the challenges of defining individual nuclei with fuzzy boundaries or in a clump, we developed an accurate nuclear segmentation method using fused two-channel images with seed-based cluster splitting and k-means algorithm, and achieved a high precision against the manual segmentation results. Next, we extracted three groups of nuclear features, among which five features were selected by minimum Redundancy Maximum Relevance (mRMR) for classifiers. After comparing the classification performances of several popular techniques, we identified that Random Forest, which achieved a mean class accuracy (MCA) of 98.69%, was the best classifier for our data set. Lastly, we demonstrated the method with two quantitative analyses of C. elegans nuclei, which led to the discovery of two possible longevity indicators. CONCLUSIONS: We produced an automatic image processing method for two-channel C. elegans nucleus-labeled fluorescence images. It frees biologists from segmenting and classifying the nuclei manually. PMID- 28915792 TI - Levosimendan combined with epinephrine improves rescue outcomes in a rat model of lipid-based resuscitation from bupivacaine-induced cardiac arrest. AB - BACKGROUND: The effectiveness of a combination of a lipid emulsion with epinephrine in reversing local anesthetic-induced cardiac arrest has been confirmed. The combination of a lipid emulsion with levosimendan, was shown to be superior to administration of a lipid emulsion alone with regard to successful resuscitation. In this study, we compared the reversal effects of levosimendan, epinephrine, and a combination of the two agents in lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. METHODS: Fifty-four adult male Sprague-Dawley rats were subjected to bupivacaine (15 mg.kg-1) -induced asystole and were then randomly divided into 3 groups. A lipid emulsion was used as the basic treatment, and administration of drug combinations varied in each group as follows: (1) levosimendan combined with epinephrine (LiEL); (2) epinephrine (LiE); and (3) levosimendan (LiL). The resuscitation outcomes were recorded and included the rate of return of spontaneous circulation (ROSC) and survival at 40 min, time to first heartbeat, time to ROSC, and cumulative dose of epinephrine. We calculated the wet-to-dry ratio of the lung, blood gas values at 40 min and bupivacaine concentration of cardiac tissue and plasma. RESULTS: The rates of ROSC in LiEL and LiE groups were higher than LiL group (P < 0.001; LiEL vs LiL, P = 0.001; LiE vs LiL, P = 0.007). The survival rate in LiEL group was higher than LiE group (P = 0.003; LiEL vs LiE, P = 0.008; LiEL vs LiL, P = 0.001). The time to first heart beat in LiEL group was shorter than LiE, LiL groups. (P < 0.001; LiE vs LiEL, P = 0.001; LiL vs LiEL, P < 0.001). The time to ROSC in LiEL group was shorter than LiE, LiL groups (P < 0.001; LiEL vs LiE, P < 0.001; LiEL vs LiL, P < 0.001). The result was similar for the bupivacaine concentration of cardiac tissue and plasma (cardiac tissue: P = 0.002; plasma: P = 0.011). Furthermore, there were significant differences in the blood-gas values at 40 min, wet-to-dry lung weight ratio, and ratio of damaged alveoli among groups. The LiEL group had the best result for all parameters (P < 0.01, P = 0.008, P < 0.001, respectively). Additionally, significantly less epinephrine was used in the LiEL group (P < 0.001). CONCLUSIONS: Levosimendan combined with epinephrine may be superior to either drug alone for lipid-based resuscitation in a rat model of bupivacaine-induced cardiac arrest. The drug combination was associated with a higher survival rate as well as decreased epinephrine consumption and lung damage. PMID- 28915793 TI - The cacao Criollo genome v2.0: an improved version of the genome for genetic and functional genomic studies. AB - BACKGROUND: Theobroma cacao L., native to the Amazonian basin of South America, is an economically important fruit tree crop for tropical countries as a source of chocolate. The first draft genome of the species, from a Criollo cultivar, was published in 2011. Although a useful resource, some improvements are possible, including identifying misassemblies, reducing the number of scaffolds and gaps, and anchoring un-anchored sequences to the 10 chromosomes. METHODS: We used a NGS based approach to significantly improve the assembly of the Belizian Criollo B97 61/B2 genome. We combined four Illumina large insert size mate paired libraries with 52x of Pacific Biosciences long reads to correct misassembled regions and reduced the number of scaffolds. We then used genotyping by sequencing (GBS) methods to increase the proportion of the assembly anchored to chromosomes. RESULTS: The scaffold number decreased from 4,792 in assembly V1 to 554 in V2 while the scaffold N50 size has increased from 0.47 Mb in V1 to 6.5 Mb in V2. A total of 96.7% of the assembly was anchored to the 10 chromosomes compared to 66.8% in the previous version. Unknown sites (Ns) were reduced from 10.8% to 5.7%. In addition, we updated the functional annotations and performed a new RefSeq structural annotation based on RNAseq evidence. CONCLUSION: Theobroma cacao Criollo genome version 2 will be a valuable resource for the investigation of complex traits at the genomic level and for future comparative genomics and genetics studies in cacao tree. New functional tools and annotations are available on the Cocoa Genome Hub ( http://cocoa-genome-hub.southgreen.fr ). PMID- 28915794 TI - Genome sequence of the ectophytic fungus Ramichloridium luteum reveals unique evolutionary adaptations to plant surface niche. AB - BACKGROUND: Ectophytic fungi occupy the waxy plant surface, an extreme environment characterized by prolonged desiccation, nutrient limitation, and exposure to solar radiation. The nature of mechanisms that facilitate adaptation to this environment remains unclear. In this study, we sequenced the complete genome of an ectophytic fungus, Ramichloridium luteum, which colonizes the surface of apple fruit, and carried out comparative genomic and transcriptome analysis. RESULTS: The R. luteum genome was 28.18 Mb and encoded 9466 genes containing 1.85% repetitive elements. Compared with cell-penetrating pathogens, genes encoding plant cell wall degrading enzymes (PCWDEs), PTH11-like G protein coupled receptors (GPCRs) and effectors were drastically reduced. In contrast, genes encoding cutinases and secretory lipases were strikingly expanded, and four of nine secretory lipases were probably acquired by horizontal gene transfer from Basidiomycota. Transcriptomic analysis revealed elevated expression of genes involved in cuticle degradation (cutinase, secretory lipase) and stress responses (melanin biosynthesis, aquaporins, lysozymes and HOG pathway). CONCLUSIONS: Taken together, our results highlight genomic features associated with evolution of surface niche adaptation by the ectophytic fungus R. luteum, namely the contraction of PCWDEs, PTH11-like GPCRs and effectors, and the expansion of cuticle degradation and stress tolerance. PMID- 28915795 TI - Future complications of chronic hepatitis C in a low-risk area: projections from the hepatitis c study in Northern Norway. AB - BACKGROUND: Hepatitis C (HCV) infection causes an asymptomatic chronic hepatitis in most affected individuals, which often remains undetected until cirrhosis and cirrhosis-related complications occur. Screening of high-risk subjects in Northern Norway has revealed a relatively low prevalence in the general population (0.24%). Despite this, late complications of HCV infection are increasing. Our object was to estimate the future prevalence and complications of chronic HCV infection in the period 2013-2050 in a low-risk area. METHODS: We have entered available data into a prognostic Markov model to project future complications to HCV infection. RESULTS: The model extrapolates the prevalence in the present cohort of HCV-infected individuals, and assumes a stable low incidence in the projection period. We predict an almost three-fold increase in the incidence of cirrhosis (68 per 100,000), of decompensated cirrhosis (21 per 100,000) and of hepatocellular carcinoma (4 per 100,000) by 2050, as well as a six-fold increase in the cumulated number of deaths from HCV-related liver disease (170 per 100,000 inhabitants). All estimates are made assuming an unchanged treatment coverage of approximately 15%. The estimated numbers can be reduced by approximately 50% for cirrhosis, and by approximately one third for the other endpoints if treatment coverage is raised to 50%. CONCLUSION: These projections from a low-prevalence area indicate a substantial rise in HCV-related morbidity and mortality in the coming years. The global HCV epidemic is of great concern and increased treatment coverage is necessary to reduce the burden of the disease. PMID- 28915796 TI - Correlates of isoniazid preventive therapy failure in child household contacts with infectious tuberculosis in high burden settings in Nairobi, Kenya - a cohort study. AB - BACKGROUND: Sub-Saharan Africa continues to document high pediatric tuberculosis (TB) burden, especially among the urban poor. One recommended preventive strategy involves tracking and isoniazid preventive therapy (IPT) for children under 5 years in close contact with infectious TB. However, sub-optimal effectiveness has been documented in diverse settings. We conducted a study to elucidate correlates to IPT strategy failure in children below 5 years in high burden settings. METHODS: A prospective longitudinal cohort study was done in informal settlings in Nairobi, where children under 5 years in household contact with recently diagnosed smear positive TB adults were enrolled. Consent was sought. Structured questionnaires administered sought information on index case treatment, socio demographics and TB knowledge. Contacts underwent baseline clinical screening exclude TB and/or pre-existing chronic conditions. Contacts were then put on daily isoniazid for 6 months and monitored for new TB disease, compliance and side effects. Follow-up continued for another 6 months. RESULTS: At baseline, 428 contacts were screened, and 14(3.2%) had evidence of TB disease, hence excluded. Of 414 contacts put on IPT, 368 (88.8%) completed the 1 year follow-up. Operational challenges were reported by 258(70%) households, while 82(22%) reported side effects. Good compliance was documented in 89% (CI:80.2-96.2). By endpoint, 6(1.6%) contacts developed evidence of new TB disease and required definitive anti-tuberculosis therapy. The main factor associated with IPT failure was under-nutrition of contacts (p = 0.023). CONCLUSION: Under-nutrition was associated with IPT failure for child contacts below 5 years in high burden, resource limited settings. IPT effectiveness could be optimized through nutrition support of contacts. PMID- 28915797 TI - Effectiveness of a 16-month multi-component and environmental school-based intervention for recovery of poor income overweight/obese children and adolescents: study protocol of the health multipliers program. AB - BACKGROUND: Excess of weight is a serious public health concern in almost all countries, afflicting people of different ages and socioeconomic backgrounds. Studies have indicated the need for developing treatment strategies that intervene directly in the obesogenic environment. This study aims to evaluate the effectiveness of a multi-component and environmental school-based intervention, lasting 16 months, on the recovery of the nutritional status of low-income children and adolescents with overweight/ obesity. METHODS/STUDY DESIGN: The study was conducted by the Center for Recovery and Nutritional Education (CREN) in Sao Paulo, Brazil. Two schools located in poor neighborhoods were selected for the intervention, between March 2016 and June 2017. The participants were all students aged 8 to 12 years from the two participating schools. At the beginning of the intervention, anthropometric measurements were carried out to assess the nutritional status of the students. For convenience, students from one of the schools were considered as the control group, while those from the other school formed the experimental group. The intervention in the experimental group (n = 438) consists of the following weekly activities at school: psychological counseling in groups, theoretical/practical nutrition workshops, and supervised physical education classes. In addition, theoretical and practical educational activities are held regularly for parents, teachers, and cooks. Students with excess of weight (>=1 body mass index [BMI] -for-age Z score, n = 138) received clinical and nutritional care periodically at the outpatient care at CREN. Students enrolled in the control group (n = 353) participated in psychological counseling groups and theoretical/practical nutrition workshops for 6 months held in the school environment to provide motivation to entire classrooms. In the following 10 months, students with excess of weight from the control group (n = 125) were invited to attend the routine outpatient care at CREN. DISCUSSION: This study is the first to assess the effectiveness of a multi-component and environmental school-based intervention for the recovery of low-income, overweight/obese children and adolescents. If positive, the results demonstrate the feasibility for the recovery of excess of weight in populations of similar conditions and age. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials - ReBEC Primary Id Number RBR-9t2jr8 . Registration Date: Nov. 30, 2016. Retrospectively registered. Protocol version: 3. PMID- 28915799 TI - Analysis of various factors affecting pupil size in patients with glaucoma. AB - BACKGROUND: Pupil size is an important factor in predicting post-operative satisfaction. We assessed the correlation between pupil size, measured by Humphrey static perimetry, and various affecting factors in patients with glaucoma. METHODS: In total, 825 eyes of 415 patients were evaluated retrospectively. Pupil size was measured with Humphrey static perimetry. Comparisons of pupil size according to the presence of glaucoma were evaluated, as were correlations between pupil size and various factors, including age, logMAR best corrected visual acuity (BCVA), retinal nerve fiber layer (RNFL) thickness, spherical equivalent, intraocular pressure, axial length, central corneal thickness, white-to-white, and the kappa angle. RESULTS: Pupil size was significantly smaller in glaucoma patients than in glaucoma suspects (p < 0.001) or the normal group (p < 0.001). Pupil size decreased significantly as age (p < 0.001) and central cornea thickness (p = 0.007) increased, and increased significantly as logMAR BCVA (p = 0.02) became worse and spherical equivalent (p = 0.007) and RNFL thickness (p = 0.042) increased. In patients older than 50 years, pupil size was significantly larger in eyes with a history of cataract surgery. CONCLUSIONS: Humphrey static perimetry can be useful in measuring pupil size. Pupil size was significantly smaller in eyes with glaucoma. Other factors affecting pupil size can be used in a preoperative evaluation when considering cataract surgery or laser refractive surgery. PMID- 28915798 TI - Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study. AB - BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered. PMID- 28915800 TI - Association of body mass index with amnestic and non-amnestic mild cognitive impairment risk in elderly. AB - BACKGROUND: Previous studies focused on the relationship between body mass index and cognitive disorder and obtained many conflicting results. This study explored the potential effects of body mass index on the risk of mild cognitive impairment (amnestic and non-amnestic) in the elderly. METHODS: The study enrolled 240 amnestic mild cognitive impairment patients, 240 non-amnestic mild cognitive impairment patients and 480 normal cognitive function controls. Data on admission and retrospective data at baseline (6 years ago) were collected from their medical records. Cognitive function was evaluated using Mini-Mental State Examination and Montreal Cognitive Assessment. RESULTS: Being underweight, overweight or obese at baseline was associated with an increased risk of amnestic mild cognitive impairment (OR: 2.30, 95%CI: 1.50 ~ 3.52; OR: 1.74, 95%CI: 1.36 ~ 2.20; OR: 1.71, 95%CI: 1.32 ~ 2.22, respectively). Being overweight or obese at baseline was also associated with an increased risk of non-amnestic mild cognitive impairment (OR: 1.51, 95%CI: 1.20 ~ 1.92; OR: 1.52, 95%CI: 1.21 ~ 1.97, respectively). In subjects with normal weights at baseline, an increased or decreased body mass index at follow-up was associated with an elevated risk of amnestic mild cognitive impairment (OR: 1.80, 95%CI: 1.10 ~ 3.05; OR: 3.96, 95%CI: 2.88 ~ 5.49, respectively), but only an increased body mass index was associated with an elevated risk of non-amnestic mild cognitive impairment (OR: 1.71, 95%CI: 1.16 ~ 2.59). CONCLUSIONS: Unhealthy body mass index levels at baseline and follow-up might impact the risk of both types of mild cognitive impairment (amnestic and non-amnestic). PMID- 28915802 TI - Determinants of pre-eclampsia/Eclampsia among women attending delivery Services in Selected Public Hospitals of Addis Ababa, Ethiopia: a case control study. AB - BACKGROUND: Pre-eclampsia is a pregnancy-specific hypertensive disorder usually occurs after 20 weeks of gestation. It is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. In Ethiopia, the major direct obstetric complications including pre-eclampsia/eclampsia account for 85% of the maternal deaths. Unlike deaths due to other direct causes, pre-eclampsia/ eclampsia related deaths appear to be increasing and linked to multiple factors, making prevention of the disease a continuous challenge. The aim of this study is to assess determinants of pre-eclampsia/eclampsiaamong women attending delivery services in selected public hospitals in Addis Ababa, Ethiopia. METHODS: Hospital based unmatched case control study design was employed. The study wasconducted in Addis Ababa among women attending delivery services in two public hospitals from December, 2015 G.C. to February, 2016 G.C. with sample size of 291 (97 cases and 194 controls). Women with pre-eclampsia/eclampsia were cases and women who had not diagnosed for pre-eclampsia/eclampsia were controls. Case-control incidence density sampling followed by interviewer administered was conducted using pretested questionnaire. The data was entered in Epi Info 7 software and exported to STATA 14 for cleaning and analysis. Descriptive statistics were used todisplay the data using tables compared between cases and controls. To compare categorical variables between cases and controls Chi-squared testwas used. Both bivariable and multivariable logistic regression analyses were computed to identify the determinants of pre-eclampsia/eclampsia. RESULTS: Factors that were found to have statistically significant association with pre-eclampsia or eclampsia were primigravida (AOR: 2.68, 95% CI: 1.38, 5.22), history of preeclampsia on prior pregnancy (AOR: 4.28, 95% CI: 1.61, 11.43), multiple pregnancy (AOR: 8.22, 95% CI: 2.97, 22.78), receiving nutritional counseling during pregnancy (AOR: 0.22, 95% CI: 0.1, 0.48) and drinking alcohol during pregnancy (AOR: 3.97, 95% CI: 1.8, 8.75). CONCLUSIONS: The study identified protective and risk factors for pre eclampsia/eclampsia. To promptly diagnose and treat pre-eclampsia, health workers should give special attention to women with primigravida and multiple pregnancy. Besides, health care providers should provide nutritional counseling during ANC, including avoiding drinking alcohol during their pregnancy. PMID- 28915801 TI - Body mass index and type 2 diabetes in Thai adults: defining risk thresholds and population impacts. AB - BACKGROUND: Body mass index (BMI) cut-off values (>25 and >30) that predict diabetes risk have been well validated in Caucasian populations but less so in Asian populations. We aimed to determine the BMI threshold associated with increased type 2 diabetes (T2DM) risk and to calculate the proportion of T2DM cases attributable to overweight and obesity in the Thai population. METHODS: Participants were those from the Thai Cohort Study who were diabetes-free in 2005 and were followed-up in 2009 and 2013 (n = 39,021). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the BMI-T2DM association. We modelled non-linear associations using restricted cubic splines. We estimated population attributable fractions (PAF) and the number of T2DM incident cases attributed to overweight and obesity. We also calculated the impact of reducing the prevalence of overweight and obesity on T2DM incidence in the Thai population. RESULTS: Non-linear modelling indicated that the points of inflection where the BMI-T2DM association became statistically significant compared to a reference of 20.00 kg/m2 were 21.60 (OR = 1.27, 95% CI 1.00-1.61) and 20.03 (OR = 1.02, 95% CI 1.02-1.03) for men and women, respectively. Approximately two-thirds of T2DM cases in Thai adults could be attributed to overweight and obesity. Annually, if prevalent obesity was 5% lower, ~13,000 cases of T2DM might be prevented in the Thai population. CONCLUSIONS: A BMI cut-point of 22 kg/m2, one point lower than the current 23 kg/m2, would be justified for defining T2DM risk in Thai adults. Lowering obesity prevalence would greatly reduce T2DM incidence. PMID- 28915803 TI - Tartrate-resistant acid phosphatase (TRAP/ACP5) promotes metastasis-related properties via TGFbeta2/TbetaR and CD44 in MDA-MB-231 breast cancer cells. AB - BACKGROUND: Tartrate-resistant acid phosphatase (TRAP/ACP5), a metalloenzyme that is characteristic for its expression in activated osteoclasts and in macrophages, has recently gained considerable focus as a driver of metastasis and was associated with clinically relevant parameters of cancer progression and cancer aggressiveness. METHODS: MDA-MB-231 breast cancer cells with different TRAP expression levels (overexpression and knockdown) were generated and characterized for protein expression and activity levels. Functional cell experiments, such as proliferation, migration and invasion assays were performed as well as global phosphoproteomic and proteomic analysis was conducted to connect molecular perturbations to the phenotypic changes. RESULTS: We identified an association between metastasis-related properties of TRAP-overexpressing MDA-MB-231 breast cancer cells and a TRAP-dependent regulation of Transforming growth factor (TGFbeta) pathway proteins and Cluster of differentiation 44 (CD44). Overexpression of TRAP increased anchorage-independent and anchorage-dependent cell growth and proliferation, induced a more elongated cellular morphology and promoted cell migration and invasion. Migration was increased in the presence of the extracellular matrix (ECM) proteins osteopontin and fibronectin and the basement membrane proteins collagen IV and laminin I. TRAP-induced properties were reverted upon shRNA-mediated knockdown of TRAP or treatment with the small molecule TRAP inhibitor 5-PNA. Global phosphoproteomics and proteomics analyses identified possible substrates of TRAP phosphatase activity or signaling intermediates and outlined a TRAP-dependent regulation of proteins involved in cell adhesion and ECM organization. Upregulation of TGFbeta isoform 2 (TGFbeta2), TGFbeta receptor type 1 (TbetaR1) and Mothers against decapentaplegic homolog 2 (SMAD2), as well as increased intracellular phosphorylation of CD44 were identified upon TRAP perturbation. Functional antibody-mediated blocking and chemical inhibition demonstrated that TRAP-dependent migration and proliferation is regulated via TGFbeta2/TbetaR, whereas proliferation beyond basal levels is regulated through CD44. CONCLUSION: Altogether, TRAP promotes metastasis-related cell properties in MDA-MB-231 breast cancer cells via TGFbeta2/TbetaR and CD44, thereby identifying a potential signaling mechanism associated to TRAP action in breast cancer cells. PMID- 28915804 TI - Prevalence and predictors of persistent pelvic girdle pain 12 years postpartum. AB - BACKGROUND: Pelvic girdle pain (PGP) is not always a self-limiting condition. Women with more pronounced persistent PGP (PPGP) report poorer health status compared to women with less pronounced symptoms. The knowledge concerning the long-term consequences of PPGP is limited, thus more knowledge in this area is needed. The overall aim was to study the prevalence and predictors of PPGP 12 years after delivery. METHODS: This is a long-term follow-up study based on a previous cohort study that commenced in 2002. New questionnaire data 12 years postpartum were collected in 2014 and early 2015. The questionnaire was distributed to a total of 624 women from the initial cohort. RESULTS: In total, 295 women (47.3%) responded to the questionnaire where 40.3% (n = 119) reported pain to a various degree and 59% (n = 174) reported no pain. Increased duration and/or persistency of pain, self-rated health, sciatica, neck and/or thoracic spinal pain, sick leave the past 12 months, treatment sought, and prescription and/or non-prescription drugs used were all associated with an statistically significant increase in the odds of reporting pain 12 years postpartum. Widespread pain was common and median expectation of improvement score was 5 on an 11-point numeric scale (interquartile range 2-7.50). More than one of five women (21.8%) reporting pain stated that they had been on sick leave the past 12 months and nearly 11% had been granted disability pension due to PPGP. No statistically significant differences were found between respondents and non respondents regarding most background variables. CONCLUSIONS: This study is unique as it is one of few long-term follow-up studies following women with PPGP of more than 11 years. The results show that spontaneous recovery with no recurrences is an unlikely scenario for a subgroup of women with PPGP. Persistency and/or duration of pain symptoms as well as widespread pain appear to be the strongest predictors of poor long-term outcome. Moreover, widespread pain is commonly associated with PPGP and may thus contribute to long-term sick leave and disability pension. A screening tool needs to be developed for the identification of women at risk of developing PPGP to enable early intervention. PMID- 28915805 TI - Antibiotic resistance: it's bad, but why isn't it worse? AB - Antibiotic natural products are ancient and so is resistance. Consequently, environmental bacteria harbor numerous and varied antibiotic resistance elements. Nevertheless, despite long histories of antibiotic production and exposure, environmental bacteria are not resistant to all known antibiotics. This means that there are barriers to the acquisition of a complete resistance armamentarium. The sources, distribution, and movement of resistance mechanisms in different microbes and bacterial populations are mosaic features that act as barriers to slow this movement, thus moderating the emergence of bacterial pan resistance. This is highly relevant to understanding the emergence of resistance in pathogenic bacteria that can inform better antibiotic management practices and influence new drug discovery. PMID- 28915807 TI - Descemet membrane detachment in femtosecond laser-assisted cataract surgery: a case report. AB - BACKGROUND: Femtosecond laser-assisted cataract surgery (FLACS) has grown in popularity among ophthalmologists as a novel technique. However, descemet membrane detachment (DMD) began to be found as the complication after FLACS. We report a case of serious DMD following FLACS due to the inappropriate incision design. CASE PRESENTATION: An 85-year-old man with apparent cornea arcus senilis underwent femtosecond laser-assisted cataract surgery in his right eye. A biplanar model was chosen for the main incision. A serious descemet membrane detachment (DMD) occurred at the end of phacoemulsification, which was connected with the main incision. However, the surgeon confused it with the transient swelling of corneal endothelium, and did not treated DMD timely. DMD was confirmed by anterior segment optical coherence tomography (AS-OCT) at the postoperative 1-month follow-up. Eventually DMD was resolved by intracameral perfluropropane (C3F8) gas injection. CONCLUSIONS: This case suggests that a careful incision separation and a triplanar incision design in FLACS may reduce the incidence of DMD in cataract surgery. PMID- 28915806 TI - Family-based intervention in adolescent restrictive eating disorders: early treatment response and low weight suppression is associated with favourable one year outcome. AB - BACKGROUND: Family-based treatments are first-line treatments for adolescents with restrictive eating disorders (ED) but have to be improved since outcome is poor for some. We have investigated the one-year outcome of a family-based intervention programme with defined and decisive interventions at the start of treatment. METHOD: Data pertaining 201 adolescents with restrictive ED with features of anorexia nervosa but not fulfilling the weight criterion starting treatment 2010-2015, had a wide range of body mass index (BMI) and of weight loss at presentation, and completed a one-year follow-up was analysed. Recovery from the ED was defined as an Eating Disorder Examination-questionnaire (EDE-Q) score < 2.0 or as not fulfilling criteria for an ED at a clinical interview. RESULTS: By EDE-Q 130 (65%) had recovered at 1 year and by clinical interview 106 (53%). According to the EDE-Q criterion recovery was independently associated with lower EDE-Q score at presentation, higher weight gain after 3 months of treatment and lower weight suppression at follow-up, weight suppression being defined as the difference between premorbid and current BMI. Not fulfilling criteria for an ED was associated with the same factors and also by higher BMI at presentation. CONCLUSION: The observations that low weight and high ED cognitions confer a poor prognosis but that rapid weight gain at the start of treatment predicts a better prognosis are presently extended to adolescents with restrictive ED with a wide range of BMI at presentation. High weight suppression at follow-up is associated with a poor prognosis and indicates the importance of taking premorbid BMI into account when setting weight targets for treatment. PMID- 28915808 TI - Fall prevention: is the STRATIFY tool the right instrument in Italian Hospital inpatient? A retrospective observational study. AB - BACKGROUND: Although several risk assessment tools are in use, uncertainties on their accuracy in detecting fall risk already exist. Choosing the most accurate tool for hospital inpatient is still a challenge for the organizations. We aimed to retrospectively assess the appropriateness of a fall risk prevention program with the STRATIFY assessment tool in detecting acute-care inpatient fall risk. METHODS: Number of falls and near falls, occurred from January 2014 to March 2015, was collected through the incident reporting web-system implemented in the hospital's intranet. We reported whether the fall risk was assessed with the STRATIFY assessment tool and, if so, which was the judgement. Primary outcome was the proportion of inpatients identified as high risk of fall among inpatients who fell (True Positive Rate), and the proportion of inpatients identified as low risk that experienced a fall howsoever (False Negative Rate). Characteristics of population and fall events were described among subgroups of low risk and high risk inpatients. RESULTS: We collected 365 incident reports from 40 hospital units, 349 (95.6%) were real falls and 16 (4.4%) were near falls. The fall risk assessment score at patient's admission had been reported in 289 (79%) of the overall incident reports. Thus, 74 (20.3%) fallers were actually not assessed with the STRATIFY, even though the majority of them presented risk recommended to be assessed. The True Positive Rate was 35.6% (n = 101, 95% CI 30% - 41.1%). The False Negative Rate was 64.4% (n = 183, 95% CI 58.9%-70%) of fallers, nevertheless they incurred in a fall. The STRATIFY mean score was 1.3 +/- 1.4; the median was 1 (IQQ 0-2). CONCLUSIONS: The prevention program using only the STRATIFY tool was found to be not adequate to screen our inpatients population. The incorrect identification of patients' needs leads to allocate resources to erroneous priorities and to untargeted interventions, decreasing healthcare performance and quality. PMID- 28915809 TI - "Maybe we should talk about it anyway": a qualitative study of understanding expectations and use of an established technology innovation in caring practices. AB - BACKGROUND: Technological innovations are strongly promoted to meet the demands posed by increased pressure on home care services and to assist ageing in place in western societies. Although heavily advocated as plug and play solutions, technologies have proven difficult and unpredictable when integrated into home care services. We need greater insight into what happens when technologies are integrated into caring practices. All technologies come with expectations as to their function. This study explores how actors who are involved with the social alarm, which is an established technology innovation, relate to, perceive and articulate these expectations of the technology in everyday living. METHODS: The article presents results from a two-case study, using a triangulation of qualitative methods in order to gain an in-depth understanding of technology in use in home care services through "thick descriptions". The study was conducted in Norway and data were analysed using a stepwise deductive-inductive analysis. RESULTS: The empirical findings demonstrate that expectations regarding the social alarm, even though it represents a simple and well-established technology, are complex and multidimensional. The notion of script and domestication provided relevant tools for exploring these expectations and for understanding how actors interpret and adapt their practices of using the technology. This enabled a more comprehensive understanding of how technology opens up for different interpretations and puts values in play. CONCLUSIONS: This article suggests exploring technology in use as scripted in multidimensional script, and offers a frame for doing so. It also reveals how technology scripts and articulation prove important for understanding the complex reality when integrated into home care practices, thus identifying how using the technology leads to the taming and unleashing of both technology and actors. The study offers an increased understanding of how and why technology is unpredictable and works differently in different contexts. Moreover, it stresses the importance of avoiding expectations of plug-and-play in a reality of complex interactions between different actors. PMID- 28915810 TI - Does one workshop on respecting cultural differences increase health professionals' confidence to improve the care of Australian Aboriginal patients with cancer? An evaluation. AB - BACKGROUND: Aboriginal Australians have worse cancer survival rates than other Australians. Reasons include fear of a cancer diagnosis, reluctance to attend mainstream health services and discrimination from health professionals. Offering health professionals education in care focusing on Aboriginal patients' needs is important. The aim of this paper was to evaluate whether participating in a workshop improved the confidence of radiation oncology health professionals in their knowledge, communication and ability to offer culturally safe healthcare to Aboriginal Australians with cancer. METHODS: Mixed methods using pre and post workshop online surveys, and one delivered 2 months later, were evaluated. Statistical analysis determined the relative proportion of participants who changed from not at all/a little confident at baseline to fairly/extremely confident immediately and 2 months after the workshop. Factor analysis identified underlying dimensions in the items and nonparametric tests recorded changes in mean dimension scores over and between times. Qualitative data was analysed for emerging themes. RESULTS: Fifty-nine participants attended the workshops, 39 (66% response rate) completed pre-workshop surveys, 32 (82% of study participants) completed post-workshop surveys and 25 (64% of study participants) completed surveys 2 months later. A significant increase in the proportion of attendees who reported fair/extreme confidence within 2 days of the workshop was found in nine of 14 items, which was sustained for all but one item 2 months later. Two additional items had a significant increase in the proportion of fair/extremely confident attendees 2 months post workshop compared to baseline. An exploratory factor analysis identified three dimensions: communication; relationships; and awareness. All dimensions' mean scores significantly improved within 2 days (p < 0.005) and persisted to 2 months. The workshop raised awareness about barriers and enablers to delivering services respectful of cultural differences, led to a willingness to reflect on pre-existing beliefs and assumptions about Aboriginal Australians that in some cases resulted in improved care. CONCLUSION: Single workshops co-delivered by an Aboriginal and non-Aboriginal presenter can be effective in building health professionals' confidence and translating into practice knowledge of respectful care of Aboriginal patients with cancer. Sustaining improvements may require integrating this approach into ongoing professional development. PMID- 28915811 TI - Strategies for the quality assessment of the health care service providers in the treatment of Gastric Cancer in Colombia. AB - BACKGROUND: While, at its inception in 1993, the health care system in Colombia was publicized as a paradigm to be copied across the developing world, numerous problems in its implementation have led to, what is now, an inefficient and crisis-ridden health system. Furthermore, as a result of inappropriate tools to measure the quality of the health service providers, several corruption scandals have arisen in the country. This study attempts to tackle this situation by proposing a strategy for the quality assessment of the health service providers (Entidades Promotoras de Salud, EPS) in the Colombian health system. In particular, as a case study, the quality of the treatment of stomach cancer is analyzed. METHODS: The study uses two complementary techniques to address the problem. These techniques are applied based on data of the treatment of gastric cancer collected on a nation-wide scale by the Colombian Ministry of Health and Welfare. First, Data Envelopment Analysis (DEA) and the Malmquist Index (MI) are used to establish the most efficient EPS's within the system, according to indicators such as opportunity indicators. Second, sequential clustering algorithm, related to process mining a field of data mining, is used to determine the medical history of all patients and to construct typical care pathways of the patients belonging to efficient and inefficient EPS's. Lastly, efforts are made to identify traits and differences between efficient and inefficient EPS's. RESULTS: Efficient and inefficient EPS were identified for the years 2010 and 2011. Additionally, a Malmquist Index was used to calculate the relative changes in the efficiency of the health providers. Using these efficiency rates, the typical treatment path of patients with gastric cancer was found for two EPSs: one efficient and another inefficient. Finally, the typical traits of the care pathways were established. CONCLUSIONS: Combining DEA and process mining proved to be a powerful approach understanding the problem and gaining valuable insight into the inner workings of the Colombian Health System, especially in terms of the treatment process performed by health care providers in critical illnesses such as cancer. However, no sufficiently compelling results were found to establish the contribution of such a combination to evaluate the quality in the delivery of health services. PMID- 28915812 TI - The economic burden of advanced gastric cancer in Taiwan. AB - BACKGROUND: Gastric cancer is one of the leading causes of cancer-related deaths in both sexes worldwide, especially in Eastern Asia. This study aimed to estimate the economic burden of advanced gastric cancer (AGC) in Taiwan. METHODS: The costs of AGC in 2013 were estimated using resource use data from a chart review study (n = 122 with AGC) and national statistics. Annual per-patient costs, where patients' follow-up periods were adjusted for, were estimated with 82 patients who had complete resource use data. The costs were composed of direct medical costs, direct non-medical costs (healthcare travel and caregiver costs), morbidity costs, and mortality costs. Relevant unit costs were retrieved mainly from literature and national statistics, and applied to the resource use data. A broad definition of morbidity and mortality costs was employed to value the productivity loss in patients with unpaid employment, economically inactive and unemployed as well as the life years after the age of retirement. Their narrow definitions were also used in sensitivity analyses, using age- and/or sex specific employment rates. Forgone future earnings/productivity loss were discounted at 3%. Annual per-patient costs were projected to estimate the total costs of AGC at the national level with an estimated number of patients with AGC (N = 2611) in Taiwan in 2013. RESULTS: The mean age of the 82 patients was 59.3 (SD: 11.9) years, and 67.1% were male. Per-patient costs were US$26,431 for direct medical costs, US$4669 for direct non-medical costs, US$5758 for morbidity costs, and US$145,990 for mortality costs (per death). These per-patient costs were projected to incur total AGC costs of US$423 million at the national-level. Mortality costs accounted for 77.3% of the total costs, followed by direct medical costs (16.3%), morbidity costs (3.6%), and direct non-medical costs (2.9%). CONCLUSION: AGC was found to exert a significant economic burden in Taiwan, incurring US$423 million in 2013. This represents about 0.08% of the Taiwanese economy. Mortality costs appeared to be the single greatest contributor to the burden, followed by direct medical costs. Early detection and providing effective treatments will help to reduce its burden on patients, caregivers and society as a whole. A poster of this study was presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, CA, USA. PMID- 28915813 TI - The relationship between burden of childhood disease and foreign aid for child health. AB - BACKGROUND: We sought to examine the relationship between child specific health aid (CHA) and burden of disease. Based on existing evidence, we hypothesized that foreign aid for child health would not be proportional to burden of disease. METHODS: In order to examine CHA and burden of disease, we obtained estimates of these parameters from established sources. Estimates of disability adjusted life years (DALYs) in children (0-5 years) were obtained from the World Health Organization for 2000 and 2012. The 10 most burdensome disease categories in each continent, excluding high-income countries, were identified for study. Descriptions of all foreign aid commitments between 1996 and 2009 were obtained from AidData, and an algorithm to designate the target diseases of the commitments was constructed. Data were examined in scatterplots for trends. RESULTS: The most burdensome childhood diseases varied by continent. In all continents, newborn diseases, vaccine-preventable diseases (lower respiratory diseases, measles, meningitis, tetanus, and pertussis), and diarrheal diseases ranked within the four most burdensome diseases. Infectious diseases such as malaria, tuberculosis, and HIV were also among the ten most burdensome diseases in sub-Saharan Africa, and non-communicable diseases were associated with much of the burden in the other continents. CHA grew from $7.4 billion in 1996 to $17.7 billion in 2009 for our study diseases. Diarrheal diseases and malnutrition received the most CHA as well as the most CHA per DALY. CHA directed at HIV increased dramatically over our study period, from $227,000 in 1996 to $3.4 billion in 2008. Little aid was directed at injuries such as drowning, car accidents, and fires, as well as complex medical diseases such as leukemia and endocrine disorders. CONCLUSION: CHA has grown significantly over the last two decades. There is no clear relationship between CHA and burden of disease. This report provides a description of foreign aid for child health, and hopes to inform policy and decision-making regarding foreign aid. PMID- 28915814 TI - Mediation effects of medication information processing and adherence on association between health literacy and quality of life. AB - BACKGROUND: To examine whether medication related information processing defined as reading of over-the-counter drug labels, understanding prescription instructions, and information seeking-and medication adherence account for the association between health literacy and quality of life, and whether these associations may be moderated by age and gender. METHODS: A sample of 305 adults in South Korea was recruited through a proportional quota sampling to take part in a cross-sectional survey on health literacy, medication-related information processing, medication adherence, and quality of life. Descriptive statistics and structural equation modeling (SEM) were performed. RESULTS: Two mediation pathways linking health literacy with quality of life were found. First, health literacy was positively associated with reading drug labels, which was subsequently linked to medication adherence and quality of life. Second, health literacy was positively associated with accurate understanding of prescription instructions, which was associated with quality of life. Age moderation was found, as the mediation by reading drug labels was significant only among young adults whereas the mediation by understanding of medication instruction was only among older adults. CONCLUSION: Reading drug labels and understanding prescription instructions explained the pathways by which health literacy affects medication adherence and quality of life. The results suggest that training skills for processing medication information can be effective to enhance the health of those with limited health literacy. PMID- 28915815 TI - Designing an implementation intervention with the Behaviour Change Wheel for health provider smoking cessation care for Australian Indigenous pregnant women. AB - BACKGROUND: Indigenous smoking rates are up to 80% among pregnant women: prevalence among pregnant Australian Indigenous women was 45% in 2014, contributing significantly to the health gap for Indigenous Australians. We aimed to develop an implementation intervention to improve smoking cessation care (SCC) for pregnant Indigenous smokers, an outcome to be achieved by training health providers at Aboriginal Medical Services (AMS) in a culturally competent approach, developed collaboratively with AMS. METHOD: The Behaviour Change Wheel (BCW), incorporating the COM-B model (capability, opportunity and motivation for behavioural interventions), provided a framework for the development of the Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy implementation intervention at provider and patient levels. We identified evidence-practice gaps through (i) systematic literature reviews, (ii) a national survey of clinicians and (iii) a qualitative study of smoking and quitting with Aboriginal mothers. We followed the three stages recommended in Michie et al.'s "Behaviour Change Wheel" guide. RESULTS: Targets identified for health provider behaviour change included the following: capability (psychological capability, knowledge and skills) by training clinicians in pharmacotherapy to assist women to quit; motivation (optimism) by presenting evidence of effectiveness, and positive testimonials from patients and clinicians; and opportunity (environmental context and resources) by promoting a whole-of-service approach and structuring consultations using a flipchart and prompts. Education and training were selected as the main intervention functions. For health providers, the delivery mode was webinar, to accommodate time and location constraints, bringing the training to the services; for patients, face-to-face consultations were supported by a booklet embedded with videos to improve patients' capability, opportunity and motivation. CONCLUSIONS: The ICAN QUIT in Pregnancy was an intervention to train health providers at Aboriginal Medical Services in how to implement culturally competent evidence-based practice including counselling and nicotine replacement therapy for pregnant patients who smoke. The BCW aided in scientifically and systematically informing this targeted implementation intervention based on the identified gaps in SCC by health providers. Multiple factors impact at systemic, provider, community and individual levels. This process was therefore important for defining the design and intervention components, prior to a conducting a pilot feasibility trial, then leading on to a full clinical trial. PMID- 28915816 TI - CRAMP deficiency leads to a pro-inflammatory phenotype and impaired phagocytosis after exposure to bacterial meningitis pathogens. AB - BACKGROUND: Antimicrobial peptides are important components of the host defence with a broad range of functions including direct antimicrobial activity and modulation of inflammation. Lack of cathelin-related antimicrobial peptide (CRAMP) was associated with higher mortality and bacterial burden and impaired neutrophil granulocyte infiltration in a model of pneumococcal meningitis. The present study was designed to characterize the effects of CRAMP deficiency on glial response and phagocytosis after exposure to bacterial stimuli. METHODS: CRAMP-knock out and wildtype glial cells were exposed to bacterial supernatants from Streptococcus pneumoniae and Neisseria meningitides or the bacterial cell wall components lipopolysaccharide and peptidoglycan. Cell viability, expression of pro- and anti-inflammatory mediators and activation of signal transduction pathways, phagocytosis rate and glial cell phenotype were investigated by means of cell viability assays, immunohistochemistry, real-time RT-PCR and Western blot. RESULTS: CRAMP-deficiency was associated with stronger expression of pro inflammatory and weakened expression of anti-inflammatory cytokines indicating a higher degree of glial cell activation even under resting-state conditions. Furthermore, increased translocation of nuclear factor 'kappa-light-chain enhancer' of activated B-cells was observed and phagocytosis of S. pneumoniae was reduced in CRAMP-deficient microglia indicating impaired antimicrobial activity. CONCLUSIONS: In conclusion, the present study detected severe alterations of the glial immune response due to lack of CRAMP. The results indicate the importance of CRAMP to maintain and regulate the delicate balance between beneficial and harmful immune response in the brain. PMID- 28915817 TI - Cultural adaptation of a pediatric functional assessment for rehabilitation outcomes research. AB - BACKGROUND: Significant racial and ethnic health care disparities experienced by Hispanic children with special health care needs (CSHCN) create barriers to enacting culturally competent rehabilitation services. One way to minimize the impact of disparities in rehabilitation is to equip practitioners with culturally relevant functional assessments to accurately determine service needs. Current approaches to culturally adapting assessments have three major limitations: use of inconsistent translation processes; current processes assess for some, but not all, elements of cultural equivalence; and limited evidence to guide decision making about whether to undertake cultural adaptation with and without language translation. The aims of this observational study are (a) to examine similarities and differences of culturally adapting a pediatric functional assessment with and without language translation, and (b) to examine the feasibility of cultural adaptation processes. METHODS: The Young Children's Participation and Environment Measure (YC-PEM), a pediatric functional assessment, underwent cultural adaptation (i.e., language translation and cognitive testing) to establish Spanish and English pilot versions for use by caregivers of young CSHCN of Mexican descent. Following language translation to develop a Spanish YC-PEM pilot version, 7 caregivers (4 Spanish-speaking; 3 English-speaking) completed cognitive testing to inform decisions regarding content revisions to English and Spanish YC-PEM versions. Participant responses were content coded to established cultural equivalencies. Coded data were summed to draw comparisons on the number of revisions needed to achieve cultural equivalence between the two versions. Feasibility was assessed according to process data and data quality. RESULTS: Results suggest more revisions are required to achieve cultural equivalence for the translated (Spanish) version of the YC-PEM. However, issues around how the participation outcome is conceptualized were identified in both versions. Feasibility results indicate that language translation processes require high resource investment, but may increase translation quality. However, use of questionnaires versus interview methods for cognitive testing may have limited data saturation. CONCLUSIONS: Results lend preliminary support to the need for and feasibility of cultural adaptation with and without language translation. Results inform decisions surrounding cultural adaptations with and without language translation and thereby enhance cultural competence and quality assessment of healthcare need within pediatric rehabilitation. PMID- 28915819 TI - Bacteriophage therapy to combat bacterial infections in poultry. AB - Infections in poultry are an economic and health problem in Europe and worldwide. The most common infections are associated with salmonellosis, colibacillosis, campylobacteriosis, and others. The prevalence of Campylobacter-positive poultry flocks in European countries varies from 18% to 90%. In the United States, the prevalence of infected flocks is nearly 90%. A similar percentage of infection has been noted for salmonellosis (about 75-90%) and E. coli (90-95%). The occurence of Clostridium perfringens is a major problem for the poultry industry, with some estimates suggesting colonization of as many as 95% of chickens, resulting in clinical or subclinical infections. In the US, annual economic losses due to Salmonella infections run from $1.188 billion to over $11.588 billion, based on an estimated 1.92 million cases. Similar costs are observed in the case of other types of infections. In 2005 economic losses in the the poultry industry due to mortalities reached 1,000,000 USD.Infections caused by these pathogens, often through poultry products, are also a serious public health issue.The progressive increase in the number of multi-drug resistant bacteria and the complete ban on the use of antibiotics in livestock feed in the EU, as well as the partial ban in the US, have led to the growth of research on the use of bacteriophages to combat bacterial infections in humans and animals.The high success rate and safety of phage therapy in comparison with antibiotics are partly due to their specificity for selected bacteria and the ability to infect only one species, serotype or strain. This mechanism does not cause the destruction of commensal bacterial flora. Phages are currently being used with success in humans and animals in targeted therapies for slow-healing infections. They have also found application in the US in eliminating pathogens from the surface of foods of animal and plant origin. At a time of growing antibiotic resistance in bacteria and the resulting restrictions on the use of antibiotics, bacteriophages can provide an alternative means of eliminating pathogens. PMID- 28915818 TI - The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control. AB - BACKGROUND: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. METHODS: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. RESULTS: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p < 0.001). In regression models, cardiovascular risk factors accounted for attenuated ACh and SNP responses in CVD, whereas HbA1c accounted for the effects of T2DM. HbA1c was associated with ACh and SNP response after adjustment for cardiovascular risk factors (adjusted standardised beta (beta) -0.096, p = <0.008 and -0.135, p < 0.001, respectively). Pre-existing CVD did not modify this association (beta -0.099; p = 0.006 and -0.138; p < 0.001, respectively). Duration of diabetes accounted for the association between HbA1c and ACh (beta 0.043; p = 0.3), but not between HbA1c and SNP (beta -0.105; p = 0.02). CONCLUSIONS: In those with T2DM and CVD, good glycaemic control is still associated with better microvascular function, whereas in those with prolonged disease this association is lost. This suggests duration of diabetes may be a better surrogate for "advanced disease" than concomitant CVD, although this requires prospective validation. PMID- 28915820 TI - Item response modeling: a psychometric assessment of the children's fruit, vegetable, water, and physical activity self-efficacy scales among Chinese children. AB - BACKGROUND: This study aimed to evaluate the psychometric properties of four self efficacy scales (i.e., self-efficacy for fruit (FSE), vegetable (VSE), and water (WSE) intakes, and physical activity (PASE)) and to investigate their differences in item functioning across sex, age, and body weight status groups using item response modeling (IRM) and differential item functioning (DIF). METHODS: Four self-efficacy scales were administrated to 763 Hong Kong Chinese children (55.2% boys) aged 8-13 years. Classical test theory (CTT) was used to examine the reliability and factorial validity of scales. IRM was conducted and DIF analyses were performed to assess the characteristics of item parameter estimates on the basis of children's sex, age and body weight status. RESULTS: All self-efficacy scales demonstrated adequate to excellent internal consistency reliability (Cronbach's alpha: 0.79-0.91). One FSE misfit item and one PASE misfit item were detected. Small DIF were found for all the scale items across children's age groups. Items with medium to large DIF were detected in different sex and body weight status groups, which will require modification. A Wright map revealed that items covered the range of the distribution of participants' self-efficacy for each scale except VSE. CONCLUSIONS: Several self-efficacy scales' items functioned differently by children's sex and body weight status. Additional research is required to modify the four self-efficacy scales to minimize these moderating influences for application. PMID- 28915821 TI - Assessment of the underlying systems involved in standing balance: the additional value of electromyography in system identification and parameter estimation. AB - BACKGROUND: Closed loop system identification (CLSIT) is a method to disentangle the contribution of underlying systems in standing balance. We investigated whether taking into account lower leg muscle activation in CLSIT could improve the reliability and accuracy of estimated parameters identifying the underlying systems. METHODS: Standing balance behaviour of 20 healthy young participants was measured using continuous rotations of the support surface (SS). The dynamic balance behaviour obtained with CLSIT was expressed by sensitivity functions of the ankle torque, body sway and muscle activation of the lower legs to the SS rotation. Balance control models, 1) without activation dynamics, 2) with activation dynamics and 3) with activation dynamics and acceleration feedback, were fitted on the data of all possible combinations of the 3 sensitivity functions. The reliability of the estimated model parameters was represented by the mean relative standard errors of the mean (mSEM) of the estimated parameters, expressed for the basic parameters, the activation dynamics parameters and the acceleration feedback parameter. To investigate the accuracy, a model validation study was performed using simulated data obtained with a comprehensive balance control model. The accuracy of the estimated model parameters was described by the mean relative difference (mDIFF) between the estimated parameters and original parameters. RESULTS: The experimental data showed a low mSEM of the basic parameters, activation dynamics parameters and acceleration feedback parameter by adding muscle activation in combination with activation dynamics and acceleration feedback to the fitted model. From the simulated data, the mDIFF of the basic parameters varied from 22.2-22.4% when estimated using the torque and body sway sensitivity functions. Adding the activation dynamics, acceleration feedback and muscle activation improved mDIFF to 13.1-15.1%. CONCLUSIONS: Adding the muscle activation in combination with the activation dynamics and acceleration feedback to CLSIT improves the accuracy and reliability of the estimated parameters and gives the possibility to separate the neural time delay, electromechanical delay and the intrinsic and reflexive dynamics. To diagnose impaired balance more specifically, it is recommended to add electromyography (EMG) to body sway (with or without torque) measurements in the assessment of the underlying systems. PMID- 28915822 TI - What hinders the uptake of computerized decision support systems in hospitals? A qualitative study and framework for implementation. AB - BACKGROUND: Advanced Computerized Decision Support Systems (CDSSs) assist clinicians in their decision-making process, generating recommendations based on up-to-date scientific evidence. Although this technology has the potential to improve the quality of patient care, its mere provision does not guarantee uptake: even where CDSSs are available, clinicians often fail to adopt their recommendations. This study examines the barriers and facilitators to the uptake of an evidence-based CDSS as perceived by diverse health professionals in hospitals at different stages of CDSS adoption. METHODS: Qualitative study conducted as part of a series of randomized controlled trials of CDSSs. The sample includes two hospitals using a CDSS and two hospitals that aim to adopt a CDSS in the future. We interviewed physicians, nurses, information technology staff, and members of the boards of directors (n = 30). We used a constant comparative approach to develop a framework for guiding implementation. RESULTS: We identified six clusters of experiences of, and attitudes towards CDSSs, which we label as "positions." The six positions represent a gradient of acquisition of control over CDSSs (from low to high) and are characterized by different types of barriers to CDSS uptake. The most severe barriers (prevalent in the first positions) include clinicians' perception that the CDSSs may reduce their professional autonomy or may be used against them in the event of medical-legal controversies. Moving towards the last positions, these barriers are substituted by technical and usability problems related to the technology interface. When all barriers are overcome, CDSSs are perceived as a working tool at the service of its users, integrating clinicians' reasoning and fostering organizational learning. CONCLUSIONS: Barriers and facilitators to the use of CDSSs are dynamic and may exist prior to their introduction in clinical contexts; providing a static list of obstacles and facilitators, irrespective of the specific implementation phase and context, may not be sufficient or useful to facilitate uptake. Factors such as clinicians' attitudes towards scientific evidences and guidelines, the quality of inter-disciplinary relationships, and an organizational ethos of transparency and accountability need to be considered when exploring the readiness of a hospital to adopt CDSSs. PMID- 28915823 TI - Patients with acute poisoning presenting to an urban emergency department of a tertiary hospital in Tanzania. AB - BACKGROUND: Poisoning is a major public health concern in sub-Saharan Africa, affecting patients of all age groups. Poisoned patients often present to the emergency department (ED) and prompt evaluation and appropriate management are imperative to ensure optimal outcomes. Unfortunately, little is known about the specific presentations of poisoned patients in East Africa. We describe the clinical and epidemiological features of patients presenting to the Muhimbili National Hospital (MNH) ED with suspected toxicological syndromes. METHODS: This prospective study enrolled a consecutive sample of ED patients who presented with a suspected toxicological syndrome from March 2013 to June 2013. Trained investigators completed a structured case report form (CRF) for each eligible patient, documenting the suspected poison, demographic information, the clinical presentation, and the ED outcome and disposition. The study data were analyzed and summarized with descriptive statistics. RESULTS: Of 8827 patients, who presented to ED-MNH, 106 (1.2%) met inclusion criteria, and all were enrolled. Among those enrolled, the median age was 28 years (interquartile range [IQR] 16 years), and 81 (76.4%) were male. Overall 55 (52%) were single, and 28 (26.4%) had professional jobs. 60 (56.6%) patients were referred from district hospitals, 86.8% of which were in Dar es Salaam. Only 13 (12.3%) of patients presented to the ED within 2 h of the toxic exposure. The etiology of poisoning included alcohol in 42 (50%), a mixture of different medications in 12 (14.3%), and snakebite in 6 (11.3%). Most exposures were intentional (63 [59.4%]) and were via the oral route (88 [83%]). The most common abnormal physical findings were altered mental status (66 [62.3%]) and tachypnoea (68 [64.2%]). One patient died in the ED and 98 (92.5%) required hospital admission. CONCLUSIONS: Most patients presenting to the ED with a toxicological syndrome were adult males with intentional exposures. The most common toxic exposure was alcohol (ethanol) intoxication and the most common abnormal findings were altered mental status and tachypnoea. More than three-quarter of patients presented after 2 h of exposure. Almost all patients were admitted to the hospital. PMID- 28915824 TI - Fucoidan from Fucus vesiculosus suppresses hepatitis B virus replication by enhancing extracellular signal-regulated Kinase activation. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a serious public health problem leading to cirrhosis and hepatocellular carcinoma. As the clinical utility of current therapies is limited, the development of new therapeutic approaches for the prevention and treatment of HBV infection is imperative. Fucoidan is a natural sulfated polysaccharide that extracted from different species of brown seaweed, which was reported to exhibit various bioactivities. However, it remains unclear whether fucoidan influences HBV replication or not. METHODS: The HBV infected mouse model was established by hydrodynamic injection of HBV replicative plasmid, and the mice were treated with saline or fucoidan respectively. Besides, we also tested the inhibitory effect of fucoidan against HBV infection in HBV transfected cell lines. RESULTS: The result showed that fucoidan from Fucus vesiculosus decreased serum HBV DNA, HBsAg and HBeAg levels and hepatic HBcAg expression in HBV-infected mice. Moreover, fucoidan treatment also suppressed intracellular HBcAg expression and the secretion of the HBV DNA as well as HBsAg and HBeAg in HBV-expressing cells. Furthermore, we proved that the inhibitory activity by fucoidan was due to the activation of the extracellular signal regulated kinase (ERK) pathway and the subsequent production of type I interferon. Using specific inhibitor of ERK pathway abrogated the fucoidan mediated inhibition of HBV replication. CONCLUSION: This study highlights that fucoidan might be served as an alternative therapeutic approach for the treatment of HBV infection. PMID- 28915825 TI - Effect of a mobile app intervention on vegetable consumption in overweight adults: a randomized controlled trial. AB - BACKGROUND: Mobile applications (apps) have been heralded as transformative tools to deliver behavioral health interventions at scale, but few have been tested in rigorous randomized controlled trials. We tested the effect of a mobile app to increase vegetable consumption among overweight adults attempting weight loss maintenance. METHODS: Overweight adults (n=135) aged 18-50 years with BMI=28-40 kg/m2 near Stanford, CA were recruited from an ongoing 12-month weight loss trial (parent trial) and randomly assigned to either the stand-alone, theory-based Vegethon mobile app (enabling goal setting, self-monitoring, and feedback and using "process motivators" including fun, surprise, choice, control, social comparison, and competition) or a wait-listed control condition. The primary outcome was daily vegetables servings, measured by an adapted Harvard food frequency questionnaire (FFQ) 8 weeks post-randomization. Daily vegetable servings from 24-hour dietary recalls, administered by trained, certified, and blinded interviewers 5 weeks post-randomization, was included as a secondary outcome. All analyses were conducted according to principles of intention-to treat. RESULTS: Daily vegetable consumption was significantly greater in the intervention versus control condition for both measures (adjusted mean difference: 2.0 servings; 95% CI: 0.1, 3.8, p=0.04 for FFQ; and 1.0 servings; 95% CI: 0.2, 1.9; p=0.02 for 24-hour recalls). Baseline vegetable consumption was a significant moderator of intervention effects (p=0.002) in which effects increased as baseline consumption increased. CONCLUSIONS: These results demonstrate the efficacy of a mobile app to increase vegetable consumption among overweight adults. Theory-based mobile interventions may present a low-cost, scalable, and effective approach to improving dietary behaviors and preventing associated chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT01826591. Registered 27 March 2013. PMID- 28915826 TI - Acupuncture lowering blood pressure for secondary prevention of stroke: a study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Stroke is the prime cause of morbidity and mortality in the general population, and hypertension will increase the recurrence and mortality of stroke. We report a protocol of a pragmatic randomized controlled trial (RCT) using blood pressure (BP)-lowering acupuncture add-on treatment to treat patients with hypertension and stroke. METHODS: This is a large-scale, multicenter, subject-, assessor- and analyst-blinded, pragmatic RCT. A total of 480 patients with hypertension and ischemic stroke will be randomly assigned to two groups: an experimental group and a control group. The experimental group will receive "HuoXueSanFeng" acupuncture combined with one antihypertensive medication in addition to routine ischemic stroke treatment. The control group will only receive one antihypertensive medication and basic treatments for ischemic stroke. HuoXueSanFeng acupuncture will be given for six sessions weekly for the first 6 weeks and three times weekly for the next 6 weeks. A 9-month follow-up will, thereafter, be conducted. Antihypertensive medication will be adjusted based on BP levels. The primary outcome will be the recurrence of stroke. The secondary outcomes including 24-h ambulatory BP, the TCM syndrome score, the Short Form 36 item Health Survey (SF-36), the National Institute of Health Stroke Scale (NIHSS), as well as the Barthel Index (BI) scale will be assessed at baseline, 6 weeks and 12 weeks post initiating treatments; cardiac ultrasound, carotid artery ultrasound, transcranial Doppler, and lower extremity ultrasound will be evaluated at baseline and 12 weeks after treatment. The safety of acupuncture will also be assessed. DISCUSSION: We aim to determine the clinical effects of controlling BP for secondary prevention of stroke with acupuncture add-on treatment. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02967484 . Registered on 13 February 2017; last updated on 27 June 2017. PMID- 28915827 TI - Evaluating the impact of a walking program in a disadvantaged area: using the RE AIM framework by mixed methods. AB - BACKGROUND: The positive health impact of physical activity (PA) is well known, yet a large proportion of the world's population remains sedentary. General PA programs are common as health promotion initiatives. However, effectiveness evaluations of such PA programs on individual and organizational aspects, which could inform the decision-making process of public health bodies are still lacking, particularly in the most socially disadvantaged areas, where health promotion schemes are particularly needed. The aim of this study was to assess the effectiveness of a Guided Walking Program in a high social vulnerability context. METHODS: A quasi-experimental, mixed methods study was conducted. The program had a duration of 6 months and a 6-month follow-up period after the intervention. Session frequency was five times a week, where sessions consisted of supervised PA combined with educational sessions. The Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework was followed to assess the program. The International Physical Activity Questionnaire (IPAQ) and accelerometers were used to measure levels of PA. Focus groups were conducted to gain a comprehensive insight on the implementation domain. RESULTS: Most subjects in the intervention (IG) (n = 74) and control (CG) (n = 74) groups were female (IG:90.5%; CG:95.9%), aged 18-49 years (IG:44.6%; CG:43.2%), received less than 1 minimum wage (IG:74.3%; CG:83.7%) and had 0-4 years of formal education (IG:52.1%; CG:46.1%). The reach of the intervention was 0.3%. The IG showed increased levels of PA at post-intervention and 6-month follow-up. However, the difference between groups was not statistically significant. Adoption data revealed that 89.5% of the professionals in the Primary Health Care Center (health center) team perceived the benefits of the program for the population. The program was independently promoted by the health center team for a further 4 months post-intervention. The qualitative data revealed that the program was discontinued due to participants' low adherence and human resource limitations in the unit's operational dynamics. CONCLUSIONS: A health promotion intervention in a socially deprived setting faces challenges but can be effective and feasible to implement. The present study informs the development of future health promotion initiatives in this context. TRIAL REGISTRATION: NCT02857127 . Registered: 30 July 2016 (retrospectively registered). PMID- 28915828 TI - MicroRNA-488 and -920 regulate the production of proinflammatory cytokines in acute gouty arthritis. AB - BACKGROUND: Gout is considered one of the most painful acute conditions caused by deposition of monosodium urate (MSU) crystals within joints. Recent studies have shown that interleukin (IL)-1beta is a key inflammatory mediator in acute gouty arthritis (GA), and its level is regulated by microRNAs (miRNAs). However, the molecular mechanisms of the regulation remain unclear. METHODS: A miRNA microarray was used to analyze the miRNA expression profiles in peripheral white blood cells (WBCs) of patients with GA. THP-1 cells were transfected with miRNA mimics, stimulated by MSU crystals, and then subjected to quantitative real-time polymerase chain reaction or Western blot analysis. Levels of IL-1beta, IL-8, and tumor necrosis factor (TNF)-alpha in culture supernatants of THP-1 cells were measured by enzyme-linked immunosorbent assay. A luciferase reporter assay was conducted to confirm the interaction of miRNA and IL-1beta 3'-untranslated regions (UTRs). RESULTS: Combining bioinformatics and miRNA expression profiles, we found five miRNAs (hsa-miR-30c-1-3p, hsa-miR-488-3p, hsa-miR-550a-3p, hsa-miR 663a, and hsa-miR-920) that possibly target IL-1beta. Then, we demonstrated that miR-488 and miR-920 were significantly decreased in the WBCs of patients with GA and that MSU crystals could inhibit expression of miR-488 and miR-920. Upregulation of miR-488 and miR-920 could suppress MSU-induced IL-1beta protein expression in THP-1 cells, but no significant difference in IL-1beta messenger RNA levels was observed. Moreover, we found that miR-488 and miR-920 could directly target the 3'-UTR of IL-1beta. Overexpression of miR-488 and miR-920 could significantly inhibit the gene and protein expression of IL-8 and TNF-alpha in MSU-induced THP-1 cells. CONCLUSIONS: This study demonstrates the roles of miR 488 and miR-920 in regulating the production of proinflammatory cytokines in the pathogenesis of GA. These findings suggest that miR-488 and miR-920 could serve as potential therapeutic targets in the treatment of GA. PMID- 28915829 TI - How often do mosquitoes bite humans in southern England? A standardised summer trial at four sites reveals spatial, temporal and site-related variation in biting rates. AB - BACKGROUND: This field-based study examined the abundance and species complement of mosquitoes (Diptera: Culicidae) attracted to humans at four sites in the United Kingdom (UK). The study used a systematic approach to directly measure feeding by mosquitoes on humans at multiple sites and using multiple volunteers. Quantifying how frequently humans are bitten in the field by mosquitoes is a fundamental parameter in assessing arthropod-borne virus transmission. METHODS: Human landing catches were conducted using a standardised protocol by multiple volunteers at four rural sites between July and August 2013. Collections commenced two hours prior to sunset and lasted for a total of four hours. To reduce bias occurring due to collection point or to the individual attractiveness of the volunteer to mosquitoes, each collection was divided into eight collection periods, with volunteers rotated by randomised Latin square design between four sampling points per site. While the aim was to collect mosquitoes prior to feeding, the source of blood meals from any engorged specimens was also identified by DNA barcoding. RESULTS: Three of the four sites yielded human biting mosquito populations for a total of 915 mosquitoes of fifteen species/species groups. Mosquito species composition and biting rates differed significantly between sites, with individual volunteers collecting between 0 and 89 mosquitoes (over 200 per hour) of up to six species per collection period. Coquillettidia richiardii (Ficalbi, 1889) was responsible for the highest recorded biting rates at any one site, reaching 161 bites per hour, whilst maximum biting rates of 55 bites per hour were recorded for Culex modestus (Ficalbi, 1889). Human-biting by Culex pipiens (L., 1758) form pipiens was also observed at two sites, but at much lower rates when compared to other species. CONCLUSIONS: Several mosquito species are responsible for human nuisance biting pressure in southern England, although human exposure to biting may be largely limited to evening outdoor activities. This study indicates Cx. modestus can be a major human-biting species in the UK whilst Cx. pipiens f. pipiens may show greater opportunistic human-biting than indicated by earlier studies. PMID- 28915830 TI - Biological effects of combined resveratrol and vitamin D3 on ovarian tissue. AB - BACKGROUND: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural antioxidant polyphenol able to exert a wide range of biological effect on several tissues. Despite its important beneficial properties, it has a low water solubility, which limits its therapeutic applications in humans. Resveratrol also acts as a phytoestrogen that modulates estrogen receptor (ER)-mediated transcription. In addition, it has been shown that ovarian tissues benefit greatly from vitamin D3, which exerts its beneficial effects through VDR receptors. The aim was to evaluate the cooperative effects of resveratrol combined with vitamin D3 on ovarian cells and tissues and some other organs as well. Moreover, the modulation of specific intracellular pathways involving ER and VDR receptors has been studied. METHODS: The experiments were performed both in vitro and in vivo, to analyze cell viability, radical oxygen species production, signal transductions through Western Blot, and resveratrol quantification by HPLC. RESULTS: Cell viability, radical oxygen species production, and intracellular pathways have been studied on CHO-K1 cells. Also, the relative mechanism activated following oral intake in female Wistar rats as animal model was investigated, evaluating bioavailability, biodistribution and signal transduction in heart, kidney, liver and ovarian tissues. Both in in vitro and in vivo experiments, resveratrol exerts more evident effects when administered in combination with vitD in ovarian cells, showing a common biphasic cooperative effect: The role of vitamin D3 in maintaining and supporting the biological activity of resveratrol has been clearly observed. Moreover, resveratrol plus vitamin D3 blood concentrations showed a biphasic absorption rate. CONCLUSIONS: Such results could be used as a fundamental data for the development of new therapies for gynecological conditions, such as hot-flashes. PMID- 28915831 TI - A synoptic overview of golden jackal parasites reveals high diversity of species. AB - The golden jackal (Canis aureus) is a species under significant and fast geographic expansion. Various parasites are known from golden jackals across their geographic range, and certain groups can be spread during their expansion, increasing the risk of cross-infection with other carnivores or even humans. The current list of the golden jackal parasites includes 194 species and was compiled on the basis of an extensive literature search published from historical times until April 2017, and is shown herein in synoptic tables followed by critical comments of the various findings. This large variety of parasites is related to the extensive geographic range, territorial mobility and a very unselective diet. The vast majority of these parasites are shared with domestic dogs or cats. The zoonotic potential is the most important aspect of species reported in the golden jackal, some of them, such as Echinococcus spp., hookworms, Toxocara spp., or Trichinella spp., having a great public health impact. Our review brings overwhelming evidence on the importance of Canis aureus as a wild reservoir of human and animal parasites. PMID- 28915832 TI - Dogs as victims of their own worms: Serodiagnosis of canine alveolar echinococcosis. AB - BACKGROUND: Besides acting as definitive hosts for Echinococcus multilocularis, dogs can become infected by the larval form of this parasite and thereby develop life-threatening alveolar echinococcosis (AE). Although AE is a zoonotic disease, most therapeutic and diagnostic approaches have been developed for human patients. In dogs, AE is typically diagnosed in the advanced stage of the disease when the parasitic mass has already caused abdominal distension. At that stage, complete resection of the parasitic mass is often impossible, leaving a guarded prognosis for the affected dogs. For humans, sensitive and specific diagnostic protocols relying on serology have been validated and are now widely used. In contrast, sensitive and specific laboratory diagnostic tools that would enable early diagnosis of canine AE are still lacking. The aim of the current study was to establish a serological protocol specifically adapted to dogs. METHODS: We tested several native and recombinant antigens (EmVF, Em2, recEm95, recEm18) in in-house ELISA, an in-house Western blot (WB), as well as a commercially available WB developed for serodiagnosing human AE (Anti-Echinococcus EUROLINE WB(r)), using a panel of known status dog sera. RESULTS: RecEm95-antigen was revealed to be the most promising antigen for use in ELISA, demonstrating 100% (95% CI: 72-100%) sensitivity and 100% (95% CI: 93-100%) specificity in our study. The in-house WB using EmVF antigen performed as well as the recEm95-ELISA. The commercial WB also correctly identified all infected dogs, coupled with a specificity of 98% (95% CI: 91-100%). CONCLUSION: The recEm95-ELISA alone or in combination with either the in-house WB or the Anti-Echinococcus EUROLINE-WB(r) (IgG) with a minor modification should be considered as the best current approach for the serological diagnosis of dogs infected with the larval stage of E. multilocularis. However, larger studies with a focus on potentially cross reacting sera should be undertaken to verify these findings. PMID- 28915833 TI - Deltopectoral flap revisited for reconstruction surgery in patients with advanced thyroid cancer: a case report. AB - BACKGROUND: We present the cases of 2 patients with invasive thyroid cancer, who underwent reconstructive surgery using a deltopectoral flap. Although the overall rate of extrathyroidal extension in patients with thyroid cancer is quite low, skin invasion is the most common pattern observed. Reconstructive surgery, involving local skin flaps, is required in these patients. The deltopectoral flap relies on the blood supply from intercostal perforators of the internal thoracic artery and usually requires skin grafting to the donor site. The internal thoracic artery is rarely sacrificed in these cases, even in an advanced surgery such as in patients with invasive thyroid cancer. CASE PRESENTATION: A 55-year old man with a distended thyroid gland presented to our hospital. He underwent advanced surgery, including skin excision, because we suspected that his tumor was thyroid cancer. The defect was covered with an ipsilateral deltopectoral flap via transposition of the flap, without skin grafting. In the second case, a 67 year-old woman with thyroid cancer that metastasized to her neck lymph nodes presented to our institution. Although the ipsilateral internal thoracic artery was sacrificed near its origin during tumor resection, the deltopectoral flap was raised in the usual manner without any complications. The skin defect caused by the tumor resection was covered with the flap. The patient had an uneventful clinical course for more than 2 years of follow-up. These 2 cases show the effectiveness of using the deltopectoral flap as a reconstructive option for patients with thyroid cancer who underwent radical surgery, resulting in a skin defect. The first case shows that this flap does not always require skin grafting to the donor site. To our knowledge, the second case may be the first report of a deltopectoral flap that was safely raised and applied with resection of the bifurcation of the ipsilateral internal thoracic artery. CONCLUSIONS: Although thyroid cancer surgery with surrounding skin excision is a rare procedure, we found that the deltopectoral flap was useful and should be the first choice for patients undergoing reconstructive surgery, whether the bifurcation of the ipsilateral internal thoracic artery is sacrificed. PMID- 28915834 TI - Skeletal muscle mechanics: questions, problems and possible solutions. AB - Skeletal muscle mechanics have been studied ever since people have shown an interest in human movement. However, our understanding of muscle contraction and muscle mechanical properties has changed fundamentally with the discovery of the sliding filament theory in 1954 and associated cross-bridge theory in 1957. Nevertheless, experimental evidence suggests that our knowledge of the mechanisms of contraction is far from complete, and muscle properties and muscle function in human movement remain largely unknown.In this manuscript, I am trying to identify some of the crucial challenges we are faced with in muscle mechanics, offer possible solutions to questions, and identify problems that might be worthwhile exploring in the future. Since it is impossible to tackle all (worthwhile) problems in a single manuscript, I identified three problems that are controversial, important, and close to my heart. They may be identified as follows: (i) mechanisms of muscle contraction, (ii) in vivo whole muscle mechanics and properties, and (iii) force-sharing among synergistic muscles. These topics are fundamental to our understanding of human movement and movement control, and they contain a series of unknowns and challenges to be explored in the future.It is my hope that this paper may serve as an inspiration for some, may challenge current beliefs in selected areas, tackle important problems in the area of muscle mechanics, physiology and movement control, and may guide and focus some of the thinking of future muscle mechanics research. PMID- 28915835 TI - Macular retinal and choroidal thickness in unilateral amblyopia using swept source optical coherence tomography. AB - BACKGROUND: To investigate macular retinal and choroidal thickness in amblyopic eyes compared to that in fellow and normal eyes using swept-source optical coherence tomography (SS-OCT). METHODS: This study examined 31 patients with hyperopic anisometropic amblyopia (6.9 +/- 3.8 years, mean +/- standard deviation), 15 patients with strabismic amblyopia without anisometropia (7.9 +/- 4.2 years), and 24 age-matched controls (7.8 +/- 3.3 years). Retinal and choroidal thickness was measured by 3D scans using SS-OCT. A 6-mm area around the fovea was automatically analyzed using the Early Treatment Diabetic Retinopathy Study map. The thickness from SS-OCT was corrected for magnification error using individual axial length, spherical refraction, cylinder refraction, and corneal radius. Retinal thickness was divided into the macular retinal nerve fiber layer (mRNFL), ganglion cell layer + inner plexiform layer (GCL+IPL), ganglion cell complex (GCC), and the inner limiting membrane to the retinal pigment epithelium (ILM-RPE) thickness. Retinal and choroidal thickness was compared among amblyopic, fellow, and normal eyes. RESULTS: In both amblyopia groups, there was no significant difference in the mRNFL, GCL+IPL, and GCC thicknesses among the amblyopic, fellow, and control eyes. In the anisometropic amblyopia group, choroidal thickness (subfovea, center 1 mm, nasal and inferior of the inner ring, nasal of the outer ring, and center 6 mm) of amblyopic eyes were significantly greater than that of fellow and normal eyes. In contrast, none of the choroidal thicknesses were significantly different among the investigated eyes in the strabismic amblyopia group. CONCLUSIONS: We found no significant difference in inner retinal thickness in patients with unilateral amblyopia. Although there were significant differences in choroidal thickness with hyperopic anisometropic amblyopia, there was no significant difference for the strabismic amblyopia. The discrepancy in choroidal thickness between the two types of amblyopia may be due to both differences in ocular size and underlying mechanism. PMID- 28915836 TI - Changes in DNA methylation in naive T helper cells regulate the pathophysiological state in minimal-change nephrotic syndrome. AB - BACKGROUND: DNA methylation plays a crucial role in regulating transcription, and changes in DNA methylation affect gene expression and disease development. Minimal change nephrotic syndrome (MCNS) has been reported to involve immunological disturbances. Since the characteristic features of the disease include recurrent relapse and sex and age preference, the disease pathogenesis may be partly related to epigenetic changes. However, little is known about these changes. METHODS: We analyzed genome-wide DNA methylation using the microarray based integrated analysis of methylation by isoschizomers method. This method was used to evaluate methylation in monocytes (patient number; n = 6) and naive T helper cells (n = 4) from the peripheral blood of MCNS patients both in relapse and following remission and that of healthy controls (n = 5). RESULTS: In total, 85 co-occurring genes were identified in naive T helper cells, while 4 such genes were identified in monocytes, which were common among the 3 following comparisons for changes in DNA methylation using sample pairs: (1) relapse versus remission, (2) relapse versus controls, and (3) remission versus controls. In 82 of 85 co occurring genes (96.5%) in naive T helper cells, the level of DNA methylation was altered according to disease activity, but was not related to disease activity in the 4 genes detected in monocytes. CONCLUSIONS: Therefore, in 82 co-occurring genes in naive T helper cells, the regulation of DNA methylation was well correlated with the clinical and pathophysiological state. Our genome-wide approach to analyze DNA methylation provides further insight into the pathogenesis of MCNS and indicates potential prediction and diagnostic tool for the disease. PMID- 28915837 TI - Professional groups driving change toward patient-centred care: interprofessional working in stroke rehabilitation in Denmark. AB - BACKGROUND: Patient-centred care based on needs has been gaining momentum in health policy and the workforce. This creates new demand for interprofessional teams and redefining roles and tasks of professionals, yet little is known on how to implement new health policies more effectively. Our aim was to analyse the role and capacity of health professions in driving organisational change in interprofessional working and patient-centred care. METHODS: A case study of the introduction of interprofessional, early discharge teams in stroke rehabilitation in Denmark was conducted with focus on day-to-day coordination of care tasks and the professional groups' interests and strategies. The study included 5 stroke teams and 17 interviews with different health professionals conducted in 2015. RESULTS: Professional groups expressed highly positive professional interest in reorganised stroke rehabilitation concerning patients, professional practice and intersectoral relations; individual professional and collective interprofessional interests strongly coincided. The corresponding strategies were driven by a shared goal of providing needs-based care for patients. Individual professionals worked independently and on behalf of the team. There was also a degree of skills transfer as individual team members screened patients on behalf of other professional groups. CONCLUSIONS: The study identified supportive factors and contexts of patient-centred care. This highlights capacity to improve health workforce governance through professional participation, which should be explored more systematically in a wider range of healthcare services. PMID- 28915838 TI - Gout and comorbidity: a nominal group study of people with gout. AB - BACKGROUND: Comorbidities are common in patients with gout, yet qualitative research is lacking. The study objective was to examine the impact of gout on comorbidities. METHODS: Nine nominal groups were conducted. Patients with gout discussed and rank-ordered their concerns in response to the question, "How does gout or its treatment affect your other conditions and their treatment?" RESULTS: Nine nominal groups had 45 gout patients, with mean age 61 years (standard deviation (SD) 10.7) and mean gout duration 14.9 years (SD 12). Of these, 62% were men, 45% African-American, 51% married and 63% were currently using allopurinol. The most frequently cited highly ranked concerns among the nine nominal groups were: (1) interaction of gout medication with medications for other medical conditions (three groups); (2) worsening of other medical comorbidities, including hospitalizations (seven groups); (3) worsening of anxiety and depression (three groups); (4) significant dietary changes for gout that contrasted with diet for other conditions (three groups); (5) new diseases diagnosed due to gout (three groups); (6) irreversible joint damage (three groups); (7) inability to exercise and weight gain (four groups); and (8) gout misdiagnosed as another health condition (three groups). Other domains ranked highly were: (1) impact of gout on daily life and activities, including the ability to work and social activities (six groups); (2) medication side effects, real and perceived (nine groups); (3) weight loss due to gout related to frequent flares (one group); and (4) cost and burden (three groups). CONCLUSIONS: Gout and the medications used for its treatment have a significant effect on comorbidities and their management. These findings provide insights into potential targets for improving outcomes in patients with gout. PMID- 28915839 TI - Risk of mortality among children, adolescents, and adults with autism spectrum disorder or attention deficit hyperactivity disorder and their first-degree relatives: a protocol for a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are childhood onset neurodevelopmental disorders that may persist into adulthood. ASD and ADHD tend to run in families and may have a significant negative impact on the health and longevity of those with the disorder and their relatives. The aim of this study will be to analyze the risk of mortality among children, adolescents, and adults with ASD or ADHD and their first-degree relatives. METHODS/DESIGN: We will conduct a systematic review and meta-analysis of observational studies. Searches of PubMed/MEDLINE, EMBASE, PsycINFO, SCOPUS, and ISI Web of Science will be used to identify epidemiological studies. Eligible studies will be observational studies reporting study-specific data for all-cause mortality or cause-specific mortality in children, adolescents, or adults with ASD or ADHD and/or their first-degree relatives. Cohort studies and case-control studies will be included. The primary outcome will be all-cause mortality. The secondary outcome will be cause-specific mortality. Two reviewers will independently screen references identified by the literature search, as well as potentially relevant full-text articles. Data will be abstracted, and study risk of bias/methodological quality will be appraised by two reviewers independently. The methodological quality of epidemiological studies will be appraised using the Newcastle-Ottawa Scale (NOS). Conflicts at all levels of screening and abstraction will be resolved through discussion. Random-effects meta-analyses of primary studies will be conducted where appropriate. Subgroup analyses for exploring statistical heterogeneity, if feasible, will include gender, age group, ethnicity, comorbidities, classification of cause of death, and relevant study characteristics. DISCUSSION: Our study will establish the extent of the epidemiological evidence underlying the risk of mortality among children, adolescents, and adults with ASD or ADHD and their first-degree relatives. We anticipate that our findings will be of interest to patients, their families, caregivers, healthcare professionals, scientists, and policy makers. Implications for future epidemiological research will be discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017059955 . PMID- 28915840 TI - Evolution and bad prognostic value of advanced glycation end products after acute heart failure: relation with body composition. AB - AIM: The role of advanced glycation end products (AGEs) and their soluble receptor (sRAGE) on the progression and prognosis of acute heart failure (HF) was analysed in relation with metabolic parameters as body composition and nutritional status. METHODS: A hundred and fifty consecutive patients were included in a prospective clinical study during hospitalization by acute HF. Detailed medical history, physical examination, electrocardiogram, echocardiogram and vein peripheral blood were taken for all patients. During the follow-up period [297 days (88-422 days)] blood samples for biochemical measurements were obtained 1 and 6 months after the inclusion. Dual-energy X-ray absorptiometry analyses were performed 1 week after discharge. RESULTS: AGEs and sRAGE levels continuously increased, up to 6 months, after acute HF, but AGEs increase was mainly observed in those patients with incident HF. Both AGEs and sRAGE levels were related with bad renal function and clinical malnutrition (CONUT score) and they were negatively related with body mass index or percentage of body fat. AGEs levels (>=40 a.u.) 1 month after discharge and basal sRAGE levels (>1000 pg/mL) were related with worse prognosis in terms of patient death and HF readmission (Log-rank <0.05 in Kaplan-Meier survival test), independently of age, gender, body mass index and other risk factors. Regression models also corroborated this finding. CONCLUSIONS: AGEs and sRAGE are bad prognostic biomarkers for HF and useful markers of HF progression. Since their levels seem to be related with clinical malnutrition and body composition these parameters could serve to modulate them. PMID- 28915842 TI - Towards the development of a wellbeing model for aboriginal and Torres Strait islander peoples living with chronic disease. AB - BACKGROUND: Re-defining the way in which care is delivered, to reflect Aboriginal and Torres Strait Islander peoples' needs and values, is essential for improving the accessibility of primary healthcare. This study focused on developing a Framework to support the quality of care and quality of life of, as well as treatment for, Aboriginal and Torres Strait Islander peoples living with chronic disease. METHODS: A team of researchers, including thirteen experienced Aboriginal healthcare professionals, came together to undertake this important work. Using a Participatory Action Approach, this study actively engaged people with local knowledge to ensure that the Framework was developed by and for Aboriginal people. RESULTS: The final Wellbeing Framework consists of two core values and four elements, each supported by four principles. Importantly, the Framework also includes practical examples of how the principles could be applied. National Reference Group members, including community representatives, policy makers and healthcare providers, reviewed and approved the final Framework. CONCLUSION: The outcome of this collaborative effort is a Framework to guide primary healthcare services to develop locally relevant, flexible approaches to care which can respond to communities' and individuals' varied understandings of wellbeing. PMID- 28915841 TI - Is there room for resilience? A scoping review and critique of substance use literature and its utilization of the concept of resilience. AB - Research in the area of illicit substance use remains preoccupied with describing and analyzing the risks of people who use drugs (PWUD), however more recently there has been a drive to use a strengths-based or resilience approach as an alternative to investigating drug use. This leads us to ask: what can be known about PWUD from the point of view of resilience? The objective of this scoping review is to analyze how the concept of resilience is defined, operationalized, and applied in substance use research. Popular health, social science, psychology, and inter-disciplinary databases namely: SCOPUS, PUBMED, PsycINFO, and Sociological Abstracts were searched. Studies were selected if they used the concept of resilience and if substance use was a key variable under investigation. A total of 77 studies were identified which provided a definition of resilience, or attempted to operationalize (e.g., via scales) the concept of resilience in some manner. Data were charted and sorted using key terms and fundamental aspects of resilience. The majority of studies focus on youth and their resistance to, or engagement in, substance use. There is also a small but growing area of research that examines recovery from substance addiction as a form of resilience. Very few studies were found that thoroughly investigated resilience among PWUD. Consistently throughout the literature drug use is presented as a 'risk factor' jeopardizing one's ability to be resilient, or drug use is seen as a 'maladaptive coping strategy', purporting one's lack of resilience. Currently, substance use research provides a substantial amount of information about the internal strengths that can assist in resisting future drug use; however there is less information about the external resources that play a role, especially for adults. Though popular, outcome-based conceptualizations of resilience are often static, concealing the potential for developing resilience over time or as conditions change. Studies of resilience among PWUD predominantly concentrate on health-related behaviours, recovery-related factors or predefined harm reduction strategies. Indeed, overall, current conceptualizations of resilience are too narrow to recognize all the potential manifestations of resilience practices in the daily lives of individuals who actively use drugs. PMID- 28915843 TI - Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats. AB - BACKGROUND: PCOs is a heterogeneous disorder with anovulation/oligo ovulation usually taken as oligo menorrhoea or amenorrhoea, hyperandrogenemia, hirsutism, acne, androgen alopecia and polycystic ovaries as the key diagnostic feathers. The study was undertaken to investigate the possible protective and ameliorating effects of GABA in Letrozole induced PCOS model in rats by targeting insulin resistance. METHODS: PCOs in Adult female rat was induced by the daily gastric administration of letrozole (1 mg/kg/day) in CMC (0.5%) for 36 days. Rats were given metformin (2 mg/kg), GABA (100 mg/kg/day) and GABA (500 mg/kg/day) along with letrozole. One group severed as vehicle control. On the 37 day, the animals were euthanized, and anthropometrical, biochemical (glucose, insulin, lipids, testosterone, Estradiol, Progesterone, oral glucose tolerance test, total protein content in ovary, cholesterol level, triglyceride, HDL, LDL), Antioxidants (CAT, POD, GSR, ROS, GSH, TBARS), and histopathological evaluation of ovaries were carried out. Daily colpocytological examination was also carried out until the termination. RESULTS: Both the doses of GABA significantly reduced body weight, body mass index and testosterone. While the levels of CAT, SOD, POD and Estradiol (E2) were significantly increased in the both doses of GABA. A favourable lipid profile, normal glucose tolerance, and decreased in the percentage of estrus smears were observed. Histopathological examination of ovary revealed a decreased in the number of cystic follicles, and decreased in the adipocytes respectively. The effects observed with GABA were comparable to that with metformin. CONCLUSION: The results suggest that GABA treatment has shown protective effect in PCOs and provide beneficial effect either by reducing insulin resistance or by inducing antioxidant defence mechanisms. PMID- 28915844 TI - Financial incentives and purchase restrictions in a food benefit program affect the types of foods and beverages purchased: results from a randomized trial. AB - BACKGROUND: This research evaluated the effects of financial incentives and purchase restrictions on food purchasing in a food benefit program for low income people. METHODS: Participants (n=279) were randomized to groups: 1) Incentive- 30% financial incentive for fruits and vegetables purchased with food benefits; 2) Restriction- no purchase of sugar-sweetened beverages, sweet baked goods, or candies with food benefits; 3) Incentive plus Restriction; or 4) Control- no incentive or restrictions. Participants received a study-specific debit card where funds were added monthly for 12-weeks. Food purchase receipts were collected over 16 weeks. Total dollars spent on grocery purchases and by targeted food categories were computed from receipts. Group differences were examined using general linear models. RESULTS: Weekly purchases of fruit significantly increased in the Incentive plus Restriction ($4.8) compared to the Restriction ($1.7) and Control ($2.1) groups (p <.01). Sugar-sweetened beverage purchases significantly decreased in the Incentive plus Restriction (-$0.8 per week) and Restriction ($-1.4 per week) groups compared to the Control group (+$1.5; p< .0001). Sweet baked goods purchases significantly decreased in the Restriction ( $0.70 per week) compared to the Control group (+$0.82 per week; p < .01). CONCLUSIONS: Paired financial incentives and restrictions on foods and beverages purchased with food program funds may support more healthful food purchases compared to no incentives or restrictions. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02643576 . PMID- 28915845 TI - Reliability and validity of a brief sleep questionnaire for children in Japan. AB - BACKGROUND: There is a dearth of sleep questionnaires with few items and confirmed reliability and validity that can be used for the early detection of sleep problems in children. The aim of this study was to develop a questionnaire with few items and assess its reliability and validity in both children at high risk of sleep disorders and a community population. METHODS: Data for analysis were derived from two populations targeted by the Children's Sleep Habits Questionnaire (CSHQ): 178 children attending elementary school and 432 children who visited a pediatric psychiatric hospital (aged 6-12 years). The new questionnaire was constructed as a subset of the CSHQ. RESULTS: The newly developed short version of the sleep questionnaire for children (19 items) had an acceptable internal consistency (0.65). Using the cutoff value of the CSHQ, the total score of the new questionnaire was confirmed to have discriminant validity (27.2 +/- 3.9 vs. 22.0 +/- 2.1, p < 0.001) and yielded a sensitivity of 0.83 and specificity of 0.78 by receiver operator characteristic curve analysis. Total score of the new questionnaire was significantly correlated with total score (r = 0.81, p < 0.001) and each subscale score (r = 0.29-0.65, p < 0.001) of the CSHQ. CONCLUSIONS: The new questionnaire demonstrated an adequate reliability and validity in both high-risk children and a community population, as well as similar screening ability to the CSHQ. It could thus be a convenient instrument to detect sleep problems in children. PMID- 28915846 TI - Impact of heat treatment on antigen detection in sera of Angiostrongylus vasorum infected dogs. AB - BACKGROUND: In the last decade serological tests for detection of circulating Angiostrongylus vasorum antigen and specific antibodies have been developed and adopted for individual diagnosis and epidemiological studies in dogs. Although confirmed positive at necropsy, antigen detection was not possible in single experimentally, as well as naturally infected dogs, possibly due to immune complex formation. The aim of this study was to evaluate the effect of heat treatment on detection of A. vasorum antigen in sera of experimentally (n = 21, 119 follow-up sera) and naturally (n = 18) infected animals. In addition, sera of dogs showing clinical signs consistent with angiostrongylosis (n = 10), of randomly selected dogs (n = 58) and of dogs with other parasitic infections (n = 15) were evaluated. Sera were subjected to heat treatment at 100 degrees C after addition of 0.5 M EDTA (dilution 1:5) and tested with ELISAs for detection of circulating A. vasorum antigen before and after treatment. RESULTS: Between 5 and 11 weeks post-inoculation (wpi) the percentage of positive untreated samples (experimentally infected dogs) increased over time from 33.3 to 90%. Single samples were still negative between 12 and 15 wpi. Overall, between 5 and 15 wpi, 50.6% (45/89) of the available samples were seropositive. From 3 to 6 wpi EDTA/heat treatment caused a change in 8/34 (23.5%) of the samples, with most (n = 6, 17.6%) converting from positive to negative. In contrast, from 7 to 10 wpi, treatment induced a change in 19/52 (36.5%) samples, with all but one converting from negative to positive. Thirteen of 18 naturally infected dogs were antigen positive before and 15 after EDTA/heat treatment, respectively. Untreated samples of 3 dogs with suspected angiostrongylosis were antigen positive, of which only one remained positive after EDTA/heat treatment. One of 58 untreated random samples was antigen positive; this sample became negative after treatment, while another turned positive. One of 15 dogs infected with other parasites than A. vasorum was positive before but negative after treatment. CONCLUSION: Although heat treatment improves A. vasorum antigen detection between 7 and 10 wpi by immune complex disruption, we do not recommend systematic pretreating sera because of reduced antigen detection between 3 and 6 wpi and impairment of antibody detection, if performed contemporaneously. PMID- 28915847 TI - Absence of ultrasound inflammation in patients presenting with arthralgia rules out the development of arthritis. AB - BACKGROUND: To decrease the burden of disease of rheumatoid arthritis (RA), patients at risk for RA need to be identified as early as possible, preferably when no clinically apparent synovitis can be detected. Up to now, it has been fairly difficult to identify those patients with arthralgia who develop inflammatory arthritis (IA), but recent studies using ultrasound (US) suggest that earlier detection is possible. We aimed to identify patients with arthralgia developing IA within 1 year using US to detect subclinical synovitis at first consultation. METHODS: In a multi-centre cohort study, we followed patients with arthralgia with at least two painful joints of the hands, feet or shoulders without clinical synovitis over 1 year. Symptom duration was < 1 year, and symptoms were not explained by other conditions. At baseline and at 6 and 12 months, data were collected for physical examinations, laboratory values and diagnoses. At baseline, we examined 26 joints ultrasonographically (bilateral metacarpophalangeal joints 2-5, proximal interphalangeal joints 2-5, wrist and metatarsophalangeal joints 2-5). Scoring was done semi-quantitatively on greyscale (GS; 0-3) and power Doppler (PD; 0-3) images. US synovitis was defined as GS >= 2 and/or PD >= 1. IA was defined as clinical soft tissue swelling. Sensitivity and specificity were used to assess the diagnostic value of US for the development of IA. Univariate logistic regression was used to analyse the association between independent variables and the incidence of IA. For multivariate logistic regression, the strongest variables (p < 0.157) were selected. Missing values for independent variables were imputed. RESULTS: A total of 196 patients were included, and 159 completed 12 months of follow-up. Thirty one (16%) patients developed IA, of whom 59% showed US synovitis at baseline. The sensitivity and specificity of US synovitis were 59% and 68%, respectively. If no joints were positive on US, negative predictive value was 89%. In the multivariate logistic regression, age (OR 1.1), the presence of morning stiffness for > 30 minutes (OR 3.3) and PD signal (OR 3.4) were associated with incident IA. CONCLUSIONS: The presence of PD signal, morning stiffness for > 30 minutes and age at baseline were independently associated with the development of IA. Regarding the value of US in the diagnostic workup of patients with early arthralgia at risk for IA, US did perform well in ruling out IA in patients who did not have US synovitis. PMID- 28915848 TI - Anemia in severe heart failure patients: does it predict prognosis? AB - BACKGROUND: Anemia is highly prevalent in heart failure (HF) patients. However, the prevalence, clinical impact and prognostic factor of anemia in heart failure patients is widely varies. The aim of this study was to evaluate the prevalence of anemia in patients with HF, to compare baseline clinical characteristic and outcomes of severe HF patients with and without anemia admitted to Gondar University Referral Hospital (GURH), Gondar, Ethiopia. METHOD: A retrospective cohort study was conducted and we assessed medical records of heart failure patients who were admitted Gondar University Referral Hospital in the period between December 02, 2010 and November 30, 2016. Kaplan Meier curve was used to analyze the survival status and log rank test was used to compare the curves. Multivariate Cox regression was used to analyze independent predictors of mortality in all HF patients. P value less than 0.05 was considered statistically significant. RESULT: Three hundred and seventy patients participated in the study. The prevalence of anemia in the study cohorts was 41.90% and majority of the participants were females (64.59%). There was a significant difference in the level of hemoglobin, creatinine, and sodium among anemic and non-anemic patients. Anemic patients with HF tend to take angiotensin converting enzyme inhibitors (ACEI) less frequently. Kaplan Meier survival curves and Log rank test (P = 0.042) showed a significant difference in the prognosis of HF patients with anemia and non - anemic. More significant difference was observed (Log rank test, P = 0.001) in the study participants based on hemoglobin level. Furthermore, multivariate Cox regression showed: advanced age, levels of lower sodium and higher creatinine, and absences of medications like ACEI and Spironolactone independently predicted overall mortality. CONCLUSION: HF patients with anemia tend to be older age, had lower hemoglobin and sodium level and higher creatinine value. Moreover, there was a significant difference in the prognosis between study cohorts, as anemic pateints tend to have a worse survival status . Even though, anemia is a significant risk marker, it is not an independent predictor of mortality in the current study. PMID- 28915849 TI - Exposure rate of VZV among women attending antenatal care clinic in Sri Lanka - a cross sectional study. AB - BACKGROUND: Varicella or chickenpox was not a notifiable disease until 2005 in Sri Lanka and only a few studies have been conducted on the epidemiology of VZV infection in the country. The anti-VZV IgG sero-prevalence among antenatal women is extremely limited and thus a selected group of antenatal clinic attendees were chosen to determine the exposure rate to VZV infection. METHODS: Women attending the antenatal clinic at Teaching Hospital, Peradeniya, Sri Lanka were selected for the study and 3 mL of venous blood was collected from 181 participants and the demographic data was obtained through a pre-tested questionnaire. Sera of the women were then tested for the presence of anti-VZV IgG using ELISA (HUMAN Diagnostics, Germany). Data was analysed using the SPSS statistical software for Windows, Version 12.0. RESULTS: Of the 181 antenatal women who took part in the study, 141 were positive for anti-VZV IgG giving a sero-prevalence of 77.9% for the past exposure to VZV. Of the 141 anti-VZV IgG positive women, 43.3% (n = 61) were from urban, 41.8% (n = 59) were from rural and 14.9% (n = 21) were from estate populations (an ethnic population living in small settlements in the tea estates whose ancestors were brought from India during the British colonial period to work in the tea plantations in Sri Lanka). Out of the 88 antenatal women with a positive history for varicella, 85 (96.6%) were positive for anti VZV IgG. The highest number of anti-VZV IgG positivity was seen in the 31-35 age group, which was 85.0% of the total number of antenatal women included in that category. An increase in the anti-VZV IgG sero-prevalence with increasing age was also noted in the study sample. CONCLUSION: Exposure rate of VZV infection as confirmed by anti-VZV IgG in the present study sample of antenatal women was 77.9%. Age specific, population based future sero-prevalence studies should be conducted in Sri Lanka to understand the anti-VZV IgG status in the country. PMID- 28915850 TI - "Love me, parents!": impact evaluation of a national social and behavioral change communication campaign on maternal health outcomes in Tanzania. AB - BACKGROUND: Despite marked improvements over the last few decades, maternal mortality in Tanzania remains among the world's highest at 454 maternal deaths per 100,000 live births. Many factors contribute to this disparity, such as a lack of attendance at antenatal care (ANC) services and low rates of delivery at a health facility with a skilled provider. The Wazazi Nipendeni (Love me, parents) social and behavioral change communication campaign was launched in Tanzania in 2012 to improve a range of maternal health outcomes, including individual birth planning, timely ANC attendance, and giving birth in a healthcare facility. METHODS: An evaluation to determine the impact of the national Wazazi Nipendeni campaign was conducted in five purposively selected regions of Tanzania using exit interviews with pregnant and post-natal women attending ANC clinics. A total of 1708 women were interviewed regarding campaign exposure, ANC attendance, and individual birth planning. RESULTS: Over one third of interviewed women (35.1%) reported exposure to the campaign in the last month. The more sources from which women reported hearing the Wazazi Nipendeni message, the more they planned for the birth of their child (beta = 0.08, p = .001). Greater numbers of types of exposure to the Wazazi Nipendeni message was associated with an increase in ANC visits (beta = 0.05, p = .004). Intervention exposure did not significantly predict the timing of the first ANC visit or HIV testing in the adjusted model, however, findings showed that exposure did predict whether women delivered at a health care facility (or not) and whether they tested for HIV with a partner in the unadjusted models. CONCLUSIONS: The Wazazi Nipendeni campaign shows promise that such a behavior change communication intervention could lead to better pregnancy and childbirth outcomes for women in low resource settings. For outcomes such as HIV testing, message exposure showed some promising effects, but demographic variables such as age and socioeconomic status appear to be important as well. PMID- 28915851 TI - Assessment of consent models as an ethical consideration in the conduct of prehospital ambulance randomised controlled clinical trials: a systematic review. AB - BACKGROUND: We sought to understand the main ethical considerations when conducting clinical trials in the prehospital ambulance based setting. METHODS: A systematic review of the literature on randomised controlled trials in ambulance settings was undertaken. A search of eight databases identified published studies involving recruitment of ambulance service users. Four independent authors undertook abstract and full-text reviews to determine eligibility and extract relevant data. The data extraction concentrated on ethical considerations, with any discussion of ethics being included for further analysis. The resultant data were combined to form a narrative synthesis. RESULTS: In all, 56 papers were identified as meeting the inclusion criteria. Issues relating to consent were the most significant theme identified. Type of consent differed depending on the condition or intervention being studied. The country in which the research took place did not appear to influence the type of consent, apart from the USA where exception from consent appeared to be most commonly used. A wide range of terms were used to describe consent. CONCLUSIONS: Consent was the main ethical consideration in published ambulance based research. A range of consent models were used ranging from informed consent to exception from consent (waiver of consent). Many studies cited international guidelines as informing their choice of consent model but diverse and sometimes confused terms were used to describe these models. This suggests that standardisation of consent models and the terminology used to describe them is warranted. PMID- 28915852 TI - A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review. AB - BACKGROUND: Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity. CASE PRESENTATION: We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency. CONCLUSION: This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target. PMID- 28915853 TI - Low threshold unmyelinated mechanoafferents can modulate pain. AB - BACKGROUND: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients. METHODS: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch. RESULTS: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038). CONCLUSIONS: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired - as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN patients. PMID- 28915854 TI - Medical therapy following hospitalization for heart failure with reduced ejection fraction and association with discharge to long-term care: a cross-sectional analysis of the REasons for Geographic And Racial Differences in Stroke (REGARDS) population. AB - BACKGROUND: Less intensive treatment for heart failure with reduced ejection fraction (HFrEF) may be appropriate for patients in long-term care settings because of limited life expectancy, frailty, comorbidities, and emphasis on quality of life. METHODS: We compared treatment patterns between REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants discharged to long-term care versus home following HFrEF hospitalizations. We examined medical records and Medicare pharmacy claims for 147 HFrEF hospitalizations among 80 participants to obtain information about discharge disposition and medication prescriptions and fills. RESULTS: Discharge to long term care followed 22 of 147 HFrEF hospitalizations (15%). Participants discharged to long-term care were more likely to be prescribed beta-blockers and less likely to be prescribed aldosterone receptor antagonists and hydralazine/isosorbide dinitrate (96%, 14%, and 5%, respectively) compared to participants discharged home (81%, 22%, and 23%, respectively). The percentages of participants discharged to long-term care and home who had claims for filled prescriptions were similar for beta-blockers (68% versus 66%) and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARBs) (45% versus 47%) after 1 year. Smaller percentages of participants discharged to long term care had claims for filled prescriptions of other medications compared to participants discharged home (diuretics: long-term care-50%, home-72%; hydralazine/isosorbide dinitrate: long-term care-5%, home-23%; aldosterone receptor antagonists: long-term care-5%, home-23%). CONCLUSIONS: Differences in medication prescriptions and fills among individuals with HFrEF discharged to long-term care versus home may reflect prioritization of some medical therapies over others for patients in long-term care. PMID- 28915855 TI - Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand. AB - BACKGROUND: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. METHOD: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. RESULT: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. CONCLUSION: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand. PMID- 28915856 TI - Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations. AB - BACKGROUND: Multiple sclerosis (MS) can result in significant mental and physical symptoms, specially muscle weakness, abnormal walking mechanics, balance problems, spasticity, fatigue, cognitive impairment and depression. Patients with MS frequently decrease physical activity due to the fear from worsening the symptoms and this can result in reconditioning. Physicians now believe that regular exercise training is a potential solution for limiting the reconditioning process and achieving an optimal level of patient activities, functions and many physical and mental symptoms without any concern about triggering the onset or exacerbation of disease symptoms or relapse. MAIN BODY: Appropriate exercise can cause noteworthy and important improvements in different areas of cardio respiratory fitness (Aerobic fitness), muscle strength, flexibility, balance, fatigue, cognition, quality of life and respiratory function in MS patients. Aerobic exercise training with low to moderate intensity can result in the improvement of aerobic fitness and reduction of fatigue in MS patients affected by mild or moderate disability. MS patients can positively adapt to resistance training which may result in improved fatigue and ambulation. Flexibility exercises such as stretching the muscles may diminish spasticity and prevent future painful contractions. Balance exercises have beneficial effects on fall rates and better balance. Some general guidelines exist for exercise recommendation in the MS population. The individualized exercise program should be designed to address a patient's chief complaint, improve strength, endurance, balance, coordination, fatigue and so on. An exercise staircase model has been proposed for exercise prescription and progression for a broad spectrum of MS patients. CONCLUSION: Exercise should be considered as a safe and effective means of rehabilitation in MS patients. Existing evidence shows that a supervised and individualized exercise program may improve fitness, functional capacity and quality of life as well as modifiable impairments in MS patients. PMID- 28915858 TI - Risk of obstetric anal sphincter injury increases with maternal age irrespective of parity: a population-based register study. AB - BACKGROUND: Obstetric anal sphincter injury (OASI) is a rare but serious outcome of vaginal birth. Based on concerns about the increasing number of women who commence childbearing later than previous generation, this study aimed at investigating age-related risk of OASI in women of different parity. METHODS: A population-based register study including 959,559 live singleton vaginal births recorded in the Swedish Medical Birth Register 1999 to 2011. In each parity group risks of OASI at age 25-29 years, 30-34 years, and >=35 years compared with age < 25 years were investigated by logistic regression analyses, adjusted for year of birth, education, region of birth, smoking, Body Mass Index, infant birthweight and fetal presentation; and in parous women, history of OASI and cesarean section. Additional analyses also adjusted for mediating factors, such as epidural analgesia, episiotomy, and instrumental delivery, and maternal age related morbidity. RESULTS: Rates of OASI were 6.6%, 2.3% and 0.9% in first, second and third births respectively. Age-related risk increased from 25-29 years in first births (Adjusted OR 1.66; 95% CI 1.59-1.72) and second births (Adjusted OR 1.78; 95% CI 1.58-2.01), and from 30-34 years in third births (Adjusted OR 1.60; 95% CI 1.00-2.56). In all parity groups the risk was doubled at age >= 35 years, compared with the respective reference group of women under 25 years. Adding mediating factors and maternal age-related morbidity only marginally reduced these risk estimates. CONCLUSION: Maternal age is an independent risk factor for OASI in first, second and third births. Although age-related risks by parity are relatively similar, more nulliparous than parous women will be exposed to OASI due to the higher baseline rate. PMID- 28915857 TI - Validity and reproducibility of a short food frequency questionnaire among patients with chronic kidney disease. AB - BACKGROUND: A balanced diet is essential to slowing the progression of chronic kidney disease (CKD) and managing the symptoms. Currently, no tool is available to easily and quickly assess energy and macronutrient intake in patients with non end-stage CKD. We aimed to develop and evaluate the validity and reproducibility of a new short 49-item food frequency questionnaire (SFFQ) adapted to patients with CKD. METHODS: The CKD-REIN study is a prospective cohort that enrolled 3033 patients with moderate or advanced CKD from a national sample of nephrology clinics. A sub-sample of 201 patients completed the SFFQ twice, at a one-year interval and were included in the reproducibility study. During this interval, 127 patients also completed six 24-h recalls and were included in the validity study. Main nutrient and dietary intakes were computed. Validity was evaluated by calculating crude, energy-adjusted and de-attenuated correlation coefficients (CC) between FFQ and the mean of the 24-h recall results. Bland-Altman plots were performed and cross-classification into quintiles of consumption of each nutrient and food group was computed. Reproducibility between the two SFFQs was evaluated by intraclass CC (ICC). RESULTS: Regarding validity, CC ranged from 0.05 to 0.79 (unadjusted CC, median: 0.40) and 0.10 to 0.59 (de-attenuated CC, median: 0.35) for food group and nutrient intakes, respectively. Five of the most important nutrients of interest in CKD, i.e. protein, calcium, phosphorus, potassium, and sodium had de-attenuated CC of 0.46, 0.43, 0.39, 0.32, and 0.12, respectively. The median of classification into the same or adjacent quintiles was 68% and 65% for food and nutrient intakes, respectively, and ranged from 63% to 69% for the five nutrients mentioned before. Bland-Altman plots showed good agreement across the range of intakes. ICC ranged from 0.18 to 0.66 (median: 0.46). CONCLUSIONS: The CKD-REIN SFFQ showed acceptable validity and reproducibility in a sample of patients with CKD, notably for CKD nutrients of importance. It can now be used in large-scale epidemiological studies to easily assess the relations between diet and CKD outcomes as well as in clinical routine. It may also serve as a basis for the development of FFQs in international CKD cohort networks. PMID- 28915859 TI - The (FTO) gene polymorphism is associated with metabolic syndrome risk in Egyptian females: a case- control study. AB - BACKGROUND: Variations within fat mass and obesity associated (FTO) gene had crosstalk with obesity risk in European and some Asian populations. This study was designed to investigate FTO rs9939609 association with metabolic syndrome (MetS) as well as biochemical parameters as plasma glucose, serum triacylglycerol (TAG), total cholesterol (TC) and transaminases enzymes in Arab female population from Egypt. METHODS: In order to achieve that, FTO gene rs9939609 (A < T) was genotyped using TaqMan SNP Genotyping Assay in a total of 197 females which were enrolled in this study. Fasting levels of serum insulin, lipid profile and plasma glucose, in addition to liver transaminases were measured. The association between the genotype distribution and MetS risk was evaluated using Chi-square and logistic regression tests in a case-control design under different genetic models. RESULTS: The association of genotype distribution with MetS was significant (chi2 = 8.6/P = 0.014) with an increased odds ratio under dominant model (OR = 1.97, P = 0.029 and 95%C.I = 1.07-3.6) and recessive model (OR = 2.95, P = 0.017 and 95%C.I = 1.22-7.22). Moreover, (AA) subjects showed significant lower HDL-C levels (P = 0.009) when compared to (TT) ones. In addition, interestingly subjects with (AA) genotype have significantly higher ALT levels (P = 0.02) that remained significant after correction of major confounders as body mass index and serum triacylglycerols but not after conservative Bonferroni adjustment. CONCLUSIONS: The present study shows for first time that FTO gene rs9939609 is genetic risk factor for metabolic syndrome in Egyptian population which may help in understanding the biology of this complex syndrome and highlighted that this association may be through HDL-C component. The association of this genetic polymorphism with ALT levels needs to be studied in other populations with larger sample size. PMID- 28915860 TI - Anatomic mapping of molecular subtypes in diffuse glioma. AB - BACKGROUND: Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular subtypes was not widely investigated. The relationship between molecular phenotype and histological subgroup were also vague based on tumor location. Our group focuses on the study of glioma anatomic location of distinctive molecular subgroups and histology subtypes, and explores the possibility of their consistency based on clinical background. METHODS: We retrospectively reviewed 143 cases with both molecular information (IDH1/TERT/1p19q) and MRI images diagnosed as cerebral diffuse gliomas. The anatomic distribution was analyzed between distinctive molecular subgroups and its relationship with histological subtypes. The influence of tumor location, molecular stratification and histology diagnosis on survival outcome was investigated as well. RESULTS: Anatomic locations of cerebral diffuse glioma indicate varied clinical outcome. Based on that, it can be stratified into five principal molecular subgroups according to IDH1/TERT/1p19q status. Triple-positive (IDH1 and TERT mutation with 1p19q codeletion) glioma tended to be oligodendroglioma present with much better clinical outcome compared to TERT mutation only group who is glioblastoma inclined (median overall survival 39 months VS 18 months). Five molecular subgroups were demonstrated with distinctive locational distribution. This kind of anatomic feature is consistent with its corresponding histological subtypes. DISCUSSION: Each molecular subgroup in glioma has unique anatomic location which indicates distinctive clinical outcome. Molecular diagnosis can be served as perfect complementary tool for the precise diagnosis. Integration of histomolecular diagnosis will be much more helpful in routine clinical practice in the future. PMID- 28915861 TI - Informed decision-making with and for people with dementia - efficacy of the PRODECIDE education program for legal representatives: protocol of a randomized controlled trial (PRODECIDE-RCT). AB - BACKGROUND: In Germany, the guardianship system provides adults who are no longer able to handle their own affairs a court-appointed legal representative, for support without restriction of legal capacity. Although these representatives only rarely are qualified in healthcare, they nevertheless play decisive roles in the decision-making processes for people with dementia. Previously, we developed an education program (PRODECIDE) to address this shortcoming and tested it for feasibility. Typical, autonomy-restricting decisions in the care of people with dementia-namely, using percutaneous endoscopic gastrostomy (PEG) or physical restrains (PR), or the prescription of antipsychotic drugs (AP)-were the subject areas trained. The training course aims to enhance the competency of legal representatives in informed decision-making. In this study, we will evaluate the efficacy of the PRODECIDE education program. METHODS: A randomized controlled trial with a six-month follow-up will be conducted to compare the PRODECIDE education program with standard care, enrolling legal representatives (N = 216). The education program lasts 10 h and comprises four modules: A, decision-making processes and methods; and B, C and D, evidence-based knowledge about PEG, PR and AP, respectively. The primary outcome measure is knowledge, which is operationalized as the understanding of decision-making processes in healthcare affairs and in setting realistic expectations about benefits and harms of PEG, PR and AP in people with dementia. Secondary outcomes are sufficient and sustainable knowledge and percentage of persons concerned affected by PEG, FEM or AP. A qualitative process evaluation will be performed. Additionally, to support implementation, a concept for translating the educational contents into e learning modules will be developed. DISCUSSION: The study results will show whether the efficacy of the education program could justify its implementation into the regular training curricula for legal representatives. Additionally, it will determine whether an e-learning course provides a valuable backup or even alternative learning strategy. TRIAL REGISTRATION: TRN: ISRCTN17960111 , Date: 01/06/2017. PMID- 28915862 TI - Self-detection of atrial fibrillation in an aged population: three-year follow-up of the LietoAF intervention study. AB - BACKGROUND: Atrial fibrillation (AF) is often asymptomatic and undiagnosed until an ischaemic stroke occurs. An irregular pulse is a key manifestation of AF. We assessed whether pulse self-palpation is feasible in screening of AF. METHODS: Altogether 205 residents of Lieto municipality aged >=75 years were randomized in 2012 to receive brief education on pulse palpation focusing on evaluating rhythm regularity. Self-detected pulse irregularity and new AF diagnoses were recorded, and the subjects' quality of life and use of health care services were assessed during a three-year follow-up. RESULTS: The subjects' median age was 78.2 [3.8] years, and 89 (43.4%) were men. Overall, 139 (68%) subjects had initial good motivation/capability for regular palpation. At four months, 112 (80.6%) subjects with good and 26 (39.4%) with inadequate motivation/capability palpated their pulse daily. At 12 months, 120 (58.5%) and at 36 months, 69 (33.7%) subjects palpated their pulse at least weekly. During the intervention, 67 (32.7%) subjects reported pulse irregularity. New AF was found in 10 (4.9%) subjects, 7 (70%) of whom had reported pulse irregularity. Pulse irregularity independently predicted new AF, but only one (0.5%) subject with new AF sought undelayed medical attention due to pulse irregularity. Quality of life and number of outpatient clinic visits remained unchanged during follow-up. CONCLUSION: Pulse palpation can be learned also by the elderly, but it is challenging to form a continuing habit. The low persistence of pulse self-palpation limits its value in the screening of AF, and strategies to promote persistence and research on alternative screening methods are needed. TRIAL REGISTRATION: http://www.ClinicalTrials.gov identifier: NCT01721005. The trial was registered retrospectively on October 26, 2012. PMID- 28915864 TI - Physical fitness and anthropometric characteristics among adolescents living in urban or rural areas of Kosovo. AB - BACKGROUND: High physical fitness levels in childhood and adolescence are associated with positive health-related outcomes later in life. Albeit many researchers investigated rural-urban differences in physical fitness, the outcomes of these studies are inconsistent and data on Kosovo are widely missing. Thus, this study aims to examine anthropometric and physical fitness parameters in 14 to 15 year old Kosovan adolescents living in rural and urban areas. METHODS: Two schools from Pristina (mostly urban population) and two schools in the surrounding villages of the district of Decan (mostly rural population) were selected. Anthropometric and physical fitness parameters were determined from a total of 354 adolescents (216 urban: 14.5 +/- 0.4 years, 138 rural: age 14.5 +/- 0.4 years) who volunteered to participate in this cross-sectional study performed in 2013/14. RESULTS: The prevalence of overweight and obesity was 18.9% in girls and 28.2% in males and excess body fat was detected in 18.2% of the girls and 15.9% of the boys with no differences between rural and urban adolescents. Rural adolescents performed slightly better in relative handgrip strength (+4.7%, p = 0.032) and running speed (10 m: +2.2%, p = 0.012; 20 m: +1.9%, p = 0.035), but no other differences were detected in standing long jump, counter movement jump, cardiorespiratory fitness and sit and reach test. A multinomial logistic regression analysis revealed that being a female was associated with a lower relative risk for overweight (RR = 0.11, 95% CI: 0.03-0.34, p < 0.001) and high body fat content (RR = 0.20, 95% CI: 0.05-0.56, p < 0.001). In addition, higher handgrip strength, longer sprinting time and lower aerobic fitness were associated with a higher relative risk for overweight and excess body fat. In contrast, lower handgrip strength increased the risk for experiencing thinness (RR = 0.92, 95% CI: 0.89-0.96, p < 0.001). CONCLUSIONS: It could be shown that there is a high prevalence of overweight and obesity, especially in 14 to 15 year old boys in Kosovo which does not differ between rural and urban areas. Worse physical performance is associated with a higher risk for overweight and obesity highlighting the importance for interventions in this area and for starting longitudinal observations of a secular trend. PMID- 28915863 TI - Lifestyle intervention to improve quality of life and prevent weight gain after renal transplantation: Design of the Active Care after Transplantation (ACT) randomized controlled trial. AB - BACKGROUND: Low physical activity and reduced physical functioning are common after renal transplantation, resulting in a reduced quality of life. Another common post-transplantation complication is poor cardio-metabolic health, which plays a main role in long-term outcomes in renal transplant recipients (RTR). It is increasingly recognized that weight gain in the first year after transplantation, especially an increase in fat mass, is a highly common contributor to cardio-metabolic risk. The aim of this study is to compare the outcomes of usual care to the effects of exercise alone, and exercise combined with dietary counseling, on physical functioning, quality of life and post transplantation weight gain in RTR. METHODS: The Active Care after Transplantation study is a multicenter randomized controlled trial with three arms in which RTR from 3 Dutch hospitals are randomized within the first year after transplantation to usual care, to exercise intervention (3 months supervised exercise 2 times per week followed by 12 months active follow-up), or to an exercise + diet intervention, consisting of the exercise training with additional dietary counseling (12 sessions over 15 months by a renal dietician). In total, 219 participants (73 per group) will be recruited. The primary outcome is the subdomain physical functioning of quality of life, (SF-36 PF). Secondary outcomes include other evaluations of quality of life (SF-36, KDQOL-SF, EQ-5D), objective measures of physical functioning (aerobic capacity and muscle strength), level of physical activity, gain in adiposity (body fat percentage by bio-electrical impedance assessment, BMI, waist circumference), and cardiometabolic risk factors (blood pressure, lipids, glucose metabolism). Furthermore, data on renal function, medical history, medication, psychological factors (motivation, kinesiophobia, coping style), nutrition knowledge, nutrition intake, nutrition status, fatigue, work participation, process evaluation and cost-effectiveness are collected. DISCUSSION: Evidence on the effectiveness of an exercise intervention, or an exercise + diet intervention on physical functioning, weight gain and cardiometabolic health in RTR is currently lacking. The outcomes of the present study may help to guide future evidence-based lifestyle care after renal transplantation. TRIAL REGISTRATION: Number: NCT01047410 . PMID- 28915865 TI - Informed consent and registry-based research - the case of the Danish circumcision registry. AB - BACKGROUND: Research into personal health data holds great potential not only for improved treatment but also for economic growth. In these years many countries are developing policies aimed at facilitating such research often under the banner of 'big data'. A central point of debate is whether the secondary use of health data requires informed consent if the data is anonymised. In 2013 the Danish Minister of Health established a new register collecting data about all ritual male childhood circumcisions in Denmark. The main purpose of the register was to enable future research into the consequences of ritual circumcision. DISCUSSION: This article is a study into the case of the Danish Circumcision Registry. We show that such a registry may lead to various forms of harm such as 1) overreaching social pressure, 2) stigmatization, 3) medicalization of a religious practice, 4) discrimination, and 5) polarised research, and that a person may therefore have a strong and legitimate interest in deciding whether or not such data should be collected and/or used in research. This casts doubt on the claim that the requirement of informed consent could and should be waived for all types of secondary research into registries. We finally sketch a new model of informed consent - Meta consent - aimed at striking a balance between the interests in promoting research and at the same time protecting the individual. Research participants may have a strong and legitimate interest in deciding whether or not their data should be collected and used for registry-based research whether or not their data is anonymised. PMID- 28915866 TI - Should manual detorsion be a routine part of treatment in testicular torsion? AB - BACKGROUND: It was aimed to investigate the efficiency and reliability of the manual detorsion (MD) procedure in patients diagnosed with testicular torsion (TT). METHODS: A retrospective analysis was made of the data of 57 patients diagnosed with TT, comprising 20 patients with successful MD (Group I), 28 patients who underwent emergency orchiopexy (Group II), and 9 patients applied with orchiectomy (Group III). The groups were compared in respect of age, and duration of pain. The success rate of MD, the time of testicular fixation (TF), any problems encountered in follow-up, and follow-up times were analyzed in Group I. Data were analyzed with P-P pilot, Mann-Whitney U, Kruskal Wallis and Chi square tests. A value of p < 0.05 was considered statistically significant. RESULTS: MD was successful and detorsion could be achieved in 20 of 26 patients. The groups were similar in respect of age (p = 0.217). The median duration of pain was 3 (1-8), 4 (1-72), and 48 (12-144) hours in Groups I, II, and III, respectively, and determined as similar in Groups I and II (p = 0.257), although a statistically significant difference was determined between the 3 groups (p < 0.001). TF was applied to Group I after median 10 (0-45) days, and no parenchymal disorder was determined in the median follow-up period of 21.5 (2-40) months. CONCLUSION: MD that can be easily and immediately performed after the diagnosis of TT decreases ischemia time. This seems to be an efficient and reliable procedure when applied together with elective orchiopexy, as a part of the treatment. PMID- 28915867 TI - The associations between workplace bullying, salivary cortisol, and long-term sickness absence: a longitudinal study. AB - BACKGROUND: Workplace stressors, such as bullying, are strongly related to subsequent long-term sickness absence, but little is known of the possible physiological mechanisms linking workplace stressors and sickness absence. The primary aim of this study was to investigate to what extent cortisol levels were associated with subsequent sickness absence and if cortisol mediated the association between workplace bullying and sickness absence. We additionally investigated possible bidirectional associations between bullying, cortisol, and long-term sickness absence. METHODS: Participants came from two Danish cohort studies, the "Psychosocial RIsk factors for Stress and MEntal disease" (PRISME) cohort and the "Workplace Bullying and Harassment" (WBH) cohort (n = 5418). Information about exposure to workplace bullying and morning and evening salivary cortisol was collected at three time points with approximately two years in between. After each data collection, all participants were followed for two years in registers, and cases with long-term sickness absence lasting 30 or more consecutive days were identified. The association between cortisol levels and subsequent sickness absence was assessed by logistic regression, while the extent to which the association between bullying and sickness absence was mediated by cortisol was quantified through natural direct and indirect effects. RESULTS: High evening cortisol was associated with a decreased risk of sickness absence (OR = 0.82, 95% CI = 0.68-0.99), but we did not find that high morning cortisol levels (OR = 0.98, 95% CI = 0.81-1.18) or high morning-to-evening slope (OR = 0.99, 95% CI = 0.82-1.18) were associated with subsequent sickness absence. We also tested for reverse causation and found that long-term sickness absence, but not salivary cortisol, was a strong risk factor for subsequent workplace bullying. There was no indication that cortisol mediated the association between workplace bullying and sickness absence. CONCLUSION: We found no straightforward and simple association between cortisol and long-term sickness absence. Furthermore, the association between workplace bullying and long-term sickness absence was not mediated by cortisol. PMID- 28915868 TI - The Cedar Project: Using Indigenous-specific determinants of health to predict substance use among young pregnant-involved Indigenous women in Canada. AB - BACKGROUND: Indigenous women in Canada have been hyper-visible in research, policy and intervention related to substance use during pregnancy; however, little is known about how the social determinants of health and substance use prior to, during, and after pregnancy intersect. The objectives of this study were to describe the social contexts of pregnant-involved young Indigenous women who use substances and to explore if an Indigenous-Specific Determinants of Health Model can predict substance use among this population. METHODS: Using descriptive statistics and hierarchical logistic regression guided by mediation analysis, the social contexts of pregnant-involved young Indigenous women who use illicit drugs' lives were explored and the Integrated Life Course and Social Determinants Model of Aboriginal Health's ability to predict heavy versus light substance use in this group was tested (N = 291). RESULTS: Important distal determinants of substance use were identified including residential school histories, as well as protective factors, such as sex abuse reporting and empirical evidence for including Indigenous-specific determinants of health as important considerations in understanding young Indigenous women's experiences with pregnancy and substance use was provided. CONCLUSIONS: This analysis provided important insight into the social contexts of women who have experiences with pregnancy as well as drug and/or alcohol use and highlighted the need to include Indigenous-specific determinants of health when examining young Indigenous women's social, political and historical contexts in relation to their experiences with pregnancy and substance use. PMID- 28915869 TI - Frequency and genotypes of Chlamydia trachomatis in patients attending the obstetrics and gynecology clinics in Jalisco, Mexico and correlation with sociodemographic, behavioral, and biological factors. AB - BACKGROUND: Chlamydia trachomatis is the causative agent of the most common bacterial sexually transmitted infection worldwide. The aim of this study was to investigate the frequency and genotypes of C. trachomatis in patients attending an obstetrics and gynecology clinic in Jalisco, Mexico and correlates them with sociodemographic, behavioral, and biological factors. METHODS: C. trachomatis detection was performed in endocervical samples from 662 patients by direct fluorescence assay (DFA) and two PCR assays that amplified the phospholipase D endonuclease superfamily protein (PLDESP) and OmpA genes. Positive samples were genotyped using PCR-restriction fragment length polymorphism assays. Sociodemographic, behavioral, and biological data were collected. RESULTS: The mean age of the study population was 31 (range, 14-78) years. C. trachomatis positivity was detected by DFA in 16.7% (n = 111), PLDESP gene amplification in 14.2% (n = 94), and OmpA gene amplification in 14.5% (n = 96) of the population. Eight C. trachomatis genotypes were detected: E (39.6%), F (29.2%), D (15.6%), K (6.3%), L2 (3.1%), G, J, and I (2.1% each). C. trachomatis infection was associated with age, marital status, pregnancy, and hormonal contraceptive use (all p = 0.01); intrauterine device use and previous premature birth (both p = 0.03); and infection during pregnancy, previous ectopic pregnancy, pelvic inflammatory disease (PID), and green vaginal discharge (all p = 0.04). C. trachomatis genotype K was more likely to be detected in women histories of >=2 sexual partners, genotype F was more likely in pregnant women, genotype L2 was more likely in women with PID, genotype D was more likely in women who had had infection during previous pregnancies, and genotype E was more likely in those with previous ectopic pregnancies and green vaginal discharge (all p = 0.01). CONCLUSIONS: The frequency of C. trachomatis in our population was higher than previously reported worldwide, but within the range reported for Mexico. Genotype E was detected most frequently in the study population. Infection by C. trachomatis and C. trachomatis genotypes K, F, D, and E was strongly associated with multiple sociodemographic, behavioral, and biological factors. C. trachomatis genotype L2 was detected in women with PID. PMID- 28915870 TI - Descriptors for unprofessional behaviours of medical students: a systematic review and categorisation. AB - BACKGROUND: Developing professionalism is a core task in medical education. Unfortunately, it has remained difficult for educators to identify medical students' unprofessionalism, because, among other reasons, there are no commonly adopted descriptors that can be used to document students' unprofessional behaviour. This study aimed to generate an overview of descriptors for unprofessional behaviour based on research evidence of real-life unprofessional behaviours of medical students. METHODS: A systematic review was conducted searching PubMed, Ebsco/ERIC, Ebsco/PsycINFO and Embase.com from inception to 2016. Articles were reviewed for admitted or witnessed unprofessional behaviours of undergraduate medical students. RESULTS: The search yielded 11,963 different studies, 46 met all inclusion criteria. We found 205 different descriptions of unprofessional behaviours, which were coded into 30 different descriptors, and subsequently classified in four behavioural themes: failure to engage, dishonest behaviour, disrespectful behaviour, and poor self-awareness. CONCLUSIONS: This overview provides a common language to describe medical students' unprofessional behaviour. The framework of descriptors is proposed as a tool for educators to denominate students' unprofessional behaviours. The found behaviours can have various causes, which should be explored in a discussion with the student about personal, interpersonal and/or institutional circumstances in which the behaviour occurred. Explicitly denominating unprofessional behaviour serves two goals: [i] creating a culture in which unprofessional behaviour is acknowledged, [ii] targeting students who need extra guidance. Both are important to avoid unprofessional behaviour among future doctors. PMID- 28915871 TI - Virtual patients in the acquisition of clinical reasoning skills: does presentation mode matter? A quasi-randomized controlled trial. AB - BACKGROUND: The objective of this study is to compare two different instructional methods in the curricular use of computerized virtual patients in undergraduate medical education. We aim to investigate whether using many short and focused cases - the key feature principle - is more effective for the learning of clinical reasoning skills than using few long and systematic cases. METHODS: We conducted a quasi-randomized, non-blinded, controlled parallel-group intervention trial in a large medical school in Southwestern Germany. During two seminar sessions, fourth- and fifth-year medical students (n = 56) worked on the differential diagnosis of the acute abdomen. The educational tool - virtual patients - was the same, but the instructional method differed: In one trial arm, students worked on multiple short cases, with the instruction being focused only on important elements ("key feature arm", n = 30). In the other trial arm, students worked on few long cases, with the instruction being comprehensive and systematic ("systematic arm", n = 26). The overall training time was the same in both arms. The students' clinical reasoning capacity was measured by a specifically developed instrument, a script concordance test. Their motivation and the perceived effectiveness of the instruction were assessed using a structured evaluation questionnaire. RESULTS: Upon completion of the script concordance test with a reference score of 80 points and a standard deviation of 5 for experts, students in the key feature arm attained a mean of 57.4 points (95% confidence interval: 50.9-63.9), and in the systematic arm, 62.7 points (57.2-68.2), with Cohen's d at 0.337. The difference is statistically non significant (p = 0.214). In the evaluation survey, students in the key feature arm indicated that they experienced more time pressure and perceived the material as more difficult. CONCLUSIONS: In this study powered for a medium effect, we could not provide empirical evidence for the hypothesis that a key feature-based instruction on multiple short cases is superior to a systematic instruction on few long cases in the curricular implementation of virtual patients. The results of the evaluation survey suggest that learners should be given enough time to work through case examples, and that caution should be taken to prevent cognitive overload. PMID- 28915872 TI - Risk factors of chronic periodontitis on healing response: a multilevel modelling analysis. AB - BACKGROUND: Chronic periodontitis is a multifactorial polygenetic disease with an increasing number of associated factors that have been identified over recent decades. Longitudinal epidemiologic studies have demonstrated that the risk factors were related to the progression of the disease. A traditional multivariate regression model was used to find risk factors associated with chronic periodontitis. However, the approach requirement of standard statistical procedures demands individual independence. Multilevel modelling (MLM) data analysis has widely been used in recent years, regarding thorough hierarchical structuring of the data, decomposing the error terms into different levels, and providing a new analytic method and framework for solving this problem. The purpose of our study is to investigate the relationship of clinical periodontal index and the risk factors in chronic periodontitis through MLM analysis and to identify high-risk individuals in the clinical setting. METHODS: Fifty-four patients with moderate to severe periodontitis were included. They were treated by means of non-surgical periodontal therapy, and then made follow-up visits regularly at 3, 6, and 12 months after therapy. Each patient answered a questionnaire survey and underwent measurement of clinical periodontal parameters. RESULTS: Compared with baseline, probing depth (PD) and clinical attachment loss (CAL) improved significantly after non-surgical periodontal therapy with regular follow-up visits at 3, 6, and 12 months after therapy. The null model and variance component models with no independent variables included were initially obtained to investigate the variance of the PD and CAL reductions across all three levels, and they showed a statistically significant difference (P < 0.001), thus establishing that MLM data analysis was necessary. Site-level had effects on PD and CAL reduction; those variables could explain 77-78% of PD reduction and 70-80% of CAL reduction at 3, 6, and 12 months. Other levels only explain 20-30% of PD and CAL reductions. Site-level had the greatest effect on PD and CAL reduction. CONCLUSIONS: Non-surgical periodontal therapy with regular follow-up visits had a remarkable curative effect. All three levels had a substantial influence on the reduction of PD and CAL. Site-level had the largest effect on PD and CAL reductions. PMID- 28915873 TI - A prospective cohort study on ambient air pollution and respiratory morbidities including childhood asthma in adolescents from the western Cape Province: study protocol. AB - BACKGROUND: There is evidence from existing literature that ambient air pollutant exposure in early childhood likely plays an important role in asthma exacerbation and other respiratory symptoms, with greater effect among asthmatic children. However, there is inconclusive evidence on the role of ambient air pollutant exposures in relation to increasing asthma prevalence as well as asthma induction in children. At the population level, little is known about the potential synergistic effects between pollen allergens and air pollutants since this type of association poses challenges in uncontrolled real life settings. In particular, data from sub-Sahara Africa is scarce and virtually absent among populations residing in informal residential settlements. METHODS/DESIGN: A prospective cohort study of 600 school children residing in four informal settlement areas with varying potential ambient air pollutant exposure levels in the Western Cape in South Africa is carried-out. The study has two follow-up periods of at least six-months apart including an embedded panel study in summer and winter. The exposure assessment component models temporal and spatial variability of air quality in the four study areas over the study duration using land-use regression modelling (LUR). Additionally, daily pollen levels (mould spores, tree, grass and weed pollen) in the study areas are recorded. In the panel study asthma symptoms and serial peak flow measurements is recorded three times daily to determine short-term serial airway changes in relation to varying ambient air quality and pollen over 10-days during winter and summer. The health outcome component of the cohort study include; the presence of asthma using a standardised ISAAC questionnaire, spirometry, fractional exhaled nitric-oxide (FeNO) and the presence of atopy (Phadiatop). DISCUSSION: This research applies state of the art exposure assessment approaches to characterize the effects of ambient air pollutants on childhood respiratory health, with a specific focus on asthma and markers of airway inflammation (FeNO) in South African informal settlement areas by considering also pollen counts and meteorological factors. The study will generate crucial data on air pollution and asthma in low income settings in sub-Sahara Africa that is lacking in the international literature. PMID- 28915874 TI - Unmet needs in the treatment of idiopathic pulmonary fibrosis-insights from patient chart review in five European countries. AB - BACKGROUND: Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis (IPF). In this analysis, treatment patterns of European patients with IPF were investigated to understand antifibrotic prescribing and identify unmet needs in IPF treatment practice. METHODS: Between February and March 2016, respiratory physicians from France, Germany, Italy, Spain, and the UK participated in an online questionnaire designed to collect information on IPF treatment patterns in patients under their care. Patients were categorized as treated (received approved antifibrotics) or untreated (did not receive approved antifibrotics, but may have received other unapproved therapies). Classification of IPF diagnosis (confirmed/suspected) and severity ('mild'/'moderate'/'severe') for each patient was based on the individual physician's report. Patients' perspectives were not recorded in this study. RESULTS: In total, 290 physicians responded to the questionnaire. Overall, 54% of patients with IPF did not receive treatment with an approved antifibrotic. More patients had a confirmed IPF diagnosis in the treated (84%) versus the untreated (51%) population. Of patients with a confirmed diagnosis, 40% did not receive treatment. The treated population was younger than the untreated population (67 vs 70 years, respectively; p <= 0.01), with more frequent multidisciplinary team evaluation (83% vs 57%, respectively; p <= 0.01). A higher proportion of untreated patients had forced vital capacity > 80% at diagnosis versus treated patients. Of patients with 'mild' IPF, 71% did not receive an approved antifibrotic versus 41% and 60% of patients with 'moderate' and 'severe' IPF, respectively. CONCLUSIONS: Despite the availability of antifibrotic therapies, many European patients with confirmed IPF do not receive approved antifibrotic treatment. Importantly, there appears to be a reluctance to treat patients with 'mild' or 'stable' disease, and instead adopt a 'watch and wait' approach. More education is required to address diagnostic uncertainty, poor understanding of IPF and its treatments, and issues of treatment access. There is a need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity. PMID- 28915875 TI - Plectranthus amboinicus essential oil and carvacrol bioactive against planktonic and biofilm of oxacillin- and vancomycin-resistant Staphylococcus aureus. AB - BACKGROUND: The emergence of multidrug-resistant bacteria is a worldwide concern and in order to find an alternative to this problem, the occurrence of antimicrobial compounds in Plectranthus amboinicus essential oil was investigated. Thus, this study aims to determine susceptibility of Staphylococcus aureus isolated from food to antibiotics, P. amboinicus essential oil (PAEO) and carvacrol. METHODS: Leaves and stem of P. amboinicus were used for extraction of essential oil (PAEO) by hydrodistillation technique and EO chemical analysis was performed by gas chromatography coupled to a mass spectrometer. S. aureus strains (n = 35) isolated from food and S. aureus ATCC 6538 were used to evaluate the antimicrobial and antibiofilm activity of PAEO and carvacrol. All strains (n = 35) were submitted to antimicrobial susceptibility profile by disk diffusion method. Determination of MIC and MBC was performed by microdilution technique and antibiofilm activity was determined by microtiter-plate technique with crystal violet assay and counting viable cells in Colony Forming Units (CFU). RESULTS: Carvacrol (88.17%) was the major component in the PAEO. Antibiotic resistance was detected in 28 S. aureus strains (80%) and 12 strains (34.3%) were oxacillin and vancomycin-resistant (OVRSA). From the 28 resistant strains, 7 (25%) showed resistance plasmid of 12,000 bp. All strains (n = 35) were sensitive to PAEO and carvacrol, with inhibition zones ranging from 16 to 38 mm and 23 to 42 mm, respectively. The lowest MIC (0.25 mg mL-1) and MBC (0.5 mg mL-1) values were observed when carvacrol was used against OVRSA. When a 0.5 mg mL-1 concentration of PAEO and carvacrol was used, no viable cells were found on S. aureus biofilm. CONCLUSION: The antibacterial effect of carvacrol and PAEO proves to be a possible alternative against planktonic forms and staphylococcal biofilm. PMID- 28915876 TI - Changes in trust and the use of Korean medicine in South Korea: a comparison of surveys in 2011 and 2014. AB - BACKGROUND: Korean medicine (KM) has been widely used in Korea. This study aimed to assess the general perceptions of KM, to investigate the patterns of its usage in 2014, and to compare the results with those of an earlier survey from 2011. METHODS: A cross-sectional study was conducted with 1000 Korean people. The questionnaire included items regarding trust in KM, reasons for distrust of KM, and visit frequency to KM clinics. This study used methods consistent with those of a 2011 survey to examine changes in attitudes over 3 years. RESULTS: Despite high rates of trust in KM, the visit frequency decreased from 69.3% in 2011 to 63.2% in 2014. Usage among young adults (in their 20s and 30s) was significantly reduced compared to all other age groups. The KM modality most commonly used by participants was acupuncture, whereas the use of moxibustion and cupping therapies has decreased since 2011. Men and women were most likely to distrust KM due to a "lack of scientific evidence" (59.3%) and "suspicion of KM safety" (47.4%), respectively. CONCLUSIONS: The findings suggested that KM use and trust in KM were slightly lower in 2014 than in 2011. The decreases were most notable among individuals in their 30s and in the use of moxibustion in KM therapy. This study aimed to produce practical insights by reviewing patterns of KM use and perceptions over time. Additional surveys must be considered to produce a more in depth analysis. PMID- 28915877 TI - Vole abundance and reindeer carcasses determine breeding activity of Arctic foxes in low Arctic Yamal, Russia. AB - BACKGROUND: High latitude ecosystems are at present changing rapidly under the influence of climate warming, and specialized Arctic species at the southern margin of the Arctic may be particularly affected. The Arctic fox (Vulpes lagopus), a small mammalian predator endemic to northern tundra areas, is able to exploit different resources in the context of varying tundra ecosystems. Although generally widespread, it is critically endangered in subarctic Fennoscandia, where a fading out of the characteristic lemming cycles and competition with abundant red foxes have been identified as main threats. We studied an Arctic fox population at the Erkuta Tundra Monitoring site in low Arctic Yamal (Russia) during 10 years in order to determine which resources support the breeding activity in this population. In the study area, lemmings have been rare during the last 15 years and red foxes are nearly absent, creating an interesting contrast to the situation in Fennoscandia. RESULTS: Arctic fox was breeding in nine of the 10 years of the study. The number of active dens was on average 2.6 (range 0-6) per 100 km2 and increased with small rodent abundance. It was also higher after winters with many reindeer carcasses, which occurred when mortality was unusually high due to icy pastures following rain-on-snow events. Average litter size was 5.2 (SD = 2.1). Scat dissection suggested that small rodents (mostly Microtus spp.) were the most important prey category. Prey remains observed at dens show that birds, notably waterfowl, were also an important resource in summer. CONCLUSIONS: The Arctic fox in southern Yamal, which is part of a species-rich low Arctic food web, seems at present able to cope with a state shift of the small rodent community from high amplitude cyclicity with lemming dominated peaks, to a vole community with low amplitude fluctuations. The estimated breeding parameters characterized the population as intermediate between the lemming fox and the coastal fox ecotype. Only continued ecosystem based monitoring will reveal their fate in a changing tundra ecosystem. PMID- 28915878 TI - The immune mechanism of Mycoplasma hyopneumoniae 168 vaccine strain through dendritic cells. AB - BACKGROUND: Mycoplasma hyopneumoniae (Mhp) causes porcine enzootic pneumonia, a disease that cause major economic losses in the pig industry. Dendritic cells (DCs), the most effective antigen-presenting cells, are widely distributed beneath respiratory epithelium, DCs uptake and present antigens to T cells, to initiate protective immune responses in different infections. In this study, we investigated the role of porcine DCs in vaccine Mhp-168 exposure. RESULTS: The antigen presenting ability of DCs were improved by vaccine Mhp-168 exposure. DCs could activate T-cell proliferation by up-regulating the antigen presenting molecule MHCII expression and co-stimulatory molecule CD80/86. However, the up regulation of IL-10 and accompany with down-regulation of IFN-gamma gene level may account for the limitation of attenuated Mhp-168 strain use as vaccine alone. CONCLUSION: These findings are benefit for exploring the protection mechanisms and the possible limitations of this attenuated Mhp-168 vaccine. PMID- 28915880 TI - Increasing bladder capacity by foot stimulation in rats with spinal cord injuries. AB - BACKGROUND: This study was to explore the possibility that foot stimulation increased bladder capacity(BC) in rats with neurogenic bladder secondary to T10 spinal cord injuries. METHODS: In 20 awake rats (stimulation group) with T10 spinal cord injuries, 5 repeat cystometrograms (CMGs) were recorded. The 1st and 2nd CMGs were performed without stimulation. The 3rd, 4th, and 5th CMGs were done separately with 1 T, 2 T, and 4 T stimulation, respectively, through a pair of pad electrodes on the skin of the hind foot. In the control group of 20 rats, 5 repeat CMGs were recorded without foot stimulation. The threshold (T) was the minimal stimulation intensity to induce an observable toe twitch. RESULTS: In the stimulation group, foot stimulation with 2 T significantly increased the BC an additional 68.9% +/- 20.82% (p < 0.05). Foot stimulation with 4 T increased the BC an additional 120.9% +/- 24.82% (p < 0.05). Compared with the control group, BC in the 1st, 2nd, and 3rd (1 T) CMG had no significant difference in the stimulation group, but the 4th (2 T) and 5th (4 T) CMGs were significantly increased (p < 0.05). CONCLUSIONS: Electrical stimulation of the foot was effective in inhibiting reflex bladder activity and increasing bladder capacity in spinal cord injury rats. PMID- 28915879 TI - The effect of sedation and/or analgesia as rescue treatment during noninvasive positive pressure ventilation in the patients with Interface intolerance after Extubation. AB - BACKGROUND: Sedation and/or analgesia can relieve the patient-ventilator asynchrony. However, whether sedation and/or analgesia can benefit the clinical outcome of the patients with interface intolerance is still unclear. METHODS: A retrospective study was performed on patients with interface intolerance who received noninvasive positive pressure ventilation (NIPPV) after extubation in seven intensive care units (ICU) of West China Hospital, Sichuan University. The primary outcome was rate of NIPPV failure (defined as need for reintubation and mechanical ventilation); Secondary outcomes were hospital mortality rate and length of ICU stay after extubation. RESULTS: A total of 80 patients with oral nasal mask (90%) and facial mask (10%) were included in the analysis. 41 out of 80 patients received sedation and/or analgesia treatment (17 used analgesia, 11 used sedation and 13 used both) at some time during NIPPV. They showed a decrease of NIPPV failure rate, (15% vs. 38%, P = 0.015; adjusted odd ratio [OR] 0.29, 95% confidence interval [CI] 0.10-0.86, P = 0.025), mortality rate (7% vs. 33%, P = 0.004; adjusted OR 0.14, 95% CI 0.03-0.60, P = 0.008), and the length of ICU stay after extubation. CONCLUSION: This clinical study suggests that sedation and/or analgesia treatment can decrease the rate of NIPPV failure, hospital mortality rate and ICU LOS in patients with interface intolerance after extubution during NIPPV. PMID- 28915882 TI - Blind free-living kiwi offer a unique window into the ecology and evolution of vertebrate vision. AB - The first report of multiple, blind, wild birds in good health suggests vision is not necessary for the survival of kiwi. PMID- 28915881 TI - High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes. AB - BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with >=50 years of T1D, the 50-Year Joslin Medalists (J50M). METHODS: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. RESULTS: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 +/- 8.4% vs 19.9 +/- 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = -0.424, p = 0.02), large (r = -0.413, p = 0.02) and intermediate (r = -0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). CONCLUSIONS: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation. PMID- 28915883 TI - Plasma trans-fatty acids levels and mortality: a cohort study based on 1999-2000 National Health and Nutrition Examination Survey (NHANES). AB - BACKGROUND: Trans-fatty acids (TFAs) occur in small amounts in nature but became widely produced by the food industry. The hazardous effects of different TFA subtypes to human health are controversial. We aimed to evaluate the association of plasma TFAs levels (elaidic acid, vaccenic acid, palmitelaidic acid, and linoelaidic acid) with mortality. METHODS: Utilizing 1999-2000 Nutrition Examination Survey (NHANES) and linked mortality data, we performed a cohort study with 1456 participants and used Cox proportional hazards models and penalized smoothing spline plots to elucidate the relationships between TFAs and all-cause, cardiovascular diseases (CVD) and cancer mortality. RESULTS: During 16,034 person-years of follow-up, a total of 221 deaths occurred. In the multivariate model, including mutual adjustment for the 4 TFA subtypes, elaidic acid associated with higher all-cause mortality (hazard ratio (HR) = 2.00, 95% confidence interval (CI) = 1.18 to 3.40, fourth quartiles versus second quartiles) and CVD mortality (HR = 1.64, 95% CI = 1.07 to 2.50, per 10 units increase). Higher palmitelaidic acid levels were associated with increased cancer mortality (HR = 2.91, 95% CI = 1.09 to 7.81, fourth quartiles versus second quartiles). A J-shaped pattern was observed in the regression curve of elaidic acid and all-cause mortality, as well palmitelaidic acid and cancer mortality. CONCLUSIONS: Plasma elaidic acid levels are associated with higher risk of all cause and CVD mortality, and palmitelaidic acid levels are associated with higher cancer mortality in later life. Further studies are needed to investigate current inconsistent results in this field and the possible underlying mechanisms. PMID- 28915884 TI - Q&A: Morphological insights into evolution. AB - In this question and answer article we discuss how evolution shapes morphology (the shape and pattern of our bodies) but also how learning about morphology, and specifically how that morphology arises during development, can shed light on mechanisms that might allow change during evolution. For this we concentrate on recent findings from our lab on how the middle ear has formed in mammals. PMID- 28915885 TI - Erratum to: Efficacy and short-term outcomes of preoperative chemoradiotherapy with intermittent oral tegafur-uracil plus leucovorin in Japanese rectal cancer patients: a single center experience retrospective analysis. PMID- 28915886 TI - Prognostic factors in patients with loco-regionally advanced gastric cancer. AB - BACKGROUND: The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC). METHODS: Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival. RESULTS: One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0-67.4) versus 4.7 months (range 0.0-28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000-2004 (5.1 months, range 0-67.4) with the period 2005-2009 (4.0 months, range 0.0-28.3). CONCLUSION: Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted. PMID- 28915887 TI - Professional fulfillment and parenting work-life balance in female physicians in Basic Sciences and medical research: a nationwide cross-sectional survey of all 80 medical schools in Japan. AB - BACKGROUND: In Japan, the field of Basic Sciences encompasses clinical, academic, and translational research, as well as the teaching of medical sciences, with both an MD and PhD typically required. In this study, it was hypothesized that the characteristics of a Basic Sciences career path could offer the professional advancement and personal fulfillment that many female medical doctors would find advantageous. Moreover, encouraging interest in Basic Sciences could help stem shortages that Japan is experiencing in medical fields, as noted in the three principal contributing factors: premature resignation of female clinicians, an imbalance of female physicians engaged in research, and a shortage of medical doctors in the Basic Sciences. This study examines the professional and personal fulfillment expressed by Japanese female medical doctors who hold positions in Basic Sciences. Topics include career advancement, interest in medical research, and greater flexibility for parenting. METHODS: A cross-sectional questionnaire survey was distributed at all 80 medical schools in Japan, directed to 228 female medical doctors whose academic rank was assistant professor or higher in departments of Basic Sciences in 2012. Chi-square tests and the binary logistic regression model were used to investigate the impact of parenthood on career satisfaction, academic rank, salary, etc. RESULTS: The survey response rate of female physicians in Basic Sciences was 54.0%. Regardless of parental status, one in three respondents cited research interest as their rationale for entering Basic Sciences, well over twice other motivations. A majority had clinical experience, with clinical duties maintained part-time by about half of respondents and particularly parents. Only one third expressed afterthoughts about relinquishing full-time clinical practice, with physicians who were parents expressing stronger regrets. Parental status had little effect on academic rank and income within the Basic Sciences, CONCLUSION: Scientific curiosity and a desire to improve community health are hallmarks of those choosing a challenging career in medicine. Therefore, it is unsurprising that interest in research is the primary motivation for a female medical doctor to choose a career in Basic Sciences. Additionally, as with many young professionals with families, female doctors seek balance in professional and private lives. Although many expressed afterthoughts relinquishing a full-time clinical practice, mothers generally benefited from greater job flexibility, with little significant effect on career development and income as Basic Scientists. PMID- 28915888 TI - Stigmatization of people who inject drugs (PWID) by pharmacists in Tajikistan: sociocultural context and implications for a pharmacy-based prevention approach. AB - BACKGROUND: Pharmacies are an important source of sterile syringes for people who inject drugs (PWID) in Tajikistan who are under high risk of HIV and hepatitis C virus. Accessibility of sterile syringes at pharmacies without prescription may depend on pharmacists' attitudes towards PWID. This qualitative inquiry examines meanings and processes of stigmatization of PWID among pharmacists and pharmacy students in Tajikistan. METHODS: We conducted semi-structured interviews with 19 pharmacists and 9 students (N = 28) in the cities of Dushanbe and Kulob, Tajikistan. The interview topics included personal attitudes towards drug use and PWID, encounters with PWID, awareness and beliefs related to drug dependence and HIV, and attitudes and practices related to providing syringes to PWID. Interview transcripts were analysed using thematic analysis methods. RESULTS: The main themes included the significance of religion in defining attitudes towards drug use, labelling of PWID, negative stereotypes (PWID are prone to crime, violence, and irrational aggression; inflict harm to families and society; are able to control drug use), emotions triggered by PWID (fear, sympathy) and discrimination against PWID (rejection, isolation, ostracism, limiting resources to PWID). The religious ban on drug use and pharmacists' moral and legal responsibility for the consequences of drug use were frequently mentioned as reasons for rejecting syringe sales. Still, many participants acknowledged the need for distributing syringes to PWID to prevent HIV. CONCLUSIONS: Stigma against PWID in Tajikistan plays an important role in shaping pharmacists' attitudes towards provision of services to this population. Local sociocultural context, in particular religious beliefs and social conservatism, may facilitate stigmatizing beliefs. PMID- 28915889 TI - Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity. AB - BACKGROUND: Nintedanib, a tyrosine kinase inhibitor that is specific for platelet derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. METHODS: Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. RESULTS: Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. CONCLUSIONS: These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function. PMID- 28915890 TI - Barriers and enablers for the development and implementation of allied health clinical practice guidelines in South African primary healthcare settings: a qualitative study. AB - BACKGROUND: The South African allied health (AH) primary healthcare (PHC) workforce is challenged with the complex rehabilitation needs of escalating patient numbers. The application of evidence-based care using clinical practice guidelines (CPGs) is one way to make efficient and effective use of resources. Although CPGs are common for AH in high-income countries, there is limited understanding of how to do this in low- to middle-income countries. This paper describes barriers and enablers for AH CPG uptake in South African PHC. METHODS: Semi-structured individual interviews were undertaken with 25 South African AH managers, policymakers, clinicians and academics to explore perspectives on CPGs. Interviews were conducted by researcher dyads, one being familiar with South African AH PHC practice and the other with CPG expertise. Rigour and transparency of data collection was ensured. Interview transcripts were analysed by structuring content into codes, categories and themes. Exemplar quotations were extracted to support themes. RESULTS: CPGs were generally perceived to be relevant to assist AH providers to address the challenges of consistently providing evidence-based care in South African PHC settings. CPGs were considered to be tools for managing clinical, social and economic complexities of AH PHC practice, particularly if CPG recommendations were contextusalised. CPG uptake was one way to deal with increasing pressures to make efficient use of scarce financial resources, and to demonstrate professional legitimacy. Themes comprised organisational infrastructures and capacities for CPG uptake, interactions between AH actors and interaction with broader political structures, the nature of AH evidence in CPGs, and effectively implementing CPGs into practice. CONCLUSION: CPGs contextualised to local circumstances offer South African PHC AH services with an efficient vehicle for putting evidence into practice. There are challenges to doing this, related to local barriers such as geography, AH training, workforce availability, scarce resources, an escalating number of patients requiring complex rehabilitation, and local knowledge. Concerted attempts to implement locally relevant CPGs for AH primary care in South Africa are required to improve widespread commitment to evidence-based care, as well as to plan efficient and effective service delivery models. PMID- 28915891 TI - Inflammatory bowel disease-specific health-related quality of life instruments: a systematic review of measurement properties. AB - BACKGROUND: This review aims to critically appraise and compare the measurement properties of inflammatory bowel disease (IBD)-specific health-related quality of life instruments. METHODS: Medline, EMBASE and ISI Web of Knowledge were searched from their inception to May 2016. IBD-specific instruments for patients with Crohn's disease, ulcerative colitis or IBD were enrolled. The basic characteristics and domains of the instruments were collected. The methodological quality of measurement properties and measurement properties of the instruments were assessed. RESULTS: Fifteen IBD-specific instruments were included, which included twelve instruments for adult IBD patients and three for paediatric IBD patients. All of the instruments were developed in North American and European countries. The following common domains were identified: IBD-related symptoms, physical, emotional and social domain. The methodological quality was satisfactory for content validity; fair in internal consistency, reliability, structural validity, hypotheses testing and criterion validity; and poor in measurement error, cross-cultural validity and responsiveness. For adult IBD patients, the IBDQ-32 and its short version (SIBDQ) had good measurement properties and were the most widely used worldwide. For paediatric IBD patients, the IMPACT-III had good measurement properties and had more translated versions. CONCLUSIONS: Most methodological quality should be promoted, especially measurement error, cross-cultural validity and responsiveness. The IBDQ-32 was the most widely used instrument with good reliability and validity, followed by the SIBDQ and IMPACT-III. Further validation studies are necessary to support the use of other instruments. PMID- 28915892 TI - Modelling the impact of the long-term use of insecticide-treated bed nets on Anopheles mosquito biting time. AB - BACKGROUND: Evidence of changing in biting and resting behaviour of the main malaria vectors has been mounting up in recent years as a result of selective pressure by the widespread and long-term use of insecticide-treated bed nets (ITNs), and indoor residual spraying. The impact of resistance behaviour on malaria intervention efficacy has important implications for the epidemiology and malaria control programmes. In this context, a theoretical framework is presented to understand the mechanisms determining the evolution of feeding behaviour under the pressure of use of ITNs. METHODS: An agent-based stochastic model simulates the impact of insecticide-treated bed nets on mosquito fitness by reducing the biting rates, as well as increasing mortality rates. The model also incorporates a heritability function that provides the necessary genetic plasticity upon which natural selection would act to maximize the fitness under the pressure of the control strategy. RESULTS: The asymptotic equilibrium distribution of mosquito population versus biting time is shown for several daily uses of ITNs, and the expected disruptive selection on this mosquito trait is observed in the simulations. The relative fitness of strains that bite at much earlier time with respect to the wild strains, when a threshold of about 50% of ITNs coverage highlights the hypothesis of a behaviour selection. A sensitivity analysis has shown that the top three parameters that play a dominant role on the mosquito fitness are the proportion of individuals using bed nets and its effectiveness, the impact of bed nets on mosquito oviposition, and the mosquito genetic plasticity related to changing in biting time. CONCLUSION: By taking the evolutionary aspect into account, the model was able to show that the long-term use of ITNs, although representing an undisputed success in reducing malaria incidence and mortality in many affected areas, is not free of undesirable side effects. From the evolutionary point of view of the parasite virulence, it should be expected that plasmodium parasites would be under pressure to reduce their virulence. This speculative hypothesis can eventually be demonstrated in the medium to long-term use of ITNs. PMID- 28915893 TI - Dosimetric comparison of different treatment modalities for stereotactic radiotherapy. AB - BACKGROUND: The modalities for performing stereotactic radiotherapy (SRT) on the brain include the cone-based linear accelerator (linac), the flattening filter free (FFF) volumetric modulated arc therapy (VMAT) linac, and tomotherapy. In this study, the cone-based linac, FFF-VMAT linac, and tomotherapy modalities were evaluated by measuring the differences in doses delivered during brain SRT and experimentally assessing the accuracy of the output radiation doses through clinical measurements. METHODS: We employed a homemade acrylic dosimetry phantom representing the head, within which a thermoluminescent dosimeter (TLD) and radiochromic EBT3 film were installed. Using the conformity/gradient index (CGI) and Paddick methods, the quality of the doses delivered by the various SRT modalities was evaluated. The quality indicators included the uniformity, conformity, and gradient indices. TLDs and EBT3 films were used to experimentally assess the accuracy of the SRT dose output. RESULTS: The dose homogeneity indices of all the treatment modalities were lower than 1.25. The cone-based linac had the best conformity for all tumors, regardless of the tumor location and size, followed by the FFF-VMAT linac; tomography was the worst-performing treatment modality in this regard. The cone-based linac had the best gradient, regardless of the tumor location and size, whereas the FFF-VMAT linac had a better gradient than tomotherapy for a large tumor diameter (28 mm). The TLD and EBT3 measurements of the dose at the center of tumors indicated that the average difference between the measurements and the calculated dose was generally less than 4%. When the 3% 3-mm gamma passing rate metric was used, the average passing rates of all three treatment modalities exceeded 98%. CONCLUSIONS: Regarding the dose, the cone-based linac had the best conformity and steepest dose gradient for tumors of different sizes and distances from the brainstem. The results of this study suggest that SRT should be performed using the cone-based linac on tumors that require treatment plans with a steep dose gradient, even as the tumor is slightly irregular, we should also consider using a high dose gradient of the cone base to treat and protect the normal tissue. If normal tissues require special protection exist at positions that are superior or inferior to the tumor, we can consider using tomotherapy or Cone base with couch at 0 degrees for treatment. PMID- 28915894 TI - Cardiovascular risk in patients with alpha-1-antitrypsin deficiency. AB - BACKGROUND: Alpha-1-antitrypsin deficiency (AATD) is a rare inherited condition caused by mutations of the SERPINA1 gene that is associated with the development of a COPD like lung disease. The comorbidities in patients with AATD-related lung diseases are not well defined. The aim of this study was to analyze the clinical phenotype of AATD patients within the German COPD cohort study COSYCONET ("COPD and SYstemic consequences-COmorbidities NETwork") cohort focusing on the distribution of comorbidities. METHOD AND RESULTS: The data from 2645 COSYCONET patients, including 139 AATD patients (110 with and 29 without augmentation therapy), were analyzed by descriptive statistics and regression analyses. We found significantly lower prevalence of cardiovascular comorbidities in AATD patients as compared to non-AATD COPD patients. After correction for age, pack years, body mass index, and sex, the differences were still significant for coronary artery disease (p = 0.002) and the prevalence of peripheral artery disease as determined by an ankle-brachial-index <= 0.9 (p = 0.035). Also the distribution of other comorbidities such as bronchiectasis differed between AATD and non-deficient COPD. CONCLUSION: AATD is associated with a lower prevalence of cardiovascular disease, the underlying mechanisms need further investigation. PMID- 28915895 TI - Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. AB - BACKGROUND: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. METHODS: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. RESULTS: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 MUg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 MUg/mL) than in those without NP-AEs (1.01 MUg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). CONCLUSION: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP AEs. PMID- 28915896 TI - Placental malaria and its effect on pregnancy outcomes in Sudanese women from Blue Nile State. AB - BACKGROUND: Malaria infection during pregnancy can result in placental malaria and is associated with adverse pregnancy outcomes particularly among primigravidae. The aim of this study was to assess the prevalence and risk factors for placental malaria and its effect on pregnancy outcomes in Blue Nile state, Sudan. METHODS: A cross-sectional hospital-based study was conducted consecutively during January 2012-December 2015 in three main hospitals in Blue Nile State, Sudan. At delivery, peripheral and placental blood samples were collected from consenting women. Finger prick blood was used for preparation of peripheral smears and for haemoglobin measurement. Smears were stained with Giemsa and examined microscopically for malaria parasites. Pregnancy outcomes in association to placental malaria were investigated. RESULTS: A total of 1149 mothers and their newborns were recruited. The mean (SD) of the age was 23.3 (5.2) years. Detection of malaria parasites was confirmed in 37.8% of the peripheral blood films and 59.3% of the placental films with Plasmodium falciparum as the only species detected. In multivariate analysis, younger age <=23.2 years old (AOR = 3.2, 95% CI 1.9-5.5; P < 0.001), primiparae (AOR = 3.9, CI 2.1-7.6; P < 0.001), secundiparae (AOR = 2.8, 95% CI 1.5-5.1; P < 0.001, no antenatal care (ANC) visits (AOR = 11.9, 95% CI 7.8-18.1; P < 0.001) and not using bed nets (AOR = 3.5, 95% CI 1.7-6.8; P < 0.001) were risk factors for placental malaria. Education and residence were not associated with placental malaria infection. Placental malaria was significantly associated with maternal anaemia (AOR = 41.6, 95% CI 23.3-74.4; P < 0.001) and low birth weight (LBW) (AOR = 25.2, 95% CI 15.1-41.3; P < 0.001). CONCLUSION: During the study, there was a high prevalence of placental malaria in Blue Nile State-Sudan, as the enhanced control activities were not practiced, leading to adverse pregnancy outcomes, such as maternal anaemia and LBW. PMID- 28915897 TI - Development of a complex intervention to promote appropriate prescribing and medication intensification in poorly controlled type 2 diabetes mellitus in Irish general practice. AB - BACKGROUND: Poorly controlled type 2 diabetes mellitus (T2DM) can be seen as failure to meet recommended targets for management of key risk factors including glycaemic control, blood pressure and lipids. Poor control of risk factors is associated with significant morbidity, mortality and healthcare costs. Failure to intensify medications for patients with poor control of T2DM when indicated is called clinical inertia and is one contributory factor to poor control of T2DM. We aimed to develop a theory and evidence-based complex intervention to improve appropriate prescribing and medication intensification in poorly controlled T2DM in Irish general practice. METHODS: The first stage of the Medical Research Council Framework for developing and evaluating complex interventions was utilised. To identify current evidence, we performed a systematic review to examine the effectiveness of interventions targeting patients with poorly controlled T2DM in community settings. The Behaviour Change Wheel theoretical approach was used to identify suitable intervention functions. Workshops, simulation, collaborations with academic partners and observation of physicians were utilised to operationalise the intervention functions and design the elements of the complex intervention. RESULTS: Our systematic review highlighted that professional-based interventions, potentially through clinical decision support systems, could address poorly controlled T2DM. Appropriate intensification of anti-glycaemic and cardiovascular medications, by general practitioners (GPs), for adults with poorly controlled T2DM was identified as the key behaviour to address clinical inertia. Psychological capability was the key driver of the behaviour, which needed to change, suggesting five key intervention functions (education, training, enablement, environmental restructuring and incentivisation) and nine key behaviour change techniques, which were operationalised into a complex intervention. The intervention has three components: (a) a training program/academic detailing of target GPs, (b) a remote finder tool to help GPs identify patients with poor control of T2DM in their practice and (c) A web-based clinical decision support system. CONCLUSIONS: This paper describes a multifaceted process including an exploration of current evidence and a thorough theoretical understanding of the predictors of the behaviour resulting in the design of a complex intervention to promote the implementation of evidence-based guidelines, through appropriate prescribing and medication intensification in poorly controlled T2DM. PMID- 28915898 TI - Physician-staffed helicopter emergency medical service has a beneficial impact on the incidence of prehospital hypoxia and secured airways on patients with severe traumatic brain injury. AB - BACKGROUND: After traumatic brain injury (TBI), hypotension, hypoxia and hypercapnia have been shown to result in secondary brain injury that can lead to increased mortality and disability. Effective prehospital assessment and treatment by emergency medical service (EMS) is considered essential for favourable outcome. The aim of this study was to evaluate the effect of a physician-staffed helicopter emergency medical service (HEMS) in the treatment of TBI patients. METHODS: This was a retrospective cohort study. Prehospital data from two periods were collected: before (EMS group) and after (HEMS group) the implementation of a physician-staffed HEMS. Unconscious prehospital patients due to severe TBI were included in the study. Unconsciousness was defined as a Glasgow coma scale (GCS) score <= 8 and was documented either on-scene, during transportation or by an on-call neurosurgeon on hospital admission. Modified Glasgow Outcome Score (GOS) was used for assessment of six-month neurological outcome and good neurological outcome was defined as GOS 4-5. RESULTS: Data from 181 patients in the EMS group and 85 patients in the HEMS group were available for neurological outcome analyses. The baseline characteristics and the first recorded vital signs of the two cohorts were similar. Good neurological outcome was more frequent in the HEMS group; 42% of the HEMS managed patients and 28% (p = 0.022) of the EMS managed patients had a good neurological recovery. The airway was more frequently secured in the HEMS group (p < 0.001). On arrival at the emergency department, the patients in the HEMS group were less often hypoxic (p = 0.024). In univariate analysis HEMS period, lower age and secured airway were associated with good neurological outcome. CONCLUSION: The introduction of a physician-staffed HEMS unit resulted in decreased incidence of prehospital hypoxia and increased the number of secured airways. This may have contributed to the observed improved neurological outcome during the HEMS period. TRIAL REGISTRATION: ClinicalTrials.gov IDNCT02659046. Registered January 15th, 2016. PMID- 28915899 TI - Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer. AB - BACKGROUND: Genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1-4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. METHODS: We performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. RESULTS: We did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). CONCLUSIONS: Our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts. PMID- 28915900 TI - A randomized phase II study to assess the effect of adjuvant immunotherapy using alpha-GalCer-pulsed dendritic cells in the patients with completely resected stage II-IIIA non-small cell lung cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: As the toxicity associated with the alpha-GalCer-pulsed dendritic cell (DC) therapy could be considered to be negligible, its addition to postoperative adjuvant chemotherapy would be expected to greatly improve the therapeutic effect, and could result in prolonged survival. The aim of the present study is to compare the therapeutic efficacy of alpha-galactosylceramide pulsed DC therapy in patients who have undergone a complete resection of stage II IIIA non-small-cell lung cancer (NSCLC) followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to that in patients who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only). METHODS: Subsequent to the complete resection of NSCLC, followed by the administration of cisplatin plus vinorelbine dual-agent combination adjuvant chemotherapy, patients who satisfy the inclusion criteria will be randomly allocated to either the alpha-GalCer-pulsed DC immune therapy group, or the standard treatment group. In total, 56 patients will be included in the study. The primary endpoint is recurrence-free survival, and the secondary endpoints are natural killer T-cell-specific immune response, the frequency of toxic effects and safety, and overall survival. DISCUSSION: In order to determine the efficacy of alpha-GalCer-pulsed DC therapy, the present study compares patients with stage II-III NSCLC who underwent complete surgical resection followed by postoperative adjuvant therapy with cisplatin plus vinorelbine, to those who did not receive additional treatment (surgical resection plus postoperative adjuvant chemotherapy only). TRIAL REGISTRATION: UMIN000010386 ( R000012145 ). Registered on 1 April 2013. UMIN-CTR is officially recognized as a registration site which satisfies ICMJE criteria. PMID- 28915902 TI - Development and clinical application of radiomics in lung cancer. AB - Since the discovery of X-rays at the end of the 19th century, medical imageology has progressed for 100 years, and medical imaging has become an important auxiliary tool for clinical diagnosis. With the launch of the human genome project (HGP) and the development of various high-throughput detection techniques, disease exploration in the post-genome era has extended beyond investigations of structural changes to in-depth analyses of molecular abnormalities in tissues, organs and cells, on the basis of gene expression and epigenetics. These techniques have given rise to genomics, proteomics, metabolomics and other systems biology subspecialties, including radiogenomics. Radiogenomics is an important revolution in the traditional visually identifiable imaging technology and constitutes a new branch, radiomics. Radiomics is aimed at extracting quantitative imaging features automatically and developing models to predict lesion phenotypes in a non-invasive manner. Here, we summarize the advent and development of radiomics, the basic process and challenges in clinical practice, with a focus on applications in pulmonary nodule evaluations, including diagnostics, pathological and molecular classifications, treatment response assessments and prognostic predictions, especially in radiotherapy. PMID- 28915901 TI - Possible effects of an early diagnosis and treatment in patients with growth hormone deficiency: the state of art. AB - Growth hormone deficiency (GHD) is a relatively uncommon and heterogeneous endocrine disorder presenting in childhood with short stature. However, during the neonatal period, the metabolic effects of GHD may to require prompt replacement therapy to avoid possible life-threatening complications. An increasing amount of data suggests the importance of an early diagnosis and treatment of GHD because of its auxological, metabolic, and neurodevelopmental features with respect to the patients diagnosed and treated later in life.The available results show favourable auxological outcomes for patients with GHD diagnosed and treated with r-hGH early in life compared with those from patients with GHD who do not receive this early diagnosis and treatment. Because delayed referral for GHD diagnosis and treatment is still frequent, these results highlight the need for more attention in the diagnosis and treatment of GHD.Despite these very encouraging data regarding metabolic and neurodevelopmental features, further studies are needed to better characterize these findings. Overall, the importance of early diagnosis and treatment of GHD needs to be addressed. PMID- 28915903 TI - A quantitative assessment of the evolution of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG). AB - BACKGROUND: We aim to delineate the progression of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG) using the International Cooperative Ataxia Rating Scale (ICARS). We sought correlation between cerebellar volumetry and clinical situation. We prospectively evaluated PMM2-CDG patients aged from 5 to 18 years through ICARS at two different time points set apart by at least 20 months. We reviewed available MRIs and performed volumetric analysis when it was possible. RESULTS: From the eligible 24, four patients were excluded due to severe mental disability (n = 2) and supratentorial lesions (n = 2). Two different ICARS evaluations separated by more than 20 months were available for 14 patients showing an improvement in the cerebellar syndrome: ICARS1: 35.71 versus ICARS2: 30.07 (p < 0.001). When we considered time, we saw an improvement of 2.64 points in the ICARS per year with an SD of 1.97 points (p < 0.001). The ICARS subscales results improved with time, reaching statistical significance in "Posture and gait" (p < 0.001), "Kinetic functions" (p = 0.04) and "Speech abnormalities" (p = 0.045). We found a negative correlation between the ICARS results and total cerebellar volume (r = -0.9, p = 0.037) in a group of five patients with available volumetric study, meaning that the higher the ICARS score, the more severe was the cerebellar atrophy. CONCLUSIONS: Our study shows a stabilization or mild improvement in the cerebellar functions of paediatric PMM2 CDG patients despite cerebellar volume loss. ICARS is a valid scale to quantify the evolution of cerebellar syndrome in PMM2-CDG patients. The availability of ICARS and other reliable and sensitive follow-up tools may prove essential for the evaluation of potential therapies. PMID- 28915905 TI - Accounting for single center effects in systematic reviews cannot be overlooked. PMID- 28915904 TI - TIGA-CUB - manualised psychoanalytic child psychotherapy versus treatment as usual for children aged 5-11 years with treatment-resistant conduct disorders and their primary carers: study protocol for a randomised controlled feasibility trial. AB - BACKGROUND: The National Institute for Health and Care Excellence (NICE) recommends evidence-based parenting programmes as a first-line intervention for conduct disorders (CD) in children aged 5-11 years. As these are not effective in 25-33% of cases, NICE has requested research into second-line interventions. Child and Adolescent Psychotherapists (CAPTs) address highly complex problems where first-line treatments have failed and there have been small-scale studies of Psychoanalytic Child Psychotherapy (PCP) for CD. A feasibility trial is needed to determine whether a confirmatory trial of manualised PCP (mPCP) versus Treatment as Usual (TaU) for CD is practicable or needs refinement. The aim of this paper is to publish the abridged protocol of this feasibility trial. METHODS AND DESIGN: TIGA-CUB (Trial on improving Inter-Generational Attachment for Children Undergoing Behaviour problems) is a two-arm, pragmatic, parallel-group, multicentre, individually randomised (1:1) controlled feasibility trial (target n = 60) with blinded outcome assessment (at 4 and 8 months), which aims to develop an optimum practicable protocol for a confirmatory, pragmatic, randomised controlled trial (RCT) (primary outcome: child's behaviour; secondary outcomes: parental reflective functioning and mental health, child and parent quality of life), comparing mPCP and TaU as second-line treatments for children aged 5-11 years with treatment-resistant CD and inter-generational attachment difficulties, and for their primary carers. Child-primary carer dyads will be recruited following a referral to, or re-referral within, National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) after an unsuccessful first line parenting intervention. PCP will be delivered by qualified CAPTs working in routine NHS clinical practice, using a trial-specific PCP manual (a brief version of established PCP clinical practice). Outcomes are: (1) feasibility of recruitment methods, (2) uptake and follow-up rates, (3) therapeutic delivery, treatment retention and attendance, intervention adherence rates, (4) follow-up data collection, and (5) statistical, health economics, process evaluation, and qualitative outcomes. DISCUSSION: TIGA-CUB will provide important information on the feasibility and potential challenges of undertaking a confirmatory RCT to evaluate the effectiveness and cost-effectiveness of mPCP. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN86725795 . Registered on 31 May 2016. PMID- 28915906 TI - Unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report. AB - BACKGROUND: We describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity. CASE PRESENTATION: A 59-year-old white man was diagnosed with metastatic wild type adenocarcinoma of the upper lobe of his right lung. After a first cycle of cisplatin and pemetrexed, he had unusually prolonged aplasia and acute kidney injury. The prolonged aplasia was caused by pemetrexed reabsorption by the ileal mucosa of the neobladder as pemetrexed was eliminated renally in an active form and is partly lipophilic. CONCLUSIONS: Pemetrexed may be reabsorbed by the ileal mucosa of the neobladder because of its hydrophobic structure and renal excretion in its active form. Acute urinary retention may maintain this phenomenon. Published data excluded a potential role for cisplatin in this toxicity; furthermore, we could not assess pemetrexed concentrations in the blood or urine as these assay techniques are not validated. Thus, care is needed when giving chemotherapy to patients with a neobladder. PMID- 28915907 TI - Effect of a mother's recorded voice on emergence from general anesthesia in pediatric patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Emergence delirium is a behavioral disturbance after general anesthesia in children and may distress both the patients and the primary caregivers, such as parents and medical staff, looking after the patients. Various medical and emotional interventions have been investigated to reduce emergence delirium; however, none are completely effective. This trial intends to assess whether the mother's recorded voice can reduce this adverse post anesthesia event and facilitate arousal from general anesthesia. METHODS/DESIGN: This is a prospective, double-blind, single-center, parallel-arm, superiority, randomized controlled trial to be conducted in participants aged 2-8 years who are undergoing elective surgery requiring general anesthesia. Participants will be randomly assigned to one of two groups: those who are stimulated to wake up by listening to their mother's recorded voice (maternal group, n = 33) or a stranger's voice (stranger group, n = 33) during anesthetic emergence. The primary outcome is the initial emergence delirium score in the post-anesthesia care unit (PACU). The secondary outcomes are hemodynamic parameters, including heart rate and mean blood pressure, the duration of time between the cessation of anesthetics and a BIS level of 60, 70 and 80, eye-opening or purposeful movement time, extubation time, total consumption of analgesics, PACU stay time, emergence delirium and pain scores during the PACU stay. DISCUSSION: This is the first randomized controlled trial to investigate the effect of a mother's recorded voice during emergence on the pediatric emergence profile after general anesthesia. It may provide prophylactic treatment options to decrease emergence delirium and enhance arousal from general anesthesia. TRIAL REGISTRATION: ClicnicalTrials.gov, ID: NCT02955680 . Registered on 2 November 2016. PMID- 28915909 TI - Differential signal sensitivities can contribute to the stability of multispecies bacterial communities. AB - BACKGROUND: Bacterial species present in multispecies microbial communities often react to the same chemical signal but at vastly different concentrations. The existence of different response thresholds with respect to the same signal molecule has been well documented in quorum sensing which is one of the best studied inter-cellular signalling mechanisms in bacteria. The biological significance of this phenomenon is still poorly understood, and cannot be easily studied in nature or in laboratory models. The aim of this study is to establish the role of differential signal response thresholds in stabilizing microbial communities. RESULTS: We tested binary competition scenarios using an agent-based model in which competing bacteria had different response levels with respect to signals, cooperation factors or both, respectively. While in previous scenarios fitter species outcompete slower growing competitors, we found that stable equilibria could form if the fitter species responded to a higher chemical concentration level than the slower growing competitor. We also found that species secreting antibiotic could form a stable community with other competing species if antibiotic production started at higher response thresholds. CONCLUSIONS: Microbial communities in nature rely on the stable coexistence of species that necessarily differ in their fitness. We found that differential response thresholds provide a simple and elegant way for keeping slower growing species within the community. High response thresholds can be considered as self restraint of the fitter species that allows metabolically useful but slower growing species to remain within a community, and thereby the metabolic repertoire of the community will be maintained. REVIEWERS: This article was reviewed by Michael Gromiha, Sebastian Maurer-Stroh, Istvan Simon and L. Aravind. PMID- 28915908 TI - Advances in paediatrics in 2016: current practices and challenges in allergy, autoimmune diseases, cardiology, endocrinology, gastroenterology, infectious diseases, neonatology, nephrology, neurology, nutrition, pulmonology. AB - This review reports main progresses in various pediatric issues published in Italian Journal of Pediatrics and in international journals in 2016. New insights in clinical features or complications of several disorders may be useful for our better understanding. They comprise severe asthma, changing features of lupus erythematosus from birth to adolescence, celiac disease, functional gastrointestinal disorders, Moebius syndrome, recurrent pneumonia. Risk factors for congenital heart defects, Kawasaki disease have been widely investigated. New diagnostic tools are available for ascertaining brucellosis, celiac disease and viral infections. The usefulness of aCGH as first-tier test is confirmed in patients with neurodevelopmental disorders. Novel information have been provided on the safety of milk for infants. Recent advances in the treatment of common disorders, including neonatal respiratory distress syndrome, hypo-glycemia in newborns, atopic dermatitis, constipation, cyclic vomiting syndrome, nephrotic syndrome, diabetes mellitus, regurgitation, short stature, secretions in children with cerebral palsy have been reported. Antipyretics treatment has been updated by national guidelines and studies have excluded side effects (e.g. asthma risk during acetaminophen therapy). Vaccinations are a painful event and several options are reported to prevent this pain. Adverse effects due to metabolic abnormalities are reported for second generation antipsychotic drugs. PMID- 28915910 TI - Colonization of the bovine uterus by Candida kefyr. AB - BACKGROUND: While fungal infections of the bovine uterus are well-known diseases in pregnant cattle, very limited knowledge exists on the presence and significance of fungi in the uterus of non-pregnant cows. Presence of fungi in the uterine lumen of postpartum (pp) cows has been reported, but little attention has been paid to this as most studies of the bovine pp uterus have focused on bacteria. CASE PRESENTATION: Microscopy of uterine lavage cytology slides of three cows from one herd revealed the presence of numerous yeast-like organisms, which were located either free in the fluid or within macrophages. Two of the cows were around 30 days pp, while the third was 7 months pp. None of the cows had been treated with antibiotics. Culturing of the flush samples was unsuccessful, but Sanger sequencing of DNA extracted from an endometrial biopsy of one of the cows revealed the presence of Candida kefyr (Kluyveromyces marxianus). Fluorescence in situ hybridization examination of endometrial tissue sections of two cows using probes targeting 18S rRNA of the K. marxianus group was performed and revealed the presence of yeast cells on the endometrium. Histology was performed and demonstrated hyphal and non-hyphal yeast-like organisms on the surface of endometrium and in the crypts. Tissue invasion was restricted to the superficial part of the epithelium and although endometrial inflammation was present, this was mild and considered as not being caused by the fungi. One of the cows became pregnant and delivered a normal calf at term, while the two others were not bred. CONCLUSIONS: Candida kefyr is commonly isolated from milk of cows with mastitis, but has not been reported in association with other diseases of cattle. The infection was present as a monoculture in all three cows, but the fungi had only colonized the uterine lumen and the endometrial surface. Only a mild non-suppurative endometrial inflammation was present, but within the uterine luminal content, many macrophages having phagocytized yeast cells were present. Re-examination of the cows did not reveal a persistent infection, so the infection probably resolved spontaneously. PMID- 28915911 TI - Timing rather than user traits mediates mood sampling on smartphones. AB - OBJECTIVE: Recent years have seen an increasing number of studies using smartphones to sample participants' mood states. Moods are usually collected by asking participants for their current mood or for a recollection of their mood states over a specific period of time. The current study investigates the reasons to favour collecting mood through current or daily mood surveys and outlines design recommendations for mood sampling using smartphones based on these findings. These recommendations are also relevant to more general smartphone sampling procedures. RESULTS: N=64 participants completed a series of surveys at the beginning and end of the study providing information such as gender, personality, or smartphone addiction score. Through a smartphone application, they reported their current mood 3 times and daily mood once per day for 8 weeks. We found that none of the examined intrinsic individual qualities had an effect on matches of current and daily mood reports. However timing played a significant role: the last followed by the first reported current mood of the day were more likely to match the daily mood. Current mood surveys should be preferred for a higher sampling accuracy, while daily mood surveys are more suitable if compliance is more important. PMID- 28915912 TI - The role of self-control and cognitive functioning in educational inequalities in adolescent smoking and binge drinking. AB - BACKGROUND: Large differences in substance use between educational levels originate at a young age, but there is limited evidence explaining these inequalities. The aim of this study was to test whether a) smoking and binge drinking are associated with lower levels of self-control and cognitive functioning, and b) associations between educational track and smoking and binge drinking, respectively, are attenuated after controlling for self-control and cognitive functioning. METHODS: This study used cross-sectional survey data of 15 to 20-year-olds (N = 191) from low, middle, and high educational tracks. We measured regular binge drinking and regular smoking (more than once a month), cognitive functioning (cognitive ability, reaction time and memory span), and self-control. Logistic regression models were used to assess the associations between educational track and smoking and binge drinking controlled for age, gender and social disadvantage, and for self-control and cognitive functioning. RESULTS: According to models that controlled for age, gender and social disadvantage only, respondents in the low educational track were more likely to drink heavily (OR = 3.25, 95% CI = 1.48-7.17) and smoke (OR = 5.74, 95% CI = 2.31 14.29) than adolescents in the high educational track. The association between educational track and binge drinking was hardly reduced after adjustment for self control and cognitive ability (OR = 2.88, 95% CI = 1.09-7.62). Adjustment for self-control and cognitive functioning, especially cognitive ability, weakened the association between education and smoking (OR = 3.40, 95% CI = 1.11-10.37). However, inequalities in smoking remained significant and substantial. CONCLUSIONS: In this study population, pre-existing variations between adolescents in terms of self-control and cognitive functioning played a minor role in educational inequalities in smoking, but not in binge drinking. PMID- 28915913 TI - Neurological outcomes and duration from cardiac arrest to the initiation of extracorporeal membrane oxygenation in patients with out-of-hospital cardiac arrest: a retrospective study. AB - BACKGROUND: We investigated the relationship between neurological outcomes and duration from cardiac arrest (CA) to the initiation of extracorporeal membrane oxygenation (ECMO) (CA-to-ECMO) in patients with out-of-hospital cardiac arrest (OHCA) treated with extracorporeal cardiopulmonary resuscitation (ECPR) and determined the ideal time at which ECPR should be performed. METHODS: During the time period in which this study was conducted, 3451 patients experienced OHCA. This study finally included 79 patients aged 18 years or older whose OHCA had been witnessed and who underwent ECPR in the emergency room between January 2011 and December 2015. Our primary endpoint was survival to hospital discharge with good neurological outcomes (a cerebral performance category of 1 or 2). RESULTS: Of the 79 patients included, 11 had good neurological outcomes. The median duration from CA-to-ECMO was significantly shorter in the good neurological outcome group (33 min, interquartile range [IQR], 27-50 vs. 46 min, IQR, 42-56: p = 0.03). After controlling for potential confounders, we found that the adjusted odds ratio of CA-to-ECMO time for a good neurological outcome was 0.92 (95% confidence interval: 0.87-0.98, p = 0.007). The area under the receiver operating characteristic curve of CA-to-ECMO for predicting a good neurological outcome was 0.71, and the optimal CA-to-ECMO cutoff time was 40 min. The dynamic probability of survival with good neurological outcomes based on CA-to-ECMO time showed that the survival rate with good neurological outcome decreased abruptly from over 30% to approximately 15% when the CA-to-ECMO time exceeded 40 min. DISCUSSION: In this study, CA-to-ECMO time was significantly shorter among patients with good neurological outcomes, and significantly associated with good neurological outcomes at hospital discharge. In addition, the probability of survival with good neurological outcome decreased when the CA-to-ECMO time exceeded 40 minutes. The indication for ECPR for patients with OHCA should include several factors. However, the duration of CPR before the initiation of ECMO is a key factor and an independent factor for good neurological outcomes in patients with OHCA treated with ECPR. Therefore, the upper limit of CA-to-ECMO time should be inevitably included in the indication for ECPR for patients with OHCA. In the present study, there was a large difference in the rate of survival to hospital discharge with good neurological outcome between the patients with a CA-to-ECMO time within 40 minutes and those whose time was over 40 minutes. Based on the present study, the time limit of the duration of CPR before the initiation of ECMO might be around 40 minutes. We should consider ECPR in patients with OHCA if they are relatively young, have a witness and no terminal disease, and the initiation of ECMO is presumed to be within this time period. CONCLUSIONS: The duration from CA-to-ECMO was significantly associated with good neurological outcomes. The indication for patients with OHCA should include a criterion for the ideal time to initiate ECPR. PMID- 28915914 TI - Paradoxical tunnel enlargement after ACL reconstruction with hamstring autografts when using beta-TCP containing interference screws for tibial aperture fixation- prospectively comparative study. AB - BACKGROUND: Tibial aperture fixation with a bioabsorbable interference screw is a popular fixation method in anterior cruciate ligament reconstruction (ACLR). An interference screw containing beta-tricalcium phosphate (beta-TCP) to improve bony integration and biocompatibility was recently introduced. This study aims to compare the clinical outcomes and radiological results of tunnel enlargement effect between the 2 bioabsorbable fixative devices of pure poly-L-lactic acid (PLLA) interference screws and beta-TCP-containing screws, for tibial interference fixation in ACLR using hamstring autografts. METHODS: Eighty consecutive patients who had undergone double-bundle ACLR between 2011 to 2012 were prospectively reviewed and randomly divided into two groups based on the type of tibial interference screw: 28 were assigned to the pure PLLA screw group (Group A), while the other 29 were assigned to the beta-TCP-containing screw fixation group (Group B). Clinical evaluations and radiological analyses were conducted in both groups with a minimum 2- year follow-up. RESULTS: There was no significant difference in subjective or objective clinical outcome between the 2 groups. In radiological analyses, the use of a beta-TCP-containing screw reduced tunnel widening in the portion of the tunnel with screw engagement compared to the pure PLLA screw, while the use of a beta-TCP-containing screw resulted in greater tunnel enlargement in the proximal portion of the tunnel without screw engagement than use of a pure PLLA screw. CONCLUSION: Use of a beta-TCP containing interference screw in tibial aperture fixation reduced tunnel enlargement in the vicinity of the screw, whereas greater enlargement occurred proximal to the screw end relative to use of a pure PLLA interference screw. These paradoxical enlargements in use of beta-TCP containing screws suggest that for reducing tunnel enlargement, the length of the interference screw should be as fit as possible with tunnel length in terms of using soft grafts. LEVEL OF EVIDENCE: II, Prospectively comparative study. TRIAL REGISTRATION: Retrospectively registered with ClinicalTrials.gov. (NCT02754674) , Date of trial registration: February 10, 2016. PMID- 28915915 TI - Nocturnal heart rate variability in 1-year-old infants analyzed by using the Least Square Cosine Spectrum Method. AB - BACKGROUND: To evaluate the dynamic nature of nocturnal heart rate variability, RR intervals recorded with a wearable heart rate sensor were analyzed using the Least Square Cosine Spectrum Method. METHODS: Six 1-year-old infants participated in the study. A wearable heart rate sensor was placed on their chest to measure RR intervals and 3-axis acceleration. Heartbeat time series were analyzed for every 30 s using the Least Square Cosine Spectrum Method, and an original parameter to quantify the regularity of respiratory-related heart rate rhythm was extracted and referred to as "RA (RA-COSPEC: Respiratory Area obtained by COSPEC)." The RA value is higher when a cosine curve is fitted to the original data series. RESULTS: The time sequential changes of RA showed cyclic changes with significant rhythm during the night. The mean cycle length of RA was 70 +/- 15 min, which is shorter than young adult's cycle in our previous study. At the threshold level of RA greater than 3, the HR was significantly decreased compared with the RA value less than 3. CONCLUSIONS: The regularity of heart rate rhythm showed dynamic changes during the night in 1-year-old infants. Significant decrease of HR at the time of higher RA suggests the increase of parasympathetic activity. We suspect that the higher RA reflects the regular respiratory pattern during the night. This analysis system may be useful for quantitative assessment of regularity and dynamic changes of nocturnal heart rate variability in infants. PMID- 28915916 TI - Effects of a "silent mentor" initiation ceremony and dissection on medical students' humanity and learning. AB - OBJECTIVES: Many medical schools in Taiwan have adopted a dignified "silent mentor" initiation ceremony to strengthen student's medical humanity and increase their learning attitudes. This ceremony consists of introductions of the body donor's conduct and deeds, wreath-laying, and a tea party. However, few empirical studies have examined the influences of the ceremony and dissection on medical humanity. This study explored if the initiation ceremony and the course can help students care more about others, develop more positive attitudes toward death, improve learning effectiveness in the course, and decrease negative emotions the first time they see a cadaver. METHODS: The Attitudes Towards Death and Love and Care subscales of the life attitude inventory, Learning Effectiveness of Gross Anatomy Laboratory Scale (LEGALS), and Emotional Reactions Towards Cadavers Scale were adopted to examine differences before (T1) and after (T2) medical students attended an initiation ceremony at a university in northern Taiwan. Whether these effects lasted to the end of the semester (T3) was also tested. RESULTS: After the ceremony, students' attitudes towards death increased, negative emotions towards cadavers decreased, but love and care and the LEGALS did not significantly change. Data from T3 showed a similar pattern, but high-level emotions (e.g., being respected, cherished, and grateful) and the LEGALS were significantly higher than those at T1. DISCUSSION: The initiation ceremony, which showed a body donor's deeds and attitudes toward life and death when they were alive, could help medical students gain more mature attitudes towards death and decreased negative emotions. Learning between T2 and T3 might have caused significant changes in high-level emotions and the LEGALS at T3. Arranging reflective writing with guided discussion by a teacher before and after the ceremony is highly recommended. PMID- 28915917 TI - Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function. AB - Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ratio, but found no differences between myopathies and controls. All-titin phosphorylation and site specific phosphorylation in the PEVK region were reduced in myopathy, which would be predicted to lower PT. Electron microscopy revealed extensive ultrastructural changes in myofibers of various hereditary myopathies and also suggested massive binding of proteins to the sarcomeric I-band region, presumably heat shock proteins (HSPs), which can translocate to elastic titin under stress conditions. Correlative immunofluorescence and immunoelectron microscopy showed that two small HSPs (HSP27 and alphaB-crystallin) and the ATP-dependent chaperone HSP90 translocated to the titin springs in myopathy. The small HSPs, but not HSP90, were upregulated in myopathic versus control muscles. The titin-binding pattern of chaperones was regularly observed in Duchenne muscular dystrophy (DMD), LGMD2A, MFM-filaminopathy, MFM-myotilinopathy, titinopathy, and inclusion body myopathy due to mutations in valosin-containing protein, but not in acquired sporadic inclusion body myositis. The three HSPs also associated with elastic titin in mouse models of DMD and MFM-filaminopathy. Mechanical measurements on skinned human myofibers incubated with exogenous small HSPs suggested that the elevated PT seen in myopathy is caused, in part, by chaperone-binding to the titin springs. Whereas this interaction may be protective in that it prevents sarcomeric protein aggregation, it also has detrimental effects on sarcomere function. Thus, we identified a novel pathological phenomenon common to many hereditary muscle disorders, which involves sarcomeric alterations. PMID- 28915918 TI - A longitudinal study of serological responses to Coxiella burnetii and shedding at kidding among intensively-managed goats supports early use of vaccines. AB - Vaccination against Coxiella burnetii, the cause of Q fever, is reportedly the only feasible strategy of eradicating infection in ruminant herds. Preventive vaccination of seronegative goats is more effective in reducing shedding of C. burnetii than vaccinating seropositive goats. The age at which goats born on heavily-contaminated farms first seroconvert to C. burnetii has not yet been documented. In a 16-month birth cohort study, the age at which goats seroconverted against C. burnetii was investigated; 95 goats were bled every 2 weeks and tested for antibodies against C. burnetii. Risk factors for seroconversion were explored and goats shedding C. burnetii were identified by testing vaginal swabs taken at the goats' first kidding using a com1 polymerase chain reaction assay. The first surge in the number of goats with IgM to C. burnetii was observed at week 9. Thus, a first vaccination not later than 8 weeks of age to control C. burnetii in highly contaminated environments is indicated. The odds of seroconversion were 2.0 times higher [95% confidence interval (CI) 1.2, 3.5] in kids born by does with serological evidence of recent infection (IgM seropositive) compared to kids born by IgM seronegative does, suggesting either in utero transmission or peri-parturient infection. The rate of seroconversion was 4.5 times higher (95% CI 2.1, 9.8) during than outside the kidding season, highlighting the risk posed by C. burnetii shed during kidding, even to goats outside the kidding herd. Shedding of C. burnetii at kidding was detected in 15 out of 41 goats infected before breeding. PMID- 28915919 TI - Project LifeSkills - a randomized controlled efficacy trial of a culturally tailored, empowerment-based, and group-delivered HIV prevention intervention for young transgender women: study protocol. AB - BACKGROUND: Transgender women in the U.S. have an alarmingly high incidence rate of HIV infection; condomless anal and vaginal sex is the primary risk behavior driving transmission. Young transgender women are the subpopulation at the highest risk for HIV. Despite this, there are no published randomized controlled efficacy trials testing interventions to reduce sexual risk for HIV among this group. This paper describes the design of a group-based intervention trial to reduce sexual risk for HIV acquisition and transmission in young transgender women. METHODS: This study, funded by the National Institutes of Health, is a randomized controlled trial of a culturally-specific, empowerment-based, and group-delivered six-session HIV prevention intervention, Project LifeSkills, among sexually active young transgender women, ages 16-29 years in Boston and Chicago. Participants are randomized (2:2:1) to either the LifeSkills intervention, standard of care only, or a diet and nutrition time- and attention matched control. At enrollment, all participants receive standardized HIV pre- and post-test counseling and screening for HIV and urogenital gonorrhea and chlamydia infections. The primary outcome is difference in the rate of change in the number of self-reported condomless anal or vaginal sex acts during the prior 4-months, assessed at baseline, 4-, 8-, and 12-month follow-up visits. DISCUSSION: Behavioral interventions to reduce sexual risk for HIV acquisition and transmission are sorely needed for young transgender women. This study will provide evidence to determine feasibility and efficacy in one of the first rigorously designed trials for this population. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01575938 , registered March 29, 2012. PMID- 28915920 TI - Current situation of H9N2 subtype avian influenza in China. AB - In China, H9N2 subtype avian influenza outbreak is firstly reported in Guangdong province in 1992. Subsequently, the disease spreads into vast majority regions nationwide and has currently become endemic there. Over vicennial genetic evolution, the viral pathogenicity and transmissibility have showed an increasing trend as year goes by, posing serious threat to poultry industry. In addition, H9N2 has demonstrated significance to public health as it could not only directly infect mankind, but also donate partial or even whole cassette of internal genes to generate novel human-lethal reassortants like H5N1, H7N9, H10N8 and H5N6 viruses. In this review, we mainly focused on the epidemiological dynamics, biological characteristics, molecular phylogeny and vaccine strategy of H9N2 subtype avian influenza virus in China to present an overview of the situation of H9N2 in China. PMID- 28915921 TI - Total intravenous anaesthesia in a goat undergoing craniectomy. AB - BACKGROUND: Cerebral coenurosis is a disease of the central nervous system in sheep and goats, and is usually fatal unless surgical relief is provided. Information regarding neuroanaesthesia in veterinary medicine in goats is scant. CASE PRESENTATION: We describe anaesthetic management of an intact female goat (2 years; 16 kg) presented for craniectomy. The goat was sedated with xylazine (0.05 mg kg-1, i.m.) and morphine (0.05 mg kg-1, i.m.). General anaesthesia was induced 20 min later with propofol and maintained with a constant rate infusion of propofol (0.2 mg kg-1 min-1). A cuffed endotracheal tube was placed and connected to a rebreathing (circle) system and mechanical ventilation with 100% oxygen was initiated. A bolus of lidocaine (1 mg kg-1), midazolam (0.25 mg kg-1) and fentanyl 2.5 MUg kg-1 was delivered via the intravenous route followed immediately by a constant rate infusion of lidocaine (50 MUg kg-1 min-1), midazolam (0.15 mg kg-1 h-1) and fentanyl (6 MUg kg-1 h-1) administered via the intravenous route throughout surgery. Craniectomy was undertaken and the goat recovered uneventfully. CONCLUSION: Total intravenous anaesthesia with propofol, lidocaine, fentanyl and midazolam could be an acceptable option for anaesthesia during intracranial surgery in goats. PMID- 28915922 TI - Recent urbanization in China is correlated with a Westernized microbiome encoding increased virulence and antibiotic resistance genes. AB - BACKGROUND: Urbanization is associated with an increased risk for a number of diseases, including obesity, diabetes, and cancer, which all also show associations with the microbiome. While microbial community composition has been shown to vary across continents and in traditional versus Westernized societies, few studies have examined urban-rural differences in neighboring communities within a single country undergoing rapid urbanization. In this study, we compared the gut microbiome, plasma metabolome, dietary habits, and health biomarkers of rural and urban people from a single Chinese province. RESULTS: We identified significant differences in the microbiota and microbiota-related plasma metabolites in rural versus recently urban subjects from the Hunan province of China. Microbes with higher relative abundance in Chinese urban samples have been associated with disease in other studies and were substantially more prevalent in the Human Microbiome Project cohort of American subjects. Furthermore, using whole metagenome sequencing, we found that urbanization was associated with a loss of microbial diversity and changes in the relative abundances of Viruses, Archaea, and Bacteria. Gene diversity, however, increased with urbanization, along with the proportion of reads associated with antibiotic resistance and virulence, which were strongly correlated with the presence of Escherichia and Shigella. CONCLUSIONS: Our data suggest that urbanization has produced convergent evolution of the gut microbial composition in American and urban Chinese populations, resulting in similar compositional patterns of abundant microbes through similar lifestyles on different continents, including a loss of potentially beneficial bacteria and an increase in potentially harmful genes via increased relative abundance of Escherichia and Shigella. PMID- 28915923 TI - Season, but not symbiont state, drives microbiome structure in the temperate coral Astrangia poculata. AB - BACKGROUND: Understanding the associations among corals, their photosynthetic zooxanthella symbionts (Symbiodinium), and coral-associated prokaryotic microbiomes is critical for predicting the fidelity and strength of coral symbioses in the face of growing environmental threats. Most coral-microbiome associations are beneficial, yet the mechanisms that determine the composition of the coral microbiome remain largely unknown. Here, we characterized microbiome diversity in the temperate, facultatively symbiotic coral Astrangia poculata at four seasonal time points near the northernmost limit of the species range. The facultative nature of this system allowed us to test seasonal influence and symbiotic state (Symbiodinium density in the coral) on microbiome community composition. RESULTS: Change in season had a strong effect on A. poculata microbiome composition. The seasonal shift was greatest upon the winter to spring transition, during which time A. poculata microbiome composition became more similar among host individuals. Within each of the four seasons, microbiome composition differed significantly from that of surrounding seawater but was surprisingly uniform between symbiotic and aposymbiotic corals, even in summer, when differences in Symbiodinium density between brown and white colonies are the highest, indicating that the observed seasonal shifts are not likely due to fluctuations in Symbiodinium density. CONCLUSIONS: Our results suggest that symbiotic state may not be a primary driver of coral microbial community organization in A. poculata, which is a surprise given the long-held assumption that excess photosynthate is of importance to coral-associated microbes. Rather, other environmental or host factors, in this case, seasonal changes in host physiology associated with winter quiescence, may drive microbiome diversity. Additional studies of A. poculata and other facultatively symbiotic corals will provide important comparisons to studies of reef-building tropical corals and therefore help to identify basic principles of coral microbiome assembly, as well as functional relationships among holobiont members. PMID- 28915924 TI - PDL1 And LDHA act as ceRNAs in triple negative breast cancer by regulating miR 34a. AB - BACKGROUD: The purpose of this study was to elucidate the regulation of programmed death ligand 1 (PDL1), lactate dehydrogenase A (LDHA) and miR-34a in triple negative breast cancer (TNBC) and to explore the function and mechanism of PDL1 and LDHA as competitive endogenous RNAs (ceRNAs) in TNBC via regulation of miR-34a. METHODS: Western blotting, quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) assays were conducted to explore the expression of PDL1, LDHA and miR-34a in TNBC and correlations between them. MTS cell viability, Transwell migration, glucose consumption and lactate production assays and flow cytometry were performed and mouse xenograft models were constructed to explore the functions and regulation of the PDL1 3'UTR and LDHA 3'UTR and miR-34a in TNBC. RESULTS: We found that PDL1 and LDHA were synchronously upregulated in TNBC cell lines and tissues. Co-expression of PDL1 and LDHA was correlated with poor outcome in TNBC. Both PDL1 and LDHA are targets of miR-34a, and the 3'UTRs of PDL1 and LDHA both have binding sites for miR-34a. The functions of PDL1 and LDHA were inhibited by miR-34a. In addition, PDL1 and LDHA acted as ceRNAs to promote the expression and function of each other through regulation of miR-34a in TNBC. CONCLUSIONS: This study provides a new theoretical basis for a novel TNBC therapeutic strategy. Simultaneously targeting PDL1 and LDHA, which would combine immunotherapy and metabolically targeted treatments, might shed some light on the treatment of breast cancer, especially TNBC. PMID- 28915925 TI - Biomechanical analysis of the posterior bony column of the lumbar spine. AB - BACKGROUND: Each part of the rear bone structure can become an anchor point for an attachment device. The objective of this study was to evaluate the stiffness and strength of different parts of the rear lumbar bone structure by axial compression damage experiments. METHODS: Five adult male lumbar bone structures from L2 to L5 were exposed. The superior and inferior articular processes, upper and lower edges of the lamina, and upper and lower edges of the spinous process were observed and isolated and then divided into six groups (n = 10). The specimens were placed between the compaction disc and the load platform in a universal testing machine, which was first preloaded to 5.0 N tension to eliminate water on the surface and then loaded to the specimen curve decline at a constant tension loading rate of 0.01 mm/s, until the specimens had been destroyed. RESULTS: Significant differences in mechanical properties were found among different parts of the rear lumbar bone structure. Compared with other parts, the lower edge of the lamina has good mechanical properties, which have a high modulus of elasticity; the superior and inferior articular processes have greater ultimate strength, which can withstand greater compressive loads; and the mechanical properties of the spinous process are poor, and it is significantly stiffer and weaker than the lamina and articular processes. CONCLUSION: These data can be useful in future spinal biomechanics research leading to better biomechanical compatibility and provide theoretical references for spinal implant materials. PMID- 28915926 TI - Antimicrobial resistance patterns of Staphylococcus species isolated from cats presented at a veterinary academic hospital in South Africa. AB - BACKGROUND: Antimicrobial resistance is becoming increasingly important in both human and veterinary medicine. This study investigated the proportion of antimicrobial resistant samples and resistance patterns of Staphylococcus isolates from cats presented at a veterinary teaching hospital in South Africa. Records of 216 samples from cats that were submitted to the bacteriology laboratory of the University of Pretoria academic veterinary hospital between 2007 and 2012 were evaluated. Isolates were subjected to antimicrobial susceptibility testing against a panel of 15 drugs using the disc diffusion method. Chi square and Fisher's exact tests were used to assess simple associations between antimicrobial resistance and age group, sex, breed and specimen type. Additionally, associations between Staphylococcus infection and age group, breed, sex and specimen type were assessed using logistic regression. RESULTS: Staphylococcus spp. isolates were identified in 17.6% (38/216) of the samples submitted and 4.6% (10/216) of these were unspeciated. The majority (61.1%,11/18) of the isolates were from skin samples, followed by otitis media (34.5%, 10/29). Coagulase Positive Staphylococcus (CoPS) comprised 11.1% (24/216) of the samples of which 7.9% (17/216) were S. intermedius group and 3.2% (7/216) were S. aureus. Among the Coagulase Negative Staphylococcus (CoNS) (1.9%, 4/216), S. felis and S. simulans each constituted 0.9% (2/216). There was a significant association between Staphylococcus spp. infection and specimen type with odds of infection being higher for ear canal and skin compared to urine specimens. There were higher proportions of samples resistant to clindamycin 34.2% (13/25), ampicillin 32.4% (2/26), lincospectin 31.6% (12/26) and penicillin-G 29.0% (11/27). Sixty three percent (24/38) of Staphylococcus spp. were resistant to one antimicrobial agent and 15.8% were multidrug resistant (MDR). MDR was more common among S. aureus 28.6% (2/7) than S. intermedius group isolates 11.8% (2/17). One S. intermedius group isolate was resistant to all beta-lactam antimicrobial agents tested. CONCLUSION: S. intermedius group was the most common cause of skin infections and antimicrobial resistance was not wide spread among cats presented at the veterinary academic hospital in South Africa. However, the presence of MDR Staphylococcus spp. and isolates resistant to all beta-lactams is of both public health and animal health concern. PMID- 28915927 TI - A decade of research into classical swine fever marker vaccine CP7_E2alf (Suvaxyn(r) CSF Marker): a review of vaccine properties. AB - Due to its impact on animal health and pig industry, classical swine fever (CSF) is still one of the most important viral diseases of pigs. To control the disease, safe and highly efficacious live attenuated vaccines exist for decades. However, until recently, the available live vaccines did not allow a serological marker concept that is essentially important to circumvent long-term trade restrictions. In 2014, a new live attenuated marker vaccine, Suvaxyn(r) CSF Marker (Zoetis), was licensed by the European Medicines Agency. This vaccine is based on pestivirus chimera "CP7_E2alf" that carries the main immunogen of CSF virus "Alfort/187", glycoprotein E2, in a bovine viral diarrhea virus type 1 backbone ("CP7"). This review summarizes the available data on design, safety, efficacy, marker diagnostics, and its possible integration into control strategies. PMID- 28915928 TI - Comparison of arthroplasty vs. osteosynthesis for displaced femoral neck fractures: a meta-analysis. AB - BACKGROUND: This meta-analysis compared clinical outcomes of arthroplasty vs. osteosynthesis for displaced femoral neck fractures. METHODS: Meta-analysis was performed on the difference in revision rate and overall mortality between participants undergoing osteosynthesis vs. total hip arthroplasty (THA), osteosynthesis vs. hemiarthroplasty (HA), or THA vs. HA. RESULTS: Pooled direct and indirect results indicated no significant difference in mortality between THA and HA (pooled OR = 0.87, 95% CI 0.55 to 1.38; P = 0.556), between THA and osteosynthesis (pooled OR = 1.17, 95% CI 0.69 to 1.99; P = 0.553), and between HA and osteosynthesis (pooled OR = 1.21, 95% CI 0.84 to 1.74; P = 0.304). Pooled direct and indirect results indicated no significant difference in revision rates between THA and HA (pooled OR = 0.90, 95% CI 0.26 to 3.19; P = 0.874). But, fewer revisions (OR = 0.19, 95% CI 0.10 to 0.34; P = 0.000) were seen in patients treated with THA than osteosynthesis and also in those treated with HA than osteosynthesis (OR = 0.12, 95% CI 0.07 to 0.20; P = 0.000). After excluding studies without showing normal cognition in inclusion criteria, pooled direct and indirect results also indicated no significant difference in mortality between THA, HA, and osteosynthesis. Similarly, there was no significant difference in revision rates between THA and HA, but HA and THA had significantly lower revision rates compared with osteosynthesis. CONCLUSIONS: There was no significant difference in overall mortality among osteosynthesis, HA, and THA. However, HA and THA had significantly lower revision rates compared with osteosynthesis. Results of the present study provide support for the use of hip arthroplasty to treat displaced fractures of the femoral neck. PMID- 28915929 TI - The combination of stem cells and tissue engineering: an advanced strategy for blood vessels regeneration and vascular disease treatment. AB - Over the past years, vascular diseases have continued to threaten human health and increase financial burdens worldwide. Transplantation of allogeneic and autologous blood vessels is the most convenient treatment. However, it could not be applied generally due to the scarcity of donors and the patient's condition. Developments in tissue engineering are contributing greatly with regard to this urgent need for blood vessels. Tissue engineering-derived blood vessels are promising alternatives for patients with aortic dissection/aneurysm. The aim of this review is to show the importance of advances in biomaterials development for the treatment of vascular disease. We also provide a comprehensive overview of the current status of tissue reconstruction from stem cells and transplantable cellular scaffold constructs, focusing on the combination of stem cells and tissue engineering for blood vessel regeneration and vascular disease treatment. PMID- 28915930 TI - Predicting activities of daily living for cancer patients using an ontology guided machine learning methodology. AB - BACKGROUND: Bio-ontologies are becoming increasingly important in knowledge representation and in the machine learning (ML) fields. This paper presents a ML approach that incorporates bio-ontologies and its application to the SEER-MHOS dataset to discover patterns of patient characteristics that impact the ability to perform activities of daily living (ADLs). Bio-ontologies are used to provide computable knowledge for ML methods to "understand" biomedical data. RESULTS: This retrospective study included 723 cancer patients from the SEER-MHOS dataset. Two ML methods were applied to create predictive models for ADL disabilities for the first year after a patient's cancer diagnosis. The first method is a standard rule learning algorithm; the second is that same algorithm additionally equipped with methods for reasoning with ontologies. The models showed that a patient's race, ethnicity, smoking preference, treatment plan and tumor characteristics including histology, staging, cancer site, and morphology were predictors for ADL performance levels one year after cancer diagnosis. The ontology-guided ML method was more accurate at predicting ADL performance levels (P < 0.1) than methods without ontologies. CONCLUSIONS: This study demonstrated that bio-ontologies can be harnessed to provide medical knowledge for ML algorithms. The presented method demonstrates that encoding specific types of hierarchical relationships to guide rule learning is possible, and can be extended to other types of semantic relationships present in biomedical ontologies. The ontology-guided ML method achieved better performance than the method without ontologies. The presented method can also be used to promote the effectiveness and efficiency of ML in healthcare, in which use of background knowledge and consistency with existing clinical expertise is critical. PMID- 28915931 TI - Nutrient Removal from Wastewater Using Microalgae: A Kinetic Evaluation and Lipid Analysis. AB - The objective of this study was to examine the performance of mixed microalgal bioreactors in treating three different types of wastewaters-kitchen wastewater (KWW), palm oil mill effluent (POME), and pharmaceutical wastewater (PWW) in semi continuous mode and to analyze the lipid content in the harvested algal biomass. The reactors were monitored for total nitrogen and phosphate removal at eight solid retention times (SRTs): 2, 4, 6, 8, 10, 12, 14, and 16 days. The nutrient uptake kinetic parameters were quantified using linearized Michaelis-Menten and Monod models at steady-state conditions. The nutrient removal efficiency and lipid production were found to be higher in KWW when compared with the other wastewaters. Saturated fatty acids (C16:0, C18:0, and C18:1) accounted for more than 60% of the algal fatty acids for all the wastewaters. The lipid is, therefore, considered suitable for synthesizing biodiesel. PMID- 28915932 TI - Evaluation of Meiofauna in the Hyporheic Zone of the Beberibe River, Pernambuco, Brazil. AB - The hyporheic environment is composed of a rich meiofauna that depends on water flow, organic matter, and oxygen. The concentration of meiofauna varies spatially (horizontal and vertical) and temporally. Several processes occur at this interface (groundwater and surface water), including biogeochemical processes involving meiofauna. A study of the hyporheic meiofauna community in the sediments of the Beberibe River, in Brazil, was conducted. Meiofauna attained peak densities of 942.8 organisms/10 cm2, with organisms distributed over six taxa, with 98% of them represented by rotifers, nematodes, and annelids. Density was higher in the dry season with an average of 653.1 organisms/10 cm2, and in more superficial sediments with an average of 739.6 organisms/10 cm2. Greater densities were found in coarser sediment with a higher percentage of organic matter. A river bank filtration (RBF) pilot project has been installed, with good results in the attenuation of contaminants and pathogens. PMID- 28915933 TI - miR-1290 Contributes to Colorectal Cancer Cell Proliferation by Targeting INPP4B. AB - Colorectal cancer (CRC) is one of the most common oncological conditions worldwide, to date. MicroRNA-1290 (miR-1290) has been demonstrated to regulate its progression. We studied the role of miR-1290 in CRC progression. The gene was upregulated in CRC tissues and cells. Its overexpression promoted CRC cell proliferation analyzed by MTT assay, colony formation assay, and soft agar growth assay. In addition, miR-1290 knockdown inhibited CRC cell proliferation. We also found that miR-1290 overexpression reduced the p27 level and increased cyclin D1 at both the mRNA and protein levels, whereas miR-1290 knockdown increased p27 and reduced cyclin D1, confirming miR-1290 promoted CRC cell proliferation. Inositol polyphosphate 4-phosphatase B (INPP4B) was the target of miR-1290. Luciferase reporter assay revealed that miR-1290 directly bound to the 3'-UTR of INPP4B; the mutated seed sites in miR-1290 abrogated this effect. Double knockdown of INPP4B and miR-1290 promoted CRC cell proliferation, suggesting miR-1290 promoted CRC cell proliferation by targeting INPP4B. PMID- 28915935 TI - Secondary ion mass spectrometry: The application in the analysis of atmospheric particulate matter. AB - Currently, considerable attention has been paid to atmospheric particulate matter (PM) investigation due to its importance in human health and global climate change. Surface characterization, single particle analysis and depth profiling of PM is important for a better understanding of its formation processes and predicting its impact on the environment and human being. Secondary ion mass spectrometry (SIMS) is a surface technique with high surface sensitivity, high spatial resolution chemical imaging and unique depth profiling capabilities. Recent research shows that SIMS has great potential in analyzing both surface and bulk chemical information of PM. In this review, we give a brief introduction of SIMS working principle and survey recent applications of SIMS in PM characterization. Particularly, analyses from different types of PM sources by various SIMS techniques were discussed concerning their advantages and limitations. The future development and needs of SIMS in atmospheric aerosol measurement are proposed with a perspective in broader environmental sciences. PMID- 28915934 TI - Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF. AB - Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes-associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in ARPKD/CHF is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Ccnd1 (cyclin D1) and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF. PMID- 28915936 TI - High sensitivity and selectivity in quantitative analysis of drugs in biological samples using 4-column multidimensional micro-UHPLC-MS enabling enhanced sample loading capacity. AB - Sensitivity is often a critical parameter in quantitative bioanalyses in drug development. For liquid-chromatography-based methods, sensitivity can be improved by reducing the column diameter, but practical sensitivity gains are limited by the reduced sample loading capacity on small internal diameter (I.D.) columns. We developed a set-up that has overcome these limitations in sample loading capacity. The set-up uses 4 columns with gradually decreasing column diameters along the flow-path (2.1 -> 1 -> 0.5 -> 0.15 mm). Samples are pre-concentrated on line on a 2.1 mm I.D. trapping column and back flushed to a 1 mm I.D. UHPLC analytical column and separated. The peak(s) of interest are transferred using heartcutting to a second trapping column (0.5 mm I.D.), which is back-flushed to a 0.15 mm I.D. micro-UHPLC analytical column for orthogonal separation. The proof of concept of the set-up was demonstrated by the simultaneous analysis of midazolam and 1'-hydroxy midazolam in plasma by injection of 80 MUL of protein precipitated plasma. The 4-column funnel set-up proved to be robust and resulted in a 10-50 times better sensitivity compared to a trap-elute approach and 250-500 fold better compared to direct micro-UHPLC analysis. A lower limit of quantification of 100 fg/mL in plasma was obtained for both probe compounds. PMID- 28915937 TI - Ultra-high performance supercritical fluid chromatography-mass spectrometry procedure for analysis of monosaccharides from plant gum binders. AB - The ultra-high performance supercritical fluid chromatography-mass spectrometry (UHPSFC/MS) procedure for analysis of native monosaccharides was developed. Chromatographic conditions were investigated to separate a mixture of four hexoses, three pentoses, two deoxyhexoses and two uronic acids. Increasing water content in methanol modifier to 5% and formic acid to 4% improved peak shapes of neutral monosaccharides and allowed complete elution of highly polar uronic acids in a single run. An Acquity HSS C18SB column outperformed other three tested stationary phases (BEH (silica), BEH 2-ethylpyridine, CSH Fluoro-Phenyl) in terms of separation of isomers and analysis time (4.5 min). Limits of detection were in the range 0.01-0.12 ng MUL-1. Owing to separation of anomers, identification of critical pairs (arabinose-xylose and glucose-galactose) was possible. Feasibility of the new method was demonstrated on plant-derived polysaccharide binders. Samples of watercolor paints, painted paper and three plant gums widely encountered in painting media (Arabic, cherry and tragacanth) were decomposed prior the analysis by microwave-assisted hydrolysis at 40 bar initial pressure using 2 mol L-1 trifluoroacetic acid. Among tested temperatures, 120 degrees C ensured appropriate hydrolysis efficiency for different types of gum and avoided excessive degradation of labile monosaccharides. Procedure recovery tested on gum Arabic was 101% with an RSD below 8%. Aqueous hydrolysates containing monosaccharides in different ratios specific to each type of plant gum were diluted or analyzed directly. Filtration of samples before hydrolysis reduced interferences from a paper support and identification of gum Arabic in watercolor painted paper samples was demonstrated. Successful identification of pure gum Arabic was confirmed for sample quantities as little as 1 MUg. Two classification approaches were compared and principal component analysis was superior to analysis based on peak area ratios of monosaccharides. The proposed procedure using UHPSFC/MS represents an interesting alternative which can compete with other chromatographic methods in the field of saccharide analysis in terms of speed, sensitivity and simplicity of workflow. PMID- 28915938 TI - A magnetic field-directed self-assembly solid contact for construction of an all solid-state polymeric membrane Ca2+-selective electrode. AB - A magnetic field-directed self-assembly solid contact has been proposed for developing an all-solid-state polymeric membrane Ca2+-selective electrode. The solid contact is prepared by physically adsorbing magnetic graphene powder on a magnetic gold electrode under the direction of the magnetic field. The proposed method for preparing solid contact avoids using the aqueous solutions and is simple, fast and general as compared to the multilayer drop-casting and electrodeposition methods. The all-solid-state Ca2+-selective electrode based on magnetic graphene as solid contact shows a stable potential response in the linear range of 1.0 * 10-6-1.0 * 10-3 M with a slope of 28.2 mV/decade, and the detection limit is about 4.0 * 10-7 M. Additionally, the magnetic graphene-based electrode shows a comparable potential stability performance to other graphene based all-solid-state ion-selective electrodes, such as reduced undesirable water layer and insensitive to the interferences of O2, CO2 and light. This work provides a favorable way to prepare solid contact for use in the field of all solid-state ion-selective electrodes. PMID- 28915939 TI - Porous organic polymers with different pore structures for sensitive solid-phase microextraction of environmental organic pollutants. AB - Adsorption capacity is the major sensitivity-limited factor in solid-phase microextraction. Due to its light-weight properties, large specific surface area and high porosity, especially tunable pore structures, the utilization of porous organic polymers as solid-phase microextraction adsorbents has attracting researchers' attentions. However, these works mostly concentrated on the utilization of specific porous organic polymers for preparing high-performance solid-phase microextraction coatings. The relationship between pore structures and adsorption performance of the porous organic polymers still remain unclear. Herein, three porous organic polymers with similar properties but different pore distributions were prepared by condensation polymerization reaction of phloroglucinol and terephthalaldehyde, which were fabricated as solid-phase microextraction coatings subsequently. The adsorption capacity of the porous organic polymers-coated fibers were evaluated by using benzene and its derivatives (i.e.,benzene, toluene, ethylbenzene and m-xylene) and polycyclic aromatic hydrocarbons as the target analytes. The results showed that the different adsorption performance of these porous organic polymers was mainly caused by their different pore volumes instead of their surface areas or pore sizes. Finally, the proposed method by using the mesoporous organic polymer coating was successfully applied to the determination of benzene and its derivatives in environmental water samples. As for analytical performance, high pre-concentration factors (74-2984), satisfactory relative recoveries (94.5 +/- 18.5-116.9 +/- 12.5%), intraday precision (2.44-5.34%), inter-day precision (4.62 7.02%), low limit of detections (LODs, 0.10-0.29 ng L-1) and limit of quantifications (LOQs, 0.33-0.96 ng L-1) were achieved under the optimal conditions. This study provides an important idea in the rational design of porous organic polymers for solid-phase microextraction or other adsorption applications. PMID- 28915940 TI - Accurate and reliable quantification of the protein surface coverage on protein functionalized nanoparticles. AB - The ability to accurately quantify the protein coverage on nanoparticles is critical for assessing the quality of the surface chemistry and the success of the functionalization process of protein-nanoparticle conjugates. Surface coverage determination is therefore an integral part in the quality control of protein-modified nanoparticles in industrial nanotechnology. In this work, a novel and conventional method was established for direct quantification of the protein surface coverage on metallic nanoparticles. Different concentrations of pepsin were conjugated to gold nanoparticles (GNPs) by a straightforward adsorptive immobilization process as a model system, and a protein quantitation methodology based on the amino acid analysis of the hydrolysate of the protein GNP conjugates was established. For this purpose, pepsin functionalized GNPs (pepsin-GNP bioconjugates) were processed via in situ hydrolysis with 6N HCl and subsequent derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC reagent). Direct quantitative amino acid analysis was performed based on measuring the intensity of AQC-glycine derivative by high-performance liquid chromatography with fluorescence detection (HPLC-FLD). The method allows for detection of surface coverages as low as 0.1 MUg mL-1 pepsin (corresponding to 2.89 * 10-9 mol L-1) in the colloidal solution. Method imprecision for replicated surface coverage determinations was <5% RSD and accuracies, as determined by % recoveries, were always in the 98-118% range. This method allows precise and accurate quantification of protein coverages, even when less than 1% of the protein in the reaction mixture is immobilized. It was found that the degree of surface coverage of adsorptively bound pepsin on GNPs correlated with the pepsin concentrations in the conjugation reaction mixtures. Washing with phosphate buffer removed weakly bound proteins, i.e. the soft protein corona. The adsorption behavior could be described by a Freundlich isotherm model. This direct and reliable method promises great potential for the accurate quantification of protein coverages of various protein-nanoparticle bioconjugates. PMID- 28915941 TI - Paper spray and Kendrick mass defect analysis of block and random ethylene oxide/propylene oxide copolymers. AB - Paper spray ionization coupled with a high-resolution time-of-flight mass spectrometer was applied to the analysis of 13 block and 2 random ethylene oxide/propylene oxide (EO/PO) copolymers as well as to standard samples of poly(ethylene oxide) and poly(propylene oxide) homopolymers. Paper spray mass spectra could be obtained rapidly and, unlike electrospray ionization, were not subject to contamination and sample carryover. For comparison, polyether samples were also measured on a MALDI/TOF system with ultrahigh mass resolving power. MALDI/high-resolution time-of-flight mass spectrometry exhibited single-charge ions characteristic of the polymer distributions whereas the paper spray mass spectra exhibited charge states ranging from one to six charges. Kendrick mass defect plots of the multiple-charge ions in the paper spray mass spectra exhibit isotopic splitting of the Kendrick mass defects, facilitating visualization of the number of charges in each series. The slope of the KMD plots can be used to estimate the percentage of ethylene oxide in the copolymers. In-source fragmentation permitted the distinction between block and random copolymers. PMID- 28915943 TI - Derivatization enhanced separation and sensitivity of long chain-free fatty acids: Application to asthma using targeted and non-targeted liquid chromatography-mass spectrometry approach. AB - Long chain-free fatty acids (LCFFAs) play pivotal roles in various physiological functions, like inflammation, insulin resistance, hypertension, immune cell behavior and other biological activities. However, the detection is obstructed by the low contents, structural diversity, high structural similarity, and matrix interference. Herein, a fast cholamine-derivatization, within 1 min at room temperature, coupled with liquid chromatography-mass spectrometry (LC-MS) approach was developed to determine LCFFAs in complex samples. After derivatization, the ionization and separation efficiency were significantly improved, which resulted in up to 2000-fold increase of sensitivity compared with non-derivatization method, and the limits of detection were at low femtogram level. As well, this approach was applied successfully in the rapid profiling or quantification of targeted and non-targeted LCFFAs in the sera of healthy human and asthma patients. The targeted metabolomics method showed that the contents of 17 PUFAs were significantly changed in asthma patients, especially hydroxyeicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acid (HPETEs) and prostaglandins (PGs). The non-targeted method resulted in the tentatively identification of 35 LCFFAs including 31 saturated and mono-unsaturated LCFFAs, and 4 bile acids, except for 27 poly-unsaturated fatty acids (PUFAs), and the multivariate analysis indicated that eicosapentaenoic acid (EPA), ursodeoxycholic acid, deoxycholic acid, isodeoxycholic acid, palmitic acid, 2-lauroleic acid and lauric acid also have significant difference between healthy and asthma groups except for 17 PUFAs. To the best of our knowledge, this is the first report on the relationship of asthma with 5(S)-, 15(S)-HPETE, 8(S)-, 11(S)-HETE, 15(S) HEPE, PGA2, PGB2, PGE1, PGF1alpha, PGJ2, and 13, 14-dehydro-15-keto PGF2alpha (DK PGF2alpha). PMID- 28915942 TI - Development of a validated LC- MS/MS method for the quantification of 19 endogenous asthma/COPD potential urinary biomarkers. AB - Obstructive airways inflammatory diseases sometimes show overlapping symptoms that hinder their early and correct diagnosis. Current clinical tests are tedious and are of inadequate specificity in special population such as the elderly and children. Therefore, we are developing tandem mass spectrometric (MS/MS) methods for targeted analysis of urine biomarkers. Recently, proton-nuclear magnetic resonance (1H-NMR) analysis proposed 50 urinary metabolites as potential diagnostic biomarkers among asthma and chronic obstructive pulmonary disease (COPD) patients. Metabolites are divided into 3 groups based on chemical nature. For group 1 (amines and phenols, 19 urinary metabolites), we developed and validated a high performance liquid chromatographic (HPLC)-MS/MS method using differential isotope labeling (DIL) with dansyl chloride. Method development included the optimization of the derivatization reaction, the MS/MS conditions, and the chromatographic separation. Linearity varied from 2 to 4800 ng/mL and the use of 13C2-labeled derivatives allowed for the correction of matrix effects as well as the unambiguous confirmation of the identity of each metabolite in the presence of interfering isomers in urine. Despite the challenges associated with method validation, the method was fully validated as per the food and drug administration (FDA) and the European medicines agency (EMA) recommendations. Validation criteria included linearity, precision, accuracy, dilution integrity, selectivity, carryover, and stability. Challenges in selectivity experiments included the isotopic contributions of the analyte towards its internal standard (IS), that was addressed via the optimization of the IS concentration. In addition, incurred sample analysis was performed to ensure that results from patient samples are accurate and reliable. The method was robust and reproducible and is currently being applied in a cohort of asthma and COPD patient urine samples for biomarker discovery purposes. PMID- 28915944 TI - A novel substrate-inspired fluorescent probe to monitor native albumin in human plasma and living cells. AB - Human albumin (HA) displays crucial roles in maintaining health and fighting diseases. Accurate determination of native HA in plasma or non-plasma samples are of immense significance in both basic research and clinical practice. Herein, a novel ratiometric two-photon fluorescent probe (N-butyl-4-(4-phenyl-benzoyloxy) 1,8-naphthalimide, BPBN) has been designed and developed for highly selective and sensitive sensing the enzymatic activities of HA, on the basis of its unique pseudo-esterase feature. BPBN exhibits excellent selectivity, high sensitivity and good reactivity under physiological conditions. As an enzymatic activity based probe, BPBN can distinguish between native HA and denatured HA, while the currently used dye-binding method cannot. The probe has been successfully applied to measure native HA in plasma samples and the secreted HA in the hepatocyte culture supernatant. BPBN has also been used for two-photon imaging of HA reabsorption in living renal cells, and the results demonstrate that this probe exhibits good cell permeability, low cytotoxicity and high imaging resolution. All these findings suggest that BPBN can be reliably used for the highly selective and sensitive detection of native HA in complex biological samples, as well as for exploring HA-associated biological processes and the physiological functions of native HA in living cells. PMID- 28915945 TI - Potentiometric sensor for non invasive lactate determination in human sweat. AB - The present work describes a non invasive lactate sensing in sweat during workout. The sensing system is based on a non-equilibrium potentiometric measure performed using disposable, chemically modified, screen printed carbon electrodes (SPCEs) that can be wetted with sweat during the exercise. The potentiometric signal, which is proportional to lactate concentration in sweat, is produced by a redox reaction activated by UV radiation, as opposed to the enzymatic reaction employed in traditional, blood-based measuring devices. The sensing system exhibits chemical selectivity toward lactate with linearity from 1 mM up to 180 mM. The dynamic linear range is suitable for measurement of lactate in sweat, which is more than 10 times concentrated than hematic lactate and reaches more than 100 mM in sweat during workout. The noninvasive measure can be repeated many times during exercise and during the recovery time in order to get personal information on the physiological and training status as well as on the physical performance. The device was successfully applied to several human subjects for the measurement of sweat lactate during prolonged cycling exercise. During the exercise sweat was simultaneously sampled on filter paper and extracted in water, and the lactate was determined by HPLC for method validation. The lactate concentration changes during the exercise reflected the intensity of physical effort. This method has perspectives in many sport disciplines as well as in health care and biomedical area. PMID- 28915946 TI - A hydrogen peroxide sensor based on TNM functionalized reduced graphene oxide grafted with highly monodisperse Pd nanoparticles. AB - Addressed herein, we report the synthesis and characterization of a tert-nonyl mercaptan (TNM) functionalized reduced graphene oxide (rGO) supported palladium (Pd) nanoparticles (NPs) (Pd/TNM@rGO) as electrochemical sensor. The highly monodisperse Pd/TNM@rGO nanocomposite was applied for electrochemical determination of hydrogen peroxide (H2O2) at a potential range of -0.6 to +0.8 V. The Pd/TNM@rGO sensor demonstrated very high activity, sensitivity, reusability and durability toward H2O2 sensing. The well dispersed Pd/TNM@rGO nanocomposite has been characterized by using several analytical techniques such as, X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), electron energy loss spectroscopy (EELS) and electrochemical impedance spectroscopy (EIS). The catalytic performance of prepared biosensor was also characterized by using cyclic voltammetry (CV) and chronoamperometry (CA) methods. The proposed H2O2 biosensor showed a broad linear range up to 12 mM, and a very low detection limit of 0.0025 MUM, with a quick response time of less than 10 s. Additionally, the biosensor exhibited great capability, reproducibility and durability for the examination of H2O2. PMID- 28915947 TI - Immunosensor array platforms based on self-assembled dithiols for the electrochemical detection of tetrodotoxins in puffer fish. AB - The recent detection of tetrodotoxins (TTXs) in European fish and shellfish has emphasized the urgent need to develop specific, selective, rapid and easy-to-use methods for their detection to assess the potential risk posed to human health. For this purpose, a dithiol self-assembled monolayer (SAM)-based immunoassay previously performed on maleimide plates (mELISA) has been adapted to gold electrode arrays for the development of an electrochemical immunosensor for TTX. The electrochemical SAM-based immunosensor designed herein, provided an oriented, stable and spaced sensing platform for the determination of TTX, attaining a limit of detection of 2.6 ng mL-1. The applicability of the biosensor array was demonstrated by the accurate quantifications obtained in the analysis of different tissues of several puffer fish species (Lagocephalus lagocephalus, L. sceleratus and Sphoeroides pachygaster) caught along the Mediterranean coast of Spain. The good agreements found between the TTX concentrations determined by the immunosensor array platforms and those determined by mELISA, surface Plasmon resonance (SPR) immunosensor and liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis, proved the feasibility of the approach. The electrochemical immunosensor enables the determination of TTXs at levels as low as 0.07 mg TTX equiv. kg-1 tissue, thus, well below the Japanese value of 2 mg TTX equiv. kg-1 tissue used as a criterion to consider puffer fish safe for consumption. Compared to the colorimetric SAM-based approach, the immunosensor array described herein shows promise towards the development of disposable, portable and compact analysis tools applicable in monitoring programs for the surveillance of fishery products. PMID- 28915948 TI - The Economics of Surgical Simulation. AB - There are massive hidden costs in the current paradigm of surgical training related to increased operative times for procedures with resident involvement and costs of medical errors. Shifting procedural training outside of the operating room through use of simulation has the potential to improve patient safety, minimize learning time to achieve competency, and increase operative efficiency. Investment in surgical simulation has the potential to reduce costs to health care systems through improved operating room efficiency and reduction of medical errors. This article explores the economic costs related to surgical training in otolaryngology and the value of investment in surgical simulation. PMID- 28915949 TI - Assessment of Surgical Skills and Competency. AB - Evaluation of surgical skills and competency are important aspects of the medical education process. Measurable and reproducible methods of assessment with objective feedback are essential components of surgical training. Objective Structured Assessment of Technical Skills (OSATS) is widely used across the medical specialties and otolaryngology-specific tools have been developed and validated for sinus and mastoid surgery. Although assessment of surgical skills can be time-consuming and requires human and financial resources, new evaluation methods and emerging technology may alleviate these barriers while also improving data collection practices. PMID- 28915950 TI - Improving Team Performance Through Simulation-Based Learning. AB - American health care is facing an epidemic of medical errors. A major cause of these errors is poor teamwork. Crisis resource management (CRM) is a set of teamwork principles derived from the airline industry. Medical simulation is an educational tool that affords health care providers a means of improving teamwork by learning and practicing CRM. This article (1) discusses the case for teaching team training, (2) reviews the principles of medical simulation as they pertain to team training, (3) provides practical guidelines for using medical simulation in otolaryngology education, (4) discusses current evidence for the efficacy of medical simulation. PMID- 28915951 TI - Male contraception: Prospects for sound and ultrasound. AB - The worldwide human population growth rate, which doubled during the 20th century, as well as the increasing fertility rate, have contributed to an increasing and evolving emphasis on contraception. With respect to female contraceptive methods, many have been developed, marketed, and are widely available. In contrast, male contraception has been limited to condoms, which pose logistical challenges, and vasectomy, which is largely irreversible. The use of sound to achieve effective and safe male contraception is a promising but unproven hypothesis. Based on the existing and incomplete totality of evidence, we hypothesize that the combination of sound with a modified ultrasonic technique in a single system will provide a practical delivery method that merges all of the appropriate and prescribed frequencies to have spermicidal qualities that may result in effective and safe male contraception. It is also plausible that any experimental male contraceptive method that heats the testicles where they can no longer produce sperm offers the possibility of a favourable benefit to risk ratio. The single system combining sound with a modified ultrasonic technique includes an acoustically suitable pad to assure proper transmission and delivery without concern for injury from the ultrasound frequencies, an amplification and regulation module, a frequency source generator, the complementary heat created along with external and targeted directionality, and various transport methods, such as wired, wireless, or remote. This methodology also offers the ability to move quickly to prototype, achieve multiple patent crossovers, secure and employ commercially available technologies, and provide the opportunity for rapid regulatory approval worldwide. These concepts have been explored in basic research in many animal species as well as humans. To achieve an adequate totality of evidence, the test of this hypothesis requires further basic research in humans to clarify the relevant mechanisms, clinical and observational epidemiologic studies to further explore the hypothesis, and large-scale randomized trials to detect the most plausible magnitude of benefits of this promising but unproven technology. It is plausible that this technology will represent a major breakthrough to combat world population growth. It is also plausible, that, to paraphrase Thomas Huxley, this beautiful hypothesis will be slain by ugly facts. PMID- 28915952 TI - IgA nephropathy during treatment with TNF-alpha blockers: Could it be predicted? AB - Immunoglobulin A (IgA) nephropathy (IgAN) may sometimes be related to exposure to pharmacological agents, among which anti-Tumor Necrosis Factor (TNF)-alpha agents. The characteristic pathological feature is a deposition of IgA-containing immune complexes in vessel walls in the kidney mesangium. The link between TNF alpha blockers and IgAN may be hypothesized examining diseases which share pathologic features. In this respect, idiopathic IgAN and Henoch Schonlein Purpura have been the object of studies revealing a pathogenetic role of aberrant glycosylation of IgA1 molecules. The Authors suggest that anti-drug antibodies against glycan structures of TNF-alpha inhibitors may cross react against serum aberrant IgA1 leading to large antigen-antibody complexes. These large polymeric IgA complexes are then able to deposit in the mesangium and activate the complement cascade. Such hypothesis may be tested by measuring serum levels of galactose-deficient IgA1 of patients developing IgAN following introduction of TNF-alpha blockers. Such a test would be useful also before administration of anti-TNF alpha agents. The presence of aberrant IgA1 may represent a contraindication for treatment with TNF blockers. PMID- 28915953 TI - Syntrophic imbalance and the etiology of bacterial endoparasitism diseases. AB - This article outlines the proposed 'syntrophic imbalance hypothesis' for etiology of bacterial endoparasitism diseases. This hypothesis involves microbes (archaea and bacteria) that exist in human body biofilms in syntrophic associations, where bacteria ferment nutrients to produce short chain fatty acids (SCFAs) that are used by methanogenic archaeons to produce methane. Overgrowth of archaea on human tissues (e.g., in association with intestines, teeth or lungs) results in excessive removal of SCFAs from the biofilms and this triggers bacteria in the free-living biofilm state to convert to the endoparasitic state and become intracellular in host cells where they incite inflammation and disease. The proposed model provides the mechanism to explain dysbiosis etiology of several human diseases, including gingivitis, leaky gut syndrome, Crohn's disease, irritable bowel syndrome, among others. PMID- 28915954 TI - Do some epithelial ovarian cancers originate from a fallopian tube ciliate cell lineage? AB - There is a general agreement that a large subpopulation of serous ovarian cancers arise from the fallopian tube mucosal epithelium. However, there is still some debate as to whether the cancers originate from a secretory or ciliate cell lineage. One well established method for determining the origin of a cell line is to document the expression of genes and proteins that are cell type specific. Lineage or tissue specific patterns of gene expression are evidence of direct decent from a given cell type within a tissue. It has recently been established that the Tumor Protein TAp73 gene (TP73) is expressed in basal epithelial cells that develop into multiciliate cells. TP73 expression is therefore a marker for basal stem cells that are predestined to differentiate into cells with motile cilia and its expression is maintained in fully differentiated multiciliate cells. Interestingly TP73 expression has also been observed in a high percentage of epithelial ovarian cancers. With this in mind, it is hypothesized that a high percentage of epithelial ovarian cancers which express TP73 originate from a ciliate cell lineage. PMID- 28915955 TI - Implications of bisphosphonate calcium ion depletion interfering with desmosome epithelial seal in osseointegrated implants and pressure ulcers. AB - Osteoporosis (OP) is a global bone disease prevalent in aging in humans, especially in older women. Bisphosphonates (BPs) are commonly used as therapy for OP as it influences hard and soft tissues calcium metabolism. Mucosal and dermal ulceration with exposure of underlying bone arises from incomplete epithelial recovery due to reduced desmosome formation deriving from lack of available calcium. Pathological situations such as bisphosphonate-related osteonecrosis of the jaw have been described. This hypothesis states other situations which demand intact functional desmosomes such as healing skin over chronic pressure points leading to pressure ulcers (as well-known as bedsores, pressure sores, pressure injuries, decubitus ulcers), and hemidesmosomes such as epithelial seals in contact with titanium surfaces will have a higher prevalence of breakdown among patients being treated with BPs. This may be proven through the diminished modulation of calcium ions due to BPs, and its effect on the formation of intercellular gap junctions. PMID- 28915956 TI - Dual inhibition of P-glycoprotein and midkine may increase therapeutic effects of anticancer drugs. AB - Multidrug resistance (MDR) to chemotherapy may significantly affect the outcome of cancer treatment. ATP-dependent drug efflux pumps, including P-glycoprotein (P gp), contribute to the resistance of various chemotherapeutic agents. Overexpression of P-gp in tumor cells induces chemoresistance via pumping the anticancer drugs out of the cells. In addition to taking part in many biological processes such as development, reproduction and repair, midkine (MK) also plays important roles in the pathogenesis of malignant diseases as well as in the regulation of MDR. Although, the mechanisms of action of P-gp and MK are different, overexpression of both proteins prevents the accumulation of many chemotherapeutics in tumor cells, leading to decreased therapeutic effects of anticancer drugs. Therefore, identification of the result of dual inhibition of P gp and MK in overcoming chemoresistance may enhance the likelihood for a more efficient chemotherapy. PMID- 28915957 TI - Modulation of heart rate and heart rate variability by n-3 long chain polyunsaturated fatty acids: Speculation on mechanism(s). AB - Heart rate (HR) and heart rate variability (HRV) are valuable markers of health. Although the underlying mechanism(s) are controversial, it is well documented that n-3 long chain polyunsaturated fatty acid (LCPUFA) intake improves HR and HRV in various populations. Autonomic modulation and/or alterations in cardiac electrophysiology are commonly cited as potential mechanisms responsible for these effects. This article reviews existing evidence for each and explores a separate mechanism which has not received much attention but has scientific merit. Based on presented evidence, it is proposed that n-3 LCPUFAs affect HR and HRV directly by autonomic modulation and indirectly by altering circulating factors, both dependently and independently of the autonomic nervous system. The evidence for changes in cardiac electrophysiology as the mechanism by which n-3 LCPUFAs affect HR and HRV needs strengthening. PMID- 28915958 TI - Alpha-1 Acid Glycoprotein (orosomucoid): An Overlooked Piece of Post Traumatic Stress Disorder Pathology? PMID- 28915959 TI - Measuring salivary blood: A potential in vivo assay to quantify platelet transfusion efficacy. AB - Salivary blood is known to increase in patients with intraoral mucosal bleeding. Mucosal bleeding is a frequent sequelae of thrombocytopenia, which is typically managed with platelet transfusion. Within the past few years, multiple different types of platelet products have become available, each with potential differences in efficacy. Typically, platelet transfusion efficacy is demonstrated by the increase in platelet count after transfusion. However this approach is complicated by the fact that activated platelets tend to produce lower post transfusion platelet counts, but may be more efficacious in a bleeding patient. Intraoral blood levels, measured by salivary transferrin, urine dipstick hemoglobin or another method, could be used as an in vivo assay to monitor a patient's response to platelet transfusion and compare different types of platelet products. PMID- 28915960 TI - Pleiotropic effects of metformin to rescue statin-induced muscle injury and insulin resistance: A proposed mechanism and potential clinical implications. AB - The 2013 American Heart Association Blood Cholesterol Guidelines increased the number of patients recommended for statin therapy in the United States to 56million. Two common statin side effects are muscle pain, referred to as "statin associated muscle symptoms", and increased risk for new onset type-2-diabetes mellitus. Up to 25% of statin users report muscle symptoms resulting in many patients being switched to lower dose or lower potency statins, or refusing statins altogether. The most likely signaling mechanisms for statin-associated muscle symptoms overlaps with the proposed mechanism of statin-induced insulin resistance. Metformin has outstanding utility in reducing insulin resistance and preventing type-2-diabetes mellitus, but has not been studied for statin associated muscle symptom rescue or prevention. The overlapping mechanisms of statin-associated muscle symptoms, statin-induced insulin resistance, and metformin intervention offers the potential to address two common and detrimental side effects of statins. As statins are the single best medication class for preventing cardiovascular events the potential for clinical benefit is large given metabolic syndrome's growing prevalence in the United States. Herein we hypothesize that metformin will rescue and prevent patients from statin associated muscle symptoms. This hypothesis can benefit two patient groups: 1) patients at risk for diabetes who are taking a statin and experiencing muscle symptoms; and 2) patients with diabetes taking metformin who are to be started on a statin. Method to test Group 1) Symptom Rescue: randomized control trial of metformin versus placebo in patients with prediabetes who are already taking a statin, and are experiencing mild-to-moderate muscle symptoms. Method to test Group 2) Symptom Prevention: meta-analysis, of statin randomized control trials, with patient level data, comparing patients taking metformin at baseline to patients not taking metformin when a statin is started. An efficient method to simulate both symptom rescue and symptom prevention is a skeletal muscle cell culture model of statin-associated muscle symptom markers. These experiments would identify if metformin reverses (rescues) or prevents markers of statin associated muscle symptoms. As metformin is recommended by the American Diabetes Association for type-2-diabetes mellitus prevention, yet not frequently used, validating this hypothesis will lead towards research and practice change including: a) decreases in the frequency of statin-associated muscle symptoms; leading to subsequent increases in statin therapy compliance; b) increases in metformin use in prediabetes with subsequent decrease in the incidence of type-2 diabetes mellitus; and c) decreases in complications of both cardiovascular disease and diabetes due to improved statin compliance and type-2-diabetes mellitus prevention. PMID- 28915961 TI - Short stem total hip arthroplasty: Potential explanations for persistent post surgical thigh pain. AB - Short stem uncemented femoral implants were developed with the aim of preserving proximal bone stock for future revisions, improving biomechanical reconstruction, aiding insertion through smaller incisions and potentially decreasing or limiting the incidence of thigh pain. Despite all the advantages of short stem designs, it remains unclear whether they are able to limit post-surgical thigh pain. In patients with short stem hip arthroplasty and persistent thigh pain, it is of the utmost importance to understand the potential etiologies of this chronic pain for selecting the appropriate treatment strategy. Therefore, this manuscript explores the hypothetical etiologies of persistent thigh pain in short stem total hip arthroplasty, including both peripheral factors (structural or biomechanical causes) and central factors (involvement of the central nervous system). First, intrinsic causes (e.g. aseptic femoral loosening and prosthetic joint infection) and extrinsic sources (e.g. muscle pathology or spinal pathology) of persistent thigh pain related to hip arthroplasty are explained. In addition, other specific peripheral causes for thigh pain related to the short stem prosthetic reconstruction (e.g. stem malalignment and micro-motion) are unraveled. Second, the etiology of persistent thigh pain after short stem hip arthroplasty is interpreted in a broader concept than the biomechanical approach where peripheral structural injury is believed to be the sole driver of persistent thigh pain. Over the past decades evidence has emerged of the involvement of sensitization of central nervous system nociceptive pathways (i.e. central sensitization) in several chronic pain disorders. In this manuscript it is explained that there might be a relevant role for altered central nociceptive processing in patients with persistent pain after joint arthroplasty or revision surgery. Recognition of a potential role for centrally-mediated changes in pain processing in total hip replacement surgery has important implications for treatment. Comprehensive treatment addressing peripheral factors as well as neurophysiological changes occurring in the nervous system may help to improve outcomes in patients with short stem hip arthroplasty and chronic thigh pain. Working within a biopsychosocial approach in orthopaedic surgery, specifically in relation to total hip arthroplasty, could be very important and may lead to more satisfaction. Further research is warranted. PMID- 28915962 TI - Horseradish and radish peroxidases eaten with fish could help explain observed associations between fish consumption and protection from age-related dementia. AB - A juxtaposition of regional cuisines and recent prospective studies of fish consumption in China and Japan points to fresh horseradish and/or radish (HRR) as possible contributors to delaying age-related dementia. The hypothesis is that the inverse association found sometimes between fish intake and cognitive decline is partially due to exposure of the oral cavity to active peroxidases from HRR served in conjunction with fish. This hypothesis can be tested by specifically looking at whether HRR is consumed with fish and whether such HRR is prepared in a way that preserves activity of HRR peroxidases. It is possible that by putting active HRR peroxidases in their mouths, elderly people supplement their age diminished salivary antioxidant capacity and break down additional hydrogen peroxide (H2O2) in the oral cavity before it can migrate into the brain, thus decreasing the incidence of brain cell death induction by chronically-elevated H2O2. Intentional exposure of the oral cavity to active HRR peroxidases could be a prophylactic for delaying dementia. Because vegetable peroxidases are inactivated by gastric juices, it will be difficult to obtain benefit from HRR peroxidases' antioxidant effect via ingestion in encapsulated dietary supplements. PMID- 28915963 TI - Hepcidin and metallothioneins as molecular base for sex-dependent differences in clinical course of experimental autoimmune encephalomyelitis in chronic iron overload. AB - Multiple sclerosis is a chronic demyelinating disease of the central nervous system characterised by inflammatory and degenerative changes. It is considered that disease arises from the influence of environmental factors on genetically susceptible individuals. Recent researches, using magnetic resonance imaging, connected iron deposits in different brain regions with demyelinating process in multiple sclerosis patients. Although iron is an essential trace element important for many biological functions it could be harmful because iron excess can induce the production of reactive oxygen species, development of oxidative stress and lipid peroxidation which leads to demyelination. In experimental autoimmune encephalomyelitis model, the most common experimental animal model for multiple sclerosis, we recently found that chronic iron overload influences the clinical course of disease in Dark Agouti rats. In female rats iron overload accelerated the onset of disease, while in male rats it accelerated the progression of disease and increased mortality rate. We hypothesize that those differences arise on molecular level in different expression of stress response proteins hepcidin and metallothioneins in male and female iron overloaded rats. They are both upregulated by metal ions in both sexes. Hepcidin is additionally upregulated by estrogen in female rats and therefore causes higher degradation of iron exporter ferroportin and sequestration of iron in the cells, lowering the possibility for the development of oxidative stress. Antioxidative effect of metallothioneins could be increased in female rats because of their ability to reversibly exchange metal ions with the estrogen receptor. In case of iron excess metallothioneins release zinc, which is normally bound to them. Zinc binds to estrogen receptor and leaves metallothioneins binding domains free for iron, causing at least provisional cytoprotective effect. To test this hypothesis, we propose to determine and compare serum levels of hepcidin and estrogen using ELISA essay as well as expression and distribution of acute stress response proteins hepcidin and metallothioneins, iron and estrogen receptor in the brain and spinal cord tissue using immunohistochemistry in control and chronic iron overloaded male and female rats in experimental autoimmune encephalomyelitis model. It would be also possible to perform the same immunohistochemistry in the brain tissue of multiple sclerosis patients post mortem. The results of experiments could contribute to better understanding of cytoprotective mechanisms in chronic iron overload that could have possible therapeutic applications in iron disturbances. In order to elucidate whether common measure of systemic iron status, like ferritin, haemoglobin concentration and transferrin saturation levels, may be used to distinguish physiologic from potentially harmful iron levels in local disease, for example multiple sclerosis and Still's disease, well designed clinical trials would be of great interest. PMID- 28915964 TI - Decreased use of spatial pattern separation in contemporary lifestyles may contribute to hippocampal atrophy and diminish mental health. AB - The spatial pattern separation process has not yet been proposed as a pivotal neural activity affecting hippocampal volume, a metric of mental health. The dentate gyrus/CA3 region is increasingly implicated in hippocampal atrophy, its putative role in spatial pattern separation appears to be impaired in mental health disorders, and performance on a task indicative of pattern separation correlates with dentate gyrus/CA3 volume. Spatial pattern separation is thought to utilize the heightened neural plasticity of newborn neurons in the dentate gyrus to distinguish highly similar aspects of scene so that these remain distinct in memory rather than lost. The level of such activity associates with BDNF secretion, which may affect neuroplasticity and therefore hippocampal volume. Distinguishing fine-grained aspects of surroundings was likely of great importance during hunting and gathering for survival in nature. However the need to make subtle environmental discriminations is much reduced in modern survival activity. Ancestrally, exploration and utilization of the spatial pattern separation process may have resulted in detection of potential food items, an activity that was likely followed by intensive effort-based reward (EBR) activity to obtain the food. EBR activity and restorative walking in nature demonstrate positive mental health benefits, while their lack indicates negative effects on mental health. Data support the hypothesis that spatial pattern separation activity and neural circuitry are separate from, and may precede, those of EBR as well as restorative walking in nature. Spatial pattern separation therefore represents an additional nature-related neural process whose modern decrease in use may negatively affect mental health. Interventions that increase spatial pattern separation experiences may enhance BDNF secretion, neuroplasticity, hippocampal volume and mental health. PMID- 28915965 TI - Can cerebellin and renalase measurements contribute to the elimination of false positive results in pheochromocytoma and paraganglioma diagnoses? PMID- 28915966 TI - Use of anthropogenic nitrogen fertilizers in agriculture is associated with per capita ethanol consumption. AB - It has previously been demonstrated that emissions of the agricultural pollutant, nitrous oxide (N2O), may be a confounder to the relationship between herbicide use and psychiatric impairments, including ADHD. This report attempts to extend this hypothesis by testing whether annual use of anthropogenic nitrogen-based fertilizers in U.S. agriculture (thought to be the most reliable indicator of environmental N2O emissions) is associated with per capita ethanol consumption patterns, a behavior often comorbid with ADHD. State estimates of anthropogenic nitrogen fertilizers from the United States Geological Survey (USGS) were obtained for the years between 1987 and 2006. Our dependent variable was annual per capita ethanol consumption. Ethanol consumption was categorized as beer, wine, spirits, and all alcoholic beverages. Least squares dummy variable method using two-ways fixed effects was utilized. Among states above the 50th percentile in farm use of anthropogenic nitrogen for all years (i.e., agricultural states), a one log-unit increase in farm use of anthropogenic nitrogen fertilizers is associated with a 0.13 gallon increase in total per capita ethanol consumption (p<0.0125). No statistically significant association between farm use of anthropogenic nitrogen and per capita ethanol consumption was found in states below the 50th percentile in farm use of anthropogenic nitrogen. The new findings are in agreement with both behavioral human studies demonstrating a link between N2O preference and alcohol and drug use history as well as molecular studies elucidating shared mechanisms between trace N2O antinociception and alcohol seeking related behaviors. PMID- 28915967 TI - The concept of protective nerve stimulation for ultrasound guided nerve blocks. AB - Regional plexus and nerve blocks are a common technique in modern anesthesia. Since ultrasound machines are available in many departments, the role of nerve stimulation is highly discussed and different approaches to perform the blocks are taken into account. Common technique for electrical nerve stimulation is searching for a stimulating threshold of 0.4-0.5mA using an impulse width of 0.1ms. We present our hypothesis of using all possible information with a new concept of protective nerve stimulation together with first data supporting our theory. In protective nerve stimulation during ultrasound guided nerve blocks a fixed current of 1.0mA (0.1ms) is used without any change during block performance. The aim is no muscular twitches before and during injection. If this way of neuro-axial blocking brings suitable effects, we should consider new currency settings to perform safer blockades with a lower risk of nerve injuries and a high patient comfort, especially in bad visibility block situations. PMID- 28915968 TI - Magnesium to counteract elastin degradation and vascular calcification in chronic obstructive pulmonary disease. AB - Accelerated elastin degradation is an important pathogenic mechanism in chronic obstructive pulmonary disease (COPD) leading to irreversible lung function loss and cardiovascular comorbidities. The rate of elastin breakdown is a predictor of mortality in patients with COPD. Decelerating elastinolysis might be an attractive therapeutic target in this debilitating condition. Vascular calcification starts in the elastin network of the arterial wall and is enhanced in patients with COPD. Elastin calcification is accompanied by an upregulation of matrix metalloproteinase gene expression and consequently a shift in the elastase/anti-elastase balance towards degradation. Magnesium can be regarded as a natural calcium antagonist and has the proven ability to ameliorate vascular calcification. Furthermore, an animal study has suggested that magnesium deficiency promotes elastin degradation. I hypothesize that inhibiting elastin calcification by means of magnesium supplementation might counteract both vascular calcification and elastin degradation in COPD. This could potentially have a favorable impact on cardiovascular and respiratory related morbidity/mortality in patients with COPD. PMID- 28915969 TI - Hyperglycemia in acute ischemic stroke: Is it time to re-evaluate our understanding? AB - Among 700,000 new and recurrent ischemic stroke patients per year, forty percent are hyperglycemic on admission. In-vitro, hyperglycemia is toxic to neurons. Acute ischemic stroke patients who are hyperglycemic on admission experience higher morbidity and mortality. Results of multiple trials have provided no evidence supporting benefit in achieving normoglycemia. On the contrary, there is some evidence that tight glycemic control in acute brain injury is associated with poor outcome. Current consensus derived guidelines from the American Heart Association/American Stroke Association recommend an upper limit of blood glucose of 140-180mg/dl, as there is no evidence to support strict control. The lack of improved outcomes with normoglycemia in this population dictates reconsideration of assumptions regarding the underlying pathophysiology of hyperglycemia. Review of the current data suggests there are two distinct pathophysiologic entities of hyperglycemia in acute ischemic stroke patients: diabetic and non-diabetic. We propose that the lack of positive results from well-designed intention-to-treat trials in hyperglycemic acute ischemic stroke patients could be attributed to treating these distinct groups as one. PMID- 28915970 TI - A new proposed mechanism of action for gastric bypass surgery: Air hypothesis. AB - Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatments for obesity and type II diabetes. RYGB was originally believed to work by mechanically restricting caloric intake or causing macronutrient malabsorption. However, such mechanical effects play no role in the remarkable efficacy of gastric bypass. Instead, mounting evidence shows that altered neuroendocrine signaling is responsible for the weight reducing effects of RYGB. The exact mechanism of this surgical response is still a mystery. Here, we propose that RYGB leads to weight loss primarily by inducing a functional shift in the gut microbiome, manifested by a relative expansion of aerobic bacteria numbers in the colon. We point to compelling evidence that gastric bypass changes the function of the microbiome by disrupting intestinal gas homeostasis, causing excessive transit of swallowed air (oxygen) into the colon. PMID- 28915971 TI - Genotrophic effect of neurotrophins - Restart of beta-cell regeneration in diabetes mellitus. AB - Type 2 diabetes mellitus is an epidemic worldwide and a proved risk factor for cardiovascular complications. In 89% of the cases, it deals, in fact, with metabolic syndrome of multifactorial etiopathogenesis. This paradigm has been generalized by the neurotrophic theory emphasizing the role of hyponeurotrophinemia of key factor. Both type 2 diabetes mellitus and metabolic syndrome are characterized by insulin resistance and pancreatic beta-cell damage. Cyclic keeping the fast enhances plasma neurotrophin levels. Fasting induces prenatal-development gene expression in adult pancreas and promotes neurogenin (Ngn)-3 gene expression to generate insulin producing beta-cells. Probably, the increased plasma and tissue levels of the nerve growth factor and brain-derived neurotrophic factor after fasting reprogramme Ngn-3 gene expression as this genotrophic action enhances Ngn-3 protein synthesis. This results in regeneration of damaged pancreatic beta-cells and restores insulin secretion in type 1 and type 2 diabetes mellitus. PMID- 28915972 TI - Suprachoroidal injection of biological agents may have a potential role in the prevention of progression and complications in high myopia. AB - The prevalence of myopia and its severe/progressive visually impairing forms is increasing all over the globe. Most of the preliminary clinical research has focused on rehabilitation and treatment of its complications. Pharmacological prevention of myopic progression has shown encouraging results recently and currently the scleral structure is believed to be responsible for disease progression. In this article, we have hypothesized injecting a biological cement in the potential space between the choroid and the sclera to halt the progressive elongation of the eye ball while preventing complications related to myopia. PMID- 28915973 TI - Compassionomics: Hypothesis and experimental approach. AB - Recent reports indicate that healthcare is experiencing a compassion crisis - an absence of (or inconsistency in) compassionate patient care. It is currently unclear if, or to what extent, this exerts significant effects on health and healthcare. Experimental data are few, and this represents a critical knowledge gap for all health sciences. We hypothesize that compassionate care is beneficial for patients (better outcomes), healthcare systems and payers (lower costs), and healthcare providers (lower burnout). Compassionomics is the branch of knowledge and scientific study of the effects of compassionate healthcare, and herein we describe a framework for hypothesis testing. If the hypotheses are confirmed, compassionate healthcare can be established in the domain of evidence-based medicine. PMID- 28915974 TI - Rapid and accurate intraoperative pathological diagnosis by artificial intelligence with deep learning technology. AB - Frozen section is widely used for intraoperative pathological diagnosis (IOPD), which is essential for intraoperative decision making. However, frozen section suffers from some drawbacks, such as time consuming and high misdiagnosis rate. Recently, artificial intelligence (AI) with deep learning technology has shown bright future in medicine. We hypothesize that AI with deep learning technology could help IOPD, with a computer trained by a dataset of intraoperative lesion images. Evidences supporting our hypothesis included the successful use of AI with deep learning technology in diagnosing skin cancer, and the developed method of deep-learning algorithm. Large size of the training dataset is critical to increase the diagnostic accuracy. The performance of the trained machine could be tested by new images before clinical use. Real-time diagnosis, easy to use and potential high accuracy were the advantages of AI for IOPD. In sum, AI with deep learning technology is a promising method to help rapid and accurate IOPD. PMID- 28915975 TI - Corrigendum to "Estimation of the minimum mRNA splicing error rate in vertebrates" [Mutat Res. 2016;784:34-38]. PMID- 28915976 TI - Foreword. PMID- 28915977 TI - Corrigendum to 'Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats' [Eur. J. Pharmacol. 773 (2016) 78-84]. PMID- 28915978 TI - Corrigendum to 'Conditioned flavor avoidance and conditioned gaping: Rat models of conditioned nausea '[European Journal of Pharmacology Volume 722, 2014, Pages 122-133]. PMID- 28915980 TI - America's White Supremacy Crisis. PMID- 28915981 TI - Transcutaneous Electrical Acupoint Stimulation Improves the Outcomes of In Vitro Fertilization: A Prospective, Randomized and Controlled Study. AB - OBJECTIVES: To explore whether transcutaneous electrical acupoint stimulation (TEAS) can improve the outcomes of in vitro fertilization (IVF). DESIGN: A prospective, randomized, and controlled study. SETTING: IVF center in a university hospital. PARTICIPANTS: Four hundred and eighty-one infertile patients with bilateral tubal blockage who were referred for IVF. Patients were randomized into four groups. INTERVENTION: TEAS was administered for 30min, respectively, at 24h before TVOR and two hours before ET. The acupoints included SP10 (Xuehai, bilateral), SP8 (Diji, bilateral), LR3 (Taichong, bilateral), ST36 (Zusanli, bilateral), EX-CA1 (Zigong, bilateral), RN4 (Guanyuan), PC6 (Neiguan, bilateral), and RN12 (Zhongwan). Based on different frequencies of TEAS, patients were grouped into a TEAS-2Hz group, a TEAS-100Hz group and a TEAS-2/100Hz group. Patients in the control group only received routine IVF treatment and no TEAS was applied on them. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of mature oocytes, normally fertilized oocytes and good-quality embryos were used to evaluate oocyte developmental competence of the patients. Data of clinical pregnancy rate (CPR), implantation rate (IR), and live birth rate (LBR) were also obtained. The levels of neuropeptide Y (NPY), transforming growth factor alpha and granulocyte colony-stimulating factor in the follicular fluids were measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: No significant differences were found between the control, TEAS-2Hz, TEAS-100Hz and TEAS-2/100Hz groups on the numbers of metaphase II oocytes, normally fertilized zygotes, early cleavage embryos or good quality embryos (P > .05). However, the CPR, IR and LBR of the TEAS-2/100Hz group were significantly higher than those of the other groups, respectively (P < .05). The NPY levels in the follicular fluids of TEAS 2/100Hz group were significantly higher than those of the other groups (P < .05). CONCLUSION: TEAS using a frequency of 2/100Hz could help to improve the IVF outcomes partly by increasing NPY levels in the follicular fluids. PMID- 28915982 TI - Living and Leading With Resilience. PMID- 28915983 TI - Single Treatment With Capsaicin 8% Patch May Reduce Pain and Sleep Interference up to 12 Weeks in Patients With Painful Diabetic Peripheral Neuropathy. PMID- 28915984 TI - A Global Perspective on Gender Roles and Identity. PMID- 28915985 TI - Why We Must Invest in Early Adolescence: Early Intervention, Lasting Impact. PMID- 28915986 TI - Exploration of Gender Norms and Socialization Among Early Adolescents: The Use of Qualitative Methods for the Global Early Adolescent Study. AB - PURPOSE: The Global Early Adolescent Study (GEAS) was launched in 2014 with the primary goal of understanding the factors in early adolescence that predispose young people to subsequent sexual risks, and conversely, those that promote healthy sexuality across different cultural contexts. The present article describes the methodology that was used for the first phase of GEAS, which consisted of conducting qualitative research to understand the gendered transitions into adolescence and the role that gender norms play within the key relationships of adolescents. Researchers from each of the sites that had completed data collection were also elicited for their feedback on the key strengths, challenges, and lessons learned from conducting research among 11- to 14-year-old adolescents. The purpose of this article is to present the description of each of the methods that were used in GEAS, as well as the researchers' perspectives of using the methods among early adolescents in their sites. METHODS: The GEAS is being implemented through a collaboration of university and nongovernmental institutions from 15 cities: Assiut (Egypt) Baltimore (U.S.), Blantyre (Malawi), Cape Town (South Africa), Cochabomba (Bolivia), Cuenca (Ecuador), Edinburgh (Scotland), Ghent (Belgium), Hanoi (Vietnam), Ile-Ife (Nigeria), Kinshasa (DRC), Nairobi (Kenya), New Delhi (India), Ouagadougou (Burkina Faso), and Shanghai (China). Approximately 30 in-depth interviews among adolescents and 30 in-depth interviews with their parent/guardian were conducted at each site, with adults and adolescents interviewed separately. To build trust and increase engagement among the adolescent participants, we used two different visual research methods: (1) timeline exercise which was small group based and (2) the Venn diagram exercise which was conducted individually and used at the start of the in-depth interview. RESULTS: The visual aspects of both the timeline and the Venn diagrams not only helped to produce data for the purposes of the study, but also were a successful way of engaging the adolescent participants across sites. While the narrative interviews produced extremely rich data, researchers did notice that there were a few challenges among the younger adolescents. Challenges were related to the length of the interview, comprehension of questions, as some of the questions were either too abstract or asked adolescents about an experience they had not yet had and therefore could not address or articulate. CONCLUSIONS: Conducting the first phase of GEAS revealed important insights for research with participants who are in this developmental phase of early adolescence. Methods that involve greater engagement and those that are visual were shown to work well irrespective of the cultural setting. PMID- 28915987 TI - Interpreting Narratives Within a Cross-National Interdisciplinary Study: A Case Study of a Collaborative Process. AB - PURPOSE: This article presents a case study of a collaborative process for the analysis of a young girl's narrative on becoming an adolescent in Shanghai. The purpose was to illuminate how interpretation of narratives can be strengthened with a diverse team of researchers. METHODS: Three different researchers, each representing a different discipline and lens for analyzing qualitative data, collaboratively analyzed and interpreted a 12-year-old girl's narrative from Shanghai as part of the Global Early Adolescent Study. Each researcher first analyzed the narrative separately with a written summary that was then analyzed for differences and similarities across the research team, along with further cross-checks of the translations of the recording. RESULTS: Throughout the analysis, we argued that the narrative was a story about gender and power: the gendered nature of socializing a girl, the interpersonal process of a mother, at the behest of a father, to press a daughter to behave in a proper, modest fashion, and the daughter learning the appropriate and proper way for adult woman to comport herself. At the same time, by bridging our interpretations together, we also came to agree that it was a story of a Chinese girl's loss of freedom and capitulation, evident in her resignation to comply with the gender norm that required that she refrain from displaying her body in a certain way at the dinner table. CONCLUSIONS: Recording our collaborative analysis process enabled us to illuminate how researchers who work on cross-national studies can combine forces of perspectives and of methods-for a compelling approach that provides a more comprehensive analysis of the underlying meanings behind an interview narrative. PMID- 28915988 TI - Learning to Be Gendered: Gender Socialization in Early Adolescence Among Urban Poor in Delhi, India, and Shanghai, China. AB - PURPOSE: The purpose of the study is to understand the gender socialization process in early adolescence. METHODS: The study was located in two disadvantaged urban communities in Delhi, India and Shanghai, China and was part of the multicountry (15) Global Early Adolescent Study. Qualitative methodologies were used with boys and girls aged 11-13 years, including 16 group-based timeline exercises and 65 narrative interviews. In addition, 58 parents of participating adolescents were interviewed. Interviews were recorded, transcribed, translated, and uploaded into Atlas.ti for coding and thematic analysis. RESULTS: Boys and girls growing up in the same community were directed onto different pathways during their transition from early to late adolescence. Adolescents and parents in both sites identified mothers as the primary actor, socializing adolescents into how to dress and behave and what gender roles to play, although fathers were also mentioned as influential. Opposite-sex interactions were restricted, and violations enforced by physical violence. In Delhi, gender roles and mobility were more strictly enforced for girls than boys. Restrictions on opposite-sex interactions were rigid for both boys and girls in Delhi and Shanghai. Sanctions, including beating, for violating norms about boy-girl relationships were more punitive than those related to dress and demeanor, especially in Delhi. Education and career expectations were notably more equitable in Shanghai. CONCLUSIONS: Parents teach their children to adhere to inequitable gender norms in both Delhi and Shanghai. However, education and career expectations for boys and girls in the two sites differed. Although gender norms varied by site according to the particular cultural and historical context, similar patterns of gender inequity reflect the underlying patriarchal system in both settings. The tendency of parents to pass on the norms they grew up with is evident, yet these results illustrate the social construction of gender through children's interaction with the social ecology, including evolving political and economic systems. Efforts to bend gender norms toward greater equality can build on these results by empowering children and parents to reflect critically on inequitable gender norms and roles and by mobilizing economic and social support at key turning points in adolescents' lives. PMID- 28915989 TI - It Begins at 10: How Gender Expectations Shape Early Adolescence Around the World. PMID- 28915990 TI - "A Boy Would Be Friends With Boys ... and a Girl ... With Girls": Gender Norms in Early Adolescent Friendships in Egypt and Belgium. AB - PURPOSE: A gender analysis was conducted to illuminate the key elements of friendships highlighted by early adolescent girls and boys in two sites for the purpose of better understanding the impact of gender norms on adolescent friendships in different contexts. METHODS: Narrative interviews with early adolescents were conducted in two sites: Assiut, Egypt (n = 37) and Ghent, Belgium (n = 30). The interviews were recorded, transcribed, translated into English, and coded using Atlas.ti for analysis. RESULTS: In both Assiut and Ghent, early adolescents reported some similarities in defining key characteristics of their same-sex friends as well as in the activities they share. However, differences were noticed among boys and girls within each site. In addition, the scope of shared activity was broader in Ghent than in Assiut. In both sites, few opposite-sex friendships were reported. Gender norms influenced choice of friends as well as the type and place of shared activities. CONCLUSIONS: Building on knowledge that adolescent friendships guide and reinforce attitudes, beliefs, and behaviors that impact immediate and long-term health, our findings indicate that gender norms inform early adolescent friendships, which may impact healthy development. PMID- 28915991 TI - Adolescent and Parental Reactions to Puberty in Nigeria and Kenya: A Cross Cultural and Intergenerational Comparison. AB - PURPOSE: This qualitative study assesses the cross-cultural and intergenerational reactions of young adolescents and parents to puberty in Ile-Ife, Nigeria, and Nairobi, Kenya. METHODS: Sixty-six boys and girls (aged 11-13 years) and their parents participated in narrative interviews conducted in English or local languages in two urban poor settings in Ile-Ife and Nairobi. All interviews were recorded, transcribed, translated, and uploaded into Atlas.ti software for coding and analysis. RESULTS: Reactions of parents and adolescents to puberty were similar across both sites, with few exceptions. Adolescents' reactions to bodily changes varied from anxiety to pride. Adolescents generally tend to desire greater privacy; trying to hide their developing bodies from others. Most female adolescents emphasized breast development as compared with menstruation as the mark for pubertal initiation, while males emphasized voice changes. Among some ethnic groups in Nairobi, parents and adolescents view male circumcision as the hallmark of adolescence. Parents in both sites reported that with pubertal changes, adolescents tend to become arrogant and engaged in sexual relationships. Parents' reported responses to puberty include: educating adolescents on bodily changes; counseling on sexual relationships; and, provision of sanitary towels to females. Parents' responses are generally focused more on daughters. Approaches used by mothers in educating adolescents varied from the provision of factual information to fear/scare tactics. Compared with their own generation, parents perceive that their own children achieve pubertal development earlier, receive more puberty-related education from mothers, and are more exposed to and influenced by media and information technologies. CONCLUSIONS: Adolescents' responses to their pubertal bodily changes include anxiety, shame, and pride. Adolescents desire greater privacy. Parents' reactions were broadly supportive of their children's pubertal transition, but mothers' communication approaches may sometimes be inappropriate in terms of using fear/scare tactics. PMID- 28915992 TI - "Boys Should Have the Courage to Ask a Girl Out": Gender Norms in Early Adolescent Romantic Relationships. AB - PURPOSE: The purpose of the study is to explore how gender norms emerge in romantic relationships among early adolescents (EAs) living in five poor urban areas. METHODS: Data were collected as part of the Global Early Adolescent Study. The current research analyzed data from interviews with 30 EAs (aged 11-13 years) living in five poor urban sites: Baltimore, Cuenca, Edinburgh, Ghent, and Nairobi. All interviews were recorded, transcribed, and analyzed in English using Atlas.ti, focusing on how EAs experience and perceive gender norms in romantic relationships. RESULTS: Across the five sites, only a few respondents described having been in love, the majority of whom were boys. Findings indicate that stereotypical gender norms about romantic relationships prevail across these cultural settings, depicting boys as romantically/sexually active and dominant, and girls as innocent with less (romantic) agency. In spite of the similarities, Nairobi was unique in that respondents referred to how sexual behavior and violence can occur within EA relationships. In all countries, heterosexuality was perceived to be the norm. Nevertheless, there were examples of EAs accepting homosexuality and expressing supportive attitudes toward equality between the sexes. CONCLUSIONS: While EAs across five different cultural settings seem to endorse stereotypical gender norms in romantic relationships, a few stories also illustrate more gender-equal attitudes. As stereotypical gender norms have a demonstrated negative effect on adolescent sexual and reproductive health and well-being, additional research is needed to understand which factors-at the interpersonal and structural level-contribute to the construction of these norms among EAs. PMID- 28915993 TI - Marching to a Different Drummer: A Cross-Cultural Comparison of Young Adolescents Who Challenge Gender Norms. AB - PURPOSE: Little is known about how gender norms regulate adolescents' lives across different cultural settings. This study aims to illustrate what is considered as violating gender norms for boys and girls in four urban poor sites as well as the consequences that follow the challenging of gender norms. METHODS: Data were collected as part of the Global Early Adolescent Study, a 15-country collaboration to explore gender norms and health in early adolescence. The current study analyzed narrative and in-depth interviews conducted in urban poor sites in two middle-income (Shanghai, China; and New Delhi, India) and two high income countries (Baltimore, U.S.; and Ghent, Belgium). A total of 238 participants, 59 boys and 70 girls aged 11-13 years old and 109 of their parents/guardians (28 male adults and 81 female adults), were interviewed. A thematic analysis was conducted across sites using Atlas.Ti 7.5 software. RESULTS: Findings revealed that although most perceptions and expressions about gender were regulated by stereotypical norms, there was a growing acceptability for girls to wear boyish clothes and engage in stereotypical masculine activities such as playing soccer/football. However, there was no comparable acceptance of boys engaging in traditional feminine behaviors. Across all sites, challenging gender norms was often found to lead to verbal, physical, and/or psychological retribution. CONCLUSIONS: While it is sometimes acceptable for young adolescents to cross gender boundaries, once it becomes clear that a behavior is socially defined as typical for the other sex, and the adolescent will face more resistance. Researchers, programmers, and clinicians working in the field of adolescent health need not only attend to those who are facing the consequences of challenging prevailing gender norms, but also to address the environment that fosters exclusion and underscores differences. PMID- 28915994 TI - Implications of the Global Early Adolescent Study's Formative Research Findings for Action and for Research. PMID- 28915995 TI - Detection and molecular characterization of feline hemoplasmas in wild felid species in Iran in the Middle East. AB - Three feline hemoplasma species exist in felids: Mycoplasma haemofelis, 'Candidatus Mycoplasma haemominutum', and 'Candidatus Mycoplasma turicensis'. The aims of the study were to determine the presence of, and molecularly characterize, any hemoplasmas in wild felids, including the endangered Persian leopard in Iran, the Middle East. Blood samples were collected from 19 wild felids, including three Persian leopards. Using species-specific hemoplasma PCRs and ELISA serological testing for feline leukaemia virus and feline immunodeficiency virus (FIV), two Persian leopards were found to be infected with 'Ca. M. haemominutum' and were seropositive for FIV. Partial 16S rRNA gene sequences were generated for these 'Ca. M. haemominutum' species and subsequent phylogenetic analysis revealed 97.70% to 99.45% sequence identity with those found in domestic cats from Iran and other countries. This study confirms the presence of 'Ca. M. haemominutum' and concurrent FIV antibody in wild felids in Iran. This represents the first report of hemoplasma in wild felids in the Middle East as well as the first report of infection in Persian leopards. PMID- 28915997 TI - Outbreak of anaplasmosis associated with novel genetic variants of Anaplasma marginale in a dairy cattle. AB - During early lactation, dairy cows may present a transient immunosuppressive state and develop anaplasmosis caused by Anaplasma marginale. In this study, clinical anaplasmosis in dairy cattle in the Thrace region of Turkey was investigated with respect to within-herd prevalence, vertical transmission, and genetic diversity. In March and September 2015, thirty lactating cows showed primary clinical signs of anaplasmosis, including fever, anaemia, decreased milk yield, anorexia, and laboured breathing. Symptoms disappeared in most cows after administration of long-acting oxytetracycline, but nine of them (30%) died. Following diagnosis based on clinical signs, microscopy and molecular findings, blood samples were collected from apparently healthy lactating cows (n=184), pregnant heifers (n=39) and newborn calves (n=24). DNA was extracted from each sample and analyzed for the presence of major surface proteins (MSPs) of A. marginale, followed by sequencing to assess diversity of isolates. Microscopic examination of erythrocytes revealed A. marginale inclusion bodies in symptomatic cows. Examination of thin blood smears showed 3.8% of the lactating, clinically asymptomatic, cows to be infected with A. marginale, while nPCR detected 31.0% positive. A. marginale infection was not detected in pregnant heifers by either method. Congenital infection was found in one calf by nPCR. This is the first report of transplacental transmission of A. marginale in Turkey. The MSP4 sequence analyses showed high genetic diversity among the isolates, presenting 97.6-99.6% homology at the amino acid level. The sequences of MSP1a amplicons revealed genetic diversity providing three new tandem repeats. PMID- 28915996 TI - Alternative strategy for visceral leishmaniosis control: HisAK70-Salmonella Choleraesuis-pulsed dendritic cells. AB - Here, we describe a novel approach that exploits an attenuated mutant of Salmonella enterica serovar Choleraesuis as carrier to deliver a plasmid encoding protein HisAK70. Subsequently, dendritic cells (DCs) were pulsed with this vaccine vector. The aim of this study was to evaluate the effectiveness of the prepared HisAK70-S. Choleraesuis-pulsed DCs (HisAK70-SAL DCs) against visceral leishmaniosis (VL). In our ex vivo model of infection, the prepared formulations could decrease parasite growth by up to 80% by augmenting the production of IL 12p40 and by reducing arginase activity (ARG). Also, BALB/c mice when immunised with this formulation showed significant reduction in parasite burden in both spleen (20% of reduction) and liver (75% of reduction). The balance of the immune ratios IFN-gamma/IL-10, TNF-alpha/IL-10, and IgG2a/IgG1 reflected the acquisition of an improved resistant phenotype in HisAK70-SAL DCs vaccinated mice compared to control mice. Our results suggest that HisAK70-SAL DCs could be a promising alternative approach for vaccine delivery that has the potential to fight Leishmania infantum (L. infantum) infection. PMID- 28915998 TI - Predictors of humoral response to recommended vaccines in HIV-infected adults. AB - Humoral response to vaccination has been found to be inadequate in individuals infected with the human immunodeficiency virus (HIV). We retrospectively assessed antibody responses to three routinely recommended vaccines, against hepatitis B, hepatitis A and S. pneumoniae, in HIV-infected individuals. Data regarding age at HIV diagnosis, years of infection, sex, nationality, HIV mode of transmission, CD4 cell count, nadir CD4 count, plasma viral load, HIV stage, insurance status, educational level and treatment with Highly Active Antiretroviral Therapy (HAART) were collected. Univariate and multivariate analysis was performed in order to detect factors associated with response to vaccination. 437 patients were assessed for hepatitis B, 627 patients for hepatitis A and 66 patients for S. pneumoniae serologic vaccine responsiveness. Regarding hepatitis B and hepatitis A, education level and insurance status were the only predictors of response. As for S. pneumoniae vaccination HAART and control of viremia were correlated with better response to vaccination. PMID- 28915999 TI - Oxidative stress in dairy cows seropositives for Neospora caninum. AB - Bovine neosporosis is caused by the protozoan Neospora caninum and is one of the major causes of abortion in cows. Cattle are intermediate hosts of this parasite and may have asymptomatic or symptomatic infections. Therefore, the aim of this study was to evaluate oxidative stress marker reactive oxygen species (ROS), thiobarbituric reactive acid substances (TBARS) levels, glutathione S-transferase (GST), adenosine deaminase (ADA), and butyrylcholinesterase (BChE) activities in dairy cows seropositives for N. caninum (asymptomatic or symptomatic). Dairy cows (n=90) were tested by immunofluorescent antibody assay (IFA) for N. caninum and divided accordingly into three groups: the group A (seronegatives, n=30), the group B (seropositives and asymptomatic, n=30), and the group C (seropositives and symptomatic, n=30). It was observed increased levels of TBARS and reduced (P<0.05) BChE activity in seropositives either asymptomatic or symptomatic animals. ROS levels and ADA activity increased, and GST activity decreased (P<0.05) only in seropositives symptomatic dairy cows (the group C) compared to seronegatives dairy cows (the group A). Based on these results, it was observed that seropositive animals showed cell damage associated with oxidative stress and inflammation, mainly in those with symptomatic infections. Increased seric ROS levels and BChE activity may have influenced N. caninum pathogenesis in symptomatic animals due to increased cell damage and exacerbated inflammatory response, leading to the development of clinical signs. PMID- 28916000 TI - Development, phenotype, and function of non-conventional B cells. AB - Three populations of B cells develop in fetal life: B1, B2 and marginal zone B cells. B1 cells play important roles in innate immunity in contrast to B2 cells that perform the conventional roles in adaptive immunity. B1 cells were first identified in mice based on their expression of CD5 and spontaneous secretion of IgM. B1 cells were subsequently found to have unique developmental, phenotype, tissue distribution, and functional characteristics that differ from B2 cells. These phenotypic and functional differences allow B1 cells to play important roles in immunity and homeostasis, but be implicated in autoimmune disease. The presence of B1 cells has been examined in other species including humans, primates, rabbits, guinea pigs, cattle, pigs, and horses. Here we review the known developmental and functional differences between B1 and B2 cells, and discuss the evidence of the presence of homologous population of cells in different species. PMID- 28916001 TI - Giardia and Cryptosporidium infections in neonatal reindeer calves: Relation to the acute phase response. AB - This longitudinal observational study was conducted to investigate the spontaneous effect of Giardia and Cryptosporidium infections on acute phase response (APR) in reindeer calves (Rangifer tarandus tarandus) in Finnish Lapland. Serum (n=609) and faecal samples (n=366) were collected from 54 reindeer calves aged zero to 33days. The samples were analysed for Giardia, Cryptosporidium, acute phase proteins (APP) and gamma-globulins. Linear regression models were used to investigate associations of early Giardia infection (before 12days of life) with the response of APPs and acquiring of passive immunity. Giardia was detected in 100% and Cryptosporidium in 23% of calves. There was a negative association between early Giardia infection and gamma-globulin concentrations (p=0.032) and a positive association with serum amyloid A (SAA) concentrations (p=0.042). The results suggest a protective effect of colostrum against Giardia infection and that early infection may induce activation of APR. PMID- 28916002 TI - Characterization of immune response in Staphylococcus aureus chronically infected bovine mammary glands during active involution. AB - The aim of this study was to characterize the immune response in Staphylococcus aureus chronically infected bovine mammary glands during active involution. Twenty-one Holstein non-pregnant cows in late lactation either uninfected or with chronic naturally acquired S. aureus intramammary infections (IMI) were included in this study. Cows were slaughtered at 7, 14 and 21 d after cessation of milking and samples for immunohistochemical analysis were taken. Protein expression of toll-like receptor 2 (TLR2) and TLR4 was significantly higher in S. aureus infected quarters than in uninfected controls at the three involution stages studied. Protein expression of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1alpha and IL-17 was significantly affected by IMI; being higher in S. aureus-infected than uninfected quarters during all evaluated stages. In S. aureus-infected and uninfected quarters protein expression of lactoferrin increased from day 7-14 of involution, decreasing significantly to day 21 in mammary quarters with chronic infections. The number of monocytes-macrophages was significantly higher in S. aureus-infected than in uninfected control quarters at 7 and 21 d of involution. The number of T lymphocytes was significantly higher in S. aureus-infected than in uninfected quarters at 7 and 14 d of involution while the number of B lymphocytes was significantly higher in S. aureus-infected than in uninfected quarters during all evaluated stages, showing a progressive increase as involution advanced. These results demonstrated a sustained and exacerbated innate and adaptive immune response during chronic S. aureus IMI, playing a critical role in the infection control during active involution. PMID- 28916003 TI - Genetic diversity and antibiotic susceptibility of Staphylococcus aureus isolates from wild boars. AB - We here report the occurrence of S. aureus in wild boars and characterize isolates genotypically and phenotypically in order to get knowledge about the occurrence of clonal lineages and genotypes in free-living wild animals. Forty one S. aureus isolates obtained from 111 wild boars hunted in Lower Saxony, Germany, were investigated and compared to human and livestock isolates. The S. aureus belonged to multilocus sequence types ST1, ST7, ST30, ST133, ST425, ST804, ST890 and to the new ST3237, ST3238, ST3255 and ST3369. The livestock associated CC398-MRSA lineage, however, was not found. In addition to well-known spa types, the new types t14999, t15000, t15001 and t15002 were detected. Macrorestriction analysis revealed a variety of different SmaI fragment patterns. Most isolates were susceptible to all antimicrobials tested, including methicillin, and resistance was detected only to ampicillin, penicillin and erythromycin. PCR analysis confirmed the presence of staphylococcal enterotoxin genes (seh) in all t127-ST1 isolates. A high degree of genetic diversity was detected with many spa types and clonal lineages previously reported in humans and livestock animals. PMID- 28916004 TI - Telemedicine for Child Collaborative or Integrated Care. AB - Telemedicine with child psychiatry specialists is a useful tool for collaborative and integrated care systems. This article reviews the workforce and care process rationale for using child psychiatric telemedicine for collaborative care, and discusses practical ways to address the technical challenges that arise when using telemedicine. Different systems of using telemedicine discussed include child psychiatry access programs, collaborative and integrated care use of telephone consultations, televideo consultations, and televideo care delivery. Telemedicine can also be used for collaboratively conducted but care review requested by third-party consultations with treatment providers or care teams. PMID- 28916005 TI - Massachusetts Child Psychiatry Access Project 2.0: A Case Study in Child Psychiatry Access Program Redesign. AB - The Massachusetts Child Psychiatry Access Program is a statewide public mental health initiative designed to provide consultation, care navigation, and education to assist pediatric primary care providers in addressing mental health problems for children and families. To improve program performance, adapt to changes in the environment of pediatric primary care services, and ensure the program's long-term sustainability, program leadership in consultation with the Massachusetts Department of Mental Health embarked on a process of redesign. The redesign process is described, moving from an initial strategic assessment of program and the planning of structural and functional changes, through transition and implementation. PMID- 28916006 TI - Using Effective Public Private Collaboration to Advance Integrated Care. AB - Integrated mental health services within health care settings have many benefits; however, several key barriers pose challenges to fully implemented and coordinated care. Collaborative, multistakeholder efforts, such as health networks, have the potential to overcome prevalent obstacles and to accelerate the dissemination of innovative clinical strategies. In addition to engaging clinical experts, efforts should also include the perspectives of families and communities, a grounding in data and evaluation, and a focus on policy and advocacy. This article describes how one community, Washington, DC, implemented a health network to improve the integration of mental health services into pediatric primary care. PMID- 28916007 TI - From Theory to Action: Children's Community Pediatrics Behavioral Health System. AB - Integrated health care models attempt to cross the barrier between behavioral and medical worlds in order to improve access to quality care that meets the needs of the whole patient. Unfortunately, the integration of behavioral health and physical health providers in one space is not enough to actually promote integration. There are many models for promoting integration and collaboration within the primary care context. This article uses the experience of the Children's Community Pediatrics Behavioral Health Services system to highlight components of collaboration that should be considered in order to successfully integrate behavioral health within a medical home. PMID- 28916008 TI - Preparing Trainees for Integrated Care: Triple Board and the Postpediatric Portal Program. AB - Training combining the disciplines of pediatrics, psychiatry, and child and adolescent psychiatry dates back to World War II, but formal combined programs began more than 3 decades ago as the Triple Board Program and 10 years ago as the Postpediatric Portal Program (PPPP). Triple board training was rigorously examined as a pilot program and ongoing surveys suggest that it provides successful training of physicians who can pass the required board examinations and contribute to clinical, academic, and administrative/advocacy endeavors. As evidence grows showing the value of integrated care, physicians with combined training will offer a unique perspective for developing systems. PMID- 28916009 TI - Incorporating Trainees' Development into a Multidisciplinary Training Model for Integrated Behavioral Health Within a Pediatric Continuity Clinic. AB - Integrated behavioral and mental health systems of care for children require multidisciplinary team members to have specific competencies and knowledge of the other disciplines' strengths and practice needs. Training models for multidisciplinary professionals should consider the developmental level of trainees. The authors describe a model of flexible scaffolding, increasing intensity, and depth of experience as trainees gain skills and knowledge. PMID- 28916010 TI - Competencies and Training Guidelines for Behavioral Health Providers in Pediatric Primary Care. AB - This article focuses on the cross-discipline training competencies needed for preparing behavioral health providers to implement integrated primary care services. After a review of current competencies in the disciplines of child and adolescent psychiatry, psychology, and social work, cross-cutting competencies for integrated training purposes are identified. These competencies are comprehensive and broad and can be modified for use in varied settings and training programs. An existing and successful integrated care training model, currently implemented at Children's Hospital of Philadelphia, is described. This model and the training competencies are discussed in the context of recommendations for future work and training. PMID- 28916011 TI - Family-Based Integrated Care (FBIC) in a Partial Hospital Program for Complex Pediatric Illness: Fostering Shifts in Family Illness Beliefs and Relationships. AB - The heuristic model of family-based integrated care (FBIC) was developed from 1998 to 2016 in the context of the development of the Hasbro Children's Partial Hospital Program (HCPHP) along with the development of a family therapy training program for Brown University child psychiatry and triple board residents. The clinical experience of the HCPHP team in treating more than 2000 patients and families in combination with the authors' experience in training residents for diverse practice settings highlights the usefulness of the FBIC paradigm for interdisciplinary family-based treatment for a broad range of illnesses and levels of care. PMID- 28916012 TI - Preliminary Outcomes from an Integrated Pediatric Mental Health Outpatient Clinic. AB - An estimated 1 in 5 children in the United States meet criteria for a diagnosable mental disorder, yet fewer than 20% receive mental health services. Unmet need for psychiatric treatment may contribute to patterns of increasing use of the emergency department. This article describes an integrated pediatric evaluation center designed to prevent the need for treatment in emergency settings by increasing access to timely and appropriate care for emergent and critical mental health needs. Preliminary results showed that the center provided rapid access to assessment and treatment services for children and adolescents presenting with a wide range of psychiatric concerns. PMID- 28916014 TI - Integrated Behavioral Health Care in Pediatric Subspecialty Clinics. AB - Comorbid behavioral and physical health conditions are accompanied by troubling symptom burden, functional impairment, and treatment complexity. Pediatric subspecialty care clinics offer an opportunity for the implementation of integrated behavioral health (BH) care models that promote resiliency. This article reviews integrated BH care in oncology, palliative care, pain, neuropsychiatry, cystic fibrosis, and transplantation. Examples include integrated care mandates, standards of care, research, and quality improvement by child and adolescent psychiatrists (CAPs) and allied BH clinicians. The role of CAPs in integrated BH care in subspecialty care is explored, focusing on cost, resource use, financial support, and patient and provider satisfaction. PMID- 28916013 TI - The Emergency Department: Challenges and Opportunities for Suicide Prevention. AB - Emergency departments (EDs) can offer life-saving suicide prevention care. This article focuses on the ED and emergency services as service delivery sites for suicide prevention. Characteristics of EDs, models of emergency care, ED screening and brief intervention models, and practice guidelines and parameters are reviewed. A care process model for youths at risk for suicide and self-harm is presented, with guidance for clinicians based on the scientific evidence. Strengthening emergency infrastructure and integrating effective suicide prevention strategies derived from scientific research are critical for advancing suicide prevention objectives. PMID- 28916015 TI - Evaluating Integrated Mental Health Care Programs for Children and Youth. AB - Evaluations of integrated care programs share many characteristics of evaluations of other complex health system interventions. However, evaluating integrated care for child and adolescent mental health poses special challenges that stem from the broad range of social, emotional, and developmental problems that need to be addressed; the need to integrate care for other family members; and the lack of evidence-based interventions already adapted for primary care settings. Integrated care programs for children's mental health need to adapt and learn on the fly, so that evaluations may best be viewed through the lens of continuous quality improvement rather than evaluations of fixed programs. PMID- 28916016 TI - Comparing Two Models of Integrated Behavioral Health Programs in Pediatric Primary Care. AB - This study examined how to design, staff, and evaluate the feasibility of 2 different models of integrated behavioral health programs in pediatric primary care across primary care sites in the Bronx, NY. Results suggest that the Behavioral Health Integration Program model of pediatric integrated care is feasible and that hiring behavioral health staff with specific training in pediatric, evidence-informed behavioral health treatments may be a critical variable in increasing outcomes such as referral rates, self-reported competency, and satisfaction. PMID- 28916017 TI - Payment for Integrated Care: Challenges and Opportunities. AB - A multidisciplinary team approach to care and robust care coordination services are primary components of almost all integrated care delivery systems. Given that these services have limited reimbursement in fee-for-service payment arrangements, integrating care in a fee-for-service environment is almost impossible. Capitated payment models hold promise for supporting integrated behavioral and physical health services. There are multiple national examples of integrated care delivery systems supported by capitated payment arrangements. PMID- 28916018 TI - Essential Elements of a Collaborative Mental Health Training Program for Primary Care. AB - Mental health integration in primary care is based on creating an environment that encourages collaboration and supports appropriate care for patients and families while offering a full range of services. Training programs for primary care practitioners should include sessions on how to build and maintain such a practice along with information on basic mental health competencies. PMID- 28916019 TI - The Basic Science of Behavior Change and Its Application to Pediatric Providers. AB - Pediatric primary care providers (PPCPs) are increasingly expected to know how to assess, diagnose, and treat a wide range of mental health problems in children and adolescents. For many PPCPs, this means learning and performing new practice behaviors that were not taught in their residency training. Typical continuing education approaches to engage PPCPs in new practices have not yielded the desired changes in provider behavior. This article summarizes behavior change principles identified through basic behavior science, adult education, and communication research, and discusses their application to a patient-centered pediatric primary care mental health curriculum. PMID- 28916021 TI - Erratum. PMID- 28916020 TI - Healthy Minds-Healthy Kids: Integrating Care. PMID- 28916022 TI - Oral dermatology: Part II. PMID- 28916023 TI - Behcet disease: New aspects. AB - Behcet disease is currently considered an "autoinflammatory disease" triggered by infection and environmental factors in genetically predisposed individuals. Although the disease is characterized by recurrent oral and genital aphthous ulcers and ocular involvement, it can affect multiple organ systems. Complex aphthosis is characterized by recurrent oral and/or genital aphthous ulcers. It is important to evaluate the patient with complex aphthosis for Behcet disease and related systemic disorders. We discuss the etiopathogenesis, clinical features, diagnostic criteria, and treatment approaches for complex aphthosis and Behcet disease in light of the current literature. PMID- 28916024 TI - Contact stomatitis. AB - Contact stomatitis occurs in up to 10% of the population. Mechanical or chemical irritation, ill-fitting dentures, and dental fillings can induce irritant contact stomatitis. Type I hypersensitivity and type IV hypersensitivity to dental products and foods are frequently responsible for the allergic types of contact stomatitis. We review the causal agents of contact stomatitis, the differential diagnoses, diagnostic testing, and potential treatment. PMID- 28916025 TI - Oral manifestations of nutritional disorders. AB - Nutritional deficiencies occur when body metabolic requirements are not matched by intake and absorption. Reasons for this discrepancy are numerous, but often social, economic, medical, and even psychiatric factors may play a role. Vitamins and minerals are required for appropriate rapid cell turnover of the oral mucosa. The oral cavity is a unique anatomic environment that may manifest early signs of nutritional disorders as well as other indicators of systemic disease. Knowledge of these oral manifestations and associated findings will allow a practitioner to consider a nutritional disorder when evaluating oral changes and, in turn, initiate appropriate therapy. A systematic approach to examination of the mouth and perioral skin is suggested. A detailed medical and social history complements the physical examination in identifying patients at risk for nutritional disorders and heightening the clinical suspicion to warrant additional nutritional screening. The rising prevalence of anorexia and bulimia, as well as fad diets, add to the population of patients at risk for vitamin and mineral deficiencies that a clinician must now consider. PMID- 28916026 TI - A diagnostic and therapeutic approach to primary burning mouth syndrome. AB - Primary burning mouth syndrome (BMS) is an oral mucosal disorder that is characterized by a chronic and often debilitating intraoral burning sensation for which no localized or systemic cause can be found. BMS most commonly affects postmenopausal women. The pathophysiology of primary BMS is not well understood. Diagnosing BMS can prove to be challenging. BMS patients can also pose a therapeutic challenge to clinicians who are consulted to evaluate these patients. Most commonly used therapies include tricyclic antidepressants, alpha-lipoic acid, clonazepam, and cognitive-behavioral therapy. Clinical judgment, patient counseling, and monitoring of pain are important. Further research is required to assess the effectiveness of serotonin and newer serotonin-noradrenalin reuptake inhibitors. PMID- 28916027 TI - Oral leukoplakia and oral cavity squamous cell carcinoma. AB - Oral leukoplakia is defined as a white oral lesion not related to another disease process. These lesions are largely asymptomatic, and the clinical relevance of oral leukoplakia is primarily tied to its association with oral cavity squamous cell carcinoma. Timely workup and effective management of these lesions can reduce the risk of malignant transformation and promote early diagnosis of invasive tumors. A biopsy should be performed promptly of any persistent or suspicious leukoplakia with subsequent management dictated by histologic findings. Benign lesions can be observed or treated with topical therapy, and dysplastic lesions should be excised. Some risk of malignant transformation remains even after treatment, and close follow-up is required. Oral cavity squamous cell carcinoma is an aggressive malignancy that can result from malignant conversion of oral leukoplakia or occur de novo. These tumors are primarily treated with surgical resection and adjuvant radiation or chemoradiation as dictated by histopathologic findings. PMID- 28916028 TI - Etiology, evaluation, and management of xerostomia. AB - Xerostomia is defined as the complaint of oral dryness. It is a condition that primarily affects older adults and can have a significant negative effect on one's quality of life. Patients with xerostomia often do not have objective signs of hyposalivation. The underlying etiology of xerostomia includes a variety of systemic diseases and local factors. Our aim is to provide a comprehensive review of the differential diagnosis, evaluation, and management of xerostomia. Prompt diagnosis and management can alleviate the clinical manifestations of this debilitating condition. PMID- 28916029 TI - Oral mucosa biology and salivary biomarkers. AB - Although the surfaces of both the skin and oral mucosa are protected by squamous epithelial cells and fall within the scope of dermatologic practice, the oral cavity contains highly specialized structures and functions distinct from other skin biology and pathologic conditions and are also the purview of clinicians who care for patients with skin and mucosal diseases. We describe the distinct features of the tongue, mucosa, and salivary glands. In particular, we examine the composition and function of the saliva, with special focus on salivary biomarkers. Within the oral cavity, saliva shows great promise as a noninvasive and sensitive marker for many systemic diseases. Biomarkers are being used as diagnostic or monitoring tools for a wide variety of diseases, including systemic lupus erythematosus, Sjogren disease, Behcet disease, and autoimmune blistering disorders, as well as premalignant and malignant lesions of the mouth. PMID- 28916030 TI - Fellowship candidate selection at the BEST Medical Center: A novel process. AB - Dr. Ida Lystic completed her MD degree at the prestigious Harvey Medical School (which has since been renamed the Harvey Provider School) and her residency in internal medicine and gastroenterology fellowship at the OTHER (Owen T. Henry and Eugene Rutherford) Medical Center. She was subsequently hired as an assistant professor at the BEST (Byron Edwards and Samuel Thompson) Medical Center in 2015. After eventually completing an extensive list of employment requirements, she was able to begin seeing patients. She had not anticipated a change in the electronic medical record systems-from the user-friendly intuitive SIMPLE (Succinct Input Making Patients' Lives Electronic) system to the complicated and challenging LEGEND (perhaps, as her colleagues had suggested, Lengthy and Excessively Graded Evaluation and Nomenclature for Diagnosis) system. Nor had she expected some of the challenges encountered in her daily clinic routine: The lack of schedulers for her patients (based on recommendations by the Optima Efficiency Consultant Group and incorporated by the BEST efficiency department) and the addition of egg timers on the doors along with a compliance spreadsheet and corrective action plan for the tardy physicians to complete to encourage punctuality (based on the assessment of the Wait Time Committee). She joined the LOST (Laboratory OverSight and Testing) Committee, because participation to support BEST Medical Center practices is strongly suggested for faculty seeking promotion; however, when the new committee chairman-who is a surgeon-was elected, the noon meetings were rescheduled for 6:00 am each month. At the request of her recently divorced department chairman, the philandering Dr. Seymore Fox, she became deputy head of the Gastroenterology Fellowship Selection Committee; she recently coordinated the selection of the physicians for next year's fellowship. The fellowship candidate selection process at the BEST Medical School is probably similar to that performed at the OTHER Medical Center; however, innovative interview techniques such as assessment for manual dexterity (with the "space race") and typing skills have been incorporated to enhance the selection of the best candidates. Dr. Ida Lystic, the gastroenterology department, and the medical school at "the BEST Medical Center" are creations of the author's imagination; yet, many of the anecdotes are based on actual events whose details have been modified to protect the guilty. PMID- 28916031 TI - Dermatosis papulosa nigra: a clinically and histopathologically distinct entity. AB - Dermatosis papulosa nigra was first described by Aldo Castellani (1874-1971) more than 90 years ago, and it has since been presumed to be a variant of seborrheic keratosis. Despite their morphologic similarities both macroscopically and microscopically, key differences have yet to be explained. These lesions also exhibit different demographics, with dermatosis papulosa nigra having a predilection for dark-skinned individuals and a female predominance. No studies to date have investigated this, but studies assessing the mechanisms of similar dermatologic conditions may yield significant clues. The additional impact of environmental factors may also be important, but much controversy exists. Further investigations into dermatosis papulosa nigra are necessary to determine its pathogenesis and whether it should be regarded as a distinct entity. PMID- 28916032 TI - Polymer inclusion membranes (PIMs) in chemical analysis - A review. AB - This review highlights the increasing interest in polymer inclusion membranes (PIMs) in analytical chemistry as they are adapted to new and novel applications. PIMs are polymer-based liquid membranes and were first introduced 50 years ago as the sensing membranes in ion-selective electrodes and optodes. More recently however, PIMs have been used for other applications in analytical chemistry such as for sample separation, sample pre-concentration, electro-driven extraction, and passive sampling, and have also been incorporated into on-line and automated analysis systems. The present review provides a general overview of the analytical chemistry applications of PIMs reported in the literature to date and illustrates their versatility for solving challenging chemical analysis problems. PMID- 28916033 TI - Ca2+ detection utilising AlGaN/GaN transistors with ion-selective polymer membranes. AB - We demonstrate highly selective and sensitive potentiometric ion sensors for calcium ion detection, operated without the use of a reference electrode. The sensors consist of AlGaN/GaN heterostructure-based transistor devices with chemical functionalisation of the gate area using poly (vinylchloride)-based (PVC) membranes having high selectivity towards calcium ions, Ca2+. The sensors exhibited stable and rapid responses when introduced to various concentrations of Ca2+. In both 0.01 M KCl and 0.01 M NaCl ionic strength buffer solutions, the sensors exhibited near Nernstian responses with detection limits of less than 10 7 M, and a linear response range between 10-7-10-2 M. Also, detection limits of less than 10-6 M were achieved for the sensors in both 0.01 M MgCl2 and 0.01 M LiCl buffer solutions. AlGaN/GaN-based devices for Ca2+ detection demonstrate excellent selectivity and response range for a wide variety of applications. This work represents an important step towards multi-ion sensing using arrays of ion selective field effect transistor (ISFET) devices. PMID- 28916034 TI - Colorimetric biosensor based on a DNAzyme primer and its application in logic gate operations for DNA screening. AB - A colorimetric biosensor for DNA screening was designed based on the conformational changes of the horseradish peroxidase (HRP)-mimicking DNAzyme. The scheme of DNA biosensing was designed based on the base pairing of DNAzyme sequence to inhibit the formation of HRP-mimicking hemin/G-quadruplex structures in the process of amplification. DNA could be amplified via the universal primer multiplex polymerase chain reaction (UP-M-PCR) and innovatively detected as color disappear in the reaction visible to the naked eye. The input of key factors and the output of optical characteristics in the reaction inspired the development of an OR logic gate operation for DNA detection. This biosensor overcomes self inhibition and amplification disparity with the help of UP-M-PCR, thereby exhibiting high specificity and high-throughput without the requirement of gel analysis work. This biosensing system also presented 1% sensitivity and approximately 180 copy numbers in triplicate. The biosensor was used to screen elements from genetically modified organisms (GMOs) and covered more than 90% of all globally authorized events in the world. The designed colorimetric biosensor is a rapid, portable and versatile tool for nucleic acids detection and diagnosis in the field. PMID- 28916035 TI - Sensitive prostate specific antigen quantification using dihydrolipoic acid surface-functionalized phosphorescent quantum dots. AB - Herein, high-quality Mn-doped ZnS quantum dots (QDs) have been synthesized using a facile approach directly in aqueous media. The surface of the obtained QDs was further modified by cap-exchange of the native cysteine shell with dihydrolipoic acid (DHLA) ligands resulting in nanocrystals with high water-stability having an intense phosphorescent signal. Covalent bioconjugation of the DHLA-coated nanoparticles with an anti-IgG antibody was then carried out. Interestingly the QD immunoprobe (QD-labelled antibodies) maintained an intense phosphorescence emission, without any significant spectral-shift (as compared to the free QDs). Coupling of an asymmetric flow field flow fractionation technique to an elemental mass spectrometry detection enabled the accurate determination of the efficiency of the bioconjugation reaction. The obtained nanoparticle-antibody bioconjugate was then applied to develop a quantitative sandwich-type phosphorescent immunoassay for Prostate Specific Antigen (PSA), and a limit of detection (LOD) of 17 pg mL-1 of PSA was achieved and allow to quantify such biomarker in samples within clinically relevant levels. Finally, the assay was validated for the quantification of PSA in the cellular media of prostate cancer cells. Obtained results proved the robustness of the proposed immunoassay based on long-lived phosphorescence measurements against eventual photoluminescent interferences significantly affecting the conventional short-lived fluorescence detection. PMID- 28916036 TI - Determination of methotrexate in spiked human blood serum using multi-frequency electrochemical immittance spectroscopy and multivariate data analysis. AB - This article describes an attempt to develop a sensor based on multi-frequency immittance spectroscopy for the determination of methotrexate (MTX) in blood serum using gold electrodes modified with antibodies. The attachment of antibodies was monitored with electrochemical immittance spectroscopy (EIS) and X ray photoelectron spectroscopy (XPS). The EIS measurements of MTX resulted in a data matrix of size 39 * 55. The data were analysed using multivariate data analysis and showed a concentration dependence and time dependence that could be separated. This allowed the calculation of a multivariate calibration model. The model showed good linear behavior on a logarithmic scale offering a detection limit of 5 * 10-12 mol L-1. PMID- 28916037 TI - Electrochemical aptasensor for human osteopontin detection using a DNA aptamer selected by SELEX. AB - A DNA aptamer with affinity and specificity for human osteopontin (OPN), a potential breast cancer biomarker, was selected using the SELEX process, considering its homology rate and the stability of its secondary structures. This aptamer exhibited a satisfactory affinity towards OPN, showing dissociation constants lower than 2.5 nM. It was further used to develop a simple, label-free electrochemical aptasensor against OPN. The aptasensor showed good sensitivity towards OPN in standard solutions, being the square wave voltammetry (SWV), compared to the cyclic voltammetry, the most sensitive technique with detection and quantification limits of 1.4 +/- 0.4 nM and 4.2 +/- 1.1 nM, respectively. It showed good reproducibility and acceptable selectivity, exhibiting low signal interferences from other proteins, as thrombin, with 2.6-10 times lower current signals-off than for OPN. The aptasensor also successfully detected OPN in spiked synthetic human plasma. Using SWV, detection and quantification limits (1.3 +/- 0.1 and 3.9 +/- 0.4 nM) within the OPN plasma levels reported for patients with breast cancer (0.4-4.5 nM) or with metastatic or recurrent breast cancer (0.9-8.4 nM) were found. Moreover, preliminary assays, using a sample of human plasma, showed that the aptasensor and the standard ELISA method quantified similar OPN levels (2.2 +/- 0.7 and 1.7 +/- 0.1 nM, respectively). Thus, our aptasensor coupled with SWV represents a promising alternative for the detection of relevant breast cancer biomarkers. PMID- 28916038 TI - A tri-metal centered metal-organic framework for solid-phase microextraction of environmental contaminants with enhanced extraction efficiency. AB - This study presents the preparation and the characterizations of six tri-metal centered metal-organic frameworks (tM-MOFs) as solid-phase microextraction (SPME) adsorbents. Possessing different proportions of Al, Ga and In atoms in their frameworks, the tM-MOF-based SPME coatings exhibited different extraction performance towards the organic pollutants. Extraction results showed that the M4 (Al0.593Ga0.167In0.240(O2C2H4)(h2fipbb)) coating exhibited the best enrichment ability among six tM-MOFs. In addition, it showed better extraction efficiency towards the analytes than three single-metal centered MOFs coatings and a commercial polydimethylsiloxane (PDMS) coating. The adsorption process of the M4 coating was physical adsorption and it was mainly affected by the diffusion process of the compound from the sample to the material, which is the same with the adsorption processes of the single-metal centered MOFs coatings. Under optimal conditions (extraction time, 3 min; NaCl concentration, 25% (w/v); desorption temperature, 270 degrees C; extraction temperature, 30 degrees C), the M4 coating achieved low detection limits (0.13-0.88 ng L-1) and good linearity (5-2000 and 5-5000 ng L-1) for benzene series compounds. The repeatabilities (n = 5) for single fiber were between 4.3 and 8.1%, while the reproducibilities (n = 3) of fiber-to-fiber were in the range of 7.9-12.7%. Finally, a M4 coated SPME fiber was successfully applied to the analysis of environmental water samples with satisfactory recoveries (80.8%-119.5%). PMID- 28916039 TI - Highly sensitive method for aldehydes detection: Application to furfurals analysis in raisin and bovine milk powder. AB - A pre-column fluorescent derivatization method based on nitrone formation has been applied to determine furfurals (e.g. furfural (F), 5-methyfurfural (5-MF) and 5-hydroxymethylfurfural (5-HMF)) in food samples for the first time. An N substituted hydroxylamine reagent 4-((hydroxyamino)butyl)-7-hydroxycoumarin (HAHC) was used to react with the aldehyde group of furfurals to form stable nitrone derivatives with high fluorescence intensities. The reactions proceeded under mild conditions in 30 min with high derivatization yields (>93%). A baseline-separation of three furfurals derivatives was subsequently achieved within 25 min on a reversed-phase column. The detection limits were at the low femtomol level (S/N = 3, 20 MUL per injection). The linear range of the calibration curve was 0.4-4000 nM with good correlation coefficients (R2 >= 0.9991). The proposed method was further applied for food sample analysis, such as bovine milk powder and raisin. Satisfactory recoveries were obtained in the range of 94.7%-103.5%. Above all, this pre-column derivatization method is simple, fast and highly sensitive, providing an effective and promising way for future studies of aldehydes in different matrices. PMID- 28916041 TI - Polydopamine-functionalized poly(ether ether ketone) tube for capillary electrophoresis-mass spectrometry. AB - Capillary electrophoresis-mass spectrometry (CE-MS) is a hyphenated technique that combines the advantages like low sample consumption, high separation efficiency, short analytical time in CE and high sensitivity, powerful molecular structure elucidation in MS. Polyimide-coated fused silica capillary has become the most dominant capillary for CE, but it suffers from swelling and aminolysis of polyimide coating when treated with organic solvents and alkaline buffer in the CE-MS interface in which the polyimide coating at the end of the capillary is exposed to the solution, and this phenomenon can result in current instability, irregular electrospray and clogging at outlet after prolonged use. In this work, poly(ether ether ketone) (PEEK) capillary was explored as separation capillary for CE-MS. The problems like swelling and aminolysis of polyimide coating were solved due to the high thermal and chemical stability of PEEK material. After modification with polydopamine, PEEK capillary (PD-PEEK) can generate adjustable electroosmotic flow and provide good separation selectivity. The zwitterion polymer of polydopamine can provide cathodic electroosmotic flow (EOF) at high pH value (pH >= 5) and anodic EOF at low pH value (pH <= 4), and the EOF mobility can also be adjusted by controlling the modification time of polydopamine. Good separation performance was obtained in the analysis for several classes of compounds including amino acids, phenols and plant hormones at rational EOF direction. Repeatability of the PD-PEEK capillary was studied, with relative standard deviations for intra-day, inter-day runs and between tubes less than 4.94%. PMID- 28916040 TI - Matrix-assisted laser desorption/ionization mass spectrometry for the analysis of polyamines in plant micro-tissues using cucurbituril as a host molecule. AB - In this study, a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) strategy using cucurbit[n]uril (CB[n]) as a host molecule is proposed for the analysis of low molecular weight (LMW) compounds in complex samples. As a proof-of-concept, CB[6] was selected as the host molecule, and endogenous polyamines in plant tissue were chosen as the target analytes. Due to the molecular recognition and mass shifting properties of CB[6], the ionic signals associated with polyamines were moved to the higher mass region (>1000 Da) after specifically binding to CB[6], while signal interference derived from the conventional organic matrix and the complex sample matrix remained in the low mass region because of the incompatibility of their molecular size with CB[6] cavities. The strategy not only facilitated the analysis of LMW compounds in complex samples by MALDI MS, but also offered high throughput by accomplishing the entire analytical procedure within 10 min. The detection of polyamine concentration showed good linearity in the range of 0.02-10.0 ng/MUL with correlation coefficients (R) greater than 0.9915. The limits of detection were 8.8-28.8 pg. The good reproducibility and reliability of the method were demonstrated by excellent intraday and interday precisions with relative standard deviations less than 7.9%, and the recovery ranged from 92.1% to 117.1%. Finally, the good sensitivity of the method allowed for the quantitative analysis of endogenous polyamine concentrations in various micro-tissues of Arabidopsis thaliana (20.0-740.0 MUg fresh weight for each sample). PMID- 28916043 TI - Nocturnal hypoglycemic alarm based on near-infrared spectroscopy: In vitro simulation studies. AB - An alarm algorithm for detecting episodes of nocturnal hypoglycemia is demonstrated in simulation studies that incorporate the use of a tissue phantom. Based on transmission spectra collected in the near-infrared combination region of 4000-5000 cm-1, pattern recognition methods are used to classify spectra into alarm and non-alarm data classes on the basis of whether or not they signify a glucose excursion below a user-defined hypoglycemic alarm threshold. A reference spectrum and corresponding glucose concentration are acquired at the start of the monitoring period, and absorbance values of subsequent spectra are computed relative to this reference. The resulting differential spectra reflect differential glucose concentrations that correspond to the differences in concentration between each spectrum and the reference. Given the alarm threshold, a database of calibration differential spectra are partitioned into those above and below the threshold. Piecewise linear discriminant analysis is then used to compute a classification model that can be applied to differential spectra collected during the monitoring period in order to identify spectra that signal glucose concentrations in the hypoglycemic range. This alarm algorithm is demonstrated in two multiple-day dynamic studies that incorporate a tissue phantom composed of films of keratin and collagen that approximate the thicknesses of the corresponding proteins found in human tissue. PMID- 28916042 TI - Urinary intermediates of tryptophan as indicators of the gut microbial metabolism. AB - While over 10% of the human metabolome is directly associated with the gut microbial metabolism, specific metabolites are largely uncharacterized. Therefore, methods for the identification and quantification of microbiota associated metabolites in biological fluids such as urine or plasma are necessary in order to elucidate the molecular basis of host-microbiota interaction. In this study, we focused on the tryptophan metabolism, employing quantitative assays by ultra-high performance liquid chromatography (UHPLC) and tandem mass spectrometry, specifically selected reaction monitoring (SRM). Metabolite standards were utilized to generate SRM library for 16 intermediates of the tryptophan metabolism which were human endogenous as well as microbiota associated based on the HMDB classification. Next, the SRM assays were utilized for screening in maternal urine samples and in dried urine specimens from neonates. The approach resulted in the discovery of microbiota-associated metabolites (methyl indole-3-acetate and methyl indol-3-propionate) previously unreported in urine samples and additionally in quantification of 8 intermediates of the tryptophan metabolism. To the best of our knowledge, this study represents the first attempt to explore previously unreported microbial metabolites in urine by UHPLC-SRM and novel methodology for simultaneous determination of microbiota modulated component of Trp metabolism. PMID- 28916044 TI - Antibiotic-affinity strategy for bioluminescent detection of viable Gram-positive bacteria using daptomycin as recognition agent. AB - A bioluminescent method was proposed for rapid detection of viable Gram-positive bacteria based on a novel antibiotic-affinity strategy on a magnetic beads (MBs) platform. Daptomycin, a highly efficient lipopeptide antibiotic for Gram-positive bacteria, was used as a recognition agent to functionalize MBs. The daptomycin functionalized MBs showed high capture and concentration efficiency for Gram positive bacteria due to the strong binding between daptomycin and bacterial cell membrane in the presence of Ca2+ ion. The captured bacteria were lysed by hexadecyl trimethyl ammonium bromide solution, followed by a bioluminescent detection of the released intracellular adenosine triphosphate. Four Gram positive bacteria, including Staphylococcus aureus, Streptococcus mutans, Bacillus subtilis and Staphylococcus epidermidis, were detected as model bacteria by this method. Under the optimal conditions, the bacteria could be detected within a linear range of 1.0 * 102-3.0 * 106 CFU mL-1, with a detection limit of 33 CFU mL-1. The whole detection procedure could be completed within 20 min. Gram negative bacteria and dead Gram-positive bacteria showed negligible interference to the detection of viable Gram-positive bacteria. The proposed method was successfully applied to quantify the amount of viable Gram-positive bacteria in cheese, milk, lake water, human urine and physiological saline injection with acceptable recovery values ranging from 75.0% to 120.0%. The strategy possessed some advantages such as high sensitivity, short assay time and simple operation, thus showed great promise for food hygiene, environment monitoring, clinical diagnosis and drug safety. PMID- 28916045 TI - Evaluation of fluorogenic substrates for Ni/Co LDHs peroxidase mimic and application for determination of inhibitory effects of antioxidant. AB - Nanomaterial-based peroxidase-mimetics are an emerging research field that promises to produce alternatives to horseradish peroxidase for a variety of applications. Generally, some peroxidase-mimetics substrates are used in acidic condition (pH <= 7). Then, it is necessary to screen some peroxidase-mimetics substrates suitable for basic condition because that some peroxidase-mimetics leached ions in acidic solution. In this paper, using Ni/Co layered double hydroxides (LDHs) as a nano-peroxidase mimic model, we evaluated three fluorogenic substrates suitable for basic condition though experimental conditions, reaction kinetic and glucose detection assay. And the detection of glucose method based on homovanillic acid (HVA) as fluorescent substrate gave wide linear range (0.02-20 MUM) and low detection limit (0.01 MUM). We also developed a novel platform that could study the inhibitory effects of ascorbic acid and glutathione based on the system of Ni/Co LDHs-HVA-H2O2. PMID- 28916046 TI - Inflammatory response and long-term behavioral assessment after neonatal CO2 pneumothorax: study in a rodent model. AB - BACKGROUND: Carbon-dioxide (CO2)-pneumothorax during minimally invasive surgery induces well-known metabolic changes. However, little is known about its impact on the central nervous system. The aim of this work is to evaluate the acute impact of CO2-pneumothorax over central cytokine response and its long-term effect on animal behavior. METHODS: This is an experimental study where neonatal Sprague-Dawley rats are submitted to CO2-pneumothorax. Peripheral and central cytokine response was evaluated 24h after insufflation, and peripheral immune cell phenotyping was evaluated 24h and 4weeks post-insufflation. Progenitor cell survival was evaluated in the hippocampal dentate gyrus, and the behavioral analysis was performed in adulthood to test cognition, anxious-like, and depressive-like behavior. RESULTS: Significantly increased IL-10 levels were observed in the cerebrospinal-fluid (CSF) of animals submitted to CO2 pneumothorax, while no differences were found in serum. Regarding pro inflammatory cytokines, no differences were observed in the periphery or centrally. CO2-pneumothorax event did not alter the survival of newborn cells in the hippocampal dentate gyrus, and no impact on long-term behavior was observed. CONCLUSIONS: Neonatal animals submitted to CO2-pneumothorax present acutely increased CSF IL-10 levels. The CO2-pneumothorax seems to result in no significant outcome over neurodevelopment as no functional behavioral alterations were observed in adulthood. PMID- 28916047 TI - Anorectal malformation & Hirschsprung's disease: A cross-sectional comparison of quality of life and bowel function to healthy controls. AB - BACKGROUND: Patients with anorectal malformation (ARM) and Hirschsprung's disease (HD) face long-term disturbance in bowel function even after definitive surgery. This study evaluates the quality of life (QOL) of patients with ARM and HD, and compares them to healthy controls using self-report questionnaires. METHODOLOGY: A prospective study was performed recruiting patients with ARM or HD from September 2013 to December 2014 who had primary surgery done in our institution at least 2 years prior to participation. Age-matched and gender-matched controls were enrolled from our patients with minor outpatient complaints. All participants completed the following PedsQLTM scales (maximum score 100): 4.0 Generic Core Scales, 3.0 General Well-Being (GWB) Scale and 2.0 Family Impact (FI) Module. All were also scored on bowel function (BFS), with a maximum score 20. Appropriate statistical analysis was performed, with significance level <0.05. RESULTS: There were 193 participants: 87 controls, 62 ARM, 44 HD. When comparing Core, GWB and FI scores, there were no significant differences between groups although controls had best scores indicating best QOL and general wellbeing, with least impact of the child's health on the family. BFS was significantly different with controls having best and ARM worst scores. There were no significant differences in scores between parent and child indicating intradyad consistency. There was significant positive correlation between BFS and Core (p<0.0001), and between BFS and GWB scores (p<0.005); and significant negative correlation between BFS and FI scores (p<0.0001). CONCLUSIONS: Bowel function impacts quality of life. Those with ARM and HD can achieve good quality of life comparable to controls, based on patient and caregiver self-reported outcomes. TYPE OF STUDY: Prospective comparative study LEVEL OF EVIDENCE: Level II. PMID- 28916048 TI - Patency of common carotid artery and internal jugular vein after a simple vessel sparing cannulation for extracorporeal membrane oxygenation support. AB - BACKGROUND: Common carotid artery and internal jugular vein are commonly cannulated for establishment of peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) support. We present our results of a vessel sparing cannulation technique for neck vessels, which helps maintain vessel patency after decannulation. METHODS: All patients who underwent ECMO, between January 2004 and January 2013 at a single center, were retrospectively reviewed. Follow up data for the patency of common carotid artery (CCA) and internal jugular vein (IJV) after decannulation were recorded. RESULTS: Twenty-four consecutive patients who were successfully decannulated after VA ECMO support who underwent vessel sparing cannulation were retrospectively reviewed. Follow up data were unavailable in 4 and 1 patient did not survive. Amongst the remaining 19 patients the median duration of ECMO support in the remaining was 7 (IQR; 4-10) days. Follow up studies documenting vessel patency were available for IJV in 18 patients and CCA in 14 patients. At a median follow up of 137days (IQR; 35-7240) 15 (78%) patients had patent IJVs and 14 (100%) patients had patent CCAs. CONCLUSION: The simple vessel sparing technique is effective in allowing restoration of the patency of the neck vessels after ECMO decannulation. LEVEL OF EVIDENCE: Case series with no comparison group (Level IV). PMID- 28916049 TI - Optical Imaging Paves the Way for Autophagy Research. AB - Autophagy is a degradation process in eukaryotic cells that recycles cellular components for nutrition supply under environmental stress and plays a double edged role in development of major human diseases. Noninvasive optical imaging enables us to clearly visualize various classes of structures involved in autophagy at macroscopic and microscopic dynamic levels. In this review, we discuss important trends of emerging optical imaging technologies used to explore autophagy and provide insights into the mechanistic investigation and structural study of autophagy in mammalian cells. Some exciting new prospects and future research directions regarding optical imaging techniques in this field are also highlighted. PMID- 28916050 TI - Reply to "Contribution of serum lipoproteins in mortality risk assessment". PMID- 28916051 TI - Statin regulates NLRP1 inflammasome expression through SREBP1: A novel anti atherosclerotic mechanism. PMID- 28916052 TI - Statin potential Nlrp1 inflammasome gene expression modulation via Srebp-1 pathway in peripheral arterial disease. PMID- 28916053 TI - Classification of Kounis syndrome. PMID- 28916054 TI - New classification of Kounis Syndrome. PMID- 28916055 TI - Bioresorbable stent thrombosis, lactic acid release and Kounis syndrome. PMID- 28916056 TI - Reply to Letter to the Editor entitled: "Bioresorbable stent thrombosis, lactic acid release and Kounis syndrome". PMID- 28916057 TI - Could low high-density lipoprotein cholesterol levels improve the performance of the CHADS2 and CHA2DS2-VASc scores in predicting new atrial fibrillation? PMID- 28916058 TI - Low high-density lipoprotein cholesterol levels improve the performance of the CHADS2 and CHA2DS2-VASc scores for the prediction of new-onset atrial fibrillation. PMID- 28916059 TI - New biomarkers in risk stratification in patients with atrial fibrillation. PMID- 28916060 TI - Is electrical cardioversion doable in atrial fibrillation without transesophageal echocardiography? PMID- 28916061 TI - MicroRNA-93 upregulation in coronary artery disease is potentially adaptive. PMID- 28916062 TI - Response by Phillips KP et al. to letter regarding article 'Long term outcomes from catheter ablation of very longstanding persistent atrial fibrillation'. PMID- 28916063 TI - Is the increased risk of thromboembolic events in adult congenital heart disease patients with atrial tachyarrhythmias accurate? PMID- 28916064 TI - Highlights of methodological approaches. PMID- 28916065 TI - LncRNA MALAT1: A potential regulator of autophagy in myocardial ischemia reperfusion injury. PMID- 28916066 TI - Drug-eluting stent failure: A complex scenario. PMID- 28916067 TI - Is the new risk factor algorithm accurate to predict frequent premature ventricular contraction-induced cardiomyopathy? PMID- 28916068 TI - Kaplan-Meier curve of retrospective study: Do not misuse it! PMID- 28916069 TI - Sirtuin 1 activation and cardioprotective role: Thy eternal summer shall not fade. PMID- 28916070 TI - Response to Red cell distribution width and risk of cardiovascular mortality: Insights from National Health and Nutrition Examination Survey (NHANES)-III. PMID- 28916071 TI - LncRNA UCA1 modulates cardiomyocyte apoptosis by targeting miR-143 in myocardial ischemia-reperfusion injury. PMID- 28916072 TI - Letter to "Safety and efficacy of drug eluting stents in patients with spontaneous coronary artery dissection" by Conrotto F et al. PMID- 28916073 TI - Mitochondrial dynamics regulate myocardial contractility and vice versa. PMID- 28916074 TI - Response by Robert et al. to the letter regarding article "Time trends in hospital admissions and mortality due to abdominal aortic aneurysms in France, 2002-2013". PMID- 28916075 TI - Dose-dependent effects of ivabradine on heart rate during maximal efforts in a woman with permanent atrial fibrillation. PMID- 28916076 TI - Should we perform invasive coronary angiography to all patients with suspected stress cardiomyopathy? PMID- 28916077 TI - D-dimer is a predictor of cardiovascular death, and new-onset atrial fibrillation in patients with systolic heart failure. PMID- 28916078 TI - DPP-4 inhibition as a therapeutic strategy to ameliorate diabetic metabolic memory. PMID- 28916079 TI - Takotsubo syndrome: Still a benign entity? PMID- 28916080 TI - PEDF ameliorates macrophage inflammation via NF-kappaB suppression. PMID- 28916081 TI - Response to: Ibn Nafis and the early description of the role of coronary arteries in blood supply of the heart. PMID- 28916082 TI - Suramin against myostatin signaling may be considered to intervene in female patients with advanced heart failure. PMID- 28916083 TI - A negative LGE is inconclusive to exclude an early cardiac amyloidosis: it's the time for a T1 mapping in clinical practice. PMID- 28916084 TI - The importance of anatomy on viewpoint of Avicenna. PMID- 28916085 TI - Avicenna or Ibn Nafis; who did mention to the role of coronary arteries in blood supply of the heart? PMID- 28916086 TI - Reply to letter to the editor "suramin against myostatin signaling may be considered to intervene in female patients with advanced heart failure". PMID- 28916087 TI - Statin and ezetimibe combination therapy: New therapeutic options for lowering Low-Density Lipoprotein Cholesterol. PMID- 28916088 TI - The impact of anatomy in Avicenna's works. PMID- 28916089 TI - Is NPY causing myocardial ischemia in patients with microvascular angina associated with its abnormal constrictor response at the microcirculation level? PMID- 28916090 TI - Reply to the letter from He et al. Is NPY causing myocardial ischemia in patients with microvascular angina associated with its abnormal constrictor response at the microcirculation level? PMID- 28916091 TI - Retraction notice to "Ivabradine as adjuvant treatment for chronic heart failure" [Int. J. Cardiol. 227 (2017) 43-50]. PMID- 28916092 TI - Cardiovascular safety of canagliflozin. PMID- 28916093 TI - Reply to: Cardiovascular safety of canagliflozin. PMID- 28916094 TI - Risk assessment of mortality in middle-aged adults. PMID- 28916095 TI - Review: Novel sensing strategies for bacterial detection based on active and passive methods driven by external field. AB - For sustainable human life, biosensing systems for contaminants or disease causing bacteria are crucial for food security, environmental improvement, and disease prevention. With an aim of enhancing the sensitivity and detection speed, many researchers have developed efficient detection methods for target bacteria. In this review, we discuss recent topics related to active and passive bacterial detection methods, including (1) optical approaches with unique functional nano- and micro-structures, and (2) electrical approaches involving mechanical modulation and electrochemical reactions. Particularly, we discuss the prospects in the development of label-free, rapid, and highly sensitive biosensors based on active detection principles with light-induced dynamics, in conjunction with dielectrophoresis-induced selective trapping. PMID- 28916096 TI - The preparation of a poly (pentaerythritol tetraglycidyl ether-co-poly ethylene imine) organic monolithic capillary column and its application in hydrophilic interaction chromatography for polar molecules. AB - An easy single-step thermal treatment "one-pot" approach for the preparation of poly (pentaerythritol tetraglycidyl ether-co-poly ethylene imine) organic monolithic capillary columns was developed successfully. The column was prepared by the epoxy-amine ring-opening polymerization of pentaerythritol tetraglycidyl ether (PTE) with poly (ethylene imine) (PEI) using acetonitrile (ACN) and polyethylene glycol 600 (PEG 600) as the porogenic system at 60 degrees C for 12 h. The obtained monolith was homogeneous and permeable. It achieved the high efficiency separation of polar molecules including amides, nucleosides, bases, phenols, and benzoic acids in capillary liquid chromatography (cLC). The highest column efficiency reached ca. 101,000 plates/m (for guanine) on monolith poly(PTE co-PEI) at 0.64 mm/s, and satisfactory chromatographic performance with column efficiencies ranged from 45,500 to 97,000 plates/m was achieved for the four amides. A typical hydrophilic interaction liquid chromatography (HILIC) retention mechanism was observed with high organic solvent contents (>60% ACN). Also, the polymer-based monolithic column was successfully applied to separate the tumor markers. Furthermore, the poly(PTE-co-PEI) monolith could be easily modified with 1, 2-epoxydodecane, which reacted with the amino groups presented on the surface of the poly(PTE-co-PEI) monolith. Hydrophobic interactions were observed during the separation of alkylbenzenes and anilines on the post-modified poly(PTE-co PEI) monolith. Together, these results confirm the feasibility of the epoxy-amine ring-opening polymerization reaction during the fabrication of a monolithic column with high efficiency for cLC applications. PMID- 28916097 TI - Determination of 99Tc in fresh water using TRU resin by ICP-MS. AB - Technetium-99 (99Tc) determination at trace level by inductively coupled plasma mass spectrometry (ICP-MS) is challenging because there is no readily available appropriate Tc isotopic tracer. A new method using Re as a recovery tracer to determine 99Tc in fresh water samples, which does not require any evaporation step, was developed. Tc(VII) and Re(VII) were pre-concentrated on a small anion exchange resin (AER) cartridge from one litre of water sample. They were then efficiently eluted from the AER using a potassium permanganate (KMnO4) solution. After the reduction of KMnO4 in 2 M sulfuric acid solution, the sample was passed through a small TRU resin cartridge. Tc(VII) and Re(VII) retained on the TRU resin were eluted using near boiling water, which can be directly used for the ICP-MS measurement. The results for method optimisation, validation and application were reported. PMID- 28916098 TI - pi-Extended triptycene-based material for capillary gas chromatographic separations. AB - Triptycene-based materials feature favorable physicochemical properties and unique molecular recognition ability that offer good potential as stationary phases for capillary gas chromatography (GC). Herein, we report the investigation of utilizing a pi-extended triptycene material (denoted as TQPP) for GC separations. As a result, the TQPP capillary column exhibited high column efficiency of 4030 plates m-1 and high-resolution performance for a wide range of analytes, especially structural and positional isomers. Interestingly, the TQPP stationary phase showed unique shape selectivity for alkanes isomers and preferential retention for analytes with halogen atoms and H-bonding nature mainly through their halogen-bonding and H-bonding interactions. In addition, the TQPP column had good repeatability and reproducibility with the RSD values of 0.02-0.34% for run-to-run, 0.09-0.80% for day-to-day and 1.4-5.2% for column-to column, respectively, and favorable thermal stability up to 280 degrees C. This work demonstrates the promising future of triptycene-based materials as a new class of stationary phases for GC separations. PMID- 28916099 TI - A modified DGT technique for the simultaneous measurement of dissolved inorganic nitrogen and phosphorus in freshwaters. AB - A modified diffusive gradients in thin films (DGT) technique uses both a mixed binding layer (PrCH and A520E resins for NH4-N and NO3-N, respectively) and multiple binding layers (Metsorb binding layer for PO4-P overlying the mixed binding layer) for the simultaneous measurement of dissolved inorganic nitrogen (nitrate and ammonium) and phosphate in freshwater (INP-DGT). High uptake and elution efficiencies were determined for a mixed (PrCH/A520E) binding gel for dissolved inorganic nitrogen and an agarose-based Metsorb binding layer for PO4 P. Diffusion coefficients (D) obtained from DGT time-series experiments (conductivity 180 MUS cm-1) for NH4-N, NO3-N and PO4-P agreed well with those measured using individual DGT techniques in previous studies, but were characterised over a wider range of ionic strengths here. D for NO3-N and PO4-P were constant over a range of ionic strengths (between 100 and 800 MUS cm-1) while the diffusion coefficient for NH4-N decreased with increasing ionic strength, as reported previously. The measurement of NH4-N, NO3-N and PO4-P using the INP-DGT was independent of pH (3.5-8.5) and quantitative over varying ionic strength ranges (up to 0.004 mol L-1 NaCl for NH4-N, up to 0.014 mol L-1 NaCl for NO3-N and over 0.1 mol L-1 NaCl for PO4-P) for a 24 h deployment time. Performance of INP-DGT in synthetic freshwaters with differing conductivity indicated the three nutrients were affected differently, with NH4-N measurements being most sensitive. Representative performance was determined for NO3-N (90-330 MUS cm-1) and PO4-P (all tested conductivities) over a 72 h deployment period and for NH4-N (<330 MUS cm-1) over a 24 h deployment period. Field validations showed that the ratios of INP-DGT concentrations to the average concentrations from grab samples were generally between 0.80 and 1.13 over 24 and 48 h deployment periods. To ensure the representative performance of INP-DGT for all three nutrients, the conductivity should not exceed 400 MUS cm-1 and deployment times should be no longer than 24 h. The results of this study have demonstrated that INP-DGT could provide a cost-effective monitoring technique for measuring time-weighted average concentrations of dissolved inorganic nutrients in many freshwaters. PMID- 28916100 TI - Improving wastewater-based epidemiology to estimate cannabis use: focus on the initial aspects of the analytical procedure. AB - Wastewater-based epidemiology is a promising and complementary tool for estimating drug use by the general population, based on the quantitative analysis of specific human metabolites of illicit drugs in urban wastewater. Cannabis is the most commonly used illicit drug and of high interest for epidemiologists. However, the inclusion of its main human urinary metabolite 11-nor-9-carboxy Delta9-tetrahydrocannabinol (THC-COOH) in wastewater-based epidemiology has presented several challenges and concentrations seem to depend heavily on environmental factors, sample preparation and analyses, commonly resulting in an underestimation. The aim of the present study is to investigate, identify and diminish the source of bias when analysing THC-COOH in wastewater. Several experiments were performed to individually assess different aspects of THC-COOH determination in wastewater, such as the number of freeze-thaw cycles, filtration, sorption to different container materials and in-sample stability, and the most suitable order of preparatory steps. Results highlighted the filtration step and adjustment of the sample pH as the most critical parameters to take into account when analysing THC-COOH in wastewater. Furthermore, the order of these initial steps of the analytical procedure is crucial. Findings were translated into a recommended best-practice protocol and an inter-laboratory study was organized with eight laboratories that tested the performance of the proposed procedure. Results were found satisfactory with z-scores <= 2. PMID- 28916101 TI - Improved analytical techniques of sulfur isotopic composition in nanomole quantities by MC-ICP-MS. AB - We propose an improved method for precise sulfur isotopic measurements by multi collector inductively coupled plasma mass spectrometry (MC-ICP-MS) in conjunction with a membrane desolvation nebulization system. The problems of sulfur loss through the membrane desolvation apparatus are carefully quantified and resolved. The method overcomes low intrinsic sulfur transmission through the instrument, which was initially 1% when operating at a desolvation temperature of 160 degrees C. Sulfur loss through the membrane desolvation apparatus was resolved by doping with sodium. A Na/S ratio of 2 mol mol-1 produced sulfur transmissions with 98% recovery. Samples of 3 nmol (100 ng) sulfur achieved an external precision of +/-0.180/00 (2 SD) for delta34S and +/-0.100/00 (2 SD) for Delta33S (uppercase delta expresses the extent of mass-independent isotopic fractionation). Measurements made on certified reference materials and in-house standards demonstrate analytical accuracy and reproducibility. We applied the method to examine microbial-induced sulfur transformation in marine sediment pore waters from the sulfate-methane transition zone. The technique is quite versatile, and can be applied to a range of materials, including natural waters and minerals. PMID- 28916102 TI - Identification of novel non-ionic, cationic, zwitterionic, and anionic polyfluoroalkyl substances using UPLC-TOF-MSE high-resolution parent ion search. AB - Poly- and perfluoroalkyl substances (poly- and per-PFASs) are a large group of organic compounds that have become the target of investigation due to their widespread occurrence in the environment and biota, coupled with their known or suspected impacts on human health. Recent studies have shown that a significant portion of poly-PFASs remain unidentified. This study presents a time-of-flight mass spectrometry approach based on continuously interleaving scans at low and high collision energies (ToF-MSE) for the rapid identification and characterization of unknown PFASs. The MSE mode allowed for the simultaneous acquisition of full-spectrum accurate mass data of both parent and fragment ions in a single chromatographic run. Specific to PFASs, the hypothesis that PFASs can be selectively detected by the ToF-MSE high-resolution parent-ion search (HRPIS) of their characteristic fragments was confirmed with certified standards of 24 poly- and per-PFAS. After being validated with these certified standards, the innovative HRPIS approach was applied to a group of commercial surfactants, which led to the identification of 47 new and 43 infrequently reported PFASs, including 40 non-ionic, 30 cationic, 15 zwitterionic, and five anionic compounds. It is envisaged that the results, especially the identification of new non-ionic PFASs, may provide important insights into the historical occupational and non occupational exposure to PFASs from the production and application of these surfactants. PMID- 28916103 TI - Controlled, synchronized actuation of microdroplets by gravity in a superhydrophobic, 3D-printed device. AB - Droplet manipulation over open surfaces allows one to perform assays with a large degree of control and high throughput, making them appealing for applications in drug screening or (bio)analysis. However, the design, manufacturing and operation of these systems comes with high technical requirements. In this study we employ a commercial, low-friction, superhydrophobic coating, Ultra-Ever Dry(r), on a 3D printed microfluidic device. The device features individual droplet compartments, which allow the manipulation of discrete droplets (10-50 MUL) actuated by gravity alone. Simply by angling the device to normal in a 3D-printed holder and rocking in a "to and fro"-fashion, a sequence of droplets can be individually transferred to an electrochemical microelectrode detector and then to waste, while preserving the (chronological) order of samples. Multiple biological fluids (i.e. human saliva, urine and rat blood and serum) were successfully tested for compatibility with the device and actuation mechanism, demonstrating low slip angles and high contact angles. Biological matrix (protein) carryover was probed and effectively mitigated by incorporating aqueous rinse droplets as part of the analysis sequence. As a proof-of-concept, the enzyme-coupled, amperometric detection of glucose was carried out on individual rat serum droplets, enabling total analysis in ~30 min, including calibration. The device is readily customizable, and the integration of droplet generation techniques and other sensor systems for different analytes of interest or applications can be realized in a plug and play fashion. PMID- 28916104 TI - Highly selective and sensitive visualization and identification of glycoproteins using multi-functionalized soluble dendrimer. AB - Glycoproteins are the most important and complex group of posttranslational modifications known in proteins. Many clinical biomarkers and therapeutic targets in cancer are glycoproteins. However, the isolation of glyco-specific antibodies and their poor stability remains a significant challenge in analytical method and diagnostic development. In this work, for the first time, we present a technology for highly efficient and selective glycosylation analysis on membrane without the use of glyco-specific antibodies. This approach, termed Nanopoly-BAV, which uses polyamidoamine dendrimers multifunctionalized with boronic acid for specific binding to glycoproteins and with biotin groups for glycoproteins visualization. The Nanopoly-BAV confers femtomolar sensitivity, exceptional glycoprotein specificity and selectivity with as high as 100000 folds for glycoproteins over nonglycoproteins. This synthetic, robust and highly selective Nanopoly-BAV has a great potential to measure cell signaling events by clearly distinguishing actual glycosylation signals from protein expression changes with superior stability. This technique may provide a powerful tool to monitor cellular signaling pathways and discovering new signaling events. PMID- 28916106 TI - Silver nanoclusters capped silica nanoparticles as a ratiometric photoluminescence nanosensor for the selective detection of I- and S2. AB - A novel and efficient approach has been established for the synthesis of silver nanoclusters capped silica nanoparticles (SiO2@AgNCs). These nanoclusters (AgNCs) capped silica nanoparticles were utilized as a novel ratiometric photoluminescence (PL) nanosensor for extremely sensitive and selective detection of I- and S2- ions. The AgNCs were prepared in situ on the silica nanoparticles through polyethyleneimine (PEI) template approach. While dual PL emissions of AgNCs (at 500 nm) and luminescent silica nanoparticles (at 602 nm) formed the basis for the ratiometric sensing. The PL emission of AgNCs was strongly quenched by I- (or S2-), while that of luminescent silica nanoparticles was hardly affected. The PL emission intensity ratio of AgNCs and the luminescent silica nanoparticles was defined as I500/I602. A good linear relationship between the I500/I602 value and the concentration of I- (or S2-) was observed, and the limit of detection (LOD) was estimated to be 57 nM for I- and 62 nM for S2-. In addition, the fluorescence images of the SiO2@AgNCs nanosensor changed from white to orange upon exposure to different concentrations of I- (or S2-) (0-250 MUM), which could be clearly distinguished by the naked eye. The SiO2@AgNCs nanosensor exhibited good selectivity against other analytes, and I- or S2- ions could be separately detected via the introduction of proper masking agents. Furthermore, the detection of I- and S2- in real water samples was also demonstrated. PMID- 28916105 TI - Selective imaging of cancer cells with a pH-activatable lysosome-targeting fluorescent probe. AB - Fluorescence imaging with tumor-specific fluorescent probe has emerged as a tool to aid surgeons in the identification and removal of tumor tissue. We report here a new lysosome-targeting fluorescent probe (NBOH) with BODIPY fluorephore to distinguish tumor tissue out of normal tissue based on different pH environment. The probe exhibited remarkable pH-dependent fluorescence behavior in a wide pH range from 3.0 to 11.0, especially a sensitive pH-dependent fluorescence change at pH range between 3.5 and 5.5, corresponding well to the acidic microenvironment of tumor cells, in aqueous solution. The response time of NBOH was extremely short and the photostability was proved to be good. Toxicity test and fluorescence cell imaging together with a sub-cellular localization study were carried out revealing its low biotoxicity and good cell membrane permeability. And NBOH was successfully applied to the imaging of tumor tissue in tumor-bearing mice suggesting potential application to surgery as a tumor specific probe. PMID- 28916107 TI - Genetically functionalized ferritin nanoparticles with a high-affinity protein binder for immunoassay and imaging. AB - Molecular detection of target molecules with high sensitivity and specificity is of great significance in bio and medical sciences. Here, we present genetically functionalized ferritin nanoparticles with a high-affinity protein binder, and their utility as a signal generator in a variety of immunoassays and imaging. As a high-affinity protein binder, human IgG-specific repebody, which is composed of LRR (Leucine-rich repeat) modules, was used. The repebody was genetically fused to the N-terminal heavy-chain ferritin, and the resulting subunits were self assembled to the repebody-ferritin nanoparticles composed of 24 subunits. The repebody-ferritin nanoparticles were shown to have a three-order of magnitude higher binding affinity toward human IgG than free repebody mainly owing to a decreased dissociation rate constant. The repebody-ferritin nanoparticles were conjugated with fluorescent dyes, and the resulting nanoparticles were used for western blotting, cell imaging, and flow cytometric analysis. The dye-labeled repebody-ferritin nanoparticles were shown to generate about 3-fold stronger fluorescent signals in immunoassays than monovalent repebody. The repebody functionalized ferritin nanoparticles can be effectively used for sensitive and specific immunoassays and imaging in many areas. PMID- 28916108 TI - A Eu(III) doped metal-organic framework conjugated with fluorescein-labeled single-stranded DNA for detection of Cu(II) and sulfide. AB - In this paper, Bio-MOF-1 is prepared as reported and then Eu3+ is introduced into it via cation exchange method. A FAM-labeled ssDNA is chosen to fabricate with the obtained Eu3+@Bio-MOF-1. A luminescent hybrid material is assembled, which can exhibit the fluorescence of Eu3+ and FAM simultaneously by adjusting the ratio of FAM-ssDNA and Eu3+@Bio-MOF-1. The sample is then used for the detecting of metal ions, results shows which has good selectively for Cu2+ (LOD = 0.14 MUM, 0-250 MUM). The introduction of Cu2+ can quench the fluorescence of FAM while the luminescent intensity of Eu3+ enhancing. After the detection of Cu2+, the Cu2+ involved hybrid system can then be further employed for the detection of S2- (LOD = 1.3 MUM, 0-50 MUM). Low concentration of S2- can make the luminescent intensity of Eu3+ decrease gradually while high concentration of S2- can further recover the luminescent of FAM, which is quenched by Cu2+. PMID- 28916109 TI - Systematic approach in Mg2+ ions analysis with a combination of tailored fluorophore design. AB - A systematic study of a series of diaza-18-crown-6 8-hydroxyquinoline (DCHQ) chemosensors, devoted to Mg(II) ion detection, was performed. Functionalization of DCHQ by peripheral substituents allowed the development of novel all-solid state optodes via inclusion inside PVC-based polymeric films. The influence on the DCHQ-based optode response of the lipophilic sites functionalization and of the nature of the plasticizer, was investigated. Fluorimetric studies on optodes sensitivity towards a number of different metal cations (Ca2+, Na+, K+, Li+, Co2+, Cd2+, Pb2+, Cu2+, Hg2+, Zn2+) and NH4+ were carried out. The results demonstrated the suitability of the DCHQ optodes to perform fast monitoring (<10s) of magnesium (II) ions. Emission light signal was sufficiently brilliant to be captured by a low-cost computer webcam. The phenyl-substituted DCHQ-Ph derivative showed the best performance with a wide range for Mg(II) ion determination between 2.7 * 10-7 and 2.2 * 10-2 mol/L. It was possible, therefore, to determine the concentrations of Mg(II) in commercial fertilizer samples by DCHQ-Ph-based optodes with acceptable results: recoveries of 96.2 104.9% and relative standard deviation (RSD, n = 6) less than 5%. Moreover, in comparison to single sensors, the use of an array composed of five optodes (the ones showing the best performances in the preliminary tests) has allowed to reduce the RSD of magnesium determination in real samples (down to 3.7% with respect to 5.5% for single optodes) and to achieve a detection limit (estimated by s/n = 3 method) as low as 4.6 * 10-7 mol/L. PMID- 28916110 TI - A fast and accurate Langmuir-type polymer microtensiometer. AB - A semi-flexible polymer microtensiometer for local surface pressure measurements of Langmuir monolayers is presented. The current device geometry and read-out method via image analysis result in a theoretical accuracy of +/-0.02mN?m-1 for a dynamic range between 0 and 75mN?m-1. The tensiometer sensitivity and dynamic range are easily tunable as they are solely based on the tensiometer spring dimensions. Finite element simulations are used to determine the response time of 20ms for a subphase viscosity of 1mPa?s. A poroviscomechanical model of the sensor is composed and the subphase viscosity is shown to dominate the transient behavior. The tensiometer performance is verified in a Langmuir trough by applying rapid local surface pressure oscillations. A Wilhelmy plate is used as an independent measurement tool and the results of both techniques correlate well. PMID- 28916111 TI - Icosahedral plant viral nanoparticles - bioinspired synthesis of nanomaterials/nanostructures. AB - Viral nanotechnology utilizes virus nanoparticles (VNPs) and virus-like nanoparticles (VLPs) of plant viruses as highly versatile platforms for materials synthesis and molecular entrapment that can be used in the nanotechnological fields, such as in next-generation nanoelectronics, nanocatalysis, biosensing and optics, and biomedical applications, such as for targeting, therapeutic delivery, and non-invasive in vivo imaging with high specificity and selectivity. In particular, plant virus capsids provide biotemplates for the production of novel nanostructured materials with organic/inorganic moieties incorporated in a very precise and controlled manner. Interestingly, capsid proteins of spherical plant viruses can self-assemble into well-organized icosahedral three-dimensional (3D) nanoscale multivalent architectures with high monodispersity and structural symmetry. Using viral genetic and protein engineering of icosahedral viruses with a variety of sizes, the interior, exterior and the interfaces between coat protein (CP) subunits can be manipulated to fabricate materials with a wide range of desirable properties allowing for biomineralization, encapsulation, infusion, controlled self-assembly, and multivalent ligand display of nanoparticles or molecules for varied applications. In this review, we discuss the various functional nanomaterials/nanostructures developed using the VNPs and VLPs of different icosahedral plant viruses and their nano(bio)technological and nanomedical applications. PMID- 28916113 TI - [Bilateral disc edema following a severe systemic viral illness]. PMID- 28916112 TI - A novel mimovirus encoding ChgA10-19 peptide with PD-L1 induces T cell tolerance and ameliorates the severity of diabetes. AB - Related studies demonstrate that type 1 diabetes (T1D) is caused by beta-cell antigen specific autoreactive CD8+ T cells. ChgA has recently been identified as the autoantigen in NOD mice and T1D patients. Therefore, attenuating the activation of ChgA specific CD8+ T cells might be a promising target for T1D therapy. The negative co-stimulatory PD-L1 inhibits T cell mediated alloimmunity and induces tolerance. In this experiment, a novel mimovirus encoding ChgA10-19 peptide with PD-L1 was constructed. The NOD.beta2m null HHD mice were administrated with mimovirus transduced DCs. After immunization, the activation and proliferation of CD8+ T cells were detected, diabetes incidence and pancreatic tissue destruction were also analyzed. The results demonstrated that transduced DCs attenuated CD8+ T cell activation and proliferation. In addition, transduced DCs inhibited CD8+ T response to ChgA stimulation, and ameliorated the severity of diabetes. These data suggested that mimovirus transduced DCs might provide novel clues for T1D therapy. PMID- 28916114 TI - [Scleritis and episcleritis]. AB - Episcleritis is generally a benign disease with a self-limited course, while scleritis is a severe ocular condition due to a risk of impaired vision in one fifth of patients and its association with systemic diseases in one third of them. Infectious scleritis, representing 8 % of the etiologies, is mainly of herpetic origin (varicella zoster and herpes simplex viruses). A systemic autoimmune disease is observed in roughly 30 % of scleritis patients: inflammatory rheumatisms (15 %), firstly rheumatoid polyarthritis, systemic vasculitides (8 %), mainly granulomatosis with polyangiitis (Wegener's) and polychondritis, and less often inflammatory bowel disease and systemic lupus erythematosus. Among the different types of scleritis, a clear distinction exists between necrotizing forms leading to decreased vision in 50 % of the cases and associated with systemic diseases in the vast majority, and non-necrotizing forms (either diffuse or nodular), with a better prognosis. However, recent publications show that necrotizing forms are much less frequent nowadays (around 5 % of the total), probably due to therapeutic innovations and progress made during the last 20 years. The medical management of scleritis requires collaboration between ophthalmologists and internists (or rheumatologists). PMID- 28916115 TI - [Retinal vein occlusions]. AB - Retinal venous occlusions comprise central retinal vein occlusion, hemiretinal vein occlusions, and branch retinal vein occlusions. They are associated with arterial hypertension and glaucoma. Retinal vein occlusions occur more frequently in males, at a median age of 55. The pathogenesis of retinal venous occlusions remains obscure. The clinical presentation of the disease is variable. In most cases, there is a unilateral visual loss over days with a painless, white and quiet eye. However, retinal venous occlusions may also present as an abrupt and profound loss of vision, or be asymptomatic. The course of the disease may be chronic, often with exacerbations. The most severe complication is the onset of extensive capillary non-perfusion, with a high risk of neovascular glaucoma. The most frequent complication is macular edema due to breakdown of the blood-retinal barrier, which can originate from the macula itself and/or from the disc. The treatment is symptomatic. Retinal venous occlusions may resolve either because of the recanalization of the affected vein, or because of the establishment of an efficient collateral circulation. Intravitreal anti-VEGF antibodies or steroids may transiently improve vision, as well as laser photocoagulation, focused or not on macroaneurysms. Visual sequelae are frequent. PMID- 28916116 TI - Excision and topical 0.04% mitomycin C for extensive and recurrent conjunctival squamous cell carcinoma in an AIDS patient. A case report. PMID- 28916117 TI - [Corneal complications of a case of vernal keratoconjonctivitis]. PMID- 28916118 TI - Benefit of combination chemotherapy and radiation stratified by grade of stage IIIC endometrial cancer. AB - OBJECTIVE: The optimal strategy for adjuvant therapy in stage IIIC endometrial cancer has not been determined. Our aim was to evaluate survival benefit of different treatments and to investigate if benefit varied by histologic grade. METHODS: We identified 199 patients with stage IIIC endometrial cancer from 2000 to 2012 through the Siteman Cancer Center registry. All patients underwent surgical staging followed by no adjuvant therapy (NAT), radiation (RT), chemotherapy (CT) or chemoradiation (CRT). The association between adjuvant treatment and overall survival was explored using Kaplan-Meier plots and multivariable Cox regression analysis. Multivariable analysis was stratified by low- or high-grade to explore the interaction between grade and treatment. RESULTS: Most patients received CRT (50.3%) followed by CT (23.1%), RT (16.1%) and NAT (10.5%). Survival after CRT was superior to NAT (p<0.001), RT (p=0.010) and CT (p<0.001). After adjusting for covariates, treatment with RT, CT and CRT led to a 57% (p=0.024), 62% (p=0.003) and 83% (p<0.001) reduction in risk of death compared to NAT, respectively. With CRT as the reference, the adjusted hazard of death was higher with NAT (5.94, p<0.001), RT (2.56, p=0.009) and CT (2.24, p=0.004). Stratifying by grade, RT and CRT led to a 67% (p=0.039) and 85% (p<0.001) reduction in death, compared to NAT in low-grade patients. CT and CRT led to a 72% (p=0.003) and 83% (p<0.001) reduction in death, compared to NAT in high-grade patients. CONCLUSIONS: Our findings suggest that CRT should be the preferred adjuvant treatment strategy for patients with stage IIIC endometrial cancer. PMID- 28916119 TI - Safety and efficacy of glycerol phenylbutyrate for management of urea cycle disorders in patients aged 2months to 2years. AB - INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB. Retrospective data up to 12months pre-switch and prospective data during initiation of therapy were used as baseline measures. The primary efficacy endpoint of the integrated analysis was the successful transition to GPB with controlled ammonia (<100MUmol/L and no clinical symptoms). Secondary endpoints included glutamine and levels of other amino acids. Safety endpoints included adverse events, hyperammonemic crises (HACs), and growth and development. RESULTS: 82% and 53% of patients completed 3 and 6months of therapy, respectively (mean 8.85months, range 6days-18.4months). Patients transitioned to GPB maintained excellent control of ammonia and glutamine levels. There were 36 HACs in 11 patients before GPB and 11 in 7 patients while on GPB, with a reduction from 2.98 to 0.88 episodes per year. Adverse events occurring in at least 10% of patients while on GPB were neutropenia, vomiting, diarrhea, pyrexia, hypophagia, cough, nasal congestion, rhinorrhea, rash/papule. CONCLUSION: GPB was safe and effective in UCD patients aged 2months to 2years. GPB use was associated with good short- and long-term control of ammonia and glutamine levels, and the annualized frequency of hyperammonemic crises was lower during the study than before the study. There was no evidence for any previously unknown toxicity of GPB. PMID- 28916120 TI - Does Early and Appropriate Antibiotic Administration Improve Mortality in Emergency Department Patients with Severe Sepsis or Septic Shock? AB - BACKGROUND: Severe sepsis and septic shock remain significant public health concerns. Appropriate emergency department management includes early recognition, hemodynamic resuscitation, source control, and prompt antibiotic administration. Current international guidelines strongly recommend administration of early and appropriate antibiotics for patients with severe sepsis and septic shock. Interestingly, a recent Cochrane Review found insufficient evidence to provide a similar recommendation on antibiotic administration. The goal of this literature search was to systematically review the available literature on early and appropriate antimicrobial therapy and provide emergency physicians an evidence based approach to antibiotic therapy for septic patients. METHODS: Four PubMed searches were completed to identify abstracts of relevant interest. We limited studies to those completed in adult humans that were composed in English between 2005 and 2015. Included studies were randomized controlled trials, meta-analyses, prospective trials, and retrospective cohort studies. These studies were identified by a rigorous search methodology. No review articles, case series, or case reports were included. Predefined criteria were used to evaluate the quality and appropriateness of selected articles as part of a structured review. RESULTS: A total of 1552 abstracts were evaluated for inclusion. After the review of these studies, 14 were included for formal review. The authors then systematically evaluated each study, which formed the basis for this clinical statement. CONCLUSIONS: Patients with severe sepsis and septic shock should receive early and appropriate antibiotics in the emergency department. Patients with septic shock who received appropriate antimicrobial therapy within 1 h of recognition had the greatest benefit in mortality. PMID- 28916121 TI - Controversies in Corticosteroid use for Sepsis. AB - BACKGROUND: Severe sepsis and septic shock are potentially deadly conditions managed in the emergency department (ED). Management centers on source control, fluid resuscitation, broad-spectrum antimicrobials, and vasopressors as needed. The use of corticosteroids is controversial. OBJECTIVE: To evaluate the evidence behind corticosteroid therapy in patients with septic shock. DISCUSSION: Septic shock is associated with severe mortality and morbidity. Cytokine release produces a systemic inflammatory state. Vasopressor-resistant septic shock warrants consideration of the disease state and other pathologies such as adrenal insufficiency. Many studies and meta-analyses have been conducted evaluating corticosteroid therapy for this population. High-dose corticosteroid therapy is associated with increased harm, but physiologic-dose corticosteroids may decrease the need for vasopressors. Mortality benefit is controversial, with much of the literature demonstrating no effect. The risk of superinfection is not suggested by the majority of studies. The Surviving Sepsis Campaign advises consideration of corticosteroids in patients with vasopressor and fluid-resistant septic shock. Patients with vasopressor-resistant septic shock with no contraindications to corticosteroids may benefit from hydrocortisone 100 mg intravenously (i.v.) every 8 h or 50 mg i.v. every 6 h. Fludrocortisone is not recommended at this time. CONCLUSIONS: Septic shock is associated with higher mortality, specifically for patients with vasopressor and fluid-refractory shock. The use of physiologic-dose steroids can reduce vasopressor requirements and improve time of shock resolution. Current literature suggests corticosteroids do not improve mortality, but further studies are required. PMID- 28916122 TI - Myasthenia Gravis and Crisis: Evaluation and Management in the Emergency Department. AB - BACKGROUND: Myasthenia gravis (MG) is an uncommon autoimmune disorder affecting the neuromuscular junction and manifesting as muscle weakness. A multitude of stressors can exacerbate MG. When symptoms are exacerbated, muscle weakness can be severe enough to result in respiratory failure, a condition known as myasthenic crisis (MC). OBJECTIVE: This review discusses risk factors, diagnosis, management, and iatrogenic avoidance of MC. DISCUSSION: MC can affect any age, ethnicity, or sex and can be precipitated with any stressor, infection being the most common. MC is a clinical diagnosis defined by respiratory failure caused by exacerbation of MG. Muscle weakness can involve any voluntary muscle. MC can be differentiated from other neuromuscular junction diseases by the presence of normal reflexes, normal sensation, lack of autonomic symptoms, lack of fasciculations, and worsening weakness with repetitive motion. Treatment should target the inciting event and airway support. All acetylcholinesterase inhibitors should be avoided in crisis, including edrophonium testing and corticosteroids initially. Respiratory support can begin with noninvasive positive-pressure ventilation, as this has been successful even in patients with bulbar weakness. If intubation is necessary, consider avoiding paralytics or use a reduced dose of nondepolarizing agents. CONCLUSIONS: MC should be in the differential of any patient with muscular weakness and respiratory compromise. Emergency department management of MC should focus on ruling out infection and respiratory support. Strong consideration should be given to beginning with noninvasive positive pressure ventilation for ventilatory support. Corticosteroids, depolarizing paralytics, and acetylcholinesterase inhibitors should be avoided in patients with MC in the emergency department. PMID- 28916123 TI - Reverse Takotsubo Cardiomyopathy and Cardiogenic Shock Associated With Methamphetamine Consumption. AB - BACKGROUND: Reverse Takotsubo cardiomyopathy is characterized by transient myocardial hypokinesia affecting predominantly the basal myocardial wall. It is a rare variant of Takotsubo cardiomyopathy affecting younger patients. CASE REPORT: We report a case of a young man who having consumed methamphetamines presented with cardiogenic shock and severe left ventricular systolic dysfunction, affecting predominantly the basal segments with sparing of the apex. After inotropic support, the left ventricular ejection fraction improved. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important that emergency physicians are aware of the danger of methamphetamine consumption, and how it can lead to potentially fatal acute cardiac syndromes, including reverse Takotsubo cardiomyopathy and cardiogenic shock. PMID- 28916124 TI - Male With Sudden Onset Abdominal Pain. PMID- 28916125 TI - Inter-institutional Variation in Use of Caesarean Delivery for Labour Dystocia. AB - OBJECTIVE: To establish the degree of variation across hospitals in the use of Caesarean delivery for the indication of labour dystocia before and after accounting for maternal, fetal, and hospital characteristics. METHODS: This study was a retrospective, population-based cohort study of nulliparous women delivering term singletons in cephalic position following labour. Delivery visits were extracted from three provincial perinatal registries in the Canadian provinces of Ontario, Alberta, and British Columbia, from 2008-2012. Crude hospital-specific rates of Caesarean delivery for labour dystocia were reported, and these rates were then stabilized to account for hospitals with low delivery volumes. Rates were then adjusted for maternal, fetal, and hospital characteristics using hierarchical logistic regression. RESULTS: Among 403 205 women delivering at 170 hospitals, the overall Caesarean delivery rate was 21.0%, and the rate of Caesarean delivery for labour dystocia was 12.7%, indicating that 60% of all Caesarean deliveries were performed in part for this indication. The middle 95% of hospitals had Caesarean delivery rates for labour dystocia ranging from 4.5% to 24.7%. Differences in maternal case mix and hospital characteristics explained only a small proportion of this variation (95% central range 6.3% 21.7%). CONCLUSION: Considerable inter-hospital variation in rates of Caesarean delivery for labour dystocia remained after accounting for differences in maternal and hospital factors. Reporting systems that monitor variation in inter institutional rates should incorporate stabilization and adjustment for case-mix differences and consider indication-specific rates of Caesarean delivery to more fairly compare hospital performance and better target interventions to reduce Caesarean delivery for specific indications. PMID- 28916126 TI - Empowerment of Women: Closing the Medical Technologies Gender Gap. PMID- 28916127 TI - Editor's Choice - Open Thoracic and Thoraco-abdominal Aortic Repair in Patients with Connective Tissue Disease. AB - OBJECTIVE/BACKGROUND: The aim is to present current results of open complex aortic repair in patients with connective tissue disease (CTD). METHODS: This was a retrospective cross-border, single centre study. From February 2000 to April 2016 72 aortic operations were performed on 65 patients with CTD (41 male, median age 41 years [range 19-70 years]). Fifty-six patients (86%) underwent at least one previous aortic repair (71 open, four endovascular), including 33 patients (51%) operated before at the site of the procedure reported here. The open procedures, counting eight emergency operations (11%), included aortic arch revision (n = 1; 1%), descending thoracic aortic repair (n = 11; 15%), TAAA type I repair (n = 12; 17%), type II repair (n = 29; 40%), type III repair (n = 12; 17%), and type IV repair (n = 5; 7%). Simultaneous repair of the ascending aorta and/or the aortic arch was performed in two (3%) and eight cases (11%), respectively. Seven patients (10%) underwent staged procedures. Median follow-up was 42 months (0.5-180 months). RESULTS: The in hospital mortality was 14% (n = 9) as a result of haemorrhage (n = 3/9), neurological (n = 3/9), cardiac (n = 2/9), and pulmonary (n = 1/9) complications. Paraplegia and paraparesis occurred in one (2%) and three patients (5%), respectively. Seven patients (11%) required temporary dialysis; none needed permanent dialysis. Major complications were revision surgery for bleeding or haematoma (n = 20/65), sepsis (n = 10/65), myocardial infarction/severe cardiac arrhythmia (n = 2/65), stroke (n = 2/65), as well as multiorgan failure, abdominal compartment syndrome, mesenteric and peripheral ischaemia (all n = 1/65). Multivariate analysis identified an operating time > 7 hours (p = .006) as an independent predictor of increased mortality. Freedom from re-intervention was 85%, 1 year survival was 80%, and overall survival was 75%. CONCLUSION: Open TAA(A) repair is a durable therapy for patients with CTD. Often being performed as revision surgery, it can be associated with relevant risks and should therefore be reserved for specialised centres. Staged procedures and thus reducing operating time, if applicable, should be preferred. PMID- 28916128 TI - Causes of failure to achieve the low density lipoprotein cholesterol therapeutic target in patients with high and very high vascular risk controlled in Lipid and Vascular Risk Units. EROMOT study. AB - OBJECTIVES: Determination of the level of achievement of the low density lipoprotein cholesterol (LDL-C) therapeutic target in patients with high and very high vascular risk treated in Lipid Units, as well as the causes of non achievement. PATIENTS AND METHOD: Multicentre retrospective observational study that included patients over 18 years with high and very high vascular risk, according to the criteria of the 2012 European Guidelines on Cardiovascular Disease Prevention, referred consecutively to Lipid Units between January and June 2012 and with follow-up two years after the first visit. RESULTS: The study included a total of 243 patients from 16 lipid units. The mean age was 52.2 years (SD 13.7), of whom 62.6% were males, and 40.3% of them were very high risk. At the first visit, 86.8% (25.1% in combination) and 95.0% (47.3% in combination) in the second visit (P<.001) were treated with lipid-lowering treatment. The therapeutic target was achieved by 28% (95 CI: 22.4-34.1). As regards the causes of non-achievement, 24.6% were related to the medication (10.3% maximum tolerated dose and 10.9% due to the appearance of adverse effects), 43.4% due to the physician (19.4% by inertia, 13.7% considering that target already reached), and 46.9% due to the patient, highlighting the therapeutic non-compliance (31,4%). CONCLUSIONS: LDL-C targets were achieved in about one-third of patients. The low adherence of the patient, followed by medical inertia are the most frequent causes that can explain these results. PMID- 28916131 TI - Chemical exposures in recently renovated low-income housing: Influence of building materials and occupant activities. AB - Health disparities in low-income communities may be linked to residential exposures to chemicals infiltrating from the outdoors and characteristics of and sources in the home. Indoor sources comprise those introduced by the occupant as well as releases from building materials. To examine the impact of renovation on indoor pollutants levels and to classify chemicals by predominant indoor sources, we collected indoor air and surface wipes from newly renovated "green" low-income housing units in Boston before and after occupancy. We targeted nearly 100 semivolatile organic compounds (SVOCs) and volatile organic compounds (VOCs), including phthalates, flame retardants, fragrance chemicals, pesticides, antimicrobials, petroleum chemicals, chlorinated solvents, and formaldehyde, as well as particulate matter. All homes had indoor air concentrations that exceeded available risk-based screening levels for at least one chemical. We categorized chemicals as primarily influenced by the occupant or as having building-related sources. While building-related chemicals observed in this study may be specific to the particular housing development, occupant-related findings might be generalizable to similar communities. Among 58 detected chemicals, we distinguished 25 as primarily occupant-related, including fragrance chemicals 6 acetyl-1,1,2,4,4,7-hexamethyltetralin (AHTN) and 1,3,4,6,7,8-hexahydro 4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran (HHCB). The pre- to post occupancy patterns of the remaining chemicals suggested important contributions from building materials for some, including dibutyl phthalate and xylene, whereas others, such as diethyl phthalate and formaldehyde, appeared to have both building and occupant sources. Chemical classification by source informs multi level exposure reduction strategies in low-income housing. PMID- 28916132 TI - The association between elevated blood lead levels and violent behavior during late adolescence: The South African Birth to Twenty Plus cohort. AB - Epidemiological studies have shown the adverse neuro-behavioral health effects of lead exposure among children, in particular. However, there is lack evidence in this regard from developing countries. The main aim of this study was to assess the association between blood lead levels (BLLs) during early adolescence and violent behavior in late adolescence. Our study sample from the Birth to Twenty Plus cohort in Soweto-Johannesburg, South Africa included 1332 study participants (684 females). BLLs were measured using blood samples collected at age 13years. Violent behavior was evaluated using data collected at ages 15 to 16years using the Youth Self Report questionnaire. First, bivariate analysis was used to examine data for an association between lead exposure in early adolescence and violent behavior items during late adolescence. Principal Component Analysis (PCA) was used for dimensionality reduction and six violent behavior components were derived. Data were further analyzed for an association between BLLs at age 13years and violent behavior using PCA derived components; to determine the specific type(s) of violent behavior associated with lead exposure. Median whole BLLs were 5.6MUg/dL (p<0.001). Seventy five percent of males and 50% of females had BLLs>=5MUg/dL. BLLs ranging from 5 to 9.99MUg/dL were associated with physical violence (p=0.03) and BLLs>=10MUg/dL were associated physical violence and fighting (p=0.02 and p=0.01, respectively). When data were analyzed using continuous BLLs physical violence was associated with lead exposure (p<0.0001). Furthermore, males were more likely to be involved in violence using a weapon (p=0.01), physical violence (p<0.0001), and robbing others (p<0.05) compared to females. The results from this study show the severe nature of violent behavior in late adolescence associated with childhood lead exposure. They highlight the urgent need for preventive measures against lead exposure among children in low or middle income countries such as South Africa. PMID- 28916130 TI - Stress and Seizures: Space, Time and Hippocampal Circuits. AB - Stress is a major trigger of seizures in people with epilepsy. Exposure to stress results in the release of several stress mediators throughout the brain, including the hippocampus, a region sensitive to stress and prone to seizures. Stress mediators interact with their respective receptors to produce distinct effects on the excitability of hippocampal neurons and networks. Crucially, these stress mediators and their actions exhibit unique spatiotemporal profiles, generating a complex combinatorial output with time- and space-dependent effects on hippocampal network excitability and seizure generation. PMID- 28916133 TI - A modified deltoid splitting approach with axillary nerve bundle mobilization for proximal humeral fracture fixation. AB - INTRODUCTION: The deltopectoral and the deltoid splitting approach are commonly used for the treatment of proximal humeral fractures. While the deltopectoral approach requires massive soft tissue devascularization, the deltoid splitting approach needs an additional skipped incision to avoid axillary nerve injury. The purpose of this study was to describe a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization in the treatment of proximal humeral fractures and to assess its radiologic and clinical outcomes. PATIENTS AND METHODS: Twenty-two consecutive patients with proximal humeral fractures were treated with minimally invasive plate osteosynthesis by using a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization. The patients were divided into two groups: 10 patients of Neer type 2 or 3 fractures vs. 12 patients of Neer type 4 fractures. The mean age of the study population was 63.5 years (range: 30-80 years). Six patients had valgus impacted fractures, and nine had fractures with medial comminution. RESULTS: Fracture union was achieved in all cases. The mean time to union was 8.6 weeks (range: 6 12 weeks). Major complications, such as avascular necrosis of the humeral head and varus collapse at the fracture site, were not observed. No patients had clinically detectable sensory deficits in the axillary nerve distribution or paralysis of the anterior deltoid muscle. The mean neck-shaft angle at the final follow-up was 136.9 degrees (range, 115 degrees -159 degrees ). The mean visual analog score for patient satisfaction was 9.1 (range, 6-10), and the mean Neer scores were 93.5 (range, 84-100). There were no significant differences between the two groups with respect to radiologic and clinical outcomes except Neer scores: 95.8 (range: 86-100) in Neer type 2 or 3 fractures and 91.7 (range: 84 99) in Neer type 4 fractures. CONCLUSION: The use of a modified anterolateral deltoid splitting approach with axillary nerve bundle mobilization in the treatment of proximal humeral fractures yielded excellent outcomes. This approach is a useful alternative to the deltopectoral or the deltoid splitting approaches in the treatment of proximal humeral fractures. PMID- 28916134 TI - Novel technique to accurately measure femoral diameter using a Thomas splint. AB - INTRODUCTION: During surgical management of femoral shaft fractures, difficulties arise when treating patients with narrow femoral diaphyseal canals, such as young patients and those with dysplastic femurs secondary to underlying pathology. Accurate pre-operative assessment of the femoral diaphyseal canal diameter would allow the surgeon to plan surgical technique and ensure appropriate equipment was available, such as narrow, unreamed or paediatric sized nails. TECHNIQUE: When secured to the patient both longitudinal rods of the main Thomas Splint component lie parallel with the femoral shaft and horizontal to the radiographic x-ray plate. The diameter of these rods are 13mm (Adult and paediatric). Using the calibration tool, we calibrate the diameter of the Thomas Splint to 13mm, accurately measuring any further detail on that radiograph, such as the diaphyseal canal diameter. CONCLUSION: Accurate knowledge pre-operatively of radiographic measurements is highly valuable to the operating surgeon. This technique can accurately measure femoral canal diameter using the Thomas splint, negates the requirement for a calibration marker, is reproducible, easy to perform, and is indispensible when faced with a patient with a narrow femoral canal in a diaphyseal femoral fracture. (181 words). PMID- 28916136 TI - Mathematical basis of improved protein subfamily classification by a HMM-based sequence filter. AB - Informative phylogenetic analysis is dependent on the presence of curated and annotated sequences. This may be complemented by the simultaneous availability of empirical data pertaining to their in vivo function. Confounding sequences, with their similarity to more than one functional cluster, can therefore, render any categorization ambiguous, subjective, and imprecise. Here, I analyze and discuss the development of a mathematical expression that can characterize a potential confounding protein sequence. Specifically, statistical descriptors of combinatorially arranged profile HMM scores are computed and evaluated. The resultant data is then incorporated into an index of sequence suitability. The sequence may then be recommended as either suitable for inclusion or be excluded all together. The index is independent of experimental data and, can, be computed from the primary structure of the protein sequence. This can be utilized to trim previously grouped sequences and can either finalize the composition of training set or reduce the search space of sequences to be tested. PMID- 28916135 TI - Genetic variation in cytokine genes and risk for transition to psychosis among individuals at ultra-high risk. PMID- 28916137 TI - Oxytocin induces penile erection and yawning when injected into the bed nucleus of the stria terminalis: Involvement of glutamic acid, dopamine, and nitric oxide. AB - Oxytocin (5-100ng), but not Arg8-vasopressin (100ng), injected unilaterally into the bed nucleus of the stria terminalis (BNST) induces penile erection and yawning in a dose-dependent manner in male rats. The minimal effective dose was 20ng for penile erection and 5ng for yawning. Oxytocin responses were abolished not only by the oxytocin receptor antagonist d(CH2)5Tyr(Me)2-Orn8-vasotocin (1MUg), but also by (+) MK-801 (1MUg), an excitatory amino acid receptor antagonist of the N-methyl-d-aspartic acid (NMDA) subtype, SCH 23390 (1MUg), a D1 receptor antagonist, but not haloperidol (1MUg), a D2 receptor antagonist, and SMTC (40MUg), an inhibitor of neuronal nitric oxide synthase, injected into the BNST 15min before oxytocin. Oxytocin-induced penile erection, but not yawning, was also abolished by CNQX (1MUg), an excitatory amino acid receptor antagonist of the AMPA subtype. In contrast, oxytocin responses were not reduced by bicuculline (20ng), a GABAA receptor antagonist, phaclofen (5MUg), a GABAB receptor antagonist, CP 376395, a CRF receptor-1 antagonist (5MUg), or astressin 2B, a CRF receptor-2 antagonist (150ng). Considering the ability of NMDA (100ng) to induce penile erection and yawning when injected into the BNST and the available evidence showing possible interaction among oxytocin, glutamic acid, and dopamine in the BNST, oxytocin possibly activates glutamatergic neurotransmission in the BNST. This in turn leads to the activation of neural pathways projecting back to the paraventricular nucleus, medial preoptic area, ventral tegmental area, and/or ventral subiculum/amygdala, thereby inducing penile erection and yawning. PMID- 28916138 TI - Peptide YY induces characteristic meal patterns of aged mice. AB - BACKGROUND & AIM: Changes in eating behavior occur in the elderly due to oral and swallowing dysfunctions. We aimed to clarify the difference between basal meal patterns of young and aged mice in relation to appetite regulating hormones. METHODS: Thirty two of young (7-week-old) and aged (23-25-month-old) C57BL/6 male mice were acclimated to a single housing and then transferred to a highly sensitive automated feeding monitoring device. Feeding behavior was monitored from the onset of the dark phase after habituation to the device. Plasma peptide YY (PYY) levels were assessed under the several feeding status or after treatment of PYY. PYY and its receptor (NPY Y2 receptor, Y2R) antagonist were intraperitoneally administered 30min before the monitoring. RESULTS: Although the basal 24-h meal amounts did not differ by age, the total meal time and frequency of minimum feeding activity (bout) were significantly increased and the average bout size and time per bout were significantly decreased in aged mice. PYY dynamics were abnormal and the temporal reduction in food intake by exogenous PYY was more prominent in aged mice than in young mice. PYY administration to young mice induced aged-like meal patterns, and Y2R antagonist administration to aged mice induced young-like meal patterns. CONCLUSIONS: Aged mice exhibited characteristic meal patterns probably due to PYY metabolism dysfunction and/or enhanced PYY-Y2R signaling, suggesting a novel method for assessing eating difficulties in aged animals and a potential target for the remedy. PMID- 28916139 TI - Online Adaptive Radiation Therapy. AB - The current paradigm of radiation therapy has the treatment planned on a snapshot dataset of the patient's anatomy taken at the time of simulation. Throughout the course of treatment, this snapshot may vary from initial simulation. Although there is the ability to image patients within the treatment room with technologies such as cone beam computed tomography, the current state of the art is largely limited to rigid-body matching and not accounting for any geometric deformations in the patient's anatomy. A plan that was once attuned to the initial simulation can become suboptimal as the treatment progresses unless improved technologies are brought to bear. Adaptive radiation therapy (ART) is an evolving paradigm that seeks to address this deficiency by accounting for ongoing changes in the patient's anatomy and/or physiology during the course of treatment, affording an increasingly more accurate targeting of disease. ART relies on several components working in concert, namely in-room treatment image guidance, deformable image registration, automatic recontouring, plan evaluation and reoptimization, dose calculation, and quality assurance. Various studies have explored how a putative ART solution would improve the current state of the art of radiation therapy-some centers have even clinically implemented online adaptation. These explorations are reviewed here for a variety of sites. PMID- 28916140 TI - An Integrative Interdisciplinary Perspective on Social Dominance Hierarchies. AB - In the course of evolution, social dominance has been a strong force shaping the organization of social systems in many species. Individuals with a better ability to represent social dominance relationships and to adapt their behavior accordingly usually achieve better access to resources, hence providing benefits in terms of reproduction, health, and wellbeing. Understanding how and to what extent our brains are affected by social dominance requires interdisciplinary efforts. Here, we integrate findings from social neuroscience, evolutionary biology, and developmental psychology to highlight how social hierarchies are learned and represented in primates. We also review neuropharmacological findings showing how dopamine, serotonin, and testosterone influence social hierarchies and we emphasize their key clinical implications on vulnerabilities to neuropsychiatric disorders. PMID- 28916141 TI - In vivo multimodal tumor imaging and photodynamic therapy with novel theranostic agents based on the porphyrazine framework-chelated gadolinium (III) cation. AB - BACKGROUND: A promising strategy for cancer diagnosis and therapy is the development of an agent for multimodal imaging and treatment. In the present paper we report on two novel multifunctional agents prepared on the porphyrazine pigment platform using a gadolinium (III) cation chelated by red-fluorescent tetrapyrrole macrocycles (GdPz1 and GdPz2). METHODS: Spectral and magnetic properties of the compounds were analyzed. Monitoring of GdPz1 and GdPz2 accumulation in the murine colon carcinoma CT26 was performed in vivo using fluorescence imaging and MRI. The photobleaching of GdPz1 or GdPz2 and tumor growth rate after photodynamic therapy (PDT) were assessed. RESULTS: GdPz1 and GdPz2 demonstrated the selective accumulation in tumor that was indicated by higher fluorescence intensity in the tumor area in comparison with the normal tissues. The results of MRI in vivo showed that GdPz1 or GdPz2 provided significant contrast enhancement of the tumor in T1 MR images. PDT with GdPz2 resulted in ~20% decrease in fluorescence intensity of the compound and the inhibition of tumor growth. CONCLUSIONS: We assessed the efficiency of two innovative Gd(III) cation-porphyrazine chelates as bimodal MR and fluorescent probes and photosensitizers for PDT and showed their potentials for tumor diagnostics and treatment. GENERAL SIGNIFICANCE: Water-soluble structures simple in preparation and administration into the body represent special interest for theranostics of tumors. Novel porphyrazine macrocycles chelating a central gadolinium cation demonstrated a good prospect as effective multimodal agents, representing a new approach to MRI and fluorescence imaging guided PDT. PMID- 28916142 TI - Effect of tranexamic acid on gross hematuria: A pilot randomized clinical trial study. AB - OBJECTIVE: Local forms of the tranexamic acid have been effective in treating many haemorrhagic cases. So that the aim of the current study is to assess the effectiveness of local tranexamic acid in controlling painless hematuria in patients referred to the emergency department. METHODS: This is a randomized, double-blind clinical trial study, which was conducted on 50 patients with complaints of painless lower urinary tract bleeding during June 2014 and August 2015. The patients were randomly divided into two groups of 25 people each, one group receiving tranexamic acid and the other given a placebo. During bladder irrigation, local tranexamic acid and the placebo were injected into the bladder via Foley catheter. Patients were examined over 24h in terms of the amount of normal saline serum used for irrigation, level of hemoglobin, and blood in urine. RESULTS: In this study it was observed that consumption of tranexamic acid significantly decreased the volume of used serum for bladder irrigation (P=0.041) and the microscopic status of urine decreased significantly in terms of the hematuria after 24h (P=0.026). However, the rate of packed cell transfusion and drop in hemoglobin levels showed no significant difference in both groups of patients (P?0.05). CONCLUSION: The results of this study showed that tranexamic acid could significantly reduce the volume of required serum for bladder irrigation to clear urine, but it had no significant effect on the drop in serum hemoglobin levels. PMID- 28916143 TI - Violent behavior by emergency department patients with an involuntary hold status. AB - BACKGROUND: Violence against health care workers has been increasing. Health care workers in emergency departments (EDs) are highly vulnerable because they provide care for patients who may have mental illness, behavioral problems, or substance use disorders (alone or in combination) and who are often evaluated during an involuntary hold. Our objective was to identify factors that may be associated with violent behavior in ED patients during involuntary holds. METHODS: Retrospective review of patients evaluated during an involuntary hold at a suburban acute care hospital ED from January 2014 through November 2015. RESULTS: Of 251 patients, 22 (9%) had violent incidents in the ED. Violent patients were more likely to have a urine drug screen positive for tricyclic antidepressants (18.2% vs 4.8%, P=0.03) and to present with substance misuse (68.2% vs 39.7%, P=0.01), specifically with marijuana (22.7% vs 9.6%, P=0.06) and alcohol (54.5% vs 24.9%, P=0.003). ED readmission rates were higher for violent patients (18.2% vs 3.9%, P=0.02). No significant difference was found between violent patients and nonviolent patients for sex, race, marital status, insurance status, medical or psychiatric condition, reason for involuntary hold, or length of stay. CONCLUSION: Violent behavior by patients evaluated during an involuntary hold in a suburban acute care hospital ED was associated with tricyclic antidepressant use, substance misuse, and higher ED readmission rates. PMID- 28916144 TI - Micronutrient Supplementation in Adults with HIV Infection: Cochrane Nursing Care Field - Cochrane Review Summary. PMID- 28916145 TI - Accept or Decline? Deciding Factors in a Voluntary HIV Testing Program for Probationers and Parolees. PMID- 28916146 TI - Chinese Sacbrood virus infection in Asian honey bees (Apis cerana cerana) and host immune responses to the virus infection. AB - Chinese Sacbrood virus (CSBV) is a positive-stranded RNAvirus that infects both the European honey bee (Apis mellifera) and the Asian honey bee (A. cerana). However, CSBV has much more devastating effects on Asian honey bees than on European honey bees, posing a serious threat to the agricultural and natural ecosystems that rely on A. cerana for pollination service. Using quantitative RT PCR method, we conducted studies to examine the CSBV infection in Asian honey bee colonies and immune responses of individual bees in response to CSBV infection. Our study showed that CSBV could cause infection in different developmental stages of workers including eggs, larvae, pupae, newly emerged workers, and foraging workers. In addition, evaluating the tissue tropism and transmission of CSBV in infected bees showed that CSBV was detected in the ovaries, spermatheca, and feces of queens as well as semen of drones of the same colonies, suggesting an existence of vertical transmission of CSBV in Asian honey bees. Further, the detection of CSBV in colony food suggests that healthy bees could pick the infection by the virus-contaminated food, and therefore, a possible existence of a food-borne transmission pathway of CSBV in Asian bee colonies. The expression analysis of transcripts (defensin, abaecin, apidaecin, and hymenoptaecin) involving innate antiviral immune pathways showed that CSBV infection could induce significant immune responses in infected bees. However, the immune responses to CSBV infection varied among different development stages with eggs exhibiting the lowest level of immune expression and forager workers exhibiting the highest level of immune gene expression. The results obtained in the study yield important insights into the mechanisms underlying disease pathogenesis of CSBV infections in Asian honey bees and provide valuable information for a rational design of disease control measures. PMID- 28916147 TI - Microbial associates of the southern mole cricket (Scapteriscus borellii) are highly pathogenic. AB - We report the isolation and identification of seven bacterial strains and one fungal strain from dead and diseased Scapteriscus borellii mole crickets collected from a golf course in southern California. Using 16S and 18S rRNA gene sequence analysis we identified the microbes as Serratia marcescens (red), S. marcescens (white), S. marcescens (purple), Achromobacter xylosoxidans, Chryseobacterium sp., Ochrobactrum anthropi, Tsukamurella tryosinosolvens, and Beauveria bassiana. We performed a dose response curve for each of these cricket associated microbial strains (except T. tryosinosolvens) and two other strains of S. marcescens (DB1140 and ATCC 13880). We found that all of these microbes except O. anthropi were highly pathogenic to D. melanogaster compared to the other strains of S. marcescens. Injecting the mole cricket associated strains of Serratia into flies killed all infected flies in <=24h. For all other strains, the median time to death of injected flies varied in a dose-dependent manner. In vivo growth assessments of these microbes suggested that the host immune system was quickly overcome. We used disease tolerance curves to better understand the host-microbe interactions. Further studies are necessary to understand in mechanistic detail the virulence mechanisms of these mole cricket associated microbes and how this association may have influenced the evolution of mole cricket immunity. PMID- 28916148 TI - Chemokine receptor - Directed imaging and therapy. AB - The C-X-C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation. The CXCR4/CXCL12 interplay can be disrupted by CXCR4 antagonists such as Plerixafor which are already in daily clinical use, i.e. for mobilization and subsequent harvesting of hematopoietic progenitor cells and stem cell transplantation. In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases. Recently, radiolabeled analogs of CXCR4 antagonists (e.g., [68Ga]Pentixafor) have been introduced which can be used for non-invasive imaging of CXCR4 expression in animal models and humans using positron emission tomography. In addition, beta emitter-labeled antagonists (i.e., [177Lu]/[90Y]Pentixather) have been used in small patient cohorts for treatment of hematological neoplasms such as lymphoma, multiple myeloma and acute myeloid leukemia. This review reports on current imaging protocols for CXCR4-directed positron emission tomography in preclinical models and in humans. Furthermore, a theranostic approach using beta emitter-labeled antagonists is highlighted. Molecular imaging of the CXCR4/CXCL12 axis can contribute to further understand the process of metastatic spread and the intra-/interindividual heterogeneity of tumors. In addition, CXCR4 directed imaging allows tracking of activated, CXCR4+ immune cells. This allows for watching inflammatory processes, thus contributing to enlighten the role of the immune system in a variety of cardiovascular and neurological diseases. PMID- 28916149 TI - Wavelet-based tracking of bacteria in unreconstructed off-axis holograms. AB - We propose an automated wavelet-based method of tracking particles in unreconstructed off-axis holograms to provide rough estimates of the presence of motion and particle trajectories in digital holographic microscopy (DHM) time series. The wavelet transform modulus maxima segmentation method is adapted and tailored to extract Airy-like diffraction disks, which represent bacteria, from DHM time series. In this exploratory analysis, the method shows potential for estimating bacterial tracks in low-particle-density time series, based on a preliminary analysis of both living and dead Serratia marcescens, and for rapidly providing a single-bit answer to whether a sample chamber contains living or dead microbes or is empty. PMID- 28916150 TI - Use of cylindrical coordinates to localize prostate cancers on MRI and prostatectomy pathology. AB - PURPOSE: To describe and test a quantitative system for designating prostate tumor location on magnetic resonance imaging (MRI) and prostatectomy. A system for describing tumor location will facilitate research correlating MRI and pathology. MATERIALS AND METHODS: The prostate cylindrical coordinate (PCC) system was developed for locating prostate tumors using 3 coordinate values. The 3 coordinate values include the angular location centered on the urethra, the radial distance to the periphery and the long axis from apex to base. To evaluate this system, 26 tumors were identified where the prostate cancer was noted by both the radiologist and the pathologist. PCC values were assigned independently to MRI lesions and corresponding tumors. Intraclass correlation coefficient (ICC) was calculated to assess agreement between PCC assigned using MRI and pathology. The coordinates were used to calculate the average distance between the centers of the same lesion measured by MRI and pathology. RESULTS: Each of the cylindrical coordinates assigned by MRI and pathology were compared and there was no significant difference. The agreement was excellent, and the ICC was 0.70 (P<0.001) for the angular coordinate, 0.81 (P<0.001) for the radial distance, and 0.94 (P<0.001) for the long axis. Compared to pathology, lesions on MRI were significantly larger (1.17 vs. 0.86cm2, P<0.001) but there was strong agreement between the measurements on MRI and pathology (ICC = 0.89, P<0.001). The distance between the centers of the lesions measured on MRI and pathology was small (10.13mm, s.d. = 8.70). CONCLUSIONS: The PCC system quantitatively characterizes lesions seen on MRI and prostatectomy pathology with good agreement. PMID- 28916151 TI - DNA aptamer generation by ExSELEX using genetic alphabet expansion with a mini hairpin DNA stabilization method. AB - A novel aptamer generation method to greatly augment the affinity and stability of DNA aptamers was developed by genetic alphabet expansion combined with mini hairpin DNA technology. The genetic alphabet expansion increases the physicochemical and structural diversities of DNA aptamers by introducing extra components, unnatural bases, as a fifth base, allowing for the enhancement of DNA aptamer affinities. Furthermore, the mini-hairpin DNA technology stabilizes DNA aptamers against nuclease digestion and thermal denaturation, by introducing an extraordinarily stable mini-hairpin DNA containing a GCGAAGC sequence. This novel method provides stabilized high-affinity DNA aptamers for diagnostic and therapeutic applications. PMID- 28916152 TI - Effects of inspiratory muscle training on cardiovascular autonomic control: A systematic review. AB - PURPOSE: To carry out a systematic review to determine if inspiratory muscle training (IMT) promotes changes in cardiovascular autonomic responses in humans. METHODS: The methodology followed the PRISMA statement for reporting systematic review analysis. MEDLINE, PEDro, SCOPUS and PubMed electronic databases were searched from the inception to March 2017. The quality assessment was performed using a PEDro scale. The articles were included if: (1) primary objective was related to the effects of IMT on the cardiovascular autonomic nervous system, and (2) randomized clinical trials and quasi-experimental studies. Exclusion criteria were reviews, short communications, letters, case studies, guidelines, theses, dissertations, qualitative studies, scientific conference abstracts, studies on animals, non-English language articles and articles addressing other breathing techniques. Outcomes evaluated were measures of cardiovascular autonomic control, represented by heart rate variability (HRV) and blood pressure variability (BPV) indexes. RESULTS: The search identified 729 citations and a total of 6 studies were included. The results demonstrated that IMT performed at low intensities can chronically promote an increase in the parasympathetic modulation and/or reduction of sympathetic cardiac modulation in patients with diabetes, hypertension, chronic heart failure and gastroesophageal reflux, when assessed by HRV spectral analysis. However, there was no study which evaluated the effects of IMT on cardiovascular autonomic control assessed by BPV. CONCLUSIONS: IMT can promote benefits for cardiac autonomic control, however the heterogeneity of populations associated with different protocols, few studies reported in the literature and the lack of randomized controlled trials make the effects of IMT on cardiovascular autonomic control inconclusive. PMID- 28916153 TI - Improving Provision of Care for Long-term Survivors of Lymphoma. AB - The progressive improvement of lymphoma therapies has led to a significant prolongation of patient survival and life expectancy. However, lymphoma survivors are at high risk of experiencing a range of early and late adverse effects associated with the extent of treatment exposure. Among these, second malignancies and cardiopulmonary diseases can be fatal, and neurocognitive dysfunction, endocrinopathy, muscle atrophy, and persistent fatigue can affect patients' quality of life for decades after treatment. Early recognition and reduction of risk factors and proper monitoring and treatment of these complications require well-defined follow-up criteria, close coordination among specialists of different disciplines, and a tailored model of survivorship care. We have summarized the major aspects of therapy-related effects in lymphoma patients, reviewed the current recommendations for follow-up protocols, and described a new hospital-based model of survivorship care provision from a recent multicenter Italian experience. PMID- 28916154 TI - Emerging new HCV strains among intravenous drug users and their route of transmission in the north eastern state of Mizoram, India. PMID- 28916155 TI - Ancestral resurrection of anthropoid estrogen receptor beta demonstrates functional consequences of positive selection. AB - Anthropoid primates arose during the Eocene approximately 55 million years ago (mya), and extant anthropoids share a most recent common ancestor ~40mya. Paleontology has been very successful at describing the morphological phenotypes of extinct anthropoids. Less well understood is the molecular biology of these extinct species as well as the phenotypic consequences of evolutionary variation in their genomes. Here we resurrect the most recent common ancestral anthropoid estrogen receptor beta gene (ESR2) and demonstrate that the function of this ancestral estrogen receptor has been maintained during human descent but was altered during early New World monkey (NWM) evolution by becoming a more potent transcriptional activator. We tested hypotheses of adaptive evolution in the protein coding sequences of ESR2, and determined that ESR2 evolved via episodic positive selection on the NWM stem lineage. We separately co-transfected ESR2 constructs for human, NWM, and the anthropoid ancestor along with reporter gene vectors and performed hormone binding dose response experiments that measure transactivation activity. We found the transactivation potentials of the ancestral and human sequences to be significantly lower (p<0.0001 in each comparison) than that of the NWM when treated with estradiol, the most prevalent estrogen. We conclude the difference in fold activation is due to positive selection in the NWM ERbeta ligand binding domain. Our study validates inferential methods for detecting adaptive evolution that predict functional consequences of nucleotide substitutions and points a way toward examining the functional consequences of positive Darwinian selection. PMID- 28916156 TI - Need to Face Liver Cirrhosis after HCV Cure with Antivirals. PMID- 28916157 TI - Diabetes, the TYK2 Gene and the Interferon Response: In Search for Environmental Causes. PMID- 28916158 TI - Pyrrolizines: Design, synthesis, anticancer evaluation and investigation of the potential mechanism of action. AB - A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72uM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC50 values in the ranges of 5.78 11.96uM and 0.1-0.78uM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b, exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2)>100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7-20%) compared to imatinib (inhibition%=1-38%). The results of cell cycle analysis, annexin V PI/FITC apoptosis assay and caspase-3/7 assay revealed that compound 12b has the ability to induce apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora kinases indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential anticancer agents. PMID- 28916159 TI - [Health status of asylum seekers and their access to medical care: Design and pilot testing of a questionnaire]. AB - BACKGROUND: Scientific evidence on the health status of asylum seekers in Germany and their access to health care is fragmentary. There is a lack of appropriate questionnaires collecting indicators of health status and health care, which enable a meaningful comparison with a reference population. This article presents experiences in designing a questionnaire and findings available from a pilot testing to pave the way to improve design and methods in future studies. MATERIALS AND METHODS: The questionnaire comprises 28 mainly closed questions on self-reported health status, access to medical care and sociodemographic indicators. In order to guarantee comparability with the general population in Germany, most questions are derived from national health surveys. The questionnaire was translated into seven languages. Pilot testing was conducted between October 2014 and February 2015 in the course of the monthly welfare payments to asylum seekers in three districts of the German federal state of Baden-Wuerttemberg. RESULTS: A total of 156 out of 614 contacted asylum seekers participated in the pilot study (response rate: 25.4 %). The completion rate for items concerning health status and health care was satisfactory (> 75 %). Several items regarding sociodemographic data and linguistically complex questions showed the lowest item response rates (< 50 %). We recommend streamlining the questionnaire and using precise, closed and culturally adapted items. CONCLUSIONS: The questionnaire proved to be expedient and practicable to assess relevant indicators of health status and health care provision. It appears that there is scope for improvement regarding the shortening and cultural adaptation of the questionnaire and the range of available translations. After addressing the mentioned limitations and further development, our approach could contribute to measuring regional disparities, differences between asylum seekers and the general population and temporal changes. In order to obtain representative data, the sampling strategy should be optimised. PMID- 28916160 TI - [Sociodemographic and health-related determinants of health care utilisation and access to primary and specialist care: Results of a nationwide population survey in Germany (2006-2016)]. AB - BACKGROUND: The aim of this paper is to identify systematic differences due to sociodemographic and health-related determinants in outpatient healthcare utilisation and access in Germany for the period from 2006 to 2016. The study focuses on frequent users and those reporting particularly long wait times for their physician appointments, and it contributes to assessing the level of health equity in Germany. METHODS: The investigation draws on nine population surveys conducted by the German National Association of Statutory Health Insurance Physicians (NASHIP), which interviewed 42,925 respondents aged 18 and above. "Frequent users" were operationalised as those respondents who reported more than ten consultations with outpatient general practitioners (GPs) and specialists (SPs) in the preceding twelve months. Respondents who experienced wait times of more than one month for their last doctor appointment were categorised as "very long wait times". Sociodemographic determinants included age, gender, educational and occupational status, population and region of place of residence, as well as type of health insurance of the respondents. Health-related factors were self assessed health status and reason for last medical consultation. Statistical analyses were conducted using bivariate and multivariate techniques (logistic regression). RESULTS: Utilisation: Frequent users of GPs and SPs are predominantly respondents in poor health, retirees and younger persons (18 to 34 years of age). Furthermore, people with a lower educational background consult their GPs significantly more often than people with higher levels of education. Also, patients with statutory health insurance coverage visit GPs more frequently than those having private health insurance, whereas the opposite holds true for SP consultations. Access: Very long wait times for GP and SP appointments were most often experienced by respondents who consult GPs and SPs for preventive medical check-ups or health screenings, have statutory health insurance, live in eastern Germany and who are above 60 years of age. In addition, people with higher levels of education are significantly more likely to experience wait times for SP appointments of more than one month than people with a lower educational background. The proportion of frequent users as well as of those reporting very long wait times for SP appointments has increased in Germany over the period examined. CONCLUSION: This study reveals that a high frequency of GP and SP consultations is primarily associated with self-assessed poor health, indicating that prioritisation is based on clinical need. In order to ensure the same needs based prioritisation in the access to outpatient healthcare, regulatory measures are required to decrease wait times of more than one month for SP appointments, with a special focus on people with statutory health insurance coverage, residents of eastern Germany and the elderly. PMID- 28916161 TI - Stable association of a Drosophila-derived microbiota with its animal partner and the nutritional environment throughout a fly population's life cycle. AB - In the past years, the fruit fly Drosophila melanogaster has been extensively used to study the relationship between animals and their associated microbes. Compared to the one of wild populations, the microbiota of laboratory-reared flies is less diverse, and comprises fewer bacterial taxa; nevertheless, the main commensal bacteria found in fly microbiota always belong to the Acetobacteraceae and Lactobacillaceae families. The bacterial communities associated with the fly are environmentally acquired, and the partners engage in a perpetual re association process. Adult flies constantly ingest and excrete microbes from and onto their feeding substrate, which are then transmitted to the next generation developing within this shared habitat. We wanted to analyze the potential changes in the bacterial community during its reciprocal transfer between the two compartments of the niche (i.e. the fly and the diet). To address this question, we used a diverse, wild-derived microbial community and analyzed its relationship with the fly population and the nutritive substrate in a given habitat. Here we show that the community was overall well maintained upon transmission to a new niche, to a new fly population and to their progeny, illustrating the stable association of a Drosophila-derived microbiota with its fly partner and the nutritional environment. These results highlight the preponderant role of the nutritional substrate in the dynamics of Drosophila/microbiota interactions, and the need to fully integrate this variable when performing such studies. PMID- 28916162 TI - Fluoride concentration and amount of dentifrice influence enamel demineralization in situ. AB - OBJECTIVES: This study evaluated the effect of conventional (CD, 1100ppm F) and low-fluoride (LFD, 550ppm F) dentifrices, applied in different quantities, on enamel demineralization, and on fluoride (F) concentrations in the dental biofilm formed in situ. METHODS: Five combinations of dentifrices and quantities were tested: placebo (P-F-free) applied on all brush bristles; LFD applied by the transversal technique (0.3g-T1) or on all bristles (0.6g-T2); and CD applied in a pea-sized amount (0.15g-T3) or by the transversal technique (0.3g-T4), in order to produce comparable intensities (F concentration in the dentifrice*amount applied to the brush). Volunteers (n=13, 20-36 years old) wore palatal devices containing 4 bovine enamel blocks, and performed cariogenic challenges (30% sucrose solution) 6*/day, and brushing 3*/day, following a double-blind, cross over and randomized protocol. On the 8th day, biofilm was collected 5 and 60min after brushing. The percentage of surface hardness loss (%SH), integrated loss of subsurface hardness (DeltaKHN) and biofilm F concentrations (solid and fluid phases) were determined. Data were analyzed by repeated-measures ANOVA, Student Newman-Keuls test, and Pearson's correlation coefficient (p<0.05). RESULTS: Significantly lower DeltaKHN was observed for treatments with higher intensity (T2 and T4) in comparison with the lower intensity (T1 and T3). A strong correlation was observed between DeltaKHN and F concentrations in total biofilm (r=-0.71) and biofilm fluid (r=-0.72) 5min after brushing. CONCLUSIONS: The treatment intensity has a significant influence on the development of caries lesions in situ. CLINICAL SIGNIFICANCE: The intensity of treatment (amount of dentifrice*concentration) during brushing seems to be a more relevant parameter of clinical efficacy than simply observing the F concentration of the product. The use of a small amount of CD significantly reduced the protective effects against enamel demineralization. PMID- 28916163 TI - Effects of small-grit grinding and glazing on mechanical behaviors and ageing resistance of a super-translucent dental zirconia. AB - OBJECTIVES: The purpose of this study is to elucidate the effects of small-grit grinding on the mechanical behaviors and ageing resistance of a super-translucent dental zirconia and to investigate the necessity of glazing for the small-grit ground zirconia. METHODS: Small-grit grinding was performed using two kinds of silicon carbide abrasive papers. The control group received no grinding. The unground surfaces and the ground surfaces were glazed by an experienced dental technician. Finally, the zirconia materials were thermally aged in water at 134 degrees C for 5h. After aforementioned treatments, we observed the surface topography and the microstructures, and measured the extent of monoclinic phase, the nano-hardness and nano-modulus of the possible transformed zone and the flexural strength. RESULTS: Small-grit grinding changed the surface topography. The zirconia microstructure did not change obviously after surface treatments and thermal ageing; however, the glaze in contact with zirconia showed cracks after thermal ageing. Small-grit grinding did not induce a phase transformation but improved the flexural strength and ageing resistance. Glazing prevented zirconia from thermal ageing but severely diminished the flexural strength. The nano hardness and nano-modulus of the surface layer were increased by ultrafine grinding. CONCLUSIONS: The results suggest that small-grit grinding is beneficial to the strength and ageing resistance of the super-translucent dental zirconia; however, glazing is not necessary and even impairs the strength for the super translucent dental zirconia. CLINICAL SIGNIFICANCE: This study is helpful to the researches about dental grinding tools and maybe useful for dentists to choose reasonable zirconia surface treatments. PMID- 28916164 TI - [Analysis of clinical relevance applied to 3methods of reducing weight in overweight or obesity followed-up for one year]. AB - OBJECTIVE: To analyse the effect of the use/implementation of 3methods to reduce weight in overweight or obese patients during one year of follow up. MATERIAL AND METHODS: The design corresponds to a double-blind, randomised, controlled clinical trial with 3arms, and 12 months of follow-up. Patients were randomised into 3intervention groups: obesity motivational intervention, with a nurse previously trained in motivational intervention by expert psychologists (G1; n=60); lower intensity consultation, non-motivational group, with digital platform support (G2; N=61), and a third group that received recommendations for weight loss and follow-up in Primary Care Clinic (G3; n=59). Anthropometric variables (weight, height, and abdominal-waist circumference) were measured, and the percentage of patients who managed to reduce their weight >=5% was considered as the main measurement of treatment effectiveness. RESULTS: All groups significantly decreased body weight at the end of the study, with a reduction in G1 (-5.6kg) followed by G2 (-4.3kg), and G3 (-1.7kg), with an overall mean: 3.9kg. The indicators of clinical relevance were in G1/G3: relative risk (RR): 4.99 (95% CI: from 2.71 to 9.18); relative risk reduction (RRR): 399.1% (171.3 to 818.0); Absolute risk reduction (RAR): 65.3% (from 51.5 to 79.1) and NNT: 2 (from 2 to 2). In the G2/G3 groups: RR: 3.01 (from 1.57 to 5.76); RRR: 200.5% (from 57.0 to 475.5); RAR: 32.8% (from 16.9 to 48.7) and NNT: 4 (from 3 to 6). In the G1/G2 groups: RR: 1.66 (from 1.25 to 2.20); RRR: 66.1% (from 25.3 to 120.1); RAR: 32.5% (from 16.6 to 48.4) and NNT: 4 (from 3 to 7). CONCLUSIONS: All 3groups were able to reduce weight. Although the group with motivational intervention achieved the greatest decrease, as well as the most favourable clinical relevance indicators. PMID- 28916165 TI - Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis. AB - BACKGROUND: MUC1 (MUC in human and Muc in animals) is a membrane-tethered mucin expressed on the apical surface of lung epithelial cells. However, in the lungs of patients with interstitial lung disease, MUC1 is aberrantly expressed in hyperplastic alveolar type II epithelial (ATII) cells and alveolar macrophages (AM), and elevated levels of extracellular MUC1 are found in bronchoalveolar lavage (BAL) fluid and the serum of these patients. While pro-fibrotic effects of extracellular MUC1 have recently been described in cultured fibroblasts, the contribution of MUC1 to the pathobiology of pulmonary fibrosis is unknown. In this study, we hypothesized that MUC1 deficiency would reduce susceptibility to pulmonary fibrosis in a mouse model of silicosis. METHODS: We employed human MUC1 transgenic mice, Muc1 deficient mice and wild-type mice on C57BL/6 background in these studies. Some mice received a one-time dose of crystalline silica instilled into their oropharynx in order to induce pulmonary fibrosis and assess the effects of Muc1 deficiency on fibrotic and inflammatory responses in the lung. RESULTS: As previously described in other mouse models of pulmonary fibrosis, we found that extracellular MUC1 levels were markedly increased in whole lung tissues, BALF and serum of human MUC1 transgenic mice after silica. We also detected an increase in total MUC1 levels in the lungs of these mice, indicating that production as well as release contributed to elevated levels after lung injury. Immunohistochemical staining revealed that increased MUC1 expression was mostly confined to ATII cells and AMs in areas of fibrotic remodeling, illustrating a pattern similar to the expression of MUC1 in human fibrotic lung tissues. However, contrary to our hypothesis, we found that Muc1 deficiency resulted in a worsening of fibrotic remodeling in the mouse lung as judged by an increase in number of silicotic nodules, an increase in lung collagen deposition and an increase in the severity of pulmonary inflammation. CONCLUSIONS: Altogether, our results indicate that Muc1 has anti-fibrotic properties in the mouse lung and suggest that elevated levels of MUC1 in patients with interstitial lung disease may serve a protective role, which aims to limit the severity of tissue remodeling in the lung. PMID- 28916167 TI - Structural neuroimaging in sport-related concussion. AB - Structural neuroimaging of athletes who have sustained a sports-related concussion (SRC) can be viewed as either standard clinical imaging or with advanced neuroimaging methods that quantitatively assess brain structure. Negative findings from conventional computed tomography (CT) or magnetic resonance imaging (MRI) are the norm in SRC. Nonetheless, these conventional measures remain the first line of neuroimaging of the athlete as they do detect clinically significant pathologies, when present, such as hemorrhagic abnormalities in the form of hematomas, contusions and mircobleeds along with regions of focal encephalomalacia or other signal abnormalities, with CT best capable of detecting skull fractures. However, advanced neuroimaging techniques hold particular promise in detecting subtle neuropathology in the athlete which standard clinical neuroimaging cannot. To best understand what conventional as well as quantitative neuroimaging methods are detecting in SRC, this review begins by covering basic neuroanatomical principles associated with mild traumatic brain injury (mTBI) and the brain regions most vulnerable to injury from SRC, as these regions define where advanced neuroimaging methods most likely detect abnormalities. Advanced MRI techniques incorporate quantitative metrics that include volume, shape, thickness along with diffusion parameters that provide a more fine-grained analysis of brain structure. With advancements in image analysis, multiple quantitative neuroimaging metrics now can be utilized in assessing SRC. Such multimodality approaches are particularly relevant and important for assessing white matter and network integrity of the brain following injury, including SRC. This review focuses just on the structural side of neuroimaging in SRC, but these techniques also are being integrated with functional neuroimaging, where the combination of the two approaches may provide superior methods in assessing the pathological effects of SRC. PMID- 28916166 TI - AntagomiR-613 protects neuronal cells from oxygen glucose deprivation/re oxygenation via increasing SphK2 expression. AB - Oxygen glucose deprivation (OGD)/re-oxygenation (OGDR) causes damages to neuronal cells. Sphingosine kinase 2 (SphK2) expression could exert neuroprotective functions. Here, we aim to induce SphK2 expression via inhibiting the anti-SphK2 microRNA: microRNA-613 ("miR-613"). In both SH-SY5Y neuronal cells and primary murine hippocampal neurons, transfection of the miR-613's specific inhibitor, antagomiR-613 ("antamiR-613"), induced miR-613 depletion and SphK2 expression. Reversely, forced over-expression of miR-613 caused SphK2 downregulation in SH SY5Y cells. OGDR-induced cytotoxicity in neuronal cells was largely attenuated by antamiR-613. SphK2 is required for antamiR-613-induced actions in neuronal cells. SphK2 knockdown (by targeted-shRNAs) or inhibition (by its inhibitor ABC294640) almost completely abolished antamiR-613-mediated neuroprotection against OGDR. Further studies showed that OGDR-induced reactive oxygen species (ROS) production, lipid peroxidation, and DNA damages in SH-SY5Y cells were largely attenuated by antamiR-613, but were intensified by miR-613 expression. Taken together, we conclude that antamiR-613 protects neuronal cells from OGDR probably via inducing SphK2 expression. PMID- 28916168 TI - Scripting a place in time. AB - Evidence in many experimental systems supports the idea that non-uniform distributions of morphogen proteins encode positional information in developing tissues. There is also strong evidence that morphogen dispersal is mediated by cytonemes and that morphogen proteins transfer from producing to receiving cells at morphogenetic synapses that form at sites of cytoneme contacts. This essay considers some implications of this mechanism and its relevance to various contexts including large single cells such as the pre-cellular Drosophila embryo and the ciliate Stentor. PMID- 28916169 TI - The large and small SPEN family proteins stimulate axon outgrowth during neurosecretory cell remodeling in Drosophila. AB - Split ends (SPEN) is the founding member of a well conserved family of nuclear proteins with critical functions in transcriptional regulation and the post transcriptional processing and nuclear export of transcripts. In animals, the SPEN proteins fall into two size classes that perform either complementary or antagonistic functions in different cellular contexts. Here, we show that the two Drosophila representatives of this family, SPEN and Spenito (NITO), regulate metamorphic remodeling of the CCAP/bursicon neurosecretory cells. CCAP/bursicon cell-targeted overexpression of SPEN had no effect on the larval morphology or the pruning back of the CCAP/bursicon cell axons at the onset of metamorphosis. During the subsequent outgrowth phase of metamorphic remodeling, overexpression of either SPEN or NITO strongly inhibited axon extension, axon branching, peripheral neuropeptide accumulation, and soma growth. Cell-targeted loss-of function alleles for both spen and nito caused similar reductions in axon outgrowth, indicating that the absolute levels of SPEN and NITO activity are critical to support the developmental plasticity of these neurons. Although nito RNAi did not affect SPEN protein levels, the phenotypes produced by SPEN overexpression were suppressed by nito RNAi. We propose that SPEN and NITO function additively or synergistically in the CCAP/bursicon neurons to regulate multiple aspects of neurite outgrowth during metamorphic remodeling. PMID- 28916170 TI - The 1h post glucose value best predicts future dysglycemia among normal glucose tolerance subjects. AB - AIM: To analyse the OGTT glycemic parameters - fasting, 1h and 2h plasma glucose values singly and in various combinations; with respect to their prediction of future dysglycemia in subjects with normal glucose tolerance (NGT). METHODS: Electronic medical records of individuals who underwent an OGTT between 1991 and 2016 at a tertiary diabetes centre were analysed. NGT subjects who had at least one more follow up OGTT (n=1356) were selected for the study. Regarding their prediction of future dysglycemia, the glycemic parameters-Fasting plasma glucose (FPG), 1h plasma glucose (1HrPG) and 2h plasma glucose (2HrPG) were analysed separately and also in different combinations. HbA1c and the combined use of HbA1c and FPG were also compared. Receiver operating characteristic (ROC) curve analysis was performed to assess the capability of various glycemic parameters to discriminate between NGT and dysglycemia. The WHO criteria were used to define dysglycemia as the presence of prediabetes (Impaired fasting glucose and/or Impaired glucose tolerance) or diabetes. RESULTS: 318(23.4%) developed prediabetes (median follow up 3.5years) and 134(10%) developed diabetes (median follow up 5.6years). The 1hrPG had a significantly higher AUC (0.684, 0.716) compared to FPG (0.560 and 0.593) and 2hrPG (0.644 and 0.618) for prediabetes and diabetes respectively. Adding the FPG or the 2hrPG to the 1HrPG did not significantly improve the AUC beyond 1HrPG alone. The 1HrPG also predicted diabetes better than HbA1c as well as the combined use of HbA1c and FPG. CONCLUSION: The 1HrPG value during OGTT is a good predictor of future dysglycemia among NGT subjects. PMID- 28916171 TI - Neurobehavioral assessment of mice following repeated oral exposures to domoic acid during prenatal development. AB - Domoic acid (DA) is an algal toxin which has been associated with significant neurotoxicity in humans, non-human primates, rodents, and marine mammals. Developmental exposure to DA is believed to result in neurotoxicity that may persist into adulthood. DA is produced by harmful algal blooms of Pseudo nitzschia, raising concerns about the consumption of contaminated seafood. We evaluated oral exposures to DA during pregnancy in mice. Doses of 0 (vehicle), 1 or 3mg/kg/d of DA were administered by gavage to C57BL/6J mice on gestational days 10 to 17. The offspring were tested for persistent neurobehavioral consequences during early development, adolescence and adulthood. Neurobehavioral tests revealed both dose- and gender-related differences in several neurobehavioral measures, including motor coordination in the rotarod test, behavior in the elevated plus maze, circadian patterns of activity in Phenotyper cages, gait as assessed in the Catwalk, and exploratory activity in the Morris water maze. This study demonstrated significant gender-specific and persistent neurobehavioral effects of repeated prenatal oral exposures to DA at low-dose levels that did not induce toxicity in dams. PMID- 28916172 TI - Biometric verification by cross-correlation analysis of 12-lead ECG patterns: Ranking of the most reliable peripheral and chest leads. AB - BACKGROUND: Electrocardiogram (ECG)-based biometrics relies on the most stable and unique beat patterns, i.e. those with maximal intra-subject and minimal inter subject waveform differences seen from different leads. We investigated methodology to evaluate those differences, aiming to rank the most prominent single and multi-lead ECG sets for biometric verification across a large population. METHODS: A clinical standard 12-lead resting ECG database, including 460 pairs of remote recordings (distanced 1year apart) was used. Inter-subject beat waveform differences were studied by cross-correlation and amplitude relations of average PQRST (500ms) and QRS (100ms) patterns, using 8 features/lead in 12-leads. Biometric verification models based on stepwise linear discriminant classifier were trained on the first half of records. True verification rate (TVR) on the remaining test data was further reported as a common mean of the correctly verified equal subjects (true acceptance rate) and correctly rejected different subjects (true rejection rate). RESULTS AND CONCLUSIONS: In single-lead ECG human identity applications, we found maximal TVR (87-89%) for the frontal plane leads (I, -aVR, II) within (0-60 degrees ) sector. Other leads were ranked: inferior (85%), lateral to septal (82-81%), with intermittent V3 drop (77.6%), suggesting anatomical landmark displacements. ECG pattern view from multi-lead sets improved TVR: chest (91.3%), limb (94.6%), 12 leads (96.3%). PMID- 28916173 TI - A new anatomical view on the vector cardiogram: The mean temporal-spatial isochrones. AB - AIM: This proof of principle study aims to show the direct relationship between cardiac anatomy and the mean cardiac activation path as captured by the 12 lead ECG derived mean temporal-spatial isochrones (mean TSI) path. METHODS: To obtain the mean TSI signal a vector cardiographic (VCG) signal is constructed from the 12 lead ECG. The construction of the VCG signal uses a model of the heart and torso with patient specific electrode extracted from a 3D photo. The propagation of the activation through the heart is captured by estimating the mean of a cardiac activation isochrone using this VCG signal. The mean TSI signal is related to the heart model in a standard view using 3 orthogonal heart views, instead of the standard body related orthogonal planes. RESULTS: The mean TSI was computed for 4 patients with the ECG containing ectopic activations like Premature ventricular contractions (PVCs) or pacemaps, and normal His-Purkinje activations. For each patient, a specific model with known electrode positions was available. For each activation, the mean TSI was shown in relation to the cardiac anatomy. The region of origin of the PVC or pacemap could easily be localized from these views. Also the initial trans-septal activation for normal His-Purkinje activations could easily be detected and related to the septum. CONCLUSION: This proof of principle study showed that the mean path of cardiac activation can be derived from the ECG and related to standard orthogonal heart views: LAO, RAO, and 4 chambers. This new methodology might help to improve the diagnostic value of the ECG, as the interpretation of the mean TSI is easier to be related to the cardiac anatomy, also for less experienced physicians. PMID- 28916174 TI - Evaluation of beat-to-beat ventricular repolarization lability from standard 12 lead ECG during acute myocardial ischemia. AB - BACKGROUND: Acute myocardial ischemia is a common cause of ventricular arrhythmias, yet recent ECG methods predicting susceptibility to ventricular tachyarrhythmia have not been fully evaluated during spontaneous ischemia. We sought to evaluate the clinical utility of alternans and non-alternans components of repolarization variability from the standard 10-second 12-lead ECG signals to risk stratify patients with acute chest pain. METHODS: We enrolled consecutive, non-traumatic, chest pain patients transported through Emergency Medical Services (EMS) to three tertiary care hospitals with cardiac catheterization lab capabilities in Pittsburgh, PA. ECG signals were manually annotated by an electrophysiologist, then automatically processed using a custom-written software. Both T wave alternans (TWA) and non-alternans repolarization variability (NARV) were calculated using the absolute RMS differences over the repolarization window between odd/even averaged beats and between consecutive averaged pairs, respectively. The primary study outcome was the presence of acute myocardial infarction (AMI) documented by cardiac angiography. RESULTS: After excluding patients with secondary repolarization changes (n=123) and those with excessive noise (n=90), our final sample included 537 patients (age 57+/-16years, 56% males). Patients with AMI (n=47, 9%) had higher TWA and NARV values (p<0.01). Mean RR correlated with TWA, and noise measures correlated with TWA and NARV, after adjusting for potential confounders. There was a high collinearity between TWA and NARV, and each was separately predictive of AMI after controlling for number of analyzed beats, noise measures, and other clinical variables. CONCLUSIONS: Despite limitations imposed by signal quality, TWA and NARV are higher in patients with AMI, even after correction for potential confounders. The clinical value of TWA and NARV derived from standard ECG using our time-domain RMS method is questionable due to the small number of beats and significant noise. PMID- 28916175 TI - Early sepsis detection in critical care patients using multiscale blood pressure and heart rate dynamics. AB - Sepsis remains a leading cause of morbidity and mortality among intensive care unit (ICU) patients. For each hour treatment initiation is delayed after diagnosis, sepsis-related mortality increases by approximately 8%. Therefore, maximizing effective care requires early recognition and initiation of treatment protocols. Antecedent signs and symptoms of sepsis can be subtle and unrecognizable (e.g., loss of autonomic regulation of vital signs), causing treatment delays and harm to the patient. In this work we investigated the utility of high-resolution blood pressure (BP) and heart rate (HR) times series dynamics for the early prediction of sepsis in patients from an urban, academic hospital, meeting the third international consensus definition of sepsis (sepsis III) during their ICU admission. Using a multivariate modeling approach we found that HR and BP dynamics at multiple time-scales are independent predictors of sepsis, even after adjusting for commonly measured clinical values and patient demographics and comorbidities. Earlier recognition and diagnosis of sepsis has the potential to decrease sepsis-related morbidity and mortality through earlier initiation of treatment protocols. PMID- 28916177 TI - Quantifying the Impact of Noninterpretive Tasks on Radiology Report Turn-Around Times. AB - PURPOSE: Traditional radiology productivity metrics do not account for noninterpretive tasks (NITs). This study aimed to systematically quantify NITs and their impact on report turn-around time (RTAT) during solo academic neuroradiology overnight coverage in the emergency department. METHODS: Retrospective analysis of 1 week of data, including phone call quantity and duration, clinician identification badge access to the reading room ("badge swipes"), suspected acute strokes, imaging examination volume, and emergency department patient volume, was performed. Univariate analyses were employed to quantify NITs. Multivariate linear regression was used to determine if NITs within an hour are predictive of RTAT of studies completed within that hour. RESULTS: Sixty-three hours of overnight neuroradiology coverage were analyzed. The mean number of phone calls per hour was 8.7 (SD: 5.7), and mean duration of phone calls per hour was 12 min (SD: 9.6 min, range 1-46). The mean number of badge swipes per hour was 2.1 (SD 1.6). The mean number of examinations (CT and MRI) performed per hour was 2.2 (SD: 1.7). Regression analyses found total duration of phone calls in an hour as the strongest independent predictor of RTAT (unstandardized beta = 4.25, P < .001). The overall multivariate model was also significant (P < .001, R2 = 0.596; adjusted R2 = 0.578). CONCLUSIONS: For every 1 min increase in total duration of calls in an hour, mean RTAT increased by 4.25 min. Standardizing capture of NITs may aid development of strategies that address productivity, communication, and value in radiology. PMID- 28916176 TI - Risk stratification of sudden cardiac death in hypertension. AB - In the United States, up to 450,000 people per year die suddenly; an average of 1 sudden death every 70s. Strategies for preventing sudden cardiac death are urgently needed. Systemic arterial hypertension is a major risk factor for sudden cardiac death and the increasing burden of hypertension is a worldwide problem. The lifetime risk of sudden cardiac death at 30years of age is higher by 30% in individuals with hypertension. Each 20/10mmHg increase in systolic/diastolic blood pressure, is associated with a 20% additional increase in sudden cardiac death risk. Theoretically, antihypertensive treatment should be an effective strategy for sudden cardiac death prevention. However, a recent meta-analysis of 15 randomized controlled trials showed that antihypertensive treatment does not reduce the incidence of sudden cardiac death. This manuscript reviews ECG predictors of sudden cardiac death and the importance of risk stratification for appropriate management of hypertension. PMID- 28916179 TI - A comparison of inhomogeneous magnetization transfer, myelin volume fraction, and diffusion tensor imaging measures in healthy children. AB - Sensitive and specific biomarkers of myelin can help define baseline brain health and development, identify and monitor disease pathology, and evaluate response to treatment where myelin content is affected. Diffusion measures such as radial diffusivity (RD) are commonly used to assess myelin content, but are not specific to myelin. Inhomogeneous magnetization transfer (ihMT) and multicomponent driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT) offer quantitative parameters (qihMT and myelin volume fraction/VFm, respectively) which are suggested to have improved sensitivity to myelin. We compared RD, qihMT, and VFm in a cohort of 23 healthy children aged 8-13 years to evaluate the similarities and differences across these measures. All 3 measures were significantly related across brain voxels, but VFm and qihMT were significantly more strongly correlated (qihMT-VFm r = 0.89) than either measure was with RD (RD-qihMT r = 0.66, RD-VFm r = -0.74; all p < 0.001). Mean parameters differed in several regions, especially in subcortical gray matter. These differences can likely be explained by unique sensitivities of each measure to non-myelin factors, such as crossing fiber geometry, axonal packing, fiber orientation, glial density, or magnetization transfer effects in a voxel. We also observed an orientation dependence of qihMT in white matter, such that qihMT decreased as fiber orientation went from parallel to perpendicular to B0. All measures appear to be sensitive to myelin content, though qihMT and VFm appear to be more specific to it than RD. Scan time, noise tolerance, and resolution requirements may inform researchers of the appropriate measure to choose for a specific application. PMID- 28916178 TI - The cerebellum's contribution to beat interval discrimination. AB - From expert percussionists to individuals who cannot dance, there are widespread differences in people's abilities to perceive and synchronize with a musical beat. The aim of our study was to identify candidate brain regions that might be associated with these abilities. For this purpose, we used Voxel-Based Morphometry to correlate inter-individual differences in performance on the Harvard Beat Assessment Tests (H-BAT) with local inter-individual variations in gray matter volumes across the entire brain space in 60 individuals. Analysis revealed significant co-variations between performances on two perceptual tasks of the Harvard Beat Assessment Tests associated with beat interval change discrimination (faster, slower) and gray matter volume variations in the cerebellum. Participant discrimination thresholds for the Beat Finding Interval Test (quarter note beat) were positively associated with gray matter volume variation in cerebellum lobule IX in the left hemisphere and crus I bilaterally. Discrimination thresholds for the Beat Interval Test (simple series of tones) revealed the tendency for a positive association with gray matter volume variations in crus I/II of the left cerebellum. Our results demonstrate the importance of the cerebellum in beat interval discrimination skills, as measured by two perceptual tasks of the Harvard Beat Assessment Tests. Current findings, in combination with evidence from patients with cerebellar degeneration and expert dancers, suggest that cerebellar gray matter and overall cerebellar integrity are important for temporal discrimination abilities. PMID- 28916180 TI - Interpreting temporal fluctuations in resting-state functional connectivity MRI. AB - Resting-state functional connectivity is a powerful tool for studying human functional brain networks. Temporal fluctuations in functional connectivity, i.e., dynamic functional connectivity (dFC), are thought to reflect dynamic changes in brain organization and non-stationary switching of discrete brain states. However, recent studies have suggested that dFC might be attributed to sampling variability of static FC. Despite this controversy, a detailed exposition of stationarity and statistical testing of dFC is lacking in the literature. This article seeks an in-depth exploration of these statistical issues at a level appealing to both neuroscientists and statisticians. We first review the statistical notion of stationarity, emphasizing its reliance on ensemble statistics. In contrast, all FC measures depend on sample statistics. An important consequence is that the space of stationary signals is much broader than expected, e.g., encompassing hidden markov models (HMM) widely used to extract discrete brain states. In other words, stationarity does not imply the absence of brain states. We then expound the assumptions underlying the statistical testing of dFC. It turns out that the two popular frameworks - phase randomization (PR) and autoregressive randomization (ARR) - generate stationary, linear, Gaussian null data. Therefore, statistical rejection can be due to non stationarity, nonlinearity and/or non-Gaussianity. For example, the null hypothesis can be rejected for the stationary HMM due to nonlinearity and non Gaussianity. Finally, we show that a common form of ARR (bivariate ARR) is susceptible to false positives compared with PR and an adapted version of ARR (multivariate ARR). Application of PR and multivariate ARR to Human Connectome Project data suggests that the stationary, linear, Gaussian null hypothesis cannot be rejected for most participants. However, failure to reject the null hypothesis does not imply that static FC can fully explain dFC. We find that first order AR models explain temporal FC fluctuations significantly better than static FC models. Since first order AR models encode both static FC and one-lag FC, this suggests the presence of dynamical information beyond static FC. Furthermore, even in subjects where the null hypothesis was rejected, AR models explain temporal FC fluctuations significantly better than a popular HMM, suggesting the lack of discrete states (as measured by resting-state fMRI). Overall, our results suggest that AR models are not only useful as a means for generating null data, but may be a powerful tool for exploring the dynamical properties of resting-state fMRI. Finally, we discuss how apparent contradictions in the growing dFC literature might be reconciled. PMID- 28916182 TI - Erratum to "Overcoming the bottleneck of platelet lysate supply in large-scale clinical expansion of adipose-derived stem cells: A comparison of fresh versus three types of platelet lysates from outdated buffy coat-derived platelet concentrates" [Cytotherapy 2017;19:222-234]. PMID- 28916183 TI - Cancer-Related Cognitive Changes. PMID- 28916181 TI - Replicability of time-varying connectivity patterns in large resting state fMRI samples. AB - The past few years have seen an emergence of approaches that leverage temporal changes in whole-brain patterns of functional connectivity (the chronnectome). In this chronnectome study, we investigate the replicability of the human brain's inter-regional coupling dynamics during rest by evaluating two different dynamic functional network connectivity (dFNC) analysis frameworks using 7 500 functional magnetic resonance imaging (fMRI) datasets. To quantify the extent to which the emergent functional connectivity (FC) patterns are reproducible, we characterize the temporal dynamics by deriving several summary measures across multiple large, independent age-matched samples. Reproducibility was demonstrated through the existence of basic connectivity patterns (FC states) amidst an ensemble of inter regional connections. Furthermore, application of the methods to conservatively configured (statistically stationary, linear and Gaussian) surrogate datasets revealed that some of the studied state summary measures were indeed statistically significant and also suggested that this class of null model did not explain the fMRI data fully. This extensive testing of reproducibility of similarity statistics also suggests that the estimated FC states are robust against variation in data quality, analysis, grouping, and decomposition methods. We conclude that future investigations probing the functional and neurophysiological relevance of time-varying connectivity assume critical importance. PMID- 28916184 TI - Role of the IL-12/IL-35 balance in patients with Sjogren syndrome. AB - BACKGROUND: An interferon signature is involved in the pathogenesis of primary Sjogren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of TH1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. OBJECTIVE: We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. METHODS: The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. RESULTS: We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. CONCLUSION: Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease. PMID- 28916185 TI - Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort. PMID- 28916187 TI - Mast cell exosomes can suppress allergic reactions by binding to IgE. PMID- 28916186 TI - Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. AB - BACKGROUND: Combined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited. OBJECTIVES: This study aims to characterize the categories of patients with CIDs in Iran clinically and genetically. METHODS: Clinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and nonsyndromic (352 patients) CIDs. Targeted DNA sequencing was performed on 243 (34.9%) patients. RESULTS: The overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of hyper-IgE syndrome (P < .001), onset of disease at greater than 5 years (P = .02), and absence of multiple affected family members (P = .04) were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ataxia telangiectasia mutated (ATM), autosomal dominant mutations in signal transducer and activator of transcription 3 (STAT3), and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower 5-year survival rate rather than those with nonsyndromic CIDs. CONCLUSIONS: This study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The effect of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients. PMID- 28916189 TI - Phosphoinositide 5-phosphatase activities control cell motility in glioblastoma: Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved. AB - Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5 phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes. Protein kinase B is one target protein and activation of the kinase will have a major impact on cell proliferation, survival and cell metabolism. Two other PIs, PI(4,5)P2 and PI(3,4)P2, are produced or used as substrates of PI 5-phosphatases (OCRL, INPP5B, SHIP1/2, SYNJ1/2, INPP5K, INPP5J, INPP5E). The inositol lipids may influence many aspects of cytoskeletal organization, lamellipodia formation and F actin polymerization. PI 5-phosphatases have been reported to control cell migration, adhesion, polarity and cell invasion particularly in cancer cells. In glioblastoma, reducing SHIP2 expression can positively or negatively affect the speed of cell migration depending on the glioblastoma cell type. The two PI 5 phosphatases SHIP2 or SKIP could be localized at the plasma membrane and can reduce either PI(3,4,5)P3 or PI(4,5)P2 abundance. In the glioblastoma 1321 N1 cells, SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration. PMID- 28916188 TI - Mast cell chymase decreases the severity of group B Streptococcus infections. AB - BACKGROUND: Group B Streptococcus (GBS) or Streptococcus agalactiae are beta hemolytic gram-positive bacteria that colonize the lower genital tracts of women and are frequently associated with infections during pregnancy. Innate immune defenses are critical for controlling GBS dissemination and systemic infection. Mast cells are resident sentinel cells that come into contact with pathogens early during colonization and infection. OBJECTIVE: We aimed to investigate the contribution of chymase to systemic GBS infection and rates of preterm birth. METHODS: Pharmacologic and genetic approaches using mice deficient in mast cell protease (MCPT) 4, the mouse functional homologue of human chymase, were used. RESULTS: Our studies show that mast cells release a protease with chymotrypsin like cleavage specificity in response to GBS. Additionally, increased GBS systemic infection and preterm births were observed in MCPT4-deficient mice versus MCPT4-sufficient mice. Furthermore, we observed that proteolytic cleavage of the host extracellular matrix protein fibronectin by peritoneal cell-derived mast cell lysates diminished GBS adherence. Consistent with this observation, the increase in GBS dissemination and preterm births observed in MCPT4-deficient mice was abolished when GBS was deficient in expression of the fibronectin-binding protein SfbA. CONCLUSIONS: Taken together, our results suggest that the protective effect of MCPT4 against GBS dissemination and preterm labor can be attributed in part to MCPT4-mediated proteolysis of fibronectin. Our studies reveal a novel role of mast cells in defense against bacterial infections. PMID- 28916190 TI - Counting the cost: Passchendaele 100. PMID- 28916192 TI - A consensus-based approach to evidence-based clinical practice. PMID- 28916191 TI - The hydro-alcoholic extracts of Sardinian wild thistles (Onopordum spp.) inhibit TNFalpha-induced IL-8 secretion and NF-kappaB pathway in human gastric epithelial AGS cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thistles species (Family: Compositae) are traditionally used in the Mediterranean area, particularly in Sardinia. They are usually gathered from the wild and used for both food and therapeutic purposes, including gastrointestinal disorders. AIM OF THE STUDY: This work aims to evaluate the anti-inflammatory activity of eight wild thistles from Sardinia, in an in vitro model of gastric inflammation, and to identify the major active compounds in the extracts. MATERIALS AND METHODS: The hydro-alcoholic extract of the aerial part of each species was prepared. After the induction of inflammation by the addition of tumor necrosis factor-alpha (TNFalpha) (10ng/mL), AGS cells were treated with extracts/pure compounds under study. The inhibition of interleukin-8 (IL-8) release, IL-8 and NF-kappaB promoter activities and NF kappaB nuclear translocation were evaluated. Extracts main components were identified by HPLC-PDA-MS/MS. RESULTS: Only Onopordum horridum Viv. and Onopordum illyricum L. hydro-alcoholic extracts reduced, in a concentration-dependent fashion, the IL-8 release and promoter activity in human gastric epithelial cells AGS. The effect was partially due to the NF-kappaB pathway impairment. Onopordum hydro-alcoholic extracts were also chemically profiled, and caffeoylquinic acid derivatives were the main compounds identified in the extract. Further investigations showed that 3,5 dicaffeoylquinic acid highly inhibited IL-8 secretion in AGS cells (IC50 0.65MUM), thus suggesting that this compound contributed, at least in part, to the anti-inflammatory activity elicited by O. illyricum extracts. CONCLUSIONS: Our results suggest that Onopordum species may exert beneficial effects against gastric inflammatory diseases. Thus, these wild plants deserve further investigations as preventive or co-adjuvant agents in gastric diseases. PMID- 28916193 TI - Ferulic acid promotes survival and differentiation of neural stem cells to prevent gentamicin-induced neuronal hearing loss. AB - Neural stem cells (NSCs) have exhibited promising potential in therapies against neuronal hearing loss. Ferulic acid (FA) has been widely reported to enhance neurogenic differentiation of different stem cells. We investigated the role of FA in promoting NSC transplant therapy to prevent gentamicin-induced neuronal hearing loss. NSCs were isolated from mouse cochlear tissues to establish in vitro culture, which were then treated with FA. The survival and differentiation of NSCs were evaluated. Subsequently, neurite outgrowth and excitability of the in vitro neuronal network were assessed. Gentamicin was used to induce neuronal hearing loss in mice, in the presence and absence of FA, followed by assessments of auditory brainstem response (ABR) and distortion product optoacoustic emissions (DPOAE) amplitude. FA promoted survival, neurosphere formation and differentiation of NSCs, as well as neurite outgrowth and excitability of in vitro neuronal network. Furthermore, FA restored ABR threshold shifts and DPOAE in gentamicin-induced neuronal hearing loss mouse model in vivo. Our data, for the first time, support potential therapeutic efficacy of FA in promoting survival and differentiation of NSCs to prevent gentamicin-induced neuronal hearing loss. PMID- 28916194 TI - Induction of cytochrome P450 mRNA in porcine primary hepatocytes cultured under serum free conditions: Comparison of freshly isolated cells and cryopreserved. AB - Primary hepatocytes are widely used in the study of dynamic events like regulation of gene expression, as they are superior to most cell-lines. However, the culturing of the hepatocytes often results in loss of phenotype, e.g. the expression of the cytochrome p450s (CYP). The present study investigated the impact of serum in the culture medium of porcine primary hepatocytes (PPH) on markers of dedifferentiation as well as the impact on CYP induction. The effects were studied in both freshly isolated primary hepatocytes as well as cryopreserved. The exclusion of serum in the culturing media were not introducing significant dedifferentiation as judged by the gene expression of alpha fetoprotein, albumin, glucose-6-phosphatase and the constitutive expression of selected transcription factors and CYP. The induction of CYP2B22 and CYP3A29 by phenobarbital and rifampicin, were greater in hepatocytes cultured without serum. The same were not observed for TCDD induced CYP1A2 expression. In conclusion, PPH cultured under serum free conditions results in little or no dedifferentiation, while being more responsive to known CYP inducers. Hence, it can be suggested that PPH cultured under serum free conditions provides a reliable hepatocyte model to investigate CYP gene regulation. PMID- 28916195 TI - Erratum to "N-acetyl aspartate concentration in the anterior cingulate cortex in patients with schizophrenia: A study of clinical and neuropsychological correlates and preliminary exploration of cognitive behaviour therapy effects" [Psychiatry Research: Neuroimaging 182(3) (2010) 251-260]. PMID- 28916196 TI - Self-reported and observed feeding practices of Rhode Island Head Start teachers: Knowing what not to do. AB - PURPOSE: Through their feeding practices, adult caregivers play an important role in shaping children's eating behaviors. However, the feeding practices of child care teachers have received little attention. The purpose of this study was to compare child care teachers' self-reported feeding practices and observed feeding practices during a preschool meal. METHODS: Rhode Island Head Start teachers (n = 85) were observed during breakfast and lunch where feeding practices were coded using a tool adapted from the Environmental Policy Assessment and Observation (EPAO) tool. Teachers completed a questionnaire adapted from the EPAO Self-Report to capture self-reported feeding practices. Agreement between reported and observed was compared by percent agreement. RESULTS: Teachers were predominantly White (89%) and female (98%). There was a higher level of agreement among self reported and observed controlling feeding practices (78.8-97.6% agreement) compared to healthful feeding practices (11.8-20.0% agreement). CONCLUSIONS: Although self-report measures are typically used to capture feeding practices, there are inconsistencies between self-report and observation measures. The inconsistencies found among healthful self-reported and observed feeding practices have implications for future research protocols, measurement refinement, and training of child care teachers. PMID- 28916197 TI - Invertebrate neuropeptides XVII. PMID- 28916198 TI - Treatment, outcome and quality of life of 1239 patients with advanced non-small cell lung cancer - final results from the prospective German TLK cohort study. AB - OBJECTIVES: Real-life data on advanced non-small cell lung cancer (NSCLC) are centrally important to complement the results from clinical trials and to improve the standard of care. We present data on the choice of systemic first- and second line treatment, number of treatment lines, survival and longitudinal data on health-related quality of life (HRQOL) of patients treated by medical oncologists in Germany. MATERIALS AND METHODS: 1239 patients with advanced NSCLC were recruited at start of first-line therapy into the prospective German clinical cohort study TLK (Tumour Registry Lung Cancer) by 107 sites between February 2010 and December 2013 and followed-up until January 2016. HRQOL was assessed using the EORTC QLQ-C30 and LC13 questionnaires. RESULTS: Most patients receive carboplatin- or cisplatin-based doublet chemotherapy in first-line treatment. The choice of platinum agent did neither influence the outcome: median overall survival (OS) was 12.2 months for carboplatin combinations (95% confidence interval [CI] 10.0-13.8) and 11.9 months for cisplatin combinations (95% CI 10.2 13.8), nor did it have a marked impact on the HRQOL. Patients receiving cisplatin were younger and fitter at start of therapy than patients receiving carboplatin or mono-chemotherapy. The longitudinal HRQOL analysis revealed the main symptoms that need to be addressed in follow-up care, irrespective of the platinum agent: fatigue, nausea, dyspnoea and pain. The patients receiving targeted therapies with tyrosine kinase inhibitors (TKIs) had a median OS of 22.1 months (95% CI 15.0-35.1) and considerably superior HRQOL. CONCLUSION: There was no difference in outcome between the platinum compounds cisplatin and carboplatin in first-line treatment of advanced NSCLC in routine care. This is the first report of longitudinal HRQOL data comparing treatments, showing no difference between carboplatin and cisplatin. PMID- 28916200 TI - Islanding detection scheme based on adaptive identifier signal estimation method. AB - This paper proposes a novel, passive-based anti-islanding method for both inverter and synchronous machine-based distributed generation (DG) units. Unfortunately, when the active/reactive power mismatches are near to zero, majority of the passive anti-islanding methods cannot detect the islanding situation, correctly. This study introduces a new islanding detection method based on exponentially damped signal estimation method. The proposed method uses adaptive identifier method for estimating of the frequency deviation of the point of common coupling (PCC) link as a target signal that can detect the islanding condition with near-zero active power imbalance. Main advantage of the adaptive identifier method over other signal estimation methods is its small sampling window. In this paper, the adaptive identifier based islanding detection method introduces a new detection index entitled decision signal by estimating of oscillation frequency of the PCC frequency and can detect islanding conditions, properly. In islanding conditions, oscillations frequency of PCC frequency reach to zero, thus threshold setting for decision signal is not a tedious job. The non islanding transient events, which can cause a significant deviation in the PCC frequency are considered in simulations. These events include different types of faults, load changes, capacitor bank switching, and motor starting. Further, for islanding events, the capability of the proposed islanding detection method is verified by near-to-zero active power mismatches. PMID- 28916201 TI - Targeting heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis. AB - Heparanase is an endoglucuronidase that uniquely cleaves the heparan sulfate side chains of heparan sulfate proteoglycans. This activity ultimately alters the structural integrity of the ECM and basement membrane that becomes more prone to cellular invasion by metastatic cancer cells and cells of the immune system. In addition, enzymatically inactive heparanase was found to facilitate the proliferation and survival of cancer cells by activation of signaling molecules such as Akt, Src, signal transducer and activation of transcription (Stat), and epidermal growth factor receptor. This function is thought to be executed by the C-terminal domain of heparanase (8c), because over expression of this domain in cancer cells accelerated signaling cascades and tumor growth. We have used the regulatory elements of the mouse mammary tumor virus (MMTV) to direct the expression heparanase and the C-domain (8c) to the mammary gland epithelium of transgenic mice. Here, we report that mammary gland branching morphogenesis is increased in MMTV-heparanase and MMTV-8c mice, associating with increased Akt, Stat5 and Src phosphorylation. Furthermore, we found that the growth of tumors generated by mouse breast cancer cells and the resulting lung metastases are enhanced in MMTV-heparanase mice, thus supporting the notion that heparanase contributed by the tumor microenvironment (i.e., normal mammary epithelium) plays a decisive role in tumorigenesis. Remarkably, MMTV-8c mice develop spontaneous tumors in their mammary and salivary glands. Although this occurs at low rates and requires long latency, it demonstrates decisively the pro-tumorigenic capacity of heparanase signaling. PMID- 28916202 TI - Breast-feeding may be associated with a reduction in specific malocclusions in primary dentition. PMID- 28916203 TI - Working length determination and instrumentation at the same time reduces average pain 24 hours after endodontic treatment compared with separate working length determination and instrumentation. PMID- 28916199 TI - ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy. AB - Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately. Here, we applied the repurposed drugs, selumetinib, an ERK inhibitor, and the ROCK inhibitor fasudil to severe SMA mice. Thereby, separately applied inhibitors as well as a combination enabled us to explore the impact of the ROCK-ERK signaling network on SMA pathophysiology. ROCK inhibition specifically ameliorated the phenotype of selumetinib-treated SMA mice demonstrating an efficient ROCK to ERK crosstalk relevant for the SMA pathophysiology. However, ERK inhibition alone aggravated the condition of SMA mice and reduced the number of motoneurons indicating a compensatory hyper activation of ERK in motoneurons. Taken together, we identified a regulatory network acting downstream of SMN depletion and upstream of the SMA pathophysiology thus being a future treatment target in combination with SMN dependent strategies. PMID- 28916204 TI - Insufficient evidence to claim that a 2-arm interdental cleaning device has better reachability and accessibility than a 1-arm interdental cleaning device. PMID- 28916205 TI - Vertical ridge augmentation in the atrophic mandible may result in bone augmentation and implant survival and success. PMID- 28916206 TI - No benefits important to patients from the use of chlorhexidine rinse as an adjunct to scaling and root planing in patients with chronic periodontitis. PMID- 28916207 TI - Mobile application reminders slightly reduce plaque and gingival index in patients undergoing orthodontic treatment with fixed appliances. PMID- 28916208 TI - Intra- and inter-session reliability of traditional and entropy-based variables describing stance on a wobble board. AB - A wobble board (WB) is a balance rehabilitation tool that is used in physiotherapy to improve strength and stability. The WB tested in this study includes a sensory module for measuring patients' tilt and rotation during stance. The aim of this study was to assess the reliability and validity of a balance measurement using a WB. Thirty healthy young adults participated in this study. The participants stood on the WB to simultaneously record the tilt of the WB and the center of pressure data using a force plate. The data were recorded during five measurement sessions on various days, with four trials each. Sways, velocities and indexes of complexity (CI) were computed. For reliability assessment, we used intra-class correlation coefficients within and between sessions; for validity, we computed Spearman correlation coefficients. The velocities and CI showed good intra-session reliability, and the sways showed mostly poor intra-session reliability. The results of inter-session reliability showed good to excellent reliability for CI, poor reliability for sways and poor to good reliability for velocities. The Spearman correlation coefficient showed excellent agreement between the mean velocities computed from the force plate and the WB. Our results confirm that the WB tested is suitable for stability assessment in young adults. PMID- 28916209 TI - Towards new strategies to manage livestock reproduction using kisspeptin analogs. AB - The discovery of the hypothalamic neuropeptide kisspeptin and its receptor (KISS1R) have dramatically improved our knowledge about the central mechanisms controlling reproduction. Kisspeptin neurons could be considered the hub where internal and external information controlling reproduction converge. The information is here elaborated and the command dispatched to GnRH neurons, the final output of the brain system controlling reproduction. Several studies have shown that in mammals administration of kisspeptin could finely modulate many aspects of reproduction from puberty to ovulation. For example in ewes kisspeptin infusion triggered ovulation during the non-breeding season and in prepubertal rat repeated injections advanced puberty onset. However, especially in livestock, the suboptimal pharmacological properties of endogenous kisspeptin, notably it short half-life and consequently its poor pharmacodynamics, fetters its use to experimental setting. To overcome this issue synthetic KISS1R agonists, mainly based on kisspeptin backbone, were created. Their more favorable pharmacological profile, longer half-life and duration of action, allowed to perform promising initial experiments for controlling ovulation and puberty. Additional experiments and further refinement of analogs would still be necessary to exploit fully the potential of targeting the kisspeptin system. Nevertheless, it is already clear that this new strategy may represent a breakthrough in the field of reproduction control. PMID- 28916210 TI - Modelling multi-site transmission of the human papillomavirus and its impact on vaccination effectiveness. AB - OBJECTIVE: Previous HPV models have only included genital transmission, when evidence suggests that transmission between several anatomical sites occurs. We compared model predictions of population-level HPV vaccination effectiveness against genital HPV16 infection in women, using a 1) uni-site (genital site), and a 2) multi-site model (genital and one extragenital site). METHODS: We developed a uni-site and a multi-site deterministic HPV transmission model, assuming natural immunity was either site-specific or systemic. Both models were calibrated to genital HPV16 prevalence (5%-7.5%), whilst the multi-site model was calibrated to HPV16 prevalence representative of oral (0%-1%) and anal (1%-7.5%) sites. For each model, we identified 2500 parameter sets that fit endemic genital and extragenital prevalences within pre-specified target ranges. In the Base-case analysis, vaccination was girls-only with 40% coverage. Vaccine efficacy was 100% for all sites with lifetime protection. The outcome was the relative reduction in genital HPV16 prevalence among women at post-vaccination equilibrium (RRprev). RRprev was stratified by extragenital prevalence pre-vaccination. RESULTS: Under assumptions of site-specific immunity, RRprev with the multi-site model was generally greater than with the uni-site model. Differences between the uni-site and multi-site models were greater when transmission from the extragenital site to the genital site was high. Under assumptions of systemic immunity, the multi site and uni-site models yielded similar RRprev in the scenario without immunity after extragenital infection. In the scenario with systemic immunity after extragenital infection, the multi-site model yielded lower predictions of RRprev than the uni-site model. CONCLUSIONS: Modelling genital-site only transmission may overestimate vaccination impact if extragenital infections contribute to systemic natural immunity or underestimate vaccination impact if a high proportion of genital infections originate from extragenital infections. Under current understanding of heterosexual HPV transmission and immunity, a substantial bias from using uni-site models in predicting vaccination effectiveness against genital HPV infection is unlikely to occur. PMID- 28916211 TI - Diaphragmatic fenestration for refractory chylothorax after congenital cardiac surgery in infants. AB - OBJECTIVE: Medically refractory chylous pleural effusion after congenital heart surgery is associated with significant morbidity and mortality, especially in infants. We reviewed our experience with diaphragmatic fenestration procedure in this group of patients. METHODS: A retrospective chart review of all patients who had diaphragmatic fenestrations for chylous effusion at our institution over a 2 year period was performed. RESULTS: A total of 9 diaphragmatic fenestration procedures were performed in 8 patients who had failed medical management of chylous pleural effusions. All procedures except 1 were performed on the right side. The median age at time of procedure was 4.6 months (range, 3 weeks to 14 months). The average time between primary congenital cardiac surgery and fenestration was 26 days (range, 4-53 days). Three patients had single ventricle repair. Average time of chest tube removal after procedure was 4 days. Average time to extubation was 3 days. All patients but 1 were able to advance to full feedings without reaccumulation of chylous effusion within 12 days. No complications developed in the patients. Recurrent effusion over a median follow up period of 19 months did not develop in the patients. CONCLUSIONS: Diaphragmatic fenestration is an effective and safe strategy for management of persistent chylous effusions after congenital cardiac surgery. PMID- 28916212 TI - Hybrid reconstruction of the aortic arch: A 15-year follow-up. PMID- 28916213 TI - Delayed surgery in patients with acute type A aortic dissection who are receiving novel oral anticoagulants. PMID- 28916214 TI - Management of acquired nonmalignant tracheoesophageal fistula: Surgical pearls. PMID- 28916215 TI - Chimney technique for aortic valve-on-valve replacement. PMID- 28916216 TI - Coronary artery bypass grafting bundled payment proposal will have significant financial impact on hospitals. AB - OBJECTIVES: The Centers for Medicare and Medicaid Services plans to institute a 5 year trial of bundled payments for coronary artery bypass grafting through 90 days after discharge. To investigate the impact, we reviewed actual inpatient costs for patients undergoing bypass surgery relative to the target price. METHODS: A total of 13,276 Medicare patients with estimated cost data underwent isolated coronary artery bypass grafting from 2008 to 2015 in 18 hospitals over 8 Medicare-defined regions within the Commonwealth of Virginia. Actual 2015 inpatient costs were compared with estimated target prices for each year of the pilot, based on the previous 3 years and stratified by Diagnosis-Related Group. RESULTS: The mean 2015 cost per patient was $50,394 with high variation (range, $27,862-$74,169). On average, hospitals would receive a refund of $17,682 in year 1, but then owe Medicare increasing amounts up to $367,985 in year 5. If 2015 were the final year of the pilot, 13 of the 18 hospitals (72%) would have owed Medicare for cost overruns averaging $614,270 (range, $67,404-$2,102,292). Costs were below the target price at 5 of 18 hospitals, and the Centers for Medicare and Medicaid Services would have paid them an extra $272,355 on average (range, $88,628-$567,429). CONCLUSIONS: Hospitals will face immediate financial pressure due to average cost increases of 3.6% per year and an automatic reduction in payment. As regional pricing is phased in, hospitals can expect to owe Medicare increasing amounts. The net effect is shifting of financial risks to hospitals, which could restrict access to care for higher-risk patients. PMID- 28916217 TI - Stereotactic body radiation therapy versus video-assisted thoracoscopic surgery in stage I lung cancer: Honesty in the face of uncertainty. PMID- 28916218 TI - Endoscopic resection and the T category: Baby steps toward risk stratification. PMID- 28916219 TI - Take a deep breath and everything will be all right.... PMID- 28916220 TI - Thoracic dumbbell-shaped paraganglioma arising in extra-adrenal area: A case report and literature review. PMID- 28916221 TI - Reduced risk of peanut sensitization following exposure through breast-feeding and early peanut introduction. AB - BACKGROUND: Recent trials have shown that avoiding peanuts during infancy increases the risk of peanut allergy; however, these studies did not address maternal peanut consumption. OBJECTIVE: We sought to investigate the relationship between maternal peanut consumption while breast-feeding, timing of direct peanut introduction, and peanut sensitization at age 7 years. METHODS: Secondary analysis of a nested cohort within the 1995 Canadian Asthma Primary Prevention Study intervention study was performed. Breast-feeding and maternal and infant peanut consumption were captured by repeated questionnaires during infancy. Skin prick testing for peanut sensitization was performed at age 7 years. RESULTS: Overall, 58.2% of mothers consumed peanuts while breast-feeding and 22.5% directly introduced peanuts to their infant by 12 months. At 7 years, 9.4% of children were sensitized to peanuts. The lowest incidence (1.7%) was observed among children whose mothers consumed peanuts while breast-feeding and directly introduced peanuts before 12 months. Incidence was significantly higher (P < .05) if mothers consumed peanuts while breast-feeding but delayed introducing peanuts to their infant beyond 12 months (15.1%), or if mothers avoided peanuts themselves but directly introduced peanuts by 12 months (17.6%). Interaction analyses controlling for study group and maternal atopy confirmed that maternal peanut consumption while breast-feeding and infant peanut consumption by 12 months were protective in combination, whereas either exposure in isolation was associated with an increased risk of sensitization (P interaction = .003). CONCLUSIONS: In this secondary analysis, maternal peanut consumption while breast feeding paired with direct introduction of peanuts in the first year of life was associated with the lowest risk of peanut sensitization, compared with all other combinations of maternal and infant peanut consumption. PMID- 28916222 TI - Estimating Vocal Effort from the Aerodynamics of Labial Fricatives: A Feasibility Study. AB - OBJECTIVE AND HYPOTHESIS: Vocal effort in loud voice is produced with increased subglottal pressure during vowels and increased supraglottal pressure during consonants. In the paper, our main objective is to check whether it was supported by a parallel increase in the airflow resistance of the laryngeal articulator and of the supralaryngeal articulator, here the lips. STUDY DESIGN AND METHOD: For this comparison, our choice fell on the fricative consonants, as their production allows perfectly synchronous air pressure and airflow measurements. Also, the calculation of the real instantaneous aerodynamic resistance is possible with fricatives-as it is with vowels-whereas it is not possible with plosives. The present feasibility study on a healthy subject is based on direct subglottal and intraoral pressures and airflow measured for /f/ or /v/ and from the contiguous vowel produced in VCVCV nonsense words at different levels of intensity. RESULTS AND CONCLUSION: The results support that the airflow resistances at the lips and that at the larynx are quite parallel. The airflow resistance at the lips during labial fricative production could provide a good picture of the laryngeal resistance during the production of continuous speech. This suggests clinical applications using both noninvasive inferred measurements of subglottal pressure variation and direct noninferred airflow measurements from more natural speech production tasks. PMID- 28916223 TI - BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis. AB - BACKGROUND AND PURPOSE: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis. MATERIAL AND METHODS: We studied the effect of the BET-bromodomain inhibitors (JQ1, PFI-1) on DGKA inducibility in primary fibroblasts. Hence, DGKA transcription was additionally induced by the radiomimetic drug bleomycin, and DGKA mRNA expression, histone H3K27 acetylation and downstream markers of profibrotic fibroblast activation after BET-bromodomain inhibition were determined. RESULTS: BET-bromodomain inhibition suppressed induction of DGKA in bleomycin-treated fibroblasts, reduced H3K27ac at the DGKA enhancer and repressed collagen marker gene expression. Alterations in fibroblast morphology and reduction of collagen deposition were observed. CONCLUSION: For the DGKA enhancer, we show that BET-bromodomain inhibitors can alter the epigenetic landscape of fibroblasts, thus counteracting profibrotic transcriptional events. Interference with epigenetic patterns of fibrosis predisposition may provide novel preventive therapies that improve radiotherapy. PMID- 28916224 TI - Lack of differences in radiation-induced immunogenicity parameters between HPV positive and HPV-negative human HNSCC cell lines. AB - BACKGROUND AND PURPOSE: Clinical studies indicate that patients with HPV/p16 associated head & neck squamous cell carcinoma (HNSCC) represent a subgroup with a better prognosis and improved response to conventional radiotherapy. Involvement of immune-based factors has been hypothesized. In the present study, we investigated radiation-induced differences in release of damage associated molecular patterns (DAMPs), cytokines and activation of dendritic cells (DCs) in HPV-positive and negative HNSCC cancer cell lines. MATERIAL AND METHODS: Calreticulin (CRT) exposure was detected on cancer cell surface. ATP, HMGB1 and cytokines were measured in culture supernatants. Maturation marker CD83 surface exposure was determined on DCs after co-incubation with irradiated tumor cells. RESULTS: There was no increase in DAMPs and cytokine profiles after radiation treatment and no difference between HPV+ and HPV- cell lines. The HPV/p16 positive SCC90 cells showed a trend for increased total CRT, HMGB1, and number of cytokines compared to all other cell lines. None of the irradiated cancer cell lines could affect DC maturation. CONCLUSIONS: Radiation treatment did not increase immunogenicity of HNSCC cell lines assessed by membrane CRT, ATP, HMGB1, cytokines production, and by activation of immature DCs. There was no difference between HPV-positive and HPV-negative cell lines. PMID- 28916225 TI - Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. AB - BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). RESULTS: The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/uL had reduced risk of intracranial recurrence compared with those with <=1000/uL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). CONCLUSIONS: In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control. PMID- 28916226 TI - [Accelerated atrioventricular junctional rhythm]. PMID- 28916227 TI - Granulocyte transfusions: A concise review for practitioners. AB - Granulocyte transfusions (GTXs) have been used to treat and prevent infections in neutropenic patients for more than 40 years, despite persistent controversy regarding their efficacy. This narrative review attempts to complement recent systematic reviews by the Cochrane Collaboration and provide both historical context and critical assessment of the most significant clinical studies published over the years. The data suggest that properly collected and promptly infused granulocytes are active against infections, both bacterial and fungal. The most important question that remains unanswered is in which patients the administration of granulocytes will be beneficial. The preponderance of evidence suggests that granulocyte transfusions may be efficacious in few select cases as a temporizing measure to control an infection that is expected (or proven) to be refractory to optimal antimicrobial treatment, and that could otherwise be controlled by marrow recovery, which is expected to happen. In this regard, they are best considered a "bridge" that grants enough time for the recipient to develop their own response to the infection. The challenges to use GTXs successfully are both clinical, in terms of timely identifying the patients who may benefit, and logistical, in terms of optimal selection of donors and collection technique. PMID- 28916228 TI - Cellular therapy injections in today's orthopedic market: A social media analysis. AB - BACKGROUND: The current state of cellular therapy for musculoskeletal conditions is at a crossroads. Marketing efforts are often outpacing clinical evidence and regulatory control. QUESTIONS/PURPOSES: This study was an effort to describe the marketing of cellular therapy in musculoskeletal medicine by evaluating the content in popular social media channels. Specifically, media posts were evaluated for the following: (1) perspective, (2) tone, (3) content and (4) visibility. PATIENT AND METHODS: Social media content related to cell therapy for musculoskeletal conditions was assessed in a search using 28 hashtags on the public domains of Instagram and Twitter over a 2-year period (2014-2016) that resulted in analysis of 698 posts. Supplemental analyses of LinkedIn and Facebook domains were also conducted. A categorical scoring system was used to analyze perspective (patient, family or friend, business or organization), tone (positive, negative), content (education, advertisement, research, media coverage or patient experience) and visibility (number of hashtags per post). Sub-analyses of the advertisement content from various perspectives (patients, physicians and businesses) were performed. RESULTS: The media perspective was most frequently from a business or organization (83%; n = 575). A total of 94% of the posts had a positive tone and only 6% had a negative tone, and the only negative posts came from patients (60% positive and 40% negative). The most common content of social media posts were advertisements, representing 68% (n = 477) of all posts; this was confirmed in the Facebook analysis. The mean number of hashtags was five per post. Sub-analyses revealed approximately half of the advertising posts originated from a single business that recruited physicians to market their cell based therapies on social media, which was confirmed in the LinkedIn analysis. CONCLUSION: The market messages related to cell-based therapies for musculoskeletal conditions available on social media are dominated by businesses that seem to use a network of physicians, apply several hashtags to enhance visibility and advertise these largely unproven modalities. The posts portray an almost exclusively positive tone, without providing a "fair balance" on the risks, benefits and limitations. PMID- 28916229 TI - Japanese Leigh syndrome case treated with EPI-743. AB - BACKGROUND: Leigh syndrome is a mitochondrial disease caused by respiratory chain deficiency, and there are no proven effective therapies. EPI-743 is a potent cellular oxidative stress protectant and results of clinical trials for mitochondrial diseases are accumulating. CASE: At 5months, a girl presented with the scarce eye movement and diminished muscle tone. She was diagnosed with Leigh encephalopathy from blood and cerebrospinal fluid lactate elevation and MRI findings. Sequence analysis for mitochondrial DNA revealed a T10158C mutation in the mitochondrial encoded ND3 gene in complex I. RESULTS: At 8months, succinate was prescribed expected to restore the electron transport chain system. After that her condition got worse and succinate was discontinued. Subsequent administration of EPI-743 improved her eye movement, fine motor movements of the extremities, and bowel movement. She is now 5years old. Although brain atrophy has progressed, she has still respiratory free time. CONCLUSION: Our patient showed visible improvement with EPI-743 treatment and the only patient surviving after 4years. There is a possibility that EPI-743 is modifying the natural course of the syndrome. PMID- 28916230 TI - Fighting against congenital hypothyroidism - Old soldiers never die. PMID- 28916231 TI - [Malrotated kidney causing prenatal giant hydronephrosis]. AB - We report the case of a malrotated right kidney associated with giant prenatal hydronephrosis due to a non vascular extrinsic ureteropelvic compression. The kidney presented an hyper-rotation of 180 degrees in relation to the original fetal position, with the renal hilum backward looking. At neonatal surgery we discover that the inferior pole of the kidney pushes laterally the ureteropelvic junction like a violin bridge. The simple uncrossing of the ureteropelvic junction from the inferior renal pole relieves the extrinsic ureteral obstacle and the giant hydronephrosis. The authors summarize the morphogenesis of the upper urinary tract which allowed to understand this rare anatomical variation. PMID- 28916232 TI - Circulating Normal IgG as Stimulator of Regulatory T Cells: Lessons from Intravenous Immunoglobulin. AB - Intravenous immunoglobulin (IVIG), a pooled normal IgG formulation prepared from thousands of healthy donors' plasma, is extensively used for the immunotherapy of autoimmune and inflammatory disorders. Recent reports demonstrate that IVIG exerts anti-inflammatory actions by stimulating the activation and expansion of regulatory T (Treg) cells by multiple mechanisms via antigen-presenting cells (APCs). PMID- 28916233 TI - Risk of pneumonia in patients with insomnia: A nationwide population-based retrospective cohort study. AB - Evidence is lacking regarding whether insomnia increases the risk of infectious disease. Accordingly, the present study examined the risk of pneumonia in patients with insomnia. This study was a population-based retrospective cohort study on a cohort of 8061 patients with insomnia and a control cohort of 16,112 patients (matched by age, sex, and year of diagnosis) from the Taiwan National Health Insurance Research Database for the 2000-2010 period. Overall incidence of pneumonia was 50.6 per 1000 person-years in the insomnia cohort, which was significantly higher than that in the control cohort (30.9 per 1000 person years). Overall, the insomnia cohort exhibited a higher risk of pneumonia (HR=2.43; CI, 2.24-2.62). By age group, the risk of pneumonia was significantly higher in the insomnia cohort for those aged <=40 years (HR=3.23, CI: 1.38-7.57), 41-65 years (HR=2.62, CI: 2.07-3.32), and >65years (CI: 2.21-2.61). Compared with the controls, the insomnia cohort exhibited a higher risk of pneumonia, particularly in young adults. PMID- 28916234 TI - Regulatory capture and financial crisis: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida, and Nisrina Outada. PMID- 28916235 TI - Corrigendum to "Influence of road markings, lane widths and driver behaviour on proximity and speed of vehicles overtaking cyclists" [Accid. Anal. Prev. 73 (2014) 100-108]. PMID- 28916236 TI - Competency - Protecting rights, for good and bad. PMID- 28916237 TI - Ethics and palliative care in the perinatal world. AB - The perinatal world is unique in its dutiful consideration of two patients along the lines of decision-making and clinical management - the fetus and the pregnant woman. The potentiality of the fetus-newborn is intertwined with the absolute considerations for the woman as autonomous patient. From prenatal diagnostics, which may be quite extensive, to potential interventions prenatally, postnatal resuscitation, and neonatal management, the fetus and newborn may be anticipated to survive with or without special needs and technology, to have a questionable or guarded prognosis, or to live only minutes to hours. This review will address the ethical ramifications for prenatal diagnostics, parental values and goals clarification, birth plans, the fluidity of decision-making over time, and the potential role of prenatal and postnatal palliative care support. PMID- 28916239 TI - Effect of Body Mass Index on Clinical Events After Acute Coronary Syndromes. AB - The association between body mass index (BMI) and major clinical events after acute coronary syndrome (ACS) remains controversial. We investigated the impact of BMI on major clinical events after ACS in a large individual patient data meta analysis. Data on 81,553 patients from 45 different countries with ACS enrolled in 8 large randomized clinical trials were included, followed up for a median of 171 days. The mean age was 63.4 +/- 11.7, 70% were male, and the mean BMI was 27.3 +/- 4.7 kg/m2. Compared with upper-normal-weight participants (BMI 21.75 to 24.9 kg/m2, reference category), underweight participants (<18.5 kg/m2) had an increased risk of death (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.10 to 1.66, p = 0.004). Both overweight subcategories, BMI 25 to 27.5 kg/m2 (HR 0.81, 95% CI 0.75 to 0.89, p <0.001) and BMI 27.5 to 29.9 kg/m2 (HR 0.84, 95% CI 0.76 to 0.92, p <0.001), and type I obesity (30 to 34.9, HR 0.81, 95% CI 0.73 to 0.89, p <0.001) had a significantly lower mortality. Type II and III obesities were not significantly associated with mortality. Mortality was lowest at a BMI of 30.9 kg/m2. Compared with normal-weight patients, overweight and obese categories were related with a significantly lower risk of bleeding and refractory ischemia. Overweight patients had a lower risk of myocardial infarction, heart failure hospitalizations, and heart failure-related deaths. There were no associations between BMI and revascularization rates or stroke. In conclusion, underweight and normal-weight patients were associated with an increased mortality risk, bleeding, ischemia, and heart failure compared with those with higher BMI after ACS. PMID- 28916238 TI - Association of midlife lipids with 20-year cognitive change: A cohort study. AB - INTRODUCTION: Existing studies predominantly consider the association of late life lipid levels and subsequent cognitive change. However, midlife rather than late-life risk factors are often most relevant to cognitive health. METHODS: We quantified the association between measured serum lipids in midlife and subsequent 20-year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study. RESULTS: Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides were associated with greater 20-year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20-year decline in memory scores and a measure summarizing performance on all three tests. High-density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness. DISCUSSION: Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20-year cognitive decline. PMID- 28916240 TI - Association Between Red Blood Cell Distribution Width and All-cause Mortality in Chronic Kidney Disease Patients: A Systematic Review and Meta-analysis. AB - BACKGROUND: Considering results among previous studies regarding the relationship of red blood cell distribution width (RDW) and all-cause mortality in chronic kidney disease (CKD) patients, we aimed to perform a comprehensive meta-analysis to evaluate the potential association between RDW and all-cause mortality in CKD patients. METHODS: We conducted a systematic literature using electronic databases (PubMed, Ovid, Embase and Web of Science) to identify the studies reporting the association between RDW and all-cause mortality in CKD patients. We searched the literatures published December 2016 or earlier. We used both fix effects and random-effects models to calculate the overall effect estimate. A sensitivity analysis and subgroup analysis were performed to find the origin of heterogeneity. RESULTS: We retrieved 9 studies with a total of 117,047 patients. For every 1% increase in RDW, the risk of all-cause mortality increased by 47% (HR 1.47, 95% CI 1.35-1.61) with no statistical heterogeneity among the studies (I2 = 44.5%, p = 0.094). When RDW was entered as a categorical variable, mortality risk was significantly increased (HR 1.84, 95% CI 1.21-2.81). Heterogeneity among the studies was observed for all-cause mortality (I2 = 82.3%, p = 0.001). We also performed a predefined subgroup analyses according to study population. We found that for every 1% increase in RDW, the risk of all-cause mortality in hemodialysis (HD) patients increased by 36% (HR 1.36, 95% CI 1.20 1.53). CONCLUSIONS: Our meta-analysis suggests that high levels of RDW probably increase the risk of all-cause mortality in CKD patients. PMID- 28916241 TI - Relationship of Echocardiographic Epicardial Fat Thickness and Epicardial Fat Volume by Computed Tomography with Coronary Artery Calcification: Data from the CAESAR Study. AB - BACKGROUND AND AIMS: No study has assessed the association between echocardiographic epicardial fat thickness (EFT) and computed tomography (CT) based epicardial fat volume (EFV) and coronary artery calcification. The aim of this study is to evaluate the association between EFT and EFV and coronary artery calcification. METHODS: Among the 2,299 individuals enrolled in the CArdiometabolic risk, Epicardial fat, and Subclinical Atherosclerosis Registry (CAESAR) study, 2,276 (1,851 men; mean age 45 +/- 8.9 years) who underwent echocardiographic EFT and CT-based EFV measurements and obtained a coronary artery calcium score (CACS) were included in this study. RESULTS: The overall prevalence of CAC >0 was 19.3%. EFT was significantly correlated with EFV (r = 0.374, p <0.001) but the k statistic showed only slight agreement (k = 0.146, p <0.001). Multivariate regression analyses adjusted for age, sex, body mass index, waist circumference, systolic blood pressure, daily alcohol intake, smoking status, and vigorous exercise and glucose, blood urea nitrogen, uric acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-sensitivity C reactive protein, and hemoglobinA1c levels revealed that an increase in the absolute values of EFT and EFV was significantly associated with the presence of coronary artery calcium (ORs [95% CIs], 2.023 [1.282-3.193] and 1.785 [1.173-2.716], respectively) and CACS (standardized beta values = 0.082 and 0.061, p = 0.001 and 0.042, respectively). CONCLUSION: These results show that EFT and EFV are associated with coronary artery calcification in Korean adults despite the relatively weak correlation between EFT and EFV. PMID- 28916242 TI - Erratum. PMID- 28916243 TI - Feasibility and Accuracy of Automated Software for Transthoracic Three Dimensional Left Ventricular Volume and Function Analysis: Comparisons with Two Dimensional Echocardiography, Three-Dimensional Transthoracic Manual Method, and Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: Recently, a new automated software package (HeartModel) was developed to obtain three-dimensional (3D) left ventricular (LV) volumes using a model based algorithm (MBA) with a "one-button" simple system and user-adjustable slider. The aims of this study were to verify the feasibility and accuracy of the MBA in comparison with other commonly used imaging techniques in a large unselected population, to evaluate possible accuracy improvements of free operator border adjustments or changes of the slider's default position, and to identify differences in method accuracy related to specific pathologies. METHODS: This prospective study included consecutive 200 patients. LV volumes and ejection fraction were obtained using the MBA and compared with the two-dimensional biplane method, the 3D full-volume (3DFV) modality, and, in 90 of 200 cases, cardiac magnetic resonance (CMR) measurements. To evaluate the optimal position of the slider with respect to the 3DFV and CMR modalities, a set of threefold cross-validation experiments was performed. Optimized and manually corrected LV volumes obtained using the MBA were also tested. Linear correlation and Bland Altman analysis were used to assess intertechnique agreement. RESULTS: Automatic volumes were feasible in 194 patients (94.5%), with a mean processing time of 29 +/- 10 sec. MBA-derived volumes correlated significantly with all evaluated methods, with slight overestimation of two-dimensional biplane and slight underestimation of CMR measurements. Higher correlations were found between MBA and 3DFV measurements, with negligible differences both in volumes (overestimation) and in LV ejection fraction (underestimation), respectively. Optimization of the user-adjustable slider position improved the correlation and markedly reduced the bias between the MBA and 3DFV or CMR. The accuracy of MBA volumes was lower in some pathologies for incorrect definition of LV endocardium. CONCLUSIONS: The MBA is highly feasible, reproducible, and rapid, and it correlates highly with the traditional 3DFV method. It may represent a valid alternative to 3DFV measurement for everyday clinical use. PMID- 28916244 TI - [How do immigrant women access health services in the Basque Country? Perceptions of health professionals]. AB - OBJECTIVE: To determine the perception of health professionals working in alternative health centres on the barriers and facilitators in the access by immigrant women to general public health services and sexual and reproductive health in the Basque Country. LOCATION: Basque Country. DESIGN: Analysis of qualitative content based on 11 individual interviews. PARTICIPANTS: Health professionals working in alternative health centres of Primary Care and sexual and reproductive health. METHOD: Data collection was performed between September and December 2015 in four alternative health centres. After transcription, the units of meaning, codes and categories were identified. RESULTS: Four categories emerged from the analysis, which represented how the characteristics of immigrant women (Tell me how you are and I will tell you how to access), the attitude of the administrative and health staff ("When they are already taken care of"), the functioning of the health system (Inflexible, passive and needs-responsive health system), and health policies ("If you do not meet the requirements, you do not go in. The law is the law") influence access to health services of immigrant women. CONCLUSIONS: This study shows that there are a considerable number of barriers and few facilitators to the access by immigrant women to public health and sexual and reproductive health services in the Basque Country. The alternative health centres were presented as favouring the improvement of the health of the immigrant population and in their access. PMID- 28916245 TI - Tetanus, diphtheria, and acellular pertussis vaccination during pregnancy and reduced risk of infant acute respiratory infections. AB - BACKGROUND: To protect infants from pertussis infection, the Advisory Committee on Immunization Practices (ACIP) recommends women receive the tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine between 27 and 36weeks of pregnancy. Here, we assessed the association between timing of maternal Tdap vaccination during pregnancy and acute respiratory infection (ARI) in infants <2months of age. METHODS: This retrospective cohort study included 99,434 infants born to active duty military women in the Department of Defense Birth and Infant Health Registry from 2006 through 2013. Multivariable log binomial regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for the association between maternal Tdap vaccination during pregnancy and infant ARI at <2months of age. RESULTS: Infants of mothers who received Tdap vaccination during pregnancy vs those who did not were 9% less likely to be diagnosed with an ARI at <2months of age (RR, 0.91; 95% CI, 0.84 0.99), and the risk was 17% lower if vaccination was received between 27 and 36weeks of pregnancy (RR, 0.83; 95% CI, 0.74-0.93). Similar results were observed when comparing mothers who received Tdap vaccination prior to pregnancy in addition to Tdap vaccination between 27 and 36weeks of pregnancy versus mothers who only received vaccination prior to pregnancy (RR, 0.85; 95% CI, 0.74-0.98). CONCLUSIONS: Maternal Tdap vaccination between 27 and 36weeks of pregnancy was consistently protective against infant ARI in the first 2months of life vs no vaccination during pregnancy, regardless of Tdap vaccination prior to pregnancy. Our findings strongly support current ACIP guidelines recommending Tdap vaccination in late pregnancy for every pregnancy. PMID- 28916246 TI - Pre-clinical toxicology considerations for vaccine development. AB - Vaccine development requires pre-clinical toxicology studies, following good laboratory practice (GLP), before first in human (phase I) use. Many factors are critical in the final outcome of any pre-clinical toxicology study. The study design is one of these critical factors and should be carefully planned to avoid any false negative and/or false positive results. Preparation is another most critical factor in a successful study. Major changes in any procedure during the course of study should be avoided by all means. For example, if the protocol specified the tail as the site of blood collection and this procedure was used for the control group at the day of necropsy, this collection site should never be replaced by another site (e.g. foot, eye, or heart) in all other treatment groups. Food restrictions and acute restraint stress affect clinical pathology data and should be avoided in rodents. Institutional Animal Care and Use Committee (IACUC) guidelines for frequent blood collections (weekly, monthly, or at necropsy) in any animal species should be strictly followed. Clinical pathology data will be profoundly affected by any diversion from the recommended volumes. If CO2 is specified in the protocol for anesthesia and/or euthanasia, ensuring enough quantity to use for all groups at necropsy is a very important factor. Using two different anesthetics in any study (e.g. CO2 vs. pentobarbital) may result in false positive or false negative results in clinical chemistry parameters. Quality assurance elements (SOPs, instrument validation, lab certification etc.) affect the data interpretation and the final outcome of any toxicology study. SOPs should be up to date and written clearly. All lab instruments should be validated and all laboratories should be certified. PMID- 28916247 TI - Comparison of two control groups for estimation of oral cholera vaccine effectiveness using a case-control study design. AB - BACKGROUND: Case-control studies to quantify oral cholera vaccine effectiveness (VE) often rely on neighbors without diarrhea as community controls. Test negative controls can be easily recruited and may minimize bias due to differential health-seeking behavior and recall. We compared VE estimates derived from community and test-negative controls and conducted bias-indicator analyses to assess potential bias with community controls. METHODS: From October 2012 through November 2016, patients with acute watery diarrhea were recruited from cholera treatment centers in rural Haiti. Cholera cases had a positive stool culture. Non-cholera diarrhea cases (test-negative controls and non-cholera diarrhea cases for bias-indicator analyses) had a negative culture and rapid test. Up to four community controls were matched to diarrhea cases by age group, time, and neighborhood. RESULTS: Primary analyses included 181 cholera cases, 157 non-cholera diarrhea cases, 716 VE community controls and 625 bias-indicator community controls. VE for self-reported vaccination with two doses was consistent across the two control groups, with statistically significant VE estimates ranging from 72 to 74%. Sensitivity analyses revealed similar, though somewhat attenuated estimates for self-reported two dose VE. Bias-indicator estimates were consistently less than one, with VE estimates ranging from 19 to 43%, some of which were statistically significant. CONCLUSIONS: OCV estimates from case-control analyses using community and test-negative controls were similar. While bias-indicator analyses suggested possible over-estimation of VE estimates using community controls, test-negative analyses suggested this bias, if present, was minimal. Test-negative controls can be a valid low-cost and time efficient alternative to community controls for OCV effectiveness estimation and may be especially relevant in emergency situations. PMID- 28916248 TI - Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth. AB - Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors asa breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen specific CD8T cells 4-6-fold over naive mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer. PMID- 28916249 TI - Diagnostic Errors: Impact of an Educational Intervention on Pediatric Primary Care. AB - INTRODUCTION: The purpose of our study was to determine the impact of an educational program on a provider's knowledge related to diagnostic errors and diagnostic reasoning strategies. METHODS: A quasi-experimental interventional study with a multimedia approach, case study discussion, and trigger-generated medical record review at two time points was conducted. Measurement tools included a test developed by the National Patient Safety Foundation, Reducing Diagnostic Errors: Strategies for Solutions Quiz, additional diagnostic reasoning questions, and a trigger-generated process to analyze medical records. RESULTS: Knowledge related to diagnostic errors statistically improved from the pretest to posttest scores with sustained 60-day differences (p < .025). Although there was a decline in the proportion of patients returning with the same chief complaint within 14 days, this was not statistically significant (p < .15). When providers were confronted with an unrecognizable clinical presentation, they reported an increased use of a "diagnostic timeout" (p < .038). DISCUSSION: Providers developed an increased awareness of the presence of diagnostic errors in the primary care setting, the contributing risk factors for a diagnostic error, and possible strategies to reduce diagnostic errors. These factors had an unexpected impact on changing the primary care practice model to enhance the continuity of patient care. PMID- 28916250 TI - Successful Integration of Pediatrics Into State Health Care Reform Efforts. AB - Health care reform in Vermont promotes patient-centered medical homes (PCMH) and multi-disciplinary community health teams to support population health. This qualitative study describes the expansion of Vermont's health care reform efforts, initially focused on adult primary care, to pediatrics through interviews with project managers and facilitators, CHT members, pediatric practitioners and care coordinators, and community-based providers. Analyses used grounded theory, identifying themes confirmed by repeat occurrence across respondents. Respondents believed that PCMH recognition and financial and community supports would improve care for pediatric patients and families. Respondents shared three main challenges with health care reform efforts: achieving PCMH recognition, adapting community health teams for pediatric patients and families, and defining roles for care coordinators. For health care reform efforts to support pediatric patients and be family-centered, states may need additional resources to understand how pediatric and adult primary care differ and how best to support pediatrics during health care reform efforts. PMID- 28916251 TI - MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor. AB - Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1=3 siblings was associated with a lower rate of vaccination. The findings may be useful to promote a vaccination policy recommending financial support to households with many children or to encourage higher uptake of vaccination in higher grade children. PMID- 28916277 TI - Circulating tumor cell as a biomarker for evaluating allogenic NK cell immunotherapy on stage IV non-small cell lung cancer. AB - In this study, we determined the number of peripheral blood circulating tumor cells (CTCs) pre- and post-NK in patients with stage IV non- small cell lung cancer (NSCLC) as a reference for understanding the relevance of any changes to the efficacy of NK cells therapy. The patients were given one to three courses of immunotherapy. CTC numbers and CTC-related gene expression were measured in the peripheral blood of 31 patients with stage IV NSCLC at 1day before and 7 and 30d after NK cells therapy using magnetic activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) combined with real-time quantitative PCR (RT-qPCR). Throughout the research, fever was the most common reaction (34.6%). The number of CTCs was 18.11+/-5.813, 15.13+/-5.984 and 10.32+/-5.623, respectively, and this decreased significantly over time. DeltaCt values for the CTC-related genes CEA, MAGE-3 and CK18 increased significantly after NK cells infusion. The expression of CEA, CK18 and MAGE-3 decreased significantly with time after NK. CTC was a useful biomarker for evaluating the efficacy of NK cells therapy on stage IV NSCLC. PMID- 28916278 TI - Microbial reduction of vanadium (V) in groundwater: Interactions with coexisting common electron acceptors and analysis of microbial community. AB - Vanadium (V) pollution in groundwater has posed serious risks to the environment and public health. Anaerobic microbial reduction can achieve efficient and cost effective remediation of V(V) pollution, but its interactions with coexisting common electron acceptors such as NO3-, Fe3+, SO42- and CO2 in groundwater remain unknown. In this study, the interactions between V(V) reduction and reduction of common electron acceptors were examined with revealing relevant microbial community and identifying dominant species. The results showed that the presence of NO3- slowed down the removal of V(V) in the early stage of the reaction but eventually led to a similar reduction efficiency (90.0% +/- 0.4% in 72-h operation) to that in the reactor without NO3-. The addition of Fe3+, SO42-, or CO2 decreased the efficiency of V(V) reduction. Furthermore, the microbial reduction of these coexisting electron acceptors was also adversely affected by the presence of V(V). The addition of V(V) as well as the extra dose of Fe3+, SO42- and CO2 decreased microbial diversity and evenness, whereas the reactor supplied with NO3- showed the increased diversity. High-throughput 16S rRNA gene pyrosequencing analysis indicated the accumulation of Geobacter, Longilinea, Syntrophobacter, Spirochaeta and Anaerolinea, which might be responsible for the reduction of multiple electron acceptors. The findings of this study have demonstrated the feasibility of anaerobic bioremediation of V(V) and the possible influence of coexisting electron acceptors commonly found in groundwater. PMID- 28916279 TI - The role of IL-6 released from pulmonary epithelial cells in diesel UFP-induced endothelial activation. AB - Diesel exhaust particles (DEP) and their ultrafine fraction (UFP) are known to induce cardiovascular effects in exposed subjects. The mechanisms leading to these outcomes are still under investigation, but the activation of respiratory endothelium is likely to be involved. Particles translocation through the air blood barrier and the release of mediators from the exposed epithelium have been suggested to participate in the process. Here we used a conditioned media in vitro model to investigate the role of epithelial-released mediators in the endothelial cells activation. Diesel UFP were sampled from a Euro 4 vehicle run over a chassis dyno and lung epithelial BEAS-2B cells were exposed for 20 h (dose 5 MUg/cm2). The exposure media were collected and used for endothelial HPMEC ST1.6R cells treatment for 24 h. The processes related to oxidative stress and inflammation were investigated in the epithelial cells, accordingly to the present knowledge on DEP toxicity. The release of IL-6 and VEGF was significantly augmented in diesel exposed cells. In endothelial cells, VCAM-1 and ICAM-1 adhesion molecules levels were increased after exposure to the conditioned media. By interfering with IL-6 binding to its endothelial receptor, we demonstrate the role of this interleukin in inducing the endothelial response. PMID- 28916280 TI - Non-linear direct effects of acid rain on leaf photosynthetic rate of terrestrial plants. AB - Anthropogenic emissions of acid precursors have enhanced global occurrence of acid rain, especially in East Asia. Acid rain directly suppresses leaf function by eroding surface waxes and cuticle and leaching base cations from mesophyll cells, while the simultaneous foliar uptake of nitrates in rainwater may directly benefit leaf photosynthesis and plant growth, suggesting a non-linear direct effect of acid rain. By synthesizing data from literature on acid rain exposure experiments, we assessed the direct effects of acid rain on leaf photosynthesis across 49 terrestrial plants in China. Our results show a non-linear direct effect of acid rain on leaf photosynthetic rate, including a neutral to positive effect above pH 5.0 and a negative effect below that pH level. The acid rain sensitivity of leaf photosynthesis showed no significant difference between herbs and woody species below pH 5.0, but the impacts above that pH level were strongly different, resulting in a significant increase in leaf photosynthetic rate of woody species and an insignificant effect on herbs. Our analysis also indicates a positive effect of the molar ratio of nitric versus sulfuric acid in the acid solution on leaf photosynthetic rate. These findings imply that rainwater acidity and the composition of acids both affect the response of leaf photosynthesis and therefore result in a non-linear direct effect. PMID- 28916281 TI - Explaining the spatiotemporal variation of fine particle number concentrations over Beijing and surrounding areas in an air quality model with aerosol microphysics. AB - In this study, a three-dimensional air quality model with detailed aerosol microphysics (NAQPMS + APM) was applied to simulate the fine particle number size distribution and to explain the spatiotemporal variation of fine particle number concentrations in different size ranges over Beijing and surrounding areas in the haze season (Jan 15 to Feb 13 in 2006). Comparison between observations and the simulation indicates that the model is able to reproduce the main features of the particle number size distribution. The high number concentration of total particles, up to 26600 cm-3 in observations and 39800 cm-3 in the simulation, indicates the severity of pollution in Beijing. We find that primary particles with secondary species coating and secondary particles together control the particle number size distribution. Secondary particles dominate particle number concentration in the nucleation mode. Primary and secondary particles together determine the temporal evolution and spatial pattern of particle number concentration in the Aitken mode. Primary particles dominate particle number concentration in the accumulation mode. Over Beijing and surrounding areas, secondary particles contribute at least 80% of particle number concentration in the nucleation mode but only 10-20% in the accumulation mode. Nucleation mode particles and accumulation mode particles are anti-phased with each other. Nucleation or primary emissions alone could not explain the formation of the particle number size distribution in Beijing. Nucleation has larger effects on ultrafine particles while primary particles emissions are efficient in producing large particles in the accumulation mode. Reduction in primary particle emissions does not always lead to a decrease in the number concentration of ultrafine particles. Measures to reduce fine particle pollution in terms of particle number concentration may be different from those addressing particle mass concentration. PMID- 28916282 TI - Chlorate origin and fate in shallow groundwater below agricultural landscapes. AB - In agricultural lowland landscapes, intensive agricultural is accompanied by a wide use of agrochemical application, like pesticides and fertilizers. The latter often causes serious environmental threats such as N compounds leaching and surface water eutrophication; additionally, since perchlorate can be present as impurities in many fertilizers, the potential presence of perchlorates and their by-products like chlorates and chlorites in shallow groundwater could be a reason of concern. In this light, the present manuscript reports the first temporal and spatial variation of chlorates, chlorites and major anions concentrations in the shallow unconfined aquifer belonging to Ferrara province (in the Po River plain). The study was made in 56 different locations to obtain insight on groundwater chemical composition and its sediment matrix interactions. During the monitoring period from 2010 to 2011, in June 2011 a nonpoint pollution of chlorates was found in the shallow unconfined aquifer belonging to Ferrara province. Detected chlorates concentrations ranged between 0.01 and 38 mg/l with an average value of 2.9 mg/l. Chlorates were found in 49 wells out of 56 and in all types of lithology constituting the shallow aquifer. Chlorates concentrations appeared to be linked to NO3-, volatile fatty acids (VFA) and oxygen reduction potential (ORP) variations. Chlorates behaviour was related to the biodegradation of perchlorates, since perchlorates are favourable electron acceptors for the oxidation of labile dissolved organic carbon (DOC) in groundwater. Further studies must take into consideration to monitor ClO4- in pore waters and groundwater to better elucidate the mass flux of ClO4- in shallow aquifers belonging to agricultural landscapes. PMID- 28916283 TI - Deuterated (d6)-dextromethorphan elicits antidepressant-like effects in mice. AB - The over-the-counter antitussive dextromethorphan (DM) may have rapid antidepressant actions based on its overlapping pharmacology with ketamine, which has shown fast antidepressant effects but whose widespread use remains limited by problematic side effects. We have previously shown that DM produces antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST) that are mediated in part through alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic (AMPA) and sigma-1 receptors, two protein targets associated with a faster onset of antidepressant efficacy. To utilize DM clinically, however, a major challenge that must be addressed is its rapid first-pass metabolism. Two strategies to inhibit metabolism of DM and maintain stable therapeutic blood levels are 1) chemically modifying DM and 2) adding quinidine, an inhibitor of the primary metabolizer of DM, the cytochrome P450 (CYP) 2D6 enzyme. The purpose of this study was to determine if modified DM (deuterated (d6)-DM) elicits antidepressant-like effects and if AMPA and sigma-1 receptors are involved. Furthermore, d6-DM was tested in conjunction with quinidine to determine if further slowing the metabolism of d6-DM affects its antidepressant like actions. In the FST and TST, d6-DM produced antidepressant-like effects. Upon further investigation in the FST, the most validated animal model for predicting antidepressant efficacy, d6-DM produced antidepressant-like effects both in the absence and presence of quinidine. However, pretreatment with neither an AMPA receptor antagonist (NBQX) nor sigma-1 receptor antagonists (BD1063, BD1047) significantly attenuated the antidepressant-like effects. The data suggest d6-DM has antidepressant-like effects, though it may be recruiting different molecular targets and/or acting through a different mix or ratio of metabolites from regular DM. PMID- 28916284 TI - Stereotactic Body Radiotherapy versus Low Dose Rate Brachytherapy for Localised Prostate Cancer: a Cost-Utility Analysis. AB - AIMS: To conduct a cost-utility analysis comparing stereotactic body radiotherapy (SBRT) with low dose rate brachytherapy (LDR-BT) for localised prostate cancer (PCa). MATERIALS AND METHODS: A decision-analytic Markov model was developed from the healthcare payer perspective to simulate the history of a 66-year-old man with low-risk PCa. The model followed patients yearly over their remaining lifetimes. Health states included 'recurrence-free', 'biochemical recurrence' (BR), 'metastatic' and 'death'. Transition probabilities were based on a retrospective cohort analysis undertaken at our institution. Utilities were derived from the literature. Costs were assigned in 2015 Canadian dollars ($) and reflected Ontario's health system and departmental costs. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratios. A willingness-to-pay threshold of $50 000/QALY was used. RESULTS: SBRT was the dominant strategy with 0.008LYs and 0.029QALYs gained and a reduction in cost of $2615. Under base case conditions, our results were sensitive to the BR probability associated with both strategies. LDR-BT becomes the preferred strategy if the BR with SBRT is 1.3*[baseline BR_SBRT] or if the BR with LDR-BT is 0.76*[baseline BR_LDR-BT]. When assuming the same BR for both strategies, LDR BT becomes marginally more effective with 0.009QALYs gained at a cost of $272 848/QALY. CONCLUSIONS: SBRT represents an economically attractive radiation strategy. Further research should be carried out to provide longer-term follow-up and high-quality evidence. PMID- 28916285 TI - Profiling of bisphenol S towards nuclear receptors activities in human reporter cell lines. AB - Bisphenol S (BPS) is heat-stable structural analog of bisphenol A (BPA), a known endocrine disruptor. Due to the effort to replace BPA with BPS, it is essential to know if BPS is suitable non-toxic replacement without reported deleterious effects of BPA. Since most of the BPA effects are ascribed to its ability to activate nuclear receptors, we screened some prominent members of this family in order to confirm or refute some recent findings. We found that BPS insignificantly activated aryl hydrocarbon receptor (AhR) in reporter gene assay and no induction of AhR target gene CYP1A1 was observed in human hepatocytes (HH). BPS was able to act like an antagonist of pregnane X receptor (PXR) in reporter gene assay, but the expression of PXR target gene CYP3A4, was only moderately affected in HH. While BPS antagonized dexamethasone-inducible glucocorticoid receptor (GR)-dependent luciferase activity in reporter gene assay (IC50=52MUM), it was not able to antagonize dexamethasone effects on GR-target genes, including GILZ, NFKBIA and IL-6. Synergistic effect of BPS (range 0.001 100MUM) and DHT (100nM) was observed at androgen receptor (AR) activity level only. In conclusion, we show that BPS had only limited effect on tested nuclear receptors. Moreover, submicromolar concentrations of BPS affected activated AR. Thus, due to the low levels of exposure for humans, BPS is probably of no regulatory concern. However, further investigation should delineate possible impact on male/female development or sexual functions. PMID- 28916286 TI - Toxicology studies of primycin-sulphate using a three-dimensional (3D) in vitro human liver aggregate model. AB - Primycin-sulphate is a highly effective compound against Gram (G) positive bacteria. It has a potentially synergistic effect with vancomycin and statins which makes primycin-sulphate a potentially very effective preparation. Primycin sulphate is currently used exclusively in topical preparations. In vitro animal hepatocyte and neuromuscular junction studies (in mice, rats, snakes, frogs) as well as in in vitro human red blood cell experiments were used to test toxicity. During these studies, the use of primycin-sulphate resulted in reduced cellular membrane integrity and modified ion channel activity. Additionally, parenteral administration of primycin-sulphate to mice, dogs, cats, rabbits and guinea pigs indicated high level of acute toxicity. The objective of this study was to reveal the cytotoxic and gene expression modifying effects of primycin-sulphate in a human system using an in vitro, three dimensional (3D) human hepatic model system. Within the 3D model, primycin-sulphate presented no acute cytotoxicity at concentrations 1MUg/ml and below. However, even at low concentrations, primycin sulphate affected gene expressions by up-regulating inflammatory cytokines (e.g., IL6), chemokines (e.g., CXCL5) and by down-regulating molecules of the lipid metabolism (e.g., peroxisome proliferator receptor (PPAR) alpha, gamma, etc). Down-regulation of PPAR alpha cannot just disrupt lipid production but can also affect cytochrome P450 metabolic enzyme (CYP) 3A4 expression, highlighting the need for extensive drug-drug interaction (DDI) studies before human oral or parenteral preparations can be developed. PMID- 28916287 TI - Effects of anti-inflammatory compounds on sulfur mustard injured cells: Recommendations and caveats suggested by in vitro cell culture models. AB - Sulfur mustard (SM) is a vesicant agent who had its first military use 100 years ago, in Ypres. Since then it has been used in several conflicts like the Iran Iraq war in the 1980s. The use of SM in Syria 2015 indicated the still existing threat. Despite decades of research no causal antidote against SM intoxication is available, so far. A SM intoxication is accompanied by necrosis, apoptosis and inflammation. To counteract the SM-induced inflammation, glucocorticoids and non steroidal anti-inflammatory compounds (NSAIDs) are recommended. Aim of this study was to evaluate the efficacy of the anti-inflammatory compounds dexamethasone, ibuprofen and diclofenac in vitro. For that purpose, two different cell culture models were used. Firstly, a monoculture of keratinocytes (HaCaT) and secondly, an established co-culture of keratinocytes (HaCaT) and immunocompetent cells (THP 1) to identify the role of immune cells in the process and to mimic the dermal physiology more closely. Both models were challenged with different SM concentrations (100, 200 and 300MUM) and treated with different anti-inflammatory compounds one hour after the SM exposure. Analytical analysis of necrosis (ToxiLight), apoptosis (CDDE) and inflammation (IL-6 and -8 ELISAs) followed 24h thereafter. Dexamethasone provided small but consistent protective effects in the monoculture. For the reduction of apoptosis, 3MUM dexamethasone was sufficient. The most effective reduction regarding interleukin (IL) production was found with 6MUM dexamethasone. Protective effects were less pronounced in co-culture, which implies, that the protective effects of dexamethasone are rather generic and not due to a modulation of the immune cells. Against our expectations, ibuprofen strongly amplified apoptosis and necrosis in SM exposed cells in the monoculture as well as the co-culture. Therefore, use of ibuprofen for treatment of SM intoxication should at least be considered most critically, if not even regarded as harmful. Diclofenac significantly reduced necrosis, apoptosis and inflammation in the co-culture in a dose-dependent manner. The greatest benefit regarding cell survival and reduction of the inflammation-marker IL-6 after a SM treatment was observed after diclofenac treatment. The protective effects of diclofenac were less pronounced in the monoculture which suggests, that diclofenac can modify the response of immune cells to SM. In conclusion, the results of our experiments, showing a benefit for diclofenac after SM exposure are in line with in vivo data of other researchers. Though, our in vitro results suggest the preferred use of diclofenac over ibuprofen. The benefit of dexamethasone is still equivocal, but low concentrations seem to have some positive effects. PMID- 28916288 TI - Anti-apoptotic and moderate anti-inflammatory effects of berberine in sulfur mustard exposed keratinocytes. AB - Skin affections after sulfur mustard (SM) exposure include erythema, blister formation and severe inflammation. An antidote or specific therapy does not exist. Anti-inflammatory compounds as well as substances counteracting SM-induced cell death are under investigation. In this study, we investigated the benzylisoquinoline alkaloide berberine (BER), a metabolite in plants like berberis vulgaris, which is used as herbal pharmaceutical in Asian countries, against SM toxicity using a well-established in vitro approach. Keratinocyte (HaCaT) mono-cultures (MoC) or HaCaT/THP-1 co-cultures (CoC) were challenged with 100, 200 or 300mM SM for 1h. Post-exposure, both MoC and CoC were treated with 10, 30 or 50MUM BER for 24h. At that time, supernatants were collected and analyzed both for interleukine (IL) 6 and 8 levels and for content of adenylate kinase (AK) as surrogate marker for cell necrosis. Cells were lysed and nucleosome formation as marker for late apoptosis was assessed. In parallel, AK in cells was determined for normalization purposes. BER treatment did not influence necrosis, but significantly decreased apoptosis. Anti-inflammatory effects were moderate, but also significant, primarily in CoC. Overall, BER has protective effects against SM toxicity in vitro. Whether this holds true should be evaluated in future in vivo studies. PMID- 28916289 TI - Breast cancer screening utilization among women from Muslim majority countries in Ontario, Canada. AB - Breast cancer screening disparities continue to prevail with immigrant women being at the forefront of the under screened population. There is a paucity of knowledge about the role of religious affiliation or cultural orientation on immigrant women's cancer screening uptake. This study examined differences in uptake of breast cancer screening among women from Muslim and non- Muslim majority countries in Ontario, Canada. A cohort of 1,851,834 screening-eligible women living in Ontario during April 1, 2013 to March 31, 2015 was created using linked health and social administrative databases. The study found that being born in a Muslim majority country was associated with lower breast cancer screening uptake after adjusting for region of origin, neighbourhood income, and primary care-related factors. However, screening uptake in Muslim majority countries varied by world region with the greatest differences found in Sub Saharan Africa and South Asia. Screening uptake was lower for women who had no primary care provider, were in a traditional fee-for service model of primary care, had a male physician, had an internationally trained physician, resided in a low income neighbourhood, and entered Canada under the family class of immigration. Religion may play a role in screening uptake, however, the variation in rates by regions of origin, immigration class, and access to primary care providers alludes to confluence of socio-demographic, cultural beliefs and practices, immigration trajectories and system level factors. Facilitating access for immigrant women to regular primary care providers, particularly female providers and enrollment in primary care models could enhance screening uptake. PMID- 28916291 TI - Re: Association of Inflammatory Cytokines With the Symptom Cluster of Pain, Fatigue, Depression, and Sleep Disturbance in Chinese Patients With Cancer. PMID- 28916290 TI - Conceptualizing a Dynamic Fall Risk Model Including Intrinsic Risks and Exposures. AB - Falls are a major cause of injury and disability in older people, leading to serious health and social consequences including fractures, poor quality of life, loss of independence, and institutionalization. To design and provide adequate prevention measures, accurate understanding and identification of person's individual fall risk is important. However, to date, the performance of fall risk models is weak compared with models estimating, for example, cardiovascular risk. This deficiency may result from 2 factors. First, current models consider risk factors to be stable for each person and not change over time, an assumption that does not reflect real-life experience. Second, current models do not consider the interplay of individual exposure including type of activity (eg, walking, undertaking transfers) and environmental risks (eg, lighting, floor conditions) in which activity is performed. Therefore, we posit a dynamic fall risk model consisting of intrinsic risk factors that vary over time and exposure (activity in context). eHealth sensor technology (eg, smartphones) begins to enable the continuous measurement of both the above factors. We illustrate our model with examples of real-world falls from the FARSEEING database. This dynamic framework for fall risk adds important aspects that may improve understanding of fall mechanisms, fall risk models, and the development of fall prevention interventions. PMID- 28916292 TI - Response. PMID- 28916294 TI - Characteristics of Older Adults in Primary Care Who May Benefit From Primary Palliative Care in the U.S. AB - CONTEXT: Older adults with advanced illness and associated symptoms may benefit from primary palliative care, but limited data exist to identify older adults in U.S. primary care to benefit from this care. OBJECTIVES: To describe U.S. primary care visits among adults aged 65 years and older with advanced illness. METHODS: Cross-sectional analysis of the National Ambulatory and Hospital Ambulatory Medical Care Surveys (2009-2011) was conducted using Chi-squared tests to compare visits without and with advanced illness with U.S. primary care defined by National Committee for Quality Assurance Palliative and End-of-Life Care Physician Performance Measurement Set International Classification of Diseases, Ninth Revision (ICD-9) codes for end-stage illness. RESULTS: Among visits by older adults to primary care, 7.9% visits were related to advanced illness. A higher proportion of advanced illness visits was among men vs. women (8.9% vs. 7.2%; P = 0.03) and adults aged 75 years and older, non-Hispanic whites (8.3%) and blacks (8.2%) vs. Hispanic (6.7%) and non-Hispanic other (2.5%) (P = 0.02), dually eligible for Medicare and Medicaid, and from patient ZIP Codes with lower median household incomes (below $32,793). A higher percentage of visits with advanced illness conditions to primary care was chronic obstructive pulmonary disease, congestive heart failure, dementia, and cancer, and symptoms reported with these visits were mostly pain, depression, anxiety, fatigue, and insomnia. CONCLUSION: In the U.S., approximately 8% primary care visits among older adults was related to advanced illness conditions. Advanced illness visits were most common among those most likely to be socioeconomically vulnerable and highlight the need to focus efforts for high-quality palliative care for these populations. PMID- 28916293 TI - Is There Ever a Role for the Unilateral Do Not Attempt Resuscitation Order in Pediatric Care? AB - Care for children as they near the end of life is difficult and very complex. More difficult still are the decisions regarding what interventions are and are not indicated during these trying times. Occasionally, families of children who are nearing the end of life disagree with the assessment of the medical team regarding these interventions. In rare cases, the medical team can be moved to enact a do not attempt resuscitation order against the wishes of the patient's parents. This article presents one such illustrative case and discusses the ethical issues relevant to such challenging clinical scenarios. The authors posit that such a unilateral do not attempt resuscitation order is only appropriate in very limited circumstances in pediatric care. Instead, focus should be placed on open discussion between parents and members of the clinical team, shared decision making, and maintenance of the clinician-parent relationship while simultaneously supporting members of the clinical team who express discomfort with parental decisions. The authors propose an alternative framework for approaching such a conflict based on clinician-parent collaboration and open communication. PMID- 28916295 TI - Utilization of Hospice Services in a Population of Patients With Huntington's Disease. AB - CONTEXT: Although the early and middle stages of Huntington's disease (HD) and its complications have been well described, less is known about the course of late-stage illness. In particular, little is known about the population of patients who enroll in hospice. OBJECTIVES: Our goal is to describe the characteristics of patients with HD who enrolled in hospice. METHODS: This is a retrospective cohort study of electronic medical record data from 12 not-for profit hospices in the United States from 2008 to 2012. RESULTS: Of the 164,032 patients admitted to these hospices, 101 (0.06%) had a primary diagnosis of HD. Their median age was 57 (IQR 48-65) and 53 (52.5%) were women. Most patients were cared for by a spouse (n = 36, 36.6%) or adult child (n = 20, 19.8%). At the time of admission, most patients were living either at home (n = 39, 38.6%) or in a nursing home (n = 41, 40.6%). All were either bedbound or could ambulate only with assistance. The most common symptom reported during enrollment in hospice was pain (n = 34, 33.7%) followed by anxiety (n = 30, 29.7%), nausea (n = 18, 17.8%), and dyspnea (n = 10, 9.9%). Patients had a median length of stay in hospice of 42 days, which was significantly longer than that of other hospice patients in the sample (17 days), P < 0.001. Of the 101 patients who were admitted to hospice, 73 died, 11 were still enrolled at the time of data analysis, and 17 left hospice either because they no longer met eligibility criteria (n = 14, 13.7%) or because they decided to seek treatment for other medical conditions (n = 3, 3.0%). Of the 73 patients who died while on hospice, most died either in a nursing home (n = 29; 40%) or a hospital (n = 27; 37%). Seventeen patients (23%) died at home. No patient that started in a facility died at home. CONCLUSION: Patients with HD are admitted to hospice at a younger age compared with other patients (57 vs. 76 years old) but have a significant symptom burden and limited functional status. Although hospice care emphasizes the importance of helping patients to remain in their homes, only a minority of these patients were able to die at home. PMID- 28916296 TI - Folate-targeted amphiphilic cyclodextrin nanoparticles incorporating a fusogenic peptide deliver therapeutic siRNA and inhibit the invasive capacity of 3D prostate cancer tumours. AB - The main barrier to the development of an effective RNA interference (RNAi) therapy is the lack of a suitable delivery vector. Modified cyclodextrins have emerged in recent years for the delivery of siRNA. In the present study, a folate targeted amphiphilic cyclodextrin was formulated using DSPE-PEG5000-folate to target prostate cancer cells. The fusogenic peptide GALA was included in the formulation to aid in the endosomal release of siRNA. Targeted nanoparticles were less than 200nm in size with a neutral surface charge. The complexes were able to bind siRNA and protect it from serum nucleases. Incubation with excess free folate resulted in a significant decrease in the uptake of targeted nanoparticles in LNCaP and PC3 cells, both of which have been reported to have differing pathways of folate uptake. There was a significant reduction in the therapeutic targets, ZEB1 and NRP1 at mRNA and protein level following treatment with targeted complexes. In preliminary functional assays using 3D spheroids, treatment of PC3 tumours with targeted complexes with ZEB1 and NRP1 siRNA resulted in more compact colonies relative to the untargeted controls and inhibited infiltration into the MatrigelTM layer. PMID- 28916297 TI - Neuro-cognition and social cognition elements of social functioning and social quality of life. AB - Previous studies have shown that deficits in social cognition mediate the association between neuro-cognition and functional outcome. Based on these findings, the current study presents an examination of the mediating role of social cognition and includes two different outcomes: social functioning assessed by objective observer and social quality of life assessed by subjective self report. Instruments measuring different aspects of social cognition, cognitive ability, social functioning and social quality of life were administered to 131 participants who had a diagnosis of a serious mental illness. Results showed that emotion recognition and attributional bias were significant mediators such that cognitive assessment was positively related to both, which in turn, were negatively related to SQoL. While one interpretation of the data suggests that deficits in emotion recognition may serve as a possible defense mechanism, future studies should re-assess this idea. PMID- 28916298 TI - Childhood trauma, depression, and sleep quality and their association with psychotic symptoms and suicidality in schizophrenia. AB - This study involved the examination of the relationship between childhood trauma and both psychotic symptoms and suicidality in patients with schizophrenia after controlling for the possible confounding factors, such as clinical features, depression, and sleep quality. The Childhood Trauma Questionnaire-Short Form, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Pittsburgh Sleep Quality Index (PSQI), and the suicidality subscale of Mini-International Neuropsychiatric Interview (MINI) were administered to 199 patients with schizophrenia. We used sequential multiple stepwise regression analyses in which positive symptoms, negative symptoms, overall psychopathology, total symptoms of schizophrenia, and suicidality were dependent variables. Depressive symptomatology and childhood physical abuse significantly contributed to positive, negative, general psychopathology, and global schizophrenia symptomatology. Interestingly, general psychopathology scores were negatively associated with childhood physical neglect. Also, subjective sleep quality significantly contributed to positive schizophrenia symptoms. Although prior suicide attempts and depression were significant antecedents of suicidal ideation, no association between suicidality and both childhood trauma and sleep was found. Childhood physical abuse could have an impact on psychopathology in schizophrenia. In addition to childhood trauma, depression, sleep disturbances, and clinical features should be considered and inquired about in the course of clinical care of schizophrenia patients. PMID- 28916299 TI - Non-canonical Wnt mediated neurogenic differentiation of human bone marrow derived mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs), which are characterized by multipotency and self-renewal, are responsible for tissue regeneration and repair. We have previously reported in adipose tissue-derived MSCs that only Wnt5a is enhanced at neurogenic differentiation, and the mechanism of differentiation is dependent on the Wnt5a/JNK pathway; however, the role of Wnt/MAPK pathway is yet to be investigated in neurogenic differentiation in BM MSCs. We compared the transcriptional expression of Wnt in neurogenic induced-hBM MSCs (NI-hBM-MSCs) with that in primary hBM-MSCs, using RT-PCR, qPCR, and western blotting. Although the expression of Wnt1 and Wnt2 was unchanged, the expression of Wnt4, Wnt5a, and Wnt11 increased after neurogenic differentiation. In addition, only the expression of frizzled class receptor (Fzd) 3 gene was increased, but not of most of the Fzds and Wnt ligands in NI-hBM-MSCs. Interestingly, Wnt4, Wnt5a, and Wnt11 gene expressions significantly increased in NI-hBM-MSCs by qPCR. In addition, the protein expression level of Wnt4 and Wnt5a, but not Wnt3, increased after neurogenic induction. Furthermore, the expressions of phosphorylated-GSK-3beta, ERK1/2, and PKC decreased; however, JNK was activated after neurogenic differentiation. Thus, non-canonical Wnts, i.e., Wnt4, Wnt5a, and Wnt11, regulate neurogenic differentiation through Fzd3 activation and the increase in downstream targets of JNK, which is one of the non-canonical pathways, in hBM-MSCs. PMID- 28916300 TI - Distinct neuronal populations in the basolateral and central amygdala are activated with acute pain, conditioned fear, and fear-conditioned analgesia. AB - Fear-conditioned analgesia (FCA) is modulated by brain areas involved in the descending inhibitory pain pathway such as the basolateral (BLA) and central amygdala (CEA). The BLA contains Ca2+/calmodulin-dependent protein kinase II (CaMKII) and parvalbumin (PV) neurons. CEA neurons are primarily inhibitory (GABAergic) that comprise enkephalin (ENK) interneurons and corticotropin releasing factor (CRF) - neurons that project to the periaqueductal grey. The purpose of our experiment was to determine the pattern of activation of CaMKII/PV and ENK/CRF neurons following the expression of acute pain, conditioned fear, and FCA. A significant reduction was observed in nociceptive behaviors in mice re exposed to a contextually-aversive environment. Using NeuN and cFos as markers for activated neurons, CaMKII, PV, ENK, or CRF were used to identify neuronal subtypes. We find that mice expressing conditioned fear displayed an increase in c-Fos/CaMKII co-localization in the lateral amygdala and BLA compared to controls. Additionally a significant increase in cFos/CRF co-localization was observed in mice expressing FCA. These results show that amygdala processing of conditioned contextual aversive, nociceptive, and FCA behaviors involve different neuronal phenotypes and neural circuits between, within, and from various amygdala nuclei. This information will be important in developing novel therapies for treating pain and emotive disorders in humans. PMID- 28916301 TI - Enhancing monoterpene alcohols in sweet potato shochu using the diglycoside specific beta-primeverosidase. AB - Monoterpene alcohols (MTAs) are characteristic flavour-imparting compounds in sweet potato shochu (Japanese distilled spirit) that are liberated following hydrolysis by specific enzymes during fermentation. In the present study, we evaluated the effect of an exogenously added diglycoside-specific beta glycosidase (beta-primeverosidase) on aroma formation during shochu brewing using various sweet potato species to address whether MTAs are predominantly present as diglycosidic precursors in raw materials. The results showed that the amount of MTAs produced from enzyme-treated mash was dramatically increased by 2- to 9-fold compared with untreated controls, and the increase varied with sweet potato species. In addition, levels of methyl salicylate, 1-octene-3-ol and ethyl benzoate were also elevated by enzyme treatment. These results indicate that a large amount of MTAs and other volatile aroma compounds are stored in the form of disaccharide beta-glycosides such as beta-primeverosides in sweet potato. This enzyme may therefore be useful for controlling aroma formation during shochu manufacturing, and may ultimately contribute to diversifying shochu quality. PMID- 28916302 TI - High-pressure tolerance of earthworm fibrinolytic and digestive enzymes. AB - Earthworms contain several digestive and therapeutic enzymes that are beneficial to our health and useful for biomass utilization. Specifically, earthworms contain potent fibrinolytic enzymes called lumbrokinases, which are highly stable even at room temperature and remain active in dried earthworm powder. However, the high-temperature sterilization method leads to the inactivation of enzymes. Therefore, we investigated the effect of high-pressure treatment (HPT) (from 0.1 MPa to 500 MPa at 25 degrees C and 50 degrees C) on the enzymatic activity of lumbrokinase (LK), alpha-amylase (AMY), endoglucanase (EG), beta-glucosidase (BGL), and lipase (LP) of the earthworm Eisenia fetida, Waki strain, and its sterilization ability in producing dietary supplement. LK showed thermo- and high pressure tolerance. In addition, HPT may have resulted in pressure-induced stabilization and activation of LK. Although AMY activity was maintained up to 400 MPa at 25 degrees C, the apparent activity decreased slightly at 50 degrees C with HPT. EG showed almost the same pattern as AMY. However, it is possible that the effects of temperature and pressure compensated each other under 100 MPa at 50 degrees C. BGL was shown to be a pressure- and temperature-sensitive enzyme, and LP showed a thermo- and high-pressure tolerance. The slight decrease in apparent activity occurred under 200 MPa at both temperatures. Furthermore, the low-temperature and pressure treatment completely sterilized the samples. These results provide a basis for the development of a novel earthworm dietary supplement with fibrinolytic and digestive activity and of high-pressure-tolerant enzymes to be used for biomass pretreatment. PMID- 28916303 TI - High-throughput flow cytometry for drug discovery: principles, applications, and case studies. AB - Flow cytometry is a technology providing multiparametric analysis of single cells or other suspension particles. High-throughput (HT) flow cytometry has become an attractive screening platform for drug discovery. In this review, we highlight the recent HT flow cytometry applications, and then focus on HT flow cytometry deployment at AstraZeneca (AZ). Practical considerations for successful HT flow cytometry assay development and screening are provided based on experience from four project case studies at AZ. We provide an overview of the scientific rationale, explain why HT flow cytometry was chosen and how HT flow cytometry assays deliver new ways to support the drug discovery process. PMID- 28916304 TI - Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm. AB - BACKGROUND: Abdominal aortic aneurysms (AAAs) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant periaortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft versus host disease, and transplant rejection. Therefore, herein, we describe the Aortic Aneurysm Repression with Mesenchymal Stem Cells (ARREST) trial, a phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. METHODS: ARREST is a phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35-45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and periaortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of computed tomography and duplex sonography. RESULTS: Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long term follow-up. CONCLUSIONS: ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this phase I trial will provide the groundwork for a larger, phase III RCT which may provide the first pharmaceutical intervention for AAA. PMID- 28916305 TI - Unusual Causes of Venous Thrombosis: Bladder Distension and Uterine Mass. AB - Thrombosis of the inferior vena cava (IVC) continues to be a rare event, and there is a scarcity of evidence with regard to its etiology. One source for IVC thrombosis is external compression from adjacent structures. In this case series, we present 1 case of IVC thrombosis caused by a severely distended bladder and a case of external iliac thrombosis caused by external compression from an abnormally enlarged uterus. The treatment of each case is varied and included novel oral anticoagulation, catheter-directed thrombolysis in conjunction with mechanical thrombectomy, or a combination of these. We conclude that the choice of therapy should be tailored on a case-by-case basis. PMID- 28916306 TI - End-To-Side versus Side-To-Side Anastomosis in Upper Limb Arteriovenous Fistula for Dialysis Access: A Systematic Review and a Meta-Analysis. AB - BACKGROUND: An arteriovenous fistula (AVF) is the best modality for hemodialysis access. The end-to-side (ETS) technique has been suggested in the literature to produce superior results to the side-to-side (STS) approach; however, in the absence of a systematic review, this practice remains debatable. METHODS: Online search for randomized controlled trials and observational studies that compared the ETS versus the STS anastomosis techniques in creating an upper limb AVF. Aims were to systematically assess the difference between both procedures in terms of access maturation, patency, and postoperative complications. RESULTS: Seven studies were included with 463 patients in the ETS group and 523 in the STS group. The difference between the 2 techniques was not significant in relation to patency rates at 3, 6, 12, and 24 months (P values: 0.28, 0.82, 0.54, and 0.21, respectively). There were fewer cases of postoperative hematoma in the ETS group; however, the difference was not significant (P = 0.09). Arterial steal syndrome was found to be significantly associated with the STS configuration in pooled analysis (pooled risk ratio = 0.11 [0.01-0.88], 95% CI, P = 0.04). CONCLUSIONS: Similar maturation rates between ETS and STS fistula configuration, however, arterial steal syndrome was significantly associated with the STS technique. ETS will likely remain as the preferred AVF configuration as it is less technically demanding. PMID- 28916307 TI - Extreme conservation of miRNA complements in opisthorchiids. AB - MicroRNAs (miRNAs) are important gene regulators that are key players in animal development and diseases. They are excreted in extracellular vesicles and because they were shown to be taken up by host cells they have been proposed as mediators of parasite-host communication, and potential biomarkers for the detection of parasitic infections from host blood. Consequently, it is crucial to precisely know the miRNA complements of medically important agents such as the liver flukes of the Opisthorchiidae. Using publicly available and new datasets we curated and reannotated the surprisingly small and variable miRNA complements previously described for Opisthorchis viverrini, O. felineus and Clonorchis sinensis. We find three highly similar miRNA complements with 53 identical and two miRNA genes with species specific sequences that signify a set of potential biomarkers and promising candidates for further investigations. PMID- 28916308 TI - Transient transfection of Cryptosporidium baileyi. AB - Here we demonstrate the transient transfection of C. baileyi. We describe the transfection of this apicomplexan parasite and the cultivation in ovo. The functionality of heterologous sequences in C. baileyi was demonstrated by the expression and detection of the mCherry protein in ovo. The mCherry protein was expressed in parasitic stages up to the oocyst stage under the control of the heterologous promoter region of the C. parvum actin gene. PMID- 28916309 TI - Uptake of cholesterol by Tetrahymena thermophila is mainly due to phagocytosis. PMID- 28916310 TI - Dietary restriction delays the secretion of senescence associated secretory phenotype by reducing DNA damage response in the process of renal aging. AB - Dietary restriction (DR) has multiple and essential effects in protecting against DNA damage in model organisms. Persistent DNA damage plays a central role in the process of aging. Senescence-associated secretory phenotype (SASP), as a product of cellular aging, can accelerate the process of cellular senescence as a feedback. In this study, we directly observed whether a DR of 30% for 6months in aged rats could retard SASP by delaying the progression of DNA damage and also found the specific mechanism. The results revealed that a 30% DR could significantly improve renal pathology and some metabolic characteristics. The biomarkers and products of DNA damage were decreased in the process of renal aging on a 30% DR. A series of SASP, notably cytokine, chemokine, and growth factor, were obviously reduced by DR during renal aging. The phosphorylation levels of NF-kappaB and IkappaBalpha in aged kidneys of DR group were markedly reduced. These findings suggest that a 30% DR for 6months can delay renal aging and reduce the accumulation of SASP by retarding the progression of DNA damage and decreasing the transcription activity of NF-kappaB, thus providing a target to delay renal aging. PMID- 28916312 TI - Lenalidomide maintenance in high risk chronic lymphocytic leukaemia: practice changing study or hypothesis generating approach? PMID- 28916311 TI - Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. AB - BACKGROUND: The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. METHODS: In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2 5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing. FINDINGS: Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11.0 (IQR 4.5-20.5) treatment cycles at data cutoff. After a median observation time of 17.9 months (IQR 9.1-28.1), the hazard ratio for progression free survival assessed by an independent review was 0.168 (95% CI 0.074-0.379). Median progression-free survival was 13.3 months (95% CI 9.9-19.7) in the placebo group and not reached (95% CI 32.3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group). INTERPRETATION: Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment. FUNDING: Celgene Corporation. PMID- 28916313 TI - Virulence of thermolable haemolysi tlh, gastroenteritis related pathogenicity tdh and trh of the pathogens Vibrio Parahemolyticus in Viable but Non-Culturable (VBNC) state. AB - In the Viable but Non-Culturable (VBNC) state, microorganisms may survive under severe external environment. In this study, the specificity and sensitivity of PMA-LAMP assay on the detection of Vibrio Parahemolyticus (V. parahemolyticus) has been developed and evaluated, with further application on a number of food borne V. parahemolyticus strains. Six primers were designed for recognizing 8 distinct targeting on tlh, tdh and trh gene. Through specific penetration through the damaged cell membrane of dead cells and intercalating into DNA, PMA could prevent DNA amplification of dead bacteria from LAMP, which enabled the differentiation of bacteria between VBNC state and dead state. The established PMA-LAMP showed significant advantage in rapidity, sensitivity and specificity, compared with regular PCR assay. The applicability had also been verified, demonstrating the PMA-LAMP was capable of detection on V. parahaemolyticus. PMID- 28916314 TI - Immunization with recombinant GntR plasmid confers protection against Brucella challenge in BALB/c mice. AB - It is essential to improve animal vaccine for brucellosis since conventional vaccines are residual virulent and poor protective effect, limit their applications. To solve these problems, the recombinant DNA vaccines were appeared, which could improve protective immunity and were attenuated to animals. In current research, the recombinant DNA vaccine (pVGntR) based on transcriptional regulator GntR of Brucella abortus (B. abortus) was constructed. The results show that pVGntR is significantly more protective than the conventional RB51 vaccine. Immunization with pVGntR increases the production of immunoglobulin G (IgG) and elicits elevated numbers of gamma interferon (IFN gamma) and interleukin-4 (IL-4). These results suggest that pVGntR is a highly efficacious vaccine candidate that confers protection against wild-type B. abortus challenge. PMID- 28916315 TI - The effect of immune modulation of Streptococcus constellatus SC10 strain upon Acinetobactor baumannii infection. AB - Acinetobacter baumannii is a tiny, plump and rod-shaped Gram-negative coccobacillus, notorious as an opportunistic pathogen, which is now being considered by CDC as a serious public health threat. Preventing colonization may be a better therapeutic choice using microbiota to protect against A. baumannii transmission. Human microbiota not only regulates immune homeostasis as well provides essential health benefits therefore discovering the interface due microbiota in host immune system will allow to recognise novel immuno- or microbe based therapies. Streptococcus constellatus frequently isolated from oral cavity was selected for this study to check if its guards against A. baumannii by improving the immune response and the immune signalling pathway. In a mouse model we explored various parameters which include mouse body weight, internal organ weight, level of sIgA and different cytokine changes to evaluate its prophylactic effect against A. baumannii. Administration of S. constellatus SC10 was able to control the weight lose induced by A. bumannii infection in both the protected and treated groups. Particularly resistant against infection was more in treated group where the different cytokine following administration of SC10 strain remarkably controlled the infection and induced more sIgA production. The level of different interleukins IL-4, IL-10, IL-12 and IFN-gamma was suppressed in treatment and protected group after exposure of S. constellatus. The excretion of sIgA following infection was many folds high in both group treated and protected groups Study suggests that SC10 L16 have potential immunomodulating effect which is able to regulate cytokines and sIgA response at the early phase of infection and modulate the further progress of clinical symptoms during infection. PMID- 28916316 TI - The Brucella melitensis M5-90DeltamanB live vaccine candidate is safer than M5-90 and confers protection against wild-type challenge in BALB/c mice. AB - Brucellosis is a globally distributed zoonotic disease that causes animal and human diseases. Although effective, the current Brucella vaccines (strain M5-90 or others) have several drawbacks. The first is their residual virulence for animals and humans and the second is their inability to differentiate natural infection from that caused by vaccination. In the present study, Brucella melitensis M5-90 manB mutant (M5-90DeltamanB) was generated to overcome these drawbacks. M5-90DeltamanB showed significantly reduced survival in macrophages and mice, and induced strong protective immunity in BALB/c mice. It elicited anti Brucella-specific IgG1 and IgG2a subtype responses and induced the secretion of gamma interferon (IFN-gamma) and interleukin-4(IL-4). Results of immune assays showed, M5-90DeltamanB immunization induced the secretion of IFN-gamma in goats, and serum samples from goats inoculated with M5-90DeltamanB were negative by Bengal Plate Test (RBPT) and Standard Tube Agglutination Test (STAT). Further, the ManB antigen also allows serological assays differentiate infections caused by wild strains from infections by vaccination. These results show that M5 90DeltamanB is a suitable attenuated vaccine candidate against virulent Brucella melitensis 16 M (16 M) infection. PMID- 28916317 TI - Presence of human herpesvirus 8 (HHV-8) DNA sequences in patients with lymphoproliferative diseases and chronic blood disorders. AB - OBJECTIVE: Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi's sarcoma (KS), but it has also been associated with different hematologic malignancies, including plasmablastic lymphoma, Multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL) and various atypical lymphoproliferative disorders. Patients with underlying lymphoproliferative diseases and chronic blood disorders who become infected with this virus are at risk for human malignancies. This small study reported the frequency of human herpesvirus 8 in 81 Iranian patients with lymphoproliferative disorders for estimation of possible factors affecting malignancy. METHODS: The laboratory records of 81 patients' peripheral blood mononuclear cell (PBMC)samples, which were tested for detection of HHV-8 open reading frame (ORF) 26 DNA by nested PCR amplification during the period from Sept. 2014 to Sept. 2015, were reviewed retrospectively at the Firouzgar Hospital, Tehran, Iran. RESULTS: Of 81 subjects, 28 were non-Hodgkin's lymphoma (NHL), 19 were Hodgkin's lymphoma (HL), 20 were acute lymphoblastic leukaemia (ALL), 11 were chronic lymphocytic leukaemia (CLL) and 2 were multiple myeloma (MM). HHV-8 was detected in 16 (19.8%) of the 81 patients. Five out of the sixteen positive patients had CLL followed by 4 NHL, 4 HL and 3ALL. CONCLUSION: We conclude that HHV-8 can be considered as one of the predisposing factors of malignancy in patients with lymphoproliferative and chronic blood disorders. Furthermore, it does not rule out the possibility that other immunological triggers and environmental risk factors may account for their etiopathogenesis. PMID- 28916318 TI - Matrix metalloproteinases-2 and -9 in Campylobacter jejuni-induced paralytic neuropathy resembling Guillain-Barre syndrome in chickens. AB - Inflammation in Guillain-Barre syndrome (GBS) is manifested by changes in matrix metalloproteinase (MMP) and pro-inflammatory cytokine expression. We investigated the expression of MMP-2, -9 and TNF-alpha and correlated it with pathological changes in sciatic nerve tissue from Campylobacter jejuni-induced chicken model for GBS. Campylobacter jejuni and placebo were fed to chickens and assessed for disease symptoms. Sciatic nerves were examined by histopathology and immunohistochemistry. Expressions of MMPs and TNF-alpha, were determined by real time PCR, and activities of MMPs by zymography. Diarrhea developed in 73.3% chickens after infection and 60.0% of them developed GBS like neuropathy. Pathology in sciatic nerves showed perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration and myelin swelling on 10th- 20th post infection day (PID). MMP-2, -9 and TNF-alpha were up-regulated in progressive phase of the disease. Enhanced MMP-2, -9 and TNF-alpha production in progressive phase correlated with sciatic nerve pathology in C. jejuni-induced GBS chicken model. PMID- 28916319 TI - Inhibition of growth and biofilm formation of clinical bacterial isolates by NiO nanoparticles synthesized from Eucalyptus globulus plants. AB - Nanotechnology based therapeutics has emerged as a promising approach for augmenting the activity of existing antimicrobials due to the unique physical and chemical properties of nanoparticles (NPs). Nickel oxide nanoparticles (NiO-NPs) have been suggested as prospective antibacterial and antitumor agent. In this study, NiO-NPs have been synthesized by a green approach using Eucalyptus globulus leaf extract and assessed for their bactericidal activity. The morphology and purity of synthesized NiO-NPs determined through various spectroscopic techniques like UV-Visible, FT-IR, XRD, EDX and electron microscopy differed considerably. The synthesized NiO-NPs were pleomorphic varying in size between 10 and 20 nm. The XRD analysis revealed the average size of NiO-NPs as 19 nm. The UV-Vis spectroscopic data showed a strong SPR of NiO-NPs with a characteristic spectral peak at 396 nm. The FTIR data revealed various functional moieties like C=C, C-N, C-H and O-H which elucidate the role of leaf biomolecules in capping and dispersal of NiO-NPs. The bioactivity assay revealed the antibacterial and anti-biofilm activity of NiO-NPs against ESbetaL (+) E. coli, P. aeruginosa, methicillin sensitive and resistant S. aureus. Growth inhibition assay demonstrated time and NiO-NPs concentration dependent decrease in the viability of treated cells. NiO-NPs induced biofilm inhibition was revealed by a sharp increase in characteristic red fluorescence of PI, while SEM images of NiO NPs treated cells were irregular shrink and distorted with obvious depressions/indentations. The results suggested significant antibacterial and antibiofilm activity of NiO-NPs which may play an important role in the management of infectious diseases affecting human health. PMID- 28916320 TI - Exosomes carring gag/env of ALV-J possess negative effect on immunocytes. AB - J subgroup avian leukosis virus (ALV-J) is an exogenous retrovirus of avian. A key feature of ALV-J infection is leading to severe immunosuppressive characteristic of diseases. Viral components of retrovirus were reported closely associated with immunosuppression, and several similarities between exosomes and retrovirus preparations have lead to the hypotheses of retrovirus hijacker exosomes pathway. In this study, we purified exosomes from DF-1 cells infected and uninfected by ALV-J. Electron microscopy and mass spectrometry (MS) analysis showed that ALV-J not only increased the production of exosomes from ALV-J infected DF-1 cells (Exo-J) but also stimulated some proteins expression, especially ALV-J components secreted in exosomes. Immunosuppressive domain peptide (ISD) of envelope subunit transmembrane (TM) and gag of ALV-J were secreted in Exo-J. It has been reported that HIV gag was budded from endosome like domains of the T cell plasma membrane. But env protein was first detected in exosomes from retrovirus infected cells. We found that Exo-J caused negative effects on splenocytes in a dose-dependant manner by flow cytometric analysis. And low dose of Exo-J activated immune activity of splenocytes, while high dose possessed immunosuppressive properties. Interestingly, Exo-J has no significant effects on the immunosuppression induced by ALV-J, and the immunosuppressive effects induced by Exo-J lower than that by ALV-J. Taken together, our data indicated that Exo-J supplied a microenvironment for the replication and transformation of ALV-J. PMID- 28916321 TI - Analysis of resistance genes in pan-resistant Myroides odoratimimus clinical strain PR63039 using whole genome sequencing. AB - To clarify the antibiotic resistance mechanisms of Myroides odoratimimus, pan resistant M. odoratimimus strain PR63039 was isolated and its genome sequenced and analyzed. Antimicrobial susceptibility testing was conducted using the Kirby Bauer disk diffusion method, and the Phoenix-100 Automated Microbiology System with a NMIC/ID-4 panel including aminoglycosides, beta-lactams, polypeptides, quinolones, sulfonamides, chloramphenicols, and tetracyclines. Single-molecule real-time whole genome sequencing was conducted using the PacBio RSII system, and genome annotation was performed using RAST and IMG ER. To characterize the genome features, a number of databases and software programs, including GC-Profile, CG viewer, the VFDB database, ISfinder, RADB, CARD, ResFinder, and PHAST, were used. M. odoratimimus isolate PR63039 was resistant to almost all antibiotics tested, suggesting pan-drug resistance. The genome consisted of a 4,366,950-bp chromosome and a 90,798-bp plasmid (p63039), which contained a large number of resistance genes and virulence factors. The distribution of the resistance genes was distinctive, and a resistance region, designated MY63039-RR, was identified. RAST analysis indicated that 108 of the annotated genes were potentially involved in virulence, disease, and defense, all of which could be associated with resistance and pathogenicity. Prophage analysis also identified two incomplete prophages in the genome of M. odoratimimus PR63039. Multiple antibiotic-resistance genes were identified, including those associated with resistance to tetracycline (tetX), macrolides (ereB, cfrA, lasE), sulfonamides (sul2, sul3), beta-lactams (blaMUS-1, blaTUS-1, blaSFB-1, blaSLB-1, blaOXA-209, blaOXA-347), and chloramphenicol (cat). Further, the presence of 18 antibiotic efflux pump-encoding resistance genes, including acrB, acrD, acrF, adeB, adeG, adeJ, amrB, ceoB, cmeB, mdsB, mexB, mexD, mexF, mtrD, smeE, mdtF, macB, likely accounts for the observed quinolone resistance of strain PR63039. To the best of our knowledge, this is the first report of the presence of the blaSFB-1, blaSLB-1, blaOXA-209, blaOXA-347, and tetX resistance genes in M. odoratimimus. PMID- 28916323 TI - Responding to Crisis: Surgeons as Leaders in Disaster Response. PMID- 28916322 TI - Intraductal Transanastomotic Stenting in Duct-to-Duct Biliary Reconstruction after Living-Donor Liver Transplantation: A Randomized Trial. AB - BACKGROUND: Biliary complications continue to be the "Achilles heel" of living donor liver transplantation (LDLT). The use of biliary stents in LDLT to reduce biliary complications is a controversial issue. We performed a randomized trial to study the impact of intraductal biliary stents on postoperative biliary complications after LDLT. STUDY DESIGN: Of the 94 LDLTs that were performed during a period of 16 months, ABO-incompatible transplants, left lobe grafts, 3 or more bile ducts on the graft, and those requiring bilioenteric drainage were excluded. Eligible patients were randomized to either a study arm (intraductal stent, n = 31) or a control arm (no stent, n = 33) by block randomization. Stratification was done, based on the number of ducts on the graft requiring anastomosis, into single (n = 20) or 2 ducts (n = 44). Ureteric stents of 3F to 5F placed across the biliary anastomosis and exiting into the duodenum for later endoscopic removal at 3 months were used. The primary end point was postoperative bile leak. RESULTS: Bile leak occurred in 15 of 64 (23.4%), the incidence was higher in the stented group compared with the control group (35.5% vs 12.1%; p = 0.03). Multiplicity of bile ducts and stenting were identified as risk factors for bile leak on multivariate analysis (p = 0.031 and p = 0.032). During a median follow-up of 2 years, biliary stricture developed in 9 patients (14.1%). Postoperative bile leak is a significant risk factor for the development of biliary stricture (p = 0.003). CONCLUSIONS: Intraductal transanastomotic biliary stenting and multiplicity of graft ducts were identified as independent risk factors for the development of postoperative biliary complications. PMID- 28916324 TI - In Vitro Investigation of the Antimicrobial Effect of Three Bisphosphonates Against Different Bacterial Strains. AB - PURPOSE: Since the first descriptions of medication-related osteonecrosis of the jaw (MRONJ) in 2003, the pathogenesis has remained unanswered. Recent histomorphometric studies have found several microorganisms, including Actinomyces, Bacillus, Fusobacterium, Staphylococcus, Streptococcus, Selenomonas, Treponema, and Candida albicans in necrotic bone. Polymerase chain reaction studies have recently confirmed the occurrence of 48 genera. Only a few studies have examined the antimicrobial effect of bisphosphonates (BPs). The influence of bacterial growth on the etiology remains unclear. The aim of the present study was the in vitro investigation of the antimicrobial effect of 3 BPs against different bacterial strains. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 48 strains from 40 species were determined in microdilution assays against pamidronic, ibandronic, and zoledronic acid. RESULTS: Growth of gram-positive oral microbiota, which account for most microorganisms in MRONJ, was present for 2 of 22 species; 6 of 26 gram-negative species and 9 of 13 anaerobes were inhibited. The MIC values were compared with the BP bone concentrations from previous reports. Of the 48 strains, 9 had an MIC or MBC less than the bone concentrations. CONCLUSIONS: The results of the present study have demonstrated that BPs have an inhibitory effect on selected bacterial species and might inhibit the growth of some relevant pathogens in osteonecrosis. However, most of the species tested were unaffected at the concentration levels assumed present in the human jawbone. The clinical relevance of these in vitro data will better be clarified with reliable data on the BP concentrations in the human jawbone. The present study has provided a first approach toward the assessment of the interaction of oral bacteria and BPs. PMID- 28916325 TI - What Is the Incidence of Implant Malpositioning and Revision Surgery After Orbital Repair? AB - PURPOSE: Postoperative radiographic examinations are the gold standard in maxillofacial surgery, except in orbital reconstruction. Therefore, the purpose of this study was to estimate the frequency of implant malposition and revision operation after orbital repair. MATERIALS AND METHODS: This retrospective cohort study was conducted in a level I trauma center at the University Hospital in Bern, Switzerland. To assess the incidence of malpositioning, a qualitative analysis of postoperative computed tomography scans, as well as comparative volumetric measurements of the orbits, was conducted. Furthermore, the incidence of and reason for secondary revision procedures were evaluated. RESULTS: From September 2008 to December 2015, a total of 71 emergency patients (73 implants) were treated at the Department of Cranio-Maxillofacial Surgery with a titanium mesh (48 male patients; mean age, 56 years). The implant position was rated as poor in 17 cases (23%) by the qualitative analysis. The volumetric assessment showed no significant results. Revision intervention was needed in 12 patients (17%) because of an unsuccessful treatment outcome causing relevant clinical symptoms. CONCLUSIONS: Patients with large orbital defects who require surgical treatment with a titanium mesh are at risk of implant malposition. Because in this study, poor positioning of the implant is the main reason for surgical revision, we postulate that a postoperative radiographic control should be obtained routinely. Only then can long-term sequelae due to inadequate reconstruction be avoided. PMID- 28916326 TI - Are Wireless Electronic Stethoscopes Useful for Respiratory Rate Monitoring During Intravenous Sedation? AB - PURPOSE: Wireless stethoscopes can measure respiratory rate noninvasively and continuously, but there are no reports of their use during dental treatment. This study evaluated the usefulness of wireless stethoscopes during dental procedures requiring intravenous sedation (IVS). MATERIALS AND METHODS: This study was a prospective cohort study. The study sample consisted of dental patients who received IVS by propofol or midazolam administration at the Nippon Dental University Hospital (Tokyo, Japan). The predictor was respiratory rate measured using the wireless stethoscope (BrRR), and the outcome variable was respiratory rate measured during capnography (RR). Pearson correlation coefficients and paired-samples t tests were used for data analysis. A P value less than .05 was considered statistically significant. RESULTS: The study sample consisted of 12 patients. BrRR and RR were significantly and positively correlated (r = 0.93, P < .01). The mean +/- standard deviation of BrRR was 14.16 +/- 2.67 and that of RR was 14.32 +/- 2.77. There was no significant difference between the 2 groups (P = .27). CONCLUSIONS: The results of this study suggest that wireless stethoscopes are suitable for monitoring respiratory rate during dental procedures requiring IVS because their use is as accurate as capnography. PMID- 28916327 TI - Glycogen metabolism in brain and neurons - astrocytes metabolic cooperation can be altered by pre- and neonatal lead (Pb) exposure. AB - Lead (Pb) is an environmental neurotoxin which particularly affects the developing brain but the molecular mechanism of its neurotoxicity still needs clarification. The aim of this paper was to examine whether pre- and neonatal exposure to Pb (concentration of Pb in rat offspring blood below the "threshold level") may affect the brain's energy metabolism in neurons and astrocytes via the amount of available glycogen. We investigated the glycogen concentration in the brain, as well as the expression of the key enzymes involved in glycogen metabolism in brain: glycogen synthase 1 (Gys1), glycogen phosphorylase (PYGM, an isoform active in astrocytes; and PYGB, an isoform active in neurons) and phosphorylase kinase beta (PHKB). Moreover, the expression of connexin 43 (Cx43) was evaluated to analyze whether Pb poisoning during the early phase of life may affect the neuron-astrocytes' metabolic cooperation. This work shows for the first time that exposure to Pb in early life can impair brain energy metabolism by reducing the amount of glycogen and decreasing the rate of its metabolism. This reduction in brain glycogen level was accompanied by a decrease in Gys1 expression. We noted a reduction in the immunoreactivity and the gene expression of both PYGB and PYGM isoform, as well as an increase in the expression of PHKB in Pb-treated rats. Moreover, exposure to Pb induced decrease in connexin 43 immunoexpression in all the brain structures analyzed, both in astrocytes as well as in neurons. Our data suggests that exposure to Pb in the pre- and neonatal periods results in a decrease in the level of brain glycogen and a reduction in the rate of its metabolism, thereby reducing glucose availability, which as a further consequence may lead to the impairment of brain energy metabolism and the metabolic cooperation between neurons and astrocytes. PMID- 28916328 TI - Primary hippocampal neuronal cell death induction after acute and repeated paraquat exposures mediated by AChE variants alteration and cholinergic and glutamatergic transmission disruption. AB - Paraquat (PQ) is a widely used non-selective contact herbicide shown to produce memory and learning deficits after acute and repeated exposure similar to those induced in Alzheimer's disease (AD). However, the complete mechanisms through which it induces these effects are unknown. On the other hand, cholinergic and glutamatergic systems, mainly in the hippocampus, are involved on learning, memory and cell viability regulation. An alteration of hippocampal cholinergic or glutamatergic transmissions or neuronal cell loss may induce these effects. In this regard, it has been suggested that PQ may induce cell death and affect cholinergic and glutamatergic transmission, which alteration could produce neuronal loss. According to these data, we hypothesized that PQ could induce hippocampal neuronal loss through cholinergic and glutamatergic transmissions alteration. To prove this hypothesis, we evaluated in hippocampal primary cell culture, the PQ toxic effects after 24h and 14 consecutive days exposure on neuronal viability and the cholinergic and glutamatergic mechanisms related to it. This study shows that PQ impaired acetylcholine levels and induced AChE inhibition and increased CHT expression only after 14days exposure, which suggests that acetylcholine levels alteration could be mediated by these actions. PQ also disrupted glutamate levels through induction of glutaminase activity. In addition, PQ induced, after 24h and 14days exposure, cell death on hippocampal neurons that was partially mediated by AChE variants alteration and cholinergic and gultamatergic transmissions disruption. Our present results provide new view of the mechanisms contributing to PQ neurotoxicity and may explain cognitive dysfunctions observed after PQ exposure. PMID- 28916329 TI - Ecological extension of the theory of evolution by natural selection from a perspective of Western and Eastern holistic philosophy. AB - Evolution by natural selection requires the following conditions: (1) a particular selective environment; (2) variation of traits in the population; (3) differential survival/reproduction among the types of organisms; and (4) heritable traits. However, the traditional (standard) model does not clearly explain how and why these conditions are generated or determined. What generates a selective environment? What generates new types? How does a certain type replace, or coexist with, others? In this paper, based on the holistic philosophy of Western and Eastern traditions, I focus on the ecosystem as a higher-level system and generator of conditions that induce the evolution of component populations; I also aim to identify the ecosystem processes that generate those conditions. In particular, I employ what I call the scientific principle of dependent-arising (SDA), which is tailored for scientific use and is based on Buddhism principle called "pratitya-samutpada" in Sanskrit. The SDA principle asserts that there exists a higher-level system, or entity, which includes a focal process of a system as a part within it; this determines or generates the conditions required for the focal process to work in a particular way. I conclude that the ecosystem generates (1) selective environments for component species through ecosystem dynamics; (2) new genetic types through lateral gene transfer, hybridization, and symbiogenesis among the component species of the ecosystem; (3) mechanistic processes of replacement of an old type with a new one. The results of this study indicate that the ecological extension of the theoretical model of adaptive evolution is required for better understanding of adaptive evolution. PMID- 28916330 TI - Brains, language and the argumentative mind in Western and Eastern societies. The fertile differences between Western-Eastern argumentative traditions. AB - The philosophical differences between Western and Eastern philosophy not only derive from general cultural ideas about reality, but as Nisbet writes (2003), are also methodological, ontological, and cognitively driven. Thus, we can see that strategies of thought and theory-generation are constrained and enabled by conceptual levels, and that the existence of differences and within these levels may be pragmatically combined in fruitful ways. At this point, I remark that there is not a single way to connect biology and culture, but at least we need to admit that brains allow the existence of minds and that these create languages, which also organize the world symbolically following a long set of (sometimes interconnected) heuristics. Throughout the paper we will see how fundamental, geographically located cultural perspectives have affected reasoning strategies and discourses, determining the main Western and Eastern Traditions. At the same time, we can conclude that different traditional perspectives allow more diversity for knowledge acquisition. PMID- 28916331 TI - Depressive-like phenotype induced by prenatal dexamethasone in mice is reversed by desipramine. AB - Exposure to prenatal insults has been associated with an increased risk for neuropsychiatric disorders, including depression, but the mechanisms are still poorly understood. Persistent alterations of the HPA axis feedback mechanism as well as adult impaired neurogenesis are believed to play a relevant role in the etiology of depression. In addition, growing evidence points at epigenetic reprogramming as a key factor. We have previously shown that prenatal exposure to the synthetic glucocorticoid dexamethasone (DEX) impairs neurogenesis and leads to late onset of depression-like behavior that does not respond to the SSRI antidepressant fluoxetine (FLX). The aims of this study were to assess the effect of DEX prenatal exposure on the morphology of hippocampal granule neurons and on the expression of genes related to plasticity; and to test whether the SNRI antidepressant desipramine (DMI), unlike FLX, could counteract the effect of prenatal-DEX. C57Bl/6 mice were exposed to DEX (0.05 mg/kg/day) in utero and received intra-hippocampal injection of GFP expressing retroviral vector for labeling of newborn granule cells at eleven months. By twelve months, DEX mice showed depression-like behavior associated with decreased neurogenesis and morphological alterations of the newborn granule cells in the dentate gyrus (DG). Furthermore DEX mice displayed altered expression of genes controlling neurogenesis and neuronal morphology, such as Cdkn1c, p16, TrkB, DISC1 and Reelin. Chronic treatment with DMI led to a significant decrease in immobility time in the forced swim test. In addition, DMI restored neurogenesis, neuronal morphology in the DG, as well as the expression of all related genes. Our results suggest that (1) prenatal DEX induces early and persistent reprogramming effects resulting in altered neurogenesis and neuronal morphology; and (2) DMI treatment reverses DEX-induced depression by restoring the expression of genes relevant to neuronal plasticity. PMID- 28916332 TI - Assessing the use of assisted reproductive technology in the United States by non United States residents. AB - OBJECTIVE: To study cross-border reproductive care (CBRC) by assessing the frequency and nature of assisted reproductive technology (ART) care that non-U.S. residents receive in the United States. DESIGN: Retrospective study of ART cycles reported to the Centers for Disease Control and Prevention's National ART Surveillance System (NASS) from 2006 to 2013. SETTING: Private and academic ART clinics. PATIENT(S): Patients who participated in ART cycles in the United States from 2006 to 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency and trend of ART use in the U.S. by non-U.S. residents, countries of residence for non-U.S. residents, differences by residence status for specific ART treatments received, and the outcomes of these ART cycles. RESULT(S): A total of 1,271,775 ART cycles were reported to NASS from 2006 to 2013. The percentage of ART cycles performed for non-U.S. residents increased from 1.2% (n = 1,683) in 2006 to 2.8% (n = 5,381) in 2013 (P<.001), with treatment delivered to residents of 147 countries. Compared with resident cycles, non-U.S. resident cycles had higher use of oocyte donation (10.6% vs. 42.6%), gestational carriers (1.6% vs. 12.4%), and preimplantation genetic diagnosis or screening (5.3% vs. 19.1%). U.S. resident and non-U.S. resident cycles had similar embryo transfer and multiple birth rates. CONCLUSION(S): This analysis showed that non-U.S. resident cycles accounted for a growing share of all U.S. ART cycles and made higher use of specialized treatment techniques. This study provides important baseline data on CBRC in the U.S. and may also prove to be useful to organizations interested in improving access to fertility treatments. PMID- 28916333 TI - Human Plasma Metabolomics Study across All Stages of Age-Related Macular Degeneration Identifies Potential Lipid Biomarkers. AB - PURPOSE: To characterize the plasma metabolomic profile of patients with age related macular degeneration (AMD) using mass spectrometry (MS). DESIGN: Cross sectional observational study. PARTICIPANTS: We prospectively recruited participants with a diagnosis of AMD and a control group (>50 years of age) without any vitreoretinal disease. METHODS: All participants underwent color fundus photography, used for AMD diagnosis and staging, according to the Age Related Eye Disease Study classification scheme. Fasting blood samples were collected and plasma was analyzed by Metabolon, Inc. (Durham, NC), using ultrahigh-performance liquid chromatography (UPLC) and high-resolution MS. Metabolon's hardware and software were used to identify peaks and control quality. Principal component analysis and multivariate regression were performed to assess differences in the metabolomic profiles of AMD patients versus controls, while controlling for potential confounders. For biological interpretation, pathway enrichment analysis of significant metabolites was performed using MetaboAnalyst. MAIN OUTCOME MEASURES: The primary outcome measures were levels of plasma metabolites in participants with AMD compared with controls and among different AMD severity stages. RESULTS: We included 90 participants with AMD (30 with early AMD, 30 with intermediate AMD, and 30 with late AMD) and 30 controls. Using UPLC and MS, 878 biochemicals were identified. Multivariate logistic regression identified 87 metabolites with levels that differed significantly between AMD patients and controls. Most of these metabolites (82.8%; n = 72), including the most significant metabolites, belonged to the lipid pathways. Analysis of variance revealed that of the 87 metabolites, 48 (55.2%) also were significantly different across the different stages of AMD. A significant enrichment of the glycerophospholipids pathway was identified (P = 4.7 * 10-9) among these metabolites. CONCLUSIONS: Participants with AMD have altered plasma metabolomic profiles compared with controls. Our data suggest that the most significant metabolites map to the glycerophospholipid pathway. These findings have the potential to improve our understanding of AMD pathogenesis, to support the development of plasma-based metabolomics biomarkers of AMD, and to identify novel targets for treatment of this blinding disease. PMID- 28916335 TI - Troxerutin abrogates mitochondrial oxidative stress and myocardial apoptosis in mice fed calorie-rich diet. AB - Mitochondrial oxidative stress plays a major role in the pathogenesis of myocardial apoptosis in metabolic syndrome (MS) patients. In this study, we investigated the effect of troxerutin (TX), an antioxidant on mitochondrial oxidative stress and apoptotic markers in heart of mice fed fat and fructose-rich diet. Adult male Mus musculus mice were fed either control diet or high fat, high fructose diet (HFFD) for 60 days to induce MS. Mice from each dietary group were divided into two on the 16th day and were either treated or untreated with TX (150 mg/kg bw, p.o) for the next 45 days. At the end of the study, mitochondrial reactive oxygen species (ROS) generation, oxidative stress markers, levels of intracellular calcium, cardiolipin content, cytochrome c release and apoptotic markers were examined in the myocardium. HFFD-feeding resulted in diminution of antioxidants and increased ROS production, lipid peroxidation and oxidatively modified adducts of 8-OHG, 4-HNE and 3-NT. Further increase in Ca2+ levels, low levels of calcium transporters and decrease in cardiolipin content were noted. Changes in the mitochondrial structure were observed by electron microscopy. Furthermore, cytochrome c release, increase in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and decrease in antiapoptotic protein (BCL-2) in HFFD-fed mice suggest myocardial apoptosis. These changes were significantly restored by TX supplementation. TX administration effectively attenuated cardiac apoptosis and exerted a protective role by increasing antioxidant potential and by improving mitochondrial function. Thus, TX could be a promising therapeutic candidate for treating cardiac disease in MS patients. PMID- 28916336 TI - Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study. AB - During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose free diet (no RTT's; adrenal medullary hyperplasia in <=5/90). These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues. PMID- 28916337 TI - Angiotensin II induces calcium-mediated autophagy in podocytes through enhancing reactive oxygen species levels. AB - As well known, abnormalities of Angiotensin II (Ang II) is closely related with glomerular damage. This study was to investigate whether Ang II could affect autophagy in podocytes via oxidative stress, and whether autophagy had a positive role in protecting podocytes impaired by Ang II. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay showed that Ang II induced podocyte death. The measurements of malondialdehyde (MDA) and H2O2 levels, and flow cytometry assay revealed that Ang II considerably increased reactive oxygen species (ROS) generation in podocytes. Meaningfully, treatment with ROS scavenger N-(mercaptopropionyl)-glycine (N-MPG) could inhibit podocyte death and attenuate accumulation of ROS induced by Ang II. The patch-clamp experiments indicated that Ang II increased the current of transient receptor potential canonical 6 (TRPC6). Moreover, measurement of Fluo-3 image showed that Ang II increased intracellular Ca2+ level, as N-MPG and La3+ impeded Ang II induced Ca2+ influx. Acridine orange staining indicated that Ang II induced accumulation of acidic vacuoles. Beclin-1 and LC3 are essential for autophagosome formation. Furthermore, as one of the selective substrates for autophagy, P62 plays a key role in the formation of cytoplasmic proteinaceous inclusion. Western blot assay presented that Ang II obviously elevated LC3-II/LC3-I ratio and expression of beclin-1, and reduced expression of P62. Meanwhile, N-MPG expectedly down-regulated autophagy in Ang II treated podocytes. Rapamycin can enhance the level of autophagy by inhibiting mTOR, and 3-methyladenine (3-MA) can inhibit autophagosome formation through blocking class III phosphatidylinositol 3-kinase. MTT assay exhibited that rapamycin significantly enhanced the cell viability, while 3-MA considerably reduced it in Ang II-treated podocytes. Consequently, this study demonstrated that Ang II could increase TRPC6 induced Ca2+ influx and enhance autophagy through increasing ROS levels in podocytes, and autophagy could protect Ang II treated podocytes. Improving TRPC6 channels and autophagy may become a new targeted therapy to relieve glomerular damage induced by Ang II. PMID- 28916338 TI - Structure-activity relationship study of small molecule inhibitors of the DEPTOR mTOR interaction. AB - DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast. This therapeutic (compound B) also prevented DEPTOR/mTOR binding in MM cells and was selectively cytotoxic to MM cells. We now present a structure-activity relationship (SAR) study around this compound as a follow-up report of this previous work. This study has led to the discovery of five new leads - namely compounds 3g, 3k, 4d, 4e and 4g - all of which have anti-myeloma cytotoxic properties superior to compound B. Due to their targeting of DEPTOR, these compounds activate mTORC1 and selectively induce MM cell apoptosis and cell cycle arrest. PMID- 28916340 TI - Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration. AB - Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3 aminopyrrolidine-containing template leading to the identification of GI restricted agonist 19 (GSK3004774). PMID- 28916339 TI - d-Amino acid mutation of PMI as potent dual peptide inhibitors of p53-MDM2/MDMX interactions. AB - According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs. PMID- 28916341 TI - Design, synthesis and biological evaluation of benzamide and phenyltetrazole derivatives with amide and urea linkers as BCRP inhibitors. AB - Breast cancer resistant protein (BCRP/ABCG2), a 72kDa plasma membrane transporter protein is a member of ABC transporter superfamily. Increased expression of BCRP causes increased efflux and therefore, reduced intracellular accumulation of many unrelated chemotherapeutic agents leading to multidrug resistance (MDR). A series of 31 benzamide and phenyltetrazole derivatives with amide and urea linkers has been synthesized to serve as potential BCRP inhibitors in order to overcome BCRP mediated MDR. The target derivatives were tested for their cytotoxicity and reversal effects in human non-small cell lung cancer cell line H460 and mitoxantrone resistant cell line H460/MX20 using the MTT assay. In the benzamide series, compounds 6 and 7 exhibited a fold resistance of 1.51 and 1.62, respectively at 10uM concentration which is similar to that of FTC, a known BCRP inhibitor. Compounds 27 and 31 were the most potent analogues in the phenyltetrazole series with amide linker with a fold resistance of 1.39 and 1.32, respectively at 10uM concentration. For the phenyltetrazole series with urea linker, 38 exhibited a fold resistance of 1.51 which is similar than that of FTC and is the most potent compound in this series. The target compounds did not exhibit reversal effect in P-gp overexpressing resistant cell line SW620/Ad300 suggesting that they are selective BCRP inhibitors. PMID- 28916342 TI - PP2A regulates signaling through hormonal receptors in breast cancer with important therapeutic implications. AB - The functional inhibition of protein phosphatase 2A (PP2A) has emerged in the last years as a common alteration in breast cancer that determines poor outcome and contributes to disease progression and aggressiveness. Furthermore, expression of estrogen receptor (ER) is a high relevant molecular event with key therapeutic implications in breast cancer, and androgen receptor (AR) signaling is involved in the pathogenesis of breast cancer and represents a novel target with crescent importance in this disease. In this review, we summarize the role of the tumor suppressor PP2A in modulating ER and AR signaling in breast cancer, the molecular mechanisms involved, and its biological and therapeutic impact. PMID- 28916343 TI - The role of a new class of long noncoding RNAs transcribed from ultraconserved regions in cancer. AB - Ultraconserved regions (UCRs) represent a relatively new class of non-coding genomic sequences highly conserved between human, rat and mouse genomes. These regions can reside within exons of protein-coding genes, despite the vast majority of them localizes within introns or intergenic regions. Several studies have undoubtedly demonstrated that most of these regions are actively transcribed in normal cells/tissues, where they contribute to regulate many cellular processes. Interestingly, these non-coding RNAs exhibit aberrant expression levels in human cancer cells and their expression profiles have been used as prognostic factors in human malignancies, as well as to unambiguously distinguish among distinct cancer types. In this review, we first describe their identification, then we provide some updated information about their genomic localization and classification. More importantly, we discuss about the available literature describing an overview of the mechanisms through which some transcribed UCRs (T-UCR) contribute to cancer progression or to the metastatic spread. To date, the interplay between T-UCRs and microRNAs is the most convincing evidence linking T-UCRs and tumorigenesis. The limitations of these studies and the future challenges to be addressed in order to understand the biological role of T-UCRs are also discussed herein. We envision that future efforts are needed to convincingly include this class of ncRNAs in the growing area of cancer therapeutics. PMID- 28916344 TI - Image-Guided Percutaneous Omental and Mesenteric Biopsy: Assessment of Technical Success Rate and Diagnostic Yield. AB - PURPOSE: To assess biopsy technique, technical success rate, and diagnostic yield of image-guided percutaneous biopsy of omental and mesenteric lesions. MATERIALS AND METHODS: This retrospective study included 186 patients (89 men, 97 women; mean [SD] age, 63 [13.8] y) who underwent percutaneous image-guided biopsy of omentum and mesentery between March 2007 and August 2015. Biopsies were performed with computed tomography (CT) (n = 172) or ultrasound (US) (n = 14) guidance using coaxial technique yielding core and fine-needle aspiration (FNA) specimens. Biopsy results were classified as diagnostic (neoplastic or nonneoplastic) or nondiagnostic based on histopathology and cytology. Technical success rate and diagnostic yield of omental and mesenteric lesions were calculated. RESULTS: There were 186 image-guided percutaneous biopsies of omental (n = 95) and mesenteric (n = 91) lesions performed. Technical success rate was 99.5% for all biopsies, 100% for omental biopsies, and 98.9% for mesenteric biopsies. Overall sensitivity was 95.5%, specificity was 100%, negative predictive value was 78.3%, and positive predictive value was 100%, which was comparable for omental and mesenteric biopsies. Core biopsies had higher diagnostic yields compared with FNA: 98.4% versus 84% overall, 99% versus 88% for omental biopsies, and 97.7% versus 80% for mesenteric biopsies. Spearman rank correlation showed no correlation between lesion size and diagnostic yield (P = .14) and lesion depth and diagnostic yield (P = .29) for both groups. There were 5 complications. CONCLUSIONS: Image-guided percutaneous omental and mesenteric biopsies have high technical success rates and diagnostic yield regardless of lesion size or depth from the skin for both omental and mesenteric specimens. PMID- 28916345 TI - Is a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients. AB - PURPOSE: To determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (99mTc) macroaggregated albumin (99mTc MAA) imaging before selective internal radiation therapy (SIRT). MATERIALS AND METHODS: In this retrospective analysis, 532 consecutive patients with primary (n = 248) or metastatic (n = 284) liver tumors were evaluated between 2006 and 2015. Variables were compared between patients in whom 99mTc MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (90Y) resin microspheres and those who were treated as initially planned. The 99mTc MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal 99mTc MAA uptake, or a mismatch between 99mTc MAA uptake and intrahepatic tumor distribution. RESULTS: LSF > 20% and gastrointestinal MAA uptake were observed in 7.5% and 3.9% of patients, respectively, and 11% presented a mismatch. Presence of a single lesion (odds ratio [OR] = 2.4) and vascular invasion (OR = 5.5) predicted LSF > 20%, and GI MAA uptake was predicted by the presence of liver metastases (OR = 3.7) and 99mTc MAA injection through the common/proper hepatic artery (OR = 4.7). Vascular invasion (OR = 4.1) was the only predictor of LSF > 20% and/or GI MAA uptake (sensitivity = 49.2%, specificity = 80.3%, negative predictive value = 92.4%). Previous antiangiogenic treatment (OR = 2.4) and presence of a single lesion (OR = 2.6) predicted mismatch. CONCLUSIONS: Imaging with 99mTc MAA is essential in SIRT workup because baseline characteristics may not adequately predict 99mTc MAA results. Nevertheless, the absence of vascular invasion potentially identifies a group of patients at low risk of SIRT contraindication/modification in whom performing SIRT in a single session (ie, pretreatment evaluation and SIRT on the same day) should be explored. PMID- 28916347 TI - Boat anchoring pressure on coastal seabed: Quantification and bias estimation using AIS data. AB - Global shipping is economically important, but has many adverse environmental effects. Anchoring contributes greatly to this adverse impact, as it is responsible for mechanical disturbance of highly sensitive marine habitats. Recovery of these ecosystems is limited by slow regrowth. Anchoring pressure on coastal seabed habitats was estimated using AIS (Automatic Identification System) data along 1800km of Mediterranean coastline between 2010 and 2015. A comparison with field observations showed that these results were most consistent for large boats (>50m). An analysis of AIS data coupled with a seabed map showed that around 30% of the habitats between 0 and -80m exhibited anchoring pressure. Posidonia oceanica seagrass beds were the most impacted habitat in terms of duration. This methodology efficiently estimates spatial and temporal anchoring pressure principally due to large boats and should interest managers of marine protected areas as much as coastline managers. PMID- 28916346 TI - Radiofrequency Ablation of T1a Renal Cell Carcinomas within Renal Transplant Allografts: Oncologic Outcomes and Graft Viability. AB - PURPOSE: To evaluate oncologic outcomes and graft viability after percutaneous radiofrequency (RF) ablation of renal cell carcinoma (RCC) developing within renal transplant allografts. MATERIALS AND METHODS: A single-institution, retrospective study reviewed all patients treated with RF ablation for RCC between February 2004 and May 2016. Ten patients were identified (age 49.6 y +/- 12.6; 9 men, 1 woman) with 12 biopsy-confirmed RCC tumors within the allograft (all T1a, mean diameter 2.0 cm +/- 0.7). Mean time from transplant to RCC diagnosis was 13.2 years +/- 6.3. RF ablation was performed on an outpatient basis using conscious sedation. Procedural efficacy, complications, oncologic outcomes, and allograft function were evaluated. Statistical analysis with t tests and Pearson correlation compared allograft function before and after RF ablation and impact of proportional ablation size to allograft volume on function after ablation. RESULTS: Technical success rate and primary technique efficacy were 100% (12/12). No local or distant RCC progression was seen at mean follow-up of 54.3 months +/- 38.7 (range, 9-136 months). Graft failure requiring hemodialysis or repeat transplantation occurred in 3 patients (26, 354, and 750 d after RF ablation), all of whom had glomerular filtration rate (GFR) < 30 mL/min/1.73 m2 before ablation. For all patients, mean GFR 6 months after RF ablation (35.8 mL/min/1.73 m2 +/- 17.7) was not significantly different (P = .8) from preprocedure GFR (36.2 mL/min/1.73 m2 +/- 14.3). Proportional volume of allograft that was ablated did not correlate with immediate or long-term GFR changes. One patient died of unrelated comorbidities 52 months after ablation. No major complications occurred. CONCLUSIONS: RF ablation of renal allograft RCC provided effective oncologic control without adverse impact on graft viability. PMID- 28916348 TI - Long-term variation of the macrobenthic community and its relationship with environmental factors in the Yangtze River estuary and its adjacent area. AB - Using data from four periods from 1959 to 2015, we report the long-term variation of the macrobenthic community in the Yangtze River estuary and its adjacent area. In total, 624 species were collected, and Polychaeta was the dominant group. Significant differences between the four periods were found. The CCA (canonical correspondence analysis) and RDA (redundancy analysis) results revealed that temperature, salinity, and depth significantly influenced the macrobenthic communities (89.6% of the species-environment relationship variance was explained by the first two axes of CCA and 94.3% was explained by RDA). The results of K dominance curves (the elevation increased over time), ABC (abundance/biomass comparison) curves (the W value changed from 0.311 to 0.167 during 1959 to 2014 2015) and the Shannon-Wiener index (log base=2; 2.29-5.03 in 1959, 2.86-4.55 in 2000-2001, 2.28-4.56 in 2011-2012, and 1.79-4.43 in 2014-2015) showed that the ecological status of the benthic study area was deteriorating. PMID- 28916349 TI - Offshore iron sand extraction in New Zealand: Potential trace metal exposure of benthic and pelagic biota. AB - Plans to exploit an offshore source of iron sand in South Taranaki Bight (STB), New Zealand, caused concerns that such exploitation may expose benthic and pelagic biota to elevated trace metal concentrations. We conducted dilute-acid extractions and standard elutriate tests to investigate the potential of this exploitation to (1) create a new seafloor with elevated trace metal content, (2) mobilise trace metals during iron sand extraction and, (3) enrich the returning process seawater, which feeds iron sand through mills, with trace metals. We found that recruits of freshly uncovered sediment may encounter higher-than natural concentrations of cadmium, nickel and chromium (but not of copper, lead, and zinc) and propose to investigate the bioavailability of these metals. Elutriate test with raw and milled iron sand revealed that, for nickel and copper, dilution of the process seawater may be required to meet the local water quality guideline. We argue that this dilution can be achieved by adjustment of the mass and seawater balance of the offshore extraction process. PMID- 28916350 TI - Quantification of marine macro-debris abundance around Vancouver Island, Canada, based on archived aerial photographs processed by projective transformation. AB - The abundance of marine macro-debris was quantified with high spatial resolution by applying an image processing technique to archived shoreline aerial photographs taken over Vancouver Island, Canada. The photographs taken from an airplane at oblique angles were processed by projective transformation for georeferencing, where five reference points were defined by comparing aerial photographs with satellite images of Google Earth. Thereafter, pixels of marine debris were extracted based on their color differences from the background beaches. The debris abundance can be evaluated by the ratio of an area covered by marine debris to that of the beach (percent cover). The horizontal distribution of percent cover of marine debris was successfully computed from 167 aerial photographs and was significantly related to offshore Ekman flows and winds (leeway drift and Stokes drift). Therefore, the estimated percent cover is useful information to determine priority sites for mitigating adverse impacts across broad areas. PMID- 28916351 TI - Using seagrasses to identify local and large-scale trends of metals in the Mediterranean Sea. AB - To manage trace metal pollution it is critical to determine how much temporal trends can be attributed to local or large-scale sources. We tracked changes in metal content in the seagrass Posidonia oceanica, along the NW Mediterranean from 2003 to 2010. While Cu, Cd and Ni showed a large inter-site variation, likely due to local factors, Fe, Mn and Pb showed little local variation and synchronous interannual variability across sites, most likely due to large-scale sources. Zn showed equal importance of local and large-scale sources of variation. Temporal trends of Ni, Zn, Cd, Cu remained almost stable. In contrast, Fe, Mn and Pb slightly increased in the last decade. These trends suggest that metals like Cu, Cd, Ni can be effectively managed at local scale. Whereas, elements like Fe, Mn and Pb have an important large-scale component that needs to be managed across the frontiers of national jurisdictions. PMID- 28916352 TI - Baseline evaluation of sediment contamination in the shallow coastal areas of Saudi Arabian Red Sea. AB - Despite the growing recognition of the importance of water and sediment quality there is still limited information on contamination levels in many regions globally including the Red Sea. This study provides a comprehensive assessment of three classes of contaminants (Polycyclic Aromatic Hydrocarbons - PAH; metals; plastics) in coastal sediments along the Saudi Arabian Red Sea mainly collected using grabs. Background concentrations are provided for metals in the region. Concentrations of metals and PAH were generally low in comparison to international guidelines. A clear relationship between the concentration of metals and anthropogenic sources was not always apparent and dust and vegetation may be relevant players in the region. Microplastic items (mainly polyethylene) were abundant (reaching up to 1gm-2 and 160piecesm-2) and in general associated with areas of high human activity. This study provides critical information for future monitoring and the development of national policies within the Red Sea region. PMID- 28916353 TI - Outcomes of adults with in-hospital cardiac arrest after implementation of the 2010 resuscitation guidelines. AB - BACKGROUND: The 2015 guidelines for cardiopulmonary resuscitation (CPR) are based on an update of the 2010 guidelines with minor revisions. It is important to assess the 2010 guidelines to ensure their efficacy, which may help promote widespread adoption of the 2015 guidelines. METHODS: We conducted a retrospective observational study in a single center that evaluated patients with in-hospital cardiac arrest (IHCA) between 2006 and 2014. Multivariable logistic regression analysis was used to evaluate associations between independent variables and outcomes. RESULTS: A total of 1525 patients were included. For patients with initial non-shockable rhythms, the elapsed time to first adrenaline injection was significantly shorter for patients who received CPR according to the 2010 guidelines (2010-CPR) than for those who were treated according to the 2005 guidelines (2005-CPR). During post-cardiac arrest care, the percentage of patients with fever was significantly lower and the implementation of critical interventions was significantly higher in patients who received 2010-CPR than in those who received 2005-CPR. After adjusting for the effects of confounding factors, patients who received 2010-CPR had improved neurological outcomes (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.05-2.93; p=0.03) and survival (OR, 1.50; 95% CI, 1.06-2.12; p=0.02) at hospital discharge than patients who received 2005-CPR. CONCLUSIONS: Hospital adoption of the 2010 guidelines may improve the neurological and survival outcomes for IHCA patients. This improvement might result from an emphasis on the importance of high-quality CPR, post-cardiac arrest care, and teamwork in the 2010 guidelines. PMID- 28916354 TI - Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. AB - BACKGROUND: Our previous studies showed that in ischemic and nonischemic heart failure (HF), the voltage-gated cardiac Na+ channel alpha subunit (SCN5A) mRNA is abnormally spliced to produce two truncated transcript variants (E28C and D) that activate the unfolded protein response (UPR). We tested whether SCN5A post transcriptional regulation was abnormal in hypertrophic cardiomyopathy (HCM). MATERIAL AND METHODS: Human heart tissue was obtained from HCM patients. The changes in relative abundances of SCN5A, its variants, splicing factors RBM25 and LUC7A, and PERK, a major effector of the UPR, were analyzed by real time RT-PCR and the expression changes were confirmed by Western Blot. RESULTS: We found reduced full-length transcript, increased SCN5A truncation variants and activation of UPR in HCM when compared to control hearts. In these patients, real time RT-PCR revealed that HCM patients had decreased SCN5A mRNA to 27.8+/-4.07% of control (P<0.01) and an increased abundance of E28C and E28D (3.4+/-0.3 and 2.8+/-0.3-fold, respectively, P<0.05). PERK mRNA increased 8.2+/-3.1 fold (P<0.01) in HCM patients. Western blot confirmed a significant increase of PERK. CONCLUSIONS: These data suggested that the full-length SCN5A was reduced in patients with HCM. This reduction was accompanied by abnormal SCN5A pre-mRNA splicing and UPR activation. These changes may contribute to the arrhythmic risk in HCM. PMID- 28916355 TI - Grouper STAT1a is involved in antiviral immune response against iridovirus and nodavirus infection. AB - Signal Transducer and Activator of Transcription 1 (STAT1) has been demonstrated to function as a critical mediator in multiple cell processes, such as cell proliferation, cell death, and innate immune response. Interestingly, two orthologues of human STAT1, including STAT1a and STAT1b genes have been identified in different fish. However, the detailed roles of fish STAT1a in virus replication still remained largely uncertain. Here, we cloned a STAT1a from orange-spotted grouper Epinephelus coioides (EcSTAT1a) and characterized its roles during fish virus infection. EcSTAT1a encoded a 751-aa peptide which shared 97% and 93% identity to STAT1 from mandarin fish (Siniperca chuatsi) and Malabar grouper (Epinephelus malabaricus), respectively. Amino acid alignment analysis showed that EcSTAT1a contained a STAT-int domain, a STAT-alpha domain, a STAT bind domain (DNA binding domain), a SH2 domain and a STAT1-TAZ2 bind domain. In examined tissues from healthy grouper, the expression of EcSTAT1a was predominant in intestine, gill and liver. In grouper cells, the relative expression levels of EcSTAT1a was significantly increased during red-spotted grouper nervous necrosis virus (RGNNV) or Singapore grouper iridovirus (SGIV) infection. Under fluorescence microscopy, we found that EcSTAT1a mainly localized in the cytoplasm. The ectopic expression of EcSTAT1a in vitro significantly delayed the cytopathic effect (CPE) progression evoked by RGNNV and SGIV. Further studies showed that the expression levels of viral genes, including SGIV major capsid protein (MCP), VP19, ICP-18, LITAF and RGNNV coat protein (CP), RNA-dependent RNA polymerase (RdRp) were all significantly reduced in EcSTAT1a overexpressing cells compared to the control vector transfected cells, suggested that EcSTAT1a exerted antiviral activity against iridovirus and nodavirus. Furthermore, overexpression of EcSTAT1a significantly increased the expression of interferon related cytokines or effectors and pro-inflammatory factors. Together, our results elucidated that EcSTAT1a might function as a critical antiviral factor by regulating the host interferon immune and inflammation response. PMID- 28916356 TI - Molecular characterization of polymeric immunoglobulin receptor and expression response to Aeromonas hydrophila challenge in Carassius auratus. AB - The polymeric immunoglobulin receptor (pIgR) plays a pivotal role in mucosal immune response by transporting polymeric immunoglobulins onto the surface of mucosal epithelia to protect animals from invading pathogens. In this study, the full-length cDNA of pIgR was firstly cloned in Qihe crucian carp (Carassius auratus), hereafter designated as CapIgR, by using reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The molecular characterization and expression of CapIgR were investigated. The full-length cDNA sequence of CapIgR was composed of 1409 bp, which included a 112 bp 5' untranslated region (UTR), a 984 bp ORF, and a 313 bp 3'-UTR, with a putative polyadenylation signal sequence AATAAA located upstream of the poly(A) tail. The deduced amino acid sequence indicated that CapIgR was a single-spanning transmembrane protein with 327 amino acids and possessed a signal peptide, an extracellular region containing two immunoglobulin-like domains, a transmembrane region, and an intracellular region. The mRNA expression levels of CapIgR were detected in different tissues of healthy C. auratus by quantitative real-time PCR, and the highest expression level was found in the liver. After Aeromonas hydrophila challenge, CapIgR expression was upregulated in different tissues at certain time points, and temporal expression changes of CapIgR fluctuated in a time-dependent manner. CapIgR exhibited rapid immune response to A. hydrophila challenge and played an important role in the immune defense of fish. These findings provided insights into the structure, function, and immune defense mechanism of CapIgR in C. auratus. This study can serve as a basis for developing disease control strategies in aquaculture. PMID- 28916357 TI - Myeloid leukemia factor functions in anti-WSSV immune reaction of kuruma shrimp, Marsupenaeus japonicus. AB - Myeloid leukemia factor (MLF) plays an important role in development, cell cycle, myeloid differentiation, and regulates the RUNX transcription factors. However, the function of MLF in immunity is still unclear. In this study, an MLF was identified and characterized in kuruma shrimp Marsupenaeus japonicus, and named as MjMLF. The full-length cDNA of MjMLF contained 1111 nucleotides, which had an opening reading frame of 816 bp encoding a protein of 272 amino acids with an MLF1-interacting protein domain. MjMLF could be ubiquitously detected in different tissues of shrimp at the transcriptional level. The expression pattern analysis showed that MjMLF could be upregulated in shrimp hemocytes and hepatopancreas after white spot syndrome virus challenge. The RNA interference and protein injection assay showed that MjMLF could inhibit WSSV replication in vivo. Flow cytometry assay showed that MjMLF could induce hemocytes apoptosis which functioned in the shrimp antiviral reaction. All the results suggested that MjMLF played an important role in the antiviral immune reaction of kuruma shrimp. The research indicated that MjMLF might function as a novel regulator to inhibit WSSV replication in shrimp. PMID- 28916358 TI - The functional characterization and comparison of two single CRD containing C type lectins with novel and typical key motifs from Portunus trituberculatus. AB - C-type lectins are a superfamily of Ca2+-dependent carbohydrate-recognition proteins, which play crucial roles in innate immunity including nonself recognition and pathogen elimination. In the present study, two single-CRD containing C-type lectins were identified from swimming crab Portunus trituberculatus (designated as PtCTL-2 and PtCTL-3). The open reading frame (ORF) of PtCTL-2 encoded polypeptides of 485 amino acids with a signal peptide and a single carbohydrate-recognition domain (CRD), while PtCTL-3's ORF encoded polypeptides of 241 amino acids with a coiled-coil region and a single-CRD. The key motifs determining carbohydrate binding specificity in PtCTL-2 and PtCTL-3 were EPR (Glu-Pro-Arg) and QPD (Gln-Pro-Asp). EPR is a motif being identified for the first time, whereas QPD is a typical motif in C-type lectins. Different PAMPs binding features of the two recombinant proteins - PtCTL-2 (rPtCTL-2) and PtCTL-3 (rPtCTL-3) have been observed in our experiments. rPtCTL-2 could bind three pathogen-associated molecular patterns (PAMPs) with relatively high affinity, including glucan, lipopolysaccharide (LPS) and peptidoglycan (PGN), while rPtCTL 3 could barely bind any of them. However, rPtCTL-2 could bind seven kinds of microbes and rPtCTL-3 could bind six kinds in microbe binding assay. Moreover, rPtCTL-2 and rPtCTL-3 exhibited similar agglutination activity against Gram positive bacteria, Gram-negative bacteria and fungi in agglutination assay. All these results illustrated that PtCTL-2 and PtCTL-3 could function as important pattern-recognition receptors (PRR) with broad nonself-recognition spectrum involved in immune defense against invaders. In addition, the results of carbohydrate binding specificity showed that PtCTL-2 with novel key motif had broad carbohydrate binding specificity, while PtCTL-3 with typical key motif possessed different carbohydrate binding specificity from the classical binding rule. Furthermore, PtCTL-2 and PtCTL-3 could also function as opsonin to enhance encapsulation of hemocytes against Ni-NTA beads. PMID- 28916359 TI - A class B scavenger receptor from Eriocheir sinensis (EsSR-B1) restricts bacteria proliferation by promoting phagocytosis. AB - Scavenger receptors (SRs) are important pattern recognition receptors (PRRs), which play significant roles in host defense against pathogens by identifying pathogen-associated molecular patterns (PAMPs). In this study, we report the cloning and characterization of a SR from Eriocheir sinensis (EsSR-B1) which is a 500 amino acid protein encoded by a gene comprised of 2726 nucleotides with a 1503 bp open reading frame. The domains of EsSR-B1 were found to be evolutionarily conserved. EsSR-B1 was widely detected in different tissues of E. sinensis and significantly up-regulated in hemocytes after stimulation by Staphyloccocus aureus or Vibrio parahaemolyticus. Recombinant EsSR-B1 protein could bind to bacteria and promote phagocytosis upon bacterial stimulation. Moreover, antimicrobial peptide expression was reduced in EsSR-B1-silenced hemocytes after challenge by S. aureus or V. parahaemolyticus. Thus, EsSR-B1 has a critical role in the binding of bacteria and subsequent promotion of hemocyte phagocytosis. PMID- 28916361 TI - Erratum to "In vivo MRI tracking of exogenous monocytes/macrophages targeting brain tumors in a rat model of glioma" [NeuroImage 37S1 (2007) S47-S58]. PMID- 28916360 TI - Trancriptome profiles of Amur sturgeon spleen in response to Yersinia ruckeri infection. AB - Yersinia ruckeri (YR) is the causative agent of yersiniosis which has caused significant economic losses in fish culture worldwide, including in Amur sturgeon (Acipenser schrenckii) culture. To better understand the mechanism of the immune responses to YR in Amur sturgeon, the transcriptomic profiles of the spleens from YR-infected and non-infected groups were obtained using RNA-seq techniques. The de novo assemblies yielded totally 145 670 unigenes from the two libraries. The total numbers of transcripts in YR-infected and non-infected groups were from 110 893 to 147 336, with the mean length varying from 560 to 631 (N50: from 882 to 1083). GO analysis revealed that 10 038 unigenes were categorized into 26 biological processes subcategories, 17 cellular components subcategories and 19 molecular functions subcategories. A total of 59 487 unigenes were annotated in the KEGG pathway and 20 pathways were related to the immune system. 1465 differently expressed genes (DEGs) were identified, including 377 up-regulated genes and 1088 down-regulated genes. 125 DEGs were found to be related to immune responses of Amur sturgeon and further divided into 16 immune-related KEGG pathways, including antigen processing and presentation, complement and coagulation cascades, T cell receptor signaling pathway, B cell receptor signaling pathway, NOD-like receptor signaling pathway, chemokine signaling pathway, etc. Eight of the DEGs were further validated by qRT-PCR. Altogether, the results obtained in this study will provide insight into the immune response of Amur sturgeon against Y. ruckeri infection. PMID- 28916362 TI - Corrigendum to "Fingerspelling, signed language, text and picture processing in deaf native signers: The role of the mid-fusiform gyrus" [NeuroImage 35 (2007) 1287-1302]. PMID- 28916363 TI - Corrigendum to "Functional MRI with active, fully implanted, deep brain stimulation systems: Safety and experimental confounds" [NeuroImage 37 (2007) 508 517]. PMID- 28916364 TI - Erratum to "Resolving sentence ambiguity with planning and working memory resources: Evidence from fMRI" [NeuroImage 37 (2007) 361-378]. PMID- 28916365 TI - Sodium phenylbutyrate abrogates African swine fever virus replication by disrupting the virus-induced hypoacetylation status of histone H3K9/K14. AB - African swine fever virus (ASFV) causes a highly lethal disease in swine for which neither a vaccine nor treatment are available. Recently, a new class of drugs that inhibit histone deacetylases enzymes (HDACs) has received an increasing interest as antiviral agents. Considering studies by others showing that valproic acid, an HDAC inhibitor (HDACi), blocks the replication of enveloped viruses and that ASFV regulates the epigenetic status of the host cell by promoting heterochromatinization and recruitment of class I HDACs to viral cytoplasmic factories, the antiviral activity of four HDACi against ASFV was evaluated in this study. Results showed that the sodium phenylbutyrate fully abrogates the ASFV replication, whereas the valproic acid leads to a significant reduction of viral progeny at 48h post-infection (-73.9%, p=0.046), as the two pan-HDAC inhibitors tested (Trichostatin A: -82.2%, p=0.043; Vorinostat: 73.9%, p=0.043). Further evaluation showed that protective effects of NaPB are dose dependent, interfering with the expression of late viral genes and reversing the ASFV-induced histone H3 lysine 9 and 14 (H3K9K14) hypoacetylation status, compatible to an open chromatin state and possibly enabling the expression of host genes non-beneficial to infection progression. Additionally, a synergic antiviral effect was detected when NaPB is combined with an ASFV-topoisomerase II poison (Enrofloxacin). Altogether, our results strongly suggest that cellular HDACs are involved in the establishment of ASFV infection and emphasize that further in vivo studies are needed to better understand the antiviral activity of HDAC inhibitors. PMID- 28916368 TI - Saving an additional 100 million lives. PMID- 28916369 TI - Antiangiogenesis to curb urothelial cancer. PMID- 28916367 TI - Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. FINDINGS: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16.6 months (95% CI 13.4-22.9; 130 [35%] patients) in the rucaparib group versus 5.4 months (3.4-6.7; 66 [35%] patients) in the placebo group (hazard ratio 0.23 [95% CI 0.16-0.34]; p<0.0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13.6 months (10.9-16.2) versus 5.4 months (5.1-5.6; 0.32 [0.24-0.42]; p<0.0001). In the intention-to-treat population, it was 10.8 months (8.3-11.4) versus 5.4 months (5.3-5.5; 0.36 [0.30-0.45]; p<0.0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). INTERPRETATION: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. FUNDING: Clovis Oncology. PMID- 28916370 TI - PARP inhibitors for targeted treatment in ovarian cancer. PMID- 28916372 TI - Tracking and controlling soft surface contamination in health care settings. AB - BACKGROUND: Study objectives were to track the transfer of microbes on soft surfaces in health care environments and determine the efficiency of an Environmental Protection Agency (EPA)-registered soft surface sanitizer in the health care environment. METHODS: Soft surfaces at 3 health care facilities were sampled for heterotrophic plate count (HPC) bacteria, Staphylococcus spp, Streptococcus pyogenes, and Escherichia coli followed by a tracer study with a virus surrogate seeded onto volunteer hands and commonly touched surfaces. The occurrence of microbial contaminants was determined along with microbial reductions using the soft surface sanitizer. Soft surfaces were swabbed pre- and postintervention. RESULTS: Tracer viruses spread to 20%-64% and 13%-41% of surfaces in long-term health care facilities and physicians' offices, respectively. Only 1 pathogen, methicillin-resistant Staphylococcus aureus, was recovered. The waiting room chairs had the highest concentration of HPC bacteria before disinfection (145.4 +/- 443.3 colony forming units [cfu]/cm2), and the privacy curtains had the lowest (39.5 +/- 84.2 cfu/cm2). Reductions of up to 98.5% were achieved with the sanitizer in health care settings and up to 99.99% under controlled laboratory conditions. CONCLUSIONS: Soft surfaces are involved in the spread of microbes throughout health care facilities. Routine application of an EPA-registered sanitizer for soft surfaces can help to reduce the microbial load and minimize exposure risks. PMID- 28916373 TI - Methods for computational disease surveillance in infection prevention and control: Statistical process control versus Twitter's anomaly and breakout detection algorithms. AB - BACKGROUND: Although not all health care-associated infections (HAIs) are preventable, reducing HAIs through targeted intervention is key to a successful infection prevention program. To identify areas in need of targeted intervention, robust statistical methods must be used when analyzing surveillance data. The objective of this study was to compare and contrast statistical process control (SPC) charts with Twitter's anomaly and breakout detection algorithms. METHODS: SPC and anomaly/breakout detection (ABD) charts were created for vancomycin resistant Enterococcus, Acinetobacter baumannii, catheter-associated urinary tract infection, and central line-associated bloodstream infection data. RESULTS: Both SPC and ABD charts detected similar data points as anomalous/out of control on most charts. The vancomycin-resistant Enterococcus ABD chart detected an extra anomalous point that appeared to be higher than the same time period in prior years. Using a small subset of the central line-associated bloodstream infection data, the ABD chart was able to detect anomalies where the SPC chart was not. DISCUSSION: SPC charts and ABD charts both performed well, although ABD charts appeared to work better in the context of seasonal variation and autocorrelation. CONCLUSIONS: Because they account for common statistical issues in HAI data, ABD charts may be useful for practitioners for analysis of HAI surveillance data. PMID- 28916374 TI - AMP-activated protein kinase protects against anoxia in Drosophila melanogaster. AB - During anoxia, proper energy maintenance is essential in order to maintain neural operation. Starvation activates AMP-activated protein kinase (AMPK), an evolutionarily conserved indicator of cellular energy status, in a cascade which modulates ATP production and consumption. We investigated the role of energetic status on anoxia tolerance in Drosophila and discovered that starvation or AMPK activation increases the speed of locomotor recovery from an anoxic coma. Using temporal and spatial genetic targeting we found that AMPK in the fat body contributes to starvation-induced fast locomotor recovery, whereas, under fed conditions, disrupting AMPK in oenocytes prolongs recovery. By evaluating spreading depolarization in the fly brain during anoxia we show that AMPK activation reduces the severity of ionic disruption and prolongs recovery of electrical activity. Further genetic targeting indicates that glial, but not neuronal, AMPK affects locomotor recovery. Together, these findings support a model in which AMPK is neuroprotective in Drosophila. PMID- 28916375 TI - Bacterial community in ancient permafrost alluvium at the Mammoth Mountain (Eastern Siberia). AB - Permanently frozen (approx. 3.5Ma) alluvial Neogene sediments exposed in the Aldan river valley at the Mammoth Mountain (Eastern Siberia) are unique, ancient, and poorly studied permafrost environments. So far, the structure of the indigenous bacterial community has remained unknown. Use of 16S metagenomic analysis with total DNA isolation using DNA Spin Kit for Soil (MO-Bio) and QIAamp DNA Stool Mini Kit (Qiagen) has revealed the major and minor bacterial lineages in the permafrost alluvium sediments. In sum, 61 Operational Taxonomic Units (OTUs) with 31,239 reads (Qiagen kit) and 15,404 reads (Mo-Bio kit) could be assigned to the known taxa. Only three phyla, Bacteroidetes, Proteobacteria and Firmicutes, comprised >5% of the OTUs abundance and accounted for 99% of the total reads. OTUs pertaining to the top families (Chitinophagaceae, Caulobacteraceae, Sphingomonadaceae, Bradyrhizobiaceae, Halomonadaceae) held >90% of reads. The abundance of Actinobacteria was less (0.7%), whereas members of other phyla (Deinococcus-Thermus, Cyanobacteria/Chloroplast, Fusobacteria, and Acidobacteria) constituted a minor fraction of reads. The bacterial community in the studied ancient alluvium differs from other permafrost sediments, mainly by predominance of Bacteroidetes (>52%). The diversity of this preserved bacterial community has the potential to cause effects unknown if prompted to thaw and spread with changing climate. Therefore, this study elicits further reason to study how reintroduction of these ancient bacteria could affect the surrounding ecosystem, including current bacterial species. PMID- 28916371 TI - Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. FINDINGS: Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4.07 months [95% CI 2.96-4.47] vs 2.76 months [2.60-2.96]; hazard ratio [HR] 0.757, 95% CI 0.607-0.943; p=0.0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24.5%, 95% CI 18.8-30.3) of 216 patients allocated ramucirumab and 31 (14.0%, 9.4-18.6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1-2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. INTERPRETATION: To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. FUNDING: Eli Lilly and Company. PMID- 28916376 TI - Transcriptome profiling of the Plutella xylostella (Lepidoptera: Plutellidae) ovary reveals genes involved in oogenesis. AB - BACKGROUND: As a specialized organ, the insect ovary performs valuable functions by ensuring fecundity and population survival. Oogenesis is the complex physiological process resulting in the production of mature eggs, which are involved in epigenetic programming, germ cell behavior, cell cycle regulation, etc. Identification of the genes involved in ovary development and oogenesis is critical to better understand the reproductive biology and screening for the potential molecular targets in Plutella xylostella, a worldwide destructive pest of economically major crops. RESULTS: Based on transcriptome sequencing, a total of 7.88Gb clean nucleotides was obtained, with 19,934 genes and 1861 new transcripts being identified. Expression profiling indicated that 61.7% of the genes were expressed (FPKM>=1) in the P. xylostella ovary. GO annotation showed that the pathways of multicellular organism reproduction and multicellular organism reproduction process, as well as gamete generation and chorion were significantly enriched. Processes that were most likely relevant to reproduction included the spliceosome, ubiquitin mediated proteolysis, endocytosis, PI3K-Akt signaling pathway, insulin signaling pathway, cAMP signaling pathway, and focal adhesion were identified in the top 20 'highly represented' KEGG pathways. Functional genes involved in oogenesis were further analyzed and validated by qRT PCR to show their potential predominant roles in P. xylostella reproduction. CONCLUSIONS: Our newly developed P. xylostella ovary transcriptome provides an overview of the gene expression profiling in this specialized tissue and the functional gene network closely related to the ovary development and oogenesis. This is the first genome-wide transcriptome dataset of P. xylostella ovary that includes a subset of functionally activated genes. This global approach will be the basis for further studies on molecular mechanisms of P. xylostella reproduction aimed at screening potential molecular targets for integrated pest management. PMID- 28916377 TI - Clinical and molecular characterization of two Chinese patients with Type 2 congenital generalized lipodystrophy. AB - BACKGROUND: Type 2 congenital generalized lipodystrophy (CGL2, OMIM 269700) is a rare autosomal recessive disease, characterized by the generalized absence of adipose tissue at birth or in early infancy. Pathogenic variants in BSCL2 gene have been reported to be responsible for CGL2. The aim of this study is to analyze the clinical and genetic characteristics of two Chinese patients with CGL2, and with particular focus on the BSCL2 gene sequence variants. METHODS: Medical history, clinical manifestations, physical examination, laboratory data, and ultrasonography findings were analyzed for the two patients with CGL2. Blood samples from both families were obtained for genetic testing. Next generation sequencing for the 2742-gene inherited disease panel were conducted. RESULTS: Two patients had similar physical appearances including a conspicuous generalized lack of body fat since birth, extreme muscularity, face with empty cheeks, hirsutism and skin hyperpigmentation especially around necks and armpits; both had intellectual disability, alone with psycho-behavioral issues including tantrum and aggression. One patient exhibited multiple signs of overgrowth such as advanced bone age and macropenis. Laboratory data revealed hypertriglyceridemia, hypercholesterolemia, and low high-density lipoprotein cholesterol concentration. Ultrasound showed hepatomegaly in both patients and renal hypertrophy in patient 2. Echocardiography exams were normal. Both were treated with low-fat, high-carbohydrate diet. Molecular testing confirmed the clinical diagnosis of CGL, specifically CGL2 by detecting a homozygous variant (c.782dupG/p.Ile262Hisfs*12) in BSCL2 gene in patient 1, and compound heterozygous mutations (c. 713G>A/p.Gly238Asp and c.782dupG/p.Ile262Hisfs*12) in patient 2. CONCLUSION: We describe two patients with classic clinical manifestations of CGL2 confirmed by genetic sequence analysis. A novel variant in BSCL2 gene was detected in one patient (c.713G>A/p.Gly238Asp). PMID- 28916378 TI - Clinical pharmacology of anti-angiogenic drugs in oncology. AB - Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring. PMID- 28916379 TI - Carboxymethyl fenugreek galactomannan-gellan gum-calcium silicate composite beads for glimepiride delivery. AB - Novel carboxymethyl fenugreek galactomannan (CFG)-gellan gum (GG)-calcium silicate (CS) composite beads were developed for controlled glimepiride (GLI) delivery. CFG having degree of carboxymethylation of 0.71 was synthesized and characterized by FTIR, DSC and XRD analyses. Subsequently, GLI-loaded hybrids were accomplished by ionotropic gelation technique employing Ca+2/Zn+2/Al+3 ions as cross-linkers. All the formulations demonstrated excellent drug encapsulation efficiency (DEE, 48-97%) and sustained drug release behaviour (Q8h, 62-94%). These quality attributes were remarkably influenced by polymer-blend (GG:CFG) ratios, cross-linker types and CS inclusion. The drug release profile of the optimized formulation (F-6) was best fitted in zero-order model with anomalous diffusion driven mechanism. It also conferred excellent ex vivo mucoadhesive property and considerable hypoglycemic effect in streptozotocin-induced diabetic rats. Furthermore, the beads were characterized for drug-excipients compatibility, drug crystallinity, thermal behaviour and surface morphology. Thus, the developed hybrid matrices are appropriate for controlled delivery of GLI for Type 2 diabetes management. PMID- 28916366 TI - Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016. AB - BACKGROUND: The UN's Sustainable Development Goals (SDGs) are grounded in the global ambition of "leaving no one behind". Understanding today's gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health related SDG indicators over the period 1990-2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030. METHODS: We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0-100, with 0 as the 2.5th percentile estimated between 1990 and 2030, and 100 as the 97.5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment. FINDINGS: Globally, the median health-related SDG index was 56.7 (IQR 31.9-66.8) in 2016 and country-level performance markedly varied, with Singapore (86.8, 95% uncertainty interval 84.6-88.9), Iceland (86.0, 84.1-87.6), and Sweden (85.6, 81.8-87.8) having the highest levels in 2016 and Afghanistan (10.9, 9.6-11.9), the Central African Republic (11.0, 8.8-13.8), and Somalia (11.3, 9.5-13.1) recording the lowest. Between 2000 and 2016, notable improvements in the UHC index were achieved by several countries, including Cambodia, Rwanda, Equatorial Guinea, Laos, Turkey, and China; however, a number of countries, such as Lesotho and the Central African Republic, but also high income countries, such as the USA, showed minimal gains. Based on projections of past trends, the median number of SDG targets attained in 2030 was five (IQR 2-8) of the 24 defined targets currently measured. Globally, projected target attainment considerably varied by SDG indicator, ranging from more than 60% of countries projected to reach targets for under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria, to less than 5% of countries projected to achieve targets linked to 11 indicator targets, including those for childhood overweight, tuberculosis, and road injury mortality. For several of the health related SDGs, meeting defined targets hinges upon substantially faster progress than what most countries have achieved in the past. INTERPRETATION: GBD 2016 provides an updated and expanded evidence base on where the world currently stands in terms of the health-related SDGs. Our improved measure of UHC offers a basis to monitor the expansion of health services necessary to meet the SDGs. Based on past rates of progress, many places are facing challenges in meeting defined health-related SDG targets, particularly among countries that are the worst off. In view of the early stages of SDG implementation, however, opportunity remains to take actions to accelerate progress, as shown by the catalytic effects of adopting the Millennium Development Goals after 2000. With the SDGs' broader, bolder development agenda, multisectoral commitments and investments are vital to make the health-related SDGs within reach of all populations. FUNDING: Bill & Melinda Gates Foundation. PMID- 28916380 TI - Roles of amino acid residues H66 and D326 in the creatine kinase activity and structural stability. AB - Creatine kinase (CK) is a key enzyme for cellular energy metabolism, catalyzing the reversible phosphoryl transfer from phosphocreatine to ADP in vertebrates. CK contains a pair of highly conserved amino acids (H66 and D326) which might play an important role in sustaining the compact structure of CK by linking its N- and C- terminal domains; however the mechanism is still unclear. In this study, spectroscopic, structural modeling and protein folding experiments suggested that D326A, H66P and H66P/D326A mutations led to disruption of the hydrogen bond between those two amino acid residues and form the partially unfolded state which made it easier to be inactivated and unfolded under environmental stresses, and more prone to form insoluble aggregates. The formation of insoluble aggregates would decrease levels of active CKs which may provide clues in CK deficiency disease. Moreover, these results indicated that the degree of synergism had closely relationship to the conformational changes of CK. Thus, our results provided clues for understanding the mechanism of amino acid residues outside the active site in regulating substrate synergism. PMID- 28916381 TI - Perspectives on the production, structural characteristics and potential applications of bioplastics derived from polyhydroxyalkanoates. AB - Since the last two decades, the use of synthetic materials has increased and become more frequent in this capitalist system. Polymers used as raw materials are usually disposed very rapidly and considered serious damages when they return to the environment. Because of this behaviour, there was an increasing in the global awareness by minimizing the waste generated, in addition to the scientific community concern for technological alternatives to solve this problem. Alternatively, biodegradable polymers are attracting special interest due to their inherent properties, which are similar to the ones of the conventional plastics. Bioplastics covers plastics made from renewable resources, including plastics that biodegrade under controlled conditions at the end of their use phase. Polyhydroxyalkanoates (PHAs) are polyesters composed of hydroxy acids, synthesized by a variety of microorganisms as intracellular carbon and energy storage. These environmentally friendly biopolymers have excellent potential in domestic, agricultural, industrial and medical field, however their production on a large scale is still limited. This review considered the most recent scientific publications on the production of bioplastics based on PHAs, their structural characteristics and the exploitation of different renewable sources of raw materials. In addition, there were also considered the main biotechnological applications of these biopolymers. PMID- 28916382 TI - Influence of beta-lactoglobulin and calcium chloride on the molecular structure and interactions of casein micelles. AB - Targeted processing of casein micelles (CM) requires a basic understanding of their molecular structure as well as their interactions with each other and with other components. In this study, angle- and concentration-dependent static and dynamic light scattering is applied to investigate changes in the molecular weight, size, and intermolecular interactions of CM after the addition of beta lactoglobulin (beta-Lg) and calcium chloride. Addition of a surplus of beta-Lg impairs the colloidal stability of CM. In the presence of 0.5wt% beta-Lg and natural calcium chloride concentrations (10mM), the molecular weight of CM is reduced and the radius of gyration is increased. Both changes can be explained by the release of alphaS2-casein and kappa-casein, which were determined in higher concentration free in solution by High performance liquid chromatography. In contrast, the structure of casein micelles is not altered by the presence of beta Lg at elevated calcium chloride concentrations. The repulsive forces between the CM show no significant dependence on beta-Lg for all calcium chloride concentrations tested. PMID- 28916384 TI - Human Immunodeficiency Virus and Aging in the Era of Effective Antiretroviral Therapy. AB - Persons living with HIV (PLWH) have accentuated risks for age-associated comorbidities. Compared to the general population, PLWH have a 2-fold higher risk of cardiovascular disease, a 3-fold increased risk of fracture, and a risk of kidney disease that is comparable to that in diabetes. Some comorbidities may present at younger ages than among the general population, suggesting the possibility of accelerated aging with HIV infection. PMID- 28916383 TI - Heterologous expression and structure-function relationship of low-temperature and alkaline active protease from Acinetobacter sp. IHB B 5011(MN12). AB - The gene encoding protease from Acinetobacter sp. IHB B 5011(MN12) was cloned and expressed in Escherichia coli BL21(DE3). The nucleotide sequence revealed 1323bp ORF encoding 441 amino acids protein with molecular weight 47.2kDa. The phylogenetic analysis showed clustering of Alp protease with subtilisin-like serine proteases of S8 family. The amino acid sequence was comprised of N terminal signal peptide 1-21 amino acids, pre-peptide 22-143 amino acids, peptidase S8 domain 144-434 amino acids, and pro-peptide 435-441 amino acids at C terminus. Three constructs with signal peptide pET-Alp, without signal peptide pET-Alp1 and peptidase S8 domain pET-Alp2 were prepared for expression in E. coli BL21(DE3). The recombinant proteins Alp1 and Alp2 expressed as inclusion bodies showed ~50kDa and ~40kDa bands, respectively. The pre-propeptide ~11kDa removed from Alp1 resulted in mature protein of ~35kDa with 1738Umg-1 specific activity. The recombinant protease was optimally active at 40 degrees C and pH 9, and stable over 10-70 degrees C and 6-12pH. The activity at low-temperature and alkaline pH was supported by high R/(R+K) ratio, more glycine, less proline, negatively charged amino acids, less salt bridges and longer loops. These properties suggested the suitability of Alp as additive in the laundry. PMID- 28916385 TI - Bacterial Pneumonia in Older Adults. AB - The incidence of pneumonia increases with age, and is particularly high in patients who reside in long-term care facilities (LTCFs). Mortality rates for pneumonia in older adults are high and have not decreased in the last decade. Atypical symptoms and exacerbation of underlying illnesses should trigger clinical suspicion of pneumonia. Risk factors for multidrug-resistant organisms are more common in older adults, particularly among LTCF residents, and should be considered when making empiric treatment decisions. Monitoring of clinical stability and underlying comorbid conditions, potential drug-drug interactions, and drug-related adverse events are important factors in managing elderly patients with pneumonia. PMID- 28916387 TI - The PTSD Psychopharmacology Working Group: Two Suggestions. PMID- 28916386 TI - Molecular Mechanisms of the R61T Mutation in Apolipoprotein E4: A Dynamic Rescue. AB - The apolipoprotein E4 (ApoE4) gene is the strongest genetic risk factor for Alzheimer's disease (AD). With respect to the other common isoforms of this protein (ApoE2 and ApoE3), ApoE4 is characterized by lower stability that underlies the formation of a stable interaction between the protein's N- and C terminal domains. AD-related cellular dysfunctions have been linked to this ApoE4 misfolded state. In this regard, it has been reported that the mutation R61T is able to rescue the deleterious cellular effects of ApoE4 by preventing the formation of the misfolded intermediate state. However, a clear description of the structural features at the basis of the R61T-ApoE4 mutant's protective effect is still missing. Recently, using extensive molecular dynamics simulations, we have identified a structural model of an ApoE4 misfolded intermediate state. Building on our previous work, here we explore the dynamical changes induced by the R61T mutation in the ApoE4 native and misfolded states. Notably, we do not observe any local changes in the domains in the R61T-ApoE4 system, rather a general loss of correlated movements in the entire protein structure. More specifically, we detect increased dynamics in the hinge region, which is essential for ApoE4 domain-domain interaction. Consistent with previously reported data on altered phospholipid and receptor binding, we hypothesize that mutations destabilizing the ApoE4 intermediate state change hinge region dynamics, which propagates to distal functional regions of the protein and modifies ApoE4's functional properties. This unique behavior of the ApoE4 hinge region provides, to our knowledge, a novel understanding of ApoE4's role in AD. PMID- 28916388 TI - Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. AB - BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA. PMID- 28916389 TI - Removal and killing of multispecies endodontic biofilms by N-acetylcysteine. AB - Removal of bacterial biofilm from the root canal system is essential for the management of endodontic disease. Here we evaluated the antibacterial effect of N acetylcysteine (NAC), a potent antioxidant and mucolytic agent, against mature multispecies endodontic biofilms consisting of Actinomyces naeslundii, Lactobacillus salivarius, Streptococcus mutans and Enterococcus faecalis on sterile human dentin blocks. The biofilms were exposed to NAC (25, 50 and 100mg/mL), saturated calcium hydroxide or 2% chlorhexidine solution for 7 days, then examined by scanning electron microscopy. The biofilm viability was measured by viable cell counts and ATP-bioluminescence assay. NAC showed greater efficacy in biofilm cell removal and killing than the other root canal medicaments. Furthermore, 100mg/mL NAC disrupted the mature multispecies endodontic biofilms completely. These results demonstrate the potential use of NAC in root canal treatment. PMID- 28916390 TI - IL-33 receptor ST2 deficiency attenuates renal ischaemia-reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice. AB - AIM: Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia-reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2-/ ) on renal IRI in euglycaemic and hyperglycaemic mice. METHODS: Hyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2-/- mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. RESULTS: Urinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2-/- mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2-/- animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. CONCLUSION: Our data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening up new avenues for future research on alarmins and diabetes in ischaemia-related diseases. PMID- 28916391 TI - Zika virus structural biology and progress in vaccine development. AB - The growing number of zika virus (ZIKV) infections plus a 20-fold increase in neonatal microcephaly in newborns in Brazil have raised alarms in many countries regarding the threat to pregnant women. Instances of microcephaly and central nervous system malformations continue to increase in ZIKV outbreak regions. ZIKV is a small enveloped positive-strand RNA virus belonging to the Flavivirus genus of the Flaviviridae family. High-resolution ZIKV structures recently identified by cryo-electron microscopy indicate that the overall ZIKV structure is similar to those of other flaviviruses. With its compact surface, ZIKV is more thermally stable than the dengue virus (DENV). ZIKV E proteins have a characteristic "herringbone" structure with a single glycosylation site. The ZIKV E protein, the major protein involved in receptor binding and fusion, is formed as a head-to tail dimer on the surfaces of viral particles. The E monomer consists of three distinct domains: DI, DII, and DIII. The finger-like DII contains a fusion loop (FL) that is inserted into the host cell endosomal membrane during pH-dependent conformational changes that drive fusion. Quaternary E:E dimer epitopes located at the interaction site of prM and E dimers can be further divided into two dimer epitopes. To date, more than 50 ZIKV vaccine candidates are now in various stages of research and development. Candidate ZIKV vaccines that are currently in phase I/II clinical trials include inactivated whole viruses, recombinant measles viral vector-based vaccines, DNA and mRNA vaccines, and a mosquito salivary peptide vaccine. Stabilized forms of ZIKV E:E dimer proteins have been successfully obtained either by introducing additional inter-subunit disulfide bond(s) in DII or via the direct assembly of E:E dimer proteins by immobilization with monomeric E proteins. The VLP-based approach is another alternative method for presenting native E:E dimer antigens among the vaccine components. Several forms of ZIKV VLPs have been reported featuring the co-expression of the prM-E, prM-E-NS1, C prM-E, and NS2B/NS3 viral genes in human cells. To minimize the effect of the cross-reactive ADE-facilitating antibodies between ZIKV and DENV, several novel mutations have been reported either in or near the FL of DII or DIII to dampen the production of cross-reactive antibodies. Future ZIKV vaccine design efforts should be focused on eliciting improved neutralizing antibodies with a reduced level of cross-reactivity to confer sterilizing immunity. PMID- 28916392 TI - Formulation, construction and analysis of kinetic models of metabolism: A review of modelling frameworks. AB - Kinetic models are critical to predict the dynamic behaviour of metabolic networks. Mechanistic kinetic models for large networks remain uncommon due to the difficulty of fitting their parameters. Recent modelling frameworks promise new ways to overcome this obstacle while retaining predictive capabilities. In this review, we present an overview of the relevant mathematical frameworks for kinetic formulation, construction and analysis. Starting with kinetic formalisms, we next review statistical methods for parameter inference, as well as recent computational frameworks applied to the construction and analysis of kinetic models. Finally, we discuss opportunities and limitations hindering the development of larger kinetic reconstructions. PMID- 28916393 TI - Towards a chromatographic similarity index to establish localised Quantitative Structure-Retention Relationships for retention prediction. III Combination of Tanimoto similarity index, logP, and retention factor ratio to identify optimal analyte training sets for ion chromatography. AB - Retention prediction for unknown compounds based on Quantitative Structure Retention Relationships (QSRR) can lead to rapid "scoping" method development in chromatography by simplifying the selection of chromatographic parameters. The use of retention factor ratio (or k-ratio) as a chromatographic similarity index can be a potent method to cluster similar compounds into a training set to generate an accurate predictive QSRR model provided that its limitation - that the method is impractical for retention prediction for unknown compounds - is successfully addressed. In this work, we propose a localised QSRR modelling approach with the aim of compensating the critical limitation in the otherwise successful k-ratio filter-based QSRR modelling. The approach is to combine a k ratio filter with both Tanimoto similarity (TS) and a DeltalogP index (i.e., logP Dual filter). QSRR models for two retention parameters (a and b) in the linear solvent strength (LSS) model in ion chromatography (IC), logk=a - blog[eluent], were generated for larger organic cations (molecular mass up to 506) on a Thermo Fisher Scientific CS17 column. The application of the developed logP-Dual filter resulted in the production of successful QSRR models for 50 organic cations out of 87 in the dataset. The predicted a- and b-values of the models were then applied to the LSS model to predict the corresponding retention times. External validation showed that QSRR models for a-, b- and tR- values with excellent accuracy and predictability (Qext(F2)2 of 0.96, 0.95, and 0.96, RMSEP of 0.06, 0.02, and 0.38min) were created successfully, and these models can be employed to speed up the "scoping" phase of method development in IC. PMID- 28916394 TI - A useful strategy based on chromatographic data combined with quality-by-design approach for food analysis applications. The case study of furanic derivatives in sugarcane honey. AB - Sugarcane honey (SCH) is one of the Madeira Island products par excellence and it is now popular worldwide. Its sui generis and peculiar sensory properties, explained by a variety of volatile compounds including furanic derivatives (FDs), arise mainly from manufacturing and storage conditions. A simple high-throughput approach based on semi-automatic microextraction by packed sorbent (MEPS) combined with ultra-high performance liquid chromatography (UHPLC) was developed and validated for identification and quantification of target FDs in sugarcane honey. A Quality-by-Design (QbD) approach was used as a powerful strategy to optimize analytical conditions for high throughput analysis of FDs in complex sugar-rich food matrices. The optimum point into MEPS-Method Operable Design: Region (MODR) was obtained with R-CX sorbent, acetonitrile (ACN) as elution solvent, three loading cycles and 500MUL of sample volume. The optimum point into UHPLC-MODR was obtained with a CORTECS column operating at a temperature of 50 degrees C, ACN as eluent and a flow rate of 125MULmin-1. The robustness was demonstrated by Monte Carlo simulation and capability analysis for estimation of residual errors. The concentration-response relationship for all FDs were described by polynomial function models, being confirmed by Fisher variance (F test). The% recoveries were in a range of 91.9-112.1%. Good method precision was observed, yielding relative standard deviations (RSDs) less than 4.9% for repeatability and 8.8% for intermediate precision. The limits of quantitation for the analytes ranged from 30.6 to 737.7MUgkg-1. The MEPSR-CX/UHPLCCORTECS-PDA method revealed an effective and potential analytical tool for SCH authenticity control based on target analysis of FDs allowing a strict control and differentiation from other similar or adulterated products. PMID- 28916395 TI - Pachydermoperiostosis: The value of molecular diagnosis. AB - BACKGROUND: Pachydermoperiostosis is a rare autosomal recessive genetic disorder characterized by the association of periostosis and pachydermia. To date, two genes involved in prostaglandin metabolism, HPGD and SLCO2A1, have been identified. PATIENTS AND METHODS: A 7-year-old girl presented digital clubbing of the hands and feet, curved nails, hyperhidrosis, and pachydermia, as well as eczema of the trunk and limbs. The diagnosis of pachydermoperiostosis was confirmed by the detection of a homozygous mutation in the HPGD gene. The second case concerned a 41-year-old male with acral and cephalic pachydermia (cutis verticis gyrata), and palmoplantar keratoderma. Bone X-rays showed changes in the distal ends of several bones. The diagnosis of pachydermoperiostosis was confirmed by the detection of a homozygous mutation in the SLCO2A1 gene. DISCUSSION: The genotype/phenotype correlation suggests that patients with SLCO2A1 mutations will develop the symptoms later in life, but that these will be more severe, with a greater likelihood of cutis verticis gyrata and joint involvement compared with patients presenting HPGD mutations. In addition, hereditary enteropathy has recently been described in patients with SLCO2A1 mutations, which could account for the gastrointestinal picture seen in the second patient. Finally, on account of cases involving myelofibrosis associated with mutations in the SLCO2A gene, these patients should have a hematologic follow-up. CONCLUSION: Given the genotype/phenotype correlations illustrated by these cases, it would appear useful to propose molecular diagnosis for patients presenting pachydermoperiostosis. PMID- 28916396 TI - Ultrafine particle transport and deposition in a large scale 17-generation lung model. AB - To understand how to assess optimally the risks of inhaled particles on respiratory health, it is necessary to comprehend the uptake of ultrafine particulate matter by inhalation during the complex transport process through a non-dichotomously bifurcating network of conduit airways. It is evident that the highly toxic ultrafine particles damage the respiratory epithelium in the terminal bronchioles. The wide range of in silico available and the limited realistic model for the extrathoracic region of the lung have improved understanding of the ultrafine particle transport and deposition (TD) in the upper airways. However, comprehensive ultrafine particle TD data for the real and entire lung model are still unavailable in the literature. Therefore, this study is aimed to provide an understanding of the ultrafine particle TD in the terminal bronchioles for the development of future therapeutics. The Euler-Lagrange (E-L) approach and ANSYS fluent (17.2) solver were used to investigate ultrafine particle TD. The physical conditions of sleeping, resting, and light activity were considered in this modelling study. A comprehensive pressure-drop along five selected path lines in different lobes was calculated. The non-linear behaviour of pressure-drops is observed, which could aid the health risk assessment system for patients with respiratory diseases. Numerical results also showed that ultrafine particle-deposition efficiency (DE) in different lobes is different for various physical activities. Moreover, the numerical results showed hot spots in various locations among the different lobes for different flow rates, which could be helpful for targeted therapeutical aerosol transport to terminal bronchioles and the alveolar region. PMID- 28916397 TI - Computational assessment of model-based wave separation using a database of virtual subjects. AB - The quantification of arterial wave reflection is an important area of interest in arterial pulse wave analysis. It can be achieved by wave separation analysis (WSA) if both the aortic pressure waveform and the aortic flow waveform are known. For better applicability, several mathematical models have been established to estimate aortic flow solely based on pressure waveforms. The aim of this study is to investigate and verify the model-based wave separation of the ARCSolver method on virtual pulse wave measurements. The study is based on an open access virtual database generated via simulations. Seven cardiac and arterial parameters were varied within physiological healthy ranges, leading to a total of 3325 virtual healthy subjects. For assessing the model-based ARCSolver method computationally, this method was used to perform WSA based on the aortic root pressure waveforms of the virtual patients. Asa reference, the values of WSA using both the pressure and flow waveforms provided by the virtual database were taken. The investigated parameters showed a good overall agreement between the model-based method and the reference. Mean differences and standard deviations were -0.05+/-0.02AU for characteristic impedance, -3.93+/-1.79mmHg for forward pressure amplitude, 1.37+/-1.56mmHg for backward pressure amplitude and 12.42+/ 4.88% for reflection magnitude. The results indicate that the mathematical blood flow model of the ARCSolver method is a feasible surrogate for a measured flow waveform and provides a reasonable way to assess arterial wave reflection non invasively in healthy subjects. PMID- 28916398 TI - In-vivo analysis of sternal angle, sternal and sternocostal kinematics in supine humans during breathing. AB - This paper aims at contributing to the understanding of the combination of in vivo sternum displacement, sternal angle variations and sternocostal joints (SCJ) kinematics of the seven first rib pairs over the inspiratory capacity (IC). Retrospective codified spiral-CT data obtained at total lung capacity (TLC), middle of inspiratory capacity (MIC) and at functional residual capacity (FRC) were used to compute kinematic parameters of the bones and joints of interest in a sample of 12 asymptomatic subjects. 3D models of rib, thoracic vertebra, manubrium and sternum were processed to determine anatomical landmarks (ALs) on each bone. These ALs were used to create local coordinate system and compute spatial transformation of ribs and manubrium relative to sternum, and sternum relative to thoracic vertebra. The rib angular displacements and associated orientation of rotation axes and joint pivot points (JPP), the sternal angle variations and the associated displacement of the sternum relative to vertebra were computed between each breathing pose at the three lung volumes. Results can be summarized as following: (1) sternum cephalic displacement ranged between 17.8 and 19.2mm over the IC; (2) the sternal angle showed a mean variation of 4.4 degrees +/-2.7 degrees over the IC; (3) ranges of rib rotation relative to sternum decreased gradually with increasing rib level; (4) axes of rotation were similarly oriented at each SCJ; (5) JPP spatial displacements showed less variations at first SCJ compared to levels underneath; (6) linear relation was demonstrated between SCJ ROMs and sternum cephalic displacement over the IC. PMID- 28916399 TI - Comment on: Long-term weight loss in laparoscopic sleeve gastrectomy. PMID- 28916400 TI - Assessing Changes in the Activity Levels of Breast Cancer Patients During Radiation Therapy. AB - BACKGROUND: Radiation therapy (RT) is often delivered after lumpectomy for women with breast cancer. A common perceived side effect of RT is fatigue, yet its exact effect on activity levels and sleep is unknown. In this study we analyzed the change in activity levels and sleep using an activity tracking device before, during, and after RT for women with early stage breast cancer and ductal carcinoma in situ who underwent adjuvant RT. PATIENTS AND METHODS: After institutional review board approval, activity levels were quantified before, during, and after RT with measurements of steps, miles walked, calories burned, and sleep metrics in 10 women fitted with activity trackers. All data were uploaded and tabulated on a secure database. Multivariable linear regressions were used to evaluate changes in these variables over time during the RT course. RESULTS: Median step count was 5047 per day (range, 2741-15,508) and distance traveled was 1.6 miles per day (range, 0.9-5.3). Step count, distance, and calories decreased by an average of 54 steps per day, 0.02 miles per day, and 3 calories per day (median calories 1822; range, 1461-2712) during RT, respectively. These changes were statistically significant (P < .001), but not clinically relevant. There was no significant change in sleep (average 6.8 hours per night; range, 5.5-8.3). CONCLUSION: RT has a minimal effect on activity or sleep in women undergoing treatment for breast cancer. Activity levels varied greatly between patients in a population of women undergoing hypofractionated RT. Because increased activity levels correlate with improved outcomes, further studies evaluating attempts to increase physical activity during as well as after treatment with radiation are warranted. PMID- 28916401 TI - CART: Cell-free and Concentrated Ascites Reinfusion Therapy against malignancy related ascites. AB - A standard strategy against ascites, a common symptom observed in cirrhotic and cancer patients, includes restriction of sodium intake and use of a diuretic. Paracentesis is a widely applied method against refractory ascites that do not react to such treatment. However, emerging fatigue and hemodynamic instability are possibly attributable to a loss of protein included in ascites. Cell-free and Concentrated Ascites Reinfusion Therapy (CART) is also applied against refractory ascites. CART comprises three processes. After ascites is first filtered to remove cell components, it is concentrated to reduce its volume. Fluid obtained through these processes, including useful proteins such as albumin and globulin, is finally reinfused intravenously. CART was reported first in the 1970s. Since then, it has been applied mainly against cirrhotic ascites with a thinner cell component. Now, its indication is expanding to include malignancy-related ascites. Additionally, CART can be applied safely against malignancy-related ascites. Its favorable effects on control of patients' symptoms are anticipated, especially on fatigue. Although related evidence has not been established, CART can be anticipated for use as a strategy against refractory ascites. PMID- 28916402 TI - The mechanisms of rejection in solid organ transplantation. AB - Organ transplantation represents the preferred treatment option for many patients in terminal organ failure. The half-life of transplanted organs, however, is still far from being satisfactory with the vast majority of the organs failing within the first two decades following transplantation. At this stage, it has become apparent that rejection (prevalently mediated by humoral events) remains the primary cause of graft loss after the first year. In this light, studies are underway to better comprehend the immune events underlying graft rejection and novel immunosuppressive strategies are being explored. In this context, therapeutic apheresis techniques, that include therapeutic plasma exchange (TPE), immunoadsorption (IA) and extracorporeal photochemotherapy (ECP), represent an important adjunct in the current immunosuppressive armamentarium. This article briefly reviews our current understanding of the immune process underlying rejection of a solid organ transplant and describes the principal areas of application of therapeutic apheresis techniques in transplantation. PMID- 28916403 TI - A case of severe acquired hypertriglyceridemia in a 7-year-old girl. AB - We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjogren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis. PMID- 28916404 TI - Diagnostic process-how to do it right? The SMART medicine initiative. PMID- 28916405 TI - Love Death-A Retrospective and Prospective Follow-Up Mortality Study Over 45 Years. AB - BACKGROUND: Although sexual activity can cause moderate stress, it can cause natural death in individuals with pre-existing illness. The aim of this study was to identify additional pre-existing health problems, sexual practices, and potential circumstances that may trigger fatal events. METHODS: This medicolegal postmortem, retrospective, and prospective study is based on data of autopsies performed at the Institute of Legal Medicine of the University hospital, Goethe University, Frankfurt/Main, Germany. OUTCOMES: Identification of pre-existing health problems, sexual practices, and potential circumstances than could trigger fatal events. RESULTS: From 1972 to 2016 (45 years) approximately 38,000 medicolegal autopsies were performed, of which 99 cases of natural death were connected to sexual activities (0.26%). Except for eight women, men represented most cases. The women's mean age was 45 years (median = 45) and the men's mean age was 57.2 years (median = 57). Causes of death were coronary heart disease (n = 28), myocardial infarction (n = 21) and reinfarction (n = 17), cerebral hemorrhage (n = 12), rupture of aortic aneurysms (n = 8), cardiomyopathy (n = 8), acute heart failure (n = 2), sudden cardiac arrest (n = 1), myocarditis (n = 1), and a combination of post myocardial infarction and cocaine intoxication (n = 1). Most cases showed increased heart weights and body mass indices. Death occurred mainly during the summer and spring and in the home of the deceased. If sexual partners were identified, 34 men died during or after sexual contact with a female prostitute, two cases at least two female prostitutes. Nine men died during or after sexual intercourse with their wife, in seven cases the sexual partner was a mistress, and in four cases the life partner. Five men died during homosexual contacts. Based on the situation 30 men were found in, death occurred during masturbation. Of the women, five died during intercourse with the life partner, two died during intercourse with a lover or friend, and in one case no information was provided. CLINICAL TRANSLATION: Natural deaths connected with sexual activity appear to be associated with male sex and pre-existing cardiovascular disorders. Most cases recorded occurred with mistresses, prostitutes, or during masturbation. If death occurs, the spouse or life partner might need psychological support. STRENGTH AND LIMITATIONS: To our knowledge, the present study contains the largest collection of postmortem data on natural deaths connected with sexual activities. However, the cases presented were of forensic interest; a larger number of undetected cases especially in the marital or stable relationship sector must be assumed. CONCLUSION: Patients should be informed about the circumstances that could trigger the "love death." Lange L, Zedler B, Verhoff MA, Parzeller M. Love Death-A Retrospective and Prospective Follow-Up Mortality Study Over 45 Years. J Sex Med 2017;14:1226-1231. PMID- 28916406 TI - General practitioners' preferences with regard to colorectal cancer screening organisation Colon cancer screening medico-legal aspects. AB - OBJECTIVE: French health authorities put general practitioners at the heart of the colorectal cancer screening. This position raises organisational issues and poses medico-legal problems for the professionals and institutions involved in these campaigns, related to the key concepts of medical decisions and suitability of standards. The objective of our study is to reveal the preferences of general practitioners related to colorectal cancer screening organisation with regard to the medico-legal risk METHODS: A discrete choice questionnaire presenting hypothetical screening scenarios was mailed to 2114 physicians from 20 French different areas. The preferences of 358 general practitioners were analysed using logistic regression models. RESULTS: The factors that have significant impact on the preferences of general practitioners are the capacity of the primary care professional in the procedure, the manner in which pre-screening information is given to patients, the manner in which screening results are given to patients, the number of reminders sent to patients who test positive and who do not undergo a colonoscopy and the remuneration of the attending physician. CONCLUSIONS: Our results reveals that current colorectal cancer screening organisation is not adapted to general practitioners preferences. This work offers the public authorities avenues for reflection on possible developments in order to optimize the involvement of general practitioners in the promotion of cancer screening programme. PMID- 28916407 TI - Corrigendum to "Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma" [J Hepatol 67 (2017) 293-301]. PMID- 28916408 TI - Robot-assisted Kidney Transplantation: The European Experience. AB - BACKGROUND: Robot-assisted kidney transplantation (RAKT) has recently been introduced to reduce the morbidity of open kidney transplantation (KT). OBJECTIVE: To evaluate perioperative and early postoperative RAKT outcomes. DESIGN, SETTING AND PARTICIPANTS: This was a multicenter prospective observational study of 120 patients who underwent RAKT, predominantly with a living donor kidney, in eight European institutions between July 2015 and May 2017, with minimum follow-up of 1 mo. The robot-assisted surgical steps were transperitoneal dissection of the external iliac vessels, venous/arterial anastomosis, graft retroperitonealization, and ureterovesical anastomosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive analysis of surgical data and their correlations with functional outcomes. RESULTS AND LIMITATIONS: The median operative and vascular suture time was 250 and 38min, respectively. The median estimated blood loss was 150ml. No major intraoperative complications occurred, although two patients needed open conversion. The median postoperative estimated glomerular filtration rate was 21.2, 45.0, 52.6, and 58.0ml/min on postoperative day 1, 3, 7, and 30, respectively. Both early and late graft function were not related to overall operating time or rewarming time. Five cases of delayed graft function (4.2%) were reported. One case (0.8%) of wound infection, three cases (2.5%) of ileus, and four cases of bleeding (3.3%; three of which required blood transfusion), managed conservatively, were observed. One case (0.8%) of deep venous thrombosis, one case (0.8%) of lymphocele, and three cases (2.5%) of transplantectomy due to massive arterial thrombosis were recorded. In five cases (4.2%), surgical exploration was performed for intraperitoneal hematoma. Limitations of the study include selection bias, the lack of an open control group, and failure to report on patient cosmetic satisfaction. CONCLUSIONS: When performed by surgeons with robotic and KT experience, RAKT is safe and reproducible in selected cases and yields excellent graft function. PATIENT SUMMARY: We present the largest reported series on robot assisted kidney transplantation. Use of a robotic technique can yield low complication rates, rapid recovery, and excellent graft function. Further investigations need to confirm our promising data. PMID- 28916409 TI - Re: Cytoreductive Nephrectomy for Renal Cell Carcinoma with Venous Tumor Thrombus. PMID- 28916410 TI - Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients. AB - It is now accepted that the ability of a protein to form amyloid fibrils could be associated both kinetic and thermodynamic protein folding parameters. A recent study from our laboratory using recombinant full-length (encompassing the variable and constant domain) immunoglobulin light chains found a strong kinetic control of the protein unfolding for these proteins. In this study, we are extending our analysis by using urine-derived Bence Jones proteins (BJPs) from five patients with light chain (AL) amyloidosis and four patients with multiple myeloma (MM). We observed lower stability in kappa proteins compared to lambda proteins (for both MM and AL proteins) in agreement with previous studies. The kinetic component of protein stability is not a universal feature of BJPs and the hysteresis observed during refolding reactions could be attributed to the inability of the protein to refold all domains. The most stable proteins exhibited 3-state unfolding transitions. While these proteins do not refold reversibly, partial refolding shows 2-state partial refolding transitions, suggesting that one of the domains (possibly the variable domain) does not refold completely. Sequences were aligned with their respective germlines and the location and nature of the mutations were analyzed. The location of the mutations were analyzed and compared with the stability and amyloidogenic properties for the proteins in this study, increasing our understanding of light chain unfolding and amyloidogenic potential. PMID- 28916411 TI - 3D fusion of coronary CT angiography and CT myocardial perfusion imaging: Intuitive assessment of morphology and function. AB - BACKGROUND: The objective of this work was to support three-dimensional fusion of coronary CT angiography (coronary CTA) and CT myocardial perfusion (CT-Perf) data visualizing coronary artery stenoses and corresponding stress-induced myocardial perfusion deficits for diagnostics of coronary artery disease. METHODS: Twelve patients undergoing coronary CTA/CT-Perf after heart transplantation were included (56 +/- 12 years, all males). CT image quality was rated. Coronary diameter stenoses >50% were documented for coronary CTA. Stress-induced perfusion deficits were noted for CT-Perf. A software was implemented facilitating 3D fusion imaging of coronary CTA/CT-Perf data. Coronary arteries and heart contours were segmented automatically. To overcome anatomical mismatch of coronary CTA/CT Perf image acquisition, perfusion values were projected on the left ventricle as visualized in coronary CTA. Three resulting datasets (coronary tree/heart contour/perfusion values) were fused for combined three-dimensional rendering. 3D fusion was compared with conventional analysis of coronary CTA/CT-Perf data and to results from catheter coronary angiography. RESULTS: CT image quality was rated good-excellent (3.5 +/- 0.5, scale 1-4). 3D fusion imaging of coronary CTA/CT-Perf data was feasible in 11/12 patients (92%). One patient (8%) was excluded from further analysis due to severe motion artifacts. 2 of 11 remaining patients (18%) showed both stress-induced perfusion deficits and relevant coronary stenoses. Using 3D fusion imaging, the ischemic region could be correlated to a culprit coronary lesion in one case (1/2 = 50%) and diagnostic findings could be rectified in the other case (1/2 = 50%). Coronary CTA was in full correspondence with catheter coronary angiography. CONCLUSION: A method for 3D fusion of coronary CTA/CT-Perf is introduced correlating relevant coronary lesions and corresponding stress-induced myocardial perfusion deficits. PMID- 28916412 TI - "Predatory" journals threatening the scientific medical press. AB - In this report, the authors analyze the revolutions (journal indexing, structuring of medical writing and reviewing, impact of information technology and transformation of the medical press's business model) that, in a very short space of time, have profoundly affected the world of medical writing, which has now come under the fire of "predatory" journals. PMID- 28916413 TI - Emerging Structural Understanding of Amyloid Fibrils by Solid-State NMR. AB - Amyloid structures at atomic resolution have remained elusive mainly because of their extensive polymorphism and because their polymeric properties have hampered structural studies by classical approaches. Progress in sample preparation, as well as solid-state NMR methods, recently enabled the determination of high resolution 3D structures of fibrils such as the amyloid-beta fibril, which is involved in Alzheimer's disease. Notably, the simultaneous but independent structure determination of Abeta1-42, a peptide that forms fibrillar deposits in the brain of Alzheimer patients, by two independent laboratories, which yielded virtually identical results, has highlighted how structures can be obtained that allow further functional investigation. PMID- 28916414 TI - Nasal care in intensive care unit patients. AB - PURPOSE: The aim of this study was to investigate nasal hygiene in intensive care patients and improve patient care using isotonic saline nasal spray. MATERIAL AND METHODS: In the study group, over a period of tendays saline nasal spray was administered four times daily. Nasal treatment was not given to the control group. Each patient was examined with a flexible nasopharyngoscope before and after the treatment and a nasal culture was taken. RESULTS: In the study group, the secretion score (1- absent; 2- serosal; 3- seropurulent and 4- purulent) mean value improved from 1.9 to 1.4. In the control group, the secretion score mean value had risen from 1.7 to 3.1. At the beginning of the study, there was no difference in secretion scores between the groups, but on the tenth day a statistically significant difference was found. CONCLUSION: The use of saline nasal spray in this group of intensive care patients was found to be effective in achieving nasal hygiene. PMID- 28916415 TI - Home to die from the intensive care unit: A qualitative descriptive study of the family's experience. AB - BACKGROUND: Many people would choose to die at home, and this can be an option for intensive care patients. However, there is limited exploration of the impact on the family. AIM: To gain insight into family members' experiences when an adult intensive care unit patient is taken home to die. METHODS: Methodology is qualitative description, utilising purposeful sampling, unstructured interviews and thematic analysis. Four participants, from two different families were interviewed. The setting was a tertiary level Intensive Care Unit in New Zealand. FINDINGS: The experience was described as a kaleidoscope of events with two main themes: 'value' family member's found in the patient going home, and their experience of the 'process'. 'Value' subthemes: going home being the patient's own decision, home as an end-of-life environment, and the patient's positive response to being at home. 'Process' subthemes: care and support received, stress of a family member being in intensive care, feeling that everything happened quickly, and concerns and uncertainties. CONCLUSION: Going home to die from the intensive care unit can be a positive but challenging experience for the family. Full collaboration between the patient, family and staff is essential, to ensure the family are appropriately supported. PMID- 28916416 TI - The central compartment - Center of controversy, confusion, and concern in management of differentiated thyroid cancer. PMID- 28916418 TI - A glimpse into a neglected population - Emerging adults. PMID- 28916417 TI - In-hospital clinical outcomes after upper gastrointestinal surgery: Data from an international observational study. AB - AIMS: Previous research suggests that patients undergoing upper gastrointestinal surgery are at high risk of poor postoperative outcomes. The aim of our study was to describe patient outcomes after elective upper gastrointestinal surgery at a global level. METHODS: Prospective analysis of data collected during an international seven-day cohort study of 474 hospitals in 27 countries. Patients undergoing elective upper gastrointestinal surgery were recruited. Outcome measures were in-hospital complications and mortality at 30-days. Results are presented as n(%) and odds ratios with 95% confidence intervals. RESULTS: 2139 patients were included, of whom 498 (23.2%) developed one or more postoperative complications, with 30 deaths (1.4%). Patients with complications had longer median hospital stay 11 (6-18) days vs. 5 (2-10) days. Infectious complications were most frequent, affecting 368 (17.2%) patients. 328 (15.3%) patients were admitted to critical care postoperatively, of whom 161 (49.1%) developed a complication with 14 deaths (4.3%). In a multivariable logistic regression model we identified age (OR 1.02 [1.01-1.03]), American Society of Anesthesiologists physical status III (OR 2.12 [1.44-3.16]) and IV (OR 3.23 [1.72-6.09]), surgery for cancer (OR 1.63 [1.27-2.11]), open procedure (OR 1.40 [1.10-1.78]), intermediate surgery (OR 1.75 [1.12-2.81]) and major surgery (OR 2.65 [1.72 4.23]) as independent risk factors for postoperative complications. Patients undergoing major surgery for upper gastrointestinal cancer experienced twice the rate of complications compared to those undergoing other procedures (224/578 patients [38.8%] versus 274/1561 patients [17.6%]). CONCLUSIONS: Complications and death are common after upper gastrointestinal surgery. Patients undergoing major surgery for cancer are at greatest risk. PMID- 28916419 TI - Development of an indirect enzyme-linked immunosorbent assay (ELISA) to differentiate antibodies against wild-type porcine reproductive and respiratory syndrome from the vaccine strain TJM-F92 based on a recombinant Nsp2 protein. AB - An accurate ELISA method to differentiate pigs infected with wild-type porcine reproductive and respiratory syndrome (PRRSV) strains from vaccinated ones would help to monitor PRRSV vaccination compliance. The recombinant protein GST-d120aa derived from the continuous deletion of 120 amino acids in the non-structural protein 2 region of the modified-live vaccine strain TJM-F92 was used to develop an indirect enzyme-linked immunosorbent assay (d120-ELISA) for differentiating serum antibodies against TJM-F92 from other PRRSV strains. At the optimized cut off value which was calculated at an S/P of 0.25, it yielded a sensitivity of 90.7% and a specificity of 95.1%. Cross-reactivity tests suggested that the d120 ELISA was PRRSV-specific. Coefficient of variations of the repeatability tests ranged between 1.41-17.02%. The results suggest that the d120-ELISA is suitable for differentiating animals infected with wild-type strains from those immunized with MLV TJM-F92. PMID- 28916420 TI - Sarah Tabrizi: timed to perfection. PMID- 28916421 TI - Arteriovenous Fistula: An Uncommon Cause of Heart Failure. PMID- 28916422 TI - Watchful Waiting in Aortic Stenosis: The Problem of Acute Decompensation. AB - BACKGROUND: Acute decompensation with heart failure, angina, or syncope may be the first indication of undiagnosed aortic stenosis, but should be uncommon when the disorder is known and managed by watchful waiting. There is a lack of information on the proportion of patients with acute decompensated aortic stenosis with and without a prior diagnosis and their outcomes. METHODS: We examined the records of patients with aortic stenosis (International Classification of Diseases code 135.0) admitted to 3 UK hospitals between January 2015 and January 2016. We determined the number of admissions with acute decompensation and the proportion in whom aortic stenosis was and was not previously known. The characteristics and outcomes in the 2 groups were compared. RESULTS: Of 684 patients with aortic stenosis, 543 (79%; 95% confidence interval [CI], 76-82) were elective admissions and 141 (21%; 95% CI, 18-24) were emergencies with acute decompensation; 86 of 141 patients (61%; 95% CI, 52-69) with known aortic stenosis were under watchful waiting and 55 of 141 patients (39%; 95% CI, 31-48) did not have a prior diagnosis. In-hospital mortality was 16% versus 13%, respectively (P = .48). There were no statistically significant differences in characteristics or clinical presentation between the 2 groups (P > .1 for all comparisons). CONCLUSIONS: Approximately 1 in 5 patients admitted to the hospital with aortic stenosis have life-threatening complications due to their disorder. More than half of such patients are actively monitored for aortic stenosis before admission, exposing shortcomings of the watchful waiting management strategy. Measures to identify symptomatic patients earlier and shorten the time between symptom onset and surgery have the potential to substantially reduce morbidity and mortality. PMID- 28916423 TI - Potentially Reversible Rapid-Onset Weakness: Recognizing Colchicine Toxicity. PMID- 28916424 TI - Predictors of epinephrine dispensing and allergy follow-up after emergency department visit for anaphylaxis. AB - BACKGROUND: National guidelines recommend that patients with anaphylaxis be prescribed an epinephrine auto-injector (EAI) and referred to an allergy/immunology (A/I) specialist. OBJECTIVE: To evaluate guideline concordance and identify predictors of EAI dispensing and A/I follow-up in patients with anaphylaxis treated in the emergency department (ED). METHODS: We identified patients seen in the ED for anaphylaxis from 2010 through 2014 from an administrative claims database using an expanded International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code algorithm. RESULTS: Of 7,790 patients identified, 46.5% had an EAI dispensed and 28.8% had A/I follow-up within 1 year after discharge. On multivariable analysis, those 65 years or older (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.30-0.41) and with a medication trigger (OR 0.24, 95% CI 0.21-0.28) had a lower likelihood of EAI dispensing. Those younger than 5 years (OR 2.67, 95% CI 2.15-3.32) and with food (OR 1.40, 95% CI 1.24-1.59) or venom (OR 4.48, 95% CI 3.51-5.72) triggers had a higher likelihood of EAI dispensing. Similarly, for A/I follow-up, the likelihood was lower for age 65 years or older (OR 0.46, 95% CI 0.39-0.54) and medication trigger (OR 0.66, 95% CI 0.56-0.78) and higher for age younger than 5 years (OR 3.15, 95% CI 2.63-3.77) and food trigger (OR 1.39, 95% CI 1.22-1.58). CONCLUSION: Overall, 46.5% of patients with anaphylaxis in the ED had EAI dispensing and 28.8% had A/I follow-up. Patient age and triggers were associated with likelihood of EAI dispensing and A/I follow-up. Post-ED visit anaphylaxis management can be improved, with the potential to decrease future morbidity and mortality risk. PMID- 28916425 TI - p38MAPK family isoform p38alpha and activating transcription factor 2 are associated with the malignant phenotypes and poor prognosis of patients with ovarian adenocarcinoma. AB - This study was to identify the biomarkers for the malignancy and poor prognosis in patients with ovarian cancer. The protein expression of p38MAPK family isoform p38alpha (p38alpha) and activating transcription factor 2 (ATF2) was measured in 120 ovarian serous adenocarcinomas and 34 normal fallopian tubes using immunohistochemistry. Stable OV-90 cells expressing p38alpha and ATF2 inhibitor were established using shRNA lentivirus. Cell proliferation, invasion, and migration were analyzed in vitro. Tumor growth and chemosensitivity were investigated in xenograft tumor models. The percentage of positive p38alpha and ATF2 expression was significantly higher in ovarian serous adenocarcinomas than that in normal fallopian tubes. Positive p38alpha and ATF2 expression were significantly associated with high clinical stage (III/IV), lymph node metastasis, and shorter overall survival. Silencing of p38alpha and ATF2 gene expression in OV-90 cells significantly inhibited cell proliferation, migration, and invasion in vitro. OV-90 cells with p38alpha and ATF2 gene being silenced grew significantly slow and were significantly sensitive to the chemotherapy compared to cells with high p38alpha and ATF2 expression. p38alpha and ATF2 expression play a crucial role in the malignant phenotypes of ovarian tumor cells and are a marker for the poor prognosis of patients with ovarian serous adenocarcinomas. PMID- 28916427 TI - Simultaneous detection and differentiation of three Potyviridae viruses in sweet potato by a multiplex TaqMan real time RT-PCR assay. AB - : A multiplex TaqMan real time RT-PCR was developed for detection and differentiation of Sweet potato virus G, Sweet potato latent virus and Sweet potato mild mottle virus in one tube. Amplification and detection of a fluorogenic cytochrome oxidase gene was included as an internal control. The assay was compared with a multiplex RT-PCR developed in the initial study for the detection and differentiation of the three viruses and host 18S rRNA. Primers and/or probes of the two assays were designed from conserved regions of each virus. The two assays were optimized for primers/probes and primer concentrations and thermal cycling conditions. Sensitivity and specificity of the assays were compared each other and with other assay. Both assays were evaluated by 74 field samples original from five different provinces of China. RESULTS: showed that the TaqMan real time RT-PCR offered rapid, sensitive, effective and reliable for the simultaneous detection and differentiation of the three viruses in sweet potato plants. The assay will be useful to quarantine and certification programs and virus surveys when large numbers of samples are tested. PMID- 28916426 TI - Prognostic relevance of tripartite motif containing 24 expression in colorectal cancer. AB - Colorectal cancer is one of the most frequent malignancies in the world. Tripartite motif containing 24 (TRIM24) is a member of the TRIM protein family and a coregulator for multiple nuclear receptors. Altered expression of TRIM24 has been shown in a spectrum of human cancers. However, the clinical role of TRIM24 in colorectal cancer remains unknown. Here, gene expression data in colorectal cancer and normal tissues were downloaded from Gene Expression Omnibus (GEO). Western blotting analysis was conducted to compare TRIM24 expression between colorectal cancer and non-cancerous tissues. Immunohistochemistry staining were performed to assess TRIM24 expression in colorectal cancer tissues, and statistical analyses were employed to evaluate the associations of TRIM24 expression with clinicopathologic features and overall survival. TRIM24 mRNA and protein levels were higher in colorectal cancer tissues than that in the normal controls. TRIM24 protein expression was positively correlated with tumor size (P=0.0269), clinical stage (P=0.0061), vital status (P=0.0110) and serum carcinoembryonic antigen levels (P=0.0176). Kaplan-Meier survival analysis indicated that patients with higher TRIM24 expression had shorter survival time than those with lower TRIM24 expression. Multivariate analyses revealed TRIM24 expression was an independent prognostic factor (P<0.001). In conclusion, our study suggests that TRIM24 may play a role in colorectal carcinogens and serve as a potential prognostic marker of human colorectal cancer. PMID- 28916428 TI - Transcatheter Occlusion of Patent Ductus Arteriosus in Preterm Infants Weighing Less Than 2 kg With the Amplatzer Duct Occluder II Additional Sizes Device. PMID- 28916429 TI - Incidence and predictors of reCurrent restenosis after drug-coated balloon Angioplasty for Restenosis of a drUg-eluting Stent: The ICARUS Cooperation. AB - INTRODUCTION AND OBJECTIVES: The incidence and predictors of recurrent restenosis after drug-coated balloon (DCB) angioplasty for drug-eluting stent (DES) restenosis remain poorly studied. We sought to evaluate the incidence and predictors of recurrent restenosis among participants in randomized controlled trials receiving DCB angioplasty for DES restenosis. METHODS: The clinical and lesion data of individuals enrolled in 6 randomized controlled trials of DCB angioplasty for DES restenosis were pooled. All patients included in this report were assigned to receive paclitaxel-coated balloon angioplasty with the SeQuent Please DCB (B Braun, Melsungen, Germany). The current analysis focused on participants with available follow-up angiography at 6 to 9 months. The incidence of recurrent restenosis, defined as diameter restenosis >= 50% in the in-segment area at follow-up angiography, and its clinical and angiographic predictors were evaluated. RESULTS: A total of 546 patients were combined in a single dataset. Angiographic follow-up at 6 to 9 months was available for 484 patients (88.6%) with 518 treated lesions. Recurrent restenosis was detected in 101 (20.8%) patients. On multivariable analysis, lesion length (OR, 1.58; 95%CI, 1.10-2.26; P=.012 for 5mm increase) and vessel size (OR, 1.42; 95%, 1.12-1.79; P=.003 for 0.5mm reduction) were independently associated with recurrent restenosis. CONCLUSIONS: In the largest cohort to date of individuals with angiographic surveillance after DCB angioplasty for DES restenosis, we demonstrated that recurrent restenosis occurs in approximately 1 out of 5 patients. Predictors of recurrent restenosis are increased lesion length and small vessel size. PMID- 28916430 TI - Therapeutic approaches to CFTR dysfunction: From discovery to drug development. AB - Cystic fibrosis (CF) mutations have complex effects on the cystic fibrosis transmembrane conductance regulator (CFTR) protein. They disrupt its processing to and stability at the plasma membrane and function as an ATP-gated Cl- channel. Here, we review therapeutic strategies to overcome defective CFTR processing and stability. Because CF mutations have multiple impacts on the assembly of CFTR protein, combination therapy with several pharmacological chaperones is likely to be required to rescue mutant CFTR expression at the plasma membrane. Alternatively, proteostasis regulators, proteins which regulate the synthesis, intracellular transport and membrane stability of CFTR might be targeted to enhance the plasma membrane expression of mutant CFTR. Finally, we consider an innovative approach to bypass CFTR dysfunction in CF, the delivery of artificial anion transporters to CF epithelia to shuttle Cl- across the apical membrane. The identification of therapies or combinations of therapies, which rescue all CF mutations, is now a priority. PMID- 28916431 TI - Cyclosporine for Chronic Spontaneous Urticaria: A Meta-Analysis and Systematic Review. AB - BACKGROUND: Despite widely recommended usage of cyclosporine A (CsA) in chronic spontaneous urticaria (CSU), there is no meta-analysis concerning its efficacy and safety. OBJECTIVE: To meta-analyze and review the efficacy and safety of CsA in CSU. METHODS: Efficacy was assessed by the relative change in urticaria activity score at 4 weeks and response rates at 4, 8, and 12 weeks. Safety was assessed by analyzing the number of patients with 1 or more adverse event. RESULTS: Eighteen studies (909 participants) including 2 randomized controlled trials were included, with 125, 363, and 266 patients with CSU receiving very low (<2 mg/kg/d), low (from 2 to< 4 mg/kg/d), and moderate (4-5 mg/kg/d) doses of CsA, respectively. After 4 weeks, the mean relative change in urticaria activity score of CsA-treated patients was -17.89, whereas that of controls was -2.3. The overall response rate to CsA treatment with low to moderate doses at 4, 8, and 12 weeks was 54%, 66%, and 73%, respectively. No studies of very low-dose CsA evaluated response rates at 4, 8, and 12 weeks. Among patients treated with very low, low, and moderate doses of CsA, 6%, 23%, and 57% experienced 1 or more adverse event, respectively. CONCLUSIONS: Given the limited number and quality of studies, our results should be interpreted with caution. CsA is effective at low to moderate doses. Adverse events appear to be dose dependent and occur in more than half the patients treated with moderate doses of CsA. We suggest that the appropriate dosage of CsA for CSU may range from 1 to 5 mg/kg/d, and 3 mg/kg/d is a reasonable starting dose for most patients. PMID- 28916432 TI - Rituximab as Induction Therapy in Eosinophilic Granulomatosis with Polyangiitis Refractory to Conventional Immunosuppressive Treatment: A 36-Month Follow-Up Analysis. AB - BACKGROUND: Rituximab (RTX) is approved for induction therapy of granulomatosis with polyangiitis and microscopic polyangiitis. In eosinophilic granulomatosis with polyangiitis (EGPA), organ-threatening manifestations are mainly treated with cyclophosphamide (CYC). RTX as treatment in EGPA has been described in small case series; however long-term data and the efficacy of RTX in EGPA refractory to CYC have not been reported yet. OBJECTIVES: To investigate the efficacy and safety of RTX and conventional immunosuppressive therapy with CYC in EGPA as induction therapy and during long-term follow-up. METHODS: Retrospective analysis of 28 patients with EGPA was done. Treatment response and disease activity were determined by Birmingham Vasculitis Activity Score, C-reactive protein, eosinophils, antineutrophil cytoplasmic antibody, and peripheral CD19+ B cells. RESULTS: Fourteen patients with EGPA treated with RTX were compared with 14 age- and sex-matched patients with EGPA treated with CYC for remission induction; 64% of the RTX-treated patients with EGPA had previously failed CYC treatment. Disease duration was longer and the number of previous immunosuppressants higher in RTX-treated patients. Five RTX-treated patients (36%) and 4 CYC-treated patients (29%) achieved complete remission. All other patients were in partial remission. There was no difference between both groups in respect to treatment response and partial and complete remission. In both treatment groups, eosinophils, C-reactive protein, and IgE levels dropped. Relapse-free survival within an observation period of 36 months was comparable between RTX- and CYC treated patients. RTX was well tolerated, but resulted in a decline in serum immunoglobulin levels. CONCLUSIONS: RTX was effective in inducing remission and during long-term follow-up in patients with EGPA, even when previously refractory to standard immunosuppressive therapy including CYC. RTX-treated patients should be monitored for hypogammaglobulinemia. PMID- 28916433 TI - Resilience in Families of Children With Autism and Sleep Problems Using Mixed Methods. AB - PURPOSE: About 80% of children with autism spectrum disorder (ASD) have sleep problems that may disrupt optimal family functioning. We explored the impact of sleep problems on families' resilience. DESIGN AND METHODS: An explanatory sequential mixed methods design was used to discern whether resilience differed between families whose children with ASD have or do not have sleep problems, to seek predictors for family hardiness/resilience, and to determine whether narrative findings support, expand, or conflict quantitative findings. RESULTS: Seventy complete surveys were returned from parents of children with ASD to compare sleep and family functioning. Fifty-seven children had sleep problems and six interviews regarding eight of these children were conducted. Parents of children with ASD and sleep problems had lower levels of resilience than those who slept well. Predictors of hardiness were social support, coping-coherence (stress management), and lower strain scores. Qualitative content analysis revealed a journey analogy with themes: finding the trailhead, dual pathways, crossing paths and choosing travel companions, forging new paths, resting along the way, and seeing the vistas. CONCLUSIONS: Qualitative findings supported quantitative findings regarding the impact of sleep problems but also expanded them by illustrating how families' resilience and children's socialization improved over time. Social support predicted family hardiness. Parents revealed that sleep issues contributed to family strains and described their progression to resilience and embracing their child. PRACTICE IMPLICATIONS: Findings support the need for community and provider advocacy and implicates a need for development of sleep interventions on behalf of families and children with ASD. PMID- 28916434 TI - Effects of ICOS+ T cell depletion via afucosylated monoclonal antibody MEDI-570 on pregnant cynomolgus monkeys and the developing offspring. AB - MEDI-570 is a fully human afucosylated monoclonal antibody (MAb) against Inducible T-cell costimulator (ICOS), highly expressed on CD4+ T follicular helper (TFH) cells. Effects of MEDI-570 were evaluated in an enhanced pre postnatal development toxicity (ePPND) study in cynomolgus monkeys. Administration to pregnant monkeys did not cause any abortifacient effects. Changes in hematology and peripheral blood T lymphocyte subsets in maternal animals and infants and the attenuated infant IgG immune response to keyhole limpet hemocyanin (KLH) were attributed to MEDI-570 pharmacology. Adverse findings included aggressive fibromatosis in one dam and two infant losses in the high dose group with anatomic pathology findings suggestive of atypical lymphoid hyperplasia. The margin of safety relative to the no observed adverse effect level (NOAEL) for the highest planned clinical dose in the Phase 1a study was 7. This study suggests that women of child bearing potential employ effective methods of contraception while being treated with MEDI-570. PMID- 28916435 TI - A novel electrochemical immunosensor based on ITO modified by carboxyl-ended silane agent for ultrasensitive detection of MAGE-1 in human serum. AB - A new, low-cost electrochemical immunosensor was developed for rapid detection of Melanoma-associated antigen 1 (MAGE-1), a cancer biomarker. The fabrication procedure of immunosensor was based on the covalent immobilization of anti-MAGE 1, biorecognition molecule, on ITO electrode by carboxyethylsilanetriol (CTES) monolayer. The biosensing MAGE-1 antigen was monitored by using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) technique. Apart from these techniques, single frequency impedance (SFI) was used for investigation of antibody-antigen interactions. Scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM) were utilized for characterization of the proposed biosensor. To fabricate highly sensitive, good stability immunosensor, some parameters were optimized. Under optimal conditions, the developed electrochemical immunosensor for MAGE-1 exhibited a dynamic range of 4 fg/mL and 200 fg/mL with a low detection limit of 1.30 fg/mL. It had acceptable repeatability (5.05%, n = 20) and good storage stability (3.58% loss after 10 weeks). Moreover, this electrochemical immunosensor has been successfully applied to the determination of MAGE-1 in human serum samples. PMID- 28916436 TI - Treating Overactive Bladder in Older Patients with a Combination of Mirabegron and Solifenacin: A Prespecified Analysis from the BESIDE Study. AB - BACKGROUND: The BESIDE study demonstrated that combination therapy (mirabegron and solifenacin 5mg) improved overactive bladder symptoms versus solifenacin 5mg or 10mg, and was well tolerated. OBJECTIVE: To ensure efficacy and safety is maintained in older patients (>65 yr), who usually experience greater symptom severity and comorbidities, a prespecified subanalysis stratified by age group was conducted. DESIGN, SETTING, AND PARTICIPANTS: Patients remaining incontinent (>=1 episode during 3-d diary) following 4-wk single-blind daily solifenacin 5mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5mg and mirabegron 25mg, increased to 50mg at wk 4), solifenacin 5mg or 10mg for 12 wk. Four cohorts stratified by age (<65 yr, >=65 yr and < 75 yr, >=75 yr) were investigated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary) and micturition frequency (key secondary), number of incontinence episodes during the 3-d diary (key secondary), and change from baseline in average daily urgency and urgency incontinence episodes. Safety included treatment-emergent adverse events and vital signs. RESULTS AND LIMITATIONS: Full analysis set included 2110 patients: 30.9% aged >=65 yr and 8.9% aged >=75 yr. At the end of treatment, daily, and 3-d incontinence daily micturitions, urgency, and urgency incontinence, were improved in each treatment group and age group; the largest reductions were observed with combination in each age cohort. There were no notable differences in vital signs or the incidence of treatment-emergent adverse events between treatment and age groups, with the exception of dry mouth, which was highest with solifenacin 10mg. CONCLUSIONS: Efficacy and safety in the overall population is maintained in older (>=65 yr) and elderly (>=75 yr) patients treated with a combination of solifenacin and mirabegron, or solifenacin monotherapy; irrespective of age, combination was associated with the greatest improvement in overactive bladder symptoms. PATIENT SUMMARY: This study investigated the effectiveness and safety of a combination of two different treatments (mirabegron 50mg and solifenacin 5mg) or solifenacin (5mg or 10mg) alone in patients aged <65 yr or >=65 yr, and <75 yr or >=75 yr with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the toilet, incontinence, and frequent urination, were improved with all treatments regardless of the patient's age, but combination treatment demonstrated the greatest benefit, and was well tolerated. PMID- 28916437 TI - Sex-specific 99th percentiles derived from the AACC Universal Sample Bank for the Roche Gen 5 cTnT assay: Comorbidities and statistical methods influence derivation of reference limits. AB - OBJECTIVES: Our purpose was to determine a) overall and sex-specific 99th percentile upper reference limits (URL) and b) influences of statistical methods and comorbidities on the URLs. METHODS: Heparin plasma from 838 normal subjects (423 men, 415 women) were obtained from the AACC (Universal Sample Bank). The cobas e602 measured cTnT (Roche Gen 5 assay); limit of detection (LoD), 3ng/L. Hemoglobin A1c (URL 6.5%), NT-proBNP (URL 125ng/L) and eGFR (60mL/min/1.73m2) were measured, along with identification of statin use, to better define normality. 99th percentile URLs were determined by the non-parametric (NP), Harrell-Davis Estimator (HDE) and Robust (R) methods. RESULTS: 355 men and 339 women remained after exclusions. Overall<50% of subjects had measureable concentrations >= LoD: 45.6% no exclusion, 43.5% after exclusion; compared to men: 68.1% no exclusion, 65.1% post exclusion; women: 22.7% no exclusion, 20.9% post exclusion. The statistical method used influenced URLs as follows: pre/post exclusion overall, NP 16/16ng/L, HDE 17/17ng/L, R not available; men NP 18/16ng/L, HDE 21/19ng/L, R 16/11ng/L; women NP 13/10ng/L, HDE 14/14ng/L, R not available. CONCLUSIONS: We demonstrated that a) the Gen 5 cTnT assay does not meet the IFCC guideline for high-sensitivity assays, b) surrogate biomarkers significantly lowers the URLs and c) statistical methods used impact URLs. Our data suggest lower sex-specific cTnT 99th percentiles than reported in the FDA approved package insert. We emphasize the importance of detailing the criteria used to include and exclude subjects for defining a healthy population and the statistical method used to calculate 99th percentiles and identify outliers. PMID- 28916438 TI - Analytical sensitivity and diagnostic performance of serum protein electrophoresis on the HYDRAGEL 30 PROTEIN(E) beta1-beta2 Sebia Hydrasys system. AB - BACKGROUND: Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) are used in the diagnosis and monitoring of plasma cell dyscrasias. IFE is considered the most sensitive method for the detection of monoclonal proteins (M-proteins), but it is not quantitative. The goal of this study was to establish the analytical sensitivity and diagnostic performance of SPE on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN(E) beta1-beta2. METHODOLOGY: Patient sera with a previously identified M-protein (IgG, IgA or IgM) were serially diluted with a normal serum pool and electrophoresed on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN(E) beta1-beta2. The SPE gels were individually interpreted by five independent observers and IFE was performed on selected samples. Limit of detection was determined as the lowest concentration of M protein band visible on the gel. SPE diagnostic performance was evaluated against the "gold standard" IFE according CLSI EP12-A2 guidelines. RESULTS: Detection limit was comparable among all M-proteins migrating in the gamma region, IgG kappa (0.18+/-0.08g/L; n=6), IgG-lambda (0.36+/-0.25g/L; n=8), IgA-kappa (0.40+/ 0.13g/L; n=7), IgA-lambda (0.37+/-0.23g/L; n=4), IgM-kappa (0.47+/-0.20g/L; n=13) and IgM-lambda (0.29+/-0.24g/L; n=6). Percentage agreement with IFE for IgG and IgA in the gamma region ranged from 65% to 100%, whereas IgM migrating in the gamma region and immunoglobulins co-migrating with alpha or beta globulins, showed poor (0-38%) agreement. CONCLUSIONS: This study evaluates the analytical sensitivity and diagnostic performance of SPE on the Sebia Hydrasys using HYDRAGEL 30 PROTEIN(E) beta1-beta2. There was acceptable agreement between SPE and IFE for IgG-kappa/lambda and IgA-kappa/lambda migrating in the gamma region, suggesting that repeating IFE for samples with these isotypes, when the previous IFE and second SPE are both negative, may not be necessary. PMID- 28916439 TI - On the path to evidence-based reporting of serum protein electrophoresis patterns in the absence of a discernible monoclonal protein - A critical review of literature and practice suggestions. PMID- 28916440 TI - White matter microstructure within the superior longitudinal fasciculus modulates the degree of response conflict indexed by N2 in healthy adults. AB - Response conflict can be induced by priming multiple responses competing for control of action in trials. The N2 is one functionally-related cognitive control index for response conflict. And yet the underlying whiter matter neural substrates of inter-individual difference in conflict N2 remain unclear. So the aim of present study was to address the white matter microstructure of the N2 responsible for conflict by directly relating the amplitude cost of the event related potential (ERP) N2 component to diffusion tensor imaging (DTI) indices in healthy subjects. Thirty healthy subjects underwent DTI scanning and electrophysiology recording during a modified Flanker task. N2 was a stimulus locked negative ERP component. Fractional anisotropy (FA) was calculated based on DTI measures and was assumed to reflect the integrity of myelinate fiber bundles. Therefore, we tested the relationship between N2 amplitude and FA in brain white matter. Results showed that FA, an index for white matter characteristics, in the right superior longitudinal fasciculus (SLF) was significantly positively associated with N2 amplitude cost. The N2 amplitude cost also predicted response time (RT) cost in the Flanker task. Higher FA was associated with larger N2 amplitude cost, suggesting that changes in white matter integrity in the SLF may account for changes in efficient transmission of fronto-parietal modulatory conflict signals. PMID- 28916441 TI - Monoamine involvement in the antidepressant-like effect induced by P2 blockade. AB - Depression is a common mental disorder that affects millions of individuals worldwide. Available monoaminergic antidepressants are far from ideal since they show delayed onset of action and are ineffective in approximately 40% of patients, thus indicating the need of new and more effective drugs. ATP signaling through P2 receptors seems to play an important role in neuropathological mechanisms involved in depression, since their pharmacological or genetic inactivation induce antidepressant-like effects in the forced swimming test (FST). However, the mechanisms involved in these effects are not completely understood. The present work investigated monoamine involvement in the antidepressant-like effect induced by non-specific P2 receptor antagonist (PPADS) administration. First, the effects of combining sub-effective doses of PPADS with sub-effective doses of fluoxetine (FLX, selective serotonin reuptake inhibitor) or reboxetine (RBX, selective noradrenaline reuptake inhibitor) were investigated in mice submitted to FST. Significant antidepressant-like effect was observed when subeffective doses of PPADS was combined with subeffective doses of either FLX or RBX, with no significant locomotor changes. Next, the effects of depleting serotonin and noradrenaline levels, by means of PCPA (p-Chlorophenylalanine) or DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively, was investigated. Both, PCPA and DSP-4 pretreatment partially attenuated PPADS-induced effects in FST, without inducing relevant locomotor changes. Our results suggest that the antidepressant-like effect of PPADS involves modulation of serotonin and noradrenaline levels in the brain. PMID- 28916442 TI - Acute stress promotes post-injury brain regeneration in fish. AB - The central nervous system and the immune system, the two major players in homeostasis, operate in the ongoing bidirectional interaction. Stress is the third player that exerts strong effect on these two 'supersystems'; yet, its impact is studied much less. In this work employing carp model, we studied the influence of preliminary stress on neural and immune networks involved in post injury brain regeneration. The relevant in vivo models of air-exposure stress and precisely directed cerebellum injury have been developed. Neuronal regeneration was evaluated by using specific tracers of cell proliferation and differentiation. Involvement of immune networks was accessed by monitoring the expression of selected T cells markers. Contrast difference between acute and chronic stress manifested in the fact that chronically stressed fish did not survive the brain injury. Neuronal regeneration appeared as a biphasic process whereas involvement of immune system proceeded as a monophasic route. In stressed fish, immune response was fast and accompanied or even preceded neuronal regeneration. In unstressed subjects, immune response took place on the second phase of neuronal regeneration. These findings imply an intrinsic regulatory impact of acute stress on neuronal and immune factors involved in post-injury brain regeneration. Stress activates both neuronal and immune defense mechanisms and thus contributes to faster regeneration. In this context, paradoxically, acute preliminary stress might be considered a distinct asset in speeding up the following post-injury brain regeneration. PMID- 28916444 TI - Treating malaria: new drugs for a new era. PMID- 28916443 TI - AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial. AB - BACKGROUND: Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS: We did a randomised, non-inferiority trial. We screened men (>=18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (>=2000 asexual P falciparum parasites per MUL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638.50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319.25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 MUL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964. FINDINGS: Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2-4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (<=grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93.9%] of 33; p=0.50) and AQ-13 was not inferior to artemether plus lumefantrine (difference -6.1%, 95% CI -14.7 to 2.4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84.8% for AQ-13 vs 31 of 33, 93.9% for artemether and lumefantrine; p=0.43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9.1%, 95% CI -5.6 to 23.8). INTERPRETATION: The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. FUNDING: US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs Wellcome Fund, US State Department, and WHO. PMID- 28916445 TI - Preparation of intracellular proteins from a white-rot fungus surrounded by polysaccharide sheath and optimization of their two-dimensional electrophoresis for proteomic studies. AB - The functions and properties of fungal sheath, an extracellular polysaccharide produced by many white-rot fungi, have been studied. However, the strong adherence of the sheath to fungal hyphae had been a major impediment in preparing intracellular proteins from the fungi and analyzing their cellular responses. To overcome this issue, we developed a rapid and easy method to remove the polysaccharide sheath using a selective lignin degrader, Ceriporiopsis subvermispora, which produces large sheath amounts in the presence of a lignin derived aromatic compound. Using this approach, we achieved thorough removal of sheath and cell disruption using beads and a solution with a high protein solubilizing power, which enabled the efficient extraction of intracellular proteins from C. subvermispora surrounded by sheath. In addition, for proteomic analysis, we investigated whether these extracted proteins were compatible with two-dimensional electrophoresis. By efficiently concentrating on protein solubilization in the first dimension and using a stacking gel in the second dimension, we successfully obtained a high-resolution proteome map of C. subvermispora. We also used the same proteins for fluorescence two-dimensional difference gel electrophoresis to obtain the quantitative protein expression profiles. These steps demonstrated that two-dimensional electrophoresis-based proteomics can be used to clarify the composition of intracellular proteins from sheath-producing white-rot fungi. PMID- 28916446 TI - Cancer-derived exosomes as a delivery platform of CRISPR/Cas9 confer cancer cell tropism-dependent targeting. AB - An intracellular delivery system for CRISPR/Cas9 is crucial for its application as a therapeutic genome editing technology in a broad range of diseases. Current vehicles carrying CRISPR/Cas9 limit in vivo delivery because of low tolerance and immunogenicity; thus, the in vivo delivery of genome editing remains challenging. Here, we report that cancer-derived exosomes function as natural carriers that can efficiently deliver CRISPR/Cas9 plasmids to cancer. Compared to epithelial cell-derived exosomes, cancer-derived exosomes provide potential vehicles for effective in vivo delivery via selective accumulation in ovarian cancer tumors of SKOV3 xenograft mice, most likely because of their cell tropism. CRISPR/Cas9 loaded exosomes can suppress expression of poly (ADP-ribose) polymerase-1 (PARP 1), resulting in the induction of apoptosis in ovarian cancer. Furthermore, the inhibition of PARP-1 by CRISPR/Cas9-mediated genome editing enhances the chemosensitivity to cisplatin, showing synergistic cytotoxicity. Based on these results, tumor-derived exosomes may be very promising for cancer therapeutics in the future. PMID- 28916447 TI - Perception of Caucasian and African faces in 5- to 9-month-old Caucasian infants: A functional near-infrared spectroscopy study. AB - Race is an important perceptual cue for face perception. In adults, other-race faces are elaborated differently and remembered less well than own-race faces. Moreover, they show a different pattern of activation at the neural level. Developmental studies demonstrated that, during the first year of life, infants start to show the same behavioral pattern as adults in race perception. However, little is known about where and how in the brain other-race perception is elaborated in this population. The present study is the first to investigate the development of different neural responses to faces of different race in infants using functional near-infrared spectroscopy (fNIRS). Specifically, a group of 5 month-old and a group of 9-month-old Caucasian infants were assessed during passing-viewing of Caucasian and African faces. Results showed a greater activation for African than for Caucasian faces for both oxy- and deoxy hemoglobin. Moreover, results suggested a tendency for a progressive specialization between 5 and 9 months of age. This is the first fNIRS study investigating the neural correlates of race perception in Caucasian infants during the first year of life. PMID- 28916448 TI - Molecular and synaptic mechanisms regulating drug-associated memories: Towards a bidirectional treatment strategy. AB - The successful treatment of substance use disorders is dependent on the establishment of a long-term abstinent state. Relapse can be suppressed by interfering with memories of drug use that are evoked by re-exposure to drug associated contexts and cues. Two strategies for accomplishing this goal are either to prevent drug-memory reconsolidation or to induce the formation of a competing, extinction memory. However, clinical attempts to prolong abstinence by behavioral modification of drug-related memories have had limited success. One approach to improve behavioral treatment strategies is to identify the molecular mechanisms that regulate these memory processes and then use pharmacological tools as supplements to improve efficacy. Still, due to the involvement of several overlapping signaling cascades in both reconsolidation and extinction, it is difficult to specifically modify one of the two processes. For example, attempting to elicit extinction may instead initiate reconsolidation, resulting in the unintentional strengthening of drug-related memories. A better approach is to identify diverging components of the two processes, whereby a single medication would simultaneously weaken reconsolidation and enhance extinction. This review will provide an overview of the neural substrates that are involved in the regulation of drug-associated memories, and will discuss emerging approaches to pharmacologically weaken these memories, including recent efforts to precisely and bidirectionally target reconsolidation and extinction. Ultimately, pharmacologically-enhanced memory-based approaches have the potential to produce more informed relapse-prevention therapies. PMID- 28916449 TI - Bio-scaffolds in organ-regeneration: Clinical potential and current challenges. AB - Cadaveric organ transplantation represents the definitive treatment option for end-stage disease but is restricted by the shortage of clinically-viable donor organs. This limitation has, in part, driven current research efforts for in vitro generation of transplantable tissue surrogates. Recent advances in organ reconstruction have been facilitated by the re-purposing of decellularized whole organs to serve as three-dimensional bio-scaffolds. Notably, studies in rodents indicate that such scaffolds retain native extracellular matrix components that provide appropriate biochemical, mechanical and physical stimuli for successful tissue/organ reconstruction. As such, they support the migration, adhesion and differentiation of reseeded primary and/or pluripotent cell populations, which mature and achieve functionality through short-term conditioning within specialized tissue bioreactors. Whilst these findings are encouraging, significant challenges remain to up-scale the present technology to accommodate human-sized organs and thereby further the translation of this approach towards clinical use. Of note, the diverse structural and cellular composition of large mammalian organ systems mean that a "one-size fits all" approach cannot be adopted either to the methods used for their decellularization or the cells required for subsequent re-population, to create fully functional entities. The present review seeks to highlight the clinical potential of decellularized organ bio-scaffolds as a route to further advance the field of tissue- and organ regeneration, and to discuss the challenges which are yet to be addressed if such a technology is ever to become a credible rival to conventional organ allo transplantation. PMID- 28916450 TI - Capsule switching of Neisseria meningitidis sequence type 7 serogroup A to serogroup X. AB - OBJECTIVES: The bacterial pathogen Neisseria meningitidis is able to escape the currently available capsule-based vaccines by undergoing capsule switching. In this study, we investigated whether capsule switching has occurred in a recently emerged sequence type (ST) 7 serogroup X isolate in China, for which currently no vaccine is available. METHODS: To identify capsule switching breakpoints, the capsule locus and flanking regions of the ST-7 serogroup X isolate and three endemic ST-7 serogroup A isolates were sequenced and compared. To obtain further insight into capsule switching frequency and length of DNA fragments involved, capsule switching assays were performed using genomic DNA containing combinations of antibiotic selection markers at various locations in the capsule locus and flanking regions. RESULTS: Sequence analyses showed that capsule switching has occurred and involved a 8450 bp serogroup X DNA fragment spanning the region from galE to ctrC. Capsule switching assays indicate that capsule switching occurs at a frequency of 6.3 * 10-6 per bacterium per MUg of DNA and predominantly involved DNA fragments of about 8.1-9.6 kb in length. CONCLUSIONS: Our results show that capsule switching in N. meningitidis occurs at high frequency and involves recombination in the flanking regions of the capsule biosynthesis genes. PMID- 28916451 TI - Switches in a genetic regulatory system under multiplicative non-Gaussian noise. AB - The non-Gaussian noise is multiplicatively introduced to model the universal fluctuation in the gene regulation of the bacteriophage lambda. To investigate the key effect of non-Gaussian noise on the genetic on/off switch dynamics from the viewpoint of quantitative analysis, we employ the high-order perturbation expansion to deduce the stationary probability density of repressor concentration and the mean first passage time from low concentration to high concentration and vice versa. The occupation probability of different concentration states can be estimated from the height and shape of the peaks of the stationary probability density, which could be used to determine the overall expression level. A further concern is the mean first passage time, also referred to as the mean switching time, which can be adopted as an important measure to characterize the adaptability of gene expression to the environmental variation. Through our investigation, it is observed that the non-Gaussian heavy-tailed noise can better induce the switches between distinct genetic expression states and additionally, it accelerates the switching process more evidently compared to the Gaussian noise and the bounded noise. PMID- 28916452 TI - Symbolic dynamics of animal interaction. AB - Since its introduction nearly two decades ago, transfer entropy has contributed to an improved understanding of cause-and-effect relationships in coupled dynamical systems from raw time series. In the context of animal behavior, transfer entropy might help explain the determinants of leadership in social groups and elucidate escape response to predator attacks. Despite its promise, the potential of transfer entropy in animal behavior is yet to be fully tested, and a number of technical challenges in information theory and statistics remain open. Here, we examine an alternative approach to the computation of transfer entropy based on symbolic dynamics. In this context, a symbol is associated with a specific locomotory bout across two or more consecutive time instants, such as reversing the swimming direction. Symbols encapsulate salient locomotory patterns and the associated permutation transfer entropy quantifies the ability to predict the patterns of an individual given those of another individual. We demonstrate this framework on an existing dataset on fish, for which we have knowledge of the underlying cause-and-effect relationship between the focal subject and the stimulus. Symbolic dynamics offers an intuitive and robust approach to study animal behavior, which could enable the inference of causal relationship from noisy experimental observations of limited duration. PMID- 28916453 TI - Making the Legal and Ethical Case for Universal Screening for Postpartum Mood and Anxiety Disorders in Pediatric Primary Care. AB - Postpartum depression (PPD), part of a larger spectrum of perinatal mood and anxiety disorders, affects up to 15% of women following the birth of an infant. Fathers may also be affected. PPD not only affects caregivers, but also impacts infants through mechanisms such as inadequate caregiver-infant interactions and non-adherence to safety practices. The negative impact on infants may extend across the life course through adulthood. This article seeks to move the needle toward universal screening for PPD using validated tools in pediatric primary care settings for new caregivers by making the legal and ethical case for this course of action in a manner that is both compelling and accessible for clinicians. Toward this end, we summarize current literature as it applies to provider responsibilities, liabilities and perspectives; and caregiver autonomy, confidentiality, and privacy. We then assess utility by balancing the benefits and burdens of this approach to practices, providers, and caregivers; and take the analysis one step further by looking across multiple populations to assess distributive justice. We conclude that there is a strong ethical case for universal screening for PPD in pediatric primary care settings using validated tools when informed consent can be obtained and appropriate follow-up services are available and accessible. Clinical considerations, practical resources, and areas ripe for future research are also addressed. PMID- 28916454 TI - Anti-Acanthamoeba activity of Tunisian Thymus capitatus essential oil and organic extracts. AB - Acanthamoeba species are free-living amoebae widely distributed in the environment and which cause serious human infections. The treatment of Acanthamoeba infections is always very difficult and not constantly effective. More efficient drugs against Acanthamoeba must be developed and medicinal plants can be useful in this case. Our research focused on the examination of the anti Acanthamoeba activity of the essential oil and the ethanolic-aqueous extract from Thymus capitatus L. The essential oil showed best activity with an IC50 of 2.73 MUg/ml. The conducted Bio-guided fractionation of thyme extract result to the identification of two active compounds against the trophozoite stage of Acanthamoeba: thymol and 2,3-dihydroxy-p-cymene. The results have clearly shown that the investigated products may be successfully used against Acanthamoeba infections. These molecules that are found in plants may be an alternative for the development of new drugs. PMID- 28916455 TI - Essential oil composition and anti Acanthamoeba studies of Teucrium ramosissimum. AB - The aim of the present study was to evaluate the chemical composition of the essential oil obtained from the aerial parts of T. ramosissimum by hydrodistillation and to investigate their anti-Acanthamoeba activity. Identification and quantification were realized by gas chromatography-mass spectrometry (GC-MS) and gas chromatography with flame ionization detection by (GC-FID). Sixty-eight compounds representing 97.78% of the essential oil were identified, of which delta-cadinene (18.63%), delta-cadinol (18.70%), beta eudesmol (12.13%), gamma-gurjunene (4.34%) and 8-cedrene (3.99%) were the main compounds. This essential oil contained a complex mixture consisting mainly on sesquiterpenes (80.62%) and monoterpene fractions (14.34%). The findings of the anti-Acanthamoeba assay indicate that T. ramosissimum essential oil have a good activity with an IC50 = 25.73 +/- 0.75 MUg/mL. PMID- 28916456 TI - Acanthamoebicidal activity of periglaucine A and betulinic acid from Pericampylus glaucus (Lam.) Merr. in vitro. AB - Acanthamoeba species are pathogenic protozoa which account for amoebic keratitis, conjunctivitis and granulomatous amoebic encephalitis. These amoebae form cysts which resist drugs and more effective acanthamoebicidal agents are needed. Medicinal plants could be useful in improving the current treatment strategies for Acanthamoeba infections. In the present study, we examined the amoebicidal effects of Pericampylus glaucus (Lam.) Merr., a medicinal plant used for the treatment of conjunctivitis in Malaysia. Pathogenic Acanthamoeba triangularis were isolated from environmental water samples and treated with different concentrations of fractions obtained from Pericampylus glaucus (Lam.) Merr. as well as main constituents for 24-72 h. Chlorhexidine was used as a reference drug. Ethanol fraction of stem showed significant (p < 0.05) inhibition of trophozoites survival. Betulinic acid and periglaucine A from this plant at 100 MUg/mL inhibited more than 70% survival of both cysts and trophozoites. The calculated therapeutic index for betulinic acid and periglaucine A was 170 and 1.5 for trophozoites stage and 3.75 and 8.5 for cysts stage. The observed amoebicidal efficacies indicate the beneficial aspects of this plant in the treatment of Acanthamoeba infection. Periglaucine A could also be of value for the treatment of Acanthamoeba infection. PMID- 28916457 TI - In vitro activity of 1H-phenalen-1-one derivatives against Acanthamoeba castellanii Neff and their mechanisms of cell death. AB - Acanthamoeba is an opportunistic pathogen which is the causal agent of a sight threatening ulceration of the cornea known as Acanthamoeba keratitis (AK) and, more rarely, an infection of the central nervous system called "granulomatous amoebic encephalitis" (GAE). The symptoms of AK are non-specific, and so it can be misdiagnosed as a viral, bacterial, or fungal keratitis. Furthermore, current therapeutic measures against AK are arduous, and show limited efficacy against the cyst stage of Acanthamoeba. 1H-Phenalen-1-one (PH) containing compounds have been isolated from plants and fungi, where they play a crucial role in the defense mechanism of plants. Natural as well as synthetic PHs exhibit a diverse range of biological activities against fungi, protozoan parasites or human cancer cells. New synthetic PHs have been tested in this study and they show a potential activity against this protozoa. PMID- 28916458 TI - Molecular identification of waterborne free living amoebae (Acanthamoeba, Naegleria and Vermamoeba) isolated from municipal drinking water and environmental sources, Semnan province, north half of Iran. AB - The present study tested 80 samples of municipal, geothermal and recreational water samples for the occurrence of waterborne free living amoebae (FLA) including Acanthamoeba, Balamuthia mandrillaris, Vahlkampfiids and Vermamoeba in Semnan province, North half of Iran. Four sets of primers including JDP1,2 primers, ITS1,2 primers (Vahlkampfiids), 16S rRNABal primers (Balamuthia mandrillaris) and NA1,2 primers (Vermamoeba) were used to confirm the morphological identification. From the 80 water samples tested in the present study, 16 (20%) were positive for the outgrowth of free living amoebae based on the morphological page key. Out of the 34 municipal water samples, 7 (20.6%) were positive for outgrowth of Free living amoeba, belonging to Vermamoeba, Naegleria and Acanthamoeba using molecular tools. Three out of the six investigated hot springs were also contaminated with Naegleria spp. Sequencing of the ITS1,2 region of the Vahlkampfiid isolates revealed the highest homology with N. gruberi (2 isolates), N. australiensis (1 isolate) and N. pagei (3 isolates). This is the first report of N. gruberi in the country. Using morphological and molecular analysis, Balamuthia mandrillaris was undetected in all the water samples. The present study further confirmed the occurrence of potentially pathogenic waterborne free living amoebae in habitats with high human activity. It is of utmost importance that more studies are conducted to evaluate the niches of B. mandrillaris and N. fowleri in Iran and worldwide. Such investigations regarding the relevance of FLA as a hazard to humans, should be brought to the notice of the health authorities. PMID- 28916459 TI - Variation in Campylobacter jejuni culturability in presence of Acanthamoeba castellanii Neff. AB - Free-living amoebae (FLA) are protozoa that are widely distributed in the environment mainly in water and soil related habitats. These amoebae have also been reported to be associated with some bacterial pathogens for humans such as Campylobacter spp. The species C. jejuni is the causative agent of about 90% of human campylobacteriosis cases worldwide and this disease may even end up in severe autoimmune sequelae as Guillain-Barre syndrome (GBS). In this study, the interactions between the strain Acanthamoeba castellanii Neff and Campylobacter jejuni was investigated. Campylobacter jejuni was coincubated with Acanthamoeba castellanii Neff trophozoites at different temperatures, in order to evaluate the C. jejuni ability to grow in presence A. castellanii culture and Acanthamoeba Conditioned Medium (ACM). C. jejuni was coincubated with A. castellanii axenic culture at different temperatures in aerobic conditions. Our results revealed that bacteria were still cultivable (Blood Agar medium, at 37 degrees C, in microaerophilic atmosphere) after a 14 days C. jejuni - A. castellanii coculture, comparing with C. jejuni alone, which was only cultivable for 24 h. PMID- 28916460 TI - The effect of viroid infection of citrus trees on the amoebicidal activity of 'Maltese half-blood' (Citrus sinensis) against trophozoite stage of Acanthamoeba castellanii Neff. AB - In order to promote a local Tunisian product, this study was designed to examine, for the first time, the anti-Acanthamoeba activity (Acanthamoeba castellanii Neff) of the essential oils of Tunisian Citrus sinensis peels (Maltese half blood) and the effect of viroid plant infection on this activity. To do so, three samples of peels' essential oils were studied: from a healthy plant (Control), a plant inoculated with Citrus exocortis viroid (CEVd) and one inoculated with hot stunt cachexia viroid (HSVd). The samples were extracted by hydrodistillation from dried peels and characterized by GC-MS. Limonene was the major component with a percentage ranging from 90.76 to 93.34% for (CEVd) sample and (Control), respectively. Anti-Acanthamoeba activity of the tested oils was determined by the Alamar Blue(r) assay. Primary results showed a strong potential anti-Acanthamoeba activity with an IC50 ranging from 36.6 to 54.58 MUg/ml for (HSVd) and (CEVd) samples, respectively. In terms of the effect of viroid infection, a strong positive correlation was observed between different chemical classes and anti Acanthamoeba activity. PMID- 28916461 TI - Metabolic engineering of Escherichia coli for the synthesis of the quadripolymer poly(glycolate-co-lactate-co-3-hydroxybutyrate-co-4-hydroxybutyrate) from glucose. AB - Escherichia coli was metabolically engineered to effectively produce a series of biopolymers consisted of four types of monomers including glycolate, lactate, 3 hydroxybutyrate and 4-hydroxybutyrate from glucose as the carbon source. The biosynthetic route of novel quadripolymers was achieved by the overexpression of a range of homologous and heterologous enzymes including isocitrate lyase, isocitrate dehydrogenase kinase/phosphatase, glyoxylate/hydroxypyruvate reductase, propionyl-CoA transferase, beta-ketothiolase, acetoacetyl-CoA reductase, succinate semialdehyde dehydrogenase, 4-hydroxybutyrate dehydrogenase, CoA transferase and PHA synthase. In shake flask cultures using Luria-Bertani medium supplemented with glucose, the recombinant E. coli reached 7.10g/l cell dry weight with 52.60wt% biopolymer content. In bioreactor study, the final cell dry weight was 19.61g/l, containing 14.29g/l biopolymer. The structure of the produced polymer was chemically characterized by proton NMR analysis. Assessment of thermal and mechanical properties demonstrated that the quadripolymer possessed decreased crystallinity and improved toughness, in comparison to poly-3 hydroxybutyrate homopolymer. This is the first study reporting efficient microbial production of the quadripolymer poly(glycolate-co-lactate-co-3 hydroxybutyrate-co-4-hydroxybutyrate) from glucose. PMID- 28916462 TI - Causation, constructors and codes. AB - Relational biology relies heavily on the enriched understanding of causal entailment that Robert Rosen's formalisation of Aristotle's four causes has made possible, although to date efficient causes and the rehabilitation of final cause have been its main focus. Formal cause has been paid rather scant attention, but, as this paper demonstrates, is crucial to our understanding of many types of processes, not necessarily biological. The graph-theoretic relational diagram of a mapping has played a key role in relational biology, and the first part of the paper is devoted to developing an explicit representation of formal cause in the diagram and how it acts in combination with efficient cause to form a mapping. I then use these representations to show how Von Neumann's universal constructor can be cast into a relational diagram in a way that avoids the logical paradox that Rosen detected in his own representation of the constructor in terms of sets and mappings. One aspect that was absent from both Von Neumann's and Rosen's treatments was the necessity of a code to translate the description (the formal cause) of the automaton to be constructed into the construction process itself. A formal definition of codes in general, and organic codes in particular, allows the relational diagram to be extended so as to capture this translation of formal cause into process. The extended relational diagram is used to exemplify causal entailment in a diverse range of processes, such as enzyme action, construction of automata, communication through the Morse code, and ribosomal polypeptide synthesis through the genetic code. PMID- 28916463 TI - Penile Prosthesis Implantation in Priapism. AB - INTRODUCTION: Priapism is defined as a full or partial erection lasting longer than 4 hours after sexual stimulation and orgasm or unrelated to sexual stimulation. The main goal of priapism management is to resolve the episode immediately to preserve erectile function and penile length. Corporal smooth muscle necrosis is likely to have already occurred, and medically refractory erectile dysfunction is expected in patients with a protracted episode. Penile prosthesis implantation (PPI) in the early or late phase of priapism can restore erectile function. AIM: To review the literature on PPI in priapism. METHODS: A PubMed search of all English-language articles published before 2017 was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement using the following search terms: penile prosthesis implantation, priapism, and corporal fibrosis. All publications reporting on PPI during or after priapism episodes were included for review. MAIN OUTCOME MEASURES: Three types of priapism were reviewed for management using PPI. Surgical techniques, outcomes, and patient satisfaction were reported. RESULTS: Early implantation (during the episode) is technically easier and has lower complication rates compared with delayed (electively, after the erectile dysfunction is observed) surgery. Immediate PPI also allows preservation of penile length, which is related to higher satisfaction rates. CONCLUSIONS: The paradigm is shifting toward immediate PPI in the management of ischemic priapism. Patients with non-ischemic priapism or recurrent priapism, even without a major ischemic episode, are at high risk for erectile dysfunction and are candidates for PPI. Yucel OB, Pazir Y, Kadioglu A. Penile Prosthesis Implantation in Priapism. Sex Med Rev 2018;6:310-318. PMID- 28916464 TI - Adhesion procedure for CAD/CAM resin crown bonding: Reduction of bond strengths due to artificial saliva contamination. AB - PURPOSE: The present study aimed to elucidate how saliva contamination affects microtensile bond strength of resin cement to CAD/CAM resin blocks and identify a decontamination method that can restore original bond strength. METHODS: The KATANA AVENCIA block (Kuraray Noritake Dental) was sandblasted on the adherend surface (P-Co group). Then, the block was contaminated with artificial saliva (Saliveht Aerosol, Teijin). Air dry (N-Co), sandblasting (Sb) and phosphate acid cleaning (AT) groups were prepared. After silane treatment, PANAVIA V5 (Kuraray Noritake Dental) was built up and microtensile bond strength (MUTBS) was measured after immersion in water (n=24 per group). Scanning electron microscopy (SEM) analysis, surface roughness and contact angle measurement of each surface were performed. RESULTS: The P-Co group showed the highest MUTBS value, and bond strength was significantly lower in the N-Co group than the other groups (P<0.001). In all groups, decreased bond strength resulted from long-term water storage. In the N-Co group, a contaminated layer was observed on the surface by SEM and the contact angle was significantly smaller than the other groups (P<0.001). In Sb and AT groups, MUTBS values that were reduced by artificial saliva contamination significantly increased but did not recover to P-Co group values (P<0.001). SEM showed no morphological difference between P-Co, Sb and AT groups. The Sb group showed increased surface roughness. CONCLUSION: The long term durability of bonds between CAD/CAM resin blocks and luting agent cement was significantly reduced by artificial saliva contamination. However, sandblasting or phosphoric acid cleaning can recover bonding effectiveness by 75-85%. PMID- 28916465 TI - Corrosive effects of fluoride on titanium under artificial biofilm. AB - PURPOSE: This study aimed to investigate the effect of sodium fluoride (NaF) on titanium corrosion using a biofilm model, taking environmental pH into account. METHODS: Streptococcus mutans cells were used as the artificial biofilm, and pH at the bacteria-titanium interface was monitored after the addition of 1% glucose with NaF (0, 225 or 900ppmF) at 37 degrees C for 90min. In an immersion test, the titanium samples were immersed in the NaF solution (0, 225 or 900ppm F; pH 4.2 or 6.5) for 30 or 90min. Before and after pH monitoring or immersion test, the electrochemical properties of the titanium surface were measured using a potentiostat. The amount of titanium eluted into the biofilm or the immersion solution was measured using inductively coupled plasma mass spectrometry. The color difference (DeltaE*ab) and gloss of the titanium surface were determined using a spectrophotometer. RESULTS: After incubation with biofilm, pH was maintained at around 6.5 in the presence of NaF. There was no significant change in titanium surface and elution, regardless of the concentration of NaF. After immersion in 900ppm NaF solution at pH 4.2, corrosive electrochemical change was induced on the surface, titanium elution and DeltaE*ab were increased, and gloss was decreased. CONCLUSIONS: NaF induces titanium corrosion in acidic environment in vitro, while NaF does not induce titanium corrosion under the biofilm because fluoride inhibits bacterial acid production. Neutral pH fluoridated agents may still be used to protect the remaining teeth, even when titanium-based prostheses are worn. PMID- 28916467 TI - Safety evaluation for ingredients used in baby care products: Consideration of diaper rash. AB - Diaper rash can adversely impact the barrier properties of skin, with potential implications for increased absorption of chemicals through the skin, and this should be accounted for in any exposure assessment used in the safety evaluation of consumer products used in the diaper ("nappy") area. In the absence of a quantitative evaluation of the potential impact of diaper rash, a default assumption of 100% dermal penetration is often made for substances applied in the diaper area. We consider here the extent, duration and severity of diaper rash and make a recommendation for conservative assumptions to incorporate into exposure assessments. Using a time-weighted average, the potential impact of diaper rash is illustrated for substances that have varying degrees of absorption through healthy skin. Results confirm that for assessments that already assume dermal absorption of 50% or higher, there is no impact on the overall exposure assessment. For substances that have a very low degree of dermal penetration (1%) through healthy skin, the impact of rash is expected to be less-than four-fold. This can be refined with additional data as there are many examples of poorly absorbed compounds for which dermal penetration is still low even for compromised skin. PMID- 28916466 TI - A multi-centered epidemiological study evaluating the validity of the treatment difficulty indices developed by the Japan Prosthodontic Society. AB - PURPOSE: The Japan Prosthodontic Society developed a multi-axis assessment protocol to evaluate the complex variations in patients who need prosthodontic care, and to classify the level of treatment difficulty. A previous report found the protocol to be sufficiently reliable. The purpose of this multi-center cohort study was to evaluate the validity of this multi-axis assessment protocol. METHODS: The treatment difficulty was evaluated using the multi-axis assessment protocol before starting prosthodontic treatment. The time required for active prosthodontic treatment, medical resources such as treatment cost, and changes in the oral health-related QOL before and after treatment, were evaluated after treatment completion. The construct validity of this protocol was assessed by the correlation between the dentist's pre-operative subjective assessment of the treatment difficulty, and the level of difficulty determined by this protocol. The predictive validity was assessed estimating the correlations between a "comprehensive level of treatment difficulty" based on the four axes of this protocol and total treatment cost, total treatment time, and changes in the oral health-related QOL before and after treatment. RESULTS: The construct validity of this protocol was well documented except for psychological assessment. Regarding the predictive validity, the comprehensive level of treatment difficulty assessed before treatment was significantly correlated with the three surrogate endpoints known to be related to the treatment difficulty (total treatment cost, treatment time, and improvement in the oral health-related QOL). To further clarify the validity of the protocol according to patients' oral condition, a subgroup analysis by defects was performed. Analyses revealed that treatment difficulty assessment before treatment was significantly related to one or two surrogate endpoints in the fully edentulous patients and the partially edentulous patients. No significant relationship was observed in the patients with mixture of full/partial edentulism and the patients with teeth problems, possibly due to the small sample size in these groups. CONCLUSION: This study revealed that the multi axis assessment protocol was sufficiently valid to predict the level of treatment difficulty in prosthodontic care in patients with fully edentulous defects and with partially edentulous defects. PMID- 28916468 TI - Dermal absorption for pesticide health risk assessment: Harmonization of study design and data reporting for North American Regulatory submissions. AB - Although an internationally-adopted in vitro dermal absorption test guideline is available (OECD Test Guideline 428), the replacement of the in vivo approach in North America for pesticide formulations has not occurred due to concern over the reliability and consistency of the in vitro results. A 2012 workshop convened a panel of experts in the conduct of in vitro studies used for pesticide risk assessment, together with North American regulators, to examine techniques for in vitro dermal absorption testing. Discussions led to the recommended "best practices" for the conduct of in vitro dermal absorption studies provided herein. The workshop participants also developed recommendations for reporting study results in order to improve the quality and consistency of the data submitted to regulatory agencies in North America. Finally, a case study is presented that illustrates the use of the "triple-pack" approach; the studies, conducted for the registration of sulfoxaflor, follow the standardized recommendations provided at the workshop. In addressing the concerns of these regulators and of the regulated community, and providing harmonized recommendations to facilitate comparative data analyses, it is anticipated that wider acceptance of in vitro dermal absorption studies alone can be achieved for pesticide risk assessment. PMID- 28916469 TI - Activity changes in the left superior temporal sulcus reflect the effects of childcare training on young female students' perceptions of infants' negative facial expressions. AB - In many developed countries, the number of infants who experience non-parent childcare is increasing, and the role of preschool teachers is becoming more important. However, little attention has been paid to the effects of childcare training on students who are studying to become preschool teachers. We used functional magnetic resonance imaging (fMRI) to investigate whether and how childcare training affects brain responses to infants' facial expressions among young females studying to become preschool teachers. Twenty-seven subjects who attended a childcare training session (i.e., the experimental group) and 28 subjects who did not attend the training (i.e., the control group) participated in this study. The participants went through fMRI scanning twice: before and after the childcare training session. They were presented with happy, neutral, and sad infant faces one by one during fMRI scanning. The present neuroimaging results revealed that the activity patterns of the left superior temporal sulcus (STS) for sad faces were modulated by the interaction between the time point of the data collection and group differences. The present results are the first to highlight the effects of childcare training on the human brain. PMID- 28916470 TI - Receptive field properties of cat perigeniculate neurons correlate with excitatory and inhibitory connectivity to LGN relay neurons. AB - The cat perigeniculate nucleus (PGN) is a visual sector of the thalamic reticular nucleus that consists of GABAergic neurons. It receives excitatory axon collateral input from relay neurons of the dorsal lateral geniculate nucleus (LGN) to which it provides inhibitory input. Thus, it is usually argued that the PGN works as feedback inhibition to the LGN. At the single neuron level, however, this circuit can also provide lateral inhibition. Which inhibition dominates in the visual circuit of the thalamus has yet to be well characterized. In this study, we conducted cross-correlation analysis of single spike trains simultaneously recorded from PGN and LGN neurons in anesthetized cats. For 12 pairs of functionally connected PGN and LGN neurons with overlapped receptive fields (RF), we quantitatively compared RF properties including the spatial frequency (SF) and temporal frequency (TF) tunings of each neuron. We found the SF and TF tunings of PGN neurons and LGN neurons were similar when there was only excitatory input from the LGN neuron to the PGN neuron, but different when the PGN neuron returned inhibitory inputs back, suggesting the circuit between PGN and LGN neurons works as lateral inhibition for these properties. PMID- 28916471 TI - The Pyk2/MCU pathway in the rat middle cerebral artery occlusion model of ischemic stroke. AB - Mitochondrial dysfunction caused by Ca2+ overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca2+ uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca2+ uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress-induced cellular apoptosis. In this study, we explored the role of the Pyk2/MCU pathway in the ischemic brain following a stroke injury. We found that the Pyk2/MCU pathway is activated in a rat cerebral ischemia model, and is responsible for mitochondrial dysfunction and neuronal apoptosis. Inhibiting the Pyk2/MCU pathway with a Pyk2 inhibitor (PF-431396) prevented mitochondrial Ca2+ overload, mitochondrial injury, proapoptotic protein release, and cell death. Interestingly, human urinary kallidinogenase (HUK) alleviated neuronal ischemic injury by inhibiting the Pyk2/MCU pathway, suggesting that the Pyk2/MCU pathway may be a protective target for ischemic stroke treatment. PMID- 28916472 TI - Characterizing thiol redox dynamics in the organogenesis stage rat embryo. AB - Precise control of the glutathione (GSH): glutathione disulfide (GSSG) balance is vital for the developing embryo, but it is not yet well understood how GSH levels and the GSH redox state are regulated, maintained, and modulated over the course of mammalian embryonic development. In this study, we characterize and connect thiol redox dynamics, protein synthesis, volumetric growth and net cysteine fluxes over the course of early organogenesis (gestational day (GD) 10-GD11.13) in the rat embryo. Our results show that despite a significant exponential growth of conceptal volumes and protein mass, the GSH: GSSG redox balance is remarkably stable during early organogenesis, with distinct redox potentials for the visceral yolk sac (VYS) (- 218mV) and the embryo proper (EMB) (- 222mV). The yolk sac was found to play a key role in maintaining GSH levels and the GSH: GSSG redox balance in the developing embryo. Based on an overall cysteine (Cys) mass balance, we show that until GD10.6, yolk sac supply of Cys, the rate-limiting precursor for GSH synthesis, is sufficient to sustain embryonic demands for its GSH synthesis and protein synthesis needs. After GD10.6, the EMB maintains the amino acid intake flux, resulting in a significant depletion of most thiols in the amniotic fluid and the yolk sac fluid. Cysteine, was found to be predominantly used for de novo protein synthesis in the developing embryo (approximately 90% of total Cys). Protein synthesis (rates) should thus be included in any quantitative assessment of GSH redox dynamics in the developing embryo. Our time-course dataset of thiol dynamics, developed exponential relationships for protein synthesis and volumetric growth, and yolk sac surface area-mediated protein influx, provide important quantitative insights in GSH redox dynamics during embryonic development and are a prerequisite to further develop quantitative 'systems biology' models for GSH metabolism in the developing embryo. PMID- 28916474 TI - Nox4 regulates the eNOS uncoupling process in aging endothelial cells. AB - ROS and its associated signaling contribute to vascular aging-associated endothelial disturbance. Since the non-effective endothelial nitric oxide synthase (eNOS) coupling status is related to vascular aging-related phenotypes, eNOS coupled/uncoupled system signaling was studied in human umbilical vein endothelial cells (HUVEC). Nitric oxide (NO) and eNOS Ser1177 were significantly decreased, whereas O2- (superoxide anion radical) increased with passage number. In aging cells, NADPH oxidase 4 (Nox4), one of the main superoxide generating enzymes, and its associated protein disulfide isomerase (PDI) chaperone were highly activated, and the resultant ER redox imbalance leads to disturbance of protein folding capability, namely endoplasmic reticulum (ER) stress, ultimately inducing dissociation between HSP90 and IRE-1alpha or PERK, decreasing HSP90 stability and dissociating the binding of eNOS from the HSP90 and leading to eNOS uncoupling. Through chemical and Nox4 siRNA approaches, Nox4 and its linked ER stress were shown to mainly contribute to eNOS uncoupling and its associated signaling, suggesting that Nox4 and its related ER stress signaling are key signals of the aging process in endothelial cells. PMID- 28916473 TI - Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation. AB - NADPH oxidases (NOX) have many biological roles, but their regulation to control production of potentially toxic ROS molecules remains unclear. A previously identified insertion sequence of 21 residues (called NIS) influences NOX activity, and its predicted flexibility makes it a good candidate for providing a dynamic switch controlling the NOX active site. We constructed NOX2 chimeras in which NIS had been deleted or exchanged with those from other NOXs (NIS1, 3 and 4). All contained functional heme and were expressed normally at the plasma membrane of differentiated PLB-985 cells. However, NOX2-DeltaNIS and NOX2-NIS1 had neither NADPH-oxidase nor reductase activity and exhibited abnormal translocation of p47phox and p67phox to the phagosomal membrane. This suggested a functional role of NIS. Interestingly after activation, NOX2-NIS3 cells exhibited superoxide overproduction compared with wild-type cells. Paradoxically, the Vmax of purified unstimulated NOX2-NIS3 was only one-third of that of WT-NOX2. We therefore hypothesized that post-translational events regulate NOX2 activity and differ between NOX2-NIS3 and WT-NOX2. We demonstrated that Ser486, a phosphorylation target of ataxia telangiectasia mutated kinase (ATM kinase) located in the NIS of NOX2 (NOX2-NIS), was phosphorylated in purified cytochrome b558 after stimulation with phorbol 12-myristate-13-acetate (PMA). Moreover, ATM kinase inhibition and a NOX2 Ser486Ala mutation enhanced NOX activity whereas a Ser486Glu mutation inhibited it. Thus, the absence of Ser486 in NIS3 could explain the superoxide overproduction in the NOX2-NIS3 mutant. These results suggest that PMA-stimulated NOX2-NIS phosphorylation by ATM kinase causes a dynamic switch that deactivates NOX2 activity. We hypothesize that this downregulation is defective in NOX2-NIS3 mutant because of the absence of Ser486. PMID- 28916475 TI - Deletion of NADH oxidase in Listeria monocytogenes promotes the bacterial infection of brain. AB - NADH oxidase (NOX) plays important roles in respiration and reactive oxygen species (ROS) generation in cells. In this study, we explored the function of NOX in Listeria monocytogenes by gene deletion. From our results, nox mutant strain (?nox) had lower H2O2 level and showed no significant alteration in bacteria growth activity. But it had enhanced invasiveness during the invasion of glial cells and mice brain compared to wildtype strain. Furthermore, several virulence genes involved in invasion, such as inlA, inlB, vip and sigB, were upregulated in ?nox, and the alterations could be restored by complementation. To explore if nox was involved in the interaction of pathogen and host, we examined the generation of host ROS including superoxide and H2O2 during infection, and found ?nox invasion leading to less superoxide and H2O2 generation. Besides, the upregulation of pro-inflammatory factors in glial cells was restrained when invaded by ?nox compared to wildtype and complementary strain. In conclusion, our study evaluated the function of nox in L. monocytogenes and indicated that nox could regulate the invasion of L. monocytogenes by regulating virulence genes expression and the interaction of host-and- pathogens. PMID- 28916476 TI - Pharmacologic ascorbate induces neuroblastoma cell death by hydrogen peroxide mediated DNA damage and reduction in cancer cell glycolysis. AB - An ascorbate-mediated production of oxidative stress has been shown to retard tumor growth. Subsequent glycolysis inhibition has been suggested. Here, we further define the mechanisms relevant to this observation. Ascorbate was cytotoxic to human neuroblastoma cells through the production of H2O2, which led to ATP depletion, inhibited GAPDH, and non-apoptotic and non-autophagic cell death. The mechanism of cytotoxicity is different when PARP-dependent DNA repair machinery is active or inhibited. Ascorbate-generated H2O2 damaged DNA, activated PARP, depleted NAD+, and reduced glycolysis flux. NAD+ supplementation prevented ATP depletion and cell death, while treatment with a PARP inhibitor, olaparib, preserved NAD+ and ATP levels but led to increased DNA double-strand breakage and did not prevent ascorbate-induced cell death. These data indicate that in cells with an intact PARP-associated DNA repair system, ascorbate-induced cell death is caused by NAD+ and ATP depletion, while in the absence of PARP activation ascorbate-induced cell death still occurs but is a consequence of ROS-induced DNA damage. In a mouse xenograft model, intraperitoneal ascorbate inhibited neuroblastoma tumor growth and prolonged survival. Collectively, these data suggest that ascorbate could be effective in the treatment of glycolysis dependent tumors. Also, in cancers that use alternative energy metabolism pathways, combining a PARP inhibitor with ascorbate treatment could be useful. PMID- 28916477 TI - NSE serum levels in extracorporeal life support patients-Relevance for neurological outcome? AB - BACKGROUND: Good neurological outcome is a major determinant after cardiac resuscitation. Extracorporeal life support may rapidly stabilize the patient, but cerebral ischemia remains a frequent complication relevant for further therapy. The aim of this study was to prove the value of NSE to indicate cerebral injury in patients with extracorporeal support after CPR. METHODS: 159 patients with CPR were included. NSE 48h peak levels and trends were tested for usability as predictive marker of brain injury, in-hospital mortality and long-term outcome. RESULTS: Overall mortality in this cohort was 53.5%. Incidence of relevant brain injury was 34.6% with severe diffuse hypoxia in 23.2%. NSE peaks were comparable in patients with and without focal ischemia, but were increased in patients with severe diffuse hypoxic injury (p<0.0001). ROC analysis (area under the curve) of peak values indicating brain injury and in-hospital mortality was 0.73 (95% confidence interval [CI] 0.65-0.82) and 0.74 (95% CI 0.66-0.81), respectively. NSE increased in 56.6% of patients with a sensitivity of 0.82 (95% CI 0.69-0.92) and a specificity of 0.43 (CI 0.0.31-0.55) indicating cerebral injury. Sensitivity and specificity of NSE peak levels >100MUg/L was 0.6 (CI 0.49-0.72) and 0.74 (CI 0.63-0.84). In-hospital mortality of patients with NSE >100MUg/L was 71.7%. 46.2% of discharged patients are in good neurological status (cerebral performance category scale [CPC] 1-2). Patients with NSE <100MUg/L showed an in hospital mortality of 36.4%, and good neurological status in 67.9%. CONCLUSION: NSE monitoring reliably indicates relevant cerebral injury in patients on extracorporeal support after cardiopulmonary resuscitation. PMID- 28916478 TI - A retrospective study of pulseless electrical activity, bedside ultrasound identifies interventions during resuscitation associated with improved survival to hospital admission. A REASON Study. AB - OBJECTIVE: Our objective was to determine whether organized or disorganized cardiac activity is associated with increased survival in patients who present in pulseless electrical activity (PEA) treated with either 1) standard advanced cardiac life support (ACLS) medications or 2) other interventions. METHODS: This was a secondary analysis of a prospective, multi-center observational study utilizing ultrasound in out-of-hospital or inemergency department PEA arrest. Bedside ultrasound was performed as ACLS protocol started and during pulse checks. Only cases with visible cardiac activity on ultrasound were included in the present analysis. Cardiac activity was categorized as disorganized (agonal twitching) or organized (contractions with changes in ventricular dimensions). Patients were categorized as receiving either standard bolus ACLS medications or alternative medications during the resuscitation (continuous adrenergic agents, thrombolytics, others). The primary outcome was survival to hospital admission. The secondary outcome was return of spontaneous circulation (ROSC). Multivariate modeling was performed to assess association between survival to hospital admission in patients with intravenous adrenergic agents and cardiac activity. RESULTS: In our cohort of 225 patients in PEA cardiac arrest with cardiac activity on ultrasound, the overall survival rate was higher in patients with organized cardiac activity than with disorganized cardiac activity. PEA cardiac arrest patients with organized cardiac activity treated with standard ACLS interventions demonstrated improved survival to hospital admission compared to those with disorganized activity (37.7% (95%CI 24.8-50.2%) versus 17.9% (95%CI 10.9-28%). PEA cardiac arrest patients with organized cardiac activity who received continuous adrenergic agents during the resuscitation and prior to ROSC demonstrated higher survival to hospital admission 45.5% (95%CI 26.9-65.4%) and ROSC 90.9% (95%CI 71.0-98.7%) compared to those with disorganized cardiac activity who received continuous adrenergic agents during the resuscitation 0% (95%CI 0-23.0%) and 47.1% (95%CI 26-69%). Regression analysis demonstrates an association between increased survival in patients receiving intravenous adrenergic agents and organized cardiac activity. CONCLUSION: Survival in patients following PEA arrest is higher in patients with organized cardiac activity. The initiation of continuous adrenergic agents during PEA was associated with improved survival to hospital admission in patients with organized cardiac activity on bedside ultrasound, but this improvement was not seen in patients in PEA with disorganized cardiac activity. Bedside ultrasound may identify a subset of patients that respond differently to ACLS interventions. PMID- 28916481 TI - Identification of 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate as a novel inhibitor to Y box binding protein-1 (YB-1) and its therapeutic actions against breast cancer. AB - In spite of advances in breast cancer treatment and early diagnosis, drug toxicity, cancer relapse, multidrug resistance and metastasis are the major impediment to the developments of efficient drugs. However, unique druggable targets of cancer cells distinct from the normal cells provide new rationale in cancer treatment. Previous reports clearly emphasize the differential expression and localization of Y box binding protein-1 (YB-1) between normal breast tissues and different stages of breast cancer. Y box binding protein-1 is DNA as well as RNA binding protein involved in transcription and translation regulation of various proteins involved in cancer progression, apoptosis, cell cycle, epithelial to mesenchymal transition (EMT) and drug resistance. Particularly, during doxorubicin (DOX) treatment and cancer relapse conditions, YB-1 expression was very high in breast cancer tissues and localized in to nucleus which further favours DOX efflux and metastasis. Moreover, siRNA mediated silencing of YB-1 reduces breast cancer progression and metastasis. In this rationale, using an array of computational methods, 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate (DPI) has been screened out as a drug-likeness antagonist to the YB-1for cancer treatment. In this study, we determined that DPI was toxic to breast cancer cell lines as individual drug as well as in combination with DOX. Moreover, immunofluorescence and confocal studies showed that DPI decreases DOX induced YB 1 nuclear translocation and increases DOX accumulation in breast cancer cell line. A G1/G0 phase cell cycle arrest and apoptosis was also induced by DPI. Moreover, DPI modulated YB-1 downstream targets such as p53, caspase-3, CDK-1 which are involved in cell cycle progression and apoptosis. Further, metastatic functional analysis revealed that DPI inhibits cell adhesion, migration, invasion in aggressive metastatic cell line and inhibits angiogenesis in chick embryonic chorioallantoic membrane (CAM) model. Meanwhile, DPI alters the expression of YB 1 downstream targets which are involved in metastasis such as VEGFR, caveolin, E cadherin, cytokeratins, desmin and vimentin in MDA-MB-231 xenograft in chick embryonic CAM membrane. The results clearly demonstrated that DPI inhibited YB-1 nuclear translocation, thereby exhibited anti-apoptotic, anti-proliferative and anti-metastatic activities and increases the therapeutic potential of commercial breast cancer drug doxorubicin. PMID- 28916479 TI - Dietary Nitrate Increases VO2peak and Performance but Does Not Alter Ventilation or Efficiency in Patients With Heart Failure With Reduced Ejection Fraction. AB - BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) exhibit lower efficiency, dyspnea, and diminished peak oxygen uptake (VO2peak) during exercise. Dietary nitrate (NO3-), a source of nitric oxide (NO), has improved these measures in some studies of other populations. We determined the effects of acute NO3- ingestion on exercise responses in 8 patients with HFrEF using a randomized, double-blind, placebo-controlled, crossover design. METHODS AND RESULTS: Plasma NO3-, nitrite (NO2-), and breath NO were measured at multiple time points and respiratory gas exchange was determined during exercise after ingestion of beetroot juice containing or devoid of 11.2 mmol of NO3-. NO3- intake increased (P < .05-0.001) plasma NO3- and NO2- and breath NO by 1469 +/- 245%, 105 +/- 34%, and 60 +/- 18%, respectively. Efficiency and ventilation during exercise were unchanged. However, NO3- ingestion increased (P < .05) VO2peak by 8 +/- 2% (ie, from 21.4 +/- 2.1 to 23.0 +/- 2.3 mL.min-1.kg-1). Time to fatigue improved (P < .05) by 7 +/- 3 % (ie, from 582 +/- 84 to 612 +/- 81 seconds). CONCLUSIONS: Acute dietary NO3- intake increases VO2peak and performance in patients with HFrEF. These data, in conjunction with our recent data demonstrating that dietary NO3- also improves muscle contractile function, suggest that dietary NO3- supplementation may be a valuable means of enhancing exercise capacity in this population. PMID- 28916480 TI - Factors Associated With Zonular Instability During Cataract Surgery in Eyes With Acute Angle Closure Attack. AB - PURPOSE: To compare the demographics and ocular characteristics, including anterior segment optical coherence tomography images and zonular instability, in eyes with a history of acute angle closure (AAC) attack and subsequent cataract surgery. DESIGN: Retrospective case-control study. METHODS: A total of 68 eyes of 56 patients with a history of AAC attack who underwent cataract surgery were enrolled. Fourteen eyes were assigned to the zonular instability (+) group and 54 were assigned to the zonular instability (-) group based on the presence of zonular instability during cataract surgery. The peak intraocular pressure, preoperative spherical equivalent (SE), axial length (AL), anterior chamber depth (ACD), and lens vault (LV) were measured and compared between 2 groups. Intereye (intraindividual) comparison was also performed. Factors associated with zonular instability were assessed. RESULTS: In the zonular instability (+) group, 9 eyes were from male and 5 from female participants. Eyes in the zonular instability (+) group showed less hyperopic SE values, longer AL, shallower ACD, and higher LV, as compared with those in the zonular instability (-) group (all P <= .001). Moreover, eyes in the zonular instability (+) group had less hyperopic SE, shallower ACD, and higher LV than their fellow eyes. Less hyperopic SE, longer AL, and higher LV were significantly associated with zonular instability on multivariate logistic regression analysis. CONCLUSIONS: Clinicians should consider the possibility of zonular instability during cataract surgery for eyes with less hyperopic SE, longer AL, and higher LV among those with a history of AAC attack. PMID- 28916482 TI - Disposition of treosulfan and its active monoepoxide in a bone marrow, liver, lungs, brain, and muscle: Studies in a rat model with clinical relevance. AB - For the recent years, the application of treosulfan (TREO)-based conditioning prior to hematopoietic stem cell transplantation (HSCT) has been increasing as an alternative to busulfan-based therapy, especially for patients presenting high risk of developing hepato-, pulmo-, and neurotoxicity. So far, the penetration of TREO and its epoxy-derivatives into central nervous system and aqueous humor of the eye has been investigated. However, lacking knowledge on the compounds distribution into the other key tissues precludes comprehensive understanding and assessment of TREO clinical efficacy and toxicity. In this paper, the disposition of TREO and its active monoepoxide (S,S-EBDM) in a bone marrow, liver, lungs, brain, and quadriceps femoris was studied in an animal model. Male and female adult Wistar rats (n=48/48) received an intraperitoneal injection of TREO at the dose of 500mg/kg b.w. Concentrations of TREO and S,S-EBDM in tissues were determined with a validated HPLC-MS/MS method. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis. Mean values of the maximal concentrations of TREO and S,S-EBDM in the organs were sex-independent and ranged from 61 to 1650MUM and 25-105MUM, respectively. No quantifiable levels of S,S-EBDM were found in the liver. Average tissue/plasma area under the curve (AUC) ratio for unbound TREO increased in the sequence: brain (0.10)=16weeks of gestation in anticoagulated patients. STUDY DESIGN: Clinicians involved in a professional listserv (2011-2013) reported cases of abortion >=16weeks of gestation in anticoagulated women. RESULTS: All 7 patients were using or had recently discontinued low molecular weight heparin (LMWH). One patient was reported to have greater than anticipated blood loss for gestational age. No patients required transfusion and no complications were reported. CONCLUSIONS: Our limited case series suggests D&E may not always be contraindicated in women with recent or current LMWH use. PMID- 28916485 TI - Moderate intravenous sedation for first trimester surgical abortion: a comparison of adverse outcomes between obese and normal-weight women. AB - OBJECTIVE: To determine if obese women experience increased rates of adverse outcomes with moderate intravenous sedation during first trimester surgical abortion compared to normal weight women. STUDY DESIGN: We performed a retrospective cohort study of all first trimester surgical abortions with moderate intravenous sedation at an outpatient facility between September 2010 and June 2015. The primary outcome was supplemental oxygen administration. Secondary outcomes included reversal agent administration, anesthesia-related adverse events, and intraoperative lowest level of consciousness (LLOC). We compared three obesity groups [I (Body Mass Index, BMI=30-34.9), II (BMI=35 39.9), and III (BMI >=40)] to normal weight women (BMI <25). We exported data from electronic medical records and reviewed adverse outcomes individually. RESULTS: Of 20,381 first trimester surgical abortion procedures, 31 (0.15%) utilized supplemental oxygen, 24 (0.12%) utilized a reversal agent, 40 (0.20%) had a presumed anesthesia-related adverse event and 184 of 19,725 (0.93%) had a documented low intraoperative LLOC. One patient (0.005%) required hospital transfer or hospitalization. Supplemental oxygen administration (obesity versus normal weight: obese I, aOR 0.52, 95% CI 0.12-2.27; II/III, aOR 1.51, 95% CI 0.50 4.54), low intraoperative LLOC, and anesthesia-related adverse events were not associated with obesity. The rate of reversal agent administration was lower among obese I, II and III women combined compared to normal weight women (aOR 0.13, 95% CI 0.02-0.96). CONCLUSIONS: Adverse outcomes were rare across all BMI categories with no detectable increased risk among obese women compared to normal weight women. IMPLICATIONS: With appropriate clinical screening, obese women can safely receive moderate intravenous sedation for first trimester surgical abortion in an outpatient clinical setting. Restrictions on moderate intravenous sedation based on BMI alone may be unnecessary. PMID- 28916486 TI - EMT, inflammation and metastasis. PMID- 28916487 TI - A novel statistical model for analyzing data of a systematic review generates optimal cutoff values for fractional exhaled nitric oxide for asthma diagnosis. AB - OBJECTIVES: Measurement of fractional exhaled nitric oxide (FENO) might substitute bronchial provocation for diagnosing asthma. However, optimal FENO thresholds for diagnosing asthma remain unclear. We reanalyzed data collected for a systematic review investigating the diagnostic accuracy of FENO measurement to exploit all available thresholds under consideration of pretest probabilities using a newly developed statistical model. STUDY DESIGN AND SETTING: One hundred and fifty data sets for a total of 53 different cutoffs extracted from 26 studies with 4,518 participants were analyzed with the multiple thresholds model. This model allows identifying thresholds at which the test is likely to perform best. RESULTS: Diagnosing asthma might only be possible in a meaningful manner when the pretest probability of asthma is at least 30%. In that case, FENO > 50 ppb leads to a positive predictive value of 0.76 [95% confidence interval (CI): 0.29-0.96]. Excluding asthma might only be possible, when the pretest probability of asthma is 30% at maximum. Then, FENO < 20 ppb leads to a negative predictive value of 0.86 (95% CI 0.66-0.95). CONCLUSION: The multiple thresholds model generates a more comprehensive and more clinically useful picture of the effects of different thresholds, which facilitates the determination of optimal thresholds for diagnosing or excluding asthma with FENO measurement. PMID- 28916488 TI - Decision making about healthcare-related tests and diagnostic test strategies. Paper 2: a review of methodological and practical challenges. AB - OBJECTIVES: In this first of a series of five articles, we provide an overview of how and why healthcare-related tests and diagnostic strategies are currently applied. We also describe how our findings can be integrated with existing frameworks for making decisions that guide the use of healthcare-related tests and diagnostic strategies. STUDY DESIGN AND SETTING: We searched MEDLINE, references of identified articles, chapters in relevant textbooks, and identified articles citing classic literature on this topic. RESULTS: We provide updated frameworks for the potential roles and applications of tests with suggested definitions and practical examples. We also discuss study designs that are commonly used to assess tests' performance and the effects of tests on people's health. These designs include diagnostic randomized controlled trials and retrospective validation. We describe the utility of these and other currently suggested designs, which questions they can answer and which ones they cannot. In addition, we summarize the challenges unique to decision-making resulting from the use of tests. CONCLUSION: This overview highlights current challenges in the application of tests in decision-making in healthcare, provides clarifications, and informs the proposed solutions. PMID- 28916489 TI - Reply to: comparative effectiveness medicines research cannot assess efficacy. PMID- 28916490 TI - Decision making about healthcare-related tests and diagnostic test strategies. Paper 3: a systematic review shows limitations in most tools designed to assess quality and develop recommendations. AB - OBJECTIVES: The objective of this study was to identify and describe critical appraisal tools designed for assessing the quality of evidence (QoE) and/or strength of recommendations (SoRs) related to health care-related tests and diagnostic strategies (HCTDSs). STUDY DESIGN AND SETTING: We conducted a systematic review to identify tools applied in guidelines, methodological articles, and systematic reviews to assess HCTDS. RESULTS: We screened 5,534 titles and abstracts, 1,004 full-text articles, and abstracted data from 330 references. We identified 29 tools and 14 modifications of existing tools for assessing QoE and SoR. Twenty-three out of 29 tools acknowledge the importance of assessing the QoE and SoR separately, but in 8, the SoR is based solely on QoE. When making decisions about the use of tests, patient values and preferences and impact on resource utilization were considered in 6 and 8 tools, respectively. There is also confusion about the terminology that describes the various factors that influence the QoE and SoR. CONCLUSION: Although at least one approach includes all relevant criteria for assessing QoE and determining SoR, more detailed guidance about how to operationalize these assessments and make related judgments will be beneficial. There is a need for a better description of the framework for using evidence to make decisions and develop recommendations about HCTDS. PMID- 28916491 TI - Controversy and debate on clinical genomics sequencing-paper 2: clinical genome wide sequencing: don't throw out the baby with the bathwater! AB - Genome-wide (exome or whole genome) sequencing with appropriate genetic counseling should be considered for any patient with a suspected Mendelian disease that has not been identified by conventional testing. Clinical genome wide sequencing provides a powerful and effective means of identifying specific genetic causes of serious disease and improving clinical care. PMID- 28916492 TI - Overcoming ocular drug delivery barriers through the use of physical forces. AB - Overcoming the physiological barriers in the eye remains a key obstacle in the field of ocular drug delivery. While ocular barriers naturally have a protective function, they also limit drug entry into the eye. Various pharmaceutical strategies, such as novel formulations and physical force-based techniques, have been investigated to weaken these barriers and transport therapeutic agents effectively to both the anterior and the posterior segments of the eye. This review summarizes and discusses the recent research progress in the field of ocular drug delivery with a focus on the application of physical methods, including electrical fields, sonophoresis, and microneedles, which can enhance penetration efficiency by transiently disrupting the ocular barriers in a minimally or non-invasive manner. PMID- 28916493 TI - Cell-mediated enzyme prodrug cancer therapies. AB - Cell-directed gene therapy is a promising new frontier for the field of targeted cancer therapies. Here we discuss the current pre-clinical and clinical use of cell-mediated enzyme prodrug therapy (EPT) directed against solid tumors and avenues for further development. We also discuss some of the challenges encountered upon translating these therapies to clinical trials. Upon sufficient development, cell-mediated enzyme prodrug therapy has the potential to maximize the distribution of therapeutic enzymes within the tumor environment, localizing conversion of prodrug to active drug at the tumor sites thereby decreasing off target toxicities. New combinatorial possibilities are also promising. For example, when combined with viral gene-delivery vehicles, this may result in new hybrid vehicles that attain heretofore unmatched levels of therapeutic gene expression within the tumor. PMID- 28916495 TI - Enzymes as key features in therapeutic cell mimicry. AB - Cell mimicry is a nature inspired concept that aims to substitute for missing or lost (sub)cellular function. This review focuses on the latest advancements in the use of enzymes in cell mimicry for encapsulated catalysis and artificial motility in synthetic bottom-up assemblies with emphasis on the biological response in cell culture or more rarely in animal models. Entities across the length scale from nano-sized enzyme mimics, sub-micron sized artificial organelles and self-propelled particles (swimmers) to micron-sized artificial cells are discussed. Although the field remains in its infancy, the primary aim of this review is to illustrate the advent of nature-mimicking artificial molecules and assemblies on their way to become a complementary alternative to their role models for diverse biomedical purposes. PMID- 28916496 TI - Designer bacteria as intratumoural enzyme biofactories. AB - Bacterial-directed enzyme prodrug therapy (BDEPT) is an emerging form of treatment for cancer. It is a biphasic variant of gene therapy in which a bacterium, armed with an enzyme that can convert an inert prodrug into a cytotoxic compound, induces tumour cell death following tumour-specific prodrug activation. BDEPT combines the innate ability of bacteria to selectively proliferate in tumours, with the capacity of prodrugs to undergo contained, compartmentalised conversion into active metabolites in vivo. Although BDEPT has undergone clinical testing, it has received limited clinical exposure, and has yet to achieve regulatory approval. In this article, we review BDEPT from the system designer's perspective, and provide detailed commentary on how the designer should strategize its development de novo. We report on contemporary advancements in this field which aim to enhance BDEPT in terms of safety and efficacy. Finally, we discuss clinical and regulatory barriers facing BDEPT, and propose promising approaches through which these hurdles may best be tackled. PMID- 28916494 TI - Transflammation: Innate immune signaling in nuclear reprogramming. AB - Induction of pluripotency in somatic cells by retroviral overexpression of four transcription factors has revolutionized the field of stem cell biology and regenerative medicine. The efficient induction of pluripotency requires the activation of innate immune signaling in a process termed "transflammation" (Lee et al., 2012). Specifically, the stimulation of pattern recognition receptors (PRRs) causes global alterations in the expression and activity of epigenetic modifiers to favor an open chromatin configuration. Activation of toll-like receptors (TLR) or RIG-1-like receptors (RLR) (Sayed et al. 2017) trigger signaling cascades that result in NFkappaB or IRF-3 mediated changes in epigenetic plasticity that facilitate reprogramming. Another form of nuclear reprogramming is so-called direct reprogramming or transdifferentiation of one somatic cell to another lineage. We have shown that transdifferentiation of human fibroblasts to endothelial cells also involves transflammation (Sayed et al., 2015). Recently, we also identified reactive oxygen species (ROS) (Zhou et al. 2016) and reactive nitrogen species (RNS) (Meng et al., 2016) as mediators of innate immune signaling in nuclear reprogramming. Innate immune signaling plays a key role in nuclear reprogramming by regulating DNA accessibility (Fig. 1). Here, we review recent progress of innate immunity signaling in nuclear reprogramming and epigenetic plasticity. PMID- 28916497 TI - Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives. AB - Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site selective intratumoral accumulation and release. Nanomedicines, such as polymer drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination. PMID- 28916498 TI - Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and tribulations. AB - Antibody directed enzyme prodrug therapy has the potential to be an effective therapy for most common solid cancers. Clinical studies with CPG2 system have shown the feasibility of this approach. The key limitation has been immunogenicity of the enzyme. Technologies now exist to eliminate this problem. Non-immunogenic enzymes in combination with prodrugs that generate potent cytotoxic drugs can provide a powerful approach to cancer therapy. ADEPT has the potential to be non -toxic to normal tissue and can therefore be combined with other modalities including immunotherapy for greater clinical benefit. PMID- 28916499 TI - (Re-)programming of subtype specific cardiomyocytes. AB - Adult cardiomyocytes (CMs) possess a highly restricted intrinsic regenerative potential - a major barrier to the effective treatment of a range of chronic degenerative cardiac disorders characterized by cellular loss and/or irreversible dysfunction and which underlies the majority of deaths in developed countries. Both stem cell programming and direct cell reprogramming hold promise as novel, potentially curative approaches to address this therapeutic challenge. The advent of induced pluripotent stem cells (iPSCs) has introduced a second pluripotent stem cell source besides embryonic stem cells (ESCs), enabling even autologous cardiomyocyte production. In addition, the recent achievement of directly reprogramming somatic cells into cardiomyocytes is likely to become of great importance. In either case, different clinical scenarios will require the generation of highly pure, specific cardiac cellular-subtypes. In this review, we discuss these themes as related to the cardiovascular stem cell and programming field, including a focus on the emergent topic of pacemaker cell generation for the development of biological pacemakers and in vitro drug testing. PMID- 28916500 TI - Early-Life stress modulates neural networks associated with habitual use of reappraisal. AB - Recent evidence shows that early life stress (ELS) is associated with altered resting-state functional connectivity (RSFC) between amygdala and the prefrontal cortex, as well as with maladaptive emotion regulation strategies and negative mood. However, the relation between ELS and maladaptive emotion regulation is not deterministic. Adaptive emotion regulation strategies such as reappraisal can also ensue from experience and learning in adulthood and can prevent negative mood. The present study aims to investigate the joint influence of ELS, in particular early-life emotional abuse (EA), and habitual use of reappraisal on amygdala-centered RSFC and mood. We examined amygdala-centered RSFC using functional magnetic resonance imaging (fMRI) in 28 healthy adults with varied exposure to early-life emotional abuse. We found that in subjects with high early life emotional abuse, reappraisal was predominantly associated with RSFC between left centromedial amygdala (CMA) and the ventrolateral prefrontal cortex (VLPFC), whereas in subjects with low early-life EA reappraisal predominantly involved RSFC between right CMA, premotor and supplementary motor regions. For subjects with high EA, reappraisal use was associated with a decrease in negative mood whereas it was associated with an increase in positive mood for subjects with low EA. The general findings of the study suggest that reappraisal use might act as a protective factor, notably for individuals who were exposed to ELS, and that this is mediated by alteration of amygdala-centered RSFC. PMID- 28916501 TI - Awakenings in rats by ultrasounds: A new animal model for paradoxical kinesia. AB - Paradoxical kinesia refers to a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. The mechanisms underlying this phenomenon are unknown due a paucity of valid animal models that faithfully reproduce paradoxical kinesia. Here, in a first experiment, we present a new method to study paradoxical kinesia by "awakening" cataleptic rats through presenting appetitive 50-kHz ultrasonic vocalizations (USV), which are typical for social situations with positive valence, like juvenile play or sexual encounters ("rat laughter"). Rats received systemic haloperidol to induce catalepsy, which was assessed by means of the bar test. During that test, 50-kHz USV, time- and amplitude-matched white noise (NOISE), or background noise (BACKGROUND) were played back and compared to SILENCE. Every animal was exposed to all four acoustic stimuli in random order, with four independent groups of rats being tested. Only when exposed to playback of appetitive 50-kHz USV, the otherwise akinetic rats rapidly started to move efficiently. The acoustic control stimuli, in contrast, did not release rats from catalepsy, despite eliciting the auditory pinna reflex and head movements towards the sound source. Moreover, in a second experiment, playback of aversive 22-kHz USV and relevant acoustic control stimuli did also not significantly affect catalepsy time. Together, our animal model provides a completely new approach to study mechanisms of paradoxical kinesia, which might help to improve behavioral therapies for Parkinson's disease and other disorders, where akinetic or cataleptic states occur. PMID- 28916502 TI - Sociability trait and regional cerebral oxidative metabolism in rats: Predominantly nonlinear relations. AB - Deficits in social behaviour are common in psychopathological conditions e.g., depression, autism and schizophrenia. In rats, sociability, defined as the engagement of an animal in non-aggressive social contact with a conspecific in a neutral arena, is as a persistent trait. To elucidate the neuroanatomy of social behaviour in animal models, long term neuronal energy metabolism was studied in rats preselected for sociability levels. Rats were divided into groups with high, medium and low sociability levels (HS, MS and LS) according to the average score of three social interaction tests, and cerebral long-term energy metabolism was assayed with cytochrome oxidase histochemistry. In the dorsomedial caudate putamen oxidative metabolism was linearly dependent on sociability, with LS-rats having the highest levels. In median preoptic nucleus, posterior paraventricular thalamus and median raphe, nonlinear relations appeared, HS- and LS-rats having lower oxidative activity than MS-animals. In the supraoptic nucleus MS-rats displayed lower oxidative activity than HS- and LS-animals. Intra-individual variability in social interaction on different testing occasions correlated positively with oxidative metabolism in the prelimbic cortex, bed nucleus of stria terminalis and caudate putamen, and negatively in the nucleus accumbens core. Conclusively, rats with different sociability levels are distinguished by long-term energy metabolism in nuclei involved in motivational behaviour, fear and vigilance; the relationship between energy metabolism and sociability appears to be predominantly nonlinear - animals with high and low expression of sociability are similarly deviant from the average; and intra-individual variability in social interaction is related to brain areas controlling motivation, stress reactivity and anxiety. PMID- 28916503 TI - Altered serotonergic and GABAergic neurotransmission in a mice model of obsessive compulsive disorder. AB - There is ample evidence that obsessive-compulsive disorder (OCD) is based on reduced serotonergic function. Replicated bidirectional selection for thermoregulatory nest-building behavior in the laboratory house mouse (Mus musculus) resulted in compulsive-like, non-compulsive-like and randomly bred control mice that represent a non-induced animal model of OCD. The present study aimed at investigating the neurochemical patterns in specific brain regions of compulsive-like (HA) versus non-compulsive-like (LA) and normal (CA) mice. The neurochemical investigation of several brain regions of the corticostriato thalamocortical circuity, i.e., nucleus caudatus (CPU), nucleus accumbens (NAc), globus pallidus (GP), hippocampus (HPC), amygdala (AM), ventral tegmental area (VTA) and substantia nigra (SN) was performed by electrochemical (serotonin and dopamine) and fluorescence (glutamate and GABA) HPLC detection. HA mice displayed significantly decreased 5-HT concentrations in the mPFC and LA mice displayed a significant increase in GABA concentrations in the mPFC. This supports the pathophysiological relevance of serotonin in the manifestation of OCD and adding to the construct validity of the non-induced mouse model of OCD. PMID- 28916504 TI - Going skin deep: A direct comparison of penetration potential of lipid-based nanovesicles on the isolated perfused human skin flap model. AB - Phospholipid-based nanocarriers are attractive drug carriers for improved local skin therapy. In the present study, the recently developed isolated perfused human skin flap (IPHSF) model was used to directly compare the skin penetration enhancing potential of the three commonly used nanocarriers, namely conventional liposomes (CLs), deformable liposomes (DLs) and solid lipid nanoparticles (SLNs). Two fluorescent markers, calcein (hydrophilic) or rhodamine (lipophilic), were incorporated individually in the three nanosystems. The nanocarrier size ranged between 200 and 300nm; the surface charge and entrapment efficiency for both markers were dependent on the lipid composition and the employed surfactant. Both carrier-associated markers could not penetrate the full thickness human skin, confirming their suitability for dermal drug delivery. CLs exhibited higher retention of both markers on the skin surface compared to DLs and SLNs, indicating a depo formation. DLs and SLNs enabled the deeper penetration of the two markers into the skin layers. In vitro and ex vivo skin penetration studies performed on the cellophane membrane and full thickness pig/human skin, respectively, confirmed the findings. In conclusion, efficient dermal drug delivery can be achieved by optimization of a lipid nanocarrier on the suitable skin-mimicking model to assure system's accumulation in the targeted skin layer. PMID- 28916505 TI - Nuclear organisation of cholinergic, catecholaminergic, serotonergic and orexinergic neurons in two relatively large-brained rodent species-The springhare (Pedetes capensis) and Beecroft's scaly-tailed squirrel (Anomalurus beecrofti). AB - The present study describes the nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic systems in the brains of the springhare and Beecroft's scaly-tailed squirrel following immunohistochemical labelling. We aimed to investigate any differences in the nuclear organization of these neural systems when compared to previous data on other species of rodents, as these two rodent species have relatively large brains - 1.2 to 1.4 times larger than would be expected for mammals of their body mass and 1.7-1.9 times larger than would be expected for rodents of their body mass. A series of coronal sections were taken through two brains of each species and immunohistochemically labelled with antibodies against choline acetyltransferase, tyrosine hydroxylase, serotonin and orexin-A. Generally, the nuclear complement of these systems revealed extensive similarities between both species and to previously studied rodents. While no differences were observed in the nuclear complement of the serotonergic and orexinergic systems, some differences were observed in the nuclear complement of the cholinergic and catecholaminergic systems. These include the presence of cholinergic neurons in the cerebral cortex and nucleus of the trapezoid body in the springhare; while the Beecroft's scaly-tailed squirrel exhibited cholinergic neurons in the pretectal area of the midbrain. For the catecholaminergic system it was observed that Beecroft's scaly-tailed squirrel possessed immunoreactive neurons in the accessory olfactory bulb. Despite these four differences, most not previously observed in rodents, the remaining complement of cholinergic and catecholaminergic nuclei were identical to that observed in other rodents, including the presence of the rodent specific catecholaminergic rostral dorsal midline medullary (C3) nucleus in the medulla oblongata. Thus, even with a significant increase in relative brain size, the overall complement of nuclei forming these systems shows minimal changes in complexity within a specific mammalian order. PMID- 28916507 TI - Cardiac Patients' Experiences and Perceptions of Social Media: Mixed-Methods Study. AB - BACKGROUND: Traditional in-person cardiac rehabilitation has substantial benefits for cardiac patients, which are offset by poor attendance. The rapid increase in social media use in older adults provides an opportunity to reach patients who are eligible for cardiac rehabilitation but unable to attend traditional face-to face groups. However, there is a paucity of research on cardiac patients' experiences and perspectives on using social media to support their health. OBJECTIVE: The aim of this study was to describe cardiac rehabilitation patients' experiences in using social media in general and their perspective on using social media, particularly Facebook, to support their cardiac health and secondary prevention efforts. METHODS: A mixed-methods study was undertaken among cardiac rehabilitation patients in both urban and rural areas. First, this study included a survey (n=284) on social media use and capability. Second, six focus group interviews were conducted with current Facebook users (n=18) to elucidate Facebook experience and perspectives. RESULTS: Social media use was low (28.0%, 79/282) but more common in participants who were under 70 years of age, employed, and had completed high school. Social media users accessed Web-based information on general health issues (65%, 51/79), medications (56%, 44/79), and heart health (43%, 34/79). Participants were motivated to invest time in using Facebook for "keeping in touch" with family and friends and to be informed by expert cardiac health professionals and fellow cardiac participants if given the opportunity. It appeared that participants who had a higher level of Facebook capability (understanding of features and the consequences of their use and efficiency in use) spent more time on Facebook and reported higher levels of "liking," commenting, or sharing posts. Furthermore, higher Facebook capability appeared to increase a participants' willingness to participate in a cardiac Facebook support group. More capable users were more receptive to the use of Facebook for cardiac rehabilitation and more likely to express interest in providing peer support. Recommended features for a cardiac rehabilitation Facebook group included a closed group, expert cardiac professional involvement, provision of cardiac health information, and ensuring trustworthiness of the group. CONCLUSIONS: Cardiac health professionals have an opportunity to capitalize on cardiac patients' motivations and social media, mostly Facebook, as well as the capability for supporting cardiac rehabilitation and secondary prevention. Participants' favored purposeful time spent on Facebook and their cardiac health provides such a purpose for a Facebook intervention. The study results will inform the development of a Facebook intervention for secondary prevention of cardiovascular disease. PMID- 28916506 TI - Blending Face-to-Face and Internet-Based Interventions for the Treatment of Mental Disorders in Adults: Systematic Review. AB - BACKGROUND: Many studies have provided evidence for the effectiveness of Internet based stand-alone interventions for mental disorders. A newer form of intervention combines the strengths of face-to-face (f2f) and Internet approaches (blended interventions). OBJECTIVE: The aim of this review was to provide an overview of (1) the different formats of blended treatments for adults, (2) the stage of treatment in which these are applied, (3) their objective in combining face-to-face and Internet-based approaches, and (4) their effectiveness. METHODS: Studies on blended concepts were identified through systematic searches in the MEDLINE, PsycINFO, Cochrane, and PubMed databases. Keywords included terms indicating face-to-face interventions ("inpatient," "outpatient," "face-to-face," or "residential treatment"), which were combined with terms indicating Internet treatment ("internet," "online," or "web") and terms indicating mental disorders ("mental health," "depression," "anxiety," or "substance abuse"). We focused on three of the most common mental disorders (depression, anxiety, and substance abuse). RESULTS: We identified 64 publications describing 44 studies, 27 of which were randomized controlled trials (RCTs). Results suggest that, compared with stand-alone face-to-face therapy, blended therapy may save clinician time, lead to lower dropout rates and greater abstinence rates of patients with substance abuse, or help maintain initially achieved changes within psychotherapy in the long-term effects of inpatient therapy. However, there is a lack of comparative outcome studies investigating the superiority of the outcomes of blended treatments in comparison with classic face-to-face or Internet-based treatments, as well as of studies identifying the optimal ratio of face-to-face and Internet sessions. CONCLUSIONS: Several studies have shown that, for common mental health disorders, blended interventions are feasible and can be more effective compared with no treatment controls. However, more RCTs on effectiveness and cost effectiveness of blended treatments, especially compared with nonblended treatments are necessary. PMID- 28916508 TI - Development of a Whole Slide Imaging System on Smartphones and Evaluation With Frozen Section Samples. AB - BACKGROUND: The aim was to develop scalable Whole Slide Imaging (sWSI), a WSI system based on mainstream smartphones coupled with regular optical microscopes. This ultra-low-cost solution should offer diagnostic-ready imaging quality on par with standalone scanners, supporting both oil and dry objective lenses of different magnifications, and reasonably high throughput. These performance metrics should be evaluated by expert pathologists and match those of high-end scanners. OBJECTIVE: The aim was to develop scalable Whole Slide Imaging (sWSI), a whole slide imaging system based on smartphones coupled with optical microscopes. This ultra-low-cost solution should offer diagnostic-ready imaging quality on par with standalone scanners, supporting both oil and dry object lens of different magnification. All performance metrics should be evaluated by expert pathologists and match those of high-end scanners. METHODS: In the sWSI design, the digitization process is split asynchronously between light-weight clients on smartphones and powerful cloud servers. The client apps automatically capture FoVs at up to 12-megapixel resolution and process them in real-time to track the operation of users, then give instant feedback of guidance. The servers first restitch each pair of FoVs, then automatically correct the unknown nonlinear distortion introduced by the lens of the smartphone on the fly, based on pair wise stitching, before finally combining all FoVs into one gigapixel VS for each scan. These VSs can be viewed using Internet browsers anywhere. In the evaluation experiment, 100 frozen section slides from patients randomly selected among in patients of the participating hospital were scanned by both a high-end Leica scanner and sWSI. All VSs were examined by senior pathologists whose diagnoses were compared against those made using optical microscopy as ground truth to evaluate the image quality. RESULTS: The sWSI system is developed for both Android and iPhone smartphones and is currently being offered to the public. The image quality is reliable and throughput is approximately 1 FoV per second, yielding a 15-by-15 mm slide under 20X object lens in approximately 30-35 minutes, with little training required for the operator. The expected cost for setup is approximately US $100 and scanning each slide costs between US $1 and $10, making sWSI highly cost-effective for infrequent or low-throughput usage. In the clinical evaluation of sample-wise diagnostic reliability, average accuracy scores achieved by sWSI-scan-based diagnoses were as follows: 0.78 for breast, 0.88 for uterine corpus, 0.68 for thyroid, and 0.50 for lung samples. The respective low-sensitivity rates were 0.05, 0.05, 0.13, and 0.25 while the respective low-specificity rates were 0.18, 0.08, 0.20, and 0.25. The participating pathologists agreed that the overall quality of sWSI was generally on par with that produced by high-end scanners, and did not affect diagnosis in most cases. Pathologists confirmed that sWSI is reliable enough for standard diagnoses of most tissue categories, while it can be used for quick screening of difficult cases. CONCLUSIONS: As an ultra-low-cost alternative to whole slide scanners, diagnosis-ready VS quality and robustness for commercial usage is achieved in the sWSI solution. Operated on main-stream smartphones installed on normal optical microscopes, sWSI readily offers affordable and reliable WSI to resource-limited or infrequent clinical users. PMID- 28916509 TI - Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China. AB - Risk stratification of human papillomavirus (HPV)-positive women is needed to avoid excessive colposcopy and overtreatment in cervical cancer screening. We aimed to evaluate the predictive value of type-specific HPV in detecting cervical cancer and precancers in a Chinese population-based cohort and provide evidence of HPV genotyping to triage HPV-positive women. We typed all Hybrid Capture 2 positive cytologic samples of 1,742 women in Shanxi Province Cervical Cancer Screening Study cohort. Cumulative risks of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) among HPV-positive women and cumulative detection rates of CIN2+ among general women by type-specific HPV were estimated during the course of 10-year follow-up. HPV 16 and HPV 52 were most prevalent types among the screening population. Ten-year cumulative risk of CIN2+ was 47.5% [95% confidence interval (CI), 31.6-62.3] for HPV 16-positive women and 46.3% (95% CI, 15.3-75.4) for HPV 31-positive women. Ten-year cumulative risks of CIN2+ among HPV 58, 39, 33, 18, and 52 positive women ranged from 34.3% to 12.0% in a decreasing order. CIN2+ risks were found to be positively associated with infection times of the same genotypes of HPV 16, 31, 33, and 58 (all Ptrend < 0.001). Cumulative detection rates of CIN2+ within 10 years were predominantly contributed by HPV 16, 31, and 58. Our results support the risk-based management of HPV-positive women using HPV genotyping and also indicate the significance of including HPV 31 and 58 apart from commonly acknowledged HPV 16 and HPV 18 in achieving better risk stratification. Cancer Prev Res; 10(12); 745-51. (c)2017 AACR. PMID- 28916510 TI - Outcomes of Telemedicine Video-Conferencing Clinic Versus In-Person Clinic Follow Up for Implantable Cardioverter-Defibrillator Recipients. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) recipients require close follow-up that can be difficult for patients who have to travel long distances for clinic follow-up. We aimed to compare clinical outcomes between ICD patients followed-up in a telemedicine video-conferencing clinic (TMVC) and a conventional in-person clinic (CIC). We hypothesized that outcomes of patients followed in the TMVC are noninferior to the CIC. METHODS AND RESULTS: This retrospective study compares time to first appropriate ICD therapy, time to first inappropriate ICD therapy, time to first shock, and overall survival in patients followed in TMVC compared with CIC between 2001 and 2016. Two hundred and eighty-seven patients were followed in the TMVC group and 236 patients in the CIC. The average age of the TMVC and CIC groups was 64.13+/-9.38 and 65.23+/-8.57 years, respectively (P=0.164). There was no difference in the modified Seattle heart failure model score between the 2 groups (-0.12+/-1.0 versus -0.21+/-0.99; P=0.287). The Charlson comorbidity index score was higher in the CIC group compared with the TMVC group (7.0 versus 6.0; P=0.01). Mean duration of follow-up was 4.8 years. Adjusted and unadjusted tests of noninferiority found TMVC was not inferior to in person follow-up for the prespecified outcomes. CONCLUSIONS: Video-conferencing ICD follow-up for patients in areas where electrophysiology subspecialty care is not available leads to outcomes that are noninferior to CIC follow-up. PMID- 28916511 TI - Failure to Treat Life-Threatening Ventricular Tachyarrhythmias in Contemporary Implantable Cardioverter-Defibrillators: Implications for Strategic Programming. AB - BACKGROUND: In clinical trials, manufacturer-specific, strategic programming of implantable cardioverter-defibrillators (ICDs), including faster detection rates, reduces unnecessary therapy but permits therapy for ventricular tachycardia/ventricular fibrillation (VF). Present consensus recommends a generic rate threshold between 185 and 200 beats per minute, which exceeds the rate tested in clinical trials for some manufacturers. In a case series, we sought to determine the relationship between programmed parameters and failure of modern ICDs to treat VF. METHODS AND RESULTS: We reviewed cases in which normally functioning ICDs failed to deliver timely therapy for VF from April 2015 to January 2017 at 4 institutions. Of 10 ambulatory patients, 5 died from untreated VF, 4 had cardiac arrests requiring external shocks, and 1 was rescued by a delayed ICD shock. VF did not satisfy programmed detection criteria in 9 patients (90%). Seven of these patients had slowest detection rates that were consistent with generic recommendations but not tested in a peer-reviewed trial for their manufacturer's ICDs. Manufacturer-specific factors interacted with fast detection rates to withhold therapy, including strict VF episode termination rules, enhancements to minimize T-wave oversensing, and features that restrict therapy to regular rhythms in ventricular tachycardia zones. Untreated VF despite recommended programming accounted for 56% of sudden deaths and 11% of all deaths during the study period. CONCLUSIONS: Complex and unanticipated interactions between manufacturer-specific features and generic programming can prevent therapy for VF. More data are needed to assess the risks and benefits of translating evidence-based detection parameters from one manufacturer to another. PMID- 28916512 TI - Strategic Programming for Implantable Cardioverter-Defibrillator Shock Reduction: Following the Greatest Happiness Principle? PMID- 28916513 TI - Telemedicine for Management of Implantable Defibrillators: Lessons Learned and a Look Toward the Future. PMID- 28916514 TI - The wisdom of investigating early developmental impairment. PMID- 28916516 TI - An uncommon manifestation of shock: Takotsubo syndrome. AB - : 76-year-old female presented following an episode of collapse. She was hypotensive with the paramedics and remained refractory despite fluid resuscitation. Her initial baseline tests revealed an elevated troponin; she subsequently underwent a coronary angiogram that showed mild coronary artery disease. Left ventriculogram was performed, which showed abnormal mid-wall ballooning and severely impaired systolic function, characteristic of Takotsubo syndrome. Echocardiogram confirmed the presence of diagnosis and presence of left ventricular outflow tract obstruction with high gradient. She was initiated on medical heart failure therapy and improved. Follow-up investigations after 2 months showed complete resolution of systolic dysfunction and symptoms. LEARNING POINTS: Takotsubo syndrome can present similarly to ACS.Early use of echocardiography in the acute setting can provide vital information.Takotsubo syndrome can result in hemodynamic instability requiring urgent interventions.Other investigative modalities can be used in conjunction with echocardiography to confirm the diagnosis of Takotsubo syndrome.Prognosis is generally good in patients with Takotsubo syndrome. PMID- 28916515 TI - Reversing thyroid-hormone-mediated repression of a HSV-1 promoter via computationally guided mutagenesis. AB - Thyroid hormones (THs) and their DNA-binding nuclear receptors (TRs) direct transcriptional regulation in diverse ways depending on the host cell environment and specific promoter characteristics of TH-sensitive genes. This study sought to elucidate the impact on transcriptional repression of nucleotide sequence or orientation within TR binding sites - the TH response elements (TREs) of TH sensitive promoters - to better understand ligand-dependent transcriptional repression of wild-type promoters. Computational analysis of the HSV-1 thymidine kinase (TK) gene TRE bound by TR and retinoid X receptor (RXR) revealed a single TRE point mutation sufficient to reverse the TRE orientation. In vitro experiments showed that the TRE point mutation had distinct impacts on promoter activity, sufficient to reverse the TH-dependent negative regulation in neuroendocrine differentiated cells. This point mutation altered the promoter's regulatory mechanism by discrete changes in transcription factor TR occupancy and altered enrichment of the repressive chromatin modification of histone-3-lysine-9 trimethyl (H3K9Me3). Insights relating to this negative TRE (nTRE) mechanism aids our understanding of other nTREs and TRE mutations associated with TH and herpes diseases. PMID- 28916517 TI - BMJ papers on ear growth and didgeridoo for sleep apnea win Ig Nobel awards. PMID- 28916518 TI - US drug maker sues to force Ireland to offer expensive Duchenne's treatment. PMID- 28916519 TI - Modeling pacemaker deterioration with age. AB - New JGP study models how sinoatrial node pacemaker activity changes in aged hearts. PMID- 28916520 TI - Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice. AB - Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron collaterals is remarkably selective for the IN compared with the cerebellar cortex. Optogenetic activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude synaptic currents, suggesting an active role in IN information processing. Monosynaptic transsynaptic rabies tracing indicated the pathway contacts multiple cell types within the IN. By contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm neurons. Together, these data indicate that the cerebellar nuclei are under afferent control independent of the cerebellar cortex, potentially diversifying its roles in motor control.SIGNIFICANCE STATEMENT The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both motor output pathways and nucleo-olivary feedback. PMID- 28916521 TI - Behavioral, Modeling, and Electrophysiological Evidence for Supramodality in Human Metacognition. AB - Human metacognition, or the capacity to introspect on one's own mental states, has been mostly characterized through confidence reports in visual tasks. A pressing question is to what extent results from visual studies generalize to other domains. Answering this question allows determining whether metacognition operates through shared, supramodal mechanisms or through idiosyncratic, modality specific mechanisms. Here, we report three new lines of evidence for decisional and postdecisional mechanisms arguing for the supramodality of metacognition. First, metacognitive efficiency correlated among auditory, tactile, visual, and audiovisual tasks. Second, confidence in an audiovisual task was best modeled using supramodal formats based on integrated representations of auditory and visual signals. Third, confidence in correct responses involved similar electrophysiological markers for visual and audiovisual tasks that are associated with motor preparation preceding the perceptual judgment. We conclude that the supramodality of metacognition relies on supramodal confidence estimates and decisional signals that are shared across sensory modalities.SIGNIFICANCE STATEMENT Metacognitive monitoring is the capacity to access, report, and regulate one's own mental states. In perception, this allows rating our confidence in what we have seen, heard, or touched. Although metacognitive monitoring can operate on different cognitive domains, we ignore whether it involves a single supramodal mechanism common to multiple cognitive domains or modality-specific mechanisms idiosyncratic to each domain. Here, we bring evidence in favor of the supramodality hypothesis by showing that participants with high metacognitive performance in one modality are likely to perform well in other modalities. Based on computational modeling and electrophysiology, we propose that supramodality can be explained by the existence of supramodal confidence estimates and by the influence of decisional cues on confidence estimates. PMID- 28916523 TI - Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD. PMID- 28916522 TI - Viral Infection Sensitizes Human Fetal Membranes to Bacterial Lipopolysaccharide by MERTK Inhibition and Inflammasome Activation. AB - Chorioamnionitis, premature rupture of fetal membranes (FMs), and subsequent preterm birth are associated with local infection and inflammation, particularly IL-1beta production. Although bacterial infections are commonly identified, other microorganisms may play a role in the pathogenesis. Because viral pandemics, such as influenza, Ebola, and Zika, are becoming more common, and pregnant women are at increased risk for associated complications, this study evaluated the impact that viral infection had on human FM innate immune responses. This study shows that a herpes viral infection of FMs sensitizes the tissue to low levels of bacterial LPS, giving rise to an exaggerated IL-1beta response. Using an ex vivo human FM explant system and an in vivo mouse model of pregnancy, we report that the mechanism by which this aggravated inflammation arises is through the inhibition of the TAM receptor, MERTK, and activation of the inflammasome. The TAM receptor ligand, growth arrest specific 6, re-establishes the normal FM response to LPS by restoring and augmenting TAM receptor and ligand expression, as well as by preventing the exacerbated IL-1beta processing and secretion. These findings indicate a novel mechanism by which viruses alter normal FM immune responses to bacteria, potentially giving rise to adverse pregnancy outcomes. PMID- 28916524 TI - New Methods To Analyze B Cell Immune Responses to Thymus-Dependent Antigen Sheep Red Blood Cells. AB - B cells contribute critically to an effective immune response by producing Ag specific Abs. During the immune response to so-called "thymus-dependent Ags," activated B cells seek T cell help and form germinal centers. In contrast, thymus independent Ags generally do not induce germinal center formation. In the germinal center, B cells undergo somatic hypermutation, affinity-based clonal expansion, and differentiation to produce plasma cells and memory B cells. Valuable insight into these processes has been gained by using model hapten carrier complexes or SRBCs. SRBCs induce robust germinal center formation in mice. Therefore, this Ag is commonly used to study germinal center responses. In contrast to haptenated Ags, thus far it has been difficult to measure the titer of Ag-specific Abs or the expansion of Ag-specific B cells after immunization with SRBCs. We have developed new, simple methods to access these parameters, thus providing new tools to study germinal center and Ab responses. PMID- 28916525 TI - Role of the gastrointestinal microbiota in small animal health and disease. AB - There is a large and emerging interest in the role of the gastrointestinal microbiota in health and disease. This paper serves to review the current knowledge and recommendations of the gastrointestinal microbiota in health and gastrointestinal disease. Further, this review evaluates the current literature and suggests guidelines for faecal microbial transplantation, a novel therapy for dysbiosis in veterinary medicine. PMID- 28916526 TI - Monoclonal Antibodies Directed against Cadherin RGD Exhibit Therapeutic Activity against Melanoma and Colorectal Cancer Metastasis. AB - Purpose: New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the alpha2beta1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAb).Experimental Design: Cadherin 17 (CDH17) fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of beta1 integrin and cell adhesion, proliferation, and invasion assays using cell lines from different cancer types (colorectal, pancreatic, melanoma, and breast cancer). Effects of the mAbs on cell signaling were determined by Western blot analysis. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development.Results: Antibodies against full-length CDH17 failed to block the binding to alpha2beta1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked CDH17 and vascular-endothelial (VE)-cadherin mediated beta1 integrin activation in melanoma and breast, pancreatic, and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases in colorectal and pancreatic cancers, and of JNK, ERK, Src, and AKT in melanoma and breast cancer. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively.Conclusions: Blocking the interaction between RGD cadherins and alpha2beta1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma, and, potentially, other cancers. Clin Cancer Res; 24(2); 433 44. (c)2017 AACRSee related commentary by Marshall, p. 253. PMID- 28916527 TI - Demethylation Therapy as a Targeted Treatment for Human Papillomavirus-Associated Head and Neck Cancer. AB - Purpose: DNA methylation in human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels.Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276-87. (c)2017 AACR. PMID- 28916528 TI - The Impact of Cryoballoon Versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation on Healthcare Utilization and Costs: An Economic Analysis From the FIRE AND ICE Trial. PMID- 28916529 TI - A Brain Phenotype for Stressor-Evoked Blood Pressure Reactivity. PMID- 28916530 TI - Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors. AB - P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the central nervous system (CNS) and affecting their pharmacokinetics, therapeutic efficacy, and safety. In the present study, the interactions of catechol-O-methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone, and tolcapone) with P gp and BCRP were investigated to determine the contribution of these transporters in their access to the brain. In vitro cellular accumulation and bidirectional transport assays were conducted in Madin-Darby canine kidney (MDCK) II, MDCK MDR1, and MDCK-BCRP cells. In vivo pharmacokinetic studies were carried out for tolcapone and BIA 9-1079 in rats, with and without elacridar, a well-known P-gp and BCRP modulator. The results suggest that BIA 9-1079, nebicapone, and tolcapone inhibit BCRP in a concentration-dependent manner. Moreover, with net flux ratios higher than 2 and decreased over 50% in the presence of verapamil or Ko143, BIA 9-1079 was identified as a P-gp substrate while BIA 9-1059, entacapone, opicapone, and nebicapone were revealed to be BCRP substrates. In vivo, brain exposure was limited for tolcapone and BIA 9-1079, although tolcapone crossed the blood-brain barrier at a greater rate and to a greater extent than BIA 9-1079. The extent of brain distribution of both compounds was significantly increased in the presence of elacridar, attesting to the involvement of efflux transporters. These findings provide relevant information and improve the understanding of the mechanisms that govern the access of these COMT inhibitors to the CNS. PMID- 28916531 TI - Diabetes, Prediabetes, and Brain Volumes and Subclinical Cerebrovascular Disease on MRI: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). AB - OBJECTIVE: To examine the associations of prediabetes, diabetes, and diabetes severity (as assessed by HbA1c and diabetes duration) with brain volumes and vascular pathology on brain MRI and to assess whether the associations of diabetes with brain volumes are mediated by brain vascular pathology. RESEARCH DESIGN AND METHODS: Cross-sectional study of 1,713 participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) (mean age 75 years, 60% female, 27% black, 30% prediabetes, and 35% diabetes) who underwent 3T brain MRI scans in 2011-2013. Participants were categorized by diabetes-HbA1c status as without diabetes (<5.7% [reference]), with prediabetes (5.7 to <6.5%), and with diabetes ([defined as prior diagnosis or HbA1c >=6.5%] <7.0% vs. >=7.0%), with further stratification by diabetes duration (<10 vs. >=10 years). RESULTS: In adjusted analyses, compared with participants without diabetes and HbA1c <5.7%, participants with prediabetes and those with diabetes and HbA1c <7.0% did not have significantly different brain volumes or vascular pathology (all P > 0.05), but those with diabetes and HbA1c >=7.0% had smaller total brain volume (beta -0.20 SDs, 95% CI -0.31, -0.09), smaller regional brain volumes (including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all P < 0.05]), and increased burden of white matter hyperintensities (WMH) (P = 0.016). Among participants with diabetes, those with HbA1c >=7.0% had smaller total and regional brain volumes and an increased burden of WMH (all P < 0.05) compared with those with HbA1c <7.0%. Similarly, participants with longer duration of diabetes (>=10 years) had smaller brain volumes and higher burden of lacunes (all P < 0.05) than those with a diabetes duration <10 years. We found no evidence for mediation by WMH in associations of diabetes with smaller brain volumes by structural equation models (all P > 0.05). CONCLUSIONS: More-severe diabetes (defined by higher HbA1c and longer disease duration) but not prediabetes or less severe diabetes was associated with smaller brain volumes and an increased burden of brain vascular pathology. No evidence was found that associations of diabetes with smaller brain volumes are mediated by brain vascular pathology, suggesting that other mechanisms may be responsible for these associations. PMID- 28916532 TI - Comparison of symptomatic and asymptomatic persons with primary age-related tauopathy. AB - OBJECTIVE: To conduct a clinicopathologic study to characterize clinical and neuropathologic features associated with cognitive impairment in participants with no neuritic amyloid plaques (primary age-related tauopathy [PART] definite) and sparse neuritic plaques (amyloid sparse). METHODS: Using the National Alzheimer's Coordinating Center database, we identified 377 individuals who were PART definite (n = 170) or amyloid sparse (n = 207), clinically examined within 1 year of death, and autopsied at 1 of 26 National Institute on Aging-funded Alzheimer's Disease Centers. Factors associated with the odds of being symptomatic (global Clinical Dementia Rating [CDR] score >0) were identified with multivariable logistic regression. RESULTS: PART-definite participants less often had a high Braak neurofibrillary tangle stage V or VI (4%) compared to amyloid sparse participants (28%, p < 0.001). Of the PART-definite participants, 98 were symptomatic and 72 asymptomatic according to their global CDR scores. PART definite participants were less often symptomatic (58%) compared with amyloid sparse participants (80%, p < 0.001). Within the PART-definite group, independent predictors of symptomatic status included depression (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 2.15-8.19), Braak stage (aOR 1.42, 95% CI 1.04 1.95), and history of stroke (aOR 8.09, 95% CI 2.63-24.82). Within the amyloid sparse group, independent predictors of symptomatic status included education (aOR 0.80, 95% CI 0.65-0.99), Braak stage (aOR 1.91, 95% CI 1.07-3.43), and amyloid angiopathy (aOR 2.75, 95% CI 1.14-6.64). CONCLUSIONS: These findings support the hypothesis that participants with PART have an amyloid-independent dementing Alzheimer disease-like temporal lobe tauopathy. PMID- 28916533 TI - Sex differences in the prevalence of genetic mutations in FTD and ALS: A meta analysis. AB - OBJECTIVE: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)-in patients clinically diagnosed with these conditions. METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models. RESULTS: Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04-1.29). Twenty three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81-1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN related FTD (RR 1.33, 95% CI 1.09-1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95-1.55). CONCLUSIONS: Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression. PMID- 28916535 TI - Spinal cord perfusion pressure predicts neurologic recovery in acute spinal cord injury. AB - OBJECTIVE: To determine whether spinal cord perfusion pressure (SCPP) as measured with a lumbar intrathecal catheter is a more predictive measure of neurologic outcome than the conventionally measured mean arterial pressure (MAP). METHODS: A total of 92 individuals with acute spinal cord injury were enrolled in this multicenter prospective observational clinical trial. MAP and CSF pressure (CSFP) were monitored during the first week postinjury. Neurologic impairment was assessed at baseline and at 6 months postinjury. We used logistic regression, systematic iterations of relative risk, and Cox proportional hazard models to examine hemodynamic patterns commensurate with neurologic outcome. RESULTS: We found that SCPP (odds ratio 1.039, p = 0.002) is independently associated with positive neurologic recovery. The relative risk for not recovering neurologic function continually increased as individuals were exposed to SCPP below 50 mm Hg. Individuals who improved in neurologic grade dropped below SCPP of 50 mm Hg fewer times than those who did not improve (p = 0.012). This effect was not observed for MAP or CSFP. Those who were exposed to SCPP below 50 mm Hg were less likely to improve from their baseline neurologic impairment grade (p = 0.0056). CONCLUSIONS: We demonstrate that maintaining SCPP above 50 mm Hg is a strong predictor of improved neurologic recovery following spinal cord injury. This suggests that SCPP (the difference between MAP and CSFP) can provide useful information to guide the hemodynamic management of patients with acute spinal cord injury. PMID- 28916536 TI - An improved way to predict neurologic recovery in acute spinal cord injury. PMID- 28916534 TI - Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. AB - OBJECTIVE: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). METHODS: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. RESULTS: A total of 382 participants at baseline, 310 participants at the week 16 20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 +/- 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6 54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]). CONCLUSIONS: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. CLINICALTRIALSGOV IDENTIFIER: NCT00088452. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine. PMID- 28916537 TI - Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients. AB - OBJECTIVE: To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption. METHODS: Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule-1 (sVCAM 1) were measured using immunoassays. Lymphocyte subsets, alpha4-integrin expression/saturation, and vascular cell adhesion molecule-1 (VCAM-1) binding were assessed using flow cytometry. RESULTS: Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 * 109 to 3.5 * 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 * 109 vs 3.5 * 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, alpha4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ~16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal. CONCLUSIONS: Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ~16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ~16 weeks after stopping natalizumab. PMID- 28916538 TI - Analysis of blood-based gene expression in idiopathic Parkinson disease. AB - OBJECTIVE: To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (<=220 samples). METHODS: Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD associated gene networks. RESULTS: A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E-6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E-4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1, ATP5A1, and VDAC3. CONCLUSIONS: We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers. PMID- 28916539 TI - Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe. AB - Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, S. cerevisiae and S. pombe Although >80% of the mRNA genes in each species were found to display APA, S. pombe showed greater 3' UTR size differences among APA isoforms than did S. cerevisiae PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway. In S. pombe, strong motifs surrounding distal PASs lead to higher abundances of long 3' UTR isoforms than short ones, a feature that is opposite in S. cerevisiae Differences in PAS placement between convergent genes lead to starkly different antisense transcript landscapes between budding and fission yeasts. In both species, short 3' UTR isoforms are more likely to be expressed when cells are growing in nutrient-rich media, although different gene groups are affected in each species. Significantly, 3' UTR shortening in S. pombe coordinates with up-regulation of expression for genes involved in translation during cell proliferation. Using S. pombe strains deficient for Pcf11 or Pab2, we show that reduced expression of 3' end processing factors lengthens 3' UTR, with Pcf11 having a more potent effect than Pab2. Taken together, our data indicate that APA mechanisms in S. pombe and S. cerevisiae are largely different: S. pombe has many of the APA features of higher species, and Pab2 in S. pombe has a different role in APA regulation than its mammalian homolog, PABPN1. PMID- 28916540 TI - Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence. AB - Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging. It interacts with multiple regions of the genome called lamina associated domains (LADs). Some LADs are cell-type specific, whereas others are conserved between cell types and are referred to as constitutive LADs (cLADs). Here, we used DamID to investigate the changes in genome-NL interactions in a model of OIS triggered by the expression of the common BRAFV600E oncogene. We found that OIS cells lose most of their cLADS, suggesting the loss of a specific mechanism that targets cLADs to the NL. In addition, multiple genes relocated to the NL. Unexpectedly, they were not repressed, implying the abrogation of the repressive activity of the NL during OIS. Finally, OIS cells displayed an increased association of telomeres with the NL. Our study reveals that senescent cells acquire a new type of LAD organization and suggests the existence of as yet unknown mechanisms that tether cLADs to the NL and repress gene expression at the NL. PMID- 28916542 TI - Comparative Effectiveness of Tumor Necrosis Factor Agents and Disease-modifying Antirheumatic Therapy in Children with Enthesitis-related Arthritis: The First Year after Diagnosis. AB - OBJECTIVE: To characterize the effect of anti-tumor necrosis factor (TNF) therapy compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) in children with enthesitis-related arthritis (ERA) over the first year after diagnosis. METHODS: We conducted a multicenter retrospective comparative effectiveness study of children diagnosed with ERA. We estimated the effect of anti-TNF therapy on clinical variables (active joint count, tender entheses count) and patient-reported pain and global assessment of disease activity over the first year after diagnosis using state-of-the-art comparative effectiveness analytic methods. RESULTS: During the study period, 217 patients newly diagnosed with ERA had a total of 965 clinic visits the first year after disease diagnosis. Children [median age 11.6 yrs, interquartile range 10-14] were treated with anti TNF monotherapy (n = 33, 15.2%), csDMARD monotherapy (n = 73, 33.6%), or both (n = 52, 23.9%) in the first year after disease diagnosis. There was a statistically significant improvement in the primary outcome, active joint count, over time in children who received an anti-TNF drug versus those who did not (p = 0.03). Additionally, use of anti-TNF therapy versus no anti-TNF therapy was associated with less patient-reported pain (p < 0.01) and improved disease activity over time as assessed by the clinical Juvenile Arthritis Disease Activity Score (p < 0.01). The magnitude of estimated effect on clinical outcomes was uniformly greater, with the exception of tender entheses count, in children treated with an anti-TNF drug versus a csDMARD. CONCLUSION: During the first year after diagnosis, anti-TNF exposure was associated with benefits for several clinically meaningful outcomes in children with enthesitis-related arthritis. PMID- 28916541 TI - A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance. AB - Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing. PMID- 28916543 TI - Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization. AB - OBJECTIVE: To evaluate the rate of somatic NLRP3 mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS). METHODS: The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the NLRP3 gene yielded negative results. Patients' DNA were subjected to amplicon-based NLRP3 deep sequencing. RESULTS: Low-level somatic NLRP3 mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). In vitro functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging. CONCLUSION: The allele frequency of somatic NLRP3 mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated. PMID- 28916545 TI - Serologic Evidence of Gut-driven Systemic Inflammation in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Accumulating evidence links juvenile idiopathic arthritis (JIA) to nonhost factors such as gut microbes. We hypothesize that children with new-onset JIA have increased intestinal bacterial translocation and circulating lipopolysaccharide (LPS). METHODS: We studied systemic treatment-naive patients with JIA [polyarticular JIA, n = 22, oligoarticular JIA, n = 31, and spondyloarthropathies (SpA), n = 16], patients with established inflammatory bowel disease-related arthritis (IBD-RA, n = 11), and 34 healthy controls. We determined circulating IgG reactivity against LPS, LPS-binding protein (LBP), alpha-1-acid glycoprotein (alpha-1AGP), and C-reactive protein (CRP) in plasma or serum from these patients and controls. Juvenile Arthritis Disease Activity Score (JADAS-27) was calculated for patients with JIA. RESULTS: Circulating anticore LPS antibody concentrations in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.024), and SpA (p = 0.001) were significantly greater than in controls, but there were no significant intergroup differences. Circulating LBP concentrations were also significantly greater in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.002), and SpA (p = 0.006) than controls, as were alpha-1AGP concentrations (p = 0.001, 0.001, and 0.003, respectively). No differences were observed between controls and patients with IBD-RA in any of the assays. Circulating concentrations of LBP and alpha 1AGP correlated strongly with CRP concentrations (r = 0.78 and r = 0.66, respectively). Anticore LPS antibody levels and CRP (r = 0.26), LBP (r = 0.24), and alpha-AGP (r = 0.22) concentrations had weaker correlations. JADAS-27 scores correlated with LBP (r = 0.66) and alpha-1AGP concentrations (r = 0.58). CONCLUSION: Children with polyarticular JIA, oligoarticular JIA, and SpA have evidence of increased exposure to gut bacterial products. These data reinforce the concept that the intestine is a source of immune stimulation in JIA. PMID- 28916546 TI - Approach to Membranous Lupus Nephritis: A Survey of Pediatric Nephrologists and Pediatric Rheumatologists. AB - OBJECTIVE: To describe treatment practices for childhood pure membranous lupus nephritis (MLN). METHODS: Survey study of Childhood Arthritis and Rheumatology Research Alliance and American Society of Pediatric Nephrology members. RESULTS: There were 117 respondents who completed the survey (60 pediatric nephrologists, 57 pediatric rheumatologists). Steroids and nonsteroid immunosuppression (NSI) were routinely used by the majority for MLN. Mycophenolate mofetil was the favored initial NSI. Nephrologists used steroids (60% vs 93%) and NSI (53% vs 87%) less often than did rheumatologists for MLN without nephrotic syndrome (NS). CONCLUSION: Pediatric rheumatologists and nephrologists both recommend steroids and NSI for children with MLN, with or without NS. PMID- 28916544 TI - Muscle Deficits in Rheumatoid Arthritis Contribute to Inferior Cortical Bone Structure and Trabecular Bone Mineral Density. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with muscle loss, osteoporosis, and fracture. We examined associations between skeletal muscle mass, strength, and quality and trabecular and cortical bone deficits in patients with RA and healthy controls. METHODS: Participants, ages 18-75 years, completed whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT) of the tibia to quantify appendicular lean mass and fat mass indices (ALMI, FMI), muscle density at the lower leg, trabecular bone density, and cortical bone thickness. Age-, sex-, and race-specific Z scores were calculated based on distributions in controls. Associations between body composition and pQCT bone outcomes were assessed in patients with RA and controls. Linear regression analyses assessed differences in bone outcomes after considering differences in body mass index (BMI) and body composition. RESULTS: The sample consisted of 112 patients with RA (55 men) and 412 controls (194 men). Compared to controls, patients with RA had greater BMI Z score (p < 0.001), lower ALMI Z score after adjustment for FMI (p = 0.02), lower muscle strength Z score (p = 0.01), and lower muscle density Z score (p < 0.001). Among RA, ALMI Z scores were positively associated with trabecular density [beta: 0.29 (0.062-0.52); p = 0.01] and cortical thickness [beta: 0.33 (0.13-0.53; p = 0.002]. Associations were similar in controls. Bone outcomes were inferior in patients with RA after adjusting for BMI, but similar to controls when adjusting for body composition. Radiographic damage and higher adiponectin levels were independently associated with inferior bone outcomes. CONCLUSION: Patients with RA exhibit deficits in cortical bone structure and trabecular density at the tibia and a preserved functional muscle-bone unit. A loss of mechanical loading may contribute to bone deficits. PMID- 28916547 TI - Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study. AB - OBJECTIVE: The aim of our study was to determine whether an automated capture and analysis system could detect differences in structure and function of sublingual microvessels in patients with systemic sclerosis (SSc) compared to healthy controls. METHODS: Intravital microscopy of the sublingual microcirculation was automatically captured and analyzed in 40 patients with SSc and 10 age-matched healthy controls. RESULTS: Total and perfused microvascular density were lower in patients with SSc compared with controls (total microvascular density: 2471 +/- 134 um/mm2 vs 3067 +/- 197 um/mm2, p = 0.020; perfused microvascular density: 1708 +/- 92 um/mm2 vs 2192 +/- 144 um/mm2, p = 0.009). However, the relative percentage of perfused to total microvascular density was similar between SSc and controls (72 +/- 2% vs 71 +/- 2%, respectively, p = 0.429). Mean red blood cell (RBC) fraction, which indicates the longitudinal tube hematocrit of microvessel segments, was lower in patients with SSc compared with controls (69 +/- 1% vs 77 +/- 1%, respectively, p < 0.001). Perfused boundary region (PBR), a marker of endothelial glycocalyx barrier properties, was higher in patients with SSc compared with controls (2.1 +/- 0.0 um vs 1.9 +/- 0.0 um, respectively, p = 0.012), suggestive of a dysfunctional glycocalyx. There was an inverse association of PBR with perfused microvascular density (r = -0.40, p = 0.004) and RBC fraction (r = -0.80, p < 0.001). CONCLUSION: Our results indicate that automated capture and analysis of sublingual microvessel segments produces detailed, objective microvascular structural and functional data that have allowed us to distinguish patients with SSc from controls. These data suggest that microvascular structural and functional abnormalities present in patients with SSc could be at least partly due to a dysfunctional glycocalyx. PMID- 28916548 TI - Do Comorbidities Play a Role in Hand Osteoarthritis Disease Burden? Data from the Hand Osteoarthritis in Secondary Care Cohort. AB - OBJECTIVE: Because the association and its clinical relevance between comorbidities and primary hand osteoarthritis (OA) disease burden is unclear, we studied this in patients with hand OA from our Hand OSTeoArthritis in Secondary care (HOSTAS) cohort. METHODS: Cross-sectional data from the HOSTAS study were used, including consecutive patients with primary hand OA. Nineteen comorbidities were assessed: 18 self-reported (modified Charlson index and osteoporosis) and obesity (body mass index >= 30 kg/m2). Mean differences were estimated between patients with versus without comorbidities, adjusted for age and sex: for general disease burden [health-related quality of life (HRQOL), Medical Outcomes Study Short Form-36 physical component scale (0-100)] and disease-specific burden [self reported hand function (0-36), pain (0-20; Australian/Canadian Hand OA Index), and tender joint count (TJC, 0-30)]. Differences above a minimal clinically important improvement/difference were considered clinically relevant. RESULTS: The study included 538 patients (mean age 61 yrs, 86% women, 88% fulfilled American College of Rheumatology classification criteria). Mean (SD) HRQOL, function, pain, and TJC were 44.7 (8), 15.6 (9), 9.3 (4), and 4.8 (5), respectively. Any comorbidity was present in 54% (287/531) of patients and this was unfavorable [adjusted mean difference presence/absence any comorbidity (95% CI): HRQOL -4.4 (-5.8 to -3.0), function 1.9 (0.4-3.3), pain 1.4 (0.6-2.1), TJC 1.3 (0.4-2.2)]. Number of comorbidities and both musculoskeletal (e.g., connective tissue disease) and nonmusculoskeletal comorbidities (e.g., pulmonary and cardiovascular disease) were associated with disease burden. Associations with HRQOL and function were clinically relevant. CONCLUSION: Comorbidities showed clinically relevant associations with disease burden. Therefore, the role of comorbidities in hand OA should be considered when interpreting disease outcomes and in patient management. PMID- 28916549 TI - Positron Emission Tomography/Computerized Tomography in Newly Diagnosed Patients with Giant Cell Arteritis Who Are Taking Glucocorticoids. AB - OBJECTIVE: Large vessel uptake on positron emission tomography/computerized tomography (PET/CT) supports the diagnosis of giant cell arteritis (GCA). Its value, however, in patients without arteritis on temporal artery biopsy and in those receiving glucocorticoids remains unknown. We compared PET/CT results in GCA patients with positive (TAB+) and negative temporal artery biopsies (TAB-), and controls. METHODS: Patients with new clinically diagnosed GCA starting treatment with glucocorticoids underwent temporal artery biopsy and PET/CT. Using a visual semiquantitative approach, 18F-fluorodeoxyglucose (FDG) uptake was scored in 8 vascular territories and summed overall to give a total score in patients and matched controls. RESULTS: Twenty-eight patients with GCA and 28 controls were enrolled. Eighteen patients with GCA were TAB+. Mean PET/CT scores after an average of 11.9 days of prednisone were higher in patients with GCA compared to controls, for both total uptake (10.34 +/- 2.72 vs 7.73 +/- 2.56; p = 0.001), and in 6 of 8 specific vascular territories. PET/CT scores were similar between TAB+ and TAB- patients with GCA. The optimal cutoff for distinguishing GCA cases from controls was a total PET/CT score of >= 9, with an area under the receiver-operating characteristic curve of 0.75, sensitivity 71.4%, and specificity 64.3%. Among patients with GCA, these measures correlated with greater total PET/CT scores: systemic symptoms (p = 0.015), lower hemoglobin (p = 0.009), and higher platelet count (p = 0.008). CONCLUSION: Vascular FDG uptake scores were increased in most patients with GCA despite exposure to prednisone; however, the sensitivity and specificity of PET/CT in this setting were lower than those previously reported. PMID- 28916550 TI - Mortality and Functionality after Stroke in Patients with Systemic Lupus Erythematosus. AB - OBJECTIVE: To investigate mortality and functional impairment after stroke in systemic lupus erythematosus (SLE). METHODS: Using Swedish nationwide registers, we identified 423 individuals with SLE and 1652 people without SLE who developed a first-ever ischemic or hemorrhagic stroke (1998-2013) and followed them until all-cause death or for 1 year. HR for death after ischemic or hemorrhagic stroke and the risk ratio of functional impairment (dependence in either transferring, toileting, or dressing) 3 months after ischemic stroke were estimated. RESULTS: One year after stroke, 22% of patients with SLE versus 16% of those without SLE died. After ischemic stroke, patients with SLE had an increased risk of death (HR 1.85, 95% CI 1.39-2.45), which was attenuated after controlling for SLE-related comorbidities (HR 1.41, 95% CI 1.04-1.91). Functional impairment at 3 months was increased in SLE by almost 2-fold (risk ratio 1.73, 95% CI 1.16-2.57). After hemorrhagic stroke, patients with SLE had an HR of 2.30 (95% CI 1.38-3.82) for death, which was increased even during the first month. CONCLUSION: Compared to subjects without SLE, mortality after ischemic stroke increases after the first month in individuals with SLE, and functionality is worse at 3 months. SLE is associated with all-cause death after hemorrhagic stroke even during the first month. A shift of focus to patient functionality and prevention of hemorrhagic strokes is required. PMID- 28916552 TI - "What I cannot create, I do not understand". PMID- 28916551 TI - Genetic Determinants of Radiographic Knee Osteoarthritis in African Americans. AB - OBJECTIVE: The etiology of knee osteoarthritis (OA), the most common form of arthritis, is complex and may differ by race or ethnicity. In recent years, genetic studies have identified many genetic variants associated with OA, but nearly all the studies were conducted in European whites and Asian Americans. Few studies have focused on the genetics of knee OA in African Americans. METHODS: We performed a genome-wide association study of radiographic knee OA in 1217 African Americans from 2 North American cohort studies: 590 subjects from the Johnston County Osteoarthritis Project and 627 subjects from the Osteoarthritis Initiative. Analyses were conducted in each cohort separately and combined in an inverse variance fixed effects metaanalysis, which were then included in pathway analyses. We additionally tested 12 single-nucleotide polymorphisms robustly associated with OA in European white populations for association in African Americans. RESULTS: We identified a genome-wide significant variant in LINC01006 (minor allele frequency 12%; p = 4.11 * 10-9) that is less common in European white populations (minor allele frequency < 3%). Five other independent loci reached suggestive significance (p < 1 * 10-6). In pathway analyses, dorsal/ventral neural tube patterning and iron ion transport pathways were significantly associated with knee OA in African Americans (false discovery rate < 0.05). We found no evidence that previously reported OA susceptibility variants in European whites were associated with knee OA in African Americans. CONCLUSION: These results highlight differences in the genetic architecture of knee OA between African American and European whites. This finding underscores the need to include more diverse populations in OA genetics studies. PMID- 28916557 TI - Study of fall risk-increasing drugs in elderly patients before and after a bone fracture. AB - BACKGROUND: Accidental falls have a significant economic and human impact. The use of certain drugs is one of the modifiable risk factors associated with these events. OBJECTIVE: The aim of this study was to determine the prevalence of use and to explore changes in treatment with fall-related drugs in patients over 65 years of age admitted as a result of a fall-related fracture. METHODS: Observational and prospective study performed in a tertiary level hospital. A list of fall risk-increasing drugs (FRIDs) was drawn up. The main study variables were number and type of FRIDs prescribed at admission and 1 month after the fracture and number, type, treating physician and place where changes in FRIDs were implemented. RESULTS: In total, 252 patients were included. At admission, 91.3% were receiving at least one FRID, mean daily use was 3.1 FRIDs and the most frequently prescribed FRIDs were diuretics (18%), renin-angiotensin system-acting agents (15.8%) and antidepressants (15%). One month later, mean daily use was 3.4 FRIDs (p=0.099) and a significant increase was detected in the use of hypnotics (p=0.003) and antidepressants (p=0.042). A total of 327 changes in treatment were recorded (1.3 changes/patient). Of the changes, 52.6% were new prescriptions, 72.2% occurred at discharge and 56.6% were ordered by a geriatrician. CONCLUSIONS: The use of FRIDs among patients with a fall-related fracture is very high. This use rises 1 month after the fracture, significantly in the case of hypnotics and antidepressants. PMID- 28916558 TI - Potential of Rice Stubble as a Reservoir of Bradyrhizobial Inoculum in Rice Legume Crop Rotation. AB - Bradyrhizobium encompasses a variety of bacteria that can live in symbiotic and endophytic associations with leguminous and nonleguminous plants, such as rice. Therefore, it can be expected that rice endophytic bradyrhizobia can be applied in the rice-legume crop rotation system. Some endophytic bradyrhizobial strains were isolated from rice (Oryza sativa L.) tissues. The rice biomass could be enhanced when supplementing bradyrhizobial strain inoculation with KNO3, NH4NO3, or urea, especially in Bradyrhizobium sp. strain SUTN9-2. In contrast, the strains which suppressed rice growth were photosynthetic bradyrhizobia and were found to produce nitric oxide (NO) in the rice root. The expression of genes involved in NO production was conducted using a quantitative reverse transcription-PCR (qRT-PCR) technique. The nirK gene expression level in Bradyrhizobium sp. strain SUT-PR48 with nitrate was higher than that of the norB gene. In contrast, the inoculation of SUTN9-2 resulted in a lower expression of the nirK gene than that of the norB gene. These results suggest that SUT-PR48 may accumulate NO more than SUTN9-2 does. Furthermore, the nifH expression of SUTN9-2 was induced in treatment without nitrogen supplementation in an endophytic association with rice. The indole-3-acetic acid (IAA) and 1-amino-cyclopropane-1 carboxylic acid (ACC) deaminase produced in planta by SUTN9-2 were also detected. Enumeration of rice endophytic bradyrhizobia from rice tissues revealed that SUTN9-2 persisted in rice tissues until rice-harvesting season. The mung bean (Vigna radiata) can be nodulated after rice stubbles were decomposed. Therefore, it is possible that rice stubbles can be used as an inoculum in the rice-legume crop rotation system under both low- and high-organic-matter soil conditions.IMPORTANCE This study shows that some rice endophytic bradyrhizobia could produce IAA and ACC deaminase and have a nitrogen fixation ability during symbiosis inside rice tissues. These characteristics may play an important role in rice growth promotion by endophytic bradyrhizobia. However, the NO-producing strains should be of concern due to a possible deleterious effect of NO on rice growth. In addition, this study reports the application of endophytic bradyrhizobia in rice stubbles, and the rice stubbles were used directly as an inoculum for a leguminous plant (mung bean). The degradation of rice stubbles leads to an increased number of SUTN9-2 in the soil and may result in increased mung bean nodulation. Therefore, the persistence of endophytic bradyrhizobia in rice tissues can be developed to use rice stubbles as an inoculum for mung bean in a rice-legume crop rotation system. PMID- 28916559 TI - Omics Analyses of Trichoderma reesei CBS999.97 and QM6a Indicate the Relevance of Female Fertility to Carbohydrate-Active Enzyme and Transporter Levels. AB - The filamentous fungus Trichoderma reesei is found predominantly in the tropics but also in more temperate regions, such as Europe, and is widely known as a producer of large amounts of plant cell wall-degrading enzymes. We sequenced the genome of the sexually competent isolate CBS999.97, which is phenotypically different from the female sterile strain QM6a but can cross sexually with QM6a. Transcriptome data for growth on cellulose showed that entire carbohydrate-active enzyme (CAZyme) families are consistently differentially regulated between these strains. We evaluated backcrossed strains of both mating types, which acquired female fertility from CBS999.97 but maintained a mostly QM6a genetic background, and we could thereby distinguish between the effects of strain background and female fertility or mating type. We found clear regulatory differences associated with female fertility and female sterility, including regulation of CAZyme and transporter genes. Analysis of carbon source utilization, transcriptomes, and secondary metabolites in these strains revealed that only a few changes in gene regulation are consistently correlated with different mating types. Different strain backgrounds (QM6a versus CBS999.97) resulted in the most significant alterations in the transcriptomes and in carbon source utilization, with decreased growth of CBS999.97 on several amino acids (for example proline or alanine), which further correlated with the downregulation of genes involved in the respective pathways. In combination, our findings support a role of fertility associated processes in physiology and gene regulation and are of high relevance for the use of sexual crossing in combining the characteristics of two compatible strains or quantitative trait locus (QTL) analysis.IMPORTANCETrichoderma reesei is a filamentous fungus with a high potential for secretion of plant cell wall degrading enzymes. We sequenced the genome of the fully fertile field isolate CBS999.97 and analyzed its gene regulation characteristics in comparison with the commonly used laboratory wild-type strain QM6a, which is not female fertile. Additionally, we also evaluated fully fertile strains with genotypes very close to that of QM6a in order to distinguish between strain-specific and fertility specific characteristics. We found that QM6a and CBS999.97 clearly differ in their growth patterns on different carbon sources, CAZyme gene regulation, and secondary metabolism. Importantly, we found altered regulation of 90 genes associated with female fertility, including CAZyme genes and transporter genes, but only minor mating type-dependent differences. Hence, when using sexual crossing in research and for strain improvement, it is important to consider female fertile and female sterile strains for comparison with QM6a and to achieve optimal performance. PMID- 28916560 TI - CmeABC multidrug efflux pump contributes to antibiotic resistance and promotes Campylobacter jejuni survival and multiplication in Acanthamoeba polyphaga. AB - Campylobacter jejuni is a foodborne pathogen recognized as the leading cause of human bacterial gastroenteritis. The wide use of antibiotics in medicine and in animal husbandry has led to an increased incidence of antibiotic resistance in Campylobacter In addition to a role in multidrug resistance, the Campylobacter CmeABC RND-type efflux pump, which is associated with multidrug resistance (MDR), may also be involved in virulence. As a vehicle of pathogenic microorganisms, the protozoan Acanthamoeba is a good model for the investigation of bacterial survival in the environment and molecular mechanisms of pathogenicity. The interaction between C. jejuni 81-176 and A. polyphaga was investigated in this study by using a modified gentamicin protection assay. In addition, a possible role for the CmeABC MDR pump in this interaction was explored. Here we report that this MDR pump is beneficial for the intracellular survival and multiplication of C. jejuni in A. polyphaga, but is dispensable for biofilm formation and motility.Importance The endosymbiotic relationship between amoebae and microbial pathogens may contribute to persistence and spreading of the latter in the environment, which has significant implications to human health. In this study we found that Campylobacter jejuni was able to survive and multiply inside Acanthamoeba. polyphaga Since these microorganisms can co-exist in the same environment (e.g. in poultry farms), the latter may increase the risk of infection with Campylobacter Our data suggests that, in addition to its role in antibiotic resistance, the CmeABC MDR efflux pump also plays a role in bacterial survival within amoebae. Furthermore, we demonstrated a synergistic effect of the CmeABC MDR efflux pump and TetO on bacterial resistance to tetracycline. Due to its role both in antibiotic resistance and virulence of C. jejuni, the CmeABC MDR efflux pump could be considered as a good target for the development of antibacterial drugs against this pathogen. PMID- 28916561 TI - Succinate Transport Is Not Essential for Symbiotic Nitrogen Fixation by Sinorhizobium meliloti or Rhizobium leguminosarum. AB - Symbiotic nitrogen fixation (SNF) is an energetically expensive process performed by bacteria during endosymbiotic relationships with plants. The bacteria require the plant to provide a carbon source for the generation of reductant to power SNF. While C4-dicarboxylates (succinate, fumarate, and malate) appear to be the primary, if not sole, carbon source provided to the bacteria, the contribution of each C4-dicarboxylate is not known. We address this issue using genetic and systems-level analyses. Expression of a malate-specific transporter (MaeP) in Sinorhizobium meliloti Rm1021 dct mutants unable to transport C4-dicarboxylates resulted in malate import rates of up to 30% that of the wild type. This was sufficient to support SNF with Medicago sativa, with acetylene reduction rates of up to 50% those of plants inoculated with wild-type S. melilotiRhizobium leguminosarum bv. viciae 3841 dct mutants unable to transport C4-dicarboxylates but expressing the maeP transporter had strong symbiotic properties, with Pisum sativum plants inoculated with these strains appearing similar to plants inoculated with wild-type R. leguminosarum This was despite malate transport rates by the mutant bacteroids being 10% those of the wild type. An RNA sequencing analysis of the combined P. sativum-R. leguminosarum nodule transcriptome was performed to identify systems-level adaptations in response to the inability of the bacteria to import succinate or fumarate. Few transcriptional changes, with no obvious pattern, were detected. Overall, these data illustrated that succinate and fumarate are not essential for SNF and that, at least in specific symbioses, l-malate is likely the primary C4-dicarboxylate provided to the bacterium.IMPORTANCE Symbiotic nitrogen fixation (SNF) is an economically and ecologically important biological process that allows plants to grow in nitrogen-poor soils without the need to apply nitrogen-based fertilizers. Much research has been dedicated to this topic to understand this process and to eventually manipulate it for agricultural gains. The work presented in this article provides new insights into the metabolic integration of the plant and bacterial partners. It is shown that malate is the only carbon source that needs to be available to the bacterium to support SNF and that, at least in some symbioses, malate, and not other C4-dicarboxylates, is likely the primary carbon provided to the bacterium. This work extends our knowledge of the minimal metabolic capabilities the bacterium requires to successfully perform SNF and may be useful in further studies aiming to optimize this process through synthetic biology approaches. The work describes an engineering approach to investigate a metabolic process that occurs between a eukaryotic host and its prokaryotic endosymbiont. PMID- 28916562 TI - Impact of coil price knowledge by the operator on the cost of aneurysm coiling. A single center study. AB - BACKGROUND: Endovascular treatment of aneurysms with coils is among the most frequent treatments in interventional neuroradiology, and represents an important expense. Each manufacturer has created several types of coils, with prices varying among brands and coil types. The objective of this study was to assess the impact of cost awareness of the exact price of each coil by the operating physician on the total cost of aneurysm coiling. MATERIALS AND METHODS: This was a comparative study conducted over 1 year in a single tertiary care center. The reference cohort and the experimental cohort consisted of all aneurysm embolization procedures performed during the first 6 months and the last 6 months, respectively. During the second period, physicians were given an information sheet with the prices of all available coils and were requested to look at the sheet during each procedure with the instruction to try to reduce the total cost of the coils used. Expenses related to the coiling procedures during each period were compared. RESULTS: 77 aneurysms (39 ruptured) in the reference cohort and 73 aneurysms (36 ruptured) in the experimental cohort were treated, respectively. There was no statistically significant difference regarding aneurysm location and mean size. The overall cost of the coiling procedures, the mean number of coils used per procedure, and the median cost of each procedure did not differ significantly between the two cohorts. CONCLUSION: Awareness of the precise price of coils by operators without any additional measure did not have a scientifically proven impact on the cost of aneurysm embolization. PMID- 28916563 TI - Incidence of retinopathy of prematurity (ROP) and ROP treatment in Switzerland 2006-2015: a population-based analysis. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a severe complication of preterm birth and can lead to severe visual impairment or even blindness if untreated. The incidence of ROP requiring treatment is increasing in some developed countries in conjunction with higher survival rates at the lower end of gestational age (GA). MATERIAL AND METHODS: The incidence of ROP and severe ROP (sROP) requiring treatment in Switzerland was analysed using the SwissNeoNet registry. We conducted a retrospective cohort analysis of very preterm infants with a GA below 32 weeks who were born between 2006 and 2015 in Switzerland. Patient characteristics were stratified according to GA. RESULTS: 9.3% and 1.8% of very preterm infants in Switzerland developed ROP of any stage and sROP, respectively. The incidence of ROP treatment was 1.2%. Patients with 24 and 25 weeks GA had the highest proportion of ROP treatment at 14.5% and 7.3%, respectively, whereas the proportion of treated infants at or above a GA of 29 weeks was 0.06%. Similarly, the risk of sROP declined strongly with increasing GA. During the observation period of 10 years, the incidence of ROP treatment ranged between 0.8% and 2.0%. Incidences of sROP or ROP treatment did not increase over time. CONCLUSION: The incidence of ROP treatment in Switzerland is low and was stable over the analysed period. The low incidence of sROP in patients with a GA of 29 weeks or more leaves room for a redefinition of ROP screening criteria. PMID- 28916564 TI - Modulation of the gut microbiome: a systematic review of the effect of bariatric surgery. AB - OBJECTIVE: Bariatric surgery is recommended for patients with obesity and type 2 diabetes. Recent evidence suggested a strong connection between gut microbiota and bariatric surgery. DESIGN: Systematic review. METHODS: The PubMed and OVID EMBASE were used, and articles concerning bariatric surgery and gut microbiota were screened. The main outcome measures were alterations of gut microbiota after bariatric surgery and correlations between gut microbiota and host metabolism. We applied the system of evidence level to evaluate the alteration of microbiota. Modulation of short-chain fatty acid and gut genetic content was also investigated. RESULTS: Totally 12 animal experiments and 9 clinical studies were included. Based on strong evidence, 4 phyla (Bacteroidetes, Fusobacteria, Verrucomicrobia and Proteobacteria) increased after surgery; within the phylum Firmicutes, Lactobacillales and Enterococcus increased; and within the phylum Proteobacteria, Gammaproteobacteria, Enterobacteriales Enterobacteriaceae and several genera and species increased. Decreased microbial groups were Firmicutes, Clostridiales, Clostridiaceae, Blautia and Dorea. However, the change in microbial diversity is still under debate. Faecalibacterium prausnitzii, Lactobacillus and Coprococcus comes are implicated in many of the outcomes, including body composition and glucose homeostasis. CONCLUSIONS: There is strong evidence to support a considerable alteration of the gut microbiome after bariatric surgery. Deeper investigations are required to confirm the mechanisms that link the gut microbiome and metabolic alterations in human metabolism. PMID- 28916565 TI - Functional specialization of two paralogous TAF12 variants by their selective association with SAGA and TFIID transcriptional regulatory complexes. PMID- 28916566 TI - Perspective: Essential Study Quality Descriptors for Data from Nutritional Epidemiologic Research. AB - Pooled analysis of secondary data increases the power of research and enables scientific discovery in nutritional epidemiology. Information on study characteristics that determine data quality is needed to enable correct reuse and interpretation of data. This study aims to define essential quality characteristics for data from observational studies in nutrition. First, a literature review was performed to get an insight on existing instruments that assess the quality of cohort, case-control, and cross-sectional studies and dietary measurement. Second, 2 face-to-face workshops were organized to determine the study characteristics that affect data quality. Third, consensus on the data descriptors and controlled vocabulary was obtained. From 4884 papers retrieved, 26 relevant instruments, containing 164 characteristics for study design and 93 characteristics for measurements, were selected. The workshop and consensus process resulted in 10 descriptors allocated to "study design" and 22 to "measurement" domains. Data descriptors were organized as an ordinal scale of items to facilitate the identification, storage, and querying of nutrition data. Further integration of an Ontology for Nutrition Studies will facilitate interoperability of data repositories. PMID- 28916568 TI - Perspective: The Paradox in Dietary Advanced Glycation End Products Research-The Source of the Serum and Urinary Advanced Glycation End Products Is the Intestines, Not the Food. AB - Inconsistent research results have impeded our understanding of the degree to which dietary advanced glycation end products (dAGEs) contribute to chronic disease. Early research suggested that Western-style fast foods, including grilled and broiled meats and French fries, contain high levels of proinflammatory advanced glycation end products (AGEs). However, recent studies with state-of-the-art ultraperformance LC-tandem mass spectrometry (UPLC-MS) found that there is no evidence that these foods have elevated levels of dAGEs relative to other foods. Paradoxically, observational research found that the intake of fruits (mainly apples), fruit juices (apple juice), vegetables, nuts, seeds, soy, and nonfat milk, which are foods synonymous with healthy eating, as well as the intake of cold breakfast cereals, whole grains (breads), and sweets, which are sources of high-fructose corn syrup (HFCS), were associated with elevated serum and urinary N-epsilon-carboxymethyl-lysine (CML). Ironically, these are the same foods found to have lower CML levels, as measured by UPLC-MS. One possible explanation for this paradox is that the source of the elevated CML is the intestines, not the food. When considered collectively, dAGE research results are consistent with the "fructositis" hypothesis, which states that intake of foods and beverages with high fructose-to-glucose ratios (HFCS sweetened foods and beverages, agave syrup, crystalline fructose, apple juice, and apple juice blends) promotes the intestinal in situ formation of readily absorbed, proinflammatory extracellular, newly identified, fructose-associated AGE, an overlooked source of immunogenic AGEs. PMID- 28916567 TI - Perspective: An Extension of the STROBE Statement for Observational Studies in Nutritional Epidemiology (STROBE-nut): Explanation and Elaboration. AB - Nutritional epidemiology is an inherently complex and multifaceted research area. Dietary intake is a complex exposure and is challenging to describe and assess, and links between diet, health, and disease are difficult to ascertain. Consequently, adequate reporting is necessary to facilitate comprehension, interpretation, and generalizability of results and conclusions. The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement is an international and collaborative initiative aiming to enhance the quality of reporting of observational studies. We previously presented a checklist of 24 reporting recommendations for the field of nutritional epidemiology, called "the STROBE-nut." The STROBE-nut is an extension of the general STROBE statement, intended to complement the STROBE recommendations to improve and standardize the reporting in nutritional epidemiology. The aim of the present article is to explain the rationale for, and elaborate on, the STROBE-nut recommendations to enhance the clarity and to facilitate the understanding of the guidelines. Examples from the published literature are used as illustrations, and references are provided for further reading. PMID- 28916569 TI - Effects of Anthocyanins on Cardiometabolic Health: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - Numerous clinical trials have examined the role of anthocyanins on cardiometabolic health, but their effects have not been quantitatively synthesized and systematically evaluated. The aim of our study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of anthocyanins on glycemic regulation and lipid profiles in both healthy populations and those with cardiometabolic diseases. The MEDLINE, EMBASE, Cochrane database, OVID EBM Reviews, and clinicaltrials.gov databases were searched until February 2017. RCTs with a duration of >=2 wk that evaluated the effects of anthocyanins on glycemic control, insulin sensitivity, and lipids as either primary or secondary outcomes were included. The Cochrane Risk of Bias tool was used to assess the study quality. Standardized mean differences (SMDs) were determined by random-effects models. Meta-regression, sensitivity, and subgroup analyses were performed to explore the influence of covariates on the overall effects. Thirty-two RCTs (1491 participants) were eligible for meta analysis. Anthocyanins significantly reduced fasting glucose (SMD: -0.31; 95% CI: -0.59, -0.04; I2 = 80.7%), 2-h postprandial glucose (SMD: -0.82; 95% CI: -1.49, 0.15; I2 = 77.7), glycated hemoglobin (SMD: -0.65; 95% CI: -1.00, -0.29; I2 = 72.7%), total cholesterol (SMD: -0.33; 95% CI: -0.62, -0.03; I2 = 86.9%), and LDL (SMD: -0.35; 95% CI: -0.66, -0.05; I2 = 85.2%). Sensitivity analyses showed that the overall effects remained similar by excluding the trials with a high or unclear risk of bias. The significant improvements in glycemic control and lipids support the benefits of anthocyanins in the prevention and management of cardiometabolic disease. Further well-designed RCTs are needed to evaluate the long-term effects of anthocyanins on metabolic profiles and to explore the optimal formula and dosage. The protocol for this review was registered at https://www.crd.york.ac.uk/PROSPERO/#index.php as CRD42016033210. PMID- 28916571 TI - Effect of Soy and Soy Isoflavones on Obesity-Related Anthropometric Measures: A Systematic Review and Meta-analysis of Randomized Controlled Clinical Trials. AB - Soy may be a suitable food for anti-obesity efforts because of its high protein and isoflavone content. We conducted this meta-analysis to evaluate potential effects of soy and soy isoflavones on weight, waist circumference, and fat mass. PubMed, MEDLINE, Scopus, EMBASE, and Cochrane databases were searched. Twenty four trials with soy and 17 trials with isoflavones passed the eligibility stage. According to the results, soy showed no overall statistically significant effect on weight, waist circumference, or fat mass, but a significant increasing effect on weight was observed in some circumstances: for instance, in obese subjects [mean difference (MD): 0.80 kg; 95% CI: 0.15, 1.45 kg; P = 0.02], with ingestions of >=40 g soy protein/d (MD: 0.94 kg; 95% CI: 0.11, 1.77 kg; P = 0.03), with short-term applications (1-3 mo) (MD: 0.45 kg; 95% CI: 0.05, 0.86 kg; P = 0.03), and when soy was compared with meat (MD: 0.36 kg; 95% CI: 0.09, 0.64 kg; P = 0.03) and whey protein (MD: 1.53 kg; 95% CI: 0.10, 2.96 kg; P = 0.04). In contrast to the effects of soy on weight, soy significantly decreased waist circumference in older ages (MD: -0.36 cm; 95% CI: -0.71, -0.01 cm; P = 0.04), in women (MD: -0.32 cm; 95% CI: -0.57, -0.08 cm; P = 0.01), and at doses of <40 g soy protein/d (MD: -0.31 cm; 95% CI: -0.57, -0.05 cm; P = 0.02). Isoflavone studies, conducted only in women, showed that isoflavones may reduce body mass index (BMI; in kg/m2) (MD: -0.26; 95% CI: -0.55, 0.04; P = 0.085), especially in dosages <100 mg/d (MD: -0.48; 95% CI: -0.90, -0.06; P = 0.02) and in intervention periods of 2-6 mo (MD: -0.28; 95% CI: -0.56, 0.00; P = 0.053), but no effect was observed in higher doses or longer intervention periods. Also, a trend for reduced BMI after consumption of isoflavones was observed in Caucasians (MD: 0.35; 95% CI: -0.74, 0.04; P = 0.08). Overall, results showed that, although soy is the major source of isoflavones, soy and isoflavones may have different impacts on weight status. PMID- 28916570 TI - Dietary (Poly)phenols, Brown Adipose Tissue Activation, and Energy Expenditure: A Narrative Review. AB - The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted. PMID- 28916572 TI - Anthropometric Indicators as Body Fat Discriminators in Children and Adolescents: A Systematic Review and Meta-Analysis. AB - We analyzed the discriminatory capacity of anthropometric indicators for body fat in children and adolescents. This systematic review and meta-analysis included cross-sectional and clinical studies comprising children and adolescents aged 2 19 y that tested the discriminatory value for body fat measured by anthropometric methods or indexes generated by anthropometric variables compared with precision methods in the diagnosis of body fat [dual-energy X-ray absorptiometry (DXA), computed tomography, air displacement plethysmography (ADP), or MRI]. Five studies met the eligibility criteria and presented high methodologic quality. The anthropometric indicators that had high discriminatory power to identify high body fat were body mass index (BMI) in males [area under the curve (AUC): 0.975] and females (AUC: 0.947), waist circumference (WC) in males (AUC: 0.975) and females (AUC: 0.959), and the waist-to-height ratio (WTHR) in males (AUC: 0.897) and females (AUC: 0.914). BMI, WC, and WTHR can be used by health professionals to assess body fat in children and adolescents. PMID- 28916573 TI - Abdominal Obesity and Risk of Hip Fracture: A Systematic Review and Meta-Analysis of Prospective Studies. AB - Data on the association between general obesity and hip fracture were summarized in a 2013 meta-analysis; however, to our knowledge, no study has examined the association between abdominal obesity and the risk of hip fracture. The present systematic review and meta-analysis of prospective studies was undertaken to summarize the association between abdominal obesity and the risk of hip fracture. We searched online databases for relevant publications up to February 2017, using relevant keywords. In total, 14 studies were included in the systematic review and 9 studies, with a total sample size of 295,674 individuals (129,964 men and 165,703 women), were included in the meta-analysis. Participants were apparently healthy and aged >=40 y. We found that abdominal obesity (defined by various waist-hip ratios) was positively associated with the risk of hip fracture (combined RR: 1.24, 95% CI: 1.05, 1.46, P = 0.01). Combining 8 effect sizes from 6 studies, we noted a marginally significant positive association between abdominal obesity (defined by various waist circumferences) and the risk of hip fracture (combined RR: 1.36; 95% CI: 0.97, 1.89, P = 0.07). This association became significant in a fixed-effects model (combined effect size: 1.40, 95% CI: 1.25, 1.58, P < 0.001). Based on 5 effect sizes, we found that a 0.1-U increase in the waist-hip ratio was associated with a 16% increase in the risk of hip fracture (combined RR: 1.16, 95% CI: 1.04, 1.29, P = 0.007), whereas a 10-cm increase in waist circumference was not significantly associated with a higher risk of hip fracture (combined RR: 1.13, 95% CI: 0.94, 1.36, P = 0.19). This association became significant, however, when we applied a fixed-effects model (combined effect size: 1.21, 95% CI: 1.15, 1.27, P < 0.001). We found that abdominal obesity was associated with a higher risk of hip fracture in 295,674 individuals. Further studies are needed to test whether there are associations between abdominal obesity and fractures at other bone sites. PMID- 28916574 TI - Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 beta Casein. AB - This is the first systematic review, to our knowledge, of published studies investigating the gastrointestinal effects of A1-type bovine beta-casein (A1) compared with A2-type bovine beta-casein (A2). The review is relevant to nutrition practice given the increasing availability and promotion in a range of countries of dairy products free of A1 for both infant and adult nutrition. In vitro and in vivo studies (all species) were included. In vivo studies were limited to oral consumption. Inclusion criteria encompassed all English-language primary research studies, but not reviews, involving milk, fresh-milk products, beta-casein, and beta-casomorphins published through 12 April 2017. Studies involving cheese and fermented milk products were excluded. Only studies with a specific gastrointestinal focus were included. However, inclusion was not delimited by specific gastrointestinal outcome nor by a specific mechanism. Inclusion criteria were satisfied by 39 studies. In vivo consumption of A1 relative to A2 delays intestinal transit in rodents via an opioid-mediated mechanism. Rodent models also link consumption of A1 to the initiation of inflammatory response markers plus enhanced Toll-like receptor expression relative to both A2 and nonmilk controls. Although most rodent responses are confirmed as opioid-mediated, there is evidence that dipeptidyl peptidase 4 stimulation in the jejunum of rodents is via a nonopioid mechanism. In humans, there is evidence from a limited number of studies that A1 consumption is also associated with delayed intestinal transit (1 clinical study) and looser stool consistency (2 clinical studies). In addition, digestive discomfort is correlated with inflammatory markers in humans for A1 but not A2. Further research is required in humans to investigate the digestive function effects of A1 relative to A2 in different populations and dietary settings. PMID- 28916575 TI - Effects of Probiotics on Necrotizing Enterocolitis, Sepsis, Intraventricular Hemorrhage, Mortality, Length of Hospital Stay, and Weight Gain in Very Preterm Infants: A Meta-Analysis. AB - Probiotics are increasingly used as a supplement to prevent adverse health outcomes in preterm infants. We conducted a systematic review, meta-analysis, and subgroup analysis of findings from randomized controlled trials (RCTs) to assess the magnitude of the effect of the probiotics on health outcomes among very-low birth-weight (VLBW) infants. Relevant articles from January 2003 to June 2017 were selected from a broad range of databases, including Medline, PubMed, Scopus, and Embase. Studies were included if they used an RCT design, involved a VLBW infant (birthweight <1500 g or gestational age <32 wk) population, included a probiotic intervention group, measured necrotizing enterocolitis (NEC) as a primary outcome, and measured sepsis, mortality, length of hospital stay, weight gain, and intraventricular hemorrhage (IVH) as additional outcomes. The initial database search yielded 132 potentially relevant articles and 32 (n = 8998 infants) RCTs were included in the final meta-analysis. Subgroup analysis was used to evaluate the effects of the moderators on the outcome variables. In the probiotics group, it was found that NEC was reduced by 37% (95% CI: 0.51%, 0.78%), sepsis by 37% (95% CI: 0.72%, 0.97%), mortality by 20% (95% CI: 0.67%, 0.95%), and length of hospital stay by 3.77 d (95% CI: -5.94, -1.60 d). These findings were all significant when compared with the control group. There was inconsistent use of strain types among some of the studies. The results indicate that probiotic consumption can significantly reduce the risk of developing medical complications associated with NEC and sepsis, reduce mortality and length of hospital stay, and promote weight gain in VLBW infants. Probiotics are more effective when taken in breast milk and formula form, consumed for <6 wk, administered with a dosage of <109 CFU/d, and include multiple strains. Probiotics are not effective in reducing the incidence of IVH in VLBW infants. PMID- 28916576 TI - Withholding Feeds and Transfusion-Associated Necrotizing Enterocolitis in Preterm Infants: A Systematic Review. AB - Limited evidence exists to support the withholding of feeds during packed red blood cell (PRBC) transfusion to reduce the incidence of transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants. The aim of the manuscript was to systematically review studies reporting the effect of implementing a policy of withholding feeds on the incidence of TANEC in preterm infants. The following databases were searched for relevant studies published between the databases' inception and December 2016: PubMed, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index of Nursing and Allied Health Literature, and Pediatric Academic Societies Abstract Archive. Other relevant sources were also searched. There were no restrictions on study design. Studies reporting on the incidence of TANEC (stage >=2 necrotizing enterocolitis within 48-72 h) after implementation of a policy of withholding feeds in the peritransfusion period in preterm infants were included. This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. There were no randomized controlled trials (RCTs). Pooled results from 7 non-RCTs (n = 7492) showed that withholding feeds during PRBC transfusion significantly reduced the incidence of TANEC (RR: 0.47; 95% CI: 0.28, 0.80; P = 0.005; I2 = 11%). The overall quality of evidence was moderate on GRADE analysis. These findings suggest that withholding feeds during the peritransfusion period may reduce the risk of TANEC in preterm infants. Adequately powered RCTs are needed to confirm these findings. PMID- 28916577 TI - Evaluation of Nutrition Interventions in Children in Conflict Zones: A Narrative Review. AB - Food and nutrition insecurity becomes increasingly worse in areas affected by armed conflict. Children affected by conflict, or in war-torn settings, face a disproportionate burden of malnutrition and poor health outcomes. As noted by humanitarian response reviews, there is a need for a stronger evidence-based response to humanitarian crises. To achieve this, we systematically searched and evaluated existing nutrition interventions carried out in conflict settings that assessed their impact on children's nutrition status. To evaluate the impact of nutrition interventions on children's nutrition and growth status, we identified published literature through EMBASE, PubMed, and Global Health by using a combination of relevant text words and Medical Subject Heading terms. Studies for this review must have included children (aged <=18 y), been conducted in conflict or postconflict settings, and assessed a nutrition intervention that measured >=1 outcome for nutrition status (i.e., stunting, wasting, or underweight). Eleven studies met the inclusion and exclusion criteria for this review. Five different nutrition interventions were identified and showed modest results in decreasing the prevalence of stunting, wasting, underweight, reduction in severe or moderate acute malnutrition or both, mortality, anemia, and diarrhea. Overall, nutrition interventions in conflict settings were associated with improved children's nutrition or growth status. Emergency nutrition programs should continue to follow recent recommendations to expand coverage and access (beyond refugee camps to rural areas) and ensure that aid and nutrition interventions are distributed equitably in all conflict-affected populations. PMID- 28916578 TI - Nutritional Sustainability: Aligning Priorities in Nutrition and Public Health with Agricultural Production. AB - Nutrition science-based dietary advice urges changes that may have a great impact on agricultural systems. For example, the 2016 Dietary Guidelines for Americans (DGA) recommends greatly increased fruit and vegetable consumption, but the present domestic production is insufficient to accommodate large-scale adoption of these guidelines. Increasing production to the extent needed to meet the DGA will necessitate changes in an already stressed agriculture and food system and will require nutrition and agriculture professionals to come together in open and collegial discourse. All involved need to understand the stress placed on the food system by increasing populations, changing diets, and changing environments, and recognize the major diet-based public health challenges. Furthermore, there is a need to understand the intricate interplay of the myriad parts of the food system and the vast amount of work necessary to make even small changes. New systems approaches are needed, especially at the research level, where nutrition, public health, agriculture, and the food industry work together to solve interconnected problems. Future well-being depends on a sustainable food system that continues to deliver optimal health with minimal impact on the environment. PMID- 28916579 TI - Comment on "Perspective: NutriGrade: A Scoring System to Assess and Judge the Meta-Evidence of Randomized Controlled Trials and Cohort Studies in Nutrition Research". PMID- 28916580 TI - Reply to JJ Meerpohl et al. PMID- 28916581 TI - Optimising impact and sustainability: a qualitative process evaluation of a complex intervention targeted at compassionate care. AB - BACKGROUND: Despite concerns about the degree of compassion in contemporary healthcare, there is a dearth of evidence for health service managers about how to promote compassionate healthcare. This paper reports on the implementation of the Creating Learning Environments for Compassionate Care (CLECC) intervention by four hospital ward nursing teams. CLECC is a workplace educational intervention focused on developing sustainable leadership and work-team practices designed to support team relational capacity and compassionate care delivery. OBJECTIVES: To identify and explain the extent to which CLECC was implemented into existing work practices by nursing staff, and to inform conclusions about how such interventions can be optimised to support compassionate care in acute settings. METHODS: Process evaluation guided by normalisation process theory. Data gathered included staff interviews (n=47), observations (n=7 over 26 hours) and ward manager questionnaires on staffing (n=4). RESULTS: Frontline staff were keen to participate in CLECC, were able to implement many of the planned activities and valued the benefits to their well-being and to patient care. Nonetheless, factors outside of the direct influence of the ward teams mediated the impact and sustainability of the intervention. These factors included an organisational culture focused on tasks and targets that constrained opportunities for staff mutual support and learning. CONCLUSIONS: Relational work in caregiving organisations depends on individual caregiver agency and on whether or not this work is adequately supported by resources, norms and relationships located in the wider system. High cognitive participation in compassionate nursing care interventions such as CLECC by senior nurse managers is likely to result in improved impact and sustainability. PMID- 28916582 TI - Treating the captors: how the ingenuity of a British military doctor saved his camp. PMID- 28916583 TI - A balance and proprioception intervention programme to enhance combat performance in military personnel. AB - BACKGROUND: Optimal functioning of the lower extremities under repeated movements on unstable surfaces is essential for military effectiveness. Intervention training to promote proprioceptive ability should be considered in order to limit the risk for musculoskeletal injuries. The aim of this study was to assess the effect of a proprioceptive intervention programme on static and dynamic postural balance among Israel Defense Forces combat soldiers. METHODS: Twenty-seven male soldiers, aged 18-20 years, from a physical fitness instructor's course, were randomly divided into two groups matched by age and army unit. The intervention group (INT) underwent 4 weeks of proprioceptive exercises for 10 min daily; the control group underwent 4 weeks of upper body stretching exercises for 10 min daily. All participants were tested pre and postintervention for both static and dynamic postural balance. RESULTS: Significant interaction (condition*pre-post test*group) was found for static postural balance, indicating that for the INT group, in condition 3 (on an unstable surface-BOSU), the post-test result was significantly better compared with the pretest result (p<0.05). Following intervention, the INT group showed significant correlations between static postural stability in condition 2 (eyes closed) and the dynamic postural stability (length of time walked on the beam following fatigue) (r ranged from 0.647 to 0.822; p<0.05). CONCLUSIONS: The proprioceptive intervention programme for combat soldiers improved static postural balance on unstable surfaces, and improved the correlation between static postural balance in the eyes closed condition and dynamic postural balance following fatigue. Further longitudinal studies are needed to verify the relationship between proprioception programmes, additional weight bearing and the reduction of subsequent injuries in combat soldiers. PMID- 28916584 TI - Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. AB - Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls (P < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls (P < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of subjects. In conclusion, our novel data suggest that low VWF levels can be associated with significant bleeding and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at www.clinicaltrials.gov as #NCT03167320. PMID- 28916590 TI - US Emergency Department Trends in Imaging for Pediatric Nontraumatic Abdominal Pain. AB - OBJECTIVES: To describe national emergency department (ED) trends in computed tomography (CT) and ultrasound imaging for the evaluation of pediatric nontraumatic abdominal pain from 2007 through 2014. METHODS: We used data from the National Hospital Ambulatory Medical Care Survey to measure trends in CT and ultrasound use among children with nontraumatic abdominal pain. We performed multivariable logistic regression to measure the strength of the association of ED type (pediatric versus general ED) with CT and ultrasound use adjusting for potential confounding variables. RESULTS: Of an estimated 21.1 million ED visits for nontraumatic abdominal pain, 14.6% (95% confidence interval [CI], 13.2% 16.0%) had CT imaging only, 10.9% (95% CI, 9.7%-12.1%) had ultrasound imaging only, and 1.9% (95% CI, 1.4%-2.4%) received both CT and ultrasound. The overall use of CT and ultrasound did not significantly change over the study period (P trend .63 and .90, respectively). CT use was lower among children treated in pediatric EDs compared with general EDs (adjusted odds ratio 0.34; 95% CI, 0.17 0.69). Conversely, ultrasound use was higher among children treated in pediatric EDs compared with general EDs (adjusted odds ratio 2.14; 95% CI, 1.29-3.55). CONCLUSIONS: CT imaging for pediatric patients with nontraumatic abdominal pain has plateaued since 2007 after the steady increase seen in the preceding 9 years. Among this population, an increased likelihood of CT imaging was demonstrated in general EDs compared with pediatric EDs, in which there was a higher likelihood of ultrasound imaging. Dissemination of pediatric-focused radiology protocols to general EDs may help optimize radiation exposure in children. PMID- 28916591 TI - Continuous Glucose Monitoring in Very Preterm Infants: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Impaired glucose control in very preterm infants is associated with increased morbidity, mortality, and poor neurologic outcome. Strategies based on insulin titration have been unsuccessful in achieving euglycemia in absence of an increase in hypoglycemia and mortality. We sought to assess whether glucose administration guided by continuous glucose monitoring (CGM) is more effective than standard of care blood glucose monitoring in maintaining euglycemia in very preterm infants. METHODS: Fifty newborns <=32 weeks' gestation or with birth weight <=1500 g were randomly assigned (1:1) within 48-hours from birth to receive computer-guided glucose infusion rate (GIR) with or without CGM. In the unblinded CGM group, the GIR adjustments were driven by CGM and rate of glucose change, whereas in the blinded CGM group the GIR was adjusted by using standard of care glucometer on the basis of blood glucose determinations. Primary outcome was percentage of time spent in euglycemic range (72-144 mg/dL). Secondary outcomes were percentage of time spent in mild (47-71 mg/dL) and severe (<47 mg/dL) hypoglycemia; percentage of time in mild (145-180 mg/dL) and severe (>180 mg/dL) hyperglycemia; and glucose variability. RESULTS: Neonates in the unblinded CGM group had a greater percentage of time spent in euglycemic range (median, 84% vs 68%, P < .001) and decreased time spent in mild (P = .04) and severe (P = .007) hypoglycemia and in severe hyperglycemia (P = .04) compared with the blinded CGM group. Use of CGM also decreased glycemic variability (SD: 21.6 +/- 5.4 mg/dL vs 27 +/- 7.2 mg/dL, P = .01; coefficient of variation: 22.8% +/- 4.2% vs 27.9% +/- 5.0%; P < .001). CONCLUSIONS: CGM-guided glucose titration can successfully increase the time spent in euglycemic range, reduce hypoglycemia, and minimize glycemic variability in preterm infants during the first week of life. PMID- 28916592 TI - Cytological and Transcriptomic Analyses Reveal Important Roles of CLE19 in Pollen Exine Formation. AB - The CLAVATA3/ESR-RELATED (CLE) peptide signals are required for cell-cell communication in several plant growth and developmental processes. However, little is known regarding the possible functions of the CLEs in the anther. Here, we show that a T-DNA insertional mutant, and dominant-negative (DN) and overexpression (OX) transgenic plants of the CLE19 gene, exhibited significantly reduced anther size and pollen grain number and abnormal pollen wall formation in Arabidopsis (Arabidopsis thaliana). Interestingly, the DN-CLE19 pollen grains showed a more extensively covered surface, but CLE19-OX pollen exine exhibited clearly missing connections in the network and lacked separation between areas that normally form the lacunae. With a combination of cell biological, genetic, and transcriptomic analyses on cle19, DN-CLE19, and CLE19-OX plants, we demonstrated that CLE19-OX plants produced highly vacuolated and swollen aborted microspores (ams)-like tapetal cells, lacked lipidic tapetosomes and elaioplasts, and had abnormal pollen primexine without obvious accumulation of sporopollenin precursors. Moreover, CLE19 is important for the normal expression of more than 1,000 genes, including the transcription factor gene AMS, 280 AMS-downstream genes, and other genes involved in pollen coat and pollen exine formation, lipid metabolism, pollen germination, and hormone metabolism. In addition, the DN CLE19(+/+) ams(-/-) plants exhibited the ams anther phenotype and ams(+/-) partially suppressed the DN-CLE19 transgene-induced pollen exine defects. These findings demonstrate that the proper amount of CLE19 signal is essential for the normal expression of AMS and its downstream gene networks in the regulation of anther development and pollen exine formation. PMID- 28916593 TI - Carnosic Acid and Carnosol, Two Major Antioxidants of Rosemary, Act through Different Mechanisms. AB - Carnosic acid, a phenolic diterpene specific to the Lamiaceae family, is highly abundant in rosemary (Rosmarinus officinalis). Despite numerous industrial and medicinal/pharmaceutical applications of its antioxidative features, this compound in planta and its antioxidant mechanism have received little attention, except a few studies of rosemary plants under natural conditions. In vitro analyses, using high-performance liquid chromatography-ultraviolet and luminescence imaging, revealed that carnosic acid and its major oxidized derivative, carnosol, protect lipids from oxidation. Both compounds preserved linolenic acid and monogalactosyldiacylglycerol from singlet oxygen and from hydroxyl radical. When applied exogenously, they were both able to protect thylakoid membranes prepared from Arabidopsis (Arabidopsis thaliana) leaves against lipid peroxidation. Different levels of carnosic acid and carnosol in two contrasting rosemary varieties correlated with tolerance to lipid peroxidation. Upon reactive oxygen species (ROS) oxidation of lipids, carnosic acid was consumed and oxidized into various derivatives, including into carnosol, while carnosol resisted, suggesting that carnosic acid is a chemical quencher of ROS. The antioxidative function of carnosol relies on another mechanism, occurring directly in the lipid oxidation process. Under oxidative conditions that did not involve ROS generation, carnosol inhibited lipid peroxidation, contrary to carnosic acid. Using spin probes and electron paramagnetic resonance detection, we confirmed that carnosic acid, rather than carnosol, is a ROS quencher. Various oxidized derivatives of carnosic acid were detected in rosemary leaves in low light, indicating chronic oxidation of this compound, and accumulated in plants exposed to stress conditions, in parallel with a loss of carnosic acid, confirming that chemical quenching of ROS by carnosic acid takes place in planta. PMID- 28916594 TI - DELLA-GAF1 Complex Is a Main Component in Gibberellin Feedback Regulation of GA20 Oxidase 2. AB - Gibberellins (GAs) are phytohormones that regulate many aspects of plant growth and development, including germination, elongation, flowering, and floral development. Negative feedback regulation contributes to homeostasis of the GA level. DELLAs are negative regulators of GA signaling and are rapidly degraded in the presence of GAs. DELLAs regulate many target genes, including AtGA20ox2 in Arabidopsis (Arabidopsis thaliana), encoding the GA-biosynthetic enzyme GA 20 oxidase. As DELLAs do not have an apparent DNA-binding motif, transcription factors that act in association with DELLA are necessary for regulating the target genes. Previous studies have identified GAI-ASSOCIATED FACTOR1 (GAF1) as such a DELLA interactor, with which DELLAs act as coactivators, and AtGA20ox2 was identified as a target gene of the DELLA-GAF1 complex. In this study, electrophoretic mobility shift and chromatin immunoprecipitation assays showed that four GAF1-binding sites exist in the AtGA20ox2 promoter. Using transgenic plants, we further evaluated the contribution of the DELLA-GAF1 complex to GA feedback regulation. Mutations in four GAF1-binding sites abolished the negative feedback of AtGA20ox2 in transgenic plants. Our results showed that GAF1-binding sites are necessary for GA feedback regulation of AtGA20ox2, suggesting that the DELLA-GAF1 complex is a main component of the GA feedback regulation of AtGA20ox2. PMID- 28916595 TI - Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy. AB - AIMS: To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers. METHODS: Clinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course. RESULTS: We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma. CONCLUSIONS: Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease. PMID- 28916596 TI - Cutaneous angiosarcoma: a current update. AB - Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm with variable clinical presentation. Although a distinct vascular tumour, cAS shares many overlapping histopathological features with other vasoformative and epithelioid tumours or 'mimickers'. cAS shows aggressive behaviour and carries a grave prognosis, thus early diagnosis is of paramount importance to achieve the best possible outcomes. Recently, several genetic studies were conducted leading to the identification of novel molecular targets in the treatment of cAS. Herein, we present a comprehensive review of cAS with discussion of its clinical, histopathological and molecular aspects, the differential diagnosis, as well as current therapies including ongoing clinical trials. PMID- 28916597 TI - Correction to: Time-Course Reduction in Patient Exposure to Radiation From Coronary Interventional Procedures: The Greater Paris Area Percutaneous Coronary Intervention Registry. PMID- 28916598 TI - Correction to: Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor. PMID- 28916599 TI - Directional Atherectomy Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel Patency: Twelve-Month Results of the DEFINITIVE AR Study. AB - BACKGROUND: Studies assessing drug-coated balloons (DCB) for the treatment of femoropopliteal artery disease are encouraging. However, challenging lesions, such as severely calcified, remain difficult to treat with DCB alone. Vessel preparation with directional atherectomy (DA) potentially improves outcomes of DCB. METHODS AND RESULTS: DEFINITIVE AR study (Directional Atherectomy Followed by a Paclitaxel-Coated Balloon to Inhibit Restenosis and Maintain Vessel Patency A Pilot Study of Anti-Restenosis Treatment) was a multicenter randomized trial designed to estimate the effect of DA before DCB to facilitate the development of future end point-driven randomized studies. One hundred two patients with claudication or rest pain were randomly assigned 1:1 to DA+DCB (n=48) or DCB alone (n=54), and 19 additional patients with severely calcified lesions were treated with DA+DCB. Mean lesion length was 11.2+/-4.0 cm for DA+DCB and 9.7+/ 4.1 cm for DCB (P=0.05). Predilation rate was 16.7% for DA+DCB versus 74.1% for DCB; postdilation rate was 6.3% for DA+DCB versus 33.3% for DCB. Technical success was superior for DA+DCB (89.6% versus 64.2%; P=0.004). Overall bail-out stenting rate was 3.7%, and rate of flow-limiting dissections was 19% for DCB and 2% for DA+DCB (P=0.01). One-year primary outcome of angiographic percent diameter stenosis was 33.6+/-17.7% for DA+DCB versus 36.4+/-17.6% for DCB (P=0.48), and clinically driven target lesion revascularization was 7.3% for DA+DCB and 8.0% for DCB (P=0.90). Duplex ultrasound patency was 84.6% for DA+DCB, 81.3% for DCB (P=0.78), and 68.8% for calcified lesions. Freedom from major adverse events at 1 year was 89.3% for DA+DCB and 90.0% for DCB (P=0.86). CONCLUSIONS: DA+DCB treatment was effective and safe, but the study was not powered to show significant differences between the 2 methods of revascularization in 1-year follow-up. An adequately powered randomized trial is warranted. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique Identifier: NCT01366482. PMID- 28916600 TI - White Blood Cell Count and Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention in the Contemporary Era: Insights From the PARIS Study (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients Registry). AB - BACKGROUND: Elevated white blood cell (WBC) count is associated with increased major adverse cardiovascular events (MACE) in the setting of acute coronary syndrome. The aim of this study was to evaluate whether similar associations persist in an all-comers population of patients undergoing percutaneous coronary intervention in the contemporary era. METHODS AND RESULTS: In the multicenter, prospective, observational PARIS study (Patterns of Non-Adherence to Anti Platelet Regimens in Stented Patients Registry), 4222 patients who underwent percutaneous coronary intervention in the United States and Europe between July 1, 2009, and December 2, 2010, were evaluated. The associations between baseline WBC and MACE (composite of cardiac death, stent thrombosis, spontaneous myocardial infarction, or target lesion revascularization) at 24-month follow-up were analyzed using multivariable Cox regression. Patients with higher WBC were more often younger, smokers, and with less comorbid risk factors compared with those with lower WBC. After adjustment for baseline and procedural characteristics, WBC remained independently associated with MACE (hazard ratio [HR] per 103 cells/MUL increase, 1.05 [95% confidence intervals (CI), 1.02-1.09]; P=0.001), cardiac death (HR, 1.10 [95% CI, 1.05-1.17]; P<0.001), and clinically indicated target revascularization (HR, 1.04 [95% CI, 1.00-1.09]; P=0.03) but not stent thrombosis (HR, 1.07 [95% CI, 0.99-1.16]; P=0.10) or spontaneous myocardial infarction (HR, 1.03 [95% CI, 0.97-1.09]; P=0.29). The association between WBC and MACE was consistent in acute coronary syndrome and non-acute coronary syndrome presentations (interaction P=0.15). CONCLUSIONS: Increased WBC is an independent predictor of MACE after percutaneous coronary intervention in a contemporary all-comers cohort. Further studies to delineate the underlying pathophysiologic role of elevated WBC across a spectrum of coronary artery disease presentations are warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00998127. PMID- 28916601 TI - Gait Speed Can Predict Advanced Clinical Outcomes in Patients Who Undergo Transcatheter Aortic Valve Replacement: Insights From a Japanese Multicenter Registry. AB - BACKGROUND: Gait speed reflects an important factor of frailty and is associated with an increased risk of late mortality in patients with cardiac disease. This study sought to assess the prognostic value of gait speed in elderly patients who underwent transcatheter aortic valve replacement. METHODS AND RESULTS: We investigated the 5-m or 15-feet gait speed (m/sec) in 1256 patients who underwent transcatheter aortic valve implantation using data from the OCEAN-TAVI Japanese multicenter registry (Optimized Catheter Valvular Intervention-Transcatheter Aortic Valve Implantation). Baseline characteristics, procedural outcomes, and all-cause mortality were compared among groups defined by differential gait speed classification: model 1, normal (>0.83 m/sec; n=563; 44.8%), slow (0.5-0.83 m/sec; n=429; 34.2%), slowest (<0.83 m/sec; n=205; 16.3%), unable to walk (n=48; 3.8%); and model 2, classification and regression tree survival model indicating the threshold of gait speed as 0.385 m/sec (>0.385 m/sec; n=1080 versus <=0.385 m/sec; n=117). The cumulative 1-year mortality rate showed significant differences in the classical gait speed groups in model 1 (7.6%, 6.6%, 18.2%, and 40.7%, respectively; P<0.001) and survival classification and regression tree group in model 2 (7.7% versus 21.9%; P<0.001). The slowest walkers and those unable to walk demonstrated independent associations with increased midterm mortality after adjustment for several confounding factors (hazard ratio, 1.83, 4.28; 95% confidence interval, 1.03-3.26, 2.22-8.72; P=0.039, <0.001, respectively). Gait speed <0.385 m/sec determined by classification and regression tree also independently associated with worse prognosis (hazard ratio, 2.40; 95% confidence interval, 1.75-5.88; P=0.001). CONCLUSIONS: Gait speed using both traditional and specific classification is useful as a potential marker for predicting vulnerable patients associated with adverse clinical outcomes after transcatheter aortic valve replacement. PMID- 28916602 TI - Validation Study of Image-Based Fractional Flow Reserve During Coronary Angiography. AB - BACKGROUND: Fractional flow reserve (FFR), an index of the hemodynamic severity of coronary stenoses, is derived from invasive measurements and requires a pressure-monitoring guidewire and hyperemic stimulus. Angiography-derived FFR measurements (FFRangio) may have several advantages. The aim of this study is to assess the diagnostic performance and interobserver reproducibility of FFRangio in patients with stable coronary artery disease. METHODS AND RESULTS: FFRangio is a computational method based on rapid flow analysis for the assessment of FFR. FFRangio uses the patient's hemodynamic data and routine angiograms to generate a complete 3-dimensional coronary tree with color-coded FFR values at any epicardial location. Hyperemic flow ratio is derived from an automatic resistance based lumped model of the entire coronary tree. A total of 203 lesions were analyzed in 184 patients from 4 centers. Values derived using FFRangio ranged from 0.5 to 0.97 (median 0.85) and correlated closely (Spearman rho=0.90; P<0.001) with the invasive FFR measurements, which ranged from 0.5 to 1 (median 0.84). In Bland-Altman analyses, the 95% limits of agreement between these methods ranged from -0.096 to 0.112. Using an FFR cutoff value of 0.80, the sensitivity, specificity, and diagnostic accuracy of FFRangio were 88%, 95%, and 93%, respectively. The intraclass coefficient between 2 blinded operators was 0.962 with a 95% confidence interval from 0.950 to 0.971, P<0.001. CONCLUSIONS: There is a high concordance between FFRangio and invasive FFR. The color-coded display of FFR values during coronary angiography facilitates the integration of physiology and anatomy for decision making on revascularization in patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03005028. PMID- 28916605 TI - Letter by Jia and Jiang Regarding Article, "Defining Prolonged Dwell Time: When Are Advanced Inferior Vena Cava Filter Retrieval Techniques Necessary? An Analysis in 762 Procedures". PMID- 28916604 TI - Coronary Perforation Complicating Percutaneous Coronary Intervention in Patients With a History of Coronary Artery Bypass Surgery: An Analysis of 309 Perforation Cases From the British Cardiovascular Intervention Society Database. AB - BACKGROUND: The evidence base for coronary perforation (CP) occurring during percutaneous coronary intervention in patients with a history of coronary artery bypass surgery (PCI-CABG) is limited and the long-term effects unclear. Using a national PCI database, the incidence, predictors, and outcomes of CP during PCI CABG were defined. METHODS AND RESULTS: Data were analyzed on all PCI-CABG procedures performed in England and Wales between 2005 and 2013. Multivariate logistic regressions and propensity scores were used to identify predictors of CP and its association with outcomes. During the study period, 309 CPs were recorded during 59 644 PCI-CABG procedures with the incidence rising from 0.32% in 2005 to 0.68% in 2013 (P<0.001 for trend). Independent associates of perforation in native vessels included age, chronic occlusive disease intervention, rotational atherectomy use, number of stents, hypertension, and female sex. In graft PCI, predictors of perforation were history of stroke, New York Heart Association class, and number of stents used. In-hospital clinical complications including Q wave myocardial infarction (2.9% versus 0.2%; P<0.001), major bleeding (14.0% versus 0.9%; P<0.001), blood transfusion (3.7% versus 0.2%; P<0.001), and death (10.0% versus 1.1%; P<0.001) were more frequent in patients with CP. A continued excess mortality occurred after perforation, with an odds ratio for 12-month mortality of 1.35 for perforation survivors compared with matched nonperforation survivors without a CP (P<0.0001). CONCLUSIONS: CP is an infrequent event during PCI-CABG but is closely associated with adverse clinical outcomes. A legacy effect of perforation on 12-month mortality was observed. PMID- 28916606 TI - Letter by Czihal and Hoffmann Regarding Article, "Prevalence of Tibial Artery and Pedal Arch Patency by Angiography in Patients With Critical Limb Ischemia and Noncompressible Ankle Brachial Index". PMID- 28916603 TI - Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis. AB - BACKGROUND: Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function. We tested the hypothesis that elamipretide plus PTRA would improve renal function, oxygenation, and RBF in patients with atherosclerotic renal artery stenosis undergoing PTRA. METHODS AND RESULTS: Inpatient studies were performed in patients with severe atherosclerotic renal artery stenosis scheduled for PTRA. Patients were treated before and during PTRA with elamipretide (0.05 mg/kg per hour intravenous infusion, n=6) or placebo (n=8). Stenotic kidney cortical/medullary perfusion and RBF were measured using contrast-enhanced multidetector CT, and renal oxygenation by 3-T blood oxygen level-dependent magnetic resonance imaging before and 3 months after PTRA. Age and basal glomerular filtration rate did not differ between groups. Blood oxygen level-dependent imaging demonstrated increased fractional hypoxia 24 hours after angiography and stenting in placebo (+47%) versus elamipretide (-6%). These were reverted to baseline 3 months later. Stenotic kidney RBF rose (202+/-29-262+/-115 mL/min; P=0.04) 3 months after PTRA in the elamipretide-treated group only. Over 3 months, systolic blood pressure decreased, and estimated glomerular filtration rate increased (P=0.003) more in the elamipretide group than in the placebo group (P=0.11). CONCLUSIONS: Adjunctive elamipretide during PTRA was associated with attenuated postprocedural hypoxia, increased RBF, and improved kidney function in this pilot trial. These data support a role for targeted mitochondrial protection to minimize procedure-associated ischemic injury and to improve outcomes of revascularization for human atherosclerotic renal artery stenosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01755858. PMID- 28916607 TI - Cauliflower-Like Appearance of Calcified Nodules Observed by Coronary Angioscopy. PMID- 28916608 TI - Gait Speed Assessment in Transcatheter Aortic Valve Replacement: A Step in the Right Direction. PMID- 28916609 TI - Response by Desai et al to Letter Regarding Article, "Defining Prolonged Dwell Time: When Are Advanced Inferior Vena Cava Filter Retrieval Techniques Necessary? An Analysis in 762 Procedures". PMID- 28916610 TI - Letter by Piciche Regarding Article, "Effect of Permanent Right Internal Mammary Artery Closure on Coronary Collateral Function and Myocardial Ischemia". PMID- 28916611 TI - Mitochondrial Protective Agents for Ischemia/Reperfusion Injury. PMID- 28916612 TI - Computing Fractional Flow Reserve From Invasive Coronary Angiography: Getting Closer. PMID- 28916613 TI - Time-Intensive Transcriptomics Reveal Temporal Patterns in the Jasmonic Acid Gene Regulatory Network. PMID- 28916616 TI - AACR Cancer Progress Report 2017: Harnessing Research Discoveries to Save Lives. PMID- 28916617 TI - Nivolumab Exposure-Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non-Small Cell Lung Cancer. AB - Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394-405. (c)2017 AACR. PMID- 28916618 TI - Mechanism of Action and Clinical Impact of Ribociclib-Letter. PMID- 28916619 TI - Mechanism of Action and Clinical Impact of Ribociclib-Response. PMID- 28916620 TI - The Anthracycline Metabolite Doxorubicinol Abolishes RyR2 Sensitivity to Physiological Changes in Luminal Ca2+ through an Interaction with Calsequestrin. AB - The chemotherapeutic anthracycline metabolite doxorubicinol (doxOL) has been shown to interact with and disrupt the function of the cardiac ryanodine receptor Ca2+ release channel (RyR2) in the sarcoplasmic reticulum (SR) membrane and the SR Ca2+ binding protein calsequestrin 2 (CSQ2). Normal increases in RyR2 activity in response to increasing diastolic SR [Ca2+] are influenced by CSQ2 and are disrupted in arrhythmic conditions. Therefore, we explored the action of doxOL on RyR2's response to changes in luminal [Ca2+] seen during diastole. DoxOL abolished the increase in RyR2 activity when luminal Ca2+ was increased from 0.1 to 1.5 mM. This was not due to RyR2 oxidation, but depended entirely on the presence of CSQ2 in the RyR2 complex. DoxOL binding to CSQ2 reduced both the Ca2+ binding capacity of CSQ2 (by 48%-58%) and its aggregation, and lowered CSQ2 association with the RyR2 complex by 67%-77%. Each of these effects on CSQ2, and the lost RyR2 response to changes in luminal [Ca2+], was duplicated by exposing native RyR2 channels to subphysiologic (<=1.0 uM) luminal [Ca2+]. We suggest that doxOL and low luminal Ca2+ both disrupt the CSQ2 polymer, and that the association of the monomeric protein with the RyR2 complex shifts the increase in RyR2 activity with increasing luminal [Ca2+] away from the physiologic [Ca2+] range. Subsequently, these changes may render the channel insensitive to changes of luminal Ca2+ that occur through the cardiac cycle. The altered interactions between CSQ2, triadin, and/or junctin and RyR2 may produce an arrhythmogenic substrate in anthracycline-induced cardiotoxicity. PMID- 28916621 TI - 64Cu-Labeled Repebody Molecules for Imaging of Epidermal Growth Factor Receptor Expressing Tumors. AB - The epidermal growth factor receptor (EGFR) is a member of the erbB family of receptors and is overexpressed in many tumor types. A repebody is a newly designed nonantibody protein scaffold for tumor targeting that contains leucine rich repeat modules. In this study, 3 64Cu-labeled anti-EGFR repebodies with different chelators were synthesized, and their biologic characteristics were assessed in cultured cells and tumor-bearing mice. Methods: Repebodies were synthesized with the chelators 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane N,N',N,"-triacetic acid trihydrochloride ([p-SCN-Bn]-NOTA), 2,2',2"-(10-(2-(2,5 dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DOTA-N-hydroxysuccinimide ester), or 1-(p isothiocyanatobenzyl)diethylenetriamine pentaacetic acid trihydrochloride ([p-SCN Bn]-DTPA) in 1.0 M NaHCO3 buffer (pH 9.2) for 24 h. Purified NOTA-, DOTA-, and DTPA-conjugated repebody were radiolabeled with 64Cu in 0.1 M NH4OAc buffer (pH 5.5). To compare the EGFR-binding affinities of the repebodies, cellular uptake studies were performed with the human non-small cell lung cancer cell line H1650 (high expression of EGFR) and the human colon adenocarcinoma cell line SW620 (low expression of EGFR). Biodistribution and small-animal PET imaging studies were performed using H1650 tumor-bearing mice. Results: Radiochemical yields of the 64Cu-labeled repebodies were approximately 70%-80%. Cellular uptake of the NOTA-, DOTA-, and DTPA-repebodies was over 4-fold higher in H1650 cells than in SW620 cells at 1 h. The 3 repebodies had accumulated specifically in H1650 tumor bearing nude mice by 1 h after intravenous injection and were retained for over 24 h, as measured by the percentage injected dose per gram of tissue (%ID/g). Tumor uptake of all repebodies increased from 1 to 6 h (at 1 h, 6.28, 8.46, and 6.91 %ID/g for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 9.4, 8.28, and 10.1 %ID/g, respectively). H1650 tumors were clearly visible after injection of each repebody, with high tumor-to-background ratios (at 1 h, 3.43, 4.89, and 2.38 for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 3.05, 4.36, and 2.08; at 24 h, 3.81, 4.58, and 2.86). Conclusion: The 3 64Cu-repebody complexes demonstrated specific and rapid uptake in EGFR-expressing tumors within 1 h and may have potential as novel EGFR imaging agents for PET. PMID- 28916614 TI - Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. AB - Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72 As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS-FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre-mRNA splicing, stress granule dynamics, and others. These exciting advances reveal the complexity of the pathogenic mechanisms of FTD and ALS and suggest promising molecular targets for future therapeutic interventions in these devastating disorders. PMID- 28916622 TI - Quantification and Determination of Normal 123I-Meta Iodobenzylguanidine Heart-to Mediastinum Ratio (HMR) from Cardiac SPECT/CT and Correlation with Planar HMR. AB - Assessment of cardiac 123I-meta iodobenzylguanidine (123I-mIBG) uptake relies on the heart-to-mediastinum ratio (HMR) derived from planar images. We have developed novel semiautomated quantitative methodologies for assessing HMR from SPECT images using a dedicated cardiac multipinhole SPECT/CT system and determined the lower limit of normal (LLN) SPECT-derived HMR and the correlation to planar-derived HMR. Methods: Twenty-one healthy volunteers were injected with 123I-mIBG and imaged using 2 different cameras. Planar images were acquired using a conventional SPECT camera equipped with parallel hole collimators, and hybrid SPECT/CT images were acquired using a dedicated cardiac SPECT system with 19 pinhole collimators interfaced with 64-slice CT. Planar HMR was calculated as per standard guidelines (manual traditional method) and elliptic region-of-interest (Elip-ROI) and region-growing (RG-ROI) techniques. SPECT HMR was quantified using a new method that incorporates various cardiac and mediastinal segmentation schemes in which upper and lower limits of the heart were determined from CT and the left ventricular ROI, and mean counts were calculated using Elip-ROI and RG ROI techniques. Mean counts in mediastinal ROI were computed from a fixed volume in 3 different regions: upper mediastinum (UM), lower mediastinum (LM), and contralateral lung (CL). HMRs were processed by 2 observers, and reproducibility was assessed by intraclass correlation coefficient and Bland-Altman analysis. Results: Planar HMR calculated using the RG-ROI method showed highest intra- and interobserver levels of agreement compared with Elip-ROI and manual traditional methods. SPECT HMR calculated on the basis of UM, LM, and CL background regions showed excellent intra- and interobserver agreement. SPECT HMR with UM resulted in highest correlation (R = 0.91) with planar HMR compared with that with LM (R = 0.74) and CL (R = 0.73). The LLN of SPECT HMR with UM and that of planar HMR was calculated as 5.5 and 1.6, respectively. The normal values of SPECT-derived HMR and planar-derived HMR were correlated linearly. Conclusion: We reconfirmed the previous planar HMR threshold and determined SPECT LLN HMR for SPECT. Planar HMR can be estimated from SPECT HMR via a simple linear regression equation, allowing use of the new cardiac-dedicated SPECT camera for 123I-mIBG imaging. PMID- 28916623 TI - Efficacy of Radioembolization with 166Ho-Microspheres in Salvage Patients with Liver Metastases: A Phase 2 Study. AB - Radioembolization of liver malignancies with 166Ho-microspheres has been shown to be safe in a phase 1 dose-escalation study. The purpose of this study was to investigate the efficacy of 166Ho radioembolization. Methods: In this prospective single-arm study, 56 patients were enrolled, all with liver metastases refractory to systemic therapy and ineligible for surgical resection. The primary outcome was a response by 2 target lesions on triphasic liver CT scans 3 mo after therapy, as assessed using RECIST, version 1.1. Secondary outcomes included overall tumor response, time to imaging progression, overall survival, toxicity, quality of life, and quantification of the microspheres on SPECT and MRI. Results: Between May 2012 and March 2015, 38 eligible patients were treated, one of whom was not evaluable. In 27 (73%) of 37 patients, the target lesions showed complete response, partial response, or stable disease (disease control) at 3 mo (95% confidence interval [CI], 57%-85%). The median overall survival was 14.5 mo (95% CI, 8.6-22.8 mo). For colorectal cancer patients (n = 23), the median overall survival was 13.4 mo (95% CI, 8.2-15.7 mo). Grade 3 or 4 toxic events after treatment (according to the Common Terminology Criteria for Adverse Events, version 4.03) included abdominal pain (in 18% of patients), nausea (8%), ascites (3%), fatigue (3%), gastric stenosis (3%), hepatic failure (3%), liver abscesses (3%), paroxysmal atrial tachycardia (3%), thoracic pain (3%), upper gastrointestinal hemorrhage (3%), and vomiting (3%). On SPECT, 166Ho could be quantified with high accuracy and precision, with a mean overestimation of 9.3% +/- 7.1% in the liver. Conclusion: Radioembolization with 166Ho-microspheres induced a tumor response with an acceptable toxicity profile in salvage patients with liver metastases. PMID- 28916624 TI - Bone Marrow and NOT Bone Metastases Is What 21st-Century Diagnostic Imaging Must Focus on When Looking for Skeletal Metastases. PMID- 28916625 TI - Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica. AB - We characterized the transcriptional response accompanying maintenance of long term sensitization (LTS) memory in the pleural ganglia of Aplysia californica using microarray (N = 8) and qPCR (N = 11 additional samples). We found that 24 h after memory induction there is strong regulation of 1198 transcripts (748 up and 450 down) in a pattern that is almost completely distinct from what is observed during memory encoding (1 h after training). There is widespread up-regulation of transcripts related to all levels of protein production, from transcription (e.g., subunits of transcription initiation factors) to translation (e.g., subunits of eIF1, eIF2, eIF3, eIF4, eIF5, and eIF2B) to activation of components of the unfolded protein response (e.g., CREB3/Luman, BiP, AATF). In addition, there are widespread changes in transcripts related to cytoskeleton function, synaptic targeting, synaptic function, neurotransmitter regulation, and neuronal signaling. Many of the transcripts identified have previously been linked to memory and plasticity (e.g., Egr, menin, TOB1, IGF2 mRNA binding protein 1/ZBP 1), though the majority are novel and/or uncharacterized. Interestingly, there is regulation that could contribute to metaplasticity potentially opposing or even eroding LTS memory (down-regulation of adenylate cyclase and a putative serotonin receptor, up-regulation of FMRFa and a FMRFa receptor). This study reveals that maintenance of a "simple" nonassociative memory is accompanied by an astonishingly complex transcriptional response. PMID- 28916626 TI - Contextual fear conditioning in zebrafish. AB - Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory. PMID- 28916627 TI - Interactions between medial prefrontal cortex and dorsomedial striatum are necessary for odor span capacity in rats: role of GluN2B-containing NMDA receptors. AB - Working memory is involved in the maintenance and manipulation of information essential for complex cognition. While the neural substrates underlying working memory capacity have been studied in humans, considerably less is known about the circuitry mediating working memory capacity in rodents. Therefore, the present experiments tested the involvement of medial prefrontal cortex (mPFC) and dorsal striatum (STR) in the odor span task (OST), a task proposed to assay working memory capacity in rodents. Initially, Long Evans rats were trained to dig in scented sand for food following a serial delayed nonmatching-to-sample rule. Temporary inactivation of dorsomedial (dm) STR significantly reduced span in well trained rats. Inactivation of mPFC or contralateral disconnection of the mPFC and dmSTR also reduced span. Infusing the GluN2B-containing NMDA receptor antagonist Ro 25-6981 into mPFC did not affect span; however, span was significantly reduced following bilateral Ro 25-6981 infusions into dmSTR or contralateral disconnection of mPFC (inactivation) and dmSTR (Ro 25-6981). These results suggest that span capacity in rats depends on GluN2B-containing NMDA receptor dependent interactions between the mPFC and the dmSTR. Therefore, interventions targeting this circuit may improve the working memory capacity impairments in patients with schizophrenia, Alzheimer's disease, and Parkinson's disease. PMID- 28916628 TI - The impact of threat of shock-induced anxiety on memory encoding and retrieval. AB - Anxiety disorders are the most common mental health disorders, and daily transient feelings of anxiety (or "stress") are ubiquitous. However, the precise impact of both transient and pathological anxiety on higher-order cognitive functions, including short- and long-term memory, is poorly understood. A clearer understanding of the anxiety-memory relationship is important as one of the core symptoms of anxiety, most prominently in post-traumatic stress disorder (PTSD), is intrusive reexperiencing of traumatic events in the form of vivid memories. This study therefore aimed to examine the impact of induced anxiety (threat of shock) on memory encoding and retrieval. Eighty-six healthy participants completed tasks assessing: visuospatial working memory, verbal recognition, face recognition, and associative memory. Critically, anxiety was manipulated within subjects: information was both encoded and retrieved under threat of shock and safe (no shock) conditions. Results revealed that visuospatial working memory was enhanced when information was encoded and subsequently retrieved under threat, and that threat impaired the encoding of faces regardless of the condition in which it was retrieved. Episodic memory and verbal short-term recognition were, however, unimpaired. These findings indicate that transient anxiety in healthy individuals has domain-specific, rather than domain-general, impacts on memory. Future studies would benefit from expanding these findings into anxiety disorder patients to delineate the differences between adaptive and maladaptive responding. PMID- 28916629 TI - Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model. AB - Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24 h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d. The prolonged odor preference memory was selective for the paired odor and was also observed using a specific HDAC6 inhibitor, tubacin, supporting a role for histone acetylation in associative memory. Immunoblot analysis showed that GluA1 receptor membrane expression in the olfactory bulbs of the TSA-treated group was significantly increased at 48 h unlike control rats without TSA. Immunohistochemistry revealed significant increase of GluA1 expression in olfactory bulb glomeruli 5 d after training. These results extend previous evidence for a close relationship between enhanced GluA1 receptor membrane expression and memory expression. Together, these findings provide a new single trial appetitive model for understanding the support and maintenance of memories of varying duration. PMID- 28916630 TI - False memories for shape activate the lateral occipital complex. AB - Previous functional magnetic resonance imaging evidence has shown that false memories arise from higher-level conscious processing regions rather than lower level sensory processing regions. In the present study, we assessed whether the lateral occipital complex (LOC)-a lower-level conscious shape processing region was associated with false memories for shape. During encoding, participants viewed intact or scrambled colored abstract shapes. During retrieval, colored disks were presented and participants indicated whether the corresponding item was previously "intact" or "scrambled." False memories for shape ("intact"/scrambled > "scrambled"/scrambled) activated LOC, which indicates lower level sensory processing regions can support false memory. PMID- 28916631 TI - Experience during early adulthood shapes the learning capacities and the number of synaptic boutons in the mushroom bodies of honey bees (Apis mellifera). AB - The honey bee mushroom bodies (MBs) are brain centers required for specific learning tasks. Here, we show that environmental conditions experienced as young adults affect the maturation of MB neuropil and performance in a MB-dependent learning task. Specifically, olfactory reversal learning was selectively impaired following early exposure to an impoverished environment lacking some of the sensory and social interactions present in the hive. In parallel, the overall number of synaptic boutons increased within the MB olfactory neuropil, whose volume remained unaffected. This suggests that experience of the rich in-hive environment promotes MB maturation and the development of MB-dependent learning capacities. PMID- 28916632 TI - Tissue-, sex-, and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin-like growth factor 2 imprinting control region. AB - Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene (NR3C1) and imprinting control region (ICR) of IGF2 and H19 genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of NR3C1 affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of IGF2/H19 affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different Nr3c1 promoters and Igf2/H19 ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the Nr3c1 CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, Nr3c1 predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. Igf2/H19 ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of Nr3c1 in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat Nr3c1 and Igf2/H19 during aging that are tissue and sex specific. PMID- 28916633 TI - Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia. AB - Chronically altered levels of circulating lipids, termed dyslipidemia, is a significant risk factor for a number of metabolic and cardiovascular morbidities. MicroRNAs (miRNAs) have emerged as important regulators of lipid balance, have been implicated in dyslipidemia, and have been proposed as candidate therapeutic targets in lipid-related disorders including atherosclerosis. A major limitation of most murine studies of miRNAs in lipid metabolic disorders is that they have been performed in just one (or very few) inbred strains, such as C57BL/6. Moreover, although individual miRNAs have been associated with lipid phenotypes, it is well understood that miRNAs likely work together in functional modules. To address these limitations, we implemented a systems genetics strategy using the Diversity Outbred (DO) mouse population. Specifically, we performed gene and miRNA expression profiling in the livers from ~300 genetically distinct DO mice after 18 wk on either a high-fat/high-cholesterol diet or a high-protein diet. Large-scale correlative analysis of these data with a wide range of cardio metabolic end points revealed a co-regulated module of miRNAs significantly associated with circulating low-density lipoprotein cholesterol (LDL-C) levels. The hubs of this module were identified as miR-199a, miR-181b, miR-27a, miR-21_ _1, and miR-24. In sum, we demonstrate that a high-fat/high-cholesterol diet robustly rewires the miRNA regulatory network, and we identify a small group of co-regulated miRNAs that may exert coordinated effects to control circulating LDL C. PMID- 28916634 TI - PPARgamma and retinol binding protein 7 form a regulatory hub promoting antioxidant properties of the endothelium. AB - Peroxisome proliferator-activated receptors (PPARs) are a family of conserved ligand-activated nuclear receptor transcription factors heterogeneously expressed in mammalian tissues. PPARgamma is recognized as a master regulator of adipogenesis, fatty acid metabolism, and glucose homeostasis, but genetic evidence also supports the concept that PPARgamma regulates the cardiovascular system, particularly vascular function and blood pressure. There is now compelling evidence that the beneficial blood pressure-lowering effects of PPARgamma activation are due to its activity in vascular smooth muscle and endothelium, through its modulation of nitric oxide-dependent vasomotor function. Endothelial PPARgamma regulates the production and bioavailability of nitric oxide, while PPARgamma in the smooth muscle regulates the vasomotor response to nitric oxide. We recently identified retinol binding protein 7 (RBP7) as a PPARgamma target gene that is specifically and selectively expressed in the endothelium. In this review, we will discuss the evidence that RBP7 is required to mediate the antioxidant effects of PPARgamma and mediate PPARgamma target gene selectivity in the endothelium. PMID- 28916636 TI - Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell. AB - Cardiac pacemaker cells, including cells of the sinoatrial node, are heterogeneous in size, morphology, and electrophysiological characteristics. The exact extent to which these cells differ electrophysiologically is unclear yet is critical to understanding their functioning. We examined major ionic currents in individual intercaval pacemaker cells (IPCs) sampled from the paracristal, intercaval region (including the sinoatrial node) that were spontaneously beating after enzymatic isolation from rabbit hearts. The beating rate was measured at baseline and after inhibition of the Ca2+ pump with cyclopiazonic acid. Thereafter, in each cell, we consecutively measured the density of funny current ( If), delayed rectifier K+ current ( IK) (a surrogate of repolarization capacity), and L-type Ca2+ current ( ICa,L) using whole cell patch clamp. The ionic current densities varied to a greater extent than previously appreciated, with some IPCs demonstrating very small or zero If . The density of none of the currents was correlated with cell size, while ICa,L and If densities were related to baseline beating rates. If density was correlated with IK density but not with that of ICa,L. Inhibition of Ca2+ cycling had a greater beating rate slowing effect in IPCs with lower If densities. Our numerical model simulation indicated that 1) IPCs with small (or zero) If or small ICa,L can operate via a major contribution of Ca2+ clock, 2) If-Ca2+-clock interplay could be important for robust pacemaking function, and 3) coupled If- IK function could regulate maximum diastolic potential. Thus, we have demonstrated marked electrophysiological heterogeneity of IPCs. This heterogeneity is manifested in basal beating rate and response to interference of Ca2+ cycling, which is linked to If. NEW & NOTEWORTHY In the present study, a hitherto unrecognized range of heterogeneity of ion currents in pacemaker cells from the intercaval region is demonstrated. Relationships between basal beating rate and L-type Ca2+ current and funny current ( If) density are uncovered, along with a positive relationship between If and delayed rectifier K+ current. Links are shown between the response to Ca2+ cycling blockade and If density. PMID- 28916635 TI - Genetics of hypertension: an assessment of progress in the spontaneously hypertensive rat. AB - The application of gene mapping methods to uncover the genetic basis of hypertension in the inbred spontaneously hypertensive rat (SHR) began over 25 yr ago. This animal provides a useful model of genetic high blood pressure, and some of its features are described. In particular, it appears to be a polygenic model of disease, and polygenes participate in human hypertension genetic risk. The SHR hypertension alleles were fixed rapidly by selective breeding in just a few generations and so are presumably common genetic variants present in the outbred Wistar strain from which SHR was created. This review provides a background to the origins and genesis of this rat line. It considers its usefulness as a model organism for a common cardiovascular disease. The progress and obstacles facing mapping are considered in depth, as are the emergence and application of other genome-wide genetic discovery approaches that have been applied to investigate this model. Candidate genes, their identification, and the evidence to support their potential role in blood pressure elevation are considered. The review assesses the progress that has arisen from this work has been limited. Consideration is given to some of the factors that have impeded progress, and prospects for advancing understanding of the genetic basis of hypertension in this model are discussed. PMID- 28916637 TI - Effect of increases in cardiac contractility on cerebral blood flow in humans. AB - The effect of acute increases in cardiac contractility on cerebral blood flow (CBF) remains unknown. We hypothesized that the external carotid artery (ECA) downstream vasculature modifies the direct influence of acute increases in heart rate and cardiac function on CBF regulation. Twelve healthy subjects received two infusions of dobutamine [first a low dose (5 MUg.kg-1.min-1) and then a high dose (15 MUg.kg-1.min-1)] for 12 min each. Cardiac output, blood flow through the internal carotid artery (ICA) and ECA, and echocardiographic measurements were performed during dobutamine infusions. Despite increases in cardiac contractility, cardiac output, and arterial pressure with dobutamine, ICA blood flow and conductance slightly decreased from resting baseline during both low- and high-dose infusions. In contrast, ECA blood flow and conductance increased appreciably during both low- and high-dose infusions. Greater ECA vascular conductance and corresponding increases in blood flow may protect overperfusion of intracranial cerebral arteries during enhanced cardiac contractility and associated increases in cardiac output and perfusion pressure. Importantly, these findings suggest that the acute increase of blood perfusion attributable to dobutamine administration does not cause cerebral overperfusion or an associated risk of cerebral vascular damage.NEW & NOTEWORTHY A dobutamine-induced increase in cardiac contractility did not increase internal carotid artery blood flow despite an increase in cardiac output and arterial blood pressure. In contrast, external carotid artery blood flow and conductance increased. This external cerebral blood flow response may assist with protecting from overperfusion of intracranial blood flow. PMID- 28916638 TI - Pharmacological and physiological assessment of serotonin formation and degradation in isolated preparations from mouse and human hearts. AB - Using transgenic (TG) mice that overexpress the human serotonin (5-HT)4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5 hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT4a receptor antagonist. Fluoxetine, an inhibitor of 5 HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias.NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT. PMID- 28916639 TI - Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report. AB - Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community. PMID- 28916640 TI - Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy. AB - BACKGROUND: Atrial fibrillation (AF), the most common sustained arrhythmia in hypertrophic cardiomyopathy (HCM), is capable of producing symptoms that impact quality of life and is associated with risk for embolic stroke. However, the influence of AF on clinical course and outcome in HCM remains incompletely resolved. METHODS: Records of 1558 consecutive patients followed at the Tufts Medical Center Hypertrophic Cardiomyopathy Institute for 4.8+/-3.4 years (from 2004 to 2014) were accessed. RESULTS: Of the 1558 patients with HCM, 304 (20%) had episodes of AF, of which 226 (74%) were confined to symptomatic paroxysmal AF (average, 5+/-5; range, 1 to >20), whereas 78 (26%) developed permanent AF, preceded by 7+/-6 paroxysmal AF episodes. At last evaluation, 277 patients (91%) are alive at 62+/-13 years of age, including 89% in New York Heart Association class I or II. No difference was found in outcome measures for patients with AF and age- and sex-matched patients with HCM without AF. Four percent of patients with AF died of HCM-related causes (n=11), with annual mortality 0.7%; mortality directly attributable to AF (thromboembolism without prophylactic anticoagulation) was 0.1% per year (n=2 patients). Patients were treated with antiarrhythmic drugs (most commonly amiodarone [n=103] or sotalol [n=78]) and AF catheter ablation (n=49) or the Maze procedure at surgical myectomy (n=72). Freedom from AF recurrence at 1 year was 44% for ablation patients and 75% with the Maze procedure (P<0.001). Embolic events were less common with anticoagulation prophylaxis (4/233, 2%) than without (9/66, 14%) (P<0.001). CONCLUSIONS: Transient symptomatic episodes of AF, often responsible for impaired quality of life, are unpredictable in frequency and timing, but amenable to effective contemporary treatments, and infrequently progress to permanent AF. AF is not a major contributor to heart failure morbidity or a cause of arrhythmic sudden death; when treated, it is associated with low disease-related mortality, no different than for patients without AF. AF is an uncommon primary cause of death in HCM virtually limited to embolic stroke, supporting a low threshold for initiating anticoagulation therapy. PMID- 28916641 TI - Inflammation and Atherosclerosis: The End of a Controversy. PMID- 28916643 TI - New NHS safety watchdog aims to promote openness and avoid "blame culture". PMID- 28916645 TI - Correction: Zika virus has oncolytic activity against glioblastoma stem cells. PMID- 28916644 TI - Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells. AB - Innate lymphoid cells (ILCs) patrol environmental interfaces to defend against infection and protect barrier integrity. Using a genetic tuning model, we demonstrate that the signal-dependent transcription factor (TF) STAT5 is critical for accumulation of all known ILC subsets in mice and reveal a hierarchy of STAT5 dependency for populating lymphoid and nonlymphoid tissues. We apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in natural killer (NK) cells, the prototypical ILC subset, and provide a systems based molecular rationale for its key functions downstream of IL-15. We also uncover surprising features of STAT5 behavior, most notably the wholesale redistribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our data position STAT5 as a central node in the TF network that instructs ILC development, homeostasis, and function and provide mechanistic insights on how it works at cellular and molecular levels. PMID- 28916646 TI - SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family. AB - OBJECTIVE: To demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes. METHODS: Combined genomic and functional validation studies (whole exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family. RESULTS: 5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10-20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype. CONCLUSIONS: Our findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset 'Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like' syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum. PMID- 28916647 TI - The Effect of Common Inversion Polymorphisms In(2L)t and In(3R)Mo on Patterns of Transcriptional Variation in Drosophila melanogaster. AB - Chromosomal inversions are a ubiquitous feature of genetic variation. Theoretical models describe several mechanisms by which inversions can drive adaptation and be maintained as polymorphisms. While inversions have been shown previously to be under selection, or contain genetic variation under selection, the specific phenotypic consequences of inversions leading to their maintenance remain unclear. Here we use genomic sequence and expression data from the Drosophila Genetic Reference Panel (DGRP) to explore the effects of two cosmopolitan inversions, In(2L)t and In(3R)Mo, on patterns of transcriptional variation. We demonstrate that each inversion has a significant effect on transcript abundance for hundreds of genes across the genome. Inversion-affected loci (IAL) appear both within inversions as well as on unlinked chromosomes. Importantly, IAL do not appear to be influenced by the previously reported genome-wide expression correlation structure. We found that five genes involved with sterol uptake, four of which are Niemann-Pick Type 2 orthologs, are upregulated in flies with In(3R)Mo but do not have SNPs in linkage disequilibrium (LD) with the inversion. We speculate that this upregulation is driven by genetic variation in mod(mdg4) that is in LD with In(3R)Mo We find that there is little evidence for a regional or position effect of inversions on gene expression at the chromosomal level, but do find evidence for the distal breakpoint of In(3R)Mo interrupting one gene and possibly disassociating the two flanking genes from regulatory elements. PMID- 28916648 TI - Genome Dynamics of Hybrid Saccharomyces cerevisiae During Vegetative and Meiotic Divisions. AB - Mutation and recombination are the major sources of genetic diversity in all organisms. In the baker's yeast, all mutation rate estimates are in homozygous background. We determined the extent of genetic change through mutation and loss of heterozygosity (LOH) in a heterozygous Saccharomyces cerevisiae genome during successive vegetative and meiotic divisions. We measured genome-wide LOH and base mutation rates during vegetative and meiotic divisions in a hybrid (S288c/YJM789) S. cerevisiae strain. The S288c/YJM789 hybrid showed nearly complete reduction in heterozygosity within 31 generations of meioses and improved spore viability. LOH in the meiotic lines was driven primarily by the mating of spores within the tetrad. The S288c/YJM789 hybrid lines propagated vegetatively for the same duration as the meiotic lines, showed variable LOH (from 2 to 3% and up to 35%). Two of the vegetative lines with extensive LOH showed frequent and large internal LOH tracts that suggest a high frequency of recombination repair. These results suggest significant LOH can occur in the S288c/YJM789 hybrid during vegetative propagation presumably due to return to growth events. The average base substitution rates for the vegetative lines (1.82 * 10-10 per base per division) and the meiotic lines (1.22 * 10-10 per base per division) are the first genome wide mutation rate estimates for a hybrid yeast. This study therefore provides a novel context for the analysis of mutation rates (especially in the context of detecting LOH during vegetative divisions), compared to previous mutation accumulation studies in yeast that used homozygous backgrounds. PMID- 28916649 TI - Genomic Prediction Within and Across Biparental Families: Means and Variances of Prediction Accuracy and Usefulness of Deterministic Equations. AB - A major application of genomic prediction (GP) in plant breeding is the identification of superior inbred lines within families derived from biparental crosses. When models for various traits were trained within related or unrelated biparental families (BPFs), experimental studies found substantial variation in prediction accuracy (PA), but little is known about the underlying factors. We used SNP marker genotypes of inbred lines from either elite germplasm or landraces of maize (Zeamays L.) as parents to generate in silico 300 BPFs of doubled-haploid lines. We analyzed PA within each BPF for 50 simulated polygenic traits, using genomic best linear unbiased prediction (GBLUP) models trained with individuals from either full-sib (FSF), half-sib (HSF), or unrelated families (URF) for various sizes ([Formula: see text]) of the training set and different heritabilities ([Formula: see text] In addition, we modified two deterministic equations for forecasting PA to account for inbreeding and genetic variance unexplained by the training set. Averaged across traits, PA was high within FSF (0.41-0.97) with large variation only for [Formula: see text] and [Formula: see text] [Formula: see text] For HSF and URF, PA was on average ~40-60% lower and varied substantially among different combinations of BPFs used for model training and prediction as well as different traits. As exemplified by HSF results, PA of across-family GP can be very low if causal variants not segregating in the training set account for a sizeable proportion of the genetic variance among predicted individuals. Deterministic equations accurately forecast the PA expected over many traits, yet cannot capture trait-specific deviations. We conclude that model training within BPFs generally yields stable PA, whereas a high level of uncertainty is encountered in across-family GP. Our study shows the extent of variation in PA that must be at least reckoned with in practice and offers a starting point for the design of training sets composed of multiple BPFs. PMID- 28916651 TI - Escherichia coli and Neisseria gonorrhoeae UvrD helicase unwinds G4 DNA structures. AB - G-quadruplex (G4) secondary structures have been implicated in various biological processes, including gene expression, DNA replication and telomere maintenance. However, unresolved G4 structures impede replication progression which can lead to the generation of DNA double-strand breaks and genome instability. Helicases have been shown to resolve G4 structures to facilitate faithful duplication of the genome. Escherichia coli UvrD (EcUvrD) helicase plays a crucial role in nucleotide excision repair, mismatch repair and in the regulation of homologous recombination. Here, we demonstrate a novel role of E. coli and Neisseria gonorrhoeae UvrD in resolving G4 tetraplexes. EcUvrD and Ngonorrhoeae UvrD were proficient in unwinding previously characterized tetramolecular G4 structures. Notably, EcUvrD was equally efficient in resolving tetramolecular and bimolecular G4 DNA that were derived from the potential G4-forming sequences from the genome of E. coli Interestingly, in addition to resolving intermolecular G4 structures, EcUvrD was robust in unwinding intramolecular G4 structures. These data for the first time provide evidence for the role of UvrD in the resolution of G4 structures, which has implications for the in vivo role of UvrD helicase in G4 DNA resolution and genome maintenance. PMID- 28916650 TI - Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress. AB - The sea cucumber, an important economic species, has encountered high mortality since 2013 in northern China because of seasonal environmental stress such as hypoxia, high temperature, and low salinity. MicroRNAs (miRNAs) are important in regulating gene expression in marine organisms in response to environmental change. In this study, high-throughput sequencing was used to investigate alterations in miRNA expression in the sea cucumber under different levels of dissolved oxygen (DO). Nine small RNA libraries were constructed from the sea cucumber respiratory trees. A total of 26 differentially expressed miRNAs, including 12 upregulated and 14 downregulated miRNAs, were observed in severe hypoxia (DO 2 mg/L) compared with mild hypoxia (DO 4 mg/L) and normoxic conditions (DO 8 mg/L). Twelve differentially expressed miRNAs were clustered in severe hypoxia. In addition, real-time PCR revealed that 14 randomly selected differentially expressed miRNAs showed significantly increased expressions in severe hypoxia and the expressions of nine miRNAs, including key miRNAs such as Aja-miR-1, Aja-miR-2008, and Aja-miR-184, were consistent with the sequencing results. Moreover, gene ontology and pathway analyses of putative target genes suggest that these miRNAs are important in redox, transport, transcription, and hydrolysis under hypoxia stress. Notably, novel-miR-1, novel-miR-2, and novel-miR 3 were specifically clustered and upregulated in severe hypoxia, which may provide new insights into novel "hypoxamiR" identification. These results will provide a basis for future studies of miRNA regulation and molecular adaptive mechanisms in sea cucumbers under hypoxia stress. PMID- 28916652 TI - LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression. AB - Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479-90. (c)2017 AACR. PMID- 28916653 TI - YAP Suppresses Lung Squamous Cell Carcinoma Progression via Deregulation of the DNp63-GPX2 Axis and ROS Accumulation. AB - Lung squamous cell carcinoma (SCC), accounting for approximately 30% of non-small cell lung cancer, is often refractory to therapy. Screening a small-molecule library, we identified digitoxin as a high potency compound for suppressing human lung SCC growth in vitro and in vivo Mechanistic investigations revealed that digitoxin attenuated YAP phosphorylation and promoted YAP nuclear sequestration. YAP activation led to excessive accumulation of reactive oxygen species (ROS) by downregulating the antioxidant enzyme GPX2 in a manner related to p63 blockade. In patient-derived xenograft models, digitoxin treatment efficiently inhibited lung SCC progression in correlation with reduced expression of YAP. Collectively, our results highlight a novel tumor-suppressor function of YAP via downregulation of GPX2 and ROS accumulation, with potential implications to improve precision medicine of human lung SCC. Cancer Res; 77(21); 5769-81. (c)2017 AACR. PMID- 28916654 TI - Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma. AB - Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Because of the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to miRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here, we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. miR-23 target genes, including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis, were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis. Cancer Res; 77(22); 6109-18. (c)2017 AACR. PMID- 28916656 TI - Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene Based Photodynamic Therapy. AB - Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH) PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. (c)2017 AACR. PMID- 28916655 TI - Tethering IL2 to Its Receptor IL2Rbeta Enhances Antitumor Activity and Expansion of Natural Killer NK92 Cells. AB - IL2 is an immunostimulatory cytokine for key immune cells including T cells and natural killer (NK) cells. Systemic IL2 supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use is restricted by its serious side effects and limited efficacy due to activation of T regulatory cells (Tregs). IL2 signaling is mediated through interactions with a multi-subunit receptor complex containing IL2Ralpha, IL2Rbeta, and IL2Rgamma. Adult natural killer (NK) cells express only IL2Rbeta and IL2Rgamma subunits and are therefore relatively insensitive to IL2. To overcome these limitations, we created a novel chimeric IL2-IL2Rbeta fusion protein of IL2 and its receptor IL2Rbeta joined via a peptide linker (CIRB). NK92 cells expressing CIRB (NK92CIRB) were highly activated and expanded indefinitely without exogenous IL2. When compared with an IL2-secreting NK92 cell line, NK92CIRB were more activated, cytotoxic, and resistant to growth inhibition. Direct contact with cancer cells enhanced the cytotoxic character of NK92CIRB cells, which displayed superior in vivo antitumor effects in mice. Overall, our results showed how tethering IL2 to its receptor IL2Rbeta eliminates the need for IL2Ralpha and IL2Rbeta, offering a new tool to selectively activate and empower immune therapy. Cancer Res; 77(21); 5938-51. (c)2017 AACR. PMID- 28916657 TI - Tenascin-C and Integrin alpha9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment. AB - Deposition of the extracellular matrix protein tenascin-C is part of the reactive stroma response, which has a critical role in prostate cancer progression. Here, we report that tenascin C is expressed in the bone endosteum and is associated with formation of prostate bone metastases. Metastatic cells cultured on osteo mimetic surfaces coated with tenascin C exhibited enhanced adhesion and colony formation as mediated by integrin alpha9beta1. In addition, metastatic cells preferentially migrated and colonized tenascin-C-coated trabecular bone xenografts in a novel system that employed chorioallantoic membranes of fertilized chicken eggs as host. Overall, our studies deepen knowledge about reactive stroma responses in the bone endosteum that accompany prostate cancer metastasis to trabecular bone, with potential implications to therapeutically target this process in patients. Cancer Res; 77(21); 5977-88. (c)2017 AACR. PMID- 28916658 TI - T Cells Deficient in Diacylglycerol Kinase zeta Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia. AB - Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKzeta) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKzeta-deficient (DGKzeta-/-) mice than wild-type mice. T cells transferred from DGKzeta-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKzeta-/- T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKzeta-deficient T cells increased the levels of IFNgamma and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKzeta may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKzeta targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676-86. (c)2017 AACR. PMID- 28916659 TI - Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance. AB - Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound 5 arose from its major suppression of CK2 mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair. In nude mice with A549/CDDP xenografts, compound 5 exhibited higher anticancer efficacy than cisplatin and chlorambucil by reversing drug resistance, displayed improved effectiveness, and had no toxicity effects. Overall, compound 5 is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance by attenuating CK2-induced MRN-dependent DSB repair. PMID- 28916660 TI - People at high risk of diabetes should undergo intensive lifestyle change, says NICE. PMID- 28916661 TI - Thank you and goodbye! PMID- 28916662 TI - The new editor greets you. PMID- 28916663 TI - Erratum: How common is clinically inactive disease in a prospective cohort of patients with juvenile idiopathic arthritis? The importance of definition. PMID- 28916665 TI - Integrin alpha4 Overexpression on Rat Mesenchymal Stem Cells Enhances Transmigration and Reduces Cerebral Embolism After Intracarotid Injection. AB - BACKGROUND AND PURPOSE: Very late antigen-4 (integrin alpha4beta1)/vascular cell adhesion molecule-1 mediates leukocyte trafficking and transendothelial migration after stroke. Mesenchymal stem cells (MSCs) typically express integrin beta1 but insufficient ITGA4 (integrin alpha4), which limits their homing after intravascular transplantation. We tested whether ITGA4 overexpression on MSCs increases cerebral homing after intracarotid transplantation and reduces MSC borne cerebral embolism. METHODS: Rat MSCs were lentivirally transduced to overexpress ITGA4. In vitro transendothelial migration was assessed using a Boyden chamber assay. Male Wistar rats intracarotidly received 0.5*106 control or modified MSCs 24 hours after sham or stroke surgery. In vivo behavior of MSCs in the cerebral vasculature was observed by intravital microscopy and single-photon emission computed tomography for up to 72 hours. RESULTS: Transendothelial migration of ITGA4-overexpressing MSCs was increased in vitro. MSCs were passively entrapped in microvessels in vivo and occasionally formed large cell aggregates causing local blood flow interruptions. MSCs were rarely found in perivascular niches or parenchyma at 72 hours post-transplantation, but ITGA4 overexpression significantly decreased cell aggregation and ameliorated the evoked cerebral embolism in stroke rats. CONCLUSIONS: ITGA4 overexpression on MSCs enhances transendothelial migration in vitro, but not in vivo, although it improves safety after intracarotid transplantation into stroke rats. PMID- 28916664 TI - Safety of Simultaneous Coronary Artery Bypass Grafting and Carotid Endarterectomy Versus Isolated Coronary Artery Bypass Grafting: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: The optimal operative strategy in patients with severe carotid artery disease undergoing coronary artery bypass grafting (CABG) is unknown. We sought to investigate the safety and efficacy of synchronous combined carotid endarterectomy and CABG as compared with isolated CABG. METHODS: Patients with asymptomatic high-grade carotid artery stenosis >=80% according to ECST (European Carotid Surgery Trial) ultrasound criteria (corresponding to >=70% NASCET [North American Symptomatic Carotid Endarterectomy Trial]) who required CABG surgery were randomly assigned to synchronous carotid endarterectomy+CABG or isolated CABG. To avoid unbalanced prognostic factor distributions, randomization was stratified by center, age, sex, and modified Rankin Scale. The primary composite end point was the rate of stroke or death at 30 days. RESULTS: From 2010 to 2014, a total of 129 patients were enrolled at 17 centers in Germany and the Czech Republic. Because of withdrawal of funding after insufficient recruitment, enrolment was terminated early. At 30 days, the rate of any stroke or death in the intention-to-treat population was 12/65 (18.5%) in patients receiving synchronous carotid endarterectomy+CABG as compared with 6/62 (9.7%) in patients receiving isolated CABG (absolute risk reduction, 8.8%; 95% confidence interval, -3.2% to 20.8%; PWALD=0.12). Also for all secondary end points at 30 days and 1 year, there was no evidence for a significant treatment-group effect although patients undergoing isolated CABG tended to have better outcomes. CONCLUSIONS: Although our results cannot rule out a treatment-group effect because of lack of power, a superiority of the synchronous combined carotid endarterectomy+CABG approach seems unlikely. Five-year follow-up of patients is still ongoing. CLINICAL TRIAL REGISTRATION: URL: https://www.controlled trials.com. Unique identifier: ISRCTN13486906. PMID- 28916666 TI - Regional Evaluation of the Severity-Based Stroke Triage Algorithm for Emergency Medical Services Using Discrete Event Simulation. AB - BACKGROUND AND PURPOSE: The Severity-Based Stroke Triage Algorithm for Emergency Medical Services endorses routing patients with suspected large vessel occlusion acute ischemic strokes directly to endovascular stroke centers (ESCs). We sought to evaluate different specifications of this algorithm within a region. METHODS: We developed a discrete event simulation environment to model patients with suspected stroke transported according to algorithm specifications, which varied by stroke severity screen and permissible additional transport time for routing patients to ESCs. We simulated King County, Washington, and Mecklenburg County, North Carolina, distributing patients geographically into census tracts. Transport time to the nearest hospital and ESC was estimated using traffic-based travel times. We assessed undertriage, overtriage, transport time, and the number needed-to-route, defined as the number of patients enduring additional transport to route one large vessel occlusion patient to an ESC. RESULTS: Undertriage was higher and overtriage was lower in King County compared with Mecklenburg County for each specification. Overtriage variation was primarily driven by screen (eg, 13%-55% in Mecklenburg County and 10%-40% in King County). Transportation time specifications beyond 20 minutes increased overtriage and decreased undertriage in King County but not Mecklenburg County. A low- versus high-specificity screen routed 3.7* more patients to ESCs. Emergency medical services spent nearly twice the time routing patients to ESCs in King County compared with Mecklenburg County. CONCLUSIONS: Our results demonstrate how discrete event simulation can facilitate informed decision making to optimize emergency medical services stroke severity-based triage algorithms. This is the first step toward developing a mature simulation to predict patient outcomes. PMID- 28916667 TI - Cost-Effectiveness of Thrombectomy in Patients With Acute Ischemic Stroke: The THRACE Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: The benefit of mechanical thrombectomy added to intravenous thrombolysis (IVT) in patients with acute ischemic stroke has been largely demonstrated. However, evidence of the economic incentive of this strategy is still limited, especially in the context of a randomized controlled trial. We aimed to analyze whether mechanical thrombectomy combined with IVT (IVMT) is cost-effective when compared with IVT alone. METHODS: Individual-level cost and outcome data were collected in the THRACE randomized controlled trial (Thrombectomie des Arteres Cerebrales) including patients with acute ischemic stroke. Patients were assigned to receive IVT or IVMT. The primary outcomes were modified Rankin Scale score of functional independence at 90 days (score 0-2) and the EuroQol-5D quality-of-life score at 1 year. RESULTS: Treating acute ischemic stroke with IVMT (n=200) versus IVT (n=202) increased the rate of functional independence by 10.9% (53.0% versus 42.1%; P=0.028), at an increased cost of $2116 (?1909), with no significant difference in mortality (12% versus 13%; P=0.70) or symptomatic intracranial hemorrhage (2% versus 2%; P=0.71). The cost per one averted case of disability was estimated at $19 379 (?17 480). The incremental cost per one quality-adjusted life year gained was $14 881 (?13 423). On sensitivity analysis, the probability of cost-effectiveness with IVMT was 84.1% in terms of cases of averted disability and 92.2% in terms of quality adjusted life years. CONCLUSIONS: Based on randomized trial data, this study demonstrates that IVMT used to treat acute ischemic stroke is cost-effective when compared with IVT alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01062698. PMID- 28916668 TI - Procedural Requirements and Certification Paradigms for Stroke Care Delivery: Perspective of Neurointerventional Professional Societies. PMID- 28916669 TI - Asymptomatic Carotid Stenosis in Cardiac Surgery Patients: Is Less More? PMID- 28916671 TI - Atrial Fibrillation Detection: Fishing for An Irregular Heartbeat Before and After Stroke. PMID- 28916670 TI - Stratifying Stroke Risk in Atrial Fibrillation: Beyond Clinical Risk Scores. PMID- 28916672 TI - Effects of Statin Intensity and Adherence on the Long-Term Prognosis After Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Statin is an established treatment for secondary prevention after ischemic stroke. However, the effects of statin intensity and adherence on the long-term prognosis after acute stroke are not well known. METHODS: This retrospective cohort study using a nationwide health insurance claim data in South Korea included patients admitted with acute ischemic stroke between 2002 and 2012. Statin adherence and intensity were determined from the prescription data for a period of 1 year after the index stroke. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. We performed multivariate Cox proportional regression analyses. RESULTS: We included 8001 patients with acute ischemic stroke. During the mean follow-up period of 4.69+/-2.72 years, 2284 patients developed a primary outcome. Compared with patients with no statin, adjusted hazard ratios (95% confidence interval) were 0.74 (0.64-0.84) for good adherence, 0.93 (0.79-1.09) for intermediate adherence, and 1.07 (0.95-1.20) for poor adherence to statin. Among the 1712 patients with good adherence, risk of adverse events was lower in patients with high-intensity statin (adjusted hazard ratio [95% confidence interval], 0.48 [0.24-0.96]) compared with those with low-intensity statin. Neither good adherence nor high intensity of statin was associated with an increased risk of hemorrhagic stroke. CONCLUSIONS: After acute ischemic stroke, high-intensity statin therapy with good adherence was significantly associated with a lower risk of adverse events. PMID- 28916673 TI - Radiographic and Clinical Brain Infarcts in Cardiac and Diagnostic Procedures: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: The incidence of periprocedural brain infarcts varies among cardiovascular procedures. In a systematic review, we compared the ratio of radiographic brain infarcts (RBI) to strokes and transient ischemic attacks across cardiac and vascular procedures. METHODS: We searched MEDLINE and 5 other databases for brain infarcts in aortic valve replacement, coronary artery bypass grafting, cardiac catheterization, and cerebral angiogram through September 2015. We followed the PRISMA (preferred reporting items for systematic reviews and meta analyses) recommendations. We defined symptomatic rate ratio (RR) as ratio of stroke plus transient ischemic attack rate to RBI rate. RESULTS: Twenty-nine studies involving 2124 subjects met the inclusion criteria. In meta-analysis of aortic valve replacements with 494 people, 69.4% (95% confidence interval (CI), 57.6%-81.4%) had RBIs, whereas 3.6% (95% CI, 2.0%-5.2%) had clinical events (RR, 0.08; 95% CI, 0.05-0.12). Coronary artery bypass grafting among 204 patients had 27.4% (95% CI, 6.0%-48.8%) RBIs and 2.4% (95% CI, 0.3%-4.5%) clinical events (RR, 0.11; 95% CI, 0.05-0.26). Cardiac catheterization among 833 people had 8.0% (95% CI, 4.1%-12.0%) RBIs, and 0.6% (95% CI, 0.1%-1.1%) had clinical events (RR, 0.16; 95% CI, 0.08-0.31). Cerebral angiogram among 593 people had 12.8% (95% CI, 6.6 19.0) RBIs and 0.6% (95% CI, 0%-13%) clinical events (RR, 0.10; 95% CI, 0.04 0.27). The RR of all procedures was 0.10 (95% CI, 0.07-0.13) without differences in the RRs across procedures (P=0.29). CONCLUSIONS: One of 10 people with periprocedural RBIs during cardiac surgeries and invasive vascular diagnostic procedures resulted in strokes or transient ischemic attacks, which may serve as a potential surrogate marker of procedural proficiency and perhaps as a predictor of risk for periprocedural strokes. PMID- 28916674 TI - Anticoagulation in Patients With Atrial Fibrillation in the Setting of Prior Hemorrhage: An Ongoing Dilemma. PMID- 28916675 TI - Atrial Fibrillation and Microbleeds. PMID- 28916676 TI - Introducing Focused Updates in Cerebrovascular Disease. PMID- 28916679 TI - Retraction: CYP1B1 Gene Polymorphisms Have Higher Risk for Endometrial Cancer, and Positive Correlations with Estrogen Receptor alpha and Estrogen Receptor beta Expressions. PMID- 28916680 TI - Variation in developmental trajectories of physiological and somatic traits in a common songbird approaching fledging. AB - In avian species, little is known about the development of physiological traits in the days preceding fledging, a critical life history transition marked by a high mortality rate. Developmental trajectory during this period may be flexible based on ecological context or hardwired, with potential costs for variation in growth in the form of oxidative stress. Patterns in development are likely to relate to variation in life history, for which seabirds and aerial insectivores have been well studied, while our focal species is a grassland ground forager, the European starling (Sturnus vulgaris). We show that changes in haematocrit, body mass and wing length are independent of year and brood quality, while changes in haemoglobin concentration are higher in low-quality broods. Moreover, we also identify higher oxidative stress in low-quality year and second broods, a potential cost for maintaining a hardwired developmental trajectory in a lower quality environment. Finally, we experimentally test the effects of food supplementation on development and maturity of chicks at fledging to show that although food increases body mass early in development, it does not change the trajectory or final maturity of chicks at fledging. Collectively this study demonstrates that some developmental changes prior to fledging may be hardwired, but may have long-term oxidative costs in low-quality environments. PMID- 28916678 TI - GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome. AB - High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. (c)2017 AACR. PMID- 28916681 TI - Circannual testis and moult cycles persist under photoperiods that disrupt circadian activity and clock gene cycles in spotted munia. AB - We investigated whether circannual rhythms underlying annual testis maturation and moult cycles are independent of duration and frequency of the light period and circadian clock control in non-photoperiodic spotted munia. Birds were subjected to an aberrant light-dark (LD) cycle (3.5 h L:3.5 h D; T7, where T is the period length of the LD cycle) and continuous light (LL, 24 h L:0 h D), with controls on 12 h L:12 h D (T24, 24 h LD cycle). We measured the behavioural activity pattern of the birds and 24 h mRNA oscillations of circadian clock genes (bmal1, clock, per2, cry1, cry2) in the hypothalamus, the putative site of seasonal timing. Diurnal munia were rhythmic in behaviour with the period of the activity-rest cycle matched to T7 and T24, and became behaviourally arrhythmic with activity scattered throughout 24 h under LL. Similarly, exposure to 3.5 h L:3.5 h D and LL caused arrhythmicity in 24 h clock gene expression, suggesting disruption of internal circadian timing at the transcriptional level; a significant rhythm was found under 12 h L:12 h D. During an exposure of 80 weeks, munia showed two to three cycles of testis maturation and wing primaries moult under all photoperiods, although with a longer period under 12L:12D. Thus, the frequency of light period under 3.5 h L:3.5 h D or LL disrupted circadian clock gene cycles, but did not affect the generation of circannual testis and moult cycles. We conclude that the prevailing light environment and hypothalamic circadian gene cycles do not exert direct control on the timing of the annual reproductive cycle in spotted munia, suggesting independent generation of the circadian and circannual rhythms in seasonally breeding species. PMID- 28916683 TI - 'Blind with hormones' red deer to begin annual rut. PMID- 28916684 TI - Screening dogs before breeding is 'now more important than ever'. PMID- 28916685 TI - Meat from non-stun slaughtered source 'must be clearly labelled' for consumers. PMID- 28916686 TI - Mind Matters Initiative looking to boost vet numbers in mental health campaign. PMID- 28916688 TI - New badger culls for England announced by Defra. PMID- 28916690 TI - Suspect drug interaction in gimmers. AB - Suspect serious adverse event associated with vaccination in gimmersMultiple congenital defects in a stillborn calfSuspected alpha mannosidosis in a bovine fetusClostridial myocarditis in a two-week-old lambOtitis media in pigs These are among matters discussed in the disease surveillance report for May 2017 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 28916691 TI - Equine colic: putting the puzzle together. PMID- 28916692 TI - Does tendon firing quicken time to recovery for superficial digital flexor tendon injury? PMID- 28916693 TI - Use of antibiotics in dogs with aseptic haemorrhagic gastroenteritis. PMID- 28916694 TI - The challenge of teaching undergraduates evidence-based veterinary medicine. AB - The Royal College of Veterinary Surgeons now lists 'How to evaluate evidence' as a day one competence for newly qualified vets. In this article, representatives from each of the veterinary schools in the UK discuss how the challenge of delivering and assessing the concepts of evidence-based veterinary medicine in a crowded undergraduate curriculum can be met. PMID- 28916695 TI - The economics of bovine viral diarrhoea eradication. PMID- 28916696 TI - Reclassification of sheep anthelmintic. PMID- 28916697 TI - Reclassification of sheep anthelmintic. PMID- 28916698 TI - Correction. PMID- 28916699 TI - Hurricane Irma: urgent aid for animals required. PMID- 28916700 TI - A small animal vet with an interest in animal behaviour. PMID- 28916702 TI - The benefits of bursaries. AB - As a vet student, Michelle Townley benefited from a student research bursary awarded by MSD Animal Health. The experiences she gained through her research helped her in clinical practice. She now works for MSD Animal Health and, by coincidence, is the company's bursary coordinator. PMID- 28916703 TI - My career-defining moment: Adrian Pratt. AB - In 2001, an industry job saved my veterinary career. After six years in clinical practice, I had failed to find the job of my dreams. I was disengaged, disenchanted and looking for a way out. I was lost on my personal development journey. PMID- 28916705 TI - The effects of the exopolysaccharide and growth rate on the morphogenesis of the terrestrial filamentous cyanobacterium Nostoc flagelliforme. AB - The terrestrial cyanobacterium Nostoc flagelliforme, which contributes to carbon and nitrogen supplies in arid and semi-arid regions, adopts a filamentous colony form. Owing to its herbal and dietary values, this species has been overexploited. Largely due to the lack of understanding on its morphogenesis, artificial cultivation has not been achieved. Additionally, it may serve as a useful model for recognizing the morphological adaptation of colonial cyanobacteria in terrestrial niches. However, it shows very slow growth in native habitats and is easily disintegrated under laboratory conditions. Thus, a novel experimental system is necessary to explore its morphogenetic mechanism. Liquid cultured N. flagelliforme has been well developed for exopolysaccharide (EPS) production, in which microscopic colonies (micro-colonies) are generally formed. In this study, we sought to gain some insight into the morphogenesis of N. flagelliforme by examining the effects of two external factors, the EPS and environmental stress-related growth rate, on the morphological shaping of micro colonies. Our findings indicate that the EPS matrix could act as a basal barrier, leading to the bending of trichomes during their elongation, while very slow growth is conducive to their straight elongation. These findings will guide future cultivation and application of this cyanobacterium for ecological improvement. PMID- 28916706 TI - The expression of Ldh-c in the skeletal muscle of plateau pika (Ochotona curzoniae) enhances adaptation to a hypoxic environment. AB - The plateau pika (Ochotona curzoniae) is a species of sprint-running alpine animals in the Qinghai-Tibet Plateau, which is a harsh highland hypoxic environment. Ldh-c is expressed in the testis, sperm and somatic tissues of plateau pika. To reveal the role and physiological mechanisms of sperm-specific lactate dehydrogenase (LDH-C4), in plateau pika to adapt to hypoxic environment, an adenoviral line of pMultiRNAi-Ldhc was constructed and injected into the bilateral biceps femoris of the hind legs. The swimming times of the pikas, and the Ldh-c expression levels, total LDH activities and ATP levels in skeletal muscle, were measured after the pikas were raised in the trapped site for 5 days. Our results showed that after Ldh-c was silenced, the sprint-running ability (swimming time) of the plateau pikas was significant decreased, and the total LDH activities and ATP levels were reduced by 28.21% and 27.88%, respectively. Our results indicated that expression of Ldh-c in the skeletal muscle of plateau pika increased anaerobic glycolysis and enhanced adaptation to highland hypoxic environments. PMID- 28916704 TI - Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation. METHODS: Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR. RESULTS: CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF. CONCLUSIONS: CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation. PMID- 28916707 TI - PQN-75 is expressed in the pharyngeal gland cells of Caenorhabditiselegans and is dispensable for germline development. AB - In Caenorhabditis elegans, five pharyngeal gland cells reside in the terminal bulb of the pharynx and extend anterior processes to five contact points in the pharyngeal lumen. Pharyngeal gland cells secrete mucin-like proteins thought to facilitate digestion, hatching, molting and assembly of the surface coat of the cuticle, but supporting evidence has been sparse. Here we show pharyngeal gland cell expression of PQN-75, a unique protein containing an N-terminal signal peptide, nucleoporin (Nup)-like phenylalanine/glycine (FG) repeats, and an extensive polyproline repeat domain with similarities to human basic salivary proline-rich pre-protein PRB2. Imaging of C-terminal tagged PQN-75 shows localization throughout pharyngeal gland cell processes but not the pharyngeal lumen; instead, aggregates of PQN-75 are occasionally found throughout the pharynx, suggesting secretion from pharyngeal gland cells into the surrounding pharyngeal muscle. PQN-75 does not affect fertility and brood size in C. elegans but confers some degree of stress resistance and thermotolerance through unknown mechanisms. PMID- 28916709 TI - CORRECTION: Surviving murine experimental sepsis affects the function and morphology of the inner ear. PMID- 28916708 TI - Architectural delineation and molecular identification of extracellular matrix in ascidian embryos and larvae. AB - The extracellular matrix (ECM) not only provides essential physical scaffolding for cellular constituents but also initiates crucial biochemical and biomechanical cues that are required for tissue morphogenesis. In this study, we utilized wheat germ agglutinin (WGA) staining to characterize the ECM architecture in ascidian embryos and larvae. The results showed three distinct populations of ECM presenting in Ciona embryogenesis: the outer layer localized at the surface of embryo, an inner layer of notochord sheath and the apical ECM secreted by the notochord. To further elucidate the precise structure of Ciona embryonic ECM, we employed scanning and transmission electron microscopy, and found that the outer membrane was relatively thick with short fibres, whereas the ECM layer in notochord sheath was not as thick as the outer membrane but more regular arranged; the lumen between notochord cells was hydrostatic and sticky. Then, we used the RNA sequencing data from the embryos and larvae of Ciona savignyi to identify ECM genes and acquire their expression patterns. We identified 115 unigenes as 67 ECM genes, and 77 unigenes showed dynamic expression changes between different stages. Our results reveal the architecture, molecular composition and dynamic expression profile of ECM in ascidian embryogenesis, and may increase understanding of the function of the ECM in chordate development. PMID- 28916710 TI - APC sets the Wnt tone necessary for cerebral cortical progenitor development. AB - Adenomatous polyposis coli (APC) regulates the activity of beta-catenin, an integral component of Wnt signaling. However, the selective role of the APC-beta catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated beta-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-beta-catenin pathway indicates that the maintenance of appropriate beta-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates beta catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. beta-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of beta-catenin or inhibition of beta-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated beta catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development. PMID- 28916711 TI - Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element. AB - Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled beta-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (gamma) and adult (delta and beta) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus. In contrast, in adult cells, the HBBP1-BGLT3 region contacts the embryonic epsilon-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the HBBP1 region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR-gamma globin contacts. These changes are accompanied by strong increases in gamma globin transcription. Notably, the effects of HBBP1 removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the HBBP1 region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new cis control elements. PMID- 28916713 TI - Amount of smoking, duration of smoking cessation and their interaction with silica exposure in the risk of rheumatoid arthritis among males: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. PMID- 28916712 TI - Identification of new channels by systematic analysis of the mitochondrial outer membrane. AB - The mitochondrial outer membrane is essential for communication between mitochondria and the rest of the cell and facilitates the transport of metabolites, ions, and proteins. All mitochondrial outer membrane channels known to date are beta-barrel membrane proteins, including the abundant voltage dependent anion channel and the cation-preferring protein-conducting channels Tom40, Sam50, and Mdm10. We analyzed outer membrane fractions of yeast mitochondria and identified four new channel activities: two anion-preferring channels and two cation-preferring channels. We characterized the cation preferring channels at the molecular level. The mitochondrial import component Mim1 forms a channel that is predicted to have an alpha-helical structure for protein import. The short-chain dehydrogenase-related protein Ayr1 forms an NADPH regulated channel. We conclude that the mitochondrial outer membrane contains a considerably larger variety of channel-forming proteins than assumed thus far. These findings challenge the traditional view of the outer membrane as an unspecific molecular sieve and indicate a higher degree of selectivity and regulation of metabolite fluxes at the mitochondrial boundary. PMID- 28916715 TI - Response to: 'Different glucosamine sulfate products generate different outcomes on osteoarthritis symptoms' by Reginster et al. PMID- 28916714 TI - Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) have reduced serum low density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL 6 blockade. We aimed to define the metabolic pathways underlying these lipid changes. METHODS: In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three intravenous infusions of the IL-6R blocker tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL. RESULTS: Serum total cholesterol (4.8 vs 5.7 mmol/L, p=0.003), LDL-c (2.9 vs 3.4 mmol/L, p=0.014) and high-density lipoprotein cholesterol (1.23 vs 1.52 mmol/L, p=0.006) increased following tocilizumab therapy. The LDL FCR fell from a state of hypercatabolism to a value approximating that of the normal population (0.53 vs 0.27 pools/day, p=0.006). Changes in FCR correlated tightly with changes in serum LDL-c and C reactive protein but not Clinical Disease Activity Index. CONCLUSIONS: Patients with RA have low serum LDL-c due to hypercatabolism of LDL particles. IL-6 blockade normalises this catabolism in a manner associating with the acute phase response (and thus hepatic IL-6 signalling) but not with RA disease activity as measured clinically. We demonstrate that IL-6 is one of the key drivers of inflammation-driven dyslipidaemia. PMID- 28916716 TI - Deregulation of microRNA expression in purified T and B lymphocytes from patients with primary Sjogren's syndrome. AB - OBJECTIVE: MicroRNAs (miRNAs) play an important role in the pathogenesis of autoimmune diseases such as primary Sjogren's syndrome (pSS). This study is the first to investigate miRNA expression patterns in purified T and B lymphocytes from patients with pSS using a high-throughput quantitative PCR (qPCR) approach. METHODS: Two independent cohorts of both patients with pSS and controls, one for discovery and one for replication, were included in this study. CD4+ T cells and CD19+ B cells were isolated from peripheral blood mononuclear cells by magnetic microbeads and expression of miRNAs was profiled using the Exiqon Human miRNome panel I analysing 372 miRNAs. A selection of differentially expressed miRNAs was replicated in the second cohort using specific qPCR assays. RESULTS: A major difference in miRNA expression patterns was observed between the lymphocyte populations from patients with pSS and controls. In CD4 T lymphocytes, hsa-let-7d 3p, hsa-miR-155-5 p, hsa-miR-222-3 p, hsa-miR-30c-5p, hsa-miR-146a-5p, hsa-miR 378a-3p and hsa-miR-28-5 p were significantly differentially expressed in both the discovery and the replication cohort. In B lymphocytes, hsa-miR-378a-3p, hsa miR-222-3 p, hsa-miR-26a-5p, hsa-miR-30b-5p and hsa-miR-19b-3p were significantly differentially expressed. Potential target mRNAs were enriched in disease relevant pathways. Expression of B-cell activating factor (BAFF) mRNA was inversely correlated with the expression of hsa-miR-30b-5p in B lymphocytes from patients with pSS and functional experiments showed increased expression of BAFF after inhibiting hsa-miR-30b-5p. CONCLUSIONS: This study demonstrates major miRNAs deregulation in T and B cells from patients with pSS in two independent cohorts, which might target genes known to be involved in the pathogenesis of pSS. PMID- 28916717 TI - NLRPs, the subcortical maternal complex and genomic imprinting. AB - Before activation of the embryonic genome, the oocyte provides many of the RNAs and proteins required for the epigenetic reprogramming and the transition to a totipotent state. Targeted disruption of a subset of oocyte-derived transcripts in mice results in early embryonic lethality and cleavage-stage embryonic arrest as highlighted by the members of the subcortical maternal complex (SCMC). Maternal-effect recessive mutations of NLRP7, KHDC3L and NLRP5 in humans are associated with variable reproductive outcomes, biparental hydatidiform moles (BiHM) and widespread multi-locus imprinting disturbances. The precise mechanism of action of these genes is unknown, but the maternal-effect phenomenon suggests a function during early pre-implantation development, while biochemical and genetic studies implement them as SCMC members or interacting partners. In this review article, we discuss the role of the NLRP family members and the SCMC proteins in the establishment of genomic imprints and post-zygotic methylation maintenance, the recent advances made in the understanding of the biology involved in BiHM formation and the wider roles of the SCMC in mammalian reproduction. PMID- 28916718 TI - Potential sperm contributions to the murine zygote predicted by in silico analysis. AB - Paternal contributions to the zygote are thought to extend beyond delivery of the genome and paternal RNAs have been linked to epigenetic transgenerational inheritance in different species. In addition, sperm-egg fusion activates several downstream processes that contribute to zygote formation, including PLC zeta mediated egg activation and maternal RNA clearance. Since a third of the preimplantation developmental period in the mouse occurs prior to the first cleavage stage, there is ample time for paternal RNAs or their encoded proteins potentially to interact and participate in early zygotic activities. To investigate this possibility, a bespoke next-generation RNA sequencing pipeline was employed for the first time to characterise and compare transcripts obtained from isolated murine sperm, MII eggs and pre-cleavage stage zygotes. Gene network analysis was then employed to identify potential interactions between paternally and maternally derived factors during the murine egg-to-zygote transition involving RNA clearance, protein clearance and post-transcriptional regulation of gene expression. Our in silico approach looked for factors in sperm, eggs and zygotes that could potentially interact co-operatively and synergistically during zygote formation. At least five sperm RNAs (Hdac11, Fbxo2, Map1lc3a, Pcbp4 and Zfp821) met these requirements for a paternal contribution, which with complementary maternal co-factors suggest a wider potential for extra-genomic paternal involvement in the developing zygote. PMID- 28916719 TI - KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C. AB - Killer cell immunoglobulin-like receptors (KIRs) are rapidly evolving species specific natural killer (NK) cell receptors associated with protection against multiple different human viral infections. We report that the activating receptor KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases in the context of major histocompatibility complex class I. We started by documenting that peptide LNPSVAATL from the hepatitis C virus (HCV) helicase binds HLA-C*0102, leading to NK cell activation through engagement of KIR2DS2. Although this region is highly conserved across HCV isolates, the sequence is not present in other flaviviral helicases. Embarking on a search for a conserved target of KIR2DS2, we show that HLA-C*0102 presents a different highly conserved peptide from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever, and Japanese encephalitis viruses, to KIR2DS2. In contrast to LNPSVAATL from HCV, these flaviviral peptides all contain an "MCHAT" motif, which is present in 61 of 63 flaviviruses. Despite the difference in the peptide sequences, we show that KIR2DS2 recognizes endogenously presented helicase peptides and that KIR2DS2 is sufficient to inhibit HCV and dengue virus replication in the context of HLA C*0102. Targeting short, but highly conserved, viral peptides provide nonrearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable, pathogenic RNA viruses. PMID- 28916720 TI - Glucose availability controls adipogenesis in mouse 3T3-L1 adipocytes via up regulation of nicotinamide metabolism. AB - Expansion of adipose tissue in response to a positive energy balance underlies obesity and occurs through both hypertrophy of existing cells and increased differentiation of adipocyte precursors (hyperplasia). To better understand the nutrient signals that promote adipocyte differentiation, we investigated the role of glucose availability in regulating adipocyte differentiation and maturation. 3T3-L1 preadipocytes were grown and differentiated in medium containing a standard differentiation hormone mixture and either 4 or 25 mm glucose. Adipocyte maturation at day 9 post-differentiation was determined by key adipocyte markers, including glucose transporter 4 (GLUT4) and adiponectin expression and Oil Red O staining of neutral lipids. We found that adipocyte differentiation and maturation required a pulse of 25 mm glucose only during the first 3 days of differentiation. Importantly, fatty acids were unable to substitute for the 25 mm glucose pulse during this period. The 25 mm glucose pulse increased adiponectin and GLUT4 expression and accumulation of neutral lipids via distinct mechanisms. Adiponectin expression and other early markers of differentiation required an increase in the intracellular pool of total NAD/P. In contrast, GLUT4 protein expression was only partially restored by increased NAD/P levels. Furthermore, GLUT4 mRNA expression was mediated by glucose-dependent activation of GLUT4 gene transcription through the cis-acting GLUT4-liver X receptor element (LXRE) promoter element. In summary, this study supports the conclusion that high glucose promotes adipocyte differentiation via distinct metabolic pathways and independently of fatty acids. This may partly explain the mechanism underlying adipocyte hyperplasia that occurs much later than adipocyte hypertrophy in the development of obesity. PMID- 28916721 TI - Loss of cardiac carnitine palmitoyltransferase 2 results in rapamycin-resistant, acetylation-independent hypertrophy. AB - Cardiac hypertrophy is closely linked to impaired fatty acid oxidation, but the molecular basis of this link is unclear. Here, we investigated the loss of an obligate enzyme in mitochondrial long-chain fatty acid oxidation, carnitine palmitoyltransferase 2 (CPT2), on muscle and heart structure, function, and molecular signatures in a muscle- and heart-specific CPT2-deficient mouse (Cpt2M /-) model. CPT2 loss in heart and muscle reduced complete oxidation of long-chain fatty acids by 87 and 69%, respectively, without altering body weight, energy expenditure, respiratory quotient, or adiposity. Cpt2M-/- mice developed cardiac hypertrophy and systolic dysfunction, evidenced by a 5-fold greater heart mass, 60-90% reduction in blood ejection fraction relative to control mice, and eventual lethality in the absence of cardiac fibrosis. The hypertrophy-inducing mammalian target of rapamycin complex 1 (mTORC1) pathway was activated in Cpt2M-/ hearts; however, daily rapamycin exposure failed to attenuate hypertrophy in Cpt2M-/- mice. Lysine acetylation was reduced by ~50% in Cpt2M-/- hearts, but trichostatin A, a histone deacetylase inhibitor that improves cardiac remodeling, failed to attenuate Cpt2M-/- hypertrophy. Strikingly, a ketogenic diet increased lysine acetylation in Cpt2M-/- hearts 2.3-fold compared with littermate control mice fed a ketogenic diet, yet it did not improve cardiac hypertrophy. Together, these results suggest that a shift away from mitochondrial fatty acid oxidation initiates deleterious hypertrophic cardiac remodeling independent of fibrosis. The data also indicate that CPT2-deficient hearts are impervious to hypertrophy attenuators, that mitochondrial metabolism regulates cardiac acetylation, and that signals derived from alterations in mitochondrial metabolism are the key mediators of cardiac hypertrophic growth. PMID- 28916723 TI - Fibroblast growth factor 2 (FGF2) regulates cytoglobin expression and activation of human hepatic stellate cells via JNK signaling. AB - Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its anti-oxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues. In HHSteC cells, treatment with a culture supplement solution that included fibroblast growth factor 2 (FGF2) increased CYGB expression with concomitant and time-dependent alpha-smooth muscle actin (alphaSMA) down regulation. We found that FGF2 is a key factor in inducing the alteration in both CYGB and alphaSMA expression in HHSteCs and primary HSCs and that FGF2 triggered the rapid phosphorylation of both c-Jun N-terminal kinase (JNK) and c-JUN. Both the JNK inhibitor PS600125 and transfection of c-JUN-targeting siRNA abrogated FGF2-mediated CYGB induction, and conversely, c-JUN overexpression induced CYGB and reduced alphaSMA expression. Chromatin immunoprecipitation analyses revealed that upon FGF2 stimulation, phospho-c-JUN bound to its consensus motif (5' TGA(C/G)TCA), located -218 to -222 bases from the transcription initiation site in the CYGB promoter. Of note, in bile duct-ligated mice, FGF2 administration ameliorated liver fibrosis and significantly reduced HSC activation. In conclusion, FGF2 triggers CYGB gene expression and deactivation of myofibroblastic human HSCs, indicating that FGF2 has therapeutic potential for managing liver fibrosis. PMID- 28916722 TI - Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing. AB - Glycogen synthase kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. In vitro kinase assays and genetic and pharmacological manipulations of GSK-3 have identified more than 100 putative GSK-3 substrates in diverse cell types. Many more have been predicted on the basis of a recurrent GSK-3 consensus motif ((pS/pT)XXX(S/T)), but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. Using stable isotope labeling of amino acids in culture (SILAC) and MS techniques to analyze the repertoire of GSK-3-dependent phosphorylation in mouse embryonic stem cells (ESCs), we found that ~2.4% of (pS/pT)XXX(S/T) sites are phosphorylated in a GSK-3-dependent manner. A comparison of WT and Gsk3a;Gsk3b knock-out (Gsk3 DKO) ESCs revealed prominent GSK-3-dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis as well as proteins that regulate transcription, translation, and cell division. Gsk3 DKO reduced phosphorylation of the splicing factors RBM8A, SRSF9, and PSF as well as the nucleolar proteins NPM1 and PHF6, and recombinant GSK-3beta phosphorylated these proteins in vitro RNA-Seq of WT and Gsk3 DKO ESCs identified ~190 genes that are alternatively spliced in a GSK-3-dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. The MS data also identified posttranscriptional regulation of protein abundance by GSK-3, with ~47 proteins (1.4%) whose levels increased and ~78 (2.4%) whose levels decreased in the absence of GSK-3. This study provides the first unbiased analysis of the GSK 3 phosphoproteome and strong evidence that GSK-3 broadly regulates alternative splicing. PMID- 28916724 TI - A novel mechanism for Ca2+/calmodulin-dependent protein kinase II targeting to L type Ca2+ channels that initiates long-range signaling to the nucleus. AB - Neuronal excitation can induce new mRNA transcription, a phenomenon called excitation-transcription (E-T) coupling. Among several pathways implicated in E-T coupling, activation of voltage-gated L-type Ca2+ channels (LTCCs) in the plasma membrane can initiate a signaling pathway that ultimately increases nuclear CREB phosphorylation and, in most cases, expression of immediate early genes. Initiation of this long-range pathway has been shown to require recruitment of Ca2+-sensitive enzymes to a nanodomain in the immediate vicinity of the LTCC by an unknown mechanism. Here, we show that activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) strongly interacts with a novel binding motif in the N terminal domain of CaV1 LTCC alpha1 subunits that is not conserved in CaV2 or CaV3 voltage-gated Ca2+ channel subunits. Mutations in the CaV1.3 alpha1 subunit N-terminal domain or in the CaMKII catalytic domain that largely prevent the in vitro interaction also disrupt CaMKII association with intact LTCC complexes isolated by immunoprecipitation. Furthermore, these same mutations interfere with E-T coupling in cultured hippocampal neurons. Taken together, our findings define a novel molecular interaction with the neuronal LTCC that is required for the initiation of a long-range signal to the nucleus that is critical for learning and memory. PMID- 28916725 TI - Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation. AB - During tissue development, transcription factors bind regulatory DNA regions called enhancers, often located at great distances from the genes they regulate, to control gene expression. The enhancer landscape during embryonic stem cell differentiation has been well characterized. By contrast, little is known about the shared and unique enhancer regulatory mechanisms in different ectodermally derived epithelial cells. Here we use ChIP sequencing (ChIP-seq) to identify domains enriched for the histone marks histone H3 lysine 4 trimethylation, histone H3 lysine 4 monomethylation, and histone H3 lysine 27 acetylation (H3K4me3, H3K4me1, and H3K27ac) and define, for the first time, the super enhancers and typical enhancers active in primary human corneal epithelial cells. We show that regulatory regions are often shared between cell types of the ectodermal lineage and that corneal epithelial super enhancers are already marked as potential regulatory domains in embryonic stem cells. Kruppel-like factor (KLF) motifs were enriched in corneal epithelial enhancers, consistent with the important roles of KLF4 and KLF5 in promoting corneal epithelial differentiation. We now show that the Kruppel family member KLF7 promotes the corneal progenitor cell state; on many genes, KLF7 antagonized the corneal differentiation-promoting KLF4. Furthermore, we found that two SNPs linked previously to corneal diseases, astigmatism, and Stevens-Johnson syndrome fall within corneal epithelial enhancers and alter their activity by disrupting transcription factor motifs that overlap these SNPs. Taken together, our work defines regulatory enhancers in corneal epithelial cells, highlights global gene-regulatory relationships shared among different epithelial cells, identifies a role for KLF7 as a KLF4 antagonist in corneal epithelial cell differentiation, and explains how two SNPs may contribute to corneal diseases. PMID- 28916726 TI - The NQO1 bioactivatable drug, beta-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism. AB - Many cancer treatments, such as those for managing recalcitrant tumors like pancreatic ductal adenocarcinoma, cause off-target toxicities in normal, healthy tissue, highlighting the need for more tumor-selective chemotherapies. beta Lapachone is bioactivated by NAD(P)H:quinone oxidoreductase 1 (NQO1). This enzyme exhibits elevated expression in most solid cancers and therefore is a potential cancer-specific target. beta-Lapachone's therapeutic efficacy partially stems from the drug's induction of a futile NQO1-mediated redox cycle that causes high levels of superoxide and then peroxide formation, which damages DNA and causes hyperactivation of poly(ADP-ribose) polymerase, resulting in extensive NAD+/ATP depletion. However, the effects of this drug on energy metabolism due to NAD+ depletion were never described. The futile redox cycle rapidly consumes O2, rendering standard assays of Krebs cycle turnover unusable. In this study, a multimodal analysis, including metabolic imaging using hyperpolarized pyruvate, points to reduced oxidative flux due to NAD+ depletion after beta-lapachone treatment of NQO1+ human pancreatic cancer cells. NAD+-sensitive pathways, such as glycolysis, flux through lactate dehydrogenase, and the citric acid cycle (as inferred by flux through pyruvate dehydrogenase), were down-regulated by beta lapachone treatment. Changes in flux through these pathways should generate biomarkers useful for in vivo dose responses of beta-lapachone treatment in humans, avoiding toxic side effects. Targeting the enzymes in these pathways for therapeutic treatment may have the potential to synergize with beta-lapachone treatment, creating unique NQO1-selective combinatorial therapies for specific cancers. These findings warrant future studies of intermediary metabolism in patients treated with beta-lapachone. PMID- 28916728 TI - Association between TLR-9 gene rs187084 polymorphism and knee osteoarthritis in a Chinese population. AB - Osteoarthritis (OA) is a complex disease that is induced by many genetic risk variants and other factors. To examine the role of toll-like receptor 9 (TLR-9) in OA patients, we conducted a case-control study involving 215 knee OA (KOA) patients and 215 controls in a Chinese population. Genotyping with a custom-by design 48-Plex single nucleotide polymorphism ScanTM Kit showed the TLR-9 gene rs187084 polymorphism was associated with an increased risk of KOA. Stratification analyses further validated this finding among old people (age >= 55 years). In conclusion, TLR-9 gene rs187084 polymorphism is positively correlated with susceptibility to KOA, especially among old people. Nevertheless, this finding should be confirmed by larger size studies with more ethnic populations. PMID- 28916727 TI - Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN-gamma released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP. PMID- 28916729 TI - Identification of differential plasma miRNA profiles in Chinese workers with occupational lead exposure. AB - Elevated lead absorptions are hazardous factors in lead-related workers. Previous studies have found its toxic impacts on nervous, circulatory, and metabolic systems. We hypothesized that alteration of miRNAs profile in plasma was closely associated with lead exposure. We analyzed to identify lead-related miRNAs in workers occupationally exposed to lead. Microarray assay was performed to detect plasma miRNA between workers with high and minimal lead exposure in the discovery stage. The following prediction of miRNAs' candidate target genes was carried out by using miRecords, STRING, and KEGG databases. We finally identified four miRNAs significantly associated with high level of blood lead. miR-520c-3p (*P=0.014), miR-211 (*P=0.019), and miR-148a (*P=0.031) were downexpressed in workers with high lead exposure and with high blood lead level (BLL), while miR-572(*P=0.027) displayed an opposite profile. Functional analysis of miRNAs displayed that these miRNAs could trigger different cellular genes and pathways. People under chronic lead exposure had a diverse 'fingerprint' plasma miRNA profile. Our study suggested that miR-520c-3p, miR-211, miR-148a, and miR-572 were the potential biomarkers for lead susceptibility in Chinese. PMID- 28916731 TI - Need for speed in accurate whole-genome data analysis: GENALICE MAP challenges BWA/GATK more than PEMapper/PECaller and Isaac. PMID- 28916730 TI - Reply to Pluss et al.: The strength of PEMapper/PECaller lies in unbiased calling using large sample sizes. PMID- 28916732 TI - IL-4-producing B cells regulate T helper cell dichotomy in type 1- and type 2 controlled diseases. AB - Interleukin-4 (IL-4)-induced T helper (Th) 2 cells promote susceptibility to the protozoan parasite Leishmania major, while conferring immunity to the intestinal trematode Schistosoma mansoni Here, we report that abrogation of IL-4 receptor alpha (IL-4Ralpha) signaling on B cells in BALB/c mice (mb1creIL-4Ralpha-/lox) transformed nonhealer BALB/c to a healer phenotype with an early type 1 and dramatically reduced type 2 immune response and an absence of ulceration and necrosis during cutaneous leishmaniasis. From adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (uMT) mice, we reveal a central role for B cell-derived IL-4 and IL-4Ralpha in the optimal induction of the susceptible type 2 phenotype to L. major infection. We further demonstrate that the absence of IL-4Ralpha signaling on B cells exacerbated S. mansoni-induced mortality and pathology in BALB/c mice, due to a diminished type 2 immune response. In both disease models, IL-4Ralpha-responsive B cells displayed increased IL-4 production as early as day 1 after infection. Together, these results demonstrate that IL-4-producing and IL-4Ralpha-responsive B cells are critical in regulating and assisting early T helper dichotomy toward Th2 responses, which are detrimental in cutaneous leishmaniasis but beneficial in acute schistosomiasis. PMID- 28916734 TI - Fishing for answers in precision cancer medicine. PMID- 28916733 TI - Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. AB - IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions. PMID- 28916736 TI - Silencing of Urothelial Carcinoma Associated 1 Inhibits the Proliferation and Migration of Medulloblastoma Cells. AB - BACKGROUND UCA1 is a long non-coding RNA that has been found to be aberrantly upregulated in various cancers. The aim of this study was to determine the expression level and function of UCA1 in medulloblastoma, the most common malignant brain tumor during childhood. MATERIAL AND METHODS Real-time PCR was used to detect the expression of UCA1 in medulloblastoma specimens and cell lines. Lentiviral-mediated expression of a short hairpin RNA (shRNA) targeting UCA1 or a negative control shRNA was also achieved with the medulloblastoma cell line, Daoy. Cell proliferation and cell cycle progression were subsequently characterized with cell counting kit (CCK)-8 and flow cytometry. Cell migration was examined in wound healing and Transwell migration assays. RESULTS Levels of UCA1 mRNA were higher in the medulloblastoma specimens (p<0.05) and cell lines (p<0.05) compared to the corresponding nontumor adjacent tissue specimens and a glioblastoma cell line, respectively. For the Daoy cells with silenced UCA1, their proliferation was reduced by 30% compared to the Daoy cells expressing a negative control shRNA (p=0.017). Cell cycle arrest in the G0/G1 phase, resulting in a decreased number of cells in the S phase, as well as reduced cell migration in both wound scratch healing (p=0.001) and Transwell migration assays (p=0.021) were also observed for the Daoy cells with silenced UCA1. CONCLUSIONS UCA1 was highly expressed in part of medulloblastoma specimens and cell lines examined. In addition, knockdown of UCA1 significantly inhibited the proliferation and migration of medulloblastoma cells in vitro. PMID- 28916735 TI - Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. AB - The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including beta catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both beta-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies. PMID- 28916737 TI - Determining Ribavirin's mechanism of action against Lassa virus infection. AB - Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin's mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin's main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response. PMID- 28916738 TI - Cold atmospheric helium plasma causes synergistic enhancement in cell death with hyperthermia and an additive enhancement with radiation. AB - Cold atmospheric plasmas (CAPs) have been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain elusive. Therefore, this study examined the effects of cold atmospheric helium plasma (He-CAP) in combination with hyperthermia (HT) 42 degrees C or radiation 5 Gy. Synergistic enhancement in the cell death with HT and an additive enhancement with radiation were observed following He-CAP treatment. The synergistic effects were accompanied by increased intracellular reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2) and superoxide (O2*-) generation was increased immediately after He-CAP treatment, but fails to initiate cell death process. Interestingly, at late hour's He-CAP-induced O2*- generation subsides, however the combined treatment showed sustained increased intracellular O2*- level, and enhanced cell death than either treatment alone. He-CAP caused marked induction of ROS in the aqueous medium, but He-CAP-induced ROS seems insufficient or not completely incorporated intra-cellularly to activate cell death machinery. The observed synergistic effects were due to the HT effects on membrane fluidity which facilitate the incorporation of He-CAP-induced ROS into the cells, thus results in the enhanced cancer cell death following combined treatment. These findings would be helpful when establishing a therapeutic strategy for CAP in combination with HT or radiation. PMID- 28916739 TI - A moso bamboo WRKY gene PeWRKY83 confers salinity tolerance in transgenic Arabidopsis plants. AB - The WRKY family are transcription factors, involved in plant development, and response to biotic and abiotic stresses. Moso bamboo is an important bamboo that has high ecological, economic and cultural value and is widely distributed in the south of China. In this study, we performed a genome-wide identification of WRKY members in moso bamboo and identified 89 members. By comparative analysis in six grass genomes, we found the WRKY gene family may have experienced or be experiencing purifying selection. Based on relative expression levels among WRKY IIc members under three abiotic stresses, PeWRKY83 functioned as a transcription factor and was selected for detailed analysis. The transgenic Arabidopsis of PeWRKY83 showed superior physiological properties compared with the WT under salt stress. Overexpression plants were less sensitive to ABA at both germination and postgermination stages and accumulated more endogenous ABA under salt stress conditions. Further studies demonstrated that overexpression of PeWRKY83 could regulate the expression of some ABA biosynthesis genes (AtAAO3, AtNCED2, AtNCED3), signaling genes (AtABI1, AtPP2CA) and responsive genes (AtRD29A, AtRD29B, AtABF1) under salt stress. Together, these results suggested that PeWRKY83 functions as a novel WRKY-related TF which plays a positive role in salt tolerance by regulating stress-induced ABA synthesis. PMID- 28916740 TI - MAD2B acts as a negative regulatory partner of TCF4 on proliferation in human dermal papilla cells. AB - Dermal papilla cells (DPCs) are important components of hair follicles and play a critical role in hair follicle development. However, the mechanisms by which DPCs induce hair follicle development remain unclear. In the present study, we identified the mitotic arrest deficient protein MAD2B as a modifier of DPCs. Overexpression of MAD2B inhibited DPC aggregative growth and proliferation induced by the Wnt signaling activator T cell factor 4 (TCF4), and decreased TCF4 induced expression and the release of hair growth-related cytokines, including hepatocyte growth factor, insulin-like growth factor-1, and vascular endothelial growth factor in DPCs. In contrast, knockdown of MAD2B promoted TCF4-induced DPC proliferation, but did not affect the expression and secretion of cytokines by TCF4-induced DPCs. These results suggest a functional antagonism between MAD2B and TCF4 in DPC-induced hair follicle development. Mechanistically, MAD2B physically interacted with TCF4 to repress TCF4 transcriptional activity via beta catenin mediation, leading to reduced beta-catenin/TCF4-dependent transactivation and Wnt signaling activity. These results demonstrate, for the first time, that MAD2B plays a negative role in TCF4-induced DPC growth and proliferation. PMID- 28916741 TI - Enhancement of water diffusion and compression performance of crosslinked alginate films with a minuscule amount of graphene oxide. AB - A series of calcium alginate composite hydrogels with several calcium chloride contents ranging from 3 to 18 wt.% with and without 0.1 wt.% of graphene oxide (GO) was prepared in order to study the effect of crosslinking and nanofilling on water diffusion and compression performance. Thus, for high crosslinker contents, these composite hydrogels exhibited ultrafast diffusion of liquid water and excellent compression properties as compared with control (0 wt.% GO and the same crosslinking). These remarkable results are produced due to calcium cations are able to crosslink alginate and also graphene oxide nanosheets to form large crosslinked GO networks inside the calcium alginate hydrogels. Besides, these crosslinked GO/calcium alginate networks present nanochannels, as confirmed by electron microscopy, able to improve significantly water diffusion. Thus, these composite materials are very promising for many industrial applications demanding low-cost hydrogels with improved mechanical and water diffusion properties. PMID- 28916742 TI - Haplotype of the Interleukin 17A gene is associated with osteitis after Bacillus Calmette-Guerin vaccination. AB - Bacillus Calmette-Guerin (BCG) osteitis was more common in Finland than elsewhere at the time when universal BCG vaccinations were given to Finnish newborns. There is evidence that IL-17 plays a role in the defense against tuberculosis. The aim of this study was to evaluate the associations of IL17A rs4711998, IL17A rs8193036 and IL17A rs2275913 single-nucleotide polymorphisms (SNPs) with the risk of BCG osteitis after newborn vaccination. IL17A rs4711998, rs8193036 and rs2275913 SNPs were determined in 131 adults had presented with BCG osteitis after newborn BCG vaccination. We analyzed, using the HaploView and PLINK programs, whether allele or haplotype frequencies of these SNPs differ between the former BCG osteitis patients and Finnish population controls. Of the three IL17A SNPs studied, rs4711998 associated nominally with BCG osteitis; minor allele frequency was 0.215 in 130 BCG osteitis cases and 0.298 in 99 controls (p = 0.034). Frequency of the second common haplotype (GTA) differed significantly between BCG osteitis cases and controls (0.296 vs. 0.184, p = 0.040 after multi testing correction). The GTA haplotype of the IL17A SNPs rs4711998, rs8193036 and rs2275913 was associated with osteitis after BCG vaccination. PMID- 28916743 TI - Comparative analysis reveals regulatory motifs at the ainS/ainR pheromone signaling locus of Vibrio fischeri. AB - Vibrio fischeri uses the AinS/AinR pheromone-signaling system to control bioluminescence and other symbiotic colonization factors. The Ain system is thought to initiate cell-cell signaling at moderate cell densities and to prime the LuxI/LuxR signaling system. Here we compared and analyzed the ain locus from two V. fischeri strains and a Vibrio salmonicida strain to explore ain regulation. The ainS and ainR genes were predicted to constitute an operon, which we corroborated using RT-PCR. Comparisons between strains revealed a stark area of conservation across the ainS-ainR junction, including a large inverted repeat in ainR. We found that this inverted repeat in cis can affect accumulation of the AinS-generated pheromone N-octanoyl homoserine lactone, which may account for the previously unexplained low-signal phenotype of a ?ainR mutant, although the mechanism behind this regulation remains elusive. We also extended the previous observation of a possible "lux box" LuxR binding site upstream of ainS by showing the conservation of this site as well as a second putative lux box. Using a plasmid-based reporter we found that LuxR can mediate repression of ainS, providing a negative feedback mechanism in the Ain/Lux signaling cascade. Our results provide new insights into the regulation, expression, and evolution of ainSR. PMID- 28916744 TI - Hydrogen sulphate-based ionic liquid-assisted electro-polymerization of PEDOT catalyst material for high-efficiency photoelectrochemical solar cells. AB - This work reports the facile, one-step electro-polymerization synthesis of poly (3,4-ethylenedioxythiophene) (PEDOT) using a 1-ethyl-3-methylimidazolium hydrogen sulphate (EMIMHSO4) ionic liquid (IL) and, for the first time its utilization as a counter electrode (CE) in dye-sensitized solar cells (DSSCs). Using the IL doped PEDOT as CE, we effectively improve the solar cell efficiency to as high as 8.52%, the highest efficiency reported in 150 mC/cm2 charge capacity, an improvement of ~52% over the control device using the bare PEDOT CE (5.63%). Besides exhibiting good electrocatalytic stability, the highest efficiency reported for the PEDOT CE-based DSSCs using hydrogen sulphate [HSO4]- anion based ILs is also higher than platinum-(Pt)-based reference cells (7.87%). This outstanding performance is attributed to the enhanced charge mobility, reduced contact resistance, improved catalytic stability, smoother surface and well adhesion. Our experimental analyses reveal that the [HSO4]- anion group of the IL bonds to the PEDOT, leading to higher electron mobility to balance the charge transport at the cathode, a better adhesion for high quality growth PEDOT CE on the substrates and superior catalytic stability. Consequently, the EMIMHSO4-doped PEDOT can successfully act as an excellent alternative green catalyst material, replacing expensive Pt catalysts, to improve performance of DSSCs. PMID- 28916745 TI - Cadmium effects on DNA and protein metabolism in oyster (Crassostrea gigas) revealed by proteomic analyses. AB - Marine molluscs, including oysters, can concentrate high levels of cadmium (Cd) in their soft tissues, but the molecular mechanisms of Cd toxicity remain speculative. In this study, Pacific oysters (Crassostrea gigas) were exposed to Cd for 9 days and their gills were subjected to proteomic analysis, which were further confirmed with transcriptomic analysis. A total of 4,964 proteins was quantified and 515 differentially expressed proteins were identified in response to Cd exposure. Gene Ontology enrichment analysis revealed that excess Cd affected the DNA and protein metabolism. Specifically, Cd toxicity resulted in the inhibition of DNA glycosylase and gap-filling and ligation enzymes expressions in base excision repair pathway, which may have decreased DNA repair capacity. At the protein level, Cd induced the heat shock protein response, initiation of protein refolding as well as degradation by ubiquitin proteasome pathway, among other effects. Excess Cd also induced antioxidant responses, particularly glutathione metabolism, which play important roles in Cd chelation and anti-oxidation. This study provided the first molecular mechanisms of Cd toxicity on DNA and protein metabolism at protein levels, and identified molecular biomarkers for Cd toxicity in oysters. PMID- 28916746 TI - High-yield production of "difficult-to-express" proteins in a continuous exchange cell-free system based on CHO cell lysates. AB - Cell-free protein synthesis (CFPS) represents a promising technology for efficient protein production targeting especially so called "difficult-to express" proteins whose synthesis is challenging in conventional in vivo protein production platforms. Chinese hamster ovary (CHO) cells are one of the most prominent and safety approved cell lines for industrial protein production. In this study we demonstrated the ability to produce high yields of various protein types including membrane proteins and single chain variable fragments (scFv) in a continuous exchange cell-free (CECF) system based on CHO cell lysate that contains endogenous microsomal structures. We showed significant improvement of protein yield compared to batch formatted reactions and proved biological activity of synthesized proteins using various analysis technologies. Optimized CECF reaction conditions led to membrane protein yields up to 980 ug/ml, which is the highest protein yield reached in a microsome containing eukaryotic cell-free system presented so far. PMID- 28916747 TI - Hormetic potential of methylglyoxal, a side-product of glycolysis, in switching tumours from growth to death. AB - Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth. PMID- 28916748 TI - alpha2-adrenoceptor-mediated inhibition in the central amygdala blocks fear conditioning. AB - The central amygdala is critical for the acquisition and expression of fear memories. This region receives a dense innervation from brainstem noradrenergic cell groups and has a high level of alpha2-adrenoceptor expression. Using whole cell electrophysiological recordings from rat brain slices, we characterise the role of pre-synaptic alpha2-adrenoceptor in modulating discrete inhibitory and excitatory connections within both the lateral and medial division of the central amygdala. The selective alpha2-adrenoceptor agonist clonidine blocked the excitatory input from the pontine parabrachial neurons onto neurons of the lateral central amygdala. In addition, clonidine blocked inhibitory connections from the medial paracapsular intercalated cell mass onto both lateral and medial central amygdala neurons. To examine the behavioural consequence of alpha2 adrenoceptor-mediated inhibition of these inputs, we infused clonidine into the central amygdala prior to contextual fear-conditioning. In contrast to vehicle infused rats, clonidine-infused animals displayed reduced levels of freezing 24 hours after training, despite showing no difference in freezing during the training session. These results reveal a role for alpha2-adrenoceptors within the central amygdala in the modulation of synaptic transmission and the formation of fear-memories. In addition, they provide further evidence for a role of the central amygdala in fear-memory formation. PMID- 28916749 TI - Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells. AB - The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations. PMID- 28916750 TI - Comprehensive multiregional analysis of molecular heterogeneity in bladder cancer. AB - Genetic alterations identified in adjacent normal appearing tissue in bladder cancer patients are indicative of a field disease. Here we assessed normal urothelium transformation and intra-tumour heterogeneity (ITH) in four patients with bladder cancer. Exome sequencing identified private acquired mutations in a lymph node metastasis and local recurrences. Deep re-sequencing revealed presence of at least three and four subclones in two patients with multifocal disease, while no demarcation of subclones was identified in the two patients with unifocal disease. Analysis of adjacent normal urothelium showed low frequency mutations in patients with multifocal disease. Expression profiling showed intra tumour and intra-patient co-existence of basal- and luminal-like tumour regions, and patients with multifocal disease had a greater degree of genomic and transcriptomic ITH, as well as transformation of adjacent normal cells, compared to patients with unifocal disease. Analysis of the adjacent urothelium may pave the way for therapies targeting the field disease. PMID- 28916751 TI - Understanding CRY2 interactions for optical control of intracellular signaling. AB - Arabidopsis cryptochrome 2 (CRY2) can simultaneously undergo light-dependent CRY2 CRY2 homo-oligomerization and CRY2-CIB1 hetero-dimerization, both of which have been widely used to optically control intracellular processes. Applications using CRY2-CIB1 interaction desire minimal CRY2 homo-oligomerization to avoid unintended complications, while those utilizing CRY2-CRY2 interaction prefer robust homo-oligomerization. However, selecting the type of CRY2 interaction has not been possible as the molecular mechanisms underlying CRY2 interactions are unknown. Here we report CRY2-CIB1 and CRY2-CRY2 interactions are governed by well separated protein interfaces at the two termini of CRY2. N-terminal charges are critical for CRY2-CIB1 interaction. Moreover, two C-terminal charges impact CRY2 homo-oligomerization, with positive charges facilitating oligomerization and negative charges inhibiting it. By engineering C-terminal charges, we develop CRY2high and CRY2low with elevated or suppressed oligomerization respectively, which we use to tune the levels of Raf/MEK/ERK signaling. These results contribute to our understanding of the mechanisms underlying light-induced CRY2 interactions and enhance the controllability of CRY2-based optogenetic systems.Cryptochrome 2 (CRY2) can form light-regulated CRY2-CRY2 homo-oligomers or CRY2-CIB1 hetero-dimers, but modulating these interactions is difficult owing to the lack of interaction mechanism. Here the authors identify the interactions facilitating homo-oligomers and introduce mutations to create low and high oligomerization versions. PMID- 28916752 TI - Direct measurement of strain-dependent solid surface stress. AB - Surface stress, also known as surface tension, is a fundamental material property of any interface. However, measurements of solid surface stress in traditional engineering materials, such as metals and oxides, have proven to be very challenging. Consequently, our understanding relies heavily on untested theories, especially regarding the strain dependence of this property. Here, we take advantage of the high compliance and large elastic deformability of a soft polymer gel to directly measure solid surface stress as a function of strain. As anticipated by theoretical work for metals, we find that the surface stress depends on the strain via a surface modulus. Remarkably, the surface modulus of our soft gels is many times larger than the zero-strain surface tension. This suggests that surface stresses can play a dominant role in solid mechanics at larger length scales than previously anticipated.Solid surface stress is a fundamental property of solid interfaces. Here authors measure the solid surface stress of a gel, and show its dependence on surface strain through a surface modulus. PMID- 28916753 TI - Automated N-Glycosylation Sequencing Of Biopharmaceuticals By Capillary Electrophoresis. AB - Comprehensive analysis of the N-linked carbohydrates of glycoproteins is gaining high recent interest in both the biopharmaceutical and biomedical fields. In addition to high resolution glycosylation profiling, sugar residue and linkage specific enzymes are also routinely used for exoglycosidase digestion based carbohydrate sequencing. This latter one, albeit introduced decades ago, still mostly practiced by following tedious and time consuming manual processes. In this paper we introduce an automated carbohydrate sequencing approach using the appropriate exoglycosidase enzymes in conjunction with the utilization of some of the features of a capillary electrophoresis (CE) instrument to speed up the process. The enzymatic reactions were accomplished within the temperature controlled sample storage compartment of a capillary electrophoresis unit and the separation capillary was also utilized for accurate delivery of the exoglycosidase enzymes. CE analysis was conducted after each digestion step obtaining in this way the sequence information of N-glycans in 60 and 128 minutes using the semi- and the fully-automated methods, respectively. PMID- 28916754 TI - Performance-based ability emotional intelligence benefits working memory capacity during performance on hot tasks. AB - Emotional intelligence (EI) is the ability to perceive, use, understand, and regulate emotions. Higher scores on this ability measured through performance tests (but no through self-reports) appears to be related to better performance on "hot" (emotionally laden) cognitive tasks. However, there are relatively few studies concerning how EI may benefit the working memory capacity (WMC). Thus, the objective of this study is to analyse the relationship between EI (as measured through a performance-based ability test, a self-report mixed test, and a self-report ability test) and the WMC during the performance of hot and "cool" (i.e., non-emotionally laden) "2-back" tasks. 203 participants completed three EI tests as well as two 2-back tasks. The results provide evidence for better performance of higher EI participants (specifically in the managing branch) measured through the performance-based ability test, but only on the hot task. For the self-report mixed model, incongruent results were found, and no correlations were obtained using the self-report ability model. The implications of these findings are discussed in terms of the validity of the various EI models. PMID- 28916755 TI - Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts. AB - O-glycosylation of the Plasmodium sporozoite surface proteins CSP and TRAP was recently identified, but the role of this modification in the parasite life cycle and its relevance to vaccine design remain unclear. Here, we identify the Plasmodium protein O-fucosyltransferase (POFUT2) responsible for O-glycosylating CSP and TRAP. Genetic disruption of POFUT2 in Plasmodium falciparum results in ookinetes that are attenuated for colonizing the mosquito midgut, an essential step in malaria transmission. Some POFUT2-deficient parasites mature into salivary gland sporozoites although they are impaired for gliding motility, cell traversal, hepatocyte invasion, and production of exoerythrocytic forms in humanized chimeric liver mice. These defects can be attributed to destabilization and incorrect trafficking of proteins bearing thrombospondin repeats (TSRs). Therefore, POFUT2 plays a similar role in malaria parasites to that in metazoans: it ensures the trafficking of Plasmodium TSR proteins as part of a non-canonical glycosylation-dependent endoplasmic reticulum protein quality control mechanism.The role of O-glycosylation in the malaria life cycle is largely unknown. Here, the authors identify a Plasmodium protein O-fucosyltransferase and show that it is important for normal trafficking of a subset of surface proteins, particularly CSP and TRAP, and efficient infection of mosquito and vertebrate hosts. PMID- 28916756 TI - Identification of the S100 fused-type protein hornerin as a regulator of tumor vascularity. AB - Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.Angiogenesis is essential for solid tumor progression. Here, the authors interrogate the proteome of pancreatic cancer endothelium via phage display and identify hornerin as a critical protein whose expression is essential to maintain the pancreatic cancer vasculature through a VEGF-independent mechanism. PMID- 28916758 TI - Role of the venus kinase receptor in the female reproductive physiology of the desert locust, Schistocerca gregaria. AB - Venus kinase receptors (VKR) are a subfamily of invertebrate receptor tyrosine kinases, which have only recently been discovered. They contain an intracellular tyrosine kinase domain and an extracellular Venus FlyTrap domain. VKRs have been functionally and pharmacologically characterized in only two invertebrate species, namely the human parasite Schistosoma mansoni and the mosquito Aedes aegypti, where they play a crucial role in oogenesis. Here, we report the characterization of a VKR in the desert locust, Schistocerca gregaria. We performed an in-depth profiling study of the SgVKR transcript levels in different tissues throughout the female adult stage. Using the RNA interference technique, the possible role of SgVKR was investigated. SgVKR knockdown had significant effects on ovarian ecdysteroid levels and on the size of oocytes during the vitellogenic stage. SgVKR is probably involved in the complex cross-talk between several important pathways regulating female reproductive physiology. Contrary to A. aegypti and S. mansoni, we cannot conclude that this receptor is essential for reproduction, since silencing SgVKR did not affect fecundity or fertility. Considering the evolutionary distance between A. aegypti and S. gregaria, as well as the differences in regulation of their female reproductive physiology, this article constitutes a valuable asset in better understanding VKRs. PMID- 28916757 TI - Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. AB - Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; however, DUX4 expression is very low, and protein has not been detected directly in patient biopsies. Efforts to model DUX4 myopathy in mice have foundered either in being too severe, or in lacking muscle phenotypes. Here we show that the endogenous facioscapulohumeral muscular dystrophy-specific DUX4 polyadenylation signal is surprisingly inefficient, and use this finding to develop an facioscapulohumeral muscular dystrophy mouse model with muscle-specific doxycycline-regulated DUX4 expression. Very low expression levels, resulting in infrequent DUX4 + myonuclei, evoke a slow progressive degenerative myopathy. The degenerative process involves inflammation and a remarkable expansion in the fibroadipogenic progenitor compartment, leading to fibrosis. These animals also show high frequency hearing deficits and impaired skeletal muscle regeneration after injury. This mouse model will facilitate in vivo testing of therapeutics, and suggests the involvement of fibroadipogenic progenitors in facioscapulohumeral muscular dystrophy.Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology. PMID- 28916759 TI - Influenza D in Italy: towards a better understanding of an emerging viral infection in swine. AB - Influenza D virus (IDV), a new member of the Orthomyxoviridae family, was first reported in 2011 in swine in Oklahoma, and consequently found in cattle across North America and Eurasia. To investigate the circulation of IDV among pigs in Italy, in the period between June 2015 and May 2016, biomolecular and virological tests were performed on 845 clinical samples collected from 448 pig farms affected by respiratory distress located in the Po Valley. Serological tests were conducted on 3698 swine sera, including archive sera collected in 2009, as well as samples collected in 2015 from the same region. Viral genome was detected in 21 (2.3%) samples from 9 herds (2%), while virus was successfully isolated from 3 samples. Genetic analysis highlighted that Italian swine IDVs are closely related to the D/swine/Oklahoma/1334/2011 cluster. Sera collected in 2015 showed a high prevalence of IDV antibody titers (11.7%), while archive sera from 2009 showed statistically significant lower positivity rates (0.6%). Our results indicate an increasing epidemiological relevance of the pathogen and the need for in-depth investigations towards understanding its pathogenesis, epidemiology and possible zoonotic potential of this emerging virus. PMID- 28916760 TI - Responses of LAI to rainfall explain contrasting sensitivities to carbon uptake between forest and non-forest ecosystems in Australia. AB - Non-forest ecosystems (predominant in semi-arid and arid regions) contribute significantly to the increasing trend and interannual variation of land carbon uptake over the last three decades, yet the mechanisms are poorly understood. By analysing the flux measurements from 23 ecosystems in Australia, we found the the correlation between gross primary production (GPP) and ecosystem respiration (Re) was significant for non-forest ecosystems, but was not for forests. In non-forest ecosystems, both GPP and Re increased with rainfall, and, consequently net ecosystem production (NEP) increased with rainfall. In forest ecosystems, GPP and Re were insensitive to rainfall. Furthermore sensitivity of GPP to rainfall was dominated by the rainfall-driven variation of LAI rather GPP per unit LAI in non forest ecosystems, which was not correctly reproduced by current land models, indicating that the mechanisms underlying the response of LAI to rainfall should be targeted for future model development. PMID- 28916761 TI - Chronic interfacing with the autonomic nervous system using carbon nanotube (CNT) yarn electrodes. AB - The ability to reliably and safely communicate chronically with small diameter (100-300 um) autonomic nerves could have a significant impact in fundamental biomedical research and clinical applications. However, this ability has remained elusive with existing neural interface technologies. Here we show a new chronic nerve interface using highly flexible materials with axon-like dimensions. The interface was implemented with carbon nanotube (CNT) yarn electrodes to chronically record neural activity from two separate autonomic nerves: the glossopharyngeal and vagus nerves. The recorded neural signals maintain a high signal-to-noise ratio (>10 dB) in chronic implant models. We further demonstrate the ability to process the neural activity to detect hypoxic and gastric extension events from the glossopharyngeal and vagus nerves, respectively. These results establish a novel, chronic platform neural interfacing technique with the autonomic nervous system and demonstrate the possibility of regulating internal organ function, leading to new bioelectronic therapies and patient health monitoring. PMID- 28916762 TI - Time-resolved analysis of DNA-protein interactions in living cells by UV laser pulses. AB - Interactions between DNA and proteins are mainly studied through chemical procedures involving bi-functional reagents, mostly formaldehyde. Chromatin immunoprecipitation is used to identify the binding between transcription factors (TFs) and chromatin, and to evaluate the occurrence and impact of histone/DNA modifications. The current bottleneck in probing DNA-protein interactions using these approaches is caused by the fact that chemical crosslinkers do not discriminate direct and indirect bindings or short-lived chromatin occupancy. Here, we describe a novel application of UV laser-induced (L-) crosslinking and demonstrate that a combination of chemical and L-crosslinking is able to distinguish between direct and indirect DNA-protein interactions in a small number of living cells. The spatial and temporal dynamics of TF bindings to chromatin and their role in gene expression regulation may thus be assessed. The combination of chemical and L-crosslinking offers an exciting and unprecedented tool for biomedical applications. PMID- 28916763 TI - Maternal diabetes causes developmental delay and death in early-somite mouse embryos. AB - Maternal diabetes causes congenital malformations and delays embryonic growth in the offspring. We investigated effects of maternal diabetes on mouse embryos during gastrulation and early organogenesis (ED7.5-11.5). Female mice were made diabetic with streptozotocin, treated with controlled-release insulin implants, and mated. Maternal blood glucose concentrations increased up to embryonic day (ED) 8.5. Maternal hyperglycemia induced severe growth retardation (approx.1 day) in 53% of the embryos on ED8.5, death in most of these embryos on ED9.5, and the termination of pregnancy on ED10.5 in litters with >20% dead embryos. Due to this selection, developmental delays and reduction in litter size were no longer observed thereafter in diabetic pregnancies. Male and female embryos were equally sensitive. High-throughput mRNA sequencing and pathway analysis of differentially expressed genes showed that retarded embryos failed to mount the adaptive suppression of gene expression that characterized non-retarded embryos (cell proliferation, cytoskeletal remodeling, oxidative phosphorylation). We conclude that failure of perigastrulation embryos of diabetic mothers to grow and survive is associated with their failure to shut down pathways that are strongly down regulated in otherwise similar non-retarded embryos. Embryos that survive the early and generalized adverse effect of maternal diabetes, therefore, appear the subset in which malformations become manifest. PMID- 28916764 TI - Rapid and reversible epigenome editing by endogenous chromatin regulators. AB - Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states. PMID- 28916765 TI - Radiation damage at the active site of human alanine:glyoxylate aminotransferase reveals that the cofactor position is finely tuned during catalysis. AB - The alanine:glyoxylate aminotransferase (AGT), a hepatocyte-specific pyridoxal-5' phosphate (PLP) dependent enzyme, transaminates L-alanine and glyoxylate to glycine and pyruvate, thus detoxifying glyoxylate and preventing pathological oxalate precipitation in tissues. In the widely accepted catalytic mechanism of the aminotransferase family, the lysine binding to PLP acts as a catalyst in the stepwise 1,3-proton transfer, interconverting the external aldimine to ketimine. This step requires protonation by a conserved aspartate of the pyridine nitrogen of PLP to enhance its ability to stabilize the carbanionic intermediate. The aspartate residue is also responsible for a significant geometrical distortion of the internal aldimine, crucial for catalysis. We present the structure of human AGT in which complete X-ray photoreduction of the Schiff base has occurred. This result, together with two crystal structures of the conserved aspartate pathogenic variant (D183N) and the molecular modeling of the transaldimination step, led us to propose that an interplay of opposite forces, which we named spring mechanism, finely tunes PLP geometry during catalysis and is essential to move the external aldimine in the correct position in order for the 1,3-proton transfer to occur. PMID- 28916766 TI - Stimulatory Secretions of Airway Epithelial Cells Accelerate Early Repair of Tracheal Epithelium. AB - Airway stem/progenitor epithelial cells (AECs) are notable for their differentiation capacities in response to lung injury. Our previous finding highlighted the regenerative capacity of AECs following transplantation in repairing tracheal injury and reducing the severity of alveolar damage associated acute lung injury in a rabbit model. The goal of this study is to further investigate the potential of AECs to re-populate the tracheal epithelium and to study their stimulatory effect on inhibiting pro-inflammatory cytokines, epithelial cell migration and proliferation, and epithelial-to-mesenchymal transition (EMT) process following tracheal injury. Two in vitro culture assays were applied in this study; the direct co-culture assay that involved a culture of decellularised tracheal epithelium explants and AECs in a rotating tube, and indirect co-culture assay that utilized microporous membrane-well chamber system to separate the partially decellularised tracheal epithelium explants and AEC culture. The co-culture assays provided evidence of the stimulatory behaviour of AECs to enhance tracheal epithelial cell proliferation and migration during early wound repair. Factors that were secreted by AECs also markedly suppressed the production of IL-1beta and IL-6 and initiated the EMT process during tracheal remodelling. PMID- 28916768 TI - Dynamics of necklace beams in nonlinear colloidal suspensions. AB - Recently, we have predicted that the modulation instability of optical vortex solitons propagating in nonlinear colloidal suspensions with exponential saturable nonlinearity leads to formation of necklace beams (NBs). Here, we investigate the dynamics of NB formation and propagation, and demonstrate a variety of optical beam structures emerging upon vortex beam propagation in engineered nonlinear colloidal medium. In particular, we show that the distance at which the NB is formed depends on the input power of the vortex beam. Moreover, we show that the NB trajectories are not necessarily tangent to the initial vortex ring, and that their velocities have components stemming both from the beam diffraction and from the beam orbital angular momentum. We also demonstrate the generation of elliptical rotating solitons and analyze the influence of losses on their propagation. Finally, we investigate the conservation of the orbital angular momentum in necklace and elliptical rotating beams. Our studies, performed in ideal lossless media and in realistic colloidal suspensions with losses, provide a detailed description of NB dynamics, and may be useful in analysis of light propagation in highly scattering colloids and biological samples. PMID- 28916767 TI - The cancer chemotherapeutic agent paclitaxel (Taxol) reduces hippocampal neurogenesis via down-regulation of vesicular zinc. AB - Chemotherapy-induced cognitive impairment (CICI) is increasingly recognized as a major unwanted side effect of an otherwise highly valuable life-saving technology. In part, this awareness is a result of increased cancer survival rates following chemotherapy. Altered hippocampal neurogenesis may play a role in mediating CICI. In particular, zinc could act as a key regulator of this process. To test this hypothesis, we administered paclitaxel (Px) to male C57BL/6 mice for set time periods and then evaluated the effects of Px treatment on hippocampal neurogenesis and vesicular zinc. We found that vesicular zinc levels and expression of zinc transporter 3 (ZnT3) were reduced in Px-treated mice, compared to vehicle-treated mice. Moreover, Px-treated mice demonstrated a significant decrease in the number of neuroblasts present. However, no difference in the number of progenitor cells were observed. In addition, zinc supplementation by treatment with ZnCl2 ameliorated the Px-induced decrease in hippocampal neurogenesis and cognitive impairment. These results suggest that via disruption of vesicular zinc stores in hippocampal mossy fiber terminals, chemotherapy may impinge upon one or more of the sequential stages involved in the maturation of new neurons derived via adult neurogenesis and thereby leads to the progressive cognitive decline associated with CICI. PMID- 28916769 TI - Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease. AB - Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 -/- mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 -/- mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 -/- mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 -/- mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing. PMID- 28916770 TI - Changes in CD73, CD39 and CD26 expression on T-lymphocytes of ANCA-associated vasculitis patients suggest impairment in adenosine generation and turn-over. AB - Extracellular adenosine, generated via the concerted action of CD39 and CD73, contributes to T-cell differentiation and function. Adenosine concentrations are furthermore influenced by adenosine deaminase binding protein CD26. Because aberrant T-cell phenotypes had been reported in anti-neutrophil cytoplasmic auto antibody (ANCA)-associated vasculitis (AAV) patients, an impaired expression of these molecules on T-cells of AAV patients was hypothesized in the present study. While in AAV patients (n = 29) CD26 was increased on CD4+ lymphocytes, CD39 and CD73 were generally reduced on patients' T-cells. In CD4+ cells significant differences in CD73 expression were confined to memory CD45RA- cells, while in CD4- lymphocytes differences were significant in both naive CD45RA+ and memory CD45RA- cells. The percentage of CD4-CD73+ cells correlated with micro-RNA (miR) 31 expression, a putative regulator of factor inhibiting hypoxia-inducible factor 1 alpha (FIH-1), inversely with serum C-reactive protein (CRP) and positively with estimated glomerular filtration rate (eGFR). No correlation with disease activity, duration, and ANCA profile was found. It remains to be assessed if a decreased CD73 and CD39 expression underlies functional impairment of lymphocytes in AAV patients. Likewise, the relations between frequencies of CD4-CD73+ cells and serum CRP or eGFR require further functional elucidation. PMID- 28916771 TI - Complete fusion of a transposon and herpesvirus created the Teratorn mobile element in medaka fish. AB - Mobile genetic elements (e.g., transposable elements and viruses) display significant diversity with various life cycles, but how novel elements emerge remains obscure. Here, we report a giant (180-kb long) transposon, Teratorn, originally identified in the genome of medaka, Oryzias latipes. Teratorn belongs to the piggyBac superfamily and retains the transposition activity. Remarkably, Teratorn is largely derived from a herpesvirus of the Alloherpesviridae family that could infect fish and amphibians. Genomic survey of Teratorn-like elements reveals that some of them exist as a fused form between piggyBac transposon and herpesvirus genome in teleosts, implying the generality of transposon-herpesvirus fusion. We propose that Teratorn was created by a unique fusion of DNA transposon and herpesvirus, leading to life cycle shift. Our study supports the idea that recombination is the key event in generation of novel mobile genetic elements. Teratorn is a large mobile genetic element originally identified in the small teleost fish medaka. Here, the authors show that Teratorn is derived from the fusion of a piggyBac superfamily DNA transposon and an alloherpesvirus and that it is widely found across teleost fish. PMID- 28916772 TI - Limits of Predictability of Cascading Overload Failures in Spatially-Embedded Networks with Distributed Flows. AB - Cascading failures are a critical vulnerability of complex information or infrastructure networks. Here we investigate the properties of load-based cascading failures in real and synthetic spatially-embedded network structures, and propose mitigation strategies to reduce the severity of damages caused by such failures. We introduce a stochastic method for optimal heterogeneous distribution of resources (node capacities) subject to a fixed total cost. Additionally, we design and compare the performance of networks with N-stable and (N-1)-stable network-capacity allocations by triggering cascades using various real-world node-attack and node-failure scenarios. We show that failure mitigation through increased node protection can be effectively achieved against single-node failures. However, mitigating against multiple node failures is much more difficult due to the combinatorial increase in possible sets of initially failing nodes. We analyze the robustness of the system with increasing protection, and find that a critical tolerance exists at which the system undergoes a phase transition, and above which the network almost completely survives an attack. Moreover, we show that cascade-size distributions measured in this region exhibit a power-law decay. Finally, we find a strong correlation between cascade sizes induced by individual nodes and sets of nodes. We also show that network topology alone is a weak predictor in determining the progression of cascading failures. PMID- 28916773 TI - Functional organization of cytoplasmic inclusion bodies in cells infected by respiratory syncytial virus. AB - Infection of cells by respiratory syncytial virus induces the formation of cytoplasmic inclusion bodies (IBs) where all the components of the viral RNA polymerase complex are concentrated. However, the exact organization and function of these IBs remain unclear. In this study, we use conventional and super resolution imaging to dissect the internal structure of IBs. We observe that newly synthetized viral mRNA and the viral transcription anti-terminator M2-1 concentrate in IB sub-compartments, which we term "IB-associated granules" (IBAGs). In contrast, viral genomic RNA, the nucleoprotein, the L polymerase and its cofactor P are excluded from IBAGs. Live imaging reveals that IBAGs are highly dynamic structures. Our data show that IBs are the main site of viral RNA synthesis. They further suggest that shortly after synthesis in IBs, viral mRNAs and M2-1 transiently concentrate in IBAGs before reaching the cytosol and suggest a novel post-transcriptional function for M2-1.Respiratory syncytial virus (RSV) induces formation of inclusion bodies (IBs) sheltering viral RNA synthesis. Here, Rincheval et al. identify highly dynamic IB-associated granules (IBAGs) that accumulate newly synthetized viral mRNA and the viral M2-1 protein but exclude viral genomic RNA and RNA polymerase complexes. PMID- 28916774 TI - The mechano-sensing role of the unique SH3 insertion in plakin domains revealed by Molecular Dynamics simulations. AB - The plakin family of proteins, important actors in cross-linking force-bearing structures in the cell, contain a curious SH3 domain insertion in their chain of spectrin repeats (SRs). While SH3 domains are known to mediate protein-protein interactions, here, its canonical binding site is autoinhibited by the preceding SR. Under force, however, this SH3 domain could be released, and possibly launch a signaling cascade. We performed large-scale force-probe molecular dynamics simulations, across two orders of magnitude of loading rates, to test this hypothesis, on two prominent members of the plakin family: desmoplakin and plectin, obligate proteins at desmosomes and hemidesmosomes, respectively. Our simulations show that force unravels the SRs and abolishes the autoinhibition of the SH3 domain, an event well separated from the unfolding of this domain. The SH3 domain is free and fully functional for a significant portion of the unfolding trajectories. The rupture forces required for the two proteins significantly decrease when the SH3 domain is removed, which implies that the SH3 domain also stabilizes this junction. Our results persist across all simulations, and support a force-sensing as well as a stabilizing role of the unique SH3 insertion, putting forward this protein family as a new class of mechano-sensors. PMID- 28916775 TI - Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized 13C magnetic resonance. AB - The mammalian brain relies primarily on glucose as a fuel to meet its high metabolic demand. Among the various techniques used to study cerebral metabolism, 13C magnetic resonance spectroscopy (MRS) allows following the fate of 13C enriched substrates through metabolic pathways. We herein demonstrate that it is possible to measure cerebral glucose metabolism in vivo with sub-second time resolution using hyperpolarized 13C MRS. In particular, the dynamic 13C-labeling of pyruvate and lactate formed from 13C-glucose was observed in real time. An ad hoc synthesis to produce [2,3,4,6,6-2H5, 3,4-13C2]-D-glucose was developed to improve the 13C signal-to-noise ratio as compared to experiments performed following [U-2H7, U-13C]-D-glucose injections. The main advantage of only labeling C3 and C4 positions is the absence of 13C-13C coupling in all downstream metabolic products after glucose is split into 3-carbon intermediates by aldolase. This unique method allows direct detection of glycolysis in vivo in the healthy brain in a noninvasive manner. PMID- 28916776 TI - Nestlings reduce their predation risk by attending to predator-information encoded within conspecific alarm calls. AB - Predation is one of the main threats to altricial nestlings, with predators often locating nests via eavesdropping on begging signals. Nestlings may be able to adjust their begging based on the current level of risk by monitoring both intra- and interspecific alarm calls near the nest. We show that noisy miner (Manorina melanocephala) nestlings can differentiate between terrestrial and aerial alarm calls of their own species, as they suppressed begging behaviour for longer in response to terrestrial rather than aerial alarm calls. This differential response is potentially due to greater danger that terrestrial calls encode. In contrast, nestlings ignored alarm calls of the sympatric grey butcherbird (Cracticus torquatus) and continued to beg but reduced begging intensity in response to the non-alarm calls of a sympatric eastern rosella (Platycercus eximius), suggesting nestlings were likely responding based upon similarity to a known signal as opposed to expressing a learnt behaviour. Results show that nestlings respond adaptively to two different intraspecific alarm signals but have not learnt to respond to the alarm calls of sympatric species. These suggest that nestlings are able to take advantage of the complex vocal repertoire that adults produce, although discernment is an issue when filtering out irrelevant stimuli. PMID- 28916778 TI - Hydrogeochemical changes before and during the 2016 Amatrice-Norcia seismic sequence (central Italy). AB - Seismic precursors are an as yet unattained frontier in earthquake studies. With the aim of making a step towards this frontier, we present a hydrogeochemical dataset associated with the 2016 Amatrice-Norcia seismic sequence (central Apennines, Italy), developed from August 24th, with an Mw 6.0 event, and culminating on October 30th, with an Mw 6.5 mainshock. The seismic sequence occurred during a seasonal depletion of hydrostructures, and the four strongest earthquakes (Mw >= 5.5) generated an abrupt uplift of the water level, recorded up to 100 km away from the mainshock area. Monitoring a set of selected springs in the central Apennines, a few hydrogeochemical anomalies were observed months before the onset of the seismic swarm, including a variation of pH values and an increase of As, V, and Fe concentrations. Cr concentrations increased immediately after the onset of the seismic sequence. On November 2016, these elements recovered to their usual low concentrations. We interpret these geochemical anomalies as reliable seismic precursors for a dilational tectonic setting. PMID- 28916777 TI - The catalytic subunit of DNA polymerase delta inhibits gammaTuRC activity and regulates Golgi-derived microtubules. AB - gamma-Tubulin ring complexes (gammaTuRCs) initiate microtubule growth and mediate microtubule attachment at microtubule-organizing centers, such as centrosomes and the Golgi complex. However, the mechanisms that control gammaTuRC-mediated microtubule nucleation have remained mostly unknown. Here, we show that the DNA polymerase delta catalytic subunit (PolD1) binds directly to gammaTuRCs and potently inhibits gammaTuRC-mediated microtubule nucleation. Whereas PolD1 depletion through RNA interference does not influence centrosome-based microtubule growth, the depletion augments microtubule nucleation at the Golgi complex. Conversely, PolD1 overexpression inhibits Golgi-based microtubule nucleation. Golgi-derived microtubules are required for the assembly and maintenance of the proper Golgi structure, and we found that alteration of PolD1 levels affects Golgi structural organization. Moreover, suppression of PolD1 expression impairs Golgi reassembly after nocodazole-induced disassembly and causes defects in Golgi reorientation and directional cell migration. Collectively, these results reveal a mechanism that controls noncentrosomal gammaTuRC activity and regulates the organization of Golgi-derived microtubules.Microtubule organization requires gamma-tubulin ring complexes (gammaTuRCs), but the mechanisms that control gammaTuRC-mediated microtubule nucleation are unclear. Here the authors show that the DNA polymerase delta catalytic subunit controls noncentrosomal gammaTuRC activity and regulates the organization of Golgi-derived microtubules. PMID- 28916779 TI - Statistical Modeling of the Default Mode Brain Network Reveals a Segregated Highway Structure. AB - We investigate the functional organization of the Default Mode Network (DMN) - an important subnetwork within the brain associated with a wide range of higher order cognitive functions. While past work has shown the whole-brain network of functional connectivity follows small-world organizational principles, subnetwork structure is less well understood. Current statistical tools, however, are not suited to quantifying the operating characteristics of functional networks as they often require threshold censoring of information and do not allow for inferential testing of the role that local processes play in determining network structure. Here, we develop the correlation Generalized Exponential Random Graph Model (cGERGM) - a statistical network model that uses local processes to capture the emergent structural properties of correlation networks without loss of information. Examining the DMN with the cGERGM, we show that, rather than demonstrating small-world properties, the DMN appears to be organized according to principles of a segregated highway - suggesting it is optimized for function specific coordination between brain regions as opposed to information integration across the DMN. We further validate our findings through assessing the power and accuracy of the cGERGM on a testbed of simulated networks representing various commonly observed brain architectures. PMID- 28916780 TI - Preserved immune functionality and high CMV-specific T-cell responses in HIV infected individuals with poor CD4+ T-cell immune recovery. AB - Poor CD4+ T-cell recovery after cART has been associated with skewed T-cell maturation, inflammation and immunosenescence; however, T-cell functionality in those individuals has not been fully characterized. In the present study, we assessed T-cell function by assessing cytokine production after polyclonal, CMV and HIV stimulations of T-cells from ART-suppressed HIV-infected individuals with CD4+ T-cell counts >350 cells/MUL (immunoconcordants) or <350 cells/MUL (immunodiscordants). A group of HIV-uninfected individuals were also included as controls. Since CMV co-infection significantly affected T-cell maturation and polyfunctionality, only CMV+ individuals were analyzed. Despite their reduced and skewed CD4+ T-cell compartment, immunodiscordant individuals showed preserved polyclonal and HIV-specific responses. However, CMV response in immunodiscordant participants was significantly different from immunoconcordant or HIV seronegative individuals. In immunodiscordant subjects, the magnitude of IFN gamma+ CD8+ and IL-2+ CD4+ T-cells in response to CMV was higher and differently associated with the CD4+ T-cell maturation profile., showing an increased frequency of naive, central memory and EMRA CMV-specific CD4+ T-cells. In conclusion, CD4+ and CD8+ T-cell polyfunctionality was not reduced in immunodiscordant individuals, although heightened CMV-specific immune responses, likely related to subclinical CMV reactivations, may be contributing to the skewed T-cell maturation and the higher risk of clinical progression observed in those individuals. PMID- 28916781 TI - 6-bromo-indirubin-3'-oxime (6BIO), a Glycogen synthase kinase-3beta inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence mediated biomolecular damage in human fibroblasts. AB - As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3beta (Gsk-3beta). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown. We report herein that treatment of human diploid skin fibroblasts with 6BIO reduced the oxidative load, conferred protection against oxidative stress-mediated DNA damage, and it also promoted the activation of antioxidant and proteostatic modules; these effects were largely phenocopied by genetic inhibition of Gsk-3. Furthermore, prolonged treatment of cells with 6BIO, although it decreased the rate of cell cycling, it significantly suppressed cellular senescence-related accumulation of biomolecular damage. Taken together, our presented findings suggest that 6BIO is a novel activator of antioxidant responses and of the proteostasis network in normal human cells; moreover, and given the low levels of biomolecules damage in 6BIO treated senescing cells, this compound likely exerts anti-tumor properties. PMID- 28916782 TI - Predicting clinical outcomes from large scale cancer genomic profiles with deep survival models. AB - Translating the vast data generated by genomic platforms into accurate predictions of clinical outcomes is a fundamental challenge in genomic medicine. Many prediction methods face limitations in learning from the high-dimensional profiles generated by these platforms, and rely on experts to hand-select a small number of features for training prediction models. In this paper, we demonstrate how deep learning and Bayesian optimization methods that have been remarkably successful in general high-dimensional prediction tasks can be adapted to the problem of predicting cancer outcomes. We perform an extensive comparison of Bayesian optimized deep survival models and other state of the art machine learning methods for survival analysis, and describe a framework for interpreting deep survival models using a risk backpropagation technique. Finally, we illustrate that deep survival models can successfully transfer information across diseases to improve prognostic accuracy. We provide an open-source software implementation of this framework called SurvivalNet that enables automatic training, evaluation and interpretation of deep survival models. PMID- 28916783 TI - Differential regulation of vaginal lipocalins (OBP, MUP) during the estrous cycle of the house mouse. AB - Female house mice produce pheromone-carrying major urinary proteins (MUPs) in a cycling manner, thus reaching the maximum urinary production just before ovulation. This is thought to occur to advertise the time of ovulation via deposited urine marks. This study aimed to characterize the protein content from the house mouse vaginal flushes to detect putative vaginal-advertising molecules for a direct identification of reproductive states. Here we show that the mouse vaginal discharge contains lipocalins including those from the odorant binding (OBP) and major urinary (MUP) protein families. OBPs were highly expressed but only slightly varied throughout the cycle, whilst several MUPs were differentially abundant. MUP20 or 'darcin', was thought to be expressed only by males. However, in females it was significantly up-regulated during estrus similarly as the recently duplicated central/group-B MUPs (sMUP17 and highly expressed sMUP9), which in the mouse urine are male biased. MUPs rise between proestrus and estrus, remain steady throughout metestrus, and are co-expressed with antimicrobial proteins. Thus, we suggest that MUPs and potentially also OBPs are important components of female vaginal advertising of the house mouse. PMID- 28916784 TI - P-body proteins regulate transcriptional rewiring to promote DNA replication stress resistance. AB - mRNA-processing (P-) bodies are cytoplasmic granules that form in eukaryotic cells in response to numerous stresses to serve as sites of degradation and storage of mRNAs. Functional P-bodies are critical for the DNA replication stress response in yeast, yet the repertoire of P-body targets and the mechanisms by which P-bodies promote replication stress resistance are unknown. In this study we identify the complete complement of mRNA targets of P-bodies during replication stress induced by hydroxyurea treatment. The key P-body protein Lsm1 controls the abundance of HHT1, ACF4, ARL3, TMA16, RRS1 and YOX1 mRNAs to prevent their toxic accumulation during replication stress. Accumulation of YOX1 mRNA causes aberrant downregulation of a network of genes critical for DNA replication stress resistance and leads to toxic acetaldehyde accumulation. Our data reveal the scope and the targets of regulation by P-body proteins during the DNA replication stress response.P-bodies form in response to stress and act as sites of mRNA storage and degradation. Here the authors identify the mRNA targets of P bodies during DNA replication stress, and show that P-body proteins act to prevent toxic accumulation of these target transcripts. PMID- 28916786 TI - Early maternal mirroring predicts infant motor system activation during facial expression observation. AB - Processing facial expressions is an essential component of social interaction, especially for preverbal infants. In human adults and monkeys, this process involves the motor system, with a neural matching mechanism believed to couple self- and other-generated facial gestures. Here, we used electroencephalography to demonstrate recruitment of the human motor system during observation and execution of facial expressions in nine-month-old infants, implicating this system in facial expression processing from a very young age. Notably, examination of early video-recorded mother-infant interactions supported the common, but as yet untested, hypothesis that maternal mirroring of infant facial gestures is central to the development of a neural matching mechanism for these gestures. Specifically, the extent to which mothers mirrored infant facial expressions at two months postpartum predicted infant motor system activity during observation of the same expressions at nine months. This suggests that maternal mirroring strengthens mappings between visual and motor representations of facial gestures, which increases infant neural sensitivity to particularly relevant cues in the early social environment. PMID- 28916787 TI - Late Permian wood-borings reveal an intricate network of ecological relationships. AB - Beetles are the most diverse group of macroscopic organisms since the mid Mesozoic. Much of beetle speciosity is attributable to myriad life habits, particularly diverse-feeding strategies involving interactions with plant substrates, such as wood. However, the life habits and early evolution of wood boring beetles remain shrouded in mystery from a limited fossil record. Here we report new material from the upper Permian (Changhsingian Stage, ca. 254-252 million-years ago) of China documenting a microcosm of ecological associations involving a polyphagan wood-borer consuming cambial and wood tissues of the conifer Ningxiaites specialis. This earliest evidence for a component community of several trophically interacting taxa is frozen in time by exceptional preservation. The combination of an entry tunnel through bark, a cambium mother gallery, and up to 11 eggs placed in lateral niches-from which emerge multi instar larval tunnels that consume cambium, wood and bark-is ecologically convergent with Early Cretaceous bark-beetle borings 120 million-years later.Numerous gaps remain in our knowledge of how groups of organisms interacted in ancient ecosystems. Here, Feng and colleagues describe a late Permian fossil wood-boring beetle microcosm, with the oldest known example of complex tunnel geometry, host tissue response, and the presence of fungi within. PMID- 28916785 TI - Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells. AB - Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the TH9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances TH9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of TH9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of TH9 activity for cancer immunotherapy.Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate TH9 homeostasis and antitumour immunity. PMID- 28916788 TI - A V0 core neuronal circuit for inspiration. AB - Breathing in mammals relies on permanent rhythmic and bilaterally synchronized contractions of inspiratory pump muscles. These motor drives emerge from interactions between critical sets of brainstem neurons whose origins and synaptic ordered organization remain obscure. Here, we show, using a virus-based transsynaptic tracing strategy from the diaphragm muscle in the mouse, that the principal inspiratory premotor neurons share V0 identity with, and are connected by, neurons of the preBotzinger complex that paces inspiration. Deleting the commissural projections of V0s results in left-right desynchronized inspiratory motor commands in reduced brain preparations and breathing at birth. This work reveals the existence of a core inspiratory circuit in which V0 to V0 synapses enabling function of the rhythm generator also direct its output to secure bilaterally coordinated contractions of inspiratory effector muscles required for efficient breathing.The developmental origin and functional organization of the brainstem breathing circuits are poorly understood. Here using virus-based circuit-mapping approaches in mice, the authors reveal the lineage, neurotransmitter phenotype, and connectivity patterns of phrenic premotor neurons, which are a crucial component of the inspiratory circuit. PMID- 28916789 TI - Whole body and hematopoietic ADAM8 deficiency does not influence advanced atherosclerotic lesion development, despite its association with human plaque progression. AB - Although A Disintegrin And Metalloproteinase 8 (ADAM8) is not crucial for tissue development and homeostasis, it has been implicated in various inflammatory diseases by regulating processes like immune cell recruitment and activation. ADAM8 expression has been associated with human atherosclerosis development and myocardial infarction, however a causal role of ADAM8 in atherosclerosis has not been investigated thus far. In this study, we examined the expression of ADAM8 in early and progressed human atherosclerotic lesions, in which ADAM8 was significantly upregulated in vulnerable lesions. In addition, ADAM8 expression was most prominent in the shoulder region of human atherosclerotic lesions, characterized by the abundance of foam cells. In mice, Adam8 was highly expressed in circulating neutrophils and in macrophages. Moreover, ADAM8 deficient mouse macrophages displayed reduced secretion of inflammatory mediators. Remarkably, however, neither hematopoietic nor whole-body ADAM8 deficiency in mice affected atherosclerotic lesion size. Additionally, except for an increase in granulocyte content in plaques of ADAM8 deficient mice, lesion morphology was unaffected. Taken together, whole body and hematopoietic ADAM8 does not contribute to advanced atherosclerotic plaque development, at least in female mice, although its expression might still be valuable as a diagnostic/prognostic biomarker to distinguish between stable and unstable lesions. PMID- 28916790 TI - Association between HOMA-IR and Lung Function in Korean Young Adults based on the Korea National Health and Nutrition Examination Survey. AB - Metabolic syndrome, including obesity and insulin resistance, has been reported to lower lung function in elderly subjects with asthma or chronic obstructive lung disease. This study aimed to find the association between lung function and insulin resistance in Korean young adults. This study used data from the Korean National Health and Nutrition Examination Survey 2011-2013, which is a representative sample of the Korean population. A total of 1,922 young adults aged 19 to 40 were included in the analysis. The association between lung function test and insulin resistance was evaluated. Weighted logistic regression analyses showed a significant negative correlation of insulin resistance with FVC% predicted (correlation coefficient gamma = -0.130, P < 0.0001), FEV1% predicted (gamma = -0.074, P = 0.004) and FEV1/FVC ratio (gamma = -0.059, P = 0.019) in young adults, especially in subjects without asthma (gamma for FVC% predicted, FEV1% predicted and FEV1/FVC ratio = -0.138, -0.092, and -0.061, respectively). This study demonstrates an inverse correlation between insulin resistance and lung function in Korean young adults. Young adults with preclinical insulin resistance have a higher risk of impaired lung function. PMID- 28916792 TI - SmartFlares fail to reflect their target transcripts levels. AB - SmartFlare probes have recently emerged as a promising tool for visualisation and quantification of specific RNAs in living cells. They are supposed to overcome the common drawbacks of current methods for RNA analysis: the need of cell fixation or lysis, or the requirements for genetic manipulations. In contrast to the traditional methods, SmartFlare probes are also presumed to provide information on RNA levels in single cells. Disappointingly, the results of our comprehensive study involving probes specific to five different transcripts, HMOX1, IL6, PTGS2, Nrg1, and ERBB4, deny the usefulness of SmartFlare probes for RNA analysis. We report a total lack of correlation between fluorescence intensities of SmartFlare probes and the levels of corresponding RNAs assessed by RT-qPCR. To ensure strong differences in the levels of analysed RNAs, their expression was modified via: (i) HMOX1-knockdown generated by CRISPR-Cas9 genome editing, (ii) hemin-mediated stimulation of HMOX1- and IL1beta-mediated stimulation of IL6- and PTGS2 transcription, (iii) lentiviral vector-mediated Nrg1 overexpression. Additionally, ERBB4-specific SmartFlare probe failed to distinguish between ERBB4-expressing and non-expressing cell lines. Finally, we demonstrated that fluorescence intensity of HMOX1-specific SmartFlare probe corresponds to the efficacy of its uptake and/or accumulation. PMID- 28916791 TI - Genomic structure and evolution of the mating type locus in the green seaweed Ulva partita. AB - The evolution of sex chromosomes and mating loci in organisms with UV systems of sex/mating type determination in haploid phases via genes on UV chromosomes is not well understood. We report the structure of the mating type (MT) locus and its evolutionary history in the green seaweed Ulva partita, which is a multicellular organism with an isomorphic haploid-diploid life cycle and mating type determination in the haploid phase. Comprehensive comparison of a total of 12.0 and 16.6 Gb of genomic next-generation sequencing data for mt- and mt+ strains identified highly rearranged MT loci of 1.0 and 1.5 Mb in size and containing 46 and 67 genes, respectively, including 23 gametologs. Molecular evolutionary analyses suggested that the MT loci diverged over a prolonged period in the individual mating types after their establishment in an ancestor. A gene encoding an RWP-RK domain-containing protein was found in the mt- MT locus but was not an ortholog of the chlorophycean mating type determination gene MID. Taken together, our results suggest that the genomic structure and its evolutionary history in the U. partita MT locus are similar to those on other UV chromosomes and that the MT locus genes are quite different from those of Chlorophyceae. PMID- 28916793 TI - Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation. AB - Oligodendrocyte (OL) maturation and axon-glial communication are required for proper myelination in the developing brain. However, physiological properties of OLs remain largely uncharacterized in different brain regions. The roles of oligodendroglial voltage-activated Na+ channels (Nav) and electrical excitability in relation to maturation to the myelinating stage are controversial, although oligodendroglial excitability is potentially important for promoting axon myelination. Here we show spiking properties of OLs and their role in axon-glial communication in the auditory brainstem. A subpopulation of pre-myelinating OLs (pre-OLs) can generate Nav1.2-driven action potentials throughout postnatal development to early adulthood. In addition, excitable pre-OLs receive glutamatergic inputs from neighboring neurons that trigger pre-OL spikes. Knockdown of Nav1.2 channels in pre-OLs alters their morphology, reduces axon-OL interactions and impairs myelination. Our results suggest that Nav1.2-driven spiking of pre-OLs is an integral component of axon-glial communication and is required for the function and maturation of OLs to promote myelination.Axon-glial communication is important for myelination. Here the authors show that during postnatal development in rats, a subpopulation of pre-myelinating oligodendrocytes in the auditory brainstem receive excitatory inputs and can generate Nav 1.2-driven action potentials, and that such process promotes myelination. PMID- 28916794 TI - Association among obesity, overweight and autism spectrum disorder: a systematic review and meta-analysis. AB - Obesity, overweight and autism spectrum disorder (ASD) remain serious public health problems. Although lots of studies have recently explored the association among obesity, overweight and ASD, the findings are inconsistent. Thus, we conducted a meta-analysis of epidemiological studies to examine the association among obesity, overweight and ASD. PubMed, Embase, and the Cochrane Library were used for literature searches to identify eligible studies published in English before November 15, 2016. Relevant studies estimating the association among obesity, overweight and ASD were included. Fifteen studies encompassing 49,937,078 participants and 1,045,538 individuals with ASD were included in this study. A random effects model was chosen to synthesize the effect sizes of individual studies. The prevalence of obesity was significantly higher in individuals with ASD than in controls (OR = 1.84, 95% confidence interval [CI]: 1.37-2.48, P < 0.001). However, the prevalence of overweight in individuals with ASD was not significantly different from that in controls (OR = 1.07, 95% CI: 0.83-1.38, P = 0.62). Both sensitivity analysis and publication bias testing revealed that the findings were robust. The meta-analysis showed a significant association between obesity and ASD. However, no significant association was identified between overweight and ASD. PMID- 28916795 TI - Effect of pressure on normal and superconducting state properties of iron based superconductor PrFeAsO0.6F y (y = 0.12, 0.14). AB - The effect of high pressure (up to 8 GPa) on normal and superconducting state properties of PrFeAsO0.6F0.12, an 1111-type iron based superconductor close to optimal doped region, has been investigated by measuring the temperature dependence of resistivity. Initially, the superconducting transition temperature (T c ) is observed to increase slowly by about 1 K as pressure (P) increases from 0 to 1.3 GPa. With further increase in pressure above 1.3 GPa, T c decreases at the rate of ~1.5 K/GPa. The normal-state resistivity decreases monotonically up to 8 GPa. We have also measured the pressure dependence of magnetization (M) on the same piece of PrFeAsO0.6F0.12 sample up to 1.1 GPa and observed T c as well as the size of the Meissner signal to increase with pressure in this low-pressure region. In contrast, for an over-doped PrFeAsO0.6F0.14 sample, magnetization measurements up to 1.06 GPa show that both T c and the Meissner signal decrease with pressure. The present study clearly reveals two distinct regions in the dome shaped (T c -P) phase diagram of PrFeAsO0.6F0.12. PMID- 28916796 TI - Low temperature plasma promoting fibroblast proliferation by activating the NF kappaB pathway and increasing cyclinD1 expression. AB - The potential applications of low temperature plasma (LTP) in wound healing have aroused the concern of many researchers. In this study, an argon atmospheric pressure plasma jet was applied to generate LTP for treatment of murine fibroblast cell (L929) cultured in vitro to investigate the effect of NF-kappaB pathway on fibroblast proliferation. The results showed that, compared with the control, L929 cells treated with plasma for less than 20 s had significant increases of proliferation; the productions of intracellular ROS, O2- and NO increased with prolongation of LTP treatment time; NF-kappaB pathway was activated by LTP in a proper dose range, and the expression of cyclinD1 in LTP treated cells increased with the same trend as cell proliferation. After RNA interference to block p65 expression, with the same treatment time, RNAi-treated cells proliferated more slowly and expressed less cyclinD1 than normal cells. Furthermore, pretreatment with N-acetyl-L-cysteine (NAC) markedly prevented the plasma-induced changes in cells. In conclusion, the proliferation of L929 cells induced by LTP was closely related to NF-kappaB signaling pathway, which might be activated by appropriate level of intracellular ROS. These novel findings can provide some theoretical reference of LTP inducing cell proliferation and promoting wound healing. PMID- 28916797 TI - Synthesis of enhanced phosphonic functional groups mesoporous silica for uranium selective adsorption from aqueous solutions. AB - Enhanced phosphonic functional group (PFG)-based mesoporous silicas (MSs) were synthesized by hydrothermal method for uranium [U(VI)] selective adsorption from aqueous solutions. Considering that PFGs are directly related to U(VI) adsorption, the main idea of this research was to synthesize enhanced PFG-MSs and consequently enhance U(VI) adsorption. We synthesized two kinds of MSs based on acetic and phosphoric acids at weakly acidic pH, which allows high-loading phosphonic functionality. The main sodium and phosphonic functionality sources were sodium metasilicate and diethylphosphatoethyltriethoxysilane (DPTS). Adsorption experiment results exhibit enhanced U(VI) adsorption capacity from 55.75 mg/g to 207.6 mg/g for acetic and phosphoric acids, respectively. This finding was due to the enhancement of PFGs by phosphoric acids. The highest adsorption selectivity was 79.82% for U(VI) among the six different elements, including Pb, As, Cu, Mo, Ni, and K. Structural characterization of the samples was performed by Fourier transform infrared, X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and Brunauer-Emmett-Teller analysis methods. Element concentrations were measured by inductively coupled plasma optical emission spectrometry. Several parameters affecting adsorption capacity, including pH, contact time, initial U(VI) concentration and solution volume, and adsorbent concentration, were also investigated. PMID- 28916798 TI - Green Perovskite Distributed Feedback Lasers. AB - A visible perovskite distributed feedback laser is fabricated for the first time. Through the use of nanocrystal pinning, highly luminescent methylammonium lead bromide films are used to produce stable lasers emitting at 550 nm, with a low threshold of 6 uJcm-2. The lasers were able to support multiple polarisations, and could be switched between transverse magnetic and transverse electric mode operation through simple tuning of the distributed feedback grating period. PMID- 28916799 TI - Exploring the excited state behavior for 2-(phenyl)imidazo[4,5-c]pyridine in methanol solvent. AB - In this present work, we theoretically investigate the excited state mechanism for the 2-(phenyl)imidazo[4,5-c]pyridine (PIP-C) molecule combined with methanol (MeOH) solvent molecules. Three MeOH molecules should be connected with PIP-C forming stable PIP-C-MeOH complex in the S0 state. Upon the photo-excitation, the hydrogen bonded wires are strengthened in the S1 state. Particularly the deprotonation process of PIP-C facilitates the excited state intermolecular proton transfer (ESIPT) process. In our work, we do verify that the ESIPT reaction should occur due to the low potential energy barrier 8.785 kcal/mol in the S1 state. While the intersection of potential energy curves of S0 and S1 states result in the nonradiation transition from S1 to S0 state, which successfully explain why the emission peak of the proton-transfer PIP-C-MeOH-PT form could not be reported in previous experiment. As a whole, this work not only put forward a new excited state mechanism for PIP-C system, but also compensates for the defects about mechanism in previous experiment. PMID- 28916800 TI - Alternative splicing complexity contributes to genetic improvement of drought resistance in the rice maintainer HuHan2B. AB - Water-saving and drought-resistantce rice (WDR) breeding practices have greatly increased grain yield and drought resistance. To study the genetic basis of adaptation to drought, transcriptome sequences from the WDR maintainer line HuHan2B and the recurrent parent HanFengB were analyzed for alternative splicing (AS) complexity. Intron retention, the dominant AS type, accounted for 42% of the observed AS events. Differential expression analysis revealed transcripts were preferentially expressed in different varieties and conditions. Based on gene ontology predictions, the biological functions of drought-induced transcripts were significantly enriched in genes involved in transcription regulation, chloroplast components and response to abiotic stimulus in HuHan2B, whereas developmental processes for reproduction were primarily enriched in HanFengB. The regulatory network of transcription factors was driven by cohorts of transcript splicing targets, resulting in more diversified regulatory relationships due to AS complexity than in our previous findings. Moreover, several genes were validated to accumulate novel splicing transcripts in a drought-induced manner. Together, these results suggest that HuHan2B and HanFengB share similar AS features but that a subset of genes with increased levels of AS involved in transcription regulatory networks may contribute an additional level of control for genetic improvement of drought resistance in rice maintainer HuHan2B through breeding. PMID- 28916801 TI - Taming active turbulence with patterned soft interfaces. AB - Active matter embraces systems that self-organize at different length and time scales, often exhibiting turbulent flows apparently deprived of spatiotemporal coherence. Here, we use a layer of a tubulin-based active gel to demonstrate that the geometry of active flows is determined by a single length scale, which we reveal in the exponential distribution of vortex sizes of active turbulence. Our experiments demonstrate that the same length scale reemerges as a cutoff for a scale-free power law distribution of swirling laminar flows when the material evolves in contact with a lattice of circular domains. The observed prevalence of this active length scale can be understood by considering the role of the topological defects that form during the spontaneous folding of microtubule bundles. These results demonstrate an unexpected strategy for active systems to adapt to external stimuli, and provide with a handle to probe the existence of intrinsic length and time scales.Active nematics consist of self-driven components that develop orientational order and turbulent flow. Here Guillamat et al. investigate an active nematic constrained in a quasi-2D geometrical setup and show that there exists an intrinsic length scale that determines the geometry in all forcing regimes. PMID- 28916802 TI - Local Juvenile Hormone activity regulates gut homeostasis and tumor growth in adult Drosophila. AB - Hormones play essential roles during development and maintaining homeostasis in adult organisms, regulating a plethora of biological processes. Generally, hormones are secreted by glands and perform a systemic action. Here we show that Juvenile Hormones (JHs), insect sesquiterpenoids synthesized by the corpora allata, are also synthesized by the adult Drosophila gut. This local, gut specific JH activity, is synthesized by and acts on the intestinal stem cell and enteroblast populations, regulating their survival and cellular growth through the JH receptors Gce/Met and the coactivator Tai. Furthermore, we show that this local JH activity is important for damage response and is necessary for intestinal tumor growth driven by activating mutations in Wnt and EGFR/Ras pathways. Together, our results identify JHs as key hormonal regulators of gut homeostasis and open the possibility that analogous hormones may play a similar role in maintaining vertebrate adult intestinal stem cell population and sustaining tumor growth. PMID- 28916804 TI - Mapping the Atomistic Structure of Graded Core/Shell Colloidal Nanocrystals. AB - Engineering the compositional gradient for core/shell semiconductor nanocrystals improves their optical properties. To date, however, the structure of graded core/shell nanocrystal emitters has only been qualitatively described. In this paper, we demonstrate an approach to quantify nanocrystal structure, selecting graded Ag-In-Se/ZnSe core/shell nanocrystals as a proof-of-concept material. A combination of multi-energy small-angle X-ray scattering and electron microscopy techniques enables us to establish the radial distribution of ZnSe with sub nanometer resolution. Using ab initio shape-retrieval analysis of X-ray scattering spectra, we further determine the average shape of nanocrystals. These results allow us to generate three-dimensional, atomistic reconstructions of graded core/shell nanocrystals. We use these reconstructions to calculate solid state Zn diffusion in the Ag-In-Se nanocrystals and the lattice mismatch between nanocrystal monolayers. Finally, we apply these findings to propose design rules for optimal shell structure and record-luminescent core/shell nanocrystals. PMID- 28916805 TI - An HDAC3-PROX1 corepressor module acts on HNF4alpha to control hepatic triglycerides. AB - The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4alpha (HNF4alpha). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis. PMID- 28916806 TI - Rewiring of neuronal networks during synaptic silencing. AB - Analyzing the connectivity of neuronal networks, based on functional brain imaging data, has yielded new insight into brain circuitry, bringing functional and effective networks into the focus of interest for understanding complex neurological and psychiatric disorders. However, the analysis of network changes, based on the activity of individual neurons, is hindered by the lack of suitable meaningful and reproducible methodologies. Here, we used calcium imaging, statistical spike time analysis and a powerful classification model to reconstruct effective networks of primary rat hippocampal neurons in vitro. This method enables the calculation of network parameters, such as propagation probability, path length, and clustering behavior through the measurement of synaptic activity at the single-cell level, thus providing a fuller understanding of how changes at single synapses translate to an entire population of neurons. We demonstrate that our methodology can detect the known effects of drug-induced neuronal inactivity and can be used to investigate the extensive rewiring processes affecting population-wide connectivity patterns after periods of induced neuronal inactivity. PMID- 28916807 TI - Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state. AB - Human immunodeficiency virus t ype 1 (H IV-1) assembles as immature particles, which require the proteolytic cleavage of structural polyprotein Gag and the clustering of envelope glycoprotein Env for infectivity. The details of mechanisms underlying Env clustering remain unknown. Here, we determine molecular dynamics of Env on the surface of individual HIV-1 particles using scanning fluorescence correlation spectroscopy on a super-resolution STED microscope. We find that Env undergoes a maturation-induced increase in mobility, highlighting diffusion as one cause for Env clustering. This mobility increase is dependent on Gag-interacting Env tail but not on changes in viral envelope lipid order. Diffusion of Env and other envelope incorporated proteins in mature HIV-1 is two orders of magnitude slower than in the plasma membrane, indicating that HIV-1 envelope is intrinsically a low mobility environment, mainly due to its general high lipid order. Our results provide insights into dynamic properties of proteins on the surface of individual virus particles.To become infectious, HIV-1 particles undergo a maturation process involving the clustering of envelope glycoprotein Env. Here, Chojnacki et al. employ super-resolution STED-FCS microscopy to study dynamics of Env molecules on HIV-1 particles and show that Env undergoes a maturation-induced increase in mobility. PMID- 28916808 TI - The effects of domestication and ontogeny on cognition in dogs and wolves. AB - Cognition is one of the most flexible tools enabling adaptation to environmental variation. Living close to humans is thought to influence social as well as physical cognition of animals throughout domestication and ontogeny. Here, we investigated to what extent physical cognition and two domains of social cognition of dogs have been affected by domestication and ontogeny. To address the effects of domestication, we compared captive wolves (n = 12) and dogs (n = 14) living in packs under the same conditions. To explore developmental effects, we compared these dogs to pet dogs (n = 12) living in human families. The animals were faced with a series of object-choice tasks, in which their response to communicative, behavioural and causal cues was tested. We observed that wolves outperformed dogs in their ability to follow causal cues, suggesting that domestication altered specific skills relating to this domain, whereas developmental effects had surprisingly no influence. All three groups performed similarly in the communicative and behavioural conditions, suggesting higher ontogenetic flexibility in the two social domains. These differences across cognitive domains need to be further investigated, by comparing domestic and non domesticated animals living in varying conditions. PMID- 28916809 TI - Thermoelectricity in vertical graphene-C60-graphene architectures. AB - Recent studies of single-molecule thermoelectricity have identified families of high-performance molecules. However, in order to translate this discovery into practical thin-film energy-harvesting devices, there is a need for an understanding of the fundamental issues arising when such junctions are placed in parallel. This is relevant because controlled scalability might be used to boost electrical and thermoelectric performance over the current single-junction paradigm. As a first step in this direction, we investigate here the properties of two C60 molecules placed in parallel and sandwiched between top and bottom graphene electrodes. In contrast with classical conductors, we find that increasing the number of parallel junctions from one to two can cause the electrical conductance to increase by more than a factor of 2. Furthermore, we show that the Seebeck coefficient is sensitive to the number of parallel molecules sandwiched between the electrodes, whereas classically it should be unchanged. This non-classical behaviour of the electrical conductance and Seebeck coefficient are due to inter-junction quantum interference, mediated by the electrodes, which leads to an enhanced response in these vertical molecular devices. PMID- 28916810 TI - Horizontal extent of the urban heat dome flow. AB - Urban heat dome flow, which is also referred to as urban heat island circulation, is important for urban ventilation and pollutant transport between adjacent cities when the background wind is weak or absent. A "dome-shaped" profile can form at the upper boundary of the urban heat island circulation. The horizontal extent of the heat dome is an important parameter for estimating the size of the area it influences. This study reviews the existing data on the horizontal extent of the urban heat dome flow, as determined by using either field measurements or numerical simulations. A simple energy balance model is applied to obtain the maximum horizontal extent of a single heat dome over the urban area, which is found to be approximately 1.5 to 3.5 times the diameter of the city's urban area at night. A linearized model is also re-analysed to calculate the horizontal extent of the urban heat dome flow. This analysis supports the results from the energy balance model. During daytime, the horizontal extent of the urban heat dome flow is found to be about 2.0 to 3.3 times the urban area's diameter, as influenced by the convective turbulent plumes in the rural area. PMID- 28916811 TI - An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. AB - GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T -> A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, alpha1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue." PMID- 28916812 TI - Size-dependent electrical transport properties in Co nanocluster-assembled granular films. AB - A series of Co nanocluster-assembled films with cluster sizes ranging from 4.5 nm to 14.7 nm were prepared by the plasma-gas-condensation method. The size dependent electrical transport properties were systematically investigated. Both of the longitudinal resistivity ([Formula: see text]) and saturated anomalous Hall resistivity ([Formula: see text]) continuously increased with the decrease of the cluster sizes (d). The [Formula: see text] firstly increased and then decreased with increasing the temperature for all samples, which could be well described by involving the thermally fluctuation-induced tunneling (FIT) process and scattering. The tunneling effect was verified to result in the invalidation of classical anomalous Hall effect (AHE) scaling relation. After deducting the contribution from tunneling effect to [Formula: see text], the AHE scaling relation between [Formula: see text] and the scattering resistivity ([Formula: see text]) by varying the temperature was reconstructed. The value of scaling exponent gamma increased with increasing Co cluster sizes. The size dependence of gamma might be qualitatively interpreted by the interface and surface-induced spin flip scattering. We also determined the scaling relation between [Formula: see text] and [Formula: see text] at 5 K by changing the Co cluster sizes, and a large value of gamma = 3.6 was obtained which might be ascribed to the surface and interfacial scattering. PMID- 28916814 TI - Expression of brown-midrib in a spontaneous sorghum mutant is linked to a 5'-UTR deletion in lignin biosynthesis gene SbCAD2. AB - Brown midrib (bmr) mutants in sorghum (Sorghum bicolor (L.) Moench) and several other C4 grasses are associated with reduced lignin concentration, altered lignin composition and improved cell wall digestibility, which are desirable properties in biomass development for the emerging lignocellulosic biofuel industry. Studying bmr mutants has considerably expanded our understanding of the molecular basis underlying lignin biosynthesis and perturbation in grasses. In this study, we performed quantitative trait locus (QTL) analysis, identified and cloned a novel cinnamyl alcohol dehydrogenase allele (SbCAD2) that has an 8-bp deletion in its 5'-untranslated region (UTR), conferring the spontaneous brown midrib trait and lignin reduction in the sorghum germplasm line PI 595743. Complementation test and gene expression analysis revealed that this non-coding region alteration is associated with the significantly reduced expression of the SbCAD2 in PI 595743 throughout its growth stages. Moreover, a promoter-GUS fusion study with transgenic Arabidopsis thaliana plants found that SbCAD2 promoter is functionally conserved, driving a specific expression pattern in lignifying vascular tissues. Taken together, our results revealed the genetic basis of bmr occurrence in this spontaneous sorghum mutant and suggested the regulatory region of the SbCAD2 can be a target site for optimizing lignin modification in sorghum and other bioenergy crops. PMID- 28916813 TI - Genome sequencing reveals metabolic and cellular interdependence in an amoeba kinetoplastid symbiosis. AB - Endosymbiotic relationships between eukaryotic and prokaryotic cells are common in nature. Endosymbioses between two eukaryotes are also known; cyanobacterium derived plastids have spread horizontally when one eukaryote assimilated another. A unique instance of a non-photosynthetic, eukaryotic endosymbiont involves members of the genus Paramoeba, amoebozoans that infect marine animals such as farmed fish and sea urchins. Paramoeba species harbor endosymbionts belonging to the Kinetoplastea, a diverse group of flagellate protists including some that cause devastating diseases. To elucidate the nature of this eukaryote-eukaryote association, we sequenced the genomes and transcriptomes of Paramoeba pemaquidensis and its endosymbiont Perkinsela sp. The endosymbiont nuclear genome is ~9.5 Mbp in size, the smallest of a kinetoplastid thus far discovered. Genomic analyses show that Perkinsela sp. has lost the ability to make a flagellum but retains hallmark features of kinetoplastid biology, including polycistronic transcription, trans-splicing, and a glycosome-like organelle. Mosaic biochemical pathways suggest extensive 'cross-talk' between the two organisms, and electron microscopy shows that the endosymbiont ingests amoeba cytoplasm, a novel form of endosymbiont-host communication. Our data reveal the cell biological and biochemical basis of the obligate relationship between Perkinsela sp. and its amoeba host, and provide a foundation for understanding pathogenicity determinants in economically important Paramoeba. PMID- 28916815 TI - Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value. AB - Immunotherapy targeting PD-1/PD-L1 axis showed benefits in cancer. Prognostic significance of tumour infiltrating lymphocytes (TILs) has been determined. We evaluated PD-L1 protein expression in tumour cells and TILs, PD-L1 mRNA level and various histopathologic factors including TILs using 167 formalin-fixed paraffin embedded tissues and 39 fresh tissue of HER2-positive breast cancer. TILs level and PD-L1 expression in tumour cells and TILs were significantly correlated one another. PD-L1 positivity in tumour cells was associated with high histologic grade and high TILs level (p < 0.001, both). High PD-L1 immunoscore in TILs and high total immunoscore (in tumour cells and TILs) of PD-L1 were correlated with high histologic grade (p = 0.001 and p < 0.001, respectively), absence of lymphovascular invasion (p = 0.012 and p = 0.007, respectively), negative hormone receptor expression (p = 0.044 and p = 0.001, respectively) and high TILs level (p < 0.001, both). High PD-L1 mRNA expression was associated with high TILs level (p < 0.001, both). PD-L1 positivity in tumour cells was associated with better disease-free survival in HR-/HER2+ breast cancer (p = 0.039). PD-L1 expression in tumour cells and TILs are significantly associated with TILs level in HER2 positive breast cancer. PD-L1 expression in tumour cells might be positive prognostic factor in HR-/HER2+ breast cancers. PMID- 28916816 TI - Striking diflubenzuron resistance in Culex pipiens, the prime vector of West Nile Virus. AB - Culex pipiens mosquitoes cause severe nuisance and transmit human diseases including West Nile. Vector control by insecticides is the main tool to prevent these diseases and diflubenzuron is one of the most effective mosquito larvicides used in many places. Here, high levels of resistance were identified in Cx. pipiens from Italy, with a Resistance Ratio of 128 fold. The phenotype was associated with mutations at amino acid I1043 (I1043M and I1043L) of the Chitin synthase gene, which showed significantly higher frequency in bioassay survivors. Both mutations have been introduced in the Drosophila melanogaster chitin synthase gene using the genome editing method CRISPR/Cas9 and validated to confer significant levels of resistance, although at different levels. The I->M mutation results in a Resistance Ratio >2,900 fold and the I->L mutation >20 fold. Two PCR based diagnostics were developed for monitoring of the resistant mutations in field populations. The findings are of major concern for public health given the importance of diflubenzuron in mosquito control in many places, the intensity of the resistance phenotype and the limited availability of alternative larvicides. PMID- 28916817 TI - Micro and nano hierachical structures of BiOI/activated carbon for efficient visible-light-photocatalytic reactions. AB - Constructing the heterojunctions or designing the novel nanostructures are thought as effective methods to improve photocatalytic activities of semiconductors. Herein, a one-step green route was developed to fabricate bismuth oxyiodide/activated carbon (BiOI/C) composite. The prepared BiOI/C exhibit obviously red shifts and increased absorption range of visible light. The presence of Bi-C bonds confirms the heterojunction, on account of which the BiOI nanosheets tightly grew on the surface of carbon and subsequently provided the hierarchical structure, sufficient interfacial interaction and high specific surface area. Significantly, the sufficient interracial interaction is beneficial to the detachment of electrons (e-)-holes (h+) pairs and the Bi-C bonds work like a bridge to rapidly transmit the e- from BiOI to carbon. What's more, the hierarchical structure of BiOI/C efficiently shortened the diffusion pathways of pollutants and the high SBET provided more exposed reaction sites. Benefiting from multiple synergistic effects, the as-prepared BiOI/C exhibited enhanced photocatalytic activities in degrading Rhodamine B (RhB) solution under visible light irradiation. The degradation rate of optimized BiOI/C reaches up to 95% in 120 min, and the efficiency is 3.36 times higher than pure BiOI. This study provides a promising strategy that activated carbon can be utilized in highly efficiency photocatalysts. PMID- 28916818 TI - Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt. AB - Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC50 = 6 uM) and downstream signaling. 4-Phenylquinolin 2(1H)-one did not alter the activity of upstream kinases including PI3K, PDK1, and mTORC2 as well as closely related kinases that affect cell proliferation and survival such as SGK1, PKA, PKC, or ERK1/2. This compound inhibited the proliferation of cancer cells but displayed less toxicity compared to inhibitors of PI3K or mTOR. Kinase profiling efforts revealed that 4-phenylquinolin-2(1H) one does not bind to the kinase active site of over 380 human kinases including Akt. However, 4-phenylquinolin-2(1H)-one interacted with the PH domain of Akt, apparently inducing a conformation that hinders S473 and T308 phosphorylation by mTORC2 and PDK1. In conclusion, we demonstrate that 4-phenylquinolin-2(1H)-one is an exquisitely selective Akt inhibitor with a distinctive molecular mechanism, and a promising lead compound for further optimization toward the development of novel cancer therapeutics. PMID- 28916819 TI - Continuous Beam Steering Through Broadside Using Asymmetrically Modulated Goubau Line Leaky-Wave Antennas. AB - Goubau line is a single-conductor transmission line, featuring easy integration and low-loss transmission properties. Here, we propose a periodic leaky-wave antenna (LWA) based on planar Goubau transmission line on a thin dielectric substrate. The leaky-wave radiations are generated by introducing periodic modulations along the Goubau line. In this way, the surface wave, which is slow wave mode supported by the Goubau line, achieves an additional momentum and hence enters the fast-wave region for radiations. By employing the periodic modulations, the proposed Goubau line LWAs are able to continuously steer the main beam from backward to forward within the operational frequency range. However, the LWAs usually suffer from a low radiation efficiency at the broadside direction. To overcome this drawback, we explore both transversally and longitudinally asymmetrical modulations to the Goubau line. Theoretical analysis, numerical simulations and experimental results are given in comparison with the symmetrical LWAs. It is demonstrated that the asymmetrical modulations significantly improve the radiation efficiency of LWAs at the broadside. Furthermore, the measurement results agree well with the numerical ones, which experimentally validates the proposed LWA structures. These novel Goubau line LWAs, experimentally demonstrated and validated at microwave frequencies, show also great potential for millimeter-wave and terahertz systems. PMID- 28916820 TI - Accumulation of minor alleles and risk prediction in schizophrenia. AB - Schizophrenia is a common neuropsychiatric disorder with a lifetime risk of 1%. Accumulation of common polygenic variations has been found to be an important risk factor. Recent studies showed a role for the enrichment of minor alleles (MAs) of SNPs in complex diseases such as Parkinson's disease. Here we similarly studied the role of genome wide MAs in schizophrenia using public datasets. Relative to matched controls, schizophrenia cases showed higher average values in minor allele content (MAC) or the average amount of MAs per subject. By risk prediction analysis based on weighted genetic risk score (wGRS) of MAs, we identified an optimal MA set consisting of 23 238 variants that could be used to predict 3.14% of schizophrenia cases, which is comparable to using 22q11 deletion to detect schizophrenia cases. Pathway enrichment analysis of these SNPs identified 30 pathways with false discovery rate (FDR) <0.02 and of significant P value, most of which are known to be linked with schizophrenia and other neurological disorders. These results suggest that MAs accumulation may be a risk factor to schizophrenia and provide a method to genetically screen for this disease. PMID- 28916821 TI - Reduced basal forebrain atrophy progression in a randomized Donepezil trial in prodromal Alzheimer's disease. AB - Acetylcholinesterase inhibitors are approved drugs currently used for the treatment of Alzheimer's disease (AD) dementia. Basal forebrain cholinergic system (BFCS) atrophy is reported to precede both entorhinal cortex atrophy and memory impairment in AD, challenging the traditional model of the temporal sequence of topographical pathology associated with AD. We studied the effect of one-year Donepezil treatment on the rate of BFCS atrophy in prodromal AD patients using a double-blind, randomized, placebo-controlled trial of Donepezil (10 mg/day). Reduced annual BFCS rates of atrophy were found in the Donepezil group compared to the Placebo treated arm. Secondary analyses on BFCS subregions demonstrated the largest treatment effects in the Nucleus Basalis of Meynert (NbM) and the medial septum/diagonal band (Ch1/2). Donepezil administered at a prodromal stage of AD seems to substantially reduce the rate of atrophy of the BFCS nuclei with highest concentration of cholinergic neurons projecting to the cortex (NbM), hippocampus and entorhinal cortex (Ch1/2). PMID- 28916823 TI - Digging into the low molecular weight peptidome with the OligoNet web server. AB - Bioactive peptides play critical roles in regulating many biological processes. Recently, natural short peptides biomarkers are drawing significant attention and are considered as "hidden treasure" of drug candidates. High resolution and high mass accuracy provided by mass spectrometry (MS)-based untargeted metabolomics would enable the rapid detection and wide coverage of the low-molecular-weight peptidome. However, translating unknown masses (<1 500 Da) into putative peptides is often limited due to the lack of automatic data processing tools and to the limit of peptide databases. The web server OligoNet responds to this challenge by attempting to decompose each individual mass into a combination of amino acids out of metabolomics datasets. It provides an additional network-based data interpretation named "Peptide degradation network" (PDN), which unravels interesting relations between annotated peptides and generates potential functional patterns. The ab initio PDN built from yeast metabolic profiling data shows a great similarity with well-known metabolic networks, and could aid biological interpretation. OligoNet allows also an easy evaluation and interpretation of annotated peptides in systems biology, and is freely accessible at https://daniellyz200608105.shinyapps.io/OligoNet/ . PMID- 28916822 TI - Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. AB - Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3-12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.Exercise is associated with biogenesis and removal of dysfunctional mitochondria. Here the authors use a mitochondrial reporter gene to demonstrate the occurrence of mitophagy following exercise in mice, and show this is dependent on AMPK and ULK1 signaling. PMID- 28916824 TI - Grip force when reaching with target uncertainty provides evidence for motor optimization over averaging. AB - When presented with competing potential reach targets and required to launch a movement before knowing which one will be cued as the target, people initially reach in the average target direction. Although this spatial averaging could arise from executing a weighted average of motor plans for the potential targets, it could also arise from planning a single, optimal movement. To test between these alternatives we used a task in which participants were required to reach to either a single target or towards two potential targets while grasping an object. A robotic device applied a lateral elastic load to the object requiring large grip forces for reaches to targets either side of midline and a minimal grip force for midline movements. As expected, in trials with two targets located either side of midline, participants initially reached straight ahead. Critically, on these trials the initial grip force was minimal, appropriate for the midline movement, and not the average of the large grip forces required for movements to the individual targets. These results indicate that under conditions of target uncertainty, people do not execute an average of planned actions but rather a single movement that optimizes motor costs. PMID- 28916825 TI - De novo transcriptome of the cosmopolitan dinoflagellate Amphidinium carterae to identify enzymes with biotechnological potential. AB - Dinoflagellates are phytoplanktonic organisms found in both freshwater and marine habitats. They are often studied because related to harmful algal blooms but they are also known to produce bioactive compounds for the treatment of human pathologies. The aim of this study was to sequence the full transcriptome of the dinoflagellate Amphidinium carterae in both nitrogen-starved and -replete culturing conditions (1) to evaluate the response to nitrogen starvation at the transcriptional level, (2) to look for possible polyketide synthases (PKSs) in the studied clone (genes that may be involved in the synthesis of bioactive compounds), (3) if present, to evaluate if nutrient starvation can influence PKS expression, (4) to look for other possible enzymes of biotechnological interest and (5) to test strain cytotoxicity on human cell lines. Results showed an increase in nitrogen metabolism and stress response in nitrogen-starved cells and confirmed the presence of a type I beta-ketosynthase. In addition, L-asparaginase (used for the treatment of Leukemia and for acrylamide reduction in food industries) and cellulase (useful for biofuel production and other industrial applications) have been identified for the first time in this species, giving new insights into possible biotechnological applications of dinoflagellates. PMID- 28916826 TI - In Vitro and In Vivo Biocompatibility Evaluation of Polyallylamine and Macromolecular Heparin Conjugates Modified Alginate Microbeads. AB - Host reactivity to biocompatible immunoisolation devices is a major challenge for cellular therapies, and a human screening model would be of great value. We designed new types of surface modified barium alginate microspheres, and evaluated their inflammatory properties using human whole blood, and the intraperitoneal response after three weeks in Wistar rats. Microspheres were modified using proprietary polyallylamine (PAV) and coupled with macromolecular heparin conjugates (Corline Heparin Conjugate, CHC). The PAV-CHC strategy resulted in uniform and stable coatings with increased anti-clot activity and low cytotoxicity. In human whole blood, PAV coating at high dose (100 ug/ml) induced elevated complement, leukocyte CD11b and inflammatory mediators, and in Wistar rats increased fibrotic overgrowth. Coating of high dose PAV with CHC significantly reduced these responses. Low dose PAV (10 ug/ml) +/- CHC and unmodified alginate microbeads showed low responses. That the human whole blood inflammatory reactions paralleled the host response shows a link between inflammatory potential and initial fibrotic response. CHC possessed anti inflammatory activity, but failed to improve overall biocompatibility. We conclude that the human whole blood assay is an efficient first-phase screening model for inflammation, and a guiding tool in development of new generation microspheres for cell encapsulation therapy. PMID- 28916827 TI - Role of RKKY torque on domain wall motion in synthetic antiferromagnetic nanowires with opposite spin Hall angles. AB - We experimentally show the effect of enhanced spin-orbit and RKKY induced torques on the current-induced motion of a pair of domain walls (DWs), which are coupled antiferromagnetically in synthetic antiferromagnetic (SAF) nanowires. The torque from the spin Hall effect (SHE) rotates the Neel DWs pair into the transverse direction, which is due to the fact that heavy metals of opposite spin Hall angles are deposited at the top and the bottom ferromagnetic interfaces. The rotation of both DWs in non-collinear fashion largely perturbs the antiferromagnetic coupling, which in turn stimulates an enhanced interlayer RKKY exchange torque that improved the DW velocity. The interplay between the SHE induced torque and the RKKY exchange torque is validated via micromagnetic simulations. In addition, the DW velocity can be further improved by increasing the RKKY exchange strength. PMID- 28916828 TI - Invasive Andropogon gayanus (Gamba grass) alters litter decomposition and nitrogen fluxes in an Australian tropical savanna. AB - The African grass Andropogon gayanus Kunth. is invading Australian savannas, altering their ecological and biogeochemical function. To assess impacts on nitrogen (N) cycling, we quantified litter decomposition and N dynamics of grass litter in native grass and A. gayanus invaded savanna using destructive in situ grass litter harvests and litterbag incubations (soil surface and aerial position). Only 30% of the A. gayanus in situ litter decomposed, compared to 61% of the native grass litter, due to the former being largely comprised of highly resistant A. gayanus stem. In contrast to the stem, A. gayanus leaf decomposition was approximately 3- and 2-times higher than the dominant native grass, Alloteropsis semilata at the surface and aerial position, respectively. Lower initial lignin concentrations, and higher consumption by termites, accounted for the greater surface decomposition rate of A. gayanus. N flux estimates suggest the N release of A. gayanus litter is insufficient to compensate for increased N uptake and N loss via fire in invaded plots. Annually burnt invaded savanna may lose up to 8.2% of the upper soil N pool over a decade. Without additional inputs via biological N fixation, A. gayanus invasion is likely to diminish the N capital of Australia's frequently burnt savannas. PMID- 28916829 TI - Tricritical wings and modulated magnetic phases in LaCrGe3 under pressure. AB - Experimental and theoretical investigations on itinerant ferromagnetic systems under pressure have shown that ferromagnetic quantum criticality is avoided either by a change of the transition order, becoming of the first order at a tricritical point, or by the appearance of modulated magnetic phases. In the first case, the application of a magnetic field reveals a wing-structure phase diagram as seen in itinerant ferromagnets such as ZrZn2 and UGe2. In the second case, no tricritical wings have been observed so far. Here, we report on the discovery of wing-structure as well as the appearance of modulated magnetic phases in the temperature-pressure-magnetic field phase diagram of LaCrGe3. Our investigation of LaCrGe3 reveals a double-wing structure indicating strong similarities with ZrZn2 and UGe2. But, unlike these simpler systems, LaCrGe3 also shows modulated magnetic phases similar to CeRuPO. This finding provides an example of an additional possibility for the phase diagram of metallic quantum ferromagnets.The study of phase transitions in quantum ferromagnets has shown that the approach to a continuous quantum ferromagnetic transition is typically interrupted by either a tricritical point or a new magnetic phase. Here the authors show that LaCrGe3 exhibits both these features in its phase diagram. PMID- 28916830 TI - The effects of different enrofloxacin dosages on clinical efficacy and resistance development in chickens experimentally infected with Salmonella Typhimurium. AB - To investigate the optimal dosage which can improve clinical efficacy and minimize resistance, pharmacokinetics/pharmacodynamics model of enrofloxacin was established. Effect of enrofloxacin treatments on clearance of Salmonella in experimentally infected chickens and simultaneously resistance selection in Salmonella and coliforms were evaluated in three treatment groups (100, PK/PD designed dosage of 4, 0.1 mg/kg b.w.) and a control group. Treatment duration was three rounds of 7-day treatment alternated with 7-day withdrawal. Results showed that 100 mg/kg b.w. of enrofloxacin completely eradicated Salmonella, but resistant coliforms (4.0-60.8%) were selected from the end of the second round's withdrawal period till the end of the experiment (days 28-42). PK/PD based dosage (4 mg/kg b.w.) effectively reduced Salmonella for the first treatment duration. However upon cessation of medication, Salmonella repopulated chickens and persisted till the end with reduced susceptibility (MICCIP = 0.03-0.25 mg/L). Low frequency (5-9.5%) of resistant coliforms was selected (days 39-42). Enrofloxacin at dosage of 0.1 mg/kg b.w. was not able to eliminate Salmonella and selected coliforms with slight decreased susceptibility (MICENR = 0.25 mg/L). In conclusion, short time treatment (7 days) of enrofloxacin at high dosage (100 mg/kg b.w.) could be effective in treating Salmonella infection while minimizing resistance selection in both Salmonella and coliforms. PMID- 28916831 TI - The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage. AB - Using primary melanocytes and HEK293 cells, we found that cAMP signaling accelerates repair of bi- and mono-functional platinum-induced DNA damage. Elevating cAMP signaling either by the agonistic MC1R ligand melanocyte stimulating hormone (MSH) or by pharmacologic cAMP induction by forskolin enhanced clearance of intrastrand cisplatin-adducts in melanocytes or MC1R transfected HEK293 cells. MC1R antagonists human beta-defensin 3 and agouti signaling protein blocked MSH- but not forskolin-mediated enhancement of platinum induced DNA damage. cAMP-enhanced repair of cisplatin-induced DNA damage was dependent on PKA-mediated phosphorylation of ATR on S435 which promoted ATR's interaction with the key NER factor xeroderma pigmentosum A (XPA) and facilitated recruitment of an XPA-ATR-pS435 complex to sites of cisplatin DNA damage. Moreover, we developed an oligonucleotide retrieval immunoprecipitation (ORiP) assay using a novel platinated-DNA substrate to establish kinetics of ATR-pS435 and XPA's associations with cisplatin-damaged DNA. Expression of a non phosphorylatable ATR-S435A construct or deletion of A kinase-anchoring protein 12 (AKAP12) impeded platinum adduct clearance and prevented cAMP-mediated enhancement of ATR and XPA's associations with cisplatin-damaged DNA, indicating that ATR phosphorylation at S435 is necessary for cAMP-enhanced repair of platinum-induced damage and protection against cisplatin-induced mutagenesis. These data implicate cAMP signaling as a critical regulator of genomic stability against platinum-induced mutagenesis. PMID- 28916832 TI - Design of Multivalent Inhibitors for Preventing Cellular Uptake. AB - Cellular entry, the first crucial step of viral infection, can be inhibited by molecules adsorbed on the virus surface. However, apart from using stronger affinity, little is known about the properties of such inhibitors that could increase their effectiveness. Our simulations showed that multivalent inhibitors can be designed to be much more efficient than their monovalent counterparts. For example, for our particular simulation model, a single multivalent inhibitor spanning 5 to 6 binding sites is enough to prevent the uptake compared to the required 1/3 of all the receptor binding sites needed to be blocked by monovalent inhibitors. Interestingly, multivalent inhibitors are more efficient in inhibiting the uptake not only due to their increased affinity but mainly due to the co-localization of the inhibited receptor binding sites at the virion's surface. Furthermore, we show that Janus-like inhibitors do not induce virus aggregation. Our findings may be generalized to other uptake processes including bacteria and drug-delivery. PMID- 28916833 TI - Inhibition of Wnt/beta-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer. AB - In a high percentage (>=85%) of both sporadic and familial adenomatous polyposis forms of colorectal cancer (CRC), the inactivation of the APC tumor suppressor gene initiates tumor formation and modulates the Wnt/beta-Catenin transduction pathways involved in the control of cell proliferation, adhesion and metastasis. Increasing evidence showed that the endocannabinoids control tumor growth and progression, both in vitro and in vivo. We evaluated the effect of Rimonabant, a Cannabinoid Receptor 1 (CB1) inverse agonist, on the Wnt/beta-Catenin pathway in HCT116 and SW48 cell lines carrying the genetic profile of metastatic CRC poorly responsive to chemotherapies. In these models, Rimonabant inhibited the Wnt/beta Catenin canonical pathway and increased beta-Catenin phosphorylation; in HCT116 cells, but not in SW48, the compound also triggered the Wnt/beta-Catenin non canonical pathway activation through induction of Wnt5A and activation of CaMKII. The Rimonabant-induced downregulation of Wnt/beta-Catenin target genes was partially ascribable to a direct inhibition of p300/KAT3B histone acetyltransferase, a coactivator of beta-Catenin dependent gene regulation. Finally, in HCT116 xenografts, Rimonabant significantly reduced tumor growth and destabilized the nuclear localization of beta-Catenin. Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of beta-Catenin. PMID- 28916834 TI - Ultrastructural Characterization of the Glomerulopathy in Alport Mice by Helium Ion Scanning Microscopy (HIM). AB - The glomerulus exercises its filtration barrier function by establishing a complex filtration apparatus consisting of podocyte foot processes, glomerular basement membrane and endothelial cells. Disruption of any component of the glomerular filtration barrier leads to glomerular dysfunction, frequently manifested as proteinuria. Ultrastructural studies of the glomerulus by transmission electron microscopy (TEM) and conventional scanning electron microscopy (SEM) have been routinely used to identify and classify various glomerular diseases. Here we report the application of newly developed helium ion scanning microscopy (HIM) to examine the glomerulopathy in a Col4a3 mutant/Alport syndrome mouse model. Our study revealed unprecedented details of glomerular abnormalities in Col4a3 mutants including distorted podocyte cell bodies and disorganized primary processes. Strikingly, we observed abundant filamentous microprojections arising from podocyte cell bodies and processes, and presence of unique bridging processes that connect the primary processes and foot processes in Alport mice. Furthermore, we detected an altered glomerular endothelium with disrupted sub-endothelial integrity. More importantly, we were able to clearly visualize the complex, three-dimensional podocyte and endothelial interface by HIM. Our study demonstrates that HIM provides nanometer resolution to uncover and rediscover critical ultrastructural characteristics of the glomerulopathy in Col4a3 mutant mice. PMID- 28916836 TI - Modeling the Deformation of the Elastin Network in the Aortic Valve. AB - This paper is concerned with proposing a suitable structurally motivated strain energy function, denoted by Weelastin network, for modeling the deformation of the elastin network within the aortic valve (AV) tissue. The AV elastin network is the main noncollagenous load-bearing component of the valve matrix, and therefore, in the context of continuum-based modeling of the AV, the Weelastin network strain energy function would essentially serve to model the contribution of the "isotropic matrix." To date, such a function has mainly been considered as either a generic neo-Hookean term or a general exponential function. In this paper, we take advantage of the established structural analogy between the network of elastin chains and the freely jointed molecular chain networks to customize a structurally motivated Weelastin network function on this basis. The ensuing stress-strain (force-stretch) relationships are thus derived and fitted to the experimental data points reported by (Vesely, 1998, "The Role of Elastin in Aortic Valve Mechanics," J. Biomech., 31, pp. 115-123) for intact AV elastin network specimens under uniaxial tension. The fitting results are then compared with those of the neo-Hookean and the general exponential models, as the frequently used models in the literature, as well as the "Arruda-Boyce" model as the gold standard of the network chain models. It is shown that our proposed Weelastin network function, together with the general exponential and the Arruda Boyce models provide excellent fits to the data, with R2 values in excess of 0.98, while the neo-Hookean function is entirely inadequate for modeling the AV elastin network. However, the general exponential function may not be amenable to rigorous interpretation, as there is no structural meaning attached to the model. It is also shown that the parameters estimated by the Arruda-Boyce model are not mathematically and structurally valid, despite providing very good fits. We thus conclude that our proposed strain energy function Weelastin network is the preferred choice for modeling the behavior of the AV elastin network and thereby the isotropic matrix. This function may therefore be superimposed onto that of the anisotropic collagen fibers family in order to develop a structurally motivated continuum-based model for the AV. PMID- 28916835 TI - Plasmon-Coupled Whispering Gallery Modes on Nanodisk Arrays for Signal Enhancements. AB - Metallic nanostructures including single and double nanodisks are successfully used to enhance the localized electric field in vicinity of microcavity in whispering gallery mode (WGM) sensor. We demonstrate numerical calculations of plasmonic coupling of WGMs to single and double nanodisk arrays on a planar substrate. We then experimentally confirmed that the resonance wavelength of WGM sensor was dramatically shifted by adoption of single and double nanodisks on the surface of microcavity in the WGM sensor. Thus, our approach provides the tunable sensitivity of WGM sensor, and has a great potential to be used in numerous areas where the single biomolecule, protein-protein folding and biomolecular interactions are involved. PMID- 28916837 TI - Primary and Secondary Consequences of Rotator Cuff Injury on Joint Stabilizing Tissues in the Shoulder. AB - Rotator cuff tears (RCTs) are one of the primary causes of shoulder pain and dysfunction in the upper extremity accounting over 4.5 million physician visits per year with 250,000 rotator cuff repairs being performed annually in the U.S. While the tear is often considered an injury to a specific tendon/tendons and consequently treated as such, there are secondary effects of RCTs that may have significant consequences for shoulder function. Specifically, RCTs have been shown to affect the joint cartilage, bone, the ligaments, as well as the remaining intact tendons of the shoulder joint. Injuries associated with the upper extremities account for the largest percent of workplace injuries. Unfortunately, the variable success rate related to RCTs motivates the need for a better understanding of the biomechanical consequences associated with the shoulder injuries. Understanding the timing of the injury and the secondary anatomic consequences that are likely to have occurred are also of great importance in treatment planning because the approach to the treatment algorithm is influenced by the functional and anatomic state of the rotator cuff and the shoulder complex in general. In this review, we summarized the contribution of RCTs to joint stability in terms of both primary (injured tendon) and secondary (remaining tissues) consequences including anatomic changes in the tissues surrounding the affected tendon/tendons. The mechanical basis of normal shoulder joint function depends on the balance between active muscle forces and passive stabilization from the joint surfaces, capsular ligaments, and labrum. Evaluating the role of all tissues working together as a system for maintaining joint stability during function is important to understand the effects of RCT, specifically in the working population, and may provide insight into root causes of shoulder injury. PMID- 28916838 TI - Functionally Distinct Tendons From Elastin Haploinsufficient Mice Exhibit Mild Stiffening and Tendon-Specific Structural Alteration. AB - Elastic fibers are present in low quantities in tendon, where they are located both within fascicles near tenocytes and more broadly in the interfascicular matrix (IFM). While elastic fibers have long been known to be significant in the mechanics of elastin-rich tissue (i.e., vasculature, skin, lungs), recent studies have suggested a mechanical role for elastic fibers in tendons that is dependent on specific tendon function. However, the exact contribution of elastin to properties of different types of tendons (e.g., positional, energy-storing) remains unknown. Therefore, this study purposed to evaluate the role of elastin in the mechanical properties and collagen alignment of functionally distinct supraspinatus tendons (SSTs) and Achilles tendons (ATs) from elastin haploinsufficient (HET) and wild type (WT) mice. Despite the significant decrease in elastin in HET tendons, a slight increase in linear stiffness of both tendons was the only significant mechanical effect of elastin haploinsufficiency. Additionally, there were significant changes in collagen nanostructure and subtle alteration to collagen alignment in the AT but not the SST. Hence, elastin may play only a minor role in tendon mechanical properties. Alternatively, larger changes to tendon mechanics may have been mitigated by developmental compensation of HET tendons and/or the role of elastic fibers may be less prominent in smaller mouse tendons compared to the larger bovine and human tendons evaluated in previous studies. Further research will be necessary to fully elucidate the influence of various elastic fiber components on structure-function relationships in functionally distinct tendons. PMID- 28916839 TI - Mathematical Model for Tissue-Level Hypoxic Response in Microfluidic Environment. AB - Availability of essential species like oxygen is critical in shaping the dynamics of tumor growth. When the intracellular oxygen level falls below normal, it initiates major cascades in cellular dynamics leading to tumor cell survival. In a cellular block with cells growing away from the blood vessel, the scenario can be aggravated for the cells further inside the block. In this study, the dynamics of intracellular species inside a colony of tumor cells are investigated by varying the cell-block thickness and cell types in a microfluidic cell culture device. The oxygen transport across the cell block is modeled through diffusion, while ascorbate (AS) transport from the extracellular medium is addressed by a concentration-dependent uptake model. The extracellular and intracellular descriptions were coupled through the consumption and traffic of species from the microchannel to the cell block. Our model shows that the onset of hypoxia is possible in HeLa cell within minutes depending on the cell location, although the nutrient supply inside the channel is maintained in normoxic levels. This eventually leads to total oxygen deprivation inside the cell block in the extreme case, representing the development of a necrotic core that maintains a dynamic balance with growing cells and scarce supply. The numerical model reveals that species concentration and hypoxic response are different for HeLa and HelaS3 cells. Results also indicate that the long-term hypoxic response from a microfluidic cellular block stays within 5% of the values of a tissue with the basal layer. The hybrid model can be very useful in designing microfluidic experiments to satisfactorily predict the tissue-level response in cancer research. PMID- 28916840 TI - A novel COL1A2 C-propeptide cleavage site mutation causing high bone mass osteogenesis imperfecta with a regional distribution pattern. AB - Osteogenesis imperfecta (OI) is typically characterized by low bone mass and increased bone fragility caused by heterozygous mutations in the type I procollagen genes (COL1A1/COL1A2). We report two cases of a 56-year-old woman and her 80-year-old mother who suffered from multiple vertebral and non-vertebral fractures with onset in early childhood. A full osteologic assessment including dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses pointed to a high bone mineral density (BMD) in the hip (DXA Z-score + 3.7 and + 3.9) but low to normal bone mass in the spine and preserved bone microstructure in the distal tibia. Serum markers of bone formation and bone resorption were elevated. Using whole exome sequencing, we identified a novel mutation in the COL1A2 gene causing a p. (Asp1120Gly) substitution at the protein level and affecting the type I procollagen C-propeptide cleavage site. In line with previously reported cases, our data independently prove the existence of an unusual phenotype of high bone mass OI caused by a mutation in the procollagen C-propeptide cleavage with a clinically persistent phenotype through adulthood. PMID- 28916842 TI - How interindividual differences in brain anatomy shape reading accuracy. AB - The capacity to read develops throughout intensive academic learning and training. Several studies have investigated the impact of reading on the brain, and particularly how the anatomy of the brain changes with reading acquisition. In the present study, we investigated the converse issue, namely whether and how reading acquisition is constrained by the anatomy of the brain. Using multimodal MRI, we found that (a) the pattern (continuous or interrupted sulcus) of the posterior part of the left lateral occipito-temporal sulcus (OTS) hosting the visual word form area (VWFA) predicts reading skills in adults; that (b) this effect is modulated by the age of reading acquisition; and that (c) the length of the OTS sulcal interruption is associated with reading skills. Because the sulcal pattern is determined in utero, our findings suggest that individual difference in reading skills can be traced back to early stages of brain development in addition to the well-established socioeconomic and educational factors. PMID- 28916841 TI - Some Liked It Hot: A Hypothesis Regarding Establishment of the Proto Mitochondrial Endosymbiont During Eukaryogenesis. AB - Eukaryotic cells are characterized by a considerable increase in subcellular compartmentalization when compared to prokaryotes. Most evidence suggests that the earliest eukaryotes consisted of mitochondria derived from an alpha proteobacterial ancestor enclosed within an archaeal host cell. However, what benefits the archaeal host and the proto-mitochondrial endosymbiont might have obtained at the beginning of this endosymbiotic relationship remains unclear. In this work, I argue that heat generated by the proto-mitochondrion initially permitted an archaeon living at high temperatures to colonize a cooler environment, thereby removing apparent limitations on cellular complexity. Furthermore, heat generation by the endosymbiont would have provided phenotypic flexibility not available through fixed alleles selected for fitness at specific temperatures. Finally, a role for heat production by the proto-mitochondrion bridges a conceptual gap between initial endosymbiont entry to the archaeal host and a later role for mitochondrial ATP production in permitting increased cellular complexity. PMID- 28916843 TI - The implicit learning of metrical and non-metrical rhythms in blind and sighted adults. AB - Forming temporal expectancies plays a crucial role in our survival as it allows us to identify the occurrence of temporal deviants that might signal potential dangers. The dynamic attending theory suggests that temporal expectancies are formed more readily for rhythms that imply a beat (i.e., metrical rhythms) compared to those that do not (i.e., nonmetrical rhythms). Moreover, metrical frameworks can be used to detect temporal deviants. Although several studies have demonstrated that congenital or early blindness correlates with modality-specific neural changes that reflect compensatory mechanisms, few have examined whether blind individuals show a learning advantage for auditory rhythms and whether learning can occur unintentionally and without awareness, that is, implicitly. We compared blind to sighted controls in their ability to implicitly learn metrical and nonmetrical auditory rhythms. We reasoned that the loss of sight in blindness might lead to improved sensitivity to rhythms and predicted that the blind learn rhythms more readily than the sighted. We further hypothesized that metrical rhythms are learned more readily than nonmetrical rhythms. Results partially confirmed our predictions; the blind group learned nonmetrical rhythms more readily than the sighted group but the blind group learned metrical rhythms less readily than the sighted group. Only the sighted group learned metrical rhythms more readily than nonmetrical rhythms. The blind group demonstrated awareness of the nonmetrical rhythms while learning was implicit for all other conditions. Findings suggest that improved deviant-sensitivity might have provided the blind group a learning advantage for nonmetrical rhythms. Future research could explore the plastic changes that affect deviance-detection and stimulus-specific adaptation in blindness. PMID- 28916846 TI - Assessment of the blood supply using the indocyanine green fluorescence method and postoperative endoscopic evaluation of anastomosis of the gastric tube during esophagectomy. AB - BACKGROUND: Postoperative anastomotic leakage is a severe complication after gastric tube reconstruction during esophagectomy. The aim of this study was to evaluate the usefulness of postoperative endoscopic assessment of anastomosis and its correlation with intraoperative indocyanine green (ICG) fluorescence assessment of the gastric tube. METHODS: We retrospectively reviewed 72 consecutive patients who underwent gastric tube reconstruction using the ICG fluorescence method during esophagectomy. Forty-six patients underwent the ICG line-marking method (LMM group; ICG before gastric tube creation). The other 26 underwent the conventional procedure and comprised the control group (ICG after gastric tube creation). Postoperative endoscopic assessment (PEA) of anastomosis was performed 7 days after surgery and results were classified as follows: grade 1 (normal or partial white coat), grade 2 (ulcer comprising less than half the circumference), and grade 3 (ulcer comprising more than half the circumference). RESULTS: Anastomotic leakage occurred in 7 of 72 patients (9.7%). The incidence of anastomotic leakage in the LMM group was tended to be lower than those in the control group (6.5% vs. 15.4%; P = 0.244). Of the 40 patients who underwent PEA, 3 (7.5%) had leakage. PEA grading was significantly associated with anastomotic leakage (P < 0.001). Better intraoperative ICG assessment was significantly associated with better endoscopic assessment grade (P = 0.041). CONCLUSION: Intraoperative ICG assessment of the gastric tube was associated with PEA grading on anastomosis during esophagectomy. PMID- 28916844 TI - Left-sided breast cancer and risks of secondary lung cancer and ischemic heart disease : Effects of modern radiotherapy techniques. AB - PURPOSE: Modern breast cancer radiotherapy techniques, such as respiratory-gated radiotherapy in deep-inspiration breath-hold (DIBH) or volumetric-modulated arc radiotherapy (VMAT) have been shown to reduce the high dose exposure of the heart in left-sided breast cancer. The aim of the present study was to comparatively estimate the excess relative and absolute risks of radiation-induced secondary lung cancer and ischemic heart disease for different modern radiotherapy techniques. METHODS: Four different treatment plans were generated for ten computed tomography data sets of patients with left-sided breast cancer, using either three-dimensional conformal radiotherapy (3D-CRT) or VMAT, in free breathing (FB) or DIBH. Dose-volume histograms were used for organ equivalent dose (OED) calculations using linear, linear-exponential, and plateau models for the lung. A linear model was applied to estimate the long-term risk of ischemic heart disease as motivated by epidemiologic data. Excess relative risk (ERR) and 10-year excess absolute risk (EAR) for radiation-induced secondary lung cancer and ischemic heart disease were estimated for different representative baseline risks. RESULTS: The DIBH maneuver resulted in a significant reduction of the ERR and estimated 10-year excess absolute risk for major coronary events compared to FB in 3D-CRT plans (p = 0.04). In VMAT plans, the mean predicted risk reduction through DIBH was less pronounced and not statistically significant (p = 0.44). The risk of radiation-induced secondary lung cancer was mainly influenced by the radiotherapy technique, with no beneficial effect through DIBH. VMAT plans correlated with an increase in 10-year EAR for radiation-induced lung cancer as compared to 3D-CRT plans (DIBH p = 0.007; FB p = 0.005, respectively). However, the EARs were affected more strongly by nonradiation-associated risk factors, such as smoking, as compared to the choice of treatment technique. CONCLUSION: The results indicate that 3D-CRT plans in DIBH pose the lowest risk for both major coronary events and secondary lung cancer. PMID- 28916845 TI - Pharmacological investigations on mast cell stabilizer and histamine receptor antagonists in vincristine-induced neuropathic pain. AB - The present study was designed to investigate the role of mast cells and mast cell-derived histamine in vincristine-induced neuropathic pain. Neuropathic pain was induced by administration of vincristine (100 MUg/kg, i.p.) over a period of 10 days, with a break of 2 days, and pain behavioural estimations including pin prick, hot plate and acetone spray tests were performed to assess mechanical and heat hyperalgesia and cold allodynia, respectively, on days 0, 14 and 28. Mast cell stabilizer, sodium cromoglycate, H1 receptor antagonist promethazine and H2 receptor antagonist ranitidine were administered over a period of 12 days. Administration of vincristine resulted in significant development of heat and mechanical hyperalgesia as well as cold allodynia. Furthermore, the pain observed was markedly elevated on the 28th day in comparison to the 14th day. Administration of sodium cromoglycate, promethazine and ranitidine significantly reduced mechanical and heat hyperalgesia and cold allodynia. However, the pain attenuating effects of ranitidine were significantly less as compared to sodium cromoglycate and promethazine, which suggests that H1 receptors play a more important role than H2 receptors in vincristine-induced neuropathic pain. It may be concluded that vincristine may degranulate mast cells to release inflammatory mediators, particularly histamine which may act through H1 (primarily H1) and H2 receptors to induce neuropathic pain. PMID- 28916847 TI - Endoscopic resection of gastric gastrointestinal stromal tumors originating from the muscularis propria layer in North America: methods and feasibility data. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. In recent years, endoscopic procedures such as endoscopic enucleation (EN) and endoscopic full-thickness resection (EFTR) have been used to resect GISTs. This study aimed to investigate the clinical efficacy, safety, and feasibility of endoscopic resection of GISTs in a North American population. METHODS: A total of 25 patients with gastric submucosal lesions (SML) underwent endoscopic resection from December 2014 to April 2016. Data from cases with histologically proven GISTs originating from the muscularis propria layer (MP-GIST) were collected. The main outcome measures were complete resection rate, operative time, postoperative complications, length of hospital stay, narcotic analgesic requirement, and follow-up outcomes. Surveillance was performed with CT abdomen, and/or EGD along with oncology follow up at 6- to 24-month intervals. RESULTS: Out of 25 gastric SML, there were 12 histologically proven MP-GIST. Five endophytic MP-GIST were removed by EN, and seven exophytic MP-GIST were removed by EFTR. All lesions were removed en bloc except for one hard to localize exophytic lesion which was completely removed piecemeal. The mean removal time was 79.7 min (range 17-180 min). Nine out of twelve patients required inpatient admission for observation with a mean length of stay of 2.08 days (range 1-4 days). No complications were noted and no narcotic analgesics were required. Pathology reports showed that one GIST was intermediate risk but all others were low-risk lesions. No recurrence has been noted thus far. CONCLUSION: Endoscopic removal of MP-GIST by a trained endoscopist appears to be safe and feasible in North American population. Further studies with greater sample size are necessary to compare endoscopic versus surgical resection of MP-GIST. Comparison of outcomes may support wider use of endoscopic techniques for GIST removal. PMID- 28916848 TI - Interleukin-17 as a predictor of sepsis in polytrauma patients: a prospective cohort study. AB - Sepsis is one of the most serious complications after major trauma, and may be associated with increased mortality. We sought to determine whether there is an association between serum levels of interleukin-17 (IL-17) at the time of admission to the intensive care unit (ICU) and the development of sepsis. We evaluated 100 adult patients with major trauma admitted to the surgical ICU over a 6-month period. Serum levels of IL-17, IL-6, and TNF-alpha were determined by enzyme-linked immunosorbent assays (ELISA). The IL-17 rs1974226 genotype was determined by real-time PCR. In both non-adjusted and adjusted analyses, IL-17 was the only biomarker significantly associated with sepsis [median serum IL-17 of 72 pg/mL in sepsis versus 37 pg/mL in those without sepsis, P = 0.0001; adjusted odds ratio (OR) 3.2, P = 0.02]. No significant association was found among IL-17 rs1974226 genotypes and related serum cytokine levels. These data suggest that elevated serum IL-17 may increase the susceptibility for septic complications in polytrauma patients and so could be a useful biomarker for trauma patient management. PMID- 28916849 TI - 1000 Consecutive Cases of Laser-Assisted Liposuction Utilizing the 1440 nm Wavelength Nd:YAG Laser: Assessing the Safety and Efficacy. AB - BACKGROUND: Liposuction remains one of the most popular aesthetic surgery procedures performed today, and it has undergone continuous refinements over the past four decades. Advancements in anesthesia, improvements in instrumentation, better understanding of fluid dynamics and the addition of energy to liposuction have led to better outcomes with improved safety and efficacy. OBJECTIVES: The purpose of this study is to review 1000 consecutive laser-assisted liposuction (LAL) cases utilizing the 1440 nm wavelength. Emphasis was placed on complication rates and the need for revision procedures. METHODS: The charts of 611 patients who underwent 1000 consecutive LAL operations were reviewed. All cases were performed either under general anesthesia or under local with sedation, and the cases were performed alone or in conjunction with other procedures. All patients went to presurgical testing and had preoperative laboratory and additional clearance by a specialist when indicated. Before and after medical photographs were obtained of all patients. All operations were done in an accredited office based operating room. Demographic information, tumescent volume, aspirate volume, surgical time, complications and other data were reviewed. RESULTS: There were one minor complication and no major complications such as burns, hospitalizations or mortalities. One patient developed a small hematoma, which was likely caused by the patient self-aspirating edema fluid during the immediate post-op period. The hematoma resolved with non-surgical management. The average laser energy applied was 15,756 J with an average total aspirate volume of 1256 cc. Fourteen anatomic areas were treated with LAL, and 59 operations were combination cases. CONCLUSION: Energy-assisted liposuction using the 1440 nm wavelength has been shown in this series to have a very low complication rate when performed alone or in combination with other aesthetic operations under local and general anesthesia. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28916850 TI - Expression of membrane-bound dehydrogenases from a mother of vinegar metagenome in Gluconobacter oxydans. AB - Acetic acid bacteria are well-known for their membrane-bound dehydrogenases rapidly oxidizing a variety of substrates in the periplasm. Since many acetic acid bacteria have not been successfully cultured in the laboratory yet, studying membrane-bound dehydrogenases directly from a metagenome of vinegar microbiota seems to be a promising way to identify novel variants of these enzymes. To this end, DNA from a mother of vinegar was isolated, sequenced, and screened for membrane-bound dehydrogenases using an in silico approach. Six metagenomic dehydrogenases were successfully expressed using an expression vector with native promoters in the acetic acid bacterium strain Gluconobacter oxydans BP.9, which is devoid of its major native membrane-bound dehydrogenases. Determining the substrates converted by these enzymes, using a whole-cell DCPIP assay, revealed one glucose dehydrogenase with an enlarged substrate spectrum additionally oxidizing aldoheptoses, D-ribose and aldotetroses, one polyol dehydrogenase with an extreme diminished spectrum but distinguishing cis and trans-1,2 cyclohexandiol and a completely new secondary alcohol dehydrogenase, which oxidizes secondary alcohols with a hydroxyl group at position 2, as long as no primary hydroxyl group is present. Three further dehydrogenases were found with substrate spectra similar to known dehydrogenases of G. oxydans 621H. PMID- 28916851 TI - Commentary: Application of Human Acellular Breast Dermal Matrix (ABDM) in Implant Based Breast Reconstruction: An Experimental Study. PMID- 28916853 TI - Ironic capture: top-down expectations exacerbate distraction in visual search. AB - Ironic processing refers to the phenomenon where attempting to resist doing something results in a person doing that very thing. Here, we report three experiments investigating the role of ironic processing in visual search. In Experiment 1, we informed observers that they could predict the location of a salient color singleton in a visual search task and found that response times were slower in that condition than in a condition where the singleton's location was random. Experiment 2 used the same experimental design but did not inform participants of the color singleton's behavior. Experiment 3 showed that the cost in the predictable condition was not due to dual task costs or block order effects and participants attempting to use the strategy showed a larger cost in the predictable condition than those who abandoned using that location foreknowledge. In this case, responses in the predictable color singleton condition were equivalent with the random color singleton condition. This suggests that having more knowledge about an upcoming, salient distractor ironically increases its interfering influence on performance. PMID- 28916854 TI - [No improved survival with adjuvant chemotherapy in node negative rectal cancer after radiochemotherapy]. PMID- 28916852 TI - Pediatric head trauma: an extensive review on imaging requisites and unique imaging findings. AB - The effects of trauma in children are different due to association with some anatomical and physiological differences compared with adults. The role of neuroimaging gains importance in early detection of traumatic brain injuries and prevention of secondary post-traumatic complications. Many algorithms are described for children with head trauma to decide the necessity of a computed tomography scan. The aims of this article are to describe differences of these algorithms, the mechanism of traumatic brain injury with radiological imaging findings in the pediatric population, and explain complications of undiagnosed traumatic brain lesions. PMID- 28916855 TI - Green approach for synthesis of zinc oxide nanoparticles from Andrographis paniculata leaf extract and evaluation of their antioxidant, anti-diabetic, and anti-inflammatory activities. AB - Bio-mediated synthesis of zinc oxide nanoparticles (ZnO NPs) was carried out by utilizing the reducing and capping potential of Andrographis paniculata leaf extract. The capped ZnO NPs were characterized using UV-Vis, XRD, FTIR, SEM, TEM and SAED analyses. FTIR analysis suggested the role of phenolic compounds, terpenoids, and proteins of A. paniculata leaf extract, in nucleation and stability of ZnO NPs. XRD pattern compared with the standard confirmed spectrum of zinc oxide particles formed in the present experiments were in the form of nanocrystals, as evidenced by the peaks at 2theta values. SEM and TEM analysis of ZnO NPs reveals those spherical and hexagonal shapes and the sizes at the range of 96-115 and 57 +/- 0.3 nm, respectively. The synthesized nanoparticles possess strong biological activities regarding anti-oxidant, anti-diabetic, and anti inflammatory potentials which could be utilized in various biological applications by the cosmetic, food and biomedical industries. PMID- 28916856 TI - A faster and simpler way of operation for Meckel's diverticulum: basal ligation combined with intraoperative frozen section. AB - BACKGROUND: The key step in Meckel's diverticulectomy (MD) is to achieve complete resection of MD along with the ectopic epithelium. Currently main treatment methods for Meckel's diverticulum are either intestinal resection and anastomosis or wedge resection. Here we introduced a new method to treat MD. The goal of this study was to investigate the clinical effects and advantages of a new operation method for Meckel's diverticulum: basal ligation combined with intraoperative frozen section. METHODS: 262 cases of Meckel's diverticulum were resected with simple basal ligation operation. Intraoperative frozen pathological section was performed to determine surgery strategies. Based on the existence of basal residual ectopic mucosa, surgery was either terminated or further wedge intestinal resection or bowel resection was performed. RESULTS: All 262 surgeries were successfully completed. Additional wedge resection or bowel resection was performed in only 23 of them due to the presence of ectopic basal residual gastric mucosa. No ectopic mucosa was found for the other cases, and the operation ended after basal ligation. All patients had no complications such as intestinal fistula, bleeding for 6 months-7.6 years after surgery. CONCLUSIONS: Intraoperative frozen pathological examination can well determine whether ectopic Meckel's diverticulum mucosa locates at the basal part. Basal ligation is a safe and effective operation method, and it can significantly shorten the operation time and postoperative fasting time. PMID- 28916857 TI - Aesthetic Training for Plastic Surgeons: Are Residents Getting Enough? AB - : Plastic Surgery is one of the most competitive specialties in the field of medicine. However, this specialty has a unique particularity: the difficulties in Aesthetic Surgery training within the residency program. Despite the fact that the full title of the specialty is Plastic, Reconstructive, and Aesthetic Surgery and that Aesthetic Surgery is a part of the examination syllabus, the actual training in the specific area is limited. One of the solutions to this problem is Fellowships. The first author describes his personal experience with Aesthetic training and how it enhanced his knowledge in the area as well as the status of Fellowships in various training programs. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 28916858 TI - An endoscopic mucosal grading system is predictive of leak in stapled rectal anastomoses. AB - BACKGROUND: Anastomotic leak is a devastating postoperative complication following rectal anastomoses associated with significant clinical and oncological implications. As a result, there is a need for novel intraoperative methods that will help predict anastomotic leak. METHODS: From 2011 to 2014, patient undergoing rectal anastomoses by colorectal surgeons at our institution underwent prospective application of intraoperative flexible endoscopy with mucosal grading. Retrospective review of patient medical records was performed. After creation of the colorectal anastomosis, application of a three-tier endoscopic mucosal grading system occurred. Grade 1 was defined as circumferentially normal appearing peri-anastomotic mucosa. Grade 2 was defined as ischemia or congestion involving <30% of either the colon or rectal mucosa. Grade 3 was defined as ischemia or congestion involving >30% of the colon or rectal mucosa or ischemia/congestion involving both sides of the staple line. RESULTS: From 2011 to 2014, a total of 106 patients were reviewed. Grade 1 anastomoses were created in 92 (86.7%) patients and Grade 2 anastomoses were created in 10 (9.4%) patients. All 4 (3.8%) Grade 3 patients underwent immediate intraoperative anastomosis takedown and re-creation, with subsequent re-classification as Grade 1. Demographic and comorbidity data were similar between Grade 1 and Grade 2 patients. Anastomotic leak rate for the entire cohort was 12.2%. Grade 1 patients demonstrated a leak rate of 9.4% (9/96) and Grade 2 patients demonstrated a leak rate of 40% (4/10). Multivariate logistic regression associated Grade 2 classification with an increased risk of anastomotic leak (OR 4.09, 95% CI 1.21 13.63, P = 0.023). CONCLUSION: Endoscopic mucosal grading is a feasible intraoperative technique that has a role following creation of a rectal anastomosis. Identification of a Grade 2 or Grade 3 anastomosis should provoke strong consideration for immediate intraoperative revision. PMID- 28916859 TI - Near-infrared cholecystocholangiography with direct intragallbladder indocyanine green injection: preliminary clinical results. AB - BACKGROUND: Near-infrared (NIR) fluorescence cholangiography by systemic administration of indocyanine green (ICG) enhances the visualization of the biliary tree anatomy. However, the simultaneous enhancement of liver parenchyma can disturb the visualization of critical details. We herein proposed a new technique of NIR cholecystocholangiography by intragallbladder ICG injection to increase the safety during laparoscopic cholecystectomy. METHODS: A total of 46 patients scheduled for laparoscopic cholecystectomy for symptomatic lithiasis (n = 21) or cholecystitis (n = 25) were enrolled. A fluorescence cholangiography by direct gallbladder injection of ICG was performed in all cases. Of them, the ICG was injected through a previously placed percutaneous transhepatic gallbladder drainage catheter (n = 18) or by intraoperative, percutaneous needle puncture of the gallbladder (n = 28). Visualization of biliary structures, including the cystic duct (CD), the common bile and hepatic ducts (CBD and CHD), the gallbladder neck, and the Hartmann's pouch (HP), was performed using White Light (served as control modality) and by NIR enhancement. RESULTS: Cholecystocholangiography provided a significantly higher rate of visualization of the CD in case of cholecystitis with mild adhesions, and an improved visualization of the HP, CBD, and CHD in case of severe inflammation, when compared to White Light observation. There were no benefits of NIR in case of non inflamed lithiasis. CONCLUSIONS: Clinical translation of NIR cholecystocholangiography has been successful with a noise-free visualization of biliary anatomy. It can be considered in difficult cases to increase the safety of laparoscopic cholecystectomy. PMID- 28916861 TI - Predictors of adherence to enhanced recovery pathway elements after laparoscopic colorectal surgery. AB - INTRODUCTION: Enhanced recovery pathways (ERP) include a bundle of evidence-based preoperative, intraoperative, and postoperative interventions that together reduce morbidity and length of stay after colorectal surgery. Increased adherence with the bundle is associated with better postoperative outcomes, but adherence is lowest in the postoperative period. Identifying risk factors for lower adherence may help design quality improvement strategies. The aim of this study was to estimate the extent to which patient, procedural, and organizational factors predict adherence to postoperative ERP elements in laparoscopic colorectal surgery. METHODS: Patients in an institutional ERP registry undergoing elective laparoscopic colorectal surgery between 2012 and 2014 were analyzed. The ERP included 10 postoperative ERP elements classified into 2 groups: those requiring patient participation (PP, 5 elements, including nutritional intake and mobilization) and those provided by the clinical team (CT, 5 elements, including removal of catheters and type of analgesia). The impact of baseline and intraoperative factors on adherence was estimated using stepwise linear regression. RESULTS: A total of 223 patients were included (mean age 60, 48% male). Mean adherence was 79% to the PP bundle (range 65-93% for individual elements), and 82% for the CT bundle (range 68-98% for individual elements). The occurrence of nausea/vomiting in the first 24 h was associated with lower adherence to both bundles. In the PP bundle, patients who arrived at the ward after 6 p.m. had lower adherence. In the CT bundle, patients who had rectal resection had lower adherence while thoracic epidural was associated with higher adherence. CONCLUSIONS: With the exception of postoperative nausea and vomiting, predictors of adherence to ERP elements after colorectal surgery differed for elements requiring patient participation and those provided by the clinical team. Strategies to improve ERP adherence should target staff education and engagement of patients at risk for lower adherence. PMID- 28916862 TI - Monitoring the response of urothelial precancerous lesions to Bacillus Calmette Guerin at the proteome level in an in vivo rat model. AB - Intravesical Bacillus Calmette-Guerin (BCG) is the best treatment modality for progression of non-muscle invasive bladder cancer. We aimed to monitor changes at the proteome level to identify putative protein biomarkers associated with the response of urothelial precancerous lesions to intravesical BCG treatment. The rats were divided into three groups (n = 10/group): control, non-treated, and BCG treated groups. The non-treated and BCG-treated groups received N-methyl-N nitrosourea intravesically. BCG Tice-strain was instilled into bladder in BCG treated group. At the endpoint of experiment, all surviving rat bladders were collected and equally divided into two portions vertically from dome to neck. Half of each bladder was assessed immunohistopathologically and the other half was used for 2D-based comparative proteomic analysis. Differentially expressed proteins were validated by Western blot analysis. Precancerous lesions of bladder cancer were more common in non-treated group (77.8%) than in BCG-treated group (50%) and the control group (0%). Greater than twofold changes occurred in the expression of a number of proteins. Among them, Rab-GDIbeta, aldehyde dehydrogenase 2 (ALDH2) and 14-3-3 zeta/delta were important since they were previously reported to be associated with cancer and their expression levels were found to be lower in BCG-treated group in comparison to the non-treated group. ALDH2 and 14-3-3 zeta/delta were also found to be highly expressed in the non treated group compared to the control group. The down-regulation of these proteins and Rab-GDIbeta was achieved with BCG; this result indicates that they may be used as putative biomarkers for monitoring changes in bladder carcinogenesis in response to BCG immunotherapy. PMID- 28916860 TI - The effect of migration on social capital and depression among older adults in China. AB - PURPOSE: An estimated 9 million elderly people accompanied their adult children to urban areas in China, raising concerns about their social capital and mental health following re-location. The aim of this study was to examine the effect of migration on social capital and depression among this population. METHODS: Multistage stratified cluster sampling was applied to recruit the migrant and urban elderly in Hangzhou from May to August, 2013. Data were collected from face to-face interviews by trained college students using a standardized questionnaire. Social capital measurements included cognitive (generalized trust and reciprocity) and structure (support from individual and social contact) aspects. Depression was measured by Geriatric Depression Scale-30 (GDS-30). Chi square tests and binary logistic regression models were used for analysis. RESULTS: A total of 1248 migrant elderly and 1322 urban elderly were eligible for analysis. After adjusting for a range of confounder factors, binary logistic regression models revealed that migrant elderly reported significantly lower levels of generalized trust [OR = 1.34, 95% CI (1.10-1.64)], reciprocity [OR = 1.55, 95% CI (1.29-1.87)], support from individual [OR = 1.96, 95% CI (1.61 2.38)] and social contact [OR = 3.27, 95% CI (2.70-3.97)]. In the full adjusted model, migrant elderly were more likely to be mentally unhealthy [OR = 1.85, 95% CI (1.44-2.36)] compared with urban elderly. CONCLUSIONS: Migrant elderly suffered from a lower mental health status and social capital than their urban counterparts in the emigrating city. Attention should focus on improving the social capital and mental health of this growing population. PMID- 28916863 TI - Intracerebral hemorrhage as a manifestation of cerebral hyperperfusion syndrome after carotid revascularization: systematic review and meta-analysis. AB - BACKGROUND: Intracerebral hemorrhage (ICH) in the context of cerebral hyperperfusion syndrome (CHS) is an uncommon but potentially lethal complication after carotid revascularization for carotid occlusive disease. Information about its incidence, risk factors and fatality is scarce. Therefore, we aimed to perform a systematic review and meta-analysis focusing on the incidence, risk factors and outcomes of ICH in the context of CHS after carotid revascularization. METHODS: We searched the PubMed and EBSCO hosts for all studies published in English about CHS in the context of carotid revascularization. Two reviewers independently assessed each study for eligibility based on predefined criteria. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the PROSPERO register was made (register no. CRD42016033190), including the pre specified protocol. RESULTS: Forty-one studies involving 28,956 participants were deemed eligible and included in our analysis. The overall quality of the included studies was fair. The pooled frequency of ICH in the context of CHS was 38% (95% CI: 26% to 51%, I2 = 84%, 24 studies), and the pooled case fatality of ICH after CHS was 51% (95% CI: 32% to 71%, I2 = 77%, 17 studies). When comparing carotid angioplasty with stenting (CAS) with carotid endarterectomy (CEA), post procedural ICH in the context of CHS was less frequent in CEA. ICH following CHS occurred less often in large series and was rare in asymptomatic patients. The most common risk factors were periprocedural hypertension and ipsilateral severe stenosis. CONCLUSIONS: ICH as a manifestation of CHS is rare, more frequent after CAS and associated with poor prognosis. Periprocedural control of hypertension can reduce its occurrence. PMID- 28916865 TI - Erratum to: Masculinity and suicidal thinking. AB - In the original publication there was an error in the calculation of scores for a number of the CMNI subscales and consequently the overall scale score. Recalculating the scores did not alter the substantive finding, and largely resulted in only small adjustments to estimates. Tables 1 and 2 are revised to show the corrected values, and revisions to the text reflecting these changes are noted. PMID- 28916864 TI - SParticle, an algorithm for the analysis of filamentous microorganisms in submerged cultures. AB - Streptomycetes are filamentous bacteria that produce a plethora of bioactive natural products and industrial enzymes. Their mycelial lifestyle typically results in high heterogeneity in bioreactors, with morphologies ranging from fragments and open mycelial mats to dense pellets. There is a strong correlation between morphology and production in submerged cultures, with small and open mycelia favouring enzyme production, while most antibiotics are produced mainly in pellets. Here we describe SParticle, a Streptomyces Particle analysis method that combines whole slide imaging with automated image analysis to characterize the morphology of submerged grown Streptomyces cultures. SParticle allows the analysis of over a thousand particles per hour, offering a high throughput method for the imaging and statistical analysis of mycelial morphologies. The software is available as a plugin for the open source software ImageJ and allows users to create custom filters for other microbes. Therefore, SParticle is a widely applicable tool for the analysis of filamentous microorganisms in submerged cultures. PMID- 28916866 TI - Laparoscopic versus open parenchymal preserving liver resections in the posterosuperior segments: a case-matched study. AB - BACKGROUND: Patients with lesions in the posterosuperior (PS) segments of the liver have been considered poor candidates for laparoscopic liver resection (LLR). This study aims to compare short-term outcomes of LLR and open liver resections (OLR) in the PS segments. METHODS: This multicenter study consisted of all patients who underwent LLR in the PS segments and all patients who underwent OLR in the PS segments between October 2011 and July 2016. Laparoscopic cases were case-matched with those who had an identical open procedure during the same period based on tumor location (same segment) and the Brisbane classification of the resection. Demographics, comorbid factors, perioperative outcomes, short-term outcomes, necessity of adjuvant chemotherapy, and the interval between surgery and initiation of adjuvant chemotherapy were compared between the two groups. Data were retrieved from a prospectively maintained electronic database. RESULTS: Both groups were comparable for age, sex, ASA score, maximum tumor diameter, and number of patients with additional liver resections outside the posterior segments. Operative time was similar in both groups (median 140 min; p = 0.92). Blood loss was less in the LLR-group (median: 150 vs. 300 ml in OLR-group). Median hospital stay was 6 days in both groups. There was no significant difference in postoperative complications (OLR-group: 31.4% vs. LLR-group: 25.7%; p = 0.60). There was no significant difference in R0 resections (LLR: 97.2 vs. 100% in OLR; p = 1.00). Tumor-free margins were less in the LLR group (LLR: 5 vs. 9.5 mm in OLR; p = 0.012). Patients undergoing LLR were treated with chemotherapy sooner compared to those undergoing OLR (41 vs. 56 days, p = 0.02). CONCLUSION: This study suggests that laparoscopic parenchymal preserving liver resections in the PS segments can be performed with comparable short-term outcomes as similar OLR. The shorter interval to chemotherapy might provide long-term oncologic benefits in patients who underwent LLR. PMID- 28916867 TI - Reorganization of Motor Representations in Patients with Brain Lesions: A Navigated Transcranial Magnetic Stimulation Study. AB - This is an explorative study applying presurgical navigated transcranial magnetic stimulation (nTMS) to investigate the spatial distributions of motor sites to reveal tumor-induced brain plasticity in patients with brain tumors. We analyzed nTMS-based motor maps derived from presurgical mapping of 100 patients with motor eloquently located brain tumors (tumors in the frontal lobe, the precentral gyrus [PrG], the postcentral gyrus [PoG], the remaining parietal lobe, or the temporal lobe). Based on these motor maps, we systematically investigated changes in motor evoked potential (MEP) counts among 4 gyri (PrG, PoG, medial frontal gyrus, and superior frontal gyrus) between subgroups of patients according to the tumor location in order to depict the tumor's influence on reorganization. When comparing patients with different tumor locations, high MEP counts were elicited less frequently by stimulating the PrG in patients with tumors directly affecting the PrG (p < 0.05). Still, in more than 50% of these patients, the MEP counts elicited by stimulating the PrG were higher than average, indicating robust motor representations within the primary motor cortex. In contrast, patients with PoG and parietal tumors primarily showed high MEP counts when stimulating the PoG (p < 0.10). The functional reorganization is not likely to induce a shift of motor function from the PrG to adjacent regions but rather leads to a reorganization within anatomical constraints, such as of the PoG. Thus, presurgical nTMS-based motor mapping sensitively depicted the tumor-induced plasticity of the motor cortex. PMID- 28916868 TI - Laparoscopic liver resection using a monopolar soft-coagulation device to provide maximum intraoperative bleeding control for the treatment of hepatocellular carcinoma. AB - BACKGROUND: The popularity of laparoscopic liver resection (LLR) is spreading, worldwide, because the intraoperative blood loss is less than for open hepatectomy and it is associated with a shorter hospitalization period [1-6]. During LLR, intraoperative hemostasis is difficult to achieve, unlike during laparotomy where bleeding can be stopped instantly [7-10]. Our LLR method for the treatment of hepatocellular carcinoma (HCC) includes maximal control of intraoperative bleeding using a monopolar soft-coagulation device. Although we use a monopolar soft-coagulation device to control bleeding during LLR, while coagulating the thin blood vessels, we also developed a maneuver (the hepatocyte crush method: HeCM) to allow liver transection to progress while liver parenchymal cells are being crushed. METHOD: Between January 2008 and March 2016, we performed total LLR on 150 hepatocellular carcinoma patients (144 partial liver resections and six left lateral sectionectomies) using the maneuver shown in the video. RESULTS: The patients had Child-Pugh Scores of grade A (n = 100), B (42), or C (n = 8) and the localizations of tumor were segment (S) 1(n = 7), S2 (19), S3 (23), S4 (28), S5 (17), S6 (26), S8 (17), and S8 (29). The median blood loss was 30 (range 0-490) g during a median surgical time of 207 (range 127-468) min. One patient required conversion to a laparotomy due to the presence of severe adhesions; none of the patients required conversion due to intraoperative hemorrhage. The peak aspartate aminotransferase (AST) level was 320 (range 57 1964) IU/L. Although some patients showed high AST levels, none showed signs of hepatic failure. The median postoperative hospital stay duration was 6 (range 3 21) days. Postoperative complications occurred in seven cases (4.7%), including intraabdominal abscesses (n = 2), wound infections (2), intraabdominal hemorrhage (1), bile duct stricture (1), and umbilical hernia (1). The mortality was zero. CONCLUSION: HeCM, combined with the use of a monopolar soft-coagulation device, is a good technique for reducing bleeding during liver resection in patients with HCC. PMID- 28916870 TI - Efficacy and immunogenicity of recombinant swinepox virus expressing the truncated S protein of a novel isolate of porcine epidemic diarrhea virus. AB - Porcine epidemic diarrhea virus (PEDV) causes significant loss to the swine industry. The emergence of novel PEDV strains in recent years has decreased the effectiveness of PEDV vaccines. We have developed a live recombinant vaccine, a swinepox virus vector that expresses a truncated S protein (rSPV-St) from a recent PEDV strain, SQ2014, and evaluated its immunogenicity and effectiveness in a swine model. Vaccination of swine with rSPV-St elicited a robust antibody response specific for the homologous PEDV SQ2014. Serum IgA titers in rSPV-St vaccinated animals were significantly higher than in those immunized with inactivated vaccines. The effectiveness of antibodies induced by the rSPV-St vaccine in protection against PEDV was tested in a passive-transfer model in which piglets were challenged with the homologous virus SQ2014 and the heterologous strain CV777. When challenged with the homologous virus, sera from rSPV-St vaccination provided complete protection. However, sera from rSPV-St vaccination did not provide any protection against the heterologous virus challenge. Amino acid sequence differences in the S proteins of the two viruses were identified within neutralizing epitopes, which might have contributed to the divergent clinical results. Our data suggest that rSPV-St is potentially an effective vaccine against infection with emerging PEDV strains. PMID- 28916869 TI - Protodioscin ameliorates oxidative stress, inflammation and histology outcome in Complete Freund's adjuvant induced arthritis rats. AB - Protective effect of protodioscin or methyl protodioscin against inflammation had been reported in various inflammation diseases. This study aimed to investigate the effect of protodioscin against Complete Freund's adjuvant (CFA)-induced arthritis rats. Rats randomly divided into model groups were injected with CFA, companied with different dose of protodioscin (50, 100, and 200 mg/kg body weight). The histology, changes in biochemical parameters and inflammatory cytokines expression were detected for anti-inflammation effect evaluation of protodioscin. CFA treatment induced arthritic rats with swelling paw, ankle inflammation, and area of lymphocyte infiltration, upregulated inflammatory cytokines (IL-1beta, TNF-alpha, cyclo-oxygenase 2, and IL-6 as well as prostaglandin E2), articular elastase, myeloperoxidase, lipid peroxidase and nitrite oxide levels, downregulated glutathione, catalase, and superoxide dismutase. In contrast, protodioscin ameliorated all the changes induced by CFA in rats, suggesting the anti-inflammatory effect of protodioscin. We concluded that protodioscin administration into CFA-induced arthritis rats protected against CFA-induced oxidative stress, neutrophil infiltration, and inflammation, suggesting the anti-inflammatory effect and the therapeutic potential of protodioscin for arthritis. PMID- 28916872 TI - Correlation of CT and Histopathology in Resorption of the Distal Long Process of the Incus. PMID- 28916871 TI - Strength and functional symmetry is associated with post-operative rehabilitation in patients following anterior cruciate ligament reconstruction. AB - PURPOSE: To investigate strength and functional symmetry during common tests in patients after anterior cruciate ligament reconstruction (ACLR), and its association with post-operative rehabilitation. METHODS: At a median 11.0 months post-surgery (range 10-14), 111 ACLR patients were assessed. A rehabilitation grading tool was employed to evaluate the duration and supervision of rehabilitation, as well as whether structured jumping, landing and agility exercises were undertaken. Patients completed the Noyes Activity Score (NSARS), maximal isokinetic knee extensor and flexor strength assessment, and a 4-hop test battery. Limb Symmetry Indices (LSIs) were calculated, presented for the entire group and also stratified by activity level. ANOVA evaluated differences between the operated and unaffected limbs across all tests. Correlations were undertaken to assess the relationship between post-operative rehabilitation and objective test LSIs. RESULTS: The unaffected limb was significantly better (p < 0.0001) than the operated limb for all tests. Only 52-61 patients (47-55%) demonstrated LSIs >= 90% for each of the hop tests. Only 34 (30.6%) and 61 (55.0%) patients were >= 90% LSI for peak quadriceps and hamstring strength, respectively. Specifically in patients actively participating in jumping, pivoting, cutting, twisting and/or turning sports, 21 patients (36.8%) still demonstrated an LSI < 90% for the single hop for distance, with 37 patients (65.0%) at < 90% for peak knee extension strength. Rehabilitation was significantly associated with the LSIs for all tests. CONCLUSION: Rehabilitation was significantly correlated with limb symmetry, and lower limb symmetry was below recommended criterion for many community-level ACLR patients, including those already engaging in riskier activities. It is clear that many patients are not undertaking the rehabilitation required to address post-operative strength and functional deficits, and are being cleared to return to sport (or are returning on their own accord) without appropriate evaluation and further guidance. LEVEL OF EVIDENCE: IV. PMID- 28916873 TI - Effects of methotrexate on the quality of oocyte maturation in vitro. AB - Methotrexate (MTX), an antifolate drug, is widely used for clinical treatment of malignancies and ectopic pregnancy. Many studies have documented that MTX has strong side-effects on rapidly dividing somatic cells. However, its side-effects on female reproductive cells have not been widely reported. Combined with in vitro culture, two-photon fluorescence imaging and three-dimensional reconstruction, this study analyzed the effects of MTX on oocyte maturation time, chromosome arrangement, karyotype, spindle morphology, and the localization of microtubule organizing centers (MTOCs). Compared with a control group (84%), the rate of germinal vesical breakdown in the MTX group dropped to 73% (P < 0.05). The rate of the first polar body extrusion in the MTX group (53%) was also below the control group (63%; P < 0.05). The rate of abnormal chromosomal arrangement in the MTX group was 60%, but 24% in the control group (P < 0.05). The matured oocyte karyotypes showed 20 univalents in both control and MTX groups, while point-shaped DAPI signals were detected in the MTX group. The rate of abnormal spindle in the MTX group was 49%, but 17% in the control group (P < 0.05). MTOCs in oocytes with normal spindles concentrated at the poles, while MTOCs in oocytes with abnormal spindles were scattered around the poles or in the ooplasm. MTX changes the structures of chromosomes and spindles, potentially by interfering with DNA methylation. The above results indicate a basis for understanding negative effects of MTX on oocyte maturation quality, and provide information for the clinical application of MTX in female patients. PMID- 28916874 TI - Development of CACTA transposon derived SCAR markers and their use in population structure analysis in Zea mays. AB - Molecular marker technologies have proven to be an important breakthrough for genetic studies, construction of linkage maps and population genetics analysis. Transposable elements (TEs) constitute major fractions of repetitive sequences in plants and offer a wide range of possible areas to be explored as molecular markers. Sequence characterized amplified region (SCAR) marker development provides us with a simple and time saving alternative approach for marker development. We employed the CACTA-TD to develop SCARs and then integrated them into linkage map and used them for population structure and genetic diversity analysis of corn inbred population. A total of 108 dominant SCAR markers were designed out of which, 32 were successfully integrated in to the linkage map of maize RIL population and the remaining were added to a physical map for references to check the distribution throughout all chromosomes. Moreover, 76 polymorphic SCARs were used for diversity analysis of corn accessions being used in Korean corn breeding program. The overall average polymorphic information content (PIC) was 0.34, expected heterozygosity was 0.324 and Shannon's information index was 0.491 with a percentage of polymorphism of 98.67%. Further analysis by associating with desirable traits may also provide some accurate trait specific tagged SCAR markers. TE linked SCARs can provide an added level of polymorphism as well as improved discriminating ability and therefore can be useful in further breeding programs to develop high yielding germplasm. PMID- 28916875 TI - Traumatic injuries to the pregnant patient: a critical literature review. AB - INTRODUCTION: Trauma during pregnancy is the leading non-obstetrical cause of maternal death and a significant public health burden. This study reviews the most common causes of trauma during pregnancy, morbidity, and mortality, and the impact upon perinatal outcomes associated with trauma, providing a management approach to pregnant trauma patients. MATERIALS AND METHODS: A systematic review of the current literature from January 2006 to July 2016 was performed. RESULTS: Fifty-one articles were identified, including a total of 95,949 patients. Motor vehicle crash was the most frequent cause of blunt trauma, followed by falls, assault both domestic and interpersonal violence, and penetrating injuries (gunshot and stab wounds). CONCLUSIONS: Trauma in pregnant women is associated with high rates of adverse maternal and neonatal outcomes. Knowledge of the mechanism of injury is important to identify the potential injuries and the complexity of the management of these patients. As in all traumatic events, prevention is of paramount importance. PMID- 28916876 TI - Expert's comment concerning Grand Rounds case entitled "Delayed post-operative tension pneumocephalus and pneumorrhachis" by D. C. Kieser et al. (Eur Spine J, 2017; DOI 10.1007/s00586-017-5268-3). PMID- 28916877 TI - Bile duct injury and morbidity following cholecystectomy: a need for improvement. AB - BACKGROUND: Bile duct injury (BDI) remains the most dreaded complication following cholecystectomy with serious repercussions for the surgeon, patient and entire healthcare system. In the absence of registries, the true incidence of BDI in the United States remains unknown. We aim to identify the incidence of BDI requiring operative intervention and overall complications after cholecystectomy. METHODS: Utilizing the Truven Marketscan(r) research database, 554,806 patients who underwent cholecystectomy in calendar years 2011-2014 were identified using ICD-9 procedure and diagnosis codes. The final study population consisted of 319,184 patients with at least 1 year of continuous enrollment and who met inclusion criteria. Patients were tracked for BDI and other complications. Hospital cost information was obtained from 2015 Premier data. RESULTS: Of the 319,184 patients who were included in the study, there were a total of 741 (0.23%) BDI identified requiring operative intervention. The majority of injuries were identified at the time of the index procedure (n = 533, 72.9%), with 102 (13.8%) identified within 30-days of surgery and the remainder (n = 106, 14.3%) between 31 and 365 days. The operative cumulative complication rate within 30 days of surgery was 9.84%. The most common complications occurring at the index procedure were intestinal disorders (1.2%), infectious (1%), and shock (0.8%). The most common complications identified within 30-days of surgery included infection (1.5%), intestinal disorders (0.7%) and systemic inflammatory response syndrome (SIRS) (0.7%) for cumulative rates of infection, intestinal disorders, shock, and SIRS of 2.0, 1.9, 1.0, and 0.8%, respectively. CONCLUSION: BDI rate requiring operative intervention have plateaued and remains at 0.23% despite increased experience with laparoscopy. Moreover, cholecystectomy is associated with a 9.84% 30-day morbidity rate. A clear opportunity is identified to improve the quality and safety of this operation. Continued attention to educational programs and techniques aimed at reducing patient harm and improving surgeon skill are imperative. PMID- 28916878 TI - [Risk-based thromboembolism prophylaxis in thyroid surgeries]. PMID- 28916880 TI - Genetic diversity and population structure of South African smallholder farmer sheep breeds determined using the OvineSNP50 beadchip. AB - A population structure study was performed in South African ovine populations using the OvineSNP50 beadchip. Blood samples were obtained from 295 sheep of which 172 had been identified as smallholder Dorpers, 4 smallholder White Dorpers, 46 purebred Dorpers, 26 purebred South African Mutton Merinos and 47 purebred Namaqua Afrikaners. Blood from the latter three breeds were obtained from a resource flock maintained on the Nortier research farm. Genetic diversity was estimated using allelic richness (A r), observed heterozygosity (H o), expected heterozygosity (H e) and inbreeding coefficient (F). Population structure analysis was performed using fastSTRUCTURE to determine the breed composition of each genotyped individual. The Namaqua Afrikaner had the lowest H e of 0.280 +/- 0.18 while the H e of smallholder Dorper, Dorper and South African Mutton Merino did not differ and were 0.364 +/- 0.13, 0.332 +/- 0.16 and 0.329 +/ 0.17, respectively. The average inbreeding coefficient was highest for the pure breeds, Namaqua Afrikaner, Dorper and South African Mutton Merino compared to the average inbreeding coefficient for the smallholder Dorper population. The smallholder Dorper were introgressed with Namaqua Afrikaner, South African Mutton Merino and White Dorpers. Similarly, the smallholder Dorper population was more genetically diverse than the purebred Dorper, South African Mutton Merino and Namaqua Afrikaner from the research farm. The higher genetic diversity among the smallholder sheep may be advantageous for their fitness and can be used to facilitate selective breeding. PMID- 28916879 TI - A score combining baseline neutrophilia and primary tumor SUVpeak measured from FDG PET is associated with outcome in locally advanced cervical cancer. AB - PURPOSE: We investigated whether a score combining baseline neutrophilia and a PET biomarker could predict outcome in patients with locally advanced cervical cancer (LACC). METHODS: Patients homogeneously treated with definitive chemoradiation plus image-guided adaptive brachytherapy (IGABT) between 2006 and 2013 were analyzed retrospectively. We divided patients into two groups depending on the PET device used: a training set (TS) and a validation set (VS). Primary tumors were semi-automatically delineated on PET images, and 11 radiomics features were calculated (LIFEx software). A PET radiomic index was selected using the time-dependent area under the curve (td-AUC) for 3-year local control (LC). We defined the neutrophil SUV grade (NSG = 0, 1 or 2) score as the number of risk factors among (i) neutrophilia (neutrophil count >7 G/L) and (ii) high risk defined from the PET radiomic index. The NSG prognostic value was evaluated for LC and overall survival (OS). RESULTS: Data from 108 patients were analyzed. Estimated 3-year LC was 72% in the TS (n = 69) and 65% in the VS (n = 39). In the TS, SUVpeak was selected as the most LC-predictive biomarker (td-AUC = 0.75), and was independent from neutrophilia (p = 0.119). Neutrophilia (HR = 2.6), high-risk SUVpeak (SUVpeak > 10, HR = 4.4) and NSG = 2 (HR = 9.2) were associated with low probability of LC in TS. In multivariate analysis, NSG = 2 was independently associated with low probability of LC (HR = 7.5, p < 0.001) and OS (HR = 5.8, p = 0.001) in the TS. Results obtained in the VS (HR = 5.2 for OS and 3.5 for LC, p < 0.02) were promising. CONCLUSION: This innovative scoring approach combining baseline neutrophilia and a PET biomarker provides an independent prognostic factor to consider for further clinical investigations. PMID- 28916881 TI - A 3D Mammometric Comparison of Implant-Based Breast Reconstruction With and Without Acellular Dermal Matrix (ADM). AB - : This retrospective study utilizes 3D imaging and mammometrics to compare implant-based breast reconstruction with and without the use of ADM. Previous studies have suggested improved aesthetic outcomes with the use of ADM, but none have been able to quantify this difference. Images were obtained at early and late time points following the expander-implant exchange procedure. Measurements included the point of maximum projection, the superior, inferior, medial and lateral volumetric distribution, and the distance from the point of maximum projection to the inframammary fold along the breast meridian. The patients' demographic information, implant size, and complication rate between the two cohorts were similar. In the early post-operative period, the patients with ADM demonstrated higher medial pole volume; however, this difference did not persist in the late post-operative period. Patients with ADM demonstrated a small but statistically significant greater point of maximum projection and length of lower pole curvature in comparison with the non-ADM cohort. In summary, the results of this study demonstrate improved mammometric measurements when ADM is used in implant-based breast reconstruction, supporting superior aesthetic outcomes in early and late post-operative time points. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28916882 TI - Evaluating a Mental Health Program for Palestinian Refugees in Lebanon. AB - Medecins sans Frontiere, an international non-governmental organization, initiated a mental health program for Palestinian refugees living in Lebanon. To evaluate the impact of the program after its completion, focus groups were conducted with three target groups: (1) patients, (2) staff, and (3) local community stakeholders. Participants voiced overall satisfaction with the program. The program provided easy access, good quality care, decreased stigma, as perceived by participants, and revealed a sense of community contentedness. In addition, several short-term outcomes were achieved, such as increasing the numbers of patients visiting the center/ receiving mental health treatment. However, lack of planning for sustainability and proper procedures for hand-over of the program constituted a major downfall. Program discontinuation posed ethical dilemmas, common in provisional interventions in underprivileged refugee communities. PMID- 28916883 TI - Different post-processing conditions for 3D bioprinted alpha-tricalcium phosphate scaffolds. AB - The development of 3D printing hardware, software and materials has enabled the production of bone substitute scaffolds for tissue engineering. Calcium phosphates cements, such as those based on alpha-tricalcium phosphate (alpha TCP), have recognized properties of osteoinductivity, osteoconductivity and resorbability and can be used to 3D print scaffolds to support and induce tissue formation and be replaced by natural bone. At present, however, the mechanical properties found for 3D printed bone scaffolds are only satisfactory for non-load bearing applications. This study varied the post-processing conditions of the 3D powder printing process of alpha-TCP cement scaffolds by either immersing the parts into binder, Ringer's solution or phosphoric acid, or by sintering in temperatures ranging from 800 to 1500 degrees C. The porosity, composition (phase changes), morphology, shrinkage and compressive strength were evaluated. The mechanical strength of the post-processed 3D printed scaffolds increased compared to the green parts and was in the range of the trabecular bone. Although the mechanical properties achieved are still low, the high porosity presented by the scaffolds can potentially result in greater bone ingrowth. The phases present in the scaffolds after the post-processing treatments were calcium-deficient hydroxyapatite, brushite, monetite, and unreacted alpha-TCP. Due to their chemical composition, the 3D printed scaffolds are expected to be resorbable, osteoinductive, and osteoconductive. PMID- 28916884 TI - A Clinical Scoring System to Predict the Clinical Sequelae of Computed Tomography Diagnosed Intussusception. AB - INTRODUCTION: Intussusception in adults is increasingly diagnosed on cross sectional imaging with a lack of clear recommendations on management. The presence of an underlying lead point is a key to guiding management as its absence can predict spontaneous resolution. We studied adult patients with computed tomography (CT) diagnosed intussusception formulate a clinical scoring system to predict the risk of an underlying lead point. METHODOLOGY: We performed a retrospective review of all adult patients who underwent CT scans of the abdomen and pelvis in our institution between 2001 and 2014. Independent associations of an underlying lead point were derived following multivariable analysis, from which a clinical scoring system was developed. RESULTS: We studied 140 patients. In multivariable analysis, six factors were found to be independently associated with the presence of an underlying lead point, namely gender, abdominal pain, CT evidence of colonic involvement, CT evidence of a lead point, distal diameter >=27 mm and minimum wall thickness >=3 mm. A nine-point clinical scoring system was developed, with a cutoff score of four or higher yielding a sensitivity and specificity of 0.75 and 0.81, respectively. CONCLUSION: Our clinical scoring system provides a quantitative tool to predict the likelihood of an underlying lead point in CT-diagnosed intussusception in adults to help guide management. PMID- 28916885 TI - Geometric analysis and clinical outcome of two cemented stems for primary total hip replacement with and without modular necks. AB - INTRODUCTION: Restoration of the physiological biomechanical principles of the hip is crucial in total hip replacement. The aim of this study was to compare an arthroplasty system with different offset options (a: Exeter(r)) with a dual modular stem (b: Profemur Xm(r)). MATERIALS AND METHODS: A local and an inertial coordinate system were used to assist the description of the components' assembly in the prosthesis. A resection line of the femoral head in standard position was added to the arthroplasties and geometric parameters were measured. The outcomes of 93 patients were clinically evaluated (a: n = 50, b: n = 43). Preoperative planning was compared to postoperative radiographs (femoral offset, leg-length), and clinical scores (HHS, WOMAC, total range of motion) were assessed preoperatively, and then 1 and 2 years after surgery. RESULTS: The Exeter(r) offers an offset range from 32.1 to 56.9 mm and the Profemur Xm(r) a range from 29.3 to 55.3 mm. The leg-length variability of the Profemur Xm(r) has a range of 25.9 mm, the Exeter(r) a range of 13.7 mm. The Profemur Xm(r) offers more possible combinations of offset and leg-length reconstruction. The neck-stem angles of the Exeter(r) range from 125.2 degrees to 126.3 degrees , of the Profemur Xm(r) from 127.2 degrees to 142.6 degrees . There was no statistically significant difference in clinical outcome and radiological parameters. CONCLUSIONS: We conclude that both stems offer a wide range of options for anatomical reconstruction of the hip resulting in similarly good clinical results. The Profemur Xm(r) stem has advantages for the reconstruction of hips that deviate from standard anatomy but has the drawback of additional corrosive wear at the stem/neck interface. PMID- 28916886 TI - Construction of fibrous bed bioreactor for enhanced succinic acid production using wastewater of dextran fermentation. AB - A new applicability of wastewater of dextran fermentation (WWDF) for biological production of succinic acid with A. succinogenes CCTCC M2012036 was reported in this work for the first time. Notably, K2CO3 was used instead of MgCO3 in the pH regulating process for operational feasibility and a cell immobilization methodology by attaching cells on cotton fibrous matrix was adopted for cell recycle. The initial sugar concentration as well as matrix usage was optimized by investigating the cell growth, succinic acid concentration and yield. A rotated fibrous bed bioreactor was designed and constructed in order to increase the total cell amount and facilitate mass transportation in the fermentation system, and an average succinic acid yield, concentration and productivity of 0.82 g/g, 56.5 g/L and 1.28 g/L/h were realized in the repeated fed-batch fermentation, respectively. This research gave light to the optimization of succinic acid production towards a more cost-effective and operable direction. PMID- 28916887 TI - Appropriate imaging utilization in Japan: a survey of accredited radiology training hospitals. AB - PURPOSE: To survey whether imaging is being performed appropriately in Japan, and to survey whether radiologists intervene to ensure imaging requests are appropriate. METHODS: An online survey was sent to radiologists at accredited radiology training hospitals. The survey included the radiologists' perspectives on whether imaging is performed appropriately at their institutions and whether they intervene if the indication for imaging is inappropriate/ambiguous. RESULTS: The response rate was 87.3% (165/189). We observed marked variability in the frequencies that imaging not recommended by the guidelines was performed among modalities and/or body parts; the responses "very frequently/frequently performed" were more common for breast cancer related imaging examinations and for head CT/MRI. The respondents frequently reported that inappropriate/ambiguous indications included requests to expand the craniocaudal range or to perform whole-body imaging. In 80% of the hospitals (132/165), radiologists contacted the physicians who requested unrecommended examinations; the number of CT and MRI examinations that full-time radiologists need to interpret in a half-day session was significantly smaller at these hospitals (median 18 vs 24, P = 0.032). CONCLUSION: We conducted a survey to investigate appropriate imaging utilization in Japan. At the hospitals with numerous examinations to interpret, full-time radiologists may find it difficult to ensure that examinations are ordered appropriately. PMID- 28916888 TI - HIV Testing Among Foreign-Born Men and Women in the United States: Results from a Nationally Representative Cross-Sectional Survey. AB - HIV disproportionately affects the foreign-born population in the United States. This analysis describes the prevalence of ever-testing for HIV among foreign-born individuals residing in the United States. Data from a national health survey of the civilian, non-institutionalized population was used to describe prevalence of ever-testing for HIV among foreign-born individuals by birth place. Multivariate logistic-regression procedures were used to determine factors associated with ever-testing for HIV among foreign-born men and women. The prevalence of ever testing for HIV among foreign-born individuals varied by region of birth ranging from 31 to 67%. Factors related to ever-testing for HIV varied by gender. Efforts need to continue in order to improve HIV testing rates among Asian foreign-born individuals, lower educated foreign-born and foreign-born gay/bisexual men. Health care providers can play an important role by counseling new arrivals regarding the importance of testing for HIV and practicing HIV risk reduction activities. PMID- 28916889 TI - Teaching peroral endoscopic myotomy (POEM) to surgeons in practice: an "into the fire" pre/post-test curriculum. AB - INTRODUCTION: With the increasing adoption of peroral endoscopic myotomy (POEM) as a first-line therapy for achalasia as well as a growing list of other indications, it is apparent that there is a need for effective training methods for both endoscopists in training and those already in practice. We present a hands-on-focused with pre- and post-testing methodology to teach these skills. METHODS: Six POEM courses were taught by 11 experienced POEM endoscopists at two independent simulation laboratories. The training curriculum included a pre training test, lectures and discussion, mentored hands-on instruction using live porcine and ex-plant models, and a post-training test. The scoring sheet for the pre- and post-tests assessed the POEM performance with a Likert-like scale measuring equipment setup, mucosotomy creation, endoscope navigation, visualization, myotomy, and closure. Participants were stratified by their experience with upper-GI endoscopy (Novices <100 cases vs. Experts >=100 cases), and their data were analyzed and compared. RESULTS: Sixty-five participants with varying degrees of experience in upper-GI endoscopy and laparoscopic achalasia cases completed the training curriculum. Participants improved knowledge scores from 69.7 +/- 17.1 (pre-test) to 87.7 +/- 10.8 (post-test) (p < 0.01). POEM performance increased from 15.1 +/- 5.1 to 25.0 +/- 5.5 (out of 30) (p < 0.01) with the greatest gains in mucosotomy [1.7-4.4 (out of 5), p < 0.01] and equipment (3.4-4.7, p < 0.01). Novices had significantly lower pre-test scores compared with Experts in upper-GI endoscopy (overall pre-score: 11.9 +/- 5.6 vs. 16.3 +/- 4.6, p < 0.01). Both groups improved significantly after the course, and there were no differences in post-test scores (overall post-score: 23.9 +/- 6.6 vs. 25.4 +/- 5.1, p = 0.34) between Novices and Experts. CONCLUSIONS: A multimodal curriculum with procedural practice was an effective curricular design for teaching POEM to practitioners. The curriculum was specifically helpful for training surgeons with less upper-GI endoscopy experience. PMID- 28916890 TI - Coronary calcium score influences referral for invasive coronary angiography after normal myocardial perfusion SPECT. AB - BACKGROUND: In patients with normal SPECT but persistent complaints, invasive angiography may exclude obstructive coronary disease. We assessed whether high coronary artery calcium (CAC) scores are associated with increased referral for invasive angiography following normal SPECT. METHODS AND RESULTS: 2286 consecutive patients (mean age 60 +/- 12, 39% male) with normal SPECT were assessed. All patients underwent simultaneous CAC scoring. Patients were categorized into four groups based on their CAC score: CAC = 0 (n = 694), CAC 1 to 100 (n = 891), CAC 101 to 400 (n = 368), and CAC >400 (n = 333). The decision to perform angiography was left to the discretion of treating physician. Follow up angiography was confined to the first 60 days after SPECT. Occurrence of MACE (late revascularization, myocardial infarction or death) was recorded. Overall, 100 patients (4.4%) underwent early angiography with increasing rates in higher CAC score groups (1.0%, 2.6%, 8.4%, and 11.7%), respectively, P < .001). A CAC score >400 (OR 3.56, 95% CI 2.19 to 5.77, P < .001) was independently associated with referral to angiography. Similarly, CAC score >400 was an independent predictor for MACE (HR 9.26, 95% CI 5.06 to 16.93). Early angiography did not influence prognosis (HR 1.57, 95% CI 0.91 to 2.73). CONCLUSIONS: CAC scoring impacts clinical decision-making and increases referral rates for invasive angiography after normal SPECT. PMID- 28916891 TI - A prospective randomized study of loop-tip versus straight-tip guidewire in wire guided biliary cannulation. AB - BACKGROUND: Wire-guided cannulation has been widely accepted as a useful technique for achieving selective biliary access because it has significantly increased the success rate of biliary cannulation compared with conventional contrast-assisted cannulation. Unlike conventional guidewires with a straight tip, a loop-tip guidewire (LGW) has a closed distal loop that may facilitate less traumatic access through the epithelial folds of the intra-duodenal biliary segments. The aim of this study was to compare the performance of a LGW with a straight-tip guidewire (SGW) in achieving successful selective biliary cannulation. METHODS: From December 2014 to December 2015, we performed 192 wire guided biliary cannulations for a naive papilla in a randomized controlled trial. Patients were randomly assigned to the LGW group (n = 96) or the SGW group (n = 96). Our study protocol did not include crossover to the other guidewire arm if randomized wire-guided cannulation proved unsuccessful within the first 10 min. RESULTS: There was no significant difference in primary successful biliary cannulation between the two groups (LGW group: 86.5%; SGW group: 77.1%; p = 0.134). The rate and the mean number of unintentional pancreatic duct cannulations during wire-guided biliary cannulation were significantly lower in the LGW group than in the SGW group (LGW group: 14.6%; SGW group: 28.1%; p = 0.034; LGW group: 0.2 +/- 0.5; SGW group: 0.6 +/- 1.3; p = 0.007). Post-ERCP pancreatitis developed in 5.2% of patients in the LGW group and 8.3% of patients in the SGW group (p = 0.567). CONCLUSIONS: The biliary cannulation rate of the LGW was not significantly different from those of conventional guidewires. Use of the LGW was associated with a lower rate of unintentional pancreatic duct cannulation during wire-guided biliary cannulation than use of the SGW. PMID- 28916892 TI - Precision in robotic rectal surgery using the da Vinci Xi system and integrated table motion, a technical note. AB - Robotic rectal surgery is becoming increasingly more popular among colorectal surgeons. However, time spent on robotic platform docking, arm clashing and undocking of the platform during the procedure are factors that surgeons often find cumbersome and time consuming. The newest surgical platform, the da Vinci Xi, coupled with integrated table motion can help to overcome these problems. This technical note aims to describe a standardised operative technique of single docking robotic rectal surgery using the da Vinci Xi system and integrated table motion. A stepwise approach of the da Vinci docking process and surgical technique is described accompanied by an intra-operative video that demonstrates this technique. We also present data collected from a prospectively maintained database. 33 consecutive rectal cancer patients (24 male, 9 female) received robotic rectal surgery with the da Vinci Xi during the preparation of this technical note. 29 (88%) patients had anterior resections, and four (12%) had abdominoperineal excisions. There were no conversions, no anastomotic leaks and no mortality. Median operation time was 331 (249-372) min, blood loss 20 (20-45) mls and length of stay 6.5 (4-8) days. 30-day readmission rate and re-operation rates were 3% (n = 1). This standardised technique of single docking robotic rectal surgery with the da Vinci Xi is safe, feasible and reproducible. The technological advances of the new robotic system facilitate the totally robotic single docking approach. PMID- 28916893 TI - Safety and prognostic impact of prophylactic laparoscopic superior mesenteric vein (No. 14v) lymph node dissection for lower-third gastric cancer: a propensity score-matched case-control study. AB - AIM: To investigate oncologic efficacy of prophylactic laparoscopic superior mesenteric vein (No. 14v) lymph node (LN) dissection for lower-third gastric cancer (LTGC). METHODS: We retrospectively collected data from 757 patients who underwent laparoscopic-assisted distal gastrectomy for LTGC. Of these patients, 102 underwent 14v LN dissection (14vD+ group), and the remaining 655 patients did not undergo 14v LN dissection (14vD- group). The outcomes were compared using a 1:1 propensity score matching method. RESULTS: After matching, 93 patients from the 14vD+ group and 93 patients from the 14vD- group with similar clinicopathological characteristics were compared. Before matching, the overall survival (OS) was similar between the two groups (P = 0.742). After matching, the OS was greater in the 14vD+ group (P = 0.025). The status of 14v dissection was not a significant prognostic factor in the survival analyses, both before and after matching. However, a stratified analysis according to the independent factors in the OS showed that the OS in the 14vD+ group was higher than that in the 14vD- group for cT2-3 patients after matching. The forest plot of OS showed that after matching the 14vD+ group had a significantly higher 3-year OS rate than the 14vD- group in cT2-3 patients. The distribution of the therapeutic index demonstrated that the index of 14v LN was similar to those of Nos. 1, 7, 8a, 9, and 11p after matching. CONCLUSIONS: Adding laparoscopic 14v dissection for laparoscopic-assisted radical distal gastrectomy was safe and might improve the OS for clinically advanced LTGC without serosal invasion. PMID- 28916894 TI - Critical appraisal of the impact of individual surgeon experience on the outcomes of laparoscopic liver resection in the modern era: collective experience of multiple surgeons at a single institution with 324 consecutive cases. AB - BACKGROUND: Most studies analyzing the learning experience of laparoscopic liver resection (LLR) focused on the experience of one or two expert pioneering surgeons. This study aims to critically analyze the impact of individual surgeon experience on the outcomes of LLR based on the contemporary collective experiences of multiple surgeons at single institution. METHODS: Retrospective review of 324 consecutive LLR from 2006 to 2016. The cases were performed by 10 surgeons over various time periods. Four surgeons had individual experience with <20 cases, four surgeons with 20-30 cases, and two surgeons with >90 cases. The cohort was divided into two groups: comparing a surgeon's experience between the first 20, 30, 40, and 50 cases with patients treated thereafter. Similarly, we performed subset analyses for anterolateral lesions, posterosuperior lesions, and major hepatectomies. RESULTS: As individual surgeons gained increasing experience, this was significantly associated with older patients being operated, decreased hand-assistance, larger tumor size, increased liver resections, increased major resections, and increased resections of tumors located at the posterosuperior segments. This resulted in significantly longer operation time and increased use of Pringle maneuver but no difference in other outcomes. Analysis of LLR for tumors in the posterosuperior segments demonstrated that there was a significant decrease in conversion rates after a surgeon had experience with 20 LLR. For major hepatectomies, there was a significant decrease in morbidity, mortality, and length of stay after acquiring experience with 20 LLR. CONCLUSION: LLR can be safely adopted today especially for lesions in the anterolateral segments. LLR for lesions in the difficult posterosuperior segments and major hepatectomies especially in cirrhosis should only be attempted by surgeons who have acquired a minimum experience with 20 LLR. PMID- 28916895 TI - The cost of conversion in robotic and laparoscopic colorectal surgery. AB - BACKGROUND: Conversion from minimally invasive to open colorectal surgery remains common and costly. Robotic colorectal surgery is associated with lower rates of conversion than laparoscopy, but institutions and payers remain concerned about equipment and implementation costs. Recognizing that reimbursement reform and bundled payments expand perspectives on cost to include the entire surgical episode, we evaluated the role of minimally invasive conversion in total payments. METHODS: This is an observational study from a linked data registry including clinical data from the Michigan Surgical Quality Collaborative and payment data from the Michigan Value Collaborative between July 2012 and April 2015. We evaluated colorectal resections initiated with open and minimally invasive approaches, and compared reported risk-adjusted and price-standardized 30-day episode payments and their components. RESULTS: We identified 1061 open, 1604 laparoscopic, and 275 robotic colorectal resections. Adjusted episode payments were significantly higher for open operations than for minimally invasive procedures completed without conversion ($19,489 vs. $15,518, p < 0.001). The conversion rate was significantly higher with laparoscopic than robotic operations (15.1 vs. 7.6%, p < 0.001). Adjusted episode payments for minimally invasive operations converted to open were significantly higher than for those completed by minimally invasive approaches ($18,098 vs. $15,518, p < 0.001). Payments for operations completed robotically were greater than those completed laparoscopically ($16,949 vs. $15,250, p < 0.001), but the difference was substantially decreased when conversion to open cases was included ($16,939 vs. $15,699, p = 0.041). CONCLUSION: Episode payments for open colorectal surgery exceed both laparoscopic and robotic minimally invasive options. Conversion to open surgery significantly increases the payments associated with minimally invasive colorectal surgery. Because conversion rates in robotic colorectal operations are half of those in laparoscopy, the excess expenditures attributable to robotics are attenuated by consideration of the cost of conversions. PMID- 28916898 TI - A Strengths-Based Case Management Intervention to Reduce HIV Viral Load Among People Who Use Drugs. AB - Engaging highly marginalized HIV positive people in sustained medical care is vital for optimized health and prevention efforts. Prior studies have found that strengths-based case management helps link people who use drugs to HIV care. We conducted a pilot to assess whether a strengths-based case management intervention may help people who use injection drugs (PWID) or smoke crack cocaine (PWSC) achieve undetectable HIV viral load. PWID and PWSC were recruited in Oakland, California using targeted sampling methods and referral from jails and were tested for HIV. HIV positive participants not receiving HIV care (n = 19) were enrolled in a pilot strengths-based case management intervention and HIV positive participants already in HIV care (n = 29) were followed as comparison participants. The intervention was conducted by a social worker and an HIV physician. Special attention was given to coordinating care as participants cycled through jail and community settings. Surveys and HIV viral load tests were conducted quarterly for up to 11 visits. HIV viral load became undetectable for significantly more participants in the intervention than in the comparison group by their last follow-up (intervention participants: 32% at baseline and 74% at last follow-up; comparison participants: 45% at baseline and 34% at last follow up; p = 0.008). In repeated measures analysis, PBO intervention participants had higher odds of achieving undetectable viral load over time than comparison participants (p = 0.033). Strengths-based case management may help this highly vulnerable group achieve undetectable HIV viral load over time. PMID- 28916896 TI - Involvement of IL-17 in Secondary Brain Injury After a Traumatic Brain Injury in Rats. AB - The pro-inflammatory activity of interleukin 17, which is produced by the IL 23/IL-17 axis, has been associated with the pathogenesis of traumatic brain injury (TBI). The study investigated the potential role of IL-17 in secondary brain injury of TBI in a rat model. Our data showed that the levels of IL-17 increased from 6 h to 7 days and peaked at 3 days, in both the CNS and serum, which were consistent with the severity of secondary brain injury. The IL-23 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment markedly decreased the expressions of IL-17 and apoptosis-associated proteins cleaved caspase-3 and increased the protein ratio of Bcl-2 (B cell lymphoma/leukemia-2)/Bax (Bcl-2 associated X protein). Meanwhile, neuronal apoptosis was reduced, and neural function was improved after SAHA treatment. This study suggests that IL-17 is involved in secondary brain injury after TBI. Administering an IL-23 inhibitor and thereby blocking the IL-23/IL-17 axis may be beneficial in the treatment of TBI. PMID- 28916897 TI - Improvement of quality of life and psychological distress after inpatient cancer rehabilitation : Results of a longitudinal observational study. AB - BACKGROUND: With the growing number of cancer survivors worldwide the need for high quality cancer rehabilitation after primary treatment is steadily increasing. The aim of the present study was to investigate change of psychological distress and health-related quality of life (HRQOL) during multidisciplinary inpatient cancer rehabilitation in a large sample of cancer survivors suffering from different cancer entities. METHODS: We analyzed data from routine HRQOL and distress monitoring at a cancer inpatient rehabilitation center. Cancer survivors completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and the Hospital Anxiety and Depression Scale (HADS) before and after multidisciplinary rehabilitation treatment. Changes of patients' functioning and symptoms were analyzed using repeated measures analysis of variance (ANOVA) and effect sizes (Cohens' d). Patients' pretreatment and posttreatment scores were compared to reference data from the German general population. RESULTS: A total of 939 patients (mean age 58.6 years, SD 11.9 years; 59.9% women) who attended rehabilitation from January 2014 to September 2015 were included in the analysis. We found clinically meaningful improvement in almost all domains of the EORTC QLQ C30 as well as in anxiety and depression (HADS). The largest improvements were found for the QLQ-C30 subscales emotional functioning (d = 0.78), fatigue (d = 0.65), and social functioning (d = 0.56). CONCLUSIONS: We found clinically meaningful improvements of patients' HRQOL, anxiety and depression during an oncological inpatient rehabilitation treatment. Our results warrant further prospective controlled studies to evaluate the long-term effectiveness of inpatient rehabilitation. PMID- 28916899 TI - Impact of surgical complications on the risk of hepatocellular carcinoma recurrence after hepatic resection. AB - Surgery-related morbidity has been identified as prognostic risk factor for tumor recurrence for several tumor types, but data regarding hepatocellular carcinoma (HCC) are limited and controversial. The aim of this study was to analyze the impact of surgical complications on the risk of HCC recurrence after hepatic resection (HR). A Retrospective study was conducted on a cohort of patients submitted to HR in a tertiary teaching hospital, between January 2006 and December 2015. 112 patients were submitted to HR during the study period. Cirrhosis was present in 84% of cases, with portal hypertension in 19.6%. The median MELD score was 8 (range 6-15). The median number of lesions per patient was 1 (range 1-5) with a mean diameter of 5.4 +/- 3.8 cm. Major HR were performed in 18.2% of cases. Overall post-op morbidity was 48.2% with Clavien-Dindo (CD) severity score >=3 in 15.2% of cases. The most frequent complications were infected biloma (19.6%) and liver failure (14%). HCC recurred in 48% of patients. At univariate analysis overall post-op complications (HR 2.313, p = 0.003), CD score >2 (HR 2.075, p = 0.047), post-op liver failure (HR 2.990, p = 0.007), post op iperbilirubinemia (HR 1.151, p = 0.049), post-op bleeding (HR 2.633, p < 0.001) and infected biloma (HR 2.696, p = 0.001) were risk factors for HCC recurrence. At multivariate analysis post-op liver failure (HR 4.081, p < 0.0001) and infected biloma (HR 2.971, p < 0.0001) maintained statistical significance for HCC recurrence. Thus Major surgical complications after HR, especially post op liver failure and infected biloma are risk factors for HCC recurrence. PMID- 28916900 TI - Were all carbapenemases created equal? Treatment of NDM-producing extensively drug-resistant Enterobacteriaceae: a case report and literature review. AB - PURPOSE: There is currently a paucity of published literature focused on the treatment of infections caused by NDM-producing organisms. METHODS: We describe a case of a bacteraemia caused by an extensively drug-resistant (XDR) New Delhi metallo-beta-lactamase (NDM)-producing Serratia marcescens and review the treatment options for XDR NDM-producing Enterobacteriaceae. RESULTS: Infections caused by New Delhi beta-lactamase (NDM)-producing Enterobacteriaceae are becoming increasingly prevalent worldwide. The presence of the enzyme results in multidrug-resistant and extensively drug-resistant phenotypes which often pose a treatment challenge. Despite this challenge, case reports and series have demonstrated good clinical outcomes with numerous treatment options in comparison to infections due to KPC-producing Enterobacteriaceae. CONCLUSIONS: Further good quality research focused on the treatment of NDM-producing Enterobacteriaceae is warranted. PMID- 28916901 TI - Pulmonic Valve Disease: Review of Pathology and Current Treatment Options. AB - PURPOSE OF REVIEW: Our review is intended to provide readers with an overview of disease processes involving the pulmonic valve, highlighting recent outcome studies and guideline-based recommendations; with focus on the two most common interventions for treating pulmonic valve disease, balloon pulmonary valvuloplasty and pulmonic valve replacement. RECENT FINDINGS: The main long-term sequelae of balloon pulmonary valvuloplasty, the gold standard treatment for pulmonic stenosis, remain pulmonic regurgitation and valvular restenosis. The balloon:annulus ratio is a major contributor to both, with high ratios resulting in greater degrees of regurgitation, and small ratios increasing risk for restenosis. Recent studies suggest that a ratio of approximately 1.2 may provide the most optimal results. Pulmonic valve replacement is currently the procedure of choice for patients with severe pulmonic regurgitation and hemodynamic sequelae or symptoms, yet it remains uncertain how it impacts long-term survival. Transcatheter pulmonic valve replacement is a rapidly evolving field and recent outcome studies suggest short and mid-term results at least equivalent to surgery. The Melody valve(r) was FDA approved for failing pulmonary surgical conduits in 2010 and for failing bioprosthetic surgical pulmonic valves in 2017 and has been extensively studied, whereas the Sapien XT valve(r), offering larger diameters, was approved for failing pulmonary conduits in 2016 and has been less extensively studied. Patients with pulmonic valve disease deserve lifelong surveillance for complications. Transcatheter pulmonic valve replacement is a novel and attractive therapeutic option, but is currently only FDA approved for patients with failing pulmonary conduits or dysfunctional surgical bioprosthetic valves. New advances will undoubtedly increase the utilization of this rapidly expanding technology. PMID- 28916902 TI - Time for standardization of SBRT planning through large scale clinical data and guideline-based approaches. PMID- 28916904 TI - Early assessment of response to induction therapy in acute myeloid leukemia using 18F-FLT PET/CT. AB - BACKGROUND: We evaluated the suitability of 18F-fluorodeoxythymidine (18F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent 18F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome. RESULTS: In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation. CONCLUSION: 18F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that 18F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML. PMID- 28916905 TI - Small cholangiolocellular carcinoma that was difficult to distinguish from cholangiocellular carcinoma: a case report. AB - BACKGROUND: Cholangiolocellular carcinoma (CoCC) is thought to be derived from hepatic progenitor cells. Because of its origin, CoCC has diverse clinicopathological and imaging findings. Here, we report a case of small CoCC that was difficult to diagnose preoperatively. CASE PRESENTATION: A 62-year-old woman was confirmed with a small liver nodule in the left lobe 2 years after a sustained virological response of hepatitis C virus. The size of the nodule was 11.9 * 6.1 mm, and 6 months later, the size increased to 12.5 * 7.8 mm. The doubling time of this tumor was 285 days. The tumor revealed peripheral early enhancement and delayed internal staining in dynamic computed tomography images and marked high intensity in diffusion-weighted magnetic resonance imaging scans. These imaging findings resembled those of cholangiocellular carcinoma (CCC). The tumor was removed by laparoscopic lateral sectionectomy. Pathological findings revealed that the tumor was composed of small cuboidal cells and showed irregular anastomosis small grand. Immunohistochemical findings showed that the tumor cells were negative for Hep-par 1 and positive for cytokeratin 19. Epithelial membrane antigen staining was positive for the membranous side of the lumen. According to these pathological findings, the tumor was diagnosed as CoCC. CONCLUSION: Although some characteristic imaging findings are reported for CoCC, they are not specific because of the variety in pathological findings. Especially, small CoCCs might have poor characteristic imaging findings and may be difficult to distinguish from CCC in the images. However, slow tumor growth might be one of the characteristics to suspect the possibility of a CoCC. PMID- 28916903 TI - Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy. AB - Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation. In the metastatic setting, chemotherapy has been the standard treatment. However, two recently published trials with immune checkpoint inhibitors in first and second line showed promising results with a tolerable safety profile and these might become the standard therapy shortly. Somatostatin receptors are expressed in many MCC but such expression is not associated with disease severity. Presently there are no biomarkers predictive of response that could help to better select patients to these new therapies, and additional research is essential. PMID- 28916906 TI - Neoadjuvant versus definitive chemoradiotherapy for locally advanced esophageal cancer : Outcomes and patterns of failure. AB - PURPOSE: Randomized trials examining neoadjuvant chemoradiotherapy followed by surgical resection (nCRT-S) and definitive CRT (dCRT) for esophageal cancer (EC) patients are hampered by use of nonstandard treatment paradigms. Outcomes of nCRT S versus dCRT in a more common patient population are lacking. We investigated local control and survival, evaluated clinical factors associated with endpoints, and assessed patterns of failure between these cohorts. METHODS: We retrospectively analyzed 130 patients with locally advanced EC receiving either dCRT or nCRT-S at our institution from 2000-2012. Inclusion criteria were curatively treated nonmetastatic EC, Karnofsky performance status >=70%, and receipt of concomitant CRT. Patients were excluded if receiving <41 Gy neoadjuvantly or <50 Gy definitively. Kaplan-Meier analysis was used to evaluate local recurrence (LR), progression-free survival (PFS), and overall survival (OS). Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes. Patterns of failure were enumerated as local, regional, or distant. RESULTS: Mean follow-up was 34.2 months. The 3-year LR was 10.8% in the nCRT-S group and 21.5% in the dCRT group (p = 0.266). Median PFS were 15.6 and 14.9 months, respectively (p = 0.549). Median OS were 20.6 and 25.9 months, respectively (p = 0.81). On univariate and multivariate analysis, none of the investigated factors was associated with outcomes, although node-positive disease showed a trend for worse OS and PFS. Most common failures in both groups were distant (dCRT 31.2% vs. nCRT-S 21.6%) followed by local in-field recurrences (dCRT 26.9% vs. nCRT-S 10.8%). CONCLUSIONS: In this institutional analysis, no significant differences regarding outcomes and patterns of failure were observed between nCRT-S and dCRT. PMID- 28916908 TI - Capsular Contracture Rate After Breast Augmentation with Periareolar Versus Other Two (Inframammary and Transaxillary) Incisions: A Meta-Analysis. AB - BACKGROUND: Capsular contracture has been the most common complication of cosmetic breast augmentation. The effect of incision pattern on capsular contracture is still unclear. This meta-analysis demonstrates current evidence with regard to the comparison of capsular contracture rate between periareolar and other two (transaxillary and inframammary) incisions. METHODS: PubMed, EMBASE, and Cochrane databases were searched up to January 2017. The results of selected studies were meta-analyzed to obtain a pooled odds ratio of the effect of periareolar versus other two incision patterns (transaxillary or inframammary incision) of breast augmentation on capsular contracture rates. In addition, subgroup analyses were performed on periareolar versus transaxillary groups and periareolar versus inframammary groups with regard to capsular contracture rate. RESULTS: Seven comparative studies were selected and meta-analyzed. Five of the seven studies reported a higher rate of capsular contracture on patients with periareolar incisions. The results showed a significantly higher rate of capsular contracture with periareolar incisions compared with other two incisions (OR, 1.83; 95% CI, 1.06-3.15, p = 0.03). Subgroup results showed no significant difference of capsular contracture between periareolar incisions and transaxillary incisions (OR, 0.94; 95% CI, 0.52-1.64, p = 0.79) and showed a significantly higher rate of capsular contracture in periareolar incisions compared to inframammary incisions (OR, 1.91; 95% CI, 1.06-3.43, p = 0.03). CONCLUSION: The results of this meta-analysis demonstrate the contributing effects of periareolar breast augmentation on the rate of capsular contracture. However, more studies with longer tracking periods and higher quality should be conducted to further verify this conclusion. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28916907 TI - Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats. AB - BACKGROUND AND OBJECTIVE: Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. RESULTS: All the pharmacokinetic parameters of piracetam including area under curve (AUC0-24), maximum plasma concentration (C max), time to reach the maximum plasma concentration (t max), elimination half-life (t 1/2), volume of distribution (V z), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC0-2) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. CONCLUSIONS: There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for brain penetration. This indicates that variables influencing brain penetration may not be limiting factors for use of piracetam in ischemic stroke. PMID- 28916909 TI - [Idiopathic cranial nerve failure]. AB - Cranial nerve lesions require a thorough diagnostic work-up and known etiologies have to be excluded before the term idiopathic can be considered. The focus of the present review is on idiopathic peripheral facial nerve paralysis (Bell's palsy) for which this terminology has been established. For all other cranial nerve lesions the typical clinical signs, established etiologies and possible diagnostic pitfalls are discussed. PMID- 28916910 TI - Encompassing ATP, DNA, insulin, and protein content for quantification and assessment of human pancreatic islets. AB - Islet transplantation has made major progress to treat patients with type 1 diabetes. Islet mass and quality are critically important to ensure successful transplantation. Currently, islet status is evaluated using insulin secretion, oxygen consumption rate, or adenosine triphosphate (ATP) measurement. These parameters are evaluated independently and do not effectively predict islet status post-transplant. Therefore, assessing human pancreatic islets by encompassing ATP, DNA, insulin, and protein content from a single tissue sample would serve as a better predictor for islet status. In this study, a single step procedure for extracting ATP, DNA, insulin, and protein content from human pancreatic islets was described and the biomolecule contents were quantified. Additionally, different mathematical calculations integrating total ATP, DNA, insulin, and protein content were randomly tested under various conditions to predict islet status. The results demonstrated that the ATP assay was efficient and the biomolecules were effectively quantified. Furthermore, the mathematical formula we developed could be optimized to predict islet status. In conclusion, our results indicate a proof-of-concept that a simple logarithmic formula can predict overall islet status for various conditions when total islet ATP, DNA, insulin, and protein content are simultaneously assessed from a single tissue sample. PMID- 28916917 TI - Update on Chinese American Childhood Obesity Prevalence in New York City. AB - Prevalence of overweight and obesity was measured in 12,275 Chinese American children and adolescents, ages 2-19, who were patients at a large federally qualified health center in 2015. Demographic characteristics sex, age, and birthplace were further stratified to explore disaggregated prevalence. Comparison of this 2015 cohort to an ethnically similar study cohort from the same health center in 2004 showed that the overall prevalence in overweight and obesity dropped to 21% from previously recorded 24%. US Born school-aged males continue to have the highest prevalence of overweight and obesity at 36%. School aged children have higher odds of being overweight or obese (OR 1.61, P < 0.001; OR 1.99, P < 0.001) compared to adolescents. Although the foreign-born females had the lowest prevalence of overweight and obesity (12%), they were the only group in 2015 to have increased prevalence in overweight and obesity since 2004 (by 5.8%). PMID- 28916912 TI - Morphological changes in tibial tunnels after anatomic anterior cruciate ligament reconstruction with hamstring tendon graft. AB - BACKGROUND: Three-dimensional (3D) reconstructed computed tomography (CT) is crucial for the reliable and accurate evaluation of tunnel enlargement after anterior cruciate ligament (ACL) reconstruction. The purposes of this study were to evaluate the tibial tunnel enlargement at the tunnel aperture and inside the tunnel and to clarify the morphological change at the tunnel footprint 1 year after the anatomic triple-bundle (ATB) ACL reconstruction using 3D CT models. METHODS: Eighteen patients with unilateral ACL rupture were evaluated. The ATB ACL reconstruction with a semitendinosus tendon autograft was performed. 3D computer models of the tibia and the three tibial tunnels were reconstructed from CT data obtained 3 weeks and 1 year after surgery. The cross-sectional areas (CSAs) of the two anterior and the one posterior tunnels were measured at the tunnel aperture and 5 and 10 mm distal from the aperture and compared between the two periods. The locations of the center and the anterior, posterior, medial, and lateral edges of each tunnel footprint were also measured and compared between the two periods. RESULTS: The CSA of the posterior tunnel was significantly enlarged at the aperture by 40.4%, whereas that of the anterior tunnels did not change significantly, although the enlargement rate was 6.1%. On the other hand, the CSA was significantly reduced at 10 mm distal from the aperture in the anterior tunnels. The enlargement rate in the posterior tunnel was significantly greater than that in the anterior tunnels at the aperture. The center of the posterior tunnel footprint significantly shifted postero-laterally. The anterior and posterior edges of the posterior tunnel footprint demonstrated a significant posterior shift, while the lateral edge significantly shifted laterally. There was no significant shift of the center or all the edges of the anterior tunnels footprint. CONCLUSIONS: The posterior tibial tunnel was significantly enlarged at the aperture by 40% with the morphological change in the postero-lateral direction reflected by the ACL fiber orientation 1 year after the ATB ACL reconstruction. The proper tibial tunnel location in the ACL reconstruction should be determined considering the tunnel enlargement in postero-lateral direction after surgery. PMID- 28916911 TI - Evaluation of thirty eight cemented pegged glenoid components with variable backside curvature: two-year minimum follow-up. AB - BACKGROUND: The PERFORMTM pegged glenoid system has been used for shoulder arthroplasty since 2012. This system offers multiple backside curvatures per size to better match variable patient anatomy. As a result, less reaming is required and subchondral bone is preserved-a critical factor in preventing glenoid migration and loosening, thus enhancing implant longevity. PURPOSE: The purpose of this study was to analyze all radiographic modifications around this new glenoid implant. METHOD: Thirty-eight shoulders which received the PERFORMTM pegged glenoid component between June 2012 and January 2014 for primary or secondary osteoarthritis were reviewed at two-years minimum follow-up. There were 13 men and 22 women with an average age of 67 years. Humeral components were an uncemented short stem implant in nine (23%) and a resurfacing implant in 29 (77%). RESULTS: At 27-months average follow-up (24-41), Constant score improved from 30 to 65 points. Range of motion improved significantly at follow-up from 100 degrees to 142 degrees for the anterior elevation, and from 15 to 40 degrees for the external rotation. Radiographic lucent lines (RLL) were observed post-operatively in eight cases (21%), and in 16 cases (42%) at the last follow up with an increase of the RLL score from 0.36 +/- 0.8 to 1.3 +/- 2 (p < 0.001) without signs of loosening (RLL > 12). One revision has been performed after anterior shoulder dislocation, rotator cuff tear and glenoid component migration. RLL score was not correlated with dominant side, sex, age, or Constant score. DISCUSSION-CONCLUSION: The cemented pegged glenoid component with multiple backside curvatures gave satisfactory results at two-years minimum follow-up for up to three years with a low RLL score. Long-term studies are mandatory to confirm these results. PMID- 28916924 TI - Detecting nonadherence without loss in efficiency: A simple extension of the crosswise model. AB - In surveys concerning sensitive behavior or attitudes, respondents often do not answer truthfully, because of social desirability bias. To elicit more honest responding, the randomized-response (RR) technique aims at increasing perceived and actual anonymity by prompting respondents to answer with a randomly modified and thus uninformative response. In the crosswise model, as a particularly promising variant of the RR, this is achieved by adding a second, nonsensitive question and by prompting respondents to answer both questions jointly. Despite increased privacy protection and empirically higher prevalence estimates of socially undesirable behaviors, evidence also suggests that some respondents might still not adhere to the instructions, in turn leading to questionable results. Herein we propose an extension of the crosswise model (ECWM) that makes it possible to detect several types of response biases with adequate power in realistic sample sizes. Importantly, the ECWM allows for testing the validity of the model's assumptions without any loss in statistical efficiency. Finally, we provide an empirical example supporting the usefulness of the ECWM. PMID- 28916914 TI - The effects of protein and fiber content on gut structure and function in zebrafish (Danio rerio). AB - Chemical reactor theory (CRT) suggests that the digestive tract functions as a chemical reactor for processing food. Presumably, gut structure and function should match diet to ensure adequate nutrient and energy uptake to maintain performance. Within CRT, dietary biochemical composition is the most important factor affecting gut structure and function in vertebrates. We fed Danio rerio (zebrafish) diets ranging from high- to moderate- to low-quality (i.e., ranging from high-protein, low-fiber to low-protein, high-fiber), and observed how gut length and surface area, as well as the activity levels of digestive enzymes (amylase, maltase, trypsin, aminopeptidase, and lipase) shifted in response to these dietary changes. Fish on the low-quality diet had the longest guts with the largest intestinal epithelial surface area and enterocyte cellular volumes. Fish on the moderate-quality diet had intermediate values of most of these parameters, and fish on the high-quality diet, the lowest. These data largely support CRT. Digestive enzyme activity levels were generally elevated in fish fed the moderate and low-quality diets, but were highest in the fish fed the moderate-quality diet, suggesting that a diet with protein levels closest to that of the natural diet of D. rerio (they are omnivorous in nature) may elicit the best gut performance. However, fish fed the carnivore diet reached the largest terminal body size. Our results support CRT in terms of gut structure; however, our enzyme results do not necessarily agree with CRT and largely depend on which enzyme is discussed. In particular, the evidence for lipase activities being elevated in the fish fed the low-protein, high-fiber diet perhaps reflects a lipid-scavenging mechanism in fish consuming high-fiber foods rather than CRT. PMID- 28916913 TI - Centromeric enrichment of LINE-1 retrotransposons and its significance for the chromosome evolution of Phyllostomid bats. AB - Despite their ubiquitous incidence, little is known about the chromosomal distribution of long interspersed elements (LINEs) in mammalian genomes. Phyllostomid bats, characterized by lineages with distinct trends of chromosomal evolution coupled with remarkable ecological and taxonomic diversity, represent good models to understand how these repetitive sequences contribute to the evolution of genome architecture and its link to lineage diversification. To test the hypothesis that LINE-1 sequences were important modifiers of bat genome architecture, we characterized the distribution of LINE-1-derived sequences on genomes of 13 phyllostomid species within a phylogenetic framework. We found massive accumulation of LINE-1 elements in the centromeres of most species: a rare phenomenon on mammalian genomes. We hypothesize that expansion of these elements has occurred early in the radiation of phyllostomids and recurred episodically. LINE-1 expansions on centromeric heterochromatin probably spurred chromosomal change before the radiation of phyllostomids into the extant 11 subfamilies and contributed to the high degree of karyotypic variation observed among different lineages. Understanding centromere architecture in a variety of taxa promises to explain how lineage-specific changes on centromere structure can contribute to karyotypic diversity while not disrupting functional constraints for proper cell division. PMID- 28916916 TI - Investigating baseline red meat slaughter operator capacity and directions for development in Lao PDR. AB - A study of operator knowledge, attitudes and practices (KAP) in red meat slaughter premise operations in northern Laos was conducted and compared with international best practice, to inform future industry development. The survey interviewed 68 (of 94 possible participants) employees from all ten commercial slaughter premises in six districts in three northern Laos provinces. This was supported by observations of slaughter premises, processes and the conduct of personnel. Descriptive analysis and linear regression modelling identified significant KAP predictor factors, and a gap analysis supported or rejected inferences from the generally low KAP scores for human and animal health, animal welfare, good manufacturing practices (GMP), work conditions and economics. The median proportion of correctly/desirably answered knowledge-related questions was 35.2% (interquartile range [IQR] = 22.2-51.9%) with 27.3% (IQR = 15.9-31.8%) for the attitude-related questions and 21.4% (IQR = 14.3-35.7%) for the practice related questions. Two districts had significantly lower KAP scores than other districts, and staff had the lowest and meat inspectors had the highest scores. This study indicates that the current KAP for red meat processing falls short of international standards and that training programmes on disease risks and prevention are important in facilitating red meat industry development. PMID- 28916919 TI - Laparoscopic liver resection for metastatic melanoma. AB - BACKGROUND: Stage IV metastatic melanoma carries a poor prognosis. In the case of melanoma liver metastasis (MLM), surgical resection may improve survival and represents a therapeutic option, with varying levels of success. Laparoscopic liver resection (LLR) for metastatic melanoma is poorly studied. The aim of this study was to analyze the outcomes of LLR in patients with MLM. MATERIALS AND METHODS: Between April 2000 and August 2013, 11 (1 cutaneous, 9 ocular and 1 unknown primary) patients underwent LLR for MLM at Oslo University Hospital Rikshospitalet and 13 procedures in total were carried out. Perioperative and oncologic outcomes were analyzed. Postoperative morbidity was classified using the Accordion classification. Kaplan-Meier method was used for survival analysis. RESULTS: A total of 23 liver specimens were resected. The median operative time was 137 (65-470) min, while the median blood loss was less than 50 (<50-900) ml. No intraoperative unfavorable incidents and 30-day mortality occurred. Median follow-up was 33 (9-92) months. Ten patients (91%) developed recurrence within a median of 5 months (2-18 months) and two patients underwent repeat LLR for recurrent liver metastases. One-, three-, and five-year overall survival rates were 82, 45 and 9%, respectively. The median overall survival was 30 (9-92) months. CONCLUSION: Perioperative morbidity and long-term survival after LLR for MLM seems to be comparable to open liver resection. Thus, LLR may be preferred over open liver resection due to the well-known advantages of laparoscopy, such as reduced pain and improved possibility for repeated resections. PMID- 28916918 TI - Mixed Blessings? Religion/Spirituality Predicts Better and Worse Screening Behaviours. AB - Some health research suggests that religious and spiritual variables positively predict health-screening behaviours. However, much of the literature on this topic has utilized exclusively religious samples, or has sampled from populations without uniform access to health care. Either of these issues may have artificially inflated the relationship between religion/spirituality and health screening behaviours. The current study used data from the 2012 Canadian Community Health Survey to examine a general sample of women from New Brunswick and Manitoba (N > 1200). Results indicated that lower levels of church attendance were positive predictors of papanicolaou tests and mammograms, while higher levels of attendance were generally associated with poorer screening behaviours. Religiosity was a uniformly non-significant predictor of screening behaviours. Finally, religious affiliation was inconsistently related to screening behaviours, but tended to favour religious non-affiliation when it was. Religion/spirituality does not appear to have a uniformly positive nor linear effect in predicting health-screening behaviours in women. PMID- 28916923 TI - Single-cell analysis reveals the relevance of foot-and-mouth disease virus persistence to emopamil-binding protein gene expression in host cells. AB - Foot-and-mouth disease virus (FMDV) infects host cells in either an acute or persistent manner. In this study, we examined the relevance of the establishment of FMDV persistence to the expression of the emopamil-binding protein (EBP) gene in 231 individual persistently infected baby hamster kidney (BHK-21) cells after passages 28, 38, and 68 (PI28, PI38, and PI68). At PI28, the stage at which persistent infection of FDMV becomes unstable, the percentage of cells carrying FMDV was 66.7%, while 80.2% of cells were EBP positive. Additionally, in 55.6% of the EBP-positive cells at PI28, EBP expression was upregulated approximately 149.9% compared to uninfected BHK-21 cells. This was the highest expression level among all cell passages measured. Interestingly, in a parallel experiment, the average EBP expression level in the whole cell population at PI28 was only slightly higher (108.2%) than that in uninfected BHK-21 cells. At PI38, 98.7% of the cells were positive for FMDV 3D (an RNA-dependent RNA polymerase enzyme gene), and its maximum expression level observed at this passage. The expression level of EBP in 78.2% of the total cells, however, was reduced significantly. At PI68, 95.8% of the cells were 3D positive, and the expression of both the EBP and 3D genes were at the lowest levels of all the passages. Our studies using single cells yielded data that are otherwise inaccessible a using whole cell population. These results suggest that the establishment of persistent infection by FMDV is a dynamic process that results from the continuous adaptation and coevolution of viruses and cells to reach an equilibrium. PMID- 28916930 TI - Tongue Image Analysis and Its Mobile App Development for Health Diagnosis. AB - Computer-aided diagnosis provides a medical procedure that assists physicians in interpretation of medical images. This work focuses on computer-aided tongue image analysis specifically, based on Traditional Chinese Medicine (TCM). Tongue diagnosis is an important component of TCM. Computerized tongue diagnosis can aid medical practitioners in capturing quantitative features to improve reliability and consistency of diagnosis. Recently, researchers have started to develop computer-aided tongue analysis algorithms based on new advancement in digital photogrammetry, image analysis, and pattern recognition technologies. In this chapter, we will describe our recent work on tongue image analysis as well as a mobile app that we developed based on this technology. PMID- 28916921 TI - Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [11C]Raclopride in Non-human Primates. AB - PURPOSE: Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP. PROCEDURES: Three cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region. RESULTS: In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman's rho = - 0.79, p = 0.03), but not with BPND (rho = - 0.25, p = 0.55). CONCLUSIONS: These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements. PMID- 28916927 TI - Genetic Test, Risk Prediction, and Counseling. AB - Advancement in technology has nurtured the new era of genetic tests for personalized medicine. In this chapter, we will introduce the current development, challenges, and the outlook of genetic test, disease risk prediction, and genetic counseling. In the first section, we will present the success cases in the areas of molecular classification of tumors, pharmacogenomics, and Mendelian disorders, and the challenges of genetic tests implementations. In the second section, common methods for genetic risk prediction models and evaluation measures will be introduced, as well as challenges in feature reliability, risk model stability, and clinical utility. In the final section, key components of genetic counseling will be introduced, covering individual communications, psychosocial concerns, risk assessments, and follow-ups. Current evidences have shown a promising future for genetic testing and risk prediction; we expect that the advancement of analytical methods, technology, integration of omics data, and the increasing clinical implementation and regulation will continue to pave the way for precision medicine in future. PMID- 28916928 TI - Newborn Screening in the Era of Precision Medicine. AB - As newborn screening success stories gained general confirmation during the past 50 years, scientists quickly discovered diagnostic tests for a host of genetic disorders that could be treated at birth. Outstanding progress in sequencing technologies over the last two decades has made it possible to comprehensively profile newborn screening (NBS) and identify clinically relevant genomic alterations. With the rapid developments in whole-genome sequencing (WGS) and whole-exome sequencing (WES) recently, we can detect newborns at the genomic level and be able to direct the appropriate diagnosis to the different individuals at the appropriate time, which is also encompassed in the concept of precision medicine. Besides, we can develop novel interventions directed at the molecular characteristics of genetic diseases in newborns. The implementation of genomics in NBS programs would provide an effective premise for the identification of the majority of genetic aberrations and primarily help in accurate guidance in treatment and better prediction. However, there are some debate correlated with the widespread application of genome sequencing in NBS due to some major concerns such as clinical analysis, result interpretation, storage of sequencing data, and communication of clinically relevant mutations to pediatricians and parents, along with the ethical, legal, and social implications (so-called ELSI). This review is focused on these critical issues and concerns about the expanding role of genomics in NBS for precision medicine. If WGS or WES is to be incorporated into NBS practice, considerations about these challenges should be carefully regarded and tackled properly to adapt the requirement of genome sequencing in the era of precision medicine. PMID- 28916920 TI - Does delayed esophagectomy after endoscopic resection affect outcomes in patients with stage T1 esophageal cancer? A propensity score-based analysis. AB - BACKGROUND: Although endoscopic resection (ER) may be sufficient treatment for early-stage esophageal cancer, additional treatment is recommended when there is a high risk of cancer recurrence. It is unclear whether delaying esophagectomy by performing and assessing the success of ER affects outcomes as compared with immediate esophagectomy without ER. Additionally, long-term survival after sequential ER and esophagectomy required further investigation. METHODS: Between 2011 and 2015, 48 patients with stage T1 esophageal cancer underwent esophagectomy after ER with curative intent at our institution. Two-to-one propensity score methods were used to identify 96 matched-control patients who were treated with esophagectomy only using baseline patient, tumor characteristics and surgical approach. Time from initial evaluation to esophagectomy, relapse-free survival, overall survival, and postoperative complications were compared between the propensity-matched groups. RESULTS: In the ER + esophagectomy group, the time from initial evaluation to esophagectomy was significantly longer than in the esophagectomy only group (114 vs. 8 days, p < 0.001). The incidence of dense adhesion (p = 0.347), operative time (p = 0.867), postoperative surgical complications (p = 0.966), and postoperative length of hospital stay (p = 0.125) were not significantly different between the groups. Moreover, recurrence-free survival and overall survival were also similar between the two groups (p = 0.411 and p = 0.817, respectively). CONCLUSIONS: Treatment of stage T1 esophageal cancer with ER prior to esophagectomy did not increase the difficulty of performing esophagectomy or the incidence of postoperative complications and did not affect survival after esophagectomy. These results suggest that ER can be recommended for patients with stage T1 cancer even if esophagectomy is warranted eventually. PMID- 28916931 TI - Physical Exercise Prescription in Metabolic Chronic Disease. AB - Metabolic syndrome as a consequence of the association to overweight, hypertension, and diabetes is at high risk of coronary events. Regular physical training has been recently promoted to reduce cardiovascular risks factors, by the improved lifestyle and also by the "anti-inflammatory effectiveness." A positive impact has been shown in case of cancer survived patients either with or without comorbidities and especially in those subjects where the inflammatory process is globally represented. The American College of Sports Medicine (ACSM) guidelines and more recently a new Italian model both support the role of "exercise as therapy" at moderate level of energy expenditure. The importance to establish the individual level of physical exercise, like a drug's dose, has induced authors in investigating this aspect in diverse diseases and in different clinical fields associated to an incorrect lifestyle habits. To reach this goal, a specific research strategy is important to spread the knowledge. PMID- 28916932 TI - Informatics for Nutritional Genetics and Genomics. AB - While traditional nutrition science is focusing on nourishing population, modern nutrition is aiming at benefiting individual people. The goal of modern nutritional research is to promote health, prevent diseases, and improve performance. With the development of modern technologies like bioinformatics, metabolomics, and molecular genetics, this goal is becoming more attainable. In this chapter, we will discuss the new concepts and technologies especially in informatics and molecular genetics and genomics, and how they have been implemented to change the nutrition science and lead to the emergence of new branches like nutrigenomics, nutrigenetics, and nutritional metabolomics. PMID- 28916922 TI - Evaluation of ZmCCT haplotypes for genetic improvement of maize hybrids. AB - KEY MESSAGE: The elite ZmCCT haplotypes which have no transposable element in the promoter could enhance maize resistance to Gibberella stalk rot and improve yield related traits, while having no or mild impact on flowering time. Therefore, they are expected to have great value in future maize breeding programs. A CCT domain containing gene, ZmCCT, is involved in both photoperiod response and stalk rot resistance in maize. At least 15 haplotypes are present at the ZmCCT locus in maize germplasm, whereas only three of them are found in Chinese commercial maize hybrids. Here, we evaluated ZmCCT haplotypes for their potential application in corn breeding. Nine resistant ZmCCT haplotypes that have no CACTA-like transposable element in the promoter were introduced into seven elite maize inbred lines by marker-assisted backcrossing. The resultant 63 converted lines had 0.7-5.1 Mb of resistant ZmCCT donor segments with over 90% recovery rates. All converted lines tested exhibited enhanced resistance to maize stalk rot but varied in photoperiod sensitivity. There was a close correlation between the hybrids and their parental lines with respect to both resistance performance and photoperiod sensitivity. Furthermore, in a given hybrid A5302/83B28, resistant ZmCCT haplotype could largely improve yield-related traits, such as ear length and 100-kernel weight, resulting in enhanced grain yield. Of nine resistant ZmCCT haplotypes, haplotype H5 exhibited excellent performance for both flowering time and stalk rot resistance and is thus expected to have potential value in future maize breeding programs. PMID- 28916926 TI - Informatics for Precision Medicine and Healthcare. AB - The past decade has witnessed great advances in biomedical informatics. Biomedical informatics is an emerging field of healthcare that aims to translate the laboratory observation into clinical practice. Smart healthcare has also developed rapidly with ubiquitous sensor and communication technologies. It is able to capture the online patient-centric phenotypic variables, thus providing a rich information base for translational biomedical informatics. Biomedical informatics and smart healthcare represent two interrelated disciplines. On one hand, biomedical informatics translates the bench discoveries into bedside, and, on the other hand, it is reciprocally informed by clinical data generated from smart healthcare. In this chapter, we will introduce the major strategies and challenges in the application of biomedical informatics technology in precision medicine and healthcare. We highlight how the informatics technology will promote the precision medicine and therefore promise the improvement of healthcare. PMID- 28916934 TI - Cohort Research in "Omics" and Preventive Medicine. AB - Cohort studies are observational studies in which the investigator determines the exposure status of subjects and then follows them for subsequent outcomes. The incidence of outcomes is observed in the exposed group and compared with that in a nonexposed group. Recently, new epidemiologic strategies have encouraged cohort research information exchange and cooperation to improve the cognition of disease etiology, such as case-cohort design and nested case-control study, which is available for "omics" data. Meanwhile, large-scale cohort studies using a prospective multiple design and long follow-ups have explored some of the challenges in preventive medicine. Cohort study can bridge the gap between the micro and macro research.This chapter is divided into three parts: 1. Basic knowledge of cohort study, which included the definition of cohort study and different types of cohort study, how to design the cohort study, data analysis for the cohort study, sources of bias in cohort studies, tools and software for cohort studies, and strengths and limitations of cohort study 2. Cohort study for "omics" data analysis, which introduced three related methodologically distinct study designs, case-cohort design for genomic cohort study, nested case-control design for transcriptomics cohort data, and population-based design for integrative "omics" cohort 3. Perspectives on cohort study including data-driven medicine and cohort research, cohort research for healthcare medicine, and cohort research for preventive medicine. PMID- 28916929 TI - Trace Elements and Healthcare: A Bioinformatics Perspective. AB - Biological trace elements are essential for human health. Imbalance in trace element metabolism and homeostasis may play an important role in a variety of diseases and disorders. While the majority of previous researches focused on experimental verification of genes involved in trace element metabolism and those encoding trace element-dependent proteins, bioinformatics study on trace elements is relatively rare and still at the starting stage. This chapter offers an overview of recent progress in bioinformatics analyses of trace element utilization, metabolism, and function, especially comparative genomics of several important metals. The relationship between individual elements and several diseases based on recent large-scale systematic studies such as genome-wide association studies and case-control studies is discussed. Lastly, developments of ionomics and its recent application in human health are also introduced. PMID- 28916939 TI - [Gray-blue spots on the body of an infant]. PMID- 28916933 TI - Interactions Between Genetics, Lifestyle, and Environmental Factors for Healthcare. AB - The occurrence and progression of diseases are strongly associated with a combination of genetic, lifestyle, and environmental factors. Understanding the interplay between genetic and nongenetic components provides deep insights into disease pathogenesis and promotes personalized strategies for people healthcare. Recently, the paradigm of systems medicine, which integrates biomedical data and knowledge at multidimensional levels, is considered to be an optimal way for disease management and clinical decision-making in the era of precision medicine. In this chapter, epigenetic-mediated genetics-lifestyle-environment interactions within specific diseases and different ethnic groups are systematically discussed, and data sources, computational models, and translational platforms for systems medicine research are sequentially presented. Moreover, feasible suggestions on precision healthcare and healthy longevity are kindly proposed based on the comprehensive review of current studies. PMID- 28916935 TI - Risk Stratification Model: Lower-Extremity Ultrasonography for Hospitalized Patients with Suspected Deep Vein Thrombosis. AB - BACKGROUND: The Wells score for deep venous thrombosis (DVT) has a high failure rate and low efficiency among inpatients. OBJECTIVE: To create and validate an inpatient-specific risk stratification model to help assess pre-test probability of DVT in hospitalized patients. DESIGN: Prospective cohort study of hospitalized patients undergoing lower-extremity ultrasonography studies (LEUS) for suspected DVT. Demographics, physical findings, medical history, medications, hospitalization, and laboratory and imaging results were collected. Samples were divided into model derivation (patients undergoing LEUS 11/1/2012-12/31/2013) and validation cohorts (LEUS 1/1/2014-5/31/2015). A DVT prediction rule was derived using the recursive partitioning algorithm (decision tree-type approach) and was then validated. PARTICIPANTS: Adult inpatients undergoing LEUS for suspected DVT from November 2012 to May 2015, excluding those with DVT in the prior 3 months, at a 793-bed, urban academic quaternary-care hospital with ~50,000 admissions annually. MAIN MEASURES: The primary outcome was the presence of proximal DVT, and the secondary outcome was the presence of any DVT (proximal or distal). Model sensitivity and specificity for predicting DVT were calculated. KEY RESULTS: Recursive partitioning yielded four variables (previous DVT, active cancer, hospitalization >= 6 days, age >= 46 years) that optimized the prediction of proximal DVT and yield in the derivation cohort. From this decision tree, we stratified a scoring system using the validation cohort, categorizing patients into low- and high-risk groups. The incidence rates of proximal DVT were 2.9% and 12.0%, and of any DVT were 5.2% and 21.0%, for the low- and high-risk groups, respectively. The AUC for the discriminatory accuracy of the Center for Evidence Based Imaging (CEBI) score for risk of proximal DVT identified on LEUS was 0.73. Model sensitivity was 98.1% for proximal and 98.1% for any DVT. CONCLUSIONS: In hospitalized adults, specific factors can help clinicians predict risk of DVT, identifying those with low pre-test probability, in whom ultrasonography can be safely avoided. PMID- 28916941 TI - Analysis of perioperative antibiotic administration in electronic medical records: correlations among patients addressed by analyzing control chart data using the batch means method. PMID- 28916937 TI - The conversion of exposures due to radon into the effective dose: the epidemiological approach. AB - The risks and dose conversion coefficients for residential and occupational exposures due to radon were determined with applying the epidemiological risk models to ICRP representative populations. The dose conversion coefficient for residential radon was estimated with a value of 1.6 mSv year-1 per 100 Bq m-3 (3.6 mSv per WLM), which is significantly lower than the corresponding value derived from the biokinetic and dosimetric models. The dose conversion coefficient for occupational exposures with applying the risk models for miners was estimated with a value of 14 mSv per WLM, which is in good accordance with the results of the dosimetric models. To resolve the discrepancy regarding residential radon, the ICRP approaches for the determination of risks and doses were reviewed. It could be shown that ICRP overestimates the risk for lung cancer caused by residential radon. This can be attributed to a wrong population weighting of the radon-induced risks in its epidemiological approach. With the approach in this work, the average risks for lung cancer were determined, taking into account the age-specific risk contributions of all individuals in the population. As a result, a lower risk coefficient for residential radon was obtained. The results from the ICRP biokinetic and dosimetric models for both, the occupationally exposed working age population and the whole population exposed to residential radon, can be brought in better accordance with the corresponding results of the epidemiological approach, if the respective relative radiation detriments and a radiation-weighting factor for alpha particles of about ten are used. PMID- 28916944 TI - Conflict of Interest and the CREATE-X Trial in the New England Journal of Medicine. AB - There is an increasing emphasis on clear disclosure of conflict of interest in medical communities, following repeated scientific frauds in clinical trials. However, incomplete COI statements continue to be prevalent in the medical community, as appears to have occurred in the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial, which was recently published in the New England Journal of Medicine. The authors of the article did not clearly report the roles of the Japan Breast Cancer Research Group, a sponsor and funder of the study, although a majority of the Japanese authors served in important positions in the organization. Furthermore, the conflict of interest related to Chugai Pharmaceutical Company, a Japanese distributor of capecitabine, was not correctly disclosed. More transparent statements of conflict of interest and clarification of sponsors and funders' roles, as well as rigorous review by academic journals are required to fairly interpret the findings of clinical trials, including and beyond the single case of the CREATE-X trial. PMID- 28916940 TI - [Holistic approach for understanding and treatment of chronic pain in old age]. PMID- 28916938 TI - ASNC imaging guidelines for nuclear cardiology procedures : Standardized reporting of nuclear cardiology procedures. PMID- 28916915 TI - Inflammatory diseases and bone fragility. AB - Systemic osteoporosis and increased fracture rates have been described in chronic inflammatory diseases such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, inflammatory bowel diseases, and chronic obstructive pulmonary disease. Most of these patients receive glucocorticoids, which have their own deleterious effects on bone. However, the other main determinant of bone fragility is the inflammation itself, as shown by the interactions between the inflammatory mediators, the actors of the immune system, and the bone remodelling. The inflammatory disease activity is thus on top of the other well known osteoporotic risk factors in these patients. Optimal control of inflammation is part of the prevention of osteoporosis, and potent anti inflammatory drugs have positive effects on surrogate markers of bone fragility. More data are needed to assess the anti-fracture efficacy of a tight control of inflammation in patients with a chronic inflammatory disorder. This review aimed at presenting different clinical aspects of inflammatory diseases which illustrate the relationships between inflammation and bone fragility. PMID- 28916945 TI - Simvastatin enhances radiation sensitivity of colorectal cancer cells. AB - INTRODUCTION: Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro. METHODS: Four colorectal cancer cell lines (SW480, DLD1, SW837, and HRT18) were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Outcome measures included ATP-based cell viability, colony formation, and protein (immunoblot) assays. RESULTS: The combination of radiation and simvastatin inhibited colony formation and cell viability of all four CRC lines, to a greater degree than either treatment alone (p < 0.01). In addition, the effects of simvastatin in this combination therapy were dose dependent, with increased concentrations resulting in more potentiated inhibitory effects. The radiosensitizing effects of simvastatin on cell viability were negated by the presence of exogenous GGPP in the media. On protein analyses of irradiated cells, simvastatin treatment inhibited phosphorylation of ERK1/2, in a dose-dependent manner, while the total levels of ERK1/2 remained stable. In addition, the combined treatment resulted in increased levels of cleaved caspase 3, indicating greater apoptotic activity in the cells treated with radiation and simvastatin together. CONCLUSIONS: Treatment with simvastatin hindered CRC cell viability and enhanced radiation sensitivity in vitro. These effects were tied to the depletion of GGPP and the decreased phosphorylation of ERK1/2, suggesting a prominent role for the EGFR-RAS-ERK1/2 pathway, through which statin enhances radiation sensitivity. PMID- 28916942 TI - Comment on "Effects of different omega-3 sources, fish oil, krill oil, and green lipped mussel against cytokine-mediated canine cartilage degradation" In Vitro Cell Dev Biol Anim. 2017 doi: 10.1007/s11626-016-0125-y. PMID- 28916946 TI - Association Between Placental Polycyclic Aromatic Hydrocarbons (PAHS), Oxidative Stress, and Preterm Delivery: A Case-Control Study. AB - Polycyclic aromatic hydrocarbons are known to disturb the antioxidant defense system, which may indirectly contribute to induction of early pregnancy in women. Therefore, the present investigation was designed to offer preliminary information about exposure to PAHs by estimating their placental levels and its association with oxidative stress as well as with preterm birth. Placenta tissue samples were drawn after delivery from 84 healthy pregnant women, recruited at a local nursing home of Agra, India, and levels of PAHs were quantified by gas chromatograph equipped with flame ionization detector. To evaluate redox status biomarkers, malondialdehyde (MDA) and glutathione (GSH) were determined in placenta tissue. Significantly elevated levels of benzo(a)pyrene and MDA while decreasing trend of GSH was found in women with preterm delivery group (study) than women with a full-term delivery group (control). Results demonstrated higher, but statistically insignificant (p > 0.05), levels of naphthalene, anthracene, fluorene, pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, indeno[1,2,3-cd]pyrene, dibenzo(ah)anthracene, and benzo(ghi)perylene in the study group than the control group. However, higher and lower molecular weight PAHs showed significant correlation for the depletion trend of GSH sights upon an example of oxidative stress mechanism. Because of limited statistical power and absence of controlled confounders, this study does not provide an ample involvement of PAHs with preterm delivery but increased MDA and decreased GSH in cases than controls gives the possible contribution of PAHs to early delivery. PMID- 28916936 TI - Does diabetes mellitus comorbidity affect in-hospital mortality and length of stay? Analysis of administrative data in an Italian Academic Hospital. AB - AIMS: Hospitalized patients with comorbid diabetes mellitus may have worse outcomes than the others. We conducted a study to assess whether comorbid diabetes affects in-hospital mortality and length of stay. METHODS: For this population-based study, we analyzed the administrative databases of the Regional Health Information System of the Region Friuli Venezia Giulia, where the Hospital of Udine is located. Hospital discharge data were linked at the individual patient level with the regional Diabetes Mellitus Registry to identify diabetic patients. For each 3-digit ICD-9-CM discharge diagnosis code, we assessed the difference in length of stay and in-hospital mortality between diabetic and non diabetic patients. We conducted both univariate and multivariate analyses, adjusted for age, sex, Charlson's comorbidity score, and urgency of hospitalization, through linear and logistic regression models. RESULTS: After adjusting for potential confounders, diabetes significantly increased the risk of in-hospital death among patients hospitalized for bacterial pneumonia (OR = 1.94) and intestinal obstruction (OR = 4.23) and length of stay among those admitted for several diagnoses, including acute myocardial infarction and acute renal failure. Admission glucose blood level was associated with in-hospital death in patients with pneumonia and intestinal obstruction, and increased length of stay for several conditions. CONCLUSIONS: Patients with diabetes mellitus who are hospitalized for other health problems may have increased risk of in-hospital death and longer hospital stay. For this reason, diabetes should be promptly recognized upon admission and properly managed. PMID- 28916950 TI - In reply: Analysis of perioperative antibiotic administration in electronic medical records: correlations among patients addressed by analyzing control chart data using the batch means method. PMID- 28916951 TI - The Box Task: A tool to design experiments for assessing visuospatial working memory. AB - The present paper describes the Box Task, a paradigm for the computerized assessment of visuospatial working memory. In this task, hidden objects have to be searched by opening closed boxes that are shown at different locations on the computer screen. The set size (i.e., number of boxes that must be searched) can be varied and different error scores can be computed that measure specific working memory processes (i.e., the number of within-search and between-search errors). The Box Task also has a developer's mode in which new stimulus displays can be designed for use in tailored experiments. The Box Task comes with a standard set of stimulus displays (including practice trials, as well as stimulus displays with 4, 6, and 8 boxes). The raw data can be analyzed easily and the results of individual participants can be aggregated into one spreadsheet for further statistical analyses. PMID- 28916947 TI - Honey bees possess a polarity-sensitive magnetoreceptor. AB - Honey bees, Apis mellifera, exploit the geomagnetic field for orientation during foraging and for alignment of their combs within hives. We tested the hypothesis that honey bees sense the polarity of magnetic fields. We created an engineered magnetic anomaly in which the magnetic field generally either converged toward a sugar reward in a watch glass, or away from it. After bees in behavioral field studies had learned to associate this anomaly with a sugar water reward, we subjected them to two experiments performed in random order. In both experiments, we presented bees with two identical sugar water rewards, one of which was randomly marked by a magnetic field anomaly. During the control experiment, the polarity of the magnetic field anomaly was maintained the same as it was during the training session. During the treatment experiment, it was reversed. We predicted that bees would not respond to the altered anomaly if they were sensitive to the polarity of the magnetic field. Our findings that bees continued to respond to the magnetic anomaly when its polarity was in its unaltered state, but did not respond to it when its polarity was reversed, support the hypothesis that honey bees possess a polarity-sensitive magnetoreceptor. PMID- 28916948 TI - Viewer discretion advised: is YouTube a friend or foe in surgical education? AB - BACKGROUND: In the current era, trainees frequently use unvetted online resources for their own education, including viewing surgical videos on YouTube. While operative videos are an important resource in surgical education, YouTube content is not selected or organized by quality but instead is ranked by popularity and other factors. This creates a potential for videos that feature poor technique or critical safety violations to become the most viewed for a given procedure. METHODS: A YouTube search for "Laparoscopic cholecystectomy" was performed. Search results were screened to exclude animations and lectures; the top ten operative videos were evaluated. Three reviewers independently analyzed each of the 10 videos. Technical skill was rated using the GOALS score. Establishment of a critical view of safety (CVS) was scored according to CVS "doublet view" score, where a score of >=5 points (out of 6) is considered satisfactory. Videos were also screened for safety concerns not listed by the previous tools. RESULTS: Median competence score was 8 (+/-1.76) and difficulty was 2 (+/-1.8). GOALS score median was 18 (+/-3.4). Only one video achieved adequate critical view of safety; median CVS score was 2 (range 0-6). Five videos were noted to have other potentially dangerous safety violations, including placing hot ultrasonic shears on the duodenum, non-clipping of the cystic artery, blind dissection in the hepatocystic triangle, and damage to the liver capsule. CONCLUSIONS: Top ranked laparoscopic cholecystectomy videos on YouTube show suboptimal technique with half of videos demonstrating concerning maneuvers and only one in ten having an adequate critical view of safety. While observing operative videos can be an important learning tool, surgical educators should be aware of the low quality of popular videos on YouTube. Dissemination of high-quality content on video sharing platforms should be a priority for surgical societies. PMID- 28916943 TI - Emergency Neurological Life Support: Acute Non-traumatic Weakness. AB - Acute non-traumatic weakness may be life-threatening if it involves the respiratory muscles and/or is associated with autonomic dysfunction. Most patients presenting with acute muscle weakness have a worsening neurological disorder that requires a rapid, systematic evaluation and detailed neurological exam to localize the disorder. Urgent laboratory tests and neuroimaging are needed to confirm the diagnosis. Because acute weakness is a common presenting sign of neurological emergencies, it was chosen as an Emergency Neurological Life Support protocol. Causes of acute non-traumatic weakness are discussed here by both presenting clinical signs and anatomical location. For each diagnosis, key features of the history, examination, investigations, and treatment are outlined in the included tables or in the "Appendix". PMID- 28916949 TI - The Latina Birth Weight Paradox: the Role of Subjective Social Status. AB - The purpose of this project was to quantitatively test differences in subjective social status scores between non-pregnant and pregnant women to determine the role of subjective social status in birth weight variation between Mexico-born and US-born Mexican-American women. Six hundred low-income pregnant and non pregnant Mexican immigrant and Mexican-American women in south Texas were surveyed for subjective social status, depression, perceived social stress, parity, and pregnancy intendedness. Psychosocial health variables, parity, and pregnancy intendedness were included due to their significant associations with low birth weight. Pregnant women had higher subjective social status scores than non-pregnant women. The difference in scores between non-pregnant and pregnant women was smaller in Mexican immigrant women than Mexican-American women. Pregnancy intendedness did not influence subjective social status in pregnant women of either sample, but having children (parity) in both samples was associated with higher subjective social status scores. Among Mexican-American women, community subjective social status was correlated with levels of depressive symptoms and perceived social stress. Subjective social status, depression, and perceived social stress were not correlated among Mexican immigrant women. Our results suggest that incorporation into the USA influences maternal mental health vis-a-vis changes in how women of reproductive age think about themselves and their gender roles in relation to others. Theoretically, our work supports mixed-method approaches to document how culture change as a result of immigration may impact maternal and infant health. Future research should test whether the effect of subjective social status on birth weight occurs when subjective social status does not correlate with depression or stress. PMID- 28916954 TI - Discrimination and Mental Health in a Representative Sample of African-American and Afro-Caribbean Youth. AB - BACKGROUND: Racism and discrimination are psychosocial stressors that affect the health of minority populations. While discrimination has been associated with poor mental health, little is known about the relationship between discrimination and mental health outcomes in youth nationally. Furthermore, mental and behavioral health consequences of discrimination may differ in different minority groups. OBJECTIVE: The goal of this study is to determine (1) how common perceptions of discrimination are in a nationally representative sample of African-American (AA) and Afro-Caribbean (AC) teens, (2) the relationship between discrimination and mental health conditions, and (3) whether discrimination has different associations with mental health in AA and AC youth. DESIGN: Cross sectional comparison study SETTING: National Survey of American Life-Adolescent Supplement, a nationwide sample of African-American and Afro-Caribbean youth drawn from a nationally representative household survey of AA and AC population PARTICIPANTS: One thousand, one hundred and seventy AA and AC youth between 13 and 17 years EXPOSURE: Experiences with discrimination (Everyday Discrimination Scale) MAIN OUTCOMES: Lifetime and past 12-month major depression and anxiety RESULTS: Ninety percent of AA and 87% of AC youth experienced discrimination. Discrimination was significantly associated with lifetime and 12-month major depression and lifetime and 12-month anxiety. There were no differences in the associations between discrimination and mental health between AA and AC youth except for lifetime anxiety: as discrimination increased, the likelihood of lifetime anxiety disorder increased at a higher rate among AC youth compared to AA. CONCLUSIONS: Discrimination is a common psychosocial stressor in African American and Afro-Caribbean youth. It is associated with poor mental health outcomes. There was no difference in the occurrence of discrimination between African-American and Afro-Caribbean youth or in its mental health consequences. PMID- 28916952 TI - Air-electron stream interactions during magnetic resonance IGRT : Skin irradiation outside the treatment field during accelerated partial breast irradiation. AB - PURPOSE: To investigate and to prevent irradiation outside the treatment field caused by an electron stream in the air generated by the magnetic field during magnetic resonance image-guided accelerated partial breast irradiation (APBI). MATERIALS AND METHODS: In all, 20 patients who received APBI with a magnetic resonance image-guided radiation therapy (MR-IGRT) system were prospectively studied. The prescription dose was 38.5 Gy in 10 fractions of 3.85 Gy and delivered with a tri-cobalt system (the ViewRay system). For each patient, primary plans were delivered for the first five fractions and modified plans with different gantry angles from those of the primary plan (in-treatment plans) were delivered for the remaining five fractions to reduce the skin dose. A 1 cm thick bolus was placed in front of the patient's jaw, ipsilateral shoulder, and arm to shield them from the electron stream. Radiochromic EBT3 films were attached to the front (towards the breast) and back (towards the head) of the bolus during treatment. Correlations between the measured values and the tumor locations, treatment times, and tumor sizes were investigated. RESULTS: For a single fraction delivery, the average areas of the measured isodoses of 14% (0.54 Gy), 12% (0.46 Gy), and 10% (0.39 Gy) at the front of the boluses were as large as 3, 10.4, and 21.4 cm2, respectively, whereas no significant dose could be measured at the back of the boluses. Statistically significant but weak correlations were observed between the measured values and the treatment times. CONCLUSION: During radiotherapy for breast cancer with an MR-IGRT system, the patient must be shielded from electron streams in the air generated by the interaction of the magnetic field with the beams of the three-cobalt treatment unit to avoid unwanted irradiation of the skin outside the treatment field. PMID- 28916955 TI - Multicenter, randomized single-port versus multiport laparoscopic surgery (SIMPLE) trial in colon cancer: an interim analysis. AB - BACKGROUND: Single-port laparoscopic surgery (SPLS) was recently introduced as an innovative minimally invasive surgery method. Retrospective studies have revealed the safety and feasibility of SPLS for colon cancer treatment. However, no prospective randomized trials have been performed. The multicenter, randomized SIMPLE (single-port versus multiport laparoscopic surgery) trial aimed to investigate short-term perioperative outcomes of SPLS for colon cancer treatment, compared with multiport laparoscopic surgery (MPLS). METHODS: Between August 2011 and April 2014, a total of 194 patients with colon cancer were recruited from seven hospitals in Korea. Patients were randomly allocated into the SPLS group (n = 99) or MPLS group (n = 95). The primary endpoint was postoperative complications. Operative, postoperative, and pathologic outcomes were analyzed after 50% of the patient study population had been recruited. RESULTS: The patients' demographic characteristics, operative times, estimated blood volume losses, numbers of harvested lymph nodes, and lengths of both resection margins were not significantly different between groups. In the SPLS group, the rates of conversion to MPLS and open surgery were 12.9 and 2.2%, respectively. Postoperative complications occurred in 10.8% of the SPLS, and 12.5% of the MPLS patients (p = 0.714). Times to functional recovery, pain scores, and amounts of analgesia were similar between groups. CONCLUSION: The results of this interim analysis suggested that SPLS is technically safe and appropriate when used for radical resection of colon cancer. (ClinicalTrials.gov Identifier: NCT01480128). PMID- 28916953 TI - Dexlansoprazole for Heartburn Relief in Adolescents with Symptomatic, Nonerosive Gastro-esophageal Reflux Disease. AB - BACKGROUND: Proton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of available medications, many patients have persisting symptoms, indicating a need for more effective agents. AIMS: To assess the safety and efficacy of dexlansoprazole dual delayed-release capsules in adolescents for treatment of symptomatic NERD. METHODS: A phase 2, open-label, multicenter study was conducted in adolescents aged 12-17 years. After a 21-day screening period, adolescents with endoscopically confirmed NERD received a daily dose of 30-mg dexlansoprazole for 4 weeks. The primary endpoint was treatment-emergent adverse events (TEAEs) experienced by >=5% of patients. The secondary endpoint was the percentage of days with neither daytime nor nighttime heartburn. Heartburn symptoms and severity were recorded daily in patient electronic diaries and independently assessed by the investigator, along with patient-reported quality of life, at the beginning and end of the study. RESULTS: Diarrhea and headache were the only TEAEs reported by >=5% of patients. Dexlansoprazole-treated patients (N = 104) reported a median 47.3% of days with neither daytime nor nighttime heartburn. Symptoms such as epigastric pain, acid regurgitation, and heartburn improved in severity for 73-80% of patients. Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire-Adolescents-Short Form symptom and impact subscale scores (scaled 1-5) each decreased by an average of 0.7 units at week 4. CONCLUSIONS: Use of 30-mg dexlansoprazole in adolescent NERD was generally well tolerated and had beneficial effects on improving heartburn symptoms and quality of life. TRIAL REGISTRATION: This study has the ClinicalTrials.gov identifier NCT01642602. PMID- 28916956 TI - Transitioning to Minimal Footwear: a Systematic Review of Methods and Future Clinical Recommendations. AB - BACKGROUND: Recent interest in barefoot running has led to the development of minimalist running shoes that are popular in distance runners. A careful transition to these shoes has been suggested and examined in the literature. However, no guidelines based on systematic evidence have been presented. The purpose of this review is to systematically examine the methods employed in the literature to transition to minimal footwear (MFW), as well as the outcomes to these studies in distance runners. In addition, MFW transition guidelines for future clinical practice will be presented based on observations from this review. METHODS: A systematic database search was employed using PubMed online as the primary database. Twenty papers were included in the final review. RESULTS: All studies implemented a prospective transition design to MFW with a detail of this transition provided, which increased MFW exposure up to an average of 60% (30-100%) at completion. Only 8/20 studies included injury prevention exercises, and 9/20 included gait retraining. The main outcomes of this transition included limited positive evidence of transitioning into MFW for running economy (n = 4 studies) and muscle development (n = 5). The injury incidence comparing running during the MFW transition (17.9 injuries per 100 participants) to matched participants in conventional running shoes (13.4 injuries per 100) appears equivocal (p = 0.219; effect size phi (phi) = 0.06 [very small]). Finally, several important recommendations for clinical practice and future research have been presented. CONCLUSIONS: It is hoped that this paper will present important first steps in unifying the process of transitioning to MFW, both for academic and clinical use. PMID- 28916958 TI - Hailey-Hailey Disease and Reduction Mammoplasty: Surgical Treatment of a Gene Mutation. PMID- 28916957 TI - Perspectives of Women Considering Bilateral Prophylactic Mastectomy and their Peers towards a Telephone-Based Peer Support Intervention. AB - Prophylactic mastectomy is an effective strategy to reduce the risk of breast cancer for women carrying a BRCA1/2 germline mutation. This decision is complex and may raise various concerns. Women considering this surgery have reported their desire to discuss the implications of this procedure with women who have undergone prophylactic mastectomy. We conducted a qualitative study to describe the topics covered during a telephone-based peer support intervention between women considering prophylactic mastectomy (recipients) and women who had undergone this surgery (peers), and to explore their perspectives regarding the intervention. Thirteen dyads were formed and data from participant logbooks and evaluation questionnaires were analyzed using a thematic content analysis. Three main dimensions emerged: physical, psychological, and social. The most frequent topics discussed were: surgery (92%), recovery (77%), pain and physical comfort (69%), impacts on intimacy and sexuality (54%), cancer-related anxiety (54%), experience related to loss of breasts (46%). Peers and recipients report that sharing experiences and thoughts about prophylactic mastectomy and the sense of mutual support within the dyad contributed significantly to their satisfaction. Special attention should be paid to the similarities between personal and medical profiles in order to create harmonious matches. PMID- 28916959 TI - Potential use of membrane bioreactor to treat petroleum refinery effluent: comprehension of dynamic of organic matter removal, fouling characteristics and membrane lifetime. AB - This study aims to evaluate membrane bioreactor (MBR) performance in a pilot scale to treat petroleum refinery effluent, and has been primarily focused on (1) investigation of dynamics of organic matter removal; (2) characterization of membrane fouling under real hazardous events; (3) evaluation of the effect of fouling on membrane lifetime; and (4) estimate the membrane lifetime. The results have shown that the MBR was able to effectively reduce COD, NH3-N, turbidity, color, phenol and toxicity, and bring them to the levels required to meet disposal and non-potable water reuse standards. The FTIR results showed that organic matter was removed by biological oxidation and/or retained by adsorption in the biological sludge, or retention in the UF membrane, and that SMP was produced during the treatment. In terms of membrane permeability, the results showed that soluble fraction of mixed liquor contributed significantly to membrane fouling. And finally, considering the concept of lifetime based on permeability decline, a membrane lifetime of 7 years is expected. PMID- 28916960 TI - A novel approach using the enhanced-view totally extraperitoneal (eTEP) technique for laparoscopic retromuscular hernia repair. AB - BACKGROUND: The enhanced-view totally extraperitoneal (eTEP) technique has been previously described for Laparoscopic Inguinal Hernia Repair. We present a novel application of the eTEP access technique for the repair of ventral and incisional hernias. METHODS: Retrospective review of consecutive laparoscopic retromuscular hernia repair cases utilizing the eTEP access approach from five hernia centers between August 2015 and October 2016 was conducted. Patient demographics, hernia characteristics, operative details, perioperative complications, and quality of life outcomes utilizing the Carolina's Comfort Scale (CCS) were included in our data analysis. RESULTS: Seventy-nine patients with mean age of 54.9 years, mean BMI of 31.1 kg/m2, and median ASA of 2.0 were included in this analysis. Thirty four percent of patients had a prior ventral or incisional hernia repair. Average mesh area of 634.4 cm2 was used for an average defect area of 132.1 cm2. Mean operative time, blood loss, and length of hospital stay were 218.9 min, 52.6 mL, and 1.8 days, respectively. There was one conversion to intraperitoneal mesh placement and one conversion to open retromuscular mesh placement. Postoperative complications consisted of seroma (n = 2) and trocar site dehiscence (n = 1). Comparison of mean pre- and postoperative CCS scores found significant improvements in pain (68%, p < 0.007) and movement limitations (87%, p < 0.004) at 6-month follow-up. There were no readmissions within 30 days and one hernia recurrence at mean follow-up of 332 +/- 122 days. CONCLUSIONS: Our initial multicenter evaluation of the eTEP access technique for ventral and incisional hernias has found the approach feasible and effective. This novel approach offers flexible port set-up optimal for laparoscopic closure of defects, along with wide mesh coverage in the retromuscular space with minimal transfascial fixation. PMID- 28916961 TI - Practical computational toolkits for dendrimers and dendrons structure design. AB - Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size. PMID- 28916962 TI - Effects of cholecystectomy on recurrent biliary complications after endoscopic treatment of common bile duct stone: a population-based cohort study. AB - BACKGROUND: The aim of this study was to evaluate the benefits of cholecystectomy on mitigating recurrent biliary complications following endoscopic treatment of common bile duct stone. METHODS: We used the data from the Taiwan National Health Insurance Research Database to conduct a population-based cohort study. Among 925 patients who received endoscopic treatment for choledocholithiasis at the first admission from 2005 to 2012, 422 received subsequent cholecystectomy and 503 had gallbladder (GB) left in situ. After propensity score matching with 1:1 ratio, the cumulative incidence of recurrent biliary complication and overall survival was analyzed with Cox's proportional hazards model. The primary endpoint of this study is recurrent biliary complications, which require intervention. RESULTS: After matching, 378 pairs of patients were identified with a median follow-up time of 53 (1-108) months. The recurrent rate of biliary complications was 8.20% in the cholecystectomy group and 24.87% in the GB in situ group (p < 0.001). In the multivariate Cox regression analysis, the only independent risk factor for recurrent biliary complications was GB left in situ (hazard ratio [HR] 3.55, 95% CI 2.36-5.33). CONCLUSIONS: Cholecystectomy after endoscopic treatment of common bile duct stone reduced the prevalence of recurrent biliary complications. PMID- 28916963 TI - Effects of different irrigation practices using treated wastewater on tomato yields, quality, water productivity, and soil and fruit mineral contents. AB - Wastewater use in agricultural irrigation is becoming a common practice in order to meet the rising water demands in arid and semi-arid regions. The study was conducted to determine the effects of the full (FI), deficit (DI), and partial root-zone drying (PRD) irrigation practices using treated municipal wastewater (TWW) and freshwater (FW) on tomato yield, water use, fruit quality, and soil and fruit heavy metal concentrations. The TWW significantly increased marketable yield compared to the FW, as well as decreased water consumption. Therefore, water use efficiency (WUE) in the TWW was significantly higher than in the FW. Although the DI and the PRD practices caused less yields, these practices significantly increased WUE values due to less irrigation water applied. The water-yield linear relationships were statistically significant. TWW significantly increased titratable acidity and vitamin C contents. Reduced irrigation provided significantly lower titratable acidity, vitamin C, and lycopene contents. TWW increased the surface soil and fruit mineral contents in response to FW. Greater increases were observed under FI, and mineral contents declined with reduction in irrigation water. Heavy metal accumulation in soils was within safe limits. However, Cd and Pb contents in fruits exceeded standard limits given by FAO/WHO. Higher metal pollution index values determined for fruits also indicated that TWW application, especially under FI, might cause health risks in long term. PMID- 28916965 TI - Factors affecting operative efficiency and post-operative convalescence in laparoendoscopic single-site (LESS) adrenalectomy. AB - BACKGROUND: Laparoendoscopic single-site (LESS) adrenalectomy is a novel challenging technique which is still under clinical evaluation. Initial reports have revealed its superiority in patient convalescence. In addition, it has been reported that some patient or anatomic factors might affect the ergonomics of LESS adrenalectomy. The aim of this study is to investigate the possible factors that might affect procedural efficiency and patient convalescence in LESS adrenalectomy. METHODS: Between October 2009 and July 2015, 105 consecutive adult patients with benign adrenal tumors, who underwent LESS retroperitoneal adrenalectomy were enrolled in this study. All the relevant peri-operative parameters were prospectively collected for later analysis. By using stepwise linear regression and stepwise selection of these peri-operative parameters, those that might affect the operative efficiency and patient convalescence were analyzed. RESULTS: Finally, 78 patients who completed follow-up and were eligible for stepwise linear regression were enrolled for final analysis. For parameters affecting operative efficiency, the fitted model revealed that patients with a pre-operative diagnosis of pheochromocytoma, a higher BMI, and an associated co morbidity of heart disease are associated with a longer operative time. In addition, the fitted model revealed that patients with a lower post-operative pain score, a delayed oral intake, and a diagnosis of non-functioning adrenal tumor were associated with a lengthier period before returning to normal activity. CONCLUSION: A higher BMI is the only anatomic factor that affects procedural efficiency in LESS adrenalectomy. In addition, post-operative pain score, time to oral intake, and a diagnosis of non-functioning adrenal tumor are the factors affecting patient convalescence. PMID- 28916964 TI - Presence of a [3Fe-4S] cluster in a PsaC variant as a functional component of the photosystem I electron transfer chain in Synechococcus sp. PCC 7002. AB - A site-directed C14G mutation was introduced into the stromal PsaC subunit of Synechococcus sp. strain PCC 7002 in vivo in order to introduce an exchangeable coordination site into the terminal FB [4Fe-4S] cluster of Photosystem I (PSI). Using an engineered PSI-less strain (psaAB deletion), psaC was deleted and replaced with recombinant versions controlled by a strong promoter, and the psaAB deletion was complemented. Modified PSI accumulated at lower levels in this strain and supported slower photoautotrophic growth than wild type. As-isolated PSI complexes containing PsaCC14G showed resonances with g values of 2.038 and 2.007 characteristic of a [3Fe-4S]1+ cluster. When the PSI complexes were illuminated at 15 K, these resonances partially disappeared and two new sets of resonances appeared. The majority set had g values of 2.05, 1.95, and 1.85, characteristic of FA-, and the minority set had g values of 2.11, 1.90, and 1.88 from FB' in the modified site. The S = 1/2 spin state of the latter implied the presence of a thiolate as the terminal ligand. The [3Fe-4S] clusters could be partially reconstituted with iron, producing a larger population of [4Fe-4S] clusters. Rates of flavodoxin reduction were identical in PSI complexes isolated from wild type and the PsaCC14G variant strain; this implied equivalent capacity for forward electron transfer in PSI complexes that contained [3Fe-4S] and [4Fe 4S] clusters. The development of this cyanobacterial strain is a first step toward translation of in vitro PSI-based biosolar molecular wire systems in vivo and provides new insights into the formation of Fe/S clusters. PMID- 28916966 TI - Evaluation of in vitro efficacy of docetaxel-loaded calcium carbonate aragonite nanoparticles (DTX-CaCO3NP) on 4T1 mouse breast cancer cell line. AB - Cockle shell-derived calcium carbonate nanoparticles have shown promising potentials as slow drug-releasing compounds in cancer chemotherapy. In this study, we evaluated the in vitro efficacy of docetaxel (DTX)-loaded CaCO3NP on 4T1 cell line. This was achieved by evaluating the following: cytotoxicity using MTT assay, fluorescence imaging, apoptosis with Annexin V assay, cell cycle analysis, scanning (SEM) and transmission electron microscopy (TEM), and scratch assay. Based on the results, DTX-CaCO3NP with a DTX concentration of 0.5 MUg/mL and above had comparable cytotoxic effects with free DTX at 24 h, while all concentrations had similar cytotoxic effect on 4T1 cells at 48 and 72 h. Fluorescence and apoptosis assay showed a higher (p < 0.05) number of apoptotic cells in both free DTX and DTX-CaCO3NP groups. Cell cycle analysis showed cycle arrest at subG0 and G2/M phases in both treatment groups. SEM showed presence of cellular blebbing, while TEM showed nuclear fragmentation, apoptosis, and vacuolation in the treatment groups. Scratch assay showed lower (p < 0.05) closure in both free DTX and DTX-CaCO3NP groups. The results from this study showed that DTX-CaCO3NP has similar anticancer effects on 4T1 cells as free DTX, and since it has a slow release rate, it is a more preferred substitute for free DTX. PMID- 28916967 TI - Combined analysis of the pre- and postoperative neutrophil-lymphocyte ratio predicts the outcomes of patients with gastric cancer. AB - PURPOSE: The neutrophil-lymphocyte ratio (NLR) is a biochemical marker of the systemic inflammatory response and has been associated with prognosis for various types of cancer. This retrospective study investigates the relationship between the pre- and postoperative NLR and the prognosis of gastric cancer patients. METHODS: The subjects were 280 patients who underwent curative surgery for histopathologically diagnosed gastric adenocarcinoma. RESULTS: The preoperative NLR was significantly correlated with tumor size, tumor depth, lymphatic invasion, venous invasion, and disease stage. In contrast, there was no correlation between the postoperative NLR and the various clinicopathological variables. Prognosis was significantly worse for patients with a high preoperative NLR than for those with a low preoperative NLR. Prognosis was also significantly worse for patients with a high postoperative NLR than for those with a low postoperative NLR. Furthermore, the prognosis was worse for gastric cancer patients whose pre- and postoperative NLRs were both high. Multivariate analysis indicated that a high pre- and postoperative NLR was an independent prognostic indicator. CONCLUSIONS: The combination of pre- and postoperative NLRs appears to be useful for predicting the prognosis of gastric cancer patients. PMID- 28916969 TI - Comparison of platelet-lymphocyte ratio and CA 19-9 in differentiating benign from malignant head masses in patients with chronic pancreatitis. AB - INTRODUCTION: Pancreatic head ductal adenocarcinoma (PDAC) and inflammatory head masses (IHM) related to chronic pancreatitis are often difficult to differentiate. PDAC produces significant inflammatory response with resultant lymphopenia and thrombocytosis. The prognostic role of platelet-lymphocyte ratio (PLR) as a tumor marker has been defined. We aimed to find the role of PLR as a diagnostic marker for PDAC in differentiating benign head mass comparing with carbohydrate antigen 19-9 (CA 19-9). METHODS: A prospective study of patients with biopsy-proven PDAC and benign IHM with underlying chronic pancreatitis from 1st November 2014 to 30th June 2016 was performed. Total blood count including platelet count and CA 19-9 were recorded and statistically analyzed. RESULTS: There was no significant difference in total leukocyte counts (7789+/-2027 vs. 7568+/-1289 cells/mm3) between PDAC (n = 34) and IHM (n = 27). However, the mean lymphocyte (2235+/-837 vs. 2701+/-631 cells/mm3) and platelet counts in mm3 (3.36+/-0.789) * 105 vs. (2.45+/-0.598) * 105 showed difference. The median PLR was 161.9 (IQR = 117.5-205.6) in PDAC and 91 (IQR = 77.2-106.6) in IHM. The median CA 19-9 (U/mL) in PDAC and IHM was 69.3 (IQR = 22.7-427.7) and 13.9 (IQR = 7.2-23.6), respectively. On plotting the receiver operator characteristic curve (ROC curve), area under the curve was maximum for PLR (88.7%) compared to CA 19-9 (77.8%) in diagnosing PDAC (p<0.0001). Using coordinates of ROC, PLR cutoff value was 113.5 (sensitivity-79.4%, specificity-92.6%, positive predictive value (PPV) 91.5%, negative predictive value (NPV)-99.7%) while CA 19-9 cutoff value was 25.3 U/mL (sensitivity-73.5%, specificity-77.8%, PPV-78.5%, NPV-74.6%). CONCLUSION: PLR may be useful to differentiate PDAC from benign IHM in patients with chronic pancreatitis. PMID- 28916968 TI - HMGB proteins and arthritis. AB - The high-mobility group box (HMGB) family includes four members: HMGB1, 2, 3 and 4. HMGB proteins have two functions. In the nucleus, HMGB proteins bind to DNA in a DNA structure-dependent but nucleotide sequence-independent manner to function in chromatin remodeling. Extracellularly, HMGB proteins function as alarmins, which are endogenous molecules released upon tissue damage to activate the immune system. HMGB1 acts as a late mediator of inflammation and contributes to prolonged and sustained systemic inflammation in subjects with rheumatoid arthritis. By contrast, Hmgb2 -/- mice represent a relevant model of aging related osteoarthritis (OA), which is associated with the suppression of HMGB2 expression in cartilage. Hmgb2 mutant mice not only develop early-onset OA but also exhibit a specific phenotype in the superficial zone (SZ) of articular cartilage. Given the similar expression and activation patterns of HMGB2 and beta catenin in articular cartilage, the loss of these pathways in the SZ of articular cartilage may lead to altered gene expression, cell death and OA-like pathogenesis. Moreover, HMGB2 regulates chondrocyte hypertrophy by mediating Runt related transcription factor 2 expression and Wnt signaling. Therefore, one possible mechanism explaining the modulation of lymphoid enhancer binding factor 1 (LEF1)-dependent transactivation by HMGB2 is that a differential interaction between HMGB2 and nuclear factors affects the transcription of genes containing LEF1-responsive elements. The multiple functions of HMGB proteins reveal the complex roles of these proteins as innate and endogenous regulators of inflammation in joints and their cooperative roles in cartilage hypertrophy as well as in the maintenance of joint tissue homeostasis. PMID- 28916970 TI - Caring for Patients' Families (or Lack of Family) in Neurocritical Care. PMID- 28916974 TI - Controlling Growth High Uniformity Indium Selenide (In2Se3) Nanowires via the Rapid Thermal Annealing Process at Low Temperature. AB - High uniformity Au-catalyzed indium selenide (In2Se3) nanowires are grown with the rapid thermal annealing (RTA) treatment via the vapor-liquid-solid (VLS) mechanism. The diameters of Au-catalyzed In2Se3 nanowires could be controlled with varied thicknesses of Au films, and the uniformity of nanowires is improved via a fast pre-annealing rate, 100 degrees C/s. Comparing with the slower heating rate, 0.1 degrees C/s, the average diameters and distributions (standard deviation, SD) of In2Se3 nanowires with and without the RTA process are 97.14 +/- 22.95 nm (23.63%) and 119.06 +/- 48.75 nm (40.95%), respectively. The in situ annealing TEM is used to study the effect of heating rate on the formation of Au nanoparticles from the as-deposited Au film. The results demonstrate that the average diameters and distributions of Au nanoparticles with and without the RTA process are 19.84 +/- 5.96 nm (30.00%) and about 22.06 +/- 9.00 nm (40.80%), respectively. It proves that the diameter size, distribution, and uniformity of Au-catalyzed In2Se3 nanowires are reduced and improved via the RTA pre-treated. The systemic study could help to control the size distribution of other nanomaterials through tuning the annealing rate, temperatures of precursor, and growth substrate to control the size distribution of other nanomaterials. Graphical Abstract Rapid thermal annealing (RTA) process proved that it can uniform the size distribution of Au nanoparticles, and then it can be used to grow the high uniformity Au-catalyzed In2Se3 nanowires via the vapor-liquid-solid (VLS) mechanism. Comparing with the general growth condition, the heating rate is slow, 0.1 degrees C/s, and the growth temperature is a relatively high growth temperature, > 650 degrees C. RTA pre-treated growth substrate can form smaller and uniform Au nanoparticles to react with the In2Se3 vapor and produce the high uniformity In2Se3 nanowires. The in situ annealing TEM is used to realize the effect of heating rate on Au nanoparticle formation from the as-deposited Au film. The byproduct of self-catalyzed In2Se3 nanoplates can be inhibited by lowering the precursors and growth temperatures. PMID- 28916972 TI - Knowledge and Attitudes Towards Clinical Depression among Community Medical Providers in Gujarat, India. AB - There is limited data on how community medical providers in India attempt to diagnose and treat depression, as well as on their general knowledge of and attitudes toward depression. A cross-sectional survey was conducted assessing knowledge and views of clinical depression with 80 non-psychiatric physicians and physician trainees recruited from community clinics and hospitals in Gujarat, India. Interviews were also held with 29 of the physicians to assess what they do in their own practices in regards to detection of and treatment of clinical depression. Although subjects showed a generally good basic understanding of the definition of clinical depression and its treatment, their responses reflected the presence of some negative and/or stigmatized attitudes toward clinical depression. Our findings raise the question of possible stigma among physicians themselves and underscore the importance of combatting physicians' stigma against and increasing awareness of how to detect and treat clinical depression. PMID- 28916973 TI - Myeloperoxidase can differentiate between sepsis and non-infectious SIRS and predicts mortality in intensive care patients with SIRS. AB - BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a clinical syndrome following inflammation. Clinically, it is difficult to distinguish SIRS following an infection, i.e., sepsis, from non-infectious SIRS. Myeloperoxidase is a hemeprotein stored in the neutrophil azurophilic granules and is one of the main pillars of neutrophil attack. Therefore, we hypothesized that myeloperoxidase can differentiate between sepsis and non-infectious SIRS in patients with systemic inflammatory response syndrome in the intensive care unit (ICU). METHODS: An observational single-center cohort study was conducted measuring myeloperoxidase in patients with SIRS in the first 48 h after admission. The outcomes were established using predefined definitions. Thirty-day mortality was retrospectively assessed. RESULTS: We found significantly higher levels of myeloperoxidase in patients with sepsis and septic shock compared to patients without sepsis (60 ng/ml versus 43 ng/ml, P = 0.002). Myeloperoxidase levels were related to 30-day mortality (P = 0.032), and high MPO levels on top of a high APACHE IV score further increased mortality risk. CONCLUSIONS: We show that myeloperoxidase is a potentially novel biomarker for sepsis in the ICU. Myeloperoxidase could eventually help in diagnosing sepsis and predicting mortality. However, more research is necessary to confirm our results. PMID- 28916982 TI - Chemical shift assignments and the secondary structure of the Est3 telomerase subunit in the yeast Hansenula polymorpha. AB - Telomerase is a multisubunit ribonucleoprotein enzyme that is essential for continuous cellular proliferation. A key role of telomerase in cancer and ageing makes it a promising target for the development of cancer therapies and treatments of other age-associated diseases, since telomerase allows unlimited proliferation potential of cells in the majority of cancer types. However, the structure and molecular mechanism of telomerase action are still poorly understood. In budding yeast, telomerase consists of the catalytic subunit, the telomerase reverse transcriptase or Est2 protein, telomerase RNA (TLC1) and two regulatory subunits, Est1 and Est3. Each of the four subunits is essential for in vivo telomerase function. Est3 interacts directly with Est1 and Est2, and stimulates Est2 catalytic activity. However, the exact role of the Est3 protein in telomerase function is still unknown. Determination of the structure, dynamic and functional properties of Est3 can bring new insights into the molecular mechanism of telomerase activity. Here we report nearly complete 1H, 13C and 15N resonance assignments of Est3 from the yeast Hansenula polymorpha. Analysis of the assigned chemical shifts allowed us to identify the protein's secondary structure and backbone dynamic properties. Structure-based sequence alignment revealed similarities in the structural organization of yeast Est3 and mammalian TPP1 proteins. PMID- 28916980 TI - Pharmacokinetics of Panax notoginseng Saponins in Adhesive and Normal Preparation of Fufang Danshen. AB - BACKGROUND AND OBJECTIVE: Fufang Danshen formula, a famous Chinese patent medicine containing Salvia miltiorrhiza, Panax notoginseng and borneol, has been widely used in the treatment of coronary heart disease. The application is restricted by low bioavailability partly due to Panax notoginseng saponins (PNS) instability and low in vivo absorption. Thus, adhesive pellets were developed to improve bioavailability. The objectives of the present study were to evaluate the adhesive preparation by describing PNS's plasma pharmacokinetics in vivo and compare adhesive micro pills with normal preparation. METHOD: LC-MS/MS method was established to analyze five ingredients, notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), ginsenoside Re (Re), and ginsenoside Rd (Rd), in rats' plasma to describe the pharmacokinetic parameters of PNS. RESULTS: The pharmacokinetic parameters were significantly different after oral administration three formulations. The results show adhesive formulations are superior to Fufang Danshen tablet (FDT); there are differences between the two adhesive, but not obvious. CONCLUSIONS: It was found that the modification with adhesive materials improved PNS bioavailability in Fufang Danshen formula. These findings provide a way for further in vivo evaluation of different formulations. PMID- 28916971 TI - Emergency Room Visits and Readmissions Following Implementation of an Enhanced Recovery After Surgery (iERAS) Program. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) guidelines have been widely promoted and supported largely due to several studies showing decreased post operative complications and length of stay. The objective of this study was to review the emergency room (ER) visits and readmission rates and reasons for both in patients who were part of the Implementation of an Enhanced Recovery After Surgery (iERAS) program for colorectal surgery. METHODS: All patients having elective colorectal surgery at 15 academic hospitals were enrolled in the iERAS program. All patients were prospectively followed until 30 days post-discharge. Data were analyzed using descriptive statistics and multivariable analysis. RESULTS: A total of 2876 patients (48% female; mean 60 years old) were enrolled. Cancer was the most frequent indication (68.2%) for surgery. Overall, the median length of stay (LOS) was 5 days. Post-discharge, 359 (11.6%) of patients had a visit to the ER not requiring admission. The most common reasons for visiting the ER were surgical site infections (SSI) (34.5%), other wound complications (10.0%), and urinary tract infections (UTI) (8.6%). In addition, a smaller proportion of patients, 260 (8.2%) required readmission. The most common reasons for readmission were ileus and nausea/vomiting (26.1%), intra-abdominal abscess (23.9%), and SSI (11.5%). Patient and disease factors associated with ER visits, on multivariable analysis, included extremes of BMI (RR 1.02, 95%CI 1.01-1.04, p = 0.002), rectal surgery versus colon surgery (RR 1.34, 95%CI 1.14-1.58, p < 0.001), and open operative approach (RR 1.63, 95%CI 1.28-2.09, p < 0.001). Independent factors associated with hospital readmissions included rectal surgery (RR 1.89, 95%CI 1.34-2.77, p < 0.001), formation of a stoma (RR 1.34, 95%CI 1.04 1.74, p = 0.026), and reoperation during first admission (RR 4.60, 95%CI 3.50 6.05, p < 0.001). Length of stay of 5 days or less was not associated with ER visits or readmission (RR 0.99, 95%CI 0.72-1.35 and RR 0.91, 95%CI 0.71-1.18, respectively). CONCLUSION: Following colorectal surgery using an ERAS pathway, shortened length of stay is not associated with an increased return to the ER or hospital readmission. The majority of return visits to the hospital are ER visits not requiring readmission and the predominant reason for return are surgical site infections and wound complications. PMID- 28916979 TI - Ventral hernia repair with poly-4-hydroxybutyrate mesh. AB - BACKGROUND: Biomaterial research has made available a biologically derived fully resorbable poly-4-hydroxybutyrate (P4HB) mesh for use in ventral and incisional hernia repair (VIHR). This study evaluates outcomes of patients undergoing VIHR with P4HB mesh. METHODS: An IRB-approved prospective pilot study was conducted to assess clinical and quality of life (QOL) outcomes for patients undergoing VIHR with P4HB mesh. Perioperative characteristics were defined. Clinical outcomes, employment status, QOL using 12-item short form survey (SF-12), and pain assessments were followed for 24 months postoperatively. RESULTS: 31 patients underwent VIHR with bioresorbable mesh via a Rives-Stoppa approach with retrorectus mesh placement. The median patient age was 52 years, median body mass index was 33 kg/m2, and just over half of the patients were female. Surgical site occurrences occurred in 19% of patients, most of which were seroma. Hernia recurrence rate was 0% (median follow-up = 414 days). Patients had significantly improved QOL at 24 months compared to baseline for SF-12 physical component summary and role emotional (p < 0.05). CONCLUSIONS: Ventral hernia repair with P4HB bioresorbable mesh results in favorable outcomes. Early hernia recurrence was not identified among the patient cohort. Quality of life improvements were noted at 24 months versus baseline for this cohort of patients with bioresorbable mesh. Use of P4HB mesh for ventral hernia repair was found to be feasible in this patient population. (ClinicalTrials.gov Identifier: NCT01863030). PMID- 28916978 TI - Tumor Biology Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Patients Presenting with Locally Advanced Breast Cancer. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) is used to convert patients with inoperable locally advanced breast cancer (LABC) to operability, but has not traditionally been used to avoid mastectomy or axillary dissection in this subset. OBJECTIVE: The purpose of this study was to determine the rates of pathologic complete response (pCR) in LABC patients, and identify factors predictive of pCR to determine if responding patients might be suitable for limited surgery. METHODS: From 2006 to 2016, 1522 patients received NAC followed by surgery; 321 had advanced disease in the breast (cT4) and/or in the nodes (cN2/N3). pCR rates were assessed by T and N stage, and receptor subtype. RESULTS: Of 321 LABC patients, 223 were cT4, 77 were cN2, and 82 were cN3. Forty three percent were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-), 23% were triple negative, and 34% were HER2+. The overall pCR rate was 25% and differed by receptor subtype (HR+/HER2- 7%, triple negative 23%, HER2+ 48%; p < 0.001). Breast pCR occurred in 27% of patients and was similar in T4 versus non-T4 disease (29% vs. 22%; p = 0.26). Nodal pCR was achieved in 38% of cN+ patients and did not differ by nodal stage (cN1 43%, cN2 36%, cN3 32%; p = 0.23). Nodal pCR was significantly more common than breast pCR (p = 0.014) across all tumor subtypes. Receptor subtype was the only predictor of overall pCR (p < 0.001). CONCLUSION: In patients with LABC, pCR after NAC was seen in 25%, and did not differ by T or N stage. Tumor biology, but not extent of disease, predicted pCR. Studies assessing the feasibility of surgical downstaging with NAC in LABC patients are warranted. PMID- 28916976 TI - Preoperative risk factors for postoperative complications in endoscopic pituitary surgery: a systematic review. AB - BACKGROUND: The ability to preoperatively predict postoperative complication risks is valuable for individual counseling and (post)operative planning, e.g. to select low-risk patients eligible for short stay surgery or those with higher risks requiring special attention. These risks however, are not well established in pituitary surgery. METHODS: We conducted a systematic review of associations between preoperative characteristics and postoperative complications of endoscopic transsphenoidal surgery according to the PRISMA guidelines. Risk of bias was assessed through the QUIPS tool. RESULTS: In total 23 articles were included, containing 5491 patients (96% pituitary adenoma). There was a wide variety regarding the nature and number of risk factors, definitions, measurement and statistics employed, and overall quality of mainly retrospective studies was low. Consistent significant associations were older age for complications in general, and intraventricular extension for cerebrospinal fluid (CSF) leaks. Associations identified in some but not all studies were younger age, increased BMI, female gender, and learning curve for CSF leaks; increased tumor size for complications in general; and Rathke's cleft cysts for diabetes insipidus. Mortality (incidence rate 1%) was not addressed as a risk factor. CONCLUSION: Based on current literature, of low to medium quality, it is not possible to comprehensively quantify risk factors for complications. Nevertheless, older age and intraventricular extension were associated with increased postoperative complications. Future research should aim at prospective data collection, reporting of outcomes, and uniformity of definitions. Only then a proper risk analysis can be performed for endoscopic pituitary surgery. PMID- 28916983 TI - Surface changes of nanotopography by carbon ion implantation to enhance the biocompatibility of silicone rubber: an in vitro study of the optimum ion fluence and adsorbed protein. AB - Lower cellular adhesion and dense fibrous capsule formation around silicone breast implants caused by lower biocompatibility is a serious clinical problem. Preliminary work has shown that ion implantation enhances cell adhesion. Whether the biocompatibility is further enhanced by higher doses of carbon ion implantation and the mechanism by which ion implantation enhances biocompatibility remain unclear. In this study, five doses of carbon ions, which gradually increase, were implanted on the surface of silicone rubber and then the surface characteristics were surveyed. Then, cell adhesion, proliferation and migration were investigated. Furthermore, the vitronectin (VN) protein was used as a model protein to investigate whether the ion implantation affected the adsorbed protein on the surface. The obtained results indicate that enhanced cytocompatibility is dose dependent when the doses of ion implantation are less than 1 * 1016 ions/cm2. However, when the doses of ion implantation are more than 1 * 1016 ions/cm2, enhanced cytocompatibility is not significant. In addition, surface physicochemical changes by ion implantation induced a conformational change of the adsorbed vitronectin protein that enhanced cytocompatibility. Together, these results suggest that the optimum value of carbon ion implantation in silicone rubber to enhance biocompatibility is 1 * 1016 ions/cm2, and ion implantation regulates conformational changes of adsorbed ECM proteins, such as VN, and mediates the expression of intracellular signals that enhance the biocompatibility of silicone rubber. The results herein provide new insights into the surface modification of implant polymer materials to enhance biocompatibility. It has potentially broad applications in the biomedical field. PMID- 28916981 TI - Expression of a novel bi-directional Brassica napus promoter in soybean. AB - The expression profile of a natural bi-directional promoter, derived from the Brassica napus EPSPS-A gene, was studied in transgenic soybean (Glycine max C.V. Maverick) lines. Two constructs, pDAB100331 and pDAB100333, were assembled to test the bi-directionality of the promoter. Two reporter genes, gfp and gusA, were employed and they were interchangeably placed in both constructs, one on each end of the promoter such that both proteins expressed divergently in each construct. In the T0 generation, GUS expression was more uniform throughout the leaf of pDAB100333 transgenic plants, where the gusA gene was expressed from the downstream or EPSPS-A end of the bi-directional promoter. Comparatively, GUS expression was more localized in the midrib and veins of the leaf of pDAB100331 transgenic plants, where the gusA gene was expressed from the upstream end of the bi-directional promoter. These observations indicated a unique expression pattern from each end of the promoter and consistently higher expression in genes expressed from the downstream end (e.g., EPSPS-A end) of the promoter in the tissues examined. The GFP expression pattern followed that of GUS when placed in the same position relative to the promoter. In the T1 generation, transcript analysis also showed higher expression of both gusA and gfp when those genes were located at the downstream end of the promoter. Accordingly, the pDAB100331 events exhibited a higher gfp/gusA transcript ratio, while pDAB100333 events produced a higher gusA/gfp transcript ratio consistent with the observations in T0 plants. These results demonstrated that the EPSPS-A gene bidirectional promoter can be effectively utilized to drive expression of two transgenes for the desired traits. PMID- 28916985 TI - Whole plastid transcriptomes reveal abundant RNA editing sites and differential editing status in Phalaenopsis aphrodite subsp. formosana. AB - BACKGROUND: RNA editing is a process of post-transcriptional level of gene regulation by nucleotide modification. Previously, the chloroplast DNA of Taiwan endemic moth orchid, P. aphrodite subsp. formosana was determined, and 44 RNA editing sites were identified from 24 plastid protein-coding transcripts of leaf tissue via RT-PCR and then conventional Sanger sequencing. However, the RNA editing status of whole-plastid transcripts in leaf and other distinct tissue types in moth orchids has not been addressed. To sensitively and extensively examine the plastid RNA editing status of moth orchid, RNA-Seq was used to investigate the editing status of whole-plastid transcripts from leaf and floral tissues by mapping the sequence reads to the corresponding cpDNA template. With the threshold of at least 5% C-to-U or U-to-C conversion events observed in sequence reads considered as RNA editing sites. RESULTS: In total, 137 edits with 126 C-to-U and 11 U-to-C conversions, including 93 newly discovered edits, were identified in plastid transcripts, representing an average of 0.09% of the nucleotides examined in moth orchid. Overall, 110 and 106 edits were present in leaf and floral tissues, respectively, with 79 edits in common. As well, 79 edits were involved in protein-coding transcripts, and the 58 nucleotide conversions caused the non-synonymous substitution. At least 32 edits showed significant (?20%) differential editing between leaf and floral tissues. Finally, RNA editing in trnM is required for the formation of a standard clover-leaf structure. CONCLUSIONS: We identified 137 edits in plastid transcripts of moth orchid, the highest number reported so far in monocots. The consequence of RNA editing in protein-coding transcripts mainly cause the amino acid change and tend to increase the hydrophobicity as well as conservation among plant phylogeny. RNA editing occurred in non-protein-coding transcripts such as tRNA, introns and untranslated regulatory regions could affect the formation and stability of secondary structure, which might play an important role in the regulation of gene expression. Furthermore, some unidentified tissue-specific factors might be required for regulating RNA editing in moth orchid. PMID- 28916988 TI - GestuRe and ACtion Exemplar (GRACE) video database: stimuli for research on manners of human locomotion and iconic gestures. AB - Human locomotion is a fundamental class of events, and manners of locomotion (e.g., how the limbs are used to achieve a change of location) are commonly encoded in language and gesture. To our knowledge, there is no openly accessible database containing normed human locomotion stimuli. Therefore, we introduce the GestuRe and ACtion Exemplar (GRACE) video database, which contains 676 videos of actors performing novel manners of human locomotion (i.e., moving from one location to another in an unusual manner) and videos of a female actor producing iconic gestures that represent these actions. The usefulness of the database was demonstrated across four norming experiments. First, our database contains clear matches and mismatches between iconic gesture videos and action videos. Second, the male actors and female actors whose action videos matched the gestures in the best possible way, perform the same actions in very similar manners and different actions in highly distinct manners. Third, all the actions in the database are distinct from each other. Fourth, adult native English speakers were unable to describe the 26 different actions concisely, indicating that the actions are unusual. This normed stimuli set is useful for experimental psychologists working in the language, gesture, visual perception, categorization, memory, and other related domains. PMID- 28916986 TI - Continuous Structured Population Models for Daphnia magna. AB - We continue our efforts in modeling Daphnia magna, a species of water flea, by proposing a continuously structured population model incorporating density dependent and density-independent fecundity and mortality rates. We collected new individual-level data to parameterize the individual demographics relating food availability and individual daphnid growth. Our model is fit to experimental data using the generalized least-squares framework, and we use cross-validation and Akaike Information Criteria to select hyper-parameters. We present our confidence intervals on parameter estimates. PMID- 28916977 TI - Tissue Transglutaminase Levels Are Not Sufficient to Diagnose Celiac Disease in North America Without Intestinal Biopsies: Don't Throw the Baby Out with the Bathwater. PMID- 28916990 TI - Transformation of anaerobic granules into aerobic granules and the succession of bacterial community. AB - In this study, we demonstrated that anaerobic granular sludge could be successfully transformed into aerobic granular sludge in a continuous up-flow reactor in 45 days. An aerobic microbial community successfully developed in the granules and high organic matter and nitrogen removal performance was achieved. Under an ammonia nitrogen loading rate of 0.8 kg N/(m3 day), ammonia nitrogen and the total nitrogen removal efficiency of the reactor reached up to 100 and 93%, respectively. An obvious bacterial community shift in granular sludge was observed during the transformation process. By comparing with the bacterial community in aerobic granules cultivated from floccular activated sludge, some bacteria (affiliated with Comamonadaceae, Xanthomonadaceae, Rhodocyclaceae, Moraxellaceae, and Nitrosomonadaceae) playing significant roles in maintaining the structures and functions of aerobic granules were identified. After the transformation, the granules could be clearly separated into the inner core and outer shell. 16S rRNA gene sequencing results indicated many bacterial species present in both the inner core and outer shell; however, their abundance differed significantly. Overall, this study confirms the feasibility of transforming anaerobic granules into aerobic granules and provides novel approaches and insights to understand the microbial ecology in granular sludge. PMID- 28916989 TI - Comparison of the Recovery Profile between Desflurane and Sevoflurane in Patients Undergoing Bariatric Surgery-a Meta-Analysis of Randomized Controlled Trials. AB - Early and clear recovery from anesthesia is the crux for preventing perioperative complications in the obese undergoing bariatric surgery. Volatile inhalation agents by virtue of high lipid solubility are expected to produce residual anesthetic effects. Prospective randomized trials comparing desflurane and sevoflurane used for anesthesia maintenance (electroencephalograph guided) during bariatric surgery published till 1st of July 2017 were searched in the medical database. Comparisons were made for surrogate markers of recovery from anesthesia that included time to eye-opening (TEo), time to tracheal-extubation (TEx), and Aldrete scores on immediately shifting to recovery (Ald-I). Five trials were included in the final analysis. Patients receiving desflurane began to respond faster by opening eyes on command (five trials) by 3.80 min (95%CI being 1.83 5.76) (random effects, P < 0.01, I2 = 78.61%), and tracheal extubation was also performed earlier (four trials) by 4.97 min (95%CI being 1.34-8.59). This meant a reduction of 37% in TEo and 33.60% in TEx over sevoflurane. Ald-I scores were higher/better with desflurane by 0.52 (95%CI being 0.19-0.84) (Fixed-effects, P < 0.01, I2 = 6.67%). Publication bias is likely for TEo (Egger's Test, X-intercept = - 8.57, P = 0.02). No airway-related complications were reported with desflurane's expedited recovery. Use of desflurane compared to sevoflurane for maintenance of anesthesia in morbidly obese patients allows attaining verbal contact faster, and tracheal extubating can be performed earlier without compromising safety. The benefits of better recovery extend into the immediate postoperative phase with patients being more awake upon shifting to the recovery. PMID- 28916987 TI - Erratum to: The impact of disability in survivors of critical illness. AB - In the Results section, under the subheading "Return to work or usual activities", the second sentence should read. PMID- 28916991 TI - Higher physical activity and lower pain levels before surgery predict non improvement of knee pain 1 year after TKA. AB - PURPOSE: The purpose of this study was to describe patterns of pain during the first year following total knee arthroplasty (TKA) and evaluate pre- and postoperative factors associated with pain and patient satisfaction at 1 year. It was hypothesized that more severe preoperative pain would be associated with more residual pain and lower patient satisfaction 1 year after surgery. METHODS: A longitudinal cohort study was performed with repeated measures of pain (0-10 numeric rating scale) and evaluation of other self-reported symptoms (Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, and Fatigue Severity Score), daily functioning (Lawton Instrumental Activities of Daily Living Scale), quality of life (EQ-5D-3L), knee function (KSS Knee and Function Score), perioperative and clinical characteristics (e.g. surgery duration, brand of implant, comorbidities), biochemical parameters (haemoglobin, C-reactive protein, creatinine), and patient satisfaction (20-item scale). Post-surgical improvement was defined as at least a two-point decrease in the patient's rating of pain interference with walking from baseline to 1 year. Hundred patients (mean age 64 +/- 8 years and 93% female) consecutively admitted for uncomplicated primary TKA participated, and 79 with complete data were included in this analysis. RESULTS: Pain generally decreased during the first postoperative year, from an average rating of 6 (SD = 3) to 1 (SD = 2). However, 18 of the 79 patients experienced no improvement in pain from baseline to 1 year. Factors associated with non-improvement of pain interference with walking after TKA included lower preoperative ratings of pain interference with walking (p < 0.001) and lower preoperative ratings of average pain (p = 0.004), active or very active levels of preoperative physical activity (p = 0.017), and higher ratings of worst pain on the first three postoperative days (p = 0.028). Pain at 1 year was the only predictor of lower patient satisfaction at 1 year. CONCLUSIONS: Patients with low preoperative pain ratings or high preoperative levels of physical activity are at increased risk of non-improvement in knee pain after TKA. This finding should be taken into consideration when selecting appropriate candidates for TKA surgery. Orthopaedic surgeons should pay particular attention to patients reporting low pain interference with walking and consider other conservative or surgical treatment options before TKA. Effective strategies for detection and treatment of TKA patients with high pain ratings at early follow-up visits also need to be developed. LEVEL OF EVIDENCE: Prognostic study, Level II. PMID- 28916975 TI - Flaxseed Oil Supplementation Improve Gene Expression Levels of PPAR-gamma, LP(a), IL-1 and TNF-alpha in Type 2 Diabetic Patients with Coronary Heart Disease. AB - This study was carried out to determine the effects of flaxseed oil administration on gene expression levels related to insulin, lipid and inflammation in overweight diabetic patients with coronary heart disease (CHD). This randomized double-blind, placebo-controlled trial was conducted among 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to intake either 1000 mg n-3 fatty acid from flaxseed oil containing 400 mg alpha Linolenic acid [ALA (18:3n-3)] (n = 30) or placebo (n = 30) twice a day for 12 weeks. Gene expression related to insulin, lipid and inflammation were quantified in peripheral blood mononuclear cells (PBMC) of diabetic patients with CHD with RT-PCR method. Results of RT-PCR demonstrated that after the 12-week intervention, compared with the placebo, flaxseed oil supplementation could up regulate gene expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) (P = 0.02) in PBMC of diabetic patients with CHD. In addition, compared with the placebo, taking flaxseed oil supplements down-regulated gene expression levels of lipoprotein(a) [LP(a)] (P = 0.001), interleukin-1 (IL-1) (P = 0.001) and tumor necrosis factor alpha (TNF-alpha) (P = 0.02) in PBMC of diabetic patients with CHD. We did not observe any significant effect of flaxseed oil supplementation on gene expression levels of low-density lipoprotein receptor (LDLR), IL-8 and transforming growth factor beta (TGF-beta) in PBMC of diabetic patients with CHD. Overall, flaxseed oil supplementation for 12 weeks in diabetic patients with CHD significantly improved gene expression levels of PPAR-gamma, LP(a), IL-1 and TNF-alpha, but did not influence LDLR, IL-8 and TGF-beta. PMID- 28916992 TI - Longevity of daily oral vitamin D3 supplementation: differences in 25OHD and 24,25(OH)2D observed 2 years after cessation of a 1-year randomised controlled trial (VICtORy RECALL). AB - : To determine how long vitamin D lasts after supplementation ceases, the marker of status was measured 2 and 3 years after a 1-year trial. Compared to placebo, the proportion of vitamin D-deficient women was still lower, if they had taken daily vitamin D3, after 2 years, indicating its longevity. INTRODUCTION: The purpose of this study was to determine longevity of vitamin D status following cessation of vitamin D3 supplementation, 2 and 3 years after a 1-year randomised, double-blind placebo controlled trial and to investigate possible predictive factors. METHODS: Caucasian non-smoking postmenopausal women randomised to ViCtORY (2009-2010), who had not taken vitamin D supplements since the trial ended, were invited to attend follow-up visits. Total 25-hydroxyvitamin D (25OHD) and 24,25-dihydroxyvitamin D (24,25OH2D) were measured by dual tandem mass spectrometry of serum samples following removal of protein and de-lipidation; the original randomised controlled trial (RCT) samples were re-analysed simultaneously. Vitamin D-binding protein (VDBP) was measured by monoclonal immunoassay. RESULTS: In March 2012 and March 2013, 159 women (mean (SD) age 67.6 (2.1) years) re-attended, equally distributed between the original treatment groups: daily vitamin D3 (400 IU, 1000 IU) and placebo. One month after the RCT ended (March 2010), the proportion of women in placebo, 400 IU and 1000 IU vitamin D3 groups, respectively, with 25OHD < 25 nmol/L was 15, 0 and 0 (chi square p < 0.001, n = 46, 44, 54). After 2 years (March 2012), it was 22, 4 and 4% (p = 0.002, n = 50, 48, 57); after 3 years, it was 23, 13 and 15% (p = 0.429, n = 48, 45, 52). The respective proportions of women with 24,25OH2D < 2.2 nmol/L were 50, 2 and 2% (1 month, p < 0.001, n = 46, 44, 54); 42, 33 and 12% (2 years, p = 0.002, n = 50, 48, 57); and 45, 27 and 29% (3 years, p = 0.138, n = 47, 45, 51). VDBP was a predictor of circulating 25OHD longevity (beta for VDBP in MUg/mL 0.736; 95% CI 0.216-1.255, p = 0.006) but not 24,25OH2D. CONCLUSION: Four hundred international units or 1000 IU of daily vitamin D3 showed benefits over placebo 2 years after supplementation ceased in keeping 25OHD > 25 nmol/L. PMID- 28917001 TI - A neural network model for familiarity and context learning during honeybee foraging flights. AB - How complex is the memory structure that honeybees use to navigate? Recently, an insect-inspired parsimonious spiking neural network model was proposed that enabled simulated ground-moving agents to follow learned routes. We adapted this model to flying insects and evaluate the route following performance in three different worlds with gradually decreasing object density. In addition, we propose an extension to the model to enable the model to associate sensory input with a behavioral context, such as foraging or homing. The spiking neural network model makes use of a sparse stimulus representation in the mushroom body and reward-based synaptic plasticity at its output synapses. In our experiments, simulated bees were able to navigate correctly even when panoramic cues were missing. The context extension we propose enabled agents to successfully discriminate partly overlapping routes. The structure of the visual environment, however, crucially determines the success rate. We find that the model fails more often in visually rich environments due to the overlap of features represented by the Kenyon cell layer. Reducing the landmark density improves the agents route following performance. In very sparse environments, we find that extended landmarks, such as roads or field edges, may help the agent stay on its route, but often act as strong distractors yielding poor route following performance. We conclude that the presented model is valid for simple route following tasks and may represent one component of insect navigation. Additional components might still be necessary for guidance and action selection while navigating along different memorized routes in complex natural environments. PMID- 28916999 TI - A simple and novel technique for regional citrate anticoagulation during intermittent hemodialysis may obviate the need for calcium monitoring. PMID- 28916996 TI - Successive Release of Tissue Inhibitors of Metalloproteinase-1 Through Graphene Oxide-Based Delivery System Can Promote Skin Regeneration. AB - The purpose of this study was to testify the hypothesis that graphene oxide (GO) could act as an appropriate vehicle for the release of tissue inhibitors of metalloproteinase-1 (TIMP-1) protein in the context of skin repair. GO characteristics were observed by scanning electron microscopy, atomic force microscopy, and thermal gravimetric analysis. After TIMP-1 absorbing GO, the release profiles of various concentrations of TIMP-1 from GO were compared. GO biocompatibility with fibroblast viability was assessed by measuring cell cycle and apoptosis. In vivo wound healing assays were used to determine the effect of TIMP-1-GO on skin regeneration. The greatest intensity of GO was 1140 nm, and the most intensity volume was 10,674.1 nm (nanometer). TIMP-1 was shown to be continuously released for at least 40 days from GO. The proliferation and viability of rat fibroblasts cultured with TIMP-1-GO were not significantly different as compared with the cells grown in GO or TIMP-1 alone (p > 0.05). Skin defect of rats treated with TIMP-1 and TIMP-1-GO showed significant differences in histological and immunohistochemical scores (p < 0.05). GO can be controlled to release carrier materials. The combination of TIMP-1 and GO promoted the progression of skin tissue regeneration in skin defect. PMID- 28916997 TI - Coupled reactions by coupled enzymes: alcohol to lactone cascade with alcohol dehydrogenase-cyclohexanone monooxygenase fusions. AB - The combination of redox enzymes for redox-neutral cascade reactions has received increasing appreciation. An example is the combination of an alcohol dehydrogenase (ADH) with a cyclohexanone monooxygenase (CHMO). The ADH can use NADP+ to oxidize cyclohexanol to form cyclohexanone and NADPH. Both products are then used by CHMO to produce epsilon-caprolactone. In this study, these two redox complementary enzymes were fused, to create a self-sufficient bifunctional enzyme that can convert alcohols to esters or lactones. Three different ADH genes were fused to a gene coding for a thermostable CHMO, in both orientations (ADH-CHMO and CHMO-ADH). All six fusion enzymes could be produced and purified. For two of the three ADHs, we found a clear difference between the two orientations: one that showed the expected ADH activity, and one that showed low to no activity. The ADH activity of each fusion enzyme correlated with its oligomerization state. All fusions retained CHMO activity, and stability was hardly affected. The TbADH TmCHMO fusion was selected to perform a cascade reaction, producing epsilon caprolactone from cyclohexanol. By circumventing substrate and product inhibition, a > 99% conversion of 200 mM cyclohexanol could be achieved in 24 h, with > 13,000 turnovers per fusion enzyme molecule. PMID- 28916998 TI - Emergency Neurologic Life Support: Meningitis and Encephalitis. AB - Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis, are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because of the value of early recognition and treatment, meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition and urgent treatment of bacterial meningitis and encephalitis. Appropriate imaging, spinal fluid analysis, and early empiric treatment are discussed. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the possibility of a central nervous system infection. Early attention to the airway and maintaining normotension are crucial steps in the treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids. PMID- 28916993 TI - Periostin in the pathogenesis of skin diseases. AB - Skin is an organ that is susceptible to damage by external injury, chronic inflammation, and autoimmunity. Tissue damage causes alterations in both the configuration and type of cells in lesional skin. This phenomenon, called tissue remodeling, is a universal biological response elicited by programmed cell death, inflammation, immune disorders, and tumorigenic, tumor proliferative, and cytoreductive activity. In this process, changes in the components of the extracellular matrix are required to provide an environment that facilitates tissue remodeling. Among these extracellular matrix components, periostin, a glycoprotein that is predominantly secreted from dermal fibroblasts, has attracted attention. Periostin localizes in the papillary dermis of normal skin, and is aberrantly expressed in the dermis of lesional skin in atopic dermatitis, scar, systemic/limited scleroderma, melanoma, cutaneous T cell lymphoma, and skin damage caused by allergic/autoimmune responses. Periostin induces processes that result in the development of dermal fibrosis, and activate or protract the immune response. The aim of this review was to summarize recent knowledge of the role of periostin in the pathogenesis of dermatoses, and to explore whether periostin is a potential therapeutic target for skin diseases. PMID- 28917006 TI - Synoptic operative reporting: assessing the completeness, accuracy, reliability, and efficiency of synoptic reporting for Roux-en-Y gastric bypass. AB - OBJECTIVE: Synoptic reporting (SR) is one solution to improve the quality of operative reports. However, SR has not been investigated in bariatric surgery despite an identified need by bariatric surgeons. SR for RYGB was developed using quality indicators (QIs) established by a national Delphi process. The objective of this study is to assess the completeness, accuracy, reliability, and efficiency of synoptic versus narrative operative reports (NR) in Roux-en-Y gastric bypass (RYGB). METHODS: A NR and SR were completed on 104 consecutive RYGBs. Two evaluators independently compared the reports to QIs. Completeness and accuracy measures were determined. Reliability was calculated using Bland-Altman plots and 95% limits of agreement (LOA). Time to complete SR and NR was also compared. RESULTS: The mean completion rate of SR was 99.8% (+/-SD 0.98%) compared to 64.0% (+/-SD 6.15%) for NR (t = 57.9, p < 0.001). All subsections of SR were >99% complete. This was significantly higher than for NR (p < 0.001) except for small bowel division details (p = 0.530). Accuracy was significantly higher for SR than NR (94.2% +/- SD 4.31% vs. 53.6% +/- SD 9.82%, respectively, p < 0.001). Rater agreement was excellent for both SR (0.11, 95% LOA -0.53 to 0.75) and NR (-0.26, 95% LOA -4.85 to 4.33) (p = 0.242), where 0 denotes perfect agreement. SR completion times were significantly shorter than NR (3:55 min +/- SD 1:26 min and 4:50 min +/- SD 0:50 min, respectively, p = 0.007). CONCLUSION: The RYGB SR is superior to NR for completeness and accuracy. This platform is also both reliable and efficient. This SR should be incorporated into clinical practice. PMID- 28916994 TI - Parity and Risk of Thyroid Cancer: a Population-Based Study in Lithuania. AB - An association between parity and thyroid cancer risk has been investigated in a number of independent studies but yielded contradictory findings. The aim of this study was to explore the association between parity and thyroid cancer risk. The population-based cohort study in Lithuanian was conducted. The study dataset based on the linkages between all records from the 2001 population census, all cancer incidence records from the Lithuanian Cancer Registry, and all death and emigration records from Statistics Lithuania for the period between 6 April 2001 and 31 December 2009. Cox's proportional hazards regression models were used to estimate the hazard ratios (HRs) for parity, age at first birth, number of children, place of residence, education, and age at census. The cohort of 868,105 women was followed for 8.6 years, and 1775 thyroid cancer cases were diagnosed during the study period. The significantly higher thyroid cancer risk was observed among parous women (HR = 1.45, 95% CI: 1.20, 1.75) and in women with 1, 2, and 3 children, after adjusting for the possible confounding effects of relevant demographic variables. The findings of this study are consistent with the hypothesis that parity might be associated with the risk of thyroid cancer in women. PMID- 28917002 TI - Comparison on effectiveness of trans-septal suturing versus nasal packing after septoplasty: a systematic review and meta-analysis. AB - This systematic review applied meta-analytic procedures to evaluate the curative effect of trans-septal suturing versus nasal packing after septoplasty. Computerized search of the published literature in PubMed, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, WANFANG, CNKI databases. Randomized trials investigating trans-septal suturing versus nasal packing following septoplasty in patients with deviated nasal septum. Adhesion, septal hematoma, bleeding, septal perforation, infection, pain, headache, or residual septal deviation per randomized patients. 19 randomized controlled trials of 1845 subjects were included. Meta-analysis showed that postoperative pain, headache, and adhesion were significantly lower in trans-septal suturing group. Nasal packing and trans-septal suturing technique appear to be equivalent with regard to postoperative bleeding, hematoma, septal perforation, infection, and residual septal deviation. Trans-septal suturing technology is not only associated with less patient pain, headache, and lower occurrence rate of adhesion after septoplasty but it also relates to higher patient satisfaction and an improved quality of life. The suturing technology can be used as a substitute for traditional nasal packing of the first-line treatment. More well-designed studies are needed to confirm the effect of trans-septal suturing following septoplasty. PMID- 28917007 TI - Specific properties of the SI and SII somatosensory areas and their effects on motor control: a system neurophysiological study. AB - Sensorimotor integration is essential for successful motor control and the somatosensory modality has been shown to have strong effects on the execution of motor plans. The primary (SI) and the secondary somatosensory (SII) cortices are known to differ in their neuroanatomical connections to prefrontal areas, as well as in their involvement to encode cognitive aspects of tactile processing. Here, we ask whether the area-specific processing architecture or the structural neuroanatomical connections with prefrontal areas determine the efficacy of sensorimotor integration processes for motor control. In a system neurophysiological study including EEG signal decomposition (i.e., residue iteration decomposition, RIDE) and source localization, we investigated this question using vibrotactile stimuli optimized for SI or SII processing. The behavioral data show that when being triggered via the SI area, inhibitory control of motor processes is stronger as when being triggered via the SII area. On a neurophysiological level, these effects were reflected in the C-cluster as a result of a temporal decomposition of EEG data, indicating that the sensory processes affecting motor inhibition modulate the response selection level. These modulations were associated with a stronger activation of the right inferior frontal gyrus extending to the right middle frontal gyrus as parts of a network known to be involved in inhibitory motor control when response inhibition is triggered over SI. In addition, areas important for sensorimotor integration like the postcentral gyrus and superior parietal cortex showed activation differences. The data suggest that connection patterns are more important for sensorimotor integration and control than the more restricted area-specific processing architecture. PMID- 28917000 TI - Routine use of mesh during hiatal closure is safe with no increase in adverse sequelae. AB - BACKGROUND: Primary laparoscopic hiatal repair with fundoplication is associated with a high recurrence rate. We wanted to evaluate the potential risks posed by routine use of onlay-mesh during hiatal closure, when compared to primary repair. METHODS: Utilizing single-institutional database, we identified patients who underwent primary laparoscopic hiatal repair from January 2005 through December 2014. Retrospective chart review was performed to determine perioperative morbidity and mortality. Long-term results were assessed by sending out a questionnaire. Results were tabulated and patients were divided into 2 groups: fundoplication with hiatal closure + absorbable or non-absorbable mesh and fundoplication with hiatal closure alone. RESULTS: A total of 505 patients underwent primary laparoscopic fundoplication. Mesh reinforcement was used in 270 patients (53.5%). There was no significant difference in the 30-day perioperative outcomes between the 2 groups. No clinically apparent erosions were noted and no mesh required removal. Standard questionnaire was sent to 475 patients; 174 (36.6%) patients responded with a median follow-up of 4.29 years. Once again, no difference was noted between the 2 groups in terms of dysphagia, heartburn, long term antacid use, or patient satisfaction. Of these, 15 patients (16.9%, 15/89) in the 'Mesh' cohort had symptomatic recurrence as compared to 19 patients (22.4%, 19/85) in the 'No Mesh' cohort (p = 0.362). A reoperation was necessary in 6 patients (6.7%) in the 'Mesh' cohort as compared to 3 patients (3.5%) in the 'No Mesh' cohort (p = 0.543). CONCLUSIONS: Onlay-mesh use in laparoscopic hiatal repair with fundoplication is safe and has similar short and long-term results as primary repair. PMID- 28917005 TI - Outcome of pediatric acute kidney injury: a multicenter prospective cohort study. AB - BACKGROUND: Acute kidney injury (AKI) is a common problem encountered in critically ill children with an increasing incidence and evolving epidemiology. AKI carries a serious morbidity and mortality in patients requiring admission to a pediatric intensive care unit (PICU). METHODS: We undertook a prospective cohort study of PICU admissions at three tertiary care hospitals in the Kingdom of Saudi Arabia over 2 years. The Kidney Disease Improving Global Outcomes (KDIGO) definition was used to diagnose AKI. RESULTS: A total of 1367 pediatrics PICU admissions were included in the study. AKI affected 511 children (37.4%), with 243 children (17.8%) classified as stage I (mild), 168 patients (12.3%) stage II (moderate), and 100 children (7.3%) were classified as stage III (severe). After adjustment for age, sex, and underlying diagnosis, in-hospital mortality was six times more likely among patients with AKI as compared to patients with normal renal function (adjusted OR: 6.5, 95% CI: 4.2-10). AKI was also a risk factor for hypertension (adjusted OR: 4.1, 95% CI: 2.8-5.9) and prolonged stay in the PICU and hospital, as it increased the average number of admission days by 10 (95% CI: 8.6-11) days in the PICU and 12 (95% CI: 10-14) days in the hospital. CONCLUSIONS: One-third of PICU admissions were complicated with AKI. AKI was associated with increased hospital mortality and the length of stay in both PICU and hospital. PMID- 28917003 TI - Effects of obesity and diabetes on rate of bone density loss. AB - : In this large registry-based study, women with diabetes had marginally greater bone mineral density (BMD) loss at the femoral neck but not at other measurement sites, whereas obesity was not associated with greater BMD loss. Our data do not support the hypothesis that rapid BMD loss explains the increased fracture risk associated with type 2 diabetes and obesity observed in prior studies. INTRODUCTION: Type 2 diabetes and obesity are associated with higher bone mineral density (BMD) which may be less protective against fracture than previously assumed. Inconsistent data suggest that rapid BMD loss may be a contributing factor. METHODS: We examined the rate of BMD loss in women with diabetes and/or obesity in a population-based BMD registry for Manitoba, Canada. We identified 4960 women aged >= 40 years undergoing baseline and follow-up BMD assessments (mean interval 4.3 years) without confounding medication use or large weight fluctuation. We calculated annualized rate of BMD change for the lumbar spine, total hip, and femoral neck in relation to diagnosed diabetes and body mass index (BMI) category. RESULTS: Baseline age-adjusted BMD was greater in women with diabetes and for increasing BMI category (all P < 0.001). In women with diabetes, unadjusted BMD loss was less at the lumbar spine (P = 0.017), non-significantly greater at the femoral neck (P = 0.085), and similar at the total hip (P = 0.488). When adjusted for age and BMI, diabetes was associated with slightly greater femoral neck BMD loss (- 0.0018 g/cm2/year, P = 0.012) but not at the lumbar spine or total hip. There was a strong linear effect of increasing BMI on attenuated BMI loss at the lumbar spine with negligible effects on hip BMD. CONCLUSIONS: Diabetes was associated with slightly greater BMD loss at the femoral neck but not at other measurement sites. BMD loss at the lumbar spine was reduced in overweight and obese women but BMI did not significantly affect hip BMD loss. PMID- 28916995 TI - Effects of environmental enrichment on self-administration of the short-acting opioid remifentanil in male rats. AB - BACKGROUND: Opioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting MU-opioid remifentanil. METHODS: Rats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21 days of age and were trained to lever press for 1 or 3 MUg/kg/infusion remifentanil in young adulthood. Acquisition of self administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated. RESULTS: In all phases, Enr rats lever pressed significantly less than Std and Iso rats, with Enr rats pressing between 9 and 40% the amount of Iso rats. Enr rats did not acquire remifentanil self-administration when trained with 1 MUg/kg/infusion, did not increase responding over increasing FR when trained at either dose, and their dose-response curves were flattened compared to Std and Iso rats. When expressed as economic demand curves, Enr rats displayed a decrease in both essential value (higher alpha) and reinforcer intensity (Q 0) compared to Std and Iso rats at the 1 MUg/kg/infusion training dose. CONCLUSION: Environmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse. PMID- 28917014 TI - More insight into the interplay of response selection and visual attention in dual-tasks: masked visual search and response selection are performed in parallel. AB - Both response selection and visual attention are limited in capacity. According to the central bottleneck model, the response selection processes of two tasks in a dual-task situation are performed sequentially. In conjunction search, visual attention is required to select the items and to bind their features (e.g., color and form), which results in a serial search process. Search time increases as items are added to the search display (i.e., set size effect). When the search display is masked, visual attention deployment is restricted to a brief period of time and target detection decreases as a function of set size. Here, we investigated whether response selection and visual attention (i.e., feature binding) rely on a common or on distinct capacity limitations. In four dual-task experiments, participants completed an auditory Task 1 and a conjunction search Task 2 that were presented with an experimentally modulated temporal interval between them (Stimulus Onset Asynchrony, SOA). In Experiment 1, Task 1 was a two choice discrimination task and the conjunction search display was not masked. In Experiment 2, the response selection difficulty in Task 1 was increased to a four choice discrimination and the search task was the same as in Experiment 1. We applied the locus-of-slack method in both experiments to analyze conjunction search time, that is, we compared the set size effects across SOAs. Similar set size effects across SOAs (i.e., additive effects of SOA and set size) would indicate sequential processing of response selection and visual attention. However, a significantly smaller set size effect at short SOA compared to long SOA (i.e., underadditive interaction of SOA and set size) would indicate parallel processing of response selection and visual attention. In both experiments, we found underadditive interactions of SOA and set size. In Experiments 3 and 4, the conjunction search display in Task 2 was masked. Task 1 was the same as in Experiments 1 and 2, respectively. In both experiments, the d' analysis revealed that response selection did not affect target detection. Overall, Experiments 1-4 indicated that neither the response selection difficulty in the auditory Task 1 (i.e., two-choice vs. four-choice) nor the type of presentation of the search display in Task 2 (i.e., not masked vs. masked) impaired parallel processing of response selection and conjunction search. We concluded that in general, response selection and visual attention (i.e., feature binding) rely on distinct capacity limitations. PMID- 28917015 TI - Metronome LKM: An open source virtual keyboard driver to measure experiment software latencies. AB - Experiment software is often used to measure reaction times gathered with keyboards or other input devices. In previous studies, the accuracy and precision of time stamps has been assessed through several means: (a) generating accurate square wave signals from an external device connected to the parallel port of the computer running the experiment software, (b) triggering the typematic repeat feature of some keyboards to get an evenly separated series of keypress events, or (c) using a solenoid handled by a microcontroller to press the input device (keyboard, mouse button, touch screen) that will be used in the experimental setup. Despite the advantages of these approaches in some contexts, none of them can isolate the measurement error caused by the experiment software itself. Metronome LKM provides a virtual keyboard to assess an experiment's software. Using this open source driver, researchers can generate keypress events using high-resolution timers and compare the time stamps collected by the experiment software with those gathered by Metronome LKM (with nanosecond resolution). Our software is highly configurable (in terms of keys pressed, intervals, SysRq activation) and runs on 2.6-4.8 Linux kernels. PMID- 28917008 TI - Peritoneal dialysis catheter function and survival are not adversely affected by obesity regardless of the operative technique used. AB - BACKGROUND: Obesity has been considered a relative contraindication to peritoneal dialysis (PD). Surprisingly, PD catheter dysfunction rates and longevity have not been studied in the growing obese ESRD population. The aim of this study was to determine the effect of patient weight on PD catheter survival in the three insertion technique categories of advanced laparoscopy (AL), basic laparoscopy (BL), and open. METHODS: We examine retrospectively collected data on 231 consecutive PD catheter insertions at the NorthShore University HealthSystem between 2004 and 2014. Three cohorts were created based on the catheter insertion technique: open, BL using selective adhesiolysis, and AL using rectus sheath tunnel, selective omentopexy, and adhesiolysis. Primary outcomes included catheter dysfunction and catheter dysfunction-free survival for each cohort by BMI: normal weight (18.5-24.9), overweight (25-29.9), obese (>=30). Nominal variables were compared using Chi-square test, continuous variables using ANOVA or Kruskal-Wallis tests, and catheter survival was assessed using the Kaplan Meier method with log-rank test. Statistical significance was established at 0.05. RESULTS: For the three BMI categories, there were no statistically significant differences in patient demographics. There were no statistically significant differences in catheter dysfunction or peri-operative complications by BMI category among all patients. This was also true in the AL cohort. Among all patients, similar 2-year dysfunction-free catheter survival was noted for normal weight, overweight, and obese patients (log-rank p = 0.79). This was also true across all insertion techniques: open (log-rank p = 0.87), BL (log-rank p = 0.41), AL (log-rank p = 0.43). In the obese cohort, the 2-year dysfunction-free catheter survival was 91.1% in AL, 83.5% in BL, and 65.7% in open (log-rank p = 0.58). CONCLUSION: Obesity does not increase complications or shorten dysfunction free PD catheter survival regardless of the operative technique used. Obesity should not be considered as a relative contraindication to PD catheter placement as it confers similar technique success to normal- and overweight individuals. PMID- 28917010 TI - Differences of alternative methods of measuring abdominal wall hernia defect size: a prospective observational study. AB - BACKGROUND: Despite the importance of defect size, there are no standardized recommendations on how to measure ventral hernias. Our aims were to determine (1) if any significant differences existed between various methods of measuring ventral hernias and (2) the effect of these methods of measurement on selection of mesh size. METHOD: A prospective study of all patients enrolled in a randomized trial assessing laparoscopic ventral hernia repair at a single institution from 3/2015 to 7/2016 was eligible for inclusion. Abdominal wall hernia defect size was determined by multiplying defect length and width obtained separately using each of five methods: radiographic (CT), intraoperative with abdomen desufflated, intraoperative with abdomen insufflated to 15 mmHg (intra abdominal aspect), intraoperative with abdomen insufflated to 15 mmHg (extra abdominal aspect), and clinical. The primary outcome was intraclass correlation between the five different methods of measurement for each patient. Secondary outcome was changes in mesh selection assuming a 5 cm overlap in each direction. RESULTS: Fifty patients met inclusion criteria for assessment. The five different measurement methods had an intraclass correlation for each patient of 0.533 (95% CI 0.373-0.697) (weak correlation) for length; 0.737 (95% CI 0.613-0.844) (moderate correlation) for width; and 0.684 (95% CI 0.544-0.810) (moderate correlation) for area. Different types of measurements affected mesh selection in up to 56% of cases. CONCLUSION: Among five common methods of measuring abdominal wall hernia defect, sizes are only weakly to moderately correlated. Further studies are needed to determine which method results in optimally sized abdominal wall prostheses and superior ventral hernia repair. PMID- 28917009 TI - Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time Controlled Release Etodolac Pellets. AB - The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis. PMID- 28917013 TI - Increasing Juniperus virginiana L. pollen in the Tulsa atmosphere: long-term trends, variability, and influence of meteorological conditions. AB - In the Tulsa area, the Cupressaceae is largely represented by eastern red cedar (Juniperus virginiana L.). The encroachment of this species into the grasslands of Oklahoma has been well documented, and it is believed this trend will continue. The pollen is known to be allergenic and is a major component of the Tulsa atmosphere in February and March. This study examined airborne Cupressaceae pollen data from 1987 to 2016 to determine long-term trends, pollen seasonal variability, and influence of meteorological variables on airborne pollen concentrations. Pollen was collected through means of a Burkard sampler and analyzed with microscopy. Daily pollen concentrations and yearly pollen metrics showed a high degree of variability. In addition, there were significant increases over time in the seasonal pollen index and in peak concentrations. These increases parallel the increasing population of J. virginiana in the region. Pollen data were split into pre- and post-peak categories for statistical analyses, which revealed significant differences in correlations of the two datasets when analyzed with meteorological conditions. While temperature and dew point, among others were significant in both datasets, other factors, like relative humidity, were significant only in one dataset. Analyses using wind direction showed that southerly and southwestern winds contributed to increased pollen concentrations. This study confirms that J. virginiana pollen has become an increasing risk for individuals sensitive to this pollen and emphasizes the need for long-term aerobiological monitoring in other areas. PMID- 28917012 TI - Operative and short-term oncologic outcomes of laparoscopic versus open liver resection for colorectal liver metastases located in the posterosuperior liver: a propensity score matching analysis. AB - BACKGROUND: Laparoscopic resection (LLR) of colorectal liver metastases (CRLM) located in the posterosuperior liver (segments 4a, 7, and 8) is challenging but has become more practical recently due to progress in operative techniques. We aimed to compare tumor-specific, perioperative, and short-term oncological outcomes after LLR and open liver resection (OLR) for CRLM. METHODS: Patients who underwent curative resection of CRLM with at least 1 tumor in the posterosuperior liver during 2012-2015 were analyzed. Tumor-specific factors associated with the adoption of LLR were analyzed by logistic regression model. One-to-one propensity score matching was used to match baseline characteristics between patients with LLR and OLR. RESULTS: The original cohort included 30 patients with LLR and 239 with OLR. Median follow-up time was 23.8 months. Logistic regression analysis showed that multiple, diameter >=30 mm, deep location, and closeness to major vessels were associated with OLR. None of the 24 patients with none or one of these factors were converted from LLR to OLR. After matching, 29 patients with LLR and 29 with OLR were analyzed. The 2 groups had similar preoperative factors. The LLR and OLR groups did not differ with respect to operative time, intraoperative bleeding, incidence of blood transfusion, surgical margin positivity, incidence of postoperative complications, and unplanned readmission within 45 days. Median length of postoperative hospital stay was significantly shorter for LLR versus OLR (4 days [1-12] vs. 5 days [4-18]; p = 0.0003). Median recurrence-free survival was similar for patients who underwent LLR versus OLR (10.6 months for LLR vs. 13.4 months for OLR; p = 0.87). CONCLUSIONS: Compared to OLR, LLR of posterosuperior CRLM is associated with significantly shorter postoperative hospital stay but otherwise similar perioperative and short-term oncological outcomes. Tumor-specific factors associated with safe and routine LLR approach despite challenging location are superficial, solitary, and small (<30 mm) CRLM not associated with major vessels. PMID- 28917016 TI - Predictors of outpatient resource utilization following ventral and incisional hernia repair. AB - INTRODUCTION: Little is known about the predictors of increased ambulatory costs following open ventral and incisional hernia repair (VIHR); however, postoperative complications would be expected to be associated with an increased burden on outpatient resources. The purpose of this study is to evaluate the impact of perioperative factors on outpatient resource utilization following VIHR. METHODS: With IRB approval, the surgery scheduling system was queried to identify all cases of VIHR done at our institution over 3 years. Cases with other procedures done at time of VIHR were excluded. National Surgical Quality Improvement Program clinical data, physician billing data which included market and payor across cases, and medical record review data were combined and evaluated in order to quantify care and predictors of usage during the 6 months postoperatively. RESULTS: Data were analyzed for 308 patients. Median patient age was 52 years (SD = 13.3), and over half were female. The number of outpatient visits to the surgical office varied from 0 to 18 [median = 2; interquartile range (IQR) = 1-3]. CDC Wound Class >1 was associated with increase of mean 1.4 visits (IQR: 0.5-2.3); p = 0.003. Component separation, longer duration of operation, and increased mesh size were also predictive of increased number of office visits (p < 0.01). Postoperative infected seroma/seroma requiring drainage added a mean 2.3 visits (IQR: 1.3-3.3), (p < 0.001); and deep wound infection added a mean 3.9 visits (IQR: 1.9-5.9) (p < 0.001). CONCLUSIONS: Postoperative complications confer a significant burden for patients and to the outpatient surgical office. In an era in which improved quality and cost-efficiency has become imperative, measures to decrease risk of postoperative complications particularly for more complex VIHR would be expected to decrease resource utilization and increase value of care. PMID- 28917018 TI - Temporal trends in utilization and outcomes of endoscopic retrograde cholangiopancreatography in acute cholangitis due to choledocholithiasis from 1998 to 2012. AB - BACKGROUND AND AIMS: Expeditious endoscopic retrograde cholangiopancreatography (ERCP) in acute cholangitis with biliary decompression is associated with better outcomes. In this study, we evaluated the temporal trends of ERCP utilization and healthcare outcomes among patients hospitalized with acute cholangitis due to choledocholithiasis (CDC) from 1998 to 2012. METHODS: We identified patients with a combined diagnosis of cholangitis and choledocholithiasis from the national inpatient sample database. The temporal trends of ERCP usage and outcomes were analyzed. Based on timing of the procedure, we arbitrarily divided ERCPs into urgent (<24 h), early(24-48 h), and delayed ERCP(>48 h) groups. In addition, trends in length of stay (LOS), hospital charges, and in-hospital mortality rates were evaluated. RESULTS: In-patient admissions for CDC increased by 105.7%. Overall ERCP rate also increased significantly from 66.5 +/- 2.3% in 1998 to 80.3 +/- 0.93% in 2012, particularly after 2006-2007. There was a significant increase in proportion of urgent and early ERCPs. In the early ERCP group, there was a significant decrease in LOS (6.4 +/- 0.43 days in 1998 to 5.8 +/- 0.24 days in 2012) and mortality rate (2.4 +/- 1.4% in 1998 to 0.33 +/- 0.33% in 2012). Hospital charges increased in all ERCP groups, but most significantly in delayed ERCP group ($20,448 +/- 1611 in 1998 to $90,566 +/- 6122 in 2012). CONCLUSION: In patient admissions for CDC and ERCP rates have increased significantly, particularly evident after 2006-2007. This may be attributed to increasing incidence of gallstones and wider implementation of Tokyo guidelines for the management of acute cholangitis. In-hospital morality and LOS reduced significantly in early ERCP group, whereas hospital charges increased most significantly in delayed ERCP group. PMID- 28917011 TI - Prevalence, predictors, and prognostic implications of PR interval prolongation in patients with heart failure. AB - AIMS: To determine the prevalence, incidence, predictors, and prognostic implications of PR interval prolongation in patients referred with suspected heart failure. METHODS AND RESULTS: Consecutive patients referred with suspected heart failure were prospectively enrolled. After excluding patients with implantable cardiac devices and atrial fibrillation, 1420 patients with heart failure and reduced ejection fraction (HeFREF) [age: median 71 (interquartile range IQR 63-78) years; men: 71%; NT-ProBNP: 1319 (583-3378) ng/L], 1094 with heart failure and normal ejection fraction (HeFNEF) [age: 76 (70-82) years; men: 47%; NT-ProBNP: 547 (321-1171) ng/L], and 1150 without heart failure [age: 68 (60 75) years; men: 51%; NT-ProBNP: 86 (46-140) ng/L] were included. The prevalence of first-degree heart block [heart rate corrected PR interval (PRc) > 200 ms] was higher in patients with heart failure (21% HeFREF, 20% HeFNEF, 9% without heart failure). In patients with HeFREF or HeFNEF, longer baseline PRc was associated with greater age, male sex, and longer QRS duration, and, in those with HeFREF, treatment with amiodarone or digoxin. Patients with heart failure in the longest PRc quartile had worse survival compared to shorter PRc quartiles, but PRc was not independently associated with survival in multivariable analysis. For patients without heart failure, shorter baseline PRc was independently associated with worse survival. CONCLUSION: PRc prolongation is common in patients with HeFREF or HeFNEF and associated with worse survival, although not an independent predictor of outcome. The results of clinical trials investigating the therapeutic potential of shortening the PR interval by pacing are awaited. PMID- 28917004 TI - Critical illness-associated diaphragm weakness. AB - Diaphragm weakness is highly prevalent in critically ill patients. It may exist prior to ICU admission and may precipitate the need for mechanical ventilation but it also frequently develops during the ICU stay. Several risk factors for diaphragm weakness have been identified; among them sepsis and mechanical ventilation play central roles. We employ the term critical illness-associated diaphragm weakness to refer to the collective effects of all mechanisms of diaphragm injury and weakness occurring in critically ill patients. Critical illness-associated diaphragm weakness is consistently associated with poor outcomes including increased ICU mortality, difficult weaning, and prolonged duration of mechanical ventilation. Bedside techniques for assessing the respiratory muscles promise to improve detection of diaphragm weakness and enable preventive or curative strategies. Inspiratory muscle training and pharmacological interventions may improve respiratory muscle function but data on clinical outcomes remain limited. PMID- 28917020 TI - Predicting opportunities to increase utilization of laparoscopy for rectal cancer. AB - BACKGROUND: Despite proven safety and efficacy, rates of laparoscopy for rectal cancer in the US are low. With reports of inferiority with laparoscopy compared to open surgery, and movements to develop accredited centers, investigating utilization and predictors of laparoscopy are warranted. Our goal was to evaluate current utilization and identify factors impacting use of laparoscopic surgery for rectal cancer. METHODS: The PremierTM Hospital Database was reviewed for elective inpatient rectal cancer resections (1/1/2010-6/30/2015). Patients were identified by ICD-9-CM diagnosis codes, and then stratified into open or laparoscopic approaches by ICD-9-CM procedure codes or billing charge. Logistic multivariable regression identified variables predictive of laparoscopy. The Cochran-Armitage test assessed trend analysis. The main outcome measures were trends in utilization and factors independently associated with use of laparoscopy. RESULTS: 3336 patients were included-43.8% laparoscopic (n = 1464) and 56.2% open (n = 1872). Use of laparoscopy increased from 37.6 to 55.3% during the study period (p < 0.0001). General surgeons performed the majority of all resections, but colorectal surgeons were more likely to approach rectal cancer laparoscopically (41.31 vs. 36.65%, OR 1.082, 95% CI [0.92, 1.27], p < 0.3363). Higher volume surgeons were more likely to use laparoscopy than low-volume surgeons (OR 3.72, 95% CI [2.64, 5.25], p < 0.0001). Younger patients (OR 1.49, 95% CI [1.03, 2.17], p = 0.036) with minor (OR 2.13, 95% CI [1.45, 3.12], p < 0.0001) or moderate illness severity (OR 1.582, 95% CI [1.08, 2.31], p < 0.0174) were more likely to receive a laparoscopic resection. Teaching hospitals (OR 0.842, 95% CI [0.710, 0.997], p = 0.0463) and hospitals in the Midwest (OR 0.69, 95% CI [0.54, 0.89], p = 0.0044) were less likely to use laparoscopy. Insurance status and hospital size did not impact use. CONCLUSIONS: Laparoscopy for rectal cancer steadily increased over the years examined. Patient, provider, and regional variables exist, with hospital status, geographic location, and colorectal specialization impacting the likelihood. However, surgeon volume had the greatest influence. These results emphasize training and surgeon-specific outcomes to increase utilization and quality in appropriate cases. PMID- 28917019 TI - The trend toward minimally invasive complex abdominal wall reconstruction: is it worth it? AB - BACKGROUND: Open abdominal wall reconstruction (AWR) was previously one of the only methods available to treat complex ventral hernias. We set out to identify the impact of laparoscopy and robotics on our AWR program by performing an economic analysis before and after the institution of minimally invasive AWR. METHODS: We retrospectively reviewed inpatient hospital costs and economic factors for a consecutive series of 104 AWR cases that utilized separation of components technique (57 open, 38 laparoscopic, 9 robotic). Patients were placed into two groups by date of procedure. Group 1 (Pre MIS) was July 2012-June 2015 which included 52 open cases. Group 2 (Post MIS) was July 2015-August 2016 which included 52 cases (5 open, 38 laparoscopic, 9 robotic). RESULTS: A total of 104 patients (52 G1 vs. 52 G2) with mean age (54.2 vs. 54.1 years, p = 0.960), BMI (34.7 vs. 32.1 kg/m2, p = 0.059), and ASA score (2.5 vs. 2.3, p = 0.232) were included in this review. Total length of stay (LOS) was significantly shorter for patients in the Post MIS group (5.3 vs. 1.4 days, p < 0.001). Although operating room (OR) supply costs were $1705 higher for the Post MIS group (p = 0.149), total hospital costs were $8628 less when compared to the Pre MIS group (p < 0.001). Multiple linear regressions identified increased BMI (p = 0.021), longer OR times (p = 0.003), and LOS (p < 0.001) as predictors of higher total costs. Factors that were predictive of longer LOS included older patients (p = 0.003) and patients with larger defect areas (p = 0.004). MIS was predictive of shorter hospital stays (p < 0.001). CONCLUSIONS: Despite an increase in operating room supply costs, transition to performing MIS AWR in cases that were previously done through an open approach decreased LOS and translated into significant overall total cost savings. PMID- 28917017 TI - Physiological Ripples (+/- 100 Hz) in Spike-Free Scalp EEGs of Children With and Without Epilepsy. AB - Pathological high frequency oscillations (HFOs, >80 Hz) are considered new biomarkers for epilepsy. They have mostly been recorded invasively, but pathological ripples (80-250 Hz) can also be found in scalp EEGs with frequent epileptiform spikes. Physiological HFOs also exist. They have been recorded invasively in hippocampus and neocortex. There are no reports of spontaneously occurring physiological HFOs recorded with scalp EEG. We aimed to study ripples in spike-free scalp EEGs. We included 23 children (6 with, 17 without epilepsy) who had an EEG without interictal epileptiform spikes recorded during sleep. We differentiated true ripples from spurious ripples such as filtering effects of sharp artifacts and high frequency components of muscle artifacts by viewing ripples simultaneously in bipolar and average montage and double-checking the unfiltered signal. We calculated mean frequency, duration and root mean square amplitude of the ripples, and studied their shape and distribution. We found ripples in EEGs of 20 out of 23 children (4 with, 16 without epilepsy). Ripples had a regular shape and occurred mostly on central and midline channels. Mean frequency was 102 Hz, mean duration 70 ms, mean root mean square amplitude 0.95 uV. Ripples occurring in normal EEGs of children without epilepsy were considered physiological; the similarity in appearance suggested that the ripples occurring in normal EEGs of children with epilepsy were also physiological. The finding that it is possible to study physiological neocortical ripples in scalp EEG paves the way for investigating their occurrence during brain development and their relation with cognitive functioning. PMID- 28917021 TI - Gynecologic cancer mortality in Trinidad and Tobago and comparisons of mortality to-incidence rate ratios across global regions. AB - PURPOSE: To examine the factors associated with gynecologic cancer mortality risks, to estimate the mortality-to-incidence rate ratios (MIR) in Trinidad and Tobago (TT), and to compare the MIRs to those of select countries. METHODS: Data on 3,915 incident gynecologic cancers reported to the National Cancer Registry of TT from 1 January 1995 to 31 December 2009 were analyzed using proportional hazards models to determine factors associated with mortality. MIRs for cervical, endometrial, and ovarian cancers were calculated using cancer registry data (TT), GLOBOCAN 2012 incidence data, and WHO Mortality Database 2012 data (WHO regions and select countries). RESULTS: Among the 3,915 incident gynecologic cancers diagnosed in TT during the study period, 1,795 (45.8%) were cervical, 1,259 (32.2%) were endometrial, and 861 (22.0%) were ovarian cancers. Older age, African ancestry, geographic residence, tumor stage, and treatment non-receipt were associated with increased gynecologic cancer mortality in TT. Compared to GLOBOCAN 2012 data, TT MIR estimates for cervical (0.49 vs. 0.53), endometrial (0.61 vs. 0.65), and ovarian cancers (0.32 vs. 0.48) were elevated. While the Caribbean region had intermediate gynecologic cancer MIRs, MIRs in TT were among the highest of the countries examined in the Caribbean region. CONCLUSIONS: Given its status as a high-income economy, the relatively high gynecologic cancer MIRs observed in TT are striking. These findings highlight the urgent need for improved cancer surveillance, screening, and treatment for these (and other) cancers in this Caribbean nation. PMID- 28917027 TI - Biophysics in Latin America. PMID- 28917022 TI - Epidemiology, pathogenesis, and management of takotsubo syndrome. AB - Takotsubo syndrome is a recently recognized acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. The typical takotsubo syndrome patient has a unique circumferential left (bi-) ventricular contraction abnormality profile that extends beyond a coronary artery supply territory and appears to follow the anatomical cardiac sympathetic innervation. The syndrome predominantly affects postmenopausal women and is often preceded by emotional or physical stress. Patients with predisposing factors such as malignancy and other chronic comorbidities are more prone to suffer from takotsubo syndrome. The pathogenesis of takotsubo syndrome is elusive. Several pathophysiological mechanisms involving myocardial ischemia (multivessel coronary artery spasm, microvascular dysfunction, aborted myocardial infarction), left ventricular outlet tract obstruction, blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomic nervous system dysfunction have been proposed. The syndrome is usually reversible; nevertheless, during the acute stage, a substantial number of patients develop severe complications such as arrhythmias, heart failure including pulmonary edema and cardiogenic shock, thromboembolism, cardiac arrest, and rupture. Treatment of precipitating factors, predisposing diseases, and complications is fundamental during the acute stage of the disease. The epidemiology, pathogenesis, and management of takotsubo syndrome are reviewed in this paper. PMID- 28917032 TI - CFS MATLAB toolbox: An experiment builder for continuous flash suppression (CFS) task. AB - CFS toolbox is an open-source collection of MATLAB functions that utilizes PsychToolbox-3 (PTB-3). It is designed to allow a researcher to create and run continuous flash suppression experiments using a variety of experimental parameters (i.e., stimulus types and locations, noise characteristics, and experiment window settings). In a CFS experiment, one of the eyes at a time is presented with a dynamically changing noise pattern, while the other eye is concurrently presented with a static target stimulus, such as a Gabor patch. Due to the strong interocular suppression created by the dominant noise pattern mask, the target stimulus is rendered invisible for an extended duration. Very little knowledge of MATLAB is required for using the toolbox; experiments are generated by modifying csv files with the required parameters, and result data are output to text files for further analysis. The open-source code is available on the project page under a Creative Commons License ( http://www.mikkonuutinen.arkku.net/CFS_toolbox/ and https://bitbucket.org/mikkonuutinen/cfs_toolbox ). PMID- 28917035 TI - SelGenAmic: An Algorithm for Selenoprotein Gene Assembly. AB - Computational methods for identifying selenoproteins have been developed rapidly in recent years. However, it is still difficult to identify the open reading frame (ORF) of eukaryotic selenoprotein gene, because the TGA codon for a selenocysteine (Sec) residue in the active center of selenoprotein is traditionally a terminal signal of protein translation. A gene assembly algorithm SelGenAmic has been constructed and presented in this chapter for identifying selenoprotein genes from eukaryotic genomes. A method based on this algorithm was developed to build an optimal TGA-containing-ORF for each TGA in a genome, followed by protein similarity analysis through conserved sequence alignments to screen out selenoprotein genes from these ORFs. This method improved the sensitivity of detecting selenoproteins from a genome due to the design that all TGAs in the genome were investigated for its possibility of decoding as a Sec residue. The method based on the SelGenAmic algorithm is capable of identifying eukaryotic selenoprotein genes from their genomes. PMID- 28917031 TI - The effect of propensity to trust and perceptions of trustworthiness on trust behaviors in dyads. AB - Research on trust has burgeoned in the last few decades. Despite the growing interest in trust, little is known about trusting behaviors in non-dichotomous trust games. The current study explored propensity to trust, trustworthiness, and trust behaviors in a new computer-mediated trust relevant task. We used multivariate multilevel survival analysis (MMSA) to analyze behaviors across time. Results indicated propensity to trust did not influence trust behaviors. However, trustworthiness perceptions influenced initial trust behaviors and trust behaviors influenced subsequent trustworthiness perceptions. Indeed, behaviors fully mediated the relationship of trustworthiness perceptions over time. The study demonstrated the utility of MMSA and the new trust game, Checkmate, as viable research methods and stimuli for assessing the loci of trust. PMID- 28917025 TI - Cardiac rehabilitation in patients who underwent primary percutaneous coronary intervention for acute myocardial infarction: determinants of programme participation and completion. AB - BACKGROUND: Hospital length of stay after acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (pPCI) has reduced, resulting in more limited patient education during admission. Therefore, systematic participation in cardiac rehabilitation (CR) has become more essential. We aimed to identify patient-related factors that are associated with participation in and completion of a CR programme. METHODS: We identified 3,871 consecutive AMI patients who underwent pPCI between 2003 and 2011. These patients were linked to the database of Capri CR, which provides dedicated, multi disciplinary CR. 'Participation' was defined as registration at Capri CR within 6 months after pPCI. CR was 'complete' if a patient undertook the final exercise test. RESULTS: In total, 1,497 patients (39%) were registered at Capri CR. Factors independently associated with CR participation included age (<50 vs. >70 year: odds ratio (OR) 7.0, 95% confidence interval (CI) 5.1-9.6), gender (men vs. women: OR 1.9, 95% CI 1.3-1.8), index diagnosis (ST-elevation myocardial infarction [STEMI] vs. non-ST-elevation myocardial infarction [NSTEMI]: OR 2.4, 95% CI 2.0-2.7) and socio-economic status (high vs. low: OR 2.0, 95% CI 1.6-2.5). The model based on these factors discriminated well (c-index 0.75). CR programme completion was 80% and was inversely related with diabetes, current smoking and previous MI. The discrimination of the model based on these factors was poor (c index 0.59). CONCLUSIONS: Only a minority of AMI/pPCI patients participated in a CR programme. Completion rates, however, were better. Increased physician and patient awareness of the benefits of CR are still needed, with focus on the elderly, women and patients with low socio-economic status. PMID- 28917023 TI - A new modification of the Duckett technique for one-stage repairing urethral plate transected hypospadias: Another option for severe hypospadias? AB - OBJECTIVES: The study aimed to evaluate the new modification of the Duckett technique in decreasing the incidence of urethral strictures for urethral plate transected hypospadias and also explored its clinical application. METHODS: Thirty-three patients (aged 7 months to 12 years, mean age 2.8 years) who underwent repair of primary hypospadias using the new one-stage urethroplasty were enrolled. Clinical data, including cosmetic and its complications, and uroflowmetry data were documented. Uroflowmetry data of 19 patients who underwent Duckett urethroplasty were used as a comparison. RESULTS: The length of the urethral defect ranged from 2.5 to 5.0 cm. The postoperative follow-up was 14-30 months. Ten patients (30.3%) had fistulas; no patients had strictures or diverticula. All ten fistulas were small (<0.5 cm) and repaired with fistula repairing operation. The appearance of the penis remained satisfactory, and the meatus was located in the normal anatomic position. Among 17 patients who underwent uroflowmetry, all patients were bell-shaped or platforms, and Q max was 7.37 +/- 2.45 ml/s. Compared with 14 of 19 patients who underwent Duckett urethroplasty, the urethral function achieved with new one-stage urethroplasty was significantly better (p < 0.05). CONCLUSIONS: The incidence of strictures was dramatically lowered in patients with proximal hypospadias. Small fistulas are common complications and can be repaired easily. Based on the uroflow pattern results, the quality of neourethra and function of it were better than Duckett urethroplasty. These preliminary results suggested that the modified procedure seems to be reliable and can be a suitable option for proximal hypospadias. PMID- 28917033 TI - SECISearch3 and Seblastian: In-Silico Tools to Predict SECIS Elements and Selenoproteins. AB - The computational identification of selenoprotein genes is complicated by the dual meaning of the UGA codon as stop and selenocysteine. SECIS elements are RNA structures essential for selenocysteine incorporation, which have been used as markers for selenoprotein genes in many bioinformatics studies. The most widely used tool for eukaryotic SECIS finding has been recently improved to its third generation, SECISearch3. This program is also a component of Seblastian, a pipeline for the identification of selenoprotein genes that employs SECIS finding as the first step. This chapter constitutes a practical guide to use SECISearch3 and Seblastian, which can be run via webservers at http://seblastian.crg.eu / or http://gladyshevlab.org/SelenoproteinPredictionServer/ . PMID- 28917030 TI - The Role of Intra-Session Exercise Sequence in the Interference Effect: A Systematic Review with Meta-Analysis. AB - BACKGROUND: There is a necessity for numerous sports to develop strength and aerobic capacity simultaneously, placing a significant demand upon the practice of effective concurrent training methods. Concurrent training requires the athlete to perform both resistance and endurance exercise within a training plan. This training paradigm has been associated with an 'interference effect', with attenuated strength adaptation in comparison to that following isolated resistance training. The effectiveness of the training programme rests on the intricacies of manipulating acute training variables, such as exercise sequence. The research, in the most part, does not provide a clarity of message as to whether intra-session exercise sequence has the potential to exacerbate or mitigate the interference effect associated with concurrent training methods. OBJECTIVE: The aim of the systematic review and meta-analysis was to assess whether intra-session concurrent exercise sequence modifies strength-based outcomes associated with the interference effect. METHODS: Ten studies were identified from a systematic review of the literature for the outcomes of lower body dynamic and static strength, lower-body hypertrophy, maximal aerobic capacity and body fat percentage. Each study examined the effect of intra-session exercise sequence on the specified outcomes, across a prolonged (>=5 weeks) concurrent training programme in healthy adults. RESULTS: Analysis of pooled data indicated that resistance-endurance exercise sequence had a positive effect for lower-body dynamic strength, in comparison to the alternate sequence (weighted mean difference, 6.91% change; 95% confidence interval 1.96, 11.87 change; p = 0.006), with no effect of exercise sequence for lower-body muscle hypertrophy (weighted mean difference, 1.15% change; 95% confidence interval -1.56, 3.87 change; p = 0.40), lower-body static strength (weighted mean difference, -0.04% change; 95% confidence interval -3.19, 3.11 change; p = 0.98), or the remaining outcomes of maximal aerobic capacity and body fat percentage (p > 0.05). CONCLUSION: These results indicate that the practice of concurrent training with a resistance followed by an endurance exercise order is beneficial for the outcome of lower-body dynamic strength, while alternating the order of stimuli offers no benefit for training outcomes associated with the interference effect. PMID- 28917026 TI - Venous Thromboembolism Rates in Transferred Patients: A Cross-Sectional Study. AB - BACKGROUND: Patients undergoing a transfer during a hospitalization may be more likely to be diagnosed with a venous thromboembolism (VTE) than patients who are not transferred. OBJECTIVE: To determine whether transferred patients have an increased prevalence of VTE diagnosis. DESIGN: This was a cross-sectional study comparing VTE diagnosis rates between transferred patients and non-transferred patients. For the years 2012-2014, the University HealthSystem Consortium database of multiple community and academic medical centers throughout the United States was parsed using ICD-9 VTE diagnosis codes and patient's point of origin. PATIENTS: Patients were included in the analysis as transferred patients if their point of origin was a skilled nursing facility, another acute care facility or another facility. Non-transferred patients were those whose point of origin was a clinic or those with a non-facility point of origin. MAIN MEASURES: The primary comparison of VTE prevalence during hospitalization between transferred and non transferred patients in the years 2012-2014. Subgroup analysis looked at level I trauma status and case mix index (CMI) to determine whether these had an effect on VTE prevalence. KEY RESULTS: From 2012 to 2014, a total of 225 unique hospitals and 12,036,029 patients were analyzed, and the prevalence of VTE in transferred patients and non-transferred patients was 3.43% and 1.91% (RR 1.80; 95% CI 1.78-1.81; P <0.001), respectively. VTE prevalence in transferred versus non-transferred patients at level I trauma centers was 3.42% versus 1.88% (RR = 1.82; 95% CI 1.80-1.85; P <0.001). The 3-year average CMI of transferred versus non-transferred patients was 3.53 versus 2.26 (P < 0.001). CONCLUSIONS: Transferred patients have a higher prevalence of VTE than non-transferred patients, regardless of level I trauma designation. Higher VTE rates in transferred versus non-transferred patients was minimally correlated with CMI. PMID- 28917038 TI - Specific Chemical Approaches for Studying Mammalian Ribosomes Complexed with Ligands Involved in Selenoprotein Synthesis. AB - Chemical approaches are very powerful tools for investigating the molecular structure and architecture of large ribonucleoprotein complexes involving ribosomes and other components of the translation system. Application of RNA nucleotide-specific and cross-linking reagents of a broad specificity range allows the researcher to obtain information on the sites of ligand binding to the ribosome and to each other as well as on the RNA rearrangements caused by the binding. Here, we describe specific chemical approaches including chemical probing and site-directed or bifunctional reagent-mediated cross-linking, which have been used for exploring the mechanism of selenocysteine insertion into a polypeptide chain by mammalian ribosomes. PMID- 28917034 TI - Selenoprofiles: A Computational Pipeline for Annotation of Selenoproteins. AB - Selenoproteins contain selenocysteine (Sec or U), the 21st amino acid, inserted in response to an in-frame UGA codon. UGA normally terminates translation, but in selenoprotein mRNAs it is recoded to specify Sec insertion. For this reason, standard gene prediction programs fail to predict Sec codons, and selenoproteins are usually misannotated in protein databases and genome projects. Selenoprofiles is a computational pipeline able to correctly annotate selenoprotein genes in genomic sequences. This program uses a SECIS-independent approach, based on homology searches, and employs curated built-in profile alignments for all known selenoprotein families. Selenoprofiles constitutes the most accurate method for predicting selenoprotein genes belonging to known families. PMID- 28917039 TI - In Vitro Translation Assays for Selenocysteine Insertion. AB - The molecular characterization of the protein and RNA factors that are required for Sec incorporation in mammals has been largely carried out using in vitro translation systems specifically modified for this purpose. This chapter outlines the various systems and modifications that have been used to decipher the mechanism of Sec incorporation. PMID- 28917029 TI - Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma. AB - PURPOSE: Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC. METHODS: A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment. RESULTS: Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities. CONCLUSIONS: Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC. PMID- 28917024 TI - Decreased percentage of peripheral naive T cells is independently associated with ischemic stroke in patients on hemodialysis. AB - PURPOSE: Cerebrovascular complications, including ischemic stroke, account for poor outcomes in patients on hemodialysis. T cell responses may be involved in the pathogenesis of ischemic stroke. We aimed to evaluate the role of naive T cells in development of ischemic stroke in patients on hemodialysis. METHODS: In this cross-sectional study, 156 patients on hemodialysis in our blood purification center were included. These patients were divided into the ischemic stroke (IS) group (61 cases) and non-ischemic stroke (non-IS) group (95 cases) according to a new diagnosis after initiation of hemodialysis. After being lysed with red blood cell lysis solution, peripheral blood was tested by flow cytometry to detect the expression of CD45RO and CCR7 in CD4 T and CD8 T cells. Correlation analysis and logistic regression analysis were conducted to identify potential independent risk factors for ischemic stroke. RESULTS: The percentage of peripheral naive T cells was lower in the IS group [median (interquartile range (IQR)) 13.9% (8.6-22.9%)] compared with the non-IS group [median (IQR) 22.7% (15.9-32.2%), P < 0.001]. Spearman correlation analysis showed that naive T cells were negatively associated with ischemic stroke (r = -0.308, P < 0.001). Multivariate logistic regression analysis showed that CD4 naive T cells had an independent negative association with ischemic stroke in patients on hemodialysis (odds ratio 0.933, 95% CI 0.883, 0.986; P = 0.013). CONCLUSION: A decrease in percentage of peripheral CD4 naive T cells is a risk factor for ischemic stroke in patients on hemodialysis. PMID- 28917037 TI - Identification and Characterization of Proteins that Bind to Selenoprotein 3' UTRs. AB - This chapter explains the use of RNase-assisted RNA chromatography. RNA affinity chromatography is a powerful technique that is used to isolate and identify proteins that bind to a specific RNA ligand. The RNA of interest is attached to beads before protein lysates are passed over the column. In traditional RNA chromatography, bound proteins are eluted with high salt or harsh detergent, which can also release proteins that are nonspecifically bound to the beads. To avoid this, a new method was developed in which RNases are used to cleave RNA from the beads, releasing only RNA binding proteins (RBPs) and leaving behind proteins that are bound to the beads (Michlewski and Caceres, RNA 16(8):1673 1678, 2010). This chapter will describe the isolation of proteins that bind specifically to the distal region of the Selenoprotein S 3' untranslated region (3' UTR). PMID- 28917040 TI - Studying Selenoprotein mRNA Translation Using RNA-Seq and Ribosome Profiling. AB - Deep sequencing of ribosome protected mRNA footprints, also called ribosome profiling or Ribo-Seq, is a relatively new methodology well suited to address questions regarding the mechanisms and efficiency of protein expression. Specifically, the ability of this technique to quantify ribosome abundance with codon resolution enables experiments aimed at studying many aspects of translation, including gene-specific translational efficiency, translation of regulatory upstream short open reading frames, sites of ribosome pausing, and most importantly for selenoproteins, the efficiency by which UGA codons are redefined to encode selenocysteine. Here, we describe a streamlined protocol that was developed in our lab to process mammalian tissue to produce the requisite matched ribosome profiling and RNA-Seq libraries for deep sequencing. PMID- 28917028 TI - Elastic and dynamic properties of membrane phase-field models. AB - Phase-field models have been extensively used to study interfacial phenomena, from solidification to vesicle dynamics. In this article, we analyze a phase field model that captures the relevant physical features that characterize biological membranes. We show that the Helfrich theory of elasticity of membranes can be applied to phase-field models, allowing to derive the expressions of the stress tensor, lateral stress profile and elastic moduli. We discuss the relevance and interpretations of these magnitudes from a phase-field perspective. Taking the sharp-interface limit we show that the membrane macroscopic equilibrium equation can be derived from the equilibrium condition of the phase field interface. We also study two dynamic models that describe the behaviour of a membrane. From the study of the relaxational behaviour of the membrane we characterize the relevant dynamics of each model, and discuss their applications. PMID- 28917036 TI - Selenocysteine tRNA[Ser]Sec, the Central Component of Selenoprotein Biosynthesis: Isolation, Identification, Modification, and Sequencing. AB - The selenocysteine (Sec) tRNA[Ser]Sec population consists of two isoforms that differ from each other by a single 2'-O-methylribosyl moiety at position 34 (Um34). These two isoforms, which are encoded in a single gene, Trsp, and modified posttranscriptionally, are involved individually in the synthesis of two subclasses of selenoproteins, designated housekeeping and stress-related selenoproteins. Techniques used in obtaining these isoforms for their characterization include extraction of RNA from mammalian cells and tissues, purifying the tRNA[Ser]Sec population by one or more procedures, and finally resolving the two isoforms from each other. Since some of the older techniques for isolating tRNA[Ser]Sec and resolving the isoforms are used in only a few laboratories, these procedures will be discussed briefly and references provided for more detailed information, while the more recently developed procedures are discussed in detail. In addition, a novel technique that was developed in sequencing tRNA[Ser]Sec for identifying their occurrence in other organisms is also presented. PMID- 28917041 TI - Modification of Selenoprotein mRNAs by Cap Tri-methylation. AB - Several selenoprotein mRNAs undergo 5' cap maturation events whereby their classical monomethylated m7G cap becomes trimethylated (m32,2,7G) by the trimethylguanosine synthase 1 (Tgs1). Here, we describe immunoprecipitation methods for the detection of endogenous m32,2,7G-capped selenoprotein mRNAs from total cell extracts or after polysome fractionation of cytoplasmic extracts. We have also developed a method for the in vitro cap hypermethylation of selenoprotein mRNA transcripts using purified Tgs1 enzyme. PMID- 28917043 TI - Quantification of SeMet and SeCys in Biological Fluids and Tissues by Liquid Chromatography Coupled to Inductively Coupled Plasma Mass Spectrometry (HPLC-ICP MS). AB - Selenium (Se) is an element readily absorbed during the intestinal tract and distributed in the body. In biological fluids, tissues, and animal products, Se is known to be present mainly in the form of a selenoamino-acid (selenomethionine (SeMet) or selenocysteine (SeCys)). Both amino-acids have different biological activities which justifies their discrimination. Here, we describe the method allowing the simultaneous determination of SeMet and SeCys in blood/plasma, animal tissues, milk, and eggs by two-dimensional Liquid Chromatography coupled to Inductively Coupled Plasma Mass Spectrometry (2D HPLC-ICP MS). PMID- 28917042 TI - Total Selenium Quantification in Biological Samples by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). AB - Selenium (Se) is an element readily absorbed during the intestinal tract, distributed in the body by means of blood and excreted mainly by urine or feces. Here, we describe the method allowing the determination of the total Se content in biological tissues and fluids by Inductively Coupled Plasma Mass Spectrometry (ICP MS). PMID- 28917046 TI - Nonradioactive Isotopic Labeling and Tracing of Selenoproteins in Cultured Cell Lines. AB - Selenium (Se) is an essential component of genetically encoded selenoproteins, in the form of a rare amino acid, namely the selenocysteine (Sec). Radioactive 75Se has been widely used to trace selenoproteins in vitro and in vivo (cell models and animals). Alternatively, its unique isotopic pattern can be used to detect and characterize nonradioactive Se-compounds in cellular extracts using molecular or elemental mass spectrometry at ppm levels. However, when studying trace levels of Se-compounds, such as selenoproteins (ppt levels), the distribution of the signal between its six naturally abundant isotopes reduces its sensitivity. Here, we describe the use of isotopically enriched forms of Se as an alternative strategy to radioactive 75Se, for the labeling and tracing of selenoproteins in cultured cell lines. PMID- 28917045 TI - Radioactive 75Se Labeling and Detection of Selenoproteins. AB - The trace element selenium (Se) is incorporated into proteins as the amino acid selenocysteine (Sec), which is cotranslationally inserted into specific proteins in response to a UGA codon. Proteins containing Sec at these specific positions are called selenoproteins. Most selenoproteins function as oxidoreductases, while some serve other important functions. There are 25 known selenoprotein genes in humans and 24 in mice. The use of Sec allows selenoproteins to be detected by a convenient method involving metabolic labeling with 75Se. Labeling of cells and whole animals are used for the examination of selenoprotein expression profiles and the investigation of selenoprotein functions. In mammals, nonspecific 75Se insertion is very low, and sensitivity and specificity of selenoprotein detection approaches that of Western blotting. This method allows for the examination of selenoprotein expression and Se metabolism in model and non-model organisms. Herein, we describe experimental protocols for analyzing selenoproteins by metabolic labeling with 75Se both in vitro and in vivo. As an example, the procedure for metabolic labeling of HEK293T human embryonic kidney cells is described in detail. This approach remains a method of choice for the detection of selenoproteins in diverse settings. PMID- 28917044 TI - Simultaneous Speciation of Selenoproteins and Selenometabolites in Plasma and Serum. AB - Selenium is an essential element incorporated to different proteins with important biological functions in connection to antioxidant activity, cancer protective properties, neurodegenerative pathologies, and prevention of effects of diabetes, among others. In addition, selenoamino acids play a basic role in the global equilibrium of key selenium-biomolecules synthesis, including selenoprotein P, selenoalbumin, and glutathione peroxidase. Homeostasis of these selenium-containing biomolecules involves different organs in living organisms including human, and bloodstream is the connection fluid in this process. Therefore, it is very important to have an analytical methodology suitable for selenium proteins and metabolites speciation in serum and plasma samples. For this purpose, a simultaneous speciation method for Se-containing biomolecules in serum/plasma is described on the basis of in series three-dimensional chromatography: size exclusion, affinity, and anion exchange high performance liquid chromatography (3D/SE-AF-AEC-HPLC), using different columns of each type and hyphenation to inductively coupled plasma-(quadrupole) mass spectrometry (ICP MS). The method allows the quantitative simultaneous analysis of selenoprotein P (SeP), extracellular glutathione peroxidase (eGPx), selenoalbumin (SeAlb), selenite, and selenate in serum (from human and mouse) using species-unspecific isotope dilution (SUID). In addition, a simplified two-dimensional approach (2D/SE-AF-HPLC-SUID-ICP-MS) is described when selenium metabolites are globally analyzed. The method provides detection limits in the range 0.2-1.3 ng of Se g-1 and avoids typical interferences in this matrix from chloride and bromide with a chromatographic runtime less than 35 min. PMID- 28917047 TI - Detection of Selenoproteins by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP MS) in Immobilized pH Gradient (IPG) Strips. AB - In contrast to other trace elements that are cofactors of enzymes and removed from proteins under denaturing conditions, Se is covalently bound to proteins when incorporated into selenoproteins, since it is a component of selenocysteine aminoacid. It implies that selenoproteins can undergo several biochemical separation methods in stringent and chaotropic conditions and still maintain the presence of selenium in the primary sequence. This feature has been used to develop a method for the detection of trace levels of human selenoproteins in cell extracts without the use of radioactive isotopes. The selenoproteins are separated as a function of their isoelectric point (pI) using iso-electrofocusing (IEF) electrophoretic strips and detected by laser ablation-inductively coupled plasma mass spectrometry (LA-ICP MS). This method, therefore referred to as IEF LA-ICP MS, allowed the detection of several selenoproteins in human cell lines, including Gpx1, Gpx4, TXNRD1, TXNRD2, and SELENOF. PMID- 28917048 TI - Imaging of Selenium by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) in 2-D Electrophoresis Gels and Biological Tissues. AB - Selenium and selenoproteins are important components of living organisms that play a role in different biological processes. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a powerful analytical technique that has been employed to obtain distribution maps of selenium in biological tissues in a direct manner, as well as in selenoproteins, previously separated by their molecular masses and isoelectric points using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). In this chapter, we present the protocols to perform LA-ICP-MS imaging experiments, allowing the distribution visualization and determination of selenium and/or selenoproteins in biological systems. PMID- 28917049 TI - Overexpression of Recombinant Selenoproteins in E. coli. AB - Expression of selenoproteins necessitates a process of decoding of a UGA codon from termination of translation to insertion of selenocysteine. The mechanisms of this process pose major challenges with regards to recombinant selenoprotein production in E. coli, which however can be overcome especially if the Sec residue is located close to the C-terminal end, as is the case for several naturally found selenoproteins. This chapter summarizes a method to achieve such a production. PMID- 28917050 TI - Preparation of Selenocysteine-Containing Forms of Human SELENOK and SELENOS. AB - Selenoprotein K (SELENOK) and Selenoprotein S (SELENOS) are the members of the endoplasmic-reticulum-associated degradation (ERAD) complex, which is responsible for translocating misfolded proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Besides its involvement in the ERAD, SELENOK was shown to bind and stabilize the palmitoyl transferase DHHC6, and thus contributes to palmitoylation. SELENOK and SELENOS reside in the ER membrane by the way of a single transmembrane helix. Both contain an intrinsically disordered region with a selenocysteine (Sec) located one or two residues away from the C-terminus. Here, we describe the preparation of the Sec-containing forms of SELENOS and SELENOK. SELENOK, which contains no native cysteines, was prepared in an E. coli cysteine auxotroph strain by exploiting the codon and the insertion machinery of Cys for the incorporation of Sec. In contrast, the preparation of SELENOS, which contains functionally important cysteine residues, relied on E. coli's native Sec incorporation mechanism. PMID- 28917052 TI - Monitoring of Methionine Sulfoxide Content and Methionine Sulfoxide Reductase Activity. AB - The sulfur-containing amino acid methionine (Met) plays critical roles in protein synthesis, methylation, and sulfur metabolism. Both in its free form and in the form of an amino acid residue, it can be oxidized to the R and S diastereomers of methionine sulfoxide (MetO). Organisms evolved methionine sulfoxide reductases (MSRs) to reduce MetO to Met, with the MSRs type A (MSRA) and type B (MSRB) being specific for the S and R forms of MetO, respectively. In mammals, the selenoprotein MSRB1 plays an important protein repair function, and its expression is tightly regulated by dietary selenium. In this chapter, we describe a protocol for determining the concentration of protein-based Met-R-O and its analysis in HEK293 cells using a genetically encoded ratiometric fluorescent biosensor MetROx. We also describe the procedure for quantifying MSR activities in cell extracts using specific substrates and a reverse phase HPLC-based method. PMID- 28917051 TI - Selenocysteine-Mediated Expressed Protein Ligation of SELENOM. AB - A sizeable fraction of the selenoproteome encodes oxidoreductases possessing a thioredoxin fold, a structural motif that is shared among a diverse group of enzymes. In these oxidoreductases, the active site is comprised of a cysteine and a selenocysteine separated by one to two amino acids. In a subset of these selenoproteins, such as human SELENOH, SELENOM, SELENOT, SELENOV, SELENOW, and SELENOF, this redox motif is positioned immediately after the first beta-sheet in a short loop, and is essential for interactions with its substrate or partners. Here, we describe the preparation of a representative member of this group, SELENOM, by selenocysteine-driven expressed protein ligation. The preparation employs a peptide bond formation between two protein fragments expressed recombinantly in E. coli. This method can be employed to prepare other selenoproteins. PMID- 28917053 TI - Selective Evaluation of Thioredoxin Reductase Enzymatic Activities. AB - Thioredoxin reductases are important oxidoreductases that keep the active site disulfide/dithiol motif of thioredoxins reduced using NADPH, thereby supporting many thioredoxin-dependent reductive pathways in cells. Mammalian thioredoxin reductases are selenoproteins that have several additional substrates beyond thioredoxins. This chapter first lists several different assays for measurement of thioredoxin reductase activities, before giving a protocol for a selective evaluation of these activities that can be used in either crude cell lysates as well as with purified enzymes. The same assay can also be easily adopted for the determination of thioredoxin activities. PMID- 28917054 TI - Association of Single Nucleotide Polymorphisms in Selenoprotein Genes with Cancer Risk. AB - Genetic association studies have linked genetic variants in the Selenium (Se) metabolism with the development of complex diseases such as cancer and helped unravel novel mechanisms underlying cancer development. The chapter describes the specificity of genetic variants in the Se metabolism, the approaches used in association studies, and the limitations of such approaches. PMID- 28917055 TI - Identification of Genetic Disorders Causing Disruption of Selenoprotein Biosynthesis. AB - Disorders of selenoprotein biosynthesis in humans, due to mutations in three genes (SECISBP2, TRU-TCA1-1, and SEPSECS) involved in the selenocysteine insertion pathway, have been described. Patients with SECISBP2 and TRU-TCA1-1 defects manifest a multisystem disorder with a biochemical signature of abnormal thyroid function tests due to the impaired activity of deiodinase selenoenzymes, myopathic features linked to SEPN1 deficiency and phenotypes resulting from increased levels of reactive oxygen species attributable to lack of antioxidant selenoenzymes. In patients harboring SEPSECS mutations, severe, progressive, cerebello-cerebral atrophy (pontocerebellar hypoplasia type 2D) dominates the phenotype and it is not known whether the disorder is associated with thyroid dysfunction. PMID- 28917056 TI - On the ambiguity of interaction and nonlinear main effects in a regime of dependent covariates. AB - The analysis of large experimental datasets frequently reveals significant interactions that are difficult to interpret within the theoretical framework guiding the research. Some of these interactions actually arise from the presence of unspecified nonlinear main effects and statistically dependent covariates in the statistical model. Importantly, such nonlinear main effects may be compatible (or, at least, not incompatible) with the current theoretical framework. In the present literature, this issue has only been studied in terms of correlated (linearly dependent) covariates. Here we generalize to nonlinear main effects (i.e., main effects of arbitrary shape) and dependent covariates. We propose a novel nonparametric method to test for ambiguous interactions where present parametric methods fail. We illustrate the method with a set of simulations and with reanalyses (a) of effects of parental education on their children's educational expectations and (b) of effects of word properties on fixation locations during reading of natural sentences, specifically of effects of length and morphological complexity of the word to be fixated next. The resolution of such ambiguities facilitates theoretical progress. PMID- 28917057 TI - The Fungal Tree of Life: from Molecular Systematics to Genome-Scale Phylogenies. AB - The kingdom Fungi is one of the more diverse clades of eukaryotes in terrestrial ecosystems, where they provide numerous ecological services ranging from decomposition of organic matter and nutrient cycling to beneficial and antagonistic associations with plants and animals. The evolutionary relationships of the kingdom have represented some of the more recalcitrant problems in systematics and phylogenetics. The advent of molecular phylogenetics, and more recently phylogenomics, has greatly advanced our understanding of the patterns and processes associated with fungal evolution, however. In this article, we review the major phyla, subphyla, and classes of the kingdom Fungi and provide brief summaries of ecologies, morphologies, and exemplar taxa. We also provide examples of how molecular phylogenetics and evolutionary genomics have advanced our understanding of fungal evolution within each of the phyla and some of the major classes. In the current classification we recognize 8 phyla, 12 subphyla, and 46 classes within the kingdom. The ancestor of fungi is inferred to be zoosporic, and zoosporic fungi comprise three lineages that are paraphyletic to the remainder of fungi. Fungi historically classified as zygomycetes do not form a monophyletic group and are paraphyletic to Ascomycota and Basidiomycota. Ascomycota and Basidiomycota are each monophyletic and collectively form the subkingdom Dikarya. PMID- 28917058 TI - Lineage tracing of genome-edited alleles reveals high fidelity axolotl limb regeneration. AB - Salamanders are unparalleled among tetrapods in their ability to regenerate many structures, including entire limbs, and the study of this ability may provide insights into human regenerative therapies. The complex structure of the limb poses challenges to the investigation of the cellular and molecular basis of its regeneration. Using CRISPR/Cas, we genetically labelled unique cell lineages within the developing axolotl embryo and tracked the frequency of each lineage within amputated and fully regenerated limbs. This allowed us, for the first time, to assess the contributions of multiple low frequency cell lineages to the regenerating limb at once. Our comparisons reveal that regenerated limbs are high fidelity replicas of the originals even after repeated amputations. PMID- 28917059 TI - Direct modulation of aberrant brain network connectivity through real-time NeuroFeedback. AB - The existence of abnormal connectivity patterns between resting state networks in neuropsychiatric disorders, including Autism Spectrum Disorder (ASD), has been well established. Traditional treatment methods in ASD are limited, and do not address the aberrant network structure. Using real-time fMRI neurofeedback, we directly trained three brain nodes in participants with ASD, in which the aberrant connectivity has been shown to correlate with symptom severity. Desired network connectivity patterns were reinforced in real-time, without participants' awareness of the training taking place. This training regimen produced large, significant long-term changes in correlations at the network level, and whole brain analysis revealed that the greatest changes were focused on the areas being trained. These changes were not found in the control group. Moreover, changes in ASD resting state connectivity following the training were correlated to changes in behavior, suggesting that neurofeedback can be used to directly alter complex, clinically relevant network connectivity patterns. PMID- 28917061 TI - Use of lipid emulsion therapy in local anesthetic overdose. AB - The use of intravenous lipid emulsion (ILE) therapy as antidote in systemic toxicity of certain agents has gained widespread support. There are increasing data suggesting use of ILE in reversing from local anesthetic-induced systemic toxicity severe, life-threatening cardiotoxicity, although findings are contradictory. Efficiency of ILE was demonstrated in animal studies in the treatment of severe impairment of cardiac functions, via a mechanism for trapping lipophilic drugs in an expanded plasma lipid compartment ("lipid sink"). In patients with hemodynamic compromise and/or cardiovascular collapse due to lipid soluble agents, ILE may be considered for resuscitation in the acute setting by emergency physicians. The most common adverse effects from standard ILE include hypertriglyceridemia, fat embolism, infection, vein irritation, pancreatitis, electrolyte disturbances and allergic reactions. The advantages of ILE include an apparent wide margin of safety, relatively low cost, long shelf-life, and ease of administration. PMID- 28917060 TI - Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase. AB - From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase. PMID- 28917062 TI - Wound infiltration with bupivacaine 0.5% with or without adrenaline does not decrease pain after thyroidectomy. A randomized controlled study. AB - OBJECTIVES: To study the effect of local wound infiltration with and without adrenaline on pain perception after thyroidectomy using the visual analog score (VAS). Methods: A prospective randomized controlled double-blinded study was conducted between May 2015 and June 2016 at The University of Jordan Hospital, Amman, Jordan. Eighty-nine patients undergoing planned thyroidectomy were included in the study. Patients were divided randomly into 3 groups: Group A, local wound infiltration with bupivacaine 0.5% was administered; Group B, bupivacaine 0.5% with adrenaline was administered; Group C (control), no infiltration was performed. Standardized thyroidectomies were performed in the 3 groups. Pain perception was measured using VAS at 2, 4, 6, 12, and 24 hours after surgery. A comparison between the 3 groups was carried out. Results: No significant differences among the 3 groups were observed at all time points (p=0.246). Visual analog scores were significantly lower at 12 and 24 hours after operations. Conclusion: Local wound infiltration with bupivacaine 0.5% does not decrease pain perception after thyroidectomy performed under general anesthesia, and adding adrenaline does not enhance its effect. PMID- 28917063 TI - Accuracy of preoperative fine needle aspiration in diagnosis of malignant parotid tumors. AB - OBJECTIVES: To determine the diagnostic accuracy of fine needle aspiration (FNA) for detecting malignant parotid tumors. Methods: We conducted a retrospective study of all patients diagnosed with benign or malignant parotid gland tumors in King Abdulaziz University Hospital, Jeddah, Saudi Arabia, between January 2004 and May 2015. The records of 65 subjects were obtained. Histopathological findings and data from FNA examinations were obtained from medical records. Twenty-three subjects were excluded due to missing FNA, histopathology results or both. The sensitivity, specificity, negative predictive value, and positive predictive value of FNA for detecting malignant lesions were estimated and compared with the gold standard, histopathology. Results: The specimens of 5 cases were insufficient for diagnosis; therefore, 38 cases were diagnosed by FNA and had histopathological reports. Three cases were diagnosed positive for cancer using histopathology and missed by FNA, 3 were diagnosed as malignant lesions using both FNA and histopathology, and 32 cases were determined benign based on histopathology and FNA analysis. The total prevalence of parotid malignancies was 15.8%. The sensitivity of FNA for detecting malignancy was 50%, and the specificity was 100%; with a positive predictive value of 100% and negative predictive value of 91.4%. Conclusion: Fine needle aspiration is a highly specific, but only moderately sensitive test. We support the use of this method as an initial tool for diagnosing parotid gland malignancies, as it is a safe, rapid, and painless procedure, compared to histopathology. PMID- 28917064 TI - A novel method for improving chest tube insertion skills among medical interns. Using biomaterial-covered mannequin. AB - OBJECTIVES: To develop a low-cost biomaterial-covered chest tube simulation model and assess its possible usefulness for developing the chest tube insertion skills among medical interns. Methods: This mannequin-based interventional study was performed in a University hospital setting. We included 63 physicians performing emergency medicine internship at the Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey, between January 2015 and March 2015. A dummy was prepared for training simulation using a display mannequin. Medical interns received instruction concerning pneumothorax and the chest tube procedure. A total of 63 medical interns participating in this interventional study were asked to insert a chest tube in a biomaterial-covered mannequin. A senior trainee scored their performance using a check list and the mean of the total scores was calculated (21 items; total score, 42). Results: The mean procedural score was 40.9 +/- 1.3 of a possible 42. The maximum score of 42 was achieved by 39.7% of the medical interns, while another 33.3% achieved a score of 41. Of the participants, 85% succeeded in inserting the tube via an appropriate technique, achieving a score of 40 or more. Conclusion: Our results indicated that this model could be useful for effective training of medical interns for chest tube insertion, which is an important skill in emergency medicine. This biomaterial covered model is inexpensive and its use can potentially be widened to improve training methods without significant financial demand. PMID- 28917065 TI - Diagnosis of mesenteric panniculitis in the multi-detector computed tomography era. Association with malignancy and surgical history. AB - OBJECTIVES: To assess the prevalence and associations of mesenteric panniculitis (MP) using multi-detector CT (MDCT). METHODS: This retrospective study included 4758 consecutive patients who underwent abdomino-pelvic MDCT between January 2012 and December 2014 at Jordan University Hospital, Amman, Jordan. Radiological database was searched for MP diagnosis and patients with suspected MP were re evaluated by an experienced radiologist to confirm the diagnosis. Data on all patients with confirmed MP diagnosis were subsequently collected and analyzed. RESULTS: Computed tomography features of MP were identified in 90 patients (41 males, 49 females), a prevalence of 1.9%. Mesenteric panniculitis was identified in both asymptomatic and symptomatic patients. Malignancy was found in 28 MP patients (31%) and 44 of the MP patients (49%) had prior history of abdomino pelvic surgery. Mesenteric panniculitis was significantly more frequently associated with prior abdomino-pelvic surgery (p=0.0001) and the likelihood of associated malignancy in patients with MP was 2.1-fold higher than in patients without MP (p=0.0013). Conclusion: Mesenteric panniculitis can be reliably diagnosed by MDCT due to its typical CT appearance. Its identification is important because of its significant association with malignancy and because it represents one of the differential diagnoses in patients with nonspecific symptoms referred for abdomino-pelvic CT. PMID- 28917066 TI - Effectiveness of the critical congenital heart disease screening program for early diagnosis of cardiac abnormalities in newborn infants. AB - OBJECTIVES: To evaluate the effectiveness of critical congenital heart disease (CCHD) screening program for early diagnosis of cardiac anomalies in newborn infants. Methods: This is a hospital-based prospective cross-sectional study conducted in the Pediatric and Neonatology Department, King Fahad Hospital at Albaha, Saudi Arabia, between February 2016 and February 2017. Results: We screened 2961 (95.4%) of 3103 patients in a nursery unit; 142 (4.6%) patients were not screened. The test was positive in 114 (3.9%) patients and negative in 2847 (96.1%). There were 94 (3.2%) false positives and 20 (0.7%) true positives. Critical cardiac defects were diagnosed in 7 (0.2%) patients of all screened infants, and severe pulmonary hypertension was diagnosed in 13 (0.4%) patients. True negative results were found in 2841(96%) patients, and no cardiac defect was diagnosed, whereas false negative results were seen in 6 (0.2%) patients diagnosed with ventricular septal defect. The sensitivity was 77%, and the specificity was very high at 97%, with a positive predictive value of 18%, and a negative predictive value of 99.8% (95% confidence interval 13.78-19.18, p=0.0001). Conclusion: Pulse oximetry was found to be easy, safe, sensitive, and highly specific for diagnosis of CCHD. PMID- 28917067 TI - Dengue fever. Clinical features of 567 consecutive patients admitted to a tertiary care center in Saudi Arabia. AB - OBJECTIVES: To delineate the clinical features and outcomes of dengue infection and to guide clinician of early diagnosis and identification of risks factors for dengue hemorrhagic fever. Methods: This study is a retrospective cross-sectional. Clinical records of 567 patients with a confirmed diagnosis of dengue infection, admitted to a single hospital in Jeddah, Saudi Arabia, between January 2010 and June 2014 were reviewed. Results: Dengue infection was most common in adult males. Sixty-eight percent of infections were in Saudi nationals. In addition to the diagnostic clinical features, leucopenia and thrombocytopenia were typical of dengue infection. Approximately 4.1% of adult patients and 7.1% of pediatric patients developed dengue hemorrhagic fever (DHF). Abdominal pain and vomiting were more common in patients developing DHF. Mean platelet count was lower in adult, but not pediatric patients developing DHF. Peak alanine aminotransferase (ALT) was higher in adult and pediatric patients developing DHF. Three patients died, 2 of them developed DHF. Ninety-eight percent of adult patients and 92% of pediatric patients made a full recovery. Conclusions: Dengue infection is common in Jeddah. Abdominal pain and vomiting, thrombocytopenia, and elevated ALT are typical of severe infection, which is more likely to be associated with significant morbidity and mortality. PMID- 28917069 TI - Knowledge, attitude and practice of antibiotic use and misuse among adults in Riyadh, Saudi Arabia. AB - OBJECTIVES: To assess the knowledge, attitude, and practice of antibiotics (ABs) use and misuse among adults living in Riyadh, Saudi Arabia. Methods: In this cross-sectional study, a self-administered questionnaire was distributed to participants from March 2016 to January 2017 in the outpatient department of King Khalid University Hospital and Dental Hospital, King Saud University, Riyadh, Saudi Arabia. The questionnaire was divided into 4 sections. The first and second section inquired regarding demographic details and knowledge of ABs. The third section assessed practice of ABs and the fourth section assessed attitude of participants towards ABs use. Questionnaires were hand delivered to respondents using convenience sampling. Statistical analysis using frequency distributions and knowledge responses of AB resistance for 'yes' and 'no' were associated with participant characteristics using Chi-square test. Results: A total of 1966 questionnaires were completed (response rate: 93.5%). Sixty-seven percent of the respondents were unaware of the meaning of ABs resistance. Sixty seven percent of respondents were unaware of ABs being harmful for children's teeth and 64.9% unaware of ABs that develop allergy and death. Twenty-four percent believed that ABs worked on viruses, 31% on cold and 21% can cure cough. Almost 51% used ABs without physician prescription while 37.5% obtained ABs directly from pharmacists without physician's prescription. Almost 42% participants discontinued ABs on alleviation of symptoms. There was significant difference in knowledge response of AB resistance and source of AB use (p=0.026), reason of AB use (p=0.038) and discontinuation of ABs (p=0.041). Conclusion: Adults showed insufficient knowledge and understanding regarding the safe use of ABs consumption among the population. PMID- 28917068 TI - Group A Streptococcal bacteraemia. Experience at King Fahad Medical City in Riyadh, Saudi Arabia. AB - OBJECTIVES: To identify clinical presentation, predisposing factors, and the outcome in patients with Group A Streptococcal bacteremia. Methods: This is a retrospective study of 33 pediatric and adult patients with Streptococcus pyogenes bacteremia, admitted at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia from 2007 to 2015. Results: Thirty-three patient records, documenting bacteremia with group A beta-hemolytic streptococcus, were reviewed. Approximately 51.5% were pediatric and 48.5% were adult patients, with a male to female ratio of 2:1. The most frequently reported complications were renal impairment (45.5%) and acute respiratory distress (21.2%), followed by localized infection (15.2%), pleural effusion (6.1%), abscess (9.1%), necrotizing fasciitis (9.1%), septic arthritis, and osteomyelitis (3%). There were 10 episodes of shock: 6 were in pediatric and 4 were in adult patients. At the end of the study period, 12.1% patients died from the illness, 81.1% recovered from illness with no sequelae, while 6.1% recovered with sequelae. Mortality was observed in 4 patients; of them, 3 were pediatric patients and one was an adult with co morbidities. Conclusions: We have noted a minimal change in the disease pattern over the 28 years in Saudi Arabia. The management of invasive GAS infection depends on an accurate and timely diagnosis with an appropriate use of antimicrobial therapy. The highest risks appear to be related to chronic illness. Invasive Group A Streptococcal infection is known to have a high mortality rate. PMID- 28917070 TI - Consumption and correlates of sweet foods, carbonated beverages, and energy drinks among primary school children in Saudi Arabia. AB - OBJECTIVES: To assess the consumption of sweets, carbonated beverages, and energy drinks along with their correlates among primary school children. Methods: A total of 725 children (7-12 years old) were randomly recruited from 10 elementary schools from Al-Baha city, Saudi Arabia in 2013, using a multi-stage stratified sampling technique and pre-tested validated questionnaire. Results: Approximately 26.1% of children reported consuming sweets on daily basis, and 63.4% consumed sweets occasionally during the week. Approximately 56.3%children were reportedly drinking carbonated beverages weekly and 17.1% in daily basis. Weekly consumption of energy drinks was reported in 21.9% and daily consumption in 4.3% of the children. Daily sweets consumption was positively associated with children age (odds ratio [OR]=1.5, 95% confidence interval [CI]: 4.5-9.5, p=0.035), consuming carbonated beverages (OR=3.4, 95% CI: 2.2-5.2, p less than 0.001), energy drinks (OR=2.5, 95% CI: 1.1-5.4, p=0.029), eating high fat food (OR= 1.6, 95% CI: 1.1 - 2.4, p=0.023), and inversely with children body mass index (BMI) (OR=0.9, 95% CI: 0.8-0.9, p less than 0.001). Consuming carbonated beverages on regular basis was positively associated with consuming energy drinks (OR=9.0, 95% CI: 4.0-21.0, p less than 0.001). Conclusion: Unhealthy dietary choices were found to be prevalent at early age. Comprehensive intervention programs should be established to prevent unhealthy dietary choices and promote healthier dietary behaviors. Qualitative studies are needed for better understanding of children's dietary behaviors. PMID- 28917071 TI - Quantitative evaluation of palatal bone thickness for the placement of orthodontic miniscrews in adults with different facial types. AB - OBJECTIVES: To quantitatively evaluate palatal bone thickness in adults with different facial types using cone beam computed tomography (CBCT). Methods: The CBCT volumetric data of 123 adults (mean age, 26.8 years) collected between August 2014 and August 2016 was retrospectively studied. The subjects were divided into a low-angle group (39 subjects), a normal-angle group (48 subjects) and a high-angle group (36 subjects) based on facial types assigned by cephalometric radiography. The thickness of the palatal bone was assessed at designated points. A repeated-measure analysis of variance (rm-ANOVA) test was used to test the relationship between facial types and palatal bone thickness. Results: Compared to the low-angle group, the high-angle group had significantly thinner palatal bones (p less than 0.05), except for the anterior-midline, anterior-medial and middle-midline areas. Conclusion: The safest zone for the placement of microimplants is the anterior part of the paramedian palate. Clinicians should pay special attention to the probability of thinner bone plates and the risk of perforation in high-angle patients. PMID- 28917072 TI - Primary extraskeletal mesenchymal chondrosarcoma arising from the iliac vein. AB - The iliac vein is an extremely rare site for mesenchymal chondrosarcoma, and patients with primary extraskeletal mesenchymal chondrosarcoma arising from a vein always suffer a very poor prognosis. We report a case of a 45-year-old female who presented with a 5-month history of left leg edema in 2015. Contrast enhanced computed tomography showed a large mass in the left iliac vein with scattered calcifications. Wide-margin resection was performed, and histopathologic and immunohistochemical analyses confirmed the presence of intraluminal mesenchymal chondrosarcoma with local invasion out of the vein wall. Due to poor patient compliance, postoperative neoadjuvant chemotherapy and radiotherapy were not started, and a bone scan performed 16 weeks postoperatively showed multiple bone metastases. The patient died on the twenty-fourth postoperative week. PMID- 28917073 TI - Effects of personality traits on collaborative performance in problem-based learning tutorials. AB - [No Abstract Available]. PMID- 28917074 TI - Editorial:Combination of Mass Spectrometry and Omics/Chemometrics Approaches to Unravel Bioactives in Natural Products Mixtures. PMID- 28917075 TI - Editorial: Structural Aspects of Protein Aggregation. PMID- 28917076 TI - Editorial: Impacts and Regulation of Dietary Nutrients on Gut Microbiome and Immunity. PMID- 28917077 TI - Pancreatic beta-Cells and Type 2 Diabetes Development. AB - Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia. In particular, type 2 diabetes (T2D) represents one of the main causes of death in the world, and those suffering from it have a lower quality of life. Although there are multiple hypotheses about the pathophysiological mechanisms that lead to the development of T2D, the effects of this pathology on pancreatic beta-cells are often ignored. We now know that in addition to genetic defects, beta-cell organellar dysfunction participates in the earliest stages of the disease; other factors also contribute to this dysfunction, such as excessive production of reactive oxygen species and a decrease in cellular volume and mass. These features usually result from increased apoptosis, which is not adequately compensated for by the characteristic regeneration mechanisms of these cells. In this study, we specifically examine the genetic, epigenetic and metabolic defects that contribute to beta-cell dysfunction and lead to the establishment of T2D, particularly the dysregulated insulin synthesis and secretion in these cells. PMID- 28917078 TI - Editorial: Management of Diabetes in Unique Populations. PMID- 28917079 TI - Insulin autoimmune syndrome (Hirata's disease) in an Italian patient: a case report and review of the literature. AB - We describe the case of a 54-year-old Caucasian Italian male experiencing episodes of hypoglycemia, occurring mainly after meals. He had never been exposed to insulin and was taking ramipril, flecainide and acetylsalicylic acid. An oral glucose tolerance test (OGTT) showed high blood glucose levels diagnostic for diabetes mellitus at 120 min and hypoglycemia with inappropriately high insulin levels at 240 min. The 72-h fasting test, abdominal computed tomography (CT) and positron emission tomography-CT were normal. Insulin autoantibodies were positive at high titers, prompting a diagnosis of insulin autoimmune syndrome (IAS). The patient was advised to take frequent, small meals and thus achieved a good control of his hypoglycemic symptoms. After 18 months of this dietary management, his insulin autoantibody levels decreased considerably but remained detectable. During an OGTT, his blood glucose levels at 120 min were now indicative of an impaired glucose tolerance rather than diabetes, and there was improvement in the glucose nadir. The patient had no other clinical or latent autoimmune diseases. Here we discuss the main features of IAS (also known as Hirata's disease) and review the cases of IAS reported in Italy to date. PMID- 28917080 TI - Hyperuricemia does not seem to be an independent risk factor for coronary heart disease. PMID- 28917081 TI - Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats. AB - BACKGROUND: Tramadol is prone to be abused alone, or in combination with 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats. METHODS: The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups. RESULTS: When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased. CONCLUSIONS: According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose. PMID- 28917082 TI - Protective effect of salusin-alpha and salusin-beta against ethanol-induced gastric ulcer in rats. AB - BACKGROUND: Alcohol consumption has been found to be associated with gastric ulcers, including gastric mucosal lesions. Salusin-alpha and salusin-beta are bioactive peptides having 28 and 20 amino acids, respectively. Salusin-alpha and salusin-beta immunoreactivity has been detected in the stomach and in the intestines. It has been reported that the salusins regulate the cytokine levels and decrease the infarct area in the heart tissue after ischemia. In this study, we investigated the effects of the salusins in the gastric injury formed with ethanol. METHODS: Thirty-two sprague Dawley male rats were randomly divided into four groups, including eight rats in each group as follows: Group 1: control; Group 2: ethanol 5 mL/kg; Group 3: ethanol 5 mL/kg+5 nmol/kg salusin-alpha; Group 4: ethanol 5 mL/kg+5 nmol/kg salusin-beta. RESULTS: The salusin-alpha level increased at a significant level in the ulcer group formed with ethanol (p<0.001); the change in the salusin-beta level is not significant. As for malondialdehyde (p<0.05) and myeloperoxidase (p<0.001), when compared with the control group, tumor necrosis factor-alpha (p<0.05) levels increased in the group to which ethanol was applied and decreased significantly with the application of salusins. Levels of GSH and IL-1beta did not change at a significant level. In addition, histopathologic analysis demonstrated that, in salusin-administered groups, mucosal injury and caspase-3 expressions were reduced. CONCLUSIONS: The suppression of salusin-alpha and salusin-beta on caspase-3 expression by means of their effects on oxidative injury and TNF-alpha levels shows that these two hormones could serve as anti-ulcerative agents. PMID- 28917083 TI - Effects of single or combined administration of salmon calcitonin and omega-3 fatty acids vs. diclofenac sodium in sodium monoiodoacetate-induced knee osteoarthritis in male Wistar rats. AB - BACKGROUND: There is a continuous search for a better therapy in osteoarthritis (OA) management. Therefore, this study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3) relative to diclofenac sodium (DF) in induced knee osteoarthritic male Wistar rats. METHODS: The 40 rats that were used in this study were divided into 8 groups (n=5 rats), viz: Normal control; OA control; OA+N-3; OA+Low dose of Sct (Sct.Lw); OA+High dose of Sct (Sct.Hi); OA+N-3+SCt.Lw; OA+N-3+Sct.Hi; and, OA+DF. OA was induced with 4 mg of sodium monoiodoacetate in 40 MUL of saline. The solution was injected into the left knee joint space of anaesthetised rats. Sct was administered at 2.5 and 5.0 IU/kg b.w. (im), whereas N-3 and DF were administered at 200 and 1 mg/kg b.w. (p.o.), respectively. Treatments commenced 9 days after the induction of OA, and they lasted for 28 days. RESULTS: Sct and/or N-3 significantly reduced c telopeptide of type 1 collagen (CTX-1), collagen type 2 alpha-1 (C2M), malondialdehyde (MDA), uric acid (UA), and interleukin-6 (IL-6), but, significantly increased superoxide dismutase (SOD) after OA induction. Both therapies had additive effects on C2M, MDA, SOD, and catalase (CAT), but, non additive actions on UA, IL-6, and CTX-1. Like the Sct and N-3, DF significantly reduced CTX-1, C2M, UA, and IL-6. However, it had no significant effect on SOD and MDA, even though it significantly reduced CAT activity. None of the therapies had significant effect on total alkaline phosphatase activity, except N-3+Sct.Lw. CONCLUSIONS: The combined, and sometimes the single administration of Sct and N-3 proved to be better therapies in OA management than DF. PMID- 28917084 TI - Evaluation of neurodevelopment of children with congenital hypothyroidism by the Denver Developmental Screening Test. AB - BACKGROUND: Thyroid hormones are essential for growth and brain development in childhood. Although congenital hypothyroidism (CH) is the most common reason for mental retardation, normal neurological development can be achieved through early and effective treatment. The aim of the present study was to evaluate the neurological development of CH patients aged 24-56 months. METHODS: The study included a total of 116 healthy control subjects and 112 patients aged 24-56 months who were diagnosed with CH during the neonatal period and were being followed up at the Pediatric Endocrinology Department, Kecioren Training and Research Hospital, between 2012 and 2015. Demographics and clinical data of interventions and outcomes were retrieved for each patient. Statistical analysis was performed using an unpaired Student's t-test to compare means and chi2 analysis to compare proportions. RESULTS: There were no significant differences between the CH and control groups with respect to gestational age, birth weight, height standard deviation scores (HSDS) and body weight standard deviation scores (BWSDS) (p>0.05). When the groups were compared according to the Denver Developmental Screening Test (DDST), no significant differences were found in terms of personal-social, fine motor skills, or language development (p=0.325, p=0.087 and p=0.636, respectively). However, a significant difference was found between the two groups with respect to gross motor development and the result of the DDST (p=0.001). No statistical difference was found between the control and patient groups on the day of starting treatment but the number of patients with an abnormal result in the DDST starting treatment at >15 days was found to be significantly higher than the number of patients starting treatment <=15 days. No associations were found between the DDST results of the CH group and the following factors: initial L-thyroxine (LT4) level, initial LT4 dose and the onset of treatment. CONCLUSIONS: The findings of this study indicate that the DDST results in patients with CH are generally good. Initiating treatment immediately after diagnosis and during the first days of life is absolutely imperative. However, in contrast to timing, we could not find strong evidence for determining the precise optimal dosage of LT4 to initiate treatment in children diagnosed with CH. Both the American Academy of Pediatrics and the European Society for Pediatric Endocrinology recommend 10-15 MUg/kg/day as the initial dose. PMID- 28917085 TI - A retrospective review of initial bisphosphonate infusion in an inpatient vs. outpatient setting for bisphosphonate naive patients. AB - BACKGROUND: The purpose of this study was to evaluate the safety and convenience of initial bisphosphonate infusion therapy in inpatient and outpatient settings for patients with low bone mineral density. METHODS: All data were collected from retrospective chart reviews of heterogeneous groups of patients. Abnormal findings prior to the infusion and side effects during the infusion were documented. Patients were contacted following the infusion to discuss post infusion adverse events. RESULTS: The majority of both outpatients (80%, n=44) and inpatients (50%, n=27) did not experience any adverse events related to the infusion. Some patients reported minor adverse events that were expected. Only one of the inpatients had a severe adverse event (SAE) after the infusion. CONCLUSIONS: For patients at low risk for severe reactions to treatment, the infusion center appears to be a safe and possibly more convenient treatment setting for both the patient and the hospital, although more expensive for the patient at our institution. PMID- 28917086 TI - Kostchyienones A and B, new antiplasmodial and cytotoxicity of limonoids from the roots of Pseudocedrela kotschyi (Schweinf.) Harms. AB - Two new limonoids, kostchyienones A (1) and B (2), along with 12 known compounds 3-14 were isolated from the roots of Pseudocedrela kostchyi. Compound (7) was isolated for the first time from a natural source. Their structures were elucidated on the basis of spectroscopic evidence. Compounds 1-6 and 13-14 gave IC50 values ranging from 0.75 to 5.62 MUg/mL for antiplasmodial activity against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum. Compound 5 showed moderate potential cytotoxicity against the HEK239T cell line with an IC50 value of 22.2+/-0.89 MUg/mL. The antiplasmodial efficacy of the isolated compounds supports the medicinal value of this plant and its potential to provide novel antimalarial drugs. PMID- 28917087 TI - Evaluation of Four Different Restorative Materials for Restoration of the Periodontal Condition of Wedge-Shaped Defect: A Comparative Study. AB - BACKGROUND This study aimed to conduct a clinical evaluation of four restorative materials for restoration of dental wedge-shaped defect (WSD) and their impacts on periodontal tissues. MATERIAL AND METHODS A total of 280 maxillary premolars with dental WSD were selected from 106 patients; the patient cases were divided into eight groups according to different combinations of restorative materials (flowable resin composites, Dyract compomers, glass ionomer cement (GIC), light curing composite resin), and WSD positions (approaching gingival and subgingival positions). Gingival crevicular fluid (GCF) volume, levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and interleukin-1beta (IL 1beta) in GCF were analyzed, while probing depth (PD), plaque index (PLI), and sulcus bleeding index (SBI) were also measured. The periodontal conditions of all patients were followed prior to restoration, as well as six months and 12 months after restoration. RESULTS After six months of restoration, the overall clinical success rates of flowable resin composites, Dyract compomers, and light-curing composite resin were greater than those of GIC. GCF volume, GCF-AST, IL-1beta levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. After 12 months of restoration, the overall clinical success rates of flowable resin composites and Dyract compomers were greater than those of light-curing composite resin and GIC. GCF volume, GCF-AST, GCF-ALP, IL-1beta levels, PD, PLI, and SBI of cases restored by GIC were higher than those restored by the other three materials. CONCLUSIONS Our study provided evidence that the clinical efficacy of flowable resin composites, Dyract compomers, and light-curing composite resin was greater than that of GIC for restoration of dental WSD. PMID- 28917088 TI - Depression, anxiety, PTSD and comorbidity in perinatal women in Turkey: A longitudinal population-based study. AB - OBJECTIVE: (a) to assess prevalence of depression, anxiety and post-traumatic stress disorder (PTSD) and their comorbidity among women during the perinatal period (b) to examine course of those disorders from pregnancy to 6 months postpartum (c) to determine the rates of new-onset cases at 4-6 weeks and 6 months postpartum. DESIGN: A longitudinal population-based study in which participants completed psychosocial measures of depression, anxiety and PTSD in pregnancy (n = 950), 4-6 weeks (n = 858) and 6 months (n = 829) after birth. SETTING: A consecutive sample of pregnant women were recruited from three maternity hospitals in three cities of Turkey: Istanbul, Ankara and Izmir. MEASURES: Edinburgh Postnatal Depression Scale (EPDS), Hospital Anxiety and Depression Scale (HADS), and Posttraumatic Diagnostic Scale (PDS) were used to assess depression, anxiety and PTSD, respectively. FINDINGS: Depression and PTSD peaked at 4-6 weeks postpartum and then fell at 6 months postpartum, whereas anxiety followed a gradually declining linear-pattern from pregnancy to 6 months postpartum. The prevalence of depression was 14.6% in pregnancy, 32.6% at 4-6 weeks and 18.5% at 6 months postpartum, respectively. The prevalence of PTSD was 5.8% in pregnancy, 11.9% at 4-6 weeks postpartum and 9.2% at 6 months postpartum. Anxiety was highest in pregnancy (29.6%) and then decreased to 24.6% 4-6 weeks after birth and to 16.2% 6 months after birth. New-onset cases were most apparent at 4-6 weeks postpartum: 24.6% for depression; 13.7% for anxiety and 8.9% for PTSD. KEY CONCLUSIONS: A relatively high prevalence of psychological disorders was identified during the perinatal period. Anxiety was most prevalent in pregnancy, and depression and PTSD were highest at 4-6 weeks postpartum. Depression was more common than anxiety 4-6 weeks and 6 months after birth and highly comorbid with anxiety throughout this period. New-onset cases were observed at both 4-6 weeks and 6 months postpartum. IMPLICATIONS: High rates of affective disorders in pregnancy and after birth highlight three main points: first, it is important to have effective perinatal screening to identify women with psychological needs; second, providing early treatment to women experiencing severe psychological problems is essential to ensure psychological well-being of those women and to prevent chronicity; and finally, psychosocial screening and interventions should be offered until at least 6 months after birth to catch new onset cases. PMID- 28917089 TI - The trehalose-specific transporter LpqY-SugABC is required for antimicrobial and anti-biofilm activity of trehalose analogues in Mycobacterium smegmatis. AB - Mycobacteria, including the bacterial pathogen that causes human tuberculosis, possess distinctive pathways for synthesizing and utilizing the non-mammalian disaccharide trehalose. Trehalose metabolism is essential for mycobacterial viability and has been linked to in vitro biofilm formation, which may bear relevance to in vivo drug tolerance. Previous research has shown that some trehalose analogues bearing modifications at the 6-position inhibit growth of various mycobacterial species. In this work, 2-, 5-, and 6-position-modified trehalose analogues were synthesized using our previously reported one-step chemoenzymatic method and shown to inhibit growth and biofilm formation in the two-to three-digit micromolar range in Mycobacterium smegmatis. The trehalose specific ABC transporter LpqY-SugABC was essential for antimicrobial and anti biofilm activity, suggesting that inhibition by monosubstituted trehalose analogues requires cellular uptake and does not proceed via direct action on extracellular targets such as antigen 85 acyltransferases or trehalose dimycolate hydrolase. Although the potency of the described compounds in in vitro growth and biofilm assays is moderate, this study reports the first trehalose-based mycobacterial biofilm inhibitors and reinforces the concept of exploiting unique sugar uptake pathways to deliver inhibitors and other chemical cargo to mycobacteria. PMID- 28917090 TI - Oleanane triterpenes with protein tyrosine phosphatase 1B inhibitory activity from aerial parts of Lantana camara collected in Indonesia and Japan. AB - During the search for new protein tyrosine phosphatase (PTP) 1B inhibitors, EtOH extracts from the aerial parts of Lantana camara L. (lantana) collected at Manado (Indonesia) and two subtropical islands in Japan (Ishigaki and Iriomote Islands, Okinawa) exhibited potent inhibitory activities against PTP1B in an enzyme assay. Four previously undescribed oleanane triterpenes were isolated together with known triterpenes and flavones from the Indonesian lantana. The EtOH extracts of lantana collected in Ishigaki and Iriomote Islands exhibited different phytochemical profiles from each other and the Indonesian lantana. Triterpenes with a 24-OH group were isolated from the Indonesian lantana only. Five known triterpene compounds were detected in the Ishigaki lantana, and two oleanane triterpenes with an ether linkage between 3beta and 25 were the main components together with five known triterpenes as minor components in the Iriomote lantana. The structures of previously undescribed compounds were assigned on the basis of their spectroscopic data. Among the compounds obtained in this study, oleanolic acid exhibited the most potent activity against PTP1B, and is used as a positive control in studies on PTP1B. PMID- 28917091 TI - Recovery from diabetes insipidus and preservation of thyroid function after craniopharyngioma removal and pituitary stalk sectioning. AB - OBJECTIVES: Craniopharyngioma is a slow-growing tumor, but long-term tumor control with maintenance of quality of life is sometimes very difficult to achieve, and hypothalamic disturbance should be strictly avoided in the treatment. However, management of the pituitary gland and/or pituitary stalk varies among surgeons and institutions. PATIENTS AND METHODS: This retrospective review identified 44 patients, 24 males and 20 females with craniopharyngiomas who were initially treated by surgery through the extended transsphenoidal approach with pituitary stalk sectioning at a single institute. If the tumor bed involved the posterior lobe of the pituitary gland, pituitary stalk, anterior and/or mid portion of the third ventricle floor, these structures were removed en bloc together with the tumor. The closest attention was paid to preserve fine arteries running along the surface of optic chiasm and the lateral walls of the third ventricle. Surgical outcome and changes in postoperative endocrinological status were investigated. RESULTS: Gross total removal was achieved in 40 of 44 patients (91%), and all patients could discharge without autonomic and/or thermal disturbances. Tumor remnants were identified with tight adhesion to the perforating arteries in 2 cases, tight adhesion to mammillary bodies in 1, and optic chiasm in 1. Administration of anti-diuretic hormone could be discontinued in 23 of 44 patients (52.3%) with improved diabetes insipidus (DI), although no patient could discontinue glucocorticoid administration. Preservation of thyroid function was achieved in another 23 of 44 patients (52.3%), and recovery from DI was correlated with preservation of thyroid function (p=0.016). CONCLUSION: Pituitary dysfunction is partially reversible even with pituitary stalk sectioning. Regrowth of tumor in the anterior and/or mid portion of the third ventricle floor including pituitary stalk can possibly be prevented by aggressive tumor removal, and co-achievement of long-term tumor control with maintenance of quality of life could be possible to preserve the lateral wall of the third ventricle. PMID- 28917094 TI - Local Postsynaptic Voltage-Gated Sodium Channel Activation in Dendritic Spines of Olfactory Bulb Granule Cells. PMID- 28917092 TI - Progressive halo-vest traction preceding posterior occipitocervical instrumented fusion for irreducible atlantoaxial dislocation and basilar invagination. AB - OBJECTIVES: Surgical treatment of irreducible atlantoaxial dislocation (IAAD) with basilar invagination (BI) is associated with high rates of severe complications, including mortality. This retrospective study investigated the safety and efficacy of progressive halo-vest traction for IAAD with BI prior to posterior occipitocervical instrumented fusion. PATIENTS AND METHODS: Between 2009 and 2013, 39 patients with IAAD with BI underwent preoperative reduction by progressive halo-vest traction for 20.82+/-4.21days. Instrumented fusion was then performed through a posterior approach. Clinical outcomes were based on pain scale and Japanese Orthopedic Association (JOA) scores. Radiographic analysis evaluated changes in atlantodental distance, McGregor's line violation, spinal canal width at the craniocervical junction, cervicomedullary angle, C2-C7 lordosis angle, and the occiput-C2 angle. RESULTS: Follow-ups ranged from 48 to 96 months. Both atlantodental distance and BI significantly improved in all patients. The rates of complete anatomical reduction were 85% for IAAD, and 95% for BI. Most of the patients reported satisfactory pain relief and improvement in daily activity; the mean JOA scores at baseline and last follow-up were 9.10 and 15.92, respectively. Although complications occurred in 10 patients (25.64%), all of which healed uneventfully. The bony fusion rate was 100%. CONCLUSION: Progressive halo-vest traction before surgery is safe and effective for reduction of IAAD with BI. The technique we describe is a promising method for treatment of complex craniocervical junction deformity. PMID- 28917093 TI - Molecular cloning and functional expression of the K+ channel KV7.1 and the regulatory subunit KCNE1 from equine myocardium. AB - BACKGROUND: The voltage-gated K+-channel KV7.1 and the subunit KCNE1, encoded by the KCNQ1 and KCNE1 genes, respectively, are responsible for termination of the cardiac action potential. In humans, mutations in these genes can predispose patients to arrhythmias and sudden cardiac death (SCD). AIM: To characterize equine KV7.1/KCNE1 currents and compare them to human KV7.1/KCNE1 currents to determine whether KV7.1/KCNE1 plays a similar role in equine and human hearts. METHODS: mRNA encoding KV7.1 and KCNE1 was isolated from equine hearts, sequenced, and cloned into expression vectors. The channel subunits were heterologously expressed in Xenopus laevis oocytes or CHO-K1 cells and characterized using voltage-clamp techniques. RESULTS: Equine KV7.1/KCNE1 expressed in CHO-K1 cells exhibited electrophysiological properties that are overall similar to the human orthologs; however, a slower deactivation was found which could result in more open channels at fast rates. CONCLUSION: The results suggest that the equine KV7.1/KCNE1 channel may be important for cardiac repolarization and this could indicate that horses are susceptible to SCD caused by mutations in KCNQ1 and KCNE1. PMID- 28917095 TI - Turning movements, vehicle offsets and ageing drivers driving behaviour at channelized and unchannelized intersections. AB - Ageing drivers experience a higher risk of intersection crashes because of their decrease in driving efficiency, including the decline in cognitive ability, head and neck flexibility, and visual acuity. Although several studies have been conducted to examine the factors associated with ageing driver crashes at intersections, little research has been conducted to examine the differences in the factors related to ageing drivers' turning paths and intersection geometric features. This study aims to improve the safety of ageing drivers at intersections by identifying the maneuvers that are risky for them and tracking their turning movements at selected intersections. We find that ageing drivers experience more crashes at intersections than younger drivers, especially crashes involving turning movements. Furthermore, ageing drivers experience more crashes at unchannelized intersections compared to channelized intersections. In addition, this study finds that ageing drivers exhibit greater and more inconsistent offsets during turning movements compared to those of younger drivers at both channelized and unchannelized intersections. Ageing drivers also tend to make relatively sharper or tighter turns than younger drivers. Hence, transportation engineers and road safety professionals should consider appropriate countermeasures to reduce the risks of crashes involving ageing drivers at intersections. PMID- 28917096 TI - How bicycle level of traffic stress correlate with reported cyclist accidents injury severities: A geospatial and mixed logit analysis. AB - Transportation agencies need efficient methods to determine how to reduce bicycle accidents while promoting cycling activities and prioritizing safety improvement investments. Many studies have used standalone methods, such as level of traffic stress (LTS) and bicycle level of service (BLOS), to better understand bicycle mode share and network connectivity for a region. However, in most cases, other studies rely on crash severity models to explain what variables contribute to the severity of bicycle related crashes. This research uniquely correlates bicycle LTS with reported bicycle crash locations for four cities in New Hampshire through geospatial mapping. LTS measurements and crash locations are compared visually using a GIS framework. Next, a bicycle injury severity model, that incorporates LTS measurements, is created through a mixed logit modeling framework. Results of the visual analysis show some geospatial correlation between higher LTS roads and "Injury" type bicycle crashes. It was determined, statistically, that LTS has an effect on the severity level of bicycle crashes and high LTS can have varying effects on severity outcome. However, it is recommended that further analyses be conducted to better understand the statistical significance and effect of LTS on injury severity. As such, this research will validate the use of LTS as a proxy for safety risk regardless of the recorded bicycle crash history. This research will help identify the clustering patterns of bicycle crashes on high-risk corridors and, therefore, assist with bicycle route planning and policy making. This paper also suggests low-cost countermeasures or treatments that can be implemented to address high risk areas. Specifically, with the goal of providing safer routes for cyclists, such countermeasures or treatments have the potential to substantially reduce the number of fatalities and severe injuries. PMID- 28917097 TI - Development of motor imagery and anticipatory action planning in children with developmental coordination disorder - A longitudinal approach. AB - Children with impaired motor coordination (or Development Coordination Disorder - DCD) have difficulty with the predictive control of movements, evidenced by cross sectional studies that show impaired motor imagery and action planning abilities. What remains unclear is whether this deficit in predictive control reflects immaturity of the motor system (a developmental delay) or some deviation from normal development (a disorder). To advance this discussion the present study used a longitudinal design to examine the development of motor imagery and action planning in children with DCD. Thirty children were included in the DCD group (aged 6-11years) and age- and gender-matched to 30 controls. The DCD group had a mABC-2 score<=16th percentile, the control group>20th percentile. Motor imagery was assessed with the hand rotation task, action planning with a test for end state comfort. Children participated in three measurements, with one year in between measurements. Results showed that children with DCD were slower and less accurate than their typically developing peers in all subsequent years but were able to improve their motor imagery ability over time. Furthermore, children with DCD showed less planning for ESC at the start of the present study, but were able to catch up with their peers during two-year follow up. These results exemplify that improvement of motor imagery and action planning ability is possible in DCD, and they lend theoretical support to the use of new training techniques that focus on training motor imagery to improve motor skills in children with DCD. PMID- 28917099 TI - A versatile bio-based material for efficiently removing toxic dyes, heavy metal ions and emulsified oil droplets from water simultaneously. AB - Developing versatile materials for effective water purification is significant for environment and water source protection. Herein, a versatile bio-based material (CH-PAA-T) was reported by simple thermal cross-linking chitosan and polyacrylic acid which exhibits excellent performances for removing insoluble oil, soluble toxic dyes and heavy metal ions from water, simultaneously. The adsorption capacities are 990.1mgg-1 for methylene blue (MB) and 135.9mgg-1 for Cu2+, which are higher than most of present advanced absorbents. The adsorption towards organic dyes possesses high selectivity which makes CH-PAA-T be able to efficiently separate dye mixtures. The stable superoleophobicity under water endows CH-PAA-T good performance to separate toluene-in-water emulsion stabilized by Tween 80. Moreover, CH-PAA-T can be recycled for 10 times with negligible reduction of efficiency. Such versatile bio-based material is a potential candidate for water purification. PMID- 28917100 TI - Assessment of fish scales waste as a low cost and eco-friendly adsorbent for removal of an azo dye: Equilibrium, kinetic and thermodynamic studies. AB - In this study, AB113 dye was successfully sequestered using a novel adsorbent made of mixed fish scales (MFS). The influence of adsorbent dosage, initial pH, temperature, initial concentration and contact time on the adsorption performance was investigated. The surface chemistry and morphology of the adsorbent were examined by FTIR, TGA and SEM. Amides, phosphate and carbonate groups were evidently responsible for the high affinity of MFS towards the dye. The adsorption equilibrium and kinetic were well described by Langmuir and pseudo second-order models, respectively. The maximum adsorption capacities of MFS were 145.3-157.3mg/g at 30-50 degrees C. The adsorption of AB113 dye onto the adsorbent was exothermic and spontaneous as reflected by the negative enthalpy and Gibbs energy changes. The results support MFS asa potential adsorbent for AB113 dye removal. PMID- 28917098 TI - Can attitudes about smoking impact cigarette cravings? AB - Cigarette cravings, especially those in response to environmental stressors and other smoking-related triggers (e.g., passing by a favorite smoking spot), are important contributors to smoking behavior and relapse. Previous studies have demonstrated significant individual differences in such cravings. This study explores the possibility that attitudes about smoking can influence the experience of cigarette craving. Consistent with classical theories of the links between cognition and motivation, we predicted that smokers who exhibit more favorable attitudes towards smoking would have greater cravings. Daily smokers (n=103, mean age=41.8years, 33% female) were instructed to imagine smoking, stress, and neutral scenarios. Cravings were measured prior to and after each exposure. Participants also completed an abridged version of the Smoking Consequence Questionnaire (SCQ) that had them rate the: 1) desirability and 2) likelihood, for eighteen separate negative smoking consequences (e.g., "The more I smoke, the more I risk my health", "People will think less of me if they see me smoking"). Findings revealed that favorable attitudes about the consequences of smoking, as measured by the SCQ-desirability index, significantly predicted cigarette cravings. Findings suggest that individual attitudes toward smoking may play an important role in better understanding cigarette cravings, which may ultimately help identify targets for more efficient and effective cognitive/attitude-based interventions for smoking cessation. PMID- 28917101 TI - Critical evaluation of post-consumption food waste composting employing thermophilic bacterial consortium. AB - Effect of single-function (oil degrading) and multi-functional bacterial consortium with zeolite as additive for post-consumption food waste (PCFW) composting was investigated through assessing the oil content reduction in a computer controlled 20-L composter. Three treatments of PCFWs combined with 10% zeolite were developed: Treatment-2 and Treatment-3 were inoculated with multi functional (BC-1) and oil degrading bacterial consortium (BC-2), respectively, while T-1 was without bacterial inoculation and served as control. Results revealed that BC-2 inoculated treatment (T-3) was superior to control treatment and marginally better than T-2 in terms of oil degradation. The reduction of oil content was >97.8% in T-3 and 92.27% in T-2, while total organic matter degradation was marginally higher in T-2 (42.95%) than T-3 (41.67%). Other parameters of compost maturity including germination test indicated that T-2 was marginally better than T-3 and significantly enhanced the oily PCFW decomposition and shortened the composting period by 20days. PMID- 28917102 TI - Performance evaluation and microbial community shift of a sequencing batch reactor under silica nanoparticles stress. AB - The performance, microbial community and enzymatic activity of a sequencing batch reactor (SBR) were evaluated at different silica nanoparticles (SiO2 NPs) concentrations. SiO2 NPs concentration at 5-30mg/L had a slight inhibitory impact on the nitrogen and COD removals, whereas the phosphorus removal was obviously inhibited at 30mg/L SiO2 NPs. The rates of nitrification, nitrite reduction and phosphorus removal decreased with the increase of SiO2 NPs concentration. The nitrate reduction rate decreased at less than 5mg/L SiO2 NPs and subsequently showed an increase at 10-30mg/L SiO2 NPs. The organic matter, nitrogen and phosphorus removal rates had similar varying tendencies to the corresponding microbial enzymatic activities under SiO2 NPs stress. Some SiO2 NPs were firstly absorbed on sludge surface and subsequently entered the interior of the microbial cells, which could exert the biological toxicity to activated sludge. The microbial community showed some obvious variations under SiO2 NPs stress. PMID- 28917103 TI - Isolation of a 2-picolinic acid-assimilating bacterium and its proposed degradation pathway. AB - Burkholderia sp. ZD1, aerobically utilizes 2-picolinic acid as a source of carbon, nitrogen and energy, was isolated. ZD1 completely degraded 2-picolinic acid when the initial concentrations ranged from 25 to 300mg/L. Specific growth rate (MU) and specific consumption rate (q) increased continually in the concentration range of 25-100mg/L, and then declined. Based on the Haldane model and Andrew's model, MUmax and qmax were calculated as 3.9 and 16.5h-1, respectively. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was used to determine the main intermediates in the degradation pathway. Moreover, attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) was innovatively used to deduce the ring cleavage mechanism of N heterocycle of 2-picolinic acid. To our knowledge, this is the first report on not only the utilization of 2-picolinic acid by a Burkholderia sp., but also applying FT-ICR-MS and ATR-FTIR for exploring the biodegradation pathway of organic compounds. PMID- 28917105 TI - Optimal conditions for flexible methane production in a demand-based operation of biogas plants. AB - The aim of the presented work was to study the methane production limits and to determine optimal conditions for flexible operation of an anaerobic reactor in order to set up an operational strategy. Punctual overloads were conducted in a laboratory-scale anaerobic reactor with readily biodegradable solid substrates, and the influences of overload intensity, baseload value and substrate used were investigated. A maximal daily value around 1000mL/L of reactor for methane production has been assessed. This value did not evolve significantly during experiment time, and conditioned the persistence of overloads as well as the flexibility margin on the reactor, which ranged from +25% to +140% on daily production. Results highlighted the fact that for a maximum flexibility, low organic loading rates are better to work with on this type of reactors. PMID- 28917104 TI - Bacteria and archaea communities in full-scale thermophilic and mesophilic anaerobic digesters treating food wastewater: Key process parameters and microbial indicators of process instability. AB - In this study, four different mesophilic and thermophilic full-scale anaerobic digesters treating food wastewater (FWW) were monitored for 1-2years in order to investigate: 1) microbial communities underpinning anaerobic digestion of FWW, 2) significant factors shaping microbial community structures, and 3) potential microbial indicators of process instability. Twenty-seven bacterial genera were identified as abundant bacteria underpinning the anaerobic digestion of FWW. Methanosaeta harundinacea, M. concilii, Methanoculleus bourgensis, M. thermophilus, and Methanobacterium beijingense were revealed as dominant methanogens. Bacterial community structures were clearly differentiated by digesters; archaeal community structures of each digester were dominated by one or two methanogen species. Temperature, ammonia, propionate, Na+, and acetate in the digester were significant factors shaping microbial community structures. The total microbial populations, microbial diversity, and specific bacteria genera showed potential as indicators of process instability in the anaerobic digestion of FWW. PMID- 28917106 TI - Cultivation of Scenedesmus acuminatus in different liquid digestates from anaerobic digestion of pulp and paper industry biosludge. AB - Different undiluted liquid digestates from mesophilic and thermophilic anaerobic digesters of pulp and paper industry biosludge with and without thermal pretreatment were characterized and utilized for cultivating Scenedesmus acuminatus. Higher S. acuminatus biomass yields were obtained in thermophilic digestates (without and with pretreatment prior to anaerobic digestion (AD): 10.2+/-2.2 and 10.8+/-1.2gL-1, respectively) than in pretreated mesophilic digestates (7.8+/-0.3gL-1), likely due to differences in concentration of sulfate, iron, and/or other minor nutrients. S. acuminatus removed over 97.4% of ammonium and 99.9% of phosphate and sulfate from the digestates. Color (74-80%) and soluble COD (29-39%) of the digestates were partially removed. Different AD processes resulted in different methane yields (18-126L CH4 kg-1VS), digestate compositions, and microalgal yields. These findings emphasize the importance of optimizing each processing step in wood-based biorefineries and provide information for pulp and paper industry development for enhancing value generation. PMID- 28917107 TI - Effects of coffee processing residues on anaerobic microorganisms and corresponding digestion performance. AB - The objective of this study was to delineate the effects of different coffee processing residues on the anaerobic microbes and corresponding digestion performance. The results elucidated that mucilage-rich feed enhanced the accumulation of methanogens, which consequently led to better digestion performance of biogas production. Fifty percent more methane and up to 3 times more net energy (heat and electricity) output were achieved by the digestion of the mucilage-rich feed (M3). The microbial community and statistical analyses further elucidated that different residues in the feed had significant impact on microbial distribution and correspondingly influenced the digestion performance. PMID- 28917108 TI - Accumulation of propionic acid during consecutive batch anaerobic digestion of commercial food waste. AB - The objective of this study was to test three different alternatives to mitigate the destabilizing effect of accumulation of ammonia and volatile fatty acids during food waste anaerobic digestion. The three options tested (low temperature, co-digestion with paper waste and trace elements addition) were compared using consecutive batch reactors. Although methane was produced efficiently (~500ml CH4gVS-1; 16l CH4lreactor-1), the concentrations of propionic acid increased gradually (up to 21.6gl-1). This caused lag phases in the methane production and eventually led to acidification at high substrate loads. The addition of trace elements improved the kinetics and allowed higher substrate loads, but could not avoid propionate accumulation. Here, it is shown for the first time that addition of activated carbon, trace elements and dilution can favor propionic acid consumption after its accumulation. These promising options should be optimized to prevent propionate accumulation. PMID- 28917109 TI - A beta-xylosidase hyper-production Penicillium oxalicum mutant enhanced ethanol production from alkali-pretreated corn stover. AB - beta-Xylosidase activity is deficient in most cellulase enzymes secreted by filamentous fungi, which limits effective enzymatic hydrolysis of hemicellulose in lignocellulose materials and resulted in accumulation of xylo-oligosaccharides that inhibit the cellulase and xylanase activitives. An endogenous beta xylosidase gene, xyl3A, was overexpressed using two types of promoters in cellulolytic P. oxalicum RE-10. The mutants RXyl, RGXyl-1 and RGXyl-2 displayed higher beta-xylosidase production than native strain RE-10 besides higher cellulase and xylanase activities, especially RGXyl-1, showing the highest beta xylosidase activity of 15.05+/-1.79IU/mL, about 29 folds higher than native strain, more than the highest level reported by literature. Enzymatic hydrolysis results indicated the cellulase RGXyl-1 not only increased glucose and xylose yields and thus resulted in high ethanol yield during the simultaneous saccharification and fermentation, but decreased the total enzyme loading compared to starting RE-10, which indicated a good prospect of industrial application in bioconversion of lignocellulose. PMID- 28917110 TI - Prevalence and predictors of potentially inappropriate prescribing of central nervous system and psychotropic drugs among elderly patients: A national population study in Korea. AB - OBJECTIVES: To investigate the prevalence of potentially inappropriate prescribing (PIP) of central nervous system and psychotropic (CNS-PS) drugs to the Korean elderly population, and to identify PIP-associated factors. METHODS: Ambulatory care visits were identified from the 2013 National Aged Patient Sample (HIRA-APS-2013) data, composed of 20% random samples of all enrollees in the universal health security program aged >=65 years. The CNS-PS section of Screening Tool of Older Person's potentially inappropriate Prescriptions (STOPP) criteria version 2 was used to identify PIP at these visits. RESULTS: A total of 24,427,069 prescription claims records and 1,122,080 patients were included in the study; 10.73% of the claims and 53.64% of the patients satisfied at least one STOPP criterion in the prescription of CNS-PS drugs. The highest prevalence of PIP was observed for the criteria of "first-generation antihistamines" (FGAH), followed by tricyclic antidepressants (TCA) in patients with prostatism and TCA in patients with dementia. The generalized estimating equation logistic regression analysis showed that the PIP of FGAH was significantly associated with polypharmacy (5-9 drugs: odds ratio (OR) 4.965, 95% confidence interval (CI) 4.936-4.994; >=10 drugs: OR 5.704, 95% CI 5.604-5.807), less severe health conditions (Charlson Comorbidity Index (CCI)=2: OR 0.852, 95% CI 0.842-0.862; CCI=1: OR 0.975, 95% CI 0.964-0.986), prescriptions from clinics (OR>1.0), and outpatient care by general practitioners (OR>1.0). CONCLUSIONS: Appropriate interventions to reduce PIP should be made, especially for the criteria that indicate a high PIP prevalence. Targeted strategies are necessary to modify the risk factors of PIP identified from this study. PMID- 28917111 TI - [11C]PF-3274167 as a PET radiotracer of oxytocin receptors: Radiosynthesis and evaluation in rat brain. AB - INTRODUCTION: Oxytocin plays a major role in the regulation of social interactions in mammals by interacting with the oxytocin receptor (OTR) expressed in the brain. Furthermore, the oxytocin system appears as a possible therapeutic target in autism spectrum disorders and other psychiatric troubles, justifying current pharmacological researches. Since no specific PET radioligand is currently available to image OTR in the brain, the aim of this study was to radiolabel the specific OTR antagonist PF-3274167 and to evaluate [11C]PF-3274167 as a potential PET tracer for OTR in rat brains. METHODS: [11C]PF-3274167 was prepared via the O-methylation of its desmethyl precursor with [11C]methyl iodide. The lipophilicity of the radioactive compound was evaluated by measuring the n-octanol-buffer partition coefficient (logD). Autoradiography experiments were performed on rat brain tissue to evaluate the in vitro distribution of the [11C]PF-3274167. MicroPET experiments were conducted with and without pre injection of ciclosporin in order to evaluate the influence of the P-glycoprotein (P-gp) on the brain uptake. RESULTS: [11C]PF-3274167 was synthesized with high radiochemical and chemical purities (>95%) and good specific activity. The measured logD was 1.93. In vitro, [11C]PF-3274167 did not show any evidence of specific binding to OTR. PET imaging showed that [11C]PF-3274167 uptake in rat brain was very low in basal conditions but increased significantly after the administration of ciclosporin, suggesting that it is a substrate of the P-gp. In the ciclosporin-pre-injected rat, however, [11C]PF-3274167 distribution did not match with the known distribution of OTR in rats. CONCLUSION: [11C]PF-3274167 is not a suitable tracer for imaging of OTR in rat brain, probably because of a too low affinity for this receptor in addition to a poor brain penetration. PMID- 28917112 TI - Paraneuraxial Nerve Blocks: A well-defined novel terminology that is clinically essential for regional anesthesia. PMID- 28917113 TI - Coagulation and complement in antiphospholipid syndrome. PMID- 28917114 TI - Prolonged anticoagulant treatment in patients with cancer: Where do we stand? PMID- 28917116 TI - Thermal- and photo-induced degradation of perfluorinated carboxylic acids: Kinetics and mechanism. AB - Perfluorinated carboxylic acids (PFCAs) of different carbon chain lengths are chemicals of concern to human health and their removal, using conventional remediation technologies, is challenging. The present paper pursuits thermal and photo-induced degradation of PFCAs (F(CF2)nCOOH, n = 1-9) under various concentrations of four different acids (HNO3, H2SO4, HCl, and H3PO4) covering a range of strong acidic to basic pH. For thermal-induced experiments, the temperature was set at 40 degrees C, 60 degrees C, and 80 degrees C at acid strengths of 0.04-18.4 M. Photo-induced experiments were conducted at pH 0.5, 7.0, and 13.0 under a light intensity of (150 +/- 10) * 100 MUW/cm2. The degradation first-order rate constant (k1, h-1) as a function of [H+] was modeled by considering equilibrium of nondissociated (F(CF2)nCOOH, HX) and dissociated (F(CF2)nCOO-, X-) species of PFCAs (HX ? X- + H+, pKa = -0.1). Species-specific rate constants, k1HX, reasonably described the trend of thermal and photo decay of PFCAs, where k1HX increased with acidity of solution and the carbon chain length of PFCAs. Mechanism of degradation of PFCAs (e.g. perfluorooctanoic acid (PFOA)) involved homolytic breakage of CC bond between alkyl and carboxyl groups, which produced radicals and subsequently decarboxylation to perfluoroheptene-1. Density functional theory (DFT) calculations supported the mechanism. The calculations indicated that a breaking of CC bond is more feasible with nondissociated HX than dissociated X- species of PFCAs and also with increase in chain length. The potential of a combination of thermal- and photo-induced processes under acidic conditions to enhance degradation of PFOA in water is presented. PMID- 28917115 TI - Comparisons of depression, anxiety, well-being, and perceptions of the built environment amongst adults seeking social, intermediate and market-rent accommodation in the former London Olympic Athletes' Village. AB - The Examining Neighbourhood Activities in Built Living Environments in London (ENABLE London) study provides a unique opportunity to examine differences in mental health and well-being amongst adults seeking social, intermediate (affordable rent), and market-rent housing in a purpose built neighbourhood (East Village, the former London 2012 Olympic Athletes' Village), specifically designed to encourage positive health behaviours. Multi-level logistic regression models examined baseline differences in levels of depression, anxiety and well-being across the housing groups. Compared with the intermediate group, those seeking social housing were more likely to be depressed, anxious and had poorer well being after adjustment for demographic and health status variables. Further adjustments for neighbourhood perceptions suggest that compared with the intermediate group, perceived neighbourhood characteristics may be an important determinant of depression amongst those seeking social housing, and lower levels of happiness the previous day amongst those seeking market-rent housing. These findings add to the extensive literature on inequalities in health, and provide a strong basis for future longitudinal work that will examine change in depression, anxiety and well-being after moving into East Village, where those seeking social housing potentially have the most to gain. PMID- 28917117 TI - Anaerobic granular sludge for simultaneous biomethanation of synthetic wastewater and CO with focus on the identification of CO-converting microorganisms. AB - CO is a main component of syngas, which can be produced from the gasification of organic wastes and biomass. CO can be converted to methane by anaerobic digestion (AD), however, it is still challenging due to its toxicity to microorganisms and limited knowledge about CO converting microorganisms. In the present study, anaerobic granular sludge (AGS) was used for the simultaneous biomethanation of wastewater and CO. Batch experiments showed that AGS tolerated CO partial pressure as high as 0.5 atm without affecting its ability for synthetic wastewater degradation, which had higher tolerance of CO compared to suspended sludge (less than 0.25 atm) as previously reported. Continuous experiments in upflow anaerobic sludge blanket (UASB) reactors showed AGS could efficiently convert synthetic wastewater and CO into methane by applying gas-recirculation. The addition of CO to UASB reactor enhanced the hydrogenotrophic CO-oxidizing pathway, resulted in the increase of extracellular polymeric substances, changed the morphology of AGS and significantly altered the microbial community compositions of AGS. The microbial species relating with CO conversion and their functions were revealed by metagenomic analysis. It showed that 23 of the 70 reconstructed genome bins (GBs), most of which were not previously characterized at genomic level, were enriched and contained genes involved in CO conversion upon CO addition. CO-converting microorganisms might be taxonomically more diverse than previously known and have multi-functions in the AD process. The reductive tricarboxylic acid (TCA) cycle in combination with the oxidation of the CO was probably crucial for CO utilization by the majority of the GBs in the present study. PMID- 28917119 TI - A mechanistic model for drug release from PLGA-based drug eluting stent: A computational study. AB - Atherosclerosis in the coronary artery is one of the leading causes of death in the world. The stenting as a minimally invasive technique was considered as an effective tool to reduce the severity of atherosclerotic stenosis. In-stent restenosis is the main drawback of the stenting in the coronary artery. Understanding the mechanism of drug release from drug-eluting stents and drug uptake in the arterial wall and obtaining more information about their functionality using mathematical modeling and numerical simulation, could be considered as a predictive tool to investigate in-stent restenosis growth which is experimentally expensive to study. In this work, the local delivery of a therapeutic agent from a PLGA-based bioabsorbable stent implanted in a coronary artery to predict the drug release as well as spatio-temporal drug distribution in a coronary artery with a vulnerable plaque is mathematically modeled and numerically simulated. The effect of copolymer ratio on drug release has been also investigated. PMID- 28917118 TI - Calibration of the comprehensive NDHA-N2O dynamics model for nitrifier-enriched biomass using targeted respirometric assays. AB - The NDHA model comprehensively describes nitrous oxide (N2O) producing pathways by both autotrophic ammonium oxidizing and heterotrophic bacteria. The model was calibrated via a set of targeted extant respirometric assays using enriched nitrifying biomass from a lab-scale reactor. Biomass response to ammonium, hydroxylamine, nitrite and N2O additions under aerobic and anaerobic conditions were tracked with continuous measurement of dissolved oxygen (DO) and N2O. The sequential addition of substrate pulses allowed the isolation of oxygen-consuming processes. The parameters to be estimated were determined by the information content of the datasets using identifiability analysis. Dynamic DO profiles were used to calibrate five parameters corresponding to endogenous, nitrite oxidation and ammonium oxidation processes. The subsequent N2O calibration was not significantly affected by the uncertainty propagated from the DO calibration because of the high accuracy of the estimates. Five parameters describing the individual contribution of three biological N2O pathways were estimated accurately (variance/mean < 10% for all estimated parameters). The NDHA model response was evaluated with statistical metrics (F-test, autocorrelation function). The 95% confidence intervals of DO and N2O predictions based on the uncertainty obtained during calibration are studied for the first time. The measured data fall within the 95% confidence interval of the predictions, indicating a good model description. Overall, accurate parameter estimation and identifiability analysis of ammonium removal significantly decreases the uncertainty propagated to N2O production, which is expected to benefit N2O model discrimination studies and reliable full scale applications. PMID- 28917120 TI - Automated arteriole and venule classification using deep learning for retinal images from the UK Biobank cohort. AB - The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image. PMID- 28917122 TI - Structure determination based on continuous diffraction from macromolecular crystals. AB - Bright and coherent X-ray sources, such free-electron lasers, have spurred large activities in developing new methods to obtain the structures of biological macromolecules. In particular, single-molecule diffraction is highly desired, as it would abolish the need for crystallization. It provides considerably more diffraction intensity information than needed to solve a structure, unlike crystal diffraction, which is usually insufficient for direct phasing. To overcome the challenge of weak scattering signals of single molecules, the direct phasing approaches in coherent diffractive imaging have been combined with crystals in several imaginative ways. One of these, using crystals with translational disorder, has been used to phase continuous femtosecond X-ray diffraction data from photosystem II complexes, offering a paradigm shift in crystallography. PMID- 28917121 TI - A formal description of middle ear pressure-regulation. AB - INTRODUCTION: Middle ear (ME) pressure-regulation (MEPR) is a homeostatic mechanism that maintains the ME-environment pressure-gradient (MEEPG) within a range optimized for "normal" hearing. OBJECTIVE: Describe MEPR using equations applicable to passive, inter-compartmental gas-exchange and determine if the predictions of that description include the increasing ME pressure observed under certain conditions and interpreted by some as evidencing gas-production by the ME mucosa. METHODS: MEPR was modeled as the combined effect of passive gas-exchanges between the ME and: perilymph via the round window membrane, the ambient environment via the tympanic membrane, and the local blood via the ME mucosa and of gas flow between the ME and nasopharynx during Eustachian tube openings. The first 3 of these exchanges are described at the species level using the Fick's diffusion equation and the last as a bulk gas transfer governed by Poiseuille's equation. The model structure is a time-iteration of the equation: PMEg(t=(i+1)Deltat) = ?s(PMEs(t=iDeltat)+(1/(betaMEsVME)?P(?Ps(PCs(t=(iDeltat) PMEs(t=(iDeltat))). There, PMEg(t=iDeltat) and PMEs(t=iDeltat) are the ME total and species-pressures at the indexed times, PCs(t=iDeltat) is the species pressure for each exchange-compartment, betaMEsVME is the product of the ME species-capacitance and volume, ?Ps is the pathway species-conductance, and ?S and ?P are operators for summing the expression over all species or exchange pathways. RESULTS: When calibrated to known values, the model predicts the empirically measured ME species-pressures and the observed time-trajectories for total ME pressure and the MEEPG under a wide variety of physiologic, pathologic and non-physiologic conditions. CONCLUSIONS: Passive inter-compartmental gas exchange is sole and sufficient to describe MEPR. PMID- 28917124 TI - Phytochemicals with NO inhibitory effects and interactions with iNOS protein from Trigonostemon howii. AB - A phytochemical investigation to obtain new NO inhibitors led to the isolation of nine compounds including one new guaiane-type sesquiterpenoid (1) and two new cleistanthane diterpenoids (2 and 3) from the stems of Trigonostemon howii. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of new compounds 1-3 were established via comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 2 and 3 possess a rare 3,4-seco-cleistanthane diterpenoid skeleton. All of the compounds showed inhibitory effects on lipopolysaccharide-induced NO production in murine microglial BV-2 cells. The further molecular docking studies indicated the strong interactions between some bioactive compounds with the iNOS protein, which revealed the possible and potential mechanism of NO inhibition of bioactive compounds. PMID- 28917123 TI - Identification of new potent inhibitor of aldose reductase from Ocimum basilicum. AB - Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3 hydroxypropyl)-3-methyl-8-beta-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6' hydroxyhex-3'-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC50 value of 2.095+/-0.77uM compare to standard sorbinil (IC50=3.14+/-0.02uM). Moreover, the compound (1) also showed multifolds higher activity (IC50=0.783+/-0.07uM) against AKR1A1 as compared to standard valproic acid (IC50=57.4+/-0.89uM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC50=4.324+/-1.25uM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases. PMID- 28917125 TI - What makes a face photo a 'good likeness'? AB - Photographs of people are commonly said to be 'good likenesses' or 'poor likenesses', and this is a concept that we readily understand. Despite this, there has been no systematic investigation of what makes an image a good likeness, or of which cognitive processes are involved in making such a judgement. In three experiments, we investigate likeness judgements for different types of images: natural images of film stars (Experiment 1), images of film stars from specific films (Experiment 2), and iconic images and face averages (Experiment 3). In all three experiments, participants rated images for likeness and completed speeded name verification tasks. We consistently show that participants are faster to identify images which they have previously rated asa good likeness compared to a poor likeness. We also consistently show that the more familiar we are with someone, the higher likeness rating we give to all images of them. A key finding is that our perception of likeness is idiosyncratic (Experiments 1 and 2), and can be tied to our specific experience of each individual (Experiment 2). We argue that likeness judgements require a comparison between the stimulus and our own representation of the person, and that this representation differs according to our prior experience with that individual. This has theoretical implications for our understanding of how we represent familiar people, and practical implications for how we go about selecting images for identity purposes such as photo-ID. PMID- 28917126 TI - Effects of a single administration of different gonadotropins on day 7 post insemination on pregnancy outcomes of rabbit does. AB - This study aimed to investigate the effects of a single administration of one of three different gonadotropins on Day 7 post-insemination on ovarian activity, progesterone (P4) concentration and pregnancy outcomes of rabbit does. Multiparous, non-lactating, V-line does were artificially inseminated after synchronization and ovulation induction with equine chorionic gonadotropin (eCG; 25 IU im) and gonadotropin releasing hormone (GnRH; 0.8 MUg buserelin im) 48 h later. On Day 7 post-inseminarion, does were randomly allocated into four groups (n = 40/group). Does of each group were intramuscularly injected with a single dose of one of physiological saline (placebo; control), GnRH (0.8 MUg buserelin), human chorionic gonadotropin (hCG; 25 IU) or eCG (25 IU). Concentration of serum P4 was determined on Days 6, 9, 11 and 18 post insemination. On Day 14 post-insemination, the ovaries and reproductive tracts of pregnant does were removed and weighed. Also, numbers of visible follicles, hemorrhagic follicles, corpora lutea of pregnancy (pCLs), new CLs (nCLs; formed after Day 7 post-insemination) and implantation sites were recorded. Conception rate, parturition rate, abortion rate, litter size/weight and litter viability were recorded. The highest (P < 0.05) reproductive tract and ovary weights were for eCG. The highest (P < 0.05) number of visible ovarian follicles was for eCG, whereas the lowest (P < 0.05) was for GnRH. Treatment with eCG increased (P < 0.05) numbers of pCLs and total implantation sites compared to the other groups. Treatment with GnRH or hCG increased (P < 0.05) number of nCLs compared to control and eCG. The highest rate of fetal loss was in does treated with GnRH. The concentration of serum P4 decreased (P < 0.05) following the treatment with GnRH and continued low until Day 18. However, it remained in line for control, hCG and eCG groups up to Day 11, then decreased (P < 0.05) for control and hCG on Day 18, being lower for hCG than control, while continued to increase for eCG up to Day 18. Compared to control, treatment with eCG improved (P < 0.05) conception and parturition rates by 24 and 22%; respectively, while GnRH and hCG treatments decreased (P < 0.05) them by 57 and 47.6%; respectively. Litter size and litter weight at birth were improved by eCG, but were adversely affectd by GnRH and hCG. In conclusion, a single administration of eCG 7 Days post-insemination could be recommended for improving pregnancy outcomes in rabbits. PMID- 28917127 TI - Differential expression of ten candidate genes regulating prostaglandin action in reproductive tissues of buffalo during estrous cycle and pregnancy. AB - Prostaglandins (PGs) are the key mediators of several female reproductive functions, including luteolysis, ovulation, fertilization, implantation, pregnancy, and parturition. The present study was conducted in buffalo endometrial and luteal tissues between nonpregnant and two stages of pregnancy (29-38 days of pregnancy, 48-56 days of pregnancy) tissue samples. The genes involved from synthesis upto receptor level effect of PGs (PGF2alpha and PGE2) were studied for their relative mRNA expression. We have collected the endometrial and luteal tissues from slaughtered animals and confirmed the stages by external examination and crown vertebral rump length measurement of the foetus. The mRNA expression of COX-2 and PGFS genes revealed high significant rise in the transcript at pregnancy stage I as compared to the late luteal phase of nonpregnant. However, EP2 and EP3 genes were highly upregulated in pregnancy stage II. The expression of PLA2G4A and PGT genes showed difference in their transcripts in pregnancy, however, the difference was nonsignificant as compared to the nonpregnant stage. The findings emerged from this study also suggested the strict regulation at COX-2 mRNA level than at synthase enzyme's level. Among the four subtypes of EP gene, we have observed highly significant expression difference in EP2 followed by EP3 after implantation. PMID- 28917128 TI - Application of ultra-high-performance liquid chromatography coupled with LTQ Orbitrap mass spectrometry for identification, confirmation and quantitation of illegal adulterated weight-loss drugs in plant dietary supplements. AB - In this paper, an ultra-high-performance liquid chromatography coupled with linear ion trap quadrupole Orbitrap high resolution mass spectrometry (UHPLC-LTQ Orbitrap HRMS) method was developed and validated for identification, confirmation and quantitation of illegal adulterated weight-loss drugs in plant dietary supplements. 13 wt-loss drugs were well separated by the gradient elution of 10mmol/L ammonium acetate - 0.05% formic acid H2O and acetonitrile at a flow rate of 0.2mL/min within 12min. The MS analysis was operated under the positive ion and in full MS/dd-MS2 (data-dependent MS2) mode. The full MS scan with resolution at 60 000 FWHM and narrow mass windows at 5ppm acquired data for identification and quantitation, and dd-MS2 scan with resolution at 15 000 FWHM obtained product ions for confirmation. The method validation showed good linearity with coefficients of determination (r2) higher than 0.9951 for all analytes. Meantime, all the LOD and LLOQ values were in the respective range of 0.3-2 and 1-9ng/g. The accuracy, intra- and inter-day precision were in the ranges of -1.7 to 3.4%, 1.7-5.0% and 1.9-4.4%, respectively. The mean recoveries ranged from 85.4 to 107.1%, while the absolute and relative matrix effect were in the corresponding range of 98.2-108.6% and 2.6-8.7%. Among 120 batches of weight loss plant dietary supplements, sibutramine and fluoxertine or both were positive in 29 samples. In general, LTQ-Orbitrap HRMS technology was a powerful tool for the analysis of illegal ingredients in dietary supplements. PMID- 28917129 TI - Residential road traffic noise and general mental health in youth: The role of noise annoyance, neighborhood restorative quality, physical activity, and social cohesion as potential mediators. AB - Given the ubiquitous nature of both noise pollution and mental disorders, their alleged association has not escaped the spotlight of public health research. The effect of traffic noise on mental health is probably mediated by other factors, which have not been elucidated sufficiently. Herein, we aimed to disentangle the pathways linking road traffic noise to general mental health in Bulgarian youth, with a focus on several candidate mediators - noise annoyance, perceived restorative quality of the living environment, physical activity, and neighborhood social cohesion. A cross-sectional sample was collected in October - December 2016 in the city of Plovdiv, Bulgaria. It consisted of 399 students aged 15-25years, recruited from two high schools and three universities. Road traffic noise exposure (Lden) was derived from the strategic noise map of Plovdiv. Mental health was measured with the 12-item form of the General Health Questionnaire (GHQ-12). Noise annoyance, perceived restorative quality of the living environment, commuting and leisure time physical activity, and neighborhood social cohesion were assessed using validated questionnaires. Analyses were based on linear regression mediation models and a structural equation modeling (SEM) to account for the hypothesized interdependencies between candidate mediators. Results showed that higher noise exposure was associated with worse mental health only indirectly. More specifically, tests of the single and parallel mediation models indicated independent indirect paths through noise annoyance, social cohesion, and physical activity. In addition, the SEM revealed that more noise annoyance was associated with less social cohesion, and in turn with worse mental health; noise annoyance was also associated with lower neighborhood restorative quality, thereby with less social cohesion and physical activity, and in turn with worse mental health. However, causality could not be established. Further research is warranted to expand our still limited understanding of these person environment interactions. PMID- 28917130 TI - Bending behaviors of fully covered biodegradable polydioxanone biliary stent for human body by finite element method. AB - This paper presents a study of the bending flexibility of fully covered biodegradable polydioxanone biliary stents (FCBPBs) developed for human body. To investigate the relationship between the bending load and structure parameter (monofilament diameter and braid-pin number), biodegradable polydioxanone biliary stents derived from braiding method were covered with membrane prepared via electrospinning method, and nine FCBPBSs were then obtained for bending test to evaluate the bending flexibility. In addition, by the finite element method, nine numerical models based on actual biliary stent were established and the bending load was calculated through the finite element method. Results demonstrate that the simulation and experimental results are in good agreement with each other, indicating that the simulation results can be provided a useful reference to the investigation of biliary stents. Furthermore, the stress distribution on FCBPBSs was studied, and the plastic dissipation analysis and plastic strain of FCBPBSs were obtained via the bending simulation. PMID- 28917131 TI - The development and psychometric testing of a Disaster Response Self-Efficacy Scale among undergraduate nursing students. AB - BACKGROUND: Disaster nurse education has received increasing importance in China. Knowing the abilities of disaster response in undergraduate nursing students is beneficial to promote teaching and learning. However, there are few valid and reliable tools that measure the abilities of disaster response in undergraduate nursing students. OBJECTIVES: To develop a self-report scale of self-efficacy in disaster response for Chinese undergraduate nursing students and test its psychometric properties. PARTICIPANTS AND SETTINGS: Nursing students (N=318) from two medical colleges were chosen by purposive sampling. METHODS: The Disaster Response Self-Efficacy Scale (DRSES) was developed and psychometrically tested. Reliability and content validity were studied. Construct validity was tested by exploratory and confirmatory factor analysis. Reliability was tested by internal consistency and test-retest reliability. RESULTS: The DRSES consisted of 3 factors and 19 items with a 5-point rating. The content validity was 0.91, Cronbach's alpha coefficient was 0.912, and the intraclass correlation coefficient for test-retest reliability was 0.953. The construct validity was good (chi2/df=2.440, RMSEA=0.068, NFI=0.907, CFI=0.942, IFI=0.430, p<0.001). CONCLUSIONS: The newly developed DRSES has proven good reliability and validity. It could therefore be used as an assessment tool to evaluate self-efficacy in disaster response for Chinese undergraduate nursing students. PMID- 28917132 TI - A novel real-time RT-PCR assay for influenza C tested in Peruvian children. AB - BACKGROUND: Influenza C virus (ICV) is associated with acute respiratory illness. Yet ICV remains under recognized, with most previous studies using only culture to identify cases. OBJECTIVES: To develop a sensitive and specific real-time RT PCR assay for ICV that allows for rapid and accurate detection in a clinical or research setting. STUDY DESIGN: Multiple ICV sequences obtained from GenBank were analyzed, including 141 hemagglutinin-esterase (HE), 106 matrix (M), and 97 nucleoprotein (NP) sequences. Primers and probes were designed based on conserved regions. Multiple primer-probe sets were tested against multiple ICV strains. RESULTS: The ICV M and NP genes offered the most conserved sequence regions. Primers and probes based on newer sequence data offered enhanced detection of ICV, especially for low titer specimens. An NP-targeted assay yielded the best performance and was capable of detecting 10-100 RNA copies per reaction. The NP assay detected multiple clinical isolates of ICV collected in a field epidemiology study conducted in Peru. CONCLUSIONS: We report a new real-time RT PCR assay for ICV with high sensitivity and specificity. PMID- 28917134 TI - The development of the Dutch version of the Fremantle Back Awareness Questionnaire. AB - BACKGROUND: Disturbed body perception may play a role in the aetiology of chronic low back pain (LBP). The Fremantle Back Awareness Questionnaire (FreBAQ) is currently the only self-report questionnaire to assess back-specific body perception in individuals with LBP. OBJECTIVES: To perform a cross-cultural adaptation of the FreBAQ into Dutch. DESIGN: Psychometric study. METHODS: A Dutch version of the FreBAQ was generated through forward-backward translation, and was completed by 73 patients with LBP and 73 controls to assess discriminant validity. Structural validity was assessed by principal component analysis. Internal consistency was assessed by the Cronbach's alpha coefficient. Construct validity was assessed by examining the relationship with clinical measures (Numerical Rating Scale pain, Oswestry Disability Index (ODI), Tampa Scale for Kinesiophobia). Test-retest reliability was assessed in a subgroup (n = 48 with LBP and 48 controls) using intraclass correlation coefficients (ICC), standard error of measurement (SEM) and minimal detectable change (MDC 95%) RESULTS: The Dutch FreBAQ showed one component with eigenvalue >2. Cronbach's alpha values were respectively 0.82 and 0.73 for the LBP and control group. ICC values were respectively 0.69 and 0.70 for the LBP and control group. In the LBP group, the SEM was 3.9 and the MDC (95%) was 10.8. The LBP group (ODI 22 +/- 21%) scored significantly higher on the Dutch FreBAQ than the control group (ODI 0%) (11 +/- 7 vs. 3 +/- 9, p < 0.001). Within the LBP group, higher Dutch FreBAQ scores correlated significantly with higher ODI scores (rho = 0.30, p = 0.010), although not with pain (rho = 0.10, p = 0.419) or kinesiophobia (r = 0.14, p = 0.226). CONCLUSIONS: The Dutch version of the FreBAQ can be considered as unidimensional and showed adequate internal consistency, sufficient test-retest reliability and adequate discriminant and construct validity in individuals with and without LBP. It can improve our understanding on back-specific perception in the Dutch speaking population with LBP. PMID- 28917136 TI - Nursing students' socialisation into practical skills. AB - Socialisation is a significant factor that shapes nursing students' learning in clinical settings. Little is known about the ways in which students learn practical skills during their clinical practice and how they are socialised into these skills. This knowledge is important for creating an optimal environment for ensuring a high standard of care and patient safety. This study aims to address this knowledge gap. An ethnographic approach was used. Data were collected by participant observations during nursing students' clinical practice in an emergency department at a university hospital in Sweden, and during informal conversations with students and their preceptors. In the analysis, four themes emerged: A reflective approach based on a theoretical framing; Multitasking situations; Shifts in an active role as a nursing student; and Styles of supervision. Students' socialisation into practical skills was shaped by several factors where preceptors played a key role. Teaching and learning styles and interactions between the preceptor and the student shaped the learning situations. A dominant discrepancy regarding whether and how reflections took place between preceptors and students was identified. This highlights the need for creating continuity between the ways that experiences are organised across the settings of learning (university-based and clinically based learning) to enhance nursing students' learning and socialisation into practical skills. PMID- 28917133 TI - Waiting for lexical access: Cochlear implants or severely degraded input lead listeners to process speech less incrementally. AB - Spoken language unfolds over time. Consequently, there are brief periods of ambiguity, when incomplete input can match many possible words. Typical listeners solve this problem by immediately activating multiple candidates which compete for recognition. In two experiments using the visual world paradigm, we examined real-time lexical competition in prelingually deaf cochlear implant (CI) users, and normal hearing (NH) adults listening to severely degraded speech. In Experiment 1, adolescent CI users and NH controls matched spoken words to arrays of pictures including pictures of the target word and phonological competitors. Eye-movements to each referent were monitored asa measure of how strongly that candidate was considered over time. Relative to NH controls, CI users showed a large delay in fixating any object, less competition from onset competitors (e.g., sandwich after hearing sandal), and increased competition from rhyme competitors (e.g., candle after hearing sandal). Experiment 2 observed the same pattern with NH listeners hearing highly degraded speech. These studies suggests that in contrast to all prior studies of word recognition in typical listeners, listeners recognizing words in severely degraded conditions can exhibit a substantively different pattern of dynamics, waiting to begin lexical access until substantial information has accumulated. PMID- 28917135 TI - Failing to learn from negative prediction errors: Obesity is associated with alterations in a fundamental neural learning mechanism. AB - Prediction errors (PEs) encode the difference between expected and actual action outcomes in the brain via dopaminergic modulation. Integration of these learning signals ensures efficient behavioral adaptation. Obesity has recently been linked to altered dopaminergic fronto-striatal circuits, thus implying impairments in cognitive domains that rely on its integrity. 28 obese and 30 lean human participants performed an implicit stimulus-response learning paradigm inside an fMRI scanner. Computational modeling and psycho-physiological interaction (PPI) analysis was utilized for assessing PE-related learning and associated functional connectivity. We show that human obesity is associated with insufficient incorporation of negative PEs into behavioral adaptation even in a non-food context, suggesting differences in a fundamental neural learning mechanism. Obese subjects were less efficient in using negative PEs to improve implicit learning performance, despite proper coding of PEs in striatum. We further observed lower functional coupling between ventral striatum and supplementary motor area in obese subjects subsequent to negative PEs. Importantly, strength of functional coupling predicted task performance and negative PE utilization. These findings show that obesity is linked to insufficient behavioral adaptation specifically in response to negative PEs, and to associated alterations in function and connectivity within the fronto-striatal system. Recognition of neural differences as a central characteristic of obesity hopefully paves the way to rethink established intervention strategies: Differential behavioral sensitivity to negative and positive PEs should be considered when designing intervention programs. Measures relying on penalization of unwanted behavior may prove less effective in obese subjects than alternative approaches. PMID- 28917137 TI - Apparent diffusion coefficient in the analysis of prostate cancer: determination of optimal b-value pair to differentiate normal from malignant tissue. AB - PURPOSE: Determining optimal b-value pair for differentiation between normal and prostate cancer (PCa) tissues. METHODS: Forty-three patients with diagnosis or PCa symptoms were included. Apparent diffusion coefficient (ADC) was estimated using minimum and maximum b-values of 0, 50, 100, 150, 200, 500s/mm2 and 500, 800, 1100, 1400, 1700 and 2000s/mm2, respectively. Diagnostic performances were evaluated when Area-under-the-curve (AUC)>95%. RESULTS: 15 of the 35 b-values pair surpassed this AUC threshold. The pair (50, 2000s/mm2) provided the highest AUC (96%) with ADC cutoff 0.89*10-3mm2/s, sensitivity 95.5%, specificity 93.2% and accuracy 94.4%. CONCLUSIONS: The best b-value pair was b=50, 2000s/mm2. PMID- 28917138 TI - Pulmonary venous anomalies causing misdiagnosis of pulmonary arteriovenous malformations. AB - PURPOSE: To investigate pulmonary venous anomaly as a cause of pulmonary arteriovenous malformation (PAVM) misdiagnosis. MATERIALS AND METHODS: We reviewed adult patients within a 7.5-year period with CT scans initially diagnosed with PAVM and subsequent conventional pulmonary angiograms. RESULTS: Pulmonary arteriography showed no PAVM on arterial phase for 10 out of 99 patients, comprising the misdiagnosed group. Four misdiagnosed patients had pulmonary venous anomalies and six had nodular lesions on CT. CONCLUSION: Pulmonary venous anomalies are vascular mimics of PAVMs that may lead to misdiagnosis. Optimal CT technique and careful imaging review are necessary to minimize inappropriate invasive angiography. PMID- 28917139 TI - A good abortion experience: A qualitative exploration of women's needs and preferences in clinical care. AB - What do women ending their pregnancies want and need to have a good clinical abortion experience? Since birth experiences are better studied, birth stories are more readily shared and many women who have had an abortion have also given birth, we sought to compare women's needs and preferences in abortion to those in birth. We conducted semi-structured intensive interviews with women who had both experiences in the United States and analyzed their intrapartum and abortion care narratives using grounded theory, identifying needs and preferences in abortion that were distinct from birth. Based on interviews with twenty women, three themes emerged: to be affirmed as moral decision-makers, to be able to determine their degree of awareness during the abortion, and to have care provided in a discreet manner to avoid being judged by others for having an abortion. These findings suggest that some women have distinctive emotional needs and preferences during abortion care, likely due to different circumstances and sociopolitical context of abortion. Tailoring services and responding to individual needs may contribute to a good abortion experience. PMID- 28917140 TI - Impact of medical subsidy disqualification on children's healthcare utilization: A difference-in-differences analysis from Japan. AB - Financial support for children's medical expenses has been introduced in many countries. Limited work has been done on price elasticity in children's healthcare demand, especially in countries other than the United States. Moreover, it remains unclear how the effects of a change in the cost sharing rate on healthcare demand would differ by medical condition. We investigated the impact of an increase in the cost sharing rate on medical service utilization among school children as a whole and for each of nine common conditions, applying a difference-in-differences approach. The study period ranged from April 1, 2012, to March 30, 2014. Participants were elementary school children in an urban area who were eligible for National Health Insurance (a community-based public insurance) during the study period and who were enrolled in the 2nd, 3rd, or 4th grade in April 2013. We collected observations from 2896 persons and 69,504 (2896 * 24 months) person-months. When elementary school children were promoted to the 4th grade, they became disqualified for a municipal medical subsidy. The control group was the children promoted to the 2nd or the 3rd grade, who remained eligible for the subsidy. All data were obtained from health insurance claims. We identified the nine most common medical conditions among the subject children, and stratified the analyses by the condition diagnosed. We found that an increase in the cost sharing rate reduced outpatient service utilization as a whole. Also, we observed an increase in inpatient service utilization, not because of worsened health conditions, but rather due to substitution of inpatient service for outpatient service. The reductions in outpatient service were heterogeneous across medical conditions; declines were sharper for mild or chronic conditions. These findings may help to characterize how a change in cost sharing rate affects health outcomes in children. PMID- 28917142 TI - Reactions of tobacco genotypes with different antioxidant capacities to powdery mildew and Tobacco mosaic virus infections. AB - The interactions of powdery mildew (Golovinomyces orontii) and Tobacco mosaic virus (TMV) with tobacco lines having down or upregulated antioxidants were investigated. Xanthi-nc, its salicylic acid-deficient NahG mutant, a paraquat sensitive Samsun (PS) and its paraquat tolerant (PT) mutant were used. Cell membrane damage caused by H2O2 was significantly higher in NahG than Xanthi, whereas it was lower in PT than in PS. Leakage of ions from PT was reduced by the powdery mildew infection. On the other hand TMV inoculation led to a 6-fold and 2 fold elevation of ion leakage from hypersensitive resistant NahG and Xanthi leaves, respectively, whereas ion leakage increased slightly from susceptible PS leaves. G. orontii infection induced ribonuclease (RNase) enzyme activity in extracts from Xanthi and NahG (about 200-250% increase) and weakly (about 20-30% increase) from PS and PT lines. Pre-treatment with protein kinase inhibitor staurosporine or protein phosphatase inhibitor okadaic acid very strongly inhibited mildew development on tobacco lines. Our experiments suggest that protein kinases inhibited by staurosporine seem to be important factors, while protein phosphatases inhibited by okadaic acid play less significant role in TMV induced lesion development. Both powdery mildew and TMV infections up-regulated the expression of PR-1b, PR-1c and WRKY12 genes in all tobacco lines to various extents. PMID- 28917143 TI - Glutathione-induced alleviation of cadmium toxicity in Zea mays. AB - Glutathione (GSH) is known to alleviate cadmium (Cd) stress in many plant species. However, the comprehensive mechanisms responsible for this effect in maize are still need more investigation. Here, a combination of physiological and molecular approaches was utilized in GSH-Cd treated maize seedlings, which revealed that GSH reversed the adverse effects of Cd, as reflected by plant growth, plant hormones, vacuole, stoma development, gene expression, etc. Plant growth, root cell viability, photosynthetic capacity, redox equilibrium, and cell ultrastructure recovery following GSH treatment, coupled with the strong up regulation of Cd tolerance-related genes (e.g., phytochelatin synthetase-like protein, MYB and WRKY transcription factors, and CYP450), demonstrated the efficient activation of cellular defense against Cd toxicity. The addition of GSH significantly elevated GSH/GSSG ratio and the activity of gamma-glutamylcysteine synthetase in both shoots and roots and markedly reduced Cd concentration in shoots. Ethylene emission rate and abscisic acid (ABA) content were significantly reduced after GSH application in the presence of Cd, except ABA content in leaves. These findings highlighted the significance of GSH in alleviating Cd stress in maize and indicate a promising strategy for safe food production. PMID- 28917141 TI - The impact of Black cancer patients' race-related beliefs and attitudes on racially-discordant oncology interactions: A field study. AB - OBJECTIVE: Both physician and patient race-related beliefs and attitudes are contributors to racial healthcare disparities, but only the former have received substantial research attention. Using data from a study conducted in the Midwestern US from 2012 to 2014, we investigated whether 114 Black cancer patients' existing race-related beliefs and attitudes would predict how they and 18 non-Black physicians (medical oncologists) would respond in subsequent clinical interactions. METHOD: At least two days before interacting with an oncologist for initial discussions of treatment options, patients completed measures of perceived past discrimination, general mistrust of physicians, and suspicion of healthcare systems; interactions were video-recorded. Measures from each interaction included patients' verbal behavior (e.g., level of verbal activity), patients' evaluations of physicians (e.g., trustworthiness), patients' perceptions of recommended treatments (e.g., confidence in treatment), physicians' evaluations of patient personal attributes (e.g., intelligence) and physicians' expectations for patient treatment success (e.g., adherence). RESULTS: As predicted, patients' race-related beliefs and attitudes differed in their associations with patient and physician responses to the interactions. Higher levels of perceived past discrimination predicted more patient verbal activity. Higher levels of mistrust also predicted less patient positive affect and more negative evaluations of physicians. Higher levels of suspicion predicted more negative evaluations of physicians and recommended treatments. Stronger patient race-related attitudes were directly or indirectly associated with lower physician perceptions of patient attributes and treatment expectations. CONCLUSION: Results provide new evidence for the role of Black patients' race related beliefs and attitudes in racial healthcare disparities and suggest the need to measure multiple beliefs and attitudes to identify these effects. PMID- 28917144 TI - Silicon improves seed germination and alleviates drought stress in lentil crops by regulating osmolytes, hydrolytic enzymes and antioxidant defense system. AB - Silicon (Si) has been widely reported to have beneficial effect on mitigating drought stress in plants. However, the effect of Si on seed germination under drought conditions is still poorly understood. This research was carried out to ascertain the role of Si to abate polyethylene glycol-6000 mediated drought stress on seed germination and seedling growth of lentil. Results showed that drought stress significantly decreased the seed germination traits and increased the concentration of osmolytes (proline, glycine betaine and soluble sugars), reactive oxygen species (hydrogen peroxide and superoxide anion) and lipid peroxides in lentil seedlings. The activities of hydrolytic enzymes and antioxidant enzymes increased significantly under osmotic stress. The application of Si significantly enhanced the plants ability to withstand drought stress conditions through increased Si content, improved antioxidants, hydrolytic enzymes activity, decreased concentration of osmolytes and reactive oxygen species. Multivariate data analysis showed statistically significant correlations among the drought-tolerance traits, whereas cluster analysis categorised the genotypes into distinct groups based on their drought-tolerance levels and improvements in expression of traits due to Si application. Thus, these results showed that Si supplementation of lentil was effective in alleviating the detrimental effects of drought stress on seed germination and increased seedling vigour. PMID- 28917145 TI - Cell wall pectin methyl-esterification and organic acids of root tips involve in aluminum tolerance in Camellia sinensis. AB - Tea plant (Camellia sinensis (O.) Kuntze) can survive from high levels of aluminum (Al) in strongly acidic soils. However, the mechanism driving its tolerance to Al, the predominant factor limiting plant growth in acid condition, is still not fully understood. Here, two-year-old rooted cuttings of C. sinensis cultivar 'Longjingchangye' were used for Al resistance experiments. We found that the tea plants grew better in the presence of 0.4 mM Al than those grew under lower concentration of Al treatments (0 and 0.1 mM) as well as higher levels treatment (2 and 4 mM), confirming that appropriate Al increased tea plant growth. Hematoxylin staining assay showed that the apical region was the main accumulator in tea plant root. Subsequently, immunolocalization of pectins in the root tip cell wall showed a rise in low-methyl-ester pectin levels and a reduction of high-methyl-ester pectin content with the increasing Al concentration of treatments. Furthermore, we observed the increased expressions of C. sinensis pectin methylesterase (CsPME) genes along with the increasing de esterified pectin levels during response to Al treatments. Additionally, the levels of organic acids increased steadily after treatment with 0.1, 0.4 or 2 mM Al, while they dropped after treatment with 4 mM Al. The organic acids secretion from root followed a similar trend. Similarly, a gradual increase in malate dehydrogenase (MDH), citrate synthase (CS) and glycolate oxidase (GO) enzyme activities and relevant metabolic genes expression were detected after the treatment of 0.1, 0.4 or 2 mM Al, while a sharp decrease was resulted from treatment with 4 mM Al. These results confirm that both pectin methylesterases and organic acids contribute to Al tolerance in C. sinensis. PMID- 28917146 TI - Construct validity and inter-rater reliability of the Gymnastic Functional Measurement Tool in the classification of female competitive gymnasts in Canada. AB - OBJECTIVES: To determine the construct validity and the inter-rater reliability of the Gymnastic Functional Measurement Tool (GFMT) within the parameters of the Canadian classification of female competitive gymnasts. DESIGN: Validity and Reliability study. SETTING: The GFMT was administered by evaluators who had no previous knowledge of the competing level of the gymnasts. To determine the construct validity, a multiple linear regression analysis was carried out between the GFMT scores and the gymnasts' competition level to obtain the coefficient of determination. To estimate the inter-rater reliability, gymnasts were simultaneously evaluated by two evaluators. Intraclass correlation coefficient (ICC) analysis was carried out for the individual score of each item as well as for the total score of the GFMT. PARTICIPANTS: Ninety (90) female gymnasts aged between the ages of 8 and 18 years old. MAIN OUTCOME: GFMT total score and individual score of each item. RESULTS: The study demonstrated an excellent relationship between the total GFMT scores and the gymnasts' competition level (r2 = 0.97). The inter-rater reliability analysis of the GFMT total score was excellent with an ICC of 0.98. CONCLUSION: Construct validity and inter-rater reliability of the GFMT in the classification of female competitive gymnasts in Canada has been demonstrated. PMID- 28917147 TI - Combined in silico approaches for the identification of novel inhibitors of human islet amyloid polypeptide (hIAPP) fibrillation. AB - Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the beta cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated beta-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of beta-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question. In this work, ligand and structure-based in silico approaches were used to identify novel fibrillation inhibitors and/or fibril binding compounds. The best pharmacophore model was used as a 3D search query for virtual screening of a compound database to identify novel molecules having the potential to be therapeutic agents against protein aggregation diseases. Docking and molecular dynamics simulation studies were used to explore the interaction pattern and mechanism of the identified novel small molecules with predicted hIAPP structure, its aggregation prone conformation and fibril forming segments. We show that catechins with galloyl group and molecules having two to three planar apolar rings bind to hIAPP structures and fibril forming segments with greater affinity. The differences in binding affinities of different compounds against several fibril forming segments of the peptide suggest that a mixture of active compounds may be required for treatment of aggregation diseases. PMID- 28917148 TI - Self-nanoemulsifying drug delivery systems of myricetin: Formulation development, characterization, and in vitro and in vivo evaluation. AB - Despite various pharmacological effects, myricetin (Myr) shows low oral bioavailability (<10%) due to its poor solubility, which limits its applications. To address this problem, self-nanoemulsifying drug delivery systems (SNEDDS) were developed by investigating the solubility of Myr in various excipients, constructing pseudo-ternary phase diagrams, and optimizing based on droplet size and emulsification efficacy after drug loading. The obtained Myr-SNEDDS were F04 (Capryol 90/Cremophor RH 40/PEG 400 4:3:3), F08 (Capryol 90/CremophorRH40/1,2 propanediol 4:3:3), F13 (Capryol 90/Cremophor EL/Transcutol HP 4:3:3) and F15 (Capryol 90/Cremephor RH 40/Transcutol HP 2:7:1), with droplet sizes less than 200nm. Additional evaluations showed that these Myr-SNEDDS formulations had fast release properties (over 90% in 1min), low cytotoxicity, and improved permeability and solubility compared with the free drug. Consequently, the oral bioavailabilities of Myr were 5.13, 6.33, 4.69 and 2.53-fold for F04, F08, F13 and F15, respectively, relative to Myr alone. The present study demonstrated that SNEDDS is a viable platform for the oral delivery of insoluble drugs such as Myr. PMID- 28917149 TI - A comparison study between electrospun polycaprolactone and piezoelectric poly(3 hydroxybutyrate-co-3-hydroxyvalerate) scaffolds for bone tissue engineering. AB - In this study, bone scaffolds composed of polycaprolactone (PCL), piezoelectric poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and a combination of poly(3 hydroxybutyrate-co-3-hydroxyvalerate) and silicate containing hydroxyapatite (PHBV-SiHA) were successfully fabricated by a conventional electrospinning process. The morphological, chemical, wetting and biological properties of the scaffolds were examined. All fabricated scaffolds are composed of randomly oriented fibres with diameters from 800nm to 12MUm. Fibre size increased with the addition of SiHA to PHBV scaffolds. Moreover, fibre surface roughness in the case of hybrid scaffolds was also increased. XRD, FTIR and Raman spectroscopy were used to analyse the chemical composition of the scaffolds, and contact angle measurements were performed to reveal the wetting behaviour of the synthesized materials. To determine the influence of the piezoelectric nature of PHBV in combination with SiHA nanoparticles on cell attachment and proliferation, PCL (non-piezoelectric), pure PHBV, and PHBV-SiHA scaffolds were seeded with human mesenchymal stem cells (hMSCs). In vitro study on hMSC adhesion, viability, spreading and osteogenic differentiation showed that the PHBV-SiHA scaffolds had the largest adhesion and differentiation abilities compared with other scaffolds. Moreover, the piezoelectric PHBV scaffolds have demonstrated better calcium deposition potential compared with non-piezoelectric PCL. The results of the study revealed pronounced advantages of hybrid PHBV-SiHA scaffolds to be used in bone tissue engineering. PMID- 28917150 TI - Efficient delivery of signal-responsive gene carriers for disease-specific gene expression via bubble liposomes and sonoporation. AB - Sonoporation is a promising method to intracellularly deliver synthetic gene carriers that have lower endocytotic uptake than viral carriers. Here, we applied sonoporation to deliver genes via polyethylene glycol (PEG)-grafted polymeric carriers that specifically respond to hyperactivated protein kinase A (PKA). PEG grafted polymeric carrier/DNA polyplexes were not efficiently delivered into cells via the endocytotic pathway because of the hydrophilic PEG layer surrounding the polyplexes. However, the delivery of polyplexes into cells was significantly increased by sonoporation. The delivered polyplexes exhibited PKA responsive transgene expression in PKA-overexpressing cells, but not in cells with low PKA activation. These results show that the sonoporation-mediated delivery of PEG-modified PKA-responsive polyplexes is a promising approach for safely applying gene therapy to abnormal cells with hyperactivated PKA. PMID- 28917151 TI - A novel self-nanoemulsifying formulation for sunitinib: Evaluation of anticancer efficacy. AB - Breast cancer is the top cancer and a main cause of death among women. The incidence of this cancer is increasing in the world. Sunitinib maleate is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor that inhibits tumor cell proliferation and angiogenesis, and has been administrated as an anticancer drug. Self-nanoemulsifying drug delivery system (SNEDDS) is an isotopic mixture of an oil, a surfactant and usually a co-surfactant, which can spontaneously form fine oil-in-water nanoemulsion in aqueous media. Here, a SNEDDS composed of 15% ethyl oleate (as an oil phase), 30% tween 80 (as a surfactant), and 55% PEG 600 (as a co-surfactant) was prepared and developed as a carrier for sunitinib. The average droplet size of sunitinib-loaded SNEDDS was 29.5+/-6.3nm with a stability of more than one month. Sunitinib release from SNEDDS was enhanced accompanied by a controlled dissolution of the drug. Cytotoxicity studies on 4T1 and MCF-7 cell lines indicated a toxicity enhancement in sunitinib by SNEDDS. To inspect the bioavailability of the drug-loaded SNEDDS after oral administration with a dose of 50mgkg-1, the maximum plasma concentration and the mean area under the plasma concentration-time curve were measured. It was found that these parameters were increased 1.45- and 1.24-times respectively, compared to a drug suspension. PMID- 28917152 TI - PEGylated thermosensitive lipid-coated hollow gold nanoshells for effective combinational chemo-photothermal therapy of pancreatic cancer. AB - Pancreatic cancer has extremely poor prognosis with an 85% mortality rate that results from aggressive and asymptomatic growth, high metastatic potential, and rapid development of resistance to already ineffective chemotherapy. In this study, plasmonic hollow gold nanoshells (GNS) coated with PEGylated thermosensitive lipids were prepared as an efficient platform to ratiometrically co-deliver two drugs, bortezomib and gemcitabine (GNS-L/GB), for combinational chemotherapy and photothermal therapy of pancreatic cancer. Bortezomib was loaded within the lipid bilayers, while gemcitabine was loaded into the hydrophilic interior of the porous GNS via an ammonium sulfate-driven pH gradient method. Physicochemical characterizations and biological studies of GNS-L/GB were performed, with the latter using cytotoxicity assays, cellular uptake and apoptosis assays, live/dead assays, and western blot analysis of pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). The nanoshells showed remotely controllable drug release when exposed to near-infrared laser for site-specific delivery. GNS-L/GB showed synergistic cytotoxicity and improved internalization by cancer cells. High-powered near-infrared continuous wave laser (lambda=808nm) effectively killed cancer cells via the photothermal effect of GNS-L/GB, irrespective of cell type in a power density-, time-, and GNS dose-dependent manner. These results suggest that this method can provide a novel approach to achieve synergistic combinational chemotherapy and photothermal therapy, even with resistant pancreatic cancer. PMID- 28917153 TI - CB7 as a drug vehicle and controlled release of drug through non ionic surfactant: Spectroscopic technique. AB - A study of the comparative drug carrier properties of cucurbituril[7] (CB7) and beta-cyclodextrin (beta-CD) with a naphthalimide derivative, [2-(2-aminoethyl)-1H benzo[deisoquinoline-1,3(2H)-dione] (NAP) and its release in aqueous solution using micellar environment, is the key research interest of this work. The profound changes in the different spectroscopic behavior have been attributed to the formation of a 1:1 inclusion complex for NAP:CB7 system. Several experimental outcomes clearly interpreted that CB7 has better drug carrier properties for NAP compared to beta-CD. It has been also focused on the systematic release of NAP molecule from CB7 by using different ionic and non ionic surfactants. Before releasing the drug molecules from CB7 the interaction between NAP and the three different types of surfactants has also been investigated separately. The selectivity of drug carrier and releaser has been monitored, using different spectroscopic techniques like absorbance, fluorescence, fluorescence decay life time and 1H NMR spectroscopy. Besides, a theoretical approach has been followed for a proper geometrical optimized structure of NAP molecule and molecular arrangement of NAP:CB7 inclusion complex. From Density Functional Theory (DFT) it has been seen that NAP molecule is oriented as a t-bone like structure in its optimized form. PMID- 28917154 TI - Neural activation in stress-related exhaustion: Cross-sectional observations and interventional effects. AB - The primary purpose of this study was to investigate the association between burnout and neural activation during working memory processing in patients with stress-related exhaustion. Additionally, we investigated the neural effects of cognitive training as part of stress rehabilitation. Fifty-five patients with clinical diagnosis of exhaustion disorder were administered the n-back task during fMRI scanning at baseline. Ten patients completed a 12-week cognitive training intervention, as an addition to stress rehabilitation. Eleven patients served as a treatment-as-usual control group. At baseline, burnout level was positively associated with neural activation in the rostral prefrontal cortex, the posterior parietal cortex and the striatum, primarily in the 2-back condition. Following stress rehabilitation, the striatal activity decreased as a function of improved levels of burnout. No significant association between burnout level and working memory performance was found, however, our findings indicate that frontostriatal neural responses related to working memory were modulated by burnout severity. We suggest that patients with high levels of burnout need to recruit additional cognitive resources to uphold task performance. Following cognitive training, increased neural activation was observed during 3-back in working memory-related regions, including the striatum, however, low sample size limits any firm conclusions. PMID- 28917155 TI - Crossing the gender boundaries: The gender experiences of male nursing students in initial nursing clinical practice in Taiwan. AB - BACKGROUND: The initial nursing clinical practice is the necessary practicum required for nursing students. Because of the changing learning style, many of them are under great pressure for environmental change and therefore their daily routine is severe affected. Interacting directly with patients in a female dominated occupation, along with the general gender stereotypes, the impact is especially significant to male nursing students than to female nursing students. PURPOSE: The purpose of this preliminary qualitative study is to explore the gendered experiences of male nursing students during their first initial nursing clinical practice. METHODS: Both focus group interviews and individual interviews are conducted with twenty-two sophomore nursing students from a university of technology in northern Taiwan, with ten male students and twelve female students. RESULTS: Two main themes emerge from the gendered experiences shared by the nursing students: Gender consciousness awakening and thus maintaining masculinity, and male advantage in the learning environments. CONCLUSIONS: The results identify the specific gendered experiences of nursing students, providing implications for future nursing education and counseling service. Further, this study may serve to promote an active yet gender-sensitive nursing education for training nursing professionals. PMID- 28917156 TI - TGFbeta1 synergizes with FLT3 ligand to induce chemoresistant quiescence in acute lymphoblastic leukemia with MLL gene rearrangements. AB - Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)beta1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFbeta1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFbeta1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL. Thus, it is likely that TGFbeta1 and FL, both abundantly produced by bone marrow stromal cells, function in a coordinated manner to render MLL+ALL cells chemoresistant, which should lead to the development of minimal residual disease (MRD) resulting in relapse. The use of inhibitors against FLT3 and TGFbeta1 may become a useful strategy for eradicating MRD in MLL+ALL. PMID- 28917158 TI - Quantitative trait locus mapping in mice identifies phospholipase Pla2g12a as novel atherosclerosis modifier. AB - BACKGROUND AND AIMS: In a previous work, a female-specific atherosclerosis risk locus on chromosome (Chr) 3 was identified in an intercross of atherosclerosis resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL receptor deficient (Ldlr-/-) background. It was the aim of the current study to identify causative genes at this locus. METHODS: We established a congenic mouse model, where FVB.Chr3B6/B6 mice carried an 80 Mb interval of distal Chr3 on an otherwise FVB.Ldlr-/- background, to validate the Chr3 locus. Candidate genes were identified using genome-wide expression analyses. Differentially expressed genes were validated using quantitative PCRs in F0 and F2 mice and their functions were investigated in pathophysiologically relevant cells. RESULTS: Fine mapping of the Chr3 locus revealed two overlapping, yet independent subloci for female atherosclerosis susceptibility: when transmitted by grandfathers to granddaughters, the B6 risk allele increased atherosclerosis and downregulated the expression of the secreted phospholipase Pla2g12a (2.6 and 2.2 fold, respectively); when inherited by grandmothers, the B6 risk allele induced vascular cell adhesion molecule 1 (Vcam1). Down-regulation of Pla2g12a and up regulation of Vcam1 were validated in female FVB.Chr3B6/B6 congenic mice, which developed 2.5 greater atherosclerotic lesions compared to littermate controls (p=0.039). Pla2g12a was highly expressed in aortic endothelial cells in vivo, and knocking-down Pla2g12a expression by RNAi in cultured vascular endothelial cells or macrophages increased their adhesion to ECs in vitro. CONCLUSIONS: Our data establish Pla2g12a as an atheroprotective candidate gene in mice, where high expression levels in ECs and macrophages may limit the recruitment and accumulation of these cells in nascent atherosclerotic lesions. PMID- 28917157 TI - Density of calcium in the ascending thoracic aorta and risk of incident cardiovascular disease events. AB - BACKGROUND AND AIMS: The volume and density of coronary artery calcium (CAC) both independently predict cardiovascular disease (CVD) beyond standard risk factors, with CAC density inversely associated with incident CVD after accounting for CAC volume. We tested the hypothesis that ascending thoracic aorta calcium (ATAC) volume and density predict incident CVD events independently of CAC. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of participants without clinical CVD at baseline. ATAC and CAC were measured from baseline cardiac computed tomography (CT). Cox regression models were used to estimate the associations of ATAC volume and density with incident coronary heart disease (CHD) events and CVD events, after adjustment for standard CVD risk factors and CAC volume and density. RESULTS: Among 6811 participants, 234 (3.4%) had prevalent ATAC and 3395 (49.8%) had prevalent CAC. Over 10.3 years, 355 CHD and 562 CVD events occurred. One-standard deviation higher ATAC density was associated with a lower risk of CHD (HR 0.48 [95% CI 0.29-0.79], p<0.01) and CVD (HR 0.56 [0.37-0.84], p<0.01) after full adjustment. ATAC volume was not associated with outcomes after full adjustment. CONCLUSIONS: ATAC was uncommon in a cohort free of clinical CVD at baseline. However, ATAC density was inversely associated with incident CHD and CVD after adjustment for CVD risk factors and CAC volume and density. PMID- 28917159 TI - The obesity-associated risk of cardiovascular disease and all-cause mortality is not lower in Inuit compared to Europeans: A cohort study of Greenlandic Inuit, Nunavik Inuit and Danes. AB - BACKGROUND AND AIMS: Inuit populations have lower levels of cardiometabolic risk factors for the same level of body mass index (BMI) or waist circumference (WC) compared to Europeans in cross-sectional studies. We aimed to compare the longitudinal associations of anthropometric measures with cardiovascular disease (CVD) and all-cause mortality in Inuit and Europeans. METHODS: Using pooled data from three population-based studies in Canada, Greenland and Denmark, we conducted a cohort study of 10,033 adult participants (765 Nunavik Inuit, 2960 Greenlandic Inuit and 6308 Europeans). Anthropometric measures collected at baseline included: BMI, WC, waist-to-hip-ratio (WHR), waist-to-height-ratio (WHtR) and a body shape index (ABSI). Information on CVD and death was retrieved from national registers or medical files. Poisson regression analyses were used to calculate incidence rates for CVD and all-cause mortality. RESULTS: During a median follow-up of 10.5 years, there were 642 CVD events and 594 deaths. Slightly higher absolute incidence rates of CVD for a given anthropometric measure were found in Nunavik Inuit compared with Greenlandic Inuit and the Europeans; however, no cohort interactions were observed. For all-cause mortality, all anthropometric measures were positively associated in the Europeans, but only ABSI in the two Inuit populations. In contrast, BMI and WC were inversely associated with mortality in the two Inuit populations. CONCLUSIONS: Inuit and Europeans have different absolute incidences of CVD and all-cause mortality, but the trends in the associations with the anthropometric measures only differ for all-cause mortality. Previous findings of a lower obesity-associated cardiometabolic risk among Inuit were not confirmed. PMID- 28917160 TI - Is Magnet(r) recognition associated with improved outcomes among critically ill children treated at freestanding children's hospitals? AB - PURPOSE: With increasing emphasis on high-quality care, we designed this study to evaluate the relationship between Magnet(r) recognition and patient outcomes in pediatric critical care. MATERIALS AND METHODS: Post hoc analysis of data from an existing administrative national database. We used inverse probability of treatment weighting and multivariate models to compare outcomes between two study groups after adjusting for confounding variables. RESULTS: A total of 823,634 pediatric patients from 41 centers were included. Of these, 454,616 patients (55.2%) were treated in 23 Magnet hospitals. The majority of baseline characteristics did not vary significantly among the two study groups. In adjusted models, there was no difference in mortality between the two groups (Magnet vs. non-Magnet; odds ratio: 0.92, 95% confidence interval: 0.77-1.11). When stratified by various subgroups, such as cardiac, non-cardiac, ECMO, cardiac arrest, respiratory failure, use of nitric oxide, genetic abnormality etc., Magnet status of the hospital did not confer a survival advantage. In a sensitivity analysis on patients from crossover hospitals only, attainment of magnet status was associated with increased hospital charges. CONCLUSIONS: This large observational study calls into question the utility of the Magnet Recognition Program among children with critical illness, at least among the freestanding children's hospitals. PMID- 28917161 TI - Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used to preclude maternal pregnancy depression. There is a growing body of literature assessing the association of prenatal exposure to SSRIs with autism spectrum disorder (ASD). The present systematic review and meta analysis reviewed the medical literature and pooled the results of the association of prenatal exposure to SSRIs with ASD. METHODS: Published investigations in English by June 2016 with keywords of selective serotonin reuptake inhibitors, SSRI, autism spectrum disorder, ASD, pregnancy, childhood, children, neurodevelopment were identified using databases PubMed and PMC, MEDLINE, EMBASE, SCOPUS, and Google Scholar. Cochran's Q statistic-value (Q), degree of freedom (df), and I2 indices (variation in odds ratio [OR] attributable to heterogeneity) were calculated to analyze the risk of heterogeneity of the within- and between-study variability. Pooled odds ratio (OR) and 95% confidence interval (CI) were reported by a Mantel-Haenszel test. RESULTS: There was a non significant heterogeneity for the included studies ([Q=3.61, df=6, P=0.730], I2=0%). The pooled results showed a significant association between prenatal SSRI exposure and ASD (OR=1.82, 95% CI=1.59-2.10, Z=8.49, P=0.00). CONCLUSION: The evidence from the present study suggests that prenatal exposure to SSRIs is associated with a higher risk of ASD. PMID- 28917163 TI - Raman and Fourier transform infrared spectroscopic study of pyromorphite vanadinite solid solutions. AB - Due to the great range of the application fields for apatites, there is a strong need to complete the data set determining the properties of these minerals. In this study, Raman and Infrared spectra of the phases from pyromorphite Pb5(PO4)3Cl - vanadinite Pb5(VO4)3Cl series were investigated. Totally, 9 samples (2 end-members and 7 solid solutions of the series) were synthesized at 25 degrees C and pH=3.5, and analyzed. In the Raman and Infrared spectra of the studied Pb-apatites, the bands typical for the vibrations in the PO4 and the VO4 tetrahedra appeared. The bands attributed to the stretching vibrations (nu1, nu3) occurred in the 1050-910cm-1 and 830-720cm-1 regions, whereas the bending vibrations (nu2, nu4) were visible at the 580-540cm-1, 430-380cm-1 and 370-290cm 1 range. The position of the bands depended on the P/(P+V) ratio in the analyzed solid, since there are differences in the ionic radii and the atomic mass of P5+ and V5+, which affect the bong lengths, bond forces and the banding energies of the substituting tetrahedra. The analysis allowed observing gradual shifts of the bands caused by the replacement of phosphorous with vanadium in the studied phases. The positions and the intensities of selected bands are proposed to serve as a semi-quantitative estimation of the chemical composition of the phases from the pyromorphite - vanadinite series. PMID- 28917162 TI - A highly selective and sensitive turn-on probe for aluminum(III) based on quinoline Schiff's base and its cell imaging. AB - A reversible Schiff's base fluorescence probe for Al3+, (3,5-dichloro-2- hydroxybenzylidene) quinoline-2-carbohydrazide (QC), based on quinoline derivative has been designed, synthesized and evaluated. The QC exhibited a high sensitivity and selectivity toward Al3+ in EtOH-H2O (v/v=1:9, pH=6) by forming a 1:1 complex with Al3+ and the detection limit of QC for Al3+ was as low as 0.012MUM. Furthermore, these results displayed that the binding of QCAl3+ was broken by F-, so this system could be used to monitor F- in the future. The enhancement fluorescence of the QC could be attributed to the inhibition of PET and ESIPT and the emergency of CHEF process induced by Al3+. More importantly, QC was not only successfully used for the determination of trace Al3+ in the tap water and the human blood serum, but was valid for fluorescence imaging of Al3+ in the Hela cells. PMID- 28917164 TI - UPLC-MS/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients. AB - In the present study, a sensitive and robust LC-MS/MS method has been developed and validated for the quantification of riluzole in human plasma and cerebrospinal fluid (CSF) in clinical samples from patients with spinal cord injury (SCI). Riluzole and its labeled internal standard (IS) were isolated from plasma and CSF by liquid-liquid extraction using ethyl acetate. Riluzole (m/z 235 >166) and IS (m/z 238->169) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode. The assay was linear in the concentration range of 0.5 (LLOQ, signal/noise ratio>10)-800ng/ml in plasma, and 1.0 (LLOQ)-800ng/ml in CSF samples. The intra- and inter-day accuracy in plasma were 94.2-110.0% and 97.8-102.0%, respectively, and those in CSF were 87.6 105.1% and 91.9-98.8%, respectively. The intra- and inter-day precision were 2.2 7.2% and 4.0-9.1%, respectively, in plasma, and 1.4-14.1% and 2.6-11.5%, respectively in CSF. Matrix effect was negligible from both matrices with signal percentages of 97.6-100.6% in plasma and 99.4-106.4% in CSF. The recoveries were >75% in plasma, >84% in CSF with low protein (53.9mg/dl), and >68% in CSF with high protein (348.2mg/dl). This method was successfully applied to quantify riluzole concentrations in plasma and CSF from patients with SCI. PMID- 28917166 TI - OMI satellite observed formaldehyde column from 2006 to 2015 over Xishuangbanna, southwest China, and validation using ground based zenith-sky DOAS. AB - Formaldehyde (HCHO) provides a proxy to reveal the isoprene and biogenic volatile organic compounds emission which plays important roles in atmospheric chemical process and climate change. The ground-based observation with zenith-sky DOAS is carried out in order to validate the HCHO columns from OMI. It has a good correlation of 0.71678 between the HCHO columns from two sources. Then we use the OMI HCHO columns from January 2006 to December 2015 to indicate the interannual variation and spatial distribution in Xishuangbanna. The HCHO concentration peaks appeared in March or April for each year significantly corresponding to the intensive fire counts at the same time, which illustrate that the high HCHO columns are strongly influenced by the biomass burning in spring. Temperature and precipitation are also the important influence factors in the seasonal variation when there is nearly no biomass burning. The spatial patterns over the past ten years strengthen the deduction from the temporal variation and show the relationship with land cover and land use, elevation and population density. It is concluded that the biogenic activity plays a role in controlling the background level of HCHO in Xishuangbanna, while biomass burning is the main driving force of high HCHO concentration. And forests are greater contributor to HCHO rather than rubber trees which cover over 20% of the land in the region. Moreover, uncertainties from HCHO slant column retrieval and AMFs calculation are discussed in detail. PMID- 28917165 TI - Cerebellar induced differential polyglot aphasia: A neurolinguistic and fMRI study. AB - Research has shown that linguistic functions in the bilingual brain are subserved by similar neural circuits as in monolinguals, but with extra-activity associated with cognitive and attentional control. Although a role for the right cerebellum in multilingual language processing has recently been acknowledged, a potential role of the left cerebellum remains largely unexplored. This paper reports the clinical and fMRI findings in a strongly right-handed (late) multilingual patient who developed differential polyglot aphasia, ataxic dysarthria and a selective decrease in executive function due to an ischemic stroke in the left cerebellum. fMRI revealed that lexical-semantic retrieval in the unaffected L1 was predominantly associated with activations in the left cortical areas (left prefrontal area and left postcentral gyrus), while naming in two affected non native languages recruited a significantly larger bilateral functional network, including the cerebellum. It is hypothesized that the left cerebellar insult resulted in decreased right prefrontal hemisphere functioning due to a loss of cerebellar impulses through the cerebello-cerebral pathways. PMID- 28917167 TI - Virtual water trade patterns in relation to environmental and socioeconomic factors: A case study for Tunisia. AB - Growing water demands put increasing pressure on local water resources, especially in water-short countries. Virtual water trade can play a key role in filling the gap between local demand and supply of water-intensive commodities. This study aims to analyse the dynamics in virtual water trade of Tunisia in relation to environmental and socio-economic factors such as GDP, irrigated land, precipitation, population and water scarcity. The water footprint of crop production is estimated using AquaCrop for six crops over the period 1981-2010. Net virtual water import (NVWI) is quantified at yearly basis. Regression models are used to investigate dynamics in NVWI in relation to the selected factors. The results show that NVWI during the study period for the selected crops is not influenced by blue water scarcity. NVWI correlates in two alternative models to either population and precipitation (model I) or to GDP and irrigated area (model II). The models are better in explaining NVWI of staple crops (wheat, barley, potatoes) than NVWI of cash crops (dates, olives, tomatoes). Using model I, we are able to explain both trends and inter-annual variability for rain-fed crops. Model II performs better for irrigated crops and is able to explain trends significantly; no significant relation is found, however, with variables hypothesized to represent inter-annual variability. PMID- 28917168 TI - Occurrence and distribution of microplastics at selected coastal sites along the southeastern United States. AB - To investigate the occurrence and distribution of microplastics in the southeastern coastal region of the United States, we quantified the amount of microplastics in sand samples from multiple coastal sites and developed a predictive model to understand the drift of plastics via ocean currents. Sand samples from eighteen National Park Service (NPS) beaches in the Southeastern Region were collected and microplastics were isolated from each sample. Microplastic counts were compared among sites and local geography was used to make inferences about sources and modes of distribution. Samples were analyzed to identify the composition of particles using Fourier transform infrared spectroscopy (FTIR). To predict the spatiotemporal distribution and movements of particles via coastal currents, a Regional Ocean Modeling System (ROMS) was applied. Microplastics were detected in each of the sampled sites although abundance among sites was highly variable. Approximately half of the samples were dominated by thread-like and fibrous materials as opposed to beads and particles. Results of FTIR suggested that 24% consisted of polyethylene terephthalate (PET), while about 68% of the fibers tested were composed of man-made cellulosic materials such as rayon. Based on published studies examining sources of microplastics, the shape of the particles found here (mostly fibers) and the presence of PET, we infer the source of microplastics in coastal areas is mainly from urban areas, such as wastewater discharge, rather than breakdown of larger marine debris drifting in the ocean. Local geographic features, e.g., the nearness of sites to large rivers and urbanized areas, explain variance in amount of microplastics among sites. Additionally, the distribution of simulated particles is explained by ocean current patterns; computer simulations were correlated with field observations, reinforcing the idea that ocean currents can be a good predictor of the fate and distribution of microplastics at the sites sampled here. PMID- 28917170 TI - How do climatic and management factors affect agricultural ecosystem services? A case study in the agro-pastoral transitional zone of northern China. AB - Agricultural ecosystem management needs to ensure food production and minimize soil erosion and nitrogen (N) leaching under climate change and increasingly intensive human activity. Thus, the mechanisms through which climatic and management factors affect crop production, soil erosion, and N leaching must be understood in order to ensure food security and sustainable agricultural development. In this study, we adopted the GIS-based Environmental Policy Integrated Climate (EPIC) model to simulate crop production, soil erosion, and N leaching, and used a partial least squares regression model to evaluate the contributions of climate variables (solar radiation, precipitation, wind speed, relative humidity, and maximum and minimum temperature) and management factors (irrigation, fertilization, and crop cultivation area) on agricultural ecosystem services (AES) in the agro-pastoral transitional zone (APTZ) of northern China. The results indicated that crop production and N leaching markedly increased, whereas soil erosion declined from 1980 to 2010 in the APTZ. Management factors had larger effects on the AES than climate change. Among the climatic variables, daily minimum temperature was the most important contributor to the variations in ecosystem services of wheat, maize, and rice. Spatial changes in the cultivated area most affected crop production, soil erosion, and N leaching for majority of the cultivated areas of the three crops, except for the wheat-cultivated area, where the dominant factor for N leaching was fertilization. Although a tradeoff existed between crop production and negative environmental effects, compromises were possible. These findings provide new insights into the effects of climatic and management factors on AES, and have practical implications for improving crop production while minimizing negative environmental impacts. PMID- 28917169 TI - Short-term associations of ambient air pollution and cause-specific emergency department visits in Guangzhou, China. AB - BACKGROUND: Evidence of association of ambient air pollution with cause-specific emergency department visits in China is still limited. This study aimed to investigate short-term associations between exposures to air pollutants and daily cause-specific emergency department visits using a large-scale multicenter database involving a total of 65 sentinel hospitals in Guangzhou, the most densely-populated city in south China, during 2013-2015. MATERIAL AND METHODS: We obtained data on 162,771 emergency department visits from 65 hospitals from the Emergency Medical Command Center in Guangzhou between January 1, 2013 and December 31, 2015. Daily air pollution data on particulate matter (PM) of aerodynamic diameter<10 and 2.5MUm (PM10, and PM2.5, respectively), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3) were collected from the Daily Quality Report of the Guangzhou Environmental Protection Bureau during the study period. Visits for neurologic, respiratory and circulatory diseases were assessed in relation to air pollutants using Poisson generalized additive models. RESULTS: Mean daily number of emergency department visits for neurologic, respiratory and circulatory diseases was 89, 24 and 35, respectively. After adjustment for other pollutants (PM2.5, PM10, NO2 and O3), meteorological factors and time-varying confounders, a 7.98-MUg/m3 (interquartile range) increment in 2 day moving average of same-day and previous-day SO2 concentrations was associated with the statistically significant increase of 4.89% (95% confidence interval: 2.86, 6.95) in neurologic emergency department visits; elevation in SO2 level (per 7.98MUg/m3) was linked to a 5.19% (95% confidence interval: 2.03, 8.44) increase in circulatory emergency department visits. Most positive links were seen during the cold season. CONCLUSIONS: The results of this study contribute to the evidence of the significant associations between SO2 and specific neurologic and circulatory conditions, and also provide insight into the planning of clinical services and emergency contingency response for air pollution exposures in Guangzhou. PMID- 28917171 TI - Ambient air pollution and daily hospital admissions for mental disorders in Shanghai, China. AB - Few studies have investigated the associations between ambient air pollution and mental disorders (MDs), especially in developing countries. We conducted a time series study to explore the associations between six criteria air pollutants and daily hospital admissions for MDs in Shanghai, China, from 2013 to 2015. The MDs data were derived from the Shanghai Health Insurance System. We used over dispersed, generalized additive models to estimate the associations after controlling for time trend, weather conditions, day of the week, and holidays. In addition, we evaluated the effect of modification by age, sex, and season. A total of 39,143 cases of hospital admissions for MDs were identified during the study period. A 10-MUg/m3 increase in 2-day, moving-average concentration of inhalable particulate matter, sulfur dioxide (SO2), and carbon monoxide was significantly associated with increments of 1.27% [95% confidence interval (CI): 0.28%, 2.26%], 6.88% (95% CI, 2.75%, 11.00%), and 0.16% (95% CI: 0.02%, 0.30%) in daily hospital admissions for MDs, respectively. We observed positive but insignificant associations of fine particulate matter, nitrogen dioxide and ozone. The estimated association of SO2 was relatively robust to the adjustment of simultaneous exposure to other pollutants. We found generally stronger associations of air pollutants with MDs in warm seasons than in cool seasons. There were no significant differences in the associations between different sex and age groups. This study suggested that short-term exposure to air pollution, especially to sulfur dioxide, was associated with increased risk of hospital admissions for MDs in Shanghai, China. PMID- 28917172 TI - Reconstruction of atmospheric trace metals pollution in Southwest China using sediments from a large and deep alpine lake: Historical trends, sources and sediment focusing. AB - Atmospheric pollution, one of the leading environmental problems in South and East Asia, and its impact on the terrestrial environmental quality remain poorly understood particularly in alpine areas where both historical and present-day mining and smelting operations might leave an imprint. Here, we reconstructed atmospheric trace metals pollution during the past century using core sediments from a large and deep alpine lake in Southwest China. The implication of in lake and/or in watershed sediment focusing in pollution quantification is discussed by analyzing 15 sediment cores. Factor analysis and enrichment factor indicated Cd, Pb and Sb as the typical pollutants. Distinct peaks of Pb and Sb pollution were observed around the 1920s, but little Pb pollution was detected in recent decades, different from other studies in similar regions. Cadmium pollution was observed until the mid-1980s synchronized with Sb. The distinctive variations in atmospheric trace metal pollution process in Southwest China highlight the regional and sub-regional sources of metal pollutants, which should be primarily attributed to non-ferrous metal smelting emissions. Both natural and anthropogenic metals showed wide concentration ranges though exhibited similar temporal trends in the 15 cores. Spatial variations of anthropogenic metals were influenced by the in-watershed pollutants remobilization, whereas, natural metals were regulated by the detrital materials in the sub-basin. In-lake sediment focusing had little influence on the spatial distributions of all metals, different from the traditional sediment focusing pattern observed in small lakes. Anthropogenic Cd accumulation in sediments ranged from 1.5 to 10.1mgm-2 in a specific core with an average of 6.5mgm-2 for the entire lake, highlighting that a reliable whole-lake pollutant budget requires an analysis of multiple cores. Our study suggests that the management of aquatic ecosystem health should take the remobilization of in-watershed stored pollutants into consideration especially under increasing human perturbation. PMID- 28917173 TI - Synthetic iron (hydr)oxide-glucose associations in subsurface soil: Effects on decomposability of mineral associated carbon. AB - Soils are a globally important reservoir of organic carbon. There is a growing understanding that interactions with soil mineral phases contribute to the accumulation and retention of otherwise degradable organic matter (OM) in soils and sediments. However, the bioavailability of organic compounds in mineral organic-associations (MOAs), especially under varying environmental conditions is not well known. To assess the impact of mineral association and warming on the decomposition of an easily respirable organic substrate (glucose), we conducted a series of laboratory incubations at different temperatures with field-collected soils from 10 to 20cm, 50-60cm, and 80-90cm depth. We added 13C-labeled glucose either directly to native soil or sorbed to one of two synthetic iron (hydr)oxide phases (goethite and ferrihydrite) that differ in crystallinity and affinity for sorbing glucose. We found that: (1) association with the Fe (hydr)oxide minerals reduced the decomposition rate of glucose by >99.5% relative to rate of decomposition for free glucose in soil; (2) the respiration rate per gram carbon did not differ appreciably with depth, suggesting a similar degree of decomposability for native C across depths and that under the incubation conditions total carbon availability represents the principal limitation on respiration under these conditions as opposed to reduced abundance of decomposers or moisture and oxygen limitations; (3) addition of free glucose enhanced native carbon respiration at all soil depths with the largest effect at 50-60cm; (4) in general respiration of the organo-mineral complex (glucose and iron-(hydr)oxide) was less temperature sensitive than was respiration of native carbon; (5) the addition of organic free mineral decreased the rate of soil respiration in the intermediate 50-60cm depth soil. The results emphasize the key role of MOAs in regulating the fluxes of carbon from soils to the atmosphere and in turn the stocks of soil carbon. PMID- 28917174 TI - Potential effects of changes in climate and emissions on distribution and fate of perfluorooctane sulfonate in the Bohai Rim, China. AB - Climate change and emissions rates of contaminants are expected to affect distribution and fate of Persistent Organic Pollutants (POPs) in the environment, however, studies on these combined factors are rare. In this study, Perfluorooctane Sulfonate (PFOS) is used as an example to assess how those two factors synthetically affect fate and disposition of POPs in the Bohai Rim of China by using the Berkeley-Trent-Urban-Rural (BETR-Urban-Rural) model. We set up three climate change scenarios and four emission scenarios to conduct the simulations. The results show that climate change could have significant effects on the transport and fate of PFOS mainly including advection, inter-compartmental transfer under the "worst case" emission scenario. For most grids, a remarkable decrease in concentrations of PFOS are predicted for fresh water and urban soil in the future, with precipitation and temperature being predominant factors, whilst for coastal water and rural soil, an increasing trend is predicted. Additionally, predicted sum of sources to the Bohai Sea increases greater than removals from the Bohai Sea in the future, adding evidence that concentrations of PFOS in coastal water will increase more in the future. Under scenarios of reduced emissions and climate change, concentrations of PFOS in each compartment decreased more rapidly over time. We suggest that assessment of future climate change impacts on fate of PFOS could take emission reductions into consideration. PMID- 28917175 TI - Currently and recently used pesticides in Central European arable soils. AB - Although large amounts of pesticides are used annually and a majority enters the soil to form short- or long-term residues, extensive soil surveys for currently used pesticides (CUPs) are scarce. To determine the status of CUPs' occurrence in arable land in Central Europe, 51 CUPs and 9 transformation products (TPs) were analysed in 75 arable soils in the Czech Republic (CR) several months after the last pesticide application. Moreover, two banned triazines (simazine and atrazine) and their TPs were analysed because of their frequent detection in CR waters. Multi-residue pesticide analysis on LC-MS/MS after soil QuEChERS extraction was used. The soils contained multiple pesticide residues frequently (e.g. 51% soils with >=5 pesticides). The levels were also noticeable (e.g. 36% soils with >=3 pesticides exceeding the threshold of 0.01mg/kg). After triazine herbicides (89% soils), conazole fungicides showed the second most frequent occurrence (73% soils) and also high levels (53% soils with total conazoles above 0.01mg/kg). Frequent occurrence was found also for chloroacetanilide TPs (25% of soils), fenpropidin (20%) and diflufenican (17%). With the exception of triazines' negative correlation to soil pH, no clear relationships were found between pesticide occurrence and soil properties. Association of simazine TPs with terbuthylazine and its target crops proved the frequent residues of this banned compound originate from terbuthylazine impurities. In contrast, frequent atrazine-2-hydroxy residue is probably a legacy of high atrazine usage in the past. The occurrence and levels of compounds were closely associated with their solubility, hydrophobicity and half-life. The results showed links to CR water monitoring findings. This study represents the first extensive survey of multiple pesticide residues in Central European arable soils, including an insight into their relationships to site and pesticide properties. PMID- 28917176 TI - Health-based ingestion exposure guidelines for Vibrio cholerae: Technical basis for water reuse applications. AB - U.S. military and allied contingency operations are increasingly occurring in locations with limited, unstable or compromised fresh water supplies. Non-potable graywater reuse is currently under assessment as a viable means to increase mission sustainability while significantly reducing the resources, logistics and attack vulnerabilities posed by transport of fresh water. Development of health based (non-potable) exposure guidelines for the potential microbial components of graywater would provide a logical and consistent human-health basis for water reuse strategies. Such health-based strategies will support not only improved water security for contingency operations, but also sustainable military operations. Dose-response assessment of Vibrio cholerae based on adult human oral exposure data were coupled with operational water exposure scenario parameters common to numerous military activities, and then used to derive health risk-based water concentrations. The microbial risk assessment approach utilized oral human exposure V. cholerae dose studies in open literature. Selected studies focused on gastrointestinal illness associated with experimental infection by specific V. cholerae serogroups most often associated with epidemics and pandemics (O1 and O139). Nonlinear dose-response model analyses estimated V. cholerae effective doses (EDs) aligned with gastrointestinal illness severity categories characterized by diarrheal purge volume. The EDs and water exposure assumptions were used to derive Risk-Based Water Concentrations (CFU/100mL) for mission critical illness severity levels over a range of water use activities common to military operations. Human dose-response studies, data and analyses indicate that ingestion exposures at the estimated ED1 (50CFU) are unlikely to be associated with diarrheal illness while ingestion exposures at the lower limit (200CFU) of the estimated ED10 are not expected to result in a level of diarrheal illness associated with degraded individual capability. The current analysis indicates that the estimated ED20 (approximately 1000CFU) represents initiation of a more advanced stage of diarrheal illness associated with clinical care. PMID- 28917177 TI - Formation of iodinated THMs during chlorination of water and wastewater in the presence of different iodine sources. AB - The formation potential of iodinated trihalomethanes (I-THMs) during chlorination of different organic precursors in the presence of various iodine sources was studied. Organic precursors included humic acid, natural organic matter from river water and wastewater effluent organic matter. Inorganic iodide and two iodinated X-ray contrast media compounds (iopamidol and diatrizoate) were used as iodine sources. The formation potential of I-THMs under different experimental conditions (chlorination contact time, iodide and bromide concentrations) was investigated. The formation of I-THM species upon chlorination of river water and humic acids rapidly increased up to 24h and then a decreasing trend was observed. Wastewater, showed a rapid formation of I-THMs within the first 6h, followed by a lower rate with extended time. Formation of I-THMs in the presence of iopamidol was more favorable regarding the other two iodine sources. CHBrClI was the dominant specie followed by CHCl2I and CHBr2I. Increasing iodide concentrations result in higher I-THMs formation. The presence of bromide enhanced the I-THMs yields and shifted towards bromine-containing species (CHBrClI and CHBr2I). PMID- 28917178 TI - Adaptive management in the context of barriers in European freshwater ecosystems. AB - Many natural habitats have been modified to accommodate for the presence of humans and their needs. Infrastructures - such as hydroelectric dams, weirs, culverts and bridges - are now a common occurrence in streams and rivers across the world. As a result, freshwater ecosystems have been altered extensively, affecting both biological and geomorphological components of the habitats. Many fish species rely on these freshwater ecosystems to complete their lifecycles, and the presence of barriers has been shown to reduce their ability to migrate and sustain healthy populations. In the long run, barriers may have severe repercussions on population densities and dynamics of aquatic animal species. There is currently an urgent need to address these issues with adequate conservation approaches. Adaptive management provides a relevant approach to managing barriers in freshwater ecosystems as it addresses the uncertainties of dealing with natural systems, and accommodates for future unexpected events, though this approach may not be suitable in all instances. A literature search on this subject yielded virtually no output. Hence, we propose a step-by-step guide for implementing adaptive management, which could be used to manage freshwater barriers. PMID- 28917179 TI - Emission reduction potentials of improved cookstoves and their issues in adoption: An Indian outlook. AB - Biomass as a fuel for cooking is a common practice in rural India, and about 700 million people use traditional stoves to meet their energy demand. However, the thermal and the combustion efficiencies of these stoves are very low, leading to an inefficient use of biomass, and also, resulting in significant indoor air pollution. Research development has however led to the development of some improved stoves viz., natural draft and forced draft for both domestic as well as large scale cooking applications and government is trying to promote them. Forced draft stoves using processed biomass fuels (pellets) have received more prominence due to their superior performance, however, higher initial cost and limited fuel distribution networks have remained the key challenges. Improved natural draft stoves too have gained attention for being relatively inexpensive, and they are more likely to hit the rural households. In this paper, we have examined the environmental benefits obtained by the use of improved stoves for two important scenarios: traditional stoves are replaced by (i)improved natural draft stoves and, (ii) by improved natural draft as well as forced draft stoves. In the best case scenario (case ii), i.e., by shifting 111 million households who currently use wood to the forced draft stoves, and another 45 million households who are dependent on dung cake and agro residues to the improved natural draft stoves, the emission reduction that can be achieved are as follows: particulate matter (PM) 875 kT, black carbon (BC) 229 kT, organic carbon (OC) 525 kT, methane (CH4)1178 kT and non methane hydrocarbon (NMHC) of 564 kT. With the promotion of only natural draft improved stoves, the total reductions would be ~12% lower than the combinational promotion. The CO2 equivalent reduction is estimated to be ~70 80 MT per year. PMID- 28917180 TI - Learning from the operation, pathology and maintenance of a bioretention system to optimize urban drainage practices. AB - LID practices for runoff control are increasingly being used as an integrated solution in urban drainage, helping to achieve hydrological balance close to the pre-urbanized period and decrease the diffuse pollution transported to urban rivers. Regarding bioretention, there is already broad knowledge about the detention of peak flows and their treatment capacity for many pollutants. However, there are still few field studies in microdrainage scale, which analyze the actual operation of these devices and raise common problems found, especially in subtropical climate. Therefore, this study aims to show what was learnt from the field operation of a bioretention cell on a micro-drainage scale, located in an urban catchment of a Brazilian city, suggesting maintenance actions as adaptations to the pathologies found. Five rainy events were monitored during the dry season, in order to carry out a preliminary analysis for critical conditions in terms of maintenance and diffuse pollution accumulation. From the first water balance results, low storage and low infiltration capacity of the soil were found as main pathologies. They led to a great amount of runoff passing directly through the cell surface and at a high velocity, resulting in soil erosion and low water retention efficiency. To overcome these problems, some structural adaptations were made over the cell, highlighting the semi-direct injection. The maintenance and adaptations proposed were suitable to avoid the erosion process, increasing the storage and improving the water retention efficiency in bioretention. They should be considered from the very initial stages, to using sites with low permeability. PMID- 28917181 TI - 137Cs and plutonium isotopes accumulation/retention in bottom sediments and soil in Lithuania: A case study of the activity concentration of anthropogenic radionuclides and their provenance before the start of operation of the Belarusian Nuclear Power Plant (NPP). AB - Knowledge of the background activity concentrations of anthropogenic radionuclides before the start of operations of the new nuclear facilities in Belarus is of great value worldwide. Inland water bodies in Lithuania (specifically the Neris River, the Nemunas River and the Curonian Lagoon) are near the site of the Belarusian NPP under construction and, for this reason, sediments and flooded soils from these sensitive areas were analysed for radiocesium and plutonium isotopes (macrophytes were analysed only for 137Cs) in 2011-2012. The 137Cs and 239+240Pu activity concentrations in bottom sediments from the Nemunas River, sampled in 1995-1996 and re-calculated to the year 2016, were compared with those of 2011-2012. The obtained activity of 137Cs in bottom sediments of the Nemunas River and Curonian Lagoon varied from 1 Bq/kg to 47.0 Bq/kg. The activity of 137Cs in the tested soils ranged from 5.3 B g/kg to 32.9 Bq/kg. The 239+240Pu activity in bottom sediments of the studied sampling sites varied between 0.016 and 0.34 Bq/kg and in flooded soils from 0.064 to 0.55 Bq/kg. The 238Pu activity values were very low or lower than the detection limit. The activity of 137Cs in macrophytes varied from values lower than the detection limit to 6 Bq/kg. A strong positive linear correlation for bottom sediments was calculated between: 239+240Pu and total organic carbon (TOC), r = 0.86, p-value 0.01; 239+240Pu and silt, r = 0.80, p-value 0.029; 137Cs and silt, r = 0.78, p value 0.04; and 137Cs and TOC, r = 0.85, p-value 0.015. The similar peculiarities of 137Cs and 239+240Pu accumulation in bottom sediments and flooded soil allow us to assume that 137Cs can be used as a tracer for 239+240Pu in the initial stage of searching for radionuclide accumulation zones. A remaining impact of the Chernobyl fallout in average comprised: in the Lower Nemunas River and Curonian Lagoon sediments - 51%, in the Middle Nemunas River -90% and in the floodplains of the Nemunas River - 59%, while the provenance of plutonium in studied bottom sediments and flooded soil was the global fallout. PMID- 28917182 TI - Analysis of functional genomes from metagenomes: Revealing the accelerated electron transfer in microbial fuel cell with rhamnolipid addition. AB - Extracellular electron transfer is the predominant electricity generation process in microbial fuel cells (MFCs). Our pervious study have proved that the anodic adsorption of rhamnolipid resulted in the Frumkin effect, which enhanced anodic microorganism attachment and accelerated anodic electron transfer. In this study, an in-depth research on the influence of rhamnolipid on functional genes of anodic biofilms metagenomes was carried out to explain its mechanism at the gene level. The result showed that the composition and distribution of functional genes in each dominant genus were different. The category of signal transduction mechanisms was the dominant function category in exoelectrogens, and its relative abundance in the metagenome significantly increased from 4.56 to 5.86% from rhamnolipid addition. Additionally, the metabolic pathway and electron flow analysis revealed that electron flows tend to choose direct electron transfer in the presence of rhamnolipids, and resulting in the increase of Coulombic efficiency from 19.10+/-0.79% to 27.39+/-1.07%. PMID- 28917184 TI - Investigation of the chemical mechanisms involved in the electropulsation of membranes at the molecular level. AB - The chemical consequences of electropulsation on giant unilamellar vesicles (GUVs), in particular the possible oxidation of unsaturated phospholipids, have been investigated by mass spectrometry, flow cytometry and absorbance methods. Pulse application induced oxidation of the GUV phospholipids and the oxidation level depended on the duration of the pulse. Light and O2 increased the level of pulse-induced lipid peroxidation whereas the presence of antioxidants either in the membrane or in the solution completely suppressed peroxidation. Importantly, pulse application did not create additional reactive oxygen species (ROS) in GUV free solution. Lipid peroxidation seems to result from a facilitation of the lipid peroxidation by the ROS already present in the solution before pulsing, not from a direct pulse-induced peroxidation. The pulse would facilitate the entrance of ROS in the core of the membrane, allowing the contact between ROS and lipid chains and provoking the oxidation. Our findings demonstrate that the application of electric pulses on cells could induce the oxidation of the membrane phospholipids since cell membranes contain unsaturated lipids. The chemical consequences of electropulsation will therefore have to be taken into account in future biomedical applications of electropulsation since oxidized phospholipids play a key role in many signaling pathways and diseases. PMID- 28917183 TI - Visualisation of an nsPEF induced calcium wave using the genetically encoded calcium indicator GCaMP in U87 human glioblastoma cells. AB - Cytosolic, synthetic chemical calcium indicators are typically used to visualise the rapid increase in intracellular calcium ion concentration that follows nanosecond pulsed electric field (nsPEF) application. This study looks at the application of genetically encoded calcium indicators (GECIs) to investigate the spatiotemporal nature of nsPEF-induced calcium signals using fluorescent live cell imaging. Calcium responses to 44kV/cm, 10ns pulses were observed in U87-MG cells expressing either a plasma membrane targeted GECI (GCaMP5-G), or one cytosolically expressed (GCaMP6-S), and compared to the response of cells loaded with cytosolic or plasma membrane targeted chemical calcium indicators. Application of 100 pulses, to cells containing plasma membrane targeted indicators, revealed a wave of calcium across the cell initiating at the cathode side. A similar spatial wave was not observed with cytosolic indicators with mobile calcium buffering properties. The speed of the wave was related to pulse application frequency and it was not propagated by calcium induced calcium release. PMID- 28917185 TI - Ghrelin and hypothalamic NPY/AgRP expression in mice are affected by chronic early-life stress exposure in a sex-specific manner. AB - Early-life stress (ES) is a risk factor for metabolic disorders (e.g. obesity) with a notoriously higher prevalence in women compared to men. However, mechanisms underlying these effects remain elusive. The development of the hypothalamic feeding and metabolic regulatory circuits occurs mostly in the early sensitive postnatal phase in rodents and is tightly regulated by the metabolic hormones leptin and ghrelin. We have previously demonstrated that chronic ES reduces circulating leptin and alters adipose tissue metabolism early and later in life similarly in both sexes. However, it is unknown whether chronic ES might also affect developmental ghrelin and insulin levels, and if it induces changes in hypothalamic feeding circuits, possibly in a sex-dependent manner. We here show that chronic ES, in the form of exposure to limited nesting and bedding material from postnatal day (P)2 to P9 in mice, affects ghrelin levels differently, depending on the form of ghrelin (acylated vs desacylated), on age (P9 vs P14) and on sex, while insulin levels were similarly increased in both sexes after ES at P9. Even though ghrelin levels were more strongly affected in ES-exposed females, hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) fiber density at P14 were similarly altered in both sexes by ES. In the paraventricular nucleus of the hypothalamus, both NPY and AgRP fiber density were increased, while in the arcuate nucleus of the hypothalamus, NPY was increased and AgRP unaltered. Additionally, the hypothalamic mRNA expression of ghrelin's receptor (i.e. growth hormone secretagogue receptor) was not affected by ES. Taken together, the specific alterations found in these important regulatory circuits after ES might contribute to an altered energy balance and feeding behavior in adulthood and thereby to an increased vulnerability to develop metabolic disorders. PMID- 28917186 TI - Compounds isolated from Eriobotrya deflexa leaves protect against ultraviolet radiation B-induced photoaging in human fibroblasts. AB - Ultraviolet (UV) irradiation leads to skin photoaging because of the upregulation of matrix metalloproteinase (MMP)-1 and downregulation of type I collagen and tissue inhibitor of metalloproteinase (TIMP)-1. Eriobotrya deflexa (Hemsl.) Nakai (Rosaceae) is a flowering plant endemic to Taiwan, and its leaves have been used as an expectorant and in antitussive folk remedy. Our previous studies have demonstrated that an E. deflexa leaf extract functions as a free radical scavenger. The current evaluated the antiphotoaging effect of partitioned fractions and specific compounds from the leaves of E. deflexa by using bioguided isolation, compound identification, and biological activity testing with UVB irradiated human fibroblasts (WS-1 cells). E. deflexa leaves were extracted with 95% ethanol and then partitioned using a sequential treatment of n-hexane, ethyl acetate, and n-butanol (n-BuOH). The bioactive n-BuOH fraction was used for isolation and purification through chromatography. The compounds were identified by analyzing their physical and spectroscopic properties. We identified eight compounds from this fraction; of these compounds, 3-O-alpha-l-rhamnopyranosyl (1'''->6")-beta-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) were isolated from E. deflexa for the first time, and they exhibited MMP-1 inhibition activity. The IC50 values were 96.5, 89.5, 93.4, and 92.8MUM for 1, 2, 5, and 7, respectively. These compounds also enhanced the expression of procollagen type I, and TIMP-1 and hyperin (2) were found to be most effective with IC50 values of 56.7 and 70.3MUM, respectively. Hyperin (2) could reduce intracellular reactive oxygen species production in UVB-irradiated WS-1 cells, with the corresponding IC50 value being 80.7MUM. Liquid chromatography triple-quadrupole mass spectrometry was used for the quantitative and chemical fingerprint analysis of active compounds. Quercetin 3-O-alpha-l-rhamnopyranosyl-(1'''->6")-beta-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) constituted 24.2+/-3.9, 5.5+/-1.0, 3.4+/-0.3, and 67.1+/-8.1mg/g of dry weight in the active n-BuOH fraction, respectively. Our results demonstrate that the extract and the isolated active compounds from E. deflexa leaves possess the potential for protection against skin photoaging. PMID- 28917187 TI - Trajectories of post-traumatic stress and externalizing psychopathology among maltreated foster care youth: A parallel process latent growth curve model. AB - Few longitudinal studies have analyzed how violence exposure (e.g. child maltreatment, witnessing community violence) influence both externalizing and Post-Traumatic Stress (PTS) symptoms among children in foster care. Data from three waves of the National Survey of Child and Adolescent Well-Being (1999-2007) (NSCAW; National Data Archive on Child Abuse and Neglect, 2002) were analyzed to investigate the change trajectories of both externalizing and PTS symptomatology among children with a substantiated report of child maltreatment by Child Protective Services (CPS) between October 1999 and December 2000. This study uses data collected at three time points: baseline and approximately 18 (Wave 3) and 36 (Wave 4) months post-baseline. The Child Behavior Checklist (CBCL) scale measured externalizing symptoms and the Post Traumatic Stress Disorder section of a version of the Trauma Symptom Checklist for Children (TSCC) provided the measure of current trauma-related symptoms or distress. Analyses were conducted using a parallel process growth curve model with a sample of n=280 maltreated youth between the ages of 8 and 15 following home removal. Findings revealed that initial levels of externalizing and PTS symptomatology were both significantly and positively related and co-develop over time. Externalizing symptom severity remained in the borderline range during the first two years in out-of-home care. Both direct and indirect forms of interpersonal violence exposure were associated with initial level of externalizing symptom and PTS symptom severity, respectively. Taken together, our results suggest an underlying process that links early violence exposure to the co-development and cumulative impact of PTS on externalizing behavior above and beyond experiences of maltreatment. We conclude by discussing the key points of intervention that result from a more nuanced understanding of the longitudinal relationship between PTS and externalizing symptoms and the effect of complex trauma on growth in these symptoms over time. PMID- 28917188 TI - Assessing the factor structure of the Childhood Trauma Questionnaire, and cumulative effect of abuse and neglect on mental health among adolescents in conflict-affected Burundi. AB - The present study aimed to examine the factor structure of the Childhood Trauma Questionnaire (CTQ; Bernstein & Fink, 1998), highlight rates of abuse and neglect among Burundian adolescents, compare these rates with those found in high-income nations, and examine the cumulative effect of multiple types of abuse and neglect on depression and PTSD symptoms. Participants were 231 adolescents and youth (M=14.9, SD=1.99, 58.4% female) from five provinces of Burundi, a country in Central Africa affected by war and political violence. Translation and back translation of the CTQ was carried out to obtain an adaptation of CTQ in Kirundi, the native language of Burundi. With the exception of one item on 'molestation' in the factor of sexual abuse, the five-factor structure of CTQ was obtained comprising latent factors, namely emotional, physical, and sexual abuse, and emotional and physical neglect. The rate of abuse and neglect ranged from 14.7 93.5% with more than 37% reporting 4 or more types of abuse and neglect experiences. Emotional abuse and neglect, and physical neglect were 2-3 times higher among Burundian adolescents when compared with studies from high-income countries using the CTQ. A cumulative effect of multiple types of abuse and neglect was found, such that, those with 4 or more types of maltreatment were higher on symptoms of depression and posttraumatic stress. Findings highlight the need for culturally sensitive, standardized, and validated measures and norms for gauging childhood maltreatment in Burundi and related need for preventative interventions on childhood maltreatment. PMID- 28917189 TI - Protective factors promoting resilience in the relation between child sexual victimization and internalizing and externalizing symptoms. AB - Sexual victimization has been one of the most frequently studied forms of child victimization. Its effects are common and diverse; however, not all children and youth exposed to sexual victimization eventually develop adjustment problems. A total of 1105 children and youth (590 male and 515 female) aged between 12 and 17 from northeastern Spain were assessed regarding their experiences of sexual victimization, symptoms of psychopathology, and protective factors. The results showed that all forms of sexual victimization were associated with higher levels of emotional and behavioral problems. However, the presence of a low Negative Cognition, high Social Skills and high Confidence seem to act buffering internalizing problems. Additionally, a significant interaction between Sexual Victimization and low Negative Cognition was observed (p<0.5), so that, low Negative Cognition was related to a lower risk of being in the clinical range for internalizing problems. Likewise, high scores on Empathy/Tolerance, Connectedness to School, Connectedness to Family and low Negative Cognition acted as promotive factors in relation to externalizing symptoms, in this case without any interaction effect. The strong relationship found with emotional and behavioral problems highlights the importance of continuing the research on the protective factors underlying resilience in the relationship between sexual victimization and psychopathological symptoms. The findings also support the multi-dimensional and specific nature of resilience and identify some of the protective factors that should be regarded as key intervention targets in adolescents with a history of sexual victimization. PMID- 28917190 TI - Posttraumatic stress symptoms and dissociation between childhood trauma and two different types of psychosis-like experience. AB - This study examined the roles of posttraumatic stress (PTS) symptoms and dissociation in the relationship between childhood trauma and two different types of psychosis-like experience, including persecutory ideation and aberrant experience, in non-psychotic psychiatric patients. From August 2015 to August 2016, among psychiatric out patients seeking treatment at the Department of Psychiatry at a major teaching medical hospital in Seoul, Korea, 169 patients who had never been diagnosed with a psychotic disorder, including schizophrenia spectrum disorder, bipolar disorder, and/or depressive disorder with psychotic features, completed the Korean Childhood Trauma Questionnaire, the Korean version of the Impact of Event Scale-Revised, the modified Korean version of the Peritraumatic Dissociation Experiences Questionnaire, and the Korean Minnesota Multiphasic Personality Inventory-2 (MMPI-2). The RC 6 (Ideas of Persecution) and RC 8 (Aberrant Experiences) of the restructured scales of the MMPI-2 were used as a measure of persecutory ideation and aberrant experience. Structural equation modeling analyses confirmed a partial mediation model in which PTS symptoms partially mediated the relationship between childhood trauma and persecutory ideation, and dissociation partially mediated the relationship between childhood trauma and aberrant experience. This implies that there are distinct mechanisms depending on the type of psychosis-like experience in relation to childhood trauma. PMID- 28917191 TI - Enhanced Arabidopsis disease resistance against Botrytis cinerea induced by sulfur dioxide. AB - Sulfur dioxide (SO2) is a common air pollutant that has complex impacts on plants. The effect of prior exposure to 30mgm-3 SO2 on defence against Botrytis cinerea (B. cinerea) in Arabidopsis thaliana and the possible mechanisms of action were investigated. The results indicated that pre-exposure to 30mgm-3 SO2 resulted in significantly enhanced resistance to B. cinerea infection. SO2 pre treatment significantly enhanced the activities of defence-related enzymes including phenylalanine ammonia-lyase (PAL), polyphenol oxidase (PPO), beta-1,3 glucanase (BGL) and chitinase (CHI). Transcripts of the defence-related genes PAL, PPO, PR2, and PR3, encoding PAL, PPO, BGL and CHI, respectively, were markedly elevated in Arabidopsis plants pre-exposed to SO2 and subsequently inoculated with B. cinerea (SO2+ treatment group) compared with those that were only treated with SO2 (SO2) or inoculated with B. cinerea (CK+). Moreover, SO2 pre-exposure also led to significant increases in the expression levels of MIR393, MIR160 and MIR167 in Arabidopsis. Meanwhile, the expression of known targets involved in the auxin signalling pathway, was negatively correlated with their corresponding miRNAs. Additionally, the transcript levels of the primary auxin-response genes GH3-like, BDL/IAA12, and AXR3/IAA17 were markedly repressed. Our findings indicate that 30mgm-3 SO2 pre-exposure enhances disease resistance against B. cinerea in Arabidopsis by priming defence responses through enhancement of defence-related gene expression and enzyme activity, and miRNA mediated suppression of the auxin signalling pathway. PMID- 28917192 TI - Mass loading and emission of thirty-seven pharmaceuticals in a typical municipal wastewater treatment plant in Hunan Province, Southern China. AB - The occurrence, fate, mass loading and environmental emission of 37 pharmaceuticals were studied through an integrated approach involving both dissolved and adsorbed phase at a typical wastewater treatment plant in Hunan Province, Southern China. The results displayed the prevalence of 24 and 23 compounds in dissolved phase of influent and effluent, respectively. Fourteen compounds were found adsorbed onto sludge with a mean concentration ranging from 0.85 to 2900MUg/kg dry weight. Twelve compounds exhibited high adsorption potential onto suspended particulate matter (SPM) with a mean fraction ranging from 8.8% (trimethoprim) to 97% (tetracycline). Furthermore, SPM showed a diverse absorbability in influent and effluent water circumstance. The overall elimination varied from -16% for lincomycin to 99% for paracetamol, while macrolides were able to withstand the whole treatment process. Mass balance analysis indicated that degradation was the predominant removal pathway for most compounds, and adsorption onto sludge combined with a minor portion of degradation explained for the reduction of tetracyclines and fluoroquinolones, whereas macrolides were recalcitrant to both two processes. The total mass loading was estimated to be up to 2800mg/d/1000 inhabitants and most compounds exhibited lower or comparable level comparing to the global published data. The total environmental emission was estimated up to be 1000mg/d/1000 inhabitants, and a value of 650mg/d/1000 inhabitants was obtained when considering merely the dissolved phase. This work would be helpful for the better understanding of ultimate fate and real pollution of pharmaceuticals in the water environment. PMID- 28917193 TI - High C-reactive protein levels are associated with depressive symptoms in schizophrenia. AB - BACKGROUND: Depressive symptoms are frequently associated with schizophrenia symptoms. C - Reactive protein (CRP), a marker of chronic inflammation, had been found elevated in patients with schizophrenia and in patients with depressive symptoms. However, the association between CRP level and depressive symptoms has been poorly investigated in patients with schizophrenia. The only study conducted found an association between high CRP levels and antidepressant consumption, but not with depressive symptoms investigated with the Calgary Depression Rating Scale for Schizophrenia (CDSS). OBJECTIVES: The aim of this study was to evaluate CRP levels and depressive symptoms in patients with schizophrenia, and to determine whether high CRP levels are associated with depressive symptoms and/or antidepressant consumption, independently of potential confounding factors, especially tobacco-smoking and metabolic syndrome. METHODS: Three hundred and seven patients with schizophrenia were enrolled in this study (mean age = 35.74 years, 69.1% male gender). Depressive symptoms was investigated with the CDSS. Patients were classified in two groups: normal CRP level (<= 3.0mg/L) and high CRP level (> 3.0mg/L). Current medication was recorded. RESULTS: 124 subjects (40.4%) were classified in the high CRP level group. After adjusting for confounding factors, these patients were found to have higher CDSS scores than those with normal CRP levels in multivariate analyses (p = 0.035, OR = 1.067, 95% CI = 1.004-1.132). No significant association between CRP levels and antidepressants consumption was found. LIMITATIONS: The size sample is relatively small. The cut-off point for high cardiovascular risk was used to define the two groups. CRP was the sole marker of inflammation in this study and was collected at only one time point. The design of this study is cross-sectional and there are no conclusions about the directionality of the association between depression and inflammation in schizophrenia. CONCLUSION: This study found an association between high rates of CRP levels and depressive symptoms in patients with schizophrenia, but no association with antidepressant consumption. Further studies are needed to investigate the impact of inflammation in schizophrenia. PMID- 28917194 TI - Selective functional dysconnectivity of the dorsal-anterior subregion of the precuneus in drug-naive major depressive disorder. AB - BACKGROUND: Patients with major depressive disorder (MDD) have shown altered resting-state functional connectivity (rsFC) of the precuneus; however, it is unknown whether rsFC of the precuneus subregions is differentially affected in this disorder. METHODS: In this study, we aimed to clarify this issue by comparing rsFC of each precuneus subregion between patients with MDD and healthy controls. Forty-seven drug-naive patients with MDD and 47 sex-, age- and education-matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). The precuneus was divided into PCun-1 (dorsal-central portion; medial area 7), PCun-2 (dorsal-anterior portion; medial area 5), PCun-3 (dorsal-posterior portion; dorsomedial parietooccipital sulcus) and PCun-4 (ventral portion; area 31). The rsFC of each precuneus subregion was compared between the two groups. RESULTS: Compared with healthy controls, patients with MDD exhibited increased rsFC between the left PCun-2 and the right fusiform gyrus, lateral prefrontal cortex, sensorimotor cortex and supramarginal gyrus. No significant inter-group difference was observed in the rsFC of other precuneus subregions. In addition, there was no difference in gray matter volume of all the precuneus subregions between patients with MDD and healthy controls. LIMITATIONS: Some of the patients had chronic MDD and relevant neuropsychological data were not collected. CONCLUSIONS: These findings suggest a selective functional dysconnectivity of the precuneus subregions in drug-naive MDD, characterized by the hyperconnnectivity between the dorsal-anterior subregion and regions involved in visual, executive control, sensorimotor and bottom-up attention functions. PMID- 28917195 TI - Uric acid in major depressive and anxiety disorders. AB - BACKGROUND: Uric acid has neuroprotective effects, owing to its antioxidant properties. Lowered antioxidant capacity, causing increased oxidative stress, may be involved in affective disorders and might be altered by antidepressants. This study investigated the association of plasma uric acid, the greatest contributor to blood antioxidant capacity, with major depressive disorder (MDD) and anxiety disorders. METHODS: Data were from the Netherlands Study of Depression and Anxiety including patients with current (N = 1648), remitted (N = 609) MDD and/or anxiety disorders (of which N = 710 antidepressant users) and 618 controls. Diagnoses were established with the Composite International Diagnostic Interview. Symptom severity was assessed with the Inventory of Depressive Symptoms-Self Report, Beck Anxiety Inventory and Fear Questionnaire. Uric acid was measured in plasma. Analyses were adjusted for sociodemographic, health and lifestyle variables. RESULTS: Plasma uric acid adjusted mean levels were lower in current MDD and/or anxiety disorder(s) (289MUmol/l) compared to remitted disorders (298MUmol/l, p < .001) and controls (299MUmol/l, p < .001; Cohen's d .10). This finding was independent of antidepressant use. Depressive (beta-.05, p = .0012), anxiety (beta-.04, p = .009) and phobic (beta-.03, p = .036) symptom severity, and symptom duration (beta-.04, p = .009) were negatively associated with uric acid. LIMITATIONS: Limitations include the lack of data on dietary intake which could be a potential confounding factor. From these cross-sectional findings, the association between uric acid and psychopathology cannot be inferred to be causal. CONCLUSION: This large scale study finds plasma uric acid levels are lower in current, but not remitted, MDD and/or anxiety disorders, according to a dose-response gradient. This suggests the involvement of decreased antioxidant status in affective disorders, and points to their potential as an avenue for treatment. PMID- 28917196 TI - Possible predictors of age at illness onset and illness duration in a cohort study comparing younger adults and older major affective patients. AB - BACKGROUND: Major affective conditions are associated with significant disability and psychosocial impairment. Whether specific socio-demographic and clinical characteristics may distinguish subgroups of patients in terms of prognosis and illness trajectories is a matter of debate. METHODS: The sample of this naturalistic cohort study included 675 currently euthymic patients with major affective disorders of which 428 (63.4%) were diagnosed with unipolar and 247 (36.6%) with bipolar disorders. RESULTS: Younger adults with a longer duration of untreated illness and residual inter-episodic symptoms were more likely to be single or divorced, students, with an earlier age of first treatment/hospitalization, longer duration of substance abuse and duration of illness than older patients who were, conversely, more likely to be widowed and retired. Multivariate analyses showed a significant positive contribution to age at illness onset by marital status, nonpsychiatric medications, substance abuse, psychiatric diagnosis (bipolar vs. unipolar), age at first treatment/hospitalization, duration of illness, and current age. According to a further analysis, we also found a significant positive contribution to duration of illness by marital status, educational level, positive history of psychiatric conditions in family, substance abuse, psychiatric diagnosis (bipolar vs. unipolar), age at illness onset, age at first treatment, and certain cardiovascular disorders. CONCLUSIONS: There are substantial socio-demographic and clinical differences that may help to distinguish specific subgroups of patients; however, additional studies are requested to replicate these results and further investigate the main factors underlying our findings. PMID- 28917197 TI - Adolescent socioeconomic status and depressive symptoms in later life: Evidence from structural equation models. AB - BACKGROUND: The complex association between socioeconomic status (SES) and depressive symptoms is not entirely understood and the existing literature does not address the relationship between early-life SES and later-life depression from a life-course perspective, incorporating mediating events. METHODS: Using data from the Wisconsin Longitudinal Study, we employed structural equation modeling to examine how SES measured at age 18 affects depressive symptoms at age 54 directly and through mediating variables college graduation, marriage, and household income level at age 36. RESULTS: The total effect of adolescent SES on later-life depressive symptoms is largely mediated through college graduation. Our final model was driven by the effects of women. The variables contributing most to depressive symptoms in women were the direct effect of being raised in a home with a low SES and the indirect effect of low adolescent SES mediated through non-completion of college. LIMITATIONS: Cohort was exclusively comprised of white, high school graduates born in 1939 (+/- 2 years). In our analysis we assume that missing values are missing at random (MAR); however, attrition both from death (excluded from our population) and from non-response could be associated with depression, i.e. missing not at random (MNAR). CONCLUSIONS: This study demonstrates the impact of completion of college, particularly among women, and supports the social mobility hypothesis to explain the relationship between adolescent socioeconomic circumstances and late-life health. PMID- 28917198 TI - Dissipation behavior and residue distribution of fluazaindolizine and its seven metabolites in tomato ecosystem based on SAX SPE procedure using HPLC-QqQ-MS/MS technique. AB - Fluazaindolizine suspension concentrate (500gL-1 SC), as a pre-commercialized product, was firstly investigated under open-field conditions. A sensitive method for simultaneous determination of fluazaindolizine and seven metabolites (IN QEK31, IN-F4106, IN-A5760, IN-UJV12, IN-UNS90, IN-QZY47 and IN-TMQ01) was established and validated using HPLC-QqQ-MS/MS technique. The LOQs of these pollutants in tomato were 0.01mgkg-1, and their recoveries were 81.1%-117% with the relative standard deviations (RSDs <11.8%). The dissipation behaviours of fluazaindolizine in soil followed first-order kinetics with the half lives of 4.6 32.4days, whilst the residues in plant were below its LOQ after 7days. The fluazaindolizine residues in soil were below 0.963mgkg-1, based on root irrigation applications (50-75mg a.i. per plant) twice and pre-harvest interval (PHI, 3days), while the residues of IN-QEK31, IN-F4106 and IN-A5760 were below 3.9mgkg-1, excluding other four metabolites (<0.01mgkg-1). The residues of fluazaindolizine in tomato were below 0.01mgkg-1, and IN-QEK31 remained 0.135mgkg 1. The current study could not only guide reasonable usage of the formulation, but also facilitate the setting of residue definition and its maximum residue limits (MRLs) of fluazaindolizine in tomato. PMID- 28917200 TI - Improved visible-light activities for degrading pollutants on TiO2/g-C3N4 nanocomposites by decorating SPR Au nanoparticles and 2,4-dichlorophenol decomposition path. AB - It has been clearly demonstrated that the visible-light photocatalytic activities of g-C3N4 (CN) for degrading 2,4-dichlorophenol (2,4-DCP) and bisphenol A (BPA) could be improved by fabricating nanocomposites with a proper amount of nanocrystalline anatase TiO2. Interestingly, the visible-light activities of the amount-optimized nanocomposite could be further improved after decorating Au nanoparticles, with 5.11- and 3.1-time improvement respectively for 2,4-DCP and BPA compared to that of CN, even much higher than that of P25 TiO2 under UV-vis irradiation. Based on the transient-state surface photovoltage responses and photoelectrochemical measurements, it is confirmed that the exceptional visible light activities of the fabricated Au-(TiO2/g-C3N4) nanocomposites are attributed to the extended visible-light response due to the surface plasmonic resonance (SPR) of decorated Au and its catalytic function, and to the enhanced charge separation by transferring electrons from CN and SPR Au to TiO2 in the nanocomposites. The highly promoted charge separation results in the effective availability of a large number of hydroxyl radicals (OH) participating in the photocatalytic oxidation process of 2,4-DCP. Furthermore, a possible mechanism of 2,4-DCP degradation is proposed according to the detailed analyses of produced intermediates. This work provides new idea for designing Au assisted nanocomposite photocatalysts for environmental remediation. PMID- 28917199 TI - Enhanced phosphorus and ciprofloxacin removal in a modified BAF system by configuring Fe-C micro electrolysis: Investigation on pollutants removal and degradation mechanisms. AB - A modified biological aerated filter (BAF) system configured Fe-C micro electrolysis was applied to enhance phosphorus and ciprofloxacin (CIP) removal. A novel sludge ceramic and sintering ferric-carbon ceramic (SFC) were separately packed into a lab-scale BAF and Fe-C micro electrolysis reactor. The BAF and Fe-C micro electrolysis coupled system was operated about 230days. The enhancement of phosphorus and ciprofloxacin removals by Fe-C micro electrolysis, the degradation mechanisms of CIP and the variations of microbial population were investigated. The removal efficiencies of chemical oxygen demand (CODcr), ammonia (NH4-N), total phosphorus (TP) and CIP reached about 95%, 95%, 80% and 85% in the combined process, respectively. Configuring Fe-C micro electrolysis significantly enhanced phosphorus and CIP removal, whereas had no promotion on N removal. Four main degradation pathways were proposed according to the LC-MS analysis. More than 12 degradation products were detected through the treatment of Fe-C micro electrolysis and only 3 biodegraded products with low concentration were identified in BAF effluent. The high-throughput sequencing analysis showed that the microbial community changed a lot under CIP pressure. The relative abundance of Sphingomonadaceae, Xanthomonadaceae, Bradyrhizobium, Helicobacter and Pseudomonas increased with CIP influent. This study provides a promising process in CIP wastewater treatment. PMID- 28917201 TI - In silico investigation of propofol binding sites in human serum albumin using explicit and implicit solvation models. AB - All-atom molecular dynamics (MD) simulations are presented on general anesthetic propofol bound to human serum albumin (HSA) due to the drug pharmacokinetics and pharmacodynamics in the circulatory system. We implemented the explicit and implicit solvation models to compare the binding affinity of propofol at the different binding sites (PR1 and PR2) in the HSA protein. Only the implicit solvation models provided the evidence in accordance with the experimental data indicating that the HSA-ligand interactions are dominanted by hydrophobic forces due to the higher drug affinity at the PR1 position with a DeltaGMM-PB/SA value of -23.44kcalmol-1. Overall, this study provides important information on the accuracy of explicit and implicit solvation models to characterize the propofol interaction with different HSA binding sites. PMID- 28917202 TI - Mechanisms of MAGUK-mediated cellular junctional complex organization. AB - Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are enriched in cellular junctions and essential for tissue development and homeostasis. Mutations of MAGUKs are linked to many human diseases including cancers, psychiatric disorders, and intellectual disabilities. MAGUKs share a common PDZ-SH3-GK tandem domain organization at the C-terminal end. In this review, we summarize the mechanistic basis governing target recognition and regulations of this binding by the PDZ-SH3-GK tandem of various MAGUKs. We also discuss recent discoveries showing unique folding features of MAGUK PDZ-SH3-GK tandems that facilitate ligand-induced oligomerization of MAGUKs and phase transition of MAGUK-assembled synaptic signaling complexes. PMID- 28917203 TI - Cognitive-behavioral correlates of proxy reports on cognitive capabilities in pediatric patients with epilepsy. AB - PURPOSE: To validate the Cognitive Problems in Children and Adolescents Questionnaire (KOPKIJ, German: Kognitive Probleme bei Kindern und Jugendlichen), a proxy report measure for recognizing cognitive problems in pediatric patients with epilepsy. METHODS: Anonymized data sets from 279 pediatric epilepsy patients were standardized in regard to the KOPKIJ results of 352 healthy children and adolescents. The KOPKIJ was related to objective routine neuropsychological assessment (NPY), and to two subjective measures, the Child Behavior Checklist questionnaire (CBCL), a proxy rating by the parents, and a questionnaire for self perceived health-related quality of life in children and adolescents (KINDL). RESULTS: Following principal component analysis of the KOPKIJ's normative data, three scales "basic functions", "academic skills", and a "total score" were differentiated, which indicated problems in 35%, 33%, and 32% of the children. Low IQ was evident in 23%, objective impairments in at least one major cognitive domain in 64% of the patients. Behavior (CBCL) and quality of life (KINDL) were impaired in 40% and 21% of the patients. Separate regression analyses revealed that objective cognitive performance (IQ, language, visual-spatial functions) explained ~30%, behavior (CBCL) and coping with the disease (KINDL) about ~40%, and clinical features (age at onset) 5-8% of the variance of the KOPKIJ scales. CONCLUSION: The parents' impressions of children's cognition obtained via the KOPKIJ only in part reflect the neuropsychological cognitive status of children and adolescents with epilepsy. They appear rather determined by the children's behavioral problems, which in real life situations indeed often co-occur with cognitive impairments. Aspects of the epilepsy only marginally influence the parents' ratings of their children's cognition. PMID- 28917204 TI - Murine IL-4Delta2 splice variant down-regulates IL-4 activities independently of IL-4Ralpha binding and STAT-6 phosphorylation. AB - IL-4 is a pleiotropic cytokine that is highly Th2 polarizing. The ratio of IL-4 and its splice variant IL-4Delta2 observed in human health and disease suggests a role for both isoforms. In the present study, the biological function of murine IL-4Delta2 and the potential mechanism of action were studied. We report for the first time the generation of a functional, recombinant murine IL-4Delta2 form which is suggestive of its possible biological role in this species. Recombinant murine IL-4Delta2 inhibited IL-4 mediated cellular processes in macrophages and lymphocytes. Specifically, (i) it reversed IL-4 mediated inhibition of IFN-gamma induced nitric oxide release by macrophages, (ii) inhibited IL-4 mediated induction of T cell proliferation, and (iii) prevented IL-4 stimulation of IgE synthesis by B cells. However, IL-4Delta2 did not compete with IL-4 for IL 4Ralpha binding and did not interfere with the downstream STAT-6 phosphorylation in T cells, suggesting an alternative mechanism for its antagonism of specific IL4-driven effects. These findings suggest that the mouse is a suitable experimental model for studies of the biology of IL-4 and its alternative splice variant. PMID- 28917205 TI - Prenatal DDT exposure and child adiposity at age 12: The CHAMACOS study. AB - OBJECTIVE: Using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort study, we assessed the association of in utero exposure to dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenylethylene (DDE) with child adiposity at age 12. METHODS: We included 240 children with o,p'-DDT, p,p'-DDT, and p,p'-DDE concentrations measured in maternal serum collected during pregnancy (ng/g lipid) and complete 12-year follow-up data. Age- and sex-specific body mass index (BMI) z-scores were calculated from CDC growth charts. Children with BMI z-scores >= 85th percentile were classified as overweight or obese. RESULTS: At 12 years, BMI z-score averaged 1.09 (+/-1.03) and 55.4% of children were overweight or obese. Prenatal DDT and DDE exposure was associated with several adiposity measures in boys but not girls. Among boys, 10-fold increases in prenatal DDT and DDE concentrations were associated with increased BMI z-score (o,p'-DDT, adj-beta=0.37, 95% CI: 0.08, 0.65; p,p'-DDT, adj-beta = 0.26, 95% CI: 0.03, 0.48; p,p'-DDE, adj-beta = 0.31, 95% CI: 0.02, 0.59). Results for girls were nonsignificant. The difference by sex persisted after considering pubertal status. CONCLUSIONS: These results support the chemical obesogen hypothesis, that in utero exposure to DDT and DDE may increase risk of obesity in males later in life. PMID- 28917206 TI - Maternal and infant outcomes following third trimester exposure to marijuana in opioid dependent pregnant women maintained on buprenorphine. AB - BACKGROUND: To determine whether maternal and infant outcomes are associated with exposure to marijuana during the third trimester in a population of opioid dependent pregnant women maintained on buprenorphine. METHODS: This retrospective cohort study of 191 maternal-infant dyads exposed to buprenorphine during pregnancy examines a variety of variables including gestational age, birthweight, method of delivery, Apgar scores at one and five minutes, duration of infant hospital stay, peak neonatal abstinence syndrome (NAS) score, duration of NAS and incidence of pharmacologic treatment of NAS in infants exposed to marijuana during the third trimester as compared to infants not exposed to marijuana during the third trimester. RESULTS: Analyses failed to support any significant relationship between marijuana use in the third trimester and a variety of maternal and infant outcomes. Two important variables - the likelihood of requiring pharmacologic treatment for NAS (27.6% in marijuana exposed infants vs. 15.7% in non-marijuana exposed infants, p=0.066) and the duration of infant hospital stay (7.7days in marijuana exposed infants vs. 6.6days in non-exposed infants, p=0.053) trended toward significance. CONCLUSIONS: Preliminary results indicate that marijuana exposure in the third trimester does not complicate the pregnancy or the delivery process. However, the severity of the infant withdrawal syndrome in the immediate postnatal period may be impacted by marijuana exposure. Because previous study of prenatal marijuana exposure has yielded mixed results, further analysis is needed to determine whether these findings are indeed significant. PMID- 28917207 TI - Exposure to ambient air pollution and the incidence of dementia: A population based cohort study. AB - INTRODUCTION: Emerging studies have implicated air pollution in the neurodegenerative processes. Less is known about the influence of air pollution, especially at the relatively low levels, on developing dementia. We conducted a population-based cohort study in Ontario, Canada, where the concentrations of pollutants are among the lowest in the world, to assess whether air pollution exposure is associated with incident dementia. METHODS: The study population comprised all Ontario residents who, on 1 April 2001, were 55-85years old, Canadian-born, and free of physician-diagnosed dementia (~2.1 million individuals). Follow-up extended until 2013. We used population-based health administrative databases with a validated algorithm to ascertain incident diagnosis of dementia as well as prevalent cases. Using satellite observations, land-use regression model, and an optimal interpolation method, we derived long term average exposure to fine particulate matter (<=2.5MUm in diameter) (PM2.5), nitrogen dioxide (NO2), and ozone (O3), respectively at the subjects' historical residences based on a population-based registry. We used multilevel spatial random-effects Cox proportional hazards models, adjusting for individual and contextual factors, such as diabetes, brain injury, and neighborhood income. We conducted various sensitivity analyses, such as lagging exposure up to 10years and considering a negative control outcome for which no (or weaker) association with air pollution is expected. RESULTS: We identified 257,816 incident cases of dementia in 2001-2013. We found a positive association between PM2.5 and dementia incidence, with a hazard ratio (HR) of 1.04 (95% confidence interval (CI): 1.03 1.05) for every interquartile-range increase in exposure to PM2.5. Similarly, NO2 was associated with increased incidence of dementia (HR=1.10; 95% CI: 1.08-1.12). No association was found for O3. These associations were robust to all sensitivity analyses examined. These estimates translate to 6.1% of dementia cases (or 15,813 cases) attributable to PM2.5 and NO2, based on the observed distribution of exposure relative to the lowest quartile in concentrations in this cohort. DISCUSSION: In this large cohort, exposure to air pollution, even at the relative low levels, was associated with higher dementia incidence. PMID- 28917208 TI - Prenatal exposure to perfluoroalkyl substances and birth outcomes in a Spanish birth cohort. AB - BACKGROUND: Prenatal perfluorooctanoate (PFOA) exposure has been associated with reduced birth weight but maternal glomerular filtration rate (GFR) may attenuate this association. Further, this association remains unclear for other perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). We estimated associations between prenatal PFAS exposure and birth outcomes, and the influence of GFR, in a Spanish birth cohort. METHODS: We measured PFHxS, PFOS, PFOA, and PFNA in 1st-trimester maternal plasma (years: 2003-2008) in 1202 mother-child pairs. Continuous birth outcomes included standardized weight, length, head circumference, and gestational age. Binary outcomes included low birth weight (LBW), small-for-gestational-age, and preterm birth. We calculated maternal GFR from plasma-creatinine measurements in the 1st-trimester of pregnancy (n=765) using the Cockcroft-Gault formula. We used mixed-effects linear and logistic models with region of residence as random effect and adjustment for maternal age, parity, pre-pregnancy BMI, and fish intake during pregnancy. RESULTS: Newborns in this study weighted on average 3263g and had a median gestational age of 39.8weeks. The most abundant PFAS were PFOS and PFOA (median: 6.05 and 2.35ng/mL, respectively). Overall, PFAS concentrations were not significantly associated to birth outcomes. PFOA, PFHxS, and PFNA showed weak, non-statistically significant associations with reduced birth weights ranging from 8.6g to 10.3g per doubling of exposure. Higher PFOS exposure was associated with an OR of 1.90 (95% CI: 0.98, 3.68) for LBW (similar in births-at-term) in boys. Maternal GFR did not confound the associations. CONCLUSIONS: In this study, PFAS showed little association with birth outcomes. Higher PFHxS, PFOA, and PFNA concentrations were non-significantly associated with reduced birth weight. The association between PFOS and LBW seemed to be sex-specific. Finally, maternal GFR measured early during pregnancy had little influence on the estimated associations. PMID- 28917209 TI - Ecological risk estimation of organophosphorus pesticides in riverine ecosystems. AB - Pesticides are of great concern because of their existence in ecosystems at trace concentrations. Worldwide pesticide use and its ecological impacts (i.e., altered environmental distribution and toxicity of pesticides) have increased over time. Exposure and toxicity studies are vital for reducing the extent of pesticide exposure and risk to the environment and humans. Regional regulatory actions may be less relevant in some regions because the contamination and distribution of pesticides vary across regions and countries. The risk quotient (RQ) method was applied to assess the potential risk of organophosphorus pesticides (OPPs), primarily focusing on riverine ecosystems. Using the available ecotoxicity data, aquatic risks from OPPs (diazinon and chlorpyrifos) in the surface water of the Langat River, Selangor, Malaysia were evaluated based on general (RQm) and worst case (RQex) scenarios. Since the ecotoxicity of quinalphos has not been well established, quinalphos was excluded from the risk assessment. The calculated RQs indicate medium risk (RQm = 0.17 and RQex = 0.66; 0.1 <= RQ < 1) of overall diazinon. The overall chlorpyrifos exposure was observed at high risk (RQ >= 1) based on RQm and RQex at 1.44 and 4.83, respectively. A contradictory trend of RQs > 1 (high risk) was observed for both the general and worst cases of chlorpyrifos, but only for the worst cases of diazinon at all sites from downstream to upstream regions. Thus, chlorpyrifos posed a higher risk than diazinon along the Langat River, suggesting that organisms and humans could be exposed to potentially high levels of OPPs. PMID- 28917210 TI - Single and mixture toxicity of abamectin and difenoconazole to adult zebrafish (Danio rerio). AB - Concerns have been raised in recent years on the potential risks related with pesticide mixtures that are likely to be present in agricultural edge-of-field waterbodies. Despite the high use of pesticides in tropical countries like Brazil, studies evaluating pesticide mixtures are especially scarce in the tropics. The insecticide abamectin and the fungicide difenoconazole are the main pesticides intensively used in Brazilian strawberry crop and are hence likely to occur simultaneously. The aim of the present study was therefore to evaluate the toxicity of abamectin, difenoconazole and their mixture to the tropical fish Danio rerio. Laboratory toxicity tests with the individual pesticides indicated 48 h-LC50 values of 59 MUg L-1 for abamectin and 1.4 mg L-1 for difenoconazole. Mixtures of the two pesticides revealed a synergistic deviation of the independent action model. Implications of study findings for the aquatic risk assessment of pesticide mixtures, especially in tropical countries and indications for future research are discussed. PMID- 28917211 TI - Bactericidal and catalytic performance of green nanocomposite based-on chitosan/carbon black fiber supported monometallic and bimetallic nanoparticles. AB - Nanoparticles were synthesized on the surface of green nanocomposite based on carbon black dispersed in chitosan (CB-CS) fibres. The nanoparticles were monometallic Co, Ag and Cu and bimetallic Co + Cu and Co + Ag. The CB-CS fibres were prepared and introduced into separate metal salt solutions containing Co2+, Ag+ and Cu2+ and mixed Co2++Cu2+ and Co2++Ag+ ions. The metal ions immobilized on the surface of CB-CS were reduced using sodium borohydride (NaBH4) as reducing agent to synthesize the corresponding zero-valent metal nanoparticles-loaded CB CS fibres. All the nanoparticles-loaded CB-CS samples were characterized using field emission-scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction techniques. When tested as catalysts, the nanoparticles-loaded CB-CS showed excellent catalytic ability for the reduction of toxic and environmentally unwanted pollutants of para-nitrophenol, congo red and methyl orange dyes. Afterwards, the antimicrobial activities of virgin and metal-loaded CB-CS fibres were tested and the metal-loaded CB-CS fibres were found to be effective against Escherichia coli. In addition, the catalyst can be recovered easily by simply removing the fibres from the reaction mixture and can be recycled several times while maintaining high catalytic efficiency. PMID- 28917212 TI - Comparative analytical and toxicological assessment of methylcyclohexanemethanol (MCHM) mixtures associated with the Elk River chemical spill. AB - On January 9, 2014, a chemical mixture containing crude methylcyclohexanemethanol (MCHM) contaminated the water supply of Charleston, West Virginia. Although the mixture was later identified as a mix of crude MCHM and stripped propylene glycol phenyl ethers, initial risk assessment focused on 4-MCHM, the predominant component of crude MCHM. The mixture's exact composition and the toxicity differences between 4-MCHM, crude MCHM, and the tank mixture were unknown. We analyzed the chemical composition of crude MCHM and the tank mixture via GC/MS and, based on identified spectra, found that crude MCHM and the tank mixture differed in chemical composition. To evaluate acute developmental toxicity, zebrafish embryos were exposed to 0, 1, 6.25, 12.5, 25, 50, or 100 parts per million (ppm; mg/L) of 4-MCHM, crude MCHM, or the tank mixture. The percent mortality and percent hatch, larval morphology alterations, and larval visual motor response test were used to establish toxicity profiles for each of the chemicals or mixtures. The acute toxicity differed between 4-MCHM, crude MCHM and the tank mixture with significant differences in survival, hatching, morphology, and locomotion at levels as low as the short-term screening level of 1 ppm, suggesting a need for further research into human health risks. This study is the first to evaluate the developmental toxicity of the tank mixture and highlights that studies evaluating risk should not assume the effects of 4-MCHM or crude MCHM are representative of the Tank 396 mixture. PMID- 28917213 TI - Hydraulic connectivity and evaporation control the water quality and sources of chromophoric dissolved organic matter in Lake Bosten in arid northwest China. AB - Lake Bosten is the largest oligosaline lake in arid northwestern China, and water from its tributaries and evaporation control the water balance of the lake. In this study, water quality and chromophoric dissolved organic matter (CDOM) absorption and fluorescence were investigated in different seasons to elucidate how hydraulic connectivity and evaporation may affect the water quality and variability of CDOM in the lake. Mean suspended solids and turbidity were significantly higher in the upstream tributaries than in the lake, the difference being notably more pronounced in the wet than in the dry season. A markedly higher mean first principal component (PC1) score, which was significantly positively related to protein-like components, and a considerably lower fluorescence peak integration ratio - IC:IT, indicative of the terrestrial humic like CDOM contribution percentage, were observed in the lake than in the upstream tributaries. Correspondingly, notably higher contribution percentages of terrestrial humic-like components were observed in the river mouth areas than in the remaining lake regions. Furthermore, significantly higher mean turbidity, and notably lower mean conductivity and salinity, were recorded in the southwestern Kaidu river mouth than in the remaining lake regions in the wet season. Notably higher mean salinity is recorded in Lake Bosten than in upstream tributaries. Autochthonous protein-like associated amino-acids and also PC1 scores increased significantly with increasing salinity. We conclude that the dynamics of water quality and CDOM composition in remote arid Lake Bosten are strongly driven by evaporation and also the hydraulic connectivity between the upstream tributaries and the downstream lake. PMID- 28917214 TI - Novel (5-nitrofurfuryl)-substituted esters of phosphonoglycine - Their synthesis and phyto- and ecotoxicological properties. AB - Since aminophosphonate-based herbicides like glyphosate are currently one of the most popular and widely applied active agent in agrochemistry, there is an urgent need for searching new compounds among this family with potential herbicidal activity, but exhibiting low toxicity against surrounding environment. Six new (5 nitrofurfuryl)-derived aminophosphonates were synthesized for the first time and apart from the only one example of N-benzylamino(5-nitrofuryl)-methylphosphonic acid, it was the first time in the history, when this class of compounds was prepared. Their prospective and real biological properties have been followed up by evaluation of their preliminary ecotoxicology. They have been then investigated in aspect of their phytotoxicity against oat (A. sativa) and common radish (R. sativus) exhibiting moderate-to-severe toxicity for these plants. The significant selectivity towards radish (up to 3 times greater toxicity against radish) was observed in some cases. Title compounds were also tested in terms of their toxicity for freshwater crustaceans H. incongruens (ostracods) and marine luminescent bacteria A. fischeri. Although their harmful action on ostracods was not too much elevated, they were found to be highly toxic for bacteria. Various aspects of their ecotoxicity are discussed in this paper. PMID- 28917215 TI - A pilot controlled trial of a cognitive dissonance-based body dissatisfaction intervention with young British men. AB - This pilot study evaluated a body image intervention for men, Body Project M. Seventy-four British undergraduate men took part in two 90-min intervention sessions, and completed standardised assessments of body image, bulimic pathology, and related outcomes at baseline, post-intervention, and 3-month follow-up. Fifty-three other men completed the questionnaires as an assessment only control group. Per-protocol analysis showed that Body Project M improved men's dissatisfaction with body fat and muscularity, body appreciation, muscularity enhancing behaviours, appearance comparisons, and internalization (ds=0.46-0.80) at post-intervention. All except dissatisfaction with muscularity and internalization were sustained at 3-month follow-up. No effects were found for bulimic pathology. Post-intervention effects for dissatisfaction with muscularity and internalization only were retained under intention-to-treat analysis. Participants were favourable towards the intervention. This study provides preliminary evidence for the acceptability and post-intervention efficacy of Body Project M. Further development of the intervention is required to improve and sustain effects. PMID- 28917216 TI - Mass-forming intrahepatic cholangiocarcinoma with portal vein tumor thrombus and bile duct tumor thrombus: A case report. AB - INTRODUCTION: We report the first case of mass-forming intrahepatic cholangiocarcinoma (ICC) with portal vein tumor thrombus (PVTT) and bile duct tumor thrombus (BDTT), where the extrahepatic bile duct was preserved with thrombectomy. PRESENTATION OF CASE: A 70-year-old male. Magnetic resonance imaging (MRI) showed the tumor extending from the hepatic hilum to the left hepatic duct with complete obstruction of the left hepatic duct and a defect at the left portal vein. We planned to perform extended left lobectomy, lymph node dissection, extra hepatic bile duct resection and reconstruction based on the diagnosis of mass-forming ICC with left portal vein and left hepatic duct infiltration (cT3N0M0 Stage III). Intraoperative cholangiography revealed a crab claw-like filling defect at the left hepatic duct, which suggested tumor thrombus. Accordingly, we performed thrombectomy. The margin of the left hepatic duct was tumor negative, so we performed extended left lobectomy, lymph node dissection and thrombectomy. Pathologically, the tumor was diagnosed as ICC (pT4N0M0 Stage IVA, vp3, b3). Tumors in the left hepatic duct and left portal vein proved to be tumor thrombus. The postoperative course was uneventful. He is doing well without recurrence. DISCUSSION: Thrombectomy is performed for hepatocellular carcinoma (HCC) with tumor thrombus. Furthermore, extrahepatic bile duct resection and reconstruction are recommended for ICC. In this case, intraoperative cholangiography was effective for precisely diagnosing. Thrombectomy could reduce surgical stress and prevent complications. CONCLUSIONS: Thrombectomy can be a valid option for ICC with tumor thrombus, as well as for HCC. PMID- 28917217 TI - Post-operative C-reactive protein profile following abdominal wall reconstruction with transversus abdominis posterior components separation. AB - INTRODUCTION: Abdominal wall reconstruction using posterior component separation with transversus abdominis release (AWTAR) produces a unique post-operative CRP profile, when compared to routine elective colorectal operations. Therefore, we aim to establish the normal post-operative C-reactive protein (poCRP) profile following AWRTAR and reduce the unnecessary invasive interventions in patients already at greater risk of septic complications. METHODS: A retrospective analysis of daily poCRP levels was performed both for patients who underwent uncomplicated AWRTAR (n=12), and a comparator group of uncomplicated open right hemicolectomies (RH) matched for age and sex (n=24). All operations in both groups were performed by a single surgeon from 2013 to 2015. RESULTS: The median (IQR) age was 62 (16) and 67 (16) years respectively, with a higher proportion of males to females in both groups (10:2 vs. 17:7). The poCRP profile follows an initial steep rise, peaking at day 2 followed by a gradual washout phase. The poCRP peak is significantly greater in the AWRTAR group compared to the RH group (274 [95%CI +/-25] vs. 160 [95%CI+/-27]; p=0.0001), with a positive correlation between day 2 CRP levels and operative length (r=0.56). CONCLUSIONS: We have demonstrated that uncomplicated AWRTAR provokes a significantly greater poCRP rise (>200) compared to that well described in the literature for uncomplicated open colectomy. As poCRP is an important marker of post-operative recovery with abnormally high levels associated with septic complications, these data should help clinicians interpret the post-operative clinical course after AWRTAR. PMID- 28917218 TI - Erythema elevatum diutinum in Crohn's disease-associated Spondyloarthritis - a rare vasculitis, an unusual association. AB - Erythema elevatum diutinum is a rare neutrophilic dermatoses with vasculitis, which presents as persistent, symmetrical, purple or brownish papules and nodules, mainly in the extensor surface of the limbs. We describe a case of erythema elevatum diutinum and polyarthritis as initial manifestations of Crohn's disease associated spondyloarthritis. A 51-year-old man, from Sao Tome e Principe, with previous history of treated tuberculosis and chronic hepatitis B infection, was admitted due to 4 months history of polyarthritis, hyperpigmented papules on the extensor surfaces, occasional episodes of bloody mucous diarrhea and significant weight loss. Histology of the skin showed neutrophilic granulocytes with marked fibrosis and moderate karyorrhexis, consistent with erythema elevatum diutinum. Colonoscopy showed erosions in sigmoid and rectum. Diagnosis of erythema elevatum diutinum secondary to Crohn's disease with associated peripheral spondyloarthritis was assumed. The patient was treated with prednisolone, sulphasalazine, metronidazole, azathioprine and tenofovir with good clinical response. As erythema elevatum diutinum can be secondary to multiple systemic diseases, including rheumatic diseases and inflammatory bowel disease, being aware and recognizing this entity can be of great importance for rheumatologists. PMID- 28917219 TI - Reuma.pt contribution to the knowledge of immune-mediated systemic rheumatic diseases. AB - : Patient registries are key instruments aimed at a better understanding of the natural history of diseases, at assessing the effectiveness of therapeutic interventions, as well as identifying rare events or outcomes that are not captured in clinical trials. However, the potential of registries goes far beyond these aspects. For example, registries promote the standardization of clinical practice, can also provide information on domains that are not routinely collected in clinical practice and can support decision-making. Being aware of the importance of registries, the Portuguese Society of Rheumatology developed the Rheumatic Diseases Portuguese Register- Reuma.pt - which proved to be an innovative instrument essential to a better understanding of systemic immune mediated rheumatic diseases. OBJECTIVE: To describe the contribution of Reuma.pt to the knowledge of systemic immune-mediated rheumatic diseases. RESULTS: Reuma.pt is widely implemented, with 77 centres actively contributing to the recruitment and follow-up of patients. Reuma.pt follows in a standardized way patients with the following systemic inflammatory rheumatic diseases: rheumatoid arthritis (n=6218), psoriatic arthritis (n=1498), spondyloarthritis (n=2529), juvenile idiopathic arthritis (n =1561), autoinflammatory syndromes (n=122), systemic lupus erythematosus (n =1718), systemic sclerosis (n=180) and vasculitis (n=221). This platform is intended for use as an electronic medical record, provides standardized assessment of patients and support to the clinical decision, thereby contributing to a better quality of care of rheumatic patients. The research based on Reuma.pt identified genetic determinants of susceptibility and response to therapy, characterized in detail systemic rheumatic diseases and their long-term impact, critically appraised the performance of instruments for monitoring the disease activity, established the effectiveness and safety of biologic therapies and identified predictors of response, and proactively engaged patients in the management of their disease. CONCLUSION: Reuma.pt is an innovative tool, widely established in the country that contributes to a clinical practice of excellence and simultaneously to increase the knowledge of systemic immune-mediated rheumatic diseases. Additionally, Reuma.pt fosters patients' participation in the management of the disease. PMID- 28917220 TI - Ultrasound assessment of skin thickness performed on fingers: a tool for estimating overall severity of skin disease in Systemic Sclerosis patients? PMID- 28917221 TI - Determining the predictive equation for height from ulnar length in the Vietnamese population. AB - BACKGROUND AND OBJECTIVES: Height is an essential measurement in clinical medicine. It allows the calculation of body mass index, ideal body weight, basic energy requirements and tidal volumes. In many patient groups, such as the critically ill, height cannot be measured easily and surrogate anthropometric measures are used. Regression equations estimating height are specific to ethnicity. We aimed to develop the regression equation for Vietnamese men and women to predict height from ulna length and so improve prescription of life saving treatment in the intensive care units. METHODS AND STUDY DESIGN: A cross sectional survey of patients and relatives at the National Hospital for Tropical Diseases was undertaken. Ulna length, standing height and weight were measured. The first two thirds of participants' data, stratified by sex and age, were allocated to a model training group, the subsequent participants entered the validation group. Linear regression equations were calculated for the model group by sex, then applied to the validation group and assessed for precision. Other international equations were also compared. RESULTS: 498 males and 496 females were recruited. There was good correlation between ulna length and height in those aged 21-64, r=0.66, p<0.001 in males and females. The regression equations were: male: height = 85.61 + (3.16 x ulna length), female: height = 85.80 + (2.97 x ulna length). Equations from other populations were less accurate. CONCLUSIONS: The regression equations calculated for men and women aged 21-64 showed good correlation and can be used to predict height in those where direct measurement is impossible. PMID- 28917222 TI - Validation of summer and winter ELISA measurements of serum 25-hydroxyvitamin D concentrations in Mongolia. AB - BACKGROUND AND OBJECTIVES: Assay cost, quality, and availability pose challenges for vitamin D surveys in limited resource settings. This study aimed to validate an inexpensive vitamin D assay (ELISA) under real-world conditions in Mongolia, the northernmost developing country, to characterize the assay's usefulness and inform the design of epidemiologic studies in similar regions. METHODS AND STUDY DESIGN: We collected paired summer and winter serum samples from 120 men and women (aged 20-57 years) in urban and rural Mongolia, analyzed each sample for 25(OH)D concentration using both Immunodiagnostic Systems ELISA and DiaSorin LIAISON 25(OH)D TOTAL, and compared the assays using multiple statistics. LIAISON was itself validated by participation in the DEQAS program. RESULTS: Correlation and agreement between assays were higher in summer (Pearson's correlation=0.60, Spearman's rank correlation=0.67, Lin's concordance correlation=0.56) than winter (rP=0.37, rS=0.43, rC=0.33), although ELISA less accurately assigned subjects to sufficiency categories in summer (percent agreement=44%) than winter (58%), during the latter of which most subjects were deficient ([25(OH)D] categories used: >75 nmol/L (optimal), 50-75 nmol/L (adequate), 25-50 nmol/L (inadequate), <25 nmol/L (deficient)). Compared with LIAISON, ELISA tended to indicate higher vitamin D status in both seasons (mean paired difference: 7.0 nmol/L (95% CI: 3.5 10.5) in summer, 5.2 nmol/L (95% CI: 2.9-7.5) in winter). CONCLUSIONS: ELISA proved useful for measuring and ranking subjects' vitamin D status in Mongolia during summer, but levels were too low in winter to sensitively discriminate between subjects, and ELISA overestimated status in both seasons. These findings have implications for the timing and interpretation, respectively, of vitamin D surveys in highly deficient populations. PMID- 28917223 TI - Validity of the Malnutrition Universal Screening Tool (MUST) in Australian hospitalized acutely unwell elderly patients. AB - BACKGROUND AND OBJECTIVES: This study validated the Malnutrition Universal Screening Tool (MUST) for nutritional screening in acutely unwell elderly patients against a reference assessment tool - Patient-Generated Subjective Global Assessment (PG-SGA). METHODS AND STUDY DESIGN: One hundred and thirty two acutely admitted general medical patients contributed data for this study. In addition to performance of MUST and PG-SGA the following nutritional parameters were measured: weight loss >5% in previous 3-6 months, handgrip strength, triceps skinfold thickness, Mid-arm circumference, Mid-arm muscle circumference (MAMC). Quality of life (QoL) was determined using the EuroQoL Questionnaire (EQ-5D 5 level). Sensitivity, specificity, predictive values and concordance were calculated to validate MUST against PG-SGA. RESULTS: MUST when compared to PG-SGA gave a sensitivity of 69.7%, specificity of 75.8%, positive predictive value of 75.4%, negative predictive value of 70.1% and kappa statistics showed 72.7% agreement (k=0.49) for detecting malnutrition. The MUST score had significant inverse correlation with body mass index, Triceps skinfold thickness and Mid-arm muscle circumference but not with Handgrip strength. Malnourished patients (PG SGA class B/C) were found to have a significantly worse QoL. CONCLUSIONS: This study demonstrates that MUST can be confidently administered with respect to validity in acutely unwell general medical elderly patients to detect malnutrition. In this study, significant recent weight loss also seems to have validity, almost comparable to MUST, for predicting the risk of malnutrition. Further research is needed to verify this finding, as a single item may be more feasible to complete than an instrument consisting of two or more items. PMID- 28917224 TI - Simple method to estimate daily sodium intake during measurement of dialysis adequacy in chronic peritoneal dialysis patients. AB - BACKGROUND AND OBJECTIVES: Restriction of dietary sodium intake for peritoneal dialysis (PD) patients is recommended, but there is limited information on the measurement and monitoring of sodium intake. We have developed a simple method to estimate daily sodium intake during the measurement of dialysis adequacy in PD patients. METHODS AND STUDY DESIGN: A total of 83 PD patients were enrolled in the study. The patients were divided into two groups based on residual renal function (RRF). We measured total sodium removal and estimated daily sodium intake using dietary recall for one day, during the assessment of dialysis adequacy. RESULTS: There were 39 patients in the RRF(-) group and 44 in the RRF(+) group. In both groups, and all patients, there were significant positive correlations between sodium intake and total sodium removal: RRF(-) group, r=0.598; RRF(+) group, r=0.577; total patients, r=0.595. There were linear relationships between dietary sodium intake and total sodium removal in both groups: RRF(-) group, sodium intake (mg/d) = 19.3 * peritoneal sodium removal (mEq/d) + 211;RRF(+) group, sodium intake (mg/d) = 15.4 * total sodium removal (mEq/d) + 609. All PD patients, sodium intake (mg/d) = 15.6 * total sodium removal (mEq/d) + 646. CONCLUSIONS: The measurement of total sodium removal during the assessment of dialysis adequacy could be an effective and simple method to estimate dietary sodium intake in PD patients. A dietary intake of 2,000 mg of sodium corresponds to a total sodium removal of approximately 87 mEq/d. PMID- 28917225 TI - Appropriate nutritional management in patients with impaired mastication and those with mild dysphagia: a multicenter study of the usefulness of novel foods processed and softened by enzymes. AB - BACKGROUND AND OBJECTIVES: Our aim was to investigate the safety of iEAT (a food that is softened by heat and enzyme homogeneous permeation) and iEAT-affected nutrition parameters, e.g., nutrition intake (calculated from the consumption rate in patients with impaired mastication and those with mild dysphagia). METHODS AND STUDY DESIGN: A multicenter, randomized, cross-over study of iEAT was conducted in 50 patients (mean age 77.0+/-11.0 years) with dysphagia due to Occasional aspiration (4 points on the Dysphagia Severity Scale [DSS]) or Oral problems (5 points) randomly assigned to the study diet (iEAT) or its opposite (the modified traditional [control] diet) for 1 week and then switched for 1 week to the opposing diet. Intake of energy, protein, lipid, carbohydrate, and sodium were evaluated along with questionnaire-assessed levels of satisfaction. RESULTS: The mean intake was significantly lower for the study diet, whereas the intakes of energy, protein, carbohydrate on day 1, intake of protein on day 7, and body weight on day 7 were significantly higher for the study diet. We found no between group differences in hematologic and blood biochemistry parameters, no diet related adverse events, greater satisfaction with the appearance of the study diet (p<0.001), and comparable levels of satisfaction with ease of eating, ease of swallowing, and taste for both diets. CONCLUSIONS: iEAT was provided to patients with mild dysphagia as safely as a blender diet or other diets usually provided at each study site, and can serve as an efficient nutrition source. PMID- 28917226 TI - Energy intake in the first week in an emergency intensive care unit may not influence clinical outcomes in critically ill, overweight Japanese patients. AB - BACKGROUND AND OBJECTIVES: The American Society for Parenteral and Enteral Nutrition recommends hypocaloric feeding for critically ill patients with a BMI of >=30.0 kg/m2. However, the cut-off value of obesity in Japan is BMI >25.0 kg/m2, due to the higher prevalence of type 2 diabetes mellitus, and cardiovascular risk factors, even at a lower BMI than in Western populations. Thus, the optimal energy intake for critically ill, overweight Asian patients is unknown. METHODS AND STUDY DESIGN: A retrospective chart review was conducted in patients with BMI of >=25.0 kg/m2 in an emergency intensive care unit (EICU). Patients were categorized into two groups by average daily energy intake during the first week in the EICU, with Group A at <50% of requirement and Group B at >=50%. RESULTS: A total of 72 patients with a median BMI of 27.5 kg/m2 were included in the study. No significant differences between the groups were observed for all-cause mortality, ICU-free days, or length of hospital stay. The number of ventilator-free days (VFDs) was significantly higher in Group A than Group B (20.0 [15.5-24.5] vs 17.0 [2.0-21.0] days; p=0.042). On multiple adjusted analysis, however, we found that %energy intake/requirement was not independently associated with VFDs (regression coefficient=0.019; 95% confidence interval, 0.115-0.076). CONCLUSIONS: Energy intake in the first week in the EICU did not influence clinical outcomes in critically ill, overweight Japanese patients. Confirmation of these results in larger, randomized trials is required. PMID- 28917227 TI - Pharmacoeconomics of parenteral nutrition in surgical and critically ill patients receiving structured triglycerides in China. AB - BACKGROUND AND OBJECTIVES: A prior meta-analysis showed favorable metabolic effects of structured triglyceride (STG) lipid emulsions in surgical and critically ill patients compared with mixed medium-chain/long-chain triglycerides (MCT/LCT) emulsions. Limited data on clinical outcomes precluded pharmacoeconomic analysis. We performed an updated meta-analysis and developed a cost model to compare overall costs for STGs vs MCT/LCTs in Chinese hospitals. METHODS AND STUDY DESIGN: We searched Medline, Embase, Wanfang Data, the China Hospital Knowledge Database, and Google Scholar for clinical trials comparing STGs to mixed MCT/LCTs in surgical or critically ill adults published between October 10, 2013 and September 19, 2015. Newly identified studies were pooled with the prior studies and an updated meta-analysis was performed. A deterministic simulation model was used to compare the effects of STGs and mixed MCT/LCT's on Chinese hospital costs. RESULTS: The literature search identified six new trials, resulting in a total of 27 studies in the updated meta-analysis. Statistically significant differences favoring STGs were observed for cumulative nitrogen balance, pre- albumin and albumin concentrations, plasma triglycerides, and liver enzymes. STGs were also associated with a significant reduction in the length of hospital stay (mean difference, -1.45 days; 95% confidence interval, -2.48 to 0.43; p=0.005) versus mixed MCT/LCTs. Cost analysis demonstrated a net cost benefit of Y675 compared with mixed MCT/LCTs. CONCLUSIONS: STGs are associated with improvements in metabolic function and reduced length of hospitalization in surgical and critically ill patients compared with mixed MCT/LCT emulsions. Cost analysis using data from Chinese hospitals showed a corresponding cost benefit. PMID- 28917228 TI - Parenteral nutrition combined with enteral feeding improves the outcome of cancer patients. AB - BACKGROUND AND OBJECTIVES: This study investigated whether total parenteral nutrition combined with enteral nutrition is associated with improved biochemical and clinical outcomes in cancer patients with gastrointestinal dysfunction. METHODS AND STUDY DESIGN: From January to December 2014, the clinical data of 68 patients in a cancer ward were retrospectively collected, and these patients were classified into two groups according to nutrition delivery, through parenteral nutrition, combined with enteral nutrition more (group A) or less (group B) than 250 kcal/day. The following variables were analyzed: the route and percentage of nutritional support, total caloric intake, age, gender, body weight, body mass index, diagnosis at admission, complications of intestinal failure, modified Glasgow Prognostic Score, co-morbidities, duration of total parenteral nutrition support, performance status scale, and plasma nutritional markers. RESULTS: A significant difference was observed between the two groups in functional capacity, including the Karnofsky index, World Health Organization/Eastern Cooperative Oncology Group score, body-weight loss, and serum albumin levels. However, no significant difference was observed in the modified Glasgow Prognostic Score. CONCLUSIONS: Cancer patients receiving total parenteral nutrition who were fed enterally more than 250 kcal/d exhibited more favorable clinical outcomes than those who were fed enterally less than 250 kcal/d. Enteral nutrition should be considered for these severely ill patients. PMID- 28917229 TI - Peanut butter increases the bioavailability and bioconversion of kale beta carotene to vitamin A. AB - BACKGROUND AND OBJECTIVES: Kale is a rich source of provitamin A- beta-carotene. This study used intrinsically labeled kale [2H9] beta-carotene to determine the effect of peanut butter on the bioconversion of kale beta-carotene to vitamin A in preschool children. METHODS AND STUDY DESIGN: Preschool children (n=37; age 12 36 mo) were randomly assigned to 50 g cooked kale (1.5 mg beta-carotene content) with either 33 g peanut butter (PBG) or with 16 g lard (LG) and a reference dose of 1 mg [13C10] retinyl acetate capsule. Blood samples were processed to serum and analyzed by Negative Chemical Ionization-Gas Chromatography Mass Spectrometry (NCI-GCMS) for the enrichments of [2H] retinol from kale [2H9] beta-carotene and [13C10] retinol from reference dose. RESULTS: The area under curves (AUCs) of molar enrichment at days 1, 2, 3, 6, 15, and 21 after the labeled doses was 56.3+/-10.5 and 84.8+/-16.2 (nmole) for [2H] retinol from LG and PBG kale [2H9] beta-carotene, respectively. The AUC of [13C10] retinol from reference dose was 432.6+/-54.9 (LG) and 560.3+/-156.7 (nmole) (PBG), respectively. The calculated beta-carotene conversion factors were 13.4+/-3.1 and 11.0+/-3.9 to 1 (p>0.05) by weight for LG and PBG, respectively. CONCLUSIONS: This study showed that peanut butter enhances the vitamin A value of kale. PMID- 28917230 TI - Energy restriction combined with green coffee bean extract affects serum adipocytokines and the body composition in obese women. AB - BACKGROUND AND OBJECTIVES: Obesity has become a public health problem and is a cause of some preventable illnesses. Among several methods for treating obesity, the use of food supplements is highly common. A commonly used food supplement is green coffee bean extract. The objective of this study was to evaluate the efficacy of green coffee bean extract combined with an energy-restricted diet on the body composition and serum adipocytokines in obese women. METHODS AND STUDY DESIGN: In this randomised clinical trial, 64 obese women aged 20-45 years were selected and divided into two groups: an intervention group (receiving 400 mg green coffee bean extract for 8 weeks) and control group (receiving placebo). All participants were on an energy-restricted diet. The body composition, leptin, adiponectin, lipid profile, free fatty acids (FFAs), and fasting blood sugar were compared between the two groups. RESULTS: We observed significant reductions in the body weight, body mass and fat mass indices, and waist-to-hip circumference ratio in both groups; however, the decrease was higher in the intervention group. Moreover, serum total cholesterol, low-density lipoprotein, leptin, and plasma free fatty acids significantly decreased in the intervention group (p<0.05) after adjustment for energy and fibre intake. The serum adiponectin concentration significantly increased in the intervention group (p<0.05). CONCLUSIONS: Green coffee bean extract combined with an energy-restricted diet affects fat accumulation and lipid metabolism and is thus an inexpensive method for weight control in obese people. PMID- 28917231 TI - Portion controlled ready-to-eat meal replacement is associated with short term weight loss: a randomised controlled trial. AB - BACKGROUND AND OBJECTIVES: Strategies to prevent and treat overweight/obesity are urgently needed. This study assessed the effect of a short-term intake of ready to-eat cereal on body weight and waist circumference of overweight/obese individuals in comparison to a control group. METHODS AND STUDY DESIGN: A randomized, controlled 2-arm trial was carried out on 101 overweight/obese (Body Mass Index - 29.2+/-2.4 kg/m2) females aged 18 to 44 years, at St. John's Medical College Hospital. The intervention group received a low fat, ready to eat cereal, replacing two meals/day for two weeks. The control group was provided with standard dietary guidelines for weight loss and energy requirements for both groups were calculated similarly. Anthropometric, dietary, appetite and health status assessments were carried out at baseline and at the end of two weeks. RESULTS: At the end of two weeks, the mean reductions in body weight and waist circumference were significantly greater in the intervention group, -0.53 kg; 95% CI (-0.86 to -0.19) for body weight and -1.39 cm; 95% CI (-1.78, -0.99) for waist circumference. The intervention group had a significantly higher increase in dietary intakes of certain vitamins, fiber and sugar, and significantly higher reductions in total and polyunsaturated fats and sodium intakes, as compared to the control group (p<=0.05). No significant differences were observed between the groups, in change of appetite, health and perception scales. CONCLUSIONS: Portion controlled, ready to eat cereal could be effective for short-term weight loss, with some improvements in the nutrient intake profile. However, studies of longer duration are needed. PMID- 28917232 TI - Compressed food with added functional oligopeptides improves performance during military endurance training. AB - BACKGROUND AND OBJECTIVES: Oligosaccharide or oligopeptide supplementation may have a significant impact on endurance performance. This study evaluated the effects of adding maltooligosaccharides (MO) or soy oligopeptides (SO) to compressed food (CF) on the physical response of soldiers to daily military training. METHODS AND STUDY DESIGN: Twelve soldiers were randomized to four diet groups: regular meals, CF, CFMO, and CFSO (crossover design). They participated in exercise tests including 90 minutes running at 55-65% VO2max and exhaustive running. Heart rates, rating of perceived exertion (RPE), and blood and urine samples were collected during exercise and recovery. RESULTS: The recovery heart rates were significantly lower with the CFMO diet compared with the other diets. Compared with all other diets, blood glucose levels were higher, post-exercise blood lactate levels were lower, and lactate clearance during recovery was higher with the CFMO diet, followed by the CFSO diet. Post-exercise levels of erythrocytes and hematocrit were significantly higher with the CFSO diet. Post exercise urine specific gravity was lower with the CFMO diet and urine pH was decreased with the CFSO diet. Blood urea nitrogen (BUN) and uric acid (UA) were significantly higher with the CFSO diet than with the other diets. There was no significant difference in skeletal and cardiac muscle injury indices and RPE among diets. CONCLUSIONS: CFMO led to better heart rate recovery, improved and maintained blood glucose and increased removal of blood lactate. CFSO accelerated removal of blood lactate during recovery, maintained oxygen supply, and increased fluid retention. PMID- 28917234 TI - Association between complement component C3 and body composition: a possible obesity inflammatory biomarker for insulin resistance. AB - BACKGROUND AND OBJECTIVES: The C3 complement component (C3) is increasingly recognized as a cardiometabolic risk factor. We aimed to examine the role of C3 in insulin resistance (IR) and its association with adiposity. METHODS AND STUDY DESIGN: Sixty-seven obese (18-35 years) participants were matched with normal weight participants from the University of Jordan. BMI, waist-hip ratio (WHpR), and waist-height ratio (WHtR) were calculated. Body percent fat mass (%FM) was determined using the bioelectrical impedance analysis. C3, insulin, and glucose serum concentrations were measured. IR was assessed by the homeostasis model assessment of IR (HOMA-IR). RESULTS: Serum concentrations of C3 and IR were significantly higher in the obese group than that in the normal body weight, regardless of gender (women: 1.2+/-0.08 and men: 1.2+/-0.08 vs women: 0.88+/-0.07 and men: 0.94+/-0.05, p<0.01; women: 3.6+/-0.34 and men: 3.9+/-0.43 vs women: 1.7+/-0.12 and men: 2.0+/-0.24, respectively; p<0.001). After adjustment for the potential confounders, BMI, waist circumference, WHtR and %FM were correlated positively with C3 (r=0.44; 0.42; 0.47; 0.43, respectively; p<0.001), and with IR (r=0.67; 0.61; 0.59; 0.59, respectively; p<0.001). C3 was correlated with IR (r=0.35, p<0.001). In linear regression analysis, C3 was not associated with IR independent of BMI (p>0.05). CONCLUSIONS: C3 may be a marker of chronic inflammatory process independently underlying IR obese individuals regardless of gender, which may have a role in the progression of IR during obesity. PMID- 28917233 TI - High prevalence of vitamin B-12 insufficiency in patients with Crohn's disease. AB - BACKGROUND AND OBJECTIVES: In Crohn's disease (CD), belonging to inflammatory bowel disease, the small intestine is involved in most cases. Most frequently affected is the distal ileum, where vitamin B-12 is specifically absorbed. Therefore, malabsorption of vitamin B-12 is quite likely to occur in patients with CD. In this study, we have studied the vitamin B-12 status in CD patients. METHODS AND STUDY DESIGN: Forty eight patients with CD were evaluated for their food intake, and circulating concentrations of vitamin B-12, folic acid, and homocysteine (Hcy) as a sensitive marker for the insufficiency of these vitamins and a risk factor of atherosclerosis. RESULTS: Plasma Hcy concentration was significantly correlated with serum vitamin B-12 concentration alone, and 60.4 % of the subjects had hyperhomocysteinemia. Receiver Operating Characteristics (ROC) analysis showed that serum concentration of vitamin B-12, but not folic acid, predicted hyperhomocysteinemia. Their intake of vitamin B-12 was much higher than the Japanese RDA, but not correlated with blood concentrations of vitamin B-12 or Hcy, probably due to malabsorption. CONCLUSIONS: Vitamin B-12 insufficiency and hyperhomocysteinemia were highly prevalent in CD patients. Recently, the significance of extra-intestinal complications of CD has been increasingly recognized, and our finding is likely to be of clinical importance. PMID- 28917235 TI - Reconfirmation of improved tolerance to a new amino acid-based formula by infants with cow's milk protein allergy. AB - BACKGROUND AND OBJECTIVES: Reasons for intolerance to commercial amino acid-based formulas (cAAF) in infants diagnosed with cow's milk protein allergy (CMA) remain unknown. We assume that minute amounts of proteins, presenting in the glucose polymers derived from corn starch (cGPs), can elicit the intolerance to the cAAFs observed in some infants with CMA. By replacing cGPs with glucose polymers derived from rice starch (rGPs), a new amino acid-based (nAAF) formula has been shown to be better tolerated than an existing cAAF. This study was carried out to corroborate the superiority of nAAF over a different commercially available cAAF. METHODS AND STUDY DESIGN: Infants with CMA aged less than 4 months underwent a double-blind, placebo-controlled food challenge. They consumed each of the 2 test formulas for 14 days before switching to the other one. Following the 28-day challenge period, infants consumed the tolerated formula for 4 weeks as an at home open challenge. RESULTS: Out of 36 infants who completed the study, 18 were intolerant to the cAAF, seven of whom (38.8%) were also intolerant to the nAAF. Eleven of the 18 infants who were intolerant to the cAAF tolerated the nAAF (p<0.01). CONCLUSIONS: This study reconfirms that substitution of rGPS for cGPs in the amino acid-based formula improves tolerance of young infants with CMA. PMID- 28917237 TI - Screening for nutritional risk in hospitalized children with liver disease. AB - BACKGROUND AND OBJECTIVES: Malnutrition is a major contributor to morbidity and mortality from pediatric liver disease. We investigated the prevalence of both malnutrition and high nutritional risk in hospitalized children with liver disease as well as the rate of in-hospital nutritional support. METHODS AND STUDY DESIGN: A total of 2,874 hospitalized children and adolescents with liver disease aged 1 to 17 years (inclusive) were enrolled. Malnutrition was screened by anthropometric measures (height-for-age, weight-for-height, weight-for-age, and BMI- for-age z-scores). The Screening Tool for Risk on Nutritional Status and Growth (STRONGkids) was used to evaluate nutritional risk status. Nutrition markers in blood, rate of nutritional support, length of hospital stay, and hospital fees were compared among nutritional risk groups. RESULTS: The overall prevalence of malnutrition was 38.6%. About 20.0% of children had high nutritional risk, and prevalence of malnutrition was markedly greater in the high nutritional risk group compared with the moderate risk group (67.9% vs 31.3%). Serum albumin and prealbumin differed significantly between high and moderate risk groups (p<0.001). Only 8.9% of children with high nutritional risk and 3.5% with moderate nutritional risk received nutrition support during hospitalization. Children with high nutritional risk had longer hospital stays and greater hospital costs (p<0.001). CONCLUSIONS: The prevalence of malnutrition is high in children with liver disease. High nutritional risk is also prevalent at admission. Albumin and prealbumin are sensitive markers for distinguishing nutritional risk groups. High nutritional risk prolongs length of stay and increases hospital costs. The nutritional support rate is still low and requires standardization. PMID- 28917236 TI - Dietary intake of heme iron and body iron status are associated with the risk of gestational diabetes mellitus: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Some potential role of iron overload in the development of diabetes mellitus have been suggested. Our study aimed to systematically assess the association between the risk of gestational diabetes mellitus (GDM) and iron intakes/body iron status. METHODS AND STUDY DESIGN: PubMed and Web of Science were searched for relevant articles. Relative risks (RR) of GDM in relation to dietary iron intakes and body iron stores were pooled with the random-effects model. Weighted mean differences of iron blood markers between GDM and non-GDM individuals were also analyzed. RESULTS: Twenty-five studies were included in the qualitative analysis, and 23 studies with 29,378 participants and 3,034 GDM patients were included in the quantitative analysis. Dietary intake of heme iron was significantly associated with GDM risk (RR=1.65, 95% CI: 1.28 to 2.12), and the pooled RR for each 1mg/day increment of heme iron intake was 1.38 (95% CI: 1.19 to 1.61). No association between GDM and the intakes of nonheme iron, total iron, or supplemental iron was detected. Body iron stores, as represented by serum ferritin level, were correlated with GDM risk (RR=1.64, 95% CI: 1.27 to 2.11). Moreover, the concentrations of both serum ferritin and serum iron were increased in GDM patients, compared with non-GDM individuals. CONCLUSIONS: Increased dietary intake of heme iron and body iron status are positively associated with the risk of GDM development in pregnant women. Future studies are warranted to better understand the role of iron in GDM development. PMID- 28917238 TI - Qualitative study of eating habits in Bruneian primary school children. AB - BACKGROUND AND OBJECTIVES: Childhood obesity is a serious public health issue globally and poor eating habits are an important contributing factor. This study aimed to explore the perceptions, practices and attitudes towards healthy eating in Bruneian primary school children. METHODS AND STUDY DESIGN: A qualitative study was conducted among 40 subjects involving 18 children (aged 9-10 years old), 12 parents and 10 teachers, who were recruited from two primary schools using convenience sampling. Five focus group discussion sessions were conducted, and recorded discussions were translated. The transcripts were entered into NVivo10 and thematic analysis was conducted. RESULTS: All participants had differing perceptions of the term 'healthy eating'. Children reported 'healthy eating' by identifying foods or food groups they perceived as healthy and unhealthy. Only a few mentioned fruits and vegetables as essential to a healthy diet. Parents mainly perceived 'healthy eating' as consuming 'any quality food' that contains 'vitamins and minerals'. Teachers described a healthy diet as including balanced and varied dietary practices, having breakfast and eating regularly at the right, set times. They also associated eating healthily with traditional, home-grown and home-cooked food. All participants had positive attitudes towards healthy eating, however most children demonstrated unhealthy eating habits and frequently consumed unhealthy foods. CONCLUSIONS: The Bruneian primary school children reported favourable knowledge despite having poor healthy eating habits. The factors influencing participants eating behavior included food preferences, familial factors (parental style and parenting knowledge), food accessibility and availability, time constraints, as well as convenience. These factors hindered them from adopting healthy eating practices. PMID- 28917239 TI - Screening for inadequate dietary vitamin B-12 intake in South Asian women using a nutrient-specific, semi-quantitative food frequency questionnaire. AB - BACKGROUND AND OBJECTIVES: A high prevalence of vitamin B-12 (B-12) deficiency among young women of South Asian origin predisposes to significant health risks for these women and their future offspring. Vegetarian or low-meat based dietary practices contribute to B-12 deficiency. This study validated a nutrient specific, semi-quantitative food frequency questionnaire (B12FFQ), developed to estimate dietary B-12 intake in South Asian women. METHODS AND STUDY DESIGN: The B12FFQ was developed, then tested in 60 apparently healthy South Asian women aged 18-50 years, living in Auckland, New Zealand. Participants recalled the frequency and quantity of vitamin B-12-containing foods consumed in the preceding three months. Pearson's correlations measured the associations between dietary B-12 intake and B-12 biomarkers (serum B-12 and holotranscobalamin [holoTC]). Likelihood of B12 insufficiency was calculated for vegetarian and non-vegetarian dietary practices. RESULTS: The B12FFQ was a valid measure of dietary B-12 intake - supported by moderate positive associations with serum B-12 (r=0.50, p<0.001, 95% CI [0.28, 0.67]) and holoTC (r=0.55, p<0.001, 95% CI [0.34, 0.71]). A dietary B-12 intake of less than 2.4 ug/day increased the likelihood of serum B-12 (X2 (1)=11.79, p=0.001) or holoTC (X2 (1)=6.33, p=0.012) insufficiency. A dietary B 12 intake of less than the recommended dietary allowance (2.4 ug/day), occurred in 61% (n=20/33) of participants with vegetarian and 22% (n=6/27) with non- vegetarian dietary practices. CONCLUSIONS: The B12FFQ provides a valid estimate of dietary B-12 intake. This easily administered food frequency questionnaire has the potential to identify low dietary B-12 intake as a contributor to B-12 depletion or deficiency. PMID- 28917240 TI - Snack and beverage consumption and preferences in a sample of Chinese children - Are they influenced by advertising? AB - BACKGROUND AND OBJECTIVES: The consumption of unhealthy snack and beverages can lead to childhood obesity, which has become a major concern globally. Television food advertisements may influence children's snack and beverages preferences. This article aims to explore children's snack and beverage consumption habits; examine the extent of television advertising for non-core (energy-dense, nutrient poor) snack and beverages; and assess the influence of television advertising on children's snack and beverages preferences in Harbin, China. METHODS AND STUDY DESIGN: The study consisted of two components, a recall survey on the snack and beverage consumption and preferences of 9-11 years old school children; and recording snack and beverage advertisements on three popular television channels. Odds Ratio (OR) was used to estimate the likelihood of children selecting particular snack and beverages as their top three choices according to whether their preferences were influenced by television advertisements. RESULTS: The majority of children consumed non-core snacks (100%) and beverages (80%) in the four weeks prior to the survey. Nearly 40% of television food advertisements were for non-core snacks and beverages. Non-core snacks (OR of 1.13) and non-core beverages (OR of 1.23) were more likely chosen as children's top three snack/beverage choices, particularly, "puffed food and tubers" snack and carbonated beverages (OR of 1.31 and 1.45, respectively). CONCLUSIONS: The snack and beverage preferences appeared to be influenced by television advertisements in this sample of Chinese children, highlighting the potential health and nutritional value of policy to reduce advertising of non-core foods in China. PMID- 28917241 TI - Dietary sodium reduction in New Zealand: influence of the Tick label. AB - BACKGROUND AND OBJECTIVES: The Tick programme of the National Heart Foundation (NHF) is the longest standing voluntary front of pack signpost nutrition logo in New Zealand. It provides a platform for collaboration with the food industry to encourage development of healthier products. This study evaluated the impact of the Tick programme on sodium in processed food. METHODS AND STUDY DESIGN: Fifty two Tick programme products from food categories known to contribute substantially to sodium intake were identified. Sales volumes (kg) from January 2011 to December 2013 were multiplied by changes in sodium content over that time, producing an estimate of programme impact. Five semi-structured interviews with industry representatives were conducted, to look at other influences for sodium reduction, and themes identified through methods of thematic analysis. RESULTS: Over the period, the Tick programme influenced food companies to remove approximately 16 tonnes of salt through the reformulation and formulation of 52 Tick-approved breakfast cereals, edible oil spreads, cooking sauces and processed poultry products. Other factors influencing sodium reduction reported by company representatives included increased consumer and industry interest in healthier product nutrition profiles and other sodium reduction programmes targeting reformulation/formulation. CONCLUSIONS: The Tick remains a credible and well recognized brand and may provide a competitive edge for participating food manufacturers in the current market. The Tick programme is effective in influencing industry to reduce sodium in processed foods in New Zealand. The combined impact of the Tick and other NHF programmes has the potential to reduce population sodium intake and improve health outcomes. PMID- 28917242 TI - Comprehensive school-based intervention to control overweight and obesity in China: a cluster randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: With prevalence of childhood obesity increasing rapidly, developing of effective and sustainable intervention strategies is becoming more and more important for the prevention of childhood obesity in China. A trial was developed to evaluate the effect of comprehensive school-based intervention on childhood obesity. METHODS AND STUDY DESIGN: A multi-center cluster randomized controlled trial was conducted among urban children (n=9,867) aged 6-13 years in 38 primary schools from six large cities. Comprehensive intervention, nutrition education and physical activity interventions were carried out among children. Nutrition education was also targeted towards teachers, parents and health workers in intervention schools. The program was implemented for 2 semesters from May 2009 to May 2010. RESULTS: The combined prevalence of overweight and obesity increased by 1.5 percent (22.7% vs 24.2%, p<0.001) in control group while 0.2 percent in comprehensive intervention group (23.6% vs 23.8%, p=0.954) after intervention (p=0.067). The effect was significantly stronger among girls than boys (-1.4% vs -0.9%, p=0.028). A significant intervention effect was found on BMI for -0.3 kg/m2 (95% confidence interval (CI): -0.4, -0.2; p<0.001), BMI z scores for -0.14 (95% CI: -0.18, 0.11; p<0.001),body fat for -0.8 percent (95% CI: -0.9, -0.6; p<0.001), waist circumference for -0.5 cm (95% CI: -0.6, -0.3; p<0.001), blood serum glucose for 0.20 mmol/L (95% CI: -0.24, -0.16; p<0.001) and cholesterol for -0.32 mmol/L (95% CI: -0.34, -0.30; p<0.001). CONCLUSIONS: We observed moderately significant effects on combined prevalence of overweight and obesity, BMI, BMI z scores, waist circumference, percentage body fat, glucose and lipid for a comprehensive school-based intervention of childhood obesity in China. PMID- 28917243 TI - Association between rice intake and all-cause mortality among Chinese adults: findings from the Jiangsu Nutrition Study. AB - BACKGROUND AND OBJECTIVES: The few studies that have assessed the association between rice intake and mortality have generated inconsistent results. We assessed whether rice intake was associated with cardiovascular disease (CVD) mortality, cancer mortality and all-cause mortality in a prospective cohort of the Chinese population. METHODS AND STUDY DESIGN: We prospectively studied 2,832 adults aged 20 years and above with a mean follow up of 10 years. Rice intake was measured by a 3-day weighed food record (WFR) in 2002. Hazard ratios (HRs) and 95% CI were calculated by competing risks regression (CVD and cancer mortality) and Cox proportional hazards analysis (all-cause mortality). RESULTS: We documented 184 deaths (including 70 CVD deaths and 63 cancer deaths) during 27,742 person-years of follow-up. No association between rice intake and all cause mortality was found. After adjusting for sociodemographic and lifestyle factors as well as energy and fat intake, HRs for CVD mortality across tertiles of rice intake were 1.00,0.47 (95% CI 0.25-0.87), and 0.49 (95% CI 0.21-1.13) (p for trend 0.049). CONCLUSIONS: There was no association between rice intake and all-cause mortality. PMID- 28917244 TI - Dietary patterns and sleep parameters in a cohort of community dwelling Australian men. AB - BACKGROUND AND OBJECTIVES: Emerging evidence suggests potential effects of nutrients/foods on sleep parameters. However, no studies have addressed the complex interactions among nutrients/foods and relate them to sleep outcomes. To investigate the associations between dietary patterns and sleep parameters (polysomnography (PSG) measured and self-reported sleep symptoms) in a large sample of community dwelling men in South Australia. METHODS AND STUDY DESIGN: Cross-sectional analysis was conducted of participants in the Men Androgen Inflammation Lifestyle Environment and Stress cohort enrolled in a sleep sub study (n=784, age 35-80 years). Dietary intake was measured by a validated food frequency questionnaire. Dietary patterns were identified by factor analysis. Sleep was assessed by an overnight home PSG and self-reported questionnaires. RESULTS: Two factors were obtained by factor analysis: Factor 1 was characterised by high intakes of vegetables, fruits, and legumes and factor 2 was characterised by processed meat, snacks, red meat and take-away foods. Three categories of the dietary patterns were defined (prudent, mixed and western) through classification of the sample according to the actual consumption higher or lower of each factor. The prudent (factor 1 dominant) and mixed dietary patterns were inversely associated with sleep onset, compared with the western dietary pattern (factor 2 dominant) (beta=-6.34 (95% CI-1.11, -11.57), beta=-4.34 (95% CI-8.34, -0.34) respectively)). The association was only significant with the prudent dietary pattern after multiple comparison adjustment. No associations were found with between dietary patterns and other sleep outcomes. CONCLUSIONS: The prudent dietary pattern was associated with a faster sleep onset, which may provide a solution for sleep management. PMID- 28917245 TI - A single-nucleotide polymorphism in transferrin is associated with soluble transferrin receptor in Chinese adolescents. AB - BACKGROUND AND OBJECTIVES: Associations between genetic variants in the hepcidin regulation pathway and iron status have been reported in previous studies. Most of these studies were conducted in populations of European descent and relatively few studies have been conducted in Chinese populations. In this study, we evaluated associations between single-nucleotide polymorphisms (SNPs) in the hepcidin regulation pathway, serum ferritin (SF) and soluble transferrin receptor (sTfR) in Chinese adolescents. METHODS AND STUDY DESIGN: In total, 692 students from rural boarding schools were selected from six cities in China. The participants were divided into case and control groups according to criteria for SF and sTfR. Furthermore, 33 SNPs in TMPRSS6, TF, TFR2, BMP2, BMP4, HJV, CYBRD1, HFE, IL6, PCSK7, HAMP, KIAA1468, and SRPRB were selected. Associations between the genetic variants and SF or sTfR were detected. RESULTS: For SF, rs4820268 in TMPRSS6 was associated with an SF <25 ng/mL status. Carriers of the G/G genotype of rs4820268 exhibited significantly lower SF levels than A allele carriers did (p=0.047). For sTfR, rs1880669 in TF, rs4901474 in BMP4, and rs7536827 in HJV were significantly associated with an sTfR >=4.4 mg/L status. However, in general linear model analysis, after adjustment for age, sex, and location, only rs1880669 exhibited a stable association with higher sTfR levels (p=0.032). CONCLUSIONS: We found rs4820268, in TMPRSS6 that was associated with a low SF level, as previously reported, and a new association between 1880669 in TF and sTfR. PMID- 28917246 TI - The promise of stereotactic body radiotherapy-next phase of integration into oncological practice. PMID- 28917247 TI - The optimism surrounding stereotactic body radiation therapy and immunomodulation. AB - In recent years, rapidly evolving radiation techniques have enabled the precise delivery of very high doses of radiation to local targets with stereotactic ablative body radiotherapy (SABR). In addition to its direct cytotoxicity, radiation and in particular SABR has powerful immunomodulatory effects resulting in immunogenic cell death and potentiation of the anti-tumour immune response. However, due to the immunosuppressive nature of non-irradiated sites of metastases, radiotherapy alone is seldom sufficient to induce the systemic response required for distant tumour rejection. Immune checkpoint inhibitors are a novel class of immunomodulatory agents shown to have robust efficacy against a number of malignancies. These drugs can augment the effects of radiotherapy by helping overcome tumour-induced immunosuppression at local and distant sites. Similarly, radiation may complement immunotherapy by priming tumours in preparation for the adaptive immune response, thereby leading to more prolonged clinical effects. This synergistic relationship has been demonstrated in laboratory models and has been extended to a number of early phase clinical studies. PMID- 28917248 TI - Stereotactic body radiation therapy for prostate cancer-a review. AB - Prostate cancer can be managed with external beam radiation therapy, delivered with either protons or photons, brachytherapy, surgery, or active surveillance. Advances in imaging and radiation therapy delivery have allowed treatment of prostate cancer using ultra-hypofractionated radiation therapy with a high dose per fraction using a technique called stereotactic body radiation therapy (SBRT). While no randomized trials have compared the efficacy of SBRT to conventionally fractionated radiation therapy (CFRT), numerous prospective trials and retrospective reviews have demonstrated the safety and efficacy of SBRT for localized prostate cancer, used either definitively or as a boost along with CFRT. Prostate cancer SBRT may be more cost effective than CFRT using intensity modulated radiation therapy (IMRT) or proton based radiation therapy. PMID- 28917249 TI - Challenges in imaging assessment following liver stereotactic body radiotherapy: pitfalls to avoid in clinical practice. AB - Stereotactic body radiotherapy (SBRT) is increasingly used in the management of unresectable liver metastases and hepatocellular carcinoma (HCC) as it allows delivery of high-dose conformal radiotherapy with limited toxicities. However, it may be difficult to differentiate viable tumour from radiotherapy-related changes after SBRT. The imaging changes observed after SBRT may also differ from those observed following conventionally fractionated radiotherapy. Hence, we aim to review the imaging changes that occur within the tumour and adjacent normal liver after SBRT which may help to identify local relapse in clinical practice. PMID- 28917250 TI - Emerging technologies in stereotactic body radiotherapy. AB - Stereotactic body radiation therapy (SBRT) stems from the initial developments of intra-cranial stereotactic radiosurgery (SRS). Despite similarity in their names and clinical goals of delivering a sufficiently high tumoricidal dose, maximal sparing of the surrounding normal tissues and a short treatment course, SBRT technologies have transformed from the early days of body frame-based treatments with X-ray verification to primarily image-guided procedures with cone-beam CT or stereoscopic X-ray systems and non-rigid body immo-bilization. As a result of the incorporation of image-guidance systems and multi-leaf col-limators into mainstream linac systems, and treatment planning systems that have also evolved to allow for routine dose calculations to permit intensity modulated radiotherapy and volumetric modulated arc therapy (VMAT), SBRT has disseminated rapidly in the community to manage many disease sites that include oligometastases, spine lesions, lung, prostate, liver, renal cell, pelvic tumors, and head and neck tumors etc. In this article, we review the physical principles and paradigms that led to the widespread adoption of SBRT practice as well as technical caveats specific to individual SBRT technologies. From the perspective of treatment delivery, we categorically described (I) C-arm linac-based SBRT technologies; (II) robotically manipulated X-band CyberKnife(r) technology; and (III) emerging specialized systems for SBRT that include integrated MRI-linear accelerators and the imaged-guided Gamma Knife Perfexion Icon system with expanded multi-isocenter treatments of skull-based tumors, head-and-neck and cervical-spine lesions. PMID- 28917251 TI - Advances in external beam stereotactic body radiotherapy: principle concerns in implementing a liver radiation program. AB - Despite significant advances in diagnosis, surgery and medical oncology, patients with primary and secondary liver cancer have some of the worst prognoses in oncology. In addition, the incidence of liver cancer is expected to increase. For this reason, centres are seeking new treatments and establishing specialized multidisciplinary teams. This article will focus on the evidence and practical data to assist in setting up or improving current process pathways, to provide an efficient and safe radiotherapy program for liver. Technical data on the primary safety concerns and components of a liver external beam radiation program will be presented. PMID- 28917252 TI - Stereotactic radiosurgery of the brain: a review of common indications. AB - Over the past half-century since Lars Leksell first utilized radiation to address deep and difficult to treat lesions of the central nervous system (CNS), intracranial stereotactic radiosurgery (SRS) has become an increasingly valued tool in the hands of neurosurgeons and radiation oncologists. Following developments in medical imaging and radiation technology, radiosurgery has evolved from its first application in movement disorders to widespread use for a varied range of malignant and benign conditions. SRS remains a powerful, minimally invasive instrument that offers additional options for intervention to a diverse patient population. In this review, we will touch upon the common indications for SRS, including its use in brain metastases, malignant gliomas, meningiomas, arteriovenous malformations (AVMs), vestibular schwannomas, pituitary adenomas, and functional disorders, as well as consider the future possibilities of combining radiosurgery with immunotherapy. PMID- 28917253 TI - Re-irradiation with stereotactic body radiation therapy (SBRT). AB - Stereotactic body radiation therapy (SBRT) is a potential treatment option for patients who develop a relapse within or marginal to a previously irradiated volume, but it seems underused because of sparse knowledge on the efficacy and morbidity related to the treatment. Normal tissues often recover some of the damage caused by the primary radiotherapy with time, but the kinetics of recovery is not clearly described in the literature. There is a growing number of publications on SBRT reirradiation, but the literature consists mainly of retrospective cohort studies. The aim of the present paper is to review studies on SBRT reirradiation in various regions where some studies have been published such as the head and neck, lung, liver, pancreas, prostate and spine. Based on the retrospective nature of the literature, the guide-lines provided by this guideline are relatively weak. In some organ systems, some advice on constraints related to reirradiated volumes and doses may be given. PMID- 28917254 TI - Stereotactic radiotherapy in oligometastatic cancer. AB - Oligometastatic cancer describes a disease state somewhere between localized and metastatic cancer. Proposed definitions of oligometastatic disease have typically used a cut-off of five or fewer sites of disease. Treatment of oligometastatic disease should have the goal of long-term local control, and in selected cases, disease remission. While several retrospective cohorts argue for surgical excision of limited metastases (metastasectomy) as the preferred treatment option for several clinical indications, limited randomized data exists for treating oligometastases. Alternatively, stereotactic ablative radiotherapy (SABR) is a radiotherapy technique that combines high radiation doses per fraction with precision targeting with the goal of achieving long-term local control of treated sites. Published cohort studies of SABR have demonstrated excellent local control rates of 70-90% in oligometastatic disease, with long-term survival in some series approaching 20-40%. A recent randomized phase 2 clinical trial by Gomez et al. demonstrated significantly improved progression free survival with aggressive consolidative therapy (surgery, radiotherapy +/- chemotherapy or SABR) in oli gometastatic non-small cell lung cancer (NSCLC). As additional randomized controlled trials are ongoing to determine the efficacy of SABR in oligometastatic disease, SABR is increasingly being used within routine clinical practice. This review article aims to sum-marize the history and current paradigm of the oligometastatic state, review recently pub-lished literature of SABR in oligometastatic cancer and discuss ongoing trials and future directions in this context. PMID- 28917255 TI - Stereotactic body radiotherapy for primary renal cell carcinoma and adrenal metastases. AB - The incidence of renal cell carcinoma (RCC) and metastatic adrenal lesions continues to rise and present evolving complexities in terms of management. Technical challenges in treatment delivery are compounded by the setting of an ageing patient population with multiple medical co-morbidities. While the standard of care treatment for both primary RCC and oligometastatic adrenal lesions has typically been surgery, a number of patients may be medically or surgically inoperable, and for whom alternative options require consideration. Additionally, in metastatic disease, surgery presents an invasive option, sometimes with unacceptable risks of perioperative morbidity and therefore is considered a less desirable option to some. Stereotactic body radiotherapy (SBRT) is an established radiotherapy technique that is rapidly being incorporated into many radiotherapy departments, particu-larly with the increasing availability and capabilities of modern linear accelerators to deliver precise image guided treatment. There are considerable advantages of SBRT including its ability to provide a non-invasive ablative treatment with very few treatment sessions, with emerging evidence showing promising rates of local control (LC) and low associated mor-bidity. This review details the use of SBRT for primary RCC as well as adrenal metastases, focusing on issues including patient selection, technical considerations, and patient out-comes. Furthermore, this review explores some recent insights into the radiobiology of RCC, the immunomodulatory effects of SBRT, and the use of systemic agents with SBRT. PMID- 28917256 TI - Postoperative stereotactic body radiotherapy for spinal metastases. AB - Spine is a common site of metastases in cancer patients. Spine surgery is indicated for select patients, typically those with mechanical instability and/or malignant epidural spinal cord (or cauda equina) compression. Although post operative conventional palliative external beam radiation therapy has been the standard of care, technical improvements in radiation planning and image-guided radiotherapy have allowed for the application of stereotactic body radiotherapy (SBRT) to the spine. Spine SBRT is intended to ablate residual tumor and optimize local control by delivering several fold greater biologically effective doses. Early clinical experience of postoperative spinal SBRT report encouraging results in terms of safety and efficacy. In this review, we summarize the clinical and technical aspects pertinent to a safe and effective practice of postoperative SBRT for spinal metastases. PMID- 28917257 TI - Exploiting molecular genomics in precision radiation oncology: a marriage of biological and physical precision. AB - Achieving local tumour control is paramount for cure in head and neck and prostate cancers. With the transition to precision radiotherapy (RT) techniques, survival rates have improved in the majority of these cancers, but a substantial proportion of 30-40% still relapse following primary treatment. Recent large scale molecular profiling studies have revealed unique biological events that could explain for tumour aggression and resistance to therapies, redefining the molecular taxonomy of head and neck and prostate cancers. Here, we reviewed the key findings from these studies, highlighting those relevant for clinical stratification. We also proposed novel combinatorial clinicomolecular models to identify subsets of patients with aggressive localised tumours and limited metastases, and to inform on the optimal management of these patients using molecular targeted agents, immunotherapy, and RT. PMID- 28917258 TI - Stereotactic body radiotherapy for early stage lung cancer-historical developments and future strategies. AB - The application of radiosurgery dose escalation extra-cranially in a moving target, surrounded by critical normal tissue, presents unique dosimetric and clinical challenges. Building on a strong foundation of robust technological advancements and well-planned clinical studies, lung stereotactic body radiotherapy (SBRT) has firmly established its place in the management of early stage non-small cell lung cancer (NSCLC). Nevertheless, favourable outcomes and long-term survival still evade a substantial proportion of patients, especially for central and larger peripheral lung tumours. In this review, we will document the historical developments of lung SBRT over the past decades, highlighting key studies, which have shaped current clinical practice. At the same time, we will address some of the recent advancements in radiation technology, molecular profiling and immunotherapy, and discuss how these important developments can lead to combinatorial strategies, which we hope will form the backbone of new clinical trials and drive better cure rates. PMID- 28917259 TI - Successful treatment with hyperbaric oxygen therapy for pneumatosis cystoides intestinalis as a complication of granulomatosis with polyangiitis: a case report. AB - BACKGROUND: Although gastrointestinal involvement in patients with granulomatosis with polyangiitis is uncommon, it is associated with mild to severe life threatening complications. We present a case of pneumatosis cystoides intestinalis in a patient with granulomatosis with polyangiitis that was treated successfully with hyperbaric oxygen. CASE PRESENTATION: A 70-year-old Japanese man with a 3-year history of granulomatosis with polyangiitis consulted our hospital with a complaint of severe back pain. Computed tomography showed a large amount of gas located in his bowel wall and mesentery. He underwent urgent exploratory laparotomy, which led to a diagnosis of pneumatosis cystoides intestinalis without intestinal perforation or necrosis. He consequently underwent 13 sessions of hyperbaric oxygen therapy and was discharged from our hospital without complications. CONCLUSIONS: Several previous reports have supported the efficacy of hyperbaric oxygen for treating pneumatosis cystoides intestinalis. The present case, however, is the first in which pneumatosis cystoides intestinalis in a patient with granulomatosis with polyangiitis was successfully treated with hyperbaric oxygen. We therefore suggest that hyperbaric oxygen therapy could be a candidate treatment for pneumatosis cystoides intestinalis in patients with granulomatosis with polyangiitis. PMID- 28917261 TI - Development of Standard Reference Material (SRM) 2973 Vitamin D Metabolites in Frozen Human Serum (High Level). AB - The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health Office of Dietary Supplements and the Vitamin D Standardization Program, has recently issued a new serum-matrix Standard Reference Material (SRM): 2973 Vitamin D Metabolites in Frozen Human Serum (High Level). SRM 2973 was designed to provide a serum material with a total 25 hydroxyvitamin D [25(OH)D] concentration near 100 nmol/L to complement the existing serum-based SRMs with values assigned for total 25(OH)D between 20 and 80 nmol/L. Values were assigned for 25-hydroxyvitamin D2 [25(OH)D2], 25 hydroxyvitamin D3 [25(OH)D3], 3-epi-25(OH)D3, and total 25(OH)D [the sum of 25(OH)D2 + 25(OH)D3] using the NIST isotope dilution LC with tandem MS (MS/MS) reference measurement procedure (RMP) and related methods. SRM 2973 has a certified value of 98.4 +/- 2.1 nmol/L for 25(OH)D3 and reference values of 1.59 +/- 0.05 nmol/L for 25(OH)D2 and 5.23 +/- 0.20 nmol/L for 3-epi-25(OH)D3. In addition, a candidate RMP for 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] based on LC-MS/MS was used to assign values to SRM 2973 and the existing SRM 972a Vitamin D Metabolites in Frozen Human Serum. Reference values for 24R,25(OH)2D3 were assigned to SRM 2973 (7.51 +/- 0.26 nmol/L) and the four levels of SRM 972a: Level 1 (6.38 +/- 0.23 nmol/L), Level 2 (3.39 +/- 0.12 nmol/L), Level 3 (3.88 +/- 0.013 nmol/L), and Level 4 (6.32 +/- 0.22 nmol/L). The development of SRM 2973 [with a higher concentration of 25(OH)D3] and the addition of values for 24R,25(OH)2D3 assigned to both SRM 972a and SRM 2973 provide laboratories involved in vitamin D measurements with improved QA tools. PMID- 28917262 TI - Determination of Several Element Levels in Hardaliye Beverages Using Flame Atomic Absorption Spectrometry After Ultrasound-Probe Extraction. AB - In the present study, concentrations of calcium (Ca), copper (Cu), magnesium (Mg), manganese (Mn), sodium (Na), and zinc (Zn) in hardaliye samples produced in Turkey were determined by flame atomic absorption spectrometry after ultrasound probe extraction (UPE), microwave-assisted extraction (MAE), and wet extraction procedures. At present, there is limited work in the literature on UPE for the determination of trace elements in beverage samples. Our single-correlation analysis showed that the elements studied with the UPE method in hardaliye were strongly correlated with the MAE procedure. The parameters affecting the UPE experimental conditions-such as ultrasound amplitude, sonication time, sample amount, extractant type, and volume-were studied. Optimal experimental conditions for the extraction of the metals with the UPE procedure were as follows: 2 min of sonication; 30% amplitude; 3 mL sample volume; 5% HNO3 extraction solution; and 1 mL extractant volume for Ca, Cu, Mg, Mn, Na, and Zn in the hardaliye samples. The results in the hardaliye samples in minimum-maximum mg/L with the UPE procedure were 33-63 for Ca, 0.10-0.27 for Cu, 3.9-14.4 for Mg, 1.0-3.2 for Mn, 32-58 for Na, and 0.39-1.1 for Zn. LODs were 0.0032, 0.012, 0.013, 0.009, 0.011, and 0.008 mg/L for Ca, Cu, Mg, Mn, Na, and Zn, respectively. The accuracy of the method was verified with a recovery test (in which recoveries between 95 and 110% were observed) and application to a NIST 1643e certified sample (trace elements in water). The UPE procedure was found to be fast, accurate, and simple, with fewer contaminants and lower concentrated reagent consumption in comparison with conventional extraction procedures. PMID- 28917263 TI - Fourier-Transform Infrared (FTIR) Spectrophotometry: An Ecofriendly Method for the Analysis of Injectable Daptomycin. AB - Daptomycin (DPT) is an important antimicrobial agent used in clinical practice because it is very active against several types of medicinally challenging Gram positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. In addition to concerns about the quality of the analytical methods used in the QC of drugs, there is also concern about the impact of these methods on the environment. The trend toward sustainable consumption is increasingly evident and has forced the pharmaceutical industry to reduce the generation of toxic waste. In this context, IR spectrophotometry stands out because it does not use organic solvents and, although it is formally accepted for the identification of individual compounds, also allows the quantification of substances. Therefore, the aim of this work was to develop and validate a green analytical method for the analysis of DPT in a lyophilized powder for injection by FTIR spectrophotometry. The method involved absorbance measurements in the spectral region of 1700-1600 cm-1. The method was properly validated and found to be linear, precise, accurate, selective, and robust for the concentration range between 0.2 and 0.6 mg/150 mg. The validated method was able to quantify DPT powder for injection and can be used as an environmentally friendly alternative for routine analysis in QC. PMID- 28917264 TI - Expression of kisspeptin protein in hypothalamus and LH profile of growing female lambs. AB - Kisspeptin (kp) is considered to be one of the major regulators of the induction of pubertal events via the activation of the gonadotrophin-releasing hormone-LH system. The aim of the present study was to analyse expression of immunoreactive (ir) kp in the hypothalamic neurons of female lambs from the neonatal to the peripubertal period (5 days to 32 weeks) in relation to the plasma LH pattern using immunohistochemistry and image analysis. Hypothalami were collected from female lambs (n=33) from the infantile, juvenile, prepubertal and peripubertal periods. The population of kp-ir perikarya was detected mainly in the arcuate nucleus and their number increased gradually from 5 to 16 weeks of age and was maintained at a high level up to the peripubertal stage. This was reflected by the significant (P<0.05) gradual increase in the percentage of hypothalamic area occupied by kp-ir neurons and increase in the number of kp-ir perikarya within the arcuate nucleus. The same pattern of kp immunoreactivity was observed in the median eminence. Plasma LH concentration increased from Week 5 to Weeks 12-16 and further increased at Week 32. LH pulse frequency increased from Week 5 to 32 (P<0.05). Thus, changes in kp expression reflected changes in the LH pattern during lamb growth. The data obtained provide evidence about the participation of kp in the mechanisms of ontogenic development of ovine reproductive processes. PMID- 28917260 TI - Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases. AB - The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed. PMID- 28917265 TI - Olaratumab: PDGFR-alpha inhibition as a novel tool in the treatment of advanced soft tissue sarcomas. AB - Advanced soft tissue sarcomas are aggressive cancers with limited therapeutic options. Recently, inhibition of platelet-derived growth factor receptor (PDGFR) alpha by the monoclonal antibody olaratumab showed promising clinical activity. If confirmed, this would be one of the first examples of targeted therapy effective in advanced soft tissue sarcomas therapy independently of the histologic subtype. Here, we reviewed the biology of the PDGF/PDGFR axis, particularly focusing on its role in cancer, and then we discussed on the effects of PDGFR-alpha inhibition in the therapy of advanced soft tissue sarcomas. PMID- 28917266 TI - Urinary biomarkers in prostate cancer detection and monitoring progression. AB - Prostate cancer (CaP) is the most common cancer in men and the second leading cause of cancer deaths in males in Australia. Although serum prostate-specific antigen (PSA) has been the most widely used biomarker in CaP detection for decades, PSA screening has limitations such as low specificity and potential association with over-diagnosis. Current biomarkers used in the clinic are not useful for the early detection of CaP, or monitoring its progression, and have limited value in predicting response to treatment. Urine is an ideal body fluid for the detection of protein markers of CaP and is emerging as a potential source for biomarker discovery. Gene-based biomarkers in urine such as prostate cancer antigen-3 (PCA3), and genes for transmembrane protease serine-2 (TMPRSS2), and glutathione S-transferase P (GSTP1) have been developed and evaluated in the past decades. Among these biomarkers, urinary PCA3 is the only one approved by the FDA in the USA for clinical use. The study of urine microRNAs (miRNAs) is another burgeoning area for investigating biomarkers to achieve a pre-biopsy prediction of CaP to contribute to early detection. The development of mass spectrometry (MS)-based proteomic techniques has sparked new searches for novel protein markers for many diseases including CaP. Urinary biomarkers for CaP represent a promising alternative or an addition to traditional biomarkers. Future success in biomarker discovery will rely on collaboration between clinics and laboratories. In addition, research efforts need to be moved from biomarker discovery to validation in a large cohort or separate population of patients and translation of these findings to clinical practice. In this review, we discuss urine as a potential source for CaP biomarker discovery, summarise important genetic urine biomarkers in CaP and focus on MS-based proteomic approaches as well as other recent developments in quantitative techniques for CaP urine biomarker discovery. PMID- 28917267 TI - Distance-delivered physical activity interventions for childhood cancer survivors: A systematic review and meta-analysis. AB - This review aimed to determine the feasibility of distance-delivered physical activity (PA) interventions in childhood cancer survivors (CCS), and assess the effect on PA levels, and physical, physiological and psychological outcomes. We searched electronic databases until May 2016, including studies following intensive treatment. Meta-analyses were conducted on randomized controlled trials. We calculated the effect of interventions on PA levels and physical, physiological and psychological health outcomes. Thirteen studies (n=270 participants) were included in the systematic review and four (n=102 participants) in the meta-analysis. Most studies used telephone to deliver interventions with contact (1/day-1/month), duration (2 weeks-1year) and timing (maintenance therapy->20years following intensive treatment) varying between interventions. Interventions yielded a mean recruitment rate=64%, retention rate=85% and adherence rate=88%. Interventions did not increase PA levels (p=0.092), but had a positive effect on physical function (p=0.008) and psychological outcomes (p=0.006). Distance-delivered PA interventions are feasible in CCS. Despite not increasing PA levels, participation may improve physical and psychological health; however, larger randomized controlled trials are warranted. PMID- 28917268 TI - Targeting androgen-independent pathways: new chances for patients with prostate cancer? AB - Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer (PC). Most patients eventually progress to a condition known as castration-resistant prostate cancer (CRPC), characterized by lack of response to ADT. Although new androgen receptor signaling (ARS) inhibitors and chemotherapeutic agents have been introduced to overcome resistance to ADT, many patients progress because of primary or acquired resistance to these agents. This comprehensive review aims at exploring the mechanisms of resistance and progression of PC, with specific focus on alterations which lead to the activation of androgen receptor (AR)-independent pathways of survival. Our work integrates available clinical and preclinical data on agents which target these pathways, assessing their potential clinical implication in specific settings of patients. Given the rising interest of the scientific community in cancer immunotherapy strategies, further attention is dedicated to the role of immune evasion in PC. PMID- 28917270 TI - Cancer-related fatigue in adolescents and young adults: A systematic review of the literature. AB - : Adolescents and young adults with cancer (AYA) represent a specific age cohort dealing with the disease in a stage of life characterized by development, upheavals, and establishment. The aim of this study was to point out the state of research on how AYA are affected by cancer-related fatigue (CRF). RESULTS: Twelve articles were included. CRF was found to be higher in AYA than in either of the comparison groups, healthy peers and older cancer patients. Most included studies did not measure CRF with multidimensional, fatigue-specific instruments. CONCLUSION: We found a gap in research concerning CRF in AYA. The existing findings suggest that CRF is a significant issue for AYA cancer patients. However, less is known about the prevalence, severity, and impact of CRF in AYA, and their treatment. This should be considered in future research, and risk and prevention factors should be ascertained. Multidimensional and fatigue-specific measuring tools should be used to do this. PMID- 28917269 TI - Triplet (FOLFOXIRI) versus doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis. AB - Uncertainty exists regarding the comparative effectiveness of triplet chemotherapy (FOLFOXIRI) as backbone first-line chemotherapy for metastatic colorectal cancer (mCRC). We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing triplet versus doublet chemotherapy (FOLFOX or FOLFIRI) as first-line therapy in mCRC. Methods and reporting followed PRISMA and SAMPL guidelines. Eight RCTs were included, comprising 1732 patients. In pooled analysis, FOLFOXIRI was associated with improvements in efficacy outcomes, notably with a 25% survival increase (95%CI: 10-37%). FOLFOXIRI was also associated with increased toxicity, with a non-significant 25% increase in the risk of patients experiencing grade >=3 adverse events (95% CI: -3 to 61%) and with a 1.83 (95% CI: 1.62-2.07) increase in the rate ratio of grade >=3 adverse events. Moderate quality evidence suggests that first-line FOLFOXIRI provides clinically meaningful efficacy benefits in this setting, at the expense of increased toxicity. Further research is warranted to better characterize safety and to evaluate the most beneficial combination with targeted agents. PMID- 28917271 TI - Cognitive impairment and chemotherapy: a brief overview. AB - Patients with cancer are experiencing long-term survival following chemotherapy, but the treatment may also be associated with short and long-term toxicity, including the possibility of cognitive dysfunction. A literature overview indicated a significant association between chemotherapy and cognitive impairment but prospective longitudinal research is warranted to examine the degree and persisting nature of this decline. Although chemotherapeutic agents are unlikely to cross the blood-brain barrier, it has been alleged that the occurrence of neurotoxicity is linked to the pro-inflammatory cytokine pathways. Moreover in most cases many other factors could play an ancillary and concomitant role. The contribution of hormone therapy as well as emotional, social, behavioural and genetic factors should always be considered. Especially physical activity and cognitive training appear promising in the management of cognitive impairment but additional studies are required to establish their efficacy. PMID- 28917272 TI - Towards personalized medicine of colorectal cancer. AB - Efforts in colorectal cancer (CRC) research aim to improve early detection and treatment for metastatic stages which could translate into better prognosis of this disease. One of the major challenges that hinder these efforts is the heterogeneous nature of CRC and involvement of diverse molecular pathways. New large-scale 'omics' technologies are making it possible to generate, analyze and interpret biological data from molecular determinants of CRC. The developments of sophisticated computational analyses would allow information from different omics platforms to be integrated, thus providing new insights into the biology of CRC. Together, these technological advances and an improved mechanistic understanding might allow CRC to be clinically managed at the level of the individual patient. This review provides an account of the current challenges in CRC management and an insight into how new technologies could allow the development of personalized medicine for CRC. PMID- 28917273 TI - Mechanisms and risk factors of thrombosis in cancer. AB - The close relationship between cancer and thrombosis is known since more than a century. Venous thromboembolism (VTE) may be the first manifestation of an occult malignancy in an otherwise healthy individual. Cancer patients commonly present with abnormalities of laboratory coagulation tests, indicating an ongoing subclinical hypercoagulable condition. The results of laboratory tests demonstrate that a process of fibrin formation and removal parallels the development of malignancy, which is of particular interest since fibrin and other clotting products are important for both thrombogenesis and tumor progression. Besides general clinical risk factors (i.e. age, previous VTE, immobility, etc.), other factors typical of cancer can increase the thrombotic risk in these patients, including the type of cancer, advanced disease stage, and cancer therapies. In addition, biological factors, including tumor cell-specific prothrombotic properties and the host cell inflammatory response to the tumor, play a central role in the pathogenesis of cancer-associated thrombosis. Cancer cells produce and release procoagulant and fibrinolytic proteins, as well as inflammatory cytokines. In addition, they are capable of directly adhering to host cells (i.e. endothelial cells, monocytes, platelets, and neutrophils), thereby stimulating additional prothrombotic properties of the host effector cells. Tumor-shed procoagulant microparticles also contribute to the patient hypercoagulable state. Finally, the changes of stromal cells of the tumor 'niche' induced by tissue factor (TF) highlight new interactions between hemostasis and cancer. Of interest, most of these mechanisms, besides activating the hemostatic system, also promote tumor growth and metastasis, and are regulated by oncogenic events. Indeed, molecular studies demonstrate that oncogenes responsible for the cellular neoplastic transformation drive the programs of hemostatic protein expression and microparticle liberation by cancer tissues. Human and animal experimental models demonstrate that activation of cancer-associated prothrombotic mechanisms parallels the development of overt thrombotic syndromes in vivo. PMID- 28917274 TI - The interventional oncologist: The fourth musketeer of cancer care. PMID- 28917275 TI - Historical, Current, and Future Intraoperative Imaging Modalities. AB - Intraoperative imaging has become widely accepted in neurosurgery in recent years. The possibility to objectively determine the extent of tumor removal is highly advantageous. If the resection is incomplete, clinicians can attempt to remove the residual tumor that was missed during the same operation. Furthermore, the positioning of implants in spinal surgery, as well as in cranial surgery, can be controlled and modified during the procedure. Intraoperative imaging acts as immediate quality control and offers improved patient safety. This article gives a brief overview of the different intraoperative imaging modalities and their potential applications in modern neurosurgery. PMID- 28917276 TI - Stereotactic Biopsy Platforms with Intraoperative Imaging Guidance. AB - The resolution and real-time navigation of intraoperative MRI (iMRI) has been leveraged in neurosurgery. We review frameless stereotactic biopsy platforms and focus on emerging technology integrating intraoperative MRI with frameless stereotaxy. Brain biopsy with iMRI allows for an accurate tissue sample with the ability to correct cannula trajectory during surgery, eliminating misdiagnosis secondary to faulty targeting. This technology allows for a percutaneous approach avoiding large incisions, obviates the need for frozen tissue evaluation, has the potential to reduce unnecessary specimen harvesting and operating room time, and optimizes safety of targeting deep brain lesions. PMID- 28917277 TI - Intraoperative MRI and Maximizing Extent of Resection. AB - Intraoperative MRI (iMRI) is a neurosurgical adjunct used to maximize the removal of glioma, the most common primary brain tumor. Increased extent of resection of gliomas has been shown to correlate with longer survival times. iMRI units are variable in design and magnet strength, which can affect patient selection and image quality. Multiple studies have shown that surgical resection of gliomas using iMRI results in increased extent of resection and survival time. Level II evidence supports the use of iMRI in the surgical treatment of glioma. PMID- 28917278 TI - Combining Functional Studies with Intraoperative MRI in Glioma Surgery. AB - Maximal safe resection is the cornerstone of treatment for low-grade and high grade gliomas. In addition to high-resolution anatomic MRI studies that highlight tumor architecture, it is important to determine the relationship of the tumor to the eloquent cortical and subcortical areas to avoid introducing or exacerbating a neurologic deficit. The goal of this review was to highlight imaging modalities that provide functional information and can be integrated with intraoperative MRI navigation to maximize the extent of resection while preserving a patient's neurologic function. PMID- 28917280 TI - A Novel Use of the Intraoperative MRI for Metastatic Spine Tumors: Laser Interstitial Thermal Therapy for Percutaneous Treatment of Epidural Metastatic Spine Disease. AB - Spinal laser interstitial thermal therapy (LITT) appears to be a promising novel modality for treatment of epidural metastatic spine disease in patients who are poor candidates for larger-scale oncologic spinal surgery and can act synergetically with spinal stereotactic radiosurgery to maximize local control and palliate pain. This technique is ideally suited for the intraoperative MRI suite to monitor the extent of the ablation in the epidural space. As percutaneous navigation, imaging, and LITT technology improve, broader applicability of this minimally invasive technique in spinal oncology is foreseen. PMID- 28917279 TI - iMRI During Transsphenoidal Surgery. AB - A variety of intraoperative MRI (iMRI) systems are in use during transsphenoidal surgery (TSS). The variations in iMRI systems include field strengths, magnet configurations, and room configurations. Most studies report that the primary utility of iMRI during TSS lies in detecting resectable tumor residuals following maximal resection with conventional technique. Stereotaxis, neuronavigation, and complication avoidance/detection are enhanced by iMRI use during TSS. The use of iMRI during TSS can lead to increased extent of resection for large tumors. Improved remission rates from hormone-secreting tumors have also been reported with iMRI use. This article discusses the history, indications, and future directions for iMRI during TSS. PMID- 28917281 TI - Magnetic Resonance Thermometry and Laser Interstitial Thermal Therapy for Brain Tumors. AB - Recent technological advancements in intraoperative imaging are shaping the way for a new era in brain tumor surgery. Magnetic resonance thermometry has provided intraoperative real-time imaging feedback for safe and effective application of laser interstitial thermal therapy (LITT) in neuro-oncology. Thermal ablation has also established itself as a surgical option in epilepsy surgery and is currently used in spine oncology with promising results. This article reviews the principles and rationale as well as the clinical application of LITT for brain tumors. It also discusses the technical nuances of the current commercially available systems. PMID- 28917282 TI - Interventional MRI-Guided Deep Brain Stimulation Lead Implantation. AB - Current knowledge of the functional anatomy of the subthalamic nucleus and globus pallidus, discovered through microelectrode recording and postoperative imaging, justifies purely anatomic targeting for deep brain stimulation (DBS). Interventional MRI (iMRI)-DBS is more anatomically accurate than traditional awake procedures and has similar clinical outcomes without increased risk or increased operative times. iMRI lead implantation allows patients to receive DBS therapy who cannot tolerate or do not agree to undergo an awake procedure. This article describes considerations for iMRI-DBS implantation in the subthalamic nucleus and globus pallidus, including patient selection, technique of electrode placement, expected outcomes, and potential complications. PMID- 28917283 TI - MRI-Guided Laser Interstitial Thermal Therapy for Epilepsy. AB - MRI-guided laser interstitial thermal therapy for epilepsy (LITT-E) has become an established, minimally invasive alternative to traditional epilepsy surgery. LITT E is particularly valuable in cases in which open surgery poses unacceptably high morbidity or patient preference precludes craniotomy. Here we present a focused review of technical details and application of LITT to both focal and generalized epilepsy. PMID- 28917284 TI - Neurosurgical Applications of High-Intensity Focused Ultrasound with Magnetic Resonance Thermometry. AB - Magnetic resonance guided focused ultrasound surgery (MRgFUS) has potential noninvasive effects on targeted tissue. MRgFUS integrates MRI and focused ultrasound surgery (FUS) into a single platform. MRI enables visualization of the target tissue and monitors ultrasound-induced effects in near real-time during FUS treatment. MRgFUS may serve as an adjunct or replace invasive surgery and radiotherapy for specific conditions. Its thermal effects ablate tumors in locations involved in movement disorders and essential tremors. Its nonthermal effects increase blood-brain barrier permeability to enhance delivery of therapeutics and other molecules. PMID- 28917285 TI - Fluorescence Imaging/Agents in Tumor Resection. AB - Intraoperative fluorescence imaging allows real-time identification of diseased tissue during surgery without being influenced by brain shift and surgery interruption. 5-Aminolevulinic acid, useful for malignant gliomas and other tumors, is the most broadly explored compound approved for fluorescence-guided resection. Intravenous fluorescein sodium has recently received attention, highlighting tumor tissue based on extravasation at the blood-brain barrier (defective in many brain tumors). Fluorescein in perfused brain, unselective extravasation in brain perturbed by surgery, and propagation with edema are concerns. Fluorescein is not approved but targeted fluorochromes with affinity to brain tumor cells, in development, may offer future advantages. PMID- 28917286 TI - Intraoperative 3D Computed Tomography: Spine Surgery. AB - Spinal instrumentation often involves placing implants without direct visualization of their trajectory or proximity to adjacent neurovascular structures. Two-dimensional fluoroscopy is commonly used to navigate implant placement, but with the advent of computed tomography, followed by the invention of a mobile scanner with an open gantry, three-dimensional (3D) navigation is now widely used. This article critically appraises the available literature to assess the influence of 3D navigation on radiation exposure, accuracy of instrumentation, operative time, and patient outcomes. Also explored is the latest technological advance in 3D neuronavigation: the manufacturing of, via 3D printers, patient-specific templates that direct implant placement. PMID- 28917287 TI - Intraoperative Computed Tomography in Cranial Neurosurgery. AB - The challenge for treating complex lesions with the aim of minimal surgery related morbidity has generated an increasing demand for sophisticated intraoperative imaging modalities. Newest generations of intraoperative computed tomography (CT) scanners offer a multitude of hardware and software improvements resulting in higher image quality that further propagates its everyday usage in the interdisciplinary operative setting. This article describes workflow and applicability of intraoperative CT scanning in cranial neurosurgery, in subspecialties like skull base or vascular neurosurgery, and its advantages and limitations. PMID- 28917288 TI - Intraoperative Imaging for Vascular Lesions. AB - Neurovascular surgery is a broad and challenging, yet exciting field within neurologic surgery. The neurovascular surgeon must be meticulous; because the brain and spinal cord are unforgiving to ischemic insults. Along with the pressures of this demanding subspecialty comes the potential to help patients recover from potentially devastating pathology to go on and lead normal, healthy lives. Several intraoperative imaging modalities are available to help maximize treatment success while reducing risk. This article reviews each of these modalities, including digital subtraction angiography, fluorescence angiography, Doppler ultrasonography, laser Doppler, laser speckle contrast imaging, neuronavigation, and neuroendoscopy. PMID- 28917289 TI - Imaging of Convective Drug Delivery in the Nervous System. AB - Convection-enhanced delivery permits the direct homogeneous delivery of small- and large-molecular-weight putative therapeutics to the nervous system in a manner that bypasses the blood-nervous system barrier. The development of co infused surrogate imaging tracers (for computed tomography and MRI) allows for the real-time, noninvasive monitoring of infusate distribution during convective delivery. Real-time image monitoring of convective distribution of therapeutic agents insures that targeted structures/nervous system regions are adequately perfused, enhances safety, informs efficacy (or lack thereof) of putative agents, and provides critical information regarding the properties of convection-enhanced delivery in normal and various pathologic tissue states. PMID- 28917290 TI - Intraoperative Ultrasound for Peripheral Nerve Applications. AB - Offering real-time, high-resolution images via intraoperative ultrasound is advantageous for a variety of peripheral nerve applications. To highlight the advantages of ultrasound, its extraoperative uses are reviewed. The current intraoperative uses, including nerve localization, real-time evaluation of peripheral nerve tumors, and implantation of leads for peripheral nerve stimulation, are reviewed. Although intraoperative peripheral nerve localization has been performed previously using guide wires and surgical dyes, the authors' approach using ultrasound-guided instrument clamps helps guide surgical dissection to the target nerve, which could lead to more timely operations and shorter incisions. PMID- 28917291 TI - Intraoperative Raman Spectroscopy. AB - Surgical excision of brain tumors provides a means of cytoreduction and diagnosis while minimizing neurologic deficit and improving overall survival. Despite advances in functional and three-dimensional stereotactic navigation and intraoperative MRI, delineating tissue in real time with physiologic confirmation is challenging. Raman spectroscopy has potential to be an important modality in the intraoperative evaluation of tissue during surgical resection. In vitro experimental studies have shown that this technique can be used to differentiate normal brain tissue from tissue with infiltrating cancer cells and dense cancerous masses with high specificity, indicating the feasibility of this method for in vivo application. PMID- 28917292 TI - Preface. PMID- 28917293 TI - PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis. PMID- 28917294 TI - Crosstalk between Muscularis Macrophages and Enteric Neurons Regulates Gastrointestinal Motility. PMID- 28917295 TI - Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12. AB - INTRODUCTION: Inactivated influenza vaccine is recommended in any stage of pregnancy, but evidence of safety in early pregnancy is limited, including for vaccines containing A/H1N1pdm2009 (pH1N1) antigen. We sought to determine if receipt of vaccine containing pH1N1 was associated with spontaneous abortion (SAB). METHODS: We conducted a case-control study over two influenza seasons (2010-11, 2011-12) in the Vaccine Safety Datalink. Cases had SAB and controls had live births or stillbirths and were matched on site, date of last menstrual period, and age. Of 919 potential cases identified using diagnosis codes, 485 were eligible and confirmed by medical record review. Exposure was defined as vaccination with inactivated influenza vaccine before the SAB date; the primary exposure window was the 1-28days before the SAB. RESULTS: The overall adjusted odds ratio (aOR) was 2.0 (95% CI, 1.1-3.6) for vaccine receipt in the 28-day exposure window; there was no association in other exposure windows. In season specific analyses, the aOR in the 1-28days was 3.7 (95% CI 1.4-9.4) in 2010-11 and 1.4 (95% CI 0.6-3.3) in 2011-12. The association was modified by influenza vaccination in the prior season (post hoc analysis). Among women who received pH1N1-containing vaccine in the previous influenza season, the aOR in the 1 28days was 7.7 (95% CI 2.2-27.3); the aOR was 1.3 (95% CI 0.7-2.7) among women not vaccinated in the previous season. This effect modification was observed in each season. CONCLUSION: SAB was associated with influenza vaccination in the preceding 28days. The association was significant only among women vaccinated in the previous influenza season with pH1N1-containing vaccine. This study does not and cannot establish a causal relationship between repeated influenza vaccination and SAB, but further research is warranted. PMID- 28917296 TI - Commentary on: "Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12". PMID- 28917297 TI - Injury-Induced HDAC5 Nuclear Export Is Essential for Axon Regeneration. PMID- 28917298 TI - High prevalence of bovine cysticercosis found during evaluation of different post mortem detection techniques in Belgian slaughterhouses. AB - Bovine cysticercosis (BCC), caused by the helminth Taenia saginata, is currently diagnosed solely by official meat inspection (MI) based on macroscopic detection of viable cysticerci or typical lesions of degenerated larvae. MI has a known low sensitivity (<16%), leading to a large proportion of infected cattle carcasses entering the human food chain and posing a risk to public health. Prevalence in Belgium based on MI results is estimated at around 0.22%. Due to the low sensitivity of MI, alternative techniques to detect BCC should be considered. This study evaluates MI, MI with additional incisions in the heart, specific antibody detection against excretory/secretory (E/S) in the Ab-ELISA and circulating antigens in the B158/B60 Ag-ELISA on 715 (101 MI-positive and 614 MI negative) samples collected from carcasses at slaughterhouses in Belgium. Full dissection of the predilection sites was considered the reference test. During the study, mostly carcasses with (very) light infections were detected containing predominantly degenerated or calcified cysticerci and only few viable cysticerci. Dissection of the predilection sites detected 144 (23%) additional infections in the 614 MI-negative carcasses. When sequentially performing first the dissection of the predilection sites, followed by the Ag-ELISA and the Ab-ELISA, an additional 36% of MI-negative carcasses were found positive for BCC, resulting in a prevalence very much higher than the above mentioned 0.22%. The B158/B60 Ag ELISA showed a sensitivity of 40% for the detection of carcasses containing viable cysticerci and a specificity of 100%, and detected 70 positive carcasses of which only 14 had been identified as positive during MI. If Ag-ELISA were implemented as a detection technique for BCC in the slaughterhouses, many infected carcasses would still not be detected due to the sensitivity of 40%. But as sensitivity increases with increasing number of cysticerci in the carcass, the infected carcasses passing inspection will be the ones containing only a few viable cysticerci and thus posing a smaller food safety problem. Ag-ELISA is preferred over the ES Ab-ELISA in this study, which had a sensitivity of 13.3% and a specificity of 91.7% in a population with overall low infection burdens. PMID- 28917300 TI - Epidemiologic studies on Theileria equi infections for grazing horses in Ili of Xinjiang province. AB - In order to found the epidemiological situation of T. equi in the horse herds in Ili Prefecture of Xinjiang Province, 723 blood samples collected from 4 counties and districts were test for T. equi through microscopic detection and Polymerase chain Reaction (PCR). In the result, we found that the 295 of 723 blood samples (40.8%) were positive for T. equi infection. The results showed that the choosed counties have a varying degrees infection. To our knowledge, this is the first time that we detected T. equi infection using the molecular techniques from Ili in Xinjiang Uygur Autonomous region. PMID- 28917299 TI - Exploitation of chemical, herbal and nanoformulated acaricides to control the cattle tick, Rhipicephalus (Boophilus) microplus - A review. AB - The tick Rhipicephalus (Boophilus) microplus is a key vector of bacterial and protozoan diseases causing heavy economic losses directly and indirectly in animal husbandry. In the past decades, the control of ticks faced some major issues, such as the rapid development of resistance in targeted vectors and non target effects on human health and the environment, due to the employ of synthetic acaricides and repellents. Eco-friendly pesticides for treating and controlling animal parasites such as ticks were mainly from medicinal plants and thus they form the richest entity for manufacturing resources for drugs. Even though there are efforts made to discover reliable plant-based acaricides to control ectoparasites in animal husbandry, the effective control of R. (B.) microplus ticks still represent a major challenge in current veterinary entomology. Recently, a wide number of promising attempts have been conducted to use herbal preparations and green-fabricated nanoparticles for the control of R. (B.) microplus. The aim of this review is to critically summarize and discuss the use of herbal preparations used in ethno-veterinary as well as green-fabricated nanoparticles as novel acaricides for the control of the cattle tick R. (B.) microplus. PMID- 28917301 TI - Cysteine protease 30 (CP30) contributes to adhesion and cytopathogenicity in feline Tritrichomonas foetus. AB - Tritrichomonas foetus (T. foetus) is a flagellated protozoan parasite that is recognized as a significant cause of diarrhea in domestic cats with a prevalence rate as high as 30%. No drugs have been shown to consistently eliminate T. foetus infection in all cats. Cysteine proteases (CPs) have been identified as mediators of T. foetus-induced adhesion-dependent cytotoxicity to the intestinal epithelium. These CPs represent novel targets for the treatment of feline trichomonosis. However, cats also produce CPs that are part of life-critical systems. Thus, parasitic CPs need to be selectively targeted to reduce the potential for host toxicity. Previous studies have demonstrated the importance of a specific CP, CP30, in mediating bovine and human trichomonad cytopathogenicity. This CP has also recently been identified in feline T. foetus, although the function of this protease in the feline genotype remains unknown. Therefore, the study objectives were to characterize the presence of CP30 in feline T. foetus isolates and to evaluate the effect of targeted inhibition of CP30 on feline T. foetus-induced adhesion dependent cytotoxicity. The presence of CP30 in feline T. foetus isolates was identified by In gel zymography and proteomic analysis, indirect immunofluorescence (IF), and flow cytometry using a rabbit polyclonal antibody that targets bovine T. foetus CP30 (alpha-CP30). The effect of inhibition of CP30 activity on T. foetus adhesion and cytotoxicity was determined using CFSE-labeled feline T. foetus and crystal violet spectrophotometric assays in a previously validated co-culture model. CP30 expression was confirmed in all feline T. foetus isolates tested by all assays. Targeted inhibition of feline T. foetus CP30 resulted in decreased T. foetus adhesion to and cytotoxicity towards IPEC-J2 monolayers compared to rabbit IgG-treated T. foetus isolates. These studies establish that CP30 is expressed by feline T. foetus isolates and may be an important virulence factor in the cytopathogenicity of feline T. foetus. The results of these studies provide strong evidence-based justification for investigation of CP30 as a novel target for the treatment of feline trichomonosis. PMID- 28917302 TI - The global seroprevalence of Toxoplasma gondii among wild boars: A systematic review and meta-analysis. AB - This systematic review and meta-analysis study was performed to evaluate the worldwide seroprevalence of Toxoplasma gondii among wild boar. We searched PubMed, Science Direct, Web of Science, Cochrane, Scopus, EBSCOhost and Google Scholar databases for studies reporting T. gondii seroprevalence in wild boars between January 1995 and March 2017. Inclusion and exclusion criteria were applied. We estimated the pooled seroprevalence of T. gondii in wild boars using a random-effects model, and evaluated overall seroprevalence in different geographical areas. A total of 43 articles that included 16788 wild boar from 23 countries fulfilled our eligibility criteria. Of these, 4759 wild boar had been defined T. gondii seropositive and we estimated the pooled worldwide seroprevalence of toxoplasmosis in wild boars to be 23% (95% CI: 19-27%). The pooled seroprevalence in North America (32%, 20-45%; odds ratio [OR] 2.09) and Europe (26%, 21-30%; OR 1.72), was higher than Asia (13%, 5-23%). The lowest seroprevalence was estimated in South America (5%, 3-8%). An increased seropositivity was observed with elevation in geographical latitude. In subgroup analyses, the pooled seroprevalence of T. gondii was higher in wild boar older than 12 months of age (28%, 22-35%; OR 1.57) compared to those up to 12 months of age (20%, 16-25%). Our findings suggest that wild boar have an important role in human infection and the epidemiological cycle of T. gondii infection. PMID- 28917303 TI - The evaluation of GM6-based ELISA and ICT as diagnostic methods on a Mongolian farm with an outbreak of non-tsetse transmitted horse trypanosomosis. AB - Trypanosoma equiperdum, which is the etiological agent of dourine, spreads through sexual intercourse in equines. Dourine (T. equiperdum) has been reported in Mongolia, where it is considered an economically important disease of horses. T. evansi has also been reported in Mongolian domestic animals. The objective of this study was to evaluate the potential application of recombinant T. evansi GM6 (rTeGM6-4r)-based diagnostic methods on a farm with an outbreak of non-tsetse transmitted horse trypanosomosis. Ninety-seven percent homology was found between the amino acid sequences of T. equiperdum GM6 and the GM6 of another Trypanozoon, which also shared the same cellular localization. This finding suggests the utility of rTeGM6-4r-based serodiagnostic methods for epidemiological studies and the diagnosis of both surra and dourine in Equidae. Fifty blood samples were examined from a herd of horses. The diagnostic value of an rTeGM6-4r-based ELISA and an rTeGM6-4r-based immunochromatographic test (ICT) were measured in comparison to a T. evansi crude antigen-based ELISA, which is a diagnostic method recommended by the OIE. However, this is not a perfect diagnostic method for trypanosomosis. Positive serum samples were detected in 46%, 42% and 28% of the tested horses using an rTeGM6-4r-based ELISA, crude antigen-based ELISA and rTeGM6-4r-based ICT, respectively. The sensitivity of rTeGM6-based ELISA was 81%, the specificity was 79%, and the agreement was moderate. We conclude that rTeGM6 4r-based ELISA and ICT represent alternative options for baseline epidemiological studies and the on-site diagnosis of horse trypanosomoses in the field, respectively. PMID- 28917304 TI - Prevalence of ticks and tick-borne pathogens: Babesia and Borrelia species in ticks infesting cats of Great Britain. AB - In a study of tick and tick-borne pathogen prevalence, between May and October 2016, 278 veterinary practices in Great Britain examined 1855 cats. Six-hundred and one cats were found to have attached ticks. The most frequently recorded tick species was Ixodes ricinus (57.1%), followed by Ixodes hexagonus (41.4%) and Ixodes trianguliceps (1.5%). Male cats, 4-6 years of age living in rural areas were most likely to be carrying a tick; hair length and tick treatment history had no significant association with attachment. For cats that were parasitized by ticks in large urban areas, I. hexagonus was the most frequent species recorded. Molecular analysis was possible for 541 individual tick samples, others were too damaged for analysis; Babesia spp., and Borrelia burgdorferi sensu lato were identified in 1.1% (n=6) and 1.8% (n=10) of these, respectively. Babesia spp. included Babesia vulpes sp. nov./Babesia microti-like (n=4) in I. hexagonus and Babesia venatorum (n=2) in I. ricinus. Borrelia burgdorferi s.l. species included Borrelia garinii (n=6) and Borrelia afzelii (n=4). The majority of B. burgorferi s.l. cases were found in I. ricinus, with B. afzelii in one I. hexagonus nymph. No Borrelia or Babesia spp. were present in I. trianguliceps. To determine a true prevalence for ticks on cats, practices that only submitted questionnaires from cats with ticks and practices that submitted fewer than 5 returns per week were removed; amongst those considered to have adhered strictly to the collection protocol, feline tick prevalence amongst cats that had access to the outdoors was 6.6%. These results show that ticks can be found on cats throughout Great Britain, which harbour a range of species of Babesia and B. burgdorferi s.l. and that cats, particularly in green spaces within urban areas, may form an important host for I. hexagonus, a known vector of pathogens. PMID- 28917305 TI - Genetic variability of cloned Cytauxzoon felis ribosomal RNA ITS1 and ITS2 genomic regions from domestic cats with varied clinical outcomes from five states. AB - Cytauxzoon felis is a tick-borne hemoparasite that causes cytauxzoonosis in domestic cats in the United States. Historically, feline cytauxzoonosis was reported to be nearly always fatal. However, increasing evidence of cats surviving acute infection and/or harboring a chronic, subclinical infection has suggested the existence of different C. felis strains that may vary in pathogenicity. In this study, the intraspecific variation of the C. felis first and second ribosomal RNA internal transcribed spacer (ITS1, ITS2) regions was assessed for any clinical outcome or geographic associations. Sequence data were obtained for 122C. felis ITS1 and ITS2 clones from 41 domestic cat blood samples from Arkansas, Kansas, Missouri, Oklahoma, and Texas. Seven previously reported ITS1 region sequences were found, and a previously undescribed 23-bp insert was detected in cloned ITS1 sequences from a domestic cat in Missouri and two cats in Oklahoma. Four previously reported ITS2 region sequences were identified, and a 40-bp insert similar to that previously reported in C. felis of a domestic cat from Arkansas and pumas was detected in 18 cloned C. felis sequences from 12 domestic cats. One clone contained both the 23-bp insert and 40-bp insert within the ITS1 and ITS2 regions, respectively. Combined ITS1 and ITS2 sequence genotypes revealed that C. felis sequences from 27 cats (72/122 clones) corresponded to four previously described genotypes, ITSa, ITSc, ITSd, and ITSn. Five clones with the novel 23-bp insert from three cat isolates represented two new genotypes, ITSaa and ITSbb. Genotypes ITScc, ITSdd, ITSee, ITSff, ITSgg, and ITShh denoted 13 clones that matched prior sequences but had no previously assigned genotype. Genotypes ITSii through ITStt comprised 32 clones that were similar to, but did not exactly match, previously described genotypes. Twenty five cats had C. felis infections with multiple ITS genotypes. Considerable C. felis genetic diversity was revealed with no significant geographic or clinical outcome associations. PMID- 28917306 TI - Evaluation of surface antigen TF1.17 in feline Tritrichomonas foetus isolates. AB - Tritrichomonas foetus (T. foetus) is a flagellated protozoa that infects the distal ileum and proximal colon of domestic cats, as well as the urogenital tract of cattle. Feline trichomonosis is recognized as a prevalent cause of chronic diarrhea in cats worldwide. The suspected route of transmission is fecal-oral, with cats in densely crowded environments at highest risk for infection. Thus, the recommended strategy for minimizing spread of infection is to identify and isolate T. foetus-positive cats from the general population. Rapid identification of infected cats can be challenging due to the inability to accurately and quickly detect the organism in samples at point of care facilities. Thus, identification of targets for use in development of a novel diagnostic test, as well as a vaccine or therapy for T. foetus infection is a significant area of research. Despite a difference in organ tropism between T. foetus genotypes, evidence exists for conserved virulence factors between feline and bovine T. foetus. The bovine T. foetus surface antigen, TF1.17, is an adhesin that is conserved across isolates. Vaccination with the purified antigen results in amelioration of cytopathogenicity and more rapid clearance of infection in cattle. We previously showed that three feline isolates of T. foetus were positive for TF1.17 antigen so we further hypothesized that TF1.17 is conserved across feline T. foetus isolates and that this antigen would represent an attractive target for development of a novel diagnostic test or therapy for feline trichomonosis. In these studies, we used monoclonal antibodies previously generated against 1.15 and 1.17 epitopes of the bovine T. foetus TF1.17 antigen, to evaluate for the presence and role of TF1.17 in the cytopathogenicity of feline T. foetus. A previously validated in vitro co-culture approach was used to model feline T. foetus infection. Immunoblotting, immunofluorescence assays, and flow cytometric analysis confirmed the presence and surface localization of antigen TF1.17 across all feline T. foetus isolates tested. Antigen TF1.17 was notably absent in the presumably nonpathogenic intestinal trichomonad, Pentatrichomonas hominis, a parasite that can be confused microscopically with T. foetus. Similar to bovine trichomoniasis, TF1.17 was found to promote T. foetus adhesion to the intestinal epithelium. These results support further characterization and development of the TF1.17 antigen as a possible target for the diagnosis and prevention of feline T. foetus infection. PMID- 28917307 TI - Evaluation of Western blot, ELISA and latex agglutination tests to detect Toxoplasma gondii serum antibodies in farmed red deer. AB - Abortion due to Toxoplasma gondii has been suspected in New Zealand farmed red deer. However, knowledge around the epidemiology and prevalence of T. gondii in farmed red deer is limited. The aim of this study was to firstly, assess the sensitivity and specificity of two commercially available assays, ELISA and latex agglutination test (LAT), for use in deer and secondly, to estimate the sero prevalence of T. gondii in red deer. A total of 252 sera from rising 2-year-old and adult hinds from 17 New Zealand red deer herds at early and late pregnancy scanning and from known aborted and/or non-aborted hinds were tested for the presence of T. gondii antibodies. Each assays' sensitivity and specificity was evaluated by both the Western Blot (WB) as a gold standard method and Bayesian latent class (BLC) analysis in the absence of a gold standard. The sensitivity and specificity for WB were 95.8% (95% credible interval: 89.5-99.2%) and 95.1% (95% credible interval: 90.6-98.1%), respectively. For the LAT at the manufacturer's recommended >=1:32 cut-off titre, the sensitivity (88.7%, 95% credible interval: 80.8-94.7%) and specificity (74.3%, 95% credible interval: 67.5-80.5%) were lower and higher than the sensitivity (76.2%, 95% credible interval: 66.7-84.5%) and specificity (89.7%, 95% credible interval: 84.5-93.9%) at a >=1:64 cut-off, using (BLC) analysis. Sensitivity and specificity of the LAT at cut-off titre of 1:32 were estimated to be 84.4% (95% CI: 74.9-90.9%) and 73.5% (95% CI: 65.8-79.9%) against WB. The LAT had better agreement with WB at cut-off titre of >=1:64 than >=1:32 (Kappa=0.63 vs 0.54). At optimised cut-off S/P of 15.5%, the sensitivity (98.8%, 95% credible interval 96.1-99.8%) and specificity (92.8%, 95% credible interval 88.9-95.7%) of the ELISA were higher and lower, respectively, than the sensitivity (85.1%, 95% credible interval 76.2 91.9%) and specificity (98.5%, 95% credible interval 96.9-99.4%) at manufacturer's cut-off S/P of 30%, from BLC analysis. The sensitivity and specificity of ELISA at S/P cut-off of 15.5% was 91.1% (95% CI: 83.2-96.1%) and 90.7% (95% CI: 85.2-94.7%), respectively, when assessed against WB. The sero prevalence from ELISA and LAT, at cut-off of S/P 15.5% and >=1:64, respectively, was not significantly different to that from WB (McNemar's Chi-square p=0.21 for ELISA and p=0.28 for LAT). PMID- 28917308 TI - Prevalence of Pentatrichomonas hominis infections in six farmed wildlife species in Jilin, China. AB - Pentatrichomonas hominis is an anaerobic flagellated protozoan that primarily parasitizes the gastrointestinal tract and is a conditional pathogen. It has an extensive host range and is well known as a potential causative agent of zoonotic disease. The objective of this study was to provide the first findings of the prevalence of P. hominis in six farmed wildlife species, sika deer (S.D.), Rex rabbits (R.R.), blue foxes (B.F.), silver foxes (S.F.), raccoon dogs (R.D.) and minks (M.), that are commercially important in Jilin Province, China. In this study, 450 faecal samples were tested for P. hominis infection by culturing and nested PCR assays. The average prevalence of P. hominis infections were as follows: S.D. 20% (26/130), R.R. 16.25% (13/80), B.F. 45% (27/60), S.F. 43.33% (26/60), R.D. 53.33% (32/60) and M. 48.33% (29/60). The prevalence in herbivores (18.57% for S.D. and R.R.) was significantly lower than that in non-herbivores (47.5%). PCR product sequencing indicated that infections were mainly caused by the P. hominis strain Changchun Canine 1, and we found a P. hominis strain with a mutated sequence, Changchun-RR, which had three mutations compared with the referenced homologous P. hominis sequences. Morphological observations of the Changchun-RR strain showed that it was similar to P. hominis. Our study suggests that P. hominis is widespread in six farmed wildlife species in Jilin Province and provides baseline information for the presence of this parasite in these animals. PMID- 28917309 TI - Toxic action of Acmella oleracea extract on the male reproductive system of Amblyomma cajennense ticks. AB - The present study evaluated through morphohistological and histochemical techniques the effects of different concentrations of crude ethanolic extract of A. oleracea (EEAO) (Jambu) on the male reproductive system of Amblyomma cajennense sensu stricto (s.s.) ticks. The toxicity of this natural chemical was stablished, signalizing the promising potential of the compound as a strategy to control ectoparasites in the near future. For the experiment, 100 males fed on host rabbits with homogeneous weight (p>0.05) were used. The ticks were divided into five groups (10 animals each): Control 1-exposed to distilled water; Control 2-exposed to ethanol 50% and DMSO 1%; Treatment 1-3-exposed to the concentrations of 6.2, 12.5 and 25mg/mL of the EEAO, respectively, diluted in ethanol 50% and DMSO 1%, with exposure by immersion. After exposure, the males were dissected for the removal of the reproductive system and subjected to routine histological analysis with HE staining and histochemical techniques (PAS for the detection of neutral polysaccharides and Bromophenol blue to detect total proteins). The exposed individuals showed alterations in the glandular complex cells; however, the testes remained intact. The secretory cells of the multilobulated accessory glands presented intense cytoplasmic vacuolation. Additionally, the synthesis and secretion were reduced in the secretion granules, mainly concerning the polysaccharides, glyco- and lipoprotein elements, substances that will constitute the seminal fluid and enable the capacitation of spermatozoa in the female genital tract and also necessary for the formation of the spermatophore, which will encapsulate the mature spermatids. The alterations were dose-dependent, i.e., more intense and severe as the concentration of the product increased. .This experiment confirmed the cytotoxic potential of A. oleracea ethanolic extract in the concentrations of 6.2, 12.5 and 25mg/mL on the reproductive system of A. cajennense s.s. male ticks. PMID- 28917310 TI - Screening of a small, well-curated natural product-based library identifies two rotenoids with potent nematocidal activity against Haemonchus contortus. AB - The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate. PMID- 28917311 TI - A new lyophilized tachyzoite based ELISA to diagnose Besnoitia spp. infection in bovids and wild ruminants improves specificity. AB - Recent studies have reported that routinely used whole or soluble Besnoitia besnoiti tachyzoite (TZ) extract-based ELISAs potentially give rise to a high number of false-positive results, which may compromise control and the epidemiological studies of bovine besnoitiosis. Thus, western blot (WB) has been recommended as a confirmatory test. In the present study, a new ELISA test that employs lyophilized tachyzoites for the first time (BbSALUVET ELISA 2.0) was developed and validated with cattle sera (n=606) under a worst-case scenario. False positive and false negative, soluble TZ extract-based BbSALUVET ELISA 1.0 reactors were overrepresented, and WB was used as the reference test. One commercial test (PrioCHECK Besnoitia Ab 2.0, which employs whole TZ extract) and a recently developed membrane-enriched ELISA (APure-BbELISA) were also tested. The three ELISAs showed high AUC values (>0.9). However, the best diagnostic performance corresponded to the BbSALUVET ELISA 2.0 and the APure-BbELISA [(92% sensitivity (Se) and 98% specificity (Sp)] followed by PrioCHECK Besnoitia Ab 2.0 (88% Se, 98% Sp, and 4.5% doubtful results). In addition, the BbSALUVET ELISA 2.0 was validated with wild ruminant sera, and excellent performance (96% Se, 97% Sp, and 4% doubtful results) was obtained again. A different antigenic composition of the lyophilized tachyzoites, compared with whole or soluble tachyzoite extracts, may be responsible for the improved diagnostic performance. This study proposes the use of the BbSALUVET ELISA 2.0 in cattle prior to entry to herds free of the disease and in valuable samples prior to a selective culling without the need of a confirmatory Western Blot test in positive samples due to its excellent specificity. PMID- 28917312 TI - First finding of nymphal stages of Linguatula serrata in a South American camelid, a vicuna from Peru. AB - Linguatula serrata, a pentastomid, was found parasitizing the lungs of a vicuna (Vicugna vicugna) from Cuzco, Peru. A total of 13 larvae were found encysted in the parenchymal tissue of the lungs. All larvae were identified as nymphal stages of L. serrata by morphological methods Diagnosis was confirmed by molecular analysis amplifying the cytochrome c oxidase 1 gene of three nymphs. Nucleotide sequences from the isolates were compared to previous sequences from GenBank, and it showed high similarity between them (>99%). This finding constitutes the first detection of L. serrata in a South American camelid. PMID- 28917313 TI - Field evaluation of poultry red mite (Dermanyssus gallinae) native and recombinant prototype vaccines. AB - Vaccination is a desirable emerging strategy to combat poultry red mite (PRM), Dermanyssus gallinae. We performed trials, in laying hens in a commercial-style cage facility, to test the vaccine efficacy of a native preparation of soluble mite extract (SME) and of a recombinant antigen cocktail vaccine containing bacterially-expressed versions of the immunogenic SME proteins Deg-SRP-1, Deg-VIT 1 and Deg-PUF-1. Hens (n=384 per group) were injected with either vaccine or adjuvant only (control group) at 12 and 17 weeks of age and then challenged with PRM 10days later. PRM counts were monitored and, at the termination of the challenge period (17 weeks post challenge), average PRM counts in cages containing birds vaccinated with SME were reduced by 78% (p<0.001), compared with those in the adjuvant-only control group. When the trial was repeated using the recombinant antigen cocktail vaccine, no statistically significant differences in mean PRM numbers were observed in cages containing vaccinated or adjuvant-only immunised birds. The roles of antigen-specific antibody levels and duration in providing vaccine-induced and exposure-related protective immunity are discussed. PMID- 28917314 TI - Evaluation of cardiopulmonary and inflammatory markers in dogs with heartworm infection treated using the slow kill method. AB - This study evaluated the changes in the levels of cardiac, hemostatic, and inflammatory biomarkers in 12 dogs with different severities of heartworm infection treated using the slow kill protocol, consisting of 6-10MUg/kg of ivermectin and 10mg/kg of doxycycline combination. The serum levels of cardiac troponin-I, D-dimer, C-reactive protein, and interleukin-6 were measured on the day of diagnosis (D0), after termination of doxycycline administration (D30), after termination of the slow kill treatment (D180), and 10 months after the initiation of therapy (D300). Heartworm antigenemia was cleared in 4/4 class I dogs, 3/4 class II dogs, and 1/4 class III dogs at the end of the therapy (D180), and in 4/4 class I, 4/4 class II, and 1/4 class III dogs at the end of the study (D300). The serum levels of the markers in class I dogs on the day of diagnosis (D0) were within the reference range, while the levels in class II and III dogs were above the reference range. Further, the serum levels of the markers in all dogs decreased significantly at the end of the study (D300), although some markers in class III dogs remained at pathological levels. This study revealed that the slow kill method should be used only as an alternative therapeutic protocol for dogs with low worm burden (class I and II). As the slow kill method alone may not effectively reduce all pathological changes in dogs with heavy worm burden and severe clinical signs (class III), adjuvant therapies including steroids and anti-thromboembolics should be used to minimize the risk of complications. PMID- 28917315 TI - Protective and risk factors associated with the presence of Toxocara spp. eggs in dog hair. AB - Toxocariasis is one of the most prevalent parasitic zoonoses in the world. The disease is principally caused by the nematode Toxocara canis, whose definitive host is the dog. The transmission of toxocariasis to humans is mainly caused by accidental ingestion of embryonated eggs of the parasite, present in the soil. Studies have shown that dog hair has the capacity to harbor eggs of the parasite and represents a risk for transmission of the zoonosis. The objective of the present study was to evaluate the frequency and factors associated with the contamination of dog hair by Toxocara spp. of animals attended and/or abandoned at a Veterinary-Teaching Hospital in Southeast Brazil. The hair samples were collected from the perineal region, and upper and lower tail regions. For analysis of the samples and recovery of Toxocara spp., the material was washed in Tween 20 and then filtered through sieves of 300MUm, 212MUm, and 38MUm. Hair samples from 165 dogs were analyzed. Of the analyzed samples, 59 (35.8%) were from puppies and 106 (64.2%) from adult animals. In the sample evaluation, 6.7% of the dogs (11/165) were contaminated, with a mean of 12.2 eggs per animal (1-70 eggs/animal) and 57.5 eggs/gram of hair. All the recovered eggs were not embryonated. There was an influence of age (puppies), breed (without defined breed), and origin (stray) of the dogs. On the other hand, deworming was a protective factor. Our results show that the risk of transmission of toxocariasis by direct contact, mainly in well-cared dogs, is low. Thus, prophylactic anthelmintic treatment and correct care regarding the hygiene of animals, especially puppies, should be recommended to reduce any risk of transmission of toxocariasis. PMID- 28917316 TI - Humoral and cytokine response elicited during immunisation with recombinant Immune Mapped protein-1 (EtIMP-1) and oocysts of Eimeria tenella. AB - Eimeria tenella, the causative agent of caecal coccidiosis, is a pathogenic gut dwelling protozoan which can cause severe morbidity and mortality in farmed chickens. Immune mapped protein-1 (IMP-1) has been identified as an anticoccidial vaccine candidate; in the present study allelic polymorphism was assessed across the IMP-1 coding sequence in E. tenella isolates from four countries and compared with the UK reference Houghton strain. Nucleotide diversity was low, limited to expansion/contraction of a CAG triplet repeat and five substitutions, three of which were non-synonymous. The EtIMP-1 coding sequence from a cloned Indian E. tenella isolate was expressed in E. coli and purified as a His-tagged thioredoxin fusion protein. An in-vivo vaccination and challenge trial was conducted to test the vaccine potential of recombinant EtIMP-1 (rEtIMP-1) and to compare post vaccination immune responses of chickens to those stimulated by live oocyst infection. Following challenge, parasite replication measured using quantitative PCR was significantly reduced in chickens that had been vaccinated with rEtIMP-1 (rIC group; 67% reduction compared to UC or unimmunised controls; 79% reduction compared to rTC group or recombinant thioredoxin mock-immunised controls, p<0.05), or the birds vaccinated by infection with oocysts (OC group, 90% compared to unimmunised controls). Chickens vaccinated with oocysts (OC) had significantly higher levels of interferon gamma in their serum post-challenge, compared to rEtIMP-1 vaccinated birds (rIC). Conversely rEtIMP-1 (rIC) vaccinated birds had significantly higher antigen specific serum IgY responses, correlating with higher serum IL-4 (both p<0.05). PMID- 28917317 TI - Hammondia heydorni: Oocyst shedding by dogs fed in vitro generated tissue cysts, and evaluation of cross-immunity between H. heydorni and Neospora caninum in mice. AB - Hammondia heydorni is a coccidian parasite believed to be nonpathogenic for naturally-infected animals, but it is biologically and genetically related to Neospora caninum, a worldwide cause of abortion in cattle. The major aim of the present work was to determine whether dogs shed H. heydorni oocysts after consuming in vitro generated tissue cysts of the parasite. In addition, we investigated cross-immunity between H. heydorni and N. caninum in mice. Two dogs were fed cultured cells containing tissue cysts of H. heydorni mixed with canned dog food, and a third dog (negative control) received only non-infected cells mixed with canned food. The two dogs that consumed in vitro produced tissue cysts shed high numbers of oocysts, which were induced to sporulate and tested positive for H. heydorni by a species-specific PCR. The third uninfected dog did not shed H. heydorni oocysts in the feces. Oocysts shed by the dogs induced the formation of encysted bradyzoites of H. heydorni on KH-R cells. Nineteen BALB/c mice were employed in the cross-immunity study. Nine mice were orally inoculated with 1*105 sporulated oocysts of H. heydorni and challenged with N. caninum tachyzoites 30days after infection with H. heydorni. Other ten mice, which did not receive H. heydorni oocysts, were infected with 2*105N. caninum tachyzoites. Thirty days after challenging with N. caninum, all mice were euthanized and N. caninum DNA in their tissues was quantified by real time PCR. No statistically significant difference in N. caninum DNA concentrations were observed between the two groups. We concluded that in vitro generated cysts of H. heydorni are biologically active, because they induced oocyst shedding in dogs. As no cross-protection occurred in mice inoculated with H. heydorni and challenged with N. caninum, it is suspected that these parasites do not express significant numbers of homologous proteins during infection, or the immune response of BALB/c mice after H. heydorni infection was not sufficient. PMID- 28917318 TI - Diversity of Spirocerca lupi in domestic dogs and black-backed jackals (Canis mesomelas) from South Africa. AB - Spirocerca lupi is a parasitic nematode that causes spirocercosis predominantly in domestic dogs. Spirocerca lupi nematode samples were collected from four regions around South Africa and analyzed to compare the genetic diversity among the regions. A total of 56 S. lupi nematodes were obtained by necropsy from domestic dogs and wild black-backed jackals (Canis mesomelas). Sixteen different haplotypes of cox1 were identified some of which are shared between regions as well as with black-backed jackal. The genetic similarity between S. lupi in domestic dogs and black-backed jackals indicates transmission between these canid species and may have potential conservation implications. PMID- 28917319 TI - Morphological and molecular analyses of Tylodelphys spp. metacercaria (Trematoda: Diplostomidae) from the vitreous humour of two freshwater fish species, Channa gachua (Ham.) and Puntius sophore (Ham.). AB - Trematodes of family Diplostomatidae consists of a large and diverse group of parasites which have larval stages that are very important pathogens of wild and cultured freshwater fishes worldwide, can cause serious impacts. Our understanding of the diplostomids diversity, though, remains deficient and limited especially in India. In the present study, the morphology and molecular characterization of Tylodelphys spp. from the vitreous humour of eye, collected from two economically important food fish, dwarf snakehead Channa gachua (Perciformes: Channidae) and pool barb Puntius sophore (Cypriniformes: Cyprinidae) were described from Bijnor and Meerut, Uttar Pradesh (U.P.), India respectively. Tylodelphys spp. were characterized morphologically by light microscopy and SEM observations. Partial sequences of the ribosomal ITS1-5.8S ITS2 gene cluster were also used for molecular identification of the species. Combined morphological and molecular analyses revealed the presence of three species of Tylodelphys: Tylodelphys sp. CG from C. gachua and Tylodelphys sp. PS 1, Tylodelphys sp. PS 2 from P. sophore respectively. This study demonstrated that molecular diversity of Tylodelphys spp. in Meerut, UP, India that may contribute to our knowledge of the diagnosis and taxonomy of diplostomids in fish. PMID- 28917320 TI - Vector-borne parasitic infections in dogs in the Baltic and Nordic countries: A questionnaire study to veterinarians on canine babesiosis and infections with Dirofilaria immitis and Dirofilaria repens. AB - Canine vector-borne diseases have been spreading northwards in Europe, and canine babesiosis and infections with Dirofilaria immitis (heartworm) and Dirofilaria repens have been diagnosed also in the Baltic and the Nordic countries. We used an online questionnaire to survey how large a proportion of veterinarians in the Baltic (Estonia, Latvia, and Lithuania) and the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) saw canine babesiosis cases and dogs infected with D. immitis and D. repens in 2016. In addition, questions regarding transmission, zoonotic potential, clinical signs, and treatment of the infections were asked. The questionnaire was completed by 122 veterinarians. In 2016, 23% of them had seen at least one case of canine babesiosis, 15% at least one dog with D. immitis infection, and 9% at least one dog with D. repens infection. A veterinarian working in the Baltic countries had 12.2 times higher odds to have seen a canine babesiosis case and 9.3 times higher odds to have seen a dog with D. repens infection than a veterinarian working in the Nordic countries did. While 48% of the veterinarians knew that canine babesiosis is not considered a zoonosis, 26% knew that D. immitis is zoonotic and 34% knew that D. repens is zoonotic. The results suggested that autochthonous cases of the three vector borne parasitic infections were seen by veterinarians in the Baltic countries, whereas most cases seen by veterinarians in the Nordic countries appeared to be imported. A substantial proportion of the veterinarians did not know whether the parasites are zoonotic. PMID- 28917321 TI - A panel of microsatellite markers to discriminate and study interactions between Haemonchus contortus and Haemonchus placei. AB - Haemonchus contortus and Haemonchus placei are two closely related economically important parasites of ruminants. Their close morphological similarity, common occurrence as co-infections and ability to hybridize makes definitive diagnosis and epidemiological studies in field populations challenging. In this paper, we describe the development of a panel of microsatellite markers that can be used to discriminate and study the genetics of these two parasite species in co infections and mixed field populations. We have identified two additional microsatellites (Hp52 and Hp53), in addition to three previously reported microsatellites (Hcms3561, Hcms53265 and Hcms36) that have a discrete set of alleles between the two species. Multilocus genotyping of worms with this 5 marker panel from 3 geographically diverse H. placei isolates and 4 geographically diverse H. contortus populations allows unambiguous species assignment of individual worms. This panel of markers should provide a valuable resource in studying the biology and epidemiology of these important ruminant parasite species in the field. PMID- 28917322 TI - High genetic diversity in Toxoplasma gondii isolates from pigs at slaughterhouses in Paraiba state, northeastern Brazil: Circulation of new genotypes and Brazilian clonal lineages. AB - The consumption of raw or undercooked pig meat containing Toxoplasma gondii cysts is an important transmission route of this protozoon to animals and humans. This study aimed to serologically diagnose, isolate and genotype T. gondii from pigs slaughtered for human consumption in the state of Paraiba, northeastern Brazil. Blood and tissue samples (heart, tongue and brain) were collected from 120 pigs at slaughterhouses in the state of Paraiba. Serological examinations were performed with an indirect immunofluorescent antibody test (IFAT) with a cut-off point of 1:64. Tissues from positive animals were subjected to bioassays in mice to isolate the parasite. A total of 12.5% (15/120) of the animals were positive according to the IFAT, with titres ranging from 64 to 2048. Viable parasites were isolated in 80% (12/15) of the bioassays. The twelve T. gondii isolates obtained in this study and an additional 13 previously described isolates were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using 11 genetic markers. Additionally, microsatellite (MS) analysis was performed using 15 markers. Nineteen of the 25 isolates completely genotyped using PCR-RFLP had 12 different genotypes, six of which were newly identified. One isolate had a mixed infection. The same 18 non-mixed isolates had 16 different genotypes based on the MS analysis. Genotype #13 (Caribbean 1), which is commonly encountered in northeastern Brazil and is probably a clonal lineage circulating in this region, was the most frequent genotype detected through both the PCR-RFLP and MS analyses. These results demonstrate that T. gondii is widespread among pigs slaughtered in the state of Paraiba. The results also confirm that this parasite has high genetic diversity in this region and that non archetypal genotypes commonly circulate between different hosts and across different regions of Brazil. PMID- 28917323 TI - Seroprevalence and first multilocus microsatellite genotyping of Neospora caninum in dairy cattle in Henan, central China. AB - Neospora caninum is one of the important causes of abortion in cattle worldwide, and losses due to neosporosis to the cattle industry are considerable. However, the knowledge of genetic characterization of this parasite is limited. The aim of the present study is to determine the prevalence and genetic characterization of N. caninum from dairy cows in Henan Province, central China. A total of 510 blood samples and 7 aborted fetuses were collected from 8 dairy farms in Henan Province. Serum antibodies to N. caninum were examined by ELISA using a recombinant tNcSRS2 protein as the coating antigen. The overall seroprevalence of N. caninum in dairy cows was 41.2% (210/510). The seropositivity rate of N. caninum in aborting cows (49.3%) was statistically significant higher than that (29.3%) in non-aborting cows (p<0.05) with an odds ratio of 2.44 (95% CI, 1.61 3.41). Statistical association was also found between farm type and the seropositivity rate of N. caninum infection in cows (p<0.01).N. caninum DNA was detected from 6 of 396 blood samples (1.5%) and 4 of 7 aborted fetuses by nested PCR based on NC5 gene, and the 10N. caninum positive DNA samples were further analyzed by multilocus microsatellite (MS) genotyping for MS4, MS5, MS6A, MS7, MS8, MS10, and MS12. Only 2 samples were successfully genotyped at all genetic loci, and two unique profiles including two novel allelic patterns were identified. To our knowledge, this study is the first report of genetic characterization of N. caninum isolates from naturally infected dairy cows based on multilocus microsatellites (more than 2 loci) in China. PMID- 28917324 TI - Targeted anthelmintic treatment of parasitic gastroenteritis in first grazing season dairy calves using daily live weight gain as an indicator. AB - Control of parasitic gastroenteritis in cattle is typically based on group treatments with anthelmintics, complemented by grazing management, where feasible. However, the almost inevitable evolution of resistance in parasitic nematodes to anthelmintics over time necessitates a reappraisal of their use in order to reduce selection pressure. One such approach is targeted selective treatment (TST), in which only individual animals that will most benefit are treated, rather than whole groups of at-risk cattle. This study was designed to assess the feasibility of implementing TST on three commercial farms, two of which were organic. A total of 104 first-grazing season (FGS), weaned dairy calves were enrolled in the study; each was weighed at monthly intervals from the start of the grazing season using scales or weigh-bands. At the same time dung and blood samples were collected in order to measure faecal egg counts (FEC) and plasma pepsinogen, respectively. A pre-determined threshhold weight gain of 0.75kg/day was used to determine those animals that would be treated; the anthelmintic used was eprinomectin. No individual animal received more than one treatment during the grazing season and all treatments were given in July or August; five animals were not treated at all because their growth rates consistently exceeded the threshold. Mean daily live weight gain over the entire grazing season ranged between 0.69 and 0.82kg/day on the three farms. Neither FEC nor pepsinogen values were significantly associated with live weight gain. Implementation of TST at farm level requires regular (monthly) handling of the animals and the use of weigh scales or tape, but can be integrated into farm management practices. This study has shown that acceptable growth rates can be achieved in FGS cattle with modest levels of treatment and correspondingly less exposure of their nematode populations to anthelmintics, which should mitigate selection pressure for resistance by increasing the size of the refugia in both hosts and pasture. PMID- 28917325 TI - Comparison of five diagnostic tests for Giardia duodenalis in fecal samples from young dogs. AB - Five diagnostic tests were compared for the diagnosis of Giardia duodenalis in fecal samples of young dogs. Fecal samples were collected from 136 healthy dogs <1year old and examined using immunofluorescence antibody microscopy (IFA) after sucrose gradient centrifugation, zinc sulfate centrifugal flotation technique (ZSCT), SNAP(r)Giardia test, and ProSpecT(r)Giardia EZ Microplate assay. In addition, polymerase chain reaction (PCR) of the 16S rRNA gene was performed. Kappa (kappa) statistic was calculated to assess diagnostic agreement between the IFA and each test. Using the IFA as the gold standard, the relative sensitivity and specificity of each test were determined. Subsequently, a Bayesian approach was used to estimate the sensitivity and specificity of each test in comparison to the IFA results. Giardia duodenalis was detected in 41% of the samples examined by IFA. The ZSCT resulted in 37% of positive samples, with a relative sensitivity and specificity of 86 and 98%, respectively. The SNAP(r)Giardia test was positive in 40% of the samples, with a relative sensitivity and specificity of 91 and 96%, respectively. The ProSpecT(r) test was positive in 51% of the samples, with a relative sensitivity and specificity of 100 and 83%, respectively. The relative sensitivity and specificity for PCR were 58 and 56%, respectively, with 55% of samples being PCR-positive. While the sensitivity and specificity estimates of each test in comparison to the IFA changed when using a Bayesian approach, the conclusions remained the same. While the ProSpecT(r) test was the most sensitive test in this study, it is not designed for dogs and more costly than the other tests. The SNAP(r)Giardia test performed similar to the ZSCT but may be more favorable because it is fast and easy to perform. Performance of the PCR was poor and the benefit of PCR may be in determining genotypes for evaluating zoonotic transfer between dogs and humans. PMID- 28917326 TI - Serum levels of cytokines in water buffaloes experimentally infected with Fasciola gigantica. AB - Fasciola gigantica infection in water buffaloes causes significant economic losses especially in developing countries. Although modulation of the host immune response by cytokine neutralization or vaccination is a promising approach to control infection with this parasite, our understanding of cytokine's dynamic during F. gigantica infection is limited. To address this, we quantified the levels of serum cytokines produced in water buffaloes following experimental infection with F. gigantica. Five buffaloes were infected via oral gavage with 500 viable F. gigantica metacercariae and blood samples were collected from buffaloes one week before infection and for 13 consecutive weeks thereafter. The levels of 10 cytokines in serum samples were simultaneously determined using ELISA. F. gigantica failed to elicit the production of various pro-inflammatory cytokines, including interleukin-1beta (IL-1beta), IL-2, IL-6, IL-12, and IFN gamma. On the other hand, evidence of a Th2 type response was detected, but only early in the course of parasite colonization and included modest increase in the levels of IL-10 and IL-13. The results also revealed suppression of the immune responses as a feature of chronic F. gigantica infection in buffaloes. Taken together, F. gigantica seems to elicit a modest Th2 response at early stage of infection in order to downregulate harmful Th1- and Th17-type inflammatory responses in experimentally infected buffaloes. The full extent of anti-F. gigantica immune response and its relation to pathogenesis requires further study. PMID- 28917327 TI - Introduction. PMID- 28917328 TI - ? PMID- 28917329 TI - ? PMID- 28917331 TI - [Polypharmacy and geriatric psychiatry]. AB - The ageing of the population is synonymous with multiple pathologies and polypharmacy, which increases risk factors. Francois-Tosquelles general hospital carried out a study into the administering of medicines within the ageing population in psychiatry and drew up an assessment of professional practices with regard to polypharmacy in geriatric psychiatry. PMID- 28917330 TI - [Oral administration of medicines in elderly patients and adaptation of galenic forms]. AB - Physiological ageing and pathologies can have an influence on the pharmacology of numerous medicines, leading to serious iatrogenic accidents, polypharmacy and incorrect use of a medicine in elderly people. An observational study carried out in a short-stay geriatric unit focused on the issues surrounding the difficulties the elderly may encounter when taking medicines and the prevalence of the manipulation of galenic forms. PMID- 28917332 TI - [Benzodiazepine withdrawal syndrome in the elderly patient]. AB - Withdrawal syndrome is a well known diagnostic entity. As the symptomatology related to this syndrome is extremely unspecific, care must be taken not to ignore withdrawal syndrome, the consequences of which, while rare, can lead to often long and complicated hospitalisations. PMID- 28917333 TI - [Nursing homes and fall in the consumption of psychotropic medications]. AB - The consumption of psychotropic drugs in elderly people remains a concern in France, including in nursing homes. A comparative analysis of prescriptions for psychotropic medication in nursing homes in 2013 and 2015 based on the computer system of the French national health insurance scheme shows a significant reduction in the prescribing of these medications. Example of a nursing home in Dijon. PMID- 28917334 TI - [Checkpoint inhibitors, the perspectives for elderly patients]. AB - The arrival of new immunotherapies, called checkpoint inhibitors, is radically changing the world of oncology. Currently, there are some twenty different cancers which may respond to this type of therapy. It is therefore important that professionals involved in the care of elderly people with cancer are already made aware of these new treatments. This article explains how these checkpoint inhibitors work and describes their efficacy and their toxicity for elderly patients. PMID- 28917335 TI - [A tool for improving the transition between hospital and community care for the elderly]. AB - The hospital-community interface represents a real challenge in the care of elderly people. A lack of coordination and communication is the main obstacle to ensuring the fluidity of this pathway. On a definite territory, a new hospital community liaison sheet was developed as the result of a collaborative approach and then evaluated. This simple, useful and effective cross-professional tool, is the first step towards improving communication between these two universes. PMID- 28917337 TI - ? PMID- 28917336 TI - [The reconstruction of meaning in dementia]. AB - Dementia brings about progressive cognitive deterioration, combining memory problems, language difficulties and thought disorders. While there is currently no treatment for the organic disorders causing the dementia, help can be given to patients to slow down the regressive processes. Psychological mediations exist to support patients in their efforts to make sense of their environment. PMID- 28917338 TI - ? PMID- 28917341 TI - Endoscopic submucosal dissection for Barrett's neoplasia: decade of experience, little progress. Is ESD thE-BEST for complex Barrett's neoplasia? PMID- 28917340 TI - Esophageal dilation for eosinophilic esophagitis: it's safe! Why aren't we doing more dilations? PMID- 28917342 TI - Endoscopic submucosal dissection in endotherapy for Barrett's esophagus-related dysplasia and neoplasia: An essential or optional technique? PMID- 28917343 TI - Long-term outcomes for cryotherapy in Barrett's esophagus with high-grade dysplasia: just cracking the ice. PMID- 28917344 TI - EUS-guided celiac ganglia neurolysis versus celiac plexus neurolysis: dying to know which is better. PMID- 28917345 TI - Bowel preparation for colonoscopy and hypokalemia: at the heart of the problem! PMID- 28917346 TI - Image-enhanced endoscopy: How far do we need to go? PMID- 28917348 TI - Risk of metachronous advanced neoplasia in patients with diminutive versus small tubular adenomas: Is the juice worth the squeeze? PMID- 28917347 TI - Optical diagnosis of early colorectal cancer: riding the highs and lows of the Japanese Narrow-Band Imaging Expert Team classification. PMID- 28917349 TI - Postcolonoscopy mortality: Bowel preparation to blame? PMID- 28917350 TI - Response. PMID- 28917351 TI - Do we really need a fully covered self-expanding metal stent for the treatment of difficult common bile duct stones? PMID- 28917352 TI - Techniques of ERCP with a conventional endoscope in pancreatoduodenectomy anatomy. PMID- 28917353 TI - Response. PMID- 28917354 TI - Endoscopic full-thickness resection with use of the over-the-scope clip: a word of caution! PMID- 28917355 TI - Response. PMID- 28917356 TI - SAGES rebuttal. PMID- 28917357 TI - Response. PMID- 28917358 TI - Erratum. PMID- 28917359 TI - Dance is more than therapy: Qualitative analysis on therapeutic dancing classes for Parkinson's. AB - OBJECTIVES: To understand the benefits and limitations of therapeutic dancing classes for people with Parkinson's disease (PD) and how best to design and implement classes. DESIGN: A stakeholder forum explored the opinions of 18 allied health clinicians, dance instructors, people with PD and caregivers. Data were thematically analysed and interpreted within a grounded theory framework. RESULTS: Four main themes were identified: (1) the need to consider the stage of disease progression when designing classes; (2) recognition that dance is more than just therapy; (3) the benefits of carefully selecting music to move by; (4) ways to design classes that are both feasible and engaging. These themes give rise to the theory that dancing classes can provide more than just therapeutic benefits. Dance affords creative expression and enables people to immerse themselves in the art-form, rather than focussing on the disease. The results highlight the benefits of enabling individuals with PD to be able to express themselves in a supportive environment that does not see them solely through the lens of Parkinson's. The feasibility of dance programs can be increased by educating dancing teachers about PD and the unique needs of people living with this condition. CONCLUSION: Well-structured dance classes can promote social connectedness and joy, in addition to facilitating movement to music and physical activity. Consumers advised that careful planning of the classes and tailoring them to participant needs optimizes outcomes. PMID- 28917360 TI - A randomized controlled clinical trial evaluating quality of life when using a simple acupressure protocol in women with primary dysmenorrhea. AB - OBJECTIVE: To evaluate a simple acupressure protocol in LIV3 and LI4 acupoints in women with primary dysmenorrhea. METHODS: This paper reports a randomized, single blinded clinical trial. 90 young women with dysmenorrhea were recruited to three groups to receive 20min acupressure every day in either LIV3 or LI4, or placebo points. Acupressure was timed five days before menstruation for three successive menstrual cycles. On menstruation, each participant completed the Wong Baker faces pain scale, and the quality of life short form -12 (QOL SF-12). RESULTS: Intensity and duration of pain between the three groups in the second and third cycles during the intervention (p<0.05) differed significantly. Significant differences were seen in all domains of QOL except for mental health (p=0.4), general health (p=0.7) and mental subscale component (p=0.12) in the second cycle, and mental health (p=0.9), and mental subscale component (p=0.14) in the third cycle. CONCLUSION: Performing the simple acupressure protocol is an effective method to decrease the intensity and duration of dysmenorrhea, and improve the QOL. Registration ID in IRCT: IRCT2016052428038N1. PMID- 28917361 TI - Immediate effects of Pilates based therapeutic exercise on postural control of young individuals with non-specific low back pain: A randomized controlled trial. AB - OBJECTIVES: Low back pain affects the person's ability to keep balance, especially in challenging conditions. The purpose of this study was to determine the immediate effects of Pilates exercises on postural sway and dynamic balance of young individuals with non-specific low back pain. DESIGN: Controlled laboratory design. SETTINGS AND MAIN OUTCOME MEASURES: Forty-six participants with non-specific low back pain were randomized to a Pilates (n=23, 10 males; age: 21.8+/-3.2years) and a control group (n=23, 9 males; age: 22.8+/-3.6years). Postural sway was assessed with a force platform and dynamic balance with the Star Excursion Balance Test, before and after the intervention or rest period. To assess postural sway, participants stood still on an unstable surface set on the force plate for 90s, with eyes closed. INTERVENTION: The intervention lasted 20min and consisted on four Pilates exercises: single leg stretch (level 1), pelvic press (level 1), swimming (level 1) and kneeling opposite arm and leg reach. RESULTS: At baseline, no differences were found between groups. The Pilates group improved in all the postural sway values (area of CoP: 11.5+/-3.4 to 9.7+/-2.7cm2, p=0.002 and CoP velocity: 2.8+/-0.6 to 2.3+/-0.5cm/s, p<0.001) and in the Star Excursion Balance Test. Control group only improved in CoP velocity, however, this improvement was significantly inferior compared to the Pilates group. CONCLUSIONS: Pilates exercises immediately improved postural sway and dynamic balance in young adults with non-specific low back pain. PMID- 28917362 TI - A comparative study of the antacid effect of some commonly consumed foods for hyperacidity in an artificial stomach model. AB - OBJECTIVES: The incorporation of certain alkalinizing vegetables, fruits, milk and its products in the diet has been known to alleviate hyperacidity. These foods help to restore the natural gastric balance and function, curb acid reflux, aid digestion, reduce the burning sensation due to hyperacidity and soothe the inflamed mucosa of the stomach. The present study evaluates and compares the antacid effect of broccoli, kale, radish, cucumber, lemon juice, cold milk and curd in an artificial stomach model. DESIGN: The pH of the test samples and their neutralizing effect on artificial gastric acid was determined and compared with that of water, the active control sodium bicarbonate and a marketed antacid preparation ENO. A modified model of Vatier's artificial stomach was used to determine the duration of consistent neutralization of artificial gastric acid by the test samples. The neutralizing capacity of the test samples was determined in vitro using the classical titration method of Fordtran. RESULTS: All test samples except lemon showed significantly higher (p<0.05 for cucumber and p<0.001 for the rest) acid neutralizing effect than water. All test samples also exhibited a significantly (p<0.001) higher duration of consistent neutralization and higher antacid capacity than water. Highest antacid activity was demonstrated by cold milk and broccoli which was comparable with ENO and sodium bicarbonate. CONCLUSION: It may be concluded that the natural food ingredients used in this study exhibited significant antacid activity, justifying their use as essential dietary components to counter hyperacidity. PMID- 28917363 TI - Effects of music and music video interventions on sleep quality: A randomized controlled trial in adults with sleep disturbances. AB - OBJECTIVES: The present study aimed to compare the effects of music and music video interventions on objective and subjective sleep quality in adults with sleep disturbances. DESIGN: A randomized controlled trial was performed on 71 adults who were recruited from the outpatient department of a hospital with 1100 beds and randomly assigned to the control, music, and music video groups. INTERVENTIONS: During the 4 test days (Days 2-5), for 30min before nocturnal sleep, the music group listened to Buddhist music and the music video group watched Buddhist music videos. They were instructed to not listen/watch to the music/MV on the first night (pretest, Day 1) and the final night (Day 6). The control group received no intervention. MAIN OUTCOME MEASURES: Sleep was assessed using a one-channel electroencephalography machine in their homes and self reported questionnaires. RESULTS: The music and music video interventions had no effect on any objective sleep parameters, as measured using electroencephalography. However, the music group had significantly longer subjective total sleep time than the music video group did (Wald chi2=6.23, p=0.04). CONCLUSION: Our study results increase knowledge regarding music interventions for sleep quality in adults with sleep disturbances. This study suggested that more research is required to strengthen the scientific knowledge of the effects of music intervention on sleep quality in adults with sleep disturbances. (ISRCTN94971645). PMID- 28917364 TI - Managing childhood and adolescent attention-deficit/hyperactivity disorder (ADHD) with exercise: A systematic review. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders affecting some 8-10% of children worldwide. Increasing research has shed light on the life course of the disorder, suggesting that majority of children with ADHD will continue to have persistent symptoms into adulthood. The mainstay of ADHD management has been pharmacologic and behavioural/psychological interventions, with little attention paid to exercise as a potential management strategy. A systematic review, examining both the short term and long-term effects of exercise on children with ADHD, is timely and necessary to guide further research in this area. METHODS: Using the keywords [exercise OR physical OR activity OR sport] AND [attention deficit hyperactivity disorder OR ADHD OR ADDH], a preliminary search on the PubMed and Ovid database yielded 613 papers published in English between 1-Jan-1980 and 1-July-2016. Full articles were also reviewed for references of interest. RESULTS: A total of 30 studies were included in this systematic review. Both short-term and long-term studies support the clinical benefits of physical activity for individuals with ADHD. Cognitive, behavioural and physical symptoms of ADHD were alleviated in most instances, and the largest intervention effects were reported for mixed exercise programs. No adverse effects arising from physical exercise were reported in any of the studies, suggesting that exercise is a well-tolerated intervention. CONCLUSION: Physical activity, in particular moderate-to-intense aerobic exercise, is a beneficial and well-tolerated intervention for children and adolescents with ADHD. Future research should include more adequately-powered trials and investigate the ideal exercise prescription. PMID- 28917365 TI - A systematic review of the efficacy and safety of Rosa damascena Mill. with an overview on its phytopharmacological properties. AB - Rosa damascena Mill. is one of the most famous ornamental plants cultivated all over the world mostly for perfumery industries. Traditionally it has been used as an astringent, analgesic, cardiac and intestinal tonic.The paucity ofauthoritative monographs urged usto summarize its clinical effectiveness and safety with acomprehensive review of the literature. "PUBMED", "SCOPUS", "WEBOF SCIENCE" were searched up to April 30, 2017 with search terms:("Rosa damascena" OR "Damask Rose"). All human studies with any mono-preparation were included. In vitro and animal studies from "PUBMED"were also reviewed and outlined. Of "1000" identified publications, twelveeligibleclinical trials were retrieved. Antimicrobial, anti-inflammatory, antioxidant, anticancer, protective neuronal, cardiac, gastrointestinal and hepatic effectsin 30 in vitro and 21 animal studies were also shown. there are promising evidences for the effectiveness and safety of Rosa damascena Mill in pain relief, but confirmatory studies withstandardized products is suggested. PMID- 28917366 TI - Complementary and alternative medicine self-care strategies for nausea in patients undergoing abdominal or pelvic irradiation for cancer: A longitudinal observational study of implementation in routine care. AB - OBJECTIVE: To longitudinally describe practice of Complementary and Alternative Medicine (CAM) self-care strategies for nausea during radiotherapy. METHODS: Two hundred patients daily registered nausea and practice of CAM self-care strategies, beside conventional antiemetic medications, for nausea during abdominal/pelvic irradiation (median five weeks) for gynecological (69%) colorectal (27%) or other tumors (4%). RESULTS: During radiotherapy, 131 (66%) experienced nausea, and 50 (25%) practiced self-care for nausea at least once, for a mean (m) of 15.9days. The six of 50 patients who stayed free from nausea practiced self-care more frequent (m=25.8days) than the 44 patients experiencing nausea (m=14.5) (p=0.013). The CAM self-care strategies were: modifying eating (80% of all self-care practicing patients, 80% of the nauseous patients versus 83% of the patients free from nausea; ns) or drinking habits (38%, 41% vs 17%; ns), taking rests (18%, 20% vs 0%; ns), physical exercising (6%, 2% vs 33%; p=0.035), acupressure (4%, 5% vs 0%; ns) and self-induced vomiting (2%, 2% vs 0%; ns). CONCLUSION: A fourth of patients undergoing emetogenic radiotherapy practiced CAM self-care for nausea, mostly by modifying eating or drinking habits. The CAM self-care practicing patients who did not become nauseous practiced self-care more frequent than the nauseous patients did. To make such self-care evidence based, we need studies evaluating its efficacy. PMID- 28917368 TI - Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis. AB - OBJECTIVES: Vasomotor symptoms (VMS), commonly reported during menopausal transition, negatively affect psychological health and health-related quality of life (HRQoL). While hormone therapy is an effective treatment, its use is limited by concerns about possible harms. Thus, many women with VMS seek nonhormonal, nonpharmacologic treatment options. However, evidence to guide clinical recommendations is inconclusive. This study reviewed the effectiveness of yoga, tai chi and qigong on vasomotor, psychological symptoms, and HRQoL in peri- or post-menopausal women. DESIGN: MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, CINAHL and the Allied and Complementary Medicine Database were searched. Researchers identified systematic reviews (SR) or RCTs that evaluated yoga, tai chi, or qigong for vasomotor, psychological symptoms, and health-related quality of life (HRQoL) in peri- or post-menopausal women. Data were abstracted on study design, participants, interventions and outcomes. Risk of bias (ROB) was assessed and updated meta-analyses were performed. RESULTS: We identified one high-quality SR (5 RCTs, 582 participants) and 3 new RCTs (345 participants) published after the SR evaluating yoga for vasomotor, psychological symptoms, and HRQoL; no studies evaluated tai chi or qigong. Updated meta-analyses indicate that, compared to controls, yoga reduced VMS (5 trials, standardized mean difference (SMD) -0.27, 95% CI -0.49 to -0.05) and psychological symptoms (6 trials, SDM 0.32; 95% CI -0.47 to -0.17). Effects on quality of life were reported infrequently. Key limitations are that adverse effects were rarely reported and outcome measures lacked standardization. CONCLUSIONS: Results from this meta analysis suggest that yoga may be a useful therapy to manage bothersome vasomotor and psychological symptoms. PMID- 28917367 TI - Perceptions of hatha yoga amongst persistently depressed individuals enrolled in a trial of yoga for depression. AB - OBJECTIVES: To understand depressed individuals' experiences in a 10-week hatha yoga program. DESIGN: In a randomized controlled trial, participants were assigned to either 10 weeks of hatha yoga classes or a health education control group. This report includes responses from participants in yoga classes. At the start of classes, average depression symptom severity level was moderate. MAIN OUTCOME MEASURES: After 10 weeks of yoga classes, we asked participants (n=50) to provide written responses to open-ended questions about what they liked about classes, what they did not like or did not find helpful, and what they learned. We analyzed qualitative data using thematic analysis. RESULTS AND CONCLUSIONS: Elements of yoga classes that may increase acceptability for depressed individuals include having instructors who promote a non-competitive and non judgmental atmosphere, who are knowledgeable and able to provide individualized attention, and who are kind and warm. Including depression-related themes in classes, teaching mindfulness, teaching breathing exercises, and providing guidance for translating class into home practice may help to make yoga effective for targeting depression. Participants' comments reinforced the importance of aspects of mindfulness, such as attention to the present moment and acceptance of one's self and one's experience, as potential mechanisms of action. Other potential mechanisms include use of breathing practices in everyday life and the biological mechanisms that underlie the positive impact of yogic breathing. The most serious concern highlighted by a few participants was the concern that the yoga classes were too difficult given their physical abilities. PMID- 28917369 TI - Emesis in patients receiving acupuncture, sham acupuncture or standard care during chemo-radiation: A randomized controlled study. AB - OBJECTIVE: To study nausea, vomiting and need for rescue antiemetics in patients receiving antiemetic acupuncture, sham acupuncture or standard care during concomitant chemotherapy during pelvic radiotherapy. METHODS: In total, 68 patients participated (75% women, mean age 56 years, 53% had gynecological, 43% colorectal, and 4% other cancer types). Fifty-seven of them were blinded randomized to verum (n=28) or sham (n=29) acupuncture, median 10 sessions. During the study period of four weeks, the patients daily registered their nausea, vomiting and consumption of antiemetics. They were compared to a reference group (n=11) receiving standard care only, who delivered these data once (after receiving mean 27Gy radiotherapy dose). RESULTS: More patients in the sham acupuncture group (17 of 20; 85%, p=0.019, RR 1.81, CI 1.06-3.09) consumed antiemetics, compared to the verum acupuncture group (8 of 17; 47%). In the standard care group, 7 of 11 (63%) consumed antiemetics. The verum acupuncture treated patients experienced lower intensity of nausea than the other patients (p=0.049). There was a non-significant tendency that more patients receiving either sham acupuncture or standard care experienced nausea (21 of 31; 68%) than patients receiving verum acupuncture (9 of 17; 53%: p=0.074, RR 1.58, CI 0.91 2.74). CONCLUSION: Patients treated with verum acupuncture needed less antiemetics and experienced milder nausea than other patients. Our study was small and many analyses lacked statistical power to detect differences; we welcome further sham-controlled efficacy studies and studies regarding the role of non-specific treatment components for experiencing antiemetic effects of acupuncture. PMID- 28917370 TI - Aromatherapies using Osmanthus fragrans oil and grapefruit oil are effective complementary treatments for anxious patients undergoing colonoscopy: A randomized controlled study. AB - BACKGROUND AND AIMS: Colonoscopy can be painful and uncomfortable. Aromatherapy is often used for the relief of anxiety or discomfort. Recently, it has been reported that olfactory stimulation induces various physiological effects. We investigated the effects of aromatherapy on anxiety and abdominal discomfort during colonoscopy. METHODS: The investigation was carried out using a randomized controlled study. Aromatherapy was performed by vapor diffusion, and each patient was given one of the following treatments: no inhalation (control group), essential-oil-less vapor (vehicle group), lavender oil (lavender group), grapefruit oil (grapefruit group), or Osmanthus fragrans oil (Osmanthus fragrans group). Following total colonoscopy procedures, each patient estimated their anxiety and abdominal discomfort using the Numeric Rating Scale. RESULTS: Total colonoscopy was performed on 361 patients. No complications caused by colonoscopy or aromatherapy were experienced. In the Osmanthus fragrans group, anxiety was significantly attenuated. The abdominal discomfort of patients who reported strong anxiety during colonoscopy was significantly attenuated in the grapefruit group and the Osmanthus fragrans group. CONCLUSION: Aromatherapies using Osmanthus fragrans oil and grapefruit oil are effective complementary treatments for anxious patients undergoing colonoscopy. PMID- 28917372 TI - Transcendental meditation for lowering blood pressure: An overview of systematic reviews and meta-analyses. AB - BACKGROUND: Transcendental meditation (TM) is a stress reduction technique that can potentially lower blood pressure (BP) safely. The American Heart Association recommends that TM may be considered in clinical practice. OBJECTIVE: To provide an overview of all systematic reviews and meta-analyses of TM on BP for evidence informed clinical decision making. METHOD: Systematic searches of PubMed, EBSCOhost, Cochrane Library, Web of Science, Embase, and PsycINFO for all systematic reviews and/or meta-analyses of randomized controlled trials (RCTs) with TM as an intervention, and outcome measures include systolic BP (SBP) and diastolic BP (DBP). Qualitative and quantitative data were synthesized. The methodological quality of the selected reviews was assessed using the AMSTAR checklist. RESULTS: Eight systematic reviews and meta-analyses are included. Among them is an Agency for Healthcare Research and Quality report, a Cochrane systematic review, 4 independent reviews, and 2 reviews from a TM related institution. The quality of most of the included reviews is fair with a mean score of 5.75/11 on the AMSTAR scale. Overall, there exists a clear trend of increasing evidence over the years supporting the efficacy of TM in lowering BP. However, some conflicting findings remain across reviews and potential risk of bias exists in many of the RCTs included in these reviews. CONCLUSION: Practising TM may potentially reduce the SBP by ~4mm Hg and DBP by ~2mm Hg. Such effect is comparable with other lifestyle interventions such as weight-loss diet and exercise. Further evidence from long-term well-designed RCTs conducted by independent researchers is needed. PMID- 28917371 TI - Cannabinoids for spasticity due to multiple sclerosis or paraplegia: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVES: Spasticity remains highly prevalent in patients with spinal cord injury and multiple sclerosis. To summarize the effects of cannabinoids compared with usual care, placebo for spasticity due to multiple sclerosis (MS) or paraplegia. METHODS: Searches of MEDLINE, EMBASE, CENTRAL and LILACS to March 2017 were performed to identify randomized controlled trials. The primary outcomes were spasticity and spasm frequency. The criteria were any patient with MS and spasticity affecting upper or lower limbs or both, and that had a confirmed diagnosis of MS based on validated criteria, or however defined by the authors of the included studies. RESULTS: 16 trials including 2597 patients were eligible. Moderate-certainty evidence suggested a non-statistically significant decrease in spasticity (standardized mean difference (SMD) 0.36 [confidential interval (CI) 95% -0.17 to 0.88; p=0.18; I2=88%]), and spasm frequency (SMD 0.04 [CI 95% -0.15 to 0.22]). There was an increase in adverse events such as dizziness (risk ratio (RR) 3.45 [CI 95% 2.71-4.4; p=0.20; I2=23%]), somnolence (RR 2.9 [CI 95% 1.98-4.23; p=0.77; I2=0%]), and nausea (RR 2.25 [CI 95% 1.62 3.13; p=0.83; I2=0%]). CONCLUSIONS: There is moderate certainty evidence regarding the impact of cannabinoids in spasticity (average 0.36 more spasticity; 0.17 fewer to 0.88 more) due to multiple sclerosis or paraplegia, and in adverse events such as dizziness (419 more dizziness/1000 over 19 weeks), somnolence (127 more somnolence/1000 over 19 weeks), and nausea (125 more somnolence/1000 over 19 weeks). PMID- 28917373 TI - Efficacy of topical Rose (Rosa damascena Mill.) oil for migraine headache: A randomized double-blinded placebo-controlled cross-over trial. AB - AIM: To evaluate the effect of topical formulation of Rosa damascena Mill. (R. damascena) oil on migraine headache, applying syndrome diffrentiation model. METHODS AND MATERIALS: Forty patients with migraine headache were randomly assigned to 2 groups of this double-blind, placebo-controlled cross-over trial. The patients were treated for the first 2 consecutive migraine headache attacks by topical R. damascena oil or placebo. Then, after one week of washout period, cross-over was done. Pain intensity of the patients' migraine headache was recorded at the beginnig and ten-sequence time schadule of attacks up to 24h. In addition, photophobia, phonophobia, and nausea and/or vomitting (N/V) of the patients were recorded as secondary outcomes. Finally, gathered data were analysed in a syndrome differentiation manner to assess the effect of R. damascena oil on Hot- and Cold-type migraine headache. RESULTS: Mean pain intensity of the patients' migraine headache in the different time-points after R. damascena oil or placebo use, was not significantly different. Additionally, regarding mean scores of N/V, photophobia, and phonophobia severity of the patients, no significant differences between the two groups were observed. Finally, applying syndrome differentiation model, the mean score of migraine headache pain intensity turned out to be significantly lower in patients with "hot" type migraine syndrome at in 30, 45, 60, 90, and 120min after R. damascena oil application compared to "cold" types (P values: 0.001, 0.001, <0.001, <0.001, and 0.02; respectively). CONCLUSION: It seems that syndrome differentiation can help in selection of patients who may benefit from the topical R. damascena oil in short-term relief of pain intensity in migraine headache. Further studies of longer follow-up and larger study population, however, are necessitated for more scientifically rigorous judgment on efficacy of R. damascena oil for patients with migraine headache. PMID- 28917374 TI - Short-term effect of add on bell pepper (Capsicum annuum var. grossum) juice with integrated approach of yoga therapy on blood glucose levels and cardiovascular functions in patients with type 2 diabetes mellitus: A randomized controlled study. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major global health problem. Though various studies have reported the beneficial effect of Yoga in patient with T2DM, there is a lack of study in combination with bell pepper and yoga. Hence, the present study aims at evaluating short-term effect of add on bell pepper juice with integrated approach of yoga therapy (IAYT) on blood glucose levels and cardiovascular variables in patients with T2DM. MATERIALS AND METHODS: Fifty T2DM subjects with the age varied from 34 to 69-years were recruited and randomly divided into either study group or control group. The study group received 100-ml of bell pepper juice (twice/day) along with IAYT while the control group received only IAYT for 4-consecutive days. Baseline and post-test assessments were taken before and after the intervention. Statistical analysis was performed using statistical package for the social sciences, version-16. RESULTS: Results of this study showed no significant difference in overall (fasting and post prandial) blood glucose level in the study group compared with control group. However, a significant reduction in Post prandial blood glucose (PPBG), systolic blood pressure (SBP), pulse pressure (PP), rate pressure product (RPP) and Double product (Do-P) was observed in the study group compared with control group. CONCLUSION: Results of this study suggest that though an addition of 100-ml of bell pepper juice (twice/day) along with IAYT is not more effective in reducing fasting blood glucose, it may be more effective in reducing PPBG, SBP, PP, RPP and Do-P than IAYT alone. PMID- 28917375 TI - Total glucosides of paeony for rheumatoid arthritis: A systematic review of randomized controlled trials. AB - BACKGROUND: Total glucosides of paeony (TGP) is commonly used to treat rheumatoid arthritis (RA) in China. However, clinical practice hasn't been well informed by evidence from appropriately conducted systematic reviews. This PRISMA-compliant systematic review aims at examining the effectiveness and safety of TGP for RA. METHODS: Randomized controlled trials (RCTs) comparing TGP with placebo, no treatment, or disease-modifying antirheumatic drugs (DMARDs) for patients with RA were retrieved by searching seven databases. Primary outcomes included disease improvement and disease remission. Secondary outcomes included adverse effects, pain, health-related quality of life, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Data extraction and analyses were conducted according to the Cochrane standards. We assessed risk of bias for each included studies and quality of evidence on pre-specified outcomes. RESULTS: Eight studies enrolling 1209 patients with active RA were included in this systematic review. On the basis of traditional DMARD(s), TGP might be beneficial for patients with RA in improvement of American College of Rheumatology (ACR) 20 response rate, ACR 50 response rate, ACR70 response rate, and in reduction of adverse effects, compared with no treatment. The overall methodological quality of included studies and the quality of evidence for each outcome were limited. CONCLUSIONS: Current trials suggested potential benefits of TGP for RA on the basis of traditional DMARD(s). Therefore, TGP may be a good choice for RA as an adjuvant therapy. However, considering the limited methodological quality and strength of evidence, high quality RCTs are warranted to support the use of TGP for RA. PMID- 28917377 TI - The effect of a beeswax, olive oil and Alkanna tinctoria (L.) Tausch mixture on burn injuries: An experimental study with a control group. AB - OBJECTIVES: This study was planned to investigate the effect of a mixture of beeswax, olive oil and A. Tinctoria (L.) Tausch on burn wounds to determine the impact on burn healing, pain during dressing changes and duration of hospital stay. METHODS: The study was conducted between May 2014 and August 2015 in the Burn Unit of Ataturk University Research Hospital. The sample of this experimental study consisted of 64 patients (31 experimental group and 33 control group) who met its inclusion criteria. While the specially prepared dressing material was applied to the experimental group, the control group was administered the clinic's routine dressing. The injuries were photographed before each dressing. Each picture was uploaded to a computer for measurement with ImageJ software. Numbers, percentages, chi square, Independent samples t-test and Mann-Whitney U tests were used to assess the data. RESULTS: The patients in the experimental and control groups had similar descriptive characteristics and burn injury features (p>0.05). The average age of the patients in the control group was 5.52+/-0.64years, and 6.68+/-1.09years in the experimental group. The majority of the patients were male (control: 54.5%, experimental: 58.1%). Boiling liquids were the most common cause of both groups' burns (control: 93.9%, experiment: 83.9%). The most common first aid practice used was the application of cold water (control: 75.0%, experimental: 43.6%). The epithelization initiation time average of the experimental group patients (3.00+/-0.85days) was found to be earlier than that of the control group patients (6.90+/-1.77days), and this difference was statistically significant (p<0.05). The mean pain scores experienced by the patients in the experimental group during dressing (8.12+/ 1.38) were determined to be lower than those of the control group (9.39+/-1.05), and this difference was statistically significant (p<0.05). It was also found that mean hospitalization durations of the patients in the experimental group (8.22+/-3.05) were shorter than those of the control group (14.42+/-7.79), and this difference was also found to be statistically significant (p<0.05). CONCLUSION: When a beeswax, olive oil and A. tinctoria (L.) Tausch mixture was applied to second degree burns, this accelerated epithelization, reduced the pain experienced during dressing changes and shortened the hospital stay durations of the patients. PMID- 28917376 TI - Ayurvedic versus conventional dietary and lifestyle counseling for mothers with burnout-syndrome: A randomized controlled pilot study including a qualitative evaluation. AB - OBJECTIVES: Ayurveda claims to be effective in the treatment of psychosomatic disorders by means of lifestyle and nutritional counseling. DESIGN: In a randomized controlled study mothers with burnout were randomized into two groups: Ayurvedic nutritional counseling (according to tradition), and conventional nutritional counseling (following the recommendations of a family doctor). Patients received five counseling sessions over twelve weeks. MAIN OUTCOME MEASURES: Outcomes included levels of burnout, quality of life, sleep, stress, depression/anxiety, and spirituality at three and six months. It also included a qualitative evaluation of the communication processes. RESULTS: We randomized thirty four patients; twenty three participants were included in the per protocol analysis. No significant differences were observed between the groups. However, significant and clinically relevant intra-group mean changes for the primary outcome burnout, and secondary outcomes sleep, stress, depression and mental health were only found in the Ayurveda group. The qualitative part of the study identified different conversational styles and counseling techniques between the two study groups. In conventional consultations questions tended to be category bound, while counseling-advice was predominantly admonitory. The Ayurvedic practitioner used open-ended interrogative forms, devices for displaying understanding, and positive re-evaluation more frequently, leading to an overall less asymmetrical interaction. CONCLUSIONS: We found positive effects for both groups, which however were more pronounced in the Ayurvedic group. The conversational and counseling techniques in the Ayurvedic group offered more opportunities for problem description by patients as well as patient-centered practice and resource-oriented recommendations by the physician. TRIAL REGISTRATION: NCT01797887. PMID- 28917378 TI - Chinese herbal medicine Dengzhan Xixin injection for acute ischemic stroke: A systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To evaluate the effectiveness and safety of Chinese herbal medicine Dengzhan Xixin (Erigeron breviscapus) injection for acute ischemic stroke. DESIGN: Systematic review and meta-analysis (CRD42016038413, http://www.crd.york.ac.uk/PROSPERO). METHODS: Six electronic databases were searched from inception to March 2016 for randomised controlled trials (RCTs) of Dengzhan Xixin (DZXX) injection for acute ischemic stroke. The methodological quality of RCTs was assessed by the Cochrane risk of bias tool. DATA SYNTHESIS: was performed using RevMan 5.3 and was presented with mean difference (MD) or relative risk (RR) and their 95% confidence interval (CI). A summary of finding table was generated by GRADEpro (version 3.6). RESULTS: Twenty-five RCTs with 2498 participants were included and all trials adopted conventional therapy (CT) in both arms. Most of the studies had high risk of bias. The addition of DZXX to CT showed no significant benefit on death (RR 0.27, 95% CI 0.05-1.63) within the treatment period (14-35 d), but showed higher Barthel index score (MD 10.20, 95% CI 8.16-12.25), lower neurological function deficit score (MD -3.99, 95% CI -5.68 to -2.30, by NFDS; MD -1.67, 95% CI -2.59 to -0.76, by NIHSS), and lower treatment failure (RR 0.40, 95% CI 0.31-0.52). Thirteen trials (52%) reported the outcome of adverse events, but no serious adverse events were reported. CONCLUSION: Low quality evidence implied that DZXX injection appeared to improve neurological function in patients with acute ischemic stroke. However, this potential benefit should be further studied in large, rigorous trials. PMID- 28917379 TI - Effectiveness and safety of acupuncture in the treatment of Parkinson's disease: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: This study aimed to examine the effectiveness and safety of acupuncture in the treatment of Parkinson's disease (PD). METHODS: English, Chinese, and Korean electronic databases were searched up to June 2016. Randomized controlled trials (RCTs) were eligible. The methodological quality was assessed using Cochrane's risk of bias tool. Meta-analysis was performed using RevMan 5.3. RESULTS: In total, 42 studies involving 2625 participants were systematically reviewed. Participants treated using combined acupuncture and conventional medication (CM) showed significant improvements in total Unified PD Rating Scale (UPDRS), UPDRS I, UPDRS II, UPDRS III, and the Webster scale compared to those treated using CM alone. The combination of electroacupuncture and CM was significantly superior to CM alone in total UPDRS, UPDRS I, UPDRS II, and UPDRS IV. Similarly, the combination of scalp electroacupuncture, acupuncture, and CM was significantly more effective than CM alone in total UPDRS. However, our meta-analysis showed that the combination of electroacupuncture and CM was not significantly more effective than CM alone in UPDRS III, the Webster, and the Tension Assessment Scale. The results also failed to show that acupuncture was significantly more effective than placebo acupuncture in total UPDRS. Overall, the methodological quality of the RCTs was low. No serious adverse events were reported. CONCLUSIONS: We found that acupuncture might be a safe and useful adjunctive treatment for patients with PD. However, because of methodological flaws in the included studies, conclusive evidence is still lacking. More rigorous and well-designed placebo-controlled trials should be conducted. PMID- 28917380 TI - The neuropsychological profile of Othello syndrome in Parkinson's disease. PMID- 28917381 TI - Uncovering burden disparity: A comparative analysis of the impact of moderate-to severe psoriasis and hidradenitis suppurativa. AB - BACKGROUND: Psoriasis and hidradenitis suppurativa (HS) exhibit distinct clinical features, but no studies have directly compared the health-related quality of life (HRQoL) in patients with moderate-to-severe manifestations of these conditions. OBJECTIVE: To determine which disease is associated with more severe HRQoL impairment. METHODS: Weighted averages of each of the following baseline HRQoL measures were determined and compared between HS and psoriasis populations from 5 clinical trials: Visual Analog Scale (VAS) for pain, Total Work Productivity Impairment, Dermatology Life Quality Index; EuroQOL 5D VAS, and Short Form-36 Health Survey. RESULTS: Compared with patients with psoriasis, patients with HS reported higher scores for VAS-pain (54.3 vs 36.1 [P < .0001]), Dermatology Life Quality Index (15.3 vs 11.3 [P < .0001]), EuroQOL 5D VAS (58.8 vs 50.8 [P < .0002]), and Total Work Productivity Impairment (35.4 vs 18.2). Patients with HS had lower Short Form-36 Health Survey scores than did patients with psoriasis (physical, 39.6 vs 49.0; mental, 41.5 vs 47.5 [both P < .0001]). LIMITATIONS: This analysis was performed using published summary data rather than patient-level data, and weighted pooled averages were compared. CONCLUSIONS: Patients with HS have a higher HRQoL burden than patients with psoriasis. This study clearly documents the needs of patients with HS and the potential impact of medical, scientific, and societal consensus for the development of more effective HS treatments. PMID- 28917382 TI - A new evidence-based risk stratification system for cutaneous squamous cell carcinoma into low, intermediate, and high risk groups with implications for management. AB - Most primary cutaneous squamous cell carcinomas are cured with surgery. A subset, however, may develop local and nodal metastasis that may eventuate in disease specific; death. This subset has been variably termed high risk. Herein, we review; an emerging body of data on the risks of these outcomes and propose an evidence-based; risk stratification for low-, intermediate-, and high-risk tumors that takes into; account both tumor and patient characteristics. Finally, we discuss a framework for; management of these tumors on the basis of data, when available, and our; recommendations when data are sparse. PMID- 28917383 TI - Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: Results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3). AB - BACKGROUND: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A, is efficacious in treating moderate-to-severe plaque psoriasis through 60 weeks. OBJECTIVE: To evaluate the efficacy and safety of ixekizumab through 108 weeks of treatment in UNCOVER-3. METHODS: Patients (N = 1346) were randomized 2:2:2:1 to 80 mg ixekizumab every 2 or 4 weeks, 50 mg etanercept twice weekly, or placebo. At week 12, patients switched to ixekizumab every 4 weeks during a long-term extension (LTE) period. Efficacy data were summarized using as-observed, multiple imputation (MI), and modified MI (mMI) methods. RESULTS: For patients (N = 385) receiving the recommended dose (ixekizumab every 2 weeks on weeks 0-12 and every 4 weeks during LTE), the 108 week as-observed, MI, and mMI response rates were 93.4%, 88.3%, and 83.6%, respectively, for patients achieving >=75% improvement from baseline in the Psoriasis Area and Severity Index, and the 108-week as-observed, MI, and mMI response rates were 82.6%, 78.3%, and 74.1%, respectively, for patients with a static Physician's Global Assessment score of 0 or 1. During LTE, 1077 (84.5%) patients reported >=1 treatment-emergent adverse event, and 85% were mild or moderate in severity. Discontinuation because of adverse events occurred in 6.4% of patients. LIMITATIONS: There was no comparison treatment group after week 12. CONCLUSION: Ixekizumab is well tolerated and demonstrates persistent efficacy through 108 weeks. PMID- 28917385 TI - Fragility fractures: A complex interaction of the health care system- the patient and the bone: Can we do better? PMID- 28917384 TI - Serious infections among a large cohort of subjects with systemically treated psoriasis. AB - BACKGROUND: Biologic therapy is effective for treatment of moderate-to-severe psoriasis but may be associated with an increased risk for serious infection. OBJECTIVE: To estimate the serious infection rate among patients with psoriasis treated with biologic as compared with nonbiologic systemic agents within a community-based health care delivery setting. METHODS: We identified 5889 adult Kaiser Permanente Northern California health plan members with psoriasis who had ever been treated with systemic therapies and calculated the incidence rates and 95% confidence intervals (CIs) for serious infections over 29,717 person-years of follow-up. Adjusted hazard ratios (aHRs) were calculated using Cox regression. RESULTS: Adjusting for age, sex, race or ethnicity, and comorbidities revealed a significantly increased risk for overall serious infection among patients treated with biologics as compared with those treated with nonbiologics (aHR, 1.31; 95% CI, 1.02-1.68). More specifically, there was a significantly elevated risk for skin and soft tissue infection (aHR, 1.75; 95% CI, 1.19-2.56) and meningitis (aHR, 9.22; 95% CI, 1.77-48.10) during periods of active biologic use. LIMITATIONS: Risk associated with individual drugs was not examined. CONCLUSION: We found an increased rate of skin and soft tissue infections among patients with psoriasis treated with biologic agents. There also was a signal suggesting increased risk for meningitis. Clinicians should be aware of these potential adverse events when prescribing biologic agents. PMID- 28917386 TI - Re: Mediastinal injury is the strongest predictor of mortality in mounted blast amongst UK deployed forces: Methodological issues. PMID- 28917387 TI - Affective reactivity to cry sounds predicts young women's reactivity and behavior in a simulated caregiving task. AB - Different populations of adults (experienced vs. inexperienced caregivers, men vs. women, abusive vs. nonabusive parents, etc.) have been reported to differ in their affective reactions to the sounds of infant crying. These differences are thought to impact caregiving behavior and, in some instances, to affect long-term outcomes for infants. There can be great intra-group variation, however, even when group differences are significant; modeling developmental process will require a finer grained approach. We have undertaken a pair of studies intended to validate the Negative Affect Scale (NA) from the PANAS as a measure of individuals' affective reactivity to cry sounds. In Study 1, 306 young women who were not yet mothers listened either to infant crying or to birdsong. The results supported the NA as a measure of reactivity to crying. In Study 2, a new sample of 301 young women listened to crying in a screening task; a group of "high reactors" (n=21) and a group of "low reactors" (n=22) then participated in a simulated caregiving situation. Individuals' affective reactivity to the caregiving simulation mirrored their affective reactivity in the screening task, and rates and overall organization of caregiving behavior differed between the groups. Changes in negative affect, then, appear to be both a result of infant crying and a determinant of some aspects of caregiving behavior. Further studies will extend these laboratory results to real infants and their caregivers, and further validate the NA as a measure of individual differences in reactivity to cry sounds. PMID- 28917388 TI - Improvised Hand Injury Treatment Using Traditional Veterinary Medicine in Ethiopia. AB - In remote wilderness environments, local people with traditional knowledge of medicinal plants are potentially important first-line health care providers. We present a case of a 31-year-old man who fell off a horse while trekking through a remote mountain landscape in Ethiopia and sustained blunt force trauma to the hand. A local mountain hut keeper examined the patient's hand and used heated leaves of the succulent plant Kalanchoe petitiana to treat a suspected metacarpal fracture. As first responder in a low-resource setting, the hut keeper relied on his traditional knowledge of ethnoveterinary medicine to improvise a treatment for a human injury in a remote mountain environment. Although in this case the outcome of the traditional intervention was positive, our analysis shows that the massage component of the intervention could have led to complications. Conversely, reports from the use of related Kalanchoe species suggest that heated Kalanchoe leaves could be useful in the compression component of traditional care for hand injuries. Validation of traditional remedies and their therapeutic potential are needed if they are to complement wilderness wound care safely and reliably. The documentation and validation of these remedies are urgently needed, as many medicinal plants and indigenous knowledge of how to use these valuable natural resources are being lost. PMID- 28917389 TI - Alternative treatment strategies for catatonia: A systematic review. AB - BACKGROUND: Catatonia is a commonly encountered syndrome, affecting 10-20% of various psychiatric populations and carrying significant medical co-morbidities. However, there are few established alternative treatment strategies when benzodiazepines are ineffective and electroconvulsive therapy is unavailable. OBJECTIVE: The authors systematically review evidence for alternative treatment strategies for catatonia using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. METHOD: The authors conducted a search of PubMed database from 1983 to August 2016 to identify articles. Eligible reports presented cases involving treatment of catatonia using modalities other than benzodiazepines or electroconvulsive therapy. RESULTS: The authors identified 72 articles, comprising 98 individual cases. N-methyl-d-aspartate-receptor antagonists, anti-epileptic drugs, and atypical antipsychotic agents appeared to have the largest number of reports supporting their effectiveness and safety in treating catatonia patients. CONCLUSIONS: Based on the case report literature, the authors propose an updated algorithm for catatonia treatment in cases where benzodiazepines fail and electroconvulsive therapy is not available. PMID- 28917390 TI - Reengagement in PTSD psychotherapy: A case-control study. AB - OBJECTIVE: This study sought to identify patient characteristics and care processes related to reengagement in VA psychotherapy. METHODS: Using national VA data, a retrospective cohort was constructed (N=24,492) of veterans who received a new PTSD diagnosis in FY08/FY09 and attended only one to five PTSD psychotherapy sessions. A nested case-control study was conducted comparing veterans who reengaged in psychotherapy (n=9649) in a 1:5 ratio with those who did not reengage by the end of FY12. Conditional logistic regression models were run to examine differences in sociodemographic, mental health, and service utilization factors between cases and controls. RESULTS: Among veterans in the study cohort, 39.4% reengaged in psychotherapy. In adjusted analyses, all measured types of health system encounters (primary care [OR=1.61], primary care mental health [OR=1.61], non-PTSD psychotherapy [OR=1.76], other non-PTSD mental health care [OR=1.43], other non-psychotherapy PTSD care [OR=3.31], emergency room [OR=1.14], and psychiatric hospitalization [OR=1.56]) were related to greater odds of reengagement in PTSD psychotherapy. CONCLUSIONS: Veterans' receipt of a broad range of care services may play an important role in reengagement in PCT psychotherapy, suggesting providers across care settings should be knowledgeable in how to support a Veteran's return to psychotherapy for PTSD. PMID- 28917391 TI - The prevalence of depression and the accuracy of depression screening tools in migraine patients. AB - OBJECTIVES: Migraine and depression are common comorbid conditions. The purpose of this study was to assess how well the Patient Health Questionnaire (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS) perform as depression screening tools in patients with migraine. METHODS: Three hundred consecutive migraine patients were recruited from a large headache center. The PHQ-9 and HADS were self-administered and validated against the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV, a gold standard for the diagnosis of depression. Sensitivity, specificity, positive predictive value, negative predictive value and receiver-operator characteristic curves were calculated for the PHQ-9 and HADS. RESULTS: At the traditional cut-point of 10, the PHQ-9 demonstrated 82.0% sensitivity and 79.9% specificity. At a cut-point of 8, the HADS demonstrated 86.5% sensitivity and specificity. The PHQ-9 algorithm performed poorly (53.8% sensitivity, 94.9% specificity). The point prevalence of depression in this study was 25.0% (95% CI 19.0-31.0), and 17.0% of patients had untreated depression. CONCLUSIONS: In this study, the PHQ-9 and HADS performed well in migraine patients attending a headache clinic, but optimal cut-points to screen for depression vary depending on the goals of the assessment. Also, migraine patients attending a headache clinic have a high prevalence of depression and many are inadequately treated. Future studies are needed to confirm these findings and to evaluate the impact of depression screening. PMID- 28917392 TI - Description of a multi-university education and collaborative care child psychiatry access program: New York State's CAP PC. AB - OBJECTIVE: Although, child mental health problems are widespread, few get adequate treatment, and there is a severe shortage of child psychiatrists. To address this public health need many states have adopted collaborative care programs to assist primary care to better assess and manage pediatric mental health concerns. This report adds to the small literature on collaborative care programs and describes one large program that covers most of New York state. PROGRAM DESCRIPTION: CAP PC, a component program of New York State's Office of Mental Health (OMH) Project TEACH, has provided education and consultation support to primary care providers covering most of New York state since 2010. The program is uniquely a five medical school collaboration with hubs at each that share one toll free number and work together to provide education and consultation support services to PCPs. METHODS: The program developed a clinical communications record to track information about all consultations which forms the basis of much of this report. 2-week surveys following consultations, annual surveys, and pre- and post-educational program evaluations have also been used to measure the success of the program. RESULTS: CAP PC has grown over the 6years of the program and has provided 8013 phone consultations to over 1500 PCPs. The program synergistically provided 17,523 CME credits of educational programming to 1200 PCPs. PCP users of the program report very high levels of satisfaction and self reported growth in confidence. CONCLUSIONS: CAP PC demonstrates that large scale collaborative consultation models for primary care are feasible to implement, popular with PCPs, and can be sustained. The program supports increased access to child mental health services in primary care and provides child psychiatric expertise for patients who would otherwise have none. PMID- 28917393 TI - Reduction in depressive symptoms in primary prevention ICD scheduled patients - One year prospective study. AB - OBJECTIVE: Implantable Cardioverter Defibrillators (ICDs), have previously been associated with the onset of depression and anxiety. The aim of this one-year prospective study was to evaluate the rate of new onset psychopathological symptoms after elective ICD implantation. METHODS: A total of 158 consecutive outpatients who were scheduled for an elective ICD implantation were diagnosed and screened based on the Mini International Neuropsychiatric Interview (MINI). Depression and anxiety were evaluated using the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A). Patient's attitude toward the ICD device was evaluated using a Visual Analog Scale (VAS). RESULTS: Patients' mean age was 64+/-12.4years; 134 (85%) were men, with the majority of patients performing the procedure for reasons of 'primary prevention'. According to the MINI diagnosis at baseline, three (2%) patients suffered from major depressive disorder and ten (6%) from dysthymia. Significant improvement in HAM-D mean scores was found between baseline, three months and one year after implantation (6.50+/-6.4; 4.10+/-5.3 and 2.7+/-4.6, respectively F(2100)=16.42; p<0.001). There was a significantly more positive attitude toward the device over time based on the VAS score [F(2122)=53.31, p<0.001]. CONCLUSIONS: ICD implantation significantly contributes to the reduction of depressive symptoms, while the overall mindset toward the ICD device was positive and improved during the one-year follow-up. PMID- 28917394 TI - Childhood maltreatment severity and alcohol use in adult psychiatric inpatients: The mediating role of emotion regulation difficulties. AB - OBJECTIVE: Emotion regulation difficulties are a potentially key mechanism underlying the association between childhood maltreatment and alcohol use in adulthood. The current study examined the mediating role of emotion regulation difficulties in the association between childhood maltreatment severity (i.e., Childhood Trauma Questionnaire total score) and past-month alcohol use severity, including alcohol consumption frequency and alcohol-related problems (i.e., number of days of alcohol problems, ratings of "bother" caused by alcohol problems, ratings of treatment importance for alcohol problems). METHOD: Participants included 111 acute-care psychiatric inpatients (45.0% female; Mage=33.5, SD=10.6), who reported at least one DSM-5 posttraumatic stress disorder Criterion A traumatic event, indexed via the Life Events Checklist for DSM-5. Participants completed questionnaires regarding childhood maltreatment, emotion regulation difficulties, and alcohol use. RESULTS: A significant indirect effect of childhood maltreatment severity via emotion regulation difficulties in relation to alcohol use severity (beta=0.07, SE=0.04, 99% CI [0.01, 0.21]) was documented. Specifically, significant indirect effects were found for childhood maltreatment severity via emotion regulation difficulties in relation to alcohol problems (beta's between 0.05 and 0.12; all 99% bootstrapped CIs with 10,000 resamples did not include 0) but not alcohol consumption. CONCLUSION: Emotion regulation difficulties may play a significant role in the association between childhood maltreatment severity and alcohol outcomes. Clinical implications are discussed. PMID- 28917395 TI - Monitoring somatic symptoms in patients with mental disorders: Sensitivity to change and minimal clinically important difference of the Somatic Symptom Scale - 8 (SSS-8). AB - OBJECTIVE: The SSS-8 is a brief questionnaire for the assessment of somatic symptom burden. This study examines its sensitivity to change and the minimal clinically important difference (MCID) in patients with mental disorders. METHOD: 55 outpatients with mental disorders completed the SSS-8 and measures of anxiety, depression, and disability before and after receiving treatment. Effect sizes and correlations between the change scores were calculated. The MCID was estimated using a one standard error of measurement threshold and the change in disability as an external criterion. RESULTS: There was a medium decline in somatic symptom burden for the complete sample (n=55, dz=0.53) and a large decline in a subgroup with very high somatic symptom burden at baseline (n=11, dz=0.94). Decreases in somatic symptom burden were associated with decreases in anxiety (r=0.68, p<0.001), depression (r=0.62, p<0.001) and disability (r=0.51, p<0.001). The MCID was estimated as a 3-point decrease. CONCLUSION: The SSS-8 is sensitive to change. A 3-point decrease reflects a clinically important improvement. Due to its brevity and sound psychometric properties, the SSS-8 is useful for monitoring somatic symptom burden. PMID- 28917396 TI - Modified bean-shaped ring segments for suture fixation of the bag-in-the-lens intraocular implant. AB - We describe a surgical technique for secondary stabilization of a bag-in-the-lens intraocular lens (BIL IOL) using 2 modified bean-shaped ring segments in cases of zonular dehiscence associated with pseudophakodonesis. The first modified bean segment is anchored in the sulcus with a suture to the sclera in the area of maximum zonular dehiscence, and the second segment is implanted in the opposite sulcus area. Both segments are placed in the BIL IOL interhaptic groove. The segments stabilize and center the BIL IOL by creating an artificial zonule that provides the necessary extra support for the IOL. PMID- 28917397 TI - Evaluation of postoperative toric intraocular lens alignment with anterior segment optical coherence tomography. AB - We describe the use of a simple tool to evaluate the postoperative alignment of toric intraocular lenses (IOLs). The entire anterior segment is scanned using anterior segment optical coherence tomography and analyzed with an internal dedicated tool. A topographic map is displayed along with an anterior segment image, including a linear axis marker centered on the corneal apex. The marker can be rotated until it is aligned with the line connecting the IOL marking dots, precisely reproducing the IOL astigmatic axis, which is measured in angle degrees. The value of the IOL astigmatic axis is compared with the value of the astigmatic axis shown in real time on the same screen in the topographic map. Evaluating the alignment of a toric IOL axis simultaneously with the topographic astigmatic axis eliminates the potential errors that result from head tilting and strictly correlates with the astigmatic correction achieved. PMID- 28917398 TI - Hydrogel ocular sealant for clear corneal incisions in cataract surgery. AB - PURPOSE: To assess the relationship between use of a hydrogel ocular sealant (Resure) to secure clear corneal incisions (CCIs) in cataract surgery and surgeon efficiency, patient symptomatology, and postoperative results. SETTING: Duke University Eye Center, Durham, North Carolina, USA. DESIGN: Retrospective case series. METHODS: A 1:1 matched cohort of hydrogel sealant exposure-discordant eyes of cataract surgery patients was retrospectively generated. Consecutive patients who had bilateral cataract surgery during the study period and in whom the hydrogel sealant was used to secure the CCI in only 1 of the 2 eyes were included in the study. The relationship between use of the hydrogel sealant and surgical time, 1-day postoperative foreign-body sensation, clinically noted corneal edema, and intraocular pressure (IOP) was evaluated. RESULTS: Ninety eyes of 45 patients were included in the study. One day postoperatively, no wound leak was found in any eye; the sealant was noted to be out of place in 2 (4.4%) of 45 cases. No statistically significant difference was found between sealant and non sealant eyes in total surgical time (P = .16) or in IOP (P = .55), corneal edema (P = 1.00), or foreign-body sensation (P = .38) 1 day postoperatively. CONCLUSION: The hydrogel sealant was not observed to affect duration of surgery or 1-day postoperative IOP, corneal edema, or foreign-body sensation. PMID- 28917399 TI - Variability in angle kappa and its influence on higher-order aberrations in pseudophakic eyes. AB - PURPOSE: To observe the variability in angle kappa in pseudophakic patients and assess its correlation with optical biometry measurements and higher-order aberrations (HOAs). SETTING: Hanusch Hospital, Vienna, Austria. DESIGN: Prospective case series. METHODS: This study included patients who had cataract surgery 3 months to 1 year before study recruitment. In all cases, Purkinje meter images were taken. In addition, partial coherence interferometry measurement (IOLMaster) of the axial intraocular lens (IOL) position was performed. In a subgroup of patients, an additional Hartmann-Shack sensor measurement was taken to assess HOAs (WASCA). RESULTS: This study comprised 395 eyes of 349 patients. The mean age of the 210 women and 139 men was 74.1 years +/- 8.6 (SD) (range 44 to 91 years). The mean tilt (pupillary axis) and decentration were 3.9 +/- 2.3 degrees (range 0.2 to 16.2 degrees) and 0.4 +/- 0.2 mm (range 0.0 to 1.7 mm), respectively. The mean angle kappa was 5.2 +/- 2.6 degrees (range 0.3 to 13.9 degrees), and the mean orientation of this modulus was 189.5 +/- 53.2 degrees (range 25.3 to 339.7 degrees). CONCLUSION: The variability in the angle kappa was high. PMID- 28917400 TI - Visual quality and performance comparison between 2 refractive rotationally asymmetric multifocal intraocular lenses. AB - PURPOSE: To compare the 12-month postoperative quality of vision and visual performance of 2 different refractive rotationally asymmetric multifocal intraocular lenses (IOLs). SETTING: Cathedral Eye Clinic, Belfast, Northern Ireland, United Kingdom. DESIGN: Retrospective case series. METHODS: Refractive lens exchange (RLE) patients were divided into 2 groups. Group A comprised eyes receiving a Lentis Mplus LS-312 MF30 IOL and Group B, eyes receiving a Lenstec SBL-3 IOL. Refraction, uncorrected (UDVA) and corrected distance visual acuities, uncorrected intermediate (UIVA) and near (UNVA) visual acuities, distance corrected intermediate and near (DCNVA) visual acuities, and quality of vision were evaluated preoperatively and up to 12 months postoperatively. RESULTS: Each group comprised 90 eyes. Both groups had a high level of quality of vision 12 months postoperatively with no significant difference between the 2 groups (P = .919). There was no significant between-group difference in mean monocular and binocular UDVA, monocular UIVA, or monocular UNVA. Group B had statistically significantly better mean monocular DCNVA (P = .049), binocular UNVA (P = .011), and binocular DCNVA (P = .035). Group B had a higher percentage of complete spectacle independence. CONCLUSIONS: Both refractive rotationally asymmetric multifocal IOLs provided an excellent level of quality of vision 12 months postoperatively. Both IOL models restored distance, intermediate, and near visual function; however the IOLs in Group B provided better near visual performance. PMID- 28917401 TI - Pseudophakic cystoid macular edema and spectral-domain optical coherence tomography-detectable central macular thickness changes with perioperative prostaglandin analogs. AB - PURPOSE: To define the incidence of cystoid macular edema (CME) and spectral domain optical coherence tomography-detectable (SD-OCT) subclinical changes in central retinal thickness in patients using prostaglandin analog (PGA) eyedrops after phacoemulsification. SETTING: Royal Bolton Hospital, Bolton, United Kingdom. DESIGN: Prospective case series. METHODS: A consecutive analysis of the incidence of postoperative CME after phacoemulsification by a single surgeon was performed in eyes of patients using PGA eyedrops between March 2010 and January 2014. The presence of CME was determined using SD-OCT (Cirrus) 3 weeks and 6 weeks postoperatively. Exclusion criteria included preexisting pathology known to predispose to CME and previous ophthalmic surgery. The paired Wilcoxon signed rank test was used to compare central retinal thickness measurements at baseline and 3 weeks and 6 weeks postoperatively. RESULTS: All 48 patients (mean age 78.4 years; 60 eyes) had uneventful surgery. There were no cases of clinically significant CME. Subclinical CME detected by SD-OCT was confirmed in 2 eyes of different patients (3.3% of eyes), 1 eye 3 weeks postoperatively and another eye at 6 weeks. Subclinical CME resolved in both cases within 8 weeks. In both cases, the difference in central retinal thickness at baseline and 6 weeks postoperatively was statistically significant (P < .05). CONCLUSIONS: The incidence of subclinical CME detectable on SD-OCT after routine phacoemulsification in patients using PGA eyedrops throughout the perioperative period was 3.3%. There were no cases of clinical CME. These findings might guide clinicians in their decision to use PGAs perioperatively. PMID- 28917402 TI - Intracameral mydriatics versus topical mydriatics in pupil dilation for phacoemulsification cataract surgery. AB - PURPOSE: To evaluate the efficacy and safety of intracameral mydriatics (lidocaine 1.0% and phenylephrine 1.5%) versus topical mydriatics (phenylephrine 2.5% and tropicamide 1.0%) in pupil dilation for phacoemulsification surgery in Malaysians. SETTING: Department of Ophthalmology, Penang General Hospital, Georgetown Penang, Malaysia. DESIGN: Prospective comparative case series. METHOD: Patients with immature cataract were randomized to the topical mydriatic group (topical group) or intracameral mydriatic group (intracameral group). Patients with small pupils and complicated cataracts were excluded. Pupil diameter changes were measured throughout the surgery. Additional pupil dilation maneuvers and complications were recorded. RESULTS: The study comprised 112 patients. There was no difference in mean pupil dilation between the intracameral group (4.86 mm +/- 0.74 [SD]) and the topical group (4.88 +/- 0.91 mm) (P = .86). However, the mean pupil size before capsulorhexis in the topical group (7.23 +/- 1.08 mm) was significantly larger than in the intracameral group (6.40 +/- 0.80 mm) (P = .01). The pupils in the intracameral group continued to dilate during surgery (0.44 +/- 0.62 mm), while those in the topical group constricted (-0.41 +/- 1.04 mm) (P < .001). Three patients in the intracameral group and 6 in the topical group required additional maneuvers for pupil dilation (P = .49). Each group had 1 complication (P = 1.00). CONCLUSIONS: Intracameral mydriatic agents dilated heavily pigmented pupils for phacoemulsification cataract surgery. However, in the early stages of surgery, pupil dilation was slower than with topical agents. PMID- 28917403 TI - Cataract surgery in patients with late-onset retinal degeneration. AB - PURPOSE: To review the outcomes in a series of patients with long anterior lens zonular fibers associated with late-onset retinal degeneration who had phacoemulsification cataract surgery. SETTING: Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom. DESIGN: Retrospective case series. METHODS: Inclusion criteria were patients with genetically confirmed late-onset retinal degeneration requiring cataract surgery. Perioperative data relating to surgery were collected. In addition, the corrected distance visual acuity (CDVA) and retinal imaging data were recorded. Selected lens capsules were examined using immunohistochemistry or scanning electron microscopy (SEM). RESULTS: Eleven eyes of 7 patients were included. The long anterior lens zonular fibers made capsulorhexis challenging; however, it was completed safely in all cases. There were no intraoperative or postoperative issues with lens stability. The CDVA improved postoperatively in those cases with intact foveal photoreceptors and retinal pigment epithelium. Over the longer term, the CDVA slowly declined because of progressive atrophy of the macula. Most patients noticed a subjective improvement in vision, even those with advanced disease at baseline. Immunohistochemistry showed that the C1QTNF5 protein was expressed within the lens capsule epithelial cells, although SEM of the long anterior lens zonular fibers showed them to be smaller in diameter than normal anterior lens zonular fibers and to be composed of a helix of fibers. CONCLUSIONS: In this small series of patients with late-onset retinal degeneration, cataract surgery was successfully performed without long-term complications involving intraocular lens stability. The objective improvement in CDVA seemed to be limited to patients with good foveal photoreceptor architecture. PMID- 28917404 TI - Clinical course and outcomes in patients with Mooren ulcer who had cataract surgery. AB - PURPOSE: To report outcomes of cataract surgery in patients with Mooren ulcer. SETTING: L.V. Prasad Eye Institute, Hyderabad, India. DESIGN: Retrospective case series. METHODS: The medical records of patients with Mooren ulcer who had cataract surgery between 2000 and 2015 were assessed. The main outcome measures were the role of preoperative immunosuppression and disease inactivity, cataract surgery safety, visual outcomes, and postoperative ulcer recurrence. RESULTS: Of 22 patients (26 eyes), the mean corneal ulceration was 6.8 clock hours +/- 2.9 (SD). Corticosteroids were the most commonly used (84.6% of the 26 eyes) preoperative immunosuppression agents and 38.5% of the 26 eyes were under maintenance immunosuppression. The median disease inactivity before surgery was 7 months. Cataract surgery was extracapsular in 10 patients, small incision in 3 patients, and phacoemulsification in 13 patients. Twenty-two eyes had scleral incisions. The median follow-up was 6 months (interquartile range, 10 months). The median corrected distance visual acuity (CDVA) improved from 1.48 logarithm of minimum angle of resolution (logMAR) before surgery to 0.30 and 0.35 logMAR at 1 month and at the last follow-up after surgery, respectively (P <= .0001). Mooren ulcer recurred in 5 eyes between 3 months and 7 years after surgery. No disease activity was seen in the immediate postoperative period. No significant risk factors for disease recurrence were noted. CONCLUSIONS: With adequate immunosuppression, cataract surgery in eyes with Mooren ulcer was safe and CDVA improved significantly with no disease reactivation immediately after surgery. No proven role of maintenance immunosuppression was observed. The type of cataract surgery had no influence on ulcer reactivation. Patients with a disease-free interval of 6 months or more before surgery and those who had scleral incisions had favorable outcomes. PMID- 28917405 TI - Comparison of refractive and keratometric astigmatism after microincision cataract surgery. AB - PURPOSE: To measure the correlation between refractive and keratometric astigmatism after microincision cataract surgery (MICS). SETTING: Takayanagi Clinic, Kushiro, Hokkaido, Japan. DESIGN: Retrospective case series. METHODS: This study evaluated patients having phacoemulsification and intraocular lens implantation through a 2.0 mm temporal clear corneal incision. Refractive astigmatism and keratometric astigmatism were described by Jackson cross-cylinder with-the-rule (J0) and oblique (J45) components and compared using linear regression analysis. RESULTS: The study comprised 90 eyes of 54 patients. The mean postoperative refractive J0 was -0.29 diopter (D) +/- 0.46 (SD), and the mean postoperative refractive J45 was -0.09 +/- 0.24 D. The multivariate model for the J0 component was postoperative J0 = 0.75 * keratometric J0 + 0.21 * preoperative J0 - 0.23 (R2 = 0.85, P < .001). The coefficient of determination of the multivariate model was higher than that of the univariate model (R2 = 0.82). The regression equation for the J45 component was postoperative J45 = 0.85 * keratometric J45 - 0.03 (R2 = 0.70, P < .001). CONCLUSION: Refractive astigmatism and keratometric astigmatism after MICS were strongly correlated. PMID- 28917406 TI - Comparison of the mechanical properties of the anterior lens capsule in senile cataract, senile cataract with trypan blue application, and pseudoexfoliation syndrome. AB - PURPOSE: To evaluate the elastic modulus, hardness, and mechanical properties of the anterior lens capsule in different types of cataract and to assess the correlation with age. SETTING: Baskent University Hospital, Department of Ophthalmology, Ankara, Turkey. DESIGN: Prospective comparative study. METHODS: Patients were divided into 3 groups. Group 1 comprised patients with senile cataract, Group 2 patients had pseudoexfoliation (PXF) syndrome, and Group 3 patients had dye-enhanced cataract surgery. The capsules were analyzed using a nanoindentation device. Young's modulus of elasticity was measured by the Oliver Pharr method and capsule hardness by the Martens method. RESULTS: The study comprised 72 patients, 24 per group. The mean Young's modulus was 7.53 GPa +/- 1.07 (SD) in Group 1, 6.01 +/- 1.25 GPa in Group 2, and 8.12 +/- 0.98 GPa in Group 3. The capsules in Group 2 were more elastic than in Group 1 and Group 3 (P < .001). The capsules in Group 3 had lower elasticity than in Group 1, although the difference was not significant (P = .94). The mean capsule stiffness was 326.41 +/- 98.40 MPa in Group 1, 210.5 +/- 52.32 MPa in Group 2, and 315.54 +/- 163.15 MPa in Group 3. The lens capsules in Group 2 were less stiff than those in Group 1 and Group 3 (P < .001). CONCLUSIONS: Capsule thickness was positively correlated with increasing age in all groups. The anterior lens capsules of patients with PXF had more elasticity and less stiffness than the other groups. Intracameral trypan blue application had no effect on capsule elasticity and stiffness. PMID- 28917407 TI - Corneal topography and keratometry changes after glued intraocular lens implantation. AB - PURPOSE: To analyze the alterations in corneal topography and keratometry (K) after glued transscleral-fixated intraocular lens (IOL) implantation. SETTING: Dr. Agarwal's Eye Hospital, Chennai, India. DESIGN: Prospective case series. METHODS: Eyes having glued IOL implantation for aphakia or subluxated lens (>180 degrees) were included. Preoperative autorefractometer and corneal topography was performed. Intraoperative parameters, namely the type, position, and incision size, flap position, and number of sutures were noted. The mean corneal curvature in a steep meridian (maximum K), flat meridian (minimum K), simulated K, pachymetry, and surgically induced astigmatism (SIA) were analyzed. RESULTS: This study evaluated 16 eyes with aphakia and 15 eyes with a subluxated over a mean follow-up of 12 months +/- 6 (SD). There was a significant reduction in mean simulated K (P = .014) after surgery. The maximum K decreased significantly (P = .002), from 44.85 +/- 2.83 diopters (D) preoperatively to 44.47 +/- 2.75 D at 6 months. The mean SIA was 1.0 +/- 0.7 D (range 0.16 to 3.6 D) and the postoperative astigmatism analysis by the Alpins method was negative (-1.8), showing relative flattening after surgery. Multiple regression analysis found no association between postoperative vision and preoperative maximum K, postoperative simulated K, incision size, and number of sutures. There was no correlation between the postoperative simulated K and incision position (P = .674), sutures (P = .881), and scleral flap position (P = .401). CONCLUSION: Glued transscleral fixation resulted in a reduction in mean corneal curvature in the steep meridian and there was significant change in corneal astigmatism. PMID- 28917409 TI - Methods for assessing forward and backward light scatter in patients with cataract. AB - PURPOSE: To compare objective methods for assessing backward and forward light scatter and psychophysical tests in patients with cataracts. SETTING: Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom. DESIGN: Prospective case series. METHODS: This study included patients scheduled for cataract surgery. Lens opacities were grouped into predominantly nuclear sclerotic, cortical, posterior subcapsular, and mixed cataracts. Backward light scatter was assessed using a rotating Scheimpflug imaging technique (Pentacam HR), forward light scatter using a straylight meter (C-Quant), and straylight using the double pass method (Optical Quality Analysis System, point-spread function [PSF] meter). The results were correlated with visual acuity under photopic conditions as well as photopic and mesopic contrast sensitivity. RESULTS: The study comprised 56 eyes of 56 patients. The mean age of the 23 men and 33 women was 71 years (range 48 to 84 years). Two patients were excluded. Of the remaining, 15 patients had predominantly nuclear sclerotic cataracts, 13 had cortical cataracts, 11 had posterior subcapsular cataracts, and 15 had mixed cataracts. Correlations between devices were low. The highest correlation was between PSF meter measurements and Scheimpflug measurements (r = 0.32). The best correlation between corrected distance visual acuity was with the PSF meter (r = 0.45). CONCLUSIONS: Forward and backward light-scatter measurements cannot be used interchangeably. Scatter as an aspect of quality of vision was independent of acuity. Measuring forward light scatter with the straylight meter can be a useful additional tool in preoperative decision-making. PMID- 28917408 TI - Refractive outcome comparison between vitreomacular interface disorders after phacovitrectomy. AB - PURPOSE: To compare the refractive accuracy of intraocular lens (IOL) power calculations between patients with vitreomacular interface disorders who had phacovitrectomy for vitreomacular traction (VMT), epiretinal membranes (ERM), and macular holes. SETTING: Baskent University Department of Ophthalmology, Ankara, Turkey. DESIGN: Retrospective case series. METHODS: Refraction results 8 weeks postoperatively were compared between phacovitrectomy (3 study groups comprising eyes with VMT with intrafoveal pseudocysts, ERM, or medium-to-large macular holes) and phacoemulsification (control group comprising eyes having phacoemulsification only). The IOLMaster 700 partial coherence interferometry (PCI) device and Haigis formula were used for all calculations. RESULTS: This study included 100 eyes (100 patients), 25 in each of the 4 groups. There was no statistically significant difference in axial length (AL) between the groups (P = .305). Differences in the preoperative macular thickness were statistically significant between all groups except between the macular hole and VMT groups. Most eyes (92%) in the VMT and macular hole groups and all eyes in the VMT and phacoemulsification groups achieved a final refraction within +/-1.00 diopter of the refractive aim. The mean prediction error and the mean absolute error did not differ significantly between the groups. In all groups, there was no significant correlation between prediction error and age, AL, preoperative refractive error, or preoperative or postoperative macular thickness (P > .05). CONCLUSIONS: The IOL power calculation with PCI yielded no difference in postoperative refraction errors between the vitreomacular interface disorders. There was no correlation with preoperative refraction, age, or preoperative or postoperative macular thickness. PMID- 28917410 TI - Influence of yellow filters on straylight measurements. AB - PURPOSE: To determine whether the yellow filters often used for glare reduction influence retinal straylight measured in healthy eyes. SETTING: Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium. DESIGN: Prospective case series. METHODS: For each eye, the spherical equivalent (SE) was determined using an autorefractometer, followed by 5 straylight measurements taken with the compensation-comparison method. The first measurement was taken with a colorless plano lens placed in front of the eye, followed by 4 other measurements with yellow filters with cutoff wavelengths at 450 nm, 511 nm, 527 nm, and 550 nm. Ametropic volunteers were corrected using an additional lens in all measurements. Age, sex, and eye color were listed. In addition to the basic measurements, base- and age-corrected and base-, age-, and SE-corrected values were calculated. RESULTS: The data from 56 right eyes of 56 healthy volunteers aged 28.7 years +/- 10.3 (SD) were assessed. The straylight of the 4 yellow filters was significantly higher than that of the plano lens (P < .001, analysis of variance [ANOVA]). The straylight also increased with higher cutoff frequencies, albeit insignificantly (P > .05, ANOVA). No significant difference was found between sexes (P = .909) or between eye colors (P > .05). CONCLUSIONS: The use of yellow filters increased retinal straylight by a small but significant amount compared with the use of unfiltered light. This suggests that the visual comfort often experienced while wearing these filters is not associated with reduced straylight. PMID- 28917411 TI - Accelerated 15 mW pulsed-light crosslinking to treat progressive keratoconus: Two year clinical results. AB - PURPOSE: To assess the clinical and microstructural results of accelerated 15 mW pulsed-light corneal crosslinking (CXL) to treat progressive keratoconus. SETTING: Siena Crosslinking Center, Siena, Italy. DESIGN: Prospective case series. METHODS: After epithelium removal (with Epi-Clear) and 10 minutes stromal soaking with riboflavin 0.1% hydroxypropyl methylcellulose solution, all eyes had 15 mW/cm2 pulsed-light epithelium-off accelerated CXL for 6 minutes of ultraviolet-A (UVA) irradiation (1 second on/1 second off), maintaining a total UVA exposure of 12 minutes at a fluence of 5.4 J/cm2. The 2-year follow-up examination included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, Scheimpflug tomography, in vivo confocal microscopy (IVCM), and spectral-domain optical coherence tomography (SD-OCT). RESULTS: The study comprised 132 eyes of 96 patients (mean age 23.7 years +/- 4.3 [SD]) with stage II keratoconus. The change in UDVA and CDVA was statistically significant, from 0.51 +/- 0.106 logarithm of the minimum angle of resolution (logMAR) at baseline to 0.309 +/- 0.074 logMAR (P = .0001) and 0.271 +/- 0.144 logMAR at baseline to 0.135 +/- 0.100 logMAR (P = .0023), respectively. Coma values measured by Scheimpflug analysis showed a statistically significant improvement beginning with the first postoperative month (P = .0004). The IVCM scans documented basal epithelial healing occurring 72 hours after treatment associated with the presence of subepithelial nerves. The SD-OCT scans performed in the central 6.0 mm of corneal diameter documented a demarcation line at a mean depth of 280 +/- 32 MUm. CONCLUSION: The 15 mW/cm2 pulsed-light epithelium-off accelerated CXL was effective and safe, stabilizing keratoconus progression through 2 years of follow up. PMID- 28917412 TI - Efficacy of different accelerated corneal crosslinking protocols for progressive keratoconus. AB - PURPOSE: To evaluate the efficacy of different accelerated corneal crosslinking (CXL) treatment protocols in patients with progressive keratoconus. SETTING: Marmara University School of Medicine, Istanbul, Turkey. DESIGN: Retrospective case series. METHODS: Patients with progressive keratoconus had 9 mW accelerated CXL (10 minutes; 9 mW/cm2), 30 mW continuous-light accelerated CXL (4 minutes; 30 mW/cm2), or 30 mW pulsed-light accelerated CXL (8 minutes [1 second on/1 second off]; 30 mW/cm2). RESULTS: Of 134 eyes, 34 eyes had conventional CXL, 45 had 9 mW accelerated CXL, 28 had 30 mW continuous-light accelerated CXL (4 minutes, 30 mW/cm2), and 27 eyes had 30 mW pulsed-light accelerated CXL. The uncorrected (UDVA) (P < .001 both) and corrected (CDVA) distance visual acuities increased in with conventional CXL and 9 mW accelerated CXL (P = .001 and P = .002, respectively). With 30 mW continuous accelerated CXL, only CDVA improved (P = .019). With 30 mW pulsed accelerated CXL, UDVA and CDVA did not change significantly (P > .05). With conventional CXL and 9 mW accelerated CXL, all keratometric (K) readings (K1, K2, mean K, maximum K) improved significantly (conventional CXL: P = .014, P = .002, P = .008, and P < .001, respectively; 9 mW accelerated CXL: all P < .001). With 30 mW, no K values changed significantly compared with baseline (all groups P > .05). CONCLUSION: Although 30 mW accelerated CXL treatment modalities appeared to be effective in stabilizing keratoconus progression, they seemed less effective in achieving topographic improvement. PMID- 28917414 TI - Chemical and physical analysis of phaco handpiece tip surfaces before and after cataract surgery. AB - PURPOSE: To evaluate the surface chemical composition and roughness of different phaco tips before and after their use during cataract surgery. SETTING: Eye Clinic, University of Trieste, Trieste, Italy. DESIGN: Experimental study. METHODS: Of the 66 tips studied, 33 (15 new, 15 after single use, and 3 after multiple uses) were studied with X-ray photoemission spectroscopy and 33 (15 new, 15 after single use, and 3 after multiple uses) were examined using scanning electron microscopy with energy dispersive X-ray spectroscopy analysis and contact profilometry. All analyses were performed on the far end of the tip. RESULTS: Used phaco tips showed signs of wear at the end of the tip, with the deposition of debris. The cutting edge appeared to be rounded and irregular. After surgery, an increase in the surface roughness was detected. The chemical analyses showed modification of the superficial alloy composition and the biological origin of some debris deposited after surgery. The deterioration and wear observed were more remarkable after multiple surgical procedures. CONCLUSIONS: Used phaco tips showed relevant signs of deterioration and deposition of biological material, mostly involving the cutting edge. Reusable tips might release remnants of previous procedures. The adoption of single-use disposable phaco tips seems to be highly advisable. PMID- 28917413 TI - Biocompatibility of intraocular lens power adjustment using a femtosecond laser in a rabbit model. AB - PURPOSE: To evaluate the biocompatibility (uveal and capsular) of intraocular lens (IOL) power adjustment by a femtosecond laser obtained through increased hydrophilicity of targeted areas within the optic, creating the ability to build a refractive-index shaping lens within an existing IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Six rabbits had phacoemulsification with bilateral implantation of a commercially available hydrophobic acrylic IOL. The postoperative power adjustment was performed 2 weeks after implantation in 1 eye of each rabbit. The animals were followed clinically for an additional 2 weeks and then killed humanely. Their globes were enucleated and bisected coronally just anterior to the equator for gross examination from the Miyake-Apple view to assess capsular bag opacification. After IOL explantation for power measurements, the globes were sectioned and processed for standard histopathology. RESULTS: Slitlamp examinations performed after the laser treatments showed the formation of small gas bubbles behind the lenses that disappeared within a few hours. No postoperative inflammation or toxicity was observed in the treated eyes, and postoperative outcomes and histopathological examination results were similar to those in untreated eyes. The power measurements showed that the change in power obtained was consistent and within +/-0.1 diopter of the target. CONCLUSIONS: Consistent and precise power changes can be induced in the optic of commercially available IOLs in vivo by using a femtosecond laser to create a refractive-index shaping lens. The laser treatment of the IOLs was biocompatible. PMID- 28917415 TI - Bilateral corneal epithelial macrocysts following hyperopic laser in situ keratomileusis. AB - A 27-year-old woman had microkeratome-assisted laser in situ keratomileusis (LASIK) for moderate bilateral hyperopia. The preoperative ophthalmologic examination was unremarkable except for minimal lissamine green staining bilaterally on the nasal conjunctiva. On the first postoperative day, the uncorrected distance visual acuity (UDVA) was 20/20 bilaterally and the corneas were clear. Four days later, the patient presented with mild blur in both eyes. Examination showed diffuse bilateral epithelial cysts encompassing the central 6.0 to 7.0 mm of the flaps with overlying diffuse lissamine green staining. The UDVA was 20/30 bilaterally. Aggressive lubrication was administered. The epithelial cysts coalesced into larger ones over subsequent visits and began regressing over several months, along with improvement in vision. At 6 months, the cysts had completely resolved, the corneas were clear, and the UDVA was 20/20. PMID- 28917416 TI - Consistency analysis of surgically induced astigmatism. PMID- 28917417 TI - Subluxated intraocular lens secondary to retinitis pigmentosa-associated zonulopathy: August consultation #1. PMID- 28917418 TI - August consultation #2. PMID- 28917419 TI - August consultation #3. PMID- 28917420 TI - August consultation #4. PMID- 28917421 TI - August consultation #6. PMID- 28917422 TI - August consultation #5. PMID- 28917423 TI - August consultation #7. PMID- 28917424 TI - Editor's Comment. PMID- 28917425 TI - Combined microinvasive glaucoma and cataract surgery in patients with pseudoexfoliation glaucoma: Clinical results of a gel stent. PMID- 28917427 TI - Reply. PMID- 28917426 TI - The devil is in...the methodology: Issues to be clarified. PMID- 28917428 TI - Erratum. PMID- 28917429 TI - Peer review: Get involved. PMID- 28917430 TI - Pursuing perfection in intraocular lens calculations: III. Criteria for analyzing outcomes. PMID- 28917431 TI - Results of Toccata(r) resurfacing PIP joint arthroplasty. A series of 32 cases at a mean follow-up of 5.9 years. AB - The objective of this study was to evaluate the long-term results of proximal interphalangeal (PIP) resurfacing arthroplasty for treating osteoarthritis: the PIP Toccata implant(r). This was a retrospective study of 32 out of 33 PIP arthroplasty cases performed with a dorsolateral or a Chamay approach by two surgeons after a minimum follow-up of 24 months. Patients were reviewed using a standardized assessment of pain, function, mobility and radiological changes. The average follow-up was 5.9 years. The mean active range of motion was 67 degrees (15-95). Radiographic analysis found osteointegration of the implant in all patients except one, in whom distal migration had no clinical consequence. Heterotopic ossifications (HO) developed in 10 of the 20 cases where the implant was inserted through a lateral approach. Intra-articular bone debris was identified in the first postoperative X-ray in most of these cases. The presence of HO was significantly correlated with decreased range of motion (P<0.05). Six patients required surgical revision and two needed implant removal and arthrodesis. Our results are comparable to other published studies of PIP resurfacing arthroplasty. It is important to remove all bone debris when using the dorsolateral approach. The PIP Toccata(r) implant is a reliable solution for treating PIP osteoarthritis but this arthroplasty procedure is demanding. PMID- 28917432 TI - Complications after treating Dupuytren's disease. A systematic literature review. AB - The objective of this study was to review the incidence of complications associated with different treatment options for patients with Dupuytren's disease. In a systematic literature review, the PubMed, EMBASE, Cochrane and Scopus databases were searched for clinical studies reporting complications after collagenase treatment, percutaneous needle fasciotomy (PNF), fasciectomy and dermofasciectomy. The incidence of complications was extracted from each study and stratified by procedure. From a total of 2251 references, 113 studies were analyzed and included with complication incidences varying from 0% to 100%. The highest number of nerve and vessel lesions were reported after fasciectomy, whereas the highest rate of edema was after collagenase injection. Accidental skin tears were mostly associated with collagenase and PNF treatment. Pooled complication incidences were 17.4% (95% CI: 11.7-23.1) for fasciectomy, 78.0% (95% CI: 59.6-96.4) for collagenase treatment, 18.9% (95% CI: -5.5-43.3) for PNF and 11.6% (95% CI: 0.0-23.2) for dermofasciectomy. Due to inconsistencies in reporting complications as well as the lack of a standardized definition, the literature does not provide evidence in favor of a specific procedure for Dupuytren's disease. A standardized definition of complications is required to improve the comparability of published results. PMID- 28917433 TI - Surveillance Imaging in Patients With Endometrial Cancer in First Remission. AB - OBJECTIVE: The clinical benefit of surveillance imaging in endometrial cancer remains undefined. This retrospective study was conducted to evaluate the positive predictive value (PPV) of surveillance imaging in endometrial cancer. METHODS: A total of 128 patients in first remission after treatment for endometrial cancer (uterine papillary serous, clear cell, stage III endometroid) who had surveillance imaging were retrospectively identified. The surveillance period was defined from the time of first-negative scan after treatment to the time when treatment was started for recurrent disease. Reports of surveillance scans were reviewed for the presence or absence of findings. The primary outcome was PPV of surveillance imaging. Cost and radiation exposure from surveillance imaging were also evaluated. RESULTS: A total of 128 patients had 707 surveillance scans (computed tomography, positron emission tomography-computed tomography with 2-deoxy-2-[18F]fluoro-d-glucose, magnetic resonance image, and bone scans). Median follow-up was 54 months (range: 9-173). Of all, 47 patients (37%) started therapy for recurrent endometrial cancer at the discretion of the treating physician. PPV of all surveillance imaging was 57.7%. Per patient, the mean number of surveillance scans was 5.6 (range: 2-21). The mean cost of imaging was $4200 (range: $1200-$18,700) and mean radiation exposure was 109.6mSV (range: 16-445mSv). CONCLUSIONS: Surveillance imaging detected a significant number of recurrences in patients with high-risk endometrial cancer at a reasonable cost related to the overall risk. Well-designed prospective imaging trials are warranted to assess the clinical benefit of surveillance imaging. PMID- 28917434 TI - Quantitative analysis of four protein biomarkers: An automated microfluidic cartridge-based method and its comparison to colorimetric ELISA. AB - Biomarker quantitation with ligand binding assays has matured greatly in recent years. This maturation has been partly in response to demands for more data points from fewer samples or less available sample volume. Multiplexing offers opportunities to acquire data for multiple analytes from single sample assay iterations, but has its own unique challenges and limitations. ProteinSimple has developed Simple PlexTM, an automated immunoassay platform consisting of microfluidic cartridge-based assays run on the Ella instrument. Ella subverts traditional multiplexing challenges by rapidly performing triplicate measurements of up to four different analytes simultaneously, each in their own respective assay vessels and all from a single sample. Here we describe a comparison of the Simple Plex platform versus colorimetric ELISA and their respective abilities to quantitate four common biomarkers (MCP-1/CCL2, VEGF-A, TNF-alpha, and IL-6) from twenty-eight healthy individual donor plasma samples. Each biomarker was tested on the two platforms on each of two days. Ella analysis required significantly reduced sample volume, manual steps, and total time. Overall, Ella was able to quantify results for all twenty-eight samples for each of the four biomarkers. In contrast, ELISA was able to measure quantifiable results within respective calibration curve ranges for MCP-1/CCL2 (96% of samples) and VEGFA (7% of samples). For TNF-alpha and IL-6, ELISA was not sensitive enough to quantify any samples in the assay ranges. This stark difference in quantitative results underscores Ella's ability to multiplex without compromising sensitivity, and has far reaching potential for biomarker panel measurement in support of diagnosis, prognosis, and monitoring of disease. PMID- 28917435 TI - Measurement of micronuclei and internal dose in mice demonstrates that 3 monochloropropane-1,2-diol (3-MCPD) has no genotoxic potency in vivo. AB - In this study 3-monochloropropane-1,2-diol (3-MCPD), a compound that appears as contaminant in refined cooking oils, has been studied with regard to genotoxicity in vivo (mice) with simultaneous measurement of internal dose using state-of-the art methodologies. Genotoxicity (chromosomal aberrations) was measured by flow cytometry with dual lasers as the frequency of micronuclei in erythrocytes in peripheral blood from BalbC mice intraperitoneally exposed to 3-MCPD (0, 50, 75, 100, 125 mg/kg). The internal doses of 3-MCPD in the mice were calculated from N (2,3-dihydroxypropyl)-valine adducts to hemoglobin (Hb), quantified at very low levels by high-resolution mass spectrometry. Convincing evidence for absence of genotoxic potency in correlation to measured internal doses in the mice was demonstrated, despite relatively high administered doses of 3-MCPD. The results are discussed in relation to another food contaminant that is formed as ester in parallel to 3-MCPD esters in oil processing, i.e. glycidol, which has been studied previously by us in a similar experimental setup. Glycidol has been shown to be genotoxic, and in addition to have ca. 1000 times higher rate of adduct formation compared to that observed for 3-MCPD. The conclusion is that at simultaneous exposure to 3-MCPD and glycidol the concern about genotoxicity would be glycidol. PMID- 28917436 TI - Comparison of the loop technique with incision and drainage for soft tissue abscesses: A systematic review and meta-analysis. AB - INTRODUCTION: Skin and soft tissue infections are a common presentation to the emergency department. Traditional management of abscesses involves a linear incision through the center of the abscess with packing placed. The loop drainage technique (LDT) is an alternate approach that may reduce pain and scarring, as well as decrease the number of follow up visits needed. This systematic review and meta-analysis aimed to compare the efficacy of the LDT with conventional incision and drainage (CID) in the treatment of soft tissue abscesses. METHODS: PubMed, CINAHL, Scopus, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and bibliographies of selected articles were assessed for all retrospective, prospective, or randomized controlled trials comparing the LDT to CID with an outcome of treatment failure, as defined by the individual study. Data were double extracted into a predefined worksheet and quality analysis was performed using the Cochrane Risk of Bias tool. Data were summarized and a meta-analysis was performed with subgroup analyses by adult versus pediatric age groups. RESULTS: This systematic review identified four studies comprising 470 total patients. Overall, the CID technique failed in 25 of 265 cases (9.43%). The LDT failed in 8 of 195 cases (4.10%). There was an odds ratio of 2.63 (95% CI 1.04 to 6.63) in favor of higher failures in the CID group. Funnel plot analysis demonstrated no evidence of publication bias. Subgroups analysis by age group demonstrated improved efficacy of the LDT in pediatric patients, but the adult subgroup did not reach statistical significance. DISCUSSION: The existing literature suggests that LDT is associated with a lower failure rate than CID. However, the data is limited by small sample sizes and predominantly retrospective study designs. Given the potential for less pain, decreased scarring, and lower associated healthcare costs, this technique should be considered for the treatment of skin and soft tissue abscesses in the ED setting, but further studies are needed. PMID- 28917437 TI - Effects of intravenous administration of fentanyl and lidocaine on hemodynamic responses following endotracheal intubation. AB - OBJECTIVES: To compare the effects of intravenous fentanyl and lidocaine on hemodynamic changes following endotracheal intubation in patients requiring Rapid Sequence Intubation (RSI) in the emergency department (ED). METHODS: A single centered, prospective, simple non-randomized, double-blind clinical trial was conducted on 96 patients who needed RSI in Edalatian ED. They were randomly divided into three groups (fentanyl group (F), lidocaine group (L), and fentanyl plus lidocaine (M) as our control group). M was administered with 3 MUgr/kg intravenous fentanyl and 1.5 MUgr/kg intravenous lidocaine, F was injected with 3g/kg intravenous fentanyl and L received 1.5mg/kg intravenous lidocaine prior to endotracheal intubation. Heart rate (HR) and mean arterial pressure (MAP) were assessed four times with the chi-square test: before, immediately after, 5 and 10 min after intubation. Intervention was discontinued for five people due to unsuccessful CPR. RESULTS: HR was notably different in F, L and M groups during four time courses (p<0.05). Comparison of MAP at measured points in all groups exhibited no significant difference (p>0.05). In fentanyl group both HR and MAP increased immediately after intubation, and significantly decreased 10 min after intubation (p<0.05). CONCLUSIONS: Overall, the result of this study shows that lidocaine effectively prevents MAP and HR fluctuations following the endotracheal intubation. According to our findings, lidocaine or the combination of fentanyl and lidocaine are able to diminish hemodynamic changes and maintain the baseline conditions of the patient, thus could act more effectively than fentanyl alone. PMID- 28917438 TI - Emergency department electrocardiogram images sent through the mobile phone: Feasibility and accuracy. PMID- 28917439 TI - Sexual history documentation in adolescents with lower abdominal pain or genitourinary complaints. PMID- 28917440 TI - Neuroticism and quality of life: Multiple mediating effects of smartphone addiction and depression. AB - The purposes of this study were to investigate the mediating effect of smartphone addiction and depression on neuroticism and quality of life. Self-reported measures of neuroticism, smart-phone addiction, depression, and quality of life were administered to 722 Chinese university students. Results showed smartphone addiction and depression were both significantly affected neuroticism and quality of life. The direct effect of neuroticism on quality of life was significant, and the chain-mediating effect of smartphone addiction and depression was also significant. In conclusion, neuroticism, smartphone addiction, and depression are important variables that worsen quality of life. PMID- 28917441 TI - Recognition of peer emotions in children with ADHD: Evidence from an animated facial expressions task. AB - A growing body of literature suggests that ADHD is associated with emotion recognition impairments that may be linked to deficient interpersonal functioning. However, our understanding of the mechanisms underlying these recognition impairments is extremely limited. Here, we used dynamic stimuli to investigate whether impaired emotion recognition in children with ADHD may be associated with impairments in perceptual sensitivity. Participants (ADHD: N = 26; Controls: N = 26) viewed video sequences of neutral faces slowly developing into one of the six basic emotional expressions (angry, happy, fearful, sad, disgusted and surprised) and were instructed to indicate via a button press the precise moment at which they were able to correctly recognize the emotional expression. The results showed that compared to controls, children with ADHD exhibited lower accuracy rates across all emotional expressions while there was no evidence for impaired perceptual sensitivity. Thus, the study provides evidence for a generalized categorization impairment across all emotional categories and is consistent with developmental delay accounts of ADHD. Future studies are needed in order to further investigate the developmental course of social cognition deficits in ADHD. PMID- 28917442 TI - ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users. AB - ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Delta9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as >= 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population. PMID- 28917443 TI - Alternative models of DSM-5 PTSD: Examining diagnostic implications. AB - The factor structure of DSM-5 posttraumatic stress disorder (PTSD) has been extensively debated with evidence supporting the recently proposed seven-factor Hybrid model. However, despite myriad studies examining PTSD symptom structure few have assessed the diagnostic implications of these proposed models. This study aimed to generate PTSD prevalence estimates derived from the 7 alternative factor models and assess whether pre-established risk factors associated with PTSD (e.g., transportation accidents and sexual victimisation) produce consistent risk estimates. Seven alternative models were estimated within a confirmatory factor analytic framework using the PTSD Checklist for DSM-5 (PCL-5). Data were analysed from a Malaysian adolescent community sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years. The results indicated that all models provided satisfactory model fit with statistical superiority for the Externalising Behaviours and seven-factor Hybrid models. The PTSD prevalence estimates varied substantially ranging from 21.8% for the DSM-5 model to 10.0% for the Hybrid model. Estimates of risk associated with PTSD were inconsistent across the alternative models, with substantial variation emerging for sexual victimisation. These findings have important implications for research and practice and highlight that more research attention is needed to examine the diagnostic implications emerging from the alternative models of PTSD. PMID- 28917444 TI - Developing a Hospital-Wide Fertility Preservation Service for Pediatric and Young Adult Patients. AB - PURPOSE: Gonadal damage is a common consequence of treatment for pediatric malignancies. Nononcologic conditions may also utilize treatments with potential impact on fertility. Models for oncology fertility preservation programs have emerged and demonstrate that a multidisciplinary team approach can have a positive impact on referral patterns, appropriate risk counseling, and access to fertility preservation options. Expansion of programmatic breadth is needed, providing improved care to nonmalignant conditions where the disease itself may impact reproductive health or treatment modalities. METHODS: With support from the Department of Pediatrics Chair's Initiative, a multidisciplinary, hospital wide Fertility Preservation Service was created at the Children's Hospital of Philadelphia. A centralized team provides fertility consults across the institution, allowing for risk-based counseling and facilitation of fertility preservation options (both standard care and experimental). RESULTS: Team structure, consult process, and available fertility options for prepubertal and pubertal males and females are described. Preinitiative and postinitiative referral patterns were analyzed. Postinitiative referrals from divisions outside oncology more than doubled (34% vs. 15% at baseline). CONCLUSIONS: A comprehensive model for fertility counseling provides accessible, high-value fertility preservation care to pediatric and young adult patients with a wide variety of diagnoses. A centralized point of contact ensures timely referrals and risk-based counseling and streamlines access to fertility preservation procedures. PMID- 28917445 TI - Margin width and local recurrence after breast conserving surgery for ductal carcinoma in situ. AB - INTRODUCTION: Ductal Carcinoma in situ (DCIS) represents 5% of symptomatic and 20 30% of screen detected cancers. Breast conserving surgery (BCS) +/- radiotherapy is performed in over 70% of women with DCIS. What constitutes an adequate margin for BCS remains unclear. METHODS: A single institution follow up study has been conducted of 466 patients with pure DCIS treated by BCS between 2000 and 2010 of whom 292 received whole breast radiotherapy and 167 did not. Patients were selected for radiotherapy based on perceived risk of in breast tumour recurrence (IBTR). Distance to nearest radial margin was measured; 10 patients had a margin width of <1 mm, 94 had widths of 1-2 mm and 362 had widths of >2 mm. There was no association of margin width and the use of radiotherapy. RESULTS: At a median follow up of 7.2 years there were 44 IBTR (27 DCIS and 17 invasive). There was no evidence that margin widths >2 mm resulted in a lower rate of IBTR than margin widths of 1-2 mm. The actuarial IBTR rates at 5 and 10 years for margins of 1-2 mm were 9.0% (95% CI +/- 5.9%) and 9.0% (95% CI +/- 5.9%) respectively and for margins of >2 mm were 8.0% (95% CI +/- 3.9%) and 13.0% (95% CI +/- 3.9%) respectively. Odds Ratio for IBTR 1-2 mm vs >2 mm was 0.839 (95% CI 0.392-1.827) p = 0.846. In a multivariate analysis only DCIS size predicted for IBTR (HR 2.73 p < 0.0001). CONCLUSION: 1 mm appears a sufficient margin width for BCS in DCIS irrespective of whether patients receive radiotherapy. PMID- 28917446 TI - Amplitude modulation rate dependent topographic organization of the auditory steady-state response in human auditory cortex. AB - Periodic modulations of an acoustic feature, such as amplitude over a certain frequency range, leads to phase locking of neural responses to the envelope of the modulation. Using electrophysiological methods this neural activity pattern, also called the auditory steady-state response (aSSR), is visible following frequency transformation of the evoked response as a clear spectral peak at the modulation frequency. Despite several studies employing the aSSR that show, for example, strongest responses for ~40 Hz and an overall right-hemispheric dominance, it has not been investigated so far to what extent within auditory cortex different modulation frequencies elicit aSSRs at a homogenous source or whether the localization of the aSSR is topographically organized in a systematic manner. The latter would be suggested by previous neuroimaging works in monkeys and humans showing a periodotopic organization within and across distinct auditory fields. However, the sluggishness of the signal from these neuroimaging works prohibit inferences with regards to the fine-temporal features of the neural response. In the present study, we employed amplitude-modulated (AM) sounds over a range between 4 and 85 Hz to elicit aSSRs while recording brain activity via magnetoencephalography (MEG). Using beamforming and a fine spatially resolved grid restricted to auditory cortical processing regions, our study revealed a topographic representation of the aSSR that depends on AM rate, in particular in the medial-lateral (bilateral) and posterior-anterior (right auditory cortex) direction. In summary, our findings confirm previous studies that showing different AM rates to elicit maximal response in distinct neural populations. They extend these findings however by also showing that these respective neural ensembles in auditory cortex actually phase lock their activity over a wide modulation frequency range. PMID- 28917448 TI - In vitro antitumor activity of novel benzimidazole-based Cu(II) complexes. AB - Four benzimidazole-based Cu(II) complexes: Cu2(p-2-bmp)2Br4 (1), Cu2(p-2-bmp)2Cl4 (2), Cu2(p-2-bmb)2(DMF)2Br4.(CHCl3) (3), and Cu(p-2-bmb)(NO3)2.(CHCl3) (4) were isolated and characterized, where p-2-bmp is 1-((2-(pyridine-2-yl)-1H benzoimidazol-1-yl)methyl)-1H-pyridine and p-2-bmb is 1-((2-(pyridin-2-yl)-1 benzoimidazol-1-yl)methyl)-1H-benzotriazole. Complexes 1 and 2 have binuclear configurations, 3 has a mononuclear structure, and 4has a one-dimensional (1-D) chain skeleton. To evaluate their potential anticancer effects on human carcinoma cells, anti-proliferation, DNA binding and cleavage, and apoptosis elicitation were examined. Compared with complexes 2, 3, and 4, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (MCF7, EC109, SH-SY5Y and QBC939), with SH-SY5Y cells demonstrating the most sensitivity. Therefore, further in-depth investigations were performed using complex 1. Absorption titration experiments, circular dichroism spectroscopic studies, and ethidium bromide displacement assays suggested that complex 1 binds to DNA through intercalation, significantly cleaves supercoiled pBR322 DNA, and inhibits DNA transcription. Cell cycle analysis revealed that SH-SY5Y cells were arrested in the G2/M phase after treatment with complex 1. Membrane permeability analysis and nuclear staining of SH-SY5Y cells showed that complex 1 could induce apoptosis. PMID- 28917447 TI - Cell penetrating peptides to dissect host-pathogen protein-protein interactions in Theileria-transformed leukocytes. AB - One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets. Theileria transformed leukocytes display high PKA activity, but PKA is an enzyme that plays key roles in multiple cellular processes; consequently genetic ablation of kinase activity gives rise to a myriad of confounding phenotypes. By contrast, ablation of a specific kinase-substrate interaction has the potential to give more refined information and we illustrate this here by describing how surgically ablating PKA interactions with BAD gives precise information on the type of glycolysis performed by Theileria-transformed leukocytes. In addition, we provide two other examples of how ablating specific protein-protein interactions in Theileria infected leukocytes leads to precise phenotypes and argue that constrained penetrating peptides have great therapeutic potential to combat infectious diseases in general. PMID- 28917449 TI - Highly potent antiobesity effect of a short-length peptide YY analog in mice. AB - Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[d Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23-36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4 hydroxy-d-proline (d-Hyp)24, isovaline (Iva)25, and gamma-methylleucine (gammaMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[d Hyp24,Iva25,Pya(4)26,Cha27,36,gammaMeLeu28,Lys30,Aib31]PYY(23-36) (31, PYY-1119) at a dose of 0.03mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction. PMID- 28917451 TI - Postinflammatory hyperpigmentation: A comprehensive overview: Epidemiology, pathogenesis, clinical presentation, and noninvasive assessment technique. AB - Postinflammatory hyperpigmentation (PIH) commonly occurs after various endogenous and exogenous stimuli, especially in dark-skinned individuals. PIH is one of the most common complications of procedures performed using laser and other light sources. The severity of PIH is determined by the inherent skin color, degree and depth of inflammation, degree of dermoepidermal junction disruption, inflammatory conditions, and the stability of melanocytes, leading to epidermal and dermal melanin pigment deposition. The depth of melanin pigment is the key factor to predict prognosis and treatment outcome. Epidermal hyperpigmentation fades more rapidly than dermal hyperpigmentation. Various inflammatory disorders can eventually result in PIH. The evaluation of pigmentation using noninvasive tools helps define the level of pigmentation in the skin, pigmentation intensity, and guides therapeutic approaches. This first article in this 2-part series discusses the epidemiology, pathogenesis, etiology, clinical presentation, differential diagnoses, and investigation using noninvasive assessment techniques that objectively determine the details of pigmentation. PMID- 28917450 TI - A novel class of Plasmodial ClpP protease inhibitors as potential antimalarial agents. AB - The prokaryotic ATP-dependent ClpP protease, localized in the relict plastid of malaria parasite, represents a potential drug target. In the present study, we utilized in silico structure-based screening and medicinal chemistry approaches to identify a novel pyrimidine series of compounds inhibiting P. falciparum ClpP protease activity and evaluated their antiparasitic activities. Structure activity relationship indicated that morpholine moiety at C2, an aromatic substitution at N3 and a 4-oxo moiety on the pyrimidine are important for potent inhibition of ClpP enzyme along with antiparasiticidal activity. Compound 33 exhibited potent antiparasitic activity (EC50 9.0+/-0.2MUM), a 9-fold improvement over the antiparasitic activity of the hit molecule 6. Treatment of blood stage P. falciparum cultures with compound 33 caused morphological and developmental abnormalities in the parasites; further, compound 33 treatment hindered apicoplast development indicating the targeting of apicoplast. PMID- 28917452 TI - Postinflammatory hyperpigmentation: A comprehensive overview: Treatment options and prevention. AB - Postinflammatory hyperpigmentation (PIH) occurs after various dermatoses, exogenous stimuli, and dermatologic procedures. The clinical course of PIH is chronic and unpredictable, although the probability of resolution of epidermal hyperpigmentation is better than those of dermal hyperpigmentation. PIH can be prevented or alleviated. When it does occur, the underlying inflammatory conditions should be sought and treated as the first step to reduce the progression of inflammation and PIH (which is an inflammatory consequence). If the inflammatory conditions subsides or there is no evidence of inflammation at the time of diagnosis, the treatments of PIH should be considered as the next step. Understanding the available treatment options helps the physician choose the appropriate treatment for each patient. Having a reproducible model for PIH is essential for the development of treatment modalities. The second article in this 2-part continuing medical education series on PIH specifically addresses the evidence that supports medical and procedural treatments of PIH and other forms of acquired hyperpigmentation. It also describes a PIH model and provides an algorithm for clinical practice along with discussion about the prevention of PIH. PMID- 28917453 TI - Systematic review and meta-analysis of the association between psoriasis and metabolic syndrome. AB - BACKGROUND: Several studies have shown a relationship between psoriasis and metabolic syndrome (MS), but no meta-analysis has been restricted to studies that adjusted for confounders. OBJECTIVE: To determine the association between psoriasis and MS. METHODS: A systematic review and meta-analysis of observational studies on psoriasis and MS in adults was performed from MEDLINE, Scopus, SciELO, Google Scholar, Science Direct, and LILACS from inception to January 2016. We performed a random effects model meta-analysis for those studies reporting adjusted odds ratios (ORs) with 95% confidence intervals (CIs). The subgroup analysis was related to geographic location, diagnosis criteria and risk of bias. RESULTS: In all, 14 papers including a total of 25,042 patients with psoriasis were analyzed. We found that MS was present in 31.4% of patients with psoriasis (OR, 1.42; 95% CI, 1.28-1.65). Middle Eastern studies (in Israel, Turkey, and Lebanon) (OR, 1.76, 95% CI, 0.86-2.67) reported a greater risk for MS than European studies (in Germany, Italy, the United Kingdom, Norway, and Denmark) (OR, 1.40; 95% CI, 1.25-1.55). LIMITATIONS: Few adjusted studies existed, and there was inconsistency between publications. CONCLUSION: Because of the increased risk for MS, clinicians should consider screening patients with psoriasis for metabolic risk factors. PMID- 28917454 TI - A phase 2a, open-label pilot study of the galectin-3 inhibitor GR-MD-02 for the treatment of moderate-to-severe plaque psoriasis. PMID- 28917455 TI - Use of capsule endoscopy to identify lesions suggestive of Crohn's disease in patients with moderate to severe psoriasis. PMID- 28917457 TI - Potential impact of biologics and emerging therapies for psoriasis and atopic dermatitis on future fertility: Reassurance to patients but more data are needed. PMID- 28917456 TI - A cross-sectional study of psoriasis triggers among different ethno-racial groups. PMID- 28917458 TI - Adherence to over-the-counter benzoyl peroxide in patients with acne. PMID- 28917459 TI - Yellow facial papules associated with frontal fibrosing alopecia: A distinct histologic pattern and response to isotretinoin. PMID- 28917460 TI - Clinical and pathologic factors associated with deep transection of biopsies of invasive melanoma. PMID- 28917461 TI - A cross-sectional survey of voriconazole prescribers: Assessing current practice and knowledge of cutaneous side effects. PMID- 28917462 TI - Human papilloma virus expression in immunocompetent patients with actinic keratosis: A case series. PMID- 28917463 TI - Lack of efficacy of apremilast in 9 patients with severe alopecia areata. PMID- 28917464 TI - The majority of patients presenting with vitiligo have a clinical sign of activity. PMID- 28917465 TI - The impact of skin hyperpigmentation and hyperchromia on quality of life: A cross sectional study. PMID- 28917466 TI - An international study of the prevalence of substance use in patients with delusional infestation. PMID- 28917467 TI - Body mass index is negatively associated with the intensity of acute zoster associated pain in Taiwanese: A cross-sectional study. PMID- 28917468 TI - Sex and leadership in academic dermatology: A nationwide survey. PMID- 28917469 TI - Prior authorizations for dermatologic medications: An American Academy of Dermatology survey of US dermatology providers and staff. PMID- 28917470 TI - Medication nonadherence in dermatology: Divergent ethical implications for patient care. PMID- 28917471 TI - Beyond JAAD October 2017: Articles of interest to dermatologists from the nondermatologic literature. PMID- 28917472 TI - "Two-step phototherapy" for treatment-resistant psoriasis on the lower extremities. PMID- 28917473 TI - Recognizing and overcoming phototherapy-induced initiation burn. PMID- 28917474 TI - Dermabrasion in earlobe repair. PMID- 28917475 TI - Interdomal sutures for nasal tip refinement and reduced wound size. PMID- 28917476 TI - Simple technique to avoid unnecessary Burow triangles. PMID- 28917477 TI - Using a slit knife to facilitate Mohs micrographic surgery in irregularly shaped areas. PMID- 28917478 TI - Reply to "Clinical and pathologic factors associated with subclinical spread of invasive melanoma": Statistical and methodological issues. PMID- 28917479 TI - Reply to: "Statistical and methodological issues". PMID- 28917480 TI - Prognosis and management of Stevens-Johnson syndrome and toxic epidermal necrolysis. PMID- 28917481 TI - Reply to: "Prognosis and management of Stevens-Johnson syndrome and toxic epidermal necrolysis". PMID- 28917482 TI - Papular eruption in a woman with Down syndrome. PMID- 28917483 TI - Recalcitrant chronic leg ulcer: An indication for patch testing for hydrocolloid dressing. PMID- 28917484 TI - Use of Wood's lamp to diagnose progressive macular hypomelanosis. PMID- 28917485 TI - Self-Expandable Metal Stent Use to Palliate Malignant Esophagorespiratory Fistulas in 88 Patients. AB - PURPOSE: To identify predictors associated with clinical outcomes (initial clinical failure, stent patency, and survival) after self-expandable metal stent (SEMS) placement for malignant esophagorespiratory fistulas (ERFs). MATERIALS AND METHODS: Using logistic and Cox regression analyses, this study reviewed 88 patients (mean age 59.4 y +/- 8.4; 84 men [95.5%] and 4 women [4.5%]) who underwent fluoroscopic SEMS placement for palliating malignant ERF from January 2000 to December 2016. RESULTS: Technical success was achieved in all patients. Initial clinical success was achieved in 78.4% (69/88; 95% confidence interval [CI], 68.7%-85.7%). Among the 69 patients in whom initial clinical success was achieved, aspiration symptoms recurred in 37.7% (26/69; 95% CI, 27.2%-49.5%). Overall major complication rate was 25.0% (22/88; 95% CI, 17.1%-35.0%). Cumulative stent patency and cumulative survival rates at 1, 3, 6, and 12 months were 72.8%, 38.9%, 32.4%, and 21.6% and 81.4%, 51.9%, 30.5%, and 13.3%, respectively. Stricture of the upper esophagus was an independent predictor of initial clinical failure (odds ratio, 3.760; 95% CI, 1.207-11.811) and shorter stent patency (hazard ratio [HR], 2.036; 95% CI, 1.170-3.544). Initial clinical failure was an independent predictor of shorter survival (HR, 2.902; 95% CI, 1.587-5.305). CONCLUSIONS: SEMS placement offers sufficient short-term relief despite considerable major complications. Stricture of the upper esophagus is an independent predictor of initial clinical failure and shorter stent patency. Initial clinical failure is an independent predictor of shorter survival. PMID- 28917486 TI - Effects of the potential probiotics Bacillus aerophilus KADR3 in inducing immunity and disease resistance in Labeo rohita. AB - The aim of the present study was to evaluate the dietary administration of Bacillus aerophilus KADR3 on enhancing the immunity and disease resistance against Aeromonas hydrophila infection in Labeo rohita. B. aerophilus culture supernatant exhibited antagonistic activity against fish pathogenic bacteria in an agar well diffusion assay. Four fish groups were fed with either of following diets containing different concentrations of B. aerophilus KADR3 (cfu g-1): 0 (control), 1 * 107 (DI), 1 * 108 (DII), and 1 * 109 (DIII) -cfu g-1. Various innate immune parameters were measured at - 3rd and 6th - week post-feeding. At the end of 6th week, fish were challenged intraperitoneally with A. hydrophila and survival percentage was recorded over 10 days post-challenge. Studied immunological parameters viz. serum lysozyme, phagocytosis, serum total protein, respiratory bursts, serum IgM levels, superoxide dismutase and alternative complement pathway activities were significantly enhanced (P < 0.05) in fish groups fed with B. aerophilus KADR3 supplemented diets, with the highest values were observed in DII (108 cfu g-1) fed group. Further, B. aerophilus supplementation at 108 cfu g-1 exhibited highest post-challenge survivability i.e. 72.83%, followed by DIII (64.19%) and DI (41.97%). Our results collectively suggest that B. aerophilus can potentially be used as probiotic strain in aquaculture to enhance the immunity and disease resistance with an optimal dietary supplementation of 108 cfu g-1. PMID- 28917487 TI - Glutamate attenuates lipopolysaccharide-induced oxidative damage and mRNA expression changes of tight junction and defensin proteins, inflammatory and apoptosis response signaling molecules in the intestine of fish. AB - The present study explored the possible preventive effects of dietary glutamate (Glu) on LPS-induced oxidative damage, mRNA expression changes of tight junction (TJ) and defensin proteins, inflammatory and apoptosis response signaling molecules in fish intestine. Young Jian carp were fed five diets supplemental graded levels of Glu (0, 4, 8, 16 and 32 g kg-1 diet) for 63 days. The results indicated that Glu supplementation depressed LPS induced the production of reactive oxygen species (ROS) and severe oxidative damage (lipid peroxidation and protein oxidation) in fish intestine, which was partially due to the increased glutathione (GSH) content and antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione-S-transferase (GST), and glutathione reductase (GR) (P < 0.05). Further investigations indicated that Glu supplementation caused elevation of those antioxidant enzyme activities are related to the up-regulation of corresponding antioxidant enzymes and the related signaling factor Nrf2 mRNA levels (P < 0.05). Meanwhile, Glu pre-treatment significantly suppressed LPS-induced COX-2 and inflammatory cytokines mRNA expression and down-regulated NF-kappaB p65 and MAPK p38 transcription. Furthermore, pre-treatment with Glu prevented LPS induced apoptosis-related gene expression (caspase 3 and 9, P < 0.05). Lastly, Glu supplementation also attenuated LPS induced intestinal barrier function-related gene TJ proteins (ZO 1, occludin1, claudin2, 3, and 7), beta-defensin1 and 3 mRNA expressions decreasing (P < 0.05). Taken together, the present results showed Glu could attenuate LPS induced the oxidative damage by Nrf2 signal pathway and depress LPS induced inflammation response (cytokines, COX-2, NF-kappaB p65, and MAPK p38), apoptosis (caspase3 and 9), and barrier function (ZO-1, occludin1, claudin2, 3 and 7, and beta-defensin 1 and 3)-related gene expression changes of fish intestine. PMID- 28917488 TI - Gene expression regulation of the TLR9 and MyD88-dependent pathways in rock bream against rock bream iridovirus (RBIV) infection. AB - Rock bream iridovirus (RBIV), which is a member of the Megalocytivirus genus, causes severe mass mortalities in rock bream in Korea. To date, the innate immune defense mechanisms of rock bream against RBIV is unclear. In this study, we assessed the expression levels of genes related to TLR9 and MyD88-dependent pathways in RBIV-infected rock bream in high, low or no mortality conditions. In the high mortality group (100% mortality at 15 days post infection (dpi)), high levels of TLR9 and MyD88 expressions (6.4- and 2.4-fold, respectively) were observed at 8 d and then reduced (0.6- and 0.1-fold, respectively) with heavy viral loads at 10 dpi (2.21 * 107/MUl). Moreover, TRAF6, IRF5, IL1beta, IL8, IL12 and TNFalpha expression levels showed no statistical significance until 10 dpi. Conversely, in the low mortality group (28% expected mortality at 35 dpi), TLR9, MyD88 and TRAF6 expression levels were significantly higher than those in the control group at several sampling points until 30 dpi. Higher levels of IRF5, IL1beta, IL8, IL12 and TNFalpha expression were also observed, however, these were not significantly different from those of the control group. In the no mortality group (0% mortality at 40 dpi), significantly higher levels of MyD88 (2 d, 4 d and 40 dpi), TRAF6 (2 dpi), IL1beta (4 dpi) and IL8 (2 d and 4 dpi) expression were observed. In summary, RBIV-infected rock bream induces innate immune response, which could be a major contributing factor to effective fish control over viral transcription. MyD88, TRAF6, IL1beta and IL8-related immune responses were activated in fish survivor condition (low or no mortality group). This is a critical factor for RBIV disease recovery; however, these immune responses did not efficiently respond in fish dead condition (high mortality group). PMID- 28917489 TI - The effects of single or combined administration of galactooligosaccharide and Pediococcus acidilactici on cutaneous mucus immune parameters, humoral immune responses and immune related genes expression in common carp (Cyprinus carpio) fingerlings. AB - The present study was performed to investigate the effects of single or combined administration of galactooligosaccharide (GOS) and Pediococcus acidilactici on cutaneous mucus immune parameters, humoral immune responses and immune related genes expression in common carp (Cyprinus carpio) fingerlings. Carps were fed experimental diets for 8 weeks as follows: non-supplemented (Control), prebiotic diet (10 g/kg GOS), probiotic diet (1 g/kg [0.9 * 107 CFU] lyophilized P. acidilactici) and synbiotic diet (10 GOS in combination with 1 g/kg [0.9 * 107 CFU] lyophilized P. acidilactici). Unlike skin mucus, the serum lysozyme activity showed no significant difference between carps fed supplemented or control diets, however, remarkable elevation of serum ACH50 activity was noticed in carps fed supplemented diet (pro-, pre- and synbiotic diets) compared control group. Besides, feeding on pro-, pre- and synbiotic supplemented diets significantly increased serum and skin mucus total Ig levels. However, no significant difference was observed between treatments and control group in case of skin mucus proteases activity. There was no significant difference between expression levels of intestinal genes of LYZ and IL1b in fish fed on pre- and synbiotic, compared to the control. However, evaluation of TNF-alpha gene expression in the intestine of carps revealed remarkable down-regulation in treated groups (p < 0.05). These results indicated positive effect of supplementation of carp diet with GOS and P. acidilactici on some mucosal or serum immune parameters. PMID- 28917490 TI - An After-School Cultural and Age-Sensitive Nutrition Education Intervention for Elementary Schoolchildren. PMID- 28917491 TI - Strengths and Challenges of the Alaska WIC Breastfeeding Peer Counselor Program: A Qualitative Study of Program Implementation. AB - OBJECTIVE: To explore the implementation of a breastfeeding (BF) peer counselor (BFPC) program with Alaska Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). METHODS: The study used focus groups, surveys, and interviews, with transcripts analyzed in Atlas.ti and survey data summarized in Microsoft Excel. RESULTS: Respondents included 33 interviewed WIC staff and BFPCs, 25 clients in focus groups, and 129 surveyed clients. Common themes included BFPCs' innovative use of texting and online support groups assisting WIC clients' BF success. The BFPCs' knowledge, accessibility, and relatability were identified as positive program elements. Challenges included BFPCs' limited hours, funding, and in-person contact with clients, and confusion about the BFPCs' role. The BFPCs and staff also described unique documentation strategies, BF training, and perceived supports and barriers to WIC clients' BF. CONCLUSIONS AND IMPLICATIONS: The implementation of a BFPC program in Alaska WIC revealed novel documentation and outreach strategies, including texting and online support groups. Findings may be translatable to other peer counseling programs. PMID- 28917492 TI - Aortic root fibroelastoma causing cardiac ischemia. PMID- 28917493 TI - Usefulness of Myocardial Annular Velocity Change During Mental Stress to Predict Cardiovascular Outcome in Patients With Coronary Artery Disease (From the Responses of Mental Stress-Induced Myocardial Ischemia to Escitalopram Treatment Trial). AB - Mental stress-induced myocardial ischemia is common and a prognostic factor of adverse cardiovascular outcomes in patients with coronary artery disease (CAD). The present study aimed at examining associations between mental stress-induced myocardial annular velocity (MAV) and cardiovascular outcome in patients with CAD. MAV, specifically, diastolic early (e'), diastolic late (a'), and systolic (s') velocities were obtained at rest and during mental stress testing in 224 patients with clinically stable CAD. Using Cox regression models, age, sex, and baseline-adjusted mental stress-induced MAV measures were examined as predictors of a priori defined composite event term that comprised all-cause mortality and/or nonfatal cardiovascular events, resulting in an unplanned hospitalization (major adverse cardiovascular events [MACE]). Median follow-up was 4 years. The sample was predominantly male, Caucasian with New York Heart Association functional class I and a mean age of 63 +/- 10.2 years. MS-induced changes in e' (hazard ratio [HR] = .73) and s' (HR = .73) were significant (p <0.05) predictors of MACE, and the change in a' (HR = .74) was marginal (p = 0.05). The pattern of the relation for each MAV measure was such that patients with a greater decrease in e' and/or s' velocity had a higher probability of experiencing an MACE, and the association of the change in a' and MACE was marginal (p = 0.05), but the same tendency. The associations between MS-induced values of e' and a' for MACE were independent of resting levels. Mental stress-induced MAV changes independently predict an adverse cardiovascular outcome in patients with stable CAD. PMID- 28917494 TI - Early Dislodgment and Migration of a Left Atrial Appendage Closure Device. AB - A 68-year-old man underwent pulmonary vein isolation with cryoballoon combined with left atrial appendage closure using a LAmbre device. The device was dislodged and embolized early after implantation with no symptoms, and it was retrieved percutaneously. An early in-hospital check of the device position after implantation is important for early recognition of any possible device-related complication. PMID- 28917496 TI - Erratum in "Relation of Household Income to Incidence of Sudden Unexpected Death in Wake County, North Carolina". PMID- 28917495 TI - Complications Associated With Implantable Cardioverter Defibrillators in Adults With Congenital Heart Disease or Left Ventricular Noncompaction Cardiomyopathy (From the NCDR(r) Implantable Cardioverter-Defibrillator Registry). AB - Patients with childhood heart disease are living longer and entering adulthood, and may undergo implantable cardioverter-defibrillator (ICD) implantation to reduce the risk of sudden death. We evaluated the characteristics of adult patients with congenital heart disease or left ventricular noncompaction cardiomyopathy (LVNC) in the National Cardiovascular Disease Registry ICD Registry and determined ICD-related in-hospital complications. Patients with LVNC or transposition of the great arteries, tetralogy of Fallot, Ebstein's anomaly, atrial septal defect, ventricular septal defect, or common ventricle were identified in the registry. In-hospital complications were compared among different diagnoses using the chi-square test for categorical variables and the F test in analyses of variance for continuous variables. A total of 3,077 patients were identified. The mean age was 48.0 +/- 16.0 years, and 39.9% were female. Single-chamber ICDs were implanted in 25.2%, dual chamber in 41.9%, and cardiac resynchronization in 30.8%. Intraprocedural or postprocedural complications occurred in 70 patients (2.3%); there were 6 in-hospital deaths (0.2%). The most frequent complications were acute lead dislodgments, pneumothorax, and hematomas. Patients with Ebstein's anomaly had the greatest complication rate (8.3%, p = 0.03). The complication rate was 1.55% in single-chamber devices, 1.86% in dual chamber, and 3.5% in cardiac resynchronization (p < 0.001). For initial implants, the complication rate was 2.55%, 1.62% in generator replacements, and 8.77% in lead revisions (p = 0.001). In conclusion, in this large contemporary adult cohort of congenital heart disease and LVNC patients who underwent ICD implant procedures, periprocedural complication rates were low. Lead-related risks predominated. PMID- 28917497 TI - Comparison of Outcome of Possible Versus Definite Infective Endocarditis Involving Prosthetic or Bioprosthetic Heart Valves. AB - The objectives of this study were to describe and compare the clinical characteristics and outcomes of patients with definite and possible infective endocarditis (IE) involving prosthetic heart valve, and to identify prognostic factors for long-term mortality, using data from an unselected cohort of consecutive patients. We studied data from 133 consecutive patients with IE involving prosthetic heart valve seen in an academic institution between 1990 and 2012. Patients were classified according to the modified Duke criteria for IE: patients with possible IE (n = 47, 35%) and patients with definite IE (n = 86, 65%). Overall, 55 patients died over a mean +/- SD follow-up of 3.6 +/- 4.1 years (median 1.8, interquartile range 4.4 years). Patients with definite IE had a higher risk of death (hazard ratio [HR] 2.21, 95% confidence interval [CI] 1.20 to 4.17 p = 0.01). Independent predictors of long-term mortality were increasing age (HR 1.05, 95% CI 1.02 to 1.08, p = 0.002), Staphylococcus aureus infection (HR 3.40, 95% CI 1.00 to 11.76; p = 0.05), infection with unknown microorganism (HR 12.50, 95% CI 2.97 to 52.63; p = 0.0006), and definite IE (HR 8.70, 95% CI 3.55 to 21.28; p <0.0001), whereas infection on pacemaker or defibrillator (HR 0.30, 95%CI 0.10 to 0.87; p = 0.03) was associated with a better prognosis. Patients with definite IE and those with possible IE who underwent surgery had a nonsignificantly better prognosis than their counterparts with no surgery. In conclusion, patients with definite IE (Duke criteria) on a prosthetic heart valve independently had a worse prognosis than those with possible IE. PMID- 28917498 TI - Personalized translational epilepsy research - Novel approaches and future perspectives: Part II: Experimental and translational approaches. AB - Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics, and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. This Part II includes the experimental and translational approaches and a discussion of the future perspectives, while the diagnostic methods, EEG network analysis, biomarkers, and personalized treatment approaches were addressed in Part I [1]. PMID- 28917499 TI - Association of sleep with sudden unexpected death in epilepsy. AB - OBJECTIVE: The objective of this study was to determine the association of sleep with sudden unexpected death in epilepsy (SUDEP). METHODS: We conducted a systematic review and meta-analysis based on literature search from databases PubMed, Web of Science, and Scopus using keywords "SUDEP", or "sudden unexpected death in epilepsy", or "sudden unexplained death in epilepsy". Sudden unexpected death in epilepsy was considered to occur during sleep if the patient was found in bed, if the SUDEP cases were documented as in sleep, or if the patient was found at bedside on the bedroom floor. RESULTS: Circadian pattern was documented in 880 of the 1025 SUDEP cases in 67 studies meeting the inclusion and exclusion criteria. Of the 880 SUDEP cases, 69.3% occurred during sleep and 30.7% occurred during wakefulness. Sudden unexpected death in epilepsy was significantly associated with sleep as compared to wakefulness (P<0.001). In the subgroup of 272 cases in which circadian pattern and age were documented, patients 40years old or younger were more likely to die in sleep than those older than 40years (OR: 2.0; 95% CI=1.0, 3.8; P=0.05). In the subgroup of 114 cases in which both circadian pattern and body position at the time of death were documented, 87.6% (95% CI=81.1%, 94.2%) of patients who died during sleep were in the prone position, whereas 52.9% (95% CI=24.7%, 81.1%) of patients who died during wakefulness were in the prone position. Patients with nocturnal seizures were 6.3 times more likely to die in a prone position than those with diurnal seizures (OR: 6.3; 95% CI=2.0, 19.5; P=0.002). CONCLUSIONS: There is a strong association of SUDEP with sleep, suggesting that sleep is a significant risk factor for SUDEP. Although the risks of SUDEP associated with sleep are unknown and likely multifactorial, the prone position might be an important contributory factor. PMID- 28917500 TI - Economic evaluation of childhood epilepsy in a resource-challenged setting: A preliminary survey. AB - BACKGROUND: Considerable disease variability exists between patients with epilepsy, and the societal costs for epilepsy care are overall high, because of high frequency in the general population especially in children from developing countries. MATERIALS AND METHODS: A cross-sectional study where children with established diagnosis of epilepsy were interviewed using a semi-structured questionnaire. Prevalence-based costs were stratified by patients' sociodemographic characteristics and socioeconomic scores (SES). The 'bottom-up' and 'human capital' approaches were used to generate estimates on the direct and indirect (productivity losses) costs of epilepsy, respectively. All estimates of the financial burden of epilepsy were analyzed from the 'societal perspective' using IBM SPSS statistics software, version 20.0. RESULTS: The study had 103 enrollees with most in the age group of 0-5years (45.6%). Majority (61.3%) belong to the low socioeconomic class (Ogunlesi SES class IV and V) and reside (80.6%) in an urban setting. The total direct and indirect costs per month were ?2,149,965.00 ($8497.88) and ?363,187.80 ($1435.52), respectively. The cost of care per patient per annum was ?292,794.50 ($1157.29), and the total cost for all the patients per year was ?30,157,833.60 ($119,200.92). Investigative procedures are the principal cost drivers (?15,861.17 or $18.15) comprising approximately 58.7% of the total direct costs per patient. CONCLUSIONS: Cost of investigations contributed immensely to the total direct cost of care in our study. With the present economic situation in the country, out-of-pocket payments may contribute significantly to catastrophic expenditures and worsening of secondary treatment gap in children with epilepsy. PMID- 28917502 TI - Fluorescence and magnetic nanocomposite Fe3O4@SiO2@Au MNPs as peroxidase mimetics for glucose detection. AB - In this paper, multifunction nanoparticles (MNPs), Fe3O4@SiO2@Au MNPs, with properties of superparamagnetism, fluorescence and peroxidase-like catalytic activity were synthesized in the aqueous phase. The synthesized composites were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier translation infrared spectrum (FT-IR) and fluorometer. The results show that the multifunctional nanomaterials have good magnetic and fluorescence properties. Then, the mimetic properties of this material were investigated. The as-synthesized Fe3O4@SiO2@Au MNPs exhibited the best catalytic activity for peroxidase substrate 3,3,5,5 tetramethylbenzidine (TMB) at the reaction temperature of 70 degrees C and pH of 3. Compared with free Fe3O4 MNPs and BSA-Au nanoclusters (NCs), the composites have better catalytic activity at higher temperature and lower pH, indicating that Fe3O4@SiO2@Au MNPs can work in more severe environment. In practical application, we have successfully established the colorimetric method for the detection of H2O2 and glucose with the detection range of 1 * 10-6 ~ 4 * 10-5 M and 5 * 10-6 ~ 3.5 * 10-4 M, and the detection limit of 6 * 10-7 M and 3.5 * 10-6 M, respectively. The method was also successfully applied in the detection of real samples. Furthermore, since the fluorescence of Fe3O4@SiO2@Au MNPs was quenched by H2O2, a method for the visual detection of glucose was established. PMID- 28917501 TI - Personalized translational epilepsy research - Novel approaches and future perspectives: Part I: Clinical and network analysis approaches. AB - Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. Part I includes the clinical phenotyping and diagnostic methods, EEG network-analysis, biomarkers, and personalized treatment approaches. In Part II, experimental and translational approaches will be discussed (Bauer et al., 2017) [1]. PMID- 28917503 TI - Food Reluctance of Preschool Children Attending Daycare Centers Is Associated with a Lower Body Mass Index. AB - BACKGROUND: Food reluctance can present as fussiness, picky eating, slowness in eating, and high satiety responsiveness. It can be associated with inadequate weight gain during early childhood. Although a majority of preschoolers attend daycare centers, associations between their eating behaviors at daycare and their body composition have not been studied. OBJECTIVE: Our aim was to develop an estimate of food reluctance and to assess the relationship between food reluctance at daycare and body mass index (BMI) and waist circumference of preschoolers. DESIGN: We conducted a cross-sectional secondary analyses. Food reluctance was estimated using weighted digital plate waste analysis. Intra rater, inter-rater, and test-retest reliability and convergent validity of the food reluctance score were tested. The food reluctance score was then compared to preschool children's BMI and waist circumference. PARTICIPANTS/SETTING: Participants included 309 children aged 3 to 5 years in 24 daycare centers across the Canadian province of New Brunswick. MAIN OUTCOME MEASURES: Preschool children's waist circumference and age-adjusted BMI derived from objectively measured height and weight were analyzed. STATISTICAL ANALYSES PERFORMED: Intraclass correlations were used to determine the reliability of the new estimate. Spearman correlation was used to compare the estimate with parental report of food reluctance. Multivariate linear regressions were used to examine the relationship between food reluctance and waist circumference and age-adjusted BMI. RESULTS: The estimated food reluctance score demonstrated excellent inter- and intra-rater reliability (intraclass correlation>0.97; P<0.0001) and good test retest reliability (intraclass correlation=0.72; P<0.0001). It also provided evidence of convergent validity through correlation with reluctance-related subscales of the Child Eating Behavior Questionnaire (rho=.53, P<0.0001). Greater demonstration of food reluctance at the daycare center was associated with a lower age-adjusted BMI (adjusted beta -1.41; 95% CI -.15 to -2.67), but was not associated with children's waist circumference (adjusted beta -.60; 95% CI -2.06 to .86). CONCLUSIONS: Signs of food reluctance can be observed in daycare and relate to lower BMI among preschoolers. PMID- 28917504 TI - Update on the Risk of Motor Vehicle Collision or Driving Impairment with Dementia: A Collaborative International Systematic Review and Meta-Analysis. AB - Guidelines that physicians use to assess fitness to drive for dementia are limited in their currency, applicability, and rigor of development. Therefore, we performed a systematic review to determine the risk of motor vehicle collisions (MVCs) or driving impairment caused by dementia, in order to update international guidelines on driving with dementia. Seven literature databases (MEDLINE, CINAHL, Embase, etc.) were searched for all research studies published after 2004 containing participants with mild, moderate, or severe dementia. From the retrieved 12,860 search results, we included nine studies in this analysis, involving 378 participants with dementia and 416 healthy controls. Two studies reported on self-/informant-reported MVC risk, one revealing a four-fold increase in MVCs per 1,000 miles driven per week in 3 years prior, and the other showing no statistically significant increase over the same time span. We found medium to large effects of dementia on driving abilities in six of the seven recent studies that examined driving impairment. We also found that persons with dementia were much more likely to fail a road test than healthy controls (RR: 10.77, 95% CI: 3.00-38.62, z = 3.65, p < 0.001), with no significant heterogeneity (chi2 = 1.50, p = 0.68, I2 = 0%) in a pooled analysis of four studies. Although the limited data regarding MVCs are equivocal, even mild stages of dementia place patients at a substantially higher risk of failing a performance-based road test and of demonstrating impaired driving abilities on the road. PMID- 28917506 TI - The plasmalogen precursor analog PPI-1011 reduces the development of L-DOPA induced dyskinesias in de novo MPTP monkeys. AB - The gold standard therapy for Parkinson's disease (PD), L-3,4 dihydroxyphenylalanine (L-DOPA), induces dyskinesias in the majority of patients after years of treatment. Ethanolamine plasmalogens (PlsEtn) play critical roles in membrane structure mediated functions and as a storage depot of polyunsaturated fatty acids such as docosahexaenoic acid. We previously showed that a PlsEtn precursor PPI-1011 reduced already established L-DOPA-induced dyskinesias (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned monkeys as a PD model. We hypothesize that development of LID can be prevented with a PPI-1011 treatment in de novo MPTP-lesioned monkeys. MPTP-lesioned monkeys were treated once daily for 28days with either L-DOPA or L-DOPA+PPI-1011 (25mg/kg). The antiparkinsonian effect of L-DOPA was maintained throughout the treatment period in MPTP-lesioned monkeys treated with L-DOPA alone and L DOPA+PPI-1011. Over the 28days of treatment, the mean dyskinesia score increased in L-DOPA-treated monkeys whereas this increase was significantly less in the L DOPA+PPI-1011 group. This was followed by a washout period of 2 weeks of both experimental groups without treatment. Then both groups were administered once during week 7 and twice during week 8 with L-DOPA with behavioral measures recorded on treatment days. MPTP monkeys of both experimental groups administered L-DOPA in experimental week 7 showed reduced LID. During week 8, the L-DOPA group showed increased LID whereas LID remained low in the group previously treated with L-DOPA+PPI-1011. The present results suggest that PPI-1011 can prevent/delay the development of LID while maintaining the antiparkinsonian activity of L-DOPA. PMID- 28917505 TI - Association of Self-Reported Discrimination and Suicide Ideation in Older Chinese Americans. AB - OBJECTIVE: This study examines racial discrimination as a potential novel risk factor for suicide ideation among older Chinese Americans. DESIGN: In a cross sectional analysis, this study drew on data collected in the Population-based Study of Chinese Elderly in Chicago on Chinese older adults age 60 + in the Greater Chicago area (N = 3,157). Thirty-day suicide ideation was a dichotomous variable, derived from items of the Physical Health Questionnaire and the Geriatric Mental State Examination-Version A. Self-reported discrimination was dichotomously coded, based on the Experiences of Discrimination instrument, which asks respondents whether they have ever experienced discrimination in nine situations because of their race/ethnicity/color. RESULTS: About 4.1% of the sample reported 30-day suicide ideation and 21.5% reported discrimination. Self reported discrimination was significantly associated with suicide ideation before and after adjusting for covariates including sociodemographic characteristics; neuroticism; social relationships; and physical, cognitive and mental health. In the fully adjusted model, those who reported discrimination had 1.9 times higher odds (OR: 1.9; 95% CI: 1.18-3.08; Wald chi2 = 6.9, df = 1, p = 0.01) of suicide ideation than those who did not. CONCLUSION: Chinese American seniors who reported discrimination had an almost twofold greater odds of 30-day suicide ideation compared with those who did not. Clinicians need to recognize the impact of discrimination on ethnic minority elders. For those who report experiencing discrimination, assessment of suicide risk may be necessary. Efforts to promote civil rights and reduce discrimination may also be a form of primary prevention of suicide. PMID- 28917507 TI - A facile gold nanoparticle-based ELISA system for detection of osteopontin in saliva: Towards oral cancer diagnostics. AB - In the current study, we emphasize that osteopontin is overexpressed in oral squamous cell carcinoma. Overexpression of osteopontin levels was confirmed by mRNA quantification studies and immunohistochemistry analysis. Based on this, a gold nanoparticle-based ELISA system was developed for non-invasive osteopontin detection. The incorporation of AuNRs (Gold nanorods) or AuNSs (Gold nanospheres) in the conventional ELISA improved the sensitivity of analyses. A considerably lowered detection limit in case of AuNR (detection limit: 0.02ngmL-1) and AuNS (detection limit: 0.03ngmL-1) modified assay was obtained as compared to commercially available OPN ELISA kit (detection limit: 0.14ngmL-1). The modified ELISA had a wide linear detection range (0.31-20ngmL-1), good reproducibility, and specificity against the tested interferents in the saliva. Finally, the nanoELISA was validated with osteopontin spiked in artificial and normal saliva samples and observed to show good recovery (95.4-97.85%), which indicates the application potential of the developed kit for real sample analysis. PMID- 28917509 TI - Transfemoral Implantation of a Balloon-Expandable Transcatheter Valve in a Rigid Mitral Annuloplasty Ring Optimized by Post-Dilatation. PMID- 28917510 TI - Subacute Massive Pulmonary Thromboembolism: A Rare Delayed Complication After Radiofrequency Ablation. PMID- 28917508 TI - Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4. AB - RATIONALE: Hydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. OBJECTIVE: We investigated the role of H2O2 in activating insulin-dependent changes in cardiac myocyte metabolic and inotropic pathways. The sources of insulin-dependent H2O2 generation were also studied. METHODS AND RESULTS: In addition to the canonical role of insulin in modulating cardiac metabolic pathways, we found that insulin also inhibited beta adrenergic-induced increases in cardiac contractility. Catalase and NADPH oxidase (NOX) inhibitors blunted activation of insulin-responsive kinases Akt and mTOR and attenuated beta adrenergic receptor-mediated responses. These insulin responses were lost in a mouse model of type 2 diabetes, suggesting a role for these H2O2-dependent pathways in the diabetic heart. The H2O2-sensitive fluorescent biosensor HyPer revealed rapid increases in cytosolic and caveolar H2O2 concentrations in response to insulin treatment, which were blocked by NOX inhibitors and attenuated in NOX2 KO and NOX4 KO mice. In NOX2 KO cardiac myocytes, insulin mediated phosphorylation of Akt and mTOR was blocked, while these responses were unaffected in cardiac myocytes from NOX4 KO mice. In contrast, insulin's effects on contractility were lost in cardiac myocytes from NOX4 KO animals but were retained in NOX2 KO mice. CONCLUSIONS: These studies identify a proximal point of bifurcation in cardiac insulin signaling through the simultaneous activation of both NOX2 and NOX4. Each NOX isoform generates H2O2 in cardiac myocytes with distinct time courses, with H2O2 derived from NOX2 augmenting Akt-dependent metabolic effects of insulin, while H2O2 from NOX4 blocks beta adrenergic increases in inotropy. These findings suggest that insulin resistance in the diabetic heart may lead to potentially deleterious potentiation of beta adrenergic responses. PMID- 28917511 TI - Successful Percutaneous Transcatheter Angioplasty of Radial Artery in Thromboangiitis Obliterans (Buerger's Disease). PMID- 28917512 TI - Grabbing the Transcatheter Valve Skirt: Bail-Out Technique for Valve Embolization During Valve-in-Valve Transcatheter Mitral Valve Replacement. PMID- 28917513 TI - Frail Elderly, the Ideal Patients for MitraClip. PMID- 28917514 TI - Routine Use of Embolic Protection During Transcatheter Aortic Valve Replacement. PMID- 28917515 TI - Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement Significantly Reduces Death and Stroke Compared With Unprotected Procedures. AB - OBJECTIVES: The aim of this study was to evaluate the impact of cerebral embolic protection on stroke-free survival in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Imaging data on cerebral embolic protection devices have demonstrated a significant reduction in number and volume of cerebral lesions. METHODS: A total of 802 consecutive patients were enrolled. The Sentinel cerebral embolic protection device (Claret Medical Inc., Santa Rosa, California) was used in 34.9% (n = 280) of consecutive patients. In 65.1% (n = 522) of patients TAVR was performed in the identical setting except without cerebral embolic protection. Neurological follow-up was done within 7 days post procedure. The primary endpoint was a composite of all-cause mortality or all stroke according to Valve Academic Research Consortium-2 criteria within 7 days. Propensity score matching was performed to account for possible confounders. RESULTS: Both filters of the device were successfully positioned in 280 of 305 (91.8%) consecutive patients. With use of cerebral embolic protection rate of disabling and nondisabling stroke was significantly reduced from 4.6% to 1.4% (p = 0.03; odds ratio: 0.29, 95% confidence interval: 0.10 to 0.93) in the propensity-matched population (n = 560). The primary endpoint occurred significantly less frequently, with 2.1% (n = 6 of 280) in the protected group compared with 6.8% (n = 19 of 280) in the control group (p = 0.01; odds ratio: 0.30; 95% confidence interval: 0.12 to 0.77). In multivariable analysis Society of Thoracic Surgeons score for mortality (p = 0.02) and TAVR without protection (p = 0.02) were independent predictors for the primary endpoint. CONCLUSIONS: In patients undergoing TAVR use of a cerebral embolic protection device demonstrated a significant higher rate of stroke-free survival compared with unprotected TAVR. PMID- 28917516 TI - Impact of Frailty on Outcomes in Patients Undergoing Percutaneous Mitral Valve Repair. AB - OBJECTIVES: The aim of this study was to describe the impact of frailty in patients undergoing percutaneous mitral valve repair (PMVR). BACKGROUND: Frailty is common in elderly patients and those with comorbidities and is associated with adverse prognosis. METHODS: Frailty according to the Fried criteria was assessed in consecutive patients admitted for PMVR. Associations of frailty with 6-week (device success, changes in 6-min walking distance and Minnesota Living With Heart Failure Questionnaire and Short Form 36 physical and mental component scores, and improvement >=1 New York Heart Association functional class) and long term outcomes during a median follow-up period of 429 days were examined. RESULTS: Of 213 patients admitted for PMVR (median age 78 years; age range 50 to 95 years; 57.3% men), 45.5% were classified as frail. Compared with nonfrail patients, frail patients had a similar device success rate (81.4% vs. 84.5%; p = 0.56) and improvement in 6-min walking distance, New York Heart Association functional class, and Short Form-36 scores but a more pronounced improvement in Minnesota Living With Heart Failure Questionnaire score (mean change -15.9 vs. 11.2 points; p = 0.002). Mortality at 6 weeks was significantly higher in frail (8.3%) compared with nonfrail (1.7%) patients (p = 0.03). Hazards of death (hazard ratio: 3.06; 95% confidence interval: 1.54 to 6.07; p = 0.001) and death or heart failure decompensation (hazard ratio: 2.03; 95% confidence interval: 1.22 to 3.39; p = 0.007) were significantly increased in frail patients during long-term follow-up, which did not change relevantly after adjustment for European System for Cardiac Operative Risk Evaluation score and N-terminal pro brain natriuretic peptide level. CONCLUSIONS: PMVR can be performed with equal efficacy and is associated with at least similar short-term functional improvement in frail patients. These results support the continued use of PMVR in frail elderly patients with the goal of palliation of heart failure symptoms and improvement in quality of life. PMID- 28917517 TI - Delayed Left Main Coronary Artery Obstruction After Radiofrequency-Induced Coronary Dissection and Spasm: Insights From Optical Frequency-Domain Imaging and Intravascular Ultrasound Imaging. PMID- 28917518 TI - Genome stability of programmed stem cell products. AB - Inherited and acquired genomic abnormalities are known to cause genetic diseases and contribute to cancer formation. Recent studies demonstrated a substantial mutational load in mouse and human embryonic and induced pluripotent stem cells (ESCs and iPSCs). Single nucleotide variants, copy number variations, and larger chromosomal abnormalities may influence the differentiation capacity of pluripotent stem cells and the functionality of their derivatives in disease modeling and drug screening, and are considered a serious risk for cellular therapies based on ESC or iPSC derivatives. This review discusses the types and origins of different genetic abnormalities in pluripotent stem cells, methods for their detection, and the mechanisms of development and enrichment during reprogramming and culture expansion. PMID- 28917519 TI - Endoscopic or arthroscopic iliopsoas tenotomy for iliopsoas impingement following total hip replacement. A prospective multicenter 64-case series. AB - INTRODUCTION: Impingement between the acetabular component and the iliopsoas tendon is a cause of anterior pain after total hip replacement (THR). Treatment can be non-operative, endoscopic or arthroscopic, or by open revision of the acetabular component. Few studies have assessed these options. The present study hypothesis was that endo/arthroscopic treatment provides rapid pain relief with a low rate of complications. METHODS: A prospective multicenter study included 64 endoscopic or arthroscopic tenotomies for impingement between the acetabular component and the iliopsoas tendon, performed in 8 centers. Mean follow-up was 8months, with a minimum of 6months and no loss to follow-up. Oxford score, patient satisfaction, anterior pain and iliopsoas strength were assessed at last follow-up. Complications and revision procedures were collated. Forty-four percent of patients underwent rehabilitation. RESULTS: At last follow-up, 92% of patients reported pain alleviation. Oxford score, muscle strength and pain in hip flexion showed significant improvement. The complications rate was 3.2%, with complete resolution. Mean hospital stay was 0.8 nights. In 2 cases, arthroscopy revealed metallosis, indicating revision of the acetabular component. The only predictive factor was acetabular projection on oblique view. Rehabilitation significantly improved muscle strength. CONCLUSION: Endoscopic or arthroscopic tenotomy for impingement between the acetabular component and the iliopsoas tendon following THR significantly alleviated anterior pain in more than 92% of cases. The low complications rate makes this the treatment of choice in case of failure of non-operative management. Arthroscopy also reorients diagnosis in case of associated joint pathology. Projection of the acetabular component on preoperative oblique view is the most predictive criterion, guiding treatment. PMID- 28917520 TI - Short-term complications in intra- and extra-articular anterior cruciate ligament reconstruction. Comparison with the literature on isolated intra-articular reconstruction. A multicenter study by the French Arthroscopy Society. AB - INTRODUCTION: Lateral tenodesis (LT) is performed to limit the risk of iterative tear following anterior cruciate ligament (ACL) reconstruction in at-risk patients. By adding an extra procedure to isolated ACL graft, LT reconstruction increases operating time and may complicate postoperative course. The objective of the present study was to evaluate the rate of early complications. The study hypothesis was that associating ALL reconstruction to ACL reconstruction does not increase the complications rate found with isolated ACL reconstruction. MATERIAL AND METHODS: A prospective multicenter study included 392 patients: 70% male; mean age, 29.9 years; treated by associated ACL and LT reconstruction. All adverse events were inventoried. RESULTS: Mean hospital stay was 2 days, with 46% day-surgery. Walking was resumed at a mean 27 days, with an advantage for patients treated by the hamstring technique. The early postoperative complications rate was 12%, with 1.7% specifically implicating LT reconstruction: pain, hematoma, stiffness in flexion and extension, and infection. There was a 5% rate of surgical revision during the first year, predominantly comprising arthrolysis for extension deficit. The 1-year recurrence rate was 2.8%. DISCUSSION: The complications rate for combined intra- and extra-articular reconstruction was no higher than for isolated intra-articular ACL reconstruction, with no increase in infection or stiffness rates. The rate of complications specific to ALL reconstruction was low, at 1.7%, and mainly involved fixation error causing lateral soft-tissue impingement. LEVEL OF EVIDENCE: IV, prospective multicenter study. PMID- 28917521 TI - Midterm results of combined intra- and extra-articular ACL reconstruction compared to historical ACL reconstruction data. Multicenter study of the French Arthroscopy Society. AB - INTRODUCTION: During anterior cruciate ligament (ACL) reconstruction procedures, anterolateral reconstruction (ALR) can also be performed to improve the knee's rotational stability. However, the effectiveness of this supplemental technique and its impact on the risk of retears and on the onset of secondary degenerative changesare controversial. HYPOTHESIS: ALR improves control over the pivot shift, reduces the retear risk and delays the appearance of secondary degenerative lesions. MATERIAL AND METHODS: Clinical examination, knee laxity measurements and X-ray evaluations were done in 478 patients with more than 3years' follow-up after combined ACL and ALR from 11 participating hospitals. The mean patient age at the time of surgery was 28years. Eighty-eight percent of the patients participated in pivot sports and 45% were competitive athletes. The findings of this study were compared to historical isolated ACL reconstruction data. RESULTS: The average follow-up was 6.8years. No detectable pivot shift was found in 83% of patients, while 12.8% of patient had a smooth glide. The side-to-side difference in anteroposterior knee laxity with maximum manual force was less than 3mm in 66% of patients and less than 5mm in 95%. The retear rate was 5.4%, with half of these patients undergoing revision ACL surgery. Secondary meniscus damage requiring surgery occurred in 6.3% of patients; the radiological osteoarthritis rate was 17.5%. DISCUSSION: When compared to historical ACL reconstruction data, combined intra- and extra-articular reconstruction does not increase the complication rate. At a mean follow-up of 6.8years, it provides better control over the pivot shift along with a low retear rate and low occurrence of secondary meniscus injuries. LEVEL OF EVIDENCE: IV, multicenter study. PMID- 28917522 TI - Does physical activity change following hip and knee replacement? Matched case control study evaluating Physical Activity Scale for the Elderly data from the Osteoarthritis Initiative. AB - OBJECTIVES: To determine whether physical activity measured using the Physical Activity Scale for the Elderly (PASE), changes during the initial 24 months post total hip (THR) or knee replacement (TKR), and how this compares to a matched non arthroplasty cohort. DESIGN: Case-controlled study analysis of a prospectively collected dataset. SETTING: USA community-based. PARTICIPANTS: 116 people post THR, 105 people post-TKR compared to 663 people who had not undergone THR or TKR, or had hip or knee osteoarthritis. Cohorts were age-, gender- and BMI-matched. MAIN OUTCOME MEASURES: Physical activity assessed using the 12-item PASE at 12 and 24 months post operatively. RESULTS: There was no significant difference in total PASE score between pre-operative to 12 months (mean: 136 vs 135 points; p=0.860) or 24 months following THR (mean: 136 vs 132 points; p=0.950). Whilst there was no significant difference in total PASE score from pre-operative to 12 months post-TKR (126 vs 121 points; p=0.930), by 24 months people following TKR reported significantly greater physical activity (126 vs 142 points; p=0.040). There was no statistically significant difference in physical activity between the normative matched and THR (p>=0.140) or TKR (p>=0.060) cohorts at 12 or 24 months post joint replacement. CONCLUSIONS: Physical activity is not appreciably different to pre-operative levels at 12 or 24 months post-THR, but was greater at 24 months following TKR. Health promotion strategies are needed to encourage greater physical activity participation following joint replacement, and particularly targeting those who undergo THR. PMID- 28917523 TI - Medium term effects of kinesio taping in patients with chronic non-specific low back pain: a randomized controlled trial. AB - BACKGROUND: Kinesio taping is a commonly used intervention for patients with chronic low back pain. However, the medium term effects of kinesio taping in these patients are unknown. OBJECTIVE: To investigate the effectiveness of kinesio taping in patients with chronic low back pain after 6 months from randomization. METHODS: This was a randomized controlled trial with a 6 months follow up. One hundred and forty eight participants were randomly assigned to the experimental (kinesio taping with skin convolutions) or control (kinesio taping without convolutions-Sham Taping) group. Participants from both groups had the tape reapplied twice a week for four weeks. The outcomes were pain, disability and global impression of recovery after 6 months. RESULTS: One participant was lost to follow up in the experimental group (n=73, response rate 99%) and two in the control group (n=72, response rate 97%). After 6 months there were no statistically significant between-group differences in pain intensity (between group difference -0.8 points, 95% CI -1.7 to 0.2), global impression of recovery (0.4, -0.7 to 1.5), or disability (-1.1, -3.0 to 0.7). CONCLUSION: Four weeks of kinesio taping treatment was no better than sham taping for patients with chronic low back pain, at 6 months follow-up. Trial Registration Number (http://www.ensaiosclinicos.gov.br/): RBR-7ggfkv (Brazilian Registry of Clinical Trials). PMID- 28917525 TI - "Y" Not? PMID- 28917524 TI - Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channel. AB - Tremor dominant Kyoto (Trdk) is an autosomal dominant mutation that appeared in F344/NSlc rats mutagenized with N-ethyl-N-nitrosourea (ENU). In this study, we characterized and genetically analyzed F344-Trdk/+ heterozygous rats. The rats exhibited a tremor that was especially evident around weaning but persisted throughout life. The tremors of F344-Trdk/+ rats were attenuated by drugs effective against essential tremor (ET) but not drugs used to treat Parkinson's disease-related tremor, indicating that the pharmacological phenotype of F344 Trdk/+ rats was similar to human ET. Using positional candidate approach, we identified the Trdk mutation as a missense substitution (c. 866T>A, p. I289N) in Kcnn2, which encodes the SK2 subunit of the small-conductance Ca2+-activated K+ channel. In vitro electrophysiological studies revealed that the I289N mutation diminished SK2 channel activity. These findings demonstrate that F344-Trdk/+ rats represent a novel model of ET, and strongly suggest that Kcnn2 is the causative gene for the tremor phenotype in F344-Trdk/+ rats. PMID- 28917526 TI - Who Makes the Best Martini? PMID- 28917528 TI - Correction. PMID- 28917527 TI - Back to the Basics: Making the Bovine Pericardial Patch "Great" Again. PMID- 28917529 TI - Bronchoprotective effect of deep inspirations in cough variant asthma: A distinguishing feature in the spectrum of airway disease? AB - PURPOSE: To assess the effect of deep inspirations (DIs) on airway behaviour in individuals with classic asthma (CA), cough variant asthma (CVA), and methacholine (MCh)-induced cough but normal airway sensitivity (COUGH) during bronchoprovocation. METHODS: Twenty-five adults (18 female; 44.8 +/- 12.3 years (Mean +/- SD); n = 9 CA, n = 9 CVA, and n = 7 COUGH) completed two single-dose MCh challenges, with and without DIs. Bronchoprotection was assessed by comparing changes in bronchoconstriction (FEV1, FVC, FEV1/FVC, FEF50, FEF25-75), gas trapping (RV, RV/TLC) and impulse oscillometry (IOS) measurements. RESULTS: The% changes in FEV1 with and without DIs were not significantly different within any group. Decreases in FEF50 and FEF25-75 were greater in CA (p = 0.041 and p = 0.029), decreases in FVC (% predicted) and FEV1/FVC(%) were less in CVA (p = 0.048 and p = 0.010), and increases in RV (L) and RV/TLC (% predicted) were less in COUGH (p = 0.007 and p = 0.028), respectively. No differences in IOS measurements were noted. CONCLUSIONS: DIs triggered bronchoconstriction in CA, bronchoprotection in CVA, and prevented gas trapping in COUGH. PMID- 28917530 TI - Overcoming key biological barriers to cancer drug delivery and efficacy. AB - Poor delivery efficiency continues to hamper the effectiveness of cancer therapeutics engineered to destroy solid tumors using different strategies such as nanocarriers, targeting agents, and matching treatments to specific genetic mutations. All contemporary systemic anti-cancer agents are dependent upon passive transvascular mechanisms for their delivery into solid tumors. The therapeutic efficacies of our current drug arsenal could be significantly improved with an active delivery strategy. Here, we discuss how drug delivery and therapeutic efficacy are greatly hindered by barriers presented by the vascular endothelial cell layer and by the aberrant nature of tumor blood vessels in general. We describe mechanisms by which molecules cross endothelial cell (EC) barriers in normal tissues and in solid tumors, including paracellular and transcellular pathways that enable passive or active transport. We also discuss specific obstacles to drug delivery that make solid tumors difficult to treat, as well strategies to overcome them and enhance drug penetration. Finally, we describe the caveolae pumping system, a promising active transport alternative to passive drug delivery across the endothelial cell barrier. Each strategy requires further testing to define its therapeutic applicability and clinical utilities. PMID- 28917531 TI - Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium. AB - The skin is an attractive organ for immunization due to the presence of a large number of epidermal and dermal antigen-presenting cells. Hollow microneedles allow for precise and non-invasive intradermal delivery of vaccines. In this study, ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles with and without TLR3 agonist poly(I:C) were prepared and administered intradermally by hollow microneedles. The capacity of the PLGA nanoparticles to induce a cytotoxic T cell response, contributing to protection against intracellular pathogens, was examined. We show that a single injection of OVA loaded PLGA nanoparticles, compared to soluble OVA, primed both adoptively transferred antigen-specific naive transgenic CD8+ and CD4+ T cells with markedly high efficiency. Applying a triple immunization protocol, PLGA nanoparticles primed also endogenous OVA-specific CD8+ T cells. Immune response, following immunization with in particular anionic PLGA nanoparticles co-encapsulated with OVA and poly(I:C), provided protection against a recombinant strain of the intracellular bacterium Listeria monocytogenes, secreting OVA. Taken together, we show that PLGA nanoparticle formulation is an excellent delivery system for protein antigen into the skin and that protective cellular immune responses can be induced using hollow microneedles for intradermal immunizations. PMID- 28917532 TI - Effects of tumor microenvironments on targeted delivery of glycol chitosan nanoparticles. AB - In cancer theranostics, the main strategy of nanoparticle-based targeted delivery system has been understood by enhanced permeability and retention (EPR) effect of macromolecules. Studies on diverse nanoparticles provide a better understanding of different EPR effects depending on their structure, physicochemical properties, and chemical modifications. Recently the tumor microenvironment has been considered as another important factor for determining tumor-targeted delivery of nanoparticles, but the correlation between EPR effects and tumor microenvironment has not yet been fully elucidated. Herein, ectopic subcutaneous tumor models presenting different tumor microenvironments were established by inoculation of SCC7, U87, HT29, PC3, and A549 cancer cell lines into athymic nude mice, respectively. In the five different types of tumor-bearing mice, tumor targeted delivery of self-assembled glycol chitosan nanoparticles (CNPs) were comparatively evaluated to identify the correlation between the tumor microenvironments and targeted delivery of CNPs. As a result, neovascularization and extents of intratumoral extracellular matrix (ECM) were both important in determining the tumor targeted delivery of CNPs. The EPR effect was maximized in the tumors which include large extent of angiogenic blood vessels and low intratumoral ECM content. This comprehensive study provides substantial evidence that the EPR effects based tumor-targeted delivery of nanoparticles can be different depending on the tumor microenvironment in individual tumors. To overcome current limitations in clinical nanomedicine, the tumor microenvironment of the patients and EPR effects in clinical tumors should also be carefully studied. PMID- 28917533 TI - Nanoparticles of a polyaspartamide-based brush copolymer for modified release of sorafenib: In vitro and in vivo evaluation. AB - In this paper, we describe the preparation of polymeric nanoparticles (NPs) loaded with sorafenib for the treatment of hepatocellular carcinoma (HCC). A synthetic brush copolymer, named PHEA-BIB-ButMA (PBB), was synthesized by Atom Trasnfer Radical Polymerization (ATRP) starting from the alpha-poly(N-2 hydroxyethyl)-d,l-aspartamide (PHEA) and poly butyl methacrylate (ButMA). Empty and sorafenib loaded PBB NPs were, then, produced by using a dialysis method and showed spherical morphology, colloidal size, negative zeta potential and the ability to allow a sustained sorafenib release in physiological environment. Sorafenib loaded PBB NPs were tested in vitro on HCC cells in order to evaluate their cytocompatibility and anticancer efficacy if compared to free drug. Furthermore, the enhanced anticancer effect of sorafenib loaded PBB NPs was demonstrated in vivo by using a xenograft model, by first allowing Hep3B cells to grow subcutaneously into nude mice and then administering sorafenib as free drug or incorporated into NPs via intraperitoneal injection. Finally, in vivo biodistribution studies were performed, showing the ability of the produced drug delivery system to accumulate in a significant manner in the solid tumor by passive targeting, thanks to the enhanced permeability and retention effect. PMID- 28917534 TI - Modeling the modified drug release from curved shape drug delivery systems - Dome Matrix(r). AB - The controlled drug release from hydrogel-based drug delivery systems is a topic of large interest for research in pharmacology. The mathematical modeling of the behavior of these systems is a tool of emerging relevance, since the simulations can be of use in the design of novel systems, in particular for complex shaped tablets. In this work a model, previously developed, was applied to complex shaped oral drug delivery systems based on hydrogels (Dome Matrix(r)). Furthermore, the model was successfully adopted in the description of drug release from partially accessible Dome Matrix(r) systems (systems with some surfaces coated). In these simulations, the erosion rate was used asa fitting parameter, and its dependence upon the surface area/volume ratio and upon the local fluid dynamics was discussed. The model parameters were determined by comparison with the drug release profile from a cylindrical tablet, then the model was successfully used for the prediction of the drug release from a Dome Matrix(r) system, for simple module configuration and for module assembled (void and piled) configurations. It was also demonstrated that, given the same initial S/V ratio, the drug release is independent upon the shape of the tablets but it is only influenced by the S/V evolution. The model reveals itself able to describe the observed phenomena, and thus it can be of use for the design of oral drug delivery systems, even if complex shaped. PMID- 28917535 TI - Selective manipulation of superparamagnetic nanoparticles for product purification and microfluidic diagnostics. AB - The needs of scalable product purification as well as the demand for sensitive diagnostics for highly dilute entities can be addressed with the utilization of tailored superparamagnetic nanoparticles. Recent developments have led to more efficient fluidic systems at different scales with suspended nanoparticles or nanoparticle aggregates. However, magnetic nanoparticle systems differ widely in properties and their applications are characterized by very specific challenges. This review summarizes advances in the synthesis of superparamagnetic particles and displays states and trends in research making use of these particles in biotechnological downstream processing and in biosensing. PMID- 28917536 TI - Birth outcomes following immunization of pregnant women with pandemic H1N1 influenza vaccine 2009-2010. AB - BACKGROUND: Following the H1N1 influenza pandemic in 2009, pregnant women were recommended to receive both seasonal (TIV) and H1N1 influenza vaccines. This study presents incidence of adverse birth and pregnancy outcomes among a population of pregnant women immunized with TIV and H1N1 vaccines at Kaiser Permanente Northern California during 2009-2010. METHODS: We telephone surveyed pregnant Kaiser Permanente Northern California members to assess non-medically attended reactions following H1N1, TIV or both vaccines during 2009-2010 (n=5365) in a separate study. Here we assessed preterm birth (<37weeks), very preterm birth (<32weeks), low birth weight (<2500 g, LBW), very low birth weight (<1500g), small for gestational age, spontaneous abortions, stillbirths and congenital anomalies among this cohort by comparing incidence and 95% confidence intervals between the following immunization groups: TIV only, H1N1 only, H1N1 prior to TIV immunization, TIV prior to H1N1 and both immunizations given at the same time. RESULTS: Results did not vary significantly between groups. Comparing H1N1 with TIV, incidence were similar for preterm births (6.37vs 6.28/100 births), very preterm births (5.30vs 8.29/1000 births), LBW (4.19vs 2.90/100 births), very LBW (4.54vs 5.52/1000 births), small for gestational age (9.99vs 9.24/1000 births), spontaneous abortion (7.10vs 6.83/1000 pregnancies), stillbirths (7.10vs 4.57/1000 pregnancies), and congenital anomalies (2.66vs 2.43/100 births). CONCLUSIONS: Although constrained by small sample size, complex vaccine groups, and differential vaccine availability during 2009-2010, this study found no difference in adverse birth outcomes between H1N1 vaccine and TIV. PMID- 28917537 TI - HBcAg produced in transgenic tobacco triggers Th1 and Th2 response when intramuscularly delivered. AB - Hepatitis B core Antigen (HBcAg) assembled into Capsid-Like Particles (CLPs) is investigated as a therapeutic vaccine in treatment of chronic hepatitis B (CHB) and in diagnostic tests or as a carrier for various epitopes. While the expression of HBcAg has been thoroughly clarified in E. coli and yeast, it has also been investigated in other expression systems. Stably transformed tobacco expressed HBcAg at a level of 110-250ug/g fresh weight, therefore in view of its large leaf biomass it offers a production platform comparable with transient expression systems regarding the final yield of HBcAg. Several extraction and purification methods were tested and finally the antigen was purified up to 43% using sucrose density gradient centrifugation. The purified HBcAg retained its antigenicity, as confirmed by ELISA and western blot, while maintaining its CLP structure as observed in TEM. In mice HBcAg intramuscularly delivered at 2*10ug triggered a significant response (serum anti-HBc titre around 150,000), being statistically equivalent to that induced by the reference antigen. Among anti-HBc IgG isotypes, IgG2a and then IgG1 were increasing during immune response. However IgG2b and IgG3 were also induced, especially in mice immunised with the plant derived antigen. Analysis of the isotype profile indicates mainly Th1 polarisation, but completed with Th2 response. Obtained results indicate a considerable potential of plant-derived HBcAg as a therapeutic vaccine, since a mixed immune response with a stronger Th1 component is particularly required for treatment of CHB. PMID- 28917538 TI - Identification of IBV QX vaccine markers : Should vaccine acceptance by authorities require similar identifications for all live IBV vaccines? AB - IBV genotype QX causes sufficient disease in Europe for several commercial companies to have started developing live attenuated vaccines. Here, one of those vaccines (L1148) was fully consensus sequenced alongside its progenitor field strain (1148-A) to determine vaccine markers, thereby enabling detection on farms. Twenty-eight single nucleotide substitutions were associated with the 1148 A attenuation, of which any combination can identify vaccine L1148 in the field. Sixteen substitutions resulted in amino acid coding changes of which half were in spike. One change in the 1b gene altered the normally highly conserved final 5 nucleotides of the transcription regulatory sequence of the S gene, common to all IBV QX genes. No mutations can currently be associated with the attenuation process. Field vaccination strategies would greatly benefit by such comparative sequence data being mandatorily submitted to regulators prior to vaccine release following a successful registration process. PMID- 28917539 TI - Hemagglutinin-specific CD4+ T-cell responses following 2009-pH1N1 inactivated split-vaccine inoculation in humans. AB - Influenza A virus remains a major threat to public health, and the inactivated split-virus vaccine is the most prevalent vaccine used worldwide. However, our knowledge about cellular immune responses to the inactivated influenza virus vaccine and its correlation with humoral responses are yet limited, which has restricted our understanding of the vaccine's protective mechanisms. Herein, in two clinical trials, T-cell responses specific for both previously identified human leucocyte antigen (HLA)-I-restricted epitopes from influenza virus and hemagglutinin (HA) protein were longitudinally investigated before, during, and after a two-dose vaccination with the inactivated 2009 pandemic H1N1 (2009-pH1N1) vaccine. A robust antibody response in all of the donors after vaccination was observed. Though no CD8+ T-cell responses to known epitopes were detected, HA specific T-cell responses were primed following vaccination, and the responses were found to be mainly CD4+ T-cell dependent. However, HA-specific T-cells circulating in peripheral blood dropped to baseline levels 6weeks after vaccination, but humoral immune responses maintained a high level for 4months post-vaccination. Significant correlations between the magnitude of the HA specific T-cell responses and hemagglutination inhibition antibody titers were demonstrated, indicating a priming role of HA-specific T-cells for humoral immune responses. In conclusion, our study indicates that HA-specific CD4+ T-cell responses can be primed by the inactivated 2009-pH1N1 vaccine, which may coordinate with the elicitation of antibody protection. These findings would benefit a better understanding of the immune protective mechanisms of the widely used inactivated 2009-pH1N1 vaccine. PMID- 28917540 TI - Galba truncatula and Fasciola hepatica: Genetic costructures and interactions with intermediate host dispersal. AB - Antagonistic interactions between hosts and parasites are key structuring forces in natural populations. Demographic factors like extinction, migration and the effective population size shape host-parasite metapopulational dynamics. Therefore, to understand the evolution of host-parasite systems it is necessary to study the distribution of the genetic variation of both entities simultaneously. In this paper, we investigate the population genetics co structure of parasites and hosts within a metapopulation of the liver fluke, Fasciola hepatica, and two of its intermediate hosts, the main intermediate host in Europe, Galba truncatula, and a new intermediate host, Omphiscola glabra, in Central France. Our results reveal an absence of specificity of flukes as regard to the two alternative hosts though O. glabra shows higher prevalence of F. hepatica. Host and parasites displayed contrasting population genetics structure with very small, highly inbred (selfing) and strongly isolated G. truncatula populations and much bigger, panmictic and more dispersive F. hepatica. This could indicate a local adaptation of the parasite and a local maladaptation of the host. We also unveil a parasite-mediated biased population genetics structure suggesting that infected G. truncatula disperse more; have higher dispersal survival than uninfected snails or, more likely, that immigrant snails are infected more often than local snails (local parasites are less adapted to local hosts). Finally, an absence, or at least an ambiguous signature of isolation by distance was observed in both host and parasite population. A very weak migration rate for G. truncatula provides a reasonable explanation for this ambiguous result. Alternatively, smaller sample sizes combined with modest migration rates might explain the difficulties to unveil the signal in F. hepatica. PMID- 28917541 TI - Determinants for medication reconciliation interventions on hospital admission and discharge: An observational multi-centre study. PMID- 28917542 TI - Break point instead of ACE: acarbose, post-load glycaemic excursions, and cardiovascular events. PMID- 28917543 TI - Pioglitazone versus sulfonylureas: cardiovascular outcomes with older diabetes drugs. PMID- 28917546 TI - Parosteal Osteosarcoma of the Distal Radius Mimicking an Osteochondroma-A Diagnostic Misadventure. AB - We present a case of a parosteal osteosarcoma mimicking an osteochondroma with atypical clinical features, radiographic findings, and histological examination. This report serves to exemplify the importance of recognizing the similarities between these 2 entities and other peculiar features that will help to differentiate between sessile osteochondromas and parosteal osteosarcomas, to prevent misdiagnosis. PMID- 28917547 TI - Growth of the New Thumb Metacarpal After Pollicization for Thumb Hypoplasia. AB - PURPOSE: To investigate the radiographic length and width of the new thumb metacarpal in relation to the middle finger proximal phalanx; to assess the incidence of premature physeal closure of the new metacarpal; and to consider whether there is a relationship between growth characteristics and the presence of union or nonunion of the new trapezium to the retained index finger metacarpal base. METHODS: Forty pollicizations were assessed with preoperative or immediate postoperative radiographs and follow-up radiographs to establish the growth characteristics of the new thumb metacarpal. Functional outcomes comprising grip strength, pinch strength, and range of motion were correlated with radiological findings of presence or absence of open physes and presence or absence of union of the new trapezium to the metacarpal base. RESULTS: The new thumb metacarpal physis was open in 28 pollicizations and closed in 12. In the latter group, all physes of the hand had closed indicating skeletal maturity. The length and width indices of the new thumb metacarpal in relation to the middle finger proximal phalanx were equivalent to or greater than the perioperative growth indices. There was a reduced postoperative length ratio in those patients with nonunion of the new trapezium to the base of the metacarpal. There was no change in strength and range of motion parameters with growth other than that related to normal improvement with age. CONCLUSIONS: We are unable to demonstrate premature physeal closure following routine pollicization. The growth of the metacarpal continues in a normal manner to skeletal maturity. A failure of union of the new trapezium to the metacarpal base may compromise growth. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28917548 TI - Volar Capsular Release After Distal Radius Fractures. AB - PURPOSE: Loss of full wrist range of motion is common after treatment of distal radius fractures. Loss of wrist extension limiting functional activities, although uncommon, can occur after volar plating of distal radius fractures. Unlike other joints in which capsular release is a common form of treatment for stiffness, this has been approached with caution in the wrist owing to concerns for carpal instability. We tested the null hypothesis that hardware removal and open volar capsular release would not lead to improved upper extremity-specific patient-reported outcome (Disabilities of the Arm, Shoulder, and Hand [DASH] questionnaire). METHODS: We conducted a retrospective chart review of patients who underwent a tenolysis of the flexor carpi radialis tendon, removal of hardware, and subperiosteal release of the volar capsule (extrinsic ligaments). The primary outcome measure was patient-reported outcome on the DASH. Secondary outcomes included wrist flexion, extension, pronation, and supination, visual analog scale for pain, and radiographs/fluoroscopy for ulnocarpal translocation. RESULTS: Eleven patients were treated with a mean follow-up of 4.5 years. Mean DASH scores improved after surgery. Mean wrist flexion, wrist extension, pronation, and supination improved after surgery. Mean visual analog scale scores did not change. The radiocarpal relationship on radiographs/fluoroscopy was normal. CONCLUSIONS: Open volar capsular release to regain wrist extension after treatment of distal radius fractures with volar locking plates is safe and effective. Patients regain wrist extension in addition to improved DASH scores. There were no radiographic/fluoroscopic or clinical signs of ulnocarpal translocation after release of the volar extrinsic ligaments. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28917550 TI - Antidiabetic potential of methanolic and flavonoid-rich leaf extracts of Synsepalum dulcificum in type 2 diabetic rats. AB - BACKGROUND: Synsepalum dulcificum is a plant indigenous to West Africa. The fruit is used to modify taste of foods to sweetness. OBJECTIVES: This study aims to investigate the antidiabetic potentials of both methanolic and flavonoid-rich leaf extracts of S. dulcificum (MSD and FSD respectively) in type 2 diabetic Wistar albino rats. MATERIALS AND METHODS: Sixty three rats were randomly distributed into nine groups of seven animals each with group 1 serving as the normal control. Groups 2 to 7 were given 10% fructose in their drinking water for 14 days, after which 40 mg/kg of streptozotocin was administered. Group 2 animals served as the diabetic control, while groups 3, 4, 5, 6 and 7 were treated with 30 mg/kg MSD, 60 mg/kg MSD, 30 mg/kg FSD, 60 mg/kg FSD and 5 mg/kg glibenclamide respectively. Groups 8 and 9, contained healthy animals, and were treated with only 60 MSD, and 60 mg/kg FSD respectively. Biochemical parameters such as liver and kidney function tests, lipid profile, as well as lipid peroxidation and antioxidant enzymes were assessed in addition to histopathology. RESULTS: It was observed that daily oral administration of MSD and FSD for 21 days significantly (p < 0.05) improved the observed pathological changes as a result of type 2 diabetes. CONCLUSION: It could be deduced from results obtained in this study that methanolic and flavonoid-rich leaf extracts of S.dulcificum have antidiabetic potential in type 2 diabetic rats. PMID- 28917551 TI - [Impact of the preservation of the branches of intercostobrachial nerve on the quality of life of patients operated for a breast cancer]. AB - AIM: The aim of this study was to assess the impact of the preservation of the intercostobrachial nerve on the quality of life of patients operated for breast cancer. METHODS: This study was ancillary to cost comparison study of axillary sentinel lymph node detection and axillary lymphadenectomy in early breast cancer. It was a prospective multicenter, observational, non-randomized study. The quality of life was assessed using two questionnaires: QLQ-C30 and specific module QLQ-BR23 Surveys have been performed before initiation of surgery, one week, and 1 month, 8 months and 12 months after discharge from hospitalization for the first surgical procedure. RESULTS: Five hundred and seventy-eight patients with preservation of intercostobrachial nerve without axillary lymph node dissection (C- P+), 85 without preservation of nerve and axillary lymph node dissection (C+P-) and 57 with preservation of nerve and axillary lymph node dissection (C+P+) have been included in the study. The changing arm symptoms score was significantly different during follow-up between the three groups (P<0.001). This difference between the two groups C- P+ and C+P+ was significant clinically at one week [16.9, IC95%: 11.9 to 22 (P<0.01)], and persisted for up to 12 months [9.9, IC95%: 3.2 a16.6 (P=0.022)]. There was no difference between the group C+P- and C+P+. Results for physical functioning score were similar. CONCLUSION: Preservation of the intercostobral nerve is not associated with better quality of life. Only axillary lymph node dissection has an impact on quality of life. PMID- 28917545 TI - Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: The effect of the alpha-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. METHODS: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in blocks by site, by a centralised computer system to receive oral acarbose (50 mg three times a day) or matched placebo, which was added to standardised cardiovascular secondary prevention therapy. All study staff and patients were masked to treatment group allocation. The primary outcome was a five-point composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure, analysed in the intention-to-treat population (all participants randomly assigned to treatment who provided written informed consent). The secondary outcomes were a three-point composite outcome (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, development of diabetes, and development of impaired renal function. The safety population comprised all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT00829660, and the International Standard Randomised Controlled Trial Number registry, number ISRCTN91899513. FINDINGS: Between March 20, 2009, and Oct 23, 2015, 6522 patients were randomly assigned and included in the intention-to-treat population, 3272 assigned to acarbose and 3250 to placebo. Patients were followed up for a median of 5.0 years (IQR 3.4-6.0) in both groups. The primary five-point composite outcome occurred in 470 (14%; 3.33 per 100 person-years) of 3272 acarbose group participants and in 479 (15%; 3.41 per 100 person-years) of 3250 placebo group participants (hazard ratio 0.98; 95% CI 0.86 1.11, p=0.73). No significant differences were seen between treatment groups for the secondary three-point composite outcome, death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function. Diabetes developed less frequently in the acarbose group (436 [13%] of 3272; 3.17 per 100 person-years) compared with the placebo group (513 [16%] of 3250; 3.84 per 100 person-years; rate ratio 0.82, 95% CI 0.71-0.94, p=0.005). Gastrointestinal disorders were the most common adverse event associated with drug discontinuation or dose changes (215 [7%] of 3263 patients in the acarbose group vs 150 [5%] of 3241 in the placebo group [p=0.0007]; safety population). Numbers of non-cardiovascular deaths (71 [2%] of 3272 vs 56 [2%] of 3250, p=0.19) and cancer deaths (ten [<1%] of 3272 vs 12 [<1%] of 3250, p=0.08) did not differ between groups. INTERPRETATION: In Chinese patients with coronary heart disease and impaired glucose tolerance, acarbose did not reduce the risk of major adverse cardiovascular events, but did reduce the incidence of diabetes. FUNDING: Bayer AG. PMID- 28917549 TI - A Multicenter Randomized Trial of a Checklist for Endotracheal Intubation of Critically Ill Adults. AB - BACKGROUND: Hypoxemia and hypotension are common complications during endotracheal intubation of critically ill adults. Verbal performance of a written, preintubation checklist may prevent these complications. We compared a written, verbally performed, preintubation checklist with usual care regarding lowest arterial oxygen saturation or lowest systolic BP experienced by critically ill adults undergoing endotracheal intubation. METHODS: A multicenter trial in which 262 adults undergoing endotracheal intubation were randomized to a written, verbally performed, preintubation checklist (checklist) or no preintubation checklist (usual care). The coprimary outcomes were lowest arterial oxygen saturation and lowest systolic BP between the time of procedural medication administration and 2 min after endotracheal intubation. RESULTS: The median lowest arterial oxygen saturation was 92% (interquartile range [IQR], 79-98) in the checklist group vs 93% (IQR, 84-100) with usual care (P = .34). The median lowest systolic BP was 112 mm Hg (IQR, 94-133) in the checklist group vs 108 mm Hg (IQR, 90-132) in the usual care group (P = .61). There was no difference between the checklist and usual care in procedure duration (120 vs 118 s; P = .49), number of laryngoscopy attempts (one vs one attempt; P = .42), or severe life-threatening procedural complications (40.8% vs 32.6%; P = .20). CONCLUSIONS: The verbal performance of a written, preprocedure checklist does not increase the lowest arterial oxygen saturation or lowest systolic BP during endotracheal intubation of critically ill adults compared with usual care. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02497729; URL: www.clinicaltrials.gov. PMID- 28917552 TI - CRISPR correction of the PRKAG2 gene mutation in the patient's induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities. AB - BACKGROUND: Mutations in the PRKAG2 gene encoding the gamma-subunit of adenosine monophosphate kinase (AMPK) cause hypertrophic cardiomyopathy (HCM) and familial Wolff-Parkinson-White (WPW) syndrome. Patients carrying the R302Q mutation in PRKAG2 present with sinus bradycardia, escape rhythms, ventricular preexcitation, supraventricular tachycardia, and atrioventricular block. This mutation affects AMPK activity and increases glycogen storage in cardiomyocytes. The link between glycogen storage, WPW syndrome, HCM, and arrhythmias remains unknown. OBJECTIVE: The purpose of this study was to investigate the pathological changes caused by the PRKAG2 mutation. We tested the hypothesis that patient's induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) display clinical aspects of the disease. METHODS: Using clustered regularly interspaced short palindromic repeats (CRISPR) technology, we corrected the mutation and then generated isogenic iPSC CMs. Action potentials were recorded from spontaneously firing and paced cardiomyocytes using the patch clamp technique. Using a microelectrode array setup, we recorded electrograms from iPSC-CMs clusters. Transmission electron microscopy was used to detect ultrastructural abnormalities in the mutated iPSC CMs. RESULTS: PRKAG2-mutated iPSC-CMs exhibited abnormal firing patterns, delayed afterdepolarizations, triggered arrhythmias, and augmented beat rate variability. Importantly, CRISPR correction eliminated the electrophysiological abnormalities, the augmented glycogen, storage, and cardiomyocyte hypertrophy. CONCLUSION: PRKAG2-mutated iPSC-CMs displayed functional and structural abnormalities, which were abolished by correcting the mutation in the patient's iPSCs using CRISPR technology. PMID- 28917554 TI - Founder populations with channelopathies and church records reveal all sorts of interesting secrets: Some are scientifically relevant. PMID- 28917553 TI - Absence of rotational activity detected using 2-dimensional phase mapping in the corresponding 3-dimensional phase maps in human persistent atrial fibrillation. AB - BACKGROUND: Current phase mapping systems for atrial fibrillation create 2 dimensional (2D) maps. This process may affect the accurate detection of rotors. We developed a 3-dimensional (3D) phase mapping technique that uses the 3D locations of basket electrodes to project phase onto patient-specific left atrial 3D surface anatomy. OBJECTIVE: We sought to determine whether rotors detected in 2D phase maps were present at the corresponding time segments and anatomical locations in 3D phase maps. METHODS: One-minute left atrial atrial fibrillation recordings were obtained in 14 patients using the basket catheter and analyzed off-line. Using the same phase values, 2D and 3D phase maps were created. Analysis involved determining the dominant propagation patterns in 2D phase maps and evaluating the presence of rotors detected in 2D phase maps in the corresponding 3D phase maps. RESULTS: Using 2D phase mapping, the dominant propagation pattern was single wavefront (36.6%) followed by focal activation (34.0%), disorganized activity (23.7%), rotors (3.3%), and multiple wavefronts (2.4%). Ten transient rotors were observed in 9 of 14 patients (64%). The mean rotor duration was 1.1 +/- 0.7 seconds. None of the 10 rotors observed in 2D phase maps were seen at the corresponding time segments and anatomical locations in 3D phase maps; 4 of 10 corresponded with single wavefronts in 3D phase maps, 2 of 10 with 2 simultaneous wavefronts, 1 of 10 with disorganized activity, and in 3 of 10 there was no coverage by the basket catheter at the corresponding 3D anatomical location. CONCLUSION: Rotors detected in 2D phase maps were not observed in the corresponding 3D phase maps. These findings may have implications for current systems that use 2D phase mapping. PMID- 28917544 TI - Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. AB - BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57.3 months. The primary outcome occurred in 105 patients (1.5 per 100 person-years) who were given pioglitazone and 108 (1.5 per 100 person-years) who were given sulfonylureas (hazard ratio 0.96, 95% CI 0.74-1.26, p=0.79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0.0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. INTERPRETATION: In this long term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society. PMID- 28917555 TI - Incidence and significance of adhesions encountered during epicardial mapping and ablation of ventricular tachycardia in patients with no history of prior cardiac surgery or pericarditis. AB - BACKGROUND: Pericardial adhesions can prevent epicardial access and restrict catheter movement during mapping and ablation of ventricular tachycardia (VT). The incidence of adhesions in patients without prior cardiac surgery or clinically evident pericarditis is not known. OBJECTIVE: To describe the incidence of pericardial adhesions and explore their impact in patients without prior cardiac surgery or pericarditis. METHODS: A retrospective search of our ablation database containing patients who underwent epicardial ablation for VT was undertaken. Adhesions were diagnosed with routine contrast pericardiography after pericardial entry. Demographics and long-term outcomes were compared between patients with and without adhesions. RESULTS: Between 2004 and 2016, successful epicardial entry was achieved in 188 of 192 attempts (98%). In 155 first-time epicardial access attempts, pericardial adhesions were diagnosed in 13 (8%). When comparing baseline demographics, there was no significant difference. However, adhesions tended to occur more frequently with severe renal impairment (2% of patients without adhesions vs 15% of patients with adhesions, P = .07). No patient with a structurally normal heart had adhesions present. Adhesions were associated with limited epicardial mapping (3% of patients without adhesions vs 85% of patients with adhesions, P < .001) and lower short-term procedural success (68% of patients without adhesions vs 46% of patients with adhesions, P = .02), but complication rates were similar. The presence of adhesions did not translate into lower VT-free survival (P = .64) or freedom from a combined end point of VT recurrence, death, or transplant at 1 year (P = .93). CONCLUSION: Adhesions may be unexpectedly encountered in patients without prior cardiac surgery or pericarditis. When present, they can limit mapping and may be associated with lower short-term success. Larger studies are required to determine their impact on long-term outcomes. PMID- 28917556 TI - Increased risk of ventricular arrhythmias in survivors of out-of-hospital cardiac arrest with chronic total coronary occlusion. AB - BACKGROUND: Chronic total occlusion (CTO) is common in out-of-hospital cardiac arrest (OHCA) survivors with coronary artery disease. It is unclear whether CTO contributes to ventricular arrhythmias in this population. OBJECTIVE: This study sought to evaluate the impact of unrevascularized CTOs on the occurrence of appropriate implantable cardioverter-defibrillator (ICD) therapy and all-cause mortality in OHCA survivors with coronary artery disease. METHODS: This was a retrospective study that included all consecutive OHCA survivors with coronary artery disease who received an ICD from December 1999 until June 2015. Study end points were appropriate ICD therapy and all-cause mortality. RESULTS: We identified 217 OHCA survivors (mean age 63 +/- 10 years; 187 men (86%)) with coronary artery disease. Unrevascularized CTO was present in 71 of 217 patients (33%) at the time of ICD implantation. During a median follow-up of 61 months (interquartile range, 28-97 months), 57 of 217 patients (26%) experienced an appropriate ICD therapy. Patients with CTO had a higher incidence of appropriate ICD therapy in comparison to patients without CTO (log-rank, P = .002). Multivariate Cox regression analysis identified CTO (hazard ratio 2.07; 95% confidence interval 1.23-3.50; P = .007) as an independent predictor of appropriate ICD therapy. The presence of CTO was not associated with a higher mortality rate (log-rank, P = .18). CONCLUSIONS: In OHCA survivors with coronary artery disease receiving an ICD for secondary prevention, CTO was an independent predictor for the occurrence of ventricular arrhythmias but not for mortality. PMID- 28917557 TI - Idiopathic ventricular arrhythmias originating from the right coronary sinus: Prevalence, electrocardiographic and electrophysiological characteristics, and catheter ablation. AB - BACKGROUND: Ventricular arrhythmias (VAs) of the right coronary cusp (RCC) are not fully characterized. OBJECTIVES: To investigate the electrocardiographic and electrophysiological characteristics, mapping and ablation of RCC-VAs. METHODS: Among 256 consecutive patients undergoing electrophysiological evaluation and ablation of VAs of ventricular outflow tract origin, data were compared among 27 RCC-VAs, 50 VAs of the septal aspect of right ventricular outflow tract (RVOT), including from pulmonary artery, and 9 VAs of left coronary cusp (LCC). RESULTS: The only electrocardiographic characteristic that differentiated VAs originating from the RCC and RVOT was the amplitude of the R wave in lead I. During VAs of the RCC, the earliest activation site (EAS) in the right ventricle was localized in the middle-posterior septal region of the RVOT. The distance between the His bundle and the EAS in the RVOT in the RCC group was shorter than that in the RVOT and LCC group; the distance <= 29.4 mm, which rules out an RVOT and LCC origin, had 92.6% sensitivity and 100% specificity for RCC-origin speculation. Double or complex potentials were recorded in RVOT middle-posterior septal area surrounding the EAS in 20 of 27 RCC-VA patients (70%). Most of the successful ablation sites (24/27) were located in the anterior and upper margin of the RCC, close to the middle-posterior septal region of the RVOT. The prepotential (P1) amplitude and the P1-to-QRS complex interval may be indicators of successful RCC-VA ablation sites. CONCLUSIONS: RCC-VAs are not uncommon and have unique electrocardiographic and electrophysiological characteristics that distinguish an RCC origin of VA from RVOT and LCC origins. Most RCC-VAs were ablated successfully in the anterior and upper aspects of the RCC. PMID- 28917559 TI - Predictors and outcomes of cardiac resynchronization therapy extended to the second generator. AB - BACKGROUND: A proportion of patients who receive cardiac resynchronization therapy with defibrillator (CRT-D) live to receive a second generator. Controversy exists on whether an implantable cardioverter-defibrillator (ICD) should be offered to patients who have normalized or near-normalized left ventricular ejection fraction (LVEF) at the time of generator replacement (GR). OBJECTIVE: The purpose of this study was to evaluate incidence of appropriate ICD therapy after CRT-D GR. METHODS: This series involved 1026 consecutive patients who underwent CRT-D implant between January 1, 2002 and December 31, 2012. Echocardiography was assessed before the initial device implant and before GR. ICDs were monitored at our device clinic in person or remotely, or both. RESULTS: Of the cohort, 227 patients (22.1%) underwent CRT-D GR at our institution. Approximately 48% of the patients who received new CRT-D generators were no longer meeting the guidelines indication for ICD use at the time of GR. These patients received subsequent appropriate ICD therapies at a significantly lower rate than those with LVEF <35% (12% vs 35%; P < .001). Of these patients, 47 (20.7%) had LVEF improvement to >=50% at the time of GR. ICD therapy for ventricular arrhythmia in the ischemic group was 18.2%, while no patient in the nonischemic group received ICD therapy from the second generator after GR. CONCLUSION: Improvement in LVEF after CRT-D GR is associated with significantly reduced incidence of appropriate ICD therapy. Ventricular arrhythmia is less likely to develop with normalized LVEF in nonischemic cardiomyopathy. PMID- 28917558 TI - Cardiac sympathectomy for the management of ventricular arrhythmias refractory to catheter ablation. AB - BACKGROUND: Catheter ablation is now a mainstay of therapy for ventricular arrhythmias (VAs). However, there are scenarios where either physiological or anatomical factors make ablation less likely to be successful. OBJECTIVE: The purpose of this study was to demonstrate that cardiac sympathetic denervation (CSD) may be an alternate therapy for patients with difficult-to-ablate VAs. METHODS: We identified all patients referred for CSD at a single center for indications other than long QT syndrome and catecholaminergic polymorphic ventricular tachycardia who had failed catheter ablation. Medical records were reviewed for medical history, procedural details, and follow-up. RESULTS: Seven cases of CSD were identified in patients who had failed prior catheter ablation or had disease not amenable to ablation. All patients had VAs refractory to antiarrhythmic drugs, with a median arrhythmia burden of 1 episode of sustained VA per month. There were no acute complications of sympathectomy. One of 7 patients (14%) underwent heart transplant. No patient had sustained VA after sympathectomy at a median follow-up of 7 months. CONCLUSION: Because of anatomical and physiological constraints, many VAs remain refractory to catheter ablation and remain a significant challenge for the electrophysiologist. While CSD has been described as a therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, data regarding its use in other cardiac conditions are sparse. This series illustrates that CSD may be a viable treatment option for patients with a variety of etiologies of VAs. PMID- 28917560 TI - Outcomes of rescue cardiopulmonary support for periprocedural acute hemodynamic decompensation in patients undergoing catheter ablation of electrical storm. AB - BACKGROUND: In patients with ventricular tachycardia or ventricular fibrillation (VT/VF) electrical storm (ES) undergoing catheter ablation (CA), hypotension due to refractory VT/VF, use of anesthesia, and cardiac stunning due to repeated implantable cardioverter-defibrillator shocks might precipitate acute hemodynamic decompensation (AHD). OBJECTIVE: We evaluated the outcomes of emergent cardiopulmonary support with extracorporeal membrane oxygenation (ECMO) to rescue AHD in patients undergoing CA of ES. METHODS: Between January 1, 2010 and December 31, 2016, 21 patients with ES (VT in 11 and premature ventricular complex-triggered VF in 10) were referred for CA and had periprocedural AHD requiring emergent ECMO support. RESULTS: In 14 patients, AHD occurred a mean of 1.5 +/- 1.7 days before the procedure. In the remaining 7 patients, AHD occurred during or shortly after the procedure. ECMO was started successfully in all patients. Ablation was performed in 18 patients (9 with VF and 9 with VT). In patients with VF, premature ventricular complex suppression was achieved in 8 of 9 (89%). In those with VT, noninducibility was achieved in 7 of 9 (78%). After a median follow-up of 10 days, 16 patients died (13 during the index admission). Death was due to refractory VT/VF in 4 patients, heart failure in 11, and noncardiac cause in 1 patient. Seven patients survived beyond 6 months postablation; 5 remained free of VT/VF and 3 ultimately received a destination therapy (heart transplantation in 2 and left ventricular [LV] assist device in 1). CONCLUSION: In patients with ES undergoing CA, the outcomes of ECMO support as rescue intervention for AHD are poor. The majority of these patients die of refractory heart failure in the short-term. Strategies to prevent AHD including preemptive use of hemodynamic support may improve survival. PMID- 28917561 TI - Cardiac rhythm analysis during ongoing cardiopulmonary resuscitation using the Analysis During Compressions with Fast Reconfirmation technology. AB - BACKGROUND: Pauses in chest compressions (CCs) have a negative association with survival from cardiac arrest. Electrocardiographic (ECG) rhythm analysis and defibrillator charging are significant contributors to CC pauses. OBJECTIVE: Accuracy of the Analysis During Compressions with Fast Reconfirmation (ADC-FR) algorithm, which features automated rhythm analysis and charging during CCs to reduce CC pauses, was retrospectively determined in a large database of ECGs from 2701 patients with out-of-hospital cardiac arrest. METHODS: The ADC-FR algorithm generated a total of 7264 advisories, of which 3575 were randomly assigned to a development data set and 3689 to a test data set. With ADC-FR, a high-pass digital filter is used to remove CC artifacts, while the underlying ECG rhythm is automatically interpreted. When CCs are paused at the end of the 2-minute cardiopulmonary resuscitation interval, a 3-second reconfirmation analysis is performed using the artifact-free ECG to confirm the shock/no-shock advisory. The sensitivity and specificity of the ADC-FR algorithm in correctly identifying shockable/nonshockable rhythms during CCs were calculated. RESULTS: In both data sets, the accuracy of the ADC-FR algorithm for each ECG rhythm exceeded the recommended performance goals, which apply to a standard artifact-free ECG analysis. Sensitivity and specificity were 97% and 99%, respectively, for the development data set and 95% and 99% for the test data set. CONCLUSION: The ADC FR algorithm is highly accurate in discriminating shockable and nonshockable rhythms and can be used to reduce CC pauses. PMID- 28917562 TI - An updated meta-analysis of novel oral anticoagulants versus vitamin K antagonists for uninterrupted anticoagulation in atrial fibrillation catheter ablation. AB - BACKGROUND: Catheter ablation is recommended as a first- or second-line rhythm control therapy for selected patients with atrial fibrillation (AF). There is a wide variability in the periprocedural management of oral anticoagulation in patients undergoing AF ablation. OBJECTIVE: We aimed to perform an updated meta analysis of novel oral anticoagulants (NOACs) vs vitamin K antagonists (VKAs) as uninterrupted anticoagulation in patients undergoing AF ablation. METHODS: Databases and conference abstracts were searched. Studies were excluded if oral anticoagulants were held at any periprocedural period. The primary outcomes were stroke or transient ischemic attack (TIA) and major bleeding. RESULTS: Twelve studies and 4962 patients were included. Stroke or TIA was rare (NOAC, 0.08%; VKA, 0.16%) and not different between groups (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.19-2.30). The incidence of silent cerebral embolic events was also not significantly different between NOACs (8%) and VKAs (9.6%) (OR 0.86; 95% CI 0.42-1.76). Major bleeding was significantly reduced in the NOAC group (0.9%) as compared with VKA-treated patients (2%) (OR 0.50; 95% CI 0.30 0.84; P < .01). This finding was confirmed in a subgroup analysis of randomized and cohort studies with matched controls (OR 0.45; 95% CI 0.24-0.83; P = .01). There was no significant difference in the outcomes of individual NOACs and VKAs, although these analyses may have been underpowered to detect minor differences in such rare outcomes. CONCLUSION: In patients undergoing AF ablation, uninterrupted periprocedural NOACs are associated with a low incidence of stroke or TIA and a significant reduction in major bleeding as compared with uninterrupted VKAs. PMID- 28917563 TI - Ligament of Marshall arrhythmogenesis and vein of Marshall ethanol: A problem with a solution. PMID- 28917564 TI - Impact of institutional procedural volume on inhospital outcomes after cardiac resynchronization therapy device implantation: US national database 2003-2011. AB - BACKGROUND: The relationship between hospital volume and outcomes for cardiac resynchronization therapy (CRT) implantations has not been well established. OBJECTIVE: The purpose of this study was to examine outcomes after CRT device implantation stratified by hospital volume using a large national inpatient database. METHODS: Using the National Inpatient Sample database, we identified all patients undergoing de novo CRT implants between 2003 and 2011. Hospitals were categorized according to tertiles of annual CRT procedural volume. Rates of inhospital adverse events including death, cardiac perforation, pneumothorax, and lead revision were examined. A multivariate logistic regression analysis was performed to compare outcomes across hospital volume categories. RESULTS: Between 2003 and 2011, 410,104 de novo CRT implantations were performed. More than half (50.9%) of hospitals performed <=16 CRT implants/y. Overall complication rates were higher in the lower-volume centers (3.9%, 3.5%, and 3.2%; P = .001) when stratified by first, second, and third tertiles of CRT volume, respectively. The lowest tertile of CRT volume was independently associated with increased inhospital all-cause mortality (adjusted odds ratio [OR] 1.37; 95% confidence interval [CI] 1.10-1.70; P = .005), any complication (adjusted OR 1.21, 95% CI 1.07-1.37; P = .003), and lead revision (adjusted OR 1.27; 95% CI 1.03-1.58; P = .03). CONCLUSION: Lower CRT hospital volume was associated with worse outcomes, including inhospital death, overall complications, and lead revision. Establishment of standards defining minimum CRT volume thresholds to identify centers of excellence may result in improved outcomes. PMID- 28917565 TI - Reply to the Editor- Contact force-sensing catheters and increased risk of atrioesophageal fistula: Is the tool to blame or the workmen? PMID- 28917566 TI - Out-of-hospital cardiac arrest due to ventricular fibrillation in children-A call to action. PMID- 28917567 TI - Pulmonary sinus of Valsalva arrhythmias: A new twist to an old story. PMID- 28917568 TI - To the Editor- Contact force-sensing catheters and increased risk of atrioesophageal fistula: Is the tool to blame or the workmen? PMID- 28917569 TI - Strain types of Staphylococcus aureus nasal isolates from persons undergoing joint replacement surgery. PMID- 28917570 TI - Detection of viable but non-culturable legionella in hospital water network following monochloramine disinfection. AB - BACKGROUND: Prevention of legionellosis remains a critical issue in healthcare settings where monochloramine (MC) disinfection was recently introduced as an alternative to chlorine dioxide in controlling Legionella spp. contamination of the hospital water network. Continuous treatments with low MC doses in some instances have induced a viable but non-culturable state (VBNC) of Legionella spp. AIM: To investigate the occurrence of such dormant cells during a long period of continuous MC treatment. METHODS: Between November 2010 and April 2015, 162 water and biofilm samples were collected and Legionella spp. isolated in accordance with standard procedures. In sampling sites where MC was <1.5mg/L, VBNC cells were investigated by ethidium monoazide bromide (EMA)-real-time polymerase chain reaction (qPCR) and 'resuscitation' test into Acanthamoeba polyphaga CCAP 1501/18. According to the Health Protection Agency protocol, free living protozoa were researched in 60 five-litre water samples. FINDINGS: In all, 136 out of 156 (87.2%) of the samples taken from sites previously positive for L. pneumophila ST269 were negative by culture, but only 47 (34.5%) negative by qPCR. Although no positive results were obtained by EMA-qPCR, four out of 22 samples associated with MC concentration of 1.3 +/- 0.5mg/L showed VBNC legionella resuscitation. The presence of the amoeba A. polyphaga in the hospital water network was demonstrated. CONCLUSION: Our study is the first report evidencing the emergence of VNBC legionella during a long period of continuous MC treatment of a hospital water network, highlighting the importance of keeping an appropriate and uninterrupted MC dosage to ensure the control of legionella colonization in hospital water supplies. PMID- 28917571 TI - Academy of Dental Materials guidance-Resin composites: Part II-Technique sensitivity (handling, polymerization, dimensional changes). AB - OBJECTIVE: The objective of this work, commissioned by the Academy of Dental Materials, was to review and critically appraise test methods to characterize properties related to critical issues for dental resin composites, including technique sensitivity and handling, polymerization, and dimensional stability, in order to provide specific guidance to investigators planning studies of these properties. METHODS: The properties that relate to each of the main clinical issues identified were ranked in terms of their priority for testing, and the specific test methods within each property were ranked. An attempt was made to focus on the tests and methods likely to be the most useful, applicable, and supported by the literature, and where possible, those showing a correlation with clinical outcomes. Certain methods are only briefly mentioned to be all inclusive. When a standard test method exists, whether from dentistry or another field, this test has been identified. Specific examples from the literature are included for each test method. RESULTS: The properties for evaluating resin composites were ranked in the priority of measurement as follows: (1) porosity, radiopacity, sensitivity to ambient light, degree of conversion, polymerization kinetics, depth of cure, polymerization shrinkage and rate, polymerization stress, and hygroscopic expansion; (2) stickiness, slump resistance, and viscosity; and (3) thermal expansion. SIGNIFICANCE: The following guidance is meant to aid the researcher in choosing the most appropriate test methods when planning studies designed to assess certain key properties and characteristics of dental resin composites, specifically technique sensitivity and handling during placement, polymerization, and dimensional stability. PMID- 28917572 TI - Double filtration plasmapheresis: Determination of the optimal albumin concentration in the supplementation fluid. AB - Many kinds of technologies have been introduced and successfully developed for therapeutic apheresis. During the DFPP treatments, the patient's blood volume (BV) often decreases with time due to albumin loss induced by inadequate albumin infusion in a supplementation fluid. We examined the change of BV by a continuous hematocrit (HCT) monitor, CRIT-LINETM, during an in vivo study for nine patients. As a result, albumin loss was fairly occurred in some DFPP treatments. The decrease of patient's BV was induced by an oncotic pressure drop due to albumin loss and often resulted in a blood pressure drop. This is a serious problem for DFPP. We should avoid the patient is suffering from these adverse effects. In order to determine the optimal concentration CS and volume VS values of a supplemented albumin solution, we introduced a variable blood volume model for albumin transport in DFPP. PMID- 28917573 TI - [Still too many pregnancies with Soriatane(r)]. PMID- 28917574 TI - [Apparent worsening of psoriasis lesions revealing methotrexate overdosage]. AB - BACKGROUND: Methotrexate (MTX) is an antimetabolite drug used in the treatment of cancers and autoimmune diseases and frequently in dermatology for cutaneous and/or arthritic psoriasis. Toxicities due to MTX overdosage are mainly cutaneous, hepatic and hematologic. Herein, we report a case of MTX overdosage presenting as an erosive and an inflammatory flare of preexisting psoriatic plaques and with new palmar lesions. PATIENTS AND METHODS: A 51-year-old male with a 6-year history of plaque psoriasis resistant to topical corticosteroids was started for the first time on MTX 20mg weekly. One week later, he presented with fever, general weakness and mucocutaneous ulcerations. Physical examination revealed inflammatory, erythematous and partially erosive annular plaques strictly confined to preexisting psoriatic lesions, along with keratotic psoriatic palmar plaques. Further questioning indicated that the patient was taking MTX 20mg daily. Investigations revealed neutropenia (1040/mm3) and skin histology showed prominent dystrophic keratinocytes and confirmed the diagnosis of methotrexate toxicity. Clinical and biological improvements were observed after cessation of MTX and treatment with folinic acid, IV hydration and urine alkalization. DISCUSSION: Skin lesions due to acute MTX toxicity are rare, but they herald later-onset pancytopenia. Identification of these cutaneous lesions might enable earlier treatment initiation. The predilection of MTX toxicity for preexisting lesions or the de novo appearance of palmoplantar pustules should not lead to the erroneous diagnosis of psoriasis flare. PMID- 28917575 TI - [A "tattoo" consultation service in a university hospital: For whom and for what purpose?] PMID- 28917576 TI - [Cancers associated with systemic sclerosis involving anti-RNA polymerase III antibodies]. AB - BACKGROUND: The incidence of cancer is increased in patients with systemic sclerosis (SSc). Further, recent studies have also shown that the presence of anti-RNA polymerase III antibodies is associated with a higher incidence of cancer in this population. PATIENTS AND METHODS: Herein we present the cases of two men aged 56 and 23 years presenting SSc without anti-Scl70 or anti-centromere antibodies but with anti-RNA polymerase III antibodies. Clinical symptoms led us to prescribe more laboratory exams and both patients were diagnosed with cancer of the nasopharyngeal area. DISCUSSION: Anti-RNA polymerase III antibodies are useful for SSc diagnosis in patients without anti-centromere or anti-Scl70 antibodies. Their presence must lead physicians to screen for associated cancer, even in the absence of clinical signs. PMID- 28917577 TI - Direct Pulp Capping with Calcium Hydroxide, Mineral Trioxide Aggregate, and Biodentine in Permanent Young Teeth with Caries: A Randomized Clinical Trial. AB - INTRODUCTION: Direct pulp capping treatment is intended to preserve pulp vitality, to avoid or retard root canal treatment, and, in cases with an open apex, to allow continued root development. Historically, calcium hydroxide (CH) was the gold standard material, but nowadays calcium silicate materials (CSMs) are displacing CH because of their high bioactivity, biocompatibility, sealing ability, and mechanical properties. However, more randomized clinical trials are needed to confirm the appropriateness of CSMs as replacement materials for CH in direct pulp capping procedures. METHODS: A randomized clinical trial was conducted that included 169 patients (mean age, 11.3 years) from the Maipo district (Chile). The inclusion criterion was patients with 1 carious permanent tooth with pulpal exposure, a candidate for a direct pulp capping procedure. The patients were randomly allocated to one of the experimental groups (CH, Biodentine, or mineral trioxide aggregate [MTA]). Clinical follow-up examinations were performed at 1 week, 3 months, 6 months, and 1 year. The Fisher exact test was performed. RESULTS: At the follow-up examination at 1 week, the patients showed 100% clinical success. At 3 months, there was 1 failure in the CH group. At 6 months, there were 4 new failures (1 in the CH group and 3 in the MTA group). At 1 year, there was another failure in the CH group. There were no statistically significant differences among the experimental groups. CONCLUSIONS: CSMs appear to be suitable materials to replace CH. Although no significant differences were found among the materials studied, Biodentine and MTA offered some advantages over CH. PMID- 28917578 TI - Emerging biomarkers for cancer immunotherapy in melanoma. AB - The treatment and prognosis of metastatic melanoma has changed substantially since the advent of novel immune checkpoint inhibitors (ICI), agents that enhance the anti-tumor immune response. Despite the success of these agents, clinically actionable biomarkers to aid patient and regimen selection are lacking. Herein, we summarize and review the evidence for candidate biomarkers of response to ICIs in melanoma. Many of these candidates can be examined as parts of a known molecular pathway of immune response, while others are clinical in nature. Due to the ability of ICIs to illicit dramatic and durable responses, well-validated biomarkers that can be effectively implemented in the clinic will require strong negative predictive values that do not limit patients with who may benefit from ICI therapy. PMID- 28917579 TI - Microcirculation in the murine liver: a computational fluid dynamic model based on 3D reconstruction from in vivo microscopy. AB - The liver is organized in hexagonal functional units - termed lobules - characterized by a rather peculiar blood microcirculation, due to the presence of a tangled network of capillaries - termed sinusoids. A better understanding of the hemodynamics that governs liver microcirculation is relevant to clinical and biological studies aimed at improving our management of liver diseases and transplantation. Herein, we built a CFD model of a 3D sinusoidal network, based on in vivo images of a physiological mouse liver obtained with a 2-photon microscope. The CFD model was developed with Fluent 16.0 (ANSYS Inc., Canonsburg, PA), particular care was taken in imposing the correct boundary conditions representing a physiological state. To account for the remaining branches of the sinusoids, a lumped parameter model was used to prescribe the correct pressure at each outlet. The effect of an adhered cell on local hemodynamics is also investigated for different occlusion degrees. The model here proposed accurately reproduces the fluid dynamics in a portion of the sinusoidal network in mouse liver. Mean velocities and mass flow rates are in agreement with literature values from in vivo measurements. Our approach provides details on local phenomena, hardly described by other computational studies, either focused on the macroscopic hepatic vasculature or based on homogeneous porous medium model. PMID- 28917580 TI - The influence of ligament modelling strategies on the predictive capability of finite element models of the human knee joint. AB - In finite element (FE) models knee ligaments can represented either by a group of one-dimensional springs, or by three-dimensional continuum elements based on segmentations. Continuum models closer approximate the anatomy, and facilitate ligament wrapping, while spring models are computationally less expensive. The mechanical properties of ligaments can be based on literature, or adjusted specifically for the subject. In the current study we investigated the effect of ligament modelling strategy on the predictive capability of FE models of the human knee joint. The effect of literature-based versus specimen-specific optimized material parameters was evaluated. Experiments were performed on three human cadaver knees, which were modelled in FE models with ligaments represented either using springs, or using continuum representations. In spring representation collateral ligaments were each modelled with three and cruciate ligaments with two single-element bundles. Stiffness parameters and pre-strains were optimized based on laxity tests for both approaches. Validation experiments were conducted to evaluate the outcomes of the FE models. Models (both spring and continuum) with subject-specific properties improved the predicted kinematics and contact outcome parameters. Models incorporating literature-based parameters, and particularly the spring models (with the representations implemented in this study), led to relatively high errors in kinematics and contact pressures. Using a continuum modelling approach resulted in more accurate contact outcome variables than the spring representation with two (cruciate ligaments) and three (collateral ligaments) single-element-bundle representations. However, when the prediction of joint kinematics is of main interest, spring ligament models provide a faster option with acceptable outcome. PMID- 28917581 TI - An engineering insight into the relationship of selective cytoskeletal impairment and biomechanics of HeLa cells. AB - It is widely accepted that the pathological state of cells is characterized by a modification of mechanical properties, affecting cellular shape and viscoelasticity as well as adhesion behaviour and motility. Thus, assessing these parameters could represent an interesting tool to monitor disease development and progression, but also the effects of drug treatments. Since biomechanical properties of cells are strongly related to cytoskeletal architecture, in this work we extensively studied the effects of selective impairments of actin microfilaments and microtubules on HeLa cells through force-deformation curves and stress relaxation tests with atomic force microscopy. Confocal microscopy was also used to display the effects of the used drugs on the cytoskeletal structure. In synergy with the aforementioned methods, stress relaxation data were used to assess the storage and loss moduli, as a complementary way to describe the influence of cytoskeletal components on cellular viscoelasticity. Our results indicate that F-actin and microtubules play a complementary role in the cell stiffness and viscoelasticity, and both are fundamental for the adhesion properties. Our data support also the application of biomechanics as a tool to study diseases and their treatments. PMID- 28917582 TI - Preterm pre-eclampsia: What every neonatologist should know. AB - Although pre-eclampsia affects 5-10% of pregnancies globally and is responsible for substantial maternal and perinatal morbidity and mortality, currently there is no cure other than delivery of the baby. Predictive screening tests based on clinical risk factors, with or without the addition of biomarkers and imaging, have been developed, but adoption into clinical practice is limited by suboptimal test performance. Once established pre-eclampsia is diagnosed, a woman is usually managed expectantly prior to 37weeks' gestation to reduce perinatal morbidity and mortality associated with iatrogenic prematurity until maternal or fetal triggers for delivery mean that risks of pregnancy prolongation outweigh the benefits. Associated fetal growth restriction is a common feature of pre-eclampsia, particularly with early-onset disease, and will influence decisions for delivery and subsequent neonatal course. Prematurity and fetal growth restriction both have potential short and long-term consequences for the infant and child. PMID- 28917583 TI - Digit ratio (2D:4D) and prenatal/perinatal sex hormones: A response to Manning and Fink (2017). PMID- 28917584 TI - Pneumatoceles in pediatric blunt trauma: Common and benign. AB - INTRODUCTION: Traumatic pneumatoceles are reported to be rare in children and to have an uncertain clinical significance. We report a single institution series of traumatic pneumatoceles to better define their frequency and clinical significance. METHODS: After obtaining approval from the IRB, data were extracted from the trauma registry of a level 1 pediatric trauma center on children diagnosed with a pulmonary contusion (International Classification of Diseases 9th edition diagnosis codes: 861.21 to 861.31) who presented between June, 2006 and September, 2016. Patient demographics, mechanism of injury, injury severity score, diagnosis and procedure codes, length of hospital stay, outcome, imaging techniques and findings with attention to the identification of a pneumatocele, were examined. RESULTS: Of the 10,229 trauma admission, 204 children were identified as having a pulmonary contusion, 25 of whom (12.3%) were diagnosed with a pneumatocele. Their mean age was 13years (3-17). Seventy-six percent (19) were male. The most common mechanism of injury was a motor vehicle collision (10), followed by falls (6), and sports (5). Sixteen children (64%) suffered a long bone fracture, 12 (48%) an abdominal solid organ injury and 3 (12%) a traumatic brain injury. The mean Injury Severity Score was 17 (9-34). Twenty three patients presented as transfers. There were no fatalities. The pneumatocele was identified on chest computerized tomography (CT) alone in 15 (60%), on chest CT and chest radiograph (CXR) in 3 (12%), the upper portions of an abdominal CT in 6 (24%) and on CXR alone in 1 (4%). Seven patients were found to have a solitary pneumatocele and 18 patients had 2 or more. The largest pneumatocele was 3.7cm in diameter. Ten children (40%) were admitted to the intensive care unit, 3 of whom required intubation. One patient (4%) had a respiratory complication: pneumonia. Three patients underwent chest tube placement for: pneumothorax, hemothorax and hemopneumothorax. No child underwent intervention specific to the pneumatocele. Seventeen (68%) patients were seen in follow-up in Trauma Clinic and the remainder by another practitioner ranging from 1week to 6months after injury. One child (4%) underwent a follow-up chest CT to rule out a congenital pulmonary malformation 6months after injury and this demonstrated complete resolution of the pneumatocele. CONCLUSION: The incidence of traumatic pneumatoceles among children with a pulmonary contusion was 12.3% in this series, but is probably higher given that only 24% were visible on radiographs and a small minority of children with pulmonary contusions underwent chest CT. Pneumatoceles are common in children with pulmonary contusions, but are usually small. The majority do not appear to be clinically significant nor require follow up imaging. LEVEL OF EVIDENCE: IV. PMID- 28917585 TI - Total urogenital sinus mobilization for ambiguous genitalia. AB - INTRODUCTION: Genital ambiguity is a very common phenomenon in disorders of sex development (DSD). According to the Chicago Consensus 2006, feminizing genitoplasty, when indicated, should be performed in the most virilized cases (Prader III to V). Advances in the knowledge of genital anatomy in DSD have enabled the development and improvement of various surgical techniques. Mobilization of the urogenital sinus (MUS), first described by Pena, has become incorporated by most surgeons. However, the proximity of the urethral sphincter prompts concern over urinary incontinence, especially for full mobilization of the urogenital sinus. OBJECTIVE: To retrospectively evaluate the short-term surgical results of feminizing genitoplasty with total mobilization of the urogenital sinus in patients with DSD. METHODS: Review of medical records of all patients undergoing feminizing genitoplasty with mobilization of the urogenital sinus. We evaluated the rates of complications from surgery and of urinary incontinence, as well as cosmetic results, according to the opinion of the surgeon and the family. RESULTS: A total of 8 patients were included in the study. The mean age at surgery was 51months. Congenital adrenal hyperplasia (CAH) was diagnosed in six patients, and gonadal dysgenesis in the other two. The vagina was separated from the urethra, with suitable distance in all cases. No patient had urinary incontinence after surgery. The mean follow-up of patients was. 20months (3-56months). In all cases, surgeons recorded being satisfied with the aesthetic result of post-surgical genitalia. The family was recorded as satisfied with the aesthetic result of the genitalia after surgery. In every case, there was no need for a second surgical procedure. CONCLUSION: The total mobilization of the urogenital sinus is a feasible and safe technique. The technique permits good cosmetic results, and urinary incontinence is absent. TYPE OF STUDY: Therapeutic study. LEVEL OF EVIDENCE: Level III. PMID- 28917586 TI - Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or Intensity modulated radiation therapy. AB - PURPOSE: To compare heart and cardiac substructure radiation exposure using intensity-modulated radiotherapy (IMRT) vs. proton beam therapy (PBT) for patients with mid- to distal esophageal cancer who received chemoradiation therapy. METHODS AND MATERIALS: We identified 727 esophageal cancer patients who received IMRT (n=477) or PBT (n=250) from March 2004 to December 2015. All patients were treated to 50.4Gy with IMRT or to 50.4 cobalt Gray equivalents with PBT. IMRT and PBT dose-volume histograms (DVHs) of the whole heart, atria, ventricles, and four coronary arteries were compared. For PBT patients, passive scattering proton therapy (PSPT; n=237) and intensity-modulated proton therapy (IMPT; n=13) DVHs were compared. RESULTS: Compared with IMRT, PBT resulted in significantly lower mean heart dose (MHD) and heart V5, V10, V20, V30, and V40as well as lower radiation exposure to the four chambers and four coronary arteries. Compared with PSPT, IMPT resulted in significantly lower heart V20, V30, and V40 but not MHD or heart V5 or V10. IMPT also resulted in significantly lower radiation doses to the left atrium, right atrium, left main coronary artery, and left circumflex artery, but not the left ventricle, right ventricle, left anterior descending artery, or right coronary artery. Factors associated with lower MHD included PBT (P<0.001), smaller planning target volume (PTV; P<0.001), and gastroesophageal junction (GEJ) tumor (P<0.001). Among PBT patients, factors associated with lower MHD included IMPT (P=0.038), beam arrangement other than AP/PA (P<0.001), smaller PTV (P<0.001), and GEJ tumor (P<0.001). CONCLUSIONS: In patients with mid- to distal esophageal cancer, PBT results in significantly lower radiation exposure to the whole heart and cardiac substructures than IMRT. Long-term studies are necessary to determine how this cardiac sparing effect impacts the development of coronary artery disease and other cardiac complications. PMID- 28917587 TI - Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control. AB - We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (<=4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT. PMID- 28917588 TI - Association between FSP, CVHI, inflammatory cytokines and the incidence of primary stroke. AB - This case-control study was designed to establish a new risk-prediction model for primary stroke using Framingham stroke profile (FSP), cerebral vascular hemodynamic indexes (CVHI) and plasma inflammatory cytokines including hs-CRP, IL 6, TNF-alpha and Lp-PLA2. A total of 101 primary stroke patients admitted to Dongguan Houjie Hospital between August 2014 and June 2015 were assigned into the case group, and 156 age- and gender-matched healthy subjects from the Houjie Community were allocated into the control group. The prognostic values of FSP, CVHI and inflammatory cytokines including high sensitive C-reactive protein (hs CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were assessed by multivariate logistic regression analysis. Seven risk-prediction models (FSP, CVHI, inflammatory cytokine, FSP+CVHI, FSP+inflammatory cytokine, CVHI+inflammatory cytokine, CVHI+FSP+inflammatory cytokine) were successfully established and the prognostic values were statistically compared by ROC curve and Z test. For FSP, the stroke risk was significantly elevated by 2.85 times when the FSP score was increased by 1 level (P=0.043), increased by 3.25 times for CVHI (P=0.036), 6.53 times for IL-6 (P=0.003), and 7.75 times for Lp-PLA2 (P=0.000). The sensitivity of FSP+CVHI+inflammatory cytokine and CVHI+inflammatory cytokine models was higher than 90%. For model specificity, the specificity of FSP+CVHI+inflammatory cytokine model alone exceeded 90%. FSP, CVHI, IL-6 and Lp-PLA2 are independent risk factors of stroke. Integrating IL-6 and Lp-PLA2 into the models can significantly enhance the risk prediction accuracy of primary stroke. Combined application of FSP+CVHI+inflammatory cytokine is of potential for risk prediction of primary stroke. PMID- 28917589 TI - A Novel RGL2-DOF6 Complex Contributes to Primary Seed Dormancy in Arabidopsis thaliana by Regulating a GATA Transcription Factor. AB - The DELLA protein RGA-LIKE2 (RGL2) is a key transcriptional repressor of gibberellic acid (GA) signaling that regulates seed germination. We identified GATA12, a gene encoding a GATA-type zinc finger transcription factor, as one of the downstream targets of RGL2 in Arabidopsis thaliana. Our data show that freshly harvested (unstratified) seeds of GATA12 antisense suppression lines have reduced dormancy compared with the wild-type, while ectopic expression lines show enhanced seed dormancy. We show that GATA12 expression is negatively regulated by GA, and its transcript levels decline dramatically under dormancy-breaking conditions such as dry storage and cold stratification of seeds. GATA12 promoter has several GAMYB- and DOF-associated motifs that are known to be GA- and RGL2 responsive, respectively. Chromatin immunoprecipitation assay showed that a protein complex containing RGL2 can bind to GATA12 promoter and thereby regulate its expression. RGL2 lacks a DNA binding domain and requires a transcription factor to induce GATA12 expression. Our data show that this RGL2-containing protein complex includes DNA BINDING1 ZINC FINGER6 (DOF6), which is a known negative regulator of germination in freshly harvested seeds. We further show that this novel RGL2-DOF6 complex is required for activating GATA12 expression, thus revealing a molecular mechanism to enforce primary seed dormancy. PMID- 28917590 TI - Karyotype Stability and Unbiased Fractionation in the Paleo-Allotetraploid Cucurbita Genomes. AB - The Cucurbita genus contains several economically important species in the Cucurbitaceae family. Here, we report high-quality genome sequences of C. maxima and C. moschata and provide evidence supporting an allotetraploidization event in Cucurbita. We are able to partition the genome into two homoeologous subgenomes based on different genetic distances to melon, cucumber, and watermelon in the Benincaseae tribe. We estimate that the two diploid progenitors successively diverged from Benincaseae around 31 and 26 million years ago (Mya), respectively, and the allotetraploidization happened at some point between 26 Mya and 3 Mya, the estimated date when C. maxima and C. moschata diverged. The subgenomes have largely maintained the chromosome structures of their diploid progenitors. Such long-term karyotype stability after polyploidization has not been commonly observed in plant polyploids. The two subgenomes have retained similar numbers of genes, and neither subgenome is globally dominant in gene expression. Allele specific expression analysis in the C. maxima * C. moschata interspecific F1 hybrid and their two parents indicates the predominance of trans-regulatory effects underlying expression divergence of the parents, and detects transgressive gene expression changes in the hybrid correlated with heterosis in important agronomic traits. Our study provides insights into polyploid genome evolution and valuable resources for genetic improvement of cucurbit crops. PMID- 28917591 TI - Increased left prefrontal brain perfusion after MRI compatible tDCS attenuates momentary ruminative self-referential thoughts. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive electrical stimulation technique, assumed to influence cognition and emotional processing. OBJECTIVE: However, it is unclear how tDCS influences spontaneous cognitive processes such as momentary self-referential thoughts on the neuronal level. METHODS: Forty healthy female volunteers participated in a single session sham-controlled crossover tDCS study while being in the MRI scanner. We measured brain perfusion (arterial spin labeling) just before and just after tDCS. Before and after the stimulation procedure, participants were scored on mood (visual analogue scales) and on the Momentary Ruminative Self-focus Inventory (MRSI). We performed a 1.5 mA, 20-min, anodal left dorsolateral prefrontal cortex, cathodal right supraorbital stimulation. RESULTS: One sham-controlled tDCS session did not result in subjective mood changes. However, as compared to before, MRSI scores significantly decreased only after active tDCS. Regression analysis revealed that this reduction in momentary ruminative self-referential thoughts was related to tDCS-related increases in left prefrontal cortical perfusion. tDCS decreased momentary self-referential thoughts, which was associated with increasing perfusion in the left prefrontal cortex. CONCLUSION: Our findings are in line with the hypothesis that tDCS of the DLPFC attenuates ruminative processes. PMID- 28917593 TI - Help! I Have a Patient With Diabetes Who Is Sick! PMID- 28917592 TI - Prefrontal versus motor cortex transcranial direct current stimulation (tDCS) effects on post-surgical opioid use. AB - BACKGROUND: Pain is often a complaint that precedes total knee arthroplasty (TKA), however the procedure itself is associated with considerable post operative pain lasting days to weeks which can predict longer-term surgical outcomes. Previously, we reported significant opioid-sparing effects of motor cortex transcranial direct current stimulation from a single-blind trial. In the present study, we used double-blind methodology to compare motor cortex tDCS and prefrontal cortex tDCS to both sham and active-control (active electrodes over non-pain modulating brain areas) tDCS. METHODS: 58 patients undergoing unilateral TKA were randomly assigned to receive 4 20-min sessions (a total of 80 min) of tDCS (2 mA) post-surgery with electrodes placed to create 4 groups: 1) MOTOR (n = 14); anode-motor/cathode-right prefrontal, 2) PREFRONTAL (n = 16); anode-left prefrontal/cathode-right-sensory, 3) ACTIVE-CONTROL (n = 15); anode-left-temporal occipital junction/cathode-medial-anterior-premotor-area, and 4) SHAM (n = 13); 0 mA-current stimulation using placements 1 or 2. Patient controlled analgesia (PCA; hydromorphone) use was tracked during the ~72-h post-surgery. RESULTS: Patients in the sham group and the active-control group used 15.4 mg (SD = 14.1) and 16.0 mg (SD = 9.7) of PCA hydromorphone respectively. There was no difference between the slopes of the cumulative PCA usage curves between these two groups (p = 0.25; ns). Patients in the prefrontal tDCS group used an average of 11.7 mg (SD = 5.0) of PCA hydromporhone, and the slope of the cumulative PCA usage curve was significantly lower than sham (p < 0.0001). However, patients in the motor tDCS group used an average of 19.6 mg (SD = 11.9) hydromorphone and the slope of the PCA use curve was significantly higher than sham (p < 0.0001). CONCLUSIONS: Results from this double-blind cortical-target-optimization study suggest that anodal transcranial direct current stimulation (tDCS) over the left prefrontal cortex may be a reasonable approach to reducing post-TKA opioid requirements. Given the unexpected finding that motor cortex failed to produce an opioid sparing effect in this follow-up trial, further research in the area of post operative cortical stimulation is still needed. PMID- 28917594 TI - Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. AB - CONTEXT: The findings of systematic reviews (SRs) and meta-analyses (MAs) are used for clinical decision making. The European Association of Urology has committed increasing resources into the development of high quality clinical guidelines based on such SRs and MAs. OBJECTIVE: In this paper, we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office. EVIDENCE ACQUISITION: The process involves explicit methods and the findings should be reproducible. When conducting a SR, the essential first step is to formulate a clear and answerable research question. An extensive literature search lays the foundation for evidence synthesis. Data are extracted independently by two reviewers and any disagreements are resolved by discussion or arbitration by a third reviewer. EVIDENCE SYNTHESIS: In SRs, data for particular outcomes in individual randomised controlled trials may be combined statistically in a meta-analysis to increase power when the studies are similar enough. Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size, resulting in heterogeneity in outcome between studies. A number of different tools are available such as Cochrane Risk of Bias assessment tool for randomised controlled trials. In circumstances where there is too much heterogeneity, or when a review has included nonrandomised comparative studies, it is more appropriate to conduct a narrative synthesis. The GRADE tool for assessing quality of evidence strives to be a structured and transparent system, which can be applied to all evidence, regardless of quality. A SR not only identifies, evaluates, and summarises the best available evidence, but also the gaps to be targeted by future studies. CONCLUSIONS: SRs and MAs are integral in developing sound clinical practice guidelines and recommendations. PATIENT SUMMARY: Clinical practice guidelines should be evidence based, and systematic reviews and meta-analyses are essential in their production. We have discussed the key steps of conducting systematic reviews and meta-analyses in this paper. PMID- 28917595 TI - Perioperative and Oncologic Outcomes of Nephrectomy and Caval Thrombectomy Using Extracorporeal Circulation and Deep Hypothermic Circulatory Arrest for Renal Cell Carcinoma Invading the Supradiaphragmatic Inferior Vena Cava and/or Right Atrium. AB - BACKGROUND: Radical nephrectomy (RN) and caval thrombectomy (CT) for renal cell carcinoma, with extracorporeal circulation (ECC) and deep hypothermic circulatory arrest (DHCA) is a challenging surgical approach. OBJECTIVE: To assess peri operative and oncologic outcomes of renal cell carcinoma patients treated with RN and CT, using ECC and DHCA. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated 46 patients who underwent RN and CT using ECC and DHCA. SURGICAL PROCEDURE: After retroperitoneal nodal dissection and RN, a cardiopulmonary bypass was placed and DHCA achieved. A combined approach through the abdomen and the thorax was described. MEASUREMENTS: Perioperative and long-term survival outcomes were reported. RESULTS AND LIMITATIONS: Median operative time and length of hospital stay were 545min and 22 d. Overall, 33 patients (72%) did not require any additional interventional or surgical treatment. Thirty-day and 90-d mortality were 11% (5/46) and 15% (7/46). The 1-yr, 2-yr, and 3-yr cancer specific mortality (CSM)-free survival rates were 77%, 62%, and 56%, respectively. After stratification, according to metastatic status at diagnosis, CSM-free survival rates were significantly lower for cM1 patients compared with cM0 patients (1-yr 46% vs 93%, 2-yr 23% vs 81%, 3-yr 23% vs 73%, p<0.01). Our study is limited by its retrospective and uncomparative nature. CONCLUSIONS: RN with CT using ECC and DHCA is a challenging procedure which requires a dedicated multidisciplinary working team to minimise complications and maximise patients' outcomes. PATIENT SUMMARY: Patients with kidney cancer and a thrombus within the inferior vena cava, which reaches above the diaphragm, can be treated with surgery. However, this kind of surgical treatment is challenging and requires a dedicated multidisciplinary team in order to accomplish the task. PMID- 28917596 TI - Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer. AB - : Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described (n=28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by a designated radiologist. Best RR for cohort A was 64%. Two patients experienced clinical progression and died before the first radiographic assessment. RR for cohort B was 21%, which was significantly lower than that for cohort A. Progression of disease occurred in 43% of cohort B patients by the end of CT. These data suggest a lack of cross resistance between CT and ICIs in MUC. Therefore, the sequencing of these drugs is likely to be important to maximise outcomes. This is particularly true after first-line ICIs as subsequent CT has significant activity. PATIENT SUMMARY: In this report, we studied the effect of chemotherapy in metastatic bladder cancer, which relapsed after immune checkpoint inhibitors. We found that the activity of chemotherapy was maintained despite previous exposure to immune therapy. This underlines the importance of sequencing these agents to maximise outcomes. PMID- 28917597 TI - Common Senses. PMID- 28917598 TI - Matrix-effect free quantitative liquid chromatography mass spectrometry analysis in complex matrices using nanoflow LC with integrated emitter tip and high dilution factors. AB - Matrix effects are probably the Achilles heel of most quantitative liquid chromatography mass spectrometry (LC-MS) methods based on electrospray ionization. This work reports the evaluation of matrix effects in challenging matrices such as food extracts, human urine or wastewater at different dilution factors using nanoflow liquid chromatography-high resolution mass spectrometry (LC-MS). For this purpose, a suite of representative low-molecular weight compounds such as pesticides, drugs of abuse, sport drugs or environmental contaminants were selected. The approach is based on the use of reversed-phase C18 nano columns furnished with an integrated emitter tip. The nanoflow LC system was combined with full-scan high resolution mass spectrometry using a HRMS (orbitrap) instrument operated at a resolution of 70000. The sensitivity achieved with this configuration enables the implementation of high dilution factors (e.g. 1:20, 1:50 or beyond). When combining nanoflow LC-MS analysis with such high dilution factors (e.g. 1:50), signal suppression was negligible in most cases, so that matrix-matched standards may eventually be skipped, simplifying laboratory workflows by using external calibration in demanding applications such as drug analysis in urine, environmental contaminants in wastewater or pesticide testing in food, thus, eliminating the need for standard addition, matrix-matched calibration or isotopically-labelled standards. PMID- 28917599 TI - Enantiomeric separation of some chiral analytes using amylose 3,5 dimethylphenylcarbamate covalently immobilized on silica by nano-liquid chromatography and capillary electrochromatography. AB - A new experimental chiral stationary phase containing amylose 3,5 dimethylphenylcarbamate immobilized onto silica gel (i-ADMPC) was packed in 100MUm I.D. fused silica capillary and used for the chiral separation of eight selected flavanone derivatives in polar organic mobile phase by using different miniaturized techniques, such as nano-liquid chromatography (nano-LC), capillary electrochromatography (CEC) and pressure-assisted CEC (pCEC). A comparative study of different elution modes in terms of chromatographic efficiency, analysis time and enantiomeric resolution was carried out. In pCEC mode, the highest chromatography performance was obtained applying +2.5kV voltage and inlet pressure 10bar. Under these conditions, the analysis times were shorter than 20min, and chromatographic efficiencies were in the range 33,000-49,000 plates/m (first eluted peak). The solvent versatility of packed i- ADMPC capillary column was also investigated. In nano-LC, the CSP was stressed under the use of strong organic solvents such as ethyl acetate, acetone and methyl t-butyl ether (MTBE). After at least 40 working hours and over 50 sample injections, the CSP resulted to be very stable allowing to achieve good repeatability employing again the mobile phase containing polar organic solvent. Enantioresolutions and chromatographic efficiencies decreased by 1.60 and 10%, respectively as the result of using above mentioned strong solvents. PMID- 28917600 TI - ATP alters protein folding and function of Escherichia coli uridine phosphorylase. AB - Uridine phosphorylase is one of the critical enzymes in the pyrimidine salvage pathway. Cells regenerate uridine for nucleotide metabolism by incorporating uracil with ribose-1-phosphate with this enzyme. Recent studies indicate that Escherichia coli uridine phosphorylase is destabilized in the presence of ATP. However, the mechanism underlying the destabilization process and its influence on uridine phosphorylase function remain to be established. Here, we comprehensively investigated the effects of ATP on protein folding and function of Escherichia coli uridine phosphorylase. Our results demonstrate that ATP apparently decreases the stability of uridine phosphorylase in a concentration dependent manner. Additionally, simply increasing the level of ATP led to a reduction of enzymatic activity to complete inhibition. Further studies showed that uridine phosphorylase accumulates as a partially unfolded state in the presence of ATP. Moreover, ATP specifically accelerated the unfolding rate of uridine phosphorylase with no observable effects on the refolding process. Our preliminary findings suggest that ATP can alter the protein folding and function of enzymes via apparent destabilization. This mechanism may be significant for proteins functioning under conditions of high levels of ATP, such as cancer cell environments. PMID- 28917601 TI - Commentary to "Neuronal defects an etiological factor in congenital pelviureteric junction obstruction?" PMID- 28917602 TI - Comparing inpatient versus outpatient bowel preparation in children and adolescents undergoing appendicovesicostomy. AB - PURPOSE: The need for mechanical inpatient bowel preparation (IBP) in reconstructive pediatric urology has come under scrutiny, secondary to literature demonstrating little benefit regarding outcomes. Starting in 2013, a majority of patients undergoing reconstructive procedures at our institution no longer underwent IBP. We hypothesized that outpatient bowel preparation (OBP) would reduce length of stay (LOS) without increasing postoperative complications after appendicovesicostomy surgery. MATERIALS AND METHODS: An institutional database of patients undergoing lower urinary tract reconstruction between May 2010 and December 2014 was reviewed. Starting in 2013, a departmental decision was made to replace IBP with OBP. Patients undergoing an augmentation cystoplasty or continent ileovesicostomy were excluded because of insufficient numbers undergoing OBP. Patients undergoing IBP were admitted 1 day prior to surgery and received polyethylene glycol/electrolyte solution. A personalized preoperative OBP was introduced in 2013. Cost data were obtained from the Pediatric Health Information System. RESULTS: Sixty-seven patients met the inclusion criteria, with 30 (44.8%) undergoing IBP. There were no differences with respect to gender, age, presence of ventriculoperitoneal shunt, body mass index, glomerular filtration rate, preoperative diagnosis, operative time, and prior or simultaneous associated surgeries (p >= 0.07). Patients undergoing an IBP had a longer median LOS (7 vs. 5 days, p = 0.0002) and a higher median cost (US$4,288, p = 0.01). Postoperative complications in both groups were uncommon and were classified as Clavien-Dindo grade 1-2, with no statistical difference (IBP 20.0% vs. OBP 5.4%, p = 0.13). No serious postoperative complication occurred, such as a dehiscence, bowel obstruction, or shunt infection. DISCUSSION: This is the first analysis of hospitalization costs and IBP, showing a higher median cost of US$4288 compared with OBP. The LOS was shorter with an OBP (figure), similar to a previous report. Similar complication rates between the groups add to the growing body of literature that avoidance of IBP is safe in pediatric lower urinary tract reconstruction. Being a retrospective review of a practice change, differences in care that influenced cost and LOS may be missing. Also, as the surgeons do not know if a usable appendix is initially present, our data may not extrapolate to all patients. Despite these potential limitations, our data support the safety of utilizing OBP in patients with a high likelihood of a usable appendix, including those undergoing a synchronous Malone antegrade continence enema via a split appendix technique. CONCLUSION: In patients undergoing an appendicovesicostomy, preoperative IBP led to longer LOS and higher costs of hospitalization. OBP was not associated with increased risks of postoperative complications. PMID- 28917603 TI - Development of the Nurses' Care Coordination Competency Scale for mechanically ventilated patients in critical care settings in Japan: Part 1 Development of a measuring instrument. AB - OBJECTIVES: To develop a draft scale measuring nurses' care coordination competency for care of mechanically ventilated patients in critical care settings. METHOD: The scale items and concepts were derived from semi-structured interviews with 28 professionals (14 nurses, eight physicians, three physical therapists, three clinical engineers) who are managing mechanically ventilated critical care patients. A grounded theory approach was used. After content validation by experts, two pilot tests were used to identify and correct non discriminating items and vague items. After expert approval, the final draft scale was completed. SETTING: Intensive care units of acute care hospitals in Japan. FINDINGS: A scale was drafted with the following six concepts including 51 items of nurses' care coordination competency: (1) understanding care coordination needs (2) devising and clearly articulating the care vision (3) aggregating and disseminating information (4) employing resources (5) promoting team cohesion (6) engaging in situation-based negotiating. The interviewed participants argued that these competencies clearly reflect the inter professional activities required for well-coordinated and individualised care and improved patient outcomes. CONCLUSIONS: These findings could be utilised to educate and train nursesand establish the awareness that coordinating care is the nurses' responsibility. Future research focusing on its validity and reliability are needed. PMID- 28917604 TI - The needs of the relatives in the adult intensive care unit: Cultural adaptation and psychometric properties of the Chilean-Spanish version of the Critical Care Family Needs Inventory. AB - INTRODUCTION: The admission of a patient to an intensive care unit is an extraordinary event for their family. Although the Critical Care Family Needs Inventory is the most commonly used questionnaire for understanding the needs of relatives of critically ill patients, no Spanish-language version is available. The aim of this study was to culturally adapt and validate theCritical Care Family Needs Inventory in a sample of Chilean relatives of intensive care patients. METHODS: The back-translated version of the inventory was culturally adapted following input from 12 intensive care and family experts. Then, it was evaluated by 10 relatives of recently transferred ICU patients and pre-tested in 10 relatives of patients that were in the intensive care unit. Psychometric properties were assessed through exploratory factor analysis and Cronbach's alpha in a sample of 251 relatives of critically ill patients. RESULTS: The Chilean Spanish version of the Critical Care Family Needs Inventoryhad minimal semantic modifications and no items were deleted. A two factor solution explained the 31% of the total instrument variance. Reliability of the scale was good (alpha=0.93), as were both factors (alpha=0.87; alpha=0.93). CONCLUSION: The Chilean-Spanish version of theCritical Care Family Needs Inventory was found valid and reliable for understanding the needs of relatives of patients in acute care settings. PMID- 28917606 TI - Argus-T Sling in 182 Male Patients: Short-term Results of a Multicenter Study. AB - OBJECTIVE: To evaluate the short-term results with Argus-T sling in patients with post-prostatectomy incontinence (PPI). MATERIALS AND METHODS: A total of 182 patients with PPI were treated with Argus-T sling at 5 urologic centers from June 2008 to March 2013. The preoperative evaluation included medical history, pad count (1-2 pads: mild PPI; 3-5 pads: moderate PPI; >5 pads: severe PPI), visual analog scale on continence, quality of life score scale, physical examination, cystoscopy, and urodynamic evaluation. Postoperative evaluation was performed 6 weeks postoperatively, and late follow-up was achieved in April 2013. We considered a successful result when patients were cured (0-1 pads/24 hours) and or improved (1-2 pads/24 hours or a reduction in pad per day usage greater than 50%). RESULTS: Twenty-one (11.8%), 96 (52.7%), and 65 (35.7%) patients have mild, moderate, and severe incontinence, respectively. At the median follow-up of 22 months, the overall success rate was 86.2%. We obtained successful results of 95% in mild incontinence, 78% in moderate incontinence and 70% in severe incontinence. In cured and improved patients, we observed a statistically significant amelioration of quality of life (P <.0001). Sling regulation was carried out in 42.9% of cases, whereas its removal occurred in 9.3% of cases. Postoperative complications were reported in 14.3% of patients. In patients with previous radiotherapy, we observed a successful result in 61.2% of cases. CONCLUSION: This study represents the first report that shows short-term results of Argus-T positioning in a large population. Argus-T seems to offer good outcomes in patients with mild and moderate PPI. PMID- 28917605 TI - Outcomes using wedge stem with full hydroxiapatite coverage with a minimum of 5 years' follow-up. AB - INTRODUCTION: Total Hip Arthroplsty (THA) using uncemented stems is a popular practice in the last decades. The implant survivorship is crtitical and a less than 10% revision at 10 years is been propesed for commercialization and use. OBJECTIVE: To analyse the clinicoradiological results of an uncemented hydroxiapatite covered wedge stem with a 5 years minimum follow up. MATERIAL AND METHODS: Prospective study, patients aged from 21-75years were included. All patients received an Element stem (Exactech) and uncemented cup with crosslink poly and 32 mm metal head, and posterior approach with piriformis retention was used. Scheduled clinical and radiographic evaluation at 3 weeks, 3-6 month, year and subsequent years using Harris Hip Score and Merle d'Aubigne Postel. Intraoperative and during follow up complications were recorded. RESULTS: One hundred and fourteen total hip replacements in 104 patients: 54 females and 50 males (52%/48%). Follow-up of 5.7 years (range, 5-6.2years). Average age 56.8years (range, 42-75years). Clinical evaluation the Merle d'Aubigne score improved 6.8 points and from the initianl Harris Hip Score 47.3 to 93.1 points at last follow up. Radiographic evaluation shows osteointegration in all stems. And in 6 cases (5.3% at 3 months subsidence was detected, average 1.4 mm (range 0-2.6 mm) with no clinical manifestation, 3 cases of subsidence were associated to intraoperative fractures (1 greater trochanter and 2 in the calcar area, all resolved with wire cerclaje). Subjective evaluation: 86 cases (82.6%) excellent, 9 patients (8.6%) good, 6 cases (5.9%) satisfactory and 3 cases (2.9%) poor. All poor results linked to the intraoperative complications. No patient lost during follow up period. No femoral pain dislocation or aseptic or loosening detected. All implants were in situ at last follow up. CONCLUSIONS: The radiological results confirm the benefits of this type of stem with good osteointegration. The clinical and subjective results are promising. With good surgical technical and without complications the risk of aseptic loosening should be absent or minimal. PMID- 28917607 TI - Selection of reliable reference genes for gene expression studies in Botrytis cinerea. AB - Botrytis cinerea is an important plant pathogen causing grey mold disease in a wide range of plant species. The aim of this study was to identify reliable reference genes that can be used for the analysis of relative gene expression in B. cinerea with quantitative real-time reverse transcription PCR (qRT-PCR). Six commonly used housekeeping genes including actin (ACT), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), ubiquitin (UBQ), ubiquitin-conjugating enzyme (UCE), alpha-tubulin (alpha-TUB) and beta-tubulin (beta-TUB) were selected to test their expression stabilities in B. cinerea treated with different concentration of oxalic acid (1, 5 and 10mM) and confronted with antagonistic Trichoderma afroharzianum. Four in silico algorithms (geNorm, BestKeeper, NormFinder and Comparative DeltaCt) were applied to evaluate the expression stabilities of these genes, and the UBQ gene was identified as the most stably expressed. It was used to normalize the expression levels of three genes related to oxalic acid production (NADPH, VEL1 and OAH) when B. cinerea was challenged by T. afroharzianum. The results of this study are useful for gene expression analysis in B. cinerea. PMID- 28917608 TI - Environmental enrichment in the absence of wheel running produces beneficial behavioural and anti-oxidative effects in rats. AB - The effects of early environmental enrichment (EE) when solving a simple spatial task in adult male rats were assessed. After weaning, rats were housed in pairs in enriched or standard cages (EE and control groups) for two and a half months. Then the rats were trained in a triangular-shaped pool to find a hidden platform whose location was defined in terms of two sources of information, a landmark outside the pool and a particular corner of the pool. As expected, enriched rats reached the platform faster than control animals. Enriched rats also performed better on a subsequent test trial without the platform with the geometry cue individually presented (in the absence of the landmark). Most importantly, the beneficial effects of the present protocol were obtained in the absence of wheel running. Additionally, the antioxidative effects in the hippocampus produced by the previous protocol are also shown. PMID- 28917609 TI - Contribution to Mentorship and Promoting Women in Science. PMID- 28917610 TI - Low-dose DHA-induced astrocyte proliferation can be attenuated by insufficient expression of BLBP in vitro. AB - Docosahexaenoic acid (DHA) is an n-3 long chain polyunsaturated fatty acid (PUFA) that is involved in a wide range of cellular processes in human cells. Brain lipid binding protein (BLBP) exhibits a high affinity for n-3 PUFAs, especially DHA, but the precise functional contributions of DHA and BLBP in astrocytes are not clear. We analyzed cell viability and the ratio of Ki67 positive cells after manipulating DHA and/or BLBP levels in cultured astrocytes, and found that low dose DHA stimulated proliferation of astrocytes, whereas this proliferative effect could be attenuated by downregulation of BLBP. Moreover, we found that astrocyte proliferation was directly regulated by BLBP independently of DHA. Taken together, low-dose DHA-induced astrocyte proliferation was disturbed by insufficient BLBP; and besides acting as a fatty acid transporter, BLBP was also involved in the proliferation of astrocytes directly. PMID- 28917611 TI - End-of-life practice patterns at U.S. adult cystic fibrosis care centers: A national retrospective chart review. AB - BACKGROUND: There are many challenges to providing end-of-life care (EOLC) to people with cystic fibrosis (CF). METHODS: Chart abstraction was used to examine EOLC in adults with CF who died between 2011 and 2013. RESULTS: We reviewed 248 deaths from 71 CF care centers. Median age at death was 29years (range 18-73). While median FEV1 was in the severe lung disease category (FEV1<40%), 38% had mild or moderate lung disease in the year preceding death. The most common location of death was the intensive care unit (ICU, 39%), and 12% of decedents were listed for lung transplant. Fewer of those dying in the ICU personally participated in advance care planning or utilized hospice or Palliative Care Services (p<0.05). CONCLUSIONS: Adults dying with CF in the United States most commonly die in an ICU, with limited and variable use of hospice and Palliative Care Services. Palliative care and advance care planning are recommended as a routine part of CF care. PMID- 28917613 TI - 3D transvaginal sonography in obstetrics and gynecology. PMID- 28917612 TI - Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes. AB - BACKGROUND: Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE: The purpose of this study was to examine the association between prepregnancy anti thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN: We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS: Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid stimulating hormone level (>2.5 vs <=2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION: Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity. PMID- 28917615 TI - Comment on: Patients' reasons for and against undergoing Roux-en-Y gastric bypass, adjustable gastric banding, and vertical sleeve gastrectomy. PMID- 28917614 TI - Age and fecundability in a North American preconception cohort study. AB - BACKGROUND: There is a well-documented decline in fertility treatment success with increasing female age; however, there are few preconception cohort studies that have examined female age and natural fertility. In addition, data on male age and fertility are inconsistent. Given the increasing number of couples who are attempting conception at older ages, a more detailed characterization of age related fecundability in the general population is of great clinical utility. OBJECTIVE: The purpose of this study was to examine the association between female and male age with fecundability. STUDY DESIGN: We conducted a web-based preconception cohort study of pregnancy planners from the United States and Canada. Participants were enrolled between June 2013 and July 2017. Eligible participants were 21-45 years old (female) or >=21 years old (male) and had not been using fertility treatments. Couples were followed until pregnancy or for up to 12 menstrual cycles. We analyzed data from 2962 couples who had been trying to conceive for <=3 cycles at study entry and reported no history of infertility. We used life-table methods to estimate the unadjusted cumulative pregnancy proportion at 6 and 12 cycles by female and male age. We used proportional probabilities regression models to estimate fecundability ratios, the per-cycle probability of conception for each age category relative to the referent (21-24 years old), and 95% confidence intervals. RESULTS: Among female patients, the unadjusted cumulative pregnancy proportion at 6 cycles of attempt time ranged from 62.0% (age 28-30 years) to 27.6% (age 40-45 years); the cumulative pregnancy proportion at 12 cycles of attempt time ranged from 79.3% (age 25-27 years old) to 55.5% (age 40-45 years old). Similar patterns were observed among male patients, although differences between age groups were smaller. After adjusting for potential confounders, we observed a nearly monotonic decline in fecundability with increasing female age, with the exception of 28-33 years, at which point fecundability was relatively stable. Fecundability ratios were 0.91 (95% confidence interval, 0.74-1.11) for ages 25-27, 0.88 (95% confidence interval, 0.72-1.08) for ages 28-30, 0.87 (95% confidence interval, 0.70-1.08) for ages 31-33, 0.82 (95% confidence interval, 0.64-1.05) for ages 34-36, 0.60 (95% confidence interval, 0.44-0.81) for ages 37-39, and 0.40 (95% confidence interval, 0.22-0.73) for ages 40-45, compared with the reference group (age, 21 24 years). The association was stronger among nulligravid women. Male age was not associated appreciably with fecundability after adjustment for female age, although the number of men >45 years old was small (n=37). CONCLUSION: In this preconception cohort study of North American pregnancy planners, increasing female age was associated with an approximately linear decline in fecundability. Although we found little association between male age and fecundability, the small number of men in our study >45 years old limited our ability to draw conclusions on fecundability in older men. PMID- 28917616 TI - Opioid Use Following Total Hip Arthroplasty: Trends and Risk Factors for Prolonged Use. AB - BACKGROUND: The purpose of this study is to answer the following questions: (1) What is the prevalence of opioid use prior to primary total hip arthroplasty (THA)? (2) What is the typical trend in opioid use following THA over the first post-operative year? (3) What are the risk factors for prolonged opioid use following primary THA? METHODS: Primary THA patients were identified in the Humana database from 2007 to 2015. Pre-operative and post-operative opioid use was measured by monthly prescription refill rates. Rates of opioid use were trended monthly for 1 year post-operatively and compared based on pre-operative opioid user (OU) status as well as other patient demographics and co-morbidities. RESULTS: In total, 37,393 THA patients were analyzed and 14,309 patients (38.2%) were pre-operative opioid users (OUs). Pre-operative opioid use was the strongest predictor for prolonged opioid use following THA, with non-opioid users filling significantly less opioid prescriptions than OUs at every time point analyzed. Younger age, female sex, and all other diagnoses analyzed were found to significantly increase the rate of opioid refilling following THA throughout the entire post-operative year. CONCLUSION: Over one-third of THA patients use opioids within 3 months prior to THA and this percentage has increased 6% during the years included in this study. Pre-operative opioid use was most predictive of increased refills of opioids following THA. These data provide an important baseline for opioid use trends following THA that can be used for future comparison while identifying risk factors for prolonged use that will be helpful to prescribers as we all work to decrease opioid use, misuse, and abuse. PMID- 28917617 TI - Change in Acetabular Cup Orientation From Supine to Standing Position and Its Effect on Wear of Highly Crosslinked Polyethylene. AB - BACKGROUND: The purpose of this study is to measure acetabular cup position and wear of the highly crosslinked polyethylene liner in the supine and standing position for patients at a minimum of 10 years after the operation. METHODS: A total of 38 patients were recruited at a mean of 12.5 years after the operation. All patients received a single acetabular cup design with a highly crosslinked liner and a 28-mm cobalt-chromium femoral head. Patients underwent supine and standing radiostereometric examinations in which the X-ray sources and detectors were positioned to obtain an anterior-posterior and cross-table lateral radiograph. Acetabular cup position and the three-dimensional wear rate were measured from the radiographs, and outcome scores were recorded for each patient. RESULTS: Anteversion significantly increased (P < .0001) a mean of 12 degrees from supine (15.1 degrees +/- 10.4 degrees ) to standing (27.2 degrees +/- 10.5 degrees ) position. Inclination also significantly increased (P = .001) a mean of 2 degrees from supine (44.4 degrees +/- 6.8 degrees ) to standing (46.3 degrees +/- 7.7 degrees ) position. There was no difference (P = .093) in wear rate between supine (0.067 +/- 0.070 mm/y) and standing (0.073 +/- 0.074 mm/y) positions. There were no correlations between cup orientation and wear rate in either position. CONCLUSION: Highly crosslinked polyethylene is a forgiving bearing material. Although adherence to the traditional acetabular position target zone is recommended, ensuring hip stability and consideration of the patient's functional position are also important objectives to consider for the acetabular position. PMID- 28917618 TI - Gap Balancing Sacrifices Joint-Line Maintenance to Improve Gap Symmetry: 5-Year Follow-Up of a Randomized Controlled Trial. AB - BACKGROUND: Gap balancing (GB) has been noted to sacrifice joint-line maintenance to improve gap symmetry. This study aims to determine whether this change affects function or quality of life in the midterm. METHODS: A prospective blinded randomized controlled trial was completed with 103 patients randomized to measured resection (n = 52) or GB (n = 51). Primary outcome measured was femoral component rotation. Secondary outcomes measured were joint-line change, gap symmetry, and function and quality-of-life outcomes. RESULTS: At 5 years, 83 of 103 patients (85%) were assessed. There was no significant difference between groups in terms of functional or quality of life outcomes. A subgroup analysis revealed that there was no significant association between those with asymmetrical flexion and/or extension or medial and/or lateral gaps during knee replacement and subsequent functional outcomes. No significant difference was detected with those with an elevated joint line and postoperative function. CONCLUSION: In the midterm, the resultant change in joint-line and maintained gap symmetry noted with GB does not result in significant change to function or quality of life. PMID- 28917619 TI - A Chlorhexidine Solution Reduces Aerobic Organism Growth in Operative Splash Basins in a Randomized Controlled Trial. AB - BACKGROUND: Despite recommendations against the use of splash basins, due to the potential of bacterial contamination, our observation has been that they continue to be used in operating theaters. In hopes of decontaminating the splash basin, we sought to determine if the addition of chlorhexidine gluconate (CHG) would eliminate aerobic bacterial growth within the splash basin. METHODS: After Institutional Review Board approval, we began enrollment in a randomized controlled trial comparing 2 splash basin solutions. Splash basins (n = 111) were randomized to either the standard of care (control) solution of sterile water or the experimental solution containing 0.05% CHG. One 20 mL aliquot was taken from the basin at the end of the surgical case and delivered to an independent laboratory. Samples were plated on tryptic soy agar (medium) and incubated at 30 degrees C-35 degrees C to encourage growth. After 48-72 hours, the agar plates were examined for growth and a standard plate count of aerobic cultures was performed. RESULTS: The sterile water group was found to have bacterial growth in 9% of samples compared to no growth in the CHG group (P = .045). The organisms included Micrococcus luteus, Staphylococcus hominis, Gram-variable coccobacilli, and unidentifiable Gram-positive rods. CONCLUSION: Given the safety and efficacy of a concentration of 0.05% CHG in reducing the bacterial contamination in the operative splash basin, it would seem that if the practice of using a splash basin in the operating theater is to be continued, the addition of an antiseptic solution such as that studied here should be considered. PMID- 28917620 TI - Disappearing everyday materials: The displacement of medical resources following disaster in Fukushima, Japan. AB - This study draws upon interviews of medical staff working in the city of Minamisoma, Japan, following the 2011 Triple Disaster. It investigates staff responses to the disruption of material resources as a consequence of the disaster and its management. The disruption of spaces, and the loss of oxygen supplies, food, and medications impacted upon staff experience and the ability of institutions to care for patients. This resulted in a restructuring of spaces and materials as workers made efforts to reconfigure and reestablish healthcare functions. This is one of the few qualitative studies which draws upon the experience and perspectives of health workers in understanding material disruption following disaster. This is particularly important since this case did not involve the breakdown of lifeline infrastructure, but rather, brought to attention the way everyday material objects shape social experience. In highlighting these effects, the paper makes the case for the social scientific investigation of the impact of disasters on healthcare, shedding light on an area of research currently dominated by disaster medicine. PMID- 28917621 TI - Effects of Latino children on their mothers' dietary intake and dietary behaviors: The role of children's acculturation and the mother-child acculturation gap. AB - RATIONALE: Research shows that acculturation is important to Latinas' dietary intake and related behaviors. Although evidence suggests children may also play a role, it remains unclear whether children's acculturation is related to mothers' dietary intake/behaviors. OBJECTIVES: We examined the relationship between Latino children's acculturation and mothers' dietary intake/behaviors. We also examined the mother-child acculturation gap to identify dyad characteristics associated with mothers' diet. METHODS: Baseline surveys were collected in 2010 from 314 Latino mother-child (7-13 years old) dyads of Mexican-origin enrolled in a family based dietary intervention in Southern California, USA. Mother's daily intake of fruits, vegetables, and sugary beverages, percent of calories from fat, weekly away-from-home eating, and percent of weekly grocery dollars spent on fruits and vegetables were assessed via self-report. Mothers' and children's bidimensional acculturation were examined using acculturation groups (e.g., assimilated, bicultural) derived from Hispanic and non-Hispanic dimensions of language. We also assessed the acculturation gap between mothers and children with the a) difference in acculturation between mothers' and children's continuous acculturation scores and b) mother-child acculturation gap typologies (e.g., traditional mothers of assimilated children). RESULTS: Findings show that having an assimilated versus a bicultural child was negatively associated with mothers' vegetable intake and positively associated with mothers' sugary beverage intake, percent of calories from fat, and frequency of away-from-home eating, regardless of mothers' acculturation. Traditional mothers of assimilated children reported more sugary beverage intake, calories from fat, and more frequent away-from-home eating than traditional mothers of bicultural children. CONCLUSION: Results suggest that children's acculturation is associated with their mothers' dietary intake/behaviors and traditional mothers of assimilated children require more attention in future research. PMID- 28917623 TI - Correction to Lancet Glob Health 2016; 5: e970-71. PMID- 28917622 TI - Does gender matter? An analysis of men's and women's accounts of responding to symptoms of lung cancer. AB - Men are often portrayed - in research studies, 'common-sense' accounts and popular media - as reluctant users of health services. They are said to avoid going to the GP whenever possible, while women are portrayed, in presumed opposition, as consulting more readily, more frequently and with less serious complaints. Such stereotypes may inadvertently encourage doctors to pay greater heed to men's symptoms in 'routine' consultations. Although previous research has challenged this view with evidence, and suggested that links between gender identities and help-seeking are complex and fluid, gender comparative studies remain uncommon, and particularly few studies (either qualitative or quantitative) compare men and women with similar morbidity. We contribute here to gender comparative research on help-seeking by investigating men's and women's accounts of responding to symptoms later diagnosed as lung cancer. A secondary analysis of qualitative interviews with 27 men and 18 women attending Scottish cancer centres revealed striking similarities between men's and women's accounts. Participants were seen as negotiating a complex and delicate balance in constructing their moral integrity as, on the one hand, responsible service users who were conscious of the demands on health care professionals' time, and as patients who did not take undue risks with their health, in the context of an illness for which people are often held culpable, on the other. In accounting for their responses to symptoms, men and women drew equally on culturally-embedded moral frameworks of stoicism and responsible service use. Regardless of gender, the accounts portrayed participants as stoic in response to illness and responsible service users; and as people seeking explanations for bodily changes and taking appropriate and timely action. Our analysis challenges simplistic, 'common-sense' views of gendered help-seeking and highlights that both men and women need support to consult their doctor for investigation of significant or concerning bodily changes. PMID- 28917624 TI - Small heat shock protein 27: An effective adjuvant for enhancement of HIV-1 Nef antigen-specific immunity. AB - Novel vaccine modalities have been designed to improve the efficiency of vaccines against HIV infections. In this way, the HIV-1 Nef protein has been known as an attractive antigenic candidate in therapeutic vaccine development. Moreover, the endogenous adjuvants such as heat shock proteins (HSPs) and high mobility group box 1 protein (HMGB1) have been suggested effectively to induce antigen-specific humoral and cellular immune responses. In this study, different Nef DNA and protein constructs were produced in eukaryotic and prokaryotic expression systems, and their immunostimulatory properties were evaluated using small heat shock protein 27 (Hsp27) and the HMGB1-derived peptide (Hp91) in a mouse model. Generally, our results indicated that the Hsp27-Nef fusion DNA or protein could significantly elicit higher humoral and cellular immune responses than Nef DNA or protein, respectively. Analysis of the immune responses demonstrated that the Hsp27-Nef fusion protein, and also the mixture of Nef and Hp91 significantly enhanced the Nef-specific T cell responses. Indeed, these regimens induced high levels of IgG2a and IFN-gamma directed toward Th1 responses and also Granzyme B secretion as compared to other immunization strategies. The immunostimulatory properties of Freund's adjuvant were significantly less than Hsp27 and Hp91 peptide in various immunization strategies. These findings showed that the use of Hsp27 and Hp91 in protein strategy could improve HIV-1 Nef-specific B- and T-cell immune responses, and also represent a promising HIV-1 vaccine candidate in future. PMID- 28917625 TI - Reduced neuroprotective potential of the mesenchymal stromal cell secretome with ex vivo expansion, age and progressive multiple sclerosis. AB - BACKGROUND: Clinical trials using ex vivo expansion of autologous mesenchymal stromal cells (MSCs) are in progress for several neurological diseases including multiple sclerosis (MS). Given that environment alters MSC function, we examined whether in vitro expansion, increasing donor age and progressive MS affect the neuroprotective properties of the MSC secretome. METHODS: Comparative analyses of neuronal survival in the presence of MSC-conditioned medium (MSCcm) isolated from control subjects (C-MSCcm) and those with MS (MS-MSCcm) were performed following (1) trophic factor withdrawal and (2) nitric oxide-induced neurotoxicity. RESULTS: Reduced neuronal survival following trophic factor withdrawal was seen in association with increasing expansion of MSCs in vitro and MSC donor age. Controlling for these factors, there was an independent, negative effect of progressive MS. In nitric oxide neurotoxicity, MSCcm-mediated neuroprotection was reduced when C-MSCcm was isolated from higher-passage MSCs and was negatively associated with increasing MSC passage number and donor age. Furthermore, the neuroprotective effect of MSCcm was lost when MSCs were isolated from patients with MS. DISCUSSION: Our findings have significant implications for MSC-based therapy in neurodegenerative conditions, particularly for autologous MSC therapy in MS. Impaired neuroprotection mediated by the MSC secretome in progressive MS may reflect reduced reparative potential of autologous MSC-based therapy in MS and it is likely that the causes must be addressed before the full potential of MSC-based therapy is realized. Additionally, we anticipate that understanding the mechanisms responsible will contribute new insights into MS pathogenesis and may also be of wider relevance to other neurodegenerative conditions. PMID- 28917626 TI - Ultrasound-assisted liposuction provides a source for functional adipose-derived stromal cells. AB - BACKGROUND AIMS: Regenerative medicine employs human mesenchymal stromal cells (MSCs) for their multi-lineage plasticity and their pro-regenerative cytokine secretome. Adipose-derived mesenchymal stromal cells (ASCs) are concentrated in fat tissue, and the ease of harvest via liposuction makes them a particularly interesting cell source. However, there are various liposuction methods, and few have been assessed regarding their impact on ASC functionality. Here we study the impact of the two most popular ultrasound-assisted liposuction (UAL) devices currently in clinical use, VASER (Solta Medical) and Lysonix 3000 (Mentor) on ASCs. METHODS: After lipoaspirate harvest and processing, we sorted for ASCs using fluorescent-assisted cell sorting based on an established surface marker profile (CD34+CD31-CD45-). ASC yield, viability, osteogenic and adipogenic differentiation capacity and in vivo regenerative performance were assessed. RESULTS: Both UAL samples demonstrated equivalent ASC yield and viability. VASER UAL ASCs showed higher osteogenic and adipogenic marker expression, but a comparable differentiation capacity was observed. Soft tissue healing and neovascularization were significantly enhanced via both UAL-derived ASCs in vivo, and there was no significant difference between the cell therapy groups. CONCLUSIONS: Taken together, our data suggest that UAL allows safe and efficient harvesting of the mesenchymal stromal cellular fraction of adipose tissue and that cells harvested via this approach are suitable for cell therapy and tissue engineering applications. PMID- 28917627 TI - Molecular and functional characterization of CD133+ stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells. AB - BACKGROUND AIMS: Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. METHODS: Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. RESULTS: We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. DISCUSSION: We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy. PMID- 28917628 TI - An engineered biomarker system to monitor and modulate immune clearance of cell therapies. AB - BACKGROUND AIMS: Cell transplants offer a new opportunity to deliver therapies with novel and complex mechanisms of action. Understanding the pharmacology of cell transplants is important to deliver this new therapy effectively. Currently, however, there are limited techniques to easily track cells after intravenous administration due to the dispersion of the graft throughout the entire body. METHODS: We herein developed an engineered cell system that secretes a luciferase enzyme to sensitively detect cell transplants independent of their locale by a simple blood test. We specifically studied a unique feature of cell transplant pharmacology-namely, immune clearance-using mesenchymal stromal cells (MSCs) as a proof-of-concept cell therapy. MSCs are a clinically relevant cell therapy that has been explored in several disease indications due to their innate properties of altering an immune response. RESULTS: Using this engineered reporter, we observed specific sensitivity of cell therapy exposure to the preparation of cells, cytolysis of MSCs in an allogeneic setting and a NK cell-mediated destruction of MSCs in an autologous setting. CONCLUSIONS: Our cellular tracking method has broader implications at large for assessing in vivo kinetics of various other cell therapies. PMID- 28917629 TI - Decision making about healthcare-related tests and diagnostic test strategies. Paper 5: a qualitative study with experts suggests that test accuracy data alone is rarely sufficient for decision making. AB - OBJECTIVES: The objective of the study was to identify the critical factors that determine recommendations and other decisions about healthcare-related tests and diagnostic strategies (HCTDS). METHODS: We used a qualitative descriptive approach and conducted semi-structured in-depth interviews with 24 international experts (informants) in evidence and decisions about HCTDS. RESULTS: Although test accuracy (TA) was the factor most commonly considered by organizations when developing recommendations about HCTDS, informants agreed that TA is necessary but rarely, if ever, sufficient and may be misleading when solely considered. The informants identified factors that are important for developing recommendations about HCTDS. Informants largely agreed that laying out the potential care pathways based on the test result is an essential early step but is rarely done in developing recommendations about HCTDS. Most informants also agreed that decision analysis could be useful for organizing the clinical, cost, and preference data relevant to the use of tests in the absence of direct evidence. However, they noted that using models is limited by the lack of resources and expertise required. CONCLUSION: Developing guidelines about HCTDS requires consideration of factors beyond TA, but implementing this may be challenging. Further development and testing of "frameworks" that can guide this process is a priority for decision makers. PMID- 28917630 TI - Decision making about healthcare-related tests and diagnostic test strategies. Paper 4: International guidelines show variability in their approaches. AB - OBJECTIVES: The objective of the study was to describe and compare current practices in developing guidelines about the use of healthcare-related tests and diagnostic strategies (HCTDS). STUDY DESIGN AND SETTING: We sampled 37 public health and clinical practice guidelines about HCTDS from various sources without language restrictions. RESULTS: Detailed descriptions of the systems used to assess the quality of evidence and develop recommendations were challenging to find within guidelines. We observed much variability among and within organizations with respect to how they develop recommendations about HCTDS. Twenty-four percent of the guidelines did not consider health benefits and harms but based decisions solely on test accuracy. We did not identify guidelines that described the main potential care pathways involving tests for a healthcare problem. In addition, we did not identify guidelines that systematically assessed, described, and referenced the evidence that linked test accuracy and patient-important outcomes. CONCLUSION: There is considerable variability among the processes used and factors considered in developing recommendations about the use of tests. This variability may be the cause for the disagreement we observed in recommendations about testing for the same condition. PMID- 28917631 TI - ? PMID- 28917632 TI - Early Structural Valve Deterioration of the Mitroflow Aortic Bioprosthesis: Will the New Anticalcification Treatment Change Anything? PMID- 28917633 TI - Safety of MitraClip Implantation in Patients With a Left Ventricular Endocardial Lead for Cardiac Resynchronization Therapy Through the Interventricular Septum. PMID- 28917634 TI - Tricuspid Percutaneous Repair With the MitraClip System: First Implant in Spain. PMID- 28917635 TI - Evolutionary analysis of nucleosome positioning sequences based on New Symmetric Relative Entropy. AB - New Symmetric Relative Entropy (NSRE) was applied innovatively to analyze the nucleosome sequences in S. cerevisiae, S. pombe and Drosophila. NSRE distributions could well reflect the characteristic differences of nucleosome sequences among three organisms, and the differences indicate a concerted evolution in the sequence usage of nucleosome. Further analysis about the nucleosomes around TSS shows that the constitutive property of +1/-1 nucleosomes in S. cerevisiae is different from that in S. pombe and Drosophila, which indicates that S. cerevisiae has a different transcription regulation mechanism based on nucleosome. However, in either case, the nucleosome dyad region is conserved and always has a higher NSRE. Base composition analysis shows that this conservative property in nucleosome dyad region is mainly determined by base A and T, and the dependence degrees on base A and T are consistent in three organisms. PMID- 28917636 TI - Parallel approach on sorting of genes in search of optimal solution. AB - An important tool for comparing genome analysis is the rearrangement event that can transform one given genome into other. For finding minimum sequence of fission and fusion, we have proposed here an algorithm and have shown a transformation example for converting the source genome into the target genome. The proposed algorithm comprises of circular sequence i.e. "cycle graph" in place of mapping. The main concept of algorithm is based on optimal result of permutation. These sorting processes are performed in constant running time by showing permutation in the form of cycle. In biological instances it has been observed that transposition occurs half of the frequency as that of reversal. In this paper we are not dealing with reversal instead commencing with the rearrangement of fission, fusion as well as transposition. PMID- 28917637 TI - Diversity of copy number variation in a worldwide population of sheep. AB - Copy number variation (CNV) represents a major source of genomic variation. We investigated the diversity of CNV distribution using SNP array data collected from a comprehensive collection of geographically dispersed sheep breeds. We identified 24,558 putative CNVs, which can be merged into 619 CNV regions, spanning 197Mb of total length and corresponding to ~6.9% of the sheep genome. Our results reveal a population differentiation in CNV between different geographical areas, including Africa, America, Asia, Southwestern Asia, Central Europe, Northern Europe and Southwestern Europe. We observed clear distinctions in CNV prevalence between diverse groups, possibly reflecting the population history of different sheep breeds. We sought to determine the gene content of CNV, and found several important CNV-overlapping genes (BTG3, PTGS1 and PSPH) which were involved in fetal muscle development, prostaglandin (PG) synthesis, and bone color. Our study generates a comprehensive CNV map, which may contribute to genome annotation in sheep. PMID- 28917638 TI - Novel antihelmintic activity of tinidazole coordination compounds. Relevance of the metal ion and structural properties. AB - The in vitro and in vivo antihelmintic activity of cobalt(II), copper(II) and zinc(II) coordination compounds of tinidazole (tnz) were investigated in cultivated spotted rose snapper, infested with dactylogyrid monogeneans. The tinidazole coordination compounds [Co(tnz)2Cl2], [Co(tnz)2Br2], [Cu(tnz)2Cl2], [Cu(tnz)2Br2], [Zn(tnz)2Cl2] and [Zn(tnz)2Br2] were synthesized and spectroscopically characterized. Their molecular structures were determined by their single crystal X-ray diffraction. The metal ions presented distorted tetrahedral geometries, with an intramolecular bifurcated lone pair SO?pi, from the sulfone group with the imidazolic ring, which contributed to the stability of the compounds in solid state and in solution. Adults of dactylogyrids were exposed in vitro to tinidazole and its coordination compounds. The effective median concentrations of copper(II) coordination compounds were lower than those of cobalt(II) and zinc(II), tnz showed no activity. In vivo oral intubation tests were carried out with [Cu(tnz)2Br2], [Zn(tnz)2Br2] and tnz on snappers infected with dactylogyrids, where the copper(II) compound showed better activity. The absorption and distribution assessment for the [Cu(tnz)2Br2], showed that copper concentrations in liver were significantly higher than in blood and gills, indicating bioaccumulation in this organ. In vivo baths of [Cu(tnz)2Br2] at 25mg/L showed an effective (95% at 8h) antihelmintic effect, while [Zn(tnz)2Br2] had low antihelmintic efficacy. This study indicates that [Cu(tnz)2Br2] has an effective antihelmintic activity towards dactylogyrids monogeneans affecting cultivated spotted red snapper. PMID- 28917639 TI - Protein oxidation involved in Cys-Tyr post-translational modification. AB - Some post-translationally modified tyrosines can perform reversible redox chemistry similar to metal cofactors. The most studied of these tyrosine modifications is the intramolecular thioether-crosslinked 3'-(S-cysteinyl) tyrosine (Cys-Tyr) in galactose oxidase. This Cu-mediated tyrosine modification in galactose oxidase involves direct electron transfer (inner-sphere) to the coordinated tyrosine. Mammalian cysteine dioxygenase enzymes also contain a Cys Tyr that is formed, presumably, through outer-sphere electron transfer from a non heme iron center ~6A away from the parent residues. An orphan protein (BF4112), amenable to UV spectroscopic characterization, has also been shown to form Cys Tyr between Tyr 52 and Cys 98 by an adjacent Cu2+ ion-loaded, mononuclear metal ion binding site. Native Cys-Tyr fluorescence under denaturing conditions provides a more robust methodology for Cys-Tyr yield determination. Cys-Tyr specificity, relative to 3,3'-dityrosine, was provided in this fluorescence assay by guanidinium chloride. Replacing Tyr 52 with Phe or the Cu2+ ion with a Zn2+ ion abolished Cys-Tyr formation. The Cys-Tyr fluorescence-based yields were decreased but not completely removed by surface Tyr mutations to Phe (Y4F/Y109F, 50%) and Cys 98 to Ser (25%). The small absorbance and fluorescence emission intensities for C98S BF4112 were surprising until a significantly red-shifted emission was observed. The red-shifted emission spectrum and monomer to dimer shift seen by reducing, denaturing SDS-PAGE demonstrate a surface tyrosyl radical product (dityrosine) when Cys 98 is replaced with Ser. These results demonstrate surface tyrosine oxidation in BF4112 during Cys-Tyr formation and that protein oxidation can be a significant side reaction in forming protein derived cofactors. PMID- 28917640 TI - Biotinylated platinum(IV) complexes designed to target cancer cells. AB - Three biotinylated platinum(IV) complexes (1-3) were designed and synthesized. The resulting platinum(IV) complexes exhibited effective cytotoxicity against the tested cancer cell lines, especially complex 1, which was 2.0-9.6-fold more potent than cisplatin. These complexes were found to be rapidly reduced to their activated platinum(II) counterparts by glutathione or ascorbic acid under biologically relevant condition. Additional molecular docking studies revealed that the biotin moieties of all Pt(IV) complexes can effectively bind with the streptavidin through the noncovalent interactions. Besides, introduction of the biotin group can obviously promote the cancer cell uptake of platinum when treated with complex 1, particularly in cisplatin-resistant SGC-7901/Cis cancer cells. Further mechanistic studies on complex 1 indicated that it activated the expression of Bax, and induced cytochrome c release from the mitochondria, and finally activated caspase-3. PMID- 28917641 TI - Changes in innervation of lumbar motoneurons and organization of premotor network following training of transected adult rats. AB - Rats with complete spinal cord transection (SCT) can recover hindlimb locomotor function under strategies combining exercise training and 5-HT agonist treatment. This recovery is expected to result from structural and functional re organization within the spinal cord below the lesion. To begin to understand the nature of this reorganization, we examined synaptic changes to identified gastrocnemius (GS) or tibialis anterior (TA) motoneurons (MNs) in SCT rats after a schedule of early exercise training and delayed 5-HT agonist treatment. In addition, we analyzed changes in distribution and number of lumbar interneurons (INs) presynaptic to GS MNs using retrograde transneuronal transport of rabies virus. In SCT-untrained rats, we found few changes in the density and size of inhibitory and excitatory inputs impinging on cell bodies of TA and GS MNs compared to intact rats, whereas there was a marked trend for a reduction in the number of premotor INs connected to GS MNs. In contrast, after training of SCT rats, a significant increase of the density of GABAergic and glycinergic axon terminals was observed on both GS and TA motoneuronal cell bodies, as well as of presynaptic P-boutons on VGLUT1 afferents. Despite these changes in innervation the number of premotor INs connected to GS MNs was similar to control values although some new connections to MNs were observed. These results suggest that adaptation of gait patterns in SCT-trained rats was accompanied by changes in the innervation of lumbar MNs while the distribution of the spinal premotor circuitry was relatively preserved. PMID- 28917642 TI - Efficient gene editing via non-viral delivery of CRISPR-Cas9 system using polymeric and hybrid microcarriers. AB - CRISPR-Cas9 is a revolutionary genome-editing technology that has enormous potential for the treatment of genetic diseases. However, the lack of efficient and safe, non-viral delivery systems has hindered its clinical application. Here, we report on the application of polymeric and hybrid microcarriers, made of degradable polymers such as polypeptides and polysaccharides and modified by silica shell, for delivery of all CRISPR-Cas9 components. We found that these microcarriers mediate more efficient transfection than a commercially available liposome-based transfection reagent (>70% vs. <50% for mRNA, >40% vs. 20% for plasmid DNA). For proof-of-concept, we delivered CRISPR-Cas9 components using our capsules to dTomato-expressing HEK293T cells-a model, in which loss of red fluorescence indicates successful gene editing. Notably, transfection of indicator cells translated in high-level dTomato knockout in approx. 70% of transfected cells. In conclusion, we have provided proof-of-principle that our micro-sized containers represent promising non-viral platforms for efficient and safe gene editing. PMID- 28917643 TI - A novel 3-dimensional electromagnetic guidance system increases intraoperative microwave antenna placement accuracy. AB - BACKGROUND: Failure to locate lesions and accurately place microwave antennas can lead to incomplete tumor ablation. The EmprintTM SX Ablation Platform employs real-time 3D-electromagnetic spatial antenna tracking to generate intraoperative laparoscopic antenna guidance. We sought to determine whether EmprintTM SX affected time/accuracy of antenna-placement in a laparoscopic training model. METHODS: Targets (7-10 mm) were set in agar within a laparoscopic training device. Novices (no surgical experience), intermediates (surgical residents), and experts (HPB-surgeons) were asked to locate and hit targets using a MWA antenna (10-ultrasound only, 10-EmprintTM SX). Time to locate target, number of attempts to hit the target, first-time hit rate, and time from initiating antenna advance to hitting the target were measured. RESULTS: Participants located 100% of targets using ultrasound, with experts taking significantly less time than novices and intermediates. Using ultrasound only, successful hit-rates were 70% for novices and 90% for intermediates and experts. Using EmprintTM SX, successful hit rates for all 3-groups were 100%, with significantly increased first-time hit rates and reduced time required to hit targets compared to ultrasound only. DISCUSSION: EmprintTM SX significantly improved accuracy and speed of antenna placement independent of experience, and was particularly beneficial for novice users. PMID- 28917644 TI - ALPPS as a salvage procedure after insufficient future liver remnant hypertrophy following portal vein occlusion. AB - BACKGROUND: A minimum future liver remnant (FLR) of 30% is required to avoid post hepatectomy liver failure (PHLF). Portal vein occlusion (PVO) is the main strategy to induce hypertrophy of the FLR, but some patients will not reach sufficient FLR hypertrophy to enable resection. Recently ALPPS has emerged as a "Salvage Procedure" for PVO failure. The aim of this study was to report the short term outcomes of ALPPS following PVO failure. METHODS: A retrospective analysis of patients enrolled within the international ALPPS Registry between October 2012 and November 2015 (NCT01924741) was performed. Patients with documented PVO failure were included. The outcomes reported included feasibility, FLR growth rate and safety of ALPPS. Complications were recorded as per Clavien Dindo classification. RESULTS: From 510 patients enrolled in the Registry there were 22 patients with previous PVO failure. Two patients were excluded due to missing data and twenty patients were analysed. All of them completed the proposed ALPPS with a medium FLR increase of 88% (23-115%) between two stages and no 90-day mortality. CONCLUSION: In experienced centers, ALPPS following PVO failure is feasible and safe. The FLR hypertrophy was similar to other ALPPS series. ALPPS is a potential rescue strategy after PVO failure. PMID- 28917645 TI - Anti-fibrinolytic and anti-microbial activities of a serine protease inhibitor from honeybee (Apis cerana) venom. AB - Bee venom contains a variety of peptide constituents, including low-molecular weight protease inhibitors. While the putative low-molecular-weight serine protease inhibitor Api m 6 containing a trypsin inhibitor-like cysteine-rich domain was identified from honeybee (Apis mellifera) venom, no anti-fibrinolytic or anti-microbial roles for this inhibitor have been elucidated. In this study, we identified an Asiatic honeybee (A. cerana) venom serine protease inhibitor (AcVSPI) that was shown to act as a microbial serine protease inhibitor and plasmin inhibitor. AcVSPI was found to consist of a trypsin inhibitor-like domain that displays ten cysteine residues. Interestingly, the AcVSPI peptide sequence exhibited high similarity to the putative low-molecular-weight serine protease inhibitor Api m 6, which suggests that AcVSPI is an allergen Api m 6-like peptide. Recombinant AcVSPI was expressed in baculovirus-infected insect cells, and it demonstrated inhibitory activity against trypsin, but not chymotrypsin. Additionally, AcVSPI has inhibitory effects against plasmin and microbial serine proteases; however, it does not have any detectable inhibitory effects on thrombin or elastase. Consistent with these inhibitory effects, AcVSPI inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products. AcVSPI also bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi as well as gram-positive and gram-negative bacteria. These findings demonstrate the anti-fibrinolytic and anti-microbial roles of AcVSPI as a serine protease inhibitor. PMID- 28917646 TI - Lights Out: An Unusual Case of Amaurosis Fugax. PMID- 28917647 TI - A Case of a Carcinoid Tumour With Diffuse Tracheal Invasion. PMID- 28917648 TI - Challenges of conducting a prospective clinical trial for older patients: Lessons learned from NCCTG N0949 (alliance). AB - OBJECTIVES: While the risk of developing colorectal cancer increases with age, there are limited prospective data regarding best treatment in the older adult population. We launched a phase III trial to evaluate difference in treatment outcome for older adults (aged >=70years) with advanced colorectal cancer. Here we review the challenges faced and reasons for poor accrual to N0949. MATERIALS AND METHODS: We describe the conceptualization, development and limited results of N0949, a randomized phase III study of fluoropyrimidine/bevacizumab with or without oxaliplatin (mFOLFOX7 or XELOX) as first line chemotherapy for metastatic colorectal cancer. Fluoropyrimidine was physician choice (e.g., 5-FU/LV or capecitabine). RESULTS: Of the projected 380 patients, only 32 patients were enrolled between the study activation in January 2011 until its closure in September 2012. Reasons for poor accrual included eligibility criteria that were too stringent, discomfort with randomizing older patients to regimens of varying intensity without considering their physical fitness, and discomfort with the use of bevacizumab in the older patient population. Several efforts were mounted to design a rationale and age-appropriate study, consider toxicities and varying study practices, and be responsive to stakeholder feedback. CONCLUSIONS: Challenges were experienced in conducting the first prospective phase III study evaluating progression-free survival of older adults with advanced colorectal cancer receiving palliative chemotherapy with fluoropyrimidine/bevacizumab with or without oxaliplatin in the USA. Future efforts to evaluate treatment outcomes in the older adult population should reflect on lessons learned in this large national effort. PMID- 28917649 TI - Evaluation of novel 111In-labeled gonadotropin-releasing hormone peptides for human prostate cancer imaging. AB - The purpose of this study was to evaluate the tumor targeting and imaging properties of novel 111In-labeled gonadotropin-releasing hormone (GnRH) peptides for human prostate cancer. Three new 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA)-linker-d-Phe-(d-Lys6-GnRH) peptides with different hydrocarbon linkers were designed to evaluate their effects on GnRH receptor binding affinities. The Aoc (aminooctanoic acid) linker was better than betaAla (3-aminopropanoic acid) and Aun (aminoundecanoic acid) linkers in retaining strong receptor binding affinity. DOTA-Aoc-d-Phe-(d-Lys6-GnRH) exhibited 6.6+/ 0.1nM GnRH receptor binding affinity. 111In-DOTA-Aoc-d-Phe-(d-Lys6-GnRH) exhibited fast tumor uptake and urinary clearance in DU145 human prostate cancer xenografted nude mice. The DU145 tumor lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using 111In-DOTA-Aoc-d-Phe (d-Lys6-GnRH) as an imaging probe, providing an insight into the design of new GnRH peptides for prostate cancer in the future. PMID- 28917650 TI - Dodecyl sorbitan ethers as antimicrobials against Gram-positive bacteria. AB - A range of amphiphilic sorbitan ethers has been synthesized in two steps from sorbitan following an acetalization/hydrogenolysis sequence. These sorbitan ethers and the acetal intermediates have been evaluated as antimicrobials against Gram-negative and Gram-positive bacteria. No antimicrobial activity was observed for Gram-negative bacteria. However, the compounds bearing a linear dodecyl chain exhibit antimicrobial activity (MIC as low as 8MUg/mL) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis and Staphylococcus aureus. Encouraged by these preliminary results, dodecyl sorbitan was tested against a range of resistant strains and was found to be active against vancomycin-, methicillin- and daptomycin-resistant strains (MIC=32-64MUg/mL). PMID- 28917651 TI - Bacteriophages as an alternative to conventional antibiotic use for the prevention or treatment of Paenibacillus larvae in honeybee hives. AB - American Foulbrood (AFB) is an infectious disease caused by the bacteria, Paenibacillus larvae. P. larvae phages were isolated and tested to determine each phages' host range amongst 59 field isolate strains of P. larvae. Three phages were selected to create a phage cocktail for the treatment of AFB infections according to the combined phages' ability to lyse all tested strains of bacteria. Studies were performed to demonstrate the safety and efficacy of the phage cocktail treatment as a replacement for traditional antibiotics for the prevention of AFB and the treatment of active infections. Safety verification studies confirmed that the phage cocktail did not adversely affect the rate of bee death even when administered as an overdose. In a comparative study of healthy hives, traditional prophylactic antibiotic treatment experienced a 38+/ 0.7% decrease in overall hive health, which was statistically lower than hive health observed in control hives. Hives treated with phage cocktail decreased 19+/-0.8%, which was not statistically different than control hives, which decreased by 10+/-1.0%. In a study of beehives at-risk for a natural infection, 100+/-0.5% of phage-treated hives were protected from AFB infection, while 80+/ 0.5% of untreated controls became infected. AFB infected hives began with an average Hitchcock score of 2.25 out of 4 and 100+/-0.5% of the hives recovered completely within two weeks of treatment with phage cocktail. While the n numbers for the latter two studies are small, the results for both the phage protection rate and the phage cure rate were statistically significant (alpha=0.05). These studies demonstrate the powerful potential of using a phage cocktail against AFB and establish phage therapy as a feasible treatment. PMID- 28917652 TI - Tilapia adropin: the localization and regulation of growth hormone gene expression in pituitary cells. AB - The peptide hormone adropin, encoded by the energy homeostasis-associated (Enho) gene, plays a role in energy homeostasis and the control of vascular function. The aim of this study was to examine the role of adropin in growth hormone (GH) gene expression at the pituitary level in tilapia. As a first step, the antiserum for the tilapia adropin was produced, and its specificity was confirmed by antiserum preabsorption and immunohistochemical staining in the tilapia pituitary. Adropin could be detected immunocytochemically in the proximal pars distalis (PPD) of the tilapia pituitary. In primary cultures of tilapia pituitary cells, tilapia adropin was effective in increasing GH mRNA levels. However, removal of endogenous adropin by immunoneutralization using adropin antiserum inhibited GH gene expression. In parallel experiments, pituitary cells co-treated with ovine pituitary adenylate cyclase activating polypeptide 38 (oPACAP38) and adropin showed a similar increase level compared to those treated with oPACAP38 alone, whereas insulin-like growth factor 1 (IGF1) not only had an inhibitory effect on basal GH mRNA levels, but also could abolish adropin stimulation of GH gene expression. In pituitary cells pretreated with actinomycin D, the half-life of GH mRNA was enhanced by adropin. Taken together, these findings suggest that adropin may serve as a novel local stimulator for GH gene expression in tilapia pituitary. PMID- 28917653 TI - Human IL6 stimulates bovine satellite cell proliferation through a Signal transducer and activator of transcription 3 (STAT3)-dependent mechanism. AB - Bovine satellite cell (bSC) myogenesis and skeletal muscle hypertrophy occur through the orchestrated actions of multiple autocrine and paracrine growth factors. Intimate to the bSC niche is IL6, a dual-purpose cytokine with proinflammatory and mitogenic properties. The objective of the experiment was to examine the effects of IL6 on proliferation and differentiation of bSC in vitro. Treatment of primary bSC cultures with recombinant bovine IL6 (bIL6) failed to alter myogenesis owing to the absence of intracellular signal transduction. The cytokine was able to stimulate phosphorylation of signal transducer and activator of transcription 3 tyrosine 705 (STAT3Y705) in Madin-Darby bovine kidney (MDBK) epithelial cells, thus demonstrating bioactivity. Media supplemented with recombinant human IL6 (hIL6) caused phosphorylation of STAT3Y705 in bSC and increased (P < 0.05) proliferation. Inclusion of a STAT3 inhibitor in the media blunted phosphorylation of the STAT3Y705 and suppressed (P < 0.05) hIL6-mediated bSC proliferation. Morphologic and biochemical measures of bSC differentiation remained unchanged (P > 0.05) following treatment for 48 h with hIL6. These results support a role for hIL6 as a bSC mitogen in vitro. The inability of bIL6 to initiate an intracellular signal in bSC requires further investigation. PMID- 28917654 TI - The anticancer functions of RIG-I-like receptors, RIG-I and MDA5, and their applications in cancer therapy. AB - Cancer is a major cause of death worldwide, and its incidence and mortality continuously increase in China. Nowadays, cancer heavily influences our health and constitutes enormous burden on society and families. Although there are many tools for cancer treatment, but the overall therapeutic effect is poor. In addition, cancer cells often develop resistance to therapy due to defective cell death or immune escape mechanisms. Therefore, it is a promising way for cancer treatment to effectively activate apoptosis and conquer immunosuppression. RIG-I like receptors (RLRs) belong to RNA-sensing pattern recognition receptors (PRRs), one of the major subsets of PRRs, and play a critical role in sensing RNA viruses and initiate host antiviral responses such as the production of type I interferons (IFNs), proinflammatory cytokines, and other immune response molecules. Recent studies have demonstrated that tumor cells could mimic viral infection to activate viral recognition of immune system and the activation of interferon response pathway. RIG-I and MDA5, two members of RLRs family, could induce growth inhibition or apoptosis of multiple types of cancer cells on the activation by RNA ligands in IFN-dependent or IFN-independent approach. Previous studies have reviewed PRRs as promising immunotherapy targets for colorectal cancer and pancreatic cancer. However, until now, a comprehensive review on the role of RLRs in the development and treatment of various cancers is still lacking. In this article, we reviewed the latest studies on the roles as well as the mechanisms of RIG-I and MDA5 in the development of various cancers and therapeutic potentials of targeting RIG-I and MDA5 for cancer treatment. PMID- 28917656 TI - Is oral all-trans retinoic acid plus danazol a refinement of second-line therapy for primary immune thrombocytopenia in adults? PMID- 28917655 TI - Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5. AB - BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), and lymphotoxin beta (LTbeta) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. METHODS AND RESULTS: LTalpha/TNFalpha/LTbeta triple knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. CONCLUSION: The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure. PMID- 28917657 TI - Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open label, phase 2 trial. AB - BACKGROUND: Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. METHODS: We did a multicentre, randomised, open label, phase 2 study of adult patients (>=18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 * 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12 month sustained response defined as platelet count of 30 * 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 * 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263. FINDINGS: From June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4.94, 95% CI 2.03-12.02, p=0.00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group. INTERPRETATION: Patients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. FUNDING: National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China. PMID- 28917659 TI - Sonification of scalp-recorded frequency-following responses (FFRs) offers improved response detection over conventional statistical metrics. AB - BACKGROUND: The human frequency-following response (FFR) is a neurophonic potential used to examine the brain's encoding of complex sounds (e.g., speech) and monitor neuroplastic changes in auditory processing. Given the FFR's low amplitude (order of nanovolts), current conventions in literature recommend collecting several thousand trials to obtain a robust evoked response with adequate signal-to-noise ratio. NEW METHOD: By exploiting the spectrotemporal fidelity of the response, we examined whether auditory playbacks (i.e., "sonifications") of the neural FFR could be used to assess the quality of running recordings and provide a stopping rule for signal averaging. RESULTS AND COMPARISON WITH EXISTING METHOD: In a listening task over headphones, naive listeners detected speech-evoked FFRs within ~500 sweeps based solely on their perception of the presence/absence of a tonal quality to the response. Moreover, response detection based on aural sonifications offered similar and in some cases a 2-3* improvement over objective statistical techniques proposed in the literature (i.e., MI, SNR, MSC, F-test, Corr). CONCLUSIONS: Our findings suggest that simply listening to FFR responses (sonifications) might offer a rapid technique to monitor real-time EEG recordings and provide a stopping rule to terminate signal averaging that performs comparably or better than current approaches. PMID- 28917658 TI - Multiple events of gene manipulation via in pouch electroporation in a marsupial model of mammalian forebrain development. AB - BACKGROUND: The technique of in utero electroporation has been widely used in eutherians, such as mice and rats, to investigate brain development by selectively manipulating gene expression in specific neuronal populations. A major challenge, however, is that surgery is required to access the embryos, affecting animal survival and limiting the number of times it can be performed within the same litter. NEW METHOD: Marsupials are born at an early stage of brain development as compared to eutherians. Forebrain neurogenesis occurs mostly postnatally, allowing electroporation to be performed while joeys develop attached to the teat. Here we describe the method of in pouch electroporation using the Australian marsupial fat-tailed dunnart (Sminthopsis crassicaudata, Dasyuridae). RESULTS: In pouch electroporation is minimally invasive, quick, successful and anatomically precise. Moreover, as no surgery is required, it can be performed several times in the same individual, and littermates can undergo independent treatments. COMPARISON WITH EXISTING METHOD: As compared to in utero electroporation in rodents, in pouch electroporation in marsupials offers unprecedented opportunities to study brain development in a minimally invasive manner. Continuous access to developing joeys during a protracted period of cortical development allows multiple and independent genetic manipulations to study the interaction of different systems during brain development. CONCLUSIONS: In pouch electroporation in marsupials offers an excellent in vivo assay to study forebrain development and evolution. By combining developmental, functional and comparative approaches, this system offers new avenues to investigate questions of biological and medical relevance, such as the precise mechanisms of brain wiring and the organismic and environmental influences on neural circuit formation. PMID- 28917660 TI - Stereotaxic 18F-FDG PET and MRI templates with three-dimensional digital atlas for statistical parametric mapping analysis of tree shrew brain. AB - BACKGROUND: Tree shrews are proposed as an alternative animal model to nonhuman primates due to their close affinity to primates. Neuroimaging techniques are widely used to study brain functions and structures of humans and animals. However, tree shrews are rarely applied in neuroimaging field partly due to the lack of available species specific analysis methods. NEW METHOD: In this study, 10 PET/CT and 10 MRI images of tree shrew brain were used to construct PET and MRI templates; based on histological atlas we reconstructed a three-dimensional digital atlas with 628 structures delineated; then the digital atlas and templates were aligned into a stereotaxic space. Finally, we integrated the digital atlas and templates into a toolbox for tree shrew brain spatial normalization, statistical analysis and results localization. RESULTS: We validated the feasibility of the toolbox by simulated data with lesions in laterodorsal thalamic nucleus (LD). The lesion volumes of simulated PET and MRI images were (12.97+/-3.91)mm3 and (7.04+/-0.84)mm3. Statistical results at p<0.005 showed the lesion volumes of PET and MRI were 13.18mm3 and 8.06mm3 in LD. COMPARISON WITH EXISTING METHOD(S): To our knowledge, we report the first PET template and digital atlas of tree shrew brain. Compared to the existing MRI templates, our MRI template was aligned into stereotaxic space. And the toolbox is the first software dedicated for tree shrew brain analysis. CONCLUSIONS: The templates and digital atlas of tree shrew brain, as well as the toolbox, facilitate the use of tree shrews in neuroimaging field. PMID- 28917661 TI - Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): Immune responses to Vacc-4x regions on p24 and changes in HIV reservoirs. AB - OBJECTIVES: The REDUC clinical study Part B investigated Vacc-4x/rhuGM-CSF therapeutic vaccination prior to HIV latency reversal using romidepsin. The main finding was a statistically significant reduction from baseline in viral reservoir measurements. Here we evaluated HIV-specific functional T-cell responses following Vacc-4x/rhuGM-CSF immunotherapy in relation to virological outcomes on the HIV reservoir. METHODS: This study, conducted in Aarhus, Denmark, enrolled participants (n = 20) with CD4>500 cells/mm3 on cART. Six Vacc-4x (1.2 mg) intradermal immunizations using rhuGM-CSF (60 MUg) as adjuvant were followed by 3 weekly intravenous infusions of romidepsin (5 mg/m2). Immune responses were determined by IFN-gamma ELISpot, T-cell proliferation to p24 15-mer peptides covering the Vacc-4x region, intracellular cytokine staining (ICS) to the entire HIVGag and viral inhibition. RESULTS: The frequency of participants with CD8+ T cell proliferation assay positivity was 8/16 (50%) at baseline, 11/15 (73%) post vaccination, 6/14 (43%) during romidepsin, and 9/15 (60%)post-romidepsin. Participants with CD8+ T-cell proliferation assay positivity post-vaccination showed reductions in total HIV DNA post-vaccination (p = 0.006; q = 0.183), post latency reversal (p = 0.005; q = 0.183), and CA-RNA reductions post-vaccination (p = 0.015; q = 0.254). Participants (40%) were defined as proliferation 'Responders' having >=2-fold increase in assay positivity post-baseline. Robust ELISpot baseline responses were found in 87.5% participants. No significant changes were observed in the proportion of polyfunctional CD8+ T-cells to HIVGag by ICS. There was a trend towards increased viral inhibition from baseline to post-vaccination (p = 0.08). CONCLUSIONS: In this 'shock and kill' approach supported by therapeutic vaccination, CD8+ T-cell proliferation represents a valuable means to monitor functional immune responses as part of the path towards functional HIV cure. PMID- 28917662 TI - Successful optic nerve regeneration in the senescent zebrafish despite age related decline of cell intrinsic and extrinsic response processes. AB - Dysfunction of the central nervous system (CNS) in neurodegenerative diseases or after brain lesions seriously affects life quality of a growing number of elderly, since the adult CNS lacks the capacity to replace or repair damaged neurons. Despite intensive research efforts, full functional recovery after CNS disease and/or injury remains challenging, especially in an aging environment. As such, there is a rising need for an aging model in which the impact of aging on successful regeneration can be studied. Here, we introduce the senescent zebrafish retinotectal system as a valuable model to elucidate the cellular and molecular processes underlying age-related decline in axonal regeneration capacities. We found both intrinsic and extrinsic response processes to be altered in aged fish. Indeed, expression levels of growth-associated genes are reduced in naive and crushed retinas, and the injury-associated increase in innate immune cell density appears delayed, suggesting retinal inflammaging in old fish. Strikingly, however, despite a clear deceleration in regeneration onset and early axon outgrowth leading to an overall slowing of optic nerve regeneration, reinnervation of the optic tectum and recovery of visual function occurs successfully in the aged zebrafish retinotectal system. PMID- 28917664 TI - Neural correlates of durable memories across the adult lifespan: brain activity at encoding and retrieval. AB - Age-related effects on brain activity during encoding and retrieval of episodic memories are well documented. However, research typically tests memory only once, shortly after encoding. Retaining information over extended periods is critical, and there are reasons to expect age-related effects on the neural correlates of durable memories. Here, we tested whether age was associated with the activity elicited by durable memories. One hundred forty-three participants (22-78 years) underwent an episodic memory experiment where item-context relationships were encoded and tested twice. Participants were scanned during encoding and the first test. Memories retained after 90 minutes but later forgotten were classified as transient, whereas memories retained after 5 weeks were classified as durable. Durable memories were associated with greater encoding activity in inferior lateral parietal and posteromedial regions and greater retrieval activity in frontal and insular regions. Older adults exhibited lower posteromedial activity during encoding and higher frontal activity during retrieval, possibly reflecting greater involvement of control processes. This demonstrates that long-lasting memories are supported by specific patterns of cortical activity that are related to age. PMID- 28917663 TI - Leucine-rich alpha2-glycoprotein overexpression in the brain contributes to memory impairment. AB - We previously reported increase in leucine-rich alpha2-glycoprotein (LRG) concentration in cerebrospinal fluid is associated with cognitive decline in humans. To investigate relationship between LRG expression in the brain and memory impairment, we analyzed transgenic mice overexpressing LRG in the brain (LRG-Tg) focusing on hippocampus. Immunostaining and Western blotting revealed age-related increase in LRG expression in hippocampal neurons in 8-, 24-, and 48 week-old controls and LRG-Tg. Y-maze and Morris water maze tests indicated retained spatial memory in 8- and 24-week-old LRG-Tg, while deteriorated in 48 week-old LRG-Tg compared with age-matched controls. Field excitatory postsynaptic potentials declined with age in LRG-Tg compared with controls at 8, 24, and 48 weeks. Paired-pulse ratio decreased with age in LRG-Tg, while increased in controls. As a result, long-term potentiation was retained in 8- and 24-week-old LRG-Tg, whereas diminished in 48-week-old LRG-Tg compared with age-matched controls. Electron microscopy observations revealed fewer synaptic vesicles and junctions in LRG-Tg compared with age-matched controls, which became significant with age. Hippocampal LRG overexpression contributes to synaptic dysfunction, which leads to memory impairment with advance of age. PMID- 28917665 TI - Improving mitochondrial function significantly reduces metabolic, visual, motor and cognitive decline in aged Drosophila melanogaster. AB - Mitochondria play a major role in aging. Over time, mutations accumulate in mitochondrial DNA leading to reduced adenosine triphosphate (ATP) production and increased production of damaging reactive oxygen species. If cells fail to cope, they die. Reduced ATP will result in declining cellular membrane potentials leading to reduced central nervous system function. However, aged mitochondrial function is improved by long wavelength light (670 nm) absorbed by cytochrome c oxidase in mitochondrial respiration. In Drosophila, lifelong 670-nm exposure extends lifespan and improves aged mobility. Here, we ask if improved mitochondrial metabolism can reduce functional senescence in metabolism, sensory, locomotor, and cognitive abilities in old flies exposed to 670 nm daily for 1 week. Exposure significantly increased cytochrome c oxidase activity, whole body energy storage, ATP and mitochondrial DNA content, and reduced reactive oxygen species. Retinal function and memory were also significantly improved to levels found in 2-week-old flies. Mobility improved by 60%. The mode of action is likely related to improved energy homeostasis increasing ATP availability for ionic ATPases critical for maintenance of neuronal membrane potentials. 670-nm light exposure may be a simple route for resolving problems of aging. PMID- 28917666 TI - Hippocampal neurophysiology is modified by a disease-associated C-terminal fragment of tau protein. AB - The accumulation of cleaved tau fragments in the brain is associated with several tauopathies. For this reason, we recently developed a transgenic mouse that selectively accumulates a C-Terminal 35 kDa human tau fragment (Tau35). These animals develop progressive motor and spatial memory impairment, paralleled by increased hippocampal glycogen synthase kinase 3beta activity. In this neurophysiological study, we focused on the CA1 subfield of the hippocampus, a brain area involved in memory encoding. The accumulation of Tau35 results in a significant increase of short-term facilitation of the synaptic response in the theta frequency range (10 Hz), without affecting basal synaptic transmission and long-term synaptic plasticity. Tau35 expression also alters the intrinsic excitability of CA1 pyramidal neurons. Thus, Tau35 presence is associated with increased and decreased excitability at hyperpolarized and depolarized potentials, respectively. These observations are paralleled by a hyperpolarization of the voltage-sensitivity of noninactivating K+ currents. Further investigation is needed to assess the causal link between such functional alterations and the cognitive and motor impairments previously observed in this model. PMID- 28917667 TI - Amyloid-beta42 clearance and neuroprotection mediated by X-box binding protein 1 signaling decline with aging in the Drosophila brain. AB - The unfolded protein response (UPR) may be pathogenically related to Alzheimer's disease. Yet, the effects of chronic amyloid-beta42 (Abeta42) accumulation and UPR activation upon neurotoxicity remain unclear. Here, we show that neuronal Abeta42 expression in Drosophila activated the inositol-requiring protein-1/X-box binding protein 1 (XBP1) UPR branch before the onset of behavioral impairment and persisted with aging. Early upregulation of hsc3/BiP, a target of XBP1 and activating transcription factor 6 pathways, was also sustained in old animals. Downregulation of XBP1 enhanced neurotoxicity and the accumulation of Abeta42 and polyubiquitinated proteins. Consistently, overexpression of spliced XBP1 reduced Abeta42 and improved geotaxis in old flies. The activation of protein kinase RNA like endoplasmic reticulum (ER) kinase contributed to the age-dependent geotaxis deficit. Spliced XBP1 gene targets ER degradation-enhancing mannosidase-like protein 1, ER degradation-enhancing mannosidase-like protein 2, and HRD1 were elevated in 5-day-old Abeta42-expressing flies as compared to controls but not in 18-day-old flies. Our results indicate that inositol-requiring protein-1/XBP1 activation is neuroprotective and enhances Abeta42 clearance. They also suggest that such response becomes inefficient with aging. PMID- 28917669 TI - Knowledge-driven computational modeling in Alzheimer's disease research: Current state and future trends. AB - Neurodegenerative diseases such as Alzheimer's disease (AD) follow a slowly progressing dysfunctional trajectory, with a large presymptomatic component and many comorbidities. Using preclinical models and large-scale omics studies ranging from genetics to imaging, a large number of processes that might be involved in AD pathology at different stages and levels have been identified. The sheer number of putative hypotheses makes it almost impossible to estimate their contribution to the clinical outcome and to develop a comprehensive view on the pathological processes driving the clinical phenotype. Traditionally, bioinformatics approaches have provided correlations and associations between processes and phenotypes. Focusing on causality, a new breed of advanced and more quantitative modeling approaches that use formalized domain expertise offer new opportunities to integrate these different modalities and outline possible paths toward new therapeutic interventions. This article reviews three different computational approaches and their possible complementarities. Process algebras, implemented using declarative programming languages such as Maude, facilitate simulation and analysis of complicated biological processes on a comprehensive but coarse-grained level. A model-driven Integration of Data and Knowledge, based on the OpenBEL platform and using reverse causative reasoning and network jump analysis, can generate mechanistic knowledge and a new, mechanism-based taxonomy of disease. Finally, Quantitative Systems Pharmacology is based on formalized implementation of domain expertise in a more fine-grained, mechanism-driven, quantitative, and predictive humanized computer model. We propose a strategy to combine the strengths of these individual approaches for developing powerful modeling methodologies that can provide actionable knowledge for rational development of preventive and therapeutic interventions. Development of these computational approaches is likely to be required for further progress in understanding and treating AD. PMID- 28917668 TI - Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production. AB - Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation associated colorectal cancer by accumulation of CD11b+Gr-1+ immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc+Lactobacillus reuteri in the gut resulted in luminal hdc gene expression and histamine production in the intestines of Hdc /- mice. This histamine-producing probiotic decreased the number and size of colon tumors and colonic uptake of [18F]-fluorodeoxyglucose by positron emission tomography in Hdc-/- mice. Administration of L. reuteri suppressed keratinocyte chemoattractant (KC), Il22, Il6, Tnf, and IL1alpha gene expression in the colonic mucosa and reduced the amounts of proinflammatory, cancer-associated cytokines, keratinocyte chemoattractant, IL-22, and IL-6, in plasma. Histamine-generating L. reuteri also decreased the relative numbers of splenic CD11b+Gr-1+ immature myeloid cells. Furthermore, an isogenic HDC-deficient L. reuteri mutant that was unable to generate histamine did not suppress carcinogenesis, indicating a significant role of the cometabolite, histamine, in suppression of chronic intestinal inflammation and colorectal tumorigenesis. These findings link luminal conversion of amino acids to biogenic amines by gut microbes and probiotic mediated suppression of colorectal neoplasia. PMID- 28917670 TI - Morphological characterization and biocontrol effects of Vibrio vulnificus phages against Vibriosis in the shrimp aquaculture environment. AB - The re-emerging field of phage therapy is the potential biocontrol agents for the transfer of virulence factor and to kill their bacterial hosts. In this study, the lytic Vibrio vulnificus phages were studied to provide a better understanding of phage-host interactions and development of phage therapy. Four new V. vulnificus phages were detected from shrimp aquaculture system, named VV1, VV2, VV3 and VV4. All lytic V. vulnificus phages are the Tectiviruses of the family Tectiviridae with typical double layered elongated icosahedral head and tailless morphology. Lytic V. vulnificus phages which infect other Vibrio isolates were further characterized by long term storage, enzymes treatment, organic solvents treatment, detergents treatment, pH stability, temperature stability, agar bioassay method and one-step growth experiment. The effects of chloroform, acetone, ethyl alcohol, methyl alcohol, ribonuclease (RNase), trypsin, protease, Triton-X100 treatments were not affected the growth of VV1, VV2, VV3 and VV4 phages. These phages (VV1-VV4) were inactivated completely with temperature (over 60 degrees C), pH (<3 or >12), lysozyme and sodium dodecyl sulfate (SDS) treatment. One-step growth experiments indicated that the latent period was at 3 h and burst size was at 37 degrees C. Agar bioassay method indicated that the percentage of inhibition was 75% (VV1) and 70% (VV2, VV3 & VV4), respectively. SDS-PAGE analysis of all V. vulnificus phages had similar protein patterns with molecular weight masses of 260, 249, 204, 148, 63, 59, 22 and 15 kDa. Hence, it could be concluded that V. vulnificus phage had a broad lytic spectrum and potential biocontrol of luminous Vibriosis in the shrimp aquaculture system. PMID- 28917671 TI - Scanning electron microscopy and histopathological observations of Beauveria bassiana infection of Colorado potato beetle larvae. AB - Beauveria bassiana is a potential candidate for use as an environmentally friendly bio-pesticide. We studied the infection process and histopathology of B. bassiana strain NDBJJ-BFG infection of the Colorado potato beetle (Leptinotarsa decemlineata) using scanning electron microscopy and hematoxylin-eosin staining of tissue sections. The results show that the fungus penetrated the insect epidermis through germ tubes and appressoria after spraying the larvae with conidial suspensions. The conidia began to germinate after 24 h and invade the epidermis. After 48 h, the conidia invaded the larvae with germ tubes and began to enter the haemocoel. By 72 h, hyphae had covered the host surface and had colonized the body cavity. The dermal layer was dissolved, muscle tissues were ruptured and adipose tissue was removed. The mycelium had damaged the intestinal wall muscles, and invaded into intestinal wall and midfield cells resulting in cell separation and tracheal deformation. After 96 h of inoculation, the internal structure of the larvae was destroyed. The research shows that B. bassiana NDBJJ BFG surface inoculation resulted in a series of histopathological changes to the potato beetle larvae that proved lethal within 72 h. This indicated that this fungus has a high pathogenicity to Colorado potato beetle larvae. PMID- 28917672 TI - Corticosteroids as Co-analgesics With Opioids for Cancer-Related Pain: A Feasibility Study. PMID- 28917673 TI - B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin for Risk Stratification in Low-Flow, Low-Gradient Aortic Stenosis: A Substudy of the TOPAS Study. AB - OBJECTIVES: The objective of this study was to determine the prognostic value of combined measures of B-type natriuretic peptide (BNP) and high-sensitivity cardiac troponin T (hsTnT) in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) who had either a preserved or reduced left ventricular ejection fraction (LVEF). BACKGROUND: An elevated BNP level is associated with increased risk of mortality in patients with LF-LG AS. The incremental prognostic value of hsTnT in these patients is unknown. METHODS: Ninety-eight patients (74 +/- 10 years; 75% men) with LF-LG AS (LVEF <50% and/or stroke volume index <35 ml/m2, mean gradient <40 mm Hg, indexed aortic valve area <0.6 cm2/m2) who were prospectively enrolled in the TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study were included. The cohort was divided into 3 groups according to BNP and hsTnT levels: group A: BNP <550 pg/ml and hsTnT <15 ng/l; group B: BNP >=550 pg/ml or hsTnT >=15 ng/l; and group C: BNP >=550 pg/ml and hsTnT >=15 ng/l. The primary endpoint was all-cause mortality. RESULTS: Twenty-seven patients (27%) were in group A, 39 (40%) were in group B, and 32 (33%) were in group C. During a median follow-up of 2.8 years, 43 patients died. Two-year mortality was higher in group C (41 +/- 9%) than in group B (23 +/- 7%) and group A (5 +/- 4%) (p = 0.002). In group B, there was no significant difference in 2-year mortality rates between the subgroup with hsTnT >=15 ng/l (n = 29) and the subgroup with BNP >=550 pg/ml (n = 10) (26 +/- 9% vs. 11 +/- 10%, respectively; p = 0.21). In multivariable analysis adjusted for age, type of treatment (aortic valve replacement vs. conservative therapy), coronary artery disease, and LVEF, being in group C remained independently associated with an increased risk of mortality (hazard ratio [HR]: 4.25; p = 0.023), and group B tended to have higher mortality (HR: 3.63; p = 0.058) compared with group A. CONCLUSIONS: This study demonstrated the usefulness of combined measures of BNP and hsTnT to enhance risk stratification in patients with LF-LG AS. Patients with elevation of both BNP and hsTnT had a markedly increased risk of mortality. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis [TOPAS]; NCT01835028). PMID- 28917674 TI - Prognostic Value of Risk Factors, Calcium Score, Coronary CTA, Myocardial Perfusion Imaging, and Invasive Coronary Angiography in Kidney Transplantation Candidates. AB - OBJECTIVES: This study sought to perform a prospective head-to-head comparison of the predictive value of clinical risk factors and a variety of cardiac imaging modalities including coronary artery calcium score (CACS), coronary computed tomography angiography (CTA), single-photon emission computed tomography (SPECT), and invasive coronary angiography (ICA) on major adverse cardiac events (MACE) and all-cause mortality in kidney transplantation candidates. BACKGROUND: Current guidelines recommend screening for coronary artery disease in kidney transplantation candidates. Furthermore, noninvasive stress imaging is recommended in current guidelines, despite its low diagnostic accuracy and uncertain prognostic value. METHODS: The study prospectively evaluated 154 patients referred for kidney transplantation. All patients underwent CACS, coronary CTA, SPECT, and ICA testing. The clinical endpoints were extracted from patients' interviews, patients' records, and registries. RESULTS: The mean follow up time was 3.7 years. In total, 27 (17.5%) patients experienced MACE, and 31 (20.1%) patients died during follow-up. In a time-to-event analysis, both risk factors and CACS significantly predicted death, but only CACS predicted MACE. Combining risk factors with CACS identified a very-low-risk cohort with a MACE event rate of 2.1%, and a 1.0% mortality rate per year. Of the diagnostic modalities, coronary CTA and ICA significantly predicted MACE, but only coronary CTA predicted death. In contrast, SPECT predicted neither MACE nor death. CONCLUSIONS: Compared with traditional risk factors and other cardiac imaging modalities, CACS and coronary CTA seem superior for risk stratification in kidney transplant candidates. Applying a combination of risk factors and CACS and subsequently coronary CTA seems to be the most appropriate strategy. (Angiographic CT of Renal Transplantation Candidate Study [ACToR]; NCT01344434). PMID- 28917676 TI - Physiological Determinants of Left Ventricular Mechanical Dispersion: A 2 Dimensional Speckle Tracking Echocardiographic Study in Healthy Volunteers. PMID- 28917675 TI - Regional Variation in Technetium Pyrophosphate Uptake in Transthyretin Cardiac Amyloidosis and Impact on Mortality. AB - OBJECTIVES: This study sought to investigate the regional uptake of technetium 99m-pyrophosphate (TcPYP) in transthyretin cardiac amyloidosis (ATTR) and its association with mortality. BACKGROUND: TcPYP nuclear scintigraphy is a diagnostic and prognostic tool in ATTR. Echocardiography has identified a pattern of regional variation in longitudinal strain (LS) with a gradient of improved strain from base to apex in ATTR. METHODS: Consecutive patients with ATTR were evaluated who underwent TcPYP nuclear scintigraphy with planar and attenuation corrected single-photon emission computed tomography (SPECT). Heart-to contralateral lung (H/CL) ratio was calculated on planar images, and left ventricular (LV) uptake was determined in each of the 17 segments using SPECT. A measure of apical-sparing of myocardial TcPYP uptake, termed the apical-sparing ratio (ASR), was calculated as basal + mid / apical counts. RESULTS: Overall, 54 patients with ATTR (age 78 +/- 9 years, 76% male, 31% hereditary ATTR) were analyzed. There was increased TcPYP uptake in basal and mid relative to apical LV segments, and an apical-sparing LS pattern on echocardiography. The right ventricle similarly showed greater uptake in basal segments. There were 26 deaths over 1.8 years median follow-up. The ASR of TcPYP uptake was associated with age adjusted all-cause mortality (p = 0.013) with worse prognosis seen at levels <2.75. Global LS was also prognostic (p = 0.01), whereas H/CL ratio and total LV uptake indexed to blood pool were not (p = 0.772 and p = 0.850, respectively). The prognostic utility of the ASR persisted in multivariable modeling (p = 0.003), whereas global LS did not. CONCLUSIONS: There is decreased TcPYP uptake in apical as compared to mid and basal segments in the LV, mimicking apical sparing LS seen on echocardiography. Regional distribution of LV TcPYP uptake is associated with mortality, whereas overall amount of uptake as measured by H/CL ratio and indexed LV SPECT uptake is not. PMID- 28917677 TI - Interventional Correction of Sinus Venosus Atrial Septal Defect and Partial Anomalous Pulmonary Venous Drainage: Procedural Planning Using 3D Printed Models. PMID- 28917678 TI - Optical Frequency Domain Imaging Versus Intravascular Ultrasound in Percutaneous Coronary Intervention (OPINION Trial): Results From the OPINION Imaging Study. AB - OBJECTIVES: The authors sought to clarify how intravascular ultrasound (IVUS) and optical coherence tomography affect percutaneous coronary intervention (PCI) with current-generation drug-eluting stents in a pre-specified substudy of the OPINION (OPtical frequency domain imaging versus INtravascular ultrasound in percutaneous coronary interventiON) trial, a multicenter, prospective, randomized, noninferiority trial comparing optical frequency domain imaging (OFDI)-guided PCI with IVUS-guided PCI. BACKGROUND: The impact of these 2 imaging modalities in guiding PCI remains unknown. METHODS: Of 829 patients enrolled in the OPINION trial, 106 were included in the present imaging substudy. Their PCI was guided by either IVUS or OFDI, but all patients were imaged by both modalities after PCI and by OFDI at 8 months. Angiographic, OFDI, and IVUS images were analyzed by independent core laboratories, and statistical analysis was done independently by a dedicated institution. RESULTS: A total of 103 patients underwent either OFDI guided (n = 54) or IVUS-guided (n = 49) PCI. Immediately after PCI, OFDI-guided PCI was associated with a smaller trend of minimum stent area (5.28 +/- 1.65 mm2 vs. 6.12 +/- 2.34 mm2; p = 0.088), fewer proximal stent-edge hematomas (p = 0.04), and fewer irregular protrusions (p = 0.014) than IVUS-guided PCI. At 8 months, the neointima area tended to be smaller in the OFDI-guided PCI group than in the IVUS-guided PCI group (0.56 +/- 0.30 mm2 vs. 0.80 +/- 0.65 mm2; p = 0.057), although the percentage of uncovered struts was significantly higher in the OFDI-guided PCI group than in the IVUS-guided PCI group (6.97 +/- 7.03% vs. 4.67 +/- 6.43%; p = 0.039). The minimum lumen area was comparable in both groups (p = 0.18). CONCLUSIONS: There were several differences in local findings between OFDI- and IVUS-guided PCI as expected given the different protocols for stent sizing in the 2 groups. The minimum lumen area at the 8-month follow-up was comparable, suggesting that OFDI- and IVUS-guided PCI are similarly feasible using the current-generation drug-eluting stents. (OPtical frequency domain imaging versus INtravascular ultrasound in percutaneous coronary interventiON; NCT01873222). PMID- 28917679 TI - Epidemiology of Left Ventricular Systolic Dysfunction and Heart Failure in the Framingham Study: An Echocardiographic Study Over 3 Decades. AB - OBJECTIVES: The purpose of this study was to describe the temporal trends in prevalence of left ventricular systolic dysfunction (LVSD) in individuals without and with heart failure (HF) in the community over a 3-decade period of observation. BACKGROUND: Temporal trends in the prevalence and management of major risk factors may affect the epidemiology of HF. METHODS: We compared the frequency, correlates, and prognosis of LVSD (left ventricular ejection fraction [LVEF] <50%) among Framingham Study participants without and with clinical HF in 3 decades (1985 to 1994, 1995 to 2004, and 2005 to 2014). RESULTS: Among participants without HF (12,857 person-observations, mean age 53 years, 56% women), the prevalence of LVSD on echocardiography decreased (3.38% in 1985 to 1994 vs. 2.2% in 2005 to 2014; p < 0.0001), whereas mean LVEF increased (65% vs. 68%; p < 0.001). The elevated risk associated with LVSD (~2- to 4-fold risk of HF or death) remained unchanged over time. Among participants with new-onset HF (n = 894, mean age 75 years, 52% women), the frequency of heart failure with preserved ejection fraction (HFpEF) increased (preserved LVEF >=50%: 41.0% in 1985 to 1994 vs. 56.17% in 2005 to 2014; p < 0.001) and heart failure with reduced ejection fraction (HFrEF) decreased (reduced LVEF <40%: 44.10% vs. 31.06%; p = 0.002), whereas heart failure with midrange LVEF remained unchanged (LVEF 40% to <50%: 14.90% vs. 12.77%; p = 0.66). Cardiovascular mortality associated with HFrEF declined across decades (hazard ratio: 0.61; 95% confidence interval: 0.39 to 0.97), but remained unchanged for heart failure with midrange LVEF and HFpEF. Approximately 47% of the observed increase in LVEF among those without HF and 75% of the rising proportion of HFpEF across decades was attributable to trends in risk factors, especially a decline in the prevalence of coronary heart disease among those with HF. CONCLUSIONS: The profile of HF in the community has changed in recent decades, with a lower prevalence of LVSD and an increased frequency of HFpEF, presumably due to concomitant risk factor trends. PMID- 28917680 TI - Effusive-Constrictive Pericarditis After Pericardiocentesis: Incidence, Associated Findings, and Natural History. AB - OBJECTIVES: This study sought to investigate the incidence, associated findings, and natural history of effusive-constrictive pericarditis (ECP) after pericardiocentesis. BACKGROUND: ECP is characterized by the coexistence of tense pericardial effusion and constriction of the heart by the visceral pericardium. Echocardiography is currently the main diagnostic tool in the assessment of pericardial disease, but limited data have been published on the incidence and prognosis of ECP diagnosed by echo-Doppler. METHODS: A total of 205 consecutive patients undergoing pericardiocentesis at Mayo Clinic, Rochester, Minnesota, were divided into 2 groups (ECP and non-ECP) based on the presence or absence of post centesis echocardiographic findings of constrictive pericarditis. Clinical, laboratory, and imaging characteristics were compared. RESULTS: ECP was subsequently diagnosed in 33 patients (16%) after pericardiocentesis. Overt clinical cardiac tamponade was present in 52% of ECP patients and 36% of non-ECP patients (p = 0.08). Post-procedure hemopericardium was more frequent in the ECP group (33% vs. 13%; p = 0.003), and a higher percentage of neutrophils and lower percentage of monocytes were noted on pericardial fluid analysis in those patients. Clinical and laboratory findings were otherwise similar. Baseline early diastolic mitral septal annular velocity was significantly higher in the ECP group. Before pericardiocentesis, respiratory variation of mitral inflow velocity, expiratory diastolic flow reversal of hepatic vein, and respirophasic septal shift were significantly more frequent in the ECP group. Fibrinous or loculated effusions were also more frequently observed in the ECP group. Four deaths occurred in the ECP group; all 4 patients had known malignancies. During median follow-up of 3.8 years (interquartile range: 0.5 to 8.3 years), only 2 patients required pericardiectomy for persistent constrictive features and symptoms. CONCLUSIONS: In a large cohort of unselected patients undergoing pericardiocentesis, 16% were found to have ECP. Pre-centesis echocardiographic findings might identify such patients. Long-term prognosis in those patients remains good, and pericardiectomy was rarely required. PMID- 28917681 TI - The Immediate Effects of Statins on Coronary Atherosclerosis: Can Phenotype Explain Outcome? PMID- 28917682 TI - The RAC Sign: Retroaortic Anomalous Coronary Artery Visualization by Transthoracic Echocardiography. PMID- 28917683 TI - Stasis Mapping Using Ultrasound: A Prospective Study in Acute Myocardial Infarction. PMID- 28917684 TI - Role of Low Endothelial Shear Stress and Plaque Characteristics in the Prediction of Nonculprit Major Adverse Cardiac Events: The PROSPECT Study. AB - OBJECTIVES: This study sought to determine whether low endothelial shear stress (ESS) adds independent prognostication for future major adverse cardiac events (MACE) in coronary lesions in patients with high-risk acute coronary syndrome (ACS) from the United States and Europe. BACKGROUND: Low ESS is a proinflammatory, proatherogenic stimulus associated with coronary plaque development, progression, and destabilization in human-like animal models and in humans. Previous natural history studies including baseline ESS characterization investigated low-risk patients. METHODS: In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of MACE attributable to untreated nonculprit (nc) coronary lesions during 3.4-year follow-up were large plaque burden (PB), small minimum lumen area (MLA), and thin-cap fibroatheroma (TCFA) morphology. In this analysis, baseline ESS of nc lesions leading to new MACE (nc-MACE lesions) and randomly selected control nc lesions without MACE (nc-non-MACE lesions) were calculated. A propensity score for ESS was constructed for each lesion, and the relationship between ESS and subsequent nc-MACE was examined. RESULTS: A total of 145 lesions were analyzed in 97 patients: 23 nc-MACE lesions (13 TCFAs, 10 thick-cap fibroatheromas [ThCFAs]), and 122 nc-non-MACE lesions (63 TCFAs, 59 ThCFAs). Low local ESS (<1.3 Pa) was strongly associated with subsequent nc-MACE compared with physiological/high ESS (>=1.3 Pa) (23 of 101 [22.8%]) versus (0 of 44 [0%]). In propensity-adjusted Cox regression, low ESS was strongly associated with MACE (hazard ratio: 4.34; 95% confidence interval: 1.89 to 10.00; p < 0.001). Categorizing plaques by anatomic risk (high risk: >=2 high-risk characteristics PB >=70%, MLA <=4 mm2, or TCFA), high anatomic risk, and low ESS were prognostically synergistic: 3-year nc-MACE rates were 52.1% versus 14.4% versus 0.0% in high-anatomic risk/low-ESS, low-anatomic risk/low-ESS, and physiological/high-ESS lesions, respectively (p < 0.0001). No lesion without low ESS led to nc-MACE during follow-up, regardless of PB, MLA, or lesion phenotype at baseline. CONCLUSIONS: Local low ESS provides incremental risk stratification of untreated coronary lesions in high-risk patients, beyond measures of PB, MLA, and morphology. PMID- 28917685 TI - Leveraging Mobile Technology to Reduce Resource-Related Health Care Disparities: Challenges and Opportunities. PMID- 28917686 TI - Pre-Renal Transplant Risk Stratification: A Perpetual Quandary. PMID- 28917687 TI - Clinical Significance of Right Ventricular Longitudinal Function Parameters After Aortic Valve Replacement. PMID- 28917690 TI - Apical to Base Gradient of Technetium-99m Pyrophosphate Myocardial Counts in Cardiac Amyloidosis: An Insight Into the Mechanism of Myocardial Strain Gradient, or Merely "Clouds That Mimic Land Before the Sailor's Eye?" PMID- 28917691 TI - The Changing Face of Heart Failure. PMID- 28917689 TI - Effect of Early Pitavastatin Therapy on Coronary Fibrous-Cap Thickness Assessed by Optical Coherence Tomography in Patients With Acute Coronary Syndrome: The ESCORT Study. AB - OBJECTIVES: The aim of the present study was to assess the effect of early statin therapy on fibrous-cap thickness in coronary plaques of patients with acute coronary syndrome (ACS) by using optical coherence tomography. BACKGROUND: Statins can contribute to the stabilization of coronary plaques. METHODS: This is a prospective, randomized, active-controlled, single-center study. Patients with ACS and untreated dyslipidemia were enrolled and randomly allocated (ratio 1:1) to either the early statin group (received pitavastatin 4 mg/day from baseline) or the late statin group (received pitavastatin 4 mg/day from 3 weeks after the baseline). Optical coherence tomography was performed at baseline, 3-week, and 36 week follow-up to assess nonculprit coronary plaques in 53 patients. RESULTS: Between baseline and 3-week follow-up, fibrous-cap thickness increased in the early statin group (140 MUm [interquartile range (IQR):120 to 170 MUm] to 160 MUm [IQR: 130 to 190 MUm]; p = 0.017), but decreased in the late statin group (135 MUm [IQR: 110 to 183 MUm] to 130 MUm [IQR: 108 to 160 MUm]; p = 0.020). The percentage of increase in fibrous-cap thickness between baseline and 3-week follow-up was significantly greater in the early statin group compared with the late statin group (8.3% [IQR: 0.0% to 21.4%] vs. -5.8% [IQR: -16.0% to 0.0%]; p < 0.001). Between baseline and 36-week follow-up, fibrous-cap thickness increased comparably in the 2 groups. CONCLUSIONS: Early therapy with pitavastatin 4 mg/day for patients with ACS provided an increase in fibrous-cap thickness in coronary plaques during the first 3 weeks of follow-up and a further increase during 36 weeks of follow-up. The study was registered with UMIN Clinical Trial Registry (Effect of PitavaStatin on Coronary Fibrous-cap Thickness-Assessment by Fourier Domain Optical CoheRence Tomography [ESCORT]; UMIN000002678). PMID- 28917688 TI - A Randomized Trial of Pocket-Echocardiography Integrated Mobile Health Device Assessments in Modern Structural Heart Disease Clinics. AB - OBJECTIVES: This study sought to determine whether mobile health (mHealth) device assessments used as clinical decision support tools at the point-of-care can reduce the time to treatment and improve long-term outcomes among patients with rheumatic and structural heart diseases (SHD). BACKGROUND: Newly developed smartphone-connected mHealth devices represent promising methods to diagnose common diseases in resource-limited areas; however, the impact of technology based care on long-term outcomes has not been rigorously evaluated. METHODS: A total of 253 patients with SHD were randomized to an initial diagnostic assessment with wireless devices in mHealth clinics (n = 139) or to standard-care (n = 114) in India. mHealth clinics were equipped with point-of-care devices including pocket-echocardiography, smartphone-connected-electrocardiogram blood pressure and oxygen measurements, activity monitoring, and portable brain natriuretic peptide laboratory testing. All individuals underwent comprehensive transthoracic echocardiography to assess the severity of SHD. The primary endpoint was the time to referral for therapy with percutaneous valvuloplasty or surgical valve replacement. Secondary endpoints included the probability of a cardiovascular hospitalization and/or death over 1 year. RESULTS: An initial mHealth assessment was associated with a shorter time to referral for valvuloplasty and/or valve replacement (83 +/- 79 days vs. 180 +/- 101 days; p <0.001) and was associated with an increased probability for valvuloplasty/valve replacement compared to standard-care (34% vs. 32%; adjusted hazard ratio: 1.54; 95% CI: 0.96 to 2.47; p = 0.07). Patients randomized to mHealth were associated with a lower risk of a hospitalization and/or death on follow-up (15% vs. 28%, adjusted hazard ratio: 0.41; 95% CI: 0.21 to 0.83; p = 0.013). CONCLUSIONS: An initial mHealth diagnostic strategy was associated with a shorter time to definitive therapy among patients with SHD in a resource-limited area and was associated with improved outcomes. (A Randomized Trial of Pocket-Echocardiography Integrated Mobile Health Device Assessments in Modern Structural Heart Disease Clinics; NCT02881398). PMID- 28917692 TI - The Stress of Plaque Prognostication. PMID- 28917693 TI - How Quickly We Forget. PMID- 28917694 TI - Multibiomarker Strategies in Aortic Stenosis. PMID- 28917695 TI - The impact of GABAergic drugs on TMS-induced brain oscillations in human motor cortex. AB - Brain responses to transcranial magnetic stimulation (TMS) as measured with electroencephalography (EEG) have so far been assessed either by TMS-evoked EEG potentials (TEPs), mostly reflecting phase-locked neuronal activity, or time frequency-representations (TFRs), reflecting oscillatory power arising from a mixture of both evoked (i.e., phase-locked) and induced (i.e., non-phase-locked) responses. Single-pulse TMS of the human primary motor cortex induces a specific pattern of oscillatory changes, characterized by an early (30-200 ms after TMS) synchronization in the alpha- and beta-bands over the stimulated sensorimotor cortex and adjacent lateral frontal cortex, followed by a late (200-400 ms) alpha and beta-desynchronization over the stimulated and contralateral sensorimotor cortex. As GABAergic inhibition plays an important role in shaping oscillatory brain activity, we sought here to understand if GABAergic inhibition contributes to these TMS-induced oscillations. We tested single oral doses of alprazolam, diazepam, zolpidem (positive modulators of the GABAA receptor), and baclofen (specific GABAB receptor agonist). Diazepam and zolpidem enhanced, and alprazolam tended to enhance while baclofen decreased the early alpha-synchronization. Alprazolam and baclofen enhanced the early beta-synchronization. Baclofen enhanced the late alpha-desynchronization, and alprazolam, diazepam and baclofen enhanced the late beta-desynchronization. The observed GABAergic drug effects on TMS-induced alpha- and beta-band oscillations were not explained by drug-induced changes on corticospinal excitability, muscle response size, or resting-state EEG power. Our results provide first insights into the pharmacological profile of TMS induced oscillatory responses of motor cortex. PMID- 28917696 TI - Brain mapping in multiple sclerosis: Lessons learned about the human brain. AB - The application of structural and functional magnetic resonance imaging (MRI) techniques in patients with multiple sclerosis (MS) has certainly helped to improve our understanding of the mechanisms responsible for clinical disability and cognitive impairment in this condition. The numerous studies performed in MS patients have also provided many lessons on the structure-function relationships in the human brain, which could be applied to healthy subjects and to patients affected by other neurological conditions. The findings have allowed a better understanding of the processes involved in the loss of function after central nervous system (CNS) damage, and clarified the substrates of specific symptoms (e.g., cognitive impairment and fatigue), which should aid clinical recovery and help in the monitoring of disease progression. In this review, important examples of how the application of different MRI techniques in MS might provide relevant information on the human brain are discussed. These include how damage to strategic white matter tracts can cause symptoms due to a disconnection mechanism and how involvement of a specific brain network, independent of the underlying pathological substrate, might determine certain symptoms. The role of functional and structural plasticity in clinical recovery (following an acute relapse or promoted by rehabilitation) and the mechanisms that might become the target of treatment aimed at function recovery are also considered. The ways in which network- and system-based analysis can reshape current understanding of the brain structure-function relationships are discussed. Finally, there is speculation about the relevance of inherited or acquired factors, such as age, comorbidity, brain reserve and cognitive reserve, which are likely to influence the relation between CNS damage and disease clinical manifestations. PMID- 28917697 TI - Trajectories of brain system maturation from childhood to older adulthood: Implications for lifespan cognitive functioning. AB - The human brain's intrinsic functional architecture reflects behavioural history and can help elucidate the neural mechanisms underlying age-related cognitive changes. To probe this issue, we used resting state (N = 586) and behavioural (N = 255) data from a lifespan sample and tested the interactions among ten intrinsic neural systems, derived from a well-established whole-brain parcellation. Our results revealed three distinguishable profiles, whose expression strengthened with increasing age and which characterized developmental differences in connectivity within the ten systems, between networks thought to underlie cognitive control and non-control systems, and among the non-control networks. The within-network connectivity profile was typified by decreased connectivity within two external processing networks (auditory/language and ventral attention). The non-control-to-non-control connectivity profile was typified by increased separation between networks involved in external processing, including language (dorsal attention, auditory) and those linked to internally generated cognitions and category learning (default mode, subcortical). Finally, the third connectivity profile was characterized by increased coupling of the three control networks (frontoparietal, salience, cingulo-opercular) with one another and with the remaining systems, particularly the subcortical and the two networks showing declining segregation with age. All three profiles showed significant associations with behavior during young adulthood, although these effects were less discernible during early development (before the age of 21) and degraded during late middle age and older adulthood. An exception to this trend was observed with respect to the within-network connectivity profile, whose "precocious" expression during early development predicted superior cognitive functioning. These findings thus help explain lifespan changes in the quality of mental processes, while also pointing to distinguishable mechanisms, which aid behavioural performance during different life stages. PMID- 28917698 TI - Introducing axonal myelination in connectomics: A preliminary analysis of g-ratio distribution in healthy subjects. AB - Microstructural imaging and connectomics are two research areas that hold great potential for investigating brain structure and function. Combining these two approaches can lead to a better and more complete characterization of the brain as a network. The aim of this work is characterizing the connectome from a novel perspective using the myelination measure given by the g-ratio. The g-ratio is the ratio of the inner to the outer diameters of a myelinated axon, whose aggregated value can now be estimated in vivo using MRI. In two different datasets of healthy subjects, we reconstructed the structural connectome and then used the g-ratio estimated from diffusion and magnetization transfer data to characterize the network structure. Significant characteristics of g-ratio weighted graphs emerged. First, the g-ratio distribution across the edges of the graph did not show the power-law distribution observed using the number of streamlines as a weight. Second, connections involving regions related to motor and sensory functions were the highest in myelin content. We also observed significant differences in terms of the hub structure and the rich-club organization suggesting that connections involving hub regions present higher myelination than peripheral connections. Taken together, these findings offer a characterization of g-ratio distribution across the connectome in healthy subjects and lay the foundations for further investigating plasticity and pathology using a similar approach. PMID- 28917699 TI - The impact of aging on subregions of the hippocampal complex in healthy adults. AB - The hippocampal complex, an anatomical composite of several subregions, is known to decrease in size with increasing age. However, studies investigating which subregions are particularly prone to age-related tissue loss revealed conflicting findings. Possible reasons for such inconsistencies may reflect differences between studies in terms of the cohorts examined or techniques applied to define and measure hippocampal subregions. In the present study, we enhanced conventional MR-based information with microscopically defined cytoarchitectonic probabilities to investigate aging effects on the hippocampal complex in a carefully selected sample of 96 healthy subjects (48 males/48 females) aged 18-69 years. We observed significant negative correlations between age and volumes of the cornu ammonis, fascia dentata, subiculum, and hippocampal-amygdaloid transition area, but not the entorhinal cortex. The estimated age-related annual atrophy rates were most pronounced in the left and right subiculum with -0.23% and -0.22%, respectively. These findings suggest age-related atrophy of the hippocampal complex overall, but with differential effects in its subregions. If confirmed in future studies, such region-specific information may prove useful for the assessment of diseases and disorders known to modulate age-related hippocampal volume loss. PMID- 28917700 TI - Use of molecular data in species-level taxonomy of parasites: A commentary. PMID- 28917701 TI - Paleoecological insights from fossil freshwater mollusks of the Kanapoi Formation (Omo-Turkana Basin, Kenya). AB - The Early Pliocene Kanapoi Formation of the Omo-Turkana Basin consists of two fluvial/deltaic sedimentary sequences with an intermediate lacustrine sequence that was deposited in Paleolake Lonyumun, the earliest large lake in the basin. Overall, the geology and vertebrate paleontology of the Kanapoi Formation are well studied, but its freshwater mollusks, despite being a major component of the benthic ecosystem, have not been subjected to in-depth study. Here I present the first treatment of these mollusks, which have been retrieved mainly from the lacustrine but also from the upper fluvial sediments, with a focus on paleoecological implications. Overall, the freshwater mollusk fauna is reasonably diverse and contains the gastropods Bellamya (Viviparidae), Melanoides (Thiaridae), Cleopatra (Paludomidae) and Gabbiella (Bithyniidae), as well as the unionoid bivalves Coelatura, Pseudobovaria (Unionidae), Aspatharia, Iridina (Iridinidae) and Etheria (Etheriidae). Material is typically recrystallized and lithified and its taphonomy suggests deposition in a system with intermediate energy, such as a beach, with post-depositional deformation and abrasion. The mollusk assemblage is indicative of perennial, fresh and well-oxygenated waters in the Kanapoi region. It suggests that Paleolake Lonyumun had largely open shores with limited vegetation and that swampy or ephemeral backwaters were rare. Overall, these findings support earlier paleoecological interpretations based on the fish assemblage of Paleolake Lonyumun at Kanapoi. Moreover, mollusk assemblages from this lake are very similar across the Omo-Turkana Basin (Nachukui, Usno, Mursi and Koobi Fora Formations) suggesting that the lacustrine paleoecological conditions found in the Kanapoi Formation existed throughout the basin. PMID- 28917702 TI - Hominin track assemblages from Okote Member deposits near Ileret, Kenya, and their implications for understanding fossil hominin paleobiology at 1.5 Ma. AB - Tracks can provide unique, direct records of behaviors of fossil organisms moving across their landscapes millions of years ago. While track discoveries have been rare in the human fossil record, over the last decade our team has uncovered multiple sediment surfaces within the Okote Member of the Koobi Fora Formation near Ileret, Kenya that contain large assemblages of ~1.5 Ma fossil hominin tracks. Here, we provide detailed information on the context and nature of each of these discoveries, and we outline the specific data that are preserved on the Ileret hominin track surfaces. We analyze previously unpublished data to refine and expand upon earlier hypotheses regarding implications for hominin anatomy and social behavior. While each of the track surfaces discovered at Ileret preserves a different amount of data that must be handled in particular ways, general patterns are evident. Overall, the analyses presented here support earlier interpretations of the ~1.5 Ma Ileret track assemblages, providing further evidence of large, human-like body sizes and possibly evidence of a group composition that could support the emergence of certain human-like patterns of social behavior. These data, used in concert with other forms of paleontological and archaeological evidence that are deposited on different temporal scales, offer unique windows through which we can broaden our understanding of the paleobiology of hominins living in East Africa at ~1.5 Ma. PMID- 28917703 TI - Distally Enlarged Feeding Artery Phenomenon in Intracranial Dural Arteriovenous Fistula: Alternative Access Route to Transarterial Intravenous Embolization. AB - BACKGROUND: Transvenous (TV) embolization is ideal for endovascular treatment of intracranial dural arteriovenous fistulas (DAVF). However, it is not always feasible because of various factors, and transarterial (TA) embolization could then be tried. We aimed to determine the incidence of distally enlarged feeding artery phenomenon and the major feeding artery in DAVF. If the TV approach is difficult and this phenomenon is observed, we could use this vessel for transarterial intravenous (TAIV) embolization as an endovascular treatment modality for DAVF. METHODS: Forty-four patients with intracranial DAVF treated by the endovascular procedure between 2009 and 2016 were retrospectively reviewed. Their clinical records, angiography reports, and embolization procedure notes were studied, and their angiographies were chronologically classified into proliferative and restrictive types. RESULTS: In 14 of 44 patients (32%), we observed the distally enlarged feeding artery phenomenon. The most common enlarged artery was the middle meningeal artery. The distally enlarged feeding artery group was predominantly the restrictive type, and the other group was proliferative in nature (P < 0.001). Of the 14 patients, 7 underwent TAIV embolization, and the other 7 underwent TV embolization. CONCLUSIONS: Distally enlarged feeding artery phenomenon was observed in 32% of patients with intracranial DAVF. This group was predominantly the restrictive type. We conclude that this phenomenon might help determine a patient's eligibility for TAIV embolization when TV embolization is difficult or impossible. PMID- 28917704 TI - Accuracy of Pedicle Screw Insertion Among 3 Image-Guided Navigation Systems: Systematic Review and Meta-Analysis. AB - BACKGROUND: Many retrospective studies of pedicle screw placement have revealed that intraoperative navigation systems provide higher accuracy rates and safety than do free-hand techniques. The accuracy of various image-guided navigation systems has been studied; however, differences have not been well defined due to the lack of adequate evidence-based comparative studies. OBJECTIVE: A meta analysis was conducted to focus on the variation in pedicle screw insertion among 3 navigation systems: a 3-dimensional fluoroscopy-based navigation system (3D FluoroNav), a 2-dimensional fluoroscopy-based navigation system (2D FluoroNav), and a conventional computed tomography navigation system (CT Nav). METHODS: We screened for comparative studies on different pedicle screw insertion navigation systems published through January 2017 using the Cochrane Library, Ovid, Web of Science, PubMed, and EMBASE databases. RESULTS: From 125 papers that were identified, 10 articles were finally chosen. The present comparative study included 8 retrospective clinical studies, 1 prospective clinical trial, and 1 randomized controlled cadaveric study. The prevalence rate of pedicle violation in the 3D FluoroNav group was significantly lower than the rates of the 2D FluoroNav group (relative risk [RR] 95%, confidence interval [CI]: 0.16-0.61, P < 0.01) and the CT Nav group (RR 95%, CI: 0.42-0.90, P = 0.01), and the rate of the CT Nav group was significantly lower than that of the 2D FluoroNav group (RR 95%, CI: 0.29-0.81, P < 0.01). CONCLUSION: Significant differences exist among CT Nav, 3D FluoroNav, and 2D FluoroNav. Our review suggests that 3D FluoroNav may be superior to the other 2 methods in reducing pedicle violation and that clinicians should consider 3D FluoroNav as a better choice. PMID- 28917706 TI - The effects of needle damage on annulus fibrosus micromechanics. AB - : Needle puncture of the intervertebral disc can initiate a mechanical and biochemical cascade leading to disc degeneration. Puncture's mechanical effects have been shown near the puncture site, mechanical effects should be observed far, relative to needle size, from the puncture site, given the disc-wide damage induced by the stab. The aim of this work was to quantify these far-field effects, and to observe the local structural damage provoked by the needle. Strips of cow tail annulus fibrosus underwent two consecutive mechanical loadings to 5% tensile strain; fifteen samples were punctured in a radial direction with a randomly assigned needle between the two loadings (needle gauges between 19 and 23). Ten samples (control group) were not punctured. During loading, the tissue strains were imaged using second harmonic generation microscopy in a <600*800um region about 4.4mm from the puncture site. After mechanical testing, the puncture site was imaged in 3D. Puncture had no significant effect on annulus elastic modulus. Imaging showed a modest change in the shearing between fibre bundles however, the linear strain between bundles, intra-bundle shear and linear strain were not significantly affected. At the puncture site, detached lumps of tissue were present. These results suggest that the mechanical effects observed in intact discs are due to the depressurization of the disc, rather than the local damage to the annulus. Needle profiles could be designed, aiming at separating fibre bundles rather than cutting through them, to avoid leaving dying tissue behind. STATEMENT OF SIGNIFICANCE: Needle puncture of the intervertebral disc can initiate a mechanical and biochemical cascade leading to disc degeneration, but the link between the local damage of the puncture and the disc-wide effects is not well understood. This work aimed at determining the micro-mechanical effects of the puncture far from its site, and to observe the damage induced by the puncture with high resolution imaging. Results show that the puncture had modest effect far from the puncture, but lumps of tissue were left by the needle, detached from the disc; these could cause further damage through friction and inflammation of the surrounding tissues. This suggests that the cascade leading to degeneration is probably driven by a biochemical response rather than disc wide mechanical effects. PMID- 28917705 TI - Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume. AB - : Salvaging or functional replacement of damaged tissue caused by stroke in the brain remains a major therapeutic challenge. In situ gelation and retention of a hydrogel bioscaffold composed of 8mg/mL extracellular matrix (ECM) can induce a robust invasion of cells within 24h and potentially promote a structural remodeling to replace lost tissue. Herein, we demonstrate a long-term retention of ECM hydrogel within the lesion cavity. A decrease of approximately 32% of ECM volume is observed over 12weeks. Lesion volume, as measured by magnetic resonance imaging and histology, was reduced by 28%, but a battery of behavioral tests (bilateral asymmetry test; footfault; rotameter) did not reveal a therapeutic or detrimental effect of the hydrogel. Glial scarring and peri-infarct astrocytosis were equivalent between untreated and treated animals, potentially indicating that permeation into host tissue is required to exert therapeutic effects. These results reveal a marked difference of biodegradation of ECM hydrogel in the stroke-damaged brain compared to peripheral soft tissue repair. Further exploration of these structure-function relationships is required to achieve a structural remodeling of the implanted hydrogel, as seen in peripheral tissues, to replace lost tissue and promote behavioral recovery. STATEMENT OF SIGNIFICANCE: In situ gelation of ECM is essential for its retention within a tissue cavity. The brain is a unique environment with restricted access that necessitates image-guided delivery through a thin needle to access tissue cavities caused by stroke, as well as other conditions, such as traumatic brain injury or glioma resection. Knowledge about a brain tissue response to implanted hydrogels remains limited, especially in terms of long-term effects and potential impact on behavioral function. We here address the long-term retention of hydrogel within the brain environment, its impact on behavioral function, as well as its ability to reduce further tissue deformation caused by stroke. This study highlights considerable differences in the brain's long-term response to an ECM hydrogel compared to peripheral soft tissue. It underlines the importance of understanding the effect of the structural presence of a hydrogel within a cavity upon host brain tissue and behavioral function. As demonstrated herein, ECM hydrogel can fill a cavity long-term to reduce further progression of the cavity, while potentially serving as a reservoir for local drug or cell delivery. PMID- 28917707 TI - Amoebicidal, antimicrobial and in vitro ROS scavenging activities of Tunisian Rubus ulmifolius Schott, methanolic extract. AB - The present study aimed to evaluate the activity of methanolic extract of Rubus ulmifolius Schott against the Acanthamoeba castellani Neff Strain as well as its antioxidant and antimicrobial effects. The tested extract has a good amoebicidal activity with low IC50 (61.785 +/- 1.322 MUg/ml) and also has significant activity against both Gram-positive (S. aureus, S. agalactiae) and Gram-negative bacteria (E. coli, S. typhimurium) and against C. albicans. The inhibition zones diameters (IZD) and minimal inhibitory concentration (MIC) values were in the range of 22.5-50 mm and 02.29-4.76 mg ml-1, respectively. In the other hand, the in vitro ROS scavenging activity was evaluated, the tested extract exhibited a good effect on the .OH radical (89.99% at a concentration of 100 MUg/ml) when compared to the ascorbic acid (68.81%). Moreover, the inhibition percentage of superoxide generation by R. ulmifolius extract at 100 MUg/ml was greater than ascorbic acid (79.55; 64.79%, respectively). Also, the tested extract showed a high percentage of H2O2 scavenging activity (99.95% at 100 MUg/ml). Our findings suggest that R. ulmifolius could be a potential source of natural antioxidant in preventing many diseases associated with oxidative stress, amoebic and bacterial infections. PMID- 28917708 TI - Type 2 diabetes mellitus BALB/c mice are more susceptible to granulomatous amoebic encephalitis: Immunohistochemical study. AB - Granulomatous amoebic encephalitis (GAE) is a chronic, difficult to resolve infection caused by amphizoic amoebae of the genus Acanthamoeba, which in most cases occurs in immunosuppressed persons or with chronic diseases such as diabetes. In this study, we describe the early events of A. culbertsoni infection of GAE in diabetic mice model. Diabetes was induced in male BALB/c mice, with a dose of streptozotocin (130 mg/kg). Healthy and diabetic mice were inoculated via intranasal with 1 * 106 trophozoites of A. culbertsoni. Then were sacrificed and fixed by perfusion at 24, 48, 72 and 96 h post-inoculation, the brains and nasopharyngeal meatus were processed to immunohistochemical analysis. Invasion of trophozoites in diabetic mice was significantly greater with respect to inoculated healthy mice. Trophozoites and scarce cysts were immunolocalized in respiratory epithelial adjacent bone tissue, olfactory nerve packets, Schwann cells and the epineurium base since early 24 h post-inoculation. After 48 h, trophozoites were observed in the respiratory epithelium, white matter of the brain, subcortical central cortex and nasopharyngeal associated lymphoid tissue (NALT). At 72 h, cysts and trophozoites were immunolocalized in the olfactory bulb with the presence of a low inflammatory infiltrate characterized by polymorphonuclear cells. Scarce amoebae were observed in the granular layer of the cerebellum without evidence of inflammation or tissue damage. No amoebas were observed at 96 h after inoculation, suggesting penetration to other tissues at this time. In line with this, no inflammatory infiltrate was observed in the surrounding tissues where the amoebae were immunolocalized, which could contribute to the rapid spread of infection, particularly in diabetic mice. All data suggest that trophozoites invade the tissues by separating the superficial cells, penetrating between the junctions without causing cytolytic effect in the adjacent cells and subsequently reaching the CNS, importantly, diabetes increases the susceptibility to amoebae infection, which could favor the GAE development. PMID- 28917709 TI - In vitro interactions of Acanthamoeba castellanii Neff and Vibrio harveyi. AB - Free-living amoebae (FLA) are opportunistic protozoa widely distributed in the environment. They are frequently found in water and soil samples, but they have also been reported to be associated with bacterial human pathogens such as Legionella spp. Campylobacter spp or Vibrio cholerae among others. Including within Vibrio spp. V. harveyi (Johnson and Shunk, 1936) is a bioluminescent marine bacteria which has been found swimming freely in tropical marine waters, being part of the stomach and intestine microflora of marine animals, and as both a primary and opportunistic pathogen of marine animals. Our aim was to study the interactions between Vibrio harveyi and Acanthamoeba castellanii Neff. Firstly, in order to analyze changes in it cultivability, V. harveyi was coincubated with A. castellanii Neff axenic culture and with Acanthamoeba Conditioned Medium (ACM) at different temperatures in aerobic conditions. Interestingly, at 4 degrees C and 18-20 degrees C bacteria were still cultivable in marine agar, at 28 degrees C, in aerobic conditions, but there weren't significant differences comparing with the controls. We also noted an enhanced migration of Acanthamoeba toward V. harveyi on non-nutrient agar plates compared to controls with no bacteria. PMID- 28917710 TI - Molecular identification of Vermamoeba vermiformis from freshwater fish in lake Taal, Philippines. AB - Free Living Amoebae (FLA) are considered ubiquitous. FLAs may infect various biological organisms which act as reservoir hosts. Infected freshwater fishes can pose a public health concern due to possible human consumption. This study aims to identify possible pathogenic FLAs present in freshwater fishes. Seventy five (75) Oreochromis niloticus were studied for the presence of FLAs. Fish organs were suspended in physiologic saline pelleted and cultured in non-nutrient agar (NNA) lawned with Escherichia coli and were incubated in 33 degrees C for 14 days. Eighteen (18) fish gills and nineteen (19) fish intestine samples presented with positive growth. Trophozoites and cystic stages of FLAs were subcultured until homogenous growth was achieved. Cells were harvested from cultured plates and DNA was extracted using Chelex resin. DNA was subjected to polymerase chain reaction using universal forward primer EukA and reverse primer EukB targeting the 18s RNA. Of the 37 plates that presented with positive amoebic growth, 9 samples showed the presence of DNAs and were sent for further purification and sequencing. Basic Local Alignment Search Tool (BLAST) results showed that protists isolated from fish organs in Lake Taal include: Eocercomonas (HM536152), Colpoda steinii (KJ607915) and Vermamoeba vermiformis (KC161965). The results showed that fresh-water fishes can harbour FLAs in the gut. It is proposed that freshwater reservoirs utilized for aquaculture be monitored for the presence of FLAs and extensive study be conducted on the pathogenicity of bacterial endosymbionts and infecting viruses to its mammalian and non-mammalian host. PMID- 28917711 TI - Crocodiles and alligators: Antiamoebic and antitumor compounds of crocodiles. AB - Crocodiles exist in unsanitary environments, feed on rotten meat, are often exposed to heavy metals such as arsenic, cadmium, cobalt, chromium, mercury, nickel, lead, selenium, tolerate high levels of radiation, and are amid the very few species to survive the catastrophic Cretaceous-Tertiary extinction event, nonetheless they can live for up to a 100 years. Moreover, as they live in unhygienic conditions, they regularly come across pathogens. Logically, we postulate that crocodiles possess mechanisms to defend themselves from noxious agents as well as protecting themselves from pathogens. To test this hypothesis, various organ lysates and serum of Crocodylus palustris were prepared. Amoebicidal assays were performed using Acanthamoeba castellanii belonging to the T4 genotype. Cytotoxicity assays were performed using Prostate cancer cells culture by measuring lactate dehydrogenase release as a marker for cell death. Growth inhibition assays were performed to determine the growth inhibitory effects of various organ lysates. Serum and heart lysates of Crocodylus palustris exhibited powerful anti-tumor activity exhibiting more than 70% Prostate cancer cell death (P < 0.05). Additionally, lysates from gall bladder and bile also showed significant host cell cytotoxicity, however intestine, lungs and brain showed partial cytotoxicity. Both sera and heart lysates of Crocodylus palustris abolished Prostate cells growth. Moreover, serum completely abolished A. castellanii viability. For the first time, these findings showed that the organ lysates of Crocodylus palustris exhibit potent anti-amoebic and anti-tumor activity. The discovery of antimicrobial and antitumor activity in crocodile will stimulate research in finding therapeutic molecules from unusual sources, and has potential for the development of novel antitumor/antimicrobial compound(s) that may also overcome drug resistance. Nevertheless, rigorous research in the next few years will be necessary to realize these expectations. PMID- 28917712 TI - Toward classification criteria for early osteoarthritis of the knee. AB - OBJECTIVE: To propose draft classification criteria for early stage osteoarthritis (OA) of the knee for use in a primary care setting. METHODS: A group of basic scientists, physician-scientists, rheumatologists, orthopedic surgeons, and physiotherapists in a workshop setting discussed potential classification criteria for early osteoarthritis of the knee. The workshop was divided into sessions around relevant topics with short state of the art presentations followed by breakout sessions, consensus discussions, and consolidation into a consensus document. RESULTS: Three classes of criteria were agreed: (1) Pain, symptoms/signs, self-reported function, and quality of life using tools such as KOOS: scoring <=85% in at least 2 out of these 4 categories; (2) Clinical examination: at least 1 present out of joint line tenderness or crepitus; (3) Knee radiographs: Kellgren & Lawrence (KL) grade of 0 or 1. MRI is at present not recommended as an aid to identify or define early OA in routine clinical practice or primary care, in light of the absence of validated consensus criteria and the high population prevalence of structural joint changes detected by this method. Biomarkers may have future utility in early OA classification, but no individual or set of biomarkers is yet robust enough. CONCLUSION: Based on our consensus proposal, draft classification criteria for early OA of the knee for use in clinical studies should include patient reported outcomes such as pain and function, together with clinical signs and KL grade 0-1 on radiographs. PMID- 28917713 TI - The BVAS is an independent predictor of cardiovascular events and cardiovascular disease-related mortality in patients with ANCA-associated vasculitis: A study of 504 cases in a single Chinese center. AB - BACKGROUND: Cardiovascular diseases (CVD) are the major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during long-term follow-up. This study investigated risk factors for cardiovascular events (CVE) and CVD-related mortality in Chinese AAV patients. METHODS: Five hundred and four AAV patients in our center were retrospectively included. The predictive value of variables associated with CVE- and CVD-related mortality were analyzed. RESULTS: During follow-up of a median duration of 38 (range 1-228) months, 117 out of 504 patients had CVE. Independent predictors of CVE were age [increase by 10 years, hazard ratio (HR) 1.436, 95% confidence interval (CI) 1.187-1.736, p = 0.000], systolic blood pressure (increase by 10mmHg, HR = 1.171, 95% CI: 1.038-1.321, p = 0.010), estimated glomerular filtration rate (eGFR) (increase by 1mL/min/1.73m2, HR = 0.992, 95% CI: 0.984-0.999, p = 0.020), high density lipoprotein level (HR = 0.530, 95% CI: 0.303-0.926, p = 0.026) and the Birmingham Vasculitis Activity Score (BVAS) (HR = 1.039, 95% CI: 1.011-1.067, p = 0.006). Forty-one patients died from CVD. Independent predictors of CVD-related mortality were age (increase by 10 years; HR = 1.732, 95% CI: 1.237-2.426, p = 0.001), eGFR (increase by 1mL/min/1.73m2, HR = 0.984, 95% CI: 0.970-0.997, p = 0.016), pre-existing CV disease (HR = 2.872, 95% CI: 1.503-5.487, p = 0.001) and BVAS (HR = 1.064, 95% CI: 1.018-1.113, p = 0.006). We further analyzed CVE- and CVD-related mortality after 2 years since diagnosis, and found BVAS were still an independent predictor of CVE- and CVD-related mortality. CONCLUSION: Besides the traditional risk factors, BVAS at presentation was an independent predictor of CVE- and CVD-related mortality in patients with AAV. PMID- 28917714 TI - Mitochondria in the nervous system: From health to disease, Part I. AB - In Part I of this Special Issue on "Mitochondria in the Nervous System: From Health to Disease", the editors bring together contributions from experts in brain mitochondrial research to provide an up-to-date overview of mitochondrial functioning in physiology and pathology. The issue provides cutting edge reviews on classical areas of mitochondrial biology that include energy substrate utilization, calcium handling, mitochondria-endoplasmic reticulum communication, and cell death regulation. Additional reviews and original research articles touch upon key mitochondrial defects seen across multiple neurodegenerative conditions, including fragmentation, loss of respiratory capacity, calcium overload, elevated reactive oxygen species generation, perturbed NAD+ metabolism, altered protein acetylation, and compromised mitophagy. Emerging links between the genetics of neurodegenerative disorders and disruption in mitochondrial function are discussed, and a new mouse model of Complex I deficiency is described. Finally, novel ways to rescue mitochondrial structure and function in acute and chronic brain injury are explored. PMID- 28917715 TI - Attentional control predicts change in bias in response to attentional bias modification. AB - Procedures that effectively modify attentional bias to negative information have been examined for their potential to be a source of therapeutic change in emotional vulnerability. However, the degree to which these procedures modify attentional bias is subject to individual differences. This generates the need to understand the mechanisms that influence attentional bias change across individuals. The present study investigated the association between individual differences in attentional control and individual differences in the magnitude of bias change evoked by an attentional bias modification procedure. The findings demonstrate that individual differences in two facets of attentional control, control of attentional inhibition and control of attentional selectivity, were positively associated with individual differences in the magnitude of attentional bias change. The present findings inform upon the cognitive mechanisms underpinning change in attentional bias, and identify a target cognitive process for research seeking to enhance the therapeutic effectiveness of attentional bias modification procedures. PMID- 28917716 TI - 58-Year-Old Woman With Diarrhea, Weakness, and Memory Loss. PMID- 28917717 TI - 20-Year-Old Woman With Postprandial Nausea, Vomiting, and Abdominal Pain. PMID- 28917718 TI - Olfactory toxicity in rats following manganese chloride nasal instillation: A pilot study. AB - Following inhalation, manganese travels along the olfactory nerve from the olfactory epithelium (OE) to the olfactory bulb (OB). Occupational exposure to inhaled manganese is associated with changes in olfactory function. This pilot study evaluated two related hypotheses: (a) intranasal manganese administration increases OE and OB manganese concentrations; and (b) intranasal manganese exposure impairs performance of previously trained rats on a go-no-go olfactory discrimination (OD) task. Male Fischer 344 rats were trained to either lever press ("go") in response to a positive conditioned stimulus (CS+: vanillin) or to do nothing ("no go") when a negative conditioned stimulus (CS-: amyl acetate) was present. Following odor training, rats were randomly assigned to either a manganese (200mM MnCl2) or 0.9% saline treatment group (n=4-5 rats/group). Administration of either saline or manganese was performed on isoflurane anesthetized rats as 40MUL bilateral intranasal instillations. Rats were retested 48h later using the vanillin/amyl acetate OD task, then euthanized, followed by collection of the OE and OB. Manganese concentrations in tissue samples were analyzed by ICP-MS. An additional cohort of rats (n=3-4/group) was instilled similarly with saline or manganese and nasal and OB pathology assessed 48h later. Manganese-exposed rats had increased manganese levels in both the OE and OB and decreased performance in the OD task when compared with control animals. Histopathological evaluation of the caudal nasal cavity showed moderate, acute to subacute suppurative inflammation of the olfactory epithelium and submucosa of the ethmoid turbinates and mild suppurative exudate in the nasal sinuses in animals given manganese. No histologic changes were evident in the OB. The nasal instillation and OD procedures developed in this study are useful methods to assess manganese - induced olfactory deficits. PMID- 28917719 TI - Polymorphisms in manganese transporters show developmental stage and sex specific associations with manganese concentrations in primary teeth. AB - BACKGROUND: Manganese (Mn) is an essential metal that can become neurotoxic at elevated levels with negative consequences on neurodevelopment. We have evaluated the influence of single nucleotide polymorphisms (SNPs) in Mn transporter genes SLC30A10 and SLC39A8 on Mn concentrations in dentine, a validated biomarker that reflects Mn tissue concentrations early in life. METHODS: The study included 195 children with variable environmental Mn exposure. Mn concentrations in dentine representing fetal, early postnatal and early childhood developmental periods were measured using laser ablation-inductively coupled plasma mass spectrometry. SLC30A10 rs12064812 (T/C) and SLC39A8 rs13107325 (C/T) were genotyped by TaqMan real time PCR and SLC30A10 rs1776029 (G/A) by pyrosequencing; and SNPs were analyzed in association with Mn in dentine. RESULTS: SLC39A8 rs13107325 rare allele (T) carriers had significantly higher Mn concentrations in postnatal dentine (110%, p=0.008). For all SNPs we also observed non-significant associations with Mn concentrations in dentine in opposite directions for fetal and early postnatal periods. Furthermore, there were significant differences in the influence of SLC30A10 rs1776929 genotypes on Mn concentrations in dentine between sexes. DISCUSSION: The findings from this study indicate that common SNPs in Mn transporters influence Mn homeostasis in early development and may therefore be important to consider in future studies of early life Mn exposure and health effects. Our results also suggest that the influence of these transporters on Mn regulation may differ by developmental stage, as well as between girls and boys. PMID- 28917720 TI - A novel mutation in the JH4 domain of JAK3 causing severe combined immunodeficiency complicated by vertebral osteomyelitis. AB - JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T B+NK- severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity. PMID- 28917721 TI - Low levels of the immunoregulator Semaphorin 4D (CD100) in sera of HIV patients. AB - INTRODUCTION: Semaphorin-4D (CD100), generated by CD4/CD8 T-cells and its receptor on B cells - CD72, play a role in immune regulation. Both have soluble forms - sCD100/sCD72. METHODS: sCD100 and sCD72 levels were determined by ELISA (MyBioSource, USA). RESULTS: 28 chronic HIV patients and 50 matched healthy volunteers participated in our study. Before treatment, CD4 T-cells counts were 267 +/- 216 cells/mcl and viral load (VL) was 586,675 +/- 1897,431 copies/ml. Two years following HAART, CD4 T-cells counts rose to 475 +/- 264 cells/mcl and VL dropped to 2050 +/- 10,539 copies/ml. CD8 T-cells counts were stable. sCD72 levels prior (4.13 +/- 2.03 ng/ml) and following HAART (3.53 +/- 2.01 ng/ml) were similar to control levels (4.51 +/- 2.66 ng/ml). sCD100 levels before (40.47 +/- 31.4 ng/ml) and following HAART (37.68 +/- 29.44 ng/ml) were significantly lower compared to controls (99.67 +/- 36.72 ng/ml) despite the significant increase in CD4 T-cells counts. CONCLUSIONS: The permanent low levels of the immunoregulator sCD100 suggest a role for CD100 in the immune dysfunction and T cells exhaustion of HIV. PMID- 28917722 TI - Asthmatic farm children show increased CD3+CD8low T-cells compared to non asthmatic farm children. PMID- 28917724 TI - Backward genotype-transcript-phenotype association mapping. AB - Genome-wide association studies have discovered a large number of genetic variants associated with complex diseases such as Alzheimer's disease. However, the genetic background of such diseases is largely unknown due to the complex mechanisms underlying genetic effects on traits, as well as a small sample size (e.g., 1000) and a large number of genetic variants (e.g., 1 million). Fortunately, datasets that contain genotypes, transcripts, and phenotypes are becoming more readily available, creating new opportunities for detecting disease associated genetic variants. In this paper, we present a novel approach called "Backward Three-way Association Mapping" (BTAM) for detecting three-way associations among genotypes, transcripts, and phenotypes. Assuming that genotypes affect transcript levels, which in turn affect phenotypes, we first find transcripts associated with the phenotypes, and then find genotypes associated with the chosen transcripts. The backward ordering of association mappings allows us to avoid a large number of association testings between all genotypes and all transcripts, making it possible to identify three-way associations with a small computational cost. In our simulation study, we demonstrate that BTAM significantly improves the statistical power over "forward" three-way association mapping that finds genotypes associated with both transcripts and phenotypes and genotype-phenotype association mapping. Furthermore, we apply BTAM on an Alzheimer's disease dataset and report top 10 genotype-transcript-phenotype associations. PMID- 28917723 TI - Increased innate type 2 immune response in house dust mite-allergic patients with allergic rhinitis. AB - Group 2 innate lymphoid cells (ILC2s) are essential in initiating and driving allergic immune responses. However, there were inconsistent findings of the ILC2 levels in allergic rhinitis (AR) patients. This study investigated the ILC2 levels in the peripheral blood of house dust mite (HDM)-sensitized AR patients and their ability to secrete type 2 cytokines. The levels of ILC2s with phenotypic ILC2 characteristics were increased in the HDM-AR patients. The AR patients' symptom score and IL-13 levels were positively associated with the ILC2s in HDM-AR patients. The epithelial cytokine stimulation induced dramatic production of IL-5 and IL-13 in PBMCs of AR patients. We successfully sorted ILC2s from AR patients and identified their ability of type 2 cytokines production. The number of ILC2s increased in the HDM-AR patients and ILC2s produced the amount of TH2 cytokines in the presence of epithelial cytokines, which suggested the important role of ILC2 in AR patients. PMID- 28917725 TI - A computational approach for phenotypic comparisons of cell populations in high dimensional cytometry data. AB - BACKGROUND: Cytometry is an experimental technique used to measure molecules expressed by cells at a single cell resolution. Recently, several technological improvements have made possible to increase greatly the number of cell markers that can be simultaneously measured. Many computational methods have been proposed to identify clusters of cells having similar phenotypes. Nevertheless, only a limited number of computational methods permits to compare the phenotypes of the cell clusters identified by different clustering approaches. These phenotypic comparisons are necessary to choose the appropriate clustering methods and settings. Because of this lack of tools, comparisons of cell cluster phenotypes are often performed manually, a highly biased and time-consuming process. RESULTS: We designed CytoCompare, an R package that performs comparisons between the phenotypes of cell clusters with the purpose of identifying similar and different ones, based on the distribution of marker expressions. For each phenotype comparison of two cell clusters, CytoCompare provides a distance measure as well as a p-value asserting the statistical significance of the difference. CytoCompare can import clustering results from various algorithms including SPADE, viSNE/ACCENSE, and Citrus, the most current widely used algorithms. Additionally, CytoCompare can generate parallel coordinates, parallel heatmaps, multidimensional scaling or circular graph representations to visualize easily cell cluster phenotypes and the comparison results. CONCLUSIONS: CytoCompare is a flexible analysis pipeline for comparing the phenotypes of cell clusters identified by automatic gating algorithms in high-dimensional cytometry data. This R package is ideal for benchmarking different clustering algorithms and associated parameters. CytoCompare is freely distributed under the GPL-3 license and is available on https://github.com/tchitchek-lab/CytoCompare. PMID- 28917726 TI - Ovulation and fertility responses for sows receiving once daily boar exposure after weaning and OvuGel(r) followed by a single fixed time post cervical artificial insemination. AB - Boar exposure is used to stimulate follicle development and estrus in sows after weaning and also to improve semen uptake and sperm transport with insemination. However, the need and value of boar exposure is uncertain when ovulation induction is used. These studies were designed to determine the effect of daily boar exposure after weaning when used with ovulation induction and fixed time post-cervical artificial insemination (PCAI). In experiment 1, sows were weaned into stalls and assigned to receive 3 min of daily fenceline boar exposure (BE, n = 7) or no boar exposure (NBE, n = 8). All sows received OvuGel at 96 h after weaning and BE or NBE 30 min prior to a single PCAI 24 h after OvuGel. Ovaries were assessed daily for follicle size from weaning until ovulation. Cervical contractions were measured 30 min following BE or NBE and before PCAI, while uterine contractions were measured for 1 h following PCAI. In experiment 2, weaned sows (n = 244) were assigned by parity to receive once daily BE for 1.5 min each day or NBE. OvuGel, PCAI and ultrasound methods were performed similarly as in experiment 1. Results from experiment 1 indicated BE did not significantly influence follicle size or measures of fertility. However, BE did increase the frequency of cervical contractions (P < 0.05), but with no effect on the uterus. Results from experiment 2 indicated BE had no effect on catheter passage for PCAI but did increase the proportion of sows ovulating within 48 h after OvuGel (77.7 vs 67.5%, P = 0.05), and tended (P = 0.10) to increase the proportion of sows inseminated 24 h before ovulation (70.3 vs. 61.0%). However, BE had no effect on adjusted farrowing rate (84.4 vs. 77.4%) or total pigs born (13.2 vs. 12.5) for BE and NBE, respectively. There were treatment and parity interactions for follicle size at time of OvuGel and at time of PCAI (P < 0.05) with BE minimizing parity effects on follicle size. Parity effects were also evident on farrowing rate and litter size when inseminations occurred >24 h from ovulation but not when inseminations occurred <=24 h before ovulation. The results indicate that boar exposure for only minutes each day after weaning had beneficial effects for improving follicle development, ovulation induction, and AI timing, most notably in parity 1 sows, but had no beneficial or detrimental effects on the ability to perform PCAI. PMID- 28917727 TI - A novel colorimetric and fluorescent probe for simultaneous detection of SO32 /HSO3- and HSO4- by different emission channels and its bioimaging in living cells. AB - A novel fluorescent probe (E)-3-ethyl-2-(4-hydroxystyryl)-1,1-di-methyl-1H-benzo [e]indolium iodide (probe EDB) based on benzo[e]indolium was synthesized, which provided the simultaneous detection of SO32-/HSO3- and HSO4- ion with different emission channels. Based on the principle of ion-induced rotation-displaced H aggregates, when treated with NaHSO4, a fluorescence enhancement at 580nm was observed with the excitation wavelength at 420nm. While, in the advantage of the nucleophilic addition of SO32- to the vinyl group, strong fluorescence was obtained at 455nm when treated with Na2SO3 with the excitation wavelength at 320nm, along with obvious color change by naked eyes. So the probe could be applied to sense SO32-/HSO3- and HSO4- ion via different excited and emission channels simultaneously. The probe was also applicable for fluorescence imagings of bisulfite and hydrosulfate in HeLa cells. PMID- 28917728 TI - Fast method for the simultaneous determination of monomethylmercury and inorganic mercury in rice and aquatic plants. AB - Recent investigations revealed that monomethylmercury (MMHg) can be absorbed and accumulated by plants, i.e. rice crops, thus becoming an important route of human exposure to MMHg through diet. The increasing concern about this fact makes that appropriate analytical methods for Hg speciation in these samples are urgently required. Therefore, the aim of this work has been the development of a fast and sensitive method which enables the simultaneous determination of MMHg and inorganic Hg in rice and aquatic plants. The proposed methodology is based on the extraction of Hg species by closed-vessel microwave heating, subsequent derivatization by ethylation and analysis by gas chromatography coupled to atomic fluorescence detection via pyrolysis (GC-pyro-AFS). A careful optimization of the extraction, using both acid (6N HNO3) and alkaline (tetramethylammonium hydroxide, TMAH) extractants, and derivatization conditions has been carried out. Spiked and unspiked aquatic plants (Typha domingensis) and CRMs certified for Total-Hg (BCR-60, BCR-482 and NCS ZC73027, corresponding to aquatic plant, lichen and rice, respectively) have been used. Under the final optimized conditions the simultaneous determination of MMHg and inorganic Hg can be carried out in less than 40min with no tedious clean-up steps. Quantitative recoveries (from 92% to 101%) were obtained in aquatic plants (Typha domingensis) and CRMs spiked with known concentrations of MMHg. For unspiked BCR-60 and BCR-482, no statistically significant differences (p=0.05) were found in Total-Hg concentrations between those obtained by the sum of species and the certified values for both acid and alkaline extraction. For the analysis of low Hg polluted samples, an additional preconcentration step by evaporation under nitrogen stream was required but adequate blanks were only obtained for acid extraction. Detection limits in the low ng/g range (0.7-1.0ng/g) were consequently achieved for both Hg species in the case of acid extraction and the analysis of NCS ZC73027 gave satisfactory results without statistically significant differences between the found and certified values (p = 0.05). PMID- 28917729 TI - HPLC-APCI-MS/MS method development and validation for determination of tocotrienols in human breast adipose tissue. AB - For the last decade, significant attention has been paid to the potential role of tocotrienols in prevention and therapy of breast cancer. Therefore, the aim of this study was to develop and validate analytical method for quantitative determination of tocotrienols (alpha-, beta-, gamma- and delta-tocotrienol) in human breast adipose tissue with the use of high performance liquid chromatography coupled with APCI-MS/MS detection. Separation of target compounds was achieved within 10min with the use of naphthylethyl Cosmosil 2.5pi-NAP column with methanol/water mixture (90:10, v/v) under isocratic elution. Adipose tissue samples were obtained from breast cancer patients and women deceased as a result of accidents. Sample preparation procedure was optimized with the application of the Plackett-Burman design and included tissue homogenization with the use of isopropanol/ethanol/aqueous 0.1% FA mixture (13:3:8, v/v), centrifugation and solid phase extraction (SPE). The method was validated in terms of linearity, precision, accuracy, stability (bench top, autosampler, postpreparative, freeze and thaw stability), matrix effect (ME), recovery (RE) and process efficiency (PE). As for all four tocotrienols ME was negligible (< 15%), precision and accuracy tests were performed with the use of tocotrienols' standard solutions within the ranges of 10.0-400.0ng/g for all four tocotrienols. As the validation requirements were met, the validated method was applied for quantitative analysis of tocotrienols in breast cancer patients. PMID- 28917730 TI - Direct and comprehensive analysis of dyes based on integrated molecular and structural information via laser desorption laser postionization mass spectrometry. AB - Laser desorption laser postionization time-of-flight mass spectrometry (LDPI TOFMS) was employed for direct analysis and determination of typical basic dyes. It was also used for the analysis and comprehensive understanding of complex materials such as blue ballpoint pen inks. Simultaneous emergences of fragmental and molecular information largely simplify and facilitate unambiguous identification of dyes via variable energy of 266nm postionization laser. More specifically, by optimizing postionization laser energy with the same energy of desorption laser, the structurally significant results show definite differences in the fragmentation patterns, which offer opportunities for discrimination of isomeric species with identical molecular weight. Moreover, relatively high spectra resolution can be acquired without the expense of sensitivity. In contrast to laser desorption/ionization mass spectrometry (LDI-MS), LDPI-MS simultaneously offers valuable molecular information about dyes in traces, solvents and additives about inks, thereby offering direct determination and comprehensive understanding of blue ballpoint inks and giving a high level of confidence to discriminate the complicated evidentiary samples. In addition, direct analysis of the inks not only allows the avoidance of the tedious sample preparation processes, significantly shortening the overall analysis time and improving throughput, but allows minimized sample consumption which is important for rare and precious samples. PMID- 28917731 TI - Chain-length dependent interfacial immunoreaction kinetics on self-assembled monolayers revealed by surface-enhanced infrared absorption spectroscopy. AB - Self-assembled monolayer (SAM) has been extensively applied as ideal interface layer for construction of biosensors. Its chain length and end functional groups determine the physical and chemical properties of the modified surfaces, which will affect the performance of constructed biosensors. Herein, we studied the influence of chain length of n-alkanethiols SAMs on the immunoreaction kinetics employing attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS). Antibody (rabbit immunoglobulin) is assembled on carboxyl terminated SAMs of n-alkanethiols with different chain lengths (n = 3, 6, 11, 16). The whole fabrication steps of the immunoassay can be monitored in situ by the ATR-SEIRAS. From the time-dependent SEIRA spectra, the interfacial immunoreaction kinetics between the immobilized antibody and antigen (goat anti rabbit immunoglobulin) can be evaluated. We found that the immunoreaction became faster with increasing the chain length of SAMs. This chain length dependent kinetics might be attributed to different orientations of the assembled antibody caused by different packing densities of SAMs. The present research offers a sensing platform to evaluate immunoassay kinetics and provides fundamentals for construction of immunoassay with high performance. PMID- 28917732 TI - Staying alive! Sensors used for monitoring cell health in bioreactors. AB - Current and next generation sensors such as pH, dissolved oxygen (dO) and temperature sensors that will help drive the use of single-use bioreactors in industry are reviewed. The current trend in bioreactor use is shifting from the traditional fixed bioreactors to the use of single-use bioreactors (SUBs). However as the shift in paradigm occurs there is now a greater need for sensor technology to play 'catch up' with the innovation of bioreactor technology. Many of the sensors still in use today rely on technology created in the 1960's such as the Clark-type dissolved oxygen sensor or glass pH electrodes. This is due to the strict requirements of sensors to monitor bioprocesses resulting in the use of traditional well understood methods, making it difficult to incorporate new sensor technology into industry. A number of advances in sensor technology have been achieved in recent years, a few of these advances and future research will also be discussed in this review. PMID- 28917733 TI - Stabilization of gas-phase uranyl complexes enables rapid speciation using electrospray ionization and ion mobility-mass spectrometry. AB - Significant challenges exist when characterizing f-element complexes in solution using traditional approaches such as electrochemical and spectroscopic techniques as they do not always capture information for lower abundance species. However, provided a metal-complex with sufficient stability, soft ionization techniques such as electrospray offer a means to quantify and probe the characteristics of such systems using mass spectrometry. Unfortunately, the gas-phase species observed in ESI-MS systems do not always reflect the solution phase distributions due to the inherent electrochemical mechanism of the electrospray process, ion transfer from ambient to low pressures conditions, and other factors that are related to droplet evaporation. Even for simple systems (e.g. hydrated cations), it is not always clear whether the distribution observed reflects the solution phase populations or whether it is simply a result of the ionization process. This complexity is further compounded in mixed solvent systems and when multiply charged species are present. Despite these challenges, the benefits of mass spectrometry with respect to speed, sensitivity, and the ability to resolve isotopes continue to drive efforts to develop techniques for the speciation of metal complexes. Using an electrospray ionization atmospheric pressure ion mobility mass spectrometer (ESI-apIMS-MS), we demonstrate an approach to stabilize simple uranyl complexes during the ionization process and mobility separation to aid speciation and isotope profile analysis. Specifically, we outline and demonstrate the capacity of ESI-apIMS-MS methods to measure mobilities of different uranyl species, in simple mixtures, by promoting stable gas phase conformations with the addition of sulfoxides (i.e. dimethyl sulfoxide (DMSO), dibutyl sulfoxide (DBSO), and methyl phenyl sulfoxide (MPSO)). Addition of these sulfoxides, as observed in the mass spectrum and mobility domain, produce stable gas-phase conformations that enable the observation of the counter anion pair while minimizing the range of ligand exchange events as the ionized complex enters the gas-phase. Other enhancements include improved data acquisition times by applying multiplexing approaches to the IMS Bradbury-Nielsen (BN) gate to realize increased ion transmission and improve ion statistics measured at the m/z detector. Analyte identification using this approach is based on a multitude of combined measured gas-phase ion metrics, which include mass measurements, isotope profiling, and experimentally determined reduced mobilities measured at the low-field limit (<2 E/N). Though geared initially towards uranyl complexes, this approach may find application in fields where both chemical speciation and isotopic profiles provide diagnostic information for a given metal. PMID- 28917734 TI - A novel benzothiazole-based fluorescent probe for cysteine detection and its application on test paper and in living cells. AB - A novel simple and readily synthesized turn-on fluorescent probe 4 (benzo[d]thiazol-2-yl)-1,3-phenylene bis(2-chloroacetate) (BPBC) for cysteine (Cys) was reported. This probe was designed based on an excited-state intramolecular proton transfer (ESIPT) dye: benzothiazole, and two chloroacetate groups present in benzothiazole as the reaction sites for Cys. It shows high selectivity and sensitivity for Cys over other amino acids including the similar structured homocysteine (Hcy) and glutathione (GSH). In addition, probe BPBC was successfully applied to bioimage intracellular Cys in living cells with low cytotoxicity. More importantly, a paper test strip system was developed with probe BPBC for Cys detection conveniently. PMID- 28917735 TI - Trace analysis of nitrite ions in environmental samples by using in-situ synthesized Zein biopolymeric nanoparticles as the novel green solid phase extractor. AB - For the first time, a novel green method using Zein biopolymeric nanoparticles as a green dispersive solid-phase extractor is reported for the separation and preconcentration of trace amount of nitrite (NO2-) ions in ppb levels. The Zein protein is a biodegradable hydrophobic plant protein that is obtained from corn and is composed of a number of hydrophobic amino acids. Zein bionanoparticles were synthesized in an anti-solvent process and used as a new biosorbent in the extraction technique. In the proposed technique, by using a standard method at first, a mixture of 1-naphthylamine and sulphanilic acid as selective regents was added to the samples, and in the presence of the nitrite ion, a red azo product was formed. After that, the ethanolic Zein solution (equal to 15mg) was injected rapidly into the sample, based on the anti-solvent process. Zein bionanoparticles (BNPs) were produced, the adsorbed colour product was separated by centrifugation, and finally samples were analysed with the spectrophotometric method. The influence of different variables such as pH, buffer and amount of buffer, amount of adsorbent and effect of time on extraction were investigated and Zein BNPs were characterized by TEM, SEM, and FT-IR techniques. The main advantages of Zein as a new solid-phase extractor are that this biopolymer is non toxic, stable, widely available, biodegradable, very hydrophobic, and can be fabricated easily. Under optimal experimental conditions, the linear correlation coefficient (r2) was found to be 0.9972 at the concentration range of 5.0 1000ngmL-1. The limit of detection was 2.3ngmL-1 (0.05MUM). This method was applied successfully for the analysis of sea and river waters as well as industrial wastewater samples. Finally, this method follows the US EPA (US Environmental Protection Agency) and WHO (World Health Organization) international standards for nitrite analysis. In addition, it has several advantages to warrant its applicability in the near future in separation science as a green biosorbent in both dispersive and normal solid-phase extraction. PMID- 28917736 TI - Off-line microextraction by packed sorbent combined with on solid support derivatization and GC-MS: Application for the analysis of five pyrethroid metabolites in urine samples. AB - A novel, fast and eco-friendly analytical method using microextraction by packed sorbent coupled to large volume injection-gas chromatography-mass spectrometry (MEPS-LVI-GC-MS) was developed for the determination of five pyrethroid metabolites (cis-2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl) cyclopropanecarboxylic acid, cis/trans-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropane-1-carboxylic acids, cis-(2,2-dibromovinyl)-2,2 dimethylcyclopropane-1-carboxylic acid and 3-phenoxybenzoic acid) in human urine. MEPS was performed off-line using a manually-operated semiautomatic syringe (eVol), and several parameters including the sample pH, extraction sorbent, washing solvent, volume and type of elution solvent and number of draw-eject cycles were optimized. Analytes were extracted from enzymatically hydrolyzed urine using a C18 solid phase with subsequent simultaneous derivatization and elution with a mixture of 1,1,1,3,3,3-hexafluoroisopropanol and diisopropylcarbodiimide in n-hexane (on-line derivatization). The optimized method was validated, with linearity established from 0.05 to 25ngmL-1 and R values > 0.99. Obtained quantification limits were in the range of 0.06-0.08ngmL 1, and the precision expressed as relative standard deviation (RSD) was below 14% for all of the analytes. The method was cross-validated with a reference approach based on liquid-liquid extraction-gas chromatography-mass spectrometry (LLE-GC MS) by analyzing 21 urine samples. PMID- 28917737 TI - 3,4-Diaminotoluene sensor development based on hydrothermally prepared MnCoxOy nanoparticles. AB - A facile hydrothermal process was used to prepare MnCoxOy nanoparticles (NPs) in alkaline medium (pH~10.5) at room temperature. The NPs were characterized by Fourier-transform infrared spectroscopy (FTIR), ultraviolet visible spectroscopy (UV/vis), field emission scanning electron microscopy (FESEM), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDS), and powder X-ray diffraction (XRD). A thin layer of NPs film as a chemical sensor was fabricated on a glassy carbon electrode (GCE) with the help of a conducting binder. The sensor was implemented successfully for the detection 3,4-DAT with reliable I-V approach at low potential. The sensor-features include good sensitivity (0.37 mAumolL-1cm-2), low detection limit (LOD=0.26+/-0.01 pmolL-1 at a signal to noise ratio of 3), low limit of quantification (LOQ=7.80+/-0.01 pmolL 1), good reliability, good reproducibility, ease of integration, and long-term stability were investigated. The sensor response towards 3,4-DAT is linear in logarithmic scale over a large concentration range (1.0 pmolL-1 to 1.0 umolL-1). This work is introduced a route for future sensitive sensor development based on MnCoxOy NPs by reliable I-V method for the detection of hazardous and carcinogenic toxins in environmental and health care fields. PMID- 28917738 TI - A simple solvent based microextraction for high performance liquid chromatographic analysis of aflatoxins in rice samples. AB - This paper describes the development of a simple solvent based microextraction, namely vortex assisted low density solvent-microextraction (VALDS-ME), followed by high performance liquid chromatography-fluorescence detection (HPLC-FD) for the simultaneous determination of four aflatoxins (AFs) including AFB1, AFB2, AFG1 and AFG2 in rice samples. In VALDS-ME, a mixture of low density solvents (1 octanol and toluene) was used as the extraction solvent. The extraction was rapidly achieved with the assistance of vortex agitation and phase separation was easily obtained after the addition of Na2SO4. The effects of various parameters on the extraction efficiency were optimized. Under the optimum conditions, high enrichment factors (42-132), low limits of detection (LODs) in the range of 0.0011-0.17MUgkg-1 and good precisions (RSDs lower than 6.2%) were obtained. AFB1 and AFG1 were detected in berry rice sample at 0.26 and 2.1MUgkg-1, respectively. The recoveries in AFs-spiked rice samples ranged from 70% to 104%. Moreover, the present method was comparable to the conventional immunoaffinity chromatography method. PMID- 28917739 TI - Determination of fluorine in copper concentrate via high-resolution graphite furnace molecular absorption spectrometry and direct solid sample analysis - Comparison of three target molecules. AB - The chemical composition of complex inorganic materials, such as copper concentrate, may influence the economics of their further processing because most smelters, and particularly the producers of high-purity electrolyte copper, have strict limitations for the permissible concentration of impurities. These components might be harmful to the quality of the products, impair the production process and be hazardous to the environment. The goal of the present work is the development of a method for the determination of fluorine in copper concentrate using high-resolution graphite furnace molecular absorption spectrometry and direct solid sample analysis. The molecular absorption of the diatomic molecule CaF was measured at 606.440nm. The molecule CaF was generated by the addition of 200ug Ca as the molecule-forming reagent; the optimized pyrolysis and vaporization temperatures were 900 degrees C and 2400 degrees C, respectively. The characteristic mass and limit of detection were 0.5ng and 3ng, respectively. Calibration curves were established using aqueous standard solutions containing the major components Cu, Fe, S and the minor component Ag in optimized concentrations. The accuracy of the method was verified using certified reference materials. Fourteen copper concentrate samples from Chile and Australia were analyzed to confirm the applicability of the method to real samples; the concentration of fluorine ranged from 34 to 5676mgkg-1. The samples were also analyzed independently at Analytik Jena by different operators, using the same equipment, but different target molecules, InF and GaF, and different operating conditions; but with a few exceptions, the results agreed quite well. The results obtained at Analytik Jena using the GaF molecule and our results obtained with CaF, with one exception, were also in agreement with the values informed by the supplier of the samples, which were obtained using ion selective electrode potentiometry after alkaline fusion. A comparison will also be made for the three target molecules and the three independently developed methods for the determination of fluorine, although all three methods used direct solid sample analysis. PMID- 28917740 TI - Switchable zipper-like thermoresponsive molecularly imprinted polymers for selective recognition and extraction of estradiol. AB - Zipper-like thermoresponsive molecularly imprinted polymers (MIPs) were prepared based on interpolymer complexation via the synergy of dual functional monomers of acrylamide (AAm) and 2-acrylamide-2-methyl propanesulfonic acid (AMPS) for selective recognition and extraction of estradiol (E2) by temperature regulation. The resulting E2-MIPs attained controlled adsorption and release of E2 in response to temperature change, with higher adsorption capacity (8.78mg/g) and stronger selectivity (imprinting factor was 3.18) at 30 degrees C compared with that at 20 and 40 degrees C; the zipper-like interpolymer interaction between poly(AAm) and poly(AMPS) enabled switchable molecular recognition. The adsorption processes obeyed Langmuir isotherm and pseudo-second-order kinetic models. High recognition selectivity of the MIPs toward E2 was achieved over its structural analogues, and good reusability was displayed over 86% recovery after six adsorption-desorption cycles. Accordingly, the E2-MIPs were empolyed as new adsorbents for selective dispersive solid-phase extraction of E2, and offered low limits of detection and quantification of 4.81 and 16.03MUg/L, respectively. Recoveries from goat milk samples ranged from 76.2% to 89.7% with the precisions (relative standard deviations, n = 3, %) of 2.8-3.7% at 30 degrees C. The intelligent E2-MIPs combining good adsorption, special recognition and temperature sensitivity proved to be a promising alternative to the selective identification and controlled extraction/removal of E2 in complicated samples by simple temperature-responsive regulation. PMID- 28917741 TI - Immobilization of cytochrome c and its application as electrochemical biosensors. AB - Cytochrome c (Cyt c) has been used as a model protein to investigate the characters of modified electrodes by many researchers. It has been also employed to construct biosensors to detect hydrogen peroxide, nitrate, superoxide, and etc. Cyt c immobilization techniques, including physical adsorption, entrapment in hydrogel or polymers, layer-by-layer assembly, Langmuir-Blodgett, and covalent attachment are discussed followed by various electrochemical methods applied in the electrode modification. The exploration of some modified protein electrodes, for example, screen printed, microperoxidase and engineered Cyt c are also presented. The preparation, characterizations and some properties of nanocomposites to modify electrode surface for immobilizing Cyt c are highlighted. This review is attempted to discuss the influences of the physical and chemical properties of the substrate materials, such as specific area and surface charge on the protein loading and electron transfer of Cyt c briefly. The comparative information of Cyt c-based electrochemical modified electrodes, such as average surface coverage, sensitivity, linear range, and detection limit of the analyte of interest is also summarized. PMID- 28917742 TI - Analysis of glutathione in the presence of acetaminophen and tyrosine via an amplified electrode with MgO/SWCNTs as a sensor in the hemolyzed erythrocyte. AB - In this study, we investigated the effect of adding MgO/SWCNTs and 2-Chloro-N'-[1 (2,5-dihydroxyphenyl) methylidene]aniline (2-CDHPMA) to a carbon paste matrix, which could act as a voltammetric sensor for the analysis of glutathione. The electrocatalytic interaction between 2-CDHPMA and glutathione was used as a factor for the analysis of this biological compound in real samples. In addition, the presence of MgO/SWCNTs can help in increasing the sensitivity of the fabricated sensor and for obtaining a low limit of detection in the analysis of glutathione. When the carbon-paste electrode was amplified with MgO/SWCNTs and 2 CDHPMA (CPE/MgO/SWCNTs/2-CDHPMA), it showed a good selectivity for the analysis of glutathione in the presence of acetaminophen and tyrosine with the separated peak potentials at ~ 280mV, ~ 570mV, and ~ 880mV for the first time. We detected a linear dynamic range between 0.05 and 700.0MUmolL-1 with the limit of detection set at ~ 10 +/- 0.3nmolL-1 for the analysis of glutathione by the square-wave voltammetric method. The CPE/MgO/SWCNTs/2-CDHPMA showed a high quality of detection of glutathione in the hemolyzed erythrocyte sample. PMID- 28917743 TI - Selection of an aptamer against Muscovy duck parvovirus for highly sensitive rapid visual detection by label-free aptasensor. AB - Muscovy duck parvovirus (MDPV) causes high mortality and morbidity in ducks. This study investigated a novel aptamer-based, label-free aptasensor detection of MDPV. In this study, we developed an ssDNA aptamer using the filtration partition and lambda exonuclease method with an affinity-based monitor and counter screening process. After 15 rounds of SELEX (systematic evolution of ligands by exponential enrichment), the ssDNA aptamer Apt-10, which specifically bound to MDPV with high affinity (Kd = 467nM) was successfully screened, and the aptamer was also found to be good specific to MDPV. The selected Apt-10 aptamer can be used to distinguish MDPV and goose parvovirus (GPV). Three-dimensional structural analysis of the Apt-10 aptamer indicated that it folded into a compact stem-loop motif, which was related to its high affinity. Finally, a label-free detection method based on unmodified gold nanoparticles and Apt-10 aptamer was developed for MDPV determination. The concentration of Apt-10 aptamer at 5MUM was optimal for MDPV determination in the label-free aptasensor. Excellent linearity was acquired and the lowest detection limit was 1.5 or 3 EID50 (50% egg infection dose) of MDPV, respectively, depending upon spectrophotometry or the naked eye were used. These results show the potential of the aptamer for the rapid detection of MDPV and antiviral research. PMID- 28917744 TI - Differentiation of cumin seeds using a metal-oxide based gas sensor array in tandem with chemometric tools. AB - Cumin is a plant of the Apiaceae family (umbelliferae) which has been used since ancient times as a medicinal plant and as a spice. The difference in the percentage of aromatic compounds in cumin obtained from different locations has led to differentiation of some species of cumin from other species. The quality and price of cumin vary according to the specie and may be an incentive for the adulteration of high value samples with low quality cultivars. An electronic nose simulates the human olfactory sense by using an array of sensors to distinguish complex smells. This makes it an alternative for the identification and classification of cumin species. The data, however, may have a complex structure, difficult to interpret. Given this, chemometric tools can be used to manipulate data with two-dimensional structure (sensor responses in time) obtained by using electronic nose sensors. In this study, an electronic nose based on eight metal oxide semiconductor sensors (MOS) and 2D-LDA (two-dimensional linear discriminant analysis), U-PLS-DA (Partial least square discriminant analysis applied to the unfolded data) and PARAFAC-LDA (Parallel factor analysis with linear discriminant analysis) algorithms were used in order to identify and classify different varieties of both cultivated and wild black caraway and cumin. The proposed methodology presented a correct classification rate of 87.1% for PARAFAC-LDA and 100% for 2D-LDA and U-PLS-DA, indicating a promising strategy for the classification different varieties of cumin, caraway and other seeds. PMID- 28917745 TI - Chlorine determination via MgCl molecule in environmental samples using high resolution continuum source graphite furnace molecular absorption spectrometry. AB - This paper describes a method development for chlorine determination through the formation of MgCl molecule, applied for the first time for Cl quantification, by high resolution continuum source graphite furnace molecular absorption spectrometry (HR-CS GF MAS) in environmental samples. Pyrolysis and vaporization temperatures were optimized as well as the use of chemical modifier. Determinations were carried out at the wavelength of 377.010 and the compromise conditions of the graphite furnace temperature program were 500 degrees C and 2500 degrees C for pyrolysis and vaporization, respectively, using 10ug of chemical modifier Pd. The concentration of reactants for the generation of MgCl molecule was optimized through Box-Behnken experimental design, using MgCl2 solution as source of chlorine. The optimum values according to the surface response were 5gL-1 Mg, 25mgL-1 of chlorine and 2% vv-1 of HNO3, condition in which the amount of Mg is at least 200 times higher than that of chloride. This excess of the forming agent ensures the complete formation of MgCl molecular species, since Cl is the limiting reactant. Certified reference materials, BCR 182 and NIST 8414, and addition and recovery tests were used to evaluate the accuracy of the method and good results were achieved at a 95% confidence level. The method was applied to direct determination of Cl in five produced water samples from offshore oil wellbore, high complex matrix, whose conventional methods require tedious treatment before the analysis. PMID- 28917746 TI - A highly selective and ratiometric fluorescent probe for cyanide by rationally altering the susceptible H-atom. AB - A highly selective and ratiometric fluorescent probe for cyanide was rationally designed and synthesized. The probe comprises a fluorophore unit of naphthalimide and a CN- acceptor of methylated trifluoroacetamide group. For these previous reported trifluoroacetamide derivative-based cyanide chemosensors, the H-atom of amide adjacent to trifluoroacetyl group is susceptible to be attacked by various anions (CN- itself, F-, AcO-, et al.) and even the solvent molecule, which resulted in the bewildered reaction mechanism and poor selectivity of the assay. In this work, the susceptible H-atom of trifluoroacetamide was artfully substituted by alkyl group. Thus a highly specific fluorescent probe was developed for cyanide sensing. Upon the nucleophilic addition of cyanide anion to the carbonyl of trifluoroacetamide moiety of the probe, the ICT process of the probe was significantly enhanced and leading to a remarkable red shift in both absorption and emission spectra of the probe. This fluorescent assay showed a linear range of 1.0-80.0uM and a LOD (limit of detection) of 0.23uM. All the investigated interference have no influence on the sensing behavior of the probe toward cyanide. Moreover, by coating on TLC plate, the probe can be utilized for practical detection of trace cyanide in water samples. PMID- 28917747 TI - Colorimetric detection of ammonia using smartphones based on localized surface plasmon resonance of silver nanoparticles. AB - In this work, a rapid and straightforward method was developed for colorimetric determination of ammonia using smartphones. The mechanisms is based on the manipulation of the surface plasmon band of silver nanoparticles (AgNPs) via the formation of Ag (NH3)2+ complex. This complex decreases the amount of AgNPs in the solution and consequently, the color intensity of the colloidal system decreases. Not only the variation in color intensity of the solution can be tracked by a UV-vis spectrophotometer, but also a smartphone can be employed to monitor the color intensity variation by RGB analysis. Ammonia, in the concentration range of 10-1000mgL-1, was successfully measured spectrophotometrically (UV-vis spectrophotometer) and colorimetrically (RGB measurement) with the detection limit of 180 and 200mgL-1, respectively. Linear relationships were also developed for both methods. Also, the response time of the developed colorimetric sensor was around 20s. Both of the colorimetric and spectrophotometric methods showed a reliable performance for determination of ammonia in the real samples. PMID- 28917748 TI - Selectivity improvement of positive photoionization ion mobility spectrometry for rapid detection of organophosphorus pesticides by switching dopant concentration. AB - Ion mobility spectrometry (IMS) opened a potential avenue for the rapid detection of organophosphorus pesticides (OPPs), though an improved selectivity of stand alone IMS was still in high demand. In this study, a stand-alone positive photoionization ion mobility spectrometry (PP-IMS) apparatus was constructed for the rapid detection of OPPs with acetone as dopant. The photoionization of acetone molecules was induced by the ultraviolet irradiation to produce the reactant ions (Ac)2H+, which were employed to ionize the OPPs including fenthion, imidan, phosphamidon, dursban, dimethoate and isocarbophos via the proton transfer reaction. Due to the difference in proton affinity, the tested OPPs exhibited the different dopant-dependent manners. Based on this observation, the switching of dopant concentration was implemented to improve the selectivity of PP-IMS for OPPs detection. For instance, a mixture of fenthion, dursban and dimethoate was tested. By switching the concentration of doped acetone from 0.07 to 2.33 to 19.94mgL-1, the ion peaks of fenthion and dursban were inhibited in succession, achieving the selective detection of dimethoate at last. In addition, another mixture of imidan and phosphamidon was initially detected by PP-IMS with a dose of 0.07mgL-1 acetone, indicating that their ion peaks were severely overlapped; when the concentration of doped acetone was switched to 19.94mgL-1, the inhibition of imidan signals promised the accurate identification of phosphamidon in mixture. Finally, the PP-IMS in combination of switching dopant concentration was applied to detect the mixed fenthion, dursban and dimethoate in Chinese cabbage, demonstrating the applicability of proposed method to real samples. PMID- 28917749 TI - Trace determination of volatile polycyclic aromatic hydrocarbons in natural waters by magnetic ionic liquid-based stir bar dispersive liquid microextraction. AB - In this work, a novel hybrid approach called stir bar dispersive liquid microextraction (SBDLME) that combines the advantages of stir bar sorptive extraction (SBSE) and dispersive liquid-liquid microextraction (DLLME) has been employed for the accurate and sensitive determination of ten polycyclic aromatic hydrocarbons (PAHs) in natural water samples. The extraction is carried out using a neodymium stir bar magnetically coated with a magnetic ionic liquid (MIL) as extraction device, in such a way that the MIL is dispersed into the solution at high stirring rates. Once the stirring is ceased, the MIL is magnetically retrieved onto the stir bar, and subsequently subjected to thermal desorption (TD) coupled to a gas chromatography-mass spectrometry (GC-MS) system. The main parameters involved in TD, as well as in the extraction step affecting the extraction efficiency (i.e., MIL amount, extraction time and ionic strength) were evaluated. Under the optimized conditions, the method was successfully validated showing good linearity, limits of detection and quantification in the low ng L-1 level, good intra- and inter-day repeatability (RSD < 13%) and good enrichment factors (18 - 717). This sensitive analytical method was applied to the determination of trace amounts of PAHs in three natural water samples (river, tap and rainwater) with satisfactory relative recovery values (84-115%), highlighting that the matrices under consideration do not affect the extraction process. PMID- 28917750 TI - Portable near infrared spectroscopy applied to fuel quality control. AB - Fuel quality control has gained interest in many countries owing to the potential damage of low-quality fuel to engines, the environment, and economy. Thus, the application of analytical techniques to verify quality control of fuels has become crucial. The portable micro-spectrometer in the near infrared region (microNIR) has gained credibility as a successful analytical technique in several quality control sectors. The possibility of real-time analysis using a nondestructive and reliable method is the main advantage of this methodology. In this work, chemometric models (PLS) were developed using microNIR data to determine the amount of biodiesel in diesel (LODBio = 0.5wt%; LOQBio = 1.8wt%; and RMSEPBio = 1.8wt%); sulfur in diesel (LODS = 2.4mgL-1; LOQS = 8.0mgL-1; and RMSEPS = 13.2mgL-1); gasoline, ethanol, and methanol in C-type gasoline (LODgas = 0.55wt%; LOQgas = 1.84wt%; and RMSEPgas = 0.81wt%; LODeth = 0.75wt%; LOQeth = 2.5wt%; and RMSEPeth = 3.81wt%; and LODmet = 0.85wt%; LOQmet = 2.84wt%; and RMSEPmet = 1.80wt%); and water, methanol, and ethanol in ethanol-hydrated fuel (EHF) (LODH2O = 0.04wt%; LOQH2O = 1.29wt%; and RMSEPH2O = 1.05wt%; LODmet = 0.52wt%; LOQmet = 1.73wt%; and RMSEPmet = 2.78wt%; and LODeth = 1.22wt%; LOQeth = 4.07wt%; and RMSEPeth = 4.41wt%). A total of 181 blends were prepared, with biodiesel and sulfur contents ranging from 0 to 100wt% and 10-500mgL-1, respectively. For gasoline blends, the gasoline, ethanol, and methanol contents ranged from 0.0 to 75.0wt%, 25.0-75.0wt%, and 0.0-50.0wt%, respectively. In the EHF control, the ethanol, water, and methanol contents ranged from 0.0 to 100.0wt%, 0.0-50.0wt%, and 0.0-50.0wt%, respectively. The proposed method presented high precision and accuracy in all cases, and the results showed that the microNIR technique had excellent performance in fuel quality control. PMID- 28917751 TI - Structural characterization of electrochemically and in vivo generated potential metabolites of selected cardiovascular drugs by EC-UHPLC/ESI-MS using an experimental design approach. AB - In the last few years, a number of studies were conducted which aimed at understanding the mechanisms of cardiovascular drug, metabolism, and there is still the need to determine the metabolites of cardiac drugs for the purpose of metabolism control. In this study, we employ a direct combination of electrochemical oxidation and mass spectrometric (EC-MS) identification for monitoring the oxidation pathway of ten cardiovascular drugs (metoprolol, propranolol, propafenone, mexiletine, oxprenolol, pirbuterol, pindolol, cicloprolol, acebutolol and atenolol). Oxidation was accomplished in an electrochemical thin-layer cell coupled on-line to electrospray ionization mass spectrometry (EC/ESI-MS). For further characterization of electrochemical products, the approach involving liquid chromatography linked to tandem mass spectrometry was used. Appropriate conditions for oxidation and identification processes with such parameters as the potential value, mobile phase (type and pH) and working electrode were optimized. Optimization was performed with the use of central composite design (CCD). Besides electrochemical oxidation of analytes (phase I of metabolic transformation), addition of glutathione (GSH) for follow up reactions (phase II conjunction) was also investigated. The electrochemical results were compared to in-vivo experiments by analyzing plasma and urine samples from patients who had been administered selected cardiovascular drugs. These results show that electrochemistry coupled to mass spectrometry turned out to be an analytical tool suitable to procure a feasible analytical base for the envisioned in vivo experiments. PMID- 28917752 TI - Facilely self-assembled magnetic nanoparticles/aptamer/carbon dots nanocomposites for highly sensitive up-conversion fluorescence turn-on detection of tetrodotoxin. AB - In this work, magnetic Fe3O4 nanoparticles (NPs) were modified with aptamer of tetrodotoxin (TTX) to form Fe3O4/aptamer complex. The self-assembling of carbon dots (CDs) and the aptamer generated Fe3O4/aptamer/CDs nanocomposites. The nanocomposites exhibited down-conversion fluorescence and up-conversion fluorescence (UCF) emissions simultaneously. When excited at a wavelength of 780nm, the UCF (peaked at 475nm) of nanocomposites increased regularly with the increase of TTX concentration [TTX]. In the [TTX] range from 0.1ngmL-1 to 0.1mgmL 1, UCF peak intensities almost linearly increased with the increase of Log [TTX], with a high linear coefficient (R2) of 0.9975 and a low detection limit of TTX (0.06ngmL-1). The nanocomposites were developed as a novel UCF turn-on probe of TTX. Experimental results confirmed the highly selective and sensitive UCF responses of the probe on TTX, over potential interferences. In real samples, the probe of TTX showed superior analysis performance with high detection recoveries. Based upon the combined advantages from spectrofluorimetric methods, CDs and UCF, the novel probe of TTX would be superior especially in real biological sample analysis, when compared to previous methods for the detection of TTX. PMID- 28917753 TI - Nuclear forensics investigation of morphological signatures in the thermal decomposition of uranyl peroxide. AB - The analytical techniques typically utilized in a nuclear forensic investigation often provide limited information regarding the process history and production conditions of interdicted nuclear material. In this study, scanning electron microscopy (SEM) analysis of the surface morphology of amorphous-UO3 samples calcined at 250, 300, 350, 400, and 450 degrees C from uranyl peroxide was performed to determine if the morphology was indicative of the synthesis route and thermal history for the samples. Thermogravimetic analysis-mass spectrometry (TGA-MS) and differential scanning calorimetry (DSC) were used to correlate transitions in the calcined material to morphological transformations. The high resolution SEM images were processed using the Morphological Analysis for Material Attribution (MAMA) software. Morphological attributes, particle area and circularity, indicated significant trends as a result of calcination temperature. The quantitative morphological analysis was able to track the process of particle fragmentation and subsequent sintering as calcination temperature was increased. At the 90% confidence interval, with 1000 segmented particles, the use of Kolmogorov-Smirnov statistical comparisons allowed discernment between all calcination temperatures for the uranyl peroxide route. PMID- 28917754 TI - Quantification of 7-aminoflunitrazepam in human urine by polymeric monolith-based capillary liquid chromatography coupled to tandem mass spectrometry. AB - Using a simple liquid-liquid extraction (LLE) procedure for sample pretreatment, 7-Aminoflunitrazepam (7-aminoFM2), a major metabolite of flunitrazepam (FM2), was determined in urine samples by polymeric monolith-based capillary liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The linearity was found in the range of 0.1-50ngmL-1 with a method detection limit (signal-to-noise ratio of 3) estimated at 0.05ngmL-1. Using the proposed method, good precision and recovery were also found in spiked urine samples at the levels of 0.5, 5.0, and 50ngmL-1 (intra-day/inter-day precision: 0.6-1.8% / 0.1-0.8%; post-spiked/pre spiked recovery: 95.4-102.9% / 96.3-102.5%). In addition, acceptable relative differences (-24.2 - 0.8%) were observed by analyzing clinical urine samples using this monolith-based capillary LC-MS/MS method compared with the results obtained by the routine GC-MC method. Using the monolithic column, no noticeable deterioration of separation efficiency or carry-over was observed for more than 200 injections of urine samples. The applicability of the developed monolith based capillary LC-MS/MS method was demonstrated by quantifying 7-aminoFM2 in various clinical urine samples. Based on these experimental results, the proposed LLE-monolith-based capillary LC-MS/MS method shows the potential for routine determination of drug metabolites in human urine for clinical and forensic applications. PMID- 28917755 TI - Identification of Trypanosomatids by detecting Single Nucleotide Fingerprints using DNA analysis by dynamic chemistry with MALDI-ToF. AB - Protozoan parasites of the Trypanosomatidae family can cause devastating diseases in humans and animals, such as Human African Trypanosomiasis or Sleeping Sickness, Chagas disease and Leishmaniasis. Currently, there are molecular assays for detecting parasitic infections and their post-treatment monitoring based on nucleic acid amplification, but there are still certain limitations which limit the development of assays that can detect and discriminate between parasite infections with a single test. Here, we present the development of a novel molecular assay for the rapid identification of Trypanosomatids, integrating DNA analysis by dynamic chemistry in conjunction with Matrix-Assisted Laser Desorption Ionization - Time-of-Flight Mass Spectrometry (MALDI-ToF). Differentiation of Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp. is now possible using a single reaction tube, and enables rapid identification of Trypanosomatids. The test is based on a singleplex PCR, using a specific primer pair that amplifies a 155 base pair segment of the 28S ribosomal RNA gene, within a conserved homology region of Trypanosomatidae species. Amplified fragments are analysed by dynamic chemistry using two abasic PNA probes and the four reactive nucleobases - containing an aldehyde functional group - with MALDI-ToF to identify unique molecular patterns created by each specie due to their single base differences (Single Nucleotide Fingerprint 'SNF') in this highly homologous region. This novel assay offers the possibility to expand routine diagnostic testing for Trypanosomatids, and monitoring of therapeutic responses to these infectious diseases. PMID- 28917756 TI - Facile synthesis of copper(II)-decorated functional mesoporous material for specific adsorption of histidine-rich proteins. AB - The Cu2+-decorated functional mesoporous material was fabricated by thermally initiated free-radical polymerization of octavinyl polyhedral oligomeric silsesquioxane. It was used as adsorbent for highly specific separation of histidine (His)-rich proteins in blood and cell lysate based on immobilized metal affinity chromatography. The functional mesoporous material (named as PPOSS-IDA Cu2+) was characterized in detail and its selectivity and binding capacity were evaluated using a His-rich protein (bovine hemoglobin, BHb) and other proteins (bovine serum albumin, myoglobin, lysozyme and horseradish peroxidase) containing fewer surface-exposed His residues as model proteins. The results indicated that PPOSS-IDA-Cu2+ exhibited large specific surface area and good selective adsorption ability and the maximum adsorption capacity for BHb was 3150mgg-1. Moreover, PPOSS-IDA-Cu2+ had excellent recyclability and the adsorption capacity of the reused material for BHb remained almost unchanged after six cycles. In addition, PPOSS-IDA-Cu2+ not only showed excellent performance for the removal of highly abundant hemoglobin in human blood, but also can be a good adsorbent for the enrichment of proteins in cell lysate. It was the first time to explore the application of Cu2+-decorated functional material as an adsorbant for the separation of proteins in cell lysate. This approach can be combined with other techniques which can remove or deplete highly abundant proteins from real biological samples to obtain more comprehensive data about low abundant His-rich proteins in proteomic analysis. PMID- 28917757 TI - Innovative thin-layer chromatographic method combined with fluorescence detection for specific determination of Febuxostat: Application in biological fluids. AB - A newly developed thin-layer chromatographic (TLC) method coupled with fluorescence detection for specific determination of Febuxostat (FEB) was designed. The proposed method adopts exposure of FEB on a developed TLC plate to hydrochloric acid vapors, resulting in a large enhancement of its weak fluorescence, permitting its specific and sensitive determination in real human plasma and urine after excitation at 345nm on 60 F254 silica gel plates using toluene-ethyl acetate-methanol-glacial acetic acid; (30:10:5:0.1,v/v/v/v) as mobile phase. The retention factor (Rf) value for FEB was 0.33 +/- 0.03 with a correlation coefficient of 0.9974 in the concentration range of 2.5-50ng/band. Upon using polynomial regression, the correlation coefficient was greatly improved (0.9999), with detection and quantification limits of 0.55 and 1.67 (ng/band), respectively. The proposed method was validated according to the International Conference of Harmonization and was successfully used for specific and selective determination of FEB in its commercial dosage form without excipient interference. Moreover, the proposed method was extended to efficient determination of the studied drug in real human plasma and urine samples in the presence of its metabolites without any interference, allowing clinical application of the proposed method for direct FEB determination in biological fluids as well as in pharmacokinetics studies and for quality control of the pharmaceutical dosage form without sample pretreatment or exhausting extraction steps. PMID- 28917758 TI - Review on investigations of antisense oligonucleotides with the use of mass spectrometry. AB - Antisense oligonucleotides have been investigated as potential drugs for years. They inhibit target gene or protein expression. The present review summarizes their modifications, modes of action, and applications of liquid chromatography coupled with mass spectrometry for qualitative and quantitative analysis of these compounds. The most recent reports on a given topic were given prominence, while some early studies were reviewed in order to provide a theoretical background. The present review covers the issues of using ion-exchange chromatography, ion pair reversed-phase high performance liquid chromatography and hydrophilic interaction chromatography for the separation of antisense oligonucleotides. The application of mass spectrometry was described with regard to the ionization type used for the determination of these potential therapeutics. Moreover, the current approaches and applications of mass spectrometry for quantitative analysis of antisense oligonucleotides and their metabolites as well as their impurities during in vitro and in vivo studies were discussed. Finally, certain conclusions and perspectives on the determination of therapeutic oligonucleotides in various samples were briefly described. PMID- 28917759 TI - Detection of aflatoxin B1 in food samples based on target-responsive aptamer cross-linked hydrogel using a handheld pH meter as readout. AB - Aflatoxin B1 (AFB1) can cause great threat to human health, so the development of convenient and portable device for sensitive detection of AFB1 is highly desired. The portable pH meter has the characters of facile operation, low cost, and easy availability. Therefore, in this study, we investigate the applicability of utilizing a pH meter as the readout to develop a portable sensor for AFB1. The specific detection of AFB1 is realized via the combination of AFB1-responsive aptamer-cross-linked hydrogel. Upon the addition of AFB1, AFB1 binds to its aptamer with high affinity in lieu of aptamer/DNA complex, causing the collapse of hydrogel network and results in the releasing of urease into the solution. The released urease can catalyse the hydrolysis of urea and result in the rise of pH value. The change of pH value has a direct relationship to the concentration of AFB1 in the range of 0.2-20uM with a detection limit of 0.1uM (S/N = 3). The proposed portable device is successfully applied to assay AFB1 in the food samples with satisfied results. PMID- 28917760 TI - Rapid and sensitive serum glucose determination using chemical labeling coupled with black phosphorus-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Monitoring the concentration of blood glucose in patients is a key component of good medical diagnoses. Therefore, developing an accurate, rapid and sensitive strategy for monitoring blood glucose is of vital importance. We proposed a strategy for serum glucose determination combining 2-(4-boronobenzyl) isoquinolin 2-ium bromide chemical labeling with black phosphorus assisted laser desorption ionization-time of flight mass spectrometry (CL-BP/ALDI-TOF MS). The entire analytical process consisted of 1min of protein precipitation and 3min of chemical labeling in a microwave oven prior to the BP/ALDI-TOF MS analysis. The analysis can be completed in 5min with high throughput and extremely low sample consumption. Good linearity for glucose was obtained with a correlation coefficient (R) of 0.9986. The limit of detection (LOD) and limit of quantification (LOQ) were 11.5 fmol and 37.5 fmol, respectively. Satisfied reproducibility and reliability were gained by evaluation of the intra- and inter day precisions with relative standard deviations (RSDs) less than 7.2% and relative recoveries ranging from 87.1% to 108.1%, respectively. The proposed strategy was also applied for the analysis of endogenous glucose in various serum samples and the results were consistent with those obtained using the hexokinase method in a clinical laboratory. Considering the results, the proposed CL-BP/ALDI TOF MS strategy has proven to be reliable, fast, and sensitive for quantitative analysis of serum glucose. PMID- 28917761 TI - Graphene nanoribbon/FePt bimetallic nanoparticles/uric acid as a novel magnetic sensing layer of screen printed electrode for sensitive determination of ampyra. AB - A novel electrochemical sensor for sensitive determination of ampyra (Am) based on graphene nanoribbons modified by iron-platinum bimetallic nanoparticles and uric acid (SPCE/FePtGNR/UA) dropped on the screen-printed carbon electrode (SPCE) surface and magnetically captured onto an SPCE working electrode surface is reported in the present work. The modified nanocomposite and sensing layer was characterized by different techniques, including cyclic voltammetry (CV), linear sweep voltammetry (LSV), electrochemical impedance spectroscopy (EIS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray powdered diffraction (XRD). Am determination by conventional electrochemical methods is not possible, because of its high redox overpotential. Therefore, the differential pulse voltammetry (DPV) signals of UA were used as a redox probe for indirect electrochemical determination of Am. The limit of detection (LOD) and linear concentration range were obtained as 0.028 and 0.08 9.0umolL-1 (3Sb/m = 3), respectively. The feasibility of the proposed method was examined by the detection of Am in biological and pharmaceutical samples with satisfactory results. The constructed electrochemical sensor was applied for fast, simple and sensitive detection of Am in real environments. PMID- 28917762 TI - Full validation of a method for the determination of drugs of abuse in non mineralized dental biofilm using liquid chromatography-tandem mass spectrometry and application to postmortem samples. AB - Alternative matrices play a major role in postmortem forensic toxicology, especially if common matrices (like body fluids or hair) are not available. Incorporation of illicit and medicinal drugs into non-mineralized dental biofilm (plaque) seems likely but has not been investigated so far. Analysis of plaque could therefore extend the spectrum of potentially used matrices in postmortem toxicology. For this reason, a rapid, simple and sensitive method for the extraction, determination and quantification of ten drugs of abuse from plaque using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and fully validated. Amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 3,4 methylenedioxyamphetamine (MDA), cocaine, benzoylecgonine, morphine, codeine and 6-acetylmorphine were extracted from 2mg of dried and powdered plaque via ultrasonication with acetonitrile. The extracts were analyzed on a triple quadrupole linear ion trap mass spectrometer in scheduled multiple reaction monitoring mode (sMRM). The method was fully validated and proved accurate, precise, selective and specific with satisfactory linearity within the calibrated ranges. The lower limit of quantification was 10-15pgmg-1 for all compounds except for MDA (100pgmg-1) and amphetamine (200pgmg-1). The method has been successfully applied to three authentic postmortem samples with known drug history. Amphetamine, MDMA, cocaine, benzoylecgonine, morphine and codeine could be detected in these cases in concentrations ranging from 18pgmg-1 for cocaine to 1400pgmg-1 for amphetamine. PMID- 28917763 TI - Expanded uncertainty associated with determination of isotope enrichment factors: Comparison of two point calculation and Rayleigh-plot. AB - The enrichment factor (epsilon) is a common way to express Isotope Effects (IEs) associated with a phenomenon. Many studies determine epsilon using a Rayleigh plot, which needs multiple data points. More recent articles describe an alternative method using the Rayleigh equation that allows the determination of epsilon using only one experimental point, but this method is often subject to controversy. However, a calculation method using two points (one experimental point and one at t0) should lead to the same results because the calculation is derived from the Rayleigh equation. But, it is frequently asked "what is the valid domain of use of this two point calculation?" The primary aim of the present work is a systematic comparison of results obtained with these two methodologies and the determination of the conditions required for the valid calculation of epsilon. In order to evaluate the efficiency of the two approaches, the expanded uncertainty (U) associated with determining epsilon has been calculated using experimental data from three published articles. The second objective of the present work is to describe how to determine the expanded uncertainty (U) associated with determining epsilon. Comparative methodologies using both Rayleigh-plot and two point calculation are detailed and it is clearly demonstrated that calculation of epsilon using a single data point can give the same result as a Rayleigh-plot provided one strict condition is respected: that the experimental value is measured at a small fraction of unreacted substrate (f < 30%). This study will help stable isotope users to present their results in a more rigorous expression: epsilon +/- U and therefore to define better the significance of an experimental results prior interpretation. Capsule: Enrichment factor can be determined through two different methods and the calculation of associated expanded uncertainty allows checking its significance. PMID- 28917764 TI - Coupling dispersive liquid-liquid microextraction to inductively coupled plasma atomic emission spectrometry: An oxymoron? AB - Coupling dispersive liquid-liquid micro-extraction (DLLME) to inductively coupled plasma atomic emission spectrometry (ICP-AES) is usually troublesome due to the limited plasma tolerance to the organic solvents usually employed for metal extraction. This work explores different coupling strategies allowing the multi element determination by ICP-AES of the solutions obtained after DLLME procedures. To this end, three of the most common extractant solvents in DLLME procedures (1-undecanol, 1-butyl-3-methyl-imidazolium hexafluorophosphate and chloroform) have been selected to face most of the main problems reported in DLLME-ICP-AES coupling (i.e., those arising from the high solvent viscosity and volatility). Results demonstrate that DLLME can be successfully coupled to ICP AES after a careful optimization of the experimental conditions. Thus, elemental analysis in 1-undecanol and 1-butyl-3-methyl-imidazolium hexafluorophosphate extracts can be achieved by ICP-AES after a simple dilution step with methanol (1:0.5). Chloroform can be directly introduced into the plasma with minimum changes in the ICP-AES configuration usually employed when operating with aqueous solutions. Diluted inorganic acid solutions (1% w w-1 either nitric or hydrochloric acids) have been successfully tested for the first time as a carrier for the introduction of organic extractants in ICP-AES. The coupling strategies proposed have been successfully applied to the multi-element analysis (Al, Cu, Fe, Mn, Ni and Zn) of different water samples (i.e. marine, tap and river) by DLLME-ICP-AES. PMID- 28917765 TI - Dihydropyridine-derived BODIPY probe for detecting exogenous and endogenous nitric oxide in mitochondria. AB - A mitochondria-targetable probe Mito-DHP for nitric oxide (NO) was designed and synthesized by introducing dihydropyridine and triphenylphosphonium (TPP) moieties into boron dipyrromethene (BODIPY) dye. Mito-DHP was able to effectively detect nitric oxide through the aromatization of dihydropyridine to fluorescent pyridine product under oxygen-free conditions. The probe Mito-DHP showed high selectivity to NO over a number of reactive oxygen/nitrogen species (ROS/RNS) as well as high sensitivity (detection limit at 25nM), pH stability and bio compatibility. Furthermore, Mito-DHP proved to target mitochondria specifically and to visualize both exogenous and endogenous NO in real time. PMID- 28917766 TI - A novel colorimetric and ratiometric fluorescent probe for visualizing SO2 derivatives in environment and living cells. AB - Monitoring sulfur dioxide (SO2) derivatives in environment is of great significance due to their harmful effects to the environment and human health. In this study, a fluorescent probe (CZBT) for SO2 derivatives was prepared from 9 ethyl-9H-carbazole-3,6-dicarboxaldehyde and 2-methyl-benzothiazolium, which displayed a noticeable color change from yellow to colorless along with a remarkable fluorescence change from yellow to blue in response to HSO3-. The probe could quantitatively determine the concentration of HSO3- with excellent selectivity, high sensitivity and low limit of detection. 1H NMR and HR-MS spectra demonstrated that a selective 1, 4-nucleophilic addition occurred on the bridge double bond in CZBT. The probe was successfully used to determine the SO2 derivatives in several real water samples with good recovery. Furthermore, the probe was employed for monitoring the level of intracellular HSO3- in HeLa (human cervical cancer) cells by fluorescence imaging. These results indicated that CZBT has a good capability for monitoring SO2 derivatives in environment and living cells. PMID- 28917767 TI - Hierarchical oxygen-implanted MoS2 nanoparticle decorated graphene for the non enzymatic electrochemical sensing of hydrogen peroxide in alkaline media. AB - Owing to the extensive applications of hydrogen peroxide (H2O2) in biological, environmental and chemical engineering, it is of great importance to investigate sensitive and selective sensing platform towards the detection of H2O2. Herein, oxygen-implanted MoS2 nanoparticles decorated graphene nanocomposite is synthesized via a facile one-pot solvothermal method for the sensitive detection of H2O2 in alkaline media. The structure and morphology of the MoS2/graphene nanocomposites were systematically characterized, showing that Mo-O bonds are formed and oxygen is implanted into the crystal structure in the nanocomposite. As a result, the MoS2/graphene composite exhibited enhanced electron transfer kinetics and excellent electro-reduction performance towards H2O2 in alkaline media. Under optimum conditions, the fabricated sensor demonstrated a wide linear response towards H2O2 in the range of 0.25-16mM with a low detection limit of 0.12MUM and high sensitivity of 269.7MUAmM-1cm-2. Besides, the constructed sensor presented a good selectivity to H2O2 with the presence of other interfering species. Therefore, the proposed sensor was successfully applied for the detection and determination of H2O2 in real sample, indicating great potential for the practical applications. PMID- 28917768 TI - Gold nanoparticle labeling with tyramide signal amplification for highly sensitive detection of alpha fetoprotein in human serum by ICP-MS. AB - In this work, we developed an immunoassay based on tyramide signal amplification (TSA) and gold nanoparticles (Au NPs) labeling for highly sensitive detection of alpha fetoprotein (AFP) by inductively coupled plasma mass spectrometry (ICP-MS). AFP was captured by anti-AFP1 coating on the 96-well plate and labeled by anti AFP2-horseradish peroxidase (HRP), in which the HRP can catalyze the deposition of biotinylated tyramine on the nearby protein. Then the streptavidin (SA)-Au NPs was labeled on the deposited biotinylated tyramine as the intensive signal probe for ICP-MS measurement. Under the optimal experimental conditions, the limit of detection of the developed method for AFP was 1.85pg/mL and the linear range was 0.005-2ng/mL. The relative standard deviation for seven replicate detections of 0.01ng/mL AFP was 5.2%. The proposed method was successfully applied to the detection of AFP in human serum with good recoveries. This strategy is highly sensitive and easy to operate, and can be extended to the sensitive detection of other biomolecules in human serum. PMID- 28917769 TI - Towards highly selective detection using metal nanoparticles: A case of silver triangular nanoplates and chlorine. AB - The article describes a novel approach towards improving selectivity of volatile compounds detection using metal nanoparticles. It is based on combination of sensitive optical detection using convenient nanoparticle-modified paper test strips and dynamic gas extraction improving selectivity to volatile compounds. A simple and inexpensive setup allowing for realization of this combination is described. Analytical prospects of the approach are shown by the example of chlorine determination in highly salted aqueous solutions using silver triangular nanoplates and digital colorimetry. The limit of detection is equal to 0.03mgL-1 and the determination range is 0.1-2mgL-1. This determination can be successfully carried out in solutions containing at least 2.105 greater molar amounts of Na+, K+, Zn2+, Cl-, SO42-, and H2PO4- with no sample pretreatment. The approach seems to be compatible with different types of nanoparticles with respect to detection of various analytes, thus having good opportunities for further development. PMID- 28917770 TI - Applicability of the direct injection liquid chromatographic tandem mass spectrometric analytical approach to the sub-ngL-1 determination of perfluoro alkyl acids in waste, surface, ground and drinking water samples. AB - The applicability of a direct injection UHPLC-MS/MS method for the analysis of several perfluoroalkyl acids (PFAAs) in a wide range of water matrices was investigated. The method is based on the direct injection of 100uL of centrifuged water sample, without any other sample treatment. Very good method detection limits (0.014-0.44ngL-1) and excellent intra and inter-day precision (RSD% values in the range 1.8-4.4% and 2.7-5.7%, respectively) were achieved, with a total analysis time of 20min per sample. A high number of samples - i.e. 8 drinking waters (DW), 12 ground waters (GW), 13 surface waters (SW), 8 influents and 11 effluents of wastewater treatment plants (WWTPIN and WWTPOUT) were processed and the extent of matrix effect (ME) was calculated, highlighting the strong prevalence of |ME| < 20%. The occurrence of |ME| > 50% was occasionally observed only for perfluorooctanesulphonic and perfluorodecanoic acids. Linear discriminant analysis highlighted the great contribution of the sample origin (i.e. DW, GW, SW, WWTPIN and WWTPOUT) to the ME. Partial least square regression (PLS) and leave-one-out cross-validation were performed in order to interpret and predict the signal suppression or enhancement phenomena as a function of physicochemical parameters of water samples (i.e. conductivity, hardness and chemical oxygen demand) and background chromatographic area. The PLS approach resulted only in an approximate screening, due to the low prediction power of the PLS models. However, for most analytes in most samples, the fitted and cross validated values were such as to correctly distinguish between | ME | higher than 20% or below this limit. PFAAs in the aforementioned water samples were quantified by means of the standard addition method, highlighting their occurrence mainly in WWTP influents and effluents, at concentrations as high as one hundred of ugL-1. PMID- 28917771 TI - Accurate and sensitive fluorescence detection of DNA based on G-quadruplex hairpin DNA. AB - A facile and cost-effective fluorescence biosensor is constructed for the accurate and sensitive determination of DNA. The G-quadruplex-forming sequence in hairpin DNA sequence (H1) is originally locked. When target DNA is present, the hairpin structure of H1 can be unfolded and part of H1 hybridized with the target DNA to form a double-stranded DNA and a G-quadruplex. The hairpin DNA sequence (H2) hybridizes with the unfolded H1 and displaces the target DNA. Finally, the displaced target DNA again hybridizes with the H1 and initiates cycle amplification. Thus, the numerous G-quadruplexs at the H1 ends are formed, resulting in the fluorescent enhancement after binding with N-methyl mesoporphyrin IX (NMM). Lower background signal improves the accuracy of assay. The enzyme-free method can detect down to 40pM and a linear range of 3 orders of magnitude. Moreover, this strategy has an ability to discriminate the target DNA from even single-base mismatched or other sequence. The proposed method has potential applications in DNA-based molecular diagnostics. PMID- 28917772 TI - Disordered photonics coupled with embedded nano-Au plasmonics inducing efficient photocurrent enhancement. AB - Spatial order used to be considered as a benefit for photonics; but recently the study of disorder has broken into people's horizons for its strong random scattering of light. In this work, disordered photonics coupled with plasmonics for efficiently enhanced photocurrent was first investigated using Au-ZnO nanowire array as a model. The embedded Au-ZnO nanowire array was facilely prepared using a template-free electrodeposition method. On the optimal plasmonic substrate, the photocurrent of disorder-enhanced Au-ZnO nanowire array is about 20-fold that of ZnO nanowire array. Both the plasmonic effect of Au NPs such as localized surface plasmons, surface plasmon polarizations and the disorder enhanced photonics in the hybrid structure are available to improve the photoelectric conversion efficiency by enhancing the trapping of the simulated sunlight and the collection of charge carriers. Herein, disordered photonics was coupled with plasmonics to explain for the enhanced photocurrent. This work also provided a facile fabricating avenue for plasmonic noble metal embedded in semiconductor devices. PMID- 28917773 TI - Redesigning flow injection after 40 years of development: Flow programming. AB - Automation of reagent based assays, by means of Flow Injection (FI), is based on sample processing, in which a sample flows continuously towards and through a detector for quantification of the target analyte. The Achilles heel of this methodology, the legacy of Auto Analyzer(r), is continuous reagent consumption, and continuous generation of chemical waste. However, flow programming, assisted by recent advances in precise pumping, combined with the lab-on-valve technique, allows the FI manifold to be designed around a single confluence point through which sample and reagents are sequentially directed by means of a series of flow reversals. This approach results in sample/reagent mixing analogous to the traditional FI, reduces sample and reagent consumption, and uses the stop flow technique for enhancement of the yield of chemical reactions. The feasibility of programmable Flow Injection (pFI) is documented by example of commonly used spectrophotometric assays of, phosphate, nitrate, nitrite and glucose. Experimental details and additional information are available in online tutorial http://www.flowinjectiontutorial.com/. PMID- 28917774 TI - FRET on lateral flow test strip to enhance sensitivity for detecting cancer biomarker. AB - Fluorescence resonance energy transfer (FRET) between fluorescein isothiocyanate (FITC) and gold nanoparticles (Au NPs) is introduced in the lateral flow strip to detect cancer biomarker CEA with the color and fluorescence dual-readout. Anti CEA monoclonal antibody coated Au NPs were on the conjugate pad and FITC labelled antibody (FITC-Ab) for CEA was coated on the test line. All the reagents were general in the lateral flow strip or commercially available and no new materials or technique were involved, which make our proposal a more universal method and easier to operate. With the addition of CEA on the sample pad, anti-CEA monoclonal antibody coated Au NPs-CEA-FITC-Ab complex formed on the test line, leading to a megascopic red line and simultaneous quenched fluorescence of FITC via FRET. The visual limit of detection (LOD) through distinguishing red color change was 10ng/mL and the LOD by differentiating fluorescence intensity was 0.1ng/mL, which was two orders of magnitude lower than that without considering fluorescence in the strip. And the linear range changed from 10-80ng/mL to 5 80ng/mL with the analysis of fluorescence change. Meanwhile, the feasibility of our method applied in real clinical samples was also confirmed. PMID- 28917775 TI - Fabrication of bi-monomer copolymer of pyrrole-indole for highly efficient solid phase microextraction of benzene derivatives. AB - A procedure for direct electrochemical deposition of poly(pyrrole-indole) on gold nanoparticles coated stainless steel wire was established, and the formation of copolymer was confirmed by infrared spectroscopy. The synthesized coating showed unique microstructure, excellent extraction efficiency (2-10 times of corresponding single-component coating), high thermal stability (up to 280 degrees C) and good durability (could be used for more than 200 times). As a novel and promising extraction coating, it was used for the headspace solid phase microextraction-gas chromatography detection of some benzene derivatives, including chlorobenzene, bromobenzene, p-bromotoluene, m-nitrotoluene and p nitrotoluene. Under the optimized conditions, their GC peak areas were linear to their concentrations in the ranges of about 0.05-100MUgL-1, and the detection limits were 0.012-0.029MUgL-1 (S/N = 3). The run-to-run RSDs were lower than 3.9% (n = 4), the fiber-to-fiber RSDs were 4.3-7.8% (n = 4). The proposed method was successfully applied to the determination of benzene derivatives mentioned above in real samples with good recoveries from 88.3% to 103.7%. PMID- 28917776 TI - Apta-nanosensors for detection and quantitative determination of acetamiprid - A pesticide residue in food and environment. AB - In an effort to achieve high sensitive and selective detection of pesticide residues, numerous nanomaterial-based aptasensors are currently being developed for acetamiprid analysis. Recently, aptamers as a potent alternative of antibodies are used in biosensing platforms. There is tremendous interest in utilizing of nanomaterial as basic building blocks and signaling elements in aptasensors. The nanomaterials have the unique optical and electrical properties. The combination of nanomaterial and aptamer technology has opened a new window in pesticide residues monitoring. In this review, recent advances and applications of optical and electrochemical nanomaterial-based aptasensors for the detection and quantitative determination of acetamiprid in details have been discussed. PMID- 28917777 TI - Molecularly imprinted polymers for the determination of organophosphorus pesticides in complex samples. AB - Organophosphorus compounds constitute an important class of pesticides whose the toxicity of which arises from the inhibition of the acetylcholinesterase enzyme. They exhibit a wide range of physico-chemical properties, thus rendering their determination in complex oil samples particularly difficult. To facilitate their analysis at the trace level in various samples (environmental waters, soils, vegetables...), molecularly imprinted polymers (MIPs) that are synthetic polymers possessing specific cavities designed for a target molecule have been prepared. Often called synthetic antibodies, MIPs can replace antibodies in different application fields. Indeed, as immunosorbents, MIPs can be used as selective sorbents for the solid phase extraction of target analytes from complex matrices or as recognition elements in sensors. Their synthesis, characterization and use as selective sorbent for the selective recognition of organophosphorus pesticides have been already largely described and are summarized in this review. PMID- 28917778 TI - Determination of volatile organic compounds in eucalyptus fast pyrolysis bio-oil by full evaporation headspace gas chromatography. AB - This paper reports a full evaporation (FE) headspace gas chromatographic (HS-GC) method for the determination of the volatile organic compounds (VOCs) in bio-oil (i.e. methanol, ethanol, acetone, acetic acid and furfural). The method uses a 4MUL sample of bio-oil in a headspace vial (ca. 20mL). Complete evaporation of the compounds was achieved after seven minutes at 90 degrees C. The method showed good precision and accuracy for methanol, ethanol, acetone and acetic acid. The recovery of furfural was low (74.3%). The results showed that the protocol can be applied for the determination of methanol, ethanol, acetone and acetic acid in bio-oil. Detection limits ranged from 0.13 to 0.16MUg. Acetic acid was the dominant analyte in the heavy bio-oil and light bio-oil analysis (113. 3 and 85.1ugmg-1, respectively), followed by methanol, ethanol, and acetone. The polymerisation of furfural was suspected as the cause of its poor quantification. PMID- 28917779 TI - "On-off" switchable tool for food sample preparation: merging molecularly imprinting technology with stimuli-responsive blocks. Current status, challenges and highlighted applications. AB - Sample preparation still remains a great challenge in the analytical workflow representing the most time-consuming and laborious step in analytical procedures. Ideally, sample pre-treatment procedures must be more selective, cheap, quick and environmental friendly. Molecular imprinting technology is a powerful tool in the development of highly selective sample preparation methodologies enabling to preconcentrate the analytes from a complex food matrix. Actually, the design and development of molecularly imprinted polymers-based functional materials that merge an enhancement of selectivity with a controllable and switchable mode of action by means of specific stimulus constitutes a hot research topic in the field of food analysis. Thus, combining the stimuli responsive mechanism and imprinting technology a new generation of materials are emerging. The application of these smart materials in sample preparation is in early stage of development, nevertheless new improvements will promote a new driven in the demanding field of food sample preparation. The new trends in the advancement of food sample preparation using these smart materials will be presented in this review and highlighted the most relevant applications in this particular area of knowledge. PMID- 28917780 TI - Quantifying biodegradable organic matter in polluted water on the basis of coulombic yield. AB - Biodegradable organic matter (BOM) in polluted water plays a key role in various biological purification technologies. The five-day biochemical oxygen demand (BOD5) index is often used to determine the amount of BOM. However, standard BOD5 assays, centering on dissolved oxygen detection, have long testing times and often show severe deviation (error >= 15%). In the present study, the coulombic yield (Q) of a bio-electrochemical degradation process was determined, and a new index for BOM quantification was proposed. The Q value represents the quantity of transferred electrons from BOM to oxygen, and the corresponding index was defined as BOMQ. By revealing Q-BOM stoichiometric relationship, we were able to perform a BOMQ assay in a microbial fuel cell involved technical platform. Experimental results verified that 5-500mgL-1 of BOMQ toward artificial wastewater samples could be directly obtained without calibration in several to dozens of hours, leaving less than 5% error. Moreover, the BOMQ assay remained accurate and precise in a wide range of optimized operational conditions. A ratio of approximately 1.0 between the values of BOMQ and BOD5 toward artificial and real wastewater samples was observed. The rapidity, accuracy, and precision of the measurement results are supported by a solid theoretical foundation. Thus, BOMQ is a promising water quality index for quantifying BOM in polluted water. PMID- 28917781 TI - Fluorescence self-quenching assay for the detection of target collagen sequences using a short probe peptide. AB - The development of novel assays to detect collagen fragments is of utmost importance for diagnostic, prognostic and therapeutic decisions in various collagen-related diseases, and one essential question is to discover probe peptides that can specifically recognize target collagen sequences. Herein we have developed the fluorescence self-quenching assay as a convenient tool to screen the capability of a series of fluorescent probe peptides of variable lengths to bind with target collagen peptides. We have revealed that the targeting ability of probe peptides is length-dependent, and have discovered a relatively short probe peptide FAM-G(POG)8 capable to identify the target peptide. We have further demonstrated that fluorescence self-quenching assay together with this short probe peptide can be applied to specifically detect the desired collagen fragment in complex biological media. Fluorescence self quenching assay provides a powerful new tool to discover effective peptides for the recognition of collagen biomarkers, and it may have great potential to identify probe peptides for various protein biomarkers involved in pathological conditions. PMID- 28917782 TI - Studies on the retention mechanism of solutes in hydrophilic interaction chromatography using stoichiometric displacement theory I. The linear relationship of lgk' vs. lg[H2O]. AB - A stoichiometric displacement model for retention (SDM-R) of small solutes and proteins based on hydrophilic interaction chromatography (HILIC) was presented. A linear equation that related the logarithm of the capacity factor of the solute to the logarithm of the concentration of water in the mobile phase was derived. The stoichiometric displacement parameters, Z (the number of water molecules required to displace a solute from ligands) and lgI (containing a number of constants that relate to the affinity of solute to the ligands) could be obtained from the slope and the intercept of the linear plots of lgk' vs. lg[H2O]. The retention behaviors and retention mechanism of 15 kinds of small solutes and 6 kinds of proteins on 5 kinds HILIC columns with different ligands were investigated with SDM-R in typical range of water concentration in mobile phase. A good linear relationship between lgk' and lg[H2O] demonstrated that the most rational retention mechanism of solute in HILIC was a stoichiometric displacement process between solute and solvent molecules with water as displacing agents, which was not only valid for small solutes, but also could be used to explain the retention mechanism of biopolymers in HILIC. Comparing with the partition and adsorption models in HILIC, SDM-R was superior to them. PMID- 28917783 TI - Intellectual modifying a bare glassy carbon electrode to fabricate a novel and ultrasensitive electrochemical biosensor: Application to determination of acrylamide in food samples. AB - Acrylamide (AA) is a neurotoxin and carcinogen which is mainly formed in foods containing large quantities of starch processed at high temperatures and its determination is very important to control the quality of foods. In this work, a novel electrochemical biosensor based on hemoglobin-dimethyldioctadecylammonium bromide (HG-DDAB)/platinum-gold-palladium three metallic alloy nanoparticles (PtAuPd NPs)/chitosan-1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (Ch-IL)/multiwalled carbon nanotubes-IL (MWCNTs IL)/glassy carbon electrode (GCE) is proposed for ultrasensitive determination of AA in food samples. Development of the biosensor is based on forming an adduct by the reaction of AA with alpha-NH2 group of N-terminal valine of HG which decreases the peak current of HG-Fe+3 reduction. The modifications were characterized by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), energy dispersive X-ray spectroscopic (EDS) and scanning electron microscopy (SEM). Under optimized conditions, the biosensor detected AA by square wave voltammetry (SWV) in two linear concentration ranges of 0.03-39.0nM and 39.0 150.0nM with a limit of detection (LOD) of 0.01nM. The biosensor was able to selective detection of AA even in the presence of high concentrations of common interferents which confirmed that the biosensor is highly selective. Also, the results obtained from further studies confirmed that the proposed biosensor has a short response time (less than 8s), good sensitivity, long term stability, repeatability, and reproducibility. Finally, the proposed biosensor was successfully applied to determine AA in potato chips and its results were comparable to those obtained by gas chromatography-mass spectrometry (GC-MS) as reference method. PMID- 28917784 TI - Green synthesis of graphitic carbon nitride nanosheet (g-C3N4) and using it as a label-free fluorosensor for detection of metronidazole via quenching of the fluorescence. AB - In this research, g-C3N4nanosheets were facilely fabricated by thermal polymerization and then exfoliated into ultrathin nanosheets through ultrasonication in water media. Low-cost C-N nanosheets prepared by melamine possessed a highly pi-conjugated structure and fluorescence property. In the present study, the g-C3N4nanosheet was used as a switch-off fluorescence sensor for rapid and sensitive sensing of metronidazole in biological fluids. These nanosheets were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. The fluorescence of the solution of the g-C3N4nanosheets was quenched effectively by metronidazole through two mechanisms: fluorescence resonance energy transfer and the formation of a donor-acceptor charge-transfer complex between pi-electron rich donors. Under optimal conditions, the detection linear range for metronidazole was found to be from 0.01 to 0.10MUgml-1, with a limit of detection (LOD) of 0.008MUgml-1 which can cover standard range of metronidazole in real samples. Moreover, the proposed method has offered a green, rapid, and sensitive probe for quantitative determination of metronidazole in drug and biological fluids. PMID- 28917785 TI - Fluorescence quenching based alkaline phosphatase activity detection. AB - Simple and fast detection of alkaline phosphatase (ALP) activity is of great importance for diagnostic and analytical applications. In this work, we report a turn-off approach for the real-time detection of ALP activity on the basis of the charge transfer induced fluorescence quenching of the Cu(BCDS)22- (BCDS = bathocuproine disulfonate) probe. Initially, ALP can enzymatically hydrolyze the substrate ascorbic acid 2-phosphate to release ascorbic acid (AA). Subsequently, the AA-mediated reduction of the Cu(BCDS)22- probe, which displays an intense photoluminescence band at the wavelength of 402nm, leads to the static quenching of fluorescence of the probe as a result of charge transfer. The underlying mechanism of the fluorescence quenching was demonstrated by quantum mechanical calculations. The Cu(BCDS)22- probe features a large Stokes shift (86nm) and is highly immune to photo bleaching. In addition, this approach is free of elaborately designed fluorescent probes and allows the detection of ALP activity in a real-time manner. Under optimal conditions, it provides a fast and sensitive detection of ALP activity within the dynamic range of 0-220mUmL-1, with a detection limit down to 0.27mUmL-1. Results demonstrate that it is highly selective, and applicable to the screening of ALP inhibitors in drug discovery. More importantly, it shows a good analytical performance for the direct detection of the endogenous ALP levels of undiluted human serum and even whole blood samples. Therefore, the proposed charge transfer based approach has great potential in diagnostic and analytical applications. PMID- 28917786 TI - Chemometric compositional analysis of phenolic compounds in fermenting samples and wines using different infrared spectroscopy techniques. AB - The wine industry requires reliable methods for the quantification of phenolic compounds during the winemaking process. Infrared spectroscopy appears as a suitable technique for process control and monitoring. The ability of Fourier transform near infrared (FT-NIR), attenuated total reflectance mid infrared (ATR MIR) and Fourier transform infrared (FT-IR) spectroscopies to predict compositional phenolic levels during red wine fermentation and aging was investigated. Prediction models containing a large number of samples collected over two vintages from several industrial fermenting tanks as well as wine samples covering a varying number of vintages were validated. FT-NIR appeared as the most accurate technique to predict the phenolic content. Although slightly less accurate models were observed, ATR-MIR and FT-IR can also be used for the prediction of the majority of phenolic measurements. Additionally, the slope and intercept test indicated a systematic error for the three spectroscopies which seems to be slightly more pronounced for HPLC generated phenolics data than for the spectrophotometric parameters. However, the results also showed that the predictions made with the three instruments are statistically comparable. The robustness of the prediction models was also investigated and discussed. PMID- 28917787 TI - Gas chromatographic-mass spectrometric analysis of urinary volatile organic metabolites: Optimization of the HS-SPME procedure and sample storage conditions. AB - Non-targeted metabolomics research of human volatile urinary metabolome can be used to identify potential biomarkers associated with the changes in metabolism related to various health disorders. To ensure reliable analysis of urinary volatile organic metabolites (VOMs) by gas chromatography-mass spectrometry (GC MS), parameters affecting the headspace-solid phase microextraction (HS-SPME) procedure have been evaluated and optimized. The influence of incubation and extraction temperatures and times, coating fibre material and salt addition on SPME efficiency was investigated by multivariate optimization methods using reduced factorial and Doehlert matrix designs. The results showed optimum values for temperature to be 60 degrees C, extraction time 50min, and incubation time 35min. The proposed conditions were applied to investigate urine samples' stability regarding different storage conditions and freeze-thaw processes. The sum of peak areas of urine samples stored at 4 degrees C, -20 degrees C, and -80 degrees C up to six months showed a time dependent decrease over time although storage at -80 degrees C resulted in a slight non-significant reduction comparing to the fresh sample. However, due to the volatile nature of the analysed compounds, more than two cycles of freezing/thawing of the sample stored for six months at -80 degrees C should be avoided whenever possible. PMID- 28917788 TI - Glass-polytetrafluoroethylene-glass based sandwich microdevice for continuous flow polymerase chain reaction and its application for fast identification of foodborne pathogens. AB - A uniquely fabricated microdevice with a glass-polytetrafluoroethylene (PTFE) glass (GPG) sandwich configuration was developed for the fast identification of foodborne pathogens by using continuous-flow polymerase chain reaction (PCR) followed by on-site fluorescence detection of PCR products. A PTFE tube was simply folded into a serpentine configuration and sandwiched between two glass slides to maintain a 2D planar structure. By using a PTFE tube, the microchannel has the advantage of seamlessness without the need for photolithography methods, and is less expensive and less time-consuming to fabricate than alternative devices. The non-porous and gas-impermeable PTFE tube ensured stable sample flow inside the microchannel. PCR conditions were optimized and evaluated by examining the effects of number of cycles and initial concentration of bacteria introduced. On-site detection of PCR products was performed using nucleic acid dye SYBR Green I. Using the GPG microdevice, Escherichia coli O157:H7 and Salmonella spp., two well-known foodborne pathogens, were amplified within 20min. Besides fast reaction, the simply fabricated microdevice demonstrated its potential as a portable device applicable for public healthcare diagnostics. PMID- 28917789 TI - Chemometric optimization of the extraction and derivatization of parabens for their determination in water samples by rotating-disk sorptive extraction and gas chromatography mass spectrometry. AB - A combination of rotating disk sorptive extraction (RDSE) using Oasis(r) HLB as the sorbent phase and gas chromatography mass spectrometry (GC-MS) has been performed for the determination of four of the most widely used parabens: methylparaben, ethylparaben, propylparaben and n-butylparaben. The extraction and derivatization of the analytes in water samples were optimized by using factorial (screening) and Doehlert designs, thus reducing the number of analyses with the concomitant reduction of time, reagents, waste, samples and cost. Thus, a RDSE method using 20mL of sample was performed. The disk was rotated at 2900rpm for 70min at room temperature. After a desorption step and evaporation of solvent, a derivatization method using 5MUL of N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) for 15min at room temperature was used previously to inject the final extract into GC-MS. The detection limits and precision (%RSD) were lower than 0.05MUgL- 1 and 9.7% for the studied compounds, respectively. Recoveries were studied using effluent samples of a wastewater treatment plant (WWTP), with values higher than 80% being obtained. The applicability and reliability of this methodology were confirmed through the analysis of tap water and influents from Santiago, Chile, with concentration values ranging from 0.57 to 0.83MUgL- 1 in influents. The main advantage of the present RDSE method is that it is significantly faster than its counterpart by SBSE and requires a considerable lower volume of derivatizing agent. PMID- 28917790 TI - A green solvent holder in electro-mediated microextraction for the extraction of phenols in water. AB - Electro-mediated microextraction (EMM) combined with micro-high performance liquid chromatography-ultraviolet detection was successfully developed for the determination of selected phenols, namely 4-chlorophenol (4CP), 2-nitrophenol (2NP) and 2,4-dichlorophenols (2,4 DCP) in water. A solvent-impregnated agarose gel disc was utilized as a solvent holder in this study. Under optimum extraction conditions, the method showed good linearity in the range of 0.1-250ugL-1, 0.3 250ugL-1 and 0.2-500ugL-1 for 4CP, 2NP and 2,4 DCP, respectively with correlation coefficients of >= 0.9975, ultra-trace LODs (0.03-0.1ugL-1) and satisfactory relative recovery average (85.0-114.1%) for the analysis of selected phenols. The proposed method was rapid and eco-friendly as the solvent holder was constructed using minute amounts of extraction solvent immobilized within the biodegradable agarose gel disc. A comparative microextraction technique termed solvent impregnated agarose gel liquid phase microextraction (AG-LPME) was re-optimized and validated for the extraction of phenols in water. The method offered good linearity, ultra-trace LODs ranging 0.1-0.5ugL-1 and satisfactory average of relative recovery (86.1-114.1%). The EMM was superior in terms of sensitivity and time-effectiveness compared to AG-LPME. Both techniques combine extraction and pre-concentration in mini-scaled approaches using an eco-friendly solvent holder that fulfil the green chemistry concept. PMID- 28917791 TI - Development of salt and pH-induced solidified floating organic droplets homogeneous liquid-liquid microextraction for extraction of ten pyrethroid insecticides in fresh fruits and fruit juices followed by gas chromatography-mass spectrometry. AB - A new microextraction method named salt and pH-induced homogeneous liquid-liquid microextraction has been developed in a home-made extraction device for the extraction and preconcentration of some pyrethroid insecticides from different fruit juice samples prior to gas chromatography-mass spectrometry. In the present work, an extraction device made from two parallel glass tubes with different lengths and diameters was used in the microextraction procedure. In this method, a homogeneous solution of a sample solution and an extraction solvent (pivalic acid) was broken by performing an acid-base reaction and the extraction solvent was produced in whole of the solution. The produced droplets of the extraction solvent went up through the solution and solidified using an ice-bath. They were collected without centrifugation step. Under the optimum conditions, limits of detection and quantification were obtained in the ranges of 0.006-0.038, and 0.023-0.134ngmL-1, respectively. The enrichment factors and extraction recoveries of the selected analytes ranged from 365-460 to 73-92%, respectively. The relative standard deviations were lower than 9% for intra- (n = 6) and inter-day (n = 4) precisions at a concentration of 1ngmL-1 of each analyte. Finally, some fruit juice samples were effectively analyzed by the proposed method. PMID- 28917792 TI - ZnO nanotubes supported molecularly imprinted polymers arrays as sensing materials for electrochemical detection of dopamine. AB - In this study, ZnO nanotubes (ZNTs) were prepared onto fluorine-doped tin oxide (FTO) glass and used as supports for MIPs arrays fabrication. Due to the imprinted cavities are always located at both inner and outer surface of ZNTs, these ZNTs supported MIPs arrays have good accessibility towards template and can be used as sensing materials for chemical sensors with high sensitivity, excellent selectivity and fast response. Using K3[Fe(CN)6] as electron probe, the fabricated electrochemical sensor shows two linear dynamic ranges (0.02-5MUM and 10-800MUM) towards dopamine. This proposed electrochemical sensor has been applied for dopamine determination with satisfied recoveries and precision. More complex human urine samples also confirmed that the proposed method has good accuracy for dopamine determination in real biological samples. These results suggest potential applicability of the proposed method and sensor in important molecule analysis. PMID- 28917793 TI - Multi-elemental Nd, Sm, Eu, Gd isotope ratio measurements by stop-flow isotachophoresis coupled to MC-ICPMS. AB - In this study, a new analytical procedure based on isotachophoresis (ITP) coupled to a multi collector inductively coupled plasma mass spectrometer named Stop-Flow ITP-MC-ICPMS is developed for exhaustive and high-precision multi-elemental isotopic characterization. We demonstrate that Stop-Flow-ITP makes it possible to stop the analytes migration several times for a duration compatible with the detector configuration changes without losing the separation performance. With this procedure, isotope ratio measurements of four lanthanides of interest for nuclear applications (Nd, Sm, Eu and Gd) were obtained with a reproducibility better than 0.4% in a single analysis with only 20ng of each element. A nebulization interface between ITP and MC-ICPMS composed of a dual inlet spray chamber and a multiple flow stream valve made it possible to perform isotopic reference standard injections for on-line mass bias correction by the sample standard bracketing approach. The flexibility of the Stop-Flow-ITP-MC-ICPMS procedure opens the way to online determination of isotope ratio measurements of multiple analytes present in a sample in a single analysis. PMID- 28917794 TI - Patterned polycaprolactone-filled glass microfiber microfluidic devices for total protein content analysis. AB - Membrane based microfluidic devices have gained much popularity in recent years, as they make possible rapid, inexpensive analytical techniques that can be applied to a wide variety of areas. The ability to modify device hydrophilicity and hydrophobicity is critically important in fabricating membrane based microfluidic devices. Polar hydrophilic membranes, such as glass microfiber (GMF) membranes, hold great potential as they are inexpensive, chemically inert, and stable. Filling of these membranes with non-polar polymers such as polycaprolactone (PCL) converts the hydrophilic GMF into a hydrophobic medium. Controlled alteration of the surface chemistry of PCL/GMF substrates allows for the fabrication of microfluidic patterns on the surface. Using this approach, we have developed a simple and rapid technique for fabrication of highly adaptable complex multidimensional (2D and 3D) microfluidic pathways on a single membrane. PCL-filled GMF media were masked and selectively exposed to oxygen radicals so that the exposed surface became permanently superhydrophilic in its behavior. The desired microfluidic pattern was cut into the mask prior to assembly and exposure, and the mask was removed after exposure to reveal the ready-to-use microfluidic device. To verify and demonstrate the performance of this novel fabrication method, a colorimetric total protein assay was applied to the determination of protein concentrations in real samples. PMID- 28917795 TI - Portable near infrared spectroscopy applied to quality control of Brazilian coffee. AB - The use of portable micro-spectrometers such as a micro near infrared region (microNIR) spectrometer is a promising technique for solving analytical problems in several areas of science. This work evaluated the potential of microNIR in quality control of Arabica coffee. Arabica coffee has a high commercial value product, motivating the development of analytical methods with high sensitivity and accuracy for detection of its adulteration. Herein, microNIR was successfully used to determine the quality of Arabica coffee by identification and quantification of adulterations such as Robusta coffee (in different roasting levels), as well as corn, peels, and sticks. MicroNIR was combined with multivariate calibration by partial least squares (PLS) and principal component analysis (PCA). A total of 125 blends were produced, containing thirteen different concentrations of the adulterants (corn and peels/sticks, and the Robusta coffee) ranging from 1 to 100wt%. Developed PCA and PLS models were also applied to monitor the quality of sixteen commercial coffee samples. The results obtained using microNIR proved the ability of the method to be efficient and capable in the prediction of adulterations with minimum quantification levels (LOQs of 5-8wt%), being able to be applied to quality control of commercial coffee samples. Therefore, microNIR can reduce and simplify the time of analysis and sample preparation step, as well as to guarantee the efficiency of real-time data acquisition owing to its portability. PMID- 28917796 TI - Simultaneous phase-inversion and imprinting based sensor for highly sensitive and selective detection of bisphenol A. AB - A novel recognition element of molecularly imprinted films (MIFs) was synthesized by wet phase inversion (WPI) on the surface of Ti/TiO2 electrode for highly selective and sensitive electrochemical detection of bisphenol A (BPA). The Ti/TiO2/MIFs sensor was constructed by casting the precursor poly(acrylonitrile co-acrylic acid) (p(AN-co-AA)) in dimethyl sulfoxide containing template molecule BPA onto the electrode and then immersing into water, resulting in simultaneous p(AN-co-AA) precipitation and BPA imprinting via the facile WPI. The imprinted sites could selectively rebind BPA through hydrogen bonding and hence lead to the equalizing current increase in amperometric detection, by which the BPA could be sensed electrochemically. Accordingly, the Ti/TiO2/MIFs sensor offered a favorable linearity within the wide range over five orders of magnitude (4.4nM 0.13mM), and a low detection limit down to 1.3nM. Excellent recognition selectivity for BPA was also attained over its analogues. Furthermore, this sensor was successfully applied to detect BPA in seawater and paper cup samples, and high recoveries were 86-110% with low relative standard deviations of 1.3 3.2%. By using BPA as a model, the MIFs-based method may provide a facile, rapid, and cost-effective way for ultrasensitive electrochemical measurements of various targeted compounds with good applicability to WPI. PMID- 28917797 TI - A rapid and specific colorimetric method for free tryptophan quantification. AB - Tryptophan is one of the eight essential amino acids and plays an important role in many biological processes. For its interaction with human health, environment and relevant commercial interest in biotechnology-based production, rapid and specific quantification method for this molecule accessible to common laboratories is badly needed. We herein reported a simple colorimetric method for free tryptophan quantification with 96-well-plate-level throughput. Our protocol firstly converted tryptophan to indole enzymatically by purified tryptophanases and then used reactivity of indole with hydroxylamine to form pink product with absorption peak at 530nm, enabling the quantification of tryptophan with simple spectrometry in just two hours. We presented that this method exhibited a linear detection range from 100MUM to 600MUM (R2 = 0.9969) with no detection towards other naturally occurring tryptophan analogs or tryptophan residues in proteins. It was very robust in complicated biological samples, as demonstrated by quantifying the titer of 36 mutated tryptophan-producing strains with Pearson correlation coefficient of 0.93 in contrast to that measured by high performance liquid chromatography (HPLC). Our method should be potent for routine free tryptophan quantification in a high-throughput manner, facilitating studies in medicine, microbiology, food chemistry, metabolic engineering, etc. PMID- 28917798 TI - Perception of olive oils sensory defects using a potentiometric taste device. AB - The capability of perceiving olive oils sensory defects and intensities plays a key role on olive oils quality grade classification since olive oils can only be classified as extra-virgin if no defect can be perceived by a human trained sensory panel. Otherwise, olive oils may be classified as virgin or lampante depending on the median intensity of the defect predominantly perceived and on the physicochemical levels. However, sensory analysis is time-consuming and requires an official sensory panel, which can only evaluate a low number of samples per day. In this work, the potential use of an electronic tongue as a taste sensor device to identify the defect predominantly perceived in olive oils was evaluated. The potentiometric profiles recorded showed that intra- and inter day signal drifts could be neglected (i.e., relative standard deviations lower than 25%), being not statistically significant the effect of the analysis day on the overall recorded E-tongue sensor fingerprints (P-value = 0.5715, for multivariate analysis of variance using Pillai's trace test), which significantly differ according to the olive oils' sensory defect (P-value = 0.0084, for multivariate analysis of variance using Pillai's trace test). Thus, a linear discriminant model based on 19 potentiometric signal sensors, selected by the simulated annealing algorithm, could be established to correctly predict the olive oil main sensory defect (fusty, rancid, wet-wood or winey-vinegary) with average sensitivity of 75 +/- 3% and specificity of 73 +/- 4% (repeated K-fold cross-validation variant: 4 folds*10 repeats). Similarly, a linear discriminant model, based on 24 selected sensors, correctly classified 92 +/- 3% of the olive oils as virgin or lampante, being an average specificity of 93 +/- 3% achieved. The overall satisfactory predictive performances strengthen the feasibility of the developed taste sensor device as a complementary methodology for olive oils' defects analysis and subsequent quality grade classification. Furthermore, the capability of identifying the type of sensory defect of an olive oil may allow establishing helpful insights regarding bad practices of olives or olive oils production, harvesting, transport and storage. PMID- 28917799 TI - A reagentless and reusable electrochemical aptamer-based sensor for rapid detection of ampicillin in complex samples. AB - We report the design and fabrication of a "signal-on" electrochemical aptamer based (E-AB) sensor for detection of ampicillin. The signaling of the sensor is based on target binding-induced changes in the conformation and flexibility of the methylene blue-modified aptamer probe. The sensor's response is fast; signal saturation can be reached in ~ 200s. Since all the sensor components are surface immobilized, it is regenerable and can be reused for at least three times. It has demonstrated good specificity and is capable of differentiating between ampicillin and structurally similar antibiotics such as amoxicillin. More importantly, it is selective enough to be employed directly in complex samples, including serum, saliva, and milk. Although both alternating current voltammetry (ACV) and square wave voltammetry (SWV) are suitable sensor characterization techniques, our results show that ACV is better suited for target analysis. Even under the optimal experimental conditions, the limit of detection of the sensor obtained in ACV (1uM) is significantly lower than that obtained in SWV (30uM). PMID- 28917800 TI - beta-Cyclodextrins incorporated multi-walled carbon nanotubes modified electrode for the voltammetric determination of the pesticide dichlorophen. AB - In this work, a glassy carbon electrode modified with beta-cyclodextrins and multi-walled carbon nanotubes (beta-CDs/MWCNTs/GCE) was constructed and applied for the square-wave adsorptive stripping voltammetric (SWAdSV) determination of the pesticide dichlorophen (Dcp). For the first time, this compound was electrochemically investigated. The voltammetric measurements were conducted in phosphate buffer (PBS) at pH 6.5 as a supporting electrolyte, and SWAdSV technique parameters were optimized. A linear calibration curve in the wide concentration range from 5.0 * 10-8molL-1 to 2.9 * 10-6molL-1 was obtained. Excellent analytical performance in terms of limit of detection (LOD) of 1.4 * 10 8molL-1 was achieved. The utility of the proposed method was verified by the quantitative analysis of Dcp in Pilica River water samples with satisfactory results. The characterization of modified electrodes was conducted by means of atomic force microscopy (AFM), electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV). Moreover, in this work, the dissociation constants (pKa) of Dcp using potentiometric pH titration were estimated. The stoichiometry of the Dcp-beta-CDs inclusion complex formed in solution was determined by proton nuclear magnetic resonance (1H NMR) spectroscopy, and a binding constant (beta2) was estimated from NMR titration studies. PMID- 28917801 TI - Development of a quantitative approach in blood plasma for low-dosed hallucinogens and opioids using LC-high resolution mass spectrometry. AB - The WHO annually reports an increasing abuse of new psychoactive substances (NPS), which are a heterogeneous group of synthetic drugs and are consumed as substitute for controlled drugs of abuse. In this work, we focused on highly potent derivatives such those of phenethylamine (2C), N-2-methoxybenzyl phenethylamine (NBOMes), lysergic acid diethylamide (LSD), and fentanyl. Severe to fatal intoxications were described due to their high potency. Therefore, they have to be taken at very low doses resulting in low blood concentration in the low ng/mL range, which is a challenge for reliable analytical detection and quantification. The aim of this work was therefore to design a simple, robust, and fast method for simultaneous detection and quantification of multiple substances of the different classes in human blood plasma using liquid chromatography (LC) high resolution (HR) mass spectrometry (MS) with alternating HR full-scan (HRFS) MS and "All-ions fragmentation" (AIF) MS. The paper contains results of the method validation according to the EMA guideline, including intra /interday accuracy and precision, matrix effects, storage and benchtop analyte stability as well as selectivity and carryover. All validation criteria were fulfilled for most tested compounds except for the NBOMe derivatives, one out of ten 2C-derivatives and butyryl fentanyl, which failed at accuracy and/or precision or at the acceptance criteria for matrix effect. Reasons for this are discussed and solutions presented. Despite some limitations, the HRFS + AIFMS analysis allowed detection of most of the analytes down to 0.1ng/mL, seamless integration of new or unexpected analytes, identification and quantification with no limitations on the number of monitored compounds, and reevaluation of the acquired data also concerning metabolism studies using group-indicating fragment ions. PMID- 28917802 TI - On-chip microfluidic generation of monodisperse bubbles for liquid interfacial tension measurement. AB - A novel microfluidic method for measuring liquid interfacial tension using monodisperse microbubbles generated in situ has been proposed. Instead of bulky gas supply used in traditional microfluidic devices, microbubbles are efficiently generated via water electrolysis in the devices. Since the bubble formation frequency is related to the interfacial tension of liquids used, thus, precisely measuring the interfacial tension of liquids in microfluidics can be achieved. In addition, it is found that during the microbubble formation, the electrochemical potential fluctuates regularly at controlled electrolysis current, and the fluctuating period depends on the microbubble generation rate. Therefore, the change in electrochemical potential can be directly used to monitor the bubble formation process, which avoids the use of an external optical detection system. As demonstration, the interfacial tension of isopentanol solutions with different concentrations was measured, and the results show good agreement with the ones obtained using the maximum bubble pressure method, confirming the accuracy of the present method. The proposed strategy offers a simple, low cost and accurate solution to measure the liquid interfacial tension confined in microfluidic channels. The present platform is easily constructed and facilely manipulated in common laboratories, which is expected to be widely used in microfluidic-based research and application fields. PMID- 28917803 TI - ATP mediated rolling circle amplification and opening DNA-gate for drug delivery to cell. AB - Here, we have developed a facile fluorometric system for the detection of adenosine triphosphate (ATP) by a rolling circle amplification (RCA) based on proximity ligation mediated amplification, and simultaneously achieved the release of the anticancer drug doxorubicin (DOX) through the mesoporous silicon system. Once the ATP molecule is present, the linker DNA will be released from the graphene oxide (GO) surface and hybridized to the template DNA of the GO surface joining with ligation enzyme. RCA reaction is followed by the addition of the phi29 DNA polymerase. The product of RCA reaction contains a base fragment complementary to the signal DNA, allowing the fluorescent oligonucleotide probe to be released from the GO surface and fluorescence is recovered. The strong fluorescence signal realized the sensitive detection of ATP. Gate DNA were modified to the surface of the mesoporous silica (MSN) by electrostatic attraction to encapsulate DOX. After the above-mentioned RCA process, its result that long DNA chain containing a base fragment complementary to gate DNA, would be hybridized to the gate DNA strand on the surface of MSN, which opened the MSN hole and released the drug DOX into cell for HeLa cell therapy. And the specificity to folate receptor overexpressed on cell surface was satisfactory which would be beneficial for cancer therapy. PMID- 28917804 TI - Development and validation of a maleimide-based enzyme-linked immunosorbent assay for the detection of tetrodotoxin in oysters and mussels. AB - The recent detection of tetrodotoxins (TTXs) in puffer fish and shellfish in Europe highlights the necessity to monitor the levels of TTXs in seafood by rapid, specific, sensitive and reliable methods in order to protect human consumers. A previous immunoassay for TTX detection in puffer fish, based on the use of self-assembled monolayers (SAMs) for the immobilization of TTX on maleimide plates (mELISA), has been modified and adapted to the analysis of oyster and mussel samples. Changing dithiol for cysteamine-based SAMs enabled reductions in the assay time and cost, while maintaining the sensitivity of the assay. The mELISA showed high selectivity for TTX since the antibody did not cross-react with co-occurring paralytic shellfish poisoning (PSP) toxins and no interferences were observed from arginine (Arg). Moreover, TTX-coated maleimide plates stored for 3 months at -20 degrees C and 4 degrees C were stable, thus when pre-prepared, the time to perform the assay is reduced. When analyzing shellfish samples, matrix effects and toxin recovery values strongly depended on the shellfish type and the sample treatment. Blank oyster extracts could be directly analyzed without solid-phase extraction (SPE) clean-up, whereas blank mussel extracts showed strong matrix effects and SPE and subsequent solvent evaporation were required for removal. However, the SPE clean-up and evaporation resulted in toxin loss. Toxin recovery values were taken as correction factors (CFs) and were applied to the quantification of TTX contents in the analysis of naturally-contaminated shellfish samples by mELISA. The lowest effective limits of detection (eLODs) were about 20 and 50ug/kg for oyster extracts without and with SPE clean-up, respectively, and about 30ug/kg for mussel extracts with both protocols, all of them substantially below the eLOD attained in the previous mELISA for puffer fish (230ug/kg). Analysis of naturally-contaminated samples by mELISA and comparison with LC-MS/MS quantifications demonstrated the viability of the approach. This mELISA is a selective and sensitive tool for the rapid detection of TTX in oyster and mussel samples showing promise to be implemented in routine monitoring programs to protect human health. PMID- 28917805 TI - Hemoglobin becomes electroactive upon interaction with surface-protected Au nanoparticles. AB - In this work, we report on the electrochemical behavior of bioconjugates prepared with gold nanoparticles (AuNP) capped with three different molecular layers (citrate anions, 6-mercaptopurine and omega-mercaptoundecanoic acid) and the protein hemoglobin (Hb). Freshly formed bioconjugates are deposited on a glassy carbon electrode and assayed for electroactivity. A pair of redox peaks with formal potential at -0.37V is obtained, in contrast with the free Hb protein that is inactive on the glassy carbon substrate. The redox response is typical for quasi-reversible processes allowing the determination of the electron transfer rate constant for the three bioconjugates. Additional evidence of the structural integrity of protein upon forming the bioconjugate is obtained by monitoring the electrochemical response of the Hb heme Fe(III)/Fe(II) redox couple as a function of solution pH. Moreover, the Hb forming the protein corona around the AuNPs show good electrocatalytic activity for the reduction of hydrogen peroxide and oxygen. It has been found that only the first layer of Hb surrounding the AuNPs are electroactive, although some part of the second layer also contribute, pointing to the role of the AuNP in the electrochemical response. PMID- 28917806 TI - Portable and low-cost colorimetric office paper-based device for phenacetin detection in seized cocaine samples. AB - An office paper-based colorimetric device is proposed as a portable, rapid, and low-cost sensor for forensic applications aiming to detect phenacetin used as adulterant in illicit seized materials such as cocaine. The proposed method uses white office paper as the substrate and wax printing technology to fabricate the detection zones. Based on the optimum conditions, a linear analytical curve was obtained for phenacetin concentrations ranging from 0 to 64.52ugmL-1, and the straight line was in accordance with the following equation: (Magenta percentage color) = 1.19 + 0.458 (CPhe/ugmL-1), R2 = 0.990. The limit of detection was calculated as 3.5ugmL-1 (3sigma/slope). The accuracy of the proposed method was evaluated using real seized cocaine samples and the spike-recovery procedure. PMID- 28917807 TI - Simultaneous determination of designer benzodiazepines in human serum using non aqueous capillary electrophoresis - Tandem mass spectrometry with successive multiple ionic - Polymer layer coated capillary. AB - A novel non-aqueous capillary electrophoresis - tandem mass spectrometry method for the simultaneous separation, identification and quantification of nine designer benzodiazepines (bentazepam, etizolam, deschloroetizolam, diclazepam, flubromazepam, flubromazolam, nimetazepam, phenazepam, and pyrazolam) was developed. A non-aqueous running electrolyte consisting of 25mM ammonium acetate with 100mM trifluoroacetic acid in acetonitrile was used. The separation was carried out using a semipermanent coated capillary (successive multiple ionic polymer coating) with a strong anodic electroosmotic flow at a negative separation voltage within twelve minutes. Electrospray ionization with a triple quadrupole mass spectrometry was utilized for the identification and quantification of selected designer benzodiazepines in a positive ionization mode. The developed method was validated and applied on the analysis of spiked serum sample following a simple liquid-liquid extraction. The LODs of the designer benzodiazepines were between 1.5 and 15.0ngmL-1. PMID- 28917808 TI - Single-drop gold nanoparticles for headspace microextraction and colorimetric assay of mercury (II) in environmental waters. AB - A novel headspace colorimetric nanosensor strategy for specific detection of Hg(II) was developed based upon analyte induced etching and amalgamation of gold nanoparticles (AuNPs). The Hg(II) was first selectively reduced to its volatile form, Hg(0), by stannous chloride (SnCl2) through chemical cold vapor generation (CVG) reaction. Then, the Hg(0) was headspace extracted into 37MUL thioglycolic acid functionalized AuNP aqueous suspension containing 10% methanol as extractant and simultaneously reacted with AuNPs through the strong metallophilic Hg-Au interaction, resulting in a red-to-blue color change. Parameters influencing the chromogenic and chemical vapor generation reactions were optimized. The limit of detections were determined as 5nM through inspection by naked-eye and 1nM based on measurements by UV-Vis spectrometer, which are below the safe limit of Hg(II) in drinking water set by the US Environmental Protection Agency, showing excellent potential for monitoring ultralow levels of Hg(II) in environmental water samples. The assay was not interfered by the presence of other common metal ions even at 1000-fold excess over Hg(II) concentration. The outstanding selectivity results from the combined effect of selective reduction of Hg(II) by SnCl2, efficient separation of sample matrix through headspace extraction, and amalgamation process that occurs specifically between Hg and AuNPs. The method was successfully applied to the visual detection of Hg(II) in environmental water samples at a 10nM spiking level, with recoveries in the range of 86.8-99.8%. More importantly, compared to classical colorimetric assays for detection of Hg(II), this method is featured with simplicity, quite high sensitivity and excellent selectivity. The method is also superior to most colorimetric methods for detection of Hg(II) in terms of its applicability to matrix-rich real samples including wastewater. PMID- 28917809 TI - Characterization of sodium tripolyphosphate and sodium citrate dehydrate residues on surfaces. AB - Sodium tripolyphosphate (STPP) and sodium citrate dihydrate (sodium citrate) are the most widely used components in detergent formulations. Here, we characterized these two components on glass surfaces to assess their possible exposures from white spots on dishwasher-washed dishes. Ultraviolet/visible near infrared spectroscopy (UV/Vis-NIR), Fourier transform infrared spectroscopy (FTIR) in the attenuated total reflectance mode (ATR-FTIR), Raman spectroscopy and laser ablation-inductively coupled plasma mass spectroscopy (LA-ICP-MS) were utilized to design calibration models for a range of STPP and sodium citrate concentrations 1-8% w/w) precipitated on glass surfaces. STPP and sodium citrate residues on the dishwasher-washed dishes were also determined quantitatively using ATR-FTIR by utilizing these calibration models. In addition, cytotoxicity assays were performed to elucidate the influence of STPP and sodium citrate on human embryonic kidney cell survival. Cell viability results showed a decreasing trend in the number of cells cultured with increasing concentrations and exposure time of STPP and sodium citrate in the medium. Cell survival was minimum on day four when cells were exposed to 84mg/kg of body/day of STPP and sodium citrate separately. This is the first report about detection and quantification of STTP and sodium citrate and assessment of cytotoxicity. Results of this study provide opportunities for the quantification of detergent residues on dishes and assessment of their possible toxicity on live cells. PMID- 28917810 TI - Nano-hemoglobin film based sextet state biomemory device by cross-linked photosensitive hapten monomer. AB - In this study, a biomemory device, consisting of hemoglobin (Hb) cross-linked by MACys-Ru(bipyr)2-MACys) photosensitive monomer cross-linkers, which have memory effect through both Ru3+/2+ in hapten monomer and Fe3+/2+ in redox active center of Hb through multi-charge transfer mechanism, has been improved. Cyclic voltammetry (CV) has been used to determine the redox property of the Hb cross linked MACys-Ru(bipyr)2-MACys) hapten. Three memory functions, writing, reading and erasing of the fabricated biomemory device, have been accomplished by chronoamperometry (CA) and open-circuit potential amperometry (OCPA). The reliability and repeatability of the biodevice consisting of the p(Hb-co-MACys Ru(bipyr)2-MACys) sextet state bio-memory layer have been analysed. The Hb film based biodevice on gold electrodes has shown >= 2 months the retention time and switched until 106 times continuous cycling without degradation in efficiency. Other hand, the topography of p(Hb-co-MACys-Ru(bipyr)2-MACys) layer on the gold surface has investigated by scanning electron microscopy (SEM) and EDX data. PMID- 28917811 TI - Electrochemical characterization of in situ functionalized gold organosulfur self assembled monolayer with conducting polymer and carbon nanotubes for determination of rutin. AB - In this study, attempts were made to present a sensitive strategy for determining rutin. To reach the goal of the study, a poly(sulfosalicylic acid) film was electropolymerized on a gold electrode, which was modified by 2 mercaptobenzothiazole self-assembled monolayer and multi-walled carbon nanotubes (PSSA/CNTs/MBT/Au). The proposed sensor was characterized by different techniques including field emission scanning electron microscopy, energy dispersive X-ray spectroscopy and Fourier transform infrared spectroscopy. The resulting sensor displayed electrocatalytic activity towards the oxidation of rutin which is attributed to the presence of the PSSA/MWCNTs nanocomposite. Under optimized conditions, the detection limit of 1.8nmolL-1 and two linear calibration ranges of 0.01-0.8 and 0.8-10.0umolL-1 were obtained for rutin determination at the PSSA/CNTs/MBT/Au electrode. The proposed modified electrode was successfully applied for the determination of rutin in orange, red apple, red onion, strawberry, oat and salvia samples. The obtained results suggest that the proposed electrode has several advantages, such as high stability, repeatability and good reproducibility and it can be used for a sensitive, selective and rapid determination of rutin. PMID- 28917813 TI - Structural impacts on the timing and amplitude of the negative BOLD response. AB - The positive (PBR) and negative BOLD responses (NBR) arising in task-fMRI display varying magnitudes and dynamics across voxels. While the effects of structure, particularly of veins, on the PBR have been studied, little is known of NBR structure relationships. Like the PBR, the NBR is often used as a surrogate marker of neuronal activation in both basic and clinical research and assessing its relationship with cortical structure may help interpret group differences. We therefore investigated how local structure affects BOLD amplitude and timing in PBR and NBR areas using multi-band fMRI during visual stimulation to obtain high temporal resolution (TR=0.45s) data combined with T1 imaging and susceptibility weighted imaging (SWI) to quantify the local densities of gray/white matter and veins, respectively. In both PBRs and NBRs, larger venous density was consistently associated with larger BOLD amplitude and delay, up to 1-2s larger relative to areas devoid of large veins. Both binary and sinusoidal visual stimulus modulation yielded similar activation maps and results, suggesting that underlying vasculature affects PBR and NBR temporal dynamics in the same manner. Accounting for structural impacts on PBR and NBR magnitude and timing could help enhance activation map accuracy, better assess functional connectivity, and better characterize neurovascular coupling. PMID- 28917812 TI - A minimum-phase Shinnar-Le Roux spectral-spatial excitation RF pulse for simultaneous water and lipid suppression in 1H-MRSI of body extremities. AB - PURPOSE: To develop a spectral-spatial (SPSP) excitation RF pulse for simultaneous water and lipid suppression in proton (1H) magnetic resonance spectroscopic imaging (MRSI) of body extremities. METHODS: An SPSP excitation pulse is designed to excite Creatine (Cr) and Choline (Cho) metabolite signals while suppressing the overwhelming water and lipid signals. The SPSP pulse is designed using a recently proposed multidimensional Shinnar-Le Roux (SLR) RF pulse design method. A minimum-phase spectral selectivity profile is used to minimize signal loss from T2* decay. RESULTS: The performance of the SPSP pulse is evaluated via Bloch equation simulations and phantom experiments. The feasibility of the proposed method is demonstrated using three-dimensional, short repetition-time, free induction decay-based 1H-MRSI in the thigh muscle at 3T. CONCLUSION: The proposed SPSP excitation pulse is useful for simultaneous water and lipid suppression. The proposed method enables new applications of high resolution 1H-MRSI in body extremities. PMID- 28917814 TI - Late-occurring nivolumab-induced cryptogenic organising pneumonia mimicking lung progression in a patient with metastatic non-small cell lung cancer. PMID- 28917815 TI - Mitigation of nitrite toxicity by increased salinity is associated with multiple physiological responses: A case study using an economically important model species, the juvenile obscure puffer (Takifugu obscurus). AB - Nitrite is a common pollutant in water and is highly toxic to aquatic animals. To reveal the mechanism of salinity in attenuating nitrite toxicity to fish, we measured the physiological responses of juvenile Takifugu obscurus exposed to nitrite concentrations (0, 10, 20, 50, and 100 mg/L) under different salinity levels (0, 10, and 20 ppt) for 96 h. Salinity increased the survival rates of juvenile T. obscurus exposed to nitrite. Changes in key hematological parameters, antioxidant system, malondialdehyde, Na+/K+-ATPase, and HSP70 indicated that nitrite induced considerable damage to juveniles; salinity mitigated the harmful effects. This finding reflects similar changing trends in both antioxidants and their gene expressions among different tissues. We applied an overall index, an integrated biomarker response (IBR), that increased under high-nitrite condition but recovered to the normal levels under salinity treatment. Analysis of the selected detection indices and IBR values showed that the overall mitigating effect of salinity on nitrite toxicity seems to be at sub-cellular level and associated with complicated physiological responses. PMID- 28917816 TI - Crystalline phase-dependent eco-toxicity of titania nanoparticles to freshwater biofilms. AB - The potential toxic impacts of different crystal phases of titania nanoparticles (TNPs) on freshwater biofilms, especially under ultraviolet C irradiation (UVC), are unknown. Here, adverse impacts of three phases (anatase, rutile, and P25, 50 mg L-1 respectively) with UVC irradiation (An-UV, Ru-UV, and P25-UV) on freshwater biofilms were conducted. Characterization experiments revealed that rutile TNPs had a higher water environment stability than anatase and P25 TNPs, possessing a stronger photocatalytic activity under UVC irradiation. Phase dependent inhibition of cell viability and significant decreases of four- and five-fold in algal biomass at 12 h of exposure were observed compared with unexposed biofilms. Moreover, phase-dependent oxidative stress resulted in remarkably significant reductions (P < 0.01) of the photosynthetic yields of the biofilms, to 40.32% (P25-UV), 48.39% (An-UV), and 46.77% (Ru-UV) of the plateau value obtained in the unexposed biofilms. A shift in community composition that manifested as a strong reduction in diatoms, indicating cyanobacteria and green algae were more tolerant than diatoms when exposed to TNPs. In terms of the toxic mechanisms, rutile TNPs resulted in apoptosis by inducing excessive intracellular reactive oxygen species (ROS) production, whereas P25 and anatase TNPs tended to catalyze enormous acellular ROS lead to cell necrosis under UVC irradiation. PMID- 28917817 TI - Mechanistic insight into degradation of endocrine disrupting chemical by hydroxyl radical: An experimental and theoretical approach. AB - Advanced oxidation processes (AOPs) based on formation of free radicals at ambient temperature and pressure are effective for treating endocrine disrupting chemicals (EDCs) in waters. In this study, we systematically investigated the degradation kinetics of bisphenol A (BPA), a representative EDC by hydroxyl radical (OH) with a combination of experimental and theoretical approaches. The second-order rate constant (k) of BPA with OH was experimentally determined to be 7.2 +/- 0.34 * 109 M-1 s-1 at pH 7.55. We also calculated the thermodynamic and kinetic behaviors for the bimolecular reactions by density functional theory (DFT) using the M05-2X method with 6-311++G** basis set and solvation model based on density (SMD). The results revealed that H-abstraction on the phenol group is the most favorable pathway for OH. The theoretical k value corrected by the Collins-Kimball approach was determined to be 1.03 * 1010 M-1 s-1, which is in reasonable agreement with the experimental observation. These results are of fundamental and practical importance in understanding the chemical interactions between OH and BPA, and aid further AOPs design in treating EDCs during wastewater treatment processes. PMID- 28917818 TI - Assessment of shipping emissions on four ports of Portugal. AB - In the last few years, ship emissions have attracted growing attention in the scientific community. The main reason is the constant increase of marine emissions over the last twenty years due to the intensification of port traffic. Thus, this study aimed to evaluate ship emissions (PM10, PM2.5, NOx, SO2, CO, CO2, N2O CH4, NMVOC, and HC) through the activity-based methodology in four of the main ports of Portugal (Leixoes, Setubal, Sines and Viana do Castelo) during 2013 and 2014. The analysis was performed according to ship types (bulk carrier, container, general cargo, passenger, Ro-Ro cargo, tanker and others) and operational modes (manoeuvring, hotelling and during cruising). Results indicated that tankers were the largest emitters in two of the four analysed ports. Regarding cruising emissions, container ships were the largest emitters. . CO2, NOx and SO2 estimated emissions represented more than 95% of the cruising and in port emissions. Results were also compared with the total national emissions reported by the Portuguese Environment Agency, and if the in-port emissions estimated in the present study would have been taken into account to these totals, emissions of NOx and SO2 would increase 15% and 24% in 2013 and 16% and 28% in 2014. Summing up ships seem to be an important source of air pollution, mainly regarding NOx and SO2. PMID- 28917819 TI - Seabirds and marine plastic debris in the northeastern Atlantic: A synthesis and recommendations for monitoring and research. AB - Marine plastic pollution is an increasing, and global, environmental issue. Numerous marine species are affected by plastic debris through entanglement, nest incorporation, and ingestion, which can lead to lethal and sub-lethal impacts. However, in the northeastern Atlantic Ocean, an area of international importance for seabirds, there has been little effort to date to assess information from studies of wildlife and plastic to better understand the spatiotemporal variation of how marine plastic affects different seabird species. To improve our understanding of seabirds and marine plastic in this region, we completed a synthesis of the published and grey literature to obtain information on all known documented cases of plastic ingestion and nest incorporation by this group. We found that of 69 seabird species that commonly occur in the northeastern Atlantic, 25 had evidence of ingesting plastic. However, data on plastic ingestion was available for only 49% of all species, with 74% of investigated species recorded ingesting plastic. We found only three published studies on nest incorporation, for the Northern Gannet (Morus bassanus) and Black-legged Kittiwake (Rissa tridactyla). For many species, sample sizes were small or not reported, and only 39% of studies were from the 21st century, whilst information from multiple countries and years was only available for 11 species. This indicates that we actually know very little about the current prevalence of plastic ingestion and nest incorporation for many species, several of them globally threatened. Furthermore, in the majority of studies, the metrics reported were inadequate to carry out robust comparisons among locations and species or perform meta-analyses. We recommend multi-jurisdictional collaboration to obtain a more comprehensive and current understanding of how marine plastic is affecting seabirds in the northeastern Atlantic Ocean. PMID- 28917820 TI - Characterization of secondary organic aerosol from photo-oxidation of gasoline exhaust and specific sources of major components. AB - To further explore the composition and distribution of secondary organic aerosol (SOA) components from the photo-oxidation of light aromatic precursors (toluene, m-xylene, and 1,3,5-trimethylbenzene (1,3,5-TMB)) and idling gasoline exhaust, a vacuum ultraviolet photoionization mass spectrometer (VUV-PIMS) was employed. Peaks of the molecular ions of the SOA components with minimum molecular fragmentation were clearly observed from the mass spectra of SOA, through the application of soft ionization methods in VUV-PIMS. The experiments comparing the exhaust-SOA and light aromatic mixture-SOA showed that the observed distributions of almost all the predominant cluster ions in the exhaust-SOA were similar to that of the mixture-SOA. Based on the characterization experiments of SOA formed from individual light aromatic precursors, the SOA components with molecular weights of 98 and 110 amu observed in the exhaust-SOA resulted from the photo oxidation of toluene and m-xylene; the components with a molecular weight of 124 amu were derived mainly from m-xylene; and the components with molecular weights of 100, 112, 128, 138, and 156 amu were mainly derived from 1,3,5-TMB. These results suggest that C7-C9 light aromatic hydrocarbons are significant SOA precursors and that major SOA components originate from gasoline exhaust. Additionally, some new light aromatic hydrocarbon-SOA components were observed for the first time using VUV-PIMS. The corresponding reaction mechanisms were also proposed in this study to enrich the knowledge base of the formation mechanisms of light aromatic hydrocarbon-SOA compounds. PMID- 28917821 TI - Circulatory-cell-mediated nanotherapeutic approaches in disease targeting. AB - Circulating blood cells, and cell-derived microvesicles, are emerging as pragmatic delivery systems that can smartly complement the already existing nanotherapeutic platforms evaluated to treat or diagnose diseases. The valuable distinctive features of circulatory cells over synthetic nanocarriers encompass their biological origin which confers immune transparence, known biodegradability, high drug loading, relatively long half-life and a targeting capacity associated with their physiological surface functionality. Absence of nuclei in red blood cells and platelets provides further rationale for their use as cargo vehicles for nucleotoxic agents. Ongoing developments in cell-based and cell-inspired nanotherapies can move drug delivery into reachable frontiers and exhibit high potentiality for translatability into clinical use. PMID- 28917823 TI - On the role of visual electrophysiology in Parkinson's disease. PMID- 28917822 TI - CHEMGENIE: integration of chemogenomics data for applications in chemical biology. AB - Increasing amounts of biological data are accumulating in the pharmaceutical industry and academic institutions. However, data does not equal actionable information, and guidelines for appropriate data capture, harmonization, integration, mining, and visualization need to be established to fully harness its potential. Here, we describe ongoing efforts at Merck & Co. to structure data in the area of chemogenomics. We are integrating complementary data from both internal and external data sources into one chemogenomics database (Chemical Genetic Interaction Enterprise; CHEMGENIE). Here, we demonstrate how this well curated database facilitates compound set design, tool compound selection, target deconvolution in phenotypic screening, and predictive model building. PMID- 28917824 TI - Parkinson's disease susceptibility variants and severity of Lewy body pathology. AB - INTRODUCTION: Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases. METHODS: 547 autopsy-confirmed cases of LBD were included and genotyped for 29 different GWAS-nominated PD risk variants. LB counts were measured in middle frontal (MF), superior temporal (ST), inferior parietal (IP), cingulate (CG), and parahippocampal (PH) gyri. RESULTS: None of the variants examined were significantly associated with LB counts in any brain region or with LBD subtype after correcting for multiple testing. Nominally significant (P < 0.05) associations with LB counts where the direction of association was in agreement with that observed in the PD GWAS meta-analysis were observed for variants in BCKDK/STX1B (MF, ST, IP) and SNCA (ST). Additionally, MIR4697 and BCKDK/STX1B variants were nominally associated with LBD subtype. CONCLUSION: The lack of a significant association between PD GWAS variants and severity of LB pathology is consistent with the generally subtle association odds ratios that have been observed in disease-risk analysis. These results also suggest that genetic factors other than the susceptibility loci may determine quantitative neuropathologic outcomes in patients with LBD. PMID- 28917825 TI - Fugitive halocarbon emissions from working face of municipal solid waste landfills in China. AB - Halocarbons are important anthropogenic greenhouse gases (GHGs) due to their long lifetime and large characteristic factors. The present study for the first time assessed the global warming potential (GWP) of fugitive halocarbon emissions from the working face of landfills in China. The national emissions of five major halocarbons (CFC-11, CFC-113, CH2Cl2, CHCl3 and CCl4) from the working face of municipal solid waste landfills in China were provided through observation-based estimations. The fluxes of halocarbons from working face of landfills were observed much higher than covered cells in landfills hence representing the hot spots of landfill emissions. The annual emissions of the halocarbons from landfills in China were 0.02-15.6kt.y-1, and their GWPs were 128-60,948kt-CO2 eq.y-1 based on their characteristic factors on a 100-year horizon. CFC-113 was the dominant species owing to its highest releasing rate (i.e. 15.4+/-19.1g.t-1) and largest characteristic factor, resulting in a GWP up to 4036+/-4855kt-CO2 eq.y-1. The annual emissions of CFC-113 from landfills (i.e. 0.61kt.y-1) made up ~76% of the total national CFC-113 emissions. The GWPs of halocarbons were estimated ~14.4% of landfill methane emissions. Therefore, fugitive halocarbons emissions from working face are significant sources of GHGs in landfill sites in China, although they comprise a small fraction of total landfill gases. PMID- 28917826 TI - Potassic zeolites from Brazilian coal ash for use as a fertilizer in agriculture. AB - Brazilian coal has an ash content ranging from 30 to 50% by weight. Consequently, its use in coal-fired thermoelectric for power production generates a lot of waste. The construction sector is the largest consumer of coal ash, but it cannot absorb the entire amount generated. Thus, other applications for coal ash should be studied in aim to optimize the use of this industrial waste. This research had as focus to synthesize potassic zeolite from of the coal ash into on potassium fertilizer for the grown wheat plant. In this work, it was used a subbituminous coal from Mina do Leao (RS, Brazil) presenting 48.7% ash content on a dry basis. Concerning the synthesis of potassic zeolite, it was adopted the conventional method of hydrothermal treatment with potassium hydroxide. A schedule of experiments was conducted in order to define the optimum condition of zeolite synthesis that was then used an alkaline solution of 5M KOH with a reaction time of 24h at 150 degrees C. According to this procedure, it was obtained a zeolite with a single crystalline phase, identified through X-ray diffraction as Merlinoite. Subsequently, it was performed a set of tests using potassic zeolite asa fertilizer for plants in a greenhouse. The synthesized potassic zeolite showed a good potential for its use as fertilizer in agriculture. PMID- 28917827 TI - Recommendations on the use of neuromonitoring in thyroid and parathyroid surgery. AB - INTRODUCTION: Thyroid and parathyroid surgery (TPTS) is associated with risk of injury to the recurrent laryngeal nerve, superior laryngeal nerve and voice changes. Intraoperative neuromonitoring (IONM), intermittent or continuous, evaluates the functional state of the laryngeal nerves and is being increasingly used. This means that points of consensus on the most controversial aspects are necessary. OBJECTIVE: To develop a support document for guidance on the use of IONM in TPTS. METHOD: Work group consensus through systematic review and the Delphi method. RESULTS: Seven sections were identified on which points of consensus were identified: indications, equipment, technique (programming and registration parameters), behaviour on loss of signal, laryngoscopy, voice and legal implications. CONCLUSIONS: IONM helps in the location and identification of the recurrent laryngeal nerve, helps during its dissection, reports on its functional status at the end of surgery and enables decision-making in the event of loss of signal in the first operated side in a scheduled bilateral thyroidectomy or previous contralateral paralysis. The accuracy of IONM depends on variables such as accomplished technique, technology and training in the correct execution of the technique and interpretation of the signal. This document is a starting point for future agreements on TPTS in each of the sections of consensus. PMID- 28917828 TI - A model of blood supply to the brain via the carotid arteries: Effects of obstructive vs. sclerotic changes. AB - The carotid artery is one of the major supply routes of blood to the brain and a common site of vascular disease. Obstructive and sclerotic disorders within the carotid artery impact local blood flow patterns as well as overall impedance and blood supply to the brain. A lumped parameter model and an experimental in-vitro flow loop were used to study the effects of local stenosis and stiffness in the carotid artery based on a family of phantoms with different degrees of stenosis and compliance. The model also allows independent examination of the effects of downstream resistance and compliance. Mild to moderate stenosis was found to lead to minimal (~1%) reduction in blood supply to the brain. Reduction in mean internal carotid artery (ICA) flow was statistically significant (p< 0.01) only above 70% stenosis. On the other hand, a three-fold increase in stiffness of the carotid artery, as might occur in aging, was found to lead to a modest yet statistically significant reduction (p< 0.01) in mean ICA flow. Effects of changing downstream resistance and compliance were examined. For a given pressure waveform, reduction in downstream compliance led to altered waveform shape and reduction in peak systolic flow rates where the mean flow rates were not altered. Increased downstream resistance resulted in drastic reduction in mean flow rates. PMID- 28917829 TI - A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2. AB - Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation. PMID- 28917830 TI - Al-Awadi-Raas-Rothschild syndrome with dental anomalies and a novel WNT7A mutation. AB - Al-Awadi-Raas-Rothschild syndrome (AARRS; OMIM 276820) is a very rare autosomal recessive limb malformation syndrome caused by WNT7A mutations. AARRS is characterized by various degrees of limb aplasia and hypoplasia. Normal intelligence and malformations of urogenital system are frequent findings. Complete loss of WNT7A function has been shown to cause AARRS, however, its partial loss leads to the milder malformation, Fuhrmann syndrome. An Indian boy affected with AARRS is reported. A novel homozygous base substitution mutation c.550A > C (p.Asn184Asp) is identified in the patient. Parents were heterozygous for the mutation. In addition to the typical features of AARRS, the patient had agenesis of the mandibular left deciduous lateral incisor. The heterozygous parents had microdontia of the maxillary left permanent third molar and taurodontism (enlarged dental pulp chamber at the expense of root) in a number of their permanent molars. Whole exome sequencing of the patient and his parents ruled out mutations in 11 known hypodontia-associated genes including WNT10A, MSX1, EDA, EDAR, EDARADD, PAX9, AXIN2, GREM2, NEMO, KRT17, and TFAP2B. In situ hybridization during tooth development showed Wnt7a expression in wild-type tooth epithelium at E14.5. All lines of evidence suggest that WNT7A has important role in tooth development and its mutation may lead to tooth agenesis, microdontia, and taurodontism. Oral examination of patients with AARRS and Fuhrmann syndromes is highly recommended. PMID- 28917831 TI - [GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines]. AB - Clinicians do not have the time or resources to consider the underlying evidence for the myriad decisions they must make each day and, as a consequence, rely on recommendations from clinical practice guidelines. Guideline panels should consider all the relevant factors (criteria) that influence a decision or recommendation in a structured, explicit, and transparent way and provide clinicians with clear and actionable recommendations. In this article, we will describe the Evidence to Decision (EtD) frameworks for clinical practice recommendations. The general structure of the EtD framework for clinical recommendations is similar to EtD frameworks for other types of recommendations and decisions, and includes formulation of the question, an assessment of the different criteria, and conclusions. Clinical recommendations require considering criteria differently, depending on whether an individual patient or a population perspective is taken. For example, from an individual patient's perspective, out of-pocket costs are an important consideration, whereas, from a population perspective, resource use (not only out-of-pocket costs) and cost effectiveness are important. From a population perspective, equity, acceptability, and feasibility are also important considerations, whereas the importance of these criteria is often limited from an individual patient perspective. Specific subgroups for which different recommendations may be required should be clearly identified and considered in relation to each criterion because judgments might vary across subgroups. This article is a translation of the original article published in the British Medical Journal. The EtD frameworks are currently used in the Clinical Practice Guideline Programme of the Spanish National Health System, co-ordinated by GuiaSalud. PMID- 28917832 TI - Hypoxia and heart regeneration: A new paradoxical approach for cardioprotection. PMID- 28917833 TI - Values-based shared decision-making in the antenatal period. AB - Despite advances in life-saving technology for critically ill neonates, challenges continue to arise for infants delivered with extreme prematurity, congenital anomalies, and genetic conditions that exceed the limits of currently available interventions. In these situations, parents are forced to make cognitively and emotionally difficult decisions, in discussion with a neonatologist, regarding how aggressively to provide supportive measures at the time of delivery and at what point burdens of therapy outweigh benefits. Current guidelines recommend that parents' values should guide these decisions; however, little is known about the values parents hold, and how those values are employed in the context of complexity, uncertainty, and emotionality of these situations. Systematic investigation of how parents derive their values and how clinicians should engage with parents about those values is necessary to guide the development of interventions to enhance shared decision-making processes, ultimately improving satisfaction, coping, and resilience and minimizing the potential for regret. PMID- 28917834 TI - Hexameric assembly of membrane fusion protein YknX of the sporulation delaying efflux pump from Bacillus amyloliquefaciens. AB - Membrane fusion proteins (MFPs) play an essential role in the action of the drug efflux pumps and protein secretion systems in bacteria. The sporulation delaying protein (SDP) efflux pump YknWXYZ has been identified in diverse Bacillus species. The MFP YknX requires the ATP-binding cassette (ABC) transporter YknYZ and the Yip1 family protein YknW to form a functional complex. To date, the crystal structure, molecular function and mechanism of action of YknX remain unknown. In this study, to characterize the structural and biochemical roles of YknX in the functional assembly of YknWXYZ from B. amyloliquefaciens, we successfully obtained crystals of the YknX protein that diffracted X-rays to a resolution of 4.4 A. We calculated an experimentally phased map using single wavelength anomalous diffraction (SAD), revealing that YknX forms a hexameric assembly similar to that of MacA from Gram-negative bacteria. The hexameric assembly of YknX exhibited a funnel-like structure with a central channel and a conical mouth. Functional studies in vitro suggest that YknX can bind directly to peptidoglycan. Our study provides an improved understanding of the assembly of the YknWXYZ efflux pump and the role of YknX in the complex. PMID- 28917835 TI - Antitumor activity, pharmacokinetics, tumor-homing effect, and hepatotoxicity of a species cross-reactive c-Met antibody. AB - The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models. PMID- 28917836 TI - Erythromycin encapsulation in nanoemulsion-based delivery systems for treatment of Helicobacter pylori infection: Protection and synergy. AB - Poorly water-soluble and unstable compounds are difficult to develop as drug products using conventional formulation techniques. The aim of the present study was to develop and evaluate a nanoformulation prepared by a hot high-pressure homogenization method, which was a scalable and solvent-free process. We successfully prepared stable nanodispersions to protect a labile antibiotic, erythromycin. The mean diameter of the dispersed droplets was approximately 150 nm, and size distribution was unimodal. Dispersion was physically stable at room temperature for over six months. Using erythromycin as a model compound, we studied its antimicrobial activity in vitro on Helicobacter pylori. Results showed that drug encapsulation improves API stability in an acidic environment and is conducive to a synergistic effect between the drug and the formulation. PMID- 28917837 TI - Memantine inhibits beta-amyloid aggregation and disassembles preformed beta amyloid aggregates. AB - Memantine, an uncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a medication for the treatment of Alzheimer's disease (AD). We previously reported that chronic treatment of AD with memantine reduces the amount of insoluble beta-amyloid (Abeta) and soluble Abeta oligomers in animal models of AD. The mechanisms by which memantine reduces Abeta levels in the brain were evaluated by determining the effect of memantine on Abeta aggregation using thioflavin T and transmission electron microscopy. Memantine inhibited the formation of Abeta(1-42) aggregates in a concentration-dependent manner, whereas amantadine, a structurally similar compound, did not affect Abeta aggregation at the same concentrations. Furthermore, memantine inhibited the formation of different types of Abeta aggregates, including Abetas carrying familial AD mutations, and disaggregated preformed Abeta(1-42) fibrils. These results suggest that the inhibition of Abeta aggregation and induction of Abeta disaggregation may be involved in the mechanisms by which memantine reduces Abeta deposition in the brain. PMID- 28917838 TI - Human SMOOTHENED inhibits human immunodeficiency virus type 1 infection. AB - Human SMOOTHENED (SMO) was identified by expression cloning as a new host factor that inhibits HIV-1 infection. Forced expression of SMO inhibited HIV-1 replication and infection with a single-round lentiviral vector, but not infection with a murine leukemia virus-based retroviral vector in human MT-4 T cells. Quantitative PCR analyses revealed that stable expression of SMO impaired formation of the integrated form of lentiviral DNA, but did not interrupt reverse transcription. This inhibition was evident in MT-4 and HUT102 human T cell lines expressing low levels of SMO mRNA, but not in SupT1 or Jurkat T cell lines expressing higher levels of SMO mRNA. Depletion of SMO mRNA in Jurkat cells facilitated HIV-1 vector infection, suggesting that endogenous SMO plays a role in limiting lentiviral infection. These results suggest that SMO inhibits HIV-1 replication after completion of reverse transcription but before integration. PMID- 28917839 TI - M2b macrophage polarization accompanied with reduction of long noncoding RNA GAS5. AB - Macrophages (Mphi) are highly plastic and change their functional phenotypes depending on microenvironmental signals. Recent studies have shown that microRNAs are involved in the polarization of Mphi. In this study, we demonstrated that the phenotype of M2bMphi [CCL1(+) IL-10(+) LIGHT(+)] switches to other phenotypes with interchangeability attained through the increased expression of growth arrest-specific 5 RNA (GAS5 RNA), a long noncoding RNA. GAS5 RNA has been described as a silencer of the CCL1 gene. Various phenotypes of Mphi were prepared from bone marrow-derived Mphi (BMDMphi) after stimulation with IFNgamma [M(IFNgamma)/M1Mphi], IL-4 [M(IL-4)/M2aMphi], LPS and immobilized IgG [M(LPS + IC)/M2bMphi], and IL-10 [M(IL-10)/M2cMphi]. BMDMphi cultured with medium [M(no)/quiescent Mphi] were used as a control. As compared to MU(no), M(IFNgamma), M(IL-4) and M(IL-10), the reduced level of GAS5 RNA was shown in M(LPS + IC). CCL1 and LIGHT mRNAs (typical biomarkers of M2bMphi) were not expressed by M(LPS + IC) transduced with a GAS5 gene using lentiviral vector. The reduction of GAS5 RNA in M(LPS + IC) was mediated by the activation of nonsense mediated RNA decay (NMD) pathway. BMDMphi overexpressed with GAS5 RNA after GAS5 gene transduction did not polarize to M2bMphi even though they were stimulated with LPS and IC in combination. These results indicate that the reduction of GAS5 RNA influenced by the NMD pathway activation leads to the Mphi polarization stimulated with LPS and IC in combination. PMID- 28917840 TI - Both nitric oxide and nitrite prevent homocysteine-induced endoplasmic reticulum stress and subsequent apoptosis via cGMP-dependent pathway in neuronal cells. AB - Growing evidence indicates that endoplasmic reticulum (ER) stress and/or ER stress-mediated apoptosis may play a role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. The present study investigated the effects of non-cytotoxic concentrations of nitric oxide (NO) and nitrite, a metabolite of NO, on ER stress and ER stress-mediated apoptosis in Neuro-2a cells exposed to homocysteine (Hcy), an endogenous ER stress inducer. Hcy induced ER stress, as confirmed by inositol-requiring enzyme 1alpha (IRE1alpha) phosphorylation and X-box-binding protein-1 (Xbp1) mRNA splicing as well as C/EBP homologous protein (CHOP) expression, and apoptosis, as verified by Annexin V-positive cells. Surprisingly, non-cytotoxic NO (S-nitrosoglutathione) and nitrite markedly reduced Hcy-induced IRE1alpha phosphorylation, Xbp1 mRNA splicing, CHOP expression, and Annexin V-positive cells, indicating the cytoprotection of NO and nitrite against Hcy-induced ER stress and apoptosis. Moreover, inhibition of sGC/cGMP pathway abolished the cytoprotective effects of NO and nitrite, whereas cellular elevation of cGMP levels mimicked the cytoprotective actions of NO and nitrite. These findings provide the first evidence showing that both NO and nitrite can reduce ER stress and subsequent apoptosis via NO-sGC-cGMP pathway in neuronal cells and suggesting that NO and/or nitrite may have therapeutic value in the treatment of ER stress-associated neurodegenerative diseases. PMID- 28917841 TI - Graphene-VP40 interactions and potential disruption of the Ebola virus matrix filaments. AB - Ebola virus infections cause hemorrhagic fever that often results in very high fatality rates. In addition to exploring vaccines, development of drugs is also essential for treating the disease and preventing the spread of the infection. The Ebola virus matrix protein VP40 exists in various conformational and oligomeric forms and is a potential pharmacological target for disrupting the virus life-cycle. Here we explored graphene-VP40 interactions using molecular dynamics simulations and graphene pelleting assays. We found that graphene sheets associate strongly with VP40 at various interfaces. We also found that the graphene is able to disrupt the C-terminal domain (CTD-CTD) interface of VP40 hexamers. This VP40 hexamer-hexamer interface is crucial in forming the Ebola viral matrix and disruption of this interface may provide a method to use graphene or similar nanoparticle based solutions as a disinfectant that can significantly reduce the spread of the disease and prevent an Ebola epidemic. PMID- 28917842 TI - Multi-scale simulations of biological systems using the OPEP coarse-grained model. AB - Biomolecules are complex machines that are optimized by evolution to properly fulfill or contribute to a variety of biochemical tasks in the cellular environment. Computer simulations based on quantum mechanics and atomistic force fields have been proven to be a powerful microscope for obtaining valuable insights into many biological, physical, and chemical processes. Many interesting phenomena involve, however, a time scale and a number of degrees of freedom, notably if crowding is considered, that cannot be explored at an atomistic resolution. To bridge the gap between reality and simulation, many different advanced computational techniques and coarse-grained (CG) models have been developed. Here, we report some applications of the CG OPEP protein model to amyloid fibril formation, the response of catch-bond proteins to two types of fluid flow, and interactive simulations to fold peptides with well-defined 3D structures or with intrinsic disorder. PMID- 28917843 TI - Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression. AB - Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex. The results show that Rapgef2-deficient RGCs exhibit a decreased ability of neurosphere formation, morphological changes represented by regression of radial glial (RG) fibers and reduced expression of AJ-constituent proteins such as N-cadherin, zonula occludens-1, E-cadherin and beta-catenin. Moreover, siRNA-mediated knockdown of Rapgef2 or Rap1A inhibits the AJ protein expression and RG fiber formation while overexpression of Rapgef2, Rapgef6, Rap1AG12V or Rap1BG12V in Rapgef2-deficient RGCs restores them. Furthermore, Rapgef2-deficient RGCs exhibit a reduction in phosphorylation of extracellular signal-regulated kinase (ERK) leading to downregulation of the expression of c-jun, which is implicated in the AJ protein expression. These results indicate a crucial role of the Rapgef2-Rap1A-ERK-c-jun pathway in regulation of the AJ formation in RGCs. PMID- 28917844 TI - Comparison of chitosan and chitosan nanoparticles on the performance and charge recombination of water-based gel electrolyte in dye sensitized solar cells. AB - In commercialization of liquid dye-sensitized solar cells (DSSCs), whose leakage, evaporation and toxicity of organic solvents are limiting factors, replacement of organic solvents with water-based gel electrolyte is recommended. This work reports on utilizing and comparison of chitosan and chitosan nanoparticle as different gelling agents in preparation of water-based gel electrolyte in fabrication of dye sensitized solar cells. All photovoltaic parameters such as open circuit voltage (Voc), fill factor (FF), short circuit current density (Jsc) and conversion efficiency (eta) were measured. For further characterization, electrochemical impedance spectroscopy (EIS) was used to study the charge transfer at Pt/electrolyte interface and charge recombination and electron transport at TiO2/dye/electrolyte interface. Significant improvements in conversion efficiency and short circuit current density of DSSCs fabricated by chitosan nanoparticle were observed that can be attributed to the higher mobility of I3-due to the lower viscosity and smaller size of chitosan nanoparticles. PMID- 28917845 TI - Influence of binding mechanism on labeling efficiency and luminous properties of fluorescent cellulose nanocrystals. AB - Cellulose nanocrystals (CNCs) have excellent properties, such as reproducibility, low biodegradability and a large amount of reactive hydroxyl groups on the surface. This study focused on the labeling efficiency and fluorescent properties of the fluorescent labeling of CNCs by means of electrostatic adsorption and covalent bonding. The CNCs in the sample were approximately 94.76% successfully labeled with dyes, and the number of dye molecules adsorbed by per CNC was approximately 208 by electrostatic adsorption. For the sample covalently linked, the efficiency of the fluorescent labeling was 95.51%, and the number of dye molecules attached to per CNC was 1038. The quenching mode of the fluorescent CNCs was dynamic quenching. The fluorescence lifetime and quantum yield of the fluorescent CNCs increased by 1-2 times compared to the free dye. A thorough investigation of the relation between the binding mechanism and the fluorescent properties in fluorescent CNCs was conducted. PMID- 28917846 TI - An efficient chitosan-derived carbon/silica microspheres supported Pd catalyst with high stability for Heck reactions. AB - To maintain stability and activity in Heck-coupling reaction, a novel composite carrier with controllable uniform size, high complex ability and mechanical intensity was fabricated in microchannel using natural N-doped biomolecule chitosan and silica as ingredients. Post carbonization increased its thermal stability and supported Pd@C/silica catalysts can be acquired after Pd loading. Only 2mg supported Pd@C/silica catalysts (0.44MUmol) can achieve high yield (>95%) in a typical Heck-coupling reaction and maintained activity even after 8 times of recycling. This type of novel porous microspheres carrier can cut down the usage of noble Pd by avoiding the leaching as well as aggregation of Pd nanoparticles, and could be widely applied in similar chemical reactions. PMID- 28917847 TI - Release of polyphenols from starch-chitosan based films containing thyme extract. AB - The release kinetics of thyme extract polyphenols (TE) from chitosan (CH), pea starch (S) and CH:S blend films in different solvents was evaluated, as well as their antioxidant activity in each release media. Pure starch films showed the fastest delivery rate and the highest delivery ratio of polyphenols, although the corresponding release media exhibited the lowest antioxidant capacity. TE provided CH based films with remarkable antioxidant activity, despite the lower polyphenol release obtained in all solvents, due to the strong polyphenols chitosan interactions. The maximum amount of polyphenols delivered was found in the acetic acid solution, due to the high solubility of CH. The incorporation of tannic acid (TA) into CH films promoted cross-linking effect, which delays the TE release rate in water and ethanol aqueous solutions, except for CH:S:TA films. Thus, the polarity of the solvents and the polyphenols-matrix interactions markedly affected the polyphenol release and the antioxidant activity of the films. PMID- 28917848 TI - Development and characterization of ricinoleic acid-based sulfhydryl thiol and ethyl cellulose blended membranes. AB - Ethyl cellulose (EC) membranes can be combined with efficient plasticizers derived from renewable resources to form supramolecular systems. In this paper, a novel ricinoleic acid-based sulfhydryl triol (STRA) was first synthesized and used as a plasticizer for EC membranes. A supramolecular membrane of EC and STRA using van der Waals forces was designed. The morphology, hydrophilic performance, thermal stability, and mechanical properties of the composites were investigated. While pure EC is brittle, its membrane ductility and hydrophilic performance can be improved by integration with STRA. The highest tensile strength was found in EC/STRA (90/10) (8.37MPa). Impressively, the EC/STRA(60/40) and EC/STRA(50/50) elongation at break values were 17.4 and 20.2 times higher, respectively, than that of pure EC. This novel ricinoleic acid-based sulfhydryl triol can be used as a feedstock for hydrophobic EC membranes. PMID- 28917849 TI - Understanding the microstructure and absorption rate of starch-based superabsorbent polymers prepared under high starch concentration. AB - From a microstructural view, the focus of this work was on the water absorption rate of starch-based superabsorbent polymers (starch-SAPs) prepared under high starch concentration (0.27:1w/w starch:water). The effects of starch amylose/amylopectin ratio were disclosed. The increase in amylopectin reduced the amount (CPAM) of polyacrylamide (PAM) in starch-SAPs but increased the ratio of starch carbons grafted with PAM, which eventually decreased the average length (LPAM) of PAM chains. The shorter PAM chains could reduce starch-SAP chain flexibility, thus inducing larger mass fractal gels in swollen starch-SAPs. In general, the increases in CPAM and LPAM were preferable for a higher water absorbent capacity (WAC), whereas the denser fractal gels reduced WAC. Interestingly, all starch-SAPs had a dual-phase absorption process with the first stage showing a higher rate than the second phase (k1>k2). The shorter PAM chains caused increases in k1 and k2. PMID- 28917850 TI - Porous composite membranes based on cellulose acetate and cellulose nanocrystals via electrospinning and electrospraying. AB - Porous and non-porous cellulose acetate (CA) - cellulose nanocrystal (CNC) electrospun nanocomposite fibers and electrosprayed-electrospun composite membranes were fabricated using two different binary solvent systems. To evaluate the expression of CNC as the active entity in the membrane, dye adsorption studies were carried out using Victoria Blue. To overcome the low surface area of thick porous fibers, a porous electrosprayed-electrospun composite has developed which exhibited 98% dye removal compared to non-porous counterparts (67.9%). The porous membrane with CNC showed an increase of 38mV in surface zeta potential compared to 9mV increases in the case of the nonporous membrane and after the dye adsorption, it maintained the negative charge, indicating that further adsorption is feasible. Moreover, the mechanical properties of porous fibers were found to be ten-fold better than that of nonporous fibers. Creating porous CA-CNC composites is demonstrated as a tool for ensuring better exposure of active materials during the adsorption reaction. PMID- 28917851 TI - Corrigendum to "Enhanced permeability and antifouling performance of cellulose acetate ultrafiltration membrane assisted by L-DOPA functionalized halloysite nanotubes" [Carbohydr. Polym. 174 (2017) 688-696]. PMID- 28917852 TI - Bio-responsive alginate-keratin composite nanogels with enhanced drug loading efficiency for cancer therapy. AB - This article presents a novel dual-stimuli responsive nanogel prepared from human hair keratin and alginate through simple crosslinking method. Keratin offer the crosslinking structure and bio-responsive ability and alginate ameliorated properties of nanogels including particle size, stability and drug loading capacity. The resultant keratin-alginate nanogels (KSA-NGs) could function as promising vectors for doxorubicin hydrochloride (DOX) with a super-high drug loading rate of 52.9% (w/w) and dual-stimuli responsive behavior to GSH and trypsin. Cellular uptake results indicated DOX loaded KSA-NGs (DOX@KSA-NGs) are efficiently internalized in 4T1 and B16 cells in vitro, with a fast DOX release into cells under intracellular GSH and trypsin levels. In vitro cytotoxicity results further manifested that DOX@KSA-NGs behaved equivalent inhibition effects on tumor cells to DOX. In vivo experiments showed that DOX@KSA-NGs had a better anti-tumor effect and lower side effects compared to free drugs. These bio responsive KSA-NGs have potential applications as nanocarriers for cancer therapy. PMID- 28917853 TI - Preparation and biological activity studies of resveratrol loaded ionically cross linked chitosan-TPP nanoparticles. AB - Nanoparticles with size range of 10-500nm can be efficiently delivered into cancer cells by the Enhanced Permeability and Retention (EPR) effect. Here, we prepared resveratrol (Res) loaded chitosan (CS) nanoparticles with the size of 172-217nm by an ionic cross-linking method, with sodium tripolyphosphate (TPP) as the cross-linking agent, to improve the stability, solubility and tumors targeting of the natural anti-cancer drug Res. The prepared Res loaded CS-TPP nanoparticles presented long-term storage stability and UV light stability. The cumulative drug release from nanoparticles in mimetic tumor tissue condition (pH 6.5) was higher than that in physiological condition (pH 7.4). Further, Res loaded CS-TPP nanoparticles maintained the antioxidant activity of Res even after UV light irradiation. Cell viability study shows that the as prepared drug loaded nanoparticles had similar antiproliferative activity on hepatocellular carcinoma cells SMMC 7721 and lower cytotoxicity on normal hepatocyte cells L02 compared with free Res. Fluorescence microscopy observation revealed that the nanoparticles were efficiently taken in by SMMC 7721 cells. This work indicates the potential use of drug loaded CS-TPP nanoparticles for the efficient delivery of bioactive Res for chemotherapy. PMID- 28917854 TI - Tilia tomentosa pectins exhibit dual mode of action on phagocytes as beta glucuronic acid monomers are abundant in their rhamnogalacturonans I. AB - Silver linden flowers contain different pectins (PSI-PSIII) with immunomodulating properties. PSI is a low-esterified pectic polysaccharide with predominant homogalacturonan region, followed by rhamnogalacturonan I (RGI) with arabinogalactan II and RGII (traces) domains. PSII and PSIII are unusual glucuronidated RGI polymers. PSIII is a unique high molecular weight RGI, having almost completely O-3 glucuronidated GalA units with >30% O-3 acetylation at the Rha units. Linden pectins induced reactive oxygen species (ROS) and NO generation from non-stimulated whole blood phagocytes and macrophages, resp., but suppressed OZP-(opsonized zymosan particles)-activated ROS generation, LPS-induced iNOS expression and NO production. This dual mode of action suggests their anti inflammatory activity, which is known for silver linden extracts. PSI expressed the highest complement fixation and macrophage-stimulating activities and was active on intestinal Peyer's patch cells. PSIII was active on non-stimulated neutrophils, as it induced beta2-integrin expression, revealing that acetylated and highly glucuronidated RGI exhibits immunomodulating properties via phagocytes. PMID- 28917856 TI - The effect of ionic and non-ionic surfactants and pH on the stability, adsorption and electrokinetic properties of the alginic acid/alumina system. AB - The influence of ionic (CTAB; SDS) and non-ionic (TX-100; TX-165 and TX-405) surfactants as well as pH of the solution on the stability, adsorption and electrokinetic properties of the alginic acid (AA)/alumina (Al2O3) suspensions was studied. The results obtained using the spectrophotometric method show that the addition of ionic surfactants is an effective way to obtain stable AA/Al2O3 suspensions whereas the changes in pH are not sufficient. Surface tension measurements together with the adsorption data show that the macromolecules of alginic acid are able to form complexes with CTAB, however, they compete for the adsorption centers on the metal oxide surface with SDS. Non-ionic surfactants do not affect alginic acid adsorption. The electrokinetic measurements (surface charge density and zeta potential measurements) prove that adsorption of alginic acid on Al2O3 with or without surfactants changes the structure or the compact and diffused parts of the electric double layer. It should be emphasized that the alginic acid/surfactant/alumina system has not been studied before which confines its possible applications in the fields of functionalized materials. PMID- 28917855 TI - Chiroplasmonic magnetic gold nanocomposites produced by one-step aqueous method using kappa-carrageenan. AB - Novel water-soluble chiroplasmonic nanobiocomposites with directly varied gold content were synthesized by a one-step redox method in water using a biocompatible polysaccharide kappa-carrageenan (industrial product from algae) as both reducing and stabilizing matrix. The influence of the reactants ratio, temperature, and pH on the reaction was studied and the optimal reaction parameters were found. The structure and the properties of composite nanomaterials were examined in solid state and aqueous solutions by using complementary physical-chemical methods X-ray diffraction analysis, transmission electron microscopy, spectroscopy of electron paramagnetic resonance, atomic absorption and optical spectroscopy, polarimetry including optical rotatory dispersion with registration of interphase-crossbred Cotton effect of a chiral polysaccharide matrix on plasmonic chromophore of gold nanoparticles, dynamic and static light scattering. The new perspective multi-purpose nanocomposites demonstrate a complex of chiroplasmonic and magnetic properties, imparted by both nanoparticles and radicals enriched chiral polysaccharide matrix. PMID- 28917858 TI - A structural study of Acacia nilotica and Acacia modesta gums. AB - Superficially similar carbohydrate polymers from similar sources can have dramatically different characteristics. This work seeks to examine the molecular properties responsible for these differences. Protons responsible for cross polarization in the anomeric region of Acacia nilotica (AN) were replaced easily by deuterium, but not for Acacia modesta (AM). Time constants describing the mobility and cross-polarization transfer were both found to be lower for AM. Variable contact time experiments showed poorer fits and more heterogeneity for AN. Solution state HSQC experiments showed a lower number of environments in the anomeric region for AM. The relaxation time T2 of AM solutions had a lower value consistent with a higher viscosity. The Tg' of solutions were -14.5 degrees C AN and -18.5 degrees C AM. These results form a largely self-consistent picture of molecular differences between AN and AM, suggesting a more compact but heterogeneous structure for AN and more branching in the case of AM. PMID- 28917857 TI - The hydrolytic efficiency and synergistic action of recombinant xylan-degrading enzymes on xylan isolated from sugarcane bagasse. AB - Understanding the interaction mechanisms between xylan and xylan-degrading enzymes is beneficial to the efficient hydrolysis of xylan. Xylan from sugarcane bagasse (SB) was extracted and characterized. The effects of heat treatment and removal of side chains of SB xylan on the hydrolytic efficiency and synergistic action of endo-beta-1,4-xylanases (HoXyn11A and AnXyn10C), beta-xylosidases (AnXln3D), and alpha-l-arabinofuranosidases (AnAxh62A) were investigated. Results indicated that heat treatment of xylan can improve the hydrolytic efficiency of xylan-degrading enzymes, and it is essential for the efficient hydrolysis of xylan by HoXyn11A. The removal of arabinofuranosyl side chains of xylan by AnAxh62A before enzymatic hydrolysis reduced the hydrolytic efficiency of HoXyn11A and AnXyn10C on xylan. AnXyn10C was more efficient than HoXyn11A in hydrolysis of xylan, whereas HoXyn11A showed better synergistic action than AnXyn10C with AnAxh62A and AnXln3D in the hydrolysis of xylan. This study provides new insights on the enzymatic hydrolysis of SB into monosaccharides and xylo-oligosaccharides. PMID- 28917859 TI - Superhydrophilic graphene oxide@electrospun cellulose nanofiber hybrid membrane for high-efficiency oil/water separation. AB - Inspired from fishscales, membranes with special surface wettability have been applied widely for the treatment of oily waste water. Herein, a novel superhydrophilic graphene oxide (GO)@electrospun cellulose nanofiber (CNF) membrane was successfully fabricated. This membrane exhibited a high separation efficiency, excellent antifouling properties, as well as a high flux for the gravity-driven oil/water separation. Moreover, the GO@CNF membrane was capable to effectively separate oil/water mixtures in a broad pH range or with a high concentration of salt, suggesting that this membrane was quite promising for future real-world practice in oil spill cleanup and oily wastewater treatment. PMID- 28917860 TI - Carbon materials derived from chitosan/cellulose cryogel-supported zeolite imidazole frameworks for potential supercapacitor application. AB - In order to promote sustainable development, green and renewable clean energy technologies continue to be developed to meet the growing demand for energy, such as supercapacitor, fuel cells and lithium-ion battery. It is urgent to develop appropriate nanomaterials for these energy technologies to reduce the volume of the device, improve the efficiency of energy conversion and enlarge the energy storage capacity. Here, chitosan/cellulose carbon cryogel (CCS/CCL) were designed and synthesized. Through the introduction of zeolite imidazole frameworks (ZIFs) into the chitosan/cellulose cryogels, the obtained materials showed a microstructure of ZIF-7 (a kind of ZIFs) coated chitosan/cellulose fibers (CS/CL). After carbonizing, the as-prepared carbonized ZIF-7@cellulose cryogel (NC@CCL, NC is carbonized ZIF-7) and carbonized ZIF-7@chitosan cryogel (NC@CCS) exhibited suitable microspore contents of 34.37% and 30%, respectively, and they both showed an internal resistance lower than 2Omega. Thereby, NC@CCL and NC@CCS exhibited a high specific capacitance of 150.4Fg-1 and 173.1Fg-1, respectively, which were much higher than those of the original materials. This approach offers a facile method for improving the strength and electronic conductivity of carbon cryogel derived from nature polymers, and also efficiently inhibits the agglomeration of cryogel during carbonization in high temperature, which opens a novel avenue for the development of carbon cryogel materials for application in energy conversion systems. PMID- 28917861 TI - Isolation and structural elucidation by 2D NMR of planteose, a major oligosaccharide in the mucilage of chia (Salvia hispanica L.) seeds. AB - An oligosaccharide was isolated in high purity and excellent yield from the water extractable mucilage of chia (Salvia hispanica L.) seeds using an optimized solid phase extraction method. LC-MS analysis showed that the compound presents a molecular mass of 504Da and trifluoroacetic acid hydrolysis revealed that it consists of galactose, glucose and fructose. Glycosidic linkage analysis showed that the oligosaccharide contains two non-reducing ends corresponding to terminal glucopyranose and terminal galactopyranose, respectively. The oligosaccharide was identified as planteose by the complete assignment of a series of 2D NMR spectra (COSY, TOCSY, ROESY, HSQC, and HMBC). The significance of the presence of planteose in chia seeds is discussed in the context of nutrition and food applications. PMID- 28917862 TI - Antibacterial hydroxypropyl methyl cellulose edible films containing nanoemulsions of Thymus daenensis essential oil for food packaging. AB - Edible films containing essential oils (EO) as natural antibacterial agents are promising systems for food preservation. In this work, nanoemulsions of Thymus daenensis EO (wild; F1 and cultivated; F2) were loaded in hydroxyl propyl methyl cellulose (HPMC) films and the effect of different parameters (polymer, plasticizer, and EO concentration) on the film properties were analyzed and optimized. Prepared HPMC films were characterized in terms of EO loading, morphology, mechanical properties, and the antibacterial activity. The results of SEM showed uniform incorporation of nanoemulsions into the edible film. Investigation of the mechanical properties of two edible films revealed a plasticizing effect of T. daenensis EO on the films. Also, edible films had noticeable antimicrobial activity against selected microorganisms, i.e. 47.0+/ 2.5mm and 22.6+/-0.5mm zone of inhibition against S. aureus for films containing F1 and F2, respectively. Incorporation of nanoemulsions into the HPMC films can be used for active food preservation. PMID- 28917863 TI - Purification, characterization and biological effect of reversing the kidney-yang deficiency of polysaccharides from semen cuscutae. AB - Semen cuscutae is a well-known Chinese medicine which has been used to nourish kidney. It is the first study to demonstrate that the polysaccharides from semen cuscutae showed significant activity of nourishing kidney-yang by increasing the levels of testosterone and estradiol, decreasing the level of blood urea nitrogen, improving immune function, possessing antioxidant effect. Three homogeneous polysaccharides were obtained by DEAE-cellulose and Sephacryl S-400 which were named as C-7WR1, C-7WR2 and C-7WR3 with average molecular weight of 7.59*104, 3.23*104 and 2.25*104 respectively. C-7WR1 was composed of fructose: mannose=0.02:1. C-7WR2 was composed of fructose: mannose: xylose: arabinose=0.01:1:0.14:0.33. C-7WR3 was composed of fructose: mannose: xylose: arabinose=0.01:1:0.10:0.47. They mainly contained mannose. Their fourier transform infrared features were similar. They all had no nucleic acid and protein. PMID- 28917864 TI - Bulk vs. Nano ZnO: Influence of fire retardant behavior on sisal fibre yarn. AB - Flame retardant functionality was imparted in sisal (leaf fibre) yarn whereas a strong scientific finding has been established between fire retardant efficacy of bulk and nano zinc oxide based formulations. Bulk and nano ZnO treated sisal yarns have been compared on the basis of their flame retardant efficacy, weight add-on% and tensile strength. Limiting oxygen index and char length of the 12% ZnO treated sisal was found to be well comparable with the 1% nano ZnO treated yarn. Further, add-on% and the tensile strength of the nano ZnO treated sample is 70-80% lower and 20% more, respectively, compared to the 12% bulk ZnO treated sisal yarn. Besides, thermo-gravimetry and char morphology of the control and both the formulation treated sisal yarn were compared and analysed to understand the pyrolysis path of the sisal yarn. The possible mechanism of attachment of ZnO to the microstructure of sisal has also been established. PMID- 28917865 TI - Physicochemical and structural properties of pregelatinized starch prepared by improved extrusion cooking technology. AB - Pregelatinized starch was made from indica rice starch using a so-called "improved extrusion cooking technology" (IECT) under 30%-70% moisture content. IECT-pregelatinized starch (IPS) had higher water solubility and water absorbability compared to native starch at low temperature. For pasting properties, the breakdown and setback viscosities of IPS were significantly (p<0.05) lower than native starch, suggesting improved gel stability and reduced short-term retrogradation. The rice starch granules lost their integrity in IPS, and formed a honeycomb-like structure with increased moisture content in the raw material. These properties can be explained in terms of molecular structural features, particularly the large reduction in the size of molecules, but without significant changes in the chain-length distributions of amylopectin component, and no significant change in amylose fraction. These results indicate that IECT is suitable for preparing IPS with desirable water solubility and gel stability properties. PMID- 28917866 TI - Rapidly growing vegetables as new sources for lignocellulose nanofibre isolation: Physicochemical, thermal and rheological characterisation. AB - Rapidly growing vegetables could be an abundant and cheap sources of lignocellulose biomass for lignocellulose nanofibre (LCNF) production. The aim of this work is to study the feasibility of using Chamaecytisus proliferus and Leucaena leucocephala for LCNF isolation by mechanical, enzymatic and TEMPO mediated oxidation pre-treatments. Characterisation of the nanofibres shows that there are significant differences in the production of LCNF depending on the raw material and pre-treatment used. XRD and FTIR analysis show that homogenisation has a strong negative effect on the crystallinity index; however, the higher lignin content of tagasaste (10%) protects the fibre, causing a smaller decrease in crystallinity. The thermal stability of LCNF is also affected by the high lignin content in the case of tagasaste, which exhibited maximum degradation temperatures of 340-315 degrees C, that were higher than those for leucaena (330 310 degrees C). A strong shear thinning behaviour was observed in most of the LCNF, which revealed a great degree of interconnectivity in the gel like-network. PMID- 28917867 TI - Nanocrystalline cellulose isolated from discarded cigarette filters. AB - We report the isolation of nanocrystalline cellulose (NCC) produced from discarded cigarette filters (DCF). The DCF were processed into cellulose via ethanolic extraction, hypochlorite bleaching, alkaline deacetylation, and then converted into NCC by sulfuric acid hydrolysis. The morphological structures of the isolated NCC established with TEM showed that the nanocrystals were needle like with a mean length of 143nm. FEGSEM showed the morphological transition of the micro-sized DCF to self-assembled NCC while EDX revealed the presence of Ti (as TiO2) in DCF, which was retained in the NCC. A NCC sample was freeze-dried and showed a specific surface area of 7.78m2/g. The crystallinity of the NCC film and freeze-dried samples were 96.77% and 94.47%, respectively. Crystallite sizes of the freeze-dried (8.4nm) and film (7.6nm) samples correlated with the mean width (8.3nm) of the NCC observed under TEM. PMID- 28917868 TI - Anti-hyperlipidemic and antioxidant effects of alkali-extractable mycelia polysaccharides by Pleurotus eryngii var. tuolensis. AB - In this study, we noted that the Al-MPS from Pleurotus eryngii var. tuolensis provoked pharmacological effects on blood lipid profiles and oxidative stress. Animal studies demonstrated that Al-MPS showed potential effects on relieving hyperlipidemia and preventing oxidative stress, reflecting by decreasing the levels of serum enzyme activities (ALP, ALT and AST), restoring the activities of antioxidant enzymes (SOD, GSH-Px, CAT and T-AOC), down-regulating the MDA and LPO contents, as well as remitting the hepatic and cardiac tissues injury, respectively. The serum levels of TC, TG, LDL-C, VLDL-C, and HDL-C on mice treated with Al-MPS (500mg/kg bw) reached 2.48+/-0.08, 1.24+/-0.03, 0.84+/-0.02, 0.34+/-0.02, and 1.80+/-0.03mmol/L, which were lower/higher against the hyperlipidemia mice. The results clearly indicated that the Al-MPS could be used as a beneficial health food and potentially natural candidate medicine in preventing the high-fat emulsion-induced hyperlipidemia. PMID- 28917869 TI - High aspect ratio phospho-calcified rock candy-like cellulose nanowhiskers of wastepaper applicable in osteogenic differentiation of hMSCs. AB - The aim of this study was to prepare cellulose nanowhiskers (CNWs) from wastepaper powder (WPP), as an environmentally friendly approach for obtaining the source material, which is a highly available and low-cost precursor for cellulose nanomaterial processing. Acid hydrolysis and calcification treatments were employed for extraction of CNWs and preparation of novel phospho-calcified cellulose nanowhiskers (PCCNWs). CNWs and PCCNWs were analyzed through optical microscopy (OM), scanning electron microscopy (SEM), Fourier-transformed infrared spectra (FTIR) and X-ray diffraction analysis (XRD). Cell behaviors in the presence of CNWs and PCCNWs were studied by MTT assay and live-dead staining. Finally, the effect of these particles on osteogenic differentiation of stem cells was evaluated based on alkaline phosphatase activity (ALP), calcium mineralization as well as von Kossa and alizarin red staining. Based on the results, PCCNWs had a positive effect on osteogenic differentiation of human mesenchymal stem cells (hMSCs) and can be used for developing new approaches for bone tissue engineering. PMID- 28917870 TI - Ultra-high pressure modified cellulosic fibres with antimicrobial properties. AB - In this work bleached E. globulus kraft pulp was doped with polyhexamethylene biguanide (PHMB) from an aqueous solution or from a suspension of silica capsules (PHMB@silica) by impregnation under atmospheric or ultra-high pressure (UHP) conditions (500MPa). The antimicrobial properties of pulps were evaluated towards gram-negative E. coli and gram-positive L. innocua bacteria. PHMB loads below 500mg per kg of pulp revealed negligible bacteriostatic properties, whereas PHMB loads of ca 3000-4000mg per kg demonstrated bactericidal properties of pulp without significant deterioration of its mechanical strength. The UHP impregnation allowed significant improvement of PHMB uptake. Thus, under equal conditions, PHMB uptake was ca 25% greater under UHP than under atmospheric pressure impregnation, whereas the leachable amounts of PHMB in both pulps were comparable. The sorption of PHMB@silica on pulp in suspension under UHP conditions was ca 17% greater than under atmospheric pressure with almost 70% increase of leachable PHMB. PMID- 28917871 TI - Inhibition of gelatinized rice starch retrogradation by rice bran protein hydrolysates. AB - The retrogradation of gelatinized rice starch (GRS) during the shelf life of a product is the biggest barrier related to starch-containing foods. The objective of this study was to produce rice bran protein hydrolysate (RBPH) using proteolytic enzymes (alcalase, flavourzyme, protamex, neutrase, bromelain, papain and trypsin) to suppress the retrogradation of GRS and understand the physical phenomena underlying the reduced retrogradation of GRS by RBPH during short- and long-term storage. Mixtures of GRS incorporated with Protamex-hydrolyzed rice bran protein at 1h (PRBPH-1) at a degree of hydrolysis of 15.1% were still fresh after storage at 4 degrees C for 14 d. The dynamic time sweep results obtained at 4 degrees C for 180min showed that PRBPH-1 reduced the storage modulus to a greater extent, indicating that PRBPH-1 suppressed the short-term retrogradation of GRS. Differential scanning calorimetry (DSC) clearly showed that PRBPH-1 significantly decreased the retrogradation enthalpy during the 28-d storage at 4 degrees C, and the retrogradation kinetics were analyzed by the Avrami model. In addition, the recrystallization of GRS based on X-ray diffraction spectroscopy was reduced from 15.41% to 4.86% when the GRS: PRBPH-1mass ratio increased from 100:0 to 100:12. Confocal laser scanning microscopy, atomic force microscopy and scanning electron microscopy demonstrated that PRBPH-1 dispersed between GRS molecules to block the formation of hydrogen bonds to inhibit the recrystallization of GRS. These findings suggested that PRBPH-1 inhibited the short- and long-term retrogradation of GRS, and can be potently employed as a natural alternatives for improving the quality and nutrition of starch-containing foods. PMID- 28917872 TI - Crystalline nanocellulose/lauric arginate complexes. AB - As a novel sustainable nanomaterial, crystalline nanocellulose (CNC) possesses many unique characteristics for emerging applications in coatings, emulsions, paints, pharmaceutical formulations, and other aqueous composite systems where interactions with oppositely charged surfactants are commonly employed. Herein, the binding interactions between sulfated CNC and a novel biologically-derived cationic surfactant lauric arginate (LAE) were comprehensively examined. Ionic strength and solution pH are two crucial factors in determining the adsorption of LAE to the CNC surface. Three different driving forces were identified for CNC LAE binding interactions. Additionally, it was found that the adsorption of LAE to the CNC surface could notably impact the surface potential, aggregation state, hydrophobicity and thermal stability of the CNC. This work provides insights on the binding interactions between oppositely charged CNC and surfactants, and highlights the significance of optimizing the concentration of surfactant required to ionically decorate CNC for its enhanced dispersion and compatibilization in non-polar polymer matrices. PMID- 28917873 TI - Bionanocomposites produced from cassava starch and oil palm mesocarp cellulose nanowhiskers. AB - Cassava starch films reinforced with cellulose nanowhiskers from oil palm mesocarp fibers were produced by casting. Nanowhiskers were obtained by sulphuric acid hydrolysis followed by microfluidization and incorporated in starch films at various loadings (1-10wt%). Morphological and mechanical characterizations showed that the reinforcing effect of oil palm cellulose nanowhiskers was significant at loadings of up to 6wt%, which was determined to be the nanowhiskers percolation threshold. Above this content, formation of agglomerates became more significant, causing a decrease in mechanical properties of starch bionanocomposites. Below percolation threshold, such as 2wt%, elongation at break increased by 70%, showing an effective reinforcing effect. Dynamic mechanical analyses revealed filler/matrix interactions through hydrogen bonding in bionanocomposites. PMID- 28917874 TI - Alginate modified with maleimide-terminated PEG as drug carriers with enhanced mucoadhesion. AB - The goal of this study was to generate a new mucoadhesive carbohydrate-based delivery system composed of alginate (Alg) backbone covalently attached to polyethylene glycol (PEG) modified with a unique functional end-group (maleimide). The immobilization of PEG-maleimide chains significantly improved the mucoadhesion properties attributed to thioether bonds creation via Michael type addition and hydrogen bonding with the mucus glycoproteins. Mucoadhesion studies using tensile and rotating cylinder assays revealed a 3.6-fold enhanced detachment force and a 2.8-fold enhanced retention time compared to the unmodified polymer, respectively. Additional indirect studies confirmed the presence of polymer-mucus glycoproteins interactions. Drug release experiments were used to evaluate the release profiles from Alg-PEG-maleimide tablets in comparison to Alg and Alg-SH tablets. Viability studies of normal human dermal fibroblasts cells depicted the non-toxic nature of Alg-PEG-maleimide. Overall, our studies disclose that PEG-maleimide substitutions on other biocompatible polymers can lead to the development of useful biomaterials for diverse biomedical applications. PMID- 28917875 TI - Collagen and hyaluronic acid hydrogel in water-in-oil microemulsion delivery systems. AB - The increase in skin related health issues has promoted interest in research on the efficacy of microemulsion in dermal and transdermal delivery of active ingredients. Here, we assessed the water-in-oil microemulsion capacity to incorporate two natural polymers, i.e. collagen and hyaluronic acid with low and high molecular weight. Systems were extensively characterized in terms of conductivity, phase inversion studies, droplet diameter, polydispersity index and rheological properties. The results of this research indicate that the structure and extent of water phase in microemulsions is governed by ratio and amount of surfactant mixture (sorbitan ester derivatives). However, results have also shown that collagen, depending upon the weight of the molecule and its surface activity, influence the droplet size of the microemulsions. While the hyaluronic acid, especially with high molecular weight, due to the water-binding ability and hydrogel formation alters the rheological properties of the microemulsion, thus providing viscous consistency of the formulation. PMID- 28917877 TI - Effects of hydrothermal-alkali and freezing-thawing pre-treatments on modification of corn starch with octenyl succinic anhydride. AB - Pre-treatments by freezing/thawing (F/T) and hydrothermal-alkali (HA) were used in the modification of starch with octenyl succinic anhydride (OSA). In comparison with OSA-modified starch prepared without pre-treatment (degree of substitution, DS=0.0172; reaction efficiency, RE=73.9%), HA pre-treatment increased the DS of OSA-starch and RE of subsequent OSA modification (0.0185 and 79.7%, respectively). In contrast, F/T pre-treatment gave the opposite results (0.0152 and 65.5%, respectively). OSA modification markedly increased the viscosities but decreased the gelatinization parameters of native starch. Esterification of starch by OSA was confirmed with Fourier transform infrared and Raman spectroscopy, which indicated markedly decreased short-range molecular orders of native starch. The present study showed that HA pre-treatment before OSA modification is an efficient way to improve the reaction efficiency of OSA with starch and thereby to modify the pasting properties of starch. F/T pre treatment did not increase the reaction efficiency of starch with OSA. PMID- 28917876 TI - Preparation of chitosan-hydroxyapatite composite mono-fiber using coagulation method and their mechanical properties. AB - Autograft has been carried out for anterior cruciate ligament (ACL) reconstruction surgery. However, it has negative aspect because patients lose their healthy ligaments from other part. We focus on a chitosan-hydroxyapatite (HAp) composite fiber as a scaffold of ligament regeneration. Chitosan- HAp composite fiber was made by using coagulation method. Chitosan-NaH2PO4 solution was coagulated with coagulation bath including calcium ion to get the mono-fiber and then treated with sodium hydroxide solution to form HAp in fiber matrix. The mechanical property of the fiber was improved by the stretching of the wet one because of the orientation of chitosan molecule and the interaction between chitosan and HAp. Maximum stress was improved with increasing of sodium dihydrogen phosphate until 0.03M. The swelling ratio of the fiber was inhibited by composited with HAp. Additionally, bone-bonding ability was confirmed by SBF soaking tests. PMID- 28917878 TI - Cellulose nanocrystals from passion fruit peels waste as antibiotic drug carrier. AB - Due to its excellent chemical and physical properties, cellulose nanocrystals (CNC) possess many potential advanced functional applications. In this study, CNC was extracted from natural product by hydrolyzing cellulose segment of passionfruit peels using sulphuric acid solution. The capability of CNC as drug carrier was tested toward tetracycline antibiotic. The drug loading processes were carried out at various pH (3-7) with the optimum uptake of tetracycline achieved at pH 3. The in vitro release of tetracycline drug was carried out in phosphoric buffer medium with two different pH conditions at 37 degrees C. The highest release of tetracycline (82.21%) was achieved at pH 7.2, while the lowest one (25.1%) was achieved at pH 2.1, where the release pattern follow a second order kinetic model. This study highlight the potential application of CNC derived from natural resources as drug carrier without harmful chemical excipients that comply with health safety, biocompatible, biodegradable. PMID- 28917879 TI - Laccase/TEMPO oxidation in the production of mechanically strong arabinoxylan and glucomannan aerogels. AB - New wheat arabinoxylan and konjac glucomannan hydrogels and aerogels were prepared by hemiacetal crosslinking induced by laccase/TEMPO (2,2,6,6 tetramethylpiperidine-1-oxyl) -catalysed oxidation, which selectively converts the primary hydroxyl groups to aldehydes. The degree of oxidation of the product aldehydes was ca. 10% of the total carbohydrates of the polysaccharides, and the determination of storage and viscous moduli of the oxidised samples showed that they had formed true hydrogels. Two freezing methods for the hydrogels, conventional freezing and ice crystal templating, were investigated for aerogel production, the ice crystal templated products especially were mechanically strong in compression test against the ice crystals' growth direction. The compressive moduli were ca. 1200kPa for wheat arabinoxylan aerogels and ca. 650kPa for konjac glucomannan aerogels. A morphological study with a scanning electron microscope revealed the inner structure of the aerogels. Ice crystal templated konjac glucomannan aerogel formed round pores with a diameter of ca. 50 100MUm. The arabinoxylan aerogel consisted of long and narrow pores with a length of a few hundred MUm and width of 50-100MUm, which had formed in the direction of the ice crystals' formation. Konjac glucomannan and wheat arabinoxylan are approved food-grade materials, and wheat arabinoxylan is particularly interesting because it can be obtained from cereal processing side streams - thus, these novel products have potential in various applications, including the food, food packaging, and pharmacological fields. PMID- 28917880 TI - Intercalated chitosan/hydroxyapatite nanocomposites: Promising materials for bone tissue engineering applications. AB - Preparation and characterization of chitosan/hydroxyapatite (CS/HA) nanocomposites displaying an intercalated structure is reported. Hydroxyapatite was synthesized through sol-gel process. Formic acid was introduced as a new solvent to obtain stable dispersions of nano-sized HA particles in polymer solution. CS/HA dispersions with HA contents of 5, 10 and 20% by weight were prepared. Self-assembling of HA nanoparticles during the drying of the solvent cast films led to the formation of homogeneous CS/HA nanocomposites. Composite films were analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), energy dispersive X-rays (EDX) analysis, Fourier transform infrared (FTIR) spectroscopy, X-rays diffraction (XRD) analysis and thermogravimetric analysis (TGA). SEM and AFM confirmed the presence of uniformly distributed HA nanoparticles on the chitosan matrix surface. XRD patterns and cross-sectional SEM images showed the formation of layered nanocomposites. Complete degradation of chitosan matrix in TGA experiments, led to the formation of nanoporous 3D scaffolds containing hydroxyapatite, beta-tricalcium phosphate and calcium pyrophosphate. CS/HA composites can be considered as promising materials for bone tissue engineering applications. PMID- 28917881 TI - Structural characterization and rheological properties of a galactomannan from Astragalus gombo Bunge seeds harvested in Algerian Sahara. AB - A water soluble polysaccharide (WSP) was extracted and purified from Astragalus gombo seeds (Fabaceae) harvested in Septentrional Sahara (Ouargla, Algeria) with a yield of 6.8% (w/w of the dry seed ground). It was characterized by gas chromatography coupled to the mass spectrometry (GC-MS), size exclusion chromatography with Multi-Angle Light Scattering analysis (SEC-MALLS), high resolution 1H and 13C NMR, and rheological measurements. The structural characterization indicated that this WSP fraction is a galactomannan with a mannose/galactose ratio of 1.7 formed by a backbone of beta-(1,4)-d mannopyranosyl residues (63%) substituted at O-6 position by a single alpha galactopyranose residue (37%). SEC-MALLS analysis revealed that this galactomannan has an average molecular mass (Mw) of 1.1*106g/mol, an intrinsic viscosity of 860mL/g and, a random coil conformation structure. Rheological analysis in semi diluted regimes shown pseudo-plastic and viscoelastic behaviour. PMID- 28917883 TI - Green cellulose-based nanocomposite catalyst: Design and facile performance in aqueous synthesis of pyranopyrimidines and pyrazolopyranopyrimidines. AB - A cellulose-based nanobiocomposite decorated with Fe3O4 nanoparticles was prepared, characterized and applied as an easily recoverable and reusable green nanocatalyst in the synthesis of pyrano[2,3-d]pyrimidine derivatives in water at room temperature. The characterization was performed by using a variety of conventional analytical instruments such as Fourier transform infrared spectra (FT-IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), vibrating sample magnetometer (VSM), thermal analysis (TGA/DTA) and inductively coupled plasma atomic emission spectroscopy (ICP-AES) analyses. Two series of pyranopyrimidine and pyrazolopyranopyrimidines derivatives were synthesized by using the present cellulose-based nanocomposite. This protocol has valuable features like high yield of the products, short reaction times, mild conditions and easy work-up procedure. In addition, the catalyst can be prepared easily with cheap and green starting materials. PMID- 28917882 TI - A review about brown algal cell walls and fucose-containing sulfated polysaccharides: Cell wall context, biomedical properties and key research challenges. AB - Studies on brown algal cell walls have entered a new phase with the concomitant discovery of novel polysaccharides present in cell walls and the establishment of a comprehensive generic model for cell wall architecture. Brown algal cell walls are composites of structurally complex polysaccharides. In this review we discuss the most recent progress in the structural composition of brown algal cell walls, emphasizing the significance of extraction and screening techniques, and the biological activities of the corresponding polysaccharides, with a specific focus on the fucose-containing sulfated polysaccharides. They include valuable marine molecules that exert a broad range of pharmacological properties such as antioxidant and anti-inflammatory activities, functions in the regulation of immune responses and of haemostasis, anti-infectious and anticancer actions. We identify the key remaining challenges in this research field. PMID- 28917884 TI - kappa-Carrageenan/locust bean gum as hard capsule gelling agents. AB - A novel gelling agent, comprising blended kappa-carrageenan (kappa-C), a seaweed polysaccharide and locust bean gum (LBG), was used to prepare hard capsules. The distinct synergism between kappa-C and LBG were verified by the textural profile analysis (TPA), FTIR and rheological measurement. Afterwards, films and hard capsules were prepared with the optimized LBG/kappa-C blend gel. And the mechanical properties and morphology of films and hard capsules were analyzed by tensile testing and SEM, respectively. The results showed that the LBG/kappa-C at 1:3 ratio could serve as an excellent gelling agent, which endowed hard capsule with the promoted mechanical properties, homogenous and smooth surface morphology. This work suggests that a novel blended LBG/kappa-C gelling agent successfully prepared for hard capsules with improving physicochemical properties. PMID- 28917885 TI - Magnetic cellulose nanocrystal nanocomposites for the development of green functional materials. AB - A magnetic cellulosic material composed of cellulose nanocrystals (CNC) and cobalt ferrite (CoFe2O4) nanoparticles was developed through evaporation-induced self-assembly (EISA). Nanoparticles demonstrated good dispersibility within the cellulose nanocrystal template. The addition of glucose to CNC network allows the development of homogeneous crack-free CNC-based films and does no modify neither the morphology nor the optical properties. In contrast, the introduction of CoFe2O4 nanoparticles produces a marked decrease in the amount of the transmitted light. 20wt.% of CoFe2O4 nanoparticles inside the CNC matrix induced a maximum magnetization value of 12.96emug-1, increased the real part of the dielectric constant (permittivity) from 10 (pure CNC film) to 12 and improved the thermostability of the nanocomposite as evidenced by the increase of the onset temperature from 165.1 to 220.4 degrees C. Those features obtained in a non petroleum-based composite provide insight into the development of the next generation of functional materials from natural origin. PMID- 28917886 TI - Hydrogen bonds and twist in cellulose microfibrils. AB - There is increasing experimental and computational evidence that cellulose microfibrils can exist in a stable twisted form. In this study, atomistic molecular dynamics (MD) simulations are performed to investigate the importance of intrachain hydrogen bonds on the twist in cellulose microfibrils. We systematically enforce or block the formation of these intrachain hydrogen bonds by either constraining dihedral angles or manipulating charges. For the majority of simulations a consistent right handed twist is observed. The exceptions are two sets of simulations that block the O2-O6' intrachain hydrogen bond, where no consistent twist is observed in multiple independent simulations suggesting that the O2-O6' hydrogen bond can drive twist. However, in a further simulation where exocyclic group rotation is also blocked, right-handed twist still develops suggesting that intrachain hydrogen bonds are not necessary to drive twist in cellulose microfibrils. PMID- 28917887 TI - A visible and controllable porphyrin-poly(ethylene glycol)/alpha-cyclodextrin hydrogel nanocomposites system for photo response. AB - The real-time controlling and tracking of the evolution and status of the hydrogel are important challenges for accurate and precise assessments. In this article, a visible and controllable hydrogel nanocomposites system for photo response was designed and developed based on a thermosensitive porphyrin poly(ethylene glycol)/alpha-cyclodextrin hydrogel loaded with multi-walled carbon nanotubes (PPEG-MWNTs/alpha-CD). The PPEG-MWNTs/alpha-CD hydrogel was simply self assembled with a carbon nanotubes dispersed porphyrin-poly(ethylene glycol) solution and an aqueous solution of alpha-cyclodextrin by homogeneous stirring. The structure and the optical and photothermal abilities of the hydrogel nanocomposites system were characterized in vitro. Moreover, the controlled disassembly of the hydrogel was monitored in real time by in vivo fluorescence imaging after subcutaneous injection using mice as models. The results demonstrated that the hydrogel disassembly can be efficiently accelerated under laser irradiation with the loading of carbon nanotubes by fluorescence imaging visualization. With the advantages of the photo response, fluorescence imaging tracking and photothermal remote controlling were combined into the hydrogel nanocomposites system. PMID- 28917888 TI - Structure of cellulose microfibrils in mature cotton fibres. AB - The structure of cellulose microfibrils in mature cotton fibres from three varieties - Gossypium hirsutum, G. barbadense and G. arboreum - has been investigated by a multi-technique approach combining small angle scattering techniques with spectroscopy and diffraction. Cellulose microfibrils present a Ibeta-rich crystalline structure with limited surface disorder. Small angle scattering (SAXS and SANS) data have been successfully fitted using a core-shell model and the results obtained indicate that the cellulose microfibrils, formed by the association of 2-3 elementary fibrils, are composed of a ca. 2nm impermeable crystalline core, surrounded by a partially hydrated paracrystalline shell, with overall cross-sections of ca. 3.6-4.7nm. Different low levels of cell wall matrix components have a strong impact on the microfibril architecture and enable moisture penetration upon hydration. Furthermore, the higher amounts of non-cellulosic components in G. barbadense result in a less dense packing of cellulose microfibrils and increased solvent accessibility. PMID- 28917889 TI - Fabrication of cellulose nanocrystal from Carex meyeriana Kunth and its application in the adsorption of methylene blue. AB - Cellulose nanocrystal (CNC) was extracted from Carex meyeriana Kunth (CMK) by a combination of TEMPO oxidation and mechanical homogenization method, and used to remove methylene blue (MB) from aqueous solution. After alkali-oxygen treatment, the aqueous biphasic system (polyethylene glycol/inorganic salt) was applied to further remove lignin from CMK. The characteriazation of CNC, and the effects of H2O2 dosage, CNC dosage, adsorption time, and initial MB concentration on the MB removal capacity of CNC were investigated. The results showed that the removal percentage of MB by CNC was raised with the increase of H2O2 and CNC dosage. The adsorption kinetics of prepared CNC followed the pseudo-second-order model, and the adsorption isotherms fitted well to the Langmuir model with a calculated maximum adsoption capacity of 217.4mg/g, which was higher than those of CNC extracted by acid hydrolysis method, indicating CNC extracted from CMK had promising potentials in the field of MB adsorption. PMID- 28917890 TI - Ultrasound assisted enzymatic hydrolysis of starch catalyzed by glucoamylase: Investigation on starch properties and degradation kinetics. AB - The present work investigates the synergistic impact of glucoamylase and ultrasound on starch hydrolysis. The extent of starch hydrolysis at different reaction parameters (ultrasonic intensity, temperature, reaction time) was analyzed. The hydrolysis extent increased with the reaction time and reached a maximum value under ultrasonic intensity of 7.20W/mL at 10min. Ultrasound did not alter the optimum enzymatic temperature but speeded up the thermal inactivation of glucoamylase. The evaluation of enzymatic kinetics and starch degradation kinetics indicated a promotion of the reaction rate and enzyme-substrate affinity. According to the thermodynamic results, sonoenzymolysis reactions require less energy than enzymolysis reactions. The measurement of molecular weight, solubility, thermal properties, and structures of the substrates revealed that sonoenzymolysis reaction generated greater impacts on starch properties. The molecular weight and radii of gyration decreased by 80.19% and 90.05% respectively while the starch solubility improved by 136.50%. PMID- 28917891 TI - Pickering emulsifiers based on hydrophobically modified small granular starches - Part I: Manufacturing and physico-chemical characterization. AB - Small granular starches from rice, quinoa and amaranth were hydrophobized by esterification with octenyl succinic anhydride (OSA) in an aqueous alkaline slurry to obtain series of modified starches at defined intervals (i.e. 0.6, 1.2, 1.8, 2.4, 3.0%). The physical and the physico-chemical properties of the starch particles were characterized by proximate analysis including protein level, amylose level and dry matter. The shape and size of the starch granules were characterized by scanning electron microscopy and light scattering. The gelatinization properties were characterized by differential scanning calorimetry. The degree of modification was determined by titration with NaOH. With regard to the emulsion formulation and in order to assess the emulsifying capacity of the small granular starches, the effect of starch type, degree of modification and starch concentration on the resulting emulsion droplet size were evaluated by light scattering and optical microscopy. Emulsifying properties were found to depend on the degree of substitution, size of the granules and the starch to oil ratio of the formulation. Quinoa starch granules, in general, had the best emulsifying capacity followed by amaranth and rice. However, in higher starch concentrations (>400mg/mL oil) and adequate levels of OSA (3.0%) amaranth performed best, having the smallest size of starches studied. PMID- 28917892 TI - A mechanism for the synergistic gelation properties of gelatin B and xanthan gum aqueous mixtures. AB - Gelatin B and xanthan gum aqueous mixtures (GB/XG, (0.2-2%)/0.2% w/v) exhibit enhanced gelling properties compared to their pure component solutions at similar compositions. The mixed gels comprise co-localized networks of GB and XG-rich domains. Our results show that these domains are composed of intermolecular complexes and their aggregates stabilized by the neutralization effect of GB, and linked together by formation of GB triple helices. GB/XG mixtures display composition-dependent microstructural transitions: from discontinuous aggregates (GB/XG ratio<=1) to a continuous GB/XG network (ratio=2-6), followed by network fragmentation (ratio=8-10). Increasing the GB Bloom index accelerates network formation and results in higher elastic modulus (G'), while increasing the XG molecular weight causes the opposite effect due to diffusion limitations. This work provides a set of fundamental guidelines to design novel thickeners and/or gelling agents based on proteins and polysaccharides, for food or pharmaceutical applications. PMID- 28917893 TI - Carboxymethyl cyclosophoraoses as a flexible pH-responsive solubilizer for pindolol. AB - In the present study, cyclosophoraoses (CyS) (beta-1,2 linked cyclic glucans, with glucopyranose units ranging from 17 to 23) isolated from Rhizobium leguminosarum biovar viciae VF-39 were modified with carboxymethyl (CM) groups, and the pH-sensitive complexation of CM CyS with pindolol was investigated. The solubility of pindolol increased 32-fold by its complexation with 5mM CM CyS at pH 10, whereas it shows no significant change at pH 3. Pindolol, a beta adrenergic blocking agent, has a hydrophobic nature at non-ionized state, and CM CyS could solubilize efficiently pindolol in a high alkaline solution. The carboxymethylation of flexible CyS allows them to present a more suitable cavity for the hydrophobic pindolol at pH 10, which is differentiated from CM beta cyclodextrin (beta-CD). It can be interpreted as that the anionic repulsion effectively modulates the flexible and distorted conformation of CyS rather than rigid annular shape of beta-CD. Resultingly, the highly solubilized CM CyS/pindolol complex was characterized by UV-vis, T1 relaxation, ROESY, DOSY NMR spectroscopy, FT-IR spectroscopy, SEM, and molecular modeling studies. The antioxidant activity of pindolol was also improved 260% in the complex compared to free pindolol. The use of flexible host molecules with pH-responsive substituents would be applied in the development of smart systems for sensing or in biomedical fields. PMID- 28917894 TI - Structural, functional and pH sensitive release characteristics of water-soluble polysaccharide from the seeds of Albizia lebbeck L. AB - Plant polysaccharides, generally regarded as safe (GRAS), are gaining importance as excipients in drug delivery. Therefore, the current paper presents the studies on structural, functional and drug release study of water soluble polysaccharide (ALPS) from seeds of Albizia lebbeck L. High swelling, water holding capacity, foam stability and lower moisture content suggests its use as additive in food preparations. The apparent molecular weight of polysaccharide was found to be 1.98*102kDa. Monosaccharide composition analysis indicated that ALPS consists of mannose (4.06%), rhamnose (22.79%), glucose (38.9%), galactose (17.84%) and xylose (16.42%). Micromeritic properties revealed that the polysaccharide possess potential for pharmaceutical applications. From the surface charge analysis, ALPS was found to be non-ionic polysaccharide. Morphological study reveals the polysaccharide with irregular particle shape and rough surface. Fourier transformed infrared spectroscopy (FTIR) study confirms the carbohydrate nature of polysaccharide. From the thermogravimetric analysis (TGA) data, the second mass loss (243-340 degrees C) attributed to polysaccharide degradation. The drug release profile reveals the use of polysaccharide for the preparation of pH sensitive pharmaceutical dosage forms. PMID- 28917895 TI - Ultrasound assisted adsorptive removal of hazardous dye Safranin O from aqueous solution using crosslinked graphene oxide-chitosan (GOCH) composite and optimization by response surface methodology (RSM) approach. AB - Chitosan (CH) was crosslinked with graphene oxide (GO) by combining solutions of CH and GO. Characterisations by ATR-FTIR, FE-SEM and XRD confirmed the formation of the GOCH composite. Removal of the dye Safranin Orange (SO) by ultrasonic adsorption from aqueous solution was tested by the composite. The removal of the cationic dye was more favourable at pH values greater than 5.2 and the optimum pH was found to be 6.5. The adsorption kinetics followed a pseudo-first order model and the rate-limiting step was identified as boundary layer diffusion from the Intraparticle diffusion model. The sonication assisted adsorption kinetic data were compared with the non-sonicated one and it was found that sonication has a marked effect on the adsorption kinetics. The Redlich Peterson adsorption isotherm described the adsorption with more resemblance to the Langmuir Model than the Freundlich Model suggesting that monolayer adsorption predominated. From Response Surface Methodology it was noted that the combined effect of pH and initial concentration was antagonistic while that of sonication time was synergistic. The optimum parameters from the RSM model were found to be pH 6.82, initial SO concentration 425mgL-1 and sonication time 25min. This was in good agreement with the experimental results. PMID- 28917896 TI - Environmental and technical feasibility of cellulose nanocrystal manufacturing from sugarcane bagasse. AB - The environmental and technical feasibility of cellulose nanocrystal production from sugarcane bagasse fibers was evaluated. First, the life cycle assessment (LCA) is presented as a methodology to investigate the most feasible form of obtainment. The environmental impacts regarding climate change and water footprint were evaluated considering a gate-to-gate process and a functional unit of 1kg. The inventory data encompassed sugarcane plantation and pretreatment, bleaching and hydrolysis for bagasse generation. The twelve scenarios for extracting nanocrystals that were investigated consisted of treatment with sodium hydroxide or sodium chlorite followed by sulfuric acid hydrolysis. All products and processes were characterized by their yield and X-ray diffraction. As a result, all scenarios showed that the pretreatment stage was the most important contributor to the environmental impact. The comparison among the scenarios showed that nanocrystals produced by processes V - NaClO2/NaOH/H2SO4/30min/1x and IX - NaClO2/NaOH/HNO3/H2SO4/30min/1x presented low water consumption and minimal contributions to climate change. Therefore, considering the LCA, yield and crystallinity, the best processes were V and IX sequences. Finally, these cellulose nanocrystals were evaluated by their chemical composition, morphology and thermal stability, exhibiting hemicellulose and lignin removal, nanometric dimensions from 8 to 12nm, high crystallinity and low thermal stability. PMID- 28917897 TI - Reduction of Au(III) by a beta-cyclodextrin polymer in acid medium. A stated unattainable reaction. AB - Gold nanoparticles (AuNPs) can be prepared from the reduction of Au(III) with cyclodextrins acting as both, reducing and capping agent. It has been stated that a basic medium (pH=9-12) is a mandatory condition to achieve such reduction. We demonstrated, for the first time, the reduction of Au(III) by a crosslinked beta cyclodextrin-epichlorohydrin polymer (betaCDP) in acid medium (pH ~3). The coordination of Au(III) to the betaCD in betaCDP polymer required a betaCD:[AuCl4]- ratio of 4:1. The same ratio was necessary to achieve a 50% of the reduction of Au(III) to Au0 within the first 24h of reaction. During this initial time, the reaction showed a concentration-dependent reduction rate while for longer times the reduction rate was diffusion-dependent. An overall mechanism to explain this dependency has been proposed. The 13C NMR spectrum identified the oxidation of the COH groups to carboxylic ones by recording a signal at 175.6ppm. Gold nanoparticles cores (AuNPs) with a diameter of 34.2+/-7.7nm, determined by Transmission Electron Microscopy (TEM), was prepared by refluxing HAuCl4 in an aqueous solution of betaCDP. The AuNPs core was capped by dimers of the betaCDP polymer as determined by Dynamic Light Scattering measurements. PMID- 28917898 TI - Physicochemical characterization, antioxidant activity of polysaccharides from Mesona chinensis Benth and their protective effect on injured NCTC-1469 cells induced by H2O2. AB - Polysaccharides MP-A, MP-U and MP-C were extracted from Mesona chinensis Benth by hot-alkali extraction (HAE), ultrasonic-assisted extraction (UAE) and cellulose enzyme assisted extraction (CAE), respectively. The yields, physicochemical properties and antioxidant of polysaccharides were investigated. Results showed that the yields of MP-A (11.14%), MP-U (10.62%) and MP-C (9.70%) were similar, and they were all heteropolysaccharides with average molecular weights of 1.9*105Da, 1.5*105Da, 1.4*105Da. Glucose, galactose, and galacturonic acid were the main monosaccharides in MP-A, MP-U and MP-C with molar ratios of 1.00:1.34:0.25, 1.00:2.49:0.19 and 1.00:2.95:0.84, respectively. MP-C extracted by CAE exhibited higher antioxidant activities in FRAP, DPPH, hydroxyl radical assays and the H2O2-induced injury cell model. The three extraction methods had only slight effects on chemical composition, while MP-C extracted by CAE exhibited the highest antioxidant activity, which could potentially be used for an addition ingredient as it was previously shown to have good gelling property in food products. PMID- 28917899 TI - Polysaccharides from brown algae Sargassum duplicatum: the structure and anticancer activity in vitro. AB - The laminaran SdL and fucoidan SdF were isolated from brown algae Sargassum duplicatum. SdL was 1,3;1,6-beta-d-glucan (1,3:1,6=6:1) with a main chain, represented by 1,3-linked glucose residues, due to NMR spectroscopy data. Single glucose residues could form branches at C6. Unusual structure of fucoidan SdF was studied by chemical and enzymatic methods, NMR spectroscopy of desulfated and deacetylated polysaccharide and mass spectrometry of fucoidan fragments labeled with 18O. Fucoidan was sulfated (31.7%) and acetylated galactofucan (Fuc:Gal~1:1) with a main chain of 1,4-linked alternating alpha-l-fucose and beta-d-galactose residues. Side chains were represented by extensive (DP>=5) 1,3-linked 2,4 disulfated alpha-l-fucose residues with branching points at C2. Fucose residues in the main chain were sulfated at C2 and less at C3, while galactose residues were sulfated at C2, C3, and less at C4, C6. The fucoidan SdF was effective against colony formation of colon cancer cells in vitro. PMID- 28917900 TI - Mineralized agar-based nanocomposite films: Potential food packaging materials with antimicrobial properties. AB - New mineralized, agar-based nanocomposite films (Zn-carbonate and Zn phosphate/agar) were produced by a combination of in situ precipitation and a casting method. The presence of minerals significantly influenced the morphology, properties and functionality of the obtained nanocomposites. Reinforcement with the Zn-mineral phase improved the mechanical properties of the carbonate mineralized films, but had a negligible effect on the phosphate-mineralized samples. Both nanocomposites showed improved optical and thermal properties, better Zn(II) release potential in a slightly acidic environment and exhibited antimicrobial activity against S. aureus. These results suggest that Zn mineralized agar nanocomposite films could be potentially used as affordable, eco friendly and active food packaging materials. PMID- 28917901 TI - Polysaccharides based injectable hydrogel compositing bio-glass for cranial bone repair. AB - Bone disease is a public health problem around the word, and it is urgent to develop novel tissue engineering scaffolds for the complicated cranial bone regeneration. The present work developed a novel triple crosslinked polysaccharides based injectable hydrogel to composite bio-glass (BG) for cranial bone repair. Dynamic mechanical analysis showed the storage modulus (G') of the hydrogel reached to ~4000Pa. While after compositing BG, G' exceeded 4500Pa. The degradation behavior of the hydrogel is influenced by hydrogel composition, crosslinking methods and degradation environment. Through compositing BG for rat cranial bone repair, excellent bone regeneration effect was achieved (chunks of "white" new tissue was detected in the defected site, HE histopathological analysis confirmed the new tissue was bone tissue). Thus, the hydrogel is suitable as the carrier of BG for bone repair, demonstrating the prepared triple crosslinked hydrogel is potential for bone tissue engineering applications. PMID- 28917902 TI - An unexpected reactivity during periodate oxidation of chitosan and the affinity of its 2, 3-di-aldehyde toward sulfa drugs. AB - In an attempt to determine the reactivity during the periodate oxidation of the vicinal amino sugar, chitosan was oxidized by KIO4 in a neutral medium. The reactivity was unexpectedly found to be low. The formation of di-aldehyde chitosan (DACT) might cause the low reactivity of chitosan oxidation. Therefore, density functional theory (DFT) calculations were carried out, which revealed that the greater stability of the cyclic amino iodate intermediate might retard the ring opening to form DACT. Furthermore, the affinity of the formation of two novel Schiff bases from the interaction of delivered DACT with two sulfa drugs [sulfanilamide and sulfathiazole] was also investigated using aldehyde content estimation. DACT and Schiff's bases were characterized by FT-IR spectroscopy, X ray diffraction, and DTA analysis. The X-ray diffraction plane (110) of DACT at the high angle side was expanded more by sulfathiazole than sulfanilamide, indicating that sulfathiazole reacted effectively with DACT. The lowest interaction of DACT with sulfa drugs could be ascribed to the lowest aldehyde content and the intramolecular hemiacetal formation that hinders the Schiff's base condensation. PMID- 28917903 TI - Carbon dioxide capture and conversion by an environmentally friendly chitosan based meso-tetrakis(4-sulfonatophenyl) porphyrin. AB - We have demonstrated the facile, environmentally friendly and sustainable preparation of chitosan based meso-tetrakis(4-sulfonatophenyl)porphyrin (CS-TPPS) for adsorption and catalytic conversion of carbon-dioxide (CO2). The ionic complexation between chitosan (CS) and meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) is confirmed by ultraviolet-visible (UV-vis) and Fourier transform infrared spectroscopy (FTIR). Physical properties, such as crystallinity, thermal stability, surface morphology and porosity were analyzed by X-ray diffraction, thermal analysis, scanning electron microscopy and BET isotherm analysis. CS-TPPS shows adsorption capacity of 0.9mmol CO2/g compared to the adsorption capacity of 0.05mmol CO2/g of pure chitosan and an adsorption capacity of 0.2mmol CO2/g of pure TPPS. It also exhibits higher conversion of CO2 and propylene oxide into cyclic carbonate (66%), compared to pure chitosan (31%). The results are encouraging, and may open new perspectives for the use of biopolymers involving porphyrin based material in environmental and industrial applications. PMID- 28917904 TI - Metal-organic framework preparation using magnetic graphene oxide-beta cyclodextrin for neonicotinoid pesticide adsorption and removal. AB - A novel magnetic copper-based metal-organic framework (M-MOF) was prepared using a Fe4O3-graphene oxide (GO)-beta-cyclodextrin (beta-CD) nanocomposite as the magnetic core and support, and used for adsorption and removal of neonicotinoid insecticide pollutants from aqueous solution. M-MOF characterization suggested that 1Fe4O3-GO-beta-CD consisted of a thin single layer with anchored Fe3O4. The M-MOF was coated on the Fe4O3-GO-beta-CD surface. The M-MOF had a large Brunauer Emmett-Teller surface area (250.33m2g-1) and high super-paramagnetism with saturation magnetization of 10.47emug-1. Adsorption model analysis showed that the equilibrium data for thiacloprid fitted Langmuir monolayer adsorption and the other insecticides tested showed Freundlich bimolecular layer adsorption. The results show that M-MOF is a promising hybrid adsorbent for rapid removal of neonicotinoid insecticide pollutants from environmental waters. PMID- 28917905 TI - Characterization of a water-soluble chitosan derivative and its potential for submucosal injection in endoscopic techniques. AB - To examine the potential of chitosan-based agents for submucosal injection in endoscopic techniques, a chitosan derivative was prepared with lactose moieties linked to the amino groups of its glucosamine units (CH-LA). After dissolving CH LA in neutral pH solutions, including physiological saline (CH-LA-S), its response to different concentrations of anionic glycosaminoglycans and proteins in the surrounding environment was examined. The CH-LA-S form changed in the presence of sulfated glycosaminoglycans (heparin, chondroitin sulfate, and mucin) and protein (fibrinogen). High concentrations of sulfated substrates in the solution caused the formation of larger structures. In contrast, in the presence of hyaluronan, 30mg/mL CH-LA-S did not form any large structures. Submucosal injection of 30mg/mL CH-LA-S into extracted swine stomachs showed a strong lifting effect of the gastric mucosa. These results indicate the potential utility of CH-LA-S as a submucosal injection for endoscopic techniques such as endoscopic submucosal dissection and mucosal resection of tumors. PMID- 28917906 TI - Comments on "Solubility parameter of chitin and chitosan" Carbohydrate Polymers 36 (1998) 121-127. AB - Results on the solubility parameters of chitin and chitosan presented in the paper DOI: 10.1016/S0144-8617(98)00020-4 were recalculated and data evaluation was redone. A number of misprints, erroneous calculations and data evaluations were found with respect to Hansen as well as total solubility parameters as derived according to group contribution methods by Hoftyzer-Van Krevelen and Hoy's system. Revised numerical data are presented. PMID- 28917907 TI - Microencapsulation of Eugenia uniflora L. juice by spray drying using fructans with different degrees of polymerisation. AB - The objective of this work was to microencapsulate pitanga (Eugenia uniflora L.) juice by spray drying, using High Performance Agave Fructans (HPAF) and High Degree of Polymerisation Agave Fructans (HDPAF) and maltodextrin (MD), respectively, as the wall materials. The physicochemical and antioxidant properties of the capsules during storage at various temperatures were evaluated. The microparticles developed using fructans HPAF and HDPAF, exhibited similar physicochemical and flow properties to those presented by the microparticles prepared with MD. The highest yield and concentration of anthocyanins after drying and during storage were found for a 1:6 core:wall material ratio. The total color change was a good indicator of the microcapsule stability. This study showed that both fructans fraction possess similar encapsulating properties to MD and that the HDPAF were more efficacious than MD at protecting the antioxidants during drying and storage. PMID- 28917908 TI - Structural elucidation of the main water-soluble polysaccharide from Rubus anatolicus roots. AB - An acidic heteropolysaccharide, RAPS-1, was isolated from the roots of Rubus anatolicus by water extraction (70 degrees C) and purification using DEAE cellulose A52 and Sephadex G-100 column chromatography. The total sugar content and specific optical rotation of RAPS-1 were 96.3% and +196 degrees , respectively. RAPS-1 had a molecular weight of 7900Da, and was composed of glucose, galactose, and glucuronic acid with a relative molar ratio of 6.2: 1.0: 1.2. Structural features of RAPS-1 were elucidated by a combination of partial acid hydrolysis, periodate oxidation and Smith degradation, methylation, GC-MS, FTIR, and NMR (13C and 1H) analysis. The results indicated that RAPS-1 had a backbone of ->4)-alpha-d-Glcp-(1-> residues, with branches attached to O-6 by alpha-d-Galp-(1-> and by alpha-d-GlcAp-(1->. PMID- 28917909 TI - Development of poly (1, 8-octanediol citrate)/chitosan blend films for tissue engineering applications. AB - Blends of poly (1, 8-octanediol citrate) (POC) and chitosan (CS) were prepared through solution casting technique. Films with different component fractions (POC/CS: 100/0, 90/10, 80/20, 70/30, 60/40, and 0/100) were successfully prepared and characterized for their mechanical, thermal, structural and morphological properties as well as biocompatibility. The incorporation of CS to POC significantly increased tensile strength and elastic modulus and presented limited influences on pH variation which is important to the biocompatibility of biomaterial implants. The assessment of surface topography indicated that blending could enhance and control the surface roughness of the pure films. POC/CS blends well-supported human dermal fibroblast cells attachment and proliferation, and thus can be used for a range of tissue engineering applications. PMID- 28917910 TI - CotA laccase-ABTS/hydrogen peroxide system: An efficient approach to produce active and decolorized chitosan-genipin films. AB - Chitosan-genipin films present a bluish-green color due to the conjugated double bonds formed when monomeric or dimeric genipin residues bridge chitosan. This phenomenon limits their use when colorless materials are required. In this work, a two-step oxidation strategy was developed aiming to remove color from chitosan genipin films while preserving their functional properties. A combined system using the recombinant CotA laccase from Bacillus subtilis mediated by 2,2' azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) followed by a H2O2 oxidation step was settled. ABTS boosted the laccase performance resulting in light brown chitosan-genipin films that were further decolorized upon immersion in a 5% H2O2 solution at pH 11.0 and 40 degrees C for 30min. The applied methodology leads to films that sustain both acidic stability and antioxidant capacity of the pristine films. Overall, the combined CotA laccase-ABTS/hydrogen peroxide developed methodology efficiently produce active and decolorized chitosan-genipin films with potential for application as eco-friendly transparent material which may have application as food packaging. PMID- 28917911 TI - Injectable glycosaminoglycan-protein nano-complex in semi-interpenetrating networks: A biphasic hydrogel for hyaline cartilage regeneration. AB - Articular hyaline cartilage regeneration remains challenging due to its less intrinsic reparability. The study develops injectable biphasic semi interpenetrating polymer networks (SIPN) hydrogel impregnated with chondroitin sulfate (ChS) nanoparticles for functional cartilage restoration. ChS loaded zein nanoparticles (~150nm) prepared by polyelectrolyte-protein complexation were interspersed into injectable SIPNs developed by blending alginate with poly(vinyl alcohol) and calcium crosslinking. The hydrogel exhibited interconnected porous microstructure (39.9+/-5.8MUm pore diameter, 57.7+/-5.9% porosity), 92% swellability and >350Pa elastic modulus. Primary chondrocytes compatibility, chondrocyte-matrix interaction with cell-cell clustering and spheroidal morphology was demonstrated in ChS loaded hydrogel and long-term (42days) proliferation was also determined. Higher fold expression of cartilage-specific genes sox9, aggrecan and collagen-II was observed in ChS loaded hydrogel while exhibiting poor expression of collagen-I. Immunoblotting of aggregan and collagen II demonstrate favorable positive influence of ChS on chondrocytes. Thus, the injectable biphasic SIPNs could be promising composition-mimetic substitute for cartilage restoration at irregular defects. PMID- 28917912 TI - A plant-based reactive ammonium phytate for use as a flame-retardant for cotton fabric. AB - A plant-based non-formaldehyde flame retardant containing high phosphorus ammonium phytate (APA) was synthesized for cotton fabric. The char length of treated cotton sample decreased to 31mm from the original 300mm. The LOI value of finished cotton fabric was as high as 43.2%, and after 30 laundering cycles, it still remained 30.5%, suggesting that APA could be used as an effective semi durable flame retardant. The TG analysis in air demonstrated that the thermal oxidation stability of treated fabric was significantly improved. Cone calorimetry results showed that the peak heat release rate and total heat release of treated sample reduced obviously comparing with that of control sample. The SEM morphologies suggested that the APA molecule penetrated into the inner space of cotton fibers. FTIR spectra implied the APA molecule grafted onto cotton fibers. Then, the effective flame retardant APA has significant potential in practical application. PMID- 28917913 TI - Microparticle-embedded fibroin/alginate beads for prolonged local release of simvastatin hydroxyacid to mesenchymal stem cells. AB - In the present work, we propose silk fibroin/alginate (SF/Alg) beads embedding simvastatin-loaded biodegradable microparticles as a versatile platform capable of tuning SVA release and in so doing osteogenic effects. In a first part of the study, microparticles of poly(lactic-co-glycolic) acid incorporating simvastatin either as lactone (SVL) or as hydroxyacid form (SVA) were prepared by spray drying. While SVA-loaded microparticles released the drug in three days, long term release of SVA could be obtained from SVL-loaded microparticles. In this latter case, SVL was promptly transformed to the osteogenic active SVA during release. When tested on mesenchymal stem cells, a time- and dose-dependent effect of SVL-loaded microparticles on cell proliferation and alkaline phosphatase (ALP) activity was found. Thereafter, SVL-loaded microparticles were embedded in SF/Alg beads to limit the initial simvastatin burst and to achieve easier implantation as well. Microparticle-embedded beads showed no cytotoxicity while ALP activity increased. If correctly exploited, the developed system may be suitable as osteogenic polymer scaffolds releasing correct amount of the drug locally for long time-frames. PMID- 28917914 TI - Structure, enzymatic transformation, anticancer activity of fucoidan and sulphated fucooligosaccharides from Sargassum horneri. AB - Structure and anticancer activity of fucoidan from Sargassum horneri and from products of its enzymatic transformation were investigated. A gene that encodes fucoidanase ffa1 in the marine bacteria F. algae was identified, cloned and the protein (FFA1) was produced in Escherichia coli. The mass of the gene product FFA1 is 111kDa. Sequence analysis has revealed that fucoidanase FFA1 belongs to the GH107 (CAZy) family. Recombinant fucoidanase FFA1 was used to produce fucooligosaccharides. Structure of 5 sulphated oligosaccharides with polymerization degree 4-10 was established by NMR-spectroscopy. The fucoidan extracted from S. horneri is almost pure fucan. The main chain of the fucoidan is established to consist mostly of the repeating ->3-alpha-l-Fucp(2SO3-)-1->4-alpha l-Fucp(2,3SO3-)-1-> fragment, with insertions of ->3-alpha-l-Fucp(2,4SO3-)-1-> fragment. Unsulphated side chains with the alpha-l-Fucp-1->2-alpha-l-Fucp-1-> structure connect to the main one at the C4 of monosaccharide residue. PMID- 28917915 TI - Synergistic effect of Chitosan-Zinc Oxide Hybrid Nanoparticles on antibiofouling and water disinfection of mixed matrix polyethersulfone nanocomposite membranes. AB - Antifouling polyethersulfone (PES) membranes for water disinfection were fabricated by incorporating varying concentrations of carbohydrate polymer chitosan and Zinc oxide hybrid nanoparticles (CS-ZnO HNPS). The CS-ZnO HNPS were prepared using chemical precipitation method and were characterized using SEM, XRD and FTIR. The membranes were then fabricated by incorporating nanoparticles of CS-ZnO HNPS with three different concentrations of 5%, 10% and 15% w/w in the casting solution of PES through phase inversion method. The influence of nano sized CS-ZnO HNPS on the properties of PES was characterized to study morphology, contact angle, water retention, surface roughness and permeability flux. The membranes with the maximum concentrations of 15% HNPS resulted in larger mean pore sizes and lowest contact angle value as compare to the pristine PES membrane. The prepared membranes exhibited significant water permeability, hydrophilicity and prevention against microbial fouling. The prepared membranes were observed to have significant antibacterial as well as antifungal properties due to the synergistic effect of chitosan and ZnO against both bacteria of the type of S. Aureus, B. Cereus, E. coli, and fungi such as S. typhi, A. fumigatus and F. solani. PMID- 28917916 TI - Quantitative investigations of xylose and arabinose substituents in hydroxypropylated and hydroxyvinylethylated arabinoxylans. AB - The chemical structures obtained by the modification of arabinoxylans with the cyclic carbonates propylene carbonate (PC) and 4-vinyl-1,3-dioxolan-2-one (VEC) with varying degrees of substitution were investigated. Therefore, a new analytical method was developed that is based on a microwave-assisted hydrolysis of the polysaccharides with trifluoroacetic acid and the reductive amination with 2-aminobenzoic acid. The peak assignment was achieved by HPLC-MS and the carbohydrate derivatives were quantified by HPLC-fluorescence. The obtained maximum molar substitution of PC-derivatized xylan (XHP) was 1.8; the molar substitution of VEC-derivatized xylan (XHVE) was 2.3. Investigations of xylose and arabinose based mono- and disubstituted derivatives revealed a preferred reaction of the cyclic carbonates with arabinose. Conversion rates were up to 2.4 times higher for monosubstitution and up to 3.0 times for disubstitution compared to xylose. Furthermore, the reaction with VEC was preferred due to higher reactivity of the newly introduced side chains. PMID- 28917917 TI - Characterization of structural cell wall polysaccharides in cattail (Typha latifolia): Evaluation as potential biofuel feedstock. AB - Second generation bioethanol produced from lignocellulosic biomass is attracting attention as an alternative energy source. In this study, a detailed knowledge of the composition and structure of common cattail (Typha latifolia L.) cell wall polysaccharides, obtained from stem or leaves, has been conducted using a wide set of techniques to evaluate this species as a potential bioethanol feedstock. Our results showed that common cattail cellulose content was high for plants in the order Poales and was accompanied by a small amount of cross-linked polysaccharides. A high degree of arabinose-substitution in xylans, a high syringyl/guaiacyl ratio in lignin and a low level of cell wall crystallinity could yield a good performance for lignocellulose saccharification. These results identify common cattail as a promising plant for use as potential bioethanol feedstock. To the best of our knowledge, this is the first in-depth analysis to be conducted of lignocellulosic material from common cattail. PMID- 28917918 TI - Chitosan composite hydrogels reinforced with natural clay nanotubes. AB - Here, chitosan composites hydrogels were prepared by addition of halloysite nanotubes (HNTs) in the chitosan KOH/LiOH/urea solution. The raw chitosan and chitosan/HNTs composite hydrogels were obtained by heat treatment at 60 degrees C for 8h and then regeneration in ethanol solution. The viscosity of the composite solution is increased with HNTs content. The Fourier transform infrared spectroscopy (FT-IR) shows that the hydrogen bonds interactions exist between the HNTs and the chitosan. X-ray diffraction (XRD) results show that the crystal structure of HNT is not changed in the composite hydrogels. The compressive property test and storage modulus determination show that the mechanical properties and anti-deformation ability of the composite hydrogel significantly increase owing to the reinforcing effect of HNTs. The composites hydrogel with 66.7% HNTs can undergo 7 times compression cycles without breaking with compressive strength of 0.71MPa at 70% deformation, while pure chitosan hydrogel is broken after bearing 5 compression cycles with compressive strength of 0.14MPa and a maximum deformation of 59%. A porous structure with pore size of 100-500MUm is found in the composite hydrogels by scanning electron microscopy (SEM), and the pore size and the swelling ratio in NaCl solution decrease by the addition of HNTs and the immersing of ethanol. Chitosan/HNTs composite hydrogels show low cytotoxicity towards MC3T3-E1 cells. Also, the composite hydrogels show a maximum drug entrapment efficiency of 45.7% for doxorubicin (DOX) which is much higher than that of pure chitosan hydrogel (27.5%). All the results illustrate that the chitosan/HNTs composite hydrogels show promising applications as biomaterials. PMID- 28917919 TI - Structural characteristics of water-soluble polysaccharides from Norway spruce (Picea abies). AB - Arabinogalactan proteins and pectic polysaccharides were isolated from greenery of Picea abies by water extraction. Main elements of their structure were determined by ion-exchange chromatography, partial acid and enzymatic hydrolysis, and NMR spectroscopy. It was established that the backbone of pectin macromolecules of greenery of P. abies is represented by segments of partially methyl-esterified and acetylated 1,4-alpha-d-galactopyranosyluronan, and partially 2-O- and/or 3-O-acetylated RG-I with side chains consisting of highly branched 1,5-alpha-l-arabinan segments. The carbohydrate part of AGP of greenery of P. abies consists of AG-II, the main chain of which is represented by 1,3-beta d-Galp and 1,3,6-beta-d-Galp residues. The side chains of AG-II are formed of 1,6 and 1,3,6-beta-d-Galp, 1,3- and 1,5-alpha-l-Araf, beta-d-GlcpA and 1,4-beta-d GlcpA, T-alpha-l-Araf, T-alpha-l-Rhap and T-alpha-l-Fucp residues. The AGPs of P. abies are also characterized by the presence of an unusual 4-O-Me-alpha-l-Fucp monosaccharide, which, as far as we know, was not found in pectins or AGP earlier. PMID- 28917920 TI - One-step hydrothermal synthesis of fluorescent nanocrystalline cellulose/carbon dot hydrogels. AB - Fluorescent nanocrystalline cellulose/carbon dots (NCC/CDs) hydrogels were successfully prepared by a facile one-step green hydrothermal carbonization process. The properties of NCC/CDs hydrogels prepared at different temperatures were investigated by fluorescence spectroscopy, transmission electron microscopy, nuclear magnetic resonance spectroscopy, X-ray diffraction, and thermogravimetric analysis. NCC/CDs hydrogels with high crystallinity, high thermal stability, and excellent fluorescence properties can be obtained by controlling the hydrothermal treatment temperature. Small rod-like NCC/CDs hydrogels with a diameter of 2-6nm, a length of 40-60nm, and the cellulose Iota structure were obtained when the hydrothermal carbonization temperature was 240 degrees C. The NCC/CDs hydrogels exhibited an excellent broad spectral response and high fluorescence stability at various pH values. Considering of the wide natural abundance of NCC and the biocompatibility of the NCC/CDs hydrogels, Preparation in this simple, green approach is attractive for future bio-medical applications. PMID- 28917921 TI - Effect of oxidized chitin nanocrystals isolated by ammonium persulfate method on the properties of carboxymethyl cellulose-based films. AB - Oxidized chitin nanocrystals (ChNCs) were isolated from crab shell chitin using ammonium persulfate (APS) method. The oxidized ChNCs were in needle shape with a diameter of 15nm, the length of 400-500nm, and crystallinity index of 93.5%. Carboxymethyl cellulose (CMC)-based films reinforced with the ChNCs (0, 1, 5, and 10wt.%) were flexible and transparent. The mechanical strength of the CMC film increased significantly (p<0.05) after blending with the ChNCs. The tensile strength (TS) and elastic modulus (EM) increased by 88% and 243% when 10wt.% of ChNCs were incorporated. Water vapor barrier property of the composite films decreased and the hydrophilicity increased compared with the neat CMC film. The oxidized ChNCs obtained using the APS method have a high potential for being used as a reinforcing filler to improve the mechanical properties of nanocomposite films for the application in food packaging, nano-papers, hydrogels as well as biomedical applications. PMID- 28917922 TI - The effects of lotus root amylopectin on the formation of whey protein isolate gels. AB - The effects of lotus root amylopectin (LRA) on the formation of whey protein isolate (WPI) gels were investigated at the concentration range from 0 to 1.0% (w/v) by determining the texteral, thermal and rheological properties. Results exhibited these properties of WPI gels could be significantly enhanced by the addition of LRA in a concentration-dependent manner. Compared the gel with free of starch, the gel strength, water holding capacity and thermal transition temperature of WPI gel containing 1% (w/v) amylopectin were enhanced by 12.7 fold, 24.9% and 3.6 degrees C, respectively. According to the analysis of scanning electron microscopy, colorimetric reaction and Fourier transform infrared spectroscopy measurements, it was concluded that the LRA-induced enhancement of WPI gel properties was possibly attributed to the formation of stable three-dimensional gel network, increased contents of reactive sulfhydryl group, CN bond and/or NH bond. Results suggested that LRA might be a good gel modifier. PMID- 28917923 TI - Effect of carboxymethylation on rheological and drug release characteristics of Terminalia catappa gum. AB - The carboxymethylation of galactomannans, arabinogalactans, arbinoxylan, etc is known to modify solubility, swelling index, rheological behaviour, powder characteristics, etc. Therefore, an attempt had been made to study the effect of carboxymethylation on Terminalia catappa (TC) gum. For this, modified Williamson synthesis reaction was utilized employing Quality by Design (QbD) approach. Grafting of carboxymethyl group on Terminalia catappa was confirmed by ATR-FTIR, H1NMR and DSC analyses. The rheological attributes revealed that the carboxymethylation of TC lowers the viscosity, enhance thermal stability (high activation energy), disentanglement was near to re-entanglement, and weak gelling characteristic. However, the soluble fluconazole loaded gel formulation of CMTC showed diffusion based kinetic model indicating good reservoir for effective application on skin/tissue surfaces. PMID- 28917924 TI - Synthesis of amphoteric curdlan derivatives for delivery of therapeutic nucleic acids. AB - Cationic polymers are powerful carriers for intracellular delivery of therapeutic nucleic acids. However, the positively charged macromolecules have considerable cytotoxicity and often induce irreversible damages to the cells and tissues, which greatly negate the clinical application of such materials as drug delivery system. Herein, we report the synthesis of novel amphoteric polymers based on curdlan, and the evaluation of their cytotoxicity as well as the nucleic acid delivery efficiency. beta-(1,3)-polyglucuronic acid, a TEMPO-oxidized derivative of curdlan, was chemically modified by conjugation of tetraethylenepentamine. The resulting amphoteric polymers, denoted tetraethylenepentamine-curdlan (TEPAC) polymers have the degree of substitution (DS) ranging from 25% to 48%. The result of MTT assay indicated that TEPAC polymers have negligible cytotoxicity on HeLa cells and A549 cells. The novel amphoteric polymers efficiently bound with plasmid DNA and delivered pcDNA-eGFP plasmid to 293T cells and induced expression of GFP 48h after the transfection. Moreover, TEPAC polymers delivered siRNA to HeLa cells and HepG2 cells in high efficiency, and induced significant RNAi for the expression of an endogenous gene. Collectively, our data demonstrate that the novel curdlan-based amphoteric polymers are biocompatible and may provide a highly efficient system for the delivery of therapeutic nucleic acids. PMID- 28917925 TI - Synthesis of synthetic mannan backbone polysaccharides found on the surface of Mycobacterium tuberculosis as a vaccine adjuvant and their immunological properties. AB - Surface components of Mycobacterium tuberculosis (Mtb) play crucial roles in modulating host immune responses. Thorough understandings of immunological properties of the Mtb's surface components are essential for the development of tuberculosis treatment and prevention. Unfortunately, the accessibility to the molecules on the surface of Mtb is limited by the structural complexity due to their various macromolecular nature and the hazard of culturing Mtb. In this study, we reveal a practical synthesis of lipomannan (LM) backbone polysaccharides - the core glycans found on Mtb's surface. A rapid synthetic approach based on a controlled polymerization was developed for the chemical synthesis of mannopyranans, the core structure of LM. The size of the LM glycans can be controlled by using specific monomer concentrations in addition to stereo- and regioselectivity derived from the versatile tricyclic orthoester mannose monomer. The immunological properties of the synthesized mannopyranans were investigated and their adjuvant potential was revealed. The adjuvanticity mechanism of the synthetic mannopyranans appears to involve the NF-kappaB and inflammasome pathways. PMID- 28917926 TI - Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin. AB - The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films. PMID- 28917927 TI - Utilizing cellulose sheets as structure promoter constructing different micro nano titanate nanotubes networks for green water purification. AB - In this work, we provide a novel strategy of constructing different micro-nano structure (arrayed, multilevel, flower-like) titanate nanotubes (TNTs) networks with cellulose sheets as structure promoter. Through cellulose self-locking and inter-locking, several micro-nano TNTs networks with higher specific surface area are obtained and applied to toxic heavy metal Pb2+ cations removal. It not only makes abundant toxic Pb2+ ions exchange with the inter-layer Na+ ions of TNTs, but also allows many Pb2+ ions to be deposited onto the TNTs surface. As expected, heavy metal Pb2+ removal performance of the as-prepared TNTs networks miraculously reaches 5.24mmolg-1. Moreover, the prepared titanate network is also exhibited a good co-removal capacity of multi-component ions (Pb2+, Sr2+ and Cs+) and superior acid/alkali adaptability. Therefore, the as-fabricated TNTs network with cellulose sheets as structure promoter could be regarded as a promising water purifier. PMID- 28917928 TI - Cell-interactive alginate-chitosan biopolymer systems with tunable mechanics and antibody release rates. AB - This work investigates techniques to produce biocompatible hydrogels with tunable stiffness without the addition of crosslinking agents or altering cell binding sites. Alginate and water-soluble chitosan salts were used to form polyelectrolyte complexes (PECs), where the storage and loss moduli could be increased by raising gelation temperatures. The largest change, a 6.5-fold increase in storage modulus, occurred when the crosslinking temperature was increased from 37 to 50 degrees C while using chitosan with chlorine counterions. Osteogenic MC3T3 cells were shown to have significantly higher proliferation on the stiffer PECs prepared at 50 degrees C compared to 37 degrees C. Gelation temperature showed minimal effect on antibody release, but the inclusion of CaSO4 provided a longer overall release where the rate was nearly linear for several weeks. However, CaSO4 inhibited the strengthening effect of increased gelation temperature. PECs containing glutamate counterions demonstrated an increase in stiffness with decreased chitosan content. PMID- 28917929 TI - Development of carboxymethyl cellulose-chitosan hybrid micro- and macroparticles for encapsulation of probiotic bacteria. AB - Novel carboxymethyl cellulose-chitosan (CMC-Cht) hybrid micro- and macroparticles were successfully prepared in aqueous media either by drop-wise addition or via nozzle-spray methods. The systems were either physically or chemically crosslinked using genipin as the reticulation agent. The macroparticles (ca. 2mm) formed are found to be essentially of the core-shell type, while the microparticles (ca. 5MUm) are apparently homogeneous. The crosslinked particles are robust, thermally resistant and less sensitive to pH changes. On the other hand, the physical systems are pH sensitive presenting a remarkable swelling at pH 7.4, while little swelling is observed at pH 2.4. Furthermore, model probiotic bacteria (Lactobacillus rhamnosus GG) was for the first time successfully encapsulated in the CMC-Cht based particles with acceptable viability count. Overall, the systems developed are highly promising for probiotic encapsulation and potential delivery in the intestinal tract with the purpose of modulating gut microbiota and improving human health. PMID- 28917930 TI - Structural characterization and rheological behavior of a heteroxylan extracted from Plantago notata Lagasca (Plantaginaceae) seeds. AB - Plantago notata (Plantaginaceae) is a spontaneous plant from Septentrional Algerian Sahara currently used by traditional healers to treat stomach disorders, inflammations or wound healing. A water-soluble polysaccharide, called PSPN (PolySaccharide fraction from Plantago Notata), was extracted and purified from the seeds of this semi-arid plant. The structural features of this mucilage were evaluated by colorimetric assays, Fourier transformed infrared spectroscopy (FT IR), gas chromatography coupled to mass spectrometry (GC/MS) and 1H/13C Nuclear Magnetic Resonance (NMR) spectroscopy. PSPN is a heteroxylan with a backbone composed of beta-(1,3)-d-Xylp and beta-(1,4)-d-Xylp highly branched, through (O) 2 and (O)-3 positions of beta-(1,4)-d-Xylp by various side chains and terminal monosaccharides such as alpha-l-Araf-(1,3)-beta-d-Xylp, beta-d-Xylp-(1,2)-beta-d Xylp, terminal Xylp or terminal Araf. The physico-chemical and rheological analysis of this polysaccharide in dilute and semi diluted regimes showed that PSPN exhibites a molecular weight of 2.3*106g/mol and a pseudoplastic behavior. PMID- 28917931 TI - Extraction of soluble arabinoxylan from enzymatically pretreated wheat bran and production of short xylo-oligosaccharides and arabinoxylo-oligosaccharides from arabinoxylan by glycoside hydrolase family 10 and 11 endoxylanases. AB - The enzymatic, ecofriendly pretreatment of wheat bran with alpha-amylase from Bacillus amyloliquifaciens or B. licheniformis at 90 degrees C for 1.5h followed by Neutrase at 50 degrees C for 4h, aqueous liquefaction at 121 degrees C for 15h and ethanol precipitation enabled the production of soluble arabinoxylan (AX) with purity of 70.9% and 68.4% (w/w) respectively. Process alternatives tried, to simplify the process and curtail the cost resulted in AX products with different purities, yields and arabinose to xylose ratio (A/X). Among the two glycoside hydrolase (GH) family endoxylanases evaluated, GH10 family hydrolysed soluble AX more efficiently with xylanase from Geobacillus stearothermophilus T-6 (GsXyn10A) producing maximum amount of quantifiable short xylo-oligosaccharides (XOS) and arabinoxylo-oligosaccharides (AXOS) (53% w/w) followed by the catalytic module of Rhodothermus marinus Xyn10A (RmXyn10A-CM) with 37% (w/w) conversion. The GH11 family endoxylanases, from Thermomyces lanuginosus (Pentopan Mono BGTM) and Neocallimastix patriciarum (NpXyn11A) gave conversions of 21% and 22% (w/w) of the soluble AX, respectively (major AXOS products were not quantified). In addition to the XOS formed such as X2, X3 and X4, the AXOS products identified were A3X and A2XX in the case of GsXyn10A and RmXyn10A-CM while Pentopan Mono BG and NpXyn11A produced XA3XX as the major AXOS product. PMID- 28917932 TI - Rewiring neutral lipids production for the de novo synthesis of wax esters in Rhodococcus opacus PD630. AB - Rhodococcus opacus PD630 accumulates significant amounts of triacylglycerols (TAG), but is not able to de novo synthesize wax esters (WE) from structural unrelated carbon sources, such as gluconate. In this study, strain PD630 was engineered to produce WE by heterologous expression of maqu_2220 gene, which encodes a fatty acyl-CoA reductase for the production of fatty alcohols in Marinobacter hydrocarbonoclasticus. Recombinant cells produced ca. 46% of WE and 54% of TAG (of total WE+TAG) from gluconate compared with the wild type, which produced 100% of TAG. Cell growth was not affected by the heterologous expression of MAQU_2220. Several saturated and monounsaturated WE species were produced by cells, with C18:C16, C16:C16 and C16:C18 as main species. The fatty acid composition of WE fraction in PD630maqu_2220 was enriched with C16:0, C18:0, whereas C16:0, C18:0 and C18:1 predominated in the TAG fraction. Significant amounts of WE and TAG were accumulated by PD630maqu_2220 from whey, an inexpensive waste material from dairy industries, without affecting cell biomass production. This is the first report on WE synthesis by R. opacus from gluconate, which demonstrates that lipid metabolism of this bacterium is flexible enough to assimilate heterologous components for the production of new lipid derivatives with industrial interest. PMID- 28917933 TI - The complete genome sequence of the actinobacterium Streptomyces glaucescens GLA.O (DSM 40922) carrying gene clusters for the biosynthesis of tetracenomycin C, 5'-hydroxy streptomycin, and acarbose. AB - The secondary metabolite acarbose is used worldwide in the clinical treatment of diabetes mellitus type 2 patients. Acarbose is a - glucosidase inhibitor and supports patients to control their blood glucose as well as their serum insulin levels. The secondary metabolite is produced by strains of the class Actinobacteria, in particular from Actinoplanes sp. SE50/110, which is a progenitor of today's production strains. Moreover, secondary metabolite clusters could also be identified in Streptomyces coelicoflavus ZG0656 as well as Streptomyces glaucescens GLA.O. In this study, the genome S. glaucescens GLA.O with focus on the acarbose biosynthesis cluster (gac-cluster) was analyzed. First, the tetracenomycin C and the 5'-hydroxy streptomycin gene clusters could be described completely. Then the gac gene region in S. glaucescens GLA.O is compared to the other known biosynthesis gene cluster. In comparison to Actinoplanes sp. SE50/110 the gac-cluster showed structural variances, like the missing homolog of the glycosyltransferase AcbD in the whole genome of S. glaucescens GLA.O. Due to the lack of the glycosyltransferase, it was of particular interest whether additional acarviose metabolites other than acarbose could be formed. For detection of acarviose metabolites biosynthesis the supernatant of S. glaucescens GLA.O grown in starch supplemented complex media was harvested at 72 and 96 hours. Although a homolog of the known glycosyltransferase is absent, the LC-MS-supported analysis revealed that a spectrum of acarviose metabolites was formed. PMID- 28917934 TI - Congenital absence of the palmaris longus muscle: A meta-analysis comparing cadaveric and functional studies. AB - The aim of our paper was to provide comprehensive data on the prevalence of absence of palmaris longus muscle (PLM) and its anatomical characteristics and conduct two separate meta-analyses comparing cadaveric and functional studies while identifying variation among different ethnic groups. An extensive search was conducted through the major electronic databases to identify eligible articles. Data extracted included prevalence of absence of PLM among subjects, ethnicity, laterality, side, and gender. Our main findings revealed that the absence of PLM is more frequently reported in functional studies. Moreover, functional tests likely overestimated the absence of PLM and recommend future studies to assess the validity of functional tests and use an imaging assessment prior to excluding the use of a palmaris longus tendon graft in patients in whom a function test identified the absence of PLM. PMID- 28917935 TI - Trends in post-mastectomy breast reconstruction types at a breast cancer tertiary referral centre before and after introduction of acellular dermal matrices. AB - BACKGROUND: Reconstructive breast surgery has continued to evolve over the last decade with a key change being the adoption of acellular dermal matrices (ADMs) as an adjunct for implant-based procedures. This retrospective observational study assesses the effect of ADMs on post-mastectomy reconstructive practice performed in a single institution. METHODS: We conducted a review of all patients undergoing breast reconstruction at a University Teaching Hospital for an 18 month period before and after adopting ADMs. Demographic, procedural and complication data for these two cohorts were compared (chi2 and Student's t tests). RESULTS: A total of 264 women (336 breasts), mean age 47.5 years, were identified: 137 before and 127 after the introduction of ADM. Implant-only reconstructions increased from 16% to 52% following the adoption of ADM (p < 0.01), whereas the proportion of both latissimus dorsi and deep inferior epigastric perforator flap reconstructions decreased significantly (31%-11% and 49%-34%, respectively, p < 0.01). The rate of early complications for the implant only procedures was not significantly different with or without ADM (26% versus 20%, respectively, p = 0.44), despite there being no difference in the rate of adjuvant radiotherapy (22% versus 35%, respectively, p = 0.30). CONCLUSIONS: This study showed that since ADM introduction to our centre, more breast reconstructions have been of the implant-only type with consequent reductions in the more complex and expensive autologous techniques. Implant-only procedures that incorporated ADM use had similar complication rates to those that did not. PMID- 28917936 TI - Editorial Comment. PMID- 28917937 TI - Pyrazole-based compounds in chitosan liposomal emulsion for antimicrobial cotton fabrics. AB - The chemistry of pyrazoles has gained increasing attention due to its diverse pharmacological properties such as antiviral, antagonist, antimicrobial, anticancer, anti-inflammatory, analgesic, anti-prostate cancer, herbicidal, acaricidal and insecticidal activities. 1-Phenyl pyrazole-3, 5-diamine, 4-[2-(4 methylphenyl) diazenyl] and 1H- pyrazole-3 (1), 5-diamine, 4-[2-(4-methylphenyl) diazenyl] (2) were synthesized, characterized and encapsulated into liposomal chitosan emulsions for textile finishing. The chemical modifications of cotton fabrics were demonstrated by infrared analysis. Retention of the fabric mechanical properties was investigated by reporting the tensile strength values. Synthesized pyrazole-based compounds were screened for cytotoxicity against skin fibroblast cell line and showed very limited toxicity for both compounds. Antimicrobial potentials of the treated cotton fabrics were tested against bacterial strains E. coli ATCC 8379 and Staphylococcus aureus ATCC 25923. PMID- 28917938 TI - The evaluation of antioxidant and antifungal properties of 6-amino-6 deoxychitosan in vitro. AB - We synthesized 6-amino-6-deoxychitosan (NCS) through a series of reactions from chitosan (CS). The antioxidant ability of CS and NCS were investigated in vitro, including that of DPPH-radical and hydrogen peroxide, reducing power, chelating abilities and inhibition of lipid peroxidation. As expected, after the introduction of amino groups, antioxidant ability had improved significantly. Especially, scavenging effect against DPPH-radical and hydrogen peroxide of NCS were 97% and 92% at 1.6mg/mL, respectively. Moreover, inhibition of lipid peroxidation was 57% at 0.1mg/mL. And the reducing power of NCS was 0.68 at 0.8mg/mL. Meanwhile, inhibitory effects against four fungi were also tested. Antifungal activity of NCS were better than those of CS and antifungal activity had improved more than 20% at 0.5mg/mL against these four kinds of plant pathogens. Based on the above results, it was reasonable to speculate that the obtained antioxidant ability and antifungal activity of NCS might benefit from amino groups on chitosan backbone. These in vitro results suggest the possibility that NCS as antioxidant compound could be effectively alleviate oxidative stress and thus inhibit the oxidative mechanisms that lead to degenerative diseases. PMID- 28917939 TI - Preparation and characterization of gelatin/alpha-TCP/SF biocomposite scaffold for bone tissue regeneration. AB - In this study, we suggest a new biocomposite scaffold composed of gelatin/alpha TCP (tricalcium phosphate)/SF (silk-fibroin) (GTS) which has enhanced mechanical strength and high level of cellular activity. To fabricate GTS scaffold, a temperature-controlled 3D printing process was used and appropriate printing conditions were selected based on rheological data. To show the feasibility as a biomedical scaffold for bone tissue regeneration, the various physical and biological results, using MG63 (osteoblast-like cells), of the GTS scaffold were compared with those of a pure gelatin (G) and gelatin/alpha-TCP (GT) composite scaffold. GTS scaffolds showed enhanced mechanical properties in dry and wet state compared to those of the G and GT scaffolds. Also, significantly high cell proliferation and differentiation of MG63 cells were observed in the GTS scaffold. Therefore, the GTS composite scaffold will be one of highly potential biomaterials to be used in bone regeneration. PMID- 28917940 TI - Natural and synthetic polymers/bioceramics/bioactive compounds-mediated cell signalling in bone tissue engineering. AB - Bone is a highly integrative and dynamic tissue of the human body. It is continually remodeled by bone cells such as osteoblasts, osteoclasts. When a fraction of a bone is damaged or deformed, stem cells and bone cells under the influence of several signaling pathways regulate bone regeneration at the particular locale. Effective therapies for bone defects can be met via bone tissue engineering which employs drug delivery systems with biomaterials to enhance cellular functions by acting on signaling pathways such as Wnt, BMP, TGF beta, and Notch. This review provides the current understanding of polymers/bioceramics/bioactive compounds as scaffolds in activation of signaling pathways for the formation of bone. PMID- 28917941 TI - Skin regeneration effect of the Glycosaminoglycans from Liparis tessellatus eggs. AB - A purified Glycosaminoglycans (GAGs) extract from L. tessellatus eggs was enzyme hydrolyzed and then fractionated with DEAE-Sepharose column chromatography. The fractions were subsequently subjected to skin regeneration effects analysis against skin fibroblast (CCD-986sk) cell lines. Fraction 3 is evidently to have tyrosinase inhibition activity by 20.1% at concentration of 50mg/mL. DOPA oxidation assay, collagenase inhibition activity assay, fibroblast proliferation assay, and production of type I C-peptide assays were done to further proof the skin regeneration effect of GAGs fractions. Results revealed that fraction 3 has effective skin regeneration activities at a concentration of 200mg/mL. PMID- 28917942 TI - In vivo and in vitro testing of native alpha-conotoxins from the injected venom of Conus purpurascens. AB - alpha-Conotoxins inhibit nicotinic acetylcholine receptors (nAChRs) and are used as probes to study cholinergic pathways in vertebrates. Model organisms, such as Drosophila melanogaster, express nAChRs in their CNS that are suitable to investigate the neuropharmacology of alpha-conotoxins in vivo. Here we report the paired nanoinjection of native alpha-conotoxin PIA and two novel alpha conotoxins, PIC and PIC[O7], from the injected venom of Conus purpurascens and electrophysiological recordings of their effects on the giant fiber system (GFS) of D. melanogaster and heterologously expressed nAChRs in Xenopus oocytes. alpha PIA caused disruption of the function of giant fiber dorsal longitudinal muscle (GF-DLM) pathway by inhibiting the Dalpha7 nAChR a homolog to the vertebrate alpha7 nAChR, whereas PIC and PIC[O7] did not. PIC and PIC[O7] reversibly inhibited ACh-evoked currents mediated by vertebrate rodent (r)alpha1beta1deltagamma, ralpha1beta1deltaepsilon and human (h)alpha3beta2, but not halpha7 nAChR subtypes expressed in Xenopus oocytes with the following selectivity: ralpha1beta1deltaepsilon > ralpha1beta1deltagamma ~ halpha3beta2 >> halpha7. Our study emphasizes the importance of loop size and alpha-conotoxin sequence specificity for receptor binding. These studies can be used for the evaluation of the neuropharmacology of novel alpha-conotoxins that can be utilized as molecular probes for diseases such as, Alzheimer's, Parkinson's, and cancer. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' PMID- 28917943 TI - Chronic fluoride exposure exacerbates headkidney pathology and causes immune commotion in Clarias gariepinus. AB - The current study was aimed to understand the effects of chronic fluoride exposure on fish immune system. African sharp tooth catfish (Clarias gariepinus) were exposed to 73.45mg/L of fluoride corresponding to 1/10 96h LC50 for 30 d and the effects on general fish health and several immune parameters were studied. Chronic fluoride exposure led to significant alteration in serum biochemical parameters including alkaline phosphatase, alanine transaminase, aspartate transaminase, triglycerides, cholesterol and blood urea nitrogen levels revealing the detrimental effect of fluoride on general fish health. Upregulation in cytochrome P450 1A expression, both at mRNA and protein level suggested that fluoride activates the detoxification machinery in headkidney (HK) of C. gariepinus. Histopathological analysis of HK from exposed fish further revealed fluoride-induced hypertrophy, increase in melano-macrophage centers (MMCs) and the development of cell-depleted regions. Fluoride reduced headkidney somatic index (HKSI) and the phagocytic potential of headkidney macrophages (HKM). It induced caspase-3-dependent headkidney leukocyte (HKL) apoptosis, elevated superoxide generation and production of pro-inflammatory cytokine TNF-alpha besides suppressed T-cell proliferation in the exposed fish. We surmise the elevation in superoxide levels coupled with increased TNF-alpha production to be plausible causes of fluoride-induced HKL apoptosis. It is concluded that chronic fluoride exposure induces structure-function alterations in HK, the primary lymphoid organ in fish leading to impairment in immune responses. PMID- 28917944 TI - Tetrabromoethylcyclohexane affects gonadal differentiation and development in the frog Pelophylax nigromaculatus. AB - Tetrabromoethylcyclohexane (TBECH), an additive brominated flame retardant, has been shown to have an androgenic activity in vitro. In the present study, we aimed to investigate the effects of TBECH on gonadal differentiation and development in the frog Pelophylax nigromaculatus, an amphibian species sensitive to androgenic chemicals, and to assess the androgenic activity of TBECH in vivo. P. nigromaculatus tadpoles were exposed to TBECH (1, 10, 100nM) from Gosner stage 24 to complete metamorphosis, and to 5alpha-dihydrotestosterone (DHT) as a positive control. We found that 1nM DHT resulted in 100% males, while the sex ratio in the solvent control group was close to 1:1. In all the TBECH treatment groups, sexually ambiguous gonads based on gross morphology and intersexualities with testicular and ovarian histological structures were found, but no abnormality occurred in the solvent control. In the 1, 10, 100nM TBECH treatment groups, the female percentages were 52%, 31%, 17%, with 36%, 56%, 66% for males and 12%, 13%, 17% for abnormal sexes, respectively. X2-test revealed significant differences in sex ratios between the three TBECH groups and the solvent control group, and the sex ratios in the two higher concentration groups were male biased. These observations show that TBECH has a masculinizing effect on gonadal differentiation and development in P. nigromaculatus, suggesting an androgenic activity of TBECH in vivo. To our knowledge, this is the first study demonstrating that TBECH could induce gonadal masculinization in an animal, which raises new concerns for reproductive risk of TBECH exposure. PMID- 28917945 TI - Toxic responses of Perna viridis hepatopancreas exposed to DDT, benzo(a)pyrene and their mixture uncovered by iTRAQ-based proteomics and NMR-based metabolomics. AB - Dichlorodiphenyltrichloroethane (DDT) and benzo(a)pyrene (BaP) are environmental estrogens (EEs) that are ubiquitous in the marine environment. In the present study, we integrated isobaric tags for relative and absolute quantitation (iTRAQ) based proteomic and nuclear magnetic resonance (NMR)-based metabolomic approaches to explore the toxic responses of green mussel hepatopancreas exposed to DDT (10MUg/L), BaP (10MUg/L) and their mixture. The metabolic responses indicated that BaP primarily disturbed energy metabolism and osmotic regulation in the hepatopancreas of the male green mussel P. viridis. Both DDT and the mixture of DDT and BaP perturbed the energy metabolism and osmotic regulation in P. viridis. The proteomic responses revealed that BaP affected the proteins involved in energy metabolism, material transformation, cytoskeleton, stress responses, reproduction and development in green mussels. DDT exposure could change the proteins involved in primary metabolism, stress responses, cytoskeleton and signal transduction. However, the mixture of DDT and BaP altered proteins associated with material and energy metabolism, stress responses, signal transduction, reproduction and development, cytoskeleton and apoptosis. This study showed that iTRAQ-based proteomic and NMR-based metabolomic approaches could effectively elucidate the essential molecular mechanism of disturbances in hepatopancreas function of green mussels exposed to environmental estrogens. PMID- 28917946 TI - Cellular uptake and intracellular localization of poly (acrylic acid) nanoparticles in a rainbow trout (Oncorhynchus mykiss) gill epithelial cell line, RTgill-W1. AB - The ever-growing production of engineered nanoparticles (NPs) for use in many agricultural, commercial, consumer, and industrial applications will lead to their accidental or intentional release into the environment. Potential routes of environmental exposure include manufacturing or transport spills, disposal of NP containing products down the drain and/or in landfills, as well as direct usage on agricultural land. Therefore, NPs will inevitably contaminate aquatic environments and interact with resident organisms. However, there is limited information regarding the mechanisms that regulate NP transport into fish from the environment. Thus, our primary objective was to elucidate the mechanism(s) underlying cellular uptake and intracellular fate of 3-9nm poly (acrylic acid) NPs loaded with the fluorescent dye Nile red using a rainbow trout (Oncorhynchus mykiss) gill epithelial cell line (RTgill-W1). In vitro measurements with NP treated RTgill-W1 cells were carried out using a combination of laser scanning confocal microscopy, flow cytometry, fluorescent biomarkers (transferrin, cholera toxin B subunit, and dextran), endocytosis inhibitors (chlorpromazine, genistein, and wortmannin), and stains (4', 6-diamidino-2-phenylindole, Hoechst 33342, CellMask Deep Red, and LysoTracker Yellow). Clathrin-mediated endocytosis (CME), caveolae-mediated endocytosis and macropinocytosis pathways were active in RTgill W1 cells, and these pathways were exploited by the non-cytotoxic NPs to enter these cells. We have demonstrated that NP uptake by RTgill-W1 cells was impeded when clathrin-coated pit formation was blocked by chlorpromazine. Furthermore, colocalization analysis revealed a moderate positive relationship between NPs and LysoTracker Yellow-positive lysosomal compartments indicating that CME was the dominant operative mechanism involved in NP internalization by RTgill-W1 cells. Overall, our results clearly show that fish gill epithelial cells internalized NPs via energy-dependent endocytotic processes. This study enhances our understanding of complex NP-cell interactions and the results obtained in vitro imply a potential risk to aquatic organisms. PMID- 28917947 TI - Effect of meal glycemic load and caffeine consumption on prolonged monotonous driving performance. AB - OBJECTIVE: Monotonous driving involves low levels of stimulation and high levels of repetition and is essentially an exercise in sustained attention and vigilance. The aim of this study was to determine the effects of consuming a high or low glycemic load meal on prolonged monotonous driving performance. The effect of consuming caffeine with a high glycemic load meal was also examined. METHOD: Ten healthy, non-diabetic participants (7 males, age 51+/-7yrs, mean+/-SD) completed a repeated measures investigation involving 3 experimental trials. On separate occasions, participants were provided one of three treatments prior to undertaking a 90min computer-based simulated drive. The 3 treatment conditions involved consuming: (1) a low glycemic load meal+placebo capsules (LGL), (2) a high glycemic load meal+placebo capsules (HGL) and (3) a high glycemic load meal+caffeine capsules (3mgkg-1 body weight) (CAF). Measures of driving performance included lateral (standard deviation of lane position (SDLP), average lane position (AVLP), total number of lane crossings (LC)) and longitudinal (average speed (AVSP) and standard deviation of speed (SDSP)) vehicle control parameters. Blood glucose levels, plasma caffeine concentrations and subjective ratings of sleepiness, alertness, mood, hunger and simulator sickness were also collected throughout each trial. RESULT: No difference in either lateral or longitudinal vehicle control parameters or subjective ratings were observed between HGL and LGL treatments. A significant reduction in SDLP (0.36+/-0.20m vs 0.41+/-0.19m, p=0.004) and LC (34.4+/-31.4 vs 56.7+/-31.5, p=0.018) was observed in the CAF trial compared to the HGL trial. However, no differences in AVLP, AVSP and SDSP or subjective ratings were detected between these two trials (p>0.05). CONCLUSION: Altering the glycemic load of a breakfast meal had no effect on measures of monotonous driving performance in non-diabetic adults. Individuals planning to undertake a prolonged monotonous drive following consumption of a morning meal may consider consuming caffeine as a means of improving vehicle control. PMID- 28917948 TI - Effects of methamphetamine on alloparental behavior in male and female prairie voles. AB - Psychostimulant abuse is associated with a variety of impairments in social functioning, including an increased frequency of depression and aggression and deficits in social cognition. Psychostimulants reduce social investigation in rats and mice; however, it is less clear how other forms of social behavior (e.g., prosocial behavior) are affected. Females are also generally more sensitive to the effects of psychostimulants on locomotion and stereotyped behavior, which suggests that females might also display greater disruption of prosocial behavior. In order to test the hypothesis that psychostimulants reduce prosocial behavior and that females are more vulnerable, we treated adult male and female prairie voles with methamphetamine for three days (0, 0.2 or 2.0mg/kg, i.p.) and examined effects on locomotion and alloparental behavior. The lower methamphetamine dose increased activity in the open field in males and reduced locomotion in females. Methamphetamine-treated males took longer to enter the pup chamber, but both sexes displayed reduced pup contact following treatment with the lower methamphetamine dose. The methamphetamine-induced reduction in prosocial behavior was not associated with changes in pup-directed aggression in males or females. In order to investigate potential mechanisms underlying these changes in behavior, we measured adrenal weights as a proxy for activation of the hypothalamic-pituitary-adrenal (HPA) axis. The higher methamphetamine dose increased adrenal weights. Collectively, these data demonstrate that methamphetamine administration reduces alloparental behavior in both sexes and that females are more sensitive to some of the effects of this drug (e.g., locomotion/stereotyped behavior and possibly stimulation of the HPA axis). PMID- 28917949 TI - Linear association between number of modifiable risk factors and multiple chronic conditions: Results from the Behavioral Risk Factor Surveillance System. AB - Multiple (>=2) chronic conditions (MCCs) are responsible for a large fraction of healthcare costs. Our aim was to examine possible associations between MCCs and composite measures of behavioral risk factors (RFs). Data were publicly available 2013 Behavioral Risk Factor Surveillance System and included 483,865 non institutionalized US adults ages >=18years. Chronic conditions included asthma, arthritis, chronic obstructive pulmonary disease, cognitive impairment, heart disease, stroke, cancer, and kidney disease. RFs included obesity, current smoking, sedentary lifestyle, inadequate fruit and vegetable consumption, and sleeping other than 7-8h, while depression, hypertension, high cholesterol, and diabetes were considered in each category. Stata was used to study associations between 2 different MCCs and 2 composite measures of RFs in both unadjusted and adjusted analysis. Over 96% of respondents reported >=1 of the 9 RFs and 71.5% reported >=1 of the chronic conditions. For each combination there was a linear increase (with similar slopes) in MCC rate with more RFs and a statistically significant increase in adjusted odds ratios (ORs) for the MCC with each additional RF. For the MCC based on 8 chronic conditions, ORs were 1.3 (95% CI 1.1, 1.6) for 1 RF, 2.3 (1.9, 2.7) for 2, 3.7 (3.1, 4.4) for 3, 5.7 (4.8, 6.8) for 4, 9.1 (7.6, 10.8) for 5, 14.6 (12.2, 17.4) for 6, 24.0 (19.7, 29.2) for 7, 38.1 (29.6, 48.9) for 8, and 100.0 (56.3, 177.8) for all 9, each vs. zero RFs. Findings highlight the need for effective integrated programs to address multiple RFs and chronic conditions. PMID- 28917950 TI - Suicide behavior and associated psychosocial factors among adolescents in Campeche, Mexico. AB - Suicide is an important public health problem that requires a preventive approach. The present study aimed at assessing suicidal behaviors and their relations with other psychosocial factors in Campeche, Mexico, in order to inform the design of potential preventive interventions. A multistage probability sample of 2386 students representative of all middle schools of the state of Campeche, Mexico, took a standardized, paper-and-pencil survey covering selected psychosocial constructs including suicide behavior, depression, drug use, familial relationships, locus of control, impulsivity, and self-esteem, among others. Latent classes were identified and multinomial logistic regression was used to analyze associations between class membership and psychosocial covariates. An estimated 8% of the middle school population in Campeche had three or more psychosocial problems in the past month including drug use, major depression episode symptoms, as well as suicidal problems like attempts and self inflicted injuries. Four latent classes were identified, one with lowest risk and three with varying characteristics in terms of binge alcohol and other drug use, depression, and suicide behaviors. Associations between psychosocial covariates and latent class were observed, as predicted based on a multi-dimensional theoretical framework. Heterogeneity across "High-Risk" groups and their potential determinants highlight the need for differentiated, specialized efforts ranging from universal to indicated interventions. Given the high level of risk factors in this population, universal preventive interventions should aim at building resiliency among youth by helping them develop an array of coping resources, as well as by creating a more nurturing psychosocial environment. PMID- 28917951 TI - A spatial analysis of race, local health-promoting resources and preventable hospitalizations. AB - INTRODUCTION: Preventable hospitalizations (PHs) for chronic conditions could have been avoided if treated with primary healthcare. PH rates are higher among African Americans, and in areas with less healthcare. Little is known about the effects of non-healthcare local health-promoting resources (LHPRs). The objective of this study is to determine associations between LHPRs and chronic PH rates in Maryland, and to assess spatial clustering of areas with high PH rates. METHODS: Hospitalizations in 2010 were obtained from the Maryland Health Services Cost Review Commission by zip code of residence. Negative binomial regressions were used to determine associations between PH rates and LHPRs by race. Clusters of zip codes with high PH rates were assessed using the spatial Scan Statistic. RESULTS: PH rates were associated with family practitioners (IRR=0.98, 95% CI=0.97-0.99), physicians' assistants (IRR=0.98, 95% CI=0.96-0.99), internists (IRR=1.02, 95% CI=1.01-1.03), teaching hospitals (IRR=1.21, 95% CI=1.04-1.40), and local health departments (IRR=1.19, 95% CI=1.03-1.37). No LHPRs were associated with PHs among whites, but African American PH rates were associated with family practitioners (IRR=0.97, 95% CI=0.94-0.99), nurse practitioners (IRR=1.03, 95% CI=1.01-1.06), teaching hospitals (IRR=1.37, 95% CI=1.08-1.75) and gyms/recreational centers (IRR=0.85, 95% CI=0.73-0.99). Clusters of areas with high PH rates varied by race. African American PH clusters had fewer family practitioners and more federally qualified health centers and teaching hospitals. CONCLUSIONS: Public health practitioners should look to LHPRs beyond physician supply or public clinics to address PHs, particularly among African Americans. Specific LHPRs could be used to target African American PH rates and clusters. PMID- 28917952 TI - Identification of potential allosteric communication pathways between functional sites of the bacterial ribosome by graph and elastic network models. AB - BACKGROUND: Accumulated evidence indicates that bacterial ribosome employs allostery throughout its structure for protein synthesis. The nature of the allosteric communication between remote functional sites remains unclear, but the contact topology and dynamics of residues may play role in transmission of a perturbation to distant sites. METHODS/RESULTS: We employ two computationally efficient approaches - graph and elastic network modeling to gain insights about the allosteric communication in ribosome. Using graph representation of the structure, we perform k-shortest pathways analysis between peptidyl transferase center-ribosomal tunnel, decoding center-peptidyl transferase center - previously reported functional sites having allosteric communication. Detailed analysis on intact structures points to common and alternative shortest pathways preferred by different states of translation. All shortest pathways capture drug target sites and allosterically important regions. Elastic network model further reveals that residues along all pathways have the ability of quickly establishing pair-wise communication and to help the propagation of a perturbation in long-ranges during functional motions of the complex. CONCLUSIONS: Contact topology and inherent dynamics of ribosome configure potential communication pathways between functional sites in different translation states. Inter-subunit bridges B2a, B3 and P-tRNA come forward for their high potential in assisting allostery during translation. Especially B3 emerges as a potential druggable site. GENERAL SIGNIFICANCE: This study indicates that the ribosome topology forms a basis for allosteric communication, which can be disrupted by novel drugs to kill drug resistant bacteria. Our computationally efficient approach not only overlaps with experimental evidence on allosteric regulation in ribosome but also proposes new druggable sites. PMID- 28917953 TI - Migratory capacity and function of dendritic cells from mesenteric afferent lymph nodes after feeding a single dose of vitamin A. AB - Lamina propria dendritic cells (DCs) have a permanent turnover with constitutive migration to mesenteric lymph nodes and replenishment by progenitors. Luminal bacteria and dietary constituents provide key signals that endow DCs their unique properties in vivo. Taking into account that the intestinal immune system is greatly influenced by retinoids, we evaluated in B6 mice 3, 8, 16 and 24 h after feeding a single dose of vitamin A phenotype and function of cells present in mesenteric afferent lymph nodes as well as signals involved in migration. We studied the frequency of CD11c+MHC-II+CD103+CD86+ and RALDH+ DCs by flow cytometry, we determined CCL-21 and D6 levels in tissue homogenates by Western blot, and we co-cultured cells isolated from afferent lymphatics with sorted CD4+ lymphocytes to assess Foxp-3 induction and homing receptor expression. Sixteen hours after vitamin A administration, DCs isolated from afferent lymphatics were able to induce homing receptors and Foxp3 expression in CD4+ lymphocytes. Our results show that a single dose of vitamin A generated a stream of signals and amplified the tolerogenic activity of DCs migrating to lymphoid tissue. PMID- 28917954 TI - "Striatal Toe Sign": False-Positive "Extensor Plantar Response" in Dystonia. PMID- 28917955 TI - Lidocaine Gel for Urethral Catheterization in Children: A Meta-Analysis. AB - OBJECTIVE: To compare the efficacy and safety of lidocaine gel vs nonanesthetic gel (NAG) in reducing transurethral bladder catheterization (TUBC) procedural pain in children. STUDY DESIGN: A systematic literature search was done using electronic medical databases and trial registries up to September 2016 with no language restrictions. Randomized controlled trials (RCTs) that assessed the efficacy and safety of lidocaine gel vs NAG in reducing TUBC-associated pain in children were screened, identified, and appraised. Risks of bias and study quality of the eligible trials were assessed according to the Cochrane Collaboration recommendations. Various pain assessment scales from the included studies were extracted as mean differences and standard deviations for each treatment group. Standardized mean differences (SMDs) were generated with 95% CIs for between-group difference estimation. Effect estimates were pooled using the inverse variance method with a random-effects model. Subgroup analysis was performed for different age groups. RESULTS: Five RCTs (with a total of 369 children) were included. Overall pooled effect estimates showed that compared with NAG, lidocaine gel has no significant benefit in decreasing TUBC-associated pain in children (SMD, -0.22; 95% CI, -0.65 to 0.21). Effect estimates from 4 studies revealed no difference in pain reduction between the lidocaine gel and NAG in children aged <4 years (SMD, 0.01; 95% CI, -0.22 to 0.24). No serious adverse events from the lidocaine gel use were reported in any of the studies. CONCLUSIONS: Lidocaine gel does not appear to reduce TUBC pain compared with NAG, specifically in children aged <4 years. PROSPERO REGISTRATION NUMBER: CRD42016050018. PMID- 28917956 TI - Bowel Dilation Diagnosed Prenatally. PMID- 28917957 TI - Betty Kirkwood: trailblazer in global health epidemiology. PMID- 28917958 TI - The path to longer and healthier lives for all Africans by 2030: the Lancet Commission on the future of health in sub-Saharan Africa. PMID- 28917959 TI - Ann Ashworth: pioneer in child nutrition. PMID- 28917960 TI - Response to an African-driven health agenda. PMID- 28917961 TI - Africa and health: a Commission to accelerate success. PMID- 28917962 TI - Longer and healthier lives for all Africans by 2030: perspectives and action of WHO AFRO. PMID- 28917963 TI - An efficient computational fluid-particle dynamics method to predict deposition in a simplified approximation of the deep lung. AB - High-fidelity simulations of the complete airway tree are still largely beyond current computational capabilities. Towards large-scale simulations of the human lung, the current study introduces a numerical methodology to predict particle deposition in a simplified approximation of the deep lung during a full breathing cycle. The geometrical model employed consists of an idealised bronchial tree that represents generations 10 to 19 of the conducting zone and a heterogeneous acinar model created using a space-filling algorithm. The computational cost of the coupled simulation is reduced by taking advantage of the flow similarity across the central conducting regions in order to decompose the bronchial tree into representative subunits. Topological information is used to account for the correct gravitational force on the particles in the representative bifurcations, emulating their transport characteristics in the actual bronchial tree. Eventually, airflow and particle transport are simulated in a single representative bifurcation and a single acinar model, resulting in great savings in computational cost. An Eulerian-Lagrangian approach has been used for solving the flow and particle equations during sinusoidal breathing in the decomposed domain. The resulting deposition estimates agree rather well with the known deposition trends reported in the literature, while offering additional insights. For 1-5MUm particles, deposition during exhalation is comparable to deposition upon inhalation, suggesting the use of breath-hold maneuvers to further increase sedimentation of these particles. Airway orientation relative to gravity was found to have a significant impact on deposition rates, especially for particles above 2MUm and to be higher in the more distal generations, due to the wider range of angles relative to the direction of gravity. In the acinus, particles in the 2-5MUm range have a quite high average deposition efficiency that reaches approximately 75% and shows considerable variation (12.4%) due to airway orientation. Finally, a simplified semi-analytical approach is introduced that can lead to even further reduction in computational costs, while incurring only a small loss in accuracy. PMID- 28917964 TI - Phenazopyridine-phthalimide nano-cocrystal: Release rate and oral bioavailability enhancement. AB - Both cocrystal and nanocrystal technologies have been widely used in the pharmaceutical development for poorly soluble drugs. However, the synergistic effects due to the integration of these two technologies have not been well investigated. The aim of this study is to develop a nano-sized cocrystal of phenazopyridine (PAP) with phthalimide (PI) to enhance the release rate and oral bioavailability of PAP. A PAP-PI nano-cocrystal with particle diameter of 21.4+/ 0.1nm was successfully prepared via a sonochemical approach and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic light scattering (DLS) analysis. An in vitro release study revealed a significant release rate enhancement for PAP PI nano-cocrystal as compared to PAP-PI cocrystal and PAP hydrochloride salt. Further, a comparative oral bioavailability study in rats indicated significant improvement in Cmax and oral bioavailability (AUC0-infinity) by 1.39- and 2.44 fold, respectively. This study demonstrated that this novel nano-cocrystal technology can be a new promising option to improve release rate and absorption of poorly soluble compounds in the pharmaceutical industry. PMID- 28917965 TI - The development of a butyrylcholinesterase porous pellet for innovative detection of cholinesterase inhibitors. AB - The aim of the presented research was the preparation of an innovative carrier with significantly improved properties for the fast and sensitive detection of cholinesterase inhibitors such as nerve agents. This innovative carrier was in the form of spherical pellets containing different amounts of Neusilin. Neusilin is a synthetic and amorphous form of magnesium aluminometasilicate with a high specific surface area, and the immobilized enzyme butyrylcholinesterase with an activity of 50nkat.g-1. Pellets were prepared by the extrusion-spheronization method and dried in a hot air oven under two conditions - at 30 degrees C for 72h and at 60 degrees C for 24h. Dried pellets were consequently impregnated with a solution containing butyrylcholinesterase. Impregnated pellets were evaluated for their quality parameters, enzymatic activity and inhibition. Activity and inhibition were tested according to the standard Ellman's method. It was observed that the addition of Neusilin significantly increased the hardness, intraparticular porosity, sphericity and activity of the carriers as well as intensity of the color transition. Therefore it is shown that these carriers have unquestionable advantages over common carriers of their kind. Drying temperatures have been shown to have no effect on properties of pellets except for a change in their size. Results were confirmed by statistical evaluation using ANOVA and PCA. PMID- 28917966 TI - Shrinkage in oral squamous cell carcinoma: An analysis of tumor and margin measurements in vivo, post-resection, and post-formalin fixation. AB - PURPOSE: To quantify changes in tumor size and tumor-free margins following surgical resection and formalin fixation of oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Nineteen patients were studied via cohort design. Between May and December 2011, measurements of tumor size and tumor-free margin were made in patients with squamous cell carcinoma of the oral cavity. Mucosal reference points were marked with sutures, representing tumor diameter and two separate resection margins. Measurements were recorded immediately before resection, after resection, and following fixation in formalin. RESULTS: The overall mean shrinkage in tumor size was 10.7% (95% CI 3.4-18.0, p=0.006). When comparing mean tumor measurements, most of the tumor size decrease (6.4%, 95% CI 0.4-12.4, p=0.039) occurred between pre- and post-excision measurements. To a lesser extent, tumor size decreased following formalin fixation. Comparison of tumor free margin measurements revealed a pre-excision to post-fixation mean decrease of 11.3% (95% CI 2.9-19.6%, p=0.011), with a statistically significant decrease of 14.9% (95% CI 8.5-21.3%, p<0.001) occurring between pre- and post-excision, and no significant decrease from post-excision to post-formalin fixation. CONCLUSION: Mucosal dimensions of both tumor and tumor-free margins in oral cavity squamous cell carcinoma specimens decrease between surgical resection and pathologic analysis. Most of this decrease occurs prior to fixation, especially for margins, and may be due to intrinsic tissue properties rather than formalin effects. PMID- 28917967 TI - Synthesis of a trisaccharide repeating unit of the O-antigen from Burkholderia cenocepacia and its dimer. AB - The trisaccharide repeating unit of an O-antigen derived from Burkholderia cenocepacia and its dimer, i.e., alpha-L-Rhap-(1 -> 3)-alpha-D-GalpNAc-(1 -> 3) beta-D-GalpNAc-O(CH2)3N3 (1) and alpha-L-Rhap-(1 -> 3)-alpha-D-GalpNAc-(1 -> 3) beta-D-GalpNAc-(1 -> 4)-alpha-L-Rhap-(1 -> 3)-alpha-D-GalpNAc-(1 -> 3)-beta-D GalpNAc-O(CH2)3N3 (2), respectively, were synthesized via a highly convergent strategy. Glycosylation of galactosaminyl acceptor 4 with galactosaminyl trichloroacetimidate donor 5 was followed by condensation of resulting disaccharide acceptor 12 with rhamnosyl imidate donor 6 to furnish stereoselectively trisaccharyl thioglycoside 3, which was used as a key and common glycosyl donor for the construction of both 1 and 2. Title molecule 1 was prepared by glycosylation of 3-azidopropanol with 3 and subsequently global deprotection, whereas coupling reaction of 3 with a trisaccharide acceptor 21 containing an 2,3-O-position acetonide-modified rhamnose residue, followed by global deprotection, generated the dimer 2 in a convergent [3 + 3] manner. PMID- 28917968 TI - The effect of fennel essential oil in combination with antibiotics on Staphylococcus aureus strains isolated from carriers. AB - An increase in the number of staphylococcal infections and carriers among medical staff has forced us to seek more and more effective antibacterial agents. Bacteria from the Staphylococcus genus possessing different mechanisms of resistance are the cause of nosocomial infections. The objective of our investigations was susceptibility of S. aureus strains isolated from nasal vestibule of medical students to fennel essential oil. The GC-MS analysis of fennel essential oil revealed eleven constituents among which a majority of trans anethole (80%) was found. The D-tests showed iMLSB (80%), cMLSB and MSB (10%) resistant phenotypes of S. aureus. The S. aureus isolates were intermediate to mupirocin (45%). Fennel essential oil increased the inhibition zone around cefoxitin, mupirocin, co-trimoxazole and ciprofloxacin with statistical significance. Our research showed that the fennel essential oil in combination with mupirocin may be considered as a natural alternative in eradication of S. aureus with iMLSB, cMLSB, MSB resistant phenotypes and is able to decrease the growth rate of antibiotic resistance. PMID- 28917969 TI - Hysterectomy for the Transgendered Male: Review of Perioperative Considerations and Surgical Techniques with Description of a Novel 2-Port Laparoscopic Approach. AB - Transgendered individuals can suffer a significant amount of psychological distress that can be alleviated through hormonal treatments and/or gender affirming surgery. The World Professional Association for Transgender Health considers a hysterectomy and bilateral salpingo-oophorectomy medically necessary gender-affirming procedures for the interested transgendered male. Several surgical approaches have been described in the literature, most of which endorse a laparoscopic approach. This review summarizes the available literature on surgical techniques in addition to reporting our institutional outcomes using a novel 2-port laparoscopic approach. Additional preoperative and perioperative considerations are needed when caring for this patient population and are reviewed. PMID- 28917970 TI - How Do Enzymes 'Meet' Nanoparticles and Nanomaterials? AB - Enzymes are fundamental biological catalysts responsible for biological regulation and metabolism. The opportunity for enzymes to 'meet' nanoparticles and nanomaterials is rapidly increasing due to growing demands for applications in nanomaterial design, environmental monitoring, biochemical engineering, and biomedicine. Therefore, understanding the nature of nanomaterial-enzyme interactions is becoming important. Since 2014, enzymes have been used to modify, degrade, or make nanoparticles/nanomaterials, while numerous nanoparticles/nanomaterials have been used as materials for enzymatic immobilization and biosensors and as enzyme mimicry. Among the various nanoparticles and nanomaterials, metal nanoparticles and carbon nanomaterials have received extensive attention due to their fascinating properties. This review provides an overview about how enzymes meet nanoparticles and nanomaterials. PMID- 28917971 TI - How Fast Is Protein-Ligand Association? AB - There is increasing interest in studying protein interactions and their role in cell biology using kinetics. However, there is confusion about the proper terminology in terms of the distinction between rates and rate constants. We recommend a more stringent use of the words speed, fast, slow, rate, and rate constant. PMID- 28917972 TI - Research on the antioxidant, wound healing, and anti-inflammatory activities and the phytochemical composition of maritime pine (Pinus pinaster Ait). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical investigations have shown that the Pinus species have been used against rheumatic pain and for wound healing in Turkish folk medicine. MATERIAL AND METHODS: In this study, phytochemical composition, antioxidant, anti-inflammatory, and wound healing activities of Maritime Pine (Pinus pinaster Ait.) that is collected in Turkey are investigated. Essential oil composition and the amount of extracts (lipophilic and hydrophilic) of maritime pine wood and fresh cone samples had been tested. RESULTS: The essential oil from cones of P. pinaster revealed the highest activities, whereas other parts of the plant did not display any appreciable wound healing, anti inflammatory, or antioxidant effects. alpha-Pinene was the main constituent of the essential oil obtained from the cones of P. pinaster. CONCLUSION: Experimental studies shown that P. pinaster's remarkable anti-inflammatory and wound healing activities support the traditional use of the plant, and suggest it could have a place in modern medicine. PMID- 28917973 TI - Inhibitory effects of Dianthi Herba ethanolic extract on inflammatory and nociceptive responses in murine macrophages and mouse models of abdominal writhing and ear edema. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dianthi Herba is a traditional herbal medicine used to treat inflammatory-related diseases including acute pyelonephritis, cystitis, laryngopharyngitis, and urethritis. AIM OF THE STUDY: We investigated the effects of Dianthi Herba ethanolic extract (DH) on lipopolysaccharide (LPS) mediated inflammatory responses in murine macrophages including RAW 264.7 cell line and mouse peritoneal macrophages as well as nociceptive and edema mouse models. MATERIALS AND METHODS: The biological effects of DH on inflammatory cytokine, mediator, and related protein production were assessed using enzyme linked immunosorbent assay (ELISA), Western blotting, and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR). Additionally, Western blotting was performed to investigate intracellular signaling pathways, and the anti-nociceptive activity of three doses of DH (100, 200, and 300mg/kg) against acetic acid-induced writhing responses and its inhibitory effects on xylene induced ear edema were researched in mice through oral administration. RESULTS: DH treatment significantly inhibited nitric oxide (NO) secretion and inflammatory cytokine production in RAW 264.7 cells and mouse peritoneal macrophages and induced heme oxygenase (HO)-1 expression. DH strongly inhibited the transcriptional activity of nuclear factor (NF)-kappaB and phosphorylation of mitogen-activated protein kinases (MAPK) in LPS-stimulated macrophages. Meanwhile, DH exerted anti-nociceptive effects on writhing responses and anti edema effects in mice. CONCLUSION: We confirmed the anti-inflammatory activities and inhibitory mechanism of DH in macrophages and clarified its inhibitory effects in vivo. These findings illustrate the therapeutic potential of DH as a natural anti-inflammatory agent. PMID- 28917974 TI - Cross-Cultural Analysis of Medicinal Plants commonly used in Ethnoveterinary Practices at South Waziristan Agency and Bajaur Agency, Federally Administrated Tribal Areas (FATA), Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In remote areas, medicinal plants have an imperative role in curing various livestock's ailments. In Pakistan, people residing in remote areas including South Waziristan Agency and Bajaur Agency depend on traditional herbal remedies for treating their domestic animals. Medicinal plants are an important part of the medical system in these Agencies. The prime goal of the current study is to explore the ethnoveterinary practices in the two regions and discuss cross-cultural consensus on the use of medicinal plants. In this study, we have given detailed description on the ethnoveterinary usage of certain medicinal plants and their recipes. Moreover, we have also elaborated the ethnoveterinary potential of certain plants in relation to their ethnomedicinal, pharmacological and phytochemicals reports. METHODOLOGY: Fieldwork comprised of two fields surveys conducted at South Waziristan Agency and Bajaur Agency. A total of 75 informants from South Waziristan Agency and 80 informants from Bajaur Agency were interviewed with the help of semi-structured questionnaires. Use reports (URs) were recorded for all the documented taxa. Data were quantitatively analyzed by using informant consensus factor (Fic) index in order to find out information homogeneity provided by the informants. To analyze the cross-cultural consensus, the recorded data were tabulated as well as shown by Venn diagram. RESULTS: Overall, 94 medicinal plant taxa were recorded in the comparative analysis. Out of these, most of the plants species (72 species) were used at Bajaur Agency than South Waziristan Agency (37 species). Cross-cultural analysis showed that only 15 medicinal plants were used in common by the indigenous communities in both Agencies, which indicates a low interregional consensus with regard to the ethnoveterinary practices of medicinal plants. Apiaceae was the dominant family in both regions by representing maximum number of plant species (11 species). Gastro intestinal complexities were common in both regions having higher Fic values (above 90). Moreover, the current investigation reported new ethnoveterinary uses of medicinal plants from South Waziristan Agency, which were Sideroxylon mascatense, Raphanus sativus, Salix babylonica, Solanum nigrum, Sophora mollis, Taraxacum campylodes and Tulipa stellata. On the other hand from Bajaur Agency, Boerhavia erecta, Celtis australis, Chamaecyparis obtusa var. obtuse, Eryngium biehersteinianum, Gossypium arboreum, Narcissus tazetta, Opuntia littoralis, Streblus asper were reported with new ethnoveterinary uses. CONCLUSIONS: The current study has an important contribution towards the preservation of indigenous plants' based knowledge. Several plants are carrying important ethnoveterinary uses being practiced by the local people mostly against the gastrointestinal disorders in both regions. Importantly, the cross-cultural approach has reported some new traditional uses of plants against livestock's diseases. Hence, this is an opportunity to investigate such plants phytopharmacologically and toxicologically for the discovery of new drug sources. PMID- 28917975 TI - The memory ameliorating effects of DHP1402, an herbal mixture, on cholinergic blockade-induced cognitive dysfunction in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F Chow (Rhamnaceae) and the roots of Codonopsis lanceolata (Siedbold & Zucc.) Benth. & Hook. f ex Trautv. (Campanulaceae), contained in the DHP1402, have long been used for treating dementia or hypomnesia as folk medicine. AIM OF THE STUDY: It has been reported that Z. jujuba var. spinosa and C. lanceolata are effective in improving cognitive function, but via different mechanisms. Therefore, in the present study, we evaluated the synergistic effects of Z. jujuba var. spinosa and C. lanceolata on scopolamine-induced memory impairment. MATERIALS AND METHODS: Scopolamine, a cholinergic muscarinic receptor antagonist, was used to induce cognitive dysfunction. We employed several behavioral tasks to estimate the synergistic effect of the seeds of Z. jujuba var. spinosa and the roots of C. lanceolata. In addition, we introduced the Western blotting, the antagonism passive avoidance task to investigate a synergistic effect of an herbal formulation. RESULTS: Synergistic effects of a combination of Z. jujuba var. spinosa and C. lanceolata at a 5:1 ratio [(w/w), DHP1402] were observed against cognitive dysfunction in the passive avoidance and Y-maze tasks. DHP1402 also ameliorated memory deficits in a dose-dependent manner in these behavioral tasks, as well as in the Morris water maze task. According to the Western blot results, the phosphorylation levels of protein kinase A (PKA), extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus were also increased in a synergistic manner after the administration of DHP1402. In addition, we found that the effects of DHP1402 on cognitive function were mediated by N-methyl-D-aspartate (NMDA) receptor signalling, based on the antagonism studies. Furthermore, we found that DHP1402 has inhibitory activity against acetylcholinesterase (AChE). CONCLUSION: DHP1402 attenuates cholinergic blockade-induced cognitive dysfunction through NMDA receptor modulation, PKA-ERK-CREB pathway activation, and AChE inhibition. Therefore, DHP1402 could be a candidate for alleviating cognitive dysfunction. PMID- 28917976 TI - Low molecular weight fucoidan ameliorates hindlimb ischemic injury in type 2 diabetic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Low molecular weight fucoidan (LMWF), extracted from Laminaria japonica Areschoug, is a traditional Chinese medicine, commonly used to alleviate edema, particularly for feet with numbness and pain. AIM OF THE STUDY: Diabetic mellitus (DM) patients are at high risk of developing peripheral arterial disease (PAD). Individuals with DM and PAD co-morbidity have a much higher risk of critical limb ischemia. LMWF showed several beneficial effects, such as anti-inflammation, anti-thrombosis, and enhancing revascularization. Therefore, we hypothesized that LMWF might be beneficial to diabetes-induced PAD, and investigated the therapeutic potential of LMWF on diabetic PAD rats. MATERIALS AND METHODS: Type 2 diabetic Goto-Kakizaki (GK) rats were made PAD by injection of sodium laurate into femoral artery. LMWF (20, 40 or 80mg/kg/day) or cilostazol (100mg/kg/day) were given to diabetic PAD rats for 4 weeks, respectively. The effects of LMWF on foot ulceration and claudication, plantar blood flow, collateral vessel formation, endothelium morphology, gastrocnemius injury, platelet aggregation, vessel vasodilation, and the expressions of inflammation factors, VEGF, eNOS, and nitric oxide were measured. RESULTS: We found that LMWF markedly ameliorated foot ulceration and claudication, and improved the plantar perfusion by reversing hyperreactive platelet aggregation, ameliorating endothelium-dependent vasodilation and revascularization on diabetic PAD rats. In addition, upregulation of several inflammatory factors, such as ICAM 1 and IL-1beta in the gastrocnemius muscles of ischemic hindlimb were suppressed by LMWF administration. And eNOS phosphorylation at Ser1177 and NO production were significantly enhanced in LMWF-treated diabetic PAD rats. CONCLUSIONS: Taken together, our findings demonstrated that LMWF exhibits therapeutic effect on hindlimb ischemia in type 2 diabetic rats likely through ameliorating endothelium eNOS dysfunction and enhancing revascularization, thus, providing a potential supplementary non-invasive treatment for diabetes-induced PAD. PMID- 28917977 TI - The role of the endocannabinoid system in the antihyperalgesic effect of Cedrus atlantica essential oil inhalation in a mouse model of postoperative pain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cedar is part of the phylum of conifers, and it's essential oil has been used for therapeutic purposes since ancient times. In our previous study, we have demonstrated that the inhalation of the Cedrus atlantica essential oil (CaEO) induces an antihyperalgesic effect in a model of postoperative pain. But the mechanism that underlies this effect is not yet fully known. AIM OF THE STUDY: This study investigates the involvement of the endocannabinoid system in the antihyperalgesic effect produced by the inhalation of CaEO in a post operative pain model. MATERIALS AND METHODS: Male Swiss mice (25-35+/-2g) were subjected to plantar incision. To assess the involvement of the endocannabinoid system, two different approaches were made: (1) by administering antagonists to the CB1 and CB2 receptors in different sites (intraperitoneal [i.p.], intraplantar [i.pl.] and intrathecal [i.t.]) and (2) by assessing the synergic effect of the inhalation of sub-effective doses of CaEO, Fatty acid hydrolase (FAAH) and Monoacylglycerol lipase (MAGL), and endocannabinoid degradation inhibitors (URB937 and JZL184, respectively). RESULTS: The antihyperalgesic effect of CaEO inhalation was prevented by pretreatment with AM281 or AM630 given by i.p. and i.t., but not i.pl. Additionally, in mice pretreated with FAAH or the MAGL inhibitors, the antihyperalgesic effect of CaEO inhalation was significantly longer, which demonstrates the involvement of the endocannabinoid system in the antihyperalgesic effect of CaEO inhalation in a preclinical model of postoperative pain. CONCLUSIONS: The present study shows that CaEO inhalation exerts an antihyperalgesic effect, possibly by the activation of the endocannabinoid system in a preclinical model of postoperative pain. It could be a new alternative to treat pain in a clinical environment. PMID- 28917978 TI - SEN1500, a novel oral amyloid-beta aggregation inhibitor, attenuates brain pathology in a mouse model of Alzheimer's disease. AB - INTRODUCTION: Amyloid-beta (Abeta) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the Abeta aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant Abeta aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain Abeta pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APPSL). MATERIALS & METHODS: APPSL transgenic mice and non-transgenic littermates were treated with SEN1500 via food pellets from three months of age for four months. At the end of the treatment, animals were tested for memory deficits using the contextual fear conditioning test and brain tissue was analyzed for soluble and insoluble amyloid-beta1-38, -40, -42, beta-amyloid plaques, beta-sheet plaque cores, as well as for astrocytosis and activated microglia. RESULTS: SEN1500 treatment lowered insoluble Abeta levels and beta amyloid plaque load in the brain compared with control-treated APPSL mice. Activated microglia were significantly reduced in the cortex but not the hippocampus of SEN1500-treated APPSL mice. Memory deficits of APPSL mice could not be rescued by SEN1500. DISCUSSION: SEN1500 is not only able to reduce Abeta pathology and activated microglia but also to improve learning and memory as previously shown, making SEN1500 a potential candidate for human AD treatment. This Abeta aggregation inhibitor could be a promising therapeutic agent for the disease-modifying treatment of AD. PMID- 28917979 TI - Plantar reflex excitability is increased in the evening in restless legs syndrome patients. AB - OBJECTIVE: To investigate if diurnal changes in spinal excitability (plantar reflex) occur in restless legs syndrome (RLS) participants compared to healthy matched controls. METHODS: Thirteen RLS participants and 13 healthy control participants' plantar reflex responses were evaluated in the evening (PM) and the morning (AM). Plantar reflex responses were assessed electromyographically, using motion analysis (kinematically) and by subjective nociception (Visual Analogue Scale). RESULTS: RLS participants showed a circadian variation in plantar reflex responses whilst control participants did not. Evening ankle angle changes were larger and faster in RLS participants compared to morning responses. In addition RLS participants displayed significantly smaller change in ankle angle and significantly slower ankle movements in the evening and the morning as well as significantly lower lateral gastrocnemius maximum amplitude in the compared to control participants. CONCLUSION: The findings of the current study support the theory of RLS circadian fluctuations in spinal excitability. An unexpected finding was decreased plantar reflex responses in RLS participants compared to healthy control participants. However this finding supports the theory of mechanical hypoesthesia in RLS. The results of this study provide further insight into the pathophysiology of RLS, highlighting that not all sensory processing is affected in the same manner. PMID- 28917980 TI - Absence of association of the Ala58Val (rs17571) CTSD gene variant with Parkinson's disease or amyotrophic lateral sclerosis in a Han Chinese population. AB - Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are neurodegenerative diseases that may share genetic risk factors. The exon variant Aal58Val (rs17571) in CTSD was recently associated with AD, leading us to examine whether it also affects risk of ALS and PD. The rs17571 variant was genotyped using the ligase detection reaction in 569 Han Chinese patients with PD, 301 patients with ALS, and healthy controls age- and gender matched to each patient group. The frequencies of genotypes and alleles were similar between each disease group and its respective control group. Similar results were obtained when patients were stratified by gender, age at disease onset or type of symptoms at disease onset. These results suggest that the CTSD rs17571 variant may not be associated with risk of ALS or PD in Han Chinese. PMID- 28917981 TI - Intranasal insulin treatment alleviates methamphetamine induced anxiety-like behavior and neuroinflammation. AB - Insulin, as a peptide hormone, has recently gained attention for its pro cognitive, anti-inflammatory and neuroprotective effects in the central nervous system (CNS). Most studies have indicated anxiogenic and neuroinflammatory effects of methamphetamine (MA) and other psychostimulants, even after periods of abstinence. The present study aimed to examine whether intranasal (IN) insulin treatment with high CNS bioavailability and minimal systemic side effects, can reverse the anxiety-like behavior and neuroinflammation induced by repeated MA administration. In male wistar rats, escalating doses of MA (1-10mg/kg, i.p.) were administrated twice a day for 10 consecutive days. IN insulin treatment (0.5IU/day, for 7days after MA discontinuation) attenuated MA-induced anxiety like behavior in the elevated plus maze task, and significantly decreased the levels of glial cell markers (GFAP and Iba1), pro-inflammatory cytokines (TNF alpha and IL-6) as well as COX2 and NF-kappaB players of neuroinflammation, in the hippocampus of MA-treated animals. These findings introduce insulin as a potential therapeutic approach for the treatment of MA aversive symptoms. PMID- 28917982 TI - Connexin hemichannels and cochlear function. AB - Connexins play vital roles in hearing, including promoting cochlear development and sustaining auditory function in the mature cochlea. Mutations in connexins expressed in the cochlear epithelium, Cx26 and Cx30, cause sensorineural deafness and in the case of Cx26, is one of the most common causes of non-syndromic, hereditary deafness. Connexins function as gap junction channels and as hemichannels, which mediate intercellular and transmembrane signaling, respectively. Both channel configurations can play important, but very different roles in the cochlea. The potential roles connexin hemichannels can play are discussed both in normal cochlear function and in promoting pathogenesis that can lead to hearing loss. PMID- 28917983 TI - Temperature dependence of speed of sound and attenuation of porcine left ventricular myocardium. AB - The temperature dependence of soft tissue acoustic properties is relevant for monitoring tissue hyperthermia. In the current work, the propagation speed and attenuation of healthy porcine left ventricular myocardium (N=5) was investigated in a frequency range relevant for clinical diagnostic imaging, i.e. 2.5-13.0MHz. Each tissue sample was held in a water bath at a temperature T=25 degrees C, heated to 45 degrees C, and allowed to cool back down to 25 degrees C. Due to initial tissue swelling, the data for decreasing temperatures was considered more reliable. In this case, the slope of the phase velocity versus temperature relation was measured to be 1.10+/-0.04m/s/ degrees C, and the slope of the attenuation was -0.11+/-0.04dB/cm/ degrees C at 10MHz, or -0.0041+/ 0.0015dB/cm/MHz1.4336/ degrees C as a function of frequency. PMID- 28917984 TI - Multi-objective optimization of asymmetric acoustic transmission with periodical structure. AB - Asymmetric acoustic wave propagation is important for control and manipulation of the acoustic wave signals in various devices. However, previous approach to find optimal asymmetric acoustic transmission (AAT) is through repeatedly adjusting the geometrical parameters, thus causing time-consuming. Here we propose a study on the multi-objective optimization of the AAT, aiming to achieve the widest working frequency range (fr) and the highest transmittance peak (eta) with regard to the design variables. For this purpose, the Radial Basis Function (RBF) neural work and finite element (FE) method are applied to obtain the valuable data in the procedure. Furthermore, local sensitivity analysis of design parameters on the fr and eta are analyzed. Ultimately, the Non-Dominated Sorting Genetic Algorithm II (NSGA-II) is adapted for getting the Pareto-optimal solutions. The optimization results show great improvement for the overall performance of the AAT, which could be potentially significant in designing various sound devices. PMID- 28917985 TI - The effect of particle shape on cellular interaction and drug delivery applications of micro- and nanoparticles. AB - Encapsulation of therapeutic agents in nanoparticles offers several benefits including improved bioavailability, site specific delivery, reduced toxicity and in vivo stability of proteins and nucleotides over conventional delivery options. These benefits are consequence of distinct in vivo pharmacokinetic and biodistribution profile of nanoparticles, which is dictated by the complex interplay of size, surface charge and surface hydrophobicity. Recently, particle shape has been identified as a new physical parameter which has exerted tremendous impact on cellular uptake and biodistribution, thereby in vivo performance of nanoparticles. Improved therapeutic efficacy of anticancer agents using non-spherical particles is the recent development in the field. Additionally, immunological response of nanoparticles was also altered when antigens were loaded in non-spherical nanovehicles. The apparent impact of particle shape inspired the new research in the field of drug delivery. The present review therefore details the research in this field. The review focuses on methods of fabrication of particles of non-spherical geometries and impact of particle shape on cellular uptake, biodistribution, tumor targeting and production of immunological responses. PMID- 28917987 TI - Development and characterisation of electrospun timolol maleate-loaded polymeric contact lens coatings containing various permeation enhancers. AB - Despite exponential growth in research relating to sustained and controlled ocular drug delivery, anatomical and chemical barriers of the eye still pose formulation challenges. Nanotechnology integration into the pharmaceutical industry has aided efforts in potential ocular drug device development. Here, the integration and in vitro effect of four different permeation enhancers (PEs) on the release of anti-glaucoma drug timolol maleate (TM) from polymeric nanofiber formulations is explored. Electrohydrodynamic (EHD) engineering, more specifically electrospinning, was used to engineer nanofibers (NFs) which coated the exterior of contact lenses. Parameters used for engineering included flow rates ranging from 8 to 15MUL/min and a novel EHD deposition system was used; capable of hosting four lenses, masked template and a ground electrode to direct charged atomised structures. SEM analysis of the electrospun structures confirmed the presence of smooth nano-fibers; whilst thermal analysis confirmed the stability of all formulations. In vitro release studies demonstrated a triphasic release; initial burst release with two subsequent sustained release phases with most of the drug being released after 24h (86.7%) Biological evaluation studies confirmed the tolerability of all formulations tested with release kinetics modelling results showing drug release was via quasi-Fickian or Fickian diffusion. There were evident differences (p<0.05) in TM release dependant on permeation enhancer. PMID- 28917988 TI - A comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery. AB - Aerosolized administration of biopharmaceuticals to the airways is a promising route for nasal and pulmonary drug delivery, but - in contrast to small molecules - little is known about the effects of aerosolization on safety and efficacy of biopharmaceuticals. Proteins are sensitive against aerosolization-associated shear stress. Tailored formulations can shield proteins and enhance permeation, but formulation development requires extensive screening approaches. Thus, the aim of this study was to develop a cell-based in vitro technology platform that includes screening of protein quality after aerosolization and transepithelial permeation. For efficient screening, a previously published aerosolization surrogate assay was used in a design of experiments approach to screen suitable formulations for an IgG and its antigen-binding fragment (Fab) as exemplary biopharmaceuticals. Efficient, dose-controlled aerosol-cell delivery was performed with the ALICE-CLOUD system containing RPMI 2650 epithelial cells at the air-liquid interface. We could demonstrate that our technology platform allows for rapid and efficient screening of formulations consisting of different excipients (here: arginine, cyclodextrin, polysorbate, sorbitol, and trehalose) to minimize aerosolization-induced protein aggregation and maximize permeation through an in vitro epithelial cell barrier. Formulations reduced aggregation of native Fab and IgG relative to vehicle up to 50% and enhanced transepithelial permeation rate up to 2.8-fold. PMID- 28917989 TI - Shear strength of pharmaceutical tablets: Theoretical considerations, evaluation and relation with the capping tendency of biconvex tablets. AB - Capping is a major industrial issue during pharmaceutical powder compression, especially in the case of biconvex tablets. Several articles proposed that capping was in fact a failure in shear. Shear strength should thus be interesting to study the capping tendency of a formulation. In this work, the ratio between the shear strength and the tensile strength obtained by diametral compression was first studied from a theoretical point of view considering different failure criteria. Then, a shear test usually performed on bilayer tablets was adapted to monolayer tablets. The shear strength obtained for 5 products, 2 of them having a known capping tendency, were compared with the strengths obtained during diametral compression test and uniaxial compression test. The results indicated that, for the formulations with a capping tendency, the ratio between the shear strength and diametral compression strength was lower than for the other products. Considering the mechanism of capping, the weakness in shear of these formulations explained their capping tendency. This was also linked with the mechanical anisotropy of the same formulations which was shown in the literature. In the cases studied in this article, the fundamental reason for the capping tendency was the anisotropic strength of the tablets. PMID- 28917990 TI - Glycerosomes: Investigation of role of 1,2-dimyristoyl-sn-glycero-3 phosphatidycholine (DMPC) on the assembling and skin delivery performances. AB - Glycerosomes were formulated using 1,2-dimyristoyl-sn-glycero-3 phosphatidycholine (DMPC), diclofenac sodium salt and 10, 20 or 30% glycerol in the water phase, while corresponding liposomes were prepared with the same amount of DMPC and diclofenac, without glycerol. The aim of the present work was to evaluate the effect of the used phospholipid on vesicle features and ability to favour diclofenac skin deposition by comparing these results with those found in previous works performed using hydrogenated soy phosphatidylcholine (P90H) and dipalmitoylphosphatidylcholine (DPPC). Liposomes and glycerosomes were multilamellar, liposomes being smaller (72+/-6nm). Interactions among glycerol, phospholipids and drug led to the formation of a non-rigid bilayer structure and a variation of the main transition temperature, which shifted to lower temperature. The addition of glycerol led to the formation of more viscous systems (from ~2.5mPa/s for basic liposomes to ~5mPa/s for glycerosomes), which improved spread ability of the formulations on the skin.Results obtained in vitro were promising using glycerosomes, irrespective of the amount of glycerol used: the amount of drug, which accumulated into and permeated through the different skin strata, was high and comparable with that obtained using P90H, suggesting that glycerosomes may represent an efficient carrier for both local effect or systemic absorption. PMID- 28917991 TI - Enhanced expression of PD-L1 and IFN-gamma on dendritic cells is associated with BCG-induced Th2 inhibition. AB - Accumulating evidence indicates that the exposure to Mycobacterium bovis bacillus Calmette-Guerin (BCG) prevents the development of allergy and the airway dendritic cells (DCs) may be involved in this protective effect. However, studies to better characterize the specific interactions between BCG and DCs and their role in this mycobacteria-mediated Th2 cell suppression are still ongoing. This study aimed to evaluate the effect of the neonatal BCG vaccination in the innate immune response in a mouse model of ovalbumin (OVA)-induced airway inflammation. BCG treated neonatal BALB/c mice were sensitized and challenged with aerosolized OVA. Twenty-four hours after the last challenge, samples were collected for analysis. The intranasal BCG treatment inhibited the allergic Th2-response by decreasing the allergen-induced eosinophilic inflammation, EPO activity, CCL11, IL-25, TSLP, IL-4 and IL-5 lung levels, and serum levels of IgE. Mycobacteria treatment increased lung levels of IL-10 and TGF-beta, and the TLR2 and TLR4 expressions by pulmonary CD11c+CD103+CD8alpha+ DCs. Additionally an enhanced expression of PD-L1 was observed besides an increased production of IFN-gamma by these cells. These results indicated that neonatal BCG vaccination inhibits key features of allergic airway inflammation, probably by promoting T regulatory immune response via an enhanced expression of TLR2, TLR4 and PD-L1 on DCs. PMID- 28917986 TI - Physicochemical properties of mucus and their impact on transmucosal drug delivery. AB - Mucus is a selective barrier to particles and molecules, preventing penetration to the epithelial surface of mucosal tissues. Significant advances in transmucosal drug delivery have recently been made and have emphasized that an understanding of the basic structure, viscoelastic properties, and interactions of mucus is of great value in the design of efficient drug delivery systems. Mucins, the primary non-aqueous component of mucus, are polymers carrying a complex and heterogeneous structure with domains that undergo a variety of molecular interactions, such as hydrophilic/hydrophobic, hydrogen bonds and electrostatic interactions. These properties are directly relevant to the numerous mucin-associated diseases, as well as delivering drugs across the mucus barrier. Therefore, in this review we discuss regional differences in mucus composition, mucus physicochemical properties, such as pore size, viscoelasticity, pH, and ionic strength. These factors are also discussed with respect to changes in mucus properties as a function of disease state. Collectively, the review seeks to provide a state of the art roadmap for researchers who must contend with this critical barrier to drug delivery. PMID- 28917993 TI - Nonsedated handheld electroretinogram as a screening test of retinal dysfunction in pediatric patients with nystagmus. AB - PURPOSE: To assess the feasibility, sensitivity, and specificity of nonsedated handheld cone flicker electroretinogram (ERG) as a screening tool to detect retinal dysfunction in children with nystagmus. METHODS: Pediatric patients at a tertiary referral center from December 2015 to July 2016 were enrolled and placed into three age-matched groups: normal, nystagmus with a retinal dystrophy, and nystagmus without a retinal dystrophy. Unsedated 30 Hz cone flicker ERG responses were obtained using a handheld device (RETeval) from both eyes of each patient using skin electrode sensors after pupillary dilation. RESULTS: A total of 71 children were enrolled; amplitudes and implicit times were successfully obtained in 65 (92%): 31 (mean age +/- SD, 5.6 +/- 2.7 years; range, 1-12 years) without nystagmus and 34 with nystagmus. Nystagmus patients were grouped by those with (n = 15; mean age, 8.5 +/- 4.5 [range, 2-17 years) and without (n = 19; mean age, 4.3 +/- 3.0 [range, 6 months-10 years]) a retinal dystrophy. The patients with retinal dystrophies had significantly smaller amplitudes and prolonged or nonmeasurable implicit times than the other two groups (P < 0.001). Among nystagmus patients, amplitude was able to discriminate between those with and without retinal dystrophies with area under curve of 0.986 (SE = 0.016; P < 0.001). An amplitude <5 MUV in combination with an implicit time of >33 ms warrants further evaluation. CONCLUSIONS: Unsedated handheld cone flicker ERG is a feasible screening test that effectively detects retinal dysfunction in children with nystagmus. In conjunction with clinical findings, the test helps reduce the need for sedated ERG in children. PMID- 28917992 TI - Securing extraocular muscles in strabismus surgery: biomechanical analysis of knot-tying technique. AB - BACKGROUND: The safe and precise reattachment of extraocular muscles requires a technical approach that minimizes any opportunity for the muscle to slip intraoperatively or postoperatively while minimizing surgical risk. Biomechanical testing can provide important quantitative information about the tensile properties of different knot configurations that may inform surgical technique. METHODS: A precision digital force gauge was used to assess the tensile strength created by different knot tying techniques and configurations in human sclera using 6-0 polyglactin 910 suture. RESULTS: The mean tensile strengths of the first knot throw formed with either one, two, or three loops, with widely separated scleral tunnels, were 5 g, 10 g, or 27 g, respectively. When the scleral tunnels are closely spaced in a "cross-swords" fashion, the mean strength of a first throw made with two loops increased to 385 g. If a first throw with two conventional loops was cinched against one of the scleral tunnels or a reversed first loop is used, the mean tensile strength increased to 112 g or 381 g, respectively, even with widely spaced scleral tunnels. CONCLUSIONS: Proper cinching or minor modification of the first knot throw provides excellent tensile strength, even with short, widely spaced scleral tunnels, comparable to that achieved with the technically more demanding crossed swords technique. Conventional, noncinched first throws are prone to slip at low force when scleral tunnels are widely separated, though the resistance increases as the number of loops increases. PMID- 28917994 TI - Use of the Masterka for complex nasolacrimal duct obstruction in children. AB - BACKGROUND: The Masterka stent has been recommended solely for treatment of simple distal membranous nasolacrimal duct obstruction (NLDO). The purpose of this study was to evaluate the Masterka stent as a primary treatment in complex forms of NLDO, including bony ductal stenosis and proximal and serial membranous obstruction. METHODS: The medical records of patients who underwent treatment for congenital nasolacrimal duct obstruction with the monocanalicular Masterka stent were reviewed retrospectively. Both simple and complex forms of NLDO were primarily treated with probing and irrigation, followed by placement of the Masterka stent. RESULTS: A total of 72 eyes (53 patients) were included: 17 cases were simple forms of NLDO; and 55 were complex. Success was achieved in 15 of 17 simple cases (88%) and 39 of 55 complex cases (71%); the overall success rate was 75%. In patients <24 months of age, success rates were 100% for simple and 78% for complex forms. CONCLUSIONS: The Masterka stent can be useful in a younger subset of patients with more complex forms of congenital NLDO. A lower success rate is noted in children >2 years of age and complex forms of NLDO, especially those with bony stenosis. PMID- 28917995 TI - Removal of a barbed fish hook from the cornea of an 8-year-old boy. AB - This video article shows the surgical removal of a three-pronged barbed fish hook from the cornea and anterior chamber of an 8-year-old boy. The advance-and-cut method is shown: the embedded barbed point of the fish hook was advanced through the cornea, its point was cut off, and the shank of the hook was withdrawn. This method was chosen due to the three-pronged configuration of the fish hook to minimize additional trauma to the eye. Other methods of fish hook removal are briefly reviewed. PMID- 28917996 TI - Poor efficacy of TNF inhibitors in non-radiographic axial spondyloarthritis in the absence of objective signs: A bicentric retrospective study. AB - OBJECTIVE: To compare BASDAI 50 response rate to TNFi in axial spondyloarthritis (axSpA) depending on the presence or not of objective signs of axSpA and to look for predictive factors of TNFi efficacy. METHODS: Patients diagnosed with axSpA according to ASAS criteria "clinical arm" and treated between January 2001 and September 2015 with TNFi were included. First group included patients with at least one objective sign such as arthritis, dactylitis, enthesitis, uveitis, inflammatory bowel disease, elevated C-reactive protein or radiological sacroiliitis, and second group included non-radiographic axSpA (nr-axSpA) patients without any objective sign corresponding to patients with inflammatory back pain and either a good response to NSAID or a SpA family history. The primary outcome was the TNFi efficacy, defined as an achievement of BASDAI 50 at 3 months. The secondary outcomes were BASDAI 50 achievement over 1 year and analysis of predictive factors of TNFi response. RESULTS: We included 84 nr-axSpA patients without any objective signs and 84 axSpA patients with objective signs (48.2% r-axSpA and 52.8% nr-axSpA). BASDAI 50 achievement rates were significantly higher in patients with objective signs than in patients without, at 3 months (45.1% versus 13.7%, P<0.0001) and at any of the visit-time points over the first year (61.9% versus 21.4%, P<0.0001). In multivariate analysis, overweight/obesity and sacroiliitis on MRI were respectively negative and positive predictive factors of TNFi efficacy in the total population at 3 months (OR=0.32, 95%CI [0.11, 0.96], P=0.041 and OR=6.92, 95% CI (2.41, 19.8), P<0.0001, respectively). CONCLUSION: TNFi should be used with caution in axSpA when objective signs are absent as only 13.7% of these patients were BASDAI 50 responders at 3 months. PMID- 28917997 TI - Lung transplantation for scleroderma: Strength in numbers. PMID- 28917998 TI - Clinical characteristics and outcomes in polyarticular septic arthritis. AB - OBJECTIVES: Septic polyarthritis is rarer than septic monoarthritis, but associated with higher mortality. Septic polyarthritis may be difficult to distinguish clinically from noninfectious inflammatory arthritis. We describe one of the largest samples of septic polyarthritis with the aim of distinguishing septic monoarthritis from polyarthritis. METHODS: We conducted a retrospective study of adults admitted to tertiary care with septic monoarthritis and polyarthritis. Baseline characteristics, microbial profiles, joint involvement, length of stay, and 60-day readmission rates were determined. RESULTS: We identified 464 and 42 cases of septic monoarthritis and polyarthritis, respectively, including 7 cases of septic polyarthritis with comorbid rheumatoid arthritis. Compared to those with septic monoarthritis, patients with septic polyarthritis were more likely to have rheumatoid arthritis (P<0.01), sepsis (P<0.01), and higher peripheral (P<0.001) and synovial (P<0.001) white blood cell counts. Operative intervention rates were similar, but mean length of stay was longer in polyarticular septic arthritis (P<0.001). Patients with septic polyarthritis with/without underlying rheumatoid arthritis were similar in terms of presenting features and outcomes, except for more frequent immunosuppressive therapy in rheumatoid arthritis (P<0.01). CONCLUSIONS: In this sample of patients with septic arthritis, patients with septic polyarthritis were more likely to have systemic infection at presentation than those with septic monoarthritis. Despite this difference, patients with septic monoarthritis and polyarthritis tended to have similar outcomes. While rheumatoid arthritis was observed more frequently among patients with septic polyarthritis, those with/without underlying rheumatoid arthritis had similar presenting features and outcomes. PMID- 28917999 TI - The two-component response regulator VdSkn7 plays key roles in microsclerotial development, stress resistance and virulence of Verticillium dahliae. AB - The fungus Verticillium dahliae causes vascular wilt disease on various plant species resulting in devastating yield losses worldwide. The capacity of V. dahliae to colonize in host plant xylem and disseminate by microsclerotia has led to studies to evaluate genes associated with pathogenesis and microsclerotia formation. Here, we identified and characterized a V. dahliae homolog to Skn7, a two-component stress response regulator of Saccharomyces cerevisiae. Results showed that melanized microsclerotia formation and conidiation were significantly inhibited in the VdSkn7 deletion mutants. VdSkn7-deficient mutants displayed severe growth defect under heat shock, cell wall perturbing agents and H2O2, and were significantly less virulent but were not sensitive to osmotic stresses compared to the wild-type strain. Finally, we demonstrated that VdSkn7 is required for the plant penetration. Taken together, our study thus provides new evidence on the functional conservation and divergence of Skn7 orthologs among fungal organisms and indicates that VdSkn7 contributes to microsclerotial development, virulence and stress response of V. dahliae. PMID- 28918000 TI - Nitric oxide prevents Aft1 activation and metabolic remodeling in frataxin deficient yeast. AB - Yeast frataxin homolog (Yfh1) is the orthologue of human frataxin, a mitochondrial protein whose deficiency causes Friedreich Ataxia. Yfh1 deficiency activates Aft1, a transcription factor governing iron homeostasis in yeast cells. Although the mechanisms causing this activation are not completely understood, it is assumed that it may be caused by iron-sulfur deficiency. However, several evidences indicate that activation of Aft1 occurs in the absence of iron-sulfur deficiency. Besides, Yfh1 deficiency also leads to metabolic remodeling (mainly consisting in a shift from respiratory to fermentative metabolism) and to induction of Yhb1, a nitric oxide (NO) detoxifying enzyme. In this work, we have used conditional Yfh1 mutant yeast strains to investigate the relationship between NO, Aft1 activation and metabolic remodeling. We have observed that NO prevents Aft1 activation caused by Yfh1 deficiency. This phenomenon is not observed when Aft1 is activated by iron scarcity or impaired iron-sulfur biogenesis. In addition, analyzing key metabolic proteins by a targeted proteomics approach, we have observed that NO prevents the metabolic remodeling caused by Yfh1 deficiency. We conclude that Aft1 activation in Yfh1-deficient yeasts is not caused by iron-sulfur deficiency or iron scarcity. Our hypothesis is that Yfh1 deficiency leads to the presence of anomalous iron species that can compromise iron bioavailability and activate a signaling cascade that results in Aft1 activation and metabolic remodeling. PMID- 28918002 TI - Effect of natural sagittal trunk lean on standing balance in untreated scoliotic girls. AB - BACKGROUND: Generally, scoliotic girls have a tendency to lean further back than a comparable group of non-scoliotic girls. To date, no study has addressed how standing balance in untreated scoliotic girls is affected by a natural backwardly or forwardly inclined trunk. METHODS: 27 able-bodied young girls and 27 young girls with a right thoracic curve were classified as leaning forward or backward according to the median of their trunk sagittal inclination. Participants stood upright barefoot. Trunk and pelvis orientations were calculated from 8 bony landmarks. Upright standing balance was assessed by 9 parameters calculated from the excursion of the center of pressure and the free moment. FINDINGS: In the anterior-posterior direction, backward scoliotic girls had a greater center of pressure range (P=0.036) and speed (P=0.015) by 10.4mm and 2.8mm/s respectively than the forward scoliotic group. Compared to their matching non-scoliotic group, the backward scoliotic girls stood more on their heels by 14.6mm (P=0.017) and display greater center of pressure speed by 2.5mm/s (P=0.028). Medio-lateral center of pressure range (P=0.018) and speed (P=0.008) were statistically higher by 8.7mm and 3.6mm/s for the backward group. Only the free moment RMS was significantly larger (P=0.045) for the backward scoliotic group when compared to the forwardly inclined scoliotic group. INTERPRETATION: Only those with a backward lean displayed statistically significant differences from both forward scoliotic girls and non-scoliotic girls. Untreated scoliotic girls with an exaggerated back extension could profit more from postural rehabilitation to improve their standing balance. PMID- 28918001 TI - In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B. AB - The free-living amoeba (FLA) Acanthamoeba sp. is an opportunistic pathogen that can cause amoebic keratitis (AK) or granulomatous amoebic encephalitis (GAE). While current treatments of AK are long with some relapses, no consensus therapy has been developed for GAE remaining lethal in 90% of the cases. In this context, efficient antiacanthamoebal drugs have to be identified. In this work, 15 drugs used in the treatment of AK or GAE or in other parasitic diseases were evaluated for their in vitro activity on A. castellanii. Hexamidine, voriconazole and clotrimazole exhibited the highest activities with IC50 values at 0.05 MUM, 0.40 MUM and 0.80 MUM, respectively, while rifampicin, metronidazole and cotrimoxazole were inactive. Among 15 drug associations evaluated, no synergistic effect was observed, and one antagonism was determined between hexamidine and chlorhexidine. Interestingly, amphotericin B was the only drug presenting an increase of IC50 as a function of treatment duration. The amoebae susceptibility to amphotericin B cultured in the presence of 250 MUM of the drug was similar to the one of a naive control, revealing that no resistant strain could be selected. However, the amoebae susceptibility always returned to an initial level at each passage. This natural and non-acquired adaptation to amphotericin B, qualified as resilience, was observed in several strains of A. castellanii and A. polyphaga. Using a pharmacological approach with effectors of different cellular mechanisms or transports, and an ultrastructural analysis of amphotericin B-treated amoebae, the involvement of several mitochondria-dependent pathways as well as multidrug resistant transporters was determined in amphotericin B resilience. Based on the observations from this study, the relevance of using amphotericin B in GAE treatments may be reconsidered, while the use of some other drugs, such as rifampicin or cotrimoxazole, is not relative to intrinsic antiacanthamoebal activity. PMID- 28918003 TI - Relevance of adding a triangular dynamic cushion on a traditional chair: A 3D analysis of seated schoolchildren. AB - BACKGROUND: Low back pain is highly prevalent in the general population and is even reported as early as at primary school. A poor sitting position has been suggested as an etiologic factor. This study analysed, in primary schoolchildren, the influence of a triangular dynamic cushion that aims to help children maintain their physiological lumbar lordosis and to induce movement to reduce the static effect of the sitting position. METHODS: Thirty 8-year-old children took part in this study. A 3D analysis combined with electromyography was used to evaluate the biomechanics and the related muscle activation in two sitting positions (with and without a triangular cushion on a horizontal stool) during a 15-minute working task. In addition, the force of the feet on the ground was assessed with a force plate. FINDINGS: The cushion improved the trunk-thighs angle, lumbar lordosis, anterior pelvis tilt, and feet support on the ground (p<0.0001). In addition, sitting on the cushion appeared to be more dynamic (p<0.05) and induced a decrease of the lumbar paravertebral muscle activity (p<0.01). INTERPRETATION: Sitting on a dynamic triangular cushion tends to favour the "ideal" siting position usually described in the literature and to decrease the level of paravertebral muscle recruitment. Seeing that sitting position is a risk factor to develop low back pain, the cushion could be a solution to prevent it. PMID- 28918004 TI - The role of oxidative stress in influenza virus infection. AB - Virus-induced oxidative stress plays an important role in the regulation of the host immune system. In this review, we provide backgrounds of the pathogenic mechanism of oxidative stress induced by influenza virus and the specific oxidant sensitive pathways, and highlight that antioxidant is one of the effective strategies against influenza virus infection. PMID- 28918005 TI - Analysing how plants in coastal wetlands respond to varying tidal regimes throughout their life cycles. AB - Important to conserve plant species in coastal wetlands throughout their life cycle. All life stages in these habitats are exposed to varying tidal cycles. It is necessary to investigate all life stages as to how they respond to varying tidal regimes. We examine three wetlands containing populations of an endangered halophyte species, each subjected to different tidal regimes: (1). wetlands completely closed to tidal cycles; (2). wetlands directly exposed to tidal cycles (3). wetlands exposed to a partially closed tidal regime. Our results showed that the most threatened stage varied between wetlands subjected to these varying tidal regimes. We hypothesis that populations of this species have adapted to these different tidal regimes. Such information is useful in developing management options for coastal wetlands and modifying future barriers restricting tidal flushing. PMID- 28918006 TI - Factors influencing organochlorine pesticides distribution in the Brisbane River Estuarine sediment, Australia. AB - Sediment samples collected from Brisbane River were analysed for organochlorine pesticide residues (OCPs). The factors influencing OCPs distribution in the sediment were investigated using multivariate analytical tools. Thirteen OCPs were detected in the sediment with concentrations ranging between below detection to 83.9ng/g, and detection frequency >90%. With the exception of dieldrin, the OCP inputs appear to be historical and may cause adverse ecological impacts. Multi-criteria ranking of the factors influencing the OCPs (except dieldrin) distribution in the sediment revealed that TOC>silt>intensive urban land use>population>seasons. Dieldrin distribution is significantly influenced by season>TOC>silt>intensive urban land use>population. The study helps to prioritise factors required for managing OCPs contamination in sediments and identification of appropriate mitigation measures. PMID- 28918007 TI - The Effect of Visual-Spatial Ability on the Learning of Robot-Assisted Surgical Skills. AB - BACKGROUND: The aim of this study was to determine the correlation of visual spatial ability with progression along the learning curve for robotic surgical skills training. METHODS: A total of 21 novice participants were recruited. All participants completed a training program consisting of 5 training sessions of 30 minutes of virtual reality (VR) simulation and 30 minutes of dry laboratory training. The VR simulation part was the subject of the present study. During VR simulation training, participants performed the basic skill exercises of Camera Targeting 1, Pick and Place, and Peg Board 1 followed by advanced skill exercises of Suture Sponge 1 and Thread the Rings. The visual-spatial ability was assessed using a mental rotation test (MRT). Pearson correlation coefficients were used to assess the relationship between the MRT score and simulator score for the aforementioned 5 tasks. Student t test was used to compare the simulator score between high- and low-MRT score groups. RESULTS: A median MRT score of 26/40 (range: 13-38) was observed. Approximately 19 participants completed the full curriculum but 2 did not complete "Thread the Rings" during the study period. A significant correlation was observed between the MRT score and simulator score only in "Suture Sponge 1" over the first 3 attempts (first: r = 0.584, p = 0.0054; second: r = 0.443, p = 0.0443; third: r = 0.4458, p = 0.0428). After the third attempt, this significant correlation was lost. Comparison of the score for "Suture Sponge 1" between the high-MRT and low-MRT scoring participants divided by a median MRT score of 26 also showed a significant difference in the score until the third trial. CONCLUSION: Our observations suggest that the spatial cognitive ability influences the initial learning of robotic suturing skills. Further studies are necessary to verify the usefulness of an individual's spatial ability to tailor the surgical training program. PMID- 28918008 TI - A finite element study on the mechanical response of the head-neck interface of hip implants under realistic forces and moments of daily activities: Part 2. AB - A finite element model was developed to investigate the effect of loading regimes caused by various daily activities on the mechanical behaviour of the head-neck taper junction in modular hip replacements. The activities included stair up, stair down, sit to stand, stand to sit, one leg standing and knee bending. To present the real mechanical environment of the junction, in addition to the force components, the frictional moments produced by the frictional sliding of the head and cup were applied to a CoCr/CoCr junction having a 12/14 taper with a proximal mismatch angle of 0.024 degrees . This study revealed that stair up with the highest fretting work per unit of length (1.62 * 104J/m) was the most critical activity, while knee bending and stand to sit with 1.96 * 103J/m were the least critical activities. For all the activities, the superolateral region of the neck was identified as the most critical region in terms of having larger values of fretting work per unit of area. This study showed also that the relative micro motions and contact stresses occurring at the head-neck interface for all the studied activities are mostly in the range of 0-38um and 0-350MPa, respectively. These ranges may be accordingly employed for conducting relevant in-vitro tests to more realistically represent the mechanical environment of taper junctions with the same materials and geometry studied in this work. PMID- 28918009 TI - Low temperature degradation of single layers of multilayered zirconia in comparison to conventional unshaded zirconia: Phase transformation and flexural strength. AB - OBJECTIVES: The aim of this study was to evaluate the transformation of yttrium stabilized tetragonal zirconia (Y-TZP) to monoclinic phase and its change in flexural strength of the various layers of multilayered zirconia (enamel layer, transition layer 1, transition layer 2 and body layer) in comparison to two conventional zirconia ceramics. Additionally, the ball-on-three-balls test was compared with a conventional biaxial flexural strength test. METHODS: The crystallographic structure of the four layers of Katana Zirconia ML (Kuraray), e.max ZirCAD (Ivoclar Vivadent) and Lava Plus (3M ESPE) was investigated by x-ray diffraction before and after hydrothermal aging in an autoclave for 5, 10, 15 and 20h. The biaxial flexural strength was examined with a piston-on-three-ball test and a ball-on-three-balls test. RESULTS: There was a significant difference of the ratio of transformation with respect to the tested materials, also between the four different layers of multilayered zirconia. After 20h of hydrothermal aging the mean ratio of monoclinic phase ranged from 9.9vol% (LAVA Plus) to 44.2vol% (Katana Zirconia ML, enamel layer). However, hydrothermal aging had no significant influence on the flexural strength of any material. Furthermore, the flexural strength measured by the ball-on-three-balls test was higher than that measured by the piston-on-three-ball test. CONCLUSION: A ratio of 40% monoclinic phase at the surface did not significantly influence the biaxial flexural strength. Both test methods provide reliable results. However, as the ball-on three balls test is less dependent on surface roughness, it might be preferred for investigations adapted to clinical reality. PMID- 28918010 TI - Corrigendum to "Extending the Distributed Lag Model framework to handle chemical mixtures" [Environ. Res. 156 (2017) 253-264]. PMID- 28918011 TI - Nucleic Acid Polymers with Accelerated Plasma and Tissue Clearance for Chronic Hepatitis B Therapy. AB - REP 2139 is a nucleic acid polymer (NAP) currently under clinical development for chronic hepatitis B (HBV) therapy. This preclinical study investigated different REP 2139 analogs that would display reduced accumulation in the serum and tissues, while retaining an antiviral effect against HBV infection. REP 2139 analogs were evaluated in human plasma, CD-1 mice, cynomolgus monkeys, and Pekin ducks. Discrete ribose transformation to 2'OH in selected riboadenosines resulted in a slow degradation in acidified human plasma that plateaued after 48 hr. REP 2165, a REP 2139 analog containing three unmodified riboadenosines equally spaced throughout the polymer, showed similar plasma clearance and tissue distribution as REP 2139 in mice and cynomolgus monkeys after a single dose. Interestingly, after repeated administration, accumulation of REP 2165 in plasma and organs was reduced, indicating a dramatically faster rate of clearance from organs after therapy was ended in both species. Both REP 2139 and REP 2165 were well tolerated at clinically relevant doses, with no alterations in liver, kidney, or hematological function. In chronic duck HBV (DHBV) infection, REP 2165 displayed significantly reduced liver accumulation after repeated dosing but retained antiviral activity similar to REP 2139. These results indicate the therapeutic potential of REP 2165 against chronic HBV infection in patients is similar to REP 2139, but with significantly reduced drug accumulation and improved tissue clearance. PMID- 28918012 TI - Gene Editing with Helper-Dependent Adenovirus Can Efficiently Introduce Multiple Changes Simultaneously over a Large Genomic Region. AB - Helper-dependent adenoviral vectors (HDAds) possess long homology arms that mediate high-efficiency gene editing. These long homology arms may permit simultaneous introduction of multiple modifications into a large genomic region or may permit a single HDAd to correct many different individual mutations spread widely across a gene. We investigated this important potential using an HDAd bearing 13 genetic markers in the region of homology to the target CFTR locus in human iPSCs and found that all markers can be simultaneously introduced into the target locus, with the two farthest markers being 22.2 kb apart. We found that genetic markers closer to the HDAd's selectable marker are more efficiency introduced into the target locus; a marker located 208 bp from the selectable marker was introduced with 100% efficiency. However, even markers 11 kb from the selectable marker were introduced at a relatively high frequency of 21.7%. Our study also revealed extensive heteroduplex DNA formation of up to 10 kb with no bias toward vector or chromosomal repair. However, mismatches escape repair at a frequency of up to 15%, leading to a genetically mixed colony and emphasizing the need for caution, especially if the donor and target sequences are not 100% homologous. PMID- 28918013 TI - miR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/beta-Catenin Signaling. AB - Cancer stem cells (CSCs) play an important role in osteosarcoma (OS) metastasis and recurrence, and both Wnt/beta-catenin and Notch signaling are essential for the development of the biological traits of CSCs. However, the mechanism that underlies the simultaneous hyperactivation of both Wnt/beta-catenin and Notch signaling in OS remains unclear. Here, we report that expression of miR-135b correlates with the overall and recurrence-free survival of OS patients, and that miR-135b has an activating effect on both Wnt/beta-catenin and Notch signaling. The overexpression of miR-135b simultaneously targets multiple negative regulators of the Wnt/beta-catenin and Notch signaling pathways, including glycogen synthase kinase-3 beta (GSK3beta), casein kinase 1a (CK1alpha), and ten eleven translocation 3 (TET3). Therefore, upregulated miR-135b promotes CSC traits, lung metastasis, and tumor recurrence in OS. Notably, antagonizing miR 135b potently inhibits OS lung metastasis, cancer cell stemness, CSC-induced tumor formation, and recurrence in xenograft animal models. These findings suggest that miR-135b mediates the constitutive activation of Wnt/beta-catenin and Notch signaling, and that the inhibition of miR-135b is a novel strategy to inhibit tumor metastasis and prevent CSC-induced recurrence in OS. PMID- 28918014 TI - Artificial Zinc-Finger Transcription Factor of A20 Suppresses Restenosis in Sprague Dawley Rats after Carotid Injury via the PPARalpha Pathway. AB - The inhibition of inflammation and vascular smooth muscle cell (VSMC) proliferation is an ideal strategy to suppress intimal hyperplasia after percutaneous transluminal angioplasty (PTA). Evidence has indicated that overexpression of A20 suppresses neointima formation, but its low transfection efficiency limits its application. Hence, we upregulated A20 expression via transfection of rAd.ATF (recombinant adenovirus vector of artificial transcription factor) and rAd.A20 in rat carotid arteries after balloon dilatation (in vivo) and isolated VSMCs (in vitro). In vivo, we found that after rAd.ATF and rAd.A20 transfection, A20 expression was markedly increased, whereas proliferating cell nuclear antigen (PCNA) and nuclear factor kappaB p65 (NF kappaBp65) protein levels were significantly decreased, and intimal hyperplasia and secretion of proinflammatory factors were significantly reduced when compared with empty vector and saline control groups. Most importantly, the rAd.ATF treated group showed more significant inhibition on intimal hyperplasia and expression of PCNA than the rAd.A20-treated group. In vitro, compared with the control group, transfection of rAd.ATF and rAd.A20 significantly increased A20 expression, which upregulated the proliferator-activated receptor (PPAR) level for both mRNA and protein, and reduced migration and proliferation of VSMCs and lipopolysaccharide (LPS)-induced inflammation. Furthermore, the PPARalpha agonist GW6471 could partially restore the effect of A20 on VSMCs. Our findings indicate that the ATF of A20 inhibits neointimal hyperplasia and, therefore, constitutes a novel potential alternative to prevent restenosis. PMID- 28918015 TI - A MicroRNA124 Target Sequence Restores Astrocyte Specificity of gfaABC1D-Driven Transgene Expression in AAV-Mediated Gene Transfer. AB - Experimentally restricting transgene expression exclusively to astrocytes has proven difficult. Using adeno-associated-virus-mediated gene transfer, we assessed two commonly used glial fibrillary acidic protein promoters: the full length version gfa2 (2,210-bp human glial fibrillary acidic protein [GFAP] promoter) and the truncated variant gfaABC1D (681-bp GFAP promoter). The capacity to drive efficient, but also cell-type specific, expression of the EGFP in astrocytes was tested both in vitro in rat primary cortical cultures as well as in vivo in the rat striatum. We observed an efficient, but not entirely astrocyte specific, gfa2-driven reporter expression. gfaABC1D exhibited a weaker activity, and most importantly, off-target, neuronal expression of the transgene occurred in a larger fraction of cells. Therefore, we explored the potential of a microRNA (miR)-specific target-sequence-based approach for abolishing off-target expression. When miR124 target sequences were incorporated into the 3' UTR, neuronal gene expression was effectively silenced. However, unexpectedly, the insertion of an additional sequence in the 3' UTR clearly diminished transgene expression. In conclusion, the gfaABC1D promoter on its own is not sufficient to specifically target transgene expression to astrocytes and is not well suited for AAV-based gene targeting, even if short promoter sequences are required. The combination with a miR de-targeting sequence represents a promising experimental strategy that eliminates off-target, neuronal expression. PMID- 28918017 TI - Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model. AB - Antisense oligonucleotides (AONs) hold promise for therapeutic splice-switching correction in many genetic diseases. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake and sufficient therapeutic efficacy is still difficult to achieve. A novel class of AONs made of tricyclo-DNA (tcDNA) is considered very promising for the treatment of Duchenne muscular dystrophy (DMD), a neuromuscular disease typically caused by frameshifting deletions or nonsense mutations in the gene-encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, and respiratory failure in addition to cognitive impairment. Herein, we report the efficacy and toxicology profile of a 13-mer tcDNA in mdx mice. We show that systemic delivery of 13-mer tcDNA allows restoration of dystrophin in skeletal muscles and to a lower extent in the brain, leading to muscle function improvement and correction of behavioral features linked to the emotional/cognitive deficiency. More importantly, tcDNA treatment was generally limited to minimal glomerular changes and few cell necroses in proximal tubules, with only slight variation in serum and urinary kidney toxicity biomarker levels. These results demonstrate an encouraging safety profile for tcDNA, albeit typical of phosphorothiate AONs, and confirm its therapeutic potential for the systemic treatment of DMD patients. PMID- 28918016 TI - Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine. AB - In the past few years, therapeutic microRNA (miRNA) and small interfering RNA (siRNA) are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape. The efforts of the biopharmaceuticals are discussed with the status of their preclinical and/or clinical trials. Here, some of the setbacks have been highlighted during the biopharmaceutical development of miRNA and siRNA as individual therapeutics. Finally, a snapshot is illustrated about pharmacokinetics, pharmacodynamics with absorption, distribution, metabolism, and excretion (ADME), which is the fundamental development process of these therapeutics, as well as the delivery system for miRNA- and siRNA-based drugs. PMID- 28918018 TI - Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma Associated Metalloprotease with Nuclear-Localized mRNA. AB - Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy. PMID- 28918019 TI - Dual Tumor-Targeting Nanocarrier System for siRNA Delivery Based on pRNA and Modified Chitosan. AB - Highly specific and efficient delivery of siRNA is still unsatisfactory. Herein, a dual tumor-targeting siRNA delivery system combining pRNA dimers with chitosan nanoparticles (CNPPs) was designed to improve the specificity and efficiency of siRNA delivery. In this dual delivery system, folate-conjugated and PEGylated chitosan nanoparticles encapsulating pRNA dimers were used as the first class of delivery system and would selectively deliver intact pRNA dimers near or into target cells. pRNA dimers simultaneously carrying siRNA and targeting aptamer, the second class of delivery system, would specifically deliver siRNA into the target cells via aptamer-mediated endocytosis or proper particle size. To certify the delivering efficiency of this dual system, CNPPs, pRNA dimers alone, chitosan nanoparticles containing siRNA with folate conjugation and PEGylation (CNPS), and chitosan nanoparticles containing pRNA dimers alone (CN) were first prepared. Then, we observed that treatment with CNPPs resulted in increased cellular uptake, higher cell apoptosis, stronger cell cytotoxicity, and more efficacious gene silencing compared to the other three formulations. Higher accumulation of siRNA in the tumor site, stronger tumor inhibition, and longer circulating time were also observed with CNPPs compared to other formulations. In conclusion, this dual nanocarrier system showed high targeting and favorable therapeutic efficacy both in vitro and in vivo. Thereby, a new approach is provided in this study for specific and efficient delivery of siRNA, which lays a foundation for the development of pRNA hexamers, which can simultaneously carry six different substances. PMID- 28918020 TI - Rationally Engineered AAV Capsids Improve Transduction and Volumetric Spread in the CNS. AB - Adeno-associated virus (AAV) is the most common vector for clinical gene therapy of the CNS. This popularity originates from a high safety record and the longevity of transgene expression in neurons. Nevertheless, clinical efficacy for CNS indications is lacking, and one reason for this is the relatively limited spread and transduction efficacy in large regions of the human brain. Using rationally designed modifications of the capsid, novel AAV capsids have been generated that improve intracellular processing and result in increased transgene expression. Here, we sought to improve AAV-mediated neuronal transduction to minimize the existing limitations of CNS gene therapy. We investigated the efficacy of CNS transduction using a variety of tyrosine and threonine capsid mutants based on AAV2, AAV5, and AAV8 capsids, as well as AAV2 mutants incapable of binding heparan sulfate (HS). We found that mutating several tyrosine residues on the AAV2 capsid significantly enhanced neuronal transduction in the striatum and hippocampus, and the ablation of HS binding also increased the volumetric spread of the vector. Interestingly, the analogous tyrosine substitutions on AAV5 and AAV8 capsids did not improve the efficacy of these serotypes. Our results demonstrate that the efficacy of CNS gene transfer can be significantly improved with minor changes to the AAV capsid and that the effect is serotype specific. PMID- 28918021 TI - In Vitro Selection of Cell-Internalizing DNA Aptamers in a Model System of Inflammatory Kidney Disease. AB - Chronic kidney disease (CKD) is a progressive pathological condition marked by a gradual loss of kidney function. Treatment of CKD is most effective when diagnosed at an early stage and patients are still asymptomatic. However, current diagnostic biomarkers (e.g., serum creatinine and urine albumin) are insufficient for prediction of the pathogenesis of the disease. To address this need, we applied a cell-SELEX (systematic evolution of ligands by exponential enrichment) approach and identified a series of DNA aptamers, which exhibit high affinity and selectivity for cytokine-stimulated cells, resembling some aspects of a CKD phenotype. The cell-SELEX approach was driven toward the enrichment of aptamers that internalize via the endosomal pathway by isolating the endosomal fractions in each selection cycle. Indeed, we demonstrated co-localization of selected aptamers with lysosomal-associated membrane protein 1 (LAMP-1), a late endosomal and lysosomal marker protein, by fluorescence in situ hybridization. These findings are consistent with binding and subsequent internalization of the aptamers into cytokine-stimulated cells. Thus, our study sets the stage for applying selected DNA aptamers as theragnostic reagents for the development of targeted therapies to combat CKD. PMID- 28918022 TI - Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs. AB - Spinocerebellar ataxia type 36 is a late-onset, slowly progressive cerebellar syndrome with motor neuron degeneration that is caused by expansions of a hexanucleotide repeat (GGCCTG) in the noncoding region of NOP56 gene, with a histopathological feature of RNA foci formation in postmortem tissues. Here, we report a cellular model using the spinocerebellar ataxia type 36 patient induced pluripotent stem cells (iPSCs). We generated iPSCs from spinocerebellar ataxia type 36 patients and differentiated them into neurons. The number of RNA-foci positive cells was increased in patient iPSCs and iPSC-derived neurons. Treatment of the 2'-O, 4'-C-ethylene-bridged nucleic acid antisense oligonucleotides (ASOs) targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to ~50% in patient iPSCs and iPSC-derived neurons. NOP56 mRNA expression levels were lower in patient iPSCs and iPSC-derived neurons than in healthy control neurons. One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons. These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36. PMID- 28918023 TI - Repression of COUP-TFI Improves Bone Marrow-Derived Mesenchymal Stem Cell Differentiation into Insulin-Producing Cells. AB - Identifying molecular mechanisms that regulate insulin expression in bone marrow derived mesenchymal stem cells (bmMSCs) can provide clues on how to stimulate the differentiation of bmMSCs into insulin-producing cells (IPCs), which can be used as a therapeutic approach against type 1 diabetes (T1D). As repression factors may inhibit differentiation, the efficiency of this process is insufficient for cell transplantation. In this study, we used the mouse insulin 2 (Ins2) promoter sequence and performed a DNA affinity precipitation assay combined with liquid chromatography-mass spectrometry to identify the transcription factor, chicken ovalbumin upstream promoter transcriptional factor I (COUP-TFI). Functionally, bmMSCs were reprogrammed into IPCs via COUP-TFI suppression and MafA overexpression. The differentiated cells expressed higher levels of genes specific for islet endocrine cells, and they released C-peptide and insulin in response to glucose stimulation. Transplantation of IPCs into streptozotocin induced diabetic mice caused a reduction in hyperglycemia. Mechanistically, COUP TFI bound to the DR1 (direct repeats with 1 spacer) element in the Ins2 promoter, thereby negatively regulating promoter activity. Taken together, the data provide a novel mechanism by which COUP-TFI acts as a negative regulator in the Ins2 promoter. The differentiation of bmMSCs into IPCs could be improved by knockdown of COUP-TFI, which may provide a novel stem cell-based therapy for T1D. PMID- 28918024 TI - Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice. AB - Spinocerebellar ataxia type 3 (SCA3) is a currently incurable neurodegenerative disorder caused by a CAG triplet expansion in exon 10 of the ATXN3 gene. The resultant expanded polyglutamine stretch in the mutant ataxin-3 protein causes a gain of toxic function, which eventually leads to neurodegeneration. One important function of ataxin-3 is its involvement in the proteasomal protein degradation pathway, and long-term downregulation of the protein may therefore not be desirable. In the current study, we made use of antisense oligonucleotides to mask predicted exonic splicing signals, resulting in exon 10 skipping from ATXN3 pre-mRNA. This led to formation of a truncated ataxin-3 protein lacking the toxic polyglutamine expansion, but retaining its ubiquitin binding and cleavage function. Repeated intracerebroventricular injections of the antisense oligonucleotides in a SCA3 mouse model led to exon skipping and formation of the modified ataxin-3 protein throughout the mouse brain. Exon skipping was long lasting, with the modified protein being detectable for at least 2.5 months after antisense oligonucleotide injection. A reduction in insoluble ataxin-3 and nuclear accumulation was observed following antisense oligonucleotide treatment, indicating a beneficial effect on pathogenicity. Together, these data suggest that exon 10 skipping is a promising therapeutic approach for SCA3. PMID- 28918025 TI - Effect of Calcium Carbonate Encapsulation on the Activity of Orally Administered CpG Oligonucleotides. AB - Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODNs) stimulate immune cells via Toll-like receptor 9 (TLR9). Because oligodeoxynucleotides (ODNs) are susceptible to gastric degradation, clinical trials designed to evaluate their therapeutic utility have relied solely on parenteral routes of administration. A strategy to improve the activity of orally delivered ODNs by reducing their susceptibility to gastrointestinal (GI) digestion via encapsulation in calcium carbonate nanoparticles (ODNcaps) was recently described. This study compares the in vitro and in vivo activity of encapsulated (ODNcaps) versus free CpG ODNs delivered orally or parenterally. ODNcaps mirrored the ability of free ODNs to stimulate splenic B cells and macrophages in vitro. ODNcaps activated immune cells in the Peyer's patches and mesenteric lymph nodes after oral delivery. Their effect on GI immunity was evaluated in studies of dextran sulfate sodium (DSS)-induced colitis and enteric infection, whereas systemic immunity was examined by monitoring their effect on lipopolysaccharide (LPS)-induced cytokine production and systemic pathogen challenge. Results indicate that orally delivered CpG ODNs predominantly induce GI rather than systemic immunity, and that calcium carbonate encapsulation does not significantly alter this behavior. PMID- 28918026 TI - Anti-fibrotic Effects of Synthetic Oligodeoxynucleotide for TGF-beta1 and Smad in an Animal Model of Liver Cirrhosis. AB - Liver fibrosis is characterized by changes in tissue architecture and extracellular matrix composition. Liver fibrosis affects not only hepatocytes but also the non-parenchymal cells such as hepatic stellate cells (HSCs), which are essential for maintaining an intact liver structure and function. Transforming growth factor beta1 (TGF-beta1) is a multifunctional cytokine that induces liver fibrosis through activation of Smad signaling pathways. To improve a new therapeutic approach, synthetic TGF-beta1/Smad oligodeoxynucleotide (ODN) was used to suppress both TGF-beta1 expression and Smad transcription factor using a combination of antisense ODN and decoy ODN. The aims of this study are to investigate the anti-fibrotic effects of TGF-beta1/Smad ODN on simultaneous suppressions of both Smad transcription factor and TGF-beta1 mRNA expression in the hepatic fibrosis model in vitro and in vivo. Synthetic TGF-beta1/Smad ODN effectively inhibits Smad binding activity and TGF-beta1 expression. TGF beta1/Smad ODN attenuated the epithelial mesenchymal transition (EMT) and activation of HSCs in TGF-beta1-induced AML12 and HSC-T6 cells. TGF-beta1/Smad ODN prevented the fibrogenesis and deposition of collagen in CCl4-treated mouse model. Synthetic TGF-beta1/Smad ODN demonstrates anti-fibrotic effects that are mediated by the suppression of fibrogenic protein and inflammatory cytokines. Therefore, synthetic TGF-beta1/Smad ODN has substantial therapeutic feasibility for the treatment of liver fibrotic diseases. PMID- 28918027 TI - Adeno-Associated Viral Vector-Mediated mTOR Inhibition by Short Hairpin RNA Suppresses Laser-Induced Choroidal Neovascularization. AB - Choroidal neovascularization (CNV) is the defining characteristic feature of the wet subtype of age-related macular degeneration (AMD) and may result in irreversible blindness. Based on anti-vascular endothelial growth factor (anti VEGF), the current therapeutic approaches to CNV are fraught with difficulties, and mammalian target of rapamycin (mTOR) has recently been proposed as a possible therapeutic target, although few studies have been conducted. Here, we show that a recombinant adeno-associated virus-delivered mTOR-inhibiting short hairpin RNA (rAAV-mTOR shRNA), which blocks the activity of both mTOR complex 1 and 2, represents a promising therapeutic approach for the treatment of CNV. Eight-week old male C57/B6 mice were treated with the short hairpin RNA (shRNA) after generating CNV lesions in the eyes via laser photocoagulation. The recombinant adeno-associated virus (rAAV) delivery vehicle was able to effectively transduce cells in the inner retina, and significantly fewer inflammatory cells and less extensive CNV were observed in the animals treated with rAAV-mTOR shRNA when compared with control- and rAAV-scrambled shRNA-treated groups. Presumably related to the reduction of CNV, increased autophagy was detected in CNV lesions treated with rAAV-mTOR shRNA, whereas significantly fewer apoptotic cells detected in the outer nuclear layer around the CNV indicate that mTOR inhibition may also have neuroprotective effects. Taken together, these results demonstrate the therapeutic potential of mTOR inhibition, resulting from rAAV-mTOR shRNA activity, in the treatment of AMD-related CNV. PMID- 28918028 TI - Human DMBT1-Derived Cell-Penetrating Peptides for Intracellular siRNA Delivery. AB - Small interfering RNA (siRNA) is a promising molecule for gene therapy, but its therapeutic administration remains problematic. Among the recently proposed vectors, cell-penetrating peptides show great promise in in vivo trials for siRNA delivery. Human protein DMBT1 (deleted in malignant brain tumor 1) is a pattern recognition molecule that interacts with polyanions and recognizes and aggregates bacteria. Taking advantage of these properties, we investigated whether specific synthetic DMBT1-derived peptides could be used to formulate nanoparticles for siRNA administration. Using an electrophoretic mobility shift assay and UV spectra, we identified two DMBT1 peptides that could encapsulate the siRNA with a self- and co-assembly mechanism. The complexes were stable for at least 2 hr in the presence of either fetal bovine serum (FBS) or RNase A, with peptide dependent time span protection. zeta-potential, circular dichroism, dynamic light scattering, and transmission electron microscopy revealed negatively charged nanoparticles with an average diameter of 10-800 nm, depending on the reaction conditions, and a spherical or rice-shaped morphology, depending on the peptide and beta-helix conformation. We successfully transfected human MCF7 cells with fluorescein isothiocyanate (FITC)-DMBT1-peptide-Cy3-siRNA complexes. Finally, DMBT1 peptides encapsulating an siRNA targeting a fluorescent reporter gene showed efficient gene silencing in MCF7-recombinant cells. These results lay the foundation for a new research line to exploit DMBT1-peptide nanocomplexes for therapeutic siRNA delivery. PMID- 28918029 TI - Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats. AB - Cardiac fibrosis is pathological damage associated with nearly all forms of heart disease. AMP-activated protein kinase (AMPK) is an evolutionary conserved energy sensing enzyme. Emerging evidences indicate that AMPK plays an important role in cardiac fibrosis and cell proliferation. However, less is known about the detailed mechanism of AMPK activation on cardiac fibrosis. In this study, we found the AMPK activation improved the impaired cardiac function of cardiac fibrosis rats and decreased interstitial fibrosis. Further results indicated AMPK activation promoted p21 and p27 and inhibited CDK2 and cyclin E protein expressions both in vivo and in vitro. Moreover, AMPK activation repressed downstream transcription factor hepatocyte nuclear factor 4 alpha (HNF-4alpha) expression and decreased the binding of HNF-4alpha to TGF-beta1 promoters, which eventually resulted in TGF-beta1 downregulation and miR-29 family upregulation. Furthermore, miR-29, in turn, inhibited the progression of cardiac fibrosis through suppressing its target CDK2. Taken together, activation of AMPK, on the one hand, upregulated p21 and p27 expression, further inhibited CDK2 and cyclin E complex, and finally suppressed the progression of cardiac fibrosis, and, on the other hand, repressed HNF-4alpha expression, further downregulated the activity of TGF-beta1 promoter, promoted miR-29 expression, and finally prevented the development of cardiac fibrosis. PMID- 28918030 TI - LncRNA TRERNA1 Function as an Enhancer of SNAI1 Promotes Gastric Cancer Metastasis by Regulating Epithelial-Mesenchymal Transition. AB - Long noncoding RNA (lncRNA) has been implicated in cancer, but little is known about the role of lncRNAs as regulators of tumor metastasis. In the present study, we demonstrate that lncRNA TRERNA1 acts like an enhancer of SNAI1 to promote cell invasion and migration and to contribute to metastasis of gastric cancer (GC). TRERNA1 is significantly unregulated in GCs and GC cell lines. Increased TRERNA1 is positively correlated with lymph node metastasis of GCs. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays revealed that TRERNA1 functions as a scaffold to recruit EZH2 to epigenetically silence epithelial-mesenchymal transition marker CDH1 by H3K27me3 of its promoter region. TRERNA1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, and metastasis. Depletion of TRERNA1 reduced cell metastasis of GCs in vivo. Taken together, our findings indicated that TRERNA1 serves as a critical effector in GC progression by regulating CDH1 at the transcription level. It is implied that TRERNA1/CDH1 is a new potential target for GC therapy. PMID- 28918031 TI - Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters. AB - Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters. In vitro evaluation of amiRs targeting the E1A, pTP, IVa2, and hexon genes of hAd5 revealed that two scAAV vectors containing three copies of amiR-pTP and three copies of amiR-E1A, or six copies of amiR-pTP, efficiently inhibited hAd5 replication and improved the viability of hAd5-infected cells. Prophylactic application of amiR-pTP/amiR-E1A- and amiR-pTP-expressing scAAV9 vectors, respectively, to immunosuppressed Syrian hamsters resulted in the reduction of hAd5 levels in the liver of up to two orders of magnitude and in reduction of liver damage. Concomitant application of the vectors also resulted in a decrease of hepatic hAd5 infection. No side effects were observed. These data demonstrate anti-adenoviral RNAi as a promising new approach to combat hAd5 infection. PMID- 28918032 TI - MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR 31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity. PMID- 28918033 TI - Six Highly Conserved Targets of RNAi Revealed in HIV-1-Infected Patients from Russia Are Also Present in Many HIV-1 Strains Worldwide. AB - RNAi has been suggested for use in gene therapy of HIV/AIDS, but the main problem is that HIV-1 is highly variable and could escape attack from the small interfering RNAs (siRNAs) due to even single nucleotide substitutions in the potential targets. To exhaustively check the variability in selected RNA targets of HIV-1, we used ultra-deep sequencing of six regions of HIV-1 from the plasma of two independent cohorts of patients from Russia. Six RNAi targets were found that are invariable in 82%-97% of viruses in both cohorts and are located inside the domains specifying reverse transcriptase (RT), integrase, vpu, gp120, and p17. The analysis of mutation frequencies and their characteristics inside the targets suggests a likely role for APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G, A3G) in G-to-A mutations and a predominant effect of RT biases in the detected variability of the virus. The lowest frequency of mutations was detected in the central part of all six targets. We also discovered that the identical RNAi targets are present in many HIV-1 strains from many countries and from all continents. The data are important for both the understanding of the patterns of HIV-1 mutability and properties of RT and for the development of gene therapy approaches using RNAi for the treatment of HIV/AIDS. PMID- 28918034 TI - A Simple and Cost-Effective Approach for In Vitro Production of Sliced siRNAs as Potent Triggers for RNAi. AB - We have studied the molecular properties of in-vitro-transcribed sliced small interfering RNAs (tsli-siRNAs) as an alternative RNAi agent for chemically synthesized siRNA. We describe here a simple and cost-effective procedure for high-purity production of tsli-siRNA using bacteriophage T7 RNA polymerases. tsli siRNAs exhibit potent gene knockdown effects, with efficacy comparable with that of chemically synthesized sli-siRNAs and classical siRNAs. Furthermore, we found that it is very easy to prepare potent tsli-siRNAs with modified bases, such as 2'-fluorine- or biotin-16-modified tsli-siRNAs. tsli-siRNAs can cause a mild innate immune response, which can be easily eliminated by alkaline phosphatase treatment. On the other hand, this feature, which can be useful as a trigger of the innate immune response, can be enhanced by polynucleotide kinase treatment. Because of the simplicity of preparation and purification, the procedure presented here could be useful for the production of RNAi or immunostimulatory reagents. PMID- 28918035 TI - lncRNA HOTAIR Contributes to 5FU Resistance through Suppressing miR-218 and Activating NF-kappaB/TS Signaling in Colorectal Cancer. AB - One major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to fluoropyrimidine (FU)-based chemotherapy. Long non-coding RNA HOTAIR has been considered as a pro-oncogene in multiple cancers. However, the precise functional mechanism of HOTAIR in chemoresistance is not well known. In this study, we investigated the biological and clinical role of HOTAIR in 5FU resistance in CRC. Our results showed that HOTAIR negatively regulated miR-218 expression in CRC through an EZH2-targeting miR-218 2 promoter regulatory axis. HOTAIR knockdown dramatically inhibited cell viability and induced G1-phase arrest by promoting miR-218 expression. VOPP1 was shown to be a functional target of miR-218, and the main downstream signaling, NF kappaB, was inactivated by HOTAIR through the suppression of miR-218 expression. Additionally, HOTAIR knockdown partially reversed 5FU resistance through promoting miR-218 and inactivating NF-kappaB signaling. Furthermore, HOTAIR restrained 5FU-induced cytotoxicity on CRC cells through promotion of thymidylate synthase expression. More importantly, high HOTAIR expression was associated with poor response to 5FU treatment. In conclusion, we demonstrated that HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF kappaB signaling in CRC. Thus, HOTAIR may serve as a promising therapeutic target for CRC patients. PMID- 28918036 TI - Therapeutic Suppression of miR-4261 Attenuates Colorectal Cancer by Targeting MCC. AB - The mutated in colorectal cancer (MCC) gene is an important colorectal tumor suppressor gene, although few studies have reported the microRNA(s) that could directly target MCC in colorectal cancer. Here, we used microRNA (miRNA) target prediction algorithms, and previously reported microarray data in human colorectal cancer found that only miR-4261 was predicted by all three databases to directly target MCC. Based on specimens from our own cohort of colorectal cancer patients, we further demonstrated that miR-4261 was overexpressed in colorectal cancer. Interestingly, overexpression of miR-4261 could enhance cell proliferation and G1/S phase transition of cell cycle, and promote cell migration in HCT116 and HT29 cells, while inhibition of miR-4261 had opposite effects. Luciferase reporter assay and western blot analysis confirmed MCC as a direct target of miR-4261. MCC small interfering RNA (siRNA) could abolish the suppressive effects of miR-4261 inhibitor on cell proliferation and migration in HCT116 and HT29 cell lines. Finally, we showed that therapeutic intervention with lentivirus-based miR-4261 sponge injection could effectively reduce tumor growth and inhibit cell proliferation in colorectal cancer xenograft. Collectively, our study is the first one to unravel the functional role of miR-4261, and it provides strong evidence that inhibition of miR-4261 through targeting of MCC might exert a therapeutic effect for colorectal cancer. PMID- 28918038 TI - Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs. AB - Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome wide selectivity screen is a valid approach to identifying and progressing safer compounds. PMID- 28918037 TI - A Novel Pak1/ATF2/miR-132 Signaling Axis Is Involved in the Hematogenous Metastasis of Gastric Cancer Cells. AB - We, along with others, have shown previously that P21-activated kinase 1 (Pak1) plays a pivotal role in gastric cancer progression and metastasis. However, whether Pak1 controls gastric cancer metastasis by regulating microRNAs (miRNAs) has never been explored. Here, we report a novel mechanism of Pak1 in tumor metastasis. A detailed examination revealed that Pak1 interacts with and phosphorylates the serine 62 residue of ATF2 and then blocks its translocation into the nucleus. We also confirmed that ATF2 binds to the promoter of miR-132 and tightly regulates its transcription, thus explaining the regulatory mechanism of miR-132 by Pak1. miR-132 also significantly reduced cell adhesion, migration, and invasion of gastric cancer cells in vitro and significantly prevented tumor metastasis in vivo. miR-132 specifically inhibited hematogenous metastasis, but not lymph node or implantation metastases. In order to further delineate the effects of the Pak1/ATF2/miR-132 cascade on gastric cancer progression, we identified several targets of miR-132 using a bioinformatics TargetScan algorithm. Notably, miR-132 reduced the expression of CD44 and fibronectin1 (FN1), and such inhibition enabled lymphocytes to home in on gastric cancer cells and induce tumor apoptosis. Taken together, our studies establish a novel cell signaling pathway and open new possibilities for therapeutic intervention of gastric cancer. PMID- 28918039 TI - CRISPR/Cas9-Mediated Knockin Application in Cell Therapy: A Non-viral Procedure for Bystander Treatment of Glioma in Mice. AB - The use of non-viral procedures, together with CRISPR/Cas9 genome-editing technology, allows the insertion of single-copy therapeutic genes at pre determined genomic sites, overcoming safety limitations resulting from random gene insertions of viral vectors with potential for genome damage. In this study, we demonstrate that combination of non-viral gene delivery and CRISPR/Cas9 mediated knockin via homology-directed repair can replace the use of viral vectors for the generation of genetically modified therapeutic cells. We custom modified human adipose mesenchymal stem cells (hAMSCs), using electroporation as a transfection method and CRISPR/Cas9-mediated knockin for the introduction and stable expression of a 3 kb DNA fragment including the eGFP (selectable marker) and a variant of the herpes simplex virus 1 thymidine kinase genes (therapeutic gene), under the control of the human elongation factor 1 alpha promoter in exon 5 of the endogenous thymidine kinase 2 gene. Using a U87 glioma model in SCID mice, we show that the therapeutic capacity of the new CRISPR/Cas9-engineered hAMSCs is equivalent to that of therapeutic hAMSCs generated by introduction of the same therapeutic gene by transduction with a lentiviral vector previously published by our group. This strategy should be of general use to other applications requiring genetic modification of therapeutic cells. PMID- 28918040 TI - Codon-Optimized P1A-Encoding DNA Vaccine: Toward a Therapeutic Vaccination against P815 Mastocytoma. AB - DNA vaccine can be modified to increase protein production and modulate immune response. To enhance the efficiency of a P815 mastocytoma DNA vaccine, the P1A gene sequence was optimized by substituting specific codons with synonymous ones while modulating the number of CpG motifs. The P815A murine antigen production was increased with codon-optimized plasmids. The number of CpG motifs within the P1A gene sequence modulated the immunogenicity by inducing a local increase in the cytokines involved in innate immunity. After prophylactic immunization with the optimized vaccines, tumor growth was significantly delayed and mice survival was improved. Consistently, a more pronounced intratumoral recruitment of CD8+ T cells and a memory response were observed. Therapeutic vaccination was able to delay tumor growth when the codon-optimized DNA vaccine containing the highest number of CpG motifs was used. Our data demonstrate the therapeutic potential of optimized P1A vaccine against P815 mastocytoma, and they show the dual role played by codon optimization on both protein production and innate immune activation. PMID- 28918041 TI - Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy. AB - Dominant-negative mutations in the genes that encode the three major alpha chains of collagen type VI, COL6A1, COL6A2, and COL6A3, account for more than 50% of Ullrich congenital muscular dystrophy patients and nearly all Bethlem myopathy patients. Gapmer antisense oligonucleotides (AONs) are usually used for gene silencing by stimulating RNA cleavage through the recruitment of an endogenous endonuclease known as RNase H to cleave the RNA strand of a DNA-RNA duplex. In this study, we exploited the application of the allele-specific silencing approach by gapmer AON as a potential therapy for Collagen-VI-related congenital muscular dystrophy (COL6-CMD). A series of AONs were designed to selectively target an 18-nt heterozygous genomic deletion in exon 15 of COL6A3 at the mRNA and pre-mRNA level. We showed that gapmer AONs can selectively suppress the expression of mutant transcripts at both pre-mRNA and mRNA levels, and that the latter strategy had a far stronger efficiency than the former. More importantly, we found that silencing of the mutant transcripts by gapmer AONs increased the deposition of collagen VI protein into the extracellular matrix, thus restoring functional protein production. Our findings provide a clear proof of concept for AON allele-specific silencing as a therapeutic approach for COL6-CMD. PMID- 28918042 TI - Electronic Structures of LNA Phosphorothioate Oligonucleotides. AB - Important oligonucleotides in anti-sense research have been investigated in silico and experimentally. This involves quantum mechanical (QM) calculations and chromatography experiments on locked nucleic acid (LNA) phosphorothioate (PS) oligonucleotides. iso-potential electrostatic surfaces are essential in this study and have been calculated from the wave functions derived from the QM calculations that provide binding information and other properties of these molecules. The QM calculations give details of the electronic structures in terms of e.g., energy and bonding, which make them distinguish or differentiate between the individual PS diastereoisomers determined by the position of sulfur atoms. Rules are derived from the electronic calculations of these molecules and include the effects of the phosphorothioate chirality and formation of electrostatic potential surfaces. Physical and electrochemical descriptors of the PS oligonucleotides are compared to the experiments in which chiral states on these molecules can be distinguished. The calculations demonstrate that electronic structure, electrostatic potential, and topology are highly sensitive to single PS configuration changes and can give a lead to understanding the activity of the molecules. PMID- 28918044 TI - Targeted Disruption of V600E-Mutant BRAF Gene by CRISPR-Cpf1. AB - BRAF-V600E (1799T > A) is one of the most frequently reported driver mutations in multiple types of cancers, and patients with such mutations could benefit from selectively inactivating the mutant allele. Near this mutation site, there are two TTTN and one NGG protospacer-adjacent motifs (PAMs) for Cpf1 and Cas9 CRISPR nucleases, respectively. The 1799T > A substitution also leads to the occurrence of a novel NGNG PAM for the EQR variant of Cas9. We examined the editing efficacy and selectivity of Cpf1, Cas9, and EQR variant to this mutation site. Only Cpf1 demonstrated robust activity to induce specific disruption of only mutant BRAF, not wild-type sequence. Cas9 recognized and cut both normal and mutant alleles, and no obvious gene editing events were observed using EQR variant. Our results support the potential applicability of Cpf1 in precision medicine through highly specific inactivation of many other gain-of-function mutations. PMID- 28918043 TI - miR-206/133b Cluster: A Weapon against Lung Cancer? AB - Lung cancer is a deadly disease that ends numerous lives around the world. MicroRNAs (miRNAs) are a group of non-coding RNAs involved in a variety of biological processes, such as cell growth, organ development, and tumorigenesis. The miR-206/133b cluster is located on the human chromosome 6p12.2, which is essential for growth and rebuilding of skeletal muscle. The miR-206/133b cluster has been verified to be dysregulated and plays a crucial role in lung cancer. miR 206 and miR-133b participate in lung tumor cell apoptosis, proliferation, migration, invasion, angiogenesis, drug resistance, and cancer treatment. The mechanisms are sophisticated, involving various target genes and molecular pathways, such as MET, EGFR, and the STAT3/HIF-1alpha/VEGF signal pathway. Hence, in this review, we summarize the role and potential mechanisms of the miR 206/133b cluster in lung cancer. PMID- 28918045 TI - Cationic Nanoliposomes Meet mRNA: Efficient Delivery of Modified mRNA Using Hemocompatible and Stable Vectors for Therapeutic Applications. AB - Synthetically modified mRNA is a unique bioactive agent, ideal for use in therapeutic applications, such as cancer vaccination or treatment of single-gene disorders. In order to facilitate mRNA transfections for future therapeutic applications, there is a need for the delivery system to achieve optimal transfection efficacy, perform with durable stability, and provide drug safety. The objective of our study was to comprehensively analyze the use of 3beta-[N (N',N'-dimethylaminoethane) carbamoyl](DC Cholesterol)/dioleoylphosphatidylethanolamine (DOPE) liposomes as a potential transfection agent for modified mRNAs. Our cationic liposomes facilitated a high degree of mRNA encapsulation and successful cell transfection efficiencies. More importantly, no negative effects on cell viability or immune reactions were detected posttransfection. Notably, the liposomes had a long-acting transfection effect on cells, resulting in a prolonged protein production of alpha-1 antitrypsin (AAT). In addition, the stability of these mRNA-loaded liposomes allowed storage for 80 days, without the loss of transfection efficacy. Finally, comprehensive analysis showed that these liposomes are fully hemocompatible with fresh human whole blood. In summary, we present an extensive analysis on the use of DC-cholesterol/DOPE liposomes as mRNA delivery vehicles. This approach provides the basis of a safe and efficient therapeutic strategy in the development of successful mRNA-based drugs. PMID- 28918047 TI - Long Noncoding RNA BC032913 as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3. AB - Long noncoding RNAs (lncRNAs) have been shown to play critical roles in the biology of various cancers. However, their expression patterns and biological functions in human colorectal cancer (CRC) remain largely unknown. The aim of this study was to explore lncRNA profiles in CRC and investigate key lncRNAs involved in CRC tumorigenesis and progression. The microarray data of six CRC and matched non-cancerous tissues revealed distinct lncRNA profiles, including 899 upregulated and 1,646 downregulated lncRNAs (p < 0.05, fold change > 2.0). Furthermore, we found that the lncRNA BC032913 was generally underexpressed in 115 CRC samples compared with normal tissues. Reduced BC032913 levels were significantly associated with an advanced tumor, lymph nodes, distant metastasis (TNM) stage and a higher risk of lymph node and distant metastases. BC032913 downregulation indicated poor overall survival in CRC patients. Moreover, BC032913 enhanced the mRNA and protein expression of TIMP3 and inhibited Wnt/beta catenin pathway activity, thus suppressing CRC metastasis in vitro and in vivo. Collectively, the obtained data show that BC032913 plays an inhibitory role in CRC aggression by upregulating TIMP3, followed by inactivation of the Wnt/beta catenin pathway. Our findings indicate that the novel lncRNA BC032913 could serve as a novel prognostic marker and effective therapeutic target for CRC. PMID- 28918049 TI - Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo. PMID- 28918048 TI - miR-133a Promotes TRAIL Resistance in Glioblastoma via Suppressing Death Receptor 5 and Activating NF-kappaB Signaling. AB - Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-kappaB family member, phosphorylated IkappaBalpha (P-IkappaBalpha), was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-kappaB signaling. PMID- 28918046 TI - MicroRNA as Therapeutic Targets for Chronic Wound Healing. AB - Wound healing is a highly complex biological process composed of three overlapping phases: inflammation, proliferation, and remodeling. Impairments at any one or more of these stages can lead to compromised healing. MicroRNAs (miRs) are non-coding RNAs that act as post-transcriptional regulators of multiple proteins and associated pathways. Thus, identification of the appropriate miR involved in the different phases of wound healing could reveal an effective third generation genetic therapy in chronic wound care. Several miRs have been shown to be upregulated or downregulated during the wound healing process. This article examines the biological processes involved in wound healing, the miR involved at each stage, and how expression levels are modulated in the chronic wound environment. Key miRs are highlighted as possible therapeutic targets, either through underexpression or overexpression, and the healing benefits are interrogated. These are prime miR candidates that could be considered as a gene therapy option for patients suffering from chronic wounds. The success of miR as a gene therapy, however, is reliant on the development of an appropriate delivery system that must be designed to overcome both extracellular and intracellular barriers. PMID- 28918051 TI - LRRK2 Antisense Oligonucleotides Ameliorate alpha-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. AB - No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking alpha synuclein (alpha-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced alpha-syn inclusions. Mice exposed to alpha-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of alpha-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition. PMID- 28918050 TI - The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease. AB - The popularization of genome-wide analyses and RNA sequencing led to the discovery that a large part of the human genome, while effectively transcribed, does not encode proteins. Long non-coding RNAs have emerged as critical regulators of gene expression in both normal and disease states. Studies of long non-coding RNAs expressed in the heart, in combination with gene association studies, revealed that these molecules are regulated during cardiovascular development and disease. Some long non-coding RNAs have been functionally implicated in cardiac pathophysiology and constitute potential therapeutic targets. Here, we review the current knowledge of the function of long non-coding RNAs in the cardiovascular system, with an emphasis on cardiovascular development and biology, focusing on hypertension, coronary artery disease, myocardial infarction, ischemia, and heart failure. We discuss potential therapeutic implications and the challenges of long non-coding RNA research, with directions for future research and translational focus. PMID- 28918052 TI - A CTLA-4 Antagonizing DNA Aptamer with Antitumor Effect. AB - The successful translation of cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade has revolutionized the concept of cancer immunotherapy. Although monoclonal antibody therapeutics remain the mainstream in clinical practice, aptamers are synthetic oligonucleotides that encompass antibody-mimicking functions. Here, we report a novel high-affinity CTLA-4-antagonizing DNA aptamer (dissociation constant, 11.84 nM), aptCTLA-4, which was identified by cell-based SELEX and high throughput sequencing. aptCTLA-4 is relatively stable in serum, promotes lymphocyte proliferation, and inhibits tumor growth in cell and animal models. Our study demonstrates the developmental pipeline of a functional CTLA-4 targeting aptamer and suggests a translational potential for aptCTLA-4. PMID- 28918053 TI - USH2A Gene Editing Using the CRISPR System. AB - Usher syndrome (USH) is a rare autosomal recessive disease and the most common inherited form of combined visual and hearing impairment. Up to 13 genes are associated with this disorder, with USH2A being the most prevalent, due partially to the recurrence rate of the c.2299delG mutation. Excluding hearing aids or cochlear implants for hearing impairment, there are no medical solutions available to treat USH patients. The repair of specific mutations by gene editing is, therefore, an interesting strategy that can be explored using the CRISPR/Cas9 system. In this study, this method of gene editing is used to target the c.2299delG mutation on fibroblasts from an USH patient carrying the mutation in homozygosis. Successful in vitro mutation repair was demonstrated using locus specific RNA-Cas9 ribonucleoproteins with subsequent homologous recombination repair induced by an engineered template supply. Effects on predicted off-target sites in the CRISPR-treated cells were discarded after a targeted deep-sequencing screen. The proven effectiveness and specificity of these correction tools, applied to the c.2299delG pathogenic variant of USH2A, indicates that the CRISPR system should be considered to further explore a potential treatment of USH. PMID- 28918055 TI - The Chromatin Structure Differentially Impacts High-Specificity CRISPR-Cas9 Nuclease Strategies. PMID- 28918054 TI - Rapid and Sensitive Detection of Breast Cancer Cells in Patient Blood with Nuclease-Activated Probe Technology. AB - A challenge for circulating tumor cell (CTC)-based diagnostics is the development of simple and inexpensive methods that reliably detect the diverse cells that make up CTCs. CTC-derived nucleases are one category of proteins that could be exploited to meet this challenge. Advantages of nucleases as CTC biomarkers include: (1) their elevated expression in many cancer cells, including cells implicated in metastasis that have undergone epithelial-to-mesenchymal transition; and (2) their enzymatic activity, which can be exploited for signal amplification in detection methods. Here, we describe a diagnostic assay based on quenched fluorescent nucleic acid probes that detect breast cancer CTCs via their nuclease activity. This assay exhibited robust performance in distinguishing breast cancer patients from healthy controls, and it is rapid, inexpensive, and easy to implement in most clinical labs. Given its broad applicability, this technology has the potential to have a substantive impact on the diagnosis and treatment of many cancers. PMID- 28918056 TI - The Therapeutic Potential of CRISPR/Cas9 Systems in Oncogene-Addicted Cancer Types: Virally Driven Cancers as a Model System. AB - The field of gene editing is undergoing unprecedented growth. The first ex vivo human clinical trial in China started in 2016, more than 1000 US patents have been filed, and there is exponential growth in publications. The ability to edit genes with high fidelity is promising for the development of new treatments for a range of diseases, particularly inherited conditions, infectious diseases, and cancers. For cancer, a major issue is the identification of driver mutations and oncogenes to target for therapeutic effect, and this requires the development of robust models with which to prove their efficacy. The challenge is that there is rarely a single critical gene. However, virally driven cancers, in which cells are addicted to the expression of a single viral oncogene in some cases, may serve as model systems for CRISPR/Cas therapies, as they did for RNAi. These models and systems offer an excellent opportunity to test both preclinical models and clinical conditions to examine the effectiveness of gene editing, and here we review the options and offer a way forward. PMID- 28918057 TI - One-Step piggyBac Transposon-Based CRISPR/Cas9 Activation of Multiple Genes. AB - Neural cell fate is determined by a tightly controlled transcription regulatory network during development. The ability to manipulate the expression of multiple transcription factors simultaneously is required to delineate the complex picture of neural cell development. Because of the limited carrying capacity of the commonly used viral vectors, such as lentiviral or retroviral vectors, it is often challenging to perform perturbation experiments on multiple transcription factors. Here we have developed a piggyBac (PB) transposon-based CRISPR activation (CRISPRa) all-in-one system, which allows for simultaneous and stable endogenous transactivation of multiple transcription factors and long non-coding RNAs. As a proof of principle, we showed that the PB-CRISPRa system could accelerate the differentiation of human induced pluripotent stem cells into neurons and astrocytes by triggering endogenous expression of different sets of transcription factors. The PB-CRISPRa system has the potential to become a convenient and robust tool in neuroscience, which can meet the needs of a variety of in vitro and in vivo gain-of-function applications. PMID- 28918058 TI - Reducible PEG-POD/DNA Nanoparticles for Gene Transfer In Vitro and In Vivo: Application in a Mouse Model of Age-Related Macular Degeneration. AB - Non-viral gene delivery systems are being developed to address limitations of viral gene delivery. Many of these non-viral systems are modeled on the properties of viruses including cell surface binding, endocytosis, endosomal escape, and nuclear targeting. Most non-viral gene transfer systems exhibit little correlation between in vitro and in vivo efficiency, hampering a systematic approach to their development. Previously, we have described a 3.5 kDa peptide (peptide for ocular delivery [POD]) that targets cell surface sialic acid. When functionalized with polyethylene glycol (PEG) via a sulfhydryl group on the N-terminal cysteine of POD, PEG-POD could compact plasmid DNA, forming 120 to 180-nm homogeneous nanoparticles. PEG-POD enabled modest gene transfer and rescue of retinal degeneration in vivo. Systematic investigation of different stages of gene transfer by PEG-POD nanoparticles was hampered by their inability to deliver genes in vitro. Herein, we describe functionalization of POD with PEG using a reducible orthopyridyl disulfide bond. These reducible nanoparticles enabled gene transfer in vitro while retaining their in vivo gene transfer properties. These reducible PEG-POD nanoparticles were utilized to deliver human FLT1 to the retina in vivo, achieving a 50% reduction in choroidal neovascularization in a murine model of age-related macular degeneration. PMID- 28918059 TI - Regulatory Role of the MicroRNA-29b-IL-6 Signaling in the Formation of Vascular Mimicry. AB - Vascular mimicry (VM) is a critical complement for microcirculation and is implicated in tumor progression. We showed that IL-6 derived from tumor cells and stroma cells promoted tumor cells to form a VM structure, whereas blocking the IL 6 signaling by RNA interference, IL-6-neutralizing antibody, or STAT3 inhibitor suppressed the VM formation of tumor cells. Mechanism investigations revealed that IL-6 stimulated VM formation by activating STAT3, in turn upregulating VE cadherin expression and MMP2 activity. Further analyses identified a positive association between the activation of IL-6-STAT3 signaling and the formation of the VM structure in human HCC tissues. However, miR-29b repressed the expression of STAT3 and MMP2 by directly binding to the 3' UTRs of their mRNAs. Consistently, both gain- and loss-of-function analyses showed that miR-29b suppressed tumor cells to form tube structures in vitro. The in vivo studies further disclosed that intratumoral injection of the miR-29b-expressing viruses significantly inhibited the IL-6-promoted VM formation in mouse xenografts, and downregulation of miR-29b was correlated with the presence of VM in human HCC tissues. This study elucidates a miR-29b-IL-6 signaling cascade and its role in VM formation, which provide potential targets for cancer therapy. PMID- 28918060 TI - Outcomes of Ahmed Glaucoma Valve Revision in Pediatric Glaucoma. AB - PURPOSE: Encapsulation of the Ahmed glaucoma valve (AGV) plate is a common cause for postoperative elevation of intraocular pressure, especially in children. Many reports have described the outcomes of AGV revision in adults. However, the outcomes of AGV revision in children are poorly documented. The aim of this study was to determine the outcomes of AGV revision in children. DESIGN: Retrospective cross-sectional study. METHODS: A retrospective chart review of patients less than 15 years of age who underwent AGV revision with a minimum postoperative follow-up of 6 months was conducted. Outcome measures included reduction in intraocular pressure from baseline, survival analysis, and reduction in the number of antiglaucoma medications. Postoperative complications were also noted. Complete success was defined as an IOP of 21 mm Hg or less without medications, while qualified success was defined as having an IOP of 21 mm Hg or less with medications. RESULTS: A total of 44 eyes met the inclusion criteria. Primary congenital glaucoma was present in 39 eyes (88.6%), aphakic glaucoma in 4 eyes (9.1%), and Peters anomaly-associated glaucoma in 1 eye (2.3%). The mean number of previous surgeries was 1.4, and the mean age was 6.7 years (range, 1.9-13 years) with a median follow-up of 12 months (range, 6-24 months). The IOP was reduced from a preoperative mean of 30.4 (+/- 10.3) to 24.9 (+/- 10.6) mm Hg at 6 months postoperatively. Kaplan-Meier analysis showed that the complete success rate at 1 month was 100% followed by a rapid decline at 6 months to 38.6%, 27.7% at 1 year, and 5.5% at 2 years. Qualified success rate was 100% at 1 month followed by a 6-month and 1-year survival rate of approximately 50% and a 2-year survival rate of approximately 16%. The median survival time was 14 months. No specific risk factors for failure were identified. Visual acuity remained unchanged following revision. The most common complication was recurrence of encapsulation with elevated IOP (15.9%). Other complications included hyphema (n = 3; 6.8%), endophthalmitis (n = 1; 2.3%), wound leak (n = 1; 2.3%), and choroidal detachment (n = 2; 4.5%). CONCLUSION: Although the short-term success rate of AGV revision in children is high, with longer follow-up the success rate decreases significantly. PMID- 28918061 TI - Improved fuzzy PID controller design using predictive functional control structure. AB - In conventional PID scheme, the ensemble control performance may be unsatisfactory due to limited degrees of freedom under various kinds of uncertainty. To overcome this disadvantage, a novel PID control method that inherits the advantages of fuzzy PID control and the predictive functional control (PFC) is presented and further verified on the temperature model of a coke furnace. Based on the framework of PFC, the prediction of the future process behavior is first obtained using the current process input signal. Then, the fuzzy PID control based on the multi-step prediction is introduced to acquire the optimal control law. Finally, the case study on a temperature model of a coke furnace shows the effectiveness of the fuzzy PID control scheme when compared with conventional PID control and fuzzy self-adaptive PID control. PMID- 28918062 TI - Detection of no-model input-output pairs in closed-loop systems. AB - The detection of no-model input-output (IO) pairs is important because it can speed up the multivariable system identification process, since all the pairs with null transfer functions are previously discarded and it can also improve the identified model quality, thus improving the performance of model based controllers. In the available literature, the methods focus just on the open-loop case, since in this case there is not the effect of the controller forcing the main diagonal in the transfer matrix to one and all the other terms to zero. In this paper, a modification of a previous method able to detect no-model IO pairs in open-loop systems is presented, but adapted to perform this duty in closed loop systems. Tests are performed by using the traditional methods and the proposed one to show its effectiveness. PMID- 28918063 TI - A PCA-Based method for determining craniofacial relationship and sexual dimorphism of facial shapes. AB - Previous studies have used principal component analysis (PCA) to investigate the craniofacial relationship, as well as sex determination using facial factors. However, few studies have investigated the extent to which the choice of principal components (PCs) affects the analysis of craniofacial relationship and sexual dimorphism. In this paper, we propose a PCA-based method for visual and quantitative analysis, using 140 samples of 3D heads (70 male and 70 female), produced from computed tomography (CT) images. There are two parts to the method. First, skull and facial landmarks are manually marked to guide the model's registration so that dense corresponding vertices occupy the same relative position in every sample. Statistical shape spaces of the skull and face in dense corresponding vertices are constructed using PCA. Variations in these vertices, captured in every principal component (PC), are visualized to observe shape variability. The correlations of skull- and face-based PC scores are analysed, and linear regression is used to fit the craniofacial relationship. We compute the PC coefficients of a face based on this craniofacial relationship and the PC scores of a skull, and apply the coefficients to estimate a 3D face for the skull. To evaluate the accuracy of the computed craniofacial relationship, the mean and standard deviation of every vertex between the two models are computed, where these models are reconstructed using real PC scores and coefficients. Second, each PC in facial space is analysed for sex determination, for which support vector machines (SVMs) are used. We examined the correlation between PCs and sex, and explored the extent to which the choice of PCs affects the expression of sexual dimorphism. Our results suggest that skull- and face-based PCs can be used to describe the craniofacial relationship and that the accuracy of the method can be improved by using an increased number of face-based PCs. The results show that the accuracy of the sex classification is related to the choice of PCs. The highest sex classification rate is 91.43% using our method. PMID- 28918064 TI - Synthesis and in vitro study of benzofuran hydrazone derivatives as novel alpha amylase inhibitor. AB - The alpha-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as alpha-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as 1HNMR and EI-MS. All screened analog shows good alpha-amylase inhibitory potentials with IC50 value ranging between 1.078+/-0.19 and 2.926+/-0.05uM when compared with acarbose having IC50=0.62+/ 0.22uM. Only nine analogs among the series such as analogs 3, 5, 7, 8, 10, 12, 21, 23 and 24 exhibit good inhibitory potential with IC50 values 1.644+/-0.128, 1.078+/-0.19, 1.245+/-0.25, 1.843+/-0.19, 1.350+/-0.24, 1.629+/-0.015, 1.353+/ 0.232, 1.359+/-0.119 and 1.488+/-0.07uM when compare with standard drug acarbose. All other analogs showed good to moderate alpha-amylase inhibitory potentials. The SAR study was conducted on the basis of substituent difference at the phenyl ring. The binding interaction between analogs and active site of enzyme was confirmed by docking studies. PMID- 28918065 TI - The role of epigenetics in lysosomal storage disorders: Uncharted territory. AB - The study of the contribution of epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, to human disease has enhanced our understanding of different cellular processes and diseased states, as well as the effect of environmental factors on phenotypic outcomes. Epigenetic studies may be particularly relevant in evaluating the clinical heterogeneity observed in monogenic disorders. The lysosomal storage disorders are Mendelian disorders characterized by a wide spectrum of associated phenotypes, ranging from neonatal presentations to symptoms that develop in late adulthood. Some lack a tight genotype/phenotype correlation. While epigenetics may explain some of the discordant phenotypes encountered in patients with the same lysosomal storage disorder, especially among patients sharing the same genotype, to date, few studies have focused on these mechanisms. We review three common epigenetic mechanisms, DNA methylation, histone modifications, and microRNAs, and highlight their applications to phenotypic variation and therapeutics. Three specific lysosomal storage diseases, Gaucher disease, Fabry disease, and Niemann-Pick type C disease are presented as prototypical disorders with vast clinical heterogeneity that may be impacted by epigenetics. Our goal is to motivate researchers to consider epigenetics as a mechanism to explain the complexities of biological functions and pathologies of these rare disorders. PMID- 28918066 TI - Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. AB - Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder. We sought to evaluate the diagnostic sensitivity and variability of the various PDC enzyme assays in females and males at the Center for Inherited Disorders of Energy Metabolism (CIDEM). CIDEM data were filtered by lactic acidosis and functional PDC deficiency in at least one cell/tissue type (blood lymphocytes, cultured fibroblasts or skeletal muscle) identifying 186 subjects (51% male and 49% female), about half were genetically resolved with 78% of those determined to have a pathogenic PDHA1 mutation. Assaying PDC in cultured fibroblasts in cases where the underlying genetic etiology is PDHA1, was highly sensitive irrespective of gender; 97% (95% confidence interval [CI]: 90%-100%) and 91% (95% CI: 82%-100%) in females and males, respectively. In contrast to the fibroblast-based testing, the lymphocyte- and muscle-based testing were not sensitive (36% [95% CI: 11%-61%, p=0.0003] and 58% [95% CI: 30%-86%, p=0.014], respectively) for identifying known PDC deficient females with pathogenic PDHA1 mutations. In males with a known PDHA1 mutation, the sensitivity of the various cell/tissue assays (75% lymphocyte, 91% fibroblast and 88% muscle) were not statistically different, and the discordance frequency due to the specific cell/tissue used for assaying PDC was 0.15+/-0.11. Based on this data, a practical diagnostic algorithm is proposed accounting for current molecular approaches, enzyme testing sensitivity, and variability due to gender, cell/tissue type used for testing, and successive repeat testing. PMID- 28918067 TI - Corrigendum to "Malaria surveillance in the Democratic Republic of the Congo: Comparison of microscopy, PCR, and rapid diagnostic test" [Diagn Microbiol Infect Dis. 2016 May;85(1):16-8. doi: 10.1016/j.Diagmicrobio.2016.01.004. Epub 2016 Jan 9]. PMID- 28918068 TI - A simple and rapid DNA extraction method for Chlamydia trachomatis detection from urogenital swabs. AB - A highly sensitive and specific Chlamydia trachomatis (CT) diagnostic test was developed by combining filtration isolation of nucleic acid (FINA) extraction with quantitative polymerase chain reaction including an internal control to identify test inhibition. A pilot study of 40 clinical specimens yielded 100% sensitivity and specificity. PMID- 28918069 TI - Studies that report unexpected positive blood cultures for Lyme borrelia - are they valid? AB - Positive blood cultures for Lyme borrelia have been well documented in untreated patients with early Lyme disease. In this report we review the validity of three studies that reported the recovery of Borrelia burgdorferi sensu lato from the blood of a high proportion of patients for whom no evidence was presented, and no claim was made, that the patients had untreated early Lyme disease. In two of the studies the patients had been treated extensively with antibiotics for Lyme disease before the cultures were obtained. Critical evaluation of the three reports suggests that they are invalid. Indeed, two subsequently published studies could not reproduce the results of one of the reports. In a published analysis of another of the reports, investigators from the Centers for Disease Control and Prevention concluded that the cultures were likely to have been contaminated. When the biologic plausibility of recovering borrelia from blood is extremely low, the level of scientific rigor required of a study that claims a positive result should be particularly high. PMID- 28918070 TI - Selective solid-phase extraction based on molecularly imprinted technology for the simultaneous determination of 20 triazole pesticides in cucumber samples using high-performance liquid chromatography-tandem mass spectrometry. AB - A selective analytical method for the simultaneous determination of 20 triazole fungicides and plant growth regulators in cucumber samples was developed using solid-phase extraction with specific molecularly imprinted polymers (MIPs) as adsorbents. The MIPs were successfully prepared by precipitation polymerization using triadimefon as the template molecule, methacrylic acid as the functional monomer, trimethylolpropane trimethacrylate as the crosslinker, and acetonitrile as the porogen. The performance and recognition mechanism for both the MIPs and non-molecularly imprinted polymers were evaluated using adsorption isotherms and adsorption kinetics. Liquid chromatography-tandem quadrupole mass spectrometry was used to identify and quantify the target analytes. The solid-phase extraction using the MIPs was rapid, convenient, and efficient for extraction and enrichment of the 20 triazole pesticides from cucumber samples. The recoveries obtained at three concentration levels (1, 2, and 10MUgL-1) ranged from 82.3% to 117.6% with relative standard deviations of less than 11.8% (n=5) for all analytes. The limits of detection for the 20 triazole pesticides were all less than 0.4MUgL-1, and were sufficient to meet international standards. PMID- 28918071 TI - The masseteric nerve: An anatomical study in Thai population with an emphasis on its use in facial reanimation. AB - BACKGROUND: The use of the masseteric nerve has been escalated as a donor nerve for facial reanimation in facial palsy patient (Wang et al., 2014; Manktelow et al., 2006; Klebuc, 2011; Bianchi et al., 2012; Zuker et al., 2000; Bae et al., 2006; Terzis, Konofaos, 2013; Terzis, Olivares, 2009; Bianchi et al., 2014). Previous studies had been done in Euro-Caucasian cadavers (Kaya et al., 2014). However, difference in anatomical details does exist between Asian and Euro Caucasian population (Tzou et al., 2005; Farkas et al., 2005). In this study, we have conducted a detailed anatomical study of masseteric nerve in adult Thai cadavers which might elaborate better details of masseteric nerve anatomy in Asian population. METHODS: Twenty eight hemifaces from 14 adult Thai non formaldehyde preserved soft cadavers were used in this study. The anatomical pathway of the masseteric nerve was defined relating to four surgical landmarks which are auricular tragus, zygomatic arch, posterior border of the temporomandibular joint, and alar base. RESULTS: The suitable starting area for the masseteric nerve dissection is 3.7 +/- 0.4 cm anterior to the auricular tragus at the level of 0.8 +/- 0.2 cm inferior to the zygomatic arch. The nerve was found 1.1 +/- 0.2 cm deep to the superficial surface of the masseteric fascia and 1.7 +/- 0.2 cm anterior to the posterior border of the temporomandibular joint. The point where the nerve giving off its first branch as it courses distally is 7.3 +/- 0.7 cm from the ipsilateral alar base. The mean diameter of this nerve is 1.59 +/- 0.42 mm. CONCLUSION: The anatomy of the masseteric nerve during its course in the muscle is consistent. In our study, the details of its anatomy is slightly different from the previous works which were performed in the Euro-Caucasian cadavers. PMID- 28918072 TI - Development of a duplex semi-nested PCR assay for detection of classical goose parvovirus and novel goose parvovirus-related virus in sick or dead ducks with short beak and dwarfism syndrome. AB - Duck short beak and dwarfism syndrome (SBDS) is an emerging infectious disease caused by a novel goose parvovirus-related virus (NGPV) in China. Until now, it remains uncertain whether the Cherry Valley ducks and mule ducks with SBDS are co infected with classical goose parvovirus (GPV) and NGPV. In this study, a duplex semi-nested PCR assay with high specificity and sensitivity was developed for detection of the two viruses. Using the duplex PCR assay, NGPV was tested positive in all the 15 duck flocks with SBDS, whereas classical GPV was not detected in all the 133 sick and dead ducks collected from East China. A total of 87 (91.58%) Cherry Valley ducks aged from 5 to 18days and 35 (92.11%) mule ducks aged from 17 to 25days were detected positive for NGPV. In the NGPV-positive ducks, the virus detection rates were 81.97% to 8.20% in heart, liver, spleen, lung, kidney, pancreas, bile, thymus, bursa of Fabricius, and brain. The results indicated that NGPV was prevalent in the duck flocks of East China, whereas classical GPV was not detected in Cherry Valley ducks and mule ducks with SBDS. NGPV has extensive tissue tropism in Cherry Valley duck and mule duck, which could invade both the central and peripheral immune organs and break through the blood-brain barrier of ducks. PMID- 28918074 TI - Rapid Adenovirus typing method for species identification. AB - Adenoviruses are characterized by a large variability, reflected by their classification in species A to G. Certain species, eg A and C, could be associated with increased clinical severity, both in immunocompetent and immunocompromised hosts suggesting that in some instances species identification provides clinically relevant information. Here we designed a novel "pVI rapid typing method" to obtain quick, simple and cost effective species assignment for Adenoviruses, thanks to combined fusion temperature (Tm) and amplicon size analysis. Rapid typing results were compared to Sanger sequencing in the hexon gene for 140 Adenovirus-positive clinical samples included in the Typadeno study. Species A and C could be identified with a 100% positive predictive value, thus confirming the value of this simple typing method. PMID- 28918073 TI - A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line. AB - A directed evolution approach was used to select for Adeno-associated virus (AAV) capsids that would exhibit more tropism toward an HIV-1 producer T cell line with the long-term goal of developing improved gene transfer vectors. A library of AAV variants was used to infect H9 T cells previously infected or uninfected by HIV-1 followed by AAV amplification with wild-type adenovirus. Six rounds of biological selection were performed, including negative selection and diversification after round three. The H9 T cells were successfully infected with all three wild-type viruses (AAV, adenovirus, and HIV-1). Four AAV cap mutants best representing the small number of variants emerging after six rounds of selection were chosen for further study. These mutant capsids were used to package an AAV vector and subsequently used to infect H9 cells that were previously infected or uninfected by HIV-1. A quantitative polymerase chain reaction assay was performed to measure cell-associated AAV genomes. Two of the four cap mutants showed a significant increase in the amount of cell-associated genomes as compared to wild-type AAV2. This study shows that directed evolution can be performed successfully to select for mutants with improved tropism for a T cell line in the presence of HIV-1. PMID- 28918075 TI - Direct detection of Trichomonas vaginalis virus in Trichomonas vaginalis positive clinical samples from the Netherlands. AB - Trichomonas vaginalis is the most common sexually transmitted parasitical infection worldwide. T. vaginalis can carry a virus: Trichomonas vaginalis virus (TVV). To date, four TVV species have been described. Few studies have investigated TVV prevalence and its clinical importance. We have developed a nested reverse-transcriptase PCR, with novel, type specific primers to directly detect TVV RNA in T. vaginalis positive clinical samples. A total of 119T. vaginalis positive clinical samples were collected in Amsterdam and "s Hertogenbosch, the Netherlands, from 2012 to 2016. For all samples T. vaginalis was genotyped using multi-locus sequence typing. The T. vaginalis positive samples segregated into a two-genotype population: type I (n=64) and type II (n=55). All were tested for TVV with the new TVV PCR. We detected 3 of the 4 TVV species. Sequencing of the amplified products showed high homology with published TVV genomes (82-100%). Half of the T. vaginalis clinical samples (n=60, 50.4%) were infected with one or more TVV species, with a preponderance for TVV infections in T. vaginalis type I (n=44, 73.3%). Clinical data was available for a subset of samples (n=34) and we observed an association between testing positive for (any) TVV and reporting urogenital symptoms (p=0.023). The nested RT PCR allowed for direct detection of TVV in T. vaginalis positive clinical samples. This may be helpful in studies and clinical settings, since T. vaginalis disease and/or treatment outcome may be influenced by the protozoa"s virus. PMID- 28918076 TI - Simultaneous detection of wheat dwarf virus, northern cereal mosaic virus, barley yellow striate mosaic virus and rice black-streaked dwarf virus in wheat by multiplex RT-PCR. AB - Wheat dwarf virus (WDV), barley yellow striate mosaic virus (BYSMV), rice black streaked dwarf virus (RBSDV) and northern cereal mosaic virus (NCMV) are four viruses infecting wheat and causing similar symptoms. In this paper, a multiplex reverse transcription polymerase chain reaction (m-RT-PCR) method has been developed for the simultaneous detection and discrimination of these viruses. The protocol uses specific primer set for each virus and produces four distinct fragments (273, 565, 783 and 1296bp), detecting the presence of RBSDV, BYSMV, WDV and NCMV, respectively. Annealing temperature, concentrations of dNTP, Taq polymerase and Mg2+ were optimized for the m-RT-PCR. The detection limit of the assay was up to 10-2 dilution. The amplification specificity of these primers was tested against a range of field samples from different regions of China, where RBSDV, BYSMV, WDV have been detected. This study fulfills the need for a rapid and specific wheat virus detection that also has the potential for investigating the epidemiology of these new viral diseases. PMID- 28918077 TI - Membrane electro-oxidizer: A new hybrid membrane system with electrochemical oxidation for enhanced organics and fouling control. AB - The synergistic combination of membrane filtration with advanced oxidation is of particular interest for next-generation wastewater treatment technologies. A membrane electro-oxidizer (MEO) hybridizing a submerged microfilter and an electrochemical cell was developed and investigated for tertiary treatment of secondary industrial (textile) wastewater effluent. Laboratory- and pilot-scale MEO systems were designed and evaluated for treatment efficiency and membrane fouling control. The MEO achieved substantial removal of color (50-90%), turbidity (>90%), and bacteria (>4 log) as well as chemical oxygen demand (13 31%) and 1,4-dioxane (~25-53%). Fluorescence-based parallel factor analysis disclosed the degradation of humic-like organics with fluorophores. Size exclusion chromatograms with organic carbon detection confirmed the removal of specific organic molecules with ~100 Da. While investigating the effects of oxidant quenching agents, reactive chlorine species and hydrogen peroxide were found to be most responsible for the anodic oxidation of secondary effluent organics. The efficacy of membrane fouling mitigation by the MEO was greater when higher electric current densities were applied, but was not dependent on the number of electrochemical cells installed. The MEO is a promising technology for enhanced organics removal with simultaneous fouling control due to its multifunctional active oxidants. PMID- 28918078 TI - Assessment of environmental impacts and operational costs of the implementation of an innovative source-separated urine treatment. AB - Innovative treatment technologies and management methods are necessary to valorise the constituents of wastewater, in particular nutrients from urine (highly concentrated and can have significant impacts related to artificial fertilizer production). The FP7 project, ValuefromUrine, proposed a new two-step process (called VFU) based on struvite precipitation and microbial electrolysis cell (MEC) to recover ammonia, which is further transformed into ammonium sulphate. The environmental and economic impacts of its prospective implementation in the Netherlands were evaluated based on life cycle assessment (LCA) methodology and operational costs. In order to tackle the lack of stable data from the pilot plant and the complex effects on wastewater treatment plant (WWTP), process simulation was coupled with LCA and costs assessment using the Python programming language. Additionally, particular attention was given to the propagation and analysis of inputs uncertainties. Five scenarios of VFU implementation were compared to the conventional treatment of 1 m3 of wastewater. Inventory data were obtained from SUMO software for the WWTP operation. LCA was based on Brightway2 software (using ecoinvent database and ReCiPe method). The results, based on 500 iterations sampled from inputs distributions (foreground parameters, ecoinvent background data and market prices), showed a significant advantage of VFU technology, both at a small and decentralized scale and at a large and centralized scale (95% confidence intervals not including zero values). The benefits mainly concern the production of fertilizers, the decreased efforts at the WWTP, the water savings from toilets flushing, as well as the lower infrastructure volumes if the WWTP is redesigned (in case of significant reduction of nutrients load in wastewater). The modelling approach, which could be applied to other case studies, improves the representativeness and the interpretation of results (e.g. complex relationships, global sensitivity analysis) but requires additional efforts (computing and engineering knowledge, longer calculation time). Finally, the sustainability assessment should be refined in the future with the development of the technology at larger scale to update these preliminary conclusions before its commercialization. PMID- 28918079 TI - Clogging of an Alpine streambed by silt-sized particles - Insights from laboratory and field experiments. AB - Clogging of streambeds by suspended particles (SP) can cause environmental problems, as it can negatively influence, e.g., habitats for macrozoobenthos, fish reproduction and groundwater recharge. This especially applies in the case of silt-sized SP. Until now, most research has dealt with coarse SP and was carried out in laboratory systems. The aims of this study are to examine (1) whether physical clogging by silt-sized SP exhibits the same dynamics and patterns as by sand-sized SP, and (2) the comparability of results between laboratory and field experiments. We carried out vertical column experiments with sand-sized bed material and silt-sized SP, which are rich in mica minerals. In laboratory experiments, we investigated the degree of clogging quantified by the reduction of porosity and hydraulic conductivity and the maximum clogging depth as a function of size and shape of bed material, size of SP, pore water flow velocity, and concentration of calcium cations. The SP were collected from an Alpine sedimentation basin, where our field experiments were carried out. To investigate the clogging process in the field, we buried columns filled with sand sized quartz in the stream bed. We found that the maximal bed-to-grain ratio where clogging still occurs is larger for silt-sized SP than for sand-sized SP. The observed clogging depths and the reduction of flow rate through the column from our laboratory experiments were comparable to those from the field. However, our field results showed that the extent of clogging strongly depends on the naturally-occurring hydrological dynamics. The field location was characterized by a more polydisperse suspension, a strongly fluctuating water regime, and high SP concentrations at times, leading to more heterogeneous and more pronounced clogging when compared to laboratory results. PMID- 28918080 TI - The tail of two models: Impact of circularity and biomass non-homogeneity on UV disinfection of wastewater flocs. AB - The effects of floc structural characteristics, i.e. shape and dense biomass distribution, were evaluated on ultraviolet (UV) disinfection resistance, represented by the tailing level of the UV dose response curve (DRC). Ellipsoid shaped flocs of similar volume and different projected circularities were constructed in-silico and a mathematical model was developed to compare their UV DRC tailing levels (indicative of UV-resistance). It was found that floc shape can significantly influence tailing level, and rounder flocs (i.e. flocs with higher circularity) were more UV-resistant. This result was confirmed experimentally by obtaining UV DRCs of two 75-90 MUm floc populations with different percentages (20% vs. 30%) of flocs with circularities higher than 0.5. The population enriched in less circular flocs (i.e. 20% flocs with circularities >0.5) had a lower tailing level (at least by 1-log) compared to the other population. The second model was developed to describe variations in UV disinfection kinetics observed in flocs with transverse vs. radial biomass non homogeneity, indicative of biofilm-originated vs. suspended flocs. The varied density hemispheres model and shell-core model were developed to simulate transverse and radial non-homogeneity, respectively. The UV DRCs were mathematically constructed and biofilm-originated flocs showed higher UV resistance compared to suspended flocs. The calculated UV DRCs agreed well with the experimental data collected from activated sludge and trickling filter flocs (no fitting parameters were used). These findings provide useful information in terms of designing/modifying upstream processes for reducing UV disinfection energy demand. PMID- 28918082 TI - Corrections. PMID- 28918083 TI - Topical fluorometholone treatment and desiccating stress change inflammatory protein expression in tears. AB - PURPOSE: It was hypothesized that tear protein biomarkers could predict the effects of topical steroid treatment and desiccating stress in patients with dry eye disease (DED). To test this concept, a randomized, double-masked, controlled clinical trial with 41 patients was conducted. METHODS: The patients were treated topically with either 0.1% fluorometholone (FML) or polyvinyl alcohol (PA). Tear samples were collected using 1 MUl glass capillaries at recruitment into the study and after a 3-week treatment period, both before and after 2 h exposure to desiccating stress, in a controlled environment chamber. Relative quantification of tear proteins was conducted by NanoLC-MSTOF using sequential window acquisition of all theoretical mass spectra (SWATH). Ocular surface integrity (corneal and conjunctival staining and conjunctival hyperemia) was selected as the key DED-related sign and analyzed with proteomic data. Analysis of covariance (ANCOVA) and linear models were used to analyze the data with R. RESULTS: 758 proteins were identified and relatively quantified from each tear sample. Analysis revealed 9 differentially expressed proteins between FML and PA treatments after 3 weeks and 7 after desiccating stress (P < 0.05). We also identified several differentially expressed proteins at the initial collection, which could be used to predict changes of conjunctival and corneal staining and conjunctival hyperemia after FML treatment and after desiccating stress. These proteins include complement C3 (C3) and calmodulin like 5 (CALML5), which could also differentiate the severity of DED at baseline. CONCLUSIONS: The identified proteins could be further used as biomarkers to identify patients most benefiting from FML treatment. PMID- 28918081 TI - Developmental alcohol exposure impairs synaptic plasticity without overtly altering microglial function in mouse visual cortex. AB - Fetal alcohol spectrum disorder (FASD), caused by gestational ethanol (EtOH) exposure, is one of the most common causes of non-heritable and life-long mental disability worldwide, with no standard treatment or therapy available. While EtOH exposure can alter the function of both neurons and glia, it is still unclear how EtOH influences brain development to cause deficits in sensory and cognitive processing later in life. Microglia play an important role in shaping synaptic function and plasticity during neural circuit development and have been shown to mount an acute immunological response to EtOH exposure in certain brain regions. Therefore, we hypothesized that microglial roles in the healthy brain could be permanently altered by early EtOH exposure leading to deficits in experience dependent plasticity. We used a mouse model of human third trimester high binge EtOH exposure, administering EtOH twice daily by subcutaneous injections from postnatal day 4 through postnatal day 9 (P4-:P9). Using a monocular deprivation model to assess ocular dominance plasticity, we found an EtOH-induced deficit in this type of visually driven experience-dependent plasticity. However, using a combination of immunohistochemistry, confocal microscopy, and in vivo two-photon microscopy to assay microglial morphology and dynamics, as well as fluorescence activated cell sorting (FACS) and RNA-seq to examine the microglial transcriptome, we found no evidence of microglial dysfunction in early adolescence. We also found no evidence of microglial activation in visual cortex acutely after early ethanol exposure, possibly because we also did not observe EtOH-induced neuronal cell death in this brain region. We conclude that early EtOH exposure caused a deficit in experience-dependent synaptic plasticity in the visual cortex that was independent of changes in microglial phenotype or function. This demonstrates that neural plasticity can remain impaired by developmental ethanol exposure even in a brain region where microglia do not acutely assume nor maintain an activated phenotype. PMID- 28918084 TI - Uranium isotopes in tree bark as a spatial tracer of environmental contamination near former uranium processing facilities in southwest Ohio. AB - Inappropriate handling of radioactive waste at nuclear facilities can introduce non-natural uranium (U) into the environment via the air or groundwater, leading to anthropogenic increases in U concentrations. Uranium isotopic analyses of natural materials (e.g. soil, plants or water) provide a means to distinguish between natural and anthropogenic U in areas near sources of radionuclides to the environment. This study examines the utility of two different tree bark transects for resolving the areal extent of U atmospheric contamination using several locations in southwest Ohio that historically processed U. This study is the first to utilize tree bark sampling transects to assess environmental contamination emanating from a nuclear facility. The former Fernald Feed Materials Production Center (FFMPC; Ross, Ohio) produced U metal from natural U ores and recycled nuclear materials from 1951 to 1989. Alba Craft Laboratory (Oxford, Ohio) machined several hundred tons of natural U metal from the FFMPC between 1952 and 1957. The Herring-Hall-Marvin Safe Company (HHM; Hamilton, Ohio) intermittently fabricated slugs rolled from natural U metal stock for use in nuclear reactors from 1943 to 1951. We have measured U concentrations and isotope signatures in tree bark sampled along an ~35 km SSE-NNW transect from the former FFMPC to the vicinity of the former Alba Craft laboratories (transect #1) and an ~20 km SW- NE (prevailing local wind direction) transect from the FFMPC to the vicinity of the former HHM (transect #2), with a focus on old trees with thick, persistent bark that could potentially record a time-integrated signature of environmental releases of U related to anthropogenic activity. Our results demonstrate the presence of anthropogenic U contamination in tree bark from the entire study area in both transects, with U concentrations within 1 km of the FFMPC up to ~400 times local background levels of 0.066 ppm. Tree bark samples from the Alba Craft and HHM transects exhibit increasing U concentrations within ~5 and ~10 km, respectively of the FFMPC. The 236U/238U isotopic ratios in tree bark from both transects increase progressively towards the FFMPC with values as high as 2.00 * 10-4 at the FFMPC. Tree bark sampled within 1 km of the FFMPC exhibits clear evidence for both enriched and depleted uranium with 235U/238U values from 0.00461 to 0.00736, with 234U/238U activity ratio ranging from 0.53 to 0.96, and 236U/238U from 6.05 * 10-5 to 1.05 * 10-4. Tree bark from transect #1 between 1 and 30 km from the FFMPC exhibits depleted and natural 235U/238U values ranging from 0.00552 to 0.00726 [234U/238U activity ratio: 0.69-1.04; 236U/238U: 2.49 * 10-6 - 2.00 * 10-4]. Tree bark from transect #2 sampled between 1 and ~20 km away from the FFMPC exhibits evidence of enriched and depleted U in the environment with 235U/238U ranging from 0.00635 to 0.00738 [234U/238U activity ratio: 0.83-0.98; 236U/238U: 1.43 * 10-5 - 2.00 * 10-4]. Results from scanning electron microscopy with energy dispersive spectrometry provides evidence for U-rich particles as the source of contamination found in tree bark growing within 1-3 km of the former FFMPC. Such observations are consistent with the previously observed 14 MUm U-rich particle identified in tree bark sampled within 1 km of the FFMPC (Conte et al., 2015). Overall, this study shows the usefulness of a tree bark sample transect to assess the areal extent of atmospheric contaminant U stemming from nuclear facilities. PMID- 28918085 TI - Positive Effects of Extracorporeal Shock Wave Therapy on Spasticity in Poststroke Patients: A Meta-Analysis. AB - BACKGROUND: Spasticity is a common and serious complication following a stroke, and many clinical research have been conducted to evaluate the effect of extracorporeal shock wave therapy (ESWT) on muscle spasticity in poststroke patients. This meta-analysis aimed to evaluate the therapeutic effect on decreasing spasticity caused by a stroke immediately and 4 weeks after the application of shock wave therapy. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for relevant studies through November 2016 using the following item: (Hypertonia OR Spasticity) and (Shock Wave or ESWT) and (Stroke). The outcomes were evaluated by Modified Ashworth Scale (MAS) grades and pooled by Stata 12.0 (Stata Corp, College Station, TX, USA). RESULTS: Six studies consisting of 9 groups were included in this meta-analysis. The MAS grades immediately after ESWT were significantly improved compared with the baseline values (standardized mean difference [SMD], -1.57; 95% confidence intervals [CIs], -2.20, -.94). Similarly, the MAS grades judged at 4 weeks after ESWT were also showed to be significantly lower than the baseline values (SMD, 1.93; 95% CIs, -2.71, -1.15). CONCLUSIONS: ESWT for the spasticity of patients after a stroke is effective, as measured by MAS grades. Moreover, no serious side effects were observed in any patients after shock wave therapy. Nevertheless, our current study with some limitations such as the limited sample size only provided limited quality of evidence; confirmation from a further systematic review or meta-analysis with large-scale, well-designed randomized control trials is required. PMID- 28918086 TI - Confidence in the Use of Direct Oral Anticoagulants in the Acute Phase of Nonvalvular Atrial Fibrillation-Related Ischemic Stroke Over the Years: A Real World Single-Center Study. AB - BACKGROUD AND AIM: The use of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) is controversial. The aims of our study were to analyze physicians' confidence in prescribing DOACs in NVAF-related AIS, the characteristics of patients receiving DOACs, and their 90-day prognosis. MATERIAL AND METHODS: Clinical records of consecutive patients admitted to our wards for NVAF-related AIS over the years 2014-2016 were reviewed. RESULTS: One hundred forty-seven patients, 72.7% females, mean age +/- standard deviation 83.4 +/- 8.8 years, were admitted to our ward for atrial fibrillation (AF)-related AIS (38 in 2014, 47 in 2015, 62 in 2016). Of these patients, 141 had NVAF-related AIS. Median length of hospital stay was 8 days (interquartile range [IQR], 6-11). In-hospital mortality was 10.8%. Ninety-eight patients (69.5%) received DOACs for secondary prevention, with increasing percentages from 2014 (62.5%) to 2016 (88%). In 88% of them, DOACs were started during hospital stay, whereas in 12% DOACs were started during ambulatory follow-up. The median time for starting DOACs was 5 days (IQR, 3-8). In patients receiving DOACs, the median National Institutes of Health Stroke Scale score was 6 (IQR, 3-12), and large ischemic lesions were present in 48%; the median modified Rankin Scale score at hospital discharge was 3 (IQR, 1-4), whereas the score at 90 days was 2 (IQR, 1-3). At the 90-day follow-up, in patients receiving DOACs, overall mortality was 3.0%, stroke recurrence was 1%, and no patients had major intracranial or extracranial bleedings. CONCLUSION: Our study suggests that physicians are becoming increasingly confident in the use of DOACs in NVAF-related AIS. The use of DOACs seems effective and safe even when started in the acute phase of stroke. PMID- 28918087 TI - Left Atrial Enlargement and Anticoagulation Status in Patients with Acute Ischemic Stroke and Atrial Fibrillation. AB - BACKGROUND: Despite anticoagulation therapy, ischemic stroke risk in atrial fibrillation (AF) remains substantial. We hypothesize that left atrial enlargement (LAE) is more prevalent in AF patients admitted with ischemic stroke who are therapeutic, as opposed to nontherapeutic, on anticoagulation. METHODS: We included consecutive patients with AF admitted with ischemic stroke between April 1, 2015, and December 31, 2016. Patients were divided into two groups based on whether they were therapeutic (warfarin with an international normalized ratio >= 2.0 or non-vitamin K oral anticoagulant with uninterrupted use in the prior 2 weeks) versus nontherapeutic on anticoagulation. Univariable and multivariable models were used to estimate associations between therapeutic anticoagulation and clinical factors, including CHADS2 score and LAE (none/mild versus moderate/severe). RESULTS: We identified 225 patients during the study period; 52 (23.1%) were therapeutic on anticoagulation. Patients therapeutic on anticoagulation were more likely to have a larger left atrial diameter in millimeters (45.6 +/- 9.2 versus 42.3 +/- 8.6, P = .032) and a higher CHADS2 score (2.9 +/- 1.1 versus 2.4 +/- 1.1, P = .03). After adjusting for the CHADS2 score, patients who had a stroke despite therapeutic anticoagulation were more likely to have moderate to severe LAE (odds ratio, 2.05; 95% confidence interval, 1.01-4.16). CONCLUSION: LAE is associated with anticoagulation failure in AF patients admitted with an ischemic stroke. This provides indirect evidence that LAE may portend failure of anticoagulation therapy in patients with AF; further studies are needed to delineate the significance of this association and improve stroke prevention strategies. PMID- 28918088 TI - Evaluation of Cerebrovascular Reactivity in Subjects with and without Obstructive Sleep Apnea. AB - BACKGROUND: Both obstructive sleep apnea (OSA) and altered cerebrovascular reactivity (CVR) are associated with increased stroke risk. Nevertheless, the incidence of abnormal CVR in patients with OSA is uncertain due to the high variability in the way CVR is measured both within and between studies. We hypothesized that a standardized CVR with a consistent vasoactive stimulus and cerebral blood flow (CBF) measure would be reduced in patients with severe OSA compared with healthy controls. METHODS: This was a prospective study in which subjects with and without OSA were administered a standardized hypercapnic stimulus, and CBF was monitored by blood oxygen level-dependent magnetic resonance signal changes, a high space and time resolved surrogate for CBF. RESULTS: Twenty-four subjects with OSA (mean age 45.9 years, apnea-hypopnea index [AHI] 26.8 per hour) and 6 control subjects (mean age 42.8 years, AHI 2.4 per hour) were included. Compared with controls, subjects with OSA had a significantly greater whole brain (.1565 versus .1094, P = .013), gray matter (.2077 versus .1423, P = .009), and white matter (.1109 versus .0768, P = .024) CVR, respectively. CONCLUSIONS: Contrary to expectations, subjects with OSA had greater CVR compared with control subjects. PMID- 28918089 TI - Urinary Incontinence and Indwelling Urinary Catheters as Predictors of Death after New-Onset Stroke: A Report of the South London Stroke Register. AB - OBJECTIVE: To explore the relationship between indwelling urinary catheters (IUCs), urinary incontinence (UI), and death in the poststroke period and to determine when, after the neurological event, UI has the best ability to predict 1-year mortality. METHODS: In a prospective observational study, 4477 patients were followed up for 1 year after a first-ever stroke. The impact of UI or urinary catheters on time to death was adjusted in a Cox model for age, sex, Glasgow Coma Scale, prestroke and poststroke Barthel Index, swallow test, motor deficit, diabetes, and year of inclusion. The predictive values of UI assessed at the maximal deficit or 7 days after a stroke were compared using receiver operating curves. RESULTS: UI at the maximal neurological deficit and urinary catheters within the first week after the stroke were present in 43.9% and 31.2% patients, respectively. They were both associated with 1-year mortality in unadjusted and adjusted analysis (hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.46-2.19, and HR, 1.84, 95% CI 1.54-2.19). Patients with UI and urinary catheters had twice the mortality rate of incontinent patients without urinary catheters (HR, 10.24; 95% CI, 8.72-12.03 versus HR, 4.70; 95% CI, 3.88 5.70; P < .001). UI assessed after 1 week performed better at predicting 1-year mortality than UI assessed at the maximal neurological deficit. CONCLUSION: IUCs in the poststroke period is associated with death, especially among incontinent patients. UI assessed at 1 week after the neurological event has the best predictive ability. PMID- 28918090 TI - Sex Differences in Outcomes after Stroke in Patients with Diabetes in Ontario, Canada. AB - BACKGROUND: Outcomes after stroke in those with diabetes are not well characterized, especially by sex and age. We sought to calculate the sex- and age specific risk of cardiovascular outcomes after ischemic stroke among those with diabetes. METHODS: Using population-based demographic and administrative health care databases in Ontario, Canada, all patients with diabetes hospitalized with index ischemic stroke between April 1, 2002, and March 31, 2012, were followed for death, stroke, and myocardial infarction (MI). The Kaplan-Meier survival analysis and Fine-Gray competing risk models estimated hazards of outcomes by sex and age, unadjusted and adjusted for demographics and vascular risk factors. RESULTS: Among 25,495 diabetic patients with index ischemic stroke, the incidence of death was higher in women than in men (14.08 per 100 person-years [95% confidence interval [CI], 13.73-14.44] versus 11.89 [11.60-12.19]) but was lower after adjustment for age and other risk factors (adjusted hazard ratio [HR], .95 [.92-.99]). Recurrent stroke incidence was similar by sex, but men were more likely to be readmitted for MI (1.99 per 100 person-years [1.89-2.10] versus 1.58 [1.49-1.68] among females). In multivariable models, females had a lower risk of readmission for any event (HR, .96 [95% CI, .93-.99]). CONCLUSIONS: In this large, population-based, retrospective study among diabetic patients with index stroke, women had a higher unadjusted death rate but lower unadjusted incidence of MI. In adjusted models, females had a lower death rate compared with males, although the increased risk of MI among males persisted. These findings confirm and quantify sex differences in outcomes after stroke in patients with diabetes. PMID- 28918092 TI - Growth-Rate Dependent Regulation of tRNA Level and Charging in Bacillus licheniformis. AB - Cellular growth crucially depends on protein synthesis and the abundance of translational components. Among them, aminoacyl-tRNAs play a central role in biosynthesis and shape the kinetics of mRNA translation, thus influencing protein production. Here, we used microarray-based approaches to determine the charging levels and tRNA abundance of Bacillus licheniformis. We observed an interesting cross-talk among tRNA expression, charging pattern, and growth rate. For a large subset of tRNAs, we found a co-regulated and augmented expression at high growth rate. Their tRNA aminoacylation level is kept relatively constant through riboswitch-regulated expression of the cognate aminoacyl-tRNA-synthetase (AARS). We show that AARSs with putative riboswitch-controlled expression are those charging tRNAs with amino acids which disfavor cell growth when individually added to the nutrient medium. Our results suggest that the riboswitch-regulated AARS expression in B. licheniformis is a powerful mechanism not only to maintain a constant ratio of aminoacyl-tRNA independent of the growth rate but concomitantly to control the intracellular level of free amino acids. PMID- 28918091 TI - Opposed Effects of Dityrosine Formation in Soluble and Aggregated alpha-Synuclein on Fibril Growth. AB - Parkinson's disease is the second most common neurodegenerative disease. It is characterized by aggregation of the protein alpha-synuclein (alpha-syn) in Lewy bodies, mitochondrial dysfunction, and increased oxidative stress in the substantia nigra. Oxidative stress leads to several modifications of biomolecules including dityrosine (DiY) crosslinking in proteins, which has recently been detected in alpha-syn in Lewy bodies from Parkinson's disease patients. Here we report that alpha-syn is highly susceptible to ultraviolet-induced DiY formation. We investigated DiY formation of alpha-syn and nine tyrosine-to-alanine mutants and monitored its effect on alpha-syn fibril formation in vitro. Ultraviolet irradiation of intrinsically disordered alpha-syn generates DiY-modified monomers and dimers, which inhibit fibril formation of unmodified alpha-syn by interfering with fibril elongation. The inhibition depends on both the DiY group and its integration into alpha-syn. When preformed alpha-syn fibrils are crosslinked by DiY formation, they gain increased resistance to denaturation. DiY-stabilized alpha-syn fibrils retain their high seeding efficiency even after being exposed to denaturant concentrations that completely depolymerize non-crosslinked seeds. Oxidative stress-associated DiY crosslinking of alpha-syn therefore entails two opposing effects: (i) inhibition of aggregation by DiY-modified monomers and dimers, and (ii) stabilization of fibrillar aggregates against potential degradation mechanisms, which can lead to promotion of aggregation, especially in the presence of secondary nucleation. PMID- 28918093 TI - Topological Structure Determination of RNA Using Small-Angle X-Ray Scattering. AB - Knowledge of RNA three-dimensional topological structures provides important insight into the relationship between RNA structural components and function. It is often likely that near-complete sets of biochemical and biophysical data containing structural restraints are not available, but one still wants to obtain knowledge about approximate topological folding of RNA. In this regard, general methods for determining such topological structures with minimum readily available restraints are lacking. Naked RNAs are difficult to crystallize and NMR spectroscopy is generally limited to small RNA fragments. By nature, sequence determines structure and all interactions that drive folding are self-contained within sequence. Nevertheless, there is little apparent correlation between primary sequences and three-dimensional folding unless supplemented with experimental or phylogenetic data. Thus, there is an acute need for a robust high throughput method that can rapidly determine topological structures of RNAs guided by some experimental data. We present here a novel method (RS3D) that can assimilate the RNA secondary structure information, small-angle X-ray scattering data, and any readily available tertiary contact information to determine the topological fold of RNA. Conformations are firstly sampled at glob level where each glob represents a nucleotide. Best-ranked glob models can be further refined against solvent accessibility data, if available, and then converted to explicit all-atom coordinates for refinement against SAXS data using the Xplor-NIH program. RS3D is widely applicable to a variety of RNA folding architectures currently present in the structure database. Furthermore, we demonstrate applicability and feasibility of the program to derive low-resolution topological structures of relatively large multi-domain RNAs. PMID- 28918094 TI - Post-acute care for children with special health care needs. AB - BACKGROUND: Almost all studies of post-acute care (PAC) focus on older persons, frequently those suffering from chronic health problems. Some research is available on PAC for the pediatric population in general. However, very few studies focus on PAC services for children with special health care needs (SHCN). OBJECTIVE: To investigate factors affecting the provision of PAC to children with SHCN. METHODS: Pooled cross-sectional data from Texas Department of State Health Services hospital discharge database from 2011-2014 were analyzed. Publicly available algorithms identified chronic conditions, complex chronic conditions, and the principal problem leading to hospitalization. Analysis involved estimating two logistic regressions, with clustered robust standard errors, concerning the likelihood of receiving PAC and where that PAC was delivered. Models included patient characteristics and conditions, as well as hospital characteristics and location. RESULTS: Only 5.8 percent of discharges for children with SHCN resulted in the provision of PAC. Two-thirds of PAC was provided in a health care facility (HCF). Severity of illness and the number of complex chronic conditions, though not the number of chronic problems, made PAC more likely. Patient demographics had no effect on PAC decisions. Hospital type and location also affected PAC decision-making. CONCLUSIONS: PAC was provided to relatively few children with SHCN, which raises questions concerning the potential underutilization of PAC for children with SHCN. Also, the provision of most PAC in a HCF (66%) seems at odds with professional judgment and family preferences indicating that health care for children with SHCN is best provided in the home. PMID- 28918095 TI - Accessibility and usability of parks and playgrounds. AB - BACKGROUND: Public parks and playgrounds are an environment for leisure activity, which all generations can enjoy at low or no financial cost. Evaluating the accessibility and usability of parks and playgrounds is crucial because their design, environment (natural and built) and safety could restrict participation of persons with disabilities. OBJECTIVE: To evaluate the accessibility and usability of 21 public parks and playgrounds in three metropolitan cities of New Zealand. Secondary aims were to compare the accessibility and usability by park type (destination or neighborhood) and deprivation level (high and low). METHODS: Twenty-one parks were evaluated. A stratified random sampling was used to select 18 parks (six from each city). Three additional parks were purposely selected (one from each city) at the request of each respective city council. The parks and playgrounds were evaluated using a customized tool. Data were analyzed using descriptive statistics. RESULTS: None of the parks we evaluated met the national standards and/or international guidelines for park and playground design. We identified potential accessibility and usability issues with car parking spaces, path surfaces and play equipment as well as lack of lighting and fencing. The presence of amenities (e.g. toilets and drinking fountains) was more common in destination parks. Fewer parks in areas of higher deprivation had accessible car parking spaces and main paths wider than 1.5 m. CONCLUSION: Our evaluation identified potential design, environmental and safety barriers to park and playground based participation for persons with disabilities across the lifespan. A larger, more comprehensive evaluation of parks and playgrounds is required. PMID- 28918096 TI - A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. AB - Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc. IC50 values of tumor growth inhibition, in-vitro and in-vivo activity along with clinical trial data. Here, we took efforts to describe essence of Aurora kinase and its inhibition which could be used to develop anti-mitotic drug for the treatment of cancer. In conclusion, we also discuss future perspectives for development of novel inhibitors and their scope in drug development process. PMID- 28918097 TI - Synthesis and bioevaluation of 1-phenyl-pyrazole-4-carboxylic acid derivatives as potent xanthine oxidoreductase inhibitors. AB - A diverse library of 1-phenyl-pyrazole-4-carboxylic acid derivatives were synthesized and evaluated for their inhibitory potency against xanthine oxidoreductase (XOR) in vitro and vivo, and the structure-activity relationship (SAR) analyses were also presented. Approximately half of the target compounds exhibited the inhibitory potency for XOR at the nanomolar level. Compounds 16c, 16d, and 16f emerged as the most potent xanthine oxidoreductase inhibitors with IC50 values of 5.7, 5.7 and 4.2 nM, respectively, in comparison to febuxostat (IC50 of 5.4 nM). Steady-state kinetics measurements indicated that 16c is a mixed-type inhibitor. A computer molecular docking study of 16c bound to XOR was performed to gain an insight into its bind mode and SAR for the series. A potassium oxonate-hypoxanthine-induced hyperuricemia model in mice was chosen to further confirm the hypouricemic effects of 16c and 16f, and the results demonstrated that 16c exhibits similar hypouricemic potency to febuxostat. PMID- 28918098 TI - Identifying novel factor XIIa inhibitors with PCA-GA-SVM developed vHTS models. AB - There currently is renewed interest in blood clotting Factor XII as a potential target for thrombosis inhibition. Historically untargeted, there is little drug information with which to start drug candidate searches. Typical high-throughput screening can identify potential drug candidates, but is inefficient. Virtual high-throughput screening can be used to raise efficiency by focusing experimental efforts on compounds predicted to be active and is applied here to identify new Factor XIIa inhibitors. We combine principal component analysis, genetic algorithm and support vector machine to create the models used in the virtual high-throughput screening. In this work, experimental data from a PubChem Bioassay was used to train predictive models of Factor XIIa inhibition activity. The models created were then used to virtually screen the entire 72 million PubChem Compound database. Experimental validation of select candidates identified by this process resulted in a 42.9% hit-rate in the first-pass and 100% hit-rate in the second-pass, suggesting the effectiveness of the approach. PMID- 28918099 TI - Role of HPV DNA testing in modern gynaecological practice. AB - The identification of some types of human papillomavirus (HPV) as necessary, but not sufficient, cause of cervical cancer has suggested the use of HPV testing in cervical cancer prevention. A large number of studies has provided evidence supporting its application (1) as primary screening test, (2) for triaging borderline cytology, (3) for follow-up after positive primary test but no abnormal histology and (4) as a test of cure. They also allowed a reasonably good definition of the appropriate policies and protocols, leading to the delivery of evidence-based guidelines resulting from a systematic review of the literature. In this chapter, we present a critical analysis of the recommendations of the main European and North American guidelines relative to industrialised countries. PMID- 28918100 TI - Transcriptomic and epigenomic biomarkers of antidepressant response. AB - BACKGROUND: Antidepressant treatment is associated with a high rate of poor response, and thus, biomarker development is warranted. METHODS: We aimed to synthesize studies investigating gene expression, small RNAs, and epigenomic biomarkers of antidepressant response. We conducted a narrative review of the literature. RESULTS: Firstly, we detailed the challenges involved, in terms of biological tissues, relevant study time frames, and mandatory statistical tools. Secondly we synthesized results obtained in gene expression studies, focusing mainly on genome-wide studies, particularly small non-coding RNA, including micro RNA and other small RNA species. In addition, we reviewed the potential biomarkers of antidepressant response arising from studies investigating DNA methylation variation and histone modifications. LIMITATIONS: We did not conduct a meta-analysis due to the heterogeneity of the study. CONCLUSION: Although promising, the field of gene expression and epigenomic biomarkers of antidepressant response is still in its infancy, and needs further development to define useful biomarkers in clinical practice. PMID- 28918101 TI - Silver diamine fluoride remineralized artificial incipient caries in permanent teeth after bacterial pH-cycling in-vitro. AB - OBJECTIVES: To investigate the remineralizing effect of 38% silver diamine fluoride (SDF) application on enamel artificial caries in adjunct to 1000ppm fluoride toothpaste compared with fluoride toothpaste alone by analyzing the mineral density, depth of remineralization, and remineralization percentage of the lesions. METHODS: Eighteen artificial caries slabs were created from the proximal surfaces of nine chemically demineralized premolars. The slabs were scanned by Micro-Computed Tomography (Micro-CT) to determine the baseline mineral density of the initial lesions and randomly allocated into 2 groups. The test group was applied with 38% SDF in adjunct to fluoride toothpaste and the control group was treated with fluoride toothpaste alone. The specimens underwent bacterial pH-cycling for 5 d and were re-evaluated using Micro-CT. The pre treatment and post-treatment mineral densities were plotted and the areas under the curves were used to calculate the remineralization percentage of both groups. RESULTS: Mineral density significantly increased in both groups after pH-cycling (p<0.05) although to different depths (control group=260MUm, test group=300MUm). The test group demonstrated a significantly higher mineral density to a depth of 120MUm and higher remineralization percentage (p<0.05) compared with the control group. CONCLUSION: The adjunctive use of 38% SDF enhances the remineralization of initial carious lesions based on mineral density, depth, and remineralization percentage compared with the use of 1000ppm fluoride toothpaste alone. SDF might be used as an adjunct to fluoride toothpaste to remineralize incipient caries lesions on smooth tooth surfaces. CLINICAL SIGNIFICANCE: In non-compliant patients, the application of 38% SDF might be used as an adjunct to fluoride toothpaste, to remineralize incipient caries lesions of permanent teeth where esthetics is not a concern. PMID- 28918102 TI - Minimal Clinically Important Difference for the Rasch Neuropsychiatric Inventory Irritability and Aggression Scale for Traumatic Brain Injury. AB - OBJECTIVE: To determine the minimal clinically important difference (MCID) for a Rasch measure derived from the Irritability/Lability and Agitation/Aggression subscales of the Neuropsychiatric Inventory (NPI)-the Rasch NPI Irritability and Aggression Scale for Traumatic Brain Injury (NPI-TBI-IA). DESIGN: Distribution based statistical methods were applied to retrospective data to determine candidates for the MCID. These candidates were evaluated by anchoring the NPI-TBI IA to Global Impression of Change (GIC) ratings by participants, significant others, and a supervising physician. SETTING: Postacute rehabilitation outpatient clinic. PARTICIPANTS: 274 cases with observer ratings; 232 cases with self ratings by participants with moderate-severe TBI at least 6 months postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: NPI-TBI-IA. RESULTS: For observer ratings on the NPI-TBI-IA, anchored comparisons found an improvement of 0.5 SD was associated with at least minimal general improvement on GIC by a significant majority (69%-80%); 0.5 SD improvement on participant NPI-TBI-IA self ratings was also associated with at least minimal improvement on the GIC by a substantial majority (77%-83%). The percentage indicating significant global improvement did not increase markedly on most ratings at higher levels of improvement on the NPI-TBI-IA. CONCLUSIONS: A 0.5 SD improvement on the NPI-TBI IA indicates the MCID for both observer and participant ratings on this measure. PMID- 28918103 TI - Rasch Analysis, Dimensionality, and Scoring of the Neuropsychiatric Inventory Irritability and Aggression Subscales in Individuals With Traumatic Brain Injury. AB - OBJECTIVES: To develop, for versions completed by individuals with traumatic brain injury (TBI) and an observer, a more precise metric for the Neuropsychiatric Inventory (NPI) Irritability and Aggression subscales using all behavioral item ratings for use with individuals with TBI and to address the dimensionality of the represented behavioral domains. DESIGN: Rasch and confirmatory factor analyses of retrospective baseline NPI data from 3 treatment studies. SETTING: Postacute rehabilitation clinic. PARTICIPANTS: NPI records (N = 525) consisting of observer ratings (n = 287) and self-ratings (n = 238) by participants with complicated mild, moderate, or severe TBI at least 6 months postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Frequency and severity ratings from NPI Irritability/Lability and Agitation/Aggression subscales. RESULTS: Confirmatory factor analyses of both observer and participant ratings showed good fit for either a 1-factor or a 2-factor solution. Consistent with this, the Rasch model also fit the data well with aggression items indicating the more severe end of the construct and irritability items populating the milder end. CONCLUSIONS: Irritability and aggression appear to represent different levels of severity of a single construct. The derived Rasch metric offers a measure of this construct based on responses to all specific items that is appropriate for parametric statistical analysis and may be useful in research and clinical assessments of individuals with TBI. PMID- 28918104 TI - Peripheral Blood Lymphocyte-to-Monocyte Ratio at Relapse Predicts Outcome for Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma in the Rituximab Era. AB - BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor prognosis, even in the rituximab era. Several studies have reported the clinical importance of the peripheral blood lymphocyte-to-monocyte ratio (LMR) in various malignancies, including lymphoma. However, the prognostic value of the LMR in relapsed/refractory DLBCL has not been well evaluated. The purpose of the present study was to investigate whether the LMR at relapse can predict clinical outcomes for relapsed/refractory DLBCL patients treated with rituximab. PATIENTS AND METHODS: We analyzed data on 74 patients with relapsed/refractory DLBCL, who were initially treated with R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone) or an R-CHOP-like regimen. RESULTS: There was a significant association between a low LMR (<= 2.6) and shorter overall survival (OS; P < .001) and progression-free survival (PFS; P < .001) compared with the high LMR group (> 2.6). Multivariate analysis showed that LMR was an independent prognostic factor for OS (P < .001) and PFS (P < .001), as was the international prognostic index (IPI) at relapse for OS. In addition, the LMR had an incremental value for OS and PFS compared with the IPI at relapse. CONCLUSION: The LMR predicts OS and PFS outcomes in relapsed/refractory DLBCL patients treated with rituximab, and might facilitate better stratification among patients in low- and intermediate-risk IPI groups. PMID- 28918105 TI - Factors influencing women's decision making in hysterectomy. AB - OBJECTIVE: To explore factors influencing how well-informed women felt about hysterectomy, influences on their decision making, and on them receiving a less invasive alternative to open surgery. METHODS: Online questionnaire, conducted in 2015-2016, of women who had received a hysterectomy in Australia, in the preceding two years. RESULTS: Questionnaires were completed by 2319/6000 women (39% response). Most women (n=2225; 96%) felt well-informed about hysterectomy. Women were more aware of the open abdominal approach (n=1798; 77%), than of less invasive vaginal (n=1552; 67%), laparoscopic (n=1540; 66%), laparoscopic-assisted (n=1303; 56%), and robotic approaches (n=289; 12%). Most women (n=1435; 62%) reported their gynaecologist was the most influential information source. Women who received information about hysterectomy from a GP (OR=1.47; 95% CI 1.15 1.90), or from a gynaecologist (OR=1.3; 95% CI 1.06-1.58), were more likely to feel better informed (p<0.01). CONCLUSION: This study is important because it helps clinicians, researchers and health policy makers to understand why many women still receive an open abdominal approach despite many learned societies recommending to avoid it if possible. PRACTICE IMPLICATIONS: Additional information, or education about avoiding open abdominal approach where possible may lead to a greater number of women receiving less-invasive types of hysterectomy in the future. PMID- 28918106 TI - Patients experiences of patient education on psychiatric inpatient wards; a systematic review. AB - OBJECTIVE: To synthesize the evidence on how patients with serious mental disorders perceived patient education on psychiatric wards and to learn more about the patient perceived benefits and limitations related to patient education and how well patient education meets the perceived needs of inpatients. METHODS: Quantitative and qualitative data were categorized and synthesized. A systematic literature search was conducted. Articles were validated using validated critical appraisal tools. Data were analyzed using inductive content analysis. RESULTS: Five articles met the inclusion criteria. The results concerned the specific population with bipolar disorder or schizophrenia. Two explanatory syntheses were aggregated: (I) Benefits and perceived barriers to receiving education and (II) Educational needs of mental health patients. Patients reported mechanical information dissemination and lack of individual and corporative discussions. Patients preferred patient education from different educational sources with respect to individual needs. CONCLUSION: Patient education were most useful when it could be tailored to an individuals specific needs and match patient preference for how to receive it. The findings did not provide evidence to support any educational methods of preference. PRACTICE IMPLICATIONS: The findings may contribute to the development of educational interventions that are perceived more helpful for in-patients suffering from serious mental disorders. PMID- 28918108 TI - Heart Failure With Recovered Ejection Fraction in African Americans: Results From the African-American Heart Failure Trial. AB - BACKGROUND: Recent studies have described the entity of heart failure with recovered ejection fraction (HFrecEF), but population-specific studies remain lacking. The aim of this study was to characterize patients enrolled in the African-American Heart Failure Trial (A-HeFT) who had significant improvement in their ejection fraction (EF) during the 1st 6 months of follow-up. METHODS AND RESULTS: Subjects with HFrecEF (improvement in EF from <35% to >40% in 6 months; n = 59) were compared with 259 subjects with heart failure and persistently reduced EF (HFrEF), defined as EF <=40% at 6-month follow-up. The effects of improvement in EF on all-cause mortality and 1st and all hospitalizations were analyzed. Compared with HFrEF, subjects with HFrecEF had a nonsignificant trend toward lower mortality (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.02 1.15; P = .068), fewer 1st HF hospitalizations (HR 0.22, 95% CI 0.07-0.71; P = .011), fewer recurrent HF hospitalizations (HR 0.13, 95% CI 0.05-0.37; P <.001), similar 1st all-cause hospitalizations (HR 0.67, 95% CI 0.39-1.15; P = .150), and fewer recurrent all-cause hospitalizations (HR 0.41, 95% CI 0.24-0.68; P <.001). CONCLUSIONS: These data confirm that, as in other populations, a small subgroup of black patients receiving standard care improve their EF with favorable outcomes. Further studies are required to determine whether myocardial recovery is permanent and the best management strategies in such patients. PMID- 28918109 TI - Precision based guidelines for sub-maximal normalisation task selection for trunk extensor EMG. AB - AIM: The object of this study was to quantify the contribution of sub-maximal normalisation to the overall variance of exposure parameters describing erector spinae (ES) activity, and to provide guidelines for task selection which minimize methodological variance. METHODS: ES EMG was measured from three locations (T9, L1 and L5 levels) on fifteen men performing a manual materials handling task in the laboratory on three separate days. Four repeats of each of eleven sub-maximal normalisation tasks (eight static, three dynamic) were collected, work data were normalised to each task and repeat, and exposure parameters calculated. The unique contribution of normalisation to the overall variance was determined for each task and exposure parameter using variance component analyses. Normalisation tasks were scored according to their relative contributions to the overall variance and coefficients of variation. RESULTS: A prone task, similar to the Biering-Sorensen test posture, was the most repeatable for all electrode locations and across all exposure parameters. Thoracic level normalisation typically showed poorer repeatability than lumbar normalisation. DISCUSSION: To maximize measurement precision, we recommend that future ES EMG studies employing sub-maximal normalisation utilise said prone task. An alternate normalisation task specific to thoracic level ES muscles may be warranted. PMID- 28918110 TI - Emergent behaviors in RBCs flows in micro-channels using digital particle image velocimetry. AB - The key points in the design of microfluidic Lab-On-a-Chips for blood tests are the simplicity of the microfluidic chip geometry, the portability of the monitoring system and the ease on-chip integration of the data analysis procedure. The majority of those, recently designed, have been used for blood separation, however their introduction, also, for pathological conditions diagnosis would be important in different biomedical contexts. To overcome this lack is necessary to establish the relation between the RBCs flow and blood viscosity changes in micro-vessels. For that, the development of methods to analyze the dynamics of the RBCs flows in networks of micro-channels becomes essential in the study of RBCs flows in micro-vascular networks. A simplification in the experimental set-up and in the approach for the data collection and analysis could contribute significantly to understand the relation between the blood non-Newtonian properties and the emergent behaviors in collective RBCs flows. In this paper, we have investigated the collective behaviors of RBCs in a micro-channel in unsteady conditions, using a simplified monitoring set-up and implementing a 2D image processing procedure based on the digital particle image velocimetry. Our experimental study consisted in the analysis of RBCs motions freely in the micro-channel and driven by an external pressure. Despite the equipment minimal complexity, the advanced signal processing method implemented has allowed a significant qualitative and quantitative classification of the RBCs behaviors and the dynamical characterization of the particles velocities along both the horizontal and vertical directions. The concurrent causes for the particles displacement as the base solution-particles interaction, particle particle interaction, and the external force due to pressure gradient were accounted in the results interpretation. The method implemented and the results obtained represent a proof of concept toward the realization of a general-purpose microfluidic LOC device for in-vitro flow analysis of RBCs collective behaviors. PMID- 28918107 TI - Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model. AB - INTRODUCTION: Chronic Fatigue Syndrome (CFS) is a poorly understood illness that is characterized by diverse somatic symptoms, hypothalamic pituitary adrenal (HPA) axis dysfunction and heightened inflammatory indicators. These symptoms are often exacerbated and accompanied by psychological distress states and depression. Since depression is known to be associated with HPA axis dysfunction and greater inflammation, a psychoneuroendocrinological (PNE) model of inflammation was examined in persons diagnosed with CFS in order to uncover underlying biopsychosocial mechanisms in this poorly understood chronic illness. METHODS: Baseline data were drawn from two randomized controlled trials testing the efficacy of different forms of psychosocial intervention, and included psychological questionnaires, di-urnal salivary cortisol, and blood samples. Data were analyzed with structural equation modeling (SEM). RESULTS: The sample (N=265) was mostly middle-aged (Mage=49.36+/-10.9, range=20-73years), Caucasian (67.7%), female (81.7%), highly educated (85.5% completed some college, college, or graduate program), and depressed (CES-D M=23.87+/-12.02, range 2-57). The SEM supporting a psychoneuroendocrinological model of immune dysregulation in CFS fit the data chi2 (12)=17.725, p=0.1243, RMSEA=0.043, CFI=0.935, SRMR=0.036. Depression was directly related to evening salivary cortisol and inflammation, such that higher evening cortisol predicted greater depressive symptoms (beta=0.215, p<0.01) and higher pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, and tumor necrosis factor-alpha [TNF-alpha] levels (beta=0.185, p<0.05), when controlling for covariates. DISCUSSION: Results highlight the role of depression, cortisol and inflammation in possible biological mechanisms involved in the pathophysiology of CFS. Time-lagged, longitudinal analyses are needed to fully explore these relationships. PMID- 28918111 TI - The timing of retears after arthroscopic rotator cuff repair. AB - BACKGROUND: Little is known about the time dependence of the failure rate of surgically repaired rotator cuffs. Retears are significant, as they are common and may lead to less satisfactory outcomes and additional operations. Their timing is critical foundational information for understanding failure mechanisms. However, this remains unclear. Currently, there exist a number of studies that have reported retear rates at specific time points. Combining data from these publications can reveal when cuffs retear, which will help inform expectations and guidelines for progression of activity after surgery. METHODS: PubMed, Medline, and Embase were searched for studies relating to rotator cuff repair. Abstracts and articles were evaluated on the basis of predefined inclusion and exclusion criteria. Data were extracted from those publications that satisfied all requirements, and regression analysis was performed. RESULTS: Thirteen articles were included in the final meta-analysis. Retear rates for medium tears increased for approximately 15 months and leveled off at approximately 20%. Retear rates for large tears progressed steadily for about 12 months and approached an upper limit of approximately 40%. Retear rates for massive tears ranged from 20% to 60%, but the distribution of retear rate over time for these cuff tears is not clear from these data. CONCLUSION: Retear rates for medium and large tears generally increase until at least 10-15 months after surgery, after which they are likely to level off. Retear rates for massive tears are variable and may follow a time course different from that of other tear sizes. Retear rates depend on size of the original tear. PMID- 28918112 TI - Radiographic and clinical comparison of pegged and keeled glenoid components using modern cementing techniques: midterm results of a prospective randomized study. AB - BACKGROUND: Glenoid component loosening remains a significant issue after anatomic shoulder arthroplasty. Pegged glenoid components have shown better lucency rates than keeled components in the short term; however, midterm to long term results have not fully been determined. We previously reported early outcomes of the current randomized controlled group of patients, with higher glenoid lucency rates in those with a keeled glenoid. The purpose of this study was to evaluate the radiographic and clinical outcomes of these components at minimum 5-year follow-up. METHODS: Fifty-nine total shoulder arthroplasties were performed in patients with primary glenohumeral osteoarthritis. Patients were randomized to receive either a pegged or keeled glenoid component. Three raters graded radiographic glenoid lucencies. Clinical outcome scores and active mobility outcomes were collected preoperatively and at yearly postoperative appointments. RESULTS: Of the 46 shoulders meeting the inclusion criteria, 38 (82.6%) were available for minimum 5-year radiographic follow-up. After an average of 7.9 years, radiographic lucency was present in 100% of pegged and 91% of keeled components (P = .617). Grade 4 or 5 lucency was present in 44% of pegged and 36% of keeled components (P = .743). There were no differences in clinical outcome scores or active mobility outcomes between shoulders with pegged and keeled components at last follow-up. Within the initial cohort, 20% of the keeled shoulders (6 of 30) and 7% of the pegged shoulders (2 of 29) underwent revision surgery (P = .263). Kaplan-Meier analysis showed no significant difference in survival rates between groups (P = .560). CONCLUSION: At an average 7.9-year follow-up, non-ingrowth, all-polyethylene pegged glenoid implants are equivalent to keeled implants with respect to radiolucency, clinical outcomes, and need for revision surgery. PMID- 28918115 TI - The interplay of endocrine therapy, steroid pathways and therapeutic resistance: Importance of androgen in breast carcinoma. AB - A great majority of breast carcinomas expresses estrogen receptor (ER) and estrogens have crucial roles in the progress of breast carcinomas. Endocrine therapy targeting ER and/or intratumoral estrogen production significantly improved clinical outcomes of the patients with ER-positive breast carcinomas. However, resistance to endocrine therapy is often observed and significant number of patients will recur after the treatment. In addition, treatment for the patients with triple-negative breast carcinomas (negative for all ER, progesterone receptor (PR) and HER2) are limited to cytotoxic chemotherapy and novel therapeutic targets need to be identified. In breast carcinoma tissues, not only ER but androgen receptor (AR) is frequently expressed, suggesting pivotal roles of androgens in the progress of breast carcinomas. Growing interest on androgen action as possible therapeutic target has been taken, but androgen action seems quite complicated in breast carcinomas and inconsistent findings has been also proposed. In this review, we will summarize recent studies regarding intratumoral androgen production and its regulation as well as distinct subset of breast carcinomas characterized by activated AR signaling and recent clinical trial targeting AR in the patients with either ER-positive and ER-negative breast carcinomas. PMID- 28918116 TI - Atherosclerotic Disease and its Relationship to Lumbar Degenerative Disk Disease, Facet Arthritis, and Stenosis With Computed Tomography Angiography. AB - BACKGROUND: The intervertebral disk is the largest avascular structure in the body. It relies on passive diffusion from arteries at the periphery of the disk for nutrition. Previous studies have suggested a correlation between vascular disease and lumbar degenerative disk disease (DDD), but the association with facet arthritis and stenosis has not been evaluated. OBJECTIVE: To evaluate the degree of lumbar artery stenosis, aortic atherosclerosis on computed tomography angiography, and its relationship to lumbar DDD, facet arthritis, and spinal canal stenosis. DESIGN: Retrospective case review. SETTING: Academic tertiary care hospital. PARTICIPANTS: Not applicable. METHODS: A total of 300 lumbar arteries (150 lumbar artery pairs of the first to fifth lumbar arteries) were evaluated on consecutive computed tomography angiography scans. Severity of vascular disease of lumbar arteries was documented as normal, mild, moderate, severe, or occluded. Aortic vascular disease was documented along the posterior wall where the lumbar arteries originate. MAIN OUTCOME MEASUREMENTS: The relationship between vascular disease with DDD, facet arthritis, and spinal canal stenosis was examined and further evaluated controlling for age. RESULTS: Lumbar artery and aortic atherosclerosis had a positive relationship with DDD, facet arthritis, and spinal stenosis that was statistically significant (P < .05) even after controlling for age. The correlation coefficient was greatest in the younger age group when looking at lumbar artery vascular disease with DDD (0.73, confidence interval 0.50-0.96, P < .0001) and aortic vascular disease with DDD (0.72, confidence interval 0.49-0.94, P < .0001). The correlation of vascular disease with facet arthritis and stenosis was not strong in the older age group. CONCLUSION: Atherosclerotic disease of the lumbar arteries and aorta correlated with lumbar DDD, facet arthritis, and spinal canal stenosis after we adjusted for age, although the correlation with facet arthritis and spinal canal stenosis was not as strong in the older age group. LEVEL OF EVIDENCE: IV. PMID- 28918114 TI - Netrins & Semaphorins: Novel regulators of the immune response. AB - Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions. PMID- 28918117 TI - Mild Traumatic Brain Injury in a High School Football Player With Familial Hemiplegic Migraine: A Case Report. AB - : Mild traumatic brain injury is a major concern in young athletes, with an estimated 1.6-3.8 million reported concussions in the United States annually. Familial hemiplegic migraine is a rare autosomal-dominant condition characterized by sporadic episodes of transient unilateral motor weakness that may begin at any age. We present a case of a 17-year-old boy with a history of familial hemiplegic migraine who suffered prolonged symptoms after a mild traumatic brain injury during sports participation. LEVEL OF EVIDENCE: V. PMID- 28918113 TI - Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart. AB - Recent advancement in mitochondrial research has significantly extended our knowledge on the role and regulation of mitochondria in health and disease. One important breakthrough is the delineation of how mitochondrial morphological changes, termed mitochondrial dynamics, are coupled to the bioenergetics and signaling functions of mitochondria. In general, it is believed that fusion leads to an increased mitochondrial respiration efficiency and resistance to stress induced dysfunction while fission does the contrary. This concept seems not applicable to adult cardiomyocytes. The mitochondria in adult cardiomyocytes exhibit fragmented morphology (tilted towards fission) and show less networking and movement as compared to other cell types. However, being the most energy demanding cells, cardiomyocytes in the adult heart possess vast number of mitochondria, high level of energy flow, and abundant mitochondrial dynamics proteins. This apparent discrepancy could be explained by recently identified new functions of the mitochondrial dynamics proteins. These "non-canonical" roles of mitochondrial dynamics proteins range from controlling inter-organelle communication to regulating cell viability and survival under metabolic stresses. Here, we summarize the newly identified non-canonical roles of mitochondrial dynamics proteins. We focus on how these fission and fusion independent roles of dynamics proteins regulate mitochondrial bioenergetics. We also discuss potential molecular mechanisms, unique intracellular location, and the cardiovascular disease relevance of these non-canonical roles of the dynamics proteins. We propose that future studies are warranted to differentiate the canonical and non canonical roles of dynamics proteins and to identify new approaches for the treatment of heart diseases. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. PMID- 28918118 TI - Case Report: Aquatic Therapy and End-Stage Dementia. AB - : A 54-year-old woman, retired due to progressive cognitive decline, was diagnosed with early-onset Alzheimer dementia. Conventional medication therapy for dementia had proven futile. Initial evaluation revealed a nonverbal female seated in a wheelchair, dependent on 2-person assist for all transfers and activities of daily living. She had been either nonresponsive or actively resistive for both activities of daily living and transfers in the 6 months before assessment. After a total of 17 1-hour therapy sessions over 19 weeks in a warm water therapy pool, she achieved the ability to tread water for 15 minutes, transfers improved to moderate-to-maximum assist from seated, and ambulation improved to 1000 feet with minimum-to-moderate assist of 2 persons. Communication increased to appropriate "yes," "no," and "okay" appropriate responses, and an occasional "thank you" and "very nice." The authors propose that her clinical progress may be related to her aquatic therapy intervention. LEVEL OF EVIDENCE: IV. PMID- 28918119 TI - Corrigendum to "Prenylflavonoids isolated from Artocarpus champeden with TRAIL resistance overcoming activity" [Phytochemistry 96 (2013) 299-304]. PMID- 28918120 TI - Moment-by-Moment in Women's Recovery: Randomized controlled trial protocol to test the efficacy of a mindfulness-based intervention on treatment retention and relapse prevention among women in residential treatment for substance use disorder. AB - Although therapeutic treatments exist for substance use disorder (SUD), about half of individuals who enter treatment leave early and relapse to substance use. Early dropout from residential treatment places individuals at risk of relapse, and women in SUD residential treatment represent a vulnerable population. Evidence gaps persist for the use of mindfulness-based interventions (MBIs) among racially and ethnically diverse women with SUDs, especially regarding the efficacy of MBIs adapted to prevent residential dropout and relapse. We previously developed and pilot tested an MBI, Moment-by-Moment in Women's Recovery (MMWR), adapted to support women with SUD during residential treatment. The 12-session MMWR program tested in the present study integrates relapse prevention, addresses literacy level and trauma experiences and mental health problems, and is relevant to issues surrounding treatment- and relapse-related stressors among women. The primary objective of the current Phase II randomized controlled trial is to adequately test the efficacy of MMWR on residential treatment retention and substance use relapse and determine psychosocial and neural mechanisms of action underlying MMWR. Participants are women in residential SUD treatment from a community-based residential site that serves mainly women who are low-income and racially and ethnically diverse. A subgroup of participants from each treatment group also completes functional and structural neuroimaging assessments before and after the intervention to explore possible structural and functional brain correlates of change associated with participation in the MMWR program. Findings are expected to inform the utility of adapting MBIs to improve treatment success among vulnerable women in SUD residential treatment. PMID- 28918121 TI - Conserved rules in embryonic development of cortical interneurons. AB - This review will focus on early aspects of cortical interneurons (cIN) development from specification to migration and final positioning in the human cerebral cortex. These mechanisms have been largely studied in the mouse model, which provides unique possibilities of genetic analysis, essential to dissect the molecular and cellular events involved in cortical development. An important goal here is to discuss the conservation and the potential divergence of these mechanisms, with a particular interest for the situation in the human embryo. We will thus cover recent works, but also revisit older studies in the light of recent data to better understand the developmental mechanisms underlying cIN differentiation in human. Because cIN are implicated in severe developmental disorders, understanding the molecular and cellular mechanisms controlling their differentiation might clarify some causes and potential therapeutic approaches to these important clinical conditions. PMID- 28918122 TI - Pre-harvest UV-C irradiation triggers VOCs accumulation with alteration of antioxidant enzymes and phytohormones in strawberry leaves. AB - Recent studies have highlighted the biological and physiological effects of pre harvest ultraviolet (UV)-C treatment on growing plants. However, little is known about the involvement of volatile organic compounds (VOCs) and their response to this treatment. In this study, strawberry plants were exposed to three different doses of UV-C radiation for seven weeks (a low dose: 9.6kJm-2; a medium dose: 15kJm-2; and a high-dose: 29.4kJm-2). Changes in VOC profiles were investigated and an attempt was made to identify factors that may be involved in the regulation of these alterations. Principle compounds analysis revealed that VOC profiles of UV-C treated samples were significantly altered with 26 VOCs being the major contributors to segregation. Among them, 18 fatty acid-derived VOCs accumulated in plants that received high and medium dose of UV-C treatments with higher lipoxygenase and alcohol dehydrogenase activities. In treated samples, the activity of the antioxidant enzymes catalase and peroxidase was inhibited, resulting in a reduced antioxidant capacity and higher lipid peroxidation. Simultaneously, jasmonic acid level was 74% higher in the high-dose group while abscisic acid content was more than 12% lower in both the medium and high-dose UV C treated samples. These results indicated that pre-harvest UV-C treatment stimulated the biosynthesis of fatty acid-derived VOCs in strawberry leaf tissue by upregulating the activity of enzymes of the LOX biosynthetic pathway and downregulating antioxidant enzyme activities. It is further suggested that the mechanisms underlying fatty acid-derived VOCs biosynthesis in UV-C treated strawberry leaves are associated with UV-C-induced changes in phytohormone profiles. PMID- 28918123 TI - Carnosic acid induces apoptosis of hepatocellular carcinoma cells via ROS mediated mitochondrial pathway. AB - Carnosic acid (CA), an important bioactive phenolic diterpene mainly found in labiate plants, exerts various biological functions, including antioxidant, anti inflammatory, antitumor, and neuroprotective activities. In the present study, we proved the deleterious effects of CA against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. In vitro, CA significantly decreased cell viability, inhibited cell proliferation and migration, enhanced apoptosis, and increased caspase-3, -8, and -9 activities in HepG2 and SMMC-7721 cells. Specifically, CA led to a decreased mitochondrial membrane potential (MMP) and increases in intracellular reactive oxygen species (ROS) levels and apoptosis related protein expression. Pre-incubation of HCC cells with N-Acetyl-l-cysteine (NAC), a ROS inhibitor, strongly suppressed CA-induced apoptotic phenomena, including reduced cell viability, excessive ROS levels, MMP decreases, and abnormal protein expression, suggesting an association of CA-induced apoptosis with oxidative stress-mediated mitochondrial pathways. In HepG2-and SMMC-7721 xenograft tumor mouse models, treatment with CA inhibited tumor growth and modulated apoptosis-related protein expression, confirming the anti-HCC effects of this chemical. Moreover, the CA-mediated anti-HCC effects associated with oxidative stress provide experimental evidence to support the potential use of CA as a drug therapy for HCC. PMID- 28918124 TI - Polyphenols reported to shift APAP-induced changes in MAPK signaling and toxicity outcomes. AB - Due to its widespread availability, acetaminophen (APAP) is the leading cause for drug-induced liver injury in many countries including United States and United Kingdom. When used as recommended, APAP is relatively safe. However, in overdose cases, increased metabolism of APAP to N-acetyl-para-benzoquinoneimine (NAPQI), a reactive metabolite, leads to glutathione (GSH) depletion, oxidative stress, and cellular injury. Throughout this process, a variety of factors play important roles in propagating toxicity, including c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family. Because of its involvement in multiple cellular processes, biomarkers associated with MAPK signaling have generated interest as a mechanistic target for protecting against APAP-induced liver injury and hepatocellular injury, in general. This review summarizes mechanistic details by which natural products, specifically those containing polyphenolic moieties, are capable of attenuating APAP-induced toxicity, at least in part through an ability to modulate MAPKs. These compounds include carnosic acid, chlorogenic acid, davallialactone, extracts from Hibiscus sabdariffa, quercetin-based compounds, and resveratrol. Despite variations in the experimental designs across these studies, common pathways and biomarkers were implicated in cytoprotection when polyphenolic compounds were given with APAP, such as enhanced antioxidant gene expression and reversal of APAP-induced changes in oxidative stress markers and MAPK signaling. Overall, an emphasis should be placed on method standardization for future studies if we are to gain a more in depth understanding of how polyphenolic moieties contribute to cytoprotection during an APAP overdose event. PMID- 28918125 TI - Iodinated chlorin p6 copper complex induces anti-proliferative effect in oral cancer cells through elevation of intracellular reactive oxygen species. AB - We investigated the anticancer chemotoxicity of previously reported iodinated chlorin p6 copper complex (ICp6-Cu), a novel chlorophyll derivative in which copper is attached to the side chain carboxylate groups via coordination. Human oral carcinoma cells NT8e, 4451 and the non-cancerous keratinocyte HaCaT cells were treated with ICp6-Cu for 48 h in dark and cell viability, proliferation and morphological alterations were examined. ICp6-Cu showed pronounced cytotoxicity in cancer cells with IC50 ~40 MUM, whereas, the viability of HaCaT cells was not affected. Cell proliferation assay revealed that ICp6-Cu at IC50 concentration led to complete inhibition of cell proliferation in both the cell lines. Cell morphology studied by confocal microscopy showed absence of cell death via necrosis or apoptosis. Instead, the treated cells displayed distinct features of non-apoptotic death such as highly vacuolated cytoplasm, lysosomal membrane permeabilization and damage to cytoskeleton F-actin filaments. In addition, ICp6 Cu treatment led to time dependent increase in the intracellular level of reactive oxygen species (ROS) and the cytotoxicity of ICp6-Cu was significantly inhibited by pre-treatment of cells with antioxidants (glutathione and trolox). These findings revealed that ICp6-Cu is a potent chemotoxic agent which can induce cytotoxic effect in cancer cells through elevation of intracellular ROS. It is suggested that ICp6-Cu may provide tumor selective chemotoxicity by exploiting difference of redox environment in normal and cancer cells. PMID- 28918126 TI - High CMV IgG antibody levels are associated to a lower CD4+ RESPONSE to antiretroviral therapy in HIV-infected women. AB - BACKGROUND: Virtually all HIV-infected women in sub-Saharan Africa have evidence of Cytomegalovirus (CMV) infection and levels of specific anti-CMV IgG have been suggested to represent more intense reactivation of subclinical infection. Studies have also shown direct influence of CMV on lymphocytes. OBJECTIVE: The aim of this study was to determine if levels of anti-CMV specific antibodies could impact on the immunological response to antiretroviral treatment (ART) in HIV-infected pregnant women. STUDY DESIGN: CMV-specific IgG were measured in HIV infected pregnant women at 26 weeks of gestation (before ART initiation). Women received ART until 6 months postpartum or indefinitely according to local guidelines at the time of the study. Immunological and virological responses were assessed 6 months and 24 months after delivery. RESULTS: A total of 81 women were studied. At baseline high levels (above the median) of specific IgG were associated to a low CD4+ cell count (P<0.001), a high viral load (P=0.003), and to an older age (P=0.051). In a multivariate model adjusting for baseline CD4+ count, baseline viral load and age, the presence of low levels of CMV IgG was the only independent predictor of a a CD4+ count above 500/mm3 24 months after delivery among women on continuous therapy. CONCLUSIONS: In this cohort, levels of CVM IgG had a significant influence on the immunological response to ART, adding information to the known impact of CMV infection in the HIV-positive population, and underlining the need of new strategies to contain the infection. PMID- 28918127 TI - Clinical, laboratory and virological data from suspected ZIKV patients in an endemic arbovirus area. AB - BACKGROUND: The emergence of Zika virus (ZIKV) presents new challenges to both clinicians and public health authorities. Overlapping clinical features between the diseases caused by ZIKV, dengue (DENV) and chikungunya (CHIKV) and the lack of validated serological assays for ZIKV make accurate diagnosis difficult. Brazilian authorities largely rely on clinical and epidemiological data for the epidemiological and clinical classifications of most ZIKV cases. OBJECTIVE: To report the laboratory and clinical profiles of patients diagnosed with Zika fever based only on clinical and epidemiological data. STUDY DESIGN: We analyzed 433 suspected cases of ZIKV identified by the attending physician based on proposed clinical criteria. The samples were also screened for ZIKV, DENV and CHIKV using PCR. RESULTS: Of the 433 patients analyzed, 168 (38.8%) were laboratory-confirmed for arboviruses: 96 were positive for ZIKV, 67 were positive for DENV (56 for DENV-2, 9 for DENV-1, and 2 for DENV-4), four were positive for co-infection with ZIKV/DENV-2, and one was positive for CHIKV. The most common signs or symptoms in the patients with laboratory-confirmed ZIKV were rash (100%), arthralgia (77.1%), fever (74.0%), myalgia (74.0%) and non-purulent conjunctivitis (69.8%). In patients with laboratory-confirmed DENV infections, the most frequently observed symptoms were rash (100%), fever (79.1%), myalgia (74.6%), headache (73.1%) and arthralgia (70.1%). The measure of association between clinical manifestations and laboratory manifestations among patients with ZIKV and DENV detected a statistically significant difference only in abdominal pain (p=0.04), leukopenia (p=0.003), and thrombocytopenia (p=0.01). CONCLUSION: Our data suggests that clinical and epidemiological criteria alone are not a good tool for ZIKV and DENV differentiation, and that laboratory diagnosis should be mandatory. PMID- 28918128 TI - Whole network, temporal and parietal lobe contributions to the earliest phases of language production. AB - We investigated whether it is possible to study the network dynamics and the anatomical regions involved in the earliest moments of picture naming by using invasive electroencephalogram (EEG) traces to predict naming errors. Four right handed participants with focal epilepsy explored with extensive stereotactic implant montages that recorded temporal, parietal and occipital regions -in two patients of both hemispheres-named a total of 228 black and white pictures in three different sessions recorded in different days. The subjects made errors that involved anomia and semantic dysphasia, which related to word frequency and not to visual complexity. Using different modalities of spectrum analysis and classification with a support vector machine (SVM) we could predict errors with rates that ranged from slightly above chance level to 100%, even in the preconscious phase, i.e., 100 msec after stimulus presentation. The highest rates were obtained using the gamma bands of all contact spectra without averaging, which implies a fine modulation of the neuronal activity at a network level. Despite no subset of nodes could match the whole set, rates close to the best prediction scores were obtained through the spectra of the temporal-parietal and temporal-occipital junction along with the temporal pole and hippocampus. When both hemispheres were explored nodes from the left side dominated in the best subsets. We argue that posterior temporal regions, especially of the dominant side, are involved very early, even in the preconscious phase (100 msec), in language production. PMID- 28918129 TI - Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover independent pathways. AB - Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (alpha-kappa) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover. We recently established a specific liquid chromatography-mass spectrometry method to analyze which PA species were generated by DGK isozymes in a cell stimulation-dependent manner. Interestingly, we determined that DGKdelta, which is closely related to the pathogenesis of type II diabetes, preferentially utilized 14:0/16:0-, 14:0/16:1-, 16:0/16:0-, 16:0/16:1-, 16:0/18:0- and 16:0/18:1-DG species (X:Y = the total number of carbon atoms: the total number of double bonds) supplied from the phosphatidylcholine-specific phospholipase C pathway, but not 18:0/20:4-DG, in high glucose-stimulated C2C12 myoblasts. Moreover, DGKalpha mainly consumed 14:0/16:0-, 16:0/18:1-, 18:0/18:1- and 18:1/18:1-DG species during cell proliferation in AKI melanoma cells. Furthermore, we found that 16:0/16:0-PA was specifically produced by DGKzeta in Neuro-2a cells during retinoic acid- and serum starvation-induced neuronal differentiation. These results indicate that DGK isozymes utilize a variety of DG molecular species derived from PI turnover independent pathways as substrates in different stimuli and cells. DGK isozymes phosphorylate various DG species to generate various PA species. It was revealed that the modes of activation of conventional and novel protein kinase isoforms by DG molecular species varied considerably. However, PA species-selective binding proteins have not been found to date. Therefore, we next attempted to identify PA species-selective binding proteins from the mouse brain and identified alpha synuclein, which has causal links to Parkinson's disease. Intriguingly, we determined that among phospholipids, including several PA species (16:0/16:0-PA, 16:0/18:1-PA, 18:1/18:1-PA, 18:0/18:0-PA and 18:0/20:4-PA); 18:1/18:1-PA was the most strongly bound PA to alpha-synuclein. Moreover, 18:1/18:1-PA strongly enhanced secondary structural changes from the random coil form to the alpha helix form and generated a multimeric and proteinase K-resistant alpha-synuclein protein. In contrast with the dogma described above, our recent studies strongly suggest that PI turnover-derived DG species and also various DG species derived from PI turnover-independent pathways are utilized by DGK isozymes. DG species supplied from distinct pathways may be utilized by DGK isozymes based on different stimuli present in different types of cells, and individual PA molecular species would have specific targets and exert their own physiological functions. PMID- 28918130 TI - Reply to: "Treatment failure after interferon-free treatment of hepatitis C as a clue of a yet undetected hepatocellular carcinoma". PMID- 28918131 TI - Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results. AB - BACKGROUND: The Baveno VI consensus meeting concluded that an early TIPS must be considered in high-risk cirrhotic patients presenting with variceal bleeding (VB) (Child B + active bleeding at endoscopy or Child C10-13 patients). Whether this therapeutic approach is feasible in a real-life setting remains unclear. AIMS: To determine (1) the proportion of patients eligible for early-TIPS among cirrhotic patients with VB, (2) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (3) the outcomes of patients who experienced early-TIPS placement in a large, national, prospective, multicentre audit including academic and non-academic centres. MATERIALS AND METHODS: All French centres recruiting gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and PHT-related bleeding were included. RESULTS: 964 patients were included (58 centres: 26 academic, 32 non-academic; patient characteristics: male sex, 77%; age, 59.6 +/- 12.1 years; aetiologies of cirrhosis (alcoholic,viral/other, 67%/15%/18%); source of bleeding (EV/GV/other, 80/11/9%); active bleeding at endoscopy 34%; Child A 21%/B 44%/C 35%. Overall, 35% of the patients were eligible for early-TIPS, but only 6.8%, displaying less severe cirrhosis underwent early-TIPS placement. The main reason for discarding TIPS was a lack of availability. The actuarial probability of survival at one year was significantly increased in early-TIPS patients (85.7+/ 0.07% vs 58.9+/-0.03%, p=0.04). The severity of liver disease was the only parameter independently associated with improved one-year survival. CONCLUSION: In this real-life study, one-third of the cirrhotic patients admitted for VB fulfilled the criteria for early-TIPS placement, whereas only 7% had access to TIPS. TIPS was restricted to patients displaying less severe cirrhosis. The severity of liver disease was the only parameter that influenced survival. PMID- 28918132 TI - Assessing precision, bias and sigma-metrics of 53 measurands of the Alinity ci system. AB - : Assay performance is dependent on the accuracy and precision of a given method. These attributes can be combined into an analytical Sigma-metric, providing a simple value for laboratorians to use in evaluating a test method's capability to meet its analytical quality requirements. Sigma-metrics were determined for 37 clinical chemistry assays, 13 immunoassays, and 3 ICT methods on the Alinity ci system. METHODS: Analytical Performance Specifications were defined for the assays, following a rationale of using CLIA goals first, then Ricos Desirable goals when CLIA did not regulate the method, and then other sources if the Ricos Desirable goal was unrealistic. A precision study was conducted at Abbott on each assay using the Alinity ci system following the CLSI EP05-A2 protocol. Bias was estimated following the CLSI EP09-A3 protocol using samples with concentrations spanning the assay's measuring interval tested in duplicate on the Alinity ci system and ARCHITECT c8000 and i2000SR systems, where testing was also performed at Abbott. Using the regression model, the %bias was estimated at an important medical decisions point. Then the Sigma-metric was estimated for each assay and was plotted on a method decision chart. The Sigma-metric was calculated using the equation: Sigma-metric=(%TEa-|%bias|)/%CV. RESULTS: The Sigma-metrics and Normalized Method Decision charts demonstrate that a majority of the Alinity assays perform at least at five Sigma or higher, at or near critical medical decision levels. CONCLUSION: More than 90% of the assays performed at Five and Six Sigma. None performed below Three Sigma. Sigma-metrics plotted on Normalized Method Decision charts provide useful evaluations of performance. The majority of Alinity ci system assays had sigma values >5 and thus laboratories can expect excellent or world class performance. Laboratorians can use these tools as aids in choosing high-quality products, further contributing to the delivery of excellent quality healthcare for patients. PMID- 28918133 TI - Short communication: Short-term intravenous amino acid infusions as a method to detect limiting amino acids in dairy cattle diets. AB - We hypothesized that the addition of limiting AA increases dry matter intake (DMI) by reducing anaplerosis and hepatic oxidation. Accordingly, the objective of this work was to examine the effects of short-term intravenous infusions of Met, Lys, and His (which are considered the most limiting AA) on DMI as a method to detect whether specific AA are limiting in dairy cow diets. We conducted 4 experiments using Holstein cows in the immediate postpartum period to address this objective. The first experiment used 4 cows 6 to 10 d postpartum (PP) in a 4 * 4 Latin square design with 1-d periods including 12 h for infusions and 12 h for recovery. Treatments were continuous infusions of 5 (low), 10 (medium), or 15% (high) of the calculated requirement of metabolizable Met, Lys, and His or 0.9% saline (control, CONT). In the second and third experiments, 8 cows (4-12 d PP) were divided into 2 groups of 4 cows, and each group received a different diet formulated to either be low in Lys (experiment 2) or Met (experiment 3). Each experiment was a crossover design with two 1-d periods with 12-h infusions (continuous) and 12 h for recovery. Treatments were 15% of the calculated requirement of metabolizable Met, Lys, and His (high), or 0.9% saline (CONT). In the fourth experiment, 5 cows (4-14 d PP) were used in a 5 * 5 Latin square design. Periods were 2 d in which treatments were continuously infused for the first 46 h. Treatments were 0.9% saline (CONT), all (Lys, Met, and His), LM (Lys and Met), LH (Lys and His), and MH (Met and His); dosages were equal to the estimated shortage in each specific AA. In each experiment, feed intake was recorded by a computerized data acquisition system, milk yield was recorded, and milk composition was analyzed for fat, protein, lactose, and milk urea nitrogen (MUN) concentrations. Treatments did not affect DMI or yield of milk or milk components in the first experiment. In the second experiment, AA treatment increased protein percentage and reduced lactose percentage but had no effect on protein and lactose yields or DMI. In the third experiment, the AA treatment tended to increase yields of milk, lactose, and protein as well as MUN concentration but did not affect DMI. In the fourth experiment, no effects were detected for DMI and milk yield, whereas the all, LH, and LM treatments reduced milk lactose concentration compared with CONT, and MH increased MUN concentration compared with CONT and other treatments. These results failed to provide support for our hypothesis that short-term addition of these potentially limiting AA will increase DMI. This may be due to our hypothesis being inaccurate or to other factors; other limiting AA could have prevented the effects of Lys, Met, and His infusions or the infusion periods could have been too short to induce a response in DMI. Accordingly, short-term infusion of AA is probably not a sensitive method to detect limiting AA in dairy cow diets. PMID- 28918134 TI - Crystallization and demineralization phenomena in washed-rind cheese. AB - This report documents an observational study of a high-moisture washed-rind cheese. Three batches of cheese were sampled on a weekly basis for 6 wk and again at wk 10. Center, under-rind, rind, and smear samples were tested for pH, moisture, and selected mineral elements. Powder x-ray diffractometry and petrographic microscopy were applied to identify and image the crystal phases. The pH of the rind increased by over 2 pH units by wk 10. The pH of the under rind increased but remained below the rind pH, whereas the center pH decreased for most of aging and only began to rise after wk 5. Diffractograms of smear material revealed the presence of 4 crystal phases: brushite, calcite, ikaite, and struvite. The phases nucleated in succession over the course of aging, with calcite and ikaite appearing around the same time. A very small amount of brushite appeared sporadically in center and under-rind samples, but otherwise no other crystallization was observed beneath the rind. Micrographs revealed that crystals in the smear grew to over 250 MUm in length by wk 10, and at least 2 different crystal phases, probably ikaite and struvite, could be differentiated by their different optical properties. The surface crystallization was accompanied by a mineral diffusion phenomenon that resulted, on average, in a 217, 95.7, and 149% increase in calcium, phosphorus, and magnesium, respectively, in the rind by wk 10. The diffusion phenomenon caused calcium, phosphorus, and magnesium to decrease, on average, by 55.0, 21.5, and 36.3%, respectively, in the center by wk 10. The present study represents the first observation of crystallization and demineralization phenomena in washed-rind cheese. PMID- 28918135 TI - Effects of addition of malic or citric acids on fermentation quality and chemical characteristics of alfalfa silage. AB - We studied the effects on alfalfa preservation and chemical composition of the addition of different levels of malic acid and citric acid at ensiling as well as the utilization efficiency of these 2 organic acids after fermentation. Alfalfa was harvested at early bloom stage. After wilting to a dry matter content of approximately 40%, the alfalfa was chopped into 1- to 2-cm pieces for ensiling. Four levels (0, 0.1, 0.5, and 1% of fresh weight) of malic acid or citric acid were applied to chopped alfalfa at ensiling with 4 replicates for each treatment, and the treated alfalfa forages were ensiled for 60 d in vacuum-sealed polyethylene bags (dimensions: 200 mm * 300 mm) packed with 200 to 230 g of fresh alfalfa per mini silo and an initial density of 0.534 g/cm3. The application of malic or citric acids at ensiling for 60 d led to lower silage pH than was observed in the control silage (0% of malic or citric acids). Application of the 2 organic acids led to higher lactic acid concentration in alfalfa silage than in the control silage except with the application rate of 1% of fresh weight. Silages treated with both organic acids had lower nonprotein nitrogen concentrations than the control silages, and the nonprotein nitrogen concentrations in ensiled forages decreased with the increase in malic or citric acid application rates. The application of the 2 organic acid additives led to lower saturated fatty acid proportions and higher polyunsaturated fatty acid proportions in ensiled alfalfa than in the control silage. The amount of malic and citric acids degraded during ensiling of alfalfa was 1.45 and 0.63 g, respectively. At the application rate of 0.5% of fresh weight, residues of malic acid and citric acid in alfalfa silage were 11.1 and 13.6 g/kg of dry matter. These results indicate that including malic or citric acids at the ensiling of alfalfa effectively improved silage fermentation quality, limited proteolysis, improved fatty acid composition of the ensiled forage, and could provide animals with additional feed additives proven to promote animal performance. However, when the application rate of both organic acids reached 1%, the concentration of lactic acid in silages decreased notably. Additionally, 0.5 and 1% application rates also increased the yeast count in ensiled alfalfa. PMID- 28918136 TI - Short communication: Cow- and quarter-level milking indicators and their associations with clinical mastitis in an automatic milking system. AB - The aim of this study was to assess associations of cow-, udder-, and quarter level factors with the risk of clinical mastitis (CM) in cows managed using an automatic milking system. The primary hypothesis was that quarter peak milk flow rate (QPMF) is associated with increased risk of CM. A retrospective, case control study was undertaken using data from a 1,549 cow farm using 20 automatic milking system units. All data from cows milked during March to December 2015 was available for analysis. Cases (n = 82) were defined as cows diagnosed with their first case of CM between 24 and 300 d in milk in the current lactation. Healthy control cows (n = 6/case) were randomly matched based on identical parity, existence of milk records during the day in milk period corresponding to the 15-d window before case diagnosis, average conductivity of <5.5 mS/cm in that window, and no history of CM in the current lactation. Logistic regression was used to estimate effects of parity, quarter position, day in milk at diagnosis of CM, average of QPMF 15 d before CM diagnosis, udder milk yield, and milking interval on the probability of CM. Of the 6 predictor variables included in the model, only milking interval was significantly associated with the increased risk of quarter CM. We concluded that in a high-production, freestall-housed North American herd using automatic milking system, milking interval, but not QPMF, was associated with risk of CM. PMID- 28918137 TI - Reticulo-rumen mass, epithelium gene expression, and systemic biomarkers of metabolism and inflammation in Holstein dairy cows fed a high-energy diet. AB - Feeding a higher-energy diet by increasing cereal grains at the expense of forage during the last 3 to 4 wk prepartum is a traditional approach to help the rumen "adapt" to the traditional diets fed at the onset of lactation. Increasing grain/concentrate in the diet changes ruminal fermentation and in sheep and goats elicits marked changes in mRNA expression of immune-related genes in ruminal epithelium. Whether such changes at the epithelial and systemic levels occur in dairy cows when the dietary energy content increases at a fixed level of concentrate is unknown. Fourteen nonpregnant, nonlactating Holstein cows were fed a control lower-energy (CON, 1.30 Mcal/kg of dry matter) diet to meet 100% of estimated nutrient requirements for 3 wk, after which half of the cows were assigned to a higher-energy diet (OVE, 1.60 Mcal/kg of dry matter) and half of the cows continued on CON for 6 wk. Levels of forage and concentrate for CON and OVE were 80 and 79% and 20 and 21%, respectively. Plasma samples were collected 1 d before slaughter to examine biomarkers of metabolism, liver function, inflammation, and oxidative stress. The reticulo-rumen mass was recorded at slaughter, and samples of epithelium were harvested from all cows. The expression of 29 genes associated with tight junctions, immune function, and nutrient transport (volatile fatty acids, urea, and trace minerals) was examined. Overfeeding energy led to consistently greater dry matter intake over time, and lowered plasma concentrations of haptoglobin, paraoxonase, bilirubin, fatty acids, and myeloperoxidase (secreted by neutrophils). In contrast, OVE resulted in greater hydroxybutyrate and cholesterol concentrations. A greater reticulo rumen mass in cows fed OVE did not alter genes associated with tight junctions (CDLN1, CDNL4, OCLN, TJP1), immune function (IL1B, IL10, NFKB1, TLR2, TLR4, TNF), oxidative stress (SOD1, SOD2), or most nutrient transporters. However, feeding OVE upregulated the acute-phase protein SAA3 by 3.5-fold and downregulated a volatile fatty acid transporter (SLC16A1) and a Fe and Cu transporter (SLC11A2). The lack of effect on mRNA expression along with lower plasma concentrations of inflammation biomarkers indicates that long-term intake of a higher-energy diet ad libitum was not detrimental to ruminal epithelium integrity. In that context, a protective function of SAA3 could be envisioned with a role in opsonizing gram negative bacteria that produce endotoxins. The long-term control of volatile fatty acid absorption and trace minerals from the rumen in cows overfed energy does not seem to be controlled at the gene transcription level. The relevance of these findings to the nutritional management of pregnant dry cows merits further research. PMID- 28918138 TI - Characterizing effects of feed restriction and glucagon-like peptide 2 administration on biomarkers of inflammation and intestinal morphology. AB - Inadequate feed consumption reduces intestinal barrier function in both ruminants and monogastrics. Objectives were to characterize how progressive feed restriction (FR) affects inflammation, metabolism, and intestinal morphology, and to investigate if glucagon-like peptide 2 (GLP2) administration influences the aforementioned responses. Twenty-eight Holstein cows (157 +/- 9 d in milk) were enrolled in 2 experimental periods. Period 1 [5 d of ad libitum (AL) feed intake] served as baseline for period 2 (5 d), during which cows received 1 of 6 treatments: (1) 100% of AL feed intake (AL100; n = 3), (2) 80% of AL feed intake (n = 5), (3) 60% of AL feed intake (n = 5), (4) 40% of AL feed intake (AL40; n = 5), (5) 40% of AL feed intake + GLP2 administration (AL40G; 75 ug/kg of BW s.c. 2*/d; n = 5), or (6) 20% of AL feed intake (n = 5). As the magnitude of FR increased, body weight and milk yield decreased linearly. Blood urea nitrogen and insulin decreased, whereas nonesterified fatty acids and liver triglyceride content increased linearly with progressive FR. Circulating endotoxin, lipopolysaccharide binding protein, haptoglobin, serum amyloid A, and lymphocytes increased or tended to increase linearly with advancing FR. Circulating haptoglobin decreased (76%) and serum amyloid A tended to decrease (57%) in AL40G relative to AL40 cows. Cows in AL100, AL40, and AL40G treatments were euthanized to evaluate intestinal histology. Jejunum villus width, crypt depth, and goblet cell area, as well as ileum villus height, crypt depth, and goblet cell area, were reduced (36, 14, 52, 22, 28, and 25%, respectively) in AL40 cows compared with AL100 controls. Ileum cellular proliferation tended to be decreased (14%) in AL40 versus AL100 cows. Relative to AL40, AL40G cows had improved jejunum and ileum morphology, including increased villus height (46 and 51%), villus height to crypt depth ratio (38 and 35%), mucosal surface area (30 and 27%), cellular proliferation (43 and 36%), and goblet cell area (59 and 41%). Colon goblet cell area was also increased (48%) in AL40G relative to AL40 cows. In summary, progressive FR increased circulating markers of inflammation, which we speculate is due to increased intestinal permeability as demonstrated by changes in intestinal architecture. Furthermore, GLP2 improved intestinal morphology and ameliorated circulating markers of inflammation. Consequently, FR is a viable model to study consequences of intestinal barrier dysfunction and administering GLP2 appears to be an effective mitigation strategy to improve gut health. PMID- 28918140 TI - Technical note: Feasibility of near infrared transmittance spectroscopy to predict cheese ripeness. AB - The aim of the study was to evaluate the feasibility of near infrared (NIR) transmittance spectroscopy to predict cheese ripeness using the ratio of water soluble nitrogen (WSN) to total nitrogen (TN) as an index of cheese maturity (WSN/TN). Fifty-two Protected Designation of Origin cow milk cheeses of 5 varieties (Asiago, Grana Padano, Montasio, Parmigiano Reggiano, and Piave) and different ripening times were available for laboratory and chemometric analyses. Reference measures of WSN and TN were matched with cheese spectral information obtained from ground samples by a NIR instrument that operated in transmittance mode for wavelengths from 850 to 1,050 nm. Prediction equations for WSN and TN were developed using (1) cross-validation on the whole data set and (2) external validation on a subset of the entire data. The WSN/TN was calculated as ratio of predicted WSN to predicted TN in cross-validation. The coefficients of determination for WSN and TN were >0.85 both in cross- and external validation. The high accuracy of the prediction equations for WSN and TN could facilitate implementation of NIR transmittance spectroscopy in the dairy industry to objectively, rapidly, and accurately monitor the ripeness of cheese through WSN/TN. PMID- 28918139 TI - Comparison of milk protein composition and rennet coagulation properties in native Swedish dairy cow breeds and high-yielding Swedish Red cows. AB - Recent studies have reported a very high frequency of noncoagulating milk in Swedish Red cows. The underlying factors are not fully understood. In this study, we explored rennet-induced coagulation properties and relative protein profiles in milk from native Swedish Mountain and Swedish Red Polled cows and compared them with a subset of noncoagulating (NC) and well-coagulating (WC) milk samples from modern Swedish Red cows. The native breeds displayed a very low prevalence of NC milk and superior milk coagulation properties compared with Swedish Red cows. The predominant variants in both native breeds were alphaS1-casein (alphaS1 CN) B, beta-CN A2 and beta-lactoglobulin (beta-LG) B. For kappa-CN, the B variant was predominant in the Swedish Mountain cows, whereas the A variant was the most frequent in the Swedish Red Polled. The native breeds displayed similar protein composition, but varied in content of alphaS1-CN with 9 phosphorylated serines (9P) form. Within the Swedish Mountain cows, we observed a strong inverse correlation between the relative concentration of kappa-CN and micelle size and a positive correlation between ionic calcium and gel firmness. For comparison, we investigated a subset of 29 NC and 28 WC milk samples, representing the extremes with regard to coagulation properties based on an initial screening of 395 Swedish Red cows. In Swedish Red, NC milk properties were found to be related to higher frequencies of beta-CN A2, kappa-CN E and A variants, as well as beta-LG B, and the predominant composite genotype of beta- and kappa-CN in the NC group was A2A2/AA. Generally, the A2A2/AA composite genotype was related to lower relative concentrations of kappa-CN isoforms and higher relative concentrations of alphaS1-, alphaS2-, and beta-CN. Compared with the group of WC milk samples, NC milk contained a higher fraction of alphaS2-CN and alpha-lactalbumin (alpha LA) but a lower fraction of alphaS1-CN 9P. In conclusion, milk from native Swedish breeds has good characteristics for cheese milk, which could be exploited in niche dairy products. In milk from Swedish Mountain cows, levels of ionic calcium seemed to be more important for rennet-induced gel firmness than variation in the relative protein profile. In Swedish Red, lower protein content as well as higher fraction of alphaS2-CN and lower fraction of alphaS1-CN 9P were related to NC milk. Further, a decrease in the frequency of the composite beta kappa-CN genotype A2A2/AA through selective breeding could have a positive effect on milk coagulation properties. PMID- 28918141 TI - Validation of commercial luminometry swabs for total bacteria and coliform counts in colostrum-feeding equipment. AB - A sufficient quantity and quality of colostrum must be fed quickly to the newborn calf while minimizing bacterial contamination. Adenosine triphosphate bioluminescence swabs offer a potential rapid on-farm alternative to assess bacterial contamination of colostrum. The objective of this study was to validate the Hygiena (Camarillo, CA) AquaSnap Total (AS), SuperSnap (SS), PRO-Clean (PC), and MicroSnap Coliform (MS) swabs as well as visual hygiene assessment for detection of elevated bacterial counts in or on colostrum-feeding equipment. From April to October 2016, 18 esophageal tube feeders, 49 nipple bottles, and 6 pails from 52 dairy farms in Ontario were evaluated for cleanliness. Following visual hygiene assessment, sterile physiological saline (15 mL) was poured into each piece of equipment, mixed for 2 min to ensure total surface coverage, and poured into a sterile collection container through the feeding end. The fluid was split into equal aliquots, with one being evaluated by conventional culture and the other evaluated using the luminometry swabs. Nonparametric receiver operator curves were used to compare the test performance of the luminescence reading (relative light units; RLU) from each type of swab to conventional bacterial culture. The area under the curve comparing the AS swab to total bacterial count (cut point >100,000 cfu/mL) was 0.89, and using a cut point of 631 RLU correctly classified 84% of samples with a sensitivity of 88% and a specificity of 77%. The area under the curve comparing the MS swab to total coliform count (cut point >10,000 cfu/mL) was 0.85, and using a cut point of 44 RLU correctly classified 89% of samples with a sensitivity of 83% and a specificity of 90%. Visual hygiene assessment, PC and SS swabs were not reliable indicators for feeding equipment cleanliness. The results suggest that the AS and MS swabs can be used as an alternative to traditional laboratory bacterial counts to evaluate cleanliness of colostrum-feeding equipment. PMID- 28918142 TI - Mortality and health treatment rates of dairy calves in automated milk feeding systems in the Upper Midwest of the United States. AB - Automated calf feeding systems are increasing in use across the United States, yet information regarding health and mortality outcomes of animals in these systems is limited. The objective of this study was to investigate the relationship between farm management practices, housing, and environmental factors with mortality and health treatment rates of preweaned dairy calves housed in groups with automated feeding systems. Farm records were collected for health treatments and mortality on 26 farms in the Upper Midwest of the United States. Relationships between factors of interest and mortality or treatment rate were calculated using a correlation analysis. Overall median annual mortality rate was 2.6 (interquartile range = 3.6; range = 0.24-13.4%), and 57% of farms reported mortality rates below 3%/yr. Farms that disinfected the navels of newborn calves had lower mortality rate (mean = 3.0%; standard error = 0.8; 78% of farms) than farms that did not disinfect (mean = 7.3%; standard error = 1.6; 22% of farms). Farm size (number of cows on site) was negatively associated [correlation coefficient (r) = -0.53], whereas the age range in calf groups was positively associated (r = 0.58) with mortality rate. Average serum total protein concentration tended to be negatively associated with annual mortality rate (r = 0.39; median = 5.4; range = 5.0-6.4 g/dL). Health treatment rate was positively associated with coliform bacterial count in feeder tube milk samples [r = 0.45; mean +/- standard deviation (SD) = 6.45 +/- 4.50 ln(cfu/mL)] and the age of calves at grouping (r = 0.50; mean +/- SD = 5.1 +/- 3.6 d). A positive trend was detected for coliform bacterial count of feeder mixing tank milk samples [r = 0.37; mean +/- SD = 3.2 +/- 6.4 ln(cfu/mL)] and calf age at weaning (r = 0.37, mean +/- SD = 57.4 +/- 9.6 d). Seasonal patterns indicated that winter was the season of highest treatment rate. Taken together, these results indicate that, although automated feeding systems can achieve mortality rates below the US average, improvements are needed in fundamental calf care practices, such as colostrum management and preventing bacterial contamination of the liquid diet and the calf environment. PMID- 28918143 TI - Short communication: Estimating lactation curves for highly inhomogeneous milk yield data of an F2 population (Charolais * German Holstein). AB - Fitting of lactation curves is a common tool to obtain the entire milk yield as well as to estimate the main curve characteristic (such as day of peak milk yield) for a lactation. These models are primarily designed for dairy cattle, but have been applied to nondairy cattle breeds and also for other species. In this study we considered milk yield data of 197 F2 crossbred cows of Charolais and German Holstein (founder breeds) for the first and the beginning of the second lactation. The F2 cows showed a high variability regarding the length of lactation, which varied between 7 and 406 d in milk for the first lactation. Thus, the data also show high variation regarding the daily and overall milk yield. To obtain complete lactation curves, we evaluated the lactation models of Ali-Schaeffer and Wilmink. To compare the 2 lactation models, we evaluated the goodness of fit using 6 evaluation criteria. The results show that the model of Ali-Schaeffer performs better on these highly inhomogeneous data, in contrast to the model of Wilmink. We discuss our findings from a statistical point of view and present possible biological reasons for the high variability regarding milk yield within the F2 population. Hence our findings may be helpful when milk yield data of crosses between dairy and beef cows (dual purpose) are investigated, whose lactation curves may not show the typical characteristics of dairy cattle. PMID- 28918144 TI - Short communication: Molecular epidemiology of Streptococcus agalactiae differs between countries. AB - Group B Streptococcus or Streptococcus agalactiae continue to be challenging for milk quality programs in countries with emerging dairy industries, such as Colombia, where high prevalence has been reported. Molecular typing of isolates is needed to understand the variability and epidemiology of this pathogen and to develop effective control and eradication programs. We characterized the molecular profile of Strep. agalactiae isolated from cows with subclinical mastitis in 21 Colombian dairy herds and measured diversity within and between herds using multilocus sequence typing. Isolates belonged to sequence type 248 [clonal complex (CC) 103; n = 30), ST1 (CC1; n = 6) or ST22 (CC22; n = 4)], whereas members of CC67/61, the dominant type in North America, were not detected. Presence of multiple clonally unrelated sequence type within a herd was common, which contrasts with the situation in European countries and suggests introduction from multiple sources. Our results demonstrate that conclusions from molecular epidemiological studies in 1 region cannot necessarily be extrapolated to other regions, and no single bovine-adapted CC of Strep. agalactiae exists in Colombia. Improvements in internal and external biosecurity will be needed to reduce Strep. agalactiae prevalence in Colombian dairy herds. PMID- 28918145 TI - Short communication: Relationship between methods for measurement of serum electrolytes and the relationship between ionized and total calcium and neutrophil oxidative burst activity in early postpartum dairy cows. AB - The objectives of this study were to (1) compare a test for serum measurement of total Ca (tCa), Mg, and P (VetTest Chemistry Analyzer, IDEXX Laboratories Inc., Westbrook, ME) to reference methods (spectrophotometric assays on a Beckman Coulter 640e automated clinical chemistry analyzer; Beckman Coulter, Brea, CA), (2) determine the relationship between ionized Ca (iCa) and reference method tCa in the immediate postpartum period, and (3) assess the relative value of these blood Ca indices as predictors of neutrophil oxidative burst activity. Samples were collected from multiparous Holstein cows (n = 33) over the first 5 d in milk. A total of 183 samples for objective 1 and 181 samples for objective 2 were available. Neutrophil oxidative burst activity was assessed once between 2 and 5 d in milk (n = 29). Linear regression demonstrated strong relationships between serum tCa, Mg, and P concentrations measured by the VetTest compared with the reference method. Bland Altman analysis indicated that the VetTest values were higher than the reference method by 0.22 mmol/L for tCa, 0.12 mmol/L for Mg, and 0.16 mmol/L for P. Compared with hypocalcemia categorized at <=2.0 or <=2.125 mmol/L with the reference method tCa, thresholds for the VetTest measured tCa of <=2.23 mmol/L (sensitivity = 87%, specificity = 89%) or <=2.30 mmol/L (sensitivity = 86%, specificity = 96%) could be used. The relationship between whole-blood iCa and reference method serum tCa differed by sampling time point after calving. Compared with identification of hypocalcemia with serum tCa measurements from the reference method (thresholds of <=2.0 and 2.125 mmol/L), a whole-blood iCa threshold of <=1.17 mmol/L resulted in the highest combined sensitivities (94 and 82%) and specificities (80 and 94%) at either threshold. Ionized Ca measurements were more consistently related to outcomes of neutrophil oxidative burst activity measured in vitro. The VetTest measurements of serum tCa reliably identified hypocalcemia when thresholds were adjusted to account for the bias of the test. The variation in the relationship between iCa and reference method tCa in the days following parturition suggest that these measures cannot be used interchangeably as indicators of Ca status. The more consistent associations between iCa and in vitro measures of neutrophil function, compared with tCa, indicated that this may be a more sensitive predictor of functional outcomes associated with postpartum Ca status. PMID- 28918146 TI - Short communication: Automated detection of behavioral changes from respiratory disease in pre-weaned calves. AB - Group housing of calves can pose a challenge in identifying respiratory disease; therefore, it is necessary to develop tools that can identify these disease events. In this experiment, pre-weaned calves (n = 30) were housed in groups with an automatic calf feeder and were fitted with an accelerometer. Step activity, lying behaviors, and feeding behaviors were recorded to determine the effect of respiratory disease. All calves were health scored twice daily, and calves with respiratory scores >=5 were diagnosed with respiratory disease (n = 10). Each diseased calf was match paired with a healthy control based on the date of disease diagnosis, breed, and age. Control calves were determined to be healthy if they had respiratory scores <=4, as well as fecal, navel, and joint scores of 0 or 1. Diseased calves were less active before, on the day of, and after respiratory disease diagnosis. Furthermore, diseased calves had reduced lying frequencies starting 2 d before diagnosis, as well as after diagnosis. Last, diseased calves consumed less milk on the day of diagnosis when compared with healthy controls. Step activity, lying bouts, and milk intake may prove to be a useful tool in identifying respiratory disease under practical farming, but this requires further research. PMID- 28918147 TI - Invited review: Effects of heat stress on dairy cattle welfare. AB - The effects of high ambient temperatures on production animals, once thought to be limited to tropical areas, has extended into northern latitudes in response to the increasing global temperature. The number of days where the temperature humidity index (THI) exceeds the comfort threshold (>72) is increasing in the northern United States, Canada, and Europe. Compounded by the increasing number of dairy animals and the intensification of production, heat stress has become one of the most important challenges facing the dairy industry today. The objectives of this review were to present an overview of the effects of heat stress on dairy cattle welfare and highlight important research gaps in the literature. We will also briefly discuss current heat abatement strategies, as well as the sustainability of future heat stress management. Heat stress has negative effects on the health and biological functioning of dairy cows through depressed milk production and reduced reproductive performance. Heat stress can also compromise the affective state of dairy cows by inducing feelings of hunger and thirst, and we have highlighted the need for research efforts to examine the potential relationship between heat stress, frustration, aggression, and pain. Little work has examined how heat stress affects an animal's natural coping behaviors, as well as how the animal's evolutionary adaptations for thermoregulation are managed in modern dairy systems. More research is needed to identify improved comprehensive cow-side measurements that can indicate real-time responses to elevated ambient temperatures and that could be incorporated into heat abatement management decisions. PMID- 28918148 TI - Mammalian target of rapamycin signaling and ubiquitin proteasome-related gene expression in 3 different skeletal muscles of colostrum- versus formula-fed calves. AB - The rates of protein turnover are higher during the neonatal period than at any other time in postnatal life. The mammalian target of rapamycin (mTOR) and the ubiquitin-proteasome system are key pathways regulating cellular protein turnover. The objectives of this study were (1) to elucidate the effect of feeding colostrum versus milk-based formula on the mRNA abundance of key components of the mTOR pathway and of the ubiquitin-proteasome system in skeletal muscle of neonatal calves and (2) to compare different muscles. German Holstein calves were fed either colostrum (COL; n = 7) or milk-based formula (FOR; n = 7) up to 4 d of life. The nutrient content in formula and colostrum was similar, but formula had lower concentrations of free branched-chain AA (BCAA) and free total AA, insulin, and insulin-like growth factor (IGF)-I than colostrum. Blood samples were taken from d 1 to 4 before morning feeding and before and 2 h after the last feeding on d 4. Muscle samples from M. longissimus dorsi (MLD), M. semitendinosus (MST), and M. masseter (MM) were collected after slaughter on d 4 at 2 h after feeding. The preprandial concentrations of free total AA and BCAA, insulin, and IGF-I in plasma changed over time but did not differ between groups. Plasma free total AA and BCAA concentrations decreased in COL, whereas they increased in FOR after feeding, resulting in higher postprandial plasma total AA and BCAA concentrations in FOR than in COL. Plasma insulin concentrations increased after feeding in both groups but were higher in COL than in FOR. Plasma IGF-I concentrations decreased in COL, whereas they remained unchanged in FOR after feeding. The mRNA abundance of mTOR and ribosomal protein S6 kinase 1 (S6K1) in 3 different skeletal muscles was greater in COL than in FOR, whereas that of eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) was unaffected by diet. The mRNA abundance of ubiquitin activating enzyme (UBA1) and ubiquitin conjugating enzyme 1 (UBE2G1) enzymes was not affected by diet, whereas that of ubiquitin conjugating enzyme 2 (UBE2G2) was greater (MLD) or tended to be greater (MM) in COL than in FOR. The mRNA abundance of atrogin-1 in MLD and MST was lower in COL than in FOR, whereas that of muscle ring finger protein-1 (MuRF1) was greater (MST) or tended to be greater (MLD). The abundance of MuRF1 mRNA was highest in MST, followed by MLD, and was lowest in MM. The results indicate that colostrum feeding may stimulate protein turnover that may result in a high rate of protein deposition in a muscle type-specific manner. Such effects seem to be mediated by the postprandial increase in plasma insulin. PMID- 28918149 TI - Predicting methane emissions of lactating Danish Holstein cows using Fourier transform mid-infrared spectroscopy of milk. AB - Enteric methane (CH4), a potent greenhouse gas, is among the main targets of mitigation practices for the dairy industry. A measurement technique that is rapid, inexpensive, easy to use, and applicable at the population level is desired to estimate CH4 emission from dairy cows. In the present study, feasibility of milk Fourier transform mid-infrared (FT-IR) spectral profiles as a predictor for CH4:CO2 ratio and CH4 production (L/d) is explained. The partial least squares regression method was used to develop the prediction models. The models were validated using different random test sets, which are independent from the training set by leaving out records of 20% cows for validation and keeping records of 80% of cows for training the model. The data set consisted of 3,623 records from 500 Danish Holstein cows from both experimental and commercial farms. For both CH4:CO2 ratio and CH4 production, low prediction accuracies were found when models were obtained using FT-IR spectra. Validated coefficient of determination (R2Val) = 0.21 with validated model error root mean squared error of prediction (RMSEP) = 0.0114 L/d for CH4:CO2 ratio, and R2Val = 0.13 with RMSEP = 111 L/d for CH4 production. The important spectral wavenumbers selected using the recursive partial least squares method represented major milk components fat, protein, and lactose regions of the spectra. When fat and protein predicted by FT IR were used instead of full spectra, a low R2Val of 0.07 was obtained for both CH4:CO2 ratio and CH4 production prediction. Other spectral wavenumbers related to lactose (carbohydrate) or additional wavenumbers related to fat or protein (amide II) are providing additional variation when using the full spectral profile. For CH4:CO2 ratio prediction, integration of FT-IR with other factors such as milk yield, herd, and lactation stage showed improvement in the prediction accuracy. However, overall prediction accuracy remained modest; R2Val increased to 0.31 with RMSEP = 0.0105. For prediction of CH4 production, the added value of FT-IR along with the aforementioned traits was marginal. These results indicated that for CH4 production prediction, FT-IR profiles reflect primarily information related to milk yield, herd, and lactation stage rather than individual milk fatty acids related to CH4 emission. Thus, it is not feasible to predict CH4 emission based on FT-IR spectra alone. PMID- 28918150 TI - Short communication: Effects of lysolecithin on milk fat synthesis and milk fatty acid profile of cows fed diets differing in fiber and unsaturated fatty acid concentration. AB - Thirteen multiparous Holstein cows were used in a crossover design that tested the effect of lysolecithin in diets differing in neutral detergent fiber (NDF) and unsaturated fatty acid (FA) concentrations. Experimental periods were 20 d in length and included two 10-d phases. A standard fiber and lower fat diet was fed the first 10 d (30.5% NDF, no added oil, lower-risk phase) and a lower NDF and higher oil diet was fed during the second 10 d (29.0% NDF and 2% oil from whole soybeans and soybean oil, high-risk phase). Treatments were control and 10 g/d of lysolecithin (LYSO) extended in a ground corn carrier. Milk was sampled on d 0, 5, and 10 of each phase for determination of fat and protein concentration and FA profile. We found no effect of treatment or treatment by time interaction for dry matter intake, milk yield, or milk protein concentration. A treatment by time interaction was observed for milk fat concentration and yield. Milk fat concentration was higher in LYSO on d 5 of the lower-risk phase, but decreased progressively in both treatments during the high-risk phase. Milk fat yield was not different among treatments during the lower-risk phase, but was lower in LYSO on d 15 and tended to be lower on d 20 during the high-risk phase. Concentrations of milk de novo FA decreased and preformed FA increased during the high-risk phase, but we found no effect of treatment or treatment by time interactions. We noted an effect of time, but no treatment or treatment by time interactions for milk trans FA isomers. Briefly, trans-11 C18:1 and cis-9,trans-11 conjugated linoleic acid progressively decreased as trans-10 C18:1 and trans-10,cis-12 conjugated linoleic acid progressively increased during the high-risk phase. The LYSO increased milk fat concentration when feeding a higher fiber and lower unsaturated FA diet, but decreased milk fat yield when feeding a lower fiber and higher unsaturated FA diet, although biohydrogenation pathways and capacity did not appear to be modified. The effect of lysolecithin on rumen fermentation warrants further investigation, but is not recommended when feeding lower fiber and higher unsaturated fat diets. PMID- 28918151 TI - Internal transcribed spacer (ITS) sequencing reveals considerable fungal diversity in dairy products. AB - Fungi are important spoilage organisms in dairy products. However, little is known about the diversity of naturally occurring spoilage fungi in raw milk and processed dairy products, due at least in part to the fact that classical fungal identification methods require considerable expertise. To gain further insight into the fungal diversity in the dairy system, we isolated fungi from raw milk, raw and pasteurized milk cheese, and yogurt using the selective dichloran rose bengal chloramphenicol agar. In total, 361 fungal isolates were obtained and further characterized by DNA sequencing of the internal transcribed spacer (ITS) region and the nuclear ribosomal large subunit (LSU) rRNA gene if needed. We conducted BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) searches of the ITS region sequences against the UNITE Database (https://unite.ut.ee/analysis.php), and selected other databases if needed, which allowed identification to the species level of 183 isolates and to the genus level of 107 of the 346 isolates that were successfully ITS sequenced. The isolates characterized represented 3 phyla and 19 genera; the most common genera isolated were Penicillium (25% of isolates), Debaryomyces (18%), and Candida (9%). This study not only provides, by using modern molecular tools, a baseline understanding of the types of fungi in dairy products, but also confirms that ITS sequencing is a useful approach for identification of fungal organisms found in the dairy food chain. PMID- 28918152 TI - Short communication: Influence of various proteolytic sources during fermentation of reconstituted corn grain silages. AB - The objective of this study was to determine the contribution of corn kernel enzymes, bacteria, fungi, and fermentation end-products (main acids and ethanol) to protein solubilization during fermentation of reconstituted corn grain silage. Flint corn kernels were ground (5-mm sieve), rehydrated to 32% of moisture, and treated with no additives (control), gamma irradiation (32 kGy), gamma irradiation + fermentation end-products (1% of lactic acid, 0.3% of acetic acid, and 0.7% of ethanol, as fed), and natamycin (1% as fed). Treated grains were ensiled in nylon-polyethylene bags and stored for 90 d. Protein solubilization was calculated for each treatment and the contributions of proteolytic sources were determined. Bacterial activity was the main contributor to proteolysis (60%) followed by corn kernel enzymes (30%), whereas fungi and fermentation end products had only minor contributions (~5% each). PMID- 28918153 TI - Linseed oil and DGAT1 K232A polymorphism: Effects on methane emission, energy and nitrogen metabolism, lactation performance, ruminal fermentation, and rumen microbial composition of Holstein-Friesian cows. AB - Complex interactions between rumen microbiota, cow genetics, and diet composition may exist. Therefore, the effect of linseed oil, DGAT1 K232A polymorphism (DGAT1), and the interaction between linseed oil and DGAT1 on CH4 and H2 emission, energy and N metabolism, lactation performance, ruminal fermentation, and rumen bacterial and archaeal composition was investigated. Twenty-four lactating Holstein-Friesian cows (i.e., 12 with DGAT1 KK genotype and 12 with DGAT1 AA genotype) were fed 2 diets in a crossover design: a control diet and a linseed oil diet (LSO) with a difference of 22 g/kg of dry matter (DM) in fat content between the 2 diets. Both diets consisted of 40% corn silage, 30% grass silage, and 30% concentrates (DM basis). Apparent digestibility, lactation performance, N and energy balance, and CH4 emission were measured in climate respiration chambers, and rumen fluid samples were collected using the oral stomach tube technique. No linseed oil by DGAT1 interactions were observed for digestibility, milk production and composition, energy and N balance, CH4 and H2 emissions, and rumen volatile fatty acid concentrations. The DGAT1 KK genotype was associated with a lower proportion of polyunsaturated fatty acids in milk fat, and with a higher milk fat and protein content, and proportion of saturated fatty acids in milk fat compared with the DGAT1 AA genotype, whereas the fat- and protein-corrected milk yield was unaffected by DGAT1. Also, DGAT1 did not affect nutrient digestibility, CH4 or H2 emission, ruminal fermentation or ruminal archaeal and bacterial concentrations. Rumen bacterial and archaeal composition was also unaffected in terms of the whole community, whereas at the genus level the relative abundances of some bacterial genera were found to be affected by DGAT1. The DGAT1 KK genotype was associated with a lower metabolizability (i.e., ratio of metabolizable to gross energy intake), and with a tendency for a lower milk N efficiency compared with the DGAT1 AA genotype. The LSO diet tended to decrease CH4 production (g/d) by 8%, and significantly decreased CH4 yield (g/kg of DM intake) by 6% and CH4 intensity (g/kg of fat- and protein-corrected milk) by 11%, but did not affect H2 emission. The LSO diet also decreased ruminal acetate molar proportion, the acetate to propionate ratio, and the archaea to bacteria ratio, whereas ruminal propionate molar proportion and milk N efficiency increased. Ruminal bacterial and archaeal composition tended to be affected by diet in terms of the whole community, with several bacterial genera found to be significantly affected by diet. These results indicate that DGAT1 does not affect enteric CH4 emission and production pathways, but that it does affect traits other than lactation characteristics, including metabolizability, N efficiency, and the relative abundance of Bifidobacterium. Additionally, linseed oil reduces CH4 emission independent of DGAT1 and affects the rumen microbiota and its fermentative activity. PMID- 28918154 TI - Hot topic: Geographical distribution and strain diversity of Lactobacillus wasatchensis isolated from cheese with unwanted gas formation. AB - Lactobacillus wasatchensis, an obligate heterofermentative nonstarter lactic acid bacteria (NSLAB) implicated in causing gas defects in aged cheeses, was originally isolated from an aged Cheddar produced in Logan, Utah. To determine the geographical distribution of this organism, we isolated slow-growing NSLAB from cheeses collected in different regions of the United States, Australia, New Zealand, and Ireland. Seven of the cheeses showed significant gas defects and 12 did not. Nonstarter lactic acid bacteria were isolated from these cheeses on de Man, Rogosa, and Sharpe medium supplemented with ribose, a preferred substrate for Lb. wasatchensis. Identification was confirmed with 16S rRNA gene sequencing and the API50CH (bioMerieux, Marcy l'Etoile, France) carbohydrate panel. Isolates were also compared with one another by using repetitive element sequence-based PCR (rep-PCR). Lactobacillus wasatchensis was isolated only from cheeses demonstrating late-gas development and was found in samples from 6 of the 7 cheeses. This supports laboratory evidence that this organism is a causative agent of late gas production defects. The rep-PCR analysis produced distinct genetic fingerprints for isolates from each cheese, indicating that Lb. wasatchensis is found in several regions across the United States and is not a local phenomenon. PMID- 28918155 TI - The binding of orally dosed hydrophobic active pharmaceutical ingredients to casein micelles in milk. AB - Casein proteins (alphaS1-, alphaS2-, beta- and kappa-casein) account for 80% of the total protein content in bovine milk and form casein micelles (average diameter = 130 nm, approximately 1015 micelles/mL). The affinity of native casein micelles with the 3 hydrophobic active pharmaceutical ingredients (API), meloxicam [351.4 g/mol; log P = 3.43; acid dissociation constant (pKa) = 4.08], flunixin (296.2 g/mol; log P = 4.1; pKa = 5.82), and thiabendazole (201.2 g/mol; log P = 2.92; pKa = 4.64), was evaluated in bovine milk collected from dosed Holstein cows. Native casein micelles were separated from raw bovine milk by mild techniques such as ultracentrifugation, diafiltration, isoelectric point precipitation (pH 4.6), and size exclusion chromatography. Acetonitrile extraction of hydrophobic API was then done, followed by quantification using HPLC-UV. For the API or metabolites meloxicam, 5-hyroxy flunixin and 5-hydroxy thiabendazole, 31 +/- 3.90, 31 +/- 1.3, and 28 +/- 0.5% of the content in milk was associated with casein micelles, respectively. Less than ~5.0% of the recovered hydrophobic API were found in the milk fat fraction, and the remaining ~65% were associated with the whey/serum fraction. A separate in vitro study showed that 66 +/- 6.4% of meloxicam, 29 +/- 0.58% of flunixin, 34 +/- 0.21% of the metabolite 5-hyroxy flunixin, 50 +/- 4.5% of thiabendazole, and 33 +/- 3.8% of metabolite 5-hydroxy thiabendazole was found partitioned into casein micelles. Our study supports the hypothesis that casein micelles are native carriers for hydrophobic compounds in bovine milk. PMID- 28918156 TI - Exploration of the bovine colostrum proteome and effects of heat treatment time on colostrum protein profile. AB - Heat treatment of colostrum is performed on modern dairy farms to reduce pathogenic contamination before hand-feeding the colostrum to newborn calves; however, limited data are available concerning effects of heat treatment on biologically active proteins in colostrum. The objective of this exploratory study was to investigate effects of heat treatment and length of heat treatment on colostrum protein profile. Colostrum samples were collected from Holstein cows within 12 h after parturition and assigned to the following groups: heat treatment at 60 degrees C for 0 (untreated control), 30, 60, or 90 min. Samples were fractionated using acid precipitation, followed by ultracentrifugation and ProteoMiner (Bio-Rad Laboratories, Hercules, CA) treatment, and tandem-mass tagging was used to comparatively assess the low abundance protein profile. A total of 162 proteins were identified with more than 2 peptides in the low abundance protein enriched fraction. Of these, 62 differed in abundance by more than 2-fold in heat-treated samples compared with the unheated control. The majority of proteins affected by heat treatment were involved in immunity, enzyme function, and transport-related processes; affected proteins included lactadherin, chitinase-3-like protein 1, and complement component C9. These results provide a foundation for further research to determine optimum heat treatment practices to ensure newborn calves are fed colostrum-containing proteins with the highest nutritional and biological value. PMID- 28918157 TI - Differential proteomic profiling of endometrium and plasma indicate the importance of hydrolysis in bovine endometritis. AB - Endometritis is an important disease of dairy cows that leads to significant economic losses in the dairy cattle industry. To investigate the alteration of proteins associated with endometritis in the dairy cow, the isobaric tags for relative and absolute quantification (iTRAQ) technique was applied to quantitatively identify differentially expressed proteins (DEP) in the endometrium and peripheral plasma of Chinese Holstein cows with endometritis. Compared with the normal (control) group, 159 DEP in the endometrium and 137 DEP in the plasma were identified in cows with endometritis. Gene ontology analysis demonstrated that the predominant endometrial DEP were primarily involved in responses to stimulus and stress processes and mainly played a role in hydrolysis in the extracellular region. The predominant plasma DEP were mainly components of the cytosol and non-membrane-bound organelles, and they were involved in the response to stress and regulation of enzyme activity. Protein-protein interaction of tissue DEP revealed that some core seed proteins, such as RAC2, ITGB2, and CDH1 in the same network as CD14, MMP3, and MMP9, had important functions in the cross-talk of pathways related to extracellular proteolysis. In summary, significant enzymatic hydrolase activity in the extracellular region is proposed as a molecular mechanism by which altered proteins may promote inflammation and hence endometritis. PMID- 28918158 TI - Recombinant expression and characterization of Lucilia cuprina CYP6G3: Activity and binding properties toward multiple pesticides. AB - The Australian sheep blowfly, Lucilia cuprina, is a primary cause of sheep flystrike and a major agricultural pest. Cytochrome P450 enzymes have been implicated in the resistance of L. cuprina to several classes of insecticides. In particular, CYP6G3 is a L. cuprina homologue of Drosophila melanogaster CYP6G1, a P450 known to confer multi-pesticide resistance. To investigate the basis of resistance, a bicistronic Escherichia coli expression system was developed to co express active L. cuprina CYP6G3 and house fly (Musca domestica) P450 reductase. Recombinant CYP6G3 showed activity towards the high-throughput screening substrates, 7-ethoxycoumarin and p-nitroanisole, but not towards p-nitrophenol, coumarin, 7-benzyloxyresorufin, or seven different luciferin derivatives (P450 GloTM substrates). The addition of house fly cytochrome b5 enhanced the kcat for p-nitroanisole dealkylation approximately two fold (17.8 +/- 0.5 vs 9.6 +/- 0.2 min-1) with little effect on KM (13 +/- 1 vs 10 +/- 1 MUM). Inhibition studies and difference spectroscopy revealed that the organochlorine compounds, DDT and endosulfan, and the organophosphate pesticides, malathion and chlorfenvinphos, bind to the active site of CYP6G3. All four pesticides showed type I binding spectra with spectral dissociation constants in the micromolar range suggesting that they may be substrates of CYP6G3. While no significant inhibition was seen with the organophosphate, diazinon, or the neonicotinoid, imidacloprid, diazinon showed weak binding in spectral assays, with a Kd value of 23 +/- 3 MUM CYP6G3 metabolised diazinon to the diazoxon and hydroxydiazinon metabolites and imidacloprid to the 5-hydroxy and olefin metabolites, consistent with a proposed role of CYP6G enzymes in metabolism of phosphorothioate and neonicotinoid insecticides in other species. PMID- 28918159 TI - Identification of circular RNA in the Bombyx mori silk gland. AB - Bombyx mori is an economically important holometabolous lepidopteran insect. In B. mori endogenous noncoding RNAs such as microRNAs (miRNAs) and Piwi-interacting RNAs play crucial biological functions in metamorphosis and sex determination. In addition, circular RNAs (circRNAs) have been recently identified as noncoding RNAs in most common model organisms and show potential as gene regulators. However, to date, there have been few studies on the circRNAs present in the B. mori genome conducted to date. Here, we identified 3916 circRNAs by deep circular transcriptome sequencing using the silk gland of B. mori. 3155 circRNAs were found to be derived from 1727 parental genes. The circRNAs displayed tissue specific expression between the middle silk gland (MSG) and posterior silk gland (PSG), with 2532 and 880 being upregulated circRNAs in the MSG and PSG, respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the parental genes from the MSG and PSG were generally annotated to similar categories and pathways. The interaction network of circRNAs and miRNAs showed that circRNAs might act as miRNA sponges or interact with miRNAs in some other way. Overall, the results revealed the complicated patterns of circRNAs in the B. mori silk gland providing a new angle from which to explore the mechanisms of complex gene regulation and efficient silk protein synthesis. PMID- 28918160 TI - Shopping for food with children: A strategy for directing their choices toward novel foods containing vegetables. AB - Involving children in the different steps of meal preparation has been suggested as a strategy for enhancing dietary habits in childhood. It has previously been shown that involving children in cooking can increase their willingness to taste novel foods and direct their food choices towards foods containing vegetables. The objective of the present study was to assess the effect of involving children in food purchasing on food choices, intake, liking and appetite. A between subject experiment was conducted with 86 children (from 8 to 10 years old). Forty three children (PURCHASE group) participated in a workshop dedicated to purchasing the necessary ingredients online for the preparation of three unfamiliar foods containing vegetables: apple and beetroot juice, zucchini tortilla sandwich and spinach cookies. Forty-three children (CONTROL group) participated instead in a creativity workshop. Afterwards, all the children were invited to choose, for an afternoon snack, between three familiar vs. unfamiliar foods: orange vs. apple and beetroot juice, potatoes vs. zucchini tortilla sandwich and chocolate vs. spinach cookie. The mean number of unfamiliar foods chosen per child was higher in the PURCHASE (0.70 +/- 0.14) vs. CONTROL (0.19 +/- 0.07) group (P = 0.003). The liking for 1 of the 3 unfamiliar foods was higher in the PURCHASE group (P < 0.05). We did not find any difference between the two groups in food intake estimation and in the levels of subjective appetite. This study demonstrates that involving children in purchasing food can help in directing their food choices towards unfamiliar foods containing vegetables. It highlights the importance of involving children in the different steps of meal preparation for decreasing food neophobia. PMID- 28918161 TI - Clinical and pathological significance of cutaneous manifestations in ANCA associated vasculitides. AB - OBJECTIVES: Cutaneous manifestations (CM) in ANCA-associated vasculitides (AAV) are frequent, but data on clinical significance and clinical-pathological correlations are lacking. METHODS: We conducted a multicenter, retrospective study including 1553 AAV patients. Clinical, biological and pathological features have been analyzed, and tissue samples from 46 biopsies were reviewed in a blind manner. RESULTS: CM were more frequent in EGPA (53.0%) and MPA (51.9%) than in GPA (36.7%). Lesions more frequently associated with GPA were oral ulcers (4.6% vs. 2.5% in EGPA and 0.3% in MPA), while pyoderma gangrenosum and palpebral xanthoma were specific to GPA. Lesions associated with MPA were segmentary edema (19.5% vs. 12.7% in EGPA and 4.3% in GPA) and livedo (12.4% vs. 0.5% and 2.6%, respectively), whereas those associated with EGPA were urticarial lesions (11.5% vs. 1.9% in GPA and 3.5% in MPA) and nodules (12,2% vs. 8.9% in GPA and 4.7% in MPA). In GPA, CM patients had more frequent vasculitis than granulomatous phenotype, and poorer relapse-free and overall survival. Pathological analysis showed vasculitis and/or granulomatous infiltrates in 87.5% of GPA, in 61.1% of EGPA and in all MPA. Vasculitis was more frequently observed in purpura and nodules, while granulomas were differently located and organized within vessels or interstitium according to the type of lesions. CONCLUSION: Each AAV seemed to be associated with a peculiar pattern of cutaneous lesions. CM are associated with poorer prognosis in GPA. Clinical-pathological correlations showed no specific feature of each AAV, whereas granulomatous infiltrates differ according to the type of lesions. PMID- 28918162 TI - How high level of anxiety in Panic Disorder can interfere in working memory? A computer simulation and electrophysiological investigation. AB - Panic disorder (PD) is characterized by repeated and unexpected attacks of intense anxiety, which are not restricted to a determined situation or circumstance. The coherence function has been used to investigate the communication among brain structures through the quantitative EEG (qEEG). The objective of this study is to analyze if there is a difference in frontoparietal gamma coherence (GC) between panic disorder patients (PDP) and healthy controls (HC) during the Visual oddball paradigm; and verify if high levels of anxiety (produced by a computer simulation) affect PDP's working memory. Nine PDP (9 female with average age of 48.8, SD: 11.16) and ten HC (1 male and 9 female with average age of 38.2, SD: 13.69) were enrolled in this study. The subjects performed the visual oddball paradigm simultaneously to the EEG record before and after the presentation of computer simulation (CS). A two-way ANOVA was applied to analyze the factors Group and the Moment for each pair of electrodes separately, and another one to analyze the reaction time variable. We verified a F3-P3 GC increased after the CS movie, demonstrating the left hemisphere participation during the anxiety processing. The greater GC in HC observed in the frontal and parietal areas (P3-Pz, F4-F8 and Fp2-F4) points to the participation of these areas with the expected behavior. The greater GC in PDP for F7-F3 and F4 P4 pairs of electrodes assumes that it produces a prejudicial "noise" during information processing, and can be associated to interference on the communication between frontal and parietal areas. This "noise" during information processing is related to PD symptoms, which should be better known in order to develop effective treatment strategies. PMID- 28918163 TI - The EU ShockOmics Project International Workshop at ICCAI'17. PMID- 28918164 TI - Telepsychiatry Consultation for Medical and Surgical Inpatient Units. AB - BACKGROUND: Telepsychiatry is becoming more commonplace in the provision of psychiatric care. Most commonly used in the outpatient setting, there is little information available in the literature as to the use of telepsychiatry for inpatient medical/surgical consultation. OBJECTIVE: We review the University of Pittsburgh Medical Center's telepsychiatry consultation program that provides consultation to an outlying community-based rural hospital. METHODS: This article examines the 69 telepsychiatry consultations that were performed from November 2014 through February 2016, looking at the patients served, common consultation questions, and patterns of diagnoses and recommendations. RESULTS: The median age of individuals undergoing telepsychiatry evaluations was 67 years, and the most common reason for consultation was for delirium. Over half of the patients consulted had a primary diagnosis of delirium, dementia, or a cognitive disorder not otherwise specified, using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnoses. In most patients, additional laboratory studies or imaging or both were requested and medication changes recommended (initiation, dose changes, and discontinuation). CONCLUSION: This report provides one of the first detailed views of the use of telepsychiatry in a remote inpatient medical setting. Findings will guide education to primary teams and will shape the development of future telepsychiatry interventions. PMID- 28918165 TI - Delirium Following Topical Application of Compounded Creams Containing Multiple Analgesic Medications in Geriatric Patients: Two New Cases. PMID- 28918167 TI - Different nutritional assessment tools as predictors of postoperative complications in patients undergoing colorectal cancer resection. AB - BACKGROUND & AIMS: Malnutrition in patients with colorectal cancer contributes to increased postoperative complications. The aim of the study was to evaluate the prognostic value of several nutritional assessment parameters: body mass index versus percentage of weight loss grading system (BMI/%WL); Patient-Generated Subjective Global Assessment (PG-SGA); standardized phase angle (SPA) by BIA; muscle strength by handgrip strength; muscle mass by computerized tomography; and the combination of muscle mass and strength in patients undergoing resection surgery. METHODS: Patients diagnosed with cancer of the colon or rectum, who were over 18 years old and were scheduled to undergo surgical treatment were invited to participate. Postoperative complications were assessed from the first day post surgery until discharge. Complications classified as Grade II or above according to the Clavien-Dindo classification were considered. Chi-square test or Fisher's exact test, bivariate analysis, Poisson regression and receiver operator characteristic (ROC) curve were utilized and p < 0.05 was considered significant. RESULTS: 84 patients were evaluated, with 28 (33.3%) presenting with Grade II postoperative complications. SPA showed no association with postoperative complications (p = 0.199). In multivariate analysis, low skeletal muscle mass showed a relative risk (RR) of 1.80 (CI: 1.02-3.17), BMI/%WL equal or higher than grade 3 had a RR of 1.90 (95% CI: 1.22-3.39). PG-SGA classified as malnutrition showed a RR of 2.08 (95% CI: 1.06-4.06); and low muscle mass plus low muscle strength showed a RR 2.13 (95% CI: 1.23-3.69). Low strength alone was not associated with postoperative complications after controlling for confounding factors (p = 0.16; 95% CI: 0.83-2.77). Low muscle mass in combination with low strength showed the highest predictive power for postoperative complications (AUC: 0.68; CI: 0.56-0.80). CONCLUSIONS: BMI/%WL > grade 3, PG-SGA defined malnutrition, low muscle mass and low muscle mass plus low strength were independent risk factors for complications controlling for confounding factors. However, low muscle mass in combination with low muscle strength were the strongest variables associated with complications. CLINICAL TRIALS IDENTIFICATION NUMBER: NCT02901132 (www.clinicaltrials.gov). PMID- 28918166 TI - High expression of CXC chemokine receptor 6 associates with poor prognosis in patients with clear cell renal cell carcinoma. AB - PURPOSE: Accumulating evidence indicates that CXC chemokine receptor 6 (CXCR6) has a crucial role in cancer development and progression, however, its role in clear cell renal cell carcinoma (ccRCC) remains obscure. The aim of this study is to investigate the prognostic value of CXCR6 expression in patients with ccRCC following surgery. MATERIALS AND METHODS: This study retrospectively included 239 patients with ccRCC who underwent nephrectomy and had paraffin tissue available at a single center. CXCR6 expression in tumor tissue was evaluated by immunohistochemistry and its associations with overall survival (OS) and recurrence-free survival (RFS) were investigated. RESULTS: A total of 47.3% tumors were considered as high expression of CXCR6, which was significantly associated with the male sex (P = 0.003) and high Fuhrman grade (P<0.001). A high expression of CXCR6 indicated a reduced OS (P<0.001) and RFS (P = 0.007). Multivariate analysis demonstrated that CXCR6 expression was an independent prognostic factor of OS (hazard ratio = 2.604; 95% CI: 1.338-5.068; P = 0.005) and RFS (hazard ratio = 1.957; 95% CI: 1.065-3.595; P = 0.031). Subgroup analysis found that CXCR6 expression could differentiate survival risks among patients with high-risk disease. Moreover, a nomogram integrating CXCR6 expression and traditional clinical and pathologic features was established and predicted postsurgical recurrence-risk well at 3- and 5-year. CONCLUSIONS: The expression of CXCR6 in tumor tissue may serve as a potential prognostic biomarker to refine clinical prognosis prediction combined with traditional clinical and pathological analysis for patients with ccRCC after surgery. PMID- 28918169 TI - What is clinical nutrition? PMID- 28918168 TI - Adherence to a Mediterranean diet is associated with lower incidence of frailty: A longitudinal cohort study. AB - BACKGROUND & AIMS: There is a paucity of data investigating the relationship between the Mediterranean diet and frailty, with no data among North American people. We aimed to investigate if adherence to a Mediterranean diet is associated with a lower incidence of frailty in a large cohort of North American people. METHODS: This study included subjects at higher risk or having knee osteoarthritis. Adherence to the Mediterranean diet was evaluated using a validated Mediterranean diet score (aMED) as proposed by Panagiotakos and classified into five categories. Frailty was defined using the Study of Osteoporotic Fracture (SOF) index as the presence of >=2 out of: (i) weight loss >=5% between baseline and the subsequent follow-up visit; (ii) inability to do five chair stands; (iii) low energy level. RESULTS: During the 8 years follow-up, of the 4421 participants initially included (mean age: 61.2 years, % of females = 58.0), the incidence of frailty was approximately half in those with a higher adherence to the Mediterranean diet (8 for 1000 person years) vs. those with a lower adherence (15 for 1000 persons-years). After adjusting for 10 potential confounders (age, sex, race, body mass index, education, smoking habits, yearly income, physical activity level, Charlson co-morbidity index and daily energy intake), participants with the highest aMED scores were found to have a significant reduction in incident frailty (hazard ratio = 0.71; 95% CIs: 0.50 0.99, p = 0.047) with respect to those in a lower category. Regarding individual components of the Mediterranean diet, low consumption of poultry was found to be associated with higher risk of frailty. CONCLUSIONS: A higher adherence to a Mediterranean diet was associated with a lower incidence of frailty over an 8 year follow-up period, even after adjusting for potential confounders. PMID- 28918170 TI - Lifestyle predictors of obese and non-obese patients with nonalcoholic fatty liver disease: A cross-sectional study. AB - BACKGROUND & AIMS: Most people with nonalcoholic fatty liver disease (NAFLD) are obese, and they usually eat more while being less physically active as compared to healthy individuals. However, little is known about the lifestyle patterns of non-obese or obese patients with NAFLD. The aim of this study was to investigate nutrition components and behavioral differences between non-obese and obese patients with NAFLD. METHODS: This is a cross-sectional study comprising of 209 patients. Nutritional components and physical activity status were compared in obese and non-obese subjects with NAFLD against healthy controls. Dietary intake was assessed using the 5-day food diary. Physical activity was measured using the protocol of Korea Health and Nutrition Examination Survey. Total and regional body composition analysis was conducted using anthropometry and tetrapolar multi frequency bio-impedance. Visceral adipose tissue, total abdominal adipose tissue, abdominal subcutaneous adipose tissue as well as liver fat were measured using abdomen tomography. RESULTS: Non-obese subjects with NAFLD had higher levels of ALT, AST, GGT, triglyceride, fasting glucose; higher carbohydrate energy ratio; higher visceral fat area, subcutaneous area, body muscle mass, fat free mass and body fat compared to subjects without NAFLD. Subjects with obesity and NAFLD had higher ALT, AST, visceral fat, fasting glucose and HOMA-IR (homeostatic model assessment-insulin resistance), and less moderate-level physical activity compared to those with obesity who do not have NAFLD. Obese subjects with NAFLD also had higher blood pressure, visceral fat area, subcutaneous fat area, body fat, body fat percent and GGT compared to non-obese subjects with NAFLD. In multivariate analysis, carbohydrate energy ratio and physical activity less than moderate-level (<2 h/week) were predictors of NAFLD in non-obese subjects independent of the visceral fat, body muscle index, total energy intake, age and sex. Physical activity less than moderate-level was a predictor of NAFLD in obese subjects with NAFLD, independent of the HOMA-IR, visceral fat, total energy intake, fat energy percent, age and sex. CONCLUSIONS: Percentage of carbohydrate intake percent and physical activity, less than moderate-level were independent predictors of NAFLD in non-obese subjects. Meanwhile, physical activity, less than moderate-level, was an independent predictor in obese subjects. PMID- 28918172 TI - Melatonin and periodontal tissues: Molecular and clinical perspectives. AB - Periodontal disease is a frequent chronic inflammatory pathology that implies the destruction of the tissues supporting the teeth, which represents a high sanitary cost. It usually appears associated with other systemic conditions such as diabetes, metabolic syndrome, depression and Alzheimer disease among others. The presence of melatonin and its receptors in the oral cavity supports the hypothesis that this hormone could play a role in homeostasis of periodontal tissues. In the present review we will discuss the potential role of melatonin, a circadian synchronizing hormone, with proved antiinflammatory and antioxidant profile, in the pathogenesis and treatment of periodontitis. Particular emphasis will be placed on the role of the indolamine in the treatment of periodontal disease when this oral condition is comorbid with other pathologies that would also benefit from the therapeutic potential of melatonin and its analogs through diverse mechanisms. PMID- 28918171 TI - The association between delirium and sarcopenia in older adult patients admitted to acute geriatrics units: Results from the GLISTEN multicenter observational study. AB - BACKGROUND & AIMS: To date, studies assessing the relationship between sarcopenia and delirium, two of the most common geriatric syndromes, are lacking. We sought to explore this association by investigating the co-occurrence of these two conditions and the independent association between them in a population of hospitalized older adults. METHODS: Cross-sectional multicenter analysis of older adults consecutively admitted to 12 acute geriatric units (AGUs). Sarcopenia was assessed upon admission by evaluating the presence of low skeletal mass index (kg/m2), and either low handgrip strength or low walking speed (European Working Group on Sarcopenia in Older People, EWGSOP criteria). Skeletal muscle mass was estimated using bioimpedance analysis. Participants underwent a comprehensive geriatric assessment upon admission; information concerning demographics, cognition (Short Portable Status Mental Questionnaire, SPMSQ) functional (Instrumental Activities of Daily Living, IADL and Basic-Activities of Daily Living, BADL), and health status (Charlson Index and specific diseases) was evaluated. The presence of delirium upon admission was ascertained as an explicit clinical diagnosis recorded by the researcher of each centre on the data form. All association estimates were reported as Prevalence Ratios (PRs) and 95% confidence intervals (CIs), using a Cox hazard proportional regression model with robust variance and constant time. RESULTS: Of the 588 analyzed patients (mean age = 80.9 +/- 6.8, 53.2% females), 199 (33.8%) had sarcopenia upon admission to the AGU. According to a multivariable Cox regression, delirium upon admission (PR 1.66, 95% CI: 1.12-2.45), IADL total score (PR 0.93, 95% CI: 0.87-0.98), Body Mass Index values (BMI) ranging from 18.5 to 25.0 (PR 1.70, 95% CI: 1.33-2.18), BMI values >18.5 (PR 2.53, 95% CI: 1.81-3.53), previous stroke (PR 1.51, 95% CI: 1.10-2.07) and chronic heart failure (CHF) (PR 1.31, 95% CI: 1.02-1.68) were significantly and independently associated with sarcopenia upon admission to the AGU. CONCLUSION: The study, carried out in a population of hospitalized older patients, shows that a diagnosis of delirium upon admission to the AGU was more frequent in those with sarcopenia than in others. Furthermore, the study found that delirium was independently associated with the risk of being sarcopenic upon admission to the AGU. Future studies are needed to confirm this association. PMID- 28918173 TI - Edited course of biomedical research: leaping forward with CRISPR. AB - Within the short few years since the report of its application in precise genome editing, CRISPR technology has become the method of choice to modify and modulate gene expression in biomedical research and therapeutic development. Subsequently, a variety of research, diagnostic, and therapeutic tools have been developed based upon CRISPR's mechanism of action. Such tools have helped to deepen the understanding of fundamental biology and broaden the horizon in the search for treatments for diseases that have been considered hard or impossible to cure. As CRISPR technology advances closer to clinical applications, its short comings are becoming more apparent, thus creating opportunities to improve the technology's efficacy, specificity, and safety profile in this setting. We will summarize the current status of CRISPR technology and discuss its future impact in this review. PMID- 28918174 TI - 14-3-3 adaptor protein-protein interactions as therapeutic targets for CNS diseases. AB - 14-3-3s are a family of ubiquitously expressed adaptor proteins that regulate hundreds of functionally diverse 'client proteins.' In humans, there are seven isoforms with conserved structure and function. 14-3-3s typically bind to client proteins at phosphorylated serine/threonine motifs via a linear binding groove. Binding can have a variety of effects on the stability, activity and/or localization of the client protein. 14-3-3s are generating significant interest as potential drug targets for their involvement in cellular homeostasis and disease. They are especially abundant in the central nervous system (CNS) and are implicated in numerous CNS diseases, often through specific interactions with disease-relevant client proteins. Several tool compounds that can modulate 14-3-3 interactions with client proteins to elicit therapeutic effects have recently been described. Here we offer a perspective on the functions of 14-3-3s in neurons and the potential development of drugs to therapeutically target 14-3-3 PPIs for CNS diseases. PMID- 28918175 TI - Characterization of Patients With Poor-Risk Metastatic Renal-Cell Carcinoma: Results From a Pooled Clinical Trials Database. AB - BACKGROUND: Poor-risk patients with metastatic renal-cell carcinoma remain poorly characterized in prospective clinical trials. Therefore, we sought to provide a comprehensive analysis of this patient population, defined by 3 widely used prognostic models, treated with targeted therapy. PATIENTS AND METHODS: We conducted a pooled retrospective analysis of 4736 metastatic renal-cell carcinoma patients treated on phase 2 and 3 clinical trials. Poor-risk patients were defined according to the Memorial Sloan Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), and Hudes risk models. Baseline characteristics, overall survival, progression-free survival, objective response rate, and adverse events were reported in poor-risk patients defined by each of the 3 models. The concordance (C)-index was used to assess the prognostic performance of the models. A subset of poor-risk patients who continued to receive treatment for > 12 months was characterized. RESULTS: Overall, we identified 1145 (24%), 904 (19%), and 1901 (40%) poor-risk patients by the IMDC, MSKCC, and Hudes models, respectively. Median overall survival was 8.5 months, 7.5 months, and 10.6 months; and median progression-free survival was 3.7 months, 3.5 months, and 4.2 months in the IMDC, MSKCC, and Hudes models, respectively. The objective response rate ranged between 10% and 14%. Additionally, 9% to 14% of poor-risk patients continued to receive treatment for > 12 months. Most importantly, the C-index was 0.826, 0.830, and 0.825 in the IMDC, MSKCC, and Hudes risk models, respectively. CONCLUSION: We demonstrate that poor-risk patients continue to have dismal outcomes and warrant alternative treatment strategies to help improve outcomes. A subset of patients experienced prolonged clinical benefit and should be further explored. PMID- 28918176 TI - Ninety Day Mortality After Radical Radiotherapy for Head and Neck Cancer. AB - AIMS: Treatment for head and neck cancers using definitive radiotherapy, with or without chemotherapy, is associated with significant acute toxicity. Our aim was to assess 90 day mortality after radical radiotherapy. A further aim was to identify patient, tumour or treatment factors associated with early death after treatment and whether these could be used to predict outcomes. MATERIALS AND METHODS: In total, 1116 patients with squamous cell pharyngeal and larynx cancer between January 2011 and December 2015 were included. Patients with T1 larynx cancer were excluded. Patients were treated using radical radiotherapy, with or without chemotherapy. Ninety day mortality was calculated using survival of less than 135 days from the planned start date for radical radiotherapy, to include early deaths during and up to 90 days after treatment. RESULTS: Overall, 90 day mortality was 4.7%. Among the subgroup of patients treated with concurrent platinum chemotherapy, the 90 day mortality rate was 0.4%. Overall survival at 1, 3 and 5 years was 84%, 62% and 53%, respectively. Factors associated with a higher risk of early death included performance status > 1, haemoglobin <100 g/l, weight < 60 kg, age > 80 years and presence of multiple comorbidities. CONCLUSION: We report excellent crude overall survival rates among our radically treated cohort of head and neck cancer patients. Several factors were associated with an increased risk of death within 90 days of completion of radical head and neck radiotherapy. Given the potential severe acute effects and the impact on patient quality of life associated with radical head and neck radiotherapy, this information is helpful to inform treatment-related discussions with patients. PMID- 28918177 TI - Photodynamic therapy in oral potentially malignant disorders-Critical literature review of existing protocols. AB - INTRODUCTION: Oral cancer is a serious public health issue. Apart from its high rate of prevalence, incidence and mortality, it can often result in more complex and expensive treatment when diagnosed late. Potentially malignant disorders (PMDs) can precede oral cancer, and are usually treated by surgical excision. However, in many cases patients are elderly and multiple interventions may be required. Photodynamic therapy (PDT) is a simple alternative, which has been successfully used in the treatment of oral PMDs. OBJECTIVE: Due to the lack of standardization regarding photosensitizers (PTSs), types of irradiation, and methods of application, the objective of this study was to analyze existing PDT protocols in an attempt to identify the one that demonstrates greater efficiency, reliability and feasibility in the treatment of oral PMDs for both researchers and clinicians. METHODS: Original clinical studies published only in English between 1993 and 2016 were searched in Pubmed/Medline database using the following keywords: photodynamic therapy; oral potentially malignant disorder; oral premalignant lesions. Review articles; experimental studies; case-reports; commentaries; and letters to the Editor were excluded from the selection. RESULTS AND CONCLUSION: Based on the 16 studies selected, the topical 5-ALA-20% PTS, associated to a LED light applied for 15min with a 7-day interval between sessions emerged as the most frequently used PDT protocol, with satisfactory results. Due to its low rate of side effects, this PDT protocol presents good potential for the treatment of oral PMDs. Further clinical studies are required to ascertain its long-term validity in preventing oral cancer. PMID- 28918178 TI - Using Imaging to Predict Treatment Response in Genitourinary Malignancies. AB - CONTEXT: Over the previous2 decades, there have been numerous advancements in the diagnostic evaluation, therapeutic management, and postoperative assessment of genitourinary malignancies. OBJECTIVE: To present a review of current and novel imaging modalities and their utility in the assessment of therapeutic response in the systemic management of renal, testicular, and prostate cancers. EVIDENCE ACQUISITION: A PubMed/Medline search of the current published literature inclusive of prospective and retrospective original research, systematic reviews, and meta-analyses was conducted evaluating imaging modalities for renal cell carcinoma, prostate cancer, and testicular cancer. All relevant literature was individually reviewed and summarized to provide a concise description of the currently available imaging modalities and their efficacy in assessing treatment response of the genitourinary malignancies targeted in this review. EVIDENCE SYNTHESIS: Conventional imaging techniques play a pivotal role in predicting the treatment response of genitourinary malignancies and have, therefore, been incorporated into clinical guidelines. Advancements in imaging technology have led to increased utilization for prognostication of a genitourinary cancer's response to therapy. CONCLUSIONS: A good understanding of current recommended imaging techniques to evaluate treatment response in genitourinary malignancies is of paramount importance for today's clinician, who faces increasing treatment modalities. PATIENT SUMMARY: In this review, we summarize available imaging modalities in the evaluation of treatment response in kidney, prostate, or testicular tumors. We believe that a good understanding of current imaging modalities is of paramount importance for healthcare providers treating these cancers. PMID- 28918179 TI - [Analysis of quality of life in patients with Chronic Obstructive Pulmonary Disorder (COPD) who give up smoking]. AB - OBJECTIVE: To analyse the impact in COPD patients' quality of life who stop smoking. PATIENTS AND METHODS: We studied a group of COPD patients who received smoking cessation treatment. All patients were treated with bronchodilators according to the severity of their disorder. This treatment was not changed during the process of smoking cessation. Patients received a smoking cessation programme that consisted of a combination of pharmacological treatment plus cognitive-behavioural treatment. All subjects fill in CAT questionnaire before starting smoking cessation programme and after 6 months of abstinence. All subjects included had stop smoking. RESULTS: The study included 59 patients, with 27 (45.8%) males, and a mean age of 61.8 (7.5) years. Mean CAT score before quitting was 18.9 (7.3) points, and after 6 months of abstinence was 8.1 (6.1) points, P=.038. Multiple regression analysis showed: a) the higher the baseline CAT score the greater is the difference after quitting, at 6 months, at same age, gender, and grade of severity of COPD, and b) the older the age, the lower is the difference between baseline CAT score and the 6 months CAT score. CONCLUSIONS: Smoking cessation is associated with improvement in the quality of life in COPD patients. Those with worse quality of life get the biggest benefit from quitting, although this difference can be diminished in ageing patients. PMID- 28918180 TI - [Reason for consultation: Weight loss]. AB - BACKGROUND AND OBJECTIVE: Unintentional weight loss is frequent reason to visit a doctor and it has multiple diagnostic possibilities. The objective of this study is to examine the background of the patients who seek consultation for weight loss and to establish the relationship between weight loss and neoplasia. METHOD: An analysis was performed on the demographic data, quantified weight loss, accompanying symptomatology, and diagnosis of patients who sought medical advice for unintentional weight loss during the year 2015. RESULTS: A total of 226 patients were included, of whom 44.2% of them had an intentional weight loss >= 5% in 6 months. The most frequent diagnosis in this group was a neoplasia, whereas in the rest of patients the most common diagnosis was a gastrointestinal disease. In light of this study we can conclude that there is a relationship between unintentional weight loss>=5% and the presence of neoplasia. CONCLUSION: An unintentional weight loss greater than 5% in the previous 6 months is associated with the presence of neoplastic diseases, and therefore requires further diagnostic study. PMID- 28918181 TI - Flared sign of flail mandible on computed tomography: an unstable fracture associated with a compromised airway. AB - A mandibular fracture alone rarely causes a life-threatening injury. The aim of this paper was to emphasise the importance of prompt identification of the radiological signs of a flail mandible in a patient with maxillofacial trauma who eventually needed definitive management of her airway. PMID- 28918182 TI - UK temporomandibular joint replacement database: a report on one-year outcomes. AB - Alloplastic temporomandibular joint (TMJ) replacements are increasingly subspecialised, and supraregional centres that treat sufficient numbers to ensure high standards are emerging. Having recently reported the introduction of a national TMJ joint replacement database that is endorsed by the British Association of TMJ Surgeons (BATS), we now present the first-year outcomes. This was a review of all data in the BATS National Case Registration of TMJ Replacement as of June 2014. A total of 252 one-year outcome records were available. Key outcomes were median (IQR) improvements in interincisal distance of 9 (4-15) mm (p<0.001) and worst-sided pain score of 6 (4-8) (p<0.001). Pain scores improved or remained static at one year in all but 3 (2%) patients. There was a significant improvement in the proportion of patients who reported a good, very good, or outstanding quality of life at one year (38% at baseline to 87% at one year; p<0.001). While outcome reports from single centres for alloplastic TMJ replacements have already been published in the United Kingdom, this is the first dedicated national database in this country that will yield valuable longitudinal follow-up data. Outcomes were comparable with smaller published series and showed improvements in pain, dietary intake, quality of life, and function, with few outliers. The database has recently moved to a new software system and we hope to publish three-year and five-year outcomes in due course. PMID- 28918183 TI - Survival after surgery for oral cancer: a 30-year experience. AB - Oral squamous cell carcinoma is the most common intraoral malignancy, for which we advocate radical primary resection with adjuvant treatment where indicated. The main aims of this paper are to identify the overall survival of a consecutive series of patients and to relate survival to clinical and pathological factors. Kaplan-Meier curves were produced for site, sex, TNM status, and use of postoperative radiotherapy. The data were analysed using IBM SPSS Statistics for Windows and probabilities of less than 0.05 were accepted as significant. A total of 921 patients were recorded in the database with a diagnosis of oral squamous cell carcinoma out of a total of 1958 with salivary gland conditions or other cancers of the head and neck (43.1%). The earliest date of diagnosis was 1973, and the data were censored at 31 March 2016. The database comprised 340 women (36.9%) and 581 men (63.1%). A total of 339 patients died (34.5%): 117 women (33.7%) and 222 men (65.5%). The mean (range) age at death was 73.4 (31.4-97.5) years for women and 68.7 (33.3-95.5) years for men (t (337)=3.28, p=0.001). Our overall survival was somewhat better than the 56% five-year survival reported for oral cancer in England in 2010, which may be a reflection of the treatment. This work supports the view that aggressive management may improve overall survival. PMID- 28918184 TI - Removal of recurrent intraorbital tumour using a system of augmented reality. AB - The most crucial step in the management of pleomorphic adenoma of the lacrimal gland is choosing the optimal approach for excision. We report the successful removal of a recurrent pleomorphic adenoma of the lacrimal gland in a 42-year-old woman using a specific microscope-based system of augmented reality. PMID- 28918185 TI - Isolated limb perfusion for locally advanced angiosarcoma in extremities: A multi centre study. AB - BACKGROUND: Angiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor alpha for locally advanced angiosarcoma. MATERIAL AND METHODS: All patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases. RESULTS: A total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1-60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%). CONCLUSION: ILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS. PMID- 28918186 TI - Health-related quality of life in melanoma patients: Impact of melanoma-related limb lymphoedema. AB - AIM: To explore health-related quality of life (HRQoL) in recurrence-free melanoma patients, with a focus on the association between melanoma-related limb lymphoedema and HRQoL. METHODS: HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the breast cancer module (EORTC QLQ-BR23) subscales body image and future perspective, the Functional Assessment for Cancer Therapy-General subscale social/family well-being and the Hospital Anxiety and Depression Scale. Data were analysed using linear and ordinal logistic regression adjusting for age and gender. RESULTS: A total of 431 melanoma patients who had undergone wide local excision and axillary or inguinal sentinel lymph node biopsy (SLNB) and/or complete lymph node dissection (CLND) participated. No patients had had recurrence of the disease or had received adjuvant radiotherapy. The HRQoL scores improved with time after surgery. Melanoma-related limb lymphoedema was present in 109 patients (25%). Patients with lymphoedema had significantly worse HRQoL scores in the EORTC QLQ-C30 subscales global health status/quality of life, role and social functioning, fatigue, pain and financial difficulties, as well as in the QLQ-BR23 body image subscale. No associations were found between the limb affected (upper or lower limb), clinical stage of lymphoedema, duration of lymphoedema or type of surgery (SLNB or CLND) and HRQoL. We found an interaction with age and gender in the associations between lymphoedema and HRQoL: younger patients and women with lymphoedema had worse social functioning and women had significantly more impaired body image. CONCLUSIONS: The negative impact of melanoma-related limb lymphoedema on HRQoL emphasises the importance of developing strategies for increasing awareness and improving prevention and treatment of lymphoedema. PMID- 28918187 TI - Surface modification of titanium substrates for enhanced osteogenetic and antibacterial properties. AB - The insufficient osseointegration and bacterial infection of titanium and its alloys remain the key challenges in their clinic applications, which may result in failure implantation. To improve osteogenetic and antibacterial properties, TiO2 nanotube arrays were fabricated on titanium substrates for loading of antibacterial drug. Then, TiO2 nanotube arrays were covered with chitosan/sodium alginate multilayer films. The successful construction of this system was verified via scanning electron microscopy and contact angle measurement. The cytocompatibility evaluation in vitro, including cytoskeleton observation, cell viability measurement, and alkaline phosphatase activity assay, confirmed that the present system was capable of accelerating the growth of osteoblasts. In addition, bacterial adhesion and viability assay verified that treated Ti substrates were capable of reducing the adhesion of bacteria. This study may provide an alternative to develop titanium-based implants for enhanced bone osseointegration and reduced bacterial infection. PMID- 28918188 TI - The effect of thiolated phospholipids on formation of supported lipid bilayers on gold substrates investigated by surface-sensitive methods. AB - Most of the model lipid membrane studies on gold involve the usage of various surface-modification strategies to rupture liposomes and induce lipid bilayer formation since liposomes with polar surfaces do not interact with bare, hydrophobic gold. In this study, a thiol-modified phospholipid, 1,2-Dipalmitoyl sn-Glycero-3-Phosphothioethanol (DPPTE) was incorporated into phosphatidylcholine (PC) based liposomes to form supported lipid bilayer (SLB) on gold surfaces without further modification. The binding kinetics of liposomes with different DPPTE ratio (0.01 to 100%mol/mol) and diameters were monitored by Quartz Crystal Microbalance with Dissipation (QCM-D). The dissipation change per frequency change, i.e. acoustic ratio, which is evaluated as a degree of the viscoelasticity, considerably decreased with the presence of DPPTE (from 162.3GHz 1 for flattened PC liposomes to ca. 89.5GHz-1 for 100% DPPTE liposomes) when compared to the results of two reference rigid monolayers and two viscoelastic layers. To assess the quality of SLB platform, the interpretation of QCM-D data was also complemented with Surface Plasmon Resonance. The optimum thiolated-lipid ratio (1%, lower thiol ratio and higher rigidity) was then used to determine the dry-lipid mass deposition, the water content and the thickness values of the SLB via viscoelastic modelling. Further surface characterization studies were performed by Atomic Force Microscopy with high spatial resolution. The results suggested that model membrane was almost continuous with minimum defects but showed more dissipative/soft nature compared to an ideal bilayer due to partially fused liposomes/overlapped lipid bilayers/multilayer islands. These local elevations distorted the planarity and led the increase of overall membrane thickness to ~7.0nm. PMID- 28918189 TI - Effects of temperature and PEG grafting density on the translocation of PEGylated nanoparticles across asymmetric lipid membrane. AB - Plasma membrane internalization of nanoparticles (NPs) is important for their biomedical applications such as drug-delivery carriers. On one hand, in order to improve their half-life in circulation, PEGylation has been widely used. However, it may hinder the NPs' membrane internalization ability. On the other hand, higher temperature could enhance the membrane permeability and may affect the NPs' ability to enter into or exit from cells. To make full use of their advantages, we systematically investigated the effects of temperature and PEG density on the translocation of PEGylated nanoparticles across the plasma asymmetric membrane of eukaryotic cells, using near-atom level coarse-grained molecular dynamics simulations. Our results showed that higher temperature could accelerate the translocation of NPs across membranes by making lipids more disorder and faster diffusion. On the contrary, steric hindrance effects of PEG would inhibit NPs' translocation process and promote lipids flip-flops. The PEG chains could rearrange themselves to minimize the contacts between PEG and lipid tails during the translocation, which was similar to 'snorkeling effect'. Moreover, lipid flip-flops were affected by PEGylated density as well as NPs' translocation direction. Higher PEG grafting density could promote lipid flip flops, but inhibit lipid extraction from bilayers. The consequence of lipid flip flop and extraction was that the membranes got more symmetric. PMID- 28918190 TI - Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. AB - Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis. PMID- 28918191 TI - Development and Validation of a Chronic Pancreatitis Prognosis Score in 2 Independent Cohorts. AB - BACKGROUND & AIMS: The clinical course of chronic pancreatitis is unpredictable. There is no model to assess disease severity or progression or predict patient outcomes. METHODS: We performed a prospective study of 91 patients with chronic pancreatitis; data were collected from patients seen at academic centers in Europe from January 2011 through April 2014. We analyzed correlations between clinical, laboratory, and imaging data with number of hospital readmissions and in-hospital days over the next 12 months; the parameters with the highest degree of correlation were used to develop a 3-stage chronic pancreatitis prognosis score (COPPS). The predictive strength was validated in 129 independent subjects identified from 2 prospective databases. RESULTS: The mean number of hospital admissions was 1.9 (95% confidence interval [CI], 1.39-2.44) and 15.2 for hospital days (95% CI, 10.76-19.71) for the development cohort and 10.9 for the validation cohort (95% CI, 7.54-14.30) (P = .08). Based on bivariate correlations, pain (numeric rating scale), level of glycated hemoglobin A1c, level of C-reactive protein, body mass index, and platelet count were used to develop the COPPS system. The patients' median COPPS was 8.9 points (range, 5 14). The system accurately discriminated stages of disease severity (low to high): A (5-6 points), B (7-9), and C (10-15). In Pearson correlation analysis of the development cohort, the COPPS correlated with hospital admissions (0.39; P < .01) and number of hospital days (0.33; P < .01). The correlation was validated in the validation set (Pearson correlation values of 0.36 and 0.44; P < .01). COPPS did not correlate with results from the Cambridge classification system. CONCLUSIONS: We developed and validated an easy to use dynamic multivariate scoring system, similar to the Child-Pugh-Score for liver cirrhosis. The COPPS allows objective monitoring of patients with chronic pancreatitis, determining risk for readmission to hospital and potential length of hospital stay. PMID- 28918192 TI - Dielectric properties of isolated adrenal chromaffin cells determined by microfluidic impedance spectroscopy. AB - Knowledge of the dielectric properties of biological cells plays an important role in numerical models aimed at understanding how high intensity ultrashort nanosecond electric pulses affect the plasma membrane and the membranes of intracellular organelles. To this end, using electrical impedance spectroscopy, the dielectric properties of isolated, neuroendocrine adrenal chromaffin cells were obtained. Measured impedance data of the cell suspension, acquired between 1kHz and 20MHz, were fit into a combination of constant phase element and Cole Cole models from which the effect of electrode polarization was extracted. The dielectric spectrum of each cell suspension was fit into a Maxwell-Wagner mixture model and the Clausius-Mossotti factor was obtained. Lastly, to extract the cellular dielectric parameters, the cell dielectric data were fit into a granular cell model representative of a chromaffin cell, which was based on the inclusion of secretory granules in the cytoplasm. Chromaffin cell parameters determined from this study were the cell and secretory granule membrane specific capacitance (1.22 and 7.10MUF/cm2, respectively), the cytoplasmic conductivity, which excludes and includes the effect of intracellular membranous structures (1.14 and 0.49S/m, respectively), and the secretory granule milieu conductivity (0.35S/m). These measurements will be crucial for incorporating into numerical models aimed at understanding the differential poration effect of nanosecond electric pulses on chromaffin cell membranes. PMID- 28918193 TI - Psychedelic pleasures: An affective understanding of the joys of tripping. AB - BACKGROUND: This paper considers the pleasures of psychedelic drugs and proposes a Deleuzian understanding of drugged pleasures as affects. In spite of a large body of work on psychedelics, not least on their therapeutic potentials, the literature is almost completely devoid of discussions of the recreational practices and pleasures of entheogenic drugs. Yet, most people do not use psychedelics because of their curative powers, but because they are fun and enjoyable ways to alter the experience of reality. METHODS: In the analytical part of the paper, I examine 100 trip reports from an internet forum in order to explore the pleasures of tripping. RESULTS: The analyses map out how drugs such as LSD and mushrooms - in combination with contextual factors such as other people, music and nature - give rise to a set of affective modifications of the drug user's capacities to feel, sense and act. CONCLUSION: In conclusion it is argued that taking seriously the large group of recreational users of hallucinogens is important not only because it broadens our understanding of how entheogenic drugs work in different bodies and settings, but also because it may enable a more productive and harm reductive transmission of knowledge between the scientific and recreational psychedelic communities. PMID- 28918194 TI - Cleaning and asthma: A systematic review and approach for effective safety assessment. AB - Research indicates a correlative relationship between asthma and use of consumer cleaning products. We conduct a systematic review of epidemiological literature on persons who use or are exposed to cleaning products, both in occupational and domestic settings, and risk of asthma or asthma-like symptoms to improve understanding of the causal relationship between exposure and asthma. A scoring method for assessing study reliability is presented. Although research indicates an association between asthma and the use of cleaning products, no study robustly investigates exposure to cleaning products or ingredients along with asthma risk. This limits determination of causal relationships between asthma and specific products or ingredients in chemical safety assessment. These limitations, and a lack of robust animal models for toxicological assessment of asthma, create the need for a weight-of-evidence (WoE) approach to examine an ingredient or product's asthmatic potential. This proposed WoE method organizes diverse lines of data (i.e., asthma, sensitization, and irritation information) through a systematic, hierarchical framework that provides qualitatively categorized conclusions using hazard bands to predict a specific product or ingredient's potential for asthma induction. This work provides a method for prioritizing chemicals as a first step for quantitative and scenario-specific safety assessments based on their potential for inducing asthmatic effects. Acetic acid is used as a case study to test this framework. PMID- 28918195 TI - Impact of body mass index and metabolic phenotypes on coronary artery disease according to glucose tolerance status. AB - OBJECTIVE: This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. METHODS: This population-based retrospective cohort study included 123,746 Japanese men aged 18-72years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI>=25kg/m2. Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. RESULTS: The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32-2.95; prediabetes: 2.91, 95% CI: 1.85-4.55; diabetes: 1.90, 95% CI: 1.18-3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94-9.56) and 7.86 (95% CI: 5.21-11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. CONCLUSION: A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status. PMID- 28918197 TI - Heterologous expression of Trametes versicolor laccase in Saccharomyces cerevisiae. AB - Laccase is used in various industrial fields, and it has been the subject of numerous studies. Trametes versicolor laccase has one of the highest redox potentials among the various forms of this enzyme. In this study, we optimized the expression of laccase in Saccharomyces cerevisiae. Optimizing the culture conditions resulted in an improvement in the expression level, and approximately 45 U/L of laccase was functionally secreted in the culture. The recombinant laccase was found to be a heavily hypermannosylated glycoprotein, and the molecular weight of the carbohydrate chain was approximately 60 kDa. These hypermannosylated glycans lowered the substrate affinity, but the optimum pH and thermo-stability were not changed by these hypermannosylated glycans. This functional expression system described here will aid in molecular evolutionary studies conducted to generate new variants of laccase. PMID- 28918196 TI - Expression and purification of human and Saccharomyces cerevisiae equilibrative nucleoside transporters. AB - Nucleosides play an essential role in the physiology of eukaryotes by acting as metabolic precursors in de novo nucleic acid synthesis and energy metabolism. Nucleosides also act as ligands for purinergic receptors. Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that aid in regulating plasmalemmal flux of purine and pyrimidine nucleosides and nucleobases. ENTs exhibit broad substrate selectivity across different isoforms and utilize diverse mechanisms to drive substrate flux across membranes. However, the molecular mechanisms and chemical determinants of ENT-mediated substrate recognition, binding, inhibition, and transport are poorly understood. To determine how ENT-mediated transport occurs at the molecular level, greater chemical insight and assays employing purified protein are essential. This article focuses on the expression and purification of human ENT1, human ENT2, and Saccharomyces cerevisiae ScENT1 using novel expression and purification strategies to isolate recombinant ENTs. ScENT1, hENT1, and hENT2 were expressed in W303 Saccharomyces cerevisiae cells and detergent solubilized from the membrane. After detergent extraction, these ENTs were further purified using immobilized metal affinity chromatography and size exclusion chromatography. This effort resulted in obtaining quantities of purified protein sufficient for future biophysical analysis. PMID- 28918198 TI - Are we missing hypoglycaemia? Elderly patients with insulin-treated diabetes present to primary care frequently with non-specific symptoms associated with hypoglycaemia. AB - INTRODUCTION: We assessed if patients with known hypoglycaemia present on other occasions with non-specific symptoms associated with (but not diagnosed as) hypoglycaemia, potentially representing missed hypoglycaemia. METHODS: 335 primary care records (5/2/12-4/2/13) from patients aged >65 (79 on insulin, 85 on sulphonylureas, 121 on metformin only, 50 without diabetes) were assessed for hypoglycaemia episodes and consultations with non-specific symptoms, "hypo clues". RESULTS: 27/79(34%) insulin-treated patients had >1 documented hypoglycaemia episode, compared to 4/85(5%) sulphonylurea-treated patients, 2/121(2%) metformin-only treated patients, and none without diabetes, p<0.001. "Hypo clue" consultations were common: 1.37 consultations/patient/year in insulin treated patients, 0.98/patient/year in sulphonylurea-treated, 0.97/patient/year in metformin only-treated, and 0.78/patient/year in non-diabetic patients, p=0.34. In insulin-treated patients with documented hypoglycaemia, 20/27(74%) attended on another occasion with a "hypo clue" symptom, compared to 21/52(40%) of those without hypoglycaemia, p=0.008. No significant difference in the other treatment groups. Nausea, falls and unsteadiness were the most discriminatory symptoms: 7/33(21%) with hypoglycaemia attended on another occasion with nausea compared to 14/302(5%) without hypoglycaemia, p=0.002; 10/33(30%) vs 36/302(12%) with falls, p=0.007; and 5/33(15%) vs 13/302(4%) with unsteadiness, p=0.023. CONCLUSIONS: Non-specific symptoms are common in those >65 years. In insulin treated patients at high hypoglycaemia risk, nausea, falls and unsteadiness should prompt consideration of hypoglycaemia. PMID- 28918199 TI - Psychosocial barriers to healthcare use among individuals with diabetes mellitus: A systematic review. AB - PURPOSE: To conduct a systematic review regarding psychosocial barriers to healthcare use in individuals with diabetes mellitus, using a well-established model of health-service use as a theoretical framework. METHODS: We used database specific controlled vocabularies and additional free text terms, and conducted searches via MEDLINE, EMBASE, PsycINFO, CINAHL, Web of Science, OVID Journals. Included studies were rated according to the UK National Institute for Health and Care Excellence (NICE) criteria. A narrative data synthesis was conducted, using the Andersen model and developing categories from the included studies. PRINCIPAL RESULTS: In total, 2923 studies were identified, and 15 finally included. We identified barriers according to the main categories "population characteristics", "norms and values", and "healthcare services" on a contextual and individual level, as well as "health status". Frequently reported barriers were "socioeconomic status", and "physician characteristics". Ethnic minorities were frequently analysed and may have specific barriers, e.g. "cultural beliefs" and "language". MAJOR CONCLUSIONS: We identified a broad range of barriers to healthcare use in individuals with diabetes mellitus. However, the number of studies is low. Further research is needed to analyse barriers in more detail considering special subgroups. PMID- 28918200 TI - Profiling the short, linear, non-disulfide bond-containing peptidome from the venom of the scorpion Tityus obscurus. AB - : Many scorpion accidents occur in the Brazilian Amazonian region and are frequently caused by Tityus obscurus. Approximately 5% of the crude venom of this species is composed of short linear, non-disulfide-bridged peptides, which have not been intensively investigated. As a consequence, only a few of these peptides have been structurally and functionally characterized to date. In the present paper, the peptide fraction of the venom was subjected to peptide profiling using an LCMS-IT-TOF/MS and MSn system. The analysis detected 320 non-disulfide bond containing peptides (NDBPs), of which twenty-seven had their sequences assigned; among them, thirteen peptides were characterized, constituting novel toxins in T. obscurus venom. Some of the novel peptides showed similarities to hypotensin-like toxins, while other peptides appear to be natural fragments of neurotoxins. The novel peptides were submitted to a series of bioassays, revealing that many are multifunctional toxins that cause, for example, pain, edema formation and hemolysis to potentiate strong inflammatory processes and alterations in the locomotion and lifting activities in the victims of stinging. Knowledge of the complex matrix of peptides composing the venom of T. obscurus will contribute to better understanding of the complex mechanism of envenoming caused by stinging accidents. SIGNIFICANCE: The scorpion Tityus obscurus causes many envenoming accidents of medical importance in Brazilian Amazon region; despite to this, very few is known about the toxinology of this animal. The knowledge about the venom composition and mechanisms of action is very important to understand the physiopathology processes related to the envenoming caused by this animal. The proteopeptidomic investigations of scorpion venoms in general have focused mainly the neurotoxins (which are disulfide bonds containing peptides) and large proteins. The short, linear, non-disulfide bonds containing peptides (NDBPs) represent up to 5% of scorpion venom compositions; however, they have been few investigated in comparison with the neurotoxins. The present study used a mass spectrometric approach to detect 320 NDBPs and to sequence 27 of them; pharmacological assays permitted to characterize 13 NDBPs as novel toxins involved with inflammation, pain and edema formation. PMID- 28918201 TI - Clinical management of pressure control ventilation: An algorithmic method of patient ventilatory management to address "forgotten but important variables". AB - Pressure controlled ventilation is a common mode of ventilation used to manage both adult and pediatric populations. However, there is very little evidence that distinguishes the efficacy of pressure controlled ventilation over that of volume controlled ventilation in the adult population. This gap in the literature may be due to the absence of a consistent and systematic algorithm for managing pressure controlled ventilation. This article provides a brief overview of the applications of both pressure controlled ventilation and volume controlled ventilation and proposes an algorithmic approach to the management of patients receiving pressure controlled ventilation. This algorithmic approach highlights the need for clinicians to have a comprehensive conceptual understanding of mechanical ventilation, pulmonary physiology, and interpretation of ventilator graphics in order to best care for patients receiving pressure controlled ventilation. The objective of identifying a systematic approach to managing pressure controlled ventilation is to provide a more generalizable and equitable approach to management of the ICU patient. Ideally, a consistent approach to managing pressure controlled ventilation in the adult population will glean more reliable information regarding actual patient outcomes, as well as the efficacy of pressure controlled ventilation when compared to volume controlled ventilation. PMID- 28918202 TI - Implementation of a risk-stratified opioid weaning protocol in a pediatric intensive care unit. AB - PURPOSE: Opioids are important in the care of critically ill children. However, their use is associated with complications including delirium, dependence, withdrawal, and bowel dysfunction. Our aim was to implement a risk-stratified opioid weaning protocol to reduce the duration of opioids without increasing the incidence of withdrawal. METHODS: A pre- and post-interventional prospective study was undertaken in a large children's hospital pediatric ICU where we implemented a risk-stratified opioid weaning protocol. Patients were included if exposed to >=7days of scheduled opioids. The primary outcome was duration of opioids and secondary outcome was hospital LOS. RESULTS: One hundred seven critically ill children met the inclusion criteria (68 pre-, 39 post intervention). Demographics, risk factors, and confounders did not differ between groups. Patients in the post-intervention group had shorter duration of opioids (17 vs. 22.5days, p=0.01) and opioid wean (12 vs. 18days, p=0.01). Despite the shorter duration of opioid wean, there was no increase in withdrawal incidence. There was no difference in the LOS (29 vs. 33days, p=0.06). CONCLUSIONS: We implemented a risk-stratified opioid weaning protocol for critically ill children that resulted in reduction in opioid exposure without an increase in withdrawal. There was no difference in the LOS. PMID- 28918203 TI - Short-term effects of preoperative beta-blocker use for isolated coronary artery bypass grafting: A systematic review and meta-analysis. AB - OBJECTIVE: The use of preoperative beta-blockers has been used as a quality standard for patients undergoing coronary artery bypass grafting (CABG). However, the benefits of beta-blockers use before CABG remain controversial. We performed a systematic review and meta-analysis to investigate the short-term effects of preoperative beta-blocker use for patients undergoing isolated CABG. METHODS: We searched PubMed, Embase, and the Cochrane Library for English articles published from inception to August 16, 2016. Observational studies comparing preoperative beta-blockers therapy or non-beta-blockers therapy were considered eligible for the current study. RESULTS: Six observational studies with 1,231,850 patients were included. The pooled analyses of unadjusted outcome (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .007) or risk-adjusted outcome (OR, 0.95; 95% CI, 0.92-0.97; P = .000) showed slight reduction in operative mortality, whereas an insignificant difference in mortality rate was observed in pooling postoperative data from propensity score analysis (OR, 0.97; 95% CI, 0.94 1.00; P = .088). Removing one study that used propensity-score covariate adjustment, subgroup analysis of propensity-matched patients (313,417 in each group) still generated a statistically nonsignificant benefit for preoperative beta-blocker use (OR, 0.97; 95% CI, 0.94-1.00; P = .093). Furthermore, the preoperative use of beta-blockers did not reduce the incidence of major postoperative complications, such as postoperative myocardial infarction, stroke, atrial fibrillation, reoperation, renal failure, prolonged ventilation, and sternal wound infection. CONCLUSIONS: Our study suggests that the use of preoperative beta-blockers did not reduce either operative mortality or the incidence of postoperative complications in patients undergoing CABG. PMID- 28918204 TI - Serum glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction after surgery for rheumatic heart disease. AB - OBJECTIVE: Postoperative cognitive dysfunction is an important complication of cardiac surgery with poor outcomes. Serum glial cell line-derived neurotrophic factor levels are decreased in patients with Alzheimer's disease, but the association between glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction is poorly understood. The present study aimed to investigate the prognostic value of postoperative serum glial cell line derived neurotrophic factor levels to predict postoperative cognitive dysfunction in patients with rheumatic heart disease undergoing heart valve replacement. METHODS: This was a prospective observational study of 80 patients undergoing elective heart valve replacement surgery from June 2015 to June 2016 at the Affiliated Hospital of Southeast Medical University. Cognitive functions were assessed 1 day before and 7 days after surgery. Serum glial cell line-derived neurotrophic factor levels were measured by an enzyme-linked immunosorbent assay before (T1) and 1 (T2), 2 (T3), and 7 (T4) days after surgery. Perioperative parameters were evaluated to assess the relationship between glial cell line derived neurotrophic factors and postoperative cognitive dysfunction. RESULTS: Postoperative cognitive dysfunction was identified in 38 patients (47.5%) 7 days after surgery. Average glial cell line-derived neurotrophic factor levels at 2 and 7 days after surgery in the postoperative cognitive dysfunction group were lower than in the nonpostoperative cognitive dysfunction group at the same time points (P < .001). DeltaGlial cell line-derived neurotrophic factor (T1-T3) and Deltaglial cell line-derived neurotrophic factor (T1-T4) were identified as good predictors of postoperative cognitive dysfunction with threshold for postoperative cognitive dysfunction detection of 49.10 and 60.90, respectively. CONCLUSIONS: The perioperative glial cell line-derived neurotrophic factor levels in patients with postoperative cognitive dysfunction were lower than in patients without postoperative cognitive dysfunction. Glial cell line-derived neurotrophic factor could be an effective predictor for the occurrence of postoperative cognitive dysfunction. The results reveal a potentially important role of decreased glial cell line-derived neurotrophic factor levels in postoperative cognitive dysfunction, with possible treatment targets. PMID- 28918205 TI - Direct closure of ventricular septal defect for left ventricular outflow tract obstruction in interrupted aortic arch. PMID- 28918206 TI - Lung cancer randomized controlled trials should compare stereotactic body radiation therapy with observation, NOT surgery. PMID- 28918208 TI - Black is the new black. PMID- 28918207 TI - The association between cardiac physiology, acquired brain injury, and postnatal brain growth in critical congenital heart disease. AB - OBJECTIVE: To assess the trajectory of perioperative brain growth in relationship to cardiac diagnosis and acquired brain injuries. METHODS: This was a cohort study of term neonates with hypoplastic left heart syndrome (HLHS) and d transposition of the great arteries (d-TGA). Subjects underwent magnetic resonance imaging of the brain pre- and postoperatively to determine the severity of brain injury and total and regional brain volumes by the use of automated morphometry. Comparisons were made by cardiac lesion and injury status. RESULTS: A total of 79 subjects were included (49, d-TGA; 30, HLHS). Subjects with HLHS had more postoperative brain injury (55.6% vs 30.4%, P = .03) and more severe brain injury (moderate-to-severe white matter [WM] injury, P = .01). Total and regional perioperative brain growth was not different by brain injury status (either pre- or postoperative). However, subjects with moderate-to-severe WM injury had a slower rate of brain growth in WM and gray matter compared with those with no injury. Subjects with HLHS had a slower rate of growth globally and in WM and deep gray matter as compared with d-TGA (total brain volume: 12 cm3/wk vs 7 cm3; WM: 2.1 cm3/wk vs 0.6 cm3; deep gray matter: 1.5 cm3/wk vs 0.7 cm3; P < .001), after we adjusted for gestational age at scan and the presence of brain injury. This difference remained after excluding subjects with moderate-to-severe WM injury. CONCLUSIONS: Neonates with HLHS have a slower rate of global and regional brain growth compared with d-TGA, likely related to inherent physiologic differences postoperatively. These findings demonstrate the complex interplay between cardiac lesion, brain injury, and brain growth. PMID- 28918209 TI - Treatment of postoperative distal anastomotic endoleak with the Amplatzer Vascular Plug II in chronic aortic arch dissection: A case report. PMID- 28918210 TI - The costs of operating under a veil of secrecy. PMID- 28918211 TI - With age comes...a missed opportunity? PMID- 28918212 TI - An alpha-glucosidase inhibitor could reduce T-wave alternans in type 2 diabetes patients. AB - BACKGROUND: We tested the hypothesis that an alpha-glucosidase inhibitor (alpha GI), miglitol, is effective in protecting the cardiovascular system in type 2 diabetes mellitus (T2DM). METHODS: We studied 19 hospitalized heart disease patients with T2DM in whom we performed continuous glucose monitoring, Holter electrocardiogram, and ambulatory blood pressure (BP) monitoring simultaneously for 48h. The alpha-GI miglitol was administered for half of the study period by a cross-over fashion. T-wave alternans (TWA), a marker of future fatal arrhythmic events, was also analyzed by Holter ECG. RESULTS: Of the 19 patients, the measures of glucose variability were significantly lower during miglitol therapy than in control period. BP variability was similar with/without miglitol. However, TWA was significantly lower during the miglitol period compared to control period (63+/-4.8 vs. 75.8+/-5.1MUV, p=0.032). CONCLUSION: An alpha-GI, miglitol, can reduce TWA by reducing the fluctuation of glucose in heart disease patients with T2DM. PMID- 28918213 TI - Myocardium at risk assessed by electrocardiographic scores and cardiovascular magnetic resonance - a MITOCARE substudy. AB - INTRODUCTION: The myocardium at risk (MaR) represents the quantitative ischemic area destined to myocardial infarction (MI) if no reperfusion therapy is initiated. Different ECG scores for MaR have been developed, but there is no consensus as to which should be preferred. OBJECTIVE: Comparisons of ECG scores and Cardiac Magnetic Resonance (CMR) for determining MaR. METHODS: MaR was determined by 3 different ECG scores, and by CMR in ST-segment elevation MI (STEMI) patients from the MITOCARE cardioprotection trial. The Aldrich score (AL) is based on the number of leads with ST-elevation for anterior MI and the sum of ST-segment elevation for inferior MI on the admission ECG. The van Hellemond score (VH) considers both the ischemic and infarcted component of the MaR by adding the AL and the QRS score, which is an estimate of final infarct size. The Hasche score is based on the maximal possible infarct size determined from the QRS score on the baseline ECG. RESULTS: Ninety-eight patients (85% male, mean age 61years) met STEMI criteria on their admission ECG and underwent CMR within 3 5days after STEMI. Mean MaR by CMR was 41.2+/-10.2 and 30.3+/-7.2 for anterior and inferior infarcts, respectively. For both anterior and inferior infarcts the Aldrich (18.2+/-5.1 and 18.6+/-6.0) and Hasche (25.3+/-9.8 and 26.4+/-8.8) scores significantly underestimated MaR compared to MaR measured by CMR. In contrast, MaR by the van Hellemond score (37.0+/-14.2 and 31.7+/-12.8) was comparable to CMR. CONCLUSION: We tested the performance of the electrocardiographic estimation of myocardium area at risk by Aldrich, Hasche and van Hellemond ECG scores in comparison to MaR measured by CMR in STEMI patients. MaR by the van Hellemond score and CMR were comparable, while Aldrich and Hasche underestimated MaR. PMID- 28918214 TI - Efficient noise-tolerant estimation of heart rate variability using single channel photoplethysmography. AB - BACKGROUND: The feasibility of using photoplethysmography (PPG) for estimating heart rate variability (HRV) has been the subject of many recent studies with contradicting results. Accurate measurement of cardiac cycles is more challenging in PPG than ECG due to its inherent characteristics. METHODS: We developed a PPG only algorithm by computing a robust set of medians of the interbeat intervals between adjacent peaks, upslopes, and troughs. Abnormal intervals are detected and excluded by applying our criteria. RESULTS: We tested our algorithm on a large database from high-risk ICU patients containing arrhythmias and significant amounts of artifact. The average difference between PPG-based and ECG-based parameters is <1% for pNN50, <1bpm for meanHR, <1ms for SDNN, <3ms for meanNN, and <4ms for SDSD and RMSSD. CONCLUSIONS: Our performance testing shows that the pulse rate variability (PRV) parameters are comparable to the HRV parameters from simultaneous ECG recordings. PMID- 28918215 TI - Words matter in aging. PMID- 28918216 TI - An aspirin a day...Does that make sense? PMID- 28918217 TI - Digging deeper into dignity. PMID- 28918218 TI - [Progression of eyelid abnormalities in a collodion baby type newborn with congenital ichthyosis]. PMID- 28918219 TI - A highly selective fluorescent chemosensor for CN- based on a novel bis(salamo) type tetraoxime ligand. AB - The optical properties of a novel chemosensor for cyanide anions based on a symmetric bis(salamo)-type ligand (H3L) were investigated by UV-Vis and fluorescence spectroscopy in MeOH/H2O (1:1 v/v) solution. Sensor H3L can selectively sense CN- based on prominent color changes among other anions. The chemosensor exhibits an apparent fluorescence enhancement at 482nm to CN- which because cyanide ions interact with CN bonds. Combining the corrected Benesi Hildebrand formula, the binding constant of the formed host-guest complex was calculated as 2.42*105M-1. Meanwhile, the detection limit of the sensor toward CN was 8.91*10-7M. It is worth noting that the designed sensor can be used for rapid detection of cyanide anions in basic pH range, and has great practical value. PMID- 28918220 TI - Synthesis and application of a highly selective copper ions fluorescent probe based on the coumarin group. AB - A highly selective copper ions fluorescent probe based on the coumarin-type Schiff base derivative 1 (probe) was produced by condensation reaction between coumarin carbohydrazide and 1H-indazole-3-carbaldehyde. The UV-vis spectroscopy showed that the maximum absorption peak of compound 1 appeared at 439nm. In the presence of Cu2+ ions, the maximum peak decreased remarkably compared with other physiological important metal ions and a new absorption peak at 500nm appeared. The job's plot experiments showed that complexes of 1:2 binding mode were formed in CH3CN:HEPES (3:2, v/v) solution. Compound 1 exhibited a strong blue fluorescence. Upon addition of copper ions, the fluorescence gradually decreased and reached a plateau with the fluorescence quenching rate up to 98.73%. The detection limit for Cu2+ ions was estimated to 0.384ppm. Fluorescent microscopy experiments demonstrated that probe 1 had potential to be used to investigate biological processes involving Cu2+ ions within living cells. PMID- 28918221 TI - A 10-minute measure of global cognition: Validation of the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS). AB - INTRODUCTION: Schizophrenia is marked by a global cognitive impairment that contributes significantly to chronic disability and unemployment. As new treatments are developed for cognition in schizophrenia, clinicians require easily administered instruments to assess cognition. We previously developed a very brief cognitive battery (Bell et al., 2005). The Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) was developed specifically to provide clinicians with a way to assess cognition in their patients with schizophrenia. Here, we report the results of a validity study comparing B-CATS to a larger neurocognitive battery, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. METHODS: Outpatients with schizophrenia (N=91) were administered the B-CATS and the non-overlapping tests of the MATRICS battery at two time points separated by 1month. They were also administered the UCSD Performance-based Skills Assessment-Brief (UPSA-B), a measure of functional capacity. RESULT: The B-CATS has an administration time of approximately 10min. It demonstrates good test-retest reliability and internal consistency. It correlates 0.76 (p<0.01) with the MATRICS battery. The shorter B CATS and the MATRICS battery correlate with the UPSA-B at 0.50 and 0.58 respectively. CONCLUSION: A 10-minute version of the B-CATS correlates highly with the "gold standard" neurocognitive battery that has an administration time of over 60min. Both measures correlate moderately with a measure of functional capacity. This brief battery was designed to allow clinicians to monitor cognitive change and better inform treatment decisions. PMID- 28918223 TI - An ecological model to factors associated with booster seat use: A population based study. AB - Belt-positioning booster seat use (BPB) is an effective technology to prevent severe child injury in cases of car crash. However, in many countries, age appropriate car restraint use for children aged 4-7 years old remains the lowest among all age groups. The aim of this study was to identify the main determinants of BPB use through a comprehensive approach. An ecological model was used to analyze individual, parent-child relationships, and neighborhood characteristics. Parents of children enrolled in the first and second grades completed a self reported questionnaire (n=745). The data were subjected to multilevel modeling. The first level examined individual and parent-child relationship variables; in addition the second level tested between neighborhood variance. According to parental self- reports, 56.6% of their children had used a BPB on each car trip during the previous month. The results indicated that the determinants positively related to BPB use were individual and parental; namely, the number of children in the family, the parents' car seat belt use, parental knowledge of children's car safety principles, and a highly authoritative parenting style. Children's temperaments and parental supervision were not associated with BPB use. At the neighborhood level, a small difference was found between neighborhoods for BPB users compared to non-users. PMID- 28918222 TI - Vision Assessments and Interventions for Infants 0-2 Years at High Risk for Cerebral Palsy: A Systematic Review. AB - We performed a systematic review and evaluated the level of evidence of vision interventions and assessments for infants at high risk for or with a diagnosis of cerebral palsy from zero to two years of age. Articles were evaluated based on the level of methodologic quality, evidence, and clinical utilization. Thirty publications with vision assessments and five with vision interventions met criteria for inclusion. Assessments included standard care neuroimaging, electrophysiology, and neuro-ophthalmologic examination techniques that are utilized clinically with any preverbal or nonverbal pediatric patient. The overall level of evidence of interventions was strong for neuroprotective interventions such as caffeine and hypothermia but weak for surgery, visual training, or developmental programs. There are few evidence-based interventions and assessments that address cerebral/cortical visual impairment-related needs of infants and toddlers at high risk for or with cerebral palsy. Recommendation guidelines include the use of three types of standard care methodologies and two types of protective interventions. PMID- 28918224 TI - Driving on urban roads: How we come to expect the 'correct' speed. AB - The subjective categories that drivers use to distinguish between different road types have been shown to influence the speeds they choose to drive but as yet we do not understand the road features that drivers use to make their discriminations. To better understand how drivers describe and categorise the roads they drive, 55 participants were recruited to drive a video of familiar urban roads in a driving simulator at the speed they would drive these roads in their own cars (using the accelerator and brake pedal in the driving simulator to adjust their speed). The participants were then asked to sort photos of the roads they had just driven into piles so that their driving would be the same on all roads in one pile but different to the other piles. Finally, they answered a series of questions about each road to indicate what speed they would drive, the safe speed for the road, their speed limit belief as well as providing ratings of comfort, difficulty and familiarity. Overall, drivers' categorisation of roads was informed by a number of factors including speed limit belief, road features and markings (including medians), road width, and presence of houses, driveways and footpaths. The participants' categories were congruent with what they thought the speed limits were, but not necessarily the actual speed limits. Mismatches between actual speed limits and speed limit beliefs appeared to result from category-level expectations about speed limits that took precedence over recent experience in the simulator. Roads that historically had a 50km/h speed limit but had been reduced to 40km/h were still regarded as 50km/h roads by the participants, underscoring the point that simply posting a sign with a lower speed limit is not enough to overcome drivers' expectations and habits associated with the visual appearance of a road. The findings provided insights into how drivers view and categorise roads, and identify specific areas that could be used to improve speed limit credibility. PMID- 28918225 TI - On the relationship between executive functions of working memory and components derived from fluid intelligence measures. AB - The aim of the current study is to provide new insights into the relationship between executive functions and intelligence measures in considering the item position effect observed in intelligence items. Raven's Advanced Progressive Matrices (APM) and Horn's LPS reasoning test were used to assess fluid intelligence which served as criterion in investigating the relationship between intelligence and executive functions. A battery of six experimental tasks measured the updating, shifting, and inhibition processes of executive functions. Data were collected from 205 university students. Fluid intelligence showed substantial correlations with the updating and inhibition processes and no correlation with the shifting process without considering the item-position effect. Next, the fixed-link model was applied to APM and LPS data separately to decompose them into an ability component and an item-position component. The results of relating the components to executive functions showed that the updating and shifting processes mainly contributed to the item-position component whereas the inhibition process was mainly associated with the ability component of each fluid intelligence test. These findings suggest that improvements in the efficiency of updating and shifting processes are likely to occur during the course of completing intelligence measures and inhibition is important for intelligence in general. PMID- 28918226 TI - Chronic central oxytocin infusion impairs sociability in mandarin voles. AB - Oxytocin (OT) has been reported to increase social contact, however some studies have related OT to reduced social contact, particularly with unfamiliar individuals. The underlying mechanisms of OT on social contact remain unclear. In this study, male mandarin vole (Microtus mandarinus), a socially monogamous rodent, was used as an animal model in which osmotic minipumps were used to intracerebroventricularly administer two dosages of OT or saline for 12 consecutive days. We examined the effect of long-term OT treatment on social behavior, anxiety levels, and levels of oxytocin, vasopressin (AVP) and dopamine (DA) receptors mRNA expression in the nucleus accumbens (NAcc), and medial amygdala (MeA). The data showed that chronic central OT infusion decreased social preference behavior (a reduction of preference for interacting with novel social stimulus relative to a novel object) concomitant to a reduction of OT receptors in the NAcc and MeA. We also found alterations in AVP and DA receptor levels in the NAcc and MeA after treatment with OT. Moreover, chronic central OT treatment did not affect levels of anxiety-related behavior in male voles. In conclusion, these results indicated that chronic OT treatment may differ from the treatment effects predicted in short-term studies, and significant dosage effects were observed. PMID- 28918227 TI - Bone Remodeling of the Distal Femur After Uncemented Total Knee Arthroplasty-A 2 Year Prospective DXA Study. AB - Loss of bone stock as a response to the bone trauma, immobilization, and stress shielding related to joint replacement surgery increases the risk of fracture of the distal femur after total knee arthroplasty. Previous studies of uncemented femoral components have reported very high levels of bone loss in the distal femur. This study investigates the adaptive bone remodeling of the distal femur after uncemented total knee arthroplasty. We performed a 2-year follow-up of 53 patients (mean age 61.5 [38-70] years, F/M = 27/26, body mass index 29.5) who because of osteoarthritis received an uncemented total knee arthroplasty. All patients received a NexGen CR-Flex Porous Femoral Component. Measurements of bone mineral density of the distal femur using dual-energy X-ray absorptiometry were performed postoperatively and after 3, 6, 12, and 24 months. Bone mineral density (g/cm2) was measured in 3 regions of interest in the periprosthetic bone of the distal femur. Repeated measures analysis of variance and Tukey post hoc test for bone mineral density changed over time (p < 0.05 were considered significant). In the distal femur, significant changes in bone mineral density were seen after 24 months of follow-up, and bone mineral density decreased by 23.6% in the anterior region behind the anterior flange of the prosthesis (p < 0.001), 10.1% in the posterior region (p < 0.001), and 5.5% in the most proximal region (p < 0.001). We found highly significant bone mineral change in the distal femur after uncemented total knee arthroplasty, most pronounced in the anterior region, where a decrease in bone mineral density of almost 25%, was seen. Taking the expected age-related decay in bone mineral density in this age group into consideration, the decrease was substantial and must be considered to predispose to periprosthetic fractures. PMID- 28918228 TI - Primary photosensitization and contact dermatitis caused by Malachra fasciata Jacq. N.V. (Malvaceae) in sheep. AB - Farmers from Paraiba state, Northeast Brazil, claim that Malachra fasciata causes cutaneous lesions in sheep. To test its toxicity the plant was harvested daily and fed ad libitum for 21 days to 3 sheep as the sole food source (# 1-3). An additional sheep (# 4) was maintained as a control. Cutaneous lesions of photosensitization initiated after 7 days and increased continuously over the next 21 days. The dose ingested varied between 129 g/kg to 175 g/kg. Alopecia, hyperemia and crusting were observed in the animals. On day 22, sheep 3 was euthanized. At necropsy, no gross or microscopic alterations were observed in the liver. Skin biopsies were performed in the remaining animals Histopathology of skin of the three sheep included acanthosis, orthokeratosis, and multifocal infiltration by lymphocytes, eosinophils and plasma cells around blood vessels and appendages in the dermis. The Splendore-Hoeppli phenomenon was observed in the dermis of sheep 2, due probably by contact dermatitis. After the end of administration Sheep 1 and 2 were protected from sunlight and the lesions regressed within two weeks. This experiment indicates that M. fasciata causes primary photosensitization and contact dermatitis in sheep. PMID- 28918229 TI - Design of modified botulinum neurotoxin A1 variants with a shorter persistence of paralysis and duration of action. AB - Botulinum neurotoxins (BoNTs) are classified by their antigenic properties into seven serotypes (A-G) and in addition by their corresponding subtypes. They are further characterized by divergent onset and duration of effect. Injections of low doses of botulinum neurotoxins cause localized muscle paralysis that is beneficial for the treatment of several medical disorders and aesthetic indications. Optimizing the therapeutic properties could offer new treatment opportunities. This report describes a rational design approach to modify the pharmacological properties by mutations in the C-terminus of BoNT/A1 light chain (LC). Toxins with C-terminal modified LC's displayed an altered onset and duration of the paralytic effect in vivo. The level of effect was dependent on the kind of the mutation in the sequence of the C-terminus. A mutant with three mutations (T420E F423M Y426F) revealed a faster onset and a shorter duration than BoNT/A1 wild type (WT). It could be shown that the C-terminus of BoNT/A1-Lc controls both onset and duration of effect. Thus, it is possible to create a mutated BoNT/A1 with different pharmacological properties which might be useful in the therapy of new indications. This strategy opens the way to design BoNT variants with novel and useful properties. PMID- 28918230 TI - Biosensing methods for determination of triglycerides: A review. AB - Triglycerides (TGs) are the major transporters of dietary fats throughout the bloodstream. Besides transporting fat, TGs also act as stored fat in adipose tissue, which is utilized during insufficient carbohydrates supply. TG level is below 150mg/dL in healthy persons. Elevated TGs level in blood over 500mg/dL is a biomarker for cardiovascular diseases, Alzheimer disease, pancreatitis and diabetes. Numerous methods are accessible for recognition of TGs, among them, most are cumbersome, time-consuming, require sample pre-treatment, high cost instrumental set-up and experienced personnel to operate. Biosensing approach overcomes these disadvantages, as these are highly specific, fast, easy, cost effective, and highly sensitive. This review article describes the classification, operating principles, merits and demerits of TG biosensors, specifically nanomaterials based biosensors. TG biosensors work ideally within 2.5-2700s, in pH range, 6.0-11.0, temperature 25-39.5 degrees C and TG concentration range, 0.001-100mM, the detection limits being in the range, 0.1nM to 0.56mM, with working potential - 0.02 to 1.2V. These biosensors measured TG level in fruit juices, beverages, sera and urine samples and reused upto 200 times over a period of 7-240 days, while stored dry at 4 degrees C. Future perspective for further improvement and commercialization of TG biosensors are discussed. PMID- 28918231 TI - Highly sensitive surface plasmon resonance biosensor for the detection of HIV related DNA based on dynamic and structural DNA nanodevices. AB - Early detection, diagnosis and treatment of human immune deficiency virus (HIV) infection is the key to reduce acquired immunodeficiency syndrome (AIDS) mortality. In our research, an innovative surface plasmon resonance (SPR) biosensing strategy has been developed for highly sensitive detection of HIV related DNA based on entropy-driven strand displacement reactions (ESDRs) and double-layer DNA tetrahedrons (DDTs). ESDRs as enzyme-free and label-free signal amplification circuit can be specifically triggered by target DNA, leading to the cyclic utilization of target DNA and the formation of plentiful double-stranded DNA (dsDNA) products. Subsequently, the dsDNA products bind to the immobilized hairpin capture probes and further combine with DDTs nanostructures. Due to the high efficiency of ESDRs and large molecular weight of DDTs, the SPR response signal was enhanced dramatically. The proposed SPR biosensor could detect target DNA sensitively and specifically in a linear range from 1pM to 150nM with a detection limit of 48fM. In addition, the whole detecting process can be accomplished in 60min with high accuracy and duplicability. In particular, the developed SPR biosensor was successfully used to analyze target DNA in complex biological sample, indicating that the developed strategy is promising for rapid and early clinical diagnosis of HIV infection. PMID- 28918232 TI - Childhood maltreatment and adolescent sexual risk behaviors: Unique, cumulative and interactive effects. AB - Child maltreatment has been associated with sexual risk behaviors. Previous investigators have typically studied only one form of maltreatment, preventing them from exploring interrelations between forms of maltreatment and their impact on sexual risk behaviors. Thus, this study aims to examine the unique, cumulative, and interactive effects of four maltreatment forms (sexual abuse, physical abuse, neglect, and witnessing interparental violence) on sexual risk behaviors. The sample comprised 1940 sexually active adolescents (Mage=15.6; 60.8% girls) attending Quebec (Canada) high schools. Regression results showed that all maltreatment forms were associated with having a higher number of sexual partners, casual sexual behavior, and a younger age at first consensual intercourse. Physical abuse and witnessing interparental violence were associated with inconsistent condom use, and physical abuse was associated with sexually transmitted infections. After controlling for all forms of maltreatment (unique effects), analyses showed that sexual abuse, physical abuse, neglect or witnessing interparental violence remained statistically associated depending on the sexual risk behavior. A greater number of forms of maltreatment was associated with more sexual risk behaviors (cumulative effect). When sexual abuse was not experienced, neglect was associated with a higher number of sexual partners (interactive effects). In general, associations between maltreatment and sexual risk behaviors were similar for both genders. The magnitude of the relationship between a specific form of child maltreatment and sexual risk behaviors may be inaccurately estimated when not controlling for other forms of maltreatment. PMID- 28918233 TI - The role of callous/unemotional traits in mediating the association between animal abuse exposure and behavior problems among children exposed to intimate partner violence. AB - Children exposed to intimate partner violence are at increased risk for concomitant exposure to maltreatment of companion animals. There is emerging evidence that childhood exposure to maltreatment of companion animals is associated with psychopathology in childhood and adulthood. However, few studies have explored developmental factors that might help to explain pathways from animal maltreatment exposure to children's maladjustment. The present study addresses this gap in the literature by examining relations between children's exposure to animal maltreatment, callous/unemotional traits (i.e., callousness, uncaring traits, and unemotional traits), and externalizing and internalizing behavior problems. A sample of 291 ethnically diverse children (55% Latino or Hispanic) between the ages of 7 and 12 was recruited from community-based domestic violence services. A meditational path model indicated that child exposure to animal maltreatment was associated with callousness (beta=0.14), which in turn was associated with greater internalizing (beta=0.32) and externalizing problems (beta=0.47). The effect of animal maltreatment exposure on externalizing problems was mediated through callousness. Results suggest that callous/unemotional traits are a potential mechanism through which childhood exposure to animal maltreatment influences subsequent behavior problems. Future research is needed to evaluate the extent to which exposure to animal maltreatment affects children's adjustment over time in the context of other co occurring adverse childhood experiences. PMID- 28918234 TI - A fatal review: Exploring how children's deaths are reported in the United States. AB - Child death reports are the leading data source used to orchestrate child fatality prevention policy. Therefore, the way in which child death is reported is crucial to how we sustain life. We sought to assess the systematic ways in which death is reported for children. Based on a qualitative analysis of medico legal investigation reports collected from a medical examiner's office and a coroner's office, we examined several indicators of data completeness, quality, site organizational structure, and consistency. We found stark differences between the two sites, as well as issues regarding death diagnosis certainty, and a general lack in consistency in the reports' content, as well as procedures performed post-mortem. We conclude that there are some flaws in our death reporting system for child populations, which have the potential to hinder reliability and accuracy of these death reports, as well as thwart their overall usefulness in prevention policies. PMID- 28918235 TI - Identification of bluetongue virus serotypes 1, 4, and 17 co-infections in sheep flocks during outbreaks in Brazil. AB - Bluetongue (BT) is a vector-borne viral disease caused by the Bluetongue virus (BTV), an Orbivirus from the Reoviridae family, affecting domestic and wild ruminants. BTV circulation in Brazil was first reported in 1978, and several serological surveys indicate that the virus is widespread, although with varied prevalence. In 2014, BT outbreaks affected sheep flocks in Rio Grande do Sul state, causing significant mortality (18.4%; 91/495) in BTV-infected sheep. In total, seven farms were monitored, and one or two sheep from each farm that died due to clinical signs of BT were necropsied. Apathy, pyrexia, anorexia, tachycardia, respiratory, and digestive disorders were noted. Additionally, an abortion was recorded in one of the monitored farms. The main gross lesions observed were pulmonary edema, anterior-ventral pulmonary consolidation, muscular necrosis in the esophagus and in the ventral serratus muscle, and hemorrhagic lesions in the heart. The blood and tissue samples were tested for BTV RNA detection by RT-qPCR targeting the segment 10. Positive samples were used for viral isolation. The isolated BTVs were typed by conventional RT-PCR targeting the segment 2 of the 26 BTV serotypes, followed by sequencing analysis. BTV-1, BTV-4 and BTV-17 were identified in the analyzed samples. Double or triple BTV co infections with these serotypes were detected. We report the occurrence of BT outbreaks related to BTV-1, BTV-4 and BTV-17 infections and co-infections causing clinical signs in sheep flocks in Southern Brazil, with significant mortality and lethality rates. PMID- 28918236 TI - Gene expression profiles of cell adhesion molecules, matrix metalloproteinases and their tissue inhibitors in canine oral tumors. AB - Perturbation of cell adhesion can be essential for tumor cell invasion and metastasis, but the current knowledge on the gene expression of molecules that mediate cell adhesion in canine oral tumors is limited. The present study aimed to investigate changes in the gene expression of cell adhesion molecules (E cadherin or CDH1, syndecan 1 or SDC1, NECTIN2 and NECTIN4), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), in canine oral tumors, including benign tumors, oral melanoma (OM) and non-tonsillar oral squamous cell carcinoma (OSCC), by quantitative real-time reverse transcription PCR. When compared with the normal gingival controls, decreased CDH1, SDC1 and NECTIN4 expression levels were observed in OSCC and OM, reflecting a possible role as cell adhesion molecules and tumor suppressors in canine oral cancers in contrast to the upregulation of MMP2 expression. Downregulated MMP7 was specifically revealed in the OM group. In the late-stage OM, the positive correlation of MMP7 and CDH1 expression was noticed as well as that of SDC1 and NECTIN4. Enhanced TIMP1 expression was shown in all tumor groups with prominent expression in the benign tumors and the early-stage OM. MMP14 expression was notable in the early-stage OM. Higher MMP9 and TIMP1 expression was observed in the acanthomatous ameloblastoma. In conclusion, this study revealed that the altered expression of cell adhesion molecules, MMP7 and MMP2 was correlated with clinicopathologic features in canine oral cancers whereas TIMP1 and MMP14 expression was probably associated with early-stage tumors; therefore, these genes might serve as molecular markers for canine oral tumors. PMID- 28918237 TI - Preface to the special issue on Gaucher disease 2017. PMID- 28918238 TI - Recent advances and future challenges in Gaucher disease. PMID- 28918240 TI - Contingency management treatment in cocaine using methadone maintained patients with and without legal problems. AB - BACKGROUND: Legal difficulties and cocaine use are prevalent in methadone maintenance patients, and they are related to one another, as well as to poor response to methadone treatment. Contingency management (CM) is efficacious for decreasing cocaine use, but the relation of CM treatment to criminal activities has rarely been studied. METHODS: This study evaluated whether baseline legal problems are related to subsequent substance use and illegal activities for cocaine using methadone maintained patients and whether CM differentially improves outcomes depending on baseline legal problems. Using data from four randomized CM trials (N=323), we compared methadone maintained patients with legal problems at the start of study participation to those without initial legal problems. RESULTS: Overall, the addition of CM to standard methadone care improved substance use outcomes regardless of initial legal problems. Endorsement of legal problems within 30days of study initiation was associated with reduced proportion of negative samples submitted during the 12-week treatment period. A significant interaction effect of baseline legal problems and treatment condition was present for subsequent self-reports of illegal activities. Those with baseline legal problems who were assigned to CM had reduced self-reports of reengagement in illegal activity throughout a six month follow-up compared to their counterparts randomized to standard care. CONCLUSIONS: Adding CM to methadone treatment improves substance use outcomes and reduces subsequent illegal activity in cocaine-using methadone patients with legal problems. PMID- 28918239 TI - Cigarette smoking quit rates among adults with and without alcohol use disorders and heavy alcohol use, 2002-2015: A representative sample of the United States population. AB - BACKGROUND: While the overall smoking quit rate has increased over time, it is not known whether the quit rate has also increased among persons with alcohol use disorders (AUDs) or heavy alcohol use (HAU). The current study examined quit rates among adults with and without AUDs and HAU over a 12-year period in a representative sample of US adults. METHODS: Data were drawn from the National Household Survey on Drug Use, an annual cross-sectional study of US persons. Quit rate (i.e., the rate of former smokers to ever smokers) was calculated annually from 2002 to 2014 (for HAU) and 2015 (for AUD). Time trends in quit rates by AUD/HAU status were tested using linear regression. RESULTS: The prevalence of past-month cigarette smoking was much higher for persons with, compared to without, AUDs (38% vs. 18%) and HAU (49% vs. 19%). In the most recent data year, the quit rate for persons with AUDs was approximately half that of persons without AUDs (26% versus 49%) and for persons with HAU was less than half that of persons without HAU (22% versus 48%). Over time, the smoking quit rate increased for persons with and without AUDs/HAU and the rate of increase was greater for persons with AUDs/HAU. Yet, quit rates for persons with AUDs and HAU remained much lower than persons without AUDs and HAU. CONCLUSIONS: It may be beneficial for public health and clinical efforts to incorporate screenings and treatment for tobacco use into programs for adults with AUDs and HAU. PMID- 28918242 TI - Predictive value of Thomsen-Friedenreich antigen activation for Streptococcus pneumoniae infection and severity in pediatric lobar pneumonia. AB - BACKGROUND: Most cases of complicated pneumonia in children are caused by pneumococcal infections. Thomsen-Friedenreich antigen (TA) is present on erythrocytes, platelets and glomeruli, and it can be activated during pneumococcal infection. The aim of this study was to investigate the predictive value of TA activation for pneumococcal infection and association with the severity of complicated pneumonia. MATERIALS AND METHODS: Patients with lobar pneumonia were routinely tested for TA at the Department of Pediatrics, Mackay Memorial Hospital from January 2010 to December 2015. We retrospectively reviewed and analyzed their charts and data including age, sex, etiology of infection, chest tube insertion or video-assisted thoracoscopic surgery, length of hospital stay, TA activation, white blood cell count and level of C reactive protein. RESULTS: A total of 142 children with lobar pneumonia were enrolled, including 35 with empyema, 31 with effusion, 11 with necrotizing pneumonia and four with lung abscess. Streptococcus pneumoniae was the most commonly identified pathogen. Twenty-two patients (15.4%) had activated TA, all of whom were infected with S. pneumoniae. TA activation had 100% specificity and 100% positive predictive value for pneumococcal infection. In the multivariate analysis in lobar pneumonia, TA activation (OR, 15.8; 95% CI, 3.0-83.5; p = 0.001), duration of fever before admission (OR, 1.2; 95% CI, 1.1-1.5; p = 0.013) and initial CRP level (OR, 1.1; 95% CI, 1.0-1.1; p = 0.004) were independent predictors of empyema. CONCLUSIONS: TA activation is a specific marker for pneumococcal pneumonia and might indicate higher risk for complicated pneumonia. PMID- 28918241 TI - Stigma experienced by patients with severe mental disorders: A nationwide multicentric study from India. AB - This study aimed to evaluate the stigma and its correlates among patients with severe mental disorders. Patients with diagnosis of schizophrenia (N = 707), bipolar disorder (N = 344) and recurrent depressive disorder (N = 352) currently in clinical remission from 14 participating centres were assessed on Internalized Stigma of Mental Illness Scale (ISMIS). Patients with diagnosis of schizophrenia experienced higher level of alienation, sterotype endorsement, discrimination experience and total stigma when compared to patients with bipolar disorder and recurrent depressive disorder. Patients with bipolar disorder experienced higher stigma than those with recurrent depressive disorder in the domain of stigma resistance only. Overall compared to affective disorder groups, higher proportion of patients with schizophrenia reported stigma in all the domains of ISMIS. In general in all the 3 diagnostic groups' stigma was associated with shorter duration of illness, shorter duration of treatment and younger age of onset. To conclude, this study suggests that compared to affective disorder, patients with schizophrenia experience higher self stigma. Higher level of stigma is experienced during the early phase of illness. Stigma intervention programs must focus on patients during the initial phase of illness in order to reduce the negative consequences of stigma. PMID- 28918244 TI - Determinants and Regulation of Protein Turnover in Yeast. AB - Protein turnover maintains the recycling needs of the proteome, and its malfunction has been linked to aging and age-related diseases. However, not all proteins turnover equally, and the factors that contribute to accelerate or slow down turnover are mostly unknown. We measured turnover rates for 3,160 proteins in exponentially growing yeast and analyzed their dependence on physical, functional, and genetic properties. We found that functional characteristics, including protein localization, complex membership, and connectivity, have greater effect on turnover than sequence elements. We also found that protein turnover and mRNA turnover are correlated. Analysis under nutrient perturbation and osmotic stress revealed that protein turnover highly depends on cellular state and is faster when proteins are being actively used. Finally, stress induced changes in protein and transcript abundance correlated with changes in protein turnover. This study provides a resource of protein turnover rates and principles to understand the recycling needs of the proteome under basal conditions and perturbation. PMID- 28918243 TI - Homeostatic systems, biocybernetics, and autonomic neuroscience. AB - In this review we describe a series of major concepts introduced during the past 150years that have contributed to our current understanding about how physiological processes required for well-being and survival are regulated. One can theorize that hierarchical networks involving input-output relationships continuously orchestrate and learn adaptive patterns of observable behaviors, cognition, memory, mood, and autonomic systems. Taken together, these networks function as "good regulators" determining levels of internal variables and act as if there were homeostatic comparators ("homeostats"). The consequences of models with vs. without homeostats remain the same in terms of allostatic load and the eventual switch from stabilizing negative feedback loops to destabilizing, pathogenic positive feedback loops. Understanding this switch seems important for comprehending senescence-related, neurodegenerative disorders that involve the autonomic nervous system. Our general proposal is that disintegration of homeostatic systems causes disorders of regulation in degenerative diseases and that medical cybernetics can inspire and rationalize new approaches to treatment and prevention. PMID- 28918245 TI - Biodiesel production from lipid of carbon dioxide sequestrating bacterium and lipase of psychrotolerant Pseudomonas sp. ISTPL3 immobilized on biochar. AB - An extracellular lipase was purified and characterized from psychrotolerant bacterium Pseudomonas sp. ISTPL3 isolated from Pangong lake. Lipase was purified by sequential methods of ammonium sulphate precipitation, dialysis, DEAE cellulose ion exchange chromatography and Sephadex G-100 gel filtration chromatography, resulting in a purification fold of 6.53 and yield of 5.45%. The molecular weight was approximately 31kDa. The purified lipase was used for transesterification of lipids produced by oleaginous chemolithotrophic bacterium Serratia sp. ISTD04 for production of biodiesel. Upon biochemical characterization, lipase was found to be alkalophilc, thermostable, active in organic polar solvents and sensitive to detergents. Further, lipase was immobilized on activated biochar to assess its transesterification efficiency during biodiesel production. Immobilized lipase gave the highest yield of fatty acid methyl esters (FAMEs) (92.23%)>unimmobilized lipase>NaOH. The immobilized lipase was assessed for its reusability and retained 75.11% of its activity after 3 cycles of biodiesel production. PMID- 28918246 TI - Synthesis of novel magnesium ferrite (MgFe2O4)/biochar magnetic composites and its adsorption behavior for phosphate in aqueous solutions. AB - In this work, magnesium ferrite (MgFe2O4)/biochar magnetic composites (MFB-MCs) were prepared and utilized to remove phosphate from aqueous solutions. MFB-MCs were synthesized via co-precipitation of Fe and Mg ions onto a precursor, followed by pyrolysis. Characterization results confirmed that MgFe2O4 nanoparticles with a cubic spinel structure were successfully embedded in the biochar matrix, and this offered magnetic separability with superparamagnetic behavior and enabled higher phosphate adsorption performance than that of pristine biochar and sole MgFe2O4 nanoparticles. Batch experiments indicated that phosphate adsorption on the MFB-MCs is highly dependent on the pH, initial phosphate concentration, and temperature, while it was less affected by ionic strength. Analysis of activation and thermodynamic parameters as well as the isosteric heat of adsorption demonstrated that the phosphate adsorption is an endothermic and physisorption process. Lastly, highly efficient recyclability of the MFB-MCs suggested that they are a promising adsorbent for phosphate removal from wastewater. PMID- 28918247 TI - Erato polymnioides - A novel Hg hyperaccumulator plant in ecuadorian rainforest acid soils with potential of microbe-associated phytoremediation. AB - Mercury (Hg) accumulation capacity was assessed in three plant species (Axonopus compressus, Erato polymnioides, and Miconia zamorensis) that grow on soils polluted by artisanal small-scale gold mines in the Ecuadorian rainforest. Individuals of three species were collected at two sampling zones: i) an intensive zone (IZ, 4.8 mg Hg kg-1 of soil) where gold extraction continues to occur, and ii) a natural zone (NZ, 0.19 mg Hg kg-1 of soil). In addition, the percentage of arbuscular mycorrhizal fungi (AMF) colonization was determined in plant roots and seven fungal morphotypes isolated from rhizospheric soil. Results suggest a facilitation role of native and pollution adapted AMF on Hg phytoaccumulation. E.g., E. polymnioides increased Hg accumulation when growing with greater AMF colonization. We concluded that E. polymnioides is a good candidate for the design of microbe-assisted strategies for Hg remediation at gold mining areas. The consortia between E. polymnioides and the AMF isolated in this study could be instrumental to get a deeper understanding of the AMF role in Hg phytoaccumulation. PMID- 28918248 TI - Total nitrogen removal, products and molecular characteristics of 14 N-containing compounds in supercritical water oxidation. AB - Supercritical water oxidation (SCWO) process of 14 N-containing compounds was investigated with residence time of 150 s, at a stable pressure of 24 MPa, temperatures of 350-500 degrees C and 500% excess oxygen, resulted in total nitrogen (TN) removal from 41 to 96%. The products of N-containing species were mainly N2, nitrate, ammonium, as well as hardly nitrite or NOX. The yield distributions of nitrate and ammonium were different: the main nitrate concentrations were obtained from the compounds containing nitro-group and diazonium, like nitrobenzene, 2-nitrophenol and eriochrome blue black R (EBBR); the predominant ammonium yields were achieved from amino-group and N-heterocyclic compounds, such as aniline, 5-chloro-2-methylaniline, 3,4-dichloroaniline, 1 methylimidazole, 1,10-phenanthroline, cyanuric acid, indole and 2,3 indolinedione. It is interesting that 2-nitroaniline, possessing both nitro- and amino-group, would dominantly decompose into N2. To explore the relationship between TN removal and molecular structural characteristics, density functional theory (DFT) method was used to calculate molecular descriptors of all 14 N containing compounds. The correlation results showed that among all the fifteen molecular descriptors, q(C)-, q(C-H)+ and F(0)x greatly affects temperature behavior of TN removal. PMID- 28918249 TI - Perinatal depression and DNA methylation of oxytocin-related genes: a study of mothers and their children. AB - The present study investigated the association of perinatal depression (PD) with differential methylation of 3 genomic regions among mother and child dyads: exon 3 within the oxytocin receptor (OXTR) gene and 2 intergenic regions (IGR) between the oxytocin (OXT) and vasopressin (AVP) genes. Maternal PD was assessed at 5 time-points during pregnancy and postpartum. Four groups were established based on Edinburgh Postnatal Depression Scale (EPDS) cut-off scores: no PD, prenatal or postpartum depressive symptoms only and persistent PD (depressive symptoms both prenatally and postpartum). Salivary DNA was collected from mothers and children at the final time-point, 2.9years postpartum. Mothers with persistent PD had significantly higher overall OXTR methylation than the other groups and this pattern extended to 16/22 individual CpG sites. For the IGR, only the region closer to the AVP gene (AVP IGR) showed significant differential methylation, with the persistent PD group displaying the lowest levels of methylation overall, but not for individual CpG sites. These results suggest that transient episodes of depression may not be associated with OXTR hypermethylation. Validation studies need to confirm the downstream biological effects of AVP IGR hypomethylation as it relates to persistent PD. Differential methylation of the OXTR and IGR regions was not observed among children exposed to maternal PD. The consequences of OXTR hypermethylation and AVP IGR hypomethylation found in mothers with persistent PDS may not only impact the OXT system, but may also compromise maternal behavior, potentially resulting in negative outcomes for the developing child. PMID- 28918250 TI - Associations of cholesteryl ester transfer protein (CETP) gene variants with predisposition to age-related macular degeneration. AB - PURPOSE: To determine the frequency of the genotypes of single nucleotide polymorphisms (SNPs) in the gene encoding cholesteryl ester transfer protein (CETP) and their associations with age-related macular degeneration (AMD) in the Lithuanian population. STUDY DESIGN: A total of 1264 subjects were examined: 251 patients with early AMD, 206 patients with exudative AMD, and 807 healthy controls. METHODS: The genotyping of CETP (rs5882, rs708272, rs3764261, rs1800775, rs2303790) was carried out using the RT-PCR. RESULTS: Binomial logistic regression analysis revealed that each copy of rs5882 allele A was associated with a 1.3-fold increased risk of exudative AMD (p=0.046). The G/A and A/A genotypes of the rs708272 polymorphism were associated with 1.5-fold and 1.7 fold increased risks of exudative AMD (p=0.049 and p=0.021, respectively). Combination of two genotypes (G/A+A/A) under the dominant model were associated with a 1.5-fold increased risk of exudative AMD (p=0.021). Analysis of rs708272 revealed that the G/A and A/A genotypes under the co-dominant model were associated with 1.5-fold and 1.7-fold increased risks of exudative AMD, respectively (OR=1.450, 95% CI=1.002-2.098; p=0.049 and OR=1.710, 95% CI=1.064 2.156; p=0.021, respectively). Both genotypes (G/A+A/A) under the dominant model were associated with the 1.5-fold increased risk of exudative AMD, as well (OR=1.514, 95% CI=1.064-2.156; p=0.021) and each additional copy A allele was associated with a 1.3-fold increased risk of exudative AMD (OR=1.316, 95% CI=1.051-1.646; p=0.016). The rs3764261 polymorphism was identified to be protective: the C/A genotype and the combination of two genotypes (C/A+A/A) were associated with 1.8-fold and 1.5-fold decreased risks of exudative AMD (p=0.001 and p=0.015, respectively). CONCLUSION: Our study identified two polymorphisms with a higher risk of AMD development (rs5882 and rs708272) and a protective polymorphism for AMD (rs3764261). PMID- 28918251 TI - HMG-box factor SoxD/Sox15 and homeodomain-containing factor Xanf1/Hesx1 directly interact and regulate the expression of Xanf1/Hesx1 during early forebrain development in Xenopus laevis. AB - The homeodomain-containing transcription factor Anf (also known as Rpx/Hesx1 in mammals) plays an important role during the forebrain development in vertebrates. Here we demonstrate the ability of the Xenopus laevis Anf, Xanf1/Hesx1, to directly bind SRY-related HMG-box-containing transcription factor SoxD/Sox15 and to cooperate with the latter during regulating of the expression of Xanf1/Hesx1 own gene. As we have shown by GST pull-down, EMSA and the luciferase reporter assays, Xanf1/Hesx1 and SoxD/Sox15 bind the Xanf1/Hesx1 promoter region counteracting the inhibitory effect of Xanf1/Hesx1 alone. This finding explains how Xanf1/Hesx1 could escape the repressive activity of its own protein during early patterning of the forebrain rudiment. PMID- 28918252 TI - A PDGF/VEGF homologue provides new insights into the nucleus grafting operation and immune response in the pearl oyster Pinctada fucata. AB - The platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF, PVF) family of proteins have been implicated in a wide range of biological functions in vertebrates, including cell proliferation, cell differentiation, cell migration, neural development and especially angiogenesis/vasculogenesis. In this study, a PVF gene, belonging to the PDGF/VEGF family, was cloned and characterized from Pinctada fucata. It contained an ORF of 1110bp encoding a putative protein of 369 amino acids. The deduced amino acid sequence presented the typical structural features of PDGF family members and the N-terminal signal peptide for secretion. Comparative phylogenetic analysis revealed that PfPVF shows relatively high identity with other invertebrate PVF homologues. Furthermore, gene expression analysis revealed that PfPVF is involved in not only the nucleus grafting operation and but also the response to immune stimulation. The study may help to increase understanding of the functions of molluscan PVF. PMID- 28918253 TI - Deep brain stimulation of the medial forebrain bundle elevates striatal dopamine concentration without affecting spontaneous or reward-induced phasic release. AB - Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) induces rapid improvement of depressive symptoms in patients suffering from treatment refractory major depressive disorder (MDD). It has been hypothesized that activation of the dopamine (DA) system contributes to this effect. To investigate whether DBS in the MFB affects DA release in the striatum, we combined DBS with fast-scan cyclic voltammetry (FSCV) in freely moving rats. Animals were implanted with a stimulating electrode at the border of the MFB and the ventral tegmental area, and a FSCV microelectrode in the ventromedial striatum to monitor extracellular DA during the acute onset of DBS and subsequent continued stimulation. DBS onset induced a significant increase in extracellular DA concentration in the ventromedial striatum that was sustained for at least 40s. However, continued DBS did not affect amplitude or frequency of so-called spontaneous phasic DA transients, nor phasic DA release in response to the delivery of unexpected food pellets. These findings suggest that effects of DBS in the MFB are mediated by an acute change in extracellular DA concentration, but more research is needed to further explore the potentially sustained duration of this effect. Together, our results provide both support and refinement of the hypothesis that MFB DBS activates the DA system: DBS induces an increase in overall ambient concentration of DA, but spontaneous or reward-associated more rapid, phasic DA dynamics are not enhanced. This knowledge improves our understanding of how DBS affects brain function and may help improve future therapies for depressive symptoms. PMID- 28918254 TI - Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration. AB - Neuroprotection is an unmet need in eye disorders characterized by retinal ganglion cell (RGC) death, such as prematurity-induced retinal degeneration, glaucoma, and age-related macular degeneration. In all these disorders excitotoxicity is a prominent component of neuronal damage, but clinical data discourage the development of NMDA receptor antagonists as neuroprotectants. Here, we show that activation of mGlu1 metabotropic glutamate receptors largely contributes to excitotoxic degeneration of RGCs. Mice at postnatal day 9 were challenged with a toxic dose of monosodium glutamate (MSG, 3g/kg), which caused the death of >70% of Brn-3a+ RGCs. Systemic administration of the mGlu1 receptor negative allosteric modulator (NAM), JNJ16259685 (2.5mg/kg, s.c.), was largely protective against MSG-induced RGC death. This treatment did not cause changes in motor behavior in the pups. We also injected MSG to crv4 mice, which lack mGlu1 receptors because of a recessive mutation of the gene encoding the mGlu1 receptor. MSG did not cause retinal degeneration in crv4 mice, whereas it retained its toxic activity in their wild-type littermates. These findings demonstrate that mGlu1 receptors play a key role in excitotoxic degeneration of RGCs, and encourage the study of mGlu1 receptor NAMs in models of retinal neurodegeneration. PMID- 28918255 TI - Microglia-mediated BAFF-BAFFR ligation promotes neuronal survival in brain ischemia injury. AB - The innate immune responses of brain to vascular occlusion are primarily orchestrated by activated microglia. However, the roles of microglia in inflammatory responses to brain ischemic injuries are controversial. Here, we report a new mechanism by which microglia confer protective effects on ischemic neuronal cells. We found that under ischemic condition, the B-cell-activating factor (BAFF) was vastly upregulated in microglia and this upregulation could at least be attributed to JAK-STAT signaling pathway activated by IFN-gamma and IL 10, which were spatio-temporally enriched in I/R-injured brain as well. Meanwhile, the expression of BAFFR, one member of BAFF receptors, was also upregulated on neurons after I/R injury. More importantly, recombinant BAFF treatment not only promoted neuronal survival under ischemic stresses in vitro but also attenuated infarct volume and neural deficit caused by middle cerebral artery occlusion (MCAO) in vivo. Furthermore, blocking BAFF-BAFFR ligation with TACI-Ig abrogated these therapeutic benefits. Taken together, these results indicate that the BAFF-BAFFR ligation bridged between microglia and neurons could play a critical neuroprotective role in I/R injury. Thus, augmenting BAFF-BAFFR signaling might represent a potential target for clinical stroke therapy. PMID- 28918256 TI - Transgene is specifically and functionally expressed in retinal inhibitory interneurons in the VGAT-ChR2-EYFP mouse. AB - Ectopic transgene expression in the retina has been reported in various transgenic mice, indicating the importance of characterizing retinal phenotypes. We examined transgene expression in the VGAT-ChR2-EYFP mouse retina by fluorescent immunohistochemistry and electrophysiology, with special emphasis on enhanced yellow fluorescent protein (EYFP) localization in retinal neuronal subtypes identified by specific markers. Strong EYFP signals were detected in both the inner and outer plexiform layers. In addition, the ChR2-EYFP fusion protein was also expressed in somata of the great majority of inhibitory interneurons, including horizontal cells and GABAergic and glycinergic amacrine cells. However, a small population of amacrine cells residing in the ganglion cell layer were not labeled by EYFP, and a part of them were cholinergic ones. In contrast, no EYFP signal was detected in the somata of retinal excitatory neurons: photoreceptors, bipolar and ganglion cells, as well as Muller glial cells. When glutamatergic transmission was blocked, bright blue light stimulation elicited inward photocurrents from amacrine cells, as well as post-synaptic inhibitory currents from ganglion cells, suggesting a functional ChR2 expression. The VGAT-ChR2-EYFP mouse therefore could be a useful animal model for dissecting retinal microcircuits when targeted labeling and/or optogenetic manipulation of retinal inhibitory neurons are required. PMID- 28918257 TI - Pathways of the inferior frontal occipital fasciculus in overt speech and reading. AB - In this study, we examined the relationship between tractography-based measures of white matter integrity (ex. fractional anisotropy [FA]) from diffusion tensor imaging (DTI) and five reading-related tasks, including rapid automatized naming (RAN) of letters, digits, and objects, and reading of real words and nonwords. Twenty university students with no reported history of reading difficulties were tested on all five tasks and their performance was correlated with diffusion measures extracted through DTI tractography. A secondary analysis using whole brain Tract-Based Spatial Statistics (TBSS) was also used to find clusters showing significant negative correlations between reaction time and FA. Results showed a significant relationship between the left inferior fronto-occipital fasciculus FA and performance on the RAN of objects task, as well as a strong relationship to nonword reading, which suggests a role for this tract in slower, non-automatic and/or resource-demanding speech tasks. There were no significant relationships between FA and the faster, more automatic speech tasks (RAN of letters and digits, and real word reading). These findings provide evidence for the role of the inferior fronto-occipital fasciculus in tasks that are highly demanding of orthography-phonology translation (e.g., nonword reading) and semantic processing (e.g., RAN object). This demonstrates the importance of the inferior fronto-occipital fasciculus in basic naming and suggests that this tract may be a sensitive predictor of rapid naming performance within the typical population. We discuss the findings in the context of current models of reading and speech production to further characterize the white matter pathways associated with basic reading processes. PMID- 28918258 TI - Olfactory function in an excitotoxic model for secondary neuronal degeneration: Role of dopaminergic interneurons. AB - Secondary neuronal degeneration (SND) occurring in Traumatic brain injury (TBI) consists in downstream destructive events affecting cells that were not or only marginally affected by the initial wound, further increasing the effects of the primary injury. Glutamate excitotoxicity is hypothesized to play an important role in SND. TBI is a common cause of olfactory dysfunction that may be spontaneous and partially recovered. The role of the glutamate excitotoxicity in the TBI-induced olfactory dysfunction is still unknown. We investigated the effects of excitotoxicity induced by bilateral N-Methyl-D-Aspartate (NMDA) OB administration in the olfactory function, OB volumes, and subventricular zone (SVZ) and OB neurogenesis in rats. NMDA OB administration induced a decrease in the number of correct choices in the olfactory discrimination tests one week after lesions (p<0.01), and a spontaneous recovery of the olfactory deficit two weeks after lesions (p<0.05). A lack of correlation between OB volumes and olfactory function was observed. An increase in SVZ neurogenesis (Ki67+ cells, PSANCAM+ cells (p<0.01) associated with an increase in OB glomerular dopaminergic immunostaining (p<0.05) were related to olfactory function recovery. The present results show that changes in OB volumes cannot explain the recovery of the olfactory function and suggest a relevant role for dopaminergic OB interneurons in the pathophysiology of recovery of loss of smell in TBI. PMID- 28918259 TI - Disrupted structural and functional connectivity networks in ischemic stroke patients. AB - Local lesions caused by stroke may result in extensive structural and functional reorganization in the brain. Previous studies of this phenomenon have focused on specific brain networks. Here, we aimed to discover abnormalities in whole-brain networks and to explore the decoupling between structural and functional connectivity in patients with stroke. Fifteen ischemic stroke patients and 23 normal controls (NCs) were recruited in this study. A graph theoretical analysis was employed to investigate the abnormal topological properties of structural and functional brain networks in patients with stroke. Both patients with stroke and NCs exhibited small-world organization in brain networks. However, compared to NCs, patients with stroke exhibited abnormal global properties characterized by a higher characteristic path length and lower global efficiency. Furthermore, patients with stroke showed altered nodal characteristics, primarily in certain motor- and cognition-related regions. Positive correlations between the nodal degree of the inferior parietal lobule and the Fugl-Meyer Assessment (FMA) score and between the nodal betweenness centrality of the posterior cingulate gyrus (PCG) and immediate recall were observed in patients with stroke. Most importantly, the strength of the structural-functional connectivity network coupling was decreased, and the coupling degree was related to the FMA score of patients, suggesting that decoupling may provide a novel biomarker for the assessment of motor impairment in patients with stroke. Thus, the topological organization of brain networks is altered in patients with stroke, and our results provide insights into the structural and functional organization of the brain after stroke from the viewpoint of network topology. PMID- 28918261 TI - Rat motor neurons caudal to a rubrospinal tract (RST) transection remain viable. AB - In the rat, the rubrospinal tract (RST) is a descending motor pathway involved in the production of skilled reaching movement. The RST originates in the red nucleus in the midbrain and runs down the spinal cord in the lateral most aspect of the dorsolateral funiculus (DLF). The RST makes monosynaptic contact with interneurons within the intermediate laminae of the cord, however a contingent of RST axons constitutes direct supraspinal input for spinal cord motor neurons. The current study investigated the effects of unilateral RST transection at cervical levels C3-4 on the population of motor neurons in both spinal segments C5-6 and L2-3. The total number of large, medium and small motor neurons in these segments was estimated with stereological techniques in both ventral horns at 1, 3, 7 and 14days post-injury. In both spinal cord segments under investigation, no change was detected in mean number of motor neurons over time, in either ventral horn. That the loss of direct supraspinal input resulting from the RST transection does not affect the viability of motor neurons caudal to the injury indicates that these neurons have the potential to be re-innervated, should the RST injury be repaired. PMID- 28918263 TI - DNA nanotechnology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy. AB - Success of tumor photothermal immunotherapy requires a system that induces heat stress in cancer cells and enhances strong anti-tumor immune responses. Here, we designed a composite-type immunostimulatory DNA hydrogel consisting of a hexapod like structured DNA (hexapodna) with CpG sequences and gold nanoparticles. Mixing of the properly designed hexapodna and oligodeoxynucleotide-modified gold nanoparticles resulted in the formation of composite-type gold nanoparticle-DNA hydrogels. Laser irradiation of the hydrogel resulted in the release of hexapodna, which efficiently stimulated immune cells to release proinflammatory cytokines. Then, EG7-OVA tumor-bearing mice received an intratumoral injection of a gold nanoparticle-DNA hydrogel, followed by laser irradiation at 780 nm. This treatment increased the local temperature and the mRNA expression of heat shock protein 70 in the tumor tissue, increased tumor-associated antigen-specific IgG levels in the serum, and induced tumor-associated antigen-specific interferon gamma production from splenocytes. Moreover, the treatment significantly retarded the tumor growth and extended the survival of the tumor-bearing mice. PMID- 28918260 TI - Organization of sensory feature selectivity in the whisker system. AB - Our sensory receptors are faced with an onslaught of different environmental inputs. Each sensory event or encounter with an object involves a distinct combination of physical energy sources impinging upon receptors. In the rodent whisker system, each primary afferent neuron located in the trigeminal ganglion innervates and responds to a single whisker and encodes a distinct set of physical stimulus properties - features - corresponding to changes in whisker angle and shape and the consequent forces acting on the whisker follicle. Here we review the nature of the features encoded by successive stages of processing along the whisker pathway. At each stage different neurons respond to distinct features, such that the population as a whole represents diverse properties. Different neuronal types also have distinct feature selectivity. Thus, neurons at the same stage of processing and responding to the same whisker nevertheless play different roles in representing objects contacted by the whisker. This diversity, combined with the precise timing and high reliability of responses, enables populations at each stage to represent a wide range of stimuli. Cortical neurons respond to more complex stimulus properties - such as correlated motion across whiskers - than those at early subcortical stages. Temporal integration along the pathway is comparatively weak: neurons up to barrel cortex (BC) are sensitive mainly to fast (tens of milliseconds) fluctuations in whisker motion. The topographic organization of whisker sensitivity is paralleled by systematic organization of neuronal selectivity to certain other physical features, but selectivity to touch and to dynamic stimulus properties is distributed in "salt and-pepper" fashion. PMID- 28918264 TI - Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory. AB - During morphogenesis and cancer metastasis, grouped cells migrate through tissues of dissimilar stiffness. Although the influence of matrix stiffness on cellular mechanosensitivity and motility are well-recognized, it remains unknown whether these matrix-dependent cellular features persist after cells move to a new microenvironment. Here, we interrogate whether priming of epithelial cells by a given matrix stiffness influences their future collective migration on a different matrix - a property we refer to as the 'mechanical memory' of migratory cells. To prime cells on a defined matrix and track their collective migration onto an adjoining secondary matrix of dissimilar stiffness, we develop a modular polyacrylamide substrate through step-by-step polymerization of different PA compositions. We report that epithelial cells primed on a stiff matrix migrate faster, display higher actomyosin expression, form larger focal adhesions, and retain nuclear YAP even after arriving onto a soft secondary matrix, as compared to their control behavior on a homogeneously soft matrix. Priming on a soft ECM causes a reverse effect. The depletion of YAP dramatically reduces this memory dependent migration. Our results present a previously unidentified regulation of mechanosensitive collective cell migration by past matrix stiffness, in which mechanical memory depends on YAP activity. PMID- 28918262 TI - Circuit changes in motor cortex during motor skill learning. AB - Motor cortex is important for motor skill learning, particularly the dexterous skills necessary for our favorite sports and careers. We are especially interested in understanding how plasticity in motor cortex contributes to skill learning. Although human studies have been helpful in understanding the importance of motor cortex in learning skilled tasks, animal models are necessary for achieving a detailed understanding of the circuitry underlying these behaviors and the changes that occur during training. We review data from these models to try to identify sites of plasticity in motor cortex, focusing on rodents asa model system. Rodent neocortex contains well-differentiated motor and sensory regions, as well as neurons expressing similar genetic markers to many of the same circuit components in human cortex. Furthermore, rodents have circuit mapping tools for labeling, targeting, and manipulating these cell types as circuit nodes. Crucially, the projection from rodent primary somatosensory cortex to primary motor cortex is a well-studied corticocortical projection and a model of sensorimotor integration. We first summarize some of the descending pathways involved in making dexterous movements, including reaching. We then describe local and long-range circuitry in mouse motor cortex, summarizing structural and functional changes associated with motor skill acquisition. We then address which specific connections might be responsible for plasticity. For insight into the range of plasticity mechanisms employed by cortex, we review plasticity in sensory systems. The similarities and differences between motor cortex plasticity and critical periods of plasticity in sensory systems are discussed. PMID- 28918265 TI - Amorphous liquid metal electrodes enabled conformable electrochemical therapy of tumors. AB - Electrochemical treatment of tumors (EChT) has recently been identified as a very effective way for local tumor therapy. However, hindered by the limited effective area of a single rigid electrode, multiple electrodes are often recruited when tackling large tumors, where too many electrodes not only complicate the clinical procedures but also aggravate patients' pain. Here we present a new conceptual electric stimulation tumor therapy through introducing the injectable liquid metal electrodes, which can adapt to complex tumor shapes so as to achieve desired therapeutic performance. This approach can offer evident merits for dealing with the complex physiological situations, especially for those irregular body cavities like stomach, colon, rectum or even blood vessel etc., which are hard to tackle otherwise. As it was disclosed from the conceptual experiments that, Unlike traditional rigid and uncomfortable electrodes, liquid metal possesses high flexibility to attach to any crooked biological position to deliver and adjust targeted electric field to fulfill anticipated tumor destruction. And such amorphous electrodes exhibit rather enhanced treatment effect of tumors. Further, we also demonstrate that EChT with liquid metal electrodes produced more electrochemical products during electrolysis. Transformations with the shapes of liquid metal provided an easily regulatable strategy to improve EChT efficiency, which can conveniently aid to achieve better output compared to multiple electrodes. In vivo EChT of tumors further clarified the effect of liquid metal electrodes in retarding tumor growth and increasing life spans. PMID- 28918267 TI - Compulsivity in opioid dependence. AB - OBJECTIVE: This study aimed to investigate the relationship between compulsivity versus impulsivity and structural MRI abnormalities in opioid dependence. METHOD: We recruited 146 participants: i) patients with a history of opioid dependence due to chronic heroin use (n=24), ii) heroin users stabilised on methadone maintenance treatment (n=48), iii) abstinent participants with a history of opioid dependence due to heroin use (n=24) and iv) healthy controls (n=50). Compulsivity was measured using Intra/Extra-Dimensional (IED) Task and impulsivity was measured using the Cambridge Gambling Task (CGT). Structural Magnetic Resonance Imaging (MRI) data were also obtained. RESULTS: As hypothesised, compulsivity was negatively associated with impulsivity (p<0.02). Testing for the neural substrates of compulsivity versus impulsivity, we found a higher compulsivity/impulsivity ratio associated with significantly decreased white matter adjacent to the nucleus accumbens, bed nucleus of stria terminalis and rostral cingulate in the abstinent group, compared to the other opioid dependent groups. In addition, self-reported duration of opioid exposure correlated negatively with bilateral globus pallidus grey matter reductions. CONCLUSION: Our findings are consistent with Volkow & Koob's addiction models and underline the important role of compulsivity versus impulsivity in opioid dependence. Our results have implications for the treatment of opioid dependence supporting the assertion of different behavioural and biological phenotypes in the opioid dependence and abstinence syndromes. PMID- 28918268 TI - A structural MRI study of excoriation (skin-picking) disorder and its relationship to clinical severity. AB - Excoriation (skin-picking) disorder (SPD) shares symptomology with other obsessive-compulsive and related disorders. Few studies, however, have examined the neurological profile of patients with SPD. This study examined differences in cortical thickness and basal ganglia structural volumes between 20 individuals with SPD and 16 healthy controls using magnetic resonance imaging (MRI). There were no significant differences in demographic variables (age, gender, education and race) between groups. All subjects completed a structural MRI scan and completed a battery of clinical assessments focusing on SPD symptom severity, depression and anxiety symptoms, and quality of life. No statistically significant differences in basal ganglia (caudate, putamen, and nucleus accumbens) structural volumes were found between groups. In individuals with SPD, increasing impulsiveness correlated positively with increased cortical thickness in the left insula, and skin picking severity correlated negatively with cortical thickness in the left supramarginal gyrus and a region encompassing the right inferior parietal, right temporal and right supramarginal gyrus. This study suggests similarities and differences exist in symptomology between SPD and the other obsessive-compulsive and related disorders. Additional neuroimaging research is needed to better delineate the underlying neurobiology of SPD. PMID- 28918269 TI - Excess social media use in normal populations is associated with amygdala striatal but not with prefrontal morphology. AB - This study aims to investigate the gray matter volume (GMV) of key neural systems possibly associated with Excess Social Media Use (ESMU) in the general user population. It employs a sex-balanced case (relatively high ESMU scores) - control (relatively low ESMU scores) design with 50 random university students who have reported varying levels of ESMU. The case and control groups included 25 subjects each. Brain volumes were calculated with Voxel-Based Morphometry techniques applied to structural MRI scans. Results based on voxel-wise and region-of-interest (ROI) analyses showed that the case group had reduced GMV in the bilateral amygdala and right ventral striatum. The GMV of the bilateral amygdala and right ventral striatum negatively correlated with ESMU scores in the voxel-wise analysis. No differences or correlations in relation to prefrontal regions were observed. Using the ROI analysis, the bilateral amygdala volumes correlated with ESMU scores, and insufficient evidence regarding the ventral striatum and ESMU was obtained. It is concluded that excess social media use in the general population is associated in part with GMV reduction in the bilateral amygdala, and possibly the striatum, but not in volumetric differences in prefrontal regions. PMID- 28918266 TI - Nanomedicine for safe healing of bone trauma: Opportunities and challenges. AB - Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches. PMID- 28918270 TI - Corrigendum to "Simulating soil organic carbon stock as affected by land cover change and climate change, Hyrcanian forests (northern Iran)" [Sci. Total Environ. 599-600 (2017) 1646-1657]. PMID- 28918271 TI - The role of sulfate-reducing prokaryotes in the coupling of element biogeochemical cycling. AB - Sulfate-reducing prokaryotes (SRP) represent a diverse group of heterotrophic and autotrophic microorganisms that are ubiquitous in anoxic habitats. In addition to their important role in both sulfur and carbon cycles, SRP are important biotic and abiotic regulators of a variety of sulfur-driven coupled biogeochemical cycling of elements, including: oxygen, nitrogen, chlorine, bromine, iodine and metal(loid)s. SRP gain energy form most of the coupling of element transformation. Once sulfate-reducing conditions are established, sulfide precipitation becomes the predominant abiotic mechanism of metal(loid)s transformation, followed by co-precipitation between metal(loid)s. Anthropogenic contamination, since the industrial revolution, has dramatically disturbed sulfur driven biogeochemical cycling; making sulfur coupled elements transformation complicated and unpredictable. We hypothesise that sulfur might be detoxication agent for the organic and inorganic toxic compounds, through the metabolic activity of SRP. This review synthesizes the recent advances in the role of SRP in coupled biogeochemical cycling of diverse elements. PMID- 28918272 TI - Impact of reduced mass of light commercial vehicles on fuel consumption, CO2 emissions, air quality, and socio-economic costs. AB - This study presents a modelling system to evaluate the impact of weight reduction in light commercial vehicles with diesel engines on air quality and greenhouse gas emissions. The PROPS model assesses the emissions of one vehicle in the aforementioned category and its corresponding reduced-weight version. The results serve as an input to the RIAT+ tool, an air quality integrated assessment modelling system. This paper applies the tools in a case study in the Lombardy region (Italy) and discusses the input data pre-processing, the PROPS-RIAT+ modelling system runs, and the results. PMID- 28918273 TI - Volatile and semivolatile emissions from the pyrolysis of almond shell loaded with heavy metals. AB - Heavy metal-loaded almond shell was subjected to pyrolysis to understand the effect of the presence of different heavy metals on its thermal degradation. Pyrolysis behavior of native and metal-loaded samples was studied by thermogravimetric analysis. Similar shapes of thermogravimetric curves indicate that the presence of cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni) and lead (Pb) did not change the main degradation pathways of almond shell. However, the temperature at which the decomposition in each stage takes place at a higher rate and char yield was considerably modified by the presence of Cr and Ni. Then, pyrolysis tests of the almond shell samples were performed in a moving tubular reactor at 700 degrees C. Gases and volatile organic compounds were collected using Tedlar bags and semivolatile organic compounds were collected using a resin as adsorbent. Significant changes were obtained in the composition of the gaseous fraction as a result of the metal impregnation. The main changes in the composition of the gas were observed for Ni-loaded sample, which presented the highest H2 and CO yields. Also, the yields of most of the light hydrocarbons decrease in the presence of metal, while the rest remain quite similar. The total PAH yields reached 103MUg/g for nickel-loaded sample (NiAS), 164MUg/g for copper loaded sample (CuAS), 172MUg/g for lead-loaded sample (PbAS), 245MUg/g for native sample (AS), 248MUg/g for cadmium-loaded sample (CdAS) and 283MUg/g for chromium loaded sample (CrAS). Nickel is the most effective in the higher aromatic tar reduction, followed by Cu and Pb, whereas the presence of Cd does not affect the total emissions of PAHs. Finally, the carcinogenic potency of the samples was calculated. Native sample and the sample loaded with Cr presented slightly higher values associated to the presence of small amounts of benzo(a)pyrene. PMID- 28918274 TI - Distribution comparison and risk assessment of free-floating and particle attached bacterial pathogens in urban recreational water: Implications for water quality management. AB - The risk of pathogen exposure in recreational water is a concern worldwide. Moreover, suspended particles, as ideal shelters for pathogens, in these waters also need attention. However, the risk caused by the pathogen-particle attachment is largely unknown. Accordingly, water samples in three recreational lakes in Beijing were collected and separated into free-floating (FL, 0.22-5MUm) and particle-attached (PA, >5MUm) fractions. Next-generation sequencing (NGS) was employed to determine the diversity of genera containing pathogens, and quantitative PCR (qPCR) was used to assess the presence of genes from Escherichia coli (uidA), Salmonella enterica (invA), Aeromonas spp. (aerA), Mycobacterium avium (16S) and Pseudomonas aeruginosa (oaa). The NGS results showed stable pathogen genera composition distinctions between the PA and FL fractions. Some genera, such as Aeromonas and Mycobacterium, exhibited higher abundances in the PA fractions. qPCR revealed that most of the gene concentrations were higher within particles than were FL fractions. Some gene levels showed correlations with the particle concentrations and lake nutrient levels. Further quantitative microbial risk assessment (QMRA) of selected strains (S. enterica and M. avium) indicated a higher health risk during secondary contact activities in lakes with more nutrients and particles. We concluded that suspended particles (mainly composed of algae) in urban recreational water might influence the pathogen distribution and could serve as reservoirs for pathogen contamination, with important management implications. PMID- 28918275 TI - The association between ambient temperature and the risk of preterm birth in China. AB - BACKGROUND: With the gradual increase of global warming, the impact of extreme temperatures on health has become a focus of attention, however, its relationship with preterm birth remains unclear. OBJECTIVES: To investigate the association between exposure to extreme temperatures and preterm birth. METHODS: Temperature exposures and birth outcomes of 1,020,471 pregnant women from 132 cities in China were investigated. The pregnancy process was divided into different pregnancy periods. Study areas were divided into three categories (cold, medium, and hot areas) according to the local average temperature by cluster analysis. Average temperature data for each province used in the cluster analysis came from the China Statistical Yearbook 2013. Logistic regression was used to compare the effects of exposure to hot and cold conditions on the outcomes of pregnancy in different periods and regions. RESULTS: A total of 1,020,471 singleton births were included, of which 73,240(7.2%) were preterm births. Compared with moderate temperatures (5th to 95th percentile), heat exposure (>95th percentile) in different periods of pregnancy increased the risk of preterm birth in hot areas. The most obvious increase was during the 3 months before pregnancy (odds ratio (OR)=1.229, 95% confidence interval (CI): 1.166-1.295). In contrast to heat exposure, cold exposure (<5th percentile) in hot areas reduced the risk of preterm birth; the protective effect was most pronounced in the 3 months before pregnancy (OR=0.784, 95% CI: 0.734-0.832). In medium and cold areas cold exposure also reduced the risk of preterm birth. The effect of exposure to extreme ambient temperatures throughout the entire pregnancy on preterm birth was similar to those of the periods above. CONCLUSIONS: Acute and chronic exposure to extreme temperatures may affect the risk of preterm birth. Extreme heat is a risk factor for preterm birth and extreme cold is a protective factor. PMID- 28918276 TI - Phytoremediation of soil co-contaminated with Cd and BDE-209 using hyperaccumulator enhanced by AM fungi and surfactant. AB - Pot experiments were conducted to investigate the uptake and translocation of both Cd and decabromodiphenyl ether (BDE-209) in Solanum nigrum, under the treatments of two arbuscular mycorrhizal fungi [AMF, Funneliformis mosseae (FM) and Rhizophagus intraradices (RI)] and surfactant beta-cyclodextrin (beta-CD). Results showed that S. nigrum treated with either FM or beta-CD significantly elevated shoot biomass and Cd concentrations and contents in shoots. The concentrations of BDE-209 in shoots and the dissipation and debromination efficiencies of BDE-209 in soil were significantly enhanced in S. nigrum treated with beta-CD, inoculated with or without AMF. Moreover, significant positive correlations were found between the BDE-209 dissipation efficiency, the BDE-209 concentrations and contents in roots, and the soil enzymatic activities (polyphenol oxidase or dehydrogenase activities) and between the Cd and BDE-209 contents in shoots or roots. Higher concentrations of lower-brominated products and total PBDEs were detected in shoots than in roots suggesting that BDE-209 might be initially absorbed by roots, then translocated to shoots, and then degraded into lower brominated products in shoots. Considering the plant uptake of Cd and BDE-209 and the efficient removal of those chemicals in soils, the combination of S. nigrum and beta-CD inoculated with or without AMF may be viable alternatives for phytoremediation of the co-contaminated soil. PMID- 28918277 TI - Lead isotopic fingerprint in human scalp hair: The case study of Iglesias mining district (Sardinia, Italy). AB - The Sulcis-Iglesiente district (SW Sardinia, Italy) has been, until recently, one of the most important Italian polymetallic mining areas for the extraction of lead. Epidemiological studies conducted over several decades have indicated this site at high risk of environmental crisis with possible adverse effects on the public health. In the present paper we discuss Pb isotope signatures in human scalp hair and road dust collected from the Sulcis-Iglesiente area in order to trace the exposure of populations to potential Pb sources. A total of 23 determinations (20 on hair samples and 3 on road dust samples) of lead isotope ratios (206Pb/207Pb and 208Pb/206Pb) were carried out. The obtained results were integrate with literature data regarding the total content of Pb in hair samples from the same study area. Hair from children living in Sant'Antioco exhibited lead isotope ratios in the ranges 1.152-1.165 for 206Pb/207Pb and 2.101-2.108 for 208Pb/206Pb, while hair samples from Iglesias resulted less radiogenic: 206Pb/207Pb~1.147-1.154 and 208Pb/206Pb~2.106-2.118. These values pointed to a multi-source mixing between the less radiogenic sources, corresponding to the Pb ore deposits, and the more radiogenic sources identified in local background. PMID- 28918278 TI - Heavy metals (As, Hg and V) and stable isotope ratios (delta13C and delta15N) in fish from Yellow River Estuary, China. AB - The Yellow River Estuary is a significant fishery, but at present there are few studies about the concentrations of arsenic (As), mercury (Hg) and vanadium (V) in fish from this area, which might cause potential health risk to fish consumers. The aim of this study was to research on the accumulation and potential sources of heavy metals in the fish of the Yellow River Estuary. Arsenic, Hg, V and stable isotope ratios (delta15N and delta13C) in 11 species of 129 fish were analyzed. Results showed that the concentrations of As and Hg were all lower than the guideline levels established by international organizations and legal limits by several countries. The mean concentrations of V in samples in this study were significantly higher than the results of previous studies on other regions. Arsenic, Hg and V significantly differed across species (P<0.05), which might be due to the different foraging habitats and dietary habits of the studied fish. Values of delta15N and delta13C in fish from the study area ranged from 5.10/00 to 14.60/00 and from -27.60/00 to -14.50/00, indicating a wide range of trophic positions and energy sources. There was evidence of bioaccumulation of Hg, which could be explained by the positive correlation between Hg concentrations and delta15N in fish. Through estimation of daily intake of inorganic As (iAs), Hg and V via fish consumption, the heavy metal contamination level of fish samples fell in an acceptable range, indicating no potentially hazardous for human health. PMID- 28918279 TI - Seasonal variation of chloro-s-triazines in the Hartbeespoort Dam catchment, South Africa. AB - Seasonal variation of eight chloro-s-triazine herbicides and seven major atrazine and terbuthylazine degradation products was monitored in the Hartbeespoort Dam catchment using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS/MS). Lake, river and groundwater were sampled from the Hartbeespoort Dam catchment over four seasons and the downstream Jukskei River was monitored during the winter season. Triazine herbicide concentrations in the Hartbeespoort Dam were in the order atrazine>simazine>propazine>ametryn>prometryn throughout the four seasons sampled. Triazine herbicide concentrations in the Hartbeespoort Dam surface water were highest in summer and gradually decreased in successive seasons of autumn, winter and spring. Terbuthylazine was the only triazine herbicide detected at all sampling sites in the Jukskei River, though atrazine recorded much higher concentrations for the N14 and Kyalami sites, with concentrations of 923 and 210ngL-1 respectively, compared to 134 and 74ngL-1 for terbuthylazine. Analytical results in conjunction with river flow data indicate that the Jukskei and Crocodile Rivers contribute the greatest triazine herbicide loads into the Hartbeespoort Dam. No triazine herbicides were detected in the fish muscle tested, showing that bioaccumulation of triazine herbicides is negligible. Atrazine and terbuthylazine metabolites were detected in the fish muscle with deethylatrazine (DEA) being detected in both catfish and carp muscle at low concentrations of 0.2 and 0.3ngg-1, respectively. Desethylterbuthylazine (DET) was detected only in catfish at a concentration of 0.3ngg-1. With atrazine herbicide groundwater concentrations being >130ngL-1 for all seasons and groundwater ?triazine herbicide concentrations ranging between 527 and 367ngL-1, triazine compounds in the Hartbeespoort Dam catchment may pose a risk to humans and wildlife in light findings of endocrine and immune disrupting atrazine effects by various researchers. PMID- 28918280 TI - From sport hunting to breeding success: Patterns of lead ammunition ingestion and its effects on an endangered raptor. AB - Lead is highly toxic for wildlife, with pernicious consequences especially in long-lived predators. The causes of lead ammunition ingestion in Bonelli's eagle (Aquila fasciata) and its effects on breeding success were studied in one of the most important populations of this endangered species in Europe. Regurgitated pellets belonging to different pairs from 2004 to 2014 were analyzed, both in the breeding (1363 pellets from 12 territories) and non-breeding (172 pellets from 9 territories) seasons. From these territories, 57 molted feathers to study lead contamination were analyzed, and breeding success was monitored for 41 breeding attempts. The occurrence of lead shots in pellets was detected using X-ray photographs. Pellets were also used to describe eagle diet. Lead shots in pellets were present in 83.3% of the territories. The frequency of occurrence of lead shots in pellets (2.81% in spring and 1.31% in autumn) was primarily related to the consumption of red-legged partridge in the breeding season (when partridges are hunted from blinds using calling lures), and secondarily to rabbit consumption in the non-breeding season (coinciding with the main hunting season). Thus, our results indicate that injured small-game were the main source of lead contamination in the Bonelli's eagle. For the first time for a raptor species, a positive relationship between the frequency of occurrence of lead shots in pellets and lead concentration in eagles' feathers has been documented. Lead concentration in feathers (mean+/-SD: 816+/-426MUgkg-1, with no sex-related differences) was high for a species that rarely eats carrion or aquatic birds (the main prey-related lead source for raptors). This had negative effects on breeding success, which could jeopardize Bonelli's eagles in other European populations that are sustained by juvenile dispersal from the study population. Our work shows that some game modalities pose a potential threat to endangered raptors. PMID- 28918281 TI - Distribution of VOCs in urban and rural atmospheres of subtropical India: Temporal variation, source attribution, ratios, OFP and risk assessment. AB - This paper reports the first study which comprises the seasonal, diurnal variability, source characterization, ozone forming potential and risk assessment of volatile organic compounds (VOCs) at three sites (two urban and one rural) in the National Capital Territory of Delhi, India. The study was performed during three seasons of the year 2013-14 and two different categories of VOCs (aromatics and halogenated) have been selected. The study used the sampling and analytical procedures of NIOSH methods. Results showed that the mean concentration of sum of VOCs (?VOC) is significantly higher at urban sites (110.0 and 137.4MUg/m3 for JN and CP, respectively) as compared to the rural site, DP (56.5MUg/m3). The contribution of individual to total VOC concentrations is noticed to be very similar at all the three sites. Most of the VOCs are observed to be significantly higher in winter followed by summer and autumn. Diurnal cycles of aromatic VOCs are highly influenced by the vehicular traffic and photochemical oxidations which showed higher and lower levels during morning/evening and daytime, respectively. Diagnostic ratios of the toluene/benzene (ranged from 0.65 to 13.9) infers the vehicular traffic might be the main contributing source in the urban sites while xylene/benzene ratio (ranged from 0.7 to 2.8) confirms the VOCs are transported to rural site from the nearby urban areas. Correlation and factor analysis suggested the sources are group of different species (traffic emissions, solvent usage and industrial) rather than single gas. The analysis of reactivity in terms of Prop-Equiv concentrations and ozone forming potential indicated that m/p xylene and toluene are the main VOC contributing to the total ozone formation in urban and rural sites, respectively. Hazard ratios and lifetime cancer risk values exceeded the permissible standards established by USEPA and WHO suggests that the people are at significant risk. PMID- 28918282 TI - Coronary artery disease and atrial fibrillation. PMID- 28918283 TI - Cardio-oncology: Novel concepts and directions. PMID- 28918285 TI - Controlling cell volume for efficient PHB production by Halomonas. AB - Bacterial morphology is decided by cytoskeleton protein MreB and cell division protein FtsZ encoded by essential genes mreB and ftsZ, respectively. Inactivating mreB and ftsZ lead to increasing cell sizes and cell lengths, respectively, yet seriously reduce cell growth ability. Here we develop a temperature-responsible plasmid expression system for compensated expression of relevant gene(s) in mreB or ftsZ disrupted recombinants H. campaniensis LS21, allowing mreB or ftsZ disrupted recombinants to grow normally at 30 degrees C in a bioreactor for 12h so that a certain cell density can be reached, followed by 36h cell size expansions or cell shape elongations at elevated 37 degrees C at which the mreB and ftsZ encoded plasmid pTKmf failed to replicate in the recombinants and thus lost themselves. Finally, 80% PHB yield increase was achieved via controllable morphology manipulated H. campaniensis LS21. It is concluded that controllable expanding cell volumes (widths or lengths) provides more spaces for accumulating more inclusion body polyhydroxybutyrate (PHB) and the resulting cell gravity precipitation benefits the final separation of cells and product during downstream. PMID- 28918284 TI - New insights into human female reproductive tract development. AB - We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Mullerian epithelium and the lower 1/5th derived from urogenital sinus epithelium, while Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Mullerian ducts) cranially and squamous epithelium of urogenital sinus caudally. Since Mullerian and urogenital sinus epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Mullerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal epithelium derives solely from urogenital sinus epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development. PMID- 28918286 TI - Identifying combinatorial biomarkers by association rule mining in the CAMD Alzheimer's database. AB - The concept of combinatorial biomarkers was conceived when it was noticed that simple biomarkers are often inadequate for recognizing and characterizing complex diseases. Here we present an algorithmic search method for complex biomarkers which may predict or indicate Alzheimer's disease (AD) and other kinds of dementia. We show that our method is universal since it can describe any Boolean function for biomarker discovery. We applied data mining techniques that are capable to uncover implication-like logical schemes with detailed quality scoring. The new SCARF program was applied for the Tucson, Arizona based Critical Path Institute's CAMD database, containing laboratory and cognitive test data for 5821 patients from the placebo arm of clinical trials of large pharmaceutical companies, and consequently, the data is much more reliable than numerous other databases for dementia. The results of our study on this larger than 5800-patient cohort suggest beneficial effects of high B12 vitamin level, negative effects of high sodium levels or high AST (aspartate aminotransferase) liver enzyme levels to cognition. As an example for a more complex and quite surprising rule: Low or normal blood glucose level with either low cholesterol or high serum sodium would also increase the probability of bad cognition with a 3.7 multiplier. The source code of the new SCARF program is publicly available at http://pitgroup.org/static/scarf.zip. PMID- 28918287 TI - Steroid hormones and persistent organic pollutants in plasma from North-eastern Atlantic pilot whales. AB - Persistent organic pollutants (POPs) are known to have endocrine disruptive effects, interfering with endogenous steroid hormones. The present study examined nine steroid hormones and their relationships with the concentrations of selected POPs in pilot whales (Globicephala melas) from the Faroe Islands, NE Atlantic. The different steroids were detected in 15 to all of the 26 individuals. High concentrations of progesterone (83.3-211.7pmol/g) and pregnenolone (PRE; 4.68 5.69pmol/g) were found in three adult females indicating that they were pregnant or ovulating. High androgen concentrations in two of the males reflected that one was adult and that one (possibly) had reached puberty. In males a significant positive and strong correlation between body length and testosterone (TS) levels was identified. Furthermore, positive and significant correlations were found between 4-OH-CB107/4'-OH-CB108 and 17beta-estradiol in males. In adult females significant positive correlations were identified between PRE and CB149 and t nonachlor, between estrone and CB138, -149, -187 and p,p'-DDE, between androstenedione and CB187, and between TS and CB-99 and -153. Although relationships between the POPs and the steroid hormones reported herein are not evidence of cause-effect relationships, the positive correlations between steroids and POPs, particularly in females, suggest that POPs may have some endocrine disrupting effects on the steroid homeostasis in this species. PMID- 28918288 TI - Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer. AB - Breast cancer is a major cause of cancer-related death in women. Antitumor T cell responses play critical therapeutic roles, including direct cytotoxicity mediated by CD8+ T cells and immunomodulatory roles mediated by CD4+ T cells. The IL-9 expressing Th9 cells are recently found to present antitumor immunity in melanoma and lung adenocarcinoma. In this study, we found that IL-9 expression in the serum and in circulating CD4+ T cells were significantly upregulated in breast cancer patients compared to healthy controls. The IL-9-expressing Th9 cells were enriched in the CCR4-CCR6-CXCR3- subset. Upon TCR stimulation, this subset also presented potent IL-10 and IL-21 expression in addition to IL-9 expression. CCR4 CCR6-CXCR3- CD4+ T cells also assisted in the killing of autologous tumor cells by CD8+ T cells, but did not initiate cytotoxicity by themselves. This enhancement in CD8+ T cell-mediated cytotoxicity was dependent on IL-9 as well as on IL-21. Interestingly, the tumor-infiltrating Th9 cells presented comparable IL 9, reduced IL-10, and elevated IL-21 expression compared with their counterparts in the peripheral blood. Together, these results demonstrated that IL-9 expressing Th9 cells were upregulated in breast cancer patients and potentially possessed antitumor roles by enhancing CD8+ T cell-mediated cytotoxicity. PMID- 28918289 TI - Effective removal of trace thallium from surface water by nanosized manganese dioxide enhanced quartz sand filtration. AB - Thallium (Tl) has drawn wide concern due to its high toxicity even at extremely low concentrations, as well as its tendency for significant accumulation in the human body and other organisms. The need to develop effective strategies for trace Tl removal from drinking water is urgent. In this study, the removal of trace Tl (0.5 MUg L-1) by conventional quartz sand filtration enhanced by nanosized manganese dioxide (nMnO2) has been investigated using typical surface water obtained from northeast China. The results indicate that nMnO2 enhanced quartz sand filtration could remove trace Tl(I) and Tl(III) efficiently through the adsorption of Tl onto nMnO2 added to a water matrix and onto nMnO2 attached on quartz sand surfaces. Tl(III)-HA complexes might be responsible for higher residual Tl(III) in the effluent compared to residual Tl(I). Competitive Ca2+ cations inhibit Tl removal to a certain extent because the Ca2+ ions will occupy the Tl adsorption site on nMnO2. Moreover, high concentrations of HA (10 mgTOC L 1), which notably complexes with and dissolves nMnO2 (more than 78%), resulted in higher residual Tl(I) and Tl(III). Tl(III)-HA complexes might also enhance Tl(III) penetration to a certain extent. Additionally, a higher pH level could enhance the removal of trace Tl from surface water. Finally, a slight increase of residual Tl was observed after backwash, followed by the reduction of the Tl concentration in the effluent to a "steady" state again. The knowledge obtained here may provide a potential strategy for drinking water treatment plants threatened by trace Tl. PMID- 28918290 TI - In situ arsenic oxidation and sorption by a Fe-Mn binary oxide waste in soil. AB - The ability of a Fe-Mn binary oxide waste to adsorb arsenic (As) in a historically contaminated soil was investigated. Initial laboratory sorption experiments indicated that arsenite [As(III)] was oxidized to arsenate [As(V)] by the Mn oxide component, with concurrent As(V) sorption to the Fe oxide. The binary oxide waste had As(III) and As(V) adsorption capacities of 70mgg-1 and 32mgg-1 respectively. X-ray Absorption Near-Edge Structure and Extended X-ray Absorption Fine Structure at the As K-edge confirmed that all binary oxide waste surface complexes were As(V) sorbed by mononuclear bidentate corner-sharing, with 2 Fe at ~3.27A. The ability of the waste to perform this coupled oxidation sorption reaction in real soils was investigated with a 10% by weight addition of the waste to an industrially As contaminated soil. Electron probe microanalysis showed As accumulation onto the Fe oxide component of the binary oxide waste, which had no As innately. The bioaccessibility of As was also significantly reduced by 7.80% (p<0.01) with binary oxide waste addition. The results indicate that Fe-Mn binary oxide wastes could provide a potential in situ remediation strategy for As and Pb immobilization in contaminated soils. PMID- 28918291 TI - Distinguished Cr(VI) capture with rapid and superior capability using polydopamine microsphere: Behavior and mechanism. AB - Toxic heavy metal containing Cr(VI) species is a serious threat for ecological environment and human beings. In this work, a new mussel-inspired polydopamine microsphere (PDA-sphere) is prepared through in situ oxidative polymerization at air condition with controllable sizes. The adsorption of Cr(VI) ions onto PDA sphere is highly pH dependent with the optimal pH ranging from 2.5 to 3.8. A rapid Cr(VI) removal can approach in 8min for equilibrium. More importantly, the prepared materials exhibit a remarkable sorption selectivity, coexisting SO42-, NO3- and Cl- ions at high levels; The applicability model further proves its effective performances with treated capacity of 42,000kg/kg sorbent, and the effluent can be reduced from 2000ppb to below 50ppb, which meets the drinking water criterions recommended by WHO. 1kg sorbent can also purify approximately 100t Cr(VI) contaminated wastewaters basing on the wastewater discharges of China. Such capacity for application ranks the top level for Cr(VI) removal. Additionally, the exhausted materials can be well regenerated by binary alkaline and salts mixtures. Such efficient adsorption can be ascribed to the well dispersed morphology as well as the strong affinity between Cr(VI) and catechol or amine groups by XPS investigation. All the results suggest that polydopamine microspheres may be ideal materials for Cr(VI) treatment in waters. PMID- 28918292 TI - Nanoscaled gold and silver: Simultaneous removal and transformation to functional materials. AB - Based on an "acid-assisted cool welding" technology which was realized by virtue of the freezing process in the presence of acid, nanoscaled gold (Au) and silver (Ag) from wastewater could be removed very facilely and efficiently. The technology was independence of the freezing temperature, size as well as shape of those nanoscaled units. Besides, some functional materials like porous nanostructures with highly and stably catalytic activity could be also obtained during the removal. Our research not only provided a new method to remove nanoscaled Ag or Au from wastewater, but also built up a unique route to transform those nano-units into functional materials simultaneously. PMID- 28918293 TI - Insight into the H2S selective catalytic oxidation performance on well-mixed Ce containing rare earth catalysts derived from MgAlCe layered double hydroxides. AB - A series of well-mixed Ce-containing MgAlCe rare earth catalysts derived from layered double hydroxides were synthesized and tested for H2S selective catalytic oxidation. Particularly, no chemisorption O-vacancies but intrinsic defect sites were present on catalyst surface. Significantly, the catalysts exhibited excellent catalytic activity, reasonable durability, and outstanding sulfur selectivity (100%) at relatively low temperatures. Furthermore, the catalyst followed a step-wise mechanism, and the catalyst deactivation was due mainly to the slower oxidation rate of Ce3+ to Ce4+ by O2 as compared to the reduction rate of Ce4+ to Ce3+ by H2S. Particularly, the added water, a Lewis base, can compete with inefficient S8 catalyst for the occupation of Lewis acid sites and active sites. Meanwhile, it can change the characteristics of catalyst surface, resulting in sulfur existing form transforming from inefficient S8 catalyst to inactive S3. Thus, lead to a decrease of deposited inefficient S8 catalyst content. Consequently, decrease the catalytic activity. PMID- 28918294 TI - Potassium channels modulate the action but not the synthesis of hydrogen sulfide in rat corpus cavernosum. AB - AIM: Hydrogen sulfide (H2S) is a newly-introduced gasotransmitter in penile tissues. However, its exact mechanism of action in mediating penile erection is not fully elucidated. The major aim of this study was to examine the role of different K+ channels in mediating the responses to H2S in the corpus cavernosum. MAIN METHODS: Tension studies using isolated rat corpus cavernosum strips were conducted. Endogenous H2S production was measured using polarographic technique. Results are expressed as mean+/-SEM. KEY FINDINGS: l-Cysteine (10-2M) stimulated rat corpus cavernosum to produce H2S. Blockade of CSE by BCA (10-3M) reduced the concentration of H2S produced from rat corpus cavernosum significantly. Addition of TEA (10-2M) or 4-AP (10-3M) didn't have a significant effect on the concentration of H2S produced. l-Cysteine (10-6-10-2M) elicited a concentration dependent relaxation response which was significantly reduced by blockade of CSE using BCA (10-3M). TEA (10-2M), 4-AP (10-3M) and TEA (10-4M) attenuated l cysteine-induced relaxation significantly. At 10-4M, l-cysteine resulted in percentage relaxation of 1.55+/-0.63, 10.94+/-1.93 and 1.93+/-0.80 in presence of TEA (10-2M), 4-AP (10-3M) and TEA (10-4M) respectively compared to 23.78+/-2.71 as control. Both glibenclamide (10-5M) and BaCl2 (3*10-5M) failed to reduce these relaxations significantly. SIGNIFICANCE: H2S-induced relaxation of rat corpus cavernosum may be mediated - at least in part - through BKca and KV channels not by KATP and Kir channels. It also seems that K+-channels do not contribute to the synthesis of H2S. PMID- 28918295 TI - Case report: Primary aortosigmoid fistula - A rare cause of lower gastrointestinal bleeding. AB - INTRODUCTION: A primary aortoenteric fistula (PAEF) is a communication between aorta and the gastrointestinal tract. It is a rare condition that is difficult to diagnose and therefore associated with a high mortality. PRESENTATION OF CASE: We report a rare case of a 66-year old man with an unstable bleeding PAEF. A salvage procedure was performed with a covered stent. Later, a sigmoidectomy was performed with resection of the fistula. Postoperatively, the patient suffered an infection that was treated well with antibiotics and he was discharged two weeks later with complete resolution of the fistula. DISCUSSION: Aortoenteric fistulas are more common secondary to previous vascular surgery of aorta, however, PAEF's involve the sigmoid in 2%. Seldom, fistulization can be due to diverticulitis that can be difficult to diagnose. CONCLUSION: Retroperitoneal bleeding from the left iliac artery is more common due to a ruptured aneurysm. This case, however, demonstrates a special PAEF formation as a very rare complication of diverticulitis. The pathophysiology of the PAEF is very unique along with the anatomic localization in the sigmoid colon and left external iliac artery. PMID- 28918296 TI - Trichobezoar with and without Rapunzel syndrome in paediatric population: A case series from a tertiary care centre of Northern India. AB - INTRODUCTION: Trichobezoars are concretions formed by accumulation of hair in stomach. Usually, trichobezoar is confined to the stomach, but rarely it may extend from the stomach to the small intestine and even colon. This is an unusual form called Rapunzel syndrome. Our experience with this rare entity of Rapunzel syndrome and interesting entity of trichobezoar is being presented with review of literature. PRESENTATION OF CASES: We, at our institute, encountered four cases of trichobezoar in last five years, out of which two were found to be of Rapunzel syndrome. All of these cases were managed successfully by open surgical intervention in view of the very large size of the mass in all the cases. DISCUSSION: The clinical presentation is highly variable ranging from asymptomatic cases diagnosed incidently to serious gastrointestinal symptoms and complications. Cases of trichobezoar have been reported in literature very infrequently but Rapunzel syndrome is extremely rare and less than 50 cases have been reported in medical literature till date. CONCLUSION: Trichobezoar leading to Rapunzel syndrome is an extremely rare entity. The clinical presentation is usually vague and non-specific. Treatment is mainly surgical because of delayed presentation in majority of the cases. Psychiatric illness is the usual association. PMID- 28918297 TI - A rare case of spontaneous rupture of an aneurysm of the right gastric artery. AB - BACKGROUND: Visceral artery aneurysms at the origin of the gastric and gastroepiploic artery are uncommon. Raptured visceral aneurysms cause high mortality and require urgent and adequate intervention and treatment. PRESENTATION OF CASE: A 65-year-old woman was transferred to the emergency department with sudden abdominal and back pain. Radiographically, we diagnosed intra-abdominal bleeding due to a ruptured aneurysm of the right gastric artery. Although her vital signs were relatively stable, transcatheter arterial embolization (TAE) could not be performed due to thrombotic occlusion of her abdominal aorta, and bilateral axillary arteries. She underwent an emergency laparotomy with ligation of the root of the right gastric artery and resection of the aneurysm, following which she showed good recovery. Histologically, the right gastric artery showed atherosclerosis with an organizing mural thrombus. DISCUSSION: Ruptured visceral aneurysms cause high mortality; therefore, rapid and adequate treatment is necessary. Achieving adequate transcatheter access might be difficult in some cases. In our case, we performed an emergency laparotomy and had good recovery. CONCLUSION: We report and discuss the literature review for a rare case of intra-abdominal bleeding from a ruptured aneurysm of the right gastric artery which was difficult to be approache by TAE. In patients with unstable vital signs or in whom it is not possible to obtain a good laparoscopic view and clear operative field, we should not hesitate to convert the procedure into an open one, and perform an emergency laparotomy. PMID- 28918298 TI - In Search of an Answer. PMID- 28918299 TI - The prosthetic rehabilitation of a patient with a lateral postsurgical defect using a 2-piece magnet-retained facial prosthesis: A clinical report. AB - Nonsurgical prosthetic interventions are often proposed after repeated grafts have failed to restore irradiated facial defects. This report describes a facial prosthetic reconstruction following ablative surgery for a sizable facial tumor by using a novel custom-made magnet-bearing substructure, which connected with an exposed part of the mandibular reconstruction plate. The defect involved the entire left lower part of the face and angle of the mentum. This reconstructive technique, together with an added surface texture with hair-like silicone strands, effectively addressed the cosmetic needs of the patient. Magnetic anchorage to an exposed reconstruction plate could be considered an option for retaining facial prostheses. The biomechanical aspects of loading and retention should be addressed before considering this prosthetic option. PMID- 28918300 TI - Dynamical properties of LFPs from mice with unilateral injection of TeNT. AB - Local field potential (LFP) recordings were performed from the visual cortex (V1) of a focal epilepsy mouse model. Epilepsy was induced by a unilateral injection of the synaptic blocker tetanus neurotoxin (TeNT). LFP signals were simultaneously recorded from V1 of both hemispheres of each animal under acute and chronic conditions (i.e. during and after the period of TeNT action). All data were analysed by using nonlinear time series methods. Suitable values of the lag time and embedding dimension for phase space reconstruction were estimated by employing well-known methods. The results showed that lag times are sensitive to the presence of TeNT. Interestingly, TeNT promoted an increase in the level of linear and nonlinear correlation of LFP signals. The values of the embedding dimension failed to show any dependence on the presence of the neurotoxin. However, a local nonlinear prediction method showed that the presence of TeNT increases the predictability, quantified by the normalized prediction error, of the neural recordings. From a neurophysiological point of view, the above results suggest that TeNT injected in one hemisphere strongly impacts the local electrical activity of the neural populations in the opposite hemisphere. We hypothesize that this could arise from a qualitative and quantitative alteration of the transmission properties of the callosal fibers. PMID- 28918301 TI - Mathematical fundamentals for the noise immunity of the genetic code. AB - : Symmetry is one of the essential and most visible patterns that can be seen in nature. Starting from the left-right symmetry of the human body, all types of symmetry can be found in crystals, plants, animals and nature as a whole. Similarly, principals of symmetry are also some of the fundamental and most useful tools in modern mathematical natural science that play a major role in theory and applications. As a consequence, it is not surprising that the desire to understand the origin of life, based on the genetic code, forces us to involve symmetry as a mathematical concept. The genetic code can be seen as a key to biological self-organisation. All living organisms have the same molecular bases an alphabet consisting of four letters (nitrogenous bases): adenine, cytosine, guanine, and thymine. Linearly ordered sequences of these bases contain the genetic information for synthesis of proteins in all forms of life. Thus, one of the most fascinating riddles of nature is to explain why the genetic code is as it is. Genetic coding possesses noise immunity which is the fundamental feature that allows to pass on the genetic information from parents to their descendants. Hence, since the time of the discovery of the genetic code, scientists have tried to explain the noise immunity of the genetic information. In this chapter we will discuss recent results in mathematical modelling of the genetic code with respect to noise immunity, in particular error-detection and error-correction. We will focus on two central properties: Degeneracy and frameshift correction. DEGENERACY: Different amino acids are encoded by different quantities of codons and a connection between this degeneracy and the noise immunity of genetic information is a long standing hypothesis. Biological implications of the degeneracy have been intensively studied and whether the natural code is a frozen accident or a highly optimised product of evolution is still controversially discussed. Symmetries in the structure of degeneracy of the genetic code are essential and give evidence of substantial advantages of the natural code over other possible ones. In the present chapter we will present a recent approach to explain the degeneracy of the genetic code by algorithmic methods from bioinformatics, and discuss its biological consequences. FRAMESHIFT CORRECTION: The biologists recognised this problem immediately after the detection of the non overlapping structure of the genetic code, i.e., coding sequences are to be read in a unique way determined by their reading frame. But how does the reading head of the ribosome recognises an error in the grouping of codons, caused by e.g. insertion or deletion of a base, that can be fatal during the translation process and may result in nonfunctional proteins? In this chapter we will discuss possible solutions to the frameshift problem with a focus on the theory of so called circular codes that were discovered in large gene populations of prokaryotes and eukaryotes in the early 90s. Circular codes allow to detect a frameshift of one or two positions and recently a beautiful theory of such codes has been developed using statistics, group theory and graph theory. PMID- 28918302 TI - A practical guide to systematic literature reviews and meta-analyses in infection prevention: Planning, challenges, and execution. AB - Systematic literature reviews and meta-analyses are important research designs used to summarize and derive conclusions about the collective evidence on a focused research question in a structured, reproducible manner. The goal of this Methodology Minute is to describe how to conduct a systematic literature review and meta-analysis using a step-by-step approach to help infection preventionists (IPs) and others in the field perform their own systematic literature review and meta-analysis, and to critically evaluate published systematic literature reviews and meta-analyses. PMID- 28918303 TI - Decoding noises in HIV computational genotyping. AB - Lack of a consistent and reliable genotyping system can critically impede HIV genomic research on pathogenesis, fitness, virulence, drug resistance, and genomic-based healthcare and treatment. At present, mis-genotyping, i.e., background noises in molecular genotyping, and its impact on epidemic surveillance is unknown. For the first time, we present a comprehensive assessment of HIV genotyping quality. HIV sequence data were retrieved from worldwide published records, and subjected to a systematic genotyping assessment pipeline. Results showed that mis-genotyped cases occurred at 4.6% globally, with some regional and high-risk population heterogeneities. Results also revealed a consistent mis-genotyping pattern in gp120 in all studied populations except the group of men who have sex with men. Our study also suggests novel virus diversities in the mis-genotyped cases. Finally, this study reemphasizes the importance of implementing a standardized genotyping pipeline to avoid genotyping disparity and to advance our understanding of virus evolution in various epidemiological settings. PMID- 28918304 TI - Haploidentical Transplantation for Older Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome. AB - Allogeneic stem cell transplantation with HLA-matched donors is increasingly used for older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It remains unclear if haploidentical stem cell transplantation (haploSCT) is a suitable option for older patients with this disease. We analyzed 43 patients with AML/MDS (median age, 61 years) who underwent a haploSCT at our institution. All patients received a fludarabine-melphalan-based reduced intensity conditioning regimen and post-transplant cyclophosphamide-based graft versus-host disease (GVHD) prophylaxis. Except for 1 patient who had early death, the remaining 42 patients (98%) engrafted donor cells. The cumulative incidences of grades II to IV and III to IV acute GVHD at 6 months were 35% and 5%, respectively, and chronic GVHD at 2 years was 9%. After a median follow-up of 19 months, 2-year overall survival, progression-free survival (PFS), and relapse incidence were 42%, 42%, and 24%, respectively. Best PFS (74% at 2 years) was seen in patients with intermediate-/good-risk cytogenetics, in first or second remission (hazard ratio, .4; P = .05), and with a younger donor (<=40 years; hazard ratio, .2; P = .01). In conclusion, these data suggest that haploidentical transplantation is safe and effective for older AML/MDS patients. Disease status, cytogenetics, and younger donor age are predictors for improved survival in older patients receiving a haploidentical transplant. PMID- 28918305 TI - Single-center experience with percutaneous lead extraction of cardiac implantable electric devices. AB - BACKGROUND: The estimated incidence of infected cardiac implantable electric devices (CIED) has recently increased to 1-2% in Japan. Extraction of long-term implanted devices is generally difficult. There are few reports about lead extraction in Japan. We describe our experience with and outcomes of lead extraction using excimer lasers, mechanical sheaths, and manual extraction. METHODS: We retrospectively analyzed the characteristics, types of devices, and indications for extraction in 29 patients with 67 leads who required CIED lead extraction at Shinshu University Hospital between April 2014 and October 2016. Mean patient age was 71 years and 25 patients were male. The indications for device extraction were infections (n=25) and non-functioning leads (n=4). RESULTS: A total of 67 leads (active fixation lead, n=28; passive fixation lead, n=39) had been implanted for a median duration of 6.3+/-5.6 years. Extractions were performed using an excimer laser sheath (n=26), laser with mechanical sheath (n=7), only mechanical sheath (Cook Vascular Inc., Leechburg, PA, USA) (n=1), and manually (n=1). The procedure was successful in all patients. There were no major or minor complications during extraction. There was no recurrence of infection after infected device extraction. Two patients were implanted with subcutaneous implantable defibrillators after extraction of the implantable cardioverter defibrillator (ICD). CONCLUSIONS: CIED lead extraction, especially of those that are adherent to the subclavian vein, can be successfully performed in Japanese subjects using an excimer laser and mechanical sheath, without complications. PMID- 28918306 TI - Smoking and risk of atrial fibrillation. AB - Ahmed et al. showed that atrial fibrillation (AF) was identified in 9.5% in smokers vs 7.8% in non-smokers (p<0.001) and smoking was associated with a 15% increased risk of AF during 10 years follow up in 11,047 participants. However, heterogeneities in the association were observed among subgroups; the association was stronger in young compared to older participants and in those with prior cardiovascular disease compared to without cardiovascular disease, also the association was significant in blacks but not in whites [1]. In this editorial, the relationship between smoking and the incidence of atrial fibrillation is reviewed. PMID- 28918307 TI - An application of Bandura's 'Four Sources of Self-Efficacy' to the self management of type 2 diabetes in people with intellectual disability: An inductive and deductive thematic analysis. AB - BACKGROUND: Little is known about the successful experiences and positive perceptions of people with intellectual disabilities (ID) self-managing Type 2 Diabetes (T2D). This study sought to address this gap using Bandura's (1977) 'Four Sources of Self-Efficacy' as a framework of enquiry. METHOD: Semi structured interviews were conducted with 10 adults with ID. Interviews were recorded, transcribed verbatim and analysed using inductive and deductive thematic analysis RESULTS: Nine sub-themes were identified following analysis of the data: 1) Mastery through knowledge; 2) Mastery through tools and strategies; 3) Mastery through autonomy; 4) Influence of social setting; 5) Positive social comparisons; 6) Positive and negative self-statements; 7) Feedback from caregivers; 8) Adjustment experiences; 9) Symptom awareness. These were mapped onto Bandura's (1977) Four Sources of efficacy enhancement model and were consistent with its proposed mechanisms. CONCLUSION: The Four Sources model serves as a useful mode of enquiry for exploring people with ID's experiences and perceptions of self-managing diabetes. It also confirms the appropriateness of Self-efficacy as a potential intervention component for this population. However, additional support may be required for people with ID to reflect meaningfully on their experiences and thus have a sense of self-efficacy. WHAT THIS PAPER ADDS: This paper builds upon the limited existing literature on people with ID self managing type 2 diabetes and provides a robust, qualitative account of the participants' experiences, whilst confirming some of the existing challenges, both for people with ID and their supporters. To self-manage with autonomy and overcome the difficulties of adjustment, further strategies such as training and education needs are highlighted. In addition, the meaning and relevance of the Self-efficacy construct is evaluated in the context of people with ID self managing T2D. This provides useful information in terms of tailoring existing mainstream T2D interventions to meet the needs of people with ID, as such programs are commonly theoretically guided by Self-efficacy. Furthermore, this evaluation provides rationale for the exploration of people with IDs' Self efficacy in relation to other chronic diseases, such as cardiovascular disease, cancer symptoms and gastrointestinal disorders. PMID- 28918308 TI - Appropriateness of different pedagogical approaches to road safety education for children with Developmental Coordination Disorder (DCD). AB - BACKGROUND: In 2016, 29% of pedestrians killed or seriously injured on the roads in Great Britain were under 15 years of age. Children with Developmental Coordination Disorder (DCD), a chronic disorder affecting the acquisition and execution of motor skills, may be more vulnerable at the roadside than typically developing (TD) children. Current methods used to teach road safety are typically knowledge-based and do not necessarily improve behaviour in real traffic situations. Virtual reality road crossing tasks may be a viable alternative. AIMS/METHODS: The present study aimed to test the road crossing accuracy of children with and without DCD in virtual reality tasks that varied the viewpoint to simulate the teaching methods currently used in road safety educational programmes. Twenty-one children with DCD and twenty-one age and gender matched TD peers were required to locate the safest road crossing sites in two conditions: allocentric (aerial viewpoint) and egocentric (first-person viewpoint). PROCEDURES/OUTCOMES: All children completed both conditions and were required to navigate either themselves or an avatar across the road using the safest crossing route. The primary outcome was accuracy defined as the number of trials, out of 10, on which the child successfully identified and used the safest crossing route. RESULTS/CONCLUSIONS: Children with DCD performed equally poorly in both conditions, while TD children were significantly more accurate in the egocentric condition. This difference cannot be explained by self-reported prior road crossing education, practice or confidence. IMPLICATIONS: While TD children may benefit from the development of an egocentric virtual reality road crossing task, multimodal methods may be needed to effectively teach road safety to children with DCD. PMID- 28918309 TI - Health and wellbeing during transition to adulthood for young people with intellectual disabilities: A qualitative study. AB - BACKGROUND: Transition to adulthood may have negative consequences for health and wellbeing in individuals with intellectual disabilities (ID), but this aspect of transition has received little investigation. This qualitative study aimed to explore the transition experiences of individuals with ID from their own perspectives, and from that of their parents, in order to identify health or wellbeing implications of transition. METHOD: Semi-structured interviews were conducted with 17 young people with mild, moderate and severe ID aged 16-27 years and with 23 parents of young people with mild, moderate, severe and profound ID aged 16-26 years. Interviews were analysed using thematic analysis, deploying both emic and etic coding categories. RESULTS: This study provides direct insights into the issues on health and wellbeing that young people with ID and their parents find important during transition. The primary health implication of transition centred on mental health and wellbeing; young people experienced heightened anxiety during transition, and themes identified as contributing to anxiety included: a lack of meaningful activity following school exit; inadequate support during transition; and difficulties associated with 'growing up'. Problem behaviours and obesity were also implicated. CONCLUSION: The transition from school needs to be better supported in order to ease anxiety for young people during this difficult period. PMID- 28918310 TI - Effect of eplerenone on markers of bone turnover in patients with primary hyperparathyroidism - The randomized, placebo-controlled EPATH trial. AB - Mineralocorticoid receptor (MR) antagonism may affect bone turnover via direct and indirect pathways involving parathyroid hormone, but randomized controlled trials are lacking. In a pre-specified analysis of the "Eplerenone in primary hyperparathyroidism" placebo-controlled, randomized trial (ISRCTN 33941607), effects of eight weeks MR-blockade with eplerenone on bone turnover markers in 97 patients with primary hyperparathyroidism were tested. Mean age was 67.5+/ 9.5years, and 76 (78.4%) were females. In analysis of covariance with adjustment for baseline values, eplerenone had no significant effect on isoform 5b of the tartrate-resistant acid phosphatase (TRAP), beta-crosslaps, N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin and bone-specific alkaline phosphatase. There was no significant cross-sectional correlation between plasma aldosterone concentration or the aldosterone-to-renin ratio and markers of bone turnover in multivariate linear regression models at baseline. These data provide first evidence from a randomized and placebo-controlled trial that short-term MR antagonism may not affect bone turnover, at least in patients with primary hyperparathyroidism. PMID- 28918311 TI - Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. AB - Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2. Here we solved the crystal structure of ALK2 in complex with LDN-212854 to define how its binding interactions compare to previously reported BMP and TGFbeta receptor inhibitors. LDN-212854 bound to the kinase hinge region as a typical type I ATP-competitive inhibitor with a single hydrogen bond to ALK2 His286. Specificity arising from the 5-quinoline moiety was associated with a distinct pattern of water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive conformation favoured by ALK2. The structure of this complex provides a template for the design of future ALK2 inhibitors under development for the treatment of FOP and other related conditions of heterotopic ossification. PMID- 28918312 TI - (Reinforcement?) Learning to forage optimally. AB - Foraging effectively is critical to the survival of all animals and this imperative is thought to have profoundly shaped brain evolution. Decisions made by foraging animals often approximate optimal strategies, but the learning and decision mechanisms generating these choices remain poorly understood. Recent work with laboratory foraging tasks in humans suggest their behaviour is poorly explained by model-free reinforcement learning, with simple heuristic strategies better describing behaviour in some tasks, and in others evidence of prospective prediction of the future state of the environment. We suggest that model-based average reward reinforcement learning may provide a common framework for understanding these apparently divergent foraging strategies. PMID- 28918313 TI - Learning with three factors: modulating Hebbian plasticity with errors. AB - Synaptic plasticity is a central theme in neuroscience. A framework of three factor learning rules provides a powerful abstraction, helping to navigate through the abundance of models of synaptic plasticity. It is well-known that the dopamine modulation of learning is related to reward, but theoretical models predict other functional roles of the modulatory third factor; it may encode errors for supervised learning, summary statistics of the population activity for unsupervised learning or attentional feedback. Specialized structures may be needed in order to generate and propagate third factors in the neural network. PMID- 28918314 TI - Empirical research evaluating the effects of non-traditional approaches to enhancing sleep in typical and clinical children and young people. AB - This paper examines the effects of non-traditional (non-behavioural and non prescription pharmaceutical) approaches to sleep in children and young people (0 18 y). A systematic search identified 79 studies that met inclusion criteria. Seventeen percent of the studies were rated as having a conclusive level of evidence, forty-two percent with preponderant evidence and forty-one percent with only suggestive evidence. There were promising indications, with certain populations only, for aromatherapy, ketogenic diets, an elimination diet (few foods diet), elimination of cow's milk, avoidance of caffeine, tryptophan with adenosine and uridine, omega-3 and omega-6, valerian, music, osteopathic manipulation and white noise. Bright light therapy and massage returned some positive results. All of these interventions warrant further, more rigorous research. There was limited or no evidence to support acupressure or acupuncture, other diets or dietary supplements, exercise or weighted blankets. Caution is needed in interpreting some studies because poorer quality studies were more likely to return positive results. Suggestions are made for the improvement of large and smaller scale research, especially conceptualization around multiple physiological measures of sleep and the adoption of research methods which are of use in clinical settings. PMID- 28918315 TI - Does cognitive behavioural therapy for insomnia improve cognitive performance? A systematic review and narrative synthesis. AB - Individuals with insomnia report difficulties pertaining to their cognitive functioning. Cognitive behavioural therapy for insomnia (CBT-I) is associated with robust, long-term improvements in sleep parameters, however less is known about the impact of CBT-I on the daytime correlates of the disorder. A systematic review and narrative synthesis was conducted in order to summarise and evaluate the evidence regarding the impact of CBT-I on cognitive functioning. Reference databases were searched and studies were included if they assessed cognitive performance as an outcome of CBT-I, using either self-report questionnaires or cognitive tests. Eighteen studies met inclusion criteria, comprising 923 individuals with insomnia symptoms. The standardised mean difference was calculated at post-intervention and follow-up. We found preliminary evidence for small to moderate effects of CBT-I on subjective measures of cognitive functioning. Few of the effects were statistically significant, likely due to small sample sizes and limited statistical power. There is a lack of evidence with regards to the impact of CBT-I on objective cognitive performance, primarily due to the small number of studies that administered an objective measure (n = 4). We conclude that adequately powered randomised controlled trials, utilising both subjective and objective measures of cognitive functioning are required. PMID- 28918316 TI - MR-guided joint reconstruction of activity and attenuation in brain PET-MR. AB - With the advent of time-of-flight (TOF) PET scanners, joint maximum-likelihood reconstruction of activity and attenuation (MLAA) maps has recently regained attention for the estimation of PET attenuation maps from emission data. However, the estimated attenuation and activity maps are scaled by unknown scaling factors. We recently demonstrated that in hybrid PET-MR, the scaling issue of this algorithm can be effectively addressed by imposing MR spatial constraints on the estimation of attenuation maps using a penalized MLAA (P-MLAA+) algorithm. With the advent of simultaneous PET-MR systems, MRI-guided PET image reconstruction has also gained attention for improving the quantitative accuracy of PET images, usually degraded by noise and partial volume effects. The aim of this study is therefore to increase the benefits of MRI information for improving the quantitative accuracy of PET images by exploiting MRI-based anatomical penalty functions to guide the reconstruction of both activity and attenuation maps during their joint estimation. We employed an anato-functional joint entropy penalty function for the reconstruction of activity and an anatomical quadratic penalty function for the reconstruction of attenuation. The resulting algorithm was referred to as P-MLAA++ since it exploits both activity and attenuation penalty functions. The performance of the P-MLAA algorithms were compared with MLAA and the widely used activity reconstruction algorithms such as maximum likelihood expectation maximization (MLEM) and penalized MLEM (P-MLEM) both corrected for attenuation using a conventional MRI segmentation-based attenuation correction (MRAC) method. The studied methods were evaluated using simulations and clinical studies taking the PET image reconstructed using reference CT-based attenuation maps as a reference. The simulation results showed that the proposed method can notably improve the visual quality of the PET images by reducing noise while preserving structural boundaries and at the same time improving the quantitative accuracy of the PET images. Our clinical reconstruction results showed that the MLEM-MRAC, P-MLEM-MRAC, MLAA, P-MLAA+ and P-MLAA++ algorithms result in, on average, quantification errors of -13.5 +/- 3.1%, -13.4 +/- 3.1%, 2.0 +/- 6.5%, -3.0 +/- 3.5% and -4.2 +/- 3.6%, respectively, in different regions of the brain. In conclusion, whilst the P-MLAA+ algorithm showed the best overall quantification performance, the proposed P-MLAA++ algorithm provided simultaneous partial volume and attenuation corrections with only a minor compromise of PET quantification. PMID- 28918317 TI - Bithionol residue analysis in animal-derived food products by an effective and rugged extraction method coupled with liquid chromatography-tandem mass spectrometry. AB - Herein, we developed a simple analytical procedure for the quantitation of bithionol residues in animal-derived food products such as porcine muscle, eggs, milk, eel, flatfish, and shrimp using a modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction method coupled with liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI+/MS-MS). Samples were extracted with 0.1% solution of formic acid in acetonitrile and the extract was purified using a C18 sorbent. Separation was performed on a Waters XBridgeTM C18 reversed-phase analytical column using 0.1% solution of formic acid/acetonitrile as the mobile phase. Six-point matrix-matched calibration indicated good linearity, with the calculated coefficients of determination (R2) being>=0.9813. Intra- and inter-day recoveries (determined at spiking levels equivalent to 1*and 2*the limit of quantitation (0.25MUg/kg)) ranged between 80.0 and 94.0%, with the corresponding relative standard deviations (RSDs) being<=8.2%. The developed experimental protocol was applied to different samples purchased from local markets in Seoul, which were tested negative for bithionol residues. In conclusion, the proposed method proved to be versatile and precise, being ideally suited for the routine detection of bithionol residues in animal-derived food products with various protein and fat contents. PMID- 28918318 TI - High sensitivity method validated to quantify estradiol in human plasma by LC MS/MS. AB - 17beta-Estradiol (E2) is an endogenous steroid in the human body. Its measurement is important for health and human biology understanding. However, E2 concentration in human plasma is in the range of pg/mL, which makes it difficult to detect. In this way, LC-MS/MS has been shown the most sensitive tool, although E2 is a weakly ionizable molecule. In this work, we validated a more sensitive and accurate method for E2 quantification in human plasma. Our extraction step ensured a cleaner chromatography, resulting in a precise measurement and highly reproducible method in the range of 2-150pg/mL. Moreover, we proved a long stability for E2 in several conditions. All results indicate that our developed method is robust and sensitive enough to apply in bioequivalence studies for E2 measurement in human plasma, even at very low concentrations. PMID- 28918319 TI - Determination of chlorogenic acids and caffeine in homemade brewed coffee prepared under various conditions. AB - Coffee, a complex mixture of more than 800 volatile compounds, is one of the most valuable commodity in the world, whereas caffeine and chlorogenic acids (CGAs) are the most common compounds. CGAs are mainly composed of caffeoylquinic acids (CQAs), dicaffeoylquinic acids (diCQAs), and feruloylquinic acids (FQAs). The major CGAs in coffee are neochlorogenic acid (3-CQA), cryptochlorogenic acid (4 CQA), and chlorogenic acid (5-CQA). Many studies have shown that it is possible to separate the isomers of FQAs by high-performance liquid chromatography (HPLC). However, some authors have shown that it is not possible to separate 4 feruloylquinic acid (4-FQA) and 5-feruloylquinic acid (5-FQA) by HPLC. Therefore, the present study was designated to investigate the chromatographic problems in the determination of CGAs (seven isomers) and caffeine using HPLC-DAD. The values of determination coefficient (R2) calculated from external-standard calibration curves were >0.998. The recovery rates conducted at 3 spiking levels ranged from 99.4% to 106.5% for the CGAs and from 98.8% to 107.1% for the caffeine. The precision values (expressed as relative standard deviations (RSDs)) were <7% and <3% for intra and interday variability, respectively. The tested procedure proved to be robust. The seven CGAs isomers except 4-FQA and 5-FQA were well distinguished and all gave good peak shapes. We have found that 4-FQA and 5-FQA could not be separated using HPLC. The method was extended to investigate the effects of different brewing conditions such as the roasting degree of green coffee bean, coffee-ground size, and numbers of boiling-water pours, on the concentration of CGAs and caffeine in homemade brewed coffee, using nine green coffee bean samples of different origins. It was reported that medium-roasted, fine-ground coffees brewed using three pours of boiling water were the healthiest coffee with fluent CGAs. PMID- 28918321 TI - Extending donor size in D-A-pi-A organic dye for dye sensitized solar cells: Anti aggregation and improving electron injection. AB - We have theoretically designed two D-A-pi-A dyes 3 and 4 based on the efficient references 1 and 2 by introducing an extra electron donor unit (D2). Via calculating the electronic structures of isolated dyes, we obtain that dyes 3 and 4 possess stronger light-harvesting efficiency imparted by the fluorescence energy transfer of D2 part, maintain comparable lifetime of excited states, and shorten the electron injection time significantly with regard to 1 and 2. Meanwhile, dye 3 positively shifts the edge of virtual states of TiO2 in a larger extent compared to its counterparts. Then after considering the alignment morphology of multiple dyes adsorbed on TiO2 surface, we find that dyes 3 and 4 manifest the capability of anti-aggregation obviously, which is evidenced by the smaller quantity of intermolecular electronic coupling compared to that of dyes 1 and 2, definitively illustrating the prominent performance of novel dyes with the bulky D2 moiety. Finally, dye 3 is screened out as the potential candidate for future application. PMID- 28918320 TI - In silico interaction analysis of cannabinoid receptor interacting protein 1b (CRIP1b) - CB1 cannabinoid receptor. AB - Cannabinoid Receptor Interacting Protein isoform 1b (CRIP1b) is known to interact with the CB1 receptor. Alternative splicing of the CNRIP1 gene produces CRIP1a and CRIP1b with a difference in the third exon only. Exons 1 and 2 encode for a functional domain in both proteins. CRIP1a is involved in regulating CB1 receptor internalization, but the function of CRIP1b is not very well characterized. Since there are significant identities in functional domains of these proteins, CRIP1b is a potential target for drug discovery. We report here predicted structure of CRIP1b followed by its interaction analysis with CB1 receptor by in-silico methods A number of complementary computational techniques, including, homology modeling, ab-initio and protein threading, were applied to generate three dimensional molecular models for CRIP1b. The computed model of CRIP1b was refined, followed by docking with C terminus of CB1 receptor to generate a model for the CRIP1b- CB1 receptor interaction. The structure of CRIP1b obtained by homology modelling using RHO_GDI-2 as template is a sandwich fold structure having beta sheets connected by loops, similar to predicted CRIP1a structure. The best scoring refined model of CRIP1b in complex with the CB1 receptor C terminus peptide showed favourable polar interactions. The overall binding pocket of CRIP1b was found to be overlapping to that of CRIP1a. The Arg82 and Cys126 of CRIP1b are involved in the majority of hydrogen bond interactions with the CB1 receptor and are possible key residues required for interactions between the CB1 receptor and CRIP1b. PMID- 28918322 TI - Time for TIGER to ROAR! Technology Informatics Guiding Education Reform. AB - Information Technology (IT) continues to evolve and develop with electronic devices and systems becoming integral to healthcare in every country. This has led to an urgent need for all professions working in healthcare to be knowledgeable and skilled in informatics. The Technology Informatics Guiding Education Reform (TIGER) Initiative was established in 2006 in the United States to develop key areas of informatics in nursing. One of these was to integrate informatics competencies into nursing curricula and life-long learning. In 2009, TIGER developed an informatics competency framework which outlines numerous IT competencies required for professional practice and this work helped increase the emphasis of informatics in nursing education standards in the United States. In 2012, TIGER expanded to the international community to help synthesise informatics competencies for nurses and pool educational resources in health IT. This transition led to a new interprofessional, interdisciplinary approach, as health informatics education needs to expand to other clinical fields and beyond. In tandem, a European Union (EU) - United States (US) Collaboration on eHealth began a strand of work which focuses on developing the IT skills of the health workforce to ensure technology can be adopted and applied in healthcare. One initiative within this is the EU*US eHealth Work Project, which started in 2016 and is mapping the current structure and gaps in health IT skills and training needs globally. It aims to increase educational opportunities by developing a model for open and scalable access to eHealth training programmes. With this renewed initiative to incorporate informatics into the education and training of nurses and other health professionals globally, it is time for educators, researchers, practitioners and policy makers to join in and ROAR with TIGER. PMID- 28918323 TI - Quantitative determination of carfilzomib in mouse plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. AB - A highly sensitive and rapid LC-MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpropamide were extracted from 5 MUL of plasma after protein precipitation with acetonitrile. Chromatographic separation was performed on Phenomenex Luna C18 column (50*2.0mm id, 3MUm). The mobile phase consisted of 0.1% formic acid in acetonitrile -0.1% formic acid in water (1:1v/v) and the flow rate was 0.3mL/min. The total chromatographic run time was 2.5min. Detection was performed on a triple quadrupole mass spectrometer equipped with positive-ion electrospray ionization by selected reaction monitoring of the transitions at m/z 720.20>100.15 (for carfilzomib) and m/z 277.05>111.05 (for the internal standard). The lower limit of quantification was 0.075ng/mL and the linear range was 0.075-1250ng/mL (r>=0.9974). All validation data, including selectivity, precision, accuracy, matrix effect, recovery, dilution integrity, stability, and incurred sample reanalysis, were well within acceptance limits. This newly developed bioanalytical method was simple, highly sensitive, required only a small volume of plasma, and was suitable for application in pharmacokinetic studies in mice that used serial blood sampling. PMID- 28918324 TI - Simultaneous determination and pharmacokinetic study of twelve bioactive compounds in rat plasma after intravenous administration of Xuebijing injection by UHPLC-Q-Orbitrap HRMS. AB - Xuebijing injection (XBJ) is a traditional Chinese herbal prescription widely used in the treatment of sepsis. Extensive studies revealed that the major bioactive constituents of XBJ injection, including phenolic acids, flavonoids, monoterpene glycosides, lactones and organic acids, play an important role in the treatment. In this study, a rapid, sensitive and accurate ultra high performance liquid chromatography - Q Exactive hybrid quadrupole - orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) method was developed for simultaneous determination of twelve bioactive compounds in rat plasma after intravenous administration of XBJ injection. A gradient elution for separation was achieved on a waters ACQUITY UHPLC(r) BEH C18 column (2.1mm*50mm, 1.7MUm) column with acetonitrile-water (containing 0.1% formic acid) as mobile phase at a flow rate of 0.2mL/min. All compounds and IS were monitored by parallel reaction monitoring assay both in positive and negative ion mode. The developed method was validated for intra-day and inter-day accuracy and precision whose values fell in the acceptable limits. Extraction recoveries at three levels of QC concentrations were all more than 80% for all compounds and IS, and matrix effects were found in the range of 80.0-120.0%. Stability results showed that all analytes were stable at the investigated conditions. The validated method was successfully applied to a pharmacokinetic study of Xuebijing injection following intravenous administration of 2.5, 5.0, 10.0mL/kg to rats respectively. And the result indicated that the pharmacokinetic behavior of XBJ injection is positively related to dosage at the range of 2.5-10mg/kg. This study will provide a meaningful basis for evaluating the rationality of XBJ injection for clinical application. PMID- 28918325 TI - A novel LC-MS/MS method for the quantitative measurement of the acetate content in pharmaceutical peptides. AB - Most pharmaceutical peptides are supplied as acetate salts and the relative amount of acetate to peptide in the final product is one quality criterion required by regulatory agencies to approve the product for clinical use. The objective of the present study was to develop a validated LC-MS/MS method that allows the quantitative determination of the acetate content in pharmaceutical peptide preparations and simultaneous monitoring and collection of qualitative and quantitative information on the peptide during manufacture and in the final product. The method uses reversed phase C18-chromatography to elute the acetate ions under acidic conditions, pH 3, followed by post-column infusion of ammonium hydroxide 0.6M, methanolic solution (30:70) at a rate of 0.5mL/hr. The acetate ions were monitored in negative polarity mass spectrometry by pseudo multiple reaction monitoring (pseudo MRM) against 1, 2- 13C labelled acetate, the internal standard used in the method. The method was linear for acetate concentrations between 0.4 and 25MUg/mL with a coefficient of determination (r2) equal to 0.9999. The minimum level of detection and minimum level of quantification were at 0.06MUg/mL and 0.18MUg/mL respectively. Accuracy of the method was judged by determining the acetate content in a commercial product of the peptide pharmaceutical tetracosactide (TCS) and parallel comparison to the amounts determined by a reversed phase HPLC method with detection at a wavelength of 210nm. The amounts determined by the two methods were in agreement with a RSD that was less than 2%. Additional confirmation of method accuracy was determined by spiking the pharmaceutical peptide with varying amounts of acetate. The recoveries ranged on average between 101 and 102% for the spiked amounts. Accuracy was also determined by calculating the percentage relative error of the predicted to actual acetate concentration in quality controls and was determined to be less than 5%. The LC-MS/MS method was precise with an intra- and inter-day RSD of less than 5%. The standard solutions were stable for at least one month when kept frozen at -80 degrees C with no loss in response and an inter-day RSD of less than 5%. The method was applied to quantify the acetate content in the clinically available product of TCS and to simultaneously evaluate the average peptide molecular weight and detect known impurities by switching from negative polarity MRM analysis to positive polarity MS analysis following the elution of the acetate peak. The method reported herein should corroborate quantitative determinations of the acetate content in pharmaceuticals by the traditional compendial HPLC method. PMID- 28918326 TI - A surrogate analyte-based liquid chromatography-tandem mass spectrometry method for the determination of endogenous cyclic nucleotides in rat brain. AB - A robust high-performance liquid chromatography tandem mass spectrometry (LC MS/MS) assay was developed and qualified for the measurement of cyclic nucleotides (cNTs) in rat brain tissue. Stable isotopically labeled 3',5'-cyclic adenosine-13C5 monophosphate (13C5-cAMP) and 3',5'-cyclic guanosine-13C,15N2 monophosphate (13C15N2-cGMP) were used as surrogate analytes to measure endogenous 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP). Pre-weighed frozen rat brain samples were rapidly homogenized in 0.4M perchloric acid at a ratio of 1:4 (w/v). Following internal standard addition and dilution, the resulting extracts were analyzed using negative ion mode electrospray ionization LC-MS/MS. The calibration curves for both analytes ranged from 5 to 2000ng/g and showed excellent linearity (r2>0.996). Relative surrogate analyte-to-analyte LC-MS/MS responses were determined to correct concentrations derived from the surrogate curves. The intra run precision (CV%) for 13C5-cAMP and 13C15N2-cGMP was below 6.6% and 7.4%, respectively, while the inter-run precision (CV%) was 8.5% and 5.8%, respectively. The intra-run accuracy (Dev%) for 13C5-cAMP and 13C15N2-cGMP was <11.9% and 10.3%, respectively, and the inter-run Dev% was <6.8% and 5.5%, respectively. Qualification experiments demonstrated high analyte recoveries, minimal matrix effects and low autosampler carryover. Acceptable frozen storage, freeze/thaw, benchtop, processed sample and autosampler stability were shown in brain sample homogenates as well as post-processed samples. The method was found to be suitable for the analysis of rat brain tissue cAMP and cGMP levels in preclinical biomarker development studies. PMID- 28918327 TI - Determination of ketamine and its main metabolites by liquid chromatography coupled to tandem mass spectrometry in pig plasma: Comparison of extraction methods. AB - A rapid, sensitive and specific liquid chromatography coupled to tandem mass spectrometry method was developed for the simultaneous quantification pig plasma of ketamine and its two principal metabolites, norketamine and dehydronorketamine. Three extraction procoles were assessed including acetonitrile precipitation, OaseTM microplate extraction, and liquid-liquid extraction. OaseTM microplate extraction induced no significant matrix effect, important signal/noise ratio and good recoveries, ranging from 82 to 87% for the considered compounds. Using this extraction procedure, the assay was linear in the dynamic range 10-3000ng/mL (R2>0.99) regardless of the analytes. Intra- and inter-day accuracies were less than 12% for all compounds and intra- and inter day precisions expressed as RSD were within <9.9%. Samples were stable in different storage conditions. High ketamine, norketamine and dehydronorketamine concentrations up to 15,000ng/mL can be determined with good precision using appropriate sample dilution. The assay was successfully applied to pig plasma samples to determine the pharmacokinetics of ketamine and the consecutive metabolites after buccal administration of a 4mg/kg ketamine base solutions. PMID- 28918328 TI - Semiautomated determination of neonicotinoids and characteristic metabolite in urine samples using TurboFlowTM coupled to ultra high performance liquid chromatography coupled to Orbitrap analyzer. AB - A semiautomated method based on ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap high resolution mass spectrometry has been developed for the determination of neonicotinoids (imidacloprid, acetamiprid, clothianidin, dinotefuran, nitenpyram, thiacloprid and thiamethoxam) and the metabolite acetamiprid-n-desmethyl in urine samples. Two automated methods were tested (solid-phase extraction "SPE" and turbulent flow chromatography "TurboFlowTM"), obtaining the best results when TurboFlowTM was applied. The total analysis time for the developed method was 14min. The optimized method was validated, obtaining suitable results for all validation parameters. Recoveries ranged from 78% to 116% meanwhile repeatability and reproducibility were evaluated obtaining values lower than 10% and 20% respectively (except for dinotefuran and nitenpyram at 0.2MUgL-1). The limit of quantification (LOQ) for all compounds was established at 0.2MUgL-1. The proposed analytical methodology was applied to analyze the target compounds in thirty six urine samples from pregnant women living in agricultural areas of Almeria (Spain). Imidacloprid, acetamiprid and acetamiprid n-desmethyl were detected in some of the samples at concentrations ranging from 0.23 to 1.57MUgL-1. Furthermore, dinotefuran was identified in two samples at trace levels. PMID- 28918329 TI - An integrated strategy for rapid discovery and identification of the sequential piperine metabolites in rats using ultra high-performance liquid chromatography/high resolution mass spectrometery. AB - Piperine, one of the major bioactive constituents isolated from natural flavorings and medicinal-culinary herbs, possesses various biological activities. In the present study, an integrated strategy based on ultra high-performance liquid chromatography/high resolution mass spectrometry was established to reveal piperine metabolism in rats. First of all, post-acquisition data-mining methods, including high resolution extracted ion chromatograms (HREICs) and multiple mass defect filtering (MMDF), were used to screen piperine metabolite candidates in a full-scan HRMS1 level. Then, parent ion list-dynamic exclusion coupled with data dependent data-acquisition method was utilized to acquire MSn datasets. In addition, the established reverse molecular assembly (RMA) approach based on paired diagnostic product ions (pDPIs) coupled with neutral loss fragments (NLFs) was used to ascertain and identify the major-to-trace piperine metabolites efficiently. And then, the calculated ClogP values were utilized to distinguish the positional isomers. As a result, a total of 148 piperine metabolites were detected and characterized tentatively. The results demonstrated that piperine mainly underwent hydrogenation, dehydrogenation, hydroxylation, glucuronide conjugation, sulfate conjugation, ring-cleavage, and their composite reactions. Our results not only provided novel and useful data to better understand the safety, toxicity and efficacy of this potential therapeutic agent, but also indicated that the proposed strategy was reliable for a rapid discovery and identification drug-related constituents in vivo. PMID- 28918331 TI - Correction. PMID- 28918330 TI - Thick target total bremsstrahlung spectra of lead compounds in the photon energy region 1-10keV by 90Sr beta particles. AB - Total bremsstrahlung spectral photon distribution generated in thick targets of lead compounds Pb(CH3COO)2.3H2O, Pb(NO3)2 and PbCl2 by 90Sr beta particles has been investigated theoretically and experimentally in the photon energy region 1 10keV. The experimental results are compared with the theoretical models describing ordinary bremsstrahlung and the theoretical model which includes polarization bremsstrahlung into ordinary bremsstrahlung, in stripped approximation. It is observed that the experimental results show better agreement with the model which describes bremsstrahlung in stripped approximation in the energy range 3-10keV. However, the results show positive deviation in the photon energy region of 1-3keV. Further, it has been found that there is a continuous decrease of polarization bremsstrahlung contribution into ordinary bremsstrahlung in the formation of total bremsstrahlung spectra with increase in photon energy. The suppression of polarization bremsstrahlung has been observed due to the presence of large fraction of low Z elements in the compounds. The results clearly indicate that polarization bremsstrahlung plays an important role in the formation of total bremsstrahlung spectra in compounds in the studied energy region. PMID- 28918332 TI - Control of absence epilepsy seizures in specific relay nuclei of thalamus. AB - In this paper, we used a classic basal ganglia-corticothalamic model(BGCT) to study the onset and control mechanism of absence epilepsy in specific relay nuclei (SRN) of thalamus. It was found that the seizure state may appear in SRN by turning the coupling strength -vsr and signal transmission delay tau on the route "Thalamic reticular nuclei (TRN) of thalamus ? SRN". With increasing of vsr, the seizure state appeared two times, and its onset mechanism has not been discussed in previous studies. The seizure activity can be well controlled by adjusting the activation level of the substantia nigra pars reticulata (SNr) in basal ganglia, which is a main output tissue to the corticothalamic system through two direct inhibitory pathways "SNr ? SRN" and "SNr ? TRN" in our model. We found that the interesting bidirectional regulation phenomenon appeared as considering the single pathway "SNr ? SRN" and "SNr ? TRN", or when they coexisted in one network, the mechanism of which is also different from some previous theoretical studies. At last, we pointed out that the mechanism obtained above can also explain the onset and control of the poly-spikes slow wave appeared in SRN by turning tau to large enough. Therefore, the results in the paper will further deepen our understanding of the generation and control mechanism of epilepsy disease. PMID- 28918333 TI - The relationship between coherence and the phase-locking value. PMID- 28918334 TI - Inner mechanism of protection of mitochondrial electron-transfer proteins against oxidative damage. Focus on hydrogen peroxide decomposition. AB - It is generally recognized that the mitochondria are the major source of reactive oxygen species including hydrogen peroxide (H2O2). Although the local concentration of H2O2 near the electron-transfer chain is potentially quite high, the chain's components are rarely found to be significantly damaged by H2O2. Our experimental data, as well as the data published by others, suggest that mitochondrial electron-transfer proteins, which are in the first line to be harmed by ROS, are well prepared to defend themselves. One of such protection mechanism involves peroxidase/catalase-like activity of all major mitochondrial respiration chain players, which catalyze the decomposition of H2O2. Understanding the molecular mechanisms, by which mitochondrial electron-transfer proteins might defend themselves against an oxidative stress and therefore being a part of the mitochondrial antioxidant system, can help to clarify many controversial experimental data. PMID- 28918335 TI - Modern diagnosis of chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) should be suspected in patients presenting persistent dyspnea three months after a pulmonary embolism or in patients presenting with acute pulmonary embolism and suggestive images on the CT-scan. For these patients, a specific diagnostic work-up should be performed. First step consists of the ventilation/perfusion (V/Q) scan which is a good screening test due to its high sensitivity and high negative predictive value. Pulmonary angiography remains the gold standard approach for the confirmation of the diagnosis and pre-surgical evaluation of CTEPH. New emerging technologies such as Dual-Energy Computed Tomography angiography (DECT) and Computed Tomography angiography (CTA) are developing and broadly available. These non invasive methods provide diagnostic information similar to conventional pulmonary angiography and surgical operability information. They are to be considered as an alternative in the diagnostic approach of patients with CTEPH as presented in the ESC/ERS guidelines. Haemodynamic measurement whiles exercising during right heart catheterization may improve diagnostic sensitivity of CTEPH and could therefore be used as a diagnostic test in patient with normal haemodynamic at rest. PMID- 28918336 TI - Total and cytosolic concentrations of twenty metals/metalloids in the liver of brown trout Salmo trutta (Linnaeus, 1758) from the karstic Croatian river Krka. AB - Total and cytosolic concentrations of twenty metals/metalloids in the liver of brown trout Salmo trutta (Linnaeus, 1758) were studied in the period from April 2015 to May 2016 at two sampling sites on Croatian river Krka, to establish if river water contamination with metals/metalloids downstream of Knin town has influenced metal bioaccumulation in S. trutta liver. Differences were observed between two sites, with higher concentrations of several elements (Ag, As, Ca, Co, Na, Se, Sr, V) found downstream of Knin town, whereas few others (Cd, Cs, Mo, Tl) were, unexpectedly, increased at the Krka River spring. However, total metal/metalloid concentrations in the liver of S. trutta from both sites of the Krka River were still mainly below previously reported levels for pristine freshwaters worldwide. The analysis of seasonal changes of metal/metalloid concentrations in S. trutta liver and their association with fish sex and size mostly indicated their independence of fish physiology, making them good indicators of water contamination and exposure level. Metal/metalloid concentrations in the metabolically available hepatic cytosolic fractions reported in this study are the first data of that kind for S. trutta liver, and the majority of analyzed elements were present in the cytosol in the quantity higher than 50% of their total concentrations, thus indicating their possible availability for toxic effects. However, the special attention should be directed to As, Cd, Cs, and Tl, which under the conditions of increased exposure tended to accumulate more within the cytosol. Although metal/metalloid concentrations in S. trutta liver were still rather low, monitoring of the Krka River water quality and of the health status of its biota is essential due to a trend of higher metal/metalloid bioaccumulation downstream of Knin town, especially taking into consideration the proximity of National Park Krka and the need for its conservation. PMID- 28918337 TI - Ecotoxicological and microbiological assessment of sewage sludge associated with sugarcane bagasse. AB - Sewage sludge (SS) obtained after sewage treatment process may contain several toxic substances. Bioremediation can decrease the toxicity of the sludge, mainly when it is associated with stimulant agents, such as sugarcane bagasse (B). Samples of pure SS (SSP); SS+B; SS+Soil; and SS+B+Soil were bioremediated for 1, 3, and 6 months (T1, T2, and T3, respectively). After each period, the cytotoxic, genotoxic, and mutagenic potentials of the solid samples and their respective aqueous extracts (aqueous eluate and percolate water) were evaluated by the Allium cepa test. A microbiological analysis of the samples was also performed after each period tested. All solid samples of SS+B (in T1, T2, and T3) and the solid sample of SSP (treatment T3) showed a significant decrease of cell division (cytotoxic effects). The aqueous eluate extracts of SS+B (T1 and T3) and SSP (T2 and T3) induced cytotoxic effect. The solid sample of SS+B (T2 and T3) and aqueous extracts of SSP (T1) were genotoxic, indicating a harmful effect of SS on A. cepa, even after 6 months of bioremediation. There was an alternation in the microbial community both in diversity and in abundance, with the predominance of nonfermenting gram-negative bacilli. The tested bioremediation periods were not sufficient for the complete detoxification of SS, and the use of B did not seem to contribute to the degradation of the pollutants to inert compounds. These data emphasize that a specific relationship should exist between the sludge characteristic and the biostimulating agent used to promote a more efficient bioremediation. These results suggest the necessity to study longer periods of biodegradation and the use of other decomposing agents for greater safety and sustainability for the agricultural use of this residue. PMID- 28918338 TI - A short-term swimming speed alteration test with nauplii of Artemia franciscana. AB - The presence of toxicant needs to be assessed within short time in order to effectively protect the aquatic environment from serious threat. Based on the observation that at high temperatures aquatic organisms become more vulnerable to stressors than those maintained at room temperature, a new test was developed. The proposed bioassay consisted in the evaluation of the swimming speed alteration (SSA) of nauplii of Artemia franciscana incubated at 39 degrees C (+/- 1) for 6h, using a Swimming Behavior Recorder system (SBR). A comparative ecotoxicological study between the 6h SSA test and the 24h mortality test was carried out in order to validate the new method in terms of sensitivity by means of EC50 values. The bioassay was applied to screen different toxicants: K2Cr2O7, Cu(SO4)2, NaClO, SDS and Sertraline hydrochloride. The EC50s calculated for the short-term SSA test and those of the mortality test showed comparable values. For all toxicants, the 6h SSA test was proved to be as sensitive as the 24h mortality test. The method developed in this study is the first temperature-based toxicity test with nauplii of Artemia franciscana and it represents an attractive assay in ecotoxicology because of its convenience in terms of time and costs, feasibility and sensitivity. PMID- 28918339 TI - Interference of dibutylphthalate on human prostate cell viability. AB - Dibutylphthalate (DBP) is an environmental pollutant widely used as plasticizer in a variety of industrial applications worldwide. This agent can be found in personal-care products, children's toy, pharmaceuticals, food products. Exposure to DBP can occur via ingestion and inhalation as well as intravenous or skin contact. DBP belongs to the family of endocrine disrupting chemicals (EDCs) and its effects on reproductive system were demonstrated both in vivo and in vitro. In the present study we evaluated the effects of DBP on human prostate adenocarcinoma epithelial cells (LNCaP) in order to highlight xenoestrogens influence on human prostate. Moreover, we have compared DBP effects with 17beta estradiol action in order to investigate possible mimetical behaviour. We have assessed the effects of both compounds on the cell viability. After then, we have evaluated the expression of genes and proteins involved in cell cycle regulation. Furthermore, we have observed the expression and the cell localization of estrogen (ERs) and androgen (AR) receptors. In conclusion, we have demonstrated that DBP interacts with estrogen hormonal receptor pathway but differently from E2. DBP alters the normal gland physiology and it is involved in the deregulation of prostate cell cycle. PMID- 28918340 TI - [Cervical lift: An update]. AB - The neck is an aesthetic unit for which a rejuvenation request is sometimes very targeted or ore often encompassed in a global surgical project of face-lift. To obtain a long lasting outcome, the plastic surgeon has to make a full, detailed, and exhaustive analysis of the neck in order to choose the best indication within the multiple surgical tools. A full clinical examination is the key point, every aspects are outlined. The numerous surgical choices are described, illustrated, and sometimes revisited in the light of targeted anatomical studies. A didactic and graduated way is used to explain the recent evolutions of the surgical tools of the cervical lifting. Complications and insufficiencies in outcomes must be identified and explained. Finally, we illustrate this development by clinical cases. The surgical improvement of the cervical region is, for us, centered on the reconstruction of a cervical retaining structure: the Cervico-Mandibular Angle Suspensor (CMAS) ligament. This element makes it possible to understand and integrate the large number of technical proposals for cervical lifting. PMID- 28918341 TI - Is first-trimester HbA1c useful in the diagnosis of gestational diabetes? AB - AIMS: To evaluate the usefulness and efficacy of first-trimester HbA1c in the diagnosis of gestational diabetes (GDM). METHODS: Prospective observational of consecutive pregnant women. All women had a first-trimester HbA1c determination and GDM screening at 24-28weeks of pregnancy using a two-step approach. A ROC curve was drawn to determine the sensitivity and specificity of HbA1c in detecting GDM and a rule-in rule-out diagnostic algorithm was proposed. The cost of the proposed algorithm was calculated. RESULTS: 152 (13.1%) of 1195 women were diagnosed of GDM. The area under the ROC curve for HbA1c to detect GDM was 0.679 (95%CI 0.631-0.727). A rule-out threshold for HbA1c of 4.8% (29mmol/mol) had 96.7% sensitivity (95%CI 93.9-99.5), 10.1% specificity (95%CI 8.3-12.0) and a negative predictive value of 95.3% (95%CI 91.3-99.3). A rule-in value of 5.6% (38mmol/mol) had a positive predictive value of 31.6% (95%CI 24.4-38.9), 89.3% specificity (95%CI 87.4-91.2) and 32.9% sensitivity (95%CI 25.4-40.4). The low positive predictive value of the rule-in threshold precludes its use for GDM diagnosis, but could be used to identify women at high risk of GDM in whom the diagnosis can be established using a one-step approach. The overall saving of the proposed algorithm would be 6.5% of the total cost with the standard strategy. CONCLUSIONS: A first-trimester HbA1c does not have sufficient sensitivity or specificity to diagnose GDM, although the use of a higher and lower threshold could simplify the diagnostic process by reducing the number of oral glucose tolerance test, associated costs and patient inconvenience. PMID- 28918342 TI - The potential effect of ultra-long insulin degludec on glycemic variability. AB - Despite the therapeutic advances in the treatment of diabetes, metabolic control instability due to glycemic variability (GV) is frequently observed in patients with diabetes on intensive insulin therapy and is associated with hyperglycemic peaks and hypoglycemic episodes. Hyperglycemia associated with GV has been implicated in the development of chronic complications due to its pro-oxidative consequences. On the other hand, hypoglycemia can be associated with increased cardiovascular risk secondarily to adrenergic activation. The ultra-long-acting insulin analogue, insulin degludec (IDeg), presents a flat and stable glucose lowering effect both in Type 1 and Type 2 diabetes patients. In pharmacodynamic studies, IDeg has been associated with a lower variability in its insulin action than other alternatives for basal insulin, which might have clinical advantages for the stability of the glycemic control. The main objective of this review is to present pharmacological and clinical data regarding the efficacy and safety of IDeg for the treatment of diabetes focusing on its effects on GV and on hypoglycemia frequency. PMID- 28918343 TI - Emotion and self in psychotic disorders: Behavioral evidence from an emotional evaluation task using verbal stimuli varying in emotional valence and self reference. AB - BACKGROUND AND OBJECTIVES: Psychotic disorders are accompanied by changes in emotional and self-referential processing. This behavioral study investigates the link between emotional and self-referential processing in 21 psychotic patients with and without symptoms of disordered self-processing and 21 healthy age matched controls during emotional evaluation of words varying in emotional valence and self-reference. METHODS: Emotional and neutral words related to the self of the reader (e.g., "my fear", "my happiness", "my books"), to the self of another person, unknown to the reader (e.g., "his fear", "his happiness", "his books") or without person reference (e.g., "the fear", "the happiness", "the books") had to be judged in reference to one's own feelings as positive, negative or neutral. RESULTS: Compared to healthy controls (HC) psychotic patients with symptoms of self-disorders (PwSD) showed significantly reduced valence congruent judgments in response to self-related (particularly positive and negative) words and no difference between self-, other-, and personally unreferenced positive words. These differences between PwSD and HC were also reflected in post experimental ratings of subjective experience. Additionally, no reaction time or memory advantage for self-related or emotional words could be found in psychotic patients irrespective of the presence of self-disorders. LIMITATIONS: The results may be preliminary due to the small sample sizes. CONCLUSIONS: Taken together, the results argue in favor of a differentiated view regarding changes in emotional experience in psychotic disorders. They provide preliminary evidence that in psychotic disorders changes in emotion and self-processing may be related to the severity of self-disorders thought to underlie disordered thinking and feeling in psychotic patients. PMID- 28918344 TI - Accesses for alcohol intoxication to the emergency department and the risk of re hospitalization: An observational retrospective study. AB - BACKGROUND: Alcohol use disorders (AUD) are a frequent cause of admission to emergency departments (EDs) for acute alcohol intoxication (AAI). Patients with AUD present a higher risk of readmission to EDs for AAI than the general population, however, the distinction between sporadic AAI and AAI in the context of AUD in the ED setting is difficult. AIMS: To analyze the epidemiological characteristics of patients admitted to EDs because of AAI and to identify factors associated with repeated admissions in order to develop a risk stratification system for patients with AUD based on objective data that can be easily applied in an ED setting. METHODS: An observational retrospective study was performed. All patients with diagnosis of AAI at admission in 2014 were enrolled. RESULTS: Five hundred and sixty-five patients were enrolled, of which 92 (16%) were admitted more than once to the ED. At multivariate analysis, factors associated with readmission were past episodes of alcohol abuse, social discomfort, previous traumas and psychiatric disorders. Basing on this parameter, a risk-score for re-hospitalization was developed. This score has a high predictive power for the risk of readmission to the ED (AROC 0.837, 95%CI 0.808 0.866), moreover, the cumulative probability of readmission within one year, increased in parallel with score value, being highest in patients presenting 3 or more risk factors. CONCLUSION: The present study demonstrates that several risk factors stratify the risk of re-hospitalization in patients admitted to EDs for AAI, allowing the identification of those presenting more severe conditions and who would likely benefit from multidisciplinary intervention. PMID- 28918345 TI - Meta-Analysis on the Impact of the Acute Care Surgery Model of Disease- and Patient-Specific Outcomes in Appendicitis and Biliary Disease. AB - BACKGROUND: The acute care surgery (ACS) model was developed to acknowledge the complexity of a traditionally fractured emergency general surgery patient population, however, there are variations in the design of ACS service models. This meta-analysis analyzes the impact of implementation of different ACS models on the outcomes for appendicitis and biliary disease. STUDY DESIGN: A systematic, English-language search of major databases was conducted. From 1,827 papers, 2 independent reviewers identified 25 studies that reported on outcomes for patients with appendicitis (n = 13), biliary disease (n = 7), or both (n = 5), before and after implementation of an ACS service. The Newcastle-Ottawa Scale was used to score quality. Outcomes were analyzed using random effect methodology and sensitivity analyses were performed. RESULTS: Significant heterogeneity existed between studies and ACS designs. The overall study quality rating was fair to poor with a moderate risk of bias. After implementation of an ACS service, there was an overall reduction in length of stay by 0.51 days (95% CI -0.81 to -0.20 days) and 0.73 days (95% CI 0.09 to 1.36 days) for appendicitis and biliary disease, respectively. Complication rates were lower after implementing ACS (odds ratio 0.65; 95% CI 0.49 to 0.86 and odds ratio 0.46; 95% CI 0.34 to 0.61). There was no difference in after-hours operating for either appendicitis or biliary disease, except when considering ACS models with dedicated theater time, which favors an ACS model (odds ratio 0.49; 95% CI 0.33 to 0.73) in appendicitis. CONCLUSIONS: The ACS model has been shown to benefit acute care surgery patients with improved access to care, fewer complications, and decreased length of stay for 2 common disease processes. The design and implementation of an ACS service can impact the magnitude of effect. PMID- 28918346 TI - Anaerobic digestion for bioenergy production: Global status, environmental and techno-economic implications, and government policies. AB - Anaerobic digestion (AD) is a mature technology that can transform organic matter into a bioenergy source - biogas (composed mainly of methane and carbon dioxide), while stabilizing waste. AD implementation around the world varies significantly, from small-scale household digesters in developing countries to large farm-scale or centralized digesters in developed countries. These differences in the implementation of AD technology are due to a complex set of conditions, including economic and environmental implications of the AD technology, and stimulus provided by a variety of polices and incentives related to agricultural systems, waste management, and renewable energy production. This review explores the current status of the AD technology worldwide and some of the environmental, economic and policy-related drivers that have shaped the implementation of this technology. The findings show that the regulations and incentives have been the primary factor influencing the steady growth of this technology, in both developing and developed countries. PMID- 28918347 TI - Anaerobic digestion of Brewery Spent Grains: Trace elements addition requirement. AB - The current study evaluates and compares the stability of anaerobic digestion of Brewery Spent Grains (BSG) with and without addition of nutrients. Based on the composition of the BSG two levels of nutrients addition were defined. Control reactor, without addition of nutrients, showed signs of instability after 3months of operation and collapsed. On the contrary, supplemented reactors led to a COD removal rate of 60% and a methane production of 280NLCH4.kg-1 VSadded. According to these results, it was possible to define an additive solution adapted to BSG degradation. PMID- 28918348 TI - Enhancing protein to extremely high content in photosynthetic bacteria during biogas slurry treatment. AB - This work proposed a novel approach to achieve an extremely high protein content in photosynthetic bacteria (PSB) using biogas slurry as a culturing medium. The results showed the protein content of PSB could be enhanced strongly to 90% in the biogas slurry, which was much higher than reported microbial protein contents. The slurry was partially purified at the same time. Dark-aerobic was more beneficial than light-anaerobic condition for protein accumulation. High salinity and high ammonia of the biogas slurry were the main causes for protein enhancement. In addition, the biogas slurry provided a good buffer system for PSB to grow. The biosynthesis mechanism of protein in PSB was explored according to theoretical analysis. During biogas slurry treatment, the activities of glutamate synthase and glutamine synthetase were increased by 26.55%, 46.95% respectively. PMID- 28918349 TI - Inhibition of anaerobic digestion processes: Applications of molecular tools. AB - Inhibition of anaerobic digestion (AD) due to perturbation caused by substrate composition and/or operating conditions can significantly reduce performance. Such perturbations could be limited by elucidating microbial community response to inhibitors and devising strategies to increase community resilience. To this end, advanced molecular methods are increasingly being applied to study the AD microbiome, a diverse community of microbial populations with complex interactions. This literature review of AD inhibition studies indicates that inhibitory concentrations are highly variable, likely stemming from differences in community structure or activity profile and previous exposure to inhibitors. More recent molecular methods such as 'omics' tools, substrate mapping, and real time sequencing are helping to unravel the complexity of AD inhibition by elucidating physiological and ecological significance of key microbial populations. The AD community must strive towards developing predictive abilities to avoid system failure (e.g., real-time tracking of an indicator species) to improve resilience of AD systems. PMID- 28918350 TI - Expression and Functional Characterization of the BNIP3 Protein in Renal Cell Carcinomas. AB - BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein 3) is a BH3-only protein that regulates apoptosis and autophagy. BNIP3 plays also an important role in hypoxia-induced cell response and is regulated by HIF1. Here, we studied a possible association of BNIP3 expression and the prognosis of patients with renal cell carcinomas (RCCs) and examined the functional relevance of BNIP3 in the regulation of cell survival and apoptosis of renal carcinoma cells. BNIP3 expression was determined by immunohistochemistry in RCC tumor tissue samples of 569 patients using a tissue microarray. Functional characterization of BNIP3 in renal carcinoma cells indicates prosurvival effects. In human RCC tumor samples, high cytoplasmic BNIP3 expression was associated with high-grade RCCs and regional lymph node metastasis. BNIP3 expression correlated negatively with disease-specific survival. Multivariate Cox regression analysis retained BNIP3 expression as an independent prognostic factor in patients without distant metastasis. Together, our studies imply that BNIP3 regulates cell survival in RCCs and its expression is an independent prognostic marker in patients with localized RCCs. PMID- 28918351 TI - Susceptibility profiles of bacteria causing urinary tract infections in Southern Tunisia. AB - OBJECTIVES: The aim of this study was to determine the epidemiological profile and antibiotic resistance of bacteria responsible for urinary tract infections (UTIs) diagnosed in the Department of Microbiology of the Hospital Regional Houcine Bouzaiene (Gafsa) in southwest Tunisia. METHODS: All cytobacteriological urine samples analysed from 1 January 2015 to 30 June 2016 were included in the study. The criteria used to define UTI were leukocyturia >104 cells/mL and bacteriuria >105 CFU/mL. RESULTS: Among 12678 urine samples, 2093 (16.5%) met the criteria of UTI. The majority of infections were in outpatients (92.1%). Gram negative bacteria were the main identified organisms (1980/2093; 94.6%), whilst Gram-positive bacteria represented only 5.4% (113/2093). The most frequently identified organisms were Enterobacteriaceae (1938/2093; 92.6%), including 1404 (67.1%) Escherichia coli and 268 (12.8%) Klebsiella pneumoniae. Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) were identified and represented 3.6% (70/1938) of the total Enterobacteriaceae. The proportion of community ESBL-E was 3.4% (61/1787). The resistance rate of E. coli and K. pneumoniae to amoxicillin and ticarcillin was elevated; however, monobactams and especially carbapenems (imipenem), colistin and amikacin retained good activity. CONCLUSIONS: Excessive use of antibiotics in hospitals and the community is responsible for the appearance of new resistance profiles; thus, routine monitoring of antibiotic resistance of uropathogenic bacteria must be performed in hospitals as well as in private laboratories in order to prescribe appropriate antibiotics. PMID- 28918352 TI - Report of the 19th Annual Meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) - TBE in a changing world. AB - The 19th meeting of the International Scientific Working Group on Tick-Borne Encephalitis (ISW-TBE) - a group of neurologists, general practitioners, clinicians, travel physicians, virologists, pediatricians and epidemiologists-was held under the title "TBE in a changing world". Key topics within virology, current epidemiological developments and investigations, expansion of risk areas, clinical aspects and cases, traveling and mobility, vaccination rates, and latest news on vaccination were presented and extensively discussed. Over the past four decades, TBE has become a growing public health challenge in Europe and parts of Asia. It may be considered a complex eco-epidemiological system, characterized by an intricate interplay between the virus, ticks and tick hosts on the one hand and human exposure strongly influenced by socioeconomic conditions on the other hand. Although the facts are simple - vaccination is the best prevention - the socioeconomic conditions keep changing, and with them the ability or willingness of people to get vaccinated. PMID- 28918353 TI - Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid. AB - Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by 1H and 195Pt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH3)2(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH3)2(PBA)2] (2), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH3)2(PBA)(suc)] (4) and cis,trans [Pt(CBDCA)(NH3)2)(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells. PMID- 28918354 TI - Indium (III) induces isolated mitochondrial permeability transition by inhibiting proton influx and triggering oxidative stress. AB - While Indium's toxicity to organs is realized, its effects on mitochondria are still under investigation. Mitochondrial permeability transition (MPT) is widely accepted in mitochondrial dysfunction approaches and its importance in metal induced mitochondrial degradation has been proposed. Since mitochondria are respiratory organelles, their interaction with free In3+ is analyzed to access structural and functional changes. Spectral methods and multimode plate reader was used to detect mitochondrial swelling, membrane potential, membrane fluidity, and inner membrane permeability. Flow cytometry was employed to detect mitochondrial reactive oxygen species (ROS) generation and transmission electron microscopy to image mitochondria. And oxygen electrode was used to measure respiratory rate, microcalorimetry to monitor long-term real-time mitochondrial metabolism. In3+ at a concentration up to 1mM induces mitochondrial swelling, membrane depolarization and inhibits the protons transportation. In3+-induced mitochondrial swelling and membrane depolarization is protected by MPT inhibitors and -SH protectors, but the influence on protons transportation is not protected. In addition, In3+ is able to accelerate the ROS production and inhibit the electron transition and respiratory chain while it stimulates long-term metabolism. Our findings show that In3+ induces MPT by inhibiting the proton channels located in the inner mitochondrial membrane and by stimulating mitochondrial oxidative stress. PMID- 28918355 TI - Gallium(III) chelates of mixed phosphonate-carboxylate triazamacrocyclic ligands relevant to nuclear medicine: Structural, stability and in vivo studies. AB - Three triaza macrocyclic ligands, H6NOTP (1,4,7-triazacyclononane-N,N',N" trimethylene phosphonic acid), H4NO2AP (1,4,7-triazacyclononane-N methylenephosphonic acid-N',N"-dimethylenecarboxylic acid), and H5NOA2P (1,4,7 triazacyclononane-N,N'-bis(methylenephosphonic acid)-N"-methylene carboxylic acid), and their gallium(III) chelates were studied in view of their potential interest as scintigraphic and PET (Positron Emission Tomography) imaging agents. A 1H, 31P and 71Ga multinuclear NMR study gave an insight on the structure, internal dynamics and stability of the chelates in aqueous solution. In particular, the analysis of 71Ga NMR spectra gave information on the symmetry of the Ga3+ coordination sphere and the stability of the chelates towards hydrolysis. The 31P NMR spectra afforded information on the protonation of the non-coordinated oxygen atoms from the pendant phosphonate groups and on the number of species in solution. The 1H NMR spectra allowed the analysis of the structure and the number of species in solution. 31P and 1H NMR titrations combined with potentiometry afforded the measurement of the protonation constants (log KHi) and the microscopic protonation scheme of the triaza macrocyclic ligands. The remarkably high thermodynamic stability constant (log KGaL=34.44 (0.04) and stepwise protonation constants of Ga(NOA2P)2- were determined by potentiometry and 69Ga and 31P NMR titrations. Biodistribution and gamma imaging studies have been performed on Wistar rats using the radiolabeled 67Ga(NO2AP)- and 67Ga(NOA2P)2-chelates, having both demonstrated to have renal excretion. The correlation of the molecular properties of the chelates with their pharmacokinetic properties has been analysed. PMID- 28918356 TI - What is the price for the Duchenne gait pattern in patients with cerebral palsy? AB - Duchenne gait is characterized by trunk lean towards the affected stance limb with the pelvis stable or elevated on the swinging limb side during single limb stance phase. We assessed the relationship between hip abduction moments and trunk kinetics in patients with cerebral palsy showing excessive lateral trunk motion. Data of 18 subjects with bilateral spastic cerebral palsy (CP) and 20 aged matched typically developing subjects (TD) were collected retrospectively. Criteria for patient selection were barefoot walking without aid presenting with excessive lateral trunk motion. Subjects had been monitored by conventional 3D gait analysis of the lower extremity including four markers for monitoring trunk motion. Post-hoc, a generic musculoskeletal full body model (OpenSim 3.3) assuming a rigid trunk articulated to the pelvis by a single ball joint was applied for analyzing joint kinematics and kinetics of the lower limb joints including this spine joint. Joint angle ranges of motion, maximum joint moments and powers in the frontal plane as well as mechanical work were calculated and averaged within groups showing prominent differences between groups in all parameters. To the best of our knowledge, this is the first work explicitly looking into the kinetics of Duchenne gait in patients with CP, clinically known as compensation for unloading hip abductor muscles. The results show that excessive lateral trunk motion may indeed be an extremely effective compensation mechanism to unload the hip abductors in single limb stance but for the price of a drastic increase in demand on trunk muscle effort and work. PMID- 28918357 TI - Long-term follow-up after tibialis anterior tendon shortening in combination with Achilles tendon lengthening in spastic equinus in cerebral palsy. AB - Using Tibialis Anterior Shortening (TATS) in combination with Achilles Tendon Lengthening (TAL) to treat spastic equinus in children with cerebral palsy (CP) was described in 2011. Short-term results have indicated a good outcome, especially an improvement of the drop foot in swing phase and the correction of equinus in stance phase. The aim of this study was to analyse the results of the long-term follow-up and to determine the relapse rate of TATS and TAL. The kinematics of the sagittal, frontal and transversal planes were measured by using instrumented 3D gait analysis at three defined time points and then described using the Gait Profile Score (GPS) and Movement Analysis Profile (MAP). The data was exported into Gaitabase and then the preoperative (T0), short- term (T1) and long-term (T2) follow-up data was statistically compared. 23 patients (mean age at index-surgery=14.9years) were included, there was a mean follow-up time of 5.8 years. 3 children (13%) have shown a relapse. The data of 12 children with spastic hemiplegia (12 legs), as well as 8 children with spastic diplegia (10 legs) has been analysed. There has been a significant (p<0.05) improvement in GPS and MAP for ankle dorsiflexion (describes equinus and drop foot) of the operated legs versus not operated legs. TATS in combination with TAL shows a satisfactory long-term result after 5.8 years in the correction of fixed equinus and drop foot in children with CP. Postoperatively all subjects were able to walk without an AFO. PMID- 28918358 TI - The role of central and medial amygdala in normal and abnormal aggression: A review of classical approaches. AB - The involvement of the amygdala in aggression is supported by overwhelming evidence. Frequently, however, the amygdala is studied as a whole, despite its complex internal organization. To reveal the role of various subdivisions, here we review the involvement of the central and medial amygdala in male rivalry aggression, maternal aggression, predatory aggression, and models of abnormal aggression where violent behavior is associated with increased or decreased arousal. We conclude that: (1) rivalry aggression is controlled by the medial amygdala; (2) predatory aggression is controlled by the central amygdala; (3) hypoarousal-associated violent aggression recruits both nuclei, (4) a specific upregulation of the medial amygdala was observed in hyperarousal-driven aggression. These patterns of amygdala activation were used to build four alternative models of the aggression circuitry, each being specific to particular forms of aggression. The separate study of the roles of amygdala subdivisions may not only improve our understanding of aggressive behavior, but also the differential control of aggression and violent behaviors of various types, including those associated with various psychopathologies. PMID- 28918359 TI - Major depressive disorder and anxiety disorders from the glial perspective: Etiological mechanisms, intervention and monitoring. AB - Despite intense ongoing research efforts, the etiology of psychiatric disorders remains incompletely understood. Among biological factors playing a role in Major Depressive Disorder (MDD) and Anxiety Disorders (ANX), emerging evidence points to the relevance of different types of glia cells and efficient neuron-glia interactions. Here, we review recent findings highlighting the involvement of central nervous system (CNS) glia in MDD and ANX etiology and treatment response. Additionally, several relatively underexplored topics will be discussed: (1) glial response to non-pharmacological therapies, (2) impact of early life adversity on glia, (3) influence of lifestyle factors on glia in the context of MDD and ANX, and (4) monitoring glial functions in patients. It can be concluded that despite the sequence of events is still unclear, alterations in glial cell types are common and somewhat overlapping in ANX, MDD and corresponding animal models. Furthermore, glia are responsive to a variety of treatment and lifestyle options. Looking forward, new research developments can lead to novel types of therapeutic or symptom-relieving approaches targeting glia. PMID- 28918360 TI - Do bacteria shape our development? Crosstalk between intestinal microbiota and HPA axis. AB - The human body contains as many bacteria in the intestine as the total number of human body cells. These bacteria have a central position in human health and disease, and would also play a role in the regulation of emotions, behavior, and even higher cognitive functions. The Hypothalamic-Pituitary-Adrenal axis (HPA axis) is a major physiological stress system that produces cortisol. This hormone is involved in responding to environmental stress and also shapes many aspects of brain development. Both the HPA axis and the intestinal microbiota show rapid and profound developmental changes during the first years of life. Early environmental disturbances can affect the development of both systems. Early adversity, for example, is known to lead to later unbalances in both, as well as to psychopathological behavior and emotions. The goal of this theoretical review is to summarize current knowledge on the developmental crosstalk between the intestinal microbiota and the HPA axis, providing a basis for understanding the development and bidirectional communication between these two essential systems in human functioning. PMID- 28918361 TI - Daytime sleepiness and related factors in nursing students. AB - BACKGROUND: Evaluation of the frequency and causes of daytime sleepiness in nursing students because it is an important factor in improving the health status of the students, controlling sleep problems, improving students' academic achievements, and maintaining a healthy lifestyle. AIM: The aim of this study was to determine the prevalence of daytime sleepiness in nursing students and the factors associated with it. DESIGN: A cross-sectional research design was used in this study. PARTICIPANTS: Nursing students (n=382). METHOD: Data were collected using a questionnaire prepared by the authors to assess socio-demographic characteristics, sleep habits, and problems of nursing students and the Epworth Sleepiness Scale (ESS), which assesses daytime sleepiness. Descriptive statistics included numbers, percentages, mean, median, and standard deviation. Mann-Whitney U test (Z) and Kruskal-Wallis (KW) analysis of variance were used for evaluating the relationship between ESS scores and independent variables. RESULTS: The prevalence of daytime sleepiness in the students was found to be 10.5%. Those in the 2nd grade, who were married, who did not consume coffee or tea, lived alone, regarded their own academic achievement as poor, and used the Internet during morning hours experienced increased daytime sleepiness. Moreover, students who talk in their sleep, grind their teeth, feel restless before sleep, experience problems in falling asleep, and wake up at night were found to experience increased daytime sleepiness. CONCLUSIONS: Daytime sleepiness is a considerably common health problem in nursing students. This study found that daytime sleepiness is associated with individual characteristics, lifestyle and consumption habits, and sleep habits. PMID- 28918362 TI - There are no no-responders to low or high resistance training volumes among older women. AB - OBJECTIVES: To assess the prevalence of non-responders to different tests and to compare the effects of different resistance training (RT) volumes on muscle strength, anthropometric and functional performance of older women. METHODS: Three hundred seventy six women performed 12weeks of RT with either low or high volume (LV, 71.29+/-5.77years and HV 69.73+/-5.88years, respectively). Both groups performed the same exercises, and all parameters were held constant except for the number of sets performed per week. LV performed 8-12 for upper and 4-6 for lower body, while HV performed 16-20 and 8-10, respectively. Before and after the training period, the participants were tested for bench press and leg press 1RM, 30-s chair stand, 30-s arm curl, six-minute walk test, sit and reach, body weight and waist circumference. RESULTS: Both groups significantly improved in all strength and functional tests and reduced their body weight and waist circumference. ANOVA revealed higher gains in the leg press 1RM, 30-s arm curls and 6-min walk test for the HV group and higher increases in the results of the sit and reach test for the LV group. However, the differences were negligible and may be attributable to a type I error due to the large sample size. Non responsiveness was not apparent in any subject, as a positive response on at least one outcome was present in every participant. CONCLUSIONS: Our results suggest that RT, even at low volume, improves waist circumference, muscle strength and physical function in the older population, with no evidence of non responsiveness. Therefore, we should not be restrictive in prescribing this type of exercise to this population. PMID- 28918363 TI - Changes in Zn homeostasis during long term culture of primary endothelial cells and effects of Zn on endothelial cell senescence. AB - Endothelial cell senescence and Zn nutritional status influence cardiovascular disease. The influence of Zn appears dichotomous, hence it is imperative to understand the relationship with cellular senescence to improve knowledge about the molecular and cellular basis of the disease. Here we aimed to determine: 1) the impact of chronic exposure to a moderately high dose of Zn on senescence of endothelial cells; 2) the changes in Zn homeostasis during the lifespan of primary cultured endothelial cells; and 3) the susceptibility of proliferating and senescent endothelial cells to cell death after short term exposure to increasing doses of Zn and of the Zn chelator TPEN. Chronic exposure to Zn accelerated senescence and untreated cells at later passages, where doubling time had increased, displayed relocation of labile Zn and altered expression of genes involved in the response to Zn toxicity, including SLC30A1, SLC39A6, SLC30A5, SLC30A10 and metallothioneins, indicating that senescent cells have altered zinc homeostasis. Most Zn-dependent genes that were expressed differently between early and late passages were correlated with changes in the expression of anti apoptotic genes. Short-term treatment with a high dose of Zn leads to cell death, but only in the population of cells at both earlier and later passages that had already entered senescence. In contrast, Zn depletion led to death of cells at earlier but not later passages, which suggests that there are sub-populations of senescent cells that are resistant to Zn depletion. This resistant senescent cell population may accumulate under conditions of Zn deficiency and contribute to vascular pathology. PMID- 28918364 TI - Volumetric changes in the aging rat brain and its impact on cognitive and locomotor functions. AB - Impairments in cognitive and locomotor functions usually occur with advanced age, as do changes in brain volume. This study was conducted to assess changes in brain volume, cognitive and locomotor functions, and oxidative stress levels in middle- to late-aged rats. Forty-four male Sprague-Dawley rats were divided into four groups: 14, 18, 23, and 27months of age. 1H magnetic resonance imaging (MRI) was performed using a 7.0-Tesla MR scanner system. The volumes of the lateral ventricles, medial prefrontal cortex (mPFC), hippocampus, striatum, cerebellum, and whole brain were measured. Open field, object recognition, and Morris water maze tests were conducted to assess cognitive and locomotor functions. Blood was taken for measurements of malondialdehyde (MDA), protein carbonyl content, and antioxidant enzyme activity. The lateral ventricle volumes were larger, whereas the mPFC, hippocampus, and striatum volumes were smaller in 27-month-old rats than in 14-month-old rats. In behavioral tasks, the 27-month-old rats showed less exploratory activity and poorer spatial learning and memory than did the 14-month old rats. Biochemical measurements likewise showed increased MDA and lower glutathione peroxidase (GPx) activity in the 27-month-old rats. In conclusion, age-related increases in oxidative stress, impairment in cognitive and locomotor functions, and changes in brain volume were observed, with the most marked impairments observed in later age. PMID- 28918365 TI - Review of breast augmentation and reconstruction for the radiologist with emphasis on MRI. AB - It is imperative to continue screening for breast cancer and/or detect tumor recurrence in patients after they have undergone breast augmentation or reconstruction. As there is an increasing role for both screening and diagnostic imaging of the post-operative breast, it is important for the radiologist to be familiar with the commonly performed surgical techniques in breast augmentation and reconstruction. Imaging of the augmented and reconstructed breast, as well as complications, will be reviewed with a focus on Magnetic Resonance Imaging (MRI). PMID- 28918366 TI - A progressive reduction in autophagic capacity contributes to induction of replicative senescence in Hs68 cells. AB - Autophagy has been implicated in delayed aging and extended longevity. Here, we aimed to study the possible effects of autophagy during the progression of replicative senescence, which is one of the major features of aging. Human foreskin fibroblasts, Hs68 cells, at an initial passage of 15 were serially cultured for several months until they reached cellular senescence. A decrease in cell proliferation was observed during the progression of senescence. Induction of replicative senescence in aged cells (at passage 40) was confirmed by senescence-associated beta-galactosidase (SA-beta-gal) activity that represents a sensitive and reliable marker for quantifying senescent cells. We detected a significantly increased percentage (%) of SA-beta-gal-positive cells at passage 40 (63%) when compared with the younger SA-beta-gal-positive cells at passage 15 (0.5%). Notably, the gradual decrease in basal autophagy coincided with replicative senescence induction. However, despite decreased basal autophagic activity in senescent cells, autophagy inducers could induce autophagy in senescent cells. RT-PCR analysis of 11 autophagy-related genes revealed that the decreased basal autophagy in senescent cells might be due to the downregulation of autophagy-regulatory proteins, but not autophagy machinery components. Moreover, the senescence phenotype was not induced in the cells in which rapamycin was added to the culture to continuously induce autophagy from passage 29 until passage 40. Together, our findings suggest that reduced basal autophagy levels due to downregulation of autophagy-regulatory proteins may be the mechanism underlying replicative senescence in Hs68 cells. PMID- 28918367 TI - 25-Hydroxycholesterol and inflammation in Lovastatin-deregulated mevalonate pathway. AB - Mevalonate pathway deregulation has been observed in several diseases, including Mevalonate kinase deficiency (MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK), encoding mevalonate kinase (MK) enzyme. MVK mutations have been reported as associated with impairment of mevalonate pathway with consequent decrease of protein prenylation levels, defective autophagy and increase of IL-1beta secretion, followed by cell death. Since 25-hydroxycholesterol (25-HC), a metabolite of cholesterol, can suppress IL-1beta production, thus reducing inflammation, we evaluated the effect of 25-HC in an in vitro model of mevalonate pathway alteration, obtained using Lovastatin. Human glioblastoma cell line (U87-MG) was chosen to mimic, at least in part, the central nervous system impairment observed in MKD; 25-HC effects were evaluated aimed at disclosing if this compound could be considered as novel potential drug for MKD. Our results showed that 25-HC is able to reduce inflammation but it is ineffective to restore autophagy flux and to decrease apoptosis levels, both caused by lower protein prenylation; so, in spite of its anti-inflammatory action it is not useful to rescue defective prenylation/autophagy impairment-driven apoptosis in Lovastatin impaired mevalonate pathway. We hypothesize the presence in the mevalonate pathway of alternative mechanisms acting between inflammation and apoptotic autophagy impairment. PMID- 28918368 TI - GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms. AB - Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the alpha/beta-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278Kfs*3, p.H588Qfs*27, p.N642Lfs*10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant alpha/beta-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis-Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity. PMID- 28918369 TI - The development of biodiversity conservation measures in China's hydro projects: A review. AB - The hydropower capacity of China ranks first in the world and accounts for approximately 20% of the total energy production in the country. While hydropower has substantially contributed to meeting China's renewable energy targets and providing clean energy to rural areas, the development of hydropower in China has been met with significant controversy. Ecologically, hydro projects alter the landscape, with potential impacts to the country's aquatic biodiversity. Over the past four decades in China, various mainstream opinions and misunderstandings have been presented concerning how to alleviate the negative impacts of hydro projects on aquatic ecosystems. This article reviews research concerning potential mitigation measures to enhance aquatic biodiversity conservation in hydro projects in China. Based on the academic attention such research has attracted, three technical measures for aquatic biodiversity conservation are considered: (1) fish passages, (2) restocking efforts and (3) river and lake renovations. This article provides a historical comparison of these three practices in China to demonstrate the advantages and disadvantages of each method. The article also reviews the relevant legislation, regulations and technical guidelines concerning China's hydro projects dating back to 1979. The dynamics in research, publications, and patents concerning these three mitigation measures are summarized to demonstrate their technological developments in the context of legislative and policy advances. Data were gathered through the China Knowledge Resource Integrated Database and the State Intellectual Property Office of the People's Republic of China. Based on the analysis provided, the article recommends an expansion of China's environmental certification system for hydro projects, more robust regional legislation to bolster the national framework, the cooperation between upstream and downstream conservation mechanisms, and better monitoring to determine the efficacy of mitigation measures. PMID- 28918370 TI - A metric study of insole foot impressions in footwear of identical twins. AB - Foot impressions are of utmost importance in crime scene investigations. Foot impressions are available in the form of barefoot prints, sock-clad footprints, and as impressions within footwear. Sometimes suspects leave their footwear at the crime scene, and the insole of this footwear may contain the foot impression of the suspect which may be important evidence linking him or her to the crime. The task of identification based on the analysis of footprints can be challenging when the footprints belonging to one of the identical twin is available for examination. The present study is based on the quantitative measures of the foot impressions in the footwear of adult identical twins. The study was conducted on four sets of female monozygotic twins from the United States of America. A total of 17 length and breadth measurements were taken on each foot impression. A combination of Reel Method and Extended Gunn Method was utilized to produce the measurements. The measurements of the foot impressions were compared among the twins on the right and the left side. Differences were found in the various footprint measurements among the twins. The study's sample size was not large enough to apply robust statistical tests, but the study is significant in that it presents the first detailed comparative analysis of a large number of measurements of insole foot impressions of adult twins. The observations derived from the study are likely to assist forensic investigations in cases involving the foot impressions of the twins. PMID- 28918371 TI - Willems method of dental age estimation in children: A systematic review and meta analysis. AB - BACKGROUND: Age estimation from dental developmental stages is considered comparatively more accurate, reliable and precise than other methods used in forensic sciences. Willems method is the revised version of Demirjian method, based on modified dental maturity scores to estimate age of children in years for both the sexes. AIMS: To test the applicability and accuracy level of Willems method of dental age estimation in diverse population samples by quantifying the variations between the chronological and estimated ages of an individual. METHODOLOGY: A systematic search of online databases (Pubmed, Scopus, Embase, Medline, Trip and Web of Science) was performed for identifying the articles utilizing Willems dental maturity scaling method for age estimation in children. All the research articles published in peer-reviewed English language journals between 2001 and January 2017 were included for present systematic review and meta-analysis. RESULTS: Out of the total 973 selected articles; thirty one studies were recruited for qualitative analysis and out of them, 15 studies were selected/identified for quantitative and meta-analysis. It was found that Willems method overestimates the age of children to a comparatively lesser extent (-0.04 and -0.02 years) than the Demirjian method (around six months). CONCLUSION: Willems method of dental age estimation gives comparatively lesser overestimations of age than other methods reported in the available literature and is thus, accurate and reliable enough to be utilized for forensic purposes. PMID- 28918372 TI - Enhanced visible-light photocatalytic nitrogen fixation over semicrystalline graphitic carbon nitride: Oxygen and sulfur co-doping for crystal and electronic structure modulation. AB - Oxygen and sulfur co-doped semicrystalline graphitic carbon nitride (HGCNOS) was synthesized by a one-pot hydrothermal method and applied in visible-light photocatalytic nitrogen fixation. Remarkably, HGCNOS exhibited a higher photocatalytic activity than pristine graphitic carbon nitride (GCN). Oxygen doping caused semicrystalline structure, making exciton dissociated at the order disorder interfaces of HGCNOS and releasing more electrons and holes. Furthermore, the conduction band position of HGCNOS was elevated by sulfur doping, promoting the reduction ability of HGCNOS. Thus, the special electronic and physicochemical structure of HGCNOS contributed to the enhanced photocatalytic activity, facilitating its application on nitrogen photofixation. PMID- 28918373 TI - Defect-free surface modification methods for solubility-tunable carbon nanotubes. AB - Although carbon nanotubes (CNTs) have outstanding physical properties, there are still challenging issues such as poor dispersibility and miscibility between organic polymers and CNTs for polymer nanocomposites. Chemical modifications (e.g., strong acid based oxidation, carboxylation, etc.) can improve dispersion properties and compatibility, but such surface modification methods often lead to damage to the pristine CNT structure and also deteriorate the mechanical properties of CNTs. Here we demonstrate a simple, defect-free and scalable method for well-dispersed CNTs in common organic solvents, using dopamine and amine terminated polyethylene glycol derivatives. This method makes it possible to prepare solubility-tunable CNTs without any severe structural deformation. As modified CNTs were successfully characterized by thermal gravimetric analysis (TGA), Fourier-transformed infrared spectroscope (FT-IR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscope (TEM). The surface modified-CNTs were well-dispersed in polar and/or non-polar common solvents. The well-dispersed CNTs can be used in a nanofiller in commercial polymers such as thermoplastic polyurethane (TPU) polymer. The CNT/TPU composite showed improved tensile strength without sacrificing elongation at break relative to those of pristine TPU. PMID- 28918374 TI - A general strategy to fabricate photonic crystal heterostructure with Programmed photonic stopband. AB - In this paper, we present a general fabrication strategy to achieve the structure control and the flexible photonic stop band regulation of (2+1) D photonic crystal heterostructures (PCHs) by layer-by-layer depositing the annealed colloidal crystal monolayers of different sphere size. The optical properties of the resulting (2+1) DPCHs with different lattice constants were systematically studied and a universal photonic stopband variation rule was proposed, which makes it possible to program any kind of stopband structure as required, such as dual- or multi-stopbands PCH and ultra-wide stopband PCH. Furthermore, PCH with dual-stopbands overlapping the excitation wavelength (E) and emission wavelength(F) of Ru complex was fabricated by finely manipulating the spheres' diameter of colloidal monolayers. And an additional 2-fold fluorescence enhancement in comparison to that on the single stopband sample was achieved. This strategy affords new opportunities for delicate engineering the photonic behaviour of PCH, and also is of great significance for the practical application based on their bandgap property. PMID- 28918375 TI - Synthesis of fluorescent dendrimers with aggregation-induced emission features through a one-pot multi-component reaction and their utilization for biological imaging. AB - Hyperbranched polymers have attracted wide research attention owing to their unique topological structure, physicochemical properties and great potential for applications such asadditives, drug delivery, catalysts and nanotechnology. Among these, the polyamidoamine(PAMAM) dendrimers are some of the most important dendrimers. However, the synthesis and biomedical applications of fluorescent PAMAM dendrimers have received only limited attention. In this work, we present a rather effective and convenient approach for synthesis of fluorescent PAMAM dendrimers with aggregation-induced emission (AIE) properties through a one-pot catalyst-free Mannich reaction under rather mild experimental conditions (e.g., low reaction temperature, air atmosphere in the presence of water). The obtained AIE-active amphiphiles (PhE-PAD) could self-assemble into fluorescent organic nanoparticles (FONs). The obtained AIE-active FONs (PhE-PAD FONs) were fully characterized, and their successful construction was confirmed by 1H NMR spectroscopy, FT-IR spectroscopy and transmission electron microscopy. Fluorescence and UV-Visible absorption spectroscopy results demonstrated that the final PhE-PAD FONs showed strong yellow fluorescence, desirable photostability and good water dispersity. The cell viability evaluation and confocal laser scanning microscope imaging results suggested that PhE-PAD FONs possessed low cytotoxicity and excellent biocompatibility. Taken together, these results demonstrate that we have developed a facile and efficient strategy for the fabrication of AIE-active FONs, which possess many desirable features for biomedical applications. PMID- 28918376 TI - Effect of precursors on the structure and activity of CuO-CoOx/gamma-Al2O3 catalysts for NO reduction by CO. AB - Catalytic reduction of NO by CO was studied over a series of CuO-CoOx/gamma-Al2O3 catalysts prepared by co-impregnation with different copper and cobalt precursors (acetate and nitrate) to evaluate the structure-activity relationship. The obtained samples were characterized in detail by means of XRD, LRS, XPS, H2-TPR and in situ FT-IR technologies. Results indicate that copper oxide is agglomerated while cobalt oxide is dispersed on gamma-Al2O3 for the catalyst prepared from copper acetate and cobalt acetate precursors (CuACoA); CuxCo3-xO4 spinel is formed and agglomerated on the catalyst prepared from copper nitrate and cobalt nitrate precursors (CuNCoN); while both copper oxide and cobalt oxide could be homogeneously dispersed for the catalyst prepared from copper nitrate and cobalt acetate precursors (CuNCoA), which exhibits the best activity for NO reduction by CO. Probably the synergistic effect between dispersed copper oxide and cobalt oxide is propitious to the oxygen transfer, which could be the reason for its high activities. Finally, a possible reaction mechanism was tentatively proposed to explore the different catalytic performances in NO reduction by CO model reaction. PMID- 28918377 TI - Stable Janus superhydrophilic/hydrophobic nickel foam for directional water transport. AB - Janus superhydrophilic/hydrophobic macroporous nickel foam for directional water transport has been demonstrated via a simple floating strategy. Water can transport from hydrophobic to superhydrophilic layer through Janus nickel foam, but cannot transfer from superhydrophilic to hydrophobic layer. This "3D water diode" Janus nickel foam shows extremely high transport rate and outstanding stability. After damaged by abrasion, its directional water transport property retains well. PMID- 28918378 TI - Enhanced fluoride removal by La-doped Li/Al layered double hydroxides. AB - In this study La intercalated Li/Al layered double hydroxide (LDH) was developed for efficient water defluoridation. The La-modified material, i.e., La doped Li/Al-LDH, exhibits more preferable fluoride adsorption than Li/Al-LDH in a broad pH range of 5-9, with the working capacity twice of the latter and seven times of magnitude higher than activated alumina. The fluoride removal kinetics is well fitted by pseudo-second order model, and the adsorption isotherm is well described by Freundlich model. Effect of pH and competing ions was examined during fluoride sequestration. The underlying mechanism for such enhanced adsorption of fluoride by La doped Li/Al-LDH was further revealed based on XPS and FTIR analysis. The presence of La and Al was found to be responsible for the satisfactory defluoridation of La doped Li/Al-LDH, and chloride replacement with fluoride occurred from both LDHs during fluoride adsorption. Also, the capacity of La doped Li/Al-LDH could be refreshed by alkaline solution (pH = 12) for cyclic runs. All the results implied that La doped Li/Al-LDH could serve asa potential adsorbent for efficient fluoride removal from water. PMID- 28918380 TI - It is not enough to grieve; we must learn from Gorakhpur. PMID- 28918379 TI - Infanrix hexa and sudden death: a review of the periodic safety update reports submitted to the European Medicines Agency. AB - There have been a number of spontaneous reports of sudden unexpected death soon after the administration of Infanrix hexa (combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type B vaccine). The manufacturer, GlaxoSmithKline (GSK), submits confidential periodic safety update reports (PSURs) on Infanrix hexa to the European Medicines Agency (EMA). The latest is the PSUR 19. Each PSUR contains an analysis of observed/expected sudden deaths, which shows that the number of observed deaths soon after immunisation is lower than that expected by chance. This commentary focuses on that aspect of the PSUR which has a bearing on policy decisions. We analysed the data provided in the PSURs. It is apparent that the deaths acknowledged in the PSUR 16 were deleted from the PSUR 19. The number of observed deaths soon after vaccination among children older than one year was significantly higher than that expected by chance once the deleted deaths were restored and included in the analysis. The manufacturer must explain the figures that have been submitted to the regulatory authorities. The procedures undertaken by the EMA to evaluate the manufacturer's claims in the PSUR need to be reviewed. The Drugs Controller General of India nearly automatically accepts drugs and vaccines approved by the EMA. There is a need to reappraise the reliance on due diligence by the EMA. PMID- 28918381 TI - Assessing decisional capacity for research participation in psychiatric patients and their relatives. AB - A cross-sectional study among adult inpatients with non-organic psychiatric disorders, and among their key relatives, assessed their comprehension and recall of key information in consent forms. It also assessed their capacity to consent to participate in two hypothetical randomised controlled trials (RCTs) with different potential risks and burdens, using structured questionnaires and recorded interviews. Of the 24 participants (12 patient-key relative dyads), seven patients (58%) and three key relatives (25%) were clinically judged to lack the capacity to consent. Of the remaining 14 participants s, less than half the patients (2/5; 40%) or relatives (3/9; 33%) accurately recalled 50% of the key information on both trials. Among the eight participants (3 patients, 5 relatives) independently assessed on the MacArthur Competence Assessment Tool for Clinical Research, the proportions judged competent for each trial varied with the criteria for defining competence. No one fulfilled the stringent competence criteria for both trials. Routine assessments of the capacity of psychiatric research participants, and of relatives providing proxy consent, appear to be warranted. However, neither suboptimal understanding of consent forms, nor incompetence determined by the use of formal assessment tools, necessarily denote an incapacity to consent to research if detailed clinical assessments indicate otherwise. Research into incorporating participants' health literacy and clinical status in formal assessments may help determine the optimal standards for defining competence. PMID- 28918382 TI - Prevalence of and risk factors for FIV and FeLV infection in two shelters in the United Kingdom (2011-2012). AB - The aims of this study were to determine the prevalence of feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) infections in cats presented to two RSPCA (Royal Society for the Prevention of Cruelty to Animals) animal rehoming centres and to identify risk factors for infection. All cats presented at each centre between August 2011 and August 2012 were subjected to a patient side test for FeLV/FIV on entry. Kittens under three months and cats euthanased within a short time of presentation were excluded from the study. Univariable and multivariable logistic regression were used to separately determine risk factors for FeLV and FIV infections. At shelter A, the prevalence of FIV infection was 11.4 per cent (54/474) and FeLV infection was 3 per cent (14/473), with two FIV/FeLV coinfections identified. At shelter B, the prevalence of FIV infection was 3 per cent (4/135) and FeLV infection was 0 per cent (0/135). Cats at shelter A were significantly more likely than those at shelter B to test positive for FIV (p=0.0024) and FeLV (p=0.048). Male cats were more likely to be infected with FIV (odds ratio 27.1, p=0.001), and thin body condition and musculoskeletal disease were associated with risk of FeLV. Overall, FIV-positive and FeLV-positive cats were significantly older (median ages 5.1 and 4.75 years, respectively) than the uninfected populations (median ages 3.4 and 3.5 years, respectively). This study shows that the prevalence of these diseases varies between shelter populations. Local knowledge combined with the risk factors identified may be useful in focusing resources for population testing strategies. PMID- 28918383 TI - Liver transplantation in children: state of the art and future perspectives. AB - In this review, we provide a state of the art of liver transplantation in children, as the procedure is now carried out for more than 30 years and most of our paediatric colleagues are managing these patients jointly with liver transplant centres. Our goal for this article is to enhance the understanding of the liver transplant process that a child and his family goes through while explaining the surgical advances and the associated complications that could happen in the immediate or long-term follow-up. We have deliberately introduced the theme that 'liver transplant is a disease' and 'not a cure', to emphasise the need for adherence with immunosuppression, a healthy lifestyle and lifelong medical follow-up. PMID- 28918384 TI - Systematic review and meta-analysis of effectiveness of preoperative embolization in surgery for metastatic spine disease. AB - BACKGROUND: Preoperative embolization (PE) may decrease intraoperative blood loss (IBL) in decompressive surgery of hypervascular spinal metastases. However, no consensus has been found in other metastases and no meta-analysis which reviewed the benefit of PE in spinal metastases has been conducted. OBJECTIVE: To assess IBL in spinal metastases surgery in a randomized controlled trial (RCT) and cohort studies comparing PE and a control group of non-embolized patients. METHODS: A systematic search of relevant publications in PubMed and EMBASE was undertaken. Inclusion criteria were RCTs and observational studies in patients with spinal metastases who underwent spine surgery and reported IBL. Meta analysis was performed using standardized mean difference (SMD) and mean difference (MD) of IBL. Heterogeneity was assessed using the I2 statistic. RESULTS: A total of 265 abstracts (126 from PubMed and 139 from Embase) were identified through database searching. The reviewers selected six studies for qualitative synthesis and meta-analysis. The pooled SMD of the included studies was 0.58 (95% CI -0.10 to 1.25, p=0.09). Sensitivity analysis revealed that, if the study by Rehak et al was omitted, the pooled SMD was significantly changed to 0.88 (95% CI 0.39 to 1.36, p<0.001) and PE reduced the IBL significantly. The pooled MD was 708.3 mL (95% CI -224.4 to 1640.9 mL, p=0.14). If the results of the Rehak et al study were omitted, the pooled MD was significantly changed to 1226.9 mL (95% CI 345.8 to 2108.1 mL, p=0.006). CONCLUSIONS: PE can be effective in reducing IBL in spinal metastases surgery in both renal cell carcinoma and mixed primary tumor groups. PMID- 28918385 TI - Wall enhancement ratio and partial wall enhancement on MRI associated with the rupture of intracranial aneurysms. AB - OBJECTIVES: To evaluate the risk factors for rupture of intracranial aneurysms (IAs) using high resolution MRI (HRMRI). METHODS: 91 consecutive patients with 106 IAs were reviewed from February 2016 to April 2017. Patients and IAs were divided into ruptured and unruptured groups. In addition to the clinical characteristics of the patients, the features of IAs (eg, shape) were evaluated by CT angiography, whereas wall thickness, enhanced patterns, and enhancement ratio (ER) were evaluated by MRI. Multiple logistic regression analysis was used to identify independent risk factors associated with the rupture of IAs. Receiver operating characteristic curve analysis was performed on the final model, and the optimal thresholds were obtained. RESULTS: ER (OR 6.638) and partial wall enhancement (PWE) (OR 6.710) were not markers of aneurysms more prone to rupture, but simply were more commonly found in the ruptured aneurysm cohort. The threshold value for ER was 61.5%. CONCLUSIONS: ER (>=61.5%) and IAs with PWE are better predictors of rupture. Increased attentions should be paid to these factors during assessment of IA rupture. PMID- 28918387 TI - Prospective comparative effectiveness cohort study comparing two models of advance care planning provision for Australian community aged care clients. AB - OBJECTIVES: Conduct a prospective comparative effectiveness cohort study comparing two models of advance care planning (ACP) provision in community aged care: ACP conducted by the client's case manager (CM) ('Facilitator') and ACP conducted by an external ACP service ('Referral') over a 6-month period. METHODS: This Australian study involved CMs and their clients. Eligible CM were English speaking, >=18 years, had expected availability for the trial and worked >=3 days per week. CMs were recruited via their organisations, sequentially allocated to a group and received education based on the group allocation. They were expected to initiate ACP with all clients and to facilitate ACP or refer for ACP. Outcomes were quantity of new ACP conversations and quantity and quality of new advance care directives (ACDs). RESULTS: 30 CMs (16 Facilitator, 14 Referral) completed the study; all 784 client's files (427 Facilitator, 357 Referral) were audited. ACP was initiated with 508 (65%) clients (293 Facilitator, 215 Referral; p<0.05); 89 (18%) of these (53 Facilitator, 36 Referral) and 41 (46%) (13 Facilitator, 28 Referral; p<0.005) completed ACDs. Most ACDs (71%) were of poor quality/not valid. A further 167 clients (facilitator 124; referral 43; p<0.005) reported ACP was in progress at study completion. CONCLUSIONS: While there were some differences, overall, models achieved similar outcomes. ACP was initiated with 65% of clients. However, fewer clients completed ACP, there was low numbers of ACDs and document quality was generally poor. The findings raise questions for future implementation and research into community ACP provision. PMID- 28918386 TI - Evaluation of previously embolized intracranial aneurysms: inter-and intra-rater reliability among neurosurgeons and interventional neuroradiologists. AB - BACKGROUND: The angiographic evaluation of previously coiled aneurysms can be difficult yet remains critical for determining re-treatment. OBJECTIVE: The main objective of this study was to determine the inter-rater reliability for both the Raymond Scale and per cent embolization among a group of neurointerventionalists evaluating previously embolized aneurysms. METHODS: A panel of 15 neurointerventionalists examined 92 distinct cases of immediate post-coil embolization and 1 year post-embolization angiographs. Each case was presented four times throughout the study, along with alterations in demographics in order to evaluate intra-rater reliability. All respondents were asked to provide the per cent embolization (0-100%) and Raymond Scale grade (1-3) for each aneurysm. Inter-rater reliability was evaluated by computing weighted kappa values (for the Raymond Scale) and intraclass correlation coefficients (ICC) for per cent embolization. RESULTS: 10 neurosurgeons and 5 interventional neuroradiologists evaluated 368 simulated cases. The agreement among all readers employing the Raymond Scale was fair (kappa=0.35) while concordance in per cent embolization was good (ICC=0.64). Clinicians with fewer than 10 years of experience demonstrated a significantly greater level of agreement than the group with greater than 10 years (kappa=0.39 and ICC=0.70 vs kappa=0.28 and ICC=0.58). When the same aneurysm was presented multiple times, clinicians demonstrated excellent consistency when assessing per cent embolization (ICC=0.82), but moderate agreement when employing the Raymond classification (kappa=0.58). CONCLUSIONS: Identifying the per cent embolization in previously coiled aneurysms resulted in good inter- and intra-rater agreement, regardless of years of experience. The strong agreement among providers employing per cent embolization may make it a valuable tool for embolization assessment in this patient population. PMID- 28918388 TI - Association of the Alternative Healthy Eating Index (AHEI-2010) with depression, stress and anxiety among Iranian military personnel. AB - INTRODUCTION: Psychological disorders have a major role in the incidence of chronic diseases and may result in reductions in the cost-effectiveness of the Armed Forces. Previous civilian studies have shown a protective association between healthy eating guidelines and mental disorders, but evidence to support this for a military population is limited. The aim of this study was to examine the association of Alternative Healthy Eating Index (AHEI-2010) with depression, stress and anxiety among Iranian military personnel. METHOD: A cross-sectional study was conducted on 246 male Army soldiers. Stress, anxiety, depression and dietary intakes were assessed. The association between variables was determined using multivariate logistic regression. RESULTS: The prevalence of depression, stress and anxiety in study participants was 15.9%, 10.6% and 27.2% respectively. Participants with the highest adherence to the AHEI-2010 had an 80% lower odds of depression than those with the lowest adherence (OR: 0.20; 95% CI 0.04 to 0.78). Such an association was also found between adherences to the AHEI-2010 and anxiety (OR: 0.28; 95% CI 0.05 to 0.95). No significant association between adherence to the AHEI-2010 and stress was found. CONCLUSION: An inverse association between adherence to the AHEI-2010 and odds of depression and anxiety was found. Further studies are required to clarify this relationship. PMID- 28918389 TI - Glucagon like peptide-1 receptor agonists for the management of obesity and non alcoholic fatty liver disease: a novel therapeutic option. AB - Obesity is a major risk factor for the development of type 2 diabetes mellitus (T2DM), and is associated with a cluster of metabolic factors that lead to poor cardiovascular outcomes. In non-alcoholic fatty liver disease (NAFLD), liver fat (triglyceride) accumulation closely mirrors adipose tissue dysfunction and insulin resistance in obesity and T2DM. It is now recognized as the most common chronic liver disease in Westernized societies, often progressing to more severe forms of the disease such as nonalcoholic steatohepatitis (NASH), or cirrhosis and hepatocellular carcinoma. However, NAFLD remains largely overlooked by healthcare providers although it affects about two-thirds of patients with obesity and it promotes the development of T2DM. NAFLD mirrors adipose tissue and systemic insulin resistance, the liver being a 'barometer' of metabolic health. Although pioglitazone is emerging as the treatment of choice for NASH in patients with insulin-resistance, or those with T2DM, many other options are being tested. Due to their overall safety and efficacy, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming one of the cornerstones for the management of both obesity and T2DM, and a novel alternative for the treatment of NAFLD. In this review, we will briefly summarize the status of GLP-1RA for the treatment of obesity and NAFLD. PMID- 28918390 TI - A glossary for big data in population and public health: discussion and commentary on terminology and research methods. AB - The volume and velocity of data are growing rapidly and big data analytics are being applied to these data in many fields. Population and public health researchers may be unfamiliar with the terminology and statistical methods used in big data. This creates a barrier to the application of big data analytics. The purpose of this glossary is to define terms used in big data and big data analytics and to contextualise these terms. We define the five Vs of big data and provide definitions and distinctions for data mining, machine learning and deep learning, among other terms. We provide key distinctions between big data and statistical analysis methods applied to big data. We contextualise the glossary by providing examples where big data analysis methods have been applied to population and public health research problems and provide brief guidance on how to learn big data analysis methods. PMID- 28918391 TI - Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study. AB - BACKGROUND/AIM: To evaluate the association of genetic polymorphisms APOE, APOE G 219T promoter, microtubule associated protein(MAPT)/tau exon 6 Ser53Pro, MAPT/tau Hist47Tyr, IL-6572 G/C and IL-6RAsp358Ala with the risk of concussion in college athletes. METHODS: A 23-centre prospective cohort study of 1056 college athletes with genotyping was completed between August 2003 and December 2012. All athletes completed baseline medical and concussion questionnaires, and post-concussion data were collected for athletes with a documented concussion. RESULTS: The study cohort consisted of 1056 athletes of mean+/-SD age 19.7+/-1.5 years, 89.3% male, 59.4% Caucasian, 35.0% African-American, 5.6% other race. The athletes participated in American football, soccer, basketball, softball, men's wrestling and club rugby. A total of 133 (12.1% prevalence) concussions occurred during an average surveillance of 3 years per athlete. We observed a significant positive association between IL-6R CC (p=0.001) and a negative association between APOE4 (p=0.03) and the risk of concussion. Unadjusted and adjusted logistic regression analysis showed a significant association between IL-6R CC and concussion (OR 3.48; 95% CI 1.58 to 7.65; p=0.002) and between the APOE4 allele and concussion (OR 0.61; 95% CI 0.38 to 0.96; p=0.04), which persisted after adjustment for confounders. CONCLUSIONS: IL-6R CC was associated with a three times greater concussion risk and APOE4 with a 40% lower risk. PMID- 28918392 TI - CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing. AB - BACKGROUND: Identification of CNVs through chromosomal microarray (CMA) testing is the first-line investigation in individuals with learning difficulties/congenital abnormalities. Although recognised that CMA testing may identify CNVs encompassing a cancer predisposition gene (CPG), limited information is available on the frequency and nature of such results. METHODS: We investigated CNV gains and losses affecting 39 CPGs in 3366 pilot index case individuals undergoing CMA testing, and then studied an extended cohort (n=10 454) for CNV losses at 105 CPGs and CNV gains at 9 proto-oncogenes implicated in inherited cancer susceptibility. RESULTS: In the pilot cohort, 31/3366 (0.92%) individuals had a CNV involving one or more of 16/39 CPGs. 30/31 CNVs involved a tumour suppressor gene (TSG), and 1/30 a proto-oncogene (gain of MET). BMPR1A, TSC2 and TMEM127 were affected in multiple cases. In the second stage analysis, 49/10 454 (0.47%) individuals in the extended cohort had 50 CNVs involving 24/105 CPGs. 43/50 CNVs involved a TSG and 7/50 a proto-oncogene (4 gains, 3 deletions). The most frequently involved genes, FLCN (n=10) and SDHA (n=7), map to the Smith Magenis and cri-du-chat regions, respectively. CONCLUSION: Incidental identification of a CNV involving a CPG is not rare and poses challenges for future cancer risk estimation. Prospective data collection from CPG-CNV cohorts ascertained incidentally and through syndromic presentations is required to determine the risks posed by specific CNVs. In particular, ascertainment and investigation of adults with CPG-CNVs and adults with learning disability and cancer, could provide important information to guide clinical management and surveillance. PMID- 28918393 TI - Improving membrane protein expression by optimizing integration efficiency. AB - The heterologous overexpression of integral membrane proteins in Escherichia coli often yields insufficient quantities of purifiable protein for applications of interest. The current study leverages a recently demonstrated link between co translational membrane integration efficiency and protein expression levels to predict protein sequence modifications that improve expression. Membrane integration efficiencies, obtained using a coarse-grained simulation approach, robustly predicted effects on expression of the integral membrane protein TatC for a set of 140 sequence modifications, including loop-swap chimeras and single residue mutations distributed throughout the protein sequence. Mutations that improve simulated integration efficiency were 4-fold enriched with respect to improved experimentally observed expression levels. Furthermore, the effects of double mutations on both simulated integration efficiency and experimentally observed expression levels were cumulative and largely independent, suggesting that multiple mutations can be introduced to yield higher levels of purifiable protein. This work provides a foundation for a general method for the rational overexpression of integral membrane proteins based on computationally simulated membrane integration efficiencies. PMID- 28918394 TI - Apolipoprotein L1 confers pH-switchable ion permeability to phospholipid vesicles. AB - Apolipoprotein L1 (ApoL1) is a human serum protein conferring resistance to African trypanosomes, and certain ApoL1 variants increase susceptibility to some progressive kidney diseases. ApoL1 has been hypothesized to function like a pore forming colicin and has been reported to have permeability effects on both intracellular and plasma membranes. Here, to gain insight into how ApoL1 may function in vivo, we used vesicle-based ion permeability, direct membrane association, and intrinsic fluorescence to study the activities of purified recombinant ApoL1. We found that ApoL1 confers chloride-selective permeability to preformed phospholipid vesicles and that this selectivity is strongly pH sensitive, with maximal activity at pH 5 and little activity above pH 7. When ApoL1 and lipid were allowed to interact at low pH and were then brought to neutral pH, chloride permeability was suppressed, and potassium permeability was activated. Both chloride and potassium permeability linearly correlated with the mass of ApoL1 in the reaction mixture, and both exhibited lipid selectivity, requiring the presence of negatively charged lipids for activity. Potassium, but not chloride, permease activity required the presence of calcium ions in both the association and activation steps. Direct assessment of ApoL1-lipid associations confirmed that ApoL1 stably associates with phospholipid vesicles, requiring low pH and the presence of negatively charged phospholipids for maximal binding. Intrinsic fluorescence of ApoL1 supported the presence of a significant structural transition when ApoL1 is mixed with lipids at low pH. This pH switchable ion-selective permeability may explain the different effects of ApoL1 reported in intracellular and plasma membrane environments. PMID- 28918395 TI - Non-invasive high-frequency oscillatory ventilation in preterm infants: a randomised controlled cross-over trial. AB - OBJECTIVE: Non-invasive high-frequency oscillatory ventilation (nHFOV) has recently been described as a novel mode of respiratory support for premature infants. This study was designed to determine whether nHFOV decreases CO2 partial pressure (pCO2) in premature infants more effectively than non-invasive continuous positive airway pressure (nCPAP). DESIGN: Non-blinded prospective randomised controlled cross-over study. SETTING: University Medical Center tertiary neonatal intensive care unit. PATIENTS: 26 premature infants of 27+/-2 weeks of gestational age after extubation or non-invasive surfactant treatment. INTERVENTIONS: Infants were treated with 4 hours of nHFOV and 4 hours of nCPAP in a cross-over design. The sequence of the ventilation mode was randomly allocated. MAIN OUTCOME MEASURES: The primary outcome measure was pCO2 of arterial or arterialised blood 4 hours after commencing the respective mode of respiratory support. Secondary outcome criteria included events of apnoea and bradycardia, respiratory rate, heart rate, pain and/or discomfort, mean airway pressure, fraction of inspired oxygen and failure of non-invasive respiratory support. RESULTS: pCO2 after 4 hours of nHFOV was similar compared with 4 hours of nCPAP (p=0.33). pCO2 was 54.8 (14.6) vs 52.7 (9.3) mm Hg mean (SD) for the nHFOV-nCPAP period (n=13) and 49.0 (8.1) vs 47.7 (9.5) mm Hg for the nCPAP-nHFOV period (n=13). There was no difference in any of the secondary outcome measures. nHFOV was terminated prematurely in five cases for predefined failure criteria (p=0.051). CONCLUSIONS: We could not demonstrate an increased carbon dioxide clearance applying nHFOV compared with nCPAP in this cohort of preterm infants. TRIAL REGISTRATION NUMBER: DRKS00007171, results. PMID- 28918396 TI - Trochlear nerve palsy. PMID- 28918397 TI - Correction: Community-based exercise interventions during pregnancy are perceived as a satisfactory and motivating form of exercise engagement. PMID- 28918398 TI - Nursing and midwifery council registration for overseas children's nurses: a perfect storm? PMID- 28918399 TI - Inactivated influenza vaccination in first trimester does not appear to increase risk of birth defects. PMID- 28918400 TI - Healthcare resource use and costs of severe, uncontrolled eosinophilic asthma in the UK general population. AB - BACKGROUND: Little is known about the prevalence of severe, uncontrolled eosinophilic asthma (SUEA) and associated costs. AIMS: We sought to determine the prevalence of SUEA and compare asthma-related healthcare resource use (HCRU) and associated costs with overall means for a general asthma population. METHODS: This cohort study evaluated anonymised medical record data (December 1989 through June 2015) from the Clinical Practice Research Datalink and the Optimum Patient Care Research Database to study UK patients with active asthma (diagnostic code and one or more drug prescriptions in the baseline year), aged 5 years and older, without concomitant COPD, and with recorded eosinophil count. SUEA was defined as two or more asthma attacks during 1 baseline year preceding a high blood eosinophil count (>=0.3*109/L) for patients prescribed long-acting beta2-agonist (LABA) and high-dosage inhaled corticosteroids (ICS) during baseline plus 1 follow-up year. We compared asthma-related HCRU and associated direct costs (2015 pounds sterling, L) during the follow-up year for SUEA versus the general asthma population. RESULTS: Of 363 558 patients with active asthma and recorded eosinophil count, 64% were women, mean (SD) age was 49 (21) years; 43% had high eosinophil counts, 7% had two or more attacks in the baseline year and 10% were prescribed high-dosage ICS/LABA for 2 study years. Overall, 2940 (0.81%; 95% CI 0.78% to 0.84%) patients had SUEA. Total mean per-patient HCRU and associated costs were four times greater for SUEA versus all patients (HCRU and cost ratios 3.9; 95% CI 3.7 to 4.1). CONCLUSIONS: Less than 1% of patients in a general asthma population had SUEA. These patients accounted for substantially greater asthma-related HCRU and costs than average patients with asthma. PMID- 28918401 TI - Return to work and lost earnings after acute respiratory distress syndrome: a 5 year prospective, longitudinal study of long-term survivors. AB - BACKGROUND: Delayed return to work is common after acute respiratory distress syndrome (ARDS), but has undergone little detailed evaluation. We examined factors associated with the timing of return to work after ARDS, along with lost earnings and shifts in healthcare coverage. METHODS: Five-year, multisite prospective, longitudinal cohort study of 138 2-year ARDS survivors hospitalised between 2004 and 2007. Employment and healthcare coverage were collected via structured interview. Predictors of time to return to work were evaluated using Fine and Grey regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data. RESULTS: Sixty-seven (49%) of the 138 2-year survivors were employed prior to ARDS. Among 64 5-year survivors, 20 (31%) never returned to work across 5-year follow-up. Predictors of delayed return to work (HR (95% CI)) included baseline Charlson Comorbidity Index (0.77 (0.59 to 0.99) per point; p=0.04), mechanical ventilation duration (0.67 (0.55 to 0.82) per day up to 5 days; p<0.001) and discharge to a healthcare facility (0.49 (0.26 to 0.93); p=0.03). Forty-nine of 64 (77%) 5-year survivors incurred lost earnings, with average (SD) losses ranging from US$38 354 (21,533) to US$43 510 (25,753) per person per year. Jobless, non-retired survivors experienced a 33% decrease in private health insurance and concomitant 37% rise in government-funded coverage. CONCLUSIONS: Across 5-year follow-up, nearly one-third of previously employed ARDS survivors never returned to work. Delayed return to work was associated with patient-related and intensive care unit/hospital-related factors, substantial lost earnings and a marked rise in government-funded healthcare coverage. These important consequences emphasise the need to design and evaluate vocation-based interventions to assist ARDS survivors return to work. PMID- 28918402 TI - Rare case of primary leiomyosarcoma of sigmoid mesocolon. AB - We experienced a rare case of primary leiomyosarcoma of sigmoid mesentery. A 45 year-old woman was presented to us with left iliac fossa mass and discomfort for 4-month duration. CT scan of abdomen and pelvis revealed a huge mass 14 cm*14 cm*16 cm occupying left iliac fossa mimicked having a large left ovarian carcinoma. She was subsequently planned for elective total abdominal hysterectomy and bilateral salpingo-oophorectomy by gynaecology team. During laparotomy, a huge mass was revealed arising from sigmoid mesentery invaded to the left lower ureter. Curative resection was done and pathological findings show the tumour being leiomyosarcoma with immunohistochemistry tests on caldesmon, desmin, smooth muscle actin and CD34 reagent all positive. Clinicopathological and literature review of this rare primary leiomyosarcoma of mesocolon was discussed in our case presentation. PMID- 28918403 TI - Successful twice interrupted therapy of HCV infection in patients with cirrhosis with hepatocellular carcinoma before and after liver transplantation. AB - We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment. PMID- 28918404 TI - Combined caesarean with splenectomy in pregnancy with portal hypertension: defining plausibility. AB - 24-year-old woman at 28 weeks gestation was referred from peripheral hospital with diagnosis of pregnancy with portal hypertension. She had received multiple transfusion for pancytopaenia in the past and had undergone endoscopic sclerotherapy for oesophageal varices. Initially, she was admitted in our hospital at 28 weeks gestation for blood transfusion and was evaluated by multispecialty team of doctors. She was advised splenectomy for transfusion dependent pancytopaenia secondary to hypersplenism in non-cirrhotic portal hypertension. She was readmitted at 36 weeks gestation. A decision for caesarean was taken owing to failed induction of labour at 38 weeks gestation. She underwent combined caesarean with splenectomy. Mother and child had an uneventful postoperative recovery and were discharged on ninth postoperative day. Preconceptional counselling, treatment of oesophageal varices and multispecialty approach was paramount in the management. Combined caesarean with splenectomy is feasible and cost-effective treatment associated with improved quality of life. Prospective clinical trials are essential to prove safety and efficacy of treatment. PMID- 28918405 TI - Renal cell carcinoma with isolated metastasis to sigmoid mesentery: a rare resectable combination. AB - Renal cell carcinoma accounts for 2%-3% of all malignancies in adults. It spreads via direct extension, lymphatic route as well as haematogenous route. Lymph nodes, lungs, bone, liver and brain are the usual sites for its metastatic spread. In the presence of limited metastatic disease with potentially resectable metastases, surgery offers the best chances of cure. In the present case, we describe a case of renal cell carcinoma with a solitary metastasis to the sigmoid mesentery in a patient with Von Hippel-Lindau syndrome. There was no retroperitoneal lymphadenopathy or tumour thrombus in the renal vein. The patient was managed with laparoscopic radical nephrectomy and excision of the sigmoid mesentery mass. At 6 months of follow-up, there is no evidence of recurrent disease. PMID- 28918406 TI - Rare cause of colonic intussusception in an adult. AB - Colonic intussusception is an uncommon phenomenon in adults. Advanced imaging has facilitated the increase in awareness of this rare disease. When present, the lead point is most often secondary to a malignancy with primary adenocarcinoma being the most frequent cause. Current surgical management involves oncologic resections for this reason. This is a report of the third ever-reported case of colonic intussusception secondary to an angiolipoma and the first in the western hemisphere. We also demonstrate that these masses are amenable to minimally invasive resection for definitive management. PMID- 28918407 TI - Burden of non-adherence to latent tuberculosis infection drug therapy and the potential cost-effectiveness of adherence interventions in Canada: a simulation study. AB - OBJECTIVE: Pharmaceutical treatment of latent tuberculosis infection (LTBI) reduces the risk of progression to active tuberculosis (TB); however, poor adherence tempers the protective effect. We aimed to estimate the health burden of non-adherence, the maximum allowable cost of hypothetical new adherence interventions to be cost-effective and the potential value of existing adherence interventions for patients with low-risk LTBI in Canada. DESIGN: A microsimulation model of LTBI progression over 25 years. SETTING: General practice in Canada. PARTICIPANTS: Individuals with LTBI who are initiating drug therapy. INTERVENTIONS: A hypothetical intervention with a range of effectiveness was evaluated. Existing drug adherence interventions including peer support, two way text messaging support, enhanced adherence counselling and adherence incentives were also evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: Simulation outcomes included healthcare costs, TB incidence, TB deaths and quality-adjusted life years (QALYs). Base case results were interpreted against a willingness-to-pay threshold of $C50 000/QALY. RESULTS: Compared with current adherence levels, full adherence to LTBI drug therapy could reduce new TB cases from 90.3 cases per 100 000 person-years to 35.9 cases per 100 000 person-years and reduce TB-related deaths from 7.9 deaths per 100 000 person-years to 3.1 deaths per 100 000 person-years. An intervention that increases relative adherence by 40% would bring the population near full adherence to drug therapy and could have a maximum allowable annual cost of approximately $C450 per person to be cost-effective. Based on estimates of effect sizes and costs of existing adherence interventions, we found that they yielded between 900 and 2400 additional QALYs per million people, reduced TB deaths by 5%-25% and were likely to be cost-effective over 25 years. CONCLUSION: Full adherence could reduce the number of future TB cases by nearly 60%, offsetting TB-related costs and health burden. Several existing interventions are could be cost-effective to help achieve this goal. PMID- 28918408 TI - Effectiveness, cost-utility and implementation of a decision aid for patients with localised prostate cancer and their partners: study protocol of a stepped wedge cluster randomised controlled trial. AB - INTRODUCTION: Patient decision aids (PDAs) have been developed to help patients make an informed choice for a treatment option. Despite proven benefits, structural implementation falls short of expectations. The present study aims to assess the effectiveness and cost-utility of the PDA among newly diagnosed patients with localised prostate cancer and their partners, alongside implementation of the PDA in routine care. METHODS/ANALYSIS: A stepped-wedge cluster randomised trial will be conducted. The PDA will be sequentially implemented in 18 hospitals in the Netherlands, over a period of 24 months. Every 3 or 6 months, a new cluster of hospitals will switch from usual care to care including a PDA.The primary outcome measure is decisional conflict experienced by the patient. Secondary outcomes comprise the patient's quality of life, treatment preferences, role in the decision making, expectations of treatment, knowledge, need for supportive care and decision regret. Furthermore, societal cost-utility will be valued. Other outcome measures considered are the partner's treatment preferences, experienced participation to decision making, quality of life, communication between patient, partner and health care professional, and the effect of prostate cancer on the relationship, social contacts and their role as caregiver. Patients and partners receiving the PDA will also be asked about their satisfaction with the PDA.Baseline assessment takes place after the treatment choice and before the start of a treatment, with follow-up assessments at 3, 6 and 12 months following the end of treatment or the day after deciding on active surveillance. Outcome measures on implementation include the implementation rate (defined as the proportion of all eligible patients who will receive a PDA) and a questionnaire for health care professionals on determinants of implementing an innovation. ETHICS AND DISSEMINATION: This study will be conducted in accordance with local laws and regulations of the Medical Ethics Committee of VU University Medical Center, Amsterdam, The Netherlands. The results from this stepped-wedge trial will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION: Nederlands Trial Register NTR TC5177, registration date: May 28th 2015.Pre-results. PMID- 28918409 TI - Qualitative interview study of parents' perspectives, concerns and experiences of the management of lower respiratory tract infections in children in primary care. AB - OBJECTIVE: To explore parents' perspectives, concerns and experiences of the management of lower respiratory tract infections (LRTIs) in children in primary care. DESIGN: Qualitative semistructured interview study. SETTING: UK primary care. PARTICIPANTS: 23 parents of children aged 6 months to 10 years presenting with LRTI in primary care. METHOD: Thematic analysis of semistructured interviews (either in person or by telephone) conducted with parents to explore their experiences and views on their children being prescribed antibiotics for LRTI. RESULTS: Four major themes were identified and these are perspectives on: (1) infection, (2) antibiotic use, (3) the general practitioner (GP) appointment and (4) decision making around prescribing. Symptomatic relief was a key concern: the most troublesome symptoms were cough, breathing difficulty, fever and malaise. Many parents were reluctant to use self-care medication, tended to support antibiotic use and believed they are effective for symptoms, illness duration and for preventing complications. However, parental expectations varied from a desire for reassurance and advice to an explicit preference for an antibiotic prescription. These preferences were shaped by: (1) the age of the child, with younger children perceived as more vulnerable because of their greater difficulty in communicating, and concerns about rapid deterioration; (2) the perceived severity of the illness; and (3) disruption to daily routine. When there was disagreement with the GP, parents described feeling dismissed, and they were critical of inconsistent prescribing when they reconsult. When agreement between the parent and the doctor featured, parents described a feeling of relief and legitimation for consulting, feeling reassured that the illness did indeed warrant a doctor's attention. CONCLUSION: Symptomatic relief is a major concern for parents. Careful exploration of expectations, and eliciting worries about key symptoms and impact on daily life will be needed to help parents understand when a no antibiotic recommendation or delayed antibiotic recommendation is made. PMID- 28918410 TI - 'Just like a normal pain', what do people with diabetes mellitus experience when having a myocardial infarction: a qualitative study recruited from UK hospitals. AB - OBJECTIVE: The objective of the study was to investigate the symptoms people with diabetes experience when having a myocardial infarction (MI), their illness narrative and how they present their symptoms to the health service. SETTING: Three London (UK) hospitals (coronary care units and medical wards). PARTICIPANTS: Patients were recruited with diabetes mellitus (DM) (types 1 and 2) with a clinical presentation of MI (ST elevated MI (STEMI), non-ST elevated MI (NSTEMI), acute MI unspecified and cardiac arrest). A total of 43 participants were recruited, and 39 interviews met the study criteria and were analysed. They were predominantly male (n=30), aged 40-90 years and white British (18/39), and just over a half were from other ethnic groups. The majority had type 2 DM (n=35), 24 had an NSTEMI, 10 had an STEMI and five had other cardiac events. DEFINITIONS OF SELECTION/EXCLUSION CRITERIA: A diagnosis of MI and DM and the ability to communicate enough English to complete the interview. Ward staff made a clinical judgement that the participant was post-treatment, clinically stable and well enough to participate. METHODS: A qualitative study using taped and transcribed interviews analysed using a thematic analysis. RESULTS: While most participants did experience chest pain, it was often not their most striking symptom. As their chest pain did not match their expectations of what a 'heart attack' should be, participants developed narratives to explain these symptoms, including the symptoms being effects of their DM ('hypos'), side effects of medication (oral hypoglycaemics) or symptoms (such as breathlessness and indigestion) related to other comorbidities, often leading to delays in seeking care. CONCLUSIONS: While truly absent chest pain during MI among people with DM was rare in this study, patients' attenuated symptoms often led to delay in seeking attention, and this may result in delays in receiving treatment. PMID- 28918411 TI - Combining CD4 recovery and CD4: CD8 ratio restoration as an indicator for evaluating the outcome of continued antiretroviral therapy: an observational cohort study. AB - OBJECTIVES: Immune recovery following highly active antiretroviral therapy (HAART) is commonly assessed by the degree of CD4 reconstitution alone. In this study, we aimed to assess immune recovery by incorporating both CD4 count and CD4:CD8 ratio. DESIGN: Observational cohort study SETTING AND PARTICIPANTS: Clinical data from Chinese HIV-positive patients attending the largest HIV service in Hong Kong and who had been on HAART for >=4 years were accessed. MAIN OUTCOME MEASURES: Optimal immune outcome was defined as a combination of a CD4 count >=500/MUL and a CD4:CD8 ratio >=0.8. RESULTS: A total of 718 patients were included for analysis (6353 person-years). At the end of year 4, 318 out of 715 patients achieved CD4 >=500/MUL, of which only 33% (105 out of 318) concurrently achieved CD4:CD8 ratio >=0.8. Patients with a pre-HAART CD8 <=800/MUL (428 out of 704) were more likely to be optimal immune outcome achievers with CD4 >=500/MUL and CD4:CD8 ratio >=0.8, the association of which was stronger after adjusting for pre-HAART CD4 counts. In a multivariable logistic model, optimal immune outcome was positively associated with male gender, younger pre-HAART age and higher pre-HAART CD4 count, longer duration of HAART and pre-HAART CD8 <=800/MUL. Treatment regimen and cumulative viral loads played no significant role in the pattern of immune recovery. CONCLUSIONS: A combination of CD4 count and CD4:CD8 ratio could be a useful approach for the characterisation of treatment outcome over time, on top of monitoring CD4 count alone. PMID- 28918412 TI - Prediction of early unplanned intensive care unit readmission in a UK tertiary care hospital: a cross-sectional machine learning approach. AB - OBJECTIVES: Unplanned readmissions to the intensive care unit (ICU) are highly undesirable, increasing variance in care, making resource planning difficult and potentially increasing length of stay and mortality in some settings. Identifying patients who are likely to suffer unplanned ICU readmission could reduce the frequency of this adverse event. SETTING: A single academic, tertiary care hospital in the UK. PARTICIPANTS: A set of 3326 ICU episodes collected between October 2014 and August 2016. All records were of patients who visited an ICU at some point during their stay. We excluded patients who were <=16 years of age; visited ICUs other than the general and neurosciences ICU; were missing crucial electronic patient record measurements; or had indeterminate ICU discharge outcomes or very early or extremely late discharge times. After exclusion, 2018 outcome-labelled episodes remained. PRIMARY AND SECONDARY OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUROC) for prediction of unplanned ICU readmission or in-hospital death within 48 hours of first ICU discharge. RESULTS: In 10-fold cross-validation, an ensemble predictor was trained on data from both the target hospital and the Medical Information Mart for Intensive Care (MIMIC-III) database and tested on the target hospital's data. This predictor discriminated between patients with the unplanned ICU readmission or death outcome and those without this outcome, attaining mean AUROC of 0.7095 (SE 0.0260), superior to the purpose-built Stability and Workload Index for Transfer (SWIFT) score (AUROC=0.6082, SE 0.0249; p=0.014, pairwise t-test). CONCLUSIONS: Despite the inherent difficulties, we demonstrate that a novel machine learning algorithm based on transfer learning could achieve good discrimination, over and above that of the treating clinicians or the value added by the SWIFT score. Accurate prediction of unplanned readmission could be used to target resources more efficiently. PMID- 28918413 TI - Post-traumatic growth and its relationship to quality of life up to 9 years after liver transplantation: a cross-sectional study in Spain. AB - OBJECTIVE: Little is known concerning post-traumatic growth (PTG) after liver transplantation. Against this backdrop the current study analysed the relationship between PTG and time since transplantation on quality of life. Furthermore, it compared PTG between liver transplant recipients and their caregivers. DESIGN: Cross-sectional case-control study. SETTING: University Hospital in Spain. PARTICIPANTS: 240 adult liver transplant recipients who had undergone only one transplantation, with no severe mental disease, were the participants of the study. Specific additional analyses were conducted on the subset of 216 participants for whom caregiver data were available. Moreover, results were compared with a previously recruited general population sample. OUTCOME MEASURES: All participants completed the Posttraumatic Growth Inventory, and recipients also filled in the 12-Item Short-Form Health Survey. Relevant sociodemographic and clinical parameters were also assessed. RESULTS: In the sample of 240 recipients, longer time since transplantation (>9 years) was associated with more pain symptoms (p=0.026). Regardless of duration, recipients showed lower scores on most quality of life dimensions than the general population. However, high PTG was associated with a significantly higher score on the vitality quality of life dimension (p=0.021). In recipients with high PTG, specific quality of life dimensions, such as bodily pain (p=0.307), vitality (p=0.890) and mental health (p=0.353), even equalled scores in the general population, whereas scores on general health surpassed them (p=0.006). Furthermore, liver transplant recipients (n=216) compared with their caregivers showed higher total PTG (p<0.001) and higher scores on the subscales relating to others (p<0.001), new possibilities (p<0.001) and appreciation of life (p<0.001). CONCLUSIONS: Our findings highlight the protective role of PTG in the long-term outcome of liver transplant recipients. Future studies should analyse and develop psychosocial interventions to strengthen PTG in transplant recipients and their caregivers. PMID- 28918414 TI - A protocol of a cross-sectional study evaluating an online tool for early career peer reviewers assessing reports of randomised controlled trials. AB - INTRODUCTION: Systematic reviews evaluating the impact of interventions to improve the quality of peer review for biomedical publications highlighted that interventions were limited and have little impact. This study aims to compare the accuracy of early career peer reviewers who use an innovative online tool to the usual peer reviewer process in evaluating the completeness of reporting and switched primary outcomes in completed reports. METHODS AND ANALYSIS: This is a cross-sectional study of individual two-arm parallel-group randomised controlled trials (RCTs) published in the BioMed Central series medical journals, BMJ, BMJ Open and Annals of Emergency Medicine and indexed with the publication type 'Randomised Controlled Trial'. First, we will develop an online tool and training module based (a) on the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist and the Explanation and Elaboration document that would be dedicated to junior peer reviewers for assessing the completeness of reporting of key items and (b) the Centre for Evidence-Based Medicine Outcome Monitoring Project process used to identify switched outcomes in completed reports of the primary results of RCTs when initially submitted. Then, we will compare the performance of early career peer reviewers who use the online tool to the usual peer review process in identifying inadequate reporting and switched outcomes in completed reports of RCTs at initial journal submission. The primary outcome will be the mean number of items accurately classified per manuscript. The secondary outcomes will be the mean number of items accurately classified per manuscript for the CONSORT items and the sensitivity, specificity and likelihood ratio to detect the item as adequately reported and to identify a switch in outcomes. We aim to include 120 RCTs and 120 early career peer reviewers. ETHICS AND DISSEMINATION: The research protocol was approved by the ethics committee of the INSERM Institutional Review Board (21 January 2016). The study is based on voluntary participation and informed written consent. TRIAL REGISTRATION NUMBER: NCT03119376. PMID- 28918415 TI - Treatment options and barriers to case management of neonatal pneumonia in India: a protocol for a scoping review. AB - INTRODUCTION: India contributes to the highest neonatal deaths globally. Case management is said to be the cornerstone of pneumonia control. Much of the published evidence focuses on children aged 1 to 59 months. This scoping review, thus, aims to identify the treatment options for and barriers to case management of neonatal pneumonia in India. METHODS AND ANALYSIS: This protocol is part of a series of three reviews on neonatal pneumonia in India. Studies addressing treatment of or barriers to case management of neonatal pneumonia in Indian context, published in English in peer-reviewed and indexed journals will be eligible for inclusion. Electronic search will be conducted on nine databases. Hand searching and snowballing will be done for published and grey literature. Selection of studies will be done in title, abstract and full-text stages. A narrative summary will be performed to summarise the details of evidence. ETHICS AND DISSEMINATION: As this is a review involving analysis of secondary data which is available in the public domain and does not involve human participants, ethical approval was not required. The findings of the study will be shared with all stakeholders of this research. Knowledge dissemination workshops will be conducted with relevant stakeholders to ultimately transfer the evidence tailored to the stakeholder (eg, policy briefs, publications, information booklets and so on). PROSPERO 2016: CRD42016045449. PMID- 28918416 TI - [The methodology and sample description of the National Survey on Addiction Problems in Hungary 2015 (NSAPH 2015)]. AB - This paper introduces the methods and methodological findings of the National Survey on Addiction Problems in Hungary (NSAPH 2015). Use patterns of smoking, alcohol use and other psychoactive substances were measured as well as that of certain behavioural addictions (problematic gambling - PGSI, DSM-V, eating disorders - SCOFF, problematic internet use - PIUQ, problematic on-line gaming - POGO, problematic social media use - FAS, exercise addictions - EAI-HU, work addiction - BWAS, compulsive buying - CBS). The paper describes the applied measurement techniques, sample selection, recruitment of respondents and the data collection strategy as well. Methodological results of the survey including reliability and validity of the measures are reported. The NSAPH 2015 research was carried out on a nationally representative sample of the Hungarian adult population aged 16-64 yrs (gross sample 2477, net sample 2274 persons) with the age group of 18-34 being overrepresented. Statistical analysis of the weight distribution suggests that weighting did not create any artificial distortion in the database leaving the representativeness of the sample unaffected. The size of the weighted sample of the 18-64 years old adult population is 1490 persons. The extent of the theoretical margin of error in the weighted sample is +/-2,5%, at a reliability level of 95% which is in line with the original data collection plans. Based on the analysis of reliability and the extent of errors beyond sampling within the context of the database we conclude that inconsistencies create relatively minor distortions in cumulative prevalence rates; consequently the database makes possible the reliable estimation of risk factors related to different substance use behaviours. The reliability indexes of measurements used for prevalence estimates of behavioural addictions proved to be appropriate, though the psychometric features in some cases suggest the presence of redundant items. The comparison of parameters of errors beyond sample selection in the current and previous data collections indicates that trend estimates and their interpretation requires outstanding attention and in some cases even correction procedures might become necessary. PMID- 28918417 TI - [Clinical features of psychotic and non-psychotic bipolar patients]. AB - BACKGROUND: Psychotic symptoms are common in the case of manic, depressive and mixed episodes of bipolar disorder; however, the assessment of delusions and hallucinations is frequently improper, thus the patients presenting also psychotic symptoms are treated based on their diagnosis of schizophrenia, schizoaffective disorder or paranoia. Psychotic symptoms in bipolar disorder result less favourable outcomes and course of illness. METHODS: 365 patients (106 males, 259 females) were hospitalized in or institution from January 1st 2015 to September 30th 2016, who were diagnosed with bipolar disorder according to the ICD-10 criteria. The number of patients presenting psychotic symptoms was 89 (24%); 55 of whom (62%) belonged to the bipolar I, and 34 (38%) belonged to the bipolar II group. As a control group of the psychotic bipolar patients, we chose 80 bipolar patients hospitalized in the above mentioned period, who did not present psychotic symptoms either at the current or their previous hospitalizations. RESULTS: We found psychotic mania in the case of 24 patients (27%, 12 males, 12 females); and the delusions were of grandiose, religious and paranoid content. The number of depressive patients presenting psychotic symptoms was 39 (44%, 30 females, 9 males); their delusions were dominantly characterized by feelings of guilt, hypochondria and impoverishment. We treated 26 patients (29%, 18 females, 8 males) with mixed episodes accompanied by psychotic symptoms; they were characterized by depressive delusions. Compared to the non-psychotic bipolar patients, in the case of psychotic bipolar patients manic and depressive episodes, bipolar I diagnosis, early onset of the disease (under the age of 20), previous suicide attempts and comorbid personality disorder were significantly more frequent at the time of hospitalization, whereas mixed affective episodes and bipolar II diagnosis dominated in the non-psychotic group. Similarly, the residual symptoms were more common in the psychotic group (64 patients 72% vs 34 patients 43%) and previous hospitalizations was higher in the psychotic group (males 10.6, females 12.5 vs. males 7.8, females 8.6). With regard to psychotic symptoms, there was no difference between the two groups in terms of positive family history, comorbid anxiety disorder or alcohol dependency. CONCLUSIONS: Early onset of the disease, bipolar I diagnosis and comorbid personality disorder were typical of psychotic bipolar patients; in addition, suicide attempts and residual symptoms were more common compared to the non-psychotic group. LIMITATIONS: The relatively lower number of patients (89 and 80 patients) and the fact that the data were processed retrospectively limit the generalizability of our results. PMID- 28918418 TI - New aspects in the pathomechanism of diseases of civilization, particularly psychosomatic disorders. Part 1. Theoretical background of a hypothesis. AB - The stress defence-cascade is mostly not biphasic as Cannon thought, the sympathicotonic stress response is preceded by a vagotonic phase called freeze response. Alteration of the carbon dioxide level plays an important role during defence-cascade as its changes interfere with stress hormones, e.g. with catecholamines, thus affecting the degree of arousal. In case of humans, learned behaviour dominates instead of instinctive, so the fight-or-flight often lags; the consequence can be persistent hypocapnia or hypercapnia. The hypoventilation or hyperventilation may continue even after a stressful situation, as tissular and renal compensation stabilizes and makes the pathological breathing patterns chronic. The organism tries to restore the original milieu interieur (sec. Claude Bernard), but this cannot succeed without restoring pCO2. The regulation operates the preservation of intracellular and extracellular pH as a priority, while neurohumoral compensations change the ionic milieu in the body's cells. Present hypothesis specifies the permanent lack or excess of carbon dioxide which can cause allostatic load by psychosomatic pathomechanism. Carbon dioxide is equivalent to stress hormones; its alterations become a means of somatization, resulting in ion-pattern changes in intracellular and extracellular spaces, consequently causing disintegration of the body's function. (See also: network theory, ripple effect, metabolic remodeling.) Intracellular ion-pattern alterations emerge new genetic phenotypes to the surface. The variety of phenotypes explains the diversity of induced diseases. The theory appreciates the role of ions by considering the instantaneous ion pattern of the cytoplasm (all the ions together) as a decisive second messenger. PMID- 28918419 TI - [About the association between antipsychotic medication and cardiovascular morbidity: epidemiology and possible background mechanisms]. AB - The history of antipsychotics began with the discovery of chlorpromazine in the 1950s. Since then this group of medications has become one of the most important element of the armamentarium of psychopharmacology. While initially these pharmacons were used in the treatment of psychotic states (including psychotic mania) in the last approximately 10-15 years new indications - such as treatment of depressive, manic and mixed states and also mood-stabilization in bipolar disorder and also the treatment of major depressive disorder - for several second generation antipsychotic (SGA) agents have been introduced. Taking this fact into consideration it is not surprising that the market of SGAs has been broadened in several countries. At the same time, safety issues have been raised related to some SGAs, mainly because of their adverse cardiometabolic effects (e.g. weight gain; dyslipidemia; disturbances of glucose metabolism). Related to this, it is worthy of note that the lifespan of patients with serious mental illness (SMIs, such as schizophrenia; bipolar disorder; major depression) is shorter than their healthy counterparts and that somatic comorbidities (mainly cardiovascular disorders) of these patients are primarily responsible for this fact. In this paper, firstly we briefly discuss the history and features of APs then we present data on the shorter than expected lifespan of patients with SMIs and also the possible background mechanisms of it (including the supposed role of AP treatment). Then we provide a short discussion on endothelial progenitor cells (EPC), their role in cardiovascular system and related clinical relevance. Eventually, we also discuss our pilot study with the aim to reveal whether there is any effect of AP therapy on the number of CD34/KDR double-positive EPCs. PMID- 28918420 TI - Computer Analysis of Glioma Transcriptome Profiling: Alternative Splicing Events. AB - Here we present the analysis of alternative splicing events on an example of glioblastoma cell culture samples using a set of computer tools in combination with database integration. The gene expression profiles of glioblastoma were obtained from cell culture samples of primary glioblastoma which were isolated and processed for RNA extraction. Transcriptome profiling of normal brain samples and glioblastoma were done by Illumina sequencing. The significant differentially expressed exon-level probes and their corresponding genes were identified using a combination of the splicing index method. Previous studies indicated that tumor specific alternative splicing is important in the regulation of gene expression and corresponding protein functions during cancer development. Multiple alternative splicing transcripts have been identified as progression markers, including generalized splicing abnormalities and tumor- and stage-specific events. We used a set of computer tools which were recently applied to analysis of gene expression in laboratory animals to study differential splicing events. We found 69 transcripts that are differentially alternatively spliced. Three cancer-associated genes were considered in detail, in particular: APP (amyloid beta precursor protein), CASC4 (cancer susceptibility candidate 4) and TP53. Such alternative splicing opens new perspectives for cancer research. PMID- 28918421 TI - Macrophage activation syndrome at the onset of glucocorticoid-resistant systemic lupus erythematosus: a case report. AB - INTRODUCTION: Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory state mediated by uncontrolled cytokine storm and haemophagocytosis. Although rarely reported, MAS might occur in systemic lupus erythematosus (SLE), notably as an inaugural manifestation. Glucocorticoids (GCs) are the cornerstone of SLE therapy. However, in some cases high doses of GCs are required to achieve remission (i.e. glucocorticoid-resistance), leading to significant side effects. CASE REPORT: A 28-year-old Romani male was admitted to our hospital for polyarthralgia, polyserositis and fatigability. The patient had high-grade fever, jaundice and generalized lymphadenopathy. Laboratory tests revealed severe mixed hemolytic autoimmune anemia, leukopenia, hepatocytolysis, coagulation abnormalities, hypertriglyceridemia, biological inflammatory syndrome, hyperferritinemia and persistent proteinuria of nephritic pattern. Imaging studies showed pleuropericardial effusion, hepatosplenomegaly and polysynovitis. Additional blood tests revealed hypocomplementemia and positive ANA, anti-dsDNA and anti-Sm antibodies. Haemophagocytosis was not identified either on bone marrow or axillary lymph node biopsy specimens. However, SLE associated MAS seemed to fit this set-up. High-dose corticotherapy (6.5 g methylprednisolone followed by prednisone, 1.5 mg/kg/day after discharge) and intravenous cyclophosphamide were necessary to induce and sustain remission. CONCLUSION: MAS is a potentially severe manifestation that should be considered at SLE onset whenever high fever and elevated serum levels of aspartate aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin and procalcitonin are noted. Early diagnosis and prompt treatment lead to remission in two thirds of cases. Glucocorticoid-resistance leads to the use of high-dose corticotherapy or immunosuppressive agents that could elicit serious side effects. New insights into the molecular mechanisms of glucocorticoid-resistance are needed in order to conceive more adequate GC-therapies. PMID- 28918422 TI - The Modern Art of Reading Computed Tomography Images of the Lungs: Quantitative CT. AB - Lung diseases are increasing in prevalence and overall burden worldwide. To stem the tide, more and more national and international guidelines are recommending the use of various diagnostic algorithms that are disease specific. There is growing consensus among the respiratory community that although patient histories and lung function testing are the minimum required for clinical examinations, these tests alone are not sufficient for disease characterization. Therefore, the use of computed tomography (CT) imaging is increasing used in clinical decision making for lung diseases. Lung diseases affect various components of lung, including the small airways, lung parenchyma, the interstitial space and the pulmonary vasculature. Quantitative CT (QCT) methods are emerging and are increasingly available using commercial software to quantify the underlying disease components, and a growing body of evidence suggests that QCT is an important tool in the clinical setting to help accurately and reproducibly detect where the disease is located in the lung, and to quantify the extent and overall severity for several lung diseases. Furthermore, this growing body of evidence has promoted the use of thoracic QCT to the point that it is now considered by many as an indispensable technology for longitudinal analysis and intervention trials. Many QCT imaging measurements are available to the respiratory physician, and the aim of this review is to introduce and describe pulmonary QCT imaging measurements and methodologies. PMID- 28918423 TI - Non-Discriminant Relationships between Leg Muscle Strength, Mass and Gait Performance in Healthy Young and Old Adults. AB - BACKGROUND: Gait speed declines with increasing age, but it is unclear if gait speed preferentially correlates with leg muscle strength or mass. OBJECTIVE: We determined the relationship between gait speed and (1) leg muscle strength measured at 3 lower extremity joints and (2) leg lean tissue mass (LTM) in healthy young (age: 25 years, n = 20) and old (age: 70 years, n = 20) adults. METHODS: Subjects were tested for maximal isokinetic hip, knee, and ankle extension torque, leg LTM by bioimpedance, and gait performance (i.e., gait speed, stride length) at preferred and maximal gait speeds. RESULTS: We found no evidence for a preferential relationship between gait performance and leg muscle strength compared with gait performance and leg LTM in healthy young and old adults. In old adults, hip extensor strength only predicted habitual gait speed (R2 = 0.29, p = 0.015), whereas ankle plantarflexion strength only predicted maximal gait speed and stride length (both R2 = 0.40, p = 0.003). CONCLUSIONS: Gait speed did not preferentially correlate with leg muscle strength or leg LTM, favoring neither outcome for predicting mobility. Thus, we recommend that both leg muscle strength and leg LTM should be tested and trained complementarily. Further, hip and ankle extension torque predicted gait performance, and thus we recommend to test and train healthy old adults by functional integrated multiarticular rather than monoarticular lower extremity strength exercises. PMID- 28918424 TI - Systemic Inflammatory Response Is a Prognostic Marker in HIV-Infected Patients with Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is increasingly prevalent in people living with HIV. Systemic inflammation is a prognostic factor requiring validation in HIV-associated HCC. AIMS: Using a multi-centre database of consecutive HCC cases, we investigated the prognostic role of a panel of inflammatory markers, including neutrophil to lymphocyte ratio (NLR), using univariate and multivariate survival analyses. RESULTS: Fifty-nine patients with HIV-associated HCC secondary to hepatitis C (69%) or B virus infection (32%) were identified. The median survival was 22 months. A raised NLR independently predicted patients' survival and was correlated with advanced Barcelona Clinic Liver Cancer stage (p = 0.003) and poor performance status (p < 0.001) but not with HIV RNA or CD4 counts. CONCLUSION: Systemic inflammation, as measured by NLR, is a prognostic determinant associated with adverse pathological features of malignancy, but not coexisting HIV infection, suggesting a tumour-promoting role of the innate immune response that warrants further investigation in mechanistic studies. PMID- 28918425 TI - Definitive Chemoradiotherapy for Anal Carcinoma: Long-Term Results Based on Consistent Time-to-Event Endpoints. AB - AIM: To report the long-term results after definitive chemoradiotherapy (CRT) for anal carcinoma, using consistent time-to-event endpoints. METHODS AND MATERIALS: Anal carcinoma patient charts were reviewed. All patients received definitive CRT. Overall survival (OS), local failure-free survival (LFFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and anal dysfunction-free survival (ADFS) were estimated. RESULTS: In total, 65 patients were included. CRT was well tolerated, with only 24.6% grade >=3 acute toxicity. Overall, the 5-year OS, LFFS, LRFFS, and DMFS were 75.3, 60.2, 74.2, and 66.2%, respectively. Early complete clinical response and tumor stage at diagnosis were the strongest predictors of OS (p = 0.04) and local failure (p = 0.03), respectively. CONCLUSIONS: In the treatment of anal cancers, excellent ADFS and OS, and valid LFFS, LRFFS, and DMFS can be achieved with definitive CRT. Adequacy of time-to-event endpoints is paramount. PMID- 28918426 TI - Aortic Isthmus Flow Recording Predicts the Outcome of the Recipient Twin after Laser Coagulation in Twin-Twin Transfusion Syndrome. AB - INTRODUCTION: The objective was to assess the prognostic value of the systolic flow through the aortic isthmus in monochorionic pregnancies complicated by twin twin transfusion syndrome (TTTS) treated by placental laser ablation. MATERIAL AND METHODS: Fetal echocardiography and outcome data of 105 cases of TTTS treated by laser photocoagulation of placental anastomoses were reviewed. Hemodynamic parameters were collected before and after treatment. The isthmic systolic index (ISI) was calculated as the peak systolic velocity/systolic nadir ratio. RESULTS: A total of 105 laser coagulations were studied. Fetal echocardiography pre- and post-laser were available in 68 cases, including 55 with data on aortic isthmic Doppler. Survival rates were 17, 22, and 61% for 0, 1, or 2 twins, respectively. At least 1 twin was delivered alive in 83% of the pregnancies. The mean gestational age at surgery was 21 weeks (range 16-26). Median ISI values were similar for donor and recipient twins, before and after laser ablation (all p > 0.05). A lower recipient ISI before laser was related to early recipient demise within 24 h (p = 0.04). DISCUSSION: A lower ISI before placental laser ablation for TTTS is associated with postoperative demise of the recipient twin. PMID- 28918427 TI - Safety of Monitored Anesthesia Care Using Propofol-Based Sedation for Pleuroscopy. AB - BACKGROUND: The optimal approach to sedation for pleuroscopy remains undefined. Propofol is the favored sedative-hypnotic for many proceduralists but has a narrow therapeutic window and the risk for oversedation is high. Propofol-based sedation administered by anesthesiologists and the routine use of end-tidal capnography and bispectral index (BIS) monitoring may attenuate risks of complications. OBJECTIVES: The purpose of our study was to evaluate the safety and efficacy of monitored anesthesia care for pleuroscopy. METHODS: We conducted a retrospective cohort study of patients who underwent pleuroscopy. The primary outcome of interest was the incidence of anesthesia complications in patients undergoing pleuroscopy. Hypoxia was defined as oxygen saturation of less than 90% for 2 min and hypotension was defined as the need for vasopressors. RESULTS: Of 199 enrolled patients, there were no significant complications attributed directly to anesthesia. Minor complications included hypoxia in 9 patients (4.5%), hypotension in 76 patients (38.2%), and insertion of a nasopharyngeal tube airway in 2 patients (1.0%). There was no significant difference in anesthesia-related complications between those with BIS monitoring and those without. Lower mean oxygen saturations (p = 0.028) and hypoxia (p = 0.021) were found in patients receiving the combination of propofol plus narcotics plus sedatives compared to those receiving propofol only, propofol plus narcotics or propofol plus sedatives. CONCLUSION: Our study demonstrates that pleuroscopy using propofol with end-tidal capnography monitoring, with or without BIS monitoring, is safe and effective. The combination of propofol with narcotics and sedatives is associated with more hypoxia and lower mean oxygen saturation compared with propofol alone, propofol plus narcotics or propofol plus sedatives. PMID- 28918428 TI - Modification of cardiovascular pharmacotherapy in palliative care patients with cancer: a narrative review. AB - Palliative care patients with cancer are treated with many drugs, especially at the end of life. Limiting polypharmacy decreases the risk of associated adverse effects, medical errors, and harmful drug interactions. The time lag to benefit from the use of many medications used for cardiovascular diseases or their risk factors, such as hypertension and hypercholesterolemia, is frequently longer than the life expectancy of palliative care patients with cancer. It is ethically appropriate to modify, and even to discontinue, cardiovascular pharmacotherapy when there is no prospect of benefit. The decision to discontinue lipid-lowering drugs and antihypertensive drugs is rather straightforward. Antithrombotic therapy may be stopped in low-risk primary prevention but not in high-risk group. Discontinuation of drugs for heart failure may provoke exacerbation of symptoms and should be considered only in the last weeks of life. PMID- 28918429 TI - Synergy of Dendritic Cell Vaccines and Avasimibe in Treatment of Head and Neck Cancer in Mice. AB - BACKGROUND The main purpose of this study was to explore the antitumor effect and mechanisms of ACAT1 inhibitor combined with CSCs-DC vaccine. MATERIAL AND METHODS We isolated HNSCC CSCs and gained CSCs antigens, then used CSCs antigens to load dendritic cells (DC) and generated a CSCs-DC vaccine. We treated mice after surgical excision of established SCC7 tumors with CSCs-DC vaccine and/or ACAT1 inhibitor, and recorded local tumor relapse and host survival. T cells and B cells were harvested from mice treated with CSCs-DC vaccine and/or ACAT1 inhibitor. We tested antibody production and the death rate of CSCs killed by T cells. RESULTS The tumors in the combined treatment group were smaller than in all other groups (P<0.01). The average survival time of the combined treatment group was 82 days and was the longest of all groups. Analysis of IgG levels secreted by B cell and CTL activity in spleens of mice found that results of the combined treatment group were the highest, and the results of the CSCs-DC group were lower than in the combined treatment group. The ACAT1 inhibitor group results were lower than in the CSCs-DC group and the combined treatment group results, but higher than in the PBS group, and the difference was statistically significant. CONCLUSIONS ACAT1 inhibitor enhanced the therapeutic effect of CSCs DC vaccine in the treatment of the mouse HNSCC postoperative recurrence model. ACAT1 may play an important role in cancer immunotherapy. PMID- 28918430 TI - Distribution of Chlamydia Trachomatis Genotypes in Infective Diseases of the Female Lower Genital Tract. AB - The purpose of this study was to investigate the distribution of Chlamydia trachomatis (CT) genotypes in infective diseases of the female lower genital tract, especially in cervical diseases. This study included 128 CT-positive women. DNA was extracted from cervical swabs. Omp1 gene PCR-RFLP and sequencing were used to confirm the subtypes of CT. The association of subtypes with age, clinical symptoms, cervical cytology, and biopsy results was further analyzed. Omp1 gene PCR-RFLP and sequencing showed that the order of prevalent CT genotypes in the female lower genital tract was D (n=38, 29.69%), followed by E (n=28, 21.88%), G (n=21, 16.41%), and F (n=16,12.50%). Genotypes J, H, and K were comparatively rare. Genotype I was not identified in our samples. Further analysis showed that patients with genotype G were more frequently co-infected with other bacteria. Genotype G was also associated with mucopurulent cervicitis (MPC) and cervical intraepithelial neoplasia (CIN). Patients with genotype E were commonly co-infected with HR-HPV. Although genotype D was the most prevalent, it was a relatively low-risk type. These results provide information on distribution of CT genotypes in infective diseases of the female lower genital tract, which is instrumental to developing a vaccine for CT. PMID- 28918431 TI - The effect of hydrazine derivatives of 3-formylchromones on angiogenic basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanoma cell line WM-115. AB - The hydrazine derivatives of benzopyrones remain an unexplored group of chemical compounds. This preliminary study investigates the influence of A-5, CH-3 and K-2 derivatives at concentrations of 1, 10, 100 nM and 1 MUM on selected biochemical factors of a melanoma cell line WM-115, with regard to their potential angiogenic properties. The studied compounds were found to influence cell proliferation, as well as total protein, bFGF and FGFR1 concentration. PMID- 28918432 TI - Reply to the letter to the editor: comment on "No superior treatment for primary osteochondral defects of the talus". PMID- 28918433 TI - Procalcitonin and C-reactive protein as early markers of postoperative intra abdominal infection in patients operated on colorectal cancer. AB - PURPOSE: The aim of this study was to evaluate the accuracy of serum procalcitonin (PCT) and C-reactive protein (CRP) for early diagnosis of postoperative intra-abdominal infections (PIAI) after elective surgery for colorectal cancer. METHODS: Prospective observational study including patients operated on for colorectal cancer between January and December of 2015 was performed. Serum PCT and CRP levels were measured before surgery and daily until postoperative day 3. RESULTS: One hundred twenty patients were included. Seven patients (5.8%) had PIAI. PCT levels were significantly higher in patients with PIAI on postoperative days 1 and 3, whereas CRP levels only were significantly more elevated on postoperative day 3. The ratio between CRP levels on postoperative day 3 and CRP levels on postoperative days 2 (CRP D3/CRP D2) and 1 (CRP D3/CRP D1) was significantly higher in patients with PIAI. PCT on postoperative day 3, for a cutoff of 0.45 ng/mL, had the best sensitivity (100%) with a specificity of 73.8%. The ratio CRP D3/CRP D1 yielded the higher specificity and positive predictive value (90.9 and 27.3%, respectively, for a cutoff of 1.8). The higher negative predictive value was obtained for PCT on postoperative days 1 and 3 (100%, with cutoff of 0.76 and 0.45 ng/mL, respectively) and for CRP on postoperative day 3 (100% with cutoff of 10 mg/dL). CONCLUSION: PCT and CRP serum levels are associated with the appearance of PIAI after colorectal cancer surgery, although the positive predictive values were low for both PCT and CRP. However, the negative predictive values were high. PMID- 28918434 TI - Improved DNA purification with quality assurance for evaluation of the microbial genetic content of constructed wetlands. AB - Efficient isolation of target DNA is a crucial first step of DNA-based metagenomic analyses of environmental samples. Insufficient quantity and purity of DNA isolated using commercial kits result in missing genetic information, especially for large-diameter substrates in constructed wetlands (CWs). Here, we addressed this problem by devising a cost-effective calcium chloride lysozyme sodium dodecyl sulfate (SDS) method (CCLS), with key improvements in the steps of humic acid removal and cell lysis. The buffer comprising Tris, EDTA, Na2O2P7 and PVPP (TENP), and skim milk, could reduce adsorption between microorganisms and substrates, and calcium chloride precipitated and removed over 94% of humic acid. This humic acid removal step, when compared to the PowerSoil DNA kit (MO BIO Laboratories Inc.) (MBKIT), significantly enhanced the DNA purity (A260/230) from 0.68 to 1.63 (p < 0.01). When gentle and extended cell lysis in CCLS replaced the short but violent bead-beating in the MBKIT, DNA yield and the amount of lysed bacteria detected by quantitative real-time polymerase chain reaction (qPCR) on average increased by 2 and 4 folds, respectively, compared to that obtained using the MBKIT (p < 0.01). Furthermore, the full-length bacterial 16S rRNA gene and nirK gene from denitrifying microorganisms were successfully amplified from CCLS generated DNA. Additionally, bacterial diversity indices of richness, Shannon, and evenness examined by denaturing gradient gel electrophoresis (DGGE) increased by 75, 30, and 7%, respectively, by CCLS compared to that using the MBKIT. Hence, the CCLS method enables improved evaluation of microbial density and diversity in CW systems. PMID- 28918435 TI - Infant avoidance training alters cellular activation patterns in prefronto-limbic circuits during adult avoidance learning: II. Cellular imaging of neurons expressing the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1). AB - Positive and negative feedback learning is essential to optimize behavioral performance. We used the two-way active avoidance (TWA) task as an experimental paradigm for negative feedback learning with the aim to test the hypothesis that neuronal ensembles activate the activity-regulated cytoskeletal (Arc/Arg3.1) protein during different phases of avoidance learning and during retrieval. A variety of studies in humans and other animals revealed that the ability of aversive feedback learning emerges postnatally. Our previous findings demonstrated that rats, which as infants are not capable to learn an active avoidance strategy, show improved avoidance learning as adults. Based on these findings, we further tested the hypothesis that specific neuronal ensembles are "tagged" during infant TWA training and then reactivated during adult re-exposure to the same learning task. Using cellular imaging by immunocytochemical detection of Arc/Arg3.1, we observed that, compared to the untrained control group, (1) only in the dentate gyrus the density of Arc/Arg3.1-expressing neurons was elevated during the acquisition phase of TWA learning, and (2) this increase in Arc/Arg3.1-expressing neurons was not specific for the TWA learning task. With respect to the effects of infant TWA training we found that compared to the naive non-pretrained group (a) the infant pretraining group displayed a higher density of Arc/Arg3.1-expressing neurons in the anterior cingulate cortex during acquisition on training day 1, and (b) the infant pretraining group displayed elevated density of Arc/Arg3.1-expressing neurons in the dentate gyrus during retrieval on test day 5. Correlation analysis for the acquisition phase revealed for the ACd that the animals which showed the highest number of avoidances and the fastest escape latencies displayed the highest density of Arc/Arg3.1 expressing neurons. Taken together, we are the first to use the synaptic plasticity protein Arc/Arg3.1 to label neuronal ensembles which are involved in different phases of active avoidance learning and whose activity patterns are changing in response to previous learning experience during infancy. Our results indicate (1) that, despite the inability to learn an active avoidance response in infancy, lasting memory traces are formed encoding the subtasks that are learned in infancy (e.g., the association of the CS and UCS, escape strategy), which are encoded in the infant brain by neuronal ensembles, which alter their synaptic connectivity via activation of specific synaptic plasticity proteins such as Arc/Arg3.1 and Egr1, and (2) that during adult training these memories can be retrieved by reactivating these neuronal ensembles and their synaptic circuits and thereby accelerate learning. PMID- 28918436 TI - Through the looking-glass challenge. PMID- 28918437 TI - Solution to measurement uncertainty challenge. PMID- 28918438 TI - No difference in outcome for open versus arthroscopic rotator cuff repair: a prospective comparative trial. AB - PURPOSE: Arthroscopic techniques tend to become the gold standard in rotator cuff repair. However, little data are reported in the literature regarding the improvement of postoperative outcomes and re-tear rate relative to conventional open surgery. The aim of this study was to compare clinical outcomes and cuff integrity after arthroscopic versus open cuff repair. METHODS: We prospectively assessed clinical outcomes and cuff integrity after an arthroscopic or open rotator cuff repair with a minimum follow-up of 12 months. Clinical evaluation was based on Constant score, Simple Shoulder Value (SSV) and American Shoulder and Elbow Score (ASES). Rotator cuff healing was explored with ultrasound. RESULTS: 44 patients in arthroscopic group A (mean age 56-year-old) and 43 in open group O (mean age 61-year-old) fulfilled the inclusion criteria. Tendons were repaired with a single row technique associated with biceps tenodesis and subacromial decompression. All objective clinical scores significantly improved postoperatively in both groups. No statistical difference was identified between group A and O regarding, respectively, Constant score (72 vs 75 points; p = 0.3), ASES score (88 vs 91 points; p = 0.3), and SSV (81 vs 85%). The overall rate of re-tear (Sugaya type IV or V) reached 7 and 9%, respectively, in group A and O (p = 0.8). CONCLUSION: This study did not prove any difference of arthroscopic over open surgery in case of rotator cuff repair regarding clinical outcome and cuff integrity at 1-year follow-up. LEVEL II: Prospective comparative study. PMID- 28918439 TI - The Gulf oil spill, miscarriage, and infertility: the GROWH study. AB - PURPOSE: To examine whether reported exposure to the Gulf oil spill (2010) was related to reproductive reported miscarriage or infertility. METHODS: 1524 women aged 18-45 recruited through prenatal and Women, Infant, and Children (WIC) clinics, and community events were interviewed about their experience of the oil spill and reproductive history. 1434 women had information on outcomes of at least one pregnancy, and 633 on a pregnancy both before and after the spill. Generalized estimating equations were used to examine the relationship between contact with oil and economic and social consequences of the spill with postponement of pregnancy, miscarriage, and infertility (time to pregnancy >12 months or reported fertility issues), with adjustment for age, race, BMI, smoking, and socioeconomic status. Results were compared for pregnancies occurring prior to and after the oil spill. RESULTS: 77 (5.1%) women reported postponing pregnancy due to the oil spill, which was more common in those with high contact with oil or overall high exposure (aOR 2.92, 95% CI 1.31-6.51). An increased risk of miscarriage was found with any exposure to the oil spill (aOR, 1.54, 95% CI 1.17-2.02). Fertility issues were more common in the overall most highly exposed women (aOR 1.88, 1.19-2.95), when the data were limited to those with pregnancies before and after. However, no particular aspect of oil spill exposure was strongly associated with the outcomes, and effects were almost as strong for pregnancies prior to the oil spill. CONCLUSIONS: The oil spill appears to have affected reproductive decision-making. The evidence is not strong that exposure to the oil spill was associated with miscarriage or infertility. PMID- 28918440 TI - Interpersonal sensitivity and persistent attenuated psychotic symptoms in adolescence. AB - Interpersonal sensitivity defines feelings of inner-fragility in the presence of others due to the expectation of criticism or rejection. Interpersonal sensitivity was found to be related to attenuated positive psychotic symptom during the prodromal phase of psychosis. The aims of this study were to examine if high level of interpersonal sensitivity at baseline are associated with the persistence of attenuated positive psychotic symptoms and general psychopathology at 18-month follow-up. A sample of 85 help-seeking individuals (mean age = 16.6, SD = 5.05) referred an Italian early detection project, completed the interpersonal sensitivity measure and the structured interview for prodromal symptoms (SIPS) at baseline and were assessed at 18-month follow-up using the SIPS. Results showed that individuals with high level of interpersonal sensitivity at baseline reported high level of attenuated positive psychotic symptoms (i.e., unusual thought content) and general symptoms (i.e., depression, irritability and low tolerance to daily stress) at follow-up. This study suggests that being "hypersensitive" to interpersonal interactions is a psychological feature associated with attenuated positive psychotic symptoms and general symptoms, such as depression and irritability, at 18-month follow-up. Assessing and treating inner-self fragilities may be an important step of early detection program to avoid the persistence of subtle but very distressing long-terms symptoms. PMID- 28918441 TI - Long-lasting subjective effects of LSD in normal subjects. AB - RATIONALE: Lysergic acid diethylamide (LSD) and other serotonergic hallucinogens can induce profound alterations of consciousness and mystical-type experiences, with reportedly long-lasting effects on subjective well-being and personality. METHODS: We investigated the lasting effects of a single dose of LSD (200 MUg) that was administered in a laboratory setting in 16 healthy participants. The following outcome measures were assessed before and 1 and 12 months after LSD administration: Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS), Death Transcendence Scale (DTS), NEO-Five Factor Inventory (NEO-FFI), and State Trait Anxiety Inventory (STAI). RESULTS: On the PEQ, positive attitudes about life and/or self, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction significantly increased at 1 and 12 months and were subjectively attributed by the subjects to the LSD experience. Five-Dimensions of Altered States of Consciousness (5D-ASC) total scores, reflecting acutely induced alterations in consciousness, and Mystical Experience Questionnaire (MEQ30) total scores correlated with changes in well-being/life satisfaction 12 months after LSD administration. No changes in negative attitudes, negative mood, antisocial/negative social effects, or negative behavior were attributed to the LSD experience. After 12 months, 10 of 14 participants rated their LSD experience as among the top 10 most meaningful experiences in their lives. Five participants rated the LSD experience among the five most spiritually meaningful experiences in their lives. On the MS and DTS, ratings of mystical experiences significantly increased 1 and 12 months after LSD administration compared with the pre-LSD screening. No relevant changes in personality measures were found. CONCLUSIONS: In healthy research subjects, the administration of a single dose of LSD (200 MUg) in a safe setting was subjectively considered a personally meaningful experience that had long-lasting subjective positive effects. TRIAL REGISTRATION: Registration identification number: NCT01878942. PMID- 28918443 TI - Brief Report: Personality Mediates the Relationship between Autism Quotient and Well-Being: A Conceptual Replication using Self-Report. AB - Autism spectrum disorder (ASD) impacts well-being across the lifespan. Individuals with ASD evidence differences in personality traits and self-concept clarity that are predictors of well-being in typically-developing individuals. The current research replicates a growing body of evidence demonstrating differences in well-being and personality between individuals low in ASD characteristics (n = 207) and individuals high in ASD characteristics (n = 46) collected from the general population using an online survey. Results were consistent in a subsample of demographically matched pairs (n = 39 per group) and relative to norms. Further, the current research provides the first evidence that openness, conscientiousness, emotional stability, and self-concept clarity mediate the relationship between ASD characteristics and well-being. PMID- 28918442 TI - The role of periostin in lung fibrosis and airway remodeling. AB - Periostin is a protein that plays a key role in development and repair within the biological matrix of the lung. As a matricellular protein that does not contribute to extracellular matrix structure, periostin interacts with other extracellular matrix proteins to regulate the composition of the matrix in the lung and other organs. In this review, we discuss the studies exploring the role of periostin to date in chronic respiratory diseases, namely asthma and idiopathic pulmonary fibrosis. Asthma is a major health problem globally affecting millions of people worldwide with significant associated morbidity and mortality. Periostin is highly expressed in the lungs of asthmatic patients, contributes to mucus secretion, airway fibrosis and remodeling and is recognized as a biomarker of Th2 high inflammation. Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by progressive aberrant fibrosis of the lung matrix and respiratory failure. It predominantly affects adults over 50 years of age and its incidence is increasing worldwide. Periostin is also highly expressed in the lungs of idiopathic pulmonary fibrosis patients. Serum levels of periostin may predict clinical progression in this disease and periostin promotes myofibroblast differentiation and type 1 collagen production to contribute to aberrant lung fibrosis. Studies to date suggest that periostin is a key player in several pathogenic mechanisms within the lung and may provide us with a useful biomarker of clinical progression in both asthma and idiopathic pulmonary fibrosis. PMID- 28918444 TI - Left atrial volume computed by 3D rotational angiography best predicts atrial fibrillation recurrence after circumferential pulmonary vein isolation. AB - Left atrium (LA) size is a well-studied predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). Yet, there is still little agreement on the best imaging technique to size the LA, and on the most appropriate sizing parameter. Volumetric assessment of LA with three-dimensional rotational angiography (3DRA LA volume index) might be a valid alternative to the commonly used transthoracic echocardiography (TTE LA volume index). The aim of our study was to investigate whether LA volume by 3DRA at the time of PVI is able to predict the risk of atrial fibrillation recurrence. We analysed 352 consecutive patients with symptomatic paroxysmal or persistent atrial fibrillation referred for PVI to our Institution. In all patients, LA volume index (LAVI) was assessed by TTE and by 3DRA. Sinus rhythm was restored after PVI in 348 patients (99%). Average TTE-LAVI and 3DRA-LAVI were 37 +/- 12 and 83 +/- 18 ml/m2, respectively. At a median follow-up of 19 (12, 24) months, 27% of patients had AF recurrence after the first PVI. At the univariate analysis, persistent AF (p < 0.01), use of anti-arrhythmic drugs (AAD) (p < 0.05) and 3DRA LAVI (p < 0.01) were significantly associated with AF recurrence. In contrast, none of the echocardiographic parameters considered, including TTE-LAVI, was associated with AF recurrence (p = 0.29). At the multivariate analysis, 3DRA-LAVI was the only independent predictor for AF recurrence (HR 1.01 [1.00-1.03], p = 0.017). Left atrial volume measured with 3DRA is superior to TTE assessment and to AF history in predicting atrial fibrillation recurrence after PVI. PMID- 28918446 TI - Favorable surgical outcomes of aldosterone-producing adenoma based on lateralization by CT imaging and hypokalemia: a non-AVS-based strategy. AB - PURPOSE: To test the efficacy of a strategy based on CT imaging and clinical characteristics on lateralizing origin of excess aldosterone secretion in primary aldosteronism. PATIENTS AND METHODS: Consecutive patients with diagnosed primary hyperaldosteronism from June 2006 to July 2012 in our center underwent adrenal surgeries without pre-operational adrenal venous sampling (AVS) if all the three criteria were met: (1) round- or oval-shaped occupational lesion of low density after contrast enhancement with diameter >1 cm on CT scan was located in one adrenal gland; (2) unequivocally normal contralateral adrenal gland; (3) serum potassium level lower than 3.5 mmol/L. Subjects who had received operation were taken into analysis and follow-ups. RESULTS: One hundred and twenty-five patients fulfilled the criteria and were recruited into our research. One hundred and twenty-two operated patients (97.6%) experienced complete resolution of hypokalemia as well as resolution or improvement in hypertension with reduction in antihypertensive medication, while 3 patients (2.4%) failed to obtain normal kalemia and continued on spironolactone therapy. At a median of 65-month (range 21-93) follow-up of these 122 subjects, 27 patients dropped out (22.1%). The 95 responding patients reported no episodes of paralysis or confirmed hypokalemia or any supplementation of potassium. Multivariate linear correlation analysis showed that plasma potassium level was correlated inversely with tumor diameter (r = 0.258, 95% CI -0.076, -0.514, p = 0.037) and basal plasma aldosterone level (r = 0.251, 95% CI -0.040, -0.464, p = 0.042). CONCLUSIONS: Most patients with typical unilateral adrenal macroadenomas, normal contralateral glands and hypokalemia could attain favorable surgical therapeutic outcomes without pre-operational AVS lateralization. PMID- 28918445 TI - Pre-emptive Intestinal Transplant: The Surgeon's Point of View. AB - Pre-emptive transplantation is a well-established practice for certain types of end-organ failure such as in the use of kidney transplantation. For irreversible intestinal failure, total parenteral nutrition (TPN) remains the gold standard, due to the suboptimal long-term results of intestinal transplantation. As such, the only role for pre-emptive transplantation, if at all, will be for patients identified to be at high risk of complications and mortality while on definitive long-term TPN. In these patients, the timing of early listing and transplantation could become life-saving, taking into account that mortality on the waiting list is still the highest for intestinal candidates. The development of simulation models or pre-transplant scoring systems could help in selecting patients based on potential outcome on TPN or with transplantation, and recent reports from high volume centers identify few underlying pathologic conditions and some TPN complications as at higher risk of increased morbidity and mortality. A pre emptive transplant could be used as a rehabilitative procedure in a well-selected case-by-case scenario, among TPN patients at risk of liver failure, repeated central line infections, mesenteric infarction, short bowel syndrome (SBS) <50 cm or with end stoma, congenital mucosal disease, desmoid tumors: These conditions must be carefully evaluated, not to underestimate the clinical stage nor to over estimate the impact of a temporary situation. At the present time, diseases with a variable and unpredictable course, such as intestinal dysmotility disorders, or quality of life and financial issues are still far from being considered as indications for a pre-emptive transplant. PMID- 28918447 TI - An improved crystal structure of C-phycoerythrin from the marine cyanobacterium Phormidium sp. A09DM. AB - C-Phycoerythrin (PE) from Phormidium sp. A09DM has been crystallized using different conditions and its structure determined to atomic resolution (1.14 A). In order for the pigment present, phycoerythrobilin (PEB), to function as an efficient light-harvesting molecule it must be held rigidly (Kupka and Scheer in Biochim Biophys Acta 1777:94-103, 2008) and, moreover, the different PEB molecules in PE must be arranged, relative to each other, so as to promote efficient energy transfer between them. This improved structure has allowed us to define in great detail the structure of the PEBs and their binding sites. These precise structural details will facilitate theoretical calculations of each PEB's spectroscopic properties. It was possible, however, to suggest a model for which chromophores contribute to the different regions of absorption spectrum and propose a tentative scheme for energy transfer. We show that some subtle differences in one of these PEB binding sites in two of the 12 subunits are caused by crystal contacts between neighboring hexamers in the crystal lattice. This explains some of the differences seen in previous lower resolution structures determined at two different pH values (Kumar et al. in Photosyn Res 129:17-28, 2016). PMID- 28918449 TI - Immunochemical Study of the Effect of F2Glc on Glycogen Synthase Translocation and Glycogen Synthesis in Isolated Rat Hepatocytes. AB - The compound 2-deoxy-2-fluoro-alpha-D-glucopyranosyl fluoride (F2Glc), which is a nonmetabolized superior glucose analogue, is a potent inhibitor of glycogen phosphorylase and pharmacological properties are reported. Glycogen phosphorylase (GP) and glycogen synthase (GS) are responsible of the degradation and synthesis, respectively, of glycogen which is a polymer of glucose units that provides a readily available source of energy in mammals. GP and GS are two key enzymes that modulate cellular glucose and glycogen levels; therefore, these proteins are suggested as potential targets for the treatment of diseases related to glycogen metabolism disorders. We studied by Western Blot technique that F2Glc decreased GP activity, and we also showed that F2Glc did not affect GS activity and its translocation from a uniform cytosolic distribution to the hepatocyte periphery, which is crucial for glycogen synthesis, using immunoblotting and immunofluorescence labeling techniques. F2Glc specifically inhibits glycogenolysis pathway and permits a greater deposition of glycogen. These observations open up the possibility of further develop drugs that act specifically on GP. The ability to selectively inhibit GP, which is a key enzyme for the release of glucose from the hepatic glycogen reserve, may represent a new approach for the treatment of hyperglycemia in type 2 diabetes. PMID- 28918448 TI - A systematic review of cost-effectiveness analysis of screening interventions for assessing the risk of venous thromboembolism in women considering combined oral contraceptives. AB - Use of combined oral contraceptives (COCs) by women increases the risk of venous thromboembolism (VTE), which can have a major impact on an individuals' quality of life. VTE is also associated with an increase in healthcare costs. Our aim was to systematically review cost-effectiveness analyses (CEAs) considering any screening for risk of VTE in women using COCs. The quality of reporting in each study was assessed, a summary of results was prepared, and the key drivers of cost effectiveness in each of the eligible CEAs were identified. A search strategy using MeSH terms was performed in MEDLINE, Embase, the Centre for Review and Dissemination (CRD) database including the Economic Evaluation Database from the UK National Health Service, and Cochrane reviews. Two reviewers independently screened and determined the final articles, and a third reviewer resolved any discrepancies. Consolidated Health Economic Evaluation Reporting Standards was used to assess the quality of reporting in terms of perspective, effectiveness measures, model structure, cost, time-horizon and discounting. Four publications (three from Europe, one from the United States) were eligible for inclusion in the review. According to current criteria, relevant elements were sometimes not captured and the sources of epidemiological and effectiveness data used in the CEAs were of limited quality. The studies varied in terms of type of costs assessed, country settings, model assumptions and uncertainty around input parameters. Key drivers of CEAs were sensitivity and specificity of the test, incidence rate of VTE, relative risk of prophylaxis, and costs of the test. The reviewed studies were too dissimilar to draw a firm conclusion on cost effectiveness analysis about universal and selective screening in high-risk groups. The new emerging diagnostic tools for identifying women at risk of developing VTE, that are more predictive and less costly, highlight the need for more studies that apply the latest evidence and utilize robust methods for cost effectiveness analysis. This information is required to improve decision making for this pertinent issue within personalized medicine. PMID- 28918450 TI - Clinical utility of the ASDAS index in comparison with BASDAI in patients with ankylosing spondylitis (Axis Study). AB - The objective of the study was to study the clinical utility of the Ankylosing Spondylitis Disease Activity Score (ASDAS) for the assessment of disease activity in ankylosing spondylitis (AS) patients, compared to the Bath Ankylosing Spondylitis Activity Index (BASDAI). This was a prospective longitudinal observational study in patients with AS (NY-modified criteria) from 23 Spanish centers. Physical and analytical data; global, lumbar, and nocturnal pain; ASDAS, BASDAI and minimally acceptable clinical status (PASS) were collected. Psychometric characteristics of both indexes were analyzed: construct validity (convergent and divergent), discriminant capacity, criterion validity (global physician and patient assessment), and sensitivity to change. The study involved 127 patients (19.7% attrition). Both BASDAI and ASDAS showed a higher correlation with patient's global assessment (r = 0.76 and 0.70, respectively) than with physician's global assessment (r = 0.67 and 0.57). Both scores allowed discriminating patients with an acceptable clinical status, although BASDAI to a greater extent than ASDAS (Cohen delta 1.72 vs 0.88 for the medical PASS). Both scores showed sensitivity to change in patients who changed from an unacceptable symptomatic state to acceptable according to PASS criteria (physician and patient) and by BASDAI 50 response criteria (Cohen delta > 0.80). BASDAI showed better criterion validity than ASDAS, both for the patient PASS (AUC 0.85 vs 0.79) and for the physician's (AUC 0.90 vs 0.79). ASDAS shows adequate performance for disease activity in patients with AS; however, in this study, its psychometric properties do not present advantages over BASDAI in terms of criterion validity, sensitivity to change or discriminative capacity; replacement of BASDAI by ASDAS is not supported by the data. PMID- 28918451 TI - Quantitative 18F-DOPA PET/CT in pheochromocytoma: the relationship between tumor secretion and its biochemical phenotype. AB - INTRODUCTION: 18F-FDOPA illustrates the properties of uptake and storage of catecholamines in pheochromocytomas (PHEOs). Until now, the relationship between 18F-FDOPA quantitative parameters and a PHEO secretory profile has not been specifically evaluated. MATERIALS AND METHODS: Fifty-six patients (56% females, median age: 47.5 yrs) with non-metastatic PHEO, evaluated by 18F-FDOPA PET/CT, were included in this retrospective study. Forty-five patients had negative genetic testing (80.4%); five patients (8.9%) had RET, two patients (3.6%) had SDHB, two had SDHD (3.6%), one patient (1.8%) had NF1, and one patient had a VHL (1.8%) mutation. Correlation between 18F-FDOPA metabolic parameters (tumor SUVmax, tumor SUVmean, tumor SUVmax/liver SUVmax, MTV 42%, total lesion uptake), urinary metanephrines (MNs), and plasma chromogranin A (CgA) were evaluated. RESULTS: All patients had positive 18F-FDOPA PET/CT. On univariate analysis, there was a strong correlation between all metabolic parameters and urinary MNs and plasma chromogranin A (CgA). The highest correlations were observed between total lesion (TL) uptake and the value of urinary MNs regardless of their nature (p = 8.10-15 and r = 0.80) and between MTV 42% and plasma CgA levels (p = 2.10-9, r = 0.74). On multivariate analysis, the correlation of uptake parameters and CgA levels did not persist further due to the relation of CgA and tumor diameter. A correlation between TL uptake and the normetanephrine/metanephrine ratio (NMN/MN) was also found, a finding that was in accordance with in vitro studies, which were found to have a higher catecholamine content in epinephrine producing PHEOs. CONCLUSION: This retrospective study shows a correlation between 18F-FDOPA uptake, especially using TL uptake, urinary MNs, and a PHEO biochemical phenotype. This illustrates that beyond its localization value, 18F-FDOPA PET further enables PHEO characterization at a specific metabolic level. PMID- 28918452 TI - Pro-oxidant status and Nrf2 levels in psoriasis vulgaris skin tissues and dimethyl fumarate-treated HaCaT cells. AB - Reactive oxygen species (ROS) contribute to pathogenesis of many inflammatory skin diseases, including psoriasis. The aim of this study is to compare antioxidant protein expression in psoriasis vulgaris (PV) skin tissues with that in normal skin tissues in vivo and to evaluate the effects of dimethyl fumarate (DMF), used for the treatment of psoriasis, on ROS generation and apoptosis in a human keratinocyte cell line HaCaT. Compared with normal skin tissues, PV skin tissues showed increased protein oxidation as well as down-regulation of Nrf2 and its regulatory proteins such as HO-1 and AKR1C3. Using HaCaT cells to model DMF induced pro-oxidant effects in the skin cells, we found that DMF treatment induced increased ROS levels and apoptotic cell death, as signified by increased proportion of cells with Annexin V-PE(+) staining and a sub-G0/G1 peak in the cell cycle. Preceding these changes, DMF treatment resulted in up-regulation of Nrf2, HO-1, and AKR1C3 proteins in these cells. Collectively, increased oxidative stress and impaired cellular anti-oxidant enzyme systems may participate in the pathogenesis of PV. DMF may exert an additive therapeutic efficacy in PV by attenuating the redox burden and subsequent oxidative damage to normal keratinocytes through activation of Nrf2 pathway relative to PV. PMID- 28918453 TI - Furan induced ovarian damage in non-diabetic and diabetic rats and cellular protective role of lycopene. AB - PURPOSE: In our work, furan, lycopene, and furan + lycopene treatments were applied to non-diabetic and diabetic female rats via gavage. METHODS: Ovarian tissue alterations with histopathology, immunohistochemistry, malondialdehyde levels, oxidative stress parameters such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and harmful effect on ovarian tissue DNA were evaluated in all groups for 28 days. RESULTS: Furan caused the changes histological, ovarian cell's DNA structure, malondialdehyde levels, antioxidant enzymes activities as in a statistically significant manner in each group. Useful effect of lycopene was determined both in non-diabetic and diabetic treatment groups against furan according to the used experimental parameters. Although some histopathological alterations were seen in diabetic and non diabetic/diabetic plus furan-treated group's ovarians, lycopene restored these variations near to normal levels in furan + lycopene treated groups for in 28 days. Additionally, the results of our immunohistochemical analysis and alterations of the oxidative stress parameters results also supported these findings. CONCLUSIONS: Our result confirms that lycopene has protective effect and significantly altered diabetes and furan-induced toxicity in the rat ovarian tissue. PMID- 28918454 TI - Assessment of thermotactile and vibrotactile thresholds for detecting sensorineural components of the hand-arm vibration syndrome (HAVS). AB - BACKGROUND: Thermotactile thresholds and vibrotactile thresholds are measured to assist the diagnosis of the sensorineural component of the hand-arm vibration syndrome (HAVS). OBJECTIVES: This study investigates whether thermotactile and vibrotactile thresholds distinguish between fingers with and without numbness and tingling. METHODS: In 60 males reporting symptoms of the hand-arm vibration syndrome, thermotactile thresholds for detecting hot and cold temperatures and vibrotactile thresholds at 31.5 and 125 Hz were measured on the index and little fingers of both hands. RESULTS: In fingers reported to suffer numbness or tingling, hot thresholds increased, cold thresholds decreased, and vibrotactile thresholds at both 31.5 and 125 Hz increased. With sensorineural symptoms on all three phalanges (i.e. numbness or tingling scores of 6), both thermotactile thresholds and both vibrotactile thresholds had sensitivities greater than 80% and specificities around 90%, with areas under the receiver operating characteristic curves around 0.9. There were correlations between all four thresholds, but cold thresholds had greater sensitivity and greater specificity on fingers with numbness or tingling on only the distal phalanx (i.e. numbness or tingling scores of 1) suggesting cold thresholds provide better indications of early sensorineural disorder. CONCLUSIONS: Thermotactile thresholds and vibrotactile thresholds can provide useful indications of sensorineural function in patients reporting symptoms of the sensorineural component of HAVS. PMID- 28918455 TI - In-hospital outcomes of acute myocardial infarction with cardiogenic shock caused by right coronary artery occlusion vs. left coronary artery occlusion. AB - In-hospital outcomes of acute myocardial infarction (AMI) with cardiogenic shock (CS) were still not satisfactory even in the primary percutaneous coronary intervention (PCI) era. The aim of this study was to compare in-hospital outcomes of AMI with CS caused by right coronary artery (RCA) occlusion vs. left coronary artery (LCA) occlusion. Consecutive 894 AMI patients from January 2010 to March 2015 were screened for inclusion. A total of 114 AMI patients with CS were included as the final study population, and were divided into the RCA group (n = 56) and LCA group (n = 58). The patient characteristics were compared between the two groups. Multivariate logistic regression analysis was performed to show whether the RCA group was associated with better outcomes even after controlling confounding factors. In-hospital mortality was significantly lower in the RCA group (8.9%) than in the LCA group (46.6%) (P < 0.001). The RCA group (vs. the LCA group) was inversely associated with in-hospital death (OR 0.08, 95% CI 0.02 0.21, P < 0.001) after controlling covariates. Aspartate transaminase value (per 50 U/L incremental: OR 1.22, 95% CI 1.03-1.45, P = 0.02), aging (per 10-year-old incremental: OR 2.14, 95% CI 1.26-3.63, P = 0.01) and using VA-ECMO (OR 22.13, 95% CI 5.22-93.90, P < 0.001) were also significantly associated with in-hospital death. In conclusion, among AMI patients with CS, IRA of RCA was significantly associated with the better in-hospital outcome. PMID- 28918456 TI - Testing a mobile mindful eating intervention targeting craving-related eating: feasibility and proof of concept. AB - Theoretically driven smartphone-delivered behavioral interventions that target mechanisms underlying eating behavior are lacking. In this study, we administered a 28-day self-paced smartphone-delivered intervention rooted in an operant conditioning theoretical framework that targets craving-related eating using mindful eating practices. At pre-intervention and 1-month post-intervention, we assessed food cravings among adult overweight or obese women (N = 104; M age = 46.2 +/- 14.1 years; M BMI = 31.5 +/- 4.5) using ecological momentary assessment via text message (SMS), self-reported eating behavior (e.g., trait food craving), and in-person weight. Seventy-eight participants (75.0%) completed the intervention within 7 months ('all completers'), and of these, 64 completed the intervention within 3 months ('timely completers'). Participants experienced significant reductions in craving-related eating (40.21% reduction; p < .001) and self-reported overeating behavior (trait food craving, p < .001; other measures ps < .01). Reductions in trait food craving were significantly correlated with weight loss for timely completers (r = .30, p = .020), this pattern of results was also evident in all completers (r = .22, p = .065). Taken together, results suggest that smartphone-delivered mindful eating training targeting craving related eating may (1) target behavior that impacts a relative metabolic pathway, and (2) represent a low-burden and highly disseminable method to reduce problematic overeating among overweight individuals. ClinicalTrials.gov registration: NCT02694731. PMID- 28918458 TI - Cadmium losses in overland flow from an agricultural soil. AB - Cadmium (Cd) transport in overland flow from agricultural soils is potentially important when trying to predict future soil Cd concentrations, but at present there is little information on the magnitude of loss from this pathway. This study measured Cd concentrations and fluxes in overland flow from a catchment where cattle winter-grazed a forage crop (kale) (Brassica oleracea) in year one and measurements continued in year two when the catchment was returned to pasture and grazed by sheep. Flow-weighted mean concentrations (FWMC) of total, particulate and dissolved Cd in overland flow events from the forage crop were 0.49, 0.41 and 0.08 MUg L-1, respectively. In contrast, no dissolved Cd was detected in overland flow from pasture, with a FWMC of total Cd of 0.09 MUg L-1. In line with the Cd concentrations, total Cd fluxes were greater from the forage crop (0.06 g Cd ha-1 year-1) than from pasture (0.04 g Cd ha-1 year-1). Cadmium losses in overland flow were relatively minor compared with those reported for other pathways such as plant uptake or subsurface flow. Further, compared to the amount of Cd that is currently added to soil in a maintenance application of phosphate fertiliser (30 kg P ha-1 year-1) which is on average 5.5 g Cd ha-1, Cd losses in overland flow represented < 1% of inputs. Measurement of Cd losses in overland flow should be undertaken at other sites to confirm the low Cd losses found in this study, along with the distribution between dissolved and particulate fractions. PMID- 28918457 TI - Effects of menthol and its interaction with nicotine-conditioned cue on nicotine seeking behavior in rats. AB - RATIONALE: Increasing clinical evidence suggests that menthol, a significant flavoring additive in tobacco products, may contribute to smoking and nicotine dependence. Relapse to smoking behavior presents a formidable challenge for the treatment of tobacco addiction. An unresolved issue is whether the mentholation of tobacco products precipitates relapse to tobacco use in abstinent smokers. OBJECTIVES: The present study examined the effects of menthol on the perseverance and relapse of nicotine-seeking behavior in rats. METHODS: Male Sprague-Dawley rats were trained to press a lever for intravenous nicotine self-administration (0.03 mg/kg/infusion) under a fixed-ratio five schedule of reinforcement. Each nicotine infusion was signaled by the presentation of a sensory stimulus that was established as a discrete nicotine-conditioned cue. Five minutes prior to the sessions, the rats received an intraperitoneal injection of menthol (0.1 mg/kg) or vehicle. In the subsequent extinction test sessions, nicotine was unavailable with or without menthol and/or the nicotine-conditioned cue. The reinstatement tests were performed the following day after the extinction criterion was met. Menthol was also tested on food-seeking responses. In a subset of nicotine trained rats, a transient receptor potential melastatin 8 (TRPM8) antagonist RQ 00203078 was given prior to menthol administration. RESULTS: Continued administration of menthol sustained responses on the previously active and nicotine-reinforced lever in the extinction tests. The readministration of menthol after extinction reinstated active lever responses. In both the extinction and the reinstatement tests, a combination of pre-session menthol administration and cue representation during the session produced a more robust behavioral effect than either menthol or the cue alone. No such effects of menthol was observed in food trained rats. RQ-00203078 did not change menthol effect on nicotine seeking. CONCLUSION: These data demonstrated that menthol specifically sustained and reinstated nicotine-seeking behavior, and this effect was independent of TRPM8 activity. These findings suggest that menthol in most tobacco products, even not menthol labeled, may contribute to the perseverance of and relapse to tobacco-seeking behavior. PMID- 28918459 TI - HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients. AB - PURPOSE: Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. EXPERIMENTAL DESIGN: A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-alpha-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. RESULTS: In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045 2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376-3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294). CONCLUSIONS: Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high density tumors. However, further external validations and functional investigations are still required. PMID- 28918460 TI - Effects of Cadmium Exposure on Metal Accumulation and Energy Metabolism of Silver Carp (Hypophthalmichthys molitrix). AB - Effects of cadmium (Cd) exposure on metal accumulation and energy metabolism of silver carp (Hypophthalmichthys molitrix) were studied during 14 days. The results showed that Cd accumulated in tissues of silver carp significantly with time and Cd concentration, as the order: liver > kidney > gill > muscle. The levels of muscle glycogen, triglyceride, and plasma triglyceride decreased significantly (p < 0.05). The levels of muscle protein, plasma glucose and lactate significantly increased during the first 8 days, and then all significantly decreased (p < 0.05). No significant alternations were observed in muscle cortisol, ATP and plasma protein (p > 0.05). The results indicate that the tissues' Cd concentrations and energy metabolism were altered by the presence of waterborne Cd, and silver carp mobilizes the muscle energy stores to cope with the increased energy demands for detoxication and repair mechanism induced by the exposure to waterborne Cd. PMID- 28918461 TI - Ethnic differences in maternal near miss. AB - PURPOSE: To evaluate the association between ethnic differences and the occurrence of maternal near miss (MNM) in the Amazon and Northeast regions of Brazil. METHODS: This is a secondary analysis of a national cross-sectional study focused on the assessment of care to pregnancy, childbirth, and infants under 1 year of age. Ethnicity was classified as white, black or indigenous. Ethnic distribution by state and region, the proportion of severe maternal complications and related procedures, and the prevalence of MNM and its criteria were calculated for the ethnic groups. Risks for MNM were estimated per sociodemographic characteristics and healthcare received by ethnic group, using prevalence ratios adjusted by all predictors and by the sampling method. RESULTS: 76% of the 16.783 women were black, 20% white and 3.5% indigenous. Around 36% reported any complication related to pregnancy and the most frequent were hemorrhage (27-31%), and infection (7.1-9.0%). The MNM ratio was higher among indigenous (53.1) and black (28.4) than in white women (25.7). For black women, the risks of MNM were lower for private prenatal care and hospital admission for conditions other than hypertension, while higher for cesarean section and peregrination. For indigenous, the risks of MNM were lower for private prenatal care, and higher for a longer time to reach the hospital. For white women, only the low number of prenatal visits increased the risk of MNM. CONCLUSIONS: The occurrence of MNM was higher for indigenous and black than for white women. PMID- 28918462 TI - Development of a new scoring system to predict 5-year incident diabetes risk in middle-aged and older Chinese. AB - AIMS: The aim of this study was to develop a new risk score system to predict 5 year incident diabetes risk among middle-aged and older Chinese population. METHODS: This prospective study included 17,690 individuals derived from the Dongfeng-Tongji cohort. Participants were recruited in 2008 and were followed until October 2013. Incident diabetes was defined as self-reported clinician diagnosed diabetes, fasting glucose >=7.0 mmol/l, or the use of insulin or oral hypoglycemic agent. A total of 1390 incident diabetic cases were diagnosed during the follow-up period. beta-Coefficients were derived from Cox proportional hazard regression model and were used to calculate the risk score. RESULTS: The diabetes risk score includes BMI, fasting glucose, hypertension, hyperlipidemia, current smoking status, and family history of diabetes. The beta-coefficients of these variables ranged from 0.139 to 1.914, and the optimal cutoff value was 1.5. The diabetes risk score was calculated by multiplying the beta-coefficients of the significant variables by 10 and rounding to the nearest integer. The score ranges from 0 to 36. The area under the receiver operating curve of the score was 0.751. At the optimal cutoff value of 15, the sensitivity and specificity were 65.6 and 72.9%, respectively. Based upon these risk factors, this model had the highest discrimination compared with several commonly used diabetes prediction models. CONCLUSIONS: The newly established diabetes risk score with six parameters appears to be a reliable screening tool to predict 5-year risk of incident diabetes in a middle-aged and older Chinese population. PMID- 28918463 TI - Apoptotic mechanisms after repeated noise trauma in the mouse medial geniculate body and primary auditory cortex. AB - A correlation between noise-induced apoptosis and cell loss has previously been shown after a single noise exposure in the cochlear nucleus, inferior colliculus, medial geniculate body (MGB) and primary auditory cortex (AI). However, repeated noise exposure is the most common situation in humans and a major risk factor for the induction of noise-induced hearing loss (NIHL). The present investigation measured cell death pathways using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in the dorsal, medial and ventral MGB (dMGB, mMGB and vMGB) and six layers of the AI (AI-1 to AI-6) in mice (NMRI strain) after a second noise exposure (double-exposure group). Therefore, a single noise exposure group has been investigated 7 (7-day-group-single) or 14 days (14-day-group single) after noise exposure (3 h, 5-20 kHz, 115 dB SPL peak-to-peak). The double exposure group received the same noise trauma for a second time 7 days after the initial exposure and was either TUNEL-stained immediately (7-day-group-double) or 1 week later (14-day-group-double) and data were compared to the corresponding single-trauma group as well as to an unexposed control group. It was shown that TUNEL increased immediately after the second noise exposure in AI-3 and stayed upregulated in the 14-day-group-double. A significant increase in TUNEL was also seen in the 14-day-group-double in vMGB, mMGB and AI-1. The present results show for the first time the influence of a repeated noise trauma on cell death mechanisms in thalamic and cortical structures and might contribute to the understanding of pathophysiological findings and psychoacoustic phenomena accompanying NIHL. PMID- 28918464 TI - What's Next in Complex Networks? Capturing the Concept of Attacking Play in Invasive Team Sports. AB - The evolution of performance analysis within sports sciences is tied to technology development and practitioner demands. However, how individual and collective patterns self-organize and interact in invasive team sports remains elusive. Social network analysis has been recently proposed to resolve some aspects of this problem, and has proven successful in capturing collective features resulting from the interactions between team members as well as a powerful communication tool. Despite these advances, some fundamental team sports concepts such as an attacking play have not been properly captured by the more common applications of social network analysis to team sports performance. In this article, we propose a novel approach to team sports performance centered on sport concepts, namely that of an attacking play. Network theory and tools including temporal and bipartite or multilayered networks were used to capture this concept. We put forward eight questions directly related to team performance to discuss how common pitfalls in the use of network tools for capturing sports concepts can be avoided. Some answers are advanced in an attempt to be more precise in the description of team dynamics and to uncover other metrics directly applied to sport concepts, such as the structure and dynamics of attacking plays. Finally, we propose that, at this stage of knowledge, it may be advantageous to build up from fundamental sport concepts toward complex network theory and tools, and not the other way around. PMID- 28918465 TI - Congenital lumbar kyphosis with skin ulceration and osteomyelitis in a myelomeningocele child: a case report. AB - INTRODUCTION: Kyphosis is a frequent problem in children with spina bifida, and this deformity may cause different complications as respiratory insufficiency, bowel dysfunction, and skin ulcers. CASE REPORT: We report on a 13-year-old myelomeningocele male with a lumbar kyphoscoliosis associated to a septic skin ulceration that resulted in an acute sepsis. An X-ray revealed a kyphosis of 110 degrees and a scoliosis of 25 degrees between T9 and L5. The wound and blood cultures showed Staphylococcus aureus colonization, and an appropriate antibiotic therapy was started. An MRI showed a wedged vertebra at T12, a laminae defects from T8 to the sacrum, and a spondylitis at T12-L1. Ulcer resection and kyphectomy from T12 to L3 were performed "en bloc," and the spine was instrumented fromT7 to S1. After the surgery, the kyphosis was corrected to 10 degrees , and the scoliosis was corrected to 0 degrees . At an 18-month follow up, a solid bony fusion was obtained, and no recurrence of skin ulcer was reported. CONCLUSION: Antibiotherapy associated to one-step "en-bloc" surgical debridement and kyphectomy should be considered as a valid option to eradicate the infection and to correct the spine deformity in kyphosis due to myelomeningocele associated to septic skin ulcer and spondylitis. PMID- 28918467 TI - Anisodamine inhibits endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation in rhabdomyolysis-induced acute kidney injury. AB - Anisodamine protects against free radical-induced cellular damage. This study aimed to investigate the protective effect of anisodamine on rhabdomyolysis induced acute kidney injury (RIAKI). C57BL/6 J mice, TXNIP-/- and NLRP3 -/- (both were C57BL/6 J background) mice were used to construct RIAKI model. Anisodamine administration was performed on RIAKI mice only. Mice were divided into control, TXNIP-KD (knock down), LNPR3-KD, and anisodamine group (n = 15 in each group). The renal injury, renal function, renal tubular cells apoptosis and expression of Caspase-1, ASC, endoplasmic reticulum (ER) stress markers IRE-1alpha, CHOP, and ATF4, and interleukin (IL-1alpha, IL-1beta, and IL-18) were detected. The knock down of TXNIP or NLRP3 expression in mice showed protective effect against RIAKI pathogenesis, as compared with the RIAKI mice. The expression of Caspase-1, ASC, and interleukins, renal injury, renal tubular cells apoptosis in TXNIP-KD and LNPR3-KD mice were significantly inhibited in comparison with the RIAKI mice. Moreover, anisodamine treatment reduced expression of ER stress markers IRE 1alpha, CHOP, and ATF4, TXNIP and NLRP3, as well as ACS, Caspase-1, IL-1alpha, IL 1beta, and IL-18, showing moderate protective effect on the changes of above factors comparing with TXNIP or NLRP3 knock down. This study declared that anisodamine showed protective effect on RIAKI model may by inhibiting ER stress associated TXNIP/NLRP3 inflammasome. PMID- 28918468 TI - Constraints affecting dairy goats milk production in Kenya. AB - In Kenya, the population of dairy goats is about 200,000 and 80% of these are reared in Mount Kenya region. They provide a quick source of milk for consumption or sale, which has an immense value especially to poor households. The small land sizes required for their rearing are especially useful in these highly populated areas. Although much research has been done on problems faced by dairy cattle farmers, limited information is available on problems faced by dairy goat farmers. Therefore, the objective of this study was to determine the constraints affecting dairy goat production in Mount Kenya region. In a cross-sectional survey, 157 farmers were interviewed on major constraints using a semi-structured questionnaire. The results from the questionnaires showed that the main problems experienced by these farmers were as follows: lack of market of milk and goats 45% (71/157), diseases 33% (52/157), high cost of concentrates 25% (38/157), lack of feed 19% (30/157), problems of unreliable buck rotation program 16.5% (26/157), and insecurity 1.8% (3/157). The study revealed that dairy goat farmers in the region faced by a number of challenges and therefore, our recommendation is there is a need for farmers to be trained on innovative ways of value chain addition and other strategies to market their milk. Additionally, the government should put resources to salvage the milk plant and association members should put firm measures to improve management. Creation of farmer awareness, treatment, and disease control measures should be instituted to improve productivity. PMID- 28918469 TI - Aversive and non-aversive memory impairment in the mucopolysaccharidosis II mouse model. AB - Hunter syndrome (MPS II, OMIM 309900) is a lysosomal storage disorder due to deficient iduronate sulphatase activity. Patients present multiple cognitive alterations, and the aim of this work was to verify if MPS II mice also present some progressive cognitive alterations. For that, MPS II mice from 2 to 6 months of age were submitted to repeated open field and inhibitory avoidance tests to evaluate memory parameters. MPS II mice presented impaired memory at 6 months evaluated by open field test. They also performed poorly in the inhibitory avoidance test from 4 months. We conclude that MPS II mice develop cognitive alterations as the disease progresses. These tests can be used in the future to study the efficacy of therapeutic approaches in the central nervous system. PMID- 28918466 TI - Mutations in context: implications of BRCA testing in diverse populations. AB - Cancer is a common non-communicable disease worldwide, although it exhibits differential population trends in incidence and mortality rates. The differences relate to population structure, environmental risk factors as well as health system organization. This article discusses the potential impact of genetic testing on population health, focusing in particular on the mutational spectrum of breast cancer susceptibility genes in diverse populations. We identify the need for improved access to, and increased investment in, comprehensive cancer risk assessment and genetic testing as well as cancer control measures that take into account lifestyle, environmental, and social factors in understudied minority groups. PMID- 28918470 TI - Assessment of glucose regulation in pregnancy after gastric bypass surgery. AB - AIMS/HYPOTHESIS: Roux-en-Y gastric bypass (RYGB) surgery is characterised by glycaemic variability. Prospective studies of glucose metabolism in pregnancy after RYGB are not available, therefore this study aimed to evaluate physiological alterations in glucose metabolism in pregnancy following RYGB. METHODS: Sixty-three pregnant women (25 who underwent RYGB, 19 non-operated obese control women and 19 normal weight control women) were included. Frequently sampled 3 h OGTTs and 1 h IVGTTs were performed between 24 and 28 weeks of gestation and, in a subgroup, were repeated at 3-6 months after delivery. RESULTS: We observed major alterations in glucose kinetics during the OGTT, including an early increase in plasma glucose followed by hypoglycaemia in 90% of women who had previously undergone RYGB. The higher degree of glycaemic variability in this group was accompanied by increased insulin, C-peptide and glucagon concentrations after oral glucose load, whereas no differences in insulin response were observed after parenteral glucose administration (RYGB vs normal weight). IVGTT data suggested improved insulin sensitivity (mean difference 0.226 * 10-4 min-1 [pmol/l]-1 [95% CI 0.104, 0.348]; p < 0.001) and disposition index in pregnancies after RYGB when compared with obese control women. However, subtle alterations in insulin action and beta cell function were still observed when comparing women who had undergone RYGB with the normal-weight control group. Moreover, we observed that fetal growth was associated with maternal glucose nadir levels and insulin secretion in offspring of those who had previously undergone RYGB. CONCLUSIONS/INTERPRETATION: Pregnancies after RYGB are affected by altered postprandial glucose, insulin and C-peptide dynamics. Insulin sensitivity is improved by RYGB, although subtle alterations in beta cell function are observed. Longitudinal studies are needed to assess potential consequences for fetal development and pregnancy outcomes. PMID- 28918471 TI - Extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation: a meta-analysis. AB - BACKGROUND: We reviewed the available literature on patients undergoing lung transplantation supported by cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO). METHODS: A systematic literature search was performed in three databases, in accordance with the PRISMA guidelines. Meta analyses were used to compare the outcomes of ECMO and CPB procedures. RESULTS: Seven observational studies met the inclusion criteria incorporating 785 patients. ECMO support showed lower rate of primary graft dysfunction, bleeding, renal failure requiring dialysis, tracheostomy, intraoperative transfusions, intubation time, and hospital stay. Total support time was greater for the ECMO supported group. No difference was reported between operative and ischemic time. CONCLUSIONS: The present study indicates that the intraoperative use of ECMO is associated with increased efficacy and safety, regarding short-term outcomes, compared to CPB. Well-designed, randomized studies, comparing ECMO to CPB, are necessary to assess their clinical outcomes further. PMID- 28918472 TI - A reliable protocol for colorimetric determination of iron oxide nanoparticle uptake by cells. AB - Size, shape, and surface properties of superparamagnetic iron oxide nanoparticles (SPIONs) can influence their interaction with biological systems, particularly the incorporation by tumor cells and consequently the biological activity and efficiency in biomedical applications. Several strategies have been used to evaluate cellular uptake of SPIONs. While qualitative methods are generally based on microscopy techniques, quantitative assays are carried out by techniques such as inductively coupled plasma-mass spectrometry and flow cytometry. However, inexpensive colorimetric methods based on equipments commonly found in chemistry and biochemistry laboratories are preferred for routine measurements. Nevertheless, colorimetric assays must be used judiciously, particularly when nanoparticles are involved, since their interaction with biological constituents tends to lead to quite underestimated results. Thus, herein described is a colorimetric protocol using 2,2'-bipyridine as chromogenic ligand, where each step was optimized and validated by total reflection X-ray fluorescence spectroscopy, realizing a highly reproducible and reliable method for determination of iron content in cells incubated with SPIONs. The limit of blank and limit of detection were determined to be as low as 0.076 and 0.143 MUg Fe/mL, using sample volumes as small as 190 MUL and a number of cells as low as 2.0 * 105. Furthermore, three different types of surface-functionalized nanoparticles were incorporated in cells and evaluated through this protocol, enabling to monitor the additive effect of o-phosphorylethanolamine (PEA) and folic acid (FA) conjugation on iron oxide nanoparticles (SPION-PEA and SPION-PEA/FA), that enhanced the uptake by HeLa cells, respectively, by four and ten times when compared to SPIONs conjugated with nonbioactive molecules. Graphical abstract Colorimetric determination of superparamagnetic iron oxide nanoparticles (SPIONs) incorporated by cells. PMID- 28918473 TI - Complete genome sequences of two insect-specific flaviviruses. AB - We determined the complete genomic sequences of two previously discovered insect specific flaviviruses, Marisma mosquito virus (MMV) and Nanay virus (NANV), using a combination of high-throughput sequencing, reverse transcription-polymerase chain reaction, 5' and 3' rapid amplification of cDNA ends and Sanger sequencing. Complete polyprotein amino acid sequence alignments revealed that the closest known relatives of MMV and NANV are Donggang virus (89% identity, 95% similarity) and Nounane virus (53% identity, 70% similarity), respectively. Phylogenetic inference is in agreement with these findings. Potential programmed -1 ribosomal frameshifting sites were bioinformatically identified in the genomes of both viruses. PMID- 28918474 TI - Induction of Immunogenic Cell Death in Lymphoma Cells by Wharton's Jelly Mesenchymal Stem Cell Conditioned Medium. AB - Strategies that induce immunogenic cell death (ICD) or downregulate CD47 or PD-L1 expression have resulted in successful therapeutic options for tumor eradication. Several groups have reported the tumoricidal effects of human umbilical cord Wharton's jelly stem cells (hWJSCs) or its conditioned medium (hWJSC-CM) on certain cancers but the mechanisms have not been elucidated. Since hWJSCs possess immunomodulatory properties, we investigated whether one of the tumoricidal mechanisms was via ICD. We first concentrated hWJSC-CM into a 3 kDa concentrate and then exposed various concentrations of this concentrate to human lymphoma cells to find out which concentration had the greatest tumoricidal effect. We observed that a 500 ug/ml concentration of the concentrate had the greatest inhibitory effect. Thereafter, lymphoma cells were exposed to 500 ug/ml of the hWJSC-CM-3 kDa concentrate and then subjected to analysis for morphology, viability, apoptosis, mitochondrial and endoplasmic reticulum stress, danger associated molecular patterns (DAMP), extracellular HMGB1, CD47 and PD-L1 markers and dendritic cell phenotype. Extensive nuclear chromatin and mitochondrial changes with significantly decreased cell viability and increased apoptosis were observed in the treated lymphoma cells compared to controls. There were also significant increases in the release of DAMPs, extracellular HMGB1 and dendritic cell activation and maturation, with concomitant decreases in CD47 and PD-L1 expression in the treated cells compared to controls. In other ongoing studies we observed increased expression of specific tumor-suppressor molecules (miRNA-146a and miRNA-126, MCP-1, IL-6, IL-8 and IL-12) in hWJSC-CM suggesting that one or more of these molecules may be the modulators of the ICD. PMID- 28918475 TI - Octopaminergic innervation and a neurohaemal release site in the antennal heart of the locust Schistocerca gregaria. AB - A detailed account is given by the octopaminergic innervation of the antennal heart in Schistocerca gregaria using various immunohistochemical methods. Anterograde axonal filling illustrates the unilateral innervation on the medial ventral surface of the pumping muscle of the antennal heart via the paired corpora cardiaca nerve III. In addition, antibody staining revealed that ascending axons of this nerve terminate at the ampullae of the antennal heart forming synaptoid structures and extensive neurohaemal release sites. Due to the innervation by two dorsal unpaired median neurons, the presence of the biogenic amines octopamine and tyramine could be visualized by immunocytochemistry in an insect antennal heart for the first time. The data suggest that tyramine acts as a precursor and not purely as an independent transmitter. While the octopaminergic fibers innervating the pumping muscle of the antennal heart indicate a cardioregulatory role, we conclude that octopamine released from the neurohaemal area is pumped into the antennae and an involvement in the modulation of the antennal sensory sensitivity is discussed. PMID- 28918476 TI - Effects of stocking density on lipid deposition and expression of lipid-related genes in Amur sturgeon (Acipenser schrenckii). AB - To investigate the correlation between lipid deposition variation and stocking density in Amur sturgeon (Acipenser schrenckii) and the possible physiological mechanism, fish were conducted in different stocking densities (LSD 5.5 kg/m3, MSD 8.0 kg/m3, and HSD 11.0 kg/m3) for 70 days and then the growth index, lipid content, lipase activities, and the mRNA expressions of lipid-related genes were examined. Results showed that fish subjected to higher stocking density presented lower final body weights (FBW), specific growth ratio (SGR), and gonad adipose tissue index (GAI) (P < 0.05). Lower lipid content was observed in the liver, gonad adipose tissue and muscle in sturgeons held in HSD group (P < 0.05). The serum concentrations of triglyceride (TG), total cholesterol (TC), and high density lipoprotein cholesterol (HDL-C) decreased significantly with increasing stocking density, while no significant change was observed for low-density lipoprotein cholesterol (LDL-C). Furthermore, the cDNAs encoding lipoprotein lipase (LPL) and hepatic lipase (HL) were isolated in Amur sturgeon, respectively. The full-length LPL cDNA was composed of 1757 bp with an open reading frame of 501 amino acids, while the complete nucleotide sequences of HL covered 1747 bp encoding 499 amino acids. In the liver, the activities and mRNA levels of LPL were markedly lower in HSD group, which were consistent with the variation tendency of HL. Fish reared in HSD group also presented lower levels of activities and mRNA expression of LPL in the muscle and gonad. Moreover, the expressions of peroxisome proliferator-activated receptor alpha (PPARalpha) in both the liver and skeletal muscle were significantly upregulated in HSD group. Overall, the results indicated that high stocking density negatively affects growth performance and lipid deposition of Amur sturgeon to a certain extent. The downregulation of LPL and HL and the upregulation of PPARalpha may be responsible for the lower lipid distribution of Amur sturgeon in higher stocking density. PMID- 28918477 TI - In vitro inhibition of HIV-1 replication in autologous CD4+ T cells indicates viral containment by multifactorial mechanisms. AB - HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibodies (NAbs) are present during chronic infection, but the relative contributions of these effector mechanisms to viral containment remain unclear. Here, using an in vitro model involving autologous CD4+ T cells, primary HIV-1 isolates, HIV-1-specific CTLs, and neutralizing monoclonal antibodies, we show that b12, a potent and broadly neutralizing monoclonal antibody to HIV-1, was able to block viral infection when preincubated with virus prior to infection, but was much less effective than CTLs at limiting virus replication when added to infected cell cultures. However, the same neutralizing antibody was able to contain viruses by antibody-dependent cell-mediated virus inhibition in vitro, which was mediated by natural killer cells (NKs) and dependent on an Fc-Fc receptor interaction. Meanwhile, bulk CTLs from HIV-1 controllers were more effective in suppression of virus replication than those from progressors. These findings indicate that control of HIV-1 replication in activated CD4+ T cells is ineffectively mediated by neutralizing antibodies alone, but that both CTLs and antibody-dependent NK mediated immune mechanisms contribute to viral containment. Our study systemically compared three major players in controlling HIV-1 infection, CTLs, NAbs, and NKs, in an autologous system and highlighted the multifactorial mechanisms for viral containment and vaccine success. PMID- 28918479 TI - Rebuttal comments. PMID- 28918478 TI - An Ibero-American inter-laboratory trial to evaluate serological tests for the detection of anti-Neospora caninum antibodies in cattle. AB - We carried out an inter-laboratory trial to compare the serological tests commonly used for the detection of specific Neospora caninum antibodies in cattle in Ibero-American countries. A total of eight laboratories participated from the following countries: Argentina (n = 4), Brazil (n = 1), Peru (n = 1), Mexico (n = 1), and Spain (n = 1). A blind panel of well-characterized cattle sera (n = 143) and sera representative of the target population (n = 351) was tested by seven in house indirect fluorescent antibody tests (IFATs 1-7) and three enzyme-linked immunosorbent assays (ELISAs 1-3; two in-house and one commercial). Diagnostic performance of the serological tests was calculated and compared according to the following criteria: (1) the "Pre-test information," which uses previous epidemiological and serological data; (2) the "Majority of tests," which classifies a serum as positive or negative according to the results obtained by most tests evaluated. Unexpectedly, six tests showed either sensitivity (Se) or specificity (Sp) values lower than 90%. In contrast, the best tests in terms of Se, Sp, and area under the ROC curve (AUC) values were IFAT 1 and optimized ELISA 1 and ELISA 2. We evaluated a high number of IFATs, which are the most widely used tests in Ibero-America. The significant discordances observed among the tests regardless of the criteria employed hinder control programs and urge the use of a common test or with similar performances to either the optimized IFAT 1 and ELISAs 1 and 2. PMID- 28918480 TI - Sgs1 helicase is required for efficient PCNA monoubiquitination and translesion DNA synthesis in Saccharomyces cerevisiae. AB - DNA-damage tolerance (DDT) is employed by eukaryotes to deal with replication blocks on the template strand, and is divided into two parallel pathways that are activated by sequential ubiquitination of proliferating cell nuclear antigen (PCNA) at the Lys164 residue. Rad6-Rad18-mediated PCNA monoubiquitination promotes translesion DNA synthesis (TLS) and the monoubiquitinated PCNA can be further polyubiquitinated by an Mms2-Ubc13-Rad5 complex, leading to error-free lesion bypass. We previously reported that the DNA helicase Sgs1 is required for error-free lesion bypass, probably through the double-Holliday junction migration and subsequent resolution. Surprisingly, a synthetic genetic array (SGA) screen using rev1 and rev3 as baits did not reveal an anticipated synthetic effect with sgs1, indicating a possible involvement of Sgs1 in TLS. Here, we report detailed genetic analyses demonstrating that Sgs1 plays a key role in efficient TLS and that it is probably required for the signaling of DNA damage leading to PCNA monoubiquitination. These studies collectively illustrate that Sgs1 participates in both branches of DDT and possibly plays a role in pathway choice. PMID- 28918482 TI - In memoriam Prof. Dr. Jurgen Kiefer. PMID- 28918481 TI - Fibrinolysis in trauma: a review. AB - : Fibrinolytic dysregulation is an important mechanism in traumatic coagulopathy. It is an incompletely understood process that consists of a spectrum ranging from excessive breakdown (hyperfibrinolysis) and the shutdown of fibrinolysis. Both hyperfibrinolysis and shutdown are associated with excess mortality and post traumatic organ failure. The pathophysiology appears to relate to endothelial injury and hypoperfusion, with several molecular markers identified in playing a role. Although there are no universally accepted diagnostic tests, viscoelastic studies appear to offer the greatest potential for timely identification of patients presenting with fibrinolytic dysregulation. Treatment is multimodal, involving prompt hemorrhage control and resuscitation, with controversy surrounding the use of antifibrinolytic drug therapy. This review presents the current evidence on the pathophysiology, diagnostic challenges, as well as the management of this hemostatic dysfunction. LEVEL OF EVIDENCE: Level III. PMID- 28918483 TI - Effects of multidisciplinary teams and an integrated follow-up electronic system on clinical pharmacist interventions in a cancer hospital. AB - Background The aim of drug therapy is to attain distinct therapeutic effects that not only improve patient's quality of life but also reduce the inherent risks associated with the therapeutic use of drugs. Pharmacists play a key role in reducing these risks by developing appropriate interventions. Whether to accept or reject the intervention made by the pharmacist is a relevant consultant's decision. Objective To evaluate the impact of electronic prompts and follow-up of rejected pharmacy interventions by clinical pharmacists in an in-patient setting. Setting Shaukat Khanum Cancer Hospital & Research Center, Lahore, Pakistan. Method The study was conducted in two phases. Data for 3 months were collected for each phase of the study. Systematic and quantifiable consensus validity was developed for rejected interventions in phase 1, based on patient outcome analyses. Severity rating was assigned to assess the significance of interventions. Electronic prompts for follow-on interventions in phase 2 were then developed and implemented, including daily review via a multidisciplinary team (MDT) approach. Main outcome measure Validity of rejected interventions, acceptance of follow-on interventions before and after re-engineering the pharmacy processes, rejection rate and severity rating of follow-on interventions. Result Of a total of 2649 and 3064 interventions that were implemented during phase 1 and phase 2, 238 (9%) and 307 (10%) were rejected, respectively. Additionally, 133 (56%) were inappropriate rejections during phase 1. The estimated reliability between pharmacists regarding rejected interventions was 0.74 (95% CI of 0.69, 0.79, p 0.000). Prospective data were analysed after implementing electronic alerts and an MDT approach. The acceptance rate of follow on interventions in phase 2 was 60% (184). Conclusion Electronic prompts for follow-on interventions together with an MDT approach enhance the optimization of pharmacotherapy, increase drug rationality and improve patient care. PMID- 28918486 TI - Elastic and inelastic light scattering spectroscopy and its possible use for label-free brain tumor typing. AB - This paper presents an approach for label-free brain tumor tissue typing. For this application, our dual modality microspectroscopy system combines inelastic Raman scattering spectroscopy and Mie elastic light scattering spectroscopy. The system enables marker-free biomedical diagnostics and records both the chemical and morphologic changes of tissues on a cellular and subcellular level. The system setup is described and the suitability for measuring morphologic features is investigated. Graphical Abstract Bimodal approach for label-free brain tumor typing. Elastic and inelastic light scattering spectra are collected laterally resolved in one measurement setup. The spectra are investigated by multivariate data analysis for assigning the tissues to specific WHO grades according to their malignancy. PMID- 28918484 TI - Drug-Herb Interactions in the Elderly Patient with IBD: a Growing Concern. AB - OPINION STATEMENT: Inflammatory bowel disease (IBD), which includes conditions such as Crohn's disease and ulcerative colitis, is becoming more prevalent with the elderly being the fastest growing group. Parallel to this, there is an increasing interest in the use of complementary and alternative medicine (CAM). Nearly half of patients with IBD have used CAM at one time. The elderly patients, however, are burdened by comorbid conditions, polypharmacy, and altered functional status. With increasing use of complementary and alternative medicine in our elderly patients with IBD, it is vital for the provider to provide counsel on drug-herb potential interactions. CAM includes herbal products, diet, dietary supplements, acupuncture, and prayer. In this paper, we will review common CAM, specifically herbs, that are used in patients with IBD including the herb background, suggested use, evidence in IBD, and most importantly, potential interactions with IBD medications used in elderly patients. Most important evidence-based adverse events and drug-herb interactions are summarized. The herbs discussed include Triticum aestivum (wheat grass), Andrographis paniculata (chiretta), Boswellia serrata, tormentil, bilberry, curcumin (turmeric), Plantago ovata (blond psyllium), Oenothera biennis (evening primrose oil), germinated barley foodstuff, an herbal preparation of myrrh, chamomile and coffee extract, chios mastic gum, wormwood (absinthe, thujone), Cannabis sativa (marijuana, THC), tripterygium wilfordii (thunder god vine), Ulmus rubra (slippery elm bark), trigonella foenugraecum (fenugreek), Dioscorea mexicana (wild yam), Harpagophytum procumbens (devil's claw), ginger, cinnamon, licorice, and peppermint. PMID- 28918485 TI - The 5-oxoprolinase is required for conidiation, sexual reproduction, virulence and deoxynivalenol production of Fusarium graminearum. AB - In eukaryotic organisms, the 5-oxoprolinase is one of the six key enzymes in the gamma-glutamyl cycle that is involved in the biosynthetic pathway of glutathione (GSH, an antioxidative tripeptide counteracting the oxidative stress). To date, little is known about the biological functions of the 5-oxoprolinase in filamentous phytopathogenic fungi. In this study, we investigated the 5 oxoprolinase in Fusarium graminearum for the first time. In F. graminearum, two paralogous genes (FgOXP1 and FgOXP2) were identified to encode the 5-oxoprolinase while only one homologous gene encoding the 5-oxoprolinase could be found in other filamentous phytopathogenic fungi or Saccharomyces cerevisiae. Deletion of FgOXP1 or FgOXP2 in F. graminearum led to significant defects in its virulence on wheat. This is likely caused by an observed decreased deoxynivalenol (DON, a mycotoxin) production in the gene deletion mutant strains as DON is one of the best characterized virulence factors of F. graminearum. The FgOXP2 deletion mutant strains were also defective in conidiation and sexual reproduction while the FgOXP1 deletion mutant strains were normal for those phenotypes. Double deletion of FgOXP1 and FgOXP2 led to more severe defects in conidiation, DON production and virulence on plants, suggesting that both FgOXP1 and FgOXP2 play a role in fungal development and plant colonization. Although transformation of MoOXP1into DeltaFgoxp1 was able to complement DeltaFgoxp1, transformation of MoOXP1 into DeltaFgoxp2 failed to restore its defects in sexual development, DON production and pathogenicity. Taken together, these results suggest that FgOXP1 and FgOXP2 are likely to have been functionally diversified and play significant roles in fungal development and full virulence in F. graminearum. PMID- 28918487 TI - Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies. AB - INTRODUCTION: We have previously shown that children who developed de novo donor specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. METHODS: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan-Meier estimator. RESULTS: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R 2 0.072; C3d: adjusted R 2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 +/- 0.18 (C1q+) vs. 0.25 +/- 0.08 (C1q-) episodes per patient (mean +/- standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q-) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30-1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d-); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d-) years; HR 0.38; 95% CI 0.15-0.97; p = 0.04]. CONCLUSION: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction. PMID- 28918488 TI - Petrobasilar, petroclival, or petrosphenoidal canal of the abducens nerve. PMID- 28918489 TI - Yersinia enterocolitica biotype 1A: a possible new trigger of reactive arthritis. AB - Yersinia enterocolitica (YE) biotype 1A is generally considered non-pathogenic, and the role of it in causing reactive musculoskeletal complications is unclear. We evaluated the capability of YE biotype 1A to induce reactive arthritis (ReA) and other reactive musculoskeletal symptoms. Analysis of self-reported musculoskeletal symptoms was supplemented with a telephone interview (with a permission to acquire copies of patient files from a local physician or hospital) and/or clinical examination of subjects with recent musculoskeletal symptoms after a positive stool culture for YE. The diagnoses of ReA and reactive tendinitis and enthesitis (ReTe) were defined as "definite" when based on clinical examination and/or on interview by phone and "probable" when based solely on the questionnaire. Of 120 subjects, who reported musculoskeletal symptoms, 100 were included in the final analysis. Among these 100 patients, 68% had YE biotype 1A, 16% YE bio/serotype 4, and 1% biotype 2 infection; the remaining 15% had different YE-like strains or a non-biotypable strain. Of the 21 patients with ReA and of the 14 patients with ReTe, the diagnosis was definite in 9 and 7 patients and probable in 12 and 7 patients, respectively. The clinical picture of ReA caused by YE biotype 1A was similar with other bio/serotypes of YE. The definite ReA due to YE biotype 1A occurred in middle-aged adults (5 men, 4 women) with the most frequently affected joints being the knees and ankles. We suggest that YE biotype 1A should be taken into account as a new trigger of ReA. PMID- 28918491 TI - Dynamics of allosteric modulation of lymphocyte function associated antigen-1 closure-open switch: unveiling the structural mechanisms associated with outside in signaling activation. AB - OBJECTIVES: To provide insight into the dynamics of the shape-shifting mechanistic events associated with the opening (activation) of Lymphocyte Function Associated Antigen-1 upon allosteric modulation by an activator, ICAM Binding Enhancer-667 (IBE-667), using molecular dynamics simulation. RESULTS: Various parameters were used to appropriately describe and understand the sequence of events that characterized its activation across the simulation period such as residual distances, TriCalpha angles; as well as the dihedral angle. Our findings revealed a significant residual fluctuation and stability difference between both systems. Also, there was a synergistic coordination of the active MIDAS site by the downward pull of the alpha7 helix upon ligand binding, which appeared to be directly proportional to each other. CONCLUSION: Allosteric binding of IBE-667, activated LFA-1 integrin as evidenced by residual motion at the MIDAS region which appears to be synergistically coordinated by the downward pull of the alpha7 helix. PMID- 28918490 TI - Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy. AB - Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-kappaB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway. PMID- 28918492 TI - Decreased plasma neuregulin 4 concentration is associated with increased high sensitivity C-reactive protein in newly diagnosed type 2 diabetes mellitus patients: a cross-sectional study. AB - AIMS: Inflammation has been reported to be involved in the pathogenesis of atherosclerosis. This principal objective of this study was to investigate if the secretion of neuregulin 4 (Nrg4), a soluble protein associated with metabolic syndrome and subclinical cardiovascular disease, is correlated with the inflammation marker high-sensitivity C-reactive protein (hs-CRP) in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). METHODS: A study group of 311 nT2DM patients was divided into three subgroups based on hs-CRP tertiles. Multiple linear regression was conducted to explore the association between plasma Nrg4 and hs-CRP levels. RESULTS: The nT2DM patients with the highest hs CRP levels (>2.46 mg/L) exhibited higher atherogenic coefficients and atherogenic index of plasma (AIP) levels, but lower levels of plasma Nrg4, as compared to those with the lowest hs-CRP levels (<0.63 mg/L). Plasma Nrg4 levels were inversely associated with white blood cell count, hs-CRP, and AIP and positively associated with high-density lipoprotein cholesterol (HDL-C), before and after adjustment for age, gender, body mass index (BMI), and body fat percentage (P < 0.01 or P < 0.05). hs-CRP was the factor most strongly associated with plasma Nrg4 levels. CONCLUSIONS: These results indicate that lower plasma Nrg4 levels may be associated with elevated hs-CRP in nT2DM patients. It generates the hypothesis that decreased levels of Nrg4 may trigger the development of atherosclerosis through its proinflammatory effects. These findings need to be confirmed by further prospective studies. PMID- 28918493 TI - Study of lesions of the lumbar endplate based on the stage of maturation of the lumbar vertebral body: the relationship between skeletal maturity and chronological age. AB - The lesion of the lumbar endplate is sometimes identified in the vertebrae of children and adolescents. The purpose of this study is to compare between skeletal maturity and chronological age. The second purpose of this study is to clarify the lesions of the lumbar endplate based on the maturation of the lumbar vertebral body. Six hundred and thirty-two (485 men and 147 women) consecutive patients were included. The mean age at the first medical examination was 13.8 years. Their skeletal maturity was evaluated based on the appearances of the secondary ossification center of L3. The area of the endplate lesions was classified into five types. The apophyseal stage was observed from 10 years old to 18 years old, and the apophyseal stage was shown the peak at 14 years old. The appearance of the apophyseal ring was observed earlier in female patients than in male patients. For the concave type, the lesion at upper level vertebra was more prevalent. The anterior and middle type of the lesion at upper level vertebra was more prevalent. For the posterior type, the lesion of the inferior rim of L4 and the lesion of the rim of L5 were more prevalent. This study emerged after comparing skeletal maturity based on the maturation of the lumbar vertebral body with the chronological age of a large number of patients and examining the lesions of the lumbar endplate based on the stage of maturation of the lumbar vertebral body. PMID- 28918494 TI - Betaine in the Brain: Characterization of Betaine Uptake, its Influence on Other Osmolytes and its Potential Role in Neuroprotection from Osmotic Stress. AB - Betaine (N-trimethylglycine), a common osmolyte, has received attention because of the number of clinical reports associating betaine supplementation with improved cognition, neuroprotection and exercise physiology. However, tissue analyses report little accumulation of betaine in brain tissue despite the presence of betaine/GABA transporters (BGT1) at the blood brain barrier and in nervous tissue, calling into question whether betaine influences neuronal function directly or indirectly. Therefore, the focus of this study was to determine what capacity nervous tissue has to accumulate betaine, specifically in the hippocampus, a region of the brain associated with learning and memory and one that is particularly susceptible to damage (e.g., seizure activity). Here we report that hippocampal slices actively accumulate betaine in a time, dose and osmolality dependent manner, resulting in peak intracellular concentrations four times extracellular concentrations within 8 h. Our data also indicate that betaine uptake differentially influences the accumulation of other osmolytes. Under isosmotic conditions, betaine uptake minimally impacted some osmolytes (e.g., glycerylphosphorylcholine and glutamate) while significantly reducing others (taurine, creatine, and myo-inositol). Under osmotic stress (hyperosmotic) conditions, we observed dramatic changes in osmolytes like glycine and glutamine key players in inhibitory neurotransmission-and little change in osmolytes such as taurine, creatine and myo-inositol when betaine was available. These data suggest that betaine may influence pathways of inhibitory neurotransmitter production/recycling in addition to serving as an osmolyte and metabolic intermediate. In sum, our data provide detailed characterization of betaine uptake in the hippocampus that implicates betaine in the modulation of hippocampal neurophysiology and neuroprotection. PMID- 28918495 TI - The Stingless Bee Melipona solani Deposits a Signature Mixture and Methyl Oleate to Mark Valuable Food Sources. AB - Stingless bees foraging for food improve recruitment by depositing chemical cues on valuable food sites or pheromone marks on vegetation. Using gas chromatography/mass spectrometry and bioassays, we showed that Melipona solani foragers leave a mixture composed mostly of long chain hydrocarbons from their abdominal cuticle plus methyl oleate from the labial gland as a scent mark on rich food sites. The composition of hydrocarbons was highly variable among individuals and varied in proportions, depending on the body part. A wide ratio of compounds present in different body parts of the bees elicited electroantennogram responses from foragers and these responses were dose dependent. Generally, in bioassays, these bees prefer to visit previously visited feeders and feeders marked with extracts from any body part of conspecifics. The mean number of visits to a feeder was enhanced when synthetic methyl oleate was added. We propose that this could be a case of multi-source odor marking, in which hydrocarbons, found in large abundance, act as a signature mixture with attraction enhanced through deposition of methyl oleate, which may indicate a rich food source. PMID- 28918496 TI - Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy. AB - Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy. PMID- 28918497 TI - Antennal and behavioral responses of Mythimna separata (Walker) to three plant volatiles. AB - The oriental armyworm, Mythimna separata, is distributed widely in eastern Asia and Australia. The response of M.separata to 27 compounds identified from plant volatiles was determined from electroantennography (EAG) and wind tunnel results, which allowed an evaluation of the possible plant volatile compounds. The highest EAG values of males were elicited by trans-2,cis-6-nonadienal, and virgin females by benzyl alcohol. The amplitude in EAG dose-response was in the range of 0.24 to 2.87 mV. In the wind tunnel bioassays, significantly more females showed behavioral responses to wilting leaves and headspace collection of Pterocarya stenoptera rather than control. In addition, significantly more females flew upwind with beta-ocimene compared with the control. The number of females that landed at the source with cis-3-hexen-1-ol, phenylethyl alcohol, trans-2-nonenal, and 2-pentylfuran was significantly different from the number that moved towards control. PMID- 28918498 TI - Modeling the Decision of Mental Health Providers to Implement Evidence-Based Children's Mental Health Services: A Discrete Choice Conjoint Experiment. AB - Using an online, cross sectional discrete choice experiment, we modeled the influence of 14 implementation attributes on the intention of 563 providers to adopt hypothetical evidence-based children's mental health practices (EBPs). Latent class analysis identified two segments. Segment 1 (12%) would complete 100% of initial training online, devote more time to training, make greater changes to their practices, and introduce only minor modifications to EBPs. Segment 2 (88%) preferred fewer changes, more modifications, less training, but more follow-up. Simulations suggest that enhanced supervisor support would increase the percentage of participants choosing the intensive training required to implement EBPs. The dissemination of EBPs needs to consider the views of segments of service providers with differing preferences regarding EBPs and implementation process design. PMID- 28918499 TI - The Levels of Circulating Proangiogenic Factors in Migraineurs. AB - Migraine has been reported as a risk factor for ischemic stroke or cardiovascular events, and dysfunction of endothelial cells has been evidenced in migraine patients. Proangiogenic factors are potential endothelial stimulators, and their disturbances can link abnormalities of endothelium with increased risk of vascular disorders. The aim of this study was to evaluate the levels of circulating proangiogenic factors in sera of migraineurs during interictal period. Fifty-two patients aged 37.9 +/- 9.6 years, fulfilling International Headache Society criteria for migraine, were included in this observational case control study. The control group included 39 healthy volunteers, matched according to age and gender. All subjects underwent full neurological examination and clinimetric evaluation with the use of: MIDAS, MIGSEV, QVM, VAS and VRS scales. Serum concentrations of vascular endothelial growth factor (VEGF), angiogenin, angiopoietin-2, thrombopoietin and Tie-2 were estimated in migraineurs and in the control group with the use of ELISA. In migraineurs during interictal period, we have found decreased serum VEGF and angiogenin concentrations compared with controls. Age of migraine onset correlated with VEGF, angiopoietin-2 and thrombopoietin concentrations. Furthermore, angiopoietin 2 level correlated with QVM score and Tie-2 with pain intensity evaluated using MIGSEV scale. In migraine patients during interictal period, depletion of VEGF and angiogenin, two cooperating proangiogenic factors, can be responsible for endothelial dysfunction and increased risk for vascular disorders. PMID- 28918500 TI - Current evidence advocates use of a new pathologic tibial tubercle-posterior cruciate ligament distance threshold in patients with patellar instability. AB - PURPOSE: To determine (1) whether a correlation exists between tibial tubercle posterior cruciate ligament (TT-PCL) and tibial tubercle-trochlear groove (TT-TG) distances in patellar instability patients; (2) reliability when measuring TT-PCL distance; (3) whether TT-PCL distances measured on MRI are equivalent to those on CT; and (4) whether a correlation exists between TT-PCL distance and number of instability events or recurrence of instability following stabilization surgery. METHODS: A systematic review was performed using PRISMA guidelines. Clinical studies investigating the relationships of TT-PCL with TT-TG on CT and/or MRI in patellar instability patients were sought. English language studies with Levels of evidence I-IV were eligible for inclusion. RESULTS: Four studies (285 subjects [300 knees] with patellar instability [74.2% female; mean age 26.1 +/- 8.2 years]; 114 controls [144 knees; 77% female; mean age 23.1 years]) were included. Mean TT-PCL of instability and control groups was 21.1 +/- 4.1 and 18.8 +/- 4.0 mm (p < 0.0001), respectively. Two studies reported significant positive (strong and moderate) correlations between TT-PCL and TT-TG MRI measurements in instability patients. All four investigations reported excellent interobserver and intraobserver reliability in MRI measurement of TT-PCL distance. No study compared TT-PCL distances on MRI and CT. No study assessed correlation between TT PCL distance and number of instability events or recurrence of instability after surgery. CONCLUSION: A moderate-to-strong positive correlation exists between TT PCL and TT-TG measurements taken from MRIs of patellar instability patients. There is excellent interobserver and intraobserver reliability when taking TT-PCL measurements using MRI. This review advocates use of a new pathologic TT-PCL threshold of 21 mm. LEVEL OF EVIDENCE: Level III, systematic review of Level II III studies. PMID- 28918503 TI - CoQ0-induced mitochondrial PTP opening triggers apoptosis via ROS-mediated VDAC1 upregulation in HL-60 leukemia cells and suppresses tumor growth in athymic nude mice/xenografted nude mice. AB - Coenzyme Q (CoQ) analogs with variable numbers of isoprenoid units have been demonstrated as anticancer and antioxidant/pro-oxidant molecules. This study examined the in vitro and in vivo antitumor and apoptosis activities of CoQ0 (2,3 dimethoxy-5-methyl-1,4-benzoquinone, zero isoprenoid side-chains) through upregulation of the Voltage-dependent anion channel 1 (VDAC1) signaling pathway on human promyelocytic leukemia. CoQ0 (0-40 MUg/mL) treatment significantly reduced HL-60 cell viability, and up-regulated mitochondrial VDAC1 expression. CoQ0 treatment triggers intracellular ROS generation, calcium release, DeltaPsim collapse and PTP opening in HL-60 cells. CoQ0 treatment induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-3 and PARP activation, and Bax/Bcl-2 dysregulation. Annexin V-PI staining indicated that CoQ0 promotes late apoptosis. Furthermore, the blockade of CoQ0-induced ROS production by antioxidant NAC pretreatment substantially attenuated CoQ0-induced apoptosis. The activation of p-GSK3beta expression, cyclophilin D inhibition, and p53 activation through ROS are involved in CoQ0-induced HL-60 apoptotic cell death. Notably, ROS-independent p38 activation is involved in CoQ0-mediated apoptosis in HL-60 cells. In addition, the silencing of VDAC1 also prevented CoQ0 induced mitochondrial translocation of Bax, activation of caspase-3, and reduction in Bcl-2. Intriguingly, VDAC1 silencing did not prevent ROS production induced by CoQ0, which in turn indicates that CoQ0 induced ROS-mediated VDAC1 and then mitochondrial apoptosis in HL-60 cells. In vivo results revealed that CoQ0 is effective in delaying tumor incidence and reducing the tumor burden in HL-60 xenografted nude mice. Taken together, CoQ0 could be a promising anticancer agent for the treatment of human promyelocytic leukemia through upregulation of VDAC1 signaling pathways. PMID- 28918502 TI - The REFINEMENT Glossary of Terms: An International Terminology for Mental Health Systems Assessment. AB - Comparing mental health systems across countries is difficult because of the lack of an agreed upon terminology covering services and related financing issues. Within the European Union project REFINEMENT, international mental health care experts applied an innovative mixed "top-down" and "bottom-up" approach following a multistep design thinking strategy to compile a glossary on mental health systems, using local services as pilots. The final REFINEMENT glossary consisted of 432 terms related to service provision, service utilisation, quality of care and financing. The aim of this study was to describe the iterative process and methodology of developing this glossary. PMID- 28918504 TI - Autism spectrum disorders and disease modeling using stem cells. AB - Autism spectrum disorders (ASD) represent a variety of disorders characterized as complex lifelong neurodevelopment disabilities, which may affect the ability of communication and socialization, including typical comportments like repetitive and stereotyped behavior. Other comorbidities are usually present, such as echolalia, hypotonia, intellectual disability and difficulties in processing figured speech. Furthermore, some ASD individuals may present certain abilities, such as eidetic memory, outstanding musical or painting talents and special mathematical skills, among others. Considering the variability of the clinical symptoms, one autistic individual can be severely affected in communication while others can speak perfectly, sometimes having a vocabulary above average in early childhood. The same variability can be seen in other clinical symptoms, thus the "spectrum" can vary from severe to mild. Induced pluripotent stem cell technology has been used to model several neurological diseases, including syndromic and non syndromic autism. We discuss how modeling the central nervous system cells in a dish may help to reach a better understanding of ASD pathology and variability, as well as personalize their treatment. PMID- 28918505 TI - Purification and characterization of skeletal muscle pyruvate kinase from the hibernating ground squirrel, Urocitellus richardsonii: potential regulation by posttranslational modification during torpor. AB - Ground squirrel torpor during winter hibernation is characterized by numerous physiological and biochemical changes, including alterations to fuel metabolism. During torpor, many tissues switch from carbohydrate to lipid catabolism, often by regulating key enzymes within glycolytic and lipolytic pathways. This study investigates the potential regulation of pyruvate kinase (PK), a key member of the glycolytic pathway, within the skeletal muscle of hibernating ground squirrels. PK was purified from the skeletal muscle of control and torpid Richardson's ground squirrels, and PK kinetics, structural stability, and posttranslational modifications were subsequently assessed. Torpid PK displayed a nearly threefold increase in K m PEP as compared to control PK when assayed at 5 degrees C. ProQ Diamond phosphoprotein staining as well as phospho-specific western blots indicated that torpid PK was significantly more phosphorylated than the euthermic control. PK from the torpid condition was also shown to possess nearly twofold acetyl content as compared to control PK. In conclusion, skeletal muscle PK from the Richardson's ground squirrel may be regulated posttranslationally between the euthermic and torpid states, and this may inhibit PK functioning during torpor in accordance with the decrease in glycolytic rate during dormancy. PMID- 28918506 TI - Young athletes after ACL reconstruction with quadriceps strength asymmetry at the time of return-to-sport demonstrate decreased knee function 1 year later. AB - PURPOSE: Quadriceps femoris (QF) strength deficits at return-to-sport (RTS) after ACL reconstruction (ACLR) contribute to decreased knee function at the same time point. However, the impact of QF strength at RTS on longitudinal function has not been examined. The purpose of this study was to test the hypothesis that young athletes after ACLR with QF strength asymmetry at RTS would demonstrate decreased knee-related function and lower proportions of functional recovery at 1 year post RTS compared to young athletes following ACLR with nearly symmetric QF strength at RTS. METHODS: Participants included 76 young athletes (74% female; mean age at RTS = 17.3 years) after primary, unilateral ACLR, cleared to RTS, and followed for 1 year after RTS. At the time of RTS, QF strength was quantified on an isokinetic dynamometer and a Limb Symmetry Index (LSI) was calculated [(involved/uninvolved) * 100%]. The cohort was subdivided into two groups based on RTS QF LSI: high quadriceps (HQ; LSI >= 90%; n = 36) and low quadriceps (LQ; LSI < 85%; n = 36). The cohort was followed for 1 year post-RTS, and knee-related function was assessed using the International Knee Documentation Committee subjective form (IKDC), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and LSI of single-leg hop tests. Functional recovery at 1 year post-RTS was defined as KOOS scores above literature-reported cut-offs. RESULTS: While the HQ group demonstrated higher symmetry on all 1 year post-RTS hop tests, only the triple-hop test (p = 0.020) was found to be statistically different. Similarly, while the HQ group scored higher on all 1 year post-RTS self-reported knee function measures, only differences on the KOOS-Sport/Rec score (p = 0.039) and IKDC score (p = 0.011) were statistically different. Additionally, the HQ group demonstrated higher proportions of functional recovery at 1 year post-RTS than the LQ group on the KOOS-Symptoms (HQ: 88.9%, LQ: 69.4%; p = 0.040) and KOOS Sport/Rec (HQ: 91.7%, LQ: 69.4%; p = 0.017). CONCLUSIONS: Young athletes after ACLR with QF strength asymmetry at RTS demonstrated decreased knee-related function and lower proportions of functional recovery at 1 year post-RTS. However, group differences did not exceed reported minimal clinically important difference values. Further study is warranted to understand factors that contribute to longitudinal knee function after ACLR. Clinicians should focus on restoring symmetric QF strength at RTS after ACLR, which may promote higher longitudinal knee function. LEVEL OF EVIDENCE: Level II, Prospective cohort study. PMID- 28918507 TI - The muscle regulatory transcription factor MyoD participates with p53 to directly increase the expression of the pro-apoptotic Bcl2 family member PUMA. AB - The muscle regulatory transcription factor MyoD is a master regulator of skeletal myoblast differentiation. We have previously reported that MyoD is also necessary for the elevated expression of the pro-apoptotic Bcl2 family member PUMA, and the ensuing apoptosis, that occurs in a subset of myoblasts induced to differentiate. Herein, we report the identification of a functional MyoD binding site within the extended PUMA promoter. In silico analysis of the murine PUMA extended promoter revealed three potential MyoD binding sites within 2 kb of the transcription start site. Expression from a luciferase reporter construct containing this 2 kb fragment was enhanced by activation of MyoD in both myoblasts and fibroblasts and diminished by silencing of MyoD in myoblasts. Experiments utilizing truncated versions of this promoter region revealed that the potential binding site at position - 857 was necessary for expression. Chromatin immunoprecipitation (ChIP) analysis confirmed binding of MyoD to the DNA region encompassing position - 857. The increase in MyoD binding to the PUMA promoter as a consequence of culture in differentiation media (DM) was comparable to the increase in MyoD binding at the myogenin promoter and was diminished in myoblasts silenced for MyoD expression. Finally, ChIP analysis using an antibody specific for the transcription factor p53 demonstrated that, in myoblasts silenced for MyoD expression, p53 binding to the PUMA promoter was diminished in response to culture in DM. These data indicate that MyoD plays a direct role in regulating PUMA expression and reveal functional consequences of MyoD expression on p53 mediated transcription of PUMA. PMID- 28918508 TI - Metabolic engineering of Schizosaccharomyces pombe to produce punicic acid, a conjugated fatty acid with nutraceutic properties. AB - Punicic acid (PuA) is a conjugated linolenic acid (C18:3Delta9c,11t,13c) with a wide range of nutraceutic effects with the potential to reduce the incidence of a number of health disorders including diabetes, obesity, and cancer. It is the main component of seed oil from Punica granatum and Trichosanthes kirilowii. Previously, production of relatively high levels of this unusual fatty acid in the seed oil of transgenic Arabidopsis thaliana plant was accomplished by the use of A. thaliana fad3/fae1 mutant high in linoleic acid (18:2?9c,12c) and by co expression of P. granatum FATTY ACID CONJUGASE (PgFADX) with Delta12-DESATURASE (FAD2). In the current study, P. granatum cDNAs governing PuA production were introduced into the yeast Schizosaccharomyces pombe. Expression of PgFADX alone resulted in production of PuA at the level of 19.6% of total fatty acids. Co expression PgFADX with PgFAD2, however, further enhanced PuA content to 25.1% of total fatty acids, the highest level reported to date for heterologous expression. Therefore, microbial systems can be considered as a potential alternative to plant sources for a source of PuA for nutraceutic applications. PMID- 28918509 TI - Effects of tetramethylpyrazine phosphate on pancreatic islet microcirculation in SD rats. AB - PURPOSES: Abnormal islet microcirculation impetus the insulin production and accelerates progression of Type 1 and 2 diabetes. In this study, we investigated whether tetramethylpyrazine phosphate (TMPP), a vasoactive substance, could regulate the islet microcirculation and insulin concentration and improve glycaemia in SD rats. METHODS: SD rats were randomly divided into two groups, the control and TMPP groups. Each group was further divided into three subgroups according to the intravenous injection of either saline, 15 or 30% glucose. The non-radioactive microsphere technique was adopted to measure the organ blood flow. Nitric oxide synthase (NOS) blocker L-NAME was used to address whether NO was involved in mediating the vasoactive effects of TMPP. RESULTS: In the TMPP group, TMPP increased the PBF (pancreatic blood flow), IBF (islet blood flow), and fIBF (fraction of islet blood flow out of pancreatic blood flow) by 57, 76 and 47%, respectively, after 30% glucose infusion, compared with the control, indicating that TMPP could regulate islet microcirculation. Furthermore, TMPP induced a 66% elevation of IBF and 37% of fIBF in the 30% glucose subgroups than the 15% ones. In 30% glucose-treated subgroups, TMPP improved the blood glucose concentration by 10%, compared with the control (19.3 +/- 0.64 vs 17.32 +/- 0.56 mmol/l, P < 0.05), without influencing the insulin secretion. Blocking NO formation prevented the enhanced PBF and IBF, evoking by TMPP with 30% glucose. CONCLUSIONS: TMPP can regulate the pancreatic islet microcirculation and possess a hypoglycemia effect after glucose infusion through affecting the islet microcirculation. PMID- 28918510 TI - Acquired hepatocerebral degeneration (AHD): a peculiar neurological impairment in advanced chronic liver disease. AB - We discuss the case of a rare and often unrecognized neurologic syndrome, called Acquired Hepatocerebral Degeneration (AHD), observed in patients with advanced liver disease and portosystemic shunts. The clinical manifestations can be very heterogeneous and in our case included a combination of cerebellar and extrapyramidal signs, arisen in a period of few days. Brain Magnetic Resonance Imaging (MRI) showed, in T1-weighted images, diffuse bilateral hyper intensities in basal ganglia and biemispheric brain and cerebellar cortices, resembling paramagnetic deposits. No other neurological impairments, like stroke, infection or neoplasia, were found. It was excluded an episode of acute hepatic encephalopathy. We also ruled out Wilsonian degeneration, iron overload and autoimmune encephalitis and we lastly found high manganese levels as the possible cause of the brain paramagnetic deposits. Even though either serum Mn determination or its accumulation in the brain are not specific for AHD, however the chronic and progressively worsening of the neurological manifestations advocated a degenerative condition, possibly AHD. We finally opted for the early restoration of liver function by OLT, and we observed complete clinical symptoms' resolution and partial MRI reversal after a follow up of 6 months. PMID- 28918511 TI - The role of major virulence factors of AIEC involved in inflammatory bowl disease a mini-review. AB - Adherent-invasive Escherichia coli (AIEC) has recently attracted more attention because it is closely related to the pathogenicity of human inflammatory bowel disease (IBD). AIEC possesses a multitude of virulence factors. Considering these virulence factors belonging to various virulence groups, including adhesins, invasins, toxins, protectins, and siderophore-mediated iron acquisition, this review summarizes the current knowledge of how the major virulence factors assisting in AIEC survive in, adhere to, and invade host cells. A comprehensive understanding of the interaction of virulence factors with host cells will provide us a new therapeutic strategy for IBD prevention and treatment. PMID- 28918512 TI - Letter to the Editor for the Manuscript the Complex Interplay of Physical Fitness, Protein Intake and Vitamin D Supplementation After Bariatric Surgery. PMID- 28918513 TI - Imaging findings of primary immunoglobulin G4-related cervical lymphadenopathy. AB - PURPOSE: The purpose of the present study was to assess imaging findings of primary immunoglobulin G4 (IgG4)-related cervical lymphadenopathy. METHODS: Five consecutive patients with clinically, serologically, and histopathologically confirmed primary IgG4-related cervical lymphadenopathy without any other organ involvement were included. All patients underwent contrast-enhanced computed tomography (CT), and four underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. We retrospectively reviewed the images and assessed the number, size, location, central necrosis, perinodal infiltration, penetrating vessels, and maximum standardized uptake values (SUVmax) of the enlarged cervical nodes. RESULTS: Thirteen enlarged cervical nodes measuring larger than 10 mm in minimum diameter were identified. The maximum and minimum diameter of enlarged nodes ranged from 1.2 to 3.2 cm (median, 1.8 cm) and from 1.0 to 1.9 cm (median, 1.2 cm), respectively. Lymphadenopathy was unilateral in all patients, and eight enlarged nodes were located at level IB (62%), one at level II (8%), three at level IV (23%), and one at level V (8%). Central necrosis was not seen in any nodes. Perinodal infiltration was seen in only one node (8%), and penetrating vessels were seen in seven nodes (54%). The median SUVmax of nine nodes was 4.45 (range, 2.08-12.44). CONCLUSION: Eight enlarged nodes (62%) were located in the submandibular region. Central necrosis was not observed in any nodes and perinodal infiltration was observed in one node (8%). PMID- 28918514 TI - Staging surgery for ulcerative colitis: more than meets the eye. PMID- 28918516 TI - Valve-sparing aortic root surgery. CON: remodeling. AB - The two major valve-sparing root replacement procedures, aortic valve reimplantation (reimplantation) and aortic root remodeling (remodeling), have advantages and disadvantages, which are reviewed herein. The main advantage of reimplantation is the resulting annular support, and the disadvantages are the unfavorable hemodynamics and relatively long procedure time. The main advantages of remodeling are the physiological hemodynamics and decreased procedure time, and the disadvantage is the lack of annular support. With technical advances and modifications, however, the differences between these two procedures have narrowed. Application of a graft with sinuses for reimplantation improves the hemodynamics, and addition of annuloplasty to remodeling provides the necessary annular support. Nevertheless, remodeling has some advantages because less root dissection is required and the procedure time is shorter and hemodynamically favorable. Thus, remodeling may be the procedure of choice for high-risk patients (such as those with acute aortic dissection, of advanced age, with reduced ventricular function, or undergoing a concomitant operation). Remodeling may also be best for young athletes because of the hemodynamic advantage. Regardless of the advantages and disadvantages, both procedures provide excellent clinical results in terms of late valve durability. Surgeons should be familiar with both techniques and properly match patients to the appropriate treatment. PMID- 28918515 TI - Oligodendrocyte-Neuron Interactions: Impact on Myelination and Brain Function. AB - In the past, glial cells were considered to be 'glue' cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function. PMID- 28918517 TI - Detecting cam-type deformities on plain radiographs: what is the optimal lateral view? AB - PURPOSE: Radial magnetic resonance imaging (MRI) is the most accurate diagnostic tool in assessing cam-type femoroacetabular impingement. Plain radiographs, however, are useful for the initial diagnosis in the daily practice and there is still debate regarding the optimal lateral view. The purpose of this study was to investigate the reliability of detecting cam deformities using the frog-leg view or the 45 degrees Dunn view by comparison with radial MRI. MATERIAL: 66 consecutive hips with plain radiographs (36 with AP and frog-leg views, 30 with AP and 45 degrees Dunn views) and radial MRI were assessed. Alpha angle measurements were obtained both for radiographs and for radial MRI reformats by two investigators. Statistics included frequency analysis, bivariate linear correlation analyses, and cross-table analyses testing the sensitivity and specificity of the radiographic projections for detecting an alpha angle larger than 55 degrees . RESULTS: The intra-class correlation revealed excellent agreement between the two raters [ICC = 0.959, CI (0.943; 0.972)]. 50% (33/66) had the maximum alpha angle in the superior-anterior aspect of the femoral head neck junction. Cam deformity was found in 40/66 cases (61%) in radial MRI. Pearson correlation demonstrated that the 45 degrees Dunn view was most accurate for the superior-anterior aspect (0.730, p < 0.05). The frog-leg view was best suited for the anterior aspect (0.703, p < 0.05). The sensitivity for detecting cam deformities in the 45 degrees Dunn view was 84 vs 62% in the frog-leg view. CONCLUSION: The frog-leg lateral radiograph does not provide reliable measurements of the alpha angle. This study highlights the importance of the 45 degrees Dunn view for early detection of femoroacetabular cam-type impingement. PMID- 28918518 TI - Micro-RNA Profiling of Exosomes from Marrow-Derived Mesenchymal Stromal Cells in Patients with Acute Myeloid Leukemia: Implications in Leukemogenesis. AB - Gene regulatory networks in AML may be influenced by microRNAs (miRs) contained in exosomes derived from bone marrow mesenchymal stromal cells (MSCs). We sequenced miRs from exosomes isolated from marrow-derived MSCs from patients with AML (n = 3) and from healthy controls (n = 3; not age-matched). Known targets of mIRs that were significantly different in AML-derived MSC exosomes compared to controls were identified. Of the five candidate miRs identified by differential packaging in exosomes, only miR-26a-5p and miR-101-3p were significantly increased in AML-derived samples while miR-23b-5p, miR-339-3p and miR-425-5p were significantly decreased. Validation of the predicted change in gene expression of the potential targets was investigated by interrogating gene expression levels from public datasets of marrow-derived CD34-selected cells from patients with AML (n = 69) and healthy donors (n = 40). Two molecules with decreased gene expression in AML (EZH2 and GSK3beta) were predicted by the miR profiling and have been previously implicated in AML while three molecules were increased in AML-derived cells and have not been previously associated with leukemogenesis (KRBA2, RRBP1 and HIST2H 2BE). In summary, profiling miRs in exosomes from AML derived MSCs allowed us to identify candidate miRs with potential relevance in AML that could yield new insights regarding leukemogenesis or new treatment strategies. PMID- 28918519 TI - Antenatally diagnosed pre-pontine arachnoid cysts with significant post-natal supratentorial progression: report of two cases. PMID- 28918520 TI - Derivation of Human Induced Pluripotent Stem Cell (iPSC) Lines and Mechanism of Pluripotency: Historical Perspective and Recent Advances. AB - Derivation of human embryonic stem cell (hES) lines in 1998 was not only a major technological breakthrough in the field of regenerative medicine; it also triggered a passionate debate about the ethical issues associated with the utilization of human embryos for derivation of hESC lines. Successful derivation of induced pluripotent stem cell (iPS) lines from human somatic cells with defined reprogramming factors by Shinya Yamanaka's group in 2007 was another breakthrough that generated enormous excitement and hope for the development of donor-specific personalized cell replacement therapies (CRT) without the ethical dilemma associated with it. As we approach twentieth anniversary of derivation of hESC lines and the tenth anniversary of isolation of donor-specific iPSC lines, this manuscript summarizes the key advances in pluripotent stem cell (PSC) research field that led to derivation of human iPSC lines, different methodologies for derivation iPSC lines and characterization of the mechanism of reprogramming. We will also review progress towards generating donor-specific somatic cell lineages from iPSC lines, especially the functional immune cell lineages, and progress towards advancing these findings to the clinic. Finally, we will discuss the challenges, such as genome instability and inherent immunogenicity of hPSC lines that need to be addressed to develop safe and effective iPSC-based CRT. PMID- 28918522 TI - Simulations and experimental investigations of the competitive adsorption of CH4 and CO2 on low-rank coal vitrinite. AB - The mechanism for the competitive adsorption of CH4 and CO2 on coal vitrinite (DV 8, maximum vitrinite reflectance R o,max = 0.58%) was revealed through simulation and experimental methods. A saturated state was reached after absorbing 17 CH4 or 22 CO2 molecules per DV-8 molecule. The functional groups (FGs) on the surface of the vitrinite can be ranked in order of decreasing CH4 and CO2 adsorption ability as follows: [-CH3] > [-C=O] > [-C-O-C-] > [-COOH] and [-C-O-C-] > [-C=O] > [-CH3] > [-COOH]. CH4 and CO2 distributed as aggregations and they were both adsorbed at the same sites on vitrinite, indicating that CO2 can replace CH4 by occupying the main adsorption sites for CH4-vitrinite. High temperatures are not conducive to the adsorption of CH4 and CO2 on vitrinite. According to the results of density functional theory (DFT) and grand canonical Monte Carlo (GCMC) calculations, vitrinite has a higher adsorption capacity for CO2 than for CH4, regardless of whether a single-component or binary adsorbate is considered. The equivalent adsorption heat (EAH) of CO2-vitrinite (23.02-23.17) is higher than that of CH4 vitrinite (9.04-9.40 kJ/mol). The EAH of CO2-vitrinite decreases more rapidly with increasing temperature than the EAH of CH4-vitrinite does, indicating in turn that the CO2-vitrinite bond weakens more quickly with increasing temperature than the CH4-vitrinite bond does. Simulation data were found to be in good accord with the corresponding experimental results. PMID- 28918521 TI - Relation of parent knowledge to glycemic control among emerging adults with type 1 diabetes: a mediational model. AB - The study goal was to examine the links of parent knowledge of children's behavior to diabetes outcomes and to test a mediational model that focused on psychological distress and self-care behavior. We recruited 132 adolescents (average age 12) and followed them to average age 23. At age 23 (n = 107), we conducted in-person interviews with these emerging adults to measure parent knowledge, psychological distress, self-care behavior and glycemic control. We used structural equation modeling to test our hypotheses with these cross sectional data. Higher levels of parent knowledge were linked to better glycemic control, and this path was mediated by reduced psychological distress and enhanced self-care behavior. Parents remain an important influence in the lives of emerging adults with type 1 diabetes. When emerging adults have a relationship with their parents in which they share general information, psychological distress may be reduced which then facilitates self-care and, ultimately, glycemic control. PMID- 28918523 TI - Focal metallic inlay resurfacing prosthesis for the treatment of localized cartilage defects of the femoral condyles: a systematic review of clinical studies. AB - PURPOSE: To systematically review the results of focal metallic inlay resurfacing prosthesis for the treatment of isolated cartilage defects of the femoral condyles. METHODS: A systematic electronic search of the PubMed database and the Cochrane Library was performed in April 2017 to identify studies that reported clinical or radiographic outcome of focal metallic inlay resurfacing prosthesis for the treatment of isolated cartilage defects of the femoral condyles. Included studies were abstracted regarding study characteristics, patient demographics, prosthetic device and location, indications and contraindications, and outcome measures. Outcome of interest included functional outcome scores, radiographic measures, complications, re-operations, and conversion to arthroplasty. The methodologic quality of the included studies was assessed with the Coleman Methodology Score. RESULTS: Six studies with a total of 186 patients met the inclusion criteria. Five studies were level IV evidence, and one was level III. The methodologic quality of the included studies was good, with a mean Coleman Methodology Score of 78. Two different implants were used: the HemiCAP(r) (five studies; 66% of study group) and UniCAP(r) (one study; 34%) implant. The mean age was 46-54 years, and the mean follow-up was 24 months to 7 years. Pre- and post operative outcome scores were compared in all six studies, and five studies reported significant improvements at the final follow-up for all scores (objective und functional KSS, KOOS, WOMAC, Tegner, HSS Knee and Function score, SF-36 and SF-12 physical component score) except for the SF-36 and SF-12 mental component score. Progression of osteoarthritis was analysed using the Kellgren Lawrence grading in three studies (30% of study group), with two studies reporting significant progression. The OARSI grading system was analysed in one study with no significant progression. The overall conversion rate to arthroplasty was 22% with considerable differences between the two implants: 9% for HemiCAP(r) and 47% for UniCAP(r). CONCLUSIONS: Focal metallic inlay resurfacing prosthesis seems to be a viable option for a carefully selected group of patients. Significant improvement in knee function and pain was observed in most patients. Uncertainty remains with regard to progression of osteoarthritis because of conflicting results and inconsistent reporting. One out of five patients has to be converted to arthroplasty after an average of 4 years. However, compared to the UniCAP(r) implant, considerable lower conversion rates were reported for the smaller HemiCAP(r) implant. LEVEL OF EVIDENCE: Systematic review of level III and IV studies, Level IV. PMID- 28918524 TI - Use of biological mesh in trans-anal treatment for recurrent recto-urethral fistula. PMID- 28918525 TI - Increasing participant motivation reduces rates of intentional and unintentional mind wandering. AB - We explored the possibility that increasing participants' motivation to perform well on a focal task can reduce mind wandering. Participants completed a sustained-attention task either with standard instructions (normal motivation), or with instructions informing them that they could be excused from the experiment early if they achieved a certain level of performance (higher motivation). Throughout the task, we assessed rates of mind wandering (both intentional and unintentional types) via thought probes. Results showed that the motivation manipulation led to significant reductions in both intentional and unintentional mind wandering as well as improvements in task performance. Most critically, we found that our simple motivation manipulation led to a dramatic reduction in probe-caught mind-wandering rates (49%) compared to a control condition (67%), which suggests the utility of motivation-based methods to reduce people's propensity to mind-wander. PMID- 28918526 TI - Coupling population dynamics with earth system models: the POPEM model. AB - Precise modeling of CO2 emissions is important for environmental research. This paper presents a new model of human population dynamics that can be embedded into ESMs (Earth System Models) to improve climate modeling. Through a system dynamics approach, we develop a cohort-component model that successfully simulates historical population dynamics with fine spatial resolution (about 1 degrees *1 degrees ). The population projections are used to improve the estimates of CO2 emissions, thus transcending the bulk approach of existing models and allowing more realistic non-linear effects to feature in the simulations. The module, dubbed POPEM (from Population Parameterization for Earth Models), is compared with current emission inventories and validated against UN aggregated data. Finally, it is shown that the module can be used to advance toward fully coupling the social and natural components of the Earth system, an emerging research path for environmental science and pollution research. PMID- 28918527 TI - Alterations in epididymal proteomics and antioxidant activity of mice exposed to fluoride. AB - It is well known that high fluoride results in low fertility. Epididymis is the important place for spermatozoa maturation, which is essential for successful fertilization. In the previous studies, fluoride was reported to damage the epididymal structure of mouse and rabbit. However, the mechanism underlying sodium fluoride (NaF)-induced epididymal toxicity has not yet been well elucidated. The aim of this study is to explore the global protein alterations in epididymis of mice exposed to NaF using the iTRAQ technique. Results showed that 211 proteins were differentially expressed in both 25 and 100 mg/L NaF groups. Some of them have been proved to be important for reproduction, such as low density lipoprotein receptor-related protein 2 (Lrp2), cytochrome c, testis specific (Cyct), sorbitol dehydrogenase (Sord), glutathione S-transferases (GSTs), acrosin, beta-defensin 126, cysteine-rich secretory protein (Crisp) 1, and Crisp2. Gene ontology (GO) analysis suggested cellular process, organelle and catalytic activity account for high percent and number of differentially expressed proteins. 171 pathways were found after the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which the representative maps, such as ribosome, focal adhesion, and phagosome, were involved. Different functional categories post-translational modification, protein turnover, chaperones; translation, ribosomal structure and biogenesis; cytoskeleton; energy production and conversion are implicated in the Cluster of Orthologous Groups (COG) of proteins analysis. Subsequently, the effect of NaF on the antioxidant activity in epididymis, especially glutathione and glutathione-related enzymes, was evaluated. Results exhibited high fluoride caused low total antioxidant capacity (T-AOC), high methane dicarboxylic aldehyde (MDA), decreased reduced glutathione (GSH), and the glutathione-related enzymes [GSH peroxidase (GPx), GSH reductase (GR), and GSH S-transferase (GST)] changes in activity, protein, and mRNA expressions. In summary, NaF decreased the antioxidant activity of epididymis, especially glutathione and glutathione-related enzymes, as well as iTRAQ results, providing new explanations for the low sperm quality induced by fluoride. PMID- 28918528 TI - Signaling of the Complement Cleavage Product Anaphylatoxin C5a Through C5aR (CD88) Contributes to Pharmacological Hematopoietic Stem Cell Mobilization. AB - Several mechanisms have been postulated for orchestrating the mobilization of hematopoietic stem/progenitor cells (HSPCs), and we previously proposed that activation of the complement cascade plays a crucial role in the initiation and execution of the egress of HSPCs from bone marrow (BM) into peripheral blood (PB). In support of this notion, we demonstrated that mice deficient in the mannan-binding lectin (MBL) pathway, which activates the proximal part of the complement cascade, as well as mice deficient in the fifth component of the complement cascade (C5), which is part of the distal part of the complement cascade, are poor mobilizers. To further narrow down on the exact mechanisms and the molecules involved, we performed studies in mice that do not express the receptor C5aR, which binds the C5 cleavage fragments, C5a and C5adesArg. We also employed the plasma stable nucleic acid aptamer AON-D21 that binds and neutralizes C5a and C5adesArg. We present evidence that mice deficient in C5aR or treated with AON-D21 are poor HSPC mobilizers, thereby establishing a critical role for the C5a/C5adesArg-C5aR axis in the mobilization process. While enhancing mobilization is of clinical importance for poor mobilizers, inhibition of the complement cascade could be of therapeutic importance in patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) or acquired hemolytic syndrome (aHUS). PMID- 28918530 TI - Exogenous and endogenous increase in fungal GGPP increased fungal Taxol production. AB - Taxol is an anticancer identified in both endophytic fungus and its host plant. Plant Taxol is a diterpenoid with geranylgeranyl diphosphate (GGPP) mediates the biosynthesis of its terpenoid moiety. Previous report has suggested that fungal Taxol may require terpenoid pathway for its biosynthesis. Here in this study, feeding a Taxol-producing endophytic fungus (Paraconiothyrium SSM001) with terpenoid precursors including isopentenyl pyrophosphate (IPP, isoprene) and GGPP enhanced Taxol production threefold and fivefold, respectively, compared to the control. Thus, we assumed that increasing the terpenoid pool size in particular GGPP by introducing a new copy number of GGPPS particularly from a Taxol producing plant might increase the production level of fungal Taxol. Agrobacterium-mediated integration of Taxus canadensis geranylgeranyl diphosphate synthase (GGPPS) gene into the Paraconiothyrium SSM001 genome was successful and increased the terpenoid pool size indicated by an increase in carotenoid level and orange to red coloration of some GGPPS-transformed SSM001 colonies. Furthermore, the integration improved the level of Taxol production threefold. Feeding a GGPPS-transformed SSM001 fungus with a GGPP precursor increased the expression level of GGPPS transcript and Taxol production. The successful increase in both terpenoid and Taxol production levels due to GGPPS gene integration into the fungal genome might be a step forward in manipulating Taxol producing endophytic fungi. Future control of the transformation time and the manipulation of the phenolic pathway could maximize the production level. PMID- 28918529 TI - Anatomic Repair of Congenitally Corrected Transposition of the Great Arteries: Single-Center Intermediate-Term Experience. AB - We present our experience for patients who have undergone an anatomic repair (AR) for congenitally corrected transposition of the great arteries (CCTGA) at the Children's Hospital of Wisconsin. A retrospective chart review of patients who underwent AR for CCTGA from 2001 to 2015 was performed. The cohort consisted of 15 patients (74% male). Median age of anatomic repair was 15 months (range 4.5 45.6 months). Four patients had a bidirectional Glenn (BDG) prior to AR. At the time of AR,-9 (60%) underwent Senning/Rastelli procedure, 4 (26.6%) had double switch operation, and 2 (13.3%) underwent only Senning with VSD closure. Median duration of follow-up was 5.5 years (0.05-14 years). Reoperations prior to discharge included BDG, revision of pulmonary venous baffle, closure of residual VSD, and pacemaker placement. Late reoperations included left ventricular outflow tract obstruction repair, conduit replacement, melody valve placement, and pacemaker implantation. At their most recent follow-up, no patient had heart failure symptoms and only 1 had severely diminished function that improved with cardiac resynchronization therapy. Moderate mitral regurgitation was noted in 15% (2/13), and severe in 7% (1/13). Moderate tricuspid regurgitation was noted in 15% (2/13). One patient, 7% (1/13), developed moderate aortic insufficiency. There was a 100% survival at the time of the most recent follow-up. Patients with CCTGA who have undergone AR have excellent functional status and mid-term survival but reinterventions are common. Longer term studies are needed to determine both the extent and spectrum of reinterventions as well as long term survival. PMID- 28918531 TI - Penetrating orbital trauma leading to trans-orbital brain herniation. AB - INTRODUCTION: Development of a posttraumatic herniation of brain parenchyma through the orbit is a rare complication of orbital roof fracture. Mostly, the injury is due to a direct impact to the frontal region resulting in orbital roof fracture with dural defect and herniation of cerebrospinal fluid or brain parenchyma. These patients present with acute or gradually progressive proptosis with impending risk of loss of vision and mandate surgical decompression of optic nerve with watertight closure of the dural defect. Bony reconstruction may be required to achieve normal contour of the orbit. MATERIALS AND METHODS: We encountered an interesting pediatric patient who presented to us with altered sensorium and progressive proptosis 3 days after a penetrating trauma to his left orbit by falling on the handle of a bicycle. The plain computerized tomography of the head (NCCT) showed a left orbital roof defect with herniation of brain matter into the orbit displacing the globe inferolaterally. A craniotomy was performed and watertight closure of the dural rent was achieved with use of autologous bone to cover the defect. CONCLUSIONS: The child improved gradually, and at 6 months follow-up, he had good cosmetic outcome with improvement of vision. PMID- 28918532 TI - An Evaluation of Specialist Mentoring for University Students with Autism Spectrum Disorders and Mental Health Conditions. AB - Mentoring is often recommended to universities as a way of supporting students with Autism Spectrum Disorders (ASD) and/or mental health conditions (MHC), but there is little literature on optimising this support. We used mixed-methods to evaluate mentees' and mentors' experiences of a specialist mentoring programme. Mentees experienced academic, social and emotional support, although subtle group differences emerged between students with ASD and MHC. The quality of the mentee mentor relationship was especially important. Mentors also reported benefits. Thematic analysis identified that effective mentoring requires a tailored partnership, which involves a personal relationship, empowerment, and building bridges into the university experience. Mentoring can effectively support students with ASD and/or MHC, but this is highly dependent on the development of tailored mentee-mentor partnerships. PMID- 28918533 TI - The associations between dietary patterns and bone health, according to the TGF beta1 T869->C polymorphism, in postmenopausal Iranian women. AB - BACKGROUND/OBJECTIVE: Recent studies have shown that dietary variants and genetic variants play a decisive role in the risk of developing osteoporosis. Therefore, the objective of the present study was to examine associations between dietary pattern and bone health, according to the TGF-beta1 T869->C polymorphism, in postmenopausal Iranian women. MATERIALS AND METHODS: In this study, 264 postmenopausal women aged from 46 to 78 years were examined. Body composition was measured by a body composition analyzer and physical activity by the short-form physical activity questionnaire. Bone mineral density was measured by the DEXA method. Dietary patterns were determined using factor analysis on 27 foods groups, employing a valid, reliable 147-item semi-quantitative food frequency questionnaire. The dietary patterns were analyzed by the factor analysis method. Blood samples were taken for measuring blood parameters. DNA samples from participants were genotyped using the RFLP-PCR method. RESULTS: Three dietary patterns were identified, namely: mediterranean diet, traditional diet, and unhealthy diet-one of which was associated with bone health. Postmenopausal women following a Mediterranean diet had lower weight and central obesity (0.05 > P). Higher adherence to a Mediterranean pattern was positively associated with Z score L2_L4 lumbar spine (0.05 > P). TGF-beta1 T869->C genotypes, after adjustment, were not directly correlated with bone mineral density and body composition (0.05 < P). Moreover, these findings demonstrated that in participants adhering to a Traditional dietary pattern, the C allele carrier group (TC and CC genotypes) had a lower L2_L4 Z-score (P = 0.05). CONCLUSION: It seems that the mediterranean diet can be a beneficial dietary pattern in the prevention of osteoporosis and obesity in postmenopausal women. Furthermore (probably in the C allele carrier group), lower vitamin D intake, coupled with adherence to a traditional dietary pattern, reduces the deposition of TGF-beta and increases the risk of lumbar spine osteoporosis. PMID- 28918534 TI - Do surgical helmet systems affect intraoperative wound contamination? A randomised controlled trial. AB - BACKGROUND: Deep infection following arthroplasty remains a devastating complication. Some registry data suggests that modern positive-pressure surgical helmet systems (SHS) are associated with a paradoxical increase in infection rates, and as such their role in arthroplasty remains unclear. The aim of this study was to investigate whether SHS increase wound contamination in total knee arthroplasty (TKA) and if this contamination can be reduced by placing tape around the gown/glove interface. METHODS: Seventy-five patients were randomised into three groups: scrubbed theatre staff wore standard surgical gowns (SG), SHS without tape at the gown/glove interface, or SHS with tape. All TKA operations were carried out by the same surgeon. Wound contamination was assessed using a wound culture technique. Blinded laboratory analysis was performed. RESULTS: There were 5/50 culture positive cases when a SHS was used compared to 0/25 when a SG was used; but this difference was not statistically significant (p = 0.16). There were 4/24 culture positive cases when SHS with tape was used compared to 1/26 when SHS without tape was used; but this difference was not statistical significant p = 0.18. CONCLUSION: We found no difference in wound contamination between SG and SHS. Addition of tape at the gown/glove interface did not alter the contamination rate. The choice of surgical gown should take into account cost, comfort and personal protection; as this study found no evidence that wound contamination rates will be altered. PMID- 28918535 TI - Bioprospecting of Novel and Bioactive Compounds from Marine Actinomycetes Isolated from South China Sea Sediments. AB - Marine actinomycetes are less investigated compared to terrestrial strains as potential sources of natural products. To date, few investigations have been performed on culturable actinomycetes associated with South China Sea sediments. In the present study, twenty-eight actinomycetes were recovered from South China Sea sediments after dereplication by traditional culture-dependent method. The 16S rRNA gene sequences analyses revealed that these strains related to five families and seven genera. Twelve representative strains possessed at least one of the biosynthetic genes coding for polyketide synthase I, II, and nonribosomal peptide synthetase. Four strains had anti-Mycobacterium phlei activities and five strains had activities against methicillin-resistant Staphylococcus aureus. 10 L scale fermentation of strains Salinispora sp. NHF45, Nocardiopsis sp. NHF48, and Streptomyces sp. NHF86 were carried out for novel and bioactive compounds discovery. Finally, we obtained a novel alpha-pyrone compound from marine Nocardiopsis sp. NHF48, an analogue of paulomenol from marine Streptomyces sp. NHF86 and a new source of rifamycin B, produced by Salinispora sp. NHF45. The present study concluded that marine actinomycetes, which we isolated from South China Sea sediments, will be a suitable source for the development of novel and bioactive compounds. PMID- 28918536 TI - A comparative study of inorganic elements in the blood of male and female Caspian pond turtles (Mauremys caspica) from the southern basin of the Caspian Sea. AB - Due to their bioaccumulation and biomagnification pathways, inorganic elements can accumulate in high-level aquatic organisms in the food web. Then, this species can be used to monitor the quality of the environment. Blood concentration of nine inorganic elements, including possible toxic metals (An, Cu, Mn, Se, As, Ni, Cd, Pb, and Hg), in 20 males and 20 females from eight different locations with high industry and agriculture activities in Iran were evaluated in this work. Additionally, size, sex, condition index, and locations were also included and analyzed. Among the essential elements, Zn and Se presented very high concentrations (56.14 +/- 2.66 and 8.44 +/- 0.77 MUg/g ww, respectively) in all locations. Regarding possible toxic elements, Pb and Cd presented concerning concentrations as well (0.52 and 0.58 MUg/g ww); this is especially true for Pb, an element found in very high concentrations in tissues of turtles from the same area in a previous study. The sex and the size of the individuals also had significant differences in concentration of Pb, Cd, As, and Hg. PMID- 28918537 TI - Reverse Genetics of Filoviruses. AB - Reverse genetics systems are used for the generation of recombinant viruses. For filoviruses, this technology has been available for more than 15 years and has been used to investigate questions regarding the molecular biology, pathogenicity, and host adaptation determinants of these viruses. Further, reporter-expressing, recombinant viruses are increasingly used as tools for screening for and characterization of candidate medical countermeasures. Thus, reverse genetics systems represent powerful research tools. Here we provide an overview of available reverse genetics systems for the generation of recombinant filoviruses, potential applications, and the achievements that have been made using these systems. PMID- 28918539 TI - Accelerating Vaccine Development During the 2013-2016 West African Ebola Virus Disease Outbreak. AB - The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks. PMID- 28918538 TI - Genetic Manipulation of Borrelia Spp. AB - The spirochetes Borrelia (Borreliella) burgdorferi and Borrelia hermsii, the etiologic agents of Lyme disease and relapsing fever, respectively, cycle in nature between an arthropod vector and a vertebrate host. They have extraordinarily unusual genomes that are highly segmented and predominantly linear. The genetic analyses of Lyme disease spirochetes have become increasingly more sophisticated, while the age of genetic investigation in the relapsing fever spirochetes is just dawning. Molecular tools available for B. burgdorferi and related species range from simple selectable markers and gene reporters to state of-the-art inducible gene expression systems that function in the animal model and high-throughput mutagenesis methodologies, despite nearly overwhelming experimental obstacles. This armamentarium has empowered borreliologists to build a formidable genetic understanding of the cellular physiology of the spirochete and the molecular pathogenesis of Lyme disease. PMID- 28918540 TI - A Mixed-Method Assessment of a Pilot Peer Advocate Intervention for Rural Gender and Sexual Minorities. AB - Mental health disparities affect lesbian, gay, bisexual, transgender, and queer (LGBTQ) people in rural America. There are few empirically-based mental health interventions for this population. This exploratory study uses a mixed-method approach to assess implementation issues related to the feasibility, acceptability, appropriateness, and preliminary impacts of a novel peer-based intervention designed to enhance support and treatment engagement among rural LGBTQ people with mental distress and/or addiction issues. Quantitative and qualitative results illuminate intervention strengths and areas for improvement. Strengths centered on enhancing social support, advocacy behaviors, and engagement in treatment. Implementation challenges and recommendations to advance the intervention model are discussed. PMID- 28918541 TI - Enzymatic Hydrolysis of Black Liquor Xylan by a Novel Xylose-Tolerant, Thermostable beta-Xylosidase from a Tropical Strain of Aureobasidium pullulans CBS 135684. AB - From three cell-associated beta-xylosidases produced by Aureobasidium pullulans CBS 135684, the principal enzyme was enriched to apparent homogeneity and found to be active at high temperatures (60-70 degrees C) over a pH range of 5-9 with a specific activity of 163.3 units (U) mg-1. The enzyme was thermostable, retaining over 80% of its initial activity after a 12-h incubation at 60 degrees C, with half-lives of 38, 22, and 10 h at 60, 65, and 70 degrees C, respectively. Moreover, it was tolerant to xylose inhibition with a K i value of 18 mM. The K m and V max values against p-nitrophenyl-beta-d-xylopyranoside were 5.57 +/- 0.27 mM and 137.0 +/- 4.8 MUmol min-1 mg-1 protein, respectively. When combining this beta-xylosidase with xylanase from the same A. pullulans strain, the rate of black liquor xylan hydrolysis was significantly improved by up to 1.6 fold. The maximum xylose yield (0.812 +/- 0.015 g g-1 dry weight) was obtained from a reaction mixture containing 10% (w/v) black liquor xylan, 6 U g-1 beta xylosidase and 16 U g-1 xylanase after incubation for 4 h at 70 degrees C and pH 6.0. PMID- 28918542 TI - Current chemotherapeutic regimens for brain metastases treatment. AB - Brain metastasis is a common complication in advanced systemic cancer, with an increasing incidence. The diagnosis of brain metastasis historically portended a dismal prognosis. The successful development of effective treatments for patients with brain metastasis is complicated by the differences among cancer subtypes, the limited understanding of the underlying pathophysiology of BM, the impact of the blood-brain barrier, and other factors. There is now renewed interest in treating this often devastating complication of cancer, and in understanding the underlying mechanisms of disease in this "sanctuary" site. Promising treatment strategies include brain-penetrant targeted therapies and immunotherapy, and strategies for enhanced delivery of therapy. This review highlights a selection of these approaches. PMID- 28918543 TI - Dietary docosahexaenoic acid decreased lipid accumulation via inducing adipocytes apoptosis of grass carp, Ctenopharygodon idella. AB - The purpose of this study was to explore the mechanism of by which docosahexaenoic acid (DHA) inhibit the accumulation of adipose tissue lipid in grass carp (Ctenopharyngodon idella). We therefore designed two semi-purified diets, namely DHA-free (control) and DHA-supplemented, and fed them to grass carp (22.19 +/- 1.76 g) for 3 and 6 weeks. DHA supplementation led to a significantly lower intraperitoneal fat index (IPFI) than that in the control group by reducing the number of adipocytes but significantly higher adipocyte size (P < 0.05). In the intraperitoneal adipose tissue, the DHA-fed group showed significantly higher peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT enhancer-binding protein (C/EBP)alpha, and sterol regulatory element-binding protein (SREBP)1c mRNA expression levels at both 3 and 6 weeks (P < 0.05). However, the ratio of the expression levels of B cell leukemia 2 (Bcl-2) and Bcl-2-associated X protein (Bax) was significantly lower in the DHA-fed group than in the control group (P < 0.05), and the protein expression levels of the apoptosis-related proteins caspase 3, caspase 8, and caspase 9 were also significantly higher (P < 0.05). Overall, although DHA promotes lipid synthesis, it is more likely that DHA could suppress the lipid accumulation in adipocytes of grass carp by inducing adipocyte apoptosis. PMID- 28918544 TI - Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy. AB - Neoadjuvant therapy has been successfully introduced in the treatment of locally advanced gastrointestinal malignancies, particularly esophageal, gastric, and rectal cancers. The effects of preoperative chemo- or radiochemotherapy can be determined by histopathological investigation of the resection specimen following this treatment. Frequent histological findings after neoadjuvant therapy include various amounts of residual tumor, inflammation, resorptive changes with infiltrates of foamy histiocytes, foreign body reactions, and scarry fibrosis. Several tumor regression grading (TRG) systems, which aim to categorize the amount of regressive changes after cytotoxic treatment in primary tumor sites, have been proposed for gastroesophageal and rectal carcinomas. These systems primarily refer to the amount of therapy-induced fibrosis in relation to the residual tumor (e.g., the Mandard, Dworak, or AJCC systems) or the estimated percentage of residual tumor in relation to the previous tumor site (e.g., the Becker, Rodel, or Rectal Cancer Regression Grading systems). TRGs provide valuable prognostic information, as in most cases, complete or subtotal tumor regression after neoadjuvant treatment is associated with better patient outcomes. This review describes the typical histopathological findings after neoadjuvant treatment, discusses the most commonly used TRG systems for gastroesophageal and rectal carcinomas, addresses the limitations and critical issues of tumor regression grading in these tumors, and describes the clinical impact of TRG. PMID- 28918545 TI - Increased Postharvest Life of TomLox B Silenced Mutants of Tomato (Solanum lycopersicum) Var. TA234. AB - A healthy lifestyle includes fruits and vegetables consumption. Tomato is one of the most consumed vegetables, although it is susceptible to physical damage through postharvest handling, thus leading to important losses. Softening is an important variable during tomato ripening; excessive softening is undesirable and leads to postharvest losses. TomloxB plays an important role in ripening, mainly in the loss of cellular integrity caused by fatty acids released from the lipid matrix of membranes that initiate oxidative deterioration, which is in turn carried into senescence. In order to increase postharvest life, we produced transgenic tomato plants via Rhizobium radiobacter with tomato lipoxygenase B (TomloxB) antisense constructs under control of the cauliflower mosaic virus (CaMV) 35S promoter. Lipoxygenase activity and firmness were measured in tomato fruit and the fatty acids profile was determined. Transgenic fruits were maintained for 40 days at room temperature in optimal conditions, whereas wild type fruits remained in similar conditions for only six days. Firmness in pink and red stages was significantly lower in wild type fruits than in two transgenic lines. Linolenic acid was the most important fatty acid consumed by lipoxygenase in both turning and pink stages of ripening. Lipoxygenase activity was smaller in transformed fruits in comparison with the wild type. These results suggest that silencing the TomloxB gene promoted significant changes in the physiology of transformed tomatoes, being the increase in postharvest life the most important. PMID- 28918546 TI - Systemic Effects of Repeated Intraocular Dexamethasone Intravitreal Implant in Diabetic Patients: A Retrospective Study. AB - INTRODUCTION: The objective of this study is to evaluate the influence of repeated intraocular dexamethasone implant (Ozurdex) injections on metabolic control in type 2 diabetic patients. METHODS: Retrospective study of 165 type 2 diabetic patients starting Ozurdex treatment who received no less than three consecutive injections. Glycated hemoglobin (HbA1c), serum creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs) were evaluated during 15 months of follow-up after Ozurdex treatment onset. RESULTS: Fifty-seven patients met inclusion criteria. Mean baseline values for HbA1c, creatinine, total cholesterol, HDL cholesterol, and TGs before treatment (7.1%, 1.3, 176.7, 51.1, and 125.6 mg/dl, respectively) were similar to mean values after Ozurdex onset (Wilcoxon test p values were 0.68, 0.41, 0.06, 0.87, and 0.33, respectively) and remained stable during the follow-up period. Mean LDL cholesterol levels increased slightly after Ozurdex treatment onset (90.1 vs 88.2 mg/dl, p = 0.04) but after 15 months of follow-up they had returned to baseline values. Transient increase in LDL cholesterol was remarkable in the group of 24 bilaterally treated patients (96.8 vs 88.4 mg/dl, p = 0.03). A third of these patients increased their baseline LDL values by more than 20%. Even with continuous injections of Ozurdex, LDL cholesterol levels also declined back to baseline by month 15. CONCLUSION: Ozurdex injections had no influence on HbA1c or renal function. Lipid profile changes were mild and transient. However, a significant temporary increase has been found in LDL cholesterol levels in patients receiving simultaneous bilateral injections. Lipid levels should be monitored in patients starting with bilateral Ozurdex injections especially in those with recent history of acute myocardial infarction. PMID- 28918547 TI - Adaptive step goals and rewards: a longitudinal growth model of daily steps for a smartphone-based walking intervention. AB - Adaptive interventions are an emerging class of behavioral interventions that allow for individualized tailoring of intervention components over time to a person's evolving needs. The purpose of this study was to evaluate an adaptive step goal + reward intervention, grounded in Social Cognitive Theory delivered via a smartphone application (Just Walk), using a mixed modeling approach. Participants (N = 20) were overweight (mean BMI = 33.8 +/- 6.82 kg/m2), sedentary adults (90% female) interested in participating in a 14-week walking intervention. All participants received a Fitbit Zip that automatically synced with Just Walk to track daily steps. Step goals and expected points were delivered through the app every morning and were designed using a pseudo-random multisine algorithm that was a function of each participant's median baseline steps. Self-report measures were also collected each morning and evening via daily surveys administered through the app. The linear mixed effects model showed that, on average, participants significantly increased their daily steps by 2650 (t = 8.25, p < 0.01) from baseline to intervention completion. A non-linear model with a quadratic time variable indicated an inflection point for increasing steps near the midpoint of the intervention and this effect was significant (t2 = -247, t = -5.01, p < 0.001). An adaptive step goal + rewards intervention using a smartphone app appears to be a feasible approach for increasing walking behavior in overweight adults. App satisfaction was high and participants enjoyed receiving variable goals each day. Future mHealth studies should consider the use of adaptive step goals + rewards in conjunction with other intervention components for increasing physical activity. PMID- 28918548 TI - Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008. AB - BACKGROUND: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. METHODS: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. RESULTS: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. CONCLUSION: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967). PMID- 28918549 TI - Loss of LHCI system affects LHCII re-distribution between thylakoid domains upon state transitions. AB - LHCI, the peripheral antenna system of Photosystem I, includes four light harvesting proteins (Lhca1-Lhca4) in higher plants, all of which are devoid in the Arabidopsis thaliana knock-out mutant DeltaLhca. PSI absorption cross-section was reduced in the mutant, thus affecting the redox balance of the photosynthetic electron chain and resulting in a more reduced PQ with respect to the wild type. DeltaLhca plants developed compensatory response by enhancing LHCII binding to PSI. However, the amplitude of state transitions, as measured from changes of chlorophyll fluorescence in vivo, was unexpectedly low than the high level of PSI LHCII supercomplex established. In order to elucidate the reasons for discrepancy, we further analyzed state transition in DeltaLhca plants. The STN7 kinase was fully active in the mutant as judged from up-regulation of LHCII phosphorylation in state II. Instead, the lateral heterogeneity of thylakoids was affected by lack of LHCI, with LHCII being enriched in stroma membranes with respect to the wild type. Re-distribution of this complex affected the overall fluorescence yield of thylakoids already in state I and minimized changes in RT fluorescence yield when LHCII did connect to PSI reaction center. We conclude that interpretation of chlorophyll fluorescence analysis of state transitions becomes problematic when applied to mutants whose thylakoid architecture is significantly modified with respect to the wild type. PMID- 28918550 TI - Advance care planning: challenges at the emergency department of a cancer care center. AB - INTRODUCTION: Code status discussions form an important part of advance care planning (ACP) as it enables physicians to respect the patient's wishes for end of-life care. However, in some cases, code status discussions can be challenging causing the physician to go against the patient's wishes and the code of medical ethics. This is especially true in an emergency setting. In this paper, we will discuss three cases of advanced cancer patients, where code status discussions posed challenges to healthcare providers. CASE REPORTS: In the first case, the patient was a 26-year-old male diagnosed with advanced osteosarcoma. Code status was discussed with him, while he was still functional, wherein he agreed to a do not-resuscitate (DNR) order. However, at the time of end-of-life care, despite of previous code status agreement, the patient's mother insisted on full code. As a result, the DNR order was reverted and the patient was intubated. The second case discusses an 83-year-old female patient with metastatic gastric cancer. Code status was extensively discussed with the patient and her son who agreed to sign a DNR order. This case posed a challenge because when the patient's condition deteriorated, her son demanded cardioversion and other aggressive treatment measures without any chest compressions or intubation. In the third case, the patient was a 40-year-old woman with advanced metastatic adenocarcinoma with neuroendocrine features of the parotid. On admission to the ED, as per the patient's wishes expressed by her husband, a DNR/DNI order was placed. However, this order had to be reverted when the patient's aunt and sister opposed vehemently to the DNR/DNI order. CONCLUSION: The three cases demonstrate the challenges that can arise in the implementation of code status order in the ED as it pertains for end-of-life care. In any scenario, respecting the patient's wishes and adherence to the code of medical ethics take precedence over any familial objections arising difficulties with coping. PMID- 28918551 TI - Bio-economic evaluation of a reduced phosphorus supplementation strategy for a cow-calf system in Brazil: a case study. AB - Fertility, weight of calves at weaning, and the economic aspects of a breeding herd receiving mineral supplements containing 75 or 12.5 g of phosphorus (P)/kg were measured from 2013 to 2016. No differences in reproduction parameters or weight at weaning were found before and after the adoption of the new scheme of mineral supplementation. Before the study, the annual cost with the formula containing more P was equivalent to 29.3 weaned beef calves; after the P reduction, the annual cost was equivalent to 2.2 to 6.8 weaned calves. After 3 years of supplementation with 12.5 g P/kg no signs of P deficiency were observed. The clinical-nutritional diagnosis of the herd indicated no cause-effect of P content of mineral supplements upon fertility or performance of healthy cows, demonstranting that the adequate forage allowance was enough to meet most P required by the cows. PMID- 28918552 TI - Long-term quality of life profile in oncology: a comparison between cancer survivors and the general population. AB - PURPOSE: Understanding the quality of life (QoL) of cancer survivors is relevant to both clinical practice and health care policy. The current study compared the QoL profile in this specific population with that of a normative sample for the general population, as well as with those of both healthy and oncological patients normative sub-samples. In addition, associations between the obtained QoL profile and the main socio-demographic and clinical characteristics of the sample were examined. METHODS: Three hundred and ninety-two adult long-term cancer survivors (i.e., people 5 + years from their cancer diagnosis who were free from it and its treatments) were enrolled during follow-up visits and compiled the Short Form 36 Health Survey. RESULTS: In comparison with the normative data for the adult general population, the present sample showed lower scores in Physical functioning, Role-physical limitation, and Role-emotional limitations (all differences were both statistically and clinically significant); the difference in Vitality was only statistically significant. In all eight SF-36 scales, scores of the present sample were clinically and statistically lower than those of the normative healthy subsample, whereas they were statistically and clinically higher than those of normative subsample which had experienced cancer, except for Role-physical limitation. The QoL profile was associated with gender (p = 0.002), age (p = 0.001), education (p < 0.001), occupational status (p < 0.001), and the presence of other health issues (p < 0.001). CONCLUSION: These data support the utility of rehabilitative programs which integrate both healthcare and social interventions. In addition, they encourage the monitoring of the health status of this specific population, within a broad frame which simultaneously takes into consideration health and QoL. PMID- 28918553 TI - Characteristic of microplastics in the atmospheric fallout from Dongguan city, China: preliminary research and first evidence. AB - Microplastic pollution has exhibited a global distribution, including seas, lakes, rivers, and terrestrial environment in recent years. However, little attention was paid on the atmospheric environment, though the fact that plastic debris can escape as wind-blown debris was previously reported. Thus, characteristics of microplastics in the atmospheric fallout from Dongguan city were preliminarily studied. Microplastics of three different polymers, i.e., PE, PP, and PS, were identified. Diverse shapes of microplastics including fiber, foam, fragment, and film were found, and fiber was the dominant shape of the microplastics. SEM images illustrated that adhering particles, grooves, pits, fractures, and flakes were the common patterns of degradation. The concentrations of non-fibrous microplastics and fibers ranged from 175 to 313 particles/m2/day in the atmospheric fallout. Thus, dust emission and deposition between atmosphere, land surface, and aquatic environment were associated with the transportation of microplastics. PMID- 28918554 TI - Genome-wide identification, classification, evolutionary analysis and gene expression patterns of the protein kinase gene family in wheat and Aegilops tauschii. AB - KEY MESSAGE: In this study we systematically identified and classified PKs in Triticum aestivum, Triticum urartu and Aegilops tauschii. Domain distribution and exon-intron structure analyses of PKs were performed, and we found conserved exon intron structures within the exon phases in the kinase domain. Collinearity events were determined, and we identified various T. aestivum PKs from polyploidizations and tandem duplication events. Global expression pattern analysis of T. aestivum PKs revealed that some PKs might participate in the signaling pathways of stress response and developmental processes. QRT-PCR of 15 selected PKs were performed under drought treatment and with infection of Fusarium graminearum to validate the prediction of microarray. The protein kinase (PK) gene superfamily is one of the largest families in plants and participates in various plant processes, including growth, development, and stress response. To better understand wheat PKs, we conducted genome-wide identification, classification, evolutionary analysis and expression profiles of wheat and Ae. tauschii PKs. We identified 3269, 1213 and 1448 typical PK genes in T. aestivum, T. urartu and Ae. tauschii, respectively, and classified them into major groups and subfamilies. Domain distributions and gene structures were analyzed and visualized. Some conserved intron-exon structures within the conserved kinase domain were found in T. aestivum, T. urartu and Ae. tauschii, as well as the primitive land plants Selaginella moellendorffii and Physcomitrella patens, revealing the important roles and conserved evolutionary history of these PKs. We analyzed the collinearity events of T. aestivum PKs and identified PKs from polyploidizations and tandem duplication events. Global expression pattern analysis of T. aestivum PKs revealed tissue-specific and stress-specific expression profiles, hinting that some wheat PKs may regulate abiotic and biotic stress response signaling pathways. QRT-PCR of 15 selected PKs were performed under drought treatment and with infection of F. graminearum to validate the prediction of microarray. Our results will provide the foundational information for further studies on the molecular functions of wheat PKs. PMID- 28918555 TI - Prognostic factors for mortality in middle-aged and older hemodialysis patients: a 5-year observational study. AB - Clinical guidelines for hemodialysis therapy have been described in an evidence based manner with most evidence from randomized control trials or retrospective studies in which all generations of the hemodialysis patients were enrolled. Therefore, the question still remains whether these guidelines can be applied to increasing older patients. This study is an observational study, including 735 patients who received maintenance hemodialysis in April 2006. At baseline, the participants' age was 62.1 +/- 12.8 years (mean +/- SD). Hemodialysis duration was 103.7 +/- 89.3 months. In a 5-year observation period (actual follow-up period: 1551 +/- 499 days), 175 patients died. Prognostic factors were investigated by multivariate analysis with Cox proportional hazard model. Next, we stratified the patients according to their age. 363 patients were included in the middle-aged patient's category between 40 and 64 years, and 314 were involved in the older patient's category between 65 and 84 years old. As a subanalysis, significant predictors of 5-year survival were examined in the age-stratified cohort. Then, Kt/V, serum beta2-microglobulin and calcium concentration were significant predictors in our entire cohort, as well as body mass index, neutrophil count, and serum sodium concentration even after adjustment for age, gender, diabetic status and hemodialysis duration. However, Kt/V, serum beta2 microglobulin and calcium concentration controlled by hemodialysis prescriptions were independent risk factors especially in older patients, not in middle-aged patients. In conclusion, hemodialysis prescriptions for lowering uremic toxins and managing mineral-bone disorder are important to decrease the risk of death even in older hemodialysis patients. PMID- 28918556 TI - Effects of pregabalin on postoperative pain after hysterectomy under spinal anesthesia with intrathecal morphine: a randomized controlled trial. AB - PURPOSE: To determine if preoperative pregabalin could decrease 24-h postoperative morphine consumption after spinal anesthesia with intrathecal morphine compared with placebo. METHODS: A randomized, double-blind, controlled trial was performed in the tertiary care center. Patients aged between 18 and 65 years who were American Society of Anesthesiologists class I-II and scheduled for abdominal hysterectomy with or without salpingo-oophorectomy were randomly allocated to a placebo or a pregabalin group. Patients received pregabalin 150 mg or placebo 1 h prior to anesthesia. Spinal anesthesia was achieved with 0.5% hyperbaric bupivacaine with morphine 0.2 mg. Intravenous patient-controlled analgesia morphine was provided postoperatively. Postoperative morphine consumption at 6, 12, and 24 h, time to first analgesic rescue, pain scores, adverse effects, and patient satisfaction were evaluated at 24 h after the operation. RESULTS: One hundred twenty-five patients were recruited and 119 patients (placebo N = 58, pregabalin N = 61) were included in the analysis. Forty seven (81.0%) patients in the placebo group and 53 (86.9%) patients in the pregabalin group required morphine in the first 24 h. Median [IQR] 24-h morphine consumption was 4.0 [1.8, 10.0] mg in the placebo group and 5.0 [2.0, 11.0] mg in the prebagalin group, p = 0.60. There were no differences in cumulative morphine consumption at 6, 12, and 24 h postoperatively. The two groups also did not differ in time to first analgesic rescue, pain scores at rest and on movement, and side effects. CONCLUSION: A single preoperative dose of pregabalin 150 mg did not reduce 24-h postoperative morphine consumption or pain scores or prolong the time to first analgesic rescue in spinal anesthesia with intrathecal morphine. PMID- 28918558 TI - Colorimetric Detection of Unamplified Rift Valley Fever Virus Genetic Material Using Unmodified Gold Nanoparticles. AB - Rift Valley fever virus (RVFV) is considered an enzootic virus in Africa. RVFV has caused several outbreaks in Egypt, sub-Saharan Africa and the Arabian Peninsula and is responsible for high mortality in ruminants and haemorrhagic fever in severe human cases. Although there are several molecular and serological diagnostic techniques used to detect this arthropod-borne virus with high sensitivity and efficiency, there is a need for a fast and reliable field screening test for rapid outbreak recording and containment. In this study, we developed a prototype point-of-care diagnostic test specific for RVFV detection using unmodified gold nanoparticles (AuNPs) that change colour in the presence of RVFV RNA, resulting in a simple but sensitive assay. The nanogold assay provides qualitative results showing the presence of the RVFV RNA in different sample types. The assay showed high accuracy and specificity, with a detection limit of 10 RNA copies/reaction, comparable with quantitative reverse transcription polymerase chain reaction. The assay result could be determined within 30 min with no need for specific detection instruments. To our knowledge, this is the first field test prototype to directly detect the RNA of RVFV without amplification using AuNPs. PMID- 28918557 TI - Biomarker levels in gingival crevicular fluid of generalized aggressive periodontitis patients after non-surgical periodontal treatment. AB - OBJECTIVES: The aim of this study was to assess the effects of non-surgical periodontal treatment on gingival crevicular fluid (GCF) cytokines in patients with generalized aggressive periodontitis (GAgP), in relation to clinical parameters. MATERIALS AND METHODS: Data were obtained from 16 GAgP patients and 15 periodontally healthy controls. Periodontal parameters and GCF biomarker levels were evaluated at baseline and repeated 3 and 6 months after treatment for GAgP subjects. Moderate and deep pocket sites were analyzed separately. The amount of interleukin (IL)-1beta, IL-9, tumor necrosis factor (TNF)-alpha, platelet-derived growth factor (PDGF-bb), and vascular endothelial growth factor (VEGF) were measured using a highly specific and sensitive multiplex bead immunoassay. RESULTS: At baseline, cytokine levels in the moderate and deep pocket sites of GAgP patients were higher than those of the healthy control sites. In GAgP group, periodontal treatment led to improvement in all examined clinical parameters and resulted in a statistically significant reduction in the total amounts of IL-1beta, VEGF, and TNF-alpha, in comparison to baseline, already 3 months after therapy in both moderate and deep pocket sites and of PDGF bb in deep sites (p < 0.01). At the concentration level, only IL-1beta and VEGF were affected. CONCLUSION: Non-surgical treatment of GAgP provided significant clinical benefits leading to a marked decrease in the GCF levels of some pro inflammatory and pro-angiogenic cytokines, but not of IL-9 and PDGF-bb. CLINICAL RELEVANCE: Although the periodontal therapy successfully decreased clinical signs of inflammation, the GCF levels of some inflammatory cytokines were still elevated. PMID- 28918559 TI - Prostate cancer screening by prostate-specific antigen (PSA); a relevant approach for the small population of the Cayman Islands. AB - INTRODUCTION: The common tool for diagnosing prostate cancer is prostate-specific antigen (PSA), but the high sensitivity and low specificity of PSA testing are the problems in clinical practice. There are no proper guidelines to investigate the suspected prostate cancer in the Cayman Islands. We correlated PSA levels with the incidence of prostate cancers by tissue diagnosis and proposed logical protocol for prostate screening by using PSA test in this small population. MATERIALS AND METHODS: A total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. The patients were divided into subgroups by baseline PSA levels as follows: <4, 4.1-10, 10.1-20, 20.1-50, 50.1-100, and >100 ng/mL and were correlated to the age and presence of cancer. RESULTS AND DISCUSSION: Benign lesions had lower PSA levels compared to cancer which generally had higher values. Only three cases that had less than 4 ng/mg were turned out to be malignant. When PSA value was more than 100 ng/mL, all the cases were malignant. Between PSA values of 4-100 ng/mL, the probability of cancer diagnosis was 56.71% (76 cancers out of 134 in this range). Limitation of PSA testing has the risk of over diagnosis and the resultant negative biopsies owing to poor specificity. Whereas the cutoff limit for cancer diagnosis still remains 4 ng/mL from our study, most of the patients can be assured of benign lesion below this level and thus morbidity associated with the biopsy can be prevented. When the PSA value is greater than 100 ng, biopsy procedure was mandatory as there were 100% cancers above this level. On the background of vast literature linking PSA to prostate cancer and its difficulty in implementing in clinical practice, we studied literature of this conflicting and complex topic and tried to bring relevant protocols to the small population of Cayman Islands for the screening of prostate cancer. In this study, a total of 165 Afro Caribbean individuals who had prostate biopsy done after the investigations for PSA levels from year 2005 to 2015 were studied retrospectively. As a result of this research work, it can be concluded that a benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman Islands. CONCLUSION: The PSA level can reassure and educate the patients towards the diagnosis of cancer of prostate in Cayman Islands. Benign diagnosis can be given with a fair certainty when the PSA was below 4 ng/mL and a level of 100 ng/mL can be very unfavorable for the patients. This study helped to solidify the cancer screening protocols in Cayman. PMID- 28918560 TI - Margin-free excision of small solid breast carcinomas using the Intact Breast Lesion Excision System(r): is it feasible? AB - BACKGROUND: The Breast Lesion Excision System(r) (BLES(r)) is a stereotactic vacuum-assisted breast biopsy device that utilizes radiofrequency in order to excise non-palpable mammographic lesions for pathologic diagnosis. The purpose of this study was to evaluate the efficacy of BLES(r) in performing complete, margin free excisions of small solid carcinomas. METHODS: Our retrospective study of prospectively enrolled patients included 50 cases of non-palpable, BIRADS >= 4, solid by means of mammography and sonography, lesions. All these patients underwent a BLES(r) breast biopsy procedure from June 2010 to June 2014 and had a malignant diagnosis. According to each patient's pathologic diagnosis, appropriate surgical treatment was recommended. Postoperatively, surgical specimens were histologically analyzed, aiming to determine whether residual malignant disease was present in the specimen cavity formatted by BLES(r). RESULTS: Ductal carcinoma in situ (DCIS) was diagnosed in 5 patients and invasive carcinoma (IC) in 45 patients, at primary BLES(r) pathology report. Tumor-free resection margins (< 0.5 and < 1 mm) were accomplished in only 8/24 subcentimeter cases (33.3%). Absence of residual disease upon surgical excision was confirmed in 23/24 subcentimeter cases (95.8%) and 2/26 of the cases measuring > 1 cm (7.69%). Statistical analysis revealed that mammographic size was the only significant prognostic factor for complete excision (i.e., with no residual disease in the biopsy cavity) of a malignant lesion. CONCLUSIONS: Our results indicate that it is possible, when using the BLES(r) device, to completely excise small (<= 10 mm) breast carcinomas that appear radiologically as solid lesions. This subset of patients should be investigated regarding the therapeutic potential of this method. PMID- 28918561 TI - Marine polysaccharides: therapeutic efficacy and biomedical applications. AB - The ocean contains numerous marine organisms, including algae, animals, and plants, from which diverse marine polysaccharides with useful physicochemical and biological properties can be extracted. In particular, fucoidan, carrageenan, alginate, and chitosan have been extensively investigated in pharmaceutical and biomedical fields owing to their desirable characteristics, such as biocompatibility, biodegradability, and bioactivity. Various therapeutic efficacies of marine polysaccharides have been elucidated, including the inhibition of cancer, inflammation, and viral infection. The therapeutic activities of these polysaccharides have been demonstrated in various settings, from in vitro laboratory-scale experiments to clinical trials. In addition, marine polysaccharides have been exploited for tissue engineering, the immobilization of biomolecules, and stent coating. Their ability to detect and respond to external stimuli, such as pH, temperature, and electric fields, has enabled their use in the design of novel drug delivery systems. Thus, along with the promising characteristics of marine polysaccharides, this review will comprehensively detail their various therapeutic, biomedical, and miscellaneous applications. PMID- 28918562 TI - CRISPR/Cas9 genome editing in wheat. AB - Genome editing has been a long-term challenge for molecular biology research, particularly for plants possess complex genome. The recently discovered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system is a versatile tool for genome editing which enables editing of multiple genes based on the guidance of small RNAs. Even though the efficiency of CRISPR/Cas9 system has been shown with several studies from diploid plants, its application remains a challenge for plants with polyploid and complex genome. Here, we applied CRISPR/Cas9 genome editing system in wheat protoplast to conduct the targeted editing of stress-responsive transcription factor genes, wheat dehydration responsive element binding protein 2 (TaDREB2) and wheat ethylene responsive factor 3 (TaERF3). Targeted genome editing of TaDREB2 and TaERF3 was achieved with transient expression of small guide RNA and Cas9 protein in wheat protoplast. The effectiveness of mutagenesis in wheat protoplast was confirmed with restriction enzyme digestion assay, T7 endonuclease assay, and sequencing. Furthermore, several off-target regions for designed sgRNAs were analyzed, and the specificity of genome editing was confirmed with amplicon sequencing. Overall results suggested that CRISPR/Cas9 genome editing system can easily be established on wheat protoplast and it has a huge potentiality for targeted manipulation of wheat genome for crop improvement purposes. PMID- 28918564 TI - MRI combined with PET-CT of different tracers to improve the accuracy of glioma diagnosis: a systematic review and meta-analysis. AB - Based on studies focusing on positron emission tomography (PET)-computed tomography (CT) combined with magnetic resonance imaging (MRI) in the diagnosis of glioma, we conducted a systematic review and meta-analysis evaluating the pros and cons and the accuracy of different examinations. PubMed and Cochrane Library were searched. The search was conducted until April 2017. Two reviewers independently conducted the literature search according to the criteria set initially. Based on the exclusion criteria, 15 articles are included in this study. Of all studies that used MRI examination, there are five involving 18F fluorodeoxyglucose-PET, five involving 11C-methionine-PET, five involving 18F fluoro-ethyl-tyrosine-PET, and three involving 18F-fluorothymidine-PET. Due to the limitations such as lack of data, small sample size, and unrepresentative studies, we use a non-quantitative methodology. MRI examination can provide the anatomy information of glioma more clearly. PET-CT examinations based on tumor metabolism using different tracers have more advantages in determining the degree of glioma malignancy and boundaries. However, information provided by PET-CT of different tracers is not the same. With respect to the novel hybrid MRI/PET examination equipment proposed in recent years, the combination of MRI and PET-CT can definitively improve the diagnostic accuracy of glioma. PMID- 28918563 TI - Development and validation of immortalized bovine mammary epithelial cell line as an in vitro model for the study of mammary gland functions. AB - This study aimed to develop a bovine mammary epithelial (BME) cell line model, which provides a possibility to determine functional properties of the bovine mammary gland. The primary cell culture was derived from bovine mammary gland tissues and processed enzymatically to obtain cell colonies with epithelial-like morphology. The cultures of BME cells were purified and optimally cultured at 37 degrees C in DMEM/F12 medium supplemented with 10% fetal bovine serum. The BME cells were identified as epithelial cell line by the evaluating the expression of keratin-18 using immunofluorescence staining. A novel gene expression system strongly enhances the expression of telomerase, has been used to immortalize BME cell line termed hTBME cell line. Interestingly, telomerase remained active even after over 60 passages of hTBME cell line, required for immortalization of BME cells. In addition, the hTBME cell line was continuously subcultured with a spontaneous epithelial-like morphology, with a great proliferation activity, and without evidence of apoptotic and necrotic effects. Further characterization showed that hTBME cell line can be continuously propagated in culture with constant chromosomal features and without tumorigenic properties. Finally, established hTBME cell line was evaluated for mammary gland specific functions. Our results demonstrated that the hTBME cell line was able to retain functional morphological structure, and functional differentiation by expression of beta (beta)-casein as in the bovine mammary gland in vivo. Taken together, our findings suggest that the established hTBME cell line can serve as a valuable tool for the study of bovine mammary gland functions. PMID- 28918565 TI - Forward genetic screens identify a role for the mitochondrial HER2 in E-2-hexenal responsiveness. AB - KEY MESSAGE: This work adds a new player, HER2, downstream of the perception of E 2-hexenal, a green leaf volatile, and shows that E-2-hexenal specifically changes the redox status of the mitochondria. It is widely accepted that plants produce and respond to green leaf volatiles (GLVs), but the molecular components involved in transducing their perception are largely unknown. The GLV E-2-hexenal inhibits root elongation in seedlings and, using this phenotype, we isolated E-2-hexenal response (her) Arabidopsis thaliana mutants. Using map-based cloning we positioned the her2 mutation to the At5g63620 locus, resulting in a phenylalanine instead of serine on position 223. Knockdown and overexpression lines of HER2 confirmed the role of HER2, which encodes an oxidoreductase, in the responsiveness to E-2-hexenal. Since E-2-hexenal is a reactive electrophile species, which are known to influence the redox status of cells, we utilized redox sensitive GFP2 (roGFP2) to determine the redox status of E-2-hexenal treated root cells. Since the signal peptide of HER2 directed mCherry to the mitochondria, we targeted the expression of roGFP2 to this organelle besides the cytosol. E-2-hexenal specifically induced a change in the redox status in the mitochondria. We did not see a difference in the redox status in her2 compared to wild-type Arabidopsis. Still, the mitochondrial redox status did not change with Z-3-hexenol, another abundant GLV. These results indicate that HER2 is involved in transducing the perception of E-2-hexenal, which changes the redox status of the mitochondria. PMID- 28918567 TI - Expansion of Parents' Undetermined Experience in Socioeducational Programs: Extending the Dialogical Self Theory. AB - The Dialogic Self Theory (DST-Hermans et al. Integrative Psychology and Behavioral Sciences, 51(4), 1-31, 2017) is extended here in its dynamic aspects through focusing on the notions of indeterminacy, emptiness and movement. Linking with Husserl, I propose moving the dialogical self (DS) from a clear position in the "repertory of the Self" to an undetermined horizon. This makes it possible to introduce "holes" (emptiness) into the schematic representation of the "repertory of the Self". Yet Husserl's concept of horizon seems to focus too much on making the indeterminable determinate. To overcome this limit, I incorporate Bergson's concept of empty form into the DST. This enables conceptualising the extension and emergence of horizon. Extending Bergson's concept of organisation, it is possible to see how the expansion of the horizon in a movement of globalisation does not necessarily entail the disorganisation of the DS but rather to its further organisation. Extending the system of DS by Hermans et al. Integrative Psychology and Behavioral Sciences, 51(4), 1-31, (2017), I open by suggesting that movements are both horizontal (between people) and vertical (between the person, the institutions and the norms) connectors. My conceptual propositions are illustrated by parents' and educators' discourses in two Canadian socio educational programs. PMID- 28918568 TI - Brief Report: An Evaluation of an Instructional Package for Teaching Sentence Construction to Students with ASD. AB - In the current study, we investigated the effects of an instructional package on the construction of sentences writing by four children ages 6-9, with autism spectrum disorder (ASD). We employed a multiple probe across behaviors design to evaluate the efficacy of the intervention package and also conducted probes to assess generalization and increases in the use of spoken sentences. Data indicated that the package was effective and produced variable levels of maintenance and generalized responding across three of the participants. Further, changes in vocal responding were observed in one of the participants. PMID- 28918566 TI - Understanding the Science of Resistance Training: An Evolutionary Perspective. AB - The history of resistance training research began with anecdotal ideas and a slow growth of research from the late 1890s through the 1970s. The mid-1970s were a nexus point when resistance training studies evolved from just strength assessments to importance in physiological systems, physical health, and physical performance capabilities for individuals interested in physical fitness through to those seeking elite athletic performances. The pursuit of understanding program design and what mediated successful programs continues today as new findings, replication of old concepts, and new visions with the latest technologies fuel both our understanding and interest in this modality. This brief review highlights some of the important scientific contributions to the evolution of our scientific study of resistance training and provides a literature base analysis for greater quantification of the origins and expanse of such investigations. PMID- 28918570 TI - Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites. AB - The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation. PMID- 28918569 TI - Highlights from the Ninth International Symposium of Thrombosis and Anticoagulation (ISTA IX), October 15, 2016, Salvador, Bahia, Brazil. AB - To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Ninth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, on October 15, 2016. This scientific program was developed by clinicians for clinicians and was promoted by two major clinical research institutes-the Brazilian Clinical Research Institute and the Duke Clinical Research Institute of the Duke University School of Medicine. Comprising academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings. PMID- 28918571 TI - The effect of communication skills training on patient-pharmacist communication in pharmacy education: a meta-analysis. AB - Communication skills in pharmacy education and practice are increasingly regarded as a crucial component. However, thus far, estimating of the overall communication skills training (CST) effects in a variety of outcomes is lacking. The aim of this study was to synthesize the effects of CST in pharmacy education by performing a meta-analysis of CST studies. We searched MEDLINE, EMBASE, ERIC, CINAHL, PsycINFO, Cochrane Library, Web of Science, Communication and Mass Media Complete (CMMC), key journals, and bibliographic databases. The effect sizes (ESs) were extracted and pooled in random effects meta-analyses. We assessed the quality of the study using the Medical Education Research Study Quality Instrument (MERSQI). From 34,737 articles, 9 studies were included in this meta analysis. The overall effect size for CST was 0.611 (95% CI 0.327-0.895), and it was statistically significant (p = 0.000). We found based on the subgroup analyses that CST has a large effect size when it used stand-alone courses, lecture-lab based courses, video recordings, feedback, training for 2 or more semesters, hours per week >=5 h and external assessments. For the CST effect, the effect sizes were ranked in order of confidence, knowledge, skills, and attitudes. The result of the meta-regression is that the total number of attendees is significantly negatively correlated with the effect sizes of the CST. The findings of the present meta-analysis provide evidence that CST in pharmacy education may act as an efficient way to improve the communication competency of students, and it may serve as a guide for pharmacy educators. PMID- 28918572 TI - Spot light on skeletal muscles: optogenetic stimulation to understand and restore skeletal muscle function. AB - Damage of peripheral nerves results in paralysis of skeletal muscle. Currently, the only treatment option to restore proper function is electrical stimulation of the innervating nerve or of the skeletal muscles directly. However this approach has low spatial and temporal precision leading to co-activation of antagonistic muscles and lacks cell-type selectivity resulting in pain or discomfort by stimulation of sensible nerves. In contrast to electrical stimulation, optogenetic methods enable spatially confined and cell-type selective stimulation of cells expressing the light sensitive channel Channelrhodopsin-2 with precise temporal control over the membrane potential. Herein we summarize the current knowledge about the use of this technology to control skeletal muscle function with the focus on the direct, non-neuronal stimulation of muscle fibers. The high temporal flexibility of using light pulses allows new stimulation patterns to investigate skeletal muscle physiology. Furthermore, the high spatial precision of focused illumination was shown to be beneficial for selective stimulation of distinct nearby muscle groups. Finally, the cell-type specific expression of the light-sensitive effector proteins in muscle fibers will allow pain-free stimulation and open new options for clinical treatments. Therefore, we believe that direct optogenetic stimulation of skeletal muscles is a very potent method for basic scientists that also harbors several distinct advantages over electrical stimulation to be considered for clinical use in the future. PMID- 28918574 TI - Fecal sludge management in developing urban centers: a review on the collection, treatment, and composting. AB - The problems posed by fecal sludge (FS) are multidimensional because most cities rapidly urbanize, which results in the increase in population, urban settlement, and waste generation. Issues concerning health and waste treatment have continued to create alarming situations. These issues had indeed interfered with the proper steps in managing FS, which contaminates the environment. FS can be used in agriculture as fertilizer because it is an excellent source of nutrients. The recent decline in crop production due to loss of soil organic component, erosion, and nutrient runoff has generated interest in the recycling of FS into soil nutrients through stabilization and composting. However, human feces are considerably liable to spread microorganisms to other persons. Thus, sanitation, stabilization, and composting should be the main objectives of FS treatment to minimize the risk to public and environmental health. This review presents an improved FS management (FSM) and technology option for soil amendment that is grouped into three headings, namely, (1) collection, (2) treatment, and (3) composting. On the basis of the literature review, the main problems associated with the collection and treatment of FS, such as inadequate tools and improper treatment processes, are summarized, and the trends and challenges that concern the applicability of each of the technologies in developing urban centers are critically reviewed. Stabilization during pretreatment before composting is suggested as the best method to reduce pathogens in FS. Results are precisely intended to be used as a support for decisions on policies and strategies for FSM and investments for improved treatment facilities. PMID- 28918573 TI - Anti-inflammatory effects of Ginkgo biloba extract against trimethyltin-induced hippocampal neuronal injury. AB - BACKGROUND: Despite the immense neuromodulatory potentials of Ginkgo biloba extract as a memory enhancer, its underlying mechanism seems inadequate particularly with regard to its anti-inflammatory properties. AIM: The objective of the present study is to investigate the protective potentials of Ginkgo biloba extract (GBE) against hippocampal neuronal injury induced by trimethyltin (TMT), a potent neurotoxicant. METHODS: Male SD rats were administered trimethyltin (8.5 mg kg-1 b.wt) single intraperitoneal (i.p.) injection, followed by Ginkgo biloba extract (100 mg kg-1 b.wt i.p) for 21 days. RESULTS: The co-administration of GBE with TMT showed marked improvement in cognitive functions. Concomitantly, there was a significant decrease in oxidative stress as evident by reduction in MDA and total ROS levels. In addition, there was a marked suppression of astrocyte activation (GFAP), transcription factor NFkappaB and proinflammatory cytokines (TNF-alpha, IL-1alpha, 1L-6), which were found to be elevated by TMT administration. Histopathological observations showed remarkable improvement in hippocampal neuronal injury in the conjunctive group. CONCLUSION: Therefore, it is suggested that Ginkgo biloba extract is an effective agent against trimethyltin-induced hippocampal neuronal loss owing to its antioxidative as well as anti-inflammatory properties. PMID- 28918575 TI - Optimum spacing between electrodes in an air-cathode single chamber microbial fuel cell with a low-cost polypropylene separator. AB - The performance of a single chamber microbial fuel cell (MFC) with a low-cost polypropylene separator was investigated at various electrode interspaces in a separator electrode assembly (SEA). The lag period was shortened (3.74-0.17 days) and voltage generation was enhanced (0.2-0.5 V) as electrode spacing was increased from 0 to 9 mm. Power density was increased from 220 to 370 mW/m2 with increased spacing. The highest power density of 488 mW/m2 was obtained in polarization analysis with 6 mm. The oxygen mass transfer coefficients with 0 mm (K o = 3.69 * 10-5 cm/s) electrode spacing were 3.8 times higher than with 9 mm (K o = 0.96 * 10-5 cm/s) spacing. Columbic efficiency (CE) was increased from 5 to 32% due to less oxygen diffusion with increase in electrode spacing, but on contrary the ohmic resistance (R oh) was increased from 2 to 4 Omega. In a long term operation (200 days), a gradual decrease in cathode potentials was observed in all electrode spacing as the main limiting factor of stable MFC performance. PMID- 28918576 TI - Effect of heat stress on rumen temperature of three breeds of cattle. AB - Thirty-six steers (12 of each Angus, Charolais, and Brahman) with an initial BW of 318.5 +/- 6.7 kg were used in a 130-day study. Two treatments were imposed: un shaded and shaded (3 m2/animal; 90% solar block shade cloth). On day 1, steers were administered with rumen temperature boluses. Rumen temperatures (T RUM) were obtained at 10 min intervals over the duration of the study to determine differences in T RUM between Bos indicus and Bos taurus cattle. Six feedlot pens (162 m2) were used with six steers (2/breed) per pen with three pens/treatment. Ambient dry bulb temperature (T A; degrees C), relative humidity (RH; %), wind speed (WS; m/s) and direction, and solar radiation (SR; W/m2) were recorded at 10 min intervals. Rainfall (mm) was collected daily at 0900 h. From these data, black globe temperature (BGT; degrees C), temperature humidity index (THI), heat load index (HLI), and accumulated heat load (AHL) were calculated. Individual T RUM were converted to an hourly average and then mean hourly T RUM were converted to a mean within hour T RUM across the 130 days. Rumen temperatures were analyzed using an autoregressive repeated measures model. The model analyzed the effect of breed (P < 0.0002), treatment (P = 0.3543), time of day (hour, h; P < 0.0001), breed * treatment (P < 0.3683), breed * h (P < 0.0001), treatment * h (P < 0.0001), breed * treatment * h (P = 0.0029), pen within treatment (P = 0.0195), and animal * breed * treatment within pen (P = 0.1041). Furthermore, there were breed * treatment * hour differences in T RUM (P = 0.0036), indicating that Bos indicus and Bos taurus regulate T RUM differently. PMID- 28918578 TI - Bringing together raptor collections in Europe for contaminant research and monitoring in relation to chemicals regulations. AB - Raptors are good sentinels of environmental contamination and there is good capability for raptor biomonitoring in Europe. Raptor biomonitoring can benefit from natural history museums (NHMs), environmental specimen banks (ESBs) and other collections (e.g. specialist raptor specimen collections). Europe's NHMs, ESBs and other collections hold large numbers of raptor specimens and samples, covering long periods of time. These collections are potentially a valuable resource for contaminant studies over time and space. There are strong needs to monitor contaminants in the environment to support EU and national chemical management. However, data on raptor specimens in NHMs, ESBs and other collections are dispersed, few are digitised, and they are thus not easy to access. Specimen coverage is patchy in terms of species, space and time. Contaminant research with raptors would be facilitated by creating a framework to link relevant collections, digitising all collections, developing a searchable meta-database covering all existing collections, making them more visible and accessible for contaminant research. This would also help identify gaps in coverage and stimulate specimen collection to fill gaps in support of prioritised contaminant monitoring. Collections can further support raptor biomonitoring by making samples available for analysis on request. PMID- 28918577 TI - Microarray-based SNP genotyping to identify genetic risk factors of triple negative breast cancer (TNBC) in South Indian population. AB - In the view of aggressive nature of Triple-Negative Breast cancer (TNBC) due to the lack of receptors (ER, PR, HER2) and high incidence of drug resistance associated with it, a case-control association study was conducted to identify the contributing genetic risk factors for Triple-negative breast cancer (TNBC). A total of 30 TNBC patients and 50 age and gender-matched controls of Indian origin were screened for 9,00,000 SNP markers using microarray-based SNP genotyping approach. The initial PLINK association analysis (p < 0.01, MAF 0.14-0.44, OR 10 24) identified 28 non-synonymous SNPs and one stop gain mutation in the exonic region as possible determinants of TNBC risk. All the 29 SNPs were annotated using ANNOVAR. The interactions between these markers were evaluated using Multifactor dimensionality reduction (MDR) analysis. The interactions were in the following order: exm408776 > exm1278309 > rs316389 > rs1651654 > rs635538 > exm1292477. Recursive partitioning analysis (RPA) was performed to construct decision tree useful in predicting TNBC risk. As shown in this analysis, rs1651654 and exm585172 SNPs are found to be determinants of TNBC risk. Artificial neural network model was used to generate the Receiver operating characteristic curves (ROC), which showed high sensitivity and specificity (AUC 0.94) of these markers. To conclude, among the 9,00,000 SNPs tested, CCDC42 exm1292477, ANXA3 exm408776, SASH1 exm585172 are found to be the most significant genetic predicting factors for TNBC. The interactions among exm408776, exm1278309, rs316389, rs1651654, rs635538, exm1292477 SNPs inflate the risk for TNBC further. Targeted analysis of these SNPs and genes alone also will have similar clinical utility in predicting TNBC. PMID- 28918580 TI - Apropos use of biological mesh in trans-anal treatment for recurrent recto urethral fistula. PMID- 28918579 TI - Analysis of Undesirable Sequelae of Sentinel Node Surgery in Breast Cancer Patients - a Prospective Cohort Study. AB - Use of sentinel lymph node biopsy limits the frequency and severity of sequelae of surgical treatment. However, the procedure itself may not be completely free of complications. The goal of this work was to analyze prospectively the occurrence of undesirable sequelae in patients undergoing sentinel lymph node biopsy as an isolated intervention in the axillary fossa. This prospective observational study was conducted on a group of 104 women. Patients were examined on five occasions: one day before the procedure, one day after the procedure, one month, three months, and six months after the procedure. At every stage of the study they were assessed for tactile sensation, range of motion in the shoulder joint, upper limb circumference, sensation abnormalities, winged scapula sign, and pain severity according to Visual Analogue Scale (VAS). In the study group we observed statistically significant differences, such as limited mobility in the shoulder joint (p <= 0.01), gradual increase in limb circumference on the operated side (p < 0.01) and pain (p <= 0.01). Despite relatively low invasiveness of the procedure, sentinel lymph node biopsy is not entirely devoid of the risk of undesirable sequelae. PMID- 28918581 TI - Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study. AB - INTRODUCTION: Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms. METHODS: This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms. RESULTS: At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating. CONCLUSION: NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted. FUNDING: Orexigen Therapeutics, Inc. PMID- 28918582 TI - Removal of endrin and dieldrin isomeric pesticides through stereoselective adsorption behavior on the graphene oxide-magnetic nanoparticles. AB - A novel stereoselective removal behavior of isomeric endrin and dieldrin pesticides from sample solution is demonstrated using nanocomposite of graphene oxide (GO) and iron oxide (Fe3O4) magnetic nanoparticles (MNPs). The removal efficiency of endrin and dieldrin was found higher when GO-MNPs was used as a separating probe than the individual use of GO and MNPs. The removal efficiency of both the pesticides was found to be more favorable when the dosage amount of GO-MNPs was 30 mg for 30-min contact time with pH 4.0 at room temperature. The good correlation of determination (R 2) with 0.975 and 0.973 values obtained for endrin and dieldrin, respectively demonstrated a well fitting of Langmuir adsorption isotherm model. The higher removal percentage (86.0%) and higher slope value of Langmuir adsorption isotherm were estimated for endrin compared to dieldrin (74.0%). The reason for higher adsorption percentage of endrin is due to the endo-position of oxygen atom in molecule favors more interaction of molecules with GO-MNPs compared to the exo-position of oxygen present in dieldrin. In addition, the higher value of R 2 for endrin and dieldrin demonstrated better suitability of pseudo-first-order and pseudo-second-order kinetic models, respectively. The advantages of the present method are use of simple UV-vis spectrophotometry for monitoring and low-cost use of GO-MNPs nanomaterial for the removal of pesticides from sample solution. PMID- 28918583 TI - Evidence for contrasting accumulation pattern of cadmium in relation to other elements in Senilia senilis and Tagelus adansoni from the Bijagos archipelago, Guinea-Bissau. AB - Shellfish harvesting in intertidal areas is a widespread and economically important activity in many countries across West Africa. However, in some areas, there is virtually no information concerning the levels of contaminants (and other elements related to nutritional aspects) in the harvested species. We collected sediments and several individuals of the West African bloody cockle Senilia senilis and of the razor clam Tagelus adansoni during the dry season of 2015 nearby three islands in the Bijagos archipelago, Guinea-Bissau. Aluminium, Ca, Fe, Mg, As, Cd, Co, Cr, Cu, Mn, Ni, Pb and Zn were determined in sediments and whole soft tissues of the two bivalves. Sediments showed uniformly low trace element concentrations, pointing to an ecosystem with low levels of trace element contamination. T. adansoni presented higher concentrations of most elements than S. senilis, with the exception of Cd that showed up to 40 times higher values in S. senilis than in T. adansoni from the same sites. Furthermore, Cd concentrations (25+/-8.7 mg kg-1, dw) in S. senilis are clearly above the maximum level established for human consumption. Future studies should clarify whether biological factors are the major responsible for this unusual situation. PMID- 28918584 TI - Fed-Batch Strategies for Production of PHA Using a Native Isolate of Halomonas venusta KT832796 Strain. AB - In this study, polyhydroxyalkanoates (PHA) accumulation by Halomonas venusta KT832796, a moderate halophilic bacteria isolated from marine source was studied. Both nutritional requirements and process parameters for submerged cultivation of the organism in bioreactor have been standardized. From the shake flask studies, glucose and ammonium citrate as carbon and nitrogen source produced maximum PHA at a ratio 20 with 3.52 g/L of dry cell weight and 70.56% of PHA content. However, ammonium sulfate as the nitrogen source was found to be more suitable for fed-batch cultivation. Several feeding strategies including pH-based fed batch and variants of pulse feeding were studied to improve the PHA levels. pH based feeding, although improved PHA level to 26 g/L, most of the carbon flux was diverted towards biomass formation; hence, the percent PHA was only 39.15% of the dry cell weight. Maximum PHA of 33.4 g/L, which corresponded to 88.12% of the dry cell, was obtained from high concentration single pulse method. There was a net 8.65-fold increase in PHA using this feeding strategy when compared to batch studies. According to our knowledge, this is the highest amount of PHA reported for a Halomonas venusta strain. PMID- 28918586 TI - Characterization of Truncated dsz Operon Responsible for Dibenzothiophene Biodesulfurization in Rhodococcus sp. FUM94. AB - Numerous desulfurizing bacteria from the Rhodococcus genus harbor conserved dsz genes responsible for the degradation of sulfur compounds through 4S pathway. This study describes a newly identified desulfurizing bacterium, Rhodococcus sp. FUM94, which unlike previously identified strains encodes a truncated dsz operon. DNA sequencing revealed a frameshift mutation in the dszA gene, which led to an alteration of 66 amino acids and deletion of other C-terminal 66 amino acids. The resulting DszA polypeptide was shorter than DszA in Rhodococcus sp. IGTS8 reference strain. Despite the truncation, desulfurizing activity of the operon was observed and attributed to the removal of an overlap of dszA and dszB genes, and lack of active site in the altered region. Desulfurization experiments resulted in specific production rate of 6.3 mmol 2-hydroxy biphenyl (kgDCW)-1 h-1 at 2 g l-1 biocatalyst concentration and 68.8% biodesulfurization yield at 20 g l 1 biocatalyst concentration, both at 271 MUM dibenzothiophene concentration which is comparable to similar wild-type biocatalysts. PMID- 28918585 TI - Prevalence and risk factors for intestinal carriage of CTX-M-type ESBLs in Enterobacteriaceae from a Thai community. AB - The incidence of infections caused by antimicrobial-resistant Enterobacteriaceae in Thailand is increasing and human intestinal flora is an important reservoir for these organisms. This study was carried out to determine the intestinal carriage of bla CTX-M extended spectrum beta-lactamase-positive Enterobacteriaceae (ESBL + E) and AmpC-positive Enterobacteriaceae in a community setting in Northern Thailand, and to identify potential risk factors for carriage. A total of 307 fecal samples were collected from healthy volunteers in Phitsanulok province, and cefotaxime-resistant Enterobacteriaceae (CtxRE) were isolated using selective media. Polymerase chain reaction (PCR) was used to detect ESBL and AmpC genes. Risk factors were analyzed using multiple logistic regression. Genotyping was performed by multilocus sequence typing (MLST) analysis. Two hundred ninety-one CtxRE isolates were obtained and Escherichia coli was the predominant organism (66.3%). The intestinal carriage rates of bla CTX-M ESBL + E and AmpC-positive Enterobacteriaceae were 52.1% and 6.2%, respectively. Comparative levels of bla CTX-M group 1 and bla CTX-M group 9 were found while bla CMY-2 was the predominant genotype among AmpC genes. Co-existence of two beta-lactamase genes in a single isolate was found in 6.5% of isolates. Consumption of undercooked meat was strongly associated with intestinal carriage of bla CTX-M ESBL + E (p = 0.003, OR = 2.133, 95% CI = 1.289-3.530). Phylogenetic grouping and MLST analysis of E. coli isolates revealed the presence of E. coli B2-ST131 (n = 8). Of these, seven carried bla CTX-M-group 9 and 1 carried bla CMY 2. Our results suggest that residents in Thailand are at high risk for developing endogenous infections caused by antibiotic-resistant Enterobacteriaceae. PMID- 28918587 TI - Genome-wide association studies of albuminuria: towards genetic stratification in diabetes? AB - Genome-wide association studies (GWAS) have been very successful in unraveling the polygenic structure of several complex diseases and traits. In the case of albuminuria, despite the large sample size achieved by some studies, results look sparse with a limited number of loci reported so far. This review searched for GWAS studies of albumin excretion, albuminuria, and proteinuria. The resulting picture sets elements of uniqueness for albuminuria GWAS with respect to other complex traits. So far, very few loci associated with albuminuria have been validated by means of genome-wide significant evidence or formal replication. With rare exceptions, the validated loci are ethnicity specific. Within a given ethnicity, variants are common and have relatively large effects, especially in the presence of diabetes. In most cases, the identified variants were functional and a biological involvement of the target genes in renal damage was established. Recently reported variants associated with albuminuria in diabetes may be potentially combined into a genetic risk score, making it possible to rank diabetic patients by increasing risk of albuminuria. Validation of this model is required. To expand the understanding of the biological basis of albumin excretion regulation, future initiatives should achieve larger sample sizes and favor a transethnic study design. PMID- 28918588 TI - A Practical Approach to Managing Hypoactive Sexual Desire Disorder in Women with Diabetes. AB - Female sexual dysfunction (FSD) is highly prevalent in women with diabetes mellitus (DM), yet it remains unaddressed, undiagnosed, and untreated. Hypoactive sexual desire disorder (HSDD) is the most common complaint among women with FSD, but there is a paucity of research into its multifactorial etiology. Flibanserin is the only therapy approved by the US Food and Drug Administration for treating acquired, generalized HSDD in premenopausal women. Women with DM diagnosed with HSDD may require a multidisciplinary approach for optimal management. PMID- 28918589 TI - Isolated pancreas rejections do not have an adverse impact on kidney graft survival whereas kidney rejections are associated with adverse pancreas graft survival in simultaneous pancreas kidney transplantation. AB - BACKGROUND AND OBJECTIVES: Diabetic Kidney Disease is associated with excessive mortality and morbidity. Simultaneous pancreas kidney transplantation (SPK) significantly improves quality of life and increases life expectancy of uremic diabetic patients. It is not known whether pancreas and kidney rejections in these transplant patients is concordant or discordant. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We analyzed clinical data on all SPK transplants performed between 2003 and 2014 at Indiana University to assess the impact of isolated or combined pancreas and kidney rejections on patient and allograft outcomes. The primary outcome of interest was kidney graft rejection within 1 year of pancreatic rejection and kidney survival in SPK patients with and without pancreatic rejection. RESULTS: Mean age of patients was 44 +/- 9 years; 61.9% were males; 88% were Caucasians. A total of 23.8% of cases had rejection [8.7% pancreatic rejection alone (PA), 4.4% had concordant pancreas and kidney (PK) rejection, and 10.7% had kidney rejection alone(KA)]. PK had a worse effect on kidney graft survival than PA (p = 0.019). Neither pancreas rejection nor kidney rejection had an adverse effect on patient survival. However, both pancreas graft failure and kidney graft failure adversely affected patient survival. Tacrolimus levels were not significantly different in all groups over a 10 year period (p = 0.4584). CONCLUSIONS: Concordant pancreas kidney rejection is synergistically deleterious to kidney graft survival. Graft failure, not graft rejection, is adversely associated with patient survival. PMID- 28918590 TI - The Role of Diet in Shaping the Chemical Signal Design of Lacertid Lizards. AB - Lizards communicate with others via chemical signals, the composition of which may vary among species. Although the selective pressures and constraints affecting chemical signal diversity at the species level remain poorly understood, the possible role of diet has been largely neglected. The chemical signals of many lizards originate from the femoral glands that exude a mixture of semiochemicals, and may be used in a variety of contexts. We analyzed the lipophilic fraction of the glandular secretions of 45 species of lacertid lizard species by gas chromatography/mass spectrometry. The proportions of nine major chemical classes (alcohols, aldehydes, fatty acids, furanones, ketones, steroids, terpenoids, tocopherols and waxy esters), the relative contributions of these different classes ('chemical diversity'), and the total number of different lipophilic compounds ('chemical richness') varied greatly among species. We examined whether interspecific differences in these chemical variables could be coupled to interspecific variation in diet using data from the literature. In addition, we compared chemical signal composition among species that almost never, occasionally, or often eat plant material. We found little support for the hypothesis that the chemical profile of a given species' secretion depends on the type of food consumed. Diet breadth did not correlate with chemical diversity or richness. The amount of plants or ants consumed did not affect the relative contribution of any of the nine major chemical classes to the secretion. Chemical diversity did not differ among lizards with different levels of plant consumption; however, chemical richness was low in species with an exclusive arthropod diet, suggesting that incorporating plants in the diet enables lizards to increase the number of compounds allocated to secretions, likely because a (partly) herbivorous diet allows them to include compounds of plant origin that are unavailable in animal prey. Still, overall, diet appears a relatively poor predictor of interspecific differences in the broad chemical profiles of secretions of lacertid lizards. PMID- 28918592 TI - Internal phosphorus load in a Mexican reservoir through sediment speciation analysis. AB - Since the sequential extraction of phosphorus (P) in sediment makes it possible to determine the P potentially available for release, in this paper, we evaluate the fractions of P in sediment profiles from Valle de Bravo reservoir, a eutrophic lake in central Mexico to determine the contributions of each fraction to the internal P load (IPL). The P fractionation scheme employs sequential extractions of sediment with O2-free water (MilliQ), bicarbonate-dithionite (BD), sodium hydroxide (NaOH), hydrochloric acid (HCl), and potassium persulfate (K2S2O8-) to obtain five P fractions. A monitoring of redox potential (Eh), pH, and total phosphorus (TP) in the bottom water of the reservoir indicated variations of these parameters during the year, observing that as Eh decreased, the P concentration increased, it was also observed that when increasing pH, P concentration also increased. Analyzing the behavior of fractions of P in sediment profiles, we found that the dominant fractions are those bound to iron and aluminum oxides, corresponding to approximately 50% of total P since P concentrations of these fractions were twice as high in the top 5 cm of the sediment profiles and decreased with increasing depth. Considering the variations of Eh and pH in the bottom water of the reservoir and that these parameters are factors that control the release of P with the fractions of P bound to Fe/Mn and Al/Fe oxides, we concluded that these fractions contribute most to P potentially available for release in the reservoir, representing a possible IPL of 23.5 +/- 1.4 t/year. PMID- 28918591 TI - Platform model describing pharmacokinetic properties of vc-MMAE antibody-drug conjugates. AB - Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds. Clinical PK data of eight vc-MMAE ADCs from eight Phase I studies were pooled. A population PK platform model for the eight ADCs was developed, where the inter-compound variability (ICV) was described explicitly, using the third random effect level (ICV), and implemented using LEVEL option of NONMEM 7.3. The PK was described by a two-compartment model with time dependent clearance. Clearance and volume of distribution increased with body weight; volume was higher for males, and clearance mildly decreased with the nominal dose. Michaelis Menten elimination had only minor effect on PK and was not included in the model. Time-dependence of clearance had no effect beyond the first dosing cycle. Clearance and central volume were similar among ADCs, with ICV of 15 and 5%, respectively. Thus, PK of acMMAE was largely comparable across different vc-MMAE ADCs. The model may be applied to predict PK-profiles of vc-MMAE ADCs under development, estimate individual exposure for the subsequent PK-pharmacodynamics (PD) analysis, and project optimal dose regimens and PK sampling times. PMID- 28918593 TI - Decline patterns and risk assessment of 10 multi-class pesticides in young sprout amaranth (Amaranthus mangostanus) under greenhouse growing conditions. AB - The present study was designed to investigate the residual decline pattern and the risk assessment of 10 different class pesticides, namely azoxystrobin, boscalid, diazinon, diethofencarb, difenoconazole, etofenprox, flubendiamide, paclobutrazol, and pyraclostrobin in young vegetative amaranth (Amaranthus mangostanus) sprayed once or twice under greenhouse growing conditions. Field incurred samples, collected at 3, 7, or 10 days after application of both treatments, were extracted and purified with the quick, easy, cheap, effective, rugged, and safe "QuEChERS" citrate-buffered method and analyzed with liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) in positive ion mode. The linearity was satisfactory with determination coefficients (R 2) falling between 0.9817 and 0.9999 and limits of detection (LOD) and quantification (LOQ) values of 0.0007 and 0.002 mg/kg, respectively. The mean recovery rate at four spiking levels (equivalent to 5, 10, 50, and 100 * LOQ) ranged from 78.1 to 131.6% with a relative standard deviation (RSD) of < 11%. Substantial differences in the initial deposit between the tested analytes were observed and clearly indicated that the structure, as well as the initial concentration of applied products, greatly affected the residue deposit. From the obtained residual data, the provisional marginal maximum residue limits (MRLs) and the pre-harvest intervals (PHI) were proposed. Risk assessment was evaluated by comparing the theoretical maximum daily intake (TMDI) with the acceptable daily intake (ADI). Herein, the TMDI was lower than the ADI (TMDI/ADI ratio <= 80% set by the Korean Ministry of Food and Drug Safety) except for difenoconazole (80.92%, marginally higher), indicating that the vegetative amaranth is not hazardous and can be consumed safely by Korean consumers. PMID- 28918594 TI - The association of knee structural pathology with pain at the knee is modified by pain at other sites in those with knee osteoarthritis. AB - The objective of this study was to investigate the associations of knee structural abnormalities with different patterns of pain. A total of 891 participants (average age 63 years; range 50 to 80 years) participated in this study. Presence of pain at the neck, back, hands, shoulders, hips, knees, and feet was assessed by questionnaire. Participants were categorized as having no pain at any site (no pain), pain only at the knee (KP), pain at other sites but not the knee (OP), and pain at the knee and other sites (KOP). T1-weighted or T2 weighted MRI of the right knee was performed to measure cartilage defects, bone marrow lesions (BMLs), and effusion-synovitis. Osteophytes and joint space narrowing were assessed by X-ray. KP, KOP, and OP were, respectively, present in 3, 43, and 42% of the participants. In multivariable analyses, KOP was associated with the presence of cartilage defects, BMLs, and osteophytes (OR 3.57 (95% CI 1.78 to 7.14), 2.37 (1.27 to 4.43), and 2.87 (1.10 to 7.51), respectively) in those with radiographic knee OA. KP was also associated with presence of these structural abnormalities as well as effusion-synovitis, and these associations were much stronger. The associations between structural abnormalities and KOP were weaker than those with KP in those with radiographic knee OA. This suggests that mechanisms mediating the association between structural pathology, localized, and generalized pain may be different, and central sensitization is possibly involved in generalized pain. Pain at other sites needs to be considered in the management and treatment of OA-related pain. PMID- 28918595 TI - Successful pregnancy in a CKD patient on a low-protein, supplemented diet: an opportunity to reflect on CKD and pregnancy in Mexico, an emerging country. AB - Pregnancy is probably the most important challenge in young women with chronic kidney disease (CKD). The challenge is greater in developing countries, in which access to dialysis is uneven, and prenatal care for CKD patients is not uniformly available. This case report summarizes some of the challenges faced by pregnant CKD women in a developing country. A 35-year-old woman, affected by an undiagnosed kidney disease, experienced preeclampsia at 24 years of age, and started dialysis in emergency at age 31 in the context of severe preeclampsia in her second pregnancy. Following slow recovery of kidney function, after 18 months of dialysis she started a moderately restricted, supplemented, low-protein diet, which allowed her to discontinue dialysis. A few months after dialysis discontinuation, she started a new pregnancy in the presence of severely reduced kidney function (serum creatinine 4.6 mg/dl at the last pre-pregnancy control). Interestingly, she discontinued nephrology and nutritional follow-up, mainly because she was worried that she would be discouraged from continuing the pregnancy, but also because she continued to feel well. She self-managed her diet in pregnancy and delivered a healthy baby, with normal intrauterine growth, at term; while the last laboratory data confirmed the presence of severe kidney function impairment, she is still dialysis-free at the time of the present report. Her story, with its happy ending, underlines the importance of dedicated programs for CKD pregnancies in developing countries and confirms the safety of moderately protein-restricted diets in pregnancy. PMID- 28918596 TI - CD5+ B lymphocytes in systemic lupus erythematosus patients: relation to disease activity. AB - B cells are essential players in the pathogenic mechanisms of systemic lupus erythematosus (SLE). Although CD5+ B cells have been considered to play a paradoxical role in preventing, rather than inducing autoimmunity, there is no consensus agreement about the proportions of CD5+ B cells population in SLE patients. So, the aim of the present study was to assess blood concentration of CD5+ B cells in patients with SLE and to evaluate their relationship with disease activity and organ damage. We recruited 100 SLE patients and 100 healthy control subjects. Based on SLE disease activity index (SLEDAI), patients were divided into two groups: active SLE (n = 50) and inactive SLE (n = 50). SLE was active when SLEDAI was >= 4. The expression of CD5+ B cells was evaluated using flow cytometry to measure the proportions and absolute numbers of the cells. The proportions of CD5+ B cells of total lymphocytes were significantly lower in SLE patients versus controls (4.1 +/- 3.9 vs 10.8 +/- 5.2%, P = <0.001). CD5+ B cells were significantly decreased in active SLE patients (3.1 +/- 2.7%) in comparison to inactive patients (5.2 +/- 3.7%) (P = 0.013). CD5+ B cells correlated positively with C3 (r = 0.328, P = 0.020) and C4 (r = 0.355, P = 0.011). CD5+ B cells were significantly decreased in SLE patients compared to healthy controls and they were significantly decreased in active SLE patients in comparison to inactive ones. PMID- 28918597 TI - Effect of vibration on postural control and gait of elderly subjects: a systematic review. AB - BACKGROUND AND AIM: Gait and balance disorders are common in the elderly populations, and their prevalence increases with age. This systematic review was performed to summarize the current evidence for subthreshold vibration interventions on postural control and gait in elderly. METHOD: A review of intervention studies including the following words in the title/abstract: insole, foot and ankle appliances, vibration, noise and elderly related to balance and gait. Databases searched included PubMed, ISI Web of Knowledge, Ovid, Scopus, and Google Scholar. Fifteen articles were selected for final evaluation. The procedure was followed using the preferred reporting items for systematic reviews and meta-analysis method. RESULTS: There was reduction in center of pressure velocity and displacement especially with eyes closed using vibration in healthy elderly subjects and this effect was greater in elderly faller and patients with more balance deficiency. Vibration programme training increased speed of walking, cadence, step time and length in stroke subjects. The vibratory insoles significantly improved performance on the Timed Up and Go and Functional Reach tests in older people. CONCLUSION: Vibration was effective on balance improvement in elderly subject especially elderly with more balance deficiency and it can improve gait parameters in patients with greater baseline variability. PMID- 28918598 TI - Triacsin C reduces lipid droplet formation and induces mitochondrial biogenesis in primary rat hepatocytes. AB - Intracellular long-chain acyl-CoA synthetases (ACSL) activate fatty acids to produce acyl-CoA, which undergoes beta-oxidation and participates in the synthesis of esterified lipids such as triacylglycerol (TAG). Imbalances in these metabolic routes are closely associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Triacsin C is one of the few compounds that inhibit TAG accumulation into lipid droplets (LD) by suppressing ACSL activity. Here we report that treatment of primary rat hepatocytes with triacsin C at concentrations lower than the IC50 (4.1 MUM) for LD formation: (i) diminished LD number in a concentration-dependent manner; (ii) increased mitochondrial amount; (iii) markedly improved mitochondrial metabolism by enhancing the beta-oxidation efficiency, electron transport chain capacity, and degree of coupling - treatment of isolated rat liver mitochondria with the same triacsin C concentrations did not affect the last two parameters; (iv) decreased the GSH/GSSG ratio and elevated the protein carbonyl level, which suggested an increased reactive oxygen species production, as observed in isolated mitochondria. The hepatocyte mitochondrial improvements were not related to either the transcriptional levels of PGC-1alpha or the content of mTOR and phosphorylated AMPK. Triacsin C at 10 MUM induced hepatocyte death by necrosis and/or apoptosis through mechanisms associated with mitochondrial permeability transition pore opening, as demonstrated by experiments using isolated mitochondria. Therefore, triacsin C at sub-IC50 concentrations modulates the lipid imbalance by shifting hepatocytes to a more oxidative state and enhancing the fatty acid consumption, which can in turn accelerate lipid oxidation and reverse NAFLD in long-term therapies. PMID- 28918599 TI - Optimal affinity ranking for automated virtual screening validated in prospective D3R grand challenges. AB - The goal of virtual screening is to generate a substantially reduced and enriched subset of compounds from a large virtual chemistry space. Critical in these efforts are methods to properly rank the binding affinity of compounds. Prospective evaluations of ranking strategies in the D3R grand challenges show that for targets with deep pockets the best correlations (Spearman rho ~ 0.5) were obtained by our submissions that docked compounds to the holo-receptors with the most chemically similar ligand. On the other hand, for targets with open pockets using multiple receptor structures is not a good strategy. Instead, docking to a single optimal receptor led to the best correlations (Spearman rho ~ 0.5), and overall performs better than any other method. Yet, choosing a suboptimal receptor for crossdocking can significantly undermine the affinity rankings. Our submissions that evaluated the free energy of congeneric compounds were also among the best in the community experiment. Error bars of around 1 kcal/mol are still too large to significantly improve the overall rankings. Collectively, our top of the line predictions show that automated virtual screening with rigid receptors perform better than flexible docking and other more complex methods. PMID- 28918600 TI - Morphology and size of blood cells of Rhinella arenarum (Hensel, 1867) as environmental health assessment in disturbed aquatic ecosystem from central Argentina. AB - Four populations of Rhinella arenarum from aquatic environments with different degrees of disturbance in central Argentina were compared to assess the ability of cytomorphology and cytomorphometry of blood cells as a hematological biomarker. A total of 93 specimens of R. arenarum (adults sexually mature) were captured during the spring. From the analysis of cell, no variations were found in terms of morphology, whereas in nuclear and cell areas and Price-Jones curves, we observed a smaller size in erythrocytes of individuals inhabiting the site most altered, "Villa Dalcar," as well as for leukocytes, lymphocytes, neutrophils, and eosinophils for the same site. This could be caused by presence of different pollutants in the lake. Furthermore, this was confirmed by the high levels of environmental variables (conductivity, total dissolved solids, and salinity) show that Villa Dalcar is the site most affected by human activities. PMID- 28918601 TI - Effects of phoxim-induced hepatotoxicity on SD rats and the protection of vitamin E. AB - Currently, public pay more attention to the adverse effect of organophosphate pesticides on human and animal health and on the environment in developing nations. Vitamin E may protect the hepatocyte and increase the function of liver. The study was to investigate the effects of phoxim-induced hepatotoxicity on Sprague Dawley (SD) rats and the protection of vitamin E. SD rats received by gavage 180 mg kg-1 (per body weight) of phoxim, 200 mg kg-1 (per body weight) of vitamin E, and phoxim + vitamin E. The results showed that exposure to phoxim elevated liver coefficient; glutamyl transpeptidase (GGT), aspartate aminotransferase, alkaline phosphatase, total bilirubin, total bile acid, and alanine aminotransferase in the serum; ROS in the liver; and the expression of p53, Bax, CYP2E1, ROS, caspase-9, caspase-8, and caspase-3, while phoxim caused a reduction of total protein, albumin, and cholinesterase in the serum; acetylcholinesterase, total antioxidant capacity, glutathione peroxidase, and glutathione in the liver; and the expression of Bcl-2. Vitamin E modified the phoxim-induced hepatotoxicity by reducing the GGT in the serum, malondialdehyde in the liver, and the expression of CYP2E1 significantly. There were no significant changes of globulin in the serum, the activity of catalase in the liver, as well as expression levels of Fas and Bad in the liver. Overall, subacute exposure to phoxim induced hepatic injury, oxidative stress damage, and cell apoptosis. Vitamin E modified phoxim-induced hepatotoxicity slightly. And, vitamin E minimized oxidative stress damage and ultrastructural changes in rat hepatocytes notably. PMID- 28918602 TI - Population Pharmacokinetics and Optimal Sampling Strategy for Model-Based Precision Dosing of Melphalan in Patients Undergoing Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy. METHODS: A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m2 by intravenous infusion. The determinant-optimal sampling strategy was explored with PopED software. Individual area under the curve estimates were generated by Bayesian estimation using full and the proposed sparse sampling data. The predictive performance of the optimal sampling strategy was evaluated based on bias and precision estimates. The feasibility of the optimal sampling strategy was tested using pharmacokinetic data from five pediatric patients. RESULTS: A two compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33 0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R 2 = 0.98; p < 0.01) with a mean bias of 2.2% and precision of 9.4%. A similar relationship was observed in children (R 2 = 0.99; p < 0.01). CONCLUSIONS: The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing. PMID- 28918603 TI - Tumor markers of uterine cervical cancer: a new scenario to guide surgical practice? AB - Since the introduction of Pap smear screening, the incidence and mortality of cervical cancer (CC) have been reduced drastically in USA and in other western states. Nevertheless, CC still remains the main cause of death from gynecological cancer in developing countries where screening programs are scant or inexistent. This evidence highlights the efficacy of screening, and the wide use of Human Papilloma Viruses (HPV) vaccines in developed countries. More and more people are, consequentially, undergoing a screening procedure, usually combined with HPV DNA test, increasing the early diagnosis of intraepithelial HPV-related lesions. The long transit time from early cervical lesion to invasive cancer provides an opportunity to identify pre-cancerous lesions where treatment result is maximum. In fact, when an invasive CC occurs, the overall survival rate strictly depends on stage of disease with an average survival of 70% at 5 years. Under the pressure of this reality, researches have made efforts to individuate cancer markers as indicator of specific cancer events. Some markers were showed to be able to detect those intraepithelial lesions have more chance to evolve to invasive forms (p16ink4a, p16, E-cadherin, Ki67, pRb, p53). Markers such as CEA, SCC-Ag, CD44, have been developed to detect invasive forms. Although cancer markers actually are not used only for early diagnosis, they may be useful in others fields of application such as evaluation and monitoring of treatments to improve diagnosis and treatment of CC. PMID- 28918604 TI - Symptom experience of multiple myeloma (syMMex) patients treated with autologous stem cell transplantation following high-dose melphalan: a descriptive longitudinal study. AB - PURPOSE: High-dose melphalan and autologous stem cell transplantation (ASCT) are associated with high symptom burden. This study aimed to explore multiple myeloma (MM) patients' experience of symptom frequency, intensity, and distress during therapy. METHODS: This descriptive longitudinal study enrolled 29 MM patients who completed the 43-item PROVIVO questionnaire, measuring symptom experience across the dimensions of frequency, intensity, and distress at four assessment points: hospital admission (T0), leucocyte nadir (T1), discharge (T2), and 30 days post discharge (T3). Symptom assessment covered five categories: (1) physical, (2) emotional, (3) cognitive, (4) male/female urogenital symptoms, and (5) follow-up care planning (e.g., financial problems). Results were displayed as heat maps and bubble graphs for each patient, differences between T0 and T4 individually assessed, and intensity (IMS) and mean distress scores (DMS) calculated on a scale from 0 to 4. RESULTS: The most frequent, intense, and distressing physical symptoms were fatigue, diarrhea, and decreased appetite. As expected, peak symptom intensity (decreased appetite 2.79) and distress (diarrhea 2.11) were reported during high-dose melphalan and the leucocyte nadir (T1). Thereafter, most symptoms' intensity and distress improved. Items on urogenital symptoms remained predominantly unanswered or patients were sexually inactive. CONCLUSIONS: PROVIVO enabled exploration of various dimensions of MM patients' symptom experiences, which differed substantially before and after ASCT. Our results suggest that high-dose melphalan, ASCT, and other intensive novel agent therapies warrant targeted symptom management programs that include focused patient support. PMID- 28918605 TI - Food or threat? Wild capuchin monkeys (Sapajus libidinosus) as both predators and prey of snakes. AB - Snakes present a hazard to primates, both as active predators and by defensive envenomation. This risk might have been a selective pressure on the evolution of primate visual and cognitive systems, leading to several behavioral traits present in human and non-human primates, such as the ability to quickly learn to fear snakes. Primates seldom prey on snakes, and humans are one of the few primate species that do. We report here another case, the wild capuchin monkey (Sapajus libidinosus), which preys on snakes. We hypothesized that capuchin monkeys, due to their behavioral plasticity, and cognitive and visual skills, would be capable of discriminating dangerous and non-dangerous snakes and behave accordingly. We recorded the behavioral patterns exhibited toward snakes in two populations of S. libidinosus living 320 km apart in Piaui, Brazil. As expected, capuchins have a fear reaction to dangerous snakes (usually venomous or constricting snakes), presenting mobbing behavior toward them. In contrast, they hunt and consume non-dangerous snakes without presenting the fear response. Our findings support the tested hypothesis that S. libidinosus are capable of differentiating snakes by level of danger: on the one hand they protect themselves from dangerous snakes, on the other hand they take opportunities to prey on non-dangerous snakes. Since capuchins and humans are both predators and prey of snakes, further studies of this complex relationship may shed light on the evolution of these traits in the human lineage. PMID- 28918607 TI - Modeling the pH and temperature dependence of aqueousphase hydroxyl radical reaction rate constants of organic micropollutants using QSPR approach. AB - Designing of advanced oxidation process (AOP) requires knowledge of the aqueous phase hydroxyl radical (?OH) reactions rate constants (k OH), which are strictly dependent upon the pH and temperature of the medium. In this study, pH- and temperature-dependent quantitative structure-property relationship (QSPR) models based on the decision tree boost (DTB) approach were developed for the prediction of k OH of diverse organic contaminants following the OECD guidelines. Experimental datasets (n = 958) pertaining to the k OH values of aqueous phase reactions at different pH (n = 470; 1.4 * 106 to 3.8 * 1010 M-1 s-1) and temperature (n = 171; 1.0 * 107 to 2.6 * 1010 M-1 s-1) were considered and molecular descriptors of the compounds were derived. The Sanderson scale electronegativity, topological polar surface area, number of double bonds, and halogen atoms in the molecule, in addition to the pH and temperature, were found to be the relevant predictors. The models were validated and their external predictivity was evaluated in terms of most stringent criteria parameters derived on the test data. High values of the coefficient of determination (R 2) and small root mean squared error (RMSE) in respective training (> 0.972, <= 0.12) and test (>= 0.936, <= 0.16) sets indicated high generalization and predictivity of the developed QSPR model. Other statistical parameters derived from the training and test data also supported the robustness of the models and their suitability for screening new chemicals within the defined chemical space. The developed QSPR models provide a valuable tool for predicting the ?OH reaction rate constants of emerging new water contaminants for their susceptibility to AOPs. PMID- 28918606 TI - Kinetic coupling of phosphate release, force generation and rate-limiting steps in the cross-bridge cycle. AB - A basic goal in muscle research is to understand how the cyclic ATPase activity of cross-bridges is converted into mechanical force. A direct approach to study the chemo-mechanical coupling between Pi release and the force-generating step is provided by the kinetics of force response induced by a rapid change in [Pi]. Classical studies on fibres using caged-Pi discovered that rapid increases in [Pi] induce fast force decays dependent on final [Pi] whose kinetics were interpreted to probe a fast force-generating step prior to Pi release. However, this hypothesis was called into question by studies on skeletal and cardiac myofibrils subjected to Pi jumps in both directions (increases and decreases in [Pi]) which revealed that rapid decreases in [Pi] trigger force rises with slow kinetics, similar to those of calcium-induced force development and mechanically induced force redevelopment at the same [Pi]. A possible explanation for this discrepancy came from imaging of individual sarcomeres in cardiac myofibrils, showing that the fast force decay upon increase in [Pi] results from so-called sarcomere 'give'. The slow force rise upon decrease in [Pi] was found to better reflect overall sarcomeres cross-bridge kinetics and its [Pi] dependence, suggesting that the force generation coupled to Pi release cannot be separated from the rate-limiting transition. The reasons for the different conclusions achieved in fibre and myofibril studies are re-examined as the recent findings on cardiac myofibrils have fundamental consequences for the coupling between Pi release, rate-limiting steps and force generation. The implications from Pi induced force kinetics of myofibrils are discussed in combination with historical and recent models of the cross-bridge cycle. PMID- 28918608 TI - Unorthodox right parasternal imaging saves the day. PMID- 28918610 TI - The Role of TNF-alpha in Aflatoxin B-1 Induced Hepatic Toxicity in Isolated Perfused Rat Liver Model. AB - Aflatoxin B-1 (AFB1) is one of the major mycotoxins causing food contamination. Previous studies have shown that AFB1 can induce carcinogenicity and toxic effects in the isolated perfused rat liver and these effects are associated with its metabolites and peroxidation activity. Here we surveyed whether these pathogenic effects of AFB1 are associated with TNF-alpha as an inflammatory cytokine in general liver damages. In this study, we used twenty male Wistar rats (250-300 g). Rats were divided into four groups. Control group was pre-treated with LPS and then perfused with KHBB. The second group was pretreated with PTX and LPS and then perfused with KHB. The third group was pre-treated with LPS and then perfused with AFB-1 and KHB. The last group was pretreated with LPS and PTX and then perfused with AFB1 and KHB. Results revealed that aflatoxin B1 significantly increased the enzyme activity of aminotransferase and levels of lipid peroxidation. Also, the levels of Glutathione decreased in the aflatoxin group significantly. TNF-alpha released in perfusate and increased in aflatoxin B1 group significantly and decreased in AFB-1+PTX. Exposure to Aflatoxin B1 may induce reactive oxygen species, so these species may induce overproduction of proinflammatory cytokines such as TNF-alpha and may cause more damage to hepatic cells. PMID- 28918611 TI - Anti-Melanogenic Activity and Cytotoxicity of Pistacia vera Hull on Human Melanoma SKMEL-3 Cells. AB - Pistacia vera seed is a common food and medicinal seed in Iran. It's hull (outer skin) as a significant byproduct of pistachio, is traditionally used as tonic, sedative and antidiarrheal and has been shown to be a rich source of antioxidants. The aim of the present study is to evaluate the anti-melanogenic activity of the pistachio hulls in order to discover a new alternative herbal agent to treat skin hyperpigmentation disorders. In this work, antioxidant and anti-tyrosinase activity of MeOH extract from Pistacia vera hull (MPH) were evaluated in vitro, respectively, by DPPH radical scavenging and mushroom tyrosinase activity assays. Then the effect of MPH on the melanin content, cellular tyrosinase activity and cytotoxicity (MTT assay) on human melanoma SKMEL 3 cell were determined followed by 72 h incubation. The results indicated that MPH had valuable DPPH radical scavenging effect and weak anti-tyrosinase activity when compared to the well-known antioxidant (BHT) and tyrosinase inhibitor (kojic acid), respectively. MPH, at a high dose (0.5 mg/mL), showed significant cytotoxic activity (~63%) and strong anti-melanogenic effect (~57%) on SKMEL-3 cells. The effect of MPH in the reduction of melanin content may be related to its cytotoxicity. The results obtained suggest that MPH can be used as an effective agent in the treatment of some skin hyperpigmentation disorders such as melanoma. PMID- 28918609 TI - Associations among Gastric Juice pH, Atrophic Gastritis, Intestinal Metaplasia and Helicobacter pylori Infection. AB - Background/Aims: Gastric juice plays a crucial role in the physiology of the stomach. The aim of this study is to evaluate associations among the pH of gastric juice, atrophic gastritis (AG), intestinal metaplasia (IM), pepsinogen, and Helicobacter pylori infection. Methods: Gastric biopsies and juice were collected from 46 subjects who underwent endoscopies at Seoul National University Bundang Hospital between November 2011 and March 2013. H. pylori, AG and IM were evaluated, and pepsinogen I or II, I/II ratio, and interleukin (IL)-1beta levels were measured. Results: The mean pH of gastric juice was higher in the H. pylori positive group (n=17) than that in the H. pylori-negative group (n=29) (4.54 vs 2.46, p=0.002). When patients were divided into pH <3 (n=28) and pH >=3 (n=18) groups, H. pylori was lower in the pH <3 group (21.4%) than in the pH >=3 group (61.1%) (p=0.007). The pH >=3 group demonstrated AG and IM more frequently than the pH <3 group in the body (p=0.047 and p=0.051, respectively) but not in the antrum. There were no differences in pepsinogen I or II, I/II ratio, and IL-1beta levels between the two groups. Conclusions: There is a relationship between chronic H. pylori infection and gastric juice pH >=3, which may originate from AG and IM in the body. PMID- 28918612 TI - Increase Concentration of Transforming Growth Factor Beta (TGF-beta) in Breast Milk of Mothers With Psychological Disorders. AB - Several studies have shown an imbalance between proinflammatory and anti inflammatory cytokines in depression and anxiety disorders. However, less attention has been paid to the role of cytokines in psychological disorder in mothers who breastfeed. This study looks at whether concentration levels of TGF beta2 are altered in anxious and depressive breastfeeding mothers. This study checked the concentration level of TGF-B2 in relation with psychological symptoms on 110 breastfeeding mothers; based on random sampling method with using of Beck Depression Inventory (BDI), General Health Questionnaire (GHQ) and Spielberger Stress Scale (STAI) in 2015 also TGF-beta2 was measured in breast milk using ELISA. We used of Pearson Correlation Method, independent t-test and one-way analysis of variance (ANOVA) to analyze the data. Psychological symptoms (Anxiety and depression) showed positive correlation with TGF-Beta level in which relationships were significant (P=0.01). Psychological problems may be uniquely associated with the level of TGF-beta in breast milk. More attention should be paid to the mental health of mothers during breastfeeding, and more research needs to be done in this subject to clarify the relationship between psychological variables with the level of TGF-beta in breast milk. PMID- 28918613 TI - Predicting Time to Reflux of Children With Antenatal Hydronephrosis: A Competing Risks Approach. AB - The aim of this study was describing methodological aspects and applying a trivariate Weibull survival model using the competing risks concept to predict time to occurrence different types of reflux (unilateral (left, right) or bilateral) in children with antenatal hydronephrosis. Data from 333 children in Pediatric Urology Research Center of Children's Hospital Medical Center, affiliated with Tehran University of Medical Sciences was used. The effect of some demographic and clinical factors on child's reflux was studied. The assumption of independent between times of different types of reflux was evaluated. Of infants 80.5% were boy. The percentage of children experienced right, left and bilateral reflux or have been censored are 15.3%, 14.1%, 60.4% and 10.2% respectively. For the time of left reflux, variables, Week of diagnosis ANH, UC, UA, HUN, HN, APD_Right, Direction of ANH, CA19-9 baby, Urethra were significant. For the time of right reflux, variables, constipation, UC, UA, HUN, APD_Right, Direction and Severity of ANH, Bladder, and finally for the time of bilateral reflux, variables, Week of diagnosis ANH, Gender, UA, HUN, HN, APD_Left, Urethra, and Bladder were significant P<0.05. In the presence of competing risks, it is inappropriate to use the Kaplan-Meier method and standard Cox model which do not take competing risks into account. Trivariate Weibull survival model using competing risks not only is able to calculate the hazard rate of variables with different type of events but also it will be able to compare the hazard rate within the same type of event with different covariates. PMID- 28918614 TI - Modifiable Co-Morbidities Trends During Hospital Admissions for Obesity in France (2009-2014). AB - Obesity is a growing public health problem in France, but modifiable co morbidities in obese patients during their hospital admissions excluding bariatric surgery are lacking. Data were extracted from the French national hospital discharge database. Data on patient admissions, age, gender, and length of stay were extracted by selecting any stay coded primary as obesity. Obesity was defined as body mass index (BMI) between 30-39 kg/m2, and morbid obesity as BMI>=40 kg/m2. Only modifiable co-morbidities frequently diagnosed during the 6 year period with a rate>=3% were chosen. The admission rate for obesity decreased by 27.2% (P<0.001) with more females than males (71.9% vs. 28.1 %; P<0.001). The main modifiable co-morbidities were hypertension (22.72%), sleep apnea (13.64%), diabetes (12.34%), vitamin D deficiency (7.09%), hyperlipidemia (6.9%), hypercholesterolemia (4.98%), and nonalcoholic steatohepatitis (4.94%). Significant decreases were observed for hypertension (14.5%), diabetes (20%), hypercholesterolemia (30%) with steeper increase for vitamin D deficiency (830.7%) and nonalcoholic steatohepatitis (165.2%). Considering obesity class, admission for obesity (BMI: 30-40 kg/m2) and morbid obesity (BMI>=40 kg/m2) increased (P<0.001) by 6% and 7% respectively. Taking into account severity in proportion, stay>3 days significantly increased by 29.2% (P<0.001). The increase in the proportion of morbid obesity, vitamin D deficiency, and nonalcoholic steatohepatitis adds further evidence on the likely adverse health consequences of modifiable obesity-related comorbidities. There is a need for Health Authorities to promoting healthy lifestyle. PMID- 28918615 TI - Predicting Difficult Laryngoscopy and Intubation With Laryngoscopic Exam Test: A New Method. AB - Airway assessment is fundamental skill for anesthesiologists and failure to maintain a patient's airway is the tremendous cause of anesthesia-related morbidity and mortality. None of the tests which have recommended for predicting difficult intubation stands out to be the best clinical test or have high diagnostic accuracy. Our study aimed to determine the utility of a new test as "laryngoscopic exam test (LET)" in predicting difficult intubation. Three hundred and eleven patients aged 16-60 years participated and completed the study. Airway assessment was carried out with modified Mallampati test, upper lip bit test and LET preoperatively, and Cormack and Lehane's grading of laryngoscopy were assessed during intubation as a gold standard, and difficult laryngoscopy was considered as Cormack and Lehane's grade IotaIotaIota or IotaV of laryngoscopic view. The incidence of difficult intubation was 6.1%. The LET showed higher sensitivity, specificity, and accuracy (P<0.05), without revealing significant differences among three tests (P=0.375). The LET is a simple bedside test and an alternative method for predicting difficult intubation. PMID- 28918616 TI - Trainee-Associated Factors and Proficiency at Percutaneous Nephrolithotomy. AB - Percutaneous nephrolithotomy (PNL) is a complicated procedure for urology trainees. This study was designed to investigate the effect of trainees' ages and previous experience, as well as the number of operated cases, on proficiency at PNL by using patient outcomes. A cross sectional observational study was designed during a five-year period. Trainees in PNL fellowship programs were included. At the end of the program, the trainees' performance in PNL was assessed regarding five competencies and scored 1-5. If the overall score was 4 or above, the trainee was considered as proficient. The trainees' age at the beginning of the program and the years passed from their residency graduation were asked and recorded. Also, the number of PNL cases operated by each trainee was obtained via their logbooks. The age, years passed from graduation, and number of operated cases were compared between two groups of proficient and non-proficient trainees. Univariate and multivariate binary logistic regression analysis was applied to estimate the effect of aforementioned variables on the occurrence of the proficiency. Forty-two trainees were included in the study. The mean and standard deviation for the overall score were 3.40 (out of 5) and 0.67, respectively. Eleven trainees (26.2%) recognized as proficient in performing PNL. Univariate regression analysis indicated that each of three variables (age, years passed from graduation and number of operated cases) had statistically significant effect on proficiency. However, the multivariate regression analysis revealed that just the number of cases had significant effect on achieving proficiency. Although it might be assumed that trainees' age negatively correlates with their scores, in fact, it is their amount of practice that makes a difference. A certain number of cases is required to be operated by a trainee in order to reach the desired competency in PNL. PMID- 28918617 TI - Right Ventricular Thrombosis Combined With Fetal Death and Acrocyanosis in Pregnancy. AB - Prepartum or postpartum right ventricular thrombosis (RVT) is an exceedingly rare and potentially lethal phenomenon in pregnancy. We here report a case of a pregnant patient with near term pregnancy admitted for dyspnea, amniotic fluids discharge and labor pain in a gynecology center that an eight-month dead fetus was diagnosed and delivered vaginally by induction. A post delivery period was complicated by aggravation of her dyspnea and pleuritic chest pain that she referred for further evaluation in our cardiac center. Physical exam revealed normal head and neck exam, and history taking revealed that her fetus had intra uterine growth failure as reported by her gynecologist. Chest exam except to left lung crackle was normal. Lower and upper left extremities were normal. However, acrocyanosis was found in tips of 4 and 5th right-hand digits. Chest x-ray revealed some linear consolidation in left lower lung lobes, and the precordial exam was normal. ECG was normal. Post delivery transthoracic echocardiography (TEE) showed a 1.5*1.5 cm mobile right ventricular clot. C-T angiography revealed obstruction of left upper lung pulmonary artery branches. Complete thrombophilia assay showed the presence of high titer of antiphospholipid, anticardiolipin antibody, and beta1 glycoprotein antibody. However, others test were normal. The patient was scheduled for cardiac surgery, and her hemodynamic was monitored by left radial artery line and central pressure venous line, and thrombus was removed from the right ventricle (RV), and subsequent anticoagulation therapy constituted. Six-month follow-up revealed no recurrence of thrombus and recovery of patient's symptoms. PMID- 28918618 TI - Concurrent Oncocytoma and Two Angiomyolipomas in a Diabetic Kidney: A Very Rare Condition. AB - Angiomyolipoma (AML) and oncocytoma are uncommon benign neoplasms of the kidney which their simultaneous occurrence in the same kidney is extremely rare. This study reports a 60-year-old diabetic woman with the rare simultaneous occurrence of three renal masses. Histologic evaluation revealed two angiomyolipomas and one oncocytoma within the same kidney, in a background of histologic features of diabetic nephropathy. Renal angiomyolipoma and oncocytoma are uncommon neoplasms, and their simultaneous occurrence in the same kidney is extremely rare. PMID- 28918619 TI - Discoid Lupus Erythematosus Presenting as Upper Eyelid Edema and Erythema. AB - Discoid Lupus Erythematosus (DLE) is an autoimmune disorder that usually occurs on sun exposed areas of head and neck. Infrequently it could be presented by palpebral involvement and rarely unilateral upper eye lid edema and erythema have been reported as the sole manifestation of DLE. We describe a 38-year-old woman with chronic left upper eye lid edema and erythema from one year ago which was induced by steroid injection for left eyebrow alopecia. Histopathologic and direct immunofluorescent studies were made on palpebral skin tissue and confirmed DLE diagnosis. Antinuclear antibody (ANA) titer was 1/160 with speckled pattern. She was treated by oral hydroxychloroquine (400 mg daily) with moderate improvement after three months. We should think about DLE in cases with chronic upper eye lid edema and erythema. The aim of this case report is to emphasize that ophthalmologist and dermatologists should be aware of different presentations of DLE in the periorbital area to prevent misdiagnosis. PMID- 28918620 TI - Conservative Management of Colonoscopic Perforation: A Case Report. AB - Colonoscopy is widely used for the diagnosis, treatment and a follow up of colorectal diseases. Perforation of the large bowel during elective colonoscopy is rare but serious life threatening complication. We report a 51-year-old woman who experienced recto sigmoid perforation during diagnostic colonoscopy. During 8 days of total hospitalization, she spent 3 days in ICU with gastrointestinal rest. The patient was hydrated and took intravenous antibiotics. In take-output and temperature were closely monitored. Serial abdominal examinations were performed to rule out peritonitis. After transferring to surgery ward in the day 4, liquid diet started slowly, and she was ambulated. At the day 8, she was discharged with the good clinical condition. Conservative management of the patients with early diagnosis of perforation and no signs and symptoms of peritonitis or sepsis could be the modality of choice. PMID- 28918621 TI - Parameters Contributing to Aging: Avicenna's Viewpoints. PMID- 28918622 TI - Emission Changes Dwarf the Influence of Feeding Habits on Temporal Trends of Per- and Polyfluoroalkyl Substances in Two Arctic Top Predators. AB - We monitored concentrations of per- and polyfluoroalkyl substances (PFASs) in relation to climate-associated changes in feeding habits and food availability in polar bears (Ursus maritimus) and arctic foxes (Vulpes lagopus) (192 plasma and 113 liver samples, respectively) sampled from Svalbard, Norway, during 1997-2014. PFASs concentrations became greater with increasing dietary trophic level, as bears and foxes consumed more marine as opposed to terrestrial food, and as the availability of sea ice habitat increased. Long-chained perfluoroalkyl carboxylates (PFCAs) in arctic foxes decreased with availability of reindeer carcasses. The ~9-14% yearly decline of C6-8 perfluoroalkyl sulfonates (PFSAs) following the cease in C6-8 PFSA precursor production in 2001 indicates that the peak exposure was mainly a result of atmospheric transport of the volatile precursors. However, the stable PFSA concentrations since 2009-2010 suggest that Svalbard biota is still exposed to ocean-transported PFSAs. Long-chain ocean transported PFCAs increased 2-4% per year and the increase in C12-14 PFCAs in polar bears tended to level off since ~2009. Emerging short-chain PFASs showed no temporal changes. Climate-related changes in feeding habits and food availability moderately affected PFAS trends. Our results indicate that PFAS concentrations in polar bears and arctic foxes are mainly affected by emissions. PMID- 28918623 TI - Intermolecular Radical Addition to Carbonyls Enabled by Visible Light Photoredox Initiated Hole Catalysis. AB - Herein, we present a novel strategy for the utilization of simple carbonyl compounds, aldehydes and ketones, as intermolecular radical acceptors. The reaction is enabled by visible light photoredox initiated hole catalysis and the in situ Bronsted acid activation of the carbonyl compound. This regioselective alkyl radical addition reaction does not require metals, ligands or additives and proceeds with a high degree of atom economy under mild conditions. The proposed mechanism is supported by both experimental and theoretical studies. PMID- 28918624 TI - Synthesis of Oligodiacetylene Derivatives from Flexible Porous Coordination Frameworks. AB - Oligodiacetylenes (ODAs) with alternating ene-yne conjugated structure are significant materials for optical and electronic properties. Due to the low solubility of ODAs in common solvents, the synthetic approaches are limited. Here we disclose a new synthetic approach of ODAs without a side alkyl chain using a porous coordination polymer (PCP) as a sacrificial template. 1,2-Bis(4 pyridyl)butadiyne, which works as a monomer, was embedded in the flexible framework of the PCP, and ODAs were synthesized via utilization of the anisotropic thermal expansion of the PCP crystal. The oligomeric state of ODAs depends on the metal ion and coligand of the precursor. PMID- 28918625 TI - On the Negative Surface Tension of Solutions and on Spontaneous Emulsification. AB - The condition of negative surface tension of a binary regular solution is discussed in this paper using the recently reconfirmed Butler equation (Langmuir 2015, 31, 5796-5804). It is shown that the surface tension becomes negative only for solutions with strong repulsion between the components. This repulsion for negative surface tension should be so strong that this phenomenon appears only within a miscibility gap, that is, in a two-phase region of macroscopic liquid solutions. Thus, for a macroscopic solution, the negative surface tension is possible only in a nonequilibrium state. However, for a nano-solution, negative surface tension is also possible in equilibrium state. It is also shown that nano and microemulsions can be thermodynamically stable against both coalescence and phase separation. Further, the thermodynamic theory of emulsion stability is developed for a three-component (A-B-C) system with A-rich droplets dispersed in a C-rich matrix, separated by the segregated B-rich layer (the solubility of B is limited in both A and C while the mutual solubility of A and C is neglected). It is shown that when a critical droplet size is achieved by forced emulsification, it is replaced by spontaneous emulsification and the droplet size is reduced further to its equilibrium value. The existence of maximum temperature of emulsion stability is shown. Using low-energy emulsification below this maximum temperature, spontaneous emulsification can appear, which is enhanced with further decrease of temperature. This finding can be applied to interpret the experimental observations on spontaneous emulsification or for the design of stable micro- and nanoemulsions. PMID- 28918626 TI - Catalytic Carbonylative Rearrangement of Norbornadiene via Dinuclear Carbon Carbon Oxidative Addition. AB - Single bonds between carbon atoms are inherently challenging to activate using transition metals; however, ring-strain release can provide the necessary thermodynamic driving force to make such processes favorable. In this report, we describe a strain-induced C-C oxidative addition of norbornadiene. The reaction is mediated by a dinuclear Ni complex, which also serves as a catalyst for the carbonylative rearrangement of norbornadiene to form a bicyclo[3.3.0] product. PMID- 28918627 TI - In Situ Neutron Depth Profiling of Lithium Metal-Garnet Interfaces for Solid State Batteries. AB - The garnet-based solid state electrolyte (SSE) is considered a promising candidate to realize all solid state lithium (Li) metal batteries. However, critical issues require additional investigation before practical applications become possible, among which high interfacial impedance and low interfacial stability remain the most challenging. In this work, neutron depth profiling (NDP), a nondestructive and uniquely Li-sensitive technique, has been used to reveal the interfacial behavior of garnet SSE in contact with metallic Li through in situ monitoring of Li plating-stripping processes. The NDP measurement demonstrates predictive capabilities for diagnosing short-circuits in solid state batteries. Two types of cells, symmetric Li/garnet/Li (LGL) cells and asymmetric Li/garnet/carbon-nanotubes (LGC), are fabricated to emulate the behavior of Li metal and Li-free Li metal anodes, respectively. The data imply the limitation of Li-free Li metal anode in forming reliable interfacial contacts, and strategies of excessive Li and better interfacial engineering need to be investigated. PMID- 28918628 TI - Breaking Benzene Aromaticity-Computational Insights into the Mechanism of the Tungsten-Containing Benzoyl-CoA Reductase. AB - Aromatic compounds are environmental pollutants with toxic and carcinogenic properties. Despite the stability of aromatic rings, bacteria are able to degrade the aromatic compounds into simple metabolites and use them as growth substrates under oxic or even under anoxic conditions. In anaerobic microorganisms, most monocyclic aromatic growth substrates are converted to the central intermediate benzoyl-coenzyme A, which is enzymatically reduced to cyclohexa-1,5-dienoyl-CoA. The strictly anaerobic bacterium Geobacter metallireducens uses the class II benzoyl-CoA reductase complex for this reaction. The catalytic BamB subunit of this complex harbors an active site tungsten-bis-pyranopterin cofactor with the metal being coordinated by five protein/cofactor-derived sulfur atoms and a sixth, so far unknown, ligand. Although BamB has been biochemically and structurally characterized, its mechanism still remains elusive. Here we use continuum electrostatic and QM/MM calculations to model benzoyl-CoA reduction by BamB. We aim to elucidate the identity of the sixth ligand of the active-site tungsten ion together with the interplay of the electron and proton transfer events during the aromatic ring reduction. On the basis of our calculations, we propose that benzoyl-CoA reduction is initiated by a hydrogen atom transfer from a W(IV) species with an aqua ligand, yielding W(V)-[OH-] and a substrate radical intermediate. In the next step, a proton-assisted second electron transfer takes place with a conserved active-site histidine serving as the second proton donor. Interestingly, our calculations suggest that the electron for the second reduction step is taken from the pyranopterin cofactors rather than from the tungsten ion. The resulting cationic radical, which is distributed over both pyranopterins, is stabilized by conserved anionic amino acid residues. The stepwise mechanism of the reduction shows similarities to the Birch reduction known from organic chemistry. However, the strict coupling of protons and electrons allows the reaction to proceed under milder conditions. PMID- 28918629 TI - Dosimetric Quantification of Coating-Related Uptake of Silver Nanoparticles. AB - The elucidation of mechanisms underlying the cellular uptake of nanoparticles (NPs) is an important topic in nanotoxicological research. Most studies dealing with silver NP uptake provide only qualitative data about internalization efficiency and do not consider NP-specific dosimetry. Therefore, we performed a comprehensive comparison of the cellular uptake of differently coated silver NPs of comparable size in different human intestinal Caco-2 cell-derived models to cover also the influence of the intestinal mucus barrier and uptake-specialized M cells. We used a combination of the Transwell system, transmission electron microscopy, atomic absorption spectroscopy, and ion beam microscopy techniques. The computational in vitro sedimentation, diffusion, and dosimetry (ISDD) model was used to determine the effective dose of the particles in vitro based on their individual physicochemical characteristics. Data indicate that silver NPs with a similar size and shape show coating-dependent differences in their uptake into Caco-2 cells. The internalization of silver NPs was enhanced in uptake specialized M-cells while the mucus did not provide a substantial barrier for NP internalization. ISDD modeling revealed a fivefold underestimation of dose response relationships of NPs in in vitro assays. In summary, the present study provides dosimetry-adjusted quantitative data about the influence of NP coating materials in cellular uptake into human intestinal cells. Underestimation of particle effects in vitro might be prevented by using dosimetry models and by considering cell models with greater proximity to the in vivo situation, such as the M-cell model. PMID- 28918630 TI - Assessing the Reliability of Material Flow Analysis Results: The Cases of Rhenium, Gallium, and Germanium in the United States Economy. AB - Decision-makers traditionally expect "hard facts" from scientific inquiry, an expectation that the results of material flow analyses (MFAs) can hardly meet. MFA limitations are attributable to incompleteness of flowcharts, limited data quality, and model assumptions. Moreover, MFA results are, for the most part, based less on empirical observation but rather on social knowledge construction processes. Developing, applying, and improving the means of evaluating and communicating the reliability of MFA results is imperative. We apply two recently proposed approaches for making quantitative statements on MFA reliability to national minor metals systems: rhenium, gallium, and germanium in the United States in 2012. We discuss the reliability of results in policy and management contexts. The first approach consists of assessing data quality based on systematic characterization of MFA data and the associated meta-information and quantifying the "information content" of MFAs. The second is a quantification of data inconsistencies indicated by the "degree of data reconciliation" between the data and the model. A high information content and a low degree of reconciliation indicate reliable or certain MFA results. This article contributes to reliability and uncertainty discourses in MFA, exemplifying the usefulness of the approaches in policy and management, and to raw material supply discussions by providing country-level information on three important minor metals often considered critical. PMID- 28918632 TI - Analysis and Sensory Evaluation of the Stereoisomers of a Homologous Series (C5 C10) of 4-Mercapto-2-alkanols. AB - A homologous series of 4-mercapto-2-alkanols (C5-C10) was used to investigate the impact of the stereochemistry on the sensory properties of a class of naturally occurring polyfunctional thiols having a 1,3-oxygen-sulfur functionality. Stereoisomers were obtained via syntheses of racemic mixtures and subsequent lipase-catalyzed kinetic resolutions. Analytical separations of the stereoisomers were achieved by capillary gas chromatography (GC) using chiral stationary phases. The absolute configurations were assigned via NMR analysis. Sensory evaluations by means of GC/olfactometry revealed odor threshold minima for the medium-chain homologues (C7-C9) of the 4-mercapto-2-alkanol stereoisomers. Except for the C5 homologue, the lowest odor thresholds were determined for the (2R,4R) configured stereoisomers. The variability in odor qualities was mainly determined by the chain length. None of the 4-mercapto-2-alkanol stereoisomers showed consistent odor qualities for all homologues. PMID- 28918631 TI - Sequential Ruthenium Catalysis for Olefin Isomerization and Oxidation: Application to the Synthesis of Unusual Amino Acids. AB - How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging alpha-tri- and tetrasubstituted alpha-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam. PMID- 28918633 TI - Axisymmetric and Nonaxisymmetric Oscillations of Sessile Compound Droplets in an Open Digital Microfluidic Platform. AB - Manipulating droplets of biological fluids in an electrowetting on dielectric (EWOD)-based digital microfluidic platform is a significant challenge because of biofouling and surface contamination. This problem is often addressed by operating in an oil environment. We study an alternate configuration of sessile compound droplets having an aqueous core surrounded by a smaller oil shell. In contrast to the conventional EWOD platform, an open digital microfluidic platform enabled by the core-shell configuration will allow electrical, mechanical, or optical probes to get unrestricted access to the droplet, thus enabling highly flexible and dynamically reconfigurable lab-on-chip systems. Understanding droplet oscillations is essential as they are known to enhance mixing. To our knowledge, this is the first study of axisymmetric and nonaxisymmetric oscillations of compound droplets actuated using EWOD platforms. Mode shapes for both axisymmetric and nonaxisymmetric oscillations were studied and explained. Enhancement in the axisymmetric oscillation of the core by decreasing the shell volume was obtained experimentally and modeled theoretically. Smaller shell volumes reduce the damping losses, allowing the appearance of nonaxisymmetric modes over a larger range of operating parameters. The oscillation frequency regime for obtaining prominent nonaxisymmetric oscillations for different shell volumes was identified. Compound droplets provide a mechanism to reduce biofouling, sample contamination, and evaporation. We demonstrate axisymmetric and nonaxisymmetric oscillations of compound droplets with the biological core of red blood cells, providing crucial first steps for promoting applications such as rapid efficient assays, mixing of biological fluids, and fluidic photonics on hysteresis-free surfaces. PMID- 28918635 TI - Optimization of the Determination Method for Dissolved Cyanobacterial Toxin BMAA in Natural Water. AB - There is a serious dispute on the existence of beta-N-methylamino-l-alanine (BMAA) in water, which is a neurotoxin that may cause amyotrophic lateral sclerosis/Parkinson's disease (ALS/PDC) and Alzheimer' disease. It is believed that a reliable and sensitive analytical method for the determination of BMAA is urgently required to resolve this dispute. In the present study, the solid phase extraction (SPE) procedure and the analytical method for dissolved BMAA in water were investigated and optimized. The results showed both derivatized and underivatized methods were qualified for the measurement of BMAA and its isomer in natural water, and the limit of detection and the precision of the two methods were comparable. Cartridge characteristics and SPE conditions could greatly affect the SPE performance, and the competition of natural organic matter is the primary factor causing the low recovery of BMAA, which was reduced from approximately 90% in pure water to 38.11% in natural water. The optimized SPE method for BMAA was a combination of rinsed SPE cartridges, controlled loading/elution rates and elution solution, evaporation at 55 degrees C, reconstitution of a solution mixture, and filtration by polyvinylidene fluoride membrane. This optimized method achieved > 88% recovery of BMAA in both algal solution and river water. The developed method can provide an efficient way to evaluate the actual concentration levels of BMAA in actual water environments and drinking water systems. PMID- 28918634 TI - Engineered Probiotic for the Inhibition of Salmonella via Tetrathionate-Induced Production of Microcin H47. AB - Complications arising from antibiotic-resistant bacteria are becoming one of the key issues in modern medicine. Members of drug-resistant Enterobacteriaceae spp. include opportunistic pathogens (e.g., Salmonella spp.) that are among the leading causes of morbidity and mortality worldwide. Overgrowth of these bacteria is considered a hallmark of intestinal dysbiosis. Microcins (small antimicrobial peptides) produced by some gut commensals can potentially cure these conditions by inhibiting these pathogens and have been proposed as a viable alternative to antibiotic treatment. In this proof-of-concept work, we leverage this idea to develop a genetically engineered prototype probiotic to inhibit Salmonella spp. upon exposure to tetrathionate, a molecule produced in the inflamed gut during the course of Salmonella infection. We developed a plasmid-based system capable of conferring the ability to detect and utilize tetrathionate, while at the same time producing microcin H47. We transferred this plasmid-based system to Escherichia coli and demonstrated the ability of the engineered strain to inhibit growth of Salmonella in anaerobic conditions while in the presence of tetrathionate, with no detectable inhibition in the absence of tetrathionate. In direct competition assays between the engineered E. coli and Salmonella, the engineered E. coli had a considerable increase in fitness advantage in the presence of 1 mM tetrathionate as compared to the absence of tetrathionate. In this work, we have demonstrated the ability to engineer a strain of E. coli capable of using an environmental signal indicative of intestinal inflammation as an inducing molecule, resulting in production of a microcin capable of inhibiting the organism responsible for the inflammation. PMID- 28918636 TI - Soluble Protein and Amino Acid Content Affects the Foam Quality of Sparkling Wine. AB - Proteins and amino acids are known to influence the foam characteristics of sparkling wines. However, it is unclear to what extent they promote foam formation and/or stability. This study aimed to investigate the effect of protein content and amino acid composition, measured via the bicinchoninic acid assay and high-performance liquid chromatography, respectively, on the foaming properties of 28 sparkling white wines, made by different production methods. Foam volume and stability were determined using a robotic pourer and computer vision algorithms. Modifications were applied to the protein determination method involving the use of yeast invertase as a standard in order to improve quantification accuracy. The protein content was found to be significantly correlated to parameters representative of foam stability, as were the amino acids arginine, asparagine, histidine, and tyrosine. Additionally, the production method was found to influence the foam collar height, which favored foaming in Methode Traditionnelle wines over other those made by production methods. Understanding the contributions of key wine constituents to the visual and mouthfeel parameters of sparkling wine will enable more efficient production of high-quality wines. PMID- 28918637 TI - Branched-Selective Intermolecular Ketone alpha-Alkylation with Unactivated Alkenes via an Enamide Directing Strategy. AB - We describe a strategy for intermolecular branched-selective alpha-alkylation of ketones using simple alkenes as the alkylating agents. Enamides derived from isoindolin-1-one provide an excellent directing template for catalytic activation of ketone alpha-positions. High branched selectivity is obtained for both aliphatic and aromatic alkenes using a cationic iridium catalyst. Preliminary mechanistic study favors an Ir-C migratory insertion pathway. PMID- 28918638 TI - A Rapid Blood Test To Determine the Active Status and Duration of Acute Viral Infection. AB - The ability to rapidly detect and diagnose acute viral infections is crucial for infectious disease control and management. Serology testing for the presence of virus-elicited antibodies in blood is one of the methods used commonly for clinical diagnosis of viral infections. However, standard serology-based tests have a significant limitation: they cannot easily distinguish active from past, historical infections. As a result, it is difficult to determine whether a patient is currently infected with a virus or not, and on an optimal course of action, based off of positive serology testing responses. Here, we report a nanoparticle-enabled blood test that can help overcome this major challenge. The new test is based on the analysis of virus-elicited immunoglobulin G (IgG) antibody present in the protein corona of a gold nanoparticle surface upon mixing the gold nanoparticles with blood sera. Studies conducted on mouse models of influenza A virus infection show that the test gives positive responses only in the presence of a recent acute viral infection, approximately between day 14 and day 21 following the infection, and becomes negative thereafter. When used together with the traditional serology testing, the nanoparticle test can determine clearly whether a positive serology response is due to a recent or historical viral infection. This new blood test can provide critical clinical information needed to optimize further treatment and/or to determine if further quarantining should be continued. PMID- 28918640 TI - Supramolecular Interaction-Assisted Fluorescence and Tunable Stimuli Responsiveness of l-Phenylalanine-Based Polymers. AB - Supramolecular host-guest interactions between randomly methylated beta cyclodextrin (RM beta-CD) and side-chain phenylalanine (Phe) and Phe-Phe dipeptide-based homopolymers have been employed for the amplification of fluorescence emission of otherwise weakly fluorescent amino acid Phe. The host guest complex has been characterized by 1H and 13C NMR spectroscopy, two dimensional rotating-frame overhauser spectroscopy, Fourier-transform infrared spectroscopy, UV-visible spectroscopy, and fluorescence spectroscopy. To gain insights into the origin of fluorescence in homopolymers, density functional theory calculations were performed where phenyl moieties inside the less polar core of beta-CD were observed to form a pi-pi coupled complex resulting in an enhanced emission. Furthermore, the complex-forming ability of Phe, the guest molecule, has been employed in tuning the cloud point temperature (TCP) of statistical copolymers derived from side-chain Phe/Phe-Phe-based methacrylate monomers and N-isopropylacrylamide. By varying the co-monomer feed ratios in the statistical copolymer and hence the concentration of RM beta-CD throughout the polymer chain, host-guest interaction-assisted broad tunability in TCP of the supramolecular polymeric complex has been achieved. PMID- 28918639 TI - Identification of Novel Hydrogen-Substituted Polyfluoroalkyl Ether Sulfonates in Environmental Matrices near Metal-Plating Facilities. AB - Environmental occurrence and behaviors of 6:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-6:2 PFESA, with trade name F-53B) have been receiving increased attention recently. Nevertheless, its potential fates under diversified conditions remain concealed. In this study, susceptibility of Cl-6:2 PFESA to reductive dehalogenation was tested in an anaerobic super-reduced cyanocobalamin assay. A rapid transformation of dosed Cl-6:2 PFESA was observed, with a hydrogen substituted polyfluoroalkyl ether sulfonate (1H-6:2 PFESA) identified as the predominant product by a nontarget screening workflow. With the aid of laboratory purified standards, hydrogen-substituted PFESA analogues (i.e., 1H-6:2 and 1H-8:2 PFESA) were further found in river water and sediment samples collected from two separate regions near metal-plating facilities. Geometric mean concentrations of 560 pg/L (river water) and 11.1 pg/g (sediment) for 1H-6:2 PFESA and 11.0 pg/L (river water) and 7.69 pg/g (sediment) for 1H-8:2 PFESA were measured, and both analytes consisted average compositions of 1% and 0.1% among the 18 monitored per and polyfluoroalkyl sulfonate and carboxylate pollutants, respectively. To our knowledge, this is the first to report existence of polyfluoroalkyl sulfonates with both hydrogen and ether functional group in the environment. PMID- 28918642 TI - Effect of an oral healthcare program on gingival health status in rural areas of South Korea. AB - INTRODUCTION: The purpose of this study was to analyze the effects of an oral health care program administered at rural public health subcenters on oral hygiene status and bleeding on probing (BOP) scores among Korean rural residents older than 40 years. METHODS: Residents older than 40 years living in two rural areas were allocated randomly by order of visit into an intervention group (n=23) and control group (n=23). Changes in plaque and BOP score were analyzed between the groups using repeated-measures ANOVA. Hierarchical multiple regression analysis was conducted to identify factors affecting changes in BOP score. RESULTS: The BoP score decreased by 22.87 in the intervention group and 0.27 in the control group between baseline and the eighth week (p<0.001). Multiple regression analysis showed that the change in BoP score (ΔBoP score) increased significantly with an increase in the reduction of the plaque (PHP) index (ΔPHP index) (t=-2.174, p<0.05) and increased significantly more in the intervention group than in the control group (t=2.143, p<0.05). CONCLUSIONS: Professional care and continuous oral health education for 8 weeks prior to scaling among adults older than 40 years living in rural environments resulted in a change in oral health behaviors and a substantial reduction in gingival bleeding. PMID- 28918643 TI - Speech-language pathology telehealth in rural and remote schools: the experience of school executive and therapy assistants. AB - INTRODUCTION: Difficulties in accessing allied health services, especially in rural and remote areas, appear to be driving the use of telehealth services to children in schools. The objectives of this study were to investigate the experiences and views of school executive staff and therapy assistants regarding the feasibility and acceptability of a speech-language pathology telehealth program for children attending schools in rural and remote New South Wales, Australia. The program, called Come N See, provided therapy interventions remotely via low-bandwidth videoconferencing, with email follow-up. Over a 12 week period, children were offered therapy blocks of six fortnightly sessions, each lasting a maximum of 30 minutes. METHODS: School executives (n=5) and therapy assistants (n=6) described factors that promoted or threatened the program's feasibility and acceptability, during semistructured interviews. Thematic content analysis with constant comparison was applied to the transcribed interviews to identify relationships in the data. RESULTS: Emergent themes related to (a) unmet speech pathology needs, (b) building relationships, (c) telehealth's advantages, (d) telehealth's disadvantages, (e) anxiety replaced by joy and confidence in growing skills, and (f) supports. CONCLUSIONS: School executive staff and therapy assistants verified that the delivery of the school based telehealth service was feasible and acceptable. However, the participants saw significant opportunities to enhance this acceptability through building into the program stronger working relationships and supports for stakeholders. These findings are important for the future development of allied health telehealth programs that are sustainable as well as effective and fit the needs of all crucial stakeholders. The results have significant implications for speech pathology clinical practice relating to technology, program planning and teamwork within telehealth programs. PMID- 28918644 TI - Anti-IgE and Anti-IL5 Biologic Therapy in the Treatment of Nasal Polyposis: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To determine the role of biologic therapy on sinonasal symptoms and objective outcomes in chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: PubMed, OVID MEDLINE, and Cochrane Central were reviewed from 2000 to 2015. Inclusion criteria included English-language studies containing original data on biologic therapy in CRSwNP patients with reported outcome measures. Two investigators independently reviewed all manuscripts and performed quality assessment and quantitative meta-analysis using validated tools. RESULTS: Of 495 abstracts identified, 7 studies fulfilled eligibility: 4 randomized control trials (RCT), 1 case-control, and 2 case series. Outcome measures included nasal polyp score (NPS,6), computer tomography score (5), and symptom scores (5). Meta analysis was performed on 5 studies: Anti-IL5 therapy (mepolizumab/reslizumab) and anti-IgE therapy (omalizumab) demonstrated a standard mean difference of NPS improvement of -0.66 (95% CI, -1.24 to -0.08) and -0.75 (95% CI, -1.93 to 0.44), respectively, between biologic therapy and placebo. Quality assessment indicated a low to moderate risk of bias for the RCTs. CONCLUSION: Biologic therapies may prove beneficial in the treatment of recalcitrant nasal polyposis in select populations. In meta-analysis, anti-IL5 therapy demonstrates a reduction in nasal polyp score. Anti-IgE therapy reduces nasal polyp score in patients with severe comorbid asthma. Additional high-level evidence is needed to assess clinical efficacy. PMID- 28918645 TI - Increasing Availability of Exposure Therapy Through Intensive Group Treatment for Childhood Anxiety and OCD. AB - Archival data were used to examine the feasibility of a 5-day, clinic-based, intensive exposure-based cognitive-behavioral group therapy for childhood anxiety disorders (CADs) and obsessive-compulsive disorder (OCD). Participants were 143 children (82 girls) aged 6 to 19 years ( M = 13.93 years, SD = 2.9 years) with CADs or OCD (or both) in 28 consecutive groups. Repeated-measures ANOVA in the subsample ( n = 57) with complete treatment data indicated positive change on all variables from pretreatment to posttreatment with few differences between CADs and OCD patients. Effect sizes were moderate to large for anxiety symptoms (parent reported = 0.74, child reported = 0.65) and impairment (parent reported = 1.02, child reported = 0.69). The intensive group protocol required fewer sessions and 36% fewer therapist-hours per patient than the individually administered protocol. The program increased treatment availability for families from diverse geographic areas ( M distance traveled to clinic = 407 miles, SD = 786.4 miles). These findings support further, well-controlled examination of the 5-day intensive group treatment protocol's efficacy and potential to increase availability of evidence-based exposure therapy. PMID- 28918647 TI - Corrigendum. PMID- 28918648 TI - Anticipatory Traumatic Reaction: Outcomes Arising From Secondary Exposure to Disasters and Large-Scale Threats. AB - Two studies, with a total of 707 participants, developed and examined the reliability and validity of a measure for anticipatory traumatic reaction (ATR), a novel construct describing a form of distress that may occur in response to threat-related media reports and discussions. Exploratory and confirmatory factor analysis resulted in a scale comprising three subscales: feelings related to future threat; preparatory thoughts and actions; and disruption to daily activities. Internal consistency was .93 for the overall ATR scale. The ATR scale demonstrated convergent validity through associations with negative affect, depression, anxiety, stress, neuroticism, and repetitive negative thinking. The scale showed discriminant validity in relationships to Big Five characteristics. The ATR scale had some overlap with a measure of posttraumatic stress disorder, but also showed substantial separate variance. This research provides preliminary evidence for the novel construct of ATR as well as a measure of the construct. The ATR scale will allow researchers to further investigate anticipatory traumatic reaction in the fields of trauma, clinical practice, and social psychology. PMID- 28918646 TI - Depletion of Gut-Resident CCR5+ Cells for HIV Cure Strategies. AB - The HIV reservoir forming at the earliest stages of infection is likely composed of CCR5+ cells, because these cells are the targets of transmissible virus. Restriction of the CCR5+ reservoir, particularly in the gut, may be needed for subsequent cure attempts. Strategies for killing or depleting CCR5+ cells have been described, but none have been tested in vivo in nonhuman primates, and the extent of achievable depletion from tissues is not known. In this study we investigate the efficacy of two novel cytotoxic treatments for targeting and eliminating CCR5+ cells in young rhesus macaques. The first, an immunotoxin consisting of the endogenous CCR5 ligand RANTES fused with Pseudomonas exotoxin (RANTES-PE38), killed CCR5+ lamina propria lymphocytes (LPLs) ex vivo, but had no detectable effect on CCR5+ LPLs in vivo. The second, a primatized bispecific antibody for CCR5 and CD3, depleted all CCR5+ cells from blood and the vast majority of such cells from the colonic mucosa (up to 96% of CD4+CCR5+). Absence of CCR5-expressing cells from blood endured for at least 1 week, while CCR5+ cells in colon were substantially replenished over the same time span. These data open an avenue to investigation of combined early ART treatment and CCR5+ reservoir depletion for cure of HIV-infected infants. PMID- 28918649 TI - Characterizing Verified Head Impacts in High School Girls' Lacrosse. AB - BACKGROUND: Girls' high school lacrosse players have higher rates of head and facial injuries than boys. Research indicates that these injuries are caused by stick, player, and ball contacts. Yet, no studies have characterized head impacts in girls' high school lacrosse. PURPOSE: To characterize girls' high school lacrosse game-related impacts by frequency, magnitude, mechanism, player position, and game situation. STUDY DESIGN: Descriptive epidemiology study. METHODS: Thirty-five female participants (mean age, 16.2 +/- 1.2 years; mean height, 1.66 +/- 0.05 m; mean weight, 61.2 +/- 6.4 kg) volunteered during 28 games in the 2014 and 2015 lacrosse seasons. Participants wore impact sensors affixed to the right mastoid process before each game. All game-related impacts recorded by the sensors were verified using game video. Data were summarized for all verified impacts in terms of frequency, peak linear acceleration (PLA), and peak rotational acceleration (PRA). Descriptive statistics and impact rates were calculated. RESULTS: Fifty-eight verified game-related impacts >=20 g were recorded (median PLA, 33.8 g; median PRA, 6151.1 rad/s2) during 467 player-games. The impact rate for all game-related verified impacts was 0.12 per athlete exposure (AE) (95% CI, 0.09-0.16), equivalent to 2.1 impacts per team game, indicating that each athlete suffered fewer than 2 head impacts per season >=20 g. Of these impacts, 28 (48.3%) were confirmed to directly strike the head, corresponding with an impact rate of 0.05 per AE (95% CI, 0.00-0.10). Overall, midfielders (n = 28, 48.3%) sustained the most impacts, followed by defenders (n = 12, 20.7%), attackers (n = 11, 19.0%), and goalies (n = 7, 12.1%). Goalies demonstrated the highest median PLA and PRA (38.8 g and 8535.0 rad/s2, respectively). The most common impact mechanisms were contact with a stick (n = 25, 43.1%) and a player (n = 17, 29.3%), followed by the ball (n = 7, 12.1%) and the ground (n = 7, 12.1%). One hundred percent of ball impacts occurred to goalies. Most impacts occurred to field players within the attack area of the field (n = 32, 55.2%) or the midfield (n = 18, 31.0%). Most (95%) impacts did not result in a penalty. CONCLUSION: The incidence of verified head impacts in girls' high school lacrosse was quite low. Ball to head impacts were associated with the highest impact magnitudes. While stick and body contacts are illegal in girls' high school lacrosse, rarely did such impacts to the head result in a penalty. The verification of impact mechanisms using video review is critical to collect impact sensor data. PMID- 28918650 TI - May the Z-Tracking Technique to Prevent Any Leakage in Insulin Injection Be an Alternative to the 10-Second Waiting Technique? PMID- 28918651 TI - A Pilot Observational Study of Hypoglycemia: Patient Reporting Using a Web-Based Portal Compared to Paper Surveys. PMID- 28918652 TI - Investigation of Pump Compatibility of Fast-Acting Insulin Aspart in Subjects With Type 1 Diabetes. AB - BACKGROUND: Ultra-fast-acting insulins, such as fast-acting insulin aspart (faster aspart), have pharmacokinetic properties that may be advantageous for patients using continuous subcutaneous insulin infusion (CSII), provided that they are compatible with and safe to use in CSII. METHODS: Randomized, double blind, parallel-group, actively controlled trial evaluating compatibility, efficacy, and safety of faster aspart in adults with type 1 diabetes using their own MiniMed Paradigm pump with Quick-Set or Silhouette infusion sets. Following run-in, subjects were randomized (2:1) to faster aspart (n = 25) or insulin aspart (n = 12) for 6 weeks. Primary endpoint was the number of microscopically confirmed episodes of infusion-set occlusions. RESULTS: No microscopically confirmed episodes of infusion-set occlusions were observed in either arm. Seven possible infusion-set occlusions were reported by five subjects (all faster aspart); none were prompted by a plug observed by the subject (prompted by unexplained hyperglycemia [n = 6] or leakage [n = 1]) and none were confirmed. Macroscopic and microscopic evaluation showed no color change or particle/crystal formation in the infusion sets. Premature infusion-set changes were reported in 44% and 16.7% of subjects in the faster aspart and insulin aspart groups, respectively. A nonsignificant trend toward better efficacy was observed with faster aspart (estimated treatment difference [ETD] [95% CI] in HbA1c change: 0.14% [-0.40, 0.11]). No new safety issues were found in either treatment group. CONCLUSIONS: Over 6 weeks of treatment, no microscopically confirmed infusion-set occlusions were observed for faster aspart or insulin aspart, indicating similar compatibility with CSII use. PMID- 28918653 TI - Setting Expectations for Successful Artificial Pancreas/Hybrid Closed Loop/Automated Insulin Delivery Adoption. PMID- 28918654 TI - Stakeholders' Perceptions Sought to Inform the Development of a Low-Cost Mobile Robot for Older Adults: A Qualitative Descriptive Study. AB - Creative solutions are needed to support community-dwelling older adults residing in a variety of settings including their house, apartment, or Supportive Apartment Living (SAL) to promote independence and reduce the risk of nursing home replacement. The objective of this study was to gain an understanding of older adults' needs for physical, mental, and social activities to support the design and functionality of a low-cost mobile assistive robot. A qualitative descriptive study was designed which included three stakeholder focus groups (caregivers, clinicians, and older adults). We held three focus groups with a total of 19 participants: one with paid caregivers ( n = 6), one with interdisciplinary clinicians ( n = 8), and one with older adults residing in SAL ( n = 5). Conventional content analysis was the analytical technique. Four themes emerged: (a) Accomplishing Everyday Tasks: activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were important from the perspectives of all three groups for the older adults to accomplish daily, as well as the "use it or lose it" attitude of the older adults; (b) Personal Connections and Meaningful Activities: for the older adults, it was important for them to engage in socialization and leisure activities, and for the caregivers and clinicians, they work to build personal relationships with the older adults; (c) Cognitive Interventions: the clinicians provided cognitive tools (including reminders, routine and designing interventions) to older adults so they can remain as safe and independent as possible in the SAL; and (d) Safety Measures: encompassed clinicians addressing safety and injury prevention and the caregivers checking in on the older adults in their SAL apartments. This work contributed to the design and functionality specifications for an autonomous low-cost mobile robot for deployment to increase the independence of older adults. PMID- 28918655 TI - What not to do in acute otitis media: the top five recommendations proposed by the Italian Society of Preventive and Social Pediatrics. AB - INTRODUCTION: With the aim to reduce inappropriate procedures and antibiotic therapy in the management of acute otitis media (AOM) in children, the Italian Society of Preventive and Social Pediatrics (SIPPS) proposed a top five list of recommendations for clinical practice. Areas covered: AOM is one of the most frequent reasons for antibiotic prescription in pediatric age. The over estimation of AOM is associated with inappropriate treatment, increased costs, adverse events and spread of antibiotic resistance. Thus, the most recent guidelines provided stringent diagnostic criteria and considered the 'watchful waiting' approach, limiting the immediate antibiotic therapy to a well characterized subgroup of children. Expert commentary: The five recommendations proposed are: 1) Do not diagnose AOM without having documented the presence of middle ear effusion 2) Do not diagnose AOM without examining the entire tympanic membrane; 3) Do not treat immediately all cases of AOM with antibiotics; 4) Do not administer ear analgesic drops until examining the whole tympanic membrane 5) Do not use macrolides in the AOM therapy. This list of top five recommendations could be a novel tool to spread the key messages on the guidelines and to promote the correct diagnostic procedures as well as a rational use of antibiotics in children. PMID- 28918656 TI - Diagnosing Kingella kingae infections in infants and young children. AB - INTRODUCTION: Kingella kingae is currently recognized as the prime etiology of skeletal system infections in children aged 6-48 months. The organism is notoriously fastidious, its growth is inhibited by synovial fluid and bone exudates, and its presence in clinical specimens is commonly missed by traditional culture methods. Areas covered: The present review discusses the use of improved laboratory methods to detect the organism in normally sterile body fluids, exudates, and upper respiratory tract specimens. Expert commentary: While inoculation of joint and bone exudates into blood culture vials dilutes the concentration of detrimental factors and significantly improves the isolation of the organism, novel PCR-based assays have enhanced sensitivity, shortened the time-to-detection of K. kingae from 3-4 days to <24 h, and enabled the bacteriological diagnosis in patients being administered antibiotic therapy. PCR based assays that amplify the 16S rRNA gene results in a 200% improvement in the diagnosis of the organism compared to culture, whereas the use of real-time PCR tests that target K. kingae-specific DNA sequences increases the detection rate by a five-fold factor and reduces the fraction of culture-negative septic arthritis and osteomyelitis in infants and young children. PMID- 28918657 TI - Direct Oral Anticoagulant Use in Atypical Thrombosis-Related Conditions. AB - OBJECTIVE: To review the published literature for evidence of the efficacy and safety of direct oral anticoagulants (DOACs) when used in the management of atypical thrombosis-related conditions. DATA SOURCES: A comprehensive MEDLINE database search (1948 to July 2017) and EMBASE search (1980 to July 2017) were conducted using the search terms direct oral anticoagulant in combination with acute coronary syndrome (ACS), antiphospholipid antibody syndrome (APLAS), and cancer-associated thrombosis (CAT). STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to studies that were conducted in humans and published in English. Clinical trials, observational studies, and case series were selected. DATA SYNTHESIS: A total of 20 published studies were selected from the literature. Only 1 randomized controlled study showed a significant reduction in cardiovascular outcomes on DOAC use in ACS patients but at the expense of increased bleeding. For the use of DOACs in APLAS, the evidence from case series seems to suggest low incidence of thromboembolic events or recurrent thrombosis in low-risk patients. Finally, in cancer patients, DOACs were comparable to warfarin in preventing CAT in 8 studies of different designs. Major bleeding with DOACs was not significantly lower than in patients who received an enoxaparin/warfarin regimen. CONCLUSIONS: Until more evidence from the ongoing clinical trials is available, DOACs may not be favorable add-on therapy in ACS patients receiving standard antiplatelet therapy but may be alternative to warfarin in preventing or treating thrombosis in low-risk APLAS patients as well as in cases of CAT in which patients have to be managed with warfarin. PMID- 28918658 TI - The role of upper airway pathology as a co-morbidity in severe asthma. AB - INTRODUCTION: Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple co-morbidities and risk factors. Several co-morbidities may contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients. Areas covered: A prevalent cluster of chronic upper airway co-morbid diseases is recognized in severe asthma. Evaluation for these disorders should always be considered in clinical practice. The aim of this review is to provide an updated overview of the prevalence, the pathogenetic mechanisms, the clinical impact and the therapeutic options for upper airway pathology in severe asthma, focusing on chronic rhinosinusitis and allergic rhinitis. Expert commentary: In the context of severe asthma, the clinical significance of upper airway co-morbidities is based on mutual interactions complicating diagnosis and management. A better analysis and understanding of phenotypes and endotypes of both upper and lower airway diseases are crucial to further develop targeted treatment. PMID- 28918659 TI - Ureaplasma-associated prenatal, perinatal, and neonatal morbidities. AB - INTRODUCTION: Ureaplasma species (spp.) have been acknowledged as major causative pathogens in chorioamnionitis and prematurity, but may also contribute to key morbidities in preterm infants. Several epidemiological and experimental data indicate an association of neonatal Ureaplasma colonization and/or infection with bronchopulmonary dysplasia. Furthermore, a potential causal relation with other inflammation-induced morbidities, such as intraventricular hemorrhage, white matter injury, necrotizing enterocolitis, and retinopathy of prematurity, has been debated. Areas covered: This review will summarize current knowledge on the role of Ureaplasma spp. in prenatal, perinatal, and neonatal morbidities, while furthermore examining mutual underlying mechanisms. We try to elaborate who is at particular risk of Ureaplasma-induced inflammation and subsequent secondary morbidities. Expert commentary: Most likely by complex interactions with immunological processes, Ureaplasma spp. can induce pro-inflammation, but may also downregulate the immune system. Tissue damage, possibly causing the above mentioned complications, is likely to result from both ways: either directly cytokine-associated, or due to a higher host vulnerability to secondary impact factors. These events are very likely to begin in prenatal stages, with the most immature preterm infants being most susceptible and at highest risk. PMID- 28918660 TI - Factors Associated With Radiographic Trapeziometacarpal Arthrosis in Patients Not Seeking Care for This Condition. AB - BACKGROUND: A common adage among hand surgeons is that the symptoms of trapeziometacarpal (TMC) arthrosis vary among patients independent of the radiographic severity. We studied factors associated with radiographic severity of TMC arthrosis, thumb pain, thumb-specific disability, pinch strength, and grip strength in patients not seeking care for TMC arthrosis. Our primary null hypothesis was that there are no factors independently associated with radiographic severity of TMC arthrosis according to the Eaton classification among patients not seeking care for TMC arthrosis. METHODS: We enrolled 59 adult patients not seeking care for TMC arthrosis. We graded patients' radiographic TMC arthrosis and asked all patients to complete a set of questionnaires: demographic survey, pain scale, TMC joint arthrosis-related symptoms and disability questionnaire (TASD), and a depression questionnaire. Metacarpophalangeal hyperextension and pinch and grip strength were measured, and the grind test and shoulder sign were performed. RESULTS: Older age was the only factor associated with more advanced radiographic pathophysiology of TMC arthrosis. One in 5 patients not seeking care for TMC arthrosis experienced thumb pain; no factors were independently associated with having pain or limitations related to TMC arthrosis. Youth and male sex were associated with stronger pinch and grip strength. CONCLUSIONS: There are a large number of patients with relatively asymptomatic TMC arthrosis. Metacarpophalangeal hyperextension and female sex may have a relationship with symptoms, but further study is needed. Our data support the concept that TMC arthrosis does not correlate with radiographic arthrosis. PMID- 28918662 TI - Utility of the iPhone 4 Gyroscope Application in the Measurement of Wrist Motion. AB - BACKGROUND: Measurement of wrist range of motion (ROM) is important to all aspects of treatment and rehabilitation of upper extremity conditions. Recently, gyroscopes have been used to measure ROM and may be more precise than manual evaluations. The purpose of this study was to evaluate the use of the iPhone gyroscope application and compare it with use of a goniometer, specifically evaluating its accuracy and ease of use. METHODS: A cross-sectional study evaluated adult Caucasian participants, with no evidence of wrist pathology. Wrist ROM measurements in 306 wrists using the 2 methods were compared. Demographic information was collected including age, sex, and occupation. Analysis included mixed models and Bland-Altman plots. RESULTS: Wrist motion was similar between the 2 methods. Technical difficulties were encountered with gyroscope use. Age was an independent predictor of ROM. CONCLUSIONS: Correct measurement of ROM is critical to guide, compare, and evaluate treatment and rehabilitation of the upper extremity. Inaccurate measurements could mislead the surgeon and harm patient adherence with therapy or surgeon instruction. An application used by the patient could improve adherence but needs to be reliable and easy to use. Evaluation is necessary before utilization of such an application. This study supports revision of the application on the iPhone to improve ease of use. PMID- 28918661 TI - Comparable Postoperative Pain Levels Using 2 Different Nerve Blocks in the Operative Treatment of Displaced Intra-articular Calcaneal Fractures. AB - BACKGROUND: The aim of this study was to compare the postoperative pain levels in patients undergoing osteosynthesis of the calcaneus with either a popliteal nerve block or an ankle block. METHODS: A retrospective analysis of all consecutive patients undergoing operative fixation of a calcaneal fracture via a sinus tarsi approach between August 2012 and April 2017 in a single foot/ankle specialized center was performed. Single-shot popliteal blocks were placed using ultrasound guidance by an anesthesiologist while ankle blocks were placed by a foot/ankle specialized surgeon. Pain levels were measured through the numerical rating scale (NRS). In total, 83 patients were included in this study; 33 received a popliteal block, and 50 received an ankle block. No statistically significant differences were present in baseline characteristics between the 2 groups. RESULTS: Comparable postoperative pain levels were observed in both groups. There was no statistically significant difference in amount of morphine used between the 2 groups. CONCLUSION: No differences were found in postoperative pain levels between patients receiving a single-shot popliteal block and patients who received a single-shot ankle block following calcaneal fracture surgery. LEVEL OF EVIDENCE: III, comparative series. PMID- 28918663 TI - Biosynthesis of gold and silver chloride nanoparticles mediated by Crataegus pinnatifida fruit extract: in vitro study of anti-inflammatory activities. AB - This research article investigates the one-pot synthesis of gold and silver chloride nanoparticles functionalized by fruit extract of Crataegus pinnatifida as reducing and stabilizing agents and their possible roles as novel anti inflammatory agents. Hawthorn (C. pinnatifida) fruits are increasingly popular as raw materials for functional foods and anti-inflammatory potential agents because of abundant flavonoids. The reduction of auric chloride and silver nitrate by the aqueous fruit extract led to the formation of gold and silver chloride nanoparticles. The nanoparticles were further characterized by field emission transmission electron microscopy indicated that CP-AuNps and CP-AgClNps were hexagonal and cubic shape, respectively. According to X-ray diffraction results, the average crystallite sizes of CP-AuNps and CP-AgClNps were 14.20 nm and 24.80 nm. The biosynthesized CP-AgClNps served as efficient antimicrobial agents against Escherichia coli and Staphylococcus aureus. Furthermore, CP-AuNps and CP AgClNps enhanced the DPPH radical scavenging activity of the fruit extract. Lastly, MTT assay of nanoparticles demonstrated low toxicity in murine macrophage (RAW264.7). Biosynthesized nanoparticles also reduced the production of the inflammatory cytokines including nitric oxide and prostaglandin E2 in lipopolysaccharide-induced RAW264.7 cells. Altogether, these findings suggest that CP-AuNps and CP-AgClNps can be used as novel drug carriers or biosensors with intrinsic anti-inflammatory activity. PMID- 28918664 TI - Outcomes of Surface Replacement Proximal Interphalangeal Joint Arthroplasty Using the Self Locking Finger Joint Implant: Minimum Two Years Follow-up. AB - BACKGROUND: The Self Locking Finger Joint (SLFJ) implant is a new type of surface replacement implant. The purpose of this study was to evaluate midterm clinical outcomes of the proximal interphalangeal (PIP) arthroplasty with the SLFJ implant. METHODS: We retrospectively studied 26 PIP joint arthroplasties using the SLFJ implant in 17 patients with osteoarthritis or posttraumatic osteoarthritis. Preoperative and postoperative range of motion, grip strength and key pinch, radiographic findings, and complications were evaluated. The Disabilities of the Arm, Shoulder, and Hand (DASH) score, visual analog scale (VAS) score, course of pain, and patient satisfaction were obtained. RESULTS: The mean follow-up time was 44 months (range, 24-76 months). The average active PIP joint arc of motion improved from 36 degrees before surgery to 44 degrees after surgery. Grip strength and key pinch showed no statistical difference between preoperative and postoperative assessments. The average DASH score and VAS score improved from 40 to 15 and from 5 to 1, respectively. Overall patient satisfaction was 94%. Ninety percent of implants showed osteointegration, and there were no radiographic signs of migration and loosening. Three joints (12%) showed abnormal heterotopic bone formation. Four joints (15%) had secondary surgery-1 joint needing joint head and socket replacement and 3 joints needing contracture release. CONCLUSIONS: Our minimum 2 years of follow-up evaluation of the SLFJ implant PIP joint arthroplasty demonstrated good pain relief and good overall patient satisfaction while maintaining joint range of motion. The SLFJ implant showed good osteointegration. Further longer-term prospective studies with various types of currently available implants are needed. PMID- 28918665 TI - Considerations in establishing bioequivalence of inhaled compounds. AB - INTRODUCTION: Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds. Areas covered: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds. Expert opinion: The ultimate goals in this field are to establish uniformity in the regulatory approaches to speed the drug submission process in different regions, clear physicians' misconception of generic inhalers, and have meaningful clinical endpoints such as improvement in patient quality of life when compared to placebo and brand name drugs. As inhalational drugs become more common for other indications such as antibiotics, the technologies developed for inhaled compounds in the treatment of chronic pulmonary diseases may be extrapolated to these other agents. PMID- 28918666 TI - Treatment options for severe traumatic brain injuries in children: current therapies, challenges, and future prospects. AB - INTRODUCTION: Severe traumatic brain injury (TBI) afflicts many children and adults worldwide, resulting in high rates of morbidity and mortality. Recent therapeutic advances have focused on both surgical and medical treatment options, but none have been proven to reduce overall morbidity and mortality in this population. Areas covered: Several emerging therapies are addressed that focus on treating related secondary injuries and other clinical sequelae post-TBI during the acute injury phase (defined by authors as up to four weeks post-injury). Information and data were obtained from a PubMed search of recent literature and through reputable websites (e.g. Centers for Disease Control, ClinicalTrials.gov). Peer-reviewed original articles, review articles, and clinical guidelines were included. Expert commentary: The ongoing challenges related to conducting rigorous clinical trials in TBI have led to largely inconclusive findings regarding emerging beneficial therapies. PMID- 28918667 TI - Poor outcomes among elderly patients hospitalized for influenza-like illness. AB - BACKGROUND AND OBJECTIVE: Global Influenza Hospital Surveillance Network is a worldwide initiative that aims to document the burden of influenza infections among acute admissions and vaccine effectiveness in particular countries. As a partner of this platform, we aimed to determine the frequency of influenza infections among acute admissions with influenza-like illness and the outcomes of enrolled patients during the 2015-2016 influenza season in selected hospitals in Turkey. PATIENTS AND METHODS: The investigators screened the hospital admission registries, chart review or available records, and screened all patients hospitalized in the previous 24-48 hours or overnight in the predefined wards or emergency room. A total of 1351 patients were screened for enrollment in five tertiary care referral hospitals in Ankara and 774 patients (57.3% of the initial screened population) were eligible for swabbing. All of the eligible patients who consented were swabbed and tested for influenza with real-time polymerase chain reaction (PCR) based methods. RESULTS: Overall, influenza positivity was detected in 142 patients (18.4%). The predominant influenza strain was A H1N1pdm09. Outcomes were worse among elderly patients, regardless of the presence of the influenza virus. Half of the patients over 65 years of age were admitted to the intensive care unit, while one third required any mode of mechanical ventilation and one fourth died in the hospital in that particular episode. CONCLUSION: These findings can guide hospitals to plan and prepare for the influenza season. Effective influenza vaccination strategies, particularly aimed at the elderly and adults with chronic diseases, can provide an opportunity for prevention of deaths due to influenza-like illness. PMID- 28918668 TI - Current status and future prospects for the development of substance abuse vaccines. AB - INTRODUCTION: Substance use disorders (SUD) are a significant threat to both individual and public health. To date, SUD pharmacotherapy has focused primarily on agonist medications (i.e. nicotine replacement therapy for tobacco use disorder; methadone and buprenorphine for opioid use disorder), antagonist medications (i.e. naltrexone for opioid use disorder), and aversive therapy (i.e. disulfiram for alcohol use disorder). Pharmacotherapeutic approaches utilizing an immunological framework for medication development represent an important focus of study for treatment of these illnesses. Areas covered: This review discusses vaccines for treatment of substance use disorders. Using PubMed ( https://www.ncbi.nlm.nih.gov/pubmed/ ), we searched both preclinical and human clinical trials of vaccines for treatment of nicotine, cocaine, methamphetamine, and opioid use disorders. In addition, we searched for recently developed strategies for enhancement of the immunologic response through alteration of conjugate molecules and adjuvants. Expert commentary: Despite challenges in human clinical trials of SUD vaccines, a number of strategies have been introduced which may ultimately improve efficacy. These challenges, as well as their implications for vaccine development, are discussed. Additionally, the optimal conditions for research study and treatment are considered. PMID- 28918669 TI - Unexpected Effects of a System-Distributed Mobile Application in Maternity Care: A Randomized Controlled Trial. AB - BACKGROUND: As pregnant mothers increasingly engage in shared decision making regarding prenatal decisions, such as induction of labor, the patient's level of activation may influence pregnancy outcomes. One potential tool to increase patient activation in the clinical setting is mobile applications. However, research is limited in comparing mobile apps with other modalities of patient education and engagement tools. AIM: This study was designed to test the effectiveness of a mobile app as a replacement for a spiral notebook guide as a patient education and engagement tool in the prenatal clinical setting. METHOD: This randomized controlled trial was conducted in the Women's Health Clinic and Family Health Clinic of three hospitals. Repeated-measures analysis of covariance was used to test intervention effects in the study sample of 205 patients. RESULTS: Mothers used a mobile app interface to more frequently record information about their pregnancy; however, across time, mothers using a mobile app reported a significant decrease in patient activation. DISCUSSION: The unexpected negative effects in the group of patients randomized to the mobile app prompt these authors to recommend that health systems pause before distributing their own version of mobile apps that may decrease patient activation. CONCLUSION: Mobile apps can be inherently empowering and engaging, but how a system encourages their use may ultimately determine their adoption and success. PMID- 28918670 TI - pH-sensitive metal-phenolic network capsules for targeted photodynamic therapy against cancer cells. AB - Photodynamic therapy (PDT) is an effective and promising method for cancer treatment, which is proposed for more than one century. However, the specific delivery of photosensitizer to target carcinoma cells to reduce the side effect is still a great challenge. This work provides a strategy to deliver photosensitizers to cancer cells by utilizing pH-sensitive polyethylene glycol metal-phenolic network (PEG-MPN) capsules to encapsulate haematoporphyrin monomethyl ether (HMME). With the assistance of folic acid (FA), HMME-doped PEG MPN capsules (MPN@HMMEs) accumulate in carcinoma cells selectively followed by releasing HMME in the lysosomes because of the physiologically relevant acidic pH environment. From the fluorescent ratiometric sensing and reactive oxygen species (ROS) regionality distribution of MPN@HMMEs, we demonstrated the encapsulated photosensitizers are diffused from lysosomes to cytoplasm. Under irradiation at 638 nm laser, ROS generated from the photosensitizers induced cancer cells undergoing apoptosis while normal cells survive. Therefore, MPN@HMME could be applied as a new strategy for targeted PDT against cancer and PEG-MPN capsules are expected to be general carries for drug delivering. PMID- 28918672 TI - Protein complexes, big data, machine learning and integrative proteomics: lessons learned over a decade of systematic analysis of protein interaction networks. AB - OVERVIEW: Elucidation of the networks of physical (functional) interactions present in cells and tissues is fundamental for understanding the molecular organization of biological systems, the mechanistic basis of essential and disease-related processes, and for functional annotation of previously uncharacterized proteins (via guilt-by-association or -correlation). After a decade in the field, we felt it timely to document our own experiences in the systematic analysis of protein interaction networks. Areas covered: Researchers worldwide have contributed innovative experimental and computational approaches that have driven the rapidly evolving field of 'functional proteomics'. These include mass spectrometry-based methods to characterize macromolecular complexes on a global-scale and sophisticated data analysis tools - most notably machine learning - that allow for the generation of high-quality protein association maps. Expert commentary: Here, we recount some key lessons learned, with an emphasis on successful workflows, and challenges, arising from our own and other groups' ongoing efforts to generate, interpret and report proteome-scale interaction networks in increasingly diverse biological contexts. PMID- 28918671 TI - Long term outcomes of severe combined immunodeficiency: therapy implications. AB - INTRODUCTION: Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has improved following hematopoietic stem cell transplantation (HCT) with the best outcomes seen following use of a matched sibling donor. However, questions remain regarding the optimal alternative donor source, appropriate use of conditioning and the impact of these decisions on immune reconstitution and other late morbidities. Areas covered: The currently available literature reporting late effects after HCT for SCID and use of alternative therapies including enzyme replacement, alternative donors and gene therapy are reviewed. A literature search was performed on Pubmed and ClinicalTrials.gov using key words 'Severe Combined Immunodeficiency', 'SCID', 'hematopoietic stem cell transplant', 'conditioning', 'gene therapy', 'SCID newborn screening', 'TREC' and 'late effects'. Expert commentary: Newborn screening has dramatically changed the clinical presentation of newborn SCID. While the majority of patients with SCID survive HCT, data regarding late effects in these patients is limited and additional studies focused on genotype specific late effects are needed. Prospective studies aimed at minimizing the use of alkylating agents and reducing late effects beyond survival are needed. Gene therapy is being developed and will likely become a more commonly used treatment that will require separate consideration of survival and late effects. PMID- 28918673 TI - Suppression of TGF-beta1 enhances chemosensitivity of cisplatin-resistant lung cancer cells through the inhibition of drug-resistant proteins. AB - Cisplatin-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC), but drug resistance occurs in most patients, leading to treatment failure. Recent studies have shown that epithelial-mesenchymal transition (EMT) is associated with drug resistance. However, the underlying mechanism is not entirely clear. In this study, first we showed significant positive correlation between the expression of ERCCl and vimentin, and significant negative correlation between the ERCCl and E-cadherin in the neoadjuvant chemotherapy group and the simple surgery group. Second, we showed that cisplatin-resistant A549 cells (A549/DDP) acquire EMT phenotype with high expression of drug resistant proteins, P-gp and ERCC1. Knockdown of TGF-beta1 may reverse EMT and significantly reduce the expression of P-gp and ERCC1. Moreover, A549/DDP cells become more sensitive to cisplatin. In summary, our results globally confirm a molecular and phenotypic association between chemoresistance and EMT of resistant tumour cells under a histological and cellular level. More importantly, silence of TGF-beta1 may enhance sensitivity to cisplatin of A549/DDP through inducing the reversal of EMT and inhibiting the expression of resistance-associated proteins. Hence, inhibition of TGF-beta1 could be considered as an effective strategy for eliminating resistant lung cancer. PMID- 28918674 TI - Consumption of Fruitflow(r) lowers blood pressure in pre-hypertensive males: a randomised, placebo controlled, double blind, cross-over study. AB - In order to investigate whether the angiotensin converting enzyme-inhibitory tomato extract Fruitflow(r) would lower blood pressure after consumption, we conducted a randomised, double-blinded, placebo-controlled human intervention study, involving 12 pre-hypertensive people in a crossover design. Consuming a single dose of 150 mg Fruitflow(r) resulted in a significant reduction in 24-hour average blood pressure as well as average wake-period and sleep-period SBP, compared to placebo. Other parameters related to blood pressure, such as 24-hour average mean arterial pressure, pulse pressure, heart rate, central aortic systolic pressure and radial augmentation index were also reduced. In addition, the platelet aggregation response to ADP, measured 24 hours after consuming Fruitflow(r), fell significantly compared to baseline, and compared to placebo. This pilot study clearly shows the beneficial effects of Fruitflow(r) on two important cardiovascular risk factors, high blood pressure and platelet hyperactivity. PMID- 28918675 TI - Editorial. PMID- 28918676 TI - Cross-cultural adaptation and psychometric properties of the Chinese tinnitus functional index. AB - OBJECTIVES: To establish the reliability, validity and responsiveness of the Chinese version of the Tinnitus Functional Index (TFI-CH) in measuring tinnitus severity in Hong Kong Chinese population. DESIGN: This is a cross-sectional psychometric validation study. STUDY SAMPLE: Subjects were 124 adult Chinese who attended the audiology clinics in a hospital setting for tinnitus treatment. RESULTS: The TFI-CH showed good internal consistency reliability (alpha = 0.94) and test-retest reliability (ICC = 0.84). Confirmatory factor analysis revealed that the TFI-CH has eight factors which are exactly the same as the original version. The TFI-CH has good convergent and divergent validity as supported by the strong correlation of the overall scale with other tinnitus-related distress measures (r = 0.86, p < 0.01) and weaker correlation with the general health status measures. Moderate to strong effect sizes obtained 3 months after initial visit indicated that the TFI-CH is responsive in detecting change in tinnitus suffering. CONCLUSIONS: The results of this study demonstrate that the TFI-CH is a reliable and valid measure which should be useful in both clinical and research settings for intake assessment and for measuring treatment-related changes in tinnitus. PMID- 28918677 TI - Prevalence of anal incontinence in a working population within a healthcare environment. AB - OBJECTIVES: Anal incontinence is a devastating affliction with several considerations that make it difficult to define in terms of epidemiology with good precision. The aim of the present work is to study the prevalence of an important disorder such as anal incontinence in a healthy working population within a sanitary environment. MATERIAL AND METHODS: A cluster of easy understanding and filling inquiry forms are distributed to 910 apparently healthy individuals at our hospital. This questionnaires include filiation data, passed medical history, presence or not of Incontinence and other symptoms such as urgency. The Cleveland Clinic Incontinence Score is also registered. RESULTS: Anal incontinence is present in a 21.2% of subjects when considered in any of it forms (flatus, liquid or solid faeces). A Clevleand Clinic Incontinence Score higher than 6 was obtained in a 7.3% of the sample and higher than 10 in 1.2%. No gender predominance has been identified. A slightly higher severity is recognised with increasing age. Obstetric and anal surgical background are the only related factors identified in the studied sample. CONCLUSIONS: Faecal incontinence is a high prevalent affliction, even among apparently healthy population. Considering the aetiologic factors that have been established, prevention during obstetric and anal surgical procedures is absolutely mandatory. PMID- 28918678 TI - The Affordable Care Act Medicaid Expansions and Personal Finance. AB - Using a novel data set from a major credit bureau, we examine the early effects of the Affordable Care Act Medicaid expansions on personal finance. We analyze less common events such as personal bankruptcy, and more common occurrences such as medical collection balances, and change in credit scores. We estimate triple difference models that compare individual outcomes across counties that expanded Medicaid versus counties that did not, and across expansion counties that had more uninsured residents versus those with fewer. Results demonstrate financial improvements in states that expanded their Medicaid programs as measured by improved credit scores, reduced balances past due as a percent of total debt, reduced probability of a medical collection balance of $1,000 or more, reduced probability of having one or more recent medical bills go to collections, reduction in the probability of experiencing a new derogatory balance of any type, reduced probability of incurring a new derogatory balance equal to $1,000 or more, and a reduction in the probability of a new bankruptcy filing. PMID- 28918679 TI - Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in alpha/beta. AB - BACKGROUND: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP). METHODS: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis. RESULTS: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on alpha/beta cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low alpha/beta. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as alpha/beta decreases. The TCP in proton therapy is less affected by interpatient variability in alpha/beta. On the other hand, patients with a lower alpha/beta would have a lower complication probability, which is counteracted by an increase in RBE as alpha/beta decreases. Toxicities in proton therapy would be more affected by alpha/beta variations compared to photon therapy. CONCLUSIONS: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of alpha/beta was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE. PMID- 28918680 TI - Transcranial direct current stimulation in disorders of consciousness: a review. AB - It is a challenge to evaluate and treat the patients with disorders of consciousness (DOC) in the clinic. Due to the huge costs of prolonged intensive care, the management of these patients raises great financial strain on families and important ethical questions. To date, several studies have attempted to specifically detect pharmacologic or non-pharmacologic effectiveness, and until now, there are no evidence-based guidelines about the treatment of patients with DOC. Recently, because of ethical and procedural limitations on the use of invasive stimulation techniques, non-invasive brain stimulation, such as the transcranial direct current stimulation (tDCS), has been investigated for improving the level of consciousness in patients with DOC. This paper briefly reviewed the key clinical investigations using tDCS with the aim of better understanding the pathophysiological mechanism of DOC or improving the level of consciousness in patients with DOC. In conclusion, some beneficial results of tDCS protocols have been shown in patients with DOC, especially targeting the left dorsolateral prefrontal cortex in minimally conscious state. However, these investigations must be continued in larger controlled, randomized, blinded and prospective studies in order to transpose these preliminary data to clinical effects. Furthermore, an encouraging perspective for the future is the combination of neurophysiological or functional neuroimaging techniques with non invasive brain stimulation to evaluate neuro-modulatory effects of stimulation in patients with DOC. PMID- 28918681 TI - Neonate auditory brainstem response repeatability with controlled force gauge bone-conducted stimulus delivery. AB - OBJECTIVE: The feasibility and repeatability of neonate auditory brainstem responses (ABRs) with a controlled hand-held applied force gauge for bone conducted stimulus delivery was examined. DESIGN: A repeated measures test-retest design was employed. STUDY SAMPLE: Participants were 27 healthy neonates. A 4000 Hz bone-conducted CE-Chirp octave band stimulus evoked the ABRs. Intra- and intertester conditions were employed with a prototype hand-held applied force gauge (Etymotic Research) attached to the superior aspect of the bone vibrator. The bone vibrator was placed in a superoposterior auricular position and held manually. The force gauge displayed a desired coupling force via an LED light indicator. RESULTS: Three sets of replicated ABRs were recorded from all neonates: initial test and retest with one tester (i.e. intratester 1 and 2) and final test with a second tester (i.e. intertester). No significant differences in intra- or intertester ABR wave V latencies or amplitudes were found (p > 0.05). Coefficients of reliability (Cronbach's alpha) were .95 and .43 for wave V latencies and amplitudes, respectively. CONCLUSIONS: A hand-held applied force gauge may be a reliable means of delivering controlled bone-conducted stimuli in ABR assessments in neonates and infants. PMID- 28918682 TI - Efficacy of technology-based interventions to increase the use of hearing protections among adolescent farmworkers. AB - OBJECTIVE: Adolescent farmworkers are exposed to loud noise during farm activities. We present a prospective study that evaluated the efficacy of low cost, technology-based intervention approaches in high schools to enhance the use of hearing protection among adolescent farmworkers. DESIGN: Six high schools in Iowa that agreed to participate in the study were divided into three equal groups through cluster-randomisation with each group receiving one of the three formats of hearing protection intervention: (a) classroom training, (b) classroom training coupled with smartphone app training and (c) computer training. Participants completed baseline (pre-training) and six-week post-intervention surveys for assessing hearing protection knowledge, attitudes and behaviour. STUDY SAMPLE: Seventy participants from six schools were initially enrolled but 50 completed both pre- and post-intervention surveys. RESULTS: In most cases, all three groups showed significant improvement in hearing protection knowledge, attitude and frequency of use from pre- to post-intervention. However, changes between groups were statistically non-significant. CONCLUSIONS: Although all three formats led to improvements on hearing protection knowledge, attitude and behaviour, the findings of the study, perhaps due to the small sample size, did not allow us to detect whether technology-based hearing protection interventions were more effective than the traditional face-to-face training for adolescent farmworkers. PMID- 28918683 TI - I-Through-We: How Supportive Social Relationships Facilitate Personal Growth. AB - Personal growth is usually considered an outcome of intrapersonal processes personal resources residing within the person. Comparatively, little research has examined the interpersonal processes underlying personal growth. We investigated how one interpersonal factor-people's relationships with others-influences personal growth. Study 1 showed that brief reminders of a supportive (vs. nonsupportive) other led people to choose a job that promoted personal growth over one that offered a higher salary. Moreover, feelings of self-confidence from thinking about a supportive (vs. nonsupportive) other mediated personal growth. Extending these results, Studies 2 and 3 demonstrated that people's perceptions of how supportive their close others are predicted personal growth in two distinct cultures with varying emphasis on individual (vs. collective) growth. Consistent with Study 1's findings, the results were also mediated by feelings of self-confidence. These findings suggest that the link between supportive relationships and personal growth may reflect a general process. PMID- 28918684 TI - Differential induction of c-Fos and phosphorylated ERK by a noxious stimulus after peripheral nerve injury. AB - PURPOSE: In this study, we compared induction of c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK) in the spinal dorsal horn after peripheral nerve injury. MATERIALS AND METHODS: We examined the spinal dorsal horn for noxious heat-induced c-Fos and p-ERK protein-like immunoreactive (c-Fos- and p-ERK-IR) neuron profiles after tibial nerve injury. The effect of administration of a MEK 1/2 inhibitor (PD98059) on noxious heat-induced c-Fos expression was also examined after tibial nerve injury. RESULTS: A large number of c-Fos- and p-ERK-IR neuron profiles were induced by noxious heat stimulation to the hindpaw in sham-operated animals. A marked reduction in the number of c Fos- and p-ERK-IR neuron profiles was observed in the medial 1/3 (tibial territory) of the dorsal horn at 3 and 7 days after nerve injury. Although c-Fos IR neuron profiles had reappeared by 14 days after injury, the number of p-ERK-IR neuron profiles remained decreased in the tibial territory of the superficial dorsal horn. Double immunofluorescence labeling for c-Fos and p-ERK induced by noxious heat stimulation to the hindpaw at different time points revealed that a large number of c-Fos-IR, but not p-ERK-IR, neuron profiles were distributed in the tibial territory after injury. Although administration of a MEK 1/2 inhibitor to the spinal cord suppressed noxious heat-induced c-Fos expression in the peroneal territory, this treatment did not alter c-Fos induction in the tibial territory after nerve injury. CONCLUSIONS: ERK phosphorylation may be involved in c-Fos induction in normal nociceptive responses, but not in exaggerated c-Fos induction after nerve injury. PMID- 28918685 TI - Executive Functions and Attachment Relationships in Children With ADHD: Links to Externalizing/Internalizing Problems, Social Skills, and Negative Mood Regulation. AB - OBJECTIVE: Theoretical models suggest multiple underlying pathways for ADHD and multiple risk factors' co-occurrence as impairing this population's affective, interpersonal, and behavioral adjustment. After comparing groups' executive functioning (EF) difficulties and attachment security with each parent, this study primarily aimed to examine four risk factors (ADHD, child-father attachment, child-mother attachment, EF) as possibly explaining children's socioemotional/behavioral measures (externalizing/internalizing behavior, social skills, negative mood regulation). METHOD: Participants were 100 children in Grades 5-6 (ages 11-12 years; M=11.45 years, SD=.50): 50 with formally diagnosed ADHD, and 50 with typical development (TD). Instruments were children's self report measures and teachers' evaluation. RESULTS: Significant group differences emerged on all EF measures and attachment relationships, and most socioemotional/behavioral measures. Findings demonstrated the significant contribution of children's ADHD, parental attachments, and, partially, EF difficulties in explaining children's socioemotional/behavioral adjustment. CONCLUSION: Children with ADHD, compared to children with TD, reported significantly larger EF deficits and a significantly higher incidence of insecure attachment to the father as well as a lower sense of trust and closeness to the mother. Outcomes highlighted the role of children's four risk factors (ADHD, child-father attachment, child-mother attachment, EF) in explaining their socioemotional/behavioral adjustment. The EF deficits contributed only to intrapersonal maladjustment. PMID- 28918686 TI - Sensitivity of post treatment positron emission tomography/computed tomography to detect inter-fractional range variations in scanned ion beam therapy. AB - BACKGROUND: Ion therapy, especially with modern scanning beam delivery, offers very sharp dose gradients for highly conformal cancer treatment. However, it is very sensitive to uncertainties of tissue stopping properties as well as to anatomical changes and setup errors, making range verification highly desirable. To this end, positron emission tomography (PET) can be used to measure decay products of beta+-emitters created in interactions inside the patient. This work investigates the sensitivity of post treatment PET/CT (computed tomography) to detect inter-fractional range variations. MATERIAL AND METHODS: Fourteen patients of different indication underwent PET/CT monitoring after selected treatment fractions with scanned proton or carbon ion beams. In addition to PET/CT measurements, PET and dose distributions were simulated on different co registered CT data. Pairs of PET data were then analyzed in terms of longitudinal shifts along the beam path, as surrogate of inter-fractional range deviations. These findings were compared to changes of dose-volume-histogram indexes and corresponding dose as well as CT shifts to disentangle the origin of possible PET shifts. RESULTS: Biological washout modeling (PET simulations) and low (<55 Bq/ml) activity concentrations (offline PET measurements, especially for 12C ions) were the main limitations for clinical treatment verification. For two selected cases, the benefit of improved washout modeling based on organ segmentation could be demonstrated. Overall, inter-fractional range shifts up to +/-3 mm could be deduced from both PET measurements and simulations, and found well correlated (typically within 1.8 mm) to anatomical changes derived from CT scans, in agreement with dose data. CONCLUSIONS: Despite known limitations of post treatment PET/CT imaging, this work indicates its potential for assessing inter-fractional changes and points to future developments for improved PET-based treatment verification. PMID- 28918687 TI - Comments on: Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate. PMID- 28918688 TI - Role and regulation of microRNAs targeting BTK in acute myelogenous leukemia. PMID- 28918689 TI - Chronic lymphocytic leukemia is becoming more complex: how to define complex karyotype? PMID- 28918690 TI - Hyoscine butylbromide and progress of labor in primigravidae: methodological concerns. PMID- 28918691 TI - Measuring Musculoskeletal Pain in Infants, Children, and Adolescents. AB - Synopsis Accurate, reliable, and timely assessment of pain is critical for effective management of musculoskeletal pain conditions. The assessment of pain in infants, children, and adolescents with and without cognitive impairment can be particularly challenging to clinicians for a number of reasons, including factors related to the consultation (eg, heterogeneous patient population, time constraints), the clinician (eg, awareness/knowledge of available pain scales), standardized assessment scales (eg, availability, psychometric properties, and application of each scale), the patient (eg, developmental stage, ability to communicate), and the context in which the interaction took place (eg, familiarity with the setting and physiological and psychological state). As a result, pain is frequently not assessed or measured during the consultation and, in many instances, underestimated and undertreated in this population. The purpose of this article is to provide clinicians with an overview of scales that may be used to measure pain in infants, children, and adolescents. Specifically, the paper reviews the various approaches to measure pain intensity; identifies factors that can influence the pain experience, expression, and assessment in infants, children, and adolescents; provides age-appropriate suggestions for measuring pain intensity in patients with and without cognitive impairment; and identifies ways to assess the impact of pain using multidimensional pain scales. J Orthop Sports Phys Ther 2017;47(10):712-730. doi:10.2519/jospt.2017.7469. PMID- 28918692 TI - The cyclin-dependent kinase 4/6 inhibitor, abemaciclib, exerts dose-dependent cytostatic and cytocidal effects and induces autophagy in multiple myeloma cells. AB - The D-type cyclin (CCND)-cyclin-dependent kinase 4/6 (CDK4/6) complex has been implicated in multiple myeloma development. We investigated the biological activity of CDK4/6 inhibitor abemaciclib on cell growth and survival in three myeloma cell lines, KMS-12-PE, RPMI 8226, and IM-9. Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all cell lines, with significant differences seen at a concentration of 320 nM. Treatment with 1 MUM abemaciclib increased the fraction of cells in the G0/G1 phase and decreased the fraction in the S-G2/M phases. Further, treatment with abemaciclib at a concentration of 3.2 MUM or more showed apparent cytocidal activity accompanied with cytoplasmic vacuolization against myeloma cells. Importantly, abemaciclib induced autophagy in a dose-dependent manner in all three cell lines. These results indicate that the CCND-CDK4/6 complex is closely tied to myeloma cell growth and survival. PMID- 28918693 TI - Cognitive control networks in OCD: A resting-state connectivity study in unmedicated patients with obsessive-compulsive disorder and their unaffected relatives. AB - OBJECTIVES: Executive network deficits are putative neurocognitive endophenotypes for obsessive-compulsive disorder (OCD). Yet, unlike alterations in fronto striatal and limbic connectivity, connectivity in the fronto-parietal (FPN) and cingulo-opercular (CON) networks involved in cognitive control has received little attention. METHODS: The coherence of FPN, CON and fronto-limbic networks was investigated in 39 unmedicated OCD patients, 16 of their unaffected siblings and 36 healthy controls using resting-state functional-connectivity MRI and a seed-based analysis approach. RESULTS: FPN and CON connectivity was similar for patients and controls. Siblings showed higher connectivity than patients within the CON, and between the CON and FPN compared to patients and controls (trend level). In OCD patients, but not in siblings, fronto-limbic hyperconnectivity was present compared to controls. In contrast to our expectations, no group differences in resting-state connectivity of the cognitive control networks were observed between OCD patients and controls. CONCLUSIONS: The increased within- and between-network connectivity in siblings, but not in patients, could indicate a mechanism of increased cognitive control that may act as a protective mechanism. None of the observed network alterations can be considered an endophenotype for OCD since differences were present in either patients or siblings, but not in both groups. PMID- 28918694 TI - Brain metabolic correlates of fatigue in Parkinson's disease: a PET study. AB - PURPOSE: The neural bases of fatigue in Parkinson's disease (PD) remain uncertain. We aimed to assess the brain metabolic correlates of fatigue in patients with PD. PATIENTS AND METHODS: Twenty-seven PD patients without clinically relevant depression (17-item Hamilton Depression Rating Scale (HAMD) score >= 14), apathy (Apathy Scale (AS) score >= 14) and excessive daytime somnolence (Epworth Sleepiness Scale (ESS) score >= 10) were evaluated with Fatigue Severity Scale (FSS). Each patient had an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale motor part. Levodopa equivalent daily dose for each patient was also calculated. The PET images were analyzed using statistical parametric mapping software. We introduced the age, educational level, HAMD scores, AS scores and ESS scores as covariates. RESULTS: High FSS scores were associated with brain hypermetabolism in areas including the right middle temporal gyrus (Brodmann area (BA) 37) and left middle occipital gyrus (BA 19). Increased FSS scores correlated with hypometabolism in regions such as the right precuneus (BA 23), left inferior frontal gyrus (BA 45) and left superior frontal gyrus (orbital part, BA 11). CONCLUSION: This study demonstrates that brain areas including frontal, temporal and parietal regions indicative of emotion, motivation and cognitive functions are involved in fatigue in PD patients. PMID- 28918695 TI - Large animal models of traumatic brain injury. AB - : Purpose/Aim: Animal models of traumatic brain injury (TBI) provide powerful tools to study TBI in a controlled, rigorous and cost-efficient manner. The mostly used animals in TBI studies so far are rodents. However, compared with rodents, large animals (e.g. swine, rabbit, sheep, ferret, etc.) show great advantages in modeling TBI due to the similarity of their brains to human brain. The aim of our review was to summarize the development and progress of common large animal TBI models in past 30 years. MATERIALS AND METHODS: Mixed published articles and books associated with large animal models of TBI were researched and summarized. RESULTS: We majorly sumed up current common large animal models of TBI, including discussion on the available research methodologies in previous studies, several potential therapies in large animal trials of TBI as well as advantages and disadvantages of these models. CONCLUSIONS: Large animal models of TBI play crucial role in determining the underlying mechanisms and screening putative therapeutic targets of TBI. PMID- 28918696 TI - Nature of Injury and Risk of Multiple Claims Among Workers in Manitoba Health Care. AB - In industrial societies, work-related musculoskeletal disorders are common among workers, frequently resulting in recurrent injuries, work disability, and multiple compensation claims. The risk of idiopathic musculoskeletal injuries is thought to be more than twice the risk of any other health problem among workers in the health care sector. This risk is highly prevalent particularly among workers whose job involves frequent physical tasks, such as patient lifting and transfer. Workers with recurrent occupational injuries are likely to submit multiple work disability claims and progress to long-term disability. The objective of this study was to explore the influence of injury type and worker characteristics on multiple compensation claims, using workers' compensation claims data. This retrospective study analyzed 11 years of secondary claims data for health care workers. Workers' occupational groups were classified based on the nature of physical tasks associated with their jobs, and the nature of work injuries was categorized into non-musculoskeletal, and traumatic and idiopathic musculoskeletal injuries. The result shows that risk of multiple injury claims increased with age, and the odds were highest for older workers aged 55 to 64 (odds ratio [OR] = 3.5). A large proportion of those who made an injury claim made multiple claims that resulted in more lost time than single injury claims. The study conclusion is that the nature of injury and work tasks are probably more significant risk factors for multiple claims than worker characteristics. PMID- 28918698 TI - Integrating a hip belt with body armour reduces the magnitude and changes the location of shoulder pressure and perceived discomfort in soldiers. AB - Soldiers carry heavy loads that may cause general discomfort, shoulder pain and injury. This study assessed if new body armour designs that incorporated a hip belt reduced shoulder pressures and improved comfort. Twenty-one Australian soldiers completed treadmill walking trials wearing six different body armours with two different loads (15 and 30 kg). Contact pressures applied to the shoulders were measured using pressure pads, and qualitative assessment of comfort and usability were acquired from questionnaires administered after walking trials. Walking with hip belt compared to no hip belt armour resulted in decreased mean and maximum shoulder pressures (p < 0.005), and 30% fewer participants experiencing shoulder discomfort (p < 0.005) in best designs, although hip discomfort did increase. Laterally concentrated shoulder pressures were associated with 1.34-times greater likelihood of discomfort (p = 0.026). Results indicate body armour and backpack designs should integrate a hip belt and distribute load closer to shoulder midline to reduce load carriage discomfort and, potentially, injury risk. Practitioner Summary: Soldiers carry heavy loads that increase their risk of discomfort and injury. New body armour designs are thought to ease this burden by transferring the load to the hips. This study demonstrated that designs incorporating a hip belt reduced shoulder pressure and shoulder discomfort compared to the current armour design. PMID- 28918699 TI - Effects of Weapons on Aggressive Thoughts, Angry Feelings, Hostile Appraisals, and Aggressive Behavior: A Meta-Analytic Review of the Weapons Effect Literature. AB - A landmark 1967 study showed that simply seeing a gun can increase aggression called the "weapons effect." Since 1967, many other studies have attempted to replicate and explain the weapons effect. This meta-analysis integrates the findings of weapons effect studies conducted from 1967 to 2017 and uses the General Aggression Model (GAM) to explain the weapons effect. It includes 151 effect-size estimates from 78 independent studies involving 7,668 participants. As predicted by the GAM, our naive meta-analytic results indicate that the mere presence of weapons increased aggressive thoughts, hostile appraisals, and aggression, suggesting a cognitive route from weapons to aggression. Weapons did not significantly increase angry feelings. Yet, a comprehensive sensitivity analysis indicated that not all naive mean estimates were robust to the presence of publication bias. In general, these results suggest that the published literature tends to overestimate the weapons effect for some outcomes and moderators. PMID- 28918700 TI - Dementia and Migration: Family Care Patterns Merging With Public Care Services. AB - This article focuses on cognitive impairment and dementia in the context of transnational migration. Based on data from focus group discussions and interviews, we conclude that to adjust to the needs of care within ethnic minority communities, it is important to consider not only the availability of household and kin members but also the present understanding of obligation and reciprocity underlying the perception of care. Another important issue to realize is that caregivers, women in particular, might feel obliged to conform to a traditional caregiver role, but without the support from a wider extended family, and in the context of other pressing roles and duties. Consequently, health personnel should be wary of stereotyping and generalizing groups through "othering" ideologies and rather try to explore, understand, and adjust to the present and often fluctuating set of needs, as well as be aware of how and by whom these needs are articulated. PMID- 28918701 TI - Supporting Family Involvement in Long-Term Residential Care: Promising Practices for Relational Care. AB - Family members and friends provide significant support for older relatives in long-term residential care (LTRC). Yet, they occupy ambiguous positions in these settings, and their relationships with LTRC staff can involve conflicts and challenges. Based on an ethnographic project carried out in North America and Europe, this article identifies practices that promote meaningful family participation in care home life. We consider instances of rewarding family involvement upon admission to LTRC, throughout the time a relative is living in a care home, and during the final stages of life. Furthermore, we identify working conditions needed to support the well-being of family/friend carers as well as residents and staff. These include greater appreciation of relational care work, time for effective communication, teamwork, and appropriate, inclusive physical spaces. Findings make visible the importance of relational care and have implications for improving living and working conditions in LTRC. PMID- 28918702 TI - Anterior thalamic nuclei deep brain stimulation reduces disruption of the blood brain barrier, albumin extravasation, inflammation and apoptosis in kainic acid induced epileptic rats. AB - Objective The therapeutic efficacy of anterior thalamic nuclei deep brain stimulation (ATN-DBS) against seizures has been largely accepted; however, the effects of ATN-DBS on disruption of the blood-brain barrier (BBB), albumin extravasation, inflammation and apoptosis still remain unclear. Methods Rats were distributed into four treatment groups: physiological saline (PS, N = 12), kainic acid (KA, N = 12), KA-sham-DBS (N = 12) and KA-DBS (N = 12). Seizures were monitored using video-electroencephalogram (EEG). One day after surgery, all rats were sacrificed. Then, samples were prepared for quantitative real-time PCR (qPCR), western blot, immunofluorescence (IF) staining, and transmission electron microscopy to evaluate the disruption of the BBB, albumin extravasation, inflammation, and apoptosis. Result Because of the KA injection, the disruption of the BBB, albumin extravasation, inflammation and apoptosis were more severe in the KA and the KA-sham-DBS groups compared to the PS group (all Ps < 0.05 or < 0.01). The ideal outcomes were observed in the KA-DBS group. ATN-DBS produced a 46.3% reduction in seizure frequency and alleviated the disruption of the BBB, albumin extravasation, inflammatory reaction and apoptosis in comparison to the KA-sham-DBS group (all Ps < 0.05 or < 0.01). Conclusion (1) Seizures can be reduced using ATN-DBS in the epileptogenic stage. (2) ATN-DBS can reduce the disruption of the BBB and albumin extravasation. (3) ATN-DBS has an anti inflammatory effect in epileptic models. PMID- 28918703 TI - A Randomized Multicenter Clinical Trial of RPH With the Simplified Milligan Morgan Hemorrhoidectomy in the Treatment of Mixed Hemorrhoids. AB - PURPOSE: To explore the safety and efficacy of Ruiyun procedure for hemorrhoids (RPH) or RPH with the simplified Milligan-Morgan hemorrhoidectomy (sMMH) in the treatment of mixed hemorrhoids. METHODS: This is a randomized, controlled, balanced, multicenter study of 3000 patients with mixed hemorrhoids. The outcomes and postoperative complications were compared between 5 types of surgeries. RESULTS: The efficacy rate was the highest in patients who received RPH+sMMH and decreased in the following order: patients who received RPH alone, MMH alone, procedure for prolapse and hemorrhoids (PPH) alone, and PPH+sMMH ( P < .05). The operation time was the shortest in patients who received RPH alone and increased in the following order: patients who received RPH+sMMH, PPH alone, MMH alone, and PPH+sMMH ( P < .01). The duration of postoperative hospitalization stay was the shortest in patients who received RPH alone and increased in the following order: PPH alone, RPH+sMMH, PPH+sMMH, and MMH alone ( P < .01). The incidence of postoperative hemorrhage, uroschesis, anal fissure, crissum hematoma or thrombosis, and anorectal stenosis was significantly lower in patients who received RPH+sMMH than in patients who received the other 4 types of surgical treatments ( P < .05, P < .01). No significant differences in postoperative rectovaginal fistula and anal incontinence were observed between the 5 groups of patients. CONCLUSIONS: RPH with or without simplified MMH can reduce the incidence of postoperative complications and improve the curative efficacy in the treatment of patients with mixed hemorrhoids. PMID- 28918704 TI - Professionalism among multicultural medical students in the United Arab Emirates. AB - BACKGROUND: Moral competencies and ethical practices of medical professionals are among the desired outcomes of academic training. Unfortunately, academic dishonesty and misconduct are reported from medical colleges across the world. This study investigates the level of academic dishonesty/misconduct among multicultural medical students. OBJECTIVE: The aim of this study is to investigate the level of academic dishonesty/misconduct among multicultural medical students. DESIGN: Validated and customized version of Dundee Polyprofessionalism Inventory-1 detailing lapses of professionalism in undergraduate health professions education was used to determine the perceived prevalence and self-reported lapses of academic integrity in this study. RESULTS: This study shows that the majority (458/554, 83%) of medical students have admitted to acts of academic dishonesty mentioned in the questionnaire. Approximately 42% (231/554) of the students have given proxy for attendance and 71% of them considered this as an offense. Similarly, 12% (66/554) have copied from the record books of others, and 86% (477/554) have considered it unethical. In addition, 5% (28/554) of the students revealed forging a teacher's signature in their record or logbooks, with 16% (91/554) of them reporting that they have seen others forge signatures. CONCLUSION: This is the first multi-center, multi cultural and multi-ethnic study involving a large number of participants that addresses academic professionalism among medical students in the Middle East. Certainly, the paucity of data limits definitive conclusions about the best approach to prevent academic misconduct in the UAE medical schools. Yet, the results of our study are anticipated not only to benefit the UAE but also to find application in the Arab world, with similar medical school programs, values, culture and tradition. PMID- 28918706 TI - Speech intelligibility benefits of frequency-lowering algorithms in adult hearing aid users: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review evaluated the effectiveness of two frequency lowering schemes, non-linear frequency compression and frequency transposition, at improving speech intelligibility for adult hearing-impaired populations. DESIGN: A systematic search of 10 electronic databases was carried out using pre defined inclusion criteria. Accepted articles were then critically appraised using the Effective Public Health Practice Project (EPHPP) Critical Appraisal Tool. Outcome results were further synthesised where possible using random effects meta-analysis to provide overall combined estimates of the treatment differences along with 95% confidence intervals. STUDY SAMPLE: A total of 20 articles were accepted for final review. RESULTS: Overall, study quality was of moderate strength. Meta-analysis found a statistically significant benefit in favour of frequency-lowering for consonant recognition testing in quiet across 145 participants with both algorithms providing comparable gains. Equivalent results were found between frequency-lowering and conventional processing on all other speech measures. CONCLUSIONS: Based on the available data, frequency lowering does seem to provide some improvement in an individual's speech intelligibility dependant on the stimulus type, although the benefits were modest. This improvement was not seen across all measures, however those who do not benefit from the technology will also not be harmed by trialling it. PMID- 28918705 TI - The learning space-interpersonal interactions between nursing students, patients, and supervisors at developing and learning care units. AB - PURPOSE: Previous research shows that the learning space is significant for students' learning in pairs in clinical practice but does not explain the meaning of the phenomenon. The aim of this study is thus to explain and understand the learning space that occurs in the interaction between the patients, the pairs of nursing students, and the supervisors on a developing and learning care unit in Sweden. METHOD: The study has been carried out with a Reflective Lifeworld Research (RLR) approach founded on hermeneutics. A total of 39 informants, consisting of 16 patients, five pairs of students (10 students), and 13 supervisors, were observed and interviewed. RESULTS: The results reveal that an interpersonal linkage between the patients, the students, and the supervisors is created within the learning space. A learning space, based on respect towards each other, creates the prerequisite for beneficial and supportive interactions that contribute to a deeper relationship. CONCLUSION: The phenomenon is complex due to its expandable nature and due to the fact that the learning space cannot be isolated from the surrounding environment. In order to exploit the potential of the learning space it is of importance to understand and consider the learning space as a whole. PMID- 28918707 TI - WDNfinder: A method for minimum driver node set detection and analysis in directed and weighted biological network. AB - Structural controllability is the generalization of traditional controllability for dynamical systems. During the last decade, interesting biological discoveries have been inferred by applied structural controllability analysis to biological networks. However, false positive/negative information (i.e. nodes and edges) widely exists in biological networks that documented in public data sources, which can hinder accurate analysis of structural controllability. In this study, we propose WDNfinder, a comprehensive analysis package that provides structural controllability with consideration of node connection strength in biological networks. When applied to the human cancer signaling network and p53-mediate DNA damage response network, WDNfinder shows high accuracy on essential nodes prediction in these networks. Compared to existing methods, WDNfinder can significantly narrow down the set of minimum driver node set (MDS) under the restriction of domain knowledge. When using p53-mediate DNA damage response network as illustration, we find more meaningful MDSs by WDNfinder. The source code is implemented in python and publicly available together with relevant data on GitHub: https://github.com/dustincys/WDNfinder . PMID- 28918708 TI - Removal of sulfadiazine and tetracycline in membrane bioreactors: linking pathway to microbial community shift. AB - In this study, the removal pathway of sulfadiazine (SDZ) and tetracycline (TC) and their roles in shaping microbial community were separately explored in two lab-scale membrane bioreactors (MBRs) operating in parallel with one control MBR. Results show that the MBR system eliminated more than 90% of TC in the feed, whereas removal efficiency of SDZ decreased from 100% to 40% with increasing SDZ concentrations (1-1000 MUg/L). Based on batch tests, biodegradation and adsorption was the main removal route for SDZ and TC, following pseudo-first order kinetic and pseudo-second-order kinetic model with a rate constant of 1.21 L/(g MLSS.d) and 1.91 h-1, respectively, in the acclimated sludge. As expected, the acclimated sludge possessed a higher removal potential for the antibiotics compared with unacclimated sludge. Notably, high-throughput sequencing revealed that the most abundant phylum Proteobacteria was resistant to TC (1-1000 MUg/L), but was suppressed by SDZ (100-1000 MUg/L). Members of the phylum TM7 were likely responsible for SDZ degradation. Overall, TC exhibited a stronger inhibitory effect on bacterial species and significantly reduced the biodiversity compared with SDZ, which could be strongly related to the persistent toxicity of TC to microbes resulting from its high adsorption potential on activated sludge. PMID- 28918709 TI - Prognosis and outcome of severe lithium poisoning. PMID- 28918710 TI - Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia. PMID- 28918711 TI - In Defense of Tradition: Religiosity, Conservatism, and Opposition to Same-Sex Marriage in North America. AB - Arguments opposing same-sex marriage are often made on religious grounds. In five studies conducted in the United States and Canada (combined N = 1,673), we observed that religious opposition to same-sex marriage was explained, at least in part, by conservative ideology and linked to sexual prejudice. In Studies 1 and 2, we discovered that the relationship between religiosity and opposition to same-sex marriage was mediated by explicit sexual prejudice. In Study 3, we saw that the mediating effect of sexual prejudice was linked to political conservatism. Finally, in Studies 4a and 4b we examined the ideological underpinnings of religious opposition to same-sex marriage in more detail by taking into account two distinct aspects of conservative ideology. Results revealed that resistance to change was more important than opposition to equality in explaining religious opposition to same-sex marriage. PMID- 28918712 TI - Anger Promotes Economic Conservatism. AB - Research suggests that certain facets of people's political ideals can be motivated by different goals. Although it is widely accepted that emotions motivate goal-directed behavior, less is known about how emotion-specific goals may influence different facets of ideology. In this research, we examine how anger affects political ideology and through what mechanisms such effects occur. Drawing on the dual-process motivational model of ideology and the functionalist perspective of emotion, we propose that anger leads people to support conservative economic ideals, which promote economic independence and discourage societal resource sharing. Four studies support our hypothesis that anger can enhance support for an election candidate espousing conservative economic ideals. We find that anger shifts people toward economic conservatism by orienting them toward competition for resources. Implications and future research on the relationship between emotions and political ideology are discussed. PMID- 28918713 TI - When Size Matters: Sensitivity to Missed Opportunity Size Increases With Stronger Assessment. AB - This research shows that the strength of assessment orientation, defined as the "aspect of self-regulation concerned with critically evaluating entities or states," increases a person's sensitivity to the size of a missed opportunity. Study 1 revealed that the experimental induction of an assessment orientation reduced the likelihood to act on a present offer after missing out on a large opportunity. Following a small missed opportunity, on the contrary, seizing the present offer was more likely. Studies 2 and 3 generalized this effect to chronic assessment orientations. In Study 4, the findings were replicated in a field study, which also demonstrated that differential value judgments explain assessors' sensitivity to the size of a missed opportunity. PMID- 28918714 TI - Is There a Dark Side to Mindfulness? Relation of Mindfulness to Criminogenic Cognitions. AB - In recent years, mindfulness-based interventions have been modified for use with inmate populations, but how this might relate to specific criminogenic cognitions has not been examined empirically. Theoretically, characteristics of mindfulness should be incompatible with distorted patterns of criminal thinking, but is this in fact the case? Among both 259 male jail inmates and 516 undergraduates, mindfulness was inversely related to the Criminogenic Cognitions Scale (CCS) through a latent variable of emotion regulation. However, in the jail sample, this mediational model also showed a direct, positive path from mindfulness to CCS, with an analogous, but nonsignificant trend in the college sample. Post hoc analyses indicate that the Nonjudgment of Self scale derived from the Mindfulness Inventory: Nine Dimensions (MI:ND) largely accounts for this apparently iatrogenic effect in both samples. Some degree of self-judgment is perhaps necessary and useful, especially among individuals involved in the criminal justice system. PMID- 28918715 TI - Bracing Later and Coping Better: Benefits of Mindfulness During a Stressful Waiting Period. AB - People frequently await uncertain news, yet research reveals that the strategies people naturally use to cope with uncertainty are largely ineffective. We tested the role of mindfulness for improving the experience of a stressful waiting period. Law graduates awaiting their bar exam results either reported their trait mindfulness (Study 1; N = 150) or were instructed to practice mindfulness meditation (Study 2; N = 90). As hypothesized, participants who were naturally more mindful or who practiced mindfulness managed their expectations more effectively by bracing for the worst later in the waiting period and perceived themselves as coping better. Additionally, participants who were low in dispositional optimism and high in intolerance of uncertainty benefited most from mindfulness (relative to control) meditation. These findings point to a simple and effective way to wait better, particularly for those most vulnerable to distress. PMID- 28918716 TI - The Existential Underpinnings of Intergroup Helping: When Normative and Defensive Motivations Collide. AB - Five studies examined defensive intergroup helping-when responsibility for an out group victim's injury decreases helping, whereas lack of responsibility increases helping when death is salient. In Study 1 ( N = 350), implicit death primes increased petition signings to allow a Palestinian child to receive medical treatment in Israel, when the child was a victim of Palestinian fire. When the child was a victim of Israeli fire, however, death primes decreased petition signings. Study 2 ( N = 200) partially replicated these effects on commitment to donate blood to an injured Palestinian child. Study 3 ( N = 162) found that moral affirmation primes moderate defensive helping effects. Study 4 ( N = 372) replicated defensive helping, but failed to replicate the moral affirmation effect found in Study 3. Study 5 ( N = 243) partially replicated defensive helping and found that different framings of existential threat moderate the effect. Overall, results indicate that self-protective concerns underlie prosocial responses to out-group members in need. PMID- 28918717 TI - Ecological Origins of Freedom: Pathogens, Heat Stress, and Frontier Topography Predict More Vertical but Less Horizontal Governmental Restriction. AB - What kinds of physical environments make for free societies? The present research investigates the effect of three different types of ecological stressors (climate stress, pathogen stress, and frontier topography) on two measurements of governmental restriction: Vertical restriction involves select persons imposing asymmetrical laws on others, while horizontal restriction involves laws that restrict most members of a society equally. Investigation 1 validates our measurements of vertical and horizontal restriction. Investigation 2 demonstrates that, across both U.S. states and a sample of nations, ecological stressors tend to cause more vertically restrictive societies but less horizontally restrictive societies. Investigation 3 demonstrates that assortative sociality partially mediates ecological stress->restriction relationships across nations, but not in U.S. states. Although some stressor-specific effects emerged (most notably, cold stress consistently showed effects in the opposite direction), these results in the main suggest that ecological stress simultaneously creates opposing pressures that push freedom in two different directions. PMID- 28918718 TI - Who Gets Social Support, Who Gives It, and How It's Related to Recipient's Mood. AB - We sought to identify personal characteristics associated with receiving and perceiving social support, and characteristics of support providers who give the most support and are perceived as the most available. In samples of students ( n = 755) and community adults ( n = 430), we found that people who were younger, female, more extraverted, more conscientious, and more open received and perceived more support. Female providers and romantic partners were associated with more support whereas coworkers were associated with less. In many cases, social support mediated associations between these characteristics and recipient mood. For instance, recipients reported they experience more positive mood and less negative mood when interacting with female providers. These associations were partly explained by increased received and perceived support from female providers. Notable differences emerged between received support and perceived support, and between the student and community samples. Implications for increasing support for poorly supported individuals are discussed. PMID- 28918719 TI - Is the prevalence of mental illness increasing in Australia? Evidence from national health surveys and administrative data, 2001-2014. AB - OBJECTIVES: To assess changes in the prevalence rates of probable common mental disorders (CMDs) and in rates of disability support pensions (DSPs) for people with psychiatric disorders in Australia between 2001 and 2014. DESIGN, SETTING AND PARTICIPANTS: Secondary analysis of data from five successive Australian national health surveys of representative samples of the working age population (18-65 years of age) and national data on DSP recipients. MAIN OUTCOME MEASURES: Prevalence of probable CMDs with very high symptom level (defined by a Kessler Psychological Distress Scale [K10] score of 30 or more) or with high symptom level (K10 score of 22 or more); the proportion of working age Australians receiving DSPs for psychiatric conditions. RESULTS: There was no change in the prevalence rate of probable CMDs with very high symptom levels between 2001 and 2014, but a slight decrease in the prevalence of probable CMDs with high symptoms levels, particularly among those under 45 years of age. Over the same period, the proportion of working age individuals receiving DSPs for psychiatric conditions increased by 51% (for trend, P < 0.001), equivalent to one additional DSP for every 182 working age Australians. CONCLUSIONS: Contrary to popular belief, the prevalence of probable CMDs in Australia was stable between 2001 and 2014. However, the proportion of the working age population receiving DSPs for psychiatric conditions increased dramatically over the same period. This conundrum is a major public health problem that should be further examined. PMID- 28918720 TI - The disparity between changes in the prevalence of mental illness and disability support rates in Australia. PMID- 28918722 TI - Psilocybin-assisted therapy for anxiety and depression: implications for euthanasia. PMID- 28918723 TI - Ultrasound as a treatment modality for neurological diseases. PMID- 28918724 TI - Why medically unexplained symptoms and health anxiety don't need to make your heart sink. PMID- 28918725 TI - High-pressure injection injury: benign appearance belies potentially devastating consequences. PMID- 28918726 TI - A day in the life: social media for clinical practice and medical education. PMID- 28918727 TI - Deconfounding confounding part 2: using directed acyclic graphs (DAGs). PMID- 28918728 TI - A rash diagnosis. PMID- 28918729 TI - The medical coalface of the heroin epidemic. PMID- 28918730 TI - Psychiatry training: survive and thrive. PMID- 28918731 TI - Broken promises and missing steps in mental health reform. PMID- 28918732 TI - Acupuncture for analgesia in the emergency department: a multicentre, randomised, equivalence and non-inferiority trial. AB - OBJECTIVES: This study aimed to assess analgesia provided by acupuncture, alone or in combination with pharmacotherapy, to patients presenting to emergency departments with acute low back pain, migraine or ankle sprain. DESIGN: A pragmatic, multicentre, randomised, assessor-blinded, equivalence and non inferiority trial of analgesia, comparing acupuncture alone, acupuncture plus pharmacotherapy, and pharmacotherapy alone for alleviating pain in the emergency department. Setting, participants: Patients presenting to emergency departments in one of four tertiary hospitals in Melbourne with acute low back pain, migraine, or ankle sprain, and with a pain score on a 10-point verbal numerical rating scale (VNRS) of at least 4. MAIN OUTCOME MEASURES: The primary outcome measure was pain at one hour (T1). Clinically relevant pain relief was defined as achieving a VNRS score below 4, and statistically relevant pain relief as a reduction in VNRS score of greater than 2 units. RESULTS: 1964 patients were assessed between January 2010 and December 2011; 528 patients with acute low back pain (270 patients), migraine (92) or ankle sprain (166) were randomised to acupuncture alone (177 patients), acupuncture plus pharmacotherapy (178) or pharmacotherapy alone (173). Equivalence and non-inferiority of treatment groups was found overall and for the low back pain and ankle sprain groups in both intention-to-treat and per protocol (PP) analyses, except in the PP equivalence testing of the ankle sprain group. 15.6% of patients had clinically relevant pain relief and 36.9% had statistically relevant pain relief at T1; there were no between-group differences. CONCLUSION: The effectiveness of acupuncture in providing acute analgesia for patients with back pain and ankle sprain was comparable with that of pharmacotherapy. Acupuncture is a safe and acceptable form of analgesia, but none of the examined therapies provided optimal acute analgesia. More effective options are needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12609000989246. PMID- 28918733 TI - Cupping: the risk of burns. PMID- 28918734 TI - The 2016 Royal Australian and New Zealand College of Psychiatrists guidelines for the management of schizophrenia and related disorders. AB - INTRODUCTION: The Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines for the management of schizophrenia and related disorders provide evidence-based recommendations for optimising treatment and prognosis. This update to the 2005 RANZCP guidelines has a greater emphasis on psychosocial treatments, physical health comorbidities and vocational rehabilitation. Main recommendations: The guidelines advise a clinical staging approach and deliver specific recommendations for:*comprehensive treatment using second generation antipsychotic agents continuously for 2-5 years;*early treatment of comorbid substance use;*community treatment after initial contact, during crises and after discharge from hospital;*physical health monitoring and management of comorbidities, particularly metabolic health;*interventions to optimise recovery of social function and return to study or work; and*management of schizophrenia in specific populations and circumstances. Changes in management as a result of the guidelines: The guidelines provide benchmarks against which the performance of services and clinical teams can be assessed. Measuring treatment response and clinical outcome is essential. General practitioners have an important role, particularly in monitoring and reducing the high cardiovascular risk in this population. Clinical services focusing on early detection, treatment and recovery need continuous funding to be proactive in implementing the guidelines and closing the gap between what is possible and what actually occurs. PMID- 28918735 TI - Suicide by health professionals: a retrospective mortality study in Australia, 2001-2012. PMID- 28918736 TI - Suicide by health professionals: a retrospective mortality study in Australia, 2001-2012. PMID- 28918738 TI - Nurturing rural doctors. PMID- 28918737 TI - Suicide by health professionals: a retrospective mortality study in Australia, 2001-2012. PMID- 28918740 TI - Methylglyoxal and Small Heat Shock Proteins. AB - Methylglyoxal is a highly reactive dicarbonyl compound formed during glucose metabolism and able to modify phospholipids, nucleic acids, and proteins belonging to the so-called dicarbonyl proteome. Small heat shock proteins participating in protection of the cell against different unfavorable conditions can be modified by methylglyoxal. The probability of methylglyoxal modification is increased in the case of distortion of glucose metabolism (diabetes), in the case of utilization of glycolysis as the main source of energy (malignancy), and/or at low rate of modified protein turnover. We have analyzed data on modification of small heat shock protein HspB1 in different tumors and under distortion of carbohydrate metabolism. Data on the effect of methylglyoxal modification on stability, chaperone-like activity, and antiapoptotic activity of HspB1 were analyzed. We discuss data on methylglyoxal modifications of lens alpha crystallins. The mutual dependence and mutual effects of methylglyoxal modification and other posttranslational modifications of lens crystallins are analyzed. We conclude that although there is no doubt that the small heat shock proteins undergo methylglyoxal modification, the physiological significance of this process remains enigmatic, and new experimental approaches should be developed for understanding how this type of modification affects functioning of small heat shock proteins in the cell. PMID- 28918741 TI - Design, Synthesis, and Some Aspects of the Biological Activity of Mitochondria Targeted Antioxidants. AB - This review summarizes for the first time data on the design and synthesis of biologically active compounds of a new generation - mitochondria-targeted antioxidants, which are natural (or synthetic) p-benzoquinones conjugated via a lipophilic linker with (triphenyl)phosphonium or ammonium cations with delocalized charge. It also describes the synthesis of mitochondria-targeted antioxidants - uncouplers of oxidative phosphorylation - based on fluorescent dyes. PMID- 28918742 TI - A New Concept of Action of Hemostatic Proteases on Inflammation, Neurotoxicity, and Tissue Regeneration. AB - Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases. PMID- 28918743 TI - EB-Family Proteins: Functions and Microtubule Interaction Mechanisms. AB - Microtubules are polymers of tubulin protein, one of the key components of cytoskeleton. They are polar filaments whose plus-ends usually oriented toward the cell periphery are more dynamic than their minus-ends, which face the center of the cell. In cells, microtubules are organized into a network that is being constantly rebuilt and renovated due to stochastic switching of its individual filaments from growth to shrinkage and back. Because of these dynamics and their mechanical properties, microtubules take part in various essential processes, from intracellular transport to search and capture of chromosomes during mitosis. Microtubule dynamics are regulated by many proteins that are located on the plus ends of these filaments. One of the most important and abundant groups of plus end-interacting proteins are EB-family proteins, which autonomously recognize structures of the microtubule growing plus-ends, modulate their dynamics, and recruit multiple partner proteins with diverse functions onto the microtubule plus-ends. In this review, we summarize the published data about the properties and functions of EB-proteins, focusing on analysis of their mechanism of interaction with the microtubule growing ends. PMID- 28918744 TI - Intracellular Cargo Transport by Kinesin-3 Motors. AB - Intracellular transport along microtubules enables cellular cargoes to efficiently reach the extremities of large, eukaryotic cells. While it would take more than 200 years for a small vesicle to diffuse from the cell body to the growing tip of a one-meter long axon, transport by a kinesin allows delivery in one week. It is clear from this example that the evolution of intracellular transport was tightly linked to the development of complex and macroscopic life forms. The human genome encodes 45 kinesins, 8 of those belonging to the family of kinesin-3 organelle transporters that are known to transport a variety of cargoes towards the plus end of microtubules. However, their mode of action, their tertiary structure, and regulation are controversial. In this review, we summarize the latest developments in our understanding of these fascinating molecular motors. PMID- 28918745 TI - Coupling of Translation Initiation and Termination Does Not Depend on the Mode of Initiation. AB - Recently we described a novel phenomenon observed during eukaryotic translation in a cell-free system: the coupling of initiation and termination on different mRNA molecules. Here we show that the phenomenon does not depend on a special mode of initiation. The mRNAs with certain leader sequences known to require different determinants for successful initiation were examined. Even in a case of using the intergenic internal ribosome entry site (IRES) of cricket paralysis virus RNA as the leader sequence, while no initiation factors are required, the effect of coupling is well expressed, including trials in the presence of hippuristanol as an inhibitor of eIF4A. Thus, the effect persists in the absence of scanning and does not depend on initiator tRNA and eIF2. The results suggest that the initiation factors are not involved in the coupling mechanism. PMID- 28918746 TI - Escherichia coli Signal Peptidase Recognizes and Cleaves Archaeal Signal Sequence. AB - Tk1884, an open reading frame encoding alpha-amylase in Thermococcus kodakarensis, was cloned with the native signal sequence and expressed in Escherichia coli. Heterologous gene expression resulted in secretion of the recombinant protein to the extracellular culture medium. Extracellular alpha amylase activity gradually increased after induction. Tk1884 was purified from the extracellular medium, and its molecular mass determined by electrospray ionization mass spectrometry indicated the cleavage of a few amino acids. The N terminal amino acid sequence of the purified Tk1884 was determined, which revealed that the signal peptide was cleaved between Ala26 and Ala27 by E. coli signal peptidase. To the best of our knowledge, this is the first report describing an archaeal signal sequence recognized and cleaved by E. coli signal peptidase. PMID- 28918747 TI - Omega-3 Polyunsaturated Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid Enhance Dexamethasone Sensitivity in Multiple Myeloma Cells by the p53/miR 34a/Bcl-2 Axis. AB - Dexamethasone is widely used in multiple myeloma (MM) for its cytotoxic effects on lymphoid cells. However, many MM patients are resistant to dexamethasone, although some can benefit from dexamethasone treatment. In this study, we noted that omega-3 polyunsaturated fatty acids (PUFAs) enhanced the dexamethasone sensitivity of MM cells by inducing cell apoptosis. q-PCR analysis revealed that miR-34a could be significantly induced by PUFAs in U266 and primary MM cells. Transfection with miR-34a antagonist or miR-34a agomir could restore or suppress the dexamethasone sensitivity in U266 cells. Both luciferase reporter assay and Western blot showed that Bcl-2 is the direct target of miR-34a in MM cells. In addition, we observed that PUFAs induced p53 protein expression in MM cells under dexamethasone administration. Furthermore, suppressing p53 by its inhibitor, Pifithrin-alpha, regulated the miR-34a expression and modulated the sensitivity to dexamethasone in U266 cells. In summary, these results suggest that PUFAs enhance dexamethasone sensitivity to MM cells through the p53/miR-34a axis with a likely contribution of Bcl-2 suppression. PMID- 28918748 TI - New Data on Programmed Risks of Death in Normal Mice and Mutants with Growth Delay. AB - Study of the lifespans of normal (non mutant) mice and growth delay mutants has shown that mortality rates for both kinds of animals exhibit reproducible fluctuations. In the case of the mutant mice, the positions of peaks on the differential mortality curves (mortality rate plotted against lifespan) coincided in different-sex groups of animals and in same-sex subgroups of animals. Differential mortality curves of the mutant mice also had a peak at 1 month of age that was absent from the differential mortality curves of the normal mice. In the case of normal animals, positions of most peaks were the same in the studied independent subgroups of males, and to a lesser extent - independent subgroups of females, which might be explained by a shift in mortality peak positions due to the reproductive activity of females. Similar positions of mortality rate peaks in the differential mortality curves for animals from independent groups and subgroups indicate the existence of increased risks of death at specific ages. The observed pattern could be due to the programming in the genome of both the periods of increased risk of death and the intermitting intervals of stable development. PMID- 28918749 TI - Effect of Low Temperature on Globin Expression, Respiratory Metabolic Enzyme Activities, and Gill Structure of Litopenaeus vannamei. AB - Low temperature frequently influences growth, development, and even survival of aquatic animals. In the present study, physiological and molecular responses to low temperature in Litopenaeus vannamei were investigated. The cDNA sequences of two oxygen-carrying proteins, cytoglobin (Cygb) and neuroglobin (Ngb), were isolated. Protein structure analysis revealed that both proteins share a globin superfamily domain. Real-time PCR analysis indicated that Cygb and Ngb mRNA levels gradually increased during decrease in temperatures from 25 to 15 degrees C and then decreased at 10 degrees C in muscle, brain, stomach, and heart, except for a continuing increase in gills, whereas they showed a different expression trend in the hepatopancreas. Hemocyanin concentration gradually reduced as the temperature decreased. Moreover, the activities of respiratory metabolic enzymes including lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH) were measured, and it was found that LDH activity gradually increased while SDH activity decreased after low-temperature treatment. Finally, damage to gill structure at low temperature was also observed, and this intensified with further decrease in temperature. Taken together, these results show that low temperature has an adverse influence in L. vannamei, which contributes to systematic understanding of the adaptation mechanisms of shrimp at low temperature. PMID- 28918750 TI - Expression, Purification, and Activity of ActhiS, a Thiazole Biosynthesis Enzyme from Acremonium chrysogenum. AB - Thiamine pyrophosphate is an essential coenzyme in all organisms. Its biosynthesis involves independent syntheses of the precursors, pyrimidine and thiazole, which are then coupled. In our previous study with overexpressed and silent mutants of ActhiS (thiazole biosynthesis enzyme from Acremonium chrysogenum), we found that the enzyme level correlated with intracellular thiamine content in A. chrysogenum. However, the exact structure and function of ActhiS remain unclear. In this study, the enzyme-bound ligand was characterized as the ADP adduct of 5-(2-hydroxyethyl)-4-methylthiazole-2-carboxylic acid (ADT) using HPLC and 1H NMR. The ligand-free ActhiS expressed in M9 minimal medium catalyzed conversion of NAD+ and glycine to ADT in the presence of iron. Furthermore, the C217 residue was identified as the sulfur donor for the thiazole moiety. These observations confirm that ActhiS is a thiazole biosynthesis enzyme in A. chrysogenum, and it serves as a sulfur source for the thiazole moiety. PMID- 28918751 TI - Editorial: Stay in Excellence. PMID- 28918753 TI - Neonatal intestinal obstruction associated with situs inversus totalis: two case reports and a review of the literature. AB - BACKGROUND: The association of neonatal intestinal obstruction with situs inversus totalis is extremely rare with only few cases reported in the literature to date. This association poses dilemmas in management. We present two such cases (of Indian origin), and briefly discuss the pertinent literature and measures to prevent unfavorable outcome. CASE PRESENTATION: Case 1: a 1-month-old preterm (1300 g) male neonate belonging to Hindu (Indian) ethnicity presented with recurrent bile-stained vomiting, non-passage of stools and epigastric fullness. A babygram and upper gastrointestinal contrast studies revealed situs inversus and suggested proximal jejunal obstruction with midgut volvulus. Exploration confirmed situs inversus totalis along with reverse rotation and midgut volvulus. There was a small gangrenous area in the proximal jejunal loop. A Ladd's procedure, resection of the gangrenous jejunal loop, and jejunojejunal anastomosis was performed. Note was made of the unusual appearance of the intestines suggestive either of fibrous or fatty infiltration. Postoperatively, our patient developed septicemia and died. Case 2: a 4-day-old female neonate belonging to Hindu (Indian) ethnicity, small (1320 g) for gestation, presented with history of non-passage of meconium since birth, refusal to accept feeds, and episodes of recurrent bilious vomiting with abdominal distension. A plain radiogram revealed situs inversus and proximal jejunal obstruction. Ultrasonography of her abdomen revealed renal dysplastic changes in both her kidneys. Laparotomy confirmed multiple jejunoileal atresias with situs inversus totalis. Resection anastomoses was performed for multiple atresias. Our patient passed a few pellets of meconium stools postoperatively; feeds were started gradually on the sixth day. Our patient gradually developed oliguria and renal failure, followed by respiratory distress and generalized edema requiring ventilatory support. She died later due to multiorgan failure. CONCLUSIONS: Clinicians should have high index of suspicion for malrotation with midgut volvulus or intestinal atresias in neonates of situs inversus presenting with bilious vomiting. The surgical treatment should follow the same surgical principles. In situs inversus, because of transposition of viscera, midgut volvulus may occur in an anticlockwise direction, hence derotation is performed clockwise. Prognosis was poor in our series because of low birth weight, late presentation, presence of gangrenous locus in the small bowel and development of septicemia in our first case and multiorgan fibrosis/dysplasia in our second case. Early diagnosis and timely referral is paramount for favorable outcome. PMID- 28918752 TI - Correlation of CSF flow using phase-contrast MRI with ventriculomegaly and CSF opening pressure in mucopolysaccharidoses. AB - BACKGROUND: Very little is known about the incidence and prevalence of hydrocephalus in patients with mucopolysaccharidoses (MPS). The biggest challenge is to distinguish communicating hydrocephalus from ventricular dilatation secondary to brain atrophy, because both conditions share common clinical and neuroradiological features. The main purpose of this study is to assess the relationship between ventriculomegaly, brain and cerebrospinal fluid (CSF) volumes, aqueductal and cervical CSF flows, and CSF opening pressure in MPS patients, and to provide potential biomarkers for abnormal CSF circulation. METHODS: Forty-three MPS patients (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A and 2 MPS VI) performed clinical and developmental tests, and T1, T2, FLAIR and phase contrast magnetic resonance imaging (MRI) followed by a lumbar puncture with the CSF opening pressure assessment. For the analysis of MRI variables, we measured the brain and CSF volumes, white matter (WM) lesion load, Evans' index, third ventricle width, callosal angle, dilated perivascular spaces (PVS), craniocervical junction stenosis, aqueductal and cervical CSF stroke volumes, and CSF glycosaminoglycans concentration. RESULTS: All the scores used to assess the supratentorial ventricles enlargement and the ventricular CSF volume presented a moderate correlation with the aqueductal CSF stroke volume (ACSV). The CSF opening pressure did not correlate either with the three measures of ventriculomegaly, or the ventricular CSF volume, or with the ACSV. Dilated PVS showed a significant association with the ventriculomegaly, ventricular CSF volume and elevated ACSV. CONCLUSIONS: In MPS patients ventriculomegaly is associated with a severe phenotype, increased cognitive decline, WM lesion severity and enlarged PVS. The authors have shown that there are associations between CSF flow measurements and measurements related to CSF volumetrics. There was also an association of volumetric measurements with the degree of dilated PVS. PMID- 28918755 TI - Mosaic Decisionmaking and Reemergent Agency after Severe Brain Injury. AB - Neuroethics Now welcomes articles addressing the ethical application of neuroscience in research and patient care, as well as its impact on society. PMID- 28918754 TI - Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. AB - BACKGROUND: A subanalysis of a randomized clinical trial indicated sepsis survival benefit from interleukin (IL)-1 blockade in patients with features of the macrophage activation-like syndrome (MALS). This study aimed to investigate the frequency of MALS and to develop a biomarker of diagnosis and prognosis. METHODS: Patients with infections and systemic inflammatory response syndrome were assigned to one test cohort (n = 3417) and a validation cohort (n = 1704). MALS was diagnosed for patients scoring positive either for the hemophagocytic syndrome score and/or having both hepatobiliary dysfunction and disseminated intravascular coagulation. Logistic regression analysis was used to estimate the predictive value of MALS for 10-day mortality in both cohorts. Ferritin, sCD163, IL-6, IL-10, IL-18, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) were measured in the blood the first 24 h; ferritin measurements were repeated in 747 patients on day 3. RESULTS: The frequency of MALS was 3.7% and 4.3% in the test and the validation cohort, respectively. In both cohorts, MALS was an independent risk factor for 10-day mortality. A ferritin level above 4420 ng/ml was accompanied by 66.7% and 66% mortality after 28 days, respectively. Ferritin levels above 4420 ng/ml were associated with an increase of IL-6, IL-18, INF-gamma, and sCD163 and a decreased IL-10/TNF-alpha ratio, indicating predominance of pro-inflammatory phenomena. Any less than 15% decrease of ferritin on day 3 was associated with more than 90% sensitivity for unfavorable outcome after 10 days. This high mortality risk was also validated in an independent Swedish cohort (n = 109). CONCLUSIONS: MALS is an independent life threatening entity in sepsis. Ferritin measurements can provide early diagnosis of MALS and may allow for specific treatment. PMID- 28918756 TI - Editorial. PMID- 28918758 TI - MEDICAL DEVICE RECALLS IN CANADA FROM 2005 TO 2015. AB - OBJECTIVES: Medical devices are ubiquitous in modern medical care. However, little is known about the epidemiology of medical devices in the healthcare marketplace, including the rate at which medical devices are subject to recalls or other advisories. We sought to study the epidemiology of medical devices in Canada, focusing on device recalls. In Canada, a recall may signify a variety of events, ranging from relatively minor field safety notifications, to removal of a product from the marketplace. METHODS: We used data from Health Canada to study medical device recalls in Canada from 2005 to 2015. We analyzed the risks of medical device recalls according to the risk class of the device (I lowest; IV highest) and the hazard priority of the recall (Type I highest potential harm; Type III lowest potential harm). RESULTS: During a 10-year period, there were 7,226 medical device recalls. Most recalls were for intermediate risk class (Class II, 40.1 percent; Class III, 38.7 percent) medical devices. Among recalled devices, 5.0 percent were judged to have a reasonable probability of serious adverse health consequences or death (Type I recall Hazard Priority classification). While the number of medical devices marketed in Canada is not known, over a similar 10-year period, 24,849 new Class II, II, and IV medical device licenses were issued by Health Canada. CONCLUSIONS: Several hundred medical device recalls occur in Canada each year. Further research is needed to characterize the nature of medical device recalls, and to explore how consumers use information about recalls. PMID- 28918759 TI - Ultrasonic bone aspirator use in endoscopic ear surgery: feasibility and safety assessed using cadaveric temporal bones. AB - OBJECTIVES: To describe the feasibility and assess the safety of using an ultrasonic bone aspirator in endoscopic ear surgery. METHODS: Five temporal bones were dissected via endoscopic ear surgery using a Sonopet ultrasonic bone aspirator. Atticoantrostomy was undertaken. Another four bones were dissected using routine endoscopic equipment and standard bone curettes in a similar manner. Feasibility and safety were assessed in terms of: dissection time, atticoantrostomy adequacy, tympanomeatal flap damage, chorda tympani nerve injury, ossicular injury, ossicular chain disruption, facial nerve exposure and dural injury. RESULTS: The time taken to perform atticoantrostomy was significantly less with the use of the ultrasonic bone aspirator as compared to conventional bone curettes. CONCLUSION: The ultrasonic bone aspirator is a feasible option in endoscopic ear surgery. It enables easy bone removal, with no additional complications and greater efficacy than traditional bone curettes. It should be a part of the armamentarium for transcanal endoscopic ear surgery. PMID- 28918757 TI - Relationship between Cognitive Performance and Measures of Neurodegeneration among Hispanic and White Non-Hispanic Individuals with Normal Cognition, Mild Cognitive Impairment, and Dementia. AB - OBJECTIVES: The aim of this study was to determine the presence and severity of potential cultural and language bias in widely used cognitive and other assessment instruments, using structural MRI measures of neurodegeneration as biomarkers of disease stage and severity. METHODS: Hispanic (n=75) and White non Hispanic (WNH) (n=90) subjects were classified as cognitively normal (CN), amnestic mild cognitive impairment (aMCI) and mild dementia. Performance on the culture-fair and educationally fair Fuld Object Memory Evaluation (FOME) and Clinical Dementia Rating Scale (CDR) between Hispanics and WNHs was equivalent, in each diagnostic group. Volumetric and visually rated measures of the hippocampus entorhinal cortex, and inferior lateral ventricles (ILV) were measured on structural MRI scans for all subjects. A series of analyses of covariance, controlling for age, depression, and education, were conducted to compare the level of neurodegeneration on these MRI measures between Hispanics and WNHs in each diagnostic group. RESULTS: Among both Hispanics and WNH groups there was a progressive decrease in volume of the hippocampus and entorhinal cortex, and an increase in volume of the ILV (indicating increasing atrophy in the regions surrounding the ILV) from CN to aMCI to mild dementia. For equivalent levels of performance on the FOME and CDR, WNHs had greater levels of neurodegeneration than did Hispanic subjects. CONCLUSIONS: Atrophy in medial temporal regions was found to be greater among WNH than Hispanic diagnostic groups, despite the lack of statistical differences in cognitive performance between these two ethnic groups. Presumably, unmeasured factors result in better cognitive performance among WNH than Hispanics for a given level of neurodegeneration. (JINS, 2018, 24, 176-187). PMID- 28918761 TI - Quality of life in bipolar disorder: towards a dynamic understanding. AB - BACKGROUND: Although quality of life (QoL) is receiving increasing attention in bipolar disorder (BD) research and practice, little is known about its naturalistic trajectory. The dual aims of this study were to prospectively investigate: (a) the trajectory of QoL under guideline-driven treatment and (b) the dynamic relationship between mood symptoms and QoL. METHODS: In total, 362 patients with BD receiving guideline-driven treatment were prospectively followed at 3-month intervals for up to 5 years. Mental (Mental Component Score - MCS) and physical (Physical Component Score - PCS) QoL were measured using the self-report SF-36. Clinician-rated symptom data were recorded for mania and depression. Multilevel modelling was used to analyse MCS and PCS over time, QoL trajectories predicted by time-lagged symptoms, and symptom trajectories predicted by time lagged QoL. RESULTS: MCS exhibited a positive trajectory, while PCS worsened over time. Investigation of temporal relationships between QoL and symptoms suggested bidirectional effects: earlier depressive symptoms were negatively associated with mental QoL, and earlier manic symptoms were negatively associated with physical QoL. Importantly, earlier MCS and PCS were both negatively associated with downstream symptoms of mania and depression. CONCLUSIONS: The present investigation illustrates real-world outcomes for QoL under guideline-driven BD treatment: improvements in mental QoL and decrements in physical QoL were observed. The data permitted investigation of dynamic interactions between QoL and symptoms, generating novel evidence for bidirectional effects and encouraging further research into this important interplay. Investigation of relevant time varying covariates (e.g. medications) was beyond scope. Future research should investigate possible determinants of QoL and the interplay between symptoms and wellbeing/satisfaction-centric measures of QoL. PMID- 28918760 TI - Effects of a school readiness intervention on hypothalamus-pituitary-adrenal axis functioning and school adjustment for children in foster care. AB - Maltreated children in foster care are at high risk for dysregulated hypothalamus pituitary-adrenal (HPA) axis functioning and educational difficulties. The present study examined the effects of a short-term school readiness intervention on HPA axis functioning in response to the start of kindergarten, a critical transition marking entry to formal schooling, and whether altered HPA axis functioning influenced children's school adjustment. Compared to a foster care comparison group, children in the intervention group showed a steeper diurnal cortisol slope on the first day of school, a pattern previously observed among nonmaltreated children. A steeper first day of school diurnal cortisol slope predicted teacher ratings of better school adjustment (i.e., academic performance, appropriate classroom behaviors, and engagement in learning) in the fall of kindergarten. Furthermore, the children's HPA axis response to the start of school mediated the effect of the intervention on school adjustment. These findings support the potential for ameliorative effects of interventions targeting critical transitional periods, such as the transition of formal schooling. This school readiness intervention appears to influence stress neurobiology, which in turn facilitates positive engagement with the school environment and better school adjustment in children who have experienced significant early adversity. PMID- 28918763 TI - Identifying Factors That May Influence Decision-Making Related to the Distribution of Patients During a Mass Casualty Incident. AB - OBJECTIVE: We aimed to identify and seek agreement on factors that may influence decision-making related to the distribution of patients during a mass casualty incident. METHODS: A qualitative thematic analysis of a literature review identified 56 unique factors related to the distribution of patients in a mass casualty incident. A modified Delphi study was conducted and used purposive sampling to identify peer reviewers that had either (1) a peer-reviewed publication within the area of disaster management or (2) disaster management experience. In round one, peer reviewers ranked the 56 factors and identified an additional 8 factors that resulted in 64 factors being ranked during the two round Delphi study. The criteria for agreement were defined as a median score greater than or equal to 7 (on a 9-point Likert scale) and a percentage distribution of 75% or greater of ratings being in the highest tertile. RESULTS: Fifty-four disaster management peer reviewers, with hospital and prehospital practice settings most represented, assessed a total of 64 factors, of which 29 factors (45%) met the criteria for agreement. CONCLUSIONS: Agreement from this formative study suggests that certain factors are influential to decision-making related to the distribution of patients during a mass casualty incident. (Disaster Med Public Health Preparedness. 2018;12:101-108). PMID- 28918762 TI - Standard comparison of local mental health care systems in eight European countries. AB - AIMS: There is a need of more quantitative standardised data to compare local Mental Health Systems (MHSs) across international jurisdictions. Problems related to terminological variability and commensurability in the evaluation of services hamper like-with-like comparisons and hinder the development of work in this area. This study was aimed to provide standard assessment and comparison of MHS in selected local areas in Europe, contributing to a better understanding of MHS and related allocation of resources at local level and to lessen the scarcity in standard service comparison in Europe. This study is part of the Seventh Framework programme REFINEMENT (Research on Financing Systems' Effect on the Quality of Mental Health Care in Europe) project. METHODS: A total of eight study areas from European countries with different systems of care (Austria, England, Finland, France, Italy, Norway, Romania, Spain) were analysed using a standard open-access classification system (Description and Evaluation of Services for Long Term Care in Europe, DESDE-LTC). All publicly funded services universally accessible to adults (>=18 years) with a psychiatric disorder were coded. Care availability, diversity and capacity were compared across these eight local MHS. RESULTS: The comparison of MHS revealed more community-oriented delivery systems in the areas of England (Hampshire) and Southern European countries (Verona - Italy and Girona - Spain). Community-oriented systems with a higher proportion of hospital care were identified in Austria (Industrieviertel) and Scandinavian countries (Sor-Trondelag in Norway and Helsinki-Uusimaa in Finland), while Loiret (France) was considered as a predominantly hospital-based system. The MHS in Suceava (Romania) was still in transition to community care. CONCLUSIONS: There is a significant variation in care availability and capacity across MHS of local areas in Europe. This information is relevant for understanding the process of implementation of community-oriented mental health care in local areas. Standard comparison of care provision in local areas is important for context analysis and policy planning. PMID- 28918764 TI - FRAGILE ENVIRONMENT, SEASONALITY AND MATERNAL AND CHILDHOOD UNDERNUTRITION IN BANGLADESH. AB - SummaryThis study assessed whether agricultural and household incomes were the same across different agro-ecological environments in Bangladesh. An in-depth analysis of the effect of unfavourable ecologies on maternal and child malnutrition was carried out. Data were from a longitudinal data set comprising a nationally representative data sample collected in 2014 and the Food Security Nutrition Surveillance Project (FSNSP) conducted in 2011 and 2012. Anthropometric indices were used to assess the nutritional status of mothers and under-five children. The key variables of interest were food seasonality and geographical location. Data were analysed using the General Linear Model and multinomial and binary logistic regression analysis. Panel data analysis showed that household income was not equal across agro-ecological zones, indicating that the fragility of the environment affects a household's ability to access food, and thus the nutritional status of mothers and children. Coastal areas of Bangladesh were found to be less dependent on agriculture, particularly cultivation, which had diminished during last few decades. Per capita income has been increasing in coastal areas of Bangladesh, led by remittance (money sent home by migrant workers) growing at 8% per year against 6% in other areas. Regression analysis showed that a household in a coastal zone earned 19% less than one in more favourable zones. Although the income from farm practices was found to be lower in unfavourable areas, the deficiency was compensated by increased non-farm incomes. The results from the FSNSP data showed that overall the rates of stunting and wasting among under-five children were 37% and 11.7%, respectively, and nearly 28% of mothers suffered from undernutrition. A highly significant regional heterogeneity in undernutrition was found, with alarmingly high levels in the Haor Basin and coastal belt areas. There were significantly higher rates of underweight and wasting in the monsoon season compared with the two harvest seasons among children under the age of five. The findings stress the importance of bringing geographical location and seasonality thinking into debates on hunger and nutrition in Bangladesh. PMID- 28918765 TI - Three-Dimensional (3D) Nanometrology Based on Scanning Electron Microscope (SEM) Stereophotogrammetry. AB - Three-dimensional (3D) reconstruction of a sample surface from scanning electron microscope (SEM) images taken at two perspectives has been known for decades. Nowadays, there exist several commercially available stereophotogrammetry software packages. For testing these software packages, in this study we used Monte Carlo simulated SEM images of virtual samples. A virtual sample is a model in a computer, and its true dimensions are known exactly, which is impossible for real SEM samples due to measurement uncertainty. The simulated SEM images can be used for algorithm testing, development, and validation. We tested two stereophotogrammetry software packages and compared their reconstructed 3D models with the known geometry of the virtual samples used to create the simulated SEM images. Both packages performed relatively well with simulated SEM images of a sample with a rough surface. However, in a sample containing nearly uniform and therefore low-contrast zones, the height reconstruction error was ~46%. The present stereophotogrammetry software packages need further improvement before they can be used reliably with SEM images with uniform zones. PMID- 28918766 TI - Measuring and Comparing Hospital Accessibility for Palm Beach County's Elderly and Nonelderly Populations During a Hurricane. AB - OBJECTIVES: To determine whether, during a hurricane, geographic accessibility to hospitals with emergency care is compromised disproportionately for the elderly than for the nonelderly. METHODS: The locations of hospitals with emergency health care and a subset of those hospitals functional during a hurricane were compared with the distribution of the elderly population at the block group level in Palm Beach County, Florida. Geographic Information Systems (GIS) proximity analysis (minimum distance to closest hospital) and cumulative distribution functions were used to measure and compare hospital accessibility during normal and hurricane conditions for the elderly and nonelderly populations. RESULTS: Accessibility to closest functional hospital during a hurricane was compromised disproportionately for the elderly. CONCLUSION: Geographic accessibility to emergency health care is compromised disproportionately for the elderly in Palm Beach County. Compounding the risk is the likelihood of the elderly experiencing a greater health care need during a hurricane. This poses a community public health crisis and calls for effective and collaborative planning between health professionals and disaster planners to address the health care needs of the elderly. (Disaster Med Public Health Preparedness. 2018; 12: 296-300). PMID- 28918767 TI - Refractive Index Imaging of Cells with Variable-Angle Near-Total Internal Reflection (TIR) Microscopy. AB - The refractive index in the interior of single cells affects the evanescent field depth in quantitative studies using total internal reflection (TIR) fluorescence, but often that index is not well known. We here present method to measure and spatially map the absolute index of refraction in a microscopic sample, by imaging a collimated light beam reflected from the substrate/buffer/cell interference at variable angles of incidence. Above the TIR critical angle (which is a strong function of refractive index), the reflection is 100%, but in the immediate sub-critical angle zone, the reflection intensity is a very strong ascending function of incidence angle. By analyzing the angular position of that edge at each location in the field of view, the local refractive index can be estimated. In addition, by analyzing the steepness of the edge, the distance-to substrate can be determined. We apply the technique to liquid calibration samples, silica beads, cultured Chinese hamster ovary cells, and primary culture chromaffin cells. The optical technique suffers from decremented lateral resolution, scattering, and interference artifacts. However, it still provides reasonable results for both refractive index (~1.38) and for distance-to substrate (~150 nm) for the cells, as well as a lateral resolution to about 1 um. PMID- 28918768 TI - Postnatal Developmental Changes in Fractal Complexity of Giemsa-Stained Chromatin in Mice Spleen Follicular Cells. AB - Although there are numerous recent works focusing on fractal properties of DNA and chromatin, many issues regarding changes in chromatin fractality during physiological aging remain unclear. In this study, we present results indicating that in mice, there is an age-related reduction of chromatin fractal complexity in a population of spleen follicular cells (SFCs). Spleen tissue was obtained from 16 mice and fixated in Carnoy solution. The youngest animal was newborn, and each animal was exactly 1 month older than the previous. We performed fractal analysis of SFC chromatin structure, stained using Giemsa technique. Fractal analysis was done in a plugin algorithm of ImageJ software. We also performed gray-level co-occurrence matrix (GLCM) analysis of all chromatin structures with the calculation of parameters such as angular second moment and inverse difference moment. Giemsa-stained SFC chromatin exhibited an age-dependent reduction of fractal dimension with statistically significant (p<0.01) linear trend. Moreover, there was a statistically significant increase of SFC chromatin lacunarity. The chromatin GLCM parameters did not significantly change. To our knowledge, this is the first study to perform fractal and GLCM analyses of SFC chromatin and to investigate potential changes of fractal parameters during postnatal development. PMID- 28918769 TI - Emergency physicians' attitudes and perceived barriers to the implementation of take-home naloxone programs in Canadian emergency departments. AB - OBJECTIVES: Rates of opioid-related deaths have reached the level of national public health crisis in Canada. Community-based opioid overdose education and naloxone distribution (OEND) programs distribute naloxone to people at risk, and the emergency department (ED) may be an underutilized setting to deliver naloxone to these people. The goal of this study was to identify Canadian emergency physicians' attitudes and perceived barriers to the implementation of take-home naloxone programs. METHODS: This was an anonymous Web-based survey of members of the Canadian Association of Emergency Physicians. Survey questions were developed by the research team and piloted for face validity and clarity. Two reminder emails were sent to non-responders at 2-week intervals. Respondent demographics were collected, and Likert scales were used to assess attitudes and barriers to the prescription of naloxone from the ED. RESULTS: A total of 459 physicians responded. The majority of respondents were male (64%), worked in urban tertiary centres (58.3%), and lived in Ontario (50.6%). Overall, attitudes to OEND were strongly positive; 86% identified a willingness to prescribe naloxone from the ED. Perceived barriers included support for patient education (57%), access to follow-up (44%), and inadequate time (37%). In addition to people at risk of overdose, 77% of respondents identified that friends and family members may also benefit. CONCLUSIONS: Canadian emergency physicians are willing to distribute take-home naloxone, but thoughtful systems are required to facilitate opioid OEND implementation. These data will inform the development of these programs, with emphasis on multidisciplinary training and education. PMID- 28918770 TI - The Forgotten Need of Disaster Relief. AB - Disasters in countries with limited resources can put the emergency preparedness of the country to the test. The first major task after a disaster is to take care of the wounded. In countries where the epidemiological transition has occurred, chronic disease can place a major strain on public health preparedness after a disaster. The purpose of this field report is to alert public health practitioners of an infrequently reported public health problem: the impact of natural disasters on adherence to chronic medications. In our experience, the most common complaint in the weeks that followed the 2016 earthquake was not having access to their chronic medications. (Disaster Med Public Health Preparedness. 2018; 12: 291-295). PMID- 28918771 TI - Falls in hospitalized geriatric psychiatry patients: high incidence, but only a few fractures. AB - Fall rates from 3.2 to 17.1 falls per 1,000 hospital days in geriatric psychiatry facilities have been reported to date. Up to 5% of the falls result in severe injuries, but data concerning medical consequences are scare. This brief report presents a retrospective analysis of one year fall protocols from a geriatric psychiatry department focusing on consequences of falls. Fall-induced injuries were rated in four categories: no injuries, mild injuries (contusions, hematomas, abrasions), moderate injuries (lacerations, dislocations), and severe injuries (fractures, cerebral hemorrhages). In total, 510 falls were registered during the study period, indicating a fall rate of 17.7 falls per 1,000 hospital days. Overall, 375 falls (73.5%) resulted in no injuries, 67 (13.1%) resulted in mild injuries, 59 (11.6%) resulted in moderate injuries, and only 9 (1.8%) falls led to severe injuries (fractures and cerebral hemorrhages). These results indicate a quite high fall rate in our sample of hospitalized geriatric psychiatry patients with only a relatively small number of severe injuries resulting from the falls. These results raise the question about the use of physical restraints and the use of bedrails in geriatric patients to prevent falls as the medical implications of falls may be less problematic than previously thought. PMID- 28918773 TI - Contribution of Prior, Multiple-, and Repetitive Surgeries to the Risk of Surgical Site Infections in the Netherlands. AB - OBJECTIVE Surveillance is an important strategy to reduce the incidence of surgical site infections (SSIs). We investigated whether prior, multiple-, or repetitive surgeries are risk factors for SSI and whether they should be preserved in the protocol of the Dutch national SSI surveillance network. METHODS Dutch national SSI surveillance data 2012-2015 were selected, including 34 commonly performed procedures from 8 major surgical specialties. Definitions of SSIs followed international standardized criteria. We used multivariable multilevel logistic regression techniques to evaluate whether prior, multiple-, or repetitive procedure(s) are risk factors for SSIs. We considered surgeries clustered within partnerships of medical specialists and within hospitals (random effects) and different baseline risks between surgical specialties (fixed effects). Several patient and surgical characteristics were considered possible confounders and were included where necessary. We performed analyses for superficial and deep SSIs combined as well as separately. RESULTS In total, 115,943 surgeries were reported by 85 hospitals; among them, 2,960 (2.6%) resulted in SSIs (49.3% deep SSIs). The odds ratio (OR) for having prior surgery was 0.94 (95% confidence interval [CI], 0.74-1.20); the OR for repetitive surgery was 2.39 (95% CI, 2.06-2.77); and the OR for multiple surgeries was1.27 (95% CI, 1.07-1.51). The latter effect was mainly caused by prolonged duration of surgery. CONCLUSIONS Multiple- and repetitive surgeries significantly increased the risk of an SSI, whereas prior surgery did not. Therefore, prior surgery is not an essential data item to include in the national SSI surveillance network. The increased risk of SSIs for multiple surgeries was mainly caused by prolonged duration of surgery, therefore, it may be sufficient to report only duration of surgery to the surveillance network, instead of both (the variables duration of surgery and multiple surgeries). Infect Control Hosp Epidemiol 2017;38:1298-1305. PMID- 28918772 TI - Incidence and risk factors for Dengue virus (DENV) infection in the first 2 years of life in a Brazilian prospective birth cohort. AB - This study assessed the incidence and risk factors for dengue virus (DENV) infection among children in a prospective birth cohort conducted in the city of Recife, a hyperendemic dengue area in Northeast Brazil. Healthy pregnant women (n = 415) residing in Recife who agreed to have their children followed were enrolled. Children were followed during their first 24 months of age (May/2011 June/2014), before the 2015 Zika virus outbreak. DENV infection was detected by reverse-transcriptase polymerase chain reaction and/or serology (anti-DENV IgM/IgG). The incidence rates per 1000 person-years (py) and its association with risk factors by age bands (0-12, >12-30 months) were estimated through Poisson regression models. Forty-nine dengue infections were detected; none progressed to severe forms. The incidence rates were 107.6/1000py (95% CI 76.8-150.6) and 93.3/1000py (95% CI 56.1-154.4) in the first and second years of age, respectively. Male children (risk ratios (RR) = 2.33; 95% CI 1.09-4.98) and those born to DENV-naive mothers (RR = 2.42; 95% CI 1.01-5.80) were at greater risk of infection in the first year of age. In the second year, children born to Caucasian/Asian descent skin colour mothers had a threefold higher risk of infection (RR = 3.34; 95% CI: 1.08-10.33). These data show the high exposure of children to DENV infection in our setting and highlight the role of biological factors in this population's susceptibility to infection. PMID- 28918774 TI - Dietary patterns and depressive symptoms in a UK cohort of men and women: a longitudinal study. AB - OBJECTIVE: There is evidence to suggest that individual components of dietary intake are associated with depressive symptoms. Studying the whole diet, through dietary patterns, has become popular as a way of overcoming intercorrelations between individual dietary components; however, there are conflicting results regarding associations between dietary patterns and depressive symptoms. We examined the associations between dietary patterns extracted using principal component analysis and depressive symptoms, taking account of potential temporal relationships. DESIGN: Depressive symptoms in parents were assessed using the Edinburgh Postnatal Depression Scale (EPDS) when the study child was 3 and 5 years of age. Scores >12 were considered indicative of the presence of clinical depressive symptoms. Diet was assessed via FFQ when the study child was 4 years of age. SETTING: Longitudinal population-based birth cohort. SUBJECTS: Mothers and fathers taking part in the Avon Longitudinal Study of Parents and Children when their study child was 3-5 years old. RESULTS: Unadjusted results suggested that increased scores on the 'processed' and 'vegetarian' patterns in women and the 'semi-vegetarian' pattern in men were associated with having EPDS scores >=13. However, after adjustment for confounders all results were attenuated. This was the case for all those with available data and when considering a sub-sample who were 'disease free' at baseline. CONCLUSIONS: We found no association between dietary patterns and depressive symptoms after taking account of potential confounding factors and the potential temporal relationship between them. This suggests that previous studies reporting positive associations may have suffered from reverse causality and/or residual confounding. PMID- 28918776 TI - [Prophylactic antibiotic therapy for hernia repair]. AB - This article aims at outlining and recommending use of prophylactic antibiotic therapy for hernia repair according to literature and newly released guidelines. We do not recommend prophylaxis for elective repair of inguinal and ventral hernias in a low infection risk environment as Denmark except in patients with incisional hernia > 10 cm or presumed increased risk for wound infection, e.g. diabetes or immunosuppression. Antibiotic prophylaxis should always be used in emergent hernia repair. We recommend a prophylactic regimen of second-generation cephalosporin given as a single dose perioperatively. PMID- 28918775 TI - Frankia asymbiotica sp. nov., a non-infective actinobacterium isolated from Morella californica root nodule. AB - The taxonomic status of strain M16386T, a nitrogen-fixing but non-nodulating isolate from Morella californica, was established on the basis of a polyphasic approach. The strain grows as branched hyphae, with vesicles and non-motile productive multilocular sporangia. It metabolizes short fatty acids, TCA cycle intermediates and carbohydrates as carbon sources, and fixes nitrogen in the absence of combined nitrogen source in the growth media. Chemotaxonomic traits of strain M16386T are consistent with its affiliation to the genus Frankia. The characteristic diamino acid in the cell wall is meso-diaminopimelic acid. Strain M16386T contains phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol, glycophospholipid and phospholipid as polar lipids; MK 9(H4) and MK-9(H6) as the predominant menaquinones; iso-C16 : 0 and C17 : 1omega8c as major fatty acids; and galactose, glucose, mannose, rhamnose and ribose as whole-cell sugars. Strain M16386T showed 98.2 % 16S rRNA gene sequence similarity with its closest phylogenetic neighbour, Frankia inefficaxDSM 45817T. Based on these results, strain M16386T (=DSM 100626T=CECT 9040T) is designated the type strain of a novel species of the genus Frankia,for which the name Frankia asymbiotica sp. nov. is proposed. PMID- 28918777 TI - [Classic psychedelic drugs and their potential therapeutic effect]. AB - Over the past decade we have witnessed a renewed scientific interest in the classic hallucinogens (psychedelic drugs). These are substances which exert their effects by an agonist action on the 5-HT2A receptors. The purpose of this paper is to provide a short review and discussion of the psychedelic drugs, their safety profile and their potential antidepressive, anxiolytic and antiaddictive effects. The article primarily focusses on the most recent clinical trials. PMID- 28918778 TI - [Monilethrix is a hereditary hair shaft disorder]. AB - Monilethrix is a rare genodermatosis with high penetrance and variable expressivity. This is a case report of a Danish family with varying phenotypical presentations. The family members were diagnosed using dermatoscopy and microscopy, which were subsequently supported by gene sequence analysis. No cure of monilethrix exists, but a single case report shows promising results using low dosage of oral minoxidil. Reducing hair dressing trauma to diminish weathering remains the best prophylaxis. PMID- 28918780 TI - [Martorells sar]. PMID- 28918779 TI - [Acutely induced diabetes mellitus in a 63-year-old female after treatment with ipilimumab for metastatic melanoma]. AB - Immune checkpoint inhibitors have improved survival rate in patients with advanced melanoma, but also have the potential to induce several adverse events. We report on a 63-year-old woman who had advanced melanoma and was admitted with diabetic ketoacidosis, which had occurred upon treatment with ipilimumab. On admission, the C-peptide level was low, and the HbA1c concentration was 50 mmol/l indicating a rapid onset of the disease. The patient had also been diagnosed with thyroiditis. Diabetes mellitus is a rare and serious side effect of treatment with ipilimumab, and we recommend being aware of this due to the rapid course. PMID- 28918781 TI - ? PMID- 28918782 TI - ? PMID- 28918783 TI - [Treatment of patellofemoral pain includes more than knee rehabiliation]. AB - Patellofemoral pain is a debilitating condition which affects one in 14 adolescents and a similar number of adults. It is characterized by peri- or retropatellar pain during loaded bending of the knee. The purpose of this review is to provide a short, up-to-date review of the diagnostics, differential diagnostics and evidence-based treatment for both adolescents and adults with patellofemoral pain. The key message is that treatments of patellofemoral pain should include a combination of patient education to support self-management and exercises to strengthen the hip and knee muscles. PMID- 28918784 TI - [Treatment of patellar instability]. AB - First-time patellar luxation appears typically in teenagers and young adults below the age of 16 years, with a prevalence of 45/100,000/year. This luxation is treated with brief limited mobility in a bandage, and with a complementary physiotherapy if the mobility is influenced afterwards. Risk factors for patellar instability are patellofemoral dysplasia, hyperlaxity, patella alta and valgus malalignment in the knee joint. In case of repeated luxation the treatment is surgical, i.e. reconstruction of the medial patellofemoral ligament recreating the medial patella-stabilizing structures. If the dysplasia is severe, tuberositas tibiae-osteotomy and trochlea plastic can correct a lateral tracking of the knee joint. Generally, patella-stabilizing surgery is successful with a reluxation rate of only a few per cent. PMID- 28918785 TI - [Algorithm for workup of acute swollen knee without previous trauma]. AB - Acute non-traumatic swelling of the knee is a common clinical challenge. The reason for the swelling has to be explored in order to give the correct treatment. This article gives an overview of possible diagnoses and suggests an algorithm for an approach to non-traumatic knee arthritis. Fundamental in the examination is a thorough patient anamnesis, which will help to differentiate between inflammatory and non-inflammatory arthritis. If there is not an obvious degenerative reason for the knee effusion, a joint aspiration followed by synovial fluid white cell count (WCC), microscopy and/or culture will add valuable information. Also, a normal C-reactive protein value together with synovial fluid WCC below 2,000 per cubic mm will make a septic arthritis diagnosis unlikely. PMID- 28918786 TI - [Treatment of meniscal pathology]. AB - The menisci play a major role in knee function regarding joint movement, stability, load distribution and load transmission. Injuries to the menisci cause pain, and meniscal tears are a common reason for patient referral. In Denmark, partial meniscectomy increased significantly until 2010, and several studies have questioned the long-term effect of meniscectomy as an overall procedure. A Danish national clinical guideline on knee meniscal pathology was published in May 2016, and this article is a short summary of updated knowledge on meniscal pathology and relevant conclusions from the guideline. PMID- 28918787 TI - [Running and causes of running-related injuries]. AB - Running is one of the most popular sports among the adult Danish population. Overuse injuries of the knee, such as runners knee, jumpers knee, patello-femoral pain syndrome and patello-femoral pre-arthrosis, are common and cause reduction of the health beneficial physical activity. Treatment should primarily focus on adjustment of training habits and physiotherapeutic guided rehabilitation. Other treatment options include changing landing pattern during running, corticosteroid injections, non-steroid anti-inflammatory drugs and ultimately surgery. PMID- 28918788 TI - [Fast-track total knee arthroplasty]. AB - Fast-track total knee arthroplasty (TKA) is a well-established concept including optimized logistics and evidence-based treatment, focusing on minimizing surgical stress and improved post-operative recovery, thus leading to lower mortality and morbidity as well as high patient satisfaction. All patients are eligible for fast-track TKA, and hence the fast-track concept should be standard at all joint replacement facilities. Future challenges of fast-track TKA include safe introduction of outpatient protocols, acute and chronic pain after surgery and optimal utilization of post-operative physiotherapy. PMID- 28918789 TI - [Treatment of anterior cruciate ligament ruptures]. AB - Anterior cruciate ligament (ACL) injuries are typically seen in cutting sports. Rehabilitation can be tried in athletes in non-cutting sports and in recreational athletes. If knee instability is experienced, the cessation of risk activities or reduction in activity level are recommended. With recurrent episodes of instability ACL-reconstruction is recommended. 65% return to sports at preinjury level after ACL-reconstruction, 18% after non-operated partial rupture and 7% after non-operated total rupture. PMID- 28918790 TI - [Bandages for knee problems]. AB - The use of knee braces is common, and there is an abundance of different brace types available both "over the counter" and as "prescription devices". The braces are used for a range of knee problems ranging from minor knee discomfort to post surgical rehabilitation. The available evidence is generally in favour of brace applications although the amount and quality of evidence is moderate to low with a positive benefit-harm balance. However, braces should generally not be used as a stand-alone or primary treatment strategy, but can be used as a potentially beneficial supplement to patients with knee disorders if needed. PMID- 28918791 TI - [Periostal avulsion of m. vastus medialis in a triathlete during competition]. AB - Periostal avulsion of m. vastus medialis is a very rare injury. To our knowledge, it has not previously been described, and there is no treatment algorithm. A 32 year-old male professional triathlete experienced this type of injury during a final sprint in a competition. He achieved a good functional result after treatment with an optimal rehabilitation regimen, and approximately four months after the injury he won a medal in a major international event. PMID- 28918792 TI - [Dural arteriovenous fistula is a rare, but treatable cause of transverse myelitis]. AB - This is a case report of a 60-year-old male admitted on suspicion of relapse of idiopathic transverse myelitis (TM), who after further diagnostic workup underwent successful closure of a dural arteriovenous fistula (DAVF). Magnetic resonance imaging in DAVF usually shows longitudinal TM, which, unlike DAVF, is also seen with the more common inflammatory or infectious causes usually showing inflammation in the cerebrospinal fluid. The natural history of DAVF is progressive. Since curable options exist, timely diagnosis is most important. PMID- 28918793 TI - [Workup and treatment of gastroparesis]. AB - Gastroparesis is defined as impaired gastric emptying without mechanical obstruction and cardinal symptoms including vomiting, nausea, early satiety, and upper abdominal pain. Most cases of gastroparesis are diabetic, idiopathic or post-operative. The correlation between symptoms and objective measures of gastroparesis is poor. Basic treatment includes dietary advices and prokinetics. Selected patients not responding to basic treatment can be offered gastric electrical stimulation. In many cases, gastroparesis is present in combination with other motility disorders, especially constipation. PMID- 28918794 TI - [Airplane travels can induce headache]. AB - Airplane headache is a common problem with 100 million passengers annually suffering from the condition. It has been suggested that the changes in the cabin pressure during take-off and landing may cause inflammation in sinus tissues. This can lead to elevated levels of prostaglandin E2 and vasodilation of cerebral arteries resulting in airplane headache. Current evidence suggests opportunities to develop a treatment plan by examining future potential drugs for reducing the prostaglandin E2 level or preventing the vasodilation of the cerebral arteries. PMID- 28918795 TI - [Acute-on-chronic liver failure]. AB - Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute decompensation of liver cirrhosis, organ failure and high short-term mortality (20-80% at one month). The main precipitants are infections and excessive alcohol intake, and the mechanistic features include a high level of systemic inflammation, macrophage activation and liver injury. The severity of ACLF is graded according to the number and extent of organ failures. Prognostic scores help predict mortality and support decisions on intensive treatment or futility. PMID- 28918796 TI - Erratum to "Recommendations for the multidisciplinary management of tuberous sclerosis complex" [MedClin(Barc)147(5) (2016) 211-216]. PMID- 28918797 TI - The Early History of Interventional Endoscopic Ultrasound. AB - Technological advances in the field of endoscopic ultrasound (EUS) have emerged, especially in the past decade, that have rapidly expanded the therapeutic potential of EUS, largely through the innovations of accessory technology that could not have happened without innovative changes to echoendoscopes. As interventional EUS continues to evolve, further expansion into previously uncharted areas will most certainly happen. PMID- 28918798 TI - New Imaging Techniques: Endoscopic Ultrasound-Guided Elastography. AB - Endoscopic ultrasound (EUS) is a major imaging method in the management of several diseases of the gastrointestinal tract and surrounding structures. Elastography is a novel technique providing additional information to standard B mode imaging on the tissue stiffness. Elastography can be performed under EUS guidance. This method has proven to be an accurate and additional tool in the evaluation of pancreatic diseases and lymph nodes analysis. Possible uses include the study of liver lesions, subepithelial masses, and many more. This article reviews current knowledge and future perspectives. PMID- 28918799 TI - New Imaging Techniques for Endoscopic Ultrasonography: Contrast-Enhanced Endoscopic Ultrasonography. AB - Conventional endoscopic ultrasonography (EUS) has limitations in the diagnosis of solid masses. Because most are depicted as a hypoechoic mass, without cytology or biopsy, it can be difficult to distinguish inflammatory masses from malignancy. Recently developed, contrast-enhanced harmonic EUS (CH-EUS) has improved characterization of digestive lesions by depicting microvessels and parenchymal perfusion, particularly for differentiating pancreatic cancer from other pancreatic solid lesions, identifying mural nodules in intraductal papillary mucinous neoplasms, and estimating malignant potential of gastrointestinal stromal tumors. CH-EUS is complementary to EUS-guided fine-needle aspiration for diagnosing pancreatic lesions, staging, and predicting chemotherapy response. PMID- 28918800 TI - New Developments in Endoscopic Ultrasound Tissue Acquisition. AB - Endoscopic ultrasound (EUS)-guided tissue acquisition has greatly evolved since the first EUS-guided fine-needle aspiration was reported nearly 25 years ago. EUS guided tissue acquisition has become the procedure of choice for sampling of the pancreas, subepithelial lesions, and other structures adjacent to the gastrointestinal tract. This review focuses on recent developments in procedural techniques and needle technologies for EUS-guided tissue acquisition. PMID- 28918801 TI - Endoscopic Ultrasonography with Fine-needle Aspiration: New Techniques for Interpretation of Endoscopic Ultrasonography Cytology and Histology Specimens. AB - Significant advances have been made in the last few years in the technologies for sampling pancreatic masses, and in the understanding of the biology of pancreatic cancer. Better and more targeted treatments are likely to become available. Because most pancreatic cancers are likely to remain unresectable at diagnosis, high-quality, high-cellularity specimens are essential. A tailored approach that considers indication, location, and treatment possibilities needs to be taken before embarking on a pancreatic biopsy. Because the demand from oncologists and patients for increasingly personalized therapy is likely to grow, optimal sampling beyond diagnostic accuracy is likely to become increasingly critical. PMID- 28918802 TI - Endoscopic Ultrasound Imaging for Diagnosing and Treating Pancreatic Cysts. AB - Cystic pancreatic lesions are increasingly diagnosed owing to the abundant use of cross-sectional imaging. Given their malignant potential, true pancreatic cysts should be considered for resection or periodic follow-up. Cystic lesions of the pancreas (CLPs) require further evaluation and management. Therefore, it is important to establish a solid diagnosis at the time of detection. Endoscopic ultrasound examination is the imaging modality of choice. Fine needle aspiration provides fluid for cytologic, biochemical, and molecular assays to classify lesions and predict biological behavior. This review provides an overview of the diagnosis and management of various types of commonly encountered true CLPs. PMID- 28918803 TI - The Role of Endoscopic Ultrasound in the Diagnosis of Autoimmune Pancreatitis. AB - Autoimmune pancreatitis (AIP) is increasingly being recognized due to improved understanding of the disease and its criteria for diagnosis. The classic type 1 AIP can be diagnosed on clinical data, but type 2 AIP requires histologic confirmation. Current criteria incorporate cross-sectional imaging and endoscopic retrograde cholangiopancreatography in the diagnosis of AIP. However, endoscopic ultrasound (EUS) will likely have an increasing role in the diagnosis through its characteristic imaging, image-enhancing techniques, and its ability to acquire tissue through either fine needle aspiration or biopsy. This article will review the diagnostic challenges of AIP and the current role of EUS. PMID- 28918804 TI - Recent Advances in Therapeutic Endosonography for Cancer Treatment. AB - Therapeutic endosonography (EUS) may play an important role in the management of cancers. EUS-guided fiducial placement has a high success rate and can aid in stereotactic radiotherapy. EUS-guided tumor ablation therapies can help in palliation of locally advanced tumors. EUS-guided antitumor injection seems to be feasible and safe in animals; initial human studies suffer from small sample size and lack of controls. Randomized, controlled trials have not shown benefit over conventional therapy. EUS celiac plexus neurolysis has gained popularity and is performed by interventional endosonographers. Large trials are needed to determine the most appropriate indications and overall usefulness of these therapies. PMID- 28918805 TI - Endoscopic Ultrasonography-Guided Techniques for Accessing and Draining the Biliary System and the Pancreatic Duct. AB - When endoscopic retrograde cholangiopancreatography (ERCP) fails to decompress the biliary system or the pancreatic duct, endoscopic ultrasonography (EUS) guided biliary or pancreatic access and drainage can be used. Data show a high success rate and acceptable adverse event rate for EUS-guided biliary drainage. The outcomes of EUS-guided biliary drainage seem equivalent to percutaneous drainage and ERCP, whereas only retrospective studies are available for pancreatic duct drainage. In this article, revision of the technical and clinical status and the current evidence of interventional EUS-guided biliary and pancreatic duct access and drainage are presented. PMID- 28918806 TI - Endoscopic Ultrasound-Guided Gastrojejunostomy. AB - Gastric outlet obstruction is a common complication of advanced upper gastrointestinal and pancreatic malignancies. Endoscopic ultrasound (EUS)-guided gastrojejunostomy is a new option that may provide a more durable solution than enteral stenting with shorter recovery time and less cost than surgical gastrojejunostomy. Techniques to perform this procedure include direct EUS-guided puncture and balloon-assisted and free-hand methods. Use of cautery-tipped lumen apposing metal stent results in higher rates of technical success and shorter procedure times. Prospective studies are needed to compare EUS-gastrojejunostomy with enteral stenting and surgical gastrojejusntomy, and to clarify indications, optimal patient selection, and most appropriate method of technically performing this procedure. PMID- 28918807 TI - Endoscopic Ultrasonography-guided Drainage of Pancreatic Collections, Including the Role of Necrosectomy. AB - In recent years, the management of symptoms of pancreatic fluid collections has shifted from surgical and percutaneous interventions to endoscopic techniques. Available data show that endoscopic drainage can be achieved with minimal morbidity and procedural-related mortality, a high degree of technical and clinical success, and acceptable risk of adverse events. Although endoscopic management of walled-off necrosis provides a durable, minimally invasive treatment option, it is still generally performed only in tertiary care medical centers because of the overall complexity of this clinical scenario. PMID- 28918808 TI - Endoscopic Ultrasound-Guided Drainage of Pelvic Fluid Collections. AB - Pelvic fluid collections can be challenging and often inaccessible because of their location and close proximity to adjacent organs and spine. This causes an increased risk for morbidity and poor outcomes. Recent advances in endoscopic ultrasound and therapeutic devices provide an effective, safe, and minimally invasive option to surgery or interventional radiology. These devices offer a relatively pain-free method that has shown good outcomes with minimal risk in recent case series, and has increasingly become the first-line treatment of choice. This article summarizes the current literature and the technique and considerations for successful drainage of these collections. PMID- 28918809 TI - Endoscopic Ultrasonography-Guided Hemostasis Techniques. AB - Endoscopic ultrasonography (EUS)-guided hemostasis is an evolving technique that has the potential to improve the care of patients with refractory variceal and nonvariceal gastrointestinal bleeding. EUS-guided treatment of fundal varices with coil and/or cyanoacrylate seems to be highly effective in active bleeding, as well as for primary and secondary bleeding prophylaxis. Reports of EUS-guided treatment of refractory nonvariceal sources of bleeding are more scarce, but show high success rates. The procedures involve a medium to high technical difficulty level, and this has been replicated worldwide. PMID- 28918810 TI - Progress in Endoscopic Ultrasonography: Training in Therapeutic or Interventional Endoscopic Ultrasonography. AB - Therapeutic endoscopic ultrasound is a rapidly expanding field, requiring training beyond the 3-year gastroenterology fellowship and at least an additional year in a structured advanced endoscopy fellowship program with mentorship from an expert at a sufficiently high-volume center. Simulation models can provide initial instruction on technique and increase familiarity with the rapidly changing devices. Trainees must also be given a graduated level of independence to perform each step and, eventually, be able to practice on a variety of endoscopic targets. With structured competency markers, trainees can learn methods to maximize success and minimize the risk of complications. PMID- 28918811 TI - Future Directions for Endoscopic Ultrasound: Where Are We Heading? AB - Endoscopic ultrasound (EUS) plays an important role as a diagnostic and therapeutic modality in gastroenterology. New developments have emerged, especially in the last decade, and are being introduced to endoscopists. The ability to readily visualize and access organs in the gastrointestinal tract has allowed endoscopists to perform new interventional procedures. EUS procedures have taken the place of conventional approaches for the treatment of various gastrointestinal diseases, including pancreatic cystic lesions. This article focuses on the advances and future of diagnostic and therapeutic EUS. PMID- 28918812 TI - Endoscopic Ultrasound Becomes a Major Interventional Tool. PMID- 28918813 TI - Progress in Endoscopic Ultrasonography. PMID- 28918814 TI - Peptide & protein ligation. PMID- 28918815 TI - Corrigendum to "Protocol for quality control in metabolic profiling of biological fluids by U(H)PLC-MS" [J. Chromatogr. B 1008 (2016) 15-25]. PMID- 28918817 TI - Unfinalisability and the authorship of life - Narratives of young-old women from Taiwan. AB - This study investigates and presents the narratives of Taiwanese women who have reached the young-old stage. The narrative interview method was used for data collection from 12 Taiwanese women. After analysing the recurring themes emerging from the women's life histories, it is found that the meanings of these Taiwanese women's narratives could not be finalised according to traditional Confucian norms. These women rebelled, resisted, and resumed authorship to make changes to their lives in a patriarchal society. The women were reflexive, and had constant struggles. The findings also reveal a prominent characteristic of Taiwanese culture that emphasises relationships. The women were able to pursue their dreams to involve themselves in self-care, leisure, aesthetic activities, and classes for their personal growth and pleasure. PMID- 28918816 TI - "They are different now" - Biographical continuity and disruption in nursing home settings. PMID- 28918818 TI - The dementias - A review and a call for a disaggregated approach. PMID- 28918819 TI - The promise of documentary theatre to counter ageism in age-friendly communities. AB - This paper discusses an innovative theatre-arts collaboration that was created to provoke public discourse about aging in a community located in the Southeastern United States in which more than one-half of residents are age 50 or older. The development and execution of the documentary theatre production are explicated and the post-performance talk-backs with the audience are shared to illustrate how it facilitated insight and dialogue among its largely older audiences. Experience with this production suggests that academics can collaborate with professional artists to promote the subjective experience of aging as a positive appreciation of self. Consequently, the play holds promise to counter deeply ingrained negative self-beliefs about aging and foster greater acceptance about the experience of others. In addition, the play represents a unique community based effort to enhance respect and social inclusion, a core domain of livability in the age-friendly community movement. PMID- 28918820 TI - On gray dancing: Constructions of age-normality through choreography and temporal codes. AB - Against the background of population aging, older peoples dance has attracted attention in research and its health promoting effects and social meanings have been brought to the fore. In this article we focus on the context and power dimensions of dance with an emphasis on the organizing of dance among older adults in terms of social discourses and age relationships. On the basis of qualitative interviews with 33 older dancers and 11 dance providers in Sweden, the study illustrates how dance is organized through social discourses on healthism and on the increasing group of older people as a powerful consumer group. The study highlights that older people and their social dance contexts are marked and subordinated in relation to younger age groups through non-verbal practices such as choreography and temporal codes. In short, dancing among older adults is not only a common health promoting and social activity, but also an arena in which age and age normality are negotiated and constructed. PMID- 28918821 TI - Explaining the continuum of social participation among older adults in Singapore: from 'closed doors' to active ageing in multi-ethnic community settings. AB - OBJECTIVES: This study aims to identify and explain the continuum in which older people in Singapore participate in community and social life, highlighting the influence of culture and policy context on social participation. METHODS: Using an ethnographic approach in a neighbourhood (n=109), we conducted focus groups with older adults of different ethnicities, exploring experiences of social participation. Next, participants took 50 photographs relating to 'lives of elders', showcasing the socio-ecological context that influenced social participation. Lastly, go-along interviews were conducted in various precincts with community leaders. RESULTS: A continuum of social participation emerged among older adults, ranging from (1) marginalization and exclusion, to (2) 'comfort-zoning' alone (3) seeking consistent social interactions, (4) expansion of social network, and (5) giving back to society. Seeking consistent social interactions was shaped by a preference for cultural grouping and ethnic values, but also a desire for emotional safety. Attitudes about expanding one's social network depended on the psychosocial adjustment of the older person to the prospect of gossip and 'trouble' of managing social relations. Despite the societal desirability of an active ageing lifestyle, cultural scripts emphasizing family meant older adults organized participation in social and community life, around family responsibilities. Institutionalizing family reliance in Singapore's welfare approach penalized lower-income older adults with little family support from accessing subsidies, and left some living on the margins. DISCUSSION: To promote inclusiveness, ageing programs should address preferences for social participation, overcoming barriers at the individual, ethnic culture and policy level. PMID- 28918822 TI - A theoretical model to explain the smart technology adoption behaviors of elder consumers (Elderadopt). AB - A growing global population of older adults is potential consumers of a category of products referred to as smart technologies, but also known as telehealth, telecare, information and communication technologies, robotics, and gerontechnology. This paper constructs a theoretical model to explain whether older people will adopt smart technology options to cope with their discrepant individual or environmental circumstances, thereby enabling them to age in place. Its proposed constructs and relationships are drawn from multiple academic disciplines and professional specialties, and an extensive literature focused on the factors influencing the acceptance of these smart technologies. It specifically examines whether older adults will substitute these new technologies for traditional coping solutions that rely on informal and formal care assistance and low technology related products. The model argues that older people will more positively evaluate smart technology alternatives when they feel more stressed because of their unmet needs, have greater resilience (stronger perceptions of self-efficacy and greater openness to new information), and are more strongly persuaded by their sources of outside messaging (external information) and their past experiences (internal information). It proposes that older people distinguish three attributes of these coping options when they appraise them: perceived efficaciousness, perceived usability, and perceived collateral damages. The more positively older people evaluate these attributes, the more likely that they will adopt these smart technology products. PMID- 28918823 TI - Impacts of organizational ties for senior centers: Findings from a collective case study in Portland, Oregon. PMID- 28918824 TI - New perspectives on healthy aging. PMID- 28918825 TI - Potassium Is Nearly Everywhere. PMID- 28918826 TI - Islamic Medicine in the Middle Ages. AB - The Islamic culture flourished between the 9th and 13th centuries. Scholars from this era made significant contributions in mathematics, science and medicine. Caliphs and physicians built hospitals that provided universal care and the foundation for medical education. Physician-scientists made significant advances in medical care, surgery and pharmacology. Notable authorities include al-Razi (865-925 CE) who wrote the Kitab al-Hawi fi al-tibb (The Comprehensive Book on Medicine), a 23-volume textbook that provided the main medical curriculum for European schools into the 14th century. Ibn Sina (980-1037 CE), an extraordinary Persian polymath, wrote al Qanun fi al-Tibb (The Canon of Medicine), an encyclopedic treatment of medicine that combined his own observations with medical information from Galen and philosophy from Aristotle. Mansur (1380-1422 CE) wrote the first color illustrated book on anatomy. Other important physicians compiled information on the use of medication from plants, advanced surgical techniques, including cataract extraction and studied physiology, including the pulmonary circulation. These books and ideas provided the basis for medical care in Europe during its recovery from the Dark Ages. PMID- 28918827 TI - Indwelling Pleural Catheters for Nonmalignant Effusions: Evidence-Based Answers to Clinical Concerns. AB - Pleural effusions occur in 1.5 million patients yearly and are a common cause of dyspnea. For nonmalignant effusions, initial treatment is directed at the underlying cause, but when effusions become refractory to medical therapy, palliative options are limited. Tunneled pleural catheters (TPCs) are commonly used for palliation of malignant effusions, but many clinicians are reluctant to recommend these devices for palliation of nonmalignant effusions, citing concerns of infection, renal failure, electrolyte disturbances and protein-loss malnutrition. Based on the published experience to date, TPCs relieve dyspnea and can result in spontaneous pleurodesis in patients with nonmalignant effusions. The infection rate compares favorably to that for malignant effusions with possible increased risk in patients with hepatic hydrothorax and posttransplant patients. Renal failure, electrolyte disturbance and protein-loss malnutrition have not been observed. TPCs are a reasonable option in select patients to palliate nonmalignant effusions refractory to maximal medical therapy. PMID- 28918828 TI - Crescentic Glomerulonephritis With Immunoglobulin G4-Related Disease. AB - Immunoglobulin G4 (IgG4)-related disease is an uncommon autoimmune disease that affects multiple organ systems. Renal involvement typically presents as tubulointerstitial nephritis and less commonly as membranous glomerulonephritis. In this case report, we discuss a 68-year-old patient who presented with rapidly progressive glomerulonephritis. His renal biopsy revealed a membranoproliferative pattern of injury with fibrocellular crescents and extensive infiltration of the tubulointerstitium with IgG4-positive plasma cells. We treated the patient with both corticosteroids and rituximab because of the aggressive nature of crescentic glomerulonephritis. The patient demonstrated a partial improvement in kidney function after 2 cycles of rituximab with a decrease in serum creatinine levels from 6.9-4.7mg/dL after 6 months from presentation. This case illustrates the importance of considering IgG4-related disease in cases of rapidly progressive glomerulonephritis and the need for effective treatments for more aggressive forms of this recently recognized disease entity. PMID- 28918829 TI - Awareness of Individual Cardiovascular Risk Factors and Self-Perception of Cardiovascular Risk in Women. AB - BACKGROUND: Cardiovascular risk factors (CVRFs) self-perception by women may be inaccurate. MATERIALS AND METHODS: A questionnaire was completed anonymously Online by women who self-reported their personal CVRF levels including age, weight, contraceptive use, menopausal status, smoking, diet and physical activities. Self-perceived risk was matched to actual cardiovascular risk according to the Framingham score. RESULTS: Among 5,240 young and middle-aged women with a high educational level, knowledge of personal CVRFs increased with age, from 51-90% for blood pressure (BP), 22-45% for blood glucose and 15-47% for blood cholesterol levels, between 30 and 65 years, respectively. This knowledge was lower for smoking compared with nonsmoking women: 62.5% vs. 74.5% for BP (P < 0.001), 22.7% vs. 33.8% for blood glucose (P < 0.001), 21.9% vs. 32.0% for cholesterol levels (P < 0.001). Knowledge of BP level was reduced among women using an estrogen-progestogen contraception (56.8% vs. 62.1%, P = 0.0031) and even more reduced among smokers (52.2%, P < 0.001). Conversely, women with leisure-time physical or sportive activity (60.5%), were less overweight or obese (22.4% vs. 34.2%, P < 0.001). They reported better knowledge of BP (72.4% vs. 68.3%, P < 0.001), blood cholesterol (31.1% vs. 26.4%, P < 0.001) and glucose levels (32.7% vs. 27.8%, P < 0.001). Self-perceived cardiovascular risk was rated low by 1,279 (20.4%), moderate by 3,710 (63.3%) and high by 893 (16.3%) women. Among 3,386 women tested using the Framingham score, 40.8% were at low, 25.2% at moderate and 33.8% at high risk. CONCLUSIONS: Knowledge of CVRFs and self perception of individual risk are inaccurate in women. Educational interventions should be emphasized. PMID- 28918830 TI - Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer. AB - BACKGROUND: Metformin (MF), a diabetic drug, has antineoplastic activity as adjuvant therapy for breast cancer and prostate cancer. MF is thought to work via inhibition of mammalian target of rapamycin and activation of p53 and liver kinase B1 via adenosine 5'-monophosphate-activated protein kinase. We investigated survival, recurrences and metastasis in patients with type 2 diabetes mellitus (DM2) along with colorectal cancer (CC) or lung cancer (LC) taking MF using the electronic medical record in Memphis Veterans Affairs Medical Center (colon, n = 202; lung, n = 180). MATERIALS AND METHODS: Patients with CC or LC and DM2 on MF were compared to controls taking any medication except MF. Recurrences, metastases, secondary cancers, survival and carcinoembryonic antigen levels were compared using t test and chi-squared test. Inclusion criteria were based on MF use, CC or LC diagnosis and DM2. RESULTS: For CC, the MF group noted fewer deaths (48% versus 76%, P < 0.001), recurrences (4% versus 19%, P = 0.002), metastases (23% versus 46%, P = 0.001), better 5-year survival rates (57% versus 37%, P = 0.004), overall survival years (5.7 versus 4.1, P = 0.007) and greater carcinoembryonic antigen decrease (72% versus 47%, P = 0.015). MF was associated with improved 5-year survival rates (29% versus 15%, P = 0.023) and overall survival years (3.4 versus 1.8, P < 0.001) in LC. CONCLUSIONS: Our study shows that MF therapy is associated with significantly better prognosis in patients with CC and improved survival in LC. Patients with CC on MF had fewer recurrences and metastases. Differences in metabolic pathways between CC and LC likely account for the differences in the effect of MF. PMID- 28918831 TI - A Comparative Analysis of Serum IgG4 Levels in Patients With IgG4-Related Disease and Other Disorders. AB - OBJECTIVE: Elevated serum IgG4 levels are an important hallmark for diagnosing IgG4-related disease (IgG4-RD) but can also be found and reported in other diseases. The present study intended to compare the serum IgG4 levels in both IgG4-RD and non-IgG4-RD and determine the serum IgG4 levels in patients with IgG4 RD before and after glucocorticoid therapy. METHODS: The study included 323 patients from Anhui Medical University Affiliated Provincial Hospital (China) and was conducted from July 2014-January 2016. A total of 25 patients were eventually diagnosed as having IgG4-RD, according to the IgG4-RD diagnostic criteria. Our study also included 108 patients with connective tissue disease, 94 patients with pancreatic lesions, 66 patients with bile duct lesions, 13 patients with carcinoma of the duodenal papilla and 20 control participants. The assay for serum IgG4 detection was peformed using the nephelometric method. RESULTS: Elevated levels of serum IgG4 (>1.35g/L) were detected in all patients with IgG4 RD, and reduced levels of serum IgG4 (<1.35g/L) were found in all patients with non-IgG4-RD. The serum IgG4 level in patients with IgG4-RD after glucocorticoid therapy was significantly lower than that before glucocorticoid therapy (t = 2.426, P = 0.04). CONCLUSIONS: High levels of IgG4 were observed in IgG4-RD. However, a diagnosis of IgG4 disease can not only be dependent on the detection of elevated serum IgG4 levels but also may need clinical manifestations, serology, histopathology and other comprehensive information for verification. PMID- 28918832 TI - Streptococcus anginosus Group Bacterial Infections. AB - BACKGROUND: The Streptococcus anginosus group (SAG) causes a variety of infections in adults. To better understand the burden of SAG infections and their associated morbidity and mortality, we conducted a retrospective analysis of these infections in adults at a tertiary care center. METHODS: A retrospective review of all cultures positive for SAG in adults and a corresponding review of the patients' medical records were conducted at a tertiary care facility in central New York. Patients with these cultures during the period of January 2007 December 2011 were included. Demographic data, area of residence, clinical features and underlying illnesses, site of infection, length of hospital stay, antibiotic susceptibility and antibiotic therapy were recorded and analyzed. RESULTS: There were 332 SAG cases; most patients were males (59%), mean age of 47 years and 84% lived in urban areas. Overall mortality was 3% with underlying conditions common such as diabetes (25%), hypertension (31%) and immunodeficiency (22%). Most of the infections were related to skin and soft tissue (72%) and polymicrobial (70%) with gram-negative anaerobes and Enterobacteriaceae commonly isolated with SAG. CONCLUSIONS: We present the largest study, thus far, reviewing the clinical presentation, management and outcome of infections due to the SAG of organisms. Notable findings from our study are the low mortality associated with SAG infection, and the propensity to present as a skin and tissue and polymicrobial infection. Our findings will assist clinicians in managing patients with SAG infections and recognizing that S anginosus may be one of several organisms responsible for infection. PMID- 28918833 TI - Recurrence of Barcelona Clinic Liver Cancer Stage A Hepatocellular Carcinoma After Hepatectomy. AB - BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) staging system is widely used to classify hepatocellular carcinoma (HCC). This study was performed to investigate the prognostic factors for patients with BCLC stage A HCC after R0 hepatectomy. METHODS: A total of 592 patients with BCLC stage A HCC following R0 hepatectomy from 1997-2012 were enrolled in this study. Kaplan-Meier analysis and Cox regression were used to analyze the risk factors associated with recurrence. Receiver operating characteristic curves were used to establish a new scoring system to evaluate the independent risk factors for recurrence. Furthermore, subgroup analyses were performed to evaluate surgical margins on tumor recurrence between the anatomic and nonanatomic resection group. RESULTS: Independent risk factors for BCLC stage A HCC recurrence were preoperative alanine transaminase >40U/L, liver cirrhosis, surgical margin <5mm, nonanatomic resection and maximum tumor diameter >5cm. Based on these 5 risk factors, we established a new scoring system, named "HCC recurrence scoring system." Patients with a high score (>=3 points, 1 point for each factor) composed the high recurrence risk group. Moreover, the subgroup analyses demonstrated that different surgical margins had no significant effect on tumor recurrence in the anatomic resection group (P = 0.408), while it had a significant effect in the nonanatomic resection group (P = 0.000). CONCLUSIONS: For patients with BCLC stage A with scores >=3 points, close postoperative follow-up and positive measures to prevent recurrence are particularly important. Anatomic resection is preferred for patients with BCLC stage A. Adequate surgical margins are necessary for patients with poor liver function. PMID- 28918834 TI - Elevated Admission Potassium Levels and 1-Year and 10-Year Mortality Among Patients With Heart Failure. AB - BACKGROUND: Limited, contradictory data exist regarding the effect of hyperkalemia on both short- and long-term all-cause mortality among hospitalized patients with heart failure (HF). METHODS: We analyzed 4,031 patients who were enrolled in the Heart Failure Survey in Israel. The study patients were grouped into 3 different potassium (K) categories. Multivariate analysis was used to determine the association of potassium levels as well as 1- and 10-year all-cause mortality. RESULTS: A total of 3,349 patients (83%) had K < 5mEq/L, whereas 461 patients (11%) had serum K >= 5mEq/L but<= 5.5mEq/L and 221 patients (6%) had K > 5.5mEq/L. Survival analysis showed that 1-year mortality rates were significantly higher among patients with K > 5.5mEq/L (40%) and those with serum K >= 5mEq/L but <= 5.5mEq/L (34%) compared to those with K < 5mEq/L (27%); (all log rank P < 0.01). Similarly, 10-year mortality rates among those with K > 5.5mEq/L were 92%, whereas among those with serum K >= 5mEq/L but <= 5.5mEq/L rates were 88%, and in those with K < 5mEq/L rates were 82%; (all log rank P < 0.001). Consistently, multivariate analysis showed that compared to patients with K < 5mEq/L, patients with K > 5.5mEq/L had an independently 51% and 31% higher mortality risk at 1 year and 10 years, respectively (1-year hazard ratio = 1.51, 95% CI: 1.04-2.2; 10 years hazard ratio = 1.31, 95% CI: 1.035-1.66), whereas patients with serum K >= 5mEq/L but <= 5.5mEq/L had comparable adjusted mortality risk to patients with K < 5mEq/L at 1 and 10 years. CONCLUSIONS: Among hospitalized patients with HF, admission K > 5.5mEq/L was independently associated with increased short- and long-term mortality, whereas serum K >= 5mEq/L but <= 5.5mEq/L was not independently associated with worse outcomes. PMID- 28918835 TI - Left Ventricular False Tendons are Associated With Left Ventricular Dilation and Impaired Systolic and Diastolic Function. AB - BACKGROUND: Left ventricular false tendons (LVFTs) are chord-like structures that traverse the LV cavity and are generally considered to be benign. However, they have been associated with arrhythmias, LV hypertrophy and LV dilation in some small studies. We hypothesize that LVFTs are associated with LV structural and functional changes assessed by echocardiography. METHODS: We retrospectively evaluated echocardiographic and clinical parameters of 126 patients identified as having LVFTs within the past 2 years and compared them to 85 age-matched controls without LVFTs. RESULTS: There were no significant differences in age (52 +/- 18 versus 54 +/- 18 years, P = 0.37), sex (55% versus 59% men, P = 0.49), race (36% versus 23% white, P = 0.07), systolic blood pressure (131 +/- 22 versus 132 +/- 23mmHg, P = 0.76) or body mass index (BMI, 31 +/- 8 versus 29 +/- 10kg/m2, P = 0.07) between controls and patients with LVFTs, respectively. Patients with LVFTs had more prevalent heart failure (43% versus 21%, P = 0.001). Patients with LVFTs had more LV dilation, were 2.5 times more likely to have moderate-to-severe mitral regurgitation, had more severe diastolic dysfunction and reduced LV systolic function (18% lower) compared with controls (all P < 0.05). After adjustment for covariates, basal and middle LVFT locations were associated with reduced LV systolic function (P < 0.01), and middle LVFTs were associated with LV dilation (P < 0.01). CONCLUSIONS: Our findings suggest that LVFTs may not be benign variants, and basal and middle LVFTs may have more deleterious effects. Further prospective studies should be performed to determine their pathophysiological significance and whether they play a causal role in LV dysfunction. PMID- 28918836 TI - Role of Microalbuminuria in Predicting Cardiovascular Mortality in Individuals With Subclinical Hypothyroidism. AB - PURPOSE: Studies suggest that subclinical hypothyroidism (SCH) is related to cardiovascular mortality (CVM). We explored the role of microalbuminuria (MIA) as a predictor of long-term CVM in population with and without SCH with normal kidney function. MATERIALS AND METHODS: We examined the National Health and Nutrition Education Survey - III database (n = 6,812). Individuals younger than 40 years, thyroid-stimulating hormone levels >=20 and <=0.35mIU/L, estimated glomerular filtration rate <60mL/minute/1.73m2 and urine albumin-to-creatinine ratio of >250mg/g in men and >355mg/g in women were excluded. SCH was defined as thyroid-stimulating hormone levels between 5 and 19.99mIU/L and serum T4 levels between 5 and 12ug/dL. MIA was defined as urine albumin-to-creatinine ratio of 17 250mg/g in men and 25-355mg/g in women. Patients were categorized into the following 4 groups: (1) no SCH or MIA, (2) MIA, but no SCH, (3) SCH, but no MIA and (4) both SCH and MIA. RESULTS: Prevalence of MIA in the subclinical hypothyroid cohort was 21% compared to 16.4% in those without SCH (P = 0.03). SCH was a significant independent predictor of MIA (n = 6,812), after adjusting for traditional risk factors (unadjusted odds ratio = 1.75; 95% CI: 1.24-2.48; P = 0.002 and adjusted odds ratio = 1.83; 95% CI: 1.2-2.79; P = 0.006). MIA was a significant independent predictor of long-term all-cause (adjusted hazard ratio = 1.7, 95% CI: 1.24-2.33) and CVM (adjusted hazard ratio = 1.72, 95% CI: 1.07-2.76) in subclinical hypothyroid individuals. CONCLUSIONS: In a cohort of subclinical hypothyroid individuals, the presence of MIA predicts increased risk of CVM as compared to nonmicroalbuminurics with SCH. Further randomized trials are needed to assess the benefits of treating microalbuminuric subclinical hypothyroid individuals and impact on CVM. PMID- 28918837 TI - Diagnostic Value of Noninvasive Computed Tomography Perfusion Imaging and Coronary Computed Tomography Angiography for Assessing Hemodynamically Significant Native Coronary Artery Lesions. AB - BACKGROUND: The objective of this study is to determine the diagnostic performance of computed tomography perfusion (CTP) with and without computed tomography angiography (CTA) in assessment of hemodynamically significant coronary artery lesions in comparison to invasive fractional flow reserve (FFR). MATERIALS AND METHODS: PubMed and Cochrane Center Register of Controlled Trials from January 2010 searched through December 2014. Nine original studies were selected evaluating the diagnostic performance of CTP with and without CTA to invasive coronary angiography in evaluation of hemodynamic significance of coronary lesions (n = 951). RESULTS: The sensitivity, specificity, LR+ and LR- and DOR of CTA+CTP were 0.85 [95% confidence interval (CI: 0.79-0.89)] 0.94 (CI: 0.91-0.97), 15.8 (CI: 7.99-31.39), 0.146 (CI: 0.08-0.26), and 147.2 (CI: 69.77 310.66). Summary Receiver Operating Characteristics (SROC) results showed area under the curve (AUC) of 0.97 indicating that CTA+CTP may detect hemodynamically significant coronary artery lesions with high accuracy. The sensitivity, specificity, LR+ and LR- and DOR of CTP were 0.83 (CI: 0.78-0.87), 0.84 (CI: 0.80 0.87) 5.26 (CI: 2.93-9.43), 0.209 (CI: 0.12-0.36), and 31.97 (CI: 11.59-88.20). CONCLUSIONS: This result suggests that CTP with CTA significantly improves diagnostic performance of coronary artery lesions compared to CTA alone and closely comparable with invasive FFR. PMID- 28918838 TI - Inhibition of Midkine Suppresses Prostate Cancer CD133+ Stem Cell Growth and Migration. AB - BACKGROUND: Midkine (MDK) is a tumor-promoting factor that is often overexpressed in various human carcinomas, and the role of MDK has not yet been fully investigated in prostate cancer stem cells. MATERIALS AND METHODS: Prostate cancer CD133+ stem cells (PCSCs) were isolated from human castration-resistant PC3 cells. PCSCs were treated with different concentrations of MDK inhibitor, iMDK, for 24-72 hours. The IC50 values were determined by the MTT test. Endogenous MDK messenger RNA expression was knocked down by small interfering RNA. Quantitative reverse transcription polymerase chain reaction, Western blot analyses and image-based cytometry were used to investigate apoptosis and cell cycle progression as well as their underlying molecular mechanisms. Cell migration was evaluated by the wound healing test. RESULTS: iMDK caused dose- and time-dependent inhibition of PCSC survival. Similar growth inhibition was also obtained by small interfering RNA-mediated knockdown of endogenous MDK expression. iMDK was shown to preferentially induce cell cycle arrest at the S and G2/M phases. Suppressed PCSC growth was also accompanied by increases in p53 and the cell cycle inhibitor p21 genes. Combinatorial treatment of iMDK with docetaxel significantly inhibited cell proliferation versus either of the agents used alone. Inhibition of MDK expression strongly suppressed the migration of PCSCs compared to untreated and docetaxel-treated cells. iMDK and the knockdown of MDK decreased p-Akt and significantly upregulated the expression of PI3K/phosphatase/tensin homolog. CONCLUSIONS: Our data indicate that MDK plays a crucial role in controlling PCSC proliferation and migration. Therefore, suppression of endogenous expression of MDK would, in combination with traditional chemotherapy drugs, be a potential treatment for PCSCs. PMID- 28918840 TI - Neuroprotective Effects of Eexenatide in a Rotenone-Induced Rat Model of Parkinson's Disease. AB - BACKROUND: Several studies suggest an association between Parkinson's disease (PD) and type 2 diabetes mellitus; these 2 diseases are both known to affect the common molecular pathways. As a synthetic agonist for the glucagon-like peptide 1 receptor, exenatide has been evaluated as a neuroprotective agent in multiple animal models. Rotenone models of PD have great potential for the investigation of PD pathology and motor and nonmotor symptoms, as well as the role of gene environment interactions in PD causation and pathogenesis. Therefore, in this study, the neurochemical, behavioral and histologic effects of exenatide on a rotenone-induced rat model of PD were examined. MATERIALS AND METHODS: Eighteen adult male rats were randomly divided into the following 3 groups (n = 6): 1 group received stereotaxical infusion of dimethyl sulfoxide (vehicle, group 1) and the others received stereotaxical infusion of rotenone (groups 2 and 3). Apomorphine-induced rotation test was applied to the rats after 10 days. Thereafter, group 2 was administered isotonic saline, whereas group 3 was administered exenatide for 28 days. RESULTS: Malondialdehyde and tumor necrosis factor alpha levels increased in the rats with PD induced by rotenone, whereas malondialdehyde and tumor necrosis factor alpha levels markedly decreased in the rats treated with exenatide. The apomorphine-induced rotation test scores of exenatide-treated rats were determined to be lower compared with the untreated group. Additionally, treatment with exenatide significantly reduced the loss of dopaminergic neurons in striatum. CONCLUSIONS: These results have shown that exenatide has neuroprotective, anti-inflammatory and antioxidant effects in a rotenone-induced rat model of PD. PMID- 28918839 TI - Prostaglandin E2 Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells. AB - BACKGROUND: Prostaglandin E2 (PGE2) regulates renin expression in renal juxtaglomerular cells. PGE2 acts through E-prostanoid (EP) receptors in the renal collecting duct (CD) to regulate sodium and water balance. CD cells express EP1 and EP4, which are linked to protein kinase C (PKC) and PKA downstream pathways, respectively. Previous studies showed that the presence of renin in the CD, and that of PKC and PKA pathways, activate its expression. The (pro)renin receptor (PRR) is also expressed in CD cells, and its activation enhances cyclooxygenase-2 (COX-2) through extracellular signal-regulated kinase (ERK). We hypothesized that PGE2 stimulates prorenin and renin synthesis leading to subsequent activation of PRR and upregulation of COX-2. METHODS: We used a mouse M-1 CD cell line that expresses EP1, EP3 and EP4 but not EP2. RESULTS: PGE2 (10-6M) treatment increased prorenin and renin protein levels at 4 and 8 hours. No differences were found at 12-hour after PGE2 treatment. Phospho-ERK was significantly augmented after 12 hours. COX-2 expression was decreased after 4 hours of PGE2 treatment, but increased after 12 hours. Interestingly, the full-length form of the PRR was upregulated only at 12 hours. PGE2-mediated phospho-ERK and COX-2 upregulation was suppressed by PRR silencing. CONCLUSIONS: Our results suggest that PGE2 induces biphasic regulation of COX-2 through renin-dependent PRR activation via EP1 and EP4 receptors. PRR-mediated increases in COX-2 expression may enhance PGE2 synthesis in CD cells serving as a buffer mechanism in conditions of activated renin-angiotensin system. PMID- 28918841 TI - Epidural Abscess in Lemierre's Syndrome. PMID- 28918842 TI - Anorectal Malignant Melanoma Presenting as Acute Pancreatitis. PMID- 28918844 TI - Purtscher-like Retinopathy. PMID- 28918843 TI - Necrobiotic Pulmonary Nodules of Rheumatoid Arthritis. PMID- 28918845 TI - Caregivers for the Elderly: Caveat Emptor. PMID- 28918846 TI - Aggressive Multiple Cystic Changes in Lung Adenocarcinoma: An Unusual Presentation. PMID- 28918847 TI - Engineering approaches to study cancer metabolism. PMID- 28918848 TI - A multi-institutional analysis of intraoperative radiotherapy for early breast cancer: Does age matter? AB - BACKGROUND: Single-session intraoperative radiation therapy (IORT) minimizes treatment demands associated with traditional whole breast radiation therapy (WBRT) but outcomes on local disease control and morbidity among the elderly is limited. METHODS: A multi-institutional retrospective registry was established from 19 centers utilizing IORT from 2007 to 2013. Patient, tumor, and treatment variables were analyzed for ages <70 and >=70. RESULTS: We evaluated 686 patients (<70 = 424; >=70 = 262) who were margin and lymph node negative. Patients <70 were more likely to have longer operative time, oncoplastic closure, higher rates of IORT used as planned boost, and receive chemotherapy and post-operative WBRT. Wound complication rates were low and not significantly different between age groups. Median follow-up was 1.06 (range 0.51-1.9) years for < 70 and 1.01 (range 0.5-1.68) years for >= 70. There were 5 (0.73%) breast recurrences (4 in <70 and 1 >= 70, p = 0.65) and no axillary recurrences during follow-up. CONCLUSIONS: IORT was associated with a low rate of wound complication and local recurrence on short-term follow-up in this cohort. PMID- 28918850 TI - Are we ready to get in the eye of the storm? PMID- 28918849 TI - Are we catching women in the safety net? Colorectal cancer outcomes by gender at a safety net hospital. AB - BACKGROUND: Our goal was to evaluate presentation and outcomes for colorectal cancer across gender in a safety net hospital (SNH). METHODS: An institutional Tumor Registry was reviewed for colorectal cancer resections 12/2009-2/2016. Patients were stratified into male and female cohorts. The main outcome measures were stage at presentation and oncologic outcomes across gender. RESULTS: 170 women (48.6%) and 180 men (51.4%) were evaluated; 129 (84.1%) females and 143 (79.4%) males underwent curative resection. There were no significant differences in prior colorectal cancer screening. On presentation, there were similar rates of stage IV disease across genders (p = 0.3). After median follow-up of 26.5 months (female) and 29.9 months (male), there were no significant differences in overall survival, survival by stage, or disease-free survival by gender (all p = 0.7). The local (1.4% females vs. 2.6% males, p = 0.7) and distant recurrence (16.6% females vs. 14.9% males, p = 0.7) were similar across gender. CONCLUSION: With equal access to treatment, there were no significant differences in overall survival, survival by stage, or local or distant recurrence rates by gender. These findings stress the importance of the SNH system, and need for continued support. PMID- 28918851 TI - Using evidence in clinical practice: A dream coming true in idiopathic pulmonary fibrosis. PMID- 28918853 TI - Hormone-related cancers and endocrine disruptors: New aspects of an old question. PMID- 28918852 TI - Erectile dysfunction and COPD - Cause or association. PMID- 28918854 TI - Erratum to "Extramammary Paget's disease of the oral mucosa and perioral skin" [Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 124 (2):e157-e163.]. PMID- 28918856 TI - Determination of molar masses of macromolecules by size exclusion chromatography light scattering not requiring knowledge of refractive index increments. AB - A new approach for the calibration of SEC-light scattering (SEC-LS) setups is proposed, which requires solely the molar mass of a reference polymer. Neither the specific refractive index increment of the calibrant nor of the analyte is required. Comparison of the molar masses derived in different solvents for a large number of chemically different polymers shows that the new approach yields the same molar masses as if molar masses were derived using dn/dc to calibrate the light scattering setup. The approach therefore allows easier determination of molar masses by SEC-LS. PMID- 28918855 TI - Ion-pair in-tube solid phase microextraction for the simultaneous determination of phthalates and their degradation products in atmospheric particulate matter. AB - An in-tube solid phase microextraction, coupled with high-performance liquid chromatography with diode array detection (IT-SPME-HPLC-DAD) method, has been developed for the simultaneous determination of 13 diesters (from dimethyl to dioctylphthalate plus diisobutyl, benzylbutyl, di-2-ethylhexyl, diisononyl and diisodecylphthalate) and 2 monoesters of phthalic acid (mono-butyl and mono-(2 ethylhexyl) phthalate) in particulate matter (PM10). Triethylamine at pH=3 was used as an ion-pair reagent with a double function, of regulating the chromatographic retention of the monoesters and the most hydrophilic diesters on a monolithic silica column, and of improving their extraction on a porous polymer with divinylbenzene-4-vinylpyridine capillary. The chromatographic separation was achieved in 13min. A previous ultrasound-assisted extraction from PM10filters was also optimized using methanol as solvent. The method detection limits were 0.09 0.52ngm-3, the inter-day precision at concentration of 20ngmL-1 was between 4.2% and 12.7% (n=15), and the average recovery was 87.3%. The average absolute IT SPME recovery was 26.2% and the linear range reached up to 109ngm-3 for most analytes. The method was applied to PM10 samples from different environments collected in Galicia (Spain). DiBP was the major phthalate, followed by its isomer DnBP in urban sites and by DEP in the suburban area. In all samples, DEHP quantified correlates with the isomers of dibutylphthalate. Total PAE concentration was between 14.5 and 245.5ngm-3. To the best of our knowledge, this is the first time that a method allows the simultaneous determination of 13 phthalates and their degradation products in particulate matter. PMID- 28918857 TI - Developing nursing competence: Future proofing nurses for the changing practice requirements of 21st century healthcare. PMID- 28918858 TI - Coronary CT angiography features of ruptured and high-risk atherosclerotic plaques: Correlation with intra-vascular ultrasound. AB - BACKGROUND: Features of ruptured and high-risk plaque have been described on coronary computed tomography angiography (coronary CTA), but not systematically assessed against intravascular ultrasound (IVUS). We examined the ability of coronary CTA to identify IVUS defined ruptured plaque and Virtual Histology Intravascular Ultrasound (VH-IVUS) defined thin-cap fibroatheroma (TCFA). METHODS: Sixty-three patients (32 with acute coronary syndrome and 31 with stable angina) underwent coronary CTA, IVUS and VH-IVUS. Plaque rupture on CTA was defined as intra-plaque contrast and its frequency compared with IVUS-defined plaque rupture. We then examined the relationship of conventional coronary CTA high-risk features (low attenuation plaque, positive remodeling, spotty calcification and the Napkin-Ring sign) in VH-IVUS-defined TCFA. We compared these with a novel index based on quantifying the ratio of necrotic core to fibrous plaque using x-ray attenuation cut-offs derived from the relationship of plaque to luminal contrast attenuation. RESULTS: Of the 71 plaques interrogated with IVUS, 39 were ruptured. Coronary CTA correctly detected 13-ruptured plaques with 3 false positives giving high specificity (91%) but low sensitivity (33%). None of the conventional coronary CTA high-risk features were significantly more frequent in the higher-risk (VH-IVUS defined thin-cap) compared with thick-cap fibroatheroma. However, the new index (necrotic core/fibrous plaque ratio) was higher in thin-cap (mean 0.90) vs. thick-cap fibroatheroma (mean 0.59), p < 0.05. CONCLUSIONS: Compared with intravascular ultrasound, coronary CTA identifies ruptured plaque with good specificity but poor sensitivity. We have identified a novel high-risk feature on coronary CTA (necrotic core/fibrous plaque ratio that is associated with VH-IVUS defined-TCFA. PMID- 28918860 TI - Prevalence of work-related common psychiatric disorders in primary care: The French Heracles study. AB - General practitioners (GP), on the frontline for individuals with mental health problems, often deal with work-related common psychiatric disorders. We aimed to determine the prevalence of work-related common psychiatric disorders in general practice and associated patients' and GPs' characteristics. HERACLES, a cross sectional study among 2019 working patients of 121 GPs in the Nord - Pas-de Calais region in France. Common psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview, patient-perceived psychological distress and GP-diagnosed psychiatric disorders. The work-relatedness of common psychiatric disorders was ascertained by the GP and/or the patient. Prevalence rates adjusted on age were calculated by sex and associated characteristics were ascertained using multilevel Poisson regression models. The prevalence of work related common psychiatric disorders ascertained using the MINI was estimated at 25.6% [23.7-27.5], 24.5% [22.6-26.4] for self-reported psychological distress and 25.8% [23.9-27.7] for GP-diagnosed psychiatric disorders. Age, history of psychiatric disorders, consultation for psychological purpose and GP's characteristics were associated with MINI-identified psychiatric disorders. The prevalence of work-related common psychiatric disorders among working adults seen in general practice is high but further studies are needed to support this results. PMID- 28918859 TI - A preliminary study of bipolar disorder type I by mass spectrometry-based serum lipidomics. AB - The present study aimed at investigating possible alterations in the serum lipid profile of euthymic patients with bipolar disorder type I (BD) compared to healthy controls (HC). Thirty-five individuals from both genders were recruited, with 14 diagnosed and treated as BD patients (BD group) and 21 healthy subjects (HC group). Clinical assessment was based on the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Young Mania Rating Scale (YMRS), and 17 items of Hamilton Depression Rating Scale (HDRS-17) data, which were used to confirm diagnosis, to verify psychiatric comorbidities, and to estimate the severity of manic and depressive symptoms. Ultra-high performance liquid chromatography (UHPLC) coupled to high resolution mass spectrometry (HRMS) was applied to analyze the lipids extracted from all serum samples from both studied groups. In this pioneer and exploratory study, we observed different serum lipid profiles for BD and HC groups, especially regarding glycerophospholipid, glycerolipid, and sphingolipid distribution. Multivariate statistical analyses indicated that 121 lipids were significantly different between BD and HC. Phosphatidylinositols were identified as the most altered lipids in BD patient sera. The results of this preliminary study reinforce the role of lipid abnormalities in BD and offer additional methodological possibilities for investigation in the field. PMID- 28918861 TI - Exercise self-efficacy correlates in people with psychosis. AB - Despite the recognition of the importance of exercise self-efficacy in exercise adoption and maintenance, previous investigations on exercise self-efficacy in people with psychosis is scarce. The present study aimed to (1) explore if exercise self-efficacy differed between stages of behavior change in Ugandan outpatients with psychosis, and (2) assess sociodemographic, clinical and motivational correlates of exercise self-efficacy. In total, 48 patients (24 women) completed the Exercise Self-Efficacy Scale (ESES), the Patient-centered Assessment and Counseling for Exercise questionnaire, the Brief Symptoms Inventory-18 (BSI-18), and questions pertaining to intrinsic motivation in the Behavioral Regulation in Exercise Questionnaire-2. Additionally, participants were asked about their exercise behavior in the past 7 days and screened for cardio-metabolic risk factors. Higher ESES-scores were observed in those in the maintenance (n = 17) versus those in the pre-action stage (n = 17) of behavior change. Higher ESES-scores were also significantly associated with lower BSI-18 somatization and higher intrinsic motivation scores. Our data indicated that health care professionals should assist patients with psychosis in interpreting physiological states during exercise. Future research should explore whether bolstering such sources of information might directly or indirectly effect exercise self-efficacy. PMID- 28918862 TI - Meta-analysis of sensorimotor gating in patients with autism spectrum disorders. AB - Prepulse inhibition (PPI) of startle response is a well-established neurophysiological marker of sensorimotor gating ability in psychiatric patients including those with autism spectrum disorders (ASD). PPI has been utilized as an indicator of the central inhibitory function and is potentially linked to the clinical features of this disease. However, it remains inconclusive whether ASD patients exhibit PPI deficits compared with healthy controls. The present meta analysis aimed to explore the pooled effect sizes of PPI in ASD patients. We searched major electronic databases from 1990 to January 2017. Seven studies, consisting of 21 individual investigations with 135 healthy controls and 99 ASD patients, were obtained. The effect size, calculated as Hedges's g and 95% confidence interval, were estimated. Overall, we found ASD patients exhibited an impaired PPI compared with healthy controls (p = 0.008). Specifically, significant PPI deficits were observed among ASD children/adolescents, compared with their healthy counterparts (p = 0.019). However, differences in PPI responses were not observed among adults. Conclusively, our results reconciled the previous studies and showed that ASD children/adolescents, but not adults, exhibit reduced sensorimotor gating function compared to healthy controls. We also suggest that the parameters of PPI are particularly important and the results should be interpreted with cautions. PMID- 28918863 TI - More haste less speed: A meta-analysis of thinking latencies during planning in people with psychosis. AB - Cognitive impairment is a core feature of psychosis, with slowed processing speed thought to be a prominent impairment in schizophrenia and first-episode psychosis. However, findings from the Stockings of Cambridge (SOC) planning task suggest changes in processing speed associated with the illness may include faster responses in early stages of planning, though findings are inconsistent. This review uses meta-analytic methods to assess thinking times in psychosis across the available literature. Studies were identified by searching PubMed, Web of Science and Google Scholar. Eligibility criteria: 1) included a sample of people with non-affective psychosis according to DSM III, DSM IV, DSM V or ICD-10 criteria; 2) employed the SOC task; 3) included a healthy control group; and 4) published in English. We identified 11 studies that employed the SOC task. Results show that people with psychosis have significantly faster initial thinking times than non-clinical participants, but significantly slower subsequent thinking times during problem execution. These findings indicate that differences in processing speed are not limited to slower responses in people with psychosis but may reflect a preference for step-by-step processing rather than planning before task execution. We suggest this style of responding is adopted to compensate for working memory impairment. PMID- 28918864 TI - Tuberculous Tracheoesophageal Fistula: A Rare Entity. PMID- 28918865 TI - The Need for Palliative Care in Chronic Respiratory Patients With Non-Malignant Disease. PMID- 28918866 TI - Diagnosis of Pulmonary Infarction by Thoracic Ultrasonography. PMID- 28918867 TI - Telomere Shortening in Idiopathic Pulmonary Fibrosis. PMID- 28918868 TI - Does the Exacerbator Phenotype in Chronic Obstructive Pulmonary Disease Really Exist? PMID- 28918869 TI - Clinical Guidelines in Asthma and Chronic Obstructive Pulmonary Disease: How Useful Are They in Clinical Practice? PMID- 28918870 TI - Explaining the differences in household food waste collection and treatment provisions between local authorities in England and Wales. AB - Separate household food waste collection for anaerobic digestion is one method used in the sustainable management of biodegradable municipal solid waste (MSW). Recycling of food waste contributes to the UK's reuse, recycling and composting targets and can help local authorities boost plateauing rates whilst encouraging landfill diversion. This study explored the reasons for differences in the provision of food waste collections, using two comparable local authorities, one with a collection in Wales (Cardiff), and the other absent of such service in England (Southampton). A PESTLE analysis investigated the political, economic, social, technological, legal and environmental impacts of separate food waste collections. The greenhouse gas impacts of the collection and treatment systems of MSW in both cities were estimated for 2012/13. Results showed significant policy and legislative differences between devolved governments, that separate food waste collections can save local authorities significant sums of money and substantially reduce greenhouse gas impacts. A survey of one hundred respondents in each city aimed to understand attitudes and behaviours towards recycling, food waste segregation, cooking and purchasing habits. The number of frequent recyclers and levels of satisfaction were higher in the authority which provided a separate food waste collection. In the area which lacked a separate collection service, over three-quarters of respondents would participate in such a scheme if it were available. PMID- 28918871 TI - [Indications and limits of ablative therapies in prostate cancer]. AB - OBJECTIVE: To perform a state of the art about indications and limits of ablative therapies for localized prostate cancer. METHODS: A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 107 articles were analysed. RESULTS: The objective to combine reduction of side effects and oncological control has induced recent development of several ablative therapies. Beyond this heterogeneity, some preferential indications appear: unilateral cancer of low risk (but with significant volume, excluding active surveillance) or intermediate risk (excluding majority of grade 4); treatment targeted the index lesion, by quarter or hemi-ablation, based on biopsy and mpMRI. In addition, indications must considered specific limits of each energy, such as gland volume and tumor localization. CONCLUSION: Based on new imaging and biopsy, ablative therapies will probably increased its role in the future in management of localize prostate cancer. The multiple ongoing trials will certainly be helpful to better define their indications and limits. PMID- 28918872 TI - [Management of ablative therapies in prostate cancer]. AB - OBJECTIVES: To describe the specific modalities of ablative therapies management in prostate cancer. MATERIALS AND METHODS: A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 61 articles were analysed. RESULTS: Development of innovations such as ablative therapies in prostate cancer induces specific modalities in their management, during pre-, per- and post-procedure. More than for classical and well-known treatments, the decision to propose an ablative therapy requires analysis and consensus of medical staff and patient's agreement. Patient's specificities and economical aspects must also be considered. Procedures and follow-up must be realized by referents actors. CONCLUSION: Indication, procedure and follow-up of ablative therapies in prostate cancer require specific modalities. They must be respected in order to optimize the results and to obtain a precise and objective evaluation for defining future indications. PMID- 28918873 TI - Use of Ganga Hospital Open Injury Severity Scoring for determination of salvage versus amputation in open type IIIB injuries of lower limbs in children-An analysis of 52 type IIIB open fractures. AB - INTRODUCTION AND AIMS: Open injuries in children are rare compared to adults. In children with major open injuries, there is no specific scoring system to guide when to amputate or salvage the limb. The use of available adult scoring systems may lead to errors in management. The role of Ganga Hospital Open Injury Severity Scoring (GHOISS) for open injuries in adults is well established and its applicability for pediatric open injuries has not been studied. This study was done to analyse the usefulness of GHOISS in pediatric open injuries and to compare it with MESS(Mangled Extremity Severity Score). METHODS: All children (0 18 years) who were admitted with Open type IIIB injuries of lower limbs between January 2008 and March 2015 were included. MESS and GHOISS were calculated for all the patients. There were 50 children with 52 type IIIB Open injuries of which 39 had open tibial fractures and 13 had open femur fractures. RESULTS: Out of 52 type IIIB open injuries, 48 were salvaged and 4 were amputated. A MESS score of 7 and above had sensitivity of 25% for amputation while GHOISS of 17 and above was found to be more accurate for determining amputation with sensitivity of 75% and specificity of 93.75%. CONCLUSION: GHOISS is a reliable predictor of injury severity in type IIIB open fractures in children and can be used as a guide for decision-making. The use of MESS score in children has a lower predictive value compared to GHOISS in deciding amputation versus salvage. A GHOISS of 17 or more has the highest sensitivity and specificity to predict amputation. PMID- 28918874 TI - The outcome of intracapsular hip fracture fixation using the Targon Femoral Neck (TFN) locking plate system or cannulated cancellous screws: A comparative study involving 2004 patients. AB - AIM: This study compares the outcome of intracapsular hip fracture fixation using the Targon Femoral Neck (TFN) locking plate system with the standard fixation using cannulated cancellous screws (CCS). PATIENTS AND METHOD: Analyses of a prospectively collected data of all patients treated for intracapsular hip fractures using the TFN system and CCS at our department over a period of 28 years. Baseline characteristics and specific outcome measures where compared. The primary outcome measure was fracture revision during the 1st year. Secondary outcome measures were fracture complications, any revision surgery, mortality and mobility status at one year after surgery. RESULTS: A total of 2004 fractures were included, a third (n=725, 36.2%) were treated using the TFN system. There were higher rates of non-union (19.5% vs 9.5%) and revision surgery (19% vs 9%) during the first year in the CCS cohort. Revision surgery was also higher in the same group during the whole of the follow-up period (22.2% vs 14.9%). The first year's mortality rate was higher in the CCS cohort (21.1% vs 17.5%) but the reduction in mobility and mobility scores was the same in both cohorts. CONCLUSION: This study includes the largest cohort of cases treated for intracapsular hip fractures using the TFN system. It demonstrated that the TFN system was associated with lower rates of non-union, revisions and re-operations for any cause. PMID- 28918875 TI - Corrigendum to "Imaging techniques for the assessment of fracture repair"[Injury 45 (Supplement (2)) (2014) S16-S22]. PMID- 28918876 TI - Evaluation of potential substrates for restenosis and thrombosis in overlapped versus edge-to-edge juxtaposed bioabsorbable scaffolds: Insights from a computed fluid dynamic study. AB - BACKGROUND/PURPOSE: Multiple BRSs and specifically the Absorb scaffold (BVS) (Abbott Vascular, Santa Clara, CA USA) have been often used to treat long diffuse coronary artery lesions. We evaluate by a computational fluid dynamic(CFD) study the impact on the intravascular fluid rheology on multiple bioabsorbable scaffolds (BRS) by standard overlapping versus edge-to-edge technique. METHODS/MATERIALS: We simulated the treatment of a real long significant coronary lesion (>70% luminal narrowing) involving the left anterior descending artery (LAD) treated with a standard or edge-to-edge technique, respectively. Simulations were performed after BVS implantations in two different conditions: 1) Edge-to-edge technique, where the scaffolds are kissed but not overlapped resulting in a luminal encroachment of 0.015cm (150MUm); 2) Standard overlapping, where the scaffolds are overlapped resulting in a luminal encroachment of 0.030cm (300MUm). After positioning the BVS across the long lesion, the implantation procedure was performed in-silico following all the usual procedural steps. RESULTS: Analysis of the wall shear stress (WSS) suggested that at the vessel wall level the WSS were lower in the overlapping zones overlapping compared to the edge-to-edge zone (?=0.061Pa, p=0.01). At the struts level the difference between the two WSS was more striking (?=1.065e-004 p=0.01) favouring the edge-to edge zone. CONCLUSIONS: Our study suggested that at both vessel wall and scaffold struts levels, there was lowering WSS when multiple BVS were implanted with the standard overlapping technique compared to the "edge-to-edge" technique. This lower WSS might represent a substrate for restenosis, early and late BVS thrombosis, potentially explaining at least in part the recent evidences of devices poor performance. PMID- 28918878 TI - Raltegravir becomes a once daily antiretroviral. PMID- 28918880 TI - Iliac Subperiosteal Hematoma with Ossification in a 15-Year-Old Boy. PMID- 28918879 TI - Axitinib-related osteonecrosis of the jaw. AB - Tyrosine kinase inhibitors (TKIs) are oral chemotherapy drugs used primarily to treat leukemias, renal cell carcinomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Within this group, a number of drugs have already been implicated in jaw necrosis. Axitinib (Inlyta) is a novel TKI currently licensed for the treatment of renal cell carcinoma. We report the first case, to our knowledge, of jaw necrosis solely related to this medication and review the literature surrounding TKIs and their implication in osteonecrosis of the jaw. PMID- 28918881 TI - Clinical Detection of Hemodynamically Significant Isolated Secundum Atrial Septal Defect. AB - The diagnosis of secundum atrial septal defect often is delayed. For 310 patients with hemodynamically significant secundum atrial septal defect undergoing closure over a 5-year period at a single medical center, this study reviews the symptoms prompting referral, limitations of physical examination and electrocardiography, and basis for initially missing the diagnosis. PMID- 28918877 TI - Raltegravir 1200 mg once daily versus raltegravir 400 mg twice daily, with tenofovir disoproxil fumarate and emtricitabine, for previously untreated HIV-1 infection: a randomised, double-blind, parallel-group, phase 3, non-inferiority trial. AB - BACKGROUND: Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation. METHODS: In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV 1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two sided 95% CI was greater than -10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233. FINDINGS: Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0.5%, 95% CI -4.2 to 5.2). Drug related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported. INTERPRETATION: A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy. FUNDING: Merck & Co, Inc. PMID- 28918883 TI - Pseudoparalysis of Parrot: A Diagnostic Aid in Congenital Syphilis. PMID- 28918884 TI - [Could you draw me a picture of chronic kidney disease, please?] PMID- 28918882 TI - Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys. AB - OBJECTIVE: To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. STUDY DESIGN: There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. RESULTS: The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7-07). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9-07). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. CONCLUSIONS: In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies. PMID- 28918885 TI - Preface. PMID- 28918886 TI - Harmful algal blooms and public health. AB - The five most commonly recognized Harmful Algal Bloom-related illnesses are ciguatera poisoning, paralytic shellfish poisoning, neurotoxic shellfish poisoning (NSP), amnesic shellfish poisoning, and diarrhetic shellfish poisoning. Although these exposures result from exposure to different toxins or toxin congeners, these clinical syndromes have much in common. Exposure occurs through the consumption of fish, shellfish, or through exposure to aerosolized NSP toxins. Routine clinical tests are not available for the diagnosis of harmful algal bloom related illnesses, there is no known antidote for exposure, and the risk of these illnesses can negatively impact local fishing and tourism industries. The absence of exposure risk or diagnostic certainty can also precipitate a chain of events that results in considerable psychological distress for coastal populations. Thus, illness prevention is of paramount importance to minimize human and public health risks. To accomplish this, further transdisciplinary research, close communication and collaboration are needed among HAB scientists, public health researchers, and local, state and tribal health departments at academic, community outreach, and policy levels. PMID- 28918887 TI - The association between razor clam consumption and memory in the CoASTAL cohort. AB - This study represents a preliminary effort to examine the potential impacts of chronic, low level domoic acid (DA) exposure on memory in the CoASTAL cohort over the first four years of data collection (Wave 1). Five hundred and thirteen adult men and women representing three Native American Tribes were studied annually with standard measures of cognition and razor clam consumption (a known vector of DA exposure) over a four-year period. In addition, a pilot metric of DA concentration exposure was used which took into consideration average DA concentration levels in source beaches, as well as the amount consumed. Based upon generalized estimating equations (GEE) analysis, controlling for age, sex, race, year, education level, tribe, and employment status, findings indicated that high razor clam consumers (15 or more per month) had isolated decrements on some measures of memory (p=0.02-0.03), with other cognitive functions unaffected. The relatively lower memory scores were still within normal limits, and were thus not clinically significant. The pilot DA exposure metric had no association with any other aspect of cognition or behavior. There is a possible association between long-term, low-level exposure to DA through heavy razor clam consumption and memory functioning. PMID- 28918888 TI - Assessment of sodium channel mutations in Makah tribal members of the U.S. Pacific Northwest as a potential mechanism of resistance to paralytic shellfish poisoning. AB - The Makah Tribe of Neah Bay, Washington, has historically relied on the subsistence harvest of coastal seafood, including shellfish, which remains an important cultural and ceremonial resource. Tribal legend describes visitors from other tribes that died from eating shellfish collected on Makah lands. These deaths were believed to be caused by paralytic shellfish poisoning, a human illness caused by ingestion of shellfish contaminated with saxitoxins, which are produced by toxin-producing marine dinoflagellates on which the shellfish feed. These paralytic shellfish toxins include saxitoxin, a potent Na+ channel antagonist that binds to the pore region of voltage gated Na+ channels. Amino acid mutations in the Na+ channel pore have been demonstrated to confer resistance to saxitoxin in softshell clam populations exposed to paralytic shellfish toxins present in their environment. Because of the notion of resistance to paralytic shellfish toxins, the study aimed to determine if a resistance strategy was possible in humans with historical exposure to toxins in shellfish. We collected, extracted and purified DNA from buccal swabs of 83 volunteer Makah tribal members and sequenced the skeletal muscle Na+ channel (Nav1.4) at nine loci to characterize potential mutations in the relevant saxitoxin binding regions. No mutations of these specific regions were identified after comparison to a reference sequence. This study suggests that any resistance of Makah tribal members to saxitoxin, if present, is not a function of Nav1.4 modification, but may be due to mutations in neuronal or cardiac sodium channels, or some other mechanism unrelated to sodium channel function. PMID- 28918889 TI - Gene expression patterns in peripheral blood leukocytes in patients with recurrent ciguatera fish poisoning: Preliminary studies. AB - Ciguatera fish poisoning (ciguatera) is a common clinical syndrome in areas where there is dependence on tropical reef fish for food. A subset of patients develops recurrent and, in some instances, chronic symptoms, which may result in substantial disability. To identify possible biomarkers for recurrent/chronic disease, and to explore correlations with immune gene expression, peripheral blood leukocyte gene expression in 10 ciguatera patients (7 recurrent and 3 acute) from the U.S. Virgin Islands, and 5 unexposed Florida controls were evaluated. Significant differences in gene expression were noted when comparing ciguatera patients and controls; however, it was not possible to differentiate between patients with acute and recurrent disease, possibly due to the small sample sizes involved. PMID- 28918890 TI - Perception of risk for domoic acid related health problems: A cross-cultural study. AB - Risk perception is a complex process that refers to the way people approach, think about, and interpret risks in their environment. An important element of risk perception is that it is culturally situated. Since HABs can present a health risk in many places around the world, looking at cultural parameters for understanding and interpreting risks is important. This study examined how two different groups of people perceive the potential health risks of low-level exposure to domoic acid (DA) through razor clam consumption. The risk perceptions of Washington State, USA coastal dwelling Native American nations (NA) were compared to that of a community sample of recreational razor clam harvesters (CRH). Overall, the findings support the hypothesis that cultural and community specific contexts impact the perception of risk of a DA related illness. Specifically, the NA sample was distinguished from the CRH group in particular, by their worries about ocean pollution, attribution of DA risks to climate change, concerns about the potential impact of DA on future generations, and feeling of being better informed than the CRH group. The CRH group was more likely to attribute the DA problem to anthropogenic or industrial causes and view the risk of health problems from DA as lower than those associated with smoking, high cholesterol, anxiety or depression, alcoholism, high blood pressure or obesity. The CRH group was also more likely to turn to the media for DA-related information. Both groups trusted the decisions of state and tribe health and natural resources officials, and demonstrated a complex pattern of findings that involved gender. In summary, risk communication and outreach activities should be designed to take into consideration the specific factors that are unique to each cultural community. PMID- 28918892 TI - Dietary assessment of domoic acid exposure: What can be learned from traditional methods and new applications for a technology assisted device. AB - Three Tribal Nations in the Pacific Northwest United States comprise the members of the CoASTAL cohort. These populations may be at risk for neurobehavioral impairment, i.e., amnesic shellfish poisoning, from shellfish consumption resulting in repeated, low-level domoic acid (DA) exposure. Previous work with this cohort confirmed a high proportion of clam consumers with varying levels of potential exposure over time. Since clams are an episodically consumed food, traditional dietary records do not fully capture exposure. Frequency questionnaires can capture accumulated doses over time and this data can be used to examine dose-response relationships with periodic studies of memory and learning. However, frequency questionnaires cannot be used to assess consumption and memory response in real time. To address this shortcoming, a modified technology assisted dietary assessment (TADA) iPod application was developed to capture images of the clam meal, sourcing data, and associated memory functioning within 24h and seven days after consumption. This methodology was piloted with razor clam meals consumed by members from the CoASTAL cohort. Preliminary findings suggest that the TADA iPod application is potentially useful in collecting real-time data with respect to razor clam consumption, as well as one day and seven day memory outcome data. This technology holds promise for addressing the challenges of other HAB related dietary exposure outcome studies. PMID- 28918891 TI - Case diagnosis and characterization of suspected paralytic shellfish poisoning in Alaska. AB - Clinical cases of paralytic shellfish poisoning (PSP) are common in Alaska, and result from human consumption of shellfish contaminated with saxitoxin (STX) and its analogues. Diagnosis of PSP is presumptive and based on recent ingestion of shellfish and presence of manifestations consistent with symptoms of PSP; diagnosis is confirmed by detection of paralytic shellfish toxins in a clinical specimen or food sample. A clinical diagnostic analytical method using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to evaluate the diagnosis of saxitoxin-induced PSP (STX-PSP) in 11 Alaskan patients using urine specimens collected between June 2010 and November 2011. Concentrations of urinary STX were corrected for creatinine concentrations to account for dilution or concentration of urine from water intake or restriction, respectively. Of the 11 patients with suspected PSP, four patients were confirmed to have STX-PSP by urine testing (24-364ng STX/g creatinine). Five patients had clinical manifestations of PSP though no STX was detected in their urine. Two patients were ruled out for STX-PSP based on non-detected urinary STX and the absence of clinical findings. Results revealed that dysphagia and dysarthria may be stronger indicators of PSP than paresthesia and nausea, which are commonly used to clinically diagnose patients with PSP. PSP can also occur from exposure to a number of STX congeners, such as gonyautoxins, however their presence in urine was not assessed in this investigation. In addition, meal remnants obtained from six presumptive PSP cases were analyzed using the Association of Official Analytical Chemists' mouse bioassay. All six samples tested positive for PSP toxins. In the future, the clinical diagnostic method can be used in conjunction with the mouse bioassay or HPLC-MS/MS to assess the extent of STX-PSP in Alaska where it has been suggested that PSP is underreported. PMID- 28918893 TI - Communities advancing the studies of Tribal nations across their lifespan: Design, methods, and baseline of the CoASTAL cohort. AB - The CoASTAL cohort represents the first community cohort assembled to study a HAB related illness. It is comprised of three Native American tribes in the Pacific NW for the purpose of studying the health impacts of chronic, low level domoic acid (DA) exposure through razor clam consumption. This cohort is at risk of DA toxicity by virtue of their geographic location (access to beaches with a history of elevated DA levels in razor clams) and the cultural and traditional significance of razor clams in their diet. In this prospective, longitudinal study, Wave 1 of the cohort was comprised of 678 members across the human lifespan, with both sexes represented within child, adult, and geriatric age groups. All participants were followed annually with standard measures of medical and social history; neuropsychological functions, psychological status, and dietary exposure. DA concentrations were measured at both public and reservation beaches where razor clams are acquired. Multiple metrics were piloted to further determine exposure. Baseline data indicated that all cognitive and psychological functions were within normal limits. In addition, there was considerable variability in razor clam exposure. Therefore, the CoASTAL cohort offers a unique opportunity to investigate the potential health effects of chronic, low level exposure to DA over time. PMID- 28918894 TI - Effect of Pneumoperitoneum and Patient Positioning on Intracranial Pressures during Laparoscopy: A Prospective Comparative Study. AB - STUDY OBJECTIVE: To evaluate the effect of pneumoperitoneum and head position during laparoscopic surgery on intracranial pressures (ICPs) using sonographic measurements of optic nerve sheath diameter (ONSD). DESIGN: Prospective observational study (Canadian Task Force classification II-1). SETTING: A tertiary-level hospital. PATIENTS: Sixty-one women aged 15 to 50 years with American Society of Anesthesiologists grade 1 risk and body mass index <= 29 kg/m2 were admitted to the hospital between November 2015 and October 2016 for elective laparoscopic surgery and were included in this study. INTERVENTION: Patients were placed in the Trendelenburg position with head down (group I; n = 33) and reverse Trendelenburg position with head up (group II; n = 28). MEASUREMENTS AND MAIN RESULTS: ONSD was measured via sonography at 4 time points: at baseline before pneumoperitoneum, after pneumoperitoneum, after patient was placed in respective position, and once pneumoperitoneum was released. Patient demographics were comparable in all respects. ICP as indicated by ONSD showed a significant increase after pneumoperitoneum (p = .0001 in group I and p = .0011 in group II). When patients were placed in either head position, ONSD showed a further increase in ICP. This increase was more pronounced in patients assuming the head-down Trendelenburg position compared with patients in reverse Trendelenburg (head-up) position. Baseline and preoperative ONSD measurements were not reached even after 5 minutes of desufflation. CONCLUSIONS: Pneumoperitoneum causes an increase in ICP. The patient position, either head up or head down as in gynecologic laparoscopic procedures, further worsens ICP. ONSD does not revert back to baseline until 5 minutes after desufflation. PMID- 28918895 TI - A method for determining exercise oscillatory ventilation in heart failure: Prognostic value and practical implications. AB - BACKGROUND: Exercise oscillatory ventilation (EOV) has been shown to be a powerful prognostic marker in chronic heart failure (CHF). However, EOV is poorly defined, its measurement lacks standardization and it is underutilized in clinical practice. The purpose of this pilot study was to investigate the prognostic value of a modified definition of EOV in patients with CHF. METHODS: Eighty-nine CHF patients (56.5+/-8.4years) (64% NYHA class III-IV) underwent cardiopulmonary exercise testing. EOV was defined as meeting all the following criteria: (1) >=3 consecutive cyclic fluctuations of ventilation during exercise; (2) average amplitude over 3 ventilatory oscillations >=5L; and (3) an average length of three oscillatory cycles 40s to 140s. Adverse cardiac events were tracked during 28+/-19months follow up. Cox proportional hazard analysis was used to determine the association between cardiac events and EOV. RESULTS: Forty-eight patients (54%) met all three criteria and were determined to have EOV. These patients exhibited significantly increased risk for adverse cardiac events [hazard ratio=2.2, 95% CI (1.2 to 4.1), p=0.011] compared to patients without EOV. After adjusting for age and established prognostic covariates (peak VO2 and VE/VCO2 slope), the modified EOV definition was the only significant variable in the multivariate model [hazard ratio=2.0, 95% CI (1.1 to 3.7), p=0.035]. CONCLUSIONS: The proposed method for determining EOV was independently associated with increased risk for adverse cardiac events in CHF patients. While larger prospective studies are needed, this definition provides a relatively simple and more objective characterization of EOV, suggesting its potential application in clinical practice. PMID- 28918896 TI - Role of circulating endothelial progenitor cells in the reparative mechanisms of stable ischemic myocardium. AB - BACKGROUND: Mobilization of endothelial progenitor cells (EPCs) into circulation from bone marrow in patients with acute myocardial infarction has strong scientific evidence; less is known about EPC mobilization in patients with stable coronary artery disease (CAD). The aim of this study was to investigate the association of stable ischemic heart disease with EPC levels in tissue and blood. METHODS: Fifty-five consecutive patients admitted to a single treatment center for valve or coronary artery bypass grafting (CABG) surgeries were included in the study. Blood samples were collected in the morning before surgery and analyzed by flow-cytometry to determine peripheral EPC levels (EPC/ml). Tissue EPC (CD34+VEGFR2+) levels were assessed on a right atrial appendage segment. RESULTS: Mean age was 76+/-5years, 48% were men, and 53% had CAD The number of CD34+ VEGFR2+ cells in the tissue of patients with CAD was significantly higher (p<0.005) and circulating EPC showed a tendency to be reduced by approximately 20% in peripheral blood of patients with CAD when compared to those without CAD. CONCLUSION: Patients with stable CAD had higher EPC density values (EPC/mm2) and were more likely to have lower EPC blood levels when compare with normal controls. PMID- 28918897 TI - Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis. AB - BACKGROUND: Atrial fibrillation occurs frequently after open-heart surgery. It is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare costs. Prophylactic administration of colchicine may mitigate post-operative atrial fibrillation (POAF). METHODS: We searched PubMed, ClinicalTrials.gov and CENTRAL databases to identify randomized controlled trials (RCTs) that; (1) compared prophylactic use of colchicine to placebo, or usual care, in patients with sinus rhythm who underwent elective open-heart surgery and (2) reported POAF-incidence. We excluded trials focused on incidence of atrial fibrillation after percutaneous interventions or colchicine treatment of diagnosed pericarditis or post-pericardiotomy-syndrome. A random-effects model was used to pool data for POAF-incidence as the primary outcome and for drug related adverse effects, major adverse events (death and stroke), and hospital length-of-stay as secondary outcomes. RESULTS: We included five RCTs (1412 patients). Colchicine treatment reduced POAF-events by 30% versus placebo or usual care (18% vs. 27%, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.84, p=0.0002). Adverse drug-related effects, especially gastrointestinal intolerance, increased with colchicine; (21% vs. 8.2%, RR 2.52, 95% CI 1.62 to 3.93, p<0.0001). However, major adverse events were unchanged (3.2% vs. 3.2%, RR 0.96, 95% CI 0.48 to 1.95, p=0.92). Length-of-stay decreased by 1.2days with colchicine (95% CI -1.89 to -0.44, p=0.002). CONCLUSION: Colchicine demonstrated superior efficacy versus usual care for prevention of atrial fibrillation after cardiac surgery. Moreover, colchicine treatment was associated with shorter hospital stays. These benefits outweigh increased risk of adverse drug-related effects; although further work is needed to minimize gastrointestinal effects. PMID- 28918899 TI - Stem-Loop Structures within mRNA Coding Sequences Activate Translation Initiation and Mediate Control by Small Regulatory RNAs. AB - Initiation is the rate-limiting step of translation, and in bacteria, mRNA secondary structure has been extensively reported as limiting the efficiency of translation by occluding the ribosome-binding site. In striking contrast with this inhibitory effect, we report here that stem-loop structures located within coding sequences instead activate translation initiation of the Escherichia coli fepA and bamA mRNAs involved in iron acquisition and outer membrane proteins assembly, respectively. Both structures promote ribosome binding in vitro, independently of their nucleotide sequence. Moreover, two small regulatory RNAs, OmrA and OmrB, base pair to and most likely disrupt the fepA stem-loop structure, thereby repressing FepA synthesis. By expanding our understanding of how mRNA cis acting elements regulate translation, these data challenge the widespread view of mRNA secondary structures as translation inhibitors and show that translation activating elements embedded in coding sequences can be targeted by small RNAs to inhibit gene expression. PMID- 28918898 TI - Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip. AB - In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein conducting channel, while oxidized Bip (Kar2) inhibits transport. Increased ER glutathione import triggers H2O2-dependent Bip oxidation through Ero1 reductive activation, which inhibits glutathione import in a negative regulatory loop. During ER stress, transport is activated by UPR-dependent Ero1 induction, and cytosolic glutathione levels increase. Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein conducting channel is permeable to small molecules, provided the driving force of a concentration gradient. PMID- 28918901 TI - mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein. AB - Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth. PMID- 28918900 TI - Transcription of Nearly All Yeast RNA Polymerase II-Transcribed Genes Is Dependent on Transcription Factor TFIID. AB - Previous studies suggested that expression of most yeast mRNAs is dominated by either transcription factor TFIID or SAGA. We re-examined the role of TFIID by rapid depletion of S. cerevisiae TFIID subunits and measurement of changes in nascent transcription. We find that transcription of nearly all mRNAs is strongly dependent on TFIID function. Degron-dependent depletion of Taf1, Taf2, Taf7, Taf11, and Taf13 showed similar transcription decreases for genes in the Taf1 depleted, Taf1-enriched, TATA-containing, and TATA-less gene classes. The magnitude of TFIID dependence varies with growth conditions, although this variation is similar genome-wide. Many studies have suggested differences in gene regulatory mechanisms between TATA and TATA-less genes, and these differences have been attributed in part to differential dependence on SAGA or TFIID. Our work indicates that TFIID participates in expression of nearly all yeast mRNAs and that differences in regulation between these two gene categories is due to other properties. PMID- 28918902 TI - mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1. AB - The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions. PMID- 28918904 TI - Comparison of Laser Doppler Imaging (LDI) and clinical assessment in differentiating between superficial and deep partial thickness burn wounds. AB - PURPOSE OF PRESENTATION/STUDY: To compare the accuracy of Laser Doppler Imaging (LDI) and clinical assessment in differentiating between superficial and deep partial thickness burns to decide whether early tangential excision and grafting or conservative management should be employed to optimize burn and patient management. STUDY PERIOD: March 2015 to November 2016. METHODS/PROCEDURE DETAILS: Ninety two wounds in 34 patients reporting within 5days of less than 40% burn surface area were included. Unstable patients, pregnant females and those who expired were excluded. The wounds were clinically assessed and LDI done concomitantly Plastic Surgeons blinded to each other's findings. Wound appearance, color, blanching, pain, hair follicle dislodgement were the clinical parameters that distinguished between superficial and deep partial thickness burns. On day 21, the wounds were again assessed for the presence of healing by the same plastic surgeons. The findings were correlated with the initial findings on LDI and clinical assessment and the results statistically analyzed. RESULTS/OUTCOME: The data of 92 burn wounds was analyzed using SPSS (ver. 17). Clinical assessment correctly identified the depth of 75 and LDI 83 wounds, giving diagnostic accuracies of 81.52% and 90.21% respectively. The sensitivity of clinical assessment was 81% and of LDI 92.75%, whereas the specificity was 82% for both. The positive predictive value was 93% for clinical assessment and 94% for LDI while the negative predictive value was 59% and 79% respectively. CONCLUSIONS: Predictive accuracy of LDI was found to be better than clinical assessment in the prediction of wound healing, the gold standard for wound healing being 21 days. As such it can prove to be a reliable and viable cost effective alternative per se to clinical assessment. PMID- 28918903 TI - SAGA Is a General Cofactor for RNA Polymerase II Transcription. AB - Prior studies suggested that SAGA and TFIID are alternative factors that promote RNA polymerase II transcription, with about 10% of genes in S. cerevisiae dependent on SAGA. We reassessed the role of SAGA by mapping its genome-wide location and role in global transcription in budding yeast. We find that SAGA maps to the UAS elements of most genes, overlapping with Mediator binding and irrespective of previous designations of SAGA- or TFIID-dominated genes. Disruption of SAGA through mutation or rapid subunit depletion reduces transcription from nearly all genes, measured by newly synthesized RNA. We also find that the acetyltransferase Gcn5 synergizes with Spt3 to promote global transcription and that Spt3 functions to stimulate TBP recruitment at all tested genes. Our data demonstrate that SAGA acts as a general cofactor required for essentially all RNA polymerase II transcription and is not consistent with the previous classification of SAGA- and TFIID-dominated genes. PMID- 28918905 TI - Raising suspicion of maltreatment from burns: Derivation and validation of the BuRN-Tool. AB - BACKGROUND: 10-25% of childhood burns arise from maltreatment. AIM: To derive and validate a clinical prediction tool to assist the recognition of suspected maltreatment. METHODS: Prospectively collected data from 1327 children with burns were analyzed using logistic regression. Regression coefficients for variables associated with 'referral for child maltreatment investigation' (112 cases) in multivariable analyses were converted to integers to derive the BuRN-Tool, scoring each child on a continuous scale. A cut-off score for referral was established from receiver operating curve analysis and optimal sensitivity and specificity values. We validated the BuRN-Tool on 787 prospectively collected novel cases. RESULTS: Variables associated with referral were: age <5years, known to social care, concerning explanation, full thickness burn, uncommon body location, bilateral pattern and supervision concern. We established 3 as cut-off score, resulting in a sensitivity and specificity for scalds of 87.5% (95% CI:61.7-98.4) and 81.5% (95% CI:77.1-85.4) respectively and for non-scalds sensitivity was 82.4% (95%CI:65.5-93.2) and specificity 78.7% (95% CI:73.9-82.9) when applied to validation data. Area under the curve was 0.87 (95% CI:0.83-0.90) for scalds and 0.85 (95% CI:0.81-0.88) for non-scalds. CONCLUSION: The BuRN-Tool is a potential adjunct to clinical decision-making, predicting which children warrant investigation for child maltreatment. The score is simple and easy to complete in an emergency department setting. PMID- 28918906 TI - Radiotherapy and the tumor microenvironment: The "macro" picture. AB - In this issue of the Biomedical Journal, we explore the inner workings of tumor associated macrophages and seek to understand how these cells can boost or limit the efficacy of radiotherapy, depending on the context. We also highlight a study revealing that staffing patterns in the intensive care unit may affect the outcome of patients with severe sepsis. Finally, we learn how an advanced imaging technique can improve endodontic treatment planning. PMID- 28918907 TI - Thioredoxin promotes survival signaling events under nitrosative/oxidative stress associated with cancer development. AB - Accumulating mutations may drive cells into the acquisition of abnormal phenotypes that are characteristic of cancer cells. Cancer cells feature profound alterations in proliferation programs that result in a new population of cells that overrides normal tissue construction and maintenance programs. To achieve this goal, cancer cells are endowed with up regulated survival signaling pathways. They also must counteract the cytotoxic effects of high levels of nitric oxide (NO) and of reactive oxygen species (ROS), which are by products of cancer cell growth. Accumulating experimental evidence associates cancer cell survival with their capacity to up-regulate antioxidant systems. Elevated expression of the antioxidant protein thioredoxin-1 (Trx1) has been correlated with cancer development. Trx1 has been characterized as a multifunctional protein, playing different roles in different cell compartments. Trx1 migrates to the nucleus in cells exposed to nitrosative/oxidative stress conditions. Trx1 nuclear migration has been related to the activation of transcription factors associated with cell survival and cell proliferation. There is a direct association between the p21Ras-ERK1/2 MAP Kinases survival signaling pathway and Trx1 nuclear migration under nitrosative stress. The expression of the cytoplasmic protein, the thioredoxin-interacting protein (Txnip), determines the change in Trx1 cellular compartmentalization. The anti-apoptotic actions of Trx1 and its denitrosylase activity occur in the cytoplasm and serve as important regulators of cell survival. Within this context, this review focuses on the participation of Trx1 in cells under nitrosative/oxidative stress in survival signaling pathways associated with cancer development. PMID- 28918909 TI - Progesterone analogues reduce plasma Epstein-Barr virus DNA load and improve pain control in recurrent/metastatic nasopharyngeal carcinoma patients under supportive care. AB - BACKGROUND: Progesterone analogues, such as megestrol acetate (MA) and medroxyprogesterone (MPA), have been used for the palliative care of cancer cachexia for decades and have proven to increase body weight and improve quality of life and performance status. The objective of this study was to determine the effect of progesterone analogue use on quality of life in terms of pain control, performance status, body weight gain, and Epstein-Barr virus (EBV) DNA load in recurrent/metastatic nasopharyngeal carcinoma (NPC) patients. METHODS: We retrospectively enrolled 41 patients with locally recurrent or metastatic NPC who received MA or MPA for cachexia management between January 2007 and February 2014. Patients who underwent aggressive treatment with intravenous chemotherapy were excluded. Body weight, performance status, pain score, and plasma EBV DNA load were used to assess quality of life before and after MA/MPA treatment. RESULTS: Of the 41 patients, 33 patients (80.5%) experienced body weight gain after progesterone analogue intervention. A significant reduction in plasma EBV DNA load was noted after progesterone analogue use (p < 0.001). In addition, median pain and Karnofsky performance scores were also significantly improved in progesterone analogue responders compared with non-responders (4 vs. 1 and 70 vs. 80, respectively; p = 0.004 and p < 0.001, respectively). CONCLUSION: Progesterone analogues improve quality of life in terms of performance status, pain control, and plasma EBV DNA load in patients with locally recurrent/metastatic NPC under palliative care. PMID- 28918910 TI - PET and MRI image fusion based on combination of 2-D Hilbert transform and IHS method. AB - BACKGROUND: The process of medical image fusion is combining two or more medical images such as Magnetic Resonance Image (MRI) and Positron Emission Tomography (PET) and mapping them to a single image as fused image. So purpose of our study is assisting physicians to diagnose and treat the diseases in the least of the time. METHODS: We used Magnetic Resonance Image (MRI) and Positron Emission Tomography (PET) as input images, so fused them based on combination of two dimensional Hilbert transform (2-D HT) and Intensity Hue Saturation (IHS) method. Evaluation metrics that we apply are Discrepancy (Dk) as an assessing spectral features and Average Gradient (AGk) as an evaluating spatial features and also Overall Performance (O.P) to verify properly of the proposed method. RESULTS: In this paper we used three common evaluation metrics like Average Gradient (AGk) and the lowest Discrepancy (Dk) and Overall Performance (O.P) to evaluate the performance of our method. Simulated and numerical results represent the desired performance of proposed method. CONCLUSIONS: Since that the main purpose of medical image fusion is preserving both spatial and spectral features of input images, so based on numerical results of evaluation metrics such as Average Gradient (AGk), Discrepancy (Dk) and Overall Performance (O.P) and also desired simulated results, it can be concluded that our proposed method can preserve both spatial and spectral features of input images. PMID- 28918908 TI - Macrophage biology plays a central role during ionizing radiation-elicited tumor response. AB - Radiation therapy is one of the major therapeutic modalities for most solid tumors. The anti-tumor effect of radiation therapy consists of the direct tumor cell killing, as well as the modulation of tumor microenvironment and the activation of immune response against tumors. Radiation therapy has been shown to promote immunogenic cells death, activate dendritic cells and enhance tumor antigen presentation and anti-tumor T cell activation. Radiation therapy also programs innate immune cells such as macrophages that leads to either radiosensitization or radioresistance, according to different tumors and different radiation regimen studied. The mechanisms underlying radiation-induced macrophage activation remain largely elusive. Various molecular players such as NF-kappaB, MAPKs, p53, reactive oxygen species, inflammasomes have been involved in these processes. The skewing to a pro-inflammatory phenotype thus results in the activation of anti-tumor immune response and enhanced radiotherapy effect. Therefore, a comprehensive understanding of the mechanism of radiation-induced macrophage activation and its role in tumor response to radiation therapy is crucial for the development of new therapeutic strategies to enhance radiation therapy efficacy. PMID- 28918911 TI - Mortality of severe septic patients between physician's high and low care volumes. AB - BACKGROUND: Patients with severe sepsis frequently require intensive care unit (ICU) admission and different ICU care models may influence their outcomes. The mortality of severe septic patients between physician's high and low care volume remains unclear. METHODS: We analyzed the data from a three-year prospective observation study, which was performed in an adult medical ICU of Chung Gung Memorial Hospital, Keelung. The data included initial bundle therapies based on the Surviving Sepsis Campaign (SSC) guidelines for patients with severe sepsis. RESULTS: Clinical data of total 484 patients with severe sepsis were recorded. Cox regression model showed that physician's care volume was an independent factor for lowering mortality in ICU patients with severe sepsis (hazard ratio 0.708; 95% confidence interval 0.514-0.974; p = 0.034). Patients treated by high care volume physician had four out of nine bundle therapies that were significantly higher in percentage following the SSC guidelines. These four therapies were renal replacement therapy, administration of low-dose steroids for septic shock, prophylaxis of gastro-intestinal bleeding, and control of hyperglycemia. CONCLUSION: High care volume physician may decrease mortality in ICU patients with severe sepsis through fitting bundle therapies for sepsis. PMID- 28918912 TI - Evaluation of the root and canal systems of maxillary molars in Taiwanese patients: A cone beam computed tomography study. AB - BACKGROUND: This study evaluated variations in root canal configuration in the maxillary permanent molars of Taiwanese patients by analyzing patients' cone beam computed tomography (CBCT) images. Comparisons were made among these configurations and those previously reported. This information may serve as a basis for improving the success rate of endodontic treatment. METHODS: The root canal systems of 114 Taiwanese patients with bilateral maxillary first or second molars were examined using CBCT images. The number of roots, canals per root, and additional mesiobuccal (MB) canals, as well as the canal configuration were enumerated and recorded. RESULTS: Of the 196 maxillary first molars examined, three (1.5%) had a single root, two (1.0%) had two roots, and 191 (97.5%) had three separate roots. Out of all first molar roots examined, 44% of mesiobuccal (MB) roots had a single canal and the remainder had a second MB (MB2) canal. Of the 212 maxillary second molars examined, 16 (7.1%) had a single root, 51 (24.2%) had two roots, 143 (67.8%) had three roots, and two (0.9%) had four separate roots. For the MB roots, 92.3% of three-rooted maxillary second molars had a single canal and the remainder had an MB2 canal. In all three-rooted maxillary first and second molars, each of the distal and palatal roots had one canal. CONCLUSIONS: The root canal configurations of the MB roots of maxillary molars were more varied than those of the distobuccal and palatal roots, and the root canal configurations of maxillary second molars were more varied than those of the first molars. These findings demonstrate CBCT as a useful clinical tool for endodontic diagnosis and treatment planning. PMID- 28918913 TI - Understanding the Dr. Jekyll and Mr. Hyde nature of apoptosis-inducing factor: future perspectives. AB - Apoptosis-inducing factor (AIF) is emerging as a key protein in regulation of basic physiological processes including phagocytosis, mitophagy and regulation of the redox state. Recent evidences suggest that the enzymatic activity of AIF may play an active role in tumor progression controlling energy metabolism and redox balance. The present manuscript briefly describes the story of this protein from its initial discovery as caspase-independent apoptotic protein, throughout its role in oxidative phosphorylation and lately involvement in tumor progression. Understanding the dualistic nature of AIF is a critical starting point to clarify its contribution in tumor metabolic balance and to develop new AIF-specific therapeutic strategies. PMID- 28918915 TI - A Life-Threatening Cause of Colitis. PMID- 28918916 TI - Olfactory deficits decrease the time resolution for trigeminal lateralization. AB - OBJECTIVES: To date the temporal resolution of the detection of almost simultaneously applied intranasal trigeminal stimuli is unknown. The aim of our study was to examine this temporal resolution in an/hyposmic subjects, who are known to have reduced trigeminal sensitivity and compare it with healthy controls. METHODS: Participants were 20 posttraumatic an/hyposmic patients, and 23 healthy controls (matched with regard to sex and age). Olfactory function was tested psychophysically using the Sniffin' Sticks test battery. Bilateral trigeminal stimulation was carried out using a birhinal high-precision olfactometer. The trigeminal stimulus used was CO2 60% v/v, the interstimulus interval ranged from 28 to 32s, stimulus duration was 200ms. Time-lags tested between right and left side of stimulation were at 40, 80, 120, 160 and 200ms. Subjects raised their left or right hand to indicate the side on which the stimulus had been perceived first. RESULTS: In both groups the accuracy in the trigeminal lateralization task increased with the time-lag but normosmic subjects significantly outperformed an/hyposmics in the 200ms time-lag condition. Normosmics significantly exceeded 50% chance level at the time-lag of 80ms, whereas an/hyposmics were only able to score above chance starting from 120ms time-lag. Lateralization scores significantly decreased with age. CONCLUSIONS: At a time lag of 200ms intranasal trigeminal stimuli can be lateralized. The reduced trigeminal sensitivity in patients with anosmia or hyposmia leads to an increased time lag required for correct perception of intranasal, almost simultaneously, applied stimuli. PMID- 28918917 TI - Leukocytapheresis in rheumatoid arthritis. AB - In this article, we discussed leukocytapheresis (LCAP) for rheumatoid arthritis (RA). Recently, a simple and practical on-line continuous LACP system has been developed. It is equipped with a direct hemoperfusion column (Cellsorba(r), Asahikasei Medical Co., Ltd.) packed with fine-diameter polyester fibers, which are commonly used to adsorb white blood cells to prevent a graft-versus-host reaction during blood transfusion. Clinical trials revealed that LCAP is a effective and safe therapy for patients with drug-resistant RA or RA complicated with vasculitis. Because the procedure is simple and requires no plasma substitutes and the volume needed for extracorporeal circulation is less than that for other plasmapheresis, LCAP might be accepted as an optional therapeutic modality for active RA that was refractory to conventional drug therapy including biological agents. The mechanism of the efficiency of LCAP on RA is unclear. LCAP may cause a reduction of activated T cells from affected joints, down-regulation of Pgp on helper T cells and restoration of Treg function, and that may modify the abnormal cytokine balance. These findings may explain some of the mechanisms by which the articular symptoms are improved by LCAP. PMID- 28918918 TI - Thoracic endovascular aortic repair in type A aortic dissection: Exciting results with unsolved problems. PMID- 28918914 TI - Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-beta Pathway. AB - BACKGROUND & AIMS: Development of hepatocellular carcinoma (HCC) is associated with alterations in the transforming growth factor-beta (TGF-beta) signaling pathway, which regulates liver inflammation and can have tumor suppressor or promoter activities. Little is known about the roles of specific members of this pathway at specific of HCC development. We took an integrated approach to identify and validate the effects of changes in this pathway in HCC and identify therapeutic targets. METHODS: We performed transcriptome analyses for a total of 488 HCCs that include data from The Cancer Genome Atlas. We also screened 301 HCCs reported in the Catalogue of Somatic Mutations in Cancer and 202 from Cancer Genome Atlas for mutations in genome sequences. We expressed mutant forms of spectrin beta, non-erythrocytic 1 (SPTBN1) in HepG2, SNU398, and SNU475 cells and measured phosphorylation, nuclear translocation, and transcriptional activity of SMAD family member 3 (SMAD3). RESULTS: We found somatic mutations in at least 1 gene whose product is a member of TGF-beta signaling pathway in 38% of HCC samples. SPTBN1 was mutated in the largest proportion of samples (12 of 202, 6%). Unsupervised clustering of transcriptome data identified a group of HCCs with activation of the TGF-beta signaling pathway (increased transcription of genes in the pathway) and a group of HCCs with inactivation of TGF-beta signaling (reduced expression of genes in this pathway). Patients with tumors with inactivation of TGF-beta signaling had shorter survival times than patients with tumors with activation of TGF-beta signaling (P = .0129). Patterns of TGF-beta signaling correlated with activation of the DNA damage response and sirtuin signaling pathways. HepG2, SNU398, and SNU475 cells that expressed the D1089Y mutant or with knockdown of SPTBN1 had increased sensitivity to DNA crosslinking agents and reduced survival compared with cells that expressed normal SPTBN1 (controls). CONCLUSIONS: In genome and transcriptome analyses of HCC samples, we found mutations in genes in the TGF-beta signaling pathway in almost 40% of samples. These correlated with changes in expression of genes in the pathways; up regulation of genes in this pathway would contribute to inflammation and fibrosis, whereas down-regulation would indicate loss of TGF-beta tumor suppressor activity. Our findings indicate that therapeutic agents for HCCs can be effective, based on genetic features of the TGF-beta pathway; agents that block TGF-beta should be used only in patients with specific types of HCCs. PMID- 28918919 TI - Patient selection and device development are crucial for thoracic endovascular aortic repair in type A aortic dissection. PMID- 28918920 TI - Thoracic endovascular aortic repair in type a aortic dissection: Inching toward an endovascular solution. PMID- 28918921 TI - Saphenous vein graft harvesting and patency: No-touch harvesting is the answer. PMID- 28918922 TI - When meat allergy meets cardiac surgery: A driver for humanized bioprosthesis. PMID- 28918923 TI - Mammalian meat allergy and advances in bioprosthetic valve technology. PMID- 28918924 TI - Challenge accepted: Social media as a stereotype change agent. PMID- 28918925 TI - Transatlantic editorial: Thoracic surgeons need recognition of competence in thoracic oncology. PMID- 28918926 TI - Subspecialty certification in thoracic oncology: Toward your next diploma. PMID- 28918927 TI - Esophageal squamous cell carcinoma and adenocarcinoma: At the Gates of Mordor. PMID- 28918928 TI - Biology is king and continues to rule. PMID- 28918929 TI - Vitamin D receptor-targeted treatment to prevent pathological dedifferentiation of pancreatic beta cells under hyperglycaemic stress. AB - Dedifferentiation has been identified as one of the causes of beta-cell failure resulting in type 2 diabetes (T2D). This study tested whether increasing vitamin D receptor (VDR) expression prevents dedifferentiation of beta cells in a high glucose state in vitro. Culturing a mouse insulinoma cell line (MIN6) in a high glucose environment decreased VDR expression. However, increased VDR following vitamin D3 (VD3) treatment improved insulin release of early-passage MIN6 and insulin index of db/- (heterozygous) islets to levels seen in normal functional islets. Treatment with VD3, its analogues and derivatives also increased the expression of essential transcription factors, such as Pdx1, MafA and VDR itself, ultimately increasing expression of Ins1 and Ins2, which might protect beta cells against dedifferentiation. VD3 agonist lithocholic acid (LCA) propionate was the most potent candidate molecule for protecting against dedifferentiation, and an e pharmacophore mapping model confirmed that LCA propionate exhibits a stabilizing conformation within the VDR binding site. This study concluded that treating db/+ islets with a VD3 analogue and/or derivatives can increase VDR activity, preventing the pathological dedifferentiation of beta cells and the onset of T2D. PMID- 28918930 TI - A parenteral docetaxel-loaded lipid microsphere with decreased 7-epidocetaxel conversion in vitro and in vivo. AB - The purpose of the study was to develop a parenteral docetaxel lipid microsphere to inhibit its 7-epidocetaxel conversion in vitro and in vivo. 7-epidocetaxel conversion as the main indicator was investigated to optimize the formulation and process. 10% medium-chain triglyceride/long-chain triglyceride (3:1) as the oil phase, egg lecithin E80 as the emulsifier and 0.02% NaHSO3 as the acidity regulator were selected to prepare docetaxel lipid microsphere. This study found that pH and temperature were dominant factors on the epimerization of docetaxel in lipid microsphere, and that optimum conditions were a pH of 5.3 and thermal sterilization conditions of 121 degrees Cautoclaving for 8min. According to the degradation kinetics, docetaxel lipid microsphere had a wider pH range where 7 epidocetaxel(%) stayed at low levels than Docetaxel for Injection, and might improve the docetaxel stability by loading drug in lecithin layer instead of altering the degradation mechanism. Docetaxel lipid microsphere decreased epimerization in plasma in vitro obviously. Pharmacokinetics of docetaxel and 7 epidocetaxel were investigated to quantify the 7-epidocetaxel conversion in vivo. The resulrs indicated that there was less conversion of docetaxel in lipid microspheres than in Docetaxel for Injection. The convert ratios were 0.61% and 3.04% respectively. In conclusion, lipid microsphere is a promising delivery system for intravenous administration of docetaxel with decreased 7-epidocetaxel conversion. PMID- 28918931 TI - Managing status dystonicus outside the intensive care setting: Time to think clonidine? PMID- 28918932 TI - Building and verifying a severity prediction model of acute pancreatitis (AP) based on BISAP, MEWS and routine test indexes. AB - PURPOSE: To discuss the value of the Bedside Index for Severity in Acute Pancreatitis (BISAP), Modified Early Warning Score (MEWS), serum Ca2+, similarly hereinafter, and red cell distribution width (RDW) for predicting the severity grade of acute pancreatitis and to develop and verify a more accurate scoring system to predict the severity of AP. METHODS: In 302 patients with AP, we calculated BISAP and MEWS scores and conducted regression analyses on the relationships of BISAP scoring, RDW, MEWS, and serum Ca2+ with the severity of AP using single-factor logistics. The variables with statistical significance in the single-factor logistic regression were used in a multi-factor logistic regression model; forward stepwise regression was used to screen variables and build a multi factor prediction model. A receiver operating characteristic curve (ROC curve) was constructed, and the significance of multi- and single-factor prediction models in predicting the severity of AP using the area under the ROC curve (AUC) was evaluated. The internal validity of the model was verified through bootstrapping. RESULTS: Among 302 patients with AP, 209 had mild acute pancreatitis (MAP) and 93 had severe acute pancreatitis (SAP). According to single-factor logistic regression analysis, we found that BISAP, MEWS and serum Ca2+ are prediction indexes of the severity of AP (P-value<0.001), whereas RDW is not a prediction index of AP severity (P-value>0.05). The multi-factor logistic regression analysis showed that BISAP and serum Ca2+ are independent prediction indexes of AP severity (P-value<0.001), and MEWS is not an independent prediction index of AP severity (P-value>0.05); BISAP is negatively related to serum Ca2+ (r=-0.330, P-value<0.001). The constructed model is as follows: ln()=7.306+1.151*BISAP-4.516*serum Ca2+. The predictive ability of each model for SAP follows the order of the combined BISAP and serum Ca2+ prediction model>Ca2+>BISAP. There is no statistical significance for the predictive ability of BISAP and serum Ca2+ (P-value>0.05); however, there is remarkable statistical significance for the predictive ability using the newly built prediction model as well as BISAP and serum Ca2+ individually (P-value<0.01). Verification of the internal validity of the models by bootstrapping is favorable. CONCLUSION: BISAP and serum Ca2+ have high predictive value for the severity of AP. However, the model built by combining BISAP and serum Ca2+ is remarkably superior to those of BISAP and serum Ca2+ individually. Furthermore, this model is simple, practical and appropriate for clinical use. PMID- 28918933 TI - Structural proteomics: Topology and relative accessibility of plant lipid droplet associated proteins. AB - : Lipid droplets are the major stock of lipids in oleaginous plant seeds. Despite their economic importance for oil production and biotechnological issues (biofuels, lubricants and plasticizers), numerous questions about their formation, structure and regulation are still unresolved. To determine water accessible domains of protein coating at lipid droplets surface, a structural proteomic approach has been performed. This technique relies on the millisecond timescale production of hydroxyl radicals by the radiolysis of water using Synchrotron X-ray white beam. Thanks to the evolution of mass spectrometry analysis techniques this approach allows the creation of a map of the solvent accessibility for proteins difficult to study by other means. Using these results, a S3 oleosin water accessibility map is proposed. This is the first time that such a map on an oleosin co-purified with plant lipid droplets and other associated protein is presented. BIOLOGICAL SIGNIFICANCE: Lipid droplet associated proteins function is linked to stability, structure and probably formation and lipid mobilization of droplets. Structure of these proteins in their native environment, at the interface between bulk water and the lipidic core of these organelles is only based on hydrophobicity plot. Using hydroxyl radical footprinting and proteomics approaches we studied water accessibility of one major protein in these droplets: S3 oleosin of Arabidopsis thaliana seeds. PMID- 28918934 TI - Reconstructive microsurgical approach for the treatment of pyoderma gangrenosum. AB - INTRODUCTION: Pyoderma gangrenosum (PG) is a rare type of autoimmune disease that results in progressive ulcers with or without previous trauma. However, PG is not well understood to date, and its treatment therefore remains a challenge. Because of the disease's systemic characteristic and the unpredictability of the clinical course, no gold standard treatment is available, especially concerning the surgical procedures to treat pyodermic lesions. Often, PG is not recognized during routine clinical practice, and standard ulcer treatment (conservative wound care, debridement, skin grafting, and local flap coverage) is initiated; this induces an autoinflammatory response, resulting in disastrous ulcers, thereby making free flap coverage necessary. The purpose of this study was to assess the outcome of microvascular free-tissue transfer as a treatment option for extended soft-tissue defects resulting from PG. MATERIALS AND METHODS: We retrospectively evaluated 8 cases in 5 patients suffering from PG of the lower extremity who received defect closure with a microvascular free-tissue transfer under immunosuppressive and corticosteroid therapy. RESULTS: The average patient age was 60 years; three were male, and two were female. Seven defects were covered with free gracilis muscle flap. One patient received an anterolateral thigh flap. The average defect size was 93 cm2. No flap loss was observed during follow-up. All patients received broad-spectrum antibiotic treatment and corticosteroids. Two patients also received infliximab. DISCUSSION AND CONCLUSION: PG once diagnosed is not a contraindication for microvascular free tissue transfer. Multidisciplinary evaluation of each case is fundamental. All surgical treatments should be performed only with sufficient protective immunosuppression therapy. If the defect requires free flap coverage, it should be considered as a surgical option despite the potential risk of a pathergic response in PG and was a safe treatment option in all our cases. In conclusion, we share our experience regarding preoperative, intraoperative, and postoperative care of patients with PG receiving free flap surgery. PMID- 28918935 TI - Dense Intra-adipose Sympathetic Arborizations Are Essential for Cold-Induced Beiging of Mouse White Adipose Tissue. AB - Efferent signals from the central nervous system represent a key layer of regulation of white adipose tissue (WAT). However, the mechanism by which efferent neural signals control WAT metabolism remains to be better understood. Here, we exploit the volume fluorescence-imaging technique to visualize the neural arborizations in mouse inguinal WAT at single-fiber resolution. The imaging reveals a dense network of sympathetic arborizations that had been previously undetected by conventional methods, with sympathetic fibers being in close apposition to > 90% of adipocytes. We demonstrate that these sympathetic fibers originate from the celiac ganglia, which are activated by cold challenge. Sympathetic-specific deletion of TrkA receptor or pharmacologic ablation by 6 hydroxydopamine abolishes these intra-adipose arborizations and, as a result, cold-induced beiging of inguinal WAT. Furthermore, we find that local sympathetic arborizations function through beta-adrenergic receptors in this beiging process. These findings uncover an essential link connecting efferent neural signals with metabolism of individual adipocytes. PMID- 28918936 TI - Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota. AB - While activation of beige thermogenesis is a promising approach for treatment of obesity-associated diseases, there are currently no known pharmacological means of inducing beiging in humans. Intermittent fasting is an effective and natural strategy for weight control, but the mechanism for its efficacy is poorly understood. Here, we show that an every-other-day fasting (EODF) regimen selectively stimulates beige fat development within white adipose tissue and dramatically ameliorates obesity, insulin resistance, and hepatic steatosis. EODF treatment results in a shift in the gut microbiota composition leading to elevation of the fermentation products acetate and lactate and to the selective upregulation of monocarboxylate transporter 1 expression in beige cells. Microbiota-depleted mice are resistance to EODF-induced beiging, while transplantation of the microbiota from EODF-treated mice to microbiota-depleted mice activates beiging and improves metabolic homeostasis. These findings provide a new gut-microbiota-driven mechanism for activating adipose tissue browning and treating metabolic diseases. PMID- 28918938 TI - Social dynamics with space structure: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida and Nisrine Outada. PMID- 28918937 TI - A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product. AB - Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes. PMID- 28918940 TI - Biological Psychiatry: A New Approach to Reviews. PMID- 28918939 TI - Corrigendum to "New vaccination strategies in liver cancer" [Cytokine Growth Factor Rev. 36 (2017) 125-129]. PMID- 28918941 TI - Modulation of gamma- and beta-Secretases as Early Prevention Against Alzheimer's Disease. AB - The genetic evidence implicating amyloid-beta in the initial stage of Alzheimer's disease is unequivocal. However, the long biochemical and cellular prodromal phases of the disease suggest that dementia is the result of a series of molecular and cellular cascades whose nature and connections remain unknown. Therefore, it is unlikely that treatments directed at amyloid-beta will have major clinical effects in the later stages of the disease. We discuss the two major candidate therapeutic targets to lower amyloid-beta in a preventive mode, i.e., gamma- and beta-secretase; the rationale behind these two targets; and the current state of the field. PMID- 28918942 TI - WITHDRAWN: Relation of Mean Platelet Volume-to-Lymphocyte Ratio and Contrast Induced Acute Kidney Injury in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28918944 TI - Optimization of epidural cortical stimulation for treatment-resistant depression. PMID- 28918943 TI - Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. OBJECTIVE: To assess therapeutic potential of VNS in a PD model. METHODS: To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), alpha-synuclein, astrocytes (GFAP) and microglia (Iba-1). RESULTS: VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN alpha-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. CONCLUSIONS: Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased alpha-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic. PMID- 28918945 TI - Hof1 and Chs4 Interact via F-BAR Domain and Sel1-like Repeats to Control Extracellular Matrix Deposition during Cytokinesis. AB - Localized extracellular matrix (ECM) remodeling is thought to stabilize the cleavage furrow and maintain cell shape during cytokinesis [1-14]. This remodeling is spatiotemporally coordinated with a cytoskeletal structure pertaining to a kingdom of life, for example the FtsZ ring in bacteria [15], the phragmoplast in plants [16], and the actomyosin ring in fungi and animals [17, 18]. Although the cytoskeletal structures have been analyzed extensively, the mechanisms of ECM remodeling remain poorly understood. In the budding yeast Saccharomyces cerevisiae, ECM remodeling refers to sequential formations of the primary and secondary septa that are catalyzed by chitin synthase-II (Chs2) and chitin synthase-III (the catalytic subunit Chs3 and its activator Chs4), respectively [18, 19]. Surprisingly, both Chs2 and Chs3 are delivered to the division site at the onset of cytokinesis [6, 20]. What keeps Chs3 inactive until secondary septum formation remains unknown. Here, we show that Hof1 binds to the Sel1-like repeats (SLRs) of Chs4 via its F-BAR domain and inhibits Chs3-mediated chitin synthesis during cytokinesis. In addition, Hof1 is required for rapid accumulation as well as efficient removal of Chs4 at the division site. This study uncovers a mechanism by which Hof1 controls timely activation of Chs3 during cytokinesis and defines a novel interaction and function for the conserved F-BAR domain and SLR that are otherwise known for their abilities to bind membrane lipids [21, 22] and scaffold protein complex formation [23]. PMID- 28918946 TI - Cooperative Behavior Emerges among Drosophila Larvae. AB - Spectacular examples of cooperative behavior emerge among a variety of animals and may serve critical roles in fitness [1, 2]. However, the rules governing such behavior have been difficult to elucidate [2]. Drosophila larvae are known to socially aggregate [3, 4] and use vision, mechanosensation, and gustation to recognize each other [5-8]. We describe here a model experimental system of cooperative behavior involving Drosophila larvae. While foraging in liquid food, larvae are observed to align themselves and coordinate their movements in order to drag a common air cavity and dig deeper. Large-scale cooperation is required to maintain contiguous air contact across the posterior breathing spiracles. On the basis of a directed genetic screen we find that vision plays a key role in cluster dynamics. Our experiments show that blind larvae form fewer clusters and dig less efficiently than wild-type and that socially isolated larvae behave as if they were blind. Furthermore, we observed that blind and socially isolated larvae do not integrate effectively into wild-type clusters. Behavioral data indicate that vision and social experience are required to coordinate precise movements between pairs of larvae, therefore increasing the degree of cooperativity within a cluster. Hence, we hypothesize that vision and social experience allow Drosophila larvae to assemble cooperative digging groups leading to more effective feeding and potential evasion of predators. Most importantly, these results indicate that control over membership of such a cooperative group can be regulated. PMID- 28918947 TI - Hormonal Signaling Cascade during an Early-Adult Critical Period Required for Courtship Memory Retention in Drosophila. AB - Formation and expression of memories are critical for context-dependent decision making. In Drosophila, a courting male rejected by a mated female subsequently courts less avidly when paired with a virgin female, a behavioral modification attributed to "courtship memory." Here we show the critical role of hormonal state for maintenance of courtship memory. Ecdysis-triggering hormone (ETH) is essential for courtship memory through regulation of juvenile hormone (JH) levels in adult males. Reduction of JH levels via silencing of ETH signaling genes impairs short-term courtship memory, a phenotype rescuable by the JH analog methoprene. JH-deficit-induced memory impairment involves rapid decay rather than failure of memory acquisition. A critical period governs memory performance during the first 3 days of adulthood. Using sex-peptide-expressing "pseudo-mated" trainers, we find that robust courtship memory elicited in the absence of aversive chemical mating cues also is dependent on ETH-JH signaling. Finally, we find that JH acts through dopaminergic neurons and conclude that an ETH-JH dopamine signaling cascade is required during a critical period for promotion of social-context-dependent memory. PMID- 28918949 TI - Old-Growth Fishes Become Scarce under Fishing. AB - Researchers have long recognized the importance of ecological differences at the species level in structuring natural communities yet until recently have often overlooked the influence of intraspecific trait variation, which can profoundly alter community dynamics [1]. Human extraction of living resources can reduce intraspecific trait variation by, for example, causing truncation of age and size structure of populations, where numbers of older individuals decline far more with exploitation than younger individuals. Age truncation can negatively affect population and community stability, increasing variability in population and community biomass [2-6], reducing productivity [7-10] and life-history diversity in traits such as the spatial and temporal pattern of reproduction and migration [4, 11-16]. Here, we quantified the extent of age truncation in 63 fished populations across five ocean regions, as measured by how much the proportions of fish in the oldest age groups declined over time. The proportion of individuals in the oldest age classes decreased significantly in 79% to 97% of populations (compared to historical or unfished values, respectively), and the magnitude of decline was greater than 90% in 32% to 41% of populations. The pervasiveness and intensity of age truncation indicates that fishing is likely reducing the stability of many marine communities. Our findings suggest that more emphasis should be given to management measures that reduce the impact of fishing on age truncation, including no-take areas, slot limits that prohibit fishing on all except a narrow range of fish sizes, and rotational harvesting. PMID- 28918948 TI - Firing of Replication Origins Frees Dbf4-Cdc7 to Target Eco1 for Destruction. AB - Robust progression through the cell-division cycle depends on the precisely ordered phosphorylation of hundreds of different proteins by cyclin-dependent kinases (CDKs) and other kinases. The order of CDK substrate phosphorylation depends on rising CDK activity, coupled with variations in substrate affinities for different CDK-cyclin complexes and the opposing phosphatases [1-4]. Here, we address the ordering of substrate phosphorylation by a second major cell-cycle kinase, Cdc7-Dbf4 or Dbf4-dependent kinase (DDK). The primary function of DDK is to initiate DNA replication by phosphorylating the Mcm2-7 replicative helicase [5 7]. DDK also phosphorylates the cohesin acetyltransferase Eco1 [8]. Sequential phosphorylations of Eco1 by CDK, DDK, and Mck1 create a phosphodegron that is recognized by the ubiquitin ligase SCFCdc4. DDK, despite being activated in early S phase, does not phosphorylate Eco1 to trigger its degradation until late S phase [8]. DDK associates with docking sites on loaded Mcm double hexamers at unfired replication origins [9, 10]. We hypothesized that these docking interactions sequester limiting amounts of DDK, delaying Eco1 phosphorylation by DDK until replication is complete. Consistent with this hypothesis, we find that overproduction of DDK leads to premature Eco1 degradation. Eco1 degradation also occurs prematurely if Mcm complex loading at origins is prevented by depletion of Cdc6, and Eco1 is stabilized if loaded Mcm complexes are prevented from firing by a Cdc45 mutant. We propose that the timing of Eco1 phosphorylation, and potentially that of other DDK substrates, is determined in part by sequestration of DDK at unfired replication origins during S phase. PMID- 28918950 TI - Power Transfer to a Human during an Electric Eel's Shocking Leap. AB - Electric eels have been the subject of investigation and curiosity for centuries [1]. They use high voltage to track [2] and control [3] prey, as well as to exhaust prey by causing involuntary fatigue through remote activation of prey muscles [4]. But their most astonishing behavior is the leaping attack, during which eels emerge from the water to directly electrify a threat [5, 6]. This unique defense has reportedly been used against both horses [7] and humans [8]. Yet the dynamics of the circuit that develops when a living animal is contacted and the electrical power transmitted to the target have not been directly investigated. In this study, the electromotive force and circuit resistances that develop during an eel's leaping behavior were determined. Next, the current that passed through a human subject during the attack was measured. The results allowed each variable in the equivalent circuit to be estimated. Findings can be extrapolated to a range of different eel sizes that might be encountered in the wild. Despite the comparatively small size of the eel used in this study, electrical currents in the target peaked at 40-50 mA, greatly exceeding thresholds for nociceptor activation reported for both humans [9] and horses [10, 11]. No subjective sensation of involuntary tetanus was reported, and aversive sensations were restricted to the affected limb. Results suggest that the main purpose of the leaping attack is to strongly deter potential eel predators by briefly causing intense pain. Apparently a strong offense is the eel's best defense. PMID- 28918951 TI - Collective Force Regulation in Anti-parallel Microtubule Gliding by Dimeric Kif15 Kinesin Motors. AB - During cell division, the mitotic kinesin-5 Eg5 generates most of the force required to separate centrosomes during spindle assembly. However, Kif15, another mitotic kinesin, can replace Eg5 function, permitting mammalian cells to acquire resistance to Eg5 poisons. Unlike Eg5, the mechanism by which Kif15 generates centrosome separation forces is unknown. Here we investigated the mechanical properties and force generation capacity of Kif15 at the single-molecule level using optical tweezers. We found that the non-motor microtubule-binding tail domain interacts with the microtubule's E-hook tail with a rupture force higher than the stall force of the motor. This allows Kif15 dimers to productively and efficiently generate forces that could potentially slide microtubules apart. Using an in vitro optical trapping and fluorescence assay, we found that Kif15 slides anti-parallel microtubules apart with gradual force buildup while parallel microtubule bundles remain stationary with a small amount of antagonizing force generated. A stochastic simulation shows the essential role of Kif15's tail domain for load storage within the Kif15-microtubule system. These results suggest a mechanism for how Kif15 rescues bipolar spindle assembly. PMID- 28918953 TI - [Superficial temporal artery pseudoaneurysm: 2 cases]. AB - BACKGROUND: Pseudoaneurysm of the superficial temporal artery causes tumefaction in the temporal region. Herein, we report two cases. PATIENTS AND METHODS: Case 1 : a 32-year-old man presented with a slightly pulsatile nodular formation measuring 2 cm in the right temporal region that had appeared nine months after traumatic injury. A diagnosis of superficial temporal artery pseudoaneurysm was considered. Excision was performed with ligation of the afferent and efferent artery. The clinical diagnosis was confirmed by histopathology. Case 2 : a 24 year-old man presented with a nonpulsatile subcutaneous tumefaction on his left temple. Surgery was proposed based on a supposed epidermal cyst. However, the perioperative aspect suggested a lesion of arterial origin and excision was performed following ligation of the afferent and efferent artery. CONCLUSION: Pseudoaneurysm of the superficial temporal artery must be considered for all temporal cutaneous formations, particularly when there is a history of trauma. The clinical diagnosis may be confirmed by Doppler ultrasound. Surgery is the treatment of reference. PMID- 28918952 TI - A Dual Function for Prickle in Regulating Frizzled Stability during Feedback Dependent Amplification of Planar Polarity. AB - The core planar polarity pathway coordinates epithelial cell polarity during animal development, and loss of its activity gives rise to a range of defects, from aberrant morphogenetic cell movements to failure to correctly orient structures, such as hairs and cilia. The core pathway functions via a mechanism involving segregation of its protein components to opposite cells ends, where they form asymmetric intracellular complexes that couple cell-cell polarity. This segregation is a self-organizing process driven by feedback interactions between the core proteins themselves. Despite intense efforts, the molecular pathways underlying feedback have proven difficult to elucidate using conventional genetic approaches. Here we investigate core protein function during planar polarization of the Drosophila wing by combining quantitative measurements of protein dynamics with loss-of-function genetics, mosaic analysis, and temporal control of gene expression. Focusing on the key core protein Frizzled, we show that its stable junctional localization is promoted by the core proteins Strabismus, Dishevelled, Prickle, and Diego. In particular, we show that the stabilizing function of Prickle on Frizzled requires Prickle activity in neighboring cells. Conversely, Prickle in the same cell has a destabilizing effect on Frizzled. This destabilizing activity is dependent on the presence of Dishevelled and blocked in the absence of Dynamin and Rab5 activity, suggesting an endocytic mechanism. Overall, our approach reveals for the first time essential in vivo stabilizing and destabilizing interactions of the core proteins required for self organization of planar polarity. PMID- 28918954 TI - Contemporary Management of Vesicoureteral Reflux. AB - CONTEXT: Vesicoureteral reflux (VUR) remains the most interesting topic of pediatric urology due to the dynamic nature of recent controversial publications. Starting from the need for a diagnosis to the necessity and effectiveness of treatment in preventing scars, VUR remains in the mist. Although recent strong evidence helped as fog lights in this blurriness, more data are required for achieving crystal clearance. This article aims to summarize and discuss the current state of the evidence regarding VUR management. OBJECTIVE: To provide a comprehensive synthesis of the main evidence in the literature on the current and contemporary management of VUR in children; to discuss conservative management with continuous antibiotic prophylaxis (CAP), especially its effectiveness and safety; and to review the current evidence regarding contemporary surgical techniques. EVIDENCE ACQUISITION: We conducted a nonsystematic review of the literature using the recent guidelines and PubMed database regarding surveillance, CAP, endoscopic, open, laparoscopic, and robot-assisted ureteral surgical treatment. EVIDENCE SYNTHESIS: Despite the striking results of previous studies revealing the ineffectiveness of CAP, more recent studies and their two fresh meta-analyses revealed a positive role for CAP in the contemporary management of VUR. One of the most interesting findings is the redundant rising of endoscopic correction and its final settlement to real indicated cases. Patient individualization in the contemporary management of VUR seems to be the keyword. The evidence in the literature showed a safe and effective use of laparoscopic and robot-assisted laparoscopic reimplantations. CONCLUSIONS: The goal of VUR treatment is to prevent the occurrence of febrile urinary tract infections and formation of scars in the renal parenchyma. The approach should be risk adapted and individualized according to current knowledge. Individual risk is influenced by the presentation age, sex, history of pyelonephritis and renal damage, grade of reflux, bladder bowel dysfunction, and circumcision status. PATIENT SUMMARY: Vesicoureteral reflux is a nonphysiological reflux of urine from the bladder through the ureters to the kidney. Treatment depends on the presentation of the vesicoureteral reflux (VUR). Therapeutic options range from watchful waiting to open surgery. This article aims to summarize and discuss the current state of the evidence regarding VUR management. PMID- 28918955 TI - Shifts in the relationship between motor unit recruitment thresholds versus derecruitment thresholds during fatigue. AB - Muscle fatigue is associated with diminished twitch force amplitude. We examined changes in the motor unit recruitment versus derecruitment threshold relationship during fatigue. Nine men (mean age = 26 years) performed repeated isometric contractions at 50% maximal voluntary contraction (MVC) knee extensor force until exhaustion. Surface electromyographic signals were detected from the vastus lateralis, and were decomposed into their constituent motor unit action potential trains. Motor unit recruitment and derecruitment thresholds and firing rates at recruitment and derecruitment were evaluated at the beginning, middle, and end of the protocol. On average, 15 motor units were studied per contraction. For the initial contraction, three subjects showed greater recruitment thresholds than derecruitment thresholds for all motor units. Five subjects showed greater recruitment thresholds than derecruitment thresholds for only low-threshold motor units at the beginning, with a mean cross-over of 31.6% MVC. As the muscle fatigued, many motor units were derecruited at progressively higher forces. In turn, decreased slopes and increased y-intercepts were observed. These shifts were complemented by increased firing rates at derecruitment relative to recruitment. As the vastus lateralis fatigued, the central nervous system's compensatory adjustments resulted in a shift of the regression line of the recruitment versus derecruitment threshold relationship. PMID- 28918957 TI - Introduction to the 2017 Founders' Lecture of the Association for Academic Surgery. AB - This year's Founders' Lecture will focus on the founding and history of the Association for Academic Surgery (AAS), as presented by five past presidents. The lecture will give the readers a unique and condensed perspective on the remarkable history of the AAS. The AAS was founded in 1967 by Dr George Zuidema with the mission to offer young academic surgeons an inclusive forum for discussion about surgical research and the opportunity for professional growth.1 Since its establishment in 1966, with a membership of only 33 people,1the organization has grown into a diverse international organization with over 2800 members. Today, the AAS embraces five core values to promote the careers of young academic surgeons: inclusion, leadership, innovation, scholarship, and mentorship. In this introduction to the brief history of the AAS, we review how this organization emerged from these principles. PMID- 28918956 TI - Healthcare utilization and expenditures for United States Medicare beneficiaries with systemic vasculitis. AB - OBJECTIVE: The Medicare federal insurance program is the most common United States insurer of patients with systemic vasculitis (SV). We compared healthcare utilization and expenditures for Medicare beneficiaries with versus without SV. METHODS: This national, retrospective study used 2010 claims and enrollment data for a 100% cohort of Medicare Part A and B beneficiaries with >=1 claim including a diagnosis for a form of SV (n = 176,498), and a randomly selected group of non SV beneficiaries (n = 46,561). Outcomes included annual counts of events in 16 categories of medical services (e.g., inpatient stays, physician visits, tests, and imaging events), and total annual Medicare and patient medical expenditures. We used linear regression with bootstrapped standard errors to compare utilization and expenditures by SV status, before and after matching on age and sex. Prescription drug fills and expenditures for SV (n = 95,157) and non-SV (n = 24,992) beneficiaries with Part D drug benefits were also compared. RESULTS: After matching, Medicare spent $11,004 more per patient in 2010 for medical services, and $773 more on prescription drugs, for SV versus non-SV beneficiaries. SV beneficiaries spent $1547 more for medical services and $211 more for prescription drugs. Except for hospice, SV beneficiaries had greater utilization of all services, including two-to-three times more dialysis events, hospital readmissions, inpatient stays, skilled nursing facility stays, and medical tests. CONCLUSIONS: The average Medicare beneficiary with SV incurs about double the annual healthcare expenditures compared to their non-SV counterparts, attributable to increased utilization of almost all categories of care. PMID- 28918958 TI - The Association for Academic Surgery 2011-present: standing on the shoulders of giants. AB - The Association for Academic Surgery (AAS), which is a society dedicated to inspiring and developing young academic surgeons, recently celebrated its 50th anniversary. Each decade since its inception has seen incredible growth. This most recent decade, from 2011 to present, has been characterized by: (1) reevaluation and clarification of the society's vision, mission, core values and organizational structure; (2) diversification of the membership and leadership; (3) support for international outreach and global surgery research; (4) expansion of its impact through social media; and (5) adaptability to a changing political climate. PMID- 28918959 TI - The Association for Academic Surgery: Its first decade. PMID- 28918960 TI - Erratum. PMID- 28918961 TI - Remembrances from an early follower and leader of the Association for Academic Surgery. AB - This reflection retraces the evolution of early followers and leaders. Social change and early contributions set the stage for the current Association for Academic Surgery. Perhaps the most important contribution was Dr. George Zuidema's theme of inclusiveness. AAS was a decade ahead of its time in that regard. PMID- 28918962 TI - The 1990s and the Association for Academic Surgery. AB - This lecture reviews the progress of the Association for Academic Surgery during the 1990s, a decade of sweeping innovations in technology, communication, and biomedical sciences; a well as a decade of transition in the demographics of surgical trainees; and a decade of new and previously unimagined possibilities for new directions in academic surgical careers. PMID- 28918964 TI - Intersphincteric fistula without external opening and to re-enter the rectum. PMID- 28918963 TI - Laparoscopic subtotal cholecystectomy: a surgical alternative to reduce complications in complex cases. AB - INTRODUCTION: Laparoscopic cholecystectomy is a common procedure in general surgery, and in complex cases it is important for the surgeon to know all the alternatives with low associated morbidity. Laparoscopic subtotal cholecystectomy should be considered as an option when a critical view of safety cannot be obtained, because it has a low complication rate and gives the advantages of minimally invasive surgery. METHODS: Retrospective study of laparoscopic subtotal cholecystectomies in an eight years period. RESULTS: A total of 1,059 laparoscopic cholecystectomies were performed; 22 were subtotal cholecystectomies, without conversion. Biliary fistula (9%) and intraabdominal collections (4.5%) were the most common complications described. No iatrogenic bile duct injuries or deaths were reported. Our follow-up period was 32months, no recurrences were reported. CONCLUSIONS: Laparoscopic subtotal cholecystectomy is a safe and effective procedure. It should be considered as an option in complex cases. PMID- 28918965 TI - Surgical treatment for esophageal cancer: Are the questions finished or are the surgeons who are finished by the questions? PMID- 28918966 TI - Reactive oxygen species and associated reactivity of peroxymonosulfate activated by soluble iron species. AB - The activation of peroxymonosulfate by iron (II), iron (III), and iron (III)-EDTA for in situ chemical oxidation (ISCO) was compared using nitrobenzene as a hydroxyl radical probe, anisole as a hydroxyl radical+sulfate radical probe, and hexachloroethane as a reductant+nucleophile probe. In addition, activated peroxymonosulfate was investigated for the treatment of the model groundwater contaminants perchloroethylene (PCE) and trichloroethylene (TCE). The relative activities of hydroxyl radical and sulfate radical in the degradation of the probe compounds and PCE and TCE were isolated using the radical scavengers tert butanol and isopropanol. Iron (II), iron (III), and iron (III)-EDTA effectively activated peroxymonosulfate to generate hydroxyl radical and sulfate radical, but only a minimal flux of reductants or nucleophiles. Iron (III)-EDTA was a more effective activator than iron (II) and iron (III), and also provided a non hydroxyl radical, non-sulfate radical degradation pathway. The contribution of sulfate radical relative to hydroxyl radical followed the order of anisole>>TCE>PCE >>nitrobenzene; i.e., sulfate radical was less dominant in the oxidation of more oxidized target compounds. Sulfate radical is often assumed to be the primary oxidant in activated peroxymonosulfate and persulfate systems, but the results of this research demonstrate that the reactivity of sulfate radical with the target compound must be considered before drawing such a conclusion. PMID- 28918967 TI - Accuracy of bedside point of care testing in critical emergency department patients. AB - BACKGROUND: Point-of-care (POC) testing reduces laboratory turn-around having the potential to improve timely diagnosis and management. We compared the accuracy of nurse performed POC and core laboratory testing and determined whether deviations between the two were clinically meaningful. METHODS: We performed a prospective, observational study on a convenience sample of 50 critical care ED patients in whom a POC chemistry and hematocrit was ordered. Blood samples were divided into 2 aliquots; one sample was tested by the treating nurse using a handheld POC device and the other sample was tested in the core laboratory. Paired comparisons of test results were performed using Pearson's correlation coefficients, Lin concordance coefficients, and Bland Altman plots. RESULTS: Mean patient age was 67, 50% were male, 82% were admitted. Pearson's correlation and Lin concordance coefficients were excellent (0.84-1.00) for all 8 analytes. Mean (95%CI) paired differences between POC and core laboratory measurements were Na+ 0.30 (-0.22 to 0.82) mmol/L, K+-0.12 (-0.14 to - 0.09) mmol/L, Cl- 2.10 (1.41 to 2.78) mmol/L, TCO2-1.68 (-2.06 to -1.30) mmol/L, glucose 2.46 (1.46 to 3.46) mg/dL, BUN, 1.69 (0.95 to 2.42) mg/dL, creatinine 0.13 (0.08 to 0.17) mg/dL, and hematocrit -0.39 (-0.93 to 0.15) %. In 3 of 400 measurements, the difference between POC and core lab exceeded the maximal clinically acceptable deviation based on physician surveys. CONCLUSIONS: Bedside POC by ED nurses is reliable and accurate and does not deviate significantly from core laboratory testing by trained technicians. PMID- 28918968 TI - Optimizing recruitment and retention of adolescents in ED research: Findings from concussion biomarker pilot study. PMID- 28918969 TI - A pitfall in magnetic stimulation for measuring central motor conduction time. PMID- 28918970 TI - Corrections. PMID- 28918971 TI - [Pulmonary nocardiosis with cerebral abscesses mimicking metastatic lung cancer: Three cases and a review of literature]. AB - Nocardiosis is an infectious disease with wide range of clinical features, which can eventually lead to death. The agent responsible belongs to the genus Nocardia that includes about fifty different species. Nocardiosis occurs mainly in immunocompromised hosts. We report here three cases of disseminated nocardiosis misdiagnosed initially as cerebral metastatic lung cancer. These patients, including two immunocompetent hosts, presented with both pulmonary and cerebral lesions. In all three patients, the diagnosis was based on magnetic resonance imaging with diffusion sequence, apparent diffusion coefficient reconstruction and neurosurgical cerebral biopsies. Treatment with an appropriate antibiotic regimen was prolonged for several months. Progress was favorable with full resolution of the neurological symptoms and the radiological abnormalities. These three cases emphasize the diagnostic challenge of nocardiosis, especially in disseminated disease. PMID- 28918972 TI - [Mycological and parasitological examinations in the management of lung infections]. AB - Pulmonary parasitic diseases are rare whereas pulmonary fungal infections are increasing. The diversity of clinical presentations requires laboratory tests to confirm the diagnosis. Direct examination of lung samples and antibody detection are the basis of parasitological diagnosis. With regard to mycoses, the range of biological tests is broader. The conventional mycological examination allows identification of any type of fungus except Pneumocystis jirovecii. Its specificity is excellent but it lacks sensitivity. Detection of antibodies, antigens or nucleic acid complements the diagnostic tools. With regard to aspergillosis, there is a broad nosological set with variable prognosis. The choice of appropriate laboratory procedures depends on the clinical presentation and patient risk factors. The search for galactomannan antigen is effective and a new technique, "Lateral Flow Device", seems very promising. The detection of antibodies is also informative but various techniques are used. A good knowledge of the performance and limitations of these techniques allows targeted prescription. The use of PCR for the diagnosis of pulmonary fungal infections has limited indications. Biological and clinical co-operation is essential for the choice and interpretation of laboratory tests for parasitic or fungal pulmonary disease. PMID- 28918973 TI - Atypical features and systemic associations in extensive cases of Grover disease: A systematic review. AB - BACKGROUND: Grover disease is an acantholytic disorder that typically occurs on the trunk of older individuals, primarily white men, in association with heat and xerosis. Cases with extensive and/or atypical distributions have been reported. OBJECTIVE: To review the literature characterizing the population, morphology, associations, and disease course of extensive or atypical eruptions of Grover disease. METHODS: A systematic literature review identified 50 articles with 69 cases. RESULTS: Patient age ranged from 14 to 83 years (mean age, 56 +/- 15), with 71% of patients being male and 29% female. Areas of involvement included the trunk (90%), upper and lower extremities (63% and 61%, respectively), face/scalp (28%), neck (21%), groin (11%), buttocks (8%), and axillae (6%). The most common associations included a history of malignancy (61%), recent chemotherapy (38%), and recent transplant (20%). LIMITATIONS: Extensive cases with typical clinical morphology may not have been examined by biopsy or reported; thus, this review may have publication bias toward more severe or atypical presentations. CONCLUSIONS: Greater variability exists among patients affected by extensive or atypical Grover disease than among those with typical disease. Malignancy is a common association, and there may be a role for immunosuppression in the pathogenesis of extensive or atypical Grover disease. PMID- 28918975 TI - Activity determination of 67Ga using 4pibeta-gamma coincidence counting. AB - The activity of a 67Ga solution was measured by means of the 4pibeta-gamma coincidence counting technique. A setup with a proportional counter and non extending dead-time modules in the two detector channels was used. The influence of the delayed state affecting the measured count rates was taken into account by using appropriate correction formulae. The analysis requires a variation of the dead time and a subsequent extrapolation to infinite dead time. An uncertainty of about 0.5% was obtained and the result was used to make an intercomparison with the SIR of the BIPM. PMID- 28918976 TI - Validation of a Portuguese version of the health-related quality of life measure for active chronic otitis media (COMQ-12). AB - INTRODUCTION: Measuring the impact on quality of life, especially after the beginning of the treatment, is becoming increasingly important in healthcare. OBJECTIVE: The aim of this study was to translate the Chronic Otitis Media Questionnaire-12 (COMQ-12) into Portuguese language and validate this version in a group of patients with chronic otitis media. METHODS: The Portuguese version of COMQ-12 was obtained by translation and back translation. Portuguese speaking patients with a history of active chronic otitis media were asked to complete the COMQ-12 Portuguese version. Cronbach's alpha coefficient was calculated for an estimation of the internal consistency of the questionnaire. RESULTS: A total of 100 patients were included in the study; 49 women and 51 men, with a mean age of 39 years (range 12-77 years, median 40 years). The average COMQ-12 score was 29, out of a maximum score of 60. Cronbach's alpha result for the Portuguese version of the COMQ-12 was 0.85, indicating a high internal consistency. The participants presented with different forms of chronic otitis media, and almost all domains of the COMQ-12 questionnaire were able to differentiate between patients with healed chronic otitis media and patients with cholesteatoma or wet tympanic membrane perforation. Showing that patients with healed chronic otitis media have a better quality of life, measured by the COMQ-12, is a first step to guarantee the questionnaire's validity. The next step will consist on routinely using the questionnaire in patients undergoing surgery for chronic otitis media in order to evaluate their quality of life after treatment. CONCLUSION: The COMQ-12 Portuguese version showed high reliability, and may be used as an assessment of quality of life in patients with chronic otitis media. PMID- 28918974 TI - Pigmentary changes in patients treated with targeted anticancer agents: A systematic review and meta-analysis. AB - BACKGROUND: The discovery of signaling networks that drive oncogenic processes has led to the development of targeted anticancer agents. The burden of pigmentary adverse events from these drugs is unknown. OBJECTIVE: To conduct a systematic review and meta-analysis of published clinical trials and determine the incidence and risk of development of targeted therapy-induced pigmentary changes. METHODS: A comprehensive search was conducted to identify studies reporting targeted therapy-induced pigmentary changes. The incidence and relative risk were calculated. Case reports and series were reviewed to understand clinical characteristics. RESULTS: A total of 8052 patients from 36 clinical trials were included. The calculated overall incidences of targeted cancer therapy-induced all-grade pigmentary changes in the skin and hair were 17.7% (95% confidence interval [CI], 11.9-25.4) and 21.5% (95% CI, 14.9-30.1), respectively. The relative risk of all-grade pigmentary changes of skin and hair were 93.7 (95% CI, 5.86-1497.164) and 20.1 (95% CI, 8.35-48.248). Across 53 case reports/series (N = 75 patients), epidermal growth factor receptor and breakpoint cluster region abelson inhibitors were the most common offending agents. LIMITATIONS: Potential under-reporting and variability in oncologists reporting these events. CONCLUSION: There is a significant risk of development of pigmentary changes during treatment with targeted anticancer therapies. Appropriate counseling and management are critical to minimize psychosocial impairment and deterioration in quality of life. PMID- 28918977 TI - Huge buccal angiomyolipoma: a rare entity. PMID- 28918978 TI - Editorial. PMID- 28918979 TI - CON: Factor Concentrates Should Not Have an Expanded Role in the Routine Management of the Bleeding Cardiac Surgical Patient. PMID- 28918980 TI - Outcomes of Aortic Valve Replacement According to Surgical Approach in Intermediate and Low Risk Patients: A Propensity Score Analysis. AB - BACKGROUND: Previous trials have shown that, among high-risk patients with aortic stenosis, survival rates are similar for transcatheter aortic-valve implantation (TAVI) and surgical aortic valve replacement. The study aimed to compare the outcomes of aortic valve replacement according to the adopted surgical approach in intermediate and low risk patients. METHODS: This is a retrospective, observational, cohort study of prospectively collected data from 421 patients undergoing isolated aortic valve replacement between 2011 and 2015. A multinomial logit propensity score model based on preoperative risk factors was used to match patients 1:1:1 between conventional replacement (CAVR), minimally invasive (MIAVR) and TAVI groups, resulting in 50 matched three cohorts. RESULTS: After multinomial logit propensity score, the three groups were comparable in terms of preoperative characteristics. Mean age and Logistic EuroSCORE I of CAVR, MIAVR and TAVI groups were (84.2+/-5.1 vs. 82.3+/-4.8 vs. 85.6+/-4.9 years; p=0.002) and (11.4+/-3.6% vs. 8.3+/-3.4% vs. 15.8+/-5.4%; p<0.001) respectively. Overall mortality rates were similar for the three patient cohorts at one year. There were no significant differences related to stroke to 30 days. In the TAVI cohort, pacemaker implantation for new-onset total atrioventricular block became necessary in 30% of patients (p<0.001) and 16% of patients had some degree of paravalvular aortic regurgitation, which was more than mild (p<0.001). Total length of stay was shorter in the TAVI group when compared with surgical groups (11.5+/-5.3 vs. 10.1+/-6.9 vs 8.5+/-3.7 days; p=0.023). After discharge, the survival rate follow-up (average follow up: 46.7 months) was 70%, 84% and 72% for three cohorts (log Rank x2=2.40, p=0.3). CONCLUSIONS: In our experience, the three aortic valve replacement approaches offer very good results. Differences in the rate of complications were found between groups. Depending on patient's characteristics the Heart-Team group must offer the best surgical approach for each patient. PMID- 28918981 TI - Potential impacts of shipping noise on marine mammals in the western Canadian Arctic. AB - As the Arctic warms and sea ice decreases, increased shipping will lead to higher ambient noise levels in the Arctic Ocean. Arctic marine mammals are vulnerable to increased noise because they use sound to survive and likely evolved in a relatively quiet soundscape. We model vessel noise propagation in the proposed western Canadian Arctic shipping corridor in order to examine impacts on marine mammals and marine protected areas (MPAs). Our model predicts that loud vessels are audible underwater when >100km away, could affect marine mammal behaviour when within 2km for icebreakers vessels, and as far as 52km for tankers. This vessel noise could have substantial impacts on marine mammals during migration and in MPAs. We suggest that locating the corridor farther north, use of marine mammal observers on vessels, and the reduction of vessel speed would help to reduce this impact. PMID- 28918982 TI - Characteristics of meso-sized plastic marine debris on 20 beaches in Korea. AB - We surveyed the abundance and accumulation patterns of mesoplastic marine debris (5-25mm) on 20 beaches in Korea. The mean abundance of it was 13.2items/m2, and the mean weight was 1.5g/m2. Hard plastic and Styrofoam were the dominant types. The proportions of hard plastic and Styrofoam were highly variable among the beaches, each accounting for 0-100% of the total debris on a given beach with 32% and 48.5% (by number) on average, respectively. Relatively lower abundances of mesoplastic marine debris compared with our previous studies were likely due by differences of the sampling areas within the beach. The samples of this research were selected from backshore, middle line, and water edge whereas they were selected from high strandline and backshore in our previous studies. It should be considered when discussing the level of mesoplastic marine debris. PMID- 28918984 TI - Corrigendum to "The relevance effect and conditionals" [Cognition 150 (2016) 26 36]. PMID- 28918983 TI - Distribution of organic contamination of sediments from Ichkeul Lake and Bizerte Lagoon, Tunisia. AB - Analyses of organochlorine pesticides (OCPs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and butyl tins (BuSn) were conducted on sediments from Ichkeul Lake-Bizerte Lagoon watershed (Tunisia). A total of 59 compounds (16 PAHs, 12 PCBs, 22 OCPs and 9 BuSn) were measured in 40 surface sediment samples collected during two campaigns. High concentrations of total PAHs were identified in the lagoon ranging from 122 to 19600ng.g-1. Several OCPs, including endrin, dieldrin, and lindane (Hexachlorocyclohexane or HCH or BHC) were found in high concentrations in Ichkeul Lake, ranging from 28 to 2012ngg-1. PAHs and OCPs varied seasonally, in response to the complex hydrology of the watershed. The concentrations of total PCBs ranged between 0.04 and 10.653ngg-1 and suggests low total PCBs sediment contamination, when compared to most international criteria. Total BuSn concentrations range between 67 and 526ng.g-1, which are relatively low when compared to most international criteria and ecological risk assessments. This is the first study of organic contamination in Ichkeul Lake (RAMSAR and UNESCO World Heritage site). PMID- 28918985 TI - Infections worsen prognosis of patients with cirrhosis irrespective of the liver disease stage. PMID- 28918986 TI - Multiparametric assessment of "fluid status" in heart failure. PMID- 28918987 TI - Diagnosing and treating Enquiry Based Learning fatigue in Graduate Entry Nursing students. AB - The use of student directed study approaches such as Enquiry Based Learning (EBL) in the design and implementation of Graduate Entry Nursing Circular is well established. The rational relates to the maximisation of graduate attributes such as motivation to learn, the ability to identify, search and assimilate relevant literature and the desire to take ownership of the direction and pace of learning. Existing alongside this however, is the observation that students remain under confident in the application of knowledge to a clinical context and frustrated with learning approaches which do not appear directly related to improving their competence in this area. We suggest the result of this is a gradual disengagement and dissatisfaction the learning forum amongst students and faculty, which we have defined as EBL fatigue. The symptoms and consequences of EBL fatigue amongst students and faculty are discussed alongside strategies which we suggest may act as preventative measures in reducing the risk of a local epidemic. PMID- 28918988 TI - At the advancing front of Chikungunya fever in Asia: Two imported cases in Hong Kong with novel amino acid changes. PMID- 28918989 TI - Improper positioning of the elevator lever of duodenoscopes may lead to sequestered bacteria that survive disinfection by automated endoscope reprocessors. AB - BACKGROUND: Some outbreaks associated with contaminated duodenoscopes have been attributed to biofilm formation. The objective of this study was to determine whether bacteria within an organic matrix could survive if the elevator lever was improperly positioned in the automated endoscope reprocessor (AER) after 1 round of reprocessing. METHODS: Duodenoscope lever cavities with an open or sealed elevator wire channel were inoculated with 6-7 Log10 of both Escherichia coli and Enterococcus faecalis in ATS2015 (Healthmark Industries, Fraser, MI) and dried for 2 hours. The duodenoscopes with the lever in the horizontal position were processed through 2 makes of AERs. The cavity was sampled using a flush-brush flush method to determine the quantity of surviving bacteria. RESULTS: E faecalis (range, 21-6 Log10 CFU) and E coli (range, 0-3 Log10 CFU) survived disinfection of sealed or unsealed elevator wire channel duodenoscopes in 2 different AERs with and without cleaning cycles. CONCLUSION: If bacteria in organic residue are under the improperly positioned lever, then just 1 round of use is sufficient for bacteria to survive both liquid chemical sterilization and liquid chemical HLD regardless of whether or not the AER had a cleaning cycle. PMID- 28918990 TI - Long-term metabolic persistence of gram-positive bacteria on health care-relevant plastic. AB - BACKGROUND: Health care-associated opportunistic pathogens Staphylococcus aureus and Enterococcus faecium persist on dry environments and can contribute to organism transmission through contact. These organisms can be monitored on surfaces by culture, molecular methods, or metabolic assays. This study was designed to determine the kinetics of bacterial persistence on acrylonitrile butadiene styrene, a plastic commonly used in the manufacture of bedrails. MATERIALS AND METHODS: Polymerase chain reaction for genomic DNA was used to confirm the presence of bacteria cells on this plastic irrespective of viability. Bacterial viability was measured by culture, ATP quantification, and a metabolic assay at time points up to and longer than 1 year. RESULTS: Polymerase chain reaction confirmed the presence of bacteria on the plastic for the entire time period studied. However, S aureus culturability was reduced after 3 and 7 weeks; neither organism was culturable after 1 year. At 7 weeks, ATP levels were reduced for both organisms, paralleling S aureus culturability but indicating that ATP quantification did not predict E faecium culturability. S aureus-reducing potential was reduced after 7 weeks, whereas E faecium-reducing potential reached the level of fresh inoculum after 12 hours in broth culture. Low but significant levels of metabolic activity were detected for each organism after 1 year. CONCLUSIONS: S aureus and E faecium cells may retain viability on plastic for longer than 1 year. PMID- 28918991 TI - Comment on: determinants associated with the correction of glomerular hyperfiltration one year after bariatric surgery. PMID- 28918992 TI - Anti-factor Xa levels in patients undergoing laparoscopic sleeve gastrectomy: 2 different dosing regimens of enoxaparin. AB - BACKGROUND: Morbidly obese patients undergoing bariatric surgery are at risk for developing venous thromboembolic events. Data regarding the appropriate dosing strategy in this special population is limited. OBJECTIVE: To evaluate 2 different dosing regimens of enoxaparin in a prospective cohort of patients undergoing laparoscopic sleeve gastrectomy. SETTING: University hospital, Israel METHODS: The study cohort consisted of 54 patients divided into 2 groups. Group I received 40 mg enoxaparin every 24 hours, and group II received 60 mg enoxaparin every 24 hours. Anti-factor Xa (FXa) levels from each patient were obtained 3 to 4 hours after administration of the third dose of enoxaparin. Levels between .2 and 0.5 U/mL were considered appropriate. Five additional patients were selected as controls. RESULTS: There were 31 patients in group I and 23 patients in group II. There was a statistically significant difference between anti-FXa levels achieved in each group: .247 U/mL in group I (range, .15-.39) versus .346 U/mL (range, .24-.8) in group II. Both groups achieved mean anti-FXa levels in the range designated appropriate with a high proportion of patients achieving appropriate levels (group I: 80.6%; group II: 91.3%). Univariate analyses found that total weight and sex were significantly correlated with anti-FXa levels. However, a multivariate analysis including enoxaparin dose found that only enoxaparin dose remained significantly correlated with anti-FXa levels. CONCLUSION: In the absence of sufficient data regarding clinical efficacy and safety of different dosing regimens both dosing regimens studied are reasonable choices for venous thromboembolic events prophylaxis after bariatric surgery. PMID- 28918993 TI - Arabidopsis thaliana cold-regulated 47 gene 5'-untranslated region enables stable high-level expression of transgenes. AB - Transgene expression is regulated through several steps, this study focuses on the mRNA translation step. The expression level of transgenes can be increased by 5'-untranslated region (5'UTR) sequences in certain genes which act as translational enhancers. On the other hand, translation in most mRNA species is repressed by growth, development, and stress events. There is a possibility that transgene mRNA is also repressed in these conditions, despite the use of a translational enhancer. Therefore, a consistently efficient translational enhancer is needed to develop a reliable transgene expression system. Herein we searched for mRNAs translated stably under different growth, development and environmental conditions using data sets of polysome fraction assays and microarray analysis. Correct 5'UTR sequences of candidate genes were determined by cap analysis of gene expression and we tested translational ability of the candidate 5'UTRs by reporter assays. We found the 5'UTR of cold-regulated 47 gene to be an effective translational enhancer, contributing to stable high-level expression under various conditions. PMID- 28918994 TI - Meaningful Methods for Increasing Human Papillomavirus Vaccination Rates: An Integrative Literature Review. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States and is a well-known cause of oropharyngeal, cervical, vaginal, vulvar, penile, and anal cancers. Despite the proven efficacy of the HPV vaccine, vaccination rates remain persistently low. Much literature has focused on attitudes toward the HPV vaccine; however, researchers have also investigated strategies clinicians can use to improve vaccination attitudes and acceptance. Such strategies include provider education, vaccine reminder/recall, and chart audit and feedback. The purpose of this integrative review is to uncover the best evidence-based practice interventions, with the aim of improving HPV knowledge, patient-provider conversations, and immunization uptake. This integrative review concludes that multicomponent interventions have a synergistic effect, resulting in increased provider vaccine support, improved patient/parental attitudes toward HPV vaccination, and increased immunization uptake. Such strategies hold much promise for today's pediatric providers as they work to combat current vaccination disparities. PMID- 28918995 TI - Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. AB - The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care. PMID- 28918996 TI - Delayed erythematous skin reaction with SERI(R)-assisted direct to implant breast reconstruction. PMID- 28918997 TI - Tolerance of latissimus dorsi in immediate breast reconstruction without implant to radiotherapy. AB - INTRODUCTION: Immediate breast reconstruction (IBR) improves the quality of life of patients who undergo mastectomy. The latissimus dorsi flap (LDF) method provides particularly good aesthetic results, but its tolerance to subsequent radiotherapy remains unclear. We thus sought to assess tolerance and esthetic results and satisfaction, as reported by patients who underwent IBR by LDF with or without subsequent radiotherapy. MATERIALS AND METHODS: We performed a retrospective case-control study in a population of women who were diagnosed with breast cancer between January 1999 and January 2014 and who had mastectomies with IBR by LDF without prostheses. We paired 29 patients who needed postoperative radiotherapy to 58 control patients who did not. These patients responded to a questionnaire to evaluate tolerance and their satisfaction with the aesthetic results of the reconstruction. RESULTS: In total, 86.2% of all patients reported "very good" or "good" overall aesthetic satisfaction. Consistency was judged as "very good" or "good" by 82.7% of control patients and by 93.1% of case patients. No statistically significant differences were identified between the two groups with regard to reconstruction results. The number of surgical procedures needed did not differ significantly between the two groups. CONCLUSION: In our study, IBR by LDF appeared to have excellent tolerance to subsequent radiotherapy, the latter having no impact on patient aesthetic satisfaction. Our results suggest that the possibility of postoperative radiotherapy should not prevent physicians from proposing this method to women who are candidates for it. PMID- 28918998 TI - Convex bone deformity after closed reduction of nasal bone fracture. AB - BACKGROUND: Nasal fracture is the most common type of facial fracture treated by plastic surgeons. Here, we clarify the postoperative deformities that frequently remain after closed reduction of fresh nasal bone fracture by three-dimensional computed tomography (3D-CT). METHODS: Hundred consecutive cases of fresh nasal bone fracture in patients treated between May 2010 and January 2016 were examined. After closed reduction, the overall appearance of the arch formed by the nasal bone and maxillary process was evaluated as 'Excellent', 'Good' or 'Fair'. Patients were also asked about their overall satisfaction with the operation, and the responses were classified as 'Satisfied', 'Neutral' or 'Dissatisfied'. RESULTS: Eighty-six patients underwent 3D-CT examination both at the time of the initial consultation and 3 months after the operation. The results were 'Excellent' in 69 patients and 'Good' in 17 patients, with none of the patients having only 'Fair' results. Convex bone deformities on one side were seen in all six bilateral type fractures evaluated as 'Good'. All patients classified as 'Excellent' reported being 'Satisfied' with the results, but some patients classified as 'Good' gave a 'Neutral' evaluation regarding their satisfaction. CONCLUSIONS: The residual deformities seen in bilateral type fractures were most notable, and they were all convex bone deformities on one side. Plastic surgeons should use ultrasonography or other reliable new methods in addition to visual inspection during the operation to successfully treat the region of the convex fracture. PMID- 28918999 TI - Diagnosis of Ehlers-Danlos syndrome after a first shoulder dislocation. AB - BACKGROUND: Shoulder dislocation is often the first symptom of Ehlers-Danlos syndrome (EDS). Whether it occurs in early-onset EDS is unknown. In most cases, surgical failure leads to the diagnosis. We aimed to determine whether clinical symptoms can signal the presence of EDS at a first dislocation. MATERIALS AND METHODS: In this retrospective study, we analyzed clinical and radiologic data for 27 patients with EDS and shoulder instability and a control population of 40 consecutive non-EDS patients undergoing surgery for an unstable shoulder. Data were collected on gender, age, single or bilateral disease, general hyperlaxity, shoulder hyperlaxity, number of dislocations or subluxations, nontraumatic onset, and pain specificity. Nerve and vascular injuries, joint disorders, and family history were recorded, and radiologic data were reported. RESULTS: Age <14 years, female sex, bilateral disorder, and general hyperlaxity were significantly more frequent in patients with EDS and a first dislocation than in those without EDS. Painless dislocation with pain after dislocation and concomitant nerve injury were more frequent in affected patients, as were hemostasis disorders and a family history of joint hyperlaxity. Bone lesions were not seen on radiographs. Only the hyperlaxity sign (external rotation >85 degrees ) did not differ between the groups. CONCLUSION: After a first dislocation in a young girl with global hyperlaxity but not necessarily shoulder hyperlaxity, painless atraumatic dislocation with pain after reduction can suggest EDS. PMID- 28919000 TI - Intraobserver and interobserver reliability of the Copeland-Levy classification for arthroscopic evaluation of subacromial impingement. AB - BACKGROUND: Defining a simple and reliable classification for acromial and bursal impingement lesions is necessary to standardize terminology, to improve communication, and to allow better evaluation of the proper treatment of impingement lesions and rotator cuff tears. The purpose of this study was to assess orthopedic surgeons' intraobserver and interobserver reliability of the Copeland-Levy classification. METHODS: Six fellowship-trained orthopedic surgeons reviewed shoulder arthroscopy videos of 69 consecutive patients who underwent shoulder arthroscopy for rotator cuff tear repair or subacromial decompression. The surgeons were asked to classify impingement lesions according to the Copeland Levy classification. One month afterward, the surgeons were requested to repeat the evaluation of the same impingement lesions. Intraobserver reliability was calculated using Cohen's weighted kappa. Interobserver reliability was calculated using Kendall's W. RESULTS: Overall intraobserver reliability for acromial and bursal lesions was kappa = 0.86 (95% confidence interval, 0.82-0.9) and kappa = 0.97 (95% confidence interval, 0.95-0.98), respectively. Interobserver reliability for acromial and bursal lesions was W = 0.87 and W = 0.92, respectively. CONCLUSION: Intraobserver and interobserver reliability of the Copeland-Levy classification among senior orthopedic surgeons is excellent. Hence, we suggest the Copeland-Levy classification be used to standardize terminology of the subacromial impingement lesion. PMID- 28919001 TI - Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. AB - BACKGROUND: Retinoic acid (RA) is known to play a role in weight regulation. Because mice without ALDH1A1, a major RA synthesizing enzyme, are resistant to diet-induced obesity, we tested a hypothesis that pharmacological inhibition of RA synthesis can suppress weight gain in a murine model of diet-induced obesity. METHODS: C57BL/6J male mice were fed a high fat diet (HFD) for 8 weeks to induce obesity and then randomized to a HFD with or without WIN 18,446, an RA synthesis inhibitor, for an additional 9 weeks. Body weight, body composition, energy expenditure, activity, and food intake were measured. Levels of retinoids, lipids, and genes involved in the metabolism of retinoid and lipids were also determined. RESULT: s Mice treated with WIN 18,446 gained significantly less weight and had decreased adipose tissue weight, adipocyte size, and macrophage infiltration in adipose tissue. In addition, we observed higher UCP1 expression in adipose tissues and decreased expression of RA responsive genes and genes involved in fatty acid synthesis in the livers and lungs of mice treated with WIN 18,446. CONCLUSIONS: Pharmacological suppression of RA synthesis via inhibition of ALDH1A1 may be a potential target for treatment of obesity. PMID- 28919002 TI - X-linked adrenoleukodystrophy in a chimpanzee due to an ABCD1 mutation reported in multiple unrelated humans. AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder leading to the accumulation of very long chain fatty acids (VLCFA) due to a mutation in the ABCD1 gene. ABCD1 mutations lead to a variety of phenotypes, including cerebral X-ALD and adrenomyeloneuropathy (AMN) in affected males and 80% of carrier females. There is no definite genotype-phenotype correlation with intrafamilial variability. Cerebral X-ALD typically presents in childhood, but can also present in juveniles and adults. The most affected tissues are the white matter of the brain and adrenal cortex. MRI demonstrates a characteristic imaging appearance in cerebral X-ALD that is used as a diagnostic tool. OBJECTIVES: We aim to correlate a mutation in the ABCD1 gene in a chimpanzee to the human disease X-ALD based on MRI features, neurologic symptoms, and plasma levels of VLCFA. METHODS: Diagnosis of X-ALD made using MRI, blood lipid profiling, and DNA sequencing. RESULTS: An 11-year-old chimpanzee showed remarkably similar features to juvenile onset cerebral X-ALD in humans including demyelination of frontal lobes and corpus callosum on MRI, elevated plasma levels of C24:0 and C26:0, and identification of the c.1661G>A ABCD1 variant. CONCLUSIONS: This case study presents the first reported case of a leukodystrophy in a great ape, and underscores the fidelity of MRI pattern recognition in this disorder across species. PMID- 28919003 TI - Inter-observer agreement in GTV delineation of bone metastases on CT and impact of MR imaging: A multicenter study. AB - BACKGROUND AND PURPOSE: The use of Stereotactic Body Radiotherapy (SBRT) for bone metastases is increasing rapidly. Therefore, knowledge of the inter-observer differences in tumor volume delineation is essential to guarantee precise dose delivery. The aim of this study is to compare inter-observer agreement in bone metastases delineated on different imaging modalities. MATERIAL AND METHODS: Twenty consecutive patients with bone metastases treated with SBRT were selected. All patients received CT and MR imaging in treatment position prior to SBRT. Five observers from three institutions independently delineated gross tumor volume (GTV) on CT alone, CT with co-registered MRI and MRI alone. Four contours per imaging modality per patient were available, as one set of contours was shared by 2 observers. Inter-observer agreement, expressed in generalized conformity index [CIgen], volumes of contours and contours center of mass (COM) were calculated per patient and imaging modality. RESULTS: Mean GTV delineated on MR (45.9+/ 52.0cm3) was significantly larger compared to CT-MR (40.2+/-49.4cm3) and CT (34.8+/-41.8cm3). A considerable variation in CIgen was found on CT (mean 0.46, range 0.15-0.75) and CT-MRI (mean 0.54, range 0.17-0.71). The highest agreement was found on MRI (mean 0.56, range 0.20-0.77). The largest variations of COM were found in anterior-posterior direction for all imaging modalities. CONCLUSIONS: Large inter-observer variation in GTV delineation exists for CT, CT-MRI and MRI. MRI-based GTV delineation resulted in larger volumes and highest consistency between observers. PMID- 28919004 TI - Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias. AB - PURPOSE: To compare toxicity and survival after stereotactic body radiotherapy (SBRT) between lung cancer patients with or without idiopathic interstitial pneumonias (IIPs), and to investigate the potential value of SBRT for the patients. METHODS: Among lung cancer patients receiving SBRT between 2005 and 2016, we evaluated those treated with a total dose of 40-60Gy in five fractions with curative intent who either were staged as cT1-4N0M0 or experienced postoperative isolated local recurrence. We analyzed the incidence of radiation pneumonitis (RP) in all patients and local recurrence and overall survival (OS) in T1a-2a patients. RESULTS: A total of 508 patients were eligible, including 42 with IIPs. The median follow-up was 32.3 (6.0-120.9) months. Significantly more patients with IIPs had grade >=3RP than did those without IIPs (12% vs. 3%, p=0.009). The 2-year local recurrence rate was low in both groups (3.4% vs. 5.6%, p=0.38). The 2-year OS rate was significantly lower in the patients with IIPs (42.2% vs. 80.9%, p<0.001), although death from lung cancer was comparable (p=0.74). CONCLUSION: SBRT achieved excellent local control with acceptable pulmonary toxicity in lung cancer patients with IIPs. SBRT can be a reasonable option for early lung cancer patients with IIPs. PMID- 28919005 TI - Ex vivo gammaH2AX radiation sensitivity assay in prostate cancer: Inter-patient and intra-patient heterogeneity. AB - INTRODUCTION: The aim of the study is to assess inter-patient and intra-patient heterogeneity in tumour cell radiosensitivity using the ex vivo gammaH2AX assay in prostate cancer specimens. METHODS: Excised specimens from untreated prostate cancer patients were cultivated 24h in media, irradiated ex vivo and fixed after 24h. Residual gammaH2AX foci were counted and the slope of the dose response was calculated. Intra-patient heterogeneity was studied from three to seven different biopsies. RESULTS: In pathology-confirmed tumour samples from 21 patients the slope of residual gammaH2AX foci and radiation dose showed a substantial heterogeneity ranging from 0.82 to 3.17 foci/Gy. No correlation was observed between the slope values and the Gleason score (p=0.37), prostate specific antigen (p=0.48) and tumour stage (p=0.89). ANOVA indicated that only in 1 out of 9 patients, biopsies from different tumour locations yielded statistically significant differences. Variance component analysis indicated higher inter patient than intra-patient variability. Bootstrap simulation study demonstrated that one biopsy is sufficient to estimate the mean value of residual gammaH2AX per dose level and account for intra-patient heterogeneity. CONCLUSIONS: In prostate cancer inter-patient heterogeneity in tumour cell radiation sensitivity is pronounced and higher than intra-patient heterogeneity supporting the further development of the gammaH2AX ex vivo assay as a biomarker for individualized treatment. PMID- 28919006 TI - Histology of non-small cell lung cancer predicts the response to stereotactic body radiotherapy. AB - BACKGROUND AND PURPOSE: To investigate the prognostic impact of different histological subtypes of non-small cell lung cancer (NSCLC) on outcome following stereotactic body radiotherapy (SBRT) for NSCLC patients. MATERIALS AND METHODS: We analyzed 126 consecutive patients with early-stage adenocarcinoma or squamous cell carcinoma treated with SBRT from 2004 to 2016. Adenocarcinoma patients were further sub-classified as high-risk or low-risk tumors. RESULTS: With a median follow-up time of 22months, 2-year overall survival (OS), local (LC), and distant control (DC) were 68%, 90% and 79%, respectively. For LC, histologic subtype was identified as major independent prognostic factor (p=0.033): while LC was 81% for squamous cell carcinoma patients, LC was significantly improved for high-risk and even more non-high-risk adenocarcinoma patients with 96% and 100%, respectively (p=0.026). The negative prognostic impact of the histologic subtype "squamous cell carcinoma" was not evident when patients received SBRT with higher total doses in EQD2 (2Gy equivalent dose): if patients were treated with a total dose in EQD2>=150Gy, no significant difference in LC for histologic subtypes was detected anymore (p=0.355). CONCLUSION: In the current study, histologic subtypes of NSCLC predicted local control probabilities following SBRT. Prospective, multi center studies are needed to evaluate the prognostic impact of histology and consecutively the need for SBRT dose adaptation. PMID- 28919007 TI - On the importance of protein diffusion in biological systems: The example of the Bicoid morphogen gradient. AB - Morphogens are proteins that form concentration gradients in embryos and developing tissues, where they act as postal codes, providing cells with positional information and allowing them to behave accordingly. Bicoid was the first discovered morphogen, and remains one of the most studied. It regulates segmentation in flies, forming a striking exponential gradient along the anterior posterior axis of early Drosophila embryos, and activating the transcription of multiple target genes in a concentration-dependent manner. In this review, the work done by us and by others to characterize the mobility of Bicoid in D. melanogaster embryos is presented. The central role played by the diffusion of Bicoid in both the establishment of the gradient and the activation of target genes is discussed, and placed in the context of the need for these processes to be all at once rapid, precise and robust. The Bicoid system, and morphogen gradients in general, remain amongst the most amazing examples of the coexistence, often observed in living systems, of small-scale disorder and large scale spatial order. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28919008 TI - Immunoadsorption in neurological disorders. AB - In recent years, immunoadsorption has been increasingly recognized as an alternative to therapeutic plasma exchange and used for the treatment of neurological disorders such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, neuromyelitis optica spectrum disorders, and multiple sclerosis, as well as autoimmune encephalitis. Unlike therapeutic plasma exchange, which requires fluid replacement with a blood solution such as fresh frozen plasma or albumin, immunoadsorption is a blood purification technique that enables the selective removal of humoral factors from separated plasma through a high-affinity adsorbent with tryptophan or phenylalanine. Although the mechanisms underlying the therapeutic effects of immunoadsorption treatment remain to be fully elucidated, they are based on the removal of pathogenic humoral factors from circulating blood, such as disease specific autoantibodies, complement, and inflammatory cytokines. The American Society for Apheresis has published evidence-based guidelines on the use of therapeutic apheresis in clinical practice, with specific instructions on 16 neurological disorders. However, the modality recommended in the guidelines for most of these disorders is therapeutic plasma exchange. This part of our review focuses on the clinical aspects of immunoadsorption. We also describe the efficacy of immunoadsorption and the evidence obtained by previous studies of the treatment of neurological disorders. Immunoadsorption could greatly improve the treatment of patients with autoimmune neurological disorders but further evidence is needed to confirm the efficacy of immunoadsorption in clinical practice. PMID- 28919009 TI - Distinct patterns of response to transfusion therapy for different chronic complications of sickle cell disease: A useful insight. AB - Two main sub-phenotypes have been described in sickle cell disease: one with higher baseline haemoglobin and a higher rate of painful crises and one with lower baseline haemoglobin, increased markers of haemolysis and a higher incidence of pulmonary hypertension, priapism and leg ulcers. We compared the patterns of response to regular automated red cell exchange transfusion over a five-year period of 21 patients with recurrent painful crises from the first group and 3 patients with pulmonary hypertension and 5 with recurrent severe stuttering priapism form the second and found them to be distinctly different. Response for pain is slow and increases gradually over years. The most pronounced clinical benefit and the one that appears first is a reduction in the severity rather than the frequency of painful crises. In contrast to the slow and gradual response we see for pain, response of patients with pulmonary hypertension and priapism is immediate with significant clinical improvement even after the first transfusion. The response appears to be directly correlated to the HbS level as the symptoms of both conditions invariably recur rapidly when transfusions are delayed or discontinued but resolve again once they are re-instituted. PMID- 28919010 TI - Germ cell proliferation and apoptosis during testicular regression in a seasonal breeding fish kept in captivity. AB - Cell proliferation and apoptosis regulate germ cells stock and sperm production, eliminate anomalous gametes, and are essential parameters to consider in fish farming. Herein, spermatogenic activity as well as germ cell proliferation and apoptosis were assessed in Leporinus taeniatus, a seasonal breeding species from the Sao Francisco River basin, Brazil. Testes of 24 adult fishes from a farming station were sampled between December and July and processed for light and transmission electron microscopy and immunohistochemistry for PCNA and TUNEL assay. The gonadosomatic index and seminiferous tubule diameters presented higher values during the breeding season (December/January and February/March), and then significantly reduced during the regression and resting stages (April/May and June/July). Phagocytosis of spermatozoa by Sertoli cells was evident during gonadal regression, but a significant number (up to 30%) remained at the tubular lumen during the resting stage. A higher PCNA/TUNEL ratio occurred in the breeding period, leading to an elevated proportion (%) of spermatogonia (GA and GB) in resting. Moreover, a higher TUNEL/PCNA ratio indicates the contribution of apoptosis to the reduction of germ cells during testicular regression. Together, these results indicate a shift in the balance between cell proliferation and apoptosis that contributes to the regulation of the spermatogenic cycle and germ cells pool of L. taeniatus kept in captivity. PMID- 28919012 TI - BRAFV600E and BRAF-inactivating mutations in NSCLC. PMID- 28919011 TI - Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. AB - BACKGROUND: BRAFV600E mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAFV600E mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAFV600E-mutant metastatic NSCLC. METHODS: In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (>=18 years of age) with previously untreated metastatic BRAFV600E mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. FINDINGS: Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15.9 months (IQR 7.8-22.0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest). INTERPRETATION: Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC. FUNDING: Novartis. PMID- 28919013 TI - Esophageal perforation and dissection due to echocardiography: Endoscopic treatment using an Over-the-Scope clip. PMID- 28919014 TI - Regulation and function of endothelial glycocalyx layer in vascular diseases. AB - In the vascular system, the endothelial surface layer (ESL) as the inner surface of blood vessels affects mechanotransduction, vascular permeability, rheology, thrombogenesis, and leukocyte adhesion. It creates barriers between endothelial cells and blood and neighbouring cells. The glycocalyx, composed of glycoconjugates and proteoglycans, is an integral component of the ESL and a key element in inter- and intracellular communication and tissue homeostasis. In pathophysiological conditions (atherosclerosis, infection, ischemia/reperfusion injury, diabetes, trauma and acute lung injury) glycocalyx-degrading factors, i.e. reactive oxygen and nitrogen species, matrix metalloproteinases, heparanase and sialidases, damage the ESL, thereby impairing endothelial functions. This leads to increased capillary permeability, leucocyte-endothelium interactions, thrombosis and vascular inflammation, the latter further driving glycocalyx destruction. The present review highlights current knowledge on the vasculoprotective role of the ESL, with specific emphasis on its remodelling in inflammatory vascular diseases and discusses its potential as a novel therapeutic target to treat vascular pathologies. PMID- 28919015 TI - Activity of Bacillus thuringiensis Cry1Ie2, Cry2Ac7, Vip3Aa11 and Cry7Ab3 proteins against Anticarsia gemmatalis, Chrysodeixis includens and Ceratoma trifurcata. AB - Transgenic soybean producing the Cry1Ac insecticidal protein from the bacterium Bacillus thuringiensis is used to control larvae of the velvetbean caterpillar (Anticarsia gemmatalis Hubner) and the soybean looper [Chrysodeixis includens (Walker)]. The main threat to the sustainability of this technology is the development of resistance, which could be delayed by using pyramiding of diverse Bt insecticidal genes. We report high activity of Cry2Ac7 and Vip3Aa11 but not Cry1Ie2 against larvae of A. gemmatalis and C. includens. In addition, we also report anti-feeding activity of Cry1Ie2 and Cry7Ab3 in adults of the bean leaf beetle [Ceratoma trifurcata (Foster)], an alternative pest of soybean. PMID- 28919016 TI - Metarhizium brunneum - An enzootic wireworm disease and evidence for its suppression by bacterial symbionts. AB - Wireworms (Coleoptera: Elateridae) are serious agricultural pests, with soil dwelling larvae attacking subterranean tissues of crop plants and their fruit when in contact with the soil surface. Researchers collect wireworms for laboratory experiments to study their behaviour and test pest control agents but frequently lose them to Metarhizium Petch (Ascomycota: Hypocreales: Clavicipitaceae) infection. We found latent M. brunneum infection in 13-100% of live, asymptomatic Agriotes obscurus and A. lineatus wireworms acquired from agricultural fields and in wireworms maintained indoors, indicating its enzootic presence. M. brunneum DNA in the wireworms maintained indoors sometimes exceeded 250pg/ug total DNA (0.025% of whole-sample DNA mass). Expressed as copies of M. brunneum DNA/g, unadulterated soil levels of M. brunneum ranged from 4037 in agricultural field soil to 721,538 in soil harbouring a wireworm collection indoors, with the prevalence of latently-infected live wireworm specimens being directly related to soil levels. M. brunneum levels in live wireworms, when regressed against relative levels of 394 bacteria species in the microbiome, were proportionally related to only four: Pantoea agglomerans, Pandoraea pnomenusa, Nocardia pseudovaccinii, and Mycobacterium frederiksbergense. All four of these bacteria have previously been reported to express antimicrobial mechanisms. Consistent with occurrences of disease immunity reported for other pathogen insect pairs, symbiotic bacteria may be suppressing M. brunneum-induced wireworm mortality. This would help explain why wireworms commonly succumb to infection after being brought into sterilized conditions, as well as the sometimes limited efficacy of M. brunneum when using it as a pest control agent in the field. PMID- 28919017 TI - Molecular characterization of lower vaginal swabs for Human papilloma virus in association with Chlamydia trachomatis infection in Cameroonian Women. AB - Human papilloma virus (HPV) infection is an etiological factor for cervical cancer development and Chlamydia trachomatis (Ct) is considered as a cofactor. Understanding the dynamics of HPV and Ct infection could help to explain the incidence of early onset of cervical cancer (CC) observed in Cameroon. Lower vaginal swabs and sera from sexually active women were analyzed for HPV and Ct infection in association with risk factors. Questionnaires were used to document patients' lifestyle and risk factors. A total of 206 women participated in the study average 28.1+/-8years (16-50 years). HPV prevalence was 23.3% with subtypes 16 and 18 at respectively 2.9% and 1%. Ct infection totalised 40.8%, of which 23.8% were HPV- Ct co-infections. HPV infection was inversely associated with age (p=0.028). We found a positive association between Ct infection and the number of sex partners (p=0.012) and a negative association with parity (p=0.032). There was no significant association between HPV and Ct infections. High rates of HPV and Ct infections could be an indicator of cervical cancer risk in the near future. There is therefore an urgent need for sensitization as well as implementation of appropriate preventive measures. PMID- 28919018 TI - De novo transcriptome assembly of the calanoid copepod Neocalanus flemingeri: A new resource for emergence from diapause. AB - Copepods, small planktonic crustaceans, are key links between primary producers and upper trophic levels, including many economically important fishes. In the subarctic North Pacific, the life cycle of copepods like Neocalanus flemingeri includes an ontogenetic migration to depth followed by a period of diapause (a type of dormancy) characterized by arrested development and low metabolic activity. The end of diapause is marked by the production of the first brood of eggs. Recent temperature anomalies in the North Pacific have raised concerns about potential negative effects on N. flemingeri. Since diapause is a developmental program, its progress can be tracked using through global gene expression. Thus, a reference transcriptome was developed as a first step towards physiological profiling of diapausing females using high-throughput Illumina sequencing. The de novo transcriptome, the first for this species was designed to investigate the diapause period. RNA-Seq reads were obtained for dormant to reproductive N. flemingeri females. A high quality de novo transcriptome was obtained by first assembling reads from each individual using Trinity software followed by clustering with CAP3 Assembly Program. This assembly consisted of 140,841transcripts (contigs). Bench-marking universal single-copy orthologs analysis identified 85% of core eukaryotic genes, with 79% predicted to be complete. Comparison with other calanoid transcriptomes confirmed its quality and degree of completeness. Trinity assembly of reads originating from multiple individuals led to fragmentation. Thus, the workflow applied here differed from the one recommended by Trinity, but was required to obtain a good assembly. PMID- 28919019 TI - Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity. AB - Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their junctions and polarity to gain a motile mesenchymal phenotype. EMT is essential during embryogenesis and adult physiological processes like wound healing, but is aberrantly activated in pathological conditions like fibrosis and cancer. A series of transcription factors (EMT-inducing transcription factor; EMT TF) regulate the induction of EMT by repressing the transcription of epithelial genes while activating mesenchymal genes through mechanisms still debated. The nuclear interaction of EMT-TFs with larger protein complexes involved in epigenetic genome modulation has attracted recent attention to explain functions of EMT-TFs during reprogramming and cellular differentiation. In this review, we discuss recent advances in understanding the interplay between epigenetic regulators and EMT transcription factors and how these findings could be used to establish new therapeutic approaches to tackle EMT-related diseases. PMID- 28919020 TI - Understanding the association between pressure ulcers and sitting in adults what does it mean for me and my carers? Seating guidelines for people, carers and health & social care professionals. AB - The aim of the publication was to develop a practical guide for people, carers and health and social care professionals on how the research and evidence base on pressure ulcer prevention and management can be applied to those who remain seated for extended periods of time. This publication was developed at the request of the Tissue Viability Society in order to revise the original seating guidelines from 2008 as evidence and subsequent care has moved forward in relation to this area. Since 2008, the costs for the prevention and management of pressure ulcers have increased significantly and there is limited published advice from health and social care organisations on seating and preventing pressure ulcers. These guidelines have been written for: Who live or work in primary, secondary, and tertiary settings. PMID- 28919021 TI - Developing the tissue viability seating guidelines. AB - BACKGROUND: Costs for the prevention and management of pressure ulcers have increased significantly with limited published advice from health and social care organisations on seating and preventing pressure ulcers. At the request of the UK Tissue Viability Society the aim of the publication was to develop a practical guide for people, carers and health and social care professionals on how the research and evidence base on pressure ulcer prevention and management can be applied to those who remain seated for extended periods of time. METHODS AND FINDINGS: The evidence base informing the guidelines was obtained by applying a triangulation of methods: a literature review, listening event and stakeholder group consultation. The purpose was to engage users and carers, academics, clinicians, inspectorate and charities, with an interest in seating, positioning and pressure management to: gather views, feedback, stories, and evidence of the current practices in the field to create a greater awareness of the issue. CONCLUSION: The new guidelines are inclusive of all people with short and long term mobility issues to include all population groups. The document includes evidence on where pressure ulcers develop when seated, risk factors, best possible seated position and what seat adjustments are required, the ideal seating assessment, interventions, self-help suggestions and key seating outcomes. The updated TVS CPGs have been informed by the best available evidence, the insights and wisdom of experts, stakeholders and people who spend extended periods of time sitting. PMID- 28919022 TI - A prospective comparison of younger and older patients' preferences for breast conserving surgery versus mastectomy in early breast cancer. PMID- 28919023 TI - The Many Shades of Dyspnea. PMID- 28919024 TI - Out of Place: Gallstone Ileus. PMID- 28919025 TI - Resident Research Experiences in Internal Medicine Residency Programs-A Nationwide Survey. PMID- 28919026 TI - A novel FAPalpha-based Z-Gly-Pro epirubicin prodrug for improving tumor-targeting chemotherapy. AB - Fibroblast activation protein-alpha (FAPalpha) is a serine protease of the post prolyl peptidase family that is specifically expressed in the majority of human epithelial tumors, but not in normal tissues. In this study, we demonstrated the anti-tumor activity of a novel targeting drug formed by conjugating epirubicin (EPI) with an FAPalpha-specific dipeptide (Z-Gly-Pro) and named it Z-GP-EPI. Consistent with this tumor-targeting delivery strategy, the results illustrated that Z-GP-EPI could release EPI efficiently after incubating with FAPalpha and could exhibit similar antitumor effects as EPI in vitro in FAPalpha over expressed tumor cells (4T1/FAPalpha+). Furthermore, the evaluation of antitumor activity of Z-GP-EPI in vivo was implemented in a 4T1/FAPalpha+ tumor-bearing mice xenograft model. Our results illustrated that Z-GP-EPI had similar antitumor effects in 4T1/FAPalpha+ tumor-bearing mice and showed no visible cardiotoxicity side effects compared with free EPI. Thus, our study indicated that this FAPalpha activated prodrug targeting strategy may provide a new mechanism for the targeted delivery of antitumor agents and improve their safety levels. PMID- 28919027 TI - Macrolactin F inhibits RANKL-mediated osteoclastogenesis by suppressing Akt, MAPK and NFATc1 pathways and promotes osteoblastogenesis through a BMP 2/smad/Akt/Runx2 signaling pathway. AB - The balance between bone formation and bone resorption is maintained by osteoblasts and osteoclasts. In the current study, macrolactin F (MF) was investigated for novel biological activity on the receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis in primary bone marrow-derived macrophages (BMMs). We found that RANKL-induced osteoclast formation and differentiation from BMMs was significantly inhibited by MF in a dose-dependent manner without cytotoxicity. RANKL-induced F-actin ring formation and bone resorption activity in BMMs which was attenuated by MF. In addition, MF suppressed the expression of osteoclast-related genes, including c-myc, RANK, tartrate-resistant acid phosphatase (TRAP), nuclear factor of activated T cells c1 (NFATc1), cathepsin K and matrix metalloproteinase 9 (MMP9). Furthermore, the protein expression NFATc1, c-Fos, MMP9, cathepsin K and phosphorylation of Jun N terminal kinase (JNK), p38 and Akt were also down-regulated by MF treatment. Interestingly, MF promoted pre-osteoblast cell differentiation on Alizarin Red mineralization activity, alkaline phosphatase (ALP) activity, and the expression of osteoblastogenic markers including Runx2, Osterix, Smad4, ALP, type I collagen alpha 1 (Col1alpha), osteopontin (OPN), and osteocalcin (OCN) via activation of the BMP-2/smad/Akt/Runx2 pathway on MC3T3-E1. Taken together, these results indicate that MF may be useful as a therapeutic agent to enhance bone health and treat osteoporosis. PMID- 28919030 TI - Investigating the familiarity effect in texture segmentation by means of event related brain potentials. AB - The familiarity effect (FE) refers to the phenomenon that it is easier to find an unfamiliar element on a background of familiar elements than vice versa. In this study, we examined the FE in texture segmentation while recording event-related brain potentials with the aim to find out which processing stages were influenced by familiarity. In two experiments, with different levels of texture homogeneity, the N1, the N2p, and the P3 components were investigated. It was found that the FE in texture segmentation is associated with a modulation of the early N1 and of the intermediate N2p component for homogeneous textures. For inhomogeneous (jittered) textures, the FE was found for the intermediate N2p and for the late P3 components, but not for the N1 component. Our findings suggest that increasing texture inhomogeneity shifts the FE occurrence to later processing stages. PMID- 28919031 TI - A pilot study to assess near infrared laparoscopy with indocyanine green (ICG) for intraoperative sentinel lymph node mapping in early colon cancer. AB - BACKGROUND: Previous attempts at sentinel lymph node (SLN) mapping in colon cancer have been compromised by ineffective tracers and the inclusion of advanced disease. This study evaluated the feasibility of fluorescence detection of SLNs with indocyanine green (ICG) for lymphatic mapping in T1/T2 clinically staged colonic malignancy. METHODS: Consecutive patients with clinical T1/T2 stage colon cancer underwent endoscopic peritumoral submucosal injection of indocyanine green (ICG) for fluorescence detection of SLN using a near-infrared (NIR) camera. All patients underwent laparoscopic complete mesocolic excision surgery. Detection rate and sensitivity of the NIR-ICG technique were the study endpoints. RESULTS: Thirty patients mean age = 68 years [range = 38-80], mean BMI = 26.2 (IQR = 24.7 28.6) were studied. Mesocolic sentinel nodes (median = 3/patient) were detected by fluorescence within the standard resection field in 27/30 patients. Overall, ten patients had lymph node metastases, with one of these patients having a failed SLN procedure. Of the 27 patients with completed SLN mapping, nine patients had histologically positive lymph nodes containing malignancy. 3/9 had positive SLNs with 6 false negatives. In five of these false negative patients, tumours were larger than 35 mm with four also being T3/T4. CONCLUSION: ICG mapping with NIR fluorescence allowed mesenteric detection of SLNs in clinical T1/T2 stage colonic cancer. CLINICALTRIALS.GOV: ID: NCT01662752. PMID- 28919032 TI - The role of preoperative axillary ultrasound and fine-needle aspiration cytology in identifying patients with extensive axillary lymph node involvement. AB - INTRODUCTION: In the recent past, both clinically node-positive and node-negative but sentinel node-positive patients underwent axillary lymph node dissection (ALND), although the two groups seem to have substantially different degree of nodal involvement. METHODS: Data on consecutive primary breast cancer patients with documented axillary ultrasound (AXUS) results who underwent ALND between January 2003 and December 2015 either because of AXUS-guided fine needle aspiration (A-FNAC) results or because of a positive sentinel lymph node were retrospectively analysed. RESULTS: After exclusions, 316 patients staged by SNB and ALND with negative AXUS or A-FNAC (group A) were compared with 159 patients having positive A-FNAC results (group B). Tumour size and the proportion of mastectomies were greater, histological grade higher and lymphovascular invasion more frequent in Group B, where palpable lymph nodes were also more common. The proportion of cases with extensive nodal involvement (pN2 and pN3 cases) was about 3 times as much in Group B (63%) than in Group A (18%). Removal of the 50 patients with palpable lymph nodes from the analysis did not greatly influence these proportions: 60% and 19% extensive nodal involvements were noted, respectively. In this series, patients with suspicious AXUS and negative A-FNAC had more often extensive nodal involvement (25%) than AXUS negative patients (17%). CONCLUSIONS: Patients in whom axillary metastases are detected by ultrasound-guided biopsy have significantly more involved nodes than SLNB positive patients, and therefore are likely to benefit from axillary treatment. PMID- 28919029 TI - Recent advances of controlled drug delivery using microfluidic platforms. AB - Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery. PMID- 28919033 TI - Non-26S Proteasome Endomembrane Trafficking Pathways in ABA Signaling. AB - The phytohormone abscisic acid (ABA) is a vital endogenous messenger that regulates diverse physiological processes in plants. The regulation of ABA signaling has been well studied at both the transcriptional and translational levels. Post-translational modification of key regulators in ABA signaling by the 26S ubiquitin proteasome pathway is well known. Recently, increasing evidence demonstrates that atypical turnover of key regulators by the endocytic trafficking pathway and autophagy also play vital roles in ABA perception, signaling, and action. We summarize and synthesize here recent findings in the field of ABA signaling. PMID- 28919034 TI - A sensitive and specific lateral flow assay for rapid detection of antibodies against glycoprotein B of Aujeszky's disease virus. AB - A direct double antibody lateral flow assay (DDA-gB-LFA) for the detection of antibodies against the glycoprotein B (gB) of Aujeszky's disease virus (ADV) in swine sera was developed. A native ADV gB was used for the preparation of a conjugate with colloidal gold particles and the immobilization on the strip membrane. The gB purified from ADV virions by immunoaffinity chromatography retained its native epitope structure after adsorption on the nitrocellulose membrane and the surface of colloidal gold particles. The diagnostic specificity and sensitivity of the DDA-gB-LFA were evaluated using 236 field swine sera. The diagnostic specificity and sensitivity of the DDA-gB-LFA compared to a commercially available gB-based ELISA were 98.0% and 98.6%, respectively, when determined with the use of the reader-detection mode, and 98.0% and 93.5%, respectively, when determined using visual detection. The DDA-gB-LFA provides a rapid, sensitive, and specific determination of ADV gB-directed antibodies in sera and can be used for the detection of ADV-exposed swine. PMID- 28919035 TI - Development of a fast and efficient method for hepatitis A virus concentration from green onion. AB - Hepatitis A virus (HAV) can cause serious liver disease and even death. HAV outbreaks are associated with the consumption of raw or minimally processed produce, making it a major public health concern. Infections have occurred despite the fact that effective HAV vaccine has been available. Development of a rapid and sensitive HAV detection method is necessary for an investigation of an HAV outbreak. Detection of HAV is complicated by the lack of a reliable culture method. In addition, due to the low infectious dose of HAV, these methods must be very sensitive. Current methods rely on efficient sample preparation and concentration steps followed by sensitive molecular detection techniques. Using green onions which was involved in most recent HAV outbreaks as a representative produce, a method of capturing virus particles was developed using carboxyl derivatized magnetic beads in this study. Carboxyl beads, like antibody-coated beads or cationic beads, detect HAV at a level as low as 100 pfu/25g of green onions. RNA from virus concentrated in this manner can be released by heat-shock (98 degrees C 5min) for molecular detection without sacrificing sensitivity. Bypassing the RNA extraction procedure saves time and removes multiple manipulation steps, which makes large scale HAV screening possible. In addition, the inclusion of beef extract and pectinase rather than NP40 in the elution buffer improved the HAV liberation from the food matrix over current methods by nearly 10 fold. The method proposed in this study provides a promising tool to improve food risk assessment and protect public health. PMID- 28919036 TI - Blends of Non-caloric Sweeteners Saccharin and Cyclamate Show Reduced Off-Taste due to TAS2R Bitter Receptor Inhibition. AB - Non-caloric sweeteners are widely used for the formulation of calorie-reduced beverages for health-conscious consumers. However, disadvantages such as undesired off-tastes limit the use of non-nutritive sweeteners. Therefore, the food industry is constantly searching for novel sweeteners and frequently resorts to using blends combining non-caloric sweeteners in a single formulation. The earliest blend allowing higher sweetness levels with reduced bitter off-taste combined saccharin with cyclamate. However, the mechanism by which sweetener blends become superior to single compounds remained obscure. By functional expression of human bitter taste receptors, we found the explanation for the phenomenon observed ~60 years ago. We demonstrate that cyclamate potently blocks the receptors responsible for saccharin's bitter off-taste. This effect occurs at concentrations where cyclamate itself does not elicit a side taste. Intriguingly, also saccharin inhibits cyclamate-activated bitter receptors. Our experiments demonstrate that heterologous assays are useful for understanding perceptual phenomena and the development of novel tastant formulations. PMID- 28919037 TI - A Link between Linearmycin Biosynthesis and Extracellular Vesicle Genesis Connects Specialized Metabolism and Bacterial Membrane Physiology. AB - Specialized metabolites support bacterial competitive fitness as antibiotics, signals, pigments, and metal scavengers. Little is known about how specialized metabolites are processed and trafficked for their diverse competitive functions. Linearmycins A and B are linear polyketides with antifungal and antibacterial activity but are colony-localized in imaging mass spectrometry of Streptomyces sp. Mg1 (S. sp. Mg1). To decipher a connection between colony localization and antibiotic activity, we identified the linearmycin gene cluster and investigated linearmycin production and distribution by S. sp. Mg1. Our results uncover a large family of variant linearmycins with limited solubility in aqueous solution. We hypothesized that extracellular vesicles may traffic the lipid-like linearmycins. We found that vesicles isolated from culture supernatants contained linearmycins. Surprisingly, abolishing production of linearmycins in S. sp. Mg1 also diminished extracellular vesicle production. Our results reveal integration of linearmycin biosynthesis with production of extracellular vesicles, suggesting a deep connection between specialized metabolism and bacterial membrane physiology. PMID- 28919038 TI - Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products. AB - Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy. PMID- 28919039 TI - A Linear Diubiquitin-Based Probe for Efficient and Selective Detection of the Deubiquitinating Enzyme OTULIN. AB - The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor kappaB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD. The only detectable cross reactivities were the labeling of USP5 (Isopeptidase T) and an ATP-dependent assembly of polyOTULIN ABP chains via Ub-activating E1 enzymes. Both cross reactivities were abolished by the removal of the C-terminal Gly in the ABP's proximal Ub, yielding the specific OTULIN probe UbG76Dha-UbDeltaG76 (OTULIN ABPDeltaG76). Pull-downs demonstrate that substrate-bound OTULIN associates with the linear ubiquitin chain assembly complex (LUBAC). Thus, we present a highly selective ABP for OTULIN that will facilitate studying the cellular function of this essential DUB. PMID- 28919042 TI - New tools for the visualization of biological pathways. AB - This paper presents several geometrically motivated techniques for the visualization of high-dimensional biological data sets. The Grassmann manifold provides a robust framework for measuring data similarity in a subspace context. Sparse radial basis function classification as a visualization technique leverages recent advances in radial basis function learning via convex optimization. In the spirit of deep belief networks, supervised centroid-encoding is proposed as a way to exploit class label information. These methods are compared to linear and nonlinear principal component analysis (autoencoders) in the context of data visualization; these approaches may perform poorly for visualization when the variance of the data is spread across more than three dimensions. In contrast, the proposed methods are shown to capture significant data structure in two or three dimensions, even when the information in the data lives in higher dimensional subspaces. To illustrate these ideas, the visualization techniques are applied to gene expression data sets that capture the host immune system's response to infection by the Ebola virus in non-human primate and collaborative cross mouse. PMID- 28919041 TI - A Split-Abl Kinase for Direct Activation in Cells. AB - To dissect the cellular roles of individual kinases, it is useful to design tools for their selective activation. We describe the engineering of a split-cAbl kinase (sKin-Abl) that is rapidly activated in cells with rapamycin and allows temporal, dose, and compartmentalization control. Our design strategy involves an empirical screen in mammalian cells and identification of split site in the N lobe. This split site leads to complete loss of activity, which can be restored upon small-molecule-induced dimerization in cells. Remarkably, the split site is transportable to the related Src Tyr kinase and the distantly related Ser/Thr kinase, AKT, suggesting broader applications to kinases. To quantify the fold induction of phosphotyrosine (pTyr) modification, we employed quantitative proteomics, NeuCode SILAC. We identified a number of known Abl substrates, including autophosphorylation sites and novel pTyr targets, 432 pTyr sites in total. We believe that this split-kinase technology will be useful for direct activation of protein kinases in cells. PMID- 28919040 TI - Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. AB - The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKalpha. CYP3A4 knockdown activated AMPKalpha, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery. PMID- 28919044 TI - Susceptibility of colistin-resistant pathogens to predatory bacteria. AB - The increase in multidrug-resistant Gram-negative bacterial infections has forced the reintroduction of antibiotics such as colistin. However, the spread of the plasmid-borne mcr-1 colistin resistance gene have moved us closer to an era of untreatable Gram-negative infections. To evaluate whether predatory bacteria could be used as a potential therapeutic to treat this upcoming threat, the ability of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus to prey on several clinically relevant mcr-1-positive, colistin-resistant isolates was evaluated. No change in the ability of the predators to prey on free swimming and biofilms of prey cells harboring mcr-1 was measured, as compared to their mcr-1 negative strain. PMID- 28919045 TI - Cover Story Enhanced intrapericardial drug delivery by PLGA nanoparticles. PMID- 28919043 TI - Neocortical dynamics during whisker-based sensory discrimination in head restrained mice. AB - A fundamental task frequently encountered by brains is to rapidly and reliably discriminate between sensory stimuli of the same modality, be it distinct auditory sounds, odors, visual patterns, or tactile textures. A key mammalian brain structure involved in discrimination behavior is the neocortex. Sensory processing not only involves the respective primary sensory area, which is crucial for perceptual detection, but additionally relies on cortico-cortical communication among several regions including higher-order sensory areas as well as frontal cortical areas. It remains elusive how these regions exchange information to process neural representations of distinct stimuli to bring about a decision and initiate appropriate behavioral responses. Likewise, it is poorly understood how these neural computations are conjured during task learning. In this review, we discuss recent studies investigating cortical dynamics during discrimination behaviors that utilize head-fixed behavioral tasks in combination with in vivo electrophysiology, two-photon calcium imaging, and cell-type specific targeting. We particularly focus on information flow in distinct cortico cortical pathways when mice use their whiskers to discriminate between different objects or different locations. Within the primary and secondary somatosensory cortices (S1 and S2, respectively) as well as vibrissae motor cortex (M1), intermingled functional representations of touch, whisking, and licking were found, which partially re-organized during discrimination learning. These findings provide first glimpses of cortico-cortical communication but emphasize that for understanding the complete process of discrimination it will be crucial to elucidate the details of how neural processing is coordinated across brain wide neuronal networks including the S1-S2-M1 triangle and cortical areas beyond. PMID- 28919046 TI - FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-beta autoinduction. AB - Bone-derived fibroblast growth factor 23 (FGF23) is an important endocrine regulator of mineral homeostasis with effects transduced by cognate FGF receptor (FGFR)1-alpha-Klotho complexes. Circulating FGF23 levels rise precipitously in patients with kidney disease and portend worse renal and cardiovascular outcomes. De novo expression of FGF23 has been found in the heart and kidney following injury but its significance remains unclear. Studies showing that exposure to chronically high FGF23 concentrations activates hypertrophic gene programs in the cardiomyocyte has spawned intense interest in other pathological off-target effects of FGF23 excess. In the kidney, observational evidence points to a concordance of ectopic renal FGF23 expression and the activation of local transforming growth factor (TGF)-beta signalling. Although we have previously shown that FGF23 activates injury-primed renal fibroblasts in vitro, our understanding of the mechanism underpinning these effects was incomplete. Here we show that in the absence of alpha-Klotho, FGF23 augments pro-fibrotic signalling cascades in injury-primed renal fibroblasts via activation of FGFR4 and upregulation of the calcium transporter, transient receptor potential cation channel 6. The resultant rise in intracellular calcium and production of mitochondrial reactive oxygen species induced expression of NFAT responsive-genes and enhanced TGF-beta1 autoinduction through non-canonical JNK-dependent pathways. Reconstitution with transmembrane alpha-Klotho, or its soluble ectodomain, restored classical Egr signalling and antagonised FGF23-driven myofibroblast differentiation. Thus, renal FGF23 may amplify local myofibroblast activation in injury and perpetuate pro-fibrotic signalling. These findings strengthen the rationale for exploring therapeutic inhibition of FGFR4 or restoration of alpha-Klotho as upstream regulators of off-target FGF23 effects. PMID- 28919047 TI - Long non-coding RNA 657 suppresses hepatocellular carcinoma cell growth by acting as a molecular sponge of miR-106a-5p to regulate PTEN expression. AB - Previous study has identified the aberrant expression of LINC00657, a long non coding RNA (lncRNA), in human breast cancer. However, the expression pattern, biological function and underlying mechanism of LINC00657 in human hepatocellular carcinoma (HCC) remain obscure. The expression levels of LINC00657 in HCC tissues and cell lines were determined by quantitative real-time PCR. CCK-8 assay, cell colony formation assay, cell cycle analysis, Transwell assay were performed to determine whether LINC00657 could affect HCC progression. Luciferase reporter assay was used to assess the target of LINC00657. Expressions of the relevant proteins were analyzed by Western blot. Herein, we found that LINC00657 was downregulated in HCC tissue specimens as well as in malignant HCC cell lines. LINC00657 overexpression inhibited the proliferation, migration and invasion of HCC cells, while LINC00657 depletion promoted both cell viability and cell invasion in vitro. We also found that LINC00657 could inhibit tumor growth in vivo. Further experiments demonstrated that down-regulated LINC00657 increased the expression of miR-106a-5p. miR-106a-5p decreased the abundances of PTEN protein, while had no impact on PTEN mRNA. Moreover, we identified that both LINC00657 and PTEN mRNA were targets of miR-106a-5p by using dual-luciferase reporter assay. Our results provide the new evidence supporting the tumor suppressive role of LINC00657 in HCC, suggesting that LINC00657 might play a role in HCC and can be a novel therapeutic target for treating HCC. PMID- 28919049 TI - Perioperative outcomes of syndromic paraganglioma and pheochromocytoma resection in patients with von Hippel-Lindau disease, multiple endocrine neoplasia type 2, or neurofibromatosis type 1. AB - BACKGROUND: Pheochromocytoma and/or paraganglioma associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2A, and von Hippel Lindau disease have different catecholamine biochemical phenotypes. We examined perioperative outcomes of pheochromocytoma/paraganglioma resection in 3 syndromic forms. METHODS: Retrospective review of patients undergoing resection of syndromic pheochromocytoma/paraganglioma from 2000 through 2016. RESULTS: Eighty one patients underwent pheochromocytoma/paraganglioma resection (multiple endocrine neoplasia type 2A, n = 36; neurofibromatosis type 1, n = 26; von Hippel Lindau disease, n = 19). Tumor size differed across groups; patients with neurofibromatosis type 1 and von Hippel-Lindau disease had the largest tumors (P = .017). Larger tumor volumes correlated with higher urine 24-hour total metanephrine (r = 0.94, P < .001; r = 0.67, P = .033; and r = 0.89, P < .001 for multiple endocrine neoplasia type 2A, von Hippel-Lindau disease, and neurofibromatosis type 1, respectively). High adrenergic secretion (24-hour urine metanepinephrine) was found in neurofibromatosis type 1 (median, 861 MUg/24 h), similar to that found in multiple endocrine neoplasia type 2A (median, 809 MUg/24 h). The highest noradrenergic secretion (24-hour urine normetanephrine) occurred with von Hippel-Lindau disease (median, 4,598 MUg/24 h), followed by neurofibromatosis type 1 and multiple endocrine neoplasia type 2A (median, 1,607 and 923 MUg/24 h, respectively). The highest graded complications occurred among patients with neurofibromatosis type 1 (P = .036). However, when comparing postoperative outcomes across 3 groups in those who had laparoscopic resection, there was no significant difference (P = .955). CONCLUSION: Patients with neurofibromatosis type 1 had the most volatile intraoperative hemodynamic course and more severe postoperative complications. These complications are related to large tumors associated with abundant catecholamine secretion and the fact that a high proportion underwent open resection. Among only patients who underwent laparoscopic procedures, there were no differences in postoperative outcomes across syndromic groups. PMID- 28919048 TI - Control of Immune Cell Homeostasis and Function by lncRNAs. AB - The immune system is composed of diverse cell types that coordinate responses to infection and maintain tissue homeostasis. In each of these cells, extracellular cues determine highly specific epigenetic landscapes and transcriptional profiles to promote immunity while maintaining homeostasis. New evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in epigenetic and transcriptional regulation in mammals. Thus, lncRNAs have emerged as key regulatory molecules of immune cell gene expression programs in response to microbial and tissue-derived cues. We review here how lncRNAs control the function and homeostasis of cell populations during immune responses, emphasizing the diverse molecular mechanisms by which lncRNAs tune highly contextualized transcriptional programs. In addition, we discuss the new challenges faced in interrogating lncRNA mechanisms and function in the immune system. PMID- 28919050 TI - Disease and treatment factors associated with lower quality of life scores in adults with multiple endocrine neoplasia type I. AB - BACKGROUND: Physical and psychosocial morbidity of multiple endocrine neoplasia type-1 is ill-defined. How disease and treatment-related factors relate to patient-reported outcomes including health-related quality of life is unknown. We hypothesized that disease and treatment burden negatively impacts health-related quality of life in adults with multiple endocrine neoplasia type-1. METHODS: Adults (>=18 years) with multiple endocrine neoplasia type-1 completed an online survey of demographics, disease features, treatments, and Patient-Reported Outcomes Measurement Information System 29-item profile measure, and scores were compared with normative US data. Multivariable modeling was performed to evaluate factors associated with decreased health-related quality of life. RESULTS: Multiple endocrine neoplasia type-1 patients (n = 207) reported worse health related quality of life compared with US normative data in all health-related quality of life domains (P < .001). Persistent hypercalcemia after parathyroid surgery was associated with higher levels of anxiety, depression, fatigue, and decreased social functioning (P < .05). Patients <45 years of age at diagnosis reported worse physical and social functioning (P < .01). Traveling >50 miles for doctor appointments and >=20 doctor appointments/year (P < .05) were associated with worse health-related quality of life. History of pancreatic neuroendocrine tumors was not associated with worse health-related quality of life. CONCLUSION: This is the largest study to assess clinical and treatment factors associated with health-related quality of life in multiple endocrine neoplasia type-1. Persistent hyperparathyroidism, increased travel distance and frequency of doctor appointments were all associated with worse health-related quality of life. PMID- 28919051 TI - Incidence and predictors of portal and splenic vein thrombosis after pure laparoscopic splenectomy. AB - BACKGROUND: Optimal modalities for diagnosis, treatment, and surveillance of portal or splenic vein thrombosis have not yet been defined. The present retrospective study aimed to investigate the role of computed tomography performed systematically before and after laparoscopic splenectomy to assess the incidence of portal or splenic vein thrombosis, predictors, and outcomes. METHODS: Computed tomography scans were obtained from 170 patients undergoing elective laparoscopic splenectomy between 2005 and 2015. Pre- and postoperative splenic vein diameter was measured at the splenoportal junction and at a distance of 2, 4, 6 cm from it. Univariate and multivariate analyses were used to identify portal or splenic vein thrombosis risk factors and predictors of treatment outcome. RESULTS: Overall, 68.2% of patients had benign hematologic diseases; 64.1% showed splenomegaly. Portal or splenic vein thrombosis occurred in 53.5% of patients (91/170), of whom 49.5% were asymptomatic. Preoperative splenic vein diameter measurements at 2, 4, and 6 cm from the splenoportal junction were significantly greater in portal or splenic vein thrombosis patients than in no portal or splenic vein thrombosis patients. Patients with splenic vein diameter >=8 mm at all measured sites had a greater risk of developing portal or splenic vein thrombosis (P = .009; odds ratio, 2.57; 95% confidence interval, 1.26-5.23). The majority of thromboses involved the distal splenic vein (45.1%, 41/91), and 41.7% of patients had thromboses located in multiple sites. Fully 71.4% showed complete resolution of portal or splenic vein thrombosis. Thrombus location at a single site predicted a favorable treatment outcome (P < .0001). CONCLUSION: Portal or splenic vein thrombosis is a frequent complication of splenectomy that occurs asymptomatically in half of cases. Computed tomography could have an important role in identifying patients at risk of developing portal or splenic vein thrombosis as well as in predicting portal or splenic vein thrombosis resolution. PMID- 28919052 TI - Lung cancer with retrograde extension into the right main pulmonary artery: Positron emission tomography/computed tomography findings. PMID- 28919053 TI - Metastasis to the corpus spongiosum of the penis in a patient with lung cancer causing acute urine retention. PMID- 28919054 TI - The little old lady's hernia. PMID- 28919055 TI - Antimicrobial resistance in women with urinary tract infection in primary care: No relation with type 2 diabetes mellitus. AB - AIMS: To determine if type 2 diabetes mellitus (T2DM) is associated with the spectrum of uropathogens and antimicrobial resistance in urinary tract infections (UTI) in primary care. METHODS: A cross-sectional study in female outpatients >=30 years with positive urine cultures. T2DM patients were 1:1 matched to controls by age group and general practitioner (GP). GPs were sent questionnaires for additional data. Uropathogens and resistance patterns were compared between patients with and without T2DM. Multivariable regression analysis was performed to assess the independent association between T2DM and resistance to first line treatments, defined as resistance to nitrofurantoin, trimethoprim, fosfomycin, ciprofloxacin, amoxicillin/clavulanic acid and/or trimethoprim/sulfamethoxazole. RESULTS: In 566 urine cultures, 680 uropathogens were found. Resistance to first line treatment antibiotics was present in 62.5% of patients. Frequencies and resistance rates of uropathogens did not differ between both groups of patients. Previous UTI and previous hospital admission were independent risk factors for resistance, but T2DM was not. CONCLUSIONS: In this study T2DM was not an independent risk factor for antimicrobial resistance in UTI in primary care. Previous UTI and hospitalisation are drivers of resistance and should be included in the decision to perform a urine culture to target first line UTI treatment. PMID- 28919056 TI - An exploration of person-centred concepts in human services: A thematic analysis of the literature. AB - Being 'person-centred' in the delivery of health and human services has become synonymous with quality care, and it is a core feature of policy reform in Australia and other Western countries. This research aimed to identify the uses, definitions and characteristics of the term 'person-centred' in the ageing, mental health and disability literature. A thematic analysis identified seven common core themes of person-centredness: honouring the person, being in relationship, facilitating participation and engagement, social inclusion/citizenship, experiencing compassionate love, being strengths/capacity focussed, and organisational characteristics. These suggest a set of higher-order experiences for people that are translated differently in different human services. There is no common definition of what it means to be person-centred, despite being a core feature of contemporary health and human service policy, and this suggests that its inclusion facilitates further misunderstanding and misinterpretation. A common understanding and policy conceptualisation of person centredness is likely to support quality outcomes in service delivery especially where organisations work across human service groups. Further research into the application and service expressions of being 'person-centred' in context is necessary. PMID- 28919057 TI - ADP-dependent phosphofructokinases from the archaeal order Methanosarcinales display redundant glucokinase activity. AB - The genome of Methanosarcinales organisms presents both ADP-dependent glucokinase and phosphofructokinase genes. However, Methanococcoides burtonii has a truncate glucokinase gene with a large deletion at the C-terminal, where the catalytic GXGD motif is located. Characterization of its phosphofructokinase annotated protein shows that is a bifunctional enzyme able to supply the absence of the glucokinase activity. Moreover, kinetic analyses of the phosphofructokinase annotated enzyme from, Methanohalobium evestigatum demonstrated that this enzyme is also bifunctional. The high conservation of the active site residues of all the enzymes from the order Methanosarcinales suggest that they should be bifunctional, as was previously reported for the ADP-dependent kinases from Methanococcales, highlighting the redundancy of the glucokinase activity in this archaeal group. The presence of active glycolytic enzymes would be important when glycogen storage of these organisms needs to be degraded to be used as energy source. Kinetic and structural information allows us to establish a substrate specificity signature that identifies specific GK or PFK, and bifunctional enzymes in this family. PMID- 28919058 TI - Fair hearing outcomes of patients recommended discharge from methadone maintenance. AB - A system known as fair hearings is a due process opportunity for patients who are involuntarily discharged from methadone maintenance treatment to challenge the discharge recommendation. We know very little about the processes and outcomes of fair hearings. For this study, we used a mixed methods approach to retrospectively analyze 73 fair hearing reports that were documented from a California methadone maintenance treatment program between 2000 and 2014. The aims of the study were to identify the reasons for involuntary discharge recommendation from methadone maintenance, describe the factors involved when fair hearing outcomes decided in favor of the clinic, and describe the factors involved when fair hearing outcomes decided in favor of the patient. We found that patient attendance at the fair hearing meeting was significantly related to the outcome ruling in favor of the patient. We organized the reasons for discharge recommendations into five categories: 1) suspected diversion, 2) behavioral/interpersonal, 3) repeated, unexcused absences, 4) co-occurring substance use, and 5) multiple sources of opioids. For each category, we use excerpts from fair hearing reports to provide context to the circumstances involved in an outcome favoring the patient or the clinic. PMID- 28919060 TI - SGLT2 inhibitors in type 1 diabetes: knocked down, but up again? PMID- 28919059 TI - Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study. AB - BACKGROUND: Post-mortem studies have not identified an association between beta amyloid or tau and rates of hippocampal atrophy in patients with Alzheimer's disease. TAR DNA binding protein 43 (TDP-43) is another protein linked to Alzheimer's disease. We aimed to investigate whether hippocampal TDP-43 is associated with increased rates of hippocampal atrophy. METHODS: In this longitudinal retrospective study, we analysed post-mortem brain tissue of all individuals with an Alzheimer's disease spectrum pathological diagnosis who had antemortem head MRI scans between Jan 1, 1999, and Dec 31, 2012, and who had been recruited into the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. We did TDP-43 immunohistochemistry and classified individuals as follows: no TDP-43 in the amygdala or hippocampus; TDP-43 restricted to the amygdala; and TDP-43 spreading into the hippocampus. Each individual was also assigned a neurofibrillary tangle stage (B1-B3), relating to the likelihood of having Alzheimer's disease. We used longitudinal FreeSurfer software and tensor-based morphometry with symmetric normalisation to calculate hippocampal volume on all serial MRI scans and used linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy and to assess the trajectory of TDP-43-associated atrophy. FINDINGS: We identified 298 individuals meeting the inclusion criteria, with 816 usable MRI scans (spanning 1.0-11.2 years of the disease) available for analysis. 141 individuals showed no TDP-43 in the amygdala or hippocampus, 33 had TDP-43 restricted to the amygdala, and 124 had TDP-43 in the hippocampus. Among individuals with a high likelihood of having Alzheimer's disease (neurofibrillary tangle stage B3; n=205), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=103, annual volume change -4.39%, 95% CI -4.82 to -3.95; p<0.0001) than did those with amygdala-only TDP-43 (n=20, -3.29%, -4.11 to -2.46; p<0.0001; difference -1.10%, 95% CI -2.02 to -0.19; p=0.02) and those without TDP-43 (n=82, -3.11%, -3.54 to -2.68; p<0.0001; difference -1.28%, -1.88 to -0.67; p<0.0001). Among individuals with an intermediate likelihood of having Alzheimer's disease (neurofibrillary tangle stage B2; n=56), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=17, annual volume change -4.05%, 95% CI -5.09 to -2.99; p<0.0001) than did those with amygdala-only TDP-43 (n=6, -1.78%, -3.04 to -0.55; p=0.004; difference -2.27%, 95% CI -3.79 to -0.67; p=0.006) and those without TDP-43 (n=33, -1.63%, -2.43 to -0.83; p=0.0002; difference -2.43%, -3.66 to -1.18; p=0.0002). Hippocampal TDP-43 was not associated with the rate of hippocampal atrophy in individuals with a low likelihood of having Alzheimer's disease (neurofibrillary tangle stage B1; n=37). The trajectory analysis suggested that increased rates of TDP-43-associated hippocampal atrophy might occur at least 10 years before death. Results were similar for FreeSurfer and tensor-based morphometry. INTERPRETATION: TDP-43 should be considered as a potential factor related to increased rates of hippocampal atrophy in patients with Alzheimer's disease. Given the importance of hippocampal atrophy in Alzheimer's disease, it is imperative that techniques are developed for detection of TDP-43 in vivo. FUNDING: US National Institute on Aging (National Institutes of Health). PMID- 28919062 TI - Progress and challenges in anti-obesity pharmacotherapy. AB - Obesity is a serious and growing worldwide health challenge. Healthy lifestyle choices are the foundation of obesity treatment. However, weight loss can lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. In other metabolic diseases, pharmacotherapy is an accepted adjunct to lifestyle. Several anti-obesity drugs have been approved in the USA, European Union, Australia, and Japan including sympathomimetics, pancreatic lipase inhibitors, GABAA receptor activators, a serotonin 2C receptor agonist, opioid antagonist, dopamine-norepinephrine reuptake inhibitor, and glucagon-like peptide 1 (GLP-1) receptor agonists. These drugs vary in their efficacy and side-effect profiles but all provide greater weight loss than do lifestyle changes alone. Even though obesity is widespread and associated with adverse health consequences, and anti-obesity drugs can help people to lose weight, very few patients use these drugs partly because of concerns about safety and efficacy, but also because of inadequate health insurance coverage. Despite great advances in our understanding of the biology of weight regulation, many clinicians still believe that patients with obesity should have the willpower to eat less. The tendency to hold the patient with obesity responsible for their condition can be a barrier to greater acceptance of anti-obesity drugs as appropriate options for treatment. Physicians should be comfortable discussing the risks and benefits of these drugs, and health insurance companies should provide reasonable coverage for their use in patients who are most likely to benefit. Although few promising anti-obesity medications are in the drug-development pipeline, the most promising drugs are novel molecules that are co-agonists for multiple gut hormones including GLP-1, glucagon, and gastric inhibitory peptide. PMID- 28919063 TI - Precision medicine: diagnosis and management of obesity. PMID- 28919064 TI - Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. AB - Genome-wide association studies (GWAS) for BMI, waist-to-hip ratio, and other adiposity traits have identified more than 300 single-nucleotide polymorphisms (SNPs). Although there is reason to hope that these discoveries will eventually lead to new preventive and therapeutic agents for obesity, this will take time because such developments require detailed mechanistic understanding of how an SNP influences phenotype (and this information is largely unavailable). Fortunately, absence of functional information has not prevented GWAS findings from providing insights into the biology of obesity. Genes near loci regulating total body mass are enriched for expression in the CNS, whereas genes for fat distribution are enriched in adipose tissue itself. Gene by environment and lifestyle interaction analyses have revealed that our increasingly obesogenic environment might be amplifying genetic risk for obesity, yet those at highest risk could mitigate this risk by increasing physical activity and possibly by avoiding specific dietary components. GWAS findings have also been used in mendelian randomisation analyses probing the causal association between obesity and its many putative complications. In supporting a causal association of obesity with diabetes, coronary heart disease, specific cancers, and other conditions, these analyses have clinical relevance in identifying which outcomes could be preventable through weight loss interventions. PMID- 28919065 TI - Metabolically healthy obesity: the low-hanging fruit in obesity treatment? AB - Obesity increases the risk of several other chronic diseases and, because of its epidemic proportions, has become a major public health problem worldwide. Alarmingly, a lower proportion of adults have tried to lose weight during the past decade than during the mid-1980s to 1990s. The first-line treatment option for obesity is lifestyle intervention. Although this approach can decrease fat mass in the short term, these beneficial effects typically do not persist. If a large amount of weight loss is not an easily achievable goal, other goals that might motivate people with obesity to adopt a healthy lifestyle should be considered. In this setting, the concept of metabolically healthy obesity is useful. Accumulating evidence suggests that, although the risk of all-cause mortality and cardiovascular events might be higher in people with metabolically healthy obesity compared with metabolically healthy people of a normal weight, the risk is substantially lower than in individuals with metabolically unhealthy obesity. Therefore, every person with obesity should be motivated to achieve a normal weight in the long term, but more moderate weight loss sufficient for the transition from metabolically unhealthy obesity to metabolically healthy obesity might also lower the risk of adverse outcomes. However, how much weight needs to be lost for this transition to occur is under debate. This transition might be supported by lifestyle factors-such as the Mediterranean diet-that affect cardiovascular risk, independent of body fat. In this Series paper, we summarise available information about the concept of metabolically healthy obesity, highlight gaps in research, and discuss how this concept can be implemented in clinical care. PMID- 28919061 TI - Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. AB - BACKGROUND: Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. METHODS: DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbA1c between >=7.7% and <=11.0% [>=61.0 mmol/mol and <=97.0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. FINDINGS: Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8.53% (70 mmol/mol; SD 0.67% [7.3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was 0.42% [95% CI -0.56 to -0.28; p<0.0001] and for dapagliflozin 10 mg vs placebo was -0.45% [-0.58 to -0.31; p<0.0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. INTERPRETATION: Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. FUNDING: AstraZeneca and Bristol-Myers Squibb. PMID- 28919066 TI - Clinical efficacy of CT-guided percutaneous huge ilio-psoas abscesses drainage combined with posterior approach surgery for the management of dorsal and lumbar spinal tuberculosis in adults. AB - PURPOSE: To evaluate the clinical efficacy of CT-guided percutaneous huge ilio psoas abscesses drainage combined with posterior approach surgery for the management of dorsal and lumbar spinal tuberculosis in 16 adult cases. METHODS: Between January 2006 and June 2013, a total of 16 dorsal and lumbar spinal tuberculosis patients with huge ilio-psoas abscesses underwent two-stage CT guided percutaneous abscesses drainage and posterior debridement, decompression, intervertebral fusion and instrumentation. Standard quadruple antituberculous chemotherapy was performed both before and after surgery. RESULT: The average follow-up period was 26.7 months (range: 18-38 months). There is no severe complication and relapse of spinal tuberculosis. The blood loss was 921.0+/ 141.3mL, operation time was 174.8+/-15.7minutes. Kyphotic angle improved from 36.6+/-10.0 degrees preoperatively to 8.1+/-1.8 degrees postoperatively with 2.2+/-1.5 degrees loss of correction at final follow-up. The solid bone fusion was achieved in all cases at average 6.6+/-2.2 months after surgery. Neurologic deficits were recovered in varying degrees except 4 cases remained the same. The postoperative quality of life significantly improved. The Oswestry Disability Index (ODI) decreased from 32.8+/-10.6 preoperatively to 14.4+/-7.9 at the final follow-up. CONCLUSION: CT-guided percutaneous drainage combined with posterior approach surgery was proved to be safe and effective for the management of dorsal and lumbar spinal tuberculosis with huge ilio-psoas abscesses in adults. LEVEL OF STUDY: Level IV, retrospective. PMID- 28919068 TI - Intubation and extubation of the ICU patient. PMID- 28919069 TI - Impact of Discontinuation of Antiplatelet Therapy Prior to Isolated Valve and Combined Coronary Artery Bypass Graft and Valve Procedures on Short and Intermediate Term Outcomes. AB - BACKGROUND: A change in cardiac surgery practice over the past decade has seen an increase in urgent or inpatient referrals for surgery, with antiplatelet therapy often continued up until surgery. This study aims to identify the optimal timing for administration of aspirin to minimise risk of perioperative morbidity and mortality. METHODS: From a prospectively compiled database collected by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, we identified 8294 patients undertaking combined CABG and valve or isolated valve procedures while discontinuing aspirin. Time points for cessation of antiplatelet therapy were categorised as follows: <2 days, 3-7 days or >7 days preoperatively. We evaluated the association of adverse in-hospital events and intermediate term survival in each time category. RESULTS: Discontinuing aspirin 3 to 7 days from surgery decreased rates of perioperative MI (HR=0.300, p=0.027), return to theatre (HR=0.560, p=0.002) reduced drain output (HR=0.757, p=0.000) and red blood cell and platelet transfusions (HR=0.719, p=0.000 and HR=0.604, p=0.000 respectively) compared to patients continuing aspirin until <2 days from the procedure. Stopping aspirin <2 days from the date of surgery increased risk of perioperative MI (HR=5.919, p=0.000), reoperation for bleeding (HR=2.076, p=0.001), returning to theatre (HR=1.781, p=0.000), ICC drain losses (HR=1.337, p=0.000) and transfusion demands for red blood cells (HR=1.381, p=0.000) and platelets (HR=1.450, p=0.000) when compared to those discontinuing aspirin >7 days from surgery. CONCLUSION: Late discontinuation of aspirin before combined coronary artery bypass graft and valve procedures results in greater rates of bleeding and transfusion requirements. Earlier discontinuation of aspirin results in no benefit in intermediate term survival. PMID- 28919067 TI - Impact of iron deficiency diagnosis using hepcidin mass spectrometry dosage methods on hospital stay and costs after a prolonged ICU stay: Study protocol for a multicentre, randomised, single-blinded medico-economic trial. AB - BACKGROUND: Iron deficiency (ID) is frequent but difficult to diagnose in critically ill patients. ID may be responsible for prolonged post-ICU hospital stays, since it results in fatigue, muscle weakness and anaemia. Hepcidin, the key iron metabolism hormone, may be a good marker of ID in these patients. The aim of this study is to determine whether using mass spectrometry hepcidin determination to diagnose (and treat) ID after prolonged ICU stays may reduce patients' subsequent hospital stays and costs in comparison with conventional (ferritin) methods. METHODS: This is a randomised, controlled, single-blinded, multicentre medico-economic study. Hepcidin quantification will be performed in anaemic (WHO criteria) critically ill adults about to be discharged, after a stay >=5days. In the intervention arm (hepcidin) results will be given to the ICU physicians, and not in the control arm. ID Treatment will be recommended in intervention arm: IV iron when hepcidin is <20MUg/L; IV iron+erythropoietin when hepcidin is between 20-41MUg/L; in the control arm: IV iron when ferritin <300MUg/L and Transferrin saturation <20%. The primary endpoint will be the number of days spent in hospital 90 days after ICU discharge and the direct hospital costs. Secondary endpoints will be anaemia and iron deficiency on D15, fatigue and the proportion of patients alive and at home on D30 and D90. DISCUSSION: The results of this study will show whether diagnosing iron deficiency using MS hepcidin determination methods is liable to reduce patients' post-ICU hospital stay and costs, as well as their anaemia and fatigue. PMID- 28919070 TI - Gender Debate on the Early Warning Signs of Acute Coronary Syndromes. PMID- 28919071 TI - Validation of the RETRIEVE (REverse TRIage EVEnts) Criteria for Same Day Return of Non-ST Elevation Acute Coronary Syndrome Patients to Referring Non-PCI Centres. AB - BACKGROUND: There are continuing bed constraints in percutaneous coronary intervention centres (PCI) so efficient patient triage from referral hospitals is pivotal. To evaluate a strategy of PCI centre (PCIC) bed-sparing we examined return of patients to referral hospitals screened by the RETRIEVE (REverse TRIage EVEnts) criteria and validated its use as a tool for screening suitability for same day transfer of non-ST-elevation acute coronary syndrome (NSTEACS) patients post PCI to their referring non-PCI centre (NPCIC). METHODS: From May 2008 to May 2011, 433 NSTEACS patients were prospectively screened for suitability for same day transfer back to the referring hospital at the completion of PCI. Of these patients, 212 were excluded from same day transfer using the RETRIEVE criteria and 221 patients met the RETRIEVE criteria and were transferred back to their NPCIC. RESULTS: Over the study period, 218 patients (98.6%) had no major adverse events. The primary endpoint (death, arrhythmia, myocardial infarction, major bleeding event, cerebrovascular accident, major vascular site complication, or requirement for return to the PCIC) was seen in only three transferred patients (1.4%). CONCLUSIONS: The RETRIEVE criteria can be used successfully to identify NSTEACS patients suitable for transfer back to NPCIC following PCI. Same day transfer to a NPCIC using the RETRIEVE criteria was associated with very low rates of major complications or repeat transfer and appears to be as safe as routine overnight observation in a PCIC. PMID- 28919073 TI - Multiple metastases to bone from squamous cell carcinoma of the oropharynx: unusual findings on positron emission tomography-computed tomography. PMID- 28919072 TI - Assessment of nicotine withdrawal-induced changes in sucrose preference in mice. AB - Anhedonia, induced by nicotine withdrawal, may serve as an important affective sign that reinforces tobacco use and smoking relapse rates in humans. Animal models provide a way to investigate the underlying neurobiological factors involved in the decrease in responding for positive affective stimuli during nicotine withdrawal and may aid in drug development for nicotine dependence. Thus, we explored the use of the sucrose preference test to measure nicotine withdrawal-induced reduction in response for positive affective stimuli in mice. C57BL/6J and knockout (KO) mice were chronically exposed to different doses of nicotine through surgically implanted subcutaneous osmotic minipumps for 14days and underwent spontaneous nicotine withdrawal on day 15. A sucrose preference time course was performed and the results were compared to another well established affective sign of nicotine withdrawal, the reduction in time spent in light side, using the Light Dark Box test. Subsequently, our results demonstrated a time-dependent and dose-related reduction in sucrose preference in nicotine withdrawn male C57BL/6J mice, indicative of a decrease in responding for positive affective stimuli. Furthermore, the sucrose preference reduction during nicotine withdrawal was consistent with decrease in time spent in the light side of the Light Dark Box test. We also found the reduction for positive affective stimuli and time spent in the light side was not present in nicotine withdrawn beta2 and alpha6 KO mice, suggesting that these nicotinic subunits are involved in the affective signs of nicotine withdrawal. Thus, this report highlights the potential utility of the sucrose preference test as a useful measure of the decrease in responding for positive affective stimuli during spontaneous nicotine withdrawal. PMID- 28919074 TI - Preoperative screening for sickle cell disease and guidance from the National Institute for Health and Care Excellence (NICE). PMID- 28919075 TI - Dermoid cyst of the submandibular gland: case report. PMID- 28919077 TI - Engineering Quantitative Trait Variation for Crop Improvement by Genome Editing. AB - Major advances in crop yields are needed in the coming decades. However, plant breeding is currently limited by incremental improvements in quantitative traits that often rely on laborious selection of rare naturally occurring mutations in gene-regulatory regions. Here, we demonstrate that CRISPR/Cas9 genome editing of promoters generates diverse cis-regulatory alleles that provide beneficial quantitative variation for breeding. We devised a simple genetic scheme, which exploits trans-generational heritability of Cas9 activity in heterozygous loss-of function mutant backgrounds, to rapidly evaluate the phenotypic impact of numerous promoter variants for genes regulating three major productivity traits in tomato: fruit size, inflorescence branching, and plant architecture. Our approach allows immediate selection and fixation of novel alleles in transgene free plants and fine manipulation of yield components. Beyond a platform to enhance variation for diverse agricultural traits, our findings provide a foundation for dissecting complex relationships between gene-regulatory changes and control of quantitative traits. PMID- 28919076 TI - Mitochondrial Priming by CD28. AB - T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses. PMID- 28919078 TI - Slp1-Emp65: A Guardian Factor that Protects Folding Polypeptides from Promiscuous Degradation. AB - Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen. The complex binds unfolded proteins and protects them from degradation during folding. In its absence, approximately 20%-30% of newly synthesized proteins that could otherwise fold are degraded. Although the Slp1-Emp65 complex hosts a broad range of clients, it is specific for soluble proteins. Taken together, these studies demonstrate the vulnerability of newly translated, actively folding polypeptides and the discovery of a new proteostasis functional class we term "guardian" that protects them from degradation. PMID- 28919079 TI - Structure of an Intron Lariat Spliceosome from Saccharomyces cerevisiae. AB - The disassembly of the intron lariat spliceosome (ILS) marks the end of a splicing cycle. Here we report a cryoelectron microscopy structure of the ILS complex from Saccharomyces cerevisiae at an average resolution of 3.5 A. The intron lariat remains bound in the spliceosome whereas the ligated exon is already dissociated. The step II splicing factors Prp17 and Prp18, along with Cwc21 and Cwc22 that stabilize the 5' exon binding to loop I of U5 small nuclear RNA (snRNA), have been released from the active site assembly. The DEAH family ATPase/helicase Prp43 binds Syf1 at the periphery of the spliceosome, with its RNA-binding site close to the 3' end of U6 snRNA. The C-terminal domain of Ntr1/Spp382 associates with the GTPase Snu114, and Ntr2 is anchored to Prp8 while interacting with the superhelical domain of Ntr1. These structural features suggest a plausible mechanism for the disassembly of the ILS complex. PMID- 28919080 TI - Regulation of glutamate transporter 1 (GLT-1) gene expression by cocaine self administration and withdrawal. AB - Downregulation of the astroglial glutamate transporter GLT-1 is observed in the nucleus accumbens (NAc) following administration of multiple drugs of abuse. The decrease in GLT-1 protein expression following cocaine self-administration is dependent on both the amount of cocaine self-administered and the length of withdrawal, with longer access to cocaine and longer withdrawal periods leading to greater decreases in GLT-1 protein. However, the mechanism(s) by which cocaine downregulates GLT-1 protein remains unknown. We used qRT-PCR to examine gene expression of GLT-1 splice isoforms (GLT-1A, GLT-1B) in the NAc, prelimbic cortex (PL) and basolateral amygdala (BLA) of rats, following two widely used models of cocaine self-administration: short-access (ShA) self-administration, and the long access (LgA) self-administration/incubation model. While downregulation of GLT-1 protein is observed following ShA cocaine self-administration and extinction, this model did not lead to a change in GLT-1A or GLT-1B gene expression in any brain region examined. Forced abstinence following ShA cocaine self administration also was without effect. In contrast, LgA cocaine self administration and prolonged abstinence significantly decreased GLT-1A gene expression in the NAc and BLA, and significantly decreased GLT-1B gene expression in the PL. No change was observed in NAc GLT-1A gene expression one day after LgA cocaine self-administration, indicating withdrawal-induced decreases in GLT-1A mRNA. In addition, LgA cocaine self-administration and withdrawal induced hypermethylation of the GLT-1 gene in the NAc. These results indicate that a decrease in NAc GLT-1 mRNA is only observed after extended access to cocaine combined with protracted abstinence, and that epigenetic mechanisms likely contribute to this effect. PMID- 28919081 TI - Body Weight and Body Mass Index in Patients with End-Stage Cystic Fibrosis Stabilize After the Start of Enteral Tube Feeding. AB - BACKGROUND: Enteral tube feeding (ETF) is widely used in patients with cystic fibrosis (CF) and end-stage lung disease, but previous studies have been limited to investigating whether ETF improves outcomes in patients with moderately or mildly impaired pulmonary function. OBJECTIVE: This study investigated body weight, body mass index (BMI; calculated as kg/m2), pulmonary function, and the presence of CF-related diabetes before and after the start of ETF. DESIGN: This was a retrospective observational study. PARTICIPANTS/SETTING: Data from 26 adult patients in an outpatient setting who had end-stage CF (19 women) and had been using ETF for at least 6 months between 2000 and 2014 were analyzed. MAIN OUTCOME MEASURES: Body weight, BMI, pulmonary function (forced expiratory volume in 1 second as percent of predicted) and incidence of CF-related diabetes from 6 months before to 6 months after starting ETF. STATISTICAL ANALYSES PERFORMED: Time effects were tested with one-way analysis of variance for data that were normally distributed and the Friedman test for non-parametric data. Correlations were tested with Pearson's r or Spearman's rho, depending on the distribution of the data. RESULTS: Mean body weight increased by 3.5 kg (95% CI 2.2 to 4.8 kg) after patients started ETF. In women, mean BMI decreased by 0.7 in the 6 months before the start of ETF (P<0.05) and increased by 1.4 in the 6 months thereafter (P<0.05). In men, BMI changes were similar (-0.8 and +1.1), but not statistically significant. Forced expiratory volume in 1 second as percent of predicted significantly decreased in time from a median of 28% to 26% at the start of ETF to 25% after 6 months (P=0.0013), with similar trends in women and men. There was no correlation between changes in weight and lung function. CF-related diabetes was already present in 12 patients and developed in 1 more patient after the start of ETF. CONCLUSIONS: ETF improved body weight and BMI but not pulmonary function in 26 patients with end-stage CF. Clinical outcomes were similar in women and men, but the sample size of men was too small to determine statistical significance. PMID- 28919083 TI - Immune response boosted in metastatic colorectal cancer. PMID- 28919084 TI - ESMO 2017 Congress. PMID- 28919085 TI - Blood transfusion strategies in elderly patients. PMID- 28919082 TI - Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined. PMID- 28919086 TI - Authors' reply to comment Blood transfusion strategies in elderly patients. PMID- 28919087 TI - Outcomes of restrictive versus liberal transfusion strategies in older adults from nine randomised controlled trials: a systematic review and meta-analysis. AB - BACKGROUND: Guidelines for patient blood management recommend restrictive transfusion practice for most adult patients. These guidelines are supported by evidence from randomised controlled trials (RCTs); however, one of the patient groups not explicitly examined in these studies is the geriatric population. We examined RCTs relevant to transfusion outcomes in older patients. Our aim was to determine whether special guidelines are warranted for geriatric patients, recognising the different pathophysiological characteristics of this group. METHODS: For this systematic review and meta-analysis, we searched PubMed, Scopus, and the Cochrane Library databases from their inception to May 5, 2017, for evidence relating to transfusion outcomes in adults aged 65 years and older. This criterion was widened to include RCTs where a substantial proportion of the study population was older than 65 years. We also included study populations of all clinical settings, and did not limit the search by date, language, or study type. For articles not in English, only available translations of the abstracts were reviewed. Studies were excluded if they did not specify age. Observational studies and duplicate patient and outcome data from studies that generated multiple publications were also excluded. We screened bibliographies of retrieved articles for additional publications. We analysed data extracted from published RCTs comparing restrictive and liberal transfusion strategies in older adults. We generated fixed effects risk ratios (RR) for pooled study data using the Mantel Haenszel method. Primary outcomes were 30-day and 90-day mortality events for patients enrolled in restrictive and liberal transfusion study groups. We included intention-to-treat outcome data in the meta-analysis when available, otherwise we used per-protocol outcome data. FINDINGS: 686 articles were identified by the search, and a further 37 by the snowball approach. Of these articles, 13 eligible papers described findings from nine RCTs (five trials investigating orthopaedic surgery, three cardiac surgery, and one oncology surgery; including 5780 patients). The risk of 30-day mortality was higher in older patients who followed a restrictive transfusion strategy than in those who followed a liberal transfusion strategy (risk ratio [RR] 1.36, 95% CI 1.05-1.74; p=0.017). The risk of 90-day mortality was also higher in those who followed a restrictive transfusion strategy than in those who followed a liberal transfusion strategy (RR 1.45, 95% CI 1.05-1.98; p=0.022). INTERPRETATION: Liberal transfusion strategies might produce better outcomes in geriatric patients than restrictive transfusion strategies. This outcome contradicts current restrictive transfusion approaches. Population ageing will challenge resources globally, and this finding has implications for blood supply and demand, and optimal care of older adults. Further research is needed to formulate evidence-based transfusion practice across clinical specialties specific to the geriatric population, and to examine resource effects. FUNDING: Australia's National Blood Authority. PMID- 28919089 TI - Response to the letter: Inspiring surgeons of the future: A school outreach event and possible solution to the imminent recruitment crisis. PMID- 28919088 TI - Resilience in mathematics after early brain injury: The roles of parental input and early plasticity. AB - Children with early focal unilateral brain injury show remarkable plasticity in language development. However, little is known about how early brain injury influences mathematical learning. Here, we examine early number understanding, comparing cardinal number knowledge of typically developing children (TD) and children with pre- and perinatal lesions (BI) between 42 and 50 months of age. We also examine how this knowledge relates to the number words children hear from their primary caregivers early in life. We find that children with BI, are, on average, slightly behind TD children in both cardinal number knowledge and later mathematical performance, and show slightly slower learning rates than TD children in cardinal number knowledge during the preschool years. We also find that parents' "number talk" to their toddlers predicts later mathematical ability for both TD children and children with BI. These findings suggest a relatively optimistic story in which neural plasticity is at play in children's mathematical development following early brain injury. Further, the effects of early number input suggest that intervening to enrich the number talk that children with BI hear during the preschool years could narrow the math achievement gap. PMID- 28919090 TI - 3D-printing for engineering the next generation of artificial trabecular bone structures. PMID- 28919091 TI - Intravenous acetaminophen as an adjunct to multimodal analgesia after total knee and hip arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis aimed to perform a meta-analysis to investigate the impact of additional intravenous acetaminophen for pain management after total joint arthroplasty (TJA). METHODS: We conducted electronic searches of Medline (1966-2017.07), PubMed (1966-2017.07), Embase (1980-2017.07), ScienceDirect (1985-2017.07) and the Cochrane Library. Randomized controlled trials (RCTs) and non-RCTs were included. The quality assessments were performed according to the Cochrane systematic review method. The primary outcomes were postoperative pain scores and opioid consumption. Meta-analysis was performed using Stata 11.0 software. RESULTS: A total of four studies were retrieved involving 865 participants. The present meta-analysis indicated that there were significant differences between groups in terms of pain scores at POD 1 (WMD = 0.954, 95% CI: -1.204 to -0.703, P = 0.000), POD 2 (WMD = -1.072, 95% CI: -2.072 to -0.073, P = 0.000), and POD 3 (WMD = -0.883, 95% CI: -1.142 to -0.624, P = 0.000). Significant differences were found regarding opioid consumption at POD 1 (WMD = -3.144, 95% CI: -4.142 to -2.146, P = 0.000), POD 2 (WMD = -5.665, 95% CI: -7.383 to -3.947, P = 0.000), and POD 3 (WMD = -3.563, 95% CI: -6.136 to -0.991, P = 0.007). CONCLUSION: Additional intravenous acetaminophen to multimodal analgesia could significantly reduce pain and opioid consumption after total joint arthroplasty with fewer adverse effects. Higher quality RCTs are required for further research. PMID- 28919092 TI - Cervical soft tissue recurrence of differentiated thyroid carcinoma after thyroidectomy indicates a poor prognosis. AB - BACKGROUND: We investigated cervical soft tissue recurrence of differentiated thyroid carcinoma (DTC) after thyroidectomy, and these lesions exhibited no evidence that they were lymph nodes (LNs). METHODS: Between January 2012 and April 2016, consecutive 6308 patients underwent thyroid surgery for DTC at our center. Among them, we encountered 21 patients with recurrent cervical soft tissue lesions, none of whom had previously undergone fine needle aspiration biopsy (FNAB). RESULTS: The 21 patients accounted for 0.33% of all 6308 patients, including twenty cases of papillary thyroid carcinoma and one case of follicular thyroid cancer. Approximately half (52.3%) of the recurrence were first detected by ultrasound (US). Eighteen lesions underwent complete preoperative US, but 6 lesions were misdiagnosed as metastatic LNs by US. Therefore, 54 age- and gender matched recurrent or persistent LNs derived from DTC were randomly selected from the same database. The soft tissue lesions (mean size, 2.30 cm) were larger than the LNs. Fewer hyperechogenic hila and punctuations were found in the group of soft tissue recurrence (P < 0.05). During follow-up, distant metastasis was detected in 38.1% of patients in the soft tissue recurrence group. The distant metastasis rates showed that local soft tissue recurrence led to a poorer prognosis than cervical LN persistence or recurrence (P = 0.00). CONCLUSIONS: Although the incidence of DTC recurrence in cervical soft tissue was low, it may be a predictor for distant recurrence. To minimize the risk, a long-term postoperative evaluation, preferably with US, should be performed. PMID- 28919093 TI - Clip closure and division instead of stapling for the last small gastric bridge between gastric pouch and remnant stomach in laparoscopic Roux-en-Y gastric bypass. AB - INTRODUCTION: Here, a modification during gastric pouch forming was implemented in laparoscopic Roux-en-Y gastric bypass (LRYGB). We aimed to examine the feasibility of metallic clip closure for the remaining small stomach bridges (<1 cm) between the pouch and the remnant stomach. METHODS: During pouch creation, after the last stapler firing, the remaining small bridge was closed with clips and divided instead of using a new stapler. Metallic clips for this aim were used in 41 of 520 LRYGP between September 2010 and January 2017. Preoperative mean body mass index (BMI) was 47.3 +/- 5.3 kg/m2 (male/female: 6/35, mean age 37.8 +/ 9.1 years). RESULTS: Gastric bridges in 41 patients were successfully closed with metallic clips and divided. In one patient, intraoperative methylene blue test was positive from the anastomosis (not from the clipped place) and repaired by intracorporeal sutures. Abdominal drain was used selectively (32%). No postoperative leakage or other complications were seen. Mean length of hospital stay was 3.8 +/- 1.1 days. Mean BMI was 30.3 +/- 6.1 kg/m2 after mean 17.6 +/- 11.3 months follow-up. CONCLUSION: In LRYGB metallic clip closure for a stomach bridge (<1 cm) between the pouch and the remnant stomach is an easy, safe and reliable method. PMID- 28919094 TI - Minimal-invasive oncosurgery in endometrial cancer: Minimal-access techniques with individualized maximal-invasiveness in lymph node extirpation. PMID- 28919096 TI - Comparison of oral and intravenous tranexamic acid in total knee and hip arthroplasty: A systematic review and meta-analysis. PMID- 28919095 TI - Laparoscopic near-infrared fluorescent imaging as an alternative option for sentinel lymph node mapping in endometrial cancer: A prospective study. AB - BACKGROUND: To evaluate feasibility of sentinel lymph node (SLN) mapping by using near-infrared fluorescent imaging and indocyanine green (NIR/ICG) integrated laparoscopic system in clinically uterine-confined endometrial cancer. MATERIALS AND METHODS: Patients with clinically early-stage endometrial cancer were included in this prospective study. ICG was injected to the uterine cervix and NIR/ICG integrated laparoscopic system (Spies Full HD D-Light P ICG technology, Karl Storz, Tuttlingen, Germany) was used during the operations. SLN and/or suspicious lymph nodes were resected. Side specific lymphadenectomy was performed when mapping was unsuccessful. Systematic lymphadenectomy was completed following SLN algorithm steps. RESULTS: Seventy-one eligible patients were analyzed. The overall, unilateral and bilateral SLN detection rates were 95.7%, 18.3%, 77.4%, respectively. There were 8 (11.2%) patients with lymph node metastasis. One of them was isolated para-aortic node metastasis. Negative predictive value, sensitivity and false negative rate for detecting lymphatic spread were 98.4%, 87.5% and 1.5%, respectively. CONCLUSION: Sentinel lymph node mapping can easily be performed with high accuracy by using NIR/ICG integrated conventional laparoscopic system in endometrial cancer and almost all lymphatic spread can be detected. PMID- 28919097 TI - J-pouch vs. side-to-end anastomosis after hand-assisted laparoscopic low anterior resection for rectal cancer: A prospective randomized trial on short and long term outcomes including life quality and functional results. AB - PURPOSE: To analyze the outcomes of j-pouch and side-to-end anastomosis in rectal cancer patients treated with laparoscopic hand-assisted low anterior resection. METHODS: Prospective trial on cases randomized to have a colonic j-pouch or a side-to-end anastomosis after low anterior resection. Demographics, characteristics of disease and treatment, perioperative results, and functional outcomes and life quality were compared between the groups. RESULTS: Seventy four patients were randomized. Reservoir creation was withdrawn in 17 (23%) patients, mostly related to reach problem (n = 11, 64.7%). Anastomotic leakage rate was significantly higher in j-pouch group (8 [27.6%] vs. 0, p = 0.004). Stoma closure could not be achieved in 16 (28.1%) patients. Life quality and functional outcomes, measured 4, 8 and 12 months after the stoma reversal, were similar. CONCLUSIONS: Colonic j-pouch and side-to-end anastomosis are similar regarding perioperative measures including operation time, rates of postoperative complications, reoperation and 30-day mortality, and hospitalization period except anastomotic leak rate, which is higher in j-pouch group. Postoperative aspects are not different in patients receiving either technique including functional outcomes and life quality for the first year after stoma closure. In our opinion, both techniques may be preferred during the daily practice while performing laparoscopic surgery; but surgeons may be aware of a possibly higher anastomotic leak rate in case of a j-pouch. PMID- 28919098 TI - Temporal regulation of sigmaB by partner-switching mechanism at a distinct growth stage in Bacillus cereus. AB - The alternative transcription factor sigmaB in Bacillus cereus governs the transcription of a number of genes that confer protection against general stress. This transcription factor is regulated by protein-protein interactions among RsbV, RsbW, sigmaB, RsbY, RsbM and RsbK, all encoded in the sigB cluster. Among these regulatory proteins, RsbV, RsbW and sigmaB comprise a partner-switching mechanism. Under normal conditions, sigmaB remains inactive by associating with anti-sigma factor RsbW, which prevents sigmaB from binding to the core RNA polymerase. During environmental stress, RsbK activates RsbY to hydrolyze phosphorylated RsbV, and the dephosphorylated RsbV then sequesters RsbW to liberate sigmaB from RsbW. Although the sigmaB partner-switching module is thought to be the core mechanism for sigmaB regulation, the actual protein protein interactions among these three proteins in the cell remain to be investigated. In the current study, we show that RsbW and RsbV form a long-lived complex under transient stress treatment, resulting in high persistent expression of RsbV, RsbW and sigmaB from mid-log phase to stationary phase. Full sequestration of RsbW by excess RsbV and increased RsbW:RsbV complex stability afforded by cellular ADP contribute to the prolonged activation of sigmaB. Interestingly, the high expression levels of RsbV, RsbW and sigmaB were dramatically decreased beginning from the transition stage to the stationary phase. Thus, protein interactions among sigmaB partner-switching components are required for the continued induction of sigmaB during environmental stress in the log phase and significant down-regulation of sigmaB is observed in the stationary phase. Our data show that sigmaB is temporally regulated in B. cereus. PMID- 28919100 TI - Where do we come from and where are we going in the treatment of premature ejaculation? PMID- 28919099 TI - Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements. AB - Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability. Abiraterone acetate is poorly water soluble which is believed to be responsible for its very low bioavailability in the fasted state and its significant positive food effect. In this work, we have successfully used in vitro dissolution, solubility and permeability measurements in biorelevant media to describe the dissolution characteristics of different abiraterone acetate formulations. Mathematical modeling of fraction dose absorbed indicated that reducing the particle size of the drug cannot be expected to result in significant improvement in bioavailability in the fasted state. In the fed state, the same formulation approach can result in a nearly complete absorption of the dose; thereby, further increasing the food effect. Using a "bottom-up" formulation method we improved both the dissolution rate and the apparent solubility of the compound. In beagle dog studies, this resulted in a ?>10-fold increase in bioavailability in the fasted state when compared to the marketed drug and the elimination of the food effect. Calculated values of fraction dose absorbed were in agreement with the observed relative bioavailability values in beagle dogs. PMID- 28919101 TI - 3+4 = 6? Implications of the stratification of localised Gleason 7 prostate cancer by number and percentage of positive biopsy cores in selecting patients for active surveillance. AB - OBJECTIVE: To determine whether the number and percentage of positive biopsy cores identify a Gleason 3+4 prostate cancer (PC) subgroup of similar biologic behaviour to Gleason 3+3. MATERIAL AND METHOD: An observational post-radical prostatectomy study was conducted of a cohort of 799 patients with localised low risk (n=582, Gleason 6, PSA <10ng/ml and cT1c-2a) and favourable intermediate PC (n=217, Gleason 3+4, PSA <=10 ng/ml and pT2abc). The Gleason 3+4 tumours were stratified by number (<=3 vs.>3) and by percentage of positive cores (<=33% vs. >33%). We analysed the tumours' association with the biochemical recurrence risk (BRR) and cancer-specific mortality (CSM). We conducted various predictive models using Cox regression and estimated (C-index) and compared their predictive capacity. RESULTS: With a median follow-up of 71 months, the BRR and CSM of the patient group with Gleason 3+4 tumours and a low number (<=3) and percentage (<=33%) of positive cores were not significantly different from those of the patients with Gleason 6 tumours. At 5 and 10 years, there were no significant differences in the number of biochemical recurrences, the probability of remaining free of biochemical recurrences, the number of deaths by PC or the probability of death by PC between the 2 groups. In contrast, the patients with Gleason 3+4 tumours and more than 33% of positive cores presented more deaths by PC than the patients with Gleason 6 tumours. At 10 years, the probability of CSM was significantly greater. This subgroup of tumours showed a significantly greater BRR (RR, 1.6; P=.02) and CSM (RR, 5.8, P<=.01) compared with the Gleason 6 tumours. The model with Gleason 3+4 stratified by the percentage of positive cores significantly improved the predictive capacity of BRR and CSM. CONCLUSIONS: Fewer than 3 cores and a percentage <33% of positive cores identifies a subgroup of Gleason 3+4 tumours with biological behaviour similar to Gleason 6 tumours. At 10 years, there were no differences in BRR and CSM between the 2 groups. These results provide evidence supporting active surveillance as an alternative for Gleason 3+4 tumours and low tumour extension in biopsy. PMID- 28919102 TI - Don't kill passive oxygenation with continuous oxygen insufflation too fast in cardiac arrest ventilation. PMID- 28919103 TI - Alterations of musculoskeletal models for a more accurate estimation of lower limb joint contact forces during normal gait: A systematic review. AB - Musculoskeletal modelling is a methodology used to investigate joint contact forces during a movement. High accuracy in the estimation of the hip or knee joint contact forces can be obtained with subject-specific models. However, construction of subject-specific models remains time consuming and expensive. The purpose of this systematic review of the literature was to identify what alterations can be made on generic (i.e. literature-based, without any subject specific measurement other than body size and weight) musculoskeletal models to obtain a better estimation of the joint contact forces. The impact of these alterations on the accuracy of the estimated joint contact forces were appraised. The systematic search yielded to 141 articles and 24 papers were included in the review. Different strategies of alterations were found: skeletal and joint model (e.g. number of degrees of freedom, knee alignment), muscle model (e.g. Hill-type muscle parameters, level of muscular redundancy), and optimisation problem (e.g. objective function, design variables, constraints). All these alterations had an impact on joint contact force accuracy, so demonstrating the potential for improving the model predictions without necessarily involving costly and time consuming medical images. However, due to discrepancies in the reported evidence about this impact and despite a high quality of the reviewed studies, it was not possible to highlight any trend defining which alteration had the largest impact. PMID- 28919104 TI - Elevated urinary monocyte chemoattractant protein-1 levels in children with Henoch-Schonlein purpura nephritis. AB - BACKGROUND: Chemokine monocyte chemoattractant protein-1 (MCP-1) has been proved as a potential urinary biomarker in nephropathies. The aim of this study was to investigate the urinary monocyte chemoattractant protein-1 (MCP-1) levels and clinical significance in Henoch-Schonlein purpura (HSP) children with and without nephritis and determine the association of MCP-1 with proteinuria. METHODS: A total of 261 HSP children-with or without nephritis-and 84 healthy control children were enrolled in this study. Of these, 126 HSP nephritis (HSPN) children were subdivided into three groups according to total urine protein in 24 h (TUP): Group A, mild proteinuria group with TUP <25 mg/kg; Group B, moderate proteinuria group with TUP >=25 mg/kg and <50 mg/kg; Group C, severe proteinuria group with TUP >=50 mg/kg. Urinary MCP-1 levels were determined by ELISA. Levels of serum creatinine (Cr), blood urea nitrogen (BUN), urinary alpha1-micro globulin (alpha1 MG), micro-albumin (mAlb), immunoglobulin G (IgG), transferrin (TRF) and TUP were performed to determine their associations with MCP-1. RESULTS: Urinary MCP-1 was significantly higher in HSPN group in comparison with HSP group and controls (P < 0.05), but no significant difference was found between the HSP group and the healthy group (P > 0.05). The levels of urinary MCP-1 increased in parallel to the enhancement of total urine protein in 24 h in HSPN patients. There were statistically significant differences among these three groups of HSPN children (p < 0.05). Urinary MCP-1 correlated positively with urinary alpha1-MG, mAlb, IgG, TRF and TUP in HSPN, whereas no correlation was observed with serum Cr and BUN. CONCLUSIONS: MCP-1 was elevated in children with HSPN and correlated with proteinuria. Urinary MCP-1 could be used as a suitable, non-invasive biomarker to provide valuable information not only for the diagnosis of HSPN, but also for evaluation of severity of renal damage. PMID- 28919105 TI - Airflow Error Measurement Due to Pneumotachograph Mask Rim Leaks. AB - Airflow during speech production is recorded using a pneumotachograph system wherein typically a mask is placed upon the face. Accurate measures of airflow require mask calibration and a complete seal of the mask rim to the face. Literature frequently cites mask rim leaks as causing flow measurement inaccuracies, but quantitative studies of the inaccuracies are needed. The purpose of this study was to determine the degree of inaccuracy of flow measurement using a Glottal Enterprises aerodynamic system for a variety of mask rim leak conditions. Air was pushed and pulled through the Glottal Enterprises mask system over a wide range of airflow with leaks simulated by small metal tubes of various cross-sectional areas placed between the mask rim and a face like calibration mold. Two leak locations, single versus multiple leaks, and two different leak tube geometries were used. Results suggest that (1) as leak area increases, the amount of leak flow increases; (2) the amount of flow leak is relatively independent of location; (3) given equivalent leak areas, multiple leak locations provide less leak flow; and (4) quasi-elliptical tubes were more resistive to airflow than rectangular tubes. A general empirical equation was obtained that relates the leak flow between the mask rim and the face, the size of the leak region, and the amount of the upstream airflow toward the mask: Leak(cm3/s) = 0.33 * Area(cm2) * Flow(cm3/s) for the range of +/-2000 cm3/s. This equation may provide researchers and clinicians with a tool for generalizing airflow leak effects. PMID- 28919106 TI - Selecting relevant features from the electronic health record for clinical code prediction. AB - A multitude of information sources is present in the electronic health record (EHR), each of which can contain clues to automatically assign diagnosis and procedure codes. These sources however show information overlap and quality differences, which complicates the retrieval of these clues. Through feature selection, a denser representation with a consistent quality and less information overlap can be obtained. We introduce and compare coverage-based feature selection methods, based on confidence and information gain. These approaches were evaluated over a range of medical specialties, with seven different medical specialties for ICD-9-CM code prediction (six at the Antwerp University Hospital and one in the MIMIC-III dataset) and two different medical specialties for ICD 10-CM code prediction. Using confidence coverage to integrate all sources in an EHR shows a consistent improvement in F-measure (49.83% for diagnosis codes on average), both compared with the baseline (44.25% for diagnosis codes on average) and with using the best standalone source (44.41% for diagnosis codes on average). Confidence coverage creates a concise patient stay representation independent of a rigid framework such as UMLS, and contains easily interpretable features. Confidence coverage has several advantages to a baseline setup. In our baseline setup, feature selection was limited to a filter removing features with less than five total occurrences in the trainingset. Prediction results improved consistently when using multiple heterogeneous sources to predict clinical codes, while reducing the number of features and the processing time. PMID- 28919107 TI - Combination of Abeta Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition. AB - Anti-Abeta clinical trials are currently under way to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and preclinical studies suggest that antiamyloid strategies are only effective if started at early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Abeta suppression could enhance plaque clearance and could improve pathologic outcomes in mice with moderate amyloid pathologic disorder. Starting at 5 months of age, tet-off amyloid precursor protein transgenic mice were treated with doxycycline (dox) to suppress further amyloid precursor protein/Abeta production, and at the same time mice were intracranially injected with adeno-associated virus 1 expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Abeta suppression and AAV1-mIL 6 showed significantly less plaque pathologic disorder than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% versus untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Abeta suppression. PMID- 28919108 TI - The Renin-Angiotensin System Regulates Neurodegeneration in a Mouse Model of Optic Neuritis. AB - The major role of the renin-angiotensin system (RAS), including that of angiotensin II (Ang II), the principal effector molecule, in the cardiovascular system is well known. Increasing evidence suggests that the RAS also plays a role in the development of autoimmune diseases. Optic neuritis (ie, inflammation of the optic nerve, with retinal ganglion cell loss) is strongly associated with multiple sclerosis. We investigated the effects of candesartan, an Ang II receptor antagonist, on optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The Ang II concentration was increased in the early phase of EAE. Oral administration of candesartan markedly attenuated demyelination of the optic nerve and spinal cord and reduced retinal ganglion cell loss and visual impairment in mice with EAE. In vitro analyses revealed that Ang II up-regulated the expression of Toll-like receptor (TLR)-4 in astrocytes via the NF-kappaB pathway. In addition, Ang II treatment enhanced lipopolysaccharide-induced production of monocyte chemoattractant protein 1 in astrocytes, and pretreatment with candesartan or SN50, an NF-kappaB inhibitor, suppressed the effects of Ang II. The novel pathway of RAS-NF-kappaB-TLR4 in glial cells identified in the present study may be a valid therapeutic target for neurodegeneration in neuroinflammatory diseases. PMID- 28919109 TI - Long-Term Measurements of Human Inflammatory Cytokines Reveal Complex Baseline Variations between Individuals. AB - Comprehensive characterization of the healthy human proteome baseline is essential for personalized medicine. Baseline data are necessary to understand the variation between individuals, as well as longitudinal variation within individuals. Many important protein biomarkers, such as cytokines, exist at extremely low or undetectable levels in the healthy state. This paper describes results from a 14-week study of healthy human subjects using ultrasensitive single-molecule array (Simoa) assays to measure both intra and intersubject variation of 15 cytokines. The results show a wide variation in the ranges of some cytokines between individuals and demonstrate that individual baseline values will be essential for predicting disease presence and progression. Although all of the studied cytokines demonstrated high temporal stability (or low intrasubject variation) over the entire study period, there were two distinct groups of cytokines that demonstrated either high (IL-8, IFN-gamma, IL-2, IL-6, and IL-1beta) or low (IL-15, TNF-alpha, IL-12 p70, IL-17A, GM-CSF, IL-12 p40, IL 10, IL-7, IL-1alpha, and IL-5) subject-to-subject variation. This work demonstrates that ultrasensitive assays are essential for characterizing human cytokines in healthy subjects. The results show that some cytokines vary by more than two orders of magnitude between individuals, making it an imperative to obtain individual baseline measurements if they are to play a role in health and disease diagnosis. PMID- 28919110 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 28919111 TI - Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle. AB - Fatty degeneration of skeletal muscle leads to muscle weakness and loss of function. Preventing fatty degeneration in skeletal muscle is important, but no drug has been used clinically. In this study, we performed drug repositioning using human platelet-derived growth factor receptor alpha (PDGFRalpha)-positive mesenchymal progenitors that have been proved to be an origin of ectopic adipocytes in skeletal muscle. We found that promethazine hydrochloride (PH) inhibits adipogenesis in a dose-dependent manner without cell toxicity. PH inhibited expression of adipogenic markers and also suppressed phosphorylation of cAMP response-element binding protein, which was reported to be a primary regulator of adipogenesis. We established a mouse model of tendon rupture with intramuscular fat deposition and confirmed that emerged ectopic adipocytes are derived from PDGFRalpha+ cells using lineage tracing mice. When these injured mice were treated with PH, formation of ectopic adipocytes was suppressed significantly. Our results show that PH inhibits PDGFRalpha+ mesenchymal progenitor-dependent ectopic adipogenesis in skeletal muscle and suggest that treatment with PH can be a promising approach to prevent fatty degeneration of skeletal muscle. PMID- 28919112 TI - Disuse Atrophy Accompanied by Intramuscular Ectopic Adipogenesis in Vastus Medialis Muscle of Advanced Osteoarthritis Patients. AB - Muscle dysfunction is the most important modifiable mediating factor in primary osteoarthritis (OA) because properly contracting muscles are a key absorber of forces acting on a joint. However, the pathological features of disuse muscle atrophy in OA patients have been rarely studied. Vastus medialis muscles of 14 female patients with OA (age range, 69 to 86 years), largely immobile for 1 or more years, were obtained during arthroplastic surgery and analyzed histologically. These were compared with female patients without arthritis, two with patellar fracture and two with patellar subluxation. Areas occupied by myofibers and adipose tissue were quantified. Large numbers of myofibers were lost in the vastus medialis of OA patients. The loss of myofibers was a possible cause of the reduction in muscle strength of the operated on knee. These changes were significantly correlated with an increase in intramuscular ectopic adipose tissue, and not observed in knees of nonarthritic patients. Resident platelet derived growth factor receptor alpha-positive mesenchymal progenitor cells contributed to ectopic adipogenesis in vastus medialis muscles of OA patients. The present study suggests that significant loss of myofibers and ectopic adipogenesis in vastus medialis muscles are common pathological features of advanced knee OA patients with long-term loss of mobility. These changes may be related to the loss of joint function in patients with knee OA. PMID- 28919114 TI - Life, death, and disability in 2016. PMID- 28919113 TI - Hepatic Tmem30a Deficiency Causes Intrahepatic Cholestasis by Impairing Expression and Localization of Bile Salt Transporters. AB - Mutations in ATP8B1 or ATP11C (members of P4-type ATPases) cause progressive familial intrahepatic cholestasis type 1 in human or intrahepatic cholestasis in mice. Transmembrane protein 30A (TMEM30A), a beta-subunit, is essential for the function of ATP8B1 and ATP11C. However, its role in the etiology of cholestasis remains poorly understood. To investigate the function of TMEM30A in bile salt (BS) homeostasis, we developed Tmem30a liver-specific knockout (LKO) mice. Tmem30a LKO mice experienced hyperbilirubinemia, hypercholanemia, inflammatory infiltration, ductular proliferation, and liver fibrosis. The expression and membrane localization of ATP8B1 and ATP11C were significantly reduced in Tmem30a LKO mice, which correlated with the impaired expression and localization of BS transporters, such as OATP1A4, OATP1B2, NTCP, BSEP, and MRP2. The proteasome inhibitor bortezomib partially restored total protein levels of BS transporters but not the localization of BS transporters in the membrane. Furthermore, the expression of nuclear receptors, including FXRalpha, RXRalpha, HNF4alpha, LRH-1, and SHP, was also down-regulated. A cholic acid-supplemented diet exacerbated the liver damage in Tmem30a LKO mice. TMEM30A deficiency led to intrahepatic cholestasis in mice by impairing the expression and localization of BS transporters and the expression of related nuclear receptors. Therefore, TMEM30A may be a novel genetic determinant of intrahepatic cholestasis. PMID- 28919120 TI - Measuring global health: motivation and evolution of the Global Burden of Disease Study. PMID- 28919121 TI - The utility of instrumented dual-task gait and tablet-based neurocognitive measurements after concussion. AB - OBJECTIVES: Quantitative and non-invasive measurements acquired by neurocognitive or gait evaluations are useful concussion management components. Emerging technology has allowed for the development of portable and objective tests which may be potentially useful across many settings where evaluations take place. Our aim was to examine the association between instrumented dual-task gait and tablet based neurocognitive outcome variables with an acute concussion. DESIGN: A total of 59 collegiate athletes were identified and tested within 5days of concussion (n=18, 50% female, 20+/-1years of age) or as a part of a baseline examination (n=41, 29% female, 19+/-1years of age). METHODS: Participants completed an instrumented dual-task gait evaluation and a tablet-based neurocognitive evaluation. Outcome variables were compared with t-tests, and a multivariable logistic regression model was constructed to identify the association between the presence of a concussion and test performance. RESULTS: Compared with controls, participants with concussion reported significantly more severe symptoms (PCSS=19.1+/-15.2 vs. 4.1+/-6.3; p<0.001), walked significantly slower during dual-task conditions (87.7+/-10.4cm/s vs. 98.1+/-15.4cm/s; p=0.01), and responded with significantly slower simple reaction times (305.2+/-32.4ms vs. 275.4+/ 22.1ms; p<0.001). After adjusting for the effect of potential confounding variables, these three variables (more severe symptoms, slower walking speed, and slower reaction time) remained independently associated with concussion (adjusted odds ratios=1.181, 0.916, and 1.043, respectively). CONCLUSIONS: Relatively simple quantitative measurements of dual-task gait and reaction time may be useful and portable clinical tests in the multifaceted assessment of concussion. PMID- 28919116 TI - Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. METHODS: We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. FINDINGS: The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72.3% (95% uncertainty interval [UI] 71.2-73.2) of deaths in 2016 with 19.3% (18.5-20.4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8.43% (8.00 8.67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006-16-age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1.80 million deaths (95% UI 1.59 million to 1.89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176-181) increase in deaths in ages 90-94 years and a 210% (208 212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2.89%); the median annualised rate of change for all other causes was lower (a decrease of 1.59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. INTERPRETATION: The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. FUNDING: Bill & Melinda Gates Foundation. PMID- 28919122 TI - Functional Movement Screen: Pain versus composite score and injury risk. AB - OBJECTIVES: The Functional Movement Screen (FMSTM) has been used as a screening tool to determine musculoskeletal injury risk using composite scores based on movement quality and/or pain. However, no direct comparisons between movement quality and pain have been quantified. DESIGN: Retrospective injury data analysis. METHODS: Male Soldiers (n=2154, 25.0+/-1.3years; 26.2+/-.7kg/m2) completed the FMS (scored from 0 points (pain) to 3 points (no pain and perfect movement quality)) with injury data over the following six months. The FMS is seven movements. Injury data were collected six months after FMS completion. Sensitivity, specificity, receiver operator characteristics and positive and negative predictive values were calculated for pain occurrence and low (<=14 points) composite score. Risk, risk ratios (RR) and 95% confidence intervals were calculated for injury risk. RESULTS: Pain was associated with slightly higher injury risk (RR=1.62) than a composite score of <=14 points (RR=1.58). When comparing injury risk between those who scored a 1, 2 or 3 on each individual movement, no differences were found (except deep squat). However, Soldiers who experienced pain on any movement had a greater injury risk than those who scored 3 points for that movement (p<0.05). A progressive increase in the relative risk occurred as the number of movements in which pain occurrence increased, so did injury risk (p<0.01). CONCLUSIONS: Pain occurrence may be a stronger indicator of injury risk than a low composite score and provides a simpler method of evaluating injury risk compared to the full FMS. PMID- 28919123 TI - Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving beta catenin. AB - Previous studies have proven that glucagon-like peptide-1 (GLP-1) and its receptor agonist exert favorable anabolic effects on skeletal metabolism. However, whether GLP-1 could directly impact osteoblast-mediated bone formation is still controversial, and the underlying molecular mechanism remains to be elucidated. Thus in this paper, we investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on murine MC3T3-E1 preosteoblasts proliferation and differentiation and explored the potential cellular basis. Our study confirmed the presence of GLP-1R in MC3T3-E1, and demonstrated that liraglutide promotes osteoblasts proliferation at an intermediate concentration (100nM) and time (48h), upregulated the expression of osteoblastogenic biomarkers at various stages, and stimulated osteoblastic mineralization. Liraglutide also elevated the intracellular cAMP level and phosphorylation of AKT, ERK and beta-catenin simultaneously with increased nuclear beta-catenin content and transcriptional activity. Pretreatment of cells with the inhibitors LY294002, PD98059, H89 and GLP-1R and beta-catenin siRNA partially blocked the liraglutide-induced signaling activation and attenuated the facilitating effect of liraglutide on MC3T3-E1 cells. Collectively, liraglutide was capable of acting upon osteoblasts directly through GLP-1R by activating PI3K/AKT, ERK1/2, cAMP/PKA/beta-cat-Ser675 signaling to promote bone formation via GLP-1R. Thus, GLP-1 analogues may be potential therapeutic strategy for the treatment of osteoporosis in diabetics. PMID- 28919124 TI - Foreword. PMID- 28919125 TI - Multi-Institution Analysis of Infection Control Practices Identifies the Subset Associated with Best Surgical Site Infection Performance: A Texas Alliance for Surgical Quality Collaborative Project. AB - BACKGROUND: In an effort to reduce surgical site infection (SSI) rates, a large number of infection control practices (ICPs), including operating room attire policies, have been recommended. However, few have proven benefits and many are costly, time-consuming, and detrimental to provider morale. The goal of this multi-institution study was to determine which ICPs are associated with lower postoperative SSI rates. STUDY DESIGN: Twenty American College of Surgeons NSQIP and Texas Alliance for Surgical Quality-affiliated hospitals completed this Quality Improvement Assessment Board-approved study. Surgeon champions at each hospital ranked current surgery, anesthesia, and nursing adherence to 38 separate ICPs in 6 categories (attire, preoperative, intraoperative, preoperative, intraoperative, antibiotics, postoperative, and reporting) on 4-point scales for general surgery cases. These data were compared with the risk-adjusted general surgery SSI odds ratios contained in the July 2016 American College of Surgeons NSQIP hospital-level, risk-adjusted reports. Compliance rates were compared between the 7 best (median SSI odds ratio, 0.64; range, 0.56 to 0.70) and 7 worst (median SSI odds ratio, 1.16; range, 0.94 to 1.65) performers using ANOVA. RESULTS: Nearly all hospitals reported maximal adherence to hair removal with clippers (Surgical Care Improvement Project measure Inf-6) and to best-practice prophylactic antibiotic metrics (Surgical Care Improvement Project measure Inf-1 3). Variable adherence was identified across many ICPs and more frequent compliance with 8 ICPs correlated with lower SSI odds ratios, including preoperative shower; skin preparation technique; using clean instruments, gowns, and gloves for wound closure and dressing changes; and transparent internal reporting of SSI data. Operating room attire ICPs, including coverage of nonscrubbed provider head and arm hair, did not correlate with SSI rates. CONCLUSIONS: This analysis suggests that the subset of ICPs that focus on perioperative patient skin and wound hygiene and transparent display of SSI data, not operating room attire policies, correlated with SSI rates. Implementation of this subset of evidence-based ICPs may improve SSI rates at lower-performing hospitals. PMID- 28919115 TI - Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0.5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP) Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86.9 years (95% UI 86.7-87.2), and for men in Singapore, at 81.3 years (78.8 83.7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, and the gap between male and female life expectancy increased with progression to higher levels of SDI. Some countries with exceptional health performance in 1990 in terms of the difference in observed to expected life expectancy at birth had slower progress on the same measure in 2016. INTERPRETATION: Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled. FUNDING: Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health. PMID- 28919127 TI - Acute appendicitis: implementing low-dose CT in clinical practice. PMID- 28919129 TI - Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors. AB - BACKGROUND: This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders. METHODS: Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h2) was estimated by linear mixed models using family membership as a random effect, with h2 indicating the portion of phenotypic variance accounted for by family membership. RESULTS: Familiality estimates highly varied for individual catatonia signs (h2=0.17-0.65), principal component analysis-derived factors (h2=0.29-0.49), number of catatonia signs present (h2=0.03-0.43) and severity of the catatonia syndrome (h2=0.25-0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h2=0.65), presence of >=5 catatonia signs (h2=0.43), a classical catatonia factor (h2=0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h2=0.59) and the diagnostic construct of psychosis with prominent catatonia features (h2=0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h2=0.40-0.47). CONCLUSIONS: The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character. PMID- 28919128 TI - Pregabalin for anxiety in patients with schizophrenia - A randomized, double blind placebo-controlled study. AB - INTRODUCTION: Anxiety is frequent in patients with schizophrenia and poses a major impact on patients perceived quality of life, daily functioning and risk of suicide. Pregabalin has shown effective in the treatment of generalized anxiety disorder and has been suggested for the treatment of anxiety in patients with schizophrenia. As evidence is sparse regarding treatment of anxiety in this patient group, we aimed to investigate the use of pregabalin for anxiety in patients with schizophrenia. METHODS: A randomized, double-blind placebo controlled study was used. Patients were randomized to either placebo or pregabalin (<=600mg/d) as add-on treatment. Primary analyses were intention-to treat based with change in Hamilton Anxiety Scale after 4 and 8weeks of treatment as primary outcome. Secondary outcomes were change in psychopathology, quality-of life, cognitive functioning and sleep. The study used centralized raters to increase accuracy and minimize baseline inflation. RESULTS: A total of 54 patients were included with 46 completing the study. Pregabalin reduced the HAM A6 score significantly compared to placebo and with a medium effect size 0.72 (p=0.01). No significant between-group difference was found for the overall HAM A14. Most common side-effects were weight gain, dizziness, sedation and increased duration of sleep. CONCLUSIONS: Although no effect was found on overall HAM-A14, pregabalin might be effective in the treatment of psychic anxiety symptoms in patients with schizophrenia with a medium effect size. PMID- 28919130 TI - The nuts and bolts of Cognitive Remediation: Exploring how different training components relate to cognitive and functional gains. AB - BACKGROUND: Cognitive Remediation (CR) is an evidence based treatment targeting cognitive and functional difficulties in people with psychosis. Despite the large number of effectiveness studies, only limited evidence exists for the active ingredients of this therapy. This study begins to fill this gap by exploring the relationship between CR ingredients, including alliance with a therapist, and therapy outcomes. METHOD: This is a secondary analysis based on data from a published randomised controlled trial comparing CR+treatment-as-usual (TAU) to TAU alone. We considered the association between CR active ingredients including errorless learning, massed practice, strategy use and therapeutic alliance on the cognitive, functioning and symptom outcomes that significantly improved following therapy. RESULTS: Forty-six of the 96 participants were randomised to CR. After therapy the CR group showed significant improvement in non-verbal memory, functioning and approaching significance, improvements in executive functions. All therapy ingredients were inter-related but strategy use alone was associated therapeutic alliance. Cognitive improvements were associated with massed practice, number of useful strategies and therapeutic alliance, but improvements in functioning were associated only with therapeutic alliance. CONCLUSIONS: These findings build the evidence base for the usefulness of specific therapy components. As for other psychological therapies it appears that therapeutic alliance may be an important factor in driving change for key CR outcomes, particularly functioning, in people with psychosis. PMID- 28919117 TI - Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016. METHODS: We estimated prevalence and incidence for 328 diseases and injuries and 2982 sequelae, their non-fatal consequences. We used DisMod-MR 2.1, a Bayesian meta regression tool, as the main method of estimation, ensuring consistency between incidence, prevalence, remission, and cause of death rates for each condition. For some causes, we used alternative modelling strategies if incidence or prevalence needed to be derived from other data. YLDs were estimated as the product of prevalence and a disability weight for all mutually exclusive sequelae, corrected for comorbidity and aggregated to cause level. We updated the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. GBD 2016 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). FINDINGS: Globally, low back pain, migraine, age-related and other hearing loss, iron-deficiency anaemia, and major depressive disorder were the five leading causes of YLDs in 2016, contributing 57.6 million (95% uncertainty interval [UI] 40.8-75.9 million [7.2%, 6.0-8.3]), 45.1 million (29.0-62.8 million [5.6%, 4.0-7.2]), 36.3 million (25.3-50.9 million [4.5%, 3.8-5.3]), 34.7 million (23.0-49.6 million [4.3%, 3.5 5.2]), and 34.1 million (23.5-46.0 million [4.2%, 3.2-5.3]) of total YLDs, respectively. Age-standardised rates of YLDs for all causes combined decreased between 1990 and 2016 by 2.7% (95% UI 2.3-3.1). Despite mostly stagnant age standardised rates, the absolute number of YLDs from non-communicable diseases has been growing rapidly across all SDI quintiles, partly because of population growth, but also the ageing of populations. The largest absolute increases in total numbers of YLDs globally were between the ages of 40 and 69 years. Age standardised YLD rates for all conditions combined were 10.4% (95% UI 9.0-11.8) higher in women than in men. Iron-deficiency anaemia, migraine, Alzheimer's disease and other dementias, major depressive disorder, anxiety, and all musculoskeletal disorders apart from gout were the main conditions contributing to higher YLD rates in women. Men had higher age-standardised rates of substance use disorders, diabetes, cardiovascular diseases, cancers, and all injuries apart from sexual violence. Globally, we noted much less geographical variation in disability than has been documented for premature mortality. In 2016, there was a less than two times difference in age-standardised YLD rates for all causes between the location with the lowest rate (China, 9201 YLDs per 100 000, 95% UI 6862-11943) and highest rate (Yemen, 14 774 YLDs per 100 000, 11 018-19 228). INTERPRETATION: The decrease in death rates since 1990 for most causes has not been matched by a similar decline in age-standardised YLD rates. For many large causes, YLD rates have either been stagnant or have increased for some causes, such as diabetes. As populations are ageing, and the prevalence of disabling disease generally increases steeply with age, health systems will face increasing demand for services that are generally costlier than the interventions that have led to declines in mortality in childhood or for the major causes of mortality in adults. Up-to-date information about the trends of disease and how this varies between countries is essential to plan for an adequate health-system response. FUNDING: Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health. PMID- 28919126 TI - Low-dose CT for the diagnosis of appendicitis in adolescents and young adults (LOCAT): a pragmatic, multicentre, randomised controlled non-inferiority trial. AB - BACKGROUND: CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults. METHODS: We did this pragmatic, multicentre, randomised controlled non-inferiority trial at 20 South Korean teaching hospitals with little experience with low-dose CT. Patients aged 15-44 years with suspected appendicitis were randomly assigned (1:1), via computer-generated random assignments (permuted block sizes of two, four, six, and eight) concealed in sequentially numbered envelopes, to receive low-dose CT (2 mSv) or standard-dose CT (<=8 mSv). Randomisation was stratified by site. Group allocation was concealed from patients, outcome assessors, and adverse event adjudicators; care providers, site pathologists, and data collectors were aware of allocation. The primary endpoint was the negative (unnecessary) appendectomy rate among all appendectomies, with a non-interiority margin of 4.5% for low-dose versus standard-dose CT. Primary analysis was by modified intention to treat, which included all patients who received an appendectomy in the group to which they were assigned. This trial is registered with ClinicalTrials.gov, number NCT01925014. FINDINGS: Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3.9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2.7%) of 601 patients in the standard-dose group (difference 1.3%, 95% CI -0.8 to 3.3; p=0.0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2.8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2.6%) of 1539 patients in the standard-dose group. One life threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group. INTERPRETATION: Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation associated cancers in the future. FUNDING: Korea Health Industry Development Institute, Seoul National University Bundang Hospital, Dasol Life Science, and Bracco Imaging Korea. PMID- 28919131 TI - Optogenetic targeting of cardiac myocytes and non-myocytes: Tools, challenges and utility. AB - In optogenetics, light-activated proteins are used to monitor and modulate cellular behaviour with light. Combining genetic targeting of distinct cellular populations with defined patterns of optical stimulation enables one to study specific cell classes in complex biological tissues. In the current study we attempted to investigate the functional relevance of heterocellular electrotonic coupling in cardiac tissue in situ. In order to do that, we used a Cre-Lox approach to express the light-gated cation channel Channelrhodopsin-2 (ChR2) specifically in either cardiac myocytes or non-myocytes. Despite high specificity when using the same Cre driver lines in a previous study in combination with a different optogenetic probe, we found patchy off-target ChR2 expression in cryo sections and extended z-stack imaging through the ventricular wall of hearts cleared using CLARITY. Based on immunohistochemical analysis, single-cell electrophysiological recordings and whole-genome sequencing, we reason that non specificity is caused on the Cre recombination level. Our study highlights the importance of careful design and validation of the Cre recombination targets for reliable cell class specific expression of optogenetic tools. PMID- 28919132 TI - The East, the West and the universal machine. AB - After reviewing the basic of theology of Universal Numbers/Machines, as detailed in Marchal (2007), I illustrate how that body of thought might be used to shed some light upon the apparent dichotomy in Eastern/Western spirituality. This paper relies entirely on my previous interdisciplinary work in mathematical logic, computer science and machine's theology, where "theology" is used here in the sense of Plato: it is the truth, or the "truth-theory" (in the sense of logicians) about a machine that the machine can either deduce from some of its primitive beliefs, or can be intuited in some sense that eventually is made clear through the modal logic of machine self-reference. Such a theology appears to be testable, because it has been shown that physics has to be necessarily retrieved from it when we assume the mechanist hypothesis in the cognitive sciences, and this in a unique precise (introspective) way, so that we only need to compare the physics of the introspective machine with the physics inferred from the human observation; and up to now, it is the only theory known to fit both the existence of personal "consciousness" (undoubtable yet unjustifiable truth) and quanta and quantum relationships (Marchal, 1998; Marchal, 2004; Marchal, 2013; Marchal, 2015). PMID- 28919133 TI - Transfer parameters for ICRP's Reference Animals and Plants in a terrestrial Mediterranean ecosystem. AB - A system for the radiological protection of the environment (or wildlife) based on Reference Animals and Plants (RAPs) has been suggested by the International Commission on Radiological Protection (ICRP). To assess whole-body activity concentrations for RAPs and the resultant internal dose rates, transfer parameters are required. However, transfer values specifically for the taxonomic families defined for the RAPs are often sparse and furthermore can be extremely site dependent. There is also a considerable geographical bias within available transfer data, with few data for Mediterranean ecosystems. In the present work, stable element concentrations (I, Li, Be, B, Na, Mg, Al, P, S, K. Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Mo, Ag, Cd, Cs, Ba, Tl, Pb and U) in terrestrial RAPs, and the corresponding whole-body concentration ratios, CRwo, were determined in two different Mediterranean ecosystems: a Pinewood and a Dehesa (grassland with disperse tree cover). The RAPs considered in the Pinewood ecosystem were Pine Tree and Wild Grass; whereas in the Dehesa ecosystem those considered were Deer, Rat, Earthworm, Bee, Frog, Duck and Wild Grass. The CRwo values estimated from these data are compared to those reported in international compilations and databases. PMID- 28919134 TI - [The eyelid-cheek junction]. AB - The eyelid-cheek junction is a key area which generates many comments: from looking tired to looking good or rested, without forgetting charm, beauty, and a youthful appearance. In spite of many interesting medical and surgical procedures, treating this area is sometimes difficult and results are not always up to our expectations. Standardized blepharoplasty, which has often been improperly used, has shown its limits. Since the latest refinements, lipostructure has revolutionised blepharoplasty and serving as a reference, it has become an established technique. Subperiostal mediofacial lift allows outstanding results at the cost of a certain technical aggressiveness. Aesthetic medicine proposes worthy alternative and/or appropriate complementary solutions. Different procedures we dispose of have been reviewed together with their assets and their limits. A codification of therapeutic indications is proposed. The positioning of the eyelid-cheek clinical junction in relation with the low orbital bone rim influences our strategy in choosing the appropriate technique. PMID- 28919137 TI - Pseudoaneurysm complicating right ventricle-to-pulmonary artery conduit surgery: Incidence and risk factors. AB - OBJECTIVES: Although pseudoaneurysm is an uncommon complication after right ventricle-to-pulmonary artery conduit placement, it has the potential to cause significant morbidity and mortality. METHODS: We performed a review of patients with pseudoaneurysms diagnosed at our institution in a 20-year period (from 1995 through 2015) and compared their clinical characteristics with a group of age- and sex-matched control patients. RESULTS: We found that younger age, smaller size, the diagnosis of tetralogy of Fallot, the use of a pulmonary homograft conduit, the presence of an unrestrictive ventricular septal defect after conduit placement, and having at least systemic right ventricular pressure were all more common in patients who had pseudoaneurysms develop. CONCLUSIONS: This study is unique in identifying both patient and surgical factors that may predispose to pseudoaneurysm development and can help inform optimal strategies to monitor and evaluate this patient population. PMID- 28919136 TI - Pilocytic astrocytoma mimicking cavernous angioma: Imaging features and histological characteristics. AB - Pilocytic astrocytoma (PA) commonly occurs during the first two decades of life. Typical locations include cerebellum, optic nerve, optic chiasm/hypothalamus and brainstem. PA should be considered in the differential diagnosis of patients with brain tumors manifesting with hemorrhagic onset. We report a case of a hemorrhagic onset of cerebellar PA in a young adult with imaging findings mimicking cavernous angioma. We also discuss imaging features and histological characteristics with a focus on the etiology of the hemorrhagic onset. PMID- 28919135 TI - Are Experiences of Discrimination Related to Poorer Dietary Intakes Among South Asians in the MASALA Study? AB - OBJECTIVE: To examine associations between self-reported discrimination and dietary intakes among South Asian (SA) people. METHODS: Data from the Mediators of Atherosclerosis in South Asians Living in America study were used to analyze the relationship between self-reported discrimination and dietary behaviors (n = 866). Self-reported discrimination was measured with the 9-item continuous Everyday Discrimination Scale. Diet was measured with a culturally tailored, validated, 163-item food frequency questionnaire for SA individuals. Dietary variables examined in these analyses included weekly consumption of fruits and vegetables and sweets. The researchers employed multiple logistic and linear regression models. RESULTS: Self-reported discrimination was unrelated to fruit and vegetable intake but was positively associated with consumption of sweets per week (P = .001). CONCLUSIONS AND IMPLICATIONS: Increased consumption of sweets may be a mechanism for SA individuals to cope with stressful experiences of discrimination. Further research examining discrimination and health behavior related coping strategies among SA people is needed. PMID- 28919138 TI - Keep pumping for life.... PMID- 28919139 TI - Is there light at the end of the tunnel for patients with severe compensatory hyperhidrosis? PMID- 28919140 TI - Minimally invasive Columbus egg. PMID- 28919141 TI - MicroRNA-30a-lysyl oxidase axis in aortic dissection pathogenesis. PMID- 28919119 TI - Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990 2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of risk factor exposure and attributable burden of disease. By providing estimates over a long time series, this study can monitor risk exposure trends critical to health surveillance and inform policy debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2016. This study included 481 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk (RR) and exposure estimates from 22 717 randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources, according to the GBD 2016 source counting methods. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. Finally, we explored four drivers of trends in attributable burden: population growth, population ageing, trends in risk exposure, and all other factors combined. FINDINGS: Since 1990, exposure increased significantly for 30 risks, did not change significantly for four risks, and decreased significantly for 31 risks. Among risks that are leading causes of burden of disease, child growth failure and household air pollution showed the most significant declines, while metabolic risks, such as body-mass index and high fasting plasma glucose, showed significant increases. In 2016, at Level 3 of the hierarchy, the three leading risk factors in terms of attributable DALYs at the global level for men were smoking (124.1 million DALYs [95% UI 111.2 million to 137.0 million]), high systolic blood pressure (122.2 million DALYs [110.3 million to 133.3 million], and low birthweight and short gestation (83.0 million DALYs [78.3 million to 87.7 million]), and for women, were high systolic blood pressure (89.9 million DALYs [80.9 million to 98.2 million]), high body mass index (64.8 million DALYs [44.4 million to 87.6 million]), and high fasting plasma glucose (63.8 million DALYs [53.2 million to 76.3 million]). In 2016 in 113 countries, the leading risk factor in terms of attributable DALYs was a metabolic risk factor. Smoking remained among the leading five risk factors for DALYs for 109 countries, while low birthweight and short gestation was the leading risk factor for DALYs in 38 countries, particularly in sub-Saharan Africa and South Asia. In terms of important drivers of change in trends of burden attributable to risk factors, between 2006 and 2016 exposure to risks explains an 9.3% (6.9-11.6) decline in deaths and a 10.8% (8.3-13.1) decrease in DALYs at the global level, while population ageing accounts for 14.9% (12.7-17.5) of deaths and 6.2% (3.9-8.7) of DALYs, and population growth for 12.4% (10.1-14.9) of deaths and 12.4% (10.1-14.9) of DALYs. The largest contribution of trends in risk exposure to disease burden is seen between ages 1 year and 4 years, where a decline of 27.3% (24.9-29.7) of the change in DALYs between 2006 and 2016 can be attributed to declines in exposure to risks. INTERPRETATION: Increasingly detailed understanding of the trends in risk exposure and the RRs for each risk outcome pair provide insights into both the magnitude of health loss attributable to risks and how modification of risk exposure has contributed to health trends. Metabolic risks warrant particular policy attention, due to their large contribution to global disease burden, increasing trends, and variable patterns across countries at the same level of development. GBD 2016 findings show that, while it has huge potential to improve health, risk modification has played a relatively small part in the past decade. FUNDING: The Bill & Melinda Gates Foundation, Bloomberg Philanthropies. PMID- 28919142 TI - Innovation in cardiothoracic surgical training. PMID- 28919144 TI - Beyond L-DOPA: hope for Parkinson's treatment and diagnosis. PMID- 28919145 TI - Outcomes of Therapy for Vulvar Manifestation of Inflammatory Bowel Disease in Adolescents. AB - BACKGROUND: Vulvar manifestations of inflammatory bowel disease (IBD) are variable in presentation and challenging to treat. We describe vulvar manifestations and treatment response in female adolescents with IBD. CASES: We identified 6 patients with vulvar manifestations of IBD and documented treatments using retrospective chart review. Vulvar symptoms occurred without gastrointestinal (GI) symptoms in 1 patient. For the remaining 5 patients, 2 had GI symptoms before the onset of vulvar symptoms (mean time difference, 4.5 years); 3 patients had vulvar symptoms precede the onset of GI symptoms (mean time difference, 3.3 years). Vulvar IBD manifestations included pain, 100% (n = 6); enlargement, "fullness" or "edema" of the labia minora or majora, 66% (n = 4); ulcers, 50% (n = 3); and abscess, 50% (n = 3). Gynecologic procedures included biopsies, incision and drainages, and partial vulvectomies. All patients were treated with multiple systemic therapies. None of the patients responded to surgical or medical treatment alone; all had recalcitrant vulvar symptoms. SUMMARY AND CONCLUSION: Vulvar manifestations of IBD might precede GI symptoms in adolescents with IBD. Treatment is challenging and in this series, systemic therapies were the most successful in achieving symptomatic improvement. PMID- 28919143 TI - Long-term safety of glycopyrrolate/eFlow(r) CS in moderate-to-very-severe COPD: Results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study. AB - BACKGROUND: The use of long-acting bronchodilators is an essential component of the management of chronic obstructive pulmonary disease (COPD). The GOLDEN 5 Phase III, randomized, active-controlled, open-label study was conducted to evaluate the long-term safety and tolerability of a nebulized glycopyrrolate formulation (SUN-101) delivered via the investigational eFlow(r) Closed System (eFlow(r) CS) nebulizer in subjects with moderate-to-very-severe COPD. METHODS: Subjects were randomized in a 4:3 ratio to nebulized glycopyrrolate 50 MUg twice daily (BID) or tiotropium 18 MUg once daily (OD) and treated for 48 weeks. Subjects represented the general COPD population with real-world characteristics including severe disease, presence of comorbidities, and receiving background COPD therapy. Primary endpoints were the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Secondary endpoints included the number of subjects with major adverse cardiovascular events (MACE); change from baseline in trough forced expiratory volume in 1 s (FEV1), and assessment of patient-reported outcomes. RESULTS: 1086 subjects received at least one dose of study drug. The overall incidence of TEAEs was comparable for subjects treated with glycopyrrolate (69.4%) or tiotropium (67.0%). Serious TEAEs occurred at similar rates in both treatment groups (glycopyrrolate, 12.3%; tiotropium, 10.5%). The most frequent TEAEs were COPD exacerbation/worsening and cough. Discontinuation due to TEAEs was higher in the glycopyrrolate group (10.0%) than the tiotropium group (2.8%) and related, in part, to the open-label study design, prior use of long-acting muscarinic antagonists and aerosol-airway interactions. Fewer subjects in the glycopyrrolate group experienced MACE (glycopyrrolate, n = 3 [0.5%]; tiotropium, n = 8 [1.7%]). Nebulized glycopyrrolate treatment resulted in improvements in trough FEV1 that were maintained over 48 weeks. Patient-reported health outcomes showed improvements, supporting the increases in trough FEV1. CONCLUSIONS: Treatment with nebulized glycopyrrolate was well tolerated over 48 weeks with the most common adverse events being COPD worsening and cough. The overall and cardiac safety and tolerability profile and improvements in pulmonary function and patient-reported health outcomes support the use of nebulized glycopyrrolate as a maintenance treatment for moderate-to-very-severe COPD. CLINICAL TRIAL REGISTRATION NUMBER: NCT02276222. PMID- 28919118 TI - Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75.2 years (95% uncertainty interval 71.9-78.6) for females and 72.0 years (68.8-75.1) for males. The lowest for females was in the Central African Republic (45.6 years [42.0-49.5]) and for males was in Lesotho (41.5 years [39.0-44.0]). From 1990 to 2016, global HALE increased by an average of 6.24 years (5.97-6.48) for both sexes combined. Global HALE increased by 6.04 years (5.74-6.27) for males and 6.49 years (6.08-6.77) for females, whereas HALE at age 65 years increased by 1.78 years (1.61-1.93) for males and 1.96 years (1.69-2.13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2.3% [ 5.9 to 0.9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16.1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation. PMID- 28919146 TI - Mullerian Agenesis in Cat Eye Syndrome and 22q11 Chromosome Abnormalities: A Case Report and Literature Review. AB - BACKGROUND: Although Mullerian agenesis is the second most common cause of primary amenorrhea the underlying etiology in most cases is unknown. Mullerian agenesis has been reported as a rare finding associated with chromosomal aberrations of the 22q11 chromosomal region including at least 1 individual with cat eye syndrome (CES) and 10 individuals with deletions or duplications of the 22q11.2 region. However, a potential link between 22q11 abnormalities and uterine malformations has been difficult to adequately ascertain because of the limited case reports in the literature. CASE: We report a second case of Mullerian agenesis in a girl with CES. A 16-year-old girl presented with bilateral colobomata, primary amenorrhea, and absence of the uterus and upper vagina on pelvic magnetic resonance imaging. Microarray analysis showed tetrasomy of the pericentromeric region of chromosome 22 diagnostic of CES. SUMMARY AND CONCLUSION: Mullerian aplasia/hypoplasia might represent a rare feature in CES and should be considered in the investigation of young girls with this syndrome. An increasing number of cases with 22q11 chromosome abnormalities and Mullerian agenesis further highlights the possibility of a gene within the 22q11 region that might mediate normal Mullerian development in girls. PMID- 28919147 TI - Pediatric Resident Training in Prepubertal Vulvar Conditions. AB - STUDY OBJECTIVE: To assess pediatric resident training in diagnosing and managing prepubertal gynecologic conditions. DESIGN: Voluntary 32-question survey e-mailed to participants. SETTING: E-mail contact through the American Academy of Pediatrics listserv. PARTICIPANTS: Seven thousand seventy-five US pediatrics and combined internal medicine-pediatric residents. INTERVENTIONS: Descriptive analysis including chi2 tests was performed on survey results. MAIN OUTCOME MEASURES: Residents' training experiences and comfort, confidence, and knowledge in evaluating pediatric gynecologic concerns. RESULTS: In the 866 of 7075 (12%) completed surveys, a greater proportion of residents reported they were "very" or "extremely" comfortable talking to parents about general pediatric topics compared with gynecologic topics (88.5% vs 30.4%; P < .001). Similarly, they reported being "very" or "extremely" confident diagnosing general pediatric conditions compared with prepubertal gynecologic conditions (87.6% vs 32.8%; P < .001). These differences were also observed according to residency year (comfort: first year, 10.2% vs third/fourth year, 39.9%; P < .001; confidence: first year, 22.5% vs third/fourth year, 37.6%; P < .001). Residents learned about vulvovaginal concerns from attendings in clinic (79.8%), residency-specific didactics (34.7%), and conferences, meetings, and workshops (24.1%). Confidence examining, diagnosing, and treating vulvovaginitis was associated with participation in any learning activity and exposure to more than 5 patients with this concern. Additional education or training in prepubertal vulvovaginal conditions was requested by 97% of residents. CONCLUSION: Our findings suggest that pediatric residents are lacking in comfort, confidence, and knowledge of prepubertal vulvovaginal conditions, especially compared with general pediatric topics. Although this improves during training, it remains low, and more education is indicated and desired by residents. PMID- 28919149 TI - Response to: On the role of visual electrophysiology in parkinson's disease. PMID- 28919148 TI - Creation and Dissemination of a Multispecialty Graduate Medical Education Curriculum in Pediatric and Adolescent Gynecology: The North American Society for Pediatric and Adolescent Gynecology Resident Education Committee Experiences. AB - STUDY OBJECTIVE: The goal was to develop a multispecialty committee to address deficiencies in pediatric and adolescent gynecology (PAG) resident education through curricular development under the auspices of the North American Society for Pediatric and Adolescent Gynecology. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A multispecialty North American committee was organized to develop short as well as long curricula in PAG through a combination of conference calls and face-to-face meetings. Content was guided by objectives of national accrediting organizations. The curricula used print as well as interactive electronic resources. RESULTS: After publication of the short and long curricula, a dissemination strategy was developed to present the information at national meetings. A curricular study was performed after introduction of the curriculum to evaluate its efficacy. Long-term plans for further curricular components and expansion of educational tools are ongoing. CONCLUSION: We gathered a diverse multispecialty group of doctors to collaborate on a unified educational goal. This committee developed and disseminated resident PAG curricula using a variety of learning tools. This curricular development and implementation can occur with a minimal financial burden. PMID- 28919150 TI - In vitro anti-tuberculosis activity of azole drugs against Mycobacterium tuberculosis clinical isolates. AB - BACKGROUND: Latent tuberculosis has been associated with the persistence of dormant Mycobacterium tuberculosis in the organism of infected individuals, who are reservoirs of the bacilli and the source for spreading the disease in the community. New active anti-TB drugs exerting their metabolic action at different stages and on latent/dormant bacilli are urgently required to avoid endogenous reactivations and to be part of treatments of multi- and extensively-drug resistant tuberculosis (M/XDR-TB). It was previously reported that azole drugs are active against M. tuberculosis. For that reason, the aims of this study were to determine the in vitro activity of azole drugs, imidazole (clotrimazole, CLO and econazole, ECO) and nitroimidazole (metronidazole, MZ and ipronidazole, IPZ), against a collection of MDR M. tuberculosis clinical isolates; and to analyze their potential use in both the LTB and the active forms of M/XDR-TB treatments. METHODS: A total of 55 MDR M. tuberculosis isolates and H37Rv were included. MZ and IPZ activity against M. tuberculosis isolates were tested using anaerobic culture conditions. The activity of ECO and CLO was measured by the minimal inhibitory concentration (MIC) using a microdilution colorimetric method. RESULTS: MZ and IPZ showed bacteriostatic activity against M. tuberculosis strains. MIC50 and MIC90 to ECO was 4.0MUg/ml, while MIC50 to CLO was 4.0MUg/ml and MIC90 was 8.0MUg/ml respectively. CONCLUSION: All azole compounds tested in the study showed inhibitory activity against MDR M. tuberculosis clinical isolates. PMID- 28919151 TI - The combined effects of ocean warming and acidification on shallow-water meiofaunal assemblages. AB - Climate change due to increased anthropogenic CO2 in the atmosphere is causing an increase in seawater temperatures referred to as ocean warming and a decrease in seawater pH, referred to as ocean acidification. The meiofauna play an important role in the ecology of marine ecosystems and the functions they provide. Using microcosms, meiofaunal assemblages were exposed to two temperatures (15 and 19 degrees C) and two pHs (pCO2 of 400 and 1000 ppm), both individually and in combination, for a period of 90 days. The hypothesis that increased temperature will increase meiofaunal abundance was not supported. The hypothesis that a reduced pH will reduce meiofaunal abundance and species richness was supported. The combination of future conditions of temperature and pH (19 degrees C and pCO2 of 1000 ppm) did not affect overall abundance but the structure of the nematode assemblage changed becoming dominated by a few opportunistic species. PMID- 28919152 TI - Erector spinae plane (ESP) block in the management of post thoracotomy pain syndrome: A case series. AB - BACKGROUND AND AIMS: Post thoracotomy pain syndrome (PTPS) remains a common complication of thoracic surgery with significant impact on patients' quality of life. Management usually involves a multidisciplinary approach that includes oral and topical analgesics, performing appropriate interventional techniques, and coordinating additional care such as physiotherapy, psychotherapy and rehabilitation. A variety of interventional procedures have been described to treat PTPS that is inadequately managed with systemic or topical analgesics. Most of these procedures are technically complex and are associated with risks and complications due to the proximity of the targets to neuraxial structures and pleura. The ultrasound-guided erector spinae plane (ESP) block is a novel technique for thoracic analgesia that promises to be a relatively simple and safe alternative to more complex and invasive techniques of neural blockade. We have explored the application of the ESP block in the management of PTPS and report our preliminary experience to illustrate its therapeutic potential. METHODS: The ESP block was performed in a pain clinic setting in a cohort of 7 patients with PTPS following thoracic surgery with lobectomy or pneumonectomy for lung cancer. The blocks were performed with ultrasound guidance by injecting 20-30mL of ropivacaine, with or without steroid, into a fascial plane between the deep surface of erector spinae muscle and the transverse processes of the thoracic vertebrae. This paraspinal tissue plane is distant from the pleura and the neuraxis, thus minimizing the risk of complications associated with injury to these structures. The patients were followed up by telephone one week after each block and reviewed in the clinic 4-6 weeks later to evaluate the analgesic response as well as the need for further injections and modification to the overall analgesic plan. RESULTS: All the patients had excellent immediate pain relief following each ESP block, and 4 out of the 7 patients experienced prolonged analgesic benefit lasting 2 weeks or more. The ESP blocks were combined with optimization of multimodal analgesia, resulting in significant improvement in the pain experience in all patients. No complications related to the blocks were seen. CONCLUSION: The results observed in this case series indicate that the ESP block may be a valuable therapeutic option in the management of PTPS. Its immediate analgesic efficacy provides patients with temporary symptomatic relief while other aspects of chronic pain management are optimized, and it may also often confer prolonged analgesia. IMPLICATIONS: The relative simplicity and safety of the ESP block offer advantages over other interventional procedures for thoracic pain; there are few contraindications, the risk of serious complications (apart from local anesthetic systemic toxicity) is minimal, and it can be performed in an outpatient clinic setting. This, combined with the immediate and profound analgesia that follows the block, makes it an attractive option in the management of intractable chronic thoracic pain. The ESP block may also be applied to management of acute pain management following thoracotomy or thoracic trauma (e.g. rib fractures), with similar analgesic benefits expected. Further studies to validate our observations are warranted. PMID- 28919153 TI - Importance for patients of feeling accepted and understood by physicians before and after multimodal pain rehabilitation. PMID- 28919154 TI - Is the search for a "pain personality" of added value to the Fear-Avoidance-Model (FAM) of chronic pain? PMID- 28919155 TI - Context sensitive regulation of pain and emotion: Development and initial validation of a scale for context insensitive avoidance. AB - BACKGROUND AND AIMS: Context insensitivity has been put forward as a potential mechanism explaining the high co-occurrence of pain and emotional distress. In the pain literature, the concept has only been introduced at a theoretical level and an assessment tool for exploring its impact is lacking. In an interpersonal setting, a core aspect of context sensitivity and insensitivity concerns when to disclose and when to avoid expressing pain and related distress. Both context insensitive disclosure and context insensitive avoidance may hamper interpersonal support and fuel the problem. This exploratory study describes an attempt to develop a self-report instrument to assess tendencies to disclose vs. avoid expressions of pain and related distress, as well as self-perceived adjustment of disclosure vs. avoidance to the context. METHODS: A pool of items was systematically developed to assess different aspects of context insensitivity, including disclosure vs. avoidance of expression. 105 participants with persistent pain were recruited at pain rehabilitation clinics (80% of the sample) and in a university setting (20% of the sample). The participants responded to the pool of items as well as to a number of validated self-report instruments covering pain, pain-related disability, pain catastrophizing, emotion regulation tendencies, self-compassion and pain acceptance. The analyses explored the factorial structure of the initial instrument, as well as the criterion and construct validity. RESULTS: The analyses confirmed a stable underlying structure of the initial scale, with four distinct factors explaining 64.4% of the total variance. However, the criterion and construct validity could only be confirmed for one of the factors, which contained items reflecting context insensitive avoidance of expression. Consequently, only this factor, demonstrating very good internal consistency, was kept in the final version of the instrument which was named context insensitive avoidance (CIA). CONCLUSIONS: We found support for the final version of our instrument, capturing one prominent aspect of context insensitivity. Avoidance of expression was related to higher ratings of pain, disability, catastrophizing and suppression as well as to lower levels of self compassion. We encourage further studies to explore the impact of context insensitive avoidance for regulating pain and associated negative emotions. Yet, more research is needed that goes beyond self-report and includes other aspects of context. It is urgent to develop systematic ways for assessing context insensitivity, as it will enhance our understanding of regulatory strategies as potential transdiagnostic mechanisms in pain and emotion. IMPLICATIONS: This tool for assessing contextually insensitive avoidance of expression could potentially be used both clinically and in future research to advance our understanding of comorbid problems with pain and emotional distress. Further research is needed to develop methods for assessing other aspects of context insensitivity to fully understand its impact in patients suffering from pain. PMID- 28919156 TI - Chronic low back pain and the transdiagnostic process: How do cognitive and emotional dysregulations contribute to the intensity of risk factors and pain? AB - BACKGROUND AND AIMS: Based on a transdiagnostic approach, this study assesses the impact of cognitive and emotional processes (difficulties in emotional regulation, impulsiveness, rumination and somatosensory amplification) on the psychological risk factors of chronic low-back pain. METHODS: The study was carried out with 256 patients with chronic low-back pain. All the variables were assessed through a booklet of 10 validated questionnaires. Multiple regression analysis and moderation analysis were performed. RESULTS: Predictors included in multiple regression models explain 3%-42% (adjusted R2) of the variance in psychological risk factors. Moreover, analyses reveal a significant moderator effect of somatosensory amplification on the link between fear-avoidance beliefs linked to work and pain intensity (F(3;250)=12.33; p=.00), of somatosensory amplification and brooding on the link between depression and functional repercussions (FR) on everyday life (F(3;252)=13.36; p=.000; F(1;252)=12.42; p=.00), of the reflection dimension of rumination on the link between the helplessness dimension of catastrophizing and FRs on sociability (F(3;252)=37.02; p=.00). There is also a moderation analysis with a significant trend concerning the lack of emotional awareness and the difficulties in controlling impulsive behaviours. CONCLUSIONS: Our results indicate an important role of some dimensions of difficulties in emotional regulation, somatosensory amplification and rumination in the increase in negative affects and dysfunctional beliefs, and in the links between those psychological risk factors and pain/disability. IMPLICATIONS: This study identifies some cognitive and emotional dysregulations substantially involved in work-related chronic pain. This contribute to put in place psychotherapeutic protocols to tackle these deficits and dysregulations in a relevant way. PMID- 28919157 TI - Ethyl-acetate fraction of Trichilia catigua restores long-term retrograde memory and reduces oxidative stress and inflammation after global cerebral ischemia in rats. AB - We originally reported that an ethyl-acetate fraction (EAF) of Trichilia catigua prevented the impairment of water maze learning and hippocampal neurodegeneration after transient global cerebral (TGCI) in mice. We extended that previous study by evaluating whether T. catigua (i) prevents the loss of long-term retrograde memory assessed in the aversive radial maze (AvRM), (ii) confers hippocampal and cortical neuroprotection, and (iii) mitigates oxidative stress and neuroinflammation in rats that are subjected to the four vessel occlusion (4-VO) model of TGCI. In the first experiment, naive rats were trained in the AvRM and then subjected to TGCI. The EAF was administered orally 30min before and 1h after TGCI, and administration continued once per day for 7days post-ischemia. In the second experiment, the EAF was administered 30min before and 1h after TGCI, and protein carbonylation and myeloperoxidase (MPO) activity were assayed 24h and 5days later, respectively. Retrograde memory performance was assessed 8, 15, and 21days post-ischemia. Ischemia caused persistent retrograde amnesia, and this effect was prevented by T. catigua. This memory protection (or preservation) persisted even after the treatment was discontinued, despite the absence of histological neuroprotection. Protein carbonyl group content and MPO activity increased around 43% and 100%, respectively, after TGCI, which were abolished by the EAF of T. catigua. The administration of EAF did not coincide with the days of memory testing. The data indicate that antioxidant and/or antiinflammatory actions in the early phase of ischemia/reperfusion contribute to the long-term antiamnesic effect of T. catigua. PMID- 28919158 TI - A role for nucleus accumbens glutamate in the expression but not the induction of behavioural sensitization to ethanol. AB - Mechanisms underlying differential sensitivity to behavioural sensitization to ethanol (EtOH) remain poorly understood, although accumulating evidence suggests a role for glutamatergic processes in the ventral striatum. Efforts to address this issue can benefit from the well-documented fact that in any given cohort, some of the mice (High sensitized; HS) show robust sensitization, while others (Low sensitized; LS) show little, if any, sensitization. Here, we examined whether this variability might be differentially associated with nucleus accumbens (NAc) glutamate processes. Male DBA mice received 5 EtOH (2.2g/kg) or saline injections twice a week and were challenged with EtOH (1.8g/kg) 2 weeks after injection 5. When an EtOH challenge was administered 2 weeks following the induction of sensitization, HS, but not LS, mice showed a robust increase in glutamate levels (67%, P<0.01) as measured by in vivo microdialysis. In a separate cohort, the mGlu2/3 agonist LY354740 (10mg/kg), given prior to the EtOH challenge, abolished the expression of sensitization. To ascertain whether enhanced release could also be observed during the induction of sensitization, glutamate levels were measured after the 1st and 5th EtOH injection and were found to be unchanged in HS mice, although briefly elevated in LS mice at injection 5. To further assess possible glutamate involvement during the induction of sensitization, sensitizing EtOH injections were co-administered with NMDAR antagonists. At the doses used, MK-801 (0.25mg/kg) and CGS 19755 (10mg/kg) blocked the expression of sensitization, but did not significantly interfere with the development of EtOH sensitization. Within the limitations of the present design, the results suggest an important role for EtOH-induced glutamate release in the NAc when sensitization is well established, but not necessarily during the development of sensitization. PMID- 28919159 TI - Host control of human papillomavirus infection and disease. AB - Most human papillomaviruses cause inapparent infections, subtly affecting epithelial homeostasis, to ensure genome persistence in the epithelial basal layer. As with conspicuous papillomas, these self-limiting lesions shed viral particles to ensure population level maintenance and depend on a balance between viral gene expression, immune cell stimulation and immune surveillance for persistence. The complex immune evasion strategies, characteristic of high-risk HPV types, also allow the deregulated viral gene expression that underlies neoplasia. Neoplasia occurs at particular epithelial sites where vulnerable cells such as the reserve or cuboidal cells of the cervical transformation zone are found. Beta papillomavirus infection can also predispose an individual with immune deficiencies to the development of cancers. The host control of HPV infections thus involves local interactions between keratinocytes and the adaptive immune response. Effective immune detection and surveillance limits overt disease, leading to HPV persistence as productive microlesions or in a true latent state. PMID- 28919160 TI - Polycystic ovary syndrome in adolescents. AB - Polycystic ovary syndrome (PCOS) typically manifests with a combination of menstrual dysfunction and evidence of hyperandrogenism in the adolescent population. No single cause has been identified; however, evidence suggests a complex interplay between genetic and environmental factors. Polycystic ovary syndrome presents a particular diagnostic challenge in adolescents as normal pubertal changes can present with a similar phenotype. Management of PCOS in the adolescent population should focus on a multi-modal approach with lifestyle modification and pharmacologic treatment to address bothersome symptoms. This chapter outlines the pathogenesis of PCOS, including the effects of obesity, insulin resistance, genetic, and environmental factors. The evolution of the diagnostic criteria of PCOS as well as specific challenges of diagnosis in the adolescent population are reviewed. Finally, evidence for lifestyle modification and pharmacologic treatments are discussed. PMID- 28919161 TI - Magnetic resonance elastography of the brain: A comparison between pigs and humans. AB - Magnetic resonance elastography holds promise as a non-invasive, easy-to-use, in vivo biomarker for neurodegenerative diseases. Throughout the past decade, pigs have gained increased popularity as large animal models for human neurodegeneration. However, the volume of a pig brain is an order of magnitude smaller than the human brain, its skull is 40% thicker, and its head is about twice as big. This raises the question to which extent established vibration devices, actuation frequencies, and analysis tools for humans translate to large animal studies in pigs. Here we explored the feasibility of using human brain magnetic resonance elastography to characterize the dynamic properties of the porcine brain. In contrast to humans, where vibration devices induce an anterior posterior displacement recorded in transverse sections, the porcine anatomy requires a dorsal-ventral displacement recorded in coronal sections. Within these settings, we applied a wide range of actuation frequencies, from 40Hz to 90Hz, and recorded the storage and loss moduli for human and porcine brains. Strikingly, we found that optimal actuation frequencies for humans translate one to-one to pigs and reliably generate shear waves for elastographic post processing. In a direct comparison, human and porcine storage and loss moduli followed similar trends and increased with increasing frequency. When translating these frequency-dependent storage and loss moduli into the frequency-independent stiffnesses and viscosities of a standard linear solid model, we found human values of MU1=1.3kPa, MU2=2.1kPa, and eta=0.025kPas and porcine values of MU1=2.0kPa, MU2=4.9kPa, and eta=0.046kPas. These results suggest that living human brain is softer and less viscous than dead porcine brain. Our study compares, for the first time, magnetic resonance elastography in human and porcine brains, and paves the way towards systematic interspecies comparison studies and ex vivo validation of magnetic resonance elastography as a whole. PMID- 28919162 TI - miR-101-1 expression pattern in Qinchuan cattle and its role in the regulation of cell differentiation. AB - MiRNAs have emerged as key regulators of skeletal muscle development, but the knowledge of miRNAs in the molecular network of muscle development remains poorly understood. In this study, we designed to examine the biological function of bovine-miR-101-1. The bovine miR-101-1 was detected in the skeletal muscle of fetal, calf and adult cattle. Its abundance was significantly higher in the skeletal muscle of calf cattle than that in fetal and adult cattle. In the course of C2C12 myoblast differentiation, the expression of miR-101-1 gradually increased. Transfected the exogenous miR-101-1 into the C2C12 myoblast could decrease myotube formation, and the mRNA expression levels of the myogenic marker genes MyOD, MyOG and MyHC were up-regulated. The protein level of MyOD, MyOG and MyHC were also up-regulated. Through TargetScan to predict the target gene of bovine miR-101-1, and the dual luciferase system was used for target gene verification. The results show that amyloid precursor protein (APP) is the target gene of miR-101-1. Therefore, our results shed light on miR-101-1 in the regulation of the skeletal muscle development. PMID- 28919163 TI - Multiplex PCR and NGS-based identification of mRNA splicing variants: Analysis of BRCA1 splicing pattern as a model. AB - Alternative pre-mRNA splicing increases transcriptome plasticity by forming naturally-occurring alternative splicing variants (ASVs). Alterations of splicing processes, caused by DNA mutations, result in aberrant splicing and the formation of aberrant mRNA isoforms. Analyses of hereditary cancer predisposition genes reveal many DNA variants with unknown clinical significance (VUS) that potentially affect pre-mRNA splicing. Therefore, a comprehensive description of ASVs is an essential prerequisite for the interpretation of germline VUS in high risk individuals. To identify ASVs in a gene of interest, we have proposed an approach based on multiplex PCR (mPCR) amplification of all theoretically possible exon-exon junctions and subsequent characterization of size-selected and pooled mPCR products by next-generation sequencing (NGS). The efficiency of this method is illustrated by a comprehensive analysis of BRCA1 ASVs in human leukocytes, normal mammary, and adipose tissues and stable cell lines. We revealed 94 BRCA1 ASVs, including 29 variants present in all tested samples. While differences in the qualitative expression of BRCA1 ASVs among the analyzed human tissues were minor, larger differences were detected between tissue and cell line samples. Compared with other ASV analysis methods, this approach represents a highly sensitive and rapid alternative for the identification of ASVs in any gene of interest. PMID- 28919164 TI - Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis. AB - BACKGROUND: Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. METHODS: The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFbeta1 stimulated and specific miRNA inhibitor treated LX-2 cells. RESULTS: We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM-receptor interaction" were remarked significant (adjusted p<0.001). Genes enriched in these pathways coupled with their regulatory miRNAs formed a functional miRNA-gene regulatory module that contains 7 miRNAs, 22 genes and 42 miRNA-gene connections. Gene interaction analysis based on String database revealed that 8 out of 22 genes were highly clustered. Finally, we experimentally confirmed a functional regulatory module containing 5 miRNAs (miR-130b-3p, miR-148a-3p, miR-345-5p, miR 378a-3p, and miR-422a) and 6 genes (COL6A1, COL6A2, COL6A3, PIK3R3, COL1A1, CCND2) associated with liver fibrosis. CONCLUSIONS: Our integrated analysis of miRNA and gene expression profiles highlighted a functional miRNA-gene regulatory module associated with liver fibrosis, which, to some extent, may provide important clues to better understand the underlying pathogenesis of liver fibrosis. PMID- 28919165 TI - Validation of the Vectra H1 portable three-dimensional photogrammetry system for facial imaging. AB - Three-dimensional (3D) surface imaging using stereophotogrammetry has become increasingly popular in clinical settings, offering advantages for surgical planning and outcome evaluation. The handheld Vectra H1 is a low-cost, highly portable system that offers several advantages over larger stationary cameras, but independent technical validation is currently lacking. In this study, 3D facial images of 26 adult participants were captured with the Vectra H1 system and the previously validated 3dMDface system. Using error magnitude statistics, 136 linear distances were compared between cameras. In addition, 3D facial surfaces from each system were registered, heat maps generated, and global root mean square (RMS) error calculated. The 136 distances were highly comparable across the two cameras, with an average technical error of measurement (TEM) value of 0.84mm (range 0.19-1.54mm). The average RMS value of the 26 surface-to surface comparisons was 0.43mm (range 0.33-0.59mm). In each case, the vast majority of the facial surface differences were within a +/-1mm threshold. Areas exceeding +/-1mm were generally limited to facial regions containing hair or subject to facial microexpressions. These results indicate that 3D facial surface images acquired with the Vectra H1 system are sufficiently accurate for most clinical applications. PMID- 28919166 TI - Kinetic analysis of oxygen dynamics under a variable work rate. AB - Measurements of oxygen uptake are central to methods for the assessment of physical fitness and endurance capabilities in athletes. Two important parameters extracted from such data of incremental exercise tests are the maximal oxygen uptake and the critical power. A commonly accepted model of the dynamics of oxygen uptake during exercise at a constant work rate comprises a constant baseline oxygen uptake, an exponential fast component, and another exponential slow component for heavy and severe work rates. We have generalized this model to variable load protocols with differential equations that naturally correspond to the standard model for a constant work rate. This provides the means for predicting the oxygen uptake response to variable load profiles including phases of recovery. The model parameters have been fitted for individual subjects from a cycle ergometer test, including the maximal oxygen uptake and critical power. The model predictions have been validated by data collected in separate tests. Our findings indicate that the oxygen kinetics for a variable exercise load can be predicted using the generalized mathematical standard model. Such models can be applied in the field where the constant work rate assumption generally is not valid. PMID- 28919167 TI - Back off! The effect of emotion on backward step initiation. AB - The distance regulation (DR) hypothesis states that actors are inclined to increase their distance from an unpleasant stimulus. The current study investigated the relation between emotion and its effect on the control of backward step initiation, which constitutes an avoidance-like behavior. Participants stepped backward on a force plate in response to neutral, high arousing pleasant and high-arousing unpleasant visual emotional stimuli. Gait initiation parameters and the results of an exploratory analysis of postural sway were compared across the emotion categories using significance testing and Bayesian statistics. Evidence was found that gait initiation parameters were largely unaffected by emotional conditions. In contrast, the exploratory analysis of postural immobility showed a significant effect: highly arousing stimuli (pleasant and unpleasant) resulted in more postural sway immediately preceding gait initiation compared to neutral stimuli. This suggests that arousal, rather than valence, affects pre-step sway. These results contradict the DR hypothesis, since avoidance gait-initiation in response to unpleasant stimuli was no different compared to pleasant stimuli. PMID- 28919168 TI - Contribution of interaction torques during dart throwing: Differences between novices and experts. AB - We examined if experts and novices show different utilization of the torque components impulses during dart throwing. Participants threw darts continuously at a dartboard aiming for the centre (target bull's eye). The upper-limb joint torque impulses were obtained through inverse dynamics with anthropometric and motion capture data as input. Depending on the joint degree of freedom (DOF) and movement phase (acceleration and follow-through), three main strategies of net torque (NET) impulse generation through joint muscle (MUS) and interaction (INT) torque impulses were highlighted. Firstly, our results showed that the elbow flexion-extension DOF leads the movement according to the joint leading hypothesis. Then, considering the acceleration phase, the analysis revealed differences in torque impulse decomposition between expert and novices. For the glenohumeral (GH) joint abduction-adduction and for wrist flexion, the INT torque impulse contributed positively to NET joint torque impulse in the group of experts unlike novices. This allowed to lower the necessary MUS torque impulse at these DOFs. Also, GH axial rotation was actively controlled by muscle torque impulse in the group of experts. During the follow-through, the experts used the INT torque impulse more proficiently than novices to break the elbow extension. The comparison between experts and novices through inverse dynamics document the link between the exploitation of interaction torques impulses and expertise in dart throwing for which the main objective is precision rather than velocity. PMID- 28919169 TI - Persistent left superior vena cava: An unusual cause of curable pulmonary hypertension. PMID- 28919170 TI - Importation of travel-related infectious diseases is increasing in South Korea: An analysis of salmonellosis, shigellosis, malaria, and dengue surveillance data. AB - BACKGROUND: International travel has an important role in transmission of emerging infectious diseases. We described the imported infectious diseases in Korea from 2003 to 2012, and to analyze association of travels with the change in the incidences. METHODS: We used National Notifiable Disease Surveillance System to investigate the incidence of salmonellosis, shigellosis, malaria, and dengue. Data from Korea Tourism Organization was used to describe the inbound and outbound travelers by their age group, gender, and purpose of travel. We assessed association between international travel and the incidence of the infectious diseases, and seasonal variability. RESULTS: Among 1849 imported cases, dengue comprised the largest number with 631 cases. The proportion of imported cases among total cases gradually increased from 4.1% in 2003 to 30.3% in 2012 (P < 0.001). There was a positive correlation between the number of travelers and the number of imported cases of shigellosis, dengue (P < 0.001), but not for malaria. Seasonal variability was observed for importation of salmonellosis, shigellosis and dengue fever (P = 0.005). CONCLUSION: International travel was associated with the incidence of imported infectious diseases in Korea. Pre-travel consultation for international travelers planned to visit endemic area should be recommended strongly. PMID- 28919171 TI - Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications. AB - In the recent years, many studies have shown that MSCs must be stimulated by pro inflammatory cytokines or other immune mediators before they can modulate immune cells in inflamed and damaged tissues. MSCs appear to be involved in inducing several regulatory immune cells, such as Tregs, Bregs, and regulatory NK cells. This new immune milieu created by MSCs may establish a tolerogenic environment that leads to an optimal condition for the treatment of immune diseases. The mechanisms of MSC action to treat immune disorders need to be further investigated in more detail. Since there have been some contradictory outcomes of clinical trials, it is necessary to perform large-scale and randomized clinical studies, such as a phase 3 placebo-controlled double-blind study of a third party MSCs to optimize MSC administration and to prove safety and efficacy of MSC treatment. MSCs offer great therapeutic promise, especially for the treatment of difficult-to-treat immune diseases. PMID- 28919172 TI - Comments on the USPSTF draft recommendation statement on menopausal hormone therapy: Primary prevention of chronic conditions. PMID- 28919173 TI - Trigeminal system in Parkinson's disease: A potential avenue to detect Parkinson specific olfactory dysfunction. AB - BACKGROUND: Olfactory dysfunction (OD) is very frequent in Parkinson's disease (PD) and observed years before diagnosis. The trigeminal system, a chemosensory system allowing for the perception of spiciness, freshness, etc., is intimately connected to the olfactory system and although usually reduced in OD the trigeminal system is not well characterized in PD. We hypothesize that measuring trigeminal sensitivity potentially allows to discriminate between OD due to PD and OD due to other causes to potentially help the development of an early diagnostic tool. OBJECTIVE: To evaluate olfactory and trigeminal sensitivity and perception in PD patients and compare them to participants with non-parkinsonian OD (NPOD) and to healthy controls. METHODS: We assessed olfactory function using "Sniffin' Sticks test" and trigeminal function with the localization task in 28 PD patients, 27 healthy controls and 21 patients with OD unrelated to PD. RESULTS: PD patients exhibited significantly higher trigeminal sensitivity than NPOD patients (p = 0.002) and performed similar to healthy controls. In contrast, PD and NPOD patients had both similar olfactory scores, significantly below healthy controls. CONCLUSION: The trigeminal system seems not to be impaired in PD patients even in the presence of OD. Measuring trigeminal sensitivity may therefore allow to differentiate PD-related OD from other forms of OD. PMID- 28919174 TI - New NIH Regulations Say Most Basic Human Brain Research Is a Clinical Trial. AB - New NIH definitions classify virtually all human brain and behavioral research as clinical trials. The new definitions will change regulatory, reporting, and funding schemes for noninvasive studies such as neuroimaging. Resulting burdens threaten the viability of basic biobehavioral science research. PMID- 28919175 TI - Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters. AB - AMPARs mediate the briefest synaptic currents in the brain by virtue of their rapid gating kinetics. However, at the mossy fiber-to-unipolar brush cell synapse in the cerebellum, AMPAR-mediated EPSCs last for hundreds of milliseconds, and it has been proposed that this time course reflects slow diffusion from a complex synaptic space. We show that upon release of glutamate, synaptic AMPARs were desensitized by transmitter by >90%. As glutamate levels subsequently fell, recovery of transmission occurred due to the presence of the AMPAR accessory protein stargazin that enhances the AMPAR response to low levels of transmitter. This gradual increase in receptor activity following desensitization accounted for the majority of synaptic transmission at this synapse. Moreover, the amplitude, duration, and shape of the synaptic response was tightly controlled by plasma membrane glutamate transporters, indicating that clearance of synaptic glutamate during the slow EPSC is dictated by an uptake process. PMID- 28919176 TI - Different approaches to establish infertile rooster. AB - Several methods have been developed to suppress spermatogenesis in recipient males before spermatogonial stem cells (SSCs) transplantation. The aim of this study was to compare two different methods of depleting endogenous spermatogenesis in recipient ROSS 308 strain adult roosters. Gamma-radiation and alkylating agent busulfan were utilized to infertilize adult roosters (ROSS 308 strain). Two radiation therapy regimes (based on 60co isotope) were conducted locally to testes using 40Gy (5*8Gy with three-day intervals) and 30Gy (3*10Gy with three-day intervals). And two different levels of busulfan 60mg(40+20) and 50mg(30+20) with 10-day intervals were injected intraperitoneally. The results showed that both radiation therapy regimes and both busulfan levels reduced sperm motility and sperm concentration significantly compared with control group. Moreover, there were no significant differences between gamma radiation and busulfan treatments in progressive and total motility of sperm reduction. Sperm concentration reached to zero at the end of the 4th week of experiment in all treatment groups. Also histological examinations revealed that both treatments could significantly reduce the diameter of seminiferous tubules and thickness of epithelium. None of the treatments had significant effect on body weight in comparison with control group and the health status of experimental roosters remained good throughout the study. Given that, the risk probability of high doses of radiation exposure and busulfan, it can be concluded that the 30Gy (3*10Gy) and 50mg (30+20) are appropriate for suppression of endogenous spermatogenesis in mature roosters. PMID- 28919177 TI - Effects of GnRHR polymorphisms on sperm quality in Chinese water buffalo. AB - Gonadotropin-releasing hormone receptor (GnRHR) plays a critical physiological role in animal reproduction and is a potential marker for improving sperm quality. In the present study, eight SNPs (g.539T>C, g.640A>G, g.655T>C, g.707T>C, g.812A>G, g.18951A>T g.16867T>C and g.18953Indel GGCAAAGTAA) were detected in the GnRHR gene from one-hundred-sixty-five water buffalo by direct sequencing and identification of overlapping peaks. All SNPs were associated significantly with the ejaculate volume and two genes (g.655T>C and g.707T>C) were correlated with sperm abnormalities. Furthermore, three haplotypes (H1:TAI, H2:CT-, and H3:TT-) were identified by linkage disequilibrium analysis and were composed of four combined genotypes. Notably, buffalo with the combined genotypes H1H2 and H1H3 had the higher ejaculate volume compared to the other combined genotypes. Among the eight SNPs and four combined genotypes, the deletion of GGCAAAGTAA at position 18953bp in GnRHR was associated significantly with a higher ejaculate volume. Moreover, the GGCAAAGTAA deletion may lead to the miR8661 binding failure and subsequent changes in GnRHR gene expression. In the present study, we demonstrate that there is a significant association between SNPs in the GnRHR gene and the sperm ejaculate volume of Chinese water buffalo. To the best of our knowledge, this study is the first to address the association between the SNPs in the GnRHR gene and the sperm quality of Chinese buffalo. PMID- 28919178 TI - The presence of abalone egg-laying hormone-like peptide in the central nervous system and ovary of the Spotted Babylon, Babylonia areolata. AB - Recently, the neuronal classification of the ivory shell Spotted Babylon, Babylonia areolata, was readily demonstrated. Regarding its importance as marine economic molluscan species, the attempt to understand the neuroendocrine regulation is necessary. This study firstly demonstrated the neurosecretory cells as well as the existence and distribution of the egg-laying hormone (ELH)-like peptide in the central nervous system (CNS) and ovary of the B. areolata. The neurosecretory cell was characterized by the cytoplasmic purple dot-like structure as stained by the Gomori's paraldehyde fuchsin. Using the anti-abalone (a) ELH, we detected the aELH-like-peptide in neurons (Nr) and neurosecretory cells (Ns) of all ganglia including the cerebral, pleural, parietal, pedal and buccal ganglia. The aELH-like peptide was also present in the neuropil of each. It was noted that not all Ns presented the aELH-like peptide. In the ovary, the aELH-like peptide was slightly detected in early developing oocytes and strongly detected in late developing oocytes and follicular cells. This study firstly reported the evidence of ELH-like peptide in the CNS and ovary of the B. areolata. The molecular cloning as well as to investigate the function of ELH in this species is needed as it will be beneficial for future applications in aquaculture. PMID- 28919179 TI - Effects of nest-deprivation on hypothalamic mesotocin in incubating native Thai hens (Gallus domesticus). AB - Avian mesotocin (MT) is homologous to oxytocin in mammals. Native Thai chickens (Gallus domesticus) strongly express maternal behaviors including incubation and rearing. However, the role of MT during incubation behavior has never been studied. The objective of this study was to determine the physiological function(s) of the MTergic system in incubation behavior in native Thai chickens. The brains were collected from incubating (INC) and nest-deprived (ND) hens at different time points (days 3, 6, 8, 10, 14, 18, and 21; n=6). Immunohistochemistry technique was used to compare the numbers of MT immunoreactive (-ir) neurons between the INC and ND hens within the Nucleus supraopticus, pars ventralis (SOv), Nucleus preopticus medialis (POM), and Nucleus paraventricularis magnocellularis (PVN). The results revealed that the numbers of MT-ir neurons within the SOv, POM, and PVN remained high during the incubating stage. The number of MT-ir neurons in the SOv was lower than that of the POM and PVN. Disruption of incubation behavior by nest deprivation caused the numbers of MT-ir neurons within the SOv, POM, and PVN to decrease throughout the observation periods. For the first time, this study demonstrates that the MTergic system within the SOv, POM, and PVN may be involved with incubation behavior. In addition, these results further suggest that the MTergic neurons in these nuclei are not only regulated by rearing behavior but also might have a role in the initiation and maintenance of incubation behavior in this tropical species. PMID- 28919181 TI - Lymphadenectomy in Gleason 7 prostate cancer: Adherence to guidelines and effect on clinical outcomes. AB - BACKGROUND: To examine usage trends, guideline adherence, and survival data for patients undergoing lymphadenectomy (LND) at the time of radical prostatectomy (RP) for Gleason 7 prostate cancer (PCa). METHODS: The SEER database was queried for all patients with nonmetastatic biopsy Gleason 7 PCa from 2004 to 2013. Distribution and trends of LND were analyzed. The Memorial-Sloan Kettering Cancer Center nomogram was applied to stratify patients based on risk of nodal disease at time of RP (<5% risk or >=5% risk). Analyses were performed to determine covariates associated with LND receipt at time of RP and cancer-specific mortality (CSM). RESULTS: A total of 78,641 patients with either G34 or G43 PCa underwent RP (59,194 and 19,447, respectively). Of these patients, 61.2% of G34 and 73.5% of G43 patients underwent LND. During this 10-year period, the proportion of G43 patients undergoing LND remained relatively stable, whereas the proportion of G34 patients undergoing LND ranged between 55.9% and 67.9%. Regional differences were a predictor of LND receipt regardless of risk stratification, but did not translate to higher risk of CSM. Receipt of LND was not predictive of improved CSM in any of the cohorts analyzed. CONCLUSIONS: The role of LND for Gleason 7 prostate adenocarcinoma is not yet standardized, as indicated by the variability of LND dissection rates. Receipt of LND did not improve CSM, and in G43 patients, it predicted higher CSM. As the effect of LND on CSM is uncertain, further evaluation of oncologic benefit in this patient population is warranted. PMID- 28919182 TI - Population-based study of the incidence and survival for intraductal carcinoma of the prostate. AB - PURPOSE: The degree to which intraductal carcinoma of the prostate (IDC-P) affects clinical course remains poorly understood owing to small sample sizes from single-center studies. We sought to determine prognostic factors and outcomes associated with IDC-P in radical prostatectomy (RP) specimens. MATERIALS AND METHODS: This is a retrospective study of RP during 2004 to 2013 using Surveillance, Epidemiology, and End Results to compare IDC-P with non-IDC-P. The effect of IDC-P on overall and disease-specific survival was assessed using Cox regression with a median follow-up of 4.8 years (interquartile range [IQR]: 2.6 7.0y; P = 0.01). Median prostate-specific antigen at diagnosis in IDC-P vs. non IDC-P was similar (P = 0.23) at 6.2 (IQR: 4.6-13.0) vs. 6.1ng/ml (IQR: 4.6-9.8). RESULTS: We identified 159,777 RP from 2004 to 2013, and 242 (0.002%) had IDC-P pathologic features. IDC-P was associated with a greater likelihood of extraprostatic stage, pT3/T4, 45.9% vs. 21.6% (P<0.001), higher grade, GS>= 7, 79.3% vs. 62.7% (P<0.001), lymph node metastases, 5.8% vs. 2.4% (P<0.001), and positive surgical margins, 25.6% vs. 19.5% (P = 0.02). IDC-P was associated with a 3-fold increase in prostate cancer-specific mortality relative to non-IDC-P (hazard ratio = 3.0, 95% CI: 1.5-5.7; P<0.01). Limitations include retrospective design and potential underreporting of IDC-P that leads to underestimation of the true effect size. CONCLUSIONS: The significance of IDC-P features has been recently recognized by the World Health Organization and it is associated with high-grade, extraprostatic features, and worse prostate cancer-specific mortality. Understanding its prognostic significance better guides adjuvant therapies and clinical trials. PMID- 28919180 TI - Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency. AB - Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept. PMID- 28919183 TI - Impact of oral vitamin D supplementation on the ocular surface in people with dry eye and/or low serum vitamin D. AB - PURPOSE: To determine the possible association between serum vitamin D levels and dry eye symptoms, and the impact of an oral vitamin D supplement. METHODS: Three linked studies were performed. (i) 29 older adult participants, (ii) 29 dry eyed participants, and (iii) 2-month vitamin D supplementation for 32 dry eyed/low serum vitamin D levelled participants. All participants were assessed by the Ocular Surface Diseases Index (OSDI) to determine dry eye symptoms, and the phenol red thread test (PRT) and/or Schirmer's tear test, tear meniscus height, non-invasive tear break up time, grading ocular surface redness and fluorescein staining of the cornea to detect the tear quality and ocular surface conditions. Blood samples were collected for serum vitamin D analysis and interleukin-6 (IL 6) levels. RESULTS: Among older adult participants, vitamin D levels were negatively correlated with dry eye symptoms, the severity of dry eye, and associated with tired eye symptom. Vitamin D levels of people with dry eye diagnosis were not correlated with OSDI scores and IL-6 levels; while IL-6 levels showed correlation with tear production. In supplement study, vitamin D levels increased by 29mol/l, while dry eye symptoms and grading of corneal staining appeared significant reductions. No significant changes in IL-6 levels. CONCLUSIONS: Low vitamin D levels (<50nmol/l) were associated with dry eye symptoms in older individuals but not those diagnosed with dry eye. Vitamin D supplement increased the vitamin D levels, and improved dry eye symptoms, the tear quality and ocular surface conditions. PMID- 28919185 TI - Epidemiology of Cervical Spine Injuries in High School Athletes Over a Ten-Year Period. AB - BACKGROUND: More than 7 million athletes participate in high school sports annually, with both the benefits of physical activity and risks of injury. Although catastrophic cervical spine injuries have been studied, limited data are available that characterize less-severe cervical spine injuries in high school athletes. OBJECTIVE: To describe and compare cervical spine injury rates and patterns among U.S. high school athletes across 24 sports over a 10-year period. DESIGN: Descriptive epidemiology study. SETTING: National sample of high schools participating in the High School Reporting Information Online injury surveillance system. PARTICIPANTS: Athletes from participating schools injured in a school sanctioned practice, competition, or performance during the 2005-2006 through 2014-2015 academic years. METHODS: Cervical spine injury data captured by the High School Reporting Information Online system during the 10-year study period were examined. Cervical spine injury was defined as any injury to the cervical spinal cord, bones, nerves, or supporting structures of the cervical spine including muscles, ligaments, and tendons. MAIN OUTCOME MEASUREMENTS: Cervical spine injury rates, diagnoses, mechanisms, and severities. RESULTS: During the study period, 1080 cervical spine injuries were reported during 35,581,036 athlete exposures for an injury rate of 3.04 per 100,000 athlete exposures. Injury rates were highest in football (10.10), wrestling (7.42), and girls' gymnastics (4.95). Muscle injuries were most common (63.1%), followed by nerve injuries (20.5%). A larger proportion of football injuries were nerve injuries compared with all other sports (injury proportion ratio 3.31; confidence interval 2.33-4.72), whereas in boys' ice hockey fractures represented a greater proportion of injuries compared with all other sports (injury proportion ratio 7.64; confidence interval 2.10-27.83). Overall, the most common mechanisms of injury were contact with another player (70.7%) and contact with playing surface (16.1%). CONCLUSIONS: Cervical spine injury rates and patterns vary by sport and gender. Characterizing these differences is the first step in developing effective, evidence-based prevention guidelines. LEVEL OF EVIDENCE: IV. PMID- 28919184 TI - Clinical significance of failure to lose weight 10 years after roux-en-y gastric bypass. AB - BACKGROUND: Although Roux-en-Y gastric bypass (RYGB) induces short-term weight loss and co-morbidity amelioration, long-term data suggest that a subset of patients return to their preoperative body mass index (BMI). OBJECTIVES: To identify the clinical implications of 10-year weight loss failure after RYGB. SETTING: An academic teaching hospital. METHODS: Adults undergoing RYGB (1985 2004) were included in this study (n = 1087). Absolute weight loss failure was defined as <=0% reduction in excess BMI 10 years after surgery. Univariate analyses compared co-morbidity rates and resolution by weight loss classification. Multivariable regression modeling analyzed preoperative predictors of 10-year percent reduction in excess BMI and weight loss failure. RESULTS: Complete follow-up was available for 617 (57%) patients with a 10-year median percent reduction in excess BMI of 57.1%; 10.2% of patients had weight loss failure. Prevalence of all co-morbidities decreased, even in patients with weight loss failure (all P<.05). Compared with patients with successful weight loss, patients with weight loss failure had similar rates of resolution of pre existing co-morbidities, except for reduced resolution of apnea and cardiac co morbidities (both P<.05). Risk factors for weight loss failure included lower BMI, nongovernmental insurance, longer travel time to hospital, and year of surgery. Nongovernmental insurance (odds ratio 2.03, P = .036) conferred the highest adjusted odds of weight loss failure. CONCLUSIONS: The vast majority of patients experience dramatic health improvement 10 years after RYGB, even though some patients fail to maintain their weight loss. Renewed focus should be placed on prevention and treatment of chronic disease, with further investigation of weight loss independent mechanisms of health improvement. PMID- 28919186 TI - Nonsurgical Treatment of Delayed-Onset Brachial Plexopathy Due to Hypertrophic Clavicular Callus: A Case Report. AB - : Clavicular fractures are common injuries that traditionally are managed nonsurgically without clinically significant sequelae. However, they may develop hypertrophic callus formation that compresses the brachial plexus. These cases may present months to years after initial injury with varying degrees of pain, paresthesia, and weakness on the affected side and usually are treated by surgical resection of the hypertrophic callus. We present a case of brachial plexopathy due to hypertrophic clavicular callus causing weakness and paresthesia. The plexopathy was confirmed with imaging and electrodiagnostic studies. This case was unusual in that resolution of symptoms was achieved nonsurgically. LEVEL OF EVIDENCE: V. PMID- 28919187 TI - [Wolfram syndrome and juvenile glaucoma: Case report]. PMID- 28919188 TI - [Contribution of multimodal imaging in the various stages of Stargardt disease]. AB - PURPOSE: To describe the contribution of multimodal imaging in the various stages of Stargardt disease (STGD). PATIENTS AND METHODS: We retrospectively reviewed 46 eyes of 23 STGD patients with identified ABCA4 mutations. All patients underwent a complete ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), fluorescein angiography (FA) and Indocyanine green angiography (ICGA). RESULTS: The mean age of patients was 25.5 years (range 8-56). Fundus examination was normal in 2 patients (subclinical stage), where SD-OCT showed localized retrofoveolar retinal pigment epithelium (RPE) thickening. FAF was normal in 1 eye and showed mild heterogeneous hyper-FAF in 3 eyes. Twelve eyes had mild salt and pepper changes in the macula (early stage) with diffuse retinal atrophy on SD-OCT and mixed hyper and hypoautofluorescence on FAF. Nine patients showed central atrophy with white yellow flecks distributed in the posterior pole and mid-periphery. This phenotype showed total foveal atrophy on SD-OCT and normal peripapillary area on FAF. Twelve eyes had a large demarcated area of RPE atrophy, pigment clumping and migration extending to the peripheral retina associated with peripapillary atrophy. These eyes showed diffuse retinochoroidal atrophy on OCT with diffuse alterations reaching the peripapillary area on FAF. On FA, it was difficult to analyze the choroidal silence sign in patients with advanced stages of the disease. A hyperfluorescent window defect pattern was also found in patients with white-yellow flecks and did not correspond exactly to them, or to the areas of peripheral autofluorescent lesions. ICGA showed hypocyanescent areas seen at intermediate and late phases with multiple cyanescent points adjacent to them. On ICGA, hypocyanescent areas were more extensive than lesions observed on FAF. CONCLUSIONS: Multimodal imaging is helpful for the diagnosis of early stages of STGD disease and to better understand its pathophysiology. FAF and mostly SD-OCT have supplanted FA in the early, especially subclinical, stages. Over all, ICGA shows more extensive damage, making this tool useful for better understanding STGD and suggesting possible direct damage to the choriocapillaris associated with RPE lesions. In advanced stages, only DNA testing can confirm the diagnosis of STGD. PMID- 28919189 TI - [Limbal conjunctival autograft in pterygium surgery: Suture versus fibrin glue in 30 cases]. PMID- 28919190 TI - ROS1-rearranged Non-Small Cell Lung Cancers With Concomitant Oncogenic Driver Alterations: About Some Rare Therapeutic Dilemmas. PMID- 28919191 TI - Benefits of the Restorative Exercise and Strength Training for Operational Resilience and Excellence Yoga Program for Chronic Low Back Pain in Service Members: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: To examine the feasibility and preliminary effectiveness of an individualized yoga program. DESIGN: Pilot randomized controlled trial. SETTING: Military medical center. PARTICIPANTS: Patients (N=68) with chronic low back pain. INTERVENTIONS: Restorative Exercise and Strength Training for Operational Resilience and Excellence (RESTORE) program (9-12 individual yoga sessions) or treatment as usual (control) for an 8-week period. MAIN OUTCOME MEASURES: The primary outcome was past 24-hour pain (Defense & Veterans Pain Rating Scale 2.0). Secondary outcomes included disability (Roland-Morris Disability Questionnaire) and physical functioning and symptom burden (Patient-Reported Outcomes Measurement Information System-29 subscales). Assessment occurred at baseline, week 4, week 8, 3-month follow-up, and 6-month follow-up. Exploratory outcomes included the proportion of participants in each group reporting clinically meaningful changes at 3- and 6-month follow-ups. RESULTS: Generalized linear mixed models with sequential Bonferroni-adjusted pairwise significance tests and chi-square analyses examined longitudinal outcomes. Secondary outcome significance tests were Bonferroni adjusted for multiple outcomes. The RESTORE group reported improved pain compared with the control group. Secondary outcomes did not retain significance after Bonferroni adjustments for multiple outcomes, although a higher proportion of RESTORE participants reported clinically meaningfully changes in all outcomes at 3-month follow-up and in symptom burden at 6-month follow-up. CONCLUSIONS: RESTORE may be a viable nonpharmacological treatment for low back pain with minimal side effects, and research efforts are needed to compare the effectiveness of RESTORE delivery formats (eg, group vs individual) with that of other treatment modalities. PMID- 28919192 TI - Magnetic resonance index of activity (MaRIA) and Clermont score are highly and equally effective MRI indices in detecting mucosal healing in Crohn's disease. AB - BACKGROUND: Magnetic resonance index of activity (MaRIA) and Clermont score are currently the two main MRI indices that have been validated compared to endoscopy in Crohn's disease (CD). AIMS: To compare the accuracy of MaRIA and Clermont score in assessing CD mucosal healing. METHODS: Fourty-four CD patients underwent prospectively and consecutively MRI and colonoscopy. RESULTS: Considering 207 segments, MaRIA>7 and Clermont score>8.4 demonstrated substantial accuracy to detect endoscopic ulcerations (73.9% and 74.0%, respectively) and presented with high specificity (82.1% and 81.3%) and high negative predictive value (NPV) (82.1% and 82.4%) for MaRIA and Clermont score, respectively. The sensitivity for detecting deep ulcerations was 90.9% for both MaRIA>11 and Clermont score>12.5, with a specificity of 82.0% and 80.0%, respectively. Among 44 patients, deep MRI remission predicted mucosal healing with specificity=85.3% and NPV=85.3% according to Barcelona criteria (no segmental MaRIA>7), and specificity=88.2% and NPV=85.7% according to Clermont criteria (no segmental Clermont score>8.4). In addition, MRI remission predicted mucosal healing with specificity=76.5% and NPV=86.7% according to Barcelona criteria (no segmental MaRIA>11), and specificity=79.4% and NPV=84.4% according to Clermont criteria (no segmental Clermont score>12.5). CONCLUSION: MaRIA and Clermont score are equally effective in detecting CD endoscopic ulcerations supporting their use as therapeutic endpoints. PMID- 28919193 TI - Association analysis of genetic variants with metabolic syndrome components in the Moroccan population. AB - This study aimed to analyze the association between UBE2E2, G6PC2, PROX1, DUSP9, ADCY5 and APOC3 polymorphisms and the risk of metabolic syndrome (MetS) in Moroccan patients. The study was applied on 316 unrelated individuals from Morocco, 177 MetS patients and 139 controls. The metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. All subjects were genotyped for the following polymorphisms: rs7612463 (UBE2E2), rs560887 (G6PC2), rs340874 (PROX1), rs5945326 (DUSP9), rs11708067 (ADCY5) and rs5128 (APOC3) using TaqMan allelic discrimination assay and PCR-RFLP. The rs5128 (APOC3) and rs340874 (PROX1) polymorphisms were found to be significantly associated with susceptibility to MetS (P=0.003 and P=0.033, respectively), with odds ratios (ORs) of 4.39 (95% CI=1.66-11.56) and 2.81 (95% CI=1.09-7.27), respectively. Two variants presented a tendency to be protector factors against MetS risk: rs5945326 in DUSP9 gene (OR=0.32; 95% CI=0.17-0.62; =0.001) and rs11708067 in ADCY5 gene (OR=0.51; 95% CI=0.28-0.95; P=0.034). No association was detected between rs7612463 (UBE2E2) and rs560887 (G6PC2) SNPs and MetS increased risk. This study suggests a potential role of rs5128, rs340874, rs5945326 and rs11708067 variants in MetS susceptibility in the Moroccan population. PMID- 28919194 TI - Discovery and characterisation of an escherichia coli ST206 strain producing NDM 5 and MCR-1 from a patient with acute diarrhoea in China. PMID- 28919195 TI - Combination therapy vs. monotherapy for Gram-negative bloodstream infection: matching by predicted prognosis. AB - The utility of empirical combination antimicrobial therapy for Gram-negative bloodstream infection (BSI) remains unclear. This retrospective, quasi experimental matched cohort study examined the impact of empirical combination therapy on mortality in patients with Gram-negative BSI. Hospitalized adults with Gram-negative BSI from 1 January 2010 to 31 December 2013 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Patients receiving combination therapy or beta-lactam monotherapy were matched 1:1 based on age, sex and Bloodstream Infection Mortality Risk Score (BSIMRS). Multivariate Cox proportional hazards regression with propensity score adjustment was used to examine overall 28-day mortality and within predefined BSIMRS categories (<5 and >=5). A total of 380 patients receiving combination therapy or monotherapy for Gram-negative BSI were included in the study. Median age was 66 years and 204 (54%) were female. Overall, 28-day mortality in patients who received combination therapy and monotherapy was 13% and 15%, respectively (P = 0.51). After stratification by BSIMRS, mortality in both combination therapy and monotherapy groups was 1.1% in patients with BSIMRS <5 (P = 0.98) and 27% and 32%, respectively, in patients with BSIMRS >=5 (P = 0.47). After adjusting for propensity to receive combination therapy, risk of mortality was not significantly different for combination therapy compared to monotherapy (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.51-1.60). This finding persisted for both subgroups of BSIMRS <5 (HR 0.96, 95% CI 0.04-24.28) and BSIMRS >=5 (HR 0.83, 95% CI 0.46-1.48). There is no survival benefit from empirical combination therapy over monotherapy in patients with Gram-negative BSI, regardless of predicted prognosis at initial presentation. PMID- 28919196 TI - IncA/C plasmids conferring high azithromycin resistance in vibrio cholerae. AB - Azithromycin (AZM) is a clinically important antibiotic against Vibrio cholerae, especially for inhibiting V. cholerae colonisation of the intestine and for the treatment of severe cholera in children and pregnant women. An IncA/C plasmid was isolated from two high minimum inhibitory concentration (MIC) AZM-resistant V. cholerae strains of the two mainly pathogenic serogroups (O1 and O139) isolated in China. In the 172 predicted open reading frames (ORFs), 16 genes were related to antibiotic resistance, of which 5 were well-defined genes associated with macrolide resistance. The five macrolide resistance genes distributed in two clusters, mphR-mrx-mph(K) and mel-mph2, flanked by insertion sequence elements and involving two kinds of resistance mechanism. Deletion of the complete region of the two clusters deceased the AZM MIC from >=64 ug/mL to <=0.5 ug/mL. This IncA/C plasmid shows great ability to accumulate antibiotic resistance genes. In addition to 11 resistance genes to other antibiotics, 5 macrolide resistance genes with different function were gathered repeatedly through transposition on one plasmid. This genotype could not be simply explained by antibiotic stress applied on the host from the environment or treatment. These phosphorylases and transmembrane transporters might be involved in the transport and metabolism of other non-antibiotic substances, enabling this kind of plasmid to propagate better in the host. PMID- 28919197 TI - Imported poultry meat as a source of extended-spectrum cephalosporin-resistant CMY-2-producing Salmonella Heidelberg and Salmonella Minnesota in the European Union, 2014-2015. AB - Extended-spectrum cephalosporin (ESC)-resistant Salmonella have been described at a low level in the EU, nevertheless the increasing importation of poultry meat could be an important source of epidemic strains carrying ESC resistance genes. This study evaluated ESC resistance and its genetic platform among Salmonella isolates from poultry meat products imported into Portugal as well as clonal relatedness of the isolates. All Salmonella isolates recovered from samples of fresh meat destined for import into the EU in the scope of Portuguese official border control (2014-2015) were studied. Antibiotic susceptibility and beta lactamase production was determined by disk diffusion/microdilution. Molecular studies included detection of genes encoding acquired AmpC and extended-spectrum beta-lactamases, plasmid-mediated quinolone resistance and other antibiotic resistance genes by PCR/sequencing, and clonality by MLST and XbaI-PFGE. Plasmid characterisation was assessed by conjugation assays, replicon typing (PCR PBRT/pMLST) and hybridisation experiments (I-CeuI/S1-PFGE nuclease). Isolates belonged to Salmonella Heidelberg (n = 6; ST15/eBG26) and Salmonella Minnesota (n = 1; ST548/eBG77) and presented multidrug-resistant profiles, including to ESCs and/or fluoroquinolones. All but one carried blaCMY-2, located on two epidemic plasmids, IncA/C (ST2, n = 5) or transferable IncI1 (ST12, n = 1). Salmonella Heidelberg was associated with five PFGE types, including one similar to an American epidemic clone. This study reveals imported poultry products as a source of uncommon and/or invasive ESC-resistant Salmonella strains in the EU. The increase of clinically relevant poultry-related serotypes in Europe must be taken into account in the current monitoring of antibiotic resistance trends and in re evaluation of food regulations. PMID- 28919198 TI - Macitentan for treatment of CTEPH: why MERIT merits attention. PMID- 28919199 TI - Increasing confidence in the therapeutic relevance of eosinophils in severe asthma. PMID- 28919200 TI - Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. AB - BACKGROUND: Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor alpha monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with severe, uncontrolled asthma. We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories. METHODS: This study is a pooled analysis of the results from the randomised, double-blind, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase 3 studies. In these studies, patients with severe, uncontrolled asthma were randomly assigned (1:1:1) to receive subcutaneous benralizumab 30 mg, either every 4 weeks or every 8 weeks (with first three doses given every 4 weeks), or placebo every 4 weeks. The primary endpoint was annual exacerbation rate (AER) ratio versus placebo, analysed by baseline eosinophil counts (>=0, >=150, >=300, or >=450 cells per MUL) and by number of exacerbations (two vs three or more) during the year before enrolment. The analyses were done in accordance with the intention-to-treat principle. FINDINGS: Of 2295 patients, 756 received benralizumab every 4 weeks, 762 received benralizumab every 8 weeks, and 777 patients received placebo. AER among patients with baseline blood eosinophil counts of at least 0 cells per MUL was 1.16 (95% CI 1.05-1.28) in patients who received placebo versus 0.75 (0.66-0.84) in patients who received benralizumab every 8 weeks (rate ratio 0.64, 0.55-0.75; p<0.0001). In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per MUL, AER was 0.73 (0.65-0.82); rate ratio versus placebo was 0.63 (0.54-0.74; p<0.0001). The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups. Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations. INTERPRETATION: These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma. FUNDING: AstraZeneca. PMID- 28919202 TI - Parenting practices and overweight status of junior high school students in China: A nationally representative study of 19,487 students from 112 schools. AB - The study aimed to examine the level of parental responsiveness and demandingness for junior high students in China and its association with child weight status; assess if it differs by student socio-demographic characteristics; and to test the association between parenting and child physical activity. Nationally representative survey data collected from 19,487 students in 112 middle schools across China in 2013-2014 academic year were analyzed in 2016. Children's anthropometrics and perceptions of parenting practices were accessed by self administered questionnaire. Multilevel logistic regression models were fit to test the association controlling for child age, sex, school region, and parental education. The majority of adolescents reported their parents were highly responsive in terms of emotional support and involvement (high: 64.1% vs. low: 9.2%), although more parents were not perceived as highly demanding (high: 21.4% vs. low: 35.5%). Children were more likely to be overweight or obese if their parents were highly responsive (OR=1.4 [95%CI: 1.2,1.6]) and demanding (OR=1.1 [95%CI: 1.0,1.3]) compared to those with medium parenting scores. Older children, boys, children with highly educated parents, or in urban schools had greater odds of being overweight or obese by receiving highly responsive parenting compared to their counterparts. Children with highly demanding or responsive parenting had longer physical activity duration and higher physical activity participation rates than their counterparts. High responsiveness and demandingness among Chinese parents were associated with the risk of child overweight and obesity. Further research is needed to examine the causal relationship between parenting practices and childhood obesity in China. PMID- 28919201 TI - Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double blind, placebo-controlled study. AB - BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn.s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73.0% of baseline in the macitentan group and to 87.2% in the placebo group (geometric means ratio 0.84, 95% CI 0.70-0.99, p=0.041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd. PMID- 28919203 TI - Process, Mechanism, and Modeling in Macroecology. AB - Macroecology has traditionally relied on descriptive characterization of large scale ecological patterns to offer narrative explanations for the origin and maintenance of those patterns. Only recently have macroecologists begun to employ models termed 'process-based' and 'mechanistic', in contrast to other areas of ecology, where such models have a longer history. Here, we define and differentiate between process-based and mechanistic features of models, and we identify and discuss important advantages of working with models possessing such features. We describe some of the risks associated with process-based and mechanistic model-centered research programs, and we propose ways to mitigate these risks. Giving process-based and mechanistic models a more central role in research programs can reinvigorate macroecology by strengthening the link between theory and data. PMID- 28919204 TI - Understanding the Processes Underpinning Patterns of Phylogenetic Regionalization. AB - A key step in understanding the distribution of biodiversity is the grouping of regions based on their shared elements. Historically, regionalization schemes have been largely species centric. Recently, there has been interest in incorporating phylogenetic information into regionalization schemes. Phylogenetic regionalization can provide novel insights into the mechanisms that generate, distribute, and maintain biodiversity. We argue that four processes (dispersal limitation, extinction, speciation, and niche conservatism) underlie the formation of species assemblages into phylogenetically distinct biogeographic units. We outline how it can be possible to distinguish among these processes, and identify centers of evolutionary radiation, museums of diversity, and extinction hotspots. We suggest that phylogenetic regionalization provides a rigorous and objective classification of regional diversity and enhances our knowledge of biodiversity patterns. PMID- 28919206 TI - Pluripotency Surveillance by Myc-Driven Competitive Elimination of Differentiating Cells. AB - The mammalian epiblast is formed by pluripotent cells able to differentiate into all tissues of the new individual. In their progression to differentiation, epiblast cells and their in vitro counterparts, embryonic stem cells (ESCs), transit from naive pluripotency through a differentiation-primed pluripotent state. During these events, epiblast cells and ESCs are prone to death, driven by competition between Myc-high cells (winners) and Myc-low cells (losers). Using live tracking of Myc levels, we show that Myc-high ESCs approach the naive pluripotency state, whereas Myc-low ESCs are closer to the differentiation-primed state. In ESC colonies, naive cells eliminate differentiating cells by cell competition, which is determined by a limitation in the time losers are able to survive persistent contact with winners. In the mouse embryo, cell competition promotes pluripotency maintenance by elimination of primed lineages before gastrulation. The mechanism described here is relevant to mammalian embryo development and induced pluripotency. PMID- 28919205 TI - Adaptive Evolution Leads to Cross-Species Incompatibility in the piRNA Transposon Silencing Machinery. AB - Reproductive isolation defines species divergence and is linked to adaptive evolution of hybrid incompatibility genes. Hybrids between Drosophila melanogaster and Drosophila simulans are sterile, and phenocopy mutations in the PIWI interacting RNA (piRNA) pathway, which silences transposons and shows pervasive adaptive evolution, and Drosophila rhino and deadlock encode rapidly evolving components of a complex that binds to piRNA clusters. We show that Rhino and Deadlock interact and co-localize in simulans and melanogaster, but simulans Rhino does not bind melanogaster Deadlock, due to substitutions in the rapidly evolving Shadow domain. Significantly, a chimera expressing the simulans Shadow domain in a melanogaster Rhino backbone fails to support piRNA production, disrupts binding to piRNA clusters, and leads to ectopic localization to bulk heterochromatin. Fusing melanogaster Deadlock to simulans Rhino, by contrast, restores localization to clusters. Deadlock binding thus directs Rhino to piRNA clusters, and Rhino-Deadlock co-evolution has produced cross-species incompatibilities, which may contribute to reproductive isolation. PMID- 28919208 TI - Genetics of clubfoot; recent progress and future perspectives. AB - Clubfoot or talipes equinovarus (TEV) is an inborn three-dimensional deformity of leg, ankle and foot. It results from structural defects of several tissues of foot and lower leg leading to abnormal positioning of foot and ankle joints. TEV can lead to long-lasting functional disability, malformation and discomfort if left untreated. Substantial progress has been achieved in the management and diagnosis of limb defects; however, not much is known about the molecular players and signalling pathways underlying TEV disorder. The homeostasis and development of the limb depends on the complex interactions between the lateral plate mesoderm cells and outer ectoderm. These complex interactions include HOX signalling and PITX1-TBX4 pathways. The susceptibility to develop TEV is determined by a number of environmental and genetic factors, although the nature and level of interplay between them remains unclear. Familial occurrence and inter and intra phenotypic variability of TEV is well documented. Variants in genes that code for contractile proteins of skeletal myofibers might play a role in the aetiology of TEV but, to date, no strong candidate genes conferring increased risk have emerged, although variants in TBX4, PITX1, HOXA, HOXC and HOXD clusters genes, NAT2 and others have been shown to be associated with TEV. The mechanisms by which variants in these genes confer risk and the nature of the physical and genetic interaction between them remains to be determined. Elucidation of genetic players and cellular pathways underlying TEV will certainly increase our understanding of the pathophysiology of this deformity. PMID- 28919209 TI - New classification of histiocytosis. PMID- 28919207 TI - Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors. AB - Axonal targeting of signaling receptors is essential for neuronal responses to extracellular cues. Here, we report that retrograde signaling by target-derived nerve growth factor (NGF) is necessary for soma-to-axon transcytosis of TrkA receptors in sympathetic neurons, and we define the molecular underpinnings of this positive feedback regulation that enhances neuronal sensitivity to trophic factors. Activated TrkA receptors are retrogradely transported in signaling endosomes from distal axons to cell bodies, where they are inserted on soma surfaces and promote phosphorylation of resident naive receptors, resulting in their internalization. Endocytosed TrkA receptors are then dephosphorylated by PTP1B, an ER-resident protein tyrosine phosphatase, prior to axonal transport. PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a "gatekeeper" mechanism that ensures targeting of inactive receptors to axons to engage with ligand. In mice, PTP1B deletion reduces axonal TrkA levels and attenuates neuron survival and target innervation under limiting NGF (NGF+/-) conditions. PMID- 28919210 TI - Acute heart failure by senil systemic amyloidosis: Case report. PMID- 28919211 TI - Asymptomatic portal vein thrombosis associated to acute cytomegalovirus infection in an immunocompetent patient. PMID- 28919212 TI - Idiopathic relapsing acute pericarditis: Report of one case with favorable response to anakinra. PMID- 28919213 TI - Treatment and complications in acquired hemophilia A. Experience from a single center. PMID- 28919214 TI - Schmallenberg disease: Can it involve human beings? PMID- 28919215 TI - Thermo-responsive in-situ forming hydrogels as barriers to prevent post-operative peritendinous adhesion. AB - : In this study, we aimed to assess whether thermo-responsive in-situ forming hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) could prevent post operative peritendinous adhesion. The clinical advantages of the thermo responsive hydrogels are acting as barrier material to block penetration of fibroblasts, providing mobility and flexibility during application and enabling injection through a small opening to fill spaces of any shape after surgery. The thermo-responsiveness of hydrogels was determined to ensure their clinic uses. By grafting hydrophilic biopolymers chitosan (CS) and hyaluronic acid (HA) to PNIPAM, the copolymer hydrogels show enhanced water retention and lubrication, while reduced volume shrinkage during phase transition. In cell culture experiments, the thermo-responsive hydrogel has good biocompatibility and reduces fibroblast penetration. In animal experiments, the effectiveness of preventing post-operative peritendinous adhesion was studied in a rabbit deep flexor tendon model. From gross examination, histology, bending angles of joints, tendon gliding excursion and pull-out force, HA-CS-PNIPAM (HACPN) was confirmed to be the best barrier material to prevent post-operative peritendinous adhesion compared to PNIPAM and CS-PNIPAM (CPN) hydrogels and a commercial barrier film Seprafilm(r). There was no significant difference in the breaking strength of HACPN-treated tendons and spontaneously healed ones, indicating HACPN hydrogel application did not interfere with normal tendon healing. We conclude that HACPN hydrogel can provide the best functional outcomes to significantly prevent post operative tendon adhesion in vivo. STATEMENT OF SIGNIFICANCE: We prepared thermo responsive in-situ forming hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) to prevent post-operative peritendinous adhesion. The injectable barrier hydrogel could have better anti-adhesive properties than current commercial products by acting as barrier material to block penetration of fibroblasts, providing mobility and flexibility during application and enabling injection through a small opening to fill spaces of any shape after surgery. The effectiveness of preventing post-operative peritendinous adhesion was studied in a rabbit deep flexor tendon model. From gross examination, histology, bending angles of joints, tendon gliding excursion and pull-out force, HA-CS-PNIPAM (HACPN) was confirmed to be the best barrier material to prevent post-operative peritendinous adhesion compared to PNIPAM and CS-PNIPAM (CPN) hydrogels and a commercial barrier film Seprafilm(r). PMID- 28919216 TI - Transient left septal and anterior fascicular block associated with type 1 electrocardiographic Brugada pattern. AB - The left septal fascicular block (LSFB) or blockage of the middle fibers of the left bundle branch is probably caused mainly by - in the developed world - the proximal obstruction of the left anterior descending artery (LAD) before its first anterior septal perforator branch (S1). The association of transient LSFB and left anterior fascicular block (LAFB) - left bifascicular block - and the electrocardiographic type 1 Brugada pattern (BrP) has not been described in the literature yet. PMID- 28919217 TI - Population-based beat-to-beat QT analysis from Holter recordings in the long QT syndrome. AB - The increasing dissemination of wearable ECG recorders (e.g. Holter, patches, and strap sensors) enables the acquisition of large amounts of data during long periods of time. However, the clinical value of these long-term continuous recordings is hindered by the lack of automatic tools to extract clinically relevant information (other than non-sinus and life-threatening rhythms) from such long-term data, particularly when targeting population-based research. In this work, we propose and test a new tool for analyzing beat-to-beat interval measurements and extracting features from Holter ECGs. Specifically, we assess the adaptation of the QT interval following sudden changes in heart rate in the primary long QT types (1 & 2). We find that in long QT syndrome type 2, certain QT adaptation patterns can indicate a higher risk for cardiac events. PMID- 28919218 TI - Cardiologist's point of view: Novel ECG biomarkers and in silico models for proarrhythmic risk prediction: Are we ready? AB - The CiPA initiative is well underway, but in its early stages. Are we ready for it? There are several issues that bear on the success of this multidisciplinary effort related to (1) the final testing paradigm that will result, (2) the way in which discrepancies in test methods will be handled, (3) commercialization of the testing methods, (4) quantitative understanding of arrhythmia risk of the 6 non hERG channels being tested, (5) validity of the CiPA drug list, and (6) ultimate clinical validation. PMID- 28919219 TI - Maria Carolina Elias: Parasites with Dynamic Genomes. PMID- 28919220 TI - Peucedanum japonicum extract attenuates allergic airway inflammation by inhibiting Th2 cell activation and production of pro-inflammatory mediators. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Peucedanum japonicum Thunberg is traditionally used to treat coughs, colds, headache and inflammatory diseases in Korea and Japan. Its effects on allergic lung inflammation have not been investigated. AIM OF THE STUDY: To investigate the anti-asthmatic effects of Peucedanum japonicum extract (PJE) using a murine model of asthma and a lipopolysaccharide (LPS)-stimulated macrophage cell line. MATERIALS AND METHODS: Mice underwent two rounds of sensitization with ovalbumin 1 week apart followed by four intranasal ovalbumin challenges on days 13-16. The control group received saline only. Two ovalbumin-sensitized groups were orally administered vehicle or PJE (200mg/kg) 5 days a week starting 1 week before the first ovalbumin sensitization. The third group was orally administered the asthma medication Montelukast (10mg/kg) on days 12-16. All animals were sacrificed on day 17. The lungs were assessed for histological features, inflammatory cell infiltration, Th2 cell activation and GATA-binding protein-3 (GATA-3) expression. The bronchoalveolar lavage fluid (BALF) was assessed for type 2 cytokine levels. The effect of PJE on the in vitro Th2 polarization of naive CD4+ splenocytes and the production of pro-inflammatory mediators and cytokines by LPS-stimulated RAW 264.7 cells was evaluated. RESULTS: PJE treatment inhibited OVA-induced inflammatory cell infiltration, eosinophilia, Th2 activation, and GATA-3 expression in the lung, reduced the interleukin (IL)-5 and IL-13 levels in BALF, down-regulated Th2 activation in vitro, and inhibited the macrophage production of inducible nitric oxide, cyclooxygenase-2, tumor necrosis factor-alpha, and IL 6. CONCLUSION: PJE attenuated allergic airway inflammation by inhibiting Th2 cell activation and macrophage production of inflammatory mediators. Peucedanum japonicum may be candidate therapy for allergic lung inflammation. PMID- 28919221 TI - Ten Year Projections for US Residency Positions: Will There be Enough Positions to Accommodate the Growing Number of U.S. Medical School Graduates? AB - OBJECTIVE: Recently, a multitude of new U.S. medical schools have been established and existing medical schools have expanded their enrollments. The National Residency Match Program (NRMP) reports that in 2016 there were 23,339 categorical residency positions offered in the match and 26,836 overall applicants with 17,789 (66.29%) of the total candidates being U.S. allopathic graduates. In view of the rapid growth of medical school graduates, the aim of this study is to determine if current trends suggest a shortage of residency positions within the next ten years. DESIGN: The total number of graduates from U.S. medical schools was obtained from the Association of American Medical Colleges (AAMC) for 2005-2014 academic years and was trended linearly for a 10 year prediction for the number of graduates. The yearly number of categorical positions filled by U.S. graduates for calendar years 2006-2015 was obtained from the NRMP and was trended longitudinally 10 years into the future. Analysis of subspecialty data focused on the comparison of differences in growth rates and potential foreseeable deficits in available categorical positions in U.S. residency programs. RESULTS: According to trended data from AAMC, the total number of graduates from U.S. medical schools has increased 1.52 percent annually (15,927 in 2005 to 18,705 in 2014); with a forecast of 22,280 U.S. medical school graduates in 2026. The growth rate of all categorical positions available in U.S. residency programs was 2.55 percent annually, predicting 29,880 positions available in 2026. In view of these results, an analysis of specific residencies was done to determine potential shortages in specific residencies. With 17.4 percent of all U.S. graduates matching into internal medicine and a 3.17 percent growth rate in residency positions, in 2026 the number of internal medicine residency positions will be 9,026 with 3,874 U.S. graduates predicted to match into these positions. In general surgery, residency positions note a growth rate of 1.55 percent. Of all U.S. graduates, 5.6 percent match into general surgery. Overall this projects 1,445 general surgery residency positions in 2026 with 1,257 U.S. graduates matching. In orthopedics with a growth rate of 1.35 percent and a match rate of 3.75 percent, there are projected to be 827 positions available with 836 U.S. graduates projected to match. CONCLUSIONS: Despite the increasing number of medical school graduates, our model suggests the rate of growth of residency positions continues to be higher than the rate of growth of U.S. medical school graduates. While there is no apparent shortage of categorical positions overall, highly competitive subspecialties like orthopedics may develop a shortage within the next ten years. PMID- 28919222 TI - Understanding active sampling strategies: Empirical approaches and implications for attention and decision research. AB - In natural behavior we actively gather information using attention and active sensing behaviors (such as shifts of gaze) to sample relevant cues. However, while attention and decision making are naturally coordinated, in the laboratory they have been dissociated. Attention is studied independently of the actions it serves. Conversely, decision theories make the simplifying assumption that the relevant information is given, and do not attempt to describe how the decision maker may learn and implement active sampling policies. In this paper I review recent studies that address questions of attentional learning, cue validity and information seeking in humans and non-human primates. These studies suggest that learning a sampling policy involves large scale interactions between networks of attention and valuation, which implement these policies based on reward maximization, uncertainty reduction and the intrinsic utility of cognitive states. I discuss the importance of using such paradigms for formalizing the role of attention, as well as devising more realistic theories of decision making that capture a broader range of empirical observations. PMID- 28919223 TI - Assumptions behind scoring source and item memory impact on conclusions about memory: A reply to Kellen and Singmann's comment (2017). PMID- 28919224 TI - Clinical factors associated with the yield of routine outpatient scalp electroencephalograms: A retrospective analysis from a tertiary hospital. AB - The routine outpatient electroencephalogram (EEG) is most often used in the diagnosis and classification of epilepsy. The diagnostic yield of outpatient EEGs is low and the clinical factors contributing to the EEG outcome have not been well established. In this study, we sought to determine the yield and the factors predicting the EEG outcome. We retrospectively analyzed 1092 routine adult EEGs that were performed in a tertiary referral center over a period of 1year. Patient demographics, sources of referral, and indications for EEG were recorded. The majority of the referrals were from neurologists (54.7%), followed by the emergency department (15.4%). The indications for requesting an EEG included patients with a provisional or established diagnosis of epilepsy (56.3%), first seizure (10.7%), and seizure mimickers (29.1%). The majority (66.7%) of the EEGs were normal, whereas 13.2% demonstrated epileptiform discharges. At the time of recording, epileptic seizures occurred in 0.6% of the cases. With logistic regression analysis, three factors were found to be significantly associated with an abnormal (epileptiform) EEG: no antiepileptic drug therapy, the age of the patient, and indication for EEG (pre-test provisional diagnosis). Patients who are not on antiepileptic drug therapy and with a diagnosis of epilepsy or seizures are more likely to have epileptiform abnormalities in EEGs. Our findings suggest that careful selection of patients is likely to improve the diagnostic yield and cost-effectiveness of routine outpatient EEG. PMID- 28919225 TI - A comparative cost analysis of the Vaccination Program for US-bound Refugees. AB - BACKGROUND: Vaccination Program for US-bound Refugees (VPR) currently provides one or two doses of some age-specific Advisory Committee on Immunization Practices (ACIP)-recommended vaccines to US-bound refugees prior to departure. METHODS: We quantified and compared the full vaccination costs for refugees using two scenarios: (1) the baseline of no VPR and (2) the current situation with VPR. Under the first scenario, refugees would be fully vaccinated after arrival in the United States. For the second scenario, refugees would receive one or two doses of selected vaccines before departure and complete the recommended vaccination schedule after arrival in the United States. We evaluated costs for the full vaccination schedule and for the subset of vaccines provided by VPR by four age stratified groups; all costs were reported in 2015 US dollars. We performed one way and probabilistic sensitivity analyses and break-even analyses to evaluate the robustness of results. RESULTS: Vaccination costs with the VPR scenario were lower than costs of the scenario without the VPR for refugees in all examined age groups. Net cost savings per person associated with the VPR were ranged from $225.93 with estimated Refugee Medical Assistance (RMA) or Medicaid payments for domestic costs to $498.42 with estimated private sector payments. Limiting the analyses to only the vaccines included in VPR, the average costs per person were 56% less for the VPR scenario with RMA/Medicaid payments. Net cost savings with the VPR scenario were sensitive to inputs for vaccination costs, domestic vaccine coverage rates, and revaccination rates, but the VPR scenario was cost savings across a range of plausible parameter estimates. CONCLUSIONS: VPR is a cost saving program that would also reduce the risk of refugees arriving while infected with a vaccine preventable disease. PMID- 28919226 TI - Validation of HAV biomarker 2A for differential diagnostic of hepatitis A infected and vaccinated individuals using multiplex serology. AB - BACKGROUND: Worldwide about 1.5 million clinical cases of hepatitis A virus (HAV) infections occur every year and increasingly countries are introducing HAV vaccination into the childhood immunization schedule with a single dose instead of the originally licenced two dose regimen. Diagnosis of acute HAV infection is determined serologically by anti-HAV-IgM detection using ELISA. Additionally anti HAV-IgG can become positive during the early phase of symptoms, but remains detectable after infection and also after vaccination against HAV. Currently no serological marker allows the differentiation of HAV vaccinated individuals and those with a past infection with HAV. Such differentiation would greatly improve evaluation of vaccination campaigns and risk assessment of HAV outbreaks. Here we tested the HAV non-structural protein 2A, important for the capsid assembly, as a biomarker for the differentiation of the immune status in previously infected and vaccinated individuals. METHODS: HAV antigens were recombinantly expressed as glutathione-S-transferase (GST) fusion proteins. Using glutathione tagged, magnetic fluorescent beads (Luminex(r)), the proteins were affinity purified and used in a multiplex serological assay. The multiplex HAV assay was validated using 381 reference sera in which the immune status HAV negative, vaccinated or infected was established using the Abbott ARCHITECT(r) HAVAb-IgM or IgG, the commercial HAV ELISA from Abnova and documentation in vaccination cards. RESULTS: HAV multiplex serology showed a sensitivity of 99% and specificity of 95% to detect anti-HAV IgG/IgM positive individuals. HAV biomarker 2A allowed the differentiation between previously infected and vaccinated individuals. HAV vaccinated individuals and previously infected individuals could be identified with 92% accuracy. CONCLUSION: HAV biomarker 2A can be used to differentiate between previously HAV-vaccinated and naturally infected individuals. Within a multiplex serological approach this assay can provide valuable novel information in the context of outbreak investigations, longitudinal population based studies and evaluations of immunization campaigns. PMID- 28919227 TI - Asymptomatic Ischemic Risks in Microsurgical Clipping for Unruptured Intracranial Aneurysms in Anterior Circulation. AB - BACKGROUND: The ischemic risk in prophylactic treatments of unruptured intracranial aneurysms (UIAs) is a serious health concern. OBJECTIVE: The aim of this study was to elucidate the incidence and characteristics of ischemic events in microsurgical clipping of anterior circulation UIAs. METHODS: Ischemic events were prospectively evaluated before and after surgery between April 2011 and March 2017. The location, volume, minimum value of apparent diffusion coefficient in high-intensity spots (HIS) on 3-T magnetic resonance diffusion-weighted imaging (DWI), and radiographic outcomes were analyzed. The relationships between DWI positivity and patient demographics, surgical procedures, and intraoperative vessel features were assessed. RESULTS: Overall, 78 consecutive patients including 29 men and 49 women (median age, 62 years; range, 24-77 years) with 99 UIAs were analyzed. A total of 10 in 78 craniotomies (13%) detected HIS on DWI, which were all asymptomatic. Seventeen HIS were shown, 5 of which were located in the basal ganglia, 6 in the white matter, and 6 in the cortex. The volume and minimum value of apparent diffusion coefficient were 180.4 +/- 31.2 mm3 and 0.56 +/- 0.03 * 10-3 mm2/second, respectively. Radiographic outcomes at follow-up showed that 71% of HIS on DWI led to irreversible brain ischemia. The maximum diameter of aneurysms, atherosclerotic features of the aneurysm wall, and procedure-related factors were associated with DWI positivity. CONCLUSIONS: The asymptomatic ischemic risk associated with microsurgical clipping was not low and most lesions were irreversible. Although the mechanism could be various, the use of clips for atherosclerosis of the aneurysm and/or parental vessels requires much attention. PMID- 28919228 TI - Stereoscopic Three-Dimensional Neuroanatomy Lectures Enhance Neurosurgical Training: Prospective Comparison with Traditional Teaching. AB - OBJECTIVE: Stereoscopic three-dimensional (3D) imaging is increasingly used in the teaching of neuroanatomy and although this is mainly aimed at undergraduate medical students, it has enormous potential for enhancing the training of neurosurgeons. This study aims to assess whether 3D lecturing is an effective method of enhancing the knowledge and confidence of neurosurgeons and how it compares with traditional two-dimensional (2D) lecturing and cadaveric training. METHODS: Three separate teaching sessions for neurosurgical trainees were organized: 1) 2D course (2D lecture + cadaveric session), 2) 3D lecture alone, and 3) 3D course (3D lecture + cadaveric session). Before and after each session, delegates were asked to complete questionnaires containing questions relating to surgical experience, anatomic knowledge, confidence in performing procedures, and perceived value of 3D, 2D, and cadaveric teaching. RESULTS: Although both 2D and 3D lectures and courses were similarly effective at improving self-rated knowledge and understanding, the 3D lecture and course were associated with significantly greater gains in confidence reported by the delegates for performing a subfrontal approach and sylvian fissure dissection. CONCLUSIONS: Stereoscopic 3D lectures provide neurosurgical trainees with greater confidence for performing standard operative approaches and enhances the benefit of subsequent practical experience in developing technical skills in cadaveric dissection. PMID- 28919229 TI - Early Outcomes of Endoscopic Contralateral Foraminal and Lateral Recess Decompression via an Interlaminar Approach in Patients with Unilateral Radiculopathy from Unilateral Foraminal Stenosis. AB - OBJECTIVE: Percutaneous endoscopic contralateral interlaminar lumbar foraminotomy (PECILF) for lumbar degenerative spinal stenosis is an established procedure. Better preservation of contralateral facet joint compared with that of the approach side has been shown with uniportal bilateral decompression. The aim of this retrospective case series was to analyze the early clinical and radiologic outcomes of stand-alone contralateral foraminotomy and lateral recess decompression using PECILF. METHODS: Twenty-six consecutive patients with unilateral lower limb radiculopathy underwent contralateral foraminotomy and lateral recess decompression using PECILF. Their clinical outcomes were evaluated with visual analog scale leg pain score, Oswestry Disability Index, and the MacNab criteria. Completeness of decompression was documented with a postoperative magnetic resonance imaging. RESULTS: Mean age for the study group was 62.9 +/- 9.2 years and the male/female ratio was 4:9. A total of 30 levels were decompressed, with 18 patients (60%) undergoing decompression at L4-L5, 9 at L5-S1 (30%), 2 at L3-L4 (6.7%), and 1 at L2-L3 (3.3%). Mean estimated blood loss was 27 +/- 15 mL per level. Mean operative duration was 48 +/- 12 minutes/level. Visual analog scale leg score improved from 7.7 +/- 1 to 1.8 +/- 0.8 (P < 0.0001). Oswestry Disability Index improved from 64.4 +/- 5.8 to 21 +/- 4.5 (P < 0.0001). Mean follow-up of the study was 13.7 +/- 2.7 months. According to the MacNab criteria, 10 patients (38.5%) had good results, 14 patients (53.8%) had excellent results, and 2 patients (7.7%) had fair results. One patient required revision surgery. CONCLUSIONS: Facet-preserving contralateral foraminotomy and lateral recess decompression with PECILF is effective for treatment of lateral recess and foraminal stenosis. Thorough decompression with acceptable early clinical outcomes and minimal perioperative morbidity can be obtained with the contralateral endoscopic approach. PMID- 28919230 TI - Morbidity and Mortality of Meningioma Resection Increases in Octogenarians. AB - BACKGROUND: The incidence of meningioma has increased drastically recently, particularly in older adults. Surgical intervention has the potential to reduce neurologic symptoms and achieve favorable, long-term outcomes. There is considerable variability in the literature examining the relationship between age and outcomes after meningioma surgery. The objective of this study was to identify the relationship between age and postoperative complications after craniotomy for resection of meningioma. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify patients undergoing craniotomy for meningioma resection between 2005 and 2012. Multivariate analysis was used to identify associations between age and postoperative complications. RESULTS: Age >80 years is an independent risk factor for any complication (odds ratio [OR], 2.374; 95% confidence interval [CI], 1.3 4.4; P = 0.015), death within 30 days of surgery (OR, 15.7; 95% CI, 3.0-81.0; P < 0.001), and length of stay >5 days (OR, 3.2; 95% CI, 1.8-5.6; P < 0.001). CONCLUSIONS: Advanced age, particularly >80 years, is an independent predictor of morbidity and mortality in patients undergoing craniotomy for resection of meningioma. As such, it should be considered in preoperative optimization and risk stratification. PMID- 28919231 TI - A Tortuous Process of Surgical Treatment for a Large Calcified Chronic Subdural Hematoma. AB - BACKGROUND: Calcified chronic subdural hematoma (CCSDH) is a rare disease for which no standard approach to treatment has been established. Reports covering both burr hole trepanation and craniotomy for CCSDH are rare. Furthermore, infection of CCSDH after the burr hole trepanation has not been reported in the literature. CASE DESCRIPTION: A 61-year-old man presented with left frontotemporoparietal CCSDH demonstrated on computed tomography (CT) scan. The patient underwent 2 separate burr hole trepanations with intraoperative irrigation and postoperative drainage. These procedures led to infection of the CCSDH. The patient eventually underwent an open craniotomy to provide complete removal of the hematoma. CONCLUSIONS: Owing to the complex contents of a CCSDH, burr hole trepanation cannot adequately drain the hematoma or relieve the mass effect. Craniotomy is a much more reliable approach for achieving complete resection of a CCSDH. PMID- 28919232 TI - Accuracy of Shape Irregularity and Density Heterogeneity on Noncontrast Computed Tomography for Predicting Hematoma Expansion in Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: This systematic review and meta-analysis was aimed to evaluate the predictive values of shape irregularity and density heterogeneity of hematoma on noncontrast computed tomography (NCCT) for hematoma expansion (HE). METHODS: A literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library. Studies about predictive values of shape regularity or density heterogeneity of hematoma on NCCT for HE in spontaneous intracerebral hemorrhage were included. Meta-analysis was performed to pool the data. Publication bias assessment, subgroup analysis, and univariate meta-regression were conducted. RESULTS: A total of 7 studies with 2294 patients were included. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of shape irregularity were 67%, 47%, 1.30, and 0.71, respectively. In contrast, the pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of density irregularity were 52%, 69%, 1.70, and 0.69, respectively. CONCLUSIONS: Considering the relatively low sensitivity and specificity, the predictive values of shape irregularity and density heterogeneity of hematoma for HE are limited. Further studies are still needed to find optimal NCCT predictors for HE in spontaneous intracerebral hemorrhage patients. PMID- 28919233 TI - Craniospinal Germinomas in Patient with Down Syndrome Successfully Treated with Standard-Dose Chemotherapy and Craniospinal Irradiation: Case Report and Literature Review. AB - BACKGROUND: Patients with Down syndrome (DS) are more likely to develop chemotherapy-related complications. The standard treatment for these patients with cancer has not yet been established, and the risks of standard chemotherapy are unclear. In this paper, a rare case of multiple craniospinal germinomas in a patient with DS, which was successfully treated with standard-dose chemotherapy combined with craniospinal irradiation, is reported. CASE DESCRIPTION: The authors report a case of multiple craniospinal germinomas in a DS patient who presented with bilateral oculomotor and facial nerve palsy and hearing loss. The patient underwent 3 courses of combination chemotherapy using a standard dose of carboplatin and etoposide and 23.4 Gy of concurrent craniospinal irradiation. Posttreatment magnetic resonance imaging showed reduction of the tumors. Both fluorodeoxyglucose- and methionine-positron emission tomography demonstrated no uptake in the residual tumors. Follow-up magnetic resonance imaging and positron emission tomography did not reveal tumor recurrence for 18 months. CONCLUSIONS: As far as we know, this is the first case of multiple craniospinal germinomas in a patient with DS who achieved a successful treatment result without fatal adverse events. The literature review indicated that disseminated germinomas may need intensive treatment to reduce recurrence risk. However, intensive chemotherapy using a combination of 3 or more anticancer drugs can increase the rate of treatment-related death during the early stage. Our case indicated that multiple craniospinal germinoma of DS patients could be treated with a standard dose of carboplatin and etoposide regimen with concurrent craniospinal irradiation along with appropriate supportive therapy and careful observation. PMID- 28919235 TI - Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking. AB - Alzheimer's disease is characterized by the self-assembly of tau and amyloid beta proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino-acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fiber diffraction, we have characterized the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulfide formation to fibril formation, we have compared the assembly of tau(297 391) under reduced and non-reducing conditions and for truncated tau carrying a C322A substitution. We show that disulfide bond formation inhibits filament assembly and that the C322A variant rapidly forms long and highly ordered PHFs. PMID- 28919234 TI - Effects of Periplasmic Chaperones and Membrane Thickness on BamA-Catalyzed Outer Membrane Protein Folding. AB - The biogenesis of outer-membrane proteins (OMPs) in gram-negative bacteria involves delivery by periplasmic chaperones to the beta-barrel assembly machinery (BAM), which catalyzes OMP insertion into the outer membrane. Here, we examine the effects of membrane thickness, the Escherichia coli periplasmic chaperones Skp and SurA, and BamA, the central subunit of the BAM complex, on the folding kinetics of a model OMP (tOmpA) using fluorescence spectroscopy, native mass spectrometry, and molecular dynamics simulations. We show that prefolded BamA promotes the release of tOmpA from Skp despite the nM affinity of the Skp:tOmpA complex. This activity is located in the BamA beta-barrel domain, but is greater when full-length BamA is present, indicating that both the beta-barrel and polypeptide transport-associated (POTRA) domains are required for maximal activity. By contrast, SurA is unable to release tOmpA from Skp, providing direct evidence against a sequential chaperone model. By varying lipid acyl chain length in synthetic liposomes we show that BamA has a greater catalytic effect on tOmpA folding in thicker bilayers, suggesting that BAM catalysis involves lowering of the kinetic barrier imposed by the hydrophobic thickness of the membrane. Consistent with this, molecular dynamics simulations reveal that increases in membrane thinning/disorder by the transmembrane domain of BamA is greatest in thicker bilayers. Finally, we demonstrate that cross-linking of the BamA barrel does not affect tOmpA folding kinetics in 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) liposomes, suggesting that lateral gating of the BamA barrel and/or hybrid barrel formation is not required, at least for the assembly of a small 8-stranded OMP in vitro. PMID- 28919236 TI - Biomarkers for diagnosis of Pediatric Acute Neuropsychiatric Syndrome (PANS) - Sensitivity and specificity of the Cunningham Panel. AB - OBJECTIVE: Pediatric Acute Neuropsychiatric Syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are conditions marked by sudden onset of obsessive-compulsive disorder (OCD), tics, or avoidant/restrictive food intake in combination with multiple psychiatric symptoms. A diagnosis of PANS or PANDAS may be supported by the Cunningham Panel, a commercially available set of immunologic assays currently in clinical use. However, the relationship between Cunningham Panel results and patient symptoms remains unclear. This study was done to assess the diagnostic accuracy of the Cunningham Panel in patients with suspected PANS or PANDAS. METHOD: All Swedish patients who had taken the Cunningham Panel prior to June 2014 (n=154) were invited and 53 patients participated in the study. Based on comprehensive psychiatric assessment (the reference standard of diagnosis), subjects were classified as PANS, PANDAS, or neither. Prior Cunningham Panel test results were collected from patient records, and new blood samples were similarly analyzed within the scope of this study. In addition, results were compared to healthy controls (n=21) and a test-retest reliability analysis was performed. RESULTS: Sensitivities of individual biomarkers in the Cunningham Panel ranged from 15 to 60%, and specificities from 28 to 92%. Positive predictive values ranged from 17 to 40%, and negative predictive values from 44 to 74%. A majority of the healthy controls had pathological Cunningham Panel results and test-retest reliability proved insufficient. CONCLUSION: Clinical use of the Cunningham Panel in diagnosing PANS or PANDAS is not supported by this study. PMID- 28919237 TI - Inflammatory responses in Multiple Sclerosis normal-appearing white matter and in non-immune mediated neurological conditions with wallerian axonal degeneration: A comparative study. AB - Inflammatory-like changes in the white matter (WM) are commonly observed in conditions of axonal degeneration by different etiologies. This study is a systematic comparison of the principal features of the inflammatory-like changes in the WM in different pathological conditions characterized by axonal damage/degeneration, focusing in particular on Multiple Sclerosis (MS) normal appearing white matter (NAWM) compared to non immune-mediated disorders. The study was performed on sections of NAWM from 15 MS cases, 11 cases of non immune mediated disorders with wallerian axonal degeneration (stroke, trauma, amyotrophic lateral sclerosis), 3 cases of viral encephalitis, 6 control cases. Common features of the inflammatory-like changes observed in all of the conditions of WM pathology were diffuse endothelial expression of VCAM-1, microglial activation with expression of M2 markers, increased expression of sphingosine receptors. Inflammation in MS NAWM was characterized, compared to non immune-mediated conditions, by higher VCAM-1 expression, higher density of perivascular lymphocytes, focal perivascular inflammation with microglial expression of M1 markers, ongoing acute axonal damage correlating with VCAM-1 expression but not with microglia activation. Inflammatory changes in MS NAWM share all the main features observed in the WM in non immune-mediated conditions with wallerian axonal degeneration (with differences to a large extent more quantitative than qualitative), but with superimposition of disease-specific perivascular inflammation and ongoing acute axonal damage. PMID- 28919238 TI - Post-blink tear film dynamics in healthy and dry eyes during spontaneous blinking. AB - PURPOSE: The aim was to investigate the dynamics of post-blink tear film leveling in natural blinking conditions (NBC) for healthy subjects and those diagnosed with dry eye syndrome (DES) and to relate this phase to the tear film surface quality (TFSQ) before the following blink. METHODS: The study included 19 healthy persons and 10 with dry eye, grouped according to symptoms and signs observed during examination. Lateral shearing interferometry was used to examine TFSQ. Post-blink tear film dynamics was modeled by an exponential function, characterized by the decay parameter b, and a constant, describing the level of the stabilized TFSQ. Pre-next-natural-blink TFSQ dynamics was modeled with a linear trend, described by a parameter A. RESULTS: The post-blink tear film dynamics reached its plateau at a significantly (P = 0.006) lower level in the normal tear film group than in the dry eye group. The median exponential decay parameter b was statistically significantly higher for the control group than for the DES group, P = 0.026. The parameter b calculated for each interblink interval was significantly correlated with the corresponding parameter A (Spearman's R = 0.35; P < 0.001). Correlation between the median b and tear film fluorescein break-up time for each subject was also found (R = 0.41, P = 0.029). CONCLUSIONS: Significantly faster leveling of post-natural-blink tear film was observed in the group with DES than in healthy eyes. This dynamic was correlated with the pre next-natural-blink TFSQ and tear film stability. The results of this pilot study support previous works that advocate the importance of polar lipids in the mechanism of tear film lipid spreading. PMID- 28919239 TI - Effect of micronutrient supplementation on IVF outcomes: a systematic review of the literature. AB - There is accumulating evidence on the importance of micronutrients in improving fertility in couples undergoing IVF therapy. Despite this, studies reporting the relevant clinical outcomes of IVF, such as pregnancy and live birth rates, are very scarce. This review aimed to systematically summarize clinical evidence on the effect of micronutrients on primary outcome parameters of IVF treatment. The literature was searched up to February 2017 through Embase and PubMed databases for relevant studies. The quality of eligible studies was assessed with the Downs and Black checklist. A total of five studies qualified for inclusion. These studies reported outcomes on 467 participants administered micronutrient supplements alone or combined with other nutrients as part of IVF therapy. There was significant heterogeneity among the interventions and study designs. However, all the studies reported a positive impact of micronutrient supplementation on clinical outcomes of IVF therapy in terms of pregnancy rate and/or live birth rate. Within the limits of this review, micronutrients appear to influence positive outcomes in couples undergoing fertility treatment. Larger clinical studies are needed to strengthen these findings so that the benefit of micronutrients can be extended to subjects undergoing IVF therapy. PMID- 28919241 TI - Cardiopulmonary Exercise Testing in Patients With Heart Failure and a Preserved Ejection Fraction: Filling the Prognostic Knowledge Gap. PMID- 28919240 TI - Single Nucleotide Variants Associated With Polygenic Hypercholesterolemia in Families Diagnosed Clinically With Familial Hypercholesterolemia. AB - INTRODUCTION AND OBJECTIVES: Approximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members. METHODS: We recruited 49 nonfamilial hypercholesterolemia genetic hypercholesterolemia families (294 participants) and calculated cholesterol gene scores, derived from single nucleotide variants in SORT1, APOB, ABCG8, APOE and LDLR and lipoprotein(a) plasma concentration. RESULTS: Risk alleles in SORT1, ABCG8, APOE, and LDLR showed a statistically significantly higher frequency in blood relatives than in the 1000 Genomes Project. However, there were no differences between affected and nonaffected members. The contribution of the cholesterol gene score to LDL-C was significantly higher in affected than in nonaffected participants (P = .048). The percentage of the LDL-C variation explained by the score was 3.1%, and this percentage increased to 6.9% in those families with the highest genetic score in the proband. CONCLUSIONS: Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. Their contribution varies greatly among families, indicating the complexity and heterogeneity of these forms of hypercholesterolemias. The gene score explains a small percentage of LDL-C, which limits its use in diagnosis. PMID- 28919242 TI - Uncovering novel repositioning opportunities using the Open Targets platform. AB - The recently developed Open Targets platform consolidates a wide range of comprehensive evidence associating known and potential drug targets with human diseases. We have harnessed the integrated data from this platform for novel drug repositioning opportunities. Our computational workflow systematically mines data from various evidence categories and presents potential repositioning opportunities for drugs that are marketed or being investigated in ongoing human clinical trials, based on evidence strength on target-disease pairing. We classified these novel target-disease opportunities in several ways: (i) number of independent counts of evidence; (ii) broad therapy area of origin; and (iii) repositioning within or across therapy areas. Finally, we elaborate on one example that was identified by this approach. PMID- 28919243 TI - Drugs - Do we need them? Applications of non-pharmaceutical therapy in anterior eye disease: A review. AB - Natural products have been in use long before the introduction of modern drug therapies and are still used in various communities worldwide for the treatment of anterior eye disease. The aim of this review is to look at the current non pharmaceutical modalities that have been tried and assess the body of existing evidence behind them. This includes alternative medicine, existing non pharmaceutical therapy and more recent low and high tech solutions. A detailed search of all available databases including MEDLINE, Pubmed and Google was made to look for English-language studies for complementary and alternative treatment modalities (CAM), natural therapies and new modalities for anterior eye disease such as blepharitis, dry eye and microbial keratitis. We have included a broad discussion ranging from traditional treatments like honey and aloe vera which have been used for centuries, to the more recent technological advances like Intense Pulsed Light (IPL), LipiFlow and photoactivated chromophore for corneal cross linking in infectious keratitis (PACK-CXL). Alternative management strategies may have a role in anterior eye diseases and have a potential in changing the way we currently approach them. Some of the available CAM could play a role if incorporated in to current management practices of not only chronic diseases like blepharitis and dry eye, but also acute conditions with significant morbidity like microbial keratitis. Further large-scale randomized control trials stratified by disease severity are required to improve our understanding and to evaluate the use of non-pharmaceutical therapy against current practice. PMID- 28919244 TI - Does synaesthesia age? Changes in the quality and consistency of synaesthetic associations. AB - Developmental grapheme-colour synaesthesia is a rare condition in which colours become automatically paired with letters or digits in the minds of certain individuals during childhood, and remain paired into adulthood. Although synaesthesia is well understood in younger adults almost nothing is known about synaesthesia in aging. We present the first evidence that aging desaturates synaesthetic colours in the minds of older synaesthetes, and we show for the first time that aging affects the key diagnostic measure of synaesthesia (consistency of colours over time). We screened ~ 4000 members of the general population to identify grapheme-colour synaesthetes, targeting both younger and older adults. We found proportionally fewer older than younger synaesthetes, not only because fewer older people self-reported the condition, but because fewer also passed the objective diagnostic test. We examined the roots of this apparent decline in grapheme-colour synaesthesia, finding that the internal mental colours of synaesthetes become less saturated in older subjects, and importantly, that low-saturated colours are linked with test-failure. We discuss what these findings mean for a novel field of aging and synaesthesia research, in terms of the lifespan development of synaesthesia and how best to diagnose synaesthesia in later life. PMID- 28919245 TI - N1 responses to images of hands in occipito-temporal event-related potentials. AB - Hands, much like faces, convey social information, instructions and intentions to an observer. While the neural processes of face perception have been widely studied, it was only recently that fMRI identified occipito-temporal areas sensitive to static images of hands as body parts. To complement these studies with fine-grained timing information, we measured event-related EEG potentials (ERPs) from 33 subjects who were presented with static images of hands versus faces, whole bodies, and inanimate objects as controls. Already at N1 latency, ~ 170ms, hand-related ERP patterns were manifest in two results: (1) significant differences in amplitudes for images of hands versus bodies in occipito-temporal N1 responses; (2) left lateralization of responses to images of hands, and also of the difference waveforms (hands minus bodies), quantifying hand-related responses. In line with fMRI studies of hand-sensitive areas distinct from extrastriate body area (EBA), the current findings provide electrophysiological evidence for hand-sensitive brain activation, occurring at a similarly early latency as N1 responses to faces. PMID- 28919246 TI - Filtered sunlight, solar powered phototherapy and other strategies for managing neonatal jaundice in low-resource settings. AB - Challenges in treating severe neonatal jaundice in low and middle-income country settings still exist at many levels. These include: a lack of awareness of causes and prevention by families, communities and even sometimes health care professionals; insufficient, ineffective, high quality affordable diagnostic and therapeutic options; limited availability of rehabilitation provision for kernicterus. Collectively these challenges lead to an unacceptably high global morbidity and mortality from severe neonatal jaundice. In the past decade, there has been an explosion of innovations addressing some of these issues and these are increasingly available for scale up. Scientists, healthcare providers, and communities are joining hands to explore educational tools, low cost screening and diagnostic options including at point-of-care and treatment modalities including filtered sunlight and solar powered phototherapy. For the first time, the possibility of eliminating the tragedy of preventable morbidity and mortality from severe NNJ is on the horizon, for all. PMID- 28919247 TI - The effect of directed photic stimulation of the pineal on experimental Parkinson's disease. AB - The role of the circadian system in Parkinson's disease (PD) is a topic of increasing scientific interest. This has emerged from recent studies demonstrating an altered response of PD patients to treatment in relation to the phase of the light/dark cycle and from other work defining the functional significance of melanocytes in PD: a cell type that the nigro-striatal dopamine (NSD) system and circadian system both contain. The present study was undertaken to determine the sensitivity of the pineal, as the final common pathway of the circadian system, to light delivered directly to the pineal via surgical implantation of LEDs. Direct photic stimulation of the pineal altered the course of experimental PD while anatomical controls receiving stimulation of the frontal cortex exhibited a negative impact on the course of recovery of these animals. These effects were closely linked to the phase of the light/dark cycle. The present results suggest that while pineal photoreceptors are regarded as vestigial, functional photo-reactivity of the pineal remains. It is inferred that melanocytes are the active cells responsible for the observed effect since they remain functionally intact in mammalian pineal even though pineal photoreceptors are functionally inert. Although the stimuli applied in the present study may be regarded as artificial this study demonstrates that brain parenchyma remains differentially reactive to direct light exposure and presents a novel mechanism in circadian structures that needs to be explored. PMID- 28919248 TI - Safety of differential radiation dosing in lymph node positive necks treated with IMRT. AB - PURPOSE: When treating head and neck squamous cell carcinoma (HNSCC) with intensity modulated radiation therapy (IMRT), it is common to use several dose levels for a lymph node positive neck: full dose (66-70 Gy) to gross cancer, intermediate dose (59-63 Gy) to higher risk neck regions, and standard dose (50 54 Gy) to lower risk neck regions. There is no consensus regarding how much of the neck should receive intermediate versus standard dose, however. METHODS AND MATERIALS: HNSCC patients treated with IMRT were identified from 2 academic medical centers between 2004 and 2016. Intermediate dose was restricted to a region of the neck 2 cm above and below the most superior and inferior involved lymph nodes; standard dose was delivered to more distal neck regions. Descriptive statistics were calculated for demographics and clinical characteristics as well as proportions for failures 2 years after treatment. Failure outside the intermediate dose region was determined by calculating confidence intervals from a modification of the Poisson distribution. RESULTS: Of the 57 necks included in this study, 17.5% experienced disease recurrence in the neck within 2 years of completing treatment. All failures were within the 2-cm margin above or below the most superior and inferior involved nodes; there were no failures outside this 2 cm margin (95% confidence interval, 0-7.7). CONCLUSIONS: The results of this study support the feasibility of treating only the neck adjacent to gross neck disease to an intermediate dose, and treating the remainder of the neck to a lower, standard dose. Although these results are encouraging, additional study of this treatment paradigm is warranted. PMID- 28919249 TI - Dosimetric predictors for acute esophagitis during radiation therapy for lung cancer: Results of a large statewide observational study. AB - PURPOSE: The purpose of this study is to identify dosimetric variables that best predict for acute esophagitis in patients treated for locally advanced non-small cell lung cancer in a prospectively accrued statewide consortium. METHODS AND MATERIALS: Patients receiving definitive radiation therapy for stage II-III non small cell lung cancer within the Michigan Radiation Oncology Quality Consortium were included in the analysis. Dose-volume histogram data were analyzed to determine absolute volumes (cc) receiving doses from 10 to 60 Gy (V10, V20, V30, V40, V50, and V60), as well as maximum dose to 2 cc (D2cc), mean dose (MD), and generalized equivalent uniform dose (gEUD). Logistic regression models were used to characterize the risk of toxicity as a function of dose and other covariates. The ability of each variable to predict esophagitis, individually or in a multivariate model, was quantified by receiver operating characteristic analysis. RESULTS: There were 533 patients who met study criteria and were included; 437 (81.9%) developed any grade of esophagitis. Significant variables on univariate analysis for grade >=2 esophagitis were concurrent chemotherapy, V20, V30, V40, V50, V60, MD, D2cc, and gEUD. For grade >=3 esophagitis, the predictive variables were: V30, V40, V50, V60, MD, D2cc, and gEUD. In multivariable modeling, gEUD was the most significant predictor of both grade >=2 and grade >=3 esophagitis. When gEUD was excluded from the model, D2cc was selected as the most predictive variable for grade >=3 esophagitis. For an estimated risk of grade >=3 esophagitis of 5%, the threshold values for gEUD and D2cc were 59.3 Gy and 68 Gy, respectively. CONCLUSIONS: In this study, we report the novel finding that gEUD and D2cc, rather than MD, were the most predictive dose metrics for severe esophagitis. To limit the estimated risk of grade >=3 esophagitis to <5%, thresholds of 59.3 Gy and 68 Gy were identified for gEUD and D2cc, respectively. PMID- 28919250 TI - Purification and characterization of a cellulase-free, thermostable endo-xylanase from Streptomyces griseorubens LH-3 and its use in biobleaching on eucalyptus kraft pulp. AB - Xylanase is an important enzyme involved in degrading xylan. In this study, an extracellular cellulase-free, thermostable endo-xylanase which was produced by Streptomyces griseorubens LH-3 with bagasse semi-cellulose as a carbon source was purified and characterized. The xylanase was purified 4-fold with a recovery yield of 21.6% by precipitation with 25-55% (NH4)2SO4, Mono Q ion exchange chromatography and sephacryl S-200 HR gel filtration chromatography. It appeared as a monomeric protein on SDS-PAGE gel and had an apparent molecular weight of 45.5 kDa with specific activity of 434 IU/mg. Using birchwood xylan as substrate, the maximum velocity (Vmax) and Michaelis-Menten constant (Km) were found to be 1.44 mg/ml and 2.05 MUmol/min mg, respectively. The purified xylanase was active at pH 4.0-8.0 with an optimum pH of 5.0. It was stable at temperatures between 30 degrees C and 50 degrees C, exhibiting maximum activity at 60 degrees C. Hg2+ and Al3+ inhibited the enzyme activity significantly. Enzymatic product analysis indicated that the enzyme was an endo-xylanase, whose hydrolysis products were mainly a series of short-chain xylooligosaccharides. Furthermore, it was used for biobleaching of eucalyptus kraft pulp, and results showed that this purified xylanase increased the brightness of the pulp by 14.5% and reduced the kappa number by 24.5%. All these industrially relevant characteristics made it had potential application in the pulp and paper industry as a biobleaching agent. PMID- 28919251 TI - Inhibition of Saccharomyces cerevisiae growth by simultaneous uptake of glucose and maltose. AB - Saccharomyces cerevisiae expresses alpha-glucoside transporters, such as MalX1p (X=1(Agt1p), 2, 3, 4, and 6), which are proton symporters. These transporters are regulated at transcriptional and posttranslational levels in the presence of glucose. Malt wort contains glucose, maltose, and maltotriose, and the assimilation of maltose is delayed as a function of glucose concentration. With the objective of increasing beer fermentation rates, we characterized alpha glucoside transporters and bred laboratory yeasts that expressed various alpha glucoside transporters for the simultaneous uptake of different sugars. Mal21p was found to be the most resistant transporter to glucose-induced degradation, and strain (HD17) expressing MAL21 grew on a medium containing glucose or maltose, but not on a medium containing both sugars (YPDM). This unexpected growth defect was observed on a medium containing glucose and >0.1% maltose but was not exhibited by a strain that constitutively expressed maltase. The defect depended on intracellular maltose concentration. Although maltose accumulation caused a surge in turgor pressure, addition of sorbitol to YPDM did not increase growth. When strain HD17 was cultivated in a medium containing only maltose, protein synthesis was inhibited at early times but subsequently resumed with reduction in accumulated maltose, but not if the medium was exchanged for YPDM. We conclude that protein synthesis was terminated under the accumulation of maltose, regardless of extracellular osmolarity, and HD17 could not resume growth, because the intracellular concentration of maltose did not decrease due to insufficient synthesis of maltase. Yeast should incorporate maltose after expressing adequate maltase in beer brewing. PMID- 28919252 TI - Mutation in the peroxin-coding gene PEX22 contributing to high malate production in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae produces organic acids such as succinate, acetate, and malate during alcoholic fermentation. Since malate contributes to the pleasant taste of sake (a Japanese alcoholic beverage), various methods for breeding high malate-producing yeast strains have been developed. Here, a high-malate-producing yeast strain F-701H was isolated. This mutant was sensitive to dimethyl succinate (DMS) and harbored a nonsense mutation in the peroxin gene PEX22, which was identified as the cause of high malate production by comparative genome analysis. This mutation, which appeared to cause Pex22p dysfunction, was sufficient to confer increased malate productivity and DMS sensitivity to yeast cells. Next, we investigated the mechanism by which this mutation led to high malate production in yeast cells. Peroxins, such as Pex22p, maintain peroxisomal biogenesis. Analysis of 29 PEX disruptants revealed an increased malate production by deletion of the genes encoding peroxins responsible for importing proteins (containing peroxisomal targeting signal 1, PTS1) into the peroxisomal matrix, and those responsible for the assembly of peroxins themselves in the peroxisomal membrane. A defect in peroxisomal malate dehydrogenase (Mdh3p), harboring endogenous PTS1, inhibited the high malate-producing phenotype in the PEX22 mutant. Moreover, Mdh3p, which was normally sorted to the peroxisomal matrix, was potentially mislocalized to the cytosol in the PEX22 mutant. This suggested that an increase in malate production resulted from the mislocalization of Mdh3p from the peroxisome to the cytoplasm due to the loss of peroxin-mediated transportation. Thus, the present study revealed a novel mechanism for organic acid productions in yeast during sake brewing. PMID- 28919253 TI - The influence of acidic media on the effect of beta-amyloid peptide on the function of glycine receptor in hippocampal neurons. AB - We have previously shown that application of beta-amyloid peptide 1-42 (Abeta) at picomolar/nanomolar concentrations caused a decrease in the peak amplitude and acceleration of desensitization of the glycine-activated chloride current (IGly) in hippocampal pyramidal neurons (Bukanova et al., 2016). The aim of this work was to study the effect of Abeta on IGly in an acidified medium. The relevance of this work is determined by the fact that the pathogenic effects of Abeta in Alzheimer's disease are usually accompanied by inflammatory processes and acidosis. The IGly was induced by 600 ms application of 100 MUM (nearly EC50) or 500 MUM (nearly saturating) glycine on isolated rat hippocampal neurons. The solution of glycine was neutral (pH 7.4) or acidic over a pH range of 5.0-7.0. It was found that 600 ms application of protons rapidly, reversibly and in dose dependent manner decreased the peak amplitude and accelerated the desensitization of IGly. The effect of H+ on IGly desensitization did not depend on glycine concentration and may be considered noncompetitive, while the effect on IGly peak disappeared at saturating glycine concentration and can be regarded as a competitive. These characteristics of the proton effects on IGly coincide with the characteristics of the Abeta effects on IGly. Experiments with joint application of Abeta and H+ showed interdependence of their effects. Addition of Abeta to perfusing solution reduced H+ effects on IGly while long pretreatment of Abeta with acid solution prevented the effects of the peptide on IGly. Our results suggest the existence of common sites for Abeta and H+ on the GlyR and indicate a mutual weakening of the inhibitory action of these molecules on IGly. PMID- 28919254 TI - Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production. AB - The high consumption of saturated lipids has been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance in peripheral tissues. However, how neurons develop insulin resistance in response to lipid overload is not fully understood. Here, we used cultured rat cortical neurons and differentiated human neuroblastoma cells to demonstrate that PA blocks insulin-induced metabolic activation, inhibits the activation of the insulin/PI3K/Akt pathway and activates mTOR kinase downstream of Akt. Despite the fact that fatty acids are not normally used as a significant source of fuel by neural cells, we also found that short-term neuronal exposure to PA reduces the NAD+/NADH ratio, indicating that PA modifies the neuronal energy balance. Finally, inhibiting mitochondrial ROS production with mitoTEMPO prevented the deleterious effect of PA on insulin signaling. This work provides novel evidence of the mechanisms behind saturated fatty acid-induced insulin resistance and its metabolic consequences on neuronal cells. PMID- 28919255 TI - SUMO proteins: Guardians of immune system. AB - Small ubiquitin-like modifier (SUMO) proteins belong to the ubiquitin-like family and act to change the function of target proteins through post-translational modifications. Through their interactions with innate immune pathways, SUMOs promote an efficient immune response to pathogenic challenge avoiding, at the same time, an excess of immune response that could lead to the development of autoimmune diseases. This report discusses the general functions of SUMO proteins; highlights SUMO involvement in the innate immune response through their role in NF-kappaB and interferon pathways; the involvement of SUMO proteins in autoimmune diseases; and reviews bacterial, viral, and parasitic interactions with SUMO pathways. In conclusion, we speculate that targeting SUMOs could represent a new therapeutic strategy against infections and autoimmunity. PMID- 28919257 TI - Seizures by the clock: Temporal patterns of psychogenic nonepileptic seizures. AB - We hypothesized that (1) the occurrence of psychogenic nonepileptic seizures (PNES) is modulated by the interaction between the 24-hour clock and the sleep wake cycle and (2) the pattern of modulation in PNES differs from epileptic seizures (ES). We sought to test our hypotheses in a cohort of patients diagnosed with PNES or ES in the setting of an epilepsy monitoring unit (EMU). We retrospectively reviewed consecutive video-EEG (VEEG) recordings of patients who underwent monitoring at the EMU of a tertiary hospital. The seizure type (PNES vs ES), onset time, and the state (sleep vs awake) were tabulated. The relationship between the onset time, the state of arousal, and the occurrence of PNES was determined using logistic regression analysis. To determine if the nature of the relationship between the state of arousal and PNES differed according to the onset time, an interaction between the onset time and the state of arousal was also fitted to the model. We studied a total of 754 seizures (ES, 437; PNES, 317) from 135 patients consisting of 71 (52.6%) females and 64 (47.4%) males with the median age of 39years (range, 18-91). We found a significant association between the state of arousal and PNES with the odds of being PNES four times higher when patients were awake (OR: 4.27, 95% CI: 2.44-7.48; p<0.0001) compared with when they were asleep. The analysis further revealed a significant interaction between the onset time and the state of arousal (p=0.004). The odds of being PNES were significantly higher if the seizure occurred when the patient was awake at night. These patterns possibly indicate the complex interaction between the sleep-wake cycle and the 24-hour time cycle in the generation of PNES. PMID- 28919256 TI - Metabolic Links between Plasma Cell Survival, Secretion, and Stress. AB - Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during and after infections, and each plasma cell produces some thousands of antibody molecules per second. This magnitude of secretion requires enormous quantities of amino acids and glycosylation sugars to properly build and fold antibodies, biosynthetic substrates to fuel endoplasmic reticulum (ER) biogenesis, and additional carbon sources to generate energy. Many of these processes are likely to be linked, thereby affording possibilities to improve vaccine design and to develop new therapies for autoimmunity. We review here aspects of plasma cell biology with an emphasis on recent studies and the relationships between intermediary metabolism, antibody production, and lifespan. PMID- 28919258 TI - Examining the time course of genital and subjective sexual responses in women and men with concurrent plethysmography and thermography. AB - Sexual response is a dynamic process, though there is limited knowledge of the time course and relationships among its psychological and physiological components. To address this gap, we concurrently assessed self-reported sexual arousal, genital temperature (with thermography), and genital vasocongestion (with vaginal photoplethysmography [VPP] or penile plethysmography [PPG]) during sexual and nonsexual films in 28 androphilic women (attracted to men) and 27 gynephilic men (attracted to women). Men and women had similarly strong agreement between subjective and genital responses (sexual concordance) with thermography, but this agreement was stronger in men than women with PPG/VPP. The time course of changes in self-reported arousal was most similar to changes in genital temperature (i.e., time to onset and peak response). Time-lagged correlations and multilevel modeling revealed changes in the strength of relationships between aspects of sexual response over time. Results highlight the dynamic nature of sexual response and drawbacks of relying on zero-order correlations to characterize sexual concordance. PMID- 28919259 TI - Ontogenic Identification and Analysis of Mesenchymal Stromal Cell Populations during Mouse Limb and Long Bone Development. AB - Bone-derived mesenchymal stromal cells (MSCs) differentiate into multiple lineages including chondro- and osteogenic fates and function in establishing the hematopoietic compartment of the bone marrow. Here, we analyze the emergence of different MSC types during mouse limb and long bone development. In particular, PDGFRalphaposSCA-1pos (PalphaS) cells and mouse skeletal stem cells (mSSCs) are detected within the PDGFRalphaposCD51pos (PalphaCD51) mesenchymal progenitors, which are the most abundant progenitors in early limb buds and developing long bones until birth. Long-bone-derived PalphaS cells and mSSCs are most prevalent in newborn mice, and molecular analysis shows that they constitute distinct progenitor populations from the earliest stages onward. Differential expression of CD90 and CD73 identifies four PalphaS subpopulations that display distinct chondro- and osteogenic differentiation potentials. Finally, we show that cartilage constructs generated from CD90pos PalphaS cells are remodeled into bone organoids encompassing functional endothelial and hematopoietic compartments, which makes these cells suited for bone tissue engineering. PMID- 28919260 TI - Blockage of the Epithelial-to-Mesenchymal Transition Is Required for Embryonic Stem Cell Derivation. AB - Pluripotent cells emanate from the inner cell mass (ICM) of the blastocyst and when cultivated under optimal conditions immortalize as embryonic stem cells (ESCs). The fundamental mechanism underlying ESC derivation has, however, remained elusive. Recently, we have devised a highly efficient approach for establishing ESCs, through inhibition of the MEK and TGF-beta pathways. This regimen provides a platform for dissecting the molecular mechanism of ESC derivation. Via temporal gene expression analysis, we reveal key genes involved in the ICM to ESC transition. We found that DNA methyltransferases play a pivotal role in efficient ESC generation. We further observed a tight correlation between ESCs and preimplantation epiblast cell-related genes and noticed that fundamental events such as epithelial-to-mesenchymal transition blockage play a key role in launching the ESC self-renewal program. Our study provides a time course transcriptional resource highlighting the dynamics of the gene regulatory network during the ICM to ESC transition. PMID- 28919261 TI - Top-Down Inhibition of BMP Signaling Enables Robust Induction of hPSCs Into Neural Crest in Fully Defined, Xeno-free Conditions. AB - Defects in neural crest development have been implicated in many human disorders, but information about human neural crest formation mostly depends on extrapolation from model organisms. Human pluripotent stem cells (hPSCs) can be differentiated into in vitro counterparts of the neural crest, and some of the signals known to induce neural crest formation in vivo are required during this process. However, the protocols in current use tend to produce variable results, and there is no consensus as to the precise signals required for optimal neural crest differentiation. Using a fully defined culture system, we have now found that the efficient differentiation of hPSCs to neural crest depends on precise levels of BMP signaling, which are vulnerable to fluctuations in endogenous BMP production. We present a method that controls for this phenomenon and could be applied to other systems where endogenous signaling can also affect the outcome of differentiation protocols. PMID- 28919262 TI - PDGFRA Is Not Essential for the Derivation and Maintenance of Mouse Extraembryonic Endoderm Stem Cell Lines. AB - Extraembryonic endoderm stem (XEN) cell lines can be derived and maintained in vitro and reflect the primitive endoderm lineage. Platelet-derived growth factor receptor alpha (PDGFRA) is thought to be essential for the derivation and maintenance of mouse XEN cell lines. Here, we have re-evaluated this requirement for PDGFRA. We derived multiple PDGFRA-deficient XEN cell lines from postimplantation and preimplantation embryos of a PDGFRA-GFP knockout strain. We also converted PDGFRA-deficient embryonic stem cell lines into XEN cell lines chemically by transient culturing with retinoic acid and Activin A. We confirmed the XEN profile of our 12 PDGFRA-deficient cell lines by immunofluorescence with various markers, by NanoString gene expression analyses, and by their contribution to the extraembryonic endoderm of chimeric embryos produced by injecting these cells into blastocysts. Thus, PDGFRA is not essential for the derivation and maintenance of XEN cell lines. PMID- 28919263 TI - Single-Cell Gene Expression Analysis of a Human ESC Model of Pancreatic Endocrine Development Reveals Different Paths to beta-Cell Differentiation. AB - The production of insulin-producing beta cells from human embryonic stem cells (hESCs) in vitro represents a promising strategy for a cell-based therapy for type 1 diabetes mellitus. To explore the cellular heterogeneity and temporal progression of endocrine progenitors and their progeny, we performed single-cell qPCR on more than 500 cells across several stages of in vitro differentiation of hESCs and compared them with human islets. We reveal distinct subpopulations along the endocrine differentiation path and an early lineage bifurcation toward either polyhormonal cells or beta-like cells. We uncover several similarities and differences with mouse development and reveal that cells can take multiple paths to the same differentiation state, a principle that could be relevant to other systems. Notably, activation of the key beta-cell transcription factor NKX6.1 can be initiated before or after endocrine commitment. The single-cell temporal resolution we provide can be used to improve the production of functional beta cells. PMID- 28919265 TI - Pretherapeutic staging of locally advanced cervical cancer: Inframesenteric paraaortic lymphadenectomy accuracy to detect paraaortic metastases in comparison with infrarenal paraaortic lymphadenectomy. AB - BACKGROUND: Extended-field chemoradiation therapy is usually performed in patients with locally advanced cervical cancer (LACC) and paraaortic (PA) node metastases. Considering the very low rate of skip metastases above inferior mesenteric artery, ilio-inframesenteric paraaortic lymph node dissection (IM PALND) seems to be an adequate pattern of PALND. Our objective was to assess the accuracy of this management to determine PA nodal status in comparison with infrarenal paraaortic lymphadenectomy (IR-PALND) in case of squamous or glandular cervical cancer. METHODS: All patients with LACC and negative MRI and PET/CT imaging at paraaortic level had laparoscopic staging (followed, if negative, by extraperitoneal paraaortic lymphadenectomy). From January 2011 to September 2015, patients who had IM-PALND were included and were compared to a previous historical series of IR-PALND patients. The two groups differed only at the upper level of dissection. Characteristics of nodal involvement at paraaortic level depending on level of dissection, PET/CT imaging and histology were studied. RESULTS: 119 women were included in our study, with 56 patients in the IM-PALND group and 63 in the IR-PALND group. In the IM-PALND group, fewer nodes were resected (p<0.001). There was no difference between the two groups regarding nodal status at paraaortic level (p=0.77). Patterns of nodal involvement were similar whichever the histological subtype of cervical cancer (squamous or glandular). CONCLUSION: IM-PALND appears to be equally effective to assess paraaortic nodal involvement in LACC for both histological subtypes - glandular and squamous carcinomas - and to select patients for extended-field chemoradiation therapy. PMID- 28919266 TI - Rock bream iridovirus (RBIV) replication in rock bream (Oplegnathus fasciatus) exposed for different time periods to susceptible water temperatures. AB - Rock bream iridovirus (RBIV) is a member of the Megalocytivirus genus that causes severe mortality to rock bream. Water temperature is known to affect the immune system and susceptibility of fish to RBIV infection. In this study, we evaluated the time dependent virus replication pattern and time required to completely eliminate virus from the rock bream body against RBIV infection at different water temperature conditions. The rock bream was exposed to the virus and held at 7 (group A1), 4 (group A2) and 2 days (group A3) at 23 degrees C before the water temperature was reduced to 17 degrees C. A total of 28% mortality was observed 24-35 days post infection (dpi) in only the 7 day exposure group at 23 degrees C. In all 23 degrees C exposure groups, virus replication peaked at 20 to 22 dpi (106-107/MUl). In recovery stages (30-100 dpi), the virus copy number was gradually reduced, from 106 to 101 with faster decreases in the shorter exposure period group at 23 degrees C. When the water temperature was increased in surviving fish from 17 to 26 degrees C at 70 dpi, they did not show any mortality or signs of disease and had low virus copy numbers (below 102/MUl). Thus, fish need at least 50 days from peaked RBIV levels (approximately 20-25 dpi) to inhibit the virus. This indicates that maintaining the fish at low water temperature (17 degrees C) for 70 days is sufficient to eradicate RBIV from fish body. Thus, RBIV could be eliminated slowly from the fish body and the virus may be completely eliminated under the threshold of causing mortality. PMID- 28919267 TI - Post-carotid Endarterectomy Hypertension. Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters. AB - OBJECTIVE/BACKGROUND: The first paper in this series observed that pre-operative baroreceptor dysfunction and poorly controlled hypertension were independently predictive for identifying patients who went on to require treatment for post endarterectomy hypertension (PEH). The second paper examines the influence of intra-operative patient, transcranial Doppler (TCD) ultrasound, and anaesthetic variables on the incidence of PEH. METHODS: In total, 106 patients underwent carotid endarterectomy (CEA) under general anaesthesia. Systolic blood pressure (SBP) changes, anaesthetic and vasoactive agents, analgesia, and post-operative pain scores, as well as TCD derived changes in middle cerebral artery (MCA) velocity during surgery were recorded. Patients who met pre-existing unit criteria for treating PEH after CEA (SBP > 170 mmHg without symptoms or SBP > 160 mmHg with headache/seizure/neurological deficit) were treated according to an established and validated protocol. RESULTS: In total, 40/106 patients (38%) required treatment for PEH following CEA (26 in theatre recovery [25%], 27 back on the vascular surgery ward [25%]), whereas seven (7%) had SBP surges > 200 mmHg on the ward. Patients requiring treatment for PEH had significantly higher pre induction SBP (174 +/- 21 mmHg vs. 153 +/- 21 mmHg; p < .001), the greatest decreases in SBP after induction of anaesthesia (median decrease 100 +/- 32 mmHg vs. 83 +/- 24 mmHg; p = .01) and were significantly more likely to experience moderate/severe pain scores post-operatively (p = .003). Logistic regression analysis of the pre- and intra-operative data revealed that higher pre-induction mean SBP and lower pre-operative (impaired) BRS were the only independent predictors of PEH. CONCLUSION: This analysis of intra-operative variables has demonstrated that patients with poorly controlled and/or labile hypertension at induction of general anaesthesia were those at greatest risk of requiring treatment for PEH in the post-operative period after CEA. No other variables, including use of vasopressors, treatment of hypotension, anaesthetic agents, or changes in MCA velocity after clamp release and restoration of flow were able to predict who might go on to require treatment for PEH. Identification of at-risk individuals and aggressive blood pressure control in the post-operative period remains the mainstay of treatment. PMID- 28919268 TI - Depression and sports-related concussion: A systematic review. AB - CONTEXT: Head injuries are risk factors for chronic depressive disorders, but this association remains poorly explored with regards to concussion. OBJECTIVES: The objective of this review was to evaluate the incidence of depressive symptoms and depression after sports-related concussion. We also endeavored to identify the response elements regarding the pathophysiology of these symptoms. METHODS: A systematic search of PubMed and Embase was conducted focusing on papers published until 1st December, 2016, according to PRISMA criteria The following MESH terms were used: (concussion or traumatic brain injury) and sport and (depression or depressive disorder). RESULTS: A depressive disorder can appear immediately after a concussion: depressive symptoms seem to be associated with the symptoms of the concussion itself. A depressive disorder can also appear later, and is often linked to the frequency and number of concussions. Furthermore, the existence of a mood disorder prior to a concussion can contribute to the onset of a depressive disorder after a concussion. LIMITS: There is an overall limit concerning the definition of a depressive disorder. In addition, when these studies had controls, they were often compared to high-level athletes; yet, practicing sport regularly is a protective factor against mood pathologies. CONCLUSIONS: Depressive symptoms after a concussion seem to be associated with postconcussion symptoms. Repeat concussions can contribute to later-onset major depressive disorders. However, playing sports can protect against major depressive disorders: thus, it is essential to evaluate concussions as accurately as possible. PMID- 28919264 TI - Prolactin Alters the Mammary Epithelial Hierarchy, Increasing Progenitors and Facilitating Ovarian Steroid Action. AB - Hormones drive mammary development and function and play critical roles in breast cancer. Epidemiologic studies link prolactin (PRL) to increased risk for aggressive cancers that express estrogen receptor alpha (ERalpha). However, in contrast to ovarian steroids, PRL actions on the mammary gland outside of pregnancy are poorly understood. We employed the transgenic NRL-PRL model to examine the effects of PRL alone and with defined estrogen/progesterone exposure on stem/progenitor activity and regulatory networks that drive epithelial differentiation. PRL increased progenitors and modulated transcriptional programs, even without ovarian steroids, and with steroids further raised stem cell activity associated with elevated canonical Wnt signaling. However, despite facilitating some steroid actions, PRL opposed steroid-driven luminal maturation and increased CD61+ luminal cells. Our findings demonstrate that PRL can powerfully influence the epithelial hierarchy alone and temper the actions of ovarian steroids, which may underlie its role in the development of breast cancer. PMID- 28919269 TI - [A rare cause of abdominal pain]. PMID- 28919270 TI - [Clinical integration programs for complex situations: Functional support and normative challenge]. PMID- 28919271 TI - [Autoimmune hepatitis: Immunological diagnosis]. AB - Autoimmune hepatopathies (AIHT) including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AIC), represent an impressive entities in clinical practice. Their pathogenesis is not perfectly elucidated. Several factors are involved in the initiation of hepatic autoimmune and inflammatory phenomena such as genetic predisposition, molecular mimicry and/or abnormalities of T-regulatory lymphocytes. AIHT have a wide spectrum of presentation, ranging from asymptomatic forms to severe acute liver failure. The diagnosis of AIHT is based on the presence of hyperglobulinemia, cytolysis, cholestasis, typical even specific circulating auto-antibodies, distinctive of AIH or PBC, and histological abnormalities as well as necrosis and inflammation. Anti-F actin, anti-LKM1, anti LC1 antibodies permit to distinguish between AIH type 1 and AIH type 2. Anti SLA/LP antibodies are rather associated to more severe hepatitis, and particularly useful for the diagnosis of seronegative AIH for other the antibodies. Due to the relevant diagnostic value of anti-M2, anti-Sp100, and anti gp210 antibodies, the diagnosis of PBC is more affordable than that of PSC and AIC. Based on clinical data, the immunological diagnosis of AIHT takes advantage of the various specialized laboratory techniques including immunofluorescence, immunodot or blot, and the Elisa systems, provided of a closer collaboration between the biologist and the physician. PMID- 28919272 TI - Cutaneous granulomas caused by subcutaneous injections of leuprorelin acetate. PMID- 28919273 TI - [Reflex sympathetic dystrophy involving the ankle and the foot in a particular pathological pregnancy: Exceptional association]. PMID- 28919274 TI - [Mobile applications for French medical students: Work in progress]. PMID- 28919275 TI - [Open haemorrhoidectomy as an ambulatory procedure, is it reasonable?] PMID- 28919276 TI - [Focus on Achalasia]. AB - The pathophysiology of achalasia is largely unknown, and involves the destruction of ganglion cell in the esophageal myenteric plexus. High-resolution esophageal manometry is the key investigation. Endoscopic pneumodilatation and laparoscopic Heller myotomy have comparable short-term success rates, around 90%. The main complication after pneumodilatation is esophageal perforation, occurring in about 1% of cases. Peroral endoscopic myotomy is a promising treatment modality, however with frequent post-procedural gastroesophageal reflux. PMID- 28919277 TI - [Accomplices under influence, teachers-lovers, "Incestigators" or pimps... Who are females child abusers?] AB - According to victimization surveys, the percentage of females among child abusers is much higher than 2 or 5% as usually reported in the devoted literature. The under-estimated percentage of child sexual abuses committed by females would result from the dissimulation of sexual acts within nursing care, a gender bias in favor of women among child protection system professionals and low disclosures. Sexual abuses committed by females are often more harmful for children than sexual abuses committed by males. Although a few female child abusers suffers from psychiatric disorders, most of them are psychologically and emotionally dependent from a man or have psychopathic, manipulative and sometimes sadistic personality traits. Female child abusers are a heterogeneous population either acting under the influence of a man or initiating actively the offending for pedophile or financial motivations. Deconstructing the persistent myths about female child abusers is necessary to better identify these women, treat them and prevent relapse. PMID- 28919278 TI - A rare tumour of the masseter muscle. PMID- 28919279 TI - Data sharing to serve ethics, transparency and reproducibility of medical science. PMID- 28919281 TI - Erratum. PMID- 28919282 TI - Impact of pancreaticoduodenal arcade dilation on postoperative outcomes after pancreaticoduodenectomy. AB - BACKGROUND: The aim of this study was to investigate the impact of pancreaticoduodenal arcade (PDA) dilation on postoperative outcomes after pancreaticoduodenectomy. METHODS: Consecutive patients submitted to pancreaticoduodenectomy between 2008 and 2016 underwent preoperative multi detector computed tomography, the images of which were re-reviewed. The patients were categorized according to the grade of PDA dilation into 3 groups (remarkably dilated, slightly-dilated, and non-dilated). RESULTS: Among the 443 patients, 25 patients (5.6%) were categorized as remarkably-dilated PDA and 24 patients (5.4%) as having slightly-dilated PDA. The patients with remarkably-dilated PDA had undergone pancreaticoduodenectomy with additional surgical maneuvers to restore celiac arterial flow as needed, and had an uneventful postoperative recovery relative to those with non-dilated PDA. In contrast, patients with slightly dilated PDA underwent only pancreaticoduodenectomy without additional surgical maneuvers, and developed clinically relevant postoperative pancreatic fistula (POPF) more frequently than those with non-dilated PDA (42% vs. 21%, P = 0.021). Moreover, slightly-dilated PDA was shown to be an independent risk factor for clinically relevant POPF (odds ratio = 2.719, P = 0.042). DISCUSSION: For patients with PDA dilation requiring pancreaticoduodenectomy, a preoperative evaluation of the vascular anatomy, intraoperative assessment of the celiac arterial flow, and additional surgical maneuvers might be necessary to reduce the risk of postoperative complications. PMID- 28919283 TI - Clinical manifestations, risk factors and prognosis of patients with Morganella morganii sepsis. AB - BACKGROUND: There are few studies of Morganella bacteremia. We evaluated risk factors and outcome of patients with Morganella bacteremia. METHODS: Medical records of patients with Morganella bacteremia were reviewed (1997-2014). Control group patients with Escherichiacoli sepsis were matched by year of diagnosis and infection acquisition site. RESULTS: The study group included 136 adult patients. Mean age and gender of study and control groups were similar. Complicated soft tissue infection was more prevalent in the study group (30% versus 3.2%, p < 0.05). The Charlson Comorbidity Index (CCI) was higher in the study group (4.3 +/ 2.5 versus 3.4 +/- 2.8, p < 0.05). Only 78 (62%) of the study patients versus 101 (83%) of the control group (p < 0.05), received appropriate empirical antibiotic treatment. A significantly higher in-hospital mortality rate (42% versus 25%, p < 0.05) as well as longer length of stay (25 +/- 22 versus 14 +/- 16 days, p < 0.05) was observed in the study group. Multivariate analysis revealed that a debilitative state, a CCI > 4, septic shock and a clinical syndrome other than UTI were all significant risk factors for mortality (p < 0.05). CONCLUSIONS: Patients with Morganellamorganii sepsis had more co morbidities and a worse degree of sepsis. There is an increased risk of inappropriate empirical treatment, longer hospitalization and higher death rate. PMID- 28919280 TI - Soluble Gamma-secretase Modulators Attenuate Alzheimer's beta-amyloid Pathology and Induce Conformational Changes in Presenilin 1. AB - A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Abeta42 peptide, which is generated from amyloid-beta precursor protein (APP) via cleavages by beta- and gamma-secretase. We have developed a class of soluble 2 aminothiazole gamma-secretase modulators (SGSMs) that preferentially decreases Abeta42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of gamma-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Abeta42 levels without affecting either alpha- and beta secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the gamma-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD. PMID- 28919284 TI - MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression - First results of a cross-sectional study. AB - BACKGROUND: Aim of this cross-sectional study was the investigation of associations between different rheumatoid arthritis (RA)-related blood parameters and periodontal condition as well as selected periodontal pathogenic bacteria in RA patients under methotrexate (MTX) immunosuppression. METHODS: Periodontal probing depth (PPD), bleeding on probing (BOP) and clinical attachment loss (CAL) were assessed. Periodontal condition was classified into: no/mild and moderate or severe periodontitis (P). Prevalence of selected periodontal pathogenic bacteria and concentration of matrix metalloproteinase 8 (MMP-8) was assessed from the gingival crevicular fluid (GCF) using PCR and ELISA, respectively. Blood samples were analyzed for the concentration of selected rheumatoid parameters. STATISTICAL ANALYSIS: t-test, Mann-Whitney-U-Test, exact Fisher tests or chi square test (p < 0.05). RESULTS: Fifty-six patients (mean age 55.07 years, 34 P, 22 no P) were included. While prevalence of periodontal pathogenic bacteria was higher in P patients, no substantial association of bacteria with blood parameters was found. In periodontal diseased participants, MMP-8 concentration in GCF (6.22 +/- 7.01 vs. 15.99 +/- 13.49; p < 0.01) and blood (2.60 +/- 3.57 vs. 5.52 +/- 5.92; p < 0.01) was increased, while no correlation between GCF and blood was found (Spearman's rho: 0.175; p = 0.23). Furthermore, higher blood concentrations of MMP-8 and tissue inhibitor of MMP (TIMP-1) were detected in patients with increased periodontal inflammation (BOP positive, p < 0.01). CONCLUSION: Periodontal inflammation appears associated to MMP-8 and TIMP-1 in blood. Thereby, clinical interaction between periodontal conditions, periodontal pathogenic bacteria and RA-related cytokines remain unclear. PMID- 28919285 TI - Department of Error. PMID- 28919286 TI - A novel optimized hybrid fuzzy logic intelligent PID controller for an interconnected multi-area power system with physical constraints and boiler dynamics. AB - In the fast developing world nowadays, load frequency control (LFC) is considered to be a most significant role for providing the power supply with good quality in the power system. To deliver a reliable power, LFC system requires highly competent and intelligent control technique. Hence, in this article, a novel hybrid fuzzy logic intelligent proportional-integral-derivative (FLiPID) controller has been proposed for LFC of interconnected multi-area power systems. A four-area interconnected thermal power system incorporated with physical constraints and boiler dynamics is considered and the adjustable parameters of the FLiPID controller are optimized using particle swarm optimization (PSO) scheme employing an integral square error (ISE) criterion. The proposed method has been established to enhance the power system performances as well as to reduce the oscillations of uncertainties due to variations in the system parameters and load perturbations. The supremacy of the suggested method is demonstrated by comparing the simulation results with some recently reported heuristic methods such as fuzzy logic proportional-integral (FLPI) and intelligent proportional-integral-derivative (PID) controllers for the same electrical power system. the investigations showed that the FLiPID controller provides a better dynamic performance and outperform compared to the other approaches in terms of the settling time, and minimum undershoots of the frequency as well as tie-line power flow deviations following a perturbation, in addition to perform appropriate settlement of integral absolute error (IAE). Finally, the sensitivity analysis of the plant is inspected by varying the system parameters and operating load conditions from their nominal values. It is observed that the suggested controller based optimization algorithm is robust and perform satisfactorily with the variations in operating load condition, system parameters and load pattern. PMID- 28919287 TI - Active fault tolerant control based on interval type-2 fuzzy sliding mode controller and non linear adaptive observer for 3-DOF laboratory helicopter. AB - In this paper, a robust controller for a three degree of freedom (3 DOF) helicopter control is proposed in presence of actuator and sensor faults. For this purpose, Interval type-2 fuzzy logic control approach (IT2FLC) and sliding mode control (SMC) technique are used to design a controller, named active fault tolerant interval type-2 Fuzzy Sliding mode controller (AFTIT2FSMC) based on non linear adaptive observer to estimate and detect the system faults for each subsystem of the 3-DOF helicopter. The proposed control scheme allows avoiding difficult modeling, attenuating the chattering effect of the SMC, reducing the rules number of the fuzzy controller. Exponential stability of the closed loop is guaranteed by using the Lyapunov method. The simulation results show that the AFTIT2FSMC can greatly alleviate the chattering effect, providing good tracking performance, even in presence of actuator and sensor faults. PMID- 28919288 TI - Control of unstable processes with time delays via ADRC. AB - Active disturbance rejection control (ADRC) treats the external disturbance and internal uncertainties as a general disturbance, and uses an extended state observer (ESO) to estimate it in real-time and feeds it back in the control loop, thus can achieve good disturbance rejection performance. However, ADRC is not quite suitable for unstable delayed processes due to its inherent structure. In this paper, a two-degree-of-freedom (2DOF) control structure is proposed for unstable time- delayed systems. Set-point tracking and disturbance rejection are separated in this structure and ADRC is solely responsible for disturbance rejection. A method to tune the ADRC parameters using all the information of the system is proposed, and robustness and performance of the proposed method are analyzed. Simulation examples show that 2DOF-ADRC can achieve good tracking and disturbance rejection performance. PMID- 28919289 TI - A solid criterion based on strict LMI without invoking equality constraint for stabilization of continuous singular systems. AB - The paper considers the stabilization issue of linear continuous singular systems by dealing with strict linear matrix inequalities (LMIs) without invoking equality constraint and proposes a complete and effective solved LMIs formulation. The criterion is necessary and sufficient condition and can be directly solved the feasible solutions with LMI toolbox and is much more tractable and reliable in numerical simulation than existing results, which involve positive semi-definite LMIs with equality constraints. The most important property of the criterion proposed in the paper is that it can overcome the drawbacks of the invalidity caused by the singularity of Omega=PET+SQ for stabilization of singular systems. Two counterexamples are presented to avoid the disadvantages of the existing condition of stabilization of continuous singular systems. PMID- 28919290 TI - Utility and limitations of long-term monitoring of atrial fibrillation using an implantable loop recorder. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia diagnosed and treated in the world. The treatment of patients' symptoms as well as the prevention of stroke and heart failure is dependent on accurate detection and characterization of AF. A variety of electrocardiographic (ECG) monitoring techniques are being used for these purposes. However, these intermittent ECG monitoring techniques have been shown to underdiagnose AF events while having limited ability to characterize AF burden and density. Continuous long-term implantable loop recorder (ILR)-based ECG monitoring has been designed to overcome these limitations. This technology is being increasingly used to diagnose episodes of AF in high-risk patients and to improve characterization of AF episodes in patients with known AF. This review aims to review the potential clinical utility of ILR-based ECG monitoring while highlighting some inherent limitations of the current technology. An understanding of these limitations is important when considering the use of ILR-based ECG monitoring and clinical decision making based on the information being stored within these devices. PMID- 28919291 TI - Towards program theory validation: Crowdsourcing the qualitative analysis of participant experiences. AB - This exploratory study examines a novel tool for validating program theory through crowdsourced qualitative analysis. It combines a quantitative pattern matching framework traditionally used in theory-driven evaluation with crowdsourcing to analyze qualitative interview data. A sample of crowdsourced participants are asked to read an interview transcript and identify whether program theory components (Activities and Outcomes) are discussed and to highlight the most relevant passage about that component. The findings indicate that using crowdsourcing to analyze qualitative data can differentiate between program theory components that are supported by a participant's experience and those that are not. This approach expands the range of tools available to validate program theory using qualitative data, thus strengthening the theory driven approach. PMID- 28919292 TI - Treatment Patterns, Health Care Resource Utilization, and Spending in Medicaid Beneficiaries Initiating Second-generation Long-acting Injectable Agents Versus Oral Atypical Antipsychotics. AB - PURPOSE: Second-generation long-acting injectable therapies (SGA-LAIs) may reduce health care resource utilization (HRU) and health care costs compared with daily oral atypical antipsychotics (OAAs) in patients with schizophrenia due to reduced dosing frequency, delivery/monitoring by a health care provider, and improved adherence. The aim of the present study was to compare treatment patterns, HRU, and Medicaid spending in patients with schizophrenia initiated on SGA-LAIs (overall and according to agent) versus OAAs. METHODS: Medicaid claims data (2010 2015) from 6 states were used to identify adult schizophrenia patients initiated on SGA-LAIs or OAAs. Treatment patterns (proportion of days covered [PDC] >=80% and persistence [no gap >=30, 60, or 90 days] to index treatment), HRU, and costs were evaluated over 12 months and compared by using multivariable logistic, Poisson, and ordinary least squares regression models, respectively. P values for HRU and cost outcomes were obtained from a nonparametric bootstrap procedure. Costs (2015 US dollars) reflect the Medicaid payer's perspective before any rebate. FINDINGS: Overall, 3307 and 21,355 patients initiated SGA-LAIs and OAAs, respectively (paliperidone palmitate LAI [PP-LAI; n = 2182], risperidone LAI [n = 968], aripiprazole LAI [n = 108], and olanzapine LAI [n = 49]). During follow-up and compared with OAA patients, SGA-LAI patients were more likely to reach PDC >=80% (odds ratio [OR], 1.28; P < 0.001) and be persistent (eg, no gap >=60 days; OR, 1.45; P < 0.001) to the index treatment. Relative to OAA patients, SGA-LAI patients had fewer long-term care days (incidence rate ratio [IRR], 0.75; P < 0.001) and home care visits (IRR, 0.75; P < 0.001) but more mental health institute (IRR, 1.16; P < 0.001) and 1-day mental health institute (IRR, 1.16; P < 0.001) admissions. Moreover, PP-LAI patients had fewer inpatient days (IRR, 0.78; P = 0.004) versus OAA patients. SGA-LAI patients had lower medical costs (mean monthly cost difference [MMCD], -$168; P < 0.001) than OAA patients, offsetting more than one half of the higher pharmacy costs (MMCD, $271; P < 0.001). Compared with OAAs, only PP-LAI was associated with significant medical cost savings (MMCD, -$225; P < 0.001). IMPLICATIONS: Medicaid beneficiaries with schizophrenia initiated on SGA-LAIs had better adherence and persistence to therapy over 12 months than patients initiated on OAAs. SGA-LAIs, particularly PP LAI, were associated with lower medical costs that successfully offset more than one half of the higher pharmacy costs relative to OAA. PMID- 28919293 TI - Correlation between histological and ultrasonographic findings of soft tissue tumors: To verify the possibility of cell-like resolution in ultrasonography. AB - BACKGROUND: The purpose of this study is to test the possibility of obtained cell like resolution in soft tissue tumors on the basis of ultrasound echotexture. METHODS: This is a prospective study consisting of 57 patients (29 females and 28 males, age range: 9-83 years, average age: 44.5 years) with palpable soft tissue mass, referred from the Departments of Orthopedics and Oncology for ultrasound (US)-guided biopsy. The study was approved by the institutional review board (IRB) of our hospital. Ultrasonographic images were recorded by still imaging in the biopsy tract in each biopsy session. Equipment included curvilinear and linear array probes. After biopsy, a radiologist and a pathologist correlated the US image and the observations regarding the histology of the tissue specimen in low-power (40 * magnification) and high-power (100-400 * magnification) fields. RESULTS: The histologic results included 22 benign and 35 malignant lesions. The echotexture of the soft tissue tumors correlated well with the cellular distribution and arrangement: the greater the number of cells and the more regular their arrangement as seen histologically, the greater is the hypoechogenicity on the ultrasound. The echogenicity of the soft tissue tumor also correlated well with the presence of fat cells, hemorrhage, cartilage, and osteoid tissue, all of which cause an increase in echogenicity. CONCLUSION: This study showed that the echotexture of soft tissue tumors can predict some details of cellular histology. PMID- 28919294 TI - Studying the efficacy of escalated dose conformal radiation therapy in prostate carcinoma - Pakistan experience. AB - BACKGROUND: Our objective in this study was to evaluate the role and benefits in terms of local toxicity and biochemical disease-free survival (bDFS) following escalated-dose conformal radiation therapy in prostate adenocarcinoma. METHODS: The study population was composed of 53 patients with histologically proven T1b T4, NO, MO prostate adenocarcinoma, having any Gleason score with prostate specific antigen (PSA) of less than 50 ng/mL at diagnosis, given escalated dose EBRT (74 Gy) during the period between January 2011 and December 2013, retrospectively and evaluated for a period of 2 years post-radiation. Patients were followed up for a period of 2 years, beginning after completion of escalated dose external beam radiotherapy (EBRT) for biochemical failure as defined in ASTRO consensus committee guidelines 1996 and investigated for gastrointestinal, genitourinary skin toxicity. RESULTS: Out of 53 patients, 35 showed no biochemical failure at the end of 2 years following the completion of definitive escalated dose conformal radiotherapy while 18 were observed to have biochemical relapse. Acute gastrointestinal grade 1 toxicity was found in 26 patients, grade 2 in 24, and grade 3 only in 3 patients. Late gastrointestinal grade 0 toxicity was found in 16 patients, grade 1 in 28, grade 2 in 7 and grade 3 only in 2 patients. Grade 1 acute genitourinary toxicity was the highest in frequency observed in 28 of the total population followed by grade 2 in 21, grade 0 and grade 3 each, only in 2 patients. Late genitourinary Grade 0 toxicity was observed in 32 patients, grade 1 in 19, grade 2 and 3 only in 1 patient of the total population, respectively. CONCLUSION: Our data were comparable to international studies of dose escalation using 3D and beneficial as compared to conventional radiation therapy delivered by 2D in terms of biochemical failure rate and treatment related toxicity. PMID- 28919295 TI - Outcomes of resection surgery for hepatocellular carcinoma: Does size matter? PMID- 28919296 TI - Ocular findings on follow-up in children who received phototherapy for neonatal jaundice. AB - BACKGROUND: To evaluate the ocular findings in children between 3 and 5 years of age who had received phototherapy in the neonatal period and to investigate whether they had phototherapy-related permanent ocular damage clinically. METHODS: The phototherapy group (n = 57) consisted of children who had undergone phototherapy for at least 24 h, and the control group (n = 43) comprised children who had not received phototherapy. Ophthalmic examinations consisted of assessment of visual acuity, convergence near point, ocular movements, ocular alignment, dynamic retinoscopy, cycloplegic refraction and biomicroscopic examination of anterior segment and posterior segment (using a 90 D lens in the latest). RESULTS: All children were orthophoric and had normal eye movements. A significant difference was found between the phototherapy group and control group regarding convergence near point 3.0 (2.0-5.0) vs 3.0 (2.0-5.0) (p = 0.018), right cycloplegic spherical equivalent 1.0 (0.0-3.0) vs 0.75 (0.0-4.75) (p = 0.011) and left cycloplegic spherical equivalent 1.0 (0.075-3.0) vs 0.75 (0.0 5.25) (p = 0.006).The study groups were similar according to cycloplegic spherical and cylindrical refractions. However, no significant difference was found between the groups regarding the need for eye glasses. CONCLUSION: Although there were significant differences between the phototherapy and the control groups according to the convergence near point and right and the left eye cycloplegic spherical equivalent, the similarity between the groups regarding the need for eyeglasses suggested that difference was clinically insignificant. PMID- 28919297 TI - Androgens and endometrium: New insights and new targets. AB - Androgens are synthesised in both the ovary and adrenals in women and play an important role in the regulation of female fertility, as well as in the aetiology of disorders such as polycystic ovarian syndrome, endometriosis and endometrial cancer. The endometrium is an androgen target tissue and the impact of AR mediated effects has been studied using human endometrial tissue samples and rodent models. In this review we highlight recent evidence that endometrial androgen biosynthesis and intracrine action is important in preparation of a tissue microenvironment that can support implantation and establishment of pregnancy. The impact of androgens on endometrial cell proliferation, in repair of the endometrial wound at the time of menstruation and in endometrial disorders is discussed. Future directions for research focused on AR function as a therapeutic target are considered. PMID- 28919298 TI - MXRA5 is decreased in preeclampsia and affects trophoblast cell invasion through the MAPK pathway. AB - Preeclampsia causes gestational failure in a significant number of women annually. Insufficient trophoblast cell invasion plays an essential role in preeclampsia pathogenesis. Matrix-remodeling associated 5 (MXRA5) is a proteoglycan involved in adhesion and matrix remodeling. This study sought to explore the role of MXRA5 in trophoblast cell invasion. Preeclamptic villi were obtained for the delineation of MXRA5 expression. Specific MXRA5 siRNA and pcDNA3.1/MXRA5 were used to manipulate MXRA5 expression in HTR-8/SVneo. Cell viability was determined by MTT and apoptosis by flow cytometry. Cell invasion was evaluated using Matrigel invasion assay. MXRA5 expression was lower in preeclamptic villi and cytotrophoblasts. Silencing MXRA5 expression in HTR 8/SVneo decreased cell viability and invasion, which were augmented by MXRA5 overexpression. Furthermore, MXRA5 modulated N-cadherin, E-cadherin, MMP-2, and MMP-9 expression through p38 MAPK and ERK1/2 signaling transduction. In addition, the expression of MXRA5 was influenced by exogenous TNF-alpha but not by IFN gamma. Overexpression of MXRA5 attenuated HTR-8/SVneo apoptosis induced by TNF alpha. MXRA5 is downregulated in preeclamptic cytotrophoblasts and can regulate trophoblast cell invasion via the MAPK pathway. PMID- 28919299 TI - The retrotransposon gag domain containing protein Rgag4 is an Ikaros target in the pituitary. AB - Previous studies have established the common and critical involvement of the zinc finger protein Ikaros in lymphoid and pituitary cell development and expansion. Key to the assembly of several transcriptional networks, we have demonstrated up regulation of Ikaros and its interacting partner the C-terminal Binding Protein (CtBP) in response to hypoxia. This prompted us to explore common transcriptional targets using a chromatin immunoprecipitate (ChIP) screen of DNA from pituitary corticotroph cells. This strategy yielded a finite list of targets common to both transcription factors that included the metalloprotease ADAMTS10. In this report, we focus on validation of a second candidate target, the retrotransposon gag domain containing protein Rgag4. We identified the ability of Ikaros to bind the Rgag4 promoter, influence its transcriptional activity, and induce endogenous gene expression. Robust expression of Rgag4 was noted in the anterior lobe of the pituitary gland which was diminished in Ikaros knockout mice. Down-regulation of Rgag4 resulted in profound reduction of hormone gene expression with diminished ACTH secretion, recapitulating the effect of Ikaros deficiency in knockout mice. The results introduce Rgag4 to the repertoire of effectors serving to couple the chromatin remodeler Ikaros with the hormonal stress response. PMID- 28919301 TI - Prostaglandins in teleost ovulation: A review of the roles with a view to comparison with prostaglandins in mammalian ovulation. AB - Prostaglandins are well known to be central regulators of vertebrate ovulation. Studies addressing the role of prostaglandins in mammalian ovulation have established that they are involved in the processes of oocyte maturation and cumulus oocyte complex expansion. In contrast, despite the first indication of the role of prostaglandins in teleost ovulation appearing 40 years ago, the mechanistic background of their role has long been unknown. However, studies conducted on medaka over the past decade have provided valuable information. Emerging evidence indicates an indispensable role of prostaglandin E2 and its receptor subtype Ptger4b in the process of follicle rupture. In this review, we summarize studies addressing the role of prostaglandins in teleost ovulation and describe recent advances. To help understand differences from and similarities to ovulation in mammalian species, the findings on the roles of prostaglandins in mammalian ovulation are discussed in parallel. PMID- 28919300 TI - The significance of cholesterol and its metabolite, 27-hydroxycholesterol in breast cancer. AB - Although significant advances in the treatment of breast cancer have been made, in particular in the use of endocrine therapy, de novo and aquired resistance to therapy, and metastatic recurrence continue to be major clinical problems. Given the high prevalence of breast cancer, new life-style or chemotherapeutic approaches are required. In this regard, cholesterol has emerged as a risk factor for the onset of breast cancer, and elevated cholesterol is associated with a poor prognosis. While treatment with cholesterol lowering medication is not associated with breast cancer risk, it does appear to be protective against recurrence. Importantly, the cholesterol axis represents a potential target for both life-style and pharmacological intervention. This review will outline the clinical and preclinical data supporting a role for cholesterol in breast cancer pathophysiology. Specific focus is given to 27-hydroxycholesterol (27-OHC; (3beta,25R)-Cholest-5-ene-3,26-diol)), a primary metabolite of cholesterol that has recently been defined as an endogenous Selective Estrogen Receptor Modulator. Future perspectives and directions are discussed. PMID- 28919302 TI - Obesity and breast cancer - Role of estrogens and the molecular underpinnings of aromatase regulation in breast adipose tissue. AB - One in eight women will develop breast cancer over their lifetime making it the most common female cancer. The cause of breast cancer is multifactorial and includes hormonal, genetic and environmental cues. Obesity is now an accepted risk factor for breast cancer in postmenopausal women, particularly for the hormone-dependent subtype of breast cancer. Obesity, which is characterized by an excess accumulation of body fat, is at the origin of chronic inflammation of white adipose tissue and is associated with dramatic changes in the biology of adipocytes leading to their dysfunction. Inflammatory factors found in the breast of obese women considerably impact estrogen signaling, mainly by driving changes in aromatase expression the enzyme responsible for estrogen production, and therefore promote tumor formation and progression. There is thus a strong link between adipose inflammation and estrogen biosynthesis and their signaling pathways converge in obese patients. This review describes how obesity-related factors can affect the risk of hormone-dependent breast cancer, highlighting the different molecular mechanisms and metabolic pathways involved in aromatase regulation, estrogen production and breast malignancy in the context of obesity. PMID- 28919304 TI - Safety of novel liposomal drugs for cancer treatment: Advances and prospects. AB - Liposome is a kind of prospective abiotic drug delivery system for cancer treatment. Novel liposomes modified with PEG, cationic lipids and highly selective molecules achieve better stability, half-life and selectivity as well as less severe side effects. However, novel liposomes are still not nontoxic. PEG on the surface of liposomes interfere the combination of cancer cells and drugs. Cationic liposomes can induce oxidative damage and cytotoxicity to normal tissues. To further improve the safety of liposomal drugs, liposomal drugs must be highly selective to cancer tissues and cancer cells, at the same time, induce minimum damage to normal cells. It is necessary to gather several advantages of novel liposomes. The ideal targeted drug delivery system is like a multistage rocket. Firstly, the liposomal drugs should be sensitive to the specific environment of cancer tissues and accumulate in there. Secondly, the liposomes could selectively combine with cancer cells by surface modification. Lastly, in cancer cells, drugs release from the carriers rapidly. What's more, form the records of clinical researches, the side effects induced by liposomal drugs, such as acute infusion reaction and hand-foot syndrome(HFS), are also unignorable. More attention should be paid to these safety problems in new liposomal drugs research and development. PMID- 28919303 TI - Acquisition of wild-type HIV-1 infection in a patient on pre-exposure prophylaxis with high intracellular concentrations of tenofovir diphosphate: a case report. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate is highly effective against acquisition of HIV infection, and only two cases of infection with a multidrug-resistant virus have been reported under adequate long-term adherence, as evidenced by tenofovir diphosphate concentrations in dried blood spots. We report a case of wild-type HIV-1 infection despite consistent use of emtricitabine and tenofovir disoproxil fumarate. METHODS: The patient participated in the Amsterdam PrEP project, a demonstration project of daily and event-driven PrEP. We did extensive testing for HIV, including plasma HIV RNA and nested PCR on bulk peripheral blood mononuclear cells (PBMCs) and sigmoid biopsies after seroconversion. FINDINGS: A 50-year-old man who has sex with men and had been on daily emtricitabine and tenofovir disoproxil fumarate for 8 months presented with fever, urinary tract infection caused by Escherichia coli, anal lymphogranuloma venereum infection, and a positive fourth-generation HIV test. We found an atypical seroconversion pattern, with initially only gp160 antibodies detected in the western blot. HIV RNA could not be detected in plasma, and nested PCR for HIV RNA and DNA on bulk PBMCs and sigmoid biopsies were negative. PrEP was discontinued; 3 weeks later HIV RNA was detected in plasma. No drug-resistant mutations were detected. Tenofovir diphosphate concentrations in dried blood spots were stable and high. INTERPRETATION: To our knowledge, this is the first detailed case report suggesting wild-type HIV-1 infection despite good adherence, evidenced by repeatedly high concentrations of tenofovir diphosphate in dried blood spots. PrEP providers need to be aware that infection can occur despite good adherence. Regular HIV testing and awareness of atypical patterns of seroconversion is highly recommended. FUNDING: ZonMw, National Institute for Public Health and the Environment, Internal GGD research funds, Aidsfonds, Stichting AmsterdamDiner Foundation, Gilead Sciences, Janssen Pharmaceutica, M A C AIDS Fund, and ViiV Healthcare. PMID- 28919305 TI - Magnolol protects pancreatic beta-cells against methylglyoxal-induced cellular dysfunction. AB - Chronic hyperglycemia aggravates insulin resistance, in part due to increased formation of advanced glycation end-products (AGEs). Methylglyoxal (MG), a major precursor of AGEs, accumulates abnormally in various tissues and organs and participates in oxidative damage. We investigated the insulinotropic benefits of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, in pancreatic beta-cells exposed to MG in vitro. When exposed to cytotoxic levels of MG for 48 h, RIN-m5F beta-cells exhibited a significant loss of viability and impaired insulin secretion, whereas pretreatment with magnolol protected against MG-induced cell death and decreased insulin secretion. Moreover, magnolol increased the expression of genes involved in beta-cell survival and function, including Ins2 and PDX1. Furthermore, magnolol increased the levels of AMPK phosphorylation, SIRT1, and PGC1alpha in RIN-5F beta-cells. In addition, magnolol increased the activity of glyoxalase I and decreased the levels of MG-modified protein adducts, which suggests that magnolol protects against MG-induced protein glycation. Taken together, the results indicate the potential application of magnolol as an intervention against MG-induced hyperglycemia. PMID- 28919306 TI - Comments on:"In vitro and in vivo pharmacokinetics and toxicity evaluation of curcumin incorporated titanium dioxide nanoparticles for biomedical applications". PMID- 28919307 TI - A journey between high altitude hypoxia and critical patient hypoxia: What can it teach us about compression and the management of critical disease? AB - High altitude sickness (hypobaric hypoxia) is a form of cellular hypoxia similar to that suffered by critically ill patients. The study of mountaineers exposed to extreme hypoxia offers the advantage of involving a relatively homogeneous and healthy population compared to those typically found in Intensive Care Units (ICUs), which are heterogeneous and generally less healthy. Knowledge of altitude physiology and pathology allows us to understanding how hypoxia affects critical patients. Comparable changes in mitochondrial biogenesis between both groups may reflect similar adaptive responses and suggest therapeutic interventions based on the protection or stimulation of such mitochondrial biogenesis. Predominance of the homozygous insertion (II) allele of the angiotensin-converting enzyme gene is present in both individuals who perform successful ascensions without oxygen above 8000 m and in critical patients who overcome certain disease conditions. PMID- 28919308 TI - Alternative splicing in cancers: From aberrant regulation to new therapeutics. AB - Alternative splicing is one of the most common mechanisms for gene regulation in humans, and plays a vital role to increase the complexity of functional proteins. In this article, we seek to provide a general review on the relationships between alternative splicing and tumorigenesis. We briefly introduce the basic rules for regulation of alternative splicing, and discuss recent advances on dynamic regulation of alternative splicing in cancers by highlighting the roles of a variety of RNA splicing factors in tumorigenesis. We further discuss several important questions regarding the splicing of long noncoding RNAs and back splicing of circular RNAs in cancers. Finally, we discuss the current technologies that can be used to manipulate alternative splicing and serve as potential cancer treatment. PMID- 28919309 TI - The heterogeneity of human Cajal-Retzius neurons. AB - The definition of a Cajal-Retzius neuron (CRN) is still controversial, in part possibly due to species differences. We review the developmental history of CRN in human neocortex and focus on two main CRN family members, transient (t) and persisting (p) CRN. They share the expression of Reelin andTbr1, complemented by p73, calretinin, CXCR4 and NOS, but differ in their moment of appearance, fate and morphology. The distinctive feature of tCRN is the axon plexus in the lower third of the marginal zone, which innervates the apical dendritic tufts of pyramidal cells and may serve as a migration substrate and waiting compartment for interneurons descending from the subpial granular layer (SGL) into the cortical plate. Around midgestation, the SGL also gives rise to a transient interneuron type, the miniature neuron, that provides the GABAergic innervation of tCRN, which eventually, through diverse signaling pathways involving p73, contribute to the demise of tCRN and the breakdown of their plexus. The pCRN appear in the last trimester of gestation and may derive from committed CRN progenitors which migrate with the SGL from the periolfactory forebrain. They lack the horizontal CR plexus, and may be implicated in cortical folding, distribution of blood vessels, and plasticity of microcircuits in the molecular layer. PMID- 28919310 TI - Cadherin-11 promotes neural crest cell spreading by reducing intracellular tension-Mapping adhesion and mechanics in neural crest explants by atomic force microscopy. AB - During development cranial neural crest cells (NCCs) display a striking transition from collective to single-cell migration, but the mechanisms enabling individual NCCs to separate from the neural crest tissue are still incompletely understood. In this study we have employed atomic force microscopy (AFM) to investigate potential adhesive and mechanical changes associated with the dissociation of individual cells from cohesive Xenopus NCC explants at early stages of migration. AFM-based single-cell force spectroscopy (SCFS) revealed a uniform distribution of cell-cell adhesion forces within NCC explants, including semi-detached leader cells in the process of delaminating from the explant edge. This suggested that dissociation from the cell sheet may not require prior weakening of cell-cell contacts. However, mapping NCC sheet elasticity by AFM microbead indentation demonstrated strongly reduced cell stiffness in semi detached leader cells compared to neighbouring cells in the NCC sheet periphery. Reduced leader cell stiffness coincided with enhanced cell spreading and high substrate traction, indicating a possible mechano-regulation of leader cell delamination. In support, AFM elasticity measurements of individual NCCs in optical side view mode demonstrated that reducing cell tension by inhibiting actomyosin contractility induces rapid spreading, possibly maximizing cell substrate interactions as a result. Depletion of cadherin-11, a classical cadherin with an essential role in NCC migration and substrate adhesion, prevented the tension reduction necessary for NCC spreading, both in individual cells and at the edge of explanted sheets. In contrast, overexpression of cadherin-11 accelerated spreading of both individual cells and delaminating leader cells. As cadherin-11 expression increases strongly during NCC migration, this suggests an important role of cadherin-11 in regulating NCC elasticity and spreading at later stages of NCC migration. We therefore propose a model in which high tension at the NCC sheet periphery prevents premature NCC spreading and delamination during early stages of migration, while a cadherin-11-dependent local decrease in cell tension promotes leader cell spreading and delamination at later stages of migration. PMID- 28919311 TI - Sensing and transport of nutrients in plants. PMID- 28919312 TI - The Combined Effects of Adaptive Control and Virtual Reality on Robot-Assisted Fine Hand Motion Rehabilitation in Chronic Stroke Patients: A Case Study. AB - Robot-assisted therapy is regarded as an effective and reliable method for the delivery of highly repetitive training that is needed to trigger neuroplasticity following a stroke. However, the lack of fully adaptive assist-as-needed control of the robotic devices and an inadequate immersive virtual environment that can promote active participation during training are obstacles hindering the achievement of better training results with fewer training sessions required. This study thus focuses on these research gaps by combining these 2 key components into a rehabilitation system, with special attention on the rehabilitation of fine hand motion skills. The effectiveness of the proposed system is tested by conducting clinical trials on a chronic stroke patient and verified through clinical evaluation methods by measuring the key kinematic features such as active range of motion (ROM), finger strength, and velocity. By comparing the pretraining and post-training results, the study demonstrates that the proposed method can further enhance the effectiveness of fine hand motion rehabilitation training by improving finger ROM, strength, and coordination. PMID- 28919313 TI - Periprocedural Outcomes of Carotid Artery Stenting in Elderly Patients. AB - BACKGROUND: Carotid artery stenting has emerged as an alternative to carotid endarterectomy especially in patients with high risk of carotid endarterectomy. Older age (>=80 years old) was recognized as one of the high risk factors of carotid endarterectomy. However, the association between older age and increased risk of adverse events for carotid artery stenting has been reported. The purpose of this study was to evaluate the association between age and periprocedural outcomes after carotid artery stenting. METHODS: A total of 126 symptomatic and asymptomatic cases of carotid artery stenosis were treated with tailored carotid artery stenting. The type of stents and embolic protection devices were chosen according to clinical and morphologic characteristics of the patients. Procedural, imaging, and clinical outcomes were retrospectively assessed and compared between the elderly patients group (>=80 years old) and the non-elderly patients group (<80 years old). RESULTS: Clinical and morphologic characteristics except for dyslipidemia were not significantly different between the 2 groups. Periprocedural neurologic complications were not significantly different between the 2 groups (P = .095). Minor stroke occurred more frequently in the elderly patients group (P = .021). However, the frequency of major stroke was not significantly different between the 2 groups (P = 1). Presence of new ischemic lesions on postprocedural examination was not significantly different between the 2 groups (P = .84). Myocardial infarction and death did not occur in either group. CONCLUSIONS: Carotid artery stenting can be performed safely in elderly patients, comparable with non-elderly patients. PMID- 28919314 TI - 24-Hour Alberta Stroke Program Early CT Score Assessment in Post-Stroke Spasticity Development in Patients with a First Documented Anterior Circulation Ischemic Stroke. AB - BACKGROUND: Neuroanatomic substrates responsible for development of post-stroke spasticity are still poorly understood. The study is focused on identification of brain regions within the territory of the middle cerebral artery associated with spasticity development. METHODS: This is a single-center prospective cohort study of first documented anterior circulation ischemic strokes with a neurologic deficit lasting >7 days (from March 2014 to September 2016, all patients are involved in a registry). Ischemic cerebral lesions within the territory of middle cerebral artery were evaluated using the Alberta Stroke Program Early CT Score (ASPECTS) on control 24-hour computed tomography or magnetic resonance imaging. Spasticity was assessed with modified Ashworth scale. RESULTS: Seventy-six patients (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen activator, 6.5% mechanical thrombectomy) fulfilled the study inclusion criteria. Forty-nine (64%) developed early elbow or wrist flexor spasticity defined as modified Ashworth scale >1 (at day 7-10), in 44 (58%) the spasticity remained present at 6 months. There were no differences between the patients who developed spasticity and those who did not when comparing admission stroke severity (National Institutes of Health Stroke Scale 5 [interquartile range {IQR} 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease). Nor was there a difference in 24-hour ASPECTS score (9 [IQR 8-10] versus 9 [IQR 7-10]). No differences were found between the groups with and without the early upper limb flexor spasticity of particular regions (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentral-postcentral gyrus, premotor cortex, supplementary motor area, posterior limb of internal capsule, and thalamus were compared. CONCLUSIONS: We did not find any middle cerebral artery territory associated with post-stroke spasticity development by detailed evaluation of ASPECTS. PMID- 28919315 TI - The Ongoing Challenge of Urinary Incontinence after Radical Prostatectomy. PMID- 28919316 TI - Editorial Comment. PMID- 28919317 TI - Editorial Comment. PMID- 28919318 TI - Corrigendum to "Assessment of a multi-modal intervention for the prevention of catheter-associated urinary tract infections" [J Hosp Infect. 2016 Oct;94(2):175 81]. PMID- 28919319 TI - A population-based description of familial clustering of Hirschsprung disease. AB - BACKGROUND: Familial recurrence of Hirschsprung disease (HSCR) is well documented, and risk estimates for relatives have been reported from various populations. We describe the familial clustering of HSCR cases using well established unbiased familial aggregation techniques within the context of a population genealogy. METHODS: Patients included 264 HSCR cases identified using ICD-9 diagnosis coding from the two largest healthcare providers in Utah who also had linked genealogy data. The GIF statistic was used to identify excess familial clustering by comparing average relatedness of cases to matched controls. In addition, relative risks (RRs) of HSCR in relatives of cases were estimated using age-, sex- and birthplace-matched disease rates, and for several diseases frequently associated with HSCR (Down syndrome, multiple endocrine neoplasia IIa, central hypoventilation syndrome, Bardet-Biedl syndrome, ventricular and atrial septal defect). RESULTS: Significant excess relatedness was observed for all HSCRs (p<1e-3). Significant RRs for HSCR were observed for first-, second-, and fourth-degree relatives of cases (RR=12.0, 10.0, and 4.6, respectively). Significant elevated risks of Down syndrome, Bardet-Biedl syndrome, and atrial and ventricular septal defects were observed for HSCR cases. CONCLUSION: This population-based survey of HSCR provides confirmation of a genetic contribution to HSCR disease and presents unbiased risk estimates that may have clinical value in predicting recurrence. LEVEL OF EVIDENCE RATING: Prognosis study, level II. PMID- 28919320 TI - Is selective echocardiography in duodenal atresia the future standard of care? AB - BACKGROUND: Duodenal atresia (DA) is associated with cardiac defects that may have perioperative care implications. Standard preoperative care includes echocardiography to identify such cardiac defects, but this dogma has been challenged. We aimed to assess selective and selective strategies for preoperative echocardiography in DA patients. METHODS: Single-center retrospective review of neonates with DA over a 16-year period was performed. Data included preoperative cardiovascular and respiratory examination, chest x ray, and echocardiography. We compared the current nonselective versus selective strategies, limiting preoperative echocardiogram to those in whom: (1) cardiac or respiratory or chest x-ray examination was abnormal, or (2) cardiac or respiratory examination was abnormal. Sensitivity, specificity, positive and negative predictive values were compared with chi-square tests. RESULTS: Seventy one of 109 (65%) consecutive neonates with DA underwent preoperative echocardiography according to a nonselective, physician-determined strategy. Forty of 71 (56%) patients had cardiac defects, including 16/40 (27%) major defects. Sixteen additional postoperative echocardiograms revealed 2 missed major defects. In the same cohort, selective strategies would have performed 17-24% fewer echocardiograms without significant detriment in performance. CONCLUSIONS: All strategies considered missed some major cardiac defects. A selective strategy, determining DA patients not requiring preoperative echocardiogram, could reduce the number of echocardiograms performed without compromising patient safety. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level II. PMID- 28919321 TI - Clinicopathological pattern and outcome of pediatric malignant ovarian germ cell tumors: South Egypt Cancer Institute experience. AB - BACKGROUND: Malignant ovarian germ cell tumors (MOGCTs) are rare and represent 1 1.5% of all cancers in children and adolescents. The aim of this study is to analyze the clinicopathological pattern at presentation and management and outcome of MOGCTs in children and adolescents. PATIENTS AND METHODS: Retrospective study included all girls diagnosed with MOGCTs between January 2005 and January 2015 in Pediatric and Surgical Oncology Departments at South Egypt Cancer Institute, Assiut University. Data were collected from patients' records including initial presentation, diagnosis (tumor markers and imaging), surgical staging and pathologic types. Management (surgical and chemotherapy details) and outcomes were also analyzed. RESULTS: Forty girls aged between 4 to 17years (mean age of 9.5years) with diagnosis of MOGCTs during study period were included. The most common presenting symptoms and signs were abdominal swelling, abdominal pain, and pelvic mass. Precocious puberty was noted in two patients. Surgical interventions in most patients were unilateral salpingo-oophorectomy (n=20). Early stages I and II were reported in 15 and 12 patients respectively, while 10 patients had stage-III disease and 3 patients had stage IV. Yolk sac tumors were reported in 27.5% of patients. All patients were treated with platinum based chemotherapy. The 7-year overall survival was higher for patients with early stages (I and II) compared with advanced stages (III and IV) (100% versus 30.8% respectively. CONCLUSIONS: Early presentation with appropriate management using fertility sparing surgery and platinum-based chemotherapy provides excellent survival with fertility preservation in children and adolescents. Based on the lower survival of patients with advanced disease, efforts should focus on increasing the awareness in the community of the importance of early diagnosis of ovarian tumors. LEVEL OF EVIDENCE: II (retrospective study). PMID- 28919322 TI - Changes in vasodilation following myocardial ischemia/reperfusion in rats. AB - BACKGROUND: Blockage of a coronary artery, usually caused by arteriosclerosis, can lead to life threatening acute myocardial infarction. Opening with PCI (percutaneous coronary intervention), may be lifesaving, but reperfusion might exacerbate the cellular damage, and changes in the endothelium are believed to be involved in this worsened outcome. AIM: The aim of the present study was to compare endothelial dependent and independent vasodilatory effect after experimental myocardial ischemia/reperfusion (I/R). METHODS: A well-established rat model of myocardial ischemia with 24 h of reperfusion was applied, followed by a study in a wire myograph. RESULTS: Endothelial NO dependent relaxation in response to carbachol, was sensitive to arterial depolarization, and was unaffected by I/R. In contrast, endothelial NO dependent ADPbetaS signalling, which was not sensitive to arterial depolarization, was significantly reduced after I/R. Following I/R, an H2O2 dependent EDH induced dilation appears in response to both of the above agonists. In addition, calcitonin gene-related peptide (CGRP) induced vasodilation was reduced. CONCLUSION: These data show that NO dependent ADPbetaS induced dilation is reduced after I/R. However, there is some compensation by released H2O2 causing an EDH. Combined with a loss of maximal dilation in response to CGRP, the reduced vasodilation could be an important factor in understanding the exacerbated damage after I/R. PMID- 28919323 TI - A systematic review of person-centered approaches to investigating patterns of trauma exposure. AB - Recent research has found that exposure to traumatic events may occur in certain patterns, rather than randomly. Person-centered analyses, and specifically latent class analysis, is becoming increasingly popular in examining patterns, or 'classes' of trauma exposure. This review aimed to identify whether there are consistent homogeneous subgroups of trauma-exposed individuals, and the relationship between these trauma classes and psychiatric diagnosis. A systematic review of the literature was completed using the databases EMBASE, MEDLINE (PubMed) and PsycINFO. From an initial yield of 189, 17 studies met inclusion criteria. All studies identified a group of individuals who had a higher likelihood of exposure to a wide range of traumas types, and this group consistently exhibited worse psychiatric outcomes than other groups. Studies differed in the nature of the other groups identified although there was often a class with high levels of sexual interpersonal trauma exposure, and a class with high levels of non-sexual interpersonal trauma. There was some evidence that risk for psychiatric disorder differed across these classes. Person-centered approaches to understanding the relationship between trauma exposure and mental health may offer ways to improve our understanding of the role trauma exposure plays in increasing vulnerability to psychiatric disorder. PMID- 28919324 TI - Pretreatment of skin using an abrasive skin preparation pad, a microneedling device or iontophoresis improves absorption of methyl aminolevulinate in ex vivo human skin. AB - BACKGROUND: Pretreatment of skin to remove scales/crusts and roughen the surface is essential to enhance the penetration of topically applied methyl aminolevulinate (MAL) prior to photodynamic therapy and to permit daylight to access all parts of the skin lesions. Numerous procedures of skin preparation are currently available. This study compared the in vitro penetration of MAL into ex vivo human skin pretreated with skin preparation pad abrasion or a microneedling device, and evaluated the effectiveness of an iontophoretic device in delivering MAL into ex vivo human skin. METHODS: Human skin samples, obtained from aesthetic surgeries, were used in this study. The thickness of the skin samples ranged between 1.44-2.87mm. Pretreatment of samples was performed with 10 passages of the Ambu(r) UnilectTM 2121M (Ambu A/S, Denmark) skin preparation pad, 8 rolling repetitions using the microneedling device Dermaroller(r) HC 902 (Dermaroller GmbH, Germany), or by an iontophoresis device (Feeligreen SA, France) for 1.5h. The effect of these pretreatment procedures on the penetration of MAL into the skin was assessed. RESULTS: Penetration in the total skin, liquid receptor and total penetration was most increased by skin preparation pad treatment, followed by microneedling and iontophoresis. Overall, MAL total penetration was increased up to 103-fold by skin preparation pad treatment, 4-fold by microneedling and 1.8 fold by iontophoresis. CONCLUSIONS: Abrasion with skin preparation pad was shown to be superior to microneedling and iontophoresis for increasing MAL penetration in ex vivo human skin. PMID- 28919325 TI - The influence of lifestyle on airborne particle surface area doses received by different Western populations. AB - In the present study, the daily dose in terms of particle surface area received by citizens living in five cities in Western countries, characterized by different lifestyle, culture, climate and built-up environment, was evaluated and compared. For this purpose, the exposure to sub-micron particle concentration levels of the population living in Barcelona (Spain), Cassino (Italy), Guilford (United Kingdom), Lund (Sweden), and Brisbane (Australia) was measured through a direct exposure assessment approach. In particular, measurements of the exposure at a personal scale were performed by volunteers (15 per each population) that used a personal particle counter for different days in order to obtain exposure data in microenvironments/activities they resided/performed. Non-smoking volunteers performing non-industrial jobs were considered in the study. Particle concentration data allowed obtaining the exposure of the population living in each city. Such data were combined in a Monte Carlo method with the time activity pattern data characteristics of each population and inhalation rate to obtain the most probable daily dose in term of particle surface area as a function of the population gender, age, and nationality. The highest daily dose was estimated for citizens living in Cassino and Guilford (>1000 mm2), whereas the lowest value was recognized for Lund citizens (around 100 mm2). Indoor air quality, and in particular cooking and eating activities, was recognized as the main influencing factor in terms of exposure (and thus dose) of the population: then confirming that lifestyle (e.g. time spent in cooking activities) strongly affect the daily dose of the population. On the contrary, a minor or negligible contribution of the outdoor microenvironments was documented. PMID- 28919327 TI - Endothelial microparticle-promoted inhibition of vascular remodeling is abrogated under hyperglycaemic conditions. AB - BACKGROUND: Endothelial microparticles (EMPs) inhibit vascular remodeling by transferring functional microRNA (miRNA) into target vascular smooth muscle cells (VSMCs). Because EMPs are increased in diabetic patients and potentially linked to vascular complications in diabetes mellitus, we sought to determine whether effects of EMPs generated under high glucose concentration on vascular remodeling might differ from EMPs derived from untreated cells. METHODS AND RESULTS: EMPs were generated from human coronary endothelial cells (HCAEC) exposed to high glucose concentrations in order to mimic diabetic conditions. These EMPs were defined as 'hyperglycaemic' EMPs (hgEMPs) and their miRNA transfer capacity and functional effects were compared with EMPs generated from 'healthy' untreated HCAECs. In vitro, the intercellular transfer of antiproliferative miRNA-126-3p from ECs to VSMCs via EMPs was significantly reduced under hyperglycaemic conditions. Additionally, EMP-mediated inhibition of the miRNA-126-3p target LRP6 and of VSMC migration and proliferation was abrogated, when hgEMPs were used. In vivo, the inhibitory effect of EMPs on neointima formation, VSMC proliferation and macrophage infiltration was abolished in mice treated with hgEMPs. CONCLUSION: Pathological hyperglycaemic conditions weaken potentially protective intercellular communication mechanisms by affecting EMP content and function. PMID- 28919326 TI - Characterization of a PKR inhibitor from the pathogenic ranavirus, Ambystoma tigrinum virus, using a heterologous vaccinia virus system. AB - Ambystoma tigrinum virus (ATV) (family Iridoviridae, genus Ranavirus) was isolated from diseased tiger salamanders (Ambystoma tigrinum stebbinsi) from the San Rafael Valley in southern Arizona, USA in 1996. Genomic sequencing of ATV, as well as other members of the genus, identified an open reading frame that has homology to the eukaryotic translation initiation factor, eIF2alpha (ATV eIF2alpha homologue, vIF2alphaH). Therefore, we asked if the ATV vIF2alphaH could also inhibit PKR. To test this hypothesis, the ATV vIF2alphaH was cloned into vaccinia virus (VACV) in place of the well-characterized VACV PKR inhibitor, E3L. Recombinant VACV expressing ATV vIF2alphaH partially rescued deletion of the VACV E3L gene. Rescue coincided with rapid degradation of PKR in infected cells. These data suggest that the salamander virus, ATV, contains a novel gene that may counteract host defenses, and this gene product may be involved in the presentation of disease caused by this environmentally important pathogen. PMID- 28919328 TI - C-peptide levels and the risk of diabetes and pre-diabetes among Chinese women with gestational diabetes. AB - AIMS: To examine the association of connecting peptide (C-peptide) and the risks of postpartum diabetes and pre-diabetes among women with prior gestational diabetes. METHODS: A cross-sectional study of 1263 women with prior gestational diabetes was carried out at 1-5years after delivery in Tianjin, China. Logistic regression was used to assess the associations of C-peptide and the risks of diabetes and pre-diabetes. RESULTS: The multivariable-adjusted odds ratios based on different levels of C-peptide (0-33%, 34-66%, 67-90%, and >90% as C-peptide cutpoints) were 1.00, 1.93 (95% confidence interval [CI] 0.85-4.39), 2.49 (95% CI 1.06-5.87), and 3.88 (95% CI 1.35-11.1) for diabetes (P for trend <0.0001), and 1.00, 1.66 (95% CI 1.18-2.36), 2.38 (95% CI 1.56-3.62) and 2.35 (95% CI 1.27 4.37) for pre-diabetes (P for trend <0.0001), respectively. Restricted cubic splines models showed a positive linear association of C-peptide as a continuous variable with the risks of type 2 diabetes and pre-diabetes. The positive association was significant when stratified by healthy weight and overweight participants. CONCLUSIONS: We found a positive association between serum C peptide levels and the risks of diabetes and pre-diabetes among Chinese women with prior gestational diabetes. Our finding suggested that elevated C-peptide levels may be a predictor of diabetes and pre-diabetes. PMID- 28919329 TI - Phospholipase Cbeta interacts with cytosolic partners to regulate cell proliferation. AB - Phospholipase Cbeta (PLCbeta) is the main effector of the Galphaq signaling pathway relaying different extracellular sensory information to generate intracellular calcium signals. Besides this classic function, we have found that PLCbeta plays an important but unknown role in regulating PC12 cell differentiation by interacting with components in the RNA-induced silencing machinery. In trying to understand the role of PLCbeta in PC12 cell differentiation, we find that over-expressing PLCbeta reduces PC12 cell proliferation while down-regulating PLCbeta increases the rate of cell proliferation. However, this behavior is not seen in other cancerous cell lines. To determine the underlying mechanism, we carried out mass spectrometry analysis of PLCbeta complexes in PC12 cells. We find that in unsynchronized cells, PLCbeta primarily binds cyclin-dependent kinase (CDK)16 whose activity plays a key role in cell proliferation. In vitro studies show a direct association between the two proteins that result in loss in CDK16 activity. When cells are arrested in the G2/M phase, a large population of PLCbeta is bound to Ago2 in a complex that contains C3PO and proteins commonly found in stress granules. Additionally, another population of PLCbeta complexes with CDK18 and cyclin B1. Fluorescence lifetime imaging microscopy (FLIM) confirms cell cycle dependent associations between PLCbeta and these other protein binding partners. Taken together, our studies suggest that PLCbeta may play an active role in mediating interactions required to move through the cell cycle. PMID- 28919330 TI - Limbic encephalitis with LGI1 antibodies in a 14-year-old boy. AB - Limbic encephalitis (LE) with antibodies against leucine-rich glioma inactivated protein 1 (LGI1) is an auto-antibody mediated disorder with characteristic symptoms as dysfunction of memory, faciobrachial dystonic seizures and neuropsychiatric symptoms as emotional lability. Limbic encephalitis with LGI1 antibodies has been known so far as a disease of adults. We describe the case of a 14-year-old boy presenting with typical dysfunction of memory and LGI1 antibodies. To the best of our knowledge, this is the youngest patient with LGI1 antibody mediated limbic encephalitis described so far. Improved knowledge of this autoimmune syndrome in children and adolescents permit rapid immunomodulatory treatment, which could help to prevent irreversible lesions, such as hippocampal atrophy. PMID- 28919331 TI - Production and characterization of monoclonal antibodies against cathepsin B and cathepsin B-Like proteins of Naegleria fowleri. AB - Naegleria fowleri causes fatal primary amoebic meningoencephalitis (PAM) in humans and experimental animals. In previous studies, cathepsin B (nfcpb) and cathepsin B-like (nfcpb-L) genes of N. fowleri were cloned, and it was suggested that refolding rNfCPB and rNfCPB-L proteins could play important roles in host tissue invasion, immune response evasion and nutrient uptake. In this study, we produced anti-NfCPB and anti-NfCPB-L monoclonal antibodies (McAb) using a cell fusion technique, and observed their immunological characteristics. Seven hybridoma cells secreting rNfCPB McAbs and three hybridoma cells secreting rNfCPB L McAbs were produced. Among these, 2C9 (monoclone for rNfCPB) and 1C8 (monoclone for rNfCPB-L) McAb showed high antibody titres and were finally selected for use. As determined by western blotting, 2C9 McAb bound to N. fowleri lysates, specifically the rNfCPB protein, which had bands of 28 kDa and 38.4 kDa. 1C8 McAb reacted with N. fowleri lysates, specifically the rNfCPB-L protein, which had bands of 24 kDa and 34 kDa. 2C9 and 1C8 monoclonal antibodies did not bind to lysates of other amoebae, such as N. gruberi, Acanthamoeba castellanii and A. polyphaga in western blot analyses. Immuno-cytochemistry analysis detected NfCPB and NfCPB-L proteins in the cytoplasm of N. fowleri trophozoites, particularly in the pseudopodia and food-cup. These results suggest that monoclonal antibodies produced against rNfCPB and rNfCPB-L proteins may be useful for further immunological study of PAM. PMID- 28919332 TI - Correlation of radical-scavenging capacity and amoebicidal activity of Matricaria recutita L. (Asteraceae). AB - Some Acanthamoeba strains are able to cause Granulomatous Amoebic Encephalitis (GAE) and Acanthamoeba keratitis (AK) worldwide because of their pathogenicity. The treatment of Acanthamoeba infections is complicated due to the existence of a highly resistant cyst stage in their life cycle. Therefore, the elucidation of novel sources of anti-Acanthamoeba agents is an urgent need. In the present study, an evaluation of the antioxidant and anti-Acanthamoeba activity of compounds in flower extracts of Tunisian chamomile (Matricaria recutita L.) was carried out. Chamomile methanol extract was the most active showing an IC50 of 66.235 +/- 0.390 MUg/ml, low toxicity levels when checked in murine macrophage toxicity model and presented also antioxidant properties. Moreover, a bio-guided fractionation of this extract was developed and led to the identification of a mixture of coumarins as the most active fraction. These results suggest a novel source of anti-Acanthamoeba compounds for the development of novel therapeutic agents against Acanthamoeba infections. PMID- 28919333 TI - Status of the effectiveness of contact lens disinfectants in Malaysia against keratitis-causing pathogens. AB - The aim of this study was (i) to assess the antimicrobial effects of contact lens disinfecting solutions marketed in Malaysia against common bacterial eye pathogens and as well as eye parasite, Acanthamoeba castellanii, and (ii) to determine whether targeting cyst wall would improve the efficacy of contact lens disinfectants. Using ISO 14729 Stand-Alone Test for disinfecting solutions, bactericidal and amoebicidal assays of six different contact lens solutions including Oxysept(r), AO SEPT PLUS, OPTI-FREE(r) pure moist(r), Renu(r) freshTM, FreshKon(r) CLEAR and COMPLETE RevitaLensTM were performed using Manufacturers Minimum recommended disinfection time (MRDT). The efficacy of contact lens solutions was determined against keratitis-causing microbes, namely: Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Acanthamoeba castellanii. In addition, using chlorhexidine as an antiamoebic compound and cellulase enzyme to disrupt cyst wall structure, we determined whether combination of both agents can enhance efficacy of marketed contact lens disinfectants against A. castellanii trophozoites and cysts, in vitro. The results revealed that all contact lens disinfectants tested showed potent bactericidal effects exhibiting 100% kill against all bacterial species tested. In contrast, none of the contact lens disinfectants had potent effects against Acanthamoeba cysts viability. When tested against trophozoites, two disinfectants, Oxysept Multipurpose and AO-sept Multipurpose showed partial amoebicidal effects. Using chlorhexidine as an antiamoebic compound and cellulase enzyme to disrupt cyst wall structure, the findings revealed that combination of both agents in contact lens disinfectants abolished viability of A. castellanii cysts and trophozoites. Given the inefficacy of contact lens disinfectants tested in this study, these findings present a significant concern to public health. These findings revealed that targeting cyst wall by using cyst wall degrading molecules in contact lens disinfecting solutions will enhance their efficacy against this devastating eye infection. PMID- 28919334 TI - Failure of molecular diagnostics of a keratitis-inducing Acanthamoeba strain. AB - An otherwise healthy 49-year-old female patient presented at the local hospital with severe keratitis in both inflamed eyes. She was a contact lens wearer and had no history of a corneal trauma. In our laboratory for medical parasitology Acanthamoebae were detected microscopically from the cornea scraping and from the fluid of the contact lens storage case after xenical culture and showed the typical cyst morphology of Acanthamoebae group II. The diagnosis of "Acanthamoeba keratitis" was established and successful therapy was provided. While the morphological microscopic method led to the correct diagnosis in this case, an in house multiplex qPCR and a commercial qPCR showed false negative results regarding Acanthamoeba sp. The subsequent sequencing revealed the Acanthamoeba genotype T4. In the present case report, the inability to detect Acanthamoebae using qPCR only is presented. Therefore, we recommend the utilization of combined different assays for optimal diagnostic purposes. PMID- 28919335 TI - The effect of resistance exercise on sleep: A systematic review of randomized controlled trials. AB - Impaired sleep quality and quantity are associated with future morbidity and mortality. Exercise may be an effective non-pharmacological intervention to improve sleep, however, little is known on the effect of resistance exercise. Thus, we performed a systematic review of the literature to determine the acute and chronic effects of resistance exercise on sleep quantity and quality. Thirteen studies were included. Chronic resistance exercise improves all aspects of sleep, with the greatest benefit for sleep quality. These benefits of isolated resistance exercise are attenuated when resistance exercise is combined with aerobic exercise and compared to aerobic exercise alone. However, the acute effects of resistance exercise on sleep remain poorly studied and inconsistent. In addition to the sleep benefits, resistance exercise training improves anxiety and depression. These results suggest that resistance exercise may be an effective intervention to improve sleep quality. Further research is needed to better understand the effects of acute resistance exercise on sleep, the physiological mechanisms underlying changes in sleep, the changes in sleep architecture with chronic resistance exercise, as well its efficacy in clinical cohorts who commonly experience sleep disturbance. Future studies should also examine time-of-day and dose-response effects to determine the optimal exercise prescription for sleep benefits. PMID- 28919336 TI - Staphylococcus aureus dry-surface biofilms are more resistant to heat treatment than traditional hydrated biofilms. AB - BACKGROUND: The importance of biofilms to clinical practice is being increasingly realized. Biofilm tolerance to antibiotics is well described but limited work has been conducted on the efficacy of heat disinfection and sterilization against biofilms. AIM: To test the susceptibility of planktonic, hydrated biofilm and dry surface biofilm forms of Staphylococcus aureus, to dry-heat and wet-heat treatments. METHODS: S. aureus was grown as both hydrated biofilm and dry-surface biofilm in the CDC biofilm generator. Biofilm was subjected to a range of temperatures in a hot-air oven (dry heat), water bath or autoclave (wet heat). FINDINGS: Dry-surface biofilms remained culture positive even when treated with the harshest dry-heat condition of 100 degrees C for 60min. Following autoclaving samples were culture negative but 62-74% of bacteria in dry-surface biofilms remained alive as demonstrated by live/dead staining and confocal microscopy. Dry surface biofilms subjected to autoclaving at 121 degrees C for up to 30min recovered and released planktonic cells. Recovery did not occur following autoclaving for longer or at 134 degrees C, at least during the time-period tested. Hydrated biofilm recovered following dry-heat treatment up to 100 degrees C for 10min but failed to recover following autoclaving despite the presence of 43-60% live cells as demonstrated by live/dead staining. CONCLUSION: S. aureus dry-surface biofilms are less susceptible to killing by dry heat and steam autoclaving than hydrated biofilms, which are less susceptible to heat treatment than planktonic suspensions. PMID- 28919337 TI - Xpert MTB/RIF Ultra: a gamechanger for tuberculous meningitis? PMID- 28919338 TI - Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV infected adults: a prospective cohort study. AB - BACKGROUND: WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. METHODS: We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0.5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0.5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. FINDINGS: From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24 68]; 10/22; p=0.0010) or culture (45% [24-68]; 10/22; p=0.0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0.014). INTERPRETATION: Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis. FUNDING: National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation. PMID- 28919339 TI - Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIalpha. AB - It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIalpha inhibitors. Although xanthone derivatives inhibit topoisomerase IIalpha-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIalpha and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step. PMID- 28919340 TI - Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF kappaB inhibitory and anti-proliferative activities. AB - Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF kappaB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-alpha-induced NF-kappaB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-kappaB inhibitory activity (IC50=2.5MUM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36.2MUM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server asa novel scaffold for developing NF-kappaB inhibitors and anti-proliferative agents in cancer chemotherapy. PMID- 28919342 TI - Mothers' Adverse Childhood Experiences and Their Young Children's Development. AB - INTRODUCTION: This study examined how mothers' Adverse Childhood Experiences (ACEs) relate to their children's developmental risk and assessed how the association is mediated through mothers' depressive symptoms and fair/poor health. METHODS: Mothers of children aged between 4 months and 4 years were recruited from the emergency department of a children's hospital between March 2012 and June 2015 and interviewed about ACEs, mothers' depressive symptoms and health status, and children's developmental risk (screened via Parents' Evaluations of Developmental Status [PEDS]). Between August and November 2016 a Cochran-Armitage test assessed trend of PEDS by ACEs. Multinomial regression models examined differences in PEDS by ACEs severity. Mediation by mothers' depressive symptoms and self-rated health was also assessed. RESULTS: Of 1,293 mothers, 56.7% reported one or more ACEs. Mothers also reported developmental risk (20.4% overall): 120 (9.2%) reported one concern and 144 (11.2%) reported two or more concerns on the PEDS. Mothers who reported household substance use, mental illness, or an incarcerated household member during childhood were more likely to report at least one child developmental concern on the PEDS. After controlling for covariates, odds of one PEDS concern were 1.86 (95% CI=1.16, 3.00) for ACEs, one to three versus none, and 2.21 (95% CI=1.26, 3.87) for ACEs four or more versus none. Adjusted odds of two or more concerns were 1.70 (95% CI=1.07, 2.72) for ACEs, one to three versus none, and 1.76 (95% CI=1.02, 3.05) for ACEs, four or more versus none. Mothers' depressive symptoms and self-rated health were potential mediators. CONCLUSIONS: Mothers' ACEs are significantly associated with their children's developmental risk. If replicated, findings suggest that addressing intergenerational trauma through focus on childhood adversity among young children's caregivers may promote child development. PMID- 28919343 TI - Characterizing pathology in erythrocytes using morphological and biophysical membrane properties: Relation to impaired hemorheology and cardiovascular function in rheumatoid arthritis. AB - The inflammatory burden of the complex rheumatoid arthritis (RA) disease affects several organ-systems, including rheological properties of blood and its formed elements. Red blood cells (RBCs) are constantly exposed to circulating dysregulated inflammatory molecules that are co-transported within the vasculature; and their membranes may be particularly vulnerable to the accompanying oxidative stress. In the current study, we investigate biophysical and ultrastructural characteristics of RBCs obtained from a cohort of patients using atomic force microscopy (AFM), scanning electron microscopy (SEM) and confocal microscopy (CM). Statistical analyses of AFM data showed that RA RBCs possessed significantly reduced membrane elasticity relative to that of RBCs from healthy individuals (P-value <0.0001). SEM imaging of RA RBCs revealed increased anisocytes and poikilocytes. Poikilocytes included knizocytes, stomatocytes, dacryocytes, irregularly contracted cells, and knot cells. CM imaging of several RA RBCs, spectrin, and band 3 protein networks portrayed the similar morphological profiles. Analyses of CM images confirmed changes to distribution of band-3 skeletal protein, a protein critical for gaseous exchange functions of the RBC and preventing membrane surface loss. Decreased membrane deformability impairs the RBC's capacity to adequately adapt its shape to navigate blood vessels, especially microvasculature, and this decrease is also reflected in the cell's morphology. Changes to morphology and deformability may also indicate loss of functional domains and/or pathological protein and lipid associations. These findings suggest that RA disease and/or its concomitant factors impact on the RBC and its membrane integrity with potential for exacerbating pathological cellular function, hemorheology, and cardiovascular function. PMID- 28919344 TI - Fluorophore labeling of a cell-penetrating peptide induces differential effects on its cellular distribution and affects cell viability. AB - Cell-penetrating peptides constitute efficient delivery vectors, and studies of their uptake and mechanism of translocation typically involve fluorophore-labeled conjugates. In the present study, the influence of a number of specific fluorophores on the physico-chemical properties and uptake-related characteristics of penetratin were studied. An array of seven fluorophores belonging to distinct structural classes was examined, and the impact of fluorophore labeling on intracellular distribution and cytotoxicity was correlated to the physico-chemical properties of the conjugates. Exposure of several mammalian cell types to fluorophore-penetratin conjugates revealed a strong structure-dependent reduction in viability (1.5- to 20-fold lower IC50 values as compared to those of non-labeled penetratin). Also, the degree of less severe effects on membrane integrity, as well as intracellular distribution patterns differed among the conjugates. Overall, neutral hydrophobic fluorophores or negatively charged fluorophores conferred less cytotoxicity as compared to the effect exerted by positively charged, hydrophobic fluorophores. The latter conjugates, however, exhibited less membrane association and more clearly defined intracellular distribution patterns. Thus, selection of the appropriate flurophore is critical. PMID- 28919345 TI - Cost effectiveness of screening for dengue infection in a UK teaching hospital. PMID- 28919346 TI - Clinical outcomes in patients hospitalized with cellulitis treated with oral clindamycin and trimethoprim/sulfamethoxazole: The role of weight-based dosing. AB - OBJECTIVES: Trimethoprim/sulfamethoxazole (TMP/SMX) and clindamycin are frequently prescribed to treat cellulitis. The primary objective was to determine if weight-based dosing of these antibiotics is associated with better outcomes in cellulitis. The secondary objective was to assess variables associated with clinical failure among hospitalized patients with cellulitis with or without cutaneous abscess. METHODS: This multi-center retrospective cohort study was conducted from January 1, 2010 to September 4, 2014. Adult patients admitted for cellulitis who received a minimum of seven days of therapy and discharged on oral clindamycin or TMP/SMX were included. Binary univariate and multivariate logistic regression analyses were performed to identify risk factors for clinical failure, including the impact of dose adequacy of clindamycin and TMP/SMX on clinical outcomes. RESULTS: A total of 208 cases met inclusion criteria. Of these cases, 120 (57.7%) received inadequate dosing of clindamycin (<10 mg/kg/day) or TMP/SMX (<5 mg TMP/kg per day) while 88 (42.3%) received adequate dosing. Clinical failure occurred in 36/120 (30%) and 15/88 (17%) of patients receiving inadequate and adequate doses, respectively (p = 0.032). Upon univariate analysis length of stay >= 7 days (OR = 2.96, p = 0.046) and inadequate dosing (OR = 2.09, p = 0.034) were associated with clinical failure. Upon multivariate analysis, inadequate dosing was independently associated with clinical failure (OR = 2.01, p = 0.032). CONCLUSION: Inadequate dosing of clindamycin and TMP/SMX is independently associated with clinical failure in patients hospitalized with cellulitis. Further prospective studies evaluating weight-based dosing of clindamycin and TMP/SMX in the setting of cellulitis are warranted. PMID- 28919341 TI - Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin. AB - The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and contribute to the pathogenesis of human diseases. The link between endogenous metabolite availability and chromatin regulation is a well-established and active area of investigation; however, whether microbial metabolites can elicit similar effects is less understood. In this review, we focus on seminal and recent research that establishes chromatin regulatory roles for both endogenous and microbial metabolites. We also highlight key physiologic and disease settings where microbial metabolite-host chromatin interactions have been established and/or may be pertinent. PMID- 28919347 TI - Invasive mold infections of the central nervous system in patients with hematologic cancer or stem cell transplantation (2000-2016): Uncommon, with improved survival but still deadly often. AB - BACKGROUND: Historically considered to have very poor outcome, there is paucity of recent data regarding invasive mold infections (IMIs) of the central nervous system (CNS) in patients with hematologic cancer (HC) or stem cell transplantation (SCT). METHODS: We reviewed the records of HC patients and/or SCT recipients who were diagnosed with CNS IMIs (EORTC/MSG criteria) at MD Anderson Cancer Center (1/1/2000-6/31/2016). Risk factors for survival at day (d) 42 post diagnosis were assessed. RESULTS: We identified 40 such patients (16 with proven infection). The incidence density was 3.8 cases/100000 patient days and mortality remained stable throughout the study period. Most patients had active HC and neutropenia at diagnosis (95% and 53% respectively). Of the 25 patients with a microbiological diagnosis, Aspergillus spp and Mucorales accounted for 85% of cases. CNS IMIs were deemed to be secondary to hematogenous spread in 31 (77%), mostly (90%) fungal pneumonia. CNS lesions typically presented as solitary ring enhancing abscesses in MRI (26; 65%). Most patients (34; 85%) received lipid AMB and were treated with combination therapy (33; 83%); Mortality 42d was 48%. In univariate analysis, lack of surgical drainage (p = 0.01), absence of giant cells (p = 0.01) and granulomas (p = 0.03) were associated with increased 42d mortality. In multivariate analysis, co-infection was associated with increased (p = 0.005), while steroid tapering was associated with decreased mortality (p = 0.01). CONCLUSIONS: Although less lethal, improved outcome in these uncommon infections was related only to immune response in histopathology, steroid tapering and possibly surgical drainage. In a contemporary 16-year cohort of 40 patients with hematologic cancer and mold infections of Central Nervous System, 42-day mortality was 48%. Improved survival was related to immune response in histopathology, absence of co-infections, corticosteroid tapering and possibly surgical drainage. PMID- 28919348 TI - Prevalence of colistin resistance in clinical isolates of Enterobacteriaceae: A four-year cross-sectional study. AB - OBJECTIVES: The objectives were to determine the prevalence of colistin resistance in clinical isolates of Enterobacteriaceae, and to gain knowledge on the epidemiological and clinical features of the patients. METHODS: All colistin resistant Enterobacteriaceae consecutively isolated from clinical samples in our institution from 2012 to 2015, were included in this cross-sectional study. Intrinsic-resistant species were excluded. Minimum inhibitory concentration was performed by gradient diffusion. Detection of plasmid-encoded colistin resistance genes mcr-1 and mcr-2 was performed by amplification. Epidemiological and clinical features were reviewed. RESULTS: Of 13579 Enterobacteriaceae isolates, 91 were colistin-resistant. The overall prevalence of colistin resistance was 0.67%. The rates were higher in Enterobacter cloacae (4.2%) than Escherichia coli (0.5%) and Klebsiella pneumoniae (0.4%). One third of the isolates were multi drug resistant (MDR). While mcr-2 was not detected, mcr-1 was detected only in E. coli. Regarding these infections, 23% were community-acquired. 89% of the patients had not received colistin previously. There were no significant differences between infections caused by mcr-1 and non-mcr-1-carrying isolates. CONCLUSIONS: Colistin resistance was not restricted to MDR isolates and to clinical settings. Most patients had no record of previous administration of colistin. PMID- 28919349 TI - Prevalence of HLA-B*5701 in a Kenyan population with HIV infection. PMID- 28919350 TI - Crystal structure of inositol 1,3,4,5,6-pentakisphosphate 2-kinase from Cryptococcus neoformans. AB - The fungal pathogen Cryptococcus neoformans is a causative agent of meningoencephalitis in humans. For its pathogenicity, the inositol polyphosphate biosynthetic pathway plays critical roles. Recently, Ipk1 from C. neoformans (CnIpk1) was identified as an inositol 1,3,4,5,6-pentakisphosphate 2-kinase that catalyzes the phosphorylation of IP5 to form IP6, a substrate for subsequent reaction to produce inositol pyrophosphates, such as PP-IP5/IP7. Furthermore, it was shown that deletion of IPK1 significantly reduces the virulence of C. neoformans, indicating that Ipk1 is a major virulence contributor. In this study, we determined a crystal structure of the apo-form of CnIpk1 at 2.35A resolution, the first structure for a fungal Ipk1, using a single-wavelength anomalous dispersion method. Even with a low sequence similarity of 26-28%, its overall structure resembles two other Ipk1 orthologs from Arabidopsis thaliana (AtIpk1) and Mus musculus (MmIpk1), and the most crucial residues in the active site are conserved. Unlike AtIpk1 and MmIpk1, however, metal-binding sites for structural stabilization and conformational variations are absent in CnIpk1. The binding environments for substrate IP5 could be inferred by the two different binding sites for sulfate ion in CnIpk1. Taken together, these observations suggest structural similarities and discrepancies for fungal Ipk1 among members of the Ipk1 family and provide structural information for the possible development of drug design for treatment of cryptococcosis. PMID- 28919351 TI - Suspension state increases reattachment of breast cancer cells by up-regulating lamin A/C. AB - Extravasation is a rate-limiting step of tumor metastasis, for which adhesion to endothelium of circulating tumor cells (CTCs) is the prerequisite. The suspension state of CTCs undergoing detachment from primary tumor is a persistent biomechanical cue, which potentially regulates the biophysical characteristics and cellular behaviors of tumor cells. In this study, breast tumor cells MDA-MB 231 in suspension culture condition were used to investigate the effect of suspension state on reattachment of CTCs. Our study demonstrated that suspension state significantly increased the adhesion ability of breast tumor cells. In addition, suspension state markedly promoted the formation of stress fibers and focal adhesions and reduced the motility in reattached breast cancer cells. Moreover, lamin A/C was reversibly accumulated at posttranscriptional level under suspension state, improving the cell stiffness of reattached breast cancer cells. Disruption of actin cytoskeleton by cytochalasin D caused lamin A/C accumulation. Conversely, decreasing actomyosin contraction by ROCK inhibitor Y27632 reduced lamin A/C level. Knocking down lamin A/C weakened the suspension-induced increase of adhesion, and also abolished the suspension-induced decrease of motility and increase of stress fibers and focal adhesion in reattaching tumor cells, suggesting a crucial role of lamin A/C. In conclusion, it was demonstrated that suspension state promoted the reattachment of breast tumor cells by up-regulating lamin A/C via cytoskeleton disruption. These findings highlight the important role of suspension state for tumor cells in tumor metastasis. PMID- 28919352 TI - Salvage brachytherapy for radiorecurrent prostate cancer: Searching for safety and success. PMID- 28919353 TI - Presepsin: A new marker of catheter related blood stream infections in pediatric patients. AB - BACKGROUND: Catheter related blood stream infections (CRBSI) are mostly preventable hospital-acquired conditions. We aimed to investigate the value of presepsin in detection of CRBSI in hospitalized children. METHODS: Hospitalized pediatric patients who had clinical suspicion of CRBSI were followed. Results of peripheral blood cultures and blood cultures from central venous catheters, procalcitonin (PCT), C-reactive protein (CRP), total white blood cell (WBC) counts were recorded. Serum samples for presepsin were studied at the same time with the samples of healthy controls. The patients with positive blood cultures were defined as proven CRBSI and with negative cultures as suspected CRBSI. RESULTS: Fifty-eight patients and 80 healthy controls were included in the study. Proven CRBSI group consisted of 36 patients (62%) with positive blood cultures and compared with the suspected CRBSI group (n = 22, 36%) with negative culture results. There was no difference between proven and suspected CRBSI groups concerning WBC, PCT, CRP and presepsin. Presepsin was significantly higher in patient groups when compared with healthy controls. The receiver operating characteristic curve area under the curve was 0.98 (%95 CI: 0.97-1) and best cut off value was 990 pg/ml. CONCLUSION: In hospitalized pediatric patients with CRBSI, presepsin may be a helpful rapid marker in early diagnosis. PMID- 28919354 TI - CT angiography for planning of percutaneous closure of a sinus venosus atrial septal defect using a covered stent. PMID- 28919355 TI - Letter to the Editor: regarding "Air pollution and cardiovascular events with special reference to labor and delivery". PMID- 28919356 TI - Reply: "Air pollution and cardiovascular events with special reference to labor and delivery". PMID- 28919357 TI - Predictors of outcome in neonatal hypoxic ischemic encephalopathy after therapeutic hypothermia. PMID- 28919358 TI - Perfused human hepatocyte microtissues identify reactive metabolite-forming and mitochondria-perturbing hepatotoxins. AB - Hepatotoxins cause liver damage via many mechanisms but the formation of reactive metabolites and/or damage to liver mitochondria are commonly implicated. We assess 3D human primary hepatocyte microtissues as a platform for hepatotoxicity studies with reactive metabolite-forming and mitochondria-perturbing compounds. We show that microtissues formed from cryopreserved human hepatocytes had bile canaliculi, transcribed mRNA from genes associated with xenobiotic metabolism and expressed functional cytochrome P450 enzymes. Hierarchical clustering was used to distinguish dose-dependent hepatotoxicity elicited by clozapine, fialuridine and acetaminophen (APAP) from control cultures and less liver-damaging compounds, olanzapine and entecavir. The regio-isomer of acetaminophen, N-acetyl-meta aminophenol (AMAP) clustered with the hepatotoxic compounds. The principal metabolites of APAP were formed and dose-dependent changes in metabolite profile similar to those seen in patient overdose was observed. The toxicological profile of APAP was indistinguishable from that of AMAP, confirming AMAP as a human hepatotoxin. Tissue oxygen consumption rate was significantly decreased within 2h of exposure to APAP or AMAP, concomitant with glutathione depletion. These data highlight the potential utility of perfused metabolically functional human liver microtissues in drug development and mechanistic toxicology. PMID- 28919359 TI - Human intestine and liver microsomal metabolic differences between C19-diester and monoester diterpenoid alkaloids from the roots of Aconitum carmichaelii Debx. AB - The roots of Aconitum carmichaelii Debx. show excellent effects against rheumatism and cardiovascular diseases, but the effective compounds, C19-diester and monoester diterpenoid alkaloids (DDAs and MDAs) are toxic for their narrow therapeutic windows. It is noteworthy to investigate intestinal metabolism of these toxic compounds mainly by oral administration, because gut also express drug-metabolizing enzymes as well as liver. This study initially focused on phase I and phase II metabolism of DDAs (including aconitine, mesaconitine and hypaconitine) and MDAs (including benzoylaconine, benzoylmesaconine and benzoylhypaconine) in human intestine microsomes (HIM), with comparison of metabolism in human liver microsomes (HLM). CYP3A in HIM mainly catalyzed phase I metabolism of DDAs and MDAs, with polarity increased. The intestinal metabolic profiles of DDAs were more various than MDAs. No glucuronide metabolites were detected, which was in agreement with HLM metabolism. The results showed that gut played an important role in detoxification of DDAs and MDAs by oral administration. Moreover, eight new metabolites from DDAs were identified in microsomes incubations by UPLC-Q-TOF-HRMS/MS. Our findings provided reference to the detoxification of DDAs and MDAs in the intestine in vivo and supplemented the phase I metabolic pathways for DDAs. PMID- 28919360 TI - The roles of antimicrobial peptide, rip-thanatin, in the midgut of Riptortus pedestris. AB - Recently, we have reported the structural determination of antimicrobial peptides (AMPs), such as riptocin, rip-defensin, and rip-thanatin, from Riptortus pedestris. However, the biological roles of AMPs in the host midgut remain elusive. Here, we compared the expression levels of AMP genes in apo-symbiotic insects with those of symbiotic insects. Interestingly, the expression level of rip-thanatin was only significantly increased in the posterior midgut region of symbiotic insects. To further determine the role of rip-thanatin, we checked antimicrobial activity in vitro. Rip-thanatin showed high antimicrobial activity and had the same structural characteristics as other reported thanatins. To find the novel function of rip-thanatin, rip-thanatin was silenced by RNA interference, and the population of gut symbionts was measured. When rip-thanatin was silenced, the symbionts' titer was increased upon bacterial infection. These results suggest that rip-thanatin functions not only as an antimicrobial peptide but also in controlling the symbionts' titer in the host midgut. PMID- 28919361 TI - Molecular characterisation, ontogeny and expression analysis of melanoma differentiation-associated factor 5 (MDA5) from Asian seabass, Lates calcarifer. AB - MDA5 is the pivotal member of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and is reported to play a crucial role in type I IFN-mediated responses against pathogen-associated molecular patterns (PAMPs), especially nucleic acids. In this study, we have identified and cloned the full-length cDNA sequence of MDA5, which comprises 3398 nucleotides and encodes for a putative protein of 978 AA length, in Asian seabass, Lates calcarifer. From the putative amino acid sequence of AsMDA5, four different conserved domains could be predicted: two N-terminal CARD domains, a DExDc domain, a HELICc domain and a C terminal RIG-1_C-RD domain. The mRNA transcript of AsMDA5 could be detected in all the 11 tissues tested in healthy animals with the highest expression in heart followed by gill and skin. The ontogenetic expression profile showed constitutive expression in developmental stages starting from unfertilized eggs, which implies the possibility of maternally acquired immunity of RLRs in offspring. The viral analogue poly I:C could modulate the AsMDA5 expression both in vivo and in vitro. In all the tissues, AsMDA5 expression was found to be highly regulated following injection with poly I:C with the highest expression observed in kidney. The expression level of AsMDA5 was found to be modulated at different time-points following challenge with Gram-negative bacterium, Vibrio alginolyticus, and Gram positive bacterium, Staphylococcus aureus. Similarly, noticeable change in AsMDA5 expression was detected in SISK cell line induced with either LPS or PGN. The observations made in this study suggest that in euryhaline marine teleosts like Asian seabass, MDA5 gene serves as one of the pivotal receptor for the detection of viral and bacterial PAMP, and might play an important antimicrobial role during early embryonic development. PMID- 28919362 TI - A homozygote TREX1 mutation in two siblings with different phenotypes: Chilblains and cerebral vasculitis. AB - Three prime repair exonuclease 1 degrades single and double stranded DNA with 3' 5' nuclease activity and its mutations are related to type 1 IFN mediated autoinflammation due to accumulated intracellular nucleic acids. To date, several cases of systemic lupus erythematosus, Aicardi-Goutieres syndrome, familial chilblain lupus, retinal vasculopathy-cerebral leukodystrophy have been reported with TREX1 mutations. Chilblain lupus is a skin disease characterized by blue reddish coloring, swelling or ulcers on acral regions of body such as fingertips, heels, nose and auricles. Central nervous system vasculitis is a prominent cause of childhood strokes. 10 families with familial chilblain lupus related to TREX1 mutations were reported previously in the literature, in which homozygote D18N variant in TREX1 gene was related to chilblains with cerebral vasculitis. In this report, whole-exome-sequencing revealed a homozygote R114C mutation in TREX1 gene was shown in two siblings with recurrent chilblains whom one of them was the second case accompanied by cerebral vasculitis in the literature. As a result, the approach of WES in clinical use revealed a novel mutation in clinically heterogenous patients to provide genetic counseling. PMID- 28919363 TI - Thoracic spinal cord and cervical vagosympathetic neuromodulation obtund nodose sensory transduction of myocardial ischemia. AB - BACKGROUND: Autonomic regulation therapy involving either vagus nerve stimulation (VNS) or spinal cord stimulation (SCS) represents emerging bioelectronic therapies for heart disease. The objective of this study was to determine if VNS and/or SCS modulate primary cardiac afferent sensory transduction of the ischemic myocardium. METHODS: Using extracellular recordings in 19 anesthetized canines, of 88 neurons evaluated, 36 ventricular-related nodose ganglia sensory neurons were identified by their functional activity responses to epicardial touch, chemical activation of their sensory neurites (epicardial veratridine) and great vessel (descending aorta or inferior vena cava) occlusion. Neural responses to 1min left anterior descending (LAD) coronary artery occlusion (CAO) were then evaluated. These interventions were then studied following either: i) SCS [T1-T3 spinal level; 50Hz, 90% motor threshold] or ii) cervical VNS [15-20Hz; 1.2* threshold]. RESULTS: LAD occlusion activated 66% of identified nodose ventricular sensory neurons (0.33+/-0.08-0.79+/-0.20Hz; baseline to CAO; p<0.002). Basal activity of cardiac-related nodose neurons was differentially reduced by VNS (0.31+/-0.11 to 0.05+/-0.02Hz; p<0.05) as compared to SCS (0.36+/-0.12 to 0.28+/ 0.14, p=0.59), with their activity response to transient LAD CAO being suppressed by either SCS (0.85+/-0.39-0.11+/-0.04Hz; p<0.03) or VNS (0.75+/-0.27-0.12+/ 0.05Hz; p<0.04). VNS did not alter evoked neural responses of cardiac-related nodose neurons to great vessel occlusion. CONCLUSIONS: Both VNS and SCS obtund ventricular ischemia induced enhancement of nodose afferent neuronal inputs to the medulla. PMID- 28919364 TI - Forward and reverse genetics approaches to uncover metabolic aging pathways in Caenorhabditis elegans. AB - The biological mechanisms of aging have been studied in depth and prominent findings in this field promote the development of new therapies for age associated disorders. Various model organisms are used for research on aging; among these, the nematode Caenorhabditis elegans has been widely used and has provided valuable knowledge in determining the regulatory mechanisms driving the aging process. Many genes involved in lifespan regulation are associated with metabolic pathways and are influenced by genetic and environmental factors. In line with this, C. elegans provides a promising platform to study such gene by environment interactions, in either a reverse or forward genetics approach. In this review, we discuss longevity mechanisms related to metabolic networks that have been discovered in C. elegans. We also highlight the use of wild populations to study the complex genetic basis of natural variation for quantitative traits that mediate longevity. PMID- 28919365 TI - Hepatic stellate cell-specific deletion of SIRT1 exacerbates liver fibrosis in mice. AB - Liver fibrosis is widely perceived as a host defense mechanism that aids tissue repair following liver injury. Excessive fibrogenesis, however, serves to disrupt normal liver structure and precedes such irrevocable human pathologies as cirrhosis and hepatocellular carcinoma. Activation of hepatic stellate cells (HSCs) is a hallmark event during liver fibrosis. In the present study we investigated the mechanism by which the lysine deacetylase SIRT1 regulates HSC activation. We report here that SIRT1 levels were decreased in the liver in different mouse models and in cultured HSCs undergoing activation. SIRT1 down regulation paralleled HDAC4 up-regulation. HDAC4 was recruited to the SIRT1 promoter during HSC activation and removed acetylated histones H3 and H4 from the SIRT1 promoter leading to SIRT1 trans-repression. HDAC4 silencing restored SIRT1 expression and attenuated HSC activation in SIRT1-dependent manner. More important, selective deletion of SIRT1 in HSCs exacerbated CCl4-induced liver fibrosis in mice. Mechanistically, SIRT1 deacetylated PPARgamma to block HSC activation. Together, our data reveal an HDAC4-SIRT1-PPARgamma axis that contributes to the regulation of HSC activation and liver fibrosis. PMID- 28919367 TI - Nup153 Interacts with Sox2 to Enable Bimodal Gene Regulation and Maintenance of Neural Progenitor Cells. AB - Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate. PMID- 28919368 TI - A Comparison of Clinical Follow-Up of Different Total Temporomandibular Joint Replacement Prostheses: A Systematic Review and Meta-Analysis. AB - PURPOSE: There are different total temporomandibular joint (TMJ) prostheses on the market but no comparison of their efficacy. The purpose of this meta-analysis was to evaluate the effectiveness of different TMJ replacement (TJR) systems. MATERIALS AND METHODS: A systematic review and meta-analysis was performed using the PubMed, Embase, Medline, and Cochrane Library search engines in May 2017 to identify qualified studies. Outcome measurements were changes in maximal incisal opening (MIO), pain, dietary limitations, and functional deficiencies from before to after TJR. Analyses of heterogeneity, sensitivity, and publication bias were performed. A fixed-effects model was used for the meta-analysis of pooled weighted mean differences in pre- versus postoperative MIO, pain, diet, and function. RESULTS: Twenty studies with 1,262 patients were included in the meta analysis. Comparison of the TJR systems showed no real difference for pre- versus postoperative MIO, pain, diet, and function. MIO and functional efficiency decreased gradually over time, but effective pain relief and improvements in dietary limitations were stable with no relevant differences during follow-up. Comparison of the custom and stock devices showed similar results for pre- and postoperative MIO, pain, function, and diet. CONCLUSION: This analysis showed no relevant difference in treatment outcomes among the TJR systems. PMID- 28919366 TI - Prevalence and risk factors for fragility fracture in systemic mastocytosis. AB - OBJECTIVES: Systemic mastocytosis (SM) is characterized by the accumulation of mast cells in tissues other than the skin. Bone involvement although frequent has not been thoroughly evaluated. Primary objective was to determine risk factors associated with fragility fractures (FF) in SM. Secondary objectives were to evaluate the ability of bone marrow tryptase (BMT) level to identify patients with FF, and to describe bone involvement in SM. METHODS: We analyzed retrospectively all consecutive patients seen in our expert center, with a diagnosis of SM according to the 2001 WHO criteria, and with complete bone assessment. We collected data about lifetime fractures, types of cutaneous manifestations, degranulation symptoms, blood and BMT levels, bone mineral density assessed by densitometry and KIT mutation. We performed a univariate analysis investigating the factors associated with FF and then a logistic multivariable regression analysis. We assessed the ability of bone marrow tryptase to identify patients with FF. RESULTS: Eighty-nine patients with SM were included. Thirty-six patients (40.4%) suffered from osteoporosis and twenty-five (28.1%) experienced lifetime FF. Univariate analysis identified age at diagnosis and disease onset, presence of telangiectasia macularis eruptiva perstans, digestive symptoms, mast cells activation symptoms, elevated BMT, low femoral and lumbar BMD, as associated with FF. Multivariate analysis identified elevated BMT, low femoral T score and older age at diagnosis as independently associated with FF. CONCLUSIONS: Low femoral T-score, BMT level, and older age at diagnosis are markers associated with FF in SM. BMT may represent an important biomarker to predict FF in SM patients. PMID- 28919369 TI - Effect of airway remodeling and hyperresponsiveness on complexity of breathing pattern in rat. AB - The complexity of respiratory dynamics is decreased, in association with disease severity, in patients with asthma. However, the pathophysiological basis of decreased complexity of breathing pattern in asthma is not clear. In the present study, we investigated the effect of airway remodeling and hyperresponsiveness induced by repeated bronchoconstriction (using methacholine) on breathing pattern in rats with or without allergen-induced sensitization. Entropy analysis of respiratory variability showed decreased irregularity (less complexity) of respiratory rhythm in this rat model of asthma. Airway remodeling and hyperresponsiveness induced by repeated bronchoconstriction also led to increased regularity of respiratory dynamics in sensitized rats. However, these airway alterations had no significant effect on the complexity of breathing pattern in non-sensitized rats. Our results indicate that mechanical respiratory alterations cannot per se attenuate the complexity of respiratory dynamics, unless there is an underlying inflammation. We suggest further studies on underlying mechanisms of breathing variability with focus on respiratory control alterations due to airway inflammation. PMID- 28919370 TI - With age a lower individual breathing reserve is associated with a higher maximal heart rate. AB - INTRODUCTION: Maximal heart rate (HRmax) is linearly declining with increasing age. Regular exercise training is supposed to partly prevent this decline, whereas sex and habitual physical activity do not. High exercise capacity is associated with a high cardiac output (HR x stroke volume) and high ventilatory requirements. Due to the close cardiorespiratory coupling, we hypothesized that the individual ventilatory response to maximal exercise might be associated with the age-related HRmax. METHODS: Retrospective analyses have been conducted on the results of 129 consecutively performed routine cardiopulmonary exercise tests. The study sample comprised healthy subjects of both sexes of a broad range of age (20-86 years). Maximal values of power output, minute ventilation, oxygen uptake and heart rate were assessed by the use of incremental cycle spiroergometry. RESULTS: Linear multivariate regression analysis revealed that in addition to age the individual breathing reserve at maximal exercise was independently predictive for HRmax. A lower breathing reserve due to a high ventilatory demand and/or a low ventilatory capacity, which is more pronounced at a higher age, was associated with higher HRmax. Age explained the observed variance in HRmax by 72% and was improved to 83% when the variable "breathing reserve" was entered. DISCUSSION: The presented findings indicate an independent association between the breathing reserve at maximal exercise and maximal heart rate, i.e. a low individual breathing reserve is associated with a higher age-related HRmax. A deeper understanding of this association has to be investigated in a more physiological scenario. PMID- 28919371 TI - Perinatal deficiency in dietary omega-3 fatty acids potentiates sucrose reward and diet-induced obesity in mice. AB - Insufficient dietary intake of essential omega-3 polyunsaturated fatty acids (N 3), especially during critical stages of development, is well-associated with negative neurological and metabolic consequences. The increased availability and intake of foods rich in saturated fat coincides with reduced N-3 consumption, yet how N-3 dietary deficiency during perinatal development modulates motivation for palatable food and interacts with a high-fat diet to affect body weight and emotional states is not clear. Pregnant C57Bl6 mice and pups were subjected to diets either deficient or adequate (control) in N-3 until postnatal day 21. Adult male N-3 deficient or control offspring were tested in a progressive ratio operant task for sucrose motivated behavior or given prolonged access to a saturated high-fat diet or chow followed by measures of energy balance and anxiety-like behavior in the elevated-plus maze and open field test. Brain fatty acid profiles were measured via gas chromatography mass spectrometry. Perinatal dietary N-3 deficiency lowered brain N-3 levels, augmented the rewarding effects of sucrose, heightened diet-induced weight gain and fat mass accumulation and diminished spontaneous physical activity. Finally, perinatal N-3 deficiency increased anxiety-like behaviour independent of diet in the open field but not in the elevated-plus maze test. Insufficient dietary N-3 during critical periods of developmental can amplify the obesogenic effects of saturated fat intake, enhance motivated behaviour for palatable foods and may elicit negative emotional states that can perpetuate overeating and obesity. PMID- 28919372 TI - Biological applications of kinetics of wetting and spreading. AB - Wetting and spreading kinetics of biological fluids has gained a substantial interest recently. The importance of these fluids in our lives has driven the pace of publications. Globally scientists have ever growing interest in understanding wetting phenomena due to its vast applications in biological fluids. It is impractical to review extremely large number of publications in the field of kinetics of complex biological fluids and cosmetic solutions on diverse surfaces. Therefore, biological and cosmetic applications of wetting and spreading dynamics are considered in the following areas: (i) Spreading of Newtonian liquids in the case of non-porous and porous substrates. It is shown that the spreading kinetics of a Newtonian droplet on non-porous and porous substrate can be defined through theoretical relations for droplet base radius on time, which agree well with the experimental results; (ii) Spreading of blood over porous substrates. It is shown that blood, which has a complex non-Newtonian rheology, can be successfully modelled with the help of simple power-law model for shear-thinning non-Newtonian liquids; (iii) Simultaneous spreading and evaporation kinetics of blood. This part enlightens different underlying mechanisms present in the wetting, spreading, evaporation and dried pattern formation of the blood droplets on solid substrates; (iv) Spreading over hair. In this part the wetting of hair tresses by aqueous solutions of two widely used by industry commercially available polymers, AculynTM 22 and AculynTM 33, are discussed. The influence of non-Newtonian rheology of these polymer solutions on the drainage of foams produced from these solutions is also briefly discussed. PMID- 28919373 TI - Treatment of chronic granulomatous disease-associated fistulising colitis with vedolizumab. PMID- 28919374 TI - Effect of Ca2+ concentration on Scenedesmus sp. growth in heterotrophic and photoautotrophic cultivation. AB - The influence of Ca2+ concentration on the growth of the microalga Scenedesmus sp. in heterotrophic and photoautotrophic cultivations was investigated. Heterotrophic growth was induced by the addition of olive mill wastewaters (9% v.v-1) to the culture. Variations in the calcium concentration affected differently biomass production depending on whether microalgae were cultivated under heterotrophic or photoautotrophic regime. In photoautotrophic regime, increasing the calcium concentration from 20 to 230mg?L-1 decreased maximum cell concentration and growth rate. In heterotrophic cultivation, cell concentration and growth rate decreased with Ca2+ concentration increasing from 20 to 80mg?L-1 but then increased with Ca2+ concentration increasing to 230mg?L-1. Increasing calcium concentration invariably promoted cell aggregation. The precipitation of calcium phosphates can explain the decreasing growth rate and cell concentration attained with increasing calcium concentration, while the influence of Ca2+ concentration on the adsorption of phenols on suspended solids can explain the enhanced growth attained at large Ca2+ concentration under heterotrophic regime. Implications of the illustrated results for industrial scale application of microalgae are thoroughly discussed. PMID- 28919375 TI - The Association Between Leukotriene-Modifying Agents and Suicidality: A Review of Literature. AB - BACKGROUND: In 2008 Food and Drug Administration issued a warning regarding a possible association between leukotriene-modifying agents and suicidality. OBJECTIVE: The warning remains controversial and this review of literature is an attempt to examine the evidence on the matter. METHODS: Literature search on PubMed. RESULTS: The data supporting a relationship between leukotriene-modifying agents and suicidality comes primarily from reviews of individual safety reports in adverse event databases; it is subject to considerable reporting bias and does not control for confounding factors. Case-control and cohort studies as well as data from clinical trials do not support an association between leukotriene modifying agents and suicidality. The data from ecological studies offers strong evidence of a lack of positive association between leukotriene-modifying agents and suicide outcomes (attempts and deaths) at the population level. Furthermore, there is no pharmacological mechanism that would explain an association between the two. CONCLUSION: Overall, the weight of higher quality evidence casts doubt on the association (especially at population level), but is not enough to conclusively disprove the association at an individual level. PMID- 28919376 TI - MicroRNA-218-5p as a Potential Target for the Treatment of Human Osteoarthritis. AB - Emerging evidence suggests that dysregulated microRNAs (miRNAs) play a pivotal role in osteoarthritis (OA), but the role of specific miRNAs remains unclear. Accordingly, we identified OA-associated miRNAs and functional validation of results. Here, we demonstrate that miR-218-5p is significantly upregulated in moderate and severe OA and correlates with scores on a modified Mankin scale. Through gain-of-function and loss-of-function studies, miR-218-5p was shown to significantly affect matrix synthesis gene expression and chondrocyte proliferation and apoptosis. Using SW1353 and C28/I2 cells, PIK3C2A mRNA was identified as a target of miR-218-5p. Downregulation of miR-218-5p dramatically promoted expression of PIK3C2A and its downstream target proteins, such as Akt, mTOR, S6, and 4EBP1. More importantly, OA mice exposed to a miR-218-5p inhibitor were protected from cartilage degradation and had reduced proteoglycan loss and reduced loss of articular chondrocyte cellularity compared with control mice. miR 218-5p is a novel inducer of cartilage destruction via modulation of PI3K/Akt/mTOR signaling. Inhibition of endogenous miR-218-5p expression/activity appears to be an attractive approach to OA treatment. PMID- 28919378 TI - Sudden death mechanisms in nonischemic cardiomyopathies: Insights gleaned from clinical implantable cardioverter-defibrillator trials. AB - Sudden cardiac death (SCD) represents a major cause of death among patients with heart failure. Although scar-based, macroreentrant ventricular tachycardia/ventricular fibrillation is the primary etiology for SCD among patients with ischemic cardiomyopathy, a more diverse set of mechanisms and substrates is likely at play for the diverse group of patients characterized by nonischemic dilated cardiomyopathy (NICM). These causes may include scar-based reentry, but also neurohormonal stimulation (sympathetic, parasympathetic, renin angiotensin-aldosterone), inflammation, and nonarrhythmic processes occurring in the context of a genetic predisposition. In addition to basic and translational science, observations from large randomized clinical trials of implantable cardioverter-defibrillators (ICDs) can also offer insight and support for specific mechanisms of SCD in these patients. This review will discuss the background of SCD in NICM, its potential mechanisms based on experimental and theoretical models, and the evidence for these mechanisms that can be derived from clinical trials of ICD therapy. PMID- 28919377 TI - Combination Cancer Therapy Using Chimeric Antigen Receptor-Engineered Natural Killer Cells as Drug Carriers. AB - The therapeutic limitations of conventional chemotherapeutic drugs include chemo resistance, tumor recurrence, and metastasis. Numerous nanoparticle-based active targeting approaches have emerged to enhance the intracellular concentration of drugs in tumor cells; however, efficient delivery of these systems to the tumor site while sparing healthy tissue remains elusive. Recently, much attention has been given to human immune-cell-directed nanoparticle drug delivery, because immune cells can traffic to the tumor and inflammatory sites. Natural killer cells are a subset of cytotoxic lymphocytes that play critical roles in cancer immunosurveillance. Engineering of the human natural killer cell line, NK92, to express chimeric antigen receptors to redirect their antitumor specificity has shown significant promise. We demonstrate that the efficacy of chemotherapy can be enhanced in vitro and in vivo while reducing off-target toxicity by using chimeric antigen receptor-engineered NK92 cells as carriers to direct drug-loaded nanoparticles to the target site. PMID- 28919379 TI - 2017 HRS expert consensus statement on cardiovascular implantable electronic device lead management and extraction. PMID- 28919380 TI - Establishing a hospital based fracture liaison service to prevent secondary insufficiency fractures. AB - In the aging population worldwide, osteoporosis is a relatively common condition and a major cause of long-term morbidity. Initial fragility fractures can lead to subsequent fractures. After a vertebral fracture, the risk of any another fracture increases 200% and that of a subsequent hip fracture increases 300%. For starting a hospital based Fracture Liaison Service (FLS) program, the nucleus is based on a physician champion, a FLS coordinator, and a nurse manager. A Fracture Liaison Service (FLS) is a multidisciplinary system approach to reducing subsequent fracture risk in patients with a recent fragility fracture due to compromised bone health by identifying them at or close to the time when they are treated at the hospital for fracture and providing them with easy access to osteoporosis care. It has been shown that when compared to other models such as referral letters to primary care physicians or endocrinologists, the FLS model results in a higher rate of diagnosis and treatment with less attrition in the posffracture phase. Insufficiency fracture care requires more than surgery to stabilize a fractured bone. The FLS program provides an opportunity to treat osteoporosis from a public health perspective rather than leaving this to the whims of individual physicians. This is achieved by providing a seamless integration of care by health care providers, nursing staff and administration. The FLS can be adapted to any model of care including academic health systems. FLS provides a holistic approach to identify patients as well as to provide evidence-based interventions to prevent subsequent fractures. The long term goal is that internationally FLS will result in in decreased fracture-related morbidity, mortality and overall health care expenditure. PMID- 28919381 TI - Correction to Lancet Glob Health 2017; 5: e924-35. PMID- 28919382 TI - Overweight and obesity in New Caledonian adults: Results from measured and adjusted self-reported anthropometric data. AB - AIMS: To estimate the overweight (OW) and obesity (Ob) prevalence and associated socio-demographic risk factors in New Caledonian adults aged 18-67years. METHODS: From a randomly selected cross-sectional population survey, self-reported (n=2513) and measured (n=736) height and weight data were collected. Separate linear regression analyses for measured weight and height were performed, using cases with both self-reported weight and height and socio-demographic variables. The final weight and height assigned to each case was either measured or predicted from the regression (n=2075). OW prevalence was defined as: Body Mass Index (BMI) >=25 and <30kg/m-2; and Ob: BMI >=30kg/m-2. Samples were weighted to the general adult population. Prevalence and Odds ratios (ORs) were calculated by gender, and adjusted for socio-demographic variables, to assess differentials in OW, Ob and OW-Ob, using multinomial and logistic regressions. RESULTS: Male (M) OW was 35% (95% CI: 31-38), Ob 29% (95% CI: 26-32) and OW-Ob 64% (95% CI: 60-67); female (F) OW was 26% (95% CI: 23-28), Ob 34% (95% CI: 31-37) and OW-Ob 60% (95% CI: 57-63). Compared to Melanesians (OR=1.0) for male/female: Polynesians had the highest prevalence of OW (1.7/1.5), Ob (4.7/3.5), and OW-Ob (3.0/2.5); New Caledonian-born Europeans had greater OW, Ob and OW-Ob (0.3/0.4) than immigrant Europeans (0.2/0.2). CONCLUSIONS: Findings contribute to obesity comparisons with other Pacific Islands, and they establish trends in New Caledonia for targeting policies and strategies of prevention. PMID- 28919383 TI - Prediction of Air Entrapment in Tableting: An Approximate Solution. AB - An approximate solution is presented for the prediction of air entrapment during tableting. Assuming weak coupling of the deformation of the solid phase, the flow of interstitial air and a set of reasonable additional geometric assumptions, the general problem is reduced to 1 dimension. Experimental values of air permeability through tablet specimens of commonly used pharmaceutical excipients were obtained using a 3D printed test cell outfitted to a powder rheometer. Using these values, combined with a numerical solution of the governing partial differential equation, parametric studies are presented that demonstrate the importance of permeability, compaction speed, tablet size, and punch-die tolerance on air entrapment. In addition, a first-order approximation of the role of entrapped air on the measured radial tensile strength of formed tablets is presented. PMID- 28919384 TI - The Combination of GIS and Biphasic to Better Predict In Vivo Dissolution of BCS Class IIb Drugs, Ketoconazole and Raloxifene. AB - The formulation developments and the in vivo assessment of Biopharmaceutical Classification System (BCS) class II drugs are challenging due to their low solubility and high permeability in the human gastrointestinal (GI) tract. Since the GI environment influences the drug dissolution of BCS class II drugs, the human GI characteristics should be incorporated into the in vitro dissolution system to predict bioperformance of BCS class II drugs. An absorptive compartment may be important in dissolution apparatus for BCS class II drugs, especially for bases (BCS IIb) because of high permeability, precipitation, and supersaturation. Thus, the in vitro dissolution system with an absorptive compartment may help predicting the in vivo phenomena of BCS class II drugs better than compendial dissolution apparatuses. In this study, an absorptive compartment (a biphasic device) was introduced to a gastrointestinal simulator. This addition was evaluated if this in vitro system could improve the prediction of in vivo dissolution for BCS class IIb drugs, ketoconazole and raloxifene, and subsequent absorption. The gastrointestinal simulator is a practical in vivo predictive tool and exhibited an improved in vivo prediction utilizing the biphasic format and thus a better tool for evaluating the bioperformance of BCS class IIb drugs than compendial apparatuses. PMID- 28919385 TI - Influences of ammonium and phosphate stimulation on metalworking fluid biofilm reactor development and performance. AB - In this study, the effects of common wastewater stimulants, namely NH4Cl and KH2PO4, on the development and performance of metalworking fluid biofilm bioreactors are presented. It is shown that biofilms flourished only when one of these components was present in limiting quantities. Biofilm yields significantly declined when both of the components were withheld from the bioreactors or when both components were provided in excess. Stimulations to the reactors using NH4Cl significantly reduced the total carbon removal performance, while stimulations using KH2PO4 resulted in significant increases in performance. Chromatographic analyses showed that the NH4Cl stimulation enhanced the removal of saturated fatty amides and diethylene glycol butyl ether from the metalworking fluid, but inhibited the removal of diisoproponolamine. Furthermore, NH4Cl additions inhibited the oil/water separation carbon removal mechanism and resulted in the re-dispersion of recalcitrant organic material. The results from this study show that metalworking fluid practitioners should take care in choosing the nutrients used for stimulating bioreactor performance and microbe development. Incorrect stimulations with NH4Cl may result in negative treatment performances due to the inhibition of amine utilisation and enhancing emulsion stability. PMID- 28919386 TI - Comparison of lacosamide versus sodium valproate in status epilepticus: A pilot study. AB - PURPOSE: The purpose of this study was to compare the efficacy and safety of lacosamide (LCM) and sodium valproate (SVA) in lorazepam (LOR)-resistant SE. METHODS: Patients with LOR-resistant SE were randomized to intravenous LCM 400mg at the rate of 60mg/kg/min or SVA 30mg/kg at the rate of 100mg/min. The SE severity score (STESS), duration of SE and its etiology, and MRI findings were noted. Primary outcome was seizure cessation for 1h, and secondary outcomes were 24h seizure remission, in-hospital death, and severe adverse events (SAE). RESULTS: Sixty-six patients were included, and their median age was 40 (range 18 90) years. Thirty-three patients each received LCM and SVA. Their demographic, clinical, STESS, etiology, and MRI findings were not significantly different. One hour seizure remission was not significantly different between LCM and SVA groups (66.7% vs 69.7%; P=0.79). Twenty-four-hour seizure freedom was insignificantly higher in SVA (20, 66.6%) compared with LCM group (15, 45.5%). Death (10 vs 12) and composite side effects (4 vs 6) were also not significantly different in LCM and SVA groups. LCM was associated with hypotension and bradycardia (1 patient), and SVA with liver dysfunction (6). CONCLUSION: In patients with LOR-resistant SE, both LCM and SVA have comparable efficacy and safety. PMID- 28919387 TI - Health-related quality of life in adolescents with epilepsy in Montenegro. AB - OBJECTIVE: The objective of this study was to establish potential risk factors for poor health-related quality of life among adolescents with epilepsy in Montenegro. MATERIAL AND METHODS: A sample of 104 adolescents with epilepsy (age: 11-19years) at a tertiary referral center in Podgorica, Montenegro, completed the validated Serbian version of the QOLIE-AD-48 questionnaire. They were divided into two groups: a group with active epilepsy (60 adolescents) and a group with inactive epilepsy (44 adolescents). Demographic and clinical data were collected. RESULTS: Adolescents with active epilepsy had low quality of life and felt the negative impact of the disease. They also had more cognitive impairments, felt more stigmatized, and had considerably more distorted perception of their health than adolescents with inactive epilepsy (p<0.05). Females reported better social support than males (p<0.05). Older males had lower grades at school (p<0.05) than the younger ones. As expected, adolescents with the highest number of seizures in the past two years had the lowest quality of life (p<0.05). CONCLUSION: In our study, the quality of life in adolescents with epilepsy was determined by severity of the disease, age, and gender. PMID- 28919388 TI - Altered brain functional connectivity induced by physical exercise may improve neuropsychological functions in patients with benign epilepsy. AB - OBJECTIVE: The objective of this study was to elucidate alteration in functional connectivity (FC) in patients with benign epilepsy with centrotemporal spikes (BECTS) as induced by physical exercise therapy and their correlation to the neuropsychological (NP) functions. METHODS: We analyzed 115 artifact- and spike free 2-second epochs extracted from resting state EEG recordings before and after 5weeks of physical exercise in eight patients with BECTS. The exact Low Resolution Electromagnetic Tomography (eLORETA) was used for source reconstruction. We evaluated the cortical current source density (CSD) power across five different frequency bands (delta, theta, alpha, beta, and gamma). Altered FC between 34 regions of interests (ROIs) was then examined using lagged phase synchronization (LPS) method. We further investigated the correlation between the altered FC measures and the changes in NP test scores. RESULTS: We observed changes in CSD power following the exercise for all frequency bands and statistically significant increases in the right temporal region for the alpha band. There were a number of altered FC between the cortical ROIs in all frequency bands of interest. Furthermore, significant correlations were observed between FC measures and NP test scores at theta and alpha bands. CONCLUSION: The increased localization power at alpha band may be an indication of the positive impact of exercise in patients with BECTS. Frequency band-specific alterations in FC among cortical regions were associated with the modulation of cognitive and NP functions. The significant correlation between FC and NP tests suggests that physical exercise may mitigate the severity of BECTS, thereby enhancing NP function. PMID- 28919389 TI - [Hepatic mucormycosis due to Rhizopus microsporus: A case report]. PMID- 28919391 TI - The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset: An update. AB - A previous retrospective analysis of substances in the ECHA CHEM database concluded that, for industrial chemicals with a 'low (sub)acute toxicity profile', further testing in the 90-day study is unlikely to change this profile (Taylor et al., 2014). We have further tested this hypothesis by assessing the outcome of substances with testing proposals for which a prediction was made in that paper that the NOAEL based on the 90-day study would be 1000 mg/kg bw/d. Indeed, for seven out of ten substances for which data was available, the profile was shown to be held. For three substances, the reduced NOAEL was explained by renal effects in the rats, two of which had been seen in the 28-day study but had been dismissed by the study submitter. We conclude that the low toxicity profile will be even more protective if the NOEL is used from the 28-day study and an independent expert view is taken of the human relevance of any effects reported in the 28-day study. PMID- 28919390 TI - [Histoplasma capsulatum bone and joint infection]. PMID- 28919392 TI - Oral mucosal irritation study in hamster to evaluate a therapeutic apparatus using hydrogen peroxide photolysis for periodontitis treatment. AB - We conducted an oral mucosal irritation study in hamsters to evaluate a therapeutic apparatus using hydrogen peroxide (H2O2) photolysis for periodontitis treatment (ISO 10993-Part 10, Annex B.3). The cheek pouches in 15 male hamsters were allocated to one of six groups. Group 1 received pure water treatment (control group). Group 2 received laser irradiation at 80 mW. Group 3 received 3% H2O2. Groups 4-6 received laser irradiation of 3% H2O2 at 80, 40, and 20 mW, respectively. The total treatment time was set at 7 min and treatment was repeated three times at approximately 1-h intervals. Macroscopic and microscopic histologic observations of the treated sites were performed immediately after each treatment and/or 24 h after the last treatment. The mean scores in macroscopic and histologic examinations in all six groups were 0. Accordingly, irritation indices calculated by subtracting the mean score in each experimental group from that in the control group (Group 1) were 0. Our results suggest that treatment with the apparatus has no mucosal irritation potential in hamster cheek pouches under test conditions simulating clinical conditions. PMID- 28919393 TI - Pseudoprogression Associated with Clinical Deterioration and Worsening Quality of Life in Malignant Pleural Mesothelioma. PMID- 28919394 TI - Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable Stage III Non-Small Cell Lung Cancer: A Phase I Study. AB - OBJECTIVES: Stereotactic body radiation therapy (SBRT) is now the standard of care in medically inoperable stage I NSCLC, yielding high rates of local control. It is unknown whether SBRT can be safely utilized in the locally advanced NSCLC setting. This multi-institution phase I study evaluated the safety of 44 Gy of conventionally fractionated thoracic radiation with concurrent chemotherapy plus dose-escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary end point of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost. METHODS: Inclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor 8 cm or smaller, and N1 or N2 lymph nodes 5 cm or smaller. Tumors were staged with positron emission tomography/computed tomography (CT), and four-dimensional CT simulation was used for radiation planning. The treatment schema was 44 Gy of thoracic radiation (2 Gy/d) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy had been delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved mediastinal lymph nodes. Consolidation chemotherapy was given at the discretion of the treating medical oncologist. Four SBRT boost dose cohorts were tested: cohort 1 (9 Gy * 2), cohort 2 (10 Gy * 5), cohort 3 (6 Gy * 5), and cohort 4 (7 Gy * 5). Patients were treated in cohorts of three patients, and the Bayesian escalation with overdose control method was used to determine the MTD of the SBRT boost. Dose-limiting toxicities (DLTs) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment. RESULTS: The study enrolled 19 patients from November 2012 to December 2016. There were four screen failures, and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). DLT developed in one patient in dose cohort 3 (n = 3) and in 2 patients in dose cohort 4 (n = 3). The calculated MTD was 6 Gy * 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients at this dose level. Thus, the calculated MTD was 6 Gy * 5; however, 10 Gy * 2 is thought to be a reasonable dose as well, given that no grade 5 toxicities occurred with that dose. CONCLUSIONS: The MTD of a SBRT boost combined with 44 Gy of thoracic chemoradiation was 6 Gy * 5. A SBRT boost dose of 10 Gy * 2 could be considered safer, with no grade 3 or higher toxicities observed at this dose level during the follow-up period in this study. PMID- 28919395 TI - Gastroprotective effect of aucubin against ethanol-induced gastric mucosal injury in mice. AB - AIMS: Aucubin, an iridoid glycoside, was isolated from seeds of Eucommia ulmoides Oliver. This study was aimed to evaluate the protective effect of aucubin against ethanol-induced gastric mucosal injury in mice. MATERIALS AND METHODS: Mice were orally administrated with aucubin (20, 40 and 80mg/kg) for 3 consecutive days. On the 3rd day, the mice of gastric mucosal injury were induced with 70% ethanol after the last administration of aucubin. Gastric tissue of mice were submitted for evaluating the severity of gastric mucosal injury. The protective effect of aucubin was evaluated by the gastric ulcer index and histological examinations and determining the levels of inflammatory cytokines, oxidative stress and some gastric mucosal protection factors. KEY FINDINGS: Prophylactic oral administration of aucubin decreased gastric ulcer indexes and histological scores. A significant decrease of myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) were observed in aucubin administrated groups. In addition, mice administrated with aucubin increased glutathione (GSH) and heat shock protein-70 (HSP-70) levels and superoxide dismutase (SOD) activity, as well as normalized the levels of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and cyclooxygenase-1 (COX-1) in gastric tissue of mice. SIGNIFICANCE: The findings of this study demonstrated that aucubin shows protective effect against ethanol-induced acute gastric mucosal injury through its anti-inflammatory and anti-oxidant effects. Furthermore, aucubin enhanced gastric mucosal protection by up-regulation of HSP-70 level and normalization of EGF, VEGF and COX-1 levels. PMID- 28919396 TI - Protective effect of chlorogenic acid on the inflammatory damage of pancreas and lung in mice with l-arginine-induced pancreatitis. AB - AIMS: Pancreatitis is characterized by inflammatory disease with severe tissue injury in pancreas, and the incidence of pancreatitis has been recently increasing. Although several treatments of acute pancreatitis have been developed, some patients have been resistant to current therapy. Chlorogenic acid (CGA) is one of the polyphenols, and is known to have an anti-inflammatory effect. In this study, we investigated the effects of CGA on experimental pancreatitis in mice. MATERIALS AND METHODS: Pancreatitis was induced by twice injection of l-arginine (5g/kg body weight). Mice were intraperitoneally injected with CGA (20mg/kg or 40mg/kg) 1h before administration of l-arginine. KEY FINDINGS: Administration of 40mg/kg of CGA decreased the histological severity of pancreatitis and pancreatitis-associated lung injury. Moreover, administration of CGA inhibited the levels of pancreatic enzyme activity. Interestingly, CGA reduced the serum and pancreatic levels of macrophage migration inhibitory factor (MIF) in mice with l-arginine-induced pancreatitis. SIGNIFICANCE: Our results suggest that CGA has an anti-inflammatory effect on l-arginine-induced pancreatitis and pancreatitis-associated lung injury. PMID- 28919397 TI - Inferring within-host bottleneck size: A Bayesian approach. AB - Recent technical developments in microbiology have led to new discoveries on the within-host dynamics of bacterial infections in laboratory animals. In particular, they have highlighted the importance of stochastic bottlenecks at the onset of invasive disease. A number of approaches exist for bottleneck-size estimation with respect to within-host bacterial infections; however, some are more appropriate than others under certain circumstances. A Bayesian comparison of several approaches is made in terms of the availability of isogenic multitype bacteria (e.g., WITS), knowledge of post-bottleneck dynamics, and the suitability of dilution with monotype bacteria. A sampling approach to bottleneck-size estimation is also introduced. The results are summarised by a guiding flowchart, which we hope will promote the use of quantitative models in microbiology to refine the analysis of animal experiment data. PMID- 28919398 TI - Controlling bovine paratuberculosis at a regional scale: Towards a decision modelling tool. AB - Johne's disease (paratuberculosis), a worldwide enzootic disease of cattle caused by Mycobacterium avium subsp. paratuberculosis (Map), mainly introduced into farms by purchasing infected animals, has a large economic impact for dairy producers. Since diagnostic tests used in routine are poorly sensitive, observing Map spread in the field is hardly possible, whereas there is a need for evaluating control strategies. Our objective was to provide a modelling framework to compare the efficacy of regional control strategies combining internal biosecurity measures and testing of traded animals, against Map spread in a metapopulation of dairy cattle herds. We represented 12,857 dairy herds located in Brittany (France), based on data from 2005 to 2013, used to calibrate herd sizes and demographic rates and to define trade events in a multiscale model of Map infection dynamics. By clustering and categorical descriptive analysis of intensive simulations of this model, based on a numerical experimental design, a large panel of control measures was explored. Their efficacy was assessed on model outputs such as the prevalence and probability of extinction at the metapopulation level. In addition, we proposed a scoring for the effort required to implement control measures and prioritized control strategies based on their theoretical epidemiological efficacy. Our results clearly indicate that eradication cannot be achieved on the mid term using available control measures. However, we identified relevant combinations of measures that lead to the control of Map spread with realistic level of implementation and coverage. The study highlights the challenge of controlling paratuberculosis in an endemically infected region as related to the poor test characteristics and frequent trade movements. Our model lays the foundations for a flexible and efficient tool to help collective animal health managers in defining relevant control strategies at a regional scale, accounting for local specificities in terms of contact network and farms' characteristics. PMID- 28919399 TI - A numerical model suggests the interplay between nuclear plasticity and stiffness during a perfusion assay. AB - Cell deformability is a necessary condition for a cell to be able to migrate, an ability that is vital both for healthy and diseased organisms. The nucleus being the largest and stiffest organelle, it often is a barrier to cell migration. It is thus essential to characterize its mechanical behaviour. First, we numerically investigate the visco-elasto-plastic properties of the isolated nucleus during a compression test. This simulation highlights the impact of the mechanical behaviour of the nuclear lamina and the nucleoplasm on the overall plasticity. Second, a whole cell model is developed to simulate a perfusion experiment to study the possible interactions between the cytoplasm and the nucleus. We analyze and discuss the role of the lamina for a wild-type cell model, and a lamin deficient one, in which the Young's modulus of the lamina is set to 1% of its nominal value. This simulation suggests an interplay between the cytoplasm and the nucleoplasm, especially in the lamin-deficient cell, showing the need of a stiffer nucleoplasm to maintain nuclear plasticity. PMID- 28919400 TI - Condom use and incident sexually transmitted infection after initiation of long acting reversible contraception. AB - BACKGROUND: Use of more effective contraception may lead to less condom use and increased incidence of sexually transmitted infection. OBJECTIVE: The objective of this study was to compare changes in condom use and incidence of sexually transmitted infection acquisition among new initiators of long-acting reversible contraceptives to those initiating non-long-acting reversible contraceptive methods. STUDY DESIGN: This is a secondary analysis of the Contraceptive CHOICE Project. We included 2 sample populations of 12-month continuous contraceptive users. The first included users with complete condom data (baseline, and 3, 6, and 12 months) (long-acting reversible contraceptive users: N = 2371; other methods: N = 575). The second included users with 12-month sexually transmitted infection data (long-acting reversible contraceptive users: N = 2102; other methods: N = 592). Self-reported condom use was assessed at baseline and at 3, 6, and 12 months following enrollment. Changes in condom use and incident sexually transmitted infection rates were compared using chi2 tests. Risk factors for sexually transmitted infection acquisition were identified using multivariable logistic regression. RESULTS: Few participants in either group reported consistent condom use across all survey time points and with all partners (long acting reversible contraceptive users: 5.2%; other methods: 11.3%; P < .001). There was no difference in change of condom use at 3, 6, and 12 months compared to baseline condom use regardless of method type (P = .65). A total of 94 incident sexually transmitted infections were documented, with long-acting reversible contraceptive users accounting for a higher proportion (3.9% vs 2.0%; P = .03). Initiation of a long-acting reversible contraceptive method was associated with increased sexually transmitted infection incidence (odds ratio, 2.0; 95% confidence ratio, 1.07-3.72). CONCLUSION: Long-acting reversible contraceptive initiators reported lower rates of consistent condom use, but did not demonstrate a change in condom use when compared to preinitiation behaviors. Long-acting reversible contraceptive users were more likely to acquire a sexually transmitted infection in the 12 months following initiation. PMID- 28919401 TI - Comment on: Predicting the difficulty of operative vaginal delivery by ultrasound measurements of the fetal head station. PMID- 28919402 TI - Reply. PMID- 28919403 TI - Reply. PMID- 28919404 TI - Emergency in the clinic: a simulation curriculum to improve outpatient safety. AB - BACKGROUND: Emergency response skills are essential when events such as seizure, anaphylaxis, or hemorrhage occur in the outpatient setting. As services and procedures increasingly move outside the hospital, training to manage complications may improve outcomes. OBJECTIVE: The objective of this study was to evaluate a simulation-based curriculum in outpatient emergency management skills with the outcome measures of graded objective performance and learner self efficacy. STUDY DESIGN: This pre- and postcurriculum study enrolled residents and fellows in Obstetrics and Gynecology and Family Medicine in a simulation-based, outpatient emergency management curriculum. Learners completed self-efficacy questionnaires and were videotaped managing 3 medical emergency scenarios (seizure, over-sedation/cardiopulmonary arrest, and hemorrhage) in the simulation laboratory both before and after completion of the curriculum. Evaluators who were blinded to training level scored the simulation performance videotapes using a graded rubric with critical action checklists. Scenario scores were assigned in 5 domains and globally. Paired t-tests were used to determine differences pre- and postcurriculum. RESULTS: Thirty residents completed the curriculum and pre- and postcurriculum testing. Subjects' objective performance scores improved in all 5 domains (P<.05) in all scenarios. When scores were stratified by level of training, all participants demonstrated global improvement. When scores were stratified by previous outpatient simulation experience, subjects with previous experience improved in all but management of excess sedation. Pre- and postcurriculum self-efficacy evaluations demonstrated improvement in all 7 measured areas: confidence, use of appropriate resources, communication skills, complex airway management, bag mask ventilation, resuscitation, and hemorrhage management. Self-efficacy assessment showed improvement in confidence managing outpatient emergencies (P=.001) and ability to communicate well in emergency situations (P<.001). CONCLUSION: A simulation-based curriculum improved both self efficacy and objectively rated performance scores in management of outpatient medical emergencies. Simulation-based curricula should be incorporated into residency education. PMID- 28919405 TI - Exploration of stable isotope analysis for tick host identification. AB - Due to the problem of tick-borne diseases, there is a need to better understand the importance of different host species in maintaining enzootic disease cycles. We explored the utility of stable isotope analysis to identify the larval hosts of questing ixodid ticks. In laboratory experiments, we used Ixodes scapularis and two host species that are important in the Lyme disease system in eastern North America. First, we tested how effectively a short-term dietary tracer (13C in corn) was reflected in molted ticks. Second, we attempted to identify the host species (either white-footed mouse (Peromyscus leucopus) or eastern chipmunk (Tamias striatus)), based on the isotopic signature of the ticks that had fed on them. The corn isotopic signal was easily detectable in the ticks that fed on corn-diet hosts despite the brief feeding period (96h). However, we were not able to differentiate between flat Ixodes scapularis nymphs that had fed as larvae on mice vs. those fed on chipmunks. Isotopic signatures of fur from mice and chipmunks were also indistinguishable, probably due to the similar diets of these two species in the wild. We conclude that, while stable isotope analysis of ticks may not be able to distinguish between ecologically similar host species, it may be useful in sorting ticks to the level of feeding guild of the host. PMID- 28919406 TI - Endoscopic management for congenital pyriform sinus fistula. PMID- 28919407 TI - How to target inter-regional phase synchronization with dual-site Transcranial Alternating Current Stimulation. AB - Large-scale synchronization of neural oscillations is a key mechanism for functional information exchange among brain areas. Dual-site Transcranial Alternating Current Stimulation (ds-TACS) has been recently introduced as non invasive technique to manipulate the temporal phase relationship of local oscillations in two connected cortical areas. While the frequency of ds-TACS is matched, the phase of stimulation is either identical (in-phase stimulation) or opposite (anti-phase stimulation) in the two cortical target areas. In-phase stimulation is thought to synchronize the endogenous oscillations and hereby to improve behavioral performance. Conversely, anti-phase stimulation is thought to desynchronize neural oscillations in the two areas, which is expected to decrease performance. Critically, in- and anti-phase ds-TACS should only differ with respect to temporal phase, while all other stimulation parameters such as focality and stimulation intensity should be matched to enable an unambiguous interpretation of the behavioral effects. Using electric field simulations based on a realistic head geometry, we tested how well this goal has been met in studies, which have employed ds-TACS up to now. Separating the induced electrical fields in their spatial and temporal components, we investigated how the chosen electrode montages determined the spatial field distribution and the generation of phase variations in the injected electric fields. Considering the basic physical mechanisms, we derived recommendations for an optimized stimulation montage. The latter allows for a principled design of in- and anti-phase ds-TACS conditions with matched spatial distributions of the electric field. This knowledge will help cognitive neuroscientists to design optimal ds-TACS configurations, which are suited to probe unambiguously the causal contribution of phase coupling to specific cognitive processes in the human brain. PMID- 28919408 TI - Neural oscillations reflect latent learning states underlying dual-context sensorimotor adaptation. AB - Recent studies have suggested that individuals can form multiple motor memories when simultaneously adapting to multiple, but oppositely-oriented perturbations. These findings predict that individuals detect the change in learning context, allowing the selective initialization and update of motor memories. However, previous electrophysiological studies of sensorimotor adaptation have not identified a neural mechanism supporting the detection of a context switch and adaptation to separate contexts. Here, we tested the hypothesis that such a mechanism is identifiable through neural oscillations measured through EEG. Human participants learned to manipulate an object in two opposite contexts (mass distribution). This task was designed based on previous work showing that people can adapt to both contexts. We found that sensorimotor alpha and beta, and medial frontal theta frequency bands all exhibited different response patterns with respect to the error in each context. To determine whether any frequency's responses to error were distinctly related to a switch in context, we predicted single-trial EEG data from a computational learning model that can adapt to multiple contexts simultaneously based on a switching mechanism. This analysis revealed that only medial frontal theta was predicted by a component of the model state that adapts to errors based on a context switch. In contrast, alpha and beta were predicted by a model state that was updated from performance errors independent of the context. These findings provide novel evidence showing that sensorimotor and medial frontal oscillations are predicted by different adaptation processes, and that changes in medial frontal activity may indicate the formation of motor memories by responding to changes in learning context. PMID- 28919409 TI - Solasodine-3-O-beta-d-glucopyranoside is hydrolyzed by a membrane glucosidase into active molecule solasodine against Candida albicans. AB - Antifungal activity of some natural molecules can be abated or blocked by efflux pumps in Candida albicans, which restricts the discovery of potential antifungal agents. Here we found that the steroidal alkaloid solasodine is active against C. albicans efflux pump-deficient strains but inert towards the wild type. However, the glucosylated solasodine-3-O-beta-d-glucopyranoside exhibits antifungal activity towards the wild type strain. Further investigation revealed that the entry of solasodine into C. albicans cells is blocked by efflux pumps. Glucosylation provides an alternative access not disturbed by efflux pumps. Once inside cells, the carried glucosylated solasodine is cleaved into the active molecule solasodine by the glucosidase, which is located in cytoplasm membrane and exhibits selective activity against hydrolyzing glucosyl natural products but not against other monosaccharide-substituted products. This glucosidase is not encoded by orf19.4031, considered homologous to steryl-beta-glucosidase encoded by the gene EGH1 in Saccharomyces cerevisiae. Our study reveals that glucosylation is an alternative approach for introducing potential antifungal activity into C. albicans cells and overcoming the drug-resistance resulting from hyperactivation of efflux pumps. PMID- 28919410 TI - Tetrabromobisphenol A disturbs zinc homeostasis in cultured cerebellar granule cells: A dual role in neurotoxicity. AB - The brominated flame retardant tetrabromobisphenol A (TBBPA) has recognized neurotoxic properties mediated by intracellular Ca2+ imbalance and oxidative stress. Although these factors are known to trigger the release of Zn2+ from intracellular stores, the effects of TBBPA on Zn2+ homeostasis in neurons and the role of Zn2+in TBBPA neurotoxicity have not yet been studied. Therefore, we investigated zinc transients in primary cultures of rat cerebellar granule cells and assessed their involvement in TBBPA neurotoxicity. The results demonstrate that TBBPA releases Zn2+ from the intracellular stores and increases its intracellular concentration, followed by Zn2+ displacement from the cells. TBBPA evoked Zn2+ transients are partially mediated by Ca2+ and ROS. Application of TPEN, Zn2+ chelator, potentiates TBBPA- and glutamate-induced 45Ca uptake, enhances TBBPA-induced ROS production and potentiates decreases in the DeltaPsim in cells treated with 25 MUM TBBPA, revealing the potential neuroprotective capacity of endogenous Zn2+. However, the administration of TPEN does not aggravate TBBPA neurotoxicity, and even slightly decreases neuronal death induced by 25 MUM TBBPA. In summary, it was shown for the first time that TBBPA interferes with the cellular Zn2+ homeostasis in neuronal cultures, and we revealed complex roles for endogenous Zn2+ in cytoprotection and TBBPA toxicity in cultured neurons. PMID- 28919411 TI - Homocysteine upregulates interleukin-17A expression via NSun2-mediated RNA methylation in T lymphocytes. AB - Interleukin-17A (IL-17A) has been proven to participate in the process of various autoimmune diseases. The elevation of plasma homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is related to various chronic inflammatory diseases. Though HHcy-induced upregulation of IL-17A expression in T lymphocytes has been examined, the way in which IL-17A is regulated remains unclear. In this study, western blotting assays showed that Hcy (100 MUM) upregulated NOP2/Sun domain family, member 2 (NSun2) expression in rat T lymphocytes. HHcy-induced upregulation of IL-17A observed in plasma of wild-type rats was markedly decreased in NSun2-/- rats in vivo. Mechanistically, by using in vitro methylation assays and high-performance liquid chromatography-mass spectrum (HPLC MS) analysis, we showed that the tRNA methyltransferase NSun2 methylated the IL 17A mRNA in an m5C pattern. The results from bisulfite sequencing indicated that NSun2 methylated IL-17A mRNA at cytosine C466 in vitro and in vivo. Furthermore, we analyzed the activity of pGL3-derived reporters bearing IL-17A mRNA fragments and found that methylation by NSun2 promoted the translation of IL-17A. In conclusion, NSun2 mediates HHcy-induced upregulation of IL-17A expression by methylating IL-17A mRNA and promoting its translation in T lymphocytes. PMID- 28919412 TI - The conformation change and tumor suppressor role of Merlin are both independent of Serine 518 phosphorylation. AB - Merlin functions as a tumor suppressor and suppresses malignant activity of cancer cells through multiple mechanisms. However, whether Serine 518 phosphorylation regulates the conformation of Merlin as well as the open-closed conformational changes affect Merlin's tumor inhibitory activity remain controversial. In this study, we used different mutants to mimic related conformational states of Merlin and investigated its physiological functions. Our results showed that the phosphorylation at Serine 518 has no influence on Merlin's conformation, subcellular localization, or cell proliferation inhibitory activity. As a fully closed conformational state, the A585W mutant loses the ability to recruit Lats2 to the cell membrane, but it does not affect its subcellular distribution or cell proliferation inhibitory activity. As a fully open conformational state, mimicking the conformation of Merlin isoform II, the DeltaEL mutant has the same physiological function as the wild type Merlin isoform I. Collectively, we provide for the first time in vivo evidence that the function of Merlin, as a tumor suppressor is independent of its conformational change. PMID- 28919413 TI - Apolipoprotein A-I attenuates LL-37-induced endothelial cell cytotoxicity. AB - The human cathelicidin peptide LL-37 has antimicrobial and anti-biofilm functions, but LL-37 may also damage the host by triggering inflammation and exerting a cytotoxic effect, thereby reducing host cell viability. Human plasma mitigates LL-37-induced host cell cytotoxicity but the underlying mechanisms are not completely understood. Apolipoprotein A-I (ApoA-I) is a plasma protein endowed with atheroprotective effects. Here, we investigate the interaction between ApoA-I and LL-37 by biochemical techniques, and furthermore assess if ApoA-I protects against LL-37-evoked cytotoxicity in human umbilical vein endothelial cells (HUVEC). Our results demonstrated that ApoA-I effectively binds LL-37. The binding of ApoA-I to LL-37 resulted in a structural rearrangement of the protein, but this interaction did not cause lower ApoA-I stability. Recombinant ApoA-I protected against LL-37-induced cytotoxicity in HUVEC and endogenous ApoA-I knockdown in HepG2 cells made the cells more sensitive to LL-37 evoked cytotoxicity. We conclude that ApoA-I physically interacts with LL-37 and antagonizes LL-37-induced down-regulation of endothelial cell viability suggesting that this mechanism counteracts endothelial cell dysfunction. PMID- 28919414 TI - Changes in related circular RNAs following ERbeta knockdown and the relationship to rBMSC osteogenesis. AB - Recently, several studies have indicated that circular RNAs (circRNAs) play significant roles in various disease; however, little is known about the chronology of estrogen receptor beta (ERbeta) deficiency and altered circRNA expression, or their relationship with osteogenesis. Herein, we show through western-blot and quantitative real-time PCR assays, that when ERbeta is silenced, the expression of osteogenesis-related proteins and mRNAs were down-regulated. We then performed RNA-Seq to analyze differential circRNA expression between the control and ERbeta knockdown group. This analysis revealed that, 146 circRNAs were differentially expressed by fold-change>=2.0, p <= 0.05, and, among this group, 68 circRNAs were down-regulated, while 78 were up-regulated. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER pathway analyses were performed to predict the function of these differentially expressed circRNAs. Finally, co-expressed targets gene, and circRNA-microRNA network were constructed for predicted miRNA sponges. This research suggested that ERbeta may through 2:27713879|27755789/2:240822115|240867796-miR-328-5p-mRNA axis to regulate osteogenic differentiation. PMID- 28919415 TI - Biophysical characterization of the interaction between heme and proteins responsible for heme transfer in Streptococcus pyogenes. AB - Streptococcus pyogenes, an important pathogen that causes a wide range of diseases, possesses the sia gene cluster, which encodes proteins involved in the heme acquisition system. Although this system was previously described, the molecular mechanism of effective heme transfer remains to be elucidated. Here, we have characterized the interactions between heme and each domain of Streptococcal hemoprotein receptor (Shr) and Streptococcal heme-binding protein (Shp). Our kinetic and thermodynamic analyses suggested that effective heme transfer within this system is achieved not only by affinity-based transfer but also by the difference of the binding driving force. The biophysical characterization of the above-mentioned interaction will lead to an indication for the selection of the target for a chemical screening of inhibitors as novel antibacterial agents based on biophysical approaches. PMID- 28919416 TI - Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay. AB - Aspergillus fumigatus is a human pathogen responsible for deadly infections in immune-compromised patients. A potential strategy for treating A. fumigatus infections is by targeting the biosynthesis of cell wall components, such as galactofuranase, which is absent in humans. Galactofuranose biosynthesis is initiated by the flavoenzyme UDP-galactopyranose mutase (UGM), which converts UDP galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UGM requires the reduced form of the flavin for activity, which is obtained by reacting with NADPH. We aimed to identify inhibitors of UGM by screening a kinase inhibitor library using ThermoFAD, a flavin fluorescence thermal shift assay. The screening assay identified flavopiridol as a compound that increased the melting temperature of A. fumigatus UGM. Further characterization showed that flavopiridol is a non-competitive inhibitor of UGM and docking studies suggest that it binds in the active site. This compound does not inhibit the prokaryotic UGM from Mycobacteria tuberculosis. PMID- 28919417 TI - ACAP3, the GTPase-activating protein specific to the small GTPase Arf6, regulates neuronal migration in the developing cerebral cortex. AB - The GTPase-activating protein (GAP) specific to the small GTPase Arf6, ACAP3, is known to regulate morphogenesis of neurons in vitro. However, physiological significance of ACAP3 in the brain development in vivo remains unclear. Here, we show that ACAP3 is involved in neuronal migration in the developing cerebral cortex of mice. Knockdown of ACAP3 in the developing cortical neurons of mice in utero significantly abrogated neuronal migration in the cortical layer, which was restored by ectopic expression of wild type of ACAP3, but not by its GAP-inactive mutant. Furthermore, morphological changes of neurons during migration in the cortical layer were impeded in ACAP3-knocked-down cortical neurons. These results provide evidence that ACAP3 plays a crucial role in migration of cortical neurons by regulating their morphological change during development of cerebral cortex. PMID- 28919418 TI - The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells. AB - Melanoma is the most common primary malignant neoplasm in adults, causing more deaths than any other skin cancer, necessitating the development of new target based approaches. Current evidence suggests SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD+ biosynthetic enzyme, together comprise a novel systemic regulatory network to play a pivotal role in cell proliferation and apoptosis. Nevertheless, how the regulation of this cofactor interfaces with signal transduction network remains poorly understood in melanoma. Here, we report NAMPT is highly expressed in melanomaassociated with poor overall survival in patients. Pharmacological and genetic inhibition of NAMPT decreased NAD+ levels and melanoma cell proliferation capacity, and NAMPT knockdown induced apoptosis through the activity of the tumor suppressor p53. Next, we demonstrate NAMPT regulates the transcription factor E2F family member 2 (E2F2) in the apoptosis process. Downstream, E2F2 control the mRNA and protein levels of SIRT1. Finally, we find NAMPT mediates the apoptosis resistance of melanoma cells through NAMPT-E2F2-SIRT1 axis, more than NAD+-driven transcriptional program. Accordingly, our results demonstrated that NAMPT is a prognostic marker in melanoma, and the identificationofNAMPT-E2F2-SIRT1 pathway establishes another link between NAMPT and apoptosis events in melanoma, with therapeutic implications for this deadly cancer. PMID- 28919419 TI - Binding mode of metal ions to the bacterial iron import protein EfeO. AB - The tripartite EfeUOB system functions as a low pH iron importer in Gram-negative bacteria. In the alginate-assimilating bacterium Sphingomonas sp. strain A1, an additional EfeO-like protein (Algp7) is encoded downstream of the efeUOB operon. Here we show the metal binding mode of Algp7, which carries a M_75 metallopeptidase motif. The Algp7 protein was purified from recombinant E. coli cells and was subsequently characterized using differential scanning fluorimetry, fluorescence spectrometry, atomic absorption spectroscopy, and X-ray crystallography. The fluorescence of a dye, SYPRO Orange, bound to denatured Algp7 in the absence and presence of metal ions was measured during heat treatment. The fluorescence profile of Algp7 in the presence of metals such as ferric, ferrous, and zinc ions, shifted to a higher temperature, suggesting that Algp7 binds these metal ions and that metal ion-bound Algp7 is more thermally stable than the ligand-free form. Algp7 was directly demonstrated to show an ability to bind copper ion by atomic absorption spectroscopy. Crystal structure of metal ion-bound Algp7 revealed that the metal ion is bound to the cleft surrounded by several acidic residues. Four residues, Glu79, Glu82, Asp96, and Glu178, distinct from the M_75 motif (His115xxGlu118), are coordinated to the metal ion. This is the first report to provide structural insights into metal binding by the bacterial EfeO element. PMID- 28919420 TI - Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab')2 fragment. AB - Antibodies and fragments thereof are, because of high selectivity for their targets, considered as potential therapeutics and biomarkers for several neurological disorders. However, due to their large molecular size, antibodies/fragments do not easily penetrate into the brain. The aim of the present study was to improve the brain distribution via adsorptive-mediated transcytosis of an amyloid-beta (Abeta) protofibril selective F(ab')2 fragment (F(ab')2-h158). F(ab')2-h158 was cationized to different extents and the specific and unspecific binding was studied in vitro. Next, cationized F(ab')2-h158 was labelled with iodine-125 and its brain distribution and pharmacokinetics was studied in mice. Cationization did not alter the in vitro affinity to Abeta protofibrils, but increased the unspecific binding somewhat. Ex vivo experiments revealed a doubling of brain concentrations compared with unmodified F(ab')2-h158 and in vivo imaging with single photon emission computed tomography (SPECT) showed that the cationized F(ab')2-h158, but not the unmodified F(ab')2-h158 could be visualized in the brain. To conclude, cationization is a means to increase brain concentrations of therapeutic antibodies or fragments and may facilitate the use of antibodies/fragments as imaging biomarkers in the brain. PMID- 28919421 TI - Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin. AB - Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) play an important role in cutaneous wound healing, and recent studies suggested that MSC derived exosomes activate several signaling pathways, which are conducive in wound healing and cell growth. In this study, we investigated the roles of exosomes that are derived from USC-CM (USC-CM Exos) in cutaneous collagen synthesis and permeation. We found that USC-CM has various growth factors associated with skin rejuvenation. Our in vitro results showed that USC-CM Exos integrate in Human Dermal Fibroblasts (HDFs) and consequently promote cell migration and collagen synthesis of HDFs. Moreover, we evaluated skin permeation of USC-CM Exos by using human skin tissues. Results showed that Exo-Green labeled USC-CM Exos approached the outermost layer of the epidermis after 3 h and gradually approached the epidermis after 18 h. Moreover, increased expressions of Collagen I and Elastin were found after 3 days of treatment on human skin. The results showed that USC-CM Exos is absorbed into human skin, it promotes Collagen I and Elastin synthesis in the skin, which are essential to skin rejuvenation and shows the potential of USC-CM integration with the cosmetics or therapeutics. PMID- 28919422 TI - Over-expression of PPARalpha in obese mice adipose tissue improves insulin sensitivity. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is important in the regulation of lipid metabolism and expressed at high levels in the liver. Although PPARalpha is also expressed in adipose tissue, little is known about the relationship between its activation and the regulation of glucose metabolism. In this study, we developed adipose tissue specific PPARalpha over-expression (OE) mice. Metabolomics and insulin tolerance tests showed that OE induces branched chain amino acid (BCAA) profile and improvement of insulin sensitivity. Furthermore, LC-MS and PCR analyses revealed that OE changes free fatty acid (FFA) profile and reduces obesity-induced inflammation. These findings suggested that PPARalpha activation in adipose tissue contributes to the improvement of glucose metabolism disorders via the enhancement of BCAA and FFA metabolism. PMID- 28919423 TI - COPS5 inhibition arrests the proliferation and growth of serous ovarian cancer cells via the elevation of p27 level. AB - The fifth component of the COP9 signalosome complex (COPS5), which plays an essential role in ubiquitin-mediated protein degradation, has been found as a prognostic biomarker for multiple cancers, however, the role of COPS5 in serous ovarian cancer (SOC) remain to be clarified. In this study, we found that COPS5 expression was significantly increased in SOC cells and tissues compared with those controls. Mechanistically, COPS5 and p27was proved to interact with each other, with COPS5 acts as a negative regulator of p27. SOC cells with COPS5 depletion were arrested in G1/G0-phase and exhibited a reduced proliferation ability and an increased cytoplasmic p27 expression. Whereas, the cells were stuck at S-phase accompanied with an elevation of nucleus p27 expression after knocking down COPS6 or blocking COPS5 by CSN5i-3. Furthermore, inhibition of COPS5 resulted in an elevation of Akt expression and sensitized SOC cells to Akt inhibitor MK2206. Suppression of COPS5 and Akt offers a potential strategy for the treatment of SOC. PMID- 28919424 TI - Adiponectin modulates the function of endothelial progenitor cells via AMPK/eNOS signaling pathway. AB - Endothelial progenitor cells have been shown to differentiate into endothelial cells and to play a pivotal role in vascular homeostasis. Adiponectin has anti atherogenic and anti-inflammatory properties via directly acting on vascular cells. The aim of the present study is to explore the effect of adiponectin on major functions involved in survival, migration, and tube formation of endothelial progenitor cells and to explore the underlying mechanism. In this study, we transferred adiponectin gene into endothelial progenitor cells via lentiviral vectors and investigated the proliferation, migration and tube formation of these transfected cells. We found that adiponectin is highly expressed in endothelial progenitor cells and promotes their proliferation, migration and tube formation. Western blot data showed that the former two processes were mediated through the AMPK/Akt/eNOS pathway, the latter via the AMPK/eNOS pathway. Use of the AMPK inhibitor (Compound C) or Akt inhibitor (MK 2206) reduced eNOS phosphorylation and attenuated adiponectin-induced endothelial progenitor cell proliferation, migration and tube formation compared to the controls (p < 0.05). Taken together, these data indicated that adiponectin promotes endothelial progenitor cell proliferation and migration via AMPK/Akt/eNOS signaling pathway and promotes tube formation through AMPK/eNOS, suggesting that adiponectin-transduced endothelial progenitor cell transplantation is a potential therapeutic target for vascular disease. PMID- 28919425 TI - Detection of oligonucleotides by PNA-peptide conjugates recognizing the biarsenical fluorescein complex FlAsH-EDT2. AB - We report the application of the arsenical complex FlAsH-EDT2 for the identification of oligonucleotide sequences. We designed PNA sequences conjugated to either a tetracysteine motif and to split tetracysteine sequences, that are recognized by FlAsH. The effect of conjugation of the PNA to the tetracysteine peptide and RNA hybridization on the fluorescence of the arsenical complex has been investigated. The reconstitution of the tetracysteine motif, starting from 15-mer PNAs conjugated to split tetracysteine sequences and hybridized to a complementary oligonucleotide was also explored. PMID- 28919426 TI - Improving glycemic control in model mice with type 2 diabetes by increasing superoxide dismutase (SOD) activity using silk fibroin hydrolysate (SFH). AB - Islet cell dysfunction in type 2 diabetes is primarily attributed to the increased apoptosis of pancreatic beta cells. Silk fibroin hydrolysate (SFH) has an effect on blood in type 2 diabetes model mice (C57BL/KsJ-db/db). However, its exact mechanism is unknown. The type 2 diabetes model mice were randomly divided into non-diabetic mice (ND), diabetic mice (DB), and diabetic mice treated with silk fibroin hydrolysate (DB-SFH). The results showed that SFH significantly decreased fasting blood glucose and hemoglobin A1c (HbA1c). The oral glucose tolerance and insulin tolerance were significantly improved in the DB-SFH group. The DB-SFH group exhibited increased superoxide dismutase (SOD) activity in the plasma, as well as increased Mn-SOD and CuZn-SOD activities in the pancreatic islets. Furthermore, the pancreatic islet cells' death was decreased in the DB SFH group. In the DB-SFH group, the protein expression of caspase-3 was significantly decreased compared with the DB group. The expression of the Nkx6.1 and Pdx1 proteins were increased in the DB-SFH group. The results suggest that SFH prevents the degeneration of pancreatic islets via increasing SOD while hyperglycemia is alleviated by maintaining beta cell mass in type 2 diabetes model mice. PMID- 28919428 TI - Metal-mediated oxidation of fluoroquinolone antibiotics in water: A review on kinetics, transformation products, and toxicity assessment. AB - Fluoroquinolones (FQs) are among the most potent antimicrobial agents, which have seen their increasing use as human and veterinary medicines to control bacterial infections. FQs have been extensively found in surface water and municipal wastewaters, which has raised great concerns due to their negative impacts to humans and ecological health. It is of utmost importance that FQs are treated before their release into the environment. This paper reviews oxidative removal of FQs using reactive oxygen (O3 and OH), sulfate radicals (SO4-), and high valent transition metal (MnVII and FeVI) species. The role of metals in enhancing the performance of reactive oxygen and sulfur species is presented. The catalysts can significantly enhance the production of OH and/or SO4- radicals. At neutral pH, the second-order rate constants (k, M-1s-1) of the reactions between FQs and oxidants follow the order as k(OH)>k(O3)>k(FeVI)>k(MnVII). Moieties involved to transform target FQs to oxidized products and participation of the catalysts in the reaction pathways are discussed. Generally, the piperazinyl ring of FQs was found as the preferential attack site by each oxidant. Meanwhile, evaluation of aquatic ecotoxicity of the transformation products of FQs by these treatments is summarized. PMID- 28919429 TI - Electrochemical synthesis of ferrate(VI) using sponge iron anode and oxidative transformations of antibiotic and pesticide. AB - Passivation of anode is a main challenge in the electrochemical synthesis of ferrate(VI) (FeVIO42-, Fe(VI)). A series of electrochemical approaches were employed including polarization curve, cyclic voltammetry, and electrochemical impedance spectroscopy (EIS) to analyze the physicochemical processes involved in electrochemical synthesis of Fe(VI) using sponge iron and cast iron anodes. The results demonstrate that the sponge iron anode achieved higher yield of Fe(VI) compared to grey cast iron anode. The optimum condition to generate Fe(VI) using sponge iron was 35-50 degrees C and 30mA/cm2. Significantly, the sponge iron anode could generate Fe(VI) for a long duration (>10h) under these conditions; possibly suitable for large scale synthesis of Fe(VI). The prepared Fe(VI) solution was used to treat antibiotic (sulfamethoxazole (SMX)) and pesticide (atrazine (ATZ)) in water. At a molar ratio of Fe(VI) to SMX as 20:1 in the pH range from 5.0 to 9.0, almost complete oxidative transformation of SMX could be obtained. Comparatively, oxidative transformation of ATZ was incomplete (~70%) even when [Fe(VI)]:[ATZ]=87 at pH 5.0-9.0. Fluorescence spectra and cytotoxicity studies suggest that the oxidative transformation products of both SMX and ATZ possess lower toxicity than the parent antibiotic and pesticide, respectively. PMID- 28919427 TI - Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1beta deficient murine hearts. AB - INTRODUCTION: Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF). MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-gamma coactivator-1beta deficient (Pgc-1beta-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES). RESULTS AND DISCUSSION: The Pgc-1beta-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1beta-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1beta-/- hearts. Pgc-1beta-/- hearts showed accelerated age dependent fibrotic change relative to WT, with young Pgc-1beta-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1beta-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change. PMID- 28919430 TI - Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice. AB - OBJECTIVE: Animal models recapitulating post-traumatic osteoarthritis (OA) suggest that subchondral bone (SCB) properties and remodeling may play major roles in disease initiation and progression. Thus, we investigated the role of SCB properties and its effects on load-induced OA progression by applying a tibial loading model on two distinct mouse strains treated with alendronate (ALN). DESIGN: Cyclic compression was applied to the left tibia of 26-week-old male C57Bl/6 (B6, low bone mass) and FVB (high bone mass) mice. Mice were treated with ALN (26 MUg/kg/day) or vehicle (VEH) for loading durations of 1, 2, or 6 weeks. Changes in articular cartilage and subchondral and epiphyseal cancellous bone were analyzed using histology and microcomputed tomography. RESULTS: FVB mice exhibited thicker cartilage, a thicker SCB plate, and higher epiphyseal cancellous bone mass and tissue mineral density than B6 mice. Loading induced cartilage pathology, osteophyte formation, and SCB changes; however, lower initial SCB mass and stiffness in B6 mice did not attenuate load-induced OA severity compared to FVB mice. By contrast, FVB mice exhibited less cartilage damage, and slower-growing and less mature osteophytes. In B6 mice, inhibiting bone remodeling via ALN treatment exacerbated cartilage pathology after 6 weeks of loading, while in FVB mice, inhibiting bone remodeling protected limbs from load-induced cartilage loss. CONCLUSIONS: Intrinsically lower SCB properties were not associated with attenuated load-induced cartilage loss. However, inhibiting bone remodeling produced differential patterns of OA pathology in animals with low compared to high SCB properties, indicating that these factors do influence load-induced OA progression. PMID- 28919431 TI - Neurocircuitry of impaired affective sound processing: A clinical disorders perspective. AB - Decoding affective meaning from sensory information is central to accurate and adaptive behavior in many natural and social contexts. Human vocalizations (speech and non-speech), environmental sounds (e.g. thunder, noise, or animal sounds) and human-produced sounds (e.g. technical sounds or music) can carry a wealth of important aversive, threatening, appealing, or pleasurable affective information that sometimes implicitly influences and guides our behavior. A deficit in processing such affective information is detrimental to adaptive environmental behavior, psychological well-being, and social interactive abilities. These deficits can originate from a diversity of psychiatric and neurological disorders, and are associated with neural dysfunctions across largely distributed brain networks. Recent neuroimaging studies in psychiatric and neurological patients outline the cortical and subcortical neurocircuitry of the complimentary and differential functional roles for affective sound processing. This points to and confirms a recently proposed distributed network rather than a single brain region underlying affective sound processing, and highlights the notion of a multi-functional process that can be differentially impaired in clinical disorders. PMID- 28919432 TI - Chronic Pain and Telomere Length in Community-Dwelling Adults: Findings From the 1999 to 2002 National Health and Nutrition Examination Survey. AB - : Chronic pain is a common condition associated with psychological distress, functional impairments, and age-associated comorbidity. Preliminary studies, on the basis of relatively small sample sizes, suggest that the combination of chronic pain and stress is associated with telomere shortening, a widely recognized marker of cellular aging. We sought to determine the cross-sectional association of chronic pain with telomere length in 7,816 community-dwelling adults ages 20 years and older who participated in the 1999 to 2002 National Health and Nutrition Examination Survey. Consistent with previous studies, leukocyte telomere length was assessed using the quantitative polymerase chain reaction method and compared with a DNA reference standard to compute a telomere to single copy gene ratio. Standardized, in-person interviews were used to identify chronic regional pain and chronic widespread pain in 784 (10.0%) and 266 (3.4%) participants, respectively. Older age, male sex, obesity, and less physical activity were associated with shorter telomere length (P <.05 for all comparisons); however, there was no association of chronic pain with telomere length. The age-adjusted means (standard error) of telomere length telomere to single copy gene ratios were 1.04 (.02), 1.03 (.02), and 1.02 (.02) in participants with no chronic pain, chronic regional pain, and chronic widespread pain, respectively (P = .69). In addition, chronic pain did not modify the effects of age, sex, race/ethnicity, education, or psychological distress on telomere length. In summary, chronic regional and widespread pain were not associated with telomere length in this nationally representative study; however, we could not determine associations of pain duration and severity with telomere length because of limitations in pain assessment data. PERSPECTIVE: The findings from the current study do not support the hypothesis that chronic pain accelerates cellular aging measured according to leukocyte telomere length. Additional population-based studies with more detailed assessments of pain and stress are needed to further investigate potential interactive effects on telomere length and other biomarkers of aging. PMID- 28919433 TI - The P2X7 receptor in dorsal root ganglia is involved in HIV gp120-associated neuropathic pain. AB - Human immunodeficiency virus (HIV)-associated neuropathic pain is common, and studies have shown that HIV envelope glycoprotein 120 (gp120) can directly stimulate primary sensory afferent neurons causing hyperalgesia. The P2X7 receptor in the dorsal root ganglia (DRG) is involved in pain transmission and is closely related to the inflammatory and immune response. In this study, we aimed to explore the role of the P2X7 receptor in gp120-induced neuropathic pain using a rat model specific for this type of pain. The results showed that mechanical hyperalgesia, thermal hyperalgesia and P2X7 expression levels were increased in rats treated with gp120. The P2X7 antagonist, brilliant blue G (BBG), decreased hyperalgesia and P2X7 expression levels in rats treated with gp120. BBG also decreased IL-1beta and TNF-alpha receptor expression and ERK1/2 phosphorylation levels and increased IL-10 expression in the gp120-treated rat DRG. In addition, P2X7 agonist (BzATP)-activated currents in DRG neurons cultured with gp120 were larger than those in control neurons, and the inhibitory effect of BBG on BzATP induced currents in gp120-treated DRG neurons was larger than that in control neurons. Therefore, inhibition of the P2X7 receptor in rat DRG relieved gp120 induced mechanical hyperalgesia and thermal hyperalgesia. PMID- 28919434 TI - Ultrasensitive microRNA-21 detection based on DNA hybridization chain reaction and SYBR Green dye. AB - It is extremely important for quantifying trace microRNAs in the biomedical applications. In this study, an ultrasensitive, rapid and efficient label-free fluorescence method was proposed and applied for detecting microRNA-21 in serum of gastric cancer patients based on DNA hybridization chain reaction (HCR). DNA H1 and DNA H2 were designed and used as hairpin probes, the HCR was proceeded in the presence of target microRNAs. Amounts of SYBR Green I dyes were used as signal molecules to intercalate long DNA concatemers from HCR, which guaranteed the model of label-free fluorescence and strong fluorescence density. The detection method showed a wide linear region from 1 fM to 105 fM, and the limit of detection was 0.2554 fM (at S/N = 3) for microRNAs. The results showed that this method had an excellent specificity and reproducibility. Furthermore, the label-free fluorescence strategy exhibited a sensitive response to microRNA-21 in real serum samples of gastric cancer patients and the results obtained were in accordance with reference method (R2 = 0.994). Overall, the proposed strategy could be satisfactory for rapid, ultrasensitive and efficient detection of microRNA-21, and held great potentials in clinic diagnosis of gastric cancer. PMID- 28919435 TI - Ultrasensitive and rapid immuno-detection of human IgE anti-therapeutic horse sera using an electrochemical immunosensor. AB - Antivenom allergy disease mediated by patient IgE is an important public health care concern. To improve detection of hypersensitive individuals prior to passive antibody therapy, an amperometric immunosensor was developed to detect reactive human IgE. Whole horse IgG3 (hoIgG3) was immobilized onto the surface of carbon or gold screen-printed electrodes through a cross-linking solution of glutaraldehyde on a chitosan film. Sera from persons with a known allergic response to hoIgG3 or non-allergic individuals was applied to the sensor. Bound human IgE (humIgE) was detected by an anti-humIgE antibody through a quantitative amperometric determination by tracking via the electrochemical reduction of the quinone generated from the hydroquinone with the application of a potential of 25 mV. The optimal immunosensor configuration detected reactive humIgE at a dilution of 1:1800 of the human sera that represent a detection limit of 0.5 pg/mL. Stability testing demonstrated that through 20 cycles of a scan, the specificity and performance remained robust. The new immunosensor successfully detected humIgE antibodies reactive against hoIgG3, which could allow the diagnosis of potential allergenic patients needing therapeutic antivenom preparations from a horse. PMID- 28919437 TI - Strategies for the enhanced intracellular delivery of nanomaterials. AB - The intracellular delivery of nanomaterials and drugs has been attracting increasing research interest, mainly because of their important effects and functions in several organelles. Targeting specific organelles can help treat or decrease the symptoms of diabetes, cancer, infectious, and autoimmune diseases. Tuning biological and chemical properties enables the creation of functionalized nanomaterials with enhanced intracellular uptake, ability to escape premature lysosome degradation, and to reach a specific target. Here, we provide an update of recent advances in the intracellular delivery mechanisms that could help drugs reach their target more efficiently. PMID- 28919438 TI - Molecular targets and pathways for the treatment of visceral leishmaniasis. AB - Visceral leishmaniasis (VL) represents the most severe form of the tropical disease, leishmaniasis. Treatment of VL is complicated because of the few clinically approved antileishmanial drugs available; emerging resistance to first line drugs; need for a temperature-controlled 'cold' supply chain; serious toxicity concerns over drugs such as amphotericin B; high cost of medication; and unavailability of clinically approved antileishmanial vaccines. Attacking potential molecular targets, specific to the parasite, is a vital step in the treatment of this and other infectious diseases. As we discuss here, comprehensive investigation of these targets could provide a promising strategy for the treatment of visceral leishmaniasis. PMID- 28919436 TI - The Notch pathway regulates the Second Mitotic Wave cell cycle independently of bHLH proteins. AB - Notch regulates both neurogenesis and cell cycle activity to coordinate precursor cell generation in the differentiating Drosophila eye. Mosaic analysis with mitotic clones mutant for Notch components was used to identify the pathway of Notch signaling that regulates the cell cycle in the Second Mitotic Wave. Although S phase entry depends on Notch signaling and on the transcription factor Su(H), the transcriptional co-activator Mam and the bHLH repressor genes of the E(spl)-Complex were not essential, although these are Su(H) coactivators and targets during the regulation of neurogenesis. The Second Mitotic Wave showed little dependence on ubiquitin ligases neuralized or mindbomb, and although the ligand Delta is required non-autonomously, partial cell cycle activity occurred in the absence of known Notch ligands. We found that myc was not essential for the Second Mitotic Wave. The Second Mitotic Wave did not require the HLH protein Extra macrochaetae, and the bHLH protein Daughterless was required only cell nonautonomously. Similar cell cycle phenotypes for Daughterless and Atonal were consistent with requirement for neuronal differentiation to stimulate Delta expression, affecting Notch activity in the Second Mitotic Wave indirectly. Therefore Notch signaling acts to regulate the Second Mitotic Wave without activating bHLH gene targets. PMID- 28919439 TI - Pih1p-Tah1p Puts a Lid on Hexameric AAA+ ATPases Rvb1/2p. AB - The Saccharomyces cerevisiae (Sc) R2TP complex affords an Hsp90-mediated and nucleotide-driven chaperone activity to proteins of small ribonucleoprotein particles (snoRNPs). The current lack of structural information on the ScR2TP complex, however, prevents a mechanistic understanding of this biological process. We characterized the structure of the ScR2TP complex made up of two AAA+ ATPases, Rvb1/2p, and two Hsp90 binding proteins, Tah1p and Pih1p, and its interaction with the snoRNP protein Nop58p by a combination of analytical ultracentrifugation, isothermal titration calorimetry, chemical crosslinking, hydrogen-deuterium exchange, and cryoelectron microscopy methods. We find that Pih1p-Tah1p interacts with Rvb1/2p cooperatively through the nucleotide-sensitive domain of Rvb1/2p. Nop58p further binds Pih1p-Tahp1 on top of the dome-shaped R2TP. Consequently, nucleotide binding releases Pih1p-Tah1p from Rvb1/2p, which offers a mechanism for nucleotide-driven binding and release of snoRNP intermediates. PMID- 28919440 TI - Structural Insight into BLM Recognition by TopBP1. AB - Topoisomerase IIbeta binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1. PMID- 28919441 TI - A Unique pH-Dependent Recognition of Methylated Histone H3K4 by PPS and DIDO. AB - The protein partner of Sans-fille (PPS) and its human homolog DIDO mediate diverse chromatin activities, including the regulation of stemness genes in embryonic stem cells and splicing in Drosophila. Here, we show that the PHD fingers of PPS and DIDO recognize the histone mark H3K4me3 in a pH-dependent manner: the binding is enhanced at high pH values but is decreased at low pH. Structural analysis reveals that the pH dependency is due to the presence of a histidine residue in the K4me3-binding aromatic cage of PPS. The pH-dependent mechanism is conserved in DIDO but is lost in yeast Bye1. Acidification of cells leads to the accelerated efflux of endogenous DIDO, indicating the pH-dependent sensing of H3K4me3 in vivo. This novel mode for the recognition of H3K4me3 establishes the PHD fingers of PPS and DIDO as unique epigenetic readers and high pH sensors and suggests a role for the histidine switch during mitosis. PMID- 28919442 TI - Structural and Functional Analysis of the C-Terminal Region of FliG, an Essential Motor Component of Vibrio Na+-Driven Flagella. AB - The flagellar motor protein complex consists of rotor and stator proteins. Their interaction generates torque of flagellum, which rotates bidirectionally, clockwise (CW) and counterclockwise. FliG, one of the rotor proteins, consists of three domains: N-terminal (FliGN), middle (FliGM), and C-terminal (FliGC). We have identified point mutations in FliGC from Vibrio alginolyticus, which affect the flagellar motility. To understand the molecular mechanisms, we explored the structural and dynamic properties of FliGC from both wild-type and motility defective mutants. From nuclear magnetic resonance analysis, changes in signal intensities and chemical shifts between wild-type and the CW-biased mutant FliGC are observed in the Calpha1-6 domain. Molecular dynamics simulations indicated the conformational dynamics of FliGC at sub-microsecond timescale, but not in the CW-biased mutant. Accordingly, we infer that the dynamic properties of atomic interactions around helix alpha1 in the Calpha1-6 domain of FliGC contribute to ensure the precise regulation of the motor switching. PMID- 28919443 TI - Fv-clasp: An Artificially Designed Small Antibody Fragment with Improved Production Compatibility, Stability, and Crystallizability. AB - Antibody fragments are frequently used as a "crystallization chaperone" to aid structural analysis of complex macromolecules that are otherwise crystallization resistant, but conventional fragment formats have not been designed for this particular application. By fusing an anti-parallel coiled-coil structure derived from the SARAH domain of human Mst1 kinase to the variable region of an antibody, we succeeded in creating a novel chimeric antibody fragment of ~37 kDa, termed "Fv-clasp," which exhibits excellent crystallization compatibility while maintaining the binding ability of the original IgG molecule. The "clasp" and the engineered disulfide bond at the bottom of the Fv suppressed the internal mobility of the fragment and shielded hydrophobic residues, likely contributing to the high heat stability and the crystallizability of the Fv-clasp. Finally, Fv clasp antibodies showed superior "chaperoning" activity over conventional Fab fragments, and facilitated the structure determination of an ectodomain fragment of integrin alpha6beta1. PMID- 28919444 TI - A new black fly species of the Simulium (Gomphostilbia) epistum species-group (Diptera: Simuliidae) from Thailand. AB - A new species of black fly, Simulium (Gomphostilbia) isanense, is described based on females, males, pupae and mature larvae from Thailand. This new species is placed in the Simulium epistum species-group of the subgenus Gomphostilbia Enderlein. It is characterized by the pupal gill with eight filaments arranged as 3+3+2 from dorsal to ventral, of which an inner filament of the ventral pair is slightly longer than its counter filament. Taxonomic notes are provided to distinguish this new species from S. (G.) angulistylum Takaoka & Davies from Peninsular Malaysia, and three other related species. The difference between this new species and S. (G.) angulistylum is supported by genetic distances using the mitochondrial COI gene. PMID- 28919445 TI - Cognitive effects of labeled addictolytic medications. AB - INTRODUCTION: Alcohol, tobacco, and illegal drug usage is pervasive throughout the world, and abuse of these substances is a major contributor to the global disease burden. Many pharmacotherapies have been developed over the last 50years to target addictive disorders. While the efficacy of these pharmacotherapies is largely recognized, their cognitive impact is less known. However, all substance abuse disorders are known to promote cognitive disorders like executive dysfunction and memory impairment. These impairments are critical for the maintenance of addictive behaviors and impede cognitive behavioral therapies that are regularly administered in association with pharmacotherapies. It is also unknown if addictolytic medications have an impact on preexisting cognitive disorders, and if this impact is modulated by the indication of prescription, i.e. abstinence, reduction or substitution, or by the specific action of the medication. METHOD: We reviewed the cognitive effects of labeled medications for tobacco addiction (varenicline, bupropion, nicotine patch and nicotine gums), alcohol addiction (naltrexone, nalmefene, baclofen, disulfiram, sodium oxybate, acamprosate), and opioid addiction (methadone, buprenorphine) in human studies. Studies were selected following MOOSE guidelines for systematic reviews of observational studies, using the keywords [Cognition] and [Cognitive disorders] and [treatment] for each medication. RESULTS: 971 articles were screened and 77 studies met the inclusion criteria and were reported in this review (for alcohol abuse, n=21, for tobacco n=22, for opioid n=34. However, very few comparative clinical trials have explored the chronic effects of addictolytic medications on cognition in addictive behaviors, and there are no clinical trials on the cognitive impact of nalmefene in patients suffering from alcohol use disorders. DISCUSSION: Although some medications seem to enhance cognition in patients suffering from cognitive disorders, others could promote cognitive impairments, and our work highlights a lack of literature on this subject. In conclusion, more comparative clinical trials are needed to better understand the cognitive impact of addictolytic medications. PMID- 28919446 TI - Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells. AB - The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-gamma, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-gamma, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-gamma producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-gamma producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process. PMID- 28919447 TI - Multi-year longitudinal profiles of cortisol and corticosterone recovered from baleen of North Atlantic right whales (Eubalaena glacialis). AB - Research into stress physiology of mysticete whales has been hampered by difficulty in obtaining repeated physiological samples from individuals over time. We investigated whether multi-year longitudinal records of glucocorticoids can be reconstructed from serial sampling along full-length baleen plates (representing ~10years of baleen growth), using baleen recovered from two female North Atlantic right whales (Eubalaena glacialis) of known reproductive history. Cortisol and corticosterone were quantified with immunoassay of subsamples taken every 4cm (representing ~60d time intervals) along a full-length baleen plate from each female. In both whales, corticosterone was significantly elevated during known pregnancies (inferred from calf sightings and necropsy data) as compared to intercalving intervals; cortisol was significantly elevated during pregnancies in one female but not the other. Within intercalving intervals, corticosterone was significantly elevated during the first year (lactation year) and/or the second year (post-lactation year) as compared to later years of the intercalving interval, while cortisol showed more variable patterns. Cortisol occasionally showed brief high elevations ("spikes") not paralleled by corticosterone, suggesting that the two glucocorticoids might be differentially responsive to certain stressors. Generally, immunoreactive corticosterone was present in higher concentration in baleen than immunoreactive cortisol; corticosterone:cortisol ratio was usually >4 and was highly variable in both individuals. Further investigation of baleen cortisol and corticosterone profiles could prove fruitful for elucidating long-term, multi-year patterns in stress physiology of large whales, determined retrospectively from stranded or archived specimens. PMID- 28919448 TI - 7alpha-Hydroxypregnenolone regulating locomotor behavior identified in the brain and pineal gland across vertebrates. AB - The brain synthesizes steroids de novo from cholesterol, which are called neurosteroids. Based on extensive studies on neurosteroids over the past thirty years, it is now accepted that neurosteroidogenesis in the brain is a conserved property across vertebrates. However, the formation of bioactive neurosteroids in the brain is still incompletely elucidated in vertebrates. In fact, we recently identified 7alpha-hydroxypregnenolone (7alpha-OH PREG) as a novel bioactive neurosteroid stimulating locomotor behavior in the brain of several vertebrates. The follow-up studies have demonstrated that the stimulatory action of brain 7alpha-OH PREG on locomotor behavior is mediated by the dopaminergic system across vertebrates. More recently, we have further demonstrated that the pineal gland, an endocrine organ located close to the brain, is a major site of the formation of bioactive neurosteroids. In addition to the brain, the pineal gland actively produces 7alpha-OH PREG de novo from cholesterol as a major pineal neurosteroid that acts on the brain to control locomotor rhythms. This review summarizes the identification, biosynthesis and mode of action of brain and pineal 7alpha-OH PREG, a new bioactive neurosteroid regulating locomotor behavior, across vertebrates. PMID- 28919449 TI - Genome editing in fishes and their applications. AB - There have been revolutionary progresses in genome engineering in the past few years. The newly-emerged genome editing technologies including zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats associated with Cas9 (CRISPR/Cas9) have enabled biological scientists to perform efficient and precise targeted genome editing in different species. Fish represent the largest group of vertebrates with many species having values for both scientific research and aquaculture industry. Genome editing technologies have found extensive applications in different fish species for basic functional studies as well asapplied research in such fields as disease modeling and aquaculture. This mini review focuses on recent advancements and applications of the new generation of genome editing technologies in fish species, with particular emphasis on their applications in understanding reproductive functions because the reproductive axis has been most systematically and best studied among others and its function has been difficult to address with reverse genetics approach. PMID- 28919450 TI - Seasonal expression of P450c17 and 5alpha-reductase-2 in the scented gland of male muskrats (Ondatra zibethicus). AB - Cytochrome P450 17A1 (P450c17) is the key enzyme required for the production of androgenic sex steroids by converting progestogens to androgens. 5alpha reductases are enzymes that convert testosterone (T) to dihydrotestosterone (DHT), which has a greater affinity for androgen receptors (AR) and stronger action than T. Our previous studies revealed that the scented glands of male muskrats expressed AR during the breeding and nonbreeding seasons. To further seek evidence of the activities of androgens in scented glands, the expression patterns of P450c17 and 5alpha-reductase 2 were investigated in the scented glands of male muskrats during the breeding and nonbreeding seasons. The weight and size of scented glands in the breeding season were significantly higher than those of the nonbreeding season. Immunohistochemical data showed that P450c17 and 5alpha-reductase 2 were presented in the glandular cells and epithelial cells of scented glands in both the seasons. The protein and mRNA expression of P450c17 and 5alpha-reductase 2 were significantly higher in the scented gland during the breeding season than those during the nonbreeding season. In addition, the levels of DHT and T in the scented gland were remarkably higher during the breeding season. Taken together, these results suggested that the scented glands of male muskrats were capable of locally synthesizing T and DHT, and T and DHT might play an important role in the scented glandular function via an autocrine or paracrine manner. PMID- 28919451 TI - Biphasic modulation of neuro- and interrenal steroidogenesis in juvenile African sharptooth catfish (Clarias gariepinus) exposed to waterborne di-(2-ethylhexyl) phthalate. AB - Receptor (i.e. genomic) and non-receptor (or non-genomic) effects of endocrine toxicology have received limited or almost non-existent attention for tropical species and regions. In the present study, we have evaluated the effects of di-(2 ethylhexyl) phthalate (DEHP) on neuro- and interrenal steroidogenesis of the African catfish (Clarias gariepinus) using molecular, immunochemical and physiological approaches. Juvenile fish (mean weight and length: 5.6+/-0.6g and 8.2+/-1.2cm, respectively), were randomly distributed into ten 120L rectangular glass tanks containing 60L of dechlorinated tap water, at 50 fish per exposure group. The fish were exposed to environmentally relevant concentrations of DEHP, consisting of 0 (ethanol solvent control), 10, 100, 200, and 400MUg DEHP/L water and performed in two replicates. Brain, liver and head kidney samples were collected at day 3, 7 and 14 after exposure, and analysed for star, p450scc, cyp19a1, cyp17, cyp11beta-, 3beta-, 17beta- and 20beta-hsd, and 17beta-ohase mRNA expression using real-time PCR. The StAR, P450scc and CYP19 proteins were measured using immunoblotting method, while estradiol-17beta (E2) and testosterone (T) were measured in liver homogenate using enzyme immunoassay (EIA). Our data showed a consistent and unique pattern of biphasic effect on star and steroidogenic enzyme genes with increases at low concentration (10MUg/L) and thereafter, a concentration-dependent decrease in both the brain and head kidney, that paralleled the expression of StAR, P450scc and CYP19 proteins. Cellular E2 and T levels showed an apparent DEHP concentration-dependent increase at day 14 of exposure. The observed consistency in the current findings and in view of previous reports on contaminants-induced alterations in neuro- and interrenal steroidogenesis, the broader toxicological and endocrine disruptor implication of our data indicate potentials for overt reproductive, metabolic, physiological and general health consequences for the exposed organisms. PMID- 28919452 TI - The affinity of transthyretin for T3 or T4 does not determine which form of the hormone accumulates in the choroid plexus. AB - Normal development of the brain is dependent on the required amounts of thyroid hormones (THs) reaching specific regions of the brain during each stage of ontogeny. Many proteins are involved with regulation of TH bioavailability in the brain: the TH distributor protein transthyretin (TTR), TH transmembrane transporters (e.g. MCT8, MCT10, LAT1, OATP1C1) and deiodinases (D1, D2 and D3) which either activate or inactivate THs. Previous studies revealed that in mammals, T4, but not T3, accumulated in the choroid plexus and then entered the cerebrospinal fluid. In all mammalian species studied so far, TTR binds T4 with higher affinity than T3, whereas TTR in non-mammalian vertebrates binds T3 with higher affinity than T4. We investigated if the form of TH preferentially bound by TTR influenced the form of the TH that accumulated in the choroid plexus and consequently other areas of the brain. We measured the mRNA levels corresponding to TTR, MCT8, MCT10, LAT1, OATP1C1, D1, D2 and D3 in the brains of chickens at 11days post-hatching. TTR, D3 and OATP1C1 expression were found to be highly concentrated in the choroid plexus. D1, MCT8 and MCT10 mRNA levels were slightly greater in the choroid plexus than in other areas of the brain while D2 mRNA levels were lower. LAT1 mRNA was evenly expressed throughout the brain. Therefore, the choroid plexus appears to be a structure which exhibits sophisticated control of TH levels within the brain. We also measured the uptake of intravenously injected 125I-T3 and 125I-T4 into brains of chickens of the same age. 125I-T4 but not 125I-T3 accumulated in the choroid plexus and optic lobes. Therefore, the form of TH preferentially bound by TTR does not determine the form of TH that accumulates in the choroid plexus and other areas of the brain. As for mammals, T3 present in the avian brain therefore seems mainly produced locally by conversion of T4 into T3 by D2. PMID- 28919453 TI - Testosterone promotes anxiolytic-like behavior in gonadectomized male rats via blockade of the 5-HT1A receptors. AB - This study was designed to examine an anxiety-like behavior in the adult gonadectomized (GDX) male rats subjected to testosterone propionate (TP) treatment alone or in combination with 8-OH-DPAT, a 5-HT1A receptor agonist, or with NAN-190, 5-HT1A receptor antagonist. Two weeks after gonadectomy, GDX rats were subjected by treatments with the solvent, TP (0.5mg/kg, s.c.), 8-OH-DPAT (0.05mg/kg, s.c.), NAN-190 (0.1mg/kg, i.p.), TP in combination with 8-OH-DPAT or NAN-190 during 14days. Anxiety behavior was assessed in the elevated plus maze (EPM) and the open field test (OFT). 8-OH-DPAT treatment failed to modify the anxiety-like behavior of GDX rats in the EPM as compared to the GDX rats given with oil solvent. NAN-190 injected alone or in combination with TP to GDX rats resulted in a significant anxiolytic-like effect as compared to the GDX given with oil solvent or TP application. Our data indicate that the combination of NAN 190 and TP is more effective than TP alone in GDX rats inducing a more profound anxiolytic-like effect in the EPM. Thus, the results of this study suggest that effects of 5-HT1A receptor agonist/antagonist can modify anxiety level in opposite direction in male rats after gonadectomy. PMID- 28919454 TI - A robust immune system conditions the response to abagovomab (anti-idiotypic monoclonal antibody mimicking the CA125 protein) vaccination in ovarian cancer patients. AB - INTRODUCTION: Despite encouraging phase I and II study results, vaccination of ovarian cancer patients with abagovomab - an anti-idiotypic mAb that mimics the ovarian cancer CA125 protein - failed to demonstrate efficacy in the phase III trial named MIMOSA (NCT00418574). We postulated that in this trial patients with a more robust immune system did respond to abagovomab but went undetected among a larger number of non-responders. We also postulated that assessment of the immune system status ahead of abagovomab administration might predict patients' propensity to respond to abagovomab. MATERIALS AND METHODS: The immune system status was assessed as percentage and absolute count of CD8+ T cells producing IFN-gamma after stimulation with Staphylococcal Enterotoxin B (SEB) in 80 patients on abagovomab and 31 patients on placebo from the MIMOSA trial ahead of treatment. Optimal cutoffs of the two variables were calculated by the web application "Cutoff Finder" as the points with most significant (log-rank test) splits based on relapse-free survival (RFS). The Kaplan-Meier curves and log-rank test served to estimate and compare RFS in patients with percentage and absolute count of IFN-gamma producing CD8+ T cells around the cutoffs. RESULTS: Patients on abagovomab with IFN-gamma producing CD8+T cell percentage above the cutoff had a better RFS (p=0.042) than those with IFN-gamma producing CD8+T cell percentage below the cutoff. Patients on abagovomab with IFN-gamma producing CD8+T cell absolute count above the cutoff had a better RFS (p=0.019) than those with IFN gamma producing CD8+T cell absolute counts below the cutoff. Consistently, the RFS of patients on abagovomab with IFN-gamma producing CD8+T cell percentage and absolute counts values below the respective cutoffs was identical to that of patients on placebo. Neither the percentage nor the absolute count of IFN-gamma producing CD8+T cells correlated with RFS in patients on placebo. CONCLUSIONS: A robust immune system is essential to obtain a clinical response in OC patients undergoing abagovomab immunotherapy whereas a robust immune system does not confer per se a survival advantage. Further work will clarify whether the results shown here apply only in the present setting or extend to other types of cancer and/or immunotherapeutic agents. PMID- 28919456 TI - Unresolved and critical issues in autoimmune rheumatic diseases. PMID- 28919455 TI - Is there a role for IL-17 in the pathogenesis of systemic sclerosis? AB - In systemic sclerosis (SSc) immuno-inflammatory events are central to disease development. Amongst other mediators of inflammation, interleukin 17 (IL-17) and Th17 cells have been reported to be increased in the peripheral blood and target organs including involved skin in SSc. They participate and amplify inflammatory responses by inducing the production of cytokines such as IL-6, chemokines such as CCL2 and CXCL8 (IL-8), matrix metalloproteinases-1, -2, -9 and the expression of adhesion molecules in stromal cells including fibroblasts and endothelial cells. In this respect, IL-17 and Th17 cells behave paradigmatically as documented in other autoimmune pathological conditions or infectious diseases. In experimental animal models of skin and lung fibrosis, IL-17 indirectly enhances the fibrotic process by favoring further inflammation by recruiting inflammatory cells, by activating and/or stimulating the production of TGF-beta and other pro fibrotic mediators, by inhibiting autophagy. Whether the findings generated in animal models of fibrosis can be translated to human SSc is unproven. Furthermore, it is controversial whether IL-17 directly promotes the transdifferentiation of human fibroblasts into myofibroblasts and enhances collagen production, with most of the available evidence against this possibility. The reductionist approach in which fibroblast in monolayers are cultured in plastic dishes under the influence of IL-17 limits the relevance of these findings. Further in vitro/ex vivo models with human tissues are being developed to investigate the real effect of IL-17 on extracellular matrix deposition, since agents blocking IL-17 are available for the clinic and it will be important to know whether their use in SSc would be beneficial or detrimental. PMID- 28919457 TI - Patterns of botulinum toxin treatment for spasticity and bleeding complications in patients with thrombotic risk. AB - The purpose of this study was to assess the prevalence of compartment syndrome or major bleeding episodes and compare compartment syndrome, patient and intervention characteristics in 110 patients with stroke (treated with Warfarin, new oral anticoagulants, antiplatelet, or no anticoagulants) treated for spasticity in deep leg compartment muscles with botulinum toxin injections [onabotulinumtoxinA (n = 77); incobotulinumtoxinA (n = 33)]. We reviewed 674 injection cycles (range 1-25 cycles per patient) and found no cases of compartment syndrome in any patient groups. PMID- 28919458 TI - Anthrax lethal toxin (LeTx) neutralization by PA domain specific antisera. AB - Anthrax associated causalities in humans and animals are implicated mainly due to the action of two exotoxins that are secreted by the bacterium Bacillus antharcis during the infection. These exotoxins comprise of three protein components namely protective antigen (PA), lethal factor (LF) and edema factor (EF). The protective antigen is the common toxin component required to form both lethal toxin (LeTx) and edema toxin (EdTx). The LeTx is formed, when PA combines with LF and EdTx is formed when PA combines with EF. Therapeutic interventions aiming to neutralize these key effectors of anthrax pathology would therefore, provide an effective means to counter the toxicity imposed by the anthrax toxins on the host. The present work describes the lethal toxin neutralization potential of polyclonal antisera developed against the individual domains of the protective antigen component of the anthrax toxin. The individual domains were produced as recombinant proteins in E. coli and validated with peptide mass fingerprinting by MALDI-TOF analysis and corresponding mice polyclonal antisera by western blotting. Each domain specific antibody titre and isotype was ascertained by ELISA. The isotyping revealed the predominance of IgG1 isotype. The toxin neutralizing potential of these domain specific antisera were evaluated by in vitro cell viability MTT assay, employing J774.1 mouse macrophage cell line against LeTx (0.25 MUg ml-1 PA and 0.125 MUg ml-1 LF concentrations). Among the four domain specific antisera, the antiserum against PA domain IV could neutralize LeTx with high efficiency. No significant neutralization of LeTx was observed with other domain specific antibodies. Results indicate that antibodies to r-PA domain IV could be explored further as therapeutic anti toxin molecule along with appropriate antibiotic regimens against anthrax. PMID- 28919459 TI - Genome content, metabolic pathways and biotechnological potential of the psychrophilic Arctic bacterium Psychrobacter sp. DAB_AL43B, a source and a host of novel Psychrobacter-specific vectors. AB - Psychrobacter sp. DAB_AL43B, isolated from ornithogenic soil collected on the Arctic island of Spitsbergen, is a newly sequenced psychrophilic strain susceptible to conjugation and electrotransformation. Its genome consists of a circular chromosome (3.3 Mb) and four plasmids (4.4-6.4kb). In silico genome mining and microarray-based phenotypic analysis were performed to describe the metabolic potential of this strain and identify possible biotechnological applications. Metabolic reconstruction indicated that DAB_AL43B prefers low molecular-weight carboxylates and amino acids as carbon and energy sources. Genetic determinants of heavy-metal resistance, anthracene degradation and possible aerobic denitrification were also identified. Comparative analyses revealed a relatively close relationship between DAB_AL43B and other sequenced Psychrobacter species. In addition, the plasmids of this strain were used as the basis for the construction of Escherichia coli-Psychrobacter spp. shuttle vectors. Taken together, the results of this work suggest that DAB_AL43B is a promising candidate as a new model strain for studies on Psychrobacter spp. PMID- 28919460 TI - A likelihood-based approach to P-value interpretation provided a novel, plausible, and clinically useful research study metric. AB - OBJECTIVES: Interpretation of clinical research findings using the paradigm of null hypothesis significance testing has a number of limitations. These include arbitrary dichotomization of results, lack of incorporation of study power and prior probability, and the confusing use of conditional probability. This study aimed to describe a novel method of P-value interpretation that would address these limitations. STUDY DESIGN AND SETTING: Published clinical research was reinterpreted using the delta likelihood ratio. The delta likelihood ratio is an application of Bayes' rule incorporating the P-value and study power. Calculation of the delta likelihood ratio allows the determination of the most likely effect size using the maximum likelihood principle. RESULTS: We showed that the delta likelihood is easily calculated and produces plausible results using the example of several previously published research studies. Empirical evidence of validity was demonstrated by simulation. CONCLUSION: The delta likelihood ratio and most likely effect size are simple and intuitive metrics to summarize research findings. The delta likelihood ratio incorporates study power and provides a continuous measure of the probability that the research result is a true effect. The most likely effect size is an easily understood metric that should aid the interpretation of research. PMID- 28919461 TI - Comparative effectiveness medicines research cannot assess efficacy. PMID- 28919462 TI - Cumulative incidence estimates in the presence of competing risks. PMID- 28919463 TI - Decision making about healthcare-related tests and diagnostic test strategies. Paper 1: a new series on testing to improve people's health. PMID- 28919464 TI - Corticothalamic network dysfunction and Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease that is characterized by progressive cognitive decline and a prominent loss of hippocampal-dependent memory. Therefore, much focus has been placed on understanding the function and dysfunction of the hippocampus in AD. However, AD is also accompanied by a number of other debilitating cognitive and behavioral alterations including deficits in attention, cognitive processing, and sleep maintenance. The underlying mechanisms that give rise to impairments in such diverse behavioral domains are unknown, and identifying them would shed insight into the multifactorial nature of AD as well as reveal potential new therapeutic targets to improve overall function in AD. We present here several lines of evidence that suggest that dysregulation of the corticothalamic network may be a common denominator that contributes to the diverse cognitive and behavioral alterations in AD. First, we will review the mechanisms by which this network regulates processes that include attention, cognitive processing, learning and memory, and sleep maintenance. Then we will review how these behavioral and cognitive domains are altered in AD. We will also discuss how dysregulation of tightly regulated activity in the corticothalamic network can give rise to non convulsive seizures and other forms of epileptiform activity that have also been documented in both AD patients and transgenic mouse models of AD. In summary, the corticothalamic network has the potential to be a master regulator of diverse cognitive and behavioral domains that are affected in AD. PMID- 28919465 TI - Uridine treatment protects against neonatal brain damage and long-term cognitive deficits caused by hyperoxia. AB - Exposure to excessive oxygen in survivors of preterm birth is one of the factors that underlie the adverse neurological outcome in later life. Various pathological changes including enhanced apoptotic activity, oxidative stress and inflammation as well as decreased neuronal survival has been demonstrated in animal models of neonatal hyperoxia. The aim of the present study was to investigate the effect of administering uridine, an anti-apoptotic agent, on cellular, molecular and behavioral consequences of hyperoxia-induced brain damage in a neonatal rat model. For five days from birth, rat pups were either subjected continuously to room air (21% oxygen) or hyperoxia (80% oxygen) and received daily intraperitoneal (i.p.) injections of saline (0.9% NaCl) or uridine (500mg/kg). Two-thirds of all pups were sacrificed on postnatal day 5 (P5) in order to investigate apoptotic cell death, myelination and number of surviving neurons. One-thirds of pups were raised through P40 in order to evaluate early reflexes, sensorimotor coordination and cognitive functions followed by investigation of neuron count and myelination. We show that uridine treatment reduces apoptotic cell death and hypomyelination while increasing the number of surviving neurons in hyperoxic pups on P5. In addition, uridine enhances learning and memory performances in periadolescent rats on P40. These data suggest that uridine administered during the course of hyperoxic insult enhances cognitive functions at periadolescent period probably by reducing apoptotic cell death and preventing hypomyelination during the neonatal period in a rat model of hyperoxia induced brain injury. PMID- 28919466 TI - Intrastriatally injected botulinum neurotoxin-A differently effects cholinergic and dopaminergic fibers in C57BL/6 mice. AB - Unilateral intrastriatal BoNT-A injection abolished apomorphine-induced rotational behavior in a rat model of hemiparkinsonism (hemi-PD) up to 6months. It was hypothesized that the beneficial effect of botulinum neurotoxin-A (BoNT-A) grounded on the reduction of the Parkinson's diseases (PD) associated striatal hypercholinism. Intrastriatal injection of BoNT-A was not cytotoxic in rat brain, but neuronal fiber swellings in the BoNT-A infiltrated striata appeared and named BoNT-A-induced varicosities (BiVs). In the rat BiVs were immunoreactive (ir) either for choline acetyltransferase (ChAT) or tyrosine hydroxylase (TH). In the present study the structural effect of unilateral intrastriatal BoNT-A injection in the naive mouse brain was analyzed to extend possible therapeutic BoNT-A applications to genetical Parkinsonian strains. We investigated the effect of a single dose of 25pg BoNT-A injected into the right caudate-putamen (CPu) for up to 9months, and of increasing doses up to 200pg on striatal volume, number of ChAT-ir interneurons, and numeric density and volume of the ChAT-ir BiVs in comparison to the uninjected hemisphere. Intrastriatal BoNT-A injection did not alter the number of ChAT-ir interneurons irrespective of survival time and dosage tested. However, the numeric density of the ChAT-ir BiVs at a dose of 25pg increased from 1 to 3months after BoNT-A, followed by a time dependent decrease. In parallel, with increasing BoNT-A survival time, the mean BiV volume increased as the number of small BiVs decreased. Interestingly, in contrast to rats we did not find TH-ir BiVs in BoNT-A injected mouse striatum. PMID- 28919467 TI - Distribution of spleen tyrosine kinase and tau phosphorylated at tyrosine 18 in a mouse model of tauopathy and in the human hippocampus. AB - PURPOSE: Spleen tyrosine kinase (Syk) has been shown to phosphorylate tyrosine 18 of tau in vitro. It has been proposed that increased immunoreactivity for double phosphorylated Syk in hippocampal neurons of Alzheimer's disease cases indicates a not yet defined neurodegenerative process. To investigate this possibility we have studied Syk and tau phosphorylated at tyrosine 18 (pTyr18) in transgenic mice and human hippocampi. METHODS: We performed immunohistochemistry, immunofluorescence labeling and Western blotting and compared the distribution of Syk double-phosphorylated at tyrosines 525 and 526 and pTyr18 in human tau transgenic pR5 mice and human hippocampi with low and high Braak stages for neurofibrillary tangle pathology. RESULTS: pTyr18 appeared early during the course of neurodegeneration in pR5 mice and was widely distributed in the pR5 brain, including neuronal somata and fiber tracts. In contrast, only strongly pTyr18- and AT100-(tau phosphorylated at Thr212 and Ser214) positive neurons with a fibrillary tau pathology in old pR5 mice and microglia displayed immunoreactivity for double-phosphorylated Syk. In human hippocampi, phosphorylated Syk was mainly present in granulovacuolar inclusions in hippocampal pyramidal neurons and did not co-locate with pTyr18 in these neurons. We observed pTyr18-positive neurons and neurons with granular pSyk immunoreactivity already at early Braak stages and their number was markedly increased in Braak stage VI. CONCLUSION: Syk appears unlikely to be the major kinase that phosphorylates tyrosine 18 of tau in tauopathy. It possibly phosphorylates tyrosine 18 of tau and regulates other tau kinases in neurons with a fibrillary tau pathology. PMID- 28919468 TI - A copper based enzyme-free fluorescence ELISA for HER2 detection. AB - We reported an enzyme-free ELISA to detect breast cancer biomarker human epidermal growth factor receptor 2 (HER2) in human serum samples. Instead of enzymes (such as horseradish peroxidase) used in traditional ELISA, CuO nanoparticles were utilized as the signal probe. Compared to traditional enzymes, CuO nanoparticles have the advantages of low cost and good stability. After dissolving CuO nanoparticles with acid, the Cu (II) ions generated catalyzed the reaction of o-phenylenediamine with ascorbic acid to produce fluorescent quinoxaline derivative molecules. The immunoassay displays high sensitivity and good selectivity towards HER2 with detection limit as low as 9.65pg.mL-1. The assay was successfully applied to the analysis of HER2 in serum of breast cancer patients. The analysis results demonstrated the HER2 level in the serum samples determined by our assay were in good agreement with those determined by commercial HER2 ELISA kit. This enzyme-free ELISA assay can be easily adapted to the detection of other analytes. With these merits, the simple, sensitive and cost effective fluorescence immunoassay shows great potential for clinical applications. PMID- 28919470 TI - Preparation and characterization of amorphous ciprofloxacin-amino acid salts. AB - The amorphization of the poorly soluble drug ciprofloxacin (CIP) may be facilitated by the use of a suitable stabilizer. In this study seven amino acids, with various side chain properties, were evaluated in this regard. Solid dispersions were prepared by ball milling 1:1 molar ratios of CIP with the amino acids, and their solid-state and pharmaceutical properties were then examined. Fully X-ray amorphous solid dispersions were obtained with aspartic acid, glutamic acid, cysteine and arginine. In each case, evidence of salt formation between the drug and amino acids was found via Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance. In contrast, semi crystalline solid dispersions were obtained with serine, alanine and glycine. The glass transition temperatures of the amorphous salts were significantly higher than those of the starting materials, and they remained fully X-ray amorphous during long-term stability studies. Significant improvements in the solubility of CIP were also observed with the amorphous salts in water and simulated biological fluids, over and above that of the corresponding physical mixtures. In permeability studies on the other hand, the amorphous aspartate and glutamate salts were found to be less permeable than the pure drug, whereas formulation as an amorphous salt containing cysteine or arginine increased the permeability of CIP. Therefore, while amorphous salt formation with amino acids appears to be a suitable means of improving the thermal stability and solubility of CIP, in some cases this is associated with a decrease in permeability. PMID- 28919469 TI - Assignment of the absolute configuration of hepatoprotective highly oxygenated triterpenoids using X-ray, ECD, NMR J-based configurational analysis and HSQC overlay experiments. AB - BACKGROUND: The plants of the genus Kadsura are widely distributed in China, South Korea, and Japan. Their roots and stems are traditionally used to treat blood diseases and pain. The main bioactive constituents of Kadsura longipedunculata comprise highly oxygenated triterpenoids. Schiartane-type nortriterpenoids showed anti-HIV, anti-HBV, and cytotoxic bioactivities. For such compounds, the absolute configuration influences the bioactivities, and hence its unambiguous determination is essential. In this work, the absolute configurations of three highly oxygenated schiartane-type nortriterpenoids were unequivocally assigned using X-ray, ECD, and J-based configuration analysis and HSQC overlay data. METHODS: The ethanol extract of Kadsura longipedunculata Finet et Gagnep was purified by column chromatography using silica, Sephadex LH-20, and ODS as substrates. To help assign the absolute configuration of schiartane-type nortriterpenoids, X-ray diffraction analysis, ECD experiment compared to ab initio computed data, DP4+ analysis, HSQC overlay, NOESY, and J-based configuration analysis were carried out. Hetero- and homo-nuclear coupling constants were extracted from HETLOC experiments. RESULTS: Three new highly oxygenated triterpenoids, micrandilactone I (1), micrandilactone J (2), and 22,23 di-epi-micrandilactone J (3) were isolated. Their 2D structures were solved using NMR and HRESIMS data and their absolute configurations were elucidated using X ray diffraction analysis, ECD experimental results compared to ab initio computed spectra, HSQC overlay, DP4+, NOESY, and J-based configuration analysis. Micrandilactone I (1) and 22,23-di-epi-micrandilactone J (3) showed moderate hepatoprotective activity against APAP-induced toxicity in HepG2 cells with cell survival rates of 53.0 and 50.2%, respectively, at 10MUM (bicyclol, 49.0%), while micrandilactone J (2) was inactive. GENERAL SIGNIFICANCE: This is the first comprehensive stereochemical assignment of a non-crystalline schiartane-type nortriterpenoid like 3. This general protocol may contribute towards solving the problems hampering the assignment of the absolute configurations of other members of this class of nortriterpenoids. PMID- 28919471 TI - Response to 'the flexible therapeutic approach to the BCLC B stage': Time for scoring systems? PMID- 28919472 TI - Reply to: "Response to 'the flexible therapeutic approach to the BCLC B stage': Time for scoring systems?" PMID- 28919473 TI - Atorvastatin alters gene expression and cholesterol synthesis in primary rainbow trout (Oncorhynchus mykiss) hepatocytes. AB - The liver is a key metabolic organ contributing significantly to both lipid and cholesterol homeostasis in vertebrates. This study examines whether the human pharmaceutical atorvastatin (ATV), which is designed to lower cholesterol biosynthesis, could disrupt lipid dynamics in fish. The study investigates the effects of ATV at a physiologically relevant exposure regimen (concentration and duration) on gene transcripts and the biosynthesis of cholesterol and other lipid and non-lipid molecules in primary rainbow trout hepatocytes. Trout hepatocytes exposed to ATV increased the transcript abundance of genes involved in lipid metabolism (HMGCR1, LDLR, PPARalpha, PPARgamma, and SREBP1) and xenobiotic metabolism (CYP3A27), and reduced cholesterol synthesis. This study demonstrates that lipid metabolism in trout hepatocytes is sensitive to the effects of ATV, and changes in gene expression occur within 3-6h after exposure. PMID- 28919474 TI - Highly efficient one-step advanced treatment of biologically pretreated coking wastewater by an integration of coagulation and adsorption process. AB - A novel integrated process of coagulation and adsorption was proposed for the advanced treatment of biologically pretreated coking wastewater. Results of laboratory, pilot, and industrial-scale experiments indicated that this one-step novel process can remove biorefractory pollutants, achieving the maximum chemical oxygen demand (COD) and cyanide removals of around 85.3% and 99.4%, respectively. Its effluent could meet the corresponding discharge standards without any further treatment, i.e., COD <30mg/L, cyanide <0.1mg/L, and improved effluent safety (lower toxicity). The easy operation and high efficiency of this method reflect its engineering-application potential in the tertiary treatment of coking wastewater. PMID- 28919475 TI - Improvement of methane content in a hydrogenotrophic anaerobic digester via the proper operation of membrane module integrated into an external-loop. AB - This work assessed the feasibility of a hydrogenotrophic biogas process integrated with a membrane module in the external-loop design. The major scope was to conduct the investigation from the perspective of the membrane unit and reveal how the operating strategy influences the efficiency of biogas formation. It was observed that the fermenter worked with an improved efficacy, indicated by the higher concentration of methane in the headspace (80-90%) when the gas loading intensity, defined as the ratio of inlet gas permeation rate and the circulation rate of the liquid phase, was adjusted to lower values (3-5.3*10-3). Such results are implying that the mass transfer of H2 into the reactor is dependent on this critical parameter. Moreover, attention should be paid to the fouling of the module under longer-term experiments to keep its performance at a sufficient level. PMID- 28919476 TI - Current status of the pilot-scale anaerobic membrane bioreactor treatments of domestic wastewaters: A critical review. AB - This review presented the performances of the pilot-scale anaerobic membrane bioreactors (AnMBRs) treating domestic wastewater. High COD removal efficiencies and low biosolids productions were achieved at HRTs comparable to conventional aerobic processes under ambient temperatures. The energy demands for fouling control in the pilot-scale AnMBRs ranged from 0.04 to 1.35kWh/m3, which is lower than those of lab-scale AnMBRs and aerobic MBRs. The energy demands for fouling control were in the order of gas sparging>particle sparging>rotating membrane AnMBR. Two major factors affecting the energy demand in gas sparging AnMBRs were specific gas demands (SGDm) and operating flux. The energy potentials in wastewater were significantly affected by the influent sulfate concentrations. Energy balances indicated that five out of nine pilot-scale AnMBRs was energy positive. However, further improvements of the AnMBRs are required to implement the energy positive wastewater treatment process. PMID- 28919477 TI - Influence of microwave heating on biogas production from Sida hermaphrodita silage. AB - This study compared the effects on biogas production of suspended sludge versus a combination of suspended sludge and immobilized biomass, and microwave versus convection heating. Biogas production was the highest in the hybrid bioreactor heated by microwaves (385L/kg VS) and also the most stable, as shown by the FOS/TAC ratio and pH. Regardless of the type of heating, biogas production was 8% higher with immobilized biomass than without. Although the lag phase of biogas production was shorter with microwave heating than without, the log phase was longer, and biogas production in the microwave heated bioreactors took about twice as long (ca. 40days) to plateau as in the conventionally heated bioreactors. These differences in the profile of biogas production are likely due to the athermal effects of microwave irradiation. PMID- 28919478 TI - Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5. AB - Statins have been proven to be effective in treating non-alcoholic fatty liver disease (NAFLD). Recently, it was reported that statins decreased the hepatic expression of perilipin 5 (Plin5), a lipid droplet (LD)-associated protein, which plays critical roles in regulating lipid accumulation and lipolysis in liver. However, the function and regulation mechanism of Plin5 have not yet been well established in NAFLD treatment with statins. In this study, we observed that atorvastatin moderately reduced the expression of Plin5 in livers without changing the protein level of Plin5 in the hepatic LD fraction of mice fed with high-fat diet (HFD). Intriguingly, atorvastatin stimulated the PKA-mediated phosphorylation of Plin5 and reduced the triglyceride (TG) accumulation in hepatocytes with overexpression of wide type (Plin5-WT) compared to serine-155 mutant Plin5 (Plin5-S155A). Moreover, PKA-stimulated FA release of purified LDs carrying Plin5-WT but not Plin5-S155A. Glucagon, a PKA activator, stimulated the phosphorylation of Plin5-WT and inhibited its interaction with CGI-58. The results indicated that atorvastatin promoted lipolysis and reduced TG accumulation in the liver by increasing PKA-mediated phosphorylation of Plin5. This new mechanism of lipid-lowering effects of atorvastatin might provide a new strategy for NAFLD treatment. PMID- 28919479 TI - FABP1 knockdown in human enterocytes impairs proliferation and alters lipid metabolism. AB - Fatty Acid-Binding Proteins (FABPs) are abundant intracellular proteins that bind long chain fatty acids (FA) and have been related with inmunometabolic diseases. Intestinal epithelial cells express two isoforms of FABPs: liver FABP (LFABP or FABP1) and intestinal FABP (IFABP or FABP2). They are thought to be associated with intracellular dietary lipid transport and trafficking towards diverse cell fates. But still their specific functions are not well understood. To study FABP1's functions, we generated an FABP1 knockdown model in Caco-2 cell line by stable antisense cDNA transfection (FABP1as). In these cells FABP1 expression was reduced up to 87%. No compensatory increase in FABP2 was observed, strengthening the idea of differential functions of both isoforms. In differentiated FABP1as cells, apical administration of oleate showed a decrease in its initial uptake rate and in long term incorporation compared with control cells. FABP1 depletion also reduced basolateral oleate secretion. The secreted oleate distribution showed an increase in FA/triacylglyceride ratio compared to control cells, probably due to FABP1's role in chylomicron assembly. Interestingly, FABP1as cells exhibited a dramatic decrease in proliferation rate. A reduction in oleate uptake as well as a decrease in its incorporation into the phospholipid fraction was observed in proliferating cells. Overall, our studies indicate that FABP1 is essential for proper lipid metabolism in differentiated enterocytes, particularly concerning fatty acids uptake and its basolateral secretion. Moreover, we show that FABP1 is required for enterocyte proliferation, suggesting that it may contribute to intestinal homeostasis. PMID- 28919481 TI - Feasibility of Implementing Group Well Baby/Well Woman Dyad Care at Federally Qualified Health Centers. AB - OBJECTIVE: Group care has been shown to be effective for delivery of infant well child care. Centering Parenting (CP) is a model of group dyad care for mothers and infants. CP might improve quality and efficiency of preventive care, particularly for low-income families. Federally qualified health centers (FQHCs) might be optimal sites for implementation, however, facilitators and barriers might be unique. The aim of this qualitative study was to assess stakeholder perspectives on the feasibility of implementing CP in FQHCs in Baltimore. METHODS: Semistructured interviews were conducted with mothers, clinicians, staff, and administrators recruited from 2 FQHCs using purposive sampling. Interviews were recorded, transcribed verbatim, and uploaded to Atlas.ti version 7.0 (Atlas.ti Scientific Software Development, GmbH Berlin, Germany) for analysis. Using an inductive thematic analysis approach, 2 investigators coded the transcripts. Matrices of key codes were developed to identify themes and patterns across stakeholder groups. RESULTS: Interviews were completed with 26 mothers and 16 clinicians, staff, and administrators. Most participants considered CP desirable. Facilitators included: peer support and education, emphasis on maternal wellness, and increased patient and clinician satisfaction. Barriers included: exposure to "others," scheduling and coordination of care, productivity, training requirements, and cost. Parenting experience did not appear to affect perspectives on CP. CONCLUSIONS: Perceptions regarding facilitators and barriers to CP implementation in FQHCs are similar to existing group well-child care literature. The benefit of emphasis on maternal wellness is a unique finding. Maternal wellness integration might make CP a particularly desirable model for implementation at FQHCs, but potential systems barriers must be addressed. PMID- 28919480 TI - Cholesterol modulates the cellular localization of Orai1 channels and its disposition among membrane domains. AB - Store Operated Calcium Entry (SOCE) is one of the most important mechanisms for calcium mobilization in to the cell. Two main proteins sustain SOCE: STIM1 that acts as the calcium sensor in the endoplasmic reticulum (ER) and Orai1 responsible for calcium influx upon depletion of ER. There are many studies indicating that SOCE is modulated by the cholesterol content of the plasma membrane (PM). However, a myriad of questions remain unanswered concerning the precise molecular mechanism by which cholesterol modulates SOCE. In the present study we found that reducing PM cholesterol results in the internalization of Orai1 channels, which can be prevented by overexpressing caveolin 1 (Cav1). Furthermore, Cav1 and Orai1 associate upon SOCE activation as revealed by FRET and coimmunoprecipitation assays. The effects of reducing cholesterol were not limited to an increased rate of Orai1 internalization, but also, affects the lateral movement of Orai1, inducing movement in a linear pattern (unobstructed diffusion) opposite to basal cholesterol conditions were most of Orai1 channels moves in a confined space, as assessed by Fluorescence Correlation Spectroscopy, Cav1 overexpression inhibited these alterations maintaining Orai1 into a confined and partially confined movement. These results not only highlight the complex effect of cholesterol regulation on SOCE, but also indicate a direct regulatory effect on Orai1 localization and compartmentalization by this lipid. PMID- 28919482 TI - Blood and Hair Aluminum Levels, Vaccine History, and Early Infant Development: A Cross-Sectional Study. AB - OBJECTIVE: To evaluate relationships between whole blood (B-Al) and hair aluminum (H-Al) levels in healthy infants and their immunization history and development. METHODS: We conducted a cross-sectional study of 9- to 13-month-old children recruited from an urban primary care center, excluding those with a history of renal disease or receipt of either aluminum-containing pharmaceuticals or parenteral nutrition. Aluminum levels were measured using inductively coupled plasma-mass spectrometry. Correlation with Bayley Scales of Infant and Toddler Development, Third Edition (BSID) and vaccine-related aluminum load was assessed via linear regression models. RESULTS: The median age of 85 participants was 287 days. B-Al (median, 15.4 ng/mL; range, 0.9-952 ng/mL) and H-Al (median 42,542 ng/g; range, 2758-211,690 ng/g) were weakly correlated (Spearman rho = 0.26; P = .03). There was no significant correlation between B-Al or H-Al and estimated aluminum load from vaccines. B-Al was not correlated with BSID composite or subscale scores. Although H-Al was not correlated with BSID scores in models including all data (n = 85), it was inversely correlated with motor composite (P < .02; Wald = 5.88) and the gross motor subscale (P = .04; Wald = 4.38) in models that excluded an extreme outlying H-Al value. CONCLUSIONS: Infant B-Al and H-Al varied considerably but did not correlate with their immunization history. Likewise, there was no correlation between B-Al and infant development or between H-Al and language or cognitive development. An inverse correlation between H-Al and BSID motor scores deserves further investigation. PMID- 28919483 TI - National Landscape of Interventions to Improve Pediatric Resident Wellness and Reduce Burnout. PMID- 28919484 TI - Lung cancer epigenetics: From knowledge to applications. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. Advances in our understanding of the genomics of lung cancer have led to substantial progress in the treatment of specific molecular subsets. Immunotherapy also emerges as a major breakthrough in lung cancer treatment. However, challenges remain as a consensual approach for early lung cancer detection remains elusive while primary or secondary drug resistance eventually leads to treatment failure in all patients with advanced disease. Furthermore, a large portion of patients are still treated with conventional chemotherapy that is only modestly effective. The last two decades have seen exponential developments in the epigenetic understanding of lung cancer. Epigenetic alterations in DNA methylation, non coding RNA expression, chromatin modeling and post transcriptional regulators are key events in each step of lung cancer pathogenesis. Here, we review the central role epigenetic disruptions play in lung cancer carcinogenesis and the acquisition of cancerous phenotype and aggressive behavior as well as in the resistance to therapy. Epigenetic disruptions could represent reliable biomarkers for lung cancer risk assessment, early diagnosis, prognosis stratification, molecular classification and prediction of treatment efficacy. The therapeutic potential of epigenetics targeted drugs in combination with chemotherapy, targeted therapy and/or immunotherapy is currently being intensively investigated. We suggest that integration of tissue-derived or circulating epigenetic biomarkers and epidrugs in clinical trial design will translate epigenetic knowledge of lung cancer into the clinic and improve lung cancer patient outcomes. PMID- 28919485 TI - The pathogenesis of Staphylococcus aureus in autoimmune diseases. AB - Autoimmune disease are defined as the attacks on host tissue by the immune system. Several factors, e.g. genetic and environmental triggers (in particular, viruses, bacteria, and other infectious pathogens) play a role in the development of autoimmune diseases. Bacterial infections are related to several autoimmune diseases, e.g. chronic inflammations and demyelination. Nowadays, an estimated 20 30% of the general human population carry Staphylococcus aureus (S. aureus). This organism can asymptomatically colonize healthy individuals. S. aureus carriers show no sign of infection and can thus spread this bacterium in the community. Several studies investigated the potential involvement of this bacterium as the etiological agents of autoimmune diseases. The present review focused on the role of S. aureus infections in the pathogenesis of autoimmune, inflammatory, and demyelinating diseases. Possible modes of the pathogenic action of bacteria are discussed in association with the ways in which S. aureus can initiate or exacerbate autoimmunity. PMID- 28919487 TI - Effect of ultrasound treatment conditions on Saccharomyces cerevisiae by response surface methodology. AB - OBJECTIVES: This study aimed to investigate the effect of different ultrasound treatment conditions on the inactivation of Saccharomyces cerevisiae with the application of response surface methodology (RSM). METHODS: Ultrasound treatment were applied on different concentrations of S. cerevisiae cells with different pH, temperature, ultrasound power, irradiating time, and pulse duty ratio. Cell viability was determined by plate counting method. Response surface methodology was used to analyze the correlation among various factors. RESULTS: Limited with low ultrasound power, lower pH value slightly improved the ultrasound treatment efficiency. Also, higher nonlethal temperature and ultrasound power, longer irradiation time, and lower pulse duty ratio facilitated the inactivation of S. cerevisiae. Cell concentration had no effect on ultrasound efficiency. CONCLUSIONS: Ultrasound power played the most important role in the ultrasound irradiation process according to RSM analyses. Information derived from this study may aid in the control of the sublethal injury of S. cerevisiae during ultrasound treatment in food industry. PMID- 28919486 TI - Resveratrol inhibits proliferation, promotes differentiation and melanogenesis in HT-144 melanoma cells through inhibition of MEK/ERK kinase pathway. AB - The present study was aimed to investigate the effect of resveratrol on the viability of HT-144 melanoma cells and formation of melanin. MTT assay was used for analysis of cell viability and western blot for determination of phospho-Mek 1/2, phospho-Erk 1/2 (Tyr-204), Mitf, PBG-D and p-CREB-1 expression. MTT assay results showed that treatment of HT-144 cells with various doses of resveratrol led to a concentration dependent inhibition of proliferation. The antiproliferative activity was significant at 15 MUM concentration of resveratrol after 24 h. Western blot analysis revealed that resveratrol caused significant reduction in the expression of phospho-extracellular signal related kinase (p ERK) and p-MEK 1/2. Additionally, tyrosinase activity was increased by 1.5-6.8 fold on increasing the concentration of resveratrol from 1 to 15 MUM. Resveratrol treatment also enhanced the expression of cAMP-response element-binding proteins (CREB) after 24 h. Furthermore resveratrol treatment up-regulated porphobilinogen deaminase (PBG-D) expression in HT-144 cells. Taken together, the study demonstrates that resveratrol treatment inhibits proliferation and promotes melanogenesis of HT-144 cells through inhibition of MEK/ERK pathway. Therefore, resveratrol has a scope for further evaluation against melanogenesis. PMID- 28919488 TI - Mast cells derived from human induced pluripotent stem cells are useful for allergen tests. AB - BACKGROUND: Several methods have been developed to detect allergen-specific IgE in sera. The passive IgE sensitization assay using human IgE receptor-expressing rat cell line RBL-2H3 is a powerful tool to detect biologically active allergen specific IgE in serum samples. However, one disadvantage is that RBL-2H3 cells are vulnerable to high concentrations of human sera. Only a few human cultured cell lines are easily applicable to the passive IgE sensitization assay. However, the use of human induced pluripotent stem cells (iPSCs) to generate human mast cells (MCs) has not yet been reported. METHODS: The nuclear factor-kappa B (NF kappaB)-responsive luciferase reporter gene was stably introduced into a human iPSC line 201B7, and the transfectants were induced to differentiate into MCs (iPSC-MCs). The iPSC-MCs were sensitized overnight with sera from subjects who were allergic to cedar pollen, ragweed pollen, mites, or house dust, and then stimulated with an extract of corresponding allergens. Activation of iPSC-MCs was evaluated by beta-hexosaminidase release, histamine release, or luciferase intensity. RESULTS: iPSCs-MCs stably expressed high-affinity IgE receptor and functionally responded to various allergens when sensitized with human sera from relevant allergic subjects. This passive IgE sensitization system, which we termed the induced mast cell activation test (iMAT), worked well even with undiluted human sera. CONCLUSIONS: iMAT may serve as a novel determining system for IgE/allergens in the clinical and research settings. PMID- 28919489 TI - Zinc chloride-induced TRPA1 activation does not contribute to toxicity in vitro. AB - The hygroscopic zinc chloride (ZnCl2) is often used to generate smoke screens. Severe adverse pulmonary health effects have been associated with inhalation of ZnCl2 smokes. The underlying molecular toxicology is not known. Recent studies have shown that the Transient Receptor Potential Channel A1 (TRPA1) is important for sensing toxic chemicals. TRPA1 was shown to be activated by Zn2+ which was linked to pain and inflammation. In the present study, we investigated whether TRPA1 activation contributes to ZnCl2-mediated toxicity in vitro. HEK wildtype (HEK-wt), TRPA1 overexpressing HEK (HEK-A1) and A549 lung cells, endogenously expressing TRPA1, were exposed to ZnCl2. Changes of intracellular calcium levels [Ca2+]i and cell viability were assessed after ZnCl2 exposure in all cell types, without or with TRPA1 inhibition. ZnCl2 increased [Ca2+]i through TRPA1 channels in a complex manner in both HEK-A1 and A549 cells while HEK-wt did not respond to ZnCl2. There was no difference in toxicity between HEK-wt and HEK-A1 cells after ZnCl2 exposure. Inhibition of TRPA1 did not influence toxicity in all investigated cells. Thus, our in vitro results support the assumption that TRPA1 does not primarily mediate toxicity of ZnCl2 and does probably not represent a therapeutic target to abate ZnCl2 toxicity. PMID- 28919490 TI - Alcohol exposure induces chick craniofacial bone defects by negatively affecting cranial neural crest development. AB - Excess alcohol consumption during pregnancy could lead to fetal alcohol syndrome (FAS). However, the molecular mechanism leading to craniofacial abnormality, a feature of FAS, is still poorly understood. The cranial neural crest cells (NCCs) contribute to the formation of the craniofacial bones. Therefore, NCCs exposed to ethanol was investigated - using chick embryos and in vitro explant culture as experimental models. We demonstrated that exposure to 2% ethanol induced craniofacial defects, which includes parietal defect, in the developing chick fetus. Immunofluorescent staining revealed that ethanol treatment downregulated Ap-2alpha, Pax7 and HNK-1 expressions by cranial NCCs. Using double immunofluorescent stainings for Ap-2alpha/pHIS3 and Ap-2alpha/c-Caspase3, we showed that ethanol treatment inhibited cranial NCC proliferation and increased NCC apoptosis, respectively. Moreover, ethanol treatment of the dorsal neuroepithelium increased Laminin, N-Cadherin and Cadherin 6B expressions while Cadherin 7 expression was repressed. In situ hybridization also revealed that ethanol treatment up-regulated Cadherin 6B expression but down-regulated slug, Msx1, FoxD3 and BMP4 expressions. In summary, our experimental results demonstrated that ethanol treatment interferes with the production of cranial NCCs by affecting the proliferation and apoptosis of these cells. In addition, ethanol affected the delamination, epithelial-mesenchymal transition (EMT) and cell migration of cranial NCCs, which may have contributed to the etiology of the craniofacial defects. PMID- 28919491 TI - Potential involvement of Fgf10/Fgfr2 and androgen receptor (AR) in renal fibrosis in adult male rat offspring subjected to prenatal exposure to di-n-butyl phthalate (DBP). AB - BACKGROUND: We previously demonstrated that maternal exposure to di-n-butyl phthalate (DBP) induces dysplasia of the kidney in newborn male offspring and renal fibrosis in adults. But the underlying mechanisms remain elusive. Fgf10/Fgfr2 and androgen receptor (AR) are known to be important for renal development. We therefore investigated whether these genes are involved in DBP induced renal fibrosis. MATERIALS AND METHODS: Using Sprague-Dawley rats and rat renal proximal tubular cells (NRK52E), we determined the potential involvement of Fgf10, Fgfr2 and AR in DBP-induced renal fibrosis. RESULTS: We found that maternal exposure to DBP induces renal fibrosis in adult male offspring. A lower serum testosterone concentration and reduced expression of Fgf10, Fgfr2 and AR were detected in these animals. These was a trend toward lower expression of Fgf10, Fgfr2 and AR in NRK52E cells subjected to DBP exposure. Furthermore, higher expression levels of TGF-beta and alpha-SMA were observed in abnormal renal tissue and DBP-treated NRK52E cells. CONCLUSION: Our findings suggest the potential involvement of Fgf10/Fgfr2 and AR in renal fibrosis of adult male rat offspring induced by prenatal exposure to DBP. The anti-androgenic effects of DBP might play an important role in this pathological process. PMID- 28919492 TI - Human platelet antigens are associated with febrile non-hemolytic transfusion reactions. AB - BACKGROUND: Febrile non-hemolytic transfusion reaction (FNHTR) is the most common type of transfusion reactions, and it could be reduced by transfusing patients with leukocyte-poor blood products. However, FNHTR still occur in certain patients transfused with leukocyte-poor red blood cell (LPR) products. It is examined whether human platelet antigen (HPA) could be a potential membrane antigen that plays a role in FNHTR. METHODS: A total of 120 inpatient subjects who transfused with LPR (60 in FNHTR group, 60 in control group) were typed for HPA-2, HPA-3, and HPA-15 using sequence specific primer-polymerase chain reaction (SSP-PCR) and electrophoresis. RESULTS: HPA-2 unmatched rate between donors and patients in FNHTR group was 18%, and only 3% unmatched rate was observed in control group (p=0.0082). FNHTR group was further classified according to the imputability. There was a significant difference (p=0.0041) between FNHTR (probable imputability, infection) group and control group, and more significant difference (p=0.0008) was seen between FNHTR (probable imputability, febrile neutropenia) group and control group. CONCLUSIONS: Those results indicated that HPA-2 might play roles on inducing FNHTR in patients suffering from infectious diseases and febrile neutropenia. HPA-2 genotyping between donors and recipients might be worth integrating in pre-transfusion testing to increase transfusion safety. PMID- 28919493 TI - Heat stress incident prevalence and tennis matchplay performance at the Australian Open. AB - OBJECTIVES: To examine the association of wet bulb globe temperature (WBGT) with the occurrence of heat-related incidents and changes in behavioural and matchplay characteristics in men's Grand Slam tennis. DESIGN: On-court calls for trainers, doctors, cooling devices and water, post-match medical consults and matchplay characteristic data were collected from 360 Australian Open matches (first 4 rounds 2014-2016). METHODS: Data were referenced against estimated WBGT and categorised into standard zones. Generalised linear models assessed the association of WBGT zone on heat-related medical incidences and matchplay variables. RESULTS: On-court calls for doctor (47% increase per zone, p=0.001), heat-related events (41%, p=0.019), cooling devices (53%, p<0.001), and post match heat-related consults (87%, p=0.014) increased with each rise in estimated WBGT zone. In WBGT's >32 degrees C and >28 degrees C, significant increases in heat-related calls (p=0.019) and calls for cooling devices (p<0.001), respectively, were evident. The number of winners (-2.5+/-0.006% per zone, p<0.001) and net approaches (-7.1+/-0.008%, p<0.001) reduced as the estimated WBGT zone increased, while return points won increased (1.75+/-0.46, p<0.001). When matches were adjusted for player quality of the opponent (Elo rating), the number of aces (5+/-0.02%, p=0.003) increased with estimated WBGT zone, whilst net approaches decreased (7.6+/-0.013%, p<0.001). CONCLUSIONS: Increased estimated WBGT increased total match doctor and trainer consults for heat related incidents, post-match heat-related consults (>32 degrees C) and cooling device callouts (>28 degrees C). However, few matchplay characteristics were noticeably affected, with only reduced net approaches and increased aces evident in higher estimated WBGT environments. PMID- 28919494 TI - Shoulder injury in water polo: A systematic review of incidence and intrinsic risk factors. AB - OBJECTIVES: Water polo is a popular water-based contact sport that involves swimming, throwing and defending. Cumulatively, these repetitive overhead activities are thought to increase the risk of shoulder injury and, subsequently to affect players' physical conditioning as well as team performance. The purpose of this review was to examine available evidence relating to shoulder injury rates and risk factors for shoulder injury in water polo. DESIGN: Systematic review METHODS: CINAHL, AUSPORT, Pubmed, Pedro and SPORTDiscus databases were searched for original research papers using the predefined terms ("water polo") AND (shoulder OR glenohumeral* OR arm OR "upper limb"). RESULTS: Twenty papers were identified as suitable for inclusion. Reported shoulder injury rates varied from 24% - 51%. Shoulder injuries were more likely to become chronic compared to all other reported injuries. Injury data during the last three World Championships indicates an increasing rate of shoulder injuries-per-year with participation in aquatic sports. Risk for shoulder injury in water polo is multi factorial. Volume of shooting, range of motion, scapular dyskinesis, strength imbalance, proprioceptive deficit and altered throwing kinematics have been proposed to be associated with an increased risk of injury. CONCLUSIONS: Although this review showed water polo to have a high propensity for shoulder injury, the descriptive nature of the included papers limited the inferences that could be drawn from the pooled literature. Future directions for research include collecting normative data for shoulder range of motion, strength ratio and proprioception with prospective analysis of these attributes in relation to injury rates and time lost. PMID- 28919495 TI - Physical exercise and cognitive function across the life span: Results of a nationwide population-based study. AB - OBJECTIVES: To examine cross-sectional and longitudinal associations between physical exercise and cognitive function across different age groups in a nationwide population-based sample of adults aged 18-79 years in Germany. DESIGN: Cross-sectional/prospective. METHODS: Cognitive function was assessed in the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1-MH, 2009-2012, n=3535), using a comprehensive neuropsychological test battery. Cognitive domain scores for executive function and memory were derived from confirmatory factor analysis. Regular physical exercise in the last three months was assessed by self-report and defined as no exercise, <2 and >=2h (hours) of exercise per week. A subgroup of DEGS1-MH participants who previously participated in the German National Health Interview and Examination Survey 1998 (GNHIES98, 1997-1999, n=1624) enabled longitudinal analyses with a mean follow-up of 12.4 years. RESULTS: Compared to no exercise, more weekly physical exercise was associated with better executive function in cross-sectional (<2h: beta=0.12; >=2h: beta=0.17; all p<0.001) and longitudinal analyses (<2h: beta=0.14, p<0.001; >=2h: beta=0.15, p=0.001) using linear regression models adjusted for age, sex, education, smoking, alcohol consumption, fruit and vegetable consumption and obesity. Slightly weaker associations were found for memory in cross-sectional (<2h: beta=0.08, p=0.009; >=2h: beta=0.08, p=0.026) and longitudinal analysis (<2h: beta=0.09, p=0.036; >=2h: beta=0.08, p=0.114). There was no evidence of interaction between physical exercise and age. CONCLUSIONS: Higher levels of physical exercise were associated with better executive function and memory in cross-sectional and longitudinal analyses with no evidence for differential effects by age. PMID- 28919496 TI - The Pandolf equation under-predicts the metabolic rate of contemporary military load carriage. AB - OBJECTIVES: This investigation assessed the accuracy of error of the Pandolf load carriage energy expenditure equation when simulating contemporary military conditions (load distribution, external load and walking speed). DESIGN: Within participant design. METHODS: Sixteen male participants completed 10 trials comprised of five walking speeds (2.5, 3.5, 4.5, 5.5 and 6.5km.h-1) and two external loads (22.7 and 38.4kg). RESULTS: The Pandolf equation demonstrated poor predictive precision, with a mean bias of 124.9W and -48.7 to 298.5W 95% limits of agreement. Furthermore, the Pandolf equation systematically under-predicted metabolic rate (p<0.05) across the 10 speed-load combinations. Predicted metabolic rate error ranged from 12-33% across all conditions with the 'moderate' walking speeds (i.e. 4.5-5.5km.h-1) yielding less prediction error (12-17%) when compared to the slower and faster walking speeds (21-33%). CONCLUSIONS: Factors such as mechanical efficiency and load distribution contribute to the impaired predictive accuracy. The authors suggest the Pandolf equation should be applied to military load carriage with caution. PMID- 28919497 TI - Body mass index predicts selected physical fitness attributes but is not associated with performance on military relevant tasks in U.S. Army Soldiers. AB - OBJECTIVES: Army body composition standards are based upon validated criteria; however, certain field-expedient methodologies (e.g., weight-for-height, body mass index [BMI]) may disqualify individuals from service who may otherwise excel on physical performance and military-relevant tasks. The purpose was to assess soldier physical performance and military-specific task/fitness performance stratified by BMI. DESIGN: Cross-sectional observational study. METHODS: Male (n=275) and female (n=46) soldiers performed a wide-array of physical fitness tests and military-specific tasks, including the Army physical fitness test (APFT). Within-sex performance data were analyzed by BMI tertile stratification or by Army Body Composition Program (ABCP) weight-for-height (calculated BMI) screening standards using ANOVA/Tukey post-hoc or independent t-tests, respectively. RESULTS: BMI stratification (higher vs. lower BMI) was associated with significant improvements in muscular strength and power, but also with decrements in speed/agility in male and female soldiers. Within the military specific tasks, a higher BMI was associated with an increased APFT 2-Mile Run time; however, performance on a 1600-m Loaded March or a Warrior Task and Battle Drill obstacle course was not related to BMI in either sex. Male and Female soldiers who did not meet ABCP screening standards demonstrated a slower 2-Mile Run time; however, not meeting the ABCP BMI standard only affected a minimal number (~6%) of soldiers' ability to pass the APFT. CONCLUSIONS: Military body composition standards require a careful balance between physical performance, health, and military readiness. Allowances should be considered where tradeoffs exist between body composition classifications and performance on physical tasks with high military relevance. PMID- 28919498 TI - Accelerated Return to Sport After Anterior Cruciate Ligament Reconstruction and Early Knee Osteoarthritis Features at 1 Year: An Exploratory Study. AB - BACKGROUND: A timely return to competitive sport is a primary goal of anterior cruciate ligament reconstruction (ACLR). It is not known whether an accelerated return to sport increases the risk of early-onset knee osteoarthritis (KOA). OBJECTIVE: To determine whether an accelerated return to sport post-ACLR (ie, <10 months) is associated with increased odds of early KOA features on magnetic resonance imaging (MRI) 1 year after surgery and to evaluate the relationship between an accelerated return to sport and early KOA features stratified by type of ACL injury (isolated or concurrent chondral/meniscal injury) and lower limb function (good or poor). DESIGN: Cross-sectional study. SETTING: Private radiology clinic and university laboratory. PARTICIPANTS: A total of 111 participants (71 male; mean age 30 +/- 8 years) 1-year post-ACLR. METHODS: Participants completed a self-report questionnaire regarding postoperative return to-sport data (specific sport, postoperative month first returned), and isotropic 3-T MRI scans were obtained. OUTCOME MEASURES: Early KOA features (bone marrow, cartilage and meniscal lesions, and osteophytes) assessed with the MRI OA Knee Score. Logistic regression analyses evaluated the odds of early KOA features with an accelerated return to sport (<10 months post-ACLR versus >=10 months or no return to sport) in the total cohort and stratified by type of ACL injury and lower limb function. RESULTS: Forty-six (41%) participants returned to competitive sport <10 months post-ACLR. An early return to sport was associated with significantly increased odds of bone marrow lesions (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3-6.0) but not cartilage (OR 1.2, 95% CI 0.5-2.6) or meniscal lesions (OR 0.8, 95% CI 0.4-1.8) or osteophytes (OR 0.6, 95% CI 0.3 1.4). In those with poor lower limb function, early return to sport exacerbated the odds of bone marrow lesions (OR 4.6, 95% CI 1.6-13.5), whereas stratified analyses for type of ACL injury did not reach statistical significance. CONCLUSION: An accelerated return to sport, particularly in the presence of poor lower limb function, may be implicated in posttraumatic KOA development. LEVEL OF EVIDENCE: IV. PMID- 28919499 TI - Comparing Electrical Stimulation With and Without Ultrasound Guidance for Phenol Neurolysis to the Musculocutaneous Nerve. AB - BACKGROUND: Ultrasound guidance is increasingly being used for neurolytic procedures that have traditionally been done with electrical stimulation (e-stim) guidance alone. Ultrasound visualization with e-stim-guided neurolysis can potentially allow adjustments in injection protocols that will reduce the volume of neurolytic agent needed to achieve clinical improvement. OBJECTIVE: This study compared e-stim only to e-stim with ultrasound guidance in phenol neurolysis of the musculocutaneous nerve (MCN) for elbow flexor spasticity. We also evaluated the ultrasound appearance of the MCN in this population. DESIGN: Retrospective review. SETTING: University hospital outpatient clinic. PARTICIPANTS: Adults (N = 167) receiving phenol neurolysis to the MCN for treatment of elbow flexor spasticity between 1997 and 2014 and adult control subjects. METHODS: For each phenol injection of the MCN, the method of guidance, volume of phenol injected, technical success, improved range of motion at the elbow postinjection, adverse effects, reason for termination of injections, and details of concomitant botulinum toxin injection were recorded. The ultrasound appearance of the MCN, including nerve cross-sectional area and shape, were recorded and compared between groups. MAIN OUTCOME MEASURES: The volume of phenol injected and MCN cross-sectional area and shape as demonstrated by ultrasound. RESULTS: The addition of ultrasound to e-stim-guided phenol neurolysis was associated with lower doses of phenol when compared to e-stim guidance alone (2.31 mL versus 3.69 mL, P < .001). With subsequent injections, the dose of phenol increased with e stim guidance (P < .001), but not with e-stim and ultrasound guidance (P = .95). Both methods of guidance had high technical success, improved ROM at elbow postinjection, and low rates of adverse events. In comparing the ultrasound appearance of the MCN in patients with spasticity to that of normal controls, there was no difference in the cross-sectional area of the nerve, but there was more variability in shape. CONCLUSIONS: Combined e-stim and ultrasound guidance during phenol neurolysis to the MCN allows a smaller volume of phenol to be used for equal effect, both at initial and repeat injection. The MCN shape was more variable in individuals with spasticity; this should be recognized so as to successfully locate the nerve to perform neurolysis. LEVEL OF EVIDENCE: IV. PMID- 28919501 TI - Structural and kinetics characterization of the F1F0-ATP synthase dimer. New repercussion of monomer-monomer contact. AB - Ustilago maydis is an aerobic basidiomycete that fully depends on oxidative phosphorylation for its supply of ATP, pointing to mitochondria as a key player in the energy metabolism of this organism. Mitochondrial F1F0-ATP synthase occurs in supramolecular structures. In this work, we isolated the monomer (640kDa) and the dimer (1280kDa) and characterized their subunit composition and kinetics of ATP hydrolysis. Mass spectrometry revealed that dimerizing subunits e and g were present in the dimer but not in the monomer. Analysis of the ATPase activity showed that both oligomers had Michaelis-Menten kinetics, but the dimer was 7 times more active than the monomer, while affinities were similar. The dimer was more sensitive to oligomycin inhibition, with a Ki of 24nM, while the monomer had a Ki of 169nM. The results suggest that the interphase between the monomers in the dimer state affects the catalytic efficiency of the enzyme and its sensitivity to inhibitors. PMID- 28919500 TI - Hydrogen and oxygen trapping at the H-cluster of [FeFe]-hydrogenase revealed by site-selective spectroscopy and QM/MM calculations. AB - [FeFe]-hydrogenases are superior hydrogen conversion catalysts. They bind a cofactor (H-cluster) comprising a four-iron and a diiron unit with three carbon monoxide (CO) and two cyanide (CN-) ligands. Hydrogen (H2) and oxygen (O2) binding at the H-cluster was studied in the C169A variant of [FeFe]-hydrogenase HYDA1, in comparison to the active oxidized (Hox) and CO-inhibited (Hox-CO) species in wildtype enzyme. 57Fe labeling of the diiron site was achieved by in vitro maturation with a synthetic cofactor analogue. Site-selective X-ray absorption, emission, and nuclear inelastic/forward scattering methods and infrared spectroscopy were combined with quantum chemical calculations to determine the molecular and electronic structure and vibrational dynamics of detected cofactor species. Hox reveals an apical vacancy at Fed in a [4Fe4S-2Fe]3 complex with the net spin on Fed whereas Hox-CO shows an apical CN- at Fed in a [4Fe4S-2Fe(CO)]3- complex with net spin sharing among Fep and Fed (proximal or distal iron ions in [2Fe]). At ambient O2 pressure, a novel H-cluster species (Hox-O2) accumulated in C169A, assigned to a [4Fe4S-2Fe(O2)]3- complex with an apical superoxide (O2-) carrying the net spin bound at Fed. H2 exposure populated the two-electron reduced Hhyd species in C169A, assigned as a [(H)4Fe4S-2Fe(H)]3- complex with the net spin on the reduced cubane, an apical hydride at Fed, and a proton at a cysteine ligand. Hox-O2 and Hhyd are stabilized by impaired O2- protonation or proton release after H2 cleavage due to interruption of the proton path towards and out of the active site. PMID- 28919502 TI - Comparison of the Memory Foam Pad Versus the Bean Bag with Shoulder Braces in Preventing Patient Displacement during Gynecologic Laparoscopic Surgery. AB - STUDY OBJECTIVE: To compare the amount of patient displacement when a memory foam pad is used versus a bean bag with shoulder braces. The secondary aim was to evaluate for postoperative extremity symptoms including pain, numbness, and weakness. DESIGN: A prospective randomized pilot study (Canadian Task Force classification I). SETTING: A single academic institution. PATIENTS: Women >=18 years of age undergoing laparoscopic or robotic gynecologic surgery. INTERVENTIONS: Patients were randomized to be positioned on the memory foam pad (group A) or the bean bag with shoulder braces (group B) preoperatively. The patients' positions were measured before and after the procedure, and the displacement was recorded. Patients were followed postoperatively and questioned regarding upper extremity or lower extremity weakness, numbness, and pain. Demographic characteristics were collected using the electronic medical record. MEASUREMENTS AND MAIN RESULTS: Forty-three patients were included in the study (22 in group A and 21 in group B). The demographic and intraoperative characteristics of the patients were similar in both groups. The patients in group A moved a mean distance of 3.80 +/- 3.32 cm, whereas those in group B moved a mean distance of 1.07 +/- 1.93 cm (p = .002). A Pearson correlation coefficient did not yield a correlation between patient displacement and age, body mass index, length of surgery, or pathology weight. In group A, 2 patients had lower extremity numbness, and 1 patient had upper extremity numbness. In group B, 1 patient had upper extremity pain, and 1 patient had both upper and lower extremity numbness. These patients had complete resolution of their symptoms within the first 2 weeks postoperatively, with the exception of 1 patient in group A whose lower extremity numbness resolved 3 months postoperatively. CONCLUSION: Positioning patients on the bean bag with shoulder braces resulted in significantly less displacement during gynecologic laparoscopic surgery when compared with the memory foam pad. All postoperative extremity numbness, weakness, and pain were temporary and resolved completely in our cohort. A larger study would be necessary to determine the true incidence of peripheral nerve injuries because these are rare complications of laparoscopic surgeries. PMID- 28919503 TI - A multilocus phylogeny of the genus Sarcohyla (Anura: Hylidae), and an investigation of species boundaries using statistical species delimitation. AB - The genus Sarcohyla is composed by 24 species endemic to Mexico. Despite the large number of phylogenetic studies focusing on the family Hylidae, the relationships among the species of Sarcohyla are still poorly known, and the scarce numbers of specimens and tissue samples available for some of the species has hampered an appropriate phylogenetic analysis. We present the most comprehensive molecular phylogenetic study of Sarcohyla to date. We included 17 species of the genus Sarcohyla using data from two mitochondrial (ND1 and 12S) and three nuclear genes (Rag-1, Rhod, and POMc). We performed phylogenetic analyses using Bayesian inference, and the absence of conflicts with strong support between the separate gene trees indicates that incomplete lineage sorting and/or introgressive hybridization are negligible. A coalescent-based species tree analysis of the four independent loci (three nuclear genes+mtDNA) mostly supports the same species-level relationships as the analysis of the concatenated data. By including new samples from additional species and localities, we find that: (1) the widely distributed species S. bistincta is a complex of at least three species, (2) another undescribed species exists in the group, (3) the species S. ephemera is not valid and it corresponds to a junior synonym of S. calthula. In addition, we conducted marginal likelihood estimation and used Bayes factors to test alternative species delimitation models for S. bistincta, the most widespread nominal species in the group. Our findings support three independent lineages of S. bistincta group, which are paraphyletic with respect to S. pentheter and S. calthula. PMID- 28919504 TI - Cryptic elevational zonation in trapdoor spiders (Araneae, Antrodiaetidae, Aliatypus janus complex) from the California southern Sierra Nevada. AB - The relative roles of ecological niche conservatism versus niche divergence in promoting montane speciation remains an important topic in biogeography. Here, our aim was to test whether lineage diversification in a species complex of trapdoor spiders corresponds with riverine barriers or with an ecological gradient associated with elevational tiering. Aliatypus janus was sampled from throughout its range, with emphasis on populations in the southern Sierra Nevada Mountains of California. We collected multi-locus genetic data to generate a species tree for A. janus and its close relatives. Coalescent based hypothesis tests were conducted to determine if genetic breaks within A. janus conform to riverine barriers. Ecological niche models (ENM) under current and Last Glacial Maximum (LGM) conditions were generated and hypothesis tests of niche conservatism and divergence were performed. Coalescent analyses reveal deeply divergent genetic lineages within A. janus, likely corresponding to cryptic species. Two primary lineages meet along an elevational gradient on the western slopes of the southern Sierra Nevada Mountains. ENMs under both current and LGM conditions indicate that these groups occupy largely non-overlapping niches. ENM hypothesis testing rejected niche identity between the two groups, and supported a sharp ecological gradient occurring where the groups meet. However, the niche similarity test indicated that the two groups may not inhabit different background niches. The Sierra Nevada Mountains provide a natural laboratory for simultaneously testing ecological niche divergence and conservatism and their role in speciation across a diverse range of taxa. Aliatypus janus represents a species complex with cryptic lineages that may have diverged due to parapatric speciation along an ecological gradient, or been maintained by the evolution of ecological niche differences following allopatric speciation. PMID- 28919505 TI - Revisiting the phylogeny of Zoanthidea (Cnidaria: Anthozoa): Staggered alignment of hypervariable sequences improves species tree inference. AB - The recent rapid proliferation of novel taxon identification in the Zoanthidea has been accompanied by a parallel propagation of gene trees as a tool of species discovery, but not a corresponding increase in our understanding of phylogeny. This disparity is caused by the trade-off between the capabilities of automated DNA sequence alignment and data content of genes applied to phylogenetic inference in this group. Conserved genes or segments are easily aligned across the order, but produce poorly resolved trees; hypervariable genes or segments contain the evolutionary signal necessary for resolution and robust support, but sequence alignment is daunting. Staggered alignments are a form of phylogeny informed sequence alignment composed of a mosaic of local and universal regions that allow phylogenetic inference to be applied to all nucleotides from both hypervariable and conserved gene segments. Comparisons between species tree phylogenies inferred from all data (staggered alignment) and hypervariable excluded data (standard alignment) demonstrate improved confidence and greater topological agreement with other sources of data for the complete-data tree. This novel phylogeny is the most comprehensive to date (in terms of taxa and data) and can serve as an expandable tool for evolutionary hypothesis testing in the Zoanthidea. Spanish language abstract available in Text S1. Translation by L. O. Swain, DePaul University, Chicago, Illinois, 60604, USA. PMID- 28919506 TI - The role of climatic cycles and trans-Saharan migration corridors in species diversification: Biogeography of Psammophis schokari group in North Africa. AB - Highlands, hydrographic systems and coastal areas have been hypothesised to form corridors across the hyperarid Sahara desert in North Africa, allowing dispersal and gene flow for non-xeric species. Here we aim to provide a genetic test for the trans-Saharan corridor model, and predict the location and stability of ecological-corridors, by combining phylogeography and palaeoclimatic modelling. The model was the Psammophis schokari (Schokari sand racer) group, fast-moving and widely distributed generalist colubrids occurring mostly in arid and semiarid scrublands. We combined dated phylogenies of mitochondrial and nuclear markers with palaeoclimatic modelling. For the phylogeographic analysis, we used 75 samples of P. schokari and P. aegyptius, and Bayesian and Maximum-Likelihood methods. For the ecological models, we used Maxent over the distribution of P. schokari and West African lineages. Models were projected to past conditions (mid Holocene, Last Glacial Maximum and Last Inter-Glacial) to infer climatic stable areas. Climatic stability was predicted to be mostly restricted to coastal areas and not spatially continuous. A putative temporary trans-Saharan corridor was identified in Eastern Sahara, with a more stable one along the Atlantic coast. Six parapatric lineages were identified within P. schokari, four occurring in North Africa. These likely diverged during the Pliocene. The Tamanraset River might have been a vicariant agent. African lineages may have experienced further subsequent diversification during the late Pleistocene. The main P. schokari refugia were probably located along the northern margins of the Sahara, allowing its North-to-South colonization. Trans-Saharan corridors seem to have played a role in P. schokari biogeography, allowing colonization of central Saharan mountains and Sahel. Some might have worked as refugia, and even the most stable corridors may have sections working as filters, depending on each climatic phase. We expect the use of trans-Saharan corridors to decrease for more mesic species or with less dispersal capabilities. PMID- 28919507 TI - Tissue-engineered magnetic cell sheet patches for advanced strategies in tendon regeneration. AB - : Tendons are powerful 3D biomechanically structures combining a few cells in an intrincated and highly hierarchical niche environment. When tendon homeostasis is compromised, restoration of functionality upon injury is limited and requires alternatives to current augmentation or replacement strategies. Cell sheet technologies are a powerful tool for the fabrication of living extracellular-rich patches towards regeneration of tenotopic defects. Thus, we originally propose the development of magnetically responsive tenogenic patches through magnetic cell sheet (magCSs) technology that enable the remote control upon implantation of the tendon-mimicking constructs. A Tenomodulin positive (TNMD+) subpopulation of cells sorted from a crude population of human adipose stem cells (hASCs) previously identified as being prone to tenogenesis was selected for the magCSs patch construction. We investigated the stability, the cellular co-location of the iron oxide nanoparticles (MNPs), as well as the morphology and mechanical properties of the developed magCSs. Moreover, the expression of tendon markers and collagenous tendon-like matrix were further assessed under the actuation of an external magnetic field. Overall, this study confirms the potential to bioengineer tendon patches using a magnetic cell sheet construction with magnetic responsiveness, good mechanoelastic properties and a tenogenic prone stem cell population envisioning cell-based functional therapies towards tendon regeneration. STATEMENT OF SIGNIFICANCE: The concept of magnetic force-based tissue engineering may assist the development of innovative solutions to treat tendon (or other tissues) disorders upon remote control of biological processes as cell migration or differentiation. Herein, we originally fabricated magnetic responsive cell sheets (magCSs) with a Tenomodulin positive subpopulation of adipose tissue derived stem cells identified to commit to the tenogenic lineage. To the best of authors knowledge, this is the first time a tendon oriented strategy resorting on magCSsis reported. Moreover, the promising role of tenogenic living constructs fabricated as magnetically responsive ECM-rich patches is highlighted, envisioning the stimulation of endogenous regenerative mechanisms. Altogether, these findings contribute to future stem cell studies and their translation toward tendon therapies. PMID- 28919508 TI - Pro-inflammatory chitosan/poly(gamma-glutamic acid) nanoparticles modulate human antigen-presenting cells phenotype and revert their pro-invasive capacity. AB - : Anticancer immune responses depend on efficient presentation of tumor antigens and co-stimulatory signals provided by antigen-presenting cells (APCs). However, it is described that immature dendritic cells (DCs) and macrophages at the tumor site may have an immunosuppressive profile, which limits the activity of effector T cells and supports tumor progression. Therapeutic targeting of these innate immune cells, either aiming at their elimination or re-polarization towards an immunostimulatory profile, has been pointed as an attractive approach to control tumor progression. In the present work, we assessed the potential of Chitosan (Ch)/Poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs) to modulate macrophages and DCs inflammatory profile and to impair their ability to promote cancer cell invasion. Interestingly, Ch/gamma-PGA NPs, prepared by co-acervation method, induced an immunostimulatory DCs phenotype, enhancing the expression of the co-stimulatory molecules CD86, CD40 and HLA-DR, and the secretion of the pro inflammatory cytokines TNF-alpha, IL-12p40 and IL-6. Furthermore, Ch/gamma-PGA NPs re-educated IL-10-stimulated macrophages towards a pro-inflammatory profile, decreasing the expression of CD163 and promoting the secretion of IL-12p40 and TNF-alpha. These alterations in the immune cells phenotype promoted CD4+ and CD8+ T cell activation/proliferation and partially inhibited APCs' ability to induce colorectal cancer cell invasion. Overall, our findings open new perspectives on the use of Ch/gamma-PGA NPs as an immunomodulatory therapy for antigen-presenting cells reprogramming, providing a new tool for anticancer therapies. STATEMENT OF SIGNIFICANCE: The immune system is responsible to detect and destroy abnormal cells preventing the development of cancer. However, the immunosuppressive tumor microenvironment can compromise the immune response favoring tumor progression. Thus, immune system modulation towards an immunostimulatory profile can improve anticancer therapies. This research focus on the development of chitosan/poly(gamma-glutamic acid) nanoparticles (NPs) to modulate human antigen presenting cells (APCs) phenotype and to counteract their pro-invasive capacity. Interestingly, Ch/gamma-PGA NPs had a prominent effect in inducing macrophages and dendritic cells immunostimulatory phenotype, thus favoring T cell proliferation and inhibiting colorectal cancer cell invasion. We propose that their combination with other immunomodulatory drugs or conventional anticancer therapies can improve patients' outcome. PMID- 28919509 TI - Molecular and macro-scale analysis of enzyme-crosslinked silk hydrogels for rational biomaterial design. AB - : Silk fibroin-based hydrogels have exciting applications in tissue engineering and therapeutic molecule delivery; however, their utility is dependent on their diffusive properties. The present study describes a molecular and macro-scale investigation of enzymatically-crosslinked silk fibroin hydrogels, and demonstrates that these systems have tunable crosslink density and diffusivity. We developed a liquid chromatography tandem mass spectroscopy (LC-MS/MS) method to assess the quantity and order of covalent tyrosine crosslinks in the hydrogels. This analysis revealed between 28 and 56% conversion of tyrosine to dityrosine, which was dependent on the silk concentration and reactant concentration. The crosslink density was then correlated with storage modulus, revealing that both crosslinking and protein concentration influenced the mechanical properties of the hydrogels. The diffusive properties of the bulk material were studied by fluorescence recovery after photobleaching (FRAP), which revealed a non-linear relationship between silk concentration and diffusivity. As a result of this work, a model for synthesizing hydrogels with known crosslink densities and diffusive properties has been established, enabling the rational design of silk hydrogels for biomedical applications. STATEMENT OF SIGNIFICANCE: Hydrogels from naturally-derived silk polymers offer versitile opportunities in the biomedical field, however, their design has largely been an empirical process. We present a fundamental study of the crosslink density, storage modulus, and diffusion behavior of enzymatically-crosslinked silk hydrogels to better inform scaffold design. These studies revealed unexpected non-linear trends in the crosslink density and diffusivity of silk hydrogels with respect to protein concentration and crosslink reagent concentration. This work demonstrates the tunable diffusivity and crosslinking in silk fibroin hydrogels, and enables the rational design of biomaterials. Further, the characterization methods presented have applications for other materials with dityrosine crosslinks, which are found in nature as post-translational modificaitons, as well as in engineered matrices such as tyramine-substituted hyaluronic acid and recombinant resilin. PMID- 28919510 TI - Magnesium (Mg) based interference screws developed for promoting tendon graft incorporation in bone tunnel in rabbits. AB - : How to enhance tendon graft incorporation into bone tunnels for achieving satisfactory healing outcomes in patients with anterior cruciate ligament reconstruction (ACLR) is one of the most challenging clinical problems in orthopaedic sports medicine. Several studies have recently reported the beneficial effects of Mg implants in bone fracture healing, indicating the use potential of Mg devices in promoting the tendon graft osteointegration. Here, we developed an innovative Mg-based interference screws for fixation of the tendon graft in rabbits underwent ACLR and investigated the biological role of Mg-based implants in the graft healing. The titanium (Ti) interference screw was used as the control. We demonstrated that Mg interference screw significantly accelerated the incorporation of the tendon graft into bone tunnels via multiscale analytical methods including scanning electronic microscopy/energy dispersive spectrometer (SEM/EDS), micro-hardness, micro-Fourier transform infrared spectroscopy (MUFTIR), and histology. Our in vivo study showed that Mg implants enhanced the recruitment of bone marrow stromal stem cells (BMSCs) towards peri-implant bone tissue, which may be ascribed to the upregulation of local TGF-beta1 and PDGF-BB. Besides, the in vitro study revealed that higher Mg ions was beneficial to the improvement of capability in cell adhesion and osteogenic differentiation of BMSCs. Thus, the enhancement in cell migration, cell adhesion and osteogenic differentiation of BMSCs may contribute to an improved tendon graft osteointegration in the Mg group. Our findings in this work may further facilitate clinical applications of Mg-based interference screws for enhancing tendon graft-bone junction healing in patients indicated for ACLR. STATEMENT OF SIGNIFICANCE: How to promote tendon-bone junction healing is one of the major challenging issues for satisfactory clinical outcomes in patients after ACL reconstruction. The improvement of bony ingrowth into the tendon graft-bone interface can enhance the tendon graft osteointegration. In this study, we applied Mg based interference screws to fix the tendon graft in rabbits and found the use of Mg screws could accelerate and significantly increase mineralized matrix formation at the tendon-bone interface in animals when compared to those with Ti screws. We elucidated the mechanism behind the favorable effects of Mg screws on the graft healing in both in vitro and in vivo studies from multiscale technologies. The optimized interface structure and function in Mg group may be ascribed to the improved cell migration capability, enhanced cell adhesion strength and promoted osteogenic differentiation ability of BMSCs under the stimuli of Mg ions degraded from implanted Mg screws. Our findings may help us broaden our thinking in the application potential of Mg interference screws in future clinical trials. PMID- 28919511 TI - Viscoelastic properties of alpha-keratin fibers in hair. AB - : Considerable viscoelasticity and strain-rate sensitivity are a characteristic of alpha-keratin fibers, which can be considered a biopolymer. The understanding of viscoelasticity is an important part of the knowledge of the overall mechanical properties of these biological materials. Here, horse and human hairs are examined to analyze the sources of this response. The dynamic mechanical response of alpha-keratin fibers over a range of frequencies and temperatures is analyzed using a dynamic mechanical analyzer. The alpha-keratin fibers behave more elastically at higher frequencies while they become more viscous at higher temperatures. A glass transition temperature of ~55 degrees C is identified. The stress relaxation behavior of alpha-keratin fibers at two strains, 0.02 and 0.25, is established and fit to a constitutive equation based on the Maxwell-Wiechert model. The constitutive equation is further compared to the experimental results within the elastic region and a good agreement is obtained. The two relaxation constants, 14s and 359s for horse hair and 11s and 207s for human hair, are related to two hierarchical levels of relaxation: the amorphous matrix intermediate filament interfaces, for the short term, and the cellular components for the long term. Results of the creep test also provide important knowledge on the uncoiling and phase transformation of the alpha-helical structure as hair is uniaxially stretched. SEM results show that horse hair has a rougher surface morphology and damaged cuticles. It also exhibits a lower strain-rate sensitivity of 0.05 compared to that of 0.11 for human hair. After the horse and human hairs are chemically treated and the disulfide bonds are cleaved, they exhibit a similar strain-rate sensitivity of ~0.05. FTIR results confirms that the human hair is more sensitive to the -S-S- cleavage, resulting in an increase of cysteic acid content. Therefore, the disulfide bonds in the matrix are experimentally identified as one source of the strain-rate sensitivity and viscoelasticity in alpha-keratin fibers. STATEMENT OF SIGNIFICANCE: Hair has outstanding mechanical strength which is equivalent to metals on a density-normalized basis. It possesses, in addition to the strength, a large ductility that is enabled by either the unfolding of the alpha helices and/or the transformation of these helices to beta sheets. We identify the deformation and failure mechanisms and connect them to the hierarchical structure, with emphasis on the significant viscoelasticity of these unique biological materials. PMID- 28919512 TI - Strontium and magnesium ions released from bioactive titanium metal promote early bone bonding in a rabbit implant model. AB - : We have previously developed the "alkali and heat treatment" method to confer bioactivity (bone-bonding ability) to titanium metal (Ti). As strontium (Sr) and magnesium (Mg) ions reportedly promote osteoblastic cell proliferation and differentiation and accelerate bone formation, we improved this method to induce the release of Sr (Sr-Ti) or Mg (Mg-Ti) ions from Ti in a previous study. Here, we evaluated the bioactivity of these novel surface treatments, Sr-Ti and Mg-Ti. In vitro evaluation of cell viability, expression of integrin beta1, beta catenin, and cyclin D1, osteogenic gene expression, alkaline phosphatase activity, and extracellular mineralization using MC3T3-E1 cells revealed that Sr Ti and Mg-Ti enhanced proliferation and osteogenic differentiation. In rabbit in vivo studies, Sr-Ti and Mg-Ti also provided greater biomechanical strength and bone-implant contact than the positive control Ti (Ca-Ti), especially at the early stage (4-8weeks), and maintained these properties for a longer period (16 24weeks). Advantages of the improved method include process simplicity, applicability for any implant shape, and lack of adverse effects on implant composition and structure. Therefore, our treatment is promising for clinical applications to achieve early bone bonding. STATEMENT OF SIGNIFICANCE: Implantation into osteoporotic bone constitutes a challenging problem because of early migration or loosening of the implant, which is primarily due to insufficient initial fixation in porotic bone. Therefore, it is desirable to provide implants with a capacity for early bone bonding. We have achieved conferring early bone bonding ability to titanium metal by releasing strontium ions or magnesium ions. Our treatment is promising for clinical applications to achieve early bone bonding of orthopedic or dental Ti-based implants. PMID- 28919513 TI - Accompanying indigenous Maya patients with complex medical needs: A patient navigation system in rural Guatemala. PMID- 28919514 TI - HZ-6d targeted HERC5 to regulate p53 ISGylation in human hepatocellular carcinoma. AB - Manipulating the posttranslational modulator of p53 is central in the regulation of its activity and function. ISGylated p53 can be degraded by the 20S proteasome. During this process, HERC5/Ceb1, an IFN-induced HECT-type E3 ligase, mediated p53 ISGylation. In this study, we indicated that HERC5 was over expressed in both HCC tissue samples and cell lines. Knockdown of HERC5 significantly induced the expression of p53, p21 and Bax/Bcl-2 in HCC cells, resulting in apoptosis augment. Whereas, opposite results were obtained by using HERC5 over-expression. On this basis, we screened a 7, 11-disubstituted quinazoline derivative HZ-6d that could bind to the HERC5 G-rich sequence in vitro. Interestingly, HZ-6d injection effectively delayed the growth of xenografts in nude mice. In vitro, HZ-6d significantly inhibited cell growth, suppressed cell migration, induced apoptosis in HCC cells. Further studies demonstrated the anti-cancer effect of HZ-6d was associated with down-regulation of HERC5 and accumulation of p53. Collectively, we demonstrated that HZ6d is a HERC5 G-quadruplex ligand with anti-tumor properties, an action that may offer an attractive idea for restoration of p53 function in cancers. PMID- 28919516 TI - Time-dependent effects of perfluorinated compounds on viability in cerebellar granule neurons: Dependence on carbon chain length and functional group attached. AB - The toxicity of long chained perfluoroalkyl acids (PFAAs) has previously been reported to be related to the length of the perfluorinated carbon chain and functional group attached. In the present study, we compared the cytotoxicity of six PFAAs, using primary cultures of rat cerebellar granule neurons (CGNs). Two perfluoroalkyl sulfonic acids (PFSAs, chain length C6 and C8) and four perfluoroalkyl carboxylic acids (PFCAs, chain length C8-C11) were studied. These PFAAs have been detected in human blood and the brain tissue of mammals. The cell viability trypan blue and MTT assays were used to determine toxicity potencies (based on LC50 values) after 24h exposure (in descending order): perfluoroundecanoic acid (PFUnDA)>=perfluorodecanoic acid (PFDA)>perfluorooctanesulfonic acid potassium salt (PFOS)>perfluorononanoic acid (PFNA)>perfluorooctanoic acid (PFOA)>perfluorohexanesulfonic acid potassium salt (PFHxS). Concentrations of the six PFAAs that produced equipotent effects after 24h exposure were used to further explore the dynamics of viability changes during this period. Therefore viability was assessed at 10, 30, 60, 90, 120 and 180min as well as 6, 12, 18 and 24h. A difference in the onset of reduction in viability was observed, occurring relatively quickly (30-60min) for PFOS, PFDA and PFUnDA, and much slower (12-24h) for PFHxS, PFOA and PFNA. A slight protective effect of vitamin E against PFOA, PFNA and PFOS-induced reduction in viability indicated a possible involvement of oxidative stress. PFOA and PFOS did not induce lipid peroxidation on their own, but significantly accelerated cumene hydroperoxide-induced lipid peroxidation. When distribution of the six PFAAs in the CGN-membrane was investigated using NanoSIMS50 imaging, two distinct patterns appeared. Whereas PFHxS, PFOS and PFUnDA aggregated in large hotspots, PFOA, PFNA and PFDA showed a more dispersed distribution pattern. In conclusion, the toxicity of the investigated PFAAs increased with increasing carbon chain length. For molecules with a similar chain length, a sulfonate functional group led to greater toxicity than a carboxyl group. PMID- 28919517 TI - Severe Toxoplasma gondii infection in a member of a NFKB2-deficient family with T and B cell dysfunction. PMID- 28919515 TI - Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity. AB - Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2h apart, of MA (2.5, 5, or 10mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7days following MA administration for analysis of DA, 3,4 dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects. PMID- 28919519 TI - Targeting immune modulatory pathways in cancer. PMID- 28919518 TI - Depressed serum IgM levels in SLE are restricted to defined subgroups. AB - Natural IgM autoantibodies have been proposed to convey protection from autoimmune pathogenesis. Herein, we investigated the IgM responses in 396 systemic lupus erythematosus (SLE) patients, divided into subgroups based on distinct autoantibody profiles. Depressed IgM levels were more common in SLE than in matched population controls. Strikingly, an autoreactivity profile defined by IgG anti-Ro/La was associated with reduced levels of specific natural IgM targeting phosphorylcholine (PC) antigens and malondialdehyde (MDA) modified protein, as well as total IgM, while no differences were detected in SLE patients with an autoreactivity profile defined by anti-cardiolipin/beta2glycoprotein-I. We also observed an association of reduced IgM levels with the HLA-DRB1*03 allelic variant among SLE patients and controls. Associations of low IgM anti-PC with cardiovascular disease were primarily found in patients without antiphospholipid antibodies. These studies further highlight the clinical relevance of depressed IgM. Our results suggest that low IgM levels in SLE patients reflect immunological and genetic differences between SLE subgroups. PMID- 28919520 TI - Antibodies against citrullinated alpha enolase peptides in primary Sjogren's syndrome. AB - Citrullinated alpha enolase (CEP-1) has been designated as a major antigenic target of antibodies against citrullinated proteins (ACPA) in patients with rheumatoid arthritis (RA). Our aim is to determine the prevalence of anti-CEP-1 in a cohort of ACPA positive (ACPA+) primary Sjogren's syndrome (pSS) patients. Anti-CEP1 titers were determined by ELISA in sera from 15 ACPA+ and 45 ACPA- age/sex matched pSS; 12 ACPA+ RA patients and 30 healthy controls (HC). Increased anti-CEP-1 antibody titers were detected in nine out of the 15 (60%) ACPA+ pSS patients and 5 out of 12 (41.7%) ACPA+ RA patients; no reactivities were detected in ACPA- pSS patients and HC. Anti-CEP-1 antibodies in the setting of pSS were associated with higher urine pH levels at baseline. CEP-1 is a major antigenic target of ACPA in patients with pSS characterizing a subgroup with distinct laboratory features. PMID- 28919521 TI - Treatment Patterns and Survival Outcomes for Patients with Small Cell Carcinoma of the Bladder. AB - BACKGROUND: Small cell carcinoma of the bladder (SCCaB) is a rare tumor without a standard treatment algorithm. Treatment patterns and survival outcomes from the National Cancer Database (NCDB) may provide insight into optimal treatment strategies. OBJECTIVE: To investigate the relationship between overall survival (OS) and treatment strategy. DESIGN, SETTING, AND PARTICIPANTS: This was an observational study of treatment-naive patients who received treatment from 2004 to 2013. Patients with cT1-4aN0M0 SCCaB were identified from the NCDB, a hospital based tumor registry that captures >70% of incident cancer cases in the USA. INTERVENTION: Treatment strategies included local therapy alone, chemotherapy (CT), radiation therapy (RT), chemoradiation therapy (CRT), radical cystectomy (RC), and RC plus chemotherapy (RC+C). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed as a function of treatment modality adjusting for patient, demographic, and tumor-related factors. The Kaplan-Meier survival method, and the log-rank test and Cox regression were used for univariable and multivariable analyses. RESULTS AND LIMITATIONS: We identified 856 patients with median follow-up of 18.3 mo. The median OS for the entire cohort was 20.7 mo (95% confidence interval [CI] 18.3-23.2) and estimated 3-yr and 5-yr OS were 37.5% and 28.2%, respectively. The most common treatment modality was CT (225 patients; 26.3%) followed by CRT (203 patients; 23.7%) and RC+C (201 patients; 23.5%). The median OS was 18.4 mo (95% CI 15.2-21.5) for CT, 34.1 mo (95% CI 22.5-45.8) for CRT, and 32.4 mo (95% CI 20.8-44.1) for RC+C. OS did not significantly differ between CRT and RC+C (p=0.42). On multivariable analysis, the best OS was associated with CRT (hazard ratio [HR] 0.41, 95% CI 0.32-0.53; p<0.0001) and RC+C (HR 0.45, 95% CI 0.34-0.59; p<0.0001). CONCLUSIONS: RC+C and CRT are associated with better OS compared to monotherapy among patients with SCCaB. PATIENT SUMMARY: Small cell carcinoma of the bladder is a rare and highly aggressive cancer. According to National Cancer Database data, radical cystectomy plus chemotherapy and chemoradiation therapy are associated with better overall survival compared to monotherapy. PMID- 28919523 TI - Thomas Mann: Vascular Fatal Illness of the Writer Who Mastered Disease Through Literary Fiction. AB - Ruptured iliac artery may initially clinically mimic an isolated inferior limb venous involvement. It was indeed an acute iliac artery dissection complicated by contained rupture and misdiagnosed as inferior limb venous thrombosis that led to the death of Thomas Mann in 1955. The details of the complex case are analyzed. Considerations of medical interest and on actuality of his work are also added. PMID- 28919522 TI - The Incidence of Ischemic Colitis after Repair of Ruptured Abdominal Aortic Aneurysms Is Decreasing in the Endovascular Era. AB - BACKGROUND: Ischemic colitis (IC) is a well-described complication of ruptured abdominal aortic aneurysms (rAAAs). The purpose of this study was to compare the incidence of IC in patients with rAAA undergoing open repair (OR) versus endovascular aneurysm repair (EVAR) at a single institution. In addition, we analyzed the incidence of IC before and after the implementation of a formal rupture AAA protocol (rEVAR protocol). METHODS: A retrospective analysis of prospectively collected data on all patients presenting with rAAA to our institution between January 2002 and October 2013 was performed. Variables were analyzed for association with IC. Comparisons were made using Pearson's chi squared test or Fisher's exact test for categorical variables, Student's t-test for continuous variables, and logistic regression for multivariate analysis. Significance was set at P < 0.05. RESULTS: Three hundred three patients with rAAA presented over the 10-year study period. One hundred ninety-one patients underwent OR and 89 patients underwent endovascular repair. Twenty-three patients died either in the emergency department, en route to the operating room, or after choosing comfort care. Predictive factors of IC included estimated blood loss, corresponding need for resuscitation, and duration of procedure. Of patients who underwent OR, the rate of IC was 21% (40/191). This was significantly higher than patients who underwent EVAR, 7% (6/89), P < 0.05. The type of intervention did not influence 30-day mortality in patients with IC. However, only 17% (1/6) of patients who had IC following EVAR required colectomy versus 48% (19/40) of patients with IC following OR (P = 0.21). Implementation of our formal rEVAR protocol decreased the incidence of IC significantly from 37.1% (36/97) to 6.4% (10/157), P < 0.001. CONCLUSIONS: The incidence of IC has decreased significantly in the endovascular era but continues to portend a poor prognosis. Implementation of a formal, multidisciplinary rEVAR protocol in our institution decreased the incidence of IC. PMID- 28919524 TI - Chitosan/ferulic acid-coated poly(epsilon-caprolactone) electrospun materials with antioxidant, antibacterial and antitumor properties. AB - Novel fibrous materials from poly(epsilon-caprolactone) (PCL), chitosan (Ch) and natural phenolic acid ferulic acid (FA) of diverse design were successfully prepared by electrospinning or electrospinning combined with dip-coating. FA incorporated in the PCL fibrous mats or in the Ch coating was in the amorphous state as evidenced by the performed differential scanning calorimetry (DSC) and X ray diffraction (XRD) analysis. The release of FA was affected by the composition and design of the polymer matrix. The incorporation of a combination of FA and Ch in the fibrous mats imparted to these materials higher killing rates against pathogenic bacteria S. aureus than that of FA-containing mats or Ch-coated mats alone. The FA-containing fibrous materials as well as those coated with Ch or Ch FA inhibited the adhesion of S. aureus bacteria. Moreover, FA preserved its antioxidant activity when incorporated in the fibers or in the Ch coating. It was found that the cytotoxicity of all types of FA-containing mats against HeLa tumor cells was higher than that of the free FA. Thus, the obtained fibrous materials can be suitable candidates for wound dressing applications and for application in local treatment of cervical tumors. PMID- 28919525 TI - Gelatin stabilization of quantum dots for improved stability and biocompatibility. AB - We herein report an aqueous synthesis of gelatin stabilized CdTe/CdS/ZnS (CSSG) core/double shell quantum dots (QDs) with improved biocompatibility. The as synthesized QDs were characterized by ultraviolet-visible (UV-vis) and photoluminescence (PL) spectroscopic techniques, x-ray diffraction technique (XRD), x-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM). The CSSG QDs revealed high photoluminescence quantum yield (PLQY) with excellent stability over a period of one year and retained 90% of its initial PLQY without any aggregation or precipitation under ambient condition. The cell viability study conducted on HeLa, cervical cancer cell lines indicated that the gelatin stabilization effectively decreased the QDs cytotoxicity by about 50%. The CSSG QDs were conjugated with transferrin (Tf) for the efficient delivery to the cancer cells followed by fluorescence imaging. The results showed that the CSSG QDs illuminates the entire cell which renders the QDs as cell labeling markers. The gelatin stabilized core/double shell QDs are potential candidates for long time fluorescent bio-imaging. PMID- 28919526 TI - Chemical crosslinking of biopolymeric scaffolds: Current knowledge and future directions of crosslinked engineered bone scaffolds. AB - Bone tissue scaffolds made from either natural or synthetic polymers are employed to promote bone healing. However, lack of sufficient or poor mechanical properties such as low integrity and stability reduces their medical applications. Crosslinking, defined as induction of chemical or physical links among polymer chains, is a simple method generally used to modify mechanical, biological and degradation properties of hydrogels. Although crosslinking through chemical reactions improves the mechanical properties of bone substitutes, most of the reagents used for this aim demonstrate undesirable effects and may exert toxic reactions. Glutaraldehyde is a widely-used chemical crosslinker with unique ability to crosslink a wide variety of biomaterials; however, many contradictory views have been recently raised on its cytotoxic effects. By keeping this limit in mind, green chemicals or natural crosslinking agents have been shown to provide desired improvements in mechanical properties of bone scaffolds. Therefore, developing more efficient crosslinking materials and methods are desirable to obtain crosslinked scaffolds with perfect properties in bone tissue engineering from different biopolymers such as collagen, gelatin, cellulose, chitosan, alginate, etc. In this review, we focused on developed or developing modalities used to improve mechanical properties of various bone scaffolds and matrices based on common crosslinking reagents. PMID- 28919527 TI - Protective effect of porcine plasma protein hydrolysates on the gelation of porcine myofibrillar protein exposed to a hydroxyl radical-generating system. AB - This study investigated the effect of different concentrations of porcine plasma protein hydrolysates (PPPH) on the gelation of porcine myofibrillar protein (MP) exposed to a hydroxyl radical-generating system (HRGS). Compared to non-oxidized MP, the oxidative modification led to a decreased penetration force and water holding capacity (WHC) (P<0.05). Meanwhile, addition of PPPH (1.5mg/mL) reduced the loss of MP gel strength and WHC induced by HRGS (P<0.05). Low-field nuclear magnetic resonance results suggested that the addition of PPPH facilitated the hydration of the protein. The results concerning molecular forces revealed that hydrophobic interactions, hydrogen bonds, and disulphide bonds are the primary forces in gel formation. Non-reducing electrophoresis indicated that the addition of PPPH reduced protein loss and aggregation. The addition of PPPH promoted the formation of a more smooth and homogeneous gel network. Our results demonstrated that PPPH effectively retarded oxidation-induced MP gel deterioration and could be used as an antioxidant in meat products. PMID- 28919528 TI - Modification of wool protein fiber with plasma and dendrimer: Effects on dyeing with cochineal. AB - In this study, plasma treatment and a poly(propylene imine) dendrimer were employed to improve the dyeability of wool fibers with cochineal natural dye. FESEM, EDX, AFM and FTIR techniques were employed to investigate the effects of these treatments on chemical and physical properties of wool fibers. The etching of the surface layer of wool fibers and increased roughness after plasma treatment was confirmed by FESEM and AFM images. EDX and FTIR analyses confirmed the creation of oxygen-containing groups and attachment of dendrimer molecules on wool fibers after plasma and dendrimer treatments respectively. The effects of different dyeing parameters on dye absorption and the applicability of different isotherm and kinetic models on the dyeing process were investigated. The results showed that the kinetics of absorption of cochineal on raw, plasma-treated and dendrimer-treated fibers was best fitted with the pseudo-second-order model and the isotherms of the dyeing processes followed the Freundlich model. PMID- 28919529 TI - Acetylation of lysine residues in apomyoglobin: Structural changes, amyloid fibrillation, and role of surface charge. AB - Post-translational modifications play important roles in conformational properties and aggregation propensities of different peptides and proteins. In the present study, we have investigated the effects of acetylation of lysine residues on the structure and aggregation properties of apomyoglobin (apoMb).All of the 19 lysine residues were modified. Far-, near-UV CD, intrinsic and acrylamide quenching fluorescence studies indicated that acetylation significantly influences conformation of apoMb by altering both its secondary and tertiary structures. A considerable decrease in ANS fluorescence intensity was observed, which also suggested disruption of the heme pocket. Dynamic light scattering indicated partial compaction of protein structure as a consequence of the shielding effect of acetylation. While the presence of well-defined mature fibrils was detected in solutions of native apoMb, acetylation promoted formation of non-toxic amorphous aggregates, with low beta-sheets content and decreased affinity for Thioflavin T, an amyloid-specific dye. Results are discussed in terms of the role of surface charge in conformational alterations of proteins and how small changes in ionic networks may affect aggregation pathways and morphology of the resulting aggregates. The physiological significance of the modification process in controlling cytotoxicity of the aggregated species is also discussed. PMID- 28919530 TI - Coproduction of protease and mannanase from Bacillus nealsonii PN-11 in solid state fermentation and their combined application as detergent additives. AB - Bacillus nealsonii PN-11 produces thermo-alkalistable mannanase and protease active in wide temperature and pH range. Optimization of coproduction of protease and mannanase from this strain and application of cocktail of these enzymes as detergent additives were studied. On optimization mannanase yield of 834Ug-1 (11.12 fold increase) and protease yield of 70Ug-1 (4.7 fold increase) could be obtained in a single fermentation. Purification and characterization of mannanase have been done earlier and protease was done during this study and has a molecular mass of 48kDa. pH and temperature optima for protease were 10.0 and 65 degrees C respectively. It was completely stable at 60 degrees C for 3h and retained >80% of activity at pH 11.0 for 1h. Both the enzymes were compatible with detergents individually and in a combination. The wash performance of the detergent on different type of stains improved when protease or mannanase were used individually. However destaining was more efficient when a combination of mannanase and protease was used. PMID- 28919531 TI - A thermostable alkaliphilic protein-disulfide isomerase from Bacillus subtilis DR8806: cloning, expression, biochemical characterization and molecular dynamics simulation. AB - Disulfide bonds are among the most important factors related to correct folding of the proteins. Protein disulfide isomerase (PDI) is the enzyme responsible for the correct formation and isomerization of these bonds. It is rarely studied so far and none of them showed industrial properties. In this study, the gene encoding for a putative PDI from Bacillus subtilis DR8806 was identified, cloned and expressed in Escherichia coli. It was encoded a 23.26kDa protein. The enzyme was purified by GST affinity chromatography with a specific activity of 1227u/mg. It was active and stable over a wide range of temperature (20-85 degrees C) and pH (4.5-10) with an optimum at 65 degrees C and pH 5.5. Its activity was enhanced by Mn2+ and Co2+ while Ag+ and Zn2+ decreased it. Some of the known PDI inhibitors such as Tocinoic acid and Bactiracin did not affect its activity. In silico analysis shows the five amino acids changes in the protein sequence regarding to the consensus sequence of PDIs, have a positive impact toward the protein thermal stability. This was further confirmed by molecular dynamics simulations. By considering the overall results, the enzyme might be a potential candidate for applications in the respective industries. PMID- 28919533 TI - Engineering Non-transgenic Gynoecious Cucumber Using an Improved Transformation Protocol and Optimized CRISPR/Cas9 System. PMID- 28919532 TI - Performance of cellulose acetate-ferric oxide nanocomposite supported metal catalysts toward the reduction of environmental pollutants. AB - Water contamination by toxic compounds has become one of the most serious problems worldwide. Catalytic reduction using metal nanoparticles offer opportunities for environmental benefits. In this study, cellulose acetate-ferric oxide nanocomposite (CA/Fe2O3) was prepared and used as support for metal nanoparticles. After adsorption of Ag, Cu or Ni ions from aqueous solutions, metal ions associated with CA/Fe2O3 were treated with sodium borohydride to prepare Ag, Cu and Ni nanoparticles loaded CA/Fe2O3. The CA/Fe2O3 supported Ag, Cu or Ni nanoparticles was evaluated as a catalyst for pollutants degradation. Silver nanoparticles (Ag@CA/Fe2O3) exhibit remarkable decomposition for methyl orange dye and p-nitrophenol in short time. The rate constant for methyl orange and p-nitrophenol were 8.58*10-3 and 4.77*10-3s-1, respectively. Besides the good catalytic activities of Ag@CA/Fe2O3, the catalyst could be easily recovered from the reaction medium by pulling the catalyst after completion of the reduction reaction. The recovered catalyst can be recycled several times if their exposure time to air was minimal. PMID- 28919534 TI - Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB. AB - Arc/Arg3.1 is a unique immediate early gene whose expression is highly dynamic and correlated with various forms of synaptic plasticity. Many previous reports highlight the complexity of mechanisms that regulate Arc/Arg3.1 expression in neurons. In the present study, the expression and regulation of Arc/Arg3.1 after glutamate treatment in primary cultured cortical neurons were investigated. We found that both Arc/Arg3.1 mRNA and Arc/Arg3.1 protein dynamically increased within 24h after glutamate treatment. The results of immunostaining showed that abundant amounts of Arc/Arg3.1 protein are presented in both soma and dendrites. The glutamate-induced increase in Arc/Arg3.1 protein levels was partially prevented by the NMDAR inhibitor DL-AP5, but not the AMPAR inhibitor NBQX. The results of calcium imaging showed that glutamate induced significant increases in intracellular calcium levels in a NMDAR-dependent manner. However, the intracellular calcium chelator BAPTA-AM had no effect on glutamate-induced upregulation of Arc/Arg3.1 protein, and alteration of cytosolic calcium ion homeostasis with A23187 and TG did not change Arc/Arg3.1 protein levels. In addition, the phosphorylation of ERK and CREB, two downstream factors of NMDAR signaling, markedly increased after glutamate exposure. Blocking ERK and CREB activation via selective inhibitors partially prevented the glutamate-induced elevation of Arc/Arg3.1 protein levels. Combined observations support a NMDAR mediated and calcium-independent mechanism by which glutamate increases Arc/Arg3.1 expression in cortical neurons. PMID- 28919535 TI - Altered gray matter volume, cerebral blood flow and functional connectivity in chronic stroke patients. AB - It is entangled connections and intensive functional interactions between cortex and subcortical structures that enable our brain to perform delicate movement, and poses plasticity to recover from stroke. However, it is still unclear how cortical structures and functions change in well-recovered patients from subcortical infarctions in motor pathway. In order to reveal neuroplasticity underlying well-recovered stroke patients, both structural (gray matter volume, GMV) and functional reorganizations (cerebral blood flow, CBF and resting-state functional connectivity, rsFC) were investigated by using multi-modal MRI. Our results showed that well-recovered stroke patients exhibited significantly increased GMV in contralesional supplementary motor area (SMA), increased CBFs in contralesional superior frontal gyrus (SFG) and supramarginal gyrus (SMG) irrespective of GMV correction. Furthermore, our results showed increased rsFC between contralesional middle temporal gyrus (MTG) and SMG. Negative correlations between CBF increases and behavior test scores were also observed, suggesting neural mechanism underlying clinical improvement. Our results suggested that neuroplasticity after chronic stroke showed in both structural and functional levels, and correlation between CBF change and clinical test suggested possible biomarker for stroke recovery. PMID- 28919536 TI - Neuroprotective effect of 5alpha-androst-3beta,5,6beta-triol on retinal ganglion cells in a rat chronic ocular hypertension model. AB - Previous studies have demonstrated that 5alpha-androst-3beta,5,6beta-triol (Triol), a synthesized steroid compound, showed notable neuroprotective effect in cultured cortical neurons. In the present study, we explored whether and how Triol have neuroprotective effect on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model. COH model was produced by injecting superparamagnetic iron oxide micro-beads into the anterior chamber, and Triol was administrated (4.8MUg/100g, i.p., once daily for 4 weeks). Immunohistochemistry experiments showed that in whole flat-mounted COH retinas, the number of CTB labeled survival RGCs was progressively reduced, while TUNEL-positive signals were significantly increased from 1 to 4 weeks after the micro-bead injection. Triol administration significantly attenuated the reduction in the number of CTB labeled RGCs, and partially reduced the increased number of TUNEL-positive signals in COH retinas. Furthermore, Triol administration partially reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and significantly rescued the activities of mitochondrial respiratory chain complex (MRCC) I/II/III in COH retinas. Our results suggest that Triol prevents RGCs from apoptotic death in COH retinas by reducing the lipid peroxidation and enhancing the activities of MRCCs. PMID- 28919537 TI - Neuroprotective effect of curcumin-I in copper-induced dopaminergic neurotoxicity in rats: A possible link with Parkinson's disease. AB - Numerous findings indicate an involvement of heavy metals in the neuropathology of several neurodegenerative disorders, especially Parkinson's disease (PD). Previous studies have demonstrated that Copper (Cu) exhibits a potent neurotoxic effect on dopaminergic neurons and triggers profound neurobehavioral alterations. Curcumin is a major component of Curcuma longa rhizomes and a powerful medicinal plant that exerts many pharmacological effects. However, the neuroprotective action of curcumin on Cu-induced dopaminergic neurotoxicity is yet to be investigated. The aim of the present study was to evaluate the impact of acute Cu intoxication (10mg/kg B.W. i.p) for 3days on the dopaminergic system and locomotor performance as well as the possible therapeutic efficacy of curcumin I (30mg/kg B.W.). Intoxicated rats showed a significant loss of Tyrosine Hydroxylase (TH) expression within substantia nigra pars compacta (SNc), ventral tegmental area (VTA) and the striatal outputs. This was correlated with a clear decrease in locomotor performance. Critically, curcumin-I co-treatment reversed these changes and showed a noticeable protective effect; both TH expression and locomotor performance was reinstated in intoxicated rats. These results demonstrate altered dopaminergic innervations following Cu intoxication and a new therapeutic potential of curcumin against Cu-induced dopaminergic neurotransmission failure. Curcumin may therefore prevent heavy metal related Parkinsonism. PMID- 28919538 TI - Roles of N-methyl-d-aspartate receptors during the sensory stimulation-evoked field potential responses in mouse cerebellar cortical molecular layer. AB - The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods. Our results showed that cerebellar surface administration of NMDA induced a dose-dependent decrease in amplitude of the facial stimulation-evoked inhibitory responses (P1) in the molecular layer, accompanied with decreases in decay time, half-width and area under curve (AUC) of P1. The IC50 of NMDA induced inhibition in amplitude of P1 was 46.5MUM. In addition, application of NMDA induced significant increases in the decay time, half-width and AUC values of the facial stimulation-evoked excitatory responses (N1) in the molecular layer. Application of an NMDAR blocker, D-APV (250MUM) abolished the facial stimulation-evoked P1 in the molecular layer. These results suggested that NMDARs play a critical role during the sensory information processing in cerebellar cortical molecular layer in vivo in mice. PMID- 28919539 TI - The Nexus Between the Documentation of End-of-Life Wishes and Awareness of Dying: A Model for Research, Education and Care. AB - The convergence of medical treatment that can extend life with written medical orders that make it possible to refuse such treatment brings the differential dynamics of contemporary end-of-life decision making into sharp focus. Communication between families and clinicians can be confusing, uncertain, and pressured when death is imminent. These situations create distress that ultimately influences the end-of-life experience for people who are dying and those who care for them. This article presents the analysis of the decisional dynamics that emerge from the intersection of the patient-family-provider awareness that death is near with the presence or absence of documentation of expressed wishes for end-of-life care. A heuristic analysis was conducted with data from three studies about urgent decision making at the end of life. Original study data included 395 surveys, in-depth interviews with 91 prehospital (paramedics and emergency medical technicians), and content analysis of 100 Medical Orders for Life Sustaining Treatment forms that led to the development of an overarching conceptual model of decision making. Four decisional contexts emerged from the intersection of awareness of dying and documentation of wishes: 1) Aware Documented, 2) Aware Undocumented, 3) Unaware Documented, and 4) Unaware Undocumented. This generalizable model, which is agnostic of setting, can help clinicians more astutely recognize the clinical situation when death is imminent, assess patients and caregivers, and intervene to help focus conversation and direct decision making. The model can also inform research, education, and care for people in some of the most vulnerable moments of life. PMID- 28919540 TI - Changes in Nurses' Knowledge, Difficulties, and Self-reported Practices Toward Palliative Care for Cancer Patients in Japan: An Analysis of Two Nationwide Representative Surveys in 2008 and 2015. AB - CONTEXT: The Cancer Control Act was passed in Japan in 2007, and various additional programs on palliative care have been implemented to improve quality of life and relieve pain and suffering in patients with cancer. However, how clinical settings have changed remains unclear. OBJECTIVES: The primary aim of the present study was to determine changes in nurses' palliative care knowledge, difficulties, and self-reported practices between 2008 and 2015. METHODS: This study was an analysis of two nationwide observational studies from 2008 to 2015. We conducted two questionnaire surveys for representative samples of nurses in designated cancer hospitals, community hospitals, and district nurse services. The measurements used the Palliative Care Knowledge Test (PCKT, range 1-100), the Palliative Care Difficulties Scale (PCDS, range 1-5), and the Palliative Care Self-Reported Practice Scale (PCPS, range 1-5). Comparisons were made using the nonpaired Student t-test and a multivariate linear regression model using two cohorts. RESULTS: We analyzed survey results for 2707 nurses in 2008 and 3649 nurses in 2015. Significant improvements were seen in PCKT, PCDS, and PCPS total scores for nurses in every work location over the seven-year study period, with PCKT total scores of 53 vs. 65 (P < 0.001; effect size = 0.60), 47 vs. 55 (P < 0.001; effect size = 0.40), and 52 vs. 55 (P = 0.118; effect size = 0.13), PCDS total scores of 3.0 vs. 2.5 (P < 0.001; effect size = 0.76), 3.4 vs. 2.8 (P < 0.001, effect size = 0.91), and 3.2 vs. 2.9 (P < 0.001; effect size = 0.53), and PCPS total scores of 3.7 vs. 4.0 (P < 0.001; effect size = 0.13), 3.5 vs. 3.8 (P < 0.001; effect size = 0.42), and 3.8 vs. 4.0 (P < 0.011; effect size = 0.21) in designated cancer hospitals, community hospitals, and district nurse services, respectively. CONCLUSION: Nurses' palliative care knowledge, difficulties, and self-reported practices improved over the seven-year study period, especially in terms of expert support in designated cancer hospitals and knowledge among nurses in designated cancer hospitals. PMID- 28919541 TI - Drugs for Treating Opioid-Induced Constipation: A Mixed Treatment Comparison Network Meta-analysis of Randomized Controlled Clinical Trials. AB - CONTEXT: Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics. OBJECTIVES: The objective of this study was to compare available interventions for the treatment of opioid-induced constipation, using principles of network meta-analysis. METHODS: Electronic databases were searched for randomized controlled clinical trials evaluating drugs used in opioid-induced constipation. Number of patients with rescue-free bowel movements (RFBM) was the primary outcome, and time for achieving RFBM, adverse events, and changes in the analgesic activity of the opioid analgesics were the secondary outcomes. Inverse variance heterogeneity model was used for direct and mixed treatment comparison analysis. Odds ratio for categorical outcomes and weighted mean difference for numerical outcomes were the effect estimates. RESULTS: We included a total of 23 studies in the systematic review and 21 in the network meta-analysis. Lubriprostone, prucalopride, naldemedine, naloxegol, alvimopan, subcutaneous, and oral methyl naltrexone were observed to perform better than placebo in terms of RFBM. Additionally, subcutaneous methyl naltrexone was significantly better than lubiprostone, naloxegol, oral methyl naltrexone, and prucalopride. Lubiprostone and naldemedine were associated with increased risks of adverse events. Subcutaneous methyl naltrexone did not significantly affect the analgesia due to background opioid use. Quality of evidence for the comparisons is either low or very low. CONCLUSION: Subcutaneous methyl naltrexone was found to perform better than other interventions for managing opioid-induced constipation. PMID- 28919542 TI - Ageing reduces light touch and vibrotactile sensitivity on the anterior lower leg and foot dorsum. AB - Cutaneous mechanoreceptors in the anterior lower leg and foot dorsum provide important information about contact with objects and movement at the knee and ankle. This cutaneous feedback contributes to static and dynamic balance control. We conducted experiment 1 to determine the effects of ageing on anterior lower leg cutaneous feedback. We measured light touch (monofilament) perceptual thresholds (MPT) at seven skin sites across the anterior lower leg and foot dorsum in 12 young (5 male, aged 21-28) and 13 older adults (8 male, aged 73-92). Results showed that older adults had ~5.5* higher MPTs across these skin sites. We conducted experiment 2 to probe how different cutaneous mechanoreceptor subtypes are affected by ageing through measures of vibrotactile perceptual threshold (VPT) at 3, 15, and 40Hz at six skin sites across the anterior lower leg and foot dorsum in 10 young (5 male, aged 21-26) and 10 older adults (3 male, aged 75-85). In this group, we also assessed functional balance using the timed up-and-go (TUG) and functional reach test (FRT). Older adults demonstrated significantly higher VPTs overall, and this effect was largest at 40Hz - a frequency primarily transmitted by fast adapting cutaneous afferents. Furthermore, higher thresholds at each frequency tended to correlate with poorer performance on the TUG within the older adult group (3Hz: r=0.550; 15Hz: r=0.689; 40Hz: r=0.663). These results suggest ageing influences cutaneous feedback from regions of the lower leg that provide important information about movement and contact. PMID- 28919543 TI - Correlation of echographic and photographic assessment of optic nerve head cupping in children. AB - PURPOSE: To determine the diagnostic value of B-scan echography in optic nerve head (ONH) cupping estimation in children. METHODS: The medical records of pediatric patients who had previously undergone examination under anesthesia and for whom both adequate B-scan echography images and optic nerve head (ONH) photographs and were available were reviewed retrospectively. The cup:disk ratio was estimated with a grading scale of 0-1.0 and rounded to the nearest tenth; degree of cupping was estimated from B-scan echography (small, medium, or large) by 5 masked graders (3 glaucoma specialists and 2 ophthalmic sonographers) on 2 separate occasions. Inter- and intraobserver agreement in echographic and photographic cupping assessment by the masked graders as well as correlation of echographic and photographic cup size estimation was evaluated. RESULTS: A total of 36 children were included. Glaucoma specialists reliably assessed cup:disk ratio with moderately good consistency across specialists (average intraclass correlation coefficient [ICC] for intraobserver agreement, 0.86; average ICC for interobserver agreement, 0.71). Sonographers were extremely reliable in assessment of cup size when examining echographic images (ICC for both inter- and intrarater variability, 1.0). Echographic estimate of cup size correlated poorly with cup:disk ratio (ICC, 0.34). CONCLUSIONS: B-scan echography is a reliable and consistent diagnostic tool in estimating the degree of ONH cupping in children and can be very useful in patients in whom direct visualization is not feasible. Failure to account for disk size may have contributed to the poor correlation between echographic cup size and photographic cup:disk ratio. PMID- 28919544 TI - Increased Level of Interleukin 6 Associates With Increased 90-Day and 1-Year Mortality in Patients With End-Stage Liver Disease. AB - BACKGROUND & AIMS: Organ allocation for liver transplantation is based on prognosis, using the model for end-stage liver disease (MELD) or MELD including serum sodium (MELD-Na) score. These scores do not consider systemic inflammation and septic complications. Blood level of C-reactive protein (CRP), in addition to the MELD score, associates with mortality in patients with end-stage liver disease, whereas levels of interleukin 6 (IL6) have not been systematically studied. METHODS: We performed a retrospective observational cohort study of 474 patients with end-stage liver disease (63.5% male; median age, 56.9 years), evaluated for liver transplantation in Germany, with at least 1 year of follow up. Data were collected on blood levels of CRP, IL6, and white blood cell count (WBC). Findings were analyzed in relation to mortality and compared with patients' MELD scores and MELD-Na scores. For survival analysis, the cohort was divided into quartiles of IL6, CRP, and WBC levels, as well as MELD scores. Log rank test and the Cox proportional hazards regression model were used to compare the groups, and area under the receiver operating characteristic (AUROC) values were calculated. RESULTS: Blood levels of IL6 and MELD scores associated with mortality: none of the patients with levels of IL6 below the first quartile (below 5.3 pg/mL) died within 1 year. In contrast, 67.7% of the patients in the highest quartile of IL6 level (37.0 pg/mL or more) died within 1 year. MELD score also correlated with mortality: among patients with MELD scores below 8.7, 0.9% died within 1 year, whereas in patients with MELD scores of 18.0 or more, 67.4% died within 1 year. The predictive value of level of IL6 (AUROC, 0.940) was higher than level of CRP (AUROC, 0.866) (P = .009) or WBC (AUROC, 0.773) (P < .001) for 90-day mortality. MELD scores associated with 90-day mortality (AUROC, 0.933) (P = .756) as did MELD-Na score (AUROC, 0.946) (P = .771). Level of IL6 associated with 1-year mortality (AUROC, 0.916) to a greater extent than liver synthesis or detoxification markers international normalized ratio (AUROC, 0.839) (P = .007) or bilirubin (AUROC 0.846) (P = .007). Level of IL6 was an independent, significant risk factor for mortality after adjustment for MELD score, MELD-Na score, level of CRP, or WBC. CONCLUSIONS: In a retrospective analysis, we found high blood levels of IL6 to associate with 90-day and 1-year mortality in patients with end-stage liver disease; its predictive value was comparable to that of MELD or MELD-Na score, and was higher than that of level of CRP or WBC. Further studies should be performed to confirm the results in different cohorts. PMID- 28919545 TI - Mechanisms behind TB, HBV, and HIV chronic infections. AB - Immune evasion is critical for pathogens to maintain their presence within hosts, giving rise to chronic infections. Here, we examine the immune evasion strategies employed by three pathogens with high medical burden, namely, tuberculosis, HIV and HBV. Establishment of chronic infection by these pathogens is a multi-step process that involves an interplay between restriction factor, innate immunity and adaptive immunity. Engagement of these host defences is intimately linked with specific steps within the pathogen replication cycles. Critical host factors are increasingly recognized to regulate immune evasion and susceptibility to disease. Fuelled by innovative technology development, the understanding of these mechanisms provides critical knowledge for rational design of vaccines and therapeutic immune strategies. PMID- 28919546 TI - Phylodynamics of the Brazilian feline immunodeficiency virus. AB - Feline immunodeficiency virus (FIV), like other retroviruses, displays large genomic divergence when different isolates are compared. In this study, 31 FIV positive samples of domestic cats from Porto Alegre, RS, Brazil were used aiming at a detailed genomic characterization and a better understanding of the molecular epidemiology of the virus in Brazil. The proviral env genes were partially amplified, sequenced and compared with another 237 sequences from different continents. We identified several Brazilian highly supported clades (A, B1, B2, C and D) that suggest independent events of introduction of FIV in Brazil. Forty six reference-sequences from the GenBank were used with our 31 sequences to infer the virus subtypes. Our sequences belong to the subtype B and three of them result from a recombination with the previously described subtype F. The other 28 Brazilian samples belonging to subtype B and another 46 Brazilian sequences from the GenBank were used to estimate the time to the most recent common ancestor of each Brazilian clade, using a Bayesian approach and a relaxed molecular clock model. The analyses of Brazilian sequences suggest several different entries of the virus in the Brazilian cat population between 1981 and 1991. PMID- 28919547 TI - Deep-sequencing to resolve complex diversity of apicomplexan parasites in platypuses and echidnas: Proof of principle for wildlife disease investigation. AB - The short-beaked echidna (Tachyglossus aculeatus) and the platypus (Ornithorhynchus anatinus) are iconic egg-laying monotremes (Mammalia: Monotremata) from Australasia. The aim of this study was to demonstrate the utility of diversity profiles in disease investigations of monotremes. Using small subunit (18S) rDNA amplicon deep-sequencing we demonstrated the presence of apicomplexan parasites and confirmed by direct and cloned amplicon gene sequencing Theileria ornithorhynchi, Theileria tachyglossi, Eimeria echidnae and Cryptosporidium fayeri. Using a combination of samples from healthy and diseased animals, we show a close evolutionary relationship between species of coccidia (Eimeria) and piroplasms (Theileria) from the echidna and platypus. The presence of E. echidnae was demonstrated in faeces and tissues affected by disseminated coccidiosis. Moreover, the presence of E. echidnae DNA in the blood of echidnas was associated with atoxoplasma-like stages in white blood cells, suggesting Hepatozoon tachyglossi blood stages are disseminated E. echidnae stages. These next-generation DNA sequencing technologies are suited to material and organisms that have not been previously characterised and for which the material is scarce. The deep sequencing approach supports traditional diagnostic methods, including microscopy, clinical pathology and histopathology, to better define the status quo. This approach is particularly suitable for wildlife disease investigation. PMID- 28919548 TI - Reconsidering the classification of tick-borne encephalitis virus within the Siberian subtype gives new insights into its evolutionary history. AB - Tick-borne encephalitis is widespread in Eurasia and transmitted by Ixodes ticks. Classification of its causative agent, tick-borne encephalitis virus (TBEV), includes three subtypes, namely Far-Eastern, European, and Siberian (TBEV-Sib), as well as a group of 886-84-like strains with uncertain taxonomic status. TBEV Sib is subdivided into three phylogenetic lineages: Baltic, Asian, and South Siberian. A reason to reconsider TBEV-Sib classification was the analysis of 186 nucleotide sequences of an E gene fragment submitted to GenBank during the last two years. Within the South-Siberian lineage, we have identified a distinct group with prototype strains Aina and Vasilchenko as an individual lineage named East Siberian. The analysis of reclassified lineages has promoted a new model of the evolutionary history of TBEV-Sib lineages and TBEV-Sib as a whole. Moreover, we present arguments supporting separation of 886-84-like strains into an individual TBEV subtype, which we propose to name Baikalian (TBEV-Bkl). PMID- 28919550 TI - Improving the genotyping resolution of Cryptosporidium hominis subtype IbA10G2 using one step PCR-based amplicon sequencing. AB - Cryptosporidium hominis gp60 subtype IbA10G2 is a common cause of cryptosporidiosis. This subtype is responsible for many waterborne outbreaks as well as sporadic cases and is considered virulent and highly important in the epidemiology of cryptosporidiosis. Due to low heterogeneity within the genome of C. hominis it has been difficult to identify epidemiological markers with higher resolution than gp60. However, new markers are required in order to improve outbreak investigations and studies of the transmission dynamics of this clinically important subtype. Based on the whole genome sequences of 17 C. hominis isolates, we have identified several differential loci and developed a new sequence based typing panel with higher resolution than gp60. An amplicon sequencing method was also developed which is based on a one-step PCR which can be sequenced using a Next Generation Sequencing (NGS) platform. Such a system provides a rapid and high-throughput workflow. A panel of nine loci with 10 single nucleotide variants (SNV) was selected and evaluated using clinical IbA10G2 isolates from sporadic, cluster and outbreak associated cases. The specimens were separated into 10 different genetic profiles named sequence types (STs). All isolates within an outbreak or cluster belonged to the same ST, including several samples from the two large waterborne outbreaks which occurred in Sweden between 2010 and 2011 indicating that these outbreaks might be linked. The results demonstrate the methods suitability for improved genotyping of C. hominis IbA10G2. PMID- 28919549 TI - The predominance of Ethiopian specific Mycobacterium tuberculosis families and minimal contribution of Mycobacterium bovis in tuberculous lymphadenitis patients in Southwest Ethiopia. AB - BACKGROUND: Ethiopia has an extremely high rate of extrapulmonary tuberculosis, dominated by tuberculous lymphadenitis (TBLN). However, little is known about Mycobacterium tuberculosis complex (MTBc) lineages responsible for TBLN in Southwest Ethiopia. METHODS: A total of 304 MTBc isolates from TBLN patients in Southwest Ethiopia were genotyped primarily by spoligotyping. Isolates of selected spoligotypes were further analyzed by 15-loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) (n=167) and qPCR-based single nucleotide polymorphism (n=38). Isolates were classified into main phylogenetic lineages and families by using the reference strain collections and identification tools available at MIRU-VNTRplus data base. Resistance to rifampicin was determined by Xpert MTB/RIF. RESULTS: The majority of isolates (248; 81.6%) belonged to the Euro-American lineage (Lineage 4), with the ill defined T and Haarlem as largest families comprising 116 (38.2%) and 43 (14.1%) isolates respectively. Of the T family, 108 isolates were classified as being part of the newly described Ethiopian families, namely Ethiopia_2 (n=44), Ethiopia_3 (n=34) and Ethiopia_H37Rv-like (n=30). Other sub-lineages included URAL (n=18), S (n=17), Uganda I (n=16), LAM (n=13), X (n=5), TUR (n=5), Uganda II (n=4) and unknown (n=19). Lineage 3 (Delhi/CAS) was the second most common lineage comprising 44 (14.5%) isolates. Interestingly, six isolates (2%) were belonged to Lineage 7, unique to Ethiopia. Lineage 1 (East-African Indian) and Lineage 2 (Beijing) were represented by 3 and 1 isolates respectively. M. bovis was identified in only two (0.7%) TBLN cases. The cluster rate was highest for Ethiopia_3 isolates showing clonal similarity with isolates from North Ethiopia. Lineage 3 was significantly associated with rifampicin resistance. CONCLUSIONS: In TBLN in Southwest Ethiopia, the recently described Ethiopia specific Lineage 4 families were predominant, followed by Lineage 3 and Lineage 4-Haarlem. The contribution of M. bovis in TBLN infection is minimal. PMID- 28919551 TI - Identification of potential antigens from non-classically secreted proteins and designing novel multitope peptide vaccine candidate against Brucella melitensis through reverse vaccinology and immunoinformatics approach. AB - Brucella melitensis is an intracellular pathogen resides in the professional and non-professional phagocytes of the host, causing zoonotic disease brucellosis. The stealthy nature of the Brucella makes it's highly pathogenic, and it is hard to eliminate the bacteria completely from the infected host. Hitherto, no licensed vaccines are available for human brucellosis. In this study, we identified potential antigens for vaccine development from non-classically secreted proteins through reverse vaccinology approach. Based on the systemic screening of non-classically secreted proteins of B. melitensis 16M, we identified nine proteins as potential vaccine candidates. Among these, Omp31 and Omp22 are known immunogens, and its role in the virulence of Brucella is known. Roles of other proteins in the pathogenesis are yet to be studied. From the nine proteins, we identified six novel antigenic epitopes that can elicit both B-cell and T-cell immune responses. Among the nine proteins, the epitopes were predicted from Omp31 immunogenic protein precursor, Omp22 protein precursor, extracellular serine protease, hypothetical membrane-associated protein, iron-regulated outer membrane protein FrpB. Further, we designed a multitope vaccine using Omp31 immunogenic protein precursor, Omp22 protein precursor, extra cellular serine protease, iron-regulated outer membrane protein FrpB, hypothetical membrane associated protein, and LPS-assembly protein LptD and polysaccharide export protein identified in the previous study. Epitopes were joined using amino acid linkers such as EAAAK and GPGPG. Cholera toxin subunit B, the nontoxic part of cholera toxin, was used as an adjuvant and it was linked to the N-terminal of the multitope vaccine candidate. The designed vaccine candidate was modeled, validated and the physicochemical properties were analyzed. Results revealed that the vaccine candidate is soluble, stable, non-allergenic, antigenic and 87% of residues of the designed vaccine candidate is located in the favored region. In conclusion, the computational analysis showed that the newly designed multitope protein could be used to develop a promising vaccine for human brucellosis. PMID- 28919552 TI - Accurate identification of Anopheles gambiae Giles trophic preferences by MALDI TOF MS. AB - The determination of the trophic preferences of the Anopheles gambiae Giles (Diptera: Culicidae) is a decisive parameter for the monitoring and the prevention of malaria risk transmission. Currently, arthropod blood feeding sources are identified using immunological or molecular biology traditional techniques. Despite the effectiveness of these methods, they present several limitations, and notably, they are time-consuming and costly techniques. A recent study demonstrated that MALDI-TOF MS could be a useful tool for the identification of blood meal origins in freshly engorged mosquitoes. However, the limited number of blood vertebrate species tested to date, did not allow an assessment of the efficiency of MALDI-TOF MS in distinguishing blood MS spectra among close host species, such as humans versus primates. Therefore, in the present study, blood from ten distinct vertebrate host species, including four domestic species, four wild species, and two primates, was selected to control the reliability of MALDI-TOF MS based identification. Host blood species-specific MS profiles, up to 24h post-feeding in engorged Anopheles abdomens, were confirmed. Blind tests underlined the high specificity of MS spectra for the recognition of each host species, preventing misidentification. Nevertheless, an accurate analysis of the results from MS spectra queried against the MS database revealed that the reliability of identification is directly linked to the comprehensiveness of the MS reference database. Finally, the rapidity, the low cost reagents, the simplicity of data analysis, and the accuracy of the tool for blood origin determination, make this proteomic strategy a promising complementary method for the elucidation of host/vector interactions. PMID- 28919554 TI - Revisiting the wandering womb: Oxytocin in endometriosis and bipolar disorder. AB - Hippocrates attributed women's high emotionality - hysteria - to a 'wandering womb'. Although hysteria diagnoses were abandoned along with the notion that displaced wombs cause emotional disturbance, recent research suggests that elevated levels of oxytocin occur in both bipolar disorder and endometriosis, a gynecological condition involving migration of endometrial tissue beyond the uterus. We propose and evaluate the hypothesis that elevated oxytocinergic system activity jointly contributes to bipolar disorder and endometriosis. First, we provide relevant background on endometriosis and bipolar disorder, and then we examine evidence for comorbidity between these conditions. We next: (1) review oxytocin's associations with personality traits, especially extraversion and openness, and how they overlap with bipolar spectrum traits; (2) describe evidence for higher oxytocinergic activity in both endometriosis and bipolar disorder; (3) examine altered hypothalamic-pituitary-gonadal axis functioning in both conditions; (4) describe data showing that medications that treat one condition can improve symptoms of the other; (5) discuss fitness-related impacts of endometriosis and bipolar disorder; and (6) review a pair of conditions, polycystic ovary syndrome and autism, that show evidence of involving reduced oxytocinergic activity, in direct contrast to endometriosis and bipolar disorder. Considered together, the bipolar spectrum and endometriosis appear to involve dysregulated high extremes of normally adaptive pleiotropy in the female oxytocin system, whereby elevated levels of oxytocinergic activity coordinate outgoing sociality with heightened fertility, apparently characterizing, overall, a faster life history. These findings should prompt a re-examination of how mind-body interactions, and the pleiotropic endocrine systems that underlie them, contribute to health and disease. PMID- 28919553 TI - Social evaluative threat with verbal performance feedback alters neuroendocrine response to stress. AB - Laboratory stress tasks such as the Trier Social Stress Test (TSST) have provided a key piece to the puzzle for how psychosocial stress impacts the hypothalamic pituitary-adrenal axis, other stress-responsive biomarkers, and ultimately wellbeing. These tasks are thought to work through biopsychosocial processes, specifically social evaluative threat and the uncontrollability heighten situational demands. The present study integrated an experimental modification to the design of the TSST to probe whether additional social evaluative threat, via negative verbal feedback about speech performance, can further alter stress reactivity in 63 men and women. This TSST study confirmed previous findings related to stress reactivity and stress recovery but extended this literature in several ways. First, we showed that additional social evaluative threat components, mid-task following the speech portion of the TSST, were still capable of enhancing the psychosocial stressor. Second, we considered stress-reactive hormones beyond cortisol to include dehydroepiandrosterone (DHEA) and testosterone, and found these hormones were also stress-responsive, and their release was coupled with one another. Third, we explored whether gain- and loss framing incentive instructions, meant to influence performance motivation by enhancing the personal relevance of task performance, impacted hormonal reactivity. Results showed that each hormone was stress reactive and further had different responses to the modified TSST compared to the original TSST. Beyond the utility of showing how the TSST can be modified with heightened social evaluative threat and incentive-framing instructions, this study informs about how these three stress-responsive hormones have differential responses to the demands of a challenge and a stressor. PMID- 28919556 TI - Measuring inotocin receptor gene expression in chronological order in ant queens. AB - In vertebrates and invertebrates, oxytocin/vasopressin-like peptides modulate a variety of behaviors. The recent discovery of the gene and receptor sequences of inotocin, the insect ortholog of oxytocin/vasopressin, opens new opportunities for understanding the role of this peptide family in regulating behaviors in the most populated class of living animals. Ants live in highly organized colonies. Once a year, they produce future queens that soon leave the nest to mate and found new colonies. During the first months of their lives, ant queens display a sequence of behaviors ranging from copulation and social interactions to violent fighting. In order to investigate the potential roles of inotocin in shaping queen behavior, we measured gene expression of the inotocin receptor in the heads of Lasius niger ant queens at different points in time. The highest levels of expression occurred early in queen life when they experience crowded conditions in their mother nests and soon thereafter set out to mate. Inotocin could thus be involved in regulating social and reproductive behaviors as reported in other animals. While oxytocin and vasopressin are also involved in aggression in mammals, we found no direct link between these behaviors and inotocin receptor expression in L. niger. Our study provides a first glimpse into the roles the inotocin receptor might play in regulating important processes in ant physiology and behavior. Further studies are needed to understand the molecular function of this complex signaling system in more detail. PMID- 28919555 TI - Disturbances of systemic and hippocampal insulin sensitivity in macrophage migration inhibitory factor (MIF) knockout male mice lead to behavioral changes associated with decreased PSA-NCAM levels. AB - Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine well known for its role in inflammation enhancement. However, a growing body of evidence is emerging on its role in energy metabolism in insulin sensitive tissues such as hippocampus, a brain region implicated in cognition, learning and memory. We hypothesized that genetic deletion of MIF may result in the specific behavioral changes, which may be linked to impairments in brain or systemic insulin sensitivity by possible changes of the hippocampal synaptic plasticity. To assess memory, exploratory behavior and anxiety, three behavioral tests were applied on Mif gene-deficient (MIF-/-) and "wild type" C57BL/6J mice (WT). The parameters of systemic and hippocampal insulin sensitivity were also determined. The impact of MIF deficiency on hippocampal plasticity was evaluated by analyzing the level of synaptosomal polysialylated-neural cell adhesion molecule (PSA-NCAM) plasticity marker and mRNA levels of different neurotrophic factors. The results showed that MIF-/- mice exhibit emphasized anxiety-like behaviors, as well as impaired recognition memory, which may be hippocampus-dependent. This behavioral phenotype was associated with impaired systemic insulin sensitivity and attenuated hippocampal insulin sensitivity, characterized by increased inhibitory Ser307 phosphorylation of insulin receptor substrate 1 (IRS1). Finally, MIF-/- mice displayed a decreased hippocampal PSA-NCAM level and unchanged Bdnf, NT-3, NT-4 and Igf-1 mRNA levels. The results suggest that the lack of MIF leads to disturbances of systemic and hippocampal insulin sensitivity, which are possibly responsible for memory deficits and anxiety, most likely through decreased PSA NCAM-mediated neuroplasticity rather than through neurotrophic factors. PMID- 28919558 TI - Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis. AB - Recent evidence has established that extracellular vesicles (EVs), including exosomes and microvesicles, form an endogenous transport system through which biomolecules, including proteins and RNA, are exchanged between cells. This endows EVs with immense potential for drug delivery and regenerative medicine applications. Understanding the biology underlying EV-based intercellular transfer of cargo is of great importance for the development of EV-based therapeutics. Here, we sought to characterize the cellular mechanisms involved in EV uptake. Internalization of fluorescently-labeled EVs was evaluated in HeLa cells, in 2D (monolayer) cell culture as well as 3D spheroids. Uptake was assessed using flow cytometry and confocal microscopy, using chemical as well as RNA interference-based inhibition of key proteins involved in individual endocytic pathways. Experiments with chemical inhibitors revealed that EV uptake depends on cholesterol and tyrosine kinase activity, which are implicated in clathrin-independent endocytosis, and on Na+/H+ exchange and phosphoinositide 3 kinase activity, which are important for macropinocytosis. Furthermore, EV internalization was inhibited by siRNA-mediated knockdown of caveolin-1, flotillin-1, RhoA, Rac1 and PAK1, but not clathrin heavy chain. Together, these results suggest that EVs enter cells predominantly via clathrin-independent endocytosis and macropinocytosis. Identification of EV components that promote their uptake via pathways that lead to functional cargo transfer might allow development of more efficient therapeutics through EV-inspired engineering. PMID- 28919557 TI - Synergistic effects of dendritic cell targeting and laser-microporation on enhancing epicutaneous skin vaccination efficacy. AB - Due to its unique immunological properties, the skin is an attractive target tissue for allergen-specific immunotherapy. In our current work, we combined a dendritic cell targeting approach with epicutaneous immunization using an ablative fractional laser to generate defined micropores in the upper layers of the skin. By coupling the major birch pollen allergen Bet v 1 to mannan from S. cerevisiae via mild periodate oxidation we generated hypoallergenic Bet-mannan neoglycoconjugates, which efficiently targeted CD14+ dendritic cells and Langerhans cells in human skin explants. Mannan conjugation resulted in sustained release from the skin and retention in secondary lymphoid organs, whereas unconjugated antigen showed fast renal clearance. In a mouse model, Bet-mannan neoglycoconjugates applied via laser-microporated skin synergistically elicited potent humoral and cellular immune responses, superior to intradermal injection. The induced antibody responses displayed IgE-blocking capacity, highlighting the therapeutic potential of the approach. Moreover, application via micropores, but not by intradermal injection, resulted in a mixed TH1/TH17-biased immune response. Our data clearly show that applying mannan-neoglycoconjugates to an organ rich in dendritic cells using laser-microporation is superior to intradermal injection. Due to their low IgE binding capacity and biodegradability, mannan neoglycoconjugates therefore represent an attractive formulation for allergen-specific epicutaneous immunotherapy. PMID- 28919559 TI - Adipokinetic hormone receptor gene identification and its role in triacylglycerol mobilization and sexual behavior in the oriental fruit fly (Bactrocera dorsalis). AB - Energy homeostasis requires continuous compensation for fluctuations in energy expenditure and availability of food resources. In insects, energy mobilization is under control of the adipokinetic hormone (AKH) where it is regulating the nutritional status by supporting the mobilization of lipids. In this study, we characterized the gene coding for the AKH receptor (AKHR) and investigated its function in the oriental fruit fly (Bactrocera dorsalis) that is economically one of the most important pest insects of tropical and subtropical fruit. Bacdo-AKHR is a typical G protein-coupled receptor (GPCR) and phylogenetic analysis confirmed that Bacdo-AKHR is closely related to insect AKHRs from other species. When expressed in Chinese hamster ovary (CHO) cells, Bacdo-AKHR exhibited a high sensitivity and selectivity for AKH peptide (EC50 = 19.3 nM). Using qPCR, the developmental stage and tissue-specific expression profiles demonstrated that Bacdo-AKHR was highly expressed in both the larval and adult stages, and also specifically in the fat body and midgut of the adult with no difference in sex. To investigate the role of AKHR in B. dorsalis, RNAi assays were performed with dsRNA against Bacdo-AKHR in adult flies of both sexes and under starvation and feeding condition. As major results, the knockdown of this gene resulted in triacylglycerol (TAG) accumulation. With RNAi-males, we observed a severe decrease in their sexual courtship activity when starved, but there was a partial rescue in copulation when refed. Also in RNAi-males, the tethered-flight duration declined compared with the control group when starved, which is confirming the dependency on energy metabolism. In RNAi-females, the sexual behavior was not affected, but their fecundity was decreased. Our findings indicate an interesting role of AKHR in the sexual behavior of males specifically. The effects are associated with TAG accumulation, and we also reported that the conserved role of AKH-mediated system in B. dorsalis is nutritional state-dependent. Hence, we provided further understanding on the multiple functions of AKH/AKHR in B. dorsalis. PMID- 28919560 TI - The Influence of Parkinson Disease on Lumbar Decompression Surgery: A Retrospective Case Control Study. AB - BACKGROUND: Parkinson disease (PD) is a major risk factor during spine surgery, and its frequency is increasing as the population ages. The study aim was to examine the influence of PD specifically on lumbar decompression surgery. METHODS: A retrospective review was performed of all patients with PD who underwent elective lumbar decompression surgery at 2 university hospital departments between December 2003 and July 2016. For each patient, 2 controls without PD were selected randomly among those who were matched for sex and age and had a similar year of surgery (+/-3) and comorbidity profile. The main outcomes were complications and reoperation rate. RESULTS: The mean follow up was 1.2 +/- 1.6 years in the PD group (n = 36) and 1.4 +/- 2.1 years in the control group (n = 72). The overall complication rate was 47.2% in the PD group and 19.4% in the control group (P < 0.01). The reoperation rate was 27.8% in the PD group and 9.7% in the control group (P = 0.02). CONCLUSIONS: There is a significantly greater rate of perioperative complications in patients with PD undergoing elective decompression surgery. Although the difference in major complication rates was minimal, minor complications were more frequent in patients with PD. PMID- 28919561 TI - Implications of Antiangiogenic Therapy on Radiographic Assessment of Brain Tumors. PMID- 28919562 TI - Operative Management of Distal Anterior Cerebral Artery Aneurysms Through a Mini Anterior Interhemispheric Approach. AB - BACKGROUND: Distal anterior cerebral artery (DACA) aneurysms, also known as pericallosal artery aneurysms, are present in 1.5%-9% of all intracranial aneurysms. Here we characterize the important microsurgical anatomy of DACAs; describe the surgical approach to treating these aneurysms with a minimally invasive surgical technique, the mini anterior interhemispheric approach (MAIA); and examine the nuances of aneurysm clipping in this region. METHODS: This was a retrospective and descriptive analysis of a series of aneurysm surgeries performed at the National Institute of Neurology and Neurosurgery in Mexico City. Cadaveric dissections were used to demonstrate relevant cerebrovascular anatomy. We analyzed patient demographic data and aneurysm characteristics. Patients' neurologic grade was evaluated using the Hunt and Kosnik (H-K) scale, and surgical outcomes were evaluated using the Glasgow Outcome Scale (GOS). Other variables were analyzed using the chi2 test. RESULTS: We analyzed a total of 32 DACA aneurysms (10 nonruptured and 22 ruptured), representing 5.8% of all aneurysms. The study cohort was 64.3% females and 35.7% males. H-K grade II was the most frequent classification (32.4%); 42.8% of patients presented with a Fisher grade IV aneurysm. Aneurysm location was classified as supra-genu, genu, or infra-genu. Eight patients had multiple aneurysms, among which 50% were located at the bifurcation of the middle cerebral artery. CONCLUSIONS: Surgical clipping through a MAIA approach is an excellent treatment option for pericallosal artery aneurysms. PMID- 28919563 TI - Reading Between the Joints-Using Spinal Magnetic Resonance Imaging for Evaluation of Instability. PMID- 28919564 TI - Intraoperative Visualization of a Spinal Arachnoid Cyst Using Pyoktanin Blue. AB - BACKGROUND: Spinal arachnoid cysts (SACs) are filled with cerebrospinal fluid, and they include the arachnoid membrane, making it difficult to distinguish the walls of the cyst from the arachnoid membrane and excise the cyst as a lump. Here we report a technique for the intraoperative visualization of SACs, involving the use of pyoktanin blue. METHODS: Four patients with spinal intradural arachnoid cysts underwent total excision of the cysts between October 2016 and April 2017. In 1 case, magnetic resonance imaging revealed the cyst clearly, but in the other cases, the cysts were unclear. All cysts were injected with 1% pyoktanin blue (Wako Pure Chemical Industries, Osaka, Japan) diluted 500 times with physiological saline before excision. When it was difficult to distinguish the cyst from the normal arachnoid membrane, 1% pyoktanin blue diluted 1000 times with physiological saline was injected into both the cyst and the subarachnoid space, and the spread of the stain was observed. RESULTS: The cysts were better visualized after pyoktanin blue injection than before injection. When it was difficult to distinguish the cyst from the normal arachnoid space, pyoktanin blue injection was useful for judging the cyst space. There were no perioperative complications, and the patients' symptoms improved partially or completely after treatment. CONCLUSIONS: Our technique of pyoktanin blue injection into SACs could make their excision easy and safe. PMID- 28919565 TI - Treatment of Large or Giant Cavernous Aneurysm Associated with Persistent Trigeminal Artery: Case Report and Review of Literature. AB - BACKGROUND: Primitive trigeminal artery (PTA) is the most common anomaly of primitive carotid-basilar anastomosis and is associated with cerebrovascular anomalies, such as aneurysm. Large or giant cavernous aneurysm associated with PTA is rare, and the treatment strategies differ in comparison with large or giant aneurysm without PTA. In this article, we report an unusual case of a giant cavernous aneurysm associated with PTA and review treatment strategies for large or giant cavernous aneurysm associated with PTA. CASE DESCRIPTION: A 38-year-old woman suffered from double vision. Magnetic resonance imaging revealed a mass lesion in the left cavernous sinus, and magnetic resonance angiography showed a giant aneurysm at the cavernous portion of the left internal carotid artery, associated with PTA. Coil embolization, distal to the PTA, was scheduled after high-flow bypass on the same day. Computed tomography scan showed no definite infarction after treatment. A 3-dimensional computed tomography showed disappearance of the aneurysm and good patency of bypass and PTA. The patient experienced improvements in symptoms and was discharged without neurologic deficits (modified Rankin Scale 0). CONCLUSIONS: The treatment strategy for large or giant cavernous aneurysm associated with PTA is different from strategies used for large or giant cavernous aneurysm without PTA. Simple ligation of internal carotid artery is inadequate because the aneurysm is supplied through the PTA, from the vertebrobasilar system. Furthermore, the treatment strategy has to be revised according to whether the PTA can be occluded. Keeping in mind PTA preservation, an appropriate strategy should be selected. PMID- 28919566 TI - Predicting Short-Term Outcome After Surgery for Primary Spinal Tumors Based on Patient Frailty. AB - OBJECTIVE: Frailty, decreased physiologic reserve and increased vulnerability to stressors beyond what is expected for normal aging, is associated with increased risk of morbidity and mortality. The objective of this study was to develop a preoperative frailty index for patients undergoing surgery for primary spinal column tumors that predicts morbidity, mortality, and length of stay. METHODS: The Nationwide Inpatient Sample database from 2002 to 2011 was used to identify patients who underwent surgery for a primary spinal tumor. The spinal tumor frailty index, consisting of 9 items, was applied to each patient. Patients were characterized as "not frail" (0), "mildly frail" (1), "moderately frail" (2), and "severely frail" (>=3). RESULTS: Inclusion criteria were met by 1589 patients. Overall major complication rate was 10.6%. Compared with patients without frailty, patients with mild (odds ratio 3.83; 95% confidence interval, 2.63 5.58), moderate (odds ratio 6.80; 95% confidence interval, 4.10-11.3), and severe frailty (odds ratio 13.05; 95% confidence interval, 6.34-26.87) had significantly increased odds of developing complications (all P < 0.001). Mean length of stay was 6.4 days +/- 0.2, 9.8 days +/- 0.6, 14.4 days +/- 1.7, and 18.3 days +/- 2.6 for patients without frailty, with mild frailty, with moderate frailty, and with severe frailty (P < 0.05 between all groups). CONCLUSIONS: Compared with patients without frailty, patients with mild, moderate, and severe frailty had significantly increased odds of developing postoperative complications. Systematic evaluation of preoperative frailty should play a key role in decision making for patients undergoing surgery for primary spinal tumors. PMID- 28919567 TI - Photoacoustic Imaging for Maximizing Glioma Resection. PMID- 28919568 TI - Robotic Stereotactic Assistance (ROSA) Utilization for Minimally Invasive Placement of Intraparenchymal Hematoma and Intraventricular Catheters. AB - BACKGROUND: In patients with supratentorial spontaneous intracerebral hemorrhage, intrahematomal catheter placement may allow for intraclot thrombolysis and drainage. Robotic assistance may be used for the stereotactic placement of catheters. CASE DESCRIPTION: A 76-year-old male presented with altered mental status and left-sided weakness. Noncontrast computed tomography of the head showed a right ganglionic intraparenchymal hemorrhage with resultant entrapment of the temporal horn. Using Robotic Stereotactic Assistance, intrahematomal and intraventricular catheters were placed. The temporal horn was immediately decompressed, and the hematoma almost completely resolved with scheduled administration of intrathecal alteplase in the ensuing 48 hours postoperatively. CONCLUSION: Frameless image-guided placement of intraparenchymal hematoma catheter using Robotic Stereotactic Assistance is safe and efficient. PMID- 28919569 TI - Spontaneous Hemorrhagic Glioblastoma Revealed by Arterial Spin Labeling. AB - We report a case of hemorrhagic tumor detected early by pseudocontinuous arterial spin labeling sequence when conventional magnetic resonance imaging sequences were not contributive. PMID- 28919570 TI - Initial Clinical Experience with AView-A Clinical Computational Platform for Intracranial Aneurysm Morphology, Hemodynamics, and Treatment Management. AB - BACKGROUND: The management of intracranial aneurysm (IA) is challenging. Clinicians often rely on varied and intuitively disparate ways of evaluating rupture risk that may only partially take into account complex hemodynamic and morphologic factors. We developed a prototype of a clinically oriented, streamlined, computational platform, AView, for rapid assessment of hemodynamics and morphometrics in clinical settings. To show the potential clinical utility of AView, we report our initial multicenter experience highlighting the possible advantages of morphologic and hemodynamic analysis of IAs. METHODS: AView software was deployed across 8 medical centers (6 in the United States, 2 in Japan). Eight clinicians were trained and used the AView software between September 2012 and January 2013. RESULTS: We present 12 illustrative cases that show the potential clinical utility of AView. For all, morphology and hemodynamics, flow visualization, and rupture resemblance score (a surrogate for rupture risk) were provided. In 3 cases, AView could confirm the clinicians' decision to treat; in 3 cases, it could suggest which aneurysms may be at greater risk among multiple aneurysms; in 5 cases, AView could provide additional information for use during treatment decisions for ambiguous situations. In one stent-assisted coiling case, flow visualization predicted that the intuitive choice for stent placement could have resulted in sacrifice of an anterior cerebral artery due to blockage by coils and led clinicians to reconsider treatment plans. CONCLUSIONS: AView has the potential to confirm decisions to treat IAs, suggest which among multiple aneurysms to treat, and guide treatment decisions. Furthermore, the flow visualization it affords can inform aneurysm treatment planning and potentially avoid poor outcomes. PMID- 28919571 TI - Reasons Why Children and Adolescents With Attention-Deficit/Hyperactivity Disorder Stop and Restart Taking Medicine. AB - OBJECTIVE: To describe the prevalence of reasons why children and adolescents stop and restart attention-deficit/hyperactivity disorder (ADHD) medicine and whether functional impairment is present after stopping medicine. METHODS: We used the prospective longitudinal cohort from the Multimodal Treatment of Study of Children With ADHD. At the 12-year follow-up, when participants were a mean of 21.1 years old, 372 participants (76% male, 64% white) reported ever taking ADHD medicine. Participants reported the age when they last stopped and/or restarted ADHD medicine and also endorsed reasons for stopping and restarting. RESULTS: Seventy-seven percent (286 of 372) reported stopping medicine for a month or longer at some time during childhood or adolescence. Participants were a mean of 13.3 years old when they last stopped medicine. The most commonly endorsed reasons for stopping medication related to 1) medicine not needed/helping, 2) adverse effects, 3) logistical barriers of getting or taking medication, and 4) social concerns or stigma. Seventeen percent (64 of 372) reported restarting medicine after stopping for a month or longer. Commonly endorsed reasons for restarting related to medicine being needed or medicine helping; and resolution of logistical barriers to getting or taking medicine. For both stopping and restarting, the proportion endorsing some reasons differed by age range, with the overall pattern suggesting that parental involvement in decisions decreased with age. Nearly all participants had impairment at the assessment after stopping, regardless of whether medication was resumed. CONCLUSIONS: Different reasons for stopping and/or restarting medicine are relevant at different times for different teens. Tailored strategies may help engage adolescents as full partners in their treatment plan. PMID- 28919573 TI - The Significance of Unknown Significance. PMID- 28919572 TI - Latino Parents' Perceptions of Pediatric Weight Counseling Terms. AB - OBJECTIVE: Little is known about Latino parents' perceptions of weight-related language in English or Spanish, particularly for counseling obese youth. We sought to identify English and Spanish weight counseling terms perceived by Latino parents across demographic groups as desirable for providers to use, motivating, and inoffensive. METHODS: Latino parents of children treated at urban safety-net clinics completed surveys in English or Spanish. Parents rated the desirable, motivating, or offensive properties of terms for excess weight using a 5-point scale. We compared parental ratings of terms and investigated the association of parent and child characteristics with parent perceptions of terms. RESULTS: A total of 525 surveys met inclusion criteria (255 English, 270 Spanish). English survey respondents rated "unhealthy weight" and "too much weight for his/her health" the most motivating and among the most desirable and least offensive terms. Spanish survey respondents found "demasiado peso para su salud" highly desirable, highly motivating, and inoffensive, and respondents valued its connection to the child's health. Commonly used clinical terms "overweight"/"sobrepeso" and "high BMI [body mass index]"/"indice de masa corporal alta" were not as desirable or as motivating. "Chubby," "fat," "gordo," and "muy gordo" were the least motivating and most offensive terms. Parents' ratings of commonly used clinical terms varied widely across demographic groups, but more desirable terms had less variability. CONCLUSIONS: "Unhealthy weight," "too much weight for his/her health," and its Spanish equivalent, "demasiado peso para su salud," were the most desirable and motivating, and the least offensive terms. Latino parents' positive perceptions of these terms occurred across parent and child characteristics, supporting their use in weight counseling. PMID- 28919574 TI - Variation in Generational Perceptions of Child Health and Well-being. AB - OBJECTIVE: To assess adults' perceptions regarding the health and well-being of children today relative to their own health and well-being as youth and the potential for intergenerational differences in those perceptions. METHODS: A cross-sectional, Internet-based survey of a nationally representative household sample was conducted using GfK Custom Research's Web-enabled KnowledgePanel, a probability-based panel representative of the US population. We assessed perceptions of children's health and well-being today compared to when respondents were growing up, including physical and mental health; and children's education, exercise, diet, health care, safety of communities, and emotional support from families, groups, and organizations. RESULTS: Overall, 1330 (65%) of 2047 adult respondents completed the survey. Only 26% of respondents believed that the current physical health of children, and 14% that the current mental health of children, is better today than when they were growing up. There was a significant trend among generations, with a greater proportion of older generations perceiving the physical health of children to be better today. Only 15% of respondents reported the chances for a child to grow up with good mental health in the future are "better" now than when they were growing up. CONCLUSIONS: Adults across all generations in the United States today view children's health as unlikely to meet the goals of the American Dream of continuous improvement. Although demographic changes require continued focus on our aging population, we must equally recognize the importance of advancing a healthy future for our nation's children, who will assume the mantle of our future. PMID- 28919576 TI - Simulation of the effects of oxygen carriers and scaffold geometry on oxygen distribution and cell growth in a channeled scaffold for engineering myocardium. AB - This study proposes a mathematical model to evaluate the impact of oxygen carriers and scaffold geometry on oxygen distribution and cell growth in a 3D cardiac construct using computational fluid dynamics (CFD). Flow equations, oxygen balance equation and cell balance equation were solved using special initial and boundary conditions. The modeling results revealed that 55% increase in cardiac cell density occurred by using 6.4% perfluorocarbon oxygen carrier (PFC) compared to pure culture medium without PFC supplementation. Moreover, the effects of the scaffold geometry on cell density were examined by changing the channel numbers and the construct length. A 30% increase in the average cells density was observed by increasing the channel numbers from 37 to 145. Furthermore, the average cell density was increased 23% by decreasing the scaffold length from 0.5 to 0.2 cm length. Overall, the average cell density of cardiac cells can be increased 2-fold by using PFC oxygen carrier and optimizing the scaffold's geometry, simultaneously. PMID- 28919575 TI - An integrative model of prostate cancer interaction with the bone microenvironment. AB - Despite advanced efforts in early diagnosis, aggressive surgical treatment, and use of targeted chemotherapies, the prognosis for many cancers is still dismal. This emphasizes the necessity to develop new strategies for understanding tumor growth and metastasis. Here we use a systems approach that combines mathematical modeling and numerical simulation to develop a predictive computational model for prostate cancer and its subversion of the bone microenvironment. This model simulates metastatic prostate cancer evolution, progressing from normal bone and hormone levels to quantifiable diseased states. The simulations clearly demonstrate phenomena similar to those found clinically in prostate cancer patients. In addition, the major prediction of this model is the existence of low and high osteogenic states that are markedly different from one another. The existence and potential realization of these steady states appear to be mediated by the Wnt signaling pathway and by the effects of PSA on TGF-beta, which encourages the bone microenvironment to evolve. The model is used to explore several potential therapeutic strategies, with some potential drug targets showing more promise than others: in particular, completely blocking Wnt and greatly increasing DKK-1 had significant positive effects, while blocking RANKL did not improve the outcome. PMID- 28919577 TI - Some properties of three alphaB-crystallin mutants carrying point substitutions in the C-terminal domain and associated with congenital diseases. AB - Physico-chemical properties of G154S, R157H and A171T mutants of alphaB crystallin (HspB5) associated with congenital human diseases including certain myopathies and cataract were investigated. Oligomers formed by G154S and A171T mutants have the size and apparent molecular weight indistinguishable from those of the wild-type HspB5, whereas the size of oligomers formed by R157H mutant is slightly smaller. All mutants are less thermostable and start to aggregate at a lower temperature than the wild-type protein. All mutants effectively interact with a triple phosphomimicking mutant of HspB1 and form large heterooligomeric complexes of similar composition. All mutants interact with HspB6 forming heterooligomeric complexes with size and composition dependent on the molar ratio of two proteins. The wild-type HspB5 and its G154S and A171T mutants form only high molecular weight (300-450 kDa) heterooligomeric complexes with HspB6, whereas the R157H mutant forms both high and low (~120 kDa) molecular weight complexes. The wild-type HspB5 and its G154S and A171T mutants form two types of heterooligomers with HspB4, whereas R157H mutant effectively forms only one type of heterooligomers with HspB4. G154S and A171T mutants have lower chaperone-like activity than the wild-type protein when subfragment S1 of myosin or betaL crystallin are used as a model substrates. With these substrates, the R157H mutant shows equal or higher chaperone activity than the wild-type HspB5. We hypothesize that the mutations in the C-terminal region modulate the binding of the IP(I/V) motif to the core alpha-crystallin domain. The R157H mutation is located in the immediate proximity of this motif. Such modulation could cause altered interaction of HspB5 with partners and substrates and eventually lead to pathological processes. PMID- 28919578 TI - Selectin-independent adhesion during ovarian cancer metastasis. AB - PURPOSE: Ovarian cancer (OvCa) progression mainly takes place by intraperitoneal spread. Adhesion of tumor cells to the mesothelial cells which form the inner surface of the peritoneum is a crucial step in this process. Cancer cells use in principle different molecules of the leukocyte adhesion cascade to facilitate adhesion. This cascade is initiated by selectin-ligand interactions followed by integrin - extracellular matrix protein interactions. Here we address the question whether all tumor cells predominantly employ selectin-dependent leukocyte-like adhesion cascade (SDAC) or whether they use integrin mediated adhesion for OvCa progression as well. METHODS: A comparative transcriptomic analysis of the human OvCa cell lines OVCAR8 and SKOV3 was performed. Intraperitoneal xenograft model of OVCAR8 cells was used to determine whether there is a correlation between SDAC gene expression and the metastatic potential of the control cells and the cells overexpressing c-Fos. Transcriptomic analysis of OVCAR8 and SKOV3 samples was performed using microarrays. RESULTS: One-third of the protein-coding genes involved in SDAC exhibited lower expression levels in OVCAR8 than in SKOV3 cells. In contrast to SKOV3 cells, c-Fos overexpression in OVCAR8 cells did not significantly influence the expression of SDAC genes. Intraperitoneal xenograft model of OVCAR8 cells unexpectedly demonstrated that the aggressiveness of OVCAR8 tumors was not depended on the c-Fos expression level and was comparable to that of SKOV3 control tumors. Gene expression analysis of tumors suggests that SKOV3-derived tumor progression was mainly depended on SDAC. Progression of OVCAR8 tumors relied on other cell adhesion molecules that do not interact with selectins. CONCLUSIONS: High expression of c Fos in ovarian cancer cells is not always associated with reduced metastatic potential. Low expression level of SDAC genes may not ensure low OvCa metastatic potential hence alternative adhesion mechanisms involving laminin-integrin interactions exist as well. PMID- 28919579 TI - MRI and Prediction of Pathologic Complete Response in the Breast and Axilla after Neoadjuvant Chemotherapy for Breast Cancer. AB - BACKGROUND: In the setting where determining extent of residual disease is key for surgical planning after neoadjuvant chemotherapy (NAC), we evaluate the reliability of MRI in predicting pathologic complete response (pCR) of the breast primary and axillary nodes after NAC. STUDY DESIGN: Patients who had MRI before and after NAC between June 2014 and August 2015 were identified in a prospective database after IRB approval. Post-NAC MRI of the breast and axillary nodes was correlated with residual disease on final pathology. Pathologic complete response was defined as absence of invasive and in situ disease. RESULTS: We analyzed 129 breast cancers. Median patient age was 50.8 years (range 27.2 to 80.6 years). Tumors were human epidermal growth factor receptor 2 amplified in 52 of 129 (40%), estrogen receptor-positive/human epidermal growth factor receptor 2 negative in 45 of 129 (35%), and triple negative in 32 of 129 (25%), with respective pCR rates of 50%, 9%, and 31%. Median tumor size pre- and post-NAC MRI were 4.1 cm and 1.45 cm, respectively. Magnetic resonance imaging had a positive predictive value of 63.4% (26 of 41) and negative predictive value of 84.1% (74 of 88) for in-breast pCR. Axillary nodes were abnormal on pre-NAC MRI in 97 patients; 65 had biopsy-confirmed metastases. The nodes normalized on post-NAC MRI in 33 of 65 (51%); axillary pCR was present in 22 of 33 (67%). In 32 patients with proven nodal metastases and abnormal nodes on post-NAC MRI, 11 achieved axillary pCR. In 32 patients with normal nodes on pre- and post-NAC MRI, 6 (19%) had metastasis on final pathology. CONCLUSIONS: Radiologic complete response by MRI does not predict pCR with adequate accuracy to replace pathologic evaluation of the breast tumor and axillary nodes. PMID- 28919580 TI - Concomitant Obesity and Metabolic Syndrome Add to the Atrial Arrhythmogenic Phenotype in Male Hypertensive Rats. AB - BACKGROUND: Besides hypertension, obesity and the metabolic syndrome have recently emerged as risk factors for atrial fibrillation. This study sought to delineate the development of an arrhythmogenic substrate for atrial fibrillation in hypertension with and without concomitant obesity and metabolic syndrome. METHODS AND RESULTS: We compared obese spontaneously hypertensive rats (SHR obese, n=7-10) with lean hypertensive controls (SHR-lean, n=7-10) and normotensive rats (n=7-10). Left atrial emptying function (MRI) and electrophysiological parameters were characterized before the hearts were harvested for histological and biochemical analyses. At the age of 38 weeks, SHR obese, but not SHR-lean, showed increased body weight and impaired glucose tolerance together with dyslipidemia compared with normotensive rats. Mean blood pressure was similarly increased in SHR-lean and SHR-obese when compared with normotensive rats (178+/-9 and 180+/-8 mm Hg [not significant] versus 118+/-5 mm Hg, P<0.01 for both), but left ventricular end-diastolic pressure was more increased in SHR-obese than in SHR-lean. Impairment of left atrial emptying function, increase in total atrial activation time, and conduction heterogeneity, as well as prolongation of inducible atrial fibrillation durations, were more pronounced in SHR-obese as compared with SHR-lean. Histological and biochemical examinations revealed enhanced triglycerides and more pronounced fibrosis in the left atrium of SHR-obese. Besides increased expression of profibrotic markers in SHR-lean and SHR-obese, the profibrotic extracellular matrix protein osteopontin was highly upregulated only in SHR-obese. CONCLUSIONS: In addition to hypertension alone, concomitant obesity and metabolic syndrome add to the atrial arrhythmogenic phenotype by impaired left atrial emptying function, local conduction abnormalities, interstitial atrial fibrosis formation, and increased propensity for atrial fibrillation. PMID- 28919582 TI - Rapamycin Inhibits Expansion of Cord Blood Derived NK and T Cell. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) is important in hematopoiesis. Despite the central role of mTOR in regulating the differentiation of immune cells, the effect of mTOR function on cord blood mononuclear cells is yet to be defined. OBJECTIVES: To evaluate the effect of mTOR inhibition, using rapamycin on the proliferation and apoptosis of cord blood mononuclear cells, as well as on the B and T cell expansion. METHODS: Cord blood mononuclear cells were cultured in the presence of IL-2, IL-7 and IL-15 cytokines and inhibited by rapamycin for 14 days. The harvested cells were evaluated at distinct time points by flow cytometry. RESULTS: The mTOR expression decreased in the presence of rapamycin on day 14. Inhibition of mTOR reduced the proliferation of the cord blood mononuclear cells, yet did not influence apoptosis. Moreover, the number of T and NK cells was significantly reduced in the presence of rapamycin, while no change was observed in the B cell expansion. CONCLUSION: mTOR signaling plays a crucial part in cord blood derived NK and T cells expansion. PMID- 28919581 TI - Antitumor Response to a Codon-Optimized HPV-16 E7/HSP70 Fusion Antigen DNA Vaccine. AB - BACKGROUND: Vaccines based on virus-like particles are effective against Human Papilloma Virus (HPV) infection; however, they have not shown a therapeutic effect against HPV-associated diseases. New immunotherapy strategies based on immune responses against tumor antigens can positively affect the clearance of HPV-associated lesions. OBJECTIVE: To generate two therapeutic fusion DNA vaccines (optimizedE7/mouseHSP70 and wildE7/mouseHSP70) to induce antitumor specific responses in mice models. METHODS: Mice were immunized with recombinant DNA vaccines. The splenocytes of immunized mice were collected and lactate dehydrogenase and IFN-gamma productions were measured after three injections in order to evaluate cytotoxic T lymphocytes (CTLs) activity. MTT assay was carried out for lymphocyte stimulation. RESULTS: The fusion DNA vaccines, specifically uE7-HSP70, elicited varying levels of IFN-gamma and CTLs responses compared to the control group (P<0.05). Furthermore, antitumor response and tumor size reduction in fusion DNA vaccines groups were significantly higher than in the negative control group (P<0.05). CONCLUSION: It is concluded that our fusion DNA vaccines considerably enhanced specific cellular responses against HPV tumor model. In addition, optimized E7 showed a notable immunogenicity and inhibitory effect on the reduction of tumor size. PMID- 28919583 TI - Polyclonal Antibody against Different Extracellular Subdomains of HER2 Induces Tumor Growth Inhibition in vitro. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) has a crucial role in several malignancies. The extracellular domain of HER2 (HER2-ECD) has been extensively employed as an important target in passive and active immunotherapy. Isolated recombinant prokaryotic HER2-ECD subdomains were previously found to be ineffective in inducing anti-tumor antibody response. OBJECTIVE: To employ recombinant eukaryotic HER2-ECD subdomains to raise anti-HER2 antibodies and determine their anti-tumor activity in vitro. METHODS: Two paired subdomains of HER2-ECD (DI+II and DIII+IV), representing Pertuzumab and Trastuzumab binding domains, respectively, along with the full extracellular domain of HER2 were generated in CHO-K1 cells. Polyclonal antibodies were raised against these subdomains and characterized using ELISA, flow cytometry, and immunoblot and their anti-tumor activity was assessed by XTT assay. The cross-reactivity of these antibodies was specified along with other members of the human HER family. RESULTS: Similar to Trastuzumab and anti-HER2-ECD antibody, anti-DI+II and DIII+IV polyclonal antibodies reacted with recombinant HER2-ECD and native HER2 expressed on tumor cells. These two polyclonal antibodies were able to inhibit the binding of Pertuzumab and Trastuzumab to HER2, respectively, and did not cross-react with other members of HER family. These antibodies were able to inhibit tumor cell growth in vitro, similar to Trastuzumab. CONCLUSION: The high immunogenicity of human HER2 DI+II and DIII+IV subdomains in rabbits and the tumor inhibitory activity of the purified specific antibodies imply that they might be suitable for active immunotherapy in formulation with appropriate adjuvants and in combination with other HER2 specific therapeutics. PMID- 28919584 TI - Reduced IFN-gamma Production in Chronic Brucellosis Patients. AB - BACKGROUND: Brucella is a well-known intracellular bacterium entailing acute and chronic illnesses in humans and domestic animals. The infection chronicity may be affected by the cell-mediated immunity and cytokine patterns. OBJECTIVE: To evaluate the patterns of T-helper cytokines in patients suffering from chronic and acute brucellosis. METHODS: In this cross-sectional study, 22 individuals with acute brucellosis, 21 individuals with chronic brucellosis, and 21 healthy individuals with the same genetic background were recruited from October 2015 to April 2016. Peripheral lymphocytes were isolated and stimulated by phytohemagglutinin (PHA) and brucella antigen in cell culture. The lymphocyte proliferation was detected by MTT assay. After collecting the supernatants, and through the use of ELISA method, we quantified the interferon gamma (IFN-gamma), interleukin (IL)-5, IL-17 and transforming growth factor-beta (TGF-beta). RESULTS: Patients with chronic brucellosis had a lower level antigen-specific stimulation index compared to those suffering from acute brucellosis (p=0.0001). Cases with chronic brucellosis had a lower level of IFN-gamma compared to cases with acute brucellosis (p=0.001). Finally, patients with chronic brucellosis had higher levels of IL-5 and TGF-beta in comparison with the acute group (p=0.01 and p=0.04, respectively). CONCLUSION: Chronic brucellosis reduces lymphocyte proliferation and TH1 cytokine secretion, but it enhances IL- 5 and TGF-beta production. Polarizing the immune responses plays a crucial part in the progression and development of chronic diseases. PMID- 28919585 TI - Association of Human Leukocyte Antigens Class I and II with Graves' Disease in Iranian Population. AB - BACKGROUND: Graves' disease (GD), a highly rampant autoimmune disorder of the thyroid gland, is responsible for 60-80% of the clinical cases of hyperthyroidism. Over the past decades, genetic association studies have identified several GD susceptibility loci in CTLA-4, TSHR and major histocompatibility complex regions. The information on the association between the human leukocyte antigens (HLA) and GD among Iranians is scarce. OBJECTIVE: To identify HLA polymorphisms that might confer susceptibility or protect against GD. METHODS: Eighty unrelated patients with a confirmed diagnosis of GD were included in the case group. The control group consisted of 180 unrelated healthy individuals with normal thyroid function tests. The polymerase chain reaction with sequence specific primers (PCR-SSP) method was used for HLA typing. RESULTS: Frequencies of HLA-A*68 (15.6% vs. 4.2%, p=0.004) and B*08 (8.8% vs. 2.5, p=0.030) were significantly higher in patients with GD compared with healthy controls. No patients with GD had HLA-A*33, whereas it was found in 7.0% of the controls (p=0.011). HLA-DQB1*0201 was significantly less frequent among patients with GD (15.6% vs. 26.8%, p=0.040). Additionally, patients with GD were significantly less bound to have HLA-DQA1*0201 (6.2% vs. 15.1%, p=0.045). Concerning allelic distributions, no noticeable difference was found between GD patients with and without Graves' ophthalmopathy (p>0.05 in all cases). CONCLUSION: In the Iranian population, HLA-A*68 and -B*08 confer susceptibility to GD, whereas HLA-A*33, -DQB1*0201, and -DQA1*0201 appear to have protective roles. PMID- 28919586 TI - Combination of Myelin Basic Protein Gene Polymorphisms with HLA-DRB1*1501 in Iranian Patients with Multiple Sclerosis. AB - BACKGROUND: Multiple sclerosis (MS), as a multifactorial autoimmune disease with complex genetic basis, causes demyelination in the central nervous system via cytokine responses to myelin antigens. Myelin basic protein (MBP) is the main protein component of the myelin sheath. HLA-DRB (human leukocyte antigen-DR beta) alleles, particularly HLA-DRB1*1501, may be of significance in the pathogenesis of MS. OBJECTIVE: To examine the association of HLA-DRB1*1501 alleles and MBP VNTR (variable number tandem repeat) polymorphism with the MS susceptibility in Iranian population. METHODS: Genomic DNA was extracted from peripheral blood. The alleles were determined by the Polymerase Chain Reaction (PCR) method in 259 MS patients and 312 healthy control individuals and analyses were carried out using Fisher's exact test. RESULTS: The frequencies of MBP VNTR genotypes (AA, AB and BB) were 47%, 42% and 11% among patients, and 45%, 43% and 12% in control subjects, respectively. HLA-DRB1*1501 allele was more frequent among patients than healthy individuals (OR=1.65, P=0.0045). The frequency of allele A and genotype A/A was significantly higher among HLA-DRB1*1501 positive patients (61% and 32%) than controls (46% and 19%) (OR=1.88, P=0.0013; A/A vs. B/B: OR=5.09, P=0.0004). The two-locus analysis of the interaction between the MBP VNTR polymorphism and the HLA-DRB1 allele showed that the HLADRB1* 1501/A haplotype was more frequent among MS patients than the healthy controls. CONCLUSION: The interaction between the HLA-DRB1*1501 allele and MBP gene may be considered as a predisposing factor in the development and pathogenesis of MS in the case of gene gene interaction. PMID- 28919588 TI - Poly I:C Delivery into J774.1 and RAW264.7 Macrophages Induces Rapid Cell Death. AB - BACKGROUND: Cytosolic double-stranded RNA (dsRNA) is an important 'molecular signature' for the detection of intracellular viral infections. Although intracellular dsRNA is a known potent inducer of apoptosis, the optimal time and dose for the onset of dsRNA-mediated apoptosis have not been studied in detail. OBJECTIVE: To perform an accurate temporal assessment of the cell death responses in dsRNA-dependent cytotoxicity. METHODS: Poly I:C (PIC), a synthetic dsRNA molecule was delivered intracellularly into J774.1 and RAW264.7 murine macrophages via electroporation. Cell viability was measured using the MTT assay and apoptosis was determined by sub-G0/G1 DNA content using flow cytometry. RESULTS: Loss of cell viability was seen as early as 3h post-electroporation of macrophages. A significant increase in the sub-G0/G1 DNA content consistent with apoptosis was observed in PIC-electroporated macrophages as early as 3h post electroporation. CONCLUSION: Intracellular PIC delivery induces rapid macrophage cell death. PMID- 28919587 TI - Human Leukocyte Antigen Class I and II Variants in Yemeni Patients with Chronic Renal Failure. AB - BACKGROUND: Human leukocyte antigens (HLAs) are found to be significant genetic factors concerning the susceptibility of an individual to certain diseases. OBJECTIVE: To determine the association between variants of class I (A and B) and class II (DRB1) HLA alleles and chronic renal failure (CRF), compared with healthy controls, in Yemen. METHODS: A case-control study in the Urology and Nephrology Center at Al-Thawra University Hospital in Sana'a, Yemen was carried out between January 2013 and December 2015 and included 187 CRF patients, and 194 healthy controls visiting the same center for kidney donation. All CRF patients in the study were on haemodialysis. The control group was confirmed to be healthy following a clinical examination by specialist physicians. Among both patients and controls, HLA class I (A and B) and class II (DRB1) HLA typing was carried out by Sequence Specific Primers (SSP) polymerase chain reaction (PCR). RESULTS: There was a significant protective function for HLA-A*30 gene (CRF 9.1% vs. con 16%, p=0.045) against CRF development. There was a high frequency of HLA-A*02, HLA-B*51 and HLA-DRB1*04 alleles in both patients and controls. CONCLUSION: No HLAs were located to have a significant association with genetic tendency to CRF in the current study population, however, certain HLA alleles, for instance in HLA-A*30, could be considered protective against CRF progress. PMID- 28919589 TI - From Woohwang Cheongsimwon* to Ginseng - The History of Medicine Use in the Joseon Era -*. AB - In Korean traditional medicine, though herbal decoction, acupuncture, and moxibustion are all used to treat diseases, restorative medicines are the most widely preferred treatment method. This paper explores the historical background of restorative herbal medicines and ginseng among the Korean public and Korean traditional medicine practice. It also seeks to clarify how social and cultural perspectives on drug use have changed since restorative medicine became mainstream during the Joseon era. Drug use tendencies were affected by the medical system of the Joseon Dynasty, patients' desires for reliable treatment, and perceptions of the human body and the causes of disease. In the late Joseon Dynasty, medicine, an industry originally monopolized by the government, began to be manufactured and traded on the free market, and medical personnel began to participate in medical activities on a large scale. As the health preserving theory became more popular and medical personnel became more accessible, medicinal preferences also changed. Specifically, whereas preference was first given to common medicines, such as Cheongsimwon, which are effective for various symptoms, restorative medicines, such as ginseng, gradually became more popular. These restorative medicines were faithful to the basic tenet of East Asian traditional medicine: to avoid disease by making the body healthy before the onset of illness. Patients' desires for safe treatment and growing competition among commercial doctors who wanted stable profits further increased the popularity of milder medicines. Ultimately, as ginseng cultivation was realized, its use expanded even further in a wave of commercialization. PMID- 28919590 TI - A Study of the Discussions on Psychiatry of Korea in the 1960s and 1970s* - From Mental Hygiene to Modern Psychiatry. AB - This study is to review the emergence of new psychiatrists, scientific rationalization, and popular internalization to reorganize the formation process of modern psychological medicine system. Unlike eugenic psychiatry from the Japanese Colonial Era, the social conditions and contexts forming autonomous system of psychiatry of Korea in the 1960s and 1970s have been concentrated. The discussion approach has been tried to secure two perspectives-treatment and criticism-at the same time and to expand the time and scope of study through the extensive texts such as newspapers, magazines, books, advertisements, and others in the 1960s and 1970s. Through formation of subject, rationalization, and popularization, this study has surveyed the characteristics of psychiatry in the 1960s and 1970s to accentuate complicated conditions and kinetic steps to systemize psychiatry as scientific field to promote treatment of patients by deviating from mental hygiene approaching national mental health from cleanliness and removal. The characteristics are summarized as follows. First, as the ethical models of good doctors, medical paternalistic doctors, and non-authoritarian symmetric doctors have been proposed as good psychiatrists by new medical specialists with experience of globality, a new subject emerges. However, there has been illegalization process of unlicensed medical practitioner excluded by the regulatory authority called "clearness." Second, the rationalization of psychiatry has been accelerated through the dispute of enactment of Mental Hygiene Law, segmentalization of concept of mental illness, and scientific characteristics. Especially, the disputes over enactment of Mental Hygiene Law focused on criminalization of mental patients brought a result to regulate the patients as the target of humanistic treatment and potential criminals at the same time. Third, popularization of psychiatry has embraced invisible mental illness into popular daily life through visual measure called medicine advertisement, and through the discussion about social neurosis, a new paradigm for diagnosis of Korean society has been proposed. Moreover, by focusing on autobiographical works with voices of patients, this article reveals a new doctor patient relationship. PMID- 28919591 TI - The Establishment and operation of Longjing Medical College - The History of Longjing Medical College as Frontier History: Focusing on its 'Disconnection' and 'Continuity'. AB - Longjing Medial College, established in Longjing, Yanbian, China on September 12, 1945, existed for about 1 year and 6 months until it was renamed as the Medical Department of Dongbei Junzheng Daxue Jilin Fenxiao in April 1947. However, there are only few records and studies on Longjing Medical College in Yanbian as well as in Korea. In order to fill the gap, this study attempted to restore the history of Longjing Medical College built in Yanbian, China immediately after the liberation. In particular, it analyzed how and why the Longjing Medical College was founded and operated, and which relations the college had with the post-war medical educational institutions, focusing on the 'disconnection' and 'continuity' in the historical sense. Since the establishment of Manchukuo, the Japanese colonial government had made it a major "frontier" and actively promoted the mass migration of Japanese and Koreans. For them, the government also set up three Exploitation Medical Schools in 1940. As a part of these three institutions, Longjing Exploitation Medical School educated more than 150 students by 1945, of which about one third was Korean. After the liberation, the Longjing Educational Alliance decided to pursue the return-movement of the Longjing Exploitation Medical School and took over the institution. On September 12, 1945, Longjing Medical College opened at the school site of Longjing Exploitation Medical School. Longjing Medical College was founded by people who had 'the perspective of Korean nationality' in an atmosphere where the 'ethnicity' of the Koreans exercised considerable power. Nevertheless, in 1946, when the Chinese Civil War began and the Yanbian region became an important base of the Chinese Communist Party, the Party began to expand and strengthen their influences in the region. Accordingly, the operation rights of Longjing Medical College were transferred to the Yanbian Administrative offices of Supervision and Government of Jirinsheng which were the administrative institution by the Chinese Communist Party in turns. In the end, Longjing Medical College was reorganized into the Medical Department of Dongbei Junzheng Daxue Jilin Fenxiao (1947. 3) and the first branch of the Chinese Medical College (1948. 1), a medical education institution focused on nurturing the medical personnel required for the Chinese Civil War. In January 1949, the first branch moved to Harbin, merged with the second branch there, and was transformed into Harbin Medical College. Afterwards, the Yanbian Koreans played a major role to establish Yanbian Medical College in a basis of the teachers and buildings left by the moving-out of the first branch(1948. 10. 1). Now, Yanbian Medical College is the official body of Yanbian University Medical Center. Longjing Medical College, which has such a complicated history, is partially 'disconnected' from the Yanbian medical educational institutions in the post-war era in terms of its possession, operation objective, and academic system. However, many of the early members of the Longjing Medical College were not only teachers and students of the Longjing Exploitation Medical School, but also a few of them continued to teach at the Medical Department of Dongbei Junzheng Daxue Jilin Fenxiao, the first branch of the Chinese Medical College, and Yanbian Medical College. Particularly, several members actively participated in the establishment of each school or in the position of the top leader of the school. Also, all the medical education institutions referred to above used the building and facilities of Longjing Exploitation Medical School until the period of Yanbian Medical College. As such, the history of Longjing Medical College as frontier history, gives us a difficult, but significant question on the meanings of 'disconnection' and 'continuity' in history and their implications. PMID- 28919592 TI - The Study on the Lives and Health Conditions of Internees in Santo Thomas Camp of Philippines - Based on McAnlis's The War in Manila (1941-1945). AB - When Japan invaded the Philippines, two missionary dentists (Dr. McAnlis and Dr. Boots) who were forced to leave Korea were captured and interned in the Santo Thomas camp in Manila. Japan continued to bombard and plunder the Philippines in the wake of the Pacific War following the Great East Asia policy, leading to serious inflation and material deficiency. More than 4,000 Allied citizens held in Santo Thomas camp without basic food and shelter. Santo Thomas Camp was equipped with the systems of the Japanese military medical officers and Western doctors of captivity based on the Geneva Conventions(1929). However, it was an unsanitary environment in a dense space, so it could not prevent endemic diseases such as dysentery and dengue fever. With the expansion of the war in Japan, prisoners in the Shanghai and Philippine prisons were not provided with medicines, cures and food for healing diseases. In May 1944, the Japanese military ordered the prisoners to reduce their ration. The war starting in September 1944, internees received 1000 kcal of food per day, and since January 1945, they received less than 800 kcal of food. This was the lowest level of food rationing in Japan's civilian prison camps. They suffered beriberi from malnutrition, and other endemic diseases. An averaged 24 kg was lost by adult men due to food shortages, and 10 percent of the 390 deaths were directly attributable to starvation. The doctors demanded food increases. The Japanese Military forced the prisoner to worship the emperor and doctors not to record malnourishment as the cause of death. During the period, the prisoners suffered from psychosomatic symptoms such as headache, diarrhea, acute inflammation, excessive smoking, and alcoholism also occurred. Thus, the San Thomas camp had many difficulties in terms of nutrition, hygiene and medical care. The Japanese military had unethical and careless medical practices in the absence of medicines. Dr. McAnlis and missionary doctors handled a lot of patients focusing mainly on examination, emergency treatment and provided the medical services needed by Philippines and foreigners as well as prisoners. Through out the war in the Great East Asia, the prisoners of Santo Thomas camp died of disease and starvation due to inhumane Japanese Policy. Appropriate dietary prescriptions and nutritional supplements are areas of medical care that treat patients' malnutrition and disease. It is also necessary to continue research because it is a responsibility related to the professionalism and ethics of medical professionals to urge them to observe the Geneva Convention. PMID- 28919593 TI - Electrocardiographic algorithms to guide the management strategy of idiopathic outflow tract ventricular arrhythmias. AB - INTRODUCTION The current guidelines of the European Society of Cardiology outlined electrocardiographic (ECG) differentiation of the site of origin (SoO) in patients with idiopathic ventricular arrhythmias (IVAs). OBJECTIVES The aim of this study was to compare 3 ECG algorithms for differentiating the SoO and to determine their diagnostic value for the management of outflow tract IVA. PATIENTS AND METHODS We analyzed 202 patients (mean age [SD]: 45 [16.7] years; 133 women [66%]) with IVAs with the inferior axis (130 premature ventricular contractions or ventricular tachycardias from the right ventricular outflow tract [RVOT]; 72, from the left ventricular outflow tract [LVOT]), who underwent successful radiofrequency catheter ablation (RFCA) using the 3-dimensional electroanatomical system. The ECGs before ablation were analyzed using custom developed software. Automated measurements were performed for the 3 algorithms: 1) novel transitional zone (TZ) index, 2) V2S/V3R, and 3) V2 transition ratio. The results were compared with the SoO of acutely successful RFCA. RESULTS The V2S/V3R algorithm predicted the left-sided SoO with a sensitivity and specificity close to 90%. The TZ index showed higher sensitivity (93%) with lower specificity (85%). In the subgroup with the transition zone in lead V3 (n = 44, 15 from the LVOT) the sensitivity and specificity of the V2-transition-ratio algorithm were 100% and 45%, respectively. The combined TZ index+V2S/V3R algorithm (LVOT was considered only when both algorithms suggested the LVOT SoO) can increase the specificity of the LVOT SoO prediction to 98% with a sensitivity of 88%. CONCLUSIONS The combined TZ-index and V2S/V3R algorithm allowed an accurate and simple identification of the SoO of IVA. A prospective study is needed to determine the strategy for skipping the RVOT mapping in patients with LVOT arrhythmias indicated by the 2 combined algorithms. PMID- 28919594 TI - Fifteen-Year Analysis of Deceased Kidney Donation: A Single Transplant Center Experience in a Region of Northern Italy. AB - BACKGROUND The rising number of patients on waiting lists for kidney transplant and the shortage of available organs has intensified efforts to increase the number of potential donors. MATERIAL AND METHODS This study investigated changes in clinical parameters among potential deceased donors in the 15-year period between 1999 and 2013 and their impact on transplantation procedure and outcomes. A total of 1634 potential deceased donors were examined and divided into 2 groups: 707 of them identified from 1999 to 2005 (Group A), and 927 from 2006 to 2013 (Group B). RESULTS The comparison between the potential donors in Group A vs. Group B revealed an increase over time in donor age (54.6+/-17.2 vs. 58.8+/ 16.3, p<0.001), a reduction in the percentage of standard donors (52.3% vs. 39.8%, p<0.001), a broader utilization of organs from expanded criteria donors, and a greater number of comorbidities, particularly cardiovascular disease and dyslipidemia. However, renal function parameters and the bioptic scores did not change significantly over the years. CONCLUSIONS These results suggest the usefulness of strategies to increase the number of potential donors suitable for organ donation, especially among elderly and marginal donors. PMID- 28919596 TI - Outcome of Pregnancy Related Acute Kidney Injury Observed in a Tertiary Care Hospital. AB - This prospective case control study was carried out in Mymensingh Medical College Hospital (MMCH) from April 2011 to March 2012. The main objective of the study was to determine the short term maternal outcome of pregnancy related Acute Kidney Injury and to identify aetiological factors and to observe clinical features of pregnancy related Acute Kidney Injury. Total 60 pregnant women with AKI were included in the study as sample and equal (60) number of pregnant women with normal renal function was taken as control. Mean ages (+/-SD) of study and control group were observed 31.6+/-6.9 years and 25.5+/-4.7 years respectively. It was observed that most patients were from rural area with low income group. Most women were multiparous and presented in third trimester and postpartum period. Majority of the study subjects did not receive antenatal care at any stage of pregnancy. Fifty (86.7%) of the study subjects were oligo-anuric, forty nine (81.7%) were edematous and fifty one (85%) were anaemic. Twenty-five (41.7%) patients presented with abnormal vaginal bleeding. Sepsis (including septic abortion and puerperal sepsis) was responsible for of Pregnancy Related AKI (PR AKI) in more than two fifths of cases. Haemorrhage (APH & PPH combined) was the next common cause of Pregnancy Related AKI (PR-AKI). Toxemia of Pregnancy was responsible in one fourth of cases. Dialysis (HD & IPD combined) was required for two fifths of the patients. Rest patients were treated conservatively with antibiotics, blood transfusion, maintenance of fluid and electrolytes balance etc. Maternal outcome of Pregnancy related acute kidney injury was considered for the period of patient's hospital staying. 56.6% patients recovered completely, 15.0% patients recovered partially, 6.7% did not recover at the time of hospital discharge; while 21.7% died. So it can be concluded that, pregnancy related acute kidney injury is a critical condition, associated with worse prognosis. PMID- 28919595 TI - A Case of Hepatorenal Syndrome and Abdominal Compartment Syndrome with High Renal Congestion. AB - BACKGROUND Hepatorenal syndrome (HRS) is a reversible renal impairment that occurs in patients with acute liver failure and advanced liver cirrhosis. HRS is due to a renal vasoconstriction that results from extreme vasodilatation. It is therefore a functional disorder, not associated with structural kidney damage. On the other hand, end-stage liver diseases are often complicated by massive ascites. Massive ascites may cause abdominal compartment syndrome (ACS), which includes impairment of renal blood flow, but there are no reports indicating that kidney lesions caused by ACS may pathologically contribute to end-stage liver diseases. CASE REPORT A 40-year-old man with acute liver failure was admitted to our hospital. He was diagnosed with type 1 HRS and showed ACS at the same time. He died 30 days after admission. There were signs of congestion in the kidneys upon dissection and advanced erythroid fullness in the renal tubules. CONCLUSIONS We report an autopsy case with HRS and ACS diagnosed with a clinical and histopathological consideration of liver and kidney. Further clinical studies are needed to improve management of renal failure in patients with acute liver failure and advanced liver cirrhosis. PMID- 28919597 TI - Quality of Life in Children with Asthma in Bangladesh. AB - Asthma is a public health problem that adversely affects different aspects of quality of life. Childhood asthma is common in Bangladesh affecting their lifestyle. The objective of the study was to assess health-related quality of life in children with bronchial asthma. A descriptive, cross-sectional study was carried out from January 2014 to December 2014 at the Outpatient Department of National Asthma Centre, Mohakhali, Dhaka among hundred sixty-two purposively selected children of both sexes with bronchial asthma aged from 7 to 17 years. Data were collected through interview with children or their parents using an interviewer-administered questionnaire based on Pediatric Asthma Quality of Life Questionnaire (PAQLQ). Data were analyzed by computer software SPSS version 16.0. The mean age was 12.5 years with a standard deviation (SD) of 2.9 years. Overwhelming majority 157(96.9%) of children were literate, while only 5(3.1%) children were illiterate. Eighty (49.4%) children were male, while 82(50.6%) female. As many as 148(91.4%) children were students, while 10(6.2%) children were engaged in some type of job and 4(2.5%) children had no occupation. Parents of 145(89.5%) children were currently married, while 10(6.2%) children had single parent and 7(4.3%) children's parents were divorced or separated. Quality of life in children with asthma decreases with age as the disease intensity increases with age. Female asthmatic children had lower overall score of Quality of life (p=0.017), as well as lower activity domain score (p<0.001). Emotional domain score was found lower in children with single parent (p=0.021) and low monthly family income (p<0.001). Furthermore, children with lower monthly family income and working children had lower Quality of life score in all domains. PMID- 28919598 TI - Risk Factors and Immediate Outcome of Very Low Birth Weight Babies (Appropriate For Gestational Age) In Newly Established SCANU, Mymensingh Medical College Hospital. AB - Low birth weight (LBW) is the most important preventable cause in the neonatal period leading to very high neonatal mortality and morbidity in developing countries like Bangladesh. A cross sectional study was conducted in the neonatology ward, Mymensingh Medical College Hospital, Mymensingh from July 2014 to December 2014 to identify the risk factors and immediate hospital outcome of Very Low Birth Weight (VLBW) Appropriate for Gestational Age (AGA) babies in context of present neonatal hospital care standard. Total 100 preterm very low birth weight babies were enrolled and selected by weight, intra uterine growth chart and new ballad score. There is slight preponderance of male babies (64%) over female babies (36%). The overall survival and mortality rate was 50% and 50% respectively in the present study. Mortality is highest (76.47%) in babies whose gestational age 28 weeks and the mortality rate gradually decrease as gestational age increases. Correlation co-efficient (r) between gestational age and number of died is -0.85. It indicates highly opposite relation between the variables, p value (<0.069) which is strong opposite relation. Mortality is highest (66.66%) in babies whose birth weight below1100gm, in comparison to those whose birth weight above 1100gm and correlation co-efficient (CC) r = -0.433 (p<0.466) which is not significant. That means not only birth weight but also other factors are responsible for mortality of very low birth weight baby. Neonatal mortality bears inverse relationship with birth weight and gestational age. This emphasized the need for large scale study which will provide the guideline for appropriate measures to be taken to combat the situation. PMID- 28919599 TI - Clinico-biochemical Profile of Women with Hyperemesis Gravidarum Admitted in a Tertiary Hospital. AB - Hyperemesis gravidarum is the most severe form of nausea and vomiting in pregnancy with poor pregnancy outcome. Hormonal changes, psychological and immunological factors are attributed to the condition. Recently, prevalence of Helicobacter pylori among women with Hyperemesis gravidarum has been revealed. A descriptive, cross-sectional study was carried out at antenatal ward, Department of Obstetrics and Gynaecology, Mymensingh Medical College Hospital, Mymensingh among thirty-six purposively selected patients with Hyperemesis gravidarum to assess the clinic-biochemical profile. Data were collected through interview, physical examinations and laboratory investigations by using case record form. Statistical analyses were performed using SPSS version 20.0 for windows. Highest number 16(44.44%) of respondents were in age group 20 to 24 years with a mean of 23.81+/-4.55 years. Majority 29(80.56%) of the women had education less than 12 years, as many as 28(77.78%) women were housewives, and at least 14(38.89%) women had unplanned pregnancies. An overwhelming majority 29(80.56%) of women had their pregnancy duration between 8 to 12 weeks. At least 20(55.56%) of women were pregnant for first time, as many as 19(52.78%) women had duration of illness for 5 to 9 weeks, and all the women had remarkable weight loss. Cent per cent women were dehydrated, and appearance of 27(75.00%) women was ill-looking. Thyroid Stimulating Hormone (TSH), total leucocyte count and serum creatinine levels were normal for cent per cent women. As many as 15(41.67%) women had hypokalaemia, while 13(36.11%) had hyponatraemia and 3(8.33%) had hypochloraemia. Patient with Hyperemesis gravidarum often presents with ill-looking appearance, vomiting over 10 times a day, dehydration, remarkable loss of body weight and anaemia. Ketonuria, hyponatraemia, hypokalaemia and hypochloraemia are not associated with severity of illness. PMID- 28919600 TI - Modified Blatchford Score for Risk Stratification in Adult Patient with Nonvariceal Upper Gastrointestinal Haemorrhage and Their Short Term Hospital Outcome. AB - Upper gastrointestinal hemorrhage (UGIH) is one of the most common and life threatening gastrointestinal emergency. There are several risk scores for risk stratification in UGIB patients. The Modified Blatchford score, which relies only on clinical and laboratory parameters, is practical in the emergency setting The Modified Blatchford scoring system also known as Glasgow Blatchford Scoring (GBS) have been developed to stratify risk of non variceal upper gastrointestinal hemorrhage or need of medical or surgical intervention, endoscopic therapy. Objective of this study is to see risk stratification by The Modified Blatchford score and short term hospital outcome in non variceal upper GI hemorrhage patients. The observational study was carried out over a period of 6 months from October, 2014 to March, 2015 in Department of Department of Medicine, Gastroenterology and Surgery Mymensingh Medical College Hospital, Mymensingh. A total of 120 patients with non variceal UGIH were taken for the study during study period. Categorical variables were reported as percentage and Means and proportions were carried out using the Chi-square test (X2-test) of different variables by SPSS software version-18.0. Patients related variables age, sex; and main outcome variables the Modified Blatchford scoring system, Risk stratification, and short term hospital outcome were observed. Age frequency among total cases were 66(55%) <60 years, 50(41.67%) from 60-79 years and 4(3.3%) 80 years or above and sex distribution were 84(70%) were male and 36(30%) were female patients. Blatchford score of patients 1(0.83%) had score 0, 1(0.83%) had score 1, 2(1.67%) had score 2, 2(1.67%) had score 3, 2(1.67%) had score 4, 3(2.5%) had score 5, 12(10%) had score 6; 15(12.5%) had score 7, 16(13.33%) had score 8, 17(14.17%) had score 9, 16(13.33%) had score 10, 15(12.5%) had score 11, 10(8.33%) had score 12, 4(3.33% ) had score 13, 1(0.83%) had score 14, 2(1.67%) had score 15 and 1(0.83%) had score 16. Risk stratification showed 54(45%) had low risk (Mean GBS score 6.19+/-1.79), 66(55%) had high risk (Mean GBS score 11.03+/-1.83) Outcome of the patients were observed that 1(0.83%) died, 54(45%) was discharged without any medical or surgical intervention, and 65(54.17%) patients' needs medical or surgical intervention such as blood transfusion and endoscopy. Among total 120 patients with upper GI hemorrhage I have found that GBS score of three or less than three is predictive of low risk of adverse outcomes and can be discharged without any intervention. PMID- 28919601 TI - Relationship between Echocardiographic Epicardial Adipose Tissue (EAT) Thickness and Angiographically Detected Coronary Artery Disease. AB - Epicardial adipose tissue (EAT) is a particular form of visceral adipose tissue deposited around the heart and there is growing evidence about the physiological and metabolic importance of EAT, especially in the association of cardiovascular risk profiles and the pathogenesis of atherosclerotic coronary artery disease. This observational, cross sectional study was done to determine the relationship between echocardiographic epicardial adipose tissue (EAT) thickness and coronary artery disease (CAD). Total 123 patients with established or suspected coronary artery disease admitted for coronary angiogram in the department of Cardiology of Bangabandhu Sheikh Mujib Medical University (BSMMU) from November 2010 to the end of April 2011 were included in this study. Epicardial adipose tissue (EAT) thickness measurements by echocardiography were compared with coronary angiographic findings. Echocardiographic epicardial adipose tissue (EAT) thickness was significantly higher in patients with CAD in comparison to those with normal coronary arteries (6.67+/-2.24mm vs. 4.61+/-1.62mm; p<0.001). Furthermore, EAT thickness increased with the severity of CAD (multi-vessel disease 7.99+/-2.12mm vs. single vessel disease 5.93+/-1.97mm; p<0.001). Gensini's score significantly correlated with EAT thickness (r=0.617, p<0.001). Optimum cut-off point (OCP) of epicardial adipose tissue (EAT) thickness as a predictor of angiographic CAD was 6.44mm with 45.31% sensitivity and 92.86% specificity [ROC area 0.756, p<0.001, 95%CI (0.66-0.85)]. Echocardiographic epicardial adipose tissue (EAT) thickness was significantly correlated with the presence and severity of angiographically detected coronary artery disease (CAD). PMID- 28919602 TI - Comparative Study of Cytology and Histopathology of Cervical Lesion in VIA Positive Patients and Its Correlation with High Risk Human Papilloma Virus. AB - Cervical cancer is the second most frequent type of cancer and leading cause of mortality among women worldwide. The present study was undertaken to assess precancerous and cancerous cervical lesion by cytology as well as HPV DNA identification and their comparison with histopathology in VIA positive cases. This descriptive, cross-sectional type of observational study was carried out in the Department of Pathology, Mymensingh Medical College in collaboration with the Department of Gynecology and Obstetrics, Mymensingh Medical College Hospital and Department of Microbiology and Hygiene in Bangladesh Agriculture University for HPV DNA detection from July 2012 to June 2013. Study was carried out among 160 VIA positive patients and selected by non-random judgment sampling from the colposcopy clinic. Out of 160 cases, only 40(25.00%) were found HPV DNA positive, while the rest 120(75.00%) cases were negative. Among positive cases 77.50% were cancerous cases and 22.50% were precancerous cases. It was further revealed that in cancerous cases, 86.11% were HPV DNA positive. PCR showed low sensitivity, probably due to sampling error and inclusion of all cases (chronic cervicitis, precancerous and cancerous lesion). The statistical value of accuracy, sensitivity and specificity of Pap smear cytology, HPV DNA test and histopathology yielded some important directives. The sensitivity values of Pap smear cytology and HPV DNA were found 87.50% and 88.89% respectively. Thus Pap smear test showed almost equal sensitivity to DNA test. The accuracy of the Pap smears and HPV DNA in this study was 88.13% and 96.88% respectively. The accuracy of Pap smears is lower than HPV DNA tests. The present study show significant relationship between cytological with HPV DNA test and histopathological diagnosis. But cytology and HPV DNA testing are not suitable as a single test. In conclusion, it can be stated that combination cytology (Pap smear), histopathology and new technologies such as HPV DNA typing would ultimately be more useful. PMID- 28919603 TI - Current Trends of Using Antimicrobials at Obstetrics and Gynaecology Department in a Tertiary Care Hospital. AB - This cross-sectional descriptive study was done to analyse the current trends of using antimicrobials in various surgical procedures at Obstetrics and Gynaecology department in Mymensingh Medical College Hospital, Mymensingh from July 2014 to June 2015. Among 300 postoperative obstetrics and gynaecological surgery cases, samples were selected as non-random purposive selection method where pattern of using antimicrobials were analysed by SPSS method 20.1 versions. The incidence of antimicrobial resistance is on continued rise with a threat to return to the pre antibiotic era. This has led to emergence of such bacterial infections which are essentially untreatable by the current armamentarium of available treatment options. Now-a-days variation of choosing antibiotic are quietly accepted in Obstetrics and Gynaecology department as prophylaxis purpose to control life threatening conditions such as postoperative wound infection, septicaemia, urinary tract infection etc. The data analysis revealed that among 300 obstetrical and gynaecological surgeries, Nitroimidazoles (93.33%), Cephalosporins (91%) and Aminoglycosides (59%) group were most commonly used antimicrobials in both obstetrics and gynaecological surgeries. Metronidazole (93.33%), Ceftriaxone (68.66%), Gentamicin (60.33%), Cefuroxime (48%), Flucloxacillin (42%), Cefixime (27%) were the most commonly used antimicrobials at obstetrics and gynaecology department. Combination of Ceftriaxone, Metronidazole and Gentamicin (37.66%), Ceftriaxone and Metronidazole (25.33%), Cefuroxime, Metronidazole and Gentamicin (16%), Ciprofloxacin, Metronidazole and Gentamicin (5.33%) were most commonly used antimicrobials postoperatively. Total mean duration of antimicrobial therapy was 10.45 days. Antibiotics are useful in prevention of infection. But indiscriminately use of antibiotics without any guideline may lead to antimicrobial resistance. So, antimicrobial surveillance committee should be formed by hospital authority to know the local using pattern of antibiotics. PMID- 28919604 TI - Correlation of Stature with Foot Length in 5-10 Years Aged Bangladeshi Children. AB - This cross sectional, descriptive and analytic type study was conducted among 5 10 years aged Bangladeshi children at different areas of Mymensingh district (Fulpur, Muktagacha, Fulbaria, Trisal and Haluaghat) on 109 Bangladeshi children (70 male and 39 female) from January 2016 to December 2016. Sample collection was done by nonrandom purposive sampling technique. Any kind of foot deformity resulting either from congenital or physical injury were excluded to construct standard measurement. The present anthropometric study was designed to construct data of 5 to 10 years aged Bangladeshi children regarding foot length, to measure correlation of stature with foot length and an attempt has been made out to grow interest among the researchers for future study and also to compare the data with the data of the people of other races. Stature of the subject was measured with the stadiometer and foot length was measured using slide calipers. The children were asked to stand with weight distributed equally on both feet. The legs were perpendicular to the feet. The mean foot length of 5, 6, 7, 8, 9 and 10 years aged male were 16.72+/-1.11cm, 17.12+/-.72cm, 19.04+/-1.27cm, 19.10+/-.76cm, 20.11+/-1.25cm and 20.88+/-1.01cm respectively and those of same aged female were 16.44+/-1.2cm, 17.85+/-0.50cm, 18.53+/-0.76cm, 19.14+/-0.58cm, 19.87+/-1.88cm and 20.95+/-1.36cm respectively. Correlation between stature and foot length was made. Foot length showed non- significant positive correlation with stature in 5 years old male and female, 6 years old male, 7 years old male and female, 8 years old male and female, 9 years old and 10 years old female. In case of 9 years and 10 years old male, it showed significant positive correlation with stature. Comparison of foot length between male and female children was done by Unpaired Students 't' test which was statistically non-significant. PMID- 28919605 TI - Current Trend of Using Anti-Hypertensives in Pregnancy and Postpartum Period in a Tertiary Level Hospital. AB - Hypertensive disorders are one of the most common disorders in pregnancy. They are amongst the major cause of maternal and perinatal morbidity and mortality. Incidence is increasing in developing countries like Bangladesh. This cross sectional descriptive study has done to observe the utilization of antihypertensive drugs in hypertensive disorders of pregnancy and conducted from January 2016 to December 2016 in the department of Pharmacology in collaboration with department of Gynecology and Obstetrics in Mymensingh Medical College Hospital, Mymensingh, Bangladesh. Non random purposive sampling technique was used. Total of 300 patients participated in the study, 281 anti partum and 19 postpartum. Age distribution showed 42% patients were in 21-25 years age group. Majority of the participants (91%) were housewife and majority (79%) came from poor socioeconomic status with below SSC education (68%). About 82% patients lived in rural area. Trimester and gravida wise distribution showed most of the participants were 3rd trimester (61%) and primigravida (57%) and only 6% patients belong to postpartum period. In this study preeclampsia was highest (63.8%) among all other types of hypertensive diseases in pregnancy. Majority of the patient were preferred for dual therapy (53%), mono therapy was used in 29% of cases. Most frequently given drug in pregnancy associated hypertension was methyldopa that is 88.33% (single 22.3%, combination 66%). Second most commonly used drug was nifidipine consisting of 47.6% but used in combination in all cases. Average number of anti hypertensive drugs prescribed per prescription was 1.87 and majorities (92%) were from essential drug list but used as trade name. Preeclampsia and eclampsia were more common among the hypertensive disorders in tertiary level hospital cases. Methyldopa was found to be the commonest prescribed antihypertensive in monotherapy and in combination. PMID- 28919606 TI - Current Trends of Using Antimicrobials and Their Sensitivity Pattern in Infectious Cases at Department of Orthopedics in a Tertiary Care Hospital. AB - This cross-sectional descriptive study was carried out to analyse the current trends of using antimicrobials at orthopaedics department in different surgical procedures and observe the antimicrobial sensitivity pattern of infective organisms in postoperative wound infection cases at the department of Orthopaedics, Mymensingh Medical College Hospital with collaboration of department of Pharmacology and Therapeutics in Mymensingh Medical College, Mymensingh from January 2016 to December 2016. Among 253 orthopaedics surgical cases Penicillins, Cephalosporins, and Aminoglycoside group were commonly prescribed antimicrobials that had been use postoperatively in most of the Orthopaedics cases. Rate of occurring postoperative wound infection was 18.58%. Pseudomonas aeruginosa (36.17%) was the predominant microorganisms in our study followed by Klebsiellae (12.77%), Proteus (10.64%), Escherichia coli and (6.38%) Enterococcus (4.25%). Pseudomonas aeruginosa exhibited sensitivities to Gentamicin (35.29%), Amikacin (35.29%). Good sensitivities patterns for Klebsiellae in our study were shown to Imipenam (100%), Gentamicin (20%). Sensitivity patterns for Proteus in our study were shown to Imipenam (80%), Gentamicin (20%). Enterococcus in our study showed good sensitivities against Imipenam (100%), Linezolid (100%). Cephalosporin generation showed more resistance. PMID- 28919607 TI - Impact of Adrenocortical Insufficiency on Clinical Parameters in Haemodynamically Stable Cirrhotic Patients with Ascites. AB - Cirrhosis has many complications regardless of the aetiology. Complications include splenomegaly, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome and hepatocellular carcinoma and also linked to abnormalities in the endocrine system, including abnormal sex hormone metabolism, thyroid disease, osteoporosis, and, most recently identified, adrenal insufficiency. This prospective cohort study was done to evaluate the impact of adrenocortical insufficiency on clinical parameters in haemodynamically stable cirrhotic patients with ascites and had been performed at the inpatient of GHPD Department, BIRDEM, Dhaka, Bangladesh from April 2011 to March 2012. A total of fifty three (53) patients fulfilling inclusion criteria were included in the study. Patients were divided into two groups: Group A (patients of normal adrenal function) and Group B (patients of insufficient adrenal function) and those were followed up for the next 6 months. In Group A, the total number of patients was 25(47%) and in Group B it was 28(53%). Between two groups, mean age difference and gender difference were not statistically significant (p value was 0.278 and 0.933, respectively). Group B patients had significant higher CLD duration (p=0.004). Haematemesis and/or maelena was significantly lower in Group B at follow up (p=0.0001) due to significant higher number of band ligation in this group (p=0.009). Hepatic encephalopathy was significantly higher in Group B at enrollment (p=0.028) and at follow up (p<0.001). During the period of follow up, significant higher number of patients had developed hepatic encephalopathy in Group B compared to Group A (p<0.05). There was statistically significant higher number of patients had SBP (p=0.031) in Group B at follow up. During the period of follow up, only 1(4%) patient in Group A and 5(18%) patients in Group B died. There was no significant difference of number of death between two groups (p=0.196). Adrenal insufficient decompensated cirrhotic patients have higher morbidities. PMID- 28919608 TI - Arthroscopic Anterior Cruciate Ligament Reconstruction with Triplet Autograft of Semitendinosus Tendon. AB - Anterior cruciate ligament (ACL) is the most commonly injured ligament occurs in young adult population, which markedly reduces activity level. Anterior cruciate ligament rupture is a threat to the homeostasis of the knee. So, reconstruction of the ACL is necessary to make them fit and return to their pre-injury activity level. The choice of graft for ACL reconstruction is a matter of debate, with the BPTB graft and quadruple graft of ST-G being the two most popular options. Use of triplet graft of semi-tendinosus tendon alone without sacrificing gracilis is another option. So hypothesis was Arthroscopic ACL reconstruction with triplet autograft of semi-tendinosus tendon alone is an effective procedure. This prospective interventional study was conducted from October 2011 to March 2013 at Dhaka Medical College Hospital, Dhaka, Bangladesh. Fourteen patients who had a unilateral anterior cruciate ligament rupture underwent arthroscopic reconstruction with triplet graft of semi-tendinosus tendon. Accelerated ACL reconstruction rehabilitation protocol was followed and final outcome evaluation done at 24 weeks according to IKDC knee examination form and Lysholm knee scoring scale. Preoperative Lysholm knee score was 52.64 and postoperative score was 90, that shows significant improvement (p<0.05). According to Lysholm knee scoring scale, excellent results (95-100 points) were obtained in 33% patients, good results (85-94 points) in 53% patients, fair and poor (7% each). For arthroscopic ACL reconstruction, choice of semi-tendinosus tendon alone preserving gracilis, comparable outcome as with BPTB/ST-G graft, can be achieved, minimizing the hamstring strength deficit. Moreover gracilis being reserved for future use in revision ACL reconstruction and/or in other reconstructive surgery. PMID- 28919609 TI - Psychiatric Disorders in Drop out from Educational Attainment Attending Mental Health Facilities: A Descriptive Cross Sectional Study. AB - Studies of the impact of mental disorders on educational attainment are rare. Mental disorders, those beginning in childhood or adolescence may increase the risk of early drop out from education. The latter has been shown to have adverse life-course consequences on individuals such as greater demand on social welfare entitlements. A descriptive cross sectional study was carried out at the department of Psychiatry, Comilla Medical College, Comilla, Bangladesh. All cases were selected from patients attending at Comilla Medical College Hospital and Private Mental Health Facilities in Comilla City from March 2015 to February 2016. We found out the psychiatric disorders and socio-demographic status of patients with educational drop out over the early life course. A total of 50 dropout patients aged 10 to 30 years who fullfiled the enrolment criteria included in the study. Sociodemographic questionnaires, diagnostic information (DSM-5 and ICD-10) as well as an account of a various level of education were used as research instruments. The Frequency tables, summary tables and appropriate graphs were prepared to describe the population characteristics and study finding. The most of the psychiatric morbidity presents in male (62%) and age group of 18-24 years (54%). In this study, anxiety disorders was 8%, behaviour/ impulse control disorders was 8%, mood disorders was 16%, substance use disorders was 24%, schizophrenia spectrum disorders was 12% and composite psychiatric disorders was 32%. Among drop out patient's non- completion of primary education was 14%, non-completion of secondary education was 20%, non- completion of higher secondary education was 24%, not entry to tertiary education was 12% and non-completion of tertiary education was 30%. Among behaviour/impulse control disorders non-completion of primary education was 6%, substance use disorders non-completion of higher secondary education was 10%, mood disorder both non-completion of higher secondary education and non-completion of tertiary education were 6%. Among composite psychiatric disorders non-completion of secondary education, non-completion of higher secondary education and non completion of tertiary education were 8%, 6% and 12% respectively. Onset of mental disorders and subsequent drop out from education was found in this study. Further multi-centered prospective and population-based studies should be designed to find out the exact situation. PMID- 28919610 TI - Open-door Laminoplasty for Multilevel Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament (OPLL) using Titanium Reconstruction Miniplate and Screws. AB - To review outcome of 25 patients who underwent open-door cervical laminoplasty for multilevel cervical spondylotic myelopathy (MCSM) and ossification of the posterior longitudinal ligament (OPLL) using titanium reconstruction miniplate and screws. Records of 18 men and 7 women aged 35 to 78 (mean, 62.6) years were reviewed retrospectively from October 2009 and October 2014 at Bangabandhu Sheikh Mujib Medical University (BSMMU) and in our private settings, Dhaka, Bangladesh. Four patients had 5 levels (C3-C7), 21 patients had 4 levels (C3-C6) decompression and 3 patients (12%) performed foraminotomies. A total of 104 laminae were opened, all of them were fixed with a titanium reconstruction miniplates. In 21 patients, a 20-hole titanium miniplate bent to the contour of a lamina was used and fixed into 4 laminae and 4 patients fixed in 5 laminae levels. In most patients, screw fixation was unicortical and no spacer or bone graft was used. Demographic and surgical data were collected and clinical outcomes were assessed with neck pain score, neck disability index and Nurick's grading. Outcome analysis was done using Odom's criteria. The mean follow-up duration was 1.8 (range, 1-5) years. Diagnoses were MCSM (n=20), OPLL (n=5). Mean estimated blood loss (EBL) was 120ml (range: 50-200), mean surgery time was 153 min (range: 75-240). Following Nurick's grading, 23 patients (92%) improved, 2 (08%) had the same Nurick grade. No intraoperative complications were noted and average hospital stay was 6.12 days (range: 5 to 9). Significance improvements in overall NDI scores occurred at 1 year follow up (p<0.002). Radiographic evaluation showed an increase in the mean sagittal diameter from 13.3mm at pretreatment to 19.4mm post surgery. Two patients developed transient C5 palsy. Open-door Laminoplasty technique is safe, easy and achieves a good canal expansion and neurological recovery and can be used as an alternative treatment for cases of MCSM and OPLL patients without instability. PMID- 28919611 TI - Incidental Thyroid Carcinoma in Patients Treated Surgically for Presumably Benign Thyroid Disease. AB - Incidental Thyroid Carcinoma (ITC) is quite high as been reported in the world's Journal. This study reviews the frequency of the ITC in patients treated surgically for otherwise benign Thyroid disease in one of the Endocrine surgery unit of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. This study was developed by the investigating the outcome of one hundred and twenty seven patient who underwent partial or total thyroidectomy for benign thyroid pathology in a single Endocrine Surgery Unit of BSMMU from January 2011 to July 2015. This observational study was done to find out the actual incidence of thyroid malignancy among the patients admitted for surgical management with thyroid pathology. All patients underwent at least FNAC and Ultrasonography of the Neck before surgery. Patients with undetermined cytology and follicular nodules were excluded from the study. Overall 19(14.96%) incidental thyroid carcinoma was recorded. Among the ITC 11(8.66%) Papillary Carcinoma, 7(5.51%) Follicular Carcinoma & 1(0.79%) is poorly differentiated carcinoma. The Overall incidence of papillary carcinoma is higher among the incidental carcinoma of Thyroid. Increased incidence associated with follicular adenoma present as an isolated thyroid nodules or multifocal lesion and should be considered malignant potential and total thyroidectomy would be the right choice as surgical management of the both cases. In case of multinodular goiter, total thyroidectomy is currently practiced in majority of the centers and our observations reinforced the attitude further. PMID- 28919612 TI - Bone Age Determination by Radiology & Imaging in Bangladesh Perspective. AB - Determination of age is one of the most important and vital demand in legal affairs, court and young sports, especially from 7-21 years. There is no established age determination table in our county. So we are dependent upon Galstaun, Bashu & Bashu and other European tables, which sometimes provide misinterpretation and variation of opinion. We should have our own table suitable for our nation. So, this prospective study was carried out in the Department of Radiology and Imaging of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2010 to June 2014 (five years) to assess the general skeletal maturity. Three hundred boys and girls of known date of birth were selected on random basis from Dhaka. Ages were limited within 7 to 21 year. Every 20 person for each age group, of them 10 were male and 10 were female. To observe the bony maturity, radiographs were taken at the end of their age belongs to. Thus a growth table is to be prepared for further evaluation. PMID- 28919613 TI - Non-invasively Measured Carotid Artery Intima-Medial Thickness May Be a More Useful Marker of Coronary Artery Disease in Diabetic than Non-Diabetic Patients. AB - Carotid intima-medial thickness has long been proposed as a surrogate marker of atherosclerotic vascular disease in other vascular beds, most notably the coronary arteries with its practical implications. This observational study aimed at exploring the relationship of a hypothetical stronger relationship of carotid intima-medial thickness with coronary artery disease in diabetic patients than non-diabetic counterparts. Thirty diabetic patients and 74 non-diabetic patients who were referred for coronary angiogram in the Departments of Cardiology Bangabandhu Sheikh Mujib Medical University and Combined Military Hospital, Dhaka Cantonment, Bangladesh from January, 2002 and December, 2003 were studied. Carotid ultrasound was done to determine intima-medial thickness and coronary angiogram to detect coronary artery lesions. Background demographic data and cardiovascular risk factors were determined. Of the 30 diabetic patients 24 subjects had CAD. Twenty two of these 24 patients showed increased carotid IMT. None of the patients without CAD had shown carotid artery intima-medial thickening (sensitivity 91% specificity 100%). In contrast, in the non-diabetic group 44 patients out of 63 with CAD showed increased carotid artery IMT. Four of the 11 non-diabetic patients without CAD showed positive carotid ultrasound study results (sensitivity 70%, specificity 63%). This study showed a strong association of coronary artery disease with carotid intima-medial thickness in diabetic patients compared to non-diabetic subjects. This finding may be applicable for Bangladeshi diabetic population. This surrogate marker of coronary artery disease can be useful in the management of diabetes as regards their prevention of coronary artery disease. The practical and clinical implications of these findings might be the pioneer study in diabetic subjects and need to be further determined in a larger community level study. PMID- 28919614 TI - Use of Acute Physiology and Chronic Health Evaluation (APACHE)-II and Red Cell Distribution Width (RDW) for Assessment of Mortality of Patients with Sepsis in ICU. AB - Critically ill patients of Intensive Care Unit (ICU) need highest level of monitoring, intense nursing care and integrated management which are very expensive and consume significant part of hospital resources. Prediction of outcome from disease has become an essential component of health science. So, various scoring systems have been developed to predict outcome of critically ill patients in ICU. There is no perfect model of severity score to predict ICU mortality. Search for new system is still remaining as continuous efforts to find the best model to get accurate information about the prognosis and outcome of critically ill patients. This observational prospective cohort study was carried out in ICU of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from March 2015 to September 2015 to evaluate the ability of mortality prediction of Acute Physiology and Chronic Health Evaluation (APACHE)-II after adding RDW. Total 62 patients, clinically diagnosed as sepsis with positive culture were included in this study after analyzing selection criteria. APACHE II score model was compared with APACHE II plus RDW score model in relation to mortality outcome assessment. Sensitivity, Specificity, Positive predictive value (PPV), Negative predictive value (NPV) and Receiver Operating Characteristic (ROC) curve were used as parameter to compare the predictive ability of the two models. The derived model APACHE II- RDW was found with higher predictive power (Pearson's correlation coefficient - 0.915) than APACHE II (Pearson's correlation coefficient - 0.885) in relation to mortality (p<0.01). Accuracy was compared by using Receiver Operating Characteristic (ROC) curve between the two models and AUROC was found higher (AUC-0.87) in case of new model compared with conventional model (AUC-0.85). So combination of RDW with APACHE-II increases the predictive ability of the scoring model in relation to mortality. PMID- 28919615 TI - Microbiology of Chronic Suppurative Otitis Media in a Tertiary Care Hospital in Bangladesh. AB - This cross sectional prospective study was carried out in the Department of Otolaryngology-Head & Neck Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU) and Department of Microbiology, University of Dhaka from July 2012 to June 2013. The objectives of this study were to identify the common microorganisms involved and the antibiograms of chronic suppurative otitis media (CSOM) patients in this tertiary care hospital in Bangladesh. A total of 117 patients clinically diagnosed of CSOM were enrolled in the study. They had chronic ear discharge & had not received any topical or systemic antibiotics for the previous five days. Swabs was taken and cultured for bacteria. The standard of isolation and identification was followed. Antimicrobial susceptibility of all aerobic bacterial isolates was performed by using modified Kirby Bauer Disk diffusion method. There were 186 positive cultures for organism from 117 patients. The most common causal organisms isolated were S. aureus (47.30%) and Pseudomonas spp. (27.40%) followed by S. epidermidis (16.10%), Klebsiella spp. (8.10%) and Escherichia coli. (1.10%). Gentamicin showed the highest sensitivity (89.8%) to S. aureus whereas erythromycin showed the lowest sensitivity (14.8%) with highest resistance (67%) to S. aureus. Pseudomonas spp. showed highest sensitivity against ciprofloxacin (78.4%) and highest resistance against cloxacillin (96.1%). Novobiocin showed the highest sensitivity (100%) followed by chloram phenicol (94.1%) to S. epidermidis. Klebsiella spp. and E. coli showed highest sensitivity against chloram phenicol. This study suggests that Staphylococcus aureus and Pseudomonas are the commonest bacteria involved in CSOM in Bangladesh and Ciprofloxacin is an important tool in the management of active CSOM. PMID- 28919616 TI - Detection of Human Papilloma virus by Molecular method from Patients Attending at Colposcopy Clinic of Mymensingh Medical College Hospital, Mymensingh. AB - Cervical cancer is the second most common cancer in women worldwide. Human papillomavirus (HPV) is considered as the main cause of invasive cervical cancer and cervical intra-epithelial neoplasia. High risk HPV DNA has been shown to be present in 99.7% of cervical cancers. So HPV DNA testing for screening of cervical cancers may play a potential role in early detection and management of cervical cancer. With above background a cross sectional study was undertaken to estimate the prevalence and to identify the associated risk factors of human Papillomavirus infection among Visual Inspection with Acetic acid (VIA) positive women attending at colposcopy clinic of Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from July 2013 to December 2014. One hundred and forty three cervical swabs for nested PCR were collected from the patients attending colposcopy clinic of MMCH, for detecting target gene of L1 region of the HPV genome. Among the 143 VIA positive patient nested PCR showed 49.6% (71/143) positive. Biopsy of 54 colposcopy positive women revealed that 16 (29.6%) cases were chronic cervicitis, 33 (61.1%) cases were mild dysplasia (C1NI), 01 (1.9%) were having moderate dysplasia (C1NII) and 04(7.4%) patients were diagnosed as invasive squamous cell carcinoma. So, high grade cervical lesions were 100% positive by nested PCR for HPV. PMID- 28919617 TI - Response & Side Effects of Injectable Labetalol in Pregnancy Induced Severe Hypertension. AB - The study was performed to assess the response & side effects of injectable Labetalol in the treatment of pregnancy induced severe hypertension. This interventional study was carried out on 72 patients having pregnancy induced severe hypertension attended in the Department of Obstetrics & Gynaecology, Mymensingh Medical College & Hospital (MMCH), Mymensingh, Bangladesh from November 2009 to October 2010. All patients were treated with intravenous Labetalol 20mg & the dose was repeated at sequential escalating dosages every 15 minutes until a therapeutic goal of systolic blood pressure <160mm of Hg & diastolic blood pressure <105mm of Hg were achieved. Among 72 respondents highest number were observed having systolic blood pressure 160-169 and 180 & above mm of Hg. The mean systolic & the diastolic blood pressure at the initiation of the study were observed 198+/-13.17mm of Hg & 119+/-8.6mm of Hg respectively. After use of injection Labetalol mean systolic blood pressure were 138.61+/-15.43mm of Hg, which is statistically significant (p value <0.001) & mean diastolic blood pressure were 96.18+/-9.7mm of Hg, which is also statistically significant (p value <0.001). It was observed that majority patients' blood pressure was controlled by 1-2 doses. It was noticed that injection Labetalol controls blood pressure in 80% antenatal cases & 86% postnatal cases. Out of 72 patients 4 cases (5.5%) experienced nausea & vomiting and only 1 case (1.1%) experienced headache. Regarding fetal outcome 48% patients delivered healthy baby, about 31% patients delivered asphyxiated baby & neonatal death were noticed in 4% cases. This study assessing the response & side effects of intravenous antihypertensive drug in the treatment of pregnancy induced severe hypertension shows that Labetalol fulfils the criteria of an antihypertensive drug for this purpose. PMID- 28919618 TI - Molecular Detection and Differentiation of Mycobacterium Tuberculosis Complex and Non-tuberculous Mycobacterium in the Clinical Specimens by Real Time PCR. AB - Mycobacteria are subdivided into three groups: the Mycobacterium tuberculosis complex, the non-tuberculous mycobacteria called NTM or MOTT (Mycobacteria Other Than Tuberculosis) and Mycobacterium leprae. Over the past few decades, the incidence of infections caused by NTM has increased world wide. The differentiation of Mycobacterium tuberculosis complex from NTM is of primary importance for infection control and choice of antimicrobial therapy. However, there is so far no report in Bangladesh about the detection of NTM and hence differentiation of MTB and NTM. Neither acid-fast bacilli (AFB) staining nor histopathology can discriminate MTB and NTM. In order to detect and differentiate Mycobacterium tuberculosis complex and NTM we used commercially available LyteStar TB/NTM Real Time PCR kit (Altona Diagnostics, Germany) and analyzed 782 clinical specimens from tuberculosis suspected patients. We have found 49 MTB and 74 NTM positive samples from variety of clinical specimens such as sputum, bronchial lavages, body fluids, tissues, needle aspirates and swabs. Many of the PCR positive specimens were AFB negative on direct microscopic examination thus, indicating strong sensitivity of PCR than AFB staining. This is the first report in the country about detection of NTM and it warrants further elaborate investigation. Moreover, our results showed that multiplex real-time PCR assay is an effective sensitive tool for the rapid identification and differentiation of MTB and NTM directly from clinical specimens. PMID- 28919619 TI - Comparison of Serum Bilirubin with Transcutaneous Bilirubinometry in Late Preterm and Term Newborn. AB - Neonatal jaundice or hyperbilirubinemia is a common occurrence in newborns. It can progress to develop kernicterus unless intervention is initiated. Severity and decision for management are usually based on serum bilirubin which needs blood sampling. Transcutaneous bilirubin measurement is a noninvasive technique and correlates closely with serum bilirubin. This Cross sectional study was done in the Department of Neonatology, Bangabandhu Sheikh Mujib Medical University from March 2013 to August 2014 to evaluate the transcutaneous bilirubin in comparison to serum bilirubin. Total 160 infants with >=35 weeks were purposively included over a period of 16 months. Neonates with less than 35 weeks, previously exposed to phototherapy, serious illness which leads to impaired circulation, who have had exchange transfusion, having major congenital malformation were excluded. Transcutaneous bilirubin measurement was performed within 30 minutes of obtaining sample for total serum bilirubin measurements. Of the enrolled infants, mean birth weight was 2631+/-520 grams, postnatal age was 4.99+/-3.02 days ranging from 2 to 25 days and mean transcutaneous bilirubin and serum bilirubin value was 14.59+/-2.55 and 13.62+/-2.86mg/dl respectively. Mean difference of transcutaneous bilirubin and serum bilirubin was 0.97+/-1.01mg/dl. In the total enrolled infant, transcutaneous bilirubin and serum bilirubin values showed significant correlation (r = 0.93, r2 = 0.876, p<0.001) and this was not affected by sex, gestational age, postnatal age, and birth weight. The area under ROC curve for transcutaneous bilirubin was 87% (p value <0.001). If the cut off value of transcutaneous bilirubin was set at 15 mg/dl, then a sensitivity of 77%, specificity of 88% and accuracy of 82% were obtained. Use of transcutaneous bilirubin can reduce need for serum bilirubin in assaying neonatal jaundice; as it showed significantly high correlation with serum bilirubin. Predictive accuracy of transcutaneous bilirubin was found to be statistically significant in comparison to serum bilirubin. PMID- 28919620 TI - Role of Serum Pepsinogen I and II Ratio in Screening of Gastric Carcinoma. AB - In spite of the global decline in its incidence and mortality, gastric carcinoma still remains a major cause of death due to cancer. Early detection of gastric carcinoma is expected to reduce mortality rates. The applications of measuring of pepsinogen I and pepsinogen II are useful in screening of gastric carcinoma. This cross sectional comparative study was done to find out the correlation of histopathological pattern of gastric carcinoma with serum pepsinogen I & II ratio in the Department of Pathology, Sylhet MAG Osmani Medical College, Sylhet, Bangladesh from January 2010 to December 2010. For these purpose 40 patients with gastric carcinoma, endoscopically visible and histopathologically proved malignant lesions were enrolled as case group. Forty subjects with normal upper GI endoscopy were taken as control. Five ml of venous blood was taken from both case and control subjects to determine serum pepsinogen I and pepsinogen II level by ELISA method, subsequently pepsinogen I and II ratio was calculated. In this study different cut off values of serum pepsinogen I and II ratio was determined and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 70.0%, 97.5% 96.6% 76.5% and 83.8% respectively, at cut off value of 6. Which is the most suitable cut off point of serum pepsinogen I and II ratio for gastric cancer screening. PMID- 28919621 TI - Association of Hypertension with Serum Estrogen Level in Postmenopausal Women. AB - Hypertension is a chronic and debilitating disease. Its complications give rise to cardiovascular diseases, stroke in Postmenopausal women. Estrogen deficiency that develops during menopause is likely the etiological factor for development of hypertension in postmenopausal women. Increased incidence of cardiovascular diseases in postmenopausal women may be due to hypertension caused by lower level of estrogen hormone. The study was carried out to observe the association of hypertension with serum estrogen level in postmenopausal women. This cross sectional study was conducted in the Department of Physiology, Dhaka Medical College, Dhaka, during the period of January 2011 to December 2011. A total number of 90 female subjects were selected from different areas of Dhaka city. Among them, 60 postmenopausal women with age ranging from 50 to 60 years were taken as study group and 30 apparently healthy premenopausal women with age ranging from 20 to 30 years were included as control group for comparison. Systolic blood pressure and diastolic blood pressure were recorded in both groups. Serum estrogen level was estimated in order to assess the hormonal level of both groups. Data was analyzed by Unpaired Student's 't' test and Pearson's co efficient (r) test as applicable. The value of systolic blood pressure was higher in postmenopausal women than those of premenopausal women and result was statistically significant. The level of diastolic blood pressure was also significantly (p<0.001) higher in postmenopausal women in comparison to those of premenopausal women. In postmenopausal women serum estrogen level was lower than premenopausal women and serum estrogen level showed negative correlation with systolic and diastolic blood pressure levels. All these correlation were statistically non significant. Present study revealed that there is association of hypertension with serum estrogen level in postmenopausal women. PMID- 28919622 TI - Incidence of Diabetes Insipidus in Postoperative Period among the Patients Undergoing Pituitary Tumour Surgery. AB - Post operative complications after pituitary tumour surgery vary according to procedure. There are several surgical procedures being done such as transcranial, transsphenoidal microsurgical and transsphenoidal endoscopic approaches. One of the commonest complications is diabetes insipidus (DI). Our main objective was to find out the incidence of diabetes insipidus in post operative period among patients undergoing surgical intervention for pituitary tumour in our institute. The presence of diabetes insipidus in the postoperative period was established by measuring serum Na+ concentration, hourly urine output and urinary specific gravity to find out the incidence of diabetes insipidus in postoperative period in relation to age, gender, tumour diameter, function of tumour (i.e., either hormone secreting or not) and operative procedure used for surgical resection of pituitary tumor. As it is the most common postoperative complication so, in this study we tried to find out how many of the patients develop diabetes insipidus in postoperative period following surgical resection of pituitary tumour. This cross sectional type of observational study was carried out in the department of Neurosurgery, BSMMU from May 2014 to October 2015 on 33 consecutive patients who underwent surgical intervention for pituitary tumour for the first time. Data was collected by using a data collection sheet. The incidence of diabetes insipidus was found 23.1% of patients in <30 year age group, 38.5% of patients in 31-40 year age group and 38.5% of patients in >=40 year age group (p=0.764). In case of distribution of patients according to gender 38.5% of male and 61.5% of female developed diabetes insipidus (p=0.073). Regarding tumour size 30.8% and 69.2% of patients developed diabetes insipidus having tumour diameter <30mm and >=30mm respectively (p=0.590). In case of operative procedure 69.2% of patients developed diabetes insipidus who was operated by transsphenoidal endoscopic approach, 23.1% and 7.7% of patients developed diabetes insipidus who underwent pituitary tumour resection through transsphenoidal microscopic approach and transcranial microscopic approach respectively (p=0.432). 17.6% of patients develop DI having functioning pituitary macroadenoma and 62.5% of patients develop DI having nonfunctioning pituitary macroadenoma. This observational study has been performed to find out the incidence of diabetes insipidus. Incidence of postoperative DI is more at or around the age of 40 years. It is slightly predominant in female. Most of the patients manifest DI in the first 24 hours of surgical intervention. Incidence of DI is low among patients having functioning pituitary macroadenoma. PMID- 28919623 TI - Outcome of Upper Gastrointestinal Surgery With or Without Nasogastric Intubation. AB - Nasogastric intubation is a common procedure with both merits and demerits. Controversies exist about the routine use of nasogastric intubation following upper gastrointestinal surgery. Good numbers of literatures were published in favour of selective nasogastric intubation pointing out some complications of routine use of nasogastric tube. In 1995, Cheatham et al. concluded in a meta analysis that although patients may develop abdominal distension or vomiting without a nasogastric tube, this is not associated with an increase in complications or length of hospital stay. For every patient requiring insertion of a nasogastric tube in the postoperative period, at least 20 patients will not require nasogastric decompression. In July 2004, Cochrane database of systemic review published the result of their systemic review on the prophylactic decompression after abdominal surgery, that review was revised and updated in 2007. According to this database, routine nasogastric intubation should be abandoned in favour of selective use of nasogastric tube. In our country some surgeons are practicing it routinely and some are not. This observation prompted us to conduct this study in order to see and compare the outcome of upper gastrointestinal surgery with and without nasogastric intubation. This will help us to make decision whether nasogastric intubation will be done routinely or not following upper gastrointestinal surgery. PMID- 28919624 TI - Frequency, Distribution of Congenital Anomaly and Associated Maternal Risk Factors. AB - This study was done to find out the maternal risk factors associated with congenital anomaly. This cross-sectional observational study was carried out in the Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital, Dhaka, Bangladesh from January 2011 to December 2011. During this study period 78 patients had pregnancy with congenital anomaly and delivered in the Department of Obstetrics and Gynaecology. Women with ultrasound report of congenitally abnormal fetus irrespective of gestational age were included. Clinical evaluation of neonates was done by experienced neonatologist. The frequency of congenital anomaly was 3.46%. Most of the women belong to age <35 years (97.43%). Congenital anomalies more commonly were seen in the primiparas (64.10%). Most frequent associated risk factor was the history of abortions (35.89%). Maternal infections during antenatal period were also high (15.58%). There were 58 males (74.35%) and 20 females (25.64%). There was positive history of delivery of congenital abnormal babies in 6 cases (7.6%). Mothers of eight cases (10.25%) had history of drug ingestion during pregnancy. Four cases (5.12%) of mothers had hypothyroidism and 6 cases of mothers (7.69%) had diabetes mellitus respectively. PMID- 28919625 TI - Van Wyk and Grumbach Syndrome: An Unusual Presentation of Hypothyroism. AB - An 18 years-old-girl presented one and half years back with the complaints of short stature, retarded growth, and menorrhagia with sudden severe lower abdominal pain; was diagnosed as bilateral ovarian cysts and underwent bilateral ovarian cystectomy. Later on she was incidentally diagnosed as a case of hypothyroidism when she had been experiencing slowly enlarging left lower abdominal mass with dull ache for the 5 month and then was transferred to the department of Endocrinology for further evaluation. Detailed work up revealed her short stature with obesity, delayed bone age and other features of hypothyroidism which was confirmed by thyroid function testing. She had enlarged left ovary with multiple follicles as shown in ultrasonography. Magnetic resonance imaging (MRI) showed sellar mass which was suspicious of macroadenoma. Levothyroxine replacement was started and she had a dramatic improvement of her problems with disappearance of the ovarian cysts and sellar mass. PMID- 28919626 TI - Addison's Disease: A Diagnostic Dilemma. AB - Adrenal insufficiency is a rare disease, but is life threatening when overlooked. Addison's disease may be an acquired form of adrenal insufficiency due to the destruction or dysfunction of the adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. Main presenting symptoms of Addison's disease such as fatigue, anorexia, vomiting and convulsion often mimics central nervous system (CNS) infections. We describe a case of Addison's disease who was initially misdiagnosed as a case of meningo-encephalitis subsequently renal tubular acidosis and finally Addison's disease. Addison's disease can remain unrecognized until acute crisis and sometimes it may be misdiagnosed. PMID- 28919627 TI - Ebstein's Anomaly Associated with Atrial Septal Defect and Wolff-Parkinson-White (WPW) Syndrome. AB - Ebstein's anomaly is a rare congenital heart disorder, accounting for <1% of all cases of congenital heart disease. It is a congenital malformation of the heart that is characterized by apical displacement of the septal and posterior tricuspid valve leaflets, leading to atrialization of the right ventricle with a variable degree of malformation and displacement of the anterior leaflet. We report the case of a 25 years old female with Ebstein's anomaly which was associated with Ostium Secundum type of atrial septal defect and WPW syndrome, who presented with dyspnea, palpitations, cyanosis, clubbing and cardiomegaly. PMID- 28919628 TI - Coronary Artery Bypass Graft with Endarterectomy and Stent Removal in Patient with Multivessel in Stent Restenosis. AB - In the age of stent deployment after balloon angioplasty. In stent restenosis (ISR) has become a major concern. Various coronary interventional measures and coronary artery bypass graft (CABG) has employed to manage the ISR. Although CABG seems to offer advantages over other coronary intervention methods in patients with multi vessel ISR; lack of appropriate graftable vessels often make the surgery difficult and end up with incomplete revascularization. Coronary endarterectomy with stent removal mitigated some of the limitations of CABG but initial results of this surgical measure were not favorable. Later, with improvement of surgical technique and meticulous anticoagulant therapy along with CABG showed promising result but till date only few cases have been reported. Here, we are reporting a case of 65 years old lady who underwent CABG along with endarterectomy with stent removal after she had developed stent restenosis in three vessels. This diabetic and hypertensive patient presented with chest pain and shortness of breath which was developed within three months of PCI with stent deployment in three vessels. Angiogram done prior to admission in the cardiac surgery department reveals restenosis in all the three stented vessels. CABG was done and three grafts given in LIMA to LAD, RSVG to OM and RCA. Endarterectomy done on LAD and RCA with stent removal from RCA. Postoperative anticoagulant therapy was strictly maintained. Patient's postoperative period remained eventless other than superficial wound infection. With skilled hand capable of handling highly technique demanding surgery and postoperative anticoagulation maintenance; endarterectomy along with CABG seems to be safe solution for multi vessel ISR with diffuse coronary artery disease. PMID- 28919629 TI - Acinar Cell Carcinoma of the Pancreas: A Case Report. AB - Acinar cell carcinoma (ACC) of the pancreas is a very rare neoplasm. We report a case of pancreatic acinar cell carcinoma involving the uncinate process of the pancreas. A 45 year old man presented with a painful upper abdominal mass without any jaundice or weight loss. Computed Tomography (CT) and Magnetic Resonance Cholangio-Pancreatography (MRCP) indicated a mass lesion in the uncinate process of the pancreas. He underwent Whipple's procedure (Pancreaticoduodenectomy). Histological slides revealed features of Acinar cell carcinoma (ACC) in the uncinate process of the pancreas and a lymph node. PMID- 28919630 TI - Deep Vein Thrombosis in A Post-Coronary Artery Bypass Grafting Patient: Successful Conservative Management. AB - Deep vein thrombosis is an alarming medical emergency. Deep vein thrombosis or deep venous thrombosis (DVT) is the formation of a blood clot (thrombus) within a deep vein predominantly in the legs. Post-Coronary Artery Bypass Grafting deep vein thrombosis is a very rare medical condition relatively in Asian. Approximately 80% of deep vein thrombosis (DVTs) is clinically asymptomatic, 20% of those that actually demonstrate signs and symptoms can be easily confused with symptoms of other commonly presenting musculoskeletal disorders. Proper medical management can reduce patient's morbidity and further burden. A 50 years old diabetic Post-Coronary Artery Bypass Grafting gentleman had been suffering for left leg swelling, high grade fever and calf muscle pain for 5 days. He had absent Arteria Dorsalis Paedis pulse on left foot, Positive Homan sign and Wells score is 7. His left leg was hugely swelled. He had normal leg hair distribution. Duplex study of Left Leg-Deep Vein Thrombosis in left lower limb (Popliteal segment) with sign of recanalization. He is also a patient of anemia of chronic disease due to hemorrhoid. Several investigations have done to find the cause of his chronic anemia. His treatment was meticulous with complete bed rest, elevation of left lower limb, heparinization, oralrivaroxaban. He had rapid recovery following treatment. Post-Coronary Artery Bypass Grafting patient should be given post-operative enoxaparin (Low molecular weight Heparin) or Heparin for 3-5 days. Early diagnosis of the disease condition reduces morbidity. Combined treatment with Rivaroxaban and Heparin is of great clinical value and outcome in a case of Post-Coronary Artery Bypass Grafting Deep Vein Thrombosis patient. PMID- 28919631 TI - Right Atrial Myxoma: An Uncommon Presentation. AB - There are two types of tumors found in the cardiac chamber. These are divided into primary intra-cardiac tumors and secondary intra-cardiac tumors. Primary intra cardiac tumors are rare and among them 29% are myxomas. Majority of them are found in the left atrium. Here, we report a case of a myxoma in the right atrium with hepatomegaly and Hepatitis B virus infection. The coexistence of all these conditions is very rare. A 52 years old patient presented with history of shortness of breath on exertion along with fever and generalized weakness for 6 months which aggravated lately for last 2 months. He was then taken for better medical care and hospitalization. On cardiac evaluation he had soft S1 and S2 over the tricuspid region on the right lower parasternal region. He had bilateral mild pitting pedal edema. On further examination, it was revealed that he had mild tender hepatomegaly with jaundice. His blood analysis for HBsAg was positive. Echocardiogram showed right atrial myxoma of 14.3cm2 almost completely occupying the right atrium and even protruding into the Inferior Venacava however not fully obstructing it. The inferior vena cava size was mildly dilated (22mm). Abdominal ultrasound report showed hepatomegaly (17.6cm) with coarse hepatic parenchyma. In this report, we emphasize the rarity of myxoma in the Right Atrium, its difficult diagnosis because of the location and the atypical presentation in the echocardiograph. PMID- 28919633 TI - Clinical presentation and outcomes in light chain amyloidosis patients with non evaluable serum free light chains. AB - Hematologic response criteria in light chain (AL) amyloidosis require the difference in involved and uninvolved free light chains (dFLC) to be at least 5 mg/dl. We describe the clinical presentation and outcomes of newly diagnosed amyloidosis patients with dFLC <5 mg/dl (non-evaluable dFLC; 14%, n=165) compared with patients with dFLC ?5 mg/dl (evaluable dFLC; 86%, n=975). Patients with non evaluable dFLC had less cardiac involvement (40% vs 80%, P<0.001), less liver involvement (11% vs 17%, P=0.04) and a trend toward less gastrointestinal involvement (18% vs 25%, P=0.08). However, significantly higher renal involvement (72% vs 56%, P=0.0002) was observed in the non-evaluable dFLC cohort. Differences in treatment patterns were observed, with 51% of treated patients undergoing upfront stem cell transplantation in the non-evaluable cohort compared with 28% in the evaluable dFLC group (P<0.001). Progression-free survival (61 vs 13 months, P<0.001) and overall survival (OS; 101 vs 29 months, P<0.001) were significantly longer in the non-evaluable dFLC cohort. Normalization of involved light chain levels and decrease in dFLC <1 mg/dl (baseline at least 2 mg/dl) were predictive of OS and associated with better dialysis-free survival and may be used for response assessment in patients with non-evaluable FLC levels. PMID- 28919634 TI - Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML reduces the risk of relapse. PMID- 28919632 TI - CD36 in chronic kidney disease: novel insights and therapeutic opportunities. AB - CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates the binding and cellular uptake of long-chain fatty acids, oxidized lipids and phospholipids, advanced oxidation protein products, thrombospondin and advanced glycation end products, and has roles in lipid accumulation, inflammatory signalling, energy reprogramming, apoptosis and kidney fibrosis. Renal CD36 is mainly expressed in tubular epithelial cells, podocytes and mesangial cells, and is markedly upregulated in the setting of chronic kidney disease (CKD). As fatty acids are the preferred energy source for proximal tubule cells, a reduction in fatty acid oxidation in CKD affects kidney lipid metabolism by disrupting the balance between fatty acid synthesis, uptake and consumption. The outcome is intracellular lipid accumulation, which has an important role in the pathogenesis of kidney fibrosis. In experimental models, antagonist blockade or genetic knockout of CD36 prevents kidney injury, suggesting that CD36 could be a novel target for therapy. Here, we discuss the regulation and post translational modification of CD36, its role in renal pathophysiology and its potential as a biomarker and as a therapeutic target for the prevention of kidney fibrosis. PMID- 28919636 TI - Parasite development: Parasites talk about growth. PMID- 28919637 TI - Development: Transcriptomic blueprints. PMID- 28919635 TI - Aspergillus fumigatus morphology and dynamic host interactions. AB - Aspergillus fumigatus is an environmental filamentous fungus that can cause life threatening disease in immunocompromised individuals. The interactions between A. fumigatus and the host environment are dynamic and complex. The host immune system needs to recognize the distinct morphological forms of A. fumigatus to control fungal growth and prevent tissue invasion, whereas the fungus requires nutrients and needs to adapt to the hostile environment by escaping immune recognition and counteracting host responses. Understanding these highly dynamic interactions is necessary to fully understand the pathogenesis of aspergillosis and to facilitate the design of new therapeutics to overcome the morbidity and mortality caused by A. fumigatus. In this Review, we describe how A. fumigatus adapts to environmental change, the mechanisms of host defence, and our current knowledge of the interplay between the host immune response and the fungus. PMID- 28919638 TI - Direct Measurements of 3D Structure, Chemistry and Mass Density During the Induction Period of C3S Hydration. AB - The reasons for the start and end of the induction period of cement hydration remain topic of controversy. One long-standing hypothesis is that a thin metastable hydrate forming on the surface of cement grains significantly reduces the particle dissolution rate; the eventual disappearance of this layer re establishes higher dissolution rates at the beginning of the acceleration period. However, the importance, or even the existence, of this metastable layer has been questioned because it cannot be directly detected in most experiments. In this work, a combined analysis using nano-tomography and nano-X-ray fluorescence makes the direct imaging of early hydration products possible. These novel X-ray imaging techniques provide quantitative measurements of 3D structure, chemical composition, and mass density of the hydration products during the induction period. This work does not observe a low density product on the surface of the particle, but does provide insights into the formation of etch pits and the subsequent hydration products that fill them. PMID- 28919639 TI - Using a narrative to spark safer sex communication. AB - OBJECTIVE: College students are a group at risk for contracting sexually transmitted infections (STIs). While they are generally well informed about STIs, they do not consistently use condoms. An important element in preventing STIs is safer sex communication, especially with a sexual partner. This may be difficult, however, because of a lack of experience in talking about safer sex or because of the absence of suitable role models. In this study, a narrative intervention was tested that was developed to provide receivers with a social script for safer sex communication. DESIGN: An experiment was conducted among college students (N = 225) who were exposed to either a narrative intervention or a non-narrative (brochure) intervention, followed by a post-test questionnaire. In the narrative condition, part of the participants completed a pre-test questionnaire before being exposed to the intervention. RESULTS: Compared to pre-test scores, the narrative positively influenced safer sex communication intentions. The results show no significant differences between post-test scores of the narrative and the non-narrative condition. Mediation analyses showed that narrative processes (identification and transportation) were positively related to safer sex communication. CONCLUSION: In this study, we investigated both the effects of a narrative intervention on safer sex communication intentions, and the mechanisms of narrative processing underlying these effects. The narrative turned out to be as effective as a brochure version with the same information. Our mediation analyses suggest that narratives can be made more persuasive by increasing the reader's involvement with the story as a whole, and with one of the characters in particular. PMID- 28919640 TI - Charon tectonics. AB - New Horizons images of Pluto's companion Charon show a variety of terrains that display extensional tectonic features, with relief surprising for this relatively small world. These features suggest a global extensional areal strain of order 1% early in Charon's history. Such extension is consistent with the presence of an ancient global ocean, now frozen. PMID- 28919641 TI - In-house or outsourced public services? A social and economic analysis of the impact of spending policy on the private wage share in OECD countries. AB - This article analyses the relationship between government spending and the distribution of private income between capital and labour. While most previous research assumes that government spending redistributes in favour of the less wealthy, I distinguish between types of expenditures that enhance the bargaining position of labour - that is, unemployment benefits, public sector employment and investment in new capital - and labour-saving and pro-business types of expenditures - that is, outsourcing to private firms. The results are derived from various panel regression techniques on a panel of 19 Organisation for Economic Co-operation and Development (OECD) countries in the period 1985-2010 and show that expenditures on public sector employment and, to a lesser extent, on new capital prevented the private wage share from declining further, even after controlling for labour market institutions, globalisation and technological change. Conversely, expenditures on outsourcing substantially contributed to reducing the private wage share. Unemployment benefits had a non-significant and negative effect on the private wage share because their increase was the consequence of higher levels of unemployment rather than policy. Implications for theory and policy are drawn, including the support for a public employment-led spending policy. PMID- 28919642 TI - Membrane Binding of Parkinson's Protein alpha-Synuclein: Effect of Phosphorylation at Positions 87 and 129 by the S to D Mutation Approach. AB - Human alpha-synuclein, a protein relevant in the brain with so-far unknown function, plays an important role in Parkinson's disease. The phosphorylation state of alphaS was related to the disease, prompting interest in this process. The presumed physiological function and the disease action of alphaS involves membrane interaction. Here, we study the effect of phosphorylation at positions 87 and 129, mimicked by the mutations S87A, S129A (nonphosphorylated) and S87D, S129D (phosphorylated) on membrane binding. Local binding is detected by spin label continuous-wave electron paramagnetic resonance. For S87A/D, six positions (27, 56, 63, 69, 76, and 90) are probed; and for S129A/D, three (27, 56, and 69). Binding to large unilamellar vesicles of 100 nm diameter of 1-palmitoyl-2-oleoyl sn-glycero-3-phospho-(1'-rac-glycerol) and 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine in a 1 : 1 composition is not affected by the phosphorylation state of S129. For phosphorylation at S87, local unbinding of alphaS from the membrane is observed. We speculate that modulating the local membrane affinity by phosphorylation could tune the way alphaS interacts with different membranes; for example, tuning its membrane fusion activity. PMID- 28919643 TI - Misconceptions in the Exploding Flask Demonstration Resolved through Students' Critical Thinking. AB - As it connects to a large set of important fundamental ideas in chemistry and analytical techniques discussed in high school chemistry curricula, we review the exploding flask demonstration. In this demonstration, methanol vapor is catalytically oxidized by a Pt wire catalyst in an open container. The exothermicity of reactions occurring at the catalytic surface heats the metal to the extent that it glows. When restricting reactant and product gas flow, conditions may favor repetitive occurrence of a small explosion. We show how mass spectrometry and infrared spectroscopy allow for unravelling the chemical background of this demonstration and discuss various ideas on how to use it in a classroom setting to engage students' critical thinking about chemical research. Along the way, we show that two commonly published ideas about the chemical background of this demonstration are incorrect, and we suggest simple tests that may be performed in a high school setting either as an addition to the demonstration or as a student research project. PMID- 28919644 TI - Heterogeneous Catalytic Oxidation of Simple Alcohols by Transition Metals. AB - The "exploding" flask demonstration presents a well-known illustration of heterogeneous catalyzed methanol oxidation. We find that for the same vapor pressure, the demonstration also works for all primary and secondary alcohols up to butanol but not for a tertiary alcohol. Also, we show that the demonstration works for a large range of transition metal catalysts. Hence, this demonstration, which is often applied for the repetitive explosions when methanol is used, may also be used to argue the requirement of initial dehydrogenation of the alcohol to an aldehyde in the catalytic reaction mechanism to support the general insensitivity to reactant molecules in heterogeneous catalysis in contrast to biological catalysis and to provide proof for activity trends as often depicted by volcano plots. PMID- 28919645 TI - Does Clean Water Make You Dirty?: Water Supply and Sanitation in the Philippines. AB - Water supply investments in developing countries may inadvertently worsen sanitation if clean water and sanitation are substitutes. This paper examines the negative correlation between the provision of piped water and household sanitary behavior in Cebu, the Philippines. In a model of household sanitation, a local externality leads to a sanitation complementarity that magnifies the compensatory response. Empirical results are consistent with the hypotheses that clean water and sanitation are substitutes and that neighbors' sanitation levels are complements. In this situation, clean water may have large unintended consequences. PMID- 28919646 TI - On the competition between weak O-H...F and C-H...F hydrogen bonds, in cooperation with C-H...O contacts, in the difluoromethane - tert-butyl alcohol cluster. AB - The 1:1 complex of tert-butyl alcohol with difluoromethane has been characterized by means of a joint experimental-computational investigation. Its rotational spectrum has been recorded by using a pulsed-jet Fourier-Transform microwave spectrometer. The experimental work has been guided and supported by accurate quantum-chemical calculations. In particular, the computed potential energy landscape pointed out the formation of three stable isomers. However, the very low interconversion barriers explain why only one isomer, showing one O-H...F and two C-H...O weak hydrogen bonds, has been experimentally characterized. The effect of the H -> tert-butyl- group substitution has been analyzed from the comparison to the difluoromethane-water adduct. PMID- 28919647 TI - Limiting Values of the one-bond C-H Spin-Spin Coupling Constants of the Imidazole Ring of Histidine at High-pH. AB - Assessment of the relative amounts of the forms of the imidazole ring of Histidine (His), namely the protonated (H+) and the tautomeric Nepsilon2-H and Ndelta1-H forms, respectively, is a challenging task in NMR spectroscopy. Indeed, their determination by direct observation of the 15N and 13C chemical shifts or the one-bond C-H, 1JCH, Spin-Spin Coupling Constants (SSCC) requires knowledge of the "canonical" limiting values of these forms in which each one is present to the extent of 100%. In particular, at high-pH, an accurate determination of these "canonical" limiting values, at which the tautomeric forms of His coexist, is an elusive problem in NMR spectroscopy. Among different NMR-based approaches to treat this problem, we focus here on the computation, at the DFT level of theory, of the high-pH limiting value for the 1JCH SSCC of the imidazole ring of His. Solvent effects were considered by using the polarizable continuum model approach. The results of this computation suggest, first, that the value of 1JCepsilon1H = 205 +/- 1.0 Hz should be adopted as the canonical high-pH limiting value for this SSCC; second, the variation of 1JCepsilon1H SSCC during tautomeric changes is minor, i.e., within +/-1Hz; and, finally, the value of 1JCdelta2H SSCC upon tautomeric changes is large (15 Hz) indicating that, at high-pH or for non protonated His at any pH, the tautomeric fractions of the imidazole ring of His can be predicted accurately as a function of the observed value of 1JCdelta2H SSCC. PMID- 28919648 TI - Optical Imaging of Large Gyroid Grains in Block Copolymer Templates by Confined Crystallization. AB - Block copolymer (BCP) self-assembly is a promising route to manufacture functional nanomaterials for applications from nanolithography to optical metamaterials. Self-assembled cubic morphologies cannot, however, be conveniently optically characterized in the lab due to their structural isotropy. Here, the aligned crystallization behavior of a semicrystalline-amorphous polyisoprene-b polystyrene-b-poly(ethylene oxide) (ISO) triblock terpolymer was utilized to visualize the grain structure of the cubic microphase-separated morphology. Upon quenching from a solvent swollen state, ISO first self-assembles into an alternating gyroid morphology, in the confinement of which the PEO crystallizes preferentially along the least tortuous pathways of the single gyroid morphology with grain sizes of hundreds of micrometers. Strikingly, the resulting anisotropic alignment of PEO crystallites gives rise to a unique optical birefringence of the alternating gyroid domains, which allows imaging of the self assembled grain structure by optical microscopy alone. This study provides insight into polymer crystallization within a tortuous three-dimensional network and establishes a useful method for the optical visualization of cubic BCP morphologies that serve as functional nanomaterial templates. PMID- 28919649 TI - Expanding STEM opportunities through inclusive STEM-focused high schools. AB - Inclusive STEM high schools (ISHSs) (where STEM is science, technology, engineering, and mathematics) admit students on the basis of interest rather than competitive examination. This study examines the central assumption behind these schools-that they provide students from subgroups underrepresented in STEM with experiences that equip them academically and attitudinally to enter and stay in the STEM pipeline. Hierarchical modeling was applied to data from student surveys and state longitudinal data records for 5113 students graduating from 39 ISHSs and 22 comprehensive high schools in North Carolina and Texas. Compared to peers from the same demographic group with similar Grade 8 achievement levels, underrepresented minority and female ISHS students in both states were more likely to undertake advanced STEM coursework. Hispanics in Texas and females in both states expressed more STEM career interest in Grade 12 if they attended an ISHS. Positive relationships between ISHS attendance and grade point average were found in the total sample and each subgroup in North Carolina. Positive ISHS advantages in terms of test scores for the total student sample were found for science in both states and for mathematics in Texas. For the various student subgroups, test score differences favored the ISHS samples but attained statistical significance only for African Americans' science achievement scores in the Texas study. PMID- 28919650 TI - Bingo! Holy play in experience-oriented society. AB - What place is there for holy play in experience-oriented society? Is it possible and useful to make analytic distinctions between the liturgical quality of events? I explored these questions by doing research on the boundaries between the religious field and the field of leisure. Fifty site visits to public events in the Netherlands (2006-2014) resulted in a collection of ethnographic data. I used the concept of play as introduced by the Dutch historian Johan Huizinga and the tools of ritual studies to explore whether these could help to produce an account of the liturgical quality of ritualized meetings. Holy play might be found in unexpected places, such as in a bingo hall. Huizinga's broad diagnosis of modernity may be outdated, but the tools he introduced remain useful to distinguish the elements that constitute late-modern meetings as more or less playful - even when this involves combinations that seem contradictory from Huizinga's own point of view. PMID- 28919651 TI - Land use change impacts on floods at the catchment scale: Challenges and opportunities for future research. AB - Research gaps in understanding flood changes at the catchment scale caused by changes in forest management, agricultural practices, artificial drainage, and terracing are identified. Potential strategies in addressing these gaps are proposed, such as complex systems approaches to link processes across time scales, long-term experiments on physical-chemical-biological process interactions, and a focus on connectivity and patterns across spatial scales. It is suggested that these strategies will stimulate new research that coherently addresses the issues across hydrology, soil and agricultural sciences, forest engineering, forest ecology, and geomorphology. PMID- 28919652 TI - CAUSAL INFERENCE WITH A GRAPHICAL HIERARCHY OF INTERVENTIONS. AB - Identifying causal parameters from observational data is fraught with subtleties due to the issues of selection bias and confounding. In addition, more complex questions of interest, such as effects of treatment on the treated and mediated effects may not always be identified even in data where treatment assignment is known and under investigator control, or may be identified under one causal model but not another. Increasingly complex effects of interest, coupled with a diversity of causal models in use resulted in a fragmented view of identification. This fragmentation makes it unnecessarily difficult to determine if a given parameter is identified (and in what model), and what assumptions must hold for this to be the case. This, in turn, complicates the development of estimation theory and sensitivity analysis procedures. In this paper, we give a unifying view of a large class of causal effects of interest, including novel effects not previously considered, in terms of a hierarchy of interventions, and show that identification theory for this large class reduces to an identification theory of random variables under interventions from this hierarchy. Moreover, we show that one type of intervention in the hierarchy is naturally associated with queries identified under the Finest Fully Randomized Causally Interpretable Structure Tree Graph (FFRCISTG) model of Robins (via the extended g-formula), and another is naturally associated with queries identified under the Non-Parametric Structural Equation Model with Independent Errors (NPSEM-IE) of Pearl, via a more general functional we call the edge g-formula. Our results motivate the study of estimation theory for the edge g-formula, since we show it arises both in mediation analysis, and in settings where treatment assignment has unobserved causes, such as models associated with Pearl's front-door criterion. PMID- 28919653 TI - Comments on "Personalized dose finding using outcome weighted learning". PMID- 28919654 TI - Protecting energy intakes against income shocks. AB - Whether and how changes in economic circumstances or household income affect individuals' diet and nutritional intakes is of substantial interest for policy purposes. This paper exploits a period of substantial income volatility in Russia to examine the extent to which, as well as how individuals protect their energy intakes in the face of unanticipated shocks to household income. Using rich data from the Russia Longitudinal Monitoring Survey, our results suggest that households use substitution, disproportionally cutting back spending on non-foods to protect spending on foods, change the composition of the consumption basket, and increase the consumption of 'cheaper' calories. Taken together, however, we find that total energy intakes as well as the nutritional composition of the diet are almost fully protected against income shocks. Specifically, we find that 12 16% of the effect of permanent income shocks on food expenditures is transmitted to energy intakes, with 84-88% protected through insurance mechanisms. PMID- 28919655 TI - The Ethics of Germline Gene Editing. AB - Germline Gene Editing (GGE) has enormous potential both as a research tool and a therapeutic intervention. While other types of gene editing are relatively uncontroversial, GGE has been strongly resisted. In this article, we analyse the ethical arguments for and against pursuing GGE by allowing and funding its development. We argue there is a strong case for pursuing GGE for the prevention of disease. We then examine objections that have been raised against pursuing GGE and argue that these fail. We conclude that the moral case in favour of pursuing GGE is stronger than the case against. This suggests that pursuing GGE is morally permissible and indeed morally desirable. PMID- 28919656 TI - Direct valorisation of waste cocoa butter triglycerides via catalytic epoxidation, ring-opening and polymerisation. AB - BACKGROUND: Development of circular economy requires significant advances in the technologies for valorisation of waste, as waste becomes new feedstock. Food waste is a particularly important feedstock, containing large variation of complex chemical functionality. Although most food waste sources are complex mixtures, waste from food processing, no longer suitable for the human food chain, may also represent relatively clean materials. One such material requiring valorisation is cocoa butter. RESULTS: Epoxidation of a triglyceride from a food waste source, processing waste cocoa butter, into the corresponding triglyceride epoxide was carried out using a modified Ishii-Venturello catalyst in batch and continuous flow reactors. The batch reactor achieved higher yields due to the significant decomposition of hydrogen peroxide in the laminar flow tubular reactor. Integral and differential models describing the reaction and the phase transfer kinetics were developed for the epoxidation of cocoa butter and the model parameters were estimated. Ring-opening of the epoxidised cocoa butter was undertaken to provide polyols of varying molecular weight (Mw = 2000-84 000 Da), hydroxyl value (27-60 mg KOH g-1) and acid value (1-173 mg KOH g-1), using either aqueous ortho-phosphoric acid (H 3 PO 4) or boron trifluoride diethyl etherate (BF 3.OEt2)-mediated oligomerisation in bulk, using hexane or tetrahydrofuran (THF) as solvents. The thermal and tensile properties of the polyurethanes obtained from the reaction of these polyols with 4,4'-methylene diphenyl diisocyanate (MDI) are described. CONCLUSION: The paper presents a complete valorisation scheme for a food manufacturing industry waste stream, starting from the initial chemical transformation, developing a process model for the design of a scaled-up process, and leading to synthesis of the final product, in this case a polymer. This work describes aspects of optimisation of the conversion route, focusing on clean synthesis and also demonstrates the interdisciplinary nature of the development projects, requiring input from different areas of chemistry, process modelling and process design. (c) 2017 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28919657 TI - An All-Digital Fast Tracking Switching Converter with a Programmable Order Loop Controller for Envelope Tracking RF Power Amplifiers. AB - This paper presents a step down, switched mode power converter for use in multi standard envelope tracking radio frequency power amplifiers (RFPA). The converter is based on a programmable order sigma delta modulator that can be configured to operate with either 1st, 2nd, 3rd or 4th order loop filters, eliminating the need for a bulky passive output filter. Output ripple, sideband noise and spectral emission requirements of different wireless standards can be met by configuring the modulator's filter order and converter's sampling frequency. The proposed converter is entirely digital and is implemented in 14nm bulk CMOS process for post layout verification. For an input voltage of 3.3V, the converter's output can be regulated to any voltage level from 0.5V to 2.5V, at a nominal switching frequency of 150MHz. It achieves a maximum efficiency of 94% at 1.5 W output power. PMID- 28919658 TI - A Single Switcher Combined Series Parallel Hybrid Envelope Tracking Amplifier for Wideband RF Power Amplifier Applications. AB - In this paper, an improved architecture for RF power amplifier envelope tracking supply modulator is presented. It consists of a single switched mode supply regulator and one linear regulator. The switched mode supply regulator has two outputs, one of which is used in conjunction with the linear regulator to provide a wideband, high efficiency power supply to the RF amplifier, whereas the second output provides a band limited high efficiency supply to the linear regulator. The design offers improved power efficiency, reduced system complexity and area savings since the dual output switched mode regulator requires one inductor and a simple control loop. The design was implemented in 14nm CMOS process and validated with simulations. The supply modulator achieves a peak efficiency of 74% with a 6 dB PAPR 20MHz LTE signal at 29dBm output power. PMID- 28919659 TI - An Enhanced Light-Load Efficiency Step Down Regulator with Fine Step Frequency Scaling. AB - This paper presents a switching DC-DC Buck converter with enhanced light-load efficiency for use in noise-sensitive applications. Low noise, spur free operation is achieved by using a sigma-delta-modulator (SigmaDelta) based controller, while light load efficiency is realized through the introduction of fine step frequency scaling (FSFS) which continuously adjusts the switching frequency of the converter with load conditions. Regulation efficiency is further improved by adoption of mode hopping (continuous conduction mode (CCM)/discontinuous conduction mode (DCM)) and utilization of a fully digital implementation. Furthermore, the presented converter maintains low output voltage ripple across its entire load range by reconfiguring the SigmaDelta modulator's quantization step and introducing dither to the loop filter. The proposed modulator was implemented in 14nm bulk CMOS process and validated with post layout simulations. It attains a peak efficiency of 95% at heavy load conditions and 79% at light loads with a maximum voltage ripple of 15mV at light loads. PMID- 28919660 TI - Collaborative SDOCT Segmentation and Analysis Software. AB - Spectral domain optical coherence tomography (SDOCT) is routinely used in the management and diagnosis of a variety of ocular diseases. This imaging modality also finds widespread use in research, where quantitative measurements obtained from the images are used to track disease progression. In recent years, the number of available scanners and imaging protocols grown and there is a distinct absence of a unified tool that is capable of visualizing, segmenting, and analyzing the data. This is especially noteworthy in longitudinal studies, where data from older scanners and/or protocols may need to be analyzed. Here, we present a graphical user interface (GUI) that allows users to visualize and analyze SDOCT images obtained from two commonly used scanners. The retinal surfaces in the scans can be segmented using a previously described method, and the retinal layer thicknesses can be compared to a normative database. If necessary, the segmented surfaces can also be corrected and the changes applied. The interface also allows users to import and export retinal layer thickness data to an SQL database, thereby allowing for the collation of data from a number of collaborating sites. PMID- 28919661 TI - DAX - The Next Generation: Towards One Million Processes on Commodity Hardware. AB - Large scale image processing demands a standardized way of not only storage but also a method for job distribution and scheduling. The eXtensible Neuroimaging Archive Toolkit (XNAT) is one of several platforms that seeks to solve the storage issues. Distributed Automation for XNAT (DAX) is a job control and distribution manager. Recent massive data projects have revealed several bottlenecks for projects with >100,000 assessors (i.e., data processing pipelines in XNAT). In order to address these concerns, we have developed a new API, which exposes a direct connection to the database rather than REST API calls to accomplish the generation of assessors. This method, consistent with XNAT, keeps a full history for auditing purposes. Additionally, we have optimized DAX to keep track of processing status on disk (called DISKQ) rather than on XNAT, which greatly reduces load on XNAT by vastly dropping the number of API calls. Finally, we have integrated DAX into a Docker container with the idea of using it as a Docker controller to launch Docker containers of image processing pipelines. Using our new API, we reduced the time to create 1,000 assessors (a sub-cohort of our case project) from 65040 seconds to 229 seconds (a decrease of over 270 fold). DISKQ, using pyXnat, allows launching of 400 jobs in under 10 seconds which previously took 2,000 seconds. Together these updates position DAX to support projects with hundreds of thousands of scans and to run them in a time efficient manner. PMID- 28919662 TI - Dermoscopy-guided reflectance confocal microscopy of skin using high-NA objective lens with integrated wide-field color camera. AB - Reflectance Confocal Microscopy, or RCM, is being increasingly used to guide diagnosis of skin lesions. The combination of widefield dermoscopy (WFD) with RCM is highly sensitive (~90%) and specific (~ 90%) for noninvasively detecting melanocytic and non-melanocytic skin lesions. The combined WFD and RCM approach is being implemented on patients to triage lesions into benign (with no biopsy) versus suspicious (followed by biopsy and pathology). Currently, however, WFD and RCM imaging are performed with separate instruments, while using an adhesive ring attached to the skin to sequentially image the same region and co-register the images. The latest small handheld RCM instruments offer no provision yet for a co registered wide-field image. This paper describes an innovative solution that integrates an ultra-miniature dermoscopy camera into the RCM objective lens, providing simultaneous wide-field color images of the skin surface and RCM images of the subsurface cellular structure. The objective lens (0.9 NA) includes a hyperhemisphere lens and an ultra-miniature CMOS color camera, commanding a 4 mm wide dermoscopy view of the skin surface. The camera obscures the central portion of the aperture of the objective lens, but the resulting annular aperture provides excellent RCM optical sectioning and resolution. Preliminary testing on healthy volunteers showed the feasibility of combined WFD and RCM imaging to concurrently show the skin surface in wide-field and the underlying microscopic cellular-level detail. The paper describes this unique integrated dermoscopic WFD/RCM lens, and shows representative images. The potential for dermoscopy guided RCM for skin cancer diagnosis is discussed. PMID- 28919663 TI - Methods for scalar-on-function regression. AB - Recent years have seen an explosion of activity in the field of functional data analysis (FDA), in which curves, spectra, images, etc. are considered as basic functional data units. A central problem in FDA is how to fit regression models with scalar responses and functional data points as predictors. We review some of the main approaches to this problem, categorizing the basic model types as linear, nonlinear and nonparametric. We discuss publicly available software packages, and illustrate some of the procedures by application to a functional magnetic resonance imaging dataset. PMID- 28919664 TI - Developmental coordination disorders and sensory processing and integration: Incidence, associations and co-morbidities. AB - INTRODUCTION: Children with developmental coordination disorder or sensory processing and integration difficulties face challenges to participation in daily living. To date there has been no exploration of the co-occurrence of developmental coordination disorders and sensory processing and integration difficulties. METHOD: Records of children meeting Diagnostic and Statistical Manual - V criteria for developmental coordination disorder (n = 93) age 5 to 12 years were examined. Data on motor skills (Movement Assessment Battery for Children - 2) and sensory processing and integration (Sensory Processing Measure) were interrogated. RESULTS: Of the total sample, 88% exhibited some or definite differences in sensory processing and integration. No apparent relationship was observed between motor coordination and sensory processing and integration. The full sample showed high rates of some difficulties in social participation, hearing, body awareness, balance and motion, and planning and ideation. Further, children with co-morbid autistic spectrum disorder showed high rates of difficulties with touch and vision. CONCLUSION: Most, but not all, children with developmental coordination disorder presented with some difficulties in sensory processing and integration that impacted on their participation in everyday activities. Sensory processing and integration difficulties differed significantly between those with and without co-morbid autistic spectrum disorder. PMID- 28919665 TI - Hurricane Imaging Radiometer (HIRAD) Wind Speed Retrievals and Validation Using Dropsondes. AB - Surface wind speed retrievals have been generated and evaluated using Hurricane Imaging Radiometer (HIRAD) measurements from flights over Hurricane Joaquin, Hurricane Patricia, Hurricane Marty, and the remnants of Tropical Storm Erika, all in 2015. Procedures are described here for producing maps of brightness temperature, which are subsequently used for retrievals of surface wind speed and rain rate across a ~50 km wide swath for each flight leg. An iterative retrieval approach has been developed to take advantage of HIRAD's measurement characteristics. Validation of the wind speed retrievals has been conducted, using 636 dropsondes released from the same WB-57 high altitude aircraft carrying HIRAD during the Tropical Cyclone Intensity (TCI) experiment. The HIRAD wind speed retrievals exhibit very small bias relative to the dropsondes, for winds tropical storm strength (17.5 m s-1) or greater. HIRAD has reduced sensitivity to winds weaker than tropical storm strength, and a small positive bias (~2 m s-1) there. Two flights with predominantly weak winds according to the dropsondes have abnormally large errors from HIRAD, and large positive biases. From the other flights, root mean square differences between HIRAD and the dropsonde winds are 4.1 m s-1 (33%) for winds below tropical storm strength, 5.6 m s-1 (25%) for tropical storm strength winds, and 6.3 m s-1 (16%) for hurricane strength winds. Mean absolute differences for those categories are 3.2 m s-1 (25%), 4.3 m s-1 (19%), and 4.8 m s-1 (12%), with bias near zero for tropical storm and hurricane strength winds. PMID- 28919666 TI - The Selection of Preschool for Immigrant and Native-born Latino Families in the United States. AB - With the national push to expand preschool education, there has been growing interest in understanding why Latino families are enrolled in preschool at lower rates than non-Latino families. This study applied the accommodations model by Meyers and Jordan (2006) to the Early Childhood Longitudinal Study-Birth Cohort (n = 5,850) to provide a more nuanced understanding of the preschool selection of U.S.- and foreign-born Latino families. Results from this investigation underscored the similarities and differences that existed in the selection behaviors of different groups of families, while also highlighting important differences within the Latino population. In general, these differences within the Latino population cut across community language use, child factors, and parents' beliefs about school readiness. Moreover, after accounting for the various selection factors, there were no longer any consistent differences in the preschool enrollment rates between Latino children and their Black and White peers. When taken together, these findings suggest that careful attention must be paid to the heterogeneity in the experiences of Latino families in navigating the preschool market. PMID- 28919667 TI - The Effect of Splitting on Random Forests. AB - The effect of a splitting rule on random forests (RF) is systematically studied for regression and classification problems. A class of weighted splitting rules, which includes as special cases CART weighted variance splitting and Gini index splitting, are studied in detail and shown to possess a unique adaptive property to signal and noise. We show for noisy variables that weighted splitting favors end-cut splits. While end-cut splits have traditionally been viewed as undesirable for single trees, we argue for deeply grown trees (a trademark of RF) end-cut splitting is useful because: (a) it maximizes the sample size making it possible for a tree to recover from a bad split, and (b) if a branch repeatedly splits on noise, the tree minimal node size will be reached which promotes termination of the bad branch. For strong variables, weighted variance splitting is shown to possess the desirable property of splitting at points of curvature of the underlying target function. This adaptivity to both noise and signal does not hold for unweighted and heavy weighted splitting rules. These latter rules are either too greedy, making them poor at recognizing noisy scenarios, or they are overly ECP aggressive, making them poor at recognizing signal. These results also shed light on pure random splitting and show that such rules are the least effective. On the other hand, because randomized rules are desirable because of their computational efficiency, we introduce a hybrid method employing random split-point selection which retains the adaptive property of weighted splitting rules while remaining computational efficient. PMID- 28919668 TI - Online Versus Face-To-Face Training of Critical Time Intervention: A Matching Cluster Randomized Trial. AB - This study examined the effectiveness of online education to providers who serve people experiencing homelessness, comparing online and face-to-face training of Critical Time Intervention (CTI), an evidence-based case management model. The authors recruited 184 staff from 19 homeless service agencies to participate in one of two training conditions: (a) Online Training + Community of Practice or (b) Face-to-Face Training + Telephone Consultation. Each group received 24 hours of instruction and support. Through baseline, follow-up, and nine-month post training surveys, the authors examined satisfaction, knowledge gains, knowledge retention, and readiness to implement CTI. While satisfaction rates were higher among participants in the face-to-face group, the two training conditions produced comparable pre/post knowledge gains. Furthermore, both groups showed increased knowledge retention scores at nine-month follow up, with the online group scoring higher than the face-to-face group. PMID- 28919669 TI - Optomagnetically Controlled Microparticles Manufactured with Glancing Angle Deposition. AB - Optical trapping and magnetic trapping are common micro-manipulation techniques for controlling colloids including micro- and nano-particles. Combining these two manipulation strategies allows for a larger range of applied forces and decoupled control of rotation and translation; each of which are beneficial properties for many applications including force spectroscopy and advanced manufacturing. However, optical trapping and magnetic trapping have conflicting material requirements inhibiting the combination of these methodologies. In this paper, anisotropic micron scaled particles capable of being simultaneously controlled by optical and magnetic trapping are synthesized using a glancing angle deposition (GLAD) technique. The anisotropic alignment of dielectric and ferromagnetic materials limits the optical scattering from the metallic components which typically prevents stable optical trapping in three dimensions. Compared to the current state of the art, the benefits of this approach are two-fold. First, the composite structure allows for larger volumes of ferromagnetic material so that larger magnetic moments may be applied without inhibiting the stability of optical trapping. Secondly, the robustness of the synthesis process is greatly improved. The dual optical and magnetic functionality of the synthesized colloids is demonstrated by simultaneously optically translating and magnetically rotating a magnetic GLAD particle using a custom designed opto-magnetic trapping system. PMID- 28919670 TI - The Moral Insignificance of Self-consciousness. AB - In this paper, I examine the claim that self-consciousness is highly morally significant, such that the fact that an entity is self-conscious generates strong moral reasons against harming or killing that entity. This claim is apparently very intuitive, but I argue it is false. I consider two ways to defend this claim: one indirect, the other direct. The best-known arguments relevant to self consciousness's significance take the indirect route. I examine them and argue that (a) in various ways they depend on unwarranted assumptions about self consciousness's functional significance, and (b) once these assumptions are undermined, motivation for these arguments dissipates. I then consider the direct route to self-consciousness's significance, which depends on claims that self consciousness has intrinsic value or final value. I argue what intrinsic or final value self-consciousness possesses is not enough to generate strong moral reasons against harming or killing. PMID- 28919671 TI - Detection of Staphylococcus aureus enterotoxigenic strains in bovine raw milk by reversed passive latex agglutination and multiplex polymerase chain reaction. AB - AIM: This review gives an outline of the assessment of enterotoxigenic Staphylococcus aureus tainting levels in raw milk from different sources in Egypt and characterization of enterotoxigenic strains utilizing a technique in light of PCR to identify genes coding for the production of staphylococcal enterotoxin (SE). The obtained data were compared with results from the application of the reversed passive latex. MATERIALS AND METHODS: Multiplex PCR and reversed passive latex agglutination (RPLA) were used. A total of 141 samples of raw milk (cow's milk=33, buffalo's milk=58, and bulk tank milk=50) were investigated for S. aureus contamination and tested for enterotoxin genes presence and toxin production. RESULTS: S. aureus was detected in 23 (16.3%) samples phenotypically and genotypically by amplification of nuc gene. The S. aureus isolates were investigated for SEs genes (sea to see) by multiplex PCR and the toxin production by these isolates was screened by RPLA. SEs genes were detected in six isolates (26.1%) molecularly; see was the most observed gene where detected in all isolates, two isolates harbored seb, and two isolates harbored sec. According to RPLA, three isolates produced SEB and SEC. CONCLUSION: The study revealed the widespread of S. aureus strains caring genes coding for toxins. The real significance of the presence of these strains or its toxins in raw milk and their possible impact a potential hazard for staphylococcal food poisoning by raw milk consumption. Therefore, detection of enterotoxigenic S. aureus strains in raw milk is necessary for consumer safety. PMID- 28919672 TI - Preparation and evaluation of Salmonella Enteritidis antigen conjugated with nanogold for screening of poultry flocks. AB - AIM: The present work aimed to develop lateral flow immunochromatographic strip (ICS) test for detection of Salmonella Enteritidis (SE) specific antibodies in chicken sera. MATERIALS AND METHODS: A rapid lateral flow immunochromatographic test (LFIT) has been developed, in which SE Group D antigen labeled with the gold chloride molecules laid on the conjugate pad. Staphylococcus aureus protein A was used as capture antibody at the test line (T) of a nitrocellulose (NC) membrane and anti-SE antigen-specific rabbit antibodies were used as capture antibody at the control line (C) of the NC strip in the lateral flow layout device. RESULTS: Using the developed LFIT, the minimal amount of SE-specific antibodies that can be detected in chicken serum sample was 1427 enzyme-linked immunosorbent assay (ELISA) unit/100 ul that was equal to 0.1 ug (Ab)/100 ul sample. 100 suspected serum samples collected from a poultry flock were tested with the prepared SE LFIT kits and the locally prepared stained Salmonella antigen, and the results were compared with those obtained from examination of these samples with Salmonella Group D antibody ELISA kit as the gold standard test. The sensitivity, specificity, and accuracy of the prepared SE-LFIT antigen kits were 94.4%, 90%, and 94%, respectively, while those obtained with stained Salmonella antigen were 88.8%, 90%, and 89%, respectively. CONCLUSION: The developed test is a simple field rapid test of high sensitivity, specificity, and accuracy that can improve and facilitates rapid field surveillance of salmonellosis among chickens. PMID- 28919673 TI - Immunization of sheep against Echinococcus granulosus with protoscolex tegumental surface antigens. AB - AIM: Cystic echinococcosis (CE) has potential economic effects to both animal products and human health. A vaccine to protect livestock against CE can be effective in reducing economic costs and increasing the livestock products. Protoscolex tegumental surface antigens (PSTSA) used to induce the production of specific antibodies against Echinococcus granulosus in sheep. The tegumental antigens were extracted from viable protoscolices by solubilization in sterile phosphate-buffered saline containing decanoyl-N-methylglucamine. MATERIALS AND METHODS: Ten lambs which were infected with CE (positive control), 10 negative control, and 10 test groups of sheep were included in the study. 300 ug emulsion of purified-PSTSA was injected intramuscularly in a two-step immunization on the first and 30 days. Sera were collected immediately before immunization and 6 times with 10-day intervals until 60 days post immunization. Thereafter, the sera were tested for antibodies by indirect hemagglutination test in microtiter plate. RESULTS: After two immunizations, all the infected animals in test group showed substantial increases in antibody titer. Statistical analysis showed a significant difference between the titer obtained in the test and negative control groups in both phases of immunization (p<0.05). CONCLUSION: The results showed that the PSTSA is a promising immunogenic compound for immunization of sheep against CE. PMID- 28919674 TI - Prevalence of enteropathogens and their antibiotic sensitivity pattern in puppies with hemorrhagic gastroenteritis. AB - AIM: Hemorrhagic gastroenteritis (HGE) ranging from mild to severe forms is commonly encountered in puppies. The aim of the study was to identify the prevalence of common enteropathogens and the antibiotic sensitivity pattern in puppies reported with HGE. MATERIALS AND METHODS: The canine HGE activity index, with little modification, was adopted to identify Grade III/severely affected puppies below 6 months of age. Fecal polymerase chain reaction (PCR) assay was employed to screen and compare the enteropathogens in puppies with hemorrhagic diarrhea and healthy control. RESULTS: Canine parvovirus 2b was identified in 90.3% of the diarrheic and 10% of the non-diarrheic healthy puppies. Clostridium difficile was identified in all the diarrheic puppies and in 80% of the healthy puppies. Among the diarrheic puppies, 17.7% were positive for Clostridium perfringens enterotoxin, 9.7% were positive for C. perfringens alpha toxin, 6.4% were positive for Escherichia coli shiga toxin, 6.4% were positive for E. coli enterotoxin (LT), and 3.2% were positive for canine distemper virus. Whereas, none of the healthy puppies were positive for these bacteria and toxins. Fecal antibiotic sensitivity test pattern revealed gentamicin to be sensitive in 95% of the cases, azithromycin in 50%, enrofloxacin in 25%, cefotaxime in 20%, and tetracycline in 5% of the cases. CONCLUSION: Parvoviral enteritis is predominant among puppies. Yet, bacteria and their toxins also play an important role in HGE. Gentamicin has higher sensitivity against the enteropathogens associated with the condition. PMID- 28919675 TI - Therapeutic uses of epicatechin in diabetes and cancer. AB - Epicatechin is a natural flavonoid found in green tea. It has been reported to possess an immense antioxidant effect which contributes to its therapeutic effect against a handful of ailments. In this review, we discuss its therapeutic role in the management of two of the most important human diseases; diabetes and cancer. The consumption of epicatechin has been shown to reduce blood glucose levels in diabetic patients, while is anticancer effect was attributed to its antioxidant properties, antiangiogenic and direct cytotoxicity to cancer cells. Although the exact mechanism of action of epicatechin is still being explored, there is no doubt that it is a promising candidate as an alternative. The significance of this review is to highlight the importance of the usage of natural products (in this case, epicatechin) as an alternative for the treatment of two potentially fatal diseases which is diabetes and cancer. The aim of this review is to educate the scientific community on the role of epicatechin in ameliorating the effects of diabetes and cancers on human while understanding the potential mechanisms of these aforementioned effects. PMID- 28919676 TI - A 3-year prospective study of the incidence of gastric ulcers in pigs slaughtered at Base Abattoir in Rwanda. AB - AIM: Determination of the incidence of gastric ulcers in pigs slaughtered at Base Abattoir in Rwanda. MATERIALS AND METHODS: Stomachs from all 5040 pigs that were slaughtered at Base Abattoir in Rwanda from August 2012 to August 2015 were examined for the presence and location of gastric ulcers. The results of the inspections were recorded and analyzed. Statistical analysis for Chi-square values was performed using the Software Package for Social Sciences version 16.0. The Z test for comparison of proportions was used and p<0.05 was considered significant. RESULTS: Overall as well as per district, significantly more male pigs than female pigs were slaughtered (p<0.05). The incidence of gastric ulcers in slaughter pigs was 12.86%. The incidence of gastric ulcers in males (13.36%) was not significantly different (p>0.05) from that in female pigs (12.84%) in all three districts. A significantly greater proportion of these ulcers (69.03%) was located in the esophageal region than in the glandular region of the stomach (30.97%) in slaughtered males (p<0.05). A significantly greater proportion of these ulcers (79.59%) was located in the esophageal region than in the glandular region of the stomach (20.41%) in slaughtered females (p<0.05). The overall incidence of esophageal ulcers (9.44%) in the slaughtered pigs was significantly (p<0.05) higher than that of glandular region ulcers (3.41%). Pigs with carcass weight over 60 kg showed a significantly (p<0.05) higher (44.44%) incidence of ulcers than those between 40 and 60 kg (33.33%) and those below 40 kg (22.22%). CONCLUSIONS: It was concluded that the incidence of gastric ulceration in slaughter pigs at Base Abattoir was not associated with source (district) or sex of pigs but was associated with the carcass weight. PMID- 28919677 TI - Influence of microclimatic ammonia levels on productive performance of different broilers' breeds estimated with univariate and multivariate approaches. AB - BACKGROUND AND AIM: Birds litter contains unutilized nitrogen in the form of uric acid that is converted into ammonia; a fact that does not only affect poultry performance but also has a negative effect on people's health around the farm and contributes in the environmental degradation. The influence of microclimatic ammonia emissions on Ross and Hubbard broilers reared in different housing systems at two consecutive seasons (fall and winter) was evaluated using a discriminant function analysis to differentiate between Ross and Hubbard breeds. MATERIALS AND METHODS: A total number of 400 air samples were collected and analyzed for ammonia levels during the experimental period. Data were analyzed using univariate and multivariate statistical methods. RESULTS: Ammonia levels were significantly higher (p< 0.01) in the Ross compared to the Hubbard breed farm, although no significant differences (p>0.05) were found between the two farms in body weight, body weight gain, feed intake, feed conversion ratio, and performance index (PI) of broilers. Body weight; weight gain and PI had increased values (p< 0.01) during fall compared to winter irrespective of broiler breed. Ammonia emissions were positively (although weekly) correlated with the ambient relative humidity (r=0.383; p< 0.01), but not with the ambient temperature (r= 0.045; p>0.05). Test of significance of discriminant function analysis did not show a classification based on the studied traits suggesting that they cannot been used as predictor variables. The percentage of correct classification was 52% and it was improved after deletion of highly correlated traits to 57%. CONCLUSION: The study revealed that broiler's growth was negatively affected by increased microclimatic ammonia concentrations and recommended the analysis of broilers' growth performance parameters data using multivariate discriminant function analysis. PMID- 28919679 TI - Effects of intramammary infusion of sage (Salvia officinalis) essential oil on milk somatic cell count, milk composition parameters and selected hematology and serum biochemical parameters in Awassi sheep with subclinical mastitis. AB - AIM: The aims of this study were to evaluate the effects of intramammary infusion of sage (Salvia officinalis) essential oil (EO) on milk somatic cell count (SCC), milk composition parameters and selected hematology and serum biochemical parameters in 20 Awassi ewes affected with subclinical mastitis. MATERIALS AND METHODS: The dried leaves of sage were used to extract the EO by hydrodistillation. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of sage EO against Staphylococcus aureus were determined by the broth dilution method. Ewes were divided randomly into three main groups and received one of the following treatments; Group 1 (n=5): Dimethyl sulfoxide (DMSO) alone (5 ml; 0.2 ml of DMSO in 4.8 ml of saline), Group 2 (n=5): Amoxicillin alone (3 ml), and Group 3 (n=10): Sage EO (5 ml of sage EO solution [0.2 ml DMSO+1 ml EO+3.8 ml sterile saline]). All treatments were administered by intramammary infusion into each teat twice per day for 3 consecutive days. Milk samples for SCC and milk components determination and whole blood samples for hematology and serum biochemical analyses were collected before treatment (T0) and at 24 (T24) and 48 (T48) h after the last treatment. RESULTS: The MIC and MBC of sage EO against S. aureus were 12.5% and 6.1%, respectively. SCC was decreased significantly (p<0.05) at T24 and T48 h in sage EO and amoxicillin treated groups. Milk fat and lactose were increased significantly (p<0.05) in sage EO and amoxicillin treated ewes while no significant changes were observed in the percentages of solids-not-fat, protein and total solids. No significant effects of sage EO treatment on any of the hematology or serum biochemical parameters were observed. There were no local or systemic side effects observed in any of the treated ewes. However, further clinical trials are warranted to determine safety and possible withdrawal times in milk before its recommendation for use in organic operations. CONCLUSION: In this study, the intramammary infusion of sage EO to ewes affected with subclinical mastitis resulted in a significant decrease in SCC 24 h and 48 h posttreatment. In addition, milk fat and lactose were increased in animals that received the EO as well as in those treated with the antibiotic. PMID- 28919678 TI - Cortisol concentration, pain and sedation scale in free roaming dogs treated with carprofen after ovariohysterectomy. AB - BACKGROUND AND AIM: One of the topic issues in animal welfare activities is the free roaming dog welfare especially in developing countries such as Serbia. The way of controlling population of free roaming dogs is their reproduction with the method of "Catch-Neuter-Release." This complex process consists of capturing free roaming dogs in public areas, sterilizing, and returning them to the public area from which they were temporarily removed. Ovariohysterectomy present the period with a high intensity of stress reaction since many veterinarians in Serbia do not use analgesia for this group of dogs. The aim of this study was to compare the serum cortisol concentration before and after ovariohysterectomy and the level of post-operative pain and sedation in a group of free roaming female dogs treated with carprofen after surgical intervention and in a group with no treatment. MATERIALS AND METHODS: The study was performed on a total of 20 female dogs under the program for free roaming dog control. Free-roaming dogs were captured in public areas by the communal animal hygiene service and were transported between 30 and 45 min to the clinic of a veterinary practice. Treatment began at 10:00 h on the next day and the bitches were kept in cages until they were returned to public locations from which they were temporarily removed to be sterilized. The G2 group received before closing the incision line carprofen in one dosage of 4 mg/kg given by subcutaneous injection into the scruff. Rescue protocol with carprofen was provided for G1 after 24 h following ovariohysterectomy same dosage as G2. Blood (2 ml) was collected from the cephalic vein of each dog in disposable plastic syringes, containing heparin (1:1000) 4 times: Before ovariohysterectomy, 30, 120 min and 24 h following ovariohysterectomy. Cortisol concentration was determined by enzyme-linked immunosorbent assay. The multifactorial pain and sedation scale were used for the assessment of pain and sedation. RESULTS: In both groups, the lowest values of serum cortisol concentration were obtained before ovariohysterectomy. Cortisol levels in both groups were significantly higher (p<0.01) 30 and 120 min after ovariohysterectomy and showed a decreasing trend toward the end of the observation period (24 h). The results obtained 15 and 30 min after the surgical intervention have revealed a statistically significant difference between the groups (p<0.05) showing that female dogs treated with carprofen had a lower value on the pain scale and a higher value on the sedation scale compared to the group with no treatment. CONCLUSION: Carprofen provides both a restful consequence of sedation and a rapid return to a more normal physiological and behavioral state in dogs after ovariohysterectomy. PMID- 28919680 TI - Effects of body conformation and udder morphology on milk yield of zebu cows in North region of Cameroon. AB - AIM: The aim of the study was to assess the effect of udder morphological characteristics on milk yield in zebu cows of Cameroon. MATERIALS AND METHODS: The diameter and height of the udder, length and diameter of the teat, and the milk yield were measured in 29 Djafun (Red Mbororo) and 19 Aku (White Fulani) cows in Lougguere zootechnical station in the North region of Cameroon. RESULTS: Overall, strong positive correlation (rp=0.60) between the diameter (240.21+/ 28.58 mm) and height (131.12+/-23.64 mm) of udders (p<0.001) and between length (39.51+/-6.44 mm) and diameter (19.85+/-3.08 mm) of teats (rp=0.78) were found in the zebu cows. Udder morphologic characteristics varied significantly (p<0.005) according to breed, lactation stage and parity, and height at whiters. There was significant (p<0.001) correlations between udder diameter (rp=0.541) and height (rp=0.549) with milk yield. CONCLUSION: This study ascertained udder morphological characteristics values in local zebu cows, and showed that udder size is strong and positively correlated to milk yield. The findings are useful in genetic improvement programs of zebu cows. PMID- 28919681 TI - Seroprevalence of bovine viral diarrhea virus in crossbred dairy cattle in Bangladesh. AB - AIM: The study was conducted to determine the seroprevalence of bovine viral diarrhea virus (BVDV) and hematological features in crossbred dairy cattle in Chittagong, Bangladesh. MATERIALS AND METHODS: The antibody against BVDV in crossbred dairy cattle serum was detected by indirect enzyme-linked immunosorbent assay. The association of different categorical variables in the prevalence of BVDV has been studied. Blood samples were collected and analyzed to know the hematological variations in the study population. RESULTS: The overall seroprevalence of BVDV in the study area was 51.1% (95% confidence interval [CI], 40.5-61.5). Among different physiological stages of animals, the highest 57.1% (95% CI, 42.2-71.2) prevalence was in case of non-pregnant animals. Aborted cows were found to be significantly (p<0.05) more seropositive 77.8% (95% CI, 52.4 93.6) than the non-aborted cows (77.8%, 95% CI, 52.4-93.6, compared to 44.7%, 95% CI, 33.3-56.6, respectively). Cows having the history of retained placenta were found more positive than without the history of retained placenta (63.2%, 95% CI, 38.4-83.7, compared to 54.7%, 95% CI, 40.4-68.4, respectively). Among the animals of different age groups, BVDV seroprevalence was higher 61.3% (95% CI, 42.2-78.2) in animals of more than 3 years up to 5 years, whereas 32% was in case of 0-1 year-old. Significant variation found in different geographical areas of the study area. Hematological analyses have shown variation between the BVDV positive and negative animals. CONCLUSION: Seroprevalence of BVDV found to be high in the study area is also economically important and cause significant damage to the production industry. Therefore, it is necessary to conduct effective control measures to reduce the burden of BVDV. PMID- 28919682 TI - Prevalence of fascioliasis (liver flukes) infection in cattle and buffaloes slaughtered at the municipal abattoir of El-Kharga, Egypt. AB - AIM: The main objectives of this study were to determine the prevalence of fascioliasis infections in cattle and buffaloes, slaughtered in El-Kharga city slaughterhouse at New Valley Governorate. MATERIALS AND METHODS: The slaughtered animals were daily inspected for liver fascioliasis allover 2016. Macroscopic fascioliasis was detected from a total of 2251 basing on animals specie, sex, season, and Fasciola spp. in addition to microscopic examination of blood, fecal samples which collected from female cattle and buffalo (50 each). RESULTS: The total prevalence rate of Fasciola sp. infection occurs in the study area were about 695/2251 (30.88%) from the total cattle and bovine slaughtered carcasses. The incidence of fascioliasis was 4/12 (33.33%) and 678/2200 (30.82%) for females and males cattle carcasses, respectively, while the infection rate in buffalo carcasses was 1/4 (25.00%) and 12/35 (34.29%) for females and males buffalo carcasses, respectively. CONCLUSION: The moderate fasciolosis infection in cattle and buffaloes slaughtered at the municipal abattoir of El-Kharga, Egypt. The highest fascioliasis infection was recorded during winter and autumn. It constitutes a major cause of economic losses at El-Kharga abattoir and threat public health. PMID- 28919684 TI - Molecular screening for hemotropic mycoplasmas in captive Barbary sheep (Ammotragus lervia) in southern Brazil. AB - AIM: This study is part of an active surveillance program for monitoring animal health status in endangered species, and was conducted to screen captive Barbary sheep (Ammotragus lervia) for hemoplasma infection. MATERIALS AND METHODS: A total of 12 blood samples were collected, DNA extracted and further tested by a pan-hemoplasma polymerase chain reaction protocol. RESULTS: Animals were clinically healthy and not infested by ectoparasites. Although housekeeping gene DNA was successfully amplified, all the Barbary sheep samples tested negative for Mycoplasma sp. CONCLUSION: Notwithstanding the negative results, molecular pathogen surveys on Barbary sheep and other exotic wild mammals may provide insights regarding infection of endangered species caused by captivity stress in association with exposure to new pathogens worldwide. PMID- 28919683 TI - Serum levels of urokinase-type plasminogen activator in healthy dogs and oncologic canine patients. AB - AIM: Urokinase plasminogen activator (uPA) has been scarcely studied in veterinary oncology. The aim of this study was to determine the uPA serum concentrations in healthy and oncologic canine patients and to investigate its potential value as a tumor biomarker. MATERIALS AND METHODS: Serum uPA concentrations of healthy and oncologic canine patients were measured by enzyme linked immunosorbent assay. Their relationships with the dogs' health status and tumor characteristics were analyzed through ANOVA and independent t-test. RESULTS: There were no significant differences between mean serum values (+/ standard deviation) of healthy dogs (0.19+/-0.13 ng/ml) and oncologic canine patients (0.22+/-0.33 ng/ml), or between dogs with benign or malignant tumors, and with or without metastases, although the latter tended to show higher uPA serum levels. CONCLUSION: This is the first study describing the uPA serum levels in dogs. Although its results do not support uPA as a tumor biomarker, higher uPA levels in dogs with metastatic neoplasms may reflect the role of the enzyme in tumor progression. PMID- 28919685 TI - Prevalence of Listeria monocytogenes, Yersinia enterocolitica, Staphylococcusaureus, and Salmonella enterica Typhimurium in meat and meat products using multiplex polymerase chain reaction. AB - AIM: The objective of the study was to investigate the occurrence of Listeria monocytogenes, Yersinia enterocolitica, Staphylococcusaureus, and Salmonella enterica Typhimurium in meat and meat products using the multiplex polymerase chain reaction (PCR) method. MATERIALS AND METHODS: The assay combined an enrichment step in tryptic soy broth with yeast extract formulated for the simultaneous growth of target pathogens, DNA isolation and multiplex PCR. A total of 1134 samples including beef (n=349), chicken (n=325), pork (n=310), chevon (n=50), and meat products (n=100) were collected from different parts of Kerala, India. All the samples were subjected to multiplex PCR analysis and culture-based detection for the four pathogens in parallel. RESULTS: Overall occurrence of L. monocytogenes was 0.08 % by cultural method. However, no L. monocytogenes was obtained by multiplex PCR method. Yersinia enterocolitica was obtained from beef and pork samples. A high prevalence of S. aureus (46.7%) was found in all types of meat samples tested. None of the samples was positive for S. Typhimurium. CONCLUSION: Multiplex PCR assay used in this study can detect more than one pathogen simultaneously by amplifying more than one target gene in a single reaction, which can save time and labor cost. PMID- 28919686 TI - High-performance liquid chromatography ultraviolet-photodiode array detection method for aflatoxin B1 in cattle feed supplements. AB - AIM: The objective of the current study is to determine the concentration of aflatoxin B1 using high-performance liquid chromatography (HPLC) with a photodiode array (PDA) detector. MATERIALS AND METHODS: Aflatoxin B1 certified reference grade from Trilogy Analytical Laboratory dissolved acetonitrile (ACN) at 10 ug/mL was using standard assessment. HPLC instruments such as ultraviolet PDA detector used a Shimadzu LC-6AD pump with DGU-20A5 degasser, communication module-20A, and PDA detector SPD-M20A with FRC-10A fraction collector. The HPLC was set isocratic method at 354 nm with a reverse-phase ODS C18 column (LiChrospher(r) 100 RP-18; diameter, 5 um) under a 20 degrees C controlled column chamber. Rheodyne(r) sample loops were performed in 20 uL capacities. The mobile phase was performed at fraction 63:26:11 H2O: methanol:ACN at pH 6.8. A total of 1 kg of feed contained 10% bread crumbs and 30% concentrated, 40% forage, and 20% soybean dregs were using commercials samples. Samples were extracted by ACN and separated with solid phase extraction ODS 1 mL than elution with mobile phase to collect at drying samples performed. The samples were ready to use after added 1 mL mobile phase than injected into the system of HPLC. RESULTS: We found that the retention time of aflatoxin B1 was approximately 10.858 min. Linearity of 0.01 0.08 ug/mL aflatoxin B1 dissolved in mobile phase was obtained at R2=0.9. These results demonstrate that these methods can be used to analyze aflatoxin B1 and gain 89-99% recovery. The limit of detection of this assay was obtained at 3.5 * 10-6 ug/mL. CONCLUSION: This method was easy to apply and suitable to analyzing at small concentrations of aflatoxin B1 in formulated product of feed cattle. PMID- 28919687 TI - Presence and characterization of Escherichia coli virulence genes isolated from diseased pigs in the central region of Argentina. AB - BACKGROUND: The main pathogen of neonatal and post weaning diarrhea and edema disease (ED) is Escherichia coli and pathotypes involved are enterotoxigenic, enteropathogenic, and shiga toxigenic (ETEC, EPEC, and STEC, respectively). Those diseases cause economic loss in pig production. AIM: The aim of this work was to evaluate the presence of strains expressing virulence markers genes and the antibiotic susceptibility profiles of E. coli from clinical cases of post weaning diarrhea and ED in farms in the central area of Argentina. MATERIALS AND METHODS: Intensive pig farms from the central region of Argentina were sampled. Intestinal mucosa swabs from pigs with diarrhea were taken, seeded on MacConkey agar plates, biochemically typified and tested by polymerase chain reaction (PCR). Antibiograms were made by disk-diffusion method. RESULTS: A total of 54 strains from clinical cases studied showed PCR findings: 88.88% (48/54) expressed at least one gene coding for a virulence factor. Colonization factors found were: 39.58% of strains had F18, 33.33% were F4 and 31.25% adhesin involved in diffuse adherence-I; 29.17%, 25%, and 2.1% expressed LT, STb, and STa, respectively. 25% were STx and 16.67% were eae positive. Only 2.1% were STx2. The most active antibiotics against most strains were gentamicin and ceftiofur, but resistance profiles against many antibiotics were found. CONCLUSION: High circulation of pathogens strains of E. coli among pigs with diarrhea with an extended antibiotic resistance profile. PMID- 28919688 TI - Vaccination with Salmonella Typhi recombinant outer membrane protein 28 induces humoral but non-protective immune response in rabbit. AB - AIM: Typhoid is one of the most important food and water borne disease causing millions of deaths over the world. Presently, there is no cost effective vaccine available in India. The outer-membrane proteins (Omps) of Salmonella have been exhibited as a potential candidate for development of subunit vaccine against typhoid. The objective of the present study was to evaluate the use of recombinant Omp 28 protein for immunization of rabbit to elucidate its protection against virulent Salmonella Typhi. MATERIALS AND METHODS: Immune potential of recombinant Omp28 was tested in New Zealand Rabbits. Rabbits were divided into two groups, i.e., control and test group. Control group was injected with phosphate buffer saline with adjuvant while test group were injected with recombinant Omp28 along with adjuvant. Rabbits were bleed and serum was collected from each rabbit. Serum was tested by Enzyme-linked immunosorbent assay (ELISA) for humoral response. Rabbits were challenged with virulent culture to test the protective immunity. RESULTS: Humoral response was provoked at 15th day and maintained till 30th day. The mean ELISA titer at 15th day was 1 : 28000 (mean titer log 10 : 4.4472) and on the 30th day was 1 : 25866 (mean titer log 10 : 4.4127). Protective immune potential of Omp 28 was assessed by challenge studies in rabbits for which vaccinated and control rabbits were challenged with 109 cells of virulent culture of S. Typhi. In control group, out of six, no rabbit could survive after 48 days while in vaccinated group, three out of six rabbit were survived. CONCLUSION: Immunization of rabbit with recombinant Omp 28 induced a strong humoral response which was exhibited by high antibody titer in ELISA. Subsequently, intraperitoneal homologous challenge of the immunized New Zealand rabbit resulted in lack of significant protection. These findings indicate that Omp 28 though provoked the humoral immunity but could not provide the protective immunity in rabbit model. PMID- 28919689 TI - Beta-lactamase antimicrobial resistance in Klebsiella and Enterobacter species isolated from healthy and diarrheic dogs in Andhra Pradesh, India. AB - AIM: The aim of this study was to characterize beta-lactamase antimicrobial resistance in Klebsiella and Enterobacter species isolated from healthy and diarrheic dogs in Andhra Pradesh. MATERIALS AND METHODS: A total of 136 rectal swabs were collected from healthy (92) and diarrheic (44) dogs, bacteriological cultured for Klebsiella and Enterobacter growth and screened for beta-lactamase antimicrobial resistance phenotypically by disc diffusion method and genotypically by polymerase chain reaction targeting blaTEM, blaSHV, blaOXA, blaCTX-M Group 1, 2, blaAmpC, blaACC, and blaMOX genes. RESULTS: A total of 33 Klebsiella and 29 Enterobacter isolates were recovered. Phenotypic beta-lactamase resistance was detected in 66.6% and 25% of Klebsiella and Enterobacter isolates, respectively, from healthy dogs and 66.6% and 60% of Klebsiella and Enterobacter isolates, respectively, from diarrheic dogs. Overall, incidence of extended spectrum beta-lactamase (ESBL) phenotype was found to be 21.2% (7/33) in Klebsiella isolates, whereas none of the Enterobacter isolates exhibited ESBL phenotype. Predominant beta-lactamase genes detected in Klebsiella species include blaSHV (84.8%), followed by blaTEM (33.3%), blaCTX-M Group 1 (15.1%), and blaOXA (6.1%) gene. Predominant beta-lactamase genes detected in Enterobacter species include blaSHV (48.2%), followed by blaTEM (24.1%), blaAmpC (13.7%), and blaOXA (10.3%) gene. CONCLUSION: The present study highlighted alarming beta lactamase resistance in Klebsiella and Enterobacter species of canine origin in India with due emphasis as indicators of antimicrobial resistance. PMID- 28919690 TI - Subchronic toxicity of Nile tilapia with different exposure routes to Microcystis aeruginosa: Histopathology, liver functions, and oxidative stress biomarkers. AB - BACKGROUND: Toxic cyanobacterial blooms (Microcystis aeruginosa contains microcystins [MCs]) have been reported to induce clinicopathological alterations as well as different oxidative stress in aquatic biota. AIM: Three-week subchronic exposure experiment was carried out on Nile tilapia, to determine their effects on fish behavior, tissues, liver functions, antioxidant enzymes, and lipid peroxidation. MATERIALS AND METHODS: Fish were exposed to four main treatments; orally fed diet plus toxic cells of M. aeruginosa (containing 3500 ug/g MC-LR), immersion in 500 ug MC-LR/L, intraperitoneal injection of M. aeruginosa MC-LR with a dose of 0.1 ml of extracted toxin at a dose of 200 MUg/kg bwt, and the fourth one served as a control group, then the fish were sacrificed at the end of 3rd week of exposure. RESULTS: The results revealed no recorded mortality with obvious behavioral changes and an enlarged liver with the congested gall bladder. Histopathology demonstrated fragmentation, hyalinization, and necrosis of the subcutaneous musculature marked fatty degeneration, and vacuolation of hepatopancreatic cells with adhesion of the secondary gill lamellae associated with severe leukocytic infiltration. Furthermore, liver functions enzymes (aspartate aminotransferase and alanine aminotransferase, and the activities of glutathione peroxidase, glutathione reductase, lipid peroxidase, and catalase enzymes) were significantly increased in all treatments starting from the 2nd week as compared to the control levels. CONCLUSION: In this context, the study addresses the possible toxicological impacts of toxic M. aeruginosa contain MC-LR to Nile tilapia, and the results investigated that MC-LR is toxic to Nile tilapia in different routes of exposure as well as different doses. PMID- 28919691 TI - Molecular etiopathology of naturally occurring reproductive diseases in female goats. AB - AIM: The aim of the present study was to investigate the molecular etiopathology of occurrence of reproductive diseases in female goats. Reproductive diseases in goats account for major economic losses to goat farmers in terms of valuable loss of offspring and animal productivity. MATERIALS AND METHODS: A total of 660 female genitalia were examined for pathological conditions (macroscopic and microscopic lesions). The etiopathological study was carried out for the presence of pathogenic organisms such as Brucella, Chlamydia, and Campylobacter in the uterus and ovary. Based on the microscopic lesions, suspected samples were subjected to diagnostic polymerase chain reaction (PCR) for various etiological agents employing 16srRNA genus specific primers for Campylobacter and Chlamydophila and OMP31 gene-based PCR for Brucella melitensis and nested PCR using ITS-1 gene primers for Toxoplasma gondii. For Brucella suspected samples, immunohistochemistry (IHC) was also performed. RESULTS: In studied female genitalia, 108 (16.30%) showed gross abnormalities with overall 23.32% occurrence of pathological conditions (macroscopic and microscopic lesions). Pathological involvement of the uterus was the highest 68 (62.96%), followed by the ovaries 27 (25%) and other organs. Major uterine condition observed was endometritis (5.60%). In uterine infections, 35 (5.30%) samples were found positive for Campylobacter spp., 12 (1.81%) samples for B. melitensis, and 3 (0.45%) samples were positive for Chlamydophila spp. Among the samples positive for B. melitensis by PCR, 3 were found positive by IHC also. Corynebacterium ovis was detected by PCR using specific primers in a case of hydrosalpinx. It was concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. CONCLUSION: The present study concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. PMID- 28919692 TI - Isolation and characterization of bacteriophages with lytic activity against common bacterial pathogens. AB - AIM: Present investigation was conducted to isolate and characterize bacteriophages with lytic activity against common bacterial pathogens. MATERIALS AND METHODS: A total of 60 samples of animal waste disposal from cattle (42) and buffalo (18) farms were collected from three different strata, i.e., top, mid, and bottom of collection tank. Samples were primarily subjected to rapid detection methods, and then isolation of phage was done by double agar layer method using Bacillus subtilis (BsH) and Escherichia coli (EH) as host system. Phages were characterized on the basis of plaque morphology, temperature, pH susceptibility, and host range. RESULTS: Recovery of phages was higher from dairy cattle farm waste (78.57%) as compared to buffalo farm waste (72.22%) and bottom layer of tank showed maximum recovery. Bacillus subtilis (91%) supported the growth of more phages as compared to E. coli (9%). Three different phage morphotypes were observed each against Bacillus subtilis (BsHR1, BsHR2, and BsHR3) and E. coli (EHR1, EHR2, and EHR3). Mean phage titer of above six phage isolates ranged between 3*1010 and 5*1012 plaque forming units/ml. Viability of phages was by, and large unaffected at 70 degrees C within 2-3 min, and phage isolates were completely inactivated below pH 3 and above 11. Coliphage EHR1 had widest host range followed by BsHR1 and BsHR2 while EHR2, EHR3, and BsHR3 had low lytic activity. CONCLUSION: It could be concluded from the present study that the Bacillus and Coli phage has wide host range and thus exhibits the potential to be used as drug substitute tool against common bacterial pathogens. PMID- 28919693 TI - Antimicrobial activity of yeasts against some pathogenic bacteria. AB - AIM: This study was designed to isolate and identify yeast species from milk and meat products, and to test their antimicrobial activity against some bacterial species. MATERIALS AND METHODS: A total of 160 milk and meat products samples were collected from random sellers and super markets in New Damietta city, Damietta, Egypt. Samples were subjected to yeast isolation procedures and tested for its antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. In addition, all yeast species isolates were subjected to polymerase chain reaction (PCR) for detection of khs (kievitone hydratase) and pelA (pectate degrading enzyme)genes. RESULTS: The recovery rate of yeasts from sausage was 20% (2/10) followed by kareish cheese, processed cheese, and butter 10% (1/10) each as well as raw milk 9% (9/100), and fruit yoghurt 30% (6/20). Different yeast species were recovered, namely, Candida kefyr (5 isolates), Saccharomyces cerevisiae (4 isolates), Candida intermedia (3 isolates), Candida tropicalis (2 isolates), Candida lusitaniae (2 isolates), and Candida krusei (1 isolate). khs gene was detected in all S. cerevisiae isolates, however, pelA gene was not detected in all identified yeast species. Antimicrobial activity of recovered yeasts against the selected bacterial species showed high activity with C. intermedia against S. aureus and E. coli, C. kefyr against E. coli, and C. lusitaniae against S. aureus. Moderate activities were obtained with C. tropicalis, C. lusitaniae, and S. cerevisiae against E. coli; meanwhile, all the tested yeasts revealed a very low antimicrobial activity against P. aeruginosa. CONCLUSION: The obtained results confirmed that some kinds of yeasts have the ability to produce antimicrobial compounds that could inhibit some pathogenic and spoilage bacteria and these antimicrobial activity of yeasts enables them to be one of the novel agents in controlling spoilage of food. PMID- 28919694 TI - Incidence of bovine clinical mastitis in Jammu region and antibiogram of isolated pathogens. AB - AIM: This study was conducted to evaluate the incidence of clinical mastitis in bovines of Jammu region, to identify the infectious organisms responsible for it, and the antimicrobial sensitivity of isolated pathogens. MATERIALS AND METHODS: The study was conducted on cases that were presented to the Medicine Division of Teaching Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, R.S. Pura, Jammu, Jammu and Kashmir. A total of 260 cases of bovines were presented from June 30, 2012, to July 01, 2013, out of which 30 cases were of clinical mastitis. The diagnosis of clinical mastitis was made on the basis of history and clinical examination of affected animals. RESULTS: Animal and quarter wise incidence of clinical mastitis were found to be 11.5% and 5.76%, respectively. Of the 23 isolates obtained, Staphylococcus aureus (60.87%) was the most frequently isolated organism, followed by coagulase negative Staphylococci (13.04%), Streptococcus uberis (4.35%), Streptococcus dysgalactiae (8.69%), and Escherichia coli (13.04%). The antimicrobial sensitivity of isolates revealed maximum sensitivity to enrofloxacin, gentamicin, amoxicillin/sulbactam, ceftriaxone/tazobactam, ceftizoxime, ampicillin/sulbactam and least sensitivity for oxytetracycline and penicillin. CONCLUSION: Staphylococcus spp. is the major causative agent of clinical mastitis in bovines of Jammu region. The causative agents of the clinical mastitis were most sensitive to enrofloxacin and gentamicin. PMID- 28919695 TI - beta-defensins: An innate defense for bovine mastitis. AB - Immune challenges are inevitable for livestock that are exposed to a varied range of adverse conditions ranging from environmental to pathogenic stresses. The beta defensins are antimicrobial peptides, belonging to "defensin" family and therefore acts as the first line of defense against the major infections occurring in dairy cattle including intramammary infections. The better resistance to mastitis displayed by Bos indicus is implicit in the fact that they have better adapted and also has more sequence variation with rare allele conserved due to lesser artificial selection pressure than that of Bos taurus. Among the 58 in silico predicted beta-defensins, only a few have been studied in the aspect of intramammary infections. The data on polymorphisms occurring in various beta-defensin genes is limited in B. indicus, indicating toward higher possibilities for exploring marker for mastitis resistance. The following review shall focus on concisely summarizing the up-to-date research on beta-defensins in B. taurus and discuss the possible scope for research in B. indicus. PMID- 28919696 TI - Potential of pomegranate fruit extract (Punica granatum Linn.) to increase vascular endothelial growth factor and platelet-derived growth factor expressions on the post-tooth extraction wound of Cavia cobaya. AB - BACKGROUND: Pomegranates fruit extracts have several activities, among others, anti-inflammatory, antibacterial, and antioxidants that have the main content punicalagin and ellagic acid. Pomegranate has the ability of various therapies through different mechanisms. Vascular endothelial growth factor (VEGF) function was to form new blood vessels produced by various cells one of them was macrophages. Platelet-derived growth factor (PDGF) was a growth factor proven chemotactic, increased fibroblast proliferation and collagen matrix production. In addition, VEGF and PDGF synergize in their ability to vascularize tissues. The PDGF function was to stabilize and regulate maturation of new blood vessels. Activities of pomegranate fruit extract were observed by measuring the increased of VEGF and PDGF expression as a marker of wound healing process. AIM: To investigate the potential of pomegranate extracts on the tooth extraction wound to increase the expression of VEGF and PDGF on the 4th day of wound healing process. MATERIALS AND METHODS: This study used 12 Cavia cobaya, which were divided into two groups, namely, the provision of 3% sodium carboxymethyl cellulose and pomegranate extract. The 12 C. cobaya would be executed on the 4th day, the lower jaw of experimental animals was taken, decalcified about 30 days. The expression of VEGF and PDGF was examined using immunohistochemical techniques. The differences of VEGF and PDGF expression were evaluated statistically using t-test. RESULTS: Statistically analysis showed that there were significant differences between control and treatment groups (p<0.05). CONCLUSION: Pomegranate fruit extract administration increased VEGF and PDGF expression on post-tooth extraction wound. PMID- 28919697 TI - 16S ribosomal RNA sequencing and molecular serotyping of Avibacterium paragallinarum isolated from Indian field conditions. AB - AIM: This study was aimed at identifying Indian field isolates of Avibacterium paragallinarum on both molecular as well as serological levels that cause infectious coryza in chickens. MATERIALS AND METHODS: Species-specific polymerase chain reaction (HPG-2 PCR), and 16S ribosomal RNA (rRNA) sequencing were employed for molecular identification. Whereas, multiplex PCR technique was used for serological identification of Indian field isolates of A. paragallinarum. RESULTS: All three field isolates were identified as A. paragallinarum using HPG 2 PCR. The species-specific PCR results were validated using 16S rRNA sequencing. The partial 16S rRNA sequences obtained from all three isolates showed 96-99% homology with the NCBI database reference strains of A. paragallinarum. The aligned partial sequences of 16S rRNA were submitted to GenBank, and accession numbers were obtained. Multiplex PCR-based molecular serotyping showed that there are three serotypes of field isolates of A. paragallinarum, namely, strain IND101 is serovar A, strain IND102 is serovar B, and strain IND103 is serovar C. CONCLUSION: HPG-2 PCR, 16S rRNA sequencing, and multiplex PCR are proved to be more accurate, sensitive, and reliable diagnostic tools for molecular and serological identification of A. paragallinarum field isolates. These diagnostic methods can substitute conventional cultural characterization and would be much valuable to formulate quick and correct prevention and control measures against this detrimental poultry pathogen. PMID- 28919698 TI - Skeletal Lead Burden of the British Royal Navy in Colonial Antigua. AB - Lead (Pb) has been known to be a cause of human poisoning since ancient times, but despite this, it was a widely used metal in the European colonial period. In this study, the relationship between Pb exposure and the demographic variables ancestry and age was explored by comparing the bone Pb levels of individuals that were of either African or European ancestry, excavated from a British Royal Navy hospital cemetery (1793-1822 CE) at English Harbour in Antigua, West Indies. More direct comparisons of Pb levels between the two ancestral groups were possible in this study because of the unsegregated nature of this cemetery. Inductively coupled plasma mass spectrometry was used to determine bulk Pb levels in cortical bone samples from the fibular diaphyses of 23 male individuals. No significant difference was found between the distributions of the Pb levels of the ancestral groups (p = 0.94). Further, no positive correlations or significant differences were found in relation to the individuals' ages and their Pb levels (p = 0.24). Levels of Ba, Ca and rare earth elements support a largely biogenic origin of lead. This is bolstered by Pb deposition patterns, generated by synchrotron X-ray fluorescence imaging for another study. The data suggest that naval personnel, regardless of ancestry at English Harbour, had very similar experiences with regard to Pb exposure. Their exposure to the toxic metal was likely not consistent over time as steady exposure would have resulted in accumulation of Pb with age. This study contributes to addressing historical questions regarding the prevalence of Pb poisoning within the British Royal Navy during the colonial period. PMID- 28919699 TI - Resonant control of polar molecules in individual sites of an optical lattice. AB - We study the resonant control of two nonreactive polar molecules in an optical lattice site, focusing on the example of RbCs. Collisional control can be achieved by tuning bound states of the intermolecular dipolar potential by varying the applied electric field or trap frequency. We consider a wide range of electric fields and trapping geometries, showing that a three-dimensional optical lattice allows significantly wider avoided crossings than free space or quasi-two dimensional geometries. Furthermore, we find that dipolar confinement-induced resonances can be created with reasonable trapping frequencies and electric fields, and have widths that will enable useful control in forthcoming experiments. PMID- 28919700 TI - Construction and Test Results of Coil 2 of a Three-Coil 800-MHz REBCO Insert for the 1.3-GHz High-Resolution NMR Magnet. AB - This paper focuses on the construction and test results of Coil 2 that is part of a trio of nested coils composing the REBCO 800 MHz insert. Upon its completion, the REBCO 800 MHz insert will be placed in the bore of a 500 MHz low temperature superconducting (LTS) NMR magnet (L500) to form the MIT 1.3 GHz high-resolution NMR magnet. Coil 2 is a stack of 32 double pancake (DP) coils wound with 6-mm wide REBCO tape using the no-insulation (NI) technique. Each pancake is wound on a stainless steel inner supporting ring to prevent the collapsing of its crossover due to the external pressure exerted by the winding pack. Coil 2 will be constructed in the following sequence: 1) after winding each DP will be individually tested in a bath of liquid nitrogen at atmospheric pressure to determine its current carrying capabilities; 2) DPs will be then assembled as a stack with interconnecting joints, and 3) as in Coil 1, each pancake will be overbanded with a stainless steel tape, this time to a thickness of 5 mm, thickness determined by a stress analysis previously performed. Finally the fully assembled Coil 2 will be tested in liquid nitrogen at 77 K and then in liquid helium at 4.2 K. We present here details of the stress analysis leading to the sizing of the DP inner supporting stainless steel ring and of the overbanding thickness required. Test results include coil index, critical current, charging time constant. PMID- 28919701 TI - Wise Additions Bridge the Gap between Social Psychology and Clinical Practice: Cognitive-Behavioral Therapy as an Exemplar. AB - Progress in clinical science, theory, and practice requires the integration of advances from multiple fields of psychology, but much integration remains to be done. The current article seeks to address the specific gap that exists between basic social psychological theories and the implementation of related therapeutic techniques. We propose several "wise additions," based upon the principles outlined by Walton (2014), intended to bridge current social psychological research with clinical psychological therapeutic practice using cognitive behavioral therapy as an example. We consider how recent advances in social psychological theories can inform the development and implementation of wise additions in clinical case conceptualization and interventions. We specifically focus on self and identity, self-affirmation, transference, social identity, and embodied cognition, five dominant areas of interest in the field that have clear clinical applications. PMID- 28919702 TI - Micro-invasive glaucoma surgery (MIGS): a review of surgical procedures using stents. AB - Over the last decade several novel surgical treatment options and devices for glaucoma have been developed. All these developments aim to cause as little trauma as possible to the eye, to safely, effectively, and sustainably reduce intraocular pressure (IOP), to produce reproducible results, and to be easy to adopt. The term "micro-invasive glaucoma surgery (MIGS)" was used for summarizing all these procedures. Currently MIGS is gaining more and more interest and popularity. The possible reduction of the number of glaucoma medications, the ab interno approach without damaging the conjunctival tissue, and the probably safer procedures compared to incisional surgical methods may explain the increased interest in MIGS. The use of glaucoma drainage implants for lowering IOP in difficult-to-treat patients has been established for a long time, however, a variety of new glaucoma micro-stents are being manufactured by using various materials and are available to increase aqueous outflow via different pathways. This review summarizes published results of randomized clinical studies and extensive case report series on these devices, including Schlemm's canal stents (iStent(r), iStent(r) inject, Hydrus), suprachoroidal stents (CyPass(r), iStent(r) Supra), and subconjunctival stents (XEN). The article summarizes the findings of published material on efficacy and safety for each of these approaches. PMID- 28919703 TI - Quality and learning curve of handheld versus stand-alone non-mydriatic cameras. AB - PURPOSE: Nowadays, complex digital imaging systems allow detailed retinal imaging without dilating patients' pupils. These so-called non-mydriatic cameras have advantages in common circumstances (eg, for screening or emergency purposes) but present limitations in terms of image quality and field of view. We compare the usefulness of two non-mydriatic camera systems (ie, a handheld versus a stand alone device) for fundus imaging. The primary outcome was image quality. The secondary outcomes were learning effects and quality grade-influencing factors. METHODS: The imaging procedures followed standard protocol and were all performed by the same investigator. Camera 1 (DRS(r)) was a stand-alone system, while Camera 2 (Smartscope(r) PRO) was a mobile system. In order to evaluate possible learning effects, we selected an examiner with no prior training in the use of these systems. The images were graded separately by two experienced and "blinded" ophthalmologists following a defined protocol. RESULTS: In total, 211 people were enrolled. Quality grade comparisons showed significantly better grades for Camera 1. Both systems achieved better quality grades for macular images than for disc centered images. No remarkable learning effects could be demonstrated. CONCLUSIONS: Both camera systems are useful for fundus imaging. The greater mobility of Camera 2 was associated with lower image quality. For screening scenarios or telemedicine, it must be determined whether image quality or mobility is more important. PMID- 28919704 TI - Secondary prevention of major cerebrovascular events with seven different statins: a multi-treatment meta-analysis. AB - BACKGROUND: Statins have been recommended for the use in atherosclerotic cardiovascular diseases, but different statins have distinct pharmacological characteristics. This multi-treatment meta-analysis aimed to evaluate the efficacy of seven statins in the secondary prevention of major cerebrovascular events (CVEs). METHODS AND ANALYSES: The PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched to identify studies published between January 1, 2011, and June 30, 2016. The included randomized controlled trials investigated the efficacy of lovastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin, pravastatin or rosuvastatin in the secondary prevention of CVEs. The primary outcomes were CVEs; the secondary outcomes were all-cause death, fatal stroke and nonfatal stroke. Meta-analysis and network meta-analysis were used for data synthesis. RESULTS: A total of 42 studies with 82,601 patients were included for analysis. In the secondary prevention of cardiovascular diseases, the major CVEs in pravastatin (risk ratio [RR] 0.87, 0.76-0.99)- and atorvastatin (RR 0.59, 0.49-0.72)-treated patients reduced significantly compared with controls. Indirect comparisons with network meta-analysis showed that RR was 0.60 (0.40-0.92) for atorvastatin compared with rosuvastatin. Compared to controls, the all-cause death was reduced by 12% in statins-treated patients (RR 0.88, 0.81-0.96). Indirect comparisons with network analysis showed a significant difference in the nonfatal stroke between fluvastatin-treated patients and lovastatin-treated patients (RR 0.28, 0.07-0.95). CONCLUSION: Different statins have distinct pharmacological characteristics, and there are differences in statistical and clinical outcomes among several statins. PMID- 28919705 TI - New insight into the pathogenesis of nail psoriasis and overview of treatment strategies. AB - Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population. The prevalence of nail involvement in psoriasis patients varies between 15% and 79%. While the nails represent a small portion of the body surface area, psoriasis in these areas can have a disproportionate influence on a patient's physical and psychosocial activities. Differential diagnosis between an onychomycosis and a psoriatic nail could be challenging; nevertheless, coexistence of onychomycosis and nail psoriasis also occurs and both are common disorders in the general population. Nail psoriasis can be difficult to treat. Treatment of nail psoriasis should consider the body surface area of skin disease, psoriatic arthritis, severity of nail disease, and the impairment in the quality of life. All patients should be tested for onychomycosis before starting a therapy. This recommendation is underlined by the fact that nail psoriasis is mostly treated by immunosuppressive drugs, like steroids, methotrexate, or biologics, which may aggravate mycotic nail infections. Conventional systemic therapy, such as use of steroids, cyclosporine, methotrexate, and retinoid in the long term, can cause organ toxicities. Currently, use of apremilast and tofacitinib favors an early healing of nail psoriasis because they act directly on the pathogenic targets, distressing the inflammatory signals associated with the initiation and maintenance of the disease activity, and as with several conventional synthetic disease modifying antirheumatic drugs, they are characterized by the convenience of oral administration. The number of treatment options has increased considerably in recent years; however, given the heterogeneity of the disease, the therapy should be personalized to individual cases. PMID- 28919706 TI - Profile of pembrolizumab in the treatment of head and neck squamous cell carcinoma: design development and place in therapy. AB - Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide, and despite advances in cytotoxic, surgical and radiation techniques, outcomes are still poor in those with both locally advanced and metastatic diseases. The need for development of better therapeutics along with a greater understanding of the relationship between the immune system and malignancies has led to a new therapeutic modality, immune modulators, particularly checkpoint inhibitors in HNSCC. It is now well recognized that HNSCC circumvents crucial pathways utilized by the immune system to escape surveillance. These hijacked pathways include impairing tumor antigen presentation machinery and co-opting checkpoint receptors. This understanding has led to the development of monoclonal antibodies targeting checkpoint receptors and has resulted in promising outcomes in HNSCC. This article describes the mechanisms that HNSCC utilizes to escape immune surveillance, clinical impact of checkpoint inhibitors (with a focus on pembrolizumab), ongoing studies, and future directions. PMID- 28919708 TI - Alginate oligosaccharide indirectly affects toll-like receptor signaling via the inhibition of microRNA-29b in aneurysm patients after endovascular aortic repair. AB - Endovascular aortic repair (EVAR) is often followed by aneurysm recurrence. Alginate oligosaccharide (AOS) has potential antitumor properties as a natural product while the related mechanisms remain unclear. Toll-like receptor (TLR) signaling is associated with inflammatory activity of aneurysm and may be affected by miR-29b. Thus, inhibitory function of AOS on aneurysms was explored by measuring the important molecules in TLR4 signaling. After EVAR, a total of 248 aortic aneurysm patients were recruited and randomly assigned into two groups: AOS group (AG, oral administration 10-mg AOS daily) and control group (CG, placebo daily). The size of residual aneurysms, aneurysm recurrence, and side effects were investigated. Aneurysm recurrence was determined by Kaplan Meier analysis. After 2 years, eight and two patients died in the CG and AG, respectively. The sizes of residual aneurysms were significantly larger in the CG than in the AG (P<0.05). The incidence of aneurysm recurrence was also significantly higher in the CG than in the AG (P<0.05). AOS treatment reduced the levels of miR-29b, TLR4, mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-kappa B), interleukin 1 (IL-1) beta, and interleukin 6 (IL-6). Overexpression and silence of miR-29b increased and reduced the level of TLR4, phospho-p65 NF-kappa B, phospho-p38 MAPK, IL-1 beta, and IL-6. Spearman's rank correlation analysis shows that the level of miR-29b is positively related to the levels of TLR4, NF-kappa B, IL-1 beta, and IL-6 (P<0.05). Thus, AOS represses aneurysm recurrence by indirectly affecting TLR signaling via miR-29b. PMID- 28919707 TI - Quantum mechanics implementation in drug-design workflows: does it really help? AB - The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry. However, the complexity of many protein-ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. The usefulness of quantum mechanics (QM) in drug-protein interaction cannot be overemphasized; however, this approach has little significance in some empirical methods. In this review, we discuss recent developments in, and application of, QM to medically relevant biomolecules. We critically discuss the different types of QM-based methods and their proposed application to incorporating them into drug-design and -discovery workflows while trying to answer a critical question: are QM-based methods of real help in drug-design and -discovery research and industry? PMID- 28919709 TI - Puerarin transport across rat nasal epithelial cells and the influence of compatibility with peoniflorin and menthol. AB - Nose-to-brain transport can provide an excellent pathway for drugs of the central nervous system. Consequently, how to make full use of this pathway in practical applications has become a focus of drug design. However, many aspects affecting drug delivery from the nose to the brain remain unclear. This study aimed to more deeply investigate the transport of puerarin and to explore the mechanism underlying the influence of compatible drugs on puerarin permeability in a primary cell model simulating the nasal mucosa. In this research, based on rat nasal epithelial cells (RNECs) cultured in vitro and cytotoxicity assays, the bidirectional transport of puerarin across RNEC monolayers and the effect of its compatibility with peoniflorin and menthol were analyzed. The apparent permeability coefficient was <1.5*10-6 cm/s, and the efflux ratio of puerarin was <2, indicating that puerarin had poor absorption and that menthol but not peoniflorin significantly improved puerarin transport. Simultaneously, through experiments, such as immunofluorescence staining, transepithelial electrical resistance measurement, rhodamine 123 efflux evaluation, the cell membrane fluorescence recovery after photobleaching test, and ATPase activity determination, the permeability promoting mechanism of menthol was confirmed to be closely related to disruption of the tight junction protein structure, to the P-glycoprotein inhibitory effect, to increased membrane fluidity, and to the promotion of enzyme activity. These results provide reliable data on nasal administration of the studied drugs and lay the foundation for a deeper investigation of the nose-brain pathway and nasal administration. PMID- 28919710 TI - Irinotecan and 5-fluorouracil-co-loaded, hyaluronic acid-modified layer-by-layer nanoparticles for targeted gastric carcinoma therapy. AB - For targeted gastric carcinoma therapy, hyaluronic acid (HA)-modified layer-by layer nanoparticles (NPs) are applied for improving anticancer treatment efficacy and reducing toxicity and side effects. The aim of this study was to develop HA modified NPs for the co-loading of irinotecan (IRN) and 5-fluorouracil (5-FU). A novel polymer-chitosan (CH)-HA hybrid formulation (HA-CH-IRN/5-FU NPs) consisting of poly(d,l-lactide-co-glycolide) (PLGA) and IRN as the core, CH and 5-FU as a shell on the core and HA as the outmost layer was prepared. Its morphology, average size, zeta potential and drug encapsulation ability were evaluated. Human gastric carcinoma cells (MGC803 cells) and cancer-bearing mice were used for the testing of in vitro cytotoxicity and in vivo antitumor efficiency of NPs. HA-CH IRN/5-FU NPs displayed enhanced antitumor activity in vitro and in vivo than non modified NPs, single drug-loaded NPs and drugs solutions. The results demonstrate that HA-CH-IRN/5-FU NPs can achieve impressive antitumor activity and the novel targeted drug delivery system offers a promising strategy for the treatment of gastric cancer. PMID- 28919711 TI - Protective role of quercetin against manganese-induced injury in the liver, kidney, and lung; and hematological parameters in acute and subchronic rat models. AB - Manganese (Mn) is an important mineral element required in trace amounts for development of the human body, while over- or chronic-exposure can cause serious organ toxicity. The current study was designed to evaluate the protective role of quercetin (Qct) against Mn-induced toxicity in the liver, kidney, lung, and hematological parameters in acute and subchronic rat models. Male Sprague Dawley rats were divided into control, Mn (100 mg/kg for acute model and 15 mg/kg for subchronic model), and Mn + Qct (25 and 50 mg/kg) groups in both acute and subchronic models. Our result revealed that Mn + Qct groups effectively reduced Mn-induced ALT, AST, and creatinine levels. However, Mn + Qct groups had effectively reversed Mn-induced alteration of complete blood count, including red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, and white blood cells. Meanwhile, the Mn + Qct groups had significantly decreased neutrophil and eosinophil and increased lymphocyte levels relative to the Mn group. Additionally, Mn + Qct groups showed a beneficial effect against Mn-induced macrophages and neutrophils. Our result demonstrated that Mn + Qct groups exhibited protective effects on Mn-induced alteration of GRP78, CHOP, and caspase 3 activities. Furthermore, histopathological observation showed that Mn + Qct groups effectively counteracted Mn-induced morphological change in the liver, kidney, and lung. Moreover, immunohistochemically Mn + Qct groups had significantly attenuated Mn-induced 8-oxo-2'-deoxyguanosine immunoreactivity. Our study suggests that Qct could be a substantially promising organ-protective agent against toxic Mn effects and perhaps against other toxic metal chemicals or drugs. PMID- 28919712 TI - Recent developments in the clinical pharmacology of rolapitant: subanalyses in specific populations. AB - Knowledge of the involvement of the neurokinin substance P in emesis has led to the development of the neurokinin-1 receptor antagonists (NK-1 RAs) for control of chemotherapy-induced nausea and vomiting (CINV), in combination with serotonin type 3 receptor antagonists and corticosteroids. The NK-1 RA rolapitant, recently approved in oral formulation, has nanomolar affinity for the NK-1 receptor, as do the other commercially available NK-1 RAs, aprepitant and netupitant. Rolapitant is rapidly absorbed and has a long half-life in comparison to aprepitant and netupitant. All three NK-1 RAs undergo metabolism by cytochrome P450 (CYP) 3A4, necessitating caution with the concomitant use of CYP3A4 inhibitors, but in contrast to aprepitant and netupitant, rolapitant does not inhibit or induce CYP3A4. However, rolapitant is a moderate inhibitor of CYP2D6, and concomitant use with CYP2D6 substrates with narrow therapeutic indices should be avoided. Aprepitant, netupitant, and rolapitant have all demonstrated efficacy in the control of delayed CINV in patients receiving moderately and highly emetogenic chemotherapy in randomized controlled trials, including over multiple cycles of chemotherapy. We reviewed recent post hoc analyses of clinical trial data demonstrating that rolapitant is efficacious in the control of CINV in patient populations with specific tumor types, namely, breast cancers, gastrointestinal/colorectal cancers, and lung cancers. In addition, we show that rolapitant has efficacy in the control of CINV in specific age groups of patients receiving chemotherapy (<65 and >=65 years of age). Overall, the safety profile of rolapitant in these specific patient populations was consistent with that observed in primary analyses of phase 3 trials. PMID- 28919713 TI - Layer-by-layer nanoparticles co-loading gemcitabine and platinum (IV) prodrugs for synergistic combination therapy of lung cancer. AB - PURPOSE: Cisplatin plus gemcitabine (GEM) is a standard regimen for the first line treatment of advanced non-small cell lung cancer. The aim of this study was to prepare biocompatible and biodegradable polymeric prodrugs and construct nanoparticles (NPs) with layer-by-layer (LbL) technique. METHODS: Platinum (Pt) (IV) complex with a carboxyl group was conjugated to the amino group of chitosan (CH), resulting in a CH-Pt conjugation with positive charge. GEM with amino group was conjugated to the carboxyl group of hyaluronic acid (HA), resulting in a HA GEM conjugation with negative charge. Novel LbL NPs consisting of the CH-Pt core and the HA-GEM layer, named as HA-GEM/CH-Pt NPs, were constructed. The physicochemical properties of the HA-GEM/CH-Pt NPs were investigated. In vitro cytotoxicity against human non-small lung cancer cells (NCl-H460 cells) was investigated, and in vivo antitumor efficiency was evaluated on mice bearing NCl H460 cells xenografts. RESULTS: HA-GEM/CH-Pt NPs have a size of about 187 nm, a zeta potential value of -21 mV and high drug encapsulation efficiency of 90%. The drug release of HA-GEM/CH-Pt NPs exhibited a sustained behavior. HA-GEM/CH-Pt NPs could significantly enhance in vitro cytotoxicity and in vivo antitumor effect against lung cancer animal model compared to the single-drug-loaded NPs and free drug solutions. CONCLUSION: The results demonstrated that the HA-GEM/CH-Pt NPs might be a promising system for the synergetic treatment of lung carcinoma. PMID- 28919714 TI - Radium 223 dichloride for prostate cancer treatment. AB - Prostate cancer is the most common malignant disease in men. Several therapeutic agents have been approved during the last 10 years. Among them, radium-223 dichloride (Xofigo(r)) is a radioactive isotope that induces irreversible DNA double-strand breaks and consequently tumor cell death. Radium-223 dichloride is a calcium-mimetic agent that specifically targets bone lesions. Radium-223 dichloride has been approved for the treatment of metastatic castration-resistant prostate cancer with symptomatic bone metastases, without known visceral metastases. In this review, first we summarize the interplay between prostate tumor cells and bone microenvironment; then, we discuss radium-223 dichloride mechanism of action and present the results of the available clinical trials and future developments for this new drug. PMID- 28919715 TI - In vitro inhibitory activities of magnolol against Candida spp. AB - Candida spp. cause various infections involving the skin, mucosa, deep tissues, and even life-threatening candidemia. They are regarded as an important pathogen of nosocomial bloodstream infection, with a high mortality rate. As a result of prolonged exposure to azoles, the therapeutic failure associated with azoles resistance has become a serious challenge in clinical situations. Therefore, novel, alternative antifungals are required urgently. In the present study, the CLSI M-27A broth microdilution method and the 2,3-Bis-(2-methoxy-4-nitro-5 sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay were used to evaluate the antifungal effects of magnolol against various standard Candida strains in planktonic mode and biofilm formation, respectively. The antifungal activity of magnolol was demonstrated in planktonic C. albicans and non-albicans Candida species, especially fluconazole-resistant Candida krusei, with the minimum inhibitory concentrations ranging from 10 to 40 MUg/mL. The BMIC90 (minimum concentration with 90% Candida biofilm inhibited) values of magnolol ranged from 20 to 160 MUg/mL, whereas the BMIC90 values of fluconazole were more than 128 MUg/mL. As an alternative and broad-spectrum antifungal agent, magnolol might be of benefit to the treatment of refractory Candida infection. PMID- 28919717 TI - The influence of goal-directed fluid therapy on the prognosis of elderly patients with hypertension and gastric cancer surgery [Retraction]. AB - [This retracts the article on p. 2113 in vol. 8.]. PMID- 28919716 TI - Palatability and physical properties of potassium-binding resin RDX7675: comparison with sodium polystyrene sulfonate. AB - BACKGROUND: Hyperkalemia is a potentially life-threatening condition that patients with heart failure or chronic kidney disease, especially those taking renin-angiotensin-aldosterone system inhibitors, are at high risk of developing. Sodium polystyrene sulfonate (SPS), a current treatment, binds potassium within the gastrointestinal tract to reduce potassium absorption. However, poor palatability limits its long-term use. RDX7675, a novel potassium binder in development for the treatment of hyperkalemia, is a calcium salt of a reengineered polystyrene sulfonate-based resin designed to have enhanced palatability. Here, the physical properties and palatability of RDX7675 and SPS are compared. METHODS: RDX7675 and SPS particle sizes were measured using wet dispersion laser diffraction. Palatability was assessed in a randomized, crossover, healthy volunteer study with two visits. At visit 1 (open label), volunteers evaluated high-viscosity, intermediate-viscosity, and water reconstituted formulations of RDX7675 (all vanilla flavor), and an equivalent reconstituted SPS (Resonium A(r)). At visit 2 (single-blind), volunteers evaluated RDX7675 as a high-viscosity formulation in vanilla, citrus, and mint flavors, and as intermediate-viscosity, low-viscosity, and reconstituted formulations in citrus flavor. Volunteers used a "sip and spit" technique to rate overall acceptability and seven individual characteristics from 1 ("dislike everything") to 9 ("like extremely"). RESULTS: RDX7675 particles were smaller than SPS particles, with a narrower size range (RDX7675, 80%, 14-52 um; SPS, 11.3 124.2 um), and had a smooth, spherical shape, in contrast to the shard-like SPS particles. Reconstituted RDX7675 was considered superior to SPS for five of the seven palatability characteristics and for overall acceptability (median, visit 1: reconstituted RDX7675, 5.0; SPS, 4.0). High-viscosity vanilla was the most highly rated RDX7675 formulation (median overall acceptability, visit 2: 7.0). CONCLUSION: The smaller, more uniformly shaped, spherical particles of RDX7675 resulted in improved palatability over SPS when reconstituted in water. The overall results are promising for future patient acceptability of RDX7675 treatment. PMID- 28919718 TI - Extended infusion versus intermittent infusion of imipenem in the treatment of ventilator-associated pneumonia. AB - BACKGROUND: Mechanical ventilation support can be the main source of ventilator associated pneumonia (VAP). VAP is a serious infection that may be associated with dangerous gram-negative bacteria mainly, and it leads to an increase in the mortality in the intensive care unit (ICU). Imipenem is one of the strongest antibiotics now available for treating VAP which is associated with gram-negative and gram-positive bacteria, and it belongs to beta-lactam antibiotic group (carbapenem). OBJECTIVE: This study tried to investigate the efficacy of imipenem against VAP when it was infused within 180 min versus the efficacy when it was infused within 30-60 min. SETTING: This study was conducted in main ICU in general hospital which consists of surgical and medical beds within 2 years. One hundred and eighty-seven patients were enrolled on it. METHOD: This study is a retrospective cohort which was conducted within 2 years. The efficacy of imipenem which was administered by intermittent infusion (30-60 min) within first year was compared with the efficacy of imipenem which was administered by extended infusion (180 min) within second year in the field of VAP curing and cost reduction. All data were collected retrospectively from patient medical files and were statistically analyzed by SPSS version 20. MAIN OUTCOME: The study was designed to measure clinical and cost reduction outcomes, mortality and hospital stay. RESULTS: The results indicated that there is a significant decrease in mortality, number of recurrent infection, and ICU stay length, and the number of mechanical ventilator days was associated with extended imipenem infusion during the second year of the study. CONCLUSION: The use of imipenem with extended infusion over 3 hours enhances its clinical outcomes in the treatment of VAP. PMID- 28919719 TI - An upper and lower bound of the Medication Possession Ratio. AB - BACKGROUND: The Medication Possession Ratio (MPR) is a ubiquitous and central measurement for adherence in the health care industry. However, attempts to standardize its calculation have failed, possibly due to the opacity of a single, static MPR, incapability of directly lending itself to a variety of studies, and challenges of comparing the value across studies. This work shows that the MPR strictly depends on the length of the time interval over which it is measured as well as on the dominant dispense quantity for short time intervals. Furthermore, removing a proportion of the patient cohort based on the number of acquisitions may also have a severe impact on the MPR. Therefore, it is suggested that the MPR is represented as a trend over a range of time intervals. To this end, an upper and lower bound of the MPR trend is developed with an upper bound acknowledging patients who change their treatment and the lower bound acknowledging patients who discontinue their treatment. PURPOSE: Introducing a representation of the MPR value as a trend rather than a static number by developing a quantitative description of an upper and lower bound of the MPR trend, while shedding light on the impacts on prefiltering the patient cohort. PATIENTS AND METHODS: Anonymized patient-level data was utilized as an example for a suggested calculation of an upper and lower bound of the MPR. RESULTS: Representation of the MPR for a predefined time interval precludes a reliable MPR assessment. A quantitative approach is suggested to generate an upper and lower trend of the MPR while emphasizing the impact on removing patients with a limited number of acquisitions. CONCLUSION: An upper and lower trend makes the MPR more transparent and allows a better comparison across different studies. Removing patients with a limited number of acquisitions should be avoided. PMID- 28919720 TI - Text messaging to decrease tuberculosis treatment attrition in TB-HIV coinfection in Uganda. AB - BACKGROUND: Low tuberculosis (TB) treatment completion rates in sub-Saharan Africa are an important driver of multidrug resistance. Mobile technology-based interventions have been shown to improve adherence to antiretroviral therapy in sub-Saharan Africa. We aimed to test the effect of a short-message service (SMS) intervention on loss to follow-up (LFU). MATERIALS AND METHODS: In this quasi experimental study, all adult, literate, HIV-infected patients with mobile phone access diagnosed with TB between November 2010 and October 2011 in an urban clinic in Uganda were eligible to receive adherence and appointment reminders and educational quizzes during the first 8 weeks of TB treatment. Their risk of LFU in the first 8 weeks of treatment was compared with that of patients starting treatment between March 2009 and August 2010 using logistic regression. RESULTS: One of 183 (0.5%) enrolled patients was lost to FU during the intervention compared to six of 302 (2.0%) in the preintervention control group (RR 0.27, 95% CI 0.03-2.07; P=0.22). The SMS intervention was rated as very helpful by 96%. Barriers identified included interrupted phone access (26%, median 14 days) and difficulties responding by SMS. The response rate to educational quizzes was below 10%. There were no unintentional disclosures of TB or HIV status due to the intervention. CONCLUSION: An SMS reminder service did not show a clear effect on short-term risk of LFU in this study, which was underpowered due to a lower baseline risk in the control group than expected. The SMS-reminder service was rated highly, and there were no breaches of confidentiality. Important technological barriers have implications for larger-scale implementation, not only for TB but also other disease modalities. PMID- 28919721 TI - Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. AB - Urea-cycle disorders are a group of rare hereditary metabolic diseases characterized by deficiencies of one of the enzymes and transporters involved in the urea cycle, which is necessary for the removal of nitrogen produced from protein breakdown. These hereditary metabolic diseases are characterized by hyperammonemia and life-threatening hyperammonemic crises. Pharmacological treatment of urea-cycle disorders involves alternative nitrogen-scavenging pathways. Sodium benzoate combines with glycine and phenylacetate/phenylbutyrate with glutamine, forming, respectively, hippuric acid and phenylacetylglutamine, which are eliminated in the urine. Among the ammonia-scavenging drugs, sodium phenylbutyrate is a well-known long-term treatment of urea-cycle disorders. It has been used since 1987 as an investigational new drug, and was approved for marketing in the US in 1996 and the EU in 1999. However, sodium phenylbutyrate has an aversive odor and taste, which may compromise patients' compliance, and many patients have reported difficulty in taking this drug. Sodium phenylbutyrate granules are a new tasteless and odor-free formulation of sodium phenylbutyrate, which is indicated in the treatment of urea-cycle disorders. This recently developed taste-masked formulation of sodium phenylbutyrate granules was designed to overcome the considerable issues that taste has on adherence to therapy. Several studies have reported the clinical experience of patients with urea-cycle disorders treated with this new tasteless formulation of sodium phenylbutyrate. Analysis of the data indicated that this taste-masked formulation of sodium phenylbutyrate granules improved quality of life for urea-cycle disorder patients. Furthermore, a postmarketing report on the use of the product has confirmed the previous observations of improved compliance, efficacy, and safety with this taste-masked formulation of sodium phenylbutyrate. PMID- 28919722 TI - Measuring dispositional optimism in patients with chronic heart failure and their healthcare providers: the validity of the Life Orientation Test-Revised. AB - The Life Orientation Test-Revised (LOT-R) measures dispositional optimism (DO) - an individual difference promoting physical and psychological well-being in healthy adults (HAs) as well as in patients with chronic heart failure (CHF) and healthcare providers (HPs). Controversy has arisen regarding the dimensionality of the LOT-R. Whereas DO was originally defined as a one-dimensional construct, empirical evidence suggests two correlated factors in the LOT-R. This study was the first attempt to identify the best factor structure of the LOT-R in patients with CHF and HPs and to evaluate its measurement invariance among subsamples of patients with CHF, HPs, and a normative sample of HAs. Its validity was also evaluated in patients with CHF. The sample comprised 543 participants (34% HAs; 34% HPs; and 32% CHF patients). Congeneric, two correlated factor, and two orthogonal factor models for the LOT-R were compared by performing confirmatory factor analysis (CFA). Measurement invariance was evaluated by considering differential item functioning (DIF) among subsamples of HPs, patients with CHF, and HAs. In patients with CHF, validity was assessed by considering associations with anxiety and depression. The CFA demonstrated the superior fit of the two orthogonal factor model. Moreover, across patients with CHF, HPs, and HAs, the results highlighted a minimal DIF with only trivial consequences. Finally, negative but weak correlations of DO with anxiety and depression confirmed the validity of the LOT-R in patients with CHF. In summary, these findings supported the validity and suitability of the LOT-R for the assessment of DO in patients with CHF, HPs, and HAs. PMID- 28919723 TI - Effect of caregivers' expressed emotion on the care burden and rehospitalization rate of schizophrenia. AB - BACKGROUND: This study assessed the effect of expressed emotion (EE) among caregivers of schizophrenia patients on their care burden and the illness rehospitalization rate. SUBJECTS AND METHODS: A total of 64 schizophrenia patients hospitalized for the first time and their key caregivers were recruited. The Chinese version of the Camberwell Family Interview (CFI-CV) was used to evaluate the EE of the key caregivers. A family burden questionnaire was used to evaluate the care burden. The patients' rehospitalization rate and medication compliance were evaluated by the self-designated criteria. The data collection was carried out at the first meeting in the hospital, at 6 months and 12 months after hospital discharge by using the same instruments. RESULTS: The subjective stress burden and subjective demand burden scores were higher in caregivers before and after discharge with statistical difference between the various observation time points (P<0.05). Significant differences were observed in the rehospitalization rate between patients with high medication adherence and low medication adherence at 12 months (P<0.01) and between patients with high expressed emotion (HEE) and low expressed emotion (LEE; P<0.05). The rehospitalization rate in patients with HEE caregivers was higher than that in those with LEE caregivers. The subjective stress burden scores were statistically significant between HEE and LEE caregivers (P<0.05). CONCLUSION: HEE is a predictor of rehospitalization rate in schizophrenic patients. The burdens of care scores are high in caregivers of schizophrenic patients. The caregivers with HEE have a high score in burden of care compared with those with LEE. PMID- 28919724 TI - Development of a core outcome set for medication review in older patients with multimorbidity and polypharmacy: a study protocol. AB - BACKGROUND: Medication review has been advocated to address the challenge of polypharmacy in older patients, yet there is no consensus on how best to evaluate its efficacy. Heterogeneity of outcomes reported in clinical trials can hinder the comparison of clinical trial findings in systematic reviews. Moreover, the outcomes that matter most to older patients might be under-reported or disregarded altogether. A core outcome set can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials in any particular field of research. As part of the European Commission-funded project, called OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly, this paper describes the methods used to develop a core outcome set for clinical trials of medication review in older patients with multimorbidity. METHODS/DESIGN: The study was designed in several steps. First, a systematic review established which outcomes were measured in published and ongoing clinical trials of medication review in older patients. Second, we undertook semistructured interviews with older patients and carers aimed at identifying additional relevant outcomes. Then, a multilanguage European Delphi survey adapted to older patients was designed. The international Delphi survey was conducted with older patients, health care professionals, researchers, and clinical experts in geriatric pharmacotherapy to validate outcomes to be included in the core outcome set. Consensus meetings were conducted to validate the results. DISCUSSION: We present the method for developing a core outcome set for medication review in older patients with multimorbidity. This study protocol could be used as a basis to develop core outcome sets in other fields of geriatric research. PMID- 28919725 TI - Correlations between satisfaction with life and selected personal resources among students of Universities of the Third Age. AB - PURPOSE: The aim of the study was to identify personal resources, including health-related resources, sense of self-efficacy, attitude to life (optimism/pessimism) and self-assessment, and to determine their relationship with satisfaction with life in members of the Universities of the Third Age (U3As) in Poland. The impact of sociodemographic factors was analyzed. MATERIALS AND METHODS: The study included 320 participants of U3As; their mean age was 67.5 years and the vast majority of them were women (92.5%). The study was a screening test based on a diagnostic survey using validated scales, Satisfaction with Life Scale (SWLS), Life Orientation Test (LOT-R) and Generalized Self-Efficacy Scale (GSES), and a survey of own design. RESULTS: Men showed significantly higher mean SWLS scores than women. SWLS scores were found to correlate significantly with LOT-R (r=0.411; P<0.001) and GSES scores (r=0.451; P<0.001). The respondents' financial situation had a significant impact on their scores in all scales: SWLS (P<0.001), LOT-R (P<0.001) and GSES (P<0.001). Educational attainment of the respondents showed a significant correlation with SWLS (P=0.004) and GSES (P=0.011). CONCLUSION: In the process of preparation for successful aging, particular emphasis should be placed on the continuous development of an individual, as it leads to the improvement of their socioeconomic status. Also, promoting positive personality traits and responsibility for one's own life, including health, is of vital importance. The study is particularly important for the early identification of individuals at risk of unsuccessful aging. PMID- 28919726 TI - Gene expression levels of the insulin-like growth factor family in patients with AMD before and after ranibizumab intravitreal injections. AB - PURPOSE: The present study focused on the assessment of the mRNA levels of the insulin-like growth factor (IGF) family in patients with the exudative form of age-related macular degeneration (AMD) before and after ranibizumab intravitreal injections. PATIENTS AND METHODS: An analysis of the expression profile of the IGF family of genes in patients with AMD was carried out using the oligonucleotide microarray and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) methods. RESULTS: In the peripheral blood mononuclear cells (PBMCs) obtained from AMD group receiving ranibizumab compared to the peripheral blood mononuclear cells from AMD group before ranibizumab treatment using oligonucleotide microarray technique, six statistically significant differentially expressed transcripts related to the IGF family were detected (unpaired t-test, p<0.05, fold change >1.5). Moreover, analysis using the real time RT-qPCR technique revealed statistically significant differences in the IGF2 and IGF2R mRNA levels (Mann-Whitney U test, p<0.05) between the two groups that were studied. Statistical analyses of both oligonucleotide microarray and real time RT-qPCR results demonstrated a significant decreased expression only for IGF2 mRNA. CONCLUSION: Our results revealed a changed expression of IGF2 mRNA after ranibizumab treatment. PMID- 28919727 TI - Five-year durability of stand-alone interspinous process decompression for lumbar spinal stenosis. AB - BACKGROUND: Lumbar spinal stenosis is the most common indication for spine surgery in older adults. Interspinous process decompression (IPD) using a stand alone spacer that functions as an extension blocker offers a minimally invasive treatment option for intermittent neurogenic claudication associated with spinal stenosis. METHODS: This study evaluated the 5-year clinical outcomes for IPD (Superion(r)) from a randomized controlled US Food and Drug Administration (FDA) noninferiority trial. Outcomes included Zurich Claudication Questionnaire (ZCQ) symptom severity (ss), physical function (pf), and patient satisfaction (ps) subdomains, leg and back pain visual analog scale (VAS), and Oswestry Disability Index (ODI). RESULTS: At 5 years, 84% of patients (74 of 88) demonstrated clinical success on at least two of three ZCQ domains. Individual ZCQ domain success rates were 75% (66 of 88), 81% (71 of 88), and 90% (79 of 88) for ZCQss, ZCQpf, and ZCQps, respectively. Leg and back pain success rates were 80% (68 of 85) and 65% (55 of 85), respectively, and the success rate for ODI was 65% (57 of 88). Percentage improvements over baseline were 42%, 39%, 75%, 66%, and 58% for ZCQss, ZCQpf, leg and back pain VAS, and ODI, respectively (all P<0.001). Within group effect sizes were classified as very large for four of five clinical outcomes (ie, >1.0; all P<0.0001). Seventy-five percent of IPD patients were free from reoperation, revision, or supplemental fixation at their index level at 5 years. CONCLUSION: After 5 years of follow-up, IPD with a stand-alone spacer provides sustained clinical benefit. PMID- 28919729 TI - Psychometric properties of the Korean version of the Pulmonary Rehabilitation Adapted Index of Self-Efficacy (PRAISE) for individuals with COPD. AB - PURPOSE: Self-efficacy is related to the emotional functioning and coping skills of an individual and is thought to be a predictor of health behaviors, which are particularly important for pulmonary rehabilitation (PR). To our knowledge, no measure of self-efficacy has been validated to explore behavior changes in the context of PR for patients with COPD in Korea. This study aimed to evaluate the psychometric properties of the Korean version of the Pulmonary Rehabilitation Adapted Index of Self-Efficacy (PRAISE). PATIENTS AND METHODS: The original scale, developed and validated by Vincent et al was translated into Korean through a process involving forward and back translation of the original scale, and transcultural adaptation was performed following the structured procedure. Content validity was assessed by a panel of 6 expert judges. In a convenience sample of 118 patients with COPD, exploratory factor analysis using principal axis factoring, followed by oblique rotation was conducted to identify construct validity, and the concurrent validity was evaluated by testing correlations between the PRAISE and 6-minute walking distance test and the PRAISE and Saint George Respiratory Questionnaire results. Internal consistency was examined by calculating Cronbach's alpha coefficients. RESULTS: Exploratory factor analysis confirmed the 2-dimensional structure of the scale constructed from the original 15-item scale. The final scale was composed of 14 items that cumulatively explained 60.3% of the total variance. The 2 factors in the scale were named "general self-efficacy" and "exercise self-efficacy." Significant correlations between the PRAISE, and 6-minute walking distance test and Saint George Respiratory Questionnaire showed the concurrent validity of the PRAISE. The Cronbach's alpha coefficient of the PRAISE was 0.93. CONCLUSION: The Korean version of the PRAISE showed adequate construct validity and reliability. These results suggest that the PRAISE is suitable for use in clinical settings as a predictor of PR behavior in Korean patients with COPD. PMID- 28919730 TI - A new functional method to choose the target lobe for lung volume reduction in emphysema - comparison with the conventional densitometric method. AB - BACKGROUND: Lung volume reduction (LVR) improves breathing mechanics by reducing hyperinflation. Lobar selection usually focuses on choosing the most destroyed emphysematous lobes as seen on an inspiratory CT scan. However, it has never been shown to what extent these densitometric CT parameters predict the least deflation of an individual lobe during expiration. The addition of expiratory CT analysis allows measurement of the extent of lobar air trapping and could therefore provide additional functional information for choice of potential treatment targets. OBJECTIVES: To determine lobar vital capacity/lobar total capacity (LVC/LTC) as a functional parameter for lobar air trapping using on an inspiratory and expiratory CT scan. To compare lobar selection by LVC/LTC with the established morphological CT density parameters. METHODS: 36 patients referred for endoscopic LVR were studied. LVC/LTC, defined as delta volume over maximum volume of a lobe, was calculated using inspiratory and expiratory CT scans. The CT morphological parameters of mean lung density (MLD), low attenuation volume (LAV), and 15th percentile of Hounsfield units (15%P) were determined on an inspiratory CT scan for each lobe. We compared and correlated LVC/LTC with MLD, LAV, and 15%P. RESULTS: There was a weak correlation between the functional parameter LVC/LTC and all inspiratory densitometric parameters. Target lobe selection using lowest lobar deflation (lowest LVC/LTC) correlated with target lobe selection based on lowest MLD in 18 patients (50.0%), with the highest LAV in 13 patients (36.1%), and with the lowest 15%P in 12 patients (33.3%). CONCLUSION: CT-based measurement of deflation (LVC/LTC) as a functional parameter correlates weakly with all densitometric CT parameters on a lobar level. Therefore, morphological criteria based on inspiratory CT densitometry partially reflect the deflation of particular lung lobes, and may be of limited value as a sole predictor for target lobe selection in LVR. PMID- 28919728 TI - Chronic obstructive pulmonary disease with mild airflow limitation: current knowledge and proposal for future research - a consensus document from six scientific societies. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, with high and growing prevalence. Its underdiagnosis and hence under-treatment is a general feature across all countries. This is particularly true for the mild or early stages of the disease, when symptoms do not yet interfere with daily living activities and both patients and doctors are likely to underestimate the presence of the disease. A diagnosis of COPD requires spirometry in subjects with a history of exposure to known risk factors and symptoms. Postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7 or less than the lower limit of normal confirms the presence of airflow limitation, the severity of which can be measured by FEV1% predicted: stage 1 defines COPD with mild airflow limitation, which means postbronchodilator FEV1 >=80% predicted. In recent years, an elegant series of studies has shown that "exclusive reliance on spirometry, in patients with mild airflow limitation, may result in underestimation of clinically important physiologic impairment". In fact, exercise tolerance, diffusing capacity, and gas exchange can be impaired in subjects at a mild stage of airflow limitation. Furthermore, growing evidence indicates that smokers without overt abnormal spirometry have respiratory symptoms and undergo therapy. This is an essential issue in COPD. In fact, on one hand, airflow limitation, even mild, can unduly limit the patient's physical activity, with deleterious consequences on quality of life and even survival; on the other hand, particularly in younger subjects, mild airflow limitation might coincide with the early stage of the disease. Therefore, we thought that it was worthwhile to analyze further and discuss this stage of "mild COPD". To this end, representatives of scientific societies from five European countries have met and developed this document to stimulate the attention of the scientific community on COPD with "mild" airflow limitation. The aim of this document is to highlight some key features of this important concept and help the practicing physician to understand better what is behind "mild" COPD. Future research should address two major issues: first, whether mild airflow limitation represents an early stage of COPD and what the mechanisms underlying the evolution to more severe stages of the disease are; and second, not far removed from the first, whether regular treatment should be considered for COPD patients with mild airflow limitation, either to prevent progression of the disease or to encourage and improve physical activity or both. PMID- 28919731 TI - Sensitization to Aspergillus fumigatus as a risk factor for bronchiectasis in COPD. AB - BACKGROUND: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap presents a possible clinical phenotype of COPD, but it is unclear why it develops in a subset of patients. We hypothesized that sensitization to Aspergillus fumigatus (A fum) is associated with bronchiectasis in COPD and occurs more frequently in vitamin D-deficient patients. METHODS: This observational study investigated sensitization to A fum in an outpatient clinical cohort of 300 COPD patients and 50 (ex-) smoking controls. Total IgE, A fum-specific IgE against the crude extract and against the recombinant antigens and A fum IgG were measured using ImmunoCAP fluoroenzyme immunoassay. Vitamin D was measured by radioimmunoassay, and computed tomography images of the lungs were scored using the modified Reiff score. RESULTS: Sensitization to A fum occurred in 18% of COPD patients compared to 4% of controls (P=0.0110). In all, 31 COPD patients (10%) were sensitized to the crude extract and 24 patients (8%) had only IgE against recombinant antigens. A fum IgG levels were significantly higher in the COPD group (P=0.0473). Within COPD, A fum-sensitized patients were more often male (P=0.0293) and more often had bronchiectasis (P=0.0297). Pseudomonas aeruginosa and Serratia marcescens were more prevalent in historical sputum samples of A fum sensitized COPD patients compared to A fum-non-sensitized COPD patients (P=0.0436). Vitamin D levels were comparable (P=0.2057). Multivariate analysis demonstrated that sensitization to recombinant f1 or f3 had a 2.8-fold increased risk for bronchiectasis (P=0.0030). CONCLUSION: These results highlight a potential role for sensitization to A fum in COPD-related bronchiectasis. PMID- 28919732 TI - Capillary PO2 does not adequately reflect arterial PO2 in hypoxemic COPD patients. AB - PURPOSE: To compare arterial (PaO2) with capillary (PcO2) partial pressure of oxygen in hypoxemic COPD patients because capillary blood gas analysis (CBG) is increasingly being used as an alternative to arterial blood gas analysis (ABG) in a non-intensive care unit setting, although the agreement between PcO2 and PaO2 has not been evaluated in hypoxemic COPD patients. PATIENTS AND METHODS: Bland Altman comparison of PaO2 and PcO2 served as the primary outcome parameter if PcO2 values were <=60 mmHg and the secondary outcome parameter if PcO2 values were <=55 mmHg. Pain associated with the measurements was assessed using a 100-mm visual analog scale. RESULTS: One hundred and two PaO2/PcO2 measurement pairs were obtained. For PcO2 values <=60 mmHg, the mean difference between PaO2 and PcO2 was 5.99+/-6.05 mmHg (limits of agreement: -5.88 to 17.85 mmHg). For PcO2 values <=55 mmHg (n=73), the mean difference was 5.33+/-5.52 mmHg (limits of agreement: -5.48 to 16.15 mmHg). If PaO2 <=55 (<=60) mmHg was set as the cut-off value, in 20.6% (30.4%) of all patients, long-term oxygen therapy have been unnecessarily prescribed if only PcO2 would have been assessed. ABG was rated as more painful compared with CBG. CONCLUSIONS: PcO2 does not adequately reflect PaO2 in hypoxemic COPD patients, which can lead to a relevant number of unnecessary long-term oxygen therapy prescriptions. PMID- 28919733 TI - Cycle ergometer and inspiratory muscle training offer modest benefit compared with cycle ergometer alone: a comprehensive assessment in stable COPD patients. AB - BACKGROUND: Cycle ergometer training (CET) has been shown to improve exercise performance of the quadriceps muscles in patients with COPD, and inspiratory muscle training (IMT) may improve the pressure-generating capacity of the inspiratory muscles. However, the effects of combined CET and IMT remain unclear and there is a lack of comprehensive assessment. MATERIALS AND METHODS: Eighty one patients with COPD were randomly allocated to three groups: 28 received 8 weeks of CET + IMT (combined training group), 27 received 8 weeks of CET alone (CET group), and 26 only received 8 weeks of free walking (control group). Comprehensive assessment including respiratory muscle strength, exercise capacity, pulmonary function, dyspnea, quality of life, emotional status, nutritional status, and body mass index, airflow obstruction, and exercise capacity index were measured before and after the pulmonary rehabilitation program. RESULTS: Respiratory muscle strength, exercise capacity, inspiratory capacity, dyspnea, quality of life, depression and anxiety, and nutritional status were all improved in the combined training and CET groups when compared with that in the control group (P<0.05) after pulmonary rehabilitation program. Inspiratory muscle strength increased significantly in the combined training group when compared with that in the CET group (DeltaPImax [maximal inspiratory pressure] 5.20+/-0.89 cmH2O vs 1.32+/-0.91 cmH2O; P<0.05). However, there were no significant differences in the other indices between the two groups (P>0.05). Patients with weakened respiratory muscles in the combined training group derived no greater benefit than those without respiratory muscle weakness (P>0.05). There were no significant differences in these indices between the patients with malnutrition and normal nutrition after pulmonary rehabilitation program (P>0.05). CONCLUSION: Combined training is more effective than CET alone for increasing inspiratory muscle strength. IMT may not be useful when combined with CET in patients with weakened inspiratory muscles. Nutritional status had slight impact on the effects of pulmonary rehabilitation. A comprehensive assessment approach can be more objective to evaluate the effects of combined CET and IMT. PMID- 28919735 TI - Essential need for rethink of COPD airway pathology: implications for new drug approaches for prevention of lung cancer as well as small airway fibrosis. PMID- 28919734 TI - Usefulness of the desaturation-distance ratio from the six-minute walk test for patients with COPD. AB - PURPOSE: A straightforward, noninvasive method is needed to assess emphysema and pulmonary hypertension (PH) in COPD patients. The desaturation-distance ratio (DDR) is an index derived from the distance traveled and level of desaturation during a six-minute walk test (6MWT); it has previously been shown to be associated with percentage of forced expiratory volume in the first second of expiration (%FEV1.0) and percentage of diffusion capacity of the lung for carbon monoxide (%DLCO). The aim of this study was to examine the associations between DDR and emphysema and PH. PATIENTS AND METHODS: We collected the following data for 74 stable COPD outpatients: lung function tests (%FEV1.0 and %DLCO), 6MWT distance and desaturation, and area of emphysema on computed tomography (percentage of low attenuation area). Enlargement of the pulmonary artery (PA) was assessed by the ratio of the diameter of the PA to that of the aorta (PA:A ratio) as an index of PH. DDR was calculated by the distance traveled and the degree of desaturation reached during a 6MWT. The relationships between study outcomes were assessed with Spearman's rank-correlation analysis. Receiver operating characteristic (ROC) curves were used to determine the threshold values with the optimum cutoff points for predicting severe or very severe airway obstruction, pulmonary diffusing capacity disorder, moderate or severe emphysema, and enlargement of the PA. RESULTS: DDR correlated significantly with %FEV1.0, %DLCO, %LAA, and PA:A ratio. DDR showed high accuracy (area under the ROC curve >0.7) for predicting severe or very severe airway obstruction, pulmonary diffusing capacity disorder, moderate or severe emphysema, and enlargement of the PA. CONCLUSION: The results suggest that DDR is a good index of emphysema and PH in COPD patients. The 6MWT is widely used to assess COPD, and DDR could help with the early diagnosis of COPD. PMID- 28919736 TI - Carbon nanotubes gathered onto silica particles lose their biomimetic properties with the cytoskeleton becoming biocompatible. AB - Carbon nanotubes (CNTs) are likely to transform the therapeutic and diagnostic fields in biomedicine during the coming years. However, the fragmented vision of their side effects and toxicity in humans has proscribed their use as nanomedicines. Most studies agree that biocompatibility depends on the state of aggregation/dispersion of CNTs under physiological conditions, but conclusions are confusing so far. This study designs an experimental setup to investigate the cytotoxic effect of individualized multiwalled CNTs compared to that of identical nanotubes assembled on submicrometric structures. Our results demonstrate how CNT cytotoxicity is directly dependent on the nanotube dispersion at a given dosage. When CNTs are gathered onto silica templates, they do not interfere with cell proliferation or survival becoming highly compatible. These results support the hypothesis that CNT cytotoxicity is due to the biomimetics of these nanomaterials with the intracellular nanofilaments. These findings provide major clues for the development of innocuous CNT-containing nanodevices and nanomedicines. PMID- 28919737 TI - Bacterial membrane vesicles as novel nanosystems for drug delivery. AB - Bacterial membrane vesicles (BMVs) are closed spherical nanostructures that are shed naturally and ubiquitously by most bacterial species both in vivo and in vitro. Researchers have elucidated their roles in long-distance transport of a wide array of cargoes, such as proteins, toxins, antigens, virulence factors, microbicidal agents and antibiotics. Given that these natural carriers are important players in intercellular communication, it has been hypothesized that they are equally well attuned for transport and delivery of exogenous therapeutic cargoes. Additionally, BMVs appear to possess specific properties that enable their utilization as drug delivery vehicles. These include their ability to evade the host immune system, protection of the therapeutic payload and natural stability. Using bioengineering approaches, BMVs have been applied as carriers of therapeutic moieties in vaccines and for targeted delivery in cancer. In this article, we explore BMVs from the perspective of understanding their applicability to drug delivery. BMV biology, including biogenesis, physiology and pathology, is briefly reviewed. Practical issues related to bioprocessing, loading of therapeutic moieties and characterization for enabling scalability and commercial viability are evaluated. Finally, challenges to clinical translation and rational design approaches for novel BMV formulations are presented. Although the realization of the full potential of BMVs in drug delivery hinges on the development of scalable approaches for their production as well as the refinement of targeting and loading methods, they are promising candidates for development of a novel generation of drug delivery vehicles in future. PMID- 28919738 TI - Surface modification of endovascular stents with rosuvastatin and heparin-loaded biodegradable nanofibers by electrospinning. AB - : This study describes the development of drug-loaded nanofibrous scaffolds as a nanocoating for endovascular stents for the local and sustained delivery of rosuvastatin (Ros) and heparin (Hep) to injured artery walls after endovascular procedures via the electrospinning process. PURPOSE: The proposed hybrid covered stents can promote re-endothelialization; improve endothelial function; reduce inflammatory reaction; inhibit neointimal hyperplasia of the injured artery wall, due to well-known pleiotropic actions of Ros; and prevent adverse events such as in-stent restenosis (ISR) and stent thrombosis (ST), through the antithrombotic action of Hep. METHODS: Biodegradable nanofibers were prepared by dissolving cellulose acetate (AC) and Ros in N,N-dimethylacetamide (DMAc) and acetone-based solvents. The polymeric solution was electrospun (e-spun) into drug-loaded AC nanofibers onto three different commercially available stents (Co-Cr stent, Ni-Ti stent, and stainless steel stent), resulting in nonwoven matrices of submicron sized fibers. Accordingly, Hep solution was further used for fibrous coating onto the engineered Ros-loaded stent. The functional encapsulation of Ros and Hep drugs into polymeric scaffolds further underwent physicochemical analysis. Morphological characterization took place via scanning electron microscopy (SEM) and atomic force microscopy (AFM) analyses, while scaffolds' wettability properties were obtained by contact angle (CA) measurements. RESULTS: The morphology of the drug-loaded AC nanofibers was smooth, with an average diameter of 200-800 nm, and after CA measurement, we concluded to the superhydrophobic nature of the engineered scaffolds. In vitro release rates of the pharmaceutical drugs were determined using a high-performance liquid chromatography assay, which showed that after the initial burst, drug release was controlled slowly by the degradation of the polymeric materials. CONCLUSION: These results imply that AC nanofibers encapsulated with Ros and Hep drugs have great potential in the development of endovascular grafts with anti-thrombogenic properties that can accelerate the re-endothelialization, reduce the neointimal hyperplasia and inflammatory reaction, and improve the endothelial function. PMID- 28919739 TI - Docetaxel-titanate nanotubes enhance radiosensitivity in an androgen-independent prostate cancer model. AB - Around 40% of high-risk prostate cancer patients who undergo radiotherapy (RT) will experience biochemical failure. Chemotherapy, such as docetaxel (DTX), can enhance the efficacy of RT. Multidrug resistance mechanisms often limit drug efficacy by decreasing intracellular concentrations of drugs in tumor cells. It is, therefore, of interest to develop nanocarriers of DTX to maintain the drug inside cancer cells and thus improve treatment efficacy. The purpose of this study was to investigate the use of titanate nanotubes (TiONts) to develop a TiONts-DTX nanocarrier and to evaluate its radiosensitizing in vivo efficacy in a prostate cancer model. In vitro cytotoxic activity of TiONts-DTX was evaluated using an MTS assay. The biodistribution of TiONts-DTX was analyzed in vivo by single-photon emission computed tomography. The benefit of TiONts-DTX associated with RT was evaluated in vivo. Eight groups with seven mice in each were used to evaluate the efficacy of the nanohybrid combined with RT: control with buffer IT injection +/- RT, free DXL +/- RT, TiONts +/- RT and TiONts-DXL +/- RT. Mouse behavior, health status and tumor volume were monitored twice a week until the tumor volume reached a maximum of 2,000 mm3. More than 70% of nanohybrids were localized inside the tumor 96 h after administration. Tumor growth was significantly slowed by TiONts-DTX associated with RT, compared with free DTX in the same conditions (P=0.013). These results suggest that TiONts-DTX improved RT efficacy and might enhance local control in high-risk localized prostate cancer. PMID- 28919740 TI - Low toxic maghemite nanoparticles for theranostic applications. AB - BACKGROUND: Iron oxide nanoparticles have numerous and versatile biological properties, ranging from direct and immediate biochemical effects to prolonged influences on tissues. Most applications have strict requirements with respect to the chemical and physical properties of such agents. Therefore, developing rational design methods of synthesis of iron oxide nanoparticles remains of vital importance in nanobiomedicine. METHODS: Low toxic superparamagnetic iron oxide nanoparticles (SPIONs) for theranostic applications in oncology having spherical shape and maghemite structure were produced using the fast microwave synthesis technique and were fully characterized by several complementary methods (transmission electron microscopy [TEM], X-ray diffraction [XRD], dynamic light scattering [DLS], X-ray photoelectron spectroscopy [XPS], X-ray absorption near edge structure [XANES], Mossbauer spectroscopy, and HeLa cells toxicity testing). RESULTS: TEM showed that the majority of the obtained nanoparticles were almost spherical and did not exceed 20 nm in diameter. The averaged DLS hydrodynamic size was found to be ~33 nm, while that of nanocrystallites estimated by XRD was16 nm. Both XRD and XPS studies evidenced the maghemite (gamma-Fe2O3) atomic and electronic structure of the synthesized nanoparticles. The XANES data analysis demonstrated the structure of the nanoparticles being similar to that of macroscopic maghemite. The Mossbauer spectroscopy revealed the gamma-Fe2O3 phase of the nanoparticles and vibration magnetometry study showed that reactive oxygen species in HeLa cells are generated both in the cytoplasm and the nucleus. CONCLUSION: Quasispherical Fe3+ SPIONs having the maghemite structure with the average size of 16 nm obtained by using the fast microwave synthesis technique are expected to be of great value for theranostic applications in oncology and multimodal anticancer therapy. PMID- 28919741 TI - Extracellular biosynthesis of silver nanoparticles using the cell-free filtrate of nematophagous fungus Duddingtonia flagrans. AB - The biosynthesis of metallic nanoparticles (NPs) using biological systems such as fungi has evolved to become an important area of nanobiotechnology. Herein, we report for the first time the extracellular synthesis of highly stable silver NPs (AgNPs) using the nematophagous fungus Duddingtonia flagrans (AC001). The fungal cell-free filtrate was analyzed by the Bradford method and 3,5-dinitrosalicylic acid assay and used to synthesize the AgNPs in the presence of a 1 mM AgNO3 solution. They have been characterized by UV-Vis spectroscopy, X-ray diffraction, transmission electron microscopy, dynamic light scattering, Zeta potential measurements, Fourier-transform infrared, and Raman spectroscopes. UV-Vis spectroscopy confirmed bioreduction, while X-ray diffractometry established the crystalline nature of the AgNPs. Dynamic light scattering and transmission electron microscopy images showed approximately 11, 38 nm monodisperse and quasispherical AgNPs. Zeta potential analysis was able to show a considerable stability of AgNPs. The N-H stretches in Fourier-transform infrared spectroscopy indicate the presence of protein molecules. The Raman bands suggest that chitinase was involved in the growth and stabilization of AgNPs, through the coating of the particles. Our results show that the NPs we synthesized have good stability, high yield, and monodispersion. PMID- 28919742 TI - Intracellular disposition of chitosan nanoparticles in macrophages: intracellular uptake, exocytosis, and intercellular transport. AB - Biodegradable nanomaterials have been widely used in numerous medical fields. To further improve such efforts, this study focused on the intracellular disposition of chitosan nanoparticles (CsNPs) in macrophages, a primary cell of the mononuclear phagocyte system (MPS). Such interactions with the MPS determine the nanoparticle retention time in the body and consequently play a significant role in their own clinical safety. In this study, various dye-labeled CsNPs (about 250 nm) were prepared, and a murine macrophage cell line (RAW 264.7) was selected as a model macrophage. The results showed two mechanisms of macrophage incorporation of CsNPs, ie, a clathrin-mediated endocytosis pathway (the primary) and phagocytosis. Following internalization, the particles partly dissociated in the cells, indicating cellular digestion of the nanoparticles. It was proved that, after intracellular uptake, a large proportion of CsNPs were exocytosed within 24 h; this excretion induced a decrease in fluorescence intensity in cells by 69%, with the remaining particles possessing difficulty being cleared. Exocytosis could be inhibited by both wortmannin and vacuolin-1, indicating that CsNP uptake was mediated by lysosomal and multivesicular body pathways, and after exocytosis, the reuptake of CsNPs by neighboring cells was verified by further experiments. This study, thus, elucidated the fate of CsNPs in macrophages as well as identified cellular disposition mechanisms, providing the basis for how CsNPs are recognized by the MPS; such information is crucial to numerous medical applications of CsNPs. PMID- 28919743 TI - NanoVelcro-captured CTC number concomitant with enhanced serum levels of MMP7 and MMP9 enables accurate prediction of metastasis and poor prognosis in patients with lung adenocarcinoma. AB - Lung adenocarcinoma (LADC) is among the most malignant cancers that frequently develops micrometastases even in early stages of the disease. Circulating tumor cell (CTC) number, matrix metalloproteinase (MMP) 7, and MMP9 show great prospects as predictive biomarkers in many tumors. However, the interactions between these biomarkers and the molecular basis of their roles in the metastasis and prognosis of LADC remain unclear. The present study revealed that an elevated CTC count and overexpression of MMP7 and MMP9 correlate with metastasis and clinical progression in LADC patients (n=143). Furthermore, MMP7 and MMP9 upregulation facilitates LADC cell migration in vitro and enhances serum CTC levels in a xenograft mouse model. More importantly, receiver operating characteristic (ROC) curves and Kaplan-Meier analysis confirmed more accurate prediction of metastasis and overall survival (OS) with a combination panel of CTC, MMP7, and MMP9. Taken together, our data show, for the first time, the involvement of MMP7 and MMP9 in the release of CTCs into the peripheral blood, and our data reveal that CTC count and expression of MMP7 and MMP9 can be used together as an effective clinical prediction panel for LADC metastasis and prognosis. PMID- 28919744 TI - Composite iron oxide-Prussian blue nanoparticles for magnetically guided T1 weighted magnetic resonance imaging and photothermal therapy of tumors. AB - Theranostic nanoparticles offer the potential for mixing and matching disparate diagnostic and therapeutic functionalities within a single nanoparticle for the personalized treatment of diseases. In this article, we present composite iron oxide-gadolinium-containing Prussian blue nanoparticles (Fe3O4@GdPB) as a novel theranostic agent for T1-weighted magnetic resonance imaging (MRI) and photothermal therapy (PTT) of tumors. These particles combine the well-described properties and safety profiles of the constituent Fe3O4 nanoparticles and gadolinium-containing Prussian blue nanoparticles. The Fe3O4@GdPB nanoparticles function both as effective MRI contrast agents and PTT agents as determined by characterizing studies performed in vitro and retain their properties in the presence of cells. Importantly, the Fe3O4@GdPB nanoparticles function as effective MRI contrast agents in vivo by increasing signal:noise ratios in T1 weighted scans of tumors and as effective PTT agents in vivo by decreasing tumor growth rates and increasing survival in an animal model of neuroblastoma. These findings demonstrate the potential of the Fe3O4@GdPB nanoparticles to function as effective theranostic agents. PMID- 28919745 TI - Dose and time effect of CdTe quantum dots on antioxidant capacities of the liver and kidneys in mice. AB - Although quantum dot (QD)-induced toxicity occurs due to free radicals, generation of oxidative stress mediated by reactive oxygen species (ROS) formation is considered an important mechanism. However, free radical mechanisms are essentially difficult to elucidate at the molecular level because most biologically relevant free radicals are highly reactive and short-lived, making them difficult to directly detect, especially in vivo. Antioxidants play an important role in preventing or, in most cases, limiting the damage caused by ROS. Healthy people and animals possess many endogenous antioxidative substances that scavenge free radicals in vivo to maintain the redox balance and genome integrity. The antioxidant capacity of an organism is highly important but seldom studied. In this study, the dose and time effects of CdTe QDs on the antioxidant capacities of the liver and kidneys were investigated in mice using the electron paramagnetic resonance (EPR) spin-trapping technique. We found that the liver and kidneys of healthy mice contain specific antioxidant capacities that scavenge .OH and .O2-. Furthermore, oxidative stress markers (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione [GSH] and malondialdehyde [MDA]) were examined. In dose course studies, the free radical scavenging efficiencies of the liver and kidneys were found to gradually decrease with increasing concentration of CdTe QD exposure. The activities and levels of SOD, CAT, GPx and MDA were observed to increase in treated groups, whereas those of GSH were reduced. The time course studies revealed that the QD-induced antioxidant efficiency reduction was time dependent with GSH decrease and could recover after a period of time. These experimental results offer new information on QD toxicity in vivo. Specifically, CdTe QDs can deplete GSH to reduce the elimination ability of the liver and kidneys for .OH and .O2-, thus inducing oxidative damage to tissues. PMID- 28919747 TI - GE11 peptide-conjugated nanoliposomes to enhance the combinational therapeutic efficacy of docetaxel and siRNA in laryngeal cancers. AB - In this study, dual therapeutic-loaded GE11 peptide-conjugated liposomes were developed and applied to enhance therapeutic efficacies of standard-of-care regimens for the treatment of laryngeal cancer. The therapeutic strategy used here was a combination treatment with the chemotherapeutic docetaxel (DTX) and siRNA against the ABCG2 gene that regulates multidrug resistance in many tumor types. Liposome-encapsulated DTX/ABCG2-siRNA molecules were targeted to recognize tumor cells of squamous morphology by conjugation to the EGFR-targeting ligand, GE11. Targeted, drug-infused liposomes were nanosized and exhibited controlled release of DTX. Presence of GE11 peptides on liposomal surfaces enhanced the quantities of liposomal constructs taken up by Hep-2 laryngeal cancer cells. GE11 peptide-conjugated liposomes also enhanced cytotoxic effects against Hep-2 laryngeal cancer cells when compared to treatment with free DTX, thereby reducing IC50 values. Additionally, GE11 peptide-conjugated liposomes had significantly increased anti-tumor and apoptotic effects. Treatments with the GDSL nanoparticle formulation inhibited tumor growth in Hep-2 xenograft-bearing nude mouse models when compared to treatments with non-targeted NP constructs. Treatment of the mouse models with GE11 peptide-conjugated liposomes mitigated toxicities observed after treatment with free DTX. Taken together, liposomal encapsulation of DTX and ABCG2-siRNA improved the anti-tumor effects of treatment with free DTX in Hep-2 cell lines, and conjugation of GE11 peptides to liposomal constructs enhanced anti-tumor efficacies and specificities in laryngeal cancer cells. PMID- 28919746 TI - In vitro and in vivo studies of a novel bacterial cellulose-based acellular bilayer nanocomposite scaffold for the repair of osteochondral defects. AB - Bacterial cellulose (BC) is a naturally occurring nanofibrous biomaterial which exhibits unique physical properties and is amenable to chemical modifications. To explore whether this versatile material can be used in the treatment of osteochondral defects (OCD), we developed and characterized novel BC-based nanocomposite scaffolds, for example, BC-hydroxyapatite (BC-HA) and BC glycosaminoglycans (BC-GAG) that mimic bone and cartilage, respectively. In vitro biocompatibility of BC-HA and BC-GAG scaffolds was established using osteosarcoma cells, human articular chondrocytes, and human adipose-derived mesenchymal stem cells. On subcutaneous implantation, the scaffolds allowed tissue ingrowth and induced no adverse immunological reactions suggesting excellent in vivo biocompatibility. Implantation of acellular bilayered scaffolds in OCD created in rat knees induced progressive regeneration of cartilage tissue, deposition of extracellular matrix, and regeneration of subchondral bone by the host cells. The results of micro-CT revealed that bone mineral density and ratio of bone volume to tissue volume were significantly higher in animals receiving bilayered scaffold as compared to the control animals. To the best of our knowledge, this study proves for the first time, the functional performance of acellular BC-based bilayered scaffolds. Thus, this strategy has great potential for clinical translation and can be used in repair of OCD. PMID- 28919748 TI - Antibacterial properties of PEKK for orthopedic applications. AB - Orthopedic implant infections have been steadily increasing while, at the same time, antibiotics developed to kill such bacteria have proven less and less effective with every passing day. It is clear that new approaches that do not rely on the use of antibiotics are needed to decrease medical device infections. Inspired by cicada wing surface topographical features, nanostructured surfaces represent a new approach for imposing antibacterial properties to biomaterials without using drugs. Moreover, new chemistries with altered surface energetics may decrease bacterial attachment and growth. In this study, a nanostructured surface was fabricated on poly-ether-ketone-ketone (PEKK), a new orthopedic implant chemistry, comprised of nanopillars with random interpillar spacing. Specifically, after 5 days, when compared to the orthopedic industry standard poly-ether-ether-ketone (PEEK), more than 37% less Staphylococcus epidermidis were found on the PEKK surface. Pseudomonas aeruginosa attachment and growth also decreased 28% after one day of culture, with around a 50% decrease after 5 days of culture when compared to PEEK. Such decreases in bacteria function were achieved without using antibiotics. In this manner, this study demonstrated for the first time, the promise that nanostructured PEKK has for numerous anti infection orthopedic implant applications. PMID- 28919749 TI - Ginsenoside Rg1 nanoparticle penetrating the blood-brain barrier to improve the cerebral function of diabetic rats complicated with cerebral infarction. AB - Diabetic cerebral infarction is with poorer prognosis and high rates of mortality. Ginsenoside Rg1 (Rg1) has a wide variety of therapeutic values for central nervous system (CNS) diseases for the neuron protective effects. However, the blood-brain barrier (BBB) restricts Rg1 in reaching the CNS. In this study, we investigated the therapeutic effects of Rg1 nanoparticle (PHRO, fabricated with gamma-PGA, L-PAE (H), Rg1, and OX26 antibody), targeting transferrin receptor, on the diabetes rats complicated with diabetic cerebral infarction in vitro and in vivo. Dynamic light scattering analysis shows the average particle size of PHRO was 79+/-18 nm and the polydispersity index =0.18. The transmission electron microscope images showed that all NPs were spherical in shape with diameters of 89+/-23 nm. PHRO released Rg1 with sustained release manner and could promote the migration of cerebrovascular endothelial cells and tube formation and even penetrated the BBB in vitro. PHRO could penetrate the BBB with high concentration in brain tissue to reduce the cerebral infarction volume and promote neuronal recovery in vivo. PHRO was promising to be a clinical treatment of diabetes mellitus with cerebral infarction. PMID- 28919750 TI - Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment. AB - BACKGROUND: Gemcitabine (GEM) is widely used as an anticancer agent in several types of solid tumors. Silver nanoparticles (AgNPs) possess unique cytotoxic features and can induce apoptosis in a variety of cancer cells. In this study, we investigated whether the combination of GEM and AgNPs can exert synergistic cytotoxic effects in the human ovarian cancer cell line A2780. METHODS: We synthesized AgNPs using resveratrol as a reducing and stabilizing agent. The synthesized nanomaterials were characterized using various analytical techniques. The anticancer effects of a combined treatment with GEM and AgNPs were evaluated using a series of cellular assays. The expression of pro- and antiapoptotic genes was measured using real-time reverse transcription polymerase chain reaction. Apoptosis was confirmed by TUNEL assay. RESULTS: In this study, combined treatment with GEM and AgNPs significantly inhibited viability and proliferation in A2780 cells. Moreover, the levels of apoptosis in cells treated with a combination of GEM and AgNPs were significantly higher compared with those in cells treated with GEM or AgNPs alone. Our data suggest that GEM and AgNPs exhibit potent apoptotic activity in human ovarian cancer cells. Combined treatment with GEM and AgNPs showed a significantly higher cytotoxic effect in ovarian cancer cells compared with that induced by either of these agents alone. CONCLUSION: Our study demonstrated that the interaction between GEM and AgNPs was cytotoxic in ovarian cancer cells. Combined treatment with GEM and AgNPs caused increased cytotoxicity and apoptosis in A2780 cells. This treatment may have therapeutic potential as targeted therapy for the treatment of ovarian cancer. To our knowledge, this study could provide evidence that AgNPs can enhance responsiveness to GEM in ovarian cancer cells and that AgNPs can potentially be used as chemosensitizing agents in ovarian cancer therapy. PMID- 28919752 TI - Zinc oxide nanoparticles induce apoptosis and autophagy in human ovarian cancer cells. AB - BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are frequently used in industrial products such as paint, surface coating, and cosmetics, and recently, they have been explored in biologic and biomedical applications. Therefore, this study was undertaken to investigate the effect of ZnO NPs on cytotoxicity, apoptosis, and autophagy in human ovarian cancer cells (SKOV3). METHODS: ZnO NPs with a crystalline size of 20 nm were characterized with various analytical techniques, including ultraviolet-visible spectroscopy, X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The cytotoxicity, apoptosis, and autophagy were examined using a series of cellular assays. RESULTS: Exposure of cells to ZnO NPs resulted in a dose-dependent loss of cell viability, and the characteristic apoptotic features such as rounding and loss of adherence, enhanced reactive oxygen species generation, and loss of mitochondrial membrane potential were observed in the ZnO NP-treated cells. Furthermore, the cells treated with ZnO NPs showed significant double-strand DNA breaks, which are gained evidences from significant number of gamma-H2AX and Rad51 expressed cells. ZnO NP-treated cells showed upregulation of p53 and LC3, indicating that ZnO NPs are able to upregulate apoptosis and autophagy. Finally, the Western blot analysis revealed upregulation of Bax, caspase-9, Rad51, gamma-H2AX, p53, and LC3 and downregulation of Bcl-2. CONCLUSION: The study findings demonstrated that the ZnO NPs are able to induce significant cytotoxicity, apoptosis, and autophagy in human ovarian cells through reactive oxygen species generation and oxidative stress. Therefore, this study suggests that ZnO NPs are suitable and inherent anticancer agents due to their several favorable characteristic features including favorable band gap, electrostatic charge, surface chemistry, and potentiation of redox cycling cascades. PMID- 28919751 TI - Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer. AB - BACKGROUND: Breast cancer is the most common malignant disease that occurs in women. Histone deacetylase (HDAC) inhibition has recently emerged as an effective and attractive target for the treatment of cancer. The aim of this study was to investigate the efficacy of a combined treatment of tubastatin A (TUB-A) and palladium nanoparticles (PdNPs) against MDA-MB-231 human breast cancer cells using two different cytotoxic agents that work by two different mechanisms, thereby decreasing the probability of chemoresistance in cancer cells and increasing the efficacy of toxicity, to provide efficient therapy for advanced stage of cancer without any undesired side effects. METHODS: PdNPs were synthesized using a novel biomolecule called R-phycoerythrin and characterized using various analytical techniques. The combinatorial effect of TUB-A and PdNPs was assessed by various cellular and biochemical assays and also by gene expression analysis. RESULTS: The biologically synthesized PdNPs had an average size of 25 nm and were spherical in shape. Treatment of MDA-MB-231 human breast cancer cells with TUB-A or PdNPs showed a dose-dependent effect on cell viability. The combination of 4 MUM TUB-A and 4 MUM PdNPs had a significant inhibitory effect on cell viability compared with either TUB-A or PdNPs alone. The combinatorial treatment also had a more pronounced effect on the inhibition of HDAC activity and enhanced apoptosis by regulating various cellular and biochemical changes. CONCLUSION: Our results suggest that there was a strong synergistic interaction between TUB-A and PdNPs in increasing apoptosis in human breast cancer cells. These data provide an important preclinical basis for future clinical trials on this drug combination. This combinatorial treatment increased therapeutic potentials, thereby demonstrating a relevant targeted therapy for breast cancer. Furthermore, we have provided the first evidence for the combinatorial effect and mechanism of toxicity of TUB-A and PdNPs in human breast cancer cells. The novelties of the study were identification of a combination therapy that consists of suitable therapeutic molecules that kill cancer cells and also exploration of two different possible mechanisms involved to reduce chemoresistance in cancer cells. PMID- 28919754 TI - Preparation of coffee oil-algae oil-based nanoemulsions and the study of their inhibition effect on UVA-induced skin damage in mice and melanoma cell growth. AB - Coffee grounds, a waste by-product generated after making coffee, contains approximately 15% coffee oil which can be used as a raw material in cosmetics. Algae oil rich in docosahexaenoic acid (DHA) has been demonstrated to possess anticancer and anti-inflammation functions. The objectives of this study were to develop a gas chromatography-mass spectrometry (GC-MS) method for the determination of fatty acids in coffee oil and algae oil and prepare a nanoemulsion for studying its inhibition effect on ultraviolet A-induced skin damage in mice and growth of melanoma cells B16-F10. A total of 8 and 5 fatty acids were separated and quantified in coffee oil and algae oil by GC-MS, respectively, with linoleic acid (39.8%) dominating in the former and DHA (33.9%) in the latter. A nanoemulsion with a particle size of 30 nm, zeta potential 72.72 mV, and DHA encapsulation efficiency 100% was prepared by using coffee oil, algae oil, surfactant (20% Span 80 and 80% Tween 80), and deionized water. Differential scanning calorimetry (DSC) analysis revealed a high stability of nanoemulsion when heated up to 110 degrees C at a pH 6, whereas no significant changes in particle size distribution and pH occurred over a 90-day storage period at 4 degrees C. Animal experiments showed that a dose of 0.1% coffee oil algae oil nanoemulsion was effective in mitigating trans-epidermal water loss, skin erythema, melanin formation, and subcutaneous blood flow. Cytotoxicity test implied effective inhibition of melanoma cell growth by nanoemulsion with an IC50 value of 26.5 ug/mL and the cell cycle arrested at G2/M phase. A dose-dependent upregulation of p53, p21, cyclin B, and cyclin A expressions and downregulation of CDK1 and CDK2 occurred. Also, both Bax and cytochrome c expressions were upregulated and bcl-2 expression downregulated, accompanied by a rise in caspase 3, caspase-8, and caspase-9 activities for apoptosis execution. Collectively, the apoptosis pathway of melanoma cells B16-F10 may involve both mitochondria and death receptor. PMID- 28919753 TI - Combination of graphene oxide-silver nanoparticle nanocomposites and cisplatin enhances apoptosis and autophagy in human cervical cancer cells. AB - BACKGROUND: Cisplatin (Cis) is a widely used chemotherapeutic drug for treating a variety of cancers, due to its ability to induce cell death in cancer cells significantly. Recently, graphene and its modified nanocomposites have gained much interest in cancer therapy, due to their unique physicochemical properties. The objective of this study was to investigate the combination effect of Cis and a reduced graphene oxide-silver nanoparticle nanocomposite (rGO-AgNPs) in human cervical cancer (HeLa) cells. MATERIALS AND METHODS: We synthesized AgNPs, rGO, and rGO-AgNP nanocomposites using C-phycocyanin. The synthesized nanomaterials were characterized using various analytical techniques. The anticancer properties of the Cis, rGO-AgNPs, and combination of Cis and rGO-AgNPs were evaluated using a series of cellular assays, such as cell viability, cell proliferation, LDH leakage, reactive oxygen species generation, and cellular levels of oxidative and antioxidative stress markers such as malondialdehyde, glutathione, SOD, and CAT. The expression of proapoptotic, antiapoptotic, and autophagy genes were measured using real-time reverse-transcription polymerase chain reaction. RESULTS: The synthesized AgNPs were well dispersed, homogeneous, and spherical, with an average size of 10 nm and uniformly distributed on graphene sheets. Cis, GO, rGO, AgNPs, and rGO-AgNPs inhibited cell viability in a dose-dependent manner. The combination of Cis and rGO-AgNPs showed significant effects on cell proliferation, cytotoxicity, and apoptosis. The combination of Cis and rGO-AgNPs had more pronounced effects on the expression of apoptotic and autophagy genes, and also significantly induced the accumulation of autophagosomes and autophagolysosomes, which was associated with the generation of reactive oxygen species. CONCLUSION: Our findings substantiated rGO-AgNPs strongly potentiating Cis-induced cytotoxicity, apoptosis, and autophagy in HeLa cells, and hence rGO AgNPs could be potentially applied to cervical cancer treatment as a powerful synergistic agent with Cis or any other chemotherapeutic agents. PMID- 28919755 TI - Synthetic high-density lipoprotein nanodisks for targeted withalongolide delivery to adrenocortical carcinoma. AB - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and has a 5-year survival rate of <35%. ACC cells require cholesterol for steroid hormone production, and this requirement is met via expression on the cell surface of a high level of SRB1, responsible for the uptake of high-density lipoproteins (HDLs), which carry and transport cholesterol in vivo. Here, we describe how this natural lipid carrier function of SRB1 can be utilized to improve the tumor targeted delivery of a novel natural product derivative - withalongolide A 4,19,27-triacetate (WGA-TA) - which has shown potent antitumor efficacy, but poor aqueous solubility. Our strategy was to use synthetic HDL (sHDL) nanodisks, which are effective in tumor-targeted delivery due to their smallness, long circulation half-life, documented safety, and ability to bind to SRB1. In this study, we prepared sHDL nanodisks using an optimized phospholipid composition combined with ApoA1 mimetic peptide (22A), which has previously been tested in clinical trials, to load WGA-TA. Following optimization, WGA-TA nanodisks showed drug encapsulation efficiency of 78%, a narrow particle size distribution (9.81+/-0.41 nm), discoid shape, and sustained drug release in phosphate buffered saline. WGA TA-sHDL nanodisks exhibited higher cytotoxicity in the ACC cell line H295R half maximal inhibitory concentration ([IC50] 0.26+/-0.045 MUM) than free WGA-TA (IC50 0.492+/-0.115 MUM, P<0.05). Fluorescent dye-loaded sHDL nanodisks efficiently accumulated in H295R adrenal carcinoma xenografts 24 hours following dosing. Moreover, daily intraperitoneal administration of 7 mg/kg WGA-TA-loaded sHDL nanodisks significantly inhibited tumor growth during 21-day administration to H295R xenograft-bearing mice compared to placebo (P<0.01). Collectively, these results suggest that WGA-TA-loaded nanodisks may represent a novel and beneficial therapeutic strategy for the treatment of ACC. PMID- 28919756 TI - Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy. AB - Mitoxantrone (MIT) is an anticancer agent with photosensitive properties that is commonly used in various cancers. Multidrug resistance (MDR) effect has been an obstacle to using MIT for cancer therapy. Photochemical internalization, on account of photodynamic therapy, has been applied to improve the therapeutic effect of cancers with MDR effect. In this study, an MIT-poly(epsilon caprolactone)-pluronic F68-poly(epsilon-caprolactone)/poly(d,l-lactide-co glycolide)-poly(ethylene glycol)-poly(d,l-lactide-co-glycolide) (MIT-PFP/PPP) mixed micelles system was applied to reverse the effect of MDR in MCF-7/ADR cells via photochemical reaction when exposed to near-infrared light. MIT-PFP/PPP mixed micelles showed effective interaction with near-infrared light at the wavelength of 660 nm and exerted great cytotoxicity in MCF-7/ADR cells with irradiation. Furthermore, MIT-PFP/PPP mixed micelles could improve reactive oxygen species (ROS) levels, decrease P-glycoprotein activity, and increase the cellular uptake of drugs with improved intracellular drug concentrations, which induced cell apoptosis in MCF-7/ADR cells under irradiation, despite MDR effect, as indicated by the increased level of cleaved poly ADP-ribose polymerase. These findings suggested that MIT-PFP/PPP mixed micelles may become a promising strategy to effectively reverse the MDR effect via photodynamic therapy in breast cancer. PMID- 28919758 TI - A case of schizophrenia comorbid for tetralogy of Fallot treated with clozapine: further considerations on a role for 22q.11.2 in the proneness for seizures. AB - We present a case of schizophrenia comorbid for tetralogy of Fallot, without chromosome 22q.11.2 deletion or duplication, treated successfully with a combination of clozapine and antiepileptic drugs. Although clozapine by itself initially triggered convulsive seizures, we continued it with co-administration of valproate and topiramate. This combined treatment did not affect cardiac function of the patient, who experienced a favorable clinical course in terms of symptomatology and functional outcomes. To our knowledge, we provide the first report on a patient with tetralogy of Fallot, in whom 22q.11.2 was not deleted and clozapine-induced seizures were observed. PMID- 28919757 TI - Once-monthly paliperidone palmitate in early stage schizophrenia - a retrospective, non-interventional 1-year study of patients with newly diagnosed schizophrenia. AB - BACKGROUND: Long-acting antipsychotic therapy may be best suited for patients in the early stage of schizophrenia, when the most can be done before disease progression associated with poor adherence occurs. We explored the patterns of use of once-monthly paliperidone palmitate (PP1M), concomitant medication use, hospitalization, and clinical outcomes of adult, newly diagnosed patients with schizophrenia receiving continuous treatment with PP1M for at least 12 months. METHODS: This was an international, multicenter, exploratory, retrospective chart review of medical records of adult patients who were newly diagnosed (not more than 1 year before initiation of PP1M treatment) with schizophrenia and who had received continuous treatment with PP1M for >=12 months in naturalistic clinical settings. RESULTS: A total of 84 (93.3%) patients were included in the analysis. All but one patient (98.8%, n=83) had received oral antipsychotic medication at least during the last month before the first PP1M administration. Three patients (3.6%) were newly hospitalized during the 12-month documentation period. The reason for hospitalization for all three was management of episode/relapse. A total of 79.2% of patients had a >=20% improvement and 47.2% had a >=50% improvement in Positive and Negative Syndrome Scale total score from baseline to endpoint. Half of patients (53.3%) showed a significant improvement, as reflected by an increase in Personal and Social Performance (PSP) total score of at least 7 points from baseline to endpoint (mean [SD] 11.9 [15.0] points; P<0.001). One quarter of patients (24.4%, n=11) moved from a PSP score of 31-70 (ie, moderate to marked functional impairment) at baseline to a PSP score of mild to no functional impairment (PSP score >=71) at endpoint. Most adverse drug reactions were mild or moderate in severity. CONCLUSION: Continuous treatment with PP1M over 12 months was associated with statistically significant and clinically meaningful improvements in psychotic symptoms, disease severity, and functional outcomes in patients with schizophrenia. PMID- 28919759 TI - Association of interleukin-33 gene polymorphisms with susceptibility to late onset Alzheimer's disease: a meta-analysis. AB - The association between interleukin-33 (IL-33) gene polymorphisms and late onset Alzheimer's disease (LOAD) remains controversial in previous studies. Thus, a meta-analysis was conducted to assess the association between the IL-33 polymorphisms (rs11792633 and rs7044343) and LOAD susceptibility. Crude odds ratio (OR) and 95% confidence interval (CI) were used to investigate the relationship strength. Sensitivity analysis was performed, and publication bias was estimated by the Begg's and Egger's tests. Overall, six independent studies involving 2,589 patients and 8,414 control samples met our inclusion criteria and were included in this meta-analysis. The results showed that IL-33 rs11792633 polymorphism had statistically significant correlation with a decreased risk of LOAD in heterozygous comparison model (OR =0.64, 95% CI =0.48-0.83), homozygote comparison model (OR =0.83, 95% CI =0.74-0.93), dominant model (OR =0.78, 95% CI =0.67-0.91), recessive model (OR =0.70, 95% CI =0.59-0.84), and allelic model (OR =0.79, 95% CI =0.69-0.91), which were also validated by stratified subgroup analysis. Additionally, there was an apparent association between the IL-33 rs7044343 variant and LOAD risk under four genetic models for overall population (heterozygous comparison model: OR =0.75, 95% CI =0.63-0.89; dominant model: OR =0.83, 95% CI =0.70-0.98; recessive model: OR =0.80, 95% CI =0.68-0.94; allelic model: OR =0.86, 95% CI =0.79-0.94) as well as Caucasian subgroup. In summary, our meta-analysis implicated that IL-33 gene polymorphisms rs11792633 and rs7044343 were significantly associated with the susceptibility of LOAD. PMID- 28919761 TI - Effects of bromadiolone poisoning on the central nervous system. AB - Cases of rodenticide poisoning (second-generation long-acting dicoumarin rodenticide, superwarfarin) have occasionally been reported. The main symptoms of bromadiolone poisoning are skin mucosa hemorrhage, digestive tract hemorrhage, and hematuresis. However, the symptoms of central nervous system toxicity have rarely been reported. Our case reports on a 41-year-old male who had no contact with bromadiolone. His main symptoms were dizziness, unsteady gait, and abnormal behavior. Laboratory test results revealed the presence of bromadiolone in his blood and urine, a longer prothrombin time, activated partial thromboplastin time, and a high international normalized ratio. Magnetic resonance imaging of the brain showed that the bilateral posterior limb of the internal capsule, splenium of corporis callosum, and bilateral centrum semiovale formed symmetrical patch distribution. The patient gradually recovered after treated with vitamin K1 and plasma transfusion. Our clinical study could pave the way to improve the detection of bromadiolone poisoning and avoid misdiagnosis. PMID- 28919760 TI - Attitudes toward antipsychotic treatment among patients with bipolar disorders and their clinicians: a systematic review. AB - INTRODUCTION: Antipsychotics are recommended as first-line therapy for acute mania and maintenance treatment of bipolar disorder; however, published literature suggests their real-world use remains limited. Understanding attitudes toward these medications may help identify barriers and inform personalized therapy. This literature review evaluated patient and clinician attitudes toward the use of antipsychotics for treating bipolar disorder. MATERIALS AND METHODS: A systematic search of the Cochrane Library, Ovid MEDLINE, Embase, and BIOSIS Previews identified English language articles published between January 1, 2000, and June 15, 2016, that reported attitudinal data from patients, health care professionals, or caregivers; treatment decision-making; or patient characteristics that predicted antipsychotic use for bipolar disorder. Results were analyzed descriptively. RESULTS: Of the 209 references identified, 11 met the inclusion criteria and were evaluated. These articles provided attitudinal information from 1,418 patients with bipolar disorder and 1,282 treating clinicians. Patients' attitudes toward antipsychotics were generally positive. Longer duration of clinical stability was associated with positive attitudes. Implementation of psychoeducational and adherence enhancement strategies could improve patient attitudes. Limited data suggest clinicians' perceptions of antipsychotic efficacy and tolerability may have the greatest impact on their prescribing patterns. Because the current real-world evidence base is inadequate, clinician attitudes may reflect a relative lack of experience using antipsychotics in patients with bipolar disorder. CONCLUSION: Although data are very limited, perceived tolerability and efficacy concerns shape both patient and clinician attitudes toward use of antipsychotic drugs in bipolar disorder. Additional studies are warranted. PMID- 28919762 TI - Risk of post-traumatic epilepsy after severe head injury in patients with at least one seizure. AB - BACKGROUND: To explore the incidence and risk factors, including type of seizures for post-traumatic epilepsy (PTE) after severe traumatic brain injury (TBI). SUBJECTS AND METHODS: This was a retrospective follow-up study of patients discharged from Liaocheng People's Hospital between March 2011 and June 2015 with a diagnosis of post-traumatic seizures. Risk factors for PTE were evaluated in 68 inpatients by using Kaplan-Meier curves and the Cox model. RESULTS: Complete clinical information was available for 68 patients. A total of 54 cases (79.4%) were diagnosed as presenting with PTE, occurring from 10 days to 179 months after severe TBI. Nineteen out of 54 cases (35.2%) had been defined as PTE within the first 6 months after the trauma, 17 cases (31.5%) within 7-12 months, 8 cases (14.8%) within 13-24 months, 2 cases (3.7%) within 25-36 months, and 8 cases (14.8%) within 37-179 months after the TBI. The Kaplan-Meier curves demonstrated that simple partial seizures, surgical treatment, and onset of seizures occurring within 6 months after injury were associated with PTE. CONCLUSIONS: The Cox model indicated that, for patients aged >34 years at the time of injury, the PTE risk was 2.55 times greater than for those aged <=34 years. In addition, simple partial seizures, surgical treatment and onset of seizures occurring within 6 months after injury were significant risk factors for the development of PTE. PMID- 28919763 TI - Sociodemographic variables and social values: relationship with work-attendance problems in Brunei public- and private-sector employees. AB - OBJECTIVE: The study investigated the degree to which selected sociodemographic variables and social values were related to work-attendance problems in a random sample of 860 Brunei public- and private-sector employees and the nature of this relationship. MATERIALS AND METHODS: This quantitative study used the field survey approach to administer research instruments directly to participants. This enabled the researchers to help participants who needed assistance in completing the measures properly, so as to increase the number of usable returns. RESULTS: Two sociodemographic variables (seeking help from a counselor/psychologist and marital status) correlated significantly with work attendance. Private-sector employees were more likely to have work-attendance problems than government workers. Both single and married employees and the chief wage earner in the household were more likely to have work-attendance issues to deal with compared to their counterparts. However, employees who sought help from a counselor/psychologist were far less likely to have work-attendance problems compared to those who did not get such help. The most significant social-value correlates with work-attendance problems were interpersonal communication, employer-employee relationship, work-stress problems, self-presentation, self regulation, self-direction, and interpersonal trust. Self-regulation, self direction, and satisfaction with work-related achievements significantly predicted work-attendance problems positively, while interpersonal communication problems and work-stress problems predicted work-attendance problems negatively. Low scorers on self-regulation and self-direction, as well as on satisfaction with work-related achievements, were more likely to have work-attendance problems compared to high scorers. However, low scorers on interpersonal communication and work-stress problems were less likely to have work-attendance problems compared to high-scoring peers. CONCLUSION: Ample evidence from this study showed that sociodemographic variables and social values contribute to work-attendance problems in various ways, and need to be incorporated in counseling interventions for affected employees. PMID- 28919764 TI - Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder. AB - OBJECTIVE: Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD. METHODS: A total of 70 children with ASD (4-6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual's behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile - third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated. RESULTS: Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group. CONCLUSION: Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions. PMID- 28919765 TI - Scopolamine alleviates involuntary lingual movements: tardive dyskinesia or dystonia? AB - Cholinergic hypofunction was believed to be associated with the pathogenesis of tardive dyskinesia, and therefore, anticholinergic treatment might exacerbate the condition. We describe herein a middle-aged male with feeble chewing movements, involuntary rolling motions of the tongue, and abnormally tightened cheeks which developed after consuming different psychotropic medications. These symptoms did not improve after routine treatment for tardive dyskinesia, but responded well to anticholinergic agents, such as scopolamine and benzhexol hydrochloride. This case extended our understanding of the complexity of extrapyramidal effects and their pharmacologic management. PMID- 28919766 TI - Cognitive behavioral therapy for somatic symptom disorders in later life: a prospective comparative explorative pilot study in two clinical populations. AB - BACKGROUND: Elderly patients with somatic symptom disorder (SSD) put a great burden on the health care delivery system. Cognitive behavioral therapy (CBT) is effective in adults with SSD. However, no studies have been conducted yet into CBT for SSD in later life. OBJECTIVES: We explored the feasibility of CBT for SSD in the elderly. METHODS: This is a prospective pilot study comparing two outpatient specialty mental health settings for adults (<60 years; n=13) and for elderly patients (>=60 years; n=9) with SSD. Intervention was 18 structured, protocoled, and supervised CBT sessions. Outcomes were somatic symptoms, pain intensity, pain disability, quality of life, depressive symptoms, and generalized anxiety symptoms. Feasibility of the CBT intervention was explored with self developed questions, both for the therapists and the patients. RESULTS: Both therapists and elderly patients evaluated the treatment as positive. Somatic symptoms improved significantly in the adult group but not in the elderly group. There was a large, significant decrease in pain intensity and pain disability in elderly patients compared to the adults. Social functioning, vitality, and anxiety symptoms improved significantly in the adults. Presence of chronic medical conditions did not influence these results. CONCLUSION: This study shows that CBT is feasible as a treatment for SSD in older adults and has encouraging results. Replication in an RCT is warranted. PMID- 28919767 TI - Relationship between subtypes and symptoms of ADHD, insomnia, and nightmares in connection with quality of life in children. AB - OBJECTIVES: This study examined the links between sleep disorders and subtypes of attention deficit-hyperactivity disorder (ADHD-inattention, ADHD-combined, ADHD hyperactive/impulsive) in childhood. We set up a hypothetical model linking different symptoms of both disorders to construct the underlying and shared pathways. By examining a sample of children with ADHD we firstly tested parts of the model. METHODS: A total of 72 children with symptoms of ADHD (aged 6-13 years; 79.2% boys) were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition and the International Classification of Sleep Disorders, third edition in regards to ADHD and sleep disorders via standardized parent-rated questionnaires. Additionally, quality of life (QoL) was assessed. Overall, 46 children fulfilled the criteria of ADHD and were medication naive. RESULTS: On average, the whole sample had clinically elevated total scores of the Children's Sleep Habits Questionnaire in the validated German version (CSHQ-DE), indicating an increased prevalence of sleep disorders in children with ADHD. In accordance to our hypothetical model, children with primarily hyperactive-impulsive ADHD showed the highest CSHQ-DE scores. Moreover, we found a high impact for insomnia in this subgroup and a high comorbid load for the mutual occurrence of insomnia and nightmares. Furthermore, QoL was reduced in our whole sample, and again intensified in children with comorbid insomnia and nightmares. CONCLUSION: We verified an elevated occurrence of sleep disorders in children with ADHD and were able to link them to specific subtypes of ADHD. These results were in line with our hypothetical model. Moreover, we found a clinically reduced QoL in mean for the whole sample, indicating the strong impact of ADHD in the lives of affected children, even intensified if children exhibited comorbid insomnia and nightmares. These results should be kept in mind regarding the treatment and therapy of this subgroup of children. Specific treatment strategies should be considered for these children. PMID- 28919768 TI - Ictal heart rate changes and the effects of vagus nerve stimulation for patients with refractory epilepsy. AB - Vagus nerve stimulation (VNS) shows long-term efficiency worldwide in most pharmacoresistant patients with epilepsy; however, there are still a small number of patients who are non-responders to VNS therapy. It has been shown that VNS treatment outcomes for drug-resistant epilepsy may be predicted by preoperative heart-rate variability measurements and that patients with epilepsy with ictal tachycardia (IT) during seizures have good responses to VNS. However, few studies have reported the efficacy of VNS in patients with epilepsy with ictal bradycardia (IB) or normal heart rate (HR), and none have explored the possible mechanisms of VNS efficacy based on different HR types. HR during seizures varies, and we presume that different HRs during seizures may impact the effects of VNS. It has been shown that blood pressure in the human body needs to be maintained through the arterial baroreflex (ABR). VNS efficacy in patients with epilepsy with IT, IB, and normal HR during seizures may be related to ABR. Mechanical signals generated by VNS are similar to the autonomic nerve pathways and, thus, we propose the hypothesis that different HRs during seizures can predict VNS efficacy in patients. If VNS is highly efficient in patients with IT during seizures, VNS in patients with a normal HR during seizures may be less efficient, and may even be inefficient in patients with IB during seizures. PMID- 28919769 TI - Evaluating the antiemetic administration consistency to prevent chemotherapy induced nausea and vomiting with the standard guidelines: a prospective observational study. AB - Nausea and vomiting (NV) are the most prevalent adverse effects of chemotherapy (CT). This study was conducted to evaluate adherence of the health care team to standard guidelines for antiemetics usage to prevent acute chemotherapy-induced nausea and vomiting (CINV) in a large CT center. A prospective study was performed during an 11-month period on patients receiving CT. A form was designed to collect patients' demographic information and their chemotherapeutic and antiemetic regimen data. The Likert scale was used to measure the effectiveness of the antiemetics in patients. In this study, the effect of patient-related risk factors on the incidence rate of CINV was examined. Based on the results, CINV events were reported by 74.4% of patients. The antiemetic regimen of 71.2% of the patients complied with the guidelines. The complete response, complete protection, and complete control end points did not differ significantly between patients undergoing guidelines-consistent prophylaxis or guidelines-inconsistent prophylaxis. The females clearly showed a higher incidence rate of CINV (P=0.001) during the first course of CT (P=0.006). A history of motion sickness did not affect the incidence of NV. The maximum compliance error occurred for the use of aprepitant, as 16.16% of the patients who were receiving aprepitant did not comply with its instructions. The results of this study highlight how CINV was controlled in this center, which was significantly lower than that of the global standard. Perhaps, factors such as noncompliance to antiemetic regimens with standard guidelines and the failure to adhere to the administration instructions of the antiemetics were involved in the incomplete control of CINV. PMID- 28919770 TI - Swollen lymph nodes may not be clinical manifestations of chronic myeloid leukemia: case report and revision of literature. AB - We present here the case of a 33-year-old Chinese female patient with synchronous double primary malignant tumors (chronic myeloid leukemia [CML] and classic Hodgkin lymphoma). This patient was admitted to our hospital because of bilateral cervical lymph node enlargement and recurrent fever for 2 weeks. The complete blood cell count revealed white blood cell counts of 18.2*109/L, hemoglobin of 9.6 g/dL, and platelet counts of 1,547*109/L. Chromosome karyotype analysis demonstrated that t(9;22)(q34;q11) was positive in all 20 cells examined. Reverse transcription polymerase chain reaction showed that the ratio of BCR/ABL1 to ABL was 45.3%. This patient was diagnosed with CML. After definite diagnosis, this patient regularly received imatinib therapy. Three months later, although complete blood count was normal, swollen lymph nodes further increased. Swollen lymph node biopsy was performed to evaluate the nature of these swollen lymph nodes, and results displayed that Hodgkin and Reed-Sternberg cells, CD30, CD15, and Epstein-Barr virus-encoded RNA was positive. In conclusion, this patient was diagnosed with synchronous double primary malignant tumors. This case report suggests that swollen lymph nodes may be due to lymphoma, rather than as a clinical manifestation of CML. PMID- 28919771 TI - The challenge of perioperative pain management in opioid-tolerant patients. AB - The increasing number of opioid users among chronic pain patients, and opioid abusers among the general population, makes perioperative pain management challenging for health care professionals. Anesthesiologists, surgeons, and nurses should be familiar with some pharmacological phenomena which are typical of opioid users and abusers, such as tolerance, physical dependence, hyperalgesia, and addiction. Inadequate pain management is very common in these patients, due to common prejudices and fears. The target of preoperative evaluation is to identify comorbidities and risk factors and recognize signs and symptoms of opioid abuse and opioid withdrawal. Clinicians are encouraged to plan perioperative pain medications and to refer these patients to psychiatrists and addiction specialists for their evaluation. The aim of this review was to give practical suggestions for perioperative management of surgical opioid-tolerant patients, together with schemes of opioid conversion for chronic pain patients assuming oral or transdermal opioids, and patients under maintenance programs with methadone, buprenorphine, or naltrexone. PMID- 28919772 TI - Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives. AB - Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I-III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from -40% to -60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH. PMID- 28919773 TI - Sickle cell retinopathy: improving care with a multidisciplinary approach. AB - Sickle cell retinopathy (SCR) is the most representative ophthalmologic complication of sickle cell disease (SCD), a hemoglobinopathy affecting both adults and children. SCR presents a wide spectrum of manifestations and may even lead to irreversible vision loss if not properly diagnosed and treated at the earliest. Over the past decade, multidisciplinary research developments have focused upon systemic, genetic, and ocular risk factors of SCR, enabling the clinician to better diagnose and manage these patients. In addition, newer imaging and testing modalities, such as spectral domain-optical coherence tomography angiography, have resulted in the detection of subclinical retinopathy related to SCD. Innovative therapy includes intravitreal injection of an anti vascular endothelial growth factor (eg, Lucentis(r) [ranibizumab] or Eylea(r) [aflibercept]) which appears comparatively safe and efficient, and may be combined with laser photocoagulation (LPC) for proliferative SCR. The effect of LPC alone does not significantly lead to the regression of advanced SCR, although it helps in avoiding hemorrhage and sight loss. This comprehensive article is based on 10-years retrospective (2007-2017) studies. It aims to present advances and recommendations in SCR theranostics while pointing out the requirement of combinatorial approaches for better management of SCR patients. To reach this goal, we identified and analyzed randomized original and review articles, clinical trials, non-randomized intervention studies, and observational studies using specified keywords in various databases (eg, Medline, Embase, Cochrane, ClinicalTrials.gov). PMID- 28919774 TI - Optimizing post-acute care in breast cancer survivors: a rehabilitation perspective. AB - Breast cancer (BC) is the most common malignancy and a leading cause of morbidity and mortality in women worldwide. Therapeutic advances and improved survival rates of women with BC have implications for long-term impact on disability, psychological function and quality of life (QoL), which may be amenable to rehabilitation. The focus of rehabilitation is on managing disability, reducing sequelae and symptoms, and enhancing participation and societal reintegration, to achieve the highest possible independence and the best QoL. Rehabilitation interventions should be considered early for maintaining functional capacity and reducing the risk of losing important abilities or independence and should be individualized depending on disease phase, functional deficits, personal requirements and specific goals. A number of interventions have been trialled to support rehabilitation input for women with BC, which include physical therapy, psychological interventions (psychotherapy, cognitive behavioral training) and others. Multidisciplinary rehabilitation and uni-disciplinary interventions such as physical therapy have been shown to be beneficial in reducing disability, and improving participation and QoL. There is a need for comprehensive assessment of health domains in BC patients using a standardized framework and a common language for describing the impact of disease at different levels, using the International Classification of Functioning, Disability and Health core sets. This will provide more detailed information on the needs of these patients, so more efficient and targeted rehabilitation interventions can be provided. PMID- 28919775 TI - Investigation of proliferation and migration of tongue squamous cell carcinoma promoted by three chemokines, MIP-3alpha, MIP-1beta, and IP-10. AB - The aim of this work was to investigate the role of chemokines in proliferation and migration of tongue squamous cell carcinoma (TSCC). Out of the 80 cytokines surveyed by a human cytokine antibody array, three chemokines, macrophage inflammatory protein-3alpha (MIP-3alpha), macrophage inflammatory protein-1beta (MIP-1beta), and interferon gamma-induced protein 10 (IP-10), showed elevated expression in TSCC cells (CAL-27 and UM-1), compared to the oral mucosal epithelial cells. Immunohistochemistry confirmed the high level of expression of MIP-3alpha in the TSCC tissues, especially in the high clinical stages. Furthermore, Western blot and immunofluorescence staining indicated that C-C chemokine receptor type 5, C-C chemokine receptor type 6, and C-X-C motif chemokine receptor 3, which are the receptors for MIP-3alpha, MIP-1beta, and IP 10, respectively, were expressed in the TSCC cells. Viability assay showed MIP 3alpha, MIP-1beta, and IP-10 led to the proliferation of the CAL-27 cells. Interestingly, MIP-1beta and IP-10 also induced apoptosis in the TSCC cells. Transwell invasion assay showed MIP-3alpha and IP-10 could increase the invasive capability of TSCC cells; consistently, the enzymatic activities of matrix metalloproteinase-2 and matrix metalloproteinase-9 increased in the MIP-3alpha- and IP-10-treated cells. In summary, our results indicate the expression of MIP 3alpha, MIP-1beta, and IP-10 increased in the TSCC cells. The elevated expression of MIP-3alpha and IP-10 promoted proliferation and migration of TSCC. These chemokines, along with their receptors, could be potential biomarkers and therapeutic targets for TSCC, especially for those in the high clinical stages. PMID- 28919777 TI - Synaptotagmin-7 is overexpressed in hepatocellular carcinoma and regulates hepatocellular carcinoma cell proliferation via Chk1-p53 signaling. AB - BACKGROUND: Synaptotagmin-7 (Syt-7) is a member of the synaptotagmin (Syt) family, which plays an important role in many physiological and pathological processes. However, to the best of our knowledge, there is no study describing its function in tumors, particularly in hepatocellular carcinoma (HCC). Therefore, in this study, we examined the role of Syt-7 in HCC and attempted to elucidate its underlying mechanism. MATERIALS AND METHODS: We examined the expression levels of Syt-7 in HCC cell lines and normal hepatocytes by real-time quantitative polymerase chain reaction analysis. The effects of Syt-7 knockdown on in vitro cell growth were assessed by Celigo image cytometry, MTT assay, colony formation assay, and cell cycle analysis. In vivo tumorigenesis was evaluated using a nude mouse model. The underlying molecular mechanism was evaluated using a PathScan Stress Signaling Antibody Array. RESULTS: Syt-7 mRNA levels were highly expressed in Huh-7 and Hep3B cells; moderately expressed in SMMC-7721, HepG2, and BEL-7402 cells; and lowly expressed in normal hepatocytes L O2. Functional experiments demonstrated that Syt-7 knockdown significantly suppressed cell proliferation and induced cell cycle arrest by increasing phosphorylation of Chk1 and p53. Furthermore, Syt-7 knockdown remarkably reduced the growth of xenograft tumors in mice. CONCLUSION: The results of this study suggest that Syt-7 plays a vital role in tumorigenesis and in the development of HCC. Syt-7 can be used as a new diagnostic and therapeutic target in HCC. PMID- 28919778 TI - Improvement of survival for non-small cell lung cancer over time. AB - Non-small cell lung cancer (NSCLC) is the main histological subtype of lung cancer, which is the leading cause of cancer death. It is unclear whether the improved survival seen at high-volume centers applies to the general population and, more importantly, whether the improvement in lung cancer survival was just a consequence of improved screening work. Data from the Surveillance, Epidemiology, and End Results (SEER) registry was used to identify 405,580 patients with NSCLC diagnosed from 1988 to 2008. The patients were divided into four groups according to the year of diagnosis. Trends of clinical characteristics were analyzed to reflect the progress of screening work. Five-year relative survivals in various subgroups were compared. The results indicated that proportion of aged, advanced, and non-surgical patients increased, whereas patients with lymph node metastasis and high histology grade decreased. Improvements in all stages of NSCLC patients were demonstrated, with relatively more significant gains for patients with localized and regional disease. After potentially curative surgical resection, remarkable improvements were observed in both cohorts with time (surgical: 52.00% 63.00%; non-surgical: 6.10%-13.50%). Specifically, patients who underwent pneumonectomy, lobectomy/bilobectomy, and partial/wedge/segmental resection all presented better survival rates. Our SEER analysis demonstrated improvements among patients in all stages of NSCLC that were deemed attributable to improved therapy and medical care for NSCLC rather than improved screening work. PMID- 28919779 TI - Nuclear factor-kappa B1 inhibits early apoptosis of glioma cells by promoting the expression of Bcl-2. AB - Glioma is one of the most common types of adult primary brain tumors, and the underlying molecular mechanisms still remain unclear. Nuclear factor-kappa B1 (NF kappaB1) is involved in a variety of malignancies and is widely expressed in malignant tumors. However, the expression of NF-kappaB1 in different grades of glioma, the correlation between NF-kappaB1 and Bcl-2 expressions in gliomas, and the research between NF-kappaB1 and early apoptosis of glioma cells have not been reported so far. In this study, the expression level of NF-kappaB1 in 31 human glioma tissues and six nonneoplastic brain tissues was determined using quantitative real-time polymerase chain reaction. Results showed that the expression of NF-kappaB1 in human glioma tissues and glioma cell lines, SHG44 and U87, was significantly higher compared to noncancerous brain tissues and that the expression increased with increasing degrees of tumor malignancy. Similar results were demonstrated with the expression of Bcl-2 in the same human glioma specimens. Flow cytometry results showed that inhibition of NF-kappaB1 expression significantly promoted apoptosis of SHG44 and U87 in human glioma cells. Western blot analysis further confirmed decreased expression of Bcl-2 protein after inhibition of NF-kappaB1 protein expression. Taken together, NF-kappaB1 overexpression inhibits early apoptosis of glioma cells and high expression of NF kappaB1 promotes the expression of antiapoptotic gene Bcl-2. Therefore, our study results provide a theoretical basis for antiapoptotic mechanism of tumor cells in association with NF-kappaB1. PMID- 28919776 TI - Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors. AB - BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression. RESULTS: Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year. CONCLUSIONS: Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer. PMID- 28919781 TI - Clinicopathological and prognostic significance of Ki-67 immunohistochemical expression in gastric cancer: a systematic review and meta-analysis. AB - The prognostic significance of Ki-67 in patients with gastric cancer (GC) remains controversial. The aim of our meta-analysis is to evaluate its association with clinicopathological characteristics and prognostic value in patients with GC. PubMed, EMBASE, and Web of Science were systematically searched up to May 2017. Twenty-two studies including 3,825 patients with GC were analyzed. The meta analysis indicated that the incidence difference of Ki-67 expression in GC patients was significant when comparing the older group to younger group (odds ratio [OR] =1.44, 95% confidence interval [CI] 1.19, 1.75), lymph node positive group to negative group (OR =1.49, 95% CI 1.20, 1.84), the large size tumor group to the small size tumor group (OR =1.27, 95% CI 1.24, 1.68) and the TNM stage III+IV group to TNM stage I+II group (OR =2.28, 95% CI 1.66, 3.12). However, no statistical differences existed in gender. The detection of Ki-67 significantly correlated with the overall survival of patients (hazard ratio =1.51, 95% CI 1.31, 1.72). Our study suggested that Ki-67 overexpression was associated with poor prognosis in GC patients. Ki-67 positive rates may be associated with age, lymph node metastasis, tumor size, and TNM staging system in GC patients. PMID- 28919780 TI - The role and significance of VEGFR2+ regulatory T cells in tumor immunity. AB - Tumor development is closely related to angiogenesis, and VEGFR2 plays an important role in tumor angiogenesis. It is broadly expressed in the blood vessels, especially in the microvessels of tumor tissues. Furthermore, VEGFR2 is detected on the surface of the cell membrane in various immune cells, such as dendritic cells, macrophages, and regulatory T cells (Tregs). Tregs, which are one of the key negative regulatory factors in tumor immune microenvironments, show high-level expression of VEGFR2 which participates in the regulation of immunosuppressive function. VEGFR2+ Tregs play a potent suppressive role in the formation of immunosuppressive microenvironments. A large number of reports have proven the synergistic effects between targeted therapy for VEGFR2 and immunotherapy. The depression of VEGFR2 activity on T cells can significantly reduce the infiltration of Tregs into the tumor tissue. Targeted therapy for VEGFR2+ Tregs also provides a new choice for the clinical treatment of malignant solid tumors. In this paper, the role and significance of VEGFR2+ Tregs in tumor immunity in recent years are reviewed. PMID- 28919782 TI - Inhibitory effects of a selective Jak2 inhibitor on adrenocorticotropic hormone production and proliferation of corticotroph tumor AtT20 cells. AB - PURPOSE: The primary cause of Cushing's disease is adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. EGFR signaling induces POMC mRNA-transcript levels and ACTH secretion from corticotroph tumors. The Jak-STAT pathway is located downstream of EGFR signaling; therefore, a Jak2 inhibitor could be an effective therapy for EGFR-related tumors. In this study, we determined the effect of a potent and selective Jak2 inhibitor, SD1029, on ACTH production and proliferation in mouse AtT20 corticotroph tumor cells. MATERIALS AND METHODS: AtT20 pituitary corticotroph tumor cells were cultured after transfection with PTTG1- or GADD45beta-specific siRNA. Expression levels of mouse POMC, PTTG1, and GADD45beta mRNAs were evaluated using quantitative real-time polymerase chain reaction. ACTH levels were measured using ACTH ELISA. Western blot analysis was performed to examine protein expression of phosphorylated STAT3/STAT3. Viable cells and DNA fragmentation were measured using a cell-proliferation assay and cell-death detection ELISA, respectively. Cellular DNA content was analyzed using fluorescence-activated cell sorting. RESULTS: SD1029 decreased POMC and PTTG1 mRNA and ACTH levels, while increasing GADD45beta levels. The drug also decreased AtT20-cell proliferation and induced apoptosis, but did not alter cell-cycle progression. SD1029 also inhibited STAT3 phosphorylation. PTTG1 knockdown inhibited POMC mRNA levels and cell proliferation. However, combined treatment with PTTG1 knockdown and SD1029 had no additive effect on POMC mRNA levels or cell proliferation. GADD45beta knockdown inhibited the SD1029-induced decrease in POMC mRNA levels and also partially inhibited the decrease in cell proliferation. CONCLUSION: Both PTTG1 and GADD45beta may be responsible, at least in part, for the Jak2-induced suppression of ACTH synthesis and cell proliferation. Accordingly, therapies that target EGFR-dependent Jak2/STAT3 may have clinical applications for treating Cushing's disease. PMID- 28919783 TI - Toll-like receptors 7 and 8 expression correlates with the expression of immune biomarkers and positively predicts the clinical outcome of patients with melanoma. AB - BACKGROUND: Toll-like receptors (TLRs) play a critical role in cancer, yet the clinical relevance of TLR7/8 expression in melanoma remains unclear. This study aimed to evaluate the prognostic value of TLR7/8 mRNA levels in melanoma and their correlation with immune biomarkers relevant to disease progression. METHODS: Normalized gene expression and corresponding clinical data of patients with skin cutaneous melanoma were obtained from two public databases: the Cancer Genome Atlas and GSE19234. Log rank (Mantel-Cox) tests were used to perform survival analysis. Multivariate survival analysis was performed on a Cox regression hazard model. Spearman correlation analyses were used to address the relationship between the expressions of TLR7/8 levels and immune biomarkers in melanoma tumors. RESULTS: Survival analysis suggested that high levels of TLR7 or TLR8 expression predicted better clinical outcome for melanoma patients (TLR7: HR =1.734, P<0.0001; TLR8: HR =2.072, P<0.0001). Moreover, multivariate survival analysis implicated TLR7 as a prognostic factor independent of age, gender, or pathological stage. Further analysis demonstrated that expression levels of TLR7/8 strongly correlated with that of dendritic cell markers and chemokines/chemokine receptors, including CCR2, CCR5, CCL3, and CCL5. Importantly, expression levels of both TLR7 and TLR8 were also highly correlated with the expressions of CD8 and other functional markers of CD8+ T cells. CONCLUSION: High gene expression of TLR7 and TLR8 in melanoma tumors is associated with high expression levels of functional markers of immune cells, which predicts longer overall survival of patients with melanoma. Our results not only provide an important reference for the clinical prognosis of melanoma but also present new implications for the design of melanoma immunotherapy. PMID- 28919784 TI - Durable complete remission of poor performance status metastatic lung adenocarcinoma patient treated with second-line erlotinib: a case report. AB - This paper presents a rare case of an elderly patient treated with erlotinib for disseminated lung adenocarcinoma with poor performance status (Eastern Cooperative Oncology Group performance status [PS]3). This treatment led to a long duration of complete remission according to Response Evaluation Criteria in Solid Tumors 1.1 - almost 7 years (81 months) of progression-free survival (PFS) and overall survival (OS) of 10 years by March 2017. The treatment with erlotinib started in September 2008 and it was well tolerated with no adverse effects. Mutation analyses (real-time polymerase chain reaction method) revealed deletion of EGFR (epidermal growth factor receptor) gene and wild-type Kirsten-ras protein gene in exon 19. In May 2015, the patient relapsed with jaundice and enlarged lymph nodes of the liver hilum, with no other metastasis, PS 2. Biopsy confirmed metastasis of lung adenocarcinoma. EGFR molecular testing did not reveal T790M mutation. Treatment was continued with gemcitabine-cisplatin chemotherapy. A total of six cycles were administered with nearly complete response and Eastern Cooperative Oncology Group performance status 0. Further on, gemcitabine monotherapy has been administered with nearly complete response maintained and OS of 10 years by March 2017. This report describes an extremely rare case of a poor performance patient with advanced metastatic adenocarcinoma harboring EGFR mutation - deletion in exon 19 - who was receiving salvage erlotinib and had a complete response with 81 months of PFS followed by a relapse and subsequent chemotherapy which led to nearly complete response, with an OS of 10 years by March 2017. Such a complete response to tyrosine kinase inhibitor therapy in a poor PS patient, with long PFS and OS achieved, justifies tyrosine kinase inhibitor treatment approach in poor PS patients with EGFR-sensitizing tumors, and furthermore points to the feasibility of administering chemotherapy at the time of relapse. PMID- 28919785 TI - Biomarker analysis and clinical relevance of TK1 on the cell membrane of Burkitt's lymphoma and acute lymphoblastic leukemia. AB - TK1 is an enzyme involved in DNA synthesis and repair. TK1 is usually found elevated in cancer patients' serum, which makes it a useful tumor proliferation biomarker that strongly correlates with cancer stage, metastatic capabilities, and recurrence risk. In this study, we show that TK1 is upregulated and localizes on the plasma membrane of Burkitt's lymphoma, acute promyelocytic leukemia, T cell leukemia, and acute lymphoblastic leukemia (ALL). Using flow cytometry, we confirmed that TK1 localizes on the surface of Raji, HL60, and Jurkat cell lines and on ALL clinical samples. Using fluorescent microscopy, we found a strong association of TK1 with the plasma membrane in Raji, HL60, and Jurkat cell lines. These findings were also confirmed by scanning electron microscopy. Our study also shows that this phenomenon does not occur on normal resting or proliferating lymphocytes. In addition, we show that membrane TK1 is found in all oligomeric forms ranging from monomer to tetramer and exhibits enzymatic activity. These findings suggest TK1 as a possible target for immunotherapy with the potential to be utilized in the treatment of hematological cancers. PMID- 28919787 TI - Computational tool for optimizing the essential oils utilization in inhibiting the bacterial growth. AB - Day after day, the importance of relying on nature in many fields such as food, medical, pharmaceutical industries, and others is increasing. Essential oils (EOs) are considered as one of the most significant natural products for use as antimicrobials, antioxidants, antitumorals, and anti-inflammatories. Optimizing the usage of EOs is a big challenge faced by the scientific researchers because of the complexity of chemical composition of every EO, in addition to the difficulties to determine the best in inhibiting the bacterial activity. The goal of this article is to present a new computational tool based on two methodologies: reduction by using rough sets and optimization with particle swarm optimization. The developed tool dubbed as Essential Oil Reduction and Optimization Tool is applied on 24 types of EOs that have been tested toward 17 different species of bacteria. PMID- 28919786 TI - Genetic variants in long noncoding RNA H19 contribute to the risk of breast cancer in a southeast China Han population. AB - The long noncoding RNA (lncRNA) H19 is a maternally expressed imprinted gene that plays important roles in tumorigenesis, progression, and metastasis. However, the association between polymorphisms on H19 and breast cancer (BC) susceptibility has remained obscure. In this case-control study, we assessed the interaction between two lncRNA H19 single-nucleotide polymorphisms (SNPs) (rs217727 C>T, rs2839698 C>T) and the risk of BC in a Chinese Han population. In total, 1,005 BC cases and 1,020 healthy controls were enrolled in this study. Correlations between genotypes and BC risk were evaluated by multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). False-positive report probability calculation was also utilized to identify false-positive associations. We observed that the rs217727 T variant was consistently significantly associated with an increased risk of BC in both codominant and dominant models (CT vs CC, OR 1.25, 95% CI 1.03-1.51; TT vs CC, OR 1.56, 95% CI 1.15-2.09; CT + TT vs CC, OR 1.31, 95% CI 1.09-1.57), and all associations remained significant after Bonferroni correction (P<0.025). Subsequent stratified analyses also revealed that associations between BC risk and rs217727 genotypes were more profound in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, and hormone receptor-positive-HER2 negative molecular subtypes (all passed the threshold for Bonferroni correction, P<0.005). These findings extend available data on the association of H19 polymorphisms and BC susceptibility. Based on these results, we encourage further large-scale studies and functional research to confirm our findings and better elucidate the underlying biological mechanisms. PMID- 28919788 TI - Innovative treatments for severe refractory asthma: how to choose the right option for the right patient? AB - The increasing understanding of the molecular biology and the etiopathogenetic mechanisms of asthma helps in identification of numerous phenotypes and endotypes, particularly for severe refractory asthma. For a decade, the only available biologic therapy that met the unmet needs of a specific group of patients with severe uncontrolled allergic asthma has been omalizumab. Recently, new biologic therapies with different mechanisms of action and targets have been approved for marketing, such as mepolizumab. Other promising drugs will be available in the coming years, such as reslizumab, benralizumab, dupilumab and lebrikizumab. Moreover, since 2010, bronchial thermoplasty has been successfully introduced for a limited number of patients. This is a nonpharmacologic endoscopic procedure which is considered a promising therapy, even though several aspects still need to be clarified. Despite the increasing availability of new therapies, one of the major problems of each treatment is still the identification of the most suitable patients. This sudden abundance of therapeutic options, sometimes partially overlapping with each other, increases the importance to identify new biomarkers useful to guide the clinician in selecting the most appropriate patients and treatments, without forgetting the drug-economic aspects seen in elevated direct cost of new therapies. The aim of this review is, therefore, to update the clinician on the state of the art of therapies available for refractory asthma and, above all, to give useful directions that will help understand the different choices that sometimes partially overlap and to dispel the possible doubts that still exist. PMID- 28919789 TI - Antifungal resistance: current trends and future strategies to combat. AB - Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug-drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non-Candida albicans species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. C. glabrata resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in Aspergillus fumigatus due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of Aspergillus, and other molds, including Scedosporium and Fusarium species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and b-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity. PMID- 28919790 TI - Exploring bacterial outer membrane barrier to combat bad bugs. AB - One of the main fundamental mechanisms of antibiotic resistance in Gram-negative bacteria comprises an effective change in the membrane permeability to antibiotics. The Gram-negative bacterial complex cell envelope comprises an outer membrane that delimits the periplasm from the exterior environment. The outer membrane contains numerous protein channels, termed as porins or nanopores, which are mainly involved in the influx of hydrophilic compounds, including antibiotics. Bacterial adaptation to reduce influx through these outer membrane proteins (Omps) is one of the crucial mechanisms behind antibiotic resistance. Thus to interpret the molecular basis of the outer membrane permeability is the current challenge. This review attempts to develop a state of knowledge pertinent to Omps and their effective role in antibiotic influx. Further, it aims to study the bacterial response to antibiotic membrane permeability and hopefully provoke a discussion toward understanding and further exploration of prospects to improve our knowledge on physicochemical parameters that direct the translocation of antibiotics through the bacterial membrane protein channels. PMID- 28919791 TI - Pegylated-interferon plus ribavirin treatment does not alter the prevalence of resistance-associated substitutions to direct-acting antivirals in HCV genotype 1a patients. AB - BACKGROUND: Direct-acting antiviral (DAA) resistance-associated substitutions (RASs) can jeopardize the effectiveness of DAAs in patients with hepatitis C virus (HCV). The selection pressure by pegylated-interferon (Peg-IFN) plus ribavirin (P/R) treatment may enhance HCV genome variation. However, whether P/R treatment alters the rate of change of RASs is still unclear. MATERIALS AND METHODS: We retrieved the genomic sequences of HCV genotype (GT) 1a patients from GenBank, which included patients naive to P/R (pre-IFN group) and those previously treated with P/R (post-IFN group). The sequences were aligned and analyzed by using MEGA 6.0 software. Clinically relevant RASs were summarized from the current medical literature. RESULTS: In the cross-sectional study, the total prevalence of clinically relevant RASs was high, independent of the treatment group (pre-IFN: 219/403 [54.34%] vs post-IFN: 67/131 [51.15%]). The high prevalence was mainly detected in the NS3 region RAS at Q80 (40.69% vs 36.64%). The RASs in the NS5A region, such as M28, Q30, L31 and Y93, were uncommon (0%-5%). Similarly, all RASs showed no difference between the two groups. One exception was the RAS at I170 in the NS3 region, which was significantly higher in the post-IFN group than in the pre-IFN group. In the longitudinal study, similar results were observed. However, no difference in RAS at I170 was observed between the two groups. Finally, no clinically relevant RASs were detected in response to the DAA regimens approved for GT 1a patients treated with P/R. CONCLUSION: Our results suggest that previous P/R treatment failure was not favorably associated with an increase in DAAs RASs present in GT1a patients. Our results support the American Association for the Study of Liver Diseases' recommendations of DAA intervention in P/R-treated GT1a patients. PMID- 28919792 TI - Clinical outcomes and nephrotoxicity of colistin loading dose for treatment of extensively drug-resistant Acinetobacter baumannii in cancer patients. AB - BACKGROUND: Colistin is a last-line defense therapy against extensively drug resistant Acinetobacter baumannii (XDR-AB). Despite a loading dose of colistin being applied in many clinical practices, studies evaluating the effect of the loading dose of colistin in cancer patients remain limited. PATIENTS AND METHODS: A retrospective cohort study of cancer patients who received either a loading or non-loading dose of colistin for treatment of XDR-AB was conducted. For each group, the clinical response, bacteriological eradication and serum creatinine were recorded. Logistic regression was applied to evaluate the effects of therapy on each of the three aforementioned outcomes. RESULTS: One hundred and two patients diagnosed with XDR-AB infections between January 2012 and December 2015 were recruited. Only 75 patients were given a loading dose of colistin. There was no significant clinical and microbiological response in patients in the loading dose group or patients in the non-loading dose group. However, 38 (50.67%) patients in the loading dose group and 6 (22.22%) patients in the non-loading dose group developed nephrotoxicity according to the RIFLE criteria (p = 0.013). Multivariate logistic regression analysis showed that independent predictors of clinical response were Charlson score >=4 and duration of colistin treatment >=10 days. Septic shock correlated with both poor clinical and microbiological response. Independent predictors for nephrotoxicity were loading dose colistin and patient's age >=60 years. CONCLUSION: Administration of colistin loading dose did not significantly increase clinical response, microbiological response or mortality rate compared to non-loading dose in cancer patients with XDR-AB related infections. However, nephrotoxicity was significantly higher when patients received loading dose colistin. PMID- 28919793 TI - Burden of uterine fibroids in Italy: epidemiology, treatment outcomes, and consumption of health care resources in more than 5,000 women. AB - BACKGROUND AND PURPOSE: Epidemiological studies on uterine fibroids (UFs) are mostly based on surveys or analyses of small samples of patients. In 50% of women, the quality of life is worsened by disease-related symptoms; furthermore, treatments imply a remarkable health care cost. The aim of this observational study was to analyze a large sample of Italian patients with UFs and to assess the epidemiology, the appropriateness of treatments, and the consumption of disease-related resources. METHODS: Data were collected through a data-linkage technique from five administrative databases. Women aged between 18 and 55 years and resident in three local health authorities (north-central-south Italy) were selected over the period from 1st January 2009 to 31st December 2015. The inclusion criteria were a surgical procedure with diagnosis of UFs or a pharmacological treatment with gonadotropin-releasing hormone (GnRH) analogs or ulipristal acetate. Besides the overall descriptive analysis, two comparisons were evaluated: surgery versus no surgery and treatment with GnRH analogs versus ulipristal acetate. RESULTS: A total of 5,665 women with UFs were selected from an overall population of 2,400,000 people. In the north, 73.6% of patients underwent surgery, as opposed to only 16.7% in the south; 70% of surgeries were hysterectomies. The average cost per patient was ?3,249 (duration of follow-up = up to 7 years). The southern district had the highest number of drug prescriptions; in particular, 49% of patients took >10 packages of GnRH analogs. CONCLUSION: This study is the first on this topic conducted in Italy using a large sample size. The analysis of resource consumption revealed a high heterogeneity in the choice of drug treatments by gynecologists (especially in the south); in the north, marked variations were seen in the rates of surgery. The long-term use of GnRH was inappropriate. PMID- 28919794 TI - Parenteral nutrition including an omega-3 fatty-acid-containing lipid emulsion for intensive care patients in China: a pharmacoeconomic analysis. AB - BACKGROUND/OBJECTIVES: Parenteral nutrition (PN) incorporating omega-3 fatty-acid enriched lipid emulsions has been shown to be cost effective in Western populations. A pharmacoeconomic evaluation was performed within the Chinese intensive care unit (ICU) setting. This assessed whether the additional acquisition cost of PN with omega-3 fatty-acid-enriched lipid emulsion (SMOFlipid) vs standard PN was offset by improved clinical outcomes that can reduce subsequent costs. MATERIALS AND METHODS: A pharmacoeconomic discrete event simulation model was developed, based on an update to efficacy data from a previous international meta-analysis, with China-specific clinical and economic input parameters. Sensitivity analyses were undertaken to assess the effects of uncertainty around input parameters. RESULTS: The model predicted that PN with an omega-3 fatty-acid-enriched lipid emulsion was more effective and less costly than PN with standard lipid emulsions for Chinese ICU patients, as follows: reduced length of overall hospital length of stay (19.48 vs 21.35 days, respectively), reduced length of ICU stay (5.03 vs 6.18 days, respectively), and prevention of 35.6% of nosocomial infections leading to a lower total cost per patient (Y47 189 [US $6937] vs Y54 783 [US $8053], respectively). Additional treatment costs were offset by savings in overall hospital and ICU stay cost, and antibiotic cost, resulting in a mean cost saving of Y7594 (US $1116) per patient. Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: PN enriched with an omega-3 fatty-acid-containing lipid emulsion vs standard PN may be effective in reducing length of hospital and ICU stay and infectious complications in Chinese ICU patients, and also decreases overall treatment costs. This results in a favorable cost-effectiveness ratio. Thus, PN enriched with an omega-3 fatty-acid-containing lipid emulsion can be seen as a win-win situation for patients, hospital administration, and health insurance companies. PMID- 28919795 TI - Type 2 diabetes in Vietnam: a cross-sectional, prevalence-based cost-of-illness study. AB - BACKGROUND: According to the International Diabetes Federation, total global health care expenditures for diabetes tripled between 2003 and 2013 because of increases in the number of people with diabetes as well as in the average expenditures per patient. This study aims to provide accurate and timely information about the economic impacts of type 2 diabetes mellitus (T2DM) in Vietnam. METHOD: The cost-of-illness estimates followed a prospective, prevalence based approach from the societal perspective of T2DM with 392 selected diabetic patients who received treatment from a public hospital in Ho Chi Minh City, Vietnam, during the 2016 fiscal year. RESULTS: In this study, the annual cost per patient estimate was US $246.10 (95% CI 228.3, 267.2) for 392 patients, which accounted for about 12% (95% CI 11, 13) of the gross domestic product per capita in 2017. That includes US $127.30, US $34.40 and US $84.40 for direct medical costs, direct nonmedical expenditures, and indirect costs, respectively. The cost of pharmaceuticals accounted for the bulk of total expenditures in our study (27.5% of total costs and 53.2% of direct medical costs). A bootstrap analysis showed that female patients had a higher cost of treatment than men at US $48.90 (95% CI 3.1, 95.0); those who received insulin and oral antidiabetics (OAD) also had a statistically significant higher cost of treatment compared to those receiving OAD, US $445.90 (95% CI 181.2, 690.6). The Gradient Boosting Regression (Ensemble method) and Lasso Regression (Generalized Linear Models) were determined to be the best models to predict the cost of T2DM (R2=65.3, mean square error [MSE]=0.94; and R2=64.75, MSE=0.96, respectively). CONCLUSION: The findings of this study serve as a reference for policy decision making in diabetes management as well as adjustment of costs for patients in order to reduce the economic impact of the disease. PMID- 28919796 TI - Psoriasis and vitiligo are close relatives. AB - BACKGROUND: Both vitiligo and psoriasis are chronic inflammatory autoimmune diseases with genetic elements. OBJECTIVE: To estimate the frequencies of psoriasis in vitiligo patients and vice versa and to compare them with healthy controls. PATIENTS AND METHODS: A total of 1000 subjects were included, 250 of them had vitiligo, 250 had psoriasis, and 500 were healthy controls. Measurement of the frequencies of vitiligo in psoriatic patients and psoriasis in vitiligo patients was carried out. Thereafter the frequencies of both diseases were assessed in healthy controls. The frequency of vitiligo among psoriatic patients was compared with that of vitiligo in healthy controls. A similar comparison was done between the frequency of psoriasis among vitiligo patients with that in healthy controls. Other comparisons were performed between the frequency of family history of psoriasis among vitiligo patients with that in healthy controls and between the frequency of family history of vitiligo in psoriatic patients with that in healthy controls. RESULTS: The frequency of psoriasis among vitiligo patients was 15 (6%) and among healthy controls was 2 (0.4%); there is a statistically significant difference (P=0.001). The frequency of vitiligo among psoriatic patients was 5 (2%) and among healthy controls was 3 (0.6%); no statistically significant difference was found (P=0.16). The family history of psoriasis among vitiligo patients was 23 (9.2%) and among healthy controls was 20 (4%); there is a significant association (P=0.043). The family history of vitiligo among psoriatic patients was 24 (9.6%) and among healthy controls was 40 (8%); the difference is statistically significant (P=0.042). CONCLUSION: The present work has confirmed the close relationship between vitiligo and psoriasis. PMID- 28919797 TI - Quality of care in inflammatory bowel disease: results of a prospective controlled cohort study in Germany (NETIBD). AB - BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) need comprehensive, interdisciplinary and cross-sectoral health care. In Germany, evidence-based care pathways have been developed to improve the quality of care of IBD patients. We aimed to evaluate the effects of the implementation of some of these recommendations on patient-related outcomes. METHODS: In a region of North Germany, outpatients with IBD were recruited by gastroenterologists (intervention group). Three activities based on the recommendations of the IBD pathways were implemented, namely, 1) patient participation in a questionnaire based assessment of 22 somatic and psychosocial problems combined with individualized care recommendations (patient activation procedure); 2) patient invitation to participate in a 2-day patient education program and 3) invitation to their gastroenterologists to participate in periodic interdisciplinary case conferences. For the control group, IBD patients receiving standard care at gastroenterology practices outside the specified region were recruited by their doctors. At baseline, 6- and 12-month follow-up, study patients were invited to complete questionnaires. Generic health-related quality of life, social participation and self-management skills were the main outcomes. RESULTS: At baseline, 349 patients were included in the study (intervention group: 189; control group: 160); 142 patients from the former and 140 from the latter group returned completed questionnaires at the 12-month follow-up. Over time, improvement in health-related quality of life and social participation was similar in both groups. Participants of the intervention group demonstrated improved self-management skills and more often followed steroid-free medication regimens. CONCLUSION: In a real-world clinical context, patient activation procedure combined with patient education and case conferences was less effective than expected. The observed beneficial effects, however, encourage the evaluation of more intensive and addressee-centered activities. PMID- 28919798 TI - Comparative effects of the omega3 polyunsaturated fatty acid derivatives resolvins E1 and D1 and protectin DX in models of inflammation and pain. AB - PURPOSE: Specialized pro-resolving lipid mediators (SPMs), also known as lipoxins, resolvins (Rvs), protectins and maresins, have been implicated in the resolution of the inflammatory process. However, a systematic comparison of their activity in the relief of inflammation and pain models is still lacking. MATERIALS AND METHODS: The effects of Rvs E1 and D1 and protectin DX (PDX) were assessed in rat paws inflamed by the standard proinflammatory stimulus carrageenan or by histamine, 5-hydroxytryptamine, substance P or prostaglandin E2. The experimental outcomes were the mechanical nociceptive threshold and increase in paw volume as a measure of pain and edema formation, respectively. The analgesic and anti-inflammatory activities of the indicated SPMs were also compared with nonsteroidal (indomethacin and celecoxib) and steroidal (dexamethasone) anti-inflammatory drugs. RESULTS: Only RvE1 and RvD1 presented analgesic and anti-inflammatory activities in the carrageenan model, and RvE1 was twice as potent as RvD1. Both substances tended to be better analgesics than anti inflammatory agents, with a modeling profile similar to steroidal anti inflammatory drugs. However, proinflammatory effects (edema formation) were also detected when the mediators histamine, 5-hydroxytryptamine or substance P replaced carrageenan as the proinflammatory stimuli. The analgesic and anti inflammatory effects of resolvins were specifically prevented by an antagonist of the leukotriene B4 receptor 1 (BLT1). CONCLUSION: Rvs, as analgesic agents, may be better therapeutic agents than nonsteroidal anti-inflammatory drugs, the current choice in the relief of pain of an inflammatory origin. However, the possibility of developing adverse effects cannot be overlooked. PMID- 28919799 TI - Maple syrup urine disease: mechanisms and management. AB - Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain alpha-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, alpha ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients. PMID- 28919800 TI - Renal sympathetic denervation increases renal blood volume per cardiac cycle: a serial magnetic resonance imaging study in resistant hypertension. AB - AIM: Preclinical studies have demonstrated improvements in renal blood flow after renal sympathetic denervation (RSDN); however, such effects are yet to be confirmed in patients with resistant hypertension. Herein, we assessed the effects of RSDN on renal artery blood flow and diameter at multiple time points post-RSDN. METHODS AND RESULTS: Patients (n=11) with systolic blood pressures >=160 mmHg despite taking three or more antihypertensive medications at maximum tolerated dose were recruited into this single-center, prospective, non-blinded study. Magnetic resonance imaging indices included renal blood flow and renal artery diameters at baseline, 1 month and 6 months. In addition to significant decreases in blood pressures (p<0.0001), total volume of blood flow per cardiac cycle increased by 20% from 6.9+/-2 mL at baseline to 8.4+/-2 mL (p=0.003) at 1 month and to 8.0+/-2 mL (p=0.04) 6 months post-procedure, with no changes in the renal blood flow. There was a significant decrease in renal artery diameters from 7+/-2 mm at baseline to 6+/-1 mm (p=0.03) at 1 month post-procedure. This decrease was associated with increases in maximum velocity of blood flow from 73+/-20 cm/s at baseline to 78+/-19 cm/s at 1 month post-procedure. Notably, both parameters reverted to 7+/-2 mm and 72+/-18 cm/s, respectively, 6 months after procedure. CONCLUSION: RSDN improves renal physiology as evidenced by significant improvements in total volume of blood flow per cardiac cycle. Additionally, for the first time, we identified a transient decrease in renal artery diameters immediately after procedure potentially caused by edema and inflammation that reverted to baseline values 6 months post-procedure. PMID- 28919801 TI - Transforming growth factor-beta1/Smad3-independent epithelial-mesenchymal transition in type I collagen glomerulopathy. AB - The glomerulofibrotic Col1a2-deficient mouse model demonstrates glomerular homotrimeric type I collagen deposition in mesangial and subendothelial spaces. In this report, we investigate the role of transforming growth factor beta1 (TGF beta1) in myofibroblast activation and epithelial-mesenchymal transition (EMT) in this glomerulopathy. Immunohistochemical analyses of glomerular alpha-sma, desmin, vimentin, and proliferating cell nuclear antigen demonstrated parietal epithelial cell proliferation and EMT in late stages of the glomerulopathy in the Col1a2-deficient mice. Glomerular TGF-beta1 RNA and protein were not elevated in 1- and 3-month-old mice as determined by quantitative reverse transcriptase polymerase chain reaction and protein immunoassay analyses. To investigate further whether TGF-beta1 plays a role in the glomerulopathy outside of the 1- and 3-month time periods, the Col1a2-deficient mice were bred with Smad3 knockout mice. If the glomerular fibrosis in the Col1a2-deficient mice is mediated by the TGF-beta1/Smad3 transcription pathway, it was hypothesized that the resultant Col1a2-deficient/Smad3-deficient mice would exhibit attenuated glomerular homotrimer deposition. However, the Col1a2-deficient/Smad3-deficient kidneys were similarly affected as compared to age-matched Col1a2-deficient kidneys, suggesting that homotrimeric type I collagen deposition in the Col1a2-deficient mouse is independent of TGF-beta1/Smad3 signaling. Deposition of homotrimeric type I collagen appears to be the initiating event in this glomerulopathy, providing evidence that EMT and myofibroblast activation occur following initiation, consistent with a secondary wound-healing response independent of TGF beta1. PMID- 28919802 TI - ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine. AB - Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood-brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment. These polymorphisms influenced baseline BMI in males (p=0.009 and 0.054, B1 and C1, respectively), changes in BMI in males after 3 (p=0.026, ABCB1) and 12 months (p=0.022, ABCC1) of CZ treatment, and level of diastolic pressure (p=0.002 and 0.051, respectively). The combination of ABCB1 + ABCC1 homozygote SNPs was associated with increased CZ and norclozapine serum levels (p=0.054 and 0.010, respectively). ABC transporter SNPs could be potential biomarkers for CZ-induced weight gain and cardiovascular complications. Further pharmacogenetic research is warranted to help clinicians with their treatment decision, including concomitant use of drugs and prevention of side effects. PMID- 28919804 TI - Morningness-eveningness and emotion dysregulation incremental validity in predicting social anxiety dimensions. AB - This study investigates the usefulness of morningness-eveningness and emotion dysregulation for better understanding of social anxiety dimensions. Specifically, associations between morningness-eveningness and incremental validity of emotion dysregulation as a predictor of social anxiety were examined. Data were obtained from a sample of normal students (N=510). Results of regression analyses showed that morningness was a significant predictor of social anxiety variables. Dimensions of emotion dysregulation had multiple associations with facets from social anxiety. Emotion dysregulation was found to be a positive predictor of social anxiety. The results expand the understanding of social anxiety and indicate how the domains of morningness-eveningness and emotion regulation could explain social anxiety in a normal population. PMID- 28919803 TI - Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease. AB - PURPOSE: Lyme disease is spreading worldwide, with multiple Borrelia species causing a broad range of clinical symptoms that mimic other illnesses. A validated Lyme disease screening questionnaire would be clinically useful for both providers and patients. Three studies evaluated such a screening tool, namely the Horowitz Multiple Systemic Infectious Disease Syndrome (MSIDS) Questionnaire. The purpose was to see if the questionnaire could accurately distinguish between Lyme patients and healthy individuals. METHODS: Study 1 examined the construct validity of the scale examining its factor structure and reliability of the questionnaire among 537 individuals being treated for Lyme disease. Study 2 involved an online sample of 999 participants, who self identified as either healthy (N=217) or suffering from Lyme now (N=782) who completed the Horowitz MSIDS Questionnaire (HMQ) along with an outdoor activity survey. We examined convergent validity among components of the scale and evaluated discriminant validity with the Big Five personality characteristics. The third study compared a sample of 236 patients with confirmed Lyme disease with an online sample of 568 healthy individuals. RESULTS: Factor analysis results identified six underlying latent dimensions; four of these overlapped with critical symptoms identified by Horowitz - neuropathy, cognitive dysfunction, musculoskeletal pain, and fatigue. The HMQ showed acceptable levels of internal reliability using Cronbach's coefficient alpha and exhibited evidence of convergent and divergent validity. Components of the HMQ correlated more highly with each other than with unrelated traits. DISCUSSION: The results consistently demonstrated that the HMQ accurately differentiated those with Lyme disease from healthy individuals. Three migratory pain survey items (persistent muscular pain, arthritic pain, and nerve pain/paresthesias) robustly identified individuals with verified Lyme disease. The results support the use of the HMQ as a valid, efficient, and low-cost screening tool for medical practitioners to decide if additional testing is warranted to distinguish between Lyme disease and other illnesses. PMID- 28919805 TI - A pilot evaluation of a computer-based psychometric test battery designed to detect impairment in patients with cirrhosis. AB - BACKGROUND: Psychometric testing is used to identify patients with cirrhosis who have developed hepatic encephalopathy (HE). Most batteries consist of a series of paper-and-pencil tests, which are cumbersome for most clinicians. A modern, easy to-use, computer-based battery would be a helpful clinical tool, given that in its minimal form, HE has an impact on both patients' quality of life and the ability to drive and operate machinery (with societal consequences). AIM: We compared the CogstateTM computer battery testing with the Psychometric Hepatic Encephalopathy Score (PHES) tests, with a view to simplify the diagnosis. METHODS: This was a prospective study of 27 patients with histologically proven cirrhosis. An analysis of psychometric testing was performed using accuracy of task performance and speed of completion as primary variables to create a correlation matrix. A stepwise linear regression analysis was performed with backward elimination, using analysis of variance. RESULTS: Strong correlations were found between the international shopping list, international shopping list delayed recall of Cogstate and the PHES digit symbol test. The Shopping List Tasks were the only tasks that consistently had P values of <0.05 in the linear regression analysis. CONCLUSION: Subtests of the Cogstate battery correlated very strongly with the digit symbol component of PHES in discriminating severity of HE. These findings would indicate that components of the current PHES battery with the international shopping list tasks of Cogstate would be discriminant and have the potential to be used easily in clinical practice. PMID- 28919806 TI - How stable are quantitative sensory testing measurements over time? Report on 10 week reliability and agreement of results in healthy volunteers. AB - BACKGROUND: Quantitative sensory testing (QST) is a diagnostic tool for the assessment of the somatosensory system. To establish QST as an outcome measure for clinical trials, the question of how similar the measurements are over time is crucial. Therefore, long-term reliability and limits of agreement of the standardized QST protocol of the German Research Network on Neuropathic Pain were tested. METHODS: QST on the lower back and hand dorsum (dominant hand) were assessed twice in 22 healthy volunteers (10 males and 12 females; mean age: 46.6+/-13.0 years), with sessions separated by 10.0+/-2.9 weeks. All measurements were performed by one investigator. To investigate long-term reliability and agreement of QST, differences between the two measurements, correlation coefficients, intraclass correlation coefficients (ICCs), Bland-Altman plots (limits of agreement), and standard error of measurement were used. RESULTS: Most parameters of the QST were reliable over 10 weeks in healthy volunteers: Almost perfect ICCs were observed for heat pain threshold (hand) and mechanical pain sensitivity (back). Substantial ICCs were observed for heat pain threshold (back), pressure pain threshold (back), mechanical pain sensitivity (hand), and vibration detection threshold (back and hand). Some QST parameters, such as cold detection threshold, exhibited low ICCs, but also very low variability. Generally, QST measures exhibited narrow limits of agreement in the Bland-Altman plots. CONCLUSION: The standardized QST protocol of the German Research Network on Neuropathic Pain is feasible to be used in treatment trials. Moreover, defining a statistically meaningful change is possible, which is a prerequisite for the use of QST in clinical trials as well as in long-term investigations of disease progression. PMID- 28919807 TI - Effect of nerve injury on the number of dorsal root ganglion neurons and autotomy behavior in adult Bax-deficient mice. AB - BACKGROUND: The proapoptotic molecule BAX, plays an important role in mitochondrial apoptotic pathway. Dorsal root ganglion (DRG) neurons depend on neurotrophic factors for survival at early developmental stages. Withdrawal of neurotrophic factors will induce apoptosis in DRG neurons, but this type of cell death can be delayed or prevented in neonatal Bax knockout (KO) mice. In adult animals, evidence also shows that DRG neurons are less dependent upon neurotrophic factors for survival. However, little is known about the effect of Bax deletion on the survival of normal and denervated DRG neurons in adult mice. METHODS: A unilateral sciatic nerve transection was performed in adult Bax KO mice and wild-type (WT) littermates. Stereological method was employed to quantify the number of lumbar-5 DRG neurons 1 month post-surgery. Nerve injury induced autotomy behavior was also examined on days 1, 3, and 7 post-surgery. RESULTS: There were significantly more neurons in contralateral DRGs of KO mice as compared with WT mice. The number of neurons was reduced in ipsilateral DRGs in both KO and WT mice. No changes in size distributions of DRG neuron profiles were detected before or after nerve injury. Injury-induced autotomy behavior developed much earlier and was more serious in KO mice. CONCLUSION: Although postnatal death or loss of DRG neurons is partially prevented by Bax deletion, this effect cannot interfere with long-term nerve injury-induced neuronal loss. The exaggerated self-amputation behavior observed in the mutant mice indicates that Bax deficiency may enhance the development of spontaneous pain following nerve injury. PMID- 28919808 TI - Looking ahead: chronic spinal pain management. PMID- 28919809 TI - Adequacy of cancer-related pain management and predictors of undertreatment at referral to a pain clinic. AB - BACKGROUND: Several guidelines have advocated the need for adequate cancer related pain (CRP) management. The pain management index (PMI) has been proposed as an auditable measure of the appropriateness for analgesic therapy. OBJECTIVES: To determine the adequacy of CRP management based on the PMI status and its patient-related predictors at the point of referral to a pain clinic (PC). METHODS: Consecutive patients referred to a PC had standardized initial assessments and status documentation on the Brief Pain Inventory (BPI) ratings; pain mechanism, using a neuropathic pain diagnostic questionnaire (the Douleur Neuropathique 4 tool); episodic pain; oral morphine equivalent daily dose; the Hospital Anxiety Depression Scale and the Emotion Thermometer scores; and cancer diagnosis, metastases, treatment, and pain duration. Predictors of "negative PMI status" [PMI(-)] were examined in logistic regression models. Variables with p<0.25 in an initial bivariable analysis were entered into a multivariable model. RESULTS: Of 371 participants, 95 (25.6%) had PMI(-), suggesting undertreatment of CRP. Both female sex and higher scores on the BPI's "interference with general activity" more strongly predicted PMI(-). Patients who received either radiotherapy or one or more adjuvant analgesics prior to the initial consultation at the PC, those who had neuropathic pain, those who had a greater need for emotional help, and those with higher BPI's "relief " scores were all less likely to be PMI(-). CONCLUSION: The potential burden of patient and family distress associated with suboptimal CRP management in one in four patients should generate major public health concern and prompt appropriate educational and health policy measures to address the deficit. PMID- 28919810 TI - A comparison between the administration of oral prolonged-release oxycodone naloxone and transdermal fentanyl in patients with moderate-to-severe cancer pain: a propensity score analysis. AB - BACKGROUND: Opioids are the most important pharmacological treatment for moderate to-severe cancer pain, but side effects limit their use. Transdermal fentanyl (TDF) and oral prolonged-release oxycodone-naloxone (OXN-PR) are effective in controlling chronic pain, with less constipation compared to other opioids. However, TDF and OXN-PR have never been directly compared. PATIENTS AND METHODS: Cancer patients with moderate-to-severe chronic pain were consecutively enrolled in two prospective 28-day trials, received either TDF or OXN-PR, and were assessed at baseline and after 7, 14, 21, and 28 days. The primary endpoint was 28-day analgesic response rate (average pain intensity decrease >=30% from baseline). Other outcome measures included opioid daily dose changes over time; need for adjuvant analgesics; number of switches; premature discontinuation; presence and severity of constipation; and other adverse drug reactions. To compare the efficacy and the safety of TDF and OXN-PR, we used the propensity score analysis to adjust for heterogeneity between the two patient groups. RESULTS: Three hundred ten out of 336 patients originally treated (119 TDF and 191 OXN-PR) were included in the comparative analysis. The amount of responders was comparable after TDF (75.3%) and OXN-PR administration (82.9%, not significant [NS]). The final opioid daily dose expressed as morphine equivalent was 113.6 mg for TDF and 44.5 mg for OXN-PR (p<0.0001). A daily opioid dose escalation >5% was less common after OXN-PR (19.3%) than after TDS administration (37.9%, p<0.0001). Opioid switches and discontinuation were similar in both groups. Severe constipation in the two groups was comparable (32.6% after TDF vs 24.7% after OXN-PR, NS). Nausea, vomiting, and dry mouth were significantly less frequent in the OXN-PR group than in the TDF group. CONCLUSION: Despite a similar analgesic activity in moderate-to-severe cancer pain, OXN-PR is characterized by lower daily dosages, less need for drug escalation, and fewer side effects compared to TDF. PMID- 28919812 TI - The effect of local/topical analgesics on incisional pain in a pig model. AB - Interest in the development of new topical/local drug administration for blocking pain at peripheral sites, with maximum drug activity and minimal systemic effects, is on the rise. In the review article by Kopsky and Stahl, four critical barriers in the process of research and development of topical analgesics were indicated. The active pharmaceutical ingredient (API) and the formulation are among the major challenges. The road to the development of such drugs passes through preclinical studies. These studies, if planned correctly, should serve as guidance for choosing the right API and formulation. Although rodent models for pain continue to provide valuable data on the mechanisms driving pain, their use in developing topical and localized treatment approaches is limited for technical (intraplate injection area is small) as well as mechanical reasons (non similarity to human skin and innervation). It has been previously shown that pigs are comparable to humans in ways that make them a better choice for evaluating topical and local analgesics. The aim of this study was to summarize several experiments that used pigs for testing postoperative pain in an incisional pain model (skin incision [SI] and skin and muscle incision [SMI]). At the end of the surgery, the animals were treated with different doses of bupivacaine solution (Marcaine(r)), bupivacaine liposomal formulation (Exparel(r)) or ropivacaine solution (Naropin). Von Frey testing demonstrated a decrease in the animals' sensitivity to mechanical stimulation expressed as an increase in the withdrawal force following local treatment. These changes reflect the clinical condition in the level as well as in the duration of the response. These data indicate a good resemblance between pig and human skin and suggest that use of these animals in the preclinical phase of developing topical analgesics can, to some extent, release the bottleneck. PMID- 28919811 TI - Response to duloxetine in chronic low back pain: exploratory post hoc analysis of a Japanese Phase III randomized study. AB - PURPOSE: Duloxetine is efficacious for chronic low back pain (CLBP). This post hoc analysis of a Japanese randomized, placebo-controlled trial (ClinicalTrials.gov, NCT01855919) assessed whether patients with CLBP with early pain reduction or treatment-related adverse events of special interest (TR-AESIs; nausea, somnolence, constipation) have enhanced responses to duloxetine. PATIENTS AND METHODS: Patients (N = 456) with CLBP for >=6 months and Brief Pain Inventory (BPI) average pain severity score of >=4 were randomized (1:1) to duloxetine 60 mg/day or placebo for 14 weeks. Primary outcome was change from baseline in BPI average pain severity score (pain reduction). Subgroup analyses included early pain reduction (>=30%, 10%-30%, or <10% at Week 4) and early TR-AESIs (with or without TR-AESIs by Week 2). Measures included changes from baseline in BPI average pain severity score and BPI Interference scores (quality of life; QOL), and response rate (>=30% or >=50% pain reduction at Week 14). RESULTS: Patients with >=30% early pain reduction (n = 108) or early TR-AESIs (n = 50) had significantly greater improvements in pain and QOL than placebo-treated patients (n = 226), whereas patients with 10%-30% (n = 63) or <10% (n = 48) pain reduction did not; patients without early TR-AESIs (n = 180) had significant improvements in pain at Week 14. Response rates (>=30%/>=50% pain reduction) were 94.4%/82.4%, 66.7%/49.2%, and 25.0%/18.8% for patients with >=30%, 10%-30%, and <10% early pain reduction, respectively, 74.0%/64.0% for patients with early TR-AESIs, 67.2%/54.4% for patients without early TR-AESIs, and 52.2%/39.4% for placebo. CONCLUSION: Early pain reduction or TR-AESIs may predict which CLBP patients are most likely to respond to duloxetine with improvements in pain and QOL. PMID- 28919813 TI - A prospective, double-blinded, randomized comparison of ultrasound-guided femoral nerve block with lateral femoral cutaneous nerve block versus standard anesthetic management for pain control during and after traumatic femur fracture repair in the pediatric population. AB - BACKGROUND: Traumatic injury of the femur resulting in femoral fracture may result in significant postoperative pain. As with other causes of acute pain, regional anesthesia may offer a benefit over conventional therapy with intravenous opioids. This study prospectively assesses the effects of femoral nerve blockade with a lateral femoral cutaneous nerve block (FN-LFCN) on intraoperative anesthetic requirements, postoperative pain scores, and opioid requirements. MATERIALS AND METHODS: Seventeen pediatric patients (age 2-18 years) undergoing surgical repair of a traumatic femur fracture fulfilled the study criteria and were randomly assigned to general anesthesia with either an FN LFCN block (n = 10) or intravenous opioids (n = 7). All patients received a general anesthetic with isoflurane for maintenance anesthesia during the surgical repair of the femur fracture. Patients randomized to the FN-LFCN block group received ultrasound-guided nerve blockade using ropivacaine (0.2%/0.5% based on patient weight). At the conclusion of surgery, the airway device was removed once tracheal extubation criteria were achieved, and patients were transported to the post-anesthesia care unit (PACU) for recovery and assessment of pain by a blinded study nurse. RESULTS: The final study cohort included 17 patients (n = 10 for FN LFCN block group; n = 7 for the intravenous opioid group). Although the median of the maximum postoperative pain scores in the regional group was 0, this did not reach statistical significance when compared to the median pain score of 3 in the intravenous opioid group. Likewise, no difference between the two groups was noted when comparing intraoperative anesthetic requirements, opioid requirements (intraoperative, in the post-anesthesia recovery room, and in the inpatient ward), and the time to first opioid requirement postoperatively in the inpatient ward. CONCLUSION: This prospective, randomized, double-blinded study failed to demonstrate a clear benefit of regional anesthesia over intravenous opioids intraoperatively and postoperatively during repair of femoral shaft fractures in the pediatric population. PMID- 28919814 TI - Clinical relevance of persistent postoperative pain after total hip replacement - a prospective observational cohort study. AB - PURPOSE: The development of persistent postoperative pain may occur following surgery, including total hip replacement. Yet, the prevalence may depend on the definition of persistent pain. This observational cohort study explored whether the prevalence of persistent pain after total hip replacement differs depending on the definition of persistent pain and evaluated the impact of ongoing pain on the patient's quality of life 6 months after surgery. PATIENTS AND METHODS: Pre- and postoperative characteristics of 125 patients undergoing elective total hip replacement were assessed and 104 patients were available for the follow-up interview, 6 months after surgery. RESULTS: Six months after surgery, between 26% and 58% of patients still reported hip pain - depending on the definition of persistent pain. Patients with moderate-to-severe persistent pain intensity (>3 on a numerical rating scale) were more restricted in their daily life activities (Chronic Pain Grade - disability score) but did not differ in reported quality of life (Short-Form 12) from those with no pain or milder pain intensity. Maximal preoperative pain intensity and body mass index were the only independent factors influencing daily function 6 months after total hip replacement. CONCLUSION: These findings support a high prevalence of persistent postoperative pain after total hip replacement and a large variability depending on the definition used. There was a close relation between physical functioning and pain as well as relevance of the patient's psychological state at the time of the operation. PMID- 28919815 TI - An acceptance-based intervention for children and adolescents with cancer experiencing acute pain - a single-subject study. AB - BACKGROUND: Children and adolescents with cancer report pain as one of their most recurrent and troublesome symptoms throughout the cancer trajectory. Pain evokes psychological distress, which in turn has an amplifying effect on the pain experience. Acceptance-based interventions for experimentally induced acute pain predict increased pain tolerance, decreased pain intensity and decreased discomfort of pain. The aim of this study was to preliminarily evaluate an acceptance-based intervention for children and adolescents with cancer experiencing acute pain, with regard to feasibility and effect on pain intensity and discomfort of pain. METHODS: This is a single-subject study with an AB design with a nonconcurrent multiple baseline. Children and adolescents aged four to 18 years undergoing cancer treatment at the Children's University Hospital, Uppsala, Sweden, reporting sustained acute pain were offered participation. Pain intensity and discomfort of pain were measured during baseline and at post-intervention. The intervention consisted of a pain exposure exercise lasting approximately 15 minutes. RESULTS: Five children participated in the study. All participants completed the intervention and reported that it had helped them to cope with the pain in the moment. All participants reported decreased discomfort of pain at post-measurement, three of whom also reported decreased pain intensity. CONCLUSION: The results suggest that an acceptance-based intervention may help children and adolescents with cancer to cope with the pain that is often associated with cancer treatment in spite of pharmacological pain management. The results are tentative but promising and warrant further investigation. PMID- 28919816 TI - CXCR4 antagonist AMD3100 elicits analgesic effect and restores the GlyRalpha3 expression against neuropathic pain. AB - OBJECTIVE: Chemokine CXCL12 and its receptor CXCR4 have been reported to play a critical role in neurogenesis and neuronal differentiation. Recently, some reports have implicated this chemokine signaling in the pathogenesis of many kinds of pain. However, its role in neuropathic pain (NP) is still largely unclear. This study explored the distribution and function of CXCR4 in spinal cord (SC) dorsal horn (DH) in a rat L5 spinal nerve ligation (SNL) model. METHODS: Rats received repeated intrathecal injection of CXCR4 antagonist AMD3100. Behavioral assessments were conducted using a traditional "up-down" method. The spinal CXCL12 contents were measured by enzyme linked immunosorbent assay. The expression and distribution of CXCR4 in the SC were determined by immunoflurescence and Western blot. GlyRalpha3 expressions were also measured by Western blot or immunofluorescence. RESULTS: SNL induced CXCL12-CXCR4 activation in the spinal DH. Intrathecal administration of AMD3100 alleviated the chronic NP against SNL (P<0.01). CXCR4 was colocalized with GlyRalpha3-positive neurons in the spinal DH at ratio >97%. Meanwhile, AMD3100 rescued the decrease of GlyRalpha3 expression (P<0.01 vs the SNL group on Day 14 and Day 21). CONCLUSION: CXCR4 antagonist can elicit analgesic effects and restore the inhibitory neurotransmission such as GlyRalpha3 against NP. PMID- 28919817 TI - SIRT1 gene polymorphisms and risk of lung cancer. AB - OBJECTIVE: Lung cancer, which is the leading cause of cancer death worldwide, is influenced by a wide variety of environmental and genetic risk factors. The silent information regulator 1 (SIRT1) gene is located on the long arm of chromosome 10 (10q21.3) and has been shown to play crucial roles in lung cancer development in previous studies. In this study, we determined whether variation in the SIRT1 gene is associated with lung cancer in Chinese population. METHODS: The case-control study comprised 246 controls and 257 non-small cell lung cancer patients, comprising 79 squamous cell carcinoma patients and 124 adenocarcinoma patients. All subjects were from Zhejiang, China. Four single-nucleotide polymorphisms of SIRT1 gene were analyzed: rs12778366 (C/T, lies in the 5' upstream), rs3758391 (C/T, lies in the 5' upstream), rs2273773 (C/T, lies in the coding) and rs4746720 (C/T, lies in the 3' untranslated region). RESULTS: No significant difference of allele and genotype frequencies was observed between the different groups. Haplotype association analysis carried out on the four single-nucleotide polymorphisms within the case-control cohort also did not reveal a significant association with lung cancer (P>0.05). CONCLUSION: The results suggest the tested SIRT1 gene polymorphisms may not contribute to lung cancer. Further studies are warranted to demonstrate the functional roles of the SIRT1 polymorphism in lung cancer. PMID- 28919818 TI - Standard of care and direct medical costs of the treatment of chronic lymphocytic leukemia among the adult population in Ukraine, Russia, and Kazakhstan: data from the LEUKOSPECT study. AB - PURPOSE: The LEUKOSPECT study aimed to describe health service utilization and to estimate the direct medical costs (DMCs) of chronic lymphocytic leukemia (CLL) in 2013 in the adult population of three post-Soviet countries - Russia, Ukraine, and Kazakhstan. As oncologic medical care is provided by federal state-owned, specialized medical institutions, the cost estimation in this study primarily informs from a state budget perspective. Patients' contributions to medical costs were not included in the cost evaluation. PATIENTS AND METHODS: This was a multinational, multicenter, retrospective study conducted in eight specialized centers (four in Russia, three in Ukraine, and one in Kazakhstan). The investigators captured data from the medical documents of all adult patients with an established CLL diagnosis before December 31, 2013, and who made at least one visit to their respective center between January 1 and December 31, 2013. RESULTS: A total of 319 adult CLL patients were enrolled (124 in Kazakhstan, 106 in Russia, and 89 in Ukraine). In 2013, the DMCs of CLL management (without CLL therapy) were ?215.40 in Kazakhstan, ?1,342.20 in Russia, and ?13,260.70 in Ukraine. Hospitalizations formed the largest proportion of total cost: 18.1%, 23.1%, and 40.4%, respectively. The mean cost of CLL medical treatment was ?13,580.60 (Russia), ?399.40 (Kazakhstan), and ?7,453.00 (Ukraine). CONCLUSION: CLL treatment standards varied across the selected countries; higher usage of biologic therapy was noted in Russia. Future research is needed to assess DMCs which include CLL treatment, which is another essential factor contributing to CLL DMCs. PMID- 28919819 TI - Migraine and risk of stroke and acute coronary syndrome in two case-control studies in the Danish population. AB - INTRODUCTION: Migraine has consistently been associated with increased risk of ischemic stroke, while the evidence for a relation with other types of stroke or coronary outcomes is limited. We examined the association between migraine and stroke and acute coronary syndrome (ACS) subtypes and the influence of potential confounding factors. METHODS: All first-time hospital contacts for stroke (n=155,216) or ACS (n=97,799) were identified in Danish National Patient Registers and matched with 2 control groups of the background population. A hospital diagnosis of migraine and use of migraine medication were the main exposures and associations (odds ratios [OR]) were estimated using multiple logistic regression. Confounding was also addressed by including use of general headache medication as a negative control exposure. RESULTS: The diagnosis of migraine was associated with increased odds of both stroke (ORcrude, age <50 years: 4.80 [95% CI: 3.75-6.21]; ORcrude, age >=50 years:1.91 [95% CI: 1.67 2.19]) and ACS (ORcrude:1.88 [95% CI: 1.53-2.32]), while the ORs for the associations between migraine medication and stroke and ACS were lower. Patients with a diagnosis of migraine or redeemed migraine medication had increased ORs of all stroke subtypes (ischemic, hemorrhagic stroke and transient ischemic attacks). The diagnosis of migraine was also associated with both angina and myocardial infarction (ST-elevation Myocardial Infarction [STEMI], non-STEMI and unspecified) with the highest OR for angina. These associations were not fully explained by adjustment for confounding co-variables or when compared with the negative control exposure that were assumed to be influenced by similar confounding factors, but no shared pathogenesis. CONCLUSION: Hospital-diagnosed migraine was associated with all stroke and ACS subtypes, with ischemic stroke and angina having the highest odds. Confounding did not explain the associations. PMID- 28919820 TI - Prediction models for the mortality risk in chronic dialysis patients: a systematic review and independent external validation study. AB - OBJECTIVE: In medicine, many more prediction models have been developed than are implemented or used in clinical practice. These models cannot be recommended for clinical use before external validity is established. Though various models to predict mortality in dialysis patients have been published, very few have been validated and none are used in routine clinical practice. The aim of the current study was to identify existing models for predicting mortality in dialysis patients through a review and subsequently to externally validate these models in the same large independent patient cohort, in order to assess and compare their predictive capacities. METHODS: A systematic review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. To account for missing data, multiple imputation was performed. The original prediction formulae were extracted from selected studies. The probability of death per model was calculated for each individual within the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD). The predictive performance of the models was assessed based on their discrimination and calibration. RESULTS: In total, 16 articles were included in the systematic review. External validation was performed in 1,943 dialysis patients from NECOSAD for a total of seven models. The models performed moderately to well in terms of discrimination, with C-statistics ranging from 0.710 (interquartile range 0.708 0.711) to 0.752 (interquartile range 0.750-0.753) for a time frame of 1 year. According to the calibration, most models overestimated the probability of death. CONCLUSION: Overall, the performance of the models was poorer in the external validation than in the original population, affirming the importance of external validation. Floege et al's models showed the highest predictive performance. The present study is a step forward in the use of a prediction model as a useful tool for nephrologists, using evidence-based medicine that combines individual clinical expertise, patients' choices, and the best available external evidence. PMID- 28919821 TI - Prevalence of fertility desire and its associated factors among 15- to 49-year old people living with HIV/AIDS in Addis Ababa, Ethiopia: a cross-sectional study design. AB - BACKGROUND: The magnitude of unprotected sex to satisfy the desire for fertility among people living with HIV/AIDS (PLHIV) may rise more due to the availability of antiretroviral therapy (ART) in most HIV-affected countries. This could, however, have the risk of passing on HIV to sexual partners and children. The aim of this study, therefore, was to determine the magnitude and factors associated with the fertility desire of reproductive-age PLHIV in Addis Ababa, Ethiopia, for research-based and timely actions. METHODS: A cross-sectional study was carried out from April to June 2016 among 442 randomly selected, reproductive-age PLHIV who had been attending ART clinics in Addis Ababa. Twelve experienced and trained nurses collected the data. The questionnaire was pretested and interviewer administered, and the interview was executed after obtaining voluntary consent from each study subject. The data were then cleaned and analyzed by using Epi Info version 3.5.4 and SPSS version 20.0, respectively. Binary logistic regression was done in order to describe the association of fertility desire with some sociodemographic and sexual behavior-related factors. RESULTS: Among the total 441 respondents, 54.6% reported the desire for fertility, 87% disclosed their HIV status, 24.3% had two or more sexual partners in the earlier year, and only 55.6% used a condom during their last sexual intercourse. In addition, current health status (AOR=2.03; 95% CI: 1.01-4.07) and partner being tested for HIV (AOR=6.31; 95% CI: 1.35-29.64) showed statistically significant associations with fertility desire during multivariate logistic regression analysis. CONCLUSION: A considerable number of PLHIV in the study area reported a desire for having children. Current health status and partner being tested for HIV were found to be factors associated with the fertility desire among PLHIV. Thus, more efforts to effectively address the health concerns related to fertility desire and risky sexual behavior among HIV-infected people of reproductive age could play a significant role in prevention and control measures against HIV/AIDS epidemic. PMID- 28919822 TI - Uterine sarcoma - current perspectives. AB - Uterine sarcomas comprise a group of rare tumors with differing tumor biology, natural history and response to treatment. Diagnosis is often made following surgery for presumed benign disease. Currently, preoperative imaging does not reliably distinguish between benign leiomyomas and other malignant pathology. Uterine leiomyosarcoma is the most common sarcoma, but other subtypes include endometrial stromal sarcoma (low grade and high grade), undifferentiated uterine sarcoma and adenosarcoma. Clinical trials have shown no definite survival benefit of adjuvant radiotherapy or chemotherapy and have been hampered by the rarity and heterogeneity of these disease types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at sarcoma reference centers. In patients with metastatic disease, systemic chemotherapy can then be considered. There is activity of a number of agents, including doxorubicin, trabectedin, gemcitabine-based chemotherapy, eribulin and pazopanib. Patients should be considered for clinical trial entry where possible. Close international collaboration is important to allow progress in this group of diseases. PMID- 28919824 TI - Strengthening participation by young women sex workers in HIV programs: reflections on a study from Bangkok, Thailand. AB - BACKGROUND: Participation is an accepted means of increasing the effectiveness of public health programs, and as such, it is considered an important component of HIV interventions targeting at-risk youth. The situation of young women sex workers in Thailand is alarming on many fronts, including that of HIV risk. As a result, HIV programs in Thailand are the key interventions undertaken in relation to young women sex workers' health. A small-scale study used semistructured interviews to explore the participation reports of five young women sex workers, as well as the related views of two community support workers, who lived and worked in Bangkok, Thailand. DISCUSSION: This study is considered in the light of current research on - as well as new opportunities and challenges offered for - participation by vulnerable groups in the context of digital society. Thematic analysis of the interview data identified barriers to participation, including the illegality of sex work, fear, and lack of trust of the authorities, as well as widespread social stigma. Such barriers resulted in young women seeking anonymity. Yet, promisingly, young women positioned themselves as experts; they are involved in peer education and are supportive of greater involvement in HIV programs, such as further educational initiatives and collective actions. CONCLUSION: There is a need for a more empowerment-oriented participation practice positioning young women sex workers as expert educators and codecision makers within a model of participation that is also accountable, such as including young women as members of program boards. Beyond current norms, there are new opportunities emerging because of the increasing availability of smartphone/Internet technology. These can support activist and codesign participation by young women sex workers in HIV programs. However, any developments in participation must maximize opportunities carefully, taking into consideration the difficult social environment faced by young women sex workers as well as the need for strategies to address illegality and stigma. PMID- 28919823 TI - Updated approaches for management of uterine fibroids. AB - Uterine anatomy and uterine fibroids (UFs) characteristics have been classically considered as almost a unique issue in gynecology and reproductive medicine. Nowadays, the management of UF pathology is undergoing an important evolution, with the patient's quality of life being the most important aspect to consider. Accordingly, surgical techniques and aggressive treatments are reserved for only those cases with heavy symptomatology, while the clinical diagnostic based on size and number of UFs remains in a second plane in these situations. Moreover, the development of several noninvasive surgical techniques, especially the appearance of ulipristal acetate as a medical etiological treatment, has substantially changed the clinical indications. As a consequence, after almost 2 decades without relevant updates, it has been necessary to update the protocols for the management of UFs in the Spanish Society of Gynecology and Obstetrics twice. Accordingly, we believe that it is necessary to translate our experience to protocolize the medical care for patients with UFs, incorporating these new therapeutic options, and selecting the best treatment for them. We highlight the importance of achieving the patient's goals and decisions by improving the clinical diagnosis for these type of pathologies, allowing enhanced personalized treatments, as well as the reduction of potential risks and unnecessary surgeries. PMID- 28919825 TI - Abdominal sacrocolpopexy with Pelvicol xenograft and concomitant Burch colposuspension. AB - PURPOSE: To evaluate the efficacy of Pelvicol xenograft use during abdominal sacrocolpopexy to repair pelvic organ prolapse (POP). PATIENTS AND METHODS: A total of 27 consecutive women with symptomatic POP were included in this study. A POP-quantification system and International Continence Society classification were used. Functional and anatomical outcomes were assessed. Subjective outcomes and physical activity after surgery were evaluated due to modified quality of life questionnaire. RESULTS: Median follow-up was 21 months (range: 16 to 41 months). Twenty-four (89%) patients were available for anatomical and subjective evaluation. Preoperative POP-quantification classification was: stage I: 11.1%, stage II: 25.9%, stage III: 48.2%, and stage IV: 14.8%. Overall, pad usage significantly decreased (mean 4.8 vs 1 pads, P=0.001). Stress urinary incontinence significantly improved after surgery in nine women (P=0.001). An additional five women were completely continent. No de-novo incontinence developed. Six women with preoperative urinary retention improved in the amount of residual urine postoperative (mean 35 vs 165 mL). Failure rate was 8.3% at 3 and 11 months after surgery, requiring a second reconstruction. There was no graft related complications or graft rejections necessitating removal occurring. Response rate of the questionnaire was 67%. Two women reported no interference in physical activity after 2 postoperative months, five women after 5 months, and five women 1 year later. Pelvic pain (vaginal pain) was partly improved in eight patients, postoperatively, and ten patients had complete resolution of pain after surgery. CONCLUSION: This study demonstrates that abdominal sacrocolpopexy is an effective surgical treatment in correcting POP. The use of Pelvicol is associated with a high recurrence rate and increased failure rate compared to traditional sacrocolpopexy with mesh. Larger clinical trials to evaluate the functional and anatomical outcomes are needed. PMID- 28919826 TI - Forehead galeal pericranial flap for single-staged total upper eyelid reconstruction in sebaceous gland carcinoma excision. AB - PURPOSE: To present a successful case of single-staged total upper eyelid reconstruction after sebaceous gland carcinoma excision by using forehead galeal pericranial flap. OBSERVATIONS: An 80-year-old female with a progressively enlarged left upper eyelid mass presented with ocular irritation, blurred vision, and gritty sensation despite topical antibiotics treatment. This multinodular mass involved the left total upper eyelid, compromised corneal surface integrity, and caused complete ptosis. Excisional biopsy confirmed advanced sebaceous gland carcinoma, which was followed by extensive excision. The resultant total upper eyelid defect was reconstructed by a forehead galeal pericranial flap accompanied by anterior and posterior lamellar grafts. For the 34-month follow-up period, patient remained symptom-free without tumor recurrence and achieved acceptable cosmetic outcome. CONCLUSION: The forehead galeal pericranial flap appears to be effective as single-staged total upper lid reconstruction following extensive sebaceous gland carcinoma excision to restore eyelid function, avoid corneal exposure, and achieve acceptable cosmesis. PMID- 28919827 TI - Is a mechanical-assist device better than manual chest compression? A randomized controlled trial. AB - BACKGROUND: Chest compression quality is a determinant of survival from sudden cardiac arrest. The CPR RsQ Assist Device (CPR RAD) is a new cardiopulmonary resuscitation device for chest compression. It is operated manually but it does not pull up on the chest on the up stroke. The aim of this study was to compare the CPR RAD with standard manual compression in terms of chest compression quality in a manikin model. METHODS: Participants were randomly assigned to either the device or manual chest compression group. Each participant performed a maximum of 4 minutes of hands-only compression with or without the device. During chest compression, the following quality parameters from the manikin were recorded: compression rate, compression depth, and correctness of hand position. RESULTS: Duration of chest compression was significantly higher in device users compared with manual compression (223.93+/-36.53 vs 179.67+/-50.81 seconds; P<0.001). The mean compression depth did not differ in a statistically significant way between manual compression and device at 2 minutes (56.42+/-6.42 vs 54.25+/-5.32; P=0.052). During the first and second minutes, compression rate was higher in cases of standard compression (133.21+/-15.95 vs 108+/-9.45; P<0.001 and 127.41+/-27.77 vs 108.5+/-9.93; P<0.001). There was no statistically significant difference in the percentage of participants who employed compression that was too shallow or exhibited incorrect hand position. CONCLUSION: The CPR RAD is more effective in chest compression compared with manual chest compression, as using the device led to better results in terms of fatigue reduction and correct compression rate than standard manual compression. PMID- 28919828 TI - Jugular bulb oxygen saturation correlates with Full Outline of Responsiveness score in severe traumatic brain injury patients. AB - BACKGROUND: Maintaining brain oxygenation status is the main goal of treatment in severe traumatic brain injury (TBI). Jugular venous oxygen saturation (SjvO2) monitoring is a technique to estimate global balance between cerebral oxygen supply and its metabolic requirement. Full Outline of Responsiveness (FOUR) score, a new consciousness measurement scoring, is expected to become an alternative for Glasgow Coma Scale (GCS) in evaluating neurologic status of patients with severe traumatic head injury, especially for those under mechanical ventilation. METHODS: A total of 63 patients with severe TBI admitted to emergency department (ED) were included in this study. SjvO2 sampling was taken every 24 hours, until 72 hours after arrival. The assessment of FOUR score was conducted directly after each blood sample for SjvO2 was taken. Spearman's rank correlation was used to determine the correlation between SjvO2 and FOUR score. Regression analysis was used to determine mortality predictors. RESULTS: From the 63 patients, a weak positive correlation between SjvO2 and FOUR score (r=0.246, p=0.052) was found upon admission. Meanwhile, strong and moderate negative correlation values were found in 48 hours (r=-0.751, p<0.001) and 72 hours (r= 0.49, p=0.002) after admission. Both FOUR score (p<0.001) and SjvO2 (p=0.04) were found to be independent mortality predictors in severe TBI. CONCLUSION: There was a negative correlation between the value of SjvO2 and FOUR score at 48 and 72 hours after admission. Both SjvO2 and FOUR score are independent mortality predictors in severe TBI. PMID- 28919829 TI - Age- and sex-related changes in hematological parameters in healthy Malawians. AB - AIM: The aim of the study was to determine how values for white blood cell (WBC) counts, hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (mcv), and platelet counts vary with age and sex in healthy Malawians. METHODS: We recruited 660 (316 male and 344 female) participants in 12 different age groups. An ethylenediaminetetraacetic acid-anticoagulated blood sample collected from each participant was analyzed using a hematological analyzer. RESULTS: WBC counts decreased with age with the lowest counts observed in the 20 to <60 years old group. Median WBC counts for 20 to <60 year old females (5.9*109/L) were significantly higher than those for men (4.7*109/L; p=0.015) of the same age. Hb and Hct increased between 5 and 10 years in males and 10 and 15 years in females to adult levels. Males aged 5 to <10 years had significantly higher Hb (13.05 g/dL) and Hct (42.50%) compared to females of the same age (10.40 g/dL and 32.55%, respectively; p<0.0001 for both parameters). Platelet counts in males, which were highest between 3 and 5 years (376*109/L), decreased to lowest counts among 5 to <10 year olds (238*109/L), while in females these decreased from 402*109/L in 6 to <10 years olds to 226*109/L in 10 to <15 year olds. mcv median values were high in neonates reaching a nadir at 13-18 months and then increased throughout life. Females aged 0 to <6 months had significantly higher mcv values (81.85 fL) than males of the same age (69.3 fL; p<0.0001). CONCLUSION: This study provides hematological values according to age and sex that are suitable for reference use in studies among Malawian subjects. PMID- 28919830 TI - Identification of patients with congenital hemophilia in a large electronic health record database. AB - BACKGROUND: Electronic health records (EHRs) are an important source of information with regard to diagnosis and treatment of rare health conditions, such as congenital hemophilia, a bleeding disorder characterized by deficiency of factor VIII (FVIII) or factor IX (FIX). OBJECTIVE: To identify patients with congenital hemophilia using EHRs. DESIGN: An EHR database study. SETTING: EHRs were accessed from Humedica between January 1, 2007, and July 31, 2013. PATIENTS: Selection criteria were applied for an initial ICD-9-CM diagnosis of 286.0 (hemophilia A) or 286.1 (hemophilia B), and confirmation of records 6 months before and 12 months after the first diagnosis. Additional selection criteria included mention of "hemophilia" and "blood" or "bleed" within physician notes identified via natural language processing. RESULTS: A total of 129 males and 35 females were identified as the analysis population. Of those patients for whom both prothrombin time and activated partial thromboplastin time test results were available, only 56% of males and 7% of females exhibited a pattern of test results consistent with congenital hemophilia (normal prothrombin time and prolonged activated partial thromboplastin time). Few patients had a prescription for a hemophilia treatment; males most commonly received Amicar (10.8%) or FVIII (9.0%), whereas females most commonly received DDAVP (11.0%). The most identifiable sites of pain were the chest and the abdomen; 41% of males and 37% of females had joint pain. To evaluate whether patients had been correctly identified with congenital hemophilia, EHRs of 6 patients were reviewed; detailed assessment of their data was found to be inconsistent with a conclusive diagnosis of congenital hemophilia. LIMITATIONS: Inconsistent coding practices may affect data integrity. CONCLUSION: A potentially high number of false positive identifications, particularly among female patients, suggests that ICD-9-CM coding alone may be insufficient to identify patient cohorts. In-depth reviews and multimodal analysis of chart notes may improve data integrity. PMID- 28919831 TI - Flipped classroom model for learning evidence-based medicine. AB - Journal club (JC), as a pedagogical strategy, has long been used in graduate medical education (GME). As evidence-based medicine (EBM) becomes a mainstay in GME, traditional models of JC present a number of insufficiencies and call for novel models of instruction. A flipped classroom model appears to be an ideal strategy to meet the demands to connect evidence to practice while creating engaged, culturally competent, and technologically literate physicians. In this article, we describe a novel model of flipped classroom in JC. We present the flow of learning activities during the online and face-to-face instruction, and then we highlight specific considerations for implementing a flipped classroom model. We show that implementing a flipped classroom model to teach EBM in a residency program not only is possible but also may constitute improved learning opportunity for residents. Follow-up work is needed to evaluate the effectiveness of this model on both learning and clinical practice. PMID- 28919832 TI - Seasonal patterns of oral antihistamine and intranasal corticosteroid purchases from Australian community pharmacies: a retrospective observational study. AB - PURPOSE: To explore patterns in the purchase of prescription and over-the-counter (OTC) oral antihistamines (OAHs) and intranasal corticosteroids (INCSs) by patients, from pharmacies in different geographical regions of Australia. PATIENTS AND METHODS: Retrospective observational study using a database containing anonymous pharmacy transaction data from 20.0% of the pharmacies in Australia that link doctor prescriptions and OTC information. Pharmacy purchases of at least one prescription or OTC rhinitis treatment during 2013 and 2014 were assessed. RESULTS: In total, 4,247,193 prescription and OTC rhinitis treatments were purchased from 909 pharmacies over 12 months. Of treatments purchased, 75.9% were OAHs and 16.6% were INCSs. OTC purchases of both treatments exceeded purchases through prescription. OTC OAHs purchasing patterns were seasonal and almost identical in the Australian Capital Territory, Victoria, Western Australia, South Australia, and New South Wales, and similar seasonal patterns for OTC INCSs were noted in most regions except for South Australia and Tasmania. Prescription purchasing patterns of both OAHs and INCSs remained unchanged throughout the year in most regions. CONCLUSION: This large-scale retrospective observational study identified seasonal purchasing patterns of OTC and prescription OAHs and INCSs in a real-world setting. It highlighted that seasonality only affects OTC purchasing patterns of OAHs and INCSs across Australia and that practitioner prescribing remains unchanged, suggesting that it is only for persistent disease. PMID- 28919833 TI - Conventional culture versus nucleic acid amplification tests for screening of urethral Neisseria gonorrhea infection among asymptomatic men who have sex with men. AB - BACKGROUND: Many methods are used to detect urethral Neisseria gonorrhea (NG) infection among asymptomatic men who have sex with men (MSM). The objective of this study was to define the performance of conventional culture compared to real time polymerase chain reaction (PCR) for diagnosis of asymptomatic urethral gonorrhea among MSM. METHODS: In this cross-sectional study, 147 clinical specimens for NG testing from asymptomatic participants were evaluated. MSM >18 years old who consented to undergo urethral swab and collection of urine samples from two clinics (one was the sexually transmitted diseases (STDs) mobile clinic and the second was the antiretroviral clinic) located in Khon Kaen, Thailand, were recruited. For conventional culture, 147 swab specimens from urethra were analyzed. For real-time PCR, the same samples and collected urine (147 urethral swab and 62 urine) were evaluated. RESULTS: Participants were predominately older aged (mean age: 28.79 years, range: 18-54), asymptomatic (99.3%), and engaged in sex with multiple partners (63% had at least two partners and 36% had at least three partners during the previous 3 months). Twenty-five MSM (17%) had history of STD, mainly human immunodeficiency virus infection. Of the 147 specimens, 42 were positive for NG detected by real-time PCR (prevalence: 28.6%, 95% confidence interval [CI]: 24.8%-32.4%), while none of the 147 MSM were positive for NG detected by conventional culture (prevalence: 0.0%, 95% CI: 0.0%-7.3%). These findings indicated that conventional culture had low sensitivity but high specificity (0.0% and 100%, respectively). We could not demonstrate that many of the factors that were identified in other studies were associated to increased (or decreased) risk of urethral gonococcal infection in our population. CONCLUSION: In asymptomatic MSM, nucleic acid amplification tests are more appropriate for screening of urethral NG infection than conventional culture. However, the culture method is necessary for monitoring emerging antimicrobial resistance and to inform gonorrhea treatment guidelines. PMID- 28919835 TI - High-resolution infrared thermography: a new tool to assess tungiasis-associated inflammation of the skin. AB - BACKGROUND: Tungiasis is highly prevalent in low- and middle-income countries but remains often under diagnosed and untreated eventually leading to chronic sequels. The objective of the study was to assess whether tungiasis-associated inflammation can be detected and quantified by high-resolution infrared thermography (HRIT) and whether after removal of the parasite inflammation resolves rapidly. METHODS: Patients with tungiasis were identified through active case finding. Clinical examination, staging, and thermal imaging as well as conventional photography were performed. In exemplary cases, the embedded sandfly was extracted and regression of inflammation was assessed by thermal imaging 4 days after extraction. RESULTS: The median perilesional temperature was significantly higher than the median temperature of the affected foot (rho = 0.480, p = 0.003). Median perilesional temperature measured by high-resolution infrared thermography was positively associated with the degree of pain (rho = 0.395, p < 0.017) and semi-quantitative scores for acute (rho = 0.380, p < 0.022) and chronic (rho = 0.337, p < 0.044) clinical pathology. Four days after surgical extraction, inflammation and hyperthermia of the affected area regressed significantly (rho = 0.457, p = 0.005). In single cases, when clinical examination was difficult, lesions were identified through HRIT. CONCLUSION: We proved that HRIT is a useful tool to assess tungiasis-associated morbidity as well as regression of clinical pathology after treatment. Additionally, HRIT might help to diagnose hidden and atypical manifestations of tungiasis. Our findings, although still preliminary, suggest that HRIT could be used for a range of infectious skin diseases prevalent in the tropics. TRIAL REGISTRATION: ISRCTN11415557, Registration date: 13 July 2011. PMID- 28919834 TI - Substance use disorders in military veterans: prevalence and treatment challenges. AB - Substance use disorders (SUDs) are a significant problem among our nation's military veterans. In the following overview, we provide information on the prevalence of SUDs among military veterans, clinical characteristics of SUDs, options for screening and evidence-based treatment, as well as relevant treatment challenges. Among psychotherapeutic approaches, behavioral interventions for the management of SUDs typically involve short-term, cognitive-behavioral therapy interventions. These interventions focus on the identification and modification of maladaptive thoughts and behaviors associated with increased craving, use, or relapse to substances. Additionally, client-centered motivational interviewing approaches focus on increasing motivation to engage in treatment and reduce substance use. A variety of pharmacotherapies have received some support in the management of SUDs, primarily to help with the reduction of craving or withdrawal symptoms. Currently approved medications as well as treatment challenges are discussed. PMID- 28919836 TI - Increase in density of genetically diverse invasive Asian shore crab (Hemigrapsus sanguineus) populations in the Gulf of Maine. AB - Hemigrapsus sanguineus, the Asian shore crab, has rapidly replaced Carcinus maenas, the green crab, as the most abundant crab on rocky shores in the northwest Atlantic since its introduction to the United States (USA) in 1988. The northern edge of this progressing invasion is the Gulf of Maine, where Asian shore crabs are only abundant in the south. We compared H. sanguineus population densities to those from published 2005 surveys and quantified genetic variation using the cytochrome c oxidase subunit I gene. We found that the range of H. sanguineus had extended northward since 2005, that population density had increased substantially (at least 10-fold at all sites), and that Asian shore crabs had become the dominant intertidal crab species in New Hampshire and southern Maine. Despite the significant increase in population density of H. sanguineus, populations only increased by a factor of 14 in Maine compared to 70 in southern New England, possibly due to cooler temperatures in the Gulf of Maine. Genetically, populations were predominantly composed of a single haplotype of Japanese, Korean, or Taiwanese origin, although an additional seven haplotypes were found. Six of these haplotypes were of Asian origin, while two are newly described. Large increases in population sizes of genetically diverse individuals in Maine will likely have a large ecological impact, causing a reduction in populations of mussels, barnacles, snails, and other crabs, similar to what has occurred at southern sites with large populations of this invasive crab species. PMID- 28919837 TI - Rethinking the measurement of energy poverty in Europe: A critical analysis of indicators and data. AB - Energy poverty - which has also been recognised via terms such as 'fuel poverty' and 'energy vulnerability' - occurs when a household experiences inadequate levels of energy services in the home. Measuring energy poverty is challenging, as it is a culturally sensitive and private condition, which is temporally and spatially dynamic. This is compounded by the limited availability of appropriate data and indicators, and lack of consensus on how energy poverty should be conceptualised and measured. Statistical indicators of energy poverty are an important and necessary part of the research and policy landscape. They carry great political weight, and are often used to guide the targeting of energy poverty measures - due to their perceived objectivity - with important consequences for both the indoor and built environment of housing. Focussing on the European Union specifically, this paper critically assesses the available statistical options for monitoring energy poverty, whilst also presenting options for improving existing data. This is examined through the lens of vulnerability thinking, by considering the ways in which policies and institutions, the built fabric and everyday practices shape energy use, alongside the manner in which energy poor households experience and address the issue on a day-to-day basis. PMID- 28919838 TI - Adherence to precautions for preventing the transmission of microorganisms in primary health care: a qualitative study. AB - BACKGROUND: Health care associated infections (HAIs) are a source of concern worldwide. No health service in any country can be considered HAI risk-free. However, there is scarcity of data on the risks to which both patients and health workers are subject in non-hospital settings. The aim of this study was to identify issues that determine the adherence of professionals to precautions for preventing transmission of microorganisms in primary health care. METHOD: This was a qualitative study, using focus groups of primary health care staff, in two Brazilian municipalities. The data were analysed using content analysis. RESULTS: Four focus groups were conducted with 20 professionals (11 community health workers, 5 nursing assistants and 4 nurses), and the analysed content was organized into four thematic categories. These categories are: low risk perception, weaknesses in knowledge, insufficient in-service training and infrastructure limitations. Participants expressed their weaknesses in knowledge of standard and transmission based precautions, mainly for hand hygiene and tuberculosis. A lack of appropriate resources and standardization in sharps disposal management was also highlighted by the participants. CONCLUSION: The study points out the need to provide in-service training for professionals on the transmission of microorganisms in primary health care to ensure adequate level of risk perception and knowledge. Further recommendations include investment to improve infrastructure to facilitate adherence to precautions and to minimize the risk of disease transmission for both patients and health care workers. PMID- 28919839 TI - Ground-up-top down: a mixed method action research study aimed at normalising research in practice for nurses and midwives. AB - BACKGROUND: Improving health, patient and system outcomes through a practice based research agenda requires infrastructural supports, leadership and capacity building approaches, at both the individual and organisational levels. Embedding research as normal nursing and midwifery practice requires a flexible approach that is responsive to the diverse clinical contexts within which care is delivered and the variable research skills and interest of clinicians. This paper reports the study protocol for research being undertaken in a Local Health District (LHD) in New South Wales (NSW) Australia. The study aims to evaluate existing nursing and midwifery research activity, culture, capacity and capability across the LHD. This information, in addition to input from key stakeholders will be used to develop a responsive, productive and sustainable research capacity building framework aimed at enculturating practice-based research activities within and across diverse clinical settings of the LHD. METHODS: A three-phased, sequential mixed-methods action research design underpinned by Normalization Process Theory (NPT). Participants will be nursing and midwifery clinicians and managers across rural and metropolitan services. A combination of survey, focus group, individual interviews and peer supported action-learning groups will be used to gather data. Quantitative data will be analysed using descriptive statistics, correlation and regression, together with thematic analysis of qualitative data to produce an integrated report. DISCUSSION: Understanding the current research activity and capacity of nurses and midwives, together with organisational supports and culture is essential to developing a productive and sustainable research environment. However, knowledge alone will not bring about change. This study will move beyond description of barriers to research participation for nurses and midwives and the promulgation of various capacity building frameworks to employ a theory driven action-oriented approach to normalisation of nursing and midwifery research practice. In doing so, our aim is to make possible the utilisation, generation and translation of practice based research that informs improved patient and service delivery outcomes. PMID- 28919840 TI - Leptin independently predicts development of sepsis and its outcome. AB - BACKGROUND: Sepsis is a life-threatening condition and obesity is related to the clinical outcome. The underlying reasons are incompletely understood, but the adipocyte derived hormones leptin and adiponectin may be involved. METHODS: Patients aged 18 years or more with documented first time sepsis events were included in a nested case-referent study if they had participated in previous health surveys. Two matched referents free of known sepsis were identified. Circulating levels of leptin and adiponectin were determined in stored plasma, and their impact on a future sepsis event and its outcome was evaluated. RESULTS: We identified 152 patients (62% women) with a sepsis event and a previous participation in a health survey. Eighty-three % had also blood samples from the acute event. Hyperleptinemia at health survey associated with a future sepsis event (OR 1.77, 95% CI 1.04-3.00) and with hospital death. After adjustment for BMI leptin remained associated with sepsis in men, but not in women. High levels in the acute phase associated with increased risk for in hospital death in women (OR 4.18, 95% CI 1.17-15.00), while being protective in men (OR 0.05, 95% CI 0.01 0.48). Furthermore, leptin increased more from baseline to the acute phase in men than in women. Adiponectin did not predict sepsis and did not relate to outcome. CONCLUSIONS: Hyperleptinemia independently predicted the development of sepsis and an unfavourable outcome in men, and inertia in the acute response related to worse outcome. PMID- 28919841 TI - A Comprehensive Comparison of Multiparty Secure Additions with Differential Privacy. AB - This paper considers the problem of secure data aggregation (mainly summation) in a distributed setting, while ensuring differential privacy of the result. We study secure multiparty addition protocols using well known security schemes: Shamir's secret sharing, perturbation-based, and various encryptions. We supplement our study with our new enhanced encryption scheme EFT, which is efficient and fault tolerant. Differential privacy of the final result is achieved by either distributed Laplace or Geometric mechanism (respectively DLPA or DGPA), while approximated differential privacy is achieved by diluted mechanisms. Distributed random noise is generated collectively by all participants, which draw random variables from one of several distributions: Gamma, Gauss, Geometric, or their diluted versions. We introduce a new distributed privacy mechanism with noise drawn from the Laplace distribution, which achieves smaller redundant noise with efficiency. We compare complexity and security characteristics of the protocols with different differential privacy mechanisms and security schemes. More importantly, we implemented all protocols and present an experimental comparison on their performance and scalability in a real distributed environment. Based on the evaluations, we identify our security scheme and Laplace DLPA as the most efficient for secure distributed data aggregation with privacy. PMID- 28919843 TI - The effects of phenylalanine on exercise-induced fat oxidation: a preliminary, double-blind, placebo-controlled, crossover trial. AB - BACKGROUND: When combined with exercise, dietary amino acid (AA) supplementation is an effective method for accelerating fat mobilization. However, the effects of single AAs combined with exercise on fat oxidation remains unclear. We hypothesized that consumption of a specific amino acid, L- phenylalanine, may result in the secretion of glucagon, and when combined with exercise may promote fat oxidation. METHODS: Six healthy, active male volunteers were randomized in a crossover study to ingest either phenylalanine (3 g/dose) or placebo. Thirty minutes after ingestion each subject performed workload trials on a cycle ergometer for 1 h at 50% of maximal oxygen consumption. RESULTS: Oral intake of phenylalanine caused a significant increase in the concentrations of plasma glycerol and glucagon during exercise. The respiratory exchange ratio was also decreased significantly following ingestion of phenylalanine. CONCLUSION: These results suggested that pre-exercise supplementation of phenylalanine may stimulate whole body fat oxidation. No serious or study-related adverse events were observed. TRIAL REGISTRATION: UMIN000027502 Registered 26 May 2017. Restrospectively registered. PMID- 28919845 TI - Subjective cognitive complaints and objective memory performance influence prompt preference for instrumental activities of daily living. AB - INTRODUCTION: Declines in memory and executive functioning often lead to difficulties completing instrumental activities of daily living (IADLs). Prompting technologies have the potential to help promote aging in place by providing support for the initiation and accurate completion of IADLs. In this study, we evaluate preferences of older adults for different levels of prompting support based on subjective and objective measures of cognitive functioning. METHOD: Participants were 170 community-dwelling older adults split into two cognitive complaint groups: cognitive complaints and few cognitive complaints. After completing six IADL tasks (e.g., organize a pillbox, cook), each participant was asked to make a specific error (e.g., leave stove on) on three of the tasks. They were then prompted to correct the error with one of three different prompt modes: verbal indirect, verbal direct, multimodal verbal direct and video. RESULTS: The cognitive complaints group reported greater preference for the multimodal prompt compared to the few cognitive complaints group. The indirect prompt was the least preferred by both groups. Furthermore, participants who recalled less on objective memory measures preferred more support in terms of prompt mode. Executive functioning did not appear to be related to prompt preference. CONCLUSION: Level of subjective cognitive complaints and objective memory performance may influence amount of support preferred in a prompt. PMID- 28919844 TI - Practical nutritional recovery strategies for elite soccer players when limited time separates repeated matches. AB - Specific guidelines that aim to facilitate the recovery of soccer players from the demands of training and a congested fixture schedule are lacking; especially in relation to evidence-based nutritional recommendations. The importance of repeated high level performance and injury avoidance while addressing the challenges of fixture scheduling, travel to away venues, and training commitments requires a strategic and practically feasible method of implementing specific nutritional strategies. Here we present evidence-based guidelines regarding nutritional recovery strategies within the context of soccer. An emphasis is placed on providing practically applicable guidelines for facilitation of recovery when multiple matches are played within a short period of time (i.e. 48 h). Following match-play, the restoration of liver and muscle glycogen stores (via consumption of ~1.2 g?kg-1?h-1 of carbohydrate) and augmentation of protein synthesis (via ~40 g of protein) should be prioritised in the first 20 min of recovery. Daily intakes of 6-10 g?kg-1 body mass of carbohydrate are recommended when limited time separates repeated matches while daily protein intakes of >1.5 g?kg-1 body mass should be targeted; possibly in the form of multiple smaller feedings (e.g., 6 * 20-40 g). At least 150% of the body mass lost during exercise should be consumed within 1 h and electrolytes added such that fluid losses are ameliorated. Strategic use of protein, leucine, creatine, polyphenols and omega-3 supplements could also offer practical means of enhancing post-match recovery. PMID- 28919846 TI - A Methylidene Group in the Phosphonic Acid Analogue of Phenylalanine Reverses the Enantiopreference of Binding to Phenylalanine Ammonia-Lyases. AB - Aromatic amino acid ammonia-lyases and aromatic amino acid 2,3-aminomutases contain the post-translationally formed prosthetic 3,5-dihydro-4-methylidene-5H imidazol-5-one (MIO) group. MIO enzymes catalyze the stereoselective synthesis of alpha- or beta-amino acid enantiomers, making these chemical processes environmentally friendly and affordable. Characterization of novel inhibitors enables structural understanding of enzyme mechanism and recognizes promising herbicide candidates as well. The present study found that both enantiomers of the aminophosphonic acid analogue of the natural substrate phenylalanine and a novel derivative bearing a methylidene at the beta-position inhibited phenylalanine ammonia-lyases (PAL), representing MIO enzymes. X-ray methods unambiguously determined the absolute configuration of all tested enantiomers during their synthesis. Enzyme kinetic measurements revealed the enantiomer of the methylidene-substituted substrate analogue as being a mirror image relation to the natural l-phenylalanine as the strongest inhibitor. Isothermal titration calorimetry (ITC) confirmed the binding constants and provided a detailed analysis of the thermodynamic driving forces of ligand binding. Molecular docking suggested that binding of the (R)- and (S)-enantiomers is possible by a mirror image packing. PMID- 28919842 TI - International society of sports nutrition position stand: nutrient timing. AB - The International Society of Sports Nutrition (ISSN) provides an objective and critical review regarding the timing of macronutrients in reference to healthy, exercising adults and in particular highly trained individuals on exercise performance and body composition. The following points summarize the position of the ISSN:Nutrient timing incorporates the use of methodical planning and eating of whole foods, fortified foods and dietary supplements. The timing of energy intake and the ratio of certain ingested macronutrients may enhance recovery and tissue repair, augment muscle protein synthesis (MPS), and improve mood states following high-volume or intense exercise.Endogenous glycogen stores are maximized by following a high-carbohydrate diet (8-12 g of carbohydrate/kg/day [g/kg/day]); moreover, these stores are depleted most by high volume exercise.If rapid restoration of glycogen is required (< 4 h of recovery time) then the following strategies should be considered:aggressive carbohydrate refeeding (1.2 g/kg/h) with a preference towards carbohydrate sources that have a high (> 70) glycemic indexthe addition of caffeine (3-8 mg/kg)combining carbohydrates (0.8 g/kg/h) with protein (0.2-0.4 g/kg/h) Extended (> 60 min) bouts of high intensity (> 70% VO2max) exercise challenge fuel supply and fluid regulation, thus carbohydrate should be consumed at a rate of ~30-60 g of carbohydrate/h in a 6-8% carbohydrate-electrolyte solution (6-12 fluid ounces) every 10-15 min throughout the entire exercise bout, particularly in those exercise bouts that span beyond 70 min. When carbohydrate delivery is inadequate, adding protein may help increase performance, ameliorate muscle damage, promote euglycemia and facilitate glycogen re-synthesis.Carbohydrate ingestion throughout resistance exercise (e.g., 3-6 sets of 8-12 repetition maximum [RM] using multiple exercises targeting all major muscle groups) has been shown to promote euglycemia and higher glycogen stores. Consuming carbohydrate solely or in combination with protein during resistance exercise increases muscle glycogen stores, ameliorates muscle damage, and facilitates greater acute and chronic training adaptations.Meeting the total daily intake of protein, preferably with evenly spaced protein feedings (approximately every 3 h during the day), should be viewed as a primary area of emphasis for exercising individuals.Ingestion of essential amino acids (EAA; approximately 10 g)either in free form or as part of a protein bolus of approximately 20-40 g has been shown to maximally stimulate muscle protein synthesis (MPS).Pre- and/or post-exercise nutritional interventions (carbohydrate + protein or protein alone) may operate as an effective strategy to support increases in strength and improvements in body composition. However, the size and timing of a pre-exercise meal may impact the extent to which post-exercise protein feeding is required.Post-exercise ingestion (immediately to 2-h post) of high-quality protein sources stimulates robust increases in MPS.In non-exercising scenarios, changing the frequency of meals has shown limited impact on weight loss and body composition, with stronger evidence to indicate meal frequency can favorably improve appetite and satiety. More research is needed to determine the influence of combining an exercise program with altered meal frequencies on weight loss and body composition with preliminary research indicating a potential benefit.Ingesting a 20-40 g protein dose (0.25-0.40 g/kg body mass/dose) of a high-quality source every three to 4 h appears to most favorably affect MPS rates when compared to other dietary patterns and is associated with improved body composition and performance outcomes.Consuming casein protein (~ 30-40 g) prior to sleep can acutely increase MPS and metabolic rate throughout the night without influencing lipolysis. PMID- 28919848 TI - Hidden Hearing Loss? No Effect of Common Recreational Noise Exposure on Cochlear Nerve Response Amplitude in Humans. AB - This study tested hypothesized relationships between noise exposure and auditory deficits. Both retrospective assessment of potential associations between noise exposure history and performance on an audiologic test battery and prospective assessment of potential changes in performance after new recreational noise exposure were completed. Methods: 32 participants (13M, 19F) with normal hearing (25-dB HL or better, 0.25-8 kHz) were asked to participate in 3 pre- and post exposure sessions including: otoscopy, tympanometry, distortion product otoacoustic emissions (DPOAEs) (f2 frequencies 1-8 kHz), pure-tone audiometry (0.25-8 kHz), Words-in-Noise (WIN) test, and electrocochleography (eCochG) measurements at 70, 80, and 90-dB nHL (click and 2-4 kHz tone-bursts). The first session was used to collect baseline data, the second session was collected the day after a loud recreational event, and the third session was collected 1-week later. Of the 32 participants, 26 completed all 3 sessions. Results: The retrospective analysis did not reveal statistically significant relationships between noise exposure history and any auditory deficits. The day after new exposure, there was a statistically significant correlation between noise "dose" and WIN performance overall, and within the 4-dB signal-to-babble ratio. In contrast, there were no statistically significant correlations between noise dose and changes in threshold, DPOAE amplitude, or AP amplitude the day after new noise exposure. Additional analyses revealed a statistically significant relationship between TTS and DPOAE amplitude at 6 kHz, with temporarily decreased DPOAE amplitude observed with increasing TTS. Conclusions: There was no evidence of auditory deficits as a function of previous noise exposure history, and no permanent changes in audiometric, electrophysiologic, or functional measures after new recreational noise exposure. There were very few participants with TTS the day after exposure - a test time selected to be consistent with previous animal studies. The largest observed TTS was approximately 20-dB. The observed pattern of small TTS suggests little risk of synaptopathy from common recreational noise exposure, and that we should not expect to observe changes in evoked potentials for this reason. No such changes were observed in this study. These data do not support suggestions that common, recreational noise exposure is likely to result in "hidden hearing loss". PMID- 28919847 TI - Sulfated hydrogel matrices direct mitogenicity and maintenance of chondrocyte phenotype through activation of FGF signaling. AB - Deciphering the roles of chemical and physical features of the extracellular matrix (ECM) is vital for developing biomimetic materials with desired cellular responses in regenerative medicine. Here, we demonstrate that sulfation of biopolymers, mimicking the proteoglycans in native tissues, induces mitogenicity, chondrogenic phenotype, and suppresses catabolic activity of chondrocytes, a cell type that resides in a highly sulfated tissue. We show through tunable modification of alginate that increased sulfation of the microenvironment promotes FGF signaling-mediated proliferation of chondrocytes in a three dimensional (3D) matrix independent of stiffness, swelling, and porosity. Furthermore, we show for the first time that a biomimetic hydrogel acts as a 3D signaling matrix to mediate a heparan sulfate/heparin-like interaction between FGF and its receptor leading to signaling cascades inducing cell proliferation, cartilage matrix production, and suppression of de-differentiation markers. Collectively, this study reveals important insights on mimicking the ECM to guide self-renewal of cells via manipulation of distinct signaling mechanisms. PMID- 28919849 TI - Interhemispheric Resting-State Functional Connectivity Predicts Severity of Idiopathic Normal Pressure Hydrocephalus. AB - Idiopathic normal pressure hydrocephalus (iNPH) is characterized by a clinical triad (gait disturbance, dementia, and urinary incontinence), and by radiological findings of enlarged ventricles reflecting disturbance of central spinal fluid circulation. A diagnosis of iNPH is sometimes challenging, and the pathophysiological mechanisms underlying the clinical symptoms of iNPH remain largely unknown. Here, we used an emerging MRI technique, resting-state functional connectivity MRI (rsfcMRI), to develop a subsidiary diagnostic technique and to explore the underlying pathophysiological mechanisms of iNPH. rsfcMRI data were obtained from 11 patients with iNPH and 11 age-matched healthy volunteers, yielding rsfcMRI-derived functional connectivity (FC) from both groups. A linear support vector machine classifier was trained to distinguish the patterns of FCs of the patients with iNPH from those of the healthy volunteers. After dimensional reduction, the support vector machine successfully classified the two groups with an accuracy of 80%. Moreover, we found that rsfcMRI-derived FC carried information to predict the severity of the triad in iNPH. FCs relevant to the classification of severity were mainly based on interhemispheric connectivity, suggesting that disruption of the corpus callosum fibers due to ventricular enlargement may explain the triad of iNPH. The present results support the usefulness of rsfcMRI as a tool to understand pathophysiology of iNPH, and also to help with its clinical diagnosis. PMID- 28919852 TI - Dendritic Properties Control Energy Efficiency of Action Potentials in Cortical Pyramidal Cells. AB - Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na+ entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na+ entry efficiency of somatic AP. Activating inward Ca2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca2+-activated outward K+ current in dendrites, however, decreases Na+ entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na+ influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption. PMID- 28919851 TI - Deficient Sleep in Mouse Models of Fragile X Syndrome. AB - In patients with fragile X syndrome (FXS), sleep problems are commonly observed but are not well characterized. In animal models of FXS (dfmr1 and Fmr1 knockout (KO)/Fxr2 heterozygote) circadian rhythmicity is affected, but sleep per se has not been examined. We used a home-cage monitoring system to assess total sleep time in both light and dark phases in Fmr1 KO mice at different developmental stages. Fmr1 KOs at P21 do not differ from controls, but genotype * phase interactions in both adult (P70 and P180) groups are statistically significant indicating that sleep in Fmr1 KOs is reduced selectively in the light phase compared to controls. Our results show the emergence of abnormal sleep in Fmr1 KOs during the later stages of brain maturation. Treatment of adult Fmr1 KO mice with a GABAB agonist, R-baclofen, did not restore sleep duration in the light phase. In adult (P70) Fmr1 KO/Fxr2 heterozygote animals, total sleep time was further reduced, once again in the light phase. Our data highlight the importance of the fragile X genes (Fmr1 and Fxr2) in sleep physiology and confirm the utility of these mouse models in enhancing our understanding of sleep disorders in FXS. PMID- 28919853 TI - p47Phox/CDK5/DRP1-Mediated Mitochondrial Fission Evokes PV Cell Degeneration in the Rat Dentate Gyrus Following Status Epilepticus. AB - Parvalbumin (PV) is one of the calcium-binding proteins, which plays an important role in the responsiveness of inhibitory neurons to an adaptation to repetitive spikes. Furthermore, PV neurons are highly vulnerable to status epilepticus (SE, prolonged seizure activity), although the underlining mechanism remains to be clarified. In the present study, we found that p47Phox expression was transiently and selectively increased in PV neurons 6 h after SE. This up-regulated p47Phox expression was accompanied by excessive mitochondrial fission. In this time point, CDK5-tyrosine 15 and dynamin-related protein 1 (DRP1)-serine 616 phosphorylations were also increased in PV cells. Apocynin (a p47Phox inhibitor) effectively mitigated PV cell loss via inhibition of CDK5/DRP1 phosphorylations and mitochondrial fragmentation induced by SE. Roscovitine (a CDK5 inhibitor) and Mdivi-1 (a DRP1 inhibitor) attenuated SE-induced PV cell loss by inhibiting aberrant mitochondrial fission. These findings suggest that p47Phox/CDK5/DRP1 may be one of the important upstream signaling pathways in PV cell degeneration induced by SE via excessive mitochondrial fragmentation. PMID- 28919850 TI - The Detection of Phase Amplitude Coupling during Sensory Processing. AB - There is increasing interest in understanding how the phase and amplitude of distinct neural oscillations might interact to support dynamic communication within the brain. In particular, previous work has demonstrated a coupling between the phase of low frequency oscillations and the amplitude (or power) of high frequency oscillations during certain tasks, termed phase amplitude coupling (PAC). For instance, during visual processing in humans, PAC has been reliably observed between ongoing alpha (8-13 Hz) and gamma-band (>40 Hz) activity. However, the application of PAC metrics to electrophysiological data can be challenging due to numerous methodological issues and lack of coherent approaches within the field. Therefore, in this article we outline the various analysis steps involved in detecting PAC, using an openly available MEG dataset from 16 participants performing an interactive visual task. Firstly, we localized gamma and alpha-band power using the Fieldtrip toolbox, and extracted time courses from area V1, defined using a multimodal parcelation scheme. These V1 responses were analyzed for changes in alpha-gamma PAC, using four common algorithms. Results showed an increase in alpha (7-13 Hz)-gamma (40-100 Hz) PAC in response to the visual grating stimulus, though specific patterns of coupling were somewhat dependent upon the algorithm employed. Additionally, post-hoc analyses showed that these results were not driven by the presence of non-sinusoidal oscillations, and that trial length was sufficient to obtain reliable PAC estimates. Finally, throughout the article, methodological issues and practical guidelines for ongoing PAC research will be discussed. PMID- 28919854 TI - PRANAS: A New Platform for Retinal Analysis and Simulation. AB - The retina encodes visual scenes by trains of action potentials that are sent to the brain via the optic nerve. In this paper, we describe a new free access user end software allowing to better understand this coding. It is called PRANAS (https://pranas.inria.fr), standing for Platform for Retinal ANalysis And Simulation. PRANAS targets neuroscientists and modelers by providing a unique set of retina-related tools. PRANAS integrates a retina simulator allowing large scale simulations while keeping a strong biological plausibility and a toolbox for the analysis of spike train population statistics. The statistical method (entropy maximization under constraints) takes into account both spatial and temporal correlations as constraints, allowing to analyze the effects of memory on statistics. PRANAS also integrates a tool computing and representing in 3D (time-space) receptive fields. All these tools are accessible through a friendly graphical user interface. The most CPU-costly of them have been implemented to run in parallel. PMID- 28919855 TI - An Improved Recurrent Neural Network for Complex-Valued Systems of Linear Equation and Its Application to Robotic Motion Tracking. AB - To obtain the online solution of complex-valued systems of linear equation in complex domain with higher precision and higher convergence rate, a new neural network based on Zhang neural network (ZNN) is investigated in this paper. First, this new neural network for complex-valued systems of linear equation in complex domain is proposed and theoretically proved to be convergent within finite time. Then, the illustrative results show that the new neural network model has the higher precision and the higher convergence rate, as compared with the gradient neural network (GNN) model and the ZNN model. Finally, the application for controlling the robot using the proposed method for the complex-valued systems of linear equation is realized, and the simulation results verify the effectiveness and superiorness of the new neural network for the complex-valued systems of linear equation. PMID- 28919857 TI - Divergent Roles of Vascular Burden and Neurodegeneration in the Cognitive Decline of Geriatric Depression Patients and Mild Cognitive Impairment Patients. AB - Both geriatric depression and mild cognitive impairment (MCI) confer an increased risk for the development of dementia. The mechanisms underlying the development of cognitive impairment in geriatric depression patients remain controversial. The present study aimed to explore the association of cognitive decline with vascular risk, white matter hyperintensity (WMH) burden and hippocampal volume in both remitted geriatric depression (RGD) subjects and amnestic mild cognitive impairment (aMCI) subjects. Forty-one RGD subjects, 51 aMCI subjects, and 64 healthy elderly subjects underwent multimodal MRI scans and neuropsychological tests at both baseline and a 35-month follow-up. According to the changing patterns (declining or stable) of global cognitive function during the follow-up period, each group was further divided into a declining subgroup and a stable subgroup. The Framingham 10-year cardiovascular risk, WMH volume and hippocampal volume were measured to assess vascular pathology and neurodegeneration, respectively. The RGD declining group displayed a higher vascular risk and greater WMH volume than the RGD stable group, whereas no such difference was found in the aMCI subjects. In contrast, the aMCI declining group displayed a smaller left hippocampal volume than the aMCI stable group, whereas no such difference was found in the RGD subjects. Furthermore, greater increases in the WHM volume correlated with greater decreases in global cognitive function in the RGD declining group, and greater decreases in the left hippocampal volume correlated with greater decreases in global cognitive function in the aMCI declining group. In conclusion, the cognitive decline in RGD patients is associated with vascular burden, whereas the cognitive decline in aMCI patients is associated with neurodegeneration. These findings could contribute to a better understanding of the specific mechanisms of the development of dementia in each condition. PMID- 28919858 TI - Safety Evaluation of Sclerotium from a Medicinal Mushroom, Lignosus cameronensis (Cultivar): Preclinical Toxicology Studies. AB - Twenty-eight days subacute toxicity studies performed in rats using sclerotial powder of Lignosus cameronensis cultivar was conducted to assess its safety for consumption prior to other scientific investigations on its medicinal benefits, nutraceutical or pharmaceutical application of the mushroom. The study was conducted at 250, 500, and 1000 mg/kg sclerotial powder of L. cameronensis cultivar (n = 5 for each respective dose, on both male and female groups) while control groups received only distilled water. At the end of the study (29th day), the animals were sacrificed followed by blood and organs collection for analysis. Subacute toxicity studies done shows that sclerotial powder of L. cameronensis cultivar at 250, 500, and 1000 mg/kg did not induce treatment related changes on behavioral patterns, gross physical appearance, growth pattern, body weight gain, values of hematological and clinical biochemical panels as well as histopathological findings on kidney, spleen, heart, lung and liver of the experimental rats. The no-observed-adverse-effect level dose for sclerotial powder of L. cameronensis cultivar in 28-days sub-acute toxicity study is determined to be 1000 mg/kg. PMID- 28919856 TI - Visualizing Hyperactivation in Neurodegeneration Based on Prefrontal Oxygenation: A Comparative Study of Mild Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls. AB - Background: Cognitive performance is relatively well preserved during early cognitive impairment owing to compensatory mechanisms. Methods: We explored functional near-infrared spectroscopy (fNIRS) alongside a semantic verbal fluency task (SVFT) to investigate any compensation exhibited by the prefrontal cortex (PFC) in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). In addition, a group of healthy controls (HC) was studied. A total of 61 volunteers (31 HC, 12 patients with MCI and 18 patients with mild AD) took part in the present study. Results: Although not statistically significant, MCI exhibited a greater mean activation of both the right and left PFC, followed by HC and mild AD. Analysis showed that in the left PFC, the time taken for HC to achieve the activation level was shorter than MCI and mild AD (p = 0.0047 and 0.0498, respectively); in the right PFC, mild AD took a longer time to achieve the activation level than HC and MCI (p = 0.0469 and 0.0335, respectively); in the right PFC, HC, and MCI demonstrated a steeper slope compared to mild AD (p = 0.0432 and 0. 0107, respectively). The results were, however, not significant when corrected by the Bonferroni-Holm method. There was also found to be a moderately positive correlation (R = 0.5886) between the oxygenation levels in the left PFC and a clinical measure [Mini-Mental State Examination (MMSE) score] in MCI subjects uniquely. Discussion: The hyperactivation in MCI coupled with a better SVFT performance may suggest neural compensation, although it is not known to what degree hyperactivation manifests as a potential indicator of compensatory mechanisms. However, hypoactivation plus a poorer SVFT performance in mild AD might indicate an inability to compensate due to the degree of structural impairment. Conclusion: Consistent with the scaffolding theory of aging and cognition, the task-elicited hyperactivation in MCI might reflect the presence of compensatory mechanisms and hypoactivation in mild AD could reflect an inability to compensate. Future studies will investigate the fNIRS parameters with a larger sample size, and their validity as prognostic biomarkers of neurodegeneration. PMID- 28919859 TI - The Dietary Constituent Falcarindiol Promotes Cholesterol Efflux from THP-1 Macrophages by Increasing ABCA1 Gene Transcription and Protein Stability. AB - We report increased cholesterol efflux from macrophages in the presence of falcarindiol, an important dietary constituent present in commonly used vegetables and medicinal plants. Falcarindiol (3-20 MUM) increased cholesterol efflux from THP-1-derived macrophages. Western blot analysis showed an increased protein level of ABCA1 upon falcarindiol exposure. Quantitative real-time PCR revealed that also ABCA1 mRNA level rise with falcarindiol (10 MUM) treatment. The effect of falcarindiol on ABCA1 protein as well as mRNA level were counteracted by co-treatment with BADGE, an antagonist of PPARgamma. Furthermore, falcarindiol significantly inhibited ABCA1 protein degradation in the presence of cycloheximide. This post-translational regulation of ABCA1 by falcarindiol occurs most likely by inhibition of lysosomal cathepsins, resulting in decreased proteolysis and extended protein half-life of ABCA1. Taken together, falcarindiol increases ABCA1 protein level by two complementary mechanisms, i.e., promoting ABCA1 gene expression and inhibiting ABCA1 protein degradation, which lead to enhanced cholesterol efflux. PMID- 28919860 TI - A Multidirectional Perspective for Novel Functional Products: In vitro Pharmacological Activities and In silico Studies on Ononis natrix subsp. hispanica. AB - The genus Ononis has important value as traditional drugs and foods. In the present work, we aimed to assess the chemical profiles and biological effects of Ononis natrix subsp. hispanica extracts (ethyl acetate, methanol, and water). For chemical profile, total and individual phenolic components were detected. For biological effects, antioxidant (DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelating assays), enzyme inhibitory (against cholinesterase, tyrosinase, alpha-amylase and alpha-glucosidase), antimicrobial, DNA protection and cytotoxic abilities were tested. The predominant phenolics were apigenin, luteolin, and quercetin in the tested extracts. Generally, the ethyl acetate and methanol extracts were noted as the most active in the antioxidant and enzyme inhibitory assays. Water extract with different concentrations indicated high level of DNA protection activity. Methanol and ethyl acetate extracts showed antibacterial effect against to Staphylococcus aureus and Staphylococcus epidermidis strains. The cytotoxic effects of O. natrix subsp. hispanica extracts on the survival of HeLa and PC3 cells were determined by MTT cell viability assay. Water and methanol extracts caused initiation of apoptosis for PC3 cell line. Furthermore, molecular docking was performed to better understand interactions between dominant phenolic compounds and selected enzymes. Our results clearly indicate that O. natrix subsp. hispanica could be considered a potential candidate for designing novel pharmaceuticals, cosmeceuticals and nutraceuticals. PMID- 28919861 TI - Lactobacillus rhamnosus GG: An Overview to Explore the Rationale of Its Use in Cancer. AB - Cancer is the second leading cause of death in the western world. In the era of precision medicine, a significant number of cancer patients can be cured with several anti-cancer therapeutic regimens. However, therapy failure may be caused by treatment side effects, such as diarrhea, especially occurring in patients with gastrointestinal or pelvic malignancies. In particular, diarrhea is one of the most frequent gastrointestinal toxicity during cancer treatment and it can result from nearly bot chemo- and radio-therapeutic strategies currently used. Diarrhea has a serious impact on patients' quality of life and treatment dosing and schedule modification due to its severity can negatively influence treatment outcomes. In this context, probiotics may play an interesting role in several human diseases with an inflammatory bowel involvement and, among these, Lactobacillus rhamnosus GG (LGG) is one of the most characterized and utilized. In particular, LGG is able to reverse intestinal dysbiosis and moderate diarrhea. Moreover, preclinical studies have documented its effects in reducing chronic inflammation associated with cancer development. This review summarizes the preclinical results of LGG on cancer cells proliferation and tumor invasion as well as the potential role of LGG use in cancer patients for the prevention and management of diarrhea associated with cancer treatment. Overall, these encouraging data support further investigation on the use of LGG in stratified patients undergoing specific therapeutic protocols, including chemotherapy and pelvic radiotherapy, in order to reduce the development of severe diarrhea and thus improve the adherence to the therapy and patients' quality of life. PMID- 28919862 TI - Changes in Dimensionality and Fractal Scaling Suggest Soft-Assembled Dynamics in Human EEG. AB - Humans are high-dimensional, complex systems consisting of many components that must coordinate in order to perform even the simplest of activities. Many behavioral studies, especially in the movement sciences, have advanced the notion of soft-assembly to describe how systems with many components coordinate to perform specific functions while also exhibiting the potential to re-structure and then perform other functions as task demands change. Consistent with this notion, within cognitive neuroscience it is increasingly accepted that the brain flexibly coordinates the networks needed to cope with changing task demands. However, evaluation of various indices of soft-assembly has so far been absent from neurophysiological research. To begin addressing this gap, we investigated task-related changes in two distinct indices of soft-assembly using the established phenomenon of EEG repetition suppression. In a repetition priming task, we assessed evidence for changes in the correlation dimension and fractal scaling exponents during stimulus-locked event-related potentials, as a function of stimulus onset and familiarity, and relative to spontaneous non-task-related activity. Consistent with predictions derived from soft-assembly, results indicated decreases in dimensionality and increases in fractal scaling exponents from resting to pre-stimulus states and following stimulus onset. However, contrary to predictions, familiarity tended to increase dimensionality estimates. Overall, the findings support the view from soft-assembly that neural dynamics should become increasingly ordered as external task demands increase, and support the broader application of soft-assembly logic in understanding human behavior and electrophysiology. PMID- 28919863 TI - Oxygen Uptake Kinetics Is Slower in Swimming Than Arm Cranking and Cycling during Heavy Intensity. AB - Oxygen uptake ([Formula: see text]) kinetics has been reported to be influenced by the activity mode. However, only few studies have compared [Formula: see text]O2 kinetics between activities in the same subjects in which they were equally trained. Therefore, this study compared the [Formula: see text]O2 kinetics response to swimming, arm cranking, and cycling within the same group of subjects within the heavy exercise intensity domain. Ten trained male triathletes (age 23.2 +/- 4.5 years; height 180.8 +/- 8.3 cm; weight 72.3 +/- 6.6 kg) completed an incremental test to exhaustion and a 6-min heavy constant-load test in the three exercise modes in random order. Gas exchange was measured by a breath-by-breath analyzer and the on-transient [Formula: see text]O2 kinetics was modeled using bi-exponential functions. [Formula: see text]O2peak was higher in cycling (65.6 +/- 4.0 ml.kg-1.min-1) than in arm cranking or swimming (48.7 +/- 8.0 and 53.0 +/- 6.7 ml.kg-1.min-1; P < 0.01), but the [Formula: see text]O2 kinetics were slower in swimming (tau1 = 31.7 +/- 6.2 s) than in arm cranking (19.3 +/- 4.2 s; P = 0.001) and cycling (12.4 +/- 3.7 s; P = 0.001). The amplitude of the primary component was lower in both arm cranking and swimming (21.9 +/- 4.7 and 28.4 +/- 5.1 ml.kg-1.min-1) compared with cycling (39.4 +/- 4.1 ml.kg-1.min-1; P = 0.001). Although the gain of the primary component was higher in arm cranking compared with cycling (15.3 +/- 4.2 and 10.7 +/- 1.3 ml.min-1.W 1; P = 0.02), the slow component amplitude, in both absolute and relative terms, did not differ between exercise modes. The slower [Formula: see text]O2 kinetics during heavy-intensity swimming is exercise-mode dependent. Besides differences in muscle mass and greater type II muscle fibers recruitment, the horizontal position adopted and the involvement of trunk and lower-body stabilizing muscles could be additional mechanisms that explain the differences between exercise modalities. PMID- 28919864 TI - beta Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation. AB - The transient outward K+ current, Ito, activates early in the cardiac myocyte action potential, to begin repolarization. Human Ito is generated primarily by two Kv4.3 potassium channel alpha subunit splice variants (Kv4.3L and Kv4.3S) that diverge only by a C-terminal, membrane-proximal, 19-residue stretch unique to Kv4.3L. Protein kinase C (PKC) phosphorylation of threonine 504 within the Kv4.3L-specific 19-residues mediates alpha-adrenergic inhibition of Ito in human heart. Kv4.3 is regulated in human heart by various beta subunits, including cytosolic KChIP2b and transmembrane KCNEs, yet their impact on the functional effects of human Kv4.3 phosphorylation has not been reported. Here, this gap in knowledge was addressed using human Kv4.3 splice variants, T504 mutants, and human beta subunits. Subunits were co-expressed in Xenopus laevis oocytes and analyzed by two-electrode voltage-clamp, using phorbol 12-myristate 13-acetate (PMA) to stimulate PKC. Unexpectedly, KChIP2b removed the inhibitory effect of PKC on Kv4.3L (but not Kv4.3L threonine phosphorylation by PKC per-se), while co expression with KCNE2, but not KCNE4, restored PKC-dependent inhibition of Kv4.3L KChIP2b to quantitatively resemble previously reported effects of alpha adrenergic modulation of human ventricular Ito. In addition, PKC accelerated recovery from inactivation of Kv4.3L-KChIP2b channels and, interestingly, of both Kv4.3L and Kv4.3S alone. Thus, beta subunits regulate the response of human Kv4.3 to PKC phosphorylation and provide a potential mechanism for modifying the response of Ito to alpha-adrenergic regulation in vivo. PMID- 28919865 TI - Coping with Salt Water Habitats: Metabolic and Oxidative Responses to Salt Intake in the Rufous-Collared Sparrow. AB - Many physiological adjustments occur in response to salt intake in several marine taxa, which manifest at different scales from changes in the concentration of individual molecules to physical traits of whole organisms. Little is known about the influence of salinity on the distribution, physiological performance, and ecology of passerines; specifically, the impact of drinking water salinity on the oxidative status of birds has been largely ignored. In this study, we evaluated whether experimental variations in the salt intake of a widely-distributed passerine (Zontotrichia capensis) could generate differences in basal (BMR) and maximum metabolic rates (Msum), as well as affect metabolic enzyme activity and oxidative status. We measured rates of energy expenditure of birds after 30-d acclimation to drink salt (SW) or tap (fresh) water (TW) and assessed changes in the activity of mitochondrial enzymes (cytochrome c oxidase and citrate synthase) in skeletal muscle, heart, and kidney. Finally, we evaluated the oxidative status of bird tissues by means of total antioxidant capacity (TAC) and superoxide dismutase activities and lipid oxidative damage (Malondialdehyde, MDA). The results revealed a significant increase in BMR but not Msum, which resulted in a reduction in factorial aerobic scope in SW- vs. TW-acclimated birds. These changes were paralleled with increased kidney and intestine masses and catabolic activities in tissues, especially in pectoralis muscle. We also found that TAC and MDA concentrations were ~120 and ~400% higher, respectively in the liver of animals acclimated to the SW- vs. TW-treatment. Our study is the first to document changes in the oxidative status in birds that persistently drink saltwater, and shows that they undergo several physiological adjustments that range that range in scale from biochemical capacities (e.g., TAC and MDA) to whole organism traits (e.g., metabolic rates). We propose that the physiological changes observed in Z. capensis acclimated to saltwater could be common phenomena in birds and likely explain selection of prey containing little salt and habitats associated with low salinity. PMID- 28919866 TI - T Wave Safety Margin during the Process of ICD Implantation As a Novel Predictor of T Wave Oversensing. AB - Introduction: T wave oversensing (TWOS) is a major drawback of implantable cardioverter defibrillator (ICD) and data on predictors of TWOS in ICD is limited. We aimed to calculate a novel index of T wave safety margin (TWSM) and assess its potential for evaluating TWOS during the procedure of ICD implantation. Methods and Results: Thirty-two consecutive patients with ICD implantation were enrolled. During each procedure of ICD implantation, different ICD generators were connected to implanted sensing lead through active-fixation leads and bridging cables. R and T wave amplitudes were measured on ICD printouts according to the gain. The ICDs were programed to the most sensitive settings to reveal possible TWOS. A novel index TWSM was calculated according to the corresponding sensing algorithm of ICD. There was discrepancy of R wave amplitudes measured by different ICDs (P < 0.01). In Fortify and Teligen ICDs, T wave amplitudes showed no difference (P > 0.05) and TWSMs were sufficiently high (post sensing: 13.0 +/- 7.6 and 28.3 +/- 16.5, respectively, post pacing: 5.0 +/- 2.2 and 4.6 +/- 0.9, respectively). In nine patients with 10 TWOS episodes detected during the procedure of ICD implantation, generators with the highest TWSM were chosen. Only one TWOS episode during pacing was recorded during the 25 +/- 7 mo follow-up period. Conclusions: We first propose the index of TWSM during ICD implantation as a potentially efficient predictor for TWOS. Evaluation of TWSM might help to reduce TWOS episodes in patients with high risk of TWOS. Prospective studies are warranted to validate this index and its potential to reduce TWOS episodes. PMID- 28919867 TI - Sulfated Cholecystokinin-8 Promotes CD36-Mediated Fatty Acid Uptake into Primary Mouse Duodenal Enterocytes. AB - Cholecystokinin (CCK) is an archetypal incretin hormone secreted by intestinal enteroendocrine cells (EEC) in response to ingested nutrients. The aim of this study was to determine whether CCK modulates enterocyte fatty acid uptake by primary mouse duodenal cells. Exposure of primary mouse duodenal cells to 10 pM sulfated CCK-8 caused a two fold increase in dodecanoic acid fatty acid (FA) uptake. The selective CCK A receptor antagonist loxiglumide (100 MUM) completely abolished the CCK-8 induced FA uptake. The CD36 fatty acid translocase-specific inhibitor sulfo-N-succinimidyl oleate (1 MUM) also completely inhibited CCK-8 induced FA uptake, as did treatment with 200 MUM phloretin. Together these data show CCK induces FA uptake into duodenal enterocytes; this action involves the CCK-RA receptor and is carrier mediated by CD36. PMID- 28919869 TI - Factors Influencing Parents' Preferences and Parents' Perceptions of Child Preferences of Picturebooks. AB - This study examined factors influencing parents' preferences and their perceptions of their children's preferences for picturebooks. First, a content analysis was conducted on a set of picturebooks (N = 87) drawn from the sample described in Wagner (2013); Then, parents (N = 149) rated the books and several content properties were examined for their ability to predict parents' preferences and their perception of their children's preferences. The initial content analysis found correlated clusters of disparate measures of complexity (linguistic, cognitive, narrative) and identified a distinctive sub-genre of modern books featuring female protagonists. The experimental preference analysis found that parents' own preferences were most influenced by the books' age and status; parents' perceptions of their children's preferences were influenced by gender, with parents perceiving their sons (but not daughters) as dis-preferring books with female protagnoists. In addition, influences of the child's reading ability and the linguistic complexity of the book on preferences suggested a sensitivity to the cultural practice of joint book-reading. PMID- 28919868 TI - The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity. AB - Psychologists usually considered the "Self" as an object of experience appearing when the individual perceives its existence within the conscious field. In accordance with such a view, the self-representing capacity of the human mind has been related to corticolimbic learning processes taking place within individual development. On the other hand, Carl Gustav Jung considered the Self as the core of our personality, in its conscious and unconscious aspects, as well as in its actual and potential forms. According to Jung, the Self originates from an inborn dynamic structure integrating the essential drives of our "brain-mind," and leading both to instinctual behavioral actions and to archetypal psychological experiences. Interestingly, recent neuroethological studies indicate that our subjective identity rests on ancient neuropsychic processes that humans share with other animals as part of their inborn constitutional repertoire. Indeed, brain activity within subcortical midline structures (SCMSs) is intrinsically related to the emergence of prototypical affective states, that not only influence our behavior in a flexible way, but alter our conscious field, giving rise to specific feelings or moods, which constitute the first form of self orientation in the world. Moreover, such affective dynamics play a central role in the organization of individual personality and in the evolution of all other (more sophisticated) psychological functions. Therefore, on the base of the convergence between contemporary cutting-edge scientific research and some psychological intuitions of Jung, we intend here to explore the first neuroevolutional layer of human mind, that we call the affective core of the Self. PMID- 28919870 TI - Stress, Time Pressure, Strategy Selection and Math Anxiety in Mathematics: A Review of the Literature. AB - We review how stress induction, time pressure manipulations and math anxiety can interfere with or modulate selection of problem-solving strategies (henceforth "strategy selection") in arithmetical tasks. Nineteen relevant articles were identified, which contain references to strategy selection and time limit (or time manipulations), with some also discussing emotional aspects in mathematical outcomes. Few of these take cognitive processes such as working memory or executive functions into consideration. We conclude that due to the sparsity of available literature our questions can only be partially answered and currently there is not much evidence of clear associations. We identify major gaps in knowledge and raise a series of open questions to guide further research. PMID- 28919872 TI - Follower-Centered Perspective on Feedback: Effects of Feedback Seeking on Identification and Feedback Environment. AB - In the formation mechanism of the feedback environment, the existing research pays attention to external feedback sources and regards individuals as objects passively accepting feedback. Thus, the external source fails to realize the individuals' need for feedback, and the feedback environment cannot provide them with useful information, leading to a feedback vacuum. The aim of this study is to examine the effect of feedback-seeking by different strategies on the supervisor-feedback environment through supervisor identification. The article consists of an empirical study with a sample of 264 employees in China; here, participants complete a series of questionnaires in three waves. After controlling for the effects of demography, the results indicate that supervisor identification partially mediates the relationship between feedback-seeking (including feedback monitoring and feedback inquiry) and the supervisor-feedback environment. Implications are also discussed. PMID- 28919871 TI - Investigating the Neural Correlates of Emotion-Cognition Interaction Using an Affective Stroop Task. AB - The human brain has the capacity to integrate various sources of information and continuously adapts our behavior according to situational needs in order to allow a healthy functioning. Emotion-cognition interactions are a key example for such integrative processing. However, the neuronal correlates investigating the effects of emotion on cognition remain to be explored and replication studies are needed. Previous neuroimaging studies have indicated an involvement of emotion and cognition related brain structures including parietal and prefrontal cortices and limbic brain regions. Here, we employed whole brain event-related functional magnetic resonance imaging (fMRI) during an affective number Stroop task and aimed at replicating previous findings using an adaptation of an existing task design in 30 healthy young adults. The Stroop task is an indicator of cognitive control and enables the quantification of interference in relation to variations in cognitive load. By the use of emotional primes (negative/neutral) prior to Stroop task performance, an emotional variation is added as well. Behavioral in scanner data showed that negative primes delayed and disrupted cognitive processing. Trials with high cognitive demand furthermore negatively influenced cognitive control mechanisms. Neuronally, the emotional primes consistently activated emotion-related brain regions (e.g., amygdala, insula, and prefrontal brain regions) while Stroop task performance lead to activations in cognition networks of the brain (prefrontal cortices, superior temporal lobe, and insula). When assessing the effect of emotion on cognition, increased cognitive demand led to decreases in neural activation in response to emotional stimuli (negative > neutral) within prefrontal cortex, amygdala, and insular cortex. Overall, these results suggest that emotional primes significantly impact cognitive performance and increasing cognitive demand leads to reduced neuronal activation in emotion related brain regions, and therefore support previous findings investigating emotion-cognition interaction in healthy adults. Moreover, emotion and cognition seem to be tightly related to each other, as indicated by shared neural networks involved in both of these processes. Emotion processing, cognitive control, and their interaction are crucial for healthy functioning and a lack thereof is related to psychiatric disorders such as, disruptive behavior disorders. Future studies may investigate the neural characteristics of children and adolescents with disruptive behavior disorders. PMID- 28919873 TI - Evaluation of the Gratitude Questionnaire in a Chinese Sample of Adults: Factorial Validity, Criterion-Related Validity, and Measurement Invariance Across Sex. AB - The Gratitude Questionnaire (GQ; McCullough et al., 2002) is one of the most widely used instruments to assess dispositional gratitude. The purpose of this study was to validate a Chinese version of the GQ by examining internal consistency, factor structure, convergent validity, and measurement invariance across sex. A total of 1151 Chinese adults were recruited to complete the GQ, Positive Affect and Negative Affect Scales, and Satisfaction with Life Scale. Confirmatory factor analysis indicated that the original unidimensional model fitted well, which is in accordance with the findings in Western populations. Furthermore, the GQ had satisfactory composite reliability and criterion-related validity with measures of life satisfaction and affective well-being. Evidence of configural, metric and scalar invariance across sex was obtained. Tests of the latent mean differences found females had higher latent mean scores than males. These findings suggest that the Chinese version of GQ is a reliable and valid tool for measuring dispositional gratitude and can generally be utilized across sex in the Chinese context. PMID- 28919874 TI - The Bodies "at the Forefront": Mentalization, Memory, and Construction of the Self during Adolescence. PMID- 28919875 TI - Psychological Support for Young Adults with Down Syndrome: Dohsa-Hou Program for Maladaptive Behaviors and Internalizing Problems. AB - Psychological and psychiatric dysfunction is a major problem in a substantial proportion of young adults with Down syndrome. Some patients develop psychiatric issues, such as depressive, obsessive-compulsive, or psychotic-like disorders, in their late adolescence or young adulthood. Furthermore, these individuals may experience moderate to severe emotional and psychological distress. Development of a psychosocial treatment to address these issues is needed in addition to psychotropic medication. The current study reports two cases of young adults with Down syndrome, who presented psychiatric symptoms and marked disruption in their daily lives. These individuals participated in a Dohsa-hou treatment program. Following treatment, adaptive levels, maladaptive behaviors, and internalizing problems were evaluated by the Vineland Adaptive Behavior Scales-II. Participants showed improvement in maladaptive behaviors and internalizing problems; however, improvement in these areas may be influenced by baseline severity of the problems. This case report suggests that Dohsa-hou could be an effective therapeutic approach for maladaptive and internalizing problems in adults with Down syndrome. PMID- 28919876 TI - Peptide Composition of Stroke Causing Emboli Correlate with Serum Markers of Atherosclerosis and Inflammation. AB - INTRODUCTION: The specific protein composition of stroke-causing emboli is unknown. Because ischemic stroke has a varied etiology, it is possible that the composition of the thrombus from which an embolus originated will have distinctive molecular characteristics reflective of the underlying pathophysiology. We used mass spectrometry to evaluate the protein composition of retrieved emboli from patients with differing stroke etiologies and correlated the protein levels to serum predictors of atherosclerosis. METHODS: Emboli from 20 consecutive acute stroke patients were retrieved by thrombectomy during routine stroke care. Thrombus proteins were extracted, digested, and multidimensional fractionation of peptides was performed. Fractionated peptides underwent nano-liquid chromatography with tandem mass spectrometry. Spectra were searched using Mascot software in which results with p < 0.05 (95% confidence interval) were considered significant and indicating identity. The results were correlated to A1C, low-density lipoprotein (LDL), and erythrocyte sedimentation rate (ESR) taken on admission. RESULTS: Eleven patients had atrial fibrillation, four had significant proximal vessel atherosclerosis, two were cryptogenic, and three had other identified stroke risk factors (left ventricular thrombus, dissection, endocarditis). Eighty-one common proteins (e.g., hemoglobin, fibrin, actin) were found in all 20 emboli. Serum LDL levels correlated with Septin-2 (rs = 0.78, p = 0.028), Phosphoglycerate Kinase 1 (rs = 0.75, p = 0.036), Integrin Alpha-M (rs = 0.68, p = 0.033) and Glucose-6-phosphate dehydrogenase (rs = 0.63, p = 0.05). Septin-7 levels inversely correlated to ESR (rs = -0.84, p = 0.01). No significant protein correlations to A1C or tPA use were found. CONCLUSION: Our exploratory study presents mass spectrometry analysis of thrombi retrieved from acute stroke patients and correlates the thrombus proteome to clinical features of the patient. Notably, we found proteins associated with inflammation (e.g., Integrin Alpha-M) in emboli from patients with high LDL. Although these findings are tempered by a small sample size, we provide preliminary support for the feasibility of utilizing proteomic analysis of emboli to discover proteins that may be used as markers for stroke etiology. PMID- 28919877 TI - Analysis of Correlation between an Accelerometer-Based Algorithm for Detecting Parkinsonian Gait and UPDRS Subscales. AB - BACKGROUND: Our group earlier developed a small monitoring device, which uses accelerometer measurements to accurately detect motor fluctuations in patients with Parkinson's (On and Off state) based on an algorithm that characterizes gait through the frequency content of strides. To further validate the algorithm, we studied the correlation of its outputs with the motor section of the Unified Parkinson's Disease Rating Scale part-III (UPDRS-III). METHOD: Seventy-five patients suffering from Parkinson's disease were asked to walk both in the Off and the On state while wearing the inertial sensor on the waist. Additionally, all patients were administered the motor section of the UPDRS in both motor phases. Tests were conducted at the patient's home. Convergence between the algorithm and the scale was evaluated by using the Spearman's correlation coefficient. RESULTS: Correlation with the UPDRS-III was moderate (rho -0.56; p < 0.001). Correlation between the algorithm outputs and the gait item in the UPDRS III was good (rho -0.73; p < 0.001). The factorial analysis of the UPDRS-III has repeatedly shown that several of its items can be clustered under the so-called Factor 1: "axial function, balance, and gait." The correlation between the algorithm outputs and this factor of the UPDRS-III was -0.67 (p < 0.01). CONCLUSION: The correlation achieved by the algorithm with the UPDRS-III scale suggests that this algorithm might be a useful tool for monitoring patients with Parkinson's disease and motor fluctuations. PMID- 28919879 TI - Automated Online Quantification Method for 18F-FDG Positron Emission Tomography/CT Improves Detection of the Epileptogenic Zone in Patients with Pharmacoresistant Epilepsy. AB - AIMS: To assess the validity of an online method to quantitatively evaluate cerebral hypometabolism in patients with pharmacoresistant focal epilepsy as a complement to the visual analysis of the 18F-FDG positron emission tomography (PET)/CT exam. METHODS: A total of 39 patients with pharmacoresistant epilepsy and probable focal cortical dysplasia [22 patients with frontal lobe epilepsy (FLE) and 17 with temporal lobe epilepsy (TLE)] underwent a presurgical evaluation including EEG, video-EEG, MRI, and 18F-FDG PET/CT. We conducted the automated quantification of their 18F-FDG PET/CT data and compared the results with those of the visual-PET analysis conducted by experienced nuclear medicine physicians. For each patient group, we calculated Cohen's Kappa coefficient for the visual and quantitative analyses, as well as each method's sensitivity, specificity, and positive and negative predictive values. RESULTS: For the TLE group, both the visual and quantitative analyses showed high agreement. Thus, although the quantitative analysis could be used as a complement, the visual analysis on its own was consistent and precise. For the FLE group, on the other hand, the visual analysis categorized almost half of the cases as normal, revealing very low agreement. For those patients, the quantitative analysis proved critical to identify the focal hypometabolism characteristic of the epileptogenic zone. Our results suggest that the quantitative analysis of 18F-FDG PET/CT data is critical for patients with extratemporal epilepsies, and especially those with subtle MRI findings. Furthermore, it can easily be used during the routine clinical evaluation of 18F-FDG PET/CT exams. SIGNIFICANCE: Our results show that quantification of 18F-FDG PET is an informative complementary method that can be added to the routine visual evaluation of patients with subtle lesions, particularly those in the frontal lobes. PMID- 28919878 TI - Postural Control in Bilateral Vestibular Failure: Its Relation to Visual, Proprioceptive, Vestibular, and Cognitive Input. AB - Patients with bilateral vestibular failure (BVF) suffer from postural and gait unsteadiness with an increased risk of falls. The aim of this study was to elucidate the differential role of otolith, semicircular canal (SSC), visual, proprioceptive, and cognitive influences on the postural stability of BVF patients. Center-of-pressure displacements were recorded by posturography under six conditions: target visibility; tonic head positions in the pitch plane; horizontal head shaking; sensory deprivation; dual task; and tandem stance. Between-group analysis revealed larger postural sway in BVF patients on eye closure; but with the eyes open, BVF did not differ from healthy controls (HCs). Head tilts and horizontal head shaking increased sway but did not differ between groups. In the dual task condition, BVF patients maintained posture indistinguishable from controls. On foam and tandem stance, postural sway was larger in BVF, even with the eyes open. The best predictor for the severity of bilateral vestibulopathy was standing on foam with eyes closed. Postural control of our BVF was indistinguishable from HCs once visual and proprioceptive feedback is provided. This distinguishes them from patients with vestibulo-cerebellar disorders or functional dizziness. It confirms previous reports and explains that postural unsteadiness of BVF patients can be missed easily if not examined by conditions of visual and/or proprioceptive deprivation. In fact, the best predictor for vestibular hypofunction (VOR gain) was examining patients standing on foam with the eyes closed. Postural sway in that condition increased with the severity of vestibular impairment but not with disease duration. In the absence of visual control, impaired otolith input destabilizes BVF with head retroflexion. Stimulating deficient SSC does not distinguish patients from controls possibly reflecting a shift of intersensory weighing toward proprioceptive-guided postural control. Accordingly, proprioceptive deprivation heavily destabilizes BVF, even when visual control is provided. PMID- 28919881 TI - Genomic and Transcriptomic Analysis of Growth-Supporting Dehalogenation of Chlorinated Methanes in Methylobacterium. AB - Bacterial adaptation to growth with toxic halogenated chemicals was explored in the context of methylotrophic metabolism of Methylobacterium extorquens, by comparing strains CM4 and DM4, which show robust growth with chloromethane and dichloromethane, respectively. Dehalogenation of chlorinated methanes initiates growth-supporting degradation, with intracellular release of protons and chloride ions in both cases. The core, variable and strain-specific genomes of strains CM4 and DM4 were defined by comparison with genomes of non-dechlorinating strains. In terms of gene content, adaptation toward dehalogenation appears limited, strains CM4 and DM4 sharing between 75 and 85% of their genome with other strains of M. extorquens. Transcript abundance in cultures of strain CM4 grown with chloromethane and of strain DM4 grown with dichloromethane was compared to growth with methanol as a reference C1 growth substrate. Previously identified strain specific dehalogenase-encoding genes were the most transcribed with chlorinated methanes, alongside other genes encoded by genomic islands (GEIs) and plasmids involved in growth with chlorinated compounds as carbon and energy source. None of the 163 genes shared by strains CM4 and DM4 but not by other strains of M. extorquens showed higher transcript abundance in cells grown with chlorinated methanes. Among the several thousand genes of the M. extorquens core genome, 12 genes were only differentially abundant in either strain CM4 or strain DM4. Of these, 2 genes of known function were detected, for the membrane-bound proton translocating pyrophosphatase HppA and the housekeeping molecular chaperone protein DegP. This indicates that the adaptive response common to chloromethane and dichloromethane is limited at the transcriptional level, and involves aspects of the general stress response as well as of a dehalogenation-specific response to intracellular hydrochloric acid production. Core genes only differentially abundant in either strain CM4 or strain DM4 total 13 and 58 CDS, respectively. Taken together, the obtained results suggest different transcriptional responses of chloromethane- and dichloromethane-degrading M. extorquens strains to dehalogenative metabolism, and substrate- and pathway-specific modes of growth optimization with chlorinated methanes. PMID- 28919880 TI - Non-Mammalian Vertebrates: Distinct Models to Assess the Role of Ion Gradients in Energy Expenditure. AB - Animals store metabolic energy as electrochemical gradients. At least 50% of mammalian energy is expended to maintain electrochemical gradients across the inner mitochondrial membrane (H+), the sarcoplasmic reticulum (Ca++), and the plasma membrane (Na+/K+). The potential energy of these gradients can be used to perform work (e.g., transport molecules, stimulate contraction, and release hormones) or can be released as heat. Because ectothermic species adapt their body temperature to the environment, they are not constrained by energetic demands that are required to maintain a constant body temperature. In fact, ectothermic species expend seven to eight times less energy than similarly sized homeotherms. Accordingly, ectotherms adopt low metabolic rates to survive cold, hypoxia, and extreme bouts of fasting that would result in energy wasting, lactic acidosis and apoptosis, or starvation in homeotherms, respectively. Ectotherms have also evolved unique applications of ion gradients to allow for localized endothermy. Endothermic avian species, which lack brown adipose tissue, have been integral in assessing the role of H+ and Ca++ cycling in skeletal muscle thermogenesis. Accordingly, the diversity of non-mammalian vertebrate species allows them to serve as unique models to better understand the role of ion gradients in heat production, metabolic flux, and adaptation to stressors, including obesity, starvation, cold, and hypoxia. PMID- 28919882 TI - Effects of Soil Pre-Treatment with Basamid(r) Granules, Brassica juncea, Raphanus sativus, and Tagetes patula on Bacterial and Fungal Communities at Two Apple Replant Disease Sites. AB - Nurseries producing apple and rose rootstock plants, apple orchards as well as rose production often experience replanting problems after several cultivations at the same site when a chemical soil disinfectant is not applied. The etiology of apple and rose replanting problems is most likely caused by soil-borne pathogen complex, defined as "replant disease (RD)". Symptoms typical of RD are reduced shoot and root growth, a smaller leaf area, a significant decrease in plant biomass, yield and fruit quality and a shorter life span. In our previous study, we showed that RD symptoms were reduced when apple rootstock M106 were grown in RD soils treated either with the soil fumigant Basamid or after biofumigation by incorporating Brassica juncea or Raphanus sativus or by growing Tagetes under field conditions compared to untreated control soil. The present study aimed at identifying potential bacterial and fungal taxa that were affected by different soil treatments and linking bacterial and fungal responders to plant performance. Miseq(r) Illumina(r) sequencing of 16S rRNA gene fragments (bacteria) and ITS regions (fungi) amplified from total community DNA extracted from soil samples taken 4 weeks after treatments were performed. Soil properties and culture history of the two RD sites greatly influenced soil microbiomes. Several bacterial genera were identified that significantly increased in treated soils such as Arthrobacter (R. sativus, both sites), Curtobacterium (Basamid, both sites), Terrimonas (Basamid and R. sativus, site A) and Ferruginibacter (B. juncea, site K and R. sativus, site A) that were also significantly and positively correlated with growth of apple M106 plants. Only few fungal genera, such as Podospora, Monographella and Mucor, were significantly promoted in soils treated with B. juncea and R. sativus (both sites). The least pronounced changes were recorded for bacterial as well as fungal communities in the RD soils planted with Tagetes. The detection of bacterial and fungal genera that were significantly increased in relative abundance in response to the treatments and that were positively correlated with plant growth suggests that management of the soil microbial community could contribute to overcome the apple RD encountered at affected sites. PMID- 28919883 TI - A PCR-Based Assay Targeting the Major Capsid Protein Gene of a Dinorna-Like ssRNA Virus That Infects Coral Photosymbionts. AB - The coral-Symbiodinium association is a critical component of coral reefs as it is the main primary producer and builds the reef's 3-dimensional structure. A breakdown of this endosymbiosis causes a loss of the dinoflagellate photosymbiont, Symbiodinium, and/or its photosynthetic pigments from the coral tissues (i.e., coral bleaching), and can lead to coral mortality. Coral bleaching has mostly been attributed to environmental stressors, and in some cases to bacterial infection. Viral lysis of Symbiodinium has been proposed as another possible cause of some instances of coral bleaching, but this hypothesis has not yet been experimentally confirmed. In this study, we used coral virome data to develop a novel PCR-based assay for examining the presence and diversity of a single-stranded RNA (ssRNA) virus by targeting its major capsid protein (MCP) gene. Illumina sequence analysis of amplicons obtained with novel primers showed 99.8% of the reads had the closest taxonomic affinity with the MCP gene of the virus, Heterocapsa circularisquama RNA virus (HcRNAV) known to infect dinoflagellates, indicating that dinorna-like viruses are commonly associated with corals on the Great Barrier Reef. A phylogenetic analysis of MCP gene sequences revealed strong coral species specificity of viral operational taxon units (OTUs). This assay allows a relatively easy and rapid evaluation of the presence and diversity of this particular viral group and will assist in enhancing our understanding of the role of viral lysis in coral bleaching. PMID- 28919887 TI - Complete Circular Genome Sequence and Temperature Independent Adaptation to Anaerobiosis of Listeria weihenstephanensis DSM 24698. AB - The aim of this study was to analyze the adaptation of the environmental Listeria weihenstephanensis DSM 24698 to anaerobiosis. The complete circular genome sequence of this species is reported and the adaptation of L. weihenstephanensis DSM 24698 to oxygen availability was investigated by global transcriptional analyses via RNAseq at 18 and 34 degrees C. A list of operons was created based on the transcriptional data. Forty-two genes were upregulated anaerobically and 62 genes were downregulated anaerobically. The oxygen dependent gene expression of selected genes was further validated via qPCR. Many of the differentially regulated genes encode metabolic enzymes indicating broad metabolic adaptations with respect to oxygen availability. Genes showing the strongest oxygen-dependent adaption encoded nitrate (narGHJI) and nitrite (nirBD) reductases. Together with the observation that nitrate supported anaerobic growth, these data indicate that L. weihenstephanensis DSM 24698 performs anaerobic nitrate respiration. The wide overlap between the oxygen-dependent transcriptional regulation at 18 and 34 degrees C suggest that temperature does not play a key role in the oxygen dependent transcriptional regulation of L. weihenstephanensis DSM 24698. PMID- 28919886 TI - DNA Adenine Methyltransferase (Dam) Overexpression Impairs Photorhabdus luminescens Motility and Virulence. AB - Dam, the most described bacterial DNA-methyltransferase, is widespread in gamma proteobacteria. Dam DNA methylation can play a role in various genes expression and is involved in pathogenicity of several bacterial species. The purpose of this study was to determine the role played by the dam ortholog identified in the entomopathogenic bacterium Photorhabdus luminescens. Complementation assays of an Escherichia coli dam mutant showed the restoration of the DNA methylation state of the parental strain. Overexpression of dam in P. luminescens did not impair growth ability in vitro. In contrast, compared to a control strain harboring an empty plasmid, a significant decrease in motility was observed in the dam overexpressing strain. A transcriptome analysis revealed the differential expression of 208 genes between the two strains. In particular, the downregulation of flagellar genes was observed in the dam-overexpressing strain. In the closely related bacterium Xenorhabdus nematophila, dam overexpression also impaired motility. In addition, the dam-overexpressing P. luminescens strain showed a delayed virulence compared to that of the control strain after injection in larvae of the lepidopteran Spodoptera littoralis. These results reveal that Dam plays a major role during P. luminescens insect infection. PMID- 28919888 TI - The Sporothrix schenckii Gene Encoding for the Ribosomal Protein L6 Has Constitutive and Stable Expression and Works as an Endogenous Control in Gene Expression Analysis. AB - Sporothrix schenckii is one of the causative agents of sporotrichosis, a worldwide-distributed mycosis that affects humans and other mammals. The interest in basic and clinical features of this organism has significantly increased in the last years, yet little progress in molecular aspects has been reported. Gene expression analysis is a set of powerful tools that helps to assess the cell response to changes in the extracellular environment, the genetic networks controlling metabolic pathways, and the adaptation to different growth conditions. Most of the quantitative methodologies used nowadays require data normalization, and this is achieved measuring the expression of endogenous control genes. Reference genes, whose expression is assumed to suffer minimal changes regardless the cell morphology, the stage of the cell cycle or the presence of harsh extracellular conditions are commonly used as controls in Northern blotting assays, microarrays, and semi-quantitative or quantitative RT PCR. Since the biology of the organisms is usually species specific, it is difficult to find a reliable group of universal genes that can be used as controls for data normalization in experiments addressing the gene expression, regardless the taxonomic classification of the organism under study. Here, we compared the transcriptional stability of the genes encoding for elongation factor 1A, Tfc1, a protein involved in transcription initiation on Pol III promoters, ribosomal protein L6, histone H2A, beta-actin, beta-tubulin, glyceraldehyde 3-phosphate dehydrogenase, UAF30, the upstream activating factor 30, and the transcription initiation factor TFIID subunit 10, during the fungal growth in different culture media and cell morphologies. Our results indicated that only the gene encoding for the ribosomal protein L6 showed a stable and constant expression. Furthermore, it displayed not transcriptional changes when S. schenckii infected larvae of Galleria mellonella or interacted with immune cells. Therefore, this gene could be used as control for data normalization in expression assays. As a proof of concept, this gene was used to assess the expression of genes encoding for glycosidases involved in the protein N-linked glycosylation pathway, a histidine kinase whose expression is regulated during the fungal dimorphism, and a glycosidase that participates in sucrose assimilation. PMID- 28919885 TI - Trypanosoma cruzi Evades the Complement System as an Efficient Strategy to Survive in the Mammalian Host: The Specific Roles of Host/Parasite Molecules and Trypanosoma cruzi Calreticulin. AB - American Trypanosomiasis is an important neglected reemerging tropical parasitism, infecting about 8 million people worldwide. Its agent, Trypanosoma cruzi, exhibits multiple mechanisms to evade the host immune response and infect host cells. An important immune evasion strategy of T. cruzi infective stages is its capacity to inhibit the complement system activation on the parasite surface, avoiding opsonizing, immune stimulating and lytic effects. Epimastigotes, the non infective form of the parasite, present in triatomine arthropod vectors, are highly susceptible to complement-mediated lysis while trypomastigotes, the infective form, present in host bloodstream, are resistant. Thus T. cruzi susceptibility to complement varies depending on the parasite stage (amastigote, trypomastigotes or epimastigote) and on the T. cruzi strain. To avoid complement mediated lysis, T. cruzi trypomastigotes express on the parasite surface a variety of complement regulatory proteins, such as glycoprotein 58/68 (gp58/68), T. cruzi complement regulatory protein (TcCRP), trypomastigote decay-accelerating factor (T-DAF), C2 receptor inhibitor trispanning (CRIT) and T. cruzi calreticulin (TcCRT). Alternatively, or concomitantly, the parasite captures components with complement regulatory activity from the host bloodstream, such as factor H (FH) and plasma membrane-derived vesicles (PMVs). All these proteins inhibit different steps of the classical (CP), alternative (AP) or lectin pathways (LP). Thus, TcCRP inhibits the CP C3 convertase assembling, gp58/68 inhibits the AP C3 convertase, T-DAF interferes with the CP and AP convertases assembling, TcCRT inhibits the CP and LP, CRIT confers ability to resist the CP and LP, FH is used by trypomastigotes to inhibit the AP convertases and PMVs inhibit the CP and LP C3 convertases. Many of these proteins have similar molecular inhibitory mechanisms. Our laboratory has contributed to elucidate the role of TcCRT in the host-parasite interplay. Thus, we have proposed that TcCRT is a pleiotropic molecule, present not only in the parasite endoplasmic reticulum, but also on the trypomastigote surface, participating in key processes to establish T. cruzi infection, such as inhibition of the complement system and serving as an important virulence factor. Additionally, TcCRT interaction with key complement components, participates as an anti-angiogenic and anti-tumor molecule, inhibiting at least in important part, tumor growth in infected animals. PMID- 28919889 TI - Dehalococcoides as a Potential Biomarker Evidence for Uncharacterized Organohalides in Environmental Samples. AB - The massive production and improper disposal of organohalides resulted in worldwide contamination in soil and water. However, their environmental survey based on chromatographic methods was hindered by challenges in testing the extremely wide variety of organohalides. Dehalococcoides as obligate organohalide respiring bacteria exclusively use organohalides as electron acceptors to support their growth, of which the presence could be coupled with organohalides and, therefore, could be employed as a biomarker of the organohalide pollution. In this study, Dehalococcoides was screened in various samples of bioreactors and subsurface environments, showing the wide distribution of Dehalococcoides in sludge and sediment. Further laboratory cultivation confirmed the dechlorination activities of those Dehalococcoides. Among those samples, Dehalococcoides accounting for 1.8% of the total microbial community was found in an anaerobic granular sludge sample collected from a full-scale bioreactor treating petroleum wastewater. Experimental evidence suggested that the influent wastewater in the bioreactor contained bromomethane which support the growth of Dehalococcoides. This study demonstrated that Dehalococcoides could be employed as a promising biomarker to test the present of organohalides in wastestreams or other environmental samples. PMID- 28919884 TI - Secretome of Intestinal Bacilli: A Natural Guard against Pathologies. AB - Current studies of human gut microbiome usually do not consider the special functional role of transient microbiota, although some of its members remain in the host for a long time and produce broad spectrum of biologically active substances. Getting into the gastrointestinal tract (GIT) with food, water and probiotic preparations, two representatives of Bacilli class, genera Bacillus and Lactobacillus, colonize epithelium blurring the boundaries between resident and transient microbiota. Despite their minor proportion in the microbiome composition, these bacteria can significantly affect both the intestinal microbiota and the entire body thanks to a wide range of secreted compounds. Recently, insufficiency and limitations of pure genome-based analysis of gut microbiota became known. Thus, the need for intense functional studies is evident. This review aims to characterize the Bacillus and Lactobacillus in GIT, as well as the functional roles of the components released by these members of microbial intestinal community. Complex of their secreted compounds is referred by us as the "bacillary secretome." The composition of the bacillary secretome, its biological effects in GIT and role in counteraction to infectious diseases and oncological pathologies in human organism is the subject of the review. PMID- 28919890 TI - Pathobiomes Differ between Two Diseases Affecting Reef Building Coralline Algae. AB - Crustose coralline algae (CCA) are major benthic calcifiers that play crucial roles in coral reef ecosystems. Two diseases affecting CCA have recently been investigated: coralline white band syndrome (CWBS) and coralline white patch disease (CWPD). These diseases can trigger major losses in CCA cover on tropical coral reefs, but their causative agents remain unknown. Here, we provide data from the first investigation of the bacterial communities associated with healthy and diseased CCA tissues. We show that Neogoniolithon mamillare diseased tissues had distinct microbial communities compared to healthy tissues and demonstrate that CWBS and CWPD were associated with different pathobiomes, indicating that they had different disease causations. CWBS tissues were composed of opportunistic bacteria, and the origin of the disease was undetermined. In contrast, a vibrio related to Vibrio tubiashii characterized the CWPD pathobiome, suggesting that it could be a putative disease agent and supporting the case of a temperature dependent disease associated with global warming. PMID- 28919891 TI - Moderate-Intensity Exercise Affects Gut Microbiome Composition and Influences Cardiac Function in Myocardial Infarction Mice. AB - Physical exercise is commonly regarded as protective against cardiovascular disease (CVD). Recent studies have reported that exercise alters the gut microbiota and that modification of the gut microbiota can influence cardiac function. Here, we focused on the relationships among exercise, the gut microbiota and cardiac function after myocardial infarction (MI). Four-week-old C57BL/6J mice were exercised on a treadmill for 4 weeks before undergoing left coronary artery ligation. Cardiac function was assessed using echocardiography. Gut microbiomes were evaluated post-exercise and post-MI using 16S rRNA gene sequencing on an Illumina HiSeq platform. Exercise training inhibited declines in cardiac output and stroke volume in post-MI mice. In addition, physical exercise and MI led to alterations in gut microbial composition. Exercise training increased the relative abundance of Butyricimonas and Akkermansia. Additionally, key operational taxonomic units were identified, including 24 lineages (mainly from Bacteroidetes, Barnesiella, Helicobacter, Parabacteroides, Porphyromonadaceae, Ruminococcaceae, and Ureaplasma) that were closely related to exercise and cardiac function. These results suggested that exercise training improved cardiac function to some extent in addition to altering the gut microbiota; therefore, they could provide new insights into the use of exercise training for the treatment of CVD. PMID- 28919892 TI - Serum-Mediated Oxidative Stress from Systemic Sclerosis Patients Affects Mesenchymal Stem Cell Function. AB - OBJECTIVES: Properties of mesenchymal stromal/stem cells (MSCs) from systemic sclerosis (SSc) patients have been reported to be altered. MSC-based therapy may therefore rely on the use of allogeneic MSCs from healthy subjects. Here, we investigated whether heterologous MSCs could exhibit altered properties following exposure to oxidative environment of SSc sera. METHODS: Human bone marrow-derived MSCs were cultured in the presence of various sera: control human serum AB (SAB), SAB with HOCl-induced AOPPs at 400 or 1,000 umol/L (SAB400 or SAB1000, respectively), or H2O2-induced AOPPs or SSc patient serum (PS). Proliferation, apoptosis, and senescence rates of MSCs were evaluated after 3, 6, and 10 days in culture. Reactive oxygen species and nitric oxide production were quantified at 24 h. Trilineage potential of differentiation was tested after 21 days in specific culture conditions and immunosuppressive function measured in a T lymphocyte proliferative assay. RESULTS: In the presence of oxidative environment of PS, MSCs retained their proliferative potential and survived for at least the first 3 days of exposure, while the number of senescent MSCs increased at day 6 and apoptosis rate at day 10. Exposure to PS enhanced the antioxidant capacity of MSCs, notably the expression of SOD2 antioxidant gene. By contrast, the osteoblastic/adipogenic potential of MSCs was increased, whereas their immunosuppressive function was slightly reduced. DISCUSSION: Although some functional properties of MSCs were affected upon culture with PS, evidence from preclinical studies and the present one suggested that MSCs can adapt to the oxidative environment and exert their therapeutic effect. PMID- 28919893 TI - RIPK3/Fas-Associated Death Domain Axis Regulates Pulmonary Immunopathology to Cryptococcal Infection Independent of Necroptosis. AB - Fas-associated death domain (FADD) and receptor interacting protein kinase 3 (RIPK3) are multifunctional regulators of cell death and immune response. Using a mouse model of cryptococcal infection, the roles of FADD and RIPK3 in anti cryptococcal defense were investigated. Deletion of RIPK3 alone led to increased inflammatory cytokine production in the Cryptococcus neoformans-infected lungs, but in combination with FADD deletion, it led to a robust Th1-biased response with M1-biased macrophage activation. Rather than being protective, these responses led to paradoxical C. neoformans expansion and rapid clinical deterioration in Ripk3-/- and Ripk3-/-Fadd-/- mice. The increased mortality of Ripk3-/- and even more accelerated mortality in Ripk3-/-Fadd-/- mice was attributed to profound pulmonary damage due to neutrophil-dominant infiltration with prominent upregulation of pro-inflammatory cytokines. This phenomenon was partially associated with selective alterations in the apoptotic frequency of some leukocyte subsets, such as eosinophils and neutrophils, in infected Ripk3-/ Fadd-/- mice. In conclusion, our study shows that RIPK3 in concert with FADD serve as physiological "brakes," preventing the development of excessive inflammation and Th1 bias, which in turn contributes to pulmonary damage and defective fungal clearance. This novel link between the protective effect of FADD and RIPK3 in antifungal defense and sustenance of immune homeostasis may be important for the development of novel immunomodulatory therapies against invasive fungal infections. PMID- 28919894 TI - Potentiation of Natural Killer Cells for Cancer Immunotherapy: A Review of Literature. AB - It is widely acknowledged that the human immune system plays a crucial role in preventing the formation and progression of innumerable types of cancer (1). The mechanisms by which this occurs are numerous, including contributions from both the innate and adaptive immune systems. As such, immunotherapy has long been believed to be an auspicious solution in the treatment of malignancy (2). Recent research has highlighted the promise of natural killer (NK) cells as a more directed immunotherapy approach. This paper will focus on the methods of potentiation of NK cells for their use in cancer therapy. PMID- 28919896 TI - VHH-Based Bispecific Antibodies Targeting Cytokine Production. AB - Proinflammatory cytokines, such as TNF, IL-6, and IL-1, play pathogenic roles in multiple diseases and are attractive targets for biologic drugs. Because proinflammatory cytokines possess non-redundant protective and immunoregulatory functions, their systemic neutralization carries the potential for unwanted side effects. Therefore, next-generation anti-cytokine therapies would seek to selectively neutralize pathogenic cytokine signaling, leaving normal function intact. Fortunately, the biology of proinflammatory cytokines provides several such opportunities. Here, we discuss various applications of bispecific antibodies targeting cytokines with specific focus on selective TNF neutralization targeted directly to the surface of specific populations of monocytes and macrophages. These bispecific antibodies combine an anti-TNF VHH with VHHs or scFvs directed against abundant surface molecules on myeloid cells and serve to limit the bioavailability of TNF produced by these cells. Such reagents may become prototypes of a novel class of anti-cytokine biologics. PMID- 28919897 TI - Altered Immune Activation and IL-23 Signaling in Response to Candida albicans in Autoimmune Polyendocrine Syndrome Type 1. AB - OBJECTIVE: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, childhood onset disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis (CMC) is one of the three major disease components and is, to date, mainly explained by the presence of neutralizing auto antibodies against cytokines [interleukin (IL)-17A, IL-17F, and IL-22] from T helper 17 cells, which are critical for the protection against fungal infections. However, patients without current auto-antibodies also present CMC and we, therefore, hypothesized that other immune mechanisms contribute to CMC in APS-1. METHODS: Whole blood was stimulated with Candida albicans (C. albicans) in a standardized assay, and immune activation was investigated by analyzing 46 secreted immune mediators. Then, peripheral blood mononuclear cells were stimulated with curdlan, a Dectin-1 agonist and IL-23 inducer, and the IL-23p19 response in monocytes was analyzed by flow cytometry. RESULTS: We found an altered immune response in APS-1 patients compared with healthy controls. Patients fail to increase the essential ILs, such as IL-2, IL-17A, IL-22, and IL 23, when stimulating whole blood with C. albicans. A significantly altered IL 23p19 response was detected in patients' monocytes upon stimulation with curdlan. CONCLUSION: APS-1 patients have an altered immune response to C. albicans including a dysregulation of IL-23p19 production in monocytes. This probably contributes to the selective susceptibility to CMC found in the majority of patients. PMID- 28919895 TI - Mind the Gaps in Tumor Immunity: Impact of Connexin-Mediated Intercellular Connections. AB - Gap junctions (GJs)-mediated intercellular communications (GJICs) are connexin (Cx)-formed plasma membrane channels that allow for the passage of small molecules between adjacent cells, and are involved in several physiopathological processes, including immune responses against cancer. In general, tumor cells are poorly coupled through GJs, mainly due to low Cx expression or reduced channel activity, suggesting that Cxs may have tumor suppressor roles. However, more recent data indicate that Cxs and/or GJICs may also in some cases promote tumor progression. This dual role of Cx channels in tumor outcome may be due, at least partially, to the fact that GJs not only interconnect cells from the same type, such as cancer cells, but also promote the intercellular communication of tumor cells with different types of cells from their microenvironment, and such diverse intercellular interactions have distinctive impact on tumor development. For example, whereas GJ-mediated interactions among tumor cells and microglia have been implicated in promotion of tumor growth, tumor cells delivery to dendritic cells of antigenic peptides through GJs have been associated with enhanced immune mediated tumor elimination. In this review, we provide an updated overview on the role of GJICs in tumor immunity, focusing on the pro-tumor and antitumor effect of GJs occurring among tumor and immune cells. Accumulated data suggest that GJICs may act as tumor suppressors or enhancers depending on whether tumor cells interact predominantly with antitumor immune cells or with stromal cells. The complex modulation of immune-tumor cell GJICs should be taken into consideration in order to potentiate current cancer immunotherapies. PMID- 28919898 TI - Chitosan Increases Tomato Root Colonization by Pochonia chlamydosporia and Their Combination Reduces Root-Knot Nematode Damage. AB - The use of biological control agents could be a non-chemical alternative for management of Meloidogyne spp. [root-knot nematodes (RKN)], the most damaging plant-parasitic nematodes for horticultural crops worldwide. Pochonia chlamydosporia is a fungal parasite of RKN eggs that can colonize endophytically roots of several cultivated plant species, but in field applications the fungus shows a low persistence and efficiency in RKN management. The combined use of P. chlamydosporia with an enhancer could help its ability to develop in soil and colonize roots, thereby increasing its efficiency against nematodes. Previous work has shown that chitosan enhances P. chlamydosporia sporulation and production of extracellular enzymes, as well as nematode egg parasitism in laboratory bioassays. This work shows that chitosan at low concentrations (up to 0.1 mg ml-1) do not affect the viability and germination of P. chlamydosporia chlamydospores and improves mycelial growth respect to treatments without chitosan. Tomato plants irrigated with chitosan (same dose limit) increased root weight and length after 30 days. Chitosan irrigation increased dry shoot and fresh root weight of tomato plants inoculated with Meloidogyne javanica, root length when they were inoculated with P. chlamydosporia, and dry shoot weight of plants inoculated with both P. chlamydosporia and M. javanica. Chitosan irrigation significantly enhanced root colonization by P. chlamydosporia, but neither nematode infection per plant nor fungal egg parasitism was affected. Tomato plants cultivated in a mid-suppressive (29.3 +/- 4.7% RKN egg infection) non-sterilized clay loam soil and irrigated with chitosan had enhanced shoot growth, reduced RKN multiplication, and disease severity. Chitosan irrigation in a highly suppressive (73.7 +/- 2.6% RKN egg infection) sterilized-sandy loam soil reduced RKN multiplication in tomato. However, chitosan did not affect disease severity or plant growth irrespective of soil sterilization. Chitosan, at an adequate dose, can be a potential tool for sustainable management of RKN. PMID- 28919900 TI - Preliminary Studies to Characterize the Temporal Variation of Micronutrient Composition of the Above Ground Organs of Maize and Correlated Uptake Rates. AB - The improvement of agronomic practices and the use of high technology in field crops contributes for significant increases in maize productivity, and may have altered the dynamics of nutrient uptake and partition by the plant. Official recommendations for fertilizer applications to the maize crop in Brazil and in many countries are based on critical soil nutrient contents and are relatively outdated. Since the factors that interact in an agricultural production system are dynamic, mathematical modeling of the growth process turns out to be an appropriate tool for these studies. Agricultural modeling can expand our knowledge about the interactions prevailing in the soil-plant-atmosphere system. The objective of this study is to propose a methodology for characterizing the micronutrient composition of different organs and their extraction, and export during maize crop development, based on modeling nutrient uptake, crop potential evapotranspiration and micronutrient partitioning in the plant, considering the production environment. This preliminary characterization study (experimental growth analysis) considers the temporal variation of the micronutrient uptake rate in the aboveground organs, which defines crop needs and the critical nutrient content of the soil solution. The methodology allowed verifying that, initially, the highest fraction of dry matter, among aboveground organs, was assigned to the leaves. After the R1 growth stage, the largest part of dry matter was partitioned to the stalk, which in this growth stage is the main storage organ of the maize plant. During the reproductive phase, the highest fraction of dry matter was conferred to the reproductive organs, due to the high demand for carbohydrates for grain filling. The micronutrient (B, Cu, Fe, Mn, and Zn) content follows a power model, with higher values for the initial growth stages of development and leveling off to minimum values at the R6 growth stage. The proposed model allows to verify that fertilizer recommendations should be related to the temporal variability of micronutrient absorption rates, in contrast to the classic recommendation based on the critical soil micronutrient content. The maximum micronutrient absorption rates occur between the reproductive R4 and R5 growth stages. These evaluations allowed to predict the maximum micronutrient requirements, considered equal to respective stalk sap concentrations. PMID- 28919899 TI - Emerging Roles and Landscape of Translating mRNAs in Plants. AB - Plants use a wide range of mechanisms to adapt to different environmental stresses. One of the earliest responses displayed under stress is rapid alterations in stress responsive gene expression that has been extensively analyzed through expression profiling such as microarrays and RNA-sequencing. Recently, expression profiling has been complemented with proteome analyses to establish a link between transcriptional and the corresponding translational changes. However, proteome profiling approaches have their own technical limitations. More recently, ribosome-associated mRNA profiling has emerged as an alternative and a robust way of identifying translating mRNAs, which are a set of mRNAs associated with ribosomes and more likely to contribute to proteome abundance. In this article, we briefly review recent studies that examined the processes affecting the abundance of translating mRNAs, their regulation during plant development and tolerance to stress conditions and plant factors affecting the selection of translating mRNA pools. This review also highlights recent findings revealing differential roles of alternatively spliced mRNAs and their translational control during stress adaptation. Overall, better understanding of processes involved in the regulation of translating mRNAs has obvious implications for improvement of stress tolerance in plants. PMID- 28919901 TI - Introgression of Shoot Fly (Atherigona soccata L. Moench) Resistance QTLs into Elite Post-rainy Season Sorghum Varieties Using Marker Assisted Backcrossing (MABC). AB - Shoot fly (Atherigona soccata L. Moench) is a serious pest in sorghum production. Management of shoot fly using insecticides is expensive and environmentally un safe. Developing host-plant resistance is the best method to manage shoot fly infestation. Number of component traits contribute for imparting shoot fly resistance in sorghum and molecular markers have been reported which were closely linked to QTLs controlling these component traits. In this study, three QTLs associated with shoot fly resistance were introgressed into elite cultivars Parbhani Moti (= SPV1411) and ICSB29004 using marker assisted backcrossing (MABC). Crosses were made between recurrent parents and the QTL donors viz., J2658, J2614, and J2714. The F1s after confirmation for QTL presence were backcrossed to recurrent parents and the resultant lines after two backcrosses were selfed thrice for advancement. The foreground selection was carried out in F1 and BCnF1 generations with 22 polymorphic markers. Forty-three evenly distributed simple sequence repeat markers in the sorghum genome were used in background selection to identify plants with higher recurrent parent genome recovery. By using two backcrosses and four rounds of selfing, six BC2F4 progenies were selected for ICSB29004 * J2658, five BC2F4 progenies were selected for ICSB29004 * J2714 and six BC2F4 progenies were selected for Parbhani Moti * J2614 crosses. Phenotyping of these lines led to the identification of two resistant lines for each QTL region present on chromosome SBI-01, SBI-07 and SBI 10 in ICSB 29004 and Parbhani Moti. All the introgression lines (ILs) showed better shoot fly resistance than the recurrent parents and their agronomic performance was the same or better than the recurrent parents. Further, the ILs had medium plant height, desirable maturity with high yield potential which makes them better candidates for commercialization. In the present study, MABC has successfully improved the shoot fly resistance in sorghum without a yield penalty. This is the first report on the use of MABC for improving shoot fly resistance in post-rainy season sorghum. PMID- 28919903 TI - The Role of Soil Solarization in India: How an Unnoticed Practice Could Support Pest Control. AB - Plant protection represents one of the strategies to fill the yield gap and to achieve food security, a key topic for India development. Analysis of climate risks for crops indicates that South Asia is one of the regions most exposed to the adverse impact on many plants that are relevant to inhabitants exposed to food safety risks. Furthermore, accumulation of pesticide residues in the aquatic and other ecosystems is becoming a significant threat in India. These perspectives require to develop programs of crop protection that can be feasible according to Indian rural development and pollution policy. Here we review the research works done on soil solarization in India. Soil solarization (also called plasticulture) is an eco-friendly soil disinfestations method for managing soil borne plant pathogens. This is the process of trapping solar energy by moist soil covered with transparent polyethylene films and chemistry, biology and physical properties of soil are involved in pest control. So far, this technique is applied in more than 50 countries, mostly in hot and humid regions. India has 29 states and these states fall under five climatic zones, from humid to arid ones. We report pest management application in different climatic zones and their effects on production, weeds, nematodes, and pathogenic microorganisms. The analysis of soil temperatures and crop protection results indicate as environmental requirement for soil solarization fits in most of Indian rural areas. Soil solarization is compatible with future Indian scenarios and may support Indian national food security programs. PMID- 28919902 TI - Expression Differences of Pigment Structural Genes and Transcription Factors Explain Flesh Coloration in Three Contrasting Kiwifruit Cultivars. AB - Fruits of kiwifruit cultivars (Actinidia chinensis and A. deliciosa) generally have green or yellow flesh when ripe. A small number of genotypes have red flesh but this coloration is usually restricted to the inner pericarp. Three kiwifruit cultivars having red ('Hongyang'), or yellow ('Jinnong-2'), or green ('Hayward') flesh were investigated for their color characteristics and pigment contents during development and ripening. The results show the yellow of the 'Jinnong-2' fruit is due to the combined effects of chlorophyll degradation and of beta carotene accumulation. The red inner pericarps of 'Hongyang' fruit are due to anthocyanin accumulation. Expression differences of the pathway genes in the inner pericarps of the three different kiwifruits suggest that stay-green (SGR) controls the degradation of chlorophylls, while lycopene beta-cyclase (LCY-beta) controls the biosynthesis of beta-carotene. The abundance of anthocyanin in the inner pericarps of the 'Hongyang' fruit is the results of high expressions of UDP flavonoid glycosyltransferases (UFGT). At the same time, expressions of anthocyanin transcription factors show that AcMYBF110 expression parallels changes in anthocyanin concentration, so seems to be a key R2R3 MYB, regulating anthocyanin biosynthesis. Further, transient color assays reveal that AcMYBF110 can autonomously induce anthocyanin accumulation in Nicotiana tabacum leaves by activating the transcription of dihydroflavonol 4-reductase (NtDFR), anthocyanidin synthase (NtANS) and NtUFGT. For basic helix-loop-helix proteins (bHLHs) and WD-repeat proteins (WD40s), expression differences show these may depend on AcMYBF110 forming a MYB-bHLH-WD40 complex to regulate anthocyanin biosynthesis, instead of it having a direct involvement. PMID- 28919904 TI - Plasticity of Sorghum Stem Biomass Accumulation in Response to Water Deficit: A Multiscale Analysis from Internode Tissue to Plant Level. AB - Sorghum is increasingly used as a biomass crop worldwide. Its genetic diversity provides a large range of stem biochemical composition suitable for various end uses as bioenergy or forage. Its drought tolerance enables it to reasonably sustain biomass production under water limited conditions. However, drought effect on the accumulation of sorghum stem biomass remains poorly understood which limits progress in crop improvement and management. This study aimed at identifying the morphological, biochemical and histological traits underlying biomass accumulation in the sorghum stem and its plasticity in response to water deficit. Two hybrids (G1, G4) different in stem biochemical composition (G4, more lignified, less sweet) were evaluated during 2 years in the field in Southern France, under two water treatments differentiated during stem elongation (irrigated; 1 month dry-down until an average soil water deficit of -8.85 bars). Plant phenology was observed weekly. At the end of the water treatment and at final harvest, plant height, stem and leaf dry-weight and the size, biochemical composition and tissue histology of internodes at 2-4 positions along the stem were measured. Stem biomass accumulation was significantly reduced by drought (in average 42% at the end of the dry-down). This was due to the reduction of the length, but not diameter, of the internodes expanded during water deficit. These internodes had more soluble sugar but lower lignin and cellulose contents. This was associated with a decrease of the areal proportion of lignified cell wall in internode outer zone whereas the areal proportion of this zone was not affected. All internodes for a given genotype and environment followed a common histochemical dynamics. Hemicellulose content and the areal proportion of inner vs. outer internode tissues were set up early during internode growth and were not drought responsive. G4 exhibited a higher drought sensitivity than G1 for plant height only. At final harvest, the stem dry weight was only 18% lower in water deficit (re-watered) compared to well-watered treatment and internodes growing during re-watering were similar to those on the well-watered plants. These results are being valorized to refine the phenotyping of sorghum diversity panels and breeding populations. PMID- 28919905 TI - Candidate Reference Genes Selection and Application for RT-qPCR Analysis in Kenaf with Cytoplasmic Male Sterility Background. AB - Cytoplasmic male sterility (CMS) is a maternally inherited trait that results in the production of dysfunctional pollen. Based on reliable reference gene normalized real-time quantitative PCR (RT-qPCR) data, examining gene expression profile can provide valuable information on the molecular mechanism of kenaf CMS. However, studies have not been conducted regarding selection of reference genes for normalizing RT-qPCR data in the CMS and maintainer lines of kenaf crop. Therefore, we studied 10 candidate reference genes (ACT3, ELF1A, G6PD, PEPKR1, TUB, TUA, CYP, GAPDH, H3, and 18S) to assess their expression stability at three stages of pollen development in CMS line 722A and maintainer line 722B of kenaf. Five computational statistical approaches (GeNorm, NormFinder, DeltaCt, BestKeeper, and RefFinder) were used to evaluate the expression stability levels of these genes. According to RefFinder and GeNorm, the combination of TUB, CYP, and PEPKR1 was identified as an internal control for the accurate normalization across all sample set, which was further confirmed by validating the expression of HcPDIL5-2a. Furthermore, the combination of TUB, CYP, and PEPKR1 was used to differentiate the expression pattern of five mitochondria F1F0-ATPase subunit genes (atp1, atp4, atp6, atp8, and atp9) by RT-qPCR during pollen development in CMS line 722A and maintainer line 722B. We found that atp1, atp6, and atp9 exhibited significantly different expression patterns during pollen development in line 722A compared with line 722B. This is the first systematic study of reference genes selection for CMS and will provide useful information for future research on the gene expressions and molecular mechanisms underlying CMS in kenaf. PMID- 28919906 TI - Screening for Natural Inhibitors of Topoisomerases I from Rhamnus davurica by Affinity Ultrafiltration and High-Performance Liquid Chromatography-Mass Spectrometry. AB - Topoisomerase I (Topo I) catalyzes topological interconversion of duplex DNA during DNA replication and transcription, and has been deemed as important antineoplastic targets. In this study, the fraction R.d-60 from ethyl acetate extracts of Rhamnus davurica showed higher inhibitory rates against SGC-7901 and HT-29 compared with the R.d-30 fraction in vitro. However, the specific active components of R.d-60 fraction remain elusive. To this end, a method based on bio affinity ultrafiltration and high performance liquid chromatography/electrospray mass spectrometry (HPLC- ESI-MS/MS) was developed to rapidly screen and identify the Topo I inhibitors in this fraction. The enrichment factors (EFs) were calculated to evaluate the binding affinities between the bioactive constituents and Topo I. As a result, eight ligands were identified and six of which with higher EFs showed more potential antitumor activity. Furthermore, antiproliferative assays in vitro (IC50 values) with two representative candidates (apigenin, quercetin) against SGC-7901, HT-29 and Hep G2 cells were conducted and further validated. Finally, the structure-activity relationships revealed that flavones contain a C2-C3 double bond of C ring exhibited higher bio affinities to Topo I than those without it. This integrated method combining Topo I ultrafiltration with HPLC-MS/MS proved to be very efficient in rapid screening and identification of potential Topo I inhibitors from the complex extracts of medicinal plants, and could be further explored as a valuable high-throughput screening platform in the early drug discovery stage. PMID- 28919907 TI - Heterotrimeric G Protein-Regulated Ca2+ Influx and PIN2 Asymmetric Distribution Are Involved in Arabidopsis thaliana Roots' Avoidance Response to Extracellular ATP. AB - Extracellular ATP (eATP) has been reported to be involved in plant growth as a primary messenger in the apoplast. Here, roots of Arabidopsis thaliana seedlings growing in jointed medium bent upon contact with ATP-containing medium to keep away from eATP, showing a marked avoidance response. Roots responded similarly to ADP and bz-ATP but did not respond to AMP and GTP. The eATP avoidance response was reduced in loss-of-function mutants of heterotrimeric G protein alpha subunit (Galpha) (gpa1-1 and gpa1-2) and enhanced in Galpha-over-expression (OE) lines (wGalpha and cGalpha). Ethylenebis(oxyethylenenitrilo) tetraacetic acid (EGTA) and Gd3+ remarkably suppressed eATP-induced root bending. ATP-stimulated Ca2+ influx was impaired in Galpha null mutants and increased in its OE lines. DR5-GFP and PIN2 were asymmetrically distributed in ATP-stimulated root tips, this effect was strongly suppressed by EGTA and diminished in Galpha null mutants. In addition, some eATP-induced genes' expression was also impaired in Galpha null mutants. Based on these results, we propose that heterotrimeric Galpha-regulated Ca2+ influx and PIN2 distribution may be key signaling events in eATP sensing and avoidance response in Arabidopsis thaliana roots. PMID- 28919908 TI - Hepatic S6K1 Partially Regulates Lifespan of Mice with Mitochondrial Complex I Deficiency. AB - The inactivation of ribosomal protein S6 kinase 1 (S6K1) recapitulates aspects of caloric restriction and mTORC1 inhibition to achieve prolonged longevity in invertebrate and mouse models. In addition to delaying normative aging, inhibition of mTORC1 extends the shortened lifespan of yeast, fly, and mouse models with severe mitochondrial disease. Here we tested whether disruption of S6K1 can recapitulate the beneficial effects of mTORC1 inhibition in the Ndufs4 knockout (NKO) mouse model of Leigh Syndrome caused by Complex I deficiency. These NKO mice develop profound neurodegeneration resulting in brain lesions and death around 50-60 days of age. Our results show that liver-specific, as well as whole body, S6K1 deletion modestly prolongs survival and delays onset of neurological symptoms in NKO mice. In contrast, we observed no survival benefit in NKO mice specifically disrupted for S6K1 in neurons or adipocytes. Body weight was reduced in WT mice upon disruption of S6K1 in adipocytes or whole body, but not altered when S6K1 was disrupted only in neurons or liver. Taken together, these data indicate that decreased S6K1 activity in liver is sufficient to delay the neurological and survival defects caused by deficiency of Complex I and suggest that mTOR signaling can modulate mitochondrial disease and metabolism via cell non-autonomous mechanisms. PMID- 28919909 TI - Photorefractive keratectomy in the management of postradial keratotomy hyperopia and astigmatism. AB - BACKGROUND: The aim of this study is to evaluate the results of photorefractive keratectomy (PRK) in the management of postoperative hyperopia and astigmatism in patients with history of radial keratotomy (RK). MATERIALS AND METHODS: This prospective nonrandomized noncomparative interventional case series enrolled consecutive eyes treated with PRK after RK. In cases, in which (1) wavefront (WF) scan was undetectable during primary examinations; and/or, (2) WF data were not transferable to the excimer laser device, patients were treated with the tissue saving (TS) mode. Patients with detectable/transferable WF were assigned to WF guided advanced personalized treatment (APT). RESULTS: Thirty-two and 47 eyes were managed by APT and TS modes, respectively. Pooled analysis of both APT and TS groups showed improvement in uncorrected distant visual acuity and corrected distant visual acuity. The amount of sphere, cylinder, corneal cylinder, spherical equivalent, defocus equivalent, and total aberration showed improvement as well. CONCLUSION: PRK seems to bring favorable outcome and safety profile in the management of post-RK hyperopia and astigmatism. It is crucial for practitioners to warn their patients about the fact that they may still have progressive refractive instability regardless of their choice on the laser method of vision correction. PMID- 28919910 TI - Chloroma of the testis in a patient with a history of acute myeloid leukemia. AB - Chloroma, or granulocytic sarcoma, is a rare extramedullary solid hematologic cancer, found concomitant with acute myeloid leukemia. It is infrequently associated with other myeloproliferative disorders or chronic myelogenous leukemia. Chloroma of the testis after allogeneic bone marrow transplantation is particularly sparsely represented in the literature. It is suggested that an appropriate panel of marker studies be performed along with clinical correlation and circumspection to avoid misleading conclusions. We report an interesting case of a 32-year-old male with a clinical history of acute myelogenous leukemia, postallogeneic peripheral blood stem cell transplantation that was found to have chloroma of the right testis. PMID- 28919911 TI - Comprehensibility of selected USP pictograms by illiterate and literate Farsi speakers: The first experience in Iran - Part I. AB - BACKGROUND: Good understanding of medication instructions is paramount to a good pharmaceutical care. The aim of our study was to examine the understandability of the selected three most applicable pictograms by participants and their recall after educational mini sessions. MATERIALS AND METHODS: First, nine experienced pharmacists selected the three most potentially applicable pictograms. Pictograms A to C were determined, respectively, "A-take medication with food," "B medication may cause drowsiness," and "C-take medication before sleep." In the second phase, we measured the comprehensibility of pictograms by three groups of participants (sample of 358): highly educated participants of two major universities of Isfahan (Groups 1 and 2), low-literate and illiterate individuals (Groups 3 and 4), and the rest were participants interviewed in three teaching pharmacies affiliated to the Isfahan School of Pharmacy (Group 5). The American National Standards Institute (ANSI) and International Organization for Standardization (ISO) were used to compare the comprehensibility of pictograms. Furthermore, five qualitative questions were asked about the impact of pictograms on several parameters. RESULTS: In the pre-follow-up period, only Group 1 (75%) understood pictogram A while pictogram B did not pass the ANSI and ISO thresholds for acceptability in none of the groups. In the pre-follow-up period, Groups 1 and 2 surpassed the ANSI threshold and Group 5 passed the ISO limit for C. In the post-follow-up period, C passed the ISO limit in Group 3. Regarding the qualitative questions, 84.1% believed that pictograms had positive impact on the correct use of medications and timing of administration. CONCLUSION: The groups with high level of literacy interpreted the pictograms better than those with lower levels of literacy. PMID- 28919913 TI - The interaction effect of body mass index and age on fat-free mass, waist-to-hip ratio, and soft lean mass. AB - BACKGROUND: Research has shown that body mass index (BMI) does not take into consideration the gender and ethnicity. The primary purpose of this study was to examine the interaction effect of the BMI and age on fat-free mass (FFM), waist to-hip ratio (WHR), and soft lean mass (SLM). The secondary purpose was to evaluate the practical significance of the findings by examining effect sizes. MATERIALS AND METHODS: The study was comparative in nature and employed a factorial design. Due to nonexperimental nature of the investigation, no causal inferences were drawn. The nonprobability sample consisted of 19,356 adults. Analysis of the data included factorial analysis of variance, analysis of simple effects, calculation of mean difference effect sizes, and data transformation. The Statistical Package for the Social Sciences version 22 was employed for the purpose of data manipulation and analysis. RESULTS: The BMI by age interaction effects on FFM, F (10, 19,338) = 28.26, P < 0.01, on WHR, F (10, 19,338) = 18.46, P < 0.01, and on SLM, F (10, 19,338) = 14.65, P < 0.01, was statistically significant and ordinal in nature. Analysis of the effect sizes, ranging from 0.30 to 1.20, showed that the BMI and age influenced the WHR but their interaction effects on FFM and SLM, ranging from 0.04 to 0.36 and 0.03 to 0.33, respectively, were mainly negligible. CONCLUSION: Based on the examination of the statistical and practical significance of the results, it is concluded that the BMI and age together can influence the WHR but their interaction effect on the FFM and SLM is questionable. PMID- 28919914 TI - Agreement of clinical examination and ultrasound methods for detection of joints involvements in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis is a chronic autoimmune disease characterized by synovial tissue inflammation and destruction of articular components which if not controlled properly, can cause disability in patients. For this reason, evaluation of disease activity and its control is very important. In recent years using sonography is promising for the evaluation of disease activity. This study aimed to compare "clinical examination" and "ultrasonography" methods in the detection of disease activity in patients with rheumatoid arthritis. MATERIALS AND METHODS: This cross-sectional study was conducted during 2015 in Al-Zahra Hospital of Isfahan. Based on the American College of Rheumatology 2010 criteria, ninety patients with rheumatoid arthritis who diagnosed by rheumatologist entered into the study. All patients, collaborator by radiologists were subjected to sonography of specific joints structures using two methods, i.e., high-resolution ultrasonography and power Doppler. RESULTS: A total of 2520 joints from ninety patients were examined by physical examination and ultrasonography that 244 joints (9.7%) in physical examination and 348 joints (13.4%) in ultrasonography were involved and the difference between the two groups was statistically significant (P < 0.001). CONCLUSION: Probably, ultrasonography can diagnose joint involvement better than physical examination in patients with Rheumatoid arthritis. PMID- 28919915 TI - Nutritional psychiatry: An evolving concept. PMID- 28919912 TI - The Isfahan Comprehensive Elderly Study: Objectives, research design, methodology, and preliminary results. AB - BACKGROUND: This paper presents the objectives, research design, methodology, and primary findings of the Isfahan Comprehensive Elderly Study (ICES). MATERIALS AND METHODS: In this cross-sectional study, 603 elderly persons (aged 60 and over) were selected by multistage cluster sampling method from Isfahan, Iran, in 2016 comprehensive questionnaires along with a detailed interview were used to collect information on personal, family, socioeconomic, health and social services characteristics, life styles, physical illnesses and chronic diseases, mental, emotional and cognition disorders, quality of life, disabilities, sleep quality, social supports, life satisfaction, self-efficacy, and of participants. RESULTS: The mean +/- standard deviation (SD) age of participants was 69.66 +/- 6.31 years, consisting of 50.75% females. About 23% of elderly persons were at the risk of malnutrition and 4.5% were current smoker. Severe and mild depression were documented in 9.3% and 30.2% among included study subjects, respectively. About half of the participants had hypertension, and 26.8% suffered from cardiovascular disease. The mean +/- SD of total score of Geriatric Depression Scale, Perceived Stress Scale, Older People's Quality of Life, Physical Activity Scale for the Elderly and Pittsburg Sleep Quality Index was 8.84 +/- 6.79, 14.76 +/- 5.92, 133.99 +/- 10.55, 142.04 +/- 120.53, and 6.17 +/- 3.44, respectively. Elderly males had significantly higher life satisfaction and self-efficacy and better cognitive function than females (P < 0.01). CONCLUSION: The findings of current study provided a comprehensive overview of the current health status and lifestyle of older adults in Isfahan city. The ICES could help policy makers to design appropriate prevention and interventional programs and policies to cover the specific needs of the elderly population. PMID- 28919916 TI - Outbreak of Zika virus disease. PMID- 28919917 TI - Anxiety but not depression is associated with metabolic syndrome: The Isfahan Healthy Heart Program. AB - BACKGROUND: Only a few studies have carried out to evaluate the association of depression and anxiety with metabolic syndrome (MetS). The aim of this study was to investigate whether the depression and anxiety are associated with MetS and its different components. MATERIALS AND METHODS: This cross-sectional study forms part of the prospective Isfahan Cohort Study. A total of 470 participants were chosen. Anxiety and depression symptoms were measured using hospital anxiety and depression scale (HADS). The MetS was diagnosed according to the American Heart Association and National Heart, Lung, and Blood Institute. One-way analysis of variance and binary logistic regression were used. RESULTS: The mean age of participants was 55.7 +/- 9.3. The prevalence of MetS in female participants with symptoms of depression (P < 0.0001), concurrent anxiety and depression (P = 0.004), anxiety (P < 0.0001), and asymptomatic individuals (P = 0.001) was significantly different when compared to male participants. Moreover, the analysis showed that having anxiety symptoms is in a negative relationship with MetS (odds ratio [OR] = 0.31; 95% confidence interval [CI] = 0.12-0.78). In addition, with each 10-year increase in age, the probability of MetS will decrease 40% (OR = 0.59; 95%Cl = 0.53-0.72). Body mass index (OR = 1.29; 95%CI = 1.21-1.37), and gender (higher age for women) (OR = 0.34; 95%CI = 0.11-0.98) had positive relationship with MetS. CONCLUSION: The study findings revealed that the prevalence of MetS in patients with anxiety was lower than the healthy subjects, while no significant association was found between depression, concurrent depression, an anxiety with MetS. PMID- 28919918 TI - Retraction: Gastrointestinal dysfunction in idiopathic Parkinsonism: A narrative review. AB - [This retracts the article on p. 126 in vol. 21, PMID: 28331512.]. PMID- 28919919 TI - Fun Is More Fun When Others Are Involved. AB - Fun activities are commonly sought and highly desired yet their affective side has received little scrutiny. The present research investigated two features of fun in two daily diary studies and one laboratory experiment. First, we examined the affective state associated with fun experiences. Second, we investigated the social context of fun, considering whether shared fun is more enjoyable than solitary fun. Findings from these studies indicated that fun is associated with both high-activation and low-activation positive affects, and that it is enhanced when experienced with others (especially friends). However, social fun was associated with increases in high-activation but not low-activation positive affect, suggesting that social interaction emphasizes energizing affective experiences. We also found that loneliness moderated the latter effects, such that lonely individuals received a weaker boost from shared compared to solitary fun. These results add to what is known about the impact of social contexts on affective experience. PMID- 28919920 TI - Virulence determinants of West Nile virus: how can these be used for vaccine design? AB - West Nile virus (WNV), a neurotropic mosquito-borne flavivirus, has become endemic in the USA and parts of Europe since 1999. There is no licensed WNV vaccine for humans. Considering the robust immunity from immunization with live, attenuated vaccines, a live WNV vaccine is an ideal platform for disease control. Animal and mosquito studies have identified a number of candidate attenuating mutations, including the structural proteins premembrane/membrane and envelope, and the nonstructural proteins NS1, NS2A, NS3, NS4A, NS4B and NS5, and the 3' UTR. Many of the mutations that have been examined attenuate WNV using different mechanisms, thus providing a greater understanding of WNV virulence while also identifying specific mutations as candidates to include in a WNV live vaccine. PMID- 28919921 TI - How do flavivirus-infected cells resist arsenite-induced stress granule formation? PMID- 28919922 TI - Anti-tumor effects of the American cockroach, Periplaneta americana. AB - Since the incidence of cancer has been on the rise due to increasing exposure to various carcinogenic factors in recent years, cancer has gradually become the first killer to the health of human beings. A growing attention has been paid to anti-cancer effects of traditional Chinese medicine (TCM) with low toxicity and good efficacy. As a kind of TCM, Periplaneta americana (P. americana) has a good effect on clinical application, and its anti-tumor effects has been increasingly well studied. In this review, the research progress on the anti-tumor effects of P. americana was summarized. The main mechanisms of its anti-tumor effects include suppression of tumor cell growth, induction of cell cycle arrest and tumor cell apoptosis, inhibition of angiogenesis, enhancement of immunity, and reversal of tumor drug resistance. This review aims to provide an overview of the research on anti-tumor effects of P. americana and aids in its further application as an anti-tumor drug. PMID- 28919923 TI - Revealing topics and their evolution in biomedical literature using Bio-DTM: a case study of ginseng. AB - BACKGROUND: Valuable scientific results on biomedicine are very rich, but they are widely scattered in the literature. Topic modeling enables researchers to discover themes from an unstructured collection of documents without any prior annotations or labels. In this paper, taking ginseng as an example, biological dynamic topic model (Bio-DTM) was proposed to conduct a retrospective study and interpret the temporal evolution of the research of ginseng. METHODS: The system of Bio-DTM mainly includes four components, documents pre-processing, bio dictionary construction, dynamic topic models, topics analysis and visualization. Scientific articles pertaining to ginseng were retrieved through text mining from PubMed. The bio-dictionary integrates MedTerms medical dictionary, the second edition of side effect resource, a dictionary of biology and HGNC database of human gene names (HGNC). A dynamic topic model, a text mining technique, was used to emphasize on capturing the development trends of topics in a sequentially collected documents. Besides the contents of topics taken on, the evolution of topics was visualized over time using ThemeRiver. RESULTS: From the topic 9, ginseng was used in dietary supplements and complementary and integrative health practices, and became very popular since the early twentieth century. Topic 6 reminded that the planting of ginseng is a major area of research and symbiosis and allelopathy of ginseng became a research hotspot in 2007. In addition, the Bio-DTM model gave an insight into the main pharmacologic effects of ginseng, such as anti-metabolic disorder effect, cardioprotective effect, anti-cancer effect, hepatoprotective effect, anti-thrombotic effect and neuroprotective effect. CONCLUSION: The Bio-DTM model not only discovers what ginseng's research involving in but also displays how these topics evolving over time. This approach can be applied to the biomedical field to conduct a retrospective study and guide future studies. PMID- 28919924 TI - Comparison of Parent Report and Direct Assessment of Child Skills in Toddlers. AB - BACKGROUND: There are unique challenges associated with measuring development in early childhood. Two primary sources of information are used: parent report and direct assessment. Each approach has strengths and weaknesses, particularly when used to identify and diagnose developmental delays. The present study aimed to evaluate consistency between parent report and direct assessment of child skills in toddlers with and without Autism Spectrum Disorder (ASD) across receptive language, expressive language, and fine motor domains. METHOD: 109 children were evaluated at an average age of two years; data on child skills were collected via parent report and direct assessment. Children were classified into three groups (i.e., ASD, Other Developmental Disorder, or Typical Development) based on DSM-IV TR diagnosis. Mixed design ANOVAs, with data source as a within subjects factor and diagnostic group as a between subjects factor, were used to assess agreement. Chi square tests of agreement were then used to examine correspondence at the item level. RESULTS: Results suggested that parent report of language and fine motor skills did not significantly differ from direct assessment, and this finding held across diagnostic groups. Item level analyses revealed that, in most cases of significant disagreement, parents reported a skill as present, but it was not seen on direct testing. CONCLUSIONS: Results indicate that parents are generally reliable reporters of child language and fine motor abilities in toddlerhood, even when their children have developmental disorders such as ASD. However, the fullest picture may be obtained by using both parent report and direct assessment. PMID- 28919925 TI - In-vitro evaluation of Polylactic acid (PLA) manufactured by fused deposition modeling. AB - BACKGROUND: With additive manufacturing (AM) individual and biocompatible implants can be generated by using suitable materials. The aim of this study was to investigate the biological effects of polylactic acid (PLA) manufactured by Fused Deposition Modeling (FDM) on osteoblasts in vitro according to European Norm / International Organization for Standardization 10,993-5. METHOD: Human osteoblasts (hFOB 1.19) were seeded onto PLA samples produced by FDM and investigated for cell viability by fluorescence staining after 24 h. Cell proliferation was measured after 1, 3, 7 and 10 days by cell-counting and cell morphology was evaluated by scanning electron microscopy. For control, we used titanium samples and polystyrene (PS). RESULTS: Cell viability showed higher viability on PLA (95,3% +/- 2.1%) than in control (91,7% +/-2,7%). Cell proliferation was highest in the control group (polystyrene) and higher on PLA samples compared to the titanium samples. Scanning electron microscopy revealed homogenous covering of sample surface with regularly spread cells on PLA as well as on titanium. CONCLUSION: The manufacturing of PLA discs from polylactic acid using FDM was successful. The in vitro investigation with human fetal osteoblasts showed no cytotoxic effects. Furthermore, FDM does not seem to alter biocompatibility of PLA. Nonetheless osteoblasts showed reduced growth on PLA compared to the polystyrene control within the cell experiments. This could be attributed to surface roughness and possible release of residual monomers. Those influences could be investigated in further studies and thus lead to improvement in the additive manufacturing process. In addition, further research focused on the effect of PLA on bone growth should follow. In summary, PLA processed in Fused Deposition Modelling seems to be an attractive material and method for reconstructive surgery because of their biocompatibility and the possibility to produce individually shaped scaffolds. PMID- 28919927 TI - Characterization of a heat-tolerant Chlorella sp. GD mutant with enhanced photosynthetic CO2 fixation efficiency and its implication as lactic acid fermentation feedstock. AB - BACKGROUND: Fermentative production of lactic acid from algae-based carbohydrates devoid of lignin has attracted great attention for its potential as a suitable alternative substrate compared to lignocellulosic biomass. RESULTS: A Chlorella sp. GD mutant with enhanced thermo-tolerance was obtained by mutagenesis using N methyl-N'-nitro-N-nitrosoguanidine to overcome outdoor high-temperature inhibition and it was used as a feedstock for fermentative lactic acid production. The indoor experiments showed that biomass, reducing sugar content, photosynthetic O2 evolution rate, photosystem II activity (Fv/Fm and Fv'/Fm'), and chlorophyll content increased as temperature, light intensity, and CO2 concentration increased. The mutant showed similar DIC affinity and initial slope of photosynthetic light response curve (alpha) as that of the wild type but had higher dissolved inorganic carbon (DIC) utilization capacity and maximum photosynthesis rate (Pmax). Moreover, the PSII activity (Fv'/Fm') in the mutant remained normal without acclimation process after being transferred to photobioreactor. This suggests that efficient utilization of incident high light and enhanced carbon fixation with its subsequent flux to carbohydrates accumulation in the mutant contributes to higher sugar and biomass productivity under enriched CO2 condition. The mutant was cultured outdoors in a photobioreactor with 6% CO2 aeration in hot summer season in southern Taiwan. The harvested biomass was subjected to separate hydrolysis and fermentation (SHF) for lactic acid production with carbohydrate concentration equivalent to 20 g/L glucose using the lactic acid-producing bacterium Lactobacillus plantarum 23. The conversion rate and yield of lactic acid were 80% and 0.43 g/g Chlorella biomass, respectively. CONCLUSIONS: These results demonstrated that the thermo-tolerant Chlorella mutant with high photosynthetic efficiency and biomass productivity under hot outdoor condition is an efficient fermentative feedstock for large scale lactic acid production. PMID- 28919926 TI - Sustaining fermentation in high-gravity ethanol production by feeding yeast to a temperature-profiled multifeed simultaneous saccharification and co-fermentation of wheat straw. AB - BACKGROUND: Considerable progress is being made in ethanol production from lignocellulosic feedstocks by fermentation, but negative effects of inhibitors on fermenting microorganisms are still challenging. Feeding preadapted cells has shown positive effects by sustaining fermentation in high-gravity simultaneous saccharification and co-fermentation (SSCF). Loss of cell viability has been reported in several SSCF studies on different substrates and seems to be the main reason for the declining ethanol production toward the end of the process. Here, we investigate how the combination of yeast preadaptation and feeding, cell flocculation, and temperature reduction improves the cell viability in SSCF of steam pretreated wheat straw. RESULTS: More than 50% cell viability was lost during the first 24 h of high-gravity SSCF. No beneficial effects of adding selected nutrients were observed in shake flask SSCF. Ethanol concentrations greater than 50 g L-1 led to significant loss of viability and prevented further fermentation in SSCF. The benefits of feeding preadapted yeast cells were marginal at later stages of SSCF. Yeast flocculation did not improve the viability but simplified cell harvest and improved the feasibility of the cell feeding strategy in demo scale. Cultivation at 30 degrees C instead of 35 degrees C increased cell survival significantly on solid media containing ethanol and inhibitors. Similarly, in multifeed SSCF, cells maintained the viability and fermentation capacity when the temperature was reduced from 35 to 30 degrees C during the process, but hydrolysis yields were compromised. By combining the yeast feeding and temperature change, an ethanol concentration of 65 g L-1, equivalent to 70% of the theoretical yield, was obtained in multifeed SSCF on pretreated wheat straw. In demo scale, the process with flocculating yeast and temperature profile resulted in 5% (w/w) ethanol, equivalent to 53% of the theoretical yield. CONCLUSIONS: Multifeed SSCF was further developed by means of a flocculating yeast and a temperature-reduction profile. Ethanol toxicity is intensified in the presence of lignocellulosic inhibitors at temperatures that are beneficial to hydrolysis in high-gravity SSCF. The counteracting effects of temperature on cell viability and hydrolysis call for more tolerant microorganisms, enzyme systems with lower temperature optimum, or full optimization of the multifeed strategy with temperature profile. PMID- 28919928 TI - The yeast Geotrichum candidum encodes functional lytic polysaccharide monooxygenases. AB - BACKGROUND: Lytic polysaccharide monooxygenases (LPMOs) are a class of powerful oxidative enzymes that have revolutionized our understanding of lignocellulose degradation. Fungal LPMOs of the AA9 family target cellulose and hemicelluloses. AA9 LPMO-coding genes have been identified across a wide range of fungal saprotrophs (Ascomycotina, Basidiomycotina, etc.), but so far they have not been found in more basal lineages. Recent genome analysis of the yeast Geotrichum candidum (Saccharomycotina) revealed the presence of several LPMO genes, which belong to the AA9 family. RESULTS: In this study, three AA9 LPMOs from G. candidum were successfully produced and biochemically characterized. The use of native signal peptides was well suited to ensure correct processing and high recombinant production of GcLPMO9A, GcLPMO9B, and GcLPMO9C in Pichia pastoris. We show that GcLPMO9A and GcLPMO9B were both active on cellulose and xyloglucan, releasing a mixture of soluble C1- and C4-oxidized oligosaccharides from cellulose. All three enzymes disrupted cellulose fibers and significantly improved the saccharification of pretreated lignocellulosic biomass upon addition to a commercial cellulase cocktail. CONCLUSIONS: The unique enzymatic arsenal of G. candidum compared to other yeasts could be beneficial for plant cell wall decomposition in a saprophytic or pathogenic context. From a biotechnological point of view, G. candidum LPMOs are promising candidates to further enhance enzyme cocktails used in biorefineries such as consolidated bioprocessing. PMID- 28919929 TI - Does physical activity benefit motor performance and learning of upper extremity tasks in older adults? - A systematic review. AB - Upper extremity motor performance declines with increasing age. However, older adults need to maintain, learn new and relearn known motor tasks. Research with young adults indicated that regular and acute physical activity might facilitate motor performance and motor learning processes. Therefore, this review aimed to examine the association between chronic physical activity and acute bouts of exercise on motor performance and motor learning in upper extremity motor tasks in older adults. Literature was searched via Cochrane library, PubMED, PsycINFO and Scopus and 27 studies met all inclusion criteria. All studies dealt with the influence of chronic physical activity on motor performance or motor learning, no appropriate study examining the influence of an acute bout of exercise in older adults was found. Results concerning the association of chronic physical activity and motor performance are mixed and seem to be influenced by the study design, kind of exercise, motor task, and exercise intensity. Regarding motor learning, a high physical activity or cardiovascular fitness level seems to boost the initial phase of motor learning; results differ with respect to motor retention. Overall, (motor-coordinative) intervention studies seem to be more promising than cross sectional studies. PMID- 28919930 TI - Effects of 12 weeks of Nordic Walking and XCO Walking training on the endurance capacity of older adults. AB - BACKGROUND: Several studies have already examined the positive effects of various forms of endurance training in patient groups and in healthy adults up to 60 years old. The aim of this study was to analyse the effects of Nordic Walking (NW) and XCO Walking (XCO) training on endurance capacity in healthy older adults, aged 60 years and older. METHODS: Twenty-three older participants (mean age: 69.9 +/- 5.4 years) were randomly assigned to either the NW group or the XCO group. All participants were measured before and after the 12 weeks of endurance training (2 sessions/week) to examine oxygen uptake (VO2) and energy consumption during an outdoor field test. In addition, heart rates were recorded and lactate samples were collected. RESULTS: NW mainly demonstrated some significant (p < 0.05) decreases in heart rate, lactate concentration at lower to moderate walking speeds, whereas XCO Walking revealed significant (p < 0.05) decreases in lactate concentration and VO2 at low to higher walking speeds. CONCLUSIONS: NW as well as XCO training increase the efficiency of the cardio-vascular system in older subjects. Both training approaches are suitable options for endurance training, which may serve to counteract age- and inactivity-related decreases in cardio vascular functioning as well as aid in maintaining overall performance in older adults. PMID- 28919931 TI - Improving Hierarchical Models Using Historical Data with Applications in High Throughput Genomics Data Analysis. AB - Modern high-throughput biotechnologies such as microarray and next generation sequencing produce a massive amount of information for each sample assayed. However, in a typical high-throughput experiment, only limited amount of data are observed for each individual feature, thus the classical 'large p, small n' problem. Bayesian hierarchical model, capable of borrowing strength across features within the same dataset, has been recognized as an effective tool in analyzing such data. However, the shrinkage effect, the most prominent feature of hierarchical features, can lead to undesirable over-correction for some features. In this work, we discuss possible causes of the over-correction problem and propose several alternative solutions. Our strategy is rooted in the fact that in the Big Data era, large amount of historical data are available which should be taken advantage of. Our strategy presents a new framework to enhance the Bayesian hierarchical model. Through simulation and real data analysis, we demonstrated superior performance of the proposed strategy. Our new strategy also enables borrowing information across different platforms which could be extremely useful with emergence of new technologies and accumulation of data from different platforms in the Big Data era. Our method has been implemented in R package "adaptiveHM", which is freely available from https://github.com/benliemory/adaptiveHM. PMID- 28919932 TI - Separating Thermodynamics from Kinetics-A New Understanding of the Transketolase Reaction. AB - Transketolase catalyzes asymmetric C-C bond formation of two highly polar compounds. Over the last 30 years, the reaction has unanimously been described in literature as irreversible because of the concomitant release of CO2 if using lithium hydroxypyruvate (LiHPA) as a substrate. Following the reaction over a longer period of time however, we have now found it to be initially kinetically controlled. Contrary to previous suggestions, for the non-natural conversion of synthetically more interesting apolar substrates, the complete change of active site polarity is therefore not necessary. From docking studies it was revealed that water and hydrogen-bond networks are essential for substrate binding, thus allowing aliphatic aldehydes to be converted in the charged active site of transketolase. PMID- 28919934 TI - Probing the Influence of Disorder on Lanthanide Luminescence Using Eu-Doped LaPO4 Nanoparticles. AB - Lanthanide-doped nanocrystals (NCs) differ from their bulk counterparts due to their large surface to volume ratio. It is generally assumed that the optical properties are not affected by size effects as electronic transitions occur within the well-shielded 4f shell of the lanthanide dopant ions. However, defects and disorder in the surface layer can affect the luminescence properties. Trivalent europium is a suitable ion to investigate the subtle influence of the surface, because of its characteristic luminescence and high sensitivity to the local environment. Here, we investigate the influence of disorder in NCs on the optical properties of lanthanide dopants by studying the inhomogeneous linewidth, emission intensity ratios, and luminescence decay curves for LaPO4:Eu3+ samples of different sizes (4 nm to bulk) and core-shell configurations (core, core isocrystalline shell, and core-silica shell). We show that the emission linewidths increase strongly for NCs. The ratio of the intensities of the forced electric dipole (ED) and magnetic dipole (MD) transitions, a measure for the local symmetry distortion around Eu3+ ions, is higher for samples with a large fraction of Eu3+ ions close to the surface. Finally, we present luminescence decay curves revealing an increased nonradiative decay rate for Eu3+ in NCs. The effects are strongest in core and core-silica shell NCs and can be reduced by growth of an isocrystalline LaPO4 shell. The present systematic study provides quantitative insight into the role of surface disorder on the optical properties of lanthanide-doped NCs. These insights are important in emerging applications of lanthanide-doped nanocrystals. PMID- 28919933 TI - How aging and bilingualism influence language processing: theoretical and neural models. AB - Healthy non-pathological aging is characterized by cognitive and neural decline, and although language is one of the more stable areas of cognition, older adults often show deficits in language production, showing word finding failures, increased slips of the tongue, and increased pauses in speech. Overall, research on language comprehension in older healthy adults show that it is more preserved than language production. Bilingualism has been shown to confer a great deal of neuroplasticity across the life span, including a number of cognitive benefits especially in executive functions such as cognitive control. Many models of bilingual language processing have been proposed to explain bilingual language processing. However, the question remains open of how such models might be modulated by age-related changes in language. Here, we discuss how current models of language processing in non-pathological aging, and models of bilingual language processing can be integrated to provide new research directions. PMID- 28919935 TI - Hybridization of Single Nanocrystals of Cs4PbBr6 and CsPbBr3. AB - Nanocrystals of all-inorganic cesium lead halide perovskites (CsPbX3, X = Cl, Br, I) feature high absorption and efficient narrow-band emission which renders them promising for future generation of photovoltaic and optoelectronic devices. Colloidal ensembles of these nanocrystals can be conveniently prepared by chemical synthesis. However, in the case of CsPbBr3, its synthesis can also yield nanocrystals of Cs4PbBr6 and the properties of the two are easily confused. Here, we investigate in detail the optical characteristics of simultaneously synthesized green-emitting CsPbBr3 and insulating Cs4PbBr6 nanocrystals. We demonstrate that, in this case, the two materials inevitably hybridize, forming nanoparticles with a spherical shape. The actual amount of these Cs4PbBr6 nanocrystals and nanohybrids increases for synthesis at lower temperatures, i.e., the condition typically used for the development of perovskite CsPbBr3 nanocrystals with smaller sizes. We use state-of-the-art electron energy loss spectroscopy to characterize nanoparticles at the single object level. This method allows distinguishing between optical characteristics of a pure Cs4PbBr6 and CsPbBr3 nanocrystal and their nanohybrid. In this way, we resolve some of the recent misconceptions concerning possible visible absorption and emission of Cs4PbBr6. Our method provides detailed structural characterization, and combined with modeling, we conclusively identify the nanospheres as CsPbBr3/Cs4PbBr6 hybrids. We show that the two phases are independent of each other's presence and merge symbiotically. Herein, the optical characteristics of the parent materials are preserved, allowing for an increased absorption in the UV due to Cs4PbBr6, accompanied by the distinctive efficient green emission resulting from CsPbBr3. PMID- 28919936 TI - Polar Applications of Spaceborne Scatterometers. AB - Wind scatterometers were originally developed for observation of near-surface winds over the ocean. They retrieve wind indirectly by measuring the normalized radar cross section (sigmao ) of the surface, and estimating the wind via a geophysical model function relating sigmao to the vector wind. The sigmao measurements have proven to be remarkably capable in studies of the polar regions where they can map snow cover; detect the freeze/thaw state of forest, tundra, and ice; map and classify sea ice; and track icebergs. Further, a long time series of scatterometer sigmao observations is available to support climate studies. In addition to fundamental scientific research, scatterometer data are operationally used for sea-ice mapping to support navigation. Scatterometers are, thus, invaluable tools for monitoring the polar regions. In this paper, a brief review of some of the polar applications of spaceborne wind scatterometer data is provided. The paper considers both C-band and Ku-band scatterometers, and the relative merits of fan-beam and pencil-beam scatterometers in polar remote sensing are discussed. PMID- 28919937 TI - Gene Meter: Accurate abundance calculations of gene expression. AB - We previously reported that thousands of transcripts in the mouse and zebrafish significantly increased in abundance in a time series spanning from life to several days after death. Transcript abundances were determined by: calibrating each microarray probe using a dilution series of pooled RNAs, fitting the probe responses to adsorption models, and back-calculating abundances using the probe signal intensity of a sample and the best fitting model. The accuracy of the abundance measurements was not assessed in our previous study because individual transcript concentrations in the calibration pool were not known. Accurate transcript abundances are highly desired for modeling the dynamics of biological systems and investigating how systems respond to perturbations. In this study, we show that accurate transcript abundances can be determined by calibrating the probes using a calibration pool of transcripts with known concentrations. Instructions for determining accurate transcript abundances using the Gene Meter approach are provided. PMID- 28919938 TI - Keep it on the edge: The post-mitotic midbody as a polarity signal unit. AB - The maintenance of the epithelial architecture during tissue proliferation is achieved by apical positioning of the midbody after cell division. Consequently, midbody mislocalization contributes to epithelial architecture disruption, a fundamental event during epithelial tumorigenesis. Studies in 3D polarized epithelial MDCK or Caco2 cell models, where midbody misplacement leads to multiple ectopic but fully polarized lumen-containing cysts, revealed that this phenotype can be caused by 2 different scenarios: the loss of mitotic spindle orientation or the loss of asymmetric abscission. In addition, we have recently proposed a third cellular mechanism where the midbody mislocalization is achieved through cytokinesis acceleration driven by the cancer-promoting phosphatase of regenerating liver (PRL)-3. Here we critically review these findings, and we furthermore present new data indicating that midbodies themselves might act as signal unit for polarization since they can infer apical characteristics to a basal membrane. PMID- 28919939 TI - Sequence and biochemical analysis of Arabidopsis SP1 protein, a regulator of organelle biogenesis. AB - Peroxisomes, chloroplasts, and mitochondria are essential eukaryotic organelles that host a suite of metabolic processes crucial to energy metabolism and development. Regulatory mechanisms of the dynamics and biogenesis of these important organelles have begun to be discovered in plants. We recently showed that, aside from its previously reported role in targeting chloroplast protein import proteins, the Arabidopsis ubiquitin E3 ligase SP1 (suppressor of ppi1 locus1) negatively regulates peroxisome matrix protein import by promoting the ubiquitination and destabilization of PEX13 and possibly PEX14 and other components of the peroxisome protein import apparatus. Here, we compared protein sequence and domain structure of SP1-like proteins in Arabidopsis and their human homolog, Mitochondrial-Anchored Protein Ligase (MAPL). We further characterized SP1 protein in respect to its membrane topology and ubiquitin E3 ligase activity. PMID- 28919940 TI - Calcitox-aging counterbalanced by endogenous farnesol-like sesquiterpenoids: An undervalued evolutionarily ancient key signaling pathway. AB - Cells are powerful miniature electrophoresis chambers, at least during part of their life cycle. They die at the moment the voltage gradient over their plasma membrane, and their ability to drive a self-generated electric current carried by inorganic ions through themselves irreversibly collapses. Senescence is likely due to the progressive, multifactorial damage to the cell's electrical system. This is the essence of the "Fading electricity theory of aging" (De Loof et al., Aging Res. Rev. 2013;12:58-66). "Biologic electric current" is not carried by electrons, but by inorganic ions. The major ones are H+, Na+, K+, Ca2+, Mg2+, Cl- and HCO3-. Ca2+ and H+ in particular are toxic to cells. At rising concentrations, they can alter the 3D-conformation of chromatin and some (e.g. cytoskeletal) proteins: Calcitox and Protontox. This paper only focuses on Calcitox and endogenous sesquiterpenoids. pH-control and Ca2+-homeostasis have been shaped to near perfection during billions of years of evolution. The role of Ca2+ in some aspects of aging, e.g., as causal to neurodegenerative diseases is still debated. The main anti-Calcitox mechanism is to keep free cytoplasmic Ca2+ as low as possible. This can be achieved by restricting the passive influx of Ca2+ through channels in the plasma membrane, and by maximizing the active extrusion of excess Ca2+ e.g., by means of different types of Ca2+-ATPases. Like there are mechanisms that antagonize the toxic effects of Reactive Oxygen Species (ROS), there must also exist endogenous tools to counteract Calcitox. During a re evaluation of which mechanism(s) exactly initiates the fast aging that accompanies induction of metamorphosis in insects, a causal relationship between absence of an endogenous sesquiterpenoid, namely the farnesol ester named "juvenile hormone," and disturbed Ca2+-homeostasis was suggested. In this paper, this line of thinking is further explored and extended to vertebrate physiology. A novel concept emerges: horseshoe-shaped sesquiterpenoids seem to act as "inbrome" agonists with the function of a "chemical valve" or "spring" in some types of multi-helix transmembrane proteins (intramolecular prenylation), from bacterial rhodopsins to some types of GPCRs and ion pumps, in particular the SERCA-Ca2+-pump. This further underpins the Fading Electricity Theory of Aging. PMID- 28919941 TI - A test of the submentalizing hypothesis: Apes' performance in a false belief task inanimate control. AB - Much debate concerns whether any nonhuman animals share with humans the ability to infer others' mental states, such as desires and beliefs. In a recent eye tracking false-belief task, we showed that great apes correctly anticipated that a human actor would search for a goal object where he had last seen it, even though the apes themselves knew that it was no longer there. In response, Heyes proposed that apes' looking behavior was guided not by social cognitive mechanisms but rather domain-general cueing effects, and suggested the use of inanimate controls to test this alternative submentalizing hypothesis. In the present study, we implemented the suggested inanimate control of our previous false-belief task. Apes attended well to key events but showed markedly fewer anticipatory looks and no significant tendency to look to the correct location. We thus found no evidence that submentalizing was responsible for apes' anticipatory looks in our false-belief task. PMID- 28919942 TI - Genome sequence of the white-rot fungus Irpex lacteus F17, a type strain of lignin degrader fungus. AB - Irpex lacteus, a cosmopolitan white-rot fungus, degrades lignin and lignin derived aromatic compounds. In this study, we report the high-quality draft genome sequence of I. lacteus F17, isolated from a decaying hardwood tree in the vicinity of Hefei, China. The genome is 44,362,654 bp, with a GC content of 49.64% and a total of 10,391 predicted protein-coding genes. In addition, a total of 18 snRNA, 842 tRNA, 15 rRNA operons and 11,710 repetitive sequences were also identified. The genomic data provides insights into the mechanisms of the efficient lignin decomposition of this strain. PMID- 28919943 TI - [Identification of Positive Youth Development Interventions]. AB - There are more people in the world in the youth stage of development than in any other stage of development. The youth in Puerto Rico faces many situations that affect their development and readiness for adulthood. Therefore, it's imperative to identify evidence-based positive youth development interventions to develop practices that help young people prevent adverse situations, promote positive experiences and encourage children and young people to be involved and committed. One hundred and forty seven interventions were identified through a traditional scientific literature review. The results reflect that the interventions mainly focused on reducing risk factors and increasing of protection factors. However, no intervention focus on fully engaging children and young people to be involved and committed to their optimal development and to their communities. Nevertheless, all identified interventions providDe tools that could be useful to foster such practices in the context of Puerto Rico. Of the 147 interventions identified, six are designed for the Puerto Rican population residing on the island. In order to make information accessible to professionals and the community, the collection of the Archivo de Programas y Practicas Basadas en Evidencia para la Prevencion has been expanded. PMID- 28919944 TI - Network Analysis on Attitudes: A Brief Tutorial. AB - In this article, we provide a brief tutorial on the estimation, analysis, and simulation on attitude networks using the programming language R. We first discuss what a network is and subsequently show how one can estimate a regularized network on typical attitude data. For this, we use open-access data on the attitudes toward Barack Obama during the 2012 American presidential election. Second, we show how one can calculate standard network measures such as community structure, centrality, and connectivity on this estimated attitude network. Third, we show how one can simulate from an estimated attitude network to derive predictions from attitude networks. By this, we highlight that network theory provides a framework for both testing and developing formalized hypotheses on attitudes and related core social psychological constructs. PMID- 28919945 TI - Distribution, karyomorphology, and morphology of Aspidistra subrotata (Asparagaceae) at different ploidy levels in limestone areas of Asia. AB - Aspidistra subrotata Y. Wan & C.C. Huang, 1987 is considered for the first time as a widespread polyploidy complex in the genus Aspidistra Ker Gawler, 1823 from limestone areas of Asia. The chromosome number of the tetraploid is 2n = 76 and the karyotype is formulated as 2n = 44 m + 8 sm + 24 st, while the chromosome number of the diploid is 2n = 38 and the karyotype formula 2n = 22 m + 4 sm + 12 st. In our studies, diploids occupy broader geographical and environmental niche spaces than tetraploids. Although the leaf-shape of Aspidistra subrotata varies quantitatively between and within diploid and/or tetraploid population(s), no obvious discontinuity in the width of leaf has been observed. The tetraploid plants may be distinguished from the diploid plants by their rigid petioles as well as thick deep green lamina. Aspidistra subrotata is therefore an interesting material to explore the formation and the evolutionary dynamics of a natural polyploid complex from limestone areas of the tropical regions. PMID- 28919946 TI - Cytogenetic characterization of Hoplias malabaricus (Bloch, 1794) from the Ctalamochita River (Cordoba, Argentina): first evidence for southernmost populations of this species complex and comments on its biogeography. AB - Hoplias malabaricus (Bloch, 1794), a predatory freshwater fish with a wide distribution throughout South America, represents a species complex with seven well characterized karyomorphs at the cytogenetic level. Although this species has been extensively studied in several Brazilian basins, data are still scarce for hydrographic systems from other South American countries. This study aims to characterize cytogenetically the Hoplias malabaricus populations from the Argentinean Central Region, close to the southernmost distribution of this species complex. A total of 32 specimens from the Ctalamochita River, a tributary of Lower Parana Basin located in the province of Cordoba, were analyzed using cytogenetic techniques (Giemsa staining, C- and Ag-NOR banding and fluorescent in situ hybridization with 18S rDNA). All the specimens showed diploid number 2n=42, chromosomic formula 22m + 20sm and absence of sexual chromosomes. Thus, the analyzed populations belong to the karyomorph named A. These populations showed a remarkable degree of divergence in their cytogenetic traits such as karyotypic formula, C-banding, NORs and 18S rDNA patterns for Hoplias malabaricus from other populations bearing the same karyomorph in the Middle and Upper Parana Basin. These findings are consistent with molecular data from a recent study (where specimens collected in the present work were included), which indicate a closer phylogenetic relationship of Hoplias malabaricus populations from the Ctalamochita River with those from the Uruguay basin and the coastal regions of South Brazil than with populations from the Middle and Upper Parana Basin. Overall, these pieces of evidence highlight the distinctive features of Hoplias malabaricus from the Ctalamochita River, and also reveal a complex history of dispersion of these populations. The present work is the first to provide cytogenetic information and include some phylogeographic aspects of Hoplias malabaricus populations living in close proximity to the southernmost extreme of its distribution area. Therefore, this study expands significantly upon the previously known geographical coverage for karyomorph A and contributes to a better understanding of the karyotypic diversification within this species complex. PMID- 28919947 TI - Genomic characterisation of Arachis porphyrocalyx (Valls & C.E. Simpson, 2005) (Leguminosae): multiple origin of Arachis species with x = 9. AB - The genus Arachis Linnaeus, 1753 comprises four species with x = 9, three belong to the section Arachis: Arachis praecox (Krapov. W.C. Greg. & Valls, 1994), Arachis palustris (Krapov. W.C. Greg. & Valls, 1994) and Arachis decora (Krapov. W.C. Greg. & Valls, 1994) and only one belongs to the section Erectoides: Arachis porphyrocalyx (Valls & C.E. Simpson, 2005). Recently, the x = 9 species of section Arachis have been assigned to G genome, the latest described so far. The genomic relationship of Arachis porphyrocalyx with these species is controversial. In the present work, we carried out a karyotypic characterisation of Arachis porphyrocalyx to evaluate its genomic structure and analyse the origin of all x = 9 Arachis species. Arachis porphyrocalyx showed a karyotype formula of 14m+4st, one pair of A chromosomes, satellited chromosomes type 8, one pair of 45S rDNA sites in the SAT chromosomes, one pair of 5S rDNA sites and pericentromeric C-DAPI+ bands in all chromosomes. Karyotype structure indicates that Arachis porphyrocalyx does not share the same genome type with the other three x = 9 species and neither with the remaining Erectoides species. Taking into account the geographic distribution, morphological and cytogenetic features, the origin of species with x = 9 of the genus Arachis cannot be unique; instead, they originated at least twice in the evolutionary history of the genus. PMID- 28919948 TI - Cytogenetic data on the agro-predatory ant Megalomyrmex incisus Smith, 1947 and its host, Mycetophylax conformis (Mayr, 1884) (Hymenoptera, Formicidae). AB - We provide the first karyotype description of the agro-predatory ant species Megalomyrmex incisus Smith, 1947 (Myrmicinae, Formicidae), and chromosome counts of its host Mycetophylax conformis (Mayr, 1884) (Myrmicinae, Formicidae) from geographically distinct populations. Colonies of both species were sampled from coastal areas of Ilheus, Bahia, Brazil, and transferred to the laboratory. Metaphase spreads were prepared from the cerebral ganglia of defecated larvae. The slides were examined and pictures of the best metaphases were taken. The chromosome number for Megalomyrmex incisus was 2n=50 and n=25. The karyotype of this species consists of 20 metacentric and 5 submetacentric pairs. Thus, the karyotype formula of the diploid set was 2K=40M + 10SM and a fundamental number FN=100. The host species Mycetophylax conformis has 2n=30 and the karyotype consisting of 11 metacentric and 4 submetacentric pairs. The karyotype formula was 2K=22M + 8SM, and a fundamental number FN=60. Megalomyrmex incisus showed a slightly higher chromosome number, placed at the marginal range of the known distribution of haploid karyotypes of the Myrmicinae. The chromosome number and chromosomal morphology of Mycetophylax conformis corresponded to those of previously studied populations, suggesting its karyotype stability. PMID- 28919949 TI - First report of B chromosomes in three neotropical thorny catfishes (Siluriformes, Doradidae). AB - The family Doradidae (Siluriformes) is an important group of fishes endemic to freshwater ecosystems in South America. Some cytogenetic studies have been conducted focused on the group; however, there are no reports on the occurrence of B chromosomes for the family. In this paper the chromosomal characteristics of Platydoras armatulus (Valenciennes, 1840), Pterodoras granulosus (Valenciennes, 1821) and Ossancora punctata (Kner, 1855) were investigated through classical cytogenetics approaches. The conventional staining reveals 2n=58 in Platydoras armatulus and Pterodoras granulosus, however with distinct karyotypic formulae, possibly originated by pericentric inversions. In Ossancora punctata a derivate karyotype was described with 2n=66 and predominance of acrocentric chromosomes. The C banding pattern was resolutive in discriminating the three species, being considered an important cytotaxonomic marker. All species showed B chromosomes totally heterochromatic with non-Mendelian segregation during meiosis and low frequencies in mitotic cells. The probably origin of these additional elements was through fragmentations of chromosomes of the standard complement, which occurred recently and independently in these three species. The diploid number observed in Ossancora punctata is an evidence of centric fusions and up to the moment it is the highest diploid number reported for Doradidae. PMID- 28919950 TI - Chromosome mapping of a Tc1-like transposon in species of the catfish Ancistrus. AB - The Tc1 mariner element is widely distributed among organisms and have been already described in different species of fish. The genus Ancistrus (Kner, 1854) has 68 nominal species and is part of an interesting taxonomic and cytogenetic group, as well as presenting a variation of chromosome number, ranging from 2n=34 to 54 chromosomes, and the existence of simple and multiple sex chromosome system and the occurrence of chromosomal polymorphisms involving chromosomes that carry the nucleolus organizer region. In this study, a repetitive element by restriction enzyme, from Ancistrus sp.1 "Flecha" was isolated, which showed similarity with a transposable element Tc1-mariner. Its chromosomal location is distributed in heterochromatic regions and along the chromosomal arms of all specimens covered in this study, confirming the pattern dispersed of this element found in other studies carried out with other species. Thus, this result reinforces the hypothesis that the sequence AnDraI is really a dispersed element isolated. As this isolated sequence showed the same pattern in all species which have different sex chromosomes systems, including in all sex chromosomes, we could know that it is not involved in sex chromosome differentiation. PMID- 28919951 TI - Origin of B chromosomes in Characidium alipioi (Characiformes, Crenuchidae) and its relationship with supernumerary chromosomes in other Characidium species. AB - B chromosomes are apparently dispensable components found in the genomes of many species that are mainly composed of repetitive DNA sequences. Among the numerous questions concerning B chromosomes, the origin of these elements has been widely studied. To date, supernumerary chromosomes have been identified in approximately 60 species of fish, including species of the genus Characidium Reinhardt, 1867 in which these elements appear to have independently originated. In this study, we used molecular cytogenetic techniques to investigate the origin of B chromosomes in a population of Characidium alipioi Travassos, 1955 and determine their relationship with the extra chromosomes of other species of the genus. The results showed that the B chromosomes of Characidium alipioi had an intraspecific origin, apparently originated independently in relation to the B chromosomes of Characidium gomesi Travassos, 1956 Characidium pterostictum Gomes, 1947 and Characidium oiticicai Travassos, 1967, since they do not share specific DNA sequences, as well as their possible ancestral chromosomes and belong to different phylogenetic clades. The shared sequences between the supernumerary chromosomes and the autosommal sm pair indicate the origin of these chromosomes. PMID- 28919952 TI - Variation in genome size and karyotype among closely related aphid parasitoids (Hymenoptera, Aphelinidae). AB - Genome sizes were measured and determined for the karyotypes of nine species of aphid parasitoids in the genus Aphelinus Dalman,1820. Large differences in genome size and karyotype were found between Aphelinus species, which is surprising given the similarity in their morphology and life history. Genome sizes estimated from flow cytometry were larger for species in the Aphelinus mali (Haldeman, 1851) complex than those for the species in the Aphelinus daucicola Kurdjumov, 1913 and Aphelinus varipes (Forster,1841) complexes. Haploid karyotypes of the Aphelinus daucicola and Aphelinus mali complexes comprised five metacentric chromosomes of similar size, whereas those of the Aphelinus varipes complex had four chromosomes, including a larger and a smaller metacentric chromosome and two small acrocentric chromosomes or a large metacentric and three smaller acrocentric chromosomes. Total lengths of female haploid chromosome sets correlated with genome sizes estimated from flow cytometry. Phylogenetic analysis of karyotypic variation revealed a chromosomal fusion together with pericentric inversions in the common ancestor of the Aphelinus varipes complex and further pericentric inversions in the clade comprising Aphelinus kurdjumovi Mercet, 1930 and Aphelinus hordei Kurdjumov, 1913. Fluorescence in situ hybridization with a 28S ribosomal DNA probe revealed a single site on chromosomes of the haploid karyotype of Aphelinus coreae Hopper & Woolley, 2012. The differences in genome size and total chromosome length between species complexes matched the phylogenetic divergence between them. PMID- 28919953 TI - Cytogenetic studies in the redtail catfish, Phractocephalus hemioliopterus (Bloch & Schneider, 1801) (Siluriformes, Pimelodidae) a giant fish from Amazon basin. AB - The objective of this study was to cytogenetically analyze Phractocephalus hemioliopterus comparing the findings with other data to infer relationships among Pimelodidae species. The results revealed a diploid number of 2n = 56 and the karyotype composed of 16 metacentric, 20 submetacentric, 6 subtelocentric and 14 acrocentric chromosomes (FN = 98). The Ag-NORs, 18S rDNA and CMA3 signals were coincident in location occupying the short arm of an acrocentric chromosome pair (23th), in a secondary constriction. The 5S rDNA genes were localized near the centromere on the short arms of one submetacentric chromosome pair. C-bands were localized predominantly in the terminal regions of chromosomes, including the AgNORs and a small metacentric pair with a conspicuous positive band on interstitial region. This chromosome pair could be considered a species-specific cytogenetic marker. PMID- 28919954 TI - Immunocytological analysis of meiotic recombination in two anole lizards (Squamata, Dactyloidae). AB - Although the evolutionary importance of meiotic recombination is not disputed, the significance of interspecies differences in the recombination rates and recombination landscapes remains under-appreciated. Recombination rates and distribution of chiasmata have been examined cytologically in many mammalian species, whereas data on other vertebrates are scarce. Immunolocalization of the protein of the synaptonemal complex (SYCP3), centromere proteins and the mismatch repair protein MLH1 was used, which is associated with the most common type of recombination nodules, to analyze the pattern of meiotic recombination in the male of two species of iguanian lizards, Anolis carolinensis Voigt, 1832 and Deiroptyx coelestinus (Cope, 1862). These species are separated by a relatively long evolutionary history although they retain the ancestral iguanian karyotype. In both species similar and extremely uneven distributions of MLH1 foci along the macrochromosome bivalents were detected: approximately 90% of crossovers were located at the distal 20% of the chromosome arm length. Almost total suppression of recombination in the intermediate and proximal regions of the chromosome arms contradicts the hypothesis that "homogenous recombination" is responsible for the low variation in GC content across the anole genome. It also leads to strong linkage disequilibrium between the genes located in these regions, which may benefit conservation of co-adaptive gene arrays responsible for the ecological adaptations of the anoles. PMID- 28919955 TI - Variability and evolutionary implications of repetitive DNA dynamics in genome of Astyanax scabripinnis (Teleostei, Characidae). AB - DNA sequences of multiple copies help in understanding evolutionary mechanisms, genomic structures and karyotype differentiation. The current study investigates the organization and distribution of different repetitive DNA in the standard complement and B chromosomes in Astyanax scabripinnis (Jenyns, 1842) chromosomes from three allopatric populations in Campos do Jordao region, Sao Paulo State, Brazil. The location of microsatellite sequences showed different chromosome distribution between Lavrinha Farm Stream (LFS) and Lake of Pedalinho (LP) populations. However, the karyotype of these populations basically followed the pattern of dispersed distribution in the A complement, conspicuous in telomeric/interstitial regions and preferential accumulation in the B chromosome. The B chromosome showed heterogeneous location of microsatellite probes CA, CAC and GA. The H3 and H4 histone genes were isolated from the total genome of the species and then the chromosomal mapping was performed by fluorescence in situ hybridization (FISH). The FISH signals showed high similarity for the probes H3 and H4 mapping in genomes of the populations analyzed. The sequences (GATA) n revealed a sex-specific trend between the chromosomal location in males and females at (LFS) and (LP) populations. Although species that comprise the Astyanax scabripinnis complex do not have morphologically differentiated sex chromosomes, the preferential GATA location - sex-associated - may represent a sex chromosome in differentiation. PMID- 28919956 TI - First karyotype description and nuclear 2C value for Myrsine (Primulaceae): comparing three species. AB - Cytogenetic studies in Primulaceae are mostly available for herbaceous species, and are focused on the chromosome number determination. An accurate karyotype characterization represents a starting point to know the morphometry and class of the chromosomes. Comparison among species within Myrsine, associating these data with the nuclear 2C value, can show changes that led the karyotype evolution. Here, we studied three Myrsine species [Myrsine coriacea (Swartz, 1788) Brown ex Roemer et Schultes, 1819, Myrsine umbellata Martius, 1841 and Myrsine parvifolia Candolle, 1841] that show different abilities to occupy the varied types of vegetation within the Brazilian Atlantic Forest. Cytogenetic characterization showed some individuals with 2n = 45 chromosomes for Myrsine parvifolia and Myrsine coriacea, with most individuals of the three species having 2n = 46. The first karyograms for Myrsine were assembled and presented morphologically identical and distinct chromosome pairs. In addition, differences in the mean 2C nuclear value and chromosome morphometry were found. Therefore, the first description of the Myrsine karyotype has been presented, as well as the nuclear 2C value. The procedures can be applied to other Myrsine species for future investigations in order to better understand its effects on the differential spatial occupation abilities shown by the species in Brazilian Atlantic Forest. PMID- 28919957 TI - A cytogenetic study of three parasitic wasp species (Hymenoptera, Chalcidoidea, Eulophidae, Trichogrammatidae) from Brazil using chromosome morphometrics and base-specific fluorochrome staining. AB - Chromosomes of three chalcid wasp species from Brazil, Palmistichus elaeisis Delvare et LaSalle, 1993, Trichospilus diatraeae Cherian et Margabandhu, 1942 (both belonging to the family Eulophidae) and Trichogramma pretiosum Riley, 1879 (Trichogrammatidae), were studied using chromosome morphometrics and base specific fluorochrome staining. The present study confirmed that these species respectively have 2n = 12, 14 and 10. Chromomycin A3 / 4', 6-diamidino-2 phenylindole (CMA3/DAPI) staining revealed a single CMA3-positive and DAPI negative band within haploid karyotypes of both Palmistichus elaeisis and Trichogramma pretiosum. This CG-rich band clearly corresponds to the nucleolus organizing region (NOR). Moreover, analogous multiple telomeric bands found on all chromosomes of Trichospilus diatraeae may also represent NORs. Certain features of karyotype evolution of the phylogenetic lineage comprising both Eulophidae and Trichogrammatidae are discussed. The results obtained during the present study demonstrate the importance of chromosome research on tropical parasitoids that remain poorly known in this respect. PMID- 28919958 TI - Further studies on Boreonectes Angus, 2010, with a molecular phylogeny of the Palaearctic species of the genus. AB - Karyotypes are given for Boreonectes emmerichi (Falkenstrom, 1936) from its type locality at Kangding, China, and for B. alpestris (Dutton & Angus, 2007) from the St Gotthard and San Bernardino passes in the Swiss Alps. A phylogeny based on sequence data from a combination of mitochondrial and nuclear genes recovered western Palaearctic species of Boreonectes as monophyletic with strong support. Boreonectes emmerichi was placed as sister to the north American forms of B. griseostriatus (De Geer, 1774), although with low support. The diversity of Palaearctic species of the B. griseostriatus species group is discussed. PMID- 28919959 TI - Chromosome mapping in Abracris flavolineata (De Geer, 1773) (Orthoptera) from the Iguacu National Park - Foz do Iguacu, Parana, Brazil. AB - In this paper, we present the cytomolecular analysis of a population of Abracris flavolineata collected in the largest fragment of the Brazilian Atlantic forest, the Iguacu National Park. The diploid number in males was 23 (22+X0), with two large pairs (1-2), 7 medium (3-9), 2 small (10-11) and the X chromosome of medium size. Heterochromatic blocks were evident in the pericentromeric regions of all chromosomes. Heterogeneity in the distribution of heterochromatin was observed, with a predominance of DAPI+ blocks. However, some chromosomes showed CMA3+ blocks and other DAPI+/CMA3+ blocks. The 18S rDNA sites were distributed on the short arms of 5 pairs. In two of these pairs, such sites were in the same chromosome bearing 5S rDNA, and one of the bivalents, they were co-located. Histone H3 genes were found on one bivalent. The results added to the existing cytogenetic studies provided evidence of great karyotypic plasticity in the species. This pliancy may be the result of vicariant events related to the geographical distribution of different populations of A. flavolineata. PMID- 28919960 TI - Karyotype characterization and comparison of three hexaploid species of Bromus Linnaeus, 1753 (Poaceae). AB - Chromosome morphometry and nuclear DNA content are useful data for cytotaxonomy and to understand the evolutionary history of different taxa. For the genus Bromus Linnaeus, 1753, distinct ploidy levels have been reported, occurring from diploid to duodecaploid species. The geographic distribution of Bromus species has been correlated with chromosome number and ploidy level. In this study, the aims were to determine the nuclear genome size and characterize the karyotype of the South American Bromus species: Bromus auleticus Trinius ex Nees, 1829, Bromus brachyanthera Doll, 1878 and Bromus catharticus Vahl, 1791. The mean nuclear 2C value ranged from 2C = 12.64 pg for B. catharticus to 2C = 17.92 pg for B. auleticus, meaning a maximum variation of 2C = 5.28 pg, equivalent to 41.70%. Despite this significant difference in 2C value, the three species exhibit the same chromosome number, 2n = 6x = 42, which confirms their hexaploid origin. Corroborating the genome size, the chromosome morphometry (total, short- and long arm length) and, consequently, the class differed among the karyotypes of the species. Based on the first karyograms for these Bromus species, some morphologically similar and several distinct chromosome pairs were found. Therefore, the karyotype characterization confirmed the hexaploid origin of the studied Bromus species, which differ in relation to the karyogram and the nuclear 2C value. Considering this, cytogenetics and flow cytometry can be used to discriminate Bromus species, contributing to taxonomy and systematic studies and providing information on the evolutionary history of this taxa. PMID- 28919961 TI - The Mugil curema species complex (Pisces, Mugilidae): a new karyotype for the Pacific white mullet mitochondrial lineage. AB - Recent molecular phylogenetic analyses have shown that the Mugil curema Valenciennes, 1836 species complex includes M. incilis Hancock, 1830, M. thoburni (Jordan & Starks, 1896) and at least four "M. curema" mitochondrial lineages, considered as cryptic species. The cytogenetic data on some representatives of the species complex have shown a high cytogenetic diversity. This research reports the results of cytogenetic and molecular analyses of white mullet collected in Ecuador. The analyzed specimens were molecularly assigned to the Mugil sp. O, the putative cryptic species present in the Pacific Ocean and showed a 2n = 46 karyotype, which is composed of 2 metacentric and 44 subtelocentric/acrocentric chromosomes. This karyotype is different from the one described for M. incilis (2n = 48) and from those of the two western Atlantic lineages Mugil curema (2n = 28), and Mugil margaritae (2n = 24). Data suggest the need for a morphological analysis to assign a species name to this Pacific lineage. PMID- 28919962 TI - A karyotype comparison between two species of bordered plant bugs (Hemiptera, Heteroptera, Largidae) by conventional chromosome staining, C-banding and rDNA FISH. AB - A cytogenetic characterization, including heterochromatin content, and the analysis of the location of rDNA genes, was performed in Largus fasciatus Blanchard, 1843 and L. rufipennis Laporte, 1832. Mitotic and meiotic analyses revealed the same diploid chromosome number 2n = 12 + X0/XX (male/female). Heterochromatin content, very scarce in both species, revealed C-blocks at both ends of autosomes and X chromosome. The most remarkable cytological feature observed between both species was the different chromosome position of the NORs. This analysis allowed us to use the NORs as a cytological marker because two clusters of rDNA genes are located at one end of one pair of autosomes in L. fasciatus, whereas a single rDNA cluster is located at one terminal region of the X chromosome in L. rufipennis. Taking into account our results and previous data obtained in other heteropteran species, the conventional staining, chromosome bandings, and rDNA-FISH provide important chromosome markers for cytotaxonomy, karyotype evolution, and chromosome structure and organization studies. PMID- 28919964 TI - Comparative analysis based on replication banding reveals the mechanism responsible for the difference in the karyotype constitution of treefrogs Ololygon and Scinax (Arboranae, Hylidae, Scinaxinae). AB - According to the recent taxonomic and phylogenetic revision of the family Hylidae, species of the former Scinax catharinae (Boulenger, 1888) clade were included in the resurrected genus Ololygon Fitzinger, 1843, while species of the Scinax ruber (Laurenti, 1768) clade were mostly included in the genus Scinax Wagler, 1830, and two were allocated to the newly created genus Julianus Duellman et al., 2016. Although all the species of the former Scinax genus shared a diploid number of 2n = 24 and the same fundamental number of chromosome arms of FN = 48, two karyotypic constitutions were unequivocally recognized, related mainly to the distinct size and morphology of the first two chromosome pairs. Some possible mechanisms for these differences had been suggested, but without any experimental evidence. In this paper, a comparison was carried out based on replication chromosome banding, obtained after DNA incorporation of 5 bromodeoxiuridine in chromosomes of Ololygon and Scinax. The obtained results revealed that the loss of repetitive segments in chromosome pairs 1 and 2 was the mechanism responsible for karyotype difference. The distinct localization of the nucleolus organizer regions in the species of both genera also differentiates the two karyotypic constitutions. PMID- 28919963 TI - Variability of NOR patterns in European water frogs of different genome composition and ploidy level. AB - We studied water frogs from a complex composed of two species: Pelophylax lessonae (Camerano, 1882) (genome LL, 2n = 26) and P. ridibundus (Pallas, 1771) (RR, 2 = 26), and their natural hybrid P. esculentus (Fitzinger, 1843) of various ploidy and genome composition (RL, 2n = 26, and RRL or RLL, 3n = 39). Tetraploids RRLL were found (4n = 52) in juveniles. We applied cytogenetic techniques: AgNO3, chromomycin A3, PI and fluorescent in situ hybridization with a 28S rDNA probe. Results obtained by silver staining corresponded well with those stained with CMA3, PI and FISH. As a rule, NORs are situated on chromosomes 10. The number of Ag-NORs visible on metaphase plates was the same as the number of Ag-nucleoli present in interphase nuclei of the same individual. In all analyzed metaphases, NORs exhibited variations in size after AgNO3 and CMA3 stainings. Sixty-six individuals (out of 407 analyzed) were polymorphic for the localization and number of NORs. Fifty-one diploids had NORs only on one chromosome of pair 10. Three triploids (LLR and RRL) displayed two NORs, and two other triploid RRL individuals displayed one, instead of expected three NORs. In ten individuals extra NORs were detected on chromosomes other than 10 (chromosomes 2 and 9). PMID- 28919965 TI - The Cerrado (Brazil) plant cytogenetics database. AB - Cerrado is a biodiversity hotspot that has lost ca. 50% of its original vegetation cover and hosts ca. 11,000 species belonging to 1,423 genera of phanerogams. For a fraction of those species some cytogenetic characteristics like chromosome numbers and C-value were available in databases, while other valuable information such as karyotype formula and banding patterns are missing. In order to integrate and share all cytogenetic information published for Cerrado species, including frequency of cytogenetic attributes and scientometrics aspects, Cerrado plant species were searched in bibliographic sources, including the 50 richest genera (with more than 45 taxa) and 273 genera with only one species in Cerrado. Determination of frequencies and the database website (http://cyto.shinyapps.io/cerrado) were developed in R. Studies were pooled by employed technique and decade, showing a rise in non-conventional cytogenetics since 2000. However, C-value estimation, heterochromatin staining and molecular cytogenetics are still not common for any family. For the richest and best sampled families, the following modal 2n counts were observed: Oxalidaceae 2n = 12, Lythraceae 2n = 30, Sapindaceae 2n = 24, Solanaceae 2n = 24, Cyperaceae 2n = 10, Poaceae 2n = 20, Asteraceae 2n = 18 and Fabaceae 2n = 26. Chromosome number information is available for only 16.1% of species, while there are genome size data for only 1.25%, being lower than the global percentages. In general, genome sizes were small, ranging from 2C = ca. 1.5 to ca. 3.5 pg. Intra-specific 2n number variation and higher 2n counts were mainly related to polyploidy, which relates to the prevalence of even haploid numbers above the mode of 2n in most major plant clades. Several orphan genera with almost no cytogenetic studies for Cerrado were identified. This effort represents a complete diagnosis for cytogenetic attributes of plants of Cerrado. PMID- 28919966 TI - Chromosomal stasis in distinct families of marine Percomorpharia from South Atlantic. AB - The weakness of physical barriers in the marine environment and the dispersal potential of fish populations have been invoked as explanations of the apparent karyotype stasis of marine Percomorpha, but several taxa remain poorly studied cytogenetically. To increase the chromosomal data in this fish group, we analyzed cytogenetically three widespread Atlantic species from distinct families: Chaetodipterus faber Broussonet, 1782 (Ephippidae), Lutjanus synagris Linnaeus, 1758 (Lutjanidae) and Rypticus randalli Courtenay, 1967 (Serranidae). The three species shared a karyotype composed of 2n=48 acrocentric chromosomes, single nucleolus organizer regions (NORs) and reduced amounts of centromeric heterochromatin. A single NOR-bearing pair was identified in all species by physical mapping of 18S rDNA while non-syntenic 5S rRNA genes were located at centromeric region of a single pair. The similar karyotypic macrostructure observed in unrelated groups of Percomorpharia reinforces the conservative karyoevolution of marine teleosteans. Nonetheless, the species could be differentiated based on the pair bearing ribosomal cistrons, revealing the importance of microstructural analyses in species with symmetric and stable karyotypes. PMID- 28919967 TI - Comparative analysis of chromosomes in the Palaearctic bush-crickets of tribe Pholidopterini (Orthoptera, Tettigoniinae). AB - The present study focused on the evolution of the karyotype in four genera of the tribe Pholidopterini: Eupholidoptera Maran, 1953, Parapholidoptera Maran, 1953, Pholidoptera Wesmael, 1838, Uvarovistia Maran, 1953. Chromosomes were analyzed using fluorescence in situ hybridization (FISH) with 18S rDNA and (TTAGG) n telomeric probes, and classical techniques, such as C-banding, silver impregnation and fluorochrome DAPI/CMA3 staining. Most species retained the ancestral diploid chromosome number 2n = 31 (male) or 32 (female), while some of the taxa, especially a group of species within genus Pholidoptera, evolved a reduced chromosome number 2n = 29. All species show the same sex determination system X0/XX. In some taxa, a pericentric inversion has changed the morphology of the ancestral acrocentric X chromosome to the biarmed X. The rDNA loci coincided with active NORs and C-band/CG-rich segments. A comparison of the location of the single rDNA/NOR in the genus Pholidoptera suggests that reduced chromosome number results from Robertsonian translocation between two pairs of autosomes, one carrying the rDNA/NOR. The results constitute a step towards better understanding of the chromosomal reorganization and evolution within the tribe Phaneropterini and the whole subfamily Tettigoniinae. PMID- 28919968 TI - A new species of Melitaea from Israel, with notes on taxonomy, cytogenetics, phylogeography and interspecific hybridization in the Melitaea persea complex (Lepidoptera, Nymphalidae). AB - Specimens with intermediate morphology are often considered to be the result of ongoing interspecific hybridization; however, this conclusion is difficult to prove without analysis of chromosomal and/or molecular markers. In the butterfly genus Melitaea, such an intermediacy can be detected in male genitalia, and is more or less regularly observed in localities where two closely related, presumably parental species are found in sympatry. Here I analyze a high altitude Melitaea population from Mt. Hermon in north Israel and show that its male genitalia are clearly differentiated from those found in phenotypically similar M. persea and M. didyma, but in some aspects intermediate between them. This hybrid-like population is unique because, although M. didyma is present on Mt. Hermon, the true, low-altitude M. persea has never been reported from Israel. Cytogenetic analysis revealed no apomorphic chromosomal characters to distinguish the Mt. Hermon population from other known taxa of the M. persea and M. didyma species groups. At the same time, DNA barcode-based phylogeographic study showed that this population is ancient. It was estimated to originate 1-1.6 million years ago in the Levantine refugium from a common ancestor with M. persea. Generally, the data obtained are incompatible with interpretation of the studied population as a taxon conspecific with M. persea or M. didyma, or a swarm of recent hybrids between M. persea and M. didyma, although the possibility of ancient homoploid hybrid speciation cannot be ruled out. I also argue that the name Melitaea montium assigned to butterflies from north Lebanon cannot be applied to the studied taxon from Mt. Hermon. Here I describe this morphologically and ecologically distinct entity as a new species Melitaea acentriasp. n., and compare it with other taxa of the M. persea complex. PMID- 28919969 TI - Karyotypic differentiation of populations of the common shrew Sorex araneus L. (Mammalia) in Belarus. AB - The common shrews, Sorex araneus Linnaeus, 1758, inhabiting the territory of Belarus, are characterized by a significant variation in the frequency of Robertsonian (Rb) translocations. The frequency clines for translocations specific of three chromosome races: the West Dvina (gm, hk, ip, no, qr), Kiev (g/m, hi, k/o, n, p, q, r), and Bialowieza (g/r, hn, ik, m/p, o, q) have already been studied in this territory. In this communication we report new data on polymorphic populations with Rb metacentrics specific of the Neroosa race (go, hi, kr, mn, p/q) in south-eastern Belarus, analyse the distribution of karyotypes in southern and central Belarus and draw particular attention to the fixation of the acrocentric variants of chromosomes in this area. The results show that certain Rb metacentrics specific of the Neroosa, West Dvina, Kiev, and Bialowieza races (namely, go and pq; ip; ko; hn and ik, respectively) are absent in many polymorphic populations. Thus, the karyotypic differentiation of S. araneus in the studied area is determined by unequal spread of different Rb translocations and by fixation of acrocentric variants of specific chromosomes. PMID- 28919970 TI - B chromosome in Plantago lagopus Linnaeus, 1753 shows preferential transmission and accumulation through unusual processes. AB - Plantago lagopus is a diploid (2n = 2x =12) weed belonging to family Plantaginaceae. We reported a novel B chromosome in this species composed of 5S and 45S ribosomal DNA and other repetitive elements. In the present work, presence of B chromosome(s) was confirmed through FISH on root tip and pollen mother cells. Several experiments were done to determine the transmission of B chromosome through male and female sex tracks. Progenies derived from the reciprocal crosses between plants with (1B) and without (0B) B chromosomes were studied. The frequency of B chromosome bearing plants was significantly higher than expected, in the progeny of 1B female * 0B male. Thus, the B chromosome seems to have preferential transmission through the female sex track, which may be due to meiotic drive. One of the most intriguing aspects of the present study was the recovery of plants having more chromosomes than the standard complement of 12 chromosomes. Such plants were isolated from the progenies of B chromosome carrying plants. The origin of these plants can be explained on the basis of a two step process; formation of unreduced gametes in 1B plants and fusion of unreduced gametes with the normal gametes or other unreduced gametes. Several molecular techniques were used which unequivocally confirmed similar genetic constitution of 1B (parent) and plants with higher number of chromosomes. PMID- 28919971 TI - B chromosome dynamics in Prochilodus costatus (Teleostei, Characiformes) and comparisons with supernumerary chromosome system in other Prochilodus species. AB - Within the genus Prochilodus Agassiz, 1829, five species are known to carry B chromosomes, i.e. chromosomes beyond the usual diploid number that have been traditionally considered as accessory for the genome. Chromosome microdissection and mapping of repetitive DNA sequences are effective tools to assess the DNA content and allow a better understanding about the origin and composition of these elements in an array of species. In this study, a novel characterization of B chromosomes in Prochilodus costatus Valenciennes, 1850 (2n=54) was reported for the first time and their sequence complementarity with the supernumerary chromosomes observed in Prochilodus lineatus (Valenciennes, 1836) and Prochilodus argenteus Agassiz, 1829 was investigated. The hybridization patterns obtained with chromosome painting using the micro B probe of P. costatus and the satDNA SATH1 mapping made it possible to assume homology of sequences between the B chromosomes of these congeneric species. Our results suggest that the origin of B chromosomes in the genus Prochilodus is a phylogenetically old event. PMID- 28919972 TI - Cytogenetic maps of homoeologous chromosomes A h01 and D h01 and their integration with the genome assembly in Gossypium hirsutum. AB - Cytogenetic maps of Gossypium hirsutum (Linnaeus, 1753) homoeologous chromosomes Ah01 and Dh01 were constructed by fluorescence in situ hybridization (FISH), using eleven homoeologous-chromosomes-shared bacterial artificial chromosomes (BACs) clones and one chromosome-specific BAC clone respectively. We compared the cytogenetic maps with the genetic linkage and draft genome assembly maps based on a standardized map unit, relative map position (RMP), which allowed a global view of the relationship of genetic and physical distances along each chromosome, and assembly quality of the draft genome assembly map. By integration of cytogenetic maps with sequence maps of the two chromosomes (Ah01 and Dh01), we inferred the locations of two scaffolds and speculated that some homologous sequences belonging to homoeologous chromosomes were removed as repetitiveness during the sequence assembly. The result offers molecular tools for cotton genomics research and also provides valuable information for the improvement of the draft genome assembly. PMID- 28919973 TI - Study of male-mediated gene flow across a hybrid zone in the common shrew (Sorex araneus) using Y chromosome. AB - Despite many studies, the impact of chromosome rearrangements on gene flow between chromosome races of the common shrew (Sorex araneus Linnaeus, 1758) remains unclear. Interracial hybrids form meiotic chromosome complexes that are associated with reduced fertility. Nevertheless comprehensive investigations of autosomal and mitochondrial markers revealed weak or no barrier to gene flow between chromosomally divergent populations. In a narrow zone of contact between the Novosibirsk and Tomsk races hybrids are produced with extraordinarily complex configurations at meiosis I. Microsatellite markers have not revealed any barrier to gene flow, but the phenotypic differentiation between races is greater than may be expected if gene flow was unrestricted. To explore this contradiction we analyzed the distribution of the Y chromosome SNP markers within this hybrid zone. The Y chromosome variants in combination with race specific autosome complements allow backcrosses to be distinguished and their proportion among individuals within the hybrid zone to be evaluated. The balanced ratio of the Y variants observed among the pure race individuals as well as backcrosses reveals no male mediated barrier to gene flow. The impact of reproductive unfitness of backcrosses on gene flow is discussed as a possible mechanism of the preservation of race-specific morphology within the hybrid zone. PMID- 28919974 TI - Kinetic and thermodynamic studies reveal chemokine homologues CC11 and CC24 with an almost identical tertiary structure have different folding pathways. AB - BACKGROUND: Proteins with low sequence identity but almost identical tertiary structure and function have been valuable to uncover the relationship between sequence, tertiary structure, folding mechanism and functions. Two homologous chemokines, CCL11 and CCL24, with low sequence identity but similar tertiary structure and function, provide an excellent model system for respective studies. RESULTS: The kinetics and thermodynamics of the two homologous chemokines were systematically characterized. Despite their similar tertiary structures, CCL11 and CCL24 show different thermodynamic stability in guanidine hydrochloride titration, with D50% = 2.20 M and 4.96 M, respectively. The kinetics curves clearly show two phases in the folding/unfolding processes of both CCL11 and CCL24, which suggests the existence of an intermediate state in their folding/unfolding processes. The folding pathway of both CCL11 and CCL24 could be well described using a folding model with an on-pathway folding intermediate. However, the folding kinetics and stability of the intermediate state of CCL11 and CCL24 are obviously different. CONCLUSION: Our results suggest homologous proteins with low sequence identity can display almost identical tertiary structure, but very different folding mechanisms, which applies to homologues in the chemokine protein family, extending the general applicability of the above observation. PMID- 28919975 TI - Mild cognitive impairment in Parkinson's disease: a distinct clinical entity? AB - BACKGROUND: Mild cognitive impairment in Parkinson's disease (PD-MCI) is a common clinical condition. Understanding its pathology and clinical features is important for early intervention before the onset of dementia. In the past, variable definitions and differences in neuropsychological batteries generated divergent results of the affected cognitive patterns. MAIN BODY: The introduction of PD-MCI criteria by the Movement Disorders Society (MDS) Task Force provides a more uniform system for defining and measuring PD-MCI and may improve the validity of future research. PD-MCI is likely to be heterogeneous since it can coexist with Alzheimer's disease and/ or Lewy body pathologies in PD. Pathogeneses of neuropsychiatric disturbances, such as depression, anxiety and apathy, are associated with PD with or without MCI. In addition, cognitive reserve formed by patients' unique life experiences may influence the outward cognitive performance despite the presence of the aforementioned pathogeneses and hence alter the diagnosis of MCI. CONCLUSION: The overlap of cognitive impairment across different neurodegenerative diseases suggests that PD-MCI is likely to result from a mixture of complex pathophysiologies, rather than being a distinct pathologic entity. Differentiating MCI from other organic symptoms in PD would facilitate novel therapeutic strategies. PMID- 28919977 TI - Efficient and selective oxidation of sulfur mustard using singlet oxygen generated by a pyrene-based metal-organic framework. AB - A pyrene-based metal-organic framework (MOF) NU-1000 was used as a heterogeneous photocatalyst for the degradation of a sulfur mustard simulant, 2-chloroethyl ethyl sulfide (CEES). Using irradiation from a commercially available and inexpensive ultraviolet (UV) light-emitting diode (LED), singlet oxygen (1O2) is generated by NU-1000 and selectively oxidizes CEES to the nontoxic product 2 chloroethyl ethyl sulfoxide (CEESO). More importantly, this method was tested on the warfare agent sulfur mustard (HD) for the first time using 1O2 and a MOF catalyst, and this method proved to be effective in oxidizing sulfur mustard to nontoxic products without forming the toxic sulfone by-product. PMID- 28919976 TI - Impacts of prenatal nutrition on animal production and performance: a focus on growth and metabolic and endocrine function in sheep. AB - The concept of foetal programming (FP) originated from human epidemiological studies, where foetal life nutrition was linked to health and disease status later in life. Since the proposal of this phenomenon, it has been evaluated in various animal models to gain further insights into the mechanisms underlying the foetal origins of health and disease in humans. In FP research, the sheep has been quite extensively used as a model for humans. In this paper we will review findings mainly from our Copenhagen sheep model, on the implications of late gestation malnutrition for growth, development, and metabolic and endocrine functions later in life, and discuss how these implications may depend on the diet fed to the animal in early postnatal life. Our results have indicated that negative implications of foetal malnutrition, both as a result of overnutrition and, particularly, late gestation undernutrition, can impair a wide range of endocrine functions regulating growth and presumably also reproductive traits. These implications are not readily observable early in postnatal life, but are increasingly manifested as the animal approaches adulthood. No intervention or cure is known that can reverse this programming in postnatal life. Our findings suggest that close to normal growth and slaughter results can be obtained at least until puberty in animals which have undergone adverse programming in foetal life, but manifestation of programming effects becomes increasingly evident in adult animals. Due to the risk of transfer of the adverse programming effects to future generations, it is therefore recommended that animals that are suspected to have undergone adverse FP are not used for reproduction. Unfortunately, no reliable biomarkers have as yet been identified that allow accurate identification of adversely programmed offspring at birth, except for very low or high birth weights, and, in pigs, characteristic changes in head shape (dolphin head). Future efforts should be therefore dedicated to identify reliable biomarkers and evaluate their effectiveness for alleviation/reversal of the adverse programming in postnatal life. Our sheep studies have shown that the adverse impacts of an extreme, high-fat diet in early postnatal life, but not prenatal undernutrition, can be largely reversed by dietary correction later in life. Thus, birth (at term) appears to be a critical set point for permanent programming in animals born precocial, such as sheep. Appropriate attention to the nutrition of the late pregnant dam should therefore be a priority in animal production systems. PMID- 28919978 TI - Controlled Substance Agreements for Opioids in a Primary Care Practice. AB - BACKGROUND: Opioids are widely prescribed for chronic non cancer pain (CNCP). Controlled substance agreements (CSAs) are intended to increase adherence and mitigate risk with opioid prescribing. We evaluated the demographic characteristics of a nd opioid dosing for patients with CNCP enrolled in CSAs in a primary care practice. METHODS: We conducted a retrospect ive cohort study of 1066 patients enrolled in CSAs between May 9, 2013 and August 15, 2016 for CNCP in a Midwest primary care practice. RESULTS: Patients were prescribed an average of 40.8 (SD +/- 57.0) morphine milligram equivalents per day (MME/day), and 21.5% of patients were receiving >=50 MME/day and 9.7% were receiving >=90 MME/day. Patients who were younger in age (>= 65 vs. < 65 years, P < 0.0001), male gender (P = 0.0001), and used tobacco (P = 0.0002) received significantly higher MME/day. Patients with more co-morbidities (Charlson Comorbidity Index, CCI) received higher MME/day (CCI > 3 vs. CCI <= 3, P = 0.03), and reported higher average pain (CCI > 3 mean 5.8 [SD +/- 2.1] vs. CCI <= 3 mean 5.3 [SD +/- 2.0], P = 0.0011). Patients on an identified tapering plan (6.9%) had higher MME/day than patients not on a tapering plan (P = 0.0002). CONCLUSIONS: CSAs present an opportunity to engage patients taking higher doses of opioids in discussions about opioid safety, appropriate dosing and tapering. CSAs could be leveraged to develop a population health management approach to the care of patients with CNCP. PMID- 28919979 TI - Reversal of fibrosis in patients with nonalcoholic steatohepatosis after gastric bypass surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) improves the pathophysiology that contributes to obesity-related nonalcoholic steatohepatitis (NASH). Whether obesity-related fibrosis improves is unclear. We hypothesized that RYGB reverses NASH and fibrosis, and indocyanine green (ICG) clearance provides a sensitive measure for detecting asymptomatic fatty liver disease. METHODS: One hundred six obese adults scheduled for RYGB had preoperative liver function assessed using standard tests and ICG clearance and core liver biopsies obtained during RYGB. Once patients lost 60% of their preoperative weight or weight loss plateaued, liver function was reassessed. Repeat liver biopsies were obtained on patients with NASH at the time of RYGB. RESULTS: RYGB improved steatosis, lobular inflammation, hepatocyte ballooning and fibrosis. Serum albumin, AST, and ALT decreased the most in patients with NASH and NASH plus fibrosis. Twenty seven (26%) patients had normal baseline liver histology and 45 (43%) had NASH or NASH plus fibrosis. Nine of 13 patients with substantial fatty liver had normalized histology after weight loss, while severity of disease in the rest had stabilized or was reduced. Mean ICG clearance in patients with normal/mild fatty liver disease and those with histological fatty livers did not differ significantly. CONCLUSIONS: RYGB surgery reverses NASH and liver fibrosis. Underlying mechanisms that facilitate improvement remain unclear. PMID- 28919980 TI - Hemicerebellitis can drive handedness shift. AB - BACKGROUND: Hemicerebellitisis a rare acquired condition, typical of the pediatric age. A residual switched handedness may develop after remission of acute cerebellar symptoms. CASE PRESENTATION: Herein we describe a motor functional MRI studyperformed in a 35-year old girl who had switched to left handedness after acute right hemicerebellitis in childhood. During left hand tapping, we observed activation in the right primary sensori-motor cortex, right supplementary motor area and left superior cerebellum. During right hand tapping bilateral activations of primary sensori-motorcortex and superior cerebellum including the vermis and activation of the right supplementary motor area were observed. We speculate that during right hand tapping both the ipsilateral and contralateralpre-central gyri and the ipsilateral cerebellum would be engaged in order to recover the tapping internal model of action. From this perspective the ipsilateral pre-central gyrus might serve as are transmission station of information from the healthy cerebellum to the contralateral pre-central gyrus. CONCLUSION: Selective damage of the right half of the cerebellum due to hemicerebellitis in childhood can drive shift of lateralized hand functions in the cerebrum. PMID- 28919981 TI - Regulation of cancer epigenomes with a histone-binding synthetic transcription factor. AB - Chromatin proteins have expanded the mammalian synthetic biology toolbox by enabling control of active and silenced states at endogenous genes. Others have reported synthetic proteins that bind DNA and regulate genes by altering chromatin marks, such as histone modifications. Previously, we reported the first synthetic transcriptional activator, the "Polycomb-based transcription factor" (PcTF) that reads histone modifications through a protein-protein interaction between the polycomb chromodomain motif and trimethylated lysine 27 of histone H3 (H3K27me3). Here, we describe the genome-wide behavior of the polycomb-based transcription factor fusion protein. Transcriptome and chromatin profiling revealed several polycomb-based transcription factor-sensitive promoter regions marked by distal H3K27me3 and proximal fusion protein binding. These results illuminate a mechanism in which polycomb-based transcription factor interactions bridge epigenomic marks with the transcription initiation complex at target genes. In three cancer-derived human cell lines tested here, some target genes encode developmental regulators and tumor suppressors. Thus, the polycomb-based transcription factor represents a powerful new fusion protein-based method for cancer research and treatment where silencing marks are translated into direct gene activation. PMID- 28919982 TI - Effective management of spasticity and impacts on weight change and resting energy expenditure in a female with spinal cord injury: a case report. AB - INTRODUCTION: The impact of muscle spasticity on weight change and energy expenditure after spinal cord injury (SCI) is not well understood. CASE PRESENTATION: This case study reports changes to body weight and resting energy expenditure (REE) in a 36-year-old female (T3 AIS A SCI; 80 kg; body mass index=28 kg m-2 at injury) requiring escalating therapies to manage severe spasticity. Body weight, spasticity medications and fasted REE (measured using indirect calorimetry, canopy hood) were recorded at 4, 16, 17, 20 and 44 months post injury. Spasticity was assessed at each time point using the Modified Ashworth Scale (MAS). At 4 months post injury, REE was high (1710 kcal per day) corresponding with severe spasticity in the lower limbs (4 on the MAS). Over the following 12 months, the patient experienced an 8 kg weight loss, visible lower limb muscle wasting and a 30% reduction in REE while requiring increasing drug therapies for spasticity. With insertion of an intrathecal Baclofen pump at 17 months and cessation of other medications, spasticity improved markedly and weight increased by 6 kg in 27 months without any significant change to REE (mean=1260 kcal+/-2%). DISCUSSION: Effective management of spasticity with intrathecal Baclofen appears to be associated with weight gain but not REE. Without body composition and activity energy expenditure data, this observation is difficult to explain. Regardless, routine weight monitoring with appropriate dietary counselling should be considered in this patient group to help prevent unintentional weight gain. PMID- 28919983 TI - Deep Learning of Tissue Fate Features in Acute Ischemic Stroke. AB - In acute ischemic stroke treatment, prediction of tissue survival outcome plays a fundamental role in the clinical decision-making process, as it can be used to assess the balance of risk vs. possible benefit when considering endovascular clot-retrieval intervention. For the first time, we construct a deep learning model of tissue fate based on randomly sampled local patches from the hypoperfusion (Tmax) feature observed in MRI immediately after symptom onset. We evaluate the model with respect to the ground truth established by an expert neurologist four days after intervention. Experiments on 19 acute stroke patients evaluated the accuracy of the model in predicting tissue fate. Results show the superiority of the proposed regional learning framework versus a single-voxel based regression model. PMID- 28919984 TI - Serum Omega-6/Omega-3 Ratio and Risk Markers for Cardiovascular Disease in an Industrial Population of Delhi. AB - High omega-6/omega-3 ratio intake promotes development of many chronic diseases. Secondary prevention studies though have demonstrated a decline in progression of many such diseases after reducing the intake, specific biochemical indices of cardiovascular disease risk markers have not been evaluated. We have evaluated the circulating levels of omega-6/omega-3 ratio and its effect on cardiovascular risk markers in India. Present study was conducted in industrial setting where employees were randomly selected. Data on their demographic characteristics were collected using pre-tested questionnaire. Fasting blood samples were collected from all the participants. Serum was separated and stored at -80 degrees C till the time of analysis. Lipids were estimated using standard kits. Fatty acids in serum were estimated by Gas chromatography. The identified Omega-3 fatty acid included were 18:3 (Alpha-linolenic acid), 20:5 (Eicosapentenoic acid) & 22:6 (Docosahexenoic acid). Among omega-6 included were 18:2 (linoleic acid), 18:3 (gamma-linolenic acid) & 20:4 (Arachidonic acid). Complete data was available for 176 participants (89% males and 11% females) with mean age of 47.23 +/- 6.00 years. The bmi of the participants was 24.88 +/- 3.43 Kg/m2 and waist circumference was 91.50 +/- 9.56 cm. The median of omega-6/omega-3 ratio in the study population was 36.69 (range: 6.21 - 183.69). The levels of total cholesterol, triglycerides, ldl-cholesterol and cholesterol/hdl ratio and apo B correlated significantly with omega-6/3 ratio. There was no correlation observed with hsCRP and LDL-particle size. A direct relationship of omega-6/omega-3 ratio with dyslipidemia was observed in our study. PMID- 28919985 TI - Human tumor-derived exosomes (TEX) regulate Treg functions via cell surface signaling rather than uptake mechanisms. AB - Tumor-derived exosomes (TEX) are ubiquitously present in the tumor microenvironment and plasma of cancer patients. TEX carry a cargo of multiple stimulatory and inhibitory molecules and deliver them to recipient cells, serving as a communication network for the tumor. The mechanisms TEX use for delivering messages to recipient cells were evaluated using PKH26-labeled TEX produced by cultured human tumor cells, exosomes produced by dendritic cells-derived exosomes (DEX), or exosomes isolated from plasma of cancer patients (EXO). Human T-cell subsets, B cells, NK cells, and monocytes were co-incubated with TEX, DEX, or EXO and binding or internalization of labeled vesicles was evaluated by confocal microscopy and/or Amnis-based flow cytometry. Vesicle-induced Ca2+ influx in recipient T cells was monitored, and TEX-induced inosine production in Treg was determined by mass spectrometry. In contrast to B cells, NK cells or monocytes, conventional T cells did not internalize labeled vesicles. Minimal exosome uptake was only evident in Treg following prolonged co-incubation with TEX. All exosomes induced Ca2+ influx in T cells, with TEX and EXO isolated from cancer patients' plasma delivering the strongest, sustained signaling to Treg. Such sustained signaling resulted in the significant upregulation of the conversion of extracellular ATP to inosine (adenosine metabolite) by Treg, suggesting that TEX signaling could have functional consequences in these recipient cells. Thus, modulation of Treg suppressor functions by TEX is mediated by mechanisms dependent on cell surface signaling and does not require TEX internalization by recipient cells. PMID- 28919986 TI - Immune biomarkers for prognosis and prediction of responses to immune checkpoint blockade in cutaneous melanoma. AB - Existing clinical, anatomopathological and molecular biomarkers fail to reliably predict the prognosis of cutaneous melanoma. Biomarkers for determining which patients receive adjuvant therapies are needed. The emergence of new technologies and the discovery of new immune populations with different prognostic values allow the immune network in the tumor to be better understood. Importantly, new molecules identified and expressed by immune cells have been shown to reduce the antitumor immune efficacy of therapies, prompting researchers to develop antibodies targeting these so-called "immune checkpoints", which have now entered the oncotherapeutic armamentarium. PMID- 28919987 TI - Programmed death ligand 1 (PD-L1) expression influences the immune-tolerogenic microenvironment in antiretroviral therapy-refractory Kaposi's sarcoma: A pilot study. AB - Upregulation of programmed death ligand 1 (PD-L1) is a mechanism of immune escape utilized by a variety of tumors. PD-L1 expression in tumor cells or in the surrounding infiltrate correlates with clinical responsiveness to novel therapies targeting the PD-1/PD-L1 immune checkpoint. In the context of HIV-1 infection, Kaposi's sarcoma (KS) is largely responsive to restoration of immunity following combination antiretroviral therapy (cART), but there is a subset that is not. We hypothesized that this subset of cART-refractory KS may utilize the PD-L1 pathway of immune escape. We found that PD-L1 expressing KS had a denser CD8+ T cell (p = 0.03) and PD-L1 positive macrophage peritumoral infiltrate (p = 0.04) to suggest the involvement of PD-L1 in shaping an immune-tolerogenic microenvironment in cART-refractory KS. The presence of PD-L1 expression in association with immune infiltrating cells provides rationale for the clinical development PD-1/PD-L1 targeted checkpoint inhibitors in cART-refractory KS. PMID- 28919988 TI - Identification of a HLA-A*0201-restricted immunogenic epitope from the universal tumor antigen DEPDC1. AB - The identification of universal tumor-specific antigens shared between multiple patients and/or multiple tumors is of great importance to overcome the practical limitations of personalized cancer immunotherapy. Recent studies support the involvement of DEPDC1 in many aspects of cancer traits, such as cell proliferation, resistance to induction of apoptosis and cell invasion, suggesting that it may play key roles in the oncogenic process. In this study, we report that DEPDC1 expression is upregulated in most types of human tumors, and closely linked to a poorer prognosis; therefore, it might be regarded as a novel universal oncoantigen potentially suitable for targeting many different cancers. In this regard, we report the identification of a HLA-A*0201 allele-restricted immunogenic DEPDC1-derived epitope, which is able to induce cytotoxic T lymphocytes (CTL) exerting a strong and specific functional response in vitro toward not only peptide-loaded cells but also triple negative breast cancer (TNBC) cells endogenously expressing the DEPDC1 protein. Such CTL are also therapeutically active against human TNBC xenografts in vivo upon adoptive transfer in immunodeficient mice. Overall, these data provide evidence that this DEPDC1-derived antigenic epitope can be exploited as a new tool for developing immunotherapeutic strategies for HLA-A*0201 patients with TNBC, and potentially many other cancers. PMID- 28919989 TI - Cyclophosphamide treatment regulates the balance of functional/exhausted tumor specific CD8+ T cells. AB - An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8+ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses. PMID- 28919990 TI - Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer associated kidney injury in mice. AB - Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer. PMID- 28919991 TI - Umbilical cord blood CD34+ progenitor-derived NK cells efficiently kill ovarian cancer spheroids and intraperitoneal tumors in NOD/SCID/IL2Rgnull mice. AB - Adoptive transfer of allogeneic natural killer (NK) cells is an attractive therapy approach against ovarian carcinoma. Here, we evaluated the potency of highly active NK cells derived from human CD34+ haematopoietic stem and progenitor cells (HSPC) to infiltrate and mediate killing of human ovarian cancer spheroids using an in vivo-like model system and mouse xenograft model. These CD56+Perforin+ HSPC-NK cells were generated under stroma-free conditions in the presence of StemRegenin-1, IL-15, and IL-12, and exerted efficient cytolytic activity and IFNgamma production toward ovarian cancer monolayer cultures. Live imaging confocal microscopy demonstrated that these HSPC-NK cells actively migrate, infiltrate, and mediate tumor cell killing in a three-dimensional multicellular ovarian cancer spheroid. Infiltration of up to 30% of total HSPC-NK cells within 8 h resulted in robust tumor spheroid destruction. Furthermore, intraperitoneal HSPC-NK cell infusions in NOD/SCID-IL2Rgammanull (NSG) mice bearing ovarian carcinoma significantly reduced tumor progression. These findings demonstrate that highly functional HSPC-NK cells efficiently destruct ovarian carcinoma spheroids in vitro and kill intraperitoneal ovarian tumors in vivo, providing great promise for effective immunotherapy through intraperitoneal HSPC NK cell adoptive transfer in ovarian carcinoma patients. PMID- 28919992 TI - Molecular and clinical characterization of TIM-3 in glioma through 1,024 samples. AB - Background: Researches on immunotherapy of glioma has been increasing exponentially in recent years. However, autoimmune-like side effects of current immune checkpoint blockade hindered the clinical application of immunotherapy in glioma. The discovery of the TIM-3, a tumor-specific immune checkpoint, has shed a new light on solution of this dilemma. We aimed at investigating the role of TIM-3 at transcriptome level and its relationship with clinical practice in glioma. Methods: A cohort of 325 glioma patients with RNA-seq data from Chinese Glioma Genome Atlas (CGGA project) was analyzed, and the results were well validated in TCGA RNA-seq data of 699 gliomas. R language was used as the main tool for statistical analysis and graphical work. Results: TIM-3 was enriched in glioblastoma (the most malignant glioma) and IDH-wildtype glioma. TIM-3 can act as a potential marker for mesenchymal molecular subtype according to TCGA transcriptional classification scheme in glioma. TIM-3 was closely related to immune functions in glioma, especially T cell mediated immune response to tumor cell and T cell mediated cytotoxicity directed against tumor cell target. Moreover, TIM-3 and PD-L1 played almost exactly the same inflammatory activation functions in glioma. Clinically, high expression of TIM-3 was an independent indicator of poor prognosis. Conclusion: The expression of TIM-3 is closely related to the pathology and molecular pathology of glioma. Meanwhile, in glioma TIM-3 plays a specific role in T cell tumor immune response. Therefore, TIM-3 is a promising target for immunotherapeutic strategies, providing an alternative treatment when glioma gains resistance to antibodies of PD-1/PD-L1. PMID- 28919993 TI - Tumor necrosis and infiltrating macrophages predict survival after curative resection for cholangiocarcinoma. AB - Background. Tumor necrosis as well as tumor-associated macrophages (TAMs) in the tumor invasive front (TIF) have been suggested to have a prognostic value in selected solid tumors, inclusive hilar cholangiocarcinoma. However, little is known regarding their influence on tumor progression and prognosis in intrahepatic cholangiocarcinoma (iCC). Methods. We analyzed surgically resected tumor specimens of human iCC (n = 88) for distribution and localization of TAMs, as defined by expression of CD68, formation of necrosis and extent of peritumoral fibrosis. Abundance of TAMs, tumor necrosis and grade of fibrosis were assessed immunohistochemically and histologically and correlated with clinicopathological characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software. Results. Patients with tumors characterized by low levels of TAMs in TIF or necrosis showed a significantly decreased 1-, 3- and 5-y recurrence-free survival and a significantly decreased overall survival, when compared with patients with tumors showing high levels of TAMs in TIF or no necrosis. Patients with high density of TAMs in TIF showed significantly lower incidence of tumor recurrence, as well (p < 0.05). Absence of tumor necrosis and TAMs in TIF were confirmed as independent prognostic variables in the multivariate survival analysis (all p < 0.05). Conclusions. High levels of TAMs in TIF or absence of histologic tumor necrosis are associated with a significantly improved recurrence-free and overall survival of patients with iCC. These results suggest TAMs and necrosis as valuable prognostic markers in routine histopathologic evaluation, and might indicate more individualized therapeutic strategies. PMID- 28919994 TI - Effect of entinostat on NK cell-mediated cytotoxicity against osteosarcoma cells and osteosarcoma lung metastasis. AB - There is a crucial need for a new therapeutic approach for osteosarcoma (OS) lung metastasis since this disease remains the main cause of mortality in OS. We previously demonstrated that natural killer (NK) cell therapy has minimal efficacy against OS metastasis. This study determined whether the histone deacetylase inhibitor entinostat could immunosensitize OS cells to NK cell lysis and increases the efficacy of NK cell therapy for OS lung metastasis. Entinostat upregulated ligands for NK cell-activating receptors (major histocompatibility complex [MHC] class I polypeptide-related chain A [MICA] and B [MICB]; UL16 binding proteins 1, 2, 5, and 6; and CD155) on OS cells both in vitro and in vivo and led to more susceptibility to NK cell-mediated cytotoxicity in vitro. Importantly, entinostat did not change NK cell viability, receptor expression, or function within the 24-h treatment. We also demonstrated two potential mechanisms by which entinostat enhanced expression of MICA and MICB on OS cells. Although entinostat upregulated ligands for the NK cell activating receptor on OS lung metastasis, it failed to augment the efficacy of NK cell therapy in our nude mouse human OS lung metastasis model. This can be partly explained by our finding that although the infused NK cells were active and functional and could penetrate into the lungs, they failed to infiltrate into the lung nodules. These challenges regarding cellular immunotherapy against solid tumors may be overcome by combination therapy, such as adding a NK cell-activating cytokine (IL-2 or IL 21). PMID- 28919996 TI - MEK inhibition and immune responses in advanced melanoma. AB - phase II and III clinical trials demonstrated modest anti- tumor activity of Binimetinib (MEK162) - a potent allosteric inhibitor of MEK1 and MEK2- in patients with advanced NRAS mutant melanoma. The analysis of the NEMO study in NRAS mutated melanoma, has shown that pre-treatment with immunotherapy improved the outcome of binimetinib therapy. We discuss this finding in the context of in vitro and in vivo effects of MEK inhibition on immuno-critical pathways and interactions. PMID- 28919995 TI - Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1beta in tumor-associated macrophages. AB - Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing gammadelta T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2 mediated induction of IL1beta in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Beta and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by gammadelta T cells, decreased neutrophil expansion and enhanced CD8+ T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro metastatic systemic inflammatory gammadelta T cell - IL17 - neutrophil axis. PMID- 28919997 TI - Increased infiltration and tolerised antigen-specific CD8+ TEM cells in tumor but not peripheral blood have no impact on survival of HCMV+ glioblastoma patients. AB - Human cytomegalovirus (HCMV) antigens in glioblastoma (GBM) present opportunities for personalised immunotherapy. However, their presence in GBM tissue is still under debate, and evidence of their impact on functional immune responses and prognosis is sparse. Here, we investigated the presence of pp65 (UL83) and immediate early 1 (IE-1) HCMV antigens in a cohort of Norwegian GBM patients (n = 177), using qPCR, immunohistochemistry, and serology. HCMV status was then used to investigate whether viral antigens influenced immune cell phenotype, infiltration, activation and patient survival. Pp65 and IE-1 were detected by qPCR in 23% and 43% of GBM patients, respectively. Furthermore, there was increased seropositivity in GBM patients relative to donors (79% vs. 48%, respectively; Logistic regression, OR = 4.05, 95%CI [1.807-9.114], P = 0.001, also when adjusted for age (OR = 2.84, 95%CI [1.110-7.275], P = 0.029). Tissue IE 1-positivity correlated with increased CD3+CD8+ T-cell infiltration (P < 0.0001), where CD8+ effector memory T (TEM) cells accounted for the majority of CD8+T cells compared with peripheral blood of HCMV+ patients (P < 0.0001), and HCMV+ (P < 0.001) and HCMV- (P < 0.001) donors. HLA-A2/B8-restricted HCMV-specific CD8+ T cells were more frequent in blood and tumor of HCMV+ GBM patients compared with seronegative patients, and donors irrespective of their serostatus. In biopsies, the HCMV-specific CD8+ TEM cells highly expressed CTLA-4 and PD-1 immune checkpoint protein markers compared with populations in peripheral blood (P < 0.001 and P < 0.0001), which expressed 3-fold greater levels of CD28 (P < 0.001 and P < 0.0001). These peripheral blood T cells correspondingly secreted higher levels of IFNgamma in response to pp65 and IE-1 peptide stimulation (P < 0.001). Thus, despite apparent increased immunogenicity of HCMV compared with tumor antigens, the T cells were tolerised, and HCMV status did not impact patient survival (Log Rank3.53 HR = 0.85 95%CI [0.564-1.290], P = 0.45). Enhancing immune functionality in the tumor microenvironment thus may improve patient outcome. PMID- 28919998 TI - Reciprocal influence of B cells and tumor macro and microenvironments in the ApcMin/+ model of colorectal cancer. AB - One of the most fascinating aspects of the immune system is its dynamism, meant as the ability to change and readapt according to the organism needs. Following an insult, we assist to the spontaneous organization of different immune cells which cooperate, locally and at distance, to build up an appropriate response. Throughout tumor progression, adaptations within the systemic tumor environment, or macroenvironment, result in the promotion of tumor growth, tumor invasion and metastasis to distal organs, but also to dramatic changes in the activity and composition of the immune system. In this work, we show the changes of the B-cell arm of the immune system following tumor progression in the ApcMin/+ model of colorectal cancer. Tumor macroenvironment leads to an increased proportion of total and IL-10-competent B cells in draining LNs while activates a differentiation route that leads to the expansion of IgA+ lymphocytes in the spleen and peritoneum. Importantly, serum IgA levels were significantly higher in ApcMin/+ than Wt mice. The peculiar involvement of IgA response in the adenomatous transformation had correlates in the gut-mucosal compartment where IgA-positive elements increased from normal mucosa to areas of low grade dysplasia while decreasing upon overt carcinomatous transformation. Altogether, our findings provide a snapshot of the tumor education of B lymphocytes in the ApcMin/+ model of colorectal cancer. Understanding how tumor macroenvironment affects the differentiation, function and distribution of B lymphocytes is pivotal to the generation of specific therapies, targeted to switching B cells to an anti-, rather than pro-, tumoral phenotype. PMID- 28919999 TI - First report of clinical responses to immunotherapy in 3 relapsing cases of chordoma after failure of standard therapies. AB - Chordoma is a rare tumor of notochordal origin, currently principally treated by surgery and/or irradiation. Here, we describe the clinical outcome of 3 consecutive patients with metastatic and locally advanced chordoma, treated with different immunotherapeutic approaches. All patients presented fast growing tumors and failure of standard therapies. One was treated with a tumor-based vaccine, the 2 others with anti-PD1 antibodies, all with impressive clinical and radiological responses. We therefore propose that chordoma is an immunogenic tumor and thus that translational and clinical research is necessary to develop rationally designed immunotherapy approaches. PMID- 28920000 TI - Oncolytic peptide LTX-315 induces an immune-mediated abscopal effect in a rat sarcoma model. AB - LTX 315 is an oncolytic peptide with potent immunological properties. In the present study, we demonstrate that intratumoral treatment with LTX-315 resulted in a complete regression and systemic immune response in a rat fibrosarcoma model. The treatment was T-cell dependent, and also resulted in an abscopal effect as demonstrated by the regression of distal non-treated lesions. Significant infiltration of CD8+ T cells was observed in both treated and non treated lesions, as shown by immunohistochemical and flow cytometric analysis. LTX-315 rapidly killed the cells in vitro with a lytic mode of action followed by the subsequent release of Danger-Associated Molecular Pattern (DAMP) molecules such as HMGB1, ATP and Cytochrome c. Together, our data demonstrate that LTX-315 represents a new approach to cancer immunotherapy, which has the potential as a novel immunotherapeutic agent. PMID- 28920001 TI - Zoledronic acid inhibits NFAT and IL-2 signaling pathways in regulatory T cells and diminishes their suppressive function in patients with metastatic cancer. AB - Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFbeta were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer. PMID- 28920003 TI - Cd226-/- natural killer cells fail to establish stable contacts with cancer cells and show impaired control of tumor metastasis in vivo. AB - CD226 is an activating receptor expressed on natural killer (NK) cells, CD8+ T cells, and other immune cells. Upon binding to its ligands expressed on target cells, CD226 activates intracellular signaling that triggers cytokine production and degranulation in NK cells. However, the role of CD226 in contact dynamics between NK and cancer cells has remained unclear. Our time-lapse images showed that individual wild-type CD226+ NK cells contacted B16F10 melanoma cells for 23.7 min, but Cd226-/- NK cells only for 12.8 min, although both NK cell subsets showed equal contact frequency over 4 h. On the surface of B16F10 cells, CD226+ cells stayed at the same site with oscillating movement (named stable contact), while Cd226-/- NK cells moved around at a velocity of 4 MUm/min (named unstable contact). Consequently, Cd226-/- NK cells did not kill B16F10 cells in vitro and did not inhibit their metastasis into the lung in vivo. Taken together, our data demonstrate that CD226 enables prolonged stable interaction between NK and cancer cells, which is needed for efficient killing of cancer cells. PMID- 28920002 TI - EP4 Antagonism by E7046 diminishes Myeloid immunosuppression and synergizes with Treg-reducing IL-2-Diphtheria toxin fusion protein in restoring anti-tumor immunity. AB - Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an IL-2 diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+ cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNgamma-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg derived immunosuppression for cancer treatment in preclinical models. PMID- 28920004 TI - Targeting myeloid derived suppressor cells with all-trans retinoic acid is highly time-dependent in therapeutic tumor vaccination. AB - Tumor immune escape is a critical problem which frequently accounts for the failure of therapeutic tumor vaccines. Among the most potent suppressors of tumor immunity are myeloid derived suppressor cells (MDSCs). MDSCs can be targeted by all-trans-retinoic-acid (atRA), which reduced their numbers and increased response rates in several vaccination studies. However, not much is known about the optimal administration interval between atRA and the vaccine as well as about its mode of action. Here we demonstrate in 2 different murine tumor models that mice unresponsive to a therapeutic vaccine harbored higher MDSC numbers than did responders. Application of atRA overcame MDSC-mediated immunosuppression and restored tumor control. Importantly, atRA was protective only when administered 3 d after vaccination (delayed treatment), whereas simultaneous administration even decreased the anti-tumor immune response and reduced survival. When analyzing the underlying mechanisms, we found that delayed, but not simultaneous atRA treatment with vaccination abrogated the suppressive capacity in monocytic MDSCs and instead caused them to upregulate MHC-class-II. Consistently, MDSCs from patients with colorectal carcinoma also failed to upregulate HLA-DR after ex vivo treatment with TLR-ligation. Overall, we demonstrate that atRA can convert non responders to responders to vaccination by suppressing MDSCs function and not only by reducing their number. Moreover, we identify a novel, strictly time dependent mode of action of atRA to be considered during immunotherapeutic protocols in the future. PMID- 28920005 TI - The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma. AB - Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation ("neoAg frequency") did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments. PMID- 28920006 TI - Dosing immunotherapy combinations: Analysis of 3,526 patients for toxicity and response patterns. AB - Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (>= 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Overall, 84 studies (N = 3,526 patients, 59 combinations) were analyzed. In 50% of studies, all drugs could be administered at full dose; 63%, in the presence of anti-PD-1/PD-L1 and 36% with anti-CTLA-4. The lowest safe starting dose for a doublet combination including a second immunotherapy was 50% of each drug; 60%, for a targeted agent. Most doublet/triplets combining anti-PD 1/PD-L1 with cytotoxics were tolerable at full doses. Response rates (median [interquartile range]) were higher for 3-drug than 2-drug combinations (53% [33 63%] (N = 23 studies) vs. 23% [14-39%]) (N = 60 studies) (p < 0.0001) with similar rates seen for targeted, cytotoxic, biologic, or additional immunotherapy combinations (p = 0.35). In conclusion, anti-PD-1/PD-L1 checkpoint inhibitors can be safely given with a variety of other immunotherapy and targeted agents, albeit at about half dose. Doublet and triplet combinations with cytotoxics could mostly be given at full doses. Anti-CTLA-4 agents compromised dosing more than anti-PD 1/PD-L1 agents. Response rates were significantly higher for 3- versus 2-drug combinations. PMID- 28920008 TI - Seven-Year Course of Borderline Personality Disorder Features: Borderline Pathology Is as Unstable as Depression during Adolescence. AB - Borderline personality disorder (PD) historically is construed as an unremitting condition with poor prognosis. The present study takes a new approach to examining stability and change in borderline PD by explaining symptom expression in terms of an unchanging foundation-termed borderline proneness-on one hand, and transitory influences on the other. We monitored borderline PD symptoms annually in a large sample of high-risk adolescent girls (N = 2,450) from ages 14 to 20. Trait-state-occasion modeling revealed that just over half (52-57%) of borderline PD symptom variation was attributable to fixed borderline proneness, whereas the remainder was subject to change across yearly measurement occasions. This degree of stability was no larger than the corresponding estimate for depression, a condition known for its variable course. Our results indicate that, contrary to its reputation, borderline pathology is not set in stone, and it fluctuates in response to situational influences. PMID- 28920009 TI - Raman Under Water - Nonlinear and Nearfield Approaches for Electrochemical Surface Science. AB - Electrochemistry is re-gaining attention among scientists because the complex interplay between electronic and chemical interfacial processes lies at the bottom of a broad range of important research disciplines like alternative energy conversion or green catalysis and synthesis. While rapid progress has been made in recent years regarding novel technological applications, the community increasingly recognizes that the understanding of the molecular processes that govern macroscopic device properties is still rather limited - which hinders a systematic and more complete exploration of novel material and functionality space. Here, we discuss advanced Raman spectroscopies as valuable analysis tools for electrochemists. The chemical nature of a material and its interaction with the environment is contained in the label-free vibrational fingerprint over a broad energy range so that organic species, solid-state materials, and hybrids thereof can be investigated alike. For surface studies, the inherently small Raman scattering cross sections can be overcome with advanced nonlinear or nearfield-based approaches that provide signal enhancements between three and seven orders of magnitude, sufficient to detect few scatterers in nano-confined spaces or adsorbate (sub)monolayers. Our article highlights how advanced Raman techniques with extreme chemical, spatial and temporal resolution constitute valuable alternative surface analysis tools and provide otherwise inaccessible information about complex interfacial (electro)chemical processes. PMID- 28920007 TI - Towards Treatment of Stargardt Disease: Workshop Organized and Sponsored by the Foundation Fighting Blindness. AB - Accumulation of fluorescent metabolic byproducts of the visual (retinoid) cycle is associated with photoreceptor and retinal pigment epithelial cell death in both Stargardt disease and atrophic (nonneovascular) age-related macular degeneration (AMD). As a consequence of this observation, small molecular inhibitors of enzymes in the visual cycle were recently tested in clinical trials as a strategy to protect the retina and retinal pigment epithelium in patients with atrophic AMD. To address the clinical translational needs for therapies aimed at both diseases, a workshop organized by the Foundation Fighting Blindness was hosted by the Department of Pharmacology at Case Western Reserve University on February 17, 2017, at the Tinkham Veale University Center, Cleveland, OH, USA. Invited speakers highlighted recent advances in the understanding of the pathophysiology of Stargardt disease, in terms of its clinical characterization and the development of endpoints for clinical trials, and discussed the comparability of therapeutic strategies between atrophic age-related macular degeneration (AMD) and Stargardt disease. Investigators speculated that reducing the concentrations of visual cycle precursor substances and/or their byproducts may provide valid therapeutic options for the treatment of Stargardt disease. Here we review the workshop's presentations in the context of published literature to help shape the aims of ongoing research endeavors and aid the development of therapies for Stargardt disease. PMID- 28920010 TI - Exploring Step-by-Step Assembly of Nanoparticle:Cytochrome Biohybrid Photoanodes. AB - Coupling light-harvesting semiconducting nanoparticles (NPs) with redox enzymes has been shown to create artificial photosynthetic systems that hold promise for the synthesis of solar fuels. High quantum yields require efficient electron transfer from the nanoparticle to the redox protein, a property that can be difficult to control. Here, we have compared binding and electron transfer between dye-sensitized TiO2 nanocrystals or CdS quantum dots and two decaheme cytochromes on photoanodes. The effect of NP surface chemistry was assessed by preparing NPs capped with amine or carboxylic acid functionalities. For the TiO2 nanocrystals, binding to the cytochromes was optimal when capped with a carboxylic acid ligand, whereas for the CdS QDs, better adhesion was observed for amine capped ligand shells. When using TiO2 nanocrystals, dye-sensitized with a phosphonated bipyridine Ru(II) dye, photocurrents are observed that are dependent on the redox state of the decaheme, confirming that electrons are transferred from the TiO2 nanocrystals to the surface via the decaheme conduit. In contrast, when CdS NPs are used, photocurrents are not dependent on the redox state of the decaheme, consistent with a model in which electron transfer from CdS to the photoanode bypasses the decaheme protein. These results illustrate that although the organic shell of NPs nanoparticles crucially affects coupling with proteinaceous material, the coupling can be difficult to predict or engineer. PMID- 28920011 TI - Perceived Racial/Ethnic Discrimination and Mental Health: a Review and Future Directions for Social Epidemiology. AB - PURPOSE OF REVIEW: Recent literature on racial or ethnic discrimination and mental health was reviewed to assess the current science and identify key areas of emphasis for social epidemiology. Objectives of this review were to: 1) Determine whether there have been advancements in the measurement and analysis of perceived discrimination; 2) Identify the use of theories and/or frameworks in perceived discrimination and mental health research; and 3) Assess the extent to which stress buffers are being considered and evaluated in the existing literature. RECENT FINDINGS: Metrics and analytic approaches used to assess discrimination remain largely unchanged. Theory and/or frameworks such as the stress and coping framework continue to be underused in majority of the studies. Adolescents and young adults experiencing racial/ethnic discrimination were at greater risk of adverse mental health outcomes, and the accumulation of stressors over the life course may have an aggregate impact on mental health. Some growth seems evident in studies examining the mediation and moderation of stress buffers and other key factors with the findings suggesting a reduction in the effects of discrimination on mental health. SUMMARY: Discrimination scales should consider the multiple social identities of a person, the context where the exposure occurs, how the stressor manifests specifically in adolescents, the historical traumas, and cumulative exposure. Life course theory and intersectionality may help guide future work. Despite existing research, gaps remain in in elucidating the effects of racial and ethnic discrimination on mental health, signaling an opportunity and a call to social epidemiologists to engage in interdisciplinary research to speed research progress. PMID- 28920012 TI - Comparative Effectiveness for Glycemic Control in Older Adults with Diabetes. AB - PURPOSE OF REVIEW: To review and summarize the current data for comparative effectiveness of glycemic control in older adults. RECENT FINDINGS: In the last several years, professional societies have released guidelines for glycemic control in older adults, generally recommending individualized HbA1c goals. However, recent observational studies demonstrate that many older adults remain aggressively managed and are at increased risk of hypoglycemia. Large randomized trials of older adults with diabetes have failed to show cardiovascular benefit from intensive glycemic control and show only minimal microvascular benefit. Additionally, a few studies suggest that suboptimal glycemic control can increase the risk for geriatric syndromes. Emerging research suggests similar safety and efficacy of glucose-lowering therapies in older versus younger adults. SUMMARY: Overall, there is a paucity of data supporting the benefit of intensive glycemic control in older adults. More research is needed in this vulnerable population. PMID- 28920014 TI - Plasma fibroblast growth factor-21 levels in patients with inborn errors of metabolism. AB - Fibroblast growth factor-21 (FGF21) levels are elevated in patients with primary mitochondrial disorders but have not been studied in patients with inborn errors of metabolism (IEM) known to have secondary mitochondrial dysfunction. We measured plasma FGF21 by ELISA in patients with and without IEM. FGF21 levels were higher in patients with IEM compared to without IEM (370 pg/dL vs. 0-65 pg/dL). Further study of FGF21 as a biomarker in IEM is warranted. PMID- 28920013 TI - Transcriptional Regulation of Stem Cell and Cancer Stem Cell Metabolism. AB - PURPOSE OF REVIEW: Metabolism is increasingly recognized as a major player in control of stem cell function and fate. How stem cell metabolism is established, maintained, and regulated is a fundamental question of biology and medicine. In this review, we discuss major metabolic programs in stem cells and cancer stem cells, with a focus on key transcription factors that shape the stem cell metabolic phenotype. RECENT FINDINGS: Cancer stem cells primarily use oxidative phosphorylation for energy generation, in contrast to normal stem cells, which rely on glycolytic metabolism with the exception of mouse embryonic stem cells. Transcription factors control the metabolic phenotype of stem cells by modulating the expression of enzymes and thus the activity of metabolic pathways. It is evident that HIF1alpha and PGC1alpha function as master regulators of glycolytic and mitochondrial metabolism, respectively. SUMMARY: Transcriptional regulation is a key mechanism for establishing specific metabolic programs in stem cells and cancer stem cells. PMID- 28920015 TI - Working with bacteria and putting bacteria to work: The biopolitics of synthetic biology for energy in the United Kingdom. AB - The UK government has made significant investment into so called 'fourth generation' biofuel technologies. These biofuels are based on engineering the metabolic pathways of bacteria in order to create products compatible with existing infrastructure. Bacteria play an important role in what is promoted as a potentially new biological industrial revolution, which could address some of the negative environmental legacies of the last. This article presents results from ethnographic research with synthetic biologists who are challenged with balancing the curiosity-driven and intrinsically fulfilling scientific task of working with bacteria, alongside the policy-driven task of putting bacteria to work for extrinsic economic gains. In addition, the scientists also have to balance these demands with a new research governance framework, Responsible Research and Innovation, which envisions technoscientific innovation will be responsive to societal concerns and work in collaboration with stakeholders and members of the public. Major themes emerging from the ethnographic research revolve around stewardship, care, responsibility and agency. An overall conflict surfaces between individual agents assuming responsibility for 'stewarding' bacteria, against funding systems and structures imposing responsibility for economic growth. We discuss these findings against the theoretical backdrop of a new concept of 'energopolitics' and an anthropology of ethics and responsibility. PMID- 28920016 TI - Comparison of T Tube Ileostomy and Bishop Koop Ileostomy for the Management of Uncomplicated Meconium Ileus. AB - BACKGROUND: Meconium ileus is a common cause of neonatal intestinal obstruction. Various surgical procedures are in practice for uncomplicated meconium ileus. Bishop Koop ileostomy allows distal passage of gut content and uses the distal absorptive area. T tube ileostomy avoids the need for gut resection and formal closure of stoma. The aim of this prospective interventional study was to compare the outcome of T-tube ileostomy and Bishop Koop ileostomy for the treatment of uncomplicated meconium ileus. MATERIALS AND METHODS: It was a prospective interventional study from January 2015 to December 2016. Patients were randomly assigned to the T-tube ileostomy group (group A) and Bishop Koop ileostomy group (group B). The patients were followed up for 6 weeks post-operatively. Surgical outcomes between the two groups were compared. RESULTS: The age range of the patients was 1 to 7 days; majority of the patients were males. Mean operation time of group A (60.76+/-5.81 minutes) and group B (87.05+/-6.49 minutes) showed significant difference (p =0.0001). After operation, mean time to start bowel movements in group A (4.90+/-1.41days) and group B (6.53+/-2.58 days) showed significant difference (p= 0.020). Times to establish oral feeding, irrigation tube removal and postoperative complications showed no significant difference. All patients that survived in the group B required formal stoma closure, while in the group A stomas closed spontaneously. One patient in the group A had intraperitoneal leakage leading to mortality after second operation. Four patients had leakage in the group B; 2 of them died. CONCLUSIONS: T-tube ileostomy was found as an effective and safe procedure for the management of uncomplicated meconium ileus. PMID- 28920017 TI - Esophageal Atresia with Tracheo-Esophageal Fistula Presenting Beyond 7 Days. AB - AIM: To describe our experience of neonates with esophageal atresia with tracheo esophageal fistula (EA with TEF) who presented after a week. DESIGN: Retrospective study of the patients of EA with TEF who presented after a week. STUDY SETTING: Department of Pediatric Surgery, Government Medical College Nagpur. Study Duration: Eight years. MATERIALS AND METHODS: Demographic information, hematological, biochemical and radiological data were obtained from the patients' medical records. The gap between two ends of the esophagus, nature of upper pouch and lower esophagus were noted intra-operatively. Outcome in terms of mortality and surgical complications were noted. In operated group, babies who survived were compared with non-survivors with respect to various preoperative variables. RESULTS: Of 52 patients, 27 babies expired during initial stabilisation period before surgery. The causes of mortality were severe pneumonitis and septicemia. One baby had associated cyanotic heart disease. Twenty-five patients with mean age of 8.28+/-1.21 days underwent surgery. Nearly two-third of them were male. All of them were born at full-term with mean birth weight of 2.47+/-0. 12 kg. More than 80% were previously hospitalised and nearly 70% babies were given feeds before present hospitalization. Mean Downe's score for respiratory distress was 5.8+/-1.49. All patients were positive for septic profile. Associated congenital anomalies were present in ten patients. Intra operatively, two ends of esophagus were either approximating or have short gap in 24 patients. All patients had well developed, thick and muscular upper oesophageal pouch. Lower esophagus at fistula was thin but dilated in 18 patients while thin and narrowed in 7 patients. However, esophageal anastomosis was possible with ease without any tension in all except one patient. There were 15 deaths in our study (13 due to pneumonitis and 2 during follow up due to aspiration). Three survivors required anti-reflux surgery. Comparison of preoperative variables of survivors and non-survivors showed a significant difference with respect to the variables like feedings, abdominal girth, immature band cells to neutrophil ratio and nature of pharyngeal or endotracheal aspirate. CONCLUSIONS: Late presentations in EA with TEF are associated with high mortality but less anastomotic complications after surgery. Preoperative factors like feedings, abdominal distension, immature band cells to neutrophil ratio and bilious pharyngeal or endotracheal aspirate are associated with high mortality. PMID- 28920019 TI - Minimal Access Surgery in Neonates. AB - Despite the significant advancement of minimally invasive surgery (MIS) in the adults and even in pediatric population, its role as the standard of care in the neonates has not yet been established among the pediatric and neonatal surgeons universally. Lots of controversies still arise though several advanced centers in the world having very experienced surgeons performing MIS for neonatal surgical conditions with promising outcomes. The unique physiological characteristics of a neonate make MIS quiet a challenging subject among these tiny babies. We have tried to look into the recent literature on the issues related to the use of MIS for the surgical management of neonates. PMID- 28920018 TI - Neonatal Sex Assignment in Disorders of Sex Development: A Philosophical Introspection. AB - Management of ambiguous genitalia is highly controversial. This condition was known previously as intersex and presently as disorders of sex development (DSD). There is no consensus regarding the choice, timing and method of sex assignment in neonates with DSD. Consensus conferences could not unify the views of various stakeholders and third parties. This article philosophically examines the nature and origin of such controversies. Misconception, bias and conflicting priorities are identified as the three cardinal sources of controversies. Conceptual duality of sexes, confused notion of sex and gender, bias towards penetrative intercourse, conflict between utopian ideals and reality, unwillingness to compromise are identified as perpetuators of controversies. Suggestions are made regarding sex assignment in various types of DSD based on the understanding of published literature and the author's personal experience. PMID- 28920020 TI - Neonatal Perforated Appendicitis Attributed to Localized Necrotizing Enterocolitis of the Appendix: A Review. AB - Neonatal appendicitis is a rare clinical entity associated with remarkable morbidity and mortality. Appendicular perforation is common and the diagnosis is usually made intra-operatively. The causative etiology of neonatal perforated appendicitis (NPA) is a subject of debate and has not been elucidated. Although many etiologic theories exist, increasing evidence suggests a subset of NPA cases may represent a form of necrotizing enterocolitis (NEC) localized to the appendix. We herein present a review of the current literature to include cases of NPA attributed to localized NEC. A high index of clinical suspicion and early laparotomy are recommended. PMID- 28920021 TI - Closed Gastroschisis. AB - Closed gastroschisis is a rare entity usually associated with intestinal atresia and short bowel syndrome. We report two cases of closed gastroschisis presenting with neonatal intestinal obstruction and para-umbilical evisceration without an abdominal defect. PMID- 28920022 TI - Familial Near-Total Intestinal Aganglionosis. AB - Near total aganglionosis represents the most extreme and rare form of Hirschsprung's disease. It can affect more than one member of family. We report three cases of near total intestinal aganglionosis in a family presenting with intestinal obstruction at birth. All of them were operated and a jejunostomy was performed. Outcome was dismal. PMID- 28920023 TI - Re-Tubularization of Highly-Ischemic Anti-Mesenteric Border (ReHAB): A Novel Bowel Preservation Technique in Complex Gastroschisis. AB - Complex gastroschisis with bowel necrosis poses an operative challenge. Surgeons must weigh the decision between resection versus preservation of ischemic bowel. As one of the leading causes of short bowel syndrome, aggressive resection in complicated gastroschisis subjects children to prolonged dependence on parenteral nutrition and its attendant complications. Herein, we describe a novel technique aimed towards bowel preservation in complex gastroschisis patients with severe bowel ischemia with the ultimate goal for enteral autonomy. PMID- 28920024 TI - Use Of Appendix As Neoureter- A Ray Of Hope. AB - A case of antenatally diagnosed hydronephrosis (later known to be PUJO complicated with urinoma and associated with hypoplasia of entire ureter) was treated using vermiform appendix as replacement. PMID- 28920025 TI - A Rare Case of Thoracoschisis. AB - A term male baby, after delivery, was found to have a 3-centimeter beefy-red mass protruding from the left chest wall, adjacent to the left nipple. Radiological imaging suggested it's origin from the left lateral liver segment. A diagnostic laparoscopy confirmed the isolated connection to the liver, elevated left hemidiaphragm, and protrusion between the ribs. The mass was excised using electrocautery, and pathologic examination showed normal liver tissue. PMID- 28920026 TI - Giant Cervico-Thoracic Cystic Hygroma in a Preterm: A Case Report. AB - Cystic hygroma is a benign, painless loculated lymphatic proliferation, which occur due to a combination of sequestration from developing lymphatic system, abnormal budding of the lymphatic system or lack of development of the normal connections between venous and lymphatic drainage. We report a case of giant cervico-thoracic cystic hygroma in a preterm neonate with management options and a brief review of literature. PMID- 28920027 TI - Rupture of Umbilical Hernia with Evisceration in a Newborn - A Case Report. AB - Most umbilical hernias in infants do not need surgery and the ring will eventually close. Occasionally few complications can arise and incarceration is most common. Spontaneous rupture of the hernia and eventual evisceration is a rarely seen complication. A 3-week-old neonate having umbilical hernia presented with rupture of the sac with evisceration of bowel within a few days of first visit. No underlying cause like umbilical sepsis was found. The baby had emergency repair of the hernia with an uneventful recovery. PMID- 28920028 TI - Type I Jejunal Atresia in Identical Twins: A Rare Occurrence. AB - Jejunoileal atresia is of familial and non-familial in origins and classified into four different types. We herein report a rare occurrence of type I jejunal atresia in identical twins who were presented with neonatal intestinal obstruction. This report points towards common etiology of atresia in our cases and factors more than vascular accident appear to be involved. PMID- 28920029 TI - Exstrophy Bladder with Low Anorectal Malformation- A Rare Association. PMID- 28920030 TI - Left-Sided Gastroschisis with Meckel's Diverticulum: A Rare Presentation. PMID- 28920031 TI - Enteroscrotal Fistula in a Neonate following Incarcerated Inguinal Hernia. PMID- 28920032 TI - Periurethral Abscess in a Neonate. PMID- 28920033 TI - Perforated Meckel's Diverticulum causing Intussusception in a Neonate. PMID- 28920034 TI - The Use of Intraoperative Transesophageal Echocardiography in Thoracic Aortic Dissection Due to Chronic Cocaine Abuse. AB - INTRODUCTION: Aortic dissection is a life threatening disease and is usually accompanied by a high rate of mortality and morbidity. Here we present a case report in which intraoperative tranesophageal echocardiography was used for intraoperative assessments of thoracic aortic dissection due to cocaine abuse. CASE PRESENTATION: A 45- year- old male was admitted to a university hospital due to severe chest pain. He was suffering from severe excruciating chest pain that had started after a psychological stress, leading to heavy cocaine abuse. He was admitted to the emergency department of the hospital, and was then transferred to the cardiac care unit to control the chest pain. The patient underwent emergent surgery. After induction of anesthesia, tranesophageal echocardiography probe was introduced gently and a full exam was done. The surgeon decided to perform a classic Bentall procedure. Cardiopulmonary bypass was started. Everything was acceptable, but bleeding was uncontrolled. The surgical team could not control the bleeding, and he passed away due to bleeding. CONCLUSIONS: This case report stresses the use of IOTEE as a means for more accurate diagnosis of the lesion under general anesthesia, especially when there is not time to do preoperative TEE, or when bedside echocardiography does not give us adequate data. PMID- 28920035 TI - Anesthesia Management of a Patient with Papillon-Lefevre Syndrome: A Case Report. AB - INTRODUCTION: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive trait; it often requires some interventions with general anesthesia because of the accompanied complications. CASE PRESENTATION: We report a 19-year-old girl with palmoplantar hyperkeratosis who presented total loss of her teeth. She was candidate to mandibular bone graft and lower jaw dental implants under general anesthesia. CONCLUSIONS: There are only a few studies about perioperative management of these patients; however, the anesthesiologists should consider a few important issues during pre-operative and intra-operative management. PMID- 28920036 TI - Hematoma Block Versus General Anesthesia in Distal Radius Fractures in Patients Over 60 Years in Trauma Emergency. AB - BACKGROUND: Distal radius fractures are among common fractures in the elderly. Regarding the age, background diseases, and possible risks, analgesia method is of great importance in this group. OBJECTIVES: The aim of this study was to compare two analgesia methods including hematoma block and general anesthesia in people over 60 years in the orthopedic emergency department. METHODS: 68 elderly patients referring to the emergency department of a medical teaching center were selected based on the inclusion criteria for a non-randomized clinical trial. The patients were placed in two groups of 34, which were matched for age and sex. Hematoma block was used as the analgesic method in one group and general anesthesia was used in the other group. These two groups were compared for pain intensity, analgesia duration, and anesthesia side effects. The SPSS software (Statistical Package for the Social Sciences, version 17.0, SPSS Inc., Chicago, Ill, USA) was used for data analysis. RESULTS: 68 elderly patients (mean age of 70.3 +/- 6.6) with a dislocated distal radius fracture which required closed reduction were examined. The duration of manipulation and surgery and discharging time were significantly different between two groups and they were all lower in the hematoma blocked group. Pain intensity evaluation indicated a statistically significant difference during initial hours after fracture reduction and fixation so that pain intensity was less in elderly patients under hematoma block than patients who underwent general anesthesia in one and six hours after surgery. Need for narcotic was 35.2% in the general anesthesia group which also showed a significant between-group difference. CONCLUSIONS: Hematoma block analgesia used in distal radius fractures of the elderly is a very safe and effective method that seems preferable to general anesthesia in emergency departments. PMID- 28920037 TI - The Management of Chronic Pain; Caught Between a Rock and a Hard Place: The Case for a Renewed Focus on Provider, Patient, and Payer Education. PMID- 28920038 TI - Comparing the Effect of Preoperative Administration of Melatonin and Passiflora incarnata on Postoperative Cognitive Disorders in Adult Patients Undergoing Elective Surgery. AB - BACKGROUND: Anxiety is a preoperative complication, which most patients encounter. The use of a premedication to reduce preoperative anxiety with minimal cognitive impairment is crucial. OBJECTIVES: This study was conducted to compare the sedative effect of preoperative melatonin and Passiflora incarnata in patients undergoing elective surgery regarding their potential for postoperative cognitive disorders. METHODS: In this clinical trial, 52 patients American society of anesthesiologists grade (ASA) I and II of both genders were selected to receive either Passiflora incarnata (1000 mg nature made) (n = 26) or melatonin (6 mg) (n = 26) as premedication one hour before surgery. Post operative pain was evaluated using the visual analogue scale (VAS). Patient's anxiety and cognitive dysfunction was evaluated with the Ramsey score and the digital symbol substitution test (DSST), respectively. All tests were carried out and evaluated at arrival in the operating room, before induction and before discharge from the post anesthesia care unit (PACU). RESULTS: There were no statistically differences between groups in VAS (P > 0.05). However, the mean score of pain was higher in the melatonin group compared to the Pssiflora incarnata group when discharged from the PACU (27.63 vs. 25.37). The anxiety scores were statistically significant in both drugs (P = 0.001), however higher sedation scores was caused by premedication with melatonin (P = 0.003 vs. 0.008). Regarding the DSST, there was a significant difference between the two groups one hour before the surgery (P = 0.04) and at the time of discharge from the PACU (P = 0.007). When evaluating each group, the Passiflora incarnata group revealed a significant difference (P = 0.003). CONCLUSIONS: Our findings show that premedication with Passiflora incarnata reduces anxiety as well as Melatonin. However, Melatonin causes less cognitive impairment compared to Passiflora incarnata. PMID- 28920039 TI - Treatment Option for Refractory Postherpetic Neuralgia - Transversus Abdominis Plane (TAP) Block: Two Case Reports. AB - Postherpetic neuralgia (PHN) is a severe neuropathic pain syndrome. The treatment of PHN is complex and refractory in some patients. We present two cases with refractory anterior abdominal wall pain due to PHN that were successfully treated with transversus abdominis plane (TAP) block. The TAP block seems to be an alternative for patients with PHN who suffer from anterior abdominal wall pain accompanied by allodynia and hyperalgesia and do not respond to the existing conservative treatments. PMID- 28920041 TI - Dexamethasone Increases the Frequency of Post-Dural Puncture Headache (PDPH): An Evidence Based Reality. PMID- 28920040 TI - Parasympathetic Cholinergic and Neuropeptide Mechanisms of Migraine. AB - CONTEXT: Migraine mechanisms remain largely uncovered for various reasons including a very high complexity of the neurophysiological mechanisms implicated in this disorder and a plethora of endogenous biologically active compounds involved in the pathological process. The functional role of parasympathetic innervation of meninges and cholinergic mechanisms of migraine are among little explored issues despite multiple evidence indirectly indicating the role of acetylcholine (ACh) and its analogues in migraine and other types of headache. In the current short review, we discuss morphological, functional, and clinical issues related to the role of ACh and its analogues such as carbachol and nicotine in this most common neurological disorder. EVIDENCE ACQUISITION: In the present work, studies published from 1953 to 2016 were investigated. Literature was searched with following keywords: acetylcholine (ACh), carbachol, nicotine, parasympathetic, mast cells, vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP). RESULTS: Parasympathetic fibers originated from SPG and trigeminal nerves can interact at the level of meninges which is considered to be the origin site of migraine pain. Here, in dura mater, ACh, VIP, and PACAP released by parasympathetic afferents can both affect mast cells provoking its degranulation and additional release of neurotransmitters, or they can directly affect trigeminal nerves inducing nociception. CONCLUSIONS: In summary, cholinergic mechanisms in migraine and other types of headache remain little elucidated and future studies should clarify the role of parasympathetic nerves and molecular mechanisms of cholinergic modulation within the nociceptive system. PMID- 28920042 TI - Mitochondrial ATP-Sensitive Potassium Channels Play a Role in Reducing Both Myocardial Infarction and Reperfusion Arrhythmia in Remote Ischemic Preconditioned Hearts. AB - BACKGROUND: Mitochondrial ATP-sensitive potassium (mKATP) channels play a role in reperfusion arrhythmias (RAs) in ischemia-reperfusion (I/R) injury. Evidence suggests that remote ischemic preconditioning (RIPC) reduces RAs, however not much is known on the mechanistic role of mKATP in RIPC. We evaluated whether mKATP channels are associated with reducing arrhythmia and infarct size in RIPC. METHODS: Isolated rat hearts received 30 minutes of regional ischemia followed by 2 hours of reperfusion through the Langendorff perfusion system. RIPC was induced by 3 cycles of 5 minutes occlusion and 5 minutes release of the bilateral femoral artery. The animals were randomly divided into 4 groups as follows: 1) CON, I/R injury but not RIPC, 2) RIPC, 3) HD+RIPC, pretreatment of the selective mKATP channel blocker, 5-hydroxydecanoate (5-HD), in RIPC, and 4) HD, pretreatment of 5 HD in CON. Cardiodynamics and infarct size were determined. The severity of arrhythmia was quantitated via the Curtis and Walker scoring system as well as the Lepran scoring system. RESULTS: RIPC significantly reduced the infarct size over AR (25.7 +/- 2.6%) compared to CON (37.0 +/- 2.6%, P < 0.05). The selective mKATP channel blocker 5-HD significantly inhibited the infarct-reducing effect of RIPC (39.3 +/- 3.0%, P < 0.05 vs. RIPC). Additionally, RIPC significantly reduced the arrhythmia score compared to CON (14.6 +/- 1.9 to 8.7 +/- 0.4, P = 0.023, by Curtis and Walker's system, 16.1 +/- 2.1 to 9.1 +/- 0.5, P = 0.006, by Lepran's system). The anti-arrhythmic effect of RIPC was blocked by 5-HD (15.5 +/- 1.6 and 16.0 +/- 1.2, by Curtis and Walker's and Lepran's system, respectively). CONCLUSIONS: The selective mKATP channel blocker, 5-HD, inhibited the infarct limitation and anti-arrhythmic effect of RIPC. The mKATP channels play a role in the reduction of both infarct size and RAs in RIPC. PMID- 28920044 TI - Effect of Multisensory Stimulation on Pain of Eye Examination in Preterm Infants. AB - BACKGROUND: Eye examination as one of the painful procedures for retinopathy of prematurity screening can cause some pain-related physiological and behavioral changes in preterm infants. Multisensory stimulation is an analgesic non pharmacological method that has analgesic effects on infants during painful procedures. OBJECTIVES: This study aimed to determine the effect of multisensory stimulation on induced pain during eye examination for retinopathy of prematurity screening in preterm infants. METHODS: In this double-blind clinical trial, 80 preterm infants were randomly divided into two groups. In the intervention group, multisensory stimulation program was performed for 15 minutes before the beginning of examination while the control group received the routine care. Pain score for each infant was recorded by premature infant pain profile. Data were analyzed using independent t-test, Mann-Whitney, and ANOVA with repeated measures by SPSS software (version 16). RESULTS: The mean gestational age was 30.4 +/- 1.7 weeks in the multisensory stimulation group and 30.6 +/- 1.8 weeks in the control group. Based on ANOVA with repeated measures, the pain score was significantly different between two groups during the assessment process (P < 0.001). The changes in pain severity during the examination were also significant between the two groups (P < 0.001); so that the pain was more intensive in the control group than the intervention group. CONCLUSIONS: Multisensory stimulation program as a safe and easy method can reduce pain in neonates and may be used as a way to reduce pain during eye examination in infants. PMID- 28920045 TI - Post-Spinal Headache: A New Possible Pathophysiology. PMID- 28920043 TI - Short Term Analgesic Effects of 5% Dextrose Epidural Injections for Chronic Low Back Pain: A Randomized Controlled Trial. AB - BACKGROUND: Hypertonic dextrose injection (prolotherapy) is reported to reduce pain including non-surgical chronic low back pain (CLBP), and subcutaneous injection of 5% dextrose is reported to reduce neurogenic pain, hyperalgesia and allodynia. The mechanism in both cases is unclear, though a direct effect of dextrose on neurogenic pain has been proposed. This study assessed the short-term analgesic effects of epidural 5% dextrose injection compared with saline for non surgical CLBP. METHODS: Randomized double-blind (injector, participant) controlled trial. Adults with moderate-to-severe non-surgical low back pain with radiation to gluteal or leg areas for at least 6 months received a single epidurogram-confirmed epidural injection of 10 mL of 5% dextrose or 0.9% saline using a published vertical caudal injection technique. The primary outcome was change in a numerical rating scale (NRS, 0 - 10 points) pain score between baseline and 15 minutes; and 2, 4, and 48 hours and 2 weeks post-injection. The secondary outcome was percentage of participants achieving 50% or more pain improvement at 4 hours. RESULTS AND CONCLUSIONS: No baseline differences existed between groups; 35 participants (54 +/- 10.7 years old; 11 female) with moderate to-severe CLBP (6.7 +/- 1.3 points) for 10.6 +/- 10.5 years. Dextrose participants reported greater NRS pain score change at 15 minutes (4.4 +/- 1.7 vs 2.4 +/- 2.8 points; P = 0.015), 2 hours (4.6 +/- 1.9 vs 1.8 +/- 2.8 points; P = 0.001), 4 hours (4.6 +/- 2.0 vs 1.4 +/- 2.3 points; P < 0.001), and 48 hours (3.0 +/- 2.3 vs 1.0 +/- 2.1 points; P = 0.012), but not at 2 weeks (2.1 +/- 2.9 vs 1.2 +/- 2.4 points; P = 0.217). Eighty four percent (16/19) of dextrose recipients and 19% (3/16) of saline recipients reported >= 50% pain reduction at 4 hours (P < 0.001). These findings suggest a neurogenic effect of 5% dextrose on pain at the dorsal root level; waning pain control at 2 weeks suggests the need to assess the effect of serial dextrose epidural injections in a long-term study with robust outcome assessment. PMID- 28920046 TI - The Effect of Intraoperative Alkali Treatment on Recovery from Atracurium-Induced Neuromuscular Blockade in Renal Transplantation: A Randomized Trial. AB - BACKGROUND: Intraoperative care and anesthesia method in patients undergoing allograft renal transplantation surgery are very necessary. Acid-base imbalance can alter neuromuscular blockade and recovery time. OBJECTIVES: The aim of the present study was to investigate the effect of acid-base balance on atracurium blockade in renal transplantation. METHODS: In this randomized-controlled trial, 31 end-stage renal disease (ESRD) patients undergoing renal transplantation were randomly assigned into two equal groups. The case group received intravenous sodium bicarbonate based on base excess in the first ABG sample, while the control group received sterile water for injection during the interval between anesthesia and beginning of surgery. Arterial blood gas (ABG) sample was drawn first prior to surgery and again at declamping time. Train-of-four (TOF) was measured before anesthesia and repeatedly after declamping time until acceptable recovery (TOF 3 of 4). The time of achieving TOF 3 was recorded and compared between the groups. RESULTS: There was no significant difference in blood pH between the groups in the first evaluation (P = 0.649). The pH and base excess (BE) in the case group significantly increased after the intervention. There was a significant decrease in after-surgery measurement of pH in the control group (P = 0.011). The mean time to achieve TOF = 3 was 23.75 +/- 5.32 and 41.80 +/- 5.2 minutes after declamping in the case and control groups, respectively. Patients in the sodium bicarbonate group achieved TOF = 3 significantly faster than the control group. CONCLUSIONS: Based on our results, intraoperative alkali and acid base imbalance treatment can reduce neuromuscular blockade and recovery time, and it can be regarded as a potential casual factor to enhance transplantation outcome. PMID- 28920047 TI - The Effects of Endotracheal Tube and i-gel(r) Supraglottic Airway Device on Respiratory Impedance: A Prospective Observational Study. AB - BACKGROUND: The forced oscillation technique (FOT) is a non-invasive means of measuring respiratory resistance and reactance. We tested our hypothesis that endotracheal intubation would cause more substantial preoperative increases in FOT parameters than a supraglottic airway device (SGD). METHODS: Forty patients requiring general anesthesia and mechanical ventilation for transurethral bladder tumor resection underwent spirometry the day before surgery. Forced oscillation was measured using a MostGraph-01 device the day before surgery and immediately after removal of the airway adjunct. Changes in respiratory resistance and reactance were compared between those intubated and those who used SGD. RESULTS: The trachea was intubated in 23 patients and SGD was used in the remaining 17 patients. Both airway adjuncts caused significant increases in preoperative respiratory resistance and reactance; however, the magnitude of the changes was significantly greater in the intubated patients. CONCLUSIONS: The SGD appears to cause less pulmonary injury than tracheal intubation. Further study is needed to illuminate the influence of mechanical ventilation, and longer-term consequences and clinical significance of the changes we found in this study. Spontaneous ventilation through an SGD may be preferable in patients with severe respiratory disease. PMID- 28920048 TI - Continuous Transversus Abdominis Plane (TAP) Block and Intraoperative Coeliac Plexus Block (CPB) for Post-Operative Analgesia Following Laparotomy: Two Case Reports. PMID- 28920049 TI - Effect of Selenium on Stress Response in Coronary Artery Bypass Graft Surgery: A Clinical Trial. AB - BACKGROUND: In spite of significant improvements in surgical and anesthetic techniques, acute stress response to surgery remains a main cause of mortality and morbidity in coronary artery bypass graft (CABG) surgery patients. Therefore, doing research to find safe and effective modalities with more cardio protective properties seems necessary. OBJECTIVES: In this study, we sought to determine whether intravenous injection of 600 MUg Selenium (Se) prior to surgery would limit stress response measured by blood sugar. METHODS: This double blind clinical trial was conducted at a referral center of cardiac surgery affiliated to Guilan University of Medical Sciences (GUMS) from June 2015 to October 2015. 73 eligible patients candidate for elective isolated CABG surgery were enrolled in the trial. They were randomly allocated to either Se group (n = 36) receiving 600 MUg Se prior to surgery or control group (n = 37). Our evaluation was based on blood sugar (BS) which was measured at four point times, including before induction of anesthesia (T0), at the end of CPB (T1), 24 hours (T2) and 48 hours (T3) after surgery. RESULTS: The data obtained from 73 patients in group S (n = 36) and group C (n = 37) were analyzed. There was no significant difference between the two groups regarding the baseline characteristics. In both groups, a sharp rise in BS levels was observed following CPB (P = 0.0001). Although the trend of BS changes was remarkable in both groups (P = 0.0001), there was no statistically significant difference between the groups at all point times including T0 (P = 0.45), T1 (P = 0.48), T2 (P = 0.92), and T3 (P = 0.42). Within the study time, our patients were monitored for any adverse effect but nothing was observed. CONCLUSIONS: This investigation showed that intravenous single dose of 600 MUg Se was safe in CABG patients, but had no positive effect on stress response to surgery. PMID- 28920050 TI - Management of Chronic Daily Headache and Psychiatric Co-Morbidities by Lifestyle Modification: Participatory Action Research Combining New Communication Media. AB - BACKGROUND: Lifestyle modification has a significant role in chronic daily headache (CDH) management. Participatory action research (PAR) can play an important role in managing chronic medical conditions. However, it has been scarcely used in CDH management. OBJECTIVES: This study aimed to empower patients with CDH to modify their lifestyle in order to reduce both their headache and related psychiatric co-morbidities in a multidisciplinary headache clinic at Baqiyatallah hospital, Tehran, IR Iran. METHODS: In the PAR plan, 37 patients (27 females) diagnosed with CDH were selected using purposeful sampling. Along with face-to-face group sessions, all available communication means such as phone calls, emails, short message system (SMS), and social media (Telegram) were used to facilitate the process. Questionnaires of health promotion lifestyle profile (HPLPII), visual analog scale (VAS), and depression-anxiety-stress scale (DASS21) were used to collect data. The data were analyzed using SPSS software. RESULTS: Mean age of the patients was 38.33 (+/- 9.7) years. Both "general pain" and "the worst imaginable pain" reduced (mean of reduction: 2.56 +/- 2.7 and 2.3 +/- 2.9, respectively, P < 0.001). > 50% of pain reduction occurred in "the worst imaginable pain" category (-1.45 +/- 2.02, P < 0.001) and mean VAS score reduced to 5.20 (+/- 2.3) compared to the start of the study (7.50 +/- 1.9, P < 0.001). Mean DASS-21 score also reduced significantly for depression (P < 0.016), anxiety (P < 0.026), and stress (P < 0.008). HPLPII score significantly improved (118.17 +/- 14.8 vs. 160.83 +/- 16.4, P < 0.001) and the highest increase was seen in the subscale of "stress management" (17.73 +/- 2.8 vs. 25.53 +/- 3.9, P < 0.001). CONCLUSIONS: The empowering PAR plan combined with new communication tools helped the CDH patients better handle their lifestyle, reduce their headache, and lower their symptoms. Further studies with better use of currently available communication tools and social media are recommended for action research to be more applicable. PMID- 28920051 TI - Comparison of 1- and 2-Minute Sitting Positions Versus Immediately Lying Down on Hemodynamic Variables After Spinal Anesthesia with Hyperbaric Bupivacaine in Elective Cesarean Section. AB - BACKGROUND: Hypotension is one of the most common complications of spinal anesthesia in parturients undergoing cesarean section. In this regard, the patient's position may affect the incidence of hypotension. OBJECTIVES: In this clinical trial, we evaluated the effects of 1- and 2-minute sitting positions versus immediately lying down after spinal anesthesia on hypotension and vasopressor requirements. METHODS: A total of 72 parturients, scheduled for cesarean section under spinal anesthesia, were randomly divided into 3 groups (24 subjects per group). Groups S1 and S2 remained in a sitting position for 1 and 2 minutes after the induction of spinal anesthesia, respectively, while group T was immediately placed in a lying position. Systolic, diastolic, and mean arterial blood pressure, as well as heart rate, was recorded at 1, 2, 3, and 5 minutes after anesthesia induction, every 5 minutes during the first 30 minutes of surgery, and then every 10 minutes until the end of surgery. P-value less than 0.05 was considered statistically significant. RESULTS: The overall frequency of hypotension was 50 (69%) cases during surgery; the reported frequency was higher in group T in comparison with group S2 (P = 0.003). The frequency of hypotension before delivery (the first 5 minutes after spinal anesthesia) was 40 (55%) cases, with a higher frequency reported in group T (20, 83%), compared to groups S1 (12, 50%) and S2 (8, 33%) (P = 0.03 and P = 0.001, respectively). The ephedrine requirement in group T (11.73 +/- 7.16 mg) was higher than the other two groups (8.69 +/- 7.57 and 7.82+/-7.95 mg in groups S1 and S2, respectively); nevertheless, the difference was not statistically significant (P = 0.19). Moreover, the difference in time to achieve T6 sensory level was only significant between group T (3.25 +/- 1.1 minutes) and group S2 (4.73 +/- 1.73 minutes) (P = 0.03). CONCLUSIONS: The present study showed that 1- or 2-minute sitting position after spinal anesthesia with 2.5 cc of hyperbaric bupivacaine in elective cesarean section results in more hemodynamic stability, compared with immediately lying down. PMID- 28920052 TI - The Effect of Intravenous Magnesium Sulfate Versus Intravenous Sufentanil on the Duration of Analgesia and Postoperative Pain in Patients with Tibia Fracture. AB - BACKGROUND: In the recent decades controlling postoperative pain has become a popular topic as it leads to the patients' wellbeing and improved life quality, while it reduces the costs for both patients and medical facilities. OBJECTIVES: This study aimed at comparing intravenous magnesium sulfate versus intravenous sufentanil on the duration of analgesia and postoperative pain in patients undergoing tibia fracture surgery. METHODS: This double blind clinical trial study was performed on 70 candidates of tibia fractures between the ages of 18 and 55 years with American society of anesthesiologists (ASA) class I and II. The patients were randomly divided to 2 groups, 1 receiving magnesium sulfate (M) and another receiving sufentanil (S). Both of the groups underwent spinal anesthesia with 10 mg bupivacaine 0.5%. One hour after ensuring the sensorimotor blockade, in the S group 0.1 ug/kg/hour and in the M group 8 mg/kg/hour was diluted in 1 liter of Ringer's solution and infused. In this study, full weakness of the lower limb was considered as the sign of sensorimotor blockade initiation. The postoperative pain intensity was measured using the Visual Analog Scale (VAS), 0, 1, 4, 8, 16, and 24 hours after the end of anesthesia duration. In case of VAS >= 3, the patients received 0.3 mg/kg pethidine, intravenously. At last, the time of requesting the first narcotic drug and the total usage of pethidine were recorded. RESULTS AND CONCLUSIONS: Sufentanil was found to be more effective than magnesium sulfate in reducing postoperative pain and the time of first narcotics request was later in patients receiving sufentanil (P < 0.05). PMID- 28920053 TI - Smoking and Lung Cancer: A Geo-Regional Perspective. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This "cocktail" of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon. PMID- 28920054 TI - Controlling Extra- and Intramacrophagic Mycobacterium abscessus by Targeting Mycolic Acid Transport. AB - Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) causing serious infections especially among cystic fibrosis patients. Extremely limited therapeutic options against M. abscessus and a rise in infections with this mycobacterium require novel chemotherapies and a better understanding of how the bacterium causes infection. Different from most RGM, M. abscessus can survive inside macrophages and persist for long durations in infected tissues. We recently delineated differences in the infective programs followed by smooth (S) and rough (R) variants of M. abscessus. Unexpectedly, we found that the S variant behaves like pathogenic slow growing mycobacteria, through maintaining a block on the phagosome maturation process and by inducing phagosome-cytosol communications. On the other hand, R variant infection triggers autophagy and apoptosis, reminiscent of the way that macrophages control RGM. However, the R variant has an exquisite capacity to form extracellular cords, allowing these bacteria to rapidly divide and evade phagocytosis. Therefore, new chemotherapeutic interventions against M. abscessus need to efficiently deal with both the reservoir of intracellular bacilli and the extracellular cords. In this context, we recently identified two chemical entities that were very effective against both M. abscessus populations. Although being structurally unrelated these two chemotypes inhibit the activity of the essential mycolic acid transporter, MmpL3. In this Perspective, we aimed to highlight recent insights into how M. abscessus interacts with phagocytic cells and how the inhibition of mycolic acid transport in this pathogenic RGM could be an efficient means to control both intracellular and extracellular populations of the bacterium. PMID- 28920055 TI - Distinguishing testicular torsion from torsion of the appendix testis by clinical features and signs in patients with acute scrotum. AB - PURPOSE: Many physicians encounter confusion and difficulty in distinguishing testicular torsion (TT) from torsion of the appendix testis (TAT) in patients with acute scrotum because of the overlapping signs and symptoms. The objective of our study was to evaluate the clinical features and signs that can help distinguish TT from TAT. PATIENTS AND METHODS: We performed a retrospective study of patients with surgically confirmed TT and TAT at our institute from January 1990 to December 2013. Clinical findings, physical examination findings, climatic conditions, laboratory data, and color Doppler ultrasound (CDUS) findings were compared between the TT and TAT groups. RESULTS: Seventy patients were included in this study (49 with TT and 21 with TAT). Patients with TT were significantly older than those with TAT (p < 0.001). The ambient temperature at onset was significantly lower in patients with TT than in patients with TAT (p = 0.038). Testicular swelling, high-riding testes, onset during sleep, high leukocyte counts, and high creatine phosphokinase levels were significantly more common in patients with TT than with TAT (p = 0.021, 0.032, 0.006, 0.003, and 0.043, respectively). Multivariate analysis showed that age and onset during sleep were significant independent factors for detection of TT. Eight patients (16.3%) underwent preoperative CDUS evaluation, and an absent or decreased blood signal in the involved testes was significantly correlated with the presence of TT (p = 0.018). CONCLUSION: In clinical features, age and onset during sleep might be helpful to distinguish TT from TAT. When supported by findings, urgent surgical exploration is warranted in patients with suspected TT based on symptoms and CDUS features. PMID- 28920056 TI - Management of refractory ischemic priapism: current perspectives. AB - OBJECTIVES: The aim of the present manuscript is to review the current literature on priapism, focusing on the state-of-the-art knowledge of both the diagnosis and the treatment of the refractory ischemic priapism (IP). METHODS: Pubmed and EMBASE search engines were used to search for words "priapism", "refractory priapism", "penile prosthesis", "diagnosis priapism", "priapism treatment", "penile fibrosis", "priapism therapy". All the studies were carefully examined by the authors and then included in the review. RESULTS: First-line treatment involves ejaculation, physical exercise and cold shower followed by corporal blood aspiration and injection of alpha-adrenoceptor agonists. Subsequently, a distal or proximal shunt may be considered. If none of the treatment is effective or the priapism episode lasts >48 hours penile prosthesis implantation could be the only option to solve the priapism and treat the ongoing erectile dysfunction. CONCLUSION: The management of IP is to achieve detumescence of persistent penile erection and to preserve erectile function after resolution of the priapic episode. On the other hand, penile fibrosis and following shortening should be prevented. Early penile prosthesis implantation in patients with refractory IP is able to solve both the priapic episode and prevent the otherwise certain penile shortening. Penile prosthesis implantation is the actual gold standard of care in cases of refractory IP. PMID- 28920058 TI - Editorial: Current Challenges in Cardiovascular Molecular Diagnostics. PMID- 28920057 TI - Amine Metabolism Is Influenced by Dietary Protein Source. AB - Growth in world population will inevitably leads to increased demand for protein for humans and animals. Protein from insects and blood plasma are being considered as possible alternatives, but more research on their nutritional quality and health effects is needed. Here, we studied the effect of dietary protein source on metabolism and metabolic amine profiles in serum and urine of mice. Groups of mice were fed semi-purified diets containing 300 g/kg of soybean meal, casein, partially delactosed whey powder, spray-dried plasma protein, wheat gluten meal, and yellow mealworm. Feed and water intake as well as body weight gain were measured for 28 days. After 14 and 28 days, serum and urine samples were collected for measurement of a large panel of amine metabolites. MetaboAnalyst 3.0 was used for analysis of the raw metabolic data. Out of 68 targeted amine metabolites, we could detect 54 in urine and 41 in blood serum. Dietary protein sources were found to have profound effects on host metabolism, particularly in systemic amine profiles, considered here as an endophenotype. We recommend serum over urine to screen for the amine metabolic endophenotype based on partial least squares discriminant analysis. We concluded that metabolites like alpha-aminobutyric acid and 1-methylhistidine are sensitive indicators of too much or too little availability of specific amino acids in the different protein diets. Furthermore, we concluded that amine metabolic profiles can be useful for assessing the nutritional quality of different protein sources. PMID- 28920059 TI - Market Impact of Foot-and-Mouth Disease Control Strategies: A UK Case Study. AB - Foot-and-mouth disease (FMD) poses a serious threat to the agricultural sector due to its highly contagious nature. Outbreaks of FMD can lead to substantial disruptions to livestock markets due to loss of production and access to international markets. In a previously FMD-free country, the use of vaccination to augment control of an FMD outbreak is increasingly being recognized as an alternative control strategy to direct slaughtering [stamping-out (SO)]. The choice of control strategy has implications on production, trade, and hence prices of the sector. Specific choice of eradication strategies depends on their costs and benefits. Economic impact assessments are often based on benefit-cost framework, which provide detailed information on the changes in profit for a farm or budget implications for a government (1). However, this framework cannot capture price effects caused by changes in production due to culling of animals; access to international markets; and consumers' reaction. These three impacts combine to affect equilibrium within commodity markets (2). This paper provides assessment of sectoral level impacts of the eradication choices of FMD outbreaks, which are typically not available from benefit-cost framework, in the context of the UK. The FAPRI-UK model, a partial equilibrium model of the agricultural sector, is utilized to investigate market outcomes of different control strategies (namely SO and vaccinate-to-die) in the case of FMD outbreaks. The outputs from the simulations of the EXODIS epidemiological model (number of animals culled/vaccinated and duration of outbreak) are used as inputs within the economic model to capture the overall price impact of the animal destruction, export ban, and consumers' response. PMID- 28920060 TI - Midkine's Role in Cardiac Pathology. AB - Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF. PMID- 28920061 TI - Biological and clinical insights offered by chemically induced liver progenitors (CLiPs). PMID- 28920062 TI - Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases. AB - Applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been documented for diseases occur in the sports system, the central nervous system, the cardiovascular system etc. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency. Although the autophagy theory has been reported, the underlying mechanisms are still poorly understood. Isolation and culture methods of mesenchymal stem cells are currently concentrate on four ways. Overall, BM-MSCs have both important research significance and clinical application value in cell replacement therapy, gene therapy and reconstruction of tissues as well as organs especially for myocardial infarction (MI). In this article, we review the biological characteristics of BM-MSCs and its research progress especially in MI. PMID- 28920063 TI - hESC-derived photoreceptors survive and integrate better in immunodeficient retina. PMID- 28920064 TI - Cone fusion confusion in photoreceptor transplantation. PMID- 28920066 TI - Investigation of a real-time location system of corneal astigmatic axis. AB - BACKGROUND: To construct a real-time computerized location system (RCLS) to analyze and display the axis of corneal astigmatism and to compare its accuracy with the Scheimpflug method. METHODS: Fifty-seven eyes of 39 volunteers with corneal astigmatism more than 1.00 diopter (D) were recruited. The RCLS was composed of a circular light-emitting diode (LED) light source, surgical microscope, surgical video system, computer and self-programming image analysis software. Scheimpflug imaging measurements (Pentacam HR, Oculus, Wetzlar, Germany) were performed on all subjects to determine the axis and power of corneal astigmatism. Thereafter, the axis of corneal astigmatism was analyzed in real-time and displayed by the RCLS on supine position, and videos were recorded. The MB-Ruler 4.0 software was used to measure the astigmatic axis. The accuracy of the RCLS was compared with the Scheimpflug method. RESULTS: The RCLS was able to display the axis of corneal astigmatism in real-time. The axial deviation of corneal astigmatism between the two methods was 0.63 +/- 3.78 degrees when astigmatism was 1.00 to 2.00 D and decreased to 0.06 +/- 1.38 degrees when astigmatism was greater than 2.00 D. A linear correlation of astigmatic axis was noted between the two methods: AxisRCLS = 1.01 * AxisScheimpflug - 1.02 (R2 = 0.998, P < 0.001). The Bland-Altman analysis revealed that the RCLS agreed sufficiently well with the Scheimpflug method. CONCLUSIONS: The RCLS can accurately analyze and display the axis for corneal astigmatism greater than 1.00 D in real-time. The RCLS simplifies marking procedures and may have potential clinical application to improve the postoperative visual outcomes in surgical correction of corneal astigmatism. PMID- 28920065 TI - The influence of sex steroid hormones on the response to trauma and burn injury. AB - Trauma and related sequelae result in disturbance of homeostatic mechanisms frequently leading to cellular dysfunction and ultimately organ and system failure. Regardless of the type and severity of injury, gender dimorphism in outcomes following trauma have been reported, with females having lower mortality than males, suggesting that sex steroid hormones (SSH) play an important role in the response of body systems to trauma. In addition, several clinical and experimental studies have demonstrated the effects of SSH on the clinical course and outcomes following injury. Animal studies have reported the ability of SSH to modulate immune, inflammatory, metabolic and organ responses following traumatic injury. This indicates that homeostatic mechanisms, via direct and indirect pathways, can be maintained by SSH at local and systemic levels and hence result in more favourable prognosis. Here, we discuss the role and mechanisms by which SSH modulates the response of the body to injury by maintaining various processes and organ functions. Such properties of sex hormones represent potential novel therapeutic strategies and further our understanding of current therapies used following injury such as oxandrolone in burn-injured patients. PMID- 28920068 TI - Tetrabenazine Versus Deutetrabenazine for Huntington's Disease: Twins or Distant Cousins? AB - BACKGROUND: Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta analytical methodology, the authors compared these molecules. METHODS: RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk-of-bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. CONCLUSION: There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head-to-head comparison between these 2 compounds in Huntington's disease. PMID- 28920067 TI - A History of Dystonia: Ancient to Modern. AB - Before 1911, when Hermann Oppenheim introduced the term dystonia, this movement disorder lacked a unifying descriptor. While words like epilepsy, apoplexy, and palsy have had their meanings since antiquity, references to dystonia are much harder to identify in historical documents. Torticollis is an exception, although there is difficulty distinguishing dystonic torticollis from congenital muscular torticollis. There are, nevertheless, possible representations of dystonia in literature and visual art from the pre-modern world. Eighteenth century systematic nosologists such as Linnaeus, de Sauvages, and Cullen had attempted to classify some spasmodic conditions, including torticollis. But only after Charcot's contributions to clinical neuroscience were the various forms of generalized and focal dystonia clearly delineated. They were categorized as nevroses: Charcot's term for conditions without an identifiable neuroanatomical cause. For a time thereafter, psychoanalytic models of dystonia based on Freud's ideas about unconscious conflicts transduced into physical symptoms were ascendant, although there was always a dissenting "organic" school. With the rise of subspecialization in movement disorders during the 1970s, the pendulum swung strongly back toward organic causation. David Marsden's clinical and electrophysiological research on the adult-onset focal dystonias was particularly important in establishing a physical basis for these disorders. We are still in a period of "living history" of dystonia, with much yet to be understood about pathophysiology. Rigidly dualistic models have crumbled in the face of evidence of electrophysiological and psychopathological overlap between organic and functional dystonia. More flexible biopsychosocial frameworks may address the demand for new diagnostic and therapeutic rationales. PMID- 28920069 TI - Assessment of Thermal Pain Sensation in Rats and Mice Using the Hargreaves Test. AB - The Hargreaves test is specifically designed to assess thermal pain sensation in rodents such as rats and mice. This test has been used in experiments involving pain sensitization or recovery of thermal pain response following neural injury and regeneration. We present here a step-by-step protocol highlighted with important notes to guide first-time users through the learning process. Additionally, we have also included representative data from a rat model of sensory denervation showing how the data can be analysed to obtain meaningful results. We hope that this protocol can also assist potential users in deciding whether the Hargreaves test is a suitable test for their experiment. PMID- 28920070 TI - Prevalence and Associated Factors of Acute Traumatic Coagulopathy; a Cross Sectional Study. AB - INTRODUCTION: Acute traumatic coagulopathy (ATC) is defined as having evidence of coagulopathy in patients with severe trauma. The aim of this preliminary study was to assess the prevalence and associated factors of ATC in severely traumatic patients presenting to emergency department (ED). METHODS: In this retrospective cross sectional study, all patients with severe traumatic injury and available coagulation profile, presenting to the EDs of two major trauma centers in Tehran, Iran, during one year, were studied. Rate of ATC was determined and the associations with various variables as well as outcome were analyzed using SPSS 21. RESULTS: 246 patients with the mean age of 36.57+/-17.11 years were included (88.2% male). The mean injury severity score (ISS) was 21.83 +/- 7.37 (16 - 54). Patients were resuscitated with 676.83 +/- 452.02 (0 - 1500) ml intravenous fluid before arriving at the ED. The maximum and minimum frequencies of ATC were 31.3% based on PTT > 36s and 2.4% based on PT > 18s, respectively. There was a significant association between the occurrence of ATC (PT ratio > 1.2) and ISS > 23 (p = 0.001), abdominal abbreviated injury score (AIS) > 3 (p = 0.003), base deficit > 4 (p = 0.019), pulse rate > 90/minute (p = 0.041), and pH < 7.30 (p = 0.043). CONCLUSION: The frequency of ATC in the present series varied from 2.4% to 31.3% based on different ATC definitions. Abdominal AIS > 3 and base deficit > 4 were among the significant independent factors related to ATC occurrence based on stepwise logistic regression analysis. PMID- 28920071 TI - Predicting the Past, Remembering the Future. AB - Rational analyses of memory suggest that retrievability of past experience depends on its usefulness for predicting the future: memory is adapted to the temporal structure of the environment. Recent research has enriched this view by applying it to semantic memory and reinforcement learning. This paper describes how multiple forms of memory can be linked via common predictive principles, possibly subserved by a shared neural substrate in the hippocampus. Predictive principles offer an explanation for a wide range of behavioral and neural phenomena, including semantic fluency, temporal contiguity effects in episodic memory, and the topological properties of hippocampal place cells. PMID- 28920072 TI - Associations between neighborhood socioeconomic environment and physical activity in Cuban immigrants. AB - Physical inactivity is a major public health concern because it is a determinant of obesity and obesity-related chronic diseases. Few longitudinal studies have examined the association between neighborhood socioeconomic (SES) environment and change in physical activity behaviors. Additionally, few studies have examined this association in immigrant groups or Hispanic subgroups such as Cubans. This research aimed to determine if neighborhood SES is associated with longitudinal change in moderate-to-vigorous physical activity (MVPA) among Cuban immigrants who participate in the Cuban Health Study in Miami, Florida. Data on 280 participants [mean age: 37.4 (+/- 4.6), 48.9% women, mean body mass index: 25.0 (+/- 2.5)] collected at baseline, 12 months and 24 months were analyzed. Minutes of MVPA were objectively measured during each data collection period using accelerometers. A neighborhood SES score was calculated for each participant's residential census tract from American Community Survey data on median household income, median housing value, educational attainment and occupation. The neighborhood SES score was grouped into tertiles, reflecting low, moderate and high neighborhood SES environment. Multilevel linear models were used to examine the relationship between neighborhood SES and change in MVPA over 24 months. At baseline, 94 (33.6%), 108 (38.6%) and 78 (27.9%) participants resided in low, moderate, and high SES neighborhoods, respectively. After adjusting for age, sex, and body mass index, no difference in average change in MVPA over time was observed between participants residing in low and moderate SES neighborhoods (p=0.48) or low and high SES neighborhoods (p=0.62). In Cuban immigrants, longitudinal change in MVPA may not vary by neighborhood socioeconomic environment. PMID- 28920073 TI - Design of pilot studies to inform the construction of composite outcome measures. AB - BACKGROUND: Composite scales have recently been proposed as outcome measures for clinical trials. For example, the Prodromal Alzheimer's Cognitive Composite (PACC) is the sum of z-score normed component measures assessing episodic memory, timed executive function, and global cognition. Alternative methods of calculating composite total scores using the weighted sum of the component measures that maximize signal-to-noise of the resulting composite score have been proposed. Optimal weights can be estimated from pilot data, but it is an open question how large a pilot trial is required to calculate reliably optimal weights. METHODS: In this manuscript, we describe the calculation of optimal weights, and use large-scale computer simulations to investigate the question of how large a pilot study sample is required to inform the calculation of optimal weights. The simulations are informed by the pattern of decline observed in cognitively normal subjects enrolled in the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument cohort study, restricting to n=75 subjects age 75 and over with an ApoE E4 risk allele and therefore likely to have an underlying Alzheimer neurodegenerative process. RESULTS: In the context of secondary prevention trials in Alzheimer's disease, and using the components of the PACC, we found that pilot studies as small as 100 are sufficient to meaningfully inform weighting parameters. Regardless of the pilot study sample size used to inform weights, the optimally weighted PACC consistently outperformed the standard PACC in terms of statistical power to detect treatment effects in a clinical trial. Pilot studies of size 300 produced weights that achieved near-optimal statistical power, and reduced required sample size relative to the standard PACC by more than half. CONCLUSIONS: These simulations suggest that modestly sized pilot studies, comparable to that of a phase 2 clinical trial, are sufficient to inform the construction of composite outcome measures. Although these findings apply only to the PACC in the context of prodromal AD, the observation that weights only have to approximate the optimal weights to achieve near-optimal performance should generalize. Performing a pilot study or phase 2 trial to inform the weighting of proposed composite outcome measures is highly cost-effective. The net effect of more efficient outcome measures is that smaller trials will be required to test novel treatments. Alternatively, second generation trials can use prior clinical trial data to inform weighting, so that greater efficiency can be achieved as we move forward. PMID- 28920075 TI - Of Mice and Men: Empirical Support for the Population-Based Social Epistasis Amplification Model (a Comment on ). AB - This commentary article offers new perspective on recent research investigating the behavioral and social ecological effects of a mutation related to autism spectrum disorders in mice. The authors explain the consistency of this research on mice with predictions advanced by a theory of the role of mutations in altering interorganismal gene-gene interactions (social epistasis) in social species including humans, known as the social epistasis amplification model. The potential significance of the mouse research for understanding contemporary human behavioral trends is explored. PMID- 28920076 TI - Falling upward with Parkinson's disease. AB - Falls can injure, even kill. No one with Parkinson's disease (PD) wants to fall by accident. However, the potential nastiness of falls does not preclude a more nuanced understanding of the personal meaning that falls can have. Rather than view falls as a problem to fear and manage solely by preventing and repairing harm, people with PD and those who care for them may recast falls as a mixed blessing. Falls may be a resource, skill, and catalyst for personal growth. We discuss how falls may give rise to opportunities in interrelated domains: capabilities, credo, character, creativity, chronemics, and connectedness. Clinicians could incorporate a positive focus across these domains to help people with PD to 'fall upward' in the sense of flourish. PMID- 28920077 TI - Mimicking the Bioactivity of Fibroblast Growth Factor-2 Using Supramolecular Nanoribbons. AB - Fibroblast growth factor (FGF-2) is a multifunctional growth factor that has pleiotropic effects in different tissues and organs. In particular, FGF-2 has a special role in angiogenesis, an important process in development, wound healing, cell survival, and differentiation. Therefore, incorporating biological agents like FGF-2 within therapeutic biomaterials is a potential strategy to create angiogenic bioactivity for the repair of damaged tissue caused by trauma or complications that arise from age and/or disease. However, the use of growth factors as therapeutic agents can be costly and does not always bring about efficient tissue repair due to rapid clearance from the targeted site. An alternative would be a stable supramolecular nanostructure with the capacity to activate the FGF-2 receptor that can also assemble into a scaffold deliverable to tissue. We report here on peptide amphiphiles that incorporate a peptide known to activate the FGF-2 receptor and peptide domains that drive its self-assembly into supramolecular nanoribbons. These FGF2-PA nanoribbons displayed the ability to increase the proliferation and migration of the human umbilical vein endothelial cells (HUVECs) in vitro to the same extent as the native FGF-2 protein at certain concentrations. We confirmed that this activity was specific to the FGFR1 signaling pathway by tracking the phosphorylation of downstream signaling effectors such ERK1/2 and pH3. These results indicated the specificity of FGF2-PA nanoribbons in activating the FGF-2 signaling pathway and its potential application as a supramolecular scaffold that can be used in vivo as an alternative to the encapsulation and delivery of the native FGF-2 protein. PMID- 28920074 TI - The mitotic checkpoint complex (MCC): looking back and forth after 15 years. AB - The mitotic checkpoint is a specialized signal transduction pathway that contributes to the fidelity of chromosome segregation. The signaling of the checkpoint originates from defective kinetochore-microtubule interactions and leads to formation of the mitotic checkpoint complex (MCC), a highly potent inhibitor of the Anaphase Promoting Complex/Cyclosome (APC/C)-the E3 ubiquitin ligase essential for anaphase onset. Many important questions concerning the MCC and its interaction with APC/C have been intensively investigated and debated in the past 15 years, such as the exact composition of the MCC, how it is assembled during a cell cycle, how it inhibits APC/C, and how the MCC is disassembled to allow APC/C activation. These efforts have culminated in recently reported structure models for human MCC:APC/C supra-complexes at near-atomic resolution that shed light on multiple aspects of the mitotic checkpoint mechanisms. However, confusing statements regarding the MCC are still scattered in the literature, making it difficult for students and scientists alike to obtain a clear picture of MCC composition, structure, function and dynamics. This review will comb through some of the most popular concepts or misconceptions about the MCC, discuss our current understandings, present a synthesized model on regulation of CDC20 ubiquitination, and suggest a few future endeavors and cautions for next phase of MCC research. PMID- 28920078 TI - NOTCH1 Activation Depletes the Pool of Side Population Stem Cells in ATL. AB - BACKGROUND: HTLV-I infection is associated with the development of adult T-cell leukemia (ATL), a malignancy characterized by a high rate of disease relapse and poor survival. Previous studies reported the existence of side population (SP) cells in HTLV-I Tax transgenic mouse models. These studies showed that these ATL like derived SP cells have both self-renewal and leukemia renewal capacity and represent Cancer Stem Cells (CSC)/Leukemia-Initiating Cells (LIC). Since CSC/LIC are resistant to conventional therapies, a better characterization is needed. METHODS: We isolated, sorted and characterized SP cells from uncultured PBMCs from ATL patients and from ATL patient-derived cell lines. We then identified several specific signaling pathways activated or suppressed in these cells. Expression of viral gene HBZ and Tax transcriptional activity was also investigated. Using gamma-secretase inhibitor (GSI, Calbiochem) and stably transduced ATL cell lines expressing TET-inducible NOTCH 1 intracellular domain (NICD), we characterized the role of activated NOTCH 1 in the maintenance of the SP cells in ATL. RESULTS: Our studies confirm the existence of SP cells in ATL samples. These cells demonstrate lower activation of NOTCH1 and Tax, and reduced expression of STAT3, beta-catenin/Wnt3 and viral HBZ. We further show that PI3K and the NOTCH1 signaling pathway have opposite functions, and constitutive activation of NOTCH1 signaling depletes the pool of SP cells in ATL-derived cell lines. CONCLUSIONS: Our results suggest that in ATL, a balance between activation of the NOTCH1 and PI3K signaling pathway is the key in the control of SP cells maintenance and may offer therapeutic opportunities. PMID- 28920079 TI - Parkin New Cargos: a New ROS Independent Role for Parkin in Regulating Cell Division. AB - Cell cycle progression requires the destruction of key cell cycle regulators by the multi-subunit E3 ligase called the anaphase promoting complex (APC/C). As the cell progresses through the cell cycle, the APC/C is sequentially activated by two highly conserved co-activators called Cdc20 and Cdh1. Importantly, APC/CCdc20 is required to degrade substrates in G2/M whereas APCCdh1 drives the cells into G1. Recently, Parkin, a monomeric E3 ligase that is required for ubiquitin mediated mitophagy following mitochondrial stress, was shown to both bind and be activated by Cdc20 or Cdh1 during the cell cycle. This mitotic role for Parkin does not require an activating phosphorylation by its usual kinase partner PINK. Rather, mitotic Parkin activity requires phosphorylation on a different serine by the polo-like kinase Plk1. Interestingly, although ParkinCdc20 and ParkinCdh1 activity is independent of the APC/C, it mediates degradation of an overlapping subset of substrates. However, unlike the APC/C, Parkin is not necessary for cell cycle progression. Despite this, loss of Parkin activity accelerates genome instability and tumor growth in xenograft models. These findings provide a mechanism behind the previously described, but poorly understood, tumor suppressor role for Parkin. Taken together, studies suggest that the APC/C and Parkin have similar and unique roles to play in cell division, possibly being dependent upon the different subcellular address of these two ligases. PMID- 28920080 TI - Lead Halide Perovskite Nanocrystals in the Research Spotlight: Stability and Defect Tolerance. AB - This Perspective outlines basic structural and optical properties of lead halide perovskite colloidal nanocrystals, highlighting differences and similarities between them and conventional II-VI and III-V semiconductor quantum dots. A detailed insight into two important issues inherent to lead halide perovskite nanocrystals then follows, namely, the advantages of defect tolerance and the necessity to improve their stability in environmental conditions. The defect tolerance of lead halide perovskites offers an impetus to search for similar attributes in other related heavy metal-free compounds. We discuss the origins of the significantly blue-shifted emission from CsPbBr3 nanocrystals and the synthetic strategies toward fabrication of stable perovskite nanocrystal materials with emission in the red and infrared parts of the optical spectrum, which are related to fabrication of mixed cation compounds guided by Goldschmidt tolerance factor considerations. We conclude with the view on perspectives of use of the colloidal perovskite nanocrystals for applications in backlighting of liquid-crystal TV displays. PMID- 28920081 TI - Modeling the Performance Limitations and Prospects of Perovskite/Si Tandem Solar Cells under Realistic Operating Conditions. AB - Perovskite/Si tandem solar cells have the potential to considerably out-perform conventional solar cells. Under standard test conditions, perovskite/Si tandem solar cells already outperform the Si single junction. Under realistic conditions, however, as we show, tandem solar cells made from current record cells are hardly more efficient than the Si cell alone. We model the performance of realistic perovskite/Si tandem solar cells under real-world climate conditions, by incorporating parasitic cell resistances, nonradiative recombination, and optical losses into the detailed-balance limit. We show quantitatively that when optimizing these parameters in the perovskite top cell, perovskite/Si tandem solar cells could reach efficiencies above 38% under realistic conditions, even while leaving the Si cell untouched. Despite the rapid efficiency increase of perovskite solar cells, our results emphasize the need for further material development, careful device design, and light management strategies, all necessary for highly efficient perovskite/Si tandem solar cells. PMID- 28920082 TI - Is a persistent central canal a risk factor for neurological injury in patients undergoing surgical correction of scoliosis? AB - BACKGROUND: Scoliosis patients with associated syringomyelia are at an increased risk of neurological injury during surgical deformity correction. The syrinx is therefore often addressed surgically prior to scoliosis correction to minimize this risk. It remains unclear if the presence of a persistent central canal (PCC) within the spinal cord also poses a similar risk. The aim of this study is to determine whether there is any evidence to suggest that patients with a PCC are also at a higher risk of neurological injury during surgical scoliosis correction. METHODS: Eleven patients with a PCC identified on pre-operative magnetic resonance imaging who had undergone correction of adolescent idiopathic scoliosis (AIS) over a 7-year study period at our institution were retrospectively identified. The incidence of abnormal intra-operative spinal cord monitoring (SCM) traces in this group was in turn compared against 44 randomly selected age- and sex-matched controls with no PCC who had also undergone surgical correction of AIS during the study period. Fisher's exact test was applied to determine whether there was a significant difference in the incidence of abnormal intra-operative SCM traces between the two groups. RESULTS: Statistical analysis demonstrated no significant difference in the incidence of abnormal intra-operative SCM signal traces between the PCC group and the control group. CONCLUSIONS: This study demonstrates no evidence to suggest a PCC increases the risk of neurological complications during scoliosis correction. We therefore suggest that surgical correction of scoliosis in patients with a PCC can be carried out safely with routine precautions. PMID- 28920083 TI - Differential alterations of intracellular [Ca2+] dynamics induced by cocaine and methylphenidate in thalamocortical ventrobasal neurons. AB - The ventrobasal (VB) thalamus relay nucleus processes information from rodents' whiskers, projecting to somatosensory cortex. Cocaine and methylphenidate (MPH) have been described to differentially alter intrinsic properties of, and spontaneous GABAergic input to, VB neurons. Here we studied using bis-fura 2 ratiometric fluorescence the effects of cocaine and MPH on intracellular [Ca2+] dynamics at the soma and dendrites of VB neurons. Cocaine increased baseline fluorescence in VB somatic and dendritic compartments. Peak and areas of fluorescence amplitudes were reduced by cocaine binge treatment in somas and dendrites at different holding potentials. MPH binge treatment did not alter ratiometric fluorescence at either somatic or dendritic levels. These novel cocaine-mediated blunting effects on intracellular [Ca2+] might account for alterations in the capacity of thalamocortical neurons to maintain gamma band oscillations, as well as their ability to integrate synaptic afferents. PMID- 28920085 TI - Baseline Prescription and One-Year Persistence of Secondary Prevention Drugs after an index Stroke in Central Ghana. AB - BACKGROUND AND PURPOSE: There is a paucity of data on persistence of secondary prevention medications among stroke survivors in resource-limited settings where stroke is on a rapid upward trajectory and its management severely challenged. To avert new cardiovascular events after stroke, preventive medications should be promptly instituted and used continuously. We report 1-year rates and determinants of persistent utilization of secondary prevention therapies after stroke in Ghana. METHODS: A retrospective observational study involving 418 stroke survivors enrolled into a Neurology clinic in a tertiary institution in central Ghana between January 2011 and December 2013. Data on demography, stroke type, risk factor profile and five secondary risk prevention medication classes namely antihypertensive, antiplatelet, statins, antidiabetic and anticoagulants were collected from patient charts. Persistence within first year after stroke was defined as continuation of all secondary preventive medications prescribed at enrollment to the Neurology clinic and it excluded 126 (~30%) patients who could not complete 12 month follow up. Data was closed for analysis in June 2015 to allow for at least 12 months of follow-up. RESULTS: Rates of utilization of secondary preventive medications and its intensity were influenced by stroke type and prevailing vascular risk factors. In decreasing order, antihypertensive, lipid-modifying, anti-platelet, anti-diabetic medications and anti-coagulants were prescribed at frequencies (%) of 394 (94.3%), 303 (72.5%), 274 (65.6%), 61 (14.6%) and 2 (0.5%) respectively at enrollment into the Neurology clinic (n=418). Overall, 92.1% of subjects (n=292) under follow-up for 1 year were persistent on secondary prevention medications initiated at enrollment into the neurology clinic with medication class specific rates of 97.5% for antihypertensive, 94.8% for anti-platelets, 94.1% for statins, 85.7% for anti diabetic and 50% for anticoagulants. Abuse of alcohol was significantly associated with non-persistence, adjusted OR (95% CI) of 3.08 (1.13-8.38). CONCLUSION: Persistence of secondary preventive medications among stroke survivors in this resource-limited setting is excellent and comparable to those in resource-replete countries. There is however the need to investigate the causes of high attrition rates from care. PMID- 28920084 TI - EFFECTS OF METHAMPHETAMINE ON LOCOMOTOR ACTIVITY AND THALAMIC GENE EXPRESSION IN LEPTIN-DEFICIENT OBESE MICE. AB - Leptin is an adipose-derived hormone that regulates energy balance. Leptin receptors are expressed in extrahypothalamic sites and several reports showed that leptin can influence feeding and locomotor behavior via direct actions on dopaminergic neurons. The leptin deficient mouse (ob/ob) has been used as an animal model of blunted leptin action, and presents with obesity and mild type 2 diabetes. We used ob/ob mice to study the effect of repeated 7-day methamphetamine (METH) administration analyzing locomotion, behavioral sensitization, and somatosensory thalamic mRNA expression of voltage-gated calcium channels and glutamatergic receptors using RT-PCR. We observed reduced METH-mediated responses in ob/ob mice associated with enhanced in mRNA expression of key voltage-gated and glutamate receptors in the somatosensory thalamus. Results described here are important for understanding the control of locomotion and thalamocortical excitability by leptin. PMID- 28920086 TI - Organic compounds generated after the flow of water through micro-orifices: Were they synthesized? AB - Micro-fluid mechanics is an important area of research in modern fluid mechanics because of its many potential industrial and biological applications. However, the field is not fully understood yet. In previous work, when passing ultrapure water (UPW) in which air was dissolved (UPW*) through micro-orifices, we found that the flow velocity decreased and stopped over time, and membranes were frequently formed in the orifice when the flow stopped. The membrane came from the dissolved air in UPW*, and membrane formation was closely related to electric charges generated in orifices by the flow. In the present paper, we clarified the components of the membrane and suggested a mechanism for membrane formation. We examined the effect of contaminants on the membrane formation and confirmed our previous results. We identified the chemical components of the membrane and those present in the UPW* itself by using an electron probe microanalyzer and found that the proportion of each element differed between the membrane and UPW*. Raman and infrared (IR) spectroscopy showed that the membrane consisted of organic substances such as carotenoids, amides, esters, and sugars. We irradiated UPW* with ultraviolet light to cut organic chains that may be left in UPW* as contaminants. We found a similar membrane and organic compounds as in nonirradiated UPW*. Furthermore, although the UPW that was kept from contact with air after it was supplied from the UPW maker (UPW0) and bubbled with Ar gas (UPW0 bubbled with Ar) formed no membrane, the UPW0 bubbled with CO2 formed thin membranes, and Raman and IR analysis showed that this membrane contained carboxylic acid salts, carotenoids, or a mixture of both. We found that electric grounding of the orifice reduces the probability of membrane formation and that the jets issuing from an aperture bear negative charges, and we assumed that the micro-orifices possess positive charges generated by flows. Consequently, we suggest that organic compounds are synthesized from nonorganic matter in air or CO2 dissolved in water by the action of hydroxyl radicals generated by flows through micro-orifices. PMID- 28920087 TI - Simultaneous removal of five triazole fungicides from synthetic solutions on activated carbons and cyclodextrin-based adsorbents. AB - In this study, an adsorption-oriented process for the removal of fungicides from polycontaminated aqueous solutions was applied. To remove triazole fungicides from aqueous mixtures of propiconazole (PROPI), tebuconazole (TEBU), epoxiconazole (EPOXI), bromuconazole (BROMU) and difenoconazole (DIFENO), several materials used as adsorbents were compared using batch experiments, namely two conventional activated carbons (ACs) and five nonconventional cross-linked cyclodextrin (CD)-based materials (alpha-CDP, beta-CDP, gamma-CDP, alphabetagamma CDP mixture, and hydroxypropyl-beta-CDP). This article presents the abatements obtained. As expected, ACs exhibited the highest levels of triazole fungicide removal: the treatment lowered the five azoles by more than 99%, and adsorption was non-selective. Concerning CD-based materials employed for the first time for the removal of fungicides from polycontaminated aqueous solutions, results were interesting in particular for hydroxypropyl-beta-CDP: 1 g of adsorbent placed in 1 L of solution containing 1 mg of each of five triazoles (5 mg in total) was able to remove over half of the fungicide amount (2.97 mg). The order obtained was the following: BROMU << PROPI ? EPOXI < TEBU << DIFENO. This indicates that, in the mixture studied, strong competition prevailed among fungicides for the binding sites. PMID- 28920088 TI - Metabolic and transcriptomic analysis of Huntington's disease model reveal changes in intracellular glucose levels and related genes. AB - Huntington's Disease (HD) is a neurodegenerative disorder caused by an expansion in a CAG-tri-nucleotide repeat that introduces a poly-glutamine stretch into the huntingtin protein (mHTT). Mutant huntingtin (mHTT) has been associated with several phenotypes including mood disorders and depression. Additionally, HD patients are known to be more susceptible to type II diabetes mellitus (T2DM), and HD mice model develops diabetes. However, the mechanism and pathways that link Huntington's disease and diabetes have not been well established. Understanding the underlying mechanisms can reveal potential targets for drug development in HD. In this study, we investigated the transcriptome of mHTT cell populations alongside intracellular glucose measurements using a functionalized nanopipette. Several genes related to glucose uptake and glucose homeostasis are affected. We observed changes in intracellular glucose concentrations and identified altered transcript levels of certain genes including Sorcs1, Hh-II and Vldlr. Our data suggest that these can be used as markers for HD progression. Sorcs1 may not only have a role in glucose metabolism and trafficking but also in glutamatergic pathways affecting trafficking of synaptic components. PMID- 28920089 TI - Cooking methods affect phytochemical composition and anti-obesity potential of soybean (Glycine max) seeds in Wistar rats. AB - This work aimed at investigating the effects of three domestic cooking methods (roasting, sprouting and boiling) on phytochemical contents (phenolic content, flavonoid, fibre), and anti-obesity (weight loss, hypoglycemic effect, serum lipids) potential of soybean seeds in obese male rats. Ten different forms were implemented, combining hulled/unhulled and raw/cooked soybean seeds using a basal and a hypercaloric diet as controls. Unhulled Roasted Soybean (URS) exhibited the highest phenolic content and a greater antioxidant activity by the FRAP assay than BHT at certain concentrations. Hulled boiled Soybean (HBS) showed the highest flavonoid content while Hulled Germinated Soybean (HGS) presented the lowest fibre content (P < 0.05). Unhulled Boiled Soybean (UBS) induced the best reduction in food intake while Unhulled Soybean Extract (USE) exhibited the greatest slimming effect. HBS exhibited the best cholesterol lowering ability; URS and Unhulled germinated Soybean (UGS) respectively induced the highest increase in HDL cholesterol levels and reduction in triglyceride levels. UBS demonstrated the highest ability to lower LDL cholesterol. UGS exhibited the highest ability to lower the postprandial blood glucose. Culinary treatments affect phytochemical content and anti-obesity potential of soybean seeds. PMID- 28920090 TI - Reconstructing coral calcification fluid dissolved inorganic carbon chemistry from skeletal boron: An exploration of potential controls on coral aragonite B/Ca. AB - The boron geochemistry of coral skeletons reflects the dissolved inorganic carbon (DIC) chemistry of the calcification fluid from which the skeletons precipitates and may be a valuable tool to investigate the effects of climate change on coral calcification. In this paper I calculate the predicted B/Ca of aragonite precipitating from seawater based fluids as a function of pH, [DIC] and [Ca2+]. I consider how different co-precipitating DIC species affect aragonite B/Ca and also estimate the impact of variations in the B(OH)4-/co-precipitating DIC aragonite partition coefficient (KD), which may be associated with changes in the DIC and Ca2+ chemistry of the calcification fluid. The coral skeletal B/Ca versus calcification fluid pH relationships reported previously can be reproduced by estimating B(OH)4- and co-precipitating DIC speciation as a function of pHCF and assuming that KD are constant i.e. unaffected by calcification fluid saturation state. Assuming that B(OH)4- co-precipitates with CO32-, then observed patterns can be reproduced by a fluid with approximately constant [DIC] i.e. increasing pHCF concentrates CO32-, as a function of DIC speciation. Assuming that B(OH)4- co-precipitates with HCO3- only or CO32- + HCO3- then the observed patterns can be reproduced if [DIC]CF and pHCF are positively related i.e. if DIC is increasingly concentrated in the calcification fluid at higher pHCF probably by CO2 diffusion into the calcification site. PMID- 28920092 TI - Thermogelling properties of purified poloxamer 407. AB - Poloxamers are triblock copolymers with a center block of hydrophobic polypropylene oxide (PPO) flanked by two hydrophilic polyethyleneoxide (PEO) blocks. Among this family of copolymers, poloxamer 407 is a non-ionic surfactant with reversible gelation properties above a particular polymer concentration and a particular temperature. Easy preparation of poloxamer 407 based sterile injectable formulations have made this copolymer a good candidate for drug delivery, specifically when controlled release of the drug is required. Previously, the applications of compendial poloxamer 407 preparations were demonstrated; however, low viscosity, poor elasticity, and sol-to-gel transition temperature (Tsol-gel) over a wide temperature range were observed. A purification process was introduced to eliminate impurities and low molecular weight copolymer molecules from the compendial poloxamer 407 resulting in higher viscosity values with Tsol-gel in a narrow temperature range. Here, poloxamer 407 was purified based on the proposed process and the rheological and analytical evaluation of the purified poloxamer 407 was conducted and compared to unpurified, compendial poloxamer 407. Then, the impact of poloxamer 407 concentration on gel formation was evaluated. For drug delivery applications, the effect of relevant buffer salts and the effect of addition of ethanol to the poloxamer 407 solutions were rheologically evaluated. PMID- 28920091 TI - Selecting pure-emotion materials from the International Affective Picture System (IAPS) by Chinese university students: A study based on intensity-ratings only. AB - There is a need to use selected pictures with pure emotion as stimulation or treatment media for basic and clinical research. Pictures from the widely-used International Affective Picture System (IAPS) contain rich emotions, but no study has clearly stated that an emotion is exclusively expressed in its putative IAPS picture to date. We hypothesize that the IAPS images contain at least pure vectors of disgust, erotism (or erotica), fear, happiness, sadness and neutral emotions. Accordingly, we have selected 108 IAPS images, each with a specific emotion, and invited 219 male and 274 female university students to rate only the intensity of the emotion conveyed in each picture. Their answers were analyzed using exploratory and confirmatory factor analysis. Four first-order factors manifested as disgust-fear, happiness-sadness, erotism, and neutral. Later, ten second-order sub-factors manifested as mutilation-disgust, vomit-disgust, food disgust, violence-fear, happiness, sadness, couple- erotism, female-erotism, male erotism, and neutral. Fifty-nine pictures for the ten sub-factors, which had established good model-fit indices, satisfactory sub-factor internal reliabilities, and prominent gender-differences in the picture intensity ratings were ultimately retained. We thus have selected a series of pure-emotion IAPS pictures, which together displayed both satisfactorily convergent and discriminant structure-validities. We did not intend to evaluate all IAPS items, but instead selected some pictures conveying pure emotions, which might help both basic and clinical researches in the future. PMID- 28920093 TI - Pyrazine analogues from wolf urine induced unlearned fear in rats. AB - Urine excreted from the common grey wolf (Canis lupus) contains a kairomone, inducing fear-related behaviors in various mammals. Numerous fear-inducing substances activate neurons at the main and/or accessory olfactory bulb (AOB), medial and central amygdala, and hypothalamus. Our previous study showed that the mixture of pyrazine analogues (P-mix) contained in wolf urine induced avoidance and fear-related behaviors in laboratory mice and Hokkaido deer (Cervus nippon yesoensis), a species native to Japan. Exposure to wolf urine or P-mix induced expression of Fos, a marker of neuronal excitation, in the AOB of mice. In the present study, we explored the effects of P-mix on fear-related behaviors and Fos expression in rats. Exposure to P-mix induced avoidance and immobilization in rats, while that to a mixture of i-amyl acetate, linalool and R(+)-limonene (O mix), which generate floral and fruity odors, induced avoidance but not immobilization. P-mix but not O-mix increased Fos-immunoreactivity of the AOB, medial and central amygdala, and hypothalamus of rats. The present results suggest that P-mix odor induces unlearned fear-related behaviors in rats. PMID- 28920094 TI - Convolutional auto-encoder for image denoising of ultra-low-dose CT. AB - OBJECTIVES: The purpose of this study was to validate a patch-based image denoising method for ultra-low-dose CT images. Neural network with convolutional auto-encoder and pairs of standard-dose CT and ultra-low-dose CT image patches were used for image denoising. The performance of the proposed method was measured by using a chest phantom. MATERIALS AND METHODS: Standard-dose and ultra low-dose CT images of the chest phantom were acquired. The tube currents for standard-dose and ultra-low-dose CT were 300 and 10 mA, respectively. Ultra-low dose CT images were denoised with our proposed method using neural network, large scale nonlocal mean, and block-matching and 3D filtering. Five radiologists and three technologists assessed the denoised ultra-low-dose CT images visually and recorded their subjective impressions of streak artifacts, noise other than streak artifacts, visualization of pulmonary vessels, and overall image quality. RESULTS: For the streak artifacts, noise other than streak artifacts, and visualization of pulmonary vessels, the results of our proposed method were statistically better than those of block-matching and 3D filtering (p-values < 0.05). On the other hand, the difference in the overall image quality between our proposed method and block-matching and 3D filtering was not statistically significant (p-value = 0.07272). The p-values obtained between our proposed method and large-scale nonlocal mean were all less than 0.05. CONCLUSION: Neural network with convolutional auto-encoder could be trained using pairs of standard dose and ultra-low-dose CT image patches. According to the visual assessment by radiologists and technologists, the performance of our proposed method was superior to that of large-scale nonlocal mean and block-matching and 3D filtering. PMID- 28920095 TI - Computational Study of Quasi-2D Liquid State in Free Standing Platinum, Silver, Gold, and Copper Monolayers. AB - Recently, freestanding atomically thick Fe metal patches up to 10 atoms wide have been fabricated experimentally in tiny pores in graphene. This concept can be extended conceptually to extended freestanding monolayers. We have therefore performed ab initio molecular dynamics simulations to evaluate the early melting stages of platinum, silver, gold, and copper freestanding metal monolayers. Our calculations show that all four freestanding monolayers will form quasi-2D liquid layers with significant out-of-plane motion and diffusion in the plane. Remarkably, we observe a 4% reduction in the Pt most likely bond length as the system enters the liquid state at 2400 K (and a lower effective spring constant), compared to the system at 1200 and 1800 K. We attribute this to the reduced average number of bonds per atom in the Pt liquid state. We used the highly accurate and reliable Density Functional Theory (DFT-D) method that includes dispersion corrections. These liquid states are found at temperatures of 2400 K, 1050 K, 1600 K, and 1400 K for platinum, silver, gold, and copper respectively. The pair correlation function drops in the liquid state, while the bond orientation order parameter is reduced to a lesser degree. Movies of the simulations can be viewed online (see Supplementary Material). PMID- 28920096 TI - Competition Effects in Visual Cortex Between Emotional Distractors and a Primary Task in Remitted Depression. AB - BACKGROUND: Attentional biases, particularly difficulty inhibiting attention to negative stimuli, are implicated in risk for major depressive disorder (MDD). The current study examined a neural measure of attentional bias using a continuous index of visuocortical engagement (steady-state visual evoked potentials [SSVEPs]) before and after a negative mood induction in a population at high-risk for MDD recurrence due to a recently remitted MDD (rMDD) episode. Additionally, we examined working memory (WM) capacity as a potential moderator of the link between rMDD and visuocortical responses. METHODS: Our sample consisted of 27 women with rMDD and 28 never-depressed women. To assess attentional inhibition to emotional stimuli, we measured frequency-tagged SSVEPs evoked from spatially superimposed task-relevant stimuli and emotional distractors (facial displays of emotion) oscillating at distinct frequencies. WM capacity was assessed during a visuospatial memory task. RESULTS: Women with rMDD, relative to never-depressed women, displayed difficulty inhibiting attention to all emotional distractors before a negative mood induction, with the strongest effect for negative distractors (sad faces). Following the mood induction, rMDD women's attention to emotional distractors remained largely unchanged. Among women with rMDD, lower WM capacity predicted greater difficulty inhibiting attention to negative and neutral distractors. CONCLUSIONS: By exploiting the phenomenon of oscillatory resonance in the visual cortex, we tracked competition in neural responses for spatially superimposed stimuli differing in valence. Results demonstrated that women with rMDD display impaired attentional inhibition of emotional distractors independent of state mood and that this bias is strongest among those with lower WM capacity. PMID- 28920097 TI - Acute CD47 Blockade During Ischemic Myocardial Reperfusion Enhances Phagocytosis Associated Cardiac Repair. AB - Our data suggest that, after a myocardial infarction, integrin-associated protein CD47 on cardiac myocytes is elevated. In culture, increased CD47 on the surface of dying cardiomyocytes impairs phagocytic removal by immune cell macrophages. After myocardial ischemia and reperfusion, acute CD47 inhibition with blocking antibodies enhanced dead myocyte clearance by cardiac phagocytes and also improved the resolution of cardiac inflammation, reduced infarct size, and preserved cardiac contractile function. Early targeting of CD47 in the myocardium after reperfusion may be a new strategy to enhance wound repair in the ischemic heart. PMID- 28920098 TI - The IL-1RI Co-Receptor TILRR (FREM1 Isoform 2) Controls Aberrant Inflammatory Responses and Development of Vascular Disease. AB - Expression of the interleukin-1 receptor type I (IL-1RI) co-receptor Toll-like and interleukin-1 receptor regulator (TILRR) is significantly increased in blood monocytes following myocardial infarction and in the atherosclerotic plaque, whereas levels in healthy tissue are low. TILRR association with IL-1RI at these sites causes aberrant activation of inflammatory genes, which underlie progression of cardiovascular disease. The authors show that genetic deletion of TILRR or antibody blocking of TILRR function reduces development of atherosclerotic plaques. Lesions exhibit decreased levels of monocytes, with increases in collagen and smooth muscle cells, characteristic features of stable plaques. The results suggest that TILRR may constitute a rational target for site and signal-specific inhibition of vascular disease. PMID- 28920099 TI - Fast Virtual Fractional Flow Reserve Based Upon Steady-State Computational Fluid Dynamics Analysis: Results From the VIRTU-Fast Study. AB - Fractional flow reserve (FFR)-guided percutaneous intervention is superior to standard assessment but remains underused. The authors have developed a novel "pseudotransient" analysis protocol for computing virtual fractional flow reserve (vFFR) based upon angiographic images and steady-state computational fluid dynamics. This protocol generates vFFR results in 189 s (cf >24 h for transient analysis) using a desktop PC, with <1% error relative to that of full-transient computational fluid dynamics analysis. Sensitivity analysis demonstrated that physiological lesion significance was influenced less by coronary or lesion anatomy (33%) and more by microvascular physiology (59%). If coronary microvascular resistance can be estimated, vFFR can be accurately computed in less time than it takes to make invasive measurements. PMID- 28920100 TI - A Urinary Fragment of Mucin-1 Subunit alpha Is a Novel Biomarker Associated With Renal Dysfunction in the General Population. AB - INTRODUCTION: Sequencing peptides included in the urinary proteome identifies the parent proteins and may reveal mechanisms underlying the pathophysiology of chronic kidney disease. METHODS: In 805 randomly recruited Flemish individuals (50.8% women; mean age, 51.1 years), we determined the estimated glomerular filtration rate (eGFR) from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We categorized eGFR according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guideline. We analyzed 74 sequenced urinary peptides with a detectable signal in more than 95% of participants. Follow-up measurements of eGFR were available in 597 participants. RESULTS: In multivariable analyses, baseline eGFR decreased (P <= 0.022) with urinary fragments of mucin-1 (standardized association size expressed in ml/min/1.73 m2, -4.48), collagen III (-2.84), and fibrinogen (-1.70) and was bi-directionally associated (P <= 0.0006) with 2 urinary collagen I fragments (+2.28 and -3.20). The eGFR changes over 5 years (follow-up minus baseline) resulted in consistent estimates (P <= 0.025) for mucin-1 (-1.85), collagen (-1.37 to 1.43) and fibrinogen (-1.45) fragments. Relative risk of having or progressing to eGFR <60 ml/min/1.73 m2 was associated with mucin-1. Partial least-squares analysis confirmed mucin-1 as the strongest urinary marker associated with decreased eGFR, with a score of 2.47 compared with 1.80 for a collagen I fragment as the next contender. Mucin-1 predicted eGFR decline to <60 ml/min/1.73 m2 over and above microalbuminuria (P = 0.011) and retained borderline significance (P = 0.05) when baseline eGFR was accounted for. DISCUSSION: In the general population, mucin-1 subunit alpha, an extracellular protein that is shed from renal tubular epithelium, is a novel biomarker associated with renal dysfunction. PMID- 28920101 TI - Potential therapeutic targets in Nrf2-dependent protection against neonatal respiratory distress disease predicted by cDNA microarray analysis and bioinformatics tools. AB - Hyperoxia exposure of newborn rodents has served as a model for bronchopulmonary dysplasia (BPD) phenotypes found in a sub-population of human premature infants. We previously demonstrated that Nrf2 modulates molecular events during saccular to-alveolar lung maturation and also has a protective role in the pathogenesis of hyperoxia-induced acute lung injury, mortality, arrest of saccular-to-alveolar transition, and lung injury, using Nrf2-deficient and wild-type neonate mice. In this review, we describe how whole-genome transcriptome analyses can identify the means through which Nrf2 transcriptionally modulates organ injury and morphology, cellular growth/proliferation, vasculature development, and immune response during BPD-like pathogenesis. We illustrate how recently developed bioinformatics tools can be used to identify sets of Nrf2-dependently modulated genes in the BPD model, and elucidate direct Nrf2 downstream targets and chemicals/drugs that may act on them. These approaches will provide significant insights into promising therapeutic agents for Nrf2-dependent treatments of complications of preterm birth like BPD. PMID- 28920102 TI - Does the Aryl Hydrocarbon Receptor Regulate Pluripotency? AB - Recent evidence from embryonic stem cells suggests that the aryl hydrocarbon receptor (AHR) plays a central role in the regulation of pluripotency, a short lived property of cells in the early blastula inner cell mass (ICM). Four key observations support this conclusion. The first is the temporal association between upregulation of AHR expression and the onset of cell differentiation, which argues for the AHR as a determinant of cell fate decisions. The second is the repression of the pluripotency factors OCT4 and NANOG by the AHR, which depresses their function and contributes to the cell's exit from pluripotency. The third is the temporal association between changes in global DNA methylation and stage-dependent AHR expression, which parallel each other during embryonic development, suggesting that AHR helps configure a repressive chromatin structure that controls differentiation. The fourth is the incidence of early developmental aberrations that take place in Ahr-null mice and cause the disruption of their embryonic program, which is likely to be a consequence of the loss of pluripotency of the Ahr-/- ICM cells. In this short review, we will focus on the modulation of pluripotency as a novel function of the AHR, and on the potentially detrimental developmental outcomes that may result from exposure to environmental toxicants. This line of enquiry brings us to the tantalizing conclusion that by activating mechanisms that modulate pluripotency, AHR regulates embryonic development. The likelihood that exposure to environmental AHR ligands might disrupt developmental processes is a reasonable corollary to this conclusion. PMID- 28920103 TI - Existence of Brain 5-HT1A-5-HT2A Isoreceptor Complexes with Antagonistic Allosteric Receptor-Receptor Interactions Regulating 5-HT1A Receptor Recognition. AB - Studies on serotonin-selective reuptake inhibitors have established that disturbances in the ascending 5-HT neuron systems and their 5-HT receptor subtypes and collateral networks to the forebrain contribute to the etiology of major depression and are targets for treatment. The therapeutic action of serotonin-selective reuptake inhibitors is of proven effectiveness, but the mechanisms underlying their effect are still unclear. There are many 5-HT subtypes involved; some need to be blocked (e.g., 5-HT2A, 5-HT3, and 5-HT7), whereas others need to be activated (e.g., postjunctional 5-HT1A and 5-HT4). These state-of-the-art developments are in line with the hypothesis that the development of major depression can involve an imbalance of the activity between different types of 5-HT isoreceptors. In the current study, using in situ proximity ligation assay (PLA), we report evidence for the existence of brain 5 HT1A-5-HT2A isoreceptor complexes validated in cellular models with bioluminescence resonance energy transfer (BRET2) assay. A high density of PLA positive clusters visualizing 5-HT1A-5-HT2A isoreceptor complexes was demonstrated in the pyramidal cell layer of the CA1-CA3 regions of the dorsal hippocampus. A marked reduction in the density of PLA-positive clusters was observed in the CA1 and CA2 regions 24 h after a forced swim test session, indicating the dynamics of this 5-HT isoreceptor complex. Using a bioinformatic approach, previous work indicates that receptors forming heterodimers demonstrate triplet amino acid homologies. The receptor interface of the 5-HT1A-5-HT2A isoreceptor dimer was shown to contain the LLG and QNA protriplets in the transmembrane and intracellular domain, respectively. The 5-HT2A agonist TCB2 markedly reduced the affinity of the 5-HT1A agonist ipsapirone for the 5-HT1A agonist binding sites in the frontal lobe using the 5-HT1A radioligand binding assay. This action was blocked by the 5-HT2A antagonist ketanserin. It is proposed that the demonstrated 5-HT1A-5-HT2A isoreceptor complexes may play a role in depression through integration of 5-HT recognition, signaling and trafficking in the plasma membrane in two major 5-HT receptor subtypes known to be involved in depression. Antagonistic allosteric receptor-receptor interactions appear to be involved in this integrative process. PMID- 28920104 TI - Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation. AB - Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd-/-) mice to term. Half of the Thbd-/- offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd-/- animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd-/- mice. However, Thbd-/- females expressing the PC transgene exhibited pregnancy induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy. PMID- 28920106 TI - Self-tracking for Mental Wellness: Understanding Expert Perspectives and Student Experiences. AB - Previous research suggests an important role for self-tracking in promoting mental wellness. Recent studies with college student populations have examined the feasibility of collecting everyday mood, activity, and social data. However, these studies do not account for students' experiences and challenges adopting self-tracking technologies to support mental wellness goals. We present two studies conducted to better understand self-tracking for stress management and mental wellness in student populations. First, focus groups and card sorting activities with 14 student health professionals reveal expert perspectives on the usefulness of tracking for three scenarios. Second, an online survey of 297 students examines personal experiences with self-tracking and attitudes toward sharing self-tracked data with others. We draw on findings from these studies to characterize students' motivations, challenges, and preferences in collecting and viewing self-tracked data related to mental wellness, and we compare findings between students with diagnosed mental illnesses and those without. We conclude with a discussion of challenges and opportunities in leveraging self-tracking for mental wellness, highlighting several design considerations. PMID- 28920105 TI - The impact of von Willebrand factor on factor VIII memory immune responses. AB - Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4+ T cells. When CD4+ T cells from primed FVIIInull mice were restimulated with recombinant human FVIII (rhF8) plus recombinant human VWF (rhVWF) in vitro, the percentages of daughter CD4+ T cells were significantly decreased compared with the groups cultured with rhF8 only. Levels of interferon-gamma and interleukin 10 were significantly lower in the rhF8 plus rhVWF groups than in the rhF8 groups. When memory B-cell pools from primed FVIIInull mice were cultured with rhF8 with or without rhVWF to induce differentiation of memory B cells into antibody-secreting cells (ASCs), the number of ASCs was significantly lower in the rhF8 plus VWF group than in the rhF8 group. When memory B-cell pools were transferred into NSGF8KO mice followed by rhF8 immunization with or without rhVWF, the titers of anti-F8 inhibitors and total immunoglobulin G were significantly higher in the rhF8 group than in the rhF8 plus rhVWF group, with an average difference of 2.23- and 2.04-fold. Together, our data demonstrate that VWF attenuates FVIII memory immune responses in HA mice. PMID- 28920107 TI - Supporting Families in Reviewing and Communicating about Radiology Imaging Studies. AB - Diagnostic radiology reports are increasingly being made available to patients and their family members. However, these reports are not typically comprehensible to lay recipients, impeding effective communication about report findings. In this paper, we present three studies informing the design of a prototype to foster patient-clinician communication about radiology report content. First, analysis of questions posted in online health forums helped us identify patients' information needs. Findings from an elicitation study with seven radiologists provided necessary domain knowledge to guide prototype design. Finally, a clinical field study with 14 pediatric patients, their parents and clinicians, revealed positive responses of each stakeholder when using the prototype to interact with and discuss the patient's current CT or MRI report and allowed us to distill three use cases: co-located communication, preparing for the consultation, and reviewing radiology data. We draw on our findings to discuss design considerations for supporting each of these use cases. PMID- 28920108 TI - Guest Editorial: The X-1 concept. PMID- 28920109 TI - Papillon-Lefevre syndrome: A series of three cases in the same family and a literature review. AB - Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder that exhibits palmoplantar keratosis and early severe periodontitis. The oral disease affects both the primary and permanent dentitions leading to premature exfoliation of teeth. Various etiologic factors, such as genetic mutations, immunologic alterations, and bacteria have been implicated in PLS. Genetic mutations leading to the loss of function of cathepsin C (CTSC) gene, located on chromosome 11q14, is considered pivotal in this condition. The present case series describes PLS in three siblings, with consanguineously married parents, who live in a remote area of Yemen. The affected children presented with prominent palmoplantar keratosis and early periodontitis with only a few remaining teeth. The severity of skin lesions in all patients exhibited seasonal variations. Based on their clinical findings, a diagnosis of PLS was made. Dentists have a significant role in the early diagnosis and management of PLS patients. PMID- 28920110 TI - Painful neuropathy caused by compression of the inferior alveolar nerve by focal osteosclerotic lesion of the mandible: A case report. AB - Osteosclerotic lesions are a common finding on dental radiographs. They are considered developmental variants of a normal bone architecture and they usually do not need any treatment. The purpose of this article is to present a rare case of osteosclerotic lesion of the mandible causing trigeminal neuropathy by compression of the alveolar nerve. The pain started with dental hypersensitivity of the mandibular right first molar. Later on, signs of irreversible molar tooth pulpitis developed. Endodontic therapy and apicoectomy did not resolve the pain, which later intensified, and painful neuropathy localized to inferior alveolar nerve developed; therefore, surgical decompression was indicated. Treating a dental patient with neuralgic pain is always a challenge, especially if there is no obvious source or reason for this type of pain. A clear evaluation and treatment protocol are important to minimize the patient's morbidity and avoid unnecessary overtreatment. PMID- 28920111 TI - Interpretation of cone beam computed tomography volumetric data: How to report findings? AB - Cone beam computed tomography (CBCT) was introduced to the dental profession at the beginning of the new millennium and has become an integral part of dental practice, especially within the surgical specialties. With advances in technology and the introduction of new-generation digital detectors, the concomitant increase in pixel resolution provided the ability to discern fine details of the anatomy. This article focuses on the methodology of CBCT interpretation and reporting. Details of reviewing the volume thoroughly are described with relevant citations. The article summarizes the overall methodical interpretation of CBCT data that is essential to every dentist who uses the technology. PMID- 28920112 TI - Implant and endodontic treatment selection are influenced by patients' demographic characteristics, insurance status, and medical history: A retrospective cohort study. AB - OBJECTIVE: The aim of this study was to examine any potential association between demographic characteristics, socioeconomic status, dental insurance, and medical and tobacco history between patients that received endodontic treatment or extraction and implant treatment in a university dental clinic. METHOD AND MATERIALS: Dental charts of patients who received root canal treatment and implant therapy were retrieved from the University of Minnesota School of Dentistry records. Age at the time of the procedure, gender, medical history, tobacco use, dental insurance status, zip code, and type of treatment provided were recorded. Patients who had both treatment modalities were excluded from the analysis. RESULTS: A total of 8,540 records of patients with a mean age of 50.66 years who have received either endodontic treatment (73.6%) or implant therapy (26.4%) were included. A statistically significant (P < .05) association was found between endodontic treatment or implant treatment as related to age, socioeconomic status, high blood pressure, asthma, thyroid disorders, arthritis, artificial joint, osteoporosis, depression, anxiety, cancer, and cancer treatment. Nonsmokers were significantly more likely to select a treatment plan with implants rather than an endodontic therapy. CONCLUSION: Within the limitations of this retrospective study, demographic parameters, insurance status, smoking, and medical history significantly affected the treatment selection between implant and endodontic treatment in a university setting. PMID- 28920113 TI - Double 1,4-addition of (thio)salicylamides/thiosalicylic acids with propiolate derivatives: a direct, general synthesis of diverse heterocyclic scaffolds. AB - A simple and practical ring-closure procedure to prepare a range of diverse heterocycles has been developed. In this transformation, a variety of substituted (thio)salicylamides and thiosalicylic acids undergo a double 1,4-addition reaction with propiolate derivatives in the presence of an inorganic base (K3PO4), as a result benzothiazinones, benzoxazinones and benzoxathiinones were prepared in good to excellent yields, respectively, even in gram scales. In addition, further transformation towards more complex structures and oxicam drug analogues has also been successfully carried out. PMID- 28920114 TI - Nano- and micromotors for cleaning polluted waters: focused review on pollutant removal mechanisms. AB - Nano- and micromotors are machines designed to self-propel and-in the process of propelling themselves-perform specialized tasks like cleaning polluted waters. These motors offer distinct advantages over conventionally static decontamination methods, owing to their ability to move around and self-mix-which heightens the interaction between their active sites and target pollutants-thus improving their speed and efficiency, which could potentially decrease treatment times and costs. In the last decade, considerable research efforts have been expended on exploring various mechanisms by which these motors can self-propel and remove pollutants, proving that the removal of oil droplets, heavy metals, and organic compounds using these synthetic motors is possible. This review highlights recent progress in the design of these nano- and micromotors for cleaning polluted waters, and gives an overview of their structure, fabrication, and propulsion methods, with a special focus on the mechanisms by which they remove pollutants-namely, either by adsorption or by degradation. A fundamental understanding of these removal mechanisms, with their attendant advantages and disadvantages, can help researchers fine-tune motor design in the future so that technical issues can be resolved before they are scaled-up for a wide variety of environmental applications. PMID- 28920115 TI - Gold nanodome SERS platform for label-free detection of protease activity. AB - Surface-enhanced Raman scattering provides a promising technology for sensitive and selective detection of protease activity by monitoring peptide cleavage. Not only are peptides and plasmonic hotspots similarly sized, Raman fingerprints also hold large potential for spectral multiplexing. Here, we use a gold-nanodome platform for real-time detection of trypsin activity on a CALNNYGGGGVRGNF substrate peptide. First, we investigate the spectral changes upon cleavage through the SERS signal of liquid-chromatography separated products. Next, we show that similar patterns are detected upon digesting surface-bound peptides. We demonstrate that the relative intensity of the fingerprints from aromatic amino acids before and after the cleavage site provides a robust figure of merit for the turnover rate. The presented method offers a generic approach for measuring protease activity, which is illustrated by developing an analogous substrate for endoproteinase Glu-C. PMID- 28920116 TI - Development of a smart activity-based probe to detect subcellular activity of asparaginyl endopeptidase in living cells. AB - We developed a smart activity-based probe that detects the activity of asparaginyl endopeptidase (AEP) in live cells to monitor the dynamics of enzyme regulation. The newly designed probe generated a turn-on fluorescence signal in response to the activity of AEP in living cells without compromising the labelling efficiency or selectivity. Our probe closely reflected the enzyme activity in its native state, detecting subcellular AEP activity in colon cancer cells and neuronal cells. PMID- 28920117 TI - HIV/HAART-associated oxidative stress is detectable by metabonomics. AB - Chronic human immunodeficiency virus (HIV) infection, separately and in combination with highly active antiretroviral therapy (HAART) is closely associated with oxidative stress (OS). Most studies demonstrating redox imbalances in HIV-infected individuals have done so using conventional biochemical methodologies. The limited simultaneous detection of multiple OS markers within one sample is a major drawback of these methodologies and can be addressed through the use of metabonomics. HIV-metabonomic studies utilizing biofluids from HAART cohorts as the investigative source, are on the increase. Data from many of these studies identified metabolic markers indicative of HIV induced OS, usually as an outcome of an untargeted metabonomics study. Untargeted studies cast a wide net for any and all detectable metabolites in complex mixtures. Given the prevalence of OS during HIV infection and antiviral treatment, it is perhaps not surprising that indicators of this malady would become evident during metabolite identification. At times, targeted studies for specific (non-OS) metabolites would also yield OS markers as an outcome. This review examines the findings of these studies by first providing the necessary background information on OS and the main ways in which free radicals/reactive oxygen species (ROS) produced during OS, cause biomolecular damage. This is followed by information on the biomarkers which come about as a result of free radical damage and the techniques used for assaying these stress indicators. The established links between elevated ROS and lowered antioxidants during HIV infection and the subsequent use of HAART is then presented followed by a review of the OS markers detected in HIV metabonomic studies to date. We identify gaps in HIV/HAART-associated OS research and finally suggest how these research gaps can be addressed through metabonomic analysis, specifically targeting the multiple markers of HIV-induced OS. PMID- 28920118 TI - Hybrid magnetic iron oxide nanoparticles with tunable field-directed self assembly. AB - We describe the synthesis of hybrid magnetic ellipsoidal nanoparticles that consist of a mixture of two different iron oxide phases, hematite (alpha-Fe2O3) and maghemite (gamma-Fe2O3), and characterize their magnetic field-driven self assembly. We demonstrate that the relative amount of the two phases can be adjusted in a continuous way by varying the reaction time during the synthesis, leading to strongly varying magnetic properties of the particles. Not only does the saturation magnetization increase dramatically as the composition of the spindles changes from hematite to maghemite, but also the direction of the induced magnetic moment changes from being parallel to the short axis of the spindle to being perpendicular to it. The magnetic dipolar interaction between the particles can be further tuned by adding a screening silica shell. Small angle X-ray scattering (SAXS) experiments reveal that at high magnetic field, magnetic dipole-dipole interaction forces the silica coated particles to self assemble into a distorted hexagonal crystal structure at high maghemite content. However, in the case of uncoated maghemite particles, the crystal structure is not very prominent. We interpret this as a consequence of the strong dipolar interaction between uncoated spindles that then become arrested during field induced self-assembly into a structure riddled with defects. PMID- 28920119 TI - Synthesis and thermal stabilities of oligonucleotides containing 2'-O,4'-C methylene bridged nucleic acid with a phenoxazine base. AB - We designed and synthesized a novel artificial 2'-O,4'-C-methylene bridged nucleic acid (2',4'-BNA/LNA) with a phenoxazine nucleobase and named this compound BNAP. Oligodeoxynucleotide (ODN) containing BNAP showed higher binding affinities toward complementary DNA and RNA as compared to ODNs bearing 2',4' BNA/LNA with 5-methylcytosine or 2'-deoxyribonucleoside with phenoxazine. Thermodynamic analysis revealed that BNAP exhibits properties associated with the phenoxazine moiety in DNA/DNA duplexes and characteristics associated with the 2',4'-BNA/LNA moiety in DNA/RNA duplexes. PMID- 28920120 TI - C60 additive-assisted crystallization in CH3NH3Pb0.75Sn0.25I3 perovskite solar cells with high stability and efficiency. AB - The development of hybrid tin (Sn)-lead (Pb) perovskite solar cells likely tackles the toxic problem with the power conversion efficiency (PCE) exceeding 17%. However, the stability problems, e.g. hysteresis effect, degeneration and oxidation, appear to be the bottleneck that limit its further development. Here, we innovatively introduced C60 at the grain boundaries throughout the CH3NH3Pb0.75Sn0.25I3 (MAPb0.75Sn0.25I3) thin film, playing a role not only in in situ passivating the interfaces and reducing the pinholes of perovskite thin films, but also in preventing the penetration of moisture and oxygen from ambient atmosphere. Electrochemical impedance spectroscopy (EIS) illustrated that the recombination lifetime of both the bulk and surface of MAPb0.75Sn0.25I3 thin films was increased by additive incorporation of C60. Dark I-V results for the electron/hole-only devices showed that the charge trap-state density decreased with C60 additive incorporated into the hybrid Sn-Pb perovskite thin films. Importantly, the hybrid Sn-Pb perovskite solar cells modified with C60 additive were demonstrated to have superior stability and efficiency when exposed to the ambient environment without encapsulation. PMID- 28920121 TI - Room-temperature Cu-catalyzed N-arylation of aliphatic amines in neat water. AB - A room-temperature and PTC-free copper-catalyzed N-arylation of aliphatic amines in neat water has been developed. Using a combination of CuI and 6,7 dihydroquinolin-8(5H)-one oxime as the catalyst and KOH as the base, a wide range of aliphatic amines are arylated with various aryl and heteroaryl halides to give the corresponding products in up to 95% yield. PMID- 28920122 TI - Survival of Verwey transition in gadolinium-doped ultrasmall magnetite nanoparticles. AB - We have demonstrated that the Verwey transition, which is highly sensitive to impurities, survives in anisotropic Gd-doped magnetite nanoparticles. Transmission electron microscopy analysis shows that the nanoparticles are uniformly distributed. X-ray photoelectron spectroscopy and EDS mapping analysis confirm Gd-doping on the nanoparticles. The Verwey transition of the Gd-doped magnetite nanoparticles is robust and the temperature dependence of the magnetic moment (zero field cooling and field cooling) shows the same behaviour as that of the Verwey transition in bulk magnetite, at a lower transition temperature (~110 K). In addition, irregularly shaped nanoparticles do not show the Verwey transition whereas square-shaped nanoparticles show the transition. Mossbauer spectral analysis shows that the slope of the magnetic hyperfine field and the electric quadrupole splitting change at the same temperature, meaning that the Verwey transition occurs at ~110 K. These results would provide new insights into understanding the Verwey transition in nano-sized materials. PMID- 28920123 TI - Passivating 1T'-MoTe2 multilayers at elevated temperatures by encapsulation. AB - Several-layer 1T'-MoTe2 decomposes very little during heating up to ~550 degrees C under flowing argon when encapsulated by multilayer hBN, as monitored by Raman scattering and optical microscopy, but largely decomposes at much lower temperatures in incompletely covered and uncovered regions. In covered regions there are small amounts of tellurium product above ~250 degrees C. PMID- 28920124 TI - A family of one-dimensional lanthanide complexes bridged by two distinct carboxylate ligands with the Dy analogue displaying magnetic relaxation behaviour. AB - A series of isostructural lanthanide one-dimensional (1D) chain complexes, [Ln(INNO)(Bza)2(H2O)2].(H2O) {INNO = isonicotinate N-oxide, Bza = benzoic acid; Nd(1), Eu(2), Gd(3), Tb(4), Dy(5), Er(6) and Y(7)}, have been successfully isolated by hydrothermal reactions utilizing two distinct carboxylates as co ligands. Due to the similar steric hindrance of the two carboxylic ligands, the neighboring lanthanide ions are bridged simultaneously by their carboxyl groups from the opposite sides to form a 1D chain structure. The shape analysis of the eight-coordinated Dy analogue 5 highlights the coordination geometry of the distorted square antiprism (D4d). The solid-state luminescence of 2 and 4 was characterized. The static magnetic analysis of the Gd analogue 3 is indicative of the dominant weak intrachain antiferromagnetic interactions via the carboxylic ligands. Dynamic magnetic measurements for 5 revealed clear slow magnetic relaxation behaviour typical for single-molecule magnets (SMMs). Compound 5 represents a very rare example, reported as a mixed carboxylate bridged lanthanide SMM. PMID- 28920125 TI - Volatile HRS asymmetry and subloops in resistive switching oxides. AB - Current-voltage characteristics of oxide-based resistive switching memories often show a pronounced asymmetry with respect to the voltage polarity in the high resistive state (HRS), where the HRS after the RESET is more conducting than the one before the SET. Here, we report that most of this HRS asymmetry is a volatile effect as the HRS obtained from a read operation differs from the one taken from the switching cycle at identical polarity and voltages. Transitions between the relaxed and the volatile excited states can be achieved via voltage sweeps, which are named subloops. The excited states are stable over time as long as a voltage is applied to the device and have a higher conductance than the stable relaxed state. Experimental data on the time and voltage dependence of the excitation and decay are presented for Ta/TaOx/Pt and Ta/ZrOx/Pt devices. The effect is not limited to one oxide or electrode material but is observed with different magnitudes (up to 10* current change) in several oxide systems. These observations describe an additional state variable of the memristive system that is controlled in a highly polarity dependent manner. PMID- 28920127 TI - Incident-angle-controlled semitransparent colored perovskite solar cells with improved efficiency exploiting a multilayer dielectric mirror. AB - See-through perovskite solar cells with high efficiency and iridescent colors are demonstrated by employing a multilayer dielectric mirror. A certain amount of visible light is used for wide color gamut semitransparent color generation, which can be easily tuned by changing an angle of incidence, and a wide range of visible light is efficiently reflected back toward a photoactive layer of the perovskite solar cells by the dielectric mirror for highly efficient light harvesting performance, thus achieving 10.12% power conversion efficiency. We also rigorously examine how the number of pairs in the multilayer dielectric mirror affects optical properties of the colored semitransparent perovskite solar cells. The described approach can open the door to a large number of applications such as building-integrated photovoltaics, self-powered wearable electronics and power-generating color filters for energy-efficient display systems. PMID- 28920126 TI - High energy product chemically synthesized exchange coupled Nd2Fe14B/alpha-Fe magnetic powders. AB - The excellent hard magnetic properties of Nd2Fe14B based magnets have an enormous range of technological applications. Exchange-coupled Nd2Fe14B/alpha-Fe magnets were chemically synthesized by a microwave assisted combustion process to produce mixed oxides, followed by a reduction diffusion process to form magnetic nano composite powder. This synthesis technique offers an inexpensive and facile platform to produce exchange coupled hard magnets. The size dependent magnetic properties were investigated. The formation mechanisms of the oxide powders and the reduction diffusion mechanism were identified. The microwave power was found to play a crucial role in determining the crystallite size. The coercivity of the powder increased with increasing particle size. Room temperature coercivity (Hc) values greater than 9 kOe and magnetization of 110 emu g-1 was obtained in particles with a mean size of ~62 nm. An energy product of 5.2 MGOe was obtained, which is the highest reported value for chemically synthesized hard magnetic Nd2Fe14B/alpha-Fe powders. PMID- 28920128 TI - Incorporation of [2H1]-(1R,2R)- and [2H1]-(1S,2R)-glycerols into the antibiotic nucleocidin in Streptomyces calvus. AB - Deuterium incorporations from [2H1]-(1R,2R) and [2H1]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5' site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5' of nucleocidin after a feeding experiment with [2H5]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic. PMID- 28920129 TI - Breastfeeding - Healthcare Professionals Need to Do More. PMID- 28920130 TI - Reasons and Factors Behind Post-Total Knee Arthroplasty Dissatisfaction in an Asian Population. AB - INTRODUCTION: Up to 20% of patients who underwent total knee arthroplasty (TKA) reported dissatisfaction with surgical outcome. Despite the multiple studies looking into the factors contributing to patients' dissatisfaction, little research has been done to examine the subjective reasons and complaints patients have post-arthroplasty. This study aimed to look at an Asian patient population which underwent TKA and examine the factors contributing to patient dissatisfaction and the reasons they were dissatisfied with their surgery. MATERIALS AND METHODS: A total of 3069 TKAs were performed between January 2011 to April 2013 in a single institution. Preoperative and postoperative variables were prospectively captured, such as standardised knee scores, knee range of motion and patient satisfaction scores. These variables were then analysed with a multiple logistic regression model to determine the statistically significant factors that contribute to patients' satisfaction. Dissatisfied patients were individually interviewed to find the reasons for their unhappiness. Preoperative variables were then analysed to identify the statistically significant factors associated with these subjective complaints. RESULTS: Minimum duration of follow up was 2 years, with an overall patient satisfaction rate of 91.3%. Preoperative variables contributing to patient dissatisfaction included female gender and better knee flexion. Postoperative variables included lesser improvement in knee flexion at 6 months postoperatively, as well as poorer scores in various validated knee scores at both 6 months and 2 years postoperatively. The top reason for dissatisfaction was pain. Weakness, another reason for patient dissatisfaction, had statistically significant preoperative predictors of increased age and poorer Short-Form 36 Physical Component Score. CONCLUSION: Although TKA has an impressive patient satisfaction rate in this Asian population, factors contributing to postoperative dissatisfaction suggest a targeted group of patients would benefit from preoperative counselling. The top reason for postoperative dissatisfaction in the study was pain. PMID- 28920131 TI - Reversible Causes in Cardiovascular Collapse at the Emergency Department Using Ultrasonography (REVIVE-US). AB - INTRODUCTION: Ultrasonographic evaluation of patients in cardiac arrest is currently not protocolised in the advanced cardiac life support (ACLS) algorithm. Potentially reversible causes may be identified using bedside ultrasonography that is ubiquitous in most emergency departments (EDs). This study aimed to evaluate the incidence of sonographically detectable reversible causes of cardiac arrest by incorporating an ultrasonography protocol into the ACLS algorithm. Secondary objectives include rates of survival to hospital admission, hospital discharge, and 30-day mortality. MATERIALS AND METHODS: We conducted a prospective study using bedside ultrasonography to evaluate for potentially reversible causes in patients with cardiac arrest at the ED of National University Hospital, Singapore, regardless of the initial electrocardiogram rhythm. A standardised ultrasonography protocol was performed during the 10 second pulse check window. RESULTS: Between June 2015 and April 2016, 104 patients were recruited, corresponding to 65% of all out-of-hospital cardiac arrest patients conveyed to the ED. Median age was 71 years (interquartile range, 55 to 80) and 71 (68.3%) patients were male. The most common rhythm on arrival was asystole (45.2%). Four (3.8%) patients had ultrasonographic findings suggestive of massive pulmonary embolism while 1 received intravenous thrombolysis and survived until discharge. Pericardial effusion without tamponade was detected in 4 (3.8%) patients and 6 (5.8%) patients had intra-abdominal free fluid. Twenty (19.2%) patients survived until admission, 2 of whom (1.9%) survived to discharge and beyond 30 days. CONCLUSION: Bedside ultrasonography can be safely incorporated into the ACLS protocol. Detection of any reversible causes may alter management and improve survival in selected patients. PMID- 28920132 TI - Geriatric Surgery Service - Our Journey Piloting in Colorectal Surgery and Future Challenges. PMID- 28920133 TI - Experience with a Community-based Multidisciplinary Memory Clinic: A Primary Care Perspective. PMID- 28920134 TI - Bullous Pesentation of Idiopathic Wells Syndrome (Eosinophilic Cellulitis). PMID- 28920135 TI - Asia's First Transapical Transcatheter Mitral Valve-in-Ring Implantation. PMID- 28920136 TI - Jaw Pain in a Pemphigus Patient on Prednisolone, Mycophenolate Mofetil and Denosumab. PMID- 28920137 TI - Analysing the impact of a case management model on the specialised palliative care multi-professional team. AB - PURPOSE: Palliative care (PC) involves many health care providers leading to a high complexity of structures that requires efficient coordination as provided by case management (CM). Our study aimed to evaluate the effects of CM newly implemented in a specialised palliative care unit by evaluating team members' tasks and time resources before (T0) and after implementation (T1). It was hypothesised that team members would be able to spend less time on organisational and administrative tasks and more time on patient care. METHODS: A prospective pre-post study design was used. Time distribution of different tasks at T0 and T1 was compared between three different professional groups: physicians, nursing staff and social work. To document their tasks and time required, a documentation form with several items for each profession was developed. Data was analysed using t tests for independent samples. RESULTS: After Bonferroni correction, a significant pre-post difference was found for the time spent on "discharge interview and discharge" as rated by the physicians (p < .001) with less time spent on this activity after CM implementation. The nursing staff had significantly more time for "conversations with patients" (p < .001) after CM implementation. Moreover, they spent significantly less time on "patient-related requests/advice by telephone" (p < .001) and "discussions with relatives/participation in family discussions" at post-assessment (p < .001). The social worker had significantly more time for "patient advice and support services" (p = .013) after CM implementation. CONCLUSIONS: Integrating CM can be time efficient and ensures team members to spend more time on their core tasks in patient care. PMID- 28920139 TI - Long-term outcomes of microvascular decompression and Gamma Knife surgery for trigeminal neuralgia: a retrospective comparison study. PMID- 28920138 TI - Study on the sediment characteristics of the snow in a typical residential community and its integrated biological treatment pattern in Harbin. AB - Winter cities have severe shortages of water resources. The effective classification and recycling of urban water resources that are available here are therefore significant for the sustainable utilization of water in winter cities, and snow is a potential water resource. In this research, the water quality of the snow and the pollutant composition in the vehicle roads of a typical residential community of Harbin are analyzed. It is concluded that there is a large amount of suspended substances, including chemical oxygen demand (COD), salt, ammonia, and oil in this snow. There are 27 main pollutants. The oily substances are dominated by hexadecane and are accompanied by toxic substances, including benzene, toluene, ethylbenzene, xylene (BTEX), and naphthalene. As snow is a carrier of pollutants, the underground space of the urban shallow green belt is proposed to be used to establish a snow-melting system that would integrate biological treatment devices. This method allows the year-round collection, storage, and utilization of rainwater for use in city planning and municipal technology, realizing multiple objectives and having a significant influence on further urban development. PMID- 28920140 TI - Frequency, location, and association with dental pathology of mucous retention cysts in the maxillary sinus. A radiographic study using cone beam computed tomography (CBCT). AB - OBJECTIVES: The purpose of the present study was to evaluate the frequency, locations, and dimensions of mucous retention cysts of the maxillary sinus and analyze potential associated dental pathology. MATERIALS AND METHODS: A total of 156 cone beam computed tomography (CBCT) scans were included in the analysis, resulting in an evaluation of 310 maxillary sinuses. The presence of mucous retention cysts (MRC) manifesting as dome-shaped radiopacities in the sinus was diagnosed. Their locations were recorded, and dimensions (mm) were measured in coronal and sagittal/axial slices. The patients were grouped into (a) patients/sinuses with MRCs (test), and (b) patients/sinuses with healthy or any other changes (control) for further comparison and evaluation. RESULTS: There were 40 sinuses (12.9%) with a presence of a total of 56 MRCs. The mean age of involved patients was 29.0 years. The analysis showed that gender, age, sinus side, status of dentition, endodontic status, and periodontal status did not have a significant influence on the presence of MRCs when compared between test and control groups. Age and endodontic status exhibited a significant association with cyst location. CONCLUSIONS: Most of the sinuses analyzed (79.5%) did not present any MRC, and only 28.6% of the cysts diagnosed were found on the floor of the maxillary sinus. The mean dimension of the MRCs measured 6.28 +/- 2.93 mm. No influencing factors on the presence or absence of MRCs were found in the present study. CLINICAL RELEVANCE: Most MRCs were not located on the floor of maxillary sinus. Future studies should assess their impact on surgical interventions in the sinus. PMID- 28920141 TI - Effects of moso bamboo (Phyllostachys edulis) invasions on soil nitrogen cycles depend on invasion stage and warming. AB - Plant invasions may alter soil nutrient cycling due to differences in physiological traits between the invader and species they displace as well as differences in responses to anthropogenic factors such as nitrogen deposition and warming. Moso bamboo is expanding its range rapidly around the world, displacing diverse forests. In addition, near expansion fronts where invasions are patchy, moso bamboo and other species each contribute soil inputs. Nitrogen transformations and greenhouse gas (GHG) emissions are important processes associated with nutrient availability and climate change that may be impacted by bamboo invasions. We collected soils from uninvaded, mixed, and bamboo forests to understand bamboo invasion effects on carbon and N cycling. We incubated soils with warming and N addition and measured net nitrification and N mineralization rates and GHG (CO2 and N2O) emissions. Mixed forest soils had higher pH and total N and lower total organic carbon and C/N than either uninvaded or bamboo forest soils. Bamboo forest soils had higher total carbon, dissolved organic carbon, and ammonium N but lower total and nitrate N than uninvaded forest soils. Soil GHG emissions did not vary among forest types at lower temperatures but bamboo forest soils had higher CO2 and lower N2O emissions at higher temperatures. While net N transformation rates were lower in bamboo and uninvaded forest soils, they were highest in mixed forest soils, indicating non-additive effects of bamboo invasions. This suggests that plant invasion effects on N transformations and GHG emissions with global change in forests partially invaded by bamboo are difficult to predict from only comparing uninvaded and bamboo-dominated areas. PMID- 28920142 TI - Acupuncture for reduction of symptom burden in multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation: a randomized sham controlled trial. AB - PURPOSE: Hematopoietic stem cell transplantation (HCT) is potentially curative for a number of hematologic malignancies, but is associated with high symptom burden. We conducted a randomized sham-controlled trial (RCT) to evaluate efficacy and safety of acupuncture as an integrative treatment for managing common symptoms during HCT. METHODS: Adult patients with multiple myeloma undergoing high-dose melphalan followed by autologous HCT (AHCT) were randomized to receive either true or sham acupuncture once daily for 5 days starting the day after chemotherapy. Patients and clinical evaluators, but not acupuncturists, were blinded to group assignment. Symptom burden, the primary outcome was assessed with the MD Anderson Symptom Inventory (MDASI) at baseline, during transplantation, and at 15 and 30 days post transplantation. RESULTS: Among 60 participants, true acupuncture produced nonsignificant reductions in overall MDASI core symptom scores and symptom interference scores during transplantation (P = .4 and .3, respectively), at 15 days (P = .10 and .3), and at 30 days posttransplantation (P = .2 and .4) relative to sham. However, true acupuncture was significantly more efficacious in reducing nausea, lack of appetite, and drowsiness at 15 days (P = .042, .025, and .010, respectively). Patients receiving sham acupuncture were more likely to increase pain medication use posttransplantation (odds ratio 5.31, P = .017). CONCLUSIONS: Acupuncture was well tolerated with few attributable adverse events. True acupuncture may prevent escalation of symptoms including nausea, lack of appetite, and drowsiness experienced by patients undergoing AHCT, and reduce the use of pain medications. These findings need to be confirmed in a future definitive study. TRIAL REGISTRATION: NCT01811862. PMID- 28920143 TI - Development of silica protective layer on pyrite surface: a column study. AB - An appealing technique to prevent and/or minimize pyrite oxidation and subsequent acid generation in mine waste sites is the formation of a protective coating on the surface of sulfide grains. To investigate the conditions for the formation of an efficient coating on pyritic tailings, column tests were performed. These tests involved the treatment with a coating solution, which was continuously recycled through the packed bed of tailings. The coating solution was consisted of SiO4-4 oxyanions, an oxidant (H2O2), and adjusted to pH 6. The effect of the volume of coating solution per mass of material (L/S ratio), Si concentration and treatment duration on coating formation was studied. Based on the results, a protective coating can be developed on the pyrite particles following treatment with a solution of 0.1 mM Si concentration, which resulted in the reduction of sulfate release by 84% compared to non-treated pyrite samples. PMID- 28920144 TI - Effects of Caatinga Plant Extracts in Planktonic Growth and Biofilm Formation in Ralstonia solanacearum. AB - This study describes the first antibiofilm and antibacterial screening for plants from Caatinga against Ralstonia solanacearum, a causal agent of bacterial wilt that presents serious difficulties in control. There were prepared 22 aqueous extracts of plants collected in the Vale do Catimbau-PE, Brazil. The potential antibacterial activity was evaluated by absorbance in OD600 and the antibiofilm activity through the crystal violet method, both of them performed in microplate against isolates of R. solanacearum biofilm formers. The results of the screening showed that Jacaranda rugosa presented antimicrobial activity higher than 90%, while Harpochilus neesianus and Myroxylon peruiferum presented antibiofilm activity higher than 50% for all tested isolates. However, Croton heliotropiifolius showed both the activities, being thus very promising for application in the control of this phytopathogen. The search for viable alternatives to the development of new bioactive compounds safe for the environment, humans, and animals from an adverse and scarce environment such as the Caatinga and encouraged us to find plants that produce effective metabolites against phytopathogenic microorganisms. This in vitro screening is important to guide the development of new products in addition to guide research studies of bioactive compounds. PMID- 28920146 TI - Cardiovascular and Mortality Risks in Migrant South Asians with Type 2 Diabetes: Are We Winning the Battle? AB - PURPOSE OF REVIEW: We seek to describe the relationship between diabetes mellitus and cardiovascular risk in migrant South Asians compared to native white Europeans, and to determine the temporal change in this relationship over recent years. RECENT FINDINGS: Recent evidence suggests that the excess mortality risk associated with diabetes is lower in the migrant South Asian population compared with white Europeans. By contrast, South Asians continue to demonstrate elevated cardiovascular morbidity compared to white Europeans, although to a lesser extent than was observed in previous decades. The excess mortality previously observed in South Asian migrants has attenuated with a lower mortality risk compared to white Europeans observed in several recent studies. We speculate that these findings may relate in part to earlier diabetes diagnosis and more prolonged exposure to cardiovascular risk factor management in the South Asian population. Further study is required to confirm these hypotheses. PMID- 28920145 TI - Impact of Drain Insertion After Perforated Peptic Ulcer Repair in a Japanese Nationwide Database Analysis. AB - BACKGROUND: Many perforated peptic ulcers (PPUs) require surgical repair due to diffuse peritonitis. However, few studies have examined the clinical effects of postoperative drainage after PPU repair. This study aimed to investigate the drain insertion rates in patients who underwent PPU repair in Japan, and to clarify the impact of drain insertion on the postoperative clinical course. METHODS: A retrospective nationwide cohort study was performed using administrative claims data of patients who had undergone PPU repair between 2010 and 2016. These patients were divided into two groups based on whether or not they had received a postoperative abdominal drain. Using propensity score matching, we compared the incidences of postoperative interventions for abdominal complications between both groups. RESULTS: A total of 4869 patients from 324 hospitals were analyzed. At the hospital level, drains were placed in all PPU repair patients in 229 (70.7%) hospitals. At the patient level, 4401 patients (90.4%) had drains inserted. The drain group was associated with a higher emergency admission rate, poorer preoperative shock status, longer anesthetic time, and a higher amount of intra-abdominal irrigation. In the propensity score matched patients, the drain group had a significantly lower incidence of postoperative interventions than the no-drain group (1.9 vs. 5.6%; risk ratio = 0.35; 95% confidence interval 0.16-0.73; P = 0.003). CONCLUSION: Postoperative drainage was performed in the majority of patients who underwent PPU repair in Japan. Drainage following PPU repair may facilitate patient recovery by reducing the need for postoperative interventions. PMID- 28920147 TI - Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. Reply to Marathe CS, Rayner CK, Jones KL, et al [letter]. PMID- 28920148 TI - Differential Gene Expression Profiles and Alternative Isoform Regulations in Gill of Nile Tilapia in Response to Acute Hypoxia. AB - Fish often encounters exposures to acute environmental hypoxia either spatially or temporally. Gill organ plays important roles in response to hypoxic stress in fish. Few studies focus on the molecular regulation mechanisms of gills under hypoxic stress. In this study, we investigated the transcriptomic response to 12 h acute hypoxia in gill of a hypoxia tolerant fish, Nile tilapia Oreochromis niloticus through RNA sequencing (RNA-Seq). We sequenced messenger RNA from three control samples and three hypoxia-treated samples. Bioinformatics analysis identified 239 differentially expressed genes (DEG) and 34 genes (DUES) that had significant differential alternative isoform regulation events in at least one exonic region in gill in response to acute hypoxia. The spatiotemporal expression analysis in five tissues (heart, liver, brain, gill, and spleen) sampled at three time points (6, 12, and 24 h) under hypoxia treatment confirmed the significant association of differential exon usages in two DUES genes (TLDC2 and SSX2IPA) with hypoxia conditions. Further functional analysis suggested several energy and immune response-related pathways, e.g., metabolic pathway and antigen processing and presentation, contained the most abundant DEG genes. We found that some GO biological processes for DEG genes were significantly enriched under hypoxic stress, such as glycolysis, metabolic process, generation of precursor metabolites and energy, and cholesterol metabolic process. Our findings suggest abundant differential gene expression changes and alternative isoform regulation events in genes involved in the hypoxia response in gill. Our results provide a basis for exploring the gene regulation mechanism under hypoxic stress in fish. PMID- 28920149 TI - Efficacy and safety of 153Sm-EDTMP as treatment of painful bone metastasis: a large single-center study. AB - PURPOSE: The purpose of this study is to assess the efficacy of 153Sm-EDTMP (Quadramet(r)) in a clinical setting. METHODS: We have conducted a retrospective study of all consecutive patients (pts) treated with 153Sm-EDTMP for painful bone metastases. At each visit (before and after treatment), four parameters were collected: (i) pain assessment according to the 10-step visual analogue scale (VAS), (ii) sleep disturbance related to pain, (iii) dose of analgesic medication, and (iv) answer to the following closed question "Do you think you obtained a benefit from treatment?" Success of treatment was defined by the combination of these four parameters. RESULTS: Three hundred seventy consecutive 153Sm-EDTMP treatments for painful bone metastases were given. Patients had the following primary tumors: breast carcinoma (153), prostate carcinoma (155), lung carcinoma (27), or other cancers (35). Fifty-eight percent of the patients had received previous external osseous radiotherapy. Ninety-seven percent of the patients were treated with concomitant analgesics and 61% were treated with diphosphonates. A clinical benefit was described in 55.0% of cases at D30. Treatment was more effective in cases of breast and prostate cancers compared with other types of primary cancers. Patients described a benefit at D30 in 62, 58, 6, and 38% of cases of breast, prostate, lung, and other cancers. The subjective efficacy was accompanied by a decrease in analgesic intake in 35.0% of cases. CONCLUSION: 153Sm-EDTMP therapy is an effective supportive treatment in patients who suffer from bone metastases, especially in patients with breast or prostate cancer. PMID- 28920150 TI - Molecular basis of Cd+2 stress response in Candida tropicalis. AB - This study examines the bioremediation potential and cadmium-induced cellular response on a molecular level in Candida tropicalis 3Aer. Spectroscopic analysis clearly illustrated the involvement of yeast cell wall components in biosorption. Cadmium bioaccumulation was confirmed by TEM, SEM, and EDX examination. TEM images revealed extracellular as well as cytoplasmic and vacuolar cadmium nanoparticle formation, further validated by presence of ycf1 gene and increased biosynthesis of GSH under cadmium stress. Fourteen proteins exhibited differential expression and during cellular redox homeostasis are found to involve in nitrogen metabolism, nucleotide biosynthesis, and carbohydrate catabolism. Interestingly, C. tropicalis 3Aer is equipped with nitrile hydratase enzyme, rarely been reported in yeast. It has the potential to remove nitriles from the environment. The Cd+2 toxicity not only caused growth stasis but also upregulated the cysteine biosynthesis, protein folding and cytoplasmic detoxification response elements. The present study suggests that C. tropicalis 3Aer is a potential candidate for bioremediating environmental pollution by Cd+2. PMID- 28920151 TI - Removal of arsenic III and V from laboratory solutions and contaminated groundwater by metallurgical slag through anion-induced precipitation. AB - Metallurgical slag was used for the simultaneous removal of high concentrations of arsenite and arsenate from laboratory solutions and severely contaminated groundwater. Apart from demonstrating the high efficiency of arsenic removal in presence of competing species, the work aims to explore the physicochemical mechanisms of the process by means of microscopy observation and a detailed statistical analysis of existing kinetic and isotherm equations. Fitting was performed by non-linear least squares using weighted residuals; ANOVA and bootstrap methods were used to compare the models. Literature suggests that the metal oxides in the slag are efficient adsorbents of As(III) and (V). However, the low surface area of the slag precludes adsorption; SEM observation provide evidence of a mechanism of co-precipitation of lixiviated cations with contaminant anions. The reaction kinetics provide essential information on the interaction between the contaminants, particularly on the common ion effect in groundwater. The Fritz-Schlunder isotherm allows modelling the saturation effect at low slag doses. The efficiency of the process is demonstrated by an arsenic removal of 99% in groundwater using 4-g slag/L, resulting in an effluent with 0.01 mg As/L, which is below Mexican and international standards for drinking water. PMID- 28920152 TI - Sentinel Node Navigation Surgery for Early Gastric Cancer: Analysis of Factors Which Affect Direction of Lymphatic Drainage. AB - BACKGROUND AND PURPOSE: We started performing sentinel node navigation surgery (SNNS) for patients with early gastric cancer (EGC) using infrared ray electronic endoscopy (IREE) with indocyanine green injection from year 2000. The EGCs usually have complex lymphatic drainage, unidirectional or multidirectional lymphatic flow. In this study, we investigated and clarified factors that affect the direction of gastric lymphatic drainage. PATIENTS AND METHOD: Consecutive 60 patients with EGC who underwent SNNS by IREE from year 2006 to 2014 were enrolled to this study. Patients' age, gender, location of tumors, operative method, previous treatment by endoscopic submucosal dissection (ESD), presence of pathological ulcerative scar and maximum tumor diameter were enrolled as parameters which may affect direction of lymphatic drainage and analyzed. RESULT: Bivariate analysis demonstrated that the presence of pathological ulcerative scar (P = 0.01), tumor location (g.c vs. a.w vs. p.w vs. l.c, P = 0.01), and maxim tumor diameter (P = 0.0003) were relevant to direction of gastric lymphatic drainage. Multivariate analysis showed that tumor location (g.c/a.w/p.w vs. l.c, odds ratio 8.227, P = 0.011) and the maximum tumor diameter (odds ratio 1.057, P = 0.037) are independent factors that affect direction of gastric lymphatic flow. Of tumors, 78% located at lesser curvature had unidirectional lymphatic drainage, and 93% of tumors whose diameter was 40 mm and more had multidirectional lymphatic drainage. CONCLUSION: Our investigation revealed that the tumor location and tumor diameter were the key factors which affect the direction of lymphatic drainage, which is useful fact to understand the complexity of gastric lymphatic drainage. PMID- 28920153 TI - Optimizing Somatostatin Analog Use in Well or Moderately Differentiated Gastroenteropancreatic Neuroendocrine Tumors. AB - BACKGROUND: Somatostatin analogues, aiming to control tumor secretion or growth, constitute the most attractive therapeutic option for patients with well differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The objective of this article is to provide a comprehensive review of the current state-of-the-art knowledge gaps and potential opportunities for future development and optimization of this therapeutic modality. METHOD: A contextualized systematic review with a narrative component was conducted using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Titles were screened, and non-English, duplicate, or irrelevant entries were excluded. Selection criteria for articles included the following: publication in English between 1995 and 2016, patients with GEP-NETs, analysis of efficacy, safety, practical management considerations, predictive factors, and/or strategies for overcoming resistance, concerning somatostatin analogs. RESULTS: Ninety-seven studies out of 2771 screened publications met the inclusion criteria (16 randomized clinical trials, 27 phase II trials, 3 phase I trials, 3 subgroup analyses of clinical trials, 1 open-label extension of a randomized trial, 1 phase IV trial, 32 observational studies, and 14 basic research articles). The nature and scope of literature was diverse with most articles dedicated to drug efficacy or indications of use (n = 49), pharmacological issues (n = 8), assessment or predictors of response (n = 4), practical management (n = 11), combination therapy or other means to overcome resistance (n = 19), receptors and signaling pathways (n = 3), and subgroup analyses (n = 3). CONCLUSION: In this appraisal, we have found some practical aspects that can help to the optimization of somatostatin analog (SSA) therapy in patients with well-differentiated GEP-NETs. We have also identified areas of uncertainty in an effort to guide clinical research in the coming years. PMID- 28920154 TI - Pharmacokinetics of doripenem in plasma and epithelial lining fluid (ELF): comparison of two dosage regimens. AB - PURPOSE: In 2014, FDA released a warning for prescription of doripenem for ventilator-associated bacterial pneumonia due to unsatisfactory clinical cure rates. The present study explores if the observed lack of efficacy might be explained by insufficient target site pharmacokinetics in intensive care patients after two different infusion schemes. METHODS: Plasma and bronchoalveolar lavage sampling was performed in 16 intubated patients with pneumonia receiving doripenem either as 1-h or as 4-h infusion. Doripenem concentrations were measured at steady state in plasma over 8 h, bronchoalvoelar lavage was performed in each patient once either after 0 h, 2 h, 4 h or 6 h. RESULTS: In plasma, mean values of Cmax, Tmax and AUC0-8 were 16.87 mg/L, 0.69 h and 52.98 mg/L*h after 1 h of infusion, and 12.94 mg/L, 3.21 h and 70.64 mg/L*h after 4 h of infusion, respectively. While the later tmax in plasma was with delay mirrored in the lung, for ELF, much lower concentrations were observed (Cmax, Tmax and AUC0-8 after 1-h infusion of 4.6 mg/L, 2 h and 15.3 mg/L*h and after 4-h infusion 6.9 mg/L, 4 h and 14.8 mg/L*h). CONCLUSION: The difference in plasma pharmacokinetics after 1-h and 4-h infusion reflects in the concentration versus time profile in the lung, but concentration at the target site was not only considerably lower but also subject to high inter-individual variability. We hypothesise that insufficient concentrations at the target site might have contributed to the previously described lack of clinical efficacy and confirmed the demand for assessment of target site pharmacokinetics in larger patient collectives. PMID- 28920155 TI - Distributions of recent gullies on hillslopes with different slopes and aspects in the Black Soil Region of Northeast China. AB - Gully erosion is an important environmental problem worldwide and the main process by which water and soil losses occur in the Black Soil Region (BSR) of Northeast China. At the end of 2012, 295,663 gullies were present in this region. However, few studies have examined the gullies of the Black Soil Region as a whole. Studying the distribution of recent gullies can reveal the pattern of gully distribution and can help predict their spatial development according to the soil and water conservation regionalization of China. This study examines the recorded gullies in the BSR of Northeast China, which is included in the first census of water resources in China and in six sub-regions of the soil and water conservation regionalization of China. Specifically, digital elevation model (DEM) data are combined with data on gullies occurring on hillslopes with different slopes and aspects to study the distribution of these features. The results illustrate that gully density, developing gully density, and the proportion of cutting land initially increase with increasing slope up to some threshold value, then decrease as the slope increases further. The patterns of stable gullies are divided into unimodal and bimodal types. Three patterns of gully intensity are identified. The areas and lengths of gullies are larger on sunny slopes, but larger numbers of gullies are present on shaded slopes. In addition, more space is available for gully development in the Hulun Buir hilly and plain sub-region and the Changbai Mountain-Wanda Mountain sub-region than in the other sub-regions. PMID- 28920156 TI - Cancer risk in the EMPA-REG OUTCOME trial. Reply to Shaikh AMY [letter] and Kohler S, Lee J, George JT et al [letter]. PMID- 28920157 TI - Mechanisms of cancer cell killing by sea cucumber-derived compounds. AB - The aim of cancer therapy is to specifically eradicate tumor cells while causing minimal damage to normal tissues and minimal side-effects. Because of this, the use of natural substances with low toxicity is a good option. Sea cucumbers are one of many potential marine animals that contain valuable nutrients and medicinal properties. The medicinal value of sea cucumbers is attributed to the presence of bioactive agents with promising biological and pharmacological properties that include cytotoxic activity, induction of apoptosis, cell cycle arrest, inhibition of tumor growth, anti-metastatic and anti-angiogenic properties, and inhibition of drug resistance. This review discusses the mechanisms of cancer cell death induced by sea cucumber-derived compounds with regard to exploring the potential use of these marine natural products for cancer therapy. PMID- 28920158 TI - Comparison of outcomes of scleral fixation with and without pars plana vitrectomy for the treatment of dislocated intraocular lens. AB - PURPOSE: To investigate the surgical outcomes of scleral fixation with either pars plana vitrectomy (ppV) or anterior vitrectomy (AV) for the treatment of dislocated intraocular lens (IOL). METHODS: By retrospective review of electronic medical records, patients with in-the-bag spontaneous IOL dislocation who underwent IOL exchange with scleral fixation were included and grouped according to the vitrectomy method: ppV (group 1) and AV (group 2). Post-operative surgical outcomes including visual acuity (log MAR), spherical equivalent, and surgically induced astigmatism (SIA) and complications were investigated and analyzed. RESULTS: After 6 months, post-operative measurements showed an average visual acuity of 0.16 +/- 0.20, spherical equivalent of -1.48 +/- 1.53D (diopters), and refractive shift of -0.19 +/- 0.44D in group 1 (n = 19). There was no statistically significant difference between the measurements of group 1 and group 2 (n = 20) (0.10 +/- 0.12, -2.00 +/- 1.71D, -0.39 +/- 0.57D, respectively) (p = 0.51, p = 0.29, p = 0.16, respectively). When analyzed by the algebraic and vector methods, group 1 did show a higher magnitude of surgically induced astigmatisms (1.61 +/- 1.50D, 2.10 +/- 1.03D, respectively) than did group 2 (0.49 +/- 1.02D, 1.31 +/- 0.83D respectively) (both p's = 0.01). There was no significant difference in the incidence of complications except for vitreoretinal complications, which were higher in group 2 (25%), compared with group 1 (0%) (p = 0.047). CONCLUSIONS: Both ppV and AV are appropriate options in patients who need IOL exchange with scleral fixation based on visual outcomes, refractive shifts, and complication rates. In terms of managing astigmatism, the AV procedure may be the better option. PMID- 28920159 TI - Integrating referral to community-based cancer information and support services in a hospital setting. AB - PURPOSE: To implement and evaluate a hospital-based referral mechanism to increase patient uptake of community-based cancer information and support services. Feasibility and acceptability of the intervention and education program was evaluated. Changes in usage of Cancer Council Victoria's cancer information and support telephone line were investigated. METHODS: A 6-month study was conducted in one metropolitan and one regional cancer treatment hospital. Clinicians attended an education session regarding referral mechanisms to Cancer Council support services. Clinicians completed a questionnaire, and consenting patients participated in a semi-structured telephone interview for the project evaluation. The number of calls made from patients at study sites was monitored. RESULTS: Fifty-two clinicians were trained and referred a total of 430 patients to the cancer information and support service during the study period. Calls from patients increased by up to 100% per month from baseline following the implementation of the referral mechanism. Staff evaluations showed support for the referral mechanism and its incorporation into routine practice. Interviews were conducted with 45 patients; most remembered receiving the referral and were positive towards the intervention. Common reasons patients gave for not acting on the referral included forgetting, lack of need, timing and burden of information. CONCLUSIONS: There is preliminary evidence that this intervention increases awareness and uptake of community-based cancer information and support services. Ongoing clinician education and improvements in patient-clinician communication are important for effective translation from referral to service uptake. Consideration of the most appropriate time in a patients' care trajectory to introduce a referral is warranted. PMID- 28920160 TI - Preoperative Albumin-Bilirubin Grade Predicts Recurrences After Radical Gastrectomy in Patients with pT2-4 Gastric Cancer. AB - BACKGROUND: The albumin-bilirubin (ALBI) score was initially developed for assessing liver dysfunction severity and was suggested to have prognostic value in patients with hepatocellular carcinoma. We aimed to evaluate the prognostic impact of ALBI grade in patients with advanced gastric cancer (GC) after radical gastrectomy. METHODS: This study included 283 patients who underwent radical gastrectomy for pT2-4 GC without preoperative treatment. ALBI was calculated as follows: (log10 bilirubin (MUmol/L) * 0.66) + (albumin (g/L) * -0.0852) and categorized into grades 1 (<=-2.60), 2 (-2.60<, <=-1.39) and 3 (-1.39<). RESULTS: The median ALBI score was -2.96, and a number of patients in ALBI grades 1, 2 and 3 were 228, 55 and 0, respectively. Patients with ALBI grade 2 had a lower administration rate of adjuvant chemotherapy than those with ALBI grade 1, whereas no significant differences were found in morbidity rate and disease stage. The ALBI grade 2 group was more likely to have shorter disease-specific and disease-free survival compared with the ALBI grade 1 group. Multivariable analysis identified ALBI grade 2 as an independent prognostic factor for disease free survival (hazard ratio 1.97, 95% confidence interval 1.10-3.47, p = 0.0242). Survival differences between ALBI grade 1 and 2 groups were increased in the patient subset that received adjuvant chemotherapy. ALBI grade 2 was correlated with a shortened duration of administration of postoperative S-1 adjuvant. CONCLUSIONS: ALBI grade serves as a simple and promising predictive factor for disease-free and disease-specific survival in patients with pT2-4 GC after radical gastrectomy. PMID- 28920161 TI - Tapered US carbon emissions during good times: what's old, what's new? AB - In light of a slow buildup in CO2 emissions since the recovery, this paper revisits the relationship between CO2 emissions and the US economy using a nonlinear autoregressive distributed lag model, in which the determinants are identified through an expanded real business cycle model. We find convincing evidence that CO2 emissions decline more rapidly during recessions than increase during expansions over the long run. Of all determinants considered, long-run asymmetry is fostered once vehicle miles traveled is controlled. This calls for a greater attention to public transportation development and vehicle miles traveled tax for slowing down stock buildup of CO2 emissions during good times. PMID- 28920162 TI - Periodontal screening and referral behaviour of general dental practitioners in Flanders. AB - OBJECTIVES: The objective of this study was to investigate the screening and referral behaviour of Flemish dentists concerning periodontitis and more specific, the use of the Dutch Periodontal Screening Index (DPSI). MATERIALS AND METHODS: An online questionnaire was electronically distributed through the different professional dental societies. It consisted of two parts: the first aimed at describing the profile of the dentist. The second part inquired the screening method, when this was applied, periodontal risk factors and referral behaviour. RESULTS: One thousand fifty dentists attended to the questionnaire. One hundred fifty-nine questionnaires were excluded since they did not match the target audience. Sixty-four percent of Flemish dentists used DPSI as a periodontal screening method, 28% screened based on probing pocket depth, 4% used solely radiographs and 4% had no screening method at all. The usage of DPSI is influenced by the year of graduation: the longer the dentists were graduated, the less they used DPSI. No influence of sex, education centre and location was found. Referral behaviour is influenced by different patient- and dentist-related factors. CONCLUSIONS: Regarding the screening behaviour, there seems a consensus among Flemish dentists that a periodontal probe should be used. For referral, there is no consensus about if and when to refer to a specialist. CLINICAL RELEVANCE: It is encouraging that 92% of the Flemish general dental practitioners use a probe when screening for periodontitis. However, DPSI is mainly used by younger dentists. An effort should be made to encourage all dentists to use this, so that in every patient, periodontitis can be detected timely, securing the best treatment outcome. PMID- 28920163 TI - Correction of whistle deformity using autologous free fat grafting: first results of a pilot study and review of the literature. AB - PURPOSE: Whistle deformities are frequent sequelae after surgical correction of cleft lip, trauma, or tumor excision. The aim of this study was to examine the role of autologous free fat grafting in the reconstruction of whistle deformity. PATIENTS: Fifteen patients with whistle deformity were enrolled in this pilot study. The mean follow-up period was 19 months. Liposuction was done followed by the replantation of an average of 2.2 ml autologous fat per patient (range 0.7-4 ml). An overcorrection was performed in all patients. RESULTS: All the patients showed improvements in whistle deformity. The mean resorption rate was 53% (range 30-80%). Three patients (20%) were not satisfied with the postoperative result. Six complications were assessed (4* feeling of pressure [27%], one hematoma [7%], one recurrent pain [7%]), but a major complication did not occur. REVIEW: We also present a review of the literature with different techniques that were described in the last 20 years. CONCLUSION: Autologous free fat graftings for reconstruction of whistle deformity represent a reliable method with a low complication rate. However, the resorption rate is unpredictable. If necessary, several autologous fat transplantations should be conducted at an interval of at least 6 months. PMID- 28920164 TI - Purification and Characterization of a Naringinase from Cryptococcus albidus. AB - Naringinase which was extracted from the fermented broth of Cryptococcus albidus was purified about 42-folds with yield 0.7% by sulfate fractionation and chromatography on Toyopearl HW-60, Fractogel DEAE-650-s, and Sepharose 6B columns. Molecular weight of protein determined by gel filtration and SDS-PAGE was 50 kDa. Naringinase of C. albidus includes high content of the dicarbonic and hydrophobic amino acids. Enzyme contains also carbohydrate component, represented by mannose, galactose, rhamnose, ribose, arabinose, xylose, and glucose. The enzyme was optimally active at pH 5.0 and 60 degrees C. Naringinase was found to exhibit specificity towards p-nitrophenyl-alpha-L-rhamnose, p-nitrophenyl-beta-D glucose, naringin, and neohesperidin. Its K m towards naringin was 0.77 mM and the V max was 36 U/mg. Naringinase was inhibited by high concentrations of reaction product-L-rhamnose. Enzyme revealed stability to 20% ethanol and 500 mM glucose in the reaction mixture that makes it possible to forecast its practical use in the food industry in the production of juices and wines. PMID- 28920165 TI - Distinctive Patterns in the Taxonomical Resolution of Bacterioplankton in the Sediment and Pore Waters of Contrasted Freshwater Lakes. AB - Bacteria assemblages in lake sediments play a key role in various biogeochemical processes, yet their association with interstitial pore waters has been scarcely investigated. In this study, we utilized Illumina next-generation amplicon sequencing of the 16S rRNA gene to characterize the seasonal bacterial communities in the sediments and pore waters of three contrasted temperate freshwater lakes, namely Pavin, Aydat, and Grangent (French Massif Central). Despite occupying seemingly similar habitats, bacterial communities differed substantially between sediments and pore waters at all seasons with low sharing of operational taxonomic units (OTUs, 6.7 to 20.3%) between them. Sediment associated bacteria were more rich and diverse than pore water bacteria, indicating a high heterogeneity in the sediment microhabitat. The changes in both sediment and pore water bacterial communities were lake and season specific. The bacterial community showed distinct differences between the lakes, with larger presence of strict anaerobes such as Syntrophus, Syntrophorhabdus, and Sulfuricurvum in the pore water and sediments of Pavin responsible for carbon and sulfur cycling. In both Aydat and Grangent, the hgcI_clade dominated throughout the study period in the pore waters. The higher representation of lesser-known transient members of lake communities such as Methylotenera in the pore waters of Aydat, and Clostridium and Sulfuricurvum in the pore and sediments of Grangent, respectively, were observed during the period of temporary anoxia in summer caused by lake stratification. Our study revealed that in the investigated lakes, the prevailing environmental factors across time and space structured and influenced the adaptation of bacterial communities to specific ecological niches. PMID- 28920166 TI - Clinical significance of Aspergillus species isolated from respiratory specimens in patients with Mycobacterium avium complex lung disease. AB - Chronic pulmonary aspergillosis (CPA) is associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). An Aspergillus-positive respiratory specimen often reflects colonization, and thus the clinical significance of Aspergillus isolation in MAC-LD patients is not well understood. The objective of this study was to investigate the clinical characteristics and outcomes of MAC-LD patients in whom Aspergillus was isolated from respiratory specimens. We performed a retrospective review of the medical records of 329 MAC LD patients. We compared the characteristics and mortality rates between patients with Aspergillus isolation and those without. All Aspergillus species detected from respiratory specimens within the follow-up period were reviewed. Aspergillus was detected in 40 (12.2%) of the 329 patients. There were no significant differences in the clinical characteristics and mortality rates between patients with and without Aspergillus isolation. Among the 40 patients with Aspergillus isolation, 9 (22.5%) developed CPA. CPA was most often caused by A. fumigatus. In the 40 Aspergillus-positive patients, patients with A. fumigatus isolation had a significantly higher mortality rate than those without (P < 0.001). The multivariate Cox proportional hazards model showed older age (P = 0.050), presence of respiratory comorbidities (P = 0.008), hypoalbuminemia (P < 0.001), and isolation of A. fumigatus (P = 0.005) to be prognostic factors for mortality in MAC-LD patients. There was no significant difference in the mortality rates between patients with Aspergillus isolation and those without. However, isolation of A. fumigatus may be associated with poor prognosis in MAC-LD patients. PMID- 28920167 TI - Comparison of efficacy between dorsal root entry zone lesioning and selective dorsal rhizotomy for spasticity of cerebral origin. AB - BACKGROUND: Severe spasticity adversely affects patient functional status and caregiving. No previous study has compared efficacy between dorsal root entry zone lesioning (DREZL) and selective dorsal rhizotomy (SDR) for reduction of spasticity. This study aimed to investigate the efficacy of DREZL and SDR for attenuating spasticity, and to compare efficacy between these two methods. METHODS: All patients who underwent DREZL, SDR, or both for treatment of intractable spasticity caused by cerebral pathology at Siriraj Hospital during 2009 to 2016 were recruited. Severity of spasticity was assessed using Modified Ashworth Scale (MAS) and Adductor Tone Rating Scale (ATRS). Ambulatory status was also evaluated. RESULTS: Fifteen patients (13 males) with a mean age of 30.3 +/- 17.5 years were included. Eight, six, and one patient underwent DREZL, SDR, and combined cervical DREZL and lumbosacral SDR, respectively. Eight of ten patients with preoperative bed-bound status had postoperative improvement in ambulatory status. Spasticity was significantly reduced in the DREZL group (p < 0.001), the SDR group (p < 0.001), and in overall analysis (p < 0.001). SDR was effective in both pediatric and adult spasticity patients. A significantly greater reduction in spasticity as assessed by MAS score (p < 0.001) and ATRS score (p = 0.015) was found in the DREZL group. Transient lower limb weakness was found in a patient who underwent SDR. CONCLUSIONS: DREZL is more effective for reducing spasticity, but is more destructive than SDR. DREZL should be preferred for bed-ridden patients, and SDR for ambulatory patients. Both operations are helpful for improving ambulatory status. Gait improvement was observed only in patients who underwent SDR. Adult patients with spasticity of cerebral origin benefit from SDR. PMID- 28920168 TI - The online measured black carbon aerosol and source orientations in the Nam Co region, Tibet. AB - Equivalent black carbon (eBC) mass concentrations were measured by an aethalometer (AE-31) in the Nam Co, central Tibet from 2010 to 2014. Different from previous filter-sampling studies (Ming et al., J Environ Sci 22(11):1748 1756, 2010; Zhao et al., Environ Sci Pollut Res 20:5827-5838, 2013), the first high-resolution online eBC measurement conducted in central Tibet is reported here, allowing to discuss the diurnal variations as well as seasonal variabilities of eBC. Average daily eBC concentration was 74 +/- 50 ng/m3, reflecting a global background level. Meteorological conditions influenced eBC concentrations largely at seasonal scale, which are higher in February-May but lower in June-January. The highest eBC concentrations (greater than 210 ng/m3) were more associated with the W and WSW winds smaller than 6 m/s. The diurnal variations of eBC showed plateaus from 10:00 to 15:00 with seasonal variations, associated with local anthropogenic activities, such as indigenous Tibetan burning animal waste and tourism traffic. The PBLHs showed a co-variance with eBC concentrations, implicating close sources. The aerosol optical depths derived from the MODIS data over the Nam Co Observatory Station (NCOS)-included sub-area (30 degrees N-40 degrees N, 90 degrees E-100 degrees E) showed significant relationship with eBC concentrations. This suggests that nearby or short-distance sources other than long-distance transported pollutants could be important contributors to eBC concentrations at the NCOS, different from the conclusions suggested by previous studies. PMID- 28920169 TI - Diagnostic value of sTREM-1, IL-8, PCT, and CRP in febrile neutropenia after autologous stem cell transplantation. AB - Infections and infectious complications are the major cause of morbidity and mortality in febrile neutropenic patients after autologous stem cell transplantation. Laboratory biomarkers are helpful for early identification of critically ill patients and optimal therapy management. Several studies in adult non-neutropenic patients proposed sTREM-1 as a superior biomarker for identification of septic patients as well as a predictor for survival in these patients compared with procalcitonin (PCT), C-reactive protein (CRP), or interleukin-8 (IL-8). Here, to assess the utility of PCT, CRP, IL-8, and sTREM-1 in febrile neutropenia, 44 patients presenting with febrile neutropenia after autologous stem cell transplantation were recruited in a single-center prospective pilot study. We analyzed PCT and CRP as well as IL-8 and sTREM-1 levels pre- and post-transplantation at defined time points. In 20 of 44 patients, concentration of sTREM-1 was under the detection level at appearance of febrile neutropenia. Mean levels of PCT, IL-8, and CRP were significantly increased in infections of critically ill patients who by dysfunction or failure of one or more organs/system depend on survival from advanced instruments of monitoring and therapy. However, all tested biomarkers could not distinguish between presence and absence of bloodstream infection. The combination of the biomarkers PCT and IL-8 achieved a high sensitivity of 90% and specificity of 74% for the identification of serious complications in febrile neutropenia, whereas the combination of CRP and PCT or IL-8 achieved a high sensitivity of 100%, but with the addition of a low specificity of 47or 41%. In conclusion, we found that the measurement of sTREM-1 concentration at presentation of febrile neutropenia is not useful to identify bacterial bloodstream infections and critically ill patients. PCT and IL-8 are useful biomarkers for the early identification of critically ill patients, compared to CRP and sTREM-1 in febrile neutropenia. PCT or IL-8 in combination with clinical parameters should be considered in routine measurement to identify critically ill patients as early as possible. PMID- 28920170 TI - Meniscal extrusion seen on ultrasonography affects the development of radiographic knee osteoarthritis: a 3-year prospective cohort study. AB - The objective of this study is to determine whether meniscal extrusion (ME) of the medial meniscus on ultrasonography affects knee osteoarthritis (KOA) progression during 3-year follow-up. Two hundred seventy volunteers (70 men, 200 women; mean age 60.5 years) participated. Weight-bearing radiographs were evaluated. All subjects had medial radiographic KOA (Kellgren-Lawrence grade [KLG], >= 2) in at least one knee at baseline (BL). KLG 2 was defined as moderate KOA (MKOA); KLG 3 and 4 were defined as severe KOA (SKOA). Medial and lateral joint space width (MJSW and LJSW) were measured at the minimum width of femoro tibial compartment. The medial and lateral osteophyte area (MOPA and LOPA) were measured. Rapid joint space narrowing progression (RP) was defined as >= 25% loss of JSW from BL. ME was measured at the medial knee joint space on the medial collateral ligament with ultrasonography. The optimal ME cut-off for RP was determined by ROC curve. The relationship between ME and the longitudinal change of radiographic parameters was elucidated by linear and logistic regression analysis. In the 460 OA knees at BL, both MOPA and LOPA increased, while only MJSW narrowed after 3 years. RP occurred in 25 knees among 281 MKOA knees and 42 among 179 SKOA knees. ME was associated with medial joint space narrowing only in the SKOA group, while the ME was associated with MOPA in the MKOA and SKOA groups. The cut-off value to detect RP was 5.5 mm only in the SKOA group. Ultrasonographic evaluation of medial ME was useful to detect radiographic KOA progression. PMID- 28920171 TI - An investigation of the host-specificity of metacercariae of species of Apophallus (Digenea: Heterophyidae) in freshwater fishes using morphological, experimental and molecular methods. AB - Metacercariae of species of the genus Apophallus Luhe, 1909, infecting the fins and skin of freshwater fishes, frequently cause black spot disease. Two species, Apophallus muehlingi (Jagerskiold, 1899) and A. donicus (Skrjabin & Lindtrop, 1919), are known to occur in Hungarian fishes. It has generally been thought that metacercariae of A. muehlingi infect cyprinid fishes, whereas those of A. donicus develop in percids. As part of a morphological, experimental and molecular study, metacercariae were collected from 99 infected specimens of five cyprinid hosts (Abramis brama, Blicca bjoerkna, Chondrostoma nasus, Squalius cephalus, Scardinius erythrophthalmus) and 18 infected specimens of two percid hosts (Gymnocephalus cernua, Perca fluviatilis) in Hungarian natural waters (Lake Balaton, River Danube). Moreover, 1024 common carp (Cyprinus carpio) specimens collected from Hungarian fish ponds were investigated for Apophallus infection, but without positive results. For reliable species identification, experimental infections of chicks were carried in order to produce adult specimens from metacercariae collected from the fins and skin of the cyprinid and percid hosts. Within 8 days, adult specimens of both A. muehlingi and A. donicus developed in chicks infected with metacercariae from the cyprinid common bream (Abramis brama) and the white bream (Blicca bjoerkna) and the ruffe (Gymnocephalus cernua), a percid, respectively. The morphology of the collected metacercariae and adult individuals developed in the feeding experiments was characterised. A molecular analysis was extended to cercarial samples from the snail Lithoglyphus naticoides and to a single adult specimen of Apophallus from a fox. Sequences of 28 specimens were analysed using molecular methods (sequencing the internal transcribed spacer region and the cytochrome oxidase I subunit). Phylogenetic analysis was executed, and the Apophallus samples clustered into three distinct branches using both genes, A. muehlingi from cyprinids, A. donicus from percids and, a third, previously unknown, Apophallus clade, also from cyprinids. PMID- 28920172 TI - Hepatocellular Carcinoma Screening Utilising Serum Alpha-Fetoprotein Measurement and Abdominal Ultrasound Is More Effective than Ultrasound Alone in Patients with Non-viral Cirrhosis. AB - PURPOSE: This study is aimed to determine the performance of alpha-fetoprotein (AFP) as part of hepatocellular carcinoma (HCC) screening in a non-viral cirrhosis population. METHODS: A retrospective audit was conducted of patients with non-viral cirrhosis over a 13 year period managed at a single centre. All patients were investigated routinely for evidence of viral hepatitis; patients with positive results were excluded from analysis. Cirrhosis was defined on basis of clinical, biochemical, and radiological investigations and examinations. All patients underwent HCC screening with 6-monthly AFP measurement and 6-12-monthly upper abdominal ultrasound (US). Diagnosis of HCC was confirmed by biopsy, definitive imaging, or natural disease progression. RESULTS: Sixty-seven patients were included (49 males, average age 58.7 years). Of 14 patients who developed HCC during the study period, 12 patients had HCC detected via screening. Of the screening diagnosed HCC cases, four (33%) patients had a normal AFP with abnormal surveillance US, three (25%) had raised AFP with normal surveillance US, and five (42%) had concurrent AFP elevation and US abnormality. Patients with raised AFP and normal surveillance US had HCC diagnosed after a progressive rise in AFP precipitated imaging with alternative modalities. Within the 53 patients who remained free of HCC, a raised AFP precipitated additional imaging on 10 occasions. HCC was diagnosed in 12 out of 64 patients over a total of 4292 screening months giving an annual incidence of 3.35%. CONCLUSIONS: Twenty-five percent of HCC occurring in non-viral cirrhosis will be detected earlier using a surveillance program incorporating both AFP and US compared to imaging alone programs. PMID- 28920173 TI - Presumptive diagnosis of multinodular vacuolating tumor: "More than meets the eye!" PMID- 28920174 TI - Features and Effects of Information Technology-Based Interventions to Improve Self-Management in Chronic Kidney Disease Patients: a Systematic Review of the Literature. AB - Slowing down the progression of chronic kidney disease (CKD) and its adverse health outcomes requires the patient's self-management and attention to treatment recommendations. Information technology (IT)-based interventions are increasingly being used to support self-management in patients with chronic diseases such as CKD. We conducted a systematic review of randomized controlled trials (RCTs) to assess the features and effects of IT-based interventions on self-management outcomes of CKD patients. A comprehensive search was conducted in Medline, Scopus, and the Cochrane Library to identify relevant papers that were published until May 2016. RCT Studies that assessed at least one automated IT tool in patients with CKD stages 1 to 5, and reported at least one self-management outcome were included. Studies were appraised for quality using the Cochrane Risk of Bias assessment tool. Out of 12,215 papers retrieved, eight study met the inclusion criteria. Interventions were delivered via smartphones/personal digital assistants (PDAs) (three studies), wearable devices (three studies), computerized systems (one study), and multiple component (one study). The studies assessed 15 outcomes, including eight clinical outcomes and seven process of care outcomes. In 12 (80%) of the 15 outcomes, the studies had revealed the effects of the interventions as statistically significant positive. These positive effects were observed in 75% of the clinical outcomes and 86% of the process of care outcomes. The evidence indicates the potential of IT-based interventions (i.e. smartphones/PDAs, wearable devices, and computerized systems) in self-management outcomes (clinical and process of care outcomes) of CKD patients. PMID- 28920175 TI - Chemoenzymatic synthesis of 3'-phosphoadenosine-5'-phosphosulfate coupling with an ATP regeneration system. AB - 3'-Phosphoadenosine-5'-phosphosulfate (PAPS) is the obligate cosubstrate and source of the sulfonate group in the chemoenzymatic synthesis of heparin, a commonly used anticoagulant drug. Previously, using ATP as the substrate, we had developed a one-pot synthesis to prepare PAPS with 47% ATP conversion efficiency. During the reaction, 47% of ATP was converted into the by-product, ADP. Here, to increase the conversion ratio of ATP to PAPS, an ATP regeneration system was developed to couple with PAPS synthesis. In the ATP regeneration system, the chemical compound, monopotassium phosphoenolpyruvate (PEP-K+), was synthesized and used as the phospho-donor. By using 3-bromopyruvic acid as the starting material, the total yield of PEP-K+ synthesis was over 50% at low cost. Then, the enzyme PykA from Escherichia coli was overexpressed, purified, and used to convert the by-product ADP into ATP. When coupled the ATP regeneration system with PAPS synthesis, the higher ratio of PEP-K+ to ADP was associated with higher ATP conversion efficiency. By using the ATP regeneration system, the conversion ratio of ATP to PAPS was increased to 98% as determined by PAMN-HPLC analysis, and 5 g of PAPS was produced in 1 L of the reaction mixture. Furthermore, the chemoenzymatic synthesized PAPS was purified and freeze-dried without observed decomposition. However, the powdery PAPS was more unstable than the PAPS sodium salt in aqueous solution at ambient temperature. This developed chemoenzymatic approach of PAPS production will contribute to the synthesis of heparin, in which PAPS is necessary as the individual sulfo-donor. PMID- 28920176 TI - Isolation and identification of antifungal peptides from Bacillus amyloliquefaciens W10. AB - Antifungal metabolites produced by Bacillus sp. W10, which was previously isolated from the tomato rhizosphere, were investigated. Strain W10 was identified as Bacillus amyloliquefaciens by analysis of its 16S rDNA and gyrB gene partial sequences. PCR analysis showed the presence of fenB, sfp, and ituD genes, coding for fengycin, surfactin, and iturin, respectively. A novel small antifungal peptide, designated 5240, produced by this strain was isolated by ammonium sulfate precipitation and Superdex 200 gel filtration chromatography. The 5240 peptide was stable at 100 degrees C for 20 min and remained active throughout a wide pH range (4-10). The antagonistic activity was not affected by protease K and trypsin. The purified 5240 peptide exhibited a broad inhibitory spectrum against various plant pathogenic fungi and was identified as iturin A (C14-C16). Moreover, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry indicated the presence of fengycin A (C14-C15), fengycin B (C16-C17), and surfactin (C13-C16) isoforms in supernatants from strain W10. These results suggest that B. amyloliquefaciens W10 has significant potential as a biocontrol agent. PMID- 28920177 TI - Molecular detection of Crimean-Congo hemorrhagic fever virus in ticks, Greece, 2012-2014. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans mainly through the bite of infected ticks. In Greece, only one clinical case has been observed, in 2008, but the seroprevalence in humans is relatively high (4.2%). To have a first insight into the circulation of CCHFV in Greece, 2000 ticks collected from livestock during 2012-2014 were tested. CCHFV was detected in 36 of the 1290 (2.8%) tick pools (1-5 ticks per pool). Two genetic lineages were identified: Europe 1 and Europe 2. Most Europe 1 sequences were obtained from Rhipicephalus sanguineus sensu lato ticks, while most Europe 2 sequences were recovered from Rhipicephalus bursa ticks. The number of collected Hyalomma marginatum ticks (the principal vector of CCHFV) was low (0.5% of ticks) and all were CCHFV negative. Since it is not known how efficient ticks of the Rhipicephalus genus are as vectors of the virus, laboratory studies will be required to explore the role of Rhipicephalus spp. ticks in CCHFV maintenance and transmission. PMID- 28920178 TI - Impact of Splenic Volume and Splenectomy on Prognosis of Hepatocellular Carcinoma Within Milan Criteria After Curative Hepatectomy. AB - BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) with portal hypertension (PH) is very poor. Splenomegaly is considered important evidence of PH. Our aim was to clarify the prognostic value of splenic volume (SV) and the effect of splenectomy on the prognosis of HCC within the Milan criteria after curative hepatectomy. METHODS: In this single-center retrospective study, we reviewed 160 patients with HCC that met the Milan criteria, including 138 who had undergone hepatectomy and 22 who had undergone hepatectomy and splenectomy between July 2004 and December 2010. SV was measured by three-dimensional computed tomography and patients allocated to three groups (high SV >=300 mL; low <300 mL; and splenectomy) to compare post-hepatectomy survival rates. RESULTS: Multivariate analyses showed that SV is an independent prognostic factor for overall and disease-free survival. The overall survival rates at 5 years in the high SV, low SV, and splenectomy groups were 39, 75, and 88%, respectively. The overall survival rate in the high SV group was significantly worse than in the low SV and splenectomy groups (P < 0.001). There was no significant difference between the low SV and splenectomy groups (P = 0.831). CONCLUSIONS: High SV is an independent predictor of post-hepatectomy HCC recurrence and overall survival. There is no significant difference in prognosis between low SV and splenectomy groups, even though the latter had high SV. Combined splenectomy with hepatectomy for HCC and PH may improve prognosis and be an appropriate alternative when liver transplantation cannot be performed. PMID- 28920179 TI - Review of Virtual Reality Treatment in Psychiatry: Evidence Versus Current Diffusion and Use. AB - PURPOSE OF REVIEW: This review provides an overview of the current evidence base for and clinical applications of the use of virtual reality (VR) in psychiatric practice, in context of recent technological developments. RECENT FINDINGS: The use of VR in psychiatric practice shows promise with much of the research demonstrating clinical effectiveness for conditions including post-traumatic stress disorder, anxiety and phobias, chronic pain, rehabilitation, and addictions. However, more research is needed before the use of VR is considered a clinical standard of practice in some areas. The recent release of first generation consumer VR products signals a change in the viability of further developing VR systems and applications. As applications increase so will the need for good quality research to best understand what makes VR effective, and when VR is not appropriate for clinical services. As the field progresses, it is hopeful that the flexibility afforded by this technology will yield superior outcomes and a better understanding of the underlying mechanisms impacting those outcomes. PMID- 28920180 TI - The American College of Physicians and the 2017 guideline for the management of acute and recurrent gout: treat to avoiding symptoms versus treat to target. PMID- 28920181 TI - Early colectomy in steroid-refractory acute severe ulcerative colitis improves operative outcome. AB - PURPOSE: Up to a third of patients with acute severe ulcerative colitis (ASUC) fail to respond to intensive steroid therapy and eventually require a salvage colectomy. We have previously reported that the mortality of emergency colectomy can be decreased by offering it within the first week of intensive medical therapy. We implemented this policy and report the results of our experience. METHODS: The clinical records of all patients with ASUC who underwent emergency colectomy after failure of medical therapy between January 2005 and July 2015 were extracted from a prospectively maintained database. The data were analysed with regard to duration of intensive medical therapy, timing of surgery, in hospital mortality and post-operative complications. RESULTS: Eighty-eight patients underwent emergency surgery for ASUC after failed medical therapy. Of these, 75 (85.2%) were operated within 7 days of initiation of intensive medical therapy [n = 51 (58%) were operated < 5 days]. One patient who was operated on day 8 following steroid therapy died postoperatively. The current post-operative mortality of 1.1% (1/88) was significantly lower than the mortality noted in the previously recorded retrospective case series [8/51 (15.6%); p = 0.001]. In addition, the incidence of overall (9/13 vs. 23/75; p = 0.012) and clinically significant (12/75 vs. 6/13; p = 0.022) complications was significantly higher in patients operated after 7 days as compared to those operated within 7 days. CONCLUSION: The policy of early colectomy, within 7 days, in patients with ASUC who fail to respond to intensive steroid-based therapy improves perioperative outcomes with significantly low in-hospital mortality and morbidity. PMID- 28920182 TI - Neovascularization and Synaptic Function Regulation with Memantine and Rosuvastatin in a Rat Model of Chronic Cerebral Hypoperfusion. AB - Cerebral hypoperfusion is an important factor in the pathogenesis of cerebrovascular diseases and neurodegenerative disorders. We investigated the effects of memantine and rosuvastatin on both neovascularization and synaptic function in a rat model of chronic cerebral hypoperfusion, which was established by the bilateral common carotid occlusion (2VO) method. We tested learning and memory ability, synaptic function, circulating endothelial progenitor cell (EPC) number, expression of neurotrophic factors, and markers of neovasculogenesis and cell proliferation after memantine and/or rosuvastatin treatment. Rats treated with memantine and/or rosuvastatin showed significant improvement in Morris water maze task and long-term potentiation (LTP) in the hippocampus, compared with untreated 2VO model rats. Circulating EPCs, expression of brain-derived neurotrophic factor, and vascular endothelial growth factor, markers of microvessel density were increased by each of the three interventions. Rosuvastatin also increased cell proliferation in the hippocampus. Combined treatment with memantine and rosuvastatin showed greater effect on enhancement of LTP and expression of neurotrophic factors than either single medication treatment alone. Both memantine and rosuvastatin improved learning and memory, enhanced neovascularization and synaptic function, and upregulated neurotrophic factors in a rat model of chronic cerebral hypoperfusion. PMID- 28920183 TI - Number of medications or number of diseases: what influences underprescribing? AB - PURPOSE: An increasing number of older adults suffer from multimorbidity and receive multiple medications. Despite that, underprescribing of potentially beneficial medications is widespread in this population. Our aim was to examine influence of polypharmacy and multimorbidity on the presence of prescribing omissions (PO) in general practice attenders. METHODS: We conducted a cross sectional study of older adults attending general practices in Slovenia who were regularly prescribed at least one medication. Patients' data was entered into a computer application evaluating the presence of START (Screening Tool to Alert doctors to Right Treatment) criteria for PO. Demographic data, CIRS-G (Cumulative Illness Rating Scale for geriatric patients) questionnaire, number of medications, and healthcare utilization data were also collected. We defined polypharmacy as five or more concurrent medications. RESULTS: Five hundred three patients were enrolled, 258 (56.7%) female. The average age was 74.9 and average value of CIRS-G index 1.48 (+/- 0.6). Patients took on average 5.6 medications and 216 (42.9%) patients had at least one PO according to START criteria. In bivariate analysis, there was a significant association between age, number of medications, polypharmacy and CIRS-G index measures, and presence of PO. In multivariate analysis, only age and number of affected CIRS-G categories significantly predicted PO (p < 0.05). CONCLUSIONS: Older patients with more affected CIRS-G categories were at higher risk for PO. Polypharmacy was not an independent risk factor for the presence of PO. A possible reason is that in multimorbid older people, physicians and patients set individual priorities to treatment instead of treating all diseases and conditions. PMID- 28920184 TI - Genetic affinity and the right to 'three-parent IVF'. AB - With the recent report of a live birth after use of mitochondrial replacement therapy, sometimes called 'three-parent IVF', the clinical application of the technique is fast becoming a reality. While the United Kingdom allows the procedure under regulatory scrutiny, it remains effectively outlawed in many other countries. We argue that such prohibitions may violate individuals' procreative rights, grounded in individuals' interest in genetic affinity. The interest in genetic affinity was recently endorsed by Singapore's highest court, reflecting an emphasis on the importance of biological ties found across the globe. We apply that reasoning to make the case for a right to 'three-parent IVF'. PMID- 28920185 TI - Motivational wheel running reverses cueing behavioural inflexibility in rodents. AB - Behavioural inflexibility and associated atypical learning behaviours are common clinical manifestations of the autism spectrum disorder (ASD) phenotype. Despite advances in our understanding of ASD, little research has been devoted to experimental interventions that might help to circumvent behavioural inflexibility in ASD. The current paper suggests that motivational locomotion in the form of wheel running can reduce behavioural inflexibility and learning impairments in an ASD rat model, and discusses how the strategy of reward-coupled locomotor activity may lead to clinical interventions for children with ASD. PMID- 28920187 TI - Sub-ablative Er,Cr:YSGG laser irradiation under all-ceramic restorations: effects on demineralization and shear bond strength. AB - This study evaluated the caries resistant effects of sub-ablative Er,Cr:YSGG laser irradiation alone and combined with fluoride in comparison with fluoride application alone on enamel prepared for veneer restorations. And also, evaluated these treatments' effects on the shear bond strength of all-ceramic veneer restorations. One hundred and thirty-five human maxillary central teeth were assigned to groups of 1a-control, 1b-laser treated, 1c-fluoride treated, 1d-laser + fluoride treated for shear bond testing and to groups of 2a-positive control(non-demineralised), 2b-laser treated, 2c-fluoride treated, 2d-laser + fluoride treated, 2e-negative control (demineralised) for microhardness testing (n = 15, N = 135). Demineralisation solutions of microhardness measurements were used for the ICP-OES elemental analysis. The parameters for laser irradiation were as follows: power output, 0.25 W; total energy density, 62.5 J/cm2 and energy density per pulse, 4.48 J/cm2 with an irradiation time of 20 s and with no water cooling. Five percent NaF varnish was used as fluoride preparate. ANOVA and Tukey HSD tests were performed (alpha = 5%). Surface treatments showed no significant effects on shear bond strength values (p = 0.579). However, significant differences were found in microhardness measurements and in elemental analysis of Ca and P amounts (p < 0.01). Surface-treated groups showed significantly high VNH values and significantly low ICP-OES values when compared with non-treated (-control) group while there were no significance among surface treated groups regarding VHN and ICP-OES values. Sub-ablative Er,Cr:YSGG treatment alone or combined with fluoride is as an effective method as at least fluoride alone for preventing the prepared enamel to demineralization with no negative effect on shear bond strength. PMID- 28920188 TI - Lung cancer incidence and mortality in China, 2009. AB - BACKGROUND: The National Central Cancer Registry (NCCR) is a governmental organization for cancer surveillance affiliated to the Bureau of Disease Control, Ministry of Health, in China. It annually collects cancer registration data from local registries and then analyzes and publishes the results to provide useful information for making anti-cancer policy, program evaluation, and etiology research. At the end of 2012, the NCCR reported cancer statistics for 2009. METHODS: By mid 2012, 104 population-based cancer registries reported cancer incidence and mortality data, including demographic information, for 2009, to the NCCR. After an evaluation procedure, a total of 72 registries' data met the criteria, which was then compiled for analysis. Individual lung cancer cases were retrieved from the national database based on the International Classification of Diseases (ICD)-10 topography code as "C33, C34," including cancers of the trachea and bronchus. The crude incidence and mortality rates of lung cancer were calculated by gender, age, and location (urban/rural). China's population in 1982 and Segi's population structures were used for age-standardized rates. RESULTS: In cancer registration areas in 2009, lung cancer was the most common cancer in China and in urban areas, the second most common cancer in rural areas. It was the leading cause of cancer death both in males and females, urban and rural areas. The incidence and mortality rates of lung cancer were higher in males than those in females, and in urban areas than in rural areas. The age-specific incidence and mortality rates showed that both rates were relatively low for those aged under 50 years, but dramatically increased and reached a peak in the age group of 80-84 years. CONCLUSION: Lung cancer is the most common cancer in China and leading cause of cancer death. Primary and secondary prevention should be carried out in each group, such as tobacco control and early detection. PMID- 28920186 TI - Investigation of cis-trans isomer dependent dermatotoxicokinetics of UV filter ethylhexyl methoxycinnamate through stratum corneum in vivo. AB - 2-Ethylhexyl methoxycinnamate (EHMC) is one of the most used ultraviolet filters in personal care products. It undergoes cis/trans isomerization in sunlight, and there is limited toxicological understanding of the effects of the cis-isomer. It is known that two geometric isomers of one compound can have different physico chemical properties and effects. However, there are no studies focusing on toxicokinetics of EHMC isomerization products to compare their potential difference in dermal exposure to cis-EHMC and trans-EHMC due to the difference in their dermatotoxicokinetics. In this study, dermal absorption of the parental trans-EHMC and its cis isomer was studied. A commercially available sunscreen lotion containing trans-EHMC and spiked with laboratory-prepared cis-EHMC was locally applied on the forearm skin of two volunteers. After 8 h of skin exposure, the stratum corneum (SC) layer was removed by tape stripping. The removed thickness of the SC was determined spectrophotometrically using a total protein assay. The concentration of both isomers in the removed SC was measured by HPLC-DAD. A new diffusion and permeability coefficient of both EHMC isomers in SC were determined by Fick's second law of diffusion in vivo. The difference in dermatotoxicokinetic parameters between the two isomers was not statistically significant. However, separate toxicological studies of isomeric forms and the determination of their dermatotoxicokinetic parameters are crucial for refinement of human risk assessment. PMID- 28920189 TI - Proton-based chemoradiation for synchronous bilateral non-small-cell lung cancers: A case report. AB - In this case report, we present the history and treatment of a 70-year-old man with synchronous bilateral non-small-cell lung cancers with proton-beam radiation. Surgical treatment was not feasible and optimized photon intensity modulated radiotherapy (IMRT) to the primary tumors would have resulted in unacceptably high normal-tissue exposures. Proton-beam radiation enabled radiation dose escalation and concurrent chemotherapy while maintaining normal tissue tolerance. PMID- 28920191 TI - Role of particle beam therapy in a trimodality approach to locally advanced non small cell lung cancer. AB - Lung cancer accounts for nearly one-fifth of all cancer deaths worldwide and is the most common cause of cancer-related death in the United States. Outcomes for locally advanced non-small cell lung cancer remain extremely poor with regards to both local control and overall survival. Modest gains in local control were obtained with the incorporation of multimodality treatment, including preoperative chemotherapy followed by surgical resection; combination chemoradiotherapy also improved survival, secondary to improved local control. While the natural progression to trimodality therapy resulted in superior local control, it did not translate to improved overall survival, secondary to increased toxicity. The additional morbidity is likely from radiation toxicity, the minimization of which will be crucial to the future success of trimodality therapy. One strategy to decrease toxicity is to utilize charged particles, such as protons, which deposit a high dose at the Bragg peak with a minimal dose beyond the peak, thereby reducing the dose to distal normal tissues. Trimodality therapy incorporating preoperative proton radiation therapy and chemotherapy, followed by surgery, is currently being evaluated as a potential strategy to achieve improved local control and overall survival in locally advanced non-small cell lung cancer. PMID- 28920190 TI - Gefitinib versus erlotinib as salvage treatment for lung adenocarcinoma patients who benefited from the initial gefitinib: A retrospective study. AB - BACKGROUND: The optimal strategy was not established for patients who initially responded to gefitinib although re-administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been proven to be an option. Gefitinib and erlotinib were compared as salvage treatment after gefitinib failure. METHODS: Thirty-eight lung adenocarcinoma patients were analyzed retrospectively as they received the second EGFR-TKIs treatment with either gefitinib or erlotinib. All of them had obtained disease control from initial gefitinib. Sixteen patients received gefitinib (G-G group) and 22 patients received erlotinib (G-E group). RESULTS: Of all patients, progress free survival (PFS) and overall survival (OS) were three and 12 months, respectively, and the disease controlled rate (DCR) of the second EGFR-TKIs treatment was 52.6%. One patient (6.3%) had partial remission (PR) and 10 (62.5%) had stable disease (SD), in the G-G group, whereas, three (13.6%) had PR and six (27.2%) had SD, in the G-E group. There was no statistical significance observed, although the DCR in the G-G group was higher than that in G-E group (68.8% vs. 40.8%, P= 0.09). Adverse events of both gefitinib and erlotinib were mild and administered. The median PFS and OS in G-G and G-E groups were similar (PFS four vs. three months; OS 22 vs. 12 months). In multivariate analysis, patients with SD in initial gefitinib treatment had significantly longer OS (P= 0.04). CONCLUSIONS: Gefitinib as well as erlotinib could be an option for patients who benefited from prior gefitinib treatment. Patients with SD in initial gefitinib obtained a significantly longer OS than those with PR. PMID- 28920192 TI - Invasive pulmonary aspergillosis and lung adenocarcinoma: Case report. AB - The spectrum of disease related to Aspergillus spp. within the lung is variable. The exact nature of any association of Aspergillus spp. either in the development or progression of lung cancer remains unexplored. Infrequent occurrences of pulmonary aspergilloma in the presence of adenocarcinoma of the lung have been reported. We present a rare case of invasive pulmonary aspergillosis associated with an accompanying finding of adenocarcinoma in a patient presenting with fever and a cavitary lung lesion. PMID- 28920193 TI - Subjective sleep quality in lung cancer patients before and after chemotherapy. AB - BACKGROUND: Sleep disturbances, such as difficulty in falling asleep, maintaining sleep, poor sleep efficiency, early awakening, and excessive daytime sleepiness, are common in patients with cancer. The aim of this study was to evaluate sleep characteristics in newly diagnosed lung cancer patients before and after three months of chemotherapy treatment. METHODS: Forty-nine patients with lung cancer, without brain metastasis, were included. Anthropometric and disease characteristics were collected. Upon diagnosis and after three months, a polysomnographic examination was conducted and the patients completed the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), the Fatigue Severity Scale (FSS) and the Medical Research Council (MRC) dyspnoea scale. RESULTS: Before chemotherapy, the mean PSQI score was 7.1 +/- 4, the FSS score was 3.92 +/- 2, and the ESS score was 6.8 +/- 4. The MRC score was low at 1.6 +/- 1.1. A significant correlation between FSS and global PSQI was revealed (r = 0.424, P < 0.01), as well as with several of the PSQI components. After chemotherapy, no statistically significant change was observed in the PSQI (mean: 6.6 +/- 4.5, t-score: 0.784, P = 0.438), or the FSS score (4.4 +/- 2.2, t-score: 1.375, P = 0.177). Sleep efficiency was significantly reduced (P = 0.008), without any change in the distribution of sleep stages. CONCLUSION: The perception of sleep quality is poor among newly diagnosed lung cancer patients and is correlated with fatigue. After chemotherapy, self-reported sleep impairment is present and sleep efficiency is reduced, without significant change in sleep architecture. PMID- 28920194 TI - Prognostic factors and survival of patients with small cell lung cancer in a northeastern Chinese population. AB - BACKGROUND: This study presents the characteristics and treatment of small cell lung cancer (SCLC) and an analysis of the factors that impact survival in northeastern Chinese populations, among both smokers and non-smokers. METHODS: A retrospective review was performed using 485 Chinese patients diagnosed with pathologically confirmed SCLC diagnoses between January 2001 and December 2007. Data on patient characteristics, treatment patterns, and outcome information was collected systematically. Univariate analysis and the Cox multivariate regression model were used to evaluate prognostic factors. RESULTS: Median survival time was 16 months in all patients, 31 months in limited stage (LS) patients, and 10 months in extensive-stage (ES) patients. Never-smoking patients (P= 0.0368) with good performance status (PS) (P= 0.0044) or with normal lactate dehydrogenase (LDH) levels (P < 0.0001), demonstrated superior survival rates. Multivariate analysis identified that cycles of chemotherapy, PS, LDH levels, recurrence or progression, and clinical stage were each independent prognostic factors applicable to all patients. In LS-SCLC, cycles of chemotherapy were the only prognostic indicator; however, cycles of chemotherapy, LDH levels, and recurrence or progression, were all significant factors in ES-SCLC. CONCLUSION: Cycles of chemotherapy, PS, LDH levels, recurrence or progression, and clinical stage were proved to be independent prognostic factors for SCLC with variant value based on the SCLC tumor stage. PMID- 28920195 TI - Twenty years of video-assisted thoracoscopic surgery: The past, present, and future. PMID- 28920196 TI - Diabetes mellitus: A significant co-morbidity in the setting of lung cancer? AB - BACKGROUND: To evaluate the effect of diabetes mellitus (DM) on clinical outcomes in patients managed surgically for non-small cell lung cancer (NSCLC). METHODS: Patients who underwent surgery for pathological I-IIIA NSCLC at Duke University from 1995-2005 were analyzed. Postoperative mortality was defined as any death occurring within 30 days of resection or during the initial hospitalization after surgery. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered a local/regional recurrence (LRR). Survival and LRR rates were estimated using the Kaplan-Meier method and compared using a log rank test. A multivariate regression analysis assessed the association between candidate factors, including DM, and disease recurrence and survival. RESULTS: Of 957 patients, DM was present in 122 (13%). DM was associated with an increased risk of postoperative mortality (7.4% vs. 3.2%, P= 0.04). However, the proportion of patients undergoing sublobar resections, mediastinal lymph node dissection, and receiving adjuvant chemotherapy, was no different among patients with or without DM. Five-year LRR rates were 27% in patients with DM, versus 21% in patients without DM (P= 0.23). Survival at five years was 43% for patients with DM, and 47% for patients without DM (P= 0.10). On multivariate analysis, DM was not independently associated with a higher risk of LRR (hazard ratio [HR] 1.33, P= 0.34), distant recurrence (HR 0.86, P= 0.58), or overall survival (HR 1.08, P= 0.63). CONCLUSIONS: Although a higher risk of postoperative mortality was noted in patients with DM, a detriment in local or distant disease control or overall survival was not observed. PMID- 28920197 TI - Efficacy of third-generation chemotherapeutic agents combined with cisplatin or carboplatin in 3100 Chinese patients with advanced non-small-cell lung cancer. AB - BACKGROUND: Recently, differences in tumor biology have been observed between Asian and Caucasian lung cancer patients, resulting in different sensitivities to targeted therapy. To date, all registered third-generation chemotherapeutic agents have been investigated mainly in Caucasians, but little is known whether this data can be transferred to an Asian population. The aim of this study was to provide evidence about the efficacy of chemotherapy in a Chinese population. METHODS: Three thousand one hundred patients with advanced non-small-cell lung cancer NSCLC, treated between 2002 and 2009 with a platinum-based doublet first line chemotherapy, including vinorelbine, gemcitabine, docetaxel or paclitaxel, were included for retrospective survival analysis. RESULTS: Overall survival (OS) was 12.1 months and progression free survival (PFS) was four months for all patients. No advantage in OS was seen for any of the four compounds. Gemcitabine was associated with a better PFS compared to the other three (P < 0.001). Docetaxel led to higher response rates, but this finding didn't reach statistical significance (P = 0,054). Chinese patients appear to have longer survival times compared to historical data in Caucasians. CONCLUSION: Our retrospective analysis suggests, that there is no difference in efficacy of third-generation chemotherapy between Asians and Caucasians. PMID- 28920198 TI - Successful treatment of a tracheal squamous cell carcinoma with a combination of cryoablation and photodynamic therapy. AB - Malignant tumors of the trachea are rare, and account for less than 0.1% of all malignancies. Because there are no guidelines based on randomized clinical trials, the choice of treatment modalities and optimal sequences have not yet been established. In most cases of malignant airway obstruction, a single modality is chosen as the treatment of choice for management, but complete ablation becomes increasingly problematic with minimal residual lesions that require additional treatment. There were few case reports of the combined use of cryoablation and photodynamic therapy to treat tracheal cancer. Therefore, we present our experience of successful tracheal cancer treatment using this combination therapy. A bronchoscopic complete regression was obtained using these two modalities, and the procedures proved to be a safe and effective treatment option based on a one-year follow-up. PMID- 28920199 TI - Late course accelerated hyperfractionation radiotherapy for locally advanced esophageal squamous cell carcinoma. AB - BACKGROUND: Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, CENTRAL, CBMdisc, and CNKI, as well as employing manual searches. The primary end points were survival and local control. The second end point was toxicities. RESULTS: Based on search criteria, we found 29 trials involving 3187 patients. Our results showed that LCAHR, compared with CFR, improved the survival and local control, and was, thus, more therapeutically beneficial. Further analysis revealed that LCAHR plus CT proved to be better for patients' survival and local control compared to LCAHR alone. Acute toxicities were increased rather than late toxicities. CONCLUSIONS: There was a significant survival and local control benefit of LCAHR over CFR, as well as LCAHR plus CT over LCAHR alone. Considering the strength of the evidence, the results of this study indicate that this regimen would be a new promising modality worth further investigation. PMID- 28920200 TI - The role of palliative chemotherapy for terminally ill patients with advanced NSCLC. AB - BACKGROUND: To evaluate the conditions of palliative chemotherapy in terminally ill patients with advanced non-small cell lung cancer (NSCLC), and to discuss the potential factors that affect the prognosis of these patients. METHODS: All 205 terminally ill patients with advanced NSCLC, who died in our hospital during the period from 2006 to 2010, were included in the study. Basic information was collected and details for the treatment of patients, related to overall survival, were evaluated. RESULTS: One hundred and fifty-nine out of 205 patients (77.6%) were treated with palliative chemotherapy. Of these, 59.7% patients were treated with palliative chemotherapy in the last three months and 27.7% patients in the last one-month, prior to their expiration, respectively. In addition, 22.0% of the 159 patients were treated with palliative chemotherapy for the first time in the last three months and 10.1% in the last month of their final days. We have shown that patients treated with palliative chemotherapy in their last three and final month had a shorter overall survival rate than those patients who were not treated with palliative chemotherapy. CONCLUSION: A large proportion of patients with advanced NSCLC received palliative chemotherapy near the end of their life. However, our results were not in favor of palliative chemotherapy in the last three or final month of life. PMID- 28920201 TI - Metastatic adenoid cystic carcinoma of external auditory canal presenting as solitary pulmonary nodule. PMID- 28920202 TI - Follicular dendritic cell sarcoma of the mediastinum: CT and 18 F-fluoro-2 deoxyglucose PET findings. AB - Mediastinal follicular dendritic cell sarcoma (FDCS) is an exceedingly rare malignant tumor. We report, herein, detailed imaging findings of mediastinal FDCS, appearing as a large, well-circumscribed, strongly enhancing mass with central coarse calcification on computed tomography, with moderately increased metabolic activity on 18 F-fluoro-2-deoxyglucose positron emission tomography. PMID- 28920203 TI - Gorham's Disease complicated with bilateral chylothorax and successfully treated with Interferon-alpha-2a. AB - Gorham's disease (GD) is rare and characterized by non-neoplastic lymphovascular proliferation and massive osteolysis. Its clinical course is usually protracted, but sometimes life threatening when vital structures are involved or when complicated with chylothorax. There is no optimal treatment guideline for GD complicated with chylothorax. Surgical ligation of thoracic duct, pleurectomy, pleurodesis, interferon-alpha-2b, and radiotherapy, are reported to manage chylothorax. We present the case of a 32-year-old man with Gorham's disease complicated by bilateral chylothorax, which was refractory to radiotherapy but remitted dramatically two weeks after interferon-alpha-2a therapy. The patient was free of relapse four months after discontinuing four-month interferon therapy. To date, only 11 cases (including ours) of GD with chylothorax have received interferon as single or salvage therapy, and 10 of them survived. Early intervention with interferon therapy can be considered as an effective treatment for GD complicated with bilateral chylothorax. PMID- 28920204 TI - Large cell neuroendocrine carcinoma: retrospective analysis of 24 cases from four oncology centers in Turkey. AB - BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is classified as a variant of large cell lung carcinoma by the World Health Organization, however, the clinical and biological behavior of LCNEC resembles small cell lung carcinoma (SCLC) with a high mitotic index and a positivity of tumor cells with neuroendocrine markers. As there have only been a small number of patients with LCNEC recorded in literature, there is no consensus about the management of this subset. In the present study, we evaluated the incidence and prognosis of LCNEC in four oncology centers in Turkey. METHOD: We analyzed 24 patients with diagnoses of LCNEC from 3138 non-small cell lung cancer patients who were diagnosed and treated between 2008 and 2010 in four different medical oncology centers in Turkey. RESULTS: The median age was 56 (range; 36-64) and most patients were male, with three women included in the study. Ten out of 24 patients (41.6%) had locally advanced or metastatic disease, therefore, surgery could not be performed. Five patients (20.8%) were staged with stage I, six (25%) with stage II, five (20.8%) with stage III, and eight (33.3%) with stage IV. All patients had a history of smoking. Nine patients received chemotherapy postoperatively. At the 14.4-month follow-up period (range; 3-59) the median overall survival (OS) and progression-free survival (PFS) rates were 32.7 and 9.5 months respectively. Tumor, node, metastasis (TNM) stage, performance status (PS) and the performance of surgery were significantly related to rates of both OS and PFS (P < 0.05). CONCLUSION: LCNEC was generally diagnosed postoperatively. Prognosis of LCNEC is poor and surgery has not proven an effective solution for long-term survival, therefore, adjuvant chemotherapy has been suggested. PMID- 28920205 TI - Low tumor blood flow assessed with perfusion CT correlates with lymphatic involvement in patients with stage T1b non-small cell lung cancer. AB - BACKGROUND: To investigate the correlation of computed tomography (CT) perfusion parameters and lymphatic involvement in patients with stage T1b non-small cell lung cancer (NSCLC). METHODS: Forty-six patients (30 men and 16 women; age range, 36-73 years; mean age, 57 years), with stage T1b non-small cell lung cancer, underwent perfusion CT before surgery. The correlations between CT perfusion parameters (blood flow, blood volume, peak enhancement intensity), tumor angiogenesis (microvessel density and maturity of microvessels of surgical specimens) and lymphatic involvement were retrospectively investigated. Receiver operator curve (ROC) analysis was used to identify the parameter threshold at which tumors had or did not have lymph node metastasis, and the corresponding sensitivity and specificity were calculated. RESULTS: A significant tendency for tumors with low blood flow and high density of immature microvessels to show lymphatic involvement was found (all P < 0.001). High correlation (r =-0.769, P < 0.001) was observed between tumor blood flow and immature microvessels. The area under ROC curves (AUC) for blood flow to detect lymph node metastasis was 0.866 (95% confidence interval, 0.766-0.966). For blood flow, the sensitivity, specificity, and accuracy of predicting lymph node metastasis were 88.9, 64.3, and 73.9% respectively, if the cutoff point was set at 43.05 mL/100 g/minute. CONCLUSIONS: Blood flow may be useful to predict lymphatic involvement before surgery in stage T1b NSCLC. PMID- 28920206 TI - Prognosis for non-small cell lung cancer patients with brain metastases. AB - PURPOSE: Brain metastasis has a poor prognosis in patients with advanced non small cell lung cancer (NSCLC). In this study, we evaluated the prognosis of NSCLC patients with brain metastases. METHODS: We analyzed a total of 313 NSCLC patients with brain metastasis. We compared the prognoses between a group of less than four (group A) and a group of more than four or equal to four (>=4) (group B) brain metastases. RESULTS: The median survival time was 334 days (group A, 164 patients, 52.4%) and 234 days (group B, 149 patients, 47.6%). Univariate analysis showed that the number of metastases, age at diagnosis of brain metastasis, smoking history, histologic type, and former stage of primary lung cancer before brain metastasis, had a significant influence. In addition, treatment for primary lung cancer lesions and brain metastasis also affected the overall survival (p < .0001). However, there was no difference in the overall survival between the two groups in the multivariate analysis. CONCLUSION: Our results show that the number of brain metastases, classified by group A (<4) or group B (>=4) did not influence the overall survival of NSCLC patients. However, the overall survival in group A was better than in group B when analyzed, except for local brain treatment modalities in sub-group analysis, suggesting that non-optimized local treatment strategies might cause an unexpected prognosis result in this retrospective study. We suggest that more prospective studies might be needed for the optimal standard treatment for brain metastasis. PMID- 28920207 TI - Neoadjuvant chemotherapy and surgery for transdiaphragmatic liver invasion of primary lung cancer. AB - A 75-year-old woman presented with intermittent dull abdominal pain, gradually exacerbating over eight months. Computed tomography demonstrated a large mass straddling both the right lower lobe of the lung and the right hepatic lobe. An 18-fluoro-2-deoxy-D-glucose positron emission computed tomography scan (PET/CT) demonstrated high accumulation in the lesion and carinal lymph nodes. Transbronchial biopsy revealed squamous cell carcinoma; thus, primary lung cancer with transdiaphragmatic invasion into the liver was diagnosed. Chemotherapy with carboplatin (AUC = 5) on day one and weekly paclitaxel (70 mg/m2 ) doses were introduced for four courses. The size of the main tumor was reduced and the mediastinal lymph node accumulation disappeared in a subsequent PET/CT. Thus, en bloc radical resection of the lung tumor by right lower lobectomy with partial resection of invaded middle lobe and the diaphragm, subsegmentectomy of the liver, and standard mediastinal dissection were undertaken. The postoperative course was uneventful and the patient was discharged on day 30. Her nutrition status dramatically improved and she gained five kilograms of body weight in two months following the resection. The patient, however, then had a fall and suffered femur and multiple pelvic fractures and died of acute pneumonia five weeks after the femur fixation and 14 weeks after the lung surgery. PMID- 28920208 TI - The reasons of false negative results of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of intrapulmonary and mediastinal malignancy. AB - Although the sensitivity can reach 99%, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a significantly high false negative rate for diagnosis and staging of thoracic malignancy. We performed this retrospective study to investigate the causes of false negative results and to improve the efficacy and accuracy of EBUS-TBNA. We reviewed all patients suspected of intrapulmonary or mediastinal malignancy who undertook EBUS-TBNA between July 2009 and August 2012 in Chinese PLA general hospital. We retrieved the pathological results of EBUS-TBNA and video-assisted thoracic surgery (VATS) and follow-up data. The sensitivity, specificity, positive predictive value and negative predictive value were calculated. 185 patients were included in this study. Diagnosis of malignancy was established on 172 patients by EBUS-TBNA, and 8 patients with negative EBUS-TBNA result gained their final diagnosis of malignancy via VATS. The sensitivity, specificity, negative predictive value and accuracy for diagnosis of malignancy for EBUS-TBNA were 96%, 100%, 33% and 96% respectively. Inadequacy of the EBUS-TBNA specimens, internal necrosis in the lymph nodes and rare cancer types contributed to the false negative EBUS-TBNA results. VATS is obligatory to explain the negative results of EBUS-TBNA in patients suspected of malignancy. PMID- 28920209 TI - Analysis of differently expressed proteins involved in metastatic niche of lung. AB - BACKGROUND: The "seed and soil" hypothesis for metastasis was a pivotal milestone in the study of malignant disease. Recently, growing studies have focused on the tumor secretory factors that may mediate preparation of the "metastatic soil." A suitable environment for the metastatic lesions was created by many inflammatory cytokines in the lung, whichwas verified by in vivo experimental models. In 2005, a pre-metastatic niche and metastatic niche modelwere suggested by David Lyden and Bethan Psaila, to delineate the interactions between malignant cells and their microenvironment at the metastatic site, whichsoon became the most importanthypothesis. However, the evidence is limited to animal models. More clinical evidence is needed to support this hypothesis. METHODS: Human lung specimens were taken from different regions within metastatic lung tissue and normal lung tissue. Differently expressed proteins were analyzed by using the two dimensional fluorescent difference gel electrophoresis (2-D DIGE) technology: about 0.5-1 cm (Tissue 1) of lung tissue was taken adjacent to the metastatic tumor; about 1 cm (Tissue 2) of lung tissue was taken far away from the metastatic tumor; and normal lung tissue of the inflammatory pseudotumor (Tissue 3) was taken at least 3 cm away from the pseudotumor. We usedmatrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF/TOFMS) analysis to identify differently expressed proteins in T1, T2, andT3 samples. RESULTS: T1 samples were different from T2 samples in the expression of 27 proteins. T2 samples had different expressions in 24 proteins, compared to T3 samples.Nine proteins were expressed differently between T1 and T3 samples. These proteins are mainly involved inenergy metabolism, protect the tumor cell from immunologic engraftment of metastatic tumor cells, and migration. Some of thesehave been reported to be related to the tumor metastatic niche hypothesis: Type VI collagen, heat shock protein 90, and Fibrinogen. CONCLUSION: The type VI collagen, heat shock protein 90, and Fibrinogen were selected aspotential niche proteins. These findings support the metastatic niche hypothesis and encourage further studies. PMID- 28920210 TI - Sebaceous-like clear cell changes in primary lung cancer. AB - We examined two cases of primary lung cancer with sebaceous-like clear cells (SLCCs), defined as clear carcinoma cells with microvacuolated cytoplasm and centrally located nuclei, which were selected from among 281 surgical/autopsy cases of lung cancer (2/281, 0.7%). Both cases were higher stage (stage IIA and IIIA), and SLCCs were intermingled with adenocarcinoma cells of usual type. They showed minute mucin staining, no evidence of glycogen, diffuse positivity for epithelial membrane antigen and carcinoembryonic antigen, focal positivity for thyroid transcription factor-1, and negativity for Napsin A and gross cystic disease fluid protein-15. Oil red O stain and ultrastructural examination in both cases failed to reveal lipid in SLCCs. SLCCs could represent non-specific changes of lung adenocarcinoma with a relatively advanced stage, and should be discriminated from true sebaceous differentiation. PMID- 28920211 TI - Clinical analysis of Gefitinib in the treatment of stage IV lung adenocarcinoma with unknown EGFR gene mutations. AB - BACKGROUND: As it is difficult to obtain enough histopathological data for epidermal growth factor receptor (EGFR) gene detection, it is necessary for us to explore how to perform EGFR-tyrosine kinase inhibitor (TKI) therapy in patients with unknown EGFR gene mutations. METHODS: We analyzed the efficacy of Gefitinib treatment and the clinical characteristics of 214 patients with stage IV lung adenocarcinoma. RESULTS: Objective response rates (ORR) and overall survival (OS) of women were higher than men; ORR of patients with rash, diarrhea, or rash associated with diarrhea, was higher than patients without those side effects. Progression-free survival (PFS) of patients with performance status (PS) scores of 1, 2, and 3 points was 8.0 +/- 1.699, 7.3 +/- 0.419, and 6.0 +/- 2.010, respectively; OS was 26.0 +/- 1.536, 16.3 +/- 1.262, and 14.3 +/- 2.389, respectively. PFS and OS of patients with rash and diarrhea were better than for those without these side effects. In males, the PFS of patients >65 years old versus <=65 years old was 13.0 +/- 2.7 months versus 5.5 +/- 0.197 months, respectively. Multivariate analysis showed that PS score, diarrhea, and rash affected the patients' PFS, while gender, PS score, and rash affected the patients' OS. CONCLUSIONS: In patients with stage IV lung adenocarcinoma and unknown EGFR gene mutations treated with Gefitinib, our findings suggest a better prognosis for female patients and those with low PS scores. PMID- 28920212 TI - Impact of extended cervical mediastinoscopy in staging of left lung carcinoma. AB - BACKGROUND: Extended cervical mediastinoscopy (ECM) is a method for staging lung carcinoma. We aimed to demonstrate the impact of ECM in the staging of lung carcinoma. METHODS: Between 1998 and 2011, 159 patients with left lung carcinoma who underwent ECM simultaneously with standard cervical mediastinoscopy (SCM), were retrospectively analyzed. Until 2006, ECM had been performed routinely (n = 90, routine ECM), however, after 2006 ECM was performed only in patients selected based on computed tomography and positron emission tomography scans (n = 69, selective ECM). RESULTS: Mediastinal lymph node metastasis was present in 36 patients by mediastinoscopy. Aortopulmonary window (APW) lymph node metastasis was present in 26 patients (10 in the routine group, 16 in the selective group), whereas the 10 patients who had mediastinal lymph node metastasis that could only be accessed by SCM, but had no APW lymph node metastasis, were excluded. The remaining 123 patients (72 in the routine group, 51 in the selective group) were identified as cN0/N1 by SCM/ECM, and lobectomy, pneumonectomy, and exploratory thoracotomy were performed on 64, 43, and 16 of these patients, respectively. According to the lymphadenectomy, APW lymph node metastasis was determined in 11 patients (seven in the routine group, four in the selective group). Sensitivity, negative predictive value (NPV), and accuracy of ECM were calculated as 0.70, 0.90, and 0.92, respectively. Staging values of routine/selective ECM protocols were 0.58/0.80, 0.89/0.91 and 0.91/0.94, respectively. The complication rate was 5% (n = 8). CONCLUSIONS: ECM has an adequate NPV and accuracy in determining metastasis to the APW lymph nodes in patients with left lung carcinoma. PMID- 28920213 TI - Incidence and mortality of female breast cancer in China, 2009. AB - BACKGROUND: The National Cancer Registration of China provides annual updates on female breast cancer incidence and mortality. METHODS: Data on female breast cancer incidence and mortality was obtained from the population-based cancer registries around China. Based on the criteria of data quality, 72 registries' data was included for further analysis. Incidence and mortality rates of female breast cancer were calculated and stratified by age, sex, and geographical area. RESULTS: Female population coverage over 72 cancer registries was 42 238 968, with 28 503 924 in urban areas and 13 735 044 in rural areas. The crude cancer incidence rate in all areas was 42.55/100 000, and the age-standardize rates by Chinese population and World population were 23.16/100 000 and 28.99/100 000, respectively. The incidence rates in urban areas were much higher than those in rural areas. The crude cancer mortality was 10.24/100 000 in all areas, and age standardized mortality rates by China and World population were 4.94/100 000 and 6.56/100 000, respectively. Age-adjusted mortality rates in urban areas were also higher than those in rural areas. Age specific incidence rates reached highest at the age group of 50-54, whereas the age specific mortality rates were highest in the age group of 85 and above. CONCLUSION: Breast cancer was the most common cancer found in Chinese women in 2009 and the disease was more prevalent in urban areas than in rural areas. Systematic interventions of cancer prevention and control are needed. PMID- 28920214 TI - Multiple endotracheal and endobronchial metastases after pneumonectomy for a primary lung cancer: A case report. AB - Endotracheal metastasis of primary lung cancer is extremely rare. We report the case of a 51-year-old male patient who had undergone right pneumonectomy for squamous cell carcinoma one year earlier. The post-operative chest computed tomography (CT) image revealed a very small endotracheal nodule with contrast enhancement. This finding was erroneously regarded as endotracheal phlegm because of the nodular size and the rarity of endotracheal metastases from primary lung cancer. This case indicates that a thorough evaluation should be performed with a high level of suspicion for malignancy when a nodule-like lesion with contrast enhancement or tracheal thickening is detected on follow-up CT scan, in patients who undergo surgery for lung cancer. PMID- 28920215 TI - Long-term results of a randomized, double-blind, and placebo-controlled phase III trial: Endostar (rh-endostatin) versus placebo in combination with vinorelbine and cisplatin in advanced non-small cell lung cancer. AB - BACKGROUND: : Phase II-III trials in patients with untreated and previously treated locally advanced or non-small cell lung cancer (NSCLC) suggested that Endostar was able to enhance the effect of platinum-based chemotherapy (NP regimen) with tolerable adverse effects. METHODS: Four hundred and eighty six patients were randomized into two arms: study arm A: NP plus Endostar (n = 322; vinorelbine, cisplatin, Endostar), and study arm B: NP plus placebo (n = 164; vinorelbine, cisplatin, 0.9% sodium chloride). Patients were treated every third week for two to six cycles. RESULTS: : Overall response rates were 35.4% in arm A and 19.5% in arm B (P = 0.0003). The median time to progression was 6.3 months for arm A and 3.6 months for B, respectively (P < 0.001). The clinical benefit rates were 73.3% in arm A and 64.0% in arm B (P = 0.035). Grade 3/4 neutropenia, anemia, and nausea/vomiting were 28.5%, 3.4%, and 8.0%, respectively, in Arm A compared with 28.2%, 3.0%, and 6.6%, respectively, in Arm B (P > 0.05). There were two treatment related deaths in arm A and one in arm B (P > 0.05). The median overall survival was longer in arm A than in arm B (P < 0.0001). CONCLUSION: : Long-term follow-up revealed that the addition of Endostar to an NP regimen can result in a significant clinical and survival benefit in advanced NSCLC patients, compared with NP alone. PMID- 28920216 TI - Clinical model to estimate the pretest probability of malignancy in patients with pulmonary focal Ground-glass Opacity. AB - BACKGROUND: Effective strategies for managing patients with pulmonary focal Ground-glass Opacity (fGGO) depend on the pretest probability of malignancy. Estimating a clinical probability of malignancy in patients with fGGOs can facilitate the selection and interpretation of subsequent diagnostic tests. METHODS : Data from patients with pulmonary fGGO lesions, who were diagnosed at Sun Yat-sen University Cancer Center, was retrospectively collected. Multiple logistic regression analysis was used to identify independent clinical predictors for malignancy and to develop a clinical predictive model to estimate the pretest probability of malignancy in patients with fGGOs. RESULTS: One hundred and sixty five pulmonary fGGO nodules were detected in 128 patients. Independent predictors for malignant fGGOs included a history of other cancers (odds ratio [OR], 0.264; 95% confidence interval [CI], 0.072 to 0.970), pleural indentation (OR, 8.766; 95% CI, 3.033-25.390), vessel-convergence sign (OR, 23.626; 95% CI, 6.200 to 90.027) and air bronchogram (OR, 7.41; 95% CI, 2.037 to 26.961). Model accuracy was satisfactory (area under the curve of the receiver operating characteristic, 0.934; 95% CI, 0.894 to 0.975), and there was excellent agreement between the predicted probability and the observed frequency of malignant fGGOs. CONCLUSIONS: We have developed a predictive model, which could be used to generate pretest probabilities of malignant fGGOs, and the equation could be incorporated into a formal decision analysis. PMID- 28920217 TI - Increased EHD1 in non-small cell lung cancer predicts poor survival. AB - BACKGROUND: One of the main challenges of lung cancer research is identifying patients at high risk for recurrence after surgical resection. We evaluated the prognostic power of four proteins in the endocytic pathway in 114 non-small cell lung cancer patients (NSCLC). METHODS: We tested the four proteins (epidermal growth factor receptor [EGFR], RAB11FIP3, EHD1, and caveolin-1), critical nodes in the endocytosis/recycling pathway, by immunohistochemistry in paraffin sections from 114 non-small cell lung cancer patients. We analyzed the correlation between our target proteins and clinical variables. Within these variables, an overall survival (OS) prediction model was constructed using Cox proportional hazard regression. RESULTS: EHD1 expression correlated with gender (P = 0.001), histology type (P < 0.001), and EGFR expression (P = 0.008), but not with any of the other clinical parameters. Statistical correlation analysis showed that the expression of EHD1 positively correlated with high level of EGFR (P < 0.001) and RAB11FIP3 (P < 0.001), and the expression of caveolin-1 positively correlated with high level of EGFR (P < 0.001) in the NSCLC samples. EHD1 expression was an OS prognostic factor for all of the patients (P = 0.009), for the group of adjuvant chemotherapy-treated patients (P = 0.006), and for the EGFR positive patients (P = 0.034). CONCLUSIONS: We identified EHD1 as a strong prognostic predictive factor in NSCLC. The expression level of EHD1 would potentially be useful in developing customized strategies for managing lung cancer, such as the selection of patients eligible for chemotherapy. PMID- 28920218 TI - Differential mitochondrial proteome analysis of human lung adenocarcinoma and normal bronchial epithelium cell lines using quantitative mass spectrometry. AB - BACKGROUND: Lung cancer is one of the higher incidences of malignant tumors around the world. At present, tumor markers CEA, CA19-9, and CA-125 in serum are used for the diagnosis of lung cancer, however, fewer studies have shown tumor markers for early diagnosis. Therefore, using quantitative mass spectrometry, differential mitochondrial proteome analysis was performed, comparing human lung adenocarcinoma and normal bronchial epithelium cells. METHODS: A human lung adenocarcinoma cell line A549 and a normal human bronchial epithelial cell line 16HBE were cultured in vitro. The cell mitochondria of the two cell lines were extracted and purified by differential centrifugation and percoll density gradient centrifugation. The integrity and purity of mitochondria were validated by electron microscopy and Western-blot. The proteins/peptides from lung cancer cells and normal cells were marked by the same amount of relative and absolute quantification of ectopic tags (iTRAQ). The mixed samples were analyzed and identified by two-dimensional liquid chromatography - tandem mass spectrometry (2D-LC-MS/MS). The proteome was analyzed with different bioinformatic tools. RESULTS: One hundred and sixty-one mitochondrial proteins were identified. One hundred and fifty-three mitochondrial proteins, which were expressed differently between 16HBE cells and A549 cells, were identified. Sixty-seven proteins were high expression, while 86 proteins were lower expression. Expression of three proteins: ornithine aminotransferase (OAT), heat shock protein beta90 (HSP90), and vimentin (VIM), was increased more than twice. Our results, in combination with the literature review, suggest that HSP90 and Vimentin may be the new tumor markers of lung cancer. PMID- 28920219 TI - Retrospective study of surgical resection in the treatment of limited stage small cell lung cancer. AB - BACKGROUND: Patients with small cell lung cancer (SCLC) are mainly treated by chemotherapy/radiotherapy, either alone or combined. Surgical resection is an optional treatment for few SCLC patients. The efficacy of surgical intervention for SCLC remains controversial. This study evaluates the validity of surgery for patients with limited stage SCLC. METHODS: We conducted a retrospective review of 59 patients with limited stage SCLC who received trimodal therapy from 2004 to 2011. Progression-free survival (PFS) and overall survival (OS) were calculated using the statistic methods of Kaplan-Meier and the log-rank test. RESULTS: Among the 59 limited stage SCLC patients, 54 patients with stage I-III SCLC received surgical treatment with curative intent, and 42.6% (23/54) patients received preoperative chemotherapy. The radical resection rate of the group of preoperative chemotherapy and the group of initial surgical resection were 82.6% (19/23) and 54.8% (17/31), respectively. The corresponding five-year survival rates were 59% and 22% with significant differences (P = 0.032 and 0.041, respectively). In total, 36 (66.7%) patients underwent radical surgery with resection of the primary mass and mediastinal lymph nodes. In the radical surgery series, five-year survival, according to stage I-III categories, were 59%, 53%, and 26%, respectively. For the 30 stage III patients, the five-year survival of the radical group of 26% was lower than the non-radical group of 67%, and PFS analysis showed similar tendencies. CONCLUSION: Preoperative chemotherapy is the most favorable initial treatment for patients with limited disease SCLC. Complete surgical resection is considered for patients with stage I and II. Surgical resection remains of no benefit for stage III SCLC patients with persistent N2/N3 after chemotherapy. PMID- 28920220 TI - False negative results and endobronchial ultrasound-guided transbronchial needle aspiration. PMID- 28920221 TI - Fully thoracoscopic versus conventional open resection for esophageal carcinoma: A perioperative comparison. AB - BACKGROUND: To compare the efficacy of patients undergoing esophagectomy for cancer in video-assisted thoracoscopic surgery (VATS) versus traditional open surgery (TOS) in the perioperative period, along with the advantages and disadvantages of each. METHODS: A retrospective analysis of 108 patients, who underwent esophagectomy between September 2011 and February 2012 in our department, was performed. Patients were divided into two groups based on operative technique (VATS vs. TOS), with 50 patients in the VATS group and 58 patients in the TOS group. Operative duration, intraoperative blood loss, intraoperative blood transfusion, number of lymph nodes harvested, postoperative pain score, period of time requiring chest tube drainage, complications, hospital stay, and hospital costs, were all statistically analyzed between the two groups. RESULTS: There was no statistical difference between the two groups with regard to operative duration or number of lymph nodes harvested. The VATS group had significantly less intraoperative blood loss, intraoperative blood transfusion, postoperative pain, earlier ambulation, shorter postoperative hospital stay, and a shorter period of time requiring chest tube drainage. The amount of drainage was significantly lower in the TOS group (P < 0.05). Pulmonary complication (pneumonia and pleural effusion) was less prevalent among the VATS group. CONCLUSION: Compared with TOS, VATS-assisted esophagectomy is less traumatic with lower intraoperative blood loss, faster recovery, and a better overall outcome. PMID- 28920222 TI - Validation of the 7th edition American Joint Committee on cancer staging system for esophageal squamous cell carcinoma. AB - BACKGROUND: The purpose of this study is to investigate the ability of the 7th edition of the American Joint Committee on Cancer tumor-nodes-metastasis (AJCC/TNM) staging system to distinguish between patients at higher risk and to predict the overall survival in patients who underwent surgical resection for esophageal squamous cell carcinoma (ESCC). METHODS: Between 1998 and 2008, 560 patients with ESCC underwent R0 tri-incisional esophagectomy at our center without neoadjuvant or adjuvant therapy. We performed univariate and multivariate analyses to identify prognostic factors for survival. RESULTS: The five-year overall survival rate was 44.1%, with a median survival of 44 months. Gender, pT status, pN status, and the retrieved lymph nodes (LNs) category (<15 vs. >=15) were found to be significant prognostic factors, whereas histology grade and tumor location were not significant prognostic factors in our analysis. When classified as all eight sub-stages, there were similar survival curves between stages IB and IIA (P = 0.799), and stages IIIC and IV (P = 0.635). Multivariate Cox proportional hazard regression analysis indicated that gender, pT category, pN category, and the retrieved LNs category (<15 vs. >=15) were significantly associated with patient survival. CONCLUSION: The 7th edition AJCC staging system proposed a new descriptor for "N" classification. Further stratification of pN status according to number of positive LNs in the 7th edition is valuable. However, we did not find tumor location and histology grade were significant prognostic factors. Moreover, adding a substantially higher threshold of LNs retrieved in the next revision of the AJCC/TNM staging system for ESCC may be more valuable. PMID- 28920223 TI - Case of mediastinal epithelioid hemangioendothelioma associated with hypertrophic osteoarthropathy and literature review. AB - Hypertrophic osteoarthropathy is commonly associated with malignancies of the lungs and stomach. A few cases associated with epithelioid hemangioendothelioma, a rare vascular soft tissue neoplasm, have been reported. Presented here is the first report of a case of hypertrophic osteoarthropathy as the initial symptom of epithelioid hemangioendothelioma of the mediastinum. A 64-year-old woman presented with pain around the long bones and diffuse puffiness of bilateral hands and feet. She had a history of multiple malignancies, all of which were in remission. She had clubbing of her fingernails and toenails. Her chest X-ray was negative. A positron emission tomography (PET) scan performed showed metabolically active soft tissue that extensively infiltrated the mediastinum, with several sites of disease involving the pericardium. Mediastinal biopsy and subsequent pleural fluid cytology obtained by thoracocentesis was consistent with metastatic epithelioid hemangioendothelioma. Our case supports that the PET scan has a valuable role in localizing malignancies in such patients who present with hypertrophic osteoarthropathy and no lung or stomach involvement. PMID- 28920224 TI - Human papillomavirus and non-small cell lung cancer. AB - Lung cancer is the most common cause of cancer-related deaths in the world, causing more than one million deaths worldwide each year. Human papillomavirus (HPV) are small non-enveloped DNA viruses that infect squamous epithelial cells. Relevant studies have reported lung cancer-related HPV infection rates that fluctuate between 10% and 80%, depending on the various research methods and geographical factors. Various scholars gathered statistics from global research reports and found that 22.4% of the patients with lung cancer presented with an HPV infection, which suggested that HPV infection may relate to the tumorigenesis of non-small cell lung cancer. This article will review the history and discovery of HPV, the correlation between HPV and lung cancer development, and carcinogenesis caused by HPV regulatory genes, such as p53, p21, p16INK4a, and genes related to hypermethylation and genome instability in lung cancer patients with HPV infection. In addition, because studies have highlighted the difference in clinical prognosis for HPV-positive and HPV-negative patients, articles demonstrating the correlation between HPV infection and prognosis for lung cancer patients will be reviewed. PMID- 28920225 TI - Case of pleural metastasis of prostate cancer. AB - The most frequent sites of prostate cancer metastases are the bone and lung. Pleural metastasis of prostate cancer is clinically rare. We report a case with solitary pleural thickening arising from the metastasis of prostate cancer. A 71 year-old man was referred to our hospital for further examination of pleural thickening detected during a chest computed tomography (CT) examination. A video assisted pleural biopsy was performed. The pathological findings showed that the tumor cells had spread from the parietal pleura to adipose tissue around the costal muscles. The tumor cells were positive for prostate-specific antigen (PSA) and negative for calretinin, cytokeratin (Ck5/6) and D2-40. These findings suggested that the pleural lesion was a metastasis of the prostate cancer. PMID- 28920226 TI - Histological types and localizations of lung cancers in patients with combined pulmonary fibrosis and emphysema. AB - BACKGROUND: Most patients with combined pulmonary fibrosis and emphysema (CPFE) are males, and heavy smokers. CPFE is more prevalent than fibrosis in patients with lung cancer, and patients with CPFE usually have a poor prognosis. This study reviewed the differences in the prevalence of lung cancer among patients with normal, fibrosis, emphysema and CPFE via chest computed tomography (CT), and the relationship between histopathology and the localizations of lung cancer. METHODS: Patients that were diagnosed with lung cancer confirmed by pathological examinations between 2003 and 2011 were retrospectively reviewed to obtain clinical, pathological, and radiological data. These patients were categorized into four groups based on chest CT findings: normal, fibrosis, emphysema and CPFE. RESULTS: Two hundred and seventy-four patients with lung cancer were classified into 146 normal, 14 fibrosis, 78 emphysema, and 36 CPFE groups. Combined centriacinar and paraseptal emphysema was common in the CPFE group. The prevalence of squamous cell carcinoma in the CPFE group was significantly higher in comparison to the normal group. The rate of peripheral localization of lung cancer in the CPFE group was significantly higher in comparison to the normal, fibrosis, and emphysema groups. The prevalence of squamous cell carcinoma of peripheral areas in the CPFE group was significantly higher in the normal and emphysema groups. CONCLUSIONS: CPFE patients demonstrated histopathological and radiological differences concerning the histological types and localization of lung cancers. PMID- 28920227 TI - Huge primary malignant melanoma of the esophagus: A case report and literature review. AB - Primary malignant melanoma of the esophagus (PMME) is a relatively rare esophageal malignancy accounting for 0.1-0.2% of all esophageal tumors. Because the tumor cells occur mainly in the esophagus mucosa and grow along the longitudinal axis in the lumen, it causes relatively late obstruction symptoms, even though the lesion is a much larger mass than found in most cases of esophagus carcinoma, protruding into the esophageal lumen. Invasive growth results in stenosis, followed by difficulty eating. A patient may not be aware of their illness until transesophageal endoscopic biopsy or postoperative pathology is confirmed. Positive expression of immunohistochemical markers human melanoma black (HMB) 45 and S-100, are the most important factors in confirming diagnosis. Because of the high degree of malignancy and the poor prognosis of PMME, upon diagnosis total or subtotal esophagectomy plus three-field systemic lymph node dissection with incisions in the left cervical, right chest, and superior belly, is critically required. In summary, early diagnosis and expanding esophageal resection may be the best approach to prevent local recurrence and distant metastasis. PMID- 28920228 TI - Brown tumor of the rib as a first presentation of primary hyperparathyroidism: Report of three cases and literature review. AB - A brown tumor is a non-neoplasm mainly caused by hyperparathyroidism. It often occurs in the pelvis, ribs, long bone shaft, clavicle, and jaw. We introduce three cases of primary hyperparathyroidism, with the first symptom of brown tumor of the ribs, and discuss the image characteristics within the literature. We then propose the value of ultrasound in the diagnosis of brown tumor. PMID- 28920229 TI - Prevalence of non-calcified pulmonary nodules in screening chest computed tomography. AB - BACKGROUND: The National Lung Screening Trial revealed that low dose computed tomography (CT) screening reduced lung cancer mortality by 20%. However, nearly all (96.4%) of the positive screening results were false-positive. A higher false positive rate (FPR) is expected in Korea, where the prevalence of tuberculosis and parasitic diseases are high. MATERIAL AND METHODS: We retrospectively reviewed the records of 1587 cases (906 males, 57.1%; 495 females, 31.2%) in which chest CT was used for health screening from 2006 to 2011 in one institution. The mean +/- standard deviation age of the subjects was 62.7 +/- 5.7 years and 495 (31.2%) subjects had a smoking history. RESULTS: Three hundred and thirty six subjects (21.2%) had non-calcified pulmonary nodules (NCPNs) described as solid nodules (n = 319), masses (n = 15) or pure or mixed ground glass opacities (n = 36). The incidence of NCPNs was 23.8% in smokers and 20.0% in non smokers (P = 0.08). During a median follow up duration of 37 months (range, 0-67 months), eight subjects were confirmed to have lung cancer. Positive predictive value (PPV) of positive CT screening was 2.4% and FPR was 97.6%. Among 495 subjects who had a smoking history, 118 subjects displayed NCPNs (23.8%) and four patients were diagnosed with lung cancer, with a PPV and FPR of 3.4% and 96.6%, respectively. CONCLUSION: CT screening has low PPV and high FPR, even in subjects with a high risk of lung cancer. PMID- 28920230 TI - Primary inflammatory myofibroblastic tumor of the diaphragm: Report of a case. AB - We report a case of primary inflammatory myofibroblastic tumor of the diaphragm in a 64-year-old man. The patient was hospitalized for a computed tomography (CT) detected large tissue mass at the left lower lung field. Complete tumor excision followed by pathological investigation was performed. Microscopically, the tumor showed staggered arrangements of spindle myoepithelial cells, lymphoblastic and eosinophil cells. Immunohistochemically, the proliferating spindle cells showed positive staining for smooth muscle actin, vimentin, CD68 and Desmin, but negative for cytokeratin, leukocyte common antigen, epithelial membrane antigen, and S-100. This is the first reported inflammatory myofibroblastic tumor of the diaphragm found in an adult. The postoperative course was uneventful and the patient had no recurrence 18 months after surgery. PMID- 28920231 TI - Airway metastasis of small cell lung carcinoma: A rare presentation. AB - Airway metastasis from primary lung carcinoma is rare and typically associated with non-small cell histology. While small cell lung cancer is a particularly aggressive form of cancer, few cases of endotracheal or endobronchial metastasis have been reported. Airway involvement can go undetected because of the spread along the perilymphatic drainage system with mostly submucosal involvement causing significant airway compromise before onset of symptoms. We present a patient with recurrent small cell lung cancer, presenting with wheezing, cough, and dyspnea as a result of metastasis to the trachea and bilateral bronchi without significant mediastinal or hilar lymphadenopathy. We discuss the related literature, as well as the suspected pathophysiology causing this unique presentation. PMID- 28920232 TI - Comparison of complete and minimal mediastinal lymph node dissection for non small cell lung cancer: Results of a prospective randomized trial. AB - BACKGROUND: To compare surgical results, pathological staging, and survival between complete and minimal mediastinal lymph node dissection for non-small cell lung cancer (NSCLC). METHODS: A randomized controlled trial was carried out in 202 patients who were assigned to undergo either skeletonized complete mediastinal lymph node dissection (CLD) or minimal mediastinal lymph node dissection (MLD). Clinical and pathological characteristics, surgical results, postoperative staging, and five-year survival were recorded for statistical analysis. RESULTS: Significantly more stations of lymph nodes were harvested through CLD, than MLD (8.9 vs. 6.2, P < 0.001). There was no difference in major complications (CLD 14.7% vs. MLD 14.0%, P = 0.884) or postoperative death (CLD 2.1% vs. MLD 1.9%, P = 0.904). No significant difference was detected in pathological staging between the two groups. The pN2 rates (27.1% vs. 24.2%), skip-mediastinal metastasis (9.3% vs. 7.4%), and multi-stational mediastinal involvement (15.0% vs. 16.8%) were similar between MLD and CLD. However, CLD had significantly better five-year survival than MLD (55.7% vs. 37.7%, P = 0.005), especially in patients with a tumor size >3 cm, pleural invasion, pN1-N2, stage II-III, adenocarcinoma, and low-differentiation carcinoma. Upon multivariate analysis, CLD, along with stage I and high-differentiation, were independent prognostic factors for better overall survival. CONCLUSIONS: Complete and minimal mediastinal dissections have similar surgical risks and mediastinal staging effect in patients with NSCLC. Minimal dissection is enough for early stage high differentiation tumors. For patients with stage II-III or low-differentiation carcinoma, skeletonized complete mediastinal dissection may improve survival compared with minimal dissection. PMID- 28920233 TI - Molecular mechanisms of LKB1 induced cell cycle arrest. AB - LKB1 is a serine/threonine protein kinase mutated in patients with Peutz-Jeghers syndrome. Biallelic inactivation of LKB1 is present in up to 30% of cases of non small cell lung cancer (NSCLC). As a tumor suppressor, LKB1 functions in arresting the cell cycle and inhibiting cell growth. LKB1 leads to induction of p21/WAF1 expression in a p53-dependent mechanism, which is mediated by cytoplasmic LKB1 initiating negative regulation of cell growth or nuclear LKB1 directly involved in transcriptional regulation of p21/WAF1. Alternatively, p53 and p21/WAF1-independent mechanism of regulating cell cycle by LKB1 is also reported. PMID- 28920234 TI - Classification and regression tree analysis of patients with non-small-cell lung cancer treated with gefitinib after chemotherapy. AB - BACKGROUND: Many randomized studies have shown that epidermal growth factor receptor (EGFR-) tyrosine kinase inhibitors (TKIs) are apparently advantageous over standard chemotherapy in non-small-cell lung cancer (NSCLC) patients with EGFR active mutation in front-line treatment. But which subgroup of advanced NSCLC could benefit from EGFR-TKIs in the second-or third-line setting remains elusive. To explore predictive factors of advanced NSCLC patients with the unknown status of EGFR mutation treated by gefitinib in the second-or third-line setting, we used classification and regression tree (CART) analysis to screen which patients would benefit more. METHODS: One hundred and fifty-five patients with advanced NSCLC previously unsuccessfully treated with platinum-based chemotherapy were included in this study. Patients received gefitinib as part of the Expanded Access Program of the China Charity Federation between 2 March 2005 and 11 May 2011. Multivariate analysis of progression-free survival (PFS) was performed using CART analysis. This method uses recursive partitioning to assess the effect of specific variables on PFS, thereby ultimately generating groups of patients with similar clinical features on PFS. RESULTS: The median PFS in patients with NSCLC who were treated with gefitinib after prior chemotherapy was 16 months (95% confidence interval [CI] 13.44-18.56). CART was performed with an initial split on adenocarcinoma differentiation, and four terminal subgroups were formed. The median PFS of the four subsets ranged from 12 to 42 months. CONCLUSIONS: Adenocarcinoma differentiation, brain metastasis and prior thoracic radiotherapy are predictors of PFS in previously treated NSCLC patients. CART can be used to identify homogeneous patient populations in clinical practice and future clinical trials. PMID- 28920235 TI - Extrathoracic malignant peripheral nerve sheath tumor of the lateral chest wall locally recurred and metastasized to peritoneum: Report of a case. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are rare, with an expected incidence of 0.0001% per year in the general population and 4.6% in patients with von Recklinghausen's disease. They are defined as any malignant tumors arising or differentiating from cells of the peripheral nerve sheath. MPNSTs can develop in various sites including the trunk and head/neck region. However, its onset on the chest wall is very rare. Here we report a case of MPNST growing outside the thorax on the chest wall. The patient developed a local recurrence twice, which caused multiple metastases to the lung and peritoneum. PMID- 28920236 TI - Are we really doing better with Hem-o-lok in VATS? AB - BACKGROUND: Due to advances in clip design, new types of surgical ligation clips are available that may reduce clip failure and improve function, but in the field of minimally invasive thoracic surgery, experience of using Hem-o-lok for pulmonary artery ligation is limited. METHODS: To assess risk factors and predictors of failure of the Hem-o-lok vascular clip, using vessels harvested from a porcine model. RESULTS: The Hem-o-lok clip had the worst holding strength compared to other clips. Its hemostatic ability for pulmonary vessels was far less stable compared with renal and hepatic vessels. The Hem-o-lok clip either leaked or burst when the vessel to which it was applied was cut flush. The clip became even more likely to fail if the vessel sleeve was mobilized too "clean." CONCLUSION: Our experiment proved that the use of Hem-o-lok clips in video-assisted thoracoscopic surgery (VATS) has some potential risk. We recommend that all possible care be taken when it is applied to pulmonary vessels during VATS. Leaving some tissues around vessels may increase the thickness of the vessel, which, in turn, may increase the holding strength. PMID- 28920237 TI - Application of liquid-based cytology test of bronchial lavage fluid in lung cancer diagnosis. AB - The aim of this study was to compare the diagnostic significance of the liquid based cytologic test (LCT) and conventional smear (CS) in bronchial lavage fluid (BLF) in lung cancer patients, as well as the evaluation of LCT applications in BLF for different types of lung cancer. A total of 210 patients were divided into two groups of LCT and CS. The positive rates of the two groups were compared by stratified analysis of different bronchoscopic appearances. The positive rate of LCT and CS groups was 35.84% and 11.835%, respectively, which indicated a statistical significance between the two groups (P < 0.001). Furthermore, the detection rate of squamous carcinoma in the LCT group was (72.7%), which was higher than that of the CS group (41.7%) (P = 0.041). However, there was no difference between the biopsy and biopsy combined with LCT groups (P = 0.417), in terms of direct bronchoscopic appearance. We concluded that LCT was superior to CS in BLF that was acquired by bronchoscopy from lung cancer patients. Moreover, LCT was better than CS in diagnosis of squamous cell carcinoma. LCT could be used as an important complement of bronchoscope biopsy and could have the potential to be widely applied. PMID- 28920238 TI - Polarization of tumor-associated macrophage is associated with tumor vascular normalization by endostatin. AB - BACKGROUND: Vascular normalization is an emerging concept in cancer treatment, but its precise mechanisms are not completely understood. The polarization of tumor-associated macrophages (TAMs) is important in tumor angiogenesis and metastasis. However, little is known about the effect of anti-angiogenic agents on the polarization of tumor-associated macrophages. Therefore, we explore the changes of TAMs polarization in the development of tumor vascular normalization induced by endostatin. METHODS: A murine xenograft model of lung cancer was treated with endostatin for 10 days. The morphology and function of tumor vasculature was examined using various techniques. Flow cytometry was carried out to assess the TAMs, and immunofluorescence was used to examine Tie-2-expressing monocytes (TEMs) in tumors. Levels of the histidine-rich glycoprotein (HRG) in tumors were measured by immunohistochemistry and Western blot. RESULTS: Tumor vessels became more normal and mature on day six in the endostatin-treated mice. During vascular normalization, the number of M2-like TAMs and TEMs in the tumors was significantly reduced, whereas the number of M1-like TAMs showed an increase on day six after endostatin treatment, although the latter was not statistically significant. The HRG in the tumors accumulated at an early stage after endostatin administration. CONCLUSIONS: The polarization of TAMs is associated with tumor vascular normalization induced by endostatin. These observations may be useful in the exploration of new strategies for anti-angiogenic treatment. PMID- 28920239 TI - Surgical treatment for bronchopleural fistula with omentum covering after pulmonary resection for non-small cell lung cancer. AB - BACKGROUND: Bronchopleural fistula is an especially severe complication with a high mortality rate. We investigated the efficiency of our surgical treatments for this severe complication. METHODS: From January 2007 to December 2009, standard surgical resections and systematic lymph node dissections for non-small cell lung cancer (NSCLC) were performed on 1178 patients at our institution. Eight patients developed bronchopleural fistulas during the postoperative follow up period, and received reoperations. Seven patients underwent additional pneumonectomies, and the omental flap, which was mobilized using a transdiaphragmatic harvesting technique through the usual thoracotomy, was used to cover postpneumonectomy bronchial stump. The other patient, who had received right side pneumonectomy and systemic lymph node dissection, received omental flap stuffing and covering without reclosure of the stump or carinal plasty. RESULTS: Bronchopleural fistulas after standard surgical resections and systematic lymph node dissections for NSCLC were observed in eight patients (0.68%) in our study. The period between pulmonary resection and the appearance of bronchopleural fistula ranged from eight to 19 days (median 11 days). Repairing of the bronchial fistula was successful in all eight patients and no development of late fistula was found during the follow-up period. Postoperative hospital stay for undergoing omentoplasty to repair the bronchial fistula ranged between 11 and 23 days (median 15 days). There were no complications related to the omentoplasty procedure. CONCLUSION: Transdiaphragmatic harvesting technique of omental flap through a thoracotomy is safe and technically feasible. Surgical treatment for postoperative bronchopleural fistula with omental flap covering is effective. PMID- 28920240 TI - Effect of spider venom on inhibition proliferation of TE13 cells in vivo and in vitro. AB - BACKGROUND: The aim of this study was to evaluate the cytotoxic and antitumor activity of spider venom (SV). METHODS: Cell proliferation and cytotoxicity were determined by 3 H-methyl thymidine incorporation ([3 H]-TDR) assay. DNA fragmentation and cell cycle kinetics were analyzed by FACS. In vivo inhibition of tumor size of nude mice by SV (5.0, 10.0, 20.0 mg/kg mice) was constructed. RESULTS: SV exhibited significant anti-cancer effects on human squamous esophageal carcinoma cells TE13, mainly as a result of cell apoptosis induced by SV. The anti-cancer effects were likely achieved through decreasing [3 H]-TdR. TE13 cells treated with SV (25, 50, 100 MUg/mL), which were arrested in the G0 /G1 phase. SV treatment leads to anti-proliferation effects, and significant apoptosis in TE13 cells with reactive oxygen species (ROS) levels can increase dramatically and decrease cellular mitochondrial membrane potential (MMP). In addition, Western blotting analysis showed that one of the pharmacological mechanisms of SV was to activate the expression of P21. In vivo testing revealed that tumor size was significantly decreased after 21 days of treatment with the venom (P < 0.01). CONCLUSIONS: Our data showed that SVs could inhibit TE13 cell proliferation in vitro and in vivo. PMID- 28920241 TI - Comparative analysis of PET findings and clinical outcome in patients with primary mediastinal seminoma. AB - BACKGROUND: Primary mediastinal seminoma is a rare neoplasm. Cisplatin-based chemotherapy is the standard treatment, but management of post-chemotherapy seminoma residuals is still controversial. We encountered four cases of primary mediastinal seminoma and reviewed the clinical characteristics and outcomes, focusing on tumor size and F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) findings after chemotherapy. METHODS: A retrospective review was performed of four consecutive patients with primary mediastinal seminoma treated in our institution between 2006 and 2010. All patients were young adult males with a median age of 31.3 years (range: 20-46 years). All patients were treated with three to four cycles of a combination of cisplatin, bleomycin, and etoposide, and FDG-PET was performed after chemotherapy. RESULTS: The response to chemotherapy was good in all patients. After chemotherapy, the findings of the FDG-PET were negative in three subjects. Two of the patients, with tumors measuring over 30 mm, underwent surgical resection for the residual mass and revealed necrotic tissues and no viable cells. A third patient remained stable without salvage surgery. The size of the residual mass in the remaining patient was less than 30 mm, but the FDP-PET result was positive and the mass considered inoperable because of the involvement of large vessels. Subsequently, radiotherapy was added for the residual tumor, but disease progression was seen seven months after the initiation of chemotherapy. CONCLUSIONS: FDG-PET findings after chemotherapy could be useful as a tool for the prediction of viable residual tumor in post chemotherapy residual mediastinal seminoma. PMID- 28920242 TI - Erratum. PMID- 28920243 TI - Lung metastasis of adenoid cystic carcinoma, which mimicked primary lung cancer. AB - We report a case of adenoid cystic carcinoma of the submandibular gland where pulmonary metastasis occurred twice 16 years after resection, and each metastasis mimicked primary lung adenocarcinoma in imaging findings. The first pulmonary relapse was clinically diagnosed as primary lung adenocarcinoma and intraoperative pathological examination showed that the tumor was an adenocarcinoma; lobectomy with mediastinal lymph node dissection was performed. However, postoperative immunohistochemical analysis showed that the tumor was a metastatic adenoid cystic carcinoma. During the secondary pulmonary relapse, although the tumor was correctly diagnosed as a metastatic adenoid cystic carcinoma by intraoperative examination, it again mimicked primary lung adenocarcinoma. PMID- 28920244 TI - Metastasis associated protein 1 correlates with Hypoxia inducible-factor 1 alpha expression and lymphangiogenesis in esophageal cancer. AB - BACKGROUND: Metastasis to regional lymph nodes represents the first step of dissemination in esophageal cancer and serves as an unfavorable prognostic indicator for disease progression. The formation of tumor lymphatic microvessels is dependent on the production of lymphangiogenic growth factors by tumor cells, such as vascular endothelial growth factor C (VEGF-C), metastasis-associated gene 1 (MTA1), and hypoxia inducible-factor l alpha (HIF-1alpha). The degree of intratumoral lymphatic microvessel density (LMVD) by immunohistochemistry is thought to influence tumor lymph node metastasis (LNM) and prognosis in various solid tumors. The aim of this study was to investigate the expression of MTA1 and HIF-1alpha in human esophageal cancer and to explore the relationship between their expression and lymphangiogenesis. METHOD: The expression of MTA1 and HIF 1alpha, and LMVD marked by D2-40 were detected using immunohistochemical staining in eighty-two human esophageal cancer cases. RESULTS: The positive rates of MTA1 and HIF-1alpha expression were 69.5% and 59.8%, respectively. The expression of MTA1 and HIF-1alpha were both correlated with LNM. In addition, MTA1 and HIF 1alpha expression has a positive correlation in human esophageal cancer; LMVD correlated significantly with LNM. LMVD in MTA1 and HIF-1alpha over-expression cases was higher than that in none or weak cases, and this difference has statistical significance. CONCLUSION: Our findings suggest that MTA1 plays an important role in lymphangiogenesis and LNM by stabilizing HIF-1alpha in esophageal cancer. The inhibition of lymphangiogenesis, MTA1, or HIF-1alpha activity may have an important therapeutic benefit in the control of esophageal cancer. PMID- 28920245 TI - EGFR and KRAS mutation analyses from specimens obtained by bronchoscopy and EBUS TBNA. AB - BACKGROUD: Procurement of tumor tissue is mandatory for a mutation analysis in patients with non-small cell lung cancer. The purpose of this study was to evaluate the usefulness of bronchoscopic biopsy and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) biopsy for detecting epidermal growth factor receptor (EGFR) and KRAS mutations in routine practice. METHODS: Tumor DNA was extracted from formalin-fixed paraffin-embedded tissues, and amplifications of exons 18-21 of EGFR and codons 12, 13 and 61 of KRAS were performed using polymerase chain reaction (PCR). PCR products were subjected to direct sequencing in both directions. RESULTS: Of 211 consecutive specimens, 201 (95.3%) were available for EGFR mutation analysis, and 196 (92.9%) were adequate for KRAS mutation analysis. EGFR and KRAS mutations were detected in 14.9% and 5.4%, respectively. A median of 16 days was spent from biopsy to the final report for either EGFR or KRAS mutation status. The detection rates for both mutations were similar between bronchoscopic biopsy and EBUS-TBNA (P > 0.05). Female gender (53.3%), never smoker (63.3%), and adenocarcinoma (96.7%) were predominant in patients with EGFR mutations. Among patients with adenocarcinoma (n = 104), the frequencies of EGFR and KRAS mutations were 27.9% and 10.6%, respectively. CONCLUSIONS: Small tissue samples obtained by bronchoscopic biopsy and EBUS-TBNA are sufficient for detecting EGFR and KRAS mutations in routine practice. Therefore, concurrent mutational analyses of small tissue samples should be considered at the time of initial diagnosis. PMID- 28920246 TI - Anterior mediastinal masses resection with cosmetic skin approach. AB - BACKGROUND: The objective of this study was to describe a cosmetic skin incision for resection of large anterior mediastinal masses, and to review our experience with this technique. METHODS: From 1999 to 2010, 55 patients with a diagnosis of large anterior mediastinal masses underwent "goblet"-shaped skin incision with midline sternotomy. The complications, mortality, details of surgery, and duration of hospital stay were observed from review. Patients were monitored via follow-up for a duration of one year after surgery. RESULTS: The mean hospital stay was nine days. Wound complications of infection were observed in one patient. There were no other complications, such as hematoma formation, necrosis of skin flap, split or infection of the sternum. No related mortality was recorded within the 30-day postoperative period. All of the patients verbalized the benefits of this technique, particularly the possibility of wearing open collared clothing, as a result of the cosmetic chest wall and a camouflaging scar below the angle of Louis. At the follow-up periods, 52 of the patients were found to be well. Three patients did not complete follow-up at our facility. CONCLUSION: Our primary experience with this procedure proved it was safe. The technique allows excellent access to the mediastinum and complete removal of large anterior mediastinal masses that are complicated with adjacent midline cardiovascular structures. This technique also provides a better cosmetic result than the standard vertical incision. PMID- 28920247 TI - Thymic carcinoma with tumor thrombus protruding into the superior vena cava and the right atrium. PMID- 28920248 TI - Radiosensitization of esophageal cancer cells ECA109 by knockdown of H2AX. AB - BACKGROUND: Genetic studies on mice have demonstrated that the key regulator of DNA damage in mammalian cells is the histone H2A variant, H2AX. We hypothesize that knockdown of H2AX will cause DNA damage pathway defects and may be able to increase the sensitivity to radiotherapy. METHODS: The formation of foci and the interaction of several important proteins in esophageal cancer ECA109, triggered by irradiation, were detected by immunofluorescence staining and Co immunoprecipitation (Co-IP) assay before and after H2AX silencing. Clone formation assay was employed to detect cell radiosensitivity and cloning formation ability also before and after H2AX silencing. Cell cycle distribution and apoptosis were detected by flow cytometry. We constructed a nude mice esophageal cancer model and detected the above contents in vivo. RESULTS: H2AX and several proteins could form foci in nuclear triggered by irradiation and establish a relationship in vitro. The foci reduced after H2AX silencing. H2AX silencing could lead to radiosensitization via a colony-forming test. The apoptosis rate increased and the cell cycle was blocked in G2-M stage after H2AX silencing in vivo. The tumor volume was decreased in the H2AX silenced group after irradiation, while the tumor only slowed down the growth rate in the control groups. CONCLUSIONS: Knockdown of H2AX induced radiosensitization of esophageal cancer ECA109 cells both in vitro and in vivo. The mechanisms include defective cell cycle checkpoints and abolishment of foci formation for several important mediator and effector proteins in the DNA damage response to irradiation (IR). PMID- 28920249 TI - FDG PET/CT for the preoperative nodal staging of non-small cell lung cancer in a tuberculosis-endemic country: Are maximum standardized uptake values useful? AB - BACKGROUND: The aim of this study was to determine an optimum standardized uptake value threshold for identifying nodal metastasis in non-small cell lung cancer (NSCLC) patients using Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) in Taiwan, a tuberculosis endemic country. The variation in standardized uptake values of nodal metastasis among different NSCLC histological subtypes was also evaluated. METHODS: We retrospectively reviewed 75 NSCLC patients who had received FDG PET/CT before surgery. The diagnostic accuracy of FDG PET/CT for the preoperative nodal staging was evaluated by histopathologic findings. RESULTS: A total of 316 nodal stations were evaluated. The sensitivity and specificity of FDG PET/CT for nodal staging were 58.6% and 81.8%, respectively, using an SUV cut-off of 2.6. With regard to the levels of mean SUVmax in true-positive and false-positive groups, there was no significant difference among different histological subtypes. CONCLUSION: The present study demonstrated that FDG PET/CT for pre-operative nodal staging using SUVmax > 2.6 is a useful tool (with a higher specificity and a higher negative predictive value) to rule out the possibility of metastatic lymphadenopathy in operable patients with NSCLC. PMID- 28920250 TI - Bronchomediastinal fistula detected accidently during palliative radiation therapy. AB - Bronchomediastinal fistula is an extremely rare complication resulting from diseases such as mediastinitis or mediastinal malignancies. In patients with lung cancer, bronchomediastinal fistula formation has rarely been reported, except during post-chemotherapy or post-radiation therapy complications. An 84-year-old visited our hospital to receive palliative radiation therapy for squamous cell carcinoma of the right main bronchus T4N2M1a. During an early course of radiation therapy, chest computed tomography (CT) scans revealed bronchomediastinal fistula between the right main bronchus and the enlarged sub-carinal lymph nodes. Radiation therapy was, therefore, discontinued and the patient received only supportive care. PMID- 28920251 TI - Video-assisted thoracic surgery lobectomy for unexpected pathologic N2 non-small cell lung cancer. AB - BACKGROUND: This study was performed to assess early and late outcomes of pathologic N2 disease unexpectedly detected in patients with non-small cell lung cancer undergoing video-assisted thoracic surgery (VATS) lobectomy for clinical stage I. METHODS: We retrospectively reviewed the clinical features of patients with unexpected N2 non-small cell lung cancer and their early and late outcomes in the VATS lobectomy group versus the open thoracotomy lobectomy group. RESULTS: The overall survival time for all 358 patients was 33.26 +/- 0.90 months. The overall survival time for 117 cases in the VATS lobectomy group was 36.02 +/- 1.44 months. The overall survival time for 241 cases in the open thoracotomy lobectomy group was 31.92 +/- 1.14 months. The survival rates for patients in the VATS lobectomy group were 92.31%, 36.75%, 5.13% at one, three, and five years, respectively. The survival rates for patients in the open thoracotomy lobectomy group were 92.12%, 21.58%, 2.49% at one, three, and five years, respectively. A significant difference was found between the two groups regarding this factor ( X 2 = 3.88 , P = 0.049). CONCLUSIONS: VATS lobectomy is feasible and safe to perform on patients with minimal N2 non-small cell lung cancer. Even if lymph node metastasis is unexpectedly detected during surgery, with rigorous preoperative evaluation and systematic lymph node dissection, there is no need to convert to open thoracotomy lobectomy. PMID- 28920252 TI - Role of new radiation techniques in the treatment of pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from the surface serosal cells of the pleural cavity. Surgery remains the main therapeutic standard in the treatment of MPM with the goal of complete gross cytoreduction of the tumor. Because MPM is a diffuse disease affecting the entire mesothelial lining of the hemithorax, surgery alone can rarely achieve adequate tumor-free resection margins. The surgical choices are pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). Radiotherapy (RT) is usually applied postoperatively with the aim to improve local control. However, the efficacy of RT is limited by the large volume of the target to be irradiated (tumor and pleural cavity) and the radiosensitivity of the nearby organs (heart, liver, lung, spinal cord, and esophagus). These factors have historically limited the effective radiation doses that can be given to the patient. There is no role for radical RT alone, but the role of RT as part of multimodality therapy is discussed. After EPP adjuvant RT to the entire hemithorax can reduce the recurrence rate and is well tolerated if strict limits to the dose to contralateral lung are applied: the V20 and V5 (the percent volume of the lung receiving more than 20Gy and 5Gy of radiation) correlate with increased lung toxicity. The use of modern sophisticated techniques allows good target coverage, more conformal high dose delivery, and clinically relevant normal tissue sparing. PMID- 28920253 TI - Phase II study of oral etoposide maintenance for patients with extensive stage small cell lung cancer who have responded to the induction on an EP regimen. AB - BACKGROUND: Maintenance therapy for extensive stage small cell lung cancer (ES SCLC) is still under debate. Many new agents fail during the maintenance course. As an active agent for SCLC, oral etoposide is worth being re-evaluated. METHODS: This phase II study was performed to evaluate the toxicity/efficacy of the maintenance of patients with oral etoposide with ES-SCLC responding (complete remission [CR] + partial remission [PR]) to the induction of four cycles of etoposide plus cisplatin (EP) chemotherapy. Maintenance therapy with oral etoposide (50 mg/m2 , day 1-14, repeated every 21 days until disease progression or unacceptable toxicity occurs) was administered. The primary endpoints were grade 3 and 4 toxicities and progression free survival (PFS). RESULTS: Fifty-four patients with ES-SCLC received standard EP regimens as induction therapy; 31 responding patients were administered oral etoposide as the maintenance treatment. The most common hematological and non-hematological toxicity of the maintenance course was neutropenia and fatigue, respectively. Median PFS was nine months (95% confidence interval (CI): 8.33~9.67 months), median overall survival (OS) was 14 months (95% CI: 11.58~16.42 months). Significantly better PFS and OS were seen in patients responding to the induction EP chemotherapy. CONCLUSIONS: Oral etoposide maintenance is safe and effective for patients with ES-SCLC who responded to the induction of EP chemotherapy. Significant survival benefit was revealed in patients completely responding to an EP regimen. Further randomized control study is warranted. PMID- 28920254 TI - Diffuse large B-cell lymphoma presenting as large anterior chest wall mass involving pleura and lung: A possible result of post-traumatic chronic inflammation. AB - A 67 year-old-man was hospitalized due to chronic pain and a large mass on the anterior chest wall. His medical history showed chest trauma in 1970, the reconstitution of the scenario revealed there was blunt trauma with swelling and rib fracture on the same side. Physical examination revealed an isolated large anterior chest wall mass. Chest radiography showed two bilateral irregular masses, chest computed tomography showed a large right chest wall tumor with pleural effusion, nodules of the right upper lobe and tumor of the left lower lobe without mediastinal lymphadenopathy. Whole body exploration showed only the chest disease. Transthoracic biopsy showed inflammatory reaction. Surgical biopsy by anterior thoracotomy of the right mass was performed under general anesthesia. Histological and immunohistological analysis revealed lymphoid diffuse large cell proliferation with positive staining of CD 20, BCL-6 and MUM1, confirming the diagnosis of diffuse large B-cell malignant lymphoma. Chemotherapy based on CHOP 21 (cyclophosphamide, doxorubicin, vincristine, and prednisolone) was administered with good response after three cycles. The patient was discharged under surveillance in good condition after the end of chemotherapy. We report an infrequent neoplasm with an unusual and subtle clinical presentation. PMID- 28920255 TI - Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer. AB - OBJECTIVE: To evaluate the efficacy and safety of nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) and to investigate the association of the status of KRAS gene mutation and epidermal growth factor receptor (EGFR) genotype with clinical outcome. METHODS: Twenty-eight patients with advanced NSCLC were enrolled in this single center, uncontrolled pilot clinical study. All the patients developed drug resistance or disease progression after first-line chemotherapy of either a docetaxel + cisplatin regimen or a vinorelbine + cisplatin regimen and then received nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy. Eight cases were stage IIIB and 20 were stage IV. An i.v. dosage regimen of 200 mg of nimotuzumab was given as a single dose, injected into the patient at days 1, 8 and 15; i.v. gemcitabine was injected at a dose of 1000 mg/m2 at days 1 and 8 and cisplatin (25 mg/m2 i.v.) at days 1, 2 and 3. Each patient received four or more therapeutic cycles. The efficacy and toxic reactions were evaluated, as well as time to progression and overall survival. RESULTS: In total, 28 patients with advanced NSCLC received 101 therapeutic cycles. The mean cycle number was 3.6. Median time to progression was 4.9 (2.5 6.5) months; median overall survival and 1-year survival rate were 9.8 months and 48.5%, respectively. There was one case of complete response, six cases of partial response, 11 cases of stable disease and 10 cases of progressive disease. Response rate was 25%, and clinical benefit rate was 64.3%. Major toxic reactions were bone marrow suppression and gastrointestinal reaction. Only one patient developed grade I acneiform eruption. CONCLUSION: Nimotuzumab combined with gemcitabine and cisplatin as second-line chemotherapy for advanced NSCLC was active and well-tolerated in this setting. Patients with EGFR amplification and KRAS gene wild type had a better prognosis. Prospective, randomized, controlled, large-scale clinical studies are needed to confirm the results. PMID- 28920256 TI - Meeting report: Current cancer perspectives from the 9th Annual Meeting of the Japanese Society of Medical Oncology. AB - The purposes of Annual Meeting of the Japanese Society of Medical Oncology (JSMO) are to provide a scientific forum among scientists and oncologist, and to bridge research findings from the molecular to clinical application. Cancer treatments can immediately benefit from all areas of oncology: the discovery and clinical application of biomarkers; development of more personalized anticancer therapy including molecular targeted agents; recent findings from clinical trials; and strategies for overcoming drug resistance. International sessions at the 9th Annual Meeting of the JSMO, held in Yokohama, Japan from July 21 to 23, 2011 addressed these issues. The meeting also held a joint symposium with the American Society of Clinical Oncology. Due to space constraints this report will highlight only topics related to thoracic cancer, including controversies in the treatment of advanced cancer, thoracic-related cancer, such as lung cancer and esophageal carcinoma, and biomarkers. PMID- 28920257 TI - Salvage treatment with erlotinib after gefitinib failure in advanced non-small cell lung cancer patients with poor performance status: A matched-pair case control study. AB - PURPOSE: Gefitinib plays an important role in non-small-cell lung cancer (NSCLC) treatment; however, progression of the disease occurs in most patients even after an initial response. The role of erlotinib after gefitinib failure has been investigated but continues to be debated, especially in heavily treated patients with poor performance status (PS). Therefore, a retrospective matched-pair case control study was carried out to evaluate the role of erlotinib after gefitinib failure in advanced NSCLC patients. METHODS: A total of 58 patients were identified. The two groups were balanced with demographic and baseline clinical characteristics. All patients had PS >=2 and most of them (89.7%) had received more than two systemic therapies before erlotinib or best supportive care (BSC). The epidermal growth factor receptor (EGFR) and KRAS genotypes were analyzed in 36 (62.1%) patients, 19 of them were in the erlotinib group. RESULTS: Median overall survival (OS) for all patients was 6 months. Median OS for patients who received erlotinib and BSC was 10 and 3 months, respectively (P= 0.001). Disease control rate (DCR) and objective response rate (ORR) were 51.7% and 10.3% in patients receiving erlotinib, respectively, while median time to progression (TTP) was 3 months. Among the 19 patients in the erlotinib group with biomarker results available, those with EGFR mutation achieved longer median TTP (P= 0.016) and better DCR (P= 0.177) than those with wild-type EGFR. CONCLUSIONS: A switch to erlotinib after gefitinib failure may represent a better therapeutic option for advanced NSCLC patients with poor PS, and an EGFR mutation seemed to be associated with better survival rate. PMID- 28920258 TI - Response to gemcitabine-platinum chemotherapy by single nucleotide polymorphisms of RRM1 and ERCC1 genes in patients with non-small-cell lung cancer. AB - BACKGROUND: RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis and the response to gemcitabine. Two single nucleotide polymorphisms (SNP) in the RRM1 gene (RR37 and RR524) impact promoter activity and are associated with prognosis. The excision repair cross-complementation group 1 protein (ERCC1) is associated with platinum resistance. A SNP of the ERCC1 gene (T19007C) has been reported as a prognostic marker in platinum-treated non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with gemcitabine and platinum (GP) as first-line chemotherapy. Adenocarcinoma was the most frequent histological type, followed by squamous cell carcinoma and then other types. SNP were analyzed with real time polymerase chain reaction using genomic DNA extracted from peripheral blood. RESULTS: Based on responses to GP patients were classified as responders or non responders. The response rate was significantly higher in patients with the RR AC CT genotype (35/64, 54.7%) compared to those with the RR CC-TT genotype (56/147, 38.1%, P= 0.025). No significant difference in response rate was observed according to ERCC1 genotype. In 128 patients with non-squamous cell lung cancer, RR AC-CT + ERCC1 CC (63.2%) and RR AC-CT + ERCC1 CT/TT (61.9%) showed higher response rates compared to RR CC-TT + ERCC1 CC (36.5%), and RR CC-TT + ERCC1 CT/TT (22.2%; P= 0.004). Progression-free and overall survival times were not different between genotypes. CONCLUSIONS: We observed significantly different responses to the GP regimen according to SNP of the RRM1 and ERCC1 genes. PMID- 28920259 TI - Higher temperature improves the efficacy of magnetic fluid hyperthermia for Lewis lung cancer in a mouse model. AB - PURPOSE: The aim of this study was to investigate the effect of a higher temperature on the efficacy of magnetic fluid hyperthermia for Lewis lung cancer in a mouse model. MATERIALS AND METHODS: Magnetic fluids were prepared in vitro and directly injected into tumors. Twenty-four hours later, the mice were subjected to an alternating magnetic field. The temperature in the tumor was increased to 46.0 degrees C, higher than the usual temperature used in hyperthermia therapy. The higher temperature was maintained for 30 min with a stable strength of magnetic field. RESULTS: Magnetic fluid hyperthermia with a higher temperature significantly inhibited the growth of the tumors (P < 0.05). The tumors completely regressed in four out of 12 mice. Histological analysis demonstrated that the tumor cells underwent apoptosis and necrosis, and the cells were arrested at the G1/G0 phase of the cell cycle. The lifespan of the treated animals also increased significantly (P < 0.05). CONCLUSIONS: Magnetic fluid hyperthermia with a higher temperature could improve the efficacy of this therapy on lung cancer. PMID- 28920260 TI - Complete remission and fatal interstitial pneumonitis related to nab-paclitaxel in refractory small cell lung cancer: A case report and review of the literature. AB - For refractory or resistant small cell lung cancer (SCLC), there is no standard treatment. We report a case of refractory SCLC achieving complete remission and then developing fatal interstitial pneumonitis after treatment with single-agent nab-paclitaxel. The relevant literature has also been reviewed. In terms of effectiveness, evidences exists that some refractory or resistant SCLC patients respond to paclitaxel, including nab-paclitaxel and solvent-based paclitaxel. Paclitaxel-related fatal interstitial pneumonitis is an uncommon event, with five fatal cases reported in the literature. It appears to occur in weekly paclitaxel treated patients and develop during the middle-to-late phase of treatment. Therefore, further randomized clinical trials should be encouraged. In our case, positive immunohistochemical analysis for caveolin-1 in the tumor vascular endothelia suggests that the complete response may have been facilitated by enhanced transportation of paclitaxel through the tumor vascular barrier via caveolin-1, despite being negative for secreted protein acidic and rich in cysteine (SPARC) in tumor cells. Further molecular investigations of gp60, caveolin-1 and SPARC will shed light on tailored treatment in this setting. PMID- 28920261 TI - Fast track program for esophagectomy patients. AB - BACKGROUND: A fast track (FT) program for esophagectomy patients is rarely used. We streamlined care using an algorithm for the postoperative care of patients who underwent esophagectomy to try to reduce hospital stays to 7 days while maintaining safety and patient satisfaction. METHODS: A consecutive series of 80 patients with esophageal carcinoma who underwent elective esophageal resection from 2007 to 2008 in our department was taken into the FT program. An algorithm for FT to guide postoperative care was used, featuring avoidance of the intensive care unit, early ambulation, removal of nasogastric tube and oral nutrition starting on postoperative day (POD) 1, with discharge on POD 7. RESULTS: All patients were operated upon through a left posterolateral thoracotomy with a cervical esophagogastrostomy. Seventy-eight (97.5%) patients completed the FT program. Discharge home was proposed for POD7. None was readmitted within 30 days of discharge. None suffered from anastomotic leakage. The time to first passage of flatus was 51.7 +/- 8.4 h. CONCLUSION: The majority of patients with esophageal carcinoma can tolerate FT surgery. Oral nutrition starting on POD1 is safe and FT surgery is feasible for patients scheduled for elective esophageal cancer resections without compromising quality. PMID- 28920262 TI - Preferred surgical procedure for posterior mediastinal neurogenic tumor. AB - AIM: To compare the outcomes of video-assisted thoracoscopic surgery (VATS) with those of thoracotomy for the removal of posterior mediastinal neurogenic tumors. METHODS: Twenty-four patients were enrolled in the VATS group and 29 were enrolled in thoracotomy group between 1996 and 2010. RESULTS: When compared with the thoracotomy group, patients in the VATS group had a shorter operation time (90 +/- 29 min vs. 136 +/- 41 min, P < 0.001), less blood loss (42 +/- 12 mL vs. 209 +/- 162 mL, P < 0.001), shorter time to extubation and discharge (2.5 +/- 0.7 days vs. 3.1 +/- 1.0 days, P= 0.027; 3.6 +/- 0.6 days vs. 4.1 +/- 1.0 days, P= 0.045). CONCLUSION: VATS is a safe and effective surgical procedure for posterior mediastinal neurogenic tumors with better outcomes than thoracotomy. PMID- 28920263 TI - Development and current status of proton therapy for lung cancer in Korea. AB - The aim of this study was to examine the current status of proton therapy in Korea and to review the dosimetric benefits of proton beam therapy (PBT) over intensity-modulated radiotherapy (IMRT) for lung cancer treatment. Data from patients treated between March 2007 and February 2011 in Korea using proton therapy were analyzed retrospectively. For comparison, IMRT and PBT in the scattering mode were planned for lung cancer patients. Dosimetric benefits and organ-specific radiation-induced cancer risks were based on comparisons of dose volume histograms (DVH) and secondary radiation doses, respectively. On average, the doses delivered by PBT to the lung, esophagus and spinal cord were 17.4%, 2.5% and 43.6% of the prescription dose, respectively, which were lower than the doses delivered by IMRT (31.5%, 11.8% and 45.3%, respectively). Although the average doses delivered by PBT to the lung and spinal cord were significantly lower than those by IMRT, these differences were reduced in the esophagus. While the average secondary dose from PBT (measured at 20-50 cm from the isocenter) was 1.33-0.86 mSv/Gy, the average secondary dose from IMRT was 3.3-1.0 mSv/Gy. Compared with IMRT techniques, PBT showed improvements in most dosimetric parameters for lung cancer patients, with lower secondary radiation doses. PMID- 28920264 TI - Mini-invasive surgery in lung cancer: Current status and future considerations. PMID- 28920265 TI - Characterization of a stem cell population in lung cancer cell line Glc-82. AB - OBJECTIVES: A side population (SP) of cells can be separated from diverse cancer cell lines by a fluorescence-activated cell sorter (FACS) and show stem cell-like characteristics. To gain more information about SP phenotypes, we performed a series of characterizations of SP cells. METHODS: We isolated SP cells from the lung cancer cell line Glc-82 via FACS. Their capability of multilineage differentiation, self-renewal and tumorigenicity were examined both in vitro and in vivo. Their sensitivity to anticancer drugs was also detected by Methyl thiazol-diphenyl tetrazolium assay. The expression of cell surface molecules including ABCG2, HERs and CD133 was analyzed with a flow cytometer. RESULTS: SP cells made up an average of 14.5% of the total cell population and were more tumorigenic than non-SP cells in vivo. The growth rate of SP cells was higher than that of the unsorted cells and non-SP cells, and the repopulation of SP cells occurred more rapidly. Moreover, the SP cells expressed elevated levels of ABCG2 protein and showed augmented resistance to multiple chemotherapeutic and targeted drugs, when compared to non-SP cells. In addition, the expression of epidermal growth factor receptor protein and CD133 were higher in SP cells than in non-SP cells. CONCLUSIONS: We suggest that the SP cells in the Glc-82 cell line are enriched with cancer stem cells. PMID- 28920266 TI - Survival and bronchial carcinoid tumors: Development of surgical techniques in a 30-year experience of 82 patients in China. AB - BACKGROUND: We aimed to identify the factors determining long-term survival after surgical management for bronchial typical carcinoid (TC) and atypical carcinoids (AC) and to compare the clinical outcome of the different surgical strategies used in the two periods of 1980-1994 and 1995-2005. METHODS: Records of 82 patients with an initial pathological diagnosis of bronchial carcinoid tumor who underwent surgical management from January 1980 to December 2009 were reviewed. Tumors were classified as TC or AC using the 2004 World Health Organization criteria. RESULTS: There were 60 TC and 22 AC. Surgical procedures included lobectomies, sleeve or bronchoplastic resections, pneumonectomies, wedge resections, and segmental resections. Significantly fewer pneumonectomies and more sleeve and bronchoplastic resections were performed after 1994. The prognosis was more favorable for TC than AC. Comparing lymph node status N0 with N1 + N2, 5- and 10-year survival was 92% and 85% vs. 61% and 41%. No patient with lymph node involvement survived more than 15 years. CONCLUSIONS: Tumor subtype and lymph node status have the greatest impact on long-term survival following surgery. AC and/or regional lymph node metastases have the worst prognosis. Formal anatomic and tissue-saving lung resection plus systematic radical mediastinal lymphadenectomy for TC and AC should be standard. PMID- 28920267 TI - Proton therapy for esophageal cancer. PMID- 28920268 TI - Characterization of solitary pulmonary nodules using double phase Tc-99m methoxyisobutylisonitrile scan: Comparison of visual and quantitative analyses. AB - BACKGROUND: We assessed the diagnostic usefulness of Tc-99m methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) for the evaluation of solitary pulmonary nodule (SPN). METHODS: Thirty five patients (17 malignant and 18 benign) were recruited. Double phase Tc-99m MIBI SPECT was performed 10 min and then 2 h after an injection of 925 MBq of Tc 99m MIBI. Visual interpretation grades of the Tc-99m MIBI scan were used for the determination of SPN characteristics. Receiver-operator curve analyses were performed for the optimal cut-off values of visual and quantitative indices for differentiation of benign and malignant SPN. RESULTS: The optimal visual grades were grade 4 and 5. When 3+ was used as the cut-off value for the detection of malignant SPN, the sensitivity and specificity of Tc-99m SPECT were 47.1% and 88.9%, respectively. The area under curve (AUC) was 0.758. The optimal planar lesions to non-lesion (L/N) ratios were 2.3 for the early image and 1.6 for the delayed image. The optimal SPECT L/N ratios were 3.1 for the early and 1.6 for the delayed image. The SPECT early L/N was superior to other quantitative indices and visual analysis. CONCLUSION: This study shows that Tc-99m MIBI SPECT is a useful non-invasive method for the evaluation of SPN. PMID- 28920269 TI - Design and application of a self-evaluation questionnaire for individuals at a high-risk of lung cancer. AB - OBJECTIVE: The purpose of this study was to establish a comprehensive evaluation system to assess the risk factors of lung cancer for the general population. METHODS: With the method of evidence-based medicine, risk factors of lung cancer were identified and their risk assignments were calculated to design the Self evaluation Scoring Questionnaire for High-risk Individuals of Lung Cancer. Studies including more than 10 000 subjects were carried the out to confirm the questionnaire's value. RESULTS: The questionnaire consisted of 15 risk factors and their risk assignments, such as sex, age, smoking, female passive smoking, previous illness histories, exposure to harmful gases, mental depression and genetic susceptibility. In the population application, data from 30 lung cancer patients revealed its desired reliability and validity. The next pre investigation, including 94 patients and 252 controls, confirmed its differentiating power, and encouraged a much larger-scale survey with 2161 subjects to determine the threshold (T) to identify high-risk individuals, the threshold was 116 points. According to this criterion, 1537 high-risk volunteers and 6556 controls were recruited to participate in a 3-year follow-up study from 2007 to 2009. There were 31 cases of lung cancer detected in the high-risk group, with a detection rate of 2.02%, significantly higher than that of the controls (5/6556, 0.08%), indicating an excellent predictive value of the questionnaire. CONCLUSIONS: The Self-evaluation Scoring Questionnaire for High-risk Individuals of Lung Cancer was a good means for evaluating the risks of lung cancer. PMID- 28920270 TI - Clinical and biologic prognostic factors in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is an extremely aggressive neoplasm of the pleura mainly attributable to asbestos exposure. Conventional medical, physical, and surgical treatments and their combinations are basically ineffective and just a few subjects experience some benefit. No definite guidelines can be provided in patient selection and therapeutic strategies. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics, which are quite unreliable, rather than by the histological or molecular features of the tumor. In the present review the impact on prognosis of classic (i.e. etiology, age, gender, histology, staging), as well as relatively new clinical factors such as quality of life, positron emission tomography assessment, and occult residual disease, are firstly evaluated. In the second section of the review several biological variables and genetic markers, which have been recently recognized as the bases of the disease onset and development, are listed and discussed. There are serum and tissue markers. The latter are mainly related to cell cycle regulation, apoptosis, and growth factor pathways. These novel factors may play an important role in defining the prognosis of the disease and, subsequently, may have a place in addressing therapy. PMID- 28920271 TI - The detection of EGFR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR-TKI. AB - BACKGROUND: The validity of epidermal growth factor receptor (EGFR) mutation in serum and plasma DNA as a surrogate of tumor tissue has been comprehensively explored. However, the concordance between peripheral blood and tumor tissue samples in EGFR mutation detection remains variable. The question as to whether real-time samples for EGFR mutation analysis are required before epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy remains unanswered. METHODS: This study included two cohorts:(i) 822 non-small cell lung cancer (NSCLC) patients with primary tumor tissue and matched plasma samples at initial diagnosis; and (ii) 207 patients with advanced NSCLC who had plasma samples taken immediately before EGFR-TKI therapy, in which 157 cases had matched tumor tissues. Denaturing High-Performance Liquid Chromatography (DHPLC) determined EGFR mutation status. RESULTS: Among a total of 822 patients with matched samples, the EGFR mutation rates were 36.3% and 32.1% in tissue and plasma samples, respectively. Concordance of EGFR mutation between two kinds of samples was 77.0% (631/822),with 63.5% (188/296) of accuracy of EGFR mutation in plasma DNA. In 207 advanced NSCLC patients who had plasma samples taken immediately before EGFR-TKI therapy, the objective response rate (ORR) after EGFR-TKI therapy was significantly higher in EGFR mutant patients than those in EGFR wild-type patients (51.4% vs. 22.6%, P < 0.001), regardless of the treatment lines of EGFR TKI. In patients with two or more lines of EGFR-TKI therapy, EGFR mutation status in plasma samples, but not in tissues, was a predictor for progression-free survival (PFS) after EGFR-TKI therapy (mutant vs. wild-type: 10.1 months vs. 3.7 months, P = 0.038). CONCLUSIONS: An EGFR mutation test using plasma DNA samples was validated and reproducible. Obtaining real-time samples for EGFR mutation detection is critical in order to predict the outcomes of EGFR-TKI. PMID- 28920272 TI - Resection of left inferior lung lobe combined and intracardiac tumor embolism under cardiopulmonary bypass. PMID- 28920273 TI - PTPN22 and CTLA-4 gene polymorphisms in resected thymomas and thymus for myasthenia gravis. AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease of striated muscle tissue mediated by autoantibodies. MG is often treated with thymectomy. Protein tyrosine phosphatase non-receptor 22 (PTPN22) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) have recently been found to be the genes that predispose to autoimmune diseases. The mechanisms of PTPN22 and CTLA-4 single nucleotide polymorphisms in resected thymomas and thymuses in MG remain unclear. METHODS: In the present study, 90 patients with thymomas, including 44 patients with MG, 46 patients without MG, and 35 MG patients without thymoma were studied, with 50 healthy people as the controls. The +1858C>T polymorphism of the PTPN22 gene and the 49A>G polymorphism of the CTLA-4 gene were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The PTPN22 -1123G>C polymorphism at the promoter site was genotyped using single allele-specific primer polymerase chain reaction (SASP-PCR). RESULTS: The PTPN22 +1858C>T polymorphism was not significantly different between the patients and the controls. Statistically significant differences in the allelic and genotypic frequencies of PTPN 22 -1123G>C and CTLA-4 49A>G were observed between the MG(+) thymoma group and the controls (P = 0.000, 0.003), but not between the MG(-) thymoma and MG-thymoma(-) groups and the controls (P = 0.192/P = 0.214 and P = 0.067/P = 0.254). Statistically significant differences in allelic and genotypic frequencies of the 49A>G for CTLA-4 were observed between the MG(+)-thymoma group and the controls (P = 0.000, P = 0.003), but not between the MG(-)-thymoma and MG thymoma(-) groups and the controls (P = 0.077/P = 0.261 and P = 0.058/P = 0.058). Individuals with the PTPN22 CC genotype and the CTLA-4 G alleles had an increased risk of developing paraneoplastic MG (odds ration [OR]= 4.722, 95% confidence interval [CI]: 1.460-15.277) compared with those with the PTPN22 G allele and the CTLA-4 AA genotype. CONCLUSION: The results show an association between the PTPN22 1123G>C genotype and thymoma-associated MG, with significant synergy with the CTLA-4 G alleles. PMID- 28920274 TI - The impact on quality of life after en-bloc resection for non-small-cell lung cancer involving the chest wall. AB - BACKGROUND: En-bloc resection for non-small cell lung cancer with chest-wall involvement may achieve a 5-year survival rate higher than 40%, but the impact on postoperative quality of life is not yet known. METHODS: Twenty-six patients undergoing en-bloc lung resections were included. Life quality ratings were assessed through a Short-Form 36 questionnaire preoperatively and at six, 12, 18 and 24 month follow-up visits. The degree of dyspnea, pain level, and flow-volume curves were also obtained at the same time periods. Changes occurring over time were analyzed by means of repeated-measure ANOVA. RESULTS: As a whole, the Physical Component Summary score declined six months postoperatively (P < 0.0001) and failed to improve thereafter. Patients with preoperative Forced Expiratory Volume in one second (FEV1 ), <80% predicted (P = 0.029), resected ribs >2 (P = 0.03), and chest wall defect >=50 cm2 (P = 0.007) experienced a greater and lasting impairment. Net postoperative decrease in FVC (P = 0.02; r = 0.48) and dyspnea worsening (P = 0.03; r =-043 at six months, P = 0.05; r =-0.39 at 12 months) were also correlated with the extent of physical deterioration, whereas age (P = 0.92), gender (P = 0.51), type of resection (P = 0.71), and adjuvant therapy (P = 0.68) did not. The Physical Component Summary didn't change significantly in patients with high pain levels (VAS >7). The Mental Component Summary score increased slightly at six months, with no difference in any patients' subgroup. CONCLUSIONS: The extent of chest wall resection, preoperative FEV1 , and postoperative decline in FVC were the main indicators of quality of life impairment after en-bloc resection for lung cancer. The impact upon quality of life should be considered in a cost-to-benefit ratio of planning this surgery in suboptimal candidates. PMID- 28920275 TI - Initial experience of video-assisted thoracic surgery left upper sleeve lobectomy for lung cancer: Case report and literature review. AB - Video-assisted thoracic surgery (VATS) sleeve lobectomy continues to represent a great challenge to thoracic surgeons. Herein we report what we believe to be the first case of thoracoscopic left upper sleeve lobectomy for lung cancer. A 61 year-old male patient with centrally located lung cancer of the left upper lobe was successfully treated by this minimally invasive technique. Based on the success of the operation, we believe that VATS left upper sleeve lobectomy is also feasible, however, surgical approaches and procedures still require further improvement. PMID- 28920276 TI - Roles of EBUS-TBNA in clinical practice. PMID- 28920277 TI - The role of pleural fluid MAGE RT-nested PCR in the diagnosis of malignant pleural effusion. AB - BACKGROUND: Melanoma antigen (MAGE) genes are expressed in tumor cells, the testis and the placenta. The purpose of this prospective study was to investigate the sensitivity, specificity, and accuracy of the carcinoembryonic antigen (CEA), MAGE reverse transcriptase-nested polymerase chain reaction (RT-nested PCR), and cytology of pleural fluid in the diagnosis of malignant pleural effusion. METHODS: Patients in whom unilateral pleural effusion was identified on chest radiography from January to December 2009 were included in the study. MAGE genes were analyzed by RT-nested PCR using MAGE A1-6 common primers. RESULTS: Of 81 enrolled patients, 46 were diagnosed as malignant pleural effusion, and 24 were diagnosed as benign pleural effusion. The diagnoses of 11 patients were not confirmed in this study. The diagnostic sensitivity, specificity, and accuracy of MAGE RT-nested PCR were 61.4%, 95.7%, and 73.1%, respectively. The diagnostic sensitivities of cytology and CEA (>5 ng/mL) were 61.4% and 75.0%, respectively. Among 17 patients with negative cytology who had malignant pleural effusion, 12 and 10 patients were positive for CEA (>5.0 ng/mL) and MAGE RT-nested PCR, respectively. However, of five patients with malignant pleural effusion that was not recognized by cytology and CEA, MAGE RT-nested PCR correctly predicted a malignant etiology in only one additional patient (20%). CONCLUSIONS: MAGE RT nested PCR seems to add little on the combination of conventional methods in the diagnosis of malignant effusion. PMID- 28920278 TI - Efficacy and safety of Abraxane in treatment of progressive and recurrent non small cell lung cancer patients: A retrospective clinical study. AB - BACKGROUND: Abraxane is a novel Cremophor-free nanoparticle paclitaxel that has been demonstrated to improve efficacy in the treatment of solid tumors. We undertook this retrospective study to evaluate the efficacy and safety of Abraxane in the progressive or recurrent non-small cell lung cancer (NSCLC) patients. METHODS: From August 2009 to April 2011, 33 patients who were diagnosed with progressive or recurrent NSCLC and treated with one or more prior platinum-based chemotherapies, were enrolled. The patients were injected with Abraxane, 260 mg/m2 , d1, and were evaluated for efficacy and safety. The treatment was repeated every three weeks unless progressive lesions or unacceptable toxicities were found. RESULTS: There were no complete response and 11 partial responses (33.3%). Patients with squamous cell carcinoma showed better responses than those with adenocarcinoma (41.7% and 21.1%, respectively). Fourteen patients had stable disease, and the disease control rate was 75.8%. The median progression-free survival was five months (95% confidence interval [CI]: 3.5-6.5). Four patients (12.1%) experienced grade 3-4 hematologic toxicities; one anemia (3.0%), two leucopenia (6.1%) and one thrombocytopenia (3.0%). Six patients (18.2%) experienced grade 3-4 non-hematologic toxicities; two abnormal hepatic functions (6.1%), one fatigue (3.0%), one peripheral neuropathy (3.0%), and two alopecia (6.1%). CONCLUSION: Recurrent and progressive NSCLC patients pretreated with platinum-based chemotherapy might benefit from Abraxane with tolerable adverse events. PMID- 28920280 TI - A case of lung cancer with first signs of hematological manifestations. PMID- 28920279 TI - Bibliometric analysis on lung cancer in China during the period of 2001-2010. PMID- 28920281 TI - Response to roles of EBUS-TBNA in clinical practice. PMID- 28920282 TI - Lung cancer and benign lung diseases in patients with serious vitamin D deficiency in eastern China. AB - BACKGROUND: Vitamin D deficiency is a global problem. OBJECTIVE: We examined the 25-hydroxyvitamin D (25(OH)D) concentrations to confirm whether patients with lung diseases in eastern China showed vitamin D deficiency and whether this deficiency was related to the risk of lung cancer. We used chemiluminescence to estimate the 25(OH)D concentrations in 250 patients from eastern China, of whom 197 had untreated stage III/IV lung cancer and 53 had benign lung diseases. RESULTS: The mean serum 25(OH)D concentration of patients with lung cancer was 10.63 +/- 7.04 ng/mL, while the mean serum of patients with benign lung disease was 9.62 +/- 6.37 ng/mL. Although there was no significant difference between the values, the mean serum concentrations of 25(OH)D obtained in patients with lung cancer and benign lung diseases were lower than the normal value (>20 ng/mL); P values in both cases were less than 0.0001. Among the 250 patients, 90 showed low serum 25(OH)D levels of <=4 ng/mL. CONCLUSIONS: Patients with lung diseases in eastern China have low serum levels of 25(OH)D, and the average serum 25(OH)D level is well below the normal vitamin D level. As the average serum 25(OH)D levels in patients with lung cancer or benign lung diseases are very low, we cannot conclude whether the low levels of 25(OH)D are a risk factor for lung cancer. PMID- 28920283 TI - Discordance of epidermal growth factor receptor mutations between primary tumors and corresponding mediastinal nodal metastases in patients operated on for stage N2 non-small cell lung cancer. AB - The discordance of epidermal growth factor receptor (EGFR) mutations between primary lung tumors and the corresponding mediastinal nodal metastases has not yet been well elucidated. We investigate the discordance of EGFR mutations between primary tumors and the corresponding mediastinal nodal metastases, and the discordance of EGFR mutations between different mediastinal lymph node stations in patients operated on for stage N2 non-small cell lung cancer (NSCLC). Two hundred and nineteen surgically resected primary tumors and their 553 corresponding mediastinal nodal metastases were evaluated for EGFR mutations in exon 19 or 21 by TaqMan real-time polymerase chain reaction (PCR) analysis. EGFR mutation was detected in 26.0% (57/219) of the primary tumors and 14.8% (82/553) of the corresponding mediastinal nodal metastases. In 162 cases with EGFR wild type in primary tumors, none of their 402 corresponding mediastinal nodal metastases had EGFR mutation. In 57 cases with EGFR mutations in primary tumors, EGFR mutations were detected in 82 of all 151 metastatic lymph node stations (54.3%), 34 cases had EGFR mutations in mediastinal nodal metastases, and 23 cases had lost the mutations in mediastinal nodal metastases. Among the 219 cases, 196 cases had at least two metastatic lymph node stations, 9.0% (18/196) of cases with multiple metastatic nodal stations exhibited discordance in EGFR mutations between different lymph node stations. The possibility of discordance in EGFR mutations between primary tumors and corresponding mediastinal nodal metastases, and between different mediastinal lymph node stations should be considered whenever these mutations are used for the selection of patients for EGFR-directed tyrosine kinase inhibitor therapy. PMID- 28920284 TI - Ewing's sarcoma family of tumors originating in the main bronchus. AB - Ewing's sarcoma family tumors (ESFT), which include Ewing's sarcoma and primitive neuroectodermal tumors (PNET), have been reported to originate in a variety of sites, mostly in the extremities. Previous reports have shown ESFT originating in the thoracic region, such as chest wall and peripheral lung. We herein report the first case of the ESFT that originated in the main bronchus. Endobronchial snare resection was followed by five courses of chemotherapy (VDC-IE; including vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide) and sequential radiation. After the treatment, the patient's condition has improved, and he has remained disease-free for the past year. PMID- 28920285 TI - Proton therapy for lung cancer. AB - Proton therapy is an emerging radiotherapy technology with the potential to improve the therapeutic index in the treatment of lung cancer patients. Since charged particles, such as protons, have a penetration length that can be modified by using different energies, protons offer the clinician the ability to modulate radiation dose deposition along the beam path. This facilitates an increase of the dose to the tumor target while minimizing the volume of normal tissue irradiation. Such precise delivery is particularly relevant in the setting of lung cancer where the targeted tissues are in close proximity to moderately radiation-sensitive organs like the spinal cord, heart, and esophagus, but are also effectively surrounded by the normal lung, which is extremely sensitive to radiation damage. Proton therapy has been investigated for the treatment of surgically curable yet medically inoperable patients as well as patients with regionally advanced disease. PMID- 28920287 TI - Endobronchial ultrasound (EBUS) with tranbronchial needle aspiration (TBNA) versus mediastinoscopy for mediastinal staging in non-small cell lung cancer (NSCLC) thoracic cancer. AB - Lung cancer is the leading cause of cancer deaths worldwide and is responsible for more cancer deaths than the next three most common cancers combined. Despite common use of the best non-invasive tests for assessing clinical stage: computed tomography (CT) and integrated positron emission tomography/computed tomography (PET/CT) using 2-deoxy-2-18-fluoro-D-glucose (FDG), the pathologic stage is often different. The status of mediastinal (N2) lymph nodes is paramount in guiding therapy towards surgery, chemotherapy, radiotherapy or a combination of these modalities. Accurate staging is mandatory for patients prior to commencing therapy. Invasive tests that afford tissue biopsies of N2 lymph nodes are: esophageal ultrasound with fine needle aspiration (EUS-FNA), endobronchial ultrasound (EBUS-TBNA), and mediastinoscopy. This review article compares the two most commonly used invasive methods to obtain tissue biopsies of mediastinal (N2) lymph nodes: mediastinoscopy and endobronchial ultrasound (EBUS). PMID- 28920286 TI - The role of endobronchial ultrasound in central early lung cancer. AB - Central early lung cancers (CELC) are tumors arising from the central airways, roentgenographically occult, which are usually diagnosed by bronchoscopy after a positive sputum cytology. Most CELCs are undetectable for conventional white light bronchoscopy (WLB) but can be identified under autofluorescence bronchoscopy (AFB). Although AFB increases the sensitivity of WLB in detecting CELC, its low specificity remains a problem. Surgery has been the most accepted treatment for CELCs; however 20-30% of patients suffering CELC tend to have multicentricities and usually present with poor cardiopulmonary status. Therefore, surgery is not suitable in most of the cases and other therapeutic options such as bronchoscopic treatments should be considered. Because most endoscopic treatments are unlikely to be curative if the tumor has spread beyond the bronchial cartilage, accurate evaluation of CELC bronchial wall invasion is critical before selecting a bronchoscopic treatment. Endobronchial ultrasound (EBUS) is a relatively new technique that has proven to be useful in the evaluation of the normal and cancer-invaded bronchial wall. Some authors have demonstrated that after adding EBUS assessment to AFB in autofluorescence positive lesions the specificity increases from 50 to 90%. Other studies have focused on the ability of EBUS to detect bronchial wall invasion in patients with CELCs. They compared the EBUS images with pathological findings of surgical specimens of patients that underwent surgery; in most of the cases the correlation between EBUS and pathological findings increased over 90%. Furthermore, in patients not eligible for surgery, EBUS has proven to predict patients expected response to endoscopic treatments. PMID- 28920288 TI - Current concepts in the management of leakages after esophagectomy. AB - Esophagectomy is a high-risk procedure that, despite advances over past years, is still associated with high morbidity and mortality. Anastomotic insufficiency is a devastating surgical complication as it is linked to postoperative morbidity and is the main cause for postoperative mortality. It can lead to sepsis and necessitate re-operation, further increasing morbidity and mortality through additional complications brought on by the repeated invasive procedures. However, not all anastomotic leakages entail such a critical course of events and can be sufficiently dealt with by less invasive measures. As a consequence, the approach to anastomotic leakage must be carefully selected in order to minimize additional procedure-related risks while ensuring adequate therapy. In this setting, less invasive treatments such as esophageal stents and clips, application of vicryl plugs in combination with fibrin glue, and endoscopic insertion of vacuum sponges, have emerged in recent years and become a viable alternative in the management of certain leakages. This review presents current algorithms for detection, classification and treatment of leakages after esophagectomy. PMID- 28920289 TI - Roles of EBUS-TBNA in non-small cell lung cancer. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial aspiration (EBUS TBNA) has the potential to improve nodal diagnosis and staging in non-small cell lung cancer (NSCLC). This study was performed to explore the roles of EBUS-TBNA in NSCLC. METHODS: From 2007 to 2009, 164 NSCLC patients were examined by EBUS TBNA. The patients were divided into a diagnosis group (n = 64) and a staging group (n = 100). RESULTS: For all patients, the diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 92.3%, 100%, 100%, 88.2%, and 95.1%, respectively. In the diagnosis group, the diagnostic sensitivity, specificity, PPV, NPV, and accuracy were 89.7%, 100%, 100%, 86.2%, and 94.4%, respectively. Thirty five patients (54.7%) positive for malignancy as determined by EBUS-TBNA avoided surgery. In the staging group, the diagnostic sensitivity, specificity, PPV, NPV, accuracy, and surgery avoidance rate were 93.8%, 100%, 100%, 89.7%, 96%, and 61%, respectively. CONCLUSIONS: EBUS-TBNA is a feasible and effective tool for NSCLC diagnosis and staging that also reduces surgery rates. Patients with NSCLC should initially undergo the less invasive EBUS-TBNA procedure for diagnosis and staging of NSCLC. However, negative findings must be confirmed by surgery. PMID- 28920290 TI - Mediastinal re-staging of non small-cell lung cancer. AB - Selected patients with non small-cell lung cancer (NSCLC) with mediastinal lymph node involvement may have a survival benefit from surgical resection, particularly if mediastinal nodal down-staging occurs after induction therapy and complete resection is achieved with lobectomy. Accurate re-staging of the mediastinum after induction therapy is therefore crucial in determining prognosis and subsequent treatment. Non-invasive imaging techniques usually require a confirmatory tissue sampling method to improve the accuracy of mediastinal re staging. As in the initial staging of the mediastinum, minimally invasive endosonography-guided needle sampling techniques such as endobronchial ultrasound guided fine-needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration show promise in re-staging the mediastinum, though invasive surgical re-staging remains the gold standard. Despite a lower sensitivity in the mediastinal re-staging of NSCLC, EBUS-TBNA with or without EUS-FNA may still be the preferred initial mediastinal re-staging technique. PMID- 28920291 TI - Primary pleural chloroma: A rare location with fatal prognosis. AB - We report an extremely unique histologically proven case of an isolated primary pleural granulocytic sarcoma (chloroma) in a 44-year-old woman who had sustained complete remission for 14 years after being treated for a Hodgkin's lymphoma. There was no history of myelogenous leukemia, which typically precedes chloroma. The prognosis was dismal as the patient died 2 weeks after diagnosis. PMID- 28920292 TI - Tachyarrhythmia secondary to cardiac metastasis as first presentation of non small-cell lung cancer. AB - We describe a man who presented at our institution with tachyarrhythmia and dyspnea. Echocardiography, magnetic resonance imaging (MRI) and computed tomography (CT) of the chest performed during hospitalization revealed a mass within the left atrium. A biopsy of the mass showed a non-small-cell lung cancer, adenocarcinoma G3. Metastatic involvement of the heart is rare; most cases are asymptomatic and diagnosed only during autopsies. Echocardiography, CT scan and MRI are complementary investigations in the evaluation of cardiac lesions. In the setting of cardiac metastatic cancer, all management is palliative. PMID- 28920293 TI - Updates on endoscopic therapy of esophageal carcinoma. AB - Endoscopic submucosal dissection (ESD) has the advantage over endoscopic mucosa resection (EMR), permitting removal of gastrointestinal neoplasms en bloc, but is associated with a relatively high risk of complications. Early esophageal cancer (EEC) is indicated when the tumors are confined to the two-third layer of the lamina propria. Esophageal stricture following semicircular or complete circular esophageal ESD is relatively frequent even if treated by multiple pre-emptive endoscopic balloon dilatation. Oral prednisolone may offer a novel, safe, and effective option for prevention of post-ESD stricture associated with ESD for extensive esophageal neoplasms. The procedures include marking, submucosal injection, circumferential mucosal incision and exfoliation of the lesion along the submucosal layer. Complete ESD can achieve a large one-piece resection, allowing precise histological assessment to prevent recurrence. Clinical outcomes of esophageal ESD have been promising, and the prognosis of EEC patients treated by ESD is likely to be excellent, though further long-term follow-up studies are warranted. Notification of a risk of perforation is essential for esophageal ESD. Bleeding during ESD can be managed with coagulation forceps, and postoperative bleeding may be reduced with routine use of the stronger acid suppressant, proton pump inhibitors. PMID- 28920294 TI - Safety and efficacy of cetuximab combined with chemotherapy in Chinese patients with advanced non-small cell lung cancer. AB - BACKGROUND: The aim of this study was to evaluate safety and efficacy of cetuximab combined with chemotherapy in Chinese patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of clinical data was conducted in patients who were given cetuximab combined with chemotherapy in the department of respiratory medicine, Peking Union Medical College Hospital between June 2008 and July 2011. All patients signed the informed consent, and consented to offer clinical information. RESULTS: Twenty-two patients were enrolled in this study. Nine patients were alive up to analysis, and the longest survival was 28.9 months. The objective response rate (ORR), disease control rate (DCR), median progression free survival (PFS), and estimated least median overall survival (OS) were 36.4%, 59.1%, 5.3 months and 10.1 months, respectively. Results for the 16 patients treated as first line setting were 50.0%, 62.5%, 6.0 months and 10.1 months, respectively. The common adverse events included skin toxicity (14, 63.6%), alanine aminotransferase elevation (7, 31.8%), hematological toxicity (5, 22.7%), allergy (1, 4.5%) and fever (5, 22.7%). CONCLUSION: Cetuximab combined with chemotherapy for Chinese patients with advanced NSCLC had promising ORR, DCR, and PFS, especially in the first line subgroup. Serious adverse events had low incidence and were manageable. PMID- 28920295 TI - Selective nodal irradiation of regionally advanced non-small-cell lung cancer with proton therapy and IMRT: A dosimetric comparison. AB - OBJECTIVES: Evaluate the dosimetric impact of selective/elective nodal treatment with dose-escalated radiotherapy for regionally advanced non-small-cell lung cancer (NSCLC) using proton therapy (PT) or intensity-modulated radiotherapy (IMRT). METHODS: Five consecutive patients with regionally advanced NSCLC underwent treatment planning for high-dose involved-field (IF) treatment (positron emission tomography-positive gross disease) with or without selective/elective nodal irradiation, defined as the extended field (EF). Four treatment plans were developed for each patient: i) IMRT to treat IF to 74 Gy (IFrT); ii) IMRT to treat high-risk nodes to 44 Gy and IF to 74 Gy (EFrT); iii) PT to treat IF to 74CGE (IFpT); and iv) PT to treat high-risk nodes to 44CGE and IF to 74CGE (EFpT). High-risk nodes were defined as mediastinal, hilar, and supraclavicular lymph node stations adjacent to foci of PET-positive gross disease. The IMRT and PT plans were isoeffective. Dose to organs at risk (OARs), including the lung, esophagus, heart and spinal cord, were evaluated. RESULTS: The average IF clinical target volume (CTV) was 397 cc (344-428), while the average EF CTV was 642 cc (530-753 cc). Comparing IMRT with PT, mean lung dose reduced 3.4 Gy/CGE and 3.7 Gy/CGE; lung V20 reduced 4% and 5% for EF and IF, respectively. CONCLUSIONS: Selective/elective nodal irradiation with protons reduces normal-lung exposure compared to selective/elective nodal irradiation with IMRT. PMID- 28920296 TI - Expression of nectin 3: Novel prognostic marker of lung adenocarcinoma. AB - BACKGROUND: We investigated the prognostic significance of the immunoglobulin like cell adhesion molecule nectin-3, a regulator of the formation of adherens junctions, in human lung adenocarcinoma. METHODS: Tumor-tissue samples of 127 patients with surgically resected lung adenocarcinoma were used for analysis of the proteins expression by immunohistochemistry. RESULTS: Of the 127 patients, 25% showed membranous expression of nectin-3, and others showed negative or cytoplasmic expression. Membranous expression of nectin-3 was found to be a prognostic factor for decreased overall survival on univariate analysis (P = 0.001). Multivariate Cox proportional hazards model analyses also revealed that membranous expression of nectin-3 turned out to be an independent prognostic factor (P = 0.048). Moreover, in tumors expressing membranous nectin-3, some tumors did not co-localize with E-cadherin, and the patients of such tumors showed poorer prognosis than other patients for overall survival on univariate analysis (P < 0.03). Conversely, membranous expression of nectin-3 with E cadherin co-localization was found to associate with good prognosis of patients. CONCLUSION: Membranous expression of nectin-3 was an independent prognostic factor of lung adenocarcinoma, and it might play an important role in progression of the tumor. PMID- 28920297 TI - Clinical characteristics of patients with lung cancer and idiopathic pulmonary fibrosis in China. AB - BACKGROUND: To identify distinguishing characteristics between patients with lung cancer and idiopathic pulmonary fibrosis (IPF-CA) and patients with IPF alone in China. METHODS: The medical records of 24 IPF-CA patients and 80 IPF patients admitted to Peking Union Medical College Hospital (PUMCH) from 1999 to 2009 were reviewed. RESULTS: The incidence of lung cancer in IPF patients in our study was 23.1% (24/104), and the percentage of patients who smoked in the IPF-CA group was higher than the IPF group (87.5% and 55.0%, respectively, P = 0.004). Three symptoms, including productive cough, hemoptysis, and chest pain, were more common in IPF-CA patients than IPF alone patients. There was no significant difference in the percentage of patients with other abnormal serum tumor markers, except that the percentage of patients with abnormal neuron specific enolase was significantly higher in the IPF-CA group than in the IPF group (28.6% vs. 7.4%, P = 0.041). The most common histology type was adenocarcinoma (33.3%). The median overall survival for IPF-CA patients and IPF patients was 7.0 months (95% confidential interval (CI), 2.51-11.49) and 14.0 months (95% CI, 1.26-26.74), respectively, with no significant difference (P = 0.327). CONCLUSION: Due to a high proportion of IPF cases complicated with lung cancer, physicians should closely observe lung cancer incidence during the IPF follow-up period. Individualized treatment for lung cancer patients with IPF is emphasized. Hence, it is important to ensure the safety of cancer treatments. PMID- 28920298 TI - Proton therapy for non-small cell lung cancer: Current evidence and future directions. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Radiation dose escalation can improve survival in NSCLC patients but is often limited by adverse effects. One promising radiotherapy modality is proton radiotherapy, which, because of its physical characteristics, delivers minimal exit dose beyond the target volume and thus results in better sparing of normal tissues than does photon radiotherapy. Passive-scattering proton therapy and intensity-modulated proton therapy have shown promise in the treatment of early-stage and locally advanced non-small cell lung cancer. However, more studies are needed to optimize proton therapy, particularly intensity-modulated proton therapy, to address motion and density changes and to guide appropriate patient selection. PMID- 28920299 TI - Prognostic factors for survival in a Chinese population presenting with advanced non-small cell lung cancer with an emphasis on smoking status: A regional, single institution, retrospective analysis of 4552 patients. AB - BACKGROUND: Lung cancer ranks as the top of cancer-related mortality in the world. Approximately 85-90% of all lung cancer cases are non-small cell lung cancer (NSCLC). For advanced NSCLC patients, the five-year survival rate is less than 5%. Previous studies have attempted to determine prognostic factors, such as smoking status, gender, ethnicity, age, and histological type. However, the results are controversial and conflict. In this study, we investigated prognostic factors in a Chinese population presenting with advanced NSCLC. METHODS: Medical records of patients with advanced NSCLC (AJCC Stage IIIB/IV) who received treatment at our institution were reviewed. Kaplan-Meier method and Cox Proportional Hazards model were performed in both univariate and multivariate analyses. RESULTS: A total of 4552 patients were entered. Among them, 1320 (29.0%) were female, 2408 non-smokers (52.9%), and all had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 0/1. Univariate analysis suggested that female gender (P < 0.001), adenocarcinoma histology (P < 0.001), age <70 (P < 0.001), and non-smoker status (P < 0.001) were associated with better survival. However, multivariate analysis demonstrated that age (hazard ratio [HR]= 1.173, 95% confidence interval [CI]: 1.085-1.268, P < 0.001), smoking status (vs. non-smokers, HR = 1.212, 95% CI: 1.123-1.308, P < 0.001), and histological type (non-adenocarcinoma vs. adenocarcinoma, HR = 1.104, 95% CI: 1.031-1.181, P = 0.004), but not gender, were independent prognostic factors. CONCLUSIONS: Smoking status, age, and histological type are independent prognostic factors in Chinese NSCLC patients presenting with advanced disease. Non-smoking status is associated with better overall survival in Chinese NSCLC patients. PMID- 28920300 TI - Prevalence, risk factors and survival of lung cancer in the idiopathic pulmonary fibrosis. AB - BACKGROUND: The aim of this study was to evaluate the prevalence, risk factors, and survival of lung cancer in patients with idiopathic pulmonary fibrosis (IPF). METHODS: IPF with lung cancer from tertiary hospitals consisted of 1685 patients who had been diagnosed between 2003 and 2007. We reviewed their medical records retrospectively to evaluate the prevalence, risk factors and prognosis of lung cancer in IPF patients. RESULTS: Among all patients with IPF, 114 cases (6.8%) had lung cancer with IPF. The incidence of lung cancer in patients with IPF was 1.03 persons per 100 person-year (25 patients/2408 years). Most cases of lung cancer (73/114, 68.9%) were located in IPF-associated areas; the lung cancer typically developed in peripheral and lower lobe areas. The study revealed that forced vital capacity (% predicted) at the initial diagnosis and development of lung cancer were independent prognostic factors in patients with IPF. CONCLUSIONS: Lung cancer in patients with IPF was significantly related with the IPF prognosis. An active evaluation should be performed in patients with IPF to detect lung cancer early. PMID- 28920301 TI - Ultrasound guided fine needle aspiration of a lung mass via a transesophageal approach using endobronchial ultrasound bronchoscope. AB - Diagnostic accuracy, safety and minimal invasiveness are well established advantages of the endobronchial ultrasound (EBUS) technique when used for lung cancer staging. Combining it with transesophageal ultrasound can offer complete mediastinal staging, extending the reach of this technique to lymph node stations that are inaccessible even by mediastinoscopy. Traditionally this has been achieved by arranging a bronchoscopist and gastroenterologist to perform the procedure on two separate occasions using two separate expensive systems. Performing the procedure with a single physician (pulmonologist) using a single scope offers logistical advantages. For this reason, the practice of fine needle aspiration (FNA) via both the transbronchial and transesophageal approach by a pulmonologist using the single EBUS scope has emerged and is likely to grow and become widely accepted in future. The present case reports illustrate the additional applicability of allowing direct puncture of a lung mass using transesophageal FNA done by a pulmonologist using a single EBUS scope as a part of the combined approach. PMID- 28920302 TI - Non-conventional radiotherapy versus conventional radiotherapy for inoperable non small-cell lung cancer: A meta-analysis of randomized clinical trials. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of non-conventional radiotherapy versus conventional radiotherapy for inoperable non small-cell lung cancer and to conduct a meta-analysis to compare these two methods of radiotherapy for inoperable NSCLC. METHODS: We included randomized controlled trials, which were compared with non-conventional radiotherapy with or without concurrent chemotherapy versus conventional radiotherapy with or without concurrent chemotherapy. RESULTS: Meta-analysis of 13 randomized controlled trials with a total of 2206 patients showed that the non-conventional radiotherapy group could significantly improve the objective response rate (OR 1.68, 95% confidence intervals (CI) 1.19-2.37) and overall survival of up to 1 year (OR 1.30, 95% CI 1.09-1.54), 2-year (OR 1.41, 95% CI 1.17-1.70), 3-year (OR 1.55, 95% CI 1.24-1.94), 4-year (OR 1.60, 95% CI 1.20-2.15), 5-year (OR 1.63, 95% CI 1.11-2.38); and local control rate in 1-year (OR 1.35, 95% CI 1.09-1.68), 2 year (OR 1.57, 95% CI 1.23-1.99), 3-year (OR 1.45, 95% CI 1.10-1.91) compared with the conventional radiotherapy group. With regard to the side effects, non conventional radiotherapy was more likely to result in level III and IV radioactive esophagitis (OR 1.64, 95% CI 1.09-2.46), but there was no significant difference in the incidence of radioactive pneumonitis (OR 0.96, 95% CI 0.67 1.39). In the subgroup analysis we found late course accelerated hyperfractionated radiotherapy (LCHRT) could obviously improve 1-year OS (OR 2.29, 95% CI 1.29-4.06), 2-year OS (OR 4.22, 95% CI 2.03-8.77), 3-year OS (OR 2.49, 95% CI 1.24-5.02) and Objective response rate (OR 2.38, 95% CI 1.17-4.83). However, hyperfractionated radiotherapy (HRT) and accelerated hyperfractionated radiotherapy (AHRT) could not improve 1-, 2-, 3-year OS or OR compared with conventional fractionation radiotherapy. CONCLUSIONS: Our findings indicate that NCRT could improve OR, reduce the risk of death by 1-5 years, and significantly increase level III and IV radioactive esophagitis incidence. The late course accelerated hyperfractionated radiotherapy (LCAHRT) group seemed to improve compared with the AHRT and conventional radiotherapy (CRT) groups. PMID- 28920303 TI - Proportion and characteristics of transient nodules in a retrospective analysis of pulmonary nodules. AB - BACKGROUND: Pulmonary nodules manifest as pure or mixed ground glass opacities (GGOs), or solid nodules. METHODS: We retrospectively surveyed 317 cases with pulmonary nodules to observe the proportion and predictive factors of transient lesions in patients with pulmonary nodules. RESULTS: At the initial computed tomography scan, 63.7% showed solid nodules, while 20.2% had mixed GGOs and 16.1% of cases manifested as pure GGOs. Nodules from 114 cases (36%) disappeared or decreased in size during follow up, while in 203 cases (64%), they did not change or became enlarged. During follow up, more than half of the GGOs resolved (66.7% in pure GGOs, 54.7% in mixed GGOs), while only 22.3% of solid nodules resolved. Between transient and persistent pulmonary nodules, significant differences were observed in age, gender, smoking history, presence of eosinophilia, size, and radiologic attenuation of nodules (solid or GGO). In multivariate analysis, age (<=55 years), size of nodules (>15 mm), eosinophilia, and GGO were significant independent predictors of transient nodules. The main causes of transient nodules were pneumonia or eosinophilic pulmonary infiltrates. CONCLUSION: Thirty-six percent of pulmonary nodules resolved spontaneously or with medical treatment. Transient nodules showed different clinical and radiological characteristics from persistent nodules. PMID- 28920304 TI - EBUS and EUS guided fine needle aspirations for molecular diagnostic analysis in lung cancer. AB - In daily clinical practice the diagnosis of lung cancer is often based on cytological specimens. These cytological samples are increasingly obtained by ultrasound-guided techniques with fine needle aspirations. Recent developments have shown that transesophageal ultrasound guided fine needle aspiration (EUS FNA) and endobronchial ultrasound guided transbronchial fine needle aspiration (EBUS-TBNA) are minimally invasive diagnostic and staging procedures that have shown to be highly sensitive and accurate. Although several studies have shown that these cytological samples allow for reliable diagnosis and sub classification of non-small cell lung cancer, cytological samples for molecular analysis are not yet routinely used. In this paper we review the current literature regarding the results of molecular analysis of samples obtained by EUS FNA and/or EBUS-TBNA, focusing on the targets for currently available treatments of non-small cell lung cancer like epidermal growth factor receptor (EGFR), Kirsten rat sarcoma oncogene (KRAS) and Echinoderm microtubule-associated protein like 4 gene anaplastic lymphoma kinase gene translocation (EML4-ALK). We conclude that the cytological samples obtained by endosonography guided fine needle aspirations (EUS and EBUS) are highly accurate for molecular analysis. This analysis can be performed reliably in the vast majority of patients in daily practice. PMID- 28920305 TI - Low-dose endostatin normalizes the structure and function of tumor vasculature and improves the delivery and anti-tumor efficacy of cytotoxic drugs in a lung cancer xenograft murine model. AB - INTRODUCTION: To some extent endostatin normalizes tumor vasculature. However, the optimum time window and optimum drug dose for tumor vascular normalization need to be explored. Here we investigate the effect of low-dose endostatin on the structure and function of tumor vasculature and the delivery and anti-tumor efficacy of cytotoxic drugs. METHODS: A lung cancer xenograft murine model was treated with low-dose endostatin for 10 days. The structure and function of the tumor vasculature were evaluated using various techniques. Paclitaxel was added in different schedules. RESULTS: Endostatin caused a significant reduction in microvessel density. Tumor vascular walls after endostatin treatment were better structured. Tumor blood perfusion was increased on day six after endostatin administration. On days three, six, and 10, Evans blue extravasation into the parenchyma of tumors was decreased. On days three and six, endostatin-treated mice had greater paclitaxel delivery. The time window of vascular normalization was approximately three to six days. On days one to three, and days four to six, combined therapy with paclitaxel significantly inhibited tumor growth. CONCLUSIONS: Low-dose endostatin aids normalization of tumor vasculature. This resulted in improved delivery of cytotoxic drugs to the tumor, which closely correlates with synergistic efficacy when combined with paclitaxel during the normalization window. PMID- 28920306 TI - Comparison of epidermal growth factor receptor mutation analysis results between surgically resected primary lung cancer and metastatic lymph nodes obtained by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: Lung cancers with mutations in the epidermal growth factor receptor (EGFR) gene respond well to treatment with EGFR inhibitors. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is considered a useful modality to obtain samples from the mediastinal and hilar lymph nodes. However, the EGFR gene status of EBUS-TBNA samples may not always match that of primary tumors. METHODS: In 14 node-positive patients diagnosed by EBUS-TBNA, EGFR mutation analysis results were compared between EBUS-TBNA samples and surgically removed primary tumors. EGFR mutation was screened with peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp followed by direct sequence analysis. For one controversial case, gene mutation analyses were performed for the multiple micro-fractions of a metastatic lymph node, which exhibited the heterogeneous immunohistochemical features. RESULTS: EBUS-TBNA diagnosed one case of exon 21 point mutations, one case of exon 19 deletion, and 12 cases of wild-type EGFR. Results were consistent with those of surgically removed primary tumors in 13 of 14 cases. One case of wild-type EGFR diagnosed by EBUS-TBNA exhibited exon 21 point mutation in the surgically removed primary tumor. The metastatic lymph node targeted by EBUS-TBNA mostly consisted of cancer cells with wild-type EGFR; however, a minor component positive for thyroid transcription factor-1 (TTF-1) and surfactant-associated protein A (PE 10) exhibited EGFR mutation. CONCLUSION: The combination of EBUS-TBNA and PNA LNA clamp is useful for EGFR mutation analysis. However, EGFR mutation status in EBUS-TBNA samples may not be consistent with that of the primary tumor when the tumor contains few EGFR mutations. PMID- 28920307 TI - The association between polymorphisms in the DNA nucleotide excision repair genes and RRM1 gene and lung cancer risk. AB - Background Although numerous studies have investigated the association between DNA repair gene variants and lung cancer risk, the results remain inconclusive and incomplete. Methods We examined variants in seven nucleotide excision repair (NER) and RRM1 genes in association with primary lung cancer risk among 385 patients with newly diagnosed primary non-small cell lung cancer and 208 cancer free controls collected from 2007 to 2009 in east China. The relationship between single nucleotide polymorphisms and risk of lung cancer was assessed by logistic regression and stratification analysis. Results The rs17655GG (ERCC5) and rs5744751CT (POLE) were associated with increased risk of lung cancer (adjusted odds ratio [OR], 2.32, 95% confidence interval [CI], 1.41-3.83; adjusted OR, 2.84, 95% CI, 1.70-4.74]. In stratification analysis, we found the increased effect of rs17655GG on the risk of lung cancer was observed among female, older subjects, or non-smokers. The heterozygote computed tomography (CT) of rs5744751 had a stronger unprotective effect on lung cancer among male, older subjects, or heavy smokers. Conclusion These results suggest that rs17655GG and rs5744751CT may be associated with lung cancer susceptibility in the Chinese population. However, these findings still need to be verified in larger confirmatory studies. PMID- 28920308 TI - Screening and identification of lung cancer metastasis-related genes by suppression subtractive hybridization. AB - BACKGROUND AND OBJECTIVE: Lung cancer metastasis is a complicated process in which multiple stages and multiple genes are involved. There is an urgent need to use new molecular biology techniques to get more systematic information and have a general idea of the molecular events that take place in lung cancer metastasis. The object of this study was to construct the subtracted cDNA libraries of different metastatic potential lung cancer cell lines, NL9980 and L9981, which were established and screened from human lung large cell carcinoma cell line, WCQH-9801. METHOD: The forward and reverse subtracted cDNA libraries were constructed in the large cell lung cancer cell lines NL9980 and L9981 with the same heredity background but different metastatic potential, by suppression subtractive hybridization (SSH). The positive clones were preliminarily screened by blue-white colony and precisely identified by PCR. The forward and reverse subtracted libraries were screened and identified by dot blot so as to obtain the clones corresponding to gene segments with differential expression. DNA sequencing was performed to analyze the sequences of differential expression segments, which were then searched and compared using the Basic Local Alignment Search Tool from The National Center for Biotechnology Information NCBI BLAST tools. Quantitative real-time reverse transcription polymerase chain reaction (RT PCR) and western blotting were performed to confirm the differential expressed genes both on RNA and protein levels. RESULTS: The forward and reverse subtracted cDNA libraries of the different large cell lung cancer cell lines with metastatic potential were successfully constructed. With blue-white colony and dot blot, 307 positive clones in the forward subtracted library and 78 positive clones in the reverse subtracted library were obtained. Fifty-five clones were successfully sequenced in the forward subtracted library while 31 clones were successfully sequenced in the reverse subtracted library. One new expressed sequence tag (EST) segment was identified from the reverse subtracted cDNA library and was successfully submitted to GenBank and embodied by GenBank. For the differentially expressed genes between L9981 and NL9980 screened by SSH, four genes, ANXA2, KRT18, ACTG1 was upregulated in L9981 cells compared to NL9980 cells. Annexin A2 (which was encoded by ANXA2), gamma-actin (which was encoded by ACTG1), and aldose reductase (which was encoded by AKR1B1) proteins were upregulated in L9981 cells compared to NL9980 cells by western blotting. CONCLUSION: The forward and reverse subtracted cDNA libraries of different metastatic potential large cell lung cancer cell lines were successfully constructed by SSH. A series of genes have been screened out to have significantly different expression levels between lung cancer cell lines NL9980 and L9981. A new EST segment that may represent a new metastasis-related gene has been identified. Consistent with the result of SSH, both quantitative real-time RT-PCR and western Blotting confirmed the upregulation of ANXA2, ACTG1 and AKR1B1 in lung cancer cell line L9981 compared with NL9980. These three genes may play important roles in lung cancer metastasis. PMID- 28920309 TI - Association between the ATF3 gene and non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for ~85% of all cases of lung cancer and has a poor prognosis. Activating transcription factor 3 (ATF3), a member of the ATF/cyclic adenosine monophosphate response element binding (ATF/cyclic response element binding) family of transcription factors, has been implicated in the pathogenesis of several types of cancer. However, whether the expression of ATF3 is aberrant in NSCLC and genetic variants, or DNA methylation of the gene contributes to the tumorigenesis of NSCLC, are largely unknown. METHODS: The expression of ATF3 in four NSCLC cell lines and normal human bronchial epithelial cell (HBEpiC) line was detected by Western blot analysis. The mutation of the 5'-flanking 1500-bp and coding sequence regions of the ATF3 gene were screened using DNA direct sequencing, and bisulfite-sodium modification sequencing was used to detect the promoter methylation status of the gene. RESULTS: up-regulated expression of ATF3 was observed in NSCLC cell lines, and there was no difference in the sequence regions of the ATF3 gene between NSCLC cells and HBEpiC cells, which were validated in lung cancer tissues and their corresponding paracarcinoma tissues. CONCLUSION: Our findings suggest that the tumorigenesis of NSCLC may particularly attribute to increased expression of ATF3 but not the genetic variants of the gene. PMID- 28920310 TI - The 12th National Lung Cancer Academic Conference in China. AB - BACKGROUND: The 12th National Lung Cancer Academic Conference was held in Wu Han, China in 2011. METHODS: The content of the conference involved recent research achievements and progress in the field of lung cancer, including the epidemiology of lung cancer and molecules, new methods and technology for early screening, molecular biology, pharmacogenomics, pathological and medical imaging, "individual therapy" based on molecular markers, surgery, radiation therapy, chemical treatment, and molecular target therapy. The theme of the Conference was "A focus on the quality of life of lung cancer patients in order to optimize individual treatment therapy." RESULTS: Many highly-respected domestic and foreign lung cancer expert specialists reported the latest achievements of their original clinical multi-center studies and clinical convert research work, as well as their prospective study results in the field of lung cancer basic and clinical research, including the complete revelation of lung cancer basic research in China, the latest results in clinical transformation, clinical treatment experience, and scientific research achievements. CONCLUSION: The conference substantially influenced China's future basic and clinical research on lung cancer, and contributed to the improvement of diagnostic and therapeutic levels on lung cancer in China. PMID- 28920311 TI - Prognostic impact of cell type under the seventh TNM staging system in resected non-small cell lung cancer. AB - OBJECTIVES: We retrospectively investigated whether histological cell type could affect patient prognosis for each stage according to the seventh edition of the TNM classification. PATIENTS AND METHODS: Clinical records of 1623 consecutive non-small cell lung cancer patients who underwent surgery between 1990 and 2007 were retrospectively reviewed. Over 92% of these patients had either adenocarcinoma (Ad; n = 1043, 64.3%) or squamous cell carcinoma (Sq; n = 452, 27.9%). RESULTS: The overall 5-year survival rates for patients of all stages with Ad, Sq, large cell carcinoma (La), and adenosquamous cell carcinoma (As) were 67%, 56%, 58%, and 41%, respectively. Ad patients experienced better survival than Sq, As, or La patients (HR: 0.66, P < 0.0001; HR: 0.38, P = 0.011; HR: 0.69, P = 0.057, respectively). Stage IA Ad patients experienced better survival than stage IA Sq patients (5-year survival; Ad/Sq = 91%/78%, log-rank test, P = 0.001). Such a difference was also observed among seventh-edition TNM stage IB patients (5-year survival; Ad/Sq = 78%/64%, log-rank test, P = 0.048), but not for sixth-edition stage IB patients. Multivariate analysis demonstrated that histological cell type is a significant prognostic factor among stage I >= T1b Ad and Sq patients. CONCLUSIONS: Survival after complete resection of new stage I >= T1b Sq patients is significantly worse than that of Ad patients, which could be partially attributed to stage migration effect in stage IB disease between the sixth and seventh editions of the TNM staging system. PMID- 28920312 TI - Solitary rectal metastasis from primary small cell lung carcinoma. AB - Lung cancer may rarely appear with a solitary rectal metastasis and no other metastases. We report the first case of primary small cell lung cancer presenting with a solitary rectal metastasis in a 62-year-old man. Chest computed tomography revealed a soft tissue lesion in the subcarinal area. Following bronchoscopic biopsy, the patient was diagnosed with small cell lung cancer. The rectal mass was incidentally found during an imaging study for staging work-up. Histological examination revealed that the rectal mass was consistent with metastasis from small cell lung cancer. We suggest that clinicians should consider the possibility of rectal metastasis in small cell lung cancer patients with rectal masses. PMID- 28920313 TI - Prognostic value of metabolic volume measured by F-18 FDG PET-CT in patients with esophageal cancer. AB - PURPOSE: The aim of this study was to evaluate the usefulness of the metabolic tumor volume (MTV) measured by F-18 Fluorodeoxyglucose positron emission tomography (FDG PET-CT) in predicting recurrence free survival (RFS) in patients with esophageal cancer. METHODS: Forty-five patients with squamous cell carcinoma, who had undergone whole-body F-18 FDG PET-CT scans before surgical resection, were included in this study. All patients were treated with Ivor-Lewis esophagectomy. The MTV was quantified within the primary tumor using the 50% threshold of the maximum standardized uptake value (SUVmax ) of the FDG uptake areas. The cutoff value of MTV50 was determined through receiver-operating characteristic curve. The Kaplan Meier method was used to find out the relationship between RFS and MTV50 . Univariate analysis and multivariate proportional hazards regression analysis were applied to test the significance of volumetric parameter of F-18 FDG PET-CT and other conventional prognostic factors for the prediction of RFS. RESULTS: Overall median follow up period was 17.87 months (range: 1.07-63.27 months). The median survival between treatment completion and recurrence was 15.5 months (range: 1.37-72.43 months). Recurrence was found in eight patients. On univariate analysis, MTV50 (P = 0.0032), N stage (P = 0.0004), American Joint Committee on Cancer stage (P = 0.0101), tumor location (P = 0.0054) and adjuvant treatment (P = 0.0373) were significant predictors of RFS. Multivariate analysis showed that the independent prognostic factors were MTV50 (P = 0.0465), N stage (P = 0.0303) and tumor location (P = 0.0270). CONCLUSION: Volume based parameter of F-18 FDG PET-CT may have a role in providing prognostic information in esophageal cancer patients who received esophagectomy. PMID- 28920314 TI - Lung cancer incidence and mortality in China, 2008. AB - BACKGROUND: To provide cancer statistics to health planners, researchers, and the public, we reported the incidence and mortality data of lung cancer in 2008 in Chinese registration areas by age, sex, and geographic area. METHODS: In 2011, 56 population-based cancer registries reported the lung cancer incidence and mortality data of 2008 to the Chinese National Central Cancer Registry. Forty one registries' data met the national criteria. The crude incidence and mortality rates of lung cancer were calculated by age, gender, and area. Age-standardized rates were calculated using the Chinese and World populations. RESULTS: The crude incidence rate for lung cancer was 54.75/100 000 (73.12/100 000 for male and 36.08/100 000 for female; 57.96/100 000 in urban and 42.80/100 000 in rural). Age-standardized rates by China population (CASR) and World population (WASR) for incidence were 24.98/100 000 and 34.07/100 000, respectively. The crude mortality rate for lung cancer was 46.07/100 000 (62.47/100 000 for male and 29.39/100 000 for female; 48.76/100 000 in urban and 36.03/100 000 in rural). The CASR and WASR for mortality were 20.09/100 000 and 27.68/100 000, respectively. Both for incidence and mortality, the rates for lung cancer were higher in males than in females, and in urban areas than in rural areas. The overall age-specific incidence and mortality rates showed that both rates were relatively low up to 35 years of age, but dramatically increased from such age, reaching a peak with subjects of 80-84 years old. CONCLUSION: The burden of lung cancer remains high in China, especially for males in urban areas. Effective intervention, such as smoking control, should be enhanced in the future. PMID- 28920315 TI - Video-assisted thoracoscopic surgery versus posterolateral thoracotomy lobectomy: A more patient-friendly approach on postoperative pain, pulmonary function and shoulder function. AB - We evaluated the physiological benefits following video-assisted thoracoscopic surgery (VATS) lobectomy or posterolateral thoracotomy (PLT) lobectomy for lung cancer patients. One hundred and three patients were included in this study, who underwent either a VATS approach (n= 51) or a PLT approach (n= 52) lobectomy for clinical stage I lung cancer. Pain scores were measured preoperatively and on postoperative day (POD) one, three, seven, 30, and 90, by using a visual analog scale. Pulmonary function and shoulder function were measured preoperatively and on POD seven, 30 and 90 by using a portable spirometer and by the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form, respectively. Postoperative pain was experienced less in the VATS group than in the PLT group on POD one, three, seven, 30, and 90 (P= 0.060, 0.055, 0.000, 0.000, 0.000, respectively). Analgesic requirements were significantly less in the VATS group than in the PLT group during hospital stay (90.2 +/- 60.8 mg vs. 119.2 +/- 70.8 mg, P= 0.028). The pain score returned to the preoperative reference level on POD seven in the VATS group, but not until POD 30 in the PLT group. The recovery of forced vital capacity (FVC) was statistically better in the VATS group on POD seven, postoperative month (POM) one, and POM three (P= 0.000, 0.000, 0.002, respectively). The recovery of forced expiratory volume in 1 second (FEV1) was better in the VATS group, but the differences were not significant. The shoulder function in the VATS group was significantly well preserved on POD seven, 30 and 90, compared with the PLT group. Lobectomy by the VATS approach generates less pain, and preserves better pulmonary function and shoulder function in the early postoperative phase. PMID- 28920317 TI - Endoscopic ultrasound bronchoscope-guided fine needle aspiration (EUS-B-FNA). PMID- 28920316 TI - Angiopoietin 2 levels in serum and bronchial lavage fluids and their relationship with cancer stages in lung cancer patients. AB - BACKGROUND: Angiopoietin 2 (Ang-2) has an important role in tumor angiogenesis. In this study, Ang-2 levels of serum and bronchioloalveolar lavage fluids (BALF) in patients with lung cancer were measured and correlated with clinical and biochemical parameters. METHODS: Thirty-five cases newly diagnosed with lung cancer and 18 controls with non-cancerous lung diseases were included in the study. Tumor histology, staging, metastasis, tumor markers, biochemical and clinical parameters were all recorded. RESULTS: Serum Ang-2 levels were significantly higher in the lung cancer group compared to the control (lung cancer median: 2.42 ng/mL [2.19-2.98], control 0.67 [0.31-1.10]; P < 0.001), whereas Ang-2 levels in BALF were lower in the lung cancer group compared to the control (lung cancer median 0.41 ng/mL [0.22-0.79], control 0.67 [0.46-1.03]; P = 0.02). In the cancer group, higher serum Ang-2 levels (r = 0.52, P < 0.001) were associated with the stage of cancer. No significant correlation was observed between BALF Ang-2 levels and non-small cell lung cancer stages and small-cell lung cancer advanced stage (P = 0.793, r = 0.07). Serum Ang-2 levels were significantly higher in distant metastasis (M1) versus no distant metastasis (M0) (M1: 2.57 ng/mL [2.38-2.87], M0: 2.22 [1.49-2.40], P = 0.01). No significant correlation was observed between BALF Ang-2 levels and M1 (r = 0.11, P = 0.53). CONCLUSIONS: Serum Ang-2 levels were significantly higher in lung cancer patients and positive correlations were observed between serum Ang-2, tumor stage, and metastasis. PMID- 28920318 TI - A thoracic surgeon's perspective on the elastofibroma dorsi: A benign tumor of the deep infrascapular region. AB - BACKGROUND: An elastofibroma is a benign, soft-tissue tumor and is important in the differential diagnosis of thoracic wall masses. Here, patients with elastofibromas who underwent thoracic surgery were retrospectively reviewed to elucidate elastofibroma formation and to facilitate the differential diagnosis. METHODS: This is a retrospective and descriptive study of a series of 30 patients with elastofibroma dorsi. The data was obtained by review of the hospital records. RESULTS: There were 27 female and three male patients (mean age, 55.13 +/- 8.7 years) with a total of 42 elastofibroma dorsi tumors (12 bilateral cases, 18 unilateral cases) diagnosed between January 2004 and October 2011. Twenty patients (67%) underwent surgery as a result of subscapular swelling and pain. In 10 (33%) asymptomatic patients, elastofibromas were found incidentally during a thoracotomy. Imaging methods in symptomatic patients included computerized tomography (15 cases), magnetic resonance (three), and ultrasonography (two). For five patients, fluorodeoxyglucose uptake values were available and revealed mild metabolic activity in the elastofibromas. Elastofibromas were significantly larger in symptomatic patients (8.15 +/- 1.9 vs. 6.2 +/- 2.3; P= 0.02). Exposure to long-term repetitive micro-trauma was a precipitating factor in 23 (77%) patients. Seroma formation, the most common surgical complication, was observed in 40% of patients. CONCLUSION: The differential diagnosis of elastofibroma dorsi is straightforward, and preoperative histology is unnecessary when the clinical, radiological, and metabolic characteristics are known. Repetitive micro-trauma may predispose to hyperproliferation of fibroelastic tissue, and genetics may also play a role. Surgical treatment can be reserved for cases with severe symptoms. PMID- 28920319 TI - Diagnostic value of autofluorescence bronchoscopy in lung cancer. AB - The role of autofluorescence bronchoscopy (AFB) was primarily investigated in regard to the detection of precancerous lesions of bronchial mucosa. Most of the results confirmed higher sensitivity for the detection of precancerous bronchial lesions, when compared to white light bronchoscopy (WLB) alone. However, it is commonly known that the specificity of AFB remains low. Our findings agree in terms of the detection of premalignant bronchial lesions and early lung cancer, but regarding the detection of synchronous lesions or in the evaluation of lung cancer extension, the specificity of AFB is significantly higher. There is still an ongoing debate in the scientific community whether or not autofluorescence should be used as a screening tool for lung cancer. Results of the majority of published series did not support the general use of AFB as a screening tool for lung cancer; however, these results suggest its use in groups of patients with a high risk of lung cancer. Despite this, some authors still do not recommend its use even in high-risk cases. In recent years, the indications for AFB have been widening and this tool may find its place in routine bronchoscopy. With new indications for AFB, such as the evaluation of tumor extension or follow up after surgical resection, bronchoscopists may make use of this tool more often. A sharp learning curve and a clear distinction between healthy and pathologically altered mucosa make this technology acceptable for inexperienced bronchoscopists. We also investigate new hardware and software improvements in AFB. The addition of backscattered light analysis, ultraviolet spectra, fluorescence-reflectance or dual digital systems could improve the diagnostic yield of this technology. PMID- 28920320 TI - Fistula to the native esophagus after pharyngogastrostomy for malignant disease: A rare phenomenon in esophageal surgery. AB - This article features the case study of a 32-year-old female patient who had undergone surgery to remove a cervical spine tumor and who later developed cervical esophagus necrosis secondary to the erosion caused by an osteosynthesis 13 years after her prosthetic cervical surgery. Barium swallow did not show anything abnormal, but after an emergency spiral computerized axial tomography (CAT) scan, a paravertebral abscess was found, along with displacement of the fixation plate and the disappearance of the esophageal silhouette on coronal sections. The patient underwent surgery to drain the abscess, extract the osteosynthesis materials and the stabilization plates, and to perform a temporary esophageal exclusion. Two months after this surgery the esophagus was reconstructed by performing a retrosternal pharyngogastrostomy without resection of the remaining cervicothoracic esophagus due to severe fibrosis and the absence of local recurrence. During the immediate post operatory period the patient developed a cervical fistula and after a month of conservative treatment, severe dysphagia was observed. Imaging tests showed a spontaneous fistula from the pharynx to the native esophagus, which prompted extraordinary treatment. Therefore, a jejunal loop was taken to the esophagus in the hiatus with a Roux-en Y anastomosis to resolve this condition. PMID- 28920321 TI - Safety and efficacy of paclitaxel liposome for elderly patients with advanced non small cell lung cancer: A multi-center prospective study. AB - BACKGROUND: Lung cancer in elderly patients poses an increasingly challenge for oncologists. The optimal treatment needs to be explored. The purpose of this study was to evaluate the safety and efficacy of the novel form of paclitaxel liposome for elderly patients with non-small cell lung cancer (NSCLC). METHODS: This multi-center prospective trial recruited patients aged at least 70 years with advanced or recurrent NSCLC. Eligibility criteria included presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 2, as well as adequate organ function. Patients received paclitaxel liposome at the escalating dose of 135 mg/m2 , 150 mg/m2 and 175 mg/m2 every three weeks. RESULTS: Forty-two patients were enrolled with a median age of 73 years (range 70-81). No complete response was observed. Partial response was obtained in 6.7%, 14.2% and 7.7% of patients, and 13.3%, 42.9% and 38.5% had stable disease from the three dose groups. In these groups, 26.7%, 21.4% and 25% of patients experienced grade 3-4 neutropenia. Time to progression was 1.2 months (95% confidence interval [CI], 1.1-1.3 months), 1.2 months (95% CI, 0.9-1.3 months) and 1.9 months (95% CI, 1.4-2.3 months), respectively. Overall survival in the dose group of 135 mg/m2 was 4.9 months (95%CI, 1.0-11.5 months) and was not reached in the other two groups. CONCLUSIONS: Paclitaxel liposome administered at the dose of 150 mg/m2 every three weeks was the safest and most effective of the three dose levels. However, the treatment achieved only mild effects. It was unnecessary to conduct further phase III randomized trials on this topic. PMID- 28920322 TI - Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: A single institution experience. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a relatively rare, aggressive neoplasm associated with asbestos exposure. Extrapleural pneumonectomy (EPP) is often performed for resectable MPM as part of a multidisciplinary treatment; however, available data on treatments for recurrence after EPP are limited. METHODS: The clinical records of consecutive MPM patients who underwent EPP at our institution from 2001 to 2010 were retrospectively reviewed. There were 10 patients who underwent EPP with or without perioperative chemotherapy; of these, recurrence was observed in eight patients. RESULTS: The overall median survival time and time to recurrence were 49.6 months and 15.4 months, respectively, after EPP. The first recurrence occurred within the ipsilateral thorax in four patients. These patients all underwent local treatments for their recurrence, including surgery or radiotherapy and with or without systemic chemotherapy. Other first recurrences were seen in the peritoneal space of two patients and in the contralateral lung of two patients. These patients received platinum-based systemic chemotherapy for their recurrence. The median survival time after the first recurrence was 17.8 months, and the 2-year survival rate was 23.4%. CONCLUSIONS: Most patients who underwent EPP developed tumor recurrences. Direct tumor extension may be a major mechanism of recurrence. Aggressive treatment for recurrent MPM after EPP, including locoregional control and/or systemic chemotherapy, was important for achieving long-term survival. PMID- 28920323 TI - nm23-H1 gene driven by hTERT promoter induces inhibition of invasive phenotype and metastasis of lung cancer xenograft in mice. AB - BACKGROUND: Lung cancer is the leading cause of cancer death in both men and women worldwide. Tumor metastasis is an essential aspect of lung cancer progression and patient death. The nm23-H1 gene has been extensively investigated as a metastasis suppressor gene. Our previous studies have revealed: that a significant relationship exists between the low-level expression nm23-H1 in primary non-small cell lung cancer (NSCLC) with increased metastasis and a poor prognosis; that L9981-nm23-H1 cells (a nm23-H1 transfactant cell) exhibited lower cell proliferation rates, more G0/G1 phase growth, and an increase in apoptosis with a dramatic decrease in the tumor cells' ability to invade than L9981 cells did; and that L9981- nm23-H1 cells also demonstrated a significantly reduced lymph node and distant metastatic capacity in vivo than L9981 cells did in nude mice. METHODS: In this study, we construct a plasmid containing the nm23-H1 gene, which was driven by the human telomerase reverse transcriptase (hTERT) promoter. We evaluated the anti-invasion and anti-metastatic effects of pGL3-hTP-nm23 on L9981, a human large cell lung cancer cell line with nm23-H1 negative expression, by transwell assay in vitro and bioluminescence in nude mice models. The toxicity of pGL3-hTP-nm23 and its effects on tumor growth were evaluated in nude mice models after gene therapy. The cell cycles, apoptosis, and proliferation of the nm23-H1 transfactant were also detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT assay) and flow cytometry (FCM). RESULTS: The results showed that the hTERT-promoter dramatically drives nm23-H1 gene expression, and induces inhibition of cell growth and migration in L9981-luc cells and MRC-5 cells in vitro. nm23-H1 also significantly inhibited the tumorigenesis and distant metastasis of L9981-luc cell in vivo. Moreover, no obvious side effect was detected in normal mouse tissues after intratumoral injection of the vector. CONCLUSION: The treatment of the nm23-H1 gene driven by hTERT promoter appears to be a promising approach for the gene therapy of nm23-H1 low-expressed tumors. PMID- 28920324 TI - Unique case of combined stage Ia atypical carcinoid, large cell neuroendocrine carcinoma and adenocarcinoma of the lung. PMID- 28920325 TI - Influence of patient characteristics on survival following treatment with helical stereotactic body radiotherapy (SBRT) in stage I non-small-cell lung cancer. AB - BACKGROUND: To determine the influence of patient and tumor characteristics on clinical outcomes in patients with early-stage non-small cell lung cancer (NSCLC) treated with helical intensity modulated stereotactic body radiotherapy (SBRT). METHODS: From March 2005 to August 2010 a total of 62 patients with biopsy proven Stage I NSCLC underwent helical SBRT with 48 Gy in 4 fractions or 60 Gy in 5 fractions. Patient and tumor characteristics including tumor stage, age, sex, tumor histology, maximal tumor diameter, and smoking history, were evaluated in regard to local control and overall survival using Kaplan-Meier survival curves and the Cox proportional hazard method. Treatment related toxicity in the patient subgroups was evaluated. RESULTS: The median follow-up was 28 months. Total cohort local control was 93.55% and 3-year overall survival (OS) was 53.4%. Those patients with Stage IA disease had a 3-year OS of 64.4% versus 32.1% for Stage IB disease (P = 0.042). Tumors classified as T1a (<=20 mm) and T1b (20-30 mm) had significantly increased overall survival compared to T2 (>30 mm) tumors (P = 0.046). There was a slight survival advantage in those patients with adenocarcinoma. No correlation between age, gender or smoking history, and overall survival was found. Nine patients had radiation related toxicity, which was increasingly more common with advancing age. CONCLUSION: Helical SBRT is an effective method to treat NSCLC and the most significant prognostic factors were tumor stage and size. There was no correlation between age, gender, and smoking history. PMID- 28920326 TI - Management of malignant pleural effusion: Options and recommended approaches. AB - There is no consensus on the best management of symptomatic malignant pleural effusion. Drainage with a small bore pleural catheter is preferred over a wide bore catheter or recurrent pleural aspiration in patients with symptomatic malignant pleural effusion, for equivalent efficacy and patient comfort. If resources allow, chemical pleurodesis under thoracoscopy, with talc as sclerosant, is preferred for fully expanded lung over bedside chemical pleurodesis in fit patients. A chronic indwelling catheter is an alternative. Controversy exists over the use of chemical pleurodesis or a long term indwelling catheter as the first line management of choice of malignant pleural effusion. Pleural effusion in the entrapped lung scenario is a problematic situation. Pleuroperitoneal shunting or decortication procedures are out of favor as they are more invasive and present more complications. Management algorithm is recommended based on the current data. PMID- 28920327 TI - Anterior mediastinal cystic seminoma. AB - Mediastinal cystic seminoma is uncommon; only 17 cases have been reported, most diagnosed postoperatively, without recurrence on follow-up, even without radiotherapy. Here, we report a mediastinal seminoma showing a unilocular cyst with enhancing thickened wall in computed tomography (CT) and septal structures in magnetic resonance imaging (MRI) in a 24-year-old man. Fluorodeoxyglucose (FDG) uptake was not significant. Histopathologically, seminoma cells were found scattered in the cyst wall. Twenty months after resection, the patient's quality of life is good, without chemotherapy or radiation. Cystic seminoma has a good prognosis and complete resection without adjuvant therapy might be sufficient for young patients of reproductive age. PMID- 28920328 TI - Incidence and mortality of breast cancer in China, 2008. AB - BACKGROUND: Female breast cancer incidence and mortality data for the duration of 2008, in China, retrieved from the National Central Cancer Registry, was analyzed. METHODS: In 2008, there were 56 registries that submitted cancer registration data. Based on the criteria of data quality, a total of 41 registries' data met the requirement and were accepted for analysis. The incidence and mortality rates of breast cancer in females were calculated, including age specific rates, age-standardized rates, proportions, and cumulative rates, stratified by areas (urban/rural). RESULTS: The number of cases included from 41 registries was 66 138 784, with 32 798 187 of these cases found in women (25 898 251 in urban areas and 6 899 936 in rural areas). There were 15 625 new cases reported and 3414 deaths of women with breast cancer, resulting in a mortality to incidence ratio of 0.22. The morphological verified rate was 91.96%, and 0.43% of cases were identified by death certificate only. The crude cancer incidence rate in all areas was 47.64/100 000, and the Age-Standardized Incidence Rates by Chinese standard population, (ASIRC) and World standard population (ASIRW) were 25.26/100 000 and 31.71/100 000, respectively. The cumulative incidence rate (0-74 years old) was 3.44%. Both crude and adjusted incidence rates in urban areas were much higher than those in rural areas. The crude cancer mortality was 10.41/100 000, and the Age-Standardized Mortality Rates by Chinese standard population (ASMRC) and by World population (ASMRW) were 4.90/100 000 and 6.48/100 000, respectively. The cumulative mortality rate (0-74 years old) was 0.071%. Age-adjusted mortality rates in urban areas were also higher than in rural areas. Age specific incidence rates peaked in age group 50-54 in all areas (108.27/100 000) and in urban areas (119.68/100 000). It reached the peak in the 55-59 age group for rural women. Age specific mortalities rose with the increase of age for both women in urban and rural areas, with mortality rates of 76.16/100 000 and 23.73/100 000 in age groups of 85 and above, respectively. CONCLUSIONS: Breast cancer is the most common cancer diagnosed in Chinese women. Preventative measures, such as health education and screening, are needed in the general population, but especially for those in the high-risk group found in urban areas. PMID- 28920329 TI - Rapid destruction of the tracheal rings and development of a huge cavity in the lung. PMID- 28920330 TI - [Oligopeptides in plant medicines cited in Chinese Pharmacopoeia]. AB - In total, 23 plant plant medicined containing oligopeptides were cited in Chinese Pharmacopoeia (1 part) of 2015 version including Rubia cordifolia, Linum usitatissimum, Aster tataricus, Psammosilene tunicoides, Pseudostellaria heterophylla, Stellaria dichotoma, Vaccaria segetalis, Dianthus superbus, Celosia argentea, Lycii Cortex, Citrus medica, C. aurantium, Panax ginseng, Parmx notoginseng, Schisandra chinensis, Sparganium stoloniferum, Euryale ferox, Ophiopogon japonicas, Pinellia ternate, Achyranthes bidentata, Physalis alkekengi, Polygonatum odoratum, and Leonuri Fructus. There were 187 oligopeptides in plant medicines above as reported. Oligopeptides consisted mainly of linear peptides and cyclic peptides. The linear peptides included dipeptides, tripeptides and pentapeptides, and cyclic peptides included cyclic, bicyclic and tricyclic peptides. The number of residues of single cyclic peptides ranged from two to twelve. Bicyclic peptides were isolated mainly from R. cordifolia and C. argentea. Modern pharmacological study showed that oligopeptides had many pharmacological effects, including antitumor, anticoagulant, antibacterial, immune suppression and so on. PMID- 28920331 TI - [Prospecting application of CRISPR/Cas9 genome editing technology in research of medicinal plants]. AB - CRISPR/Cas9 genome editing technology is a newly discovered genome editing technology in recent years.It has been widely used in many fields such as gene therapy, gene function research, animal model-making,cropvariety improvement and so on. This article briefly introduces the CRISPR/Cas9 genome editing system, and discusses its potential applications in the research of medicinal plants, including functional genomics studies, secondary metabolism and synthetic biology research of important active components and molecular breeding research. CRISPR/Cas9 genome editing technology provides a new method for the research of medicinal plants. PMID- 28920332 TI - [Advance in study on hepatoprotective effects and its mechanism of polysaccharides]. AB - Liver damage is the pathologic status in the liver system, which can lead to cirrhosis, fibrosis and cancer of the liver. So to search for effective drugs on prevention and treatment of anti-hepatic lesion have already attracted broad concern in the world. Polysaccharides widely exist in plants, microorganisms and animals, and have high efficiency but low toxicity properties. Therefore, polysaccharides had been the hotspot in the research field of liver-protecting medicines, and had undergone great progresses. In this study, the hepatoprotective effects and its mechanism of polysaccharides were summarized and reviewed, and the market prospects of development and application were prospected. The research result indicated that polysaccharides derived from plants, microorganisms, animals which had significant effects on liver protection. Results also showed that polysaccharides showed the protective effect on chemical liver injury by anti-oxidation, alleviating calcium overload, adjusting the function of mitochondria, and the protective effect on immune liver injury by regulating cytokine secretion, blocking the complement system activity, inhibiting inflammatory mediator expression, suppressing hepatocyte apoptosis. Polysaccharides had rich resource, diverse bio-effects, abundance approaches and multitarget. Therefore, there is huge potential for developing polysaccharides as novel hepatoprotective medicine candidates. PMID- 28920333 TI - [Research progress of ellagitannin intestinal metabolite urolithins]. AB - Ellagitannins is a kind of phenolic compounds with many biological activities. Recent studies have found that the effective ingredients of these compounds have close relationship with their colon-derived bacteria metabolites, that is urolithins. The objective of this study was to review the structure characteristics, types and distribution of urolithins, improvement in diseases related to prostate, breast and colon, as well as anti-cancer, anti-oxidation, anti-inflammation and other biological activities. The present review will lay the foundation for development and utilization of urolithins. PMID- 28920334 TI - [Suitable investigation method of exploration and suggestions for investigating Chinese materia medica resources from wetland and artificial water of Hongze Lake region]. AB - According to the technology requirements of the fourth national survey of Chinese Materia Medica resources (pilot), suitable investigation method of exploration and suggestions for investigating Chinese Materia Medica resources was proposed based on the type of wetland and artificial water of Hongze Lake region. Environment of Hongze Lake and overview of wetland, present situation of ecology and vegetation and vegetation distribution were analyzed. Establishment of survey plan, selection of sample area and sample square and confirmation of representative water area survey plan were all suggested. The present study provide references for improving Chinese materia medica resources survey around Hongze Lake, and improving the technical specifications. It also provide references for investigating Chinese Materia Medica resources survey on similar ecological environment under the condition of artificial intervention. PMID- 28920335 TI - [Cloning and expression analysis of a tyrosine decarboxylase gene from Rehmannia glutinosa]. AB - Tyrosine decarboxylase (TyrDC) is an important enzyme in the secondary metabolism of several plant species, and was hypothesized to play a key role in the biosynthesis of phenylethanoid glycosides. Based on the transcriptome data, we cloned the full-length cDNA (GenBank accession NO. KU640395) of RgTyDC gene from Rehmannia glutinosa, and then performed bioinformatic analysis of the sequence. Further, we detected the expression pattern in different organs and hair roots treated with four elicitors by qRT-PCR. The results showed that the full length of RgTyDC cDNA was 1 530 bp encoding 509 amino acids. The molecular weight of the putative RgTyDC protein was about 56.6 kDa and the theoretical isoelectric point was 6.25. The RgTyDC indicated the highest homology with Sesamum indicum SiTyDC and Erythranthe guttata EgTyDC, both of them were reached 88%. RgTyDC highly expressed in R. glutinosa leaf, especially in senescing leaf, and rarely expressed in tuberous root. After the treatment of SA and MeJA, the relative expression level of RgTyDC mRNA was substantially increased. The results provide a foundation for exploring the molecular function of RgTyDC involved in phenylethanoid glycosides biosynthesis. PMID- 28920336 TI - [Study on relationship between effective components and soil enzyme activity in different growth patterns of Panax ginseng]. AB - Study on 5 effective components and 6 soil enzyme activities of 2 different growth patterns, analyse the dates with the canonical correlation analysis, In order to reveal the relations between the effective components and soil enzyme activities. The result showed that they had a great relation between the effective components and soil enzyme activities, the activity of the same enzyme in humus soil was higher than that in farmland soil. Growth pattern of farmland soil, if the invertase and phosphatase activity were too high, which would inhibit the accumulation of total ginsenoside, water-miscible total proteins and total amino acid; Growth pattern of humus soil, if the invertase, urease and phosphatase activity were too high, which would inhibit the accumulation of total ginsenoside and the total essential oils. Integral soil enzyme activity can be used as a index of soil quality, which, together with other growth factors. The appropriate enzyme activity can accelerate the circulation and transformation of all kinds of material in the soil, improve effectively components accumulation. PMID- 28920337 TI - [Ecological basis of epiphytic Dendrobium officinale growth on cliff]. AB - In order to make Dendrobium officinale return to the nature, the temperature and humidity in whole days of the built rock model with different slopes and aspects in the natural distribution of wild D. officinale in Tianmu Mountain were recorded by MH-WS01 automatic recorder. The results showed that the slope has a significant impact on the extreme temperature on the surface of the rocks. In summer, the extreme temperature on the surface of horizontal or soft rock can reach to 69.4 C, while the temperatures were lower than 50 C on the vertical rock. In winter, the temperatures on the surface of vertical rock were higher and the low temperature duration was shorter than those on the horizontal or soft rock. Also, the humidity of the rocks was significantly influenced by the slope. The monthly average humidity on the surface of vertical rock was above 80%RH. Furthermore, the aspect had a significant impact on the temperature and humidity on the surface of the rocks, but had no significant effect on the daily mean temperature and extreme temperature on the surface of vertical rock. Therefore, the slope affects the survival of D. officinale by affecting the extreme temperature of rocks and affects the growth of D. officinale by affecting the humidity. The choice of slope is the key to the success of cliff epiphytic cultivation for D. officinale. PMID- 28920338 TI - [Isolation and identification of berberine from endophytic fungi HL-Y-3]. AB - The endophytic fungi HL-Y-3, which was isolated from the healthy leaves of Coptis chinensis, produced berberine when grown in the PDA culture medium. The presence of berberine was confirmed by the chromatographic and spectroscopic analyses. The yield of berberine was recorded as 9.313 MUg*g-1 by HPLC. The strain HL-Y-3 was identified as Alternaria sp.by morphological observation and 5.8S rDNA-ITS sequence analysis.The separation and purification of constituents were performed by PTLC. The mass spectrometry (MS) of the analyte was shown to be identical with authentic berberine.Further analysis with nuclear magnetic resonance (NMR) spectroscopy to showed that the chemical structure of the fungal berberine was identical with authentic berberine. The research provided new resources for the utilization of berberine. PMID- 28920339 TI - [Optimization of drying process for Scrophulariae Radix by multivariate statistical analysis]. AB - To establish the suitable modern drying processing parameters for Scrophulariae Radix (SR). With reference to the traditional drying processing method of SR and the characteristics of modern drying equipment, the drying process for SR was simulated as the following three stages: temperature-controlled drying-tempering temperature-controlled drying. Eighteen batches of SR samples were obtained by the drying methods after the orthogonal design experiment with seven factors namely temperature, wind speed, and target moisture for the first stage, tempering time and temperature, as well as temperature and wind speed for the second stage. UPLC-TQ-MS was applied for determination of nine target compounds including catalpol, harpagide, verbascoside, ferulic acid, angroside-C, aucubin, harpagoside, cinnamic acid and ursolic acid in those dried samples and another 19 batches of SR samples collected from genuine producing area. Principal Component Analysis (PCA) was performed, and total energy consumption was also taken into consideration for analysis and evaluation. Results showed that the optimal drying processing method for SR was as follows: drying temperature of 60 C, drying wind speed of 50 Hz, and 50% for target moisture in the first stage; 24 h for tempering time and temperature of 20 C in the second stage; drying temperature of 60 C, and drying wind speed of 30 Hz in the third stage. The medicinal materials with optimized modern drying processing method were extremely similar to those collected from genuine producing area in the aspect of both external properties and target compounds, and they were in line with the 2015 version of "Chinese Pharmacopoeia" requirements. In addition, they could help to shorten the drying time and increase the efficiency of primary processing, and thus promote the normalization and standardization of primary drying processing for SR. PMID- 28920340 TI - [In vitro transdermal permeation and penetration properties for transfersomes of brucine]. AB - To prepare the liposomes and transfersomes of brucine, characterize their pharmaceutical properties, and compare their in vitro transdermal permeation properties. The liposomes and transfersomes of brucine were prepared by ammonium sulfate gradient method to investigate their pharmaceutical properties such as the particle size, encapsulation efficiency and deformation. The transdermal permeation properties in vitro of liposome and transfersomes from different prescriptions were compared by using modified Franz-diffustion cells with rat skin as the transdermal barrier. The results showed that the particle size of liposomes and transfersomes for brucine ranged from 100 nm to 150 nm, with even distribution for particle size. As compared with the soybean phosphatidylcholine (SPC) transfersomes, the encapsulation efficiency of complex phospholipid transfersomes was significantly improved. The deformation index of complex phospholipid transfersomes in brucine was 2.09 times and 1.76 times as much as SPC liposomes and SPC transfersomes respectively. The steady state flux of complex phospholipid transfersomes was 3.43 times and 1.41 times as much as SPC liposomes and SPC transfersomes. The steady state flux of the physical mixture of brucine and blank complex phospholipid transfersomes was 2.20 times as much as brucine solution. The concentration of complex phospholipid had effect on transdermal permeation of blank transfersomes. In conclusion, as compared with liposomes, the permeation behavior of transfersomes was significantly improved; complex phospholipid technology can improve the membrane phase behavior of transfersomes, and further improve the deformation index and transdermal flux of transfersomes; in addition, blank transfersomes have promoting effect on transdermal absorption of brucine. PMID- 28920341 TI - [Effect of different DE values of malto-dextrin on properties for Schisandrae Chinensis Fructus spray-dried powder]. AB - The purpose of this study was to compare the effect of different DE values of malto-dextrin on Schisandrae Chinensis Fructus spray-dried powder. The glass transition temperature (Tg) of the spray-dried powder, powder properties and microscopic morphology were determined, and then the moisture absorption isotherms and the glass transition temperature were used to predict its storage stability. The study showed that after adding malto-dextrin, the powder rate was increased; moisture content was decreased; Tg was increased; mobility got better; produced spherical microstructure; and Tg was increased with the decrease of DE value. The water activity-equilibrium moisture content (aw-EMC) relationship in GAB models showed, the moisture absorption of powder was increased with the rising of DE value; and the equilibrium moisture content-glass transition temperature (EMC-Tg) relationship in Gordon-Taylor models showed that, Tg was decreased with the increase of moisture content. As a result, the storage critical condition of the spray-dried powder was improved, and along with the decrease of DE value, the critical water activity and the critical water content were increased. Therefore, the smaller the DE value, the greater the stability of the spray-dried powder. PMID- 28920342 TI - [Fingerprint of Dazhu Hongjingtian capsule by HPLC-DAD-QTOF-MS]. AB - A method was established to analyze the fingerprint of Dazhu Hongjingtian capsule by HPLC-DAD.The separation was performed on Agilent Eclipse Plus-C18(4.6 mm*250 mm, 5 MUm) with methanol-0.1% formic acid solution as the mobile phase for gradient elution at a flow rate of 1.0 mL*min-1; the detection wavelength was set at 276 nm and column temperature was set at 35 C. A total of 10 batches of samples were detected by the above method, and based on their fingerprint by using Similarity Evaluation System for Chromatographic Fingerprint of TCM (2004A), 21 common chromatographic peaks were determined and after the individual common peak whose peak area was greater than 50% of the total peak area was deducted, the similarity results of these samples were analyzed and compared. The results showed that the similarity of 10 batches of samples was all higher than 0.940. HPLC/Q-TOF-MS was used to identify the common chromatographic peaks in the fingerprint and determine the molecular formulas of twenty-one common chromatographic peaks. The structures of 11 fingerprint peaks were tentatively identified based on the control products and mass spectrometry information. This was the first time to establish fingerprint by using HPLC method and identify fingerprint peaks by using HPLC/Q-TOF-MS. This method has good precision, stability and repeatability, and could provide basis for quality evaluation of Dazhu Hongjingtian capsule. PMID- 28920343 TI - [Identification of dominant microbes from traditional Chinese medicine Pinelliae Rhizoma Fermentata]. AB - To investigate the microbial species, amount changes as well as the isolation and identification of domain strains at different fermentation time points of Pinelliae Rhizoma Fermentata, and provide basis for exploring the mechanism of Pinelliae Rhizoma Fermentata processing. Five samples were chosen at the time points (0, 18, 36, 54, 72 h) of Pinelliae Rhizoma Fermentata processing. Bacteria, mold and yeast from the samples were cultured; their colonies were counted, and the dominant strains were isolated and purified. The dominant bacteria and dominant fungi were identified by 16S rDNA and 26S rDNA sequencing respectively. The results showed that the bacteria count was low with slow and smooth changes in the fermentation process;while mold and yeast grew dramatically after 54 h culturing and reached 1*107 CFU*mL-1 at the end of fermentation. Through the NCBI homology alignment and phylogenetic tree construction, the dominant bacteria were identified as Streptomyces sp., Bacillus pumilus, B. subtilis, B. aryabhattai and other Bacillus sp.; the dominant yeast was identified as Meyerozyma guilliermondii; the dominant mold were identified as Paecilomyces variotii, Byssochlamys spectabilis, and Aspergillus niger in the processing of Pinelliae Rhizoma Fermentata. The results indicated that multiple microbe species, especially yeast and mold, played a role in the fermentation processing of Pinelliae Rhizoma Fermentata. M. guilliermondii, P. variotii, P. variotii and A. niger and Bacillus sp. can be the crucial factors in the processing of Pinelliae Rhizoma Fermentata. PMID- 28920344 TI - [Determination of four coumarin constituents before and after Angelicae Dahuricae Radix stewed with yellow rice wine and research on its mutual transformation mechanism]. AB - To determine the contents of oxypeucedanin, oxypeucedanin hydrate, byakangelicol and byak-angelicin both before and after Angelicae Dahuricae Radix was stewed with yellow rice wine by high-performance liquid chromatography, and study the mutual transformation mechanisms of oxypeucedanin into oxypeucedanin hydrate, as well as byakangelicol into byak-angelicin. The research results indicated that the contents of oxypeucedanin and byakangelicol were decreased, but the contents of oxypeucedanin hydrate and byak-angelicin were increased after Angelicae Dahuricae Radix was processed with yellow rice wine. The contents' changes of these chemical compounds were due to the ring opening reaction of epoxy compounds, such as oxypeucedanin and byakangelicol under the weak acidity and heating conditions of yellow rice wine. This research could provide a scientific basis for the processing mechanism of Angelicae Dahuricae Radix with yellow rice wine stewing. PMID- 28920345 TI - [Two new triterpenoid glycosides from leaves of Ilex latifolia]. AB - Two new triterpenoid glycosides, latifolosides R and S (1 and 2), were isolated from the leaves of Ilex latifolia by various column chromatographic methods. Their structures were elucidated based on NMR spectroscopic data and chemical evidence. PMID- 28920346 TI - [Chemical constituents from Phellinus igniarius and their anti-tumor activity in vitro]. AB - Eleven compounds were isolated and purified from Phellinus igniarius by column chromatography on silica gel, Sephedax LH-20, RP-8, MCI and preparative TLC. Their structures were identified as 3alpha-hydroxyfriedel-2-one (1), 3 hydroxyfriedel-3-en-2-one (2), ergosta-4, 6, 8 (14), 22-tetraen-3-one (3), ergosterol peroxide (4), uracil (5), uridine (6), 4-(3, 4-dihydroxyphenyl)-3 butene-2-one (7), protocatechualdehyde (8), inotilone (9), inoscavinA (10) and phellibaumin E (11), respectively, on the basis of NMR and MS data analysis. Among them, compounds 1, 2, 5, and 6 were firstly obtained from this genus. In vitro cytotoxic activity of compounds 1-11 was screened by Cell Titer-GLo Reagent, on 41 human tumor cell strains and 2 hamster normal cell strains via high-throughput screening. Compounds 2-4 exhibit significant cytotoxic activity against NOMO-1 and SKM-1 acute myeloid leukemia cell lines, and compounds 2 and 3 showed good selectivity to NOMO-1 with IC50 values of 0.795 5, 1.828 MUmol*L-1and SKM-1 with IC50 values of higher than 10 MUmol*L-1. Compound 7 showed remarkable antitumor activities against H526 Human lung cancer cell line, DU145 prostate cancer cell line and HEL erythroleukemia cell line with IC50 values of 0.533 4, 1.885, 1.057 MUmol*L-1, respectively. Other compounds had no or weak antitumor effect. In addition, all compounds had no significant effect on hamster normal cell lines CHL and CHO with IC50 values of higher than 10 MUmol*L-1, which showed that all compounds had no toxic effect on normal cells. PMID- 28920347 TI - [Sesquiterpenes from stems of Schisandra henryi var. henryi]. AB - The dried stems of Schisandra henryi var. henryi were extracted with 95% ethanol and the extracts were further subjected to partition, affording the ethyl acetate extracts(EtOAc Extrs.).The EtOAc Extrs.were separated and purified with silica gel and octadecyl-silylated silica gel column chromatography, preparative HPLC and preparative TLC. Thirteen known compounds were obtained and identified by spectral methods including MS and NMR, all of which were elucidated as t cadinol(1), cadinane-4beta,5alpha,10beta-triol(2), cadinane-5alpha, 10alpha-diol 2-ene(3), oxyphyllenodiols A(4), 1beta, 4beta-dihydroxyeudesman-11-ene(5), cyperusol C(6), (7R)-opposit-4(15)-ene-1beta,7-diol(7), dysodensiol E(8), epi guaidiol A(9), aromadendrane-4beta,10beta-diol(10), tricyclohumuladiol(11), caryolane-1,9beta-diol(12), and guaidiol A(13). Compounds 3, 5-10, and 13 were separated from the genus for the first time, while compounds 1-13 were separated from this species for the first time. PMID- 28920348 TI - [Research on quality standards of Aleuritopteris Herba]. AB - This study aims to establish quality standards of Aleuritopteris Herba (AH), which could supply scientific evidence for the quality control of AH. The morphological and microscopic identification characters were reformulated. The tests of water content, total ash, acid-insoluble ash and ethanol-soluble extractives of AH were carried out according to the methods recorded in appendix of Chinese Pharmacopeia (2010 edition, volume 1). The TLC method was established by using aleuritopesis A [2,19-diol(2beta,4alpha)-16-enekaureniod] and reference herb as references. With preparation of aleuritopesis A[2,19-diol(2beta,4alpha) 16-enekaureniod] reference substance, the content of aleuritopesis A in AH was determined by HPLC. As a result, the macroscopic identification, microscopic features and TLC methods were specific and simple. The water content, total ash, acid-insoluble ash and ethanol-soluble extractive and the content of aleuritopesis A of all samples varied in the ranges of 8.8%-10.9%, 7.6%-11.4%, 2.5%-4.2%, 9.3%-10.2% and 0.56%-0.71%, respectively. The improved quality standard can be used to evaluate and guarantee the quality of AH comprehensively. PMID- 28920349 TI - [Screening for differentially-expressed proteins in ovary of primary dysmenorrheal mice with Xiangfu Siwu decoction administration using nano LC-LTQ Orbitrap-MS/MS]. AB - To study the mechanism of Xiangfu Siwu decoction in treating primary dysmenorrhea, differentially-expressed proteins in ovary of primary dysmenorrheal mice with Xiangfu Siwu decoction administration were screened based on proteome technology using nano LC-LTQ-Orbitrap-MS/MS. Estradiol benzoate and oxytocin were used to produce dysmenorrheal mice model. The model mice were orally administrated with Xiangfu Siwu decoction for 3 days, and 1 h after the last administration, the ovary samples were collected. After protein denaturation, reduction, alkylation, desalination and enzymatic hydrolysis, identification was carried out by nano LC-LTQ-Orbitrap-MS/MS technology. The obtained data was processed by using Thermo Proteome discoverer 1.4 software. The differentially expressed proteins were screened and identified, and their biological information was also analyzed. The significant differentially-expressed protein was checked using Western blot technology in ovary samples. A total of 106 differentially expressed proteins were identified during the normal, model and administration group. Most of them participate cellular processes. Adherens junction and focal adhesion pathways play a regulatory role in various cell signaling pathways. Protein ADRM1 was validated. Compared to the normal group, it was up-regulated expression in the model group. After administration, the expression of ADRM1 was down-regulated. Through the comparative analysis, a series of differentially expressed proteins involved in primary dysmenorrheal mice with Xiangfu Siwu decoction administration were obtained. Protein ADRM1 may become a target for Xiangfu Siwu decoction. PMID- 28920350 TI - [Discovery of potential LXRbeta agonists from Chinese herbs using molecular simulation methods]. AB - Liver X receptor beta (LXRbeta) has been a new target in the treatment of hyperlipemia, which was related to the cholesterol homeostasis. In this study, the quantitative pharmacophores were constructed by 3D-QSAR pharmacophore (Hypogen) method based on the LXRbeta agonists. The optimal pharmacophore model containing one hydrogen bond acceptor, two hydrophobics and one ring aromatic was obtained based on five assessment indictors, including the correlation between predicted value and experimental value of the compounds in training set (correlation), Deltacost of the models (Deltacost), hit rate of active compounds (HRA), identification of effectiveness index (IEI) and comprehensive evaluation index (CAI). And the values of the five assessment indicators were 0.95, 128.65, 84.44%, 2.58 and 2.18 respectively. The best model as a query to screen the traditional Chinese medicine database (TCMD), a list of 309 compounds was obtained andwere then refined using Libdock program. Finally, based on the screening rules of the Libdock score of initial compound and the key interactions between initial compound and receptor, four compounds, demethoxycurcumin, isolicoflavonol, licochalcone E and silydianin, were selected as potential LXRbeta agonists. The molecular simulation methods were high-efficiency and time saving to obtainthe potential LXRbeta agonists, which could provide assistance for further researchingnovel anti-hyperlipidemia drugs. PMID- 28920351 TI - [Exploring pharmacological principle of Artemisia carvifolia with textmining technology]. AB - To explore the pharmacological principle of Artemisia carvifolia,the text mining technique was used. All the references of A. carvifolia were collected from PubMed database, and then the rules of the main ingredient,relative diseases, organs, tissues, proteins and metabolites were analyzed. Finally, a network was set up. Then it was found that the main ingredients included sesquiterpenoids,flavonoids,and volatileoils.The diseases such as malaria, cerebral malaria, falciparum malaria, visceral leishmaniasis and systemic lupus erythematosus were often treated with A. carvifolia. In association in organ were the liver, skin, trachea,lungs,and spleen.Correlations with tissues were mainly including macrophages, T lymphocytes, blood vessels, epithelial cells.The protein was correlation with it involved CYP450, PI3K, TNF-alpha, AASDPPT, DNA polymerase and so on. Comprehensive and systematic treatment principle of A. carvifolia was obtained by text mining, which was helpful in clinical application. PMID- 28920352 TI - [Effects of Xiangsha Liujunzi decoction on TLR signal pathway in gastric mucosa tissues of rats with Helicobacter pylori-induced chronic atrophic gastritis]. AB - To explore the effects and mechanism of Xiangsha Liujunzi decoction on TLR signal pathway in gastric mucosa tissues of rats with Helicobacter pylori-related gastritis, sixty SD rats were randomly divided into control group, model group, high concentration of Xiangsha Liujunzi decoction group, moderate concentration of Xiangsha Liujunzi decoction group, low concentrations of Xiangsha Liujunzi decoction group and SB203580-treated group, with 10 rats in each group. SD rats of Hp-associated chronic atrophic gastritis models were established by intragastric gavage of Helicobacter pylori (HP) suspension. Changes in the gastric mucosa of rats were assessed by histopathology. ELISA was applied to detect the expressions of TNF-alpha and IL-6 in the serum, and the activity of iNOS in gastric mucosa. The content of NO in the gastric mucosa was tested by nitrate reductive enzymatic. The expressions of TLR2, TLR4, P38MAPK, NF-kappaB were detected by QPCR and Western-blot. The results indicated that the clinical symptoms of rats and pathological changes of gastric mucosa were improved in Xiangsha Liujunzi decoction group. Compared with normal control group, the protein expressions of TLR2, TLR4, p-P38MAPK and NF-kappaB in gastric mucosa of model group rats increased (P<0.01) with the levels of TNF-alpha and IL-6 in the serum, and the activity of iNOS and the content of NO in gastric mucosa increased. Compared with model group, the expressions decreased in Xiangsha Liujunzi decoction group, especially in the high concentration of Xiangsha Liujunzi decoction group(P<0.01), with gradually increased rate of HP eradication and decreased pathological grades of chronic atrophic gastritis. The serum level of TNF-alpha and IL-6 decreased from (24.313+/-2.261) MUg*L -1 to (15.195+/ 1.235) MUg*L-1(P<0.01) and from (77.416+/-8.095) MUg*L -1 to (33.150+/-2.532) MUg*L -1 (P<0.01), and the activity of iNOS and the content of NO in gastric mucosa decreased from (1.530+/-0.206) U*mg -1 to (0.802+/-0.091) U*mg -1 (P<0.01) and from (0.907+/-0.032) mmol*g -1 to (0.335+/-0.026) mmol*g -1 (P<0.01) after the treatment of high concentration of Xiangsha Liujunzi decoction. All the effects increased with the increasing dosage of Xiangsha Liujunzi decoction from 0.324 g*mg -1 to 1.296 g*mg -1. The protein expressions of NF-kappaB decreased in the gastric mucosa after treated with P38MAPK specific inhibitor-SB203580. In the rats model, HP infection results in chronic atrophic gastritis through the activation of TLR2, TLR4/MAPK/NF-kappaB/iNOS/NO signal pathway. Xiangsha Liujunzi decoction can eradicate H. pylori and alleviate chronic atrophic gastric mucosal inflammation. The treatment is effective and safe to cure HP-induced chronic atrophic gastritis. PMID- 28920353 TI - [Comparative metabolism of three amide alkaloids from Piper longum in five different species of liver microsomes]. AB - Piperine, piperlonguminine and pellitorine are three major amide alkaloids from Piper longum, showing a variety of pharmacological activities. In order to investigate the different metabolism pathways of these compounds in five species of liver microsomes in vitro, the data of full mass spectrum, and MS2, MS3 spectra of these three alkaloids were collected and analyzed by using ultra-high performance liquid chromatography coupled with a LTQ-orbitrap mass spectrometer (UHPLC-LTQ-Orbitrap MS); gragment ion information was collected and combined with fragmentation regularities of mass spectra and accurate mass spectrometry data of metabolites, to compare the metabolism difference of three amide alkaloids in liver microsomes of human, rhesus monkey, Beagle dogs, rats and mice. 3 metabolites of piperine, 2 metabolites of piperlonguminine and 1 metabolite of pellitorine were identified quickly. The results showed that the major metabolic pathways of these amide alkaloids in liver microsomes were methylenedioxy group demethylation and oxidation reaction, and metabolic rates were different between species. This study provides basis for further research on in vivo metabolism of piperine analogues from Piper longum. PMID- 28920354 TI - [Meta-analysis on efficacy of Fuke Qianjin tablets (capsules) combined with antibiotics in treatment of endometritis]. AB - To systemically evaluate the clinical efficacy of Fuke Qianjin tablets combined with antibiotics in the treatment of endometritis. The databases such as PubMed, CNKI, VIP and WanFang Data were searched to collect the randomized controlled trials(RCTs) about Fuke Qianjin tablets combined with antibiotics for endometritis since 2010. According to the Cochrane Reviewer's Handbook, two reviewers independently screened the literature, extracted the data and assessed the methodological quality of the included studies. Then the Meta-analysis was performed by using RevMan 5.3 software. 16 RCTs were included, involving 2 299 patients. Meta-analysis showed that after endometritis was treated by Fuke Qianjin tablets combined with antibiotics, the thickness of endometrium was higher than that in antibiotics group[MD=1.20, 95%CI (1.10, 1.29), P<0.000 01]; the occurrence rate of normal menstrual cycle[OR=1.46,95%CI (1.21, 1.77), P=0.000 1] and total effective rate [OR=1.19, 95%CI (1.15, 1.24), P<0.000 01] were increased ; the irregular vaginal bleeding [OR=0.21, 95%CI (0.14, 0.30), P<0.000 01] and inflammatory reactions[OR=0.19, 95%CI (0.10, 0.37)] were reduced. In short, Fuke Qianjin tablets combined with antibiotics have better effects than antibiotics alone for endometritis, so it is worthy to be recommended for clinical application. PMID- 28920355 TI - [Clinical analysis of two diagnosis methods for herb-induced liver injury]. AB - To compare the consistency and difference of herb-induced liver injury between two methods in guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China (2016) and guidelines for the diagnosis and treatment of drug-induced liver injury in China(2015). This retrospective analysis included 390 patients with herb-induced liver injury who had a history of suspicious Chinese herbal medicines or patent medicines; the patients with integrative Chinese and western medicines were excluded from this study. The results indicated that there were 14(4%) extremely probable patients (>8 points), 185(47%) highly probable patients (6-8 points) and 191(49%) probable patients(3-5 points) in 390 cases with guidelines for diagnosis and treatment of drug-induced liver injury of China (2015). While when guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China (2016) was used for 390 patients, the results indicated that there were 5 (1%) cases with proven diagnosis, 163(42%) cases with clinical diagnosis, and 222(57%) cases with suspected diagnosis. Statistics showed that two methods had a consistency of 43% and difference of 14%. The research results showed that Guidelines for clinical diagnosis and treatment of liver injury related to Chinese herbal medicine in China(2016) was more suitable for the diagnosis of herb-induced liver injury. Due to the limitations of retrospective case study, further more prospective studies would be needed. PMID- 28920356 TI - [Efficacy and safety of Choudongning capsule (CDN)in children with Tourette's syndrome of spleen deficiency and phlegm accumulation]. AB - To evaluate the efficacy and safety of Choudongning (CDN)capsule in children with Tourette's syndrome of spleen deficiency and phlegm accumulation through a randomized double-blind three-arm controlled phase III study in 588 patients from 8 hospitals. The included patients were randomly divided into test group, positive control group and placebo group at the ratio of 3?1?1. Patients in the test group orally took CDN capsules and simulated Tiapridal tablets; the patients in positive control group took Tiapridal tablets and simulated CDN capsules; whereas the patients in placebo group orally took the simulated agents of the above two drugs. The treatment course was 6 weeks for three groups. The global grading rates, YGTSS scores and its factor scores, the degree of social function damage, as well as traditional Chinese medicine syndrome efficacy were evaluated as the outcome measures on efficacy. The AEs/ADRs, vital signs and laboratory testing were observed as outcome measures on safety. The total effective rate of YGTSS was 75.92% in the test group, 72.65% in the positive control group, and 37.29% in the placebo group. Non inferiority test stands between the test group and the positive control group, and they were superior to placebo group in efficacy with statistical difference. Significant difference had also been found among the 3 groups in YGTSS tics score, motor tics score, vocal tics, degree of social function damage and traditional Chinese medicine syndrome efficacy. During the study, there were 5 (1.42%)ADRs in the test group, 10 (8.55%)in the positive control group and 3 (2.54%)in the placebo group. The incidence of ADRs in the test group was lower than that in the positive control group, with statistical difference. It is clear to say that CDN capsule can effectively treat the Tourette's syndrome of spleen deficiency and phlegm accumulation. Its efficacy is not inferior to the commonly used Tiapridal tablets, with even less adverse reactions, so it has clinical application value. PMID- 28920357 TI - [Investigation, collation and research of traditional Dai medicine of China]. AB - In order to find out the composition, characteristics and traditional utilization characteristics of Dai medicine and promote the rational protection, inheritance and utilization of the resources and traditional knowledge of Dai medicine in China, the resources of traditional Dai medicine have been investigated systematically and the traditional knowledge of Dai medicine have been analyzed in the article. We found out that there were altogether 1 077 kinds of traditional Dai medicine in China and among which 272 were the first time recorded in the condition of Dai folk medical uses. There were 1 053 plant medicines which belong to 169 family and 694 genus. These plant medicines mainly distributed in the southern, west southern and east southern area of Yunnan province, the southern area of Guangxi, Guangdong, Guizhou, Sichuan, Fujian province and tropical, subtropical district as Taiwan, and more than 94.49% plant medicines could be found in Yunnan province. From the point of plant life form, they were major herbaceous or shrubby plants; When it is used as medicinal part, root and rhizome of plants account for the highest proportion, the next were whole plant and leaves. From nature, flavor and channel tropism points of view, the largest proportion of Dai medicines were cool, bitter-tasted and possesses water element. In terms of treatment of disease types, most of the drugs can treat gastrointestinal diseases, next were drugs that could be used to treat upper respiratory infection, traumatological and rheumatic diseases, urinary infection, gynecological diseases, hepatopathy, puerperium fever and diseases caused by poisonous insects and beast of prey bite. The study revealed that the resources of traditional Dai medicine and traditional knowledge of application were abundant in China, but the resources of traditional Dai medicine and traditional knowledge of application were faced with the risk of gradually reduce and loss. The article suggested that we should take measures to strengthen the study of protection and utilization of important traditional Dai medicine and endangered resources along with the protection and transmission of traditional knowledge of Dai nationalistic medicine. PMID- 28920358 TI - [Production suitability regionalization study of Pinus massoniana]. AB - The distribution, yield and sample information data of Pinus massoniana was obtained by document literature and sample investigation. Based on sample data from 12 provinces including 414 sample plots and environment factors in China,the distribution regionalization of P. massoniana was predicted by using Maxent and spatial analysis function of ArcGIS. The results showed that the northernmost distribution of P. massoniana was 33.5 degrees north latitude, and it mainly distributed in the southeast in China. Based on plant age, plant height, yield per plant and other growth index from 414 sample plots, combined vegetation form and other data, the growth regionalization of P. massoniana was carried out by using SPSS and related functions of ArcGIS. The results showed that Fujian, Guizhou and Guangxi had a lager distribution area of P. massoniana, meanwhile, it had a relatively higher yield of fresh pine needles. The relational model between environmental factors and shikimic acid,and procyanidin, and the total lignans was constructed by using SPSS regression analysis method. Then the spatial calculation function of ArcGIS was used tocarry out the quality regionalization of P. massoniana based on the relational model. The results showed that east of Sichuan, Guizhou, Chongqing had a good pine needles quality. Based on the distribution, growth and quality regionalization, the production suitability regionalization of P. massoniana was carried out. The results showed that the optimal planting base region mainly distributed in east of Sichuan, middle and east of Guizhou, and east of Guangxi. PMID- 28920359 TI - [Production regionalization study of Glycyrrhiza uralensis]. AB - The distribution information of Glycyrrhiza uralensis was collected by interview investigation and field survey, and 46 related environmental factors were collected, some kinds of functional chemical constituents of G.uralensis were analyzed. Integrated climate, topography and other related ecological factors, the habitat suitability study was conducted based on Arc geographic information system(ArcGIS),and maximum entropy model. The AUC of ROC curve was both above 0.95, indicating that the predictive results with the maximum model were highly precise. The results showed that 5 major ecological factors have obvious influence on ecology suitability distributions of G. uralensis, including July average temperature, soil sub category, Dec precipitation, vegetation types and standard deviation of seasonal variation in temperature, et al. It is suitable for the living habits of the G. uralensis, adequate light, low rainfall, summer heat and large temperature difference between day and night, which is suitable for distribution in the northern temperate plains and mountains. In addition, the ecological suitability regionalization based on the chemical constituents of G.uralensis also provides a new suitable distribution area other than the traditional distribution area, which provides a scientific basis for the reasonable introduction of G.uralensis. PMID- 28920360 TI - [Production regionalization study of Lycii Fructus]. AB - The distribution information of Lycii Fructus was collected by interview investigation and field survey, and 46 related environmental factors were collected, some kinds of functional chemical constituents the of Lycii Fructus were analyzed. Integrated climate, topography and other related ecological factors, the habitat suitability study was conducted based on Arc geographic information system(ArcGIS),and maximum entropy model. The AUC of ROC curve was both above 0.95, indicating that the predictive results with the maximum model were highly precise. The results showed that 5 major ecological factors had obvious influence on ecology suitability distributions of Lycii Fructus, including soil pH, soil subclass, vegetation type and in August the average temperature et al. It is suitable for the living habits of the Lycii Fructus, dry, cool weather, more hardy, drought-resistant, alkali soil, which is suitable for distribution in the northern temperate plains. In addition, the ecological suitability regionalization based on the chemical constituents of Lycii Fructus also provides a new suitable distribution area other than the traditional distribution area, which provides a scientific basis for the reasonable introduction of Lycii Fructus. PMID- 28920361 TI - [Quality regionalization study on Gentianae Macrophyllae Radix]. AB - The 79 samples of Gentianae Macrophyllae Radix were collected based on the distributed information by document literature. Based on sample information, and using the regression model of Gentianae Macrophyllae Radix index component and environmental factors, and combined with the prediction results of ecological suitability by MaxEnt and principal component analysis results of index component, the space distribution of Gentianae Macrophyllae Radix was estimated with the spatial analysis function of ArcGIS. The results showed that it had a higher comprehensive quality in south of Shaanxi, south of Gansu, middle of Sichuan and southeast of Xizang. The study results were coinciding with the producing regions of Gentianae Macrophyllae Radix. It can provide reference for Gentianae Macrophyllae Radix resource conservation, development and utilization. PMID- 28920362 TI - [Production regionalization study of Chinese angelica based on MaxEnt model]. AB - The distribution information of Chinese angelica was collected by interview investigation and field survey, and 43 related environmental factors were collected, some kinds of functional chemical constituents of Angelica sinensis were analyzed. Integrated climate, topography and other related ecological factors, the habitat suitability study was conducted based on Arc geographic information system(ArcGIS),and maximum entropy model. Application of R language to establish the relationship between the effective component of Chinese angelica and enviromental factors model, using ArcGIS software space to carry out space calculation method for the quality regionalization of Chinese angelica. The results showed that 4 major ecological factors had obvious influence on ecology suitability distributions of Chinese angelica, including altitude, soil sub category, May precipitation and the warmest month of the highest temperature, et al. It is suitable for the living habits of the Chinese angelica, cold and humid climate, which is suitable for the deep area of the soil. In addition, the ecological suitability regionalization based on the effect of Chinese angelica also provides a new suitable distribution area other than the traditional distribution area, which provides a scientific basis for the reasonable introduction of Chinese angelica. PMID- 28920363 TI - [Study on suitable distribution areas of Grifola umbellate in Sichuan province based on remote sensing and GIS]. AB - Grifola umbellate is the important medicinal materials in China which has a very high medicinal value. This study analyzedthe suitable distribution areasof G. umbellate and provided scientific basis for determining G. umbellate planting regions and planning production distribution reasonably. The suitable distribution areas of G. umbellate in Sichuan province was researched based on TM, ETM+, and DEM data,the key ecological factors that affect the growth of G. umbellate were extracted, including elevation, slope, aspect, average annual temperature,average annual precipitation,forest information,soil information, following remote sensing and GIS techniques, combining field researchdata. The results showed that the G. umbellate resources in Sichuan province were mainly distributed in Pingwu, Beichuan, Licountry, Yanyuan, Xichang, Dechang, Yanbian, Miyi, Huidong, Panzhihua and so on, the suitability distribution areas is 276.214 4 km2 approximately and accounting for more than 0.143 3% of the total area.According to the related document information and the field investigation, showed that the suitability distribution based on RS and GIS were corresponded with the actual distribution areas of G. umbellate. PMID- 28920364 TI - [Ecological suitability regionalization for Gastrodia elata in Zhaotong based on Maxent and ArcGIS]. AB - In this paper, the potential distribution information and ecological suitability regionalization for Gastrodia elata in Zhaotong were studied based on the climate, terrain, soil and vegetation factors analysis by Maxent and ArcGIS. The results showed that the highly potential distribution (suitability index>0.6) mainly located in Zhaotong, Yunnan province(Zhenxiong,Yiliang and Daguan county, with an area of 2 872 km2), and Bijie, Guizhou province (Hezhang,Bijie,Weining county, 1 251 km2). The AUC of ROC curve was above 0.99, indicating that the predictive results with the Maxent model were highly precise. The main ecological factors determining the potential distribution were the altitude, average rainfall in November, average rainfall in October, vegetation types, average rainfall in March, average rainfall in April,soil types,isothermal characteristic and average rainfall in June. The environmental variables in the highly potential areas were determined as altitude around 1 450-2 200 m,annual average temperature around 18.0-20.4 C,annual average precipitation around 900 mm,yellow soil or yellow brown soil,and acid sandy loam or slightly acidic sandy loam.The results will provide valuable references for plantation regionalization and the siting for imitation wild planting of G. elata in Zhaotong. PMID- 28920365 TI - [Climatic division of Blumea balsamifera in Guizhou province based on topographical conditions]. AB - According to the meteorological index of the growth of Blumea balsamifera, and by using the climate and geographic date recorded in the main meteorological stations for 54 years(1960-2014) in Guizhou province, the authors established a regression model between climate division factors and geographic information for the possible planting area. Considering integrated various factors including climate factor, gradient and elevation, based on GIS technology, ascertain the planting area of B. balsamifera. Combined with the land use condition of Guizhou province based on RS, analyzed the distribution rule of the synthesis index, climatic divisions of B. balsamifera in Guizhou were divided into 3 areas (the most suitable, suitable, sub-suitable) objectively. There are 3 areas can plant B. balsamifera (the southwest, the south and the north). The most suitable climate area has 76.98 km2, the suitable climate area has 156.04 km2, and the sub suitable climate area has 235.43 km2. PMID- 28920366 TI - [Habitat suitability and quality division of Mentha haplocalyx]. AB - In this study, ecological factors, occurrence records, the essential oil components content were used to predict the potential geographical distribution and quality division of Mentha haplocalyx in China based on the MaxEnt modeling and geographic information system(GIS). The AUC of ROC curve was above 0.950,indicating that the predictive results with the maximum model were highly precise. The results showed that the main environmental factors determining the potential distribution were annual average precipitation (the contribution rate, 45.87%), mean temperature of wettest quarter (11.92%), mean temperature of warmest quarter (7.84%), average monthly precipitation of May (6.80%), standard deviation of seasonal temperature variation (4.42%), mean temperature of the coldest quarter (3.47%) and altitude (2.92%). The environmental variables in the highly potential areas were determined as annual average precipitation around [530,1 465] mm, mean temperature of wettest quarter around [24.5,29] C, mean temperature of the warmest quarter around [25.5,29] C, average monthly precipitation of May around [67,133] mm, standard deviation of temperature seasonal change around [8 333,9 643], mean temperature of the coldest quarter around [1.7,8.3] C and the altitude around [0,165] mm. The best quality distribution of M. haplocalyx was mainly located in Jiangsu, Anhui, Shandong, Zhejiang and Heilongjiang. The zoning results basically coincide with the actual situation. The quality division of M. haplocalyx can be used for providing a scientific basis for selection of artificial planting base and guidance of its production. PMID- 28920367 TI - [Ecology suitability study of Chinese materia medica Gentianae Macrophyllae Radix]. AB - This paper is aimed to predict ecology suitability distribution of Gentianae Macrophyllae Radix and search the main ecological factors affecting the suitability distribution. The 313 distribution information about G. macrophylla, 186 distribution information about G. straminea, 343 distribution information about G. dauricaand 131 distribution information about G. crasicaulis were collected though investigation and network sharing platform data . The ecology suitable distribution factors for production Gentianae Macrophyllae Radix was analyzed respectively by the software of ArcGIS and MaxEnt with 55 environmental factors. The result of MaxEnt prediction was very well (AUC was above 0.9). The results of predominant factors analysis showed that precipitation and altitude were all the major factors impacting the ecology suitable of Getiana Macrophylla Radix production. G. macrophylla ecology suitable region was mainly concentrated in south of Gansu, Shanxi, central of Shaanxi and east of Qinghai provinces. G. straminea ecology suitable region was mainly concentrated in southwest of Gansu, east of Qinghai, north and northwest of Sichuan, east of Xizang province. G. daurica ecology suitable region was mainly concentrated in south and southwest of Gansu, east of Qinghai, Shanxi and north of Shaanxi province. G. crasicaulis ecology suitable region was mainly concentrated in Sichuan and north of Yunnan, east of Xizang, south of Gansu and east of Qinghai province. The ecological suitability distribution result of Gentianae Macrophyllae Radix was consistent with each species actual distribution. The study could provide reference for the collection and protection of wild resources, meanwhile, provide the basis for the selection of cultivation area of Gentiana Macrophylla Radix. PMID- 28920368 TI - [Study on ecological suitability of Gardenia jasminoides based on ArcGIS and Maxent model]. AB - The application of ArcGIS and Maxent modelto analyze the ecological suitability of Gardenia jasminoides.Taking 85 batches of Gardenia as the basis of analysis, the selection of ecological factors for the growth of Gardenia. The results showed that the average precipitation in April, the average precipitation in November and the average precipitation in August were the most important factors affecting the growth of Gardenia. The relative concentration of Gardenia suitable growth region,north to the south of Shaanxi province, south of Henan, central Anhui, south to the north of Hainan province, west to central Sichuan province, east of Zhejiang coastal area, northeast of Taiwan. PMID- 28920369 TI - [Cultural regionalization for Coptis chinensis based on 3S technology platform I. Study on growth suitability for Coptis chinensis based on ecological factors analysis by Maxent and ArcGIS model]. AB - At the urgent request of Coptis chinensis planting,growth suitability as assessment indicators for C. chinensis cultivation was proposed and analyzed in this paper , based on chemical quality determination and ecological fators analysis by Maxent and ArcGIS model. Its potential distribution areas at differernt suitability grade and regionalization map were formulated based on statistical theory and growth suitability theory. The results showed that the most suitable habitats is some parts of Chongqing and Hubei province, such as Shizhu, Lichuan, Wulong, Wuxi, Enshi. There are seven ecological factor is the main ecological factors affect the growth of Coptidis Rhizoma, including altitude, precipitation in February and September and the rise of precipitation and altitude is conducive to the accumulation of total alkaloid content in C. chinensis. Therefore, The results of the study not only illustrates the most suitable for the surroundings of Coptidis Rhizoma, also helpful to further research and practice of cultivation regionalization, wild resource monitoring and large-scale cultivation of traditional Chinese medicine plants. PMID- 28920371 TI - [Study of genuineness based on changes of ancient herbal origin--taking Astragalus membranaceus and Salvia miltiorrhiza as examples]. AB - Basically, Dao-di hers are produced in specific area which has a long history, good quality, good medicine, curative effect. However genuine medicinal material area in history is not static, this makes the establishment of genuine medicinal material origin and the in-depth research be very difficult. This paper has profoundly analyzed the origin of different historical periods taking Astragalus membranaceus and Salvia miltiorrhiza as examples, and then summarized the reasons of herbal origin changes from the humanities, social and natural three aspects. This paper provides a basis for establishment and the further research of high quality genuine producing area. PMID- 28920370 TI - [Functional production regionalization for Fritillariae Cirrhosae Bulbus based on growth and quality suitability assessment]. AB - The major contributing factors for growth of endangered medicinal plants of Fritillariae Cirrhosae Bulbus were screened on the GIS platform by using the MaxEnt model, and spatial distribution data of the medicine quality suitability were generated by geostatistics interpolation based on reported measured data of ecology and quality suitability assessment. On this basis, a functional production cultivation regionalization with high feasibility and operability were formatted for protection, wild monitoring, and cultivation of this plant by fuzzy superposition of spatial suitability data of ecology and quality, as well as integrated with land use and cover data. Therefore, a novel assessment and regionalization method were presented for ecology, growth and quality suitability of the Chinese traditional medicinal plants. This method is expected to overcome shortage of traditional regionalization methods difficult to distinguish the contribution of ecological factors and quality factors, which provide an innovative theory and methodology for regionalization, and is helpful to practical application of wild resource protection, monitoring, and commercialization cultivation for traditional Chinese medicinal plants. PMID- 28920372 TI - [Research progress on potential liver toxic components in traditional Chinese medicine]. AB - In recent years, the proportion of traditional Chinese medicine in scientific research and its clinical use increased gradually. The research result also becomes more and more valuable, but in the process of using traditional Chinese medicine, it also needs to pay more attention. With the gradual deepening of the toxicity of traditional Chinese medicine, some traditional Chinese medicines have also been found to have the potential toxicity, with the exception of some traditional toxicity Chinese medicine. Traditional Chinese medicine in the growth, processing, processing, transportation and other aspects of pollution or deterioration will also cause the side effects to the body. Clinical practice should be based on the theory of traditional Chinese medicine to guide rational drug use and follow the symptomatic medication, the principle of proper compatibility. The constitution of the patients are different, except for a few varieties of traditional Chinese medicines are natural herbs with hepatotoxicity, liver toxicity of most of the traditional Chinese medicine has idiosyncratic features. The liver plays an important role in drug metabolism. It is easy to be damaged by drugs. Therefore, the study of traditional Chinese medicine potential liver toxicity and its toxic components has become one of the basic areas of traditional Chinese medicine research. Based on the review of the literatures, this paper summarizes the clinical classification of liver toxicity, the pathogenesis of target cell injury, and systematically summarizes the mechanism of liver toxicity and toxic mechanism of traditional Chinese medicine. This paper provided ideas for the study of potential liver toxicity of traditional Chinese medicine and protection for clinical safety of traditional Chinese medicine. PMID- 28920373 TI - [Application of gut microbiota in research of Chinese medicines]. AB - This article summarizes the research progress in recent years on interactions between Chinese medicines and gut microbiota based on the physiological functions of gut microbiota, including imbalance impacts of toxic/irritating Chinese medicines on gut microbiota, prognosis effects of Chinese medicines on gut microbiota imbalance, metabolism effects of gut microbiota on Chinese medicine components, and co-metabolism effects between gut microbiota and host. We would think and prospect the specific biological effects of Chinese medicines, gut microbiota structures and the relations between endogenous metabolites from "gut microbiota and host co-metabolism". All of these aim to investigate biological mechanisms and effective components of Chinese medicines based on gut microbiota and offer a new strategy for promoting safe and effective application of Chinese medicines. PMID- 28920374 TI - [Application of natural plant pigment in hair dyes]. AB - With the development of living condition, more and more people tend to show unique personality, thus hair dyes as hair cosmetics are highly favored. By the year 2012, the global sales of hair dye had exceeded $15 billion, with a sustained growth at a rate of 8%-10% annually. However, the harm caused by long term use of hair dyes has aroused widespread public concern, so people begin to seek non-toxic or low toxic natural plant hair dyes. The types of commonly used hair dyes and the corresponding dyeing mechanisms were summarized in this manuscript, and the representative natural botanic dyes were listed. Thereafter, their effective fractions, constituents and application status were described. In addition, the values of botanic hair dyes and their broad market prospect were discussed. Finally, the problems that exist in the research and development of plant hair dyes were issued. This review may help to provide thought for developing novel, green and ecological natural plant hair dyes. PMID- 28920375 TI - [Preparation of tanshinone IIA loaded nanostructured lipid carrier and its in vitro transdermal permeation characteristics]. AB - To prepare tanshinone IIA loaded nanostructured lipid carrier (Tan IIA-NLC), and study its in vitro transdermal permeation characteristics. The Tan IIA-NLC was prepared by high pressure homogenization technology and optimized by Box-Behnken design-response surface method, and it was characterized in terms of morphology, particle size, zeta potention, et al. The transdermal permeation of Tan IIA-NLC was evaluated by using Franz diffusion cells. The results showed that, the optimal formulation was as follows: drug/lipid materials ratio 88, GMS/MCT ratio 2, emulsifier concentration 1%, average particle size (182+/-14) nm, polydispersity index PDI (0.190 6+/-0.024 5), zeta potential (-27.8+/- 5.4) mV, encapsulation efficiency EE (86.44%+/-9.26%) and drug loading DL (0.98%+/-0.18%), respectively. The in vitro transdermal permeation results showed that as compared with Tan IIA solution, Tan IIA-NLC had lower transdermal permeation amount after applying drug for 24 h, but its retention in the epidermis was 3.18 times that of solution. These results indicated that the prepared Tan IIA-NLC could effectively increase the regention of Tan IIA in the epidermis, and had a broad application prospect. PMID- 28920376 TI - [Response surface method for optimization of asiatic acid nanoparticles modified with PEG and its enhancing effects on intestinal absorption]. AB - A solvent diffusion method was used to prepare pegylated asiatic acid (AA) loaded nanostructured lipid carriers (p-AA-NLC). Then central composite design-response surface method was used to obtain optimum condition for preparation technology of p-AA-NLC, where PEG/lipid ratio was 8.0% and AA/lipid ratio was 22.0%. Under the optimum condition, the system had particle size of (111.2+/-2.9) nm, Zeta potential of (-37.1+/-0.9) mV, drug loading of (15.4+/-0.2)% and entrapment efficiency greater than 90%. The deviations between observed values and predicated values were all below 5%, indicating that the established model had a good predictability. Meanwhile, a low-speed single pass perfusion model of rat in situ was set up to estimate the absorption kinetics of p-AA-NLC in small intestine, where the effective permeability (Peff), absorption rate constant (Ka) and other parameters were used to evaluate the drug absorption. It turned out that Peff and Ka in p-AA-NLC group were significantly higher than those in unmodified group (P<0.05), indicating that asiatic acid loaded nanostructured lipid carriers (AA-NLC) could enhance the effects on intestinal absorption after being modified with hydrophilic PEG. PMID- 28920377 TI - [Rapid identification of chemical components in Congrong Zonggan capsule by UPLC Q-TOF-MS/MS]. AB - This study was aimed to qualitatively analyze the chemical components in Congrong Zonggan capsule by using ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry method (UPLC-Q-TOF-MS/MS). An Agilent SB-C18 Rapid Resolution HD (3.0 mm*100 mm,1.8 MUm) was used with acetonitrile (A) - 0.1% formic acid solution (B) as the mobile phase for gradient elution. The flow rate was 0.2 mL*min-1; the detection wavelength was set at 330 nm and the column temperature was maintained at 30 C. Electrospray ion (ESI) source was applied for the qualitative analysis under the negative ion mode. Finally, based on comparison with standard samples, database matching analysis and reviewing relevant literature, 41 compounds were identified from Congrong Zonggan capsule. This method could be used to rapidly detect the chemical components in Congrong Zonggan capsule, providing reference for the quality control of Congrong Zonggan capsule and laying a foundation for the further study on active components mechanism. PMID- 28920378 TI - [Chemical constituents from Polygonum multiflorum]. AB - Six compounds were isolated from the ethyl acetate extract of the tuberous root of Polygonum multiflorum by silical gel, ODS revsered-phase silica gel, Sephadex LH-20, and preparative HPLC. The structures were elucidated as column chromatography over: 2, 3, 5, 4'-tetrahydroxystilbene-2-O-(2"-O-p-hydroxybenzoyl) beta-D-glucoside(1),2, 3, 5, 4'-tetrahydroxystilbene-2-O-beta-D-glucoside(2),2, 4, 6, 4'-tetrahydroxystilbene-2-O-beta-D-glucoside(3), emodin-8-O-beta-D glucopyranoside(4), physcion-8-O-beta-D-glucopyranoside(5), and 8-O-methyl emodin(6) on the basis of spectral analysis. Compound 1 is a new stilbene glycoside. PMID- 28920379 TI - [A new sesquiterpene from seeds of Cassia occidentalis and its cytotoxicity]. AB - For the purpose of finding new bioactive agents from ethnic medicines, the chemical study on Dai Medicine Cassia occidentalis was carried out. The chemical constituents from the seeds of C. occidentalis were isolated by column chromatographic methods on silica gel, MCI-Gel resin, Sephadex LH-20, and high performance liquid chromatography. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. The cytotoxicity of the compound for NB4, A549, SHSY5Y, PC3, and MCF7 cells line was also assayed by using the MTT method. Two sesquiterpenes (1 and 2) were isolated from this plant. Compound 1 is a new compound and named as methyl 6 (hydroxymethyl)-4-isopropyl-7-methoxynaphthalene-1-carboxylate. Compound 1 also displayed high cytotoxicity with the tested cancer cell-lines. PMID- 28920380 TI - [Chemical constituents of Myripnois dioica]. AB - To study the chemical constituents of the aerial parts of Myripnois dioica. Twelve compounds were separated from the 95% ethanol extract of M. dioica by using various chromatographic techniques. Their stuctures were identified on the basis of their physicochemical properties and spectral data as 8-desoxyurospermal A(1), zaluzanin C(2), dehydrozaluzanin C(3), glucozaluzanin C(4), macrocliniside B(5), macrocliniside I(6), taraxinic acid-14-O-beta-D-glucopyranoside(7), ainsliaside B(8), apigenin(9), luteolin(10), apigenin-7-O-beta-D glucopyranoside(11), and luteolin-7-O-beta-D-glucopyranoside(12). Except for compound 8, the other compounds were isolated from this genus for the first time. Compound 8 was found to decrease blood glucose level properly in alloxan-induced diabetic mice. PMID- 28920381 TI - [Evaluation analysis of alkaloids in seed of Sophora flavescens from Shanxi province and exploration of its utilization value]. AB - According to the research strategy of resource chemistry of Chinese medicinal materials and Chinese medicinal resources recycling utilization, this study intends to explore the potential resource-oriented utilization value of the seed of Sophora flavescens by contrasting with its kindred plant S. alopecuroides. This study established a rapid UPLC-Q-TOF-MS/MS and UPLC-TQ-MS/MS method to determine the alkaloids in the seed of S. flavescens. Results of UPLC-Q-TOF-MS/MS analysis showed that the alkaloids in the seed of S. flavescens were highly similar with S. alopecuroides.In the determination of 7 kinds of alkaloids, the total content was 11.203 and 15.506 mg*g-1 in the seed of S. flavescens and S. alopecuroides, respectively. The content of oxymatrine, oxysophocarpine and sophoridine is high in the seed of S. flavescens. The results indicated that the seeds of S. flavescens. could be an important material resource to obtain alkaloids. PMID- 28920382 TI - [Study on HPLC fingerprint and chemical constituent difference of different species of Aurantii Fructus Immaturus]. AB - This study is to establish an HPLC fingerprint by HPLC-DAD method and simultaneous quantitative analysis of 17 components of 18 batches of Citrus aurantium and 10 batches of C. sinensis. The separation was performed on an Agilent Poroshell 120 SB-C18 (4.6 mm*100 mm,2.7 MUm) column with the gradient elution of methanol-0.1% formic acid water, the flow was 0.6 mL*min-1. The detection wavelength was set at 318 nm. The column temperature was maintained at 30 C. The data calculation was performed with similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine (Version 2004A) together with SIMCA-P 13.0 software to clarify the differential marker between these two different species of Aurantii Fructus Immaturus. This method has good precision stability and repeatability that could provide basis for quality control and evaluation of Aurantii Fructus Immaturus. PMID- 28920383 TI - [Identification of multidrug resistance gene MDR1 associated microRNA of salvianolic acid A reversal in lung cancer]. AB - This paper was aimed to investigate the microRNA associated with multidrug resistance gene MDR1 of salvianolic acid A reversal in lung cance. Human lung cancer A549 cells were divided into normal control group and drug group, and the MDR1 expression levels were determined by real-time quantitative PCR. MicroRNA expression profiling of normal control group and drug group were detected by using the latest microRNA microarray. Quantitative RT-PCR was used to validate the differentially expressed miRNA. Forecast of miRNA associated with MDR1 multi resistant genes of up-regulated miRNA. Experimental results showed that the dosage of MDR1 expression level significantly lowered compared with control group. The miRNA expression spectrum analyses of human lung cancer A549 cells to drug group and the control group were detected by microRNA microarray, 426 differentially expressed miRNA were screened out. Then target prediction were performed for difference up-expression of miRNA and found that there were four obvious increase of miRNA associated with MDR1 multi-resistant genes. Real-time quantitative PCR for 4 microRNA verification, the results were consistent with the chip. So the author considered that salvianolic acid A down lung cancer multidrug resistance gene MDR1 is likely to be affected by the miRNA expression and regulation of target genes, to further clarify the traditional Chinese medicine to reverse multi-drug resistant mechanism provides the experimental basis. PMID- 28920384 TI - [Puerarin alleviates cognitive impairment and tau hyperphosphorylation in APP/PS1 transgenic mice]. AB - To observe the effect of puerarin on learning and memory function and tau phosphorylation in APP/PS1 transgenic mice, drugs were administered to 3-month old APP/PS1 transgenic mice. Learning and memory function of mice were assessed by Morris water maze test 3 months after treatment. Animals were decapitated after behavioral test. The levels of Abeta were detected by ELISA, the expression of protein [tau, phosphorylated tau, GSK3beta and p-GSK3beta(Ser9)] were assessed by Western blot. Morris water maze test showed that the escape latency of APP/PS1 double transgenic mice was significantly longer than that of the normal control group, and the residence time of the original quadrant was significantly shorter. The escape latency of puerarin group was significantly shorter and the residence time of the original quadrant was prolonged compared with the model group. Compared with the normal control group, the levels of Abeta in the cortex of APP/PS1 transgenic mice were increased, the expression of phosphorylated tau was significantly increased, and the expression of phosphorylated GSK3beta(Ser9) protein was decreased. Treatment with puerarin, the latency of APP/PS1 transgenic mice was significantly reduced, the level of Abeta was decreased, the expression of phosphorylated tau was significantly decreased, and the expression of phosphorylated GSK3beta(Ser9) protein was increased. Puerarin improves the learning and memory impairment by reducing the formation of Abeta, activating the GSK3beta signaling pathway, inhibiting the phosphorylation of tau in APP/PS1 double transgenic mice. PMID- 28920385 TI - [Protection mechanisms of hesperidin on mouse with insulin resistance]. AB - To explore the effects of hesperidin on glycolipid metabolic disorders and its mechanism in mice induced by high-fat diet, 40 male C57 mice were randomly divided into control group, OB group, low dose group (OB+ hes-low) and high dose group (OB+ hes-high) according to the diet. After 16 weeks, the body weight, liver index and visceral fat index in all mice were detected. The glucose metabolism indications (blood glucose, insulin levels and HOMA-IR) and serum lipid levels were evaluated. The mRNA expression of insulin signaling pathway genes(IR, IRS1, Glut2, Glut4), lipid metabolism pathway genes(SREBP-1c, FAS, ACC, PPARalpha) and AMPK were analyzed by Real-time PCR. After 16-week feeding, the indicators in OB group were higher than those in control group, including body weight, body fat deposition, serum glucose, serum lipid, serum insulin and HOMA IR index (P<0.05). And impaired glucose tolerance occurred in the OB group (P<0.05). Treating with hesperidin, whether in low or high dose, attenuated these changes (P<0.05), especially in high dose group(P<0.05). Hesperidin, especially in high dose, upregulated the mRNA expressions of AMPK (P<0.05), which had impact on the gene expressions of insulin signaling pathway (IR, IRS-1, Glut2/4) (P<0.05) and lipid metabolism related genes (SREBP-1c and Fas and ACC) (P<0.05). The activatory effect of hesperidin on the mRNA expressions of PPARalpha was also observed (P<0.05), especially in high dose group (P<0.05). Hesperidin inhibits obesity, hyperglycemia, hyperlipemia and attenuates insulin resistance. These effects might be closed related to the activation of AMPK, which regulate the insulin signaling pathway and lipid metabolism. PMID- 28920386 TI - [In vitro effects of Genkwa Flos chloroform extract on activity of human liver microsomes UGTs and UGT1A1]. AB - To predict the mechanism of liver injury induced by Genkwa Flos, we investigated the effect of chloroform extract on UGTs and UGT1A1 activities of the liver microsomes in rat and human. In the present study, 4-nitrophenol(4-NP) and beta estradiol were elected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC. The results showed that there were 1.00% of apigenin, 6.40% of hydroxygenkwanin and 18.38% of genkwanin in chloroform extract; and total diterpene mass fraction was 31.40%. Compared with the control group, chloroform extract could significantly inhibit the activity of UGTs in rat liver microsomes(RLM) system, while the inhibitory effect was not obvious in human liver microsomes(HLM) system. UGT1A1 activity was inhibited by chloroform extract in rat liver microsomes and human liver microsomes (based on genkwanin, IC50=8.76, 10.36 MUmol*L-1). The inhibition types were non-competitive inhibition(RLM) and uncompetitive inhibition(HLM). In conclusion, the results indicated that chloroform extract showed different inhibitory effects on UGTs and UGT1A1 activity, which may be one of the mechanisms of liver injury induced by Genkwa Flos. PMID- 28920387 TI - [Textual research of diao,ji,li,tiao,di]. AB - Many medicine names were recorded in Shuowen Jiezi. The later scholars interpreted these names, but they had different standpoints on the relationship between the name and nature of some medicines. In this study, the medicine names of diao, ji, li, tiao, and di with greater different standpoints were verified by textual research. Shuowen Jiezi, Erya, Guangya and previous annotations of these exegesis books were combined with herbal literature to summarize and analyze the relevant content. The herbal content in exegesis books were compared with the records in herbal literature to hackle the relationship between name and nature of medicines, clarify the lexical meaning and illustrate the efficacy of the medicines. Meanwhile, the value of herbalism in these exegesis books was explored. PMID- 28920388 TI - [Advances in anti-staling brewer's yeast]. AB - Brewer's yeast is crucial in beer fermentation, mainly beer flavor diversity and stability. Beer flavor stability is one of the most influential beer quality aspects, and screening or breeding brewer's yeast with enhanced anti-staling capacity will be an effective solution. In recent decades, with the progress of genetic engineering and detailed description of brewer's yeast genome, great efforts have been made to improve brewer's yeast. This review highlights recent advances in classical and genetic engineering improvement of yeasts to produce more antioxidant compounds or less beer aging substances and precursors. Therein, improvement targets, evaluation methods and development strategies of anti staling brewer's yeast are also discussed. Furthermore, hotspot and future trend of anti-staling yeast strain development are also proposed. PMID- 28920389 TI - [Research progress in multi-enzyme regulation of genetically engineered bacteria producing lycopene]. AB - Lycopene plays a crucial role in the biosynthesis pathway of 2-methyl-derythritol 4-phosphate (MEP) and mevalonic acid (MVA). It is a representative product of isoprenoid family, and a typical product of multi-enzyme catalytic reaction in organism. In this paper, we first introduced the general regulation methods in multi-enzyme synthesis reaction, including the construction of multi gene co expression plasmid, gene order regulation, promoter and ribosome binding site regulation, gene knockout and replacement, aiming at the optimization strategies of multi-enzyme catalytic reaction in lycopene synthesis pathway. Meanwhile, we introduced several new regulation methods in multi-enzyme reaction, including multi-fragment assembly technology, artificial scaffold self-assembly methods and so on. At last, we summarized the application of these multi-enzyme regulation methods in lycopene synthesis. These methods provide a great inspiration and research foundation for the construction of lycopene-producing strains with high yield. PMID- 28920390 TI - [Advance of heterologous expression study of eukaryote-origin laccases]. AB - Laccases are enzymes belonging to the group of multi-copper oxidases. These enzymes are widely distributed in insects, plants, fungi and bacteria. In general, laccases can oxidize an exceptionally high number of substrates, so they have broad applications in textile, pulp, food and the degradation of lignin. However, low yield, low activity and thermo-instability of laccase in nature limit the application of laccase. High efficient heterologous expression of the protein is an effective way for solving this problem. Here, we summarize the research advances of heterologous expression of eukaryote-origin laccases. We focus on the overexpression of eukaryote-origin laccases using different expression system and the method for improving the production yield and enzyme activity in yeast cells. Information provided in this review would be helpful for researchers in the field. PMID- 28920391 TI - [Progress in metabolic engineering of beta-carotene synthesis]. AB - beta-carotene is an important natural plant pigment and has various physiological functions in organisms. With the proposition of systematic biology and progress in carotenoids biosynthesis since the 1960s, metabolic engineering has played a significant role in enhancing carotenoid production. In this review, we present beta-carotene's traditional production methods and metabolic engineering strategies for constructing beta-carotene-producing strains. Meanwhile, main problems and corresponding solutions to improve beta-carotene yield of engineered strains were further analyzed, for further efficient microbial production of beta carotene. PMID- 28920392 TI - [Strategies to improve the folding and modification of recombinant proteins: a review]. AB - Gene expression technology has made great progress with the continuous developments and researches of molecular biology. Though many systems to produce recombinant proteins have been studied, none of them is available so far to satisfy the needs completely. With the increasing demands of bioactive peptides and protein drugs, expression quantity and correct posttranslational folding and modifications are also needed under the circumstance which can make proteins more close to native conformation and higher activity and stability. Based on our previous work, we summarized the factors affecting the folding and modifications of recombinant proteins correctly from five aspects, including expression system and hosts, secretory expression, coexpression, fusion expression, and the culture conditions, as well as improvement strategies. PMID- 28920393 TI - [Survival elongation of Pseudomonas aeruginosa improves power output of microbial fuel cells]. AB - The secondary metabolites, phenazine products, produced by Pseudomonas aeruginosa can mediate the electrons transfer in microbial fuel cells (MFCs). How increase the total electricity production in MFCs by improving the characteristics of Pseudomonas aeruginosa is one of research hot spots and problems. In this study, P. aeruginosa strain SJTD-1 and its knockout mutant strain SJTD-1 (DeltamvaT) were used to construct MFCs, and the discharge processes of the two MFCs were analyzed to determine the key factors to electricity yields. Results indicated that not only phenazine but also the viable cells in the fermentation broth were essential for the discharge of MFCs. The mutant strain SJTD-1 (DeltamvaT) could produce more phenazine products and continue discharging over 160 hours in MFCs, more than that of the wild-type SJTD-1 strain (90 hours discharging time). The total electricity generated by SJTD-1 (DeltamvaT) strain could achieve 2.32 J in the fermentation process, much higher than the total 1.30 J electricity of the wild-type SJTD-1 strain. Further cell growth analysis showed that the mutant strain SJTD-1 (DeltamvaT) could keep a longer stationary period, survive much longer in MFCs and therefore, discharge more electron than those of the wild-type SJTD-1 strain. Therefore, the cell survival elongation of P. aeruginosa in MFCs could enhance its discharging time and improve the overall energy yield. This work could give a clue to improve the characteristics of MFCs using genetic engineering strain, and could promote related application studies on MFCs. PMID- 28920394 TI - [Bioinformatic analysis and characterization of myxobacteria laccase-like multicopper oxidases]. AB - Laccase is a widely-used environment-friendly copper-containing oxidase found in many plants, insects and fungi. Recently, more and more laccases are also found in bacteria. Myxobacteria are an important bacteria resource. However, myxobacteria are much more difficult to isolate and purify than other bacteria. We used bioinformatic approach to screen myxobacteria proteomes available in NCBI. Based on conserved sequences of four copper binding sites in multicopper oxidase, 30 potential laccase sequences were obtained. Among them, nine genes were synthesized and expressed in Escherichia coli BL21 (DE3). Seven proteins showed laccase activity when tested with traditional laccase substrates. One protein, named rSC-2, was chosen for further research because it exhibited the highest activity towards 2,6-dimethyl phenol (DMP). The molecular weight of rSC-2 was 57 kDa. Its specific activity to DMP was 0.27 U/mg. The optimal temperature and the optimal pH were 60 C and 7.0, respectively. About 50% of the original activity was retained after incubation at 60 C and pH 7.0-8.0 for 1 h. Metals showed different effects on rSC-2. rSC-2 activity was enhanced by several metalsat concentration of 1 mmol/L, such as Ca2+ and Mn2+. With a higher concentration of 5 mmol/L, the activity of rSC-2 was apparently inhibited. This is the first report of bioinformatics screening myxobacteria laccases in combination with expression in E. coli. PMID- 28920396 TI - [Inhibition of chitin oligosaccharide on dyslipidemia and the potential molecular mechanism exploration]. AB - The inhibitory effect of NACOS on dyslipidemia and potential molecular mechanisms by in vitro and in vivo experiments were investigated. For in vitro study, four experimental groups were designed by using HepG2 cells, including the control group, palmitic acid (PA) treatment alone group, NACOS treatment alone group and NACOS + PA treatment group. For in vivo study, male C57BL/6 mice were divided into four groups (n=5) at random including the normal control group (NCD), high fat diet (HFD) group, NACOS treatment alone group, NACOS+HFD group, which were treated for 20 weeks. The used methods in this study were as follows: the observation of lipid droplet deposition in HepG2 cells by oil red O staining, the detection of mRNA levels of lipid metabolism-related regulators and inflammatory cytokine by RT-PCR method, the monitoring of MAPKs and PI3K/Akt pathway activation by Western blotting method. The in vitro study shows that, NACOS had no toxicity on the viability of HepG2 cells at 25-100 MUg/mL and significantly reduced the deposition of lipid droplet. Also, based on both in vitro and in vivo investigation, NACOS evidently down-regulated the expression of lipid metabolism related regulators (PGC1alpha, Cox5b, Mcad) and inflammatory cytokine (IL-1beta) at mRNA level (P<0.05 or 0.01), and suppressed the activation of p38, ERK1/2 and Akt in HepG2 cells and lever tissues from HFD-fed mice (P<0.05 or 0.01). Based on the above, NACOS may inhibit the oxidation of liver mitochondrial fatty acid and the lipid biosynthesis, block the inflammatory responses and prevent the HepG2 cells and C57BL/6 mice from lipidemia. PMID- 28920395 TI - [Inhibition of Fusarium graminearum by silver nanoparticles]. AB - Silver nanoparticles were prepared by chemical reduction. Fusarium graminearum was used as the test strain. To study the inhibition of F. graminearum by silver nanoparticles, we studied the activities of protective enzymes superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and the contents of osmotic adjustment substances soluble protein, soluble sugar and malonaldehyde (MDA) in F. graminearum. Silver nanoparticles inhibited F. graminearum and the inhibitory effect was increased with the concentration of silver nanoparticles. The inhibition rate of 10 MUg/mL silver nanoparticles was more than 90% and EC50 was 0.59 MUg/mL. When the treating time prolonged (2, 4, 6, 8 and 10 h), the activity of SOD, CAT and POD increased firstly and then declined. SOD, POD and CAT reached the maximum at 4 hours, and decreased to minimum at 10 hours. Silver nanoparticles also increased the MDA content and reduced the soluble sugar and protein contents in pathogens. These results indicated that cell integrity was destroyed in the presence of silver. This may be one of the inhibiting mechanisms of silver nanoparticles on the growth of F. graminearum. PMID- 28920397 TI - [Effects of interleukin-34 expressed by human bone marrow derived mesenchymal stem cells on THP-1 cells]. AB - To construct recombinant eukaryotic expression plasmid vector of human IL-34 gene, and to study the effects of IL-34 expressed by human bone marrow-derived mesenchymal stem cells (hBM-MSCs) on THP-1 cells. Full-length IL-34 encoding sequence was amplified by PCR. And this fragment was cloned into the plasmid pIRES2-EGFP. Western blotting and ELISA were used to analyze the expression of IL 34 in hBM-MSCs. THP-1 cells were cultured with hBM-MSCs medium containing IL-34 protein. Real-time PCR detected the effects of IL-34 on the expression of IL-10 and TNFalpha in THP-1 cells. Restrictive enzyme analysis and sequencing demonstrated that IL-34 eukaryotic expression vector was successfully constructed. IL-34 protein expressed by hBM-MSCs could promote IL-10 and TNFalpha expression in THP-1 cells. Those results show that IL-34 expressed by hBM-MSCs has regulating effect on THP-1 cells. PMID- 28920398 TI - [Fermentation, purification and immunogenicity evaluation of hepatitis E virus like particles expressed in Hansenula polymorpha]. AB - To develop a new recombinant hepatitis E vaccine, we used Hansenula polymorpha expression system to express recombinant hepatitis E virus-like particles (HEV VLPs), to construct a recombinant engineered strain HP/HEV2.3. The fermentation conditions and purification process were studied next. The first working seed lots were fermented in liquid culture, and the fermentation products were collected, then crushed, clarified, purified by ultrafiltration, silica gel adsorbed and desorbed, concentrated by ultrafiltration, purified by liquid chromatography and sterilized by filtration. The purity reached 99% with a yield of 33%. Electron microscopy analysis revealed that both the purified recombinant HEV VLPs from HP/HEV2.3 and natural hepatitis E virus particles appear identical of being 32 nm. The resulting DNA sequence obtained from VLPs is identical to the published HEV sequence. The SDS-PAGE analysis has revealed that the protein molecular weight of the HEV VLPs is 56 kDa, and the expression product HEV VLPs were accumulated up to 26% of total cellular protein. The expression level is 1.0 g/L. Western blotting, enzyme-linked immunosorbent assay (ELISA) results of the protein and ED50 of the vaccine showed that the HEV VLPs have good antigenicity and immunogenicity. In summary, the recombinant HEV VLPs from Hansenula polymorpha can be used in the manufacture of a new genetically engineered vaccine against hepatitis E. PMID- 28920399 TI - [ATDC-5 growth promoted by sustained-releasing chitosan microspheres loading TGF beta1 in artificial cartilage scaffolds]. AB - In order to promote the growth of chondrocyte ATDC-5 in collagen type II hyaluronic acid-chondroitin sulfate composite scaffolds constructed previously in vitro, the sustained-releasing chitosan microspheres loading TGF-beta1 were prepared by emulsification and cross-linking. In addition, ATDC-5 was inoculated into the scaffolds incorporating the chitosan microspheres with TGF-beta1. Results show that the morphology of microsphere was round and uniform, mean diameter was about 100 nm, absorption rate was up to 983.7%+/-4.38%.When the microsphere was incubated under the condition of 107 U/L lysozyme, the degradation rate was only 51.0%+/-1.8% on day 28. Moreover, to compare the effect of TGF-beta1, the growth of ATDC-5 in different scaffolds was observed by MTT assay and fluorescence staining test. According to the cumulative release curve, TGF-beta1 was released quickly at initial 24 h, then gradually decelerated, finally reached the plateau after 120 h. MTT assay and fluorescence staining test demonstrated that the scaffolds were suitable for ATDC-5 growth and proliferation, as well as, suggested that the sustained-releasing chitosan microspheres loading TGF-beta1 could significantly promote the growth of ATDC-5. PMID- 28920400 TI - [Production of gastric-mucosa protective collagen III by Pichia pastoris]. AB - To improve collagen production by recombinant Pichia pastoris, we applied Placket Burman and Box-Behnken design to optimize the fermentation medium. Through Placket-Burman design, three variables in the medium (concentration of yeast extract, peptone and glycerol) were selected for having significant effect on cell dry weight. Through Box-Behnken design regression coefficients analysis, a secondary degree polynomial equation was established, and the optimum levels of the three variables were yeast extract 1.13%, peptone 1.61% and glycerol 0.86%. During the growth period, an average cell dry weight of 4.41 g/L was obtained after 12 h fermentation, increased by 26%. Through high density fermentation, the production of recombinant human collagen (III) was up to 4.71 g/L in 22 L fermentor. The recombinant human collagen (III) exhibited good results to repair acetic acid induced gastric ulcer in rats. PMID- 28920401 TI - [Prediction of protein subcellular locations by ensemble of improved K-nearest neighbor]. AB - Adaboost algorithm with improved K-nearest neighbor classifiers is proposed to predict protein subcellular locations. Improved K-nearest neighbor classifier uses three sequence feature vectors including amino acid composition, dipeptide and pseudo amino acid composition of protein sequence. K-nearest neighbor uses Blast in classification stage. The overall success rates by the jackknife test on two data sets of CH317 and Gram1253 are 92.4% and 93.1%. Adaboost algorithm with the novel K-nearest neighbor improved by Blast is an effective method for predicting subcellular locations of proteins. PMID- 28920402 TI - [Preparation and transformation optimization for supercompetent B. subtilis SCK6 cells]. AB - Bacillus subtilis is Gram-positive aerobic bacterium and widely used as a heterologous protein expression host because of its safety and high protein secretion property. However, comparing to Escherichia coli, the low transformation efficiency limits the application of B. subtilis as a host cell for directed evolution of heterologous enzymes. Therefore, we optimized the competent cell preparation conditions for conventional plasmid, including the alteration of the medium, the concentration of inducer, the plasmid type, and other parameters. Compared with the original LB medium, YN medium improved the transformation efficiency by about 4 folds. The transformation efficiency enhanced by about 2 folds under induction with 1.5% xylose for 2 h. In addition, with plasmids prepared from E. coli GM272 strain the transformation efficiency increased by about 3 folds. Combining all these findings, the transformation efficiency of pDG1730 plasmid under the optimized conditions could reach 106 CFU/MUg, which was 2 orders of magnitude higher than that the original. Our findings provide references for directed evolution of enzymes and metabolic engineering in Bacillus subtilis. PMID- 28920403 TI - Comparison of bacterial communities in leachate from decomposing bovine carcasses. AB - OBJECTIVE: Burial is associated with environmental effects such as the contamination of ground or surface water with biological materials generated during the decomposition process. Therefore, bacterial communities in leachates originating from the decomposing bovine carcasses were investigated. METHODS: To understand the process of bovine (Hanwoo) carcass decomposition, we simulated burial using a lab-scale reactor with a volume of 5.15 m3. Leachate samples from 3 carcasses were collected using a peristaltic pump once a month for a period of 5 months, and bacterial communities in samples were identified by pyrosequencing of the 16S rRNA gene. RESULTS: We obtained a total of 110,442 reads from the triplicate samples of various sampling time points (total of 15 samples), and found that the phylum Firmicutes was dominant at most sampling times. Differences in the bacterial communities at the various time points were observed among the triplicate samples. The bacterial communities sampled at 4 months showed the most different compositions. The genera Pseudomonas and Psychrobacter in the phylum Proteobacteria were dominant in all of the samples obtained after 3 months. Bacillaceae, Clostridium, and Clostridiales were found to be predominant after 4 months in the leachate from one carcass, whereas Planococcaceae was found to be a dominant in samples obtained at the first and second months from the other two carcasses. The results showed that potentially pathogenic microbes such as Clostridium derived from bovine leachate could dominate the soil environment of a burial site. CONCLUSION: Our results indicated that the composition of bacterial communities in leachates of a decomposing bovine shifted continuously during the experimental period, with significant changes detected after 4 months of burial. PMID- 28920404 TI - Effects of zearalenone on the localization and expression of the growth hormone receptor gene in the uteri of post-weaning piglets. AB - OBJECTIVE: In this study, we investigated the adverse effects of dietary zearalenone (ZEA) (0.5 to 1.5 mg/kg diet) on the localization and expression of the growth hormone receptor (GHR) in the uteri of post-weaning gilts and explored alternative mechanism of the reproductive toxicity of ZEA on piglets. METHODS: A total of forty healthy piglets (Duroc*Landrace*Large White) aged 28 d were selected for study. Piglets were transferred to single cages after 10 days' adaptation on an obstetric table. The animals were allocated to one of four treatments: a normal basal diet supplemented with 0 (Control), 0.5 (ZEA0.5), 1.0 (ZEA1.0), or 1.5 (ZEA1.5) mg/kg purified ZEA, and fed for 35 d after the 10-d adaptation. Analyzed ZEA concentrations in the diets were 0, 0.52+/-0.07, 1.04+/ 0.03, and 1.51+/-0.13 mg/kg, respectively. At the end of the feeding trial, piglets were euthanized after being fasted for 12 h. Two samples of uterine tissue from each pig were rapidly collected, one of which was stored at -80 degrees C for analysis of the relative mRNA and protein expression of GHR, and the second was promptly fixed in Bouin's solution for immunohistochemical analysis. RESULTS: The relative weight of the uteri and thickness of the myometrium and endometrium increased linearly (p<0.001) and quadratically (p<0.001) with an increasing level of ZEA. The results of immunohistochemical analysis indicated that GHR immunoreactive substance was mainly localizated in the cytoplasm of uterine smooth muscle, glandular epithelial, luminal epithelial, stromal, and vascular endothelial cells. In contrast, nuclear staining was rarely observed. The immunoreactive integrated optic density of GHR in the myometrium, luminal epithelium, glandular epithelium, and whole uteri of weaning gilts increased linearly (p<0.001) and quadratically (p<0.05) with an increasing level of ZEA. The mRNA and protein expression of GHR in the uteri of weaning gilts increased linearly (p<0.001) and quadratically (p<0.05) with an increasing level of ZEA. CONCLUSION: In conclusion, ZEA at a concentration of 0.5 mg/kg was sufficient to significantly thicken the myometrium and endometrium, and at a concentration of 1.0 mg/kg induced a high level of GHR expression to promote growth and development of the uteri. This revealed an alternative molecular mechanism whereby ZEA induces growth and development of the uteri and provides a theoretical basis for the revision of Chinese feed hygiene standards. PMID- 28920405 TI - Effects of processing, particle size and moisturizing of sorghum-based feeds on pellet quality and broiler production. AB - OBJECTIVE: This study aimed to assess the effect of pelleted and expanded sorghum based feeds prepared with different moisture levels and particle size of ingredients on metabolizable energy, ileal digestibility of amino acids and broiler performance. METHODS: The experiment was performed with 720 male broiler chicks of the Cobb strain, with treatments of six replications, with 15 birds each; they were arranged in a completely randomized design and 2*2*2 factorial scheme (pelleted or expanded feed processing, 0.8% or 1.6% moisture addition in the mixer, and particle size of 650 or 850 microns). RESULTS: Higher pellet quality (pellets, % and pellet durability index [PDI]) was obtained in expanded diets and inclusion of 1.6% moisture. The particle size of 850 microns increased the PDI of final diet. All studied treatments had no significant effect on weight gain and broiler carcass and cut yields. Lower feed conversion occurred for birds fed pelleted feed at 42 d. The highest apparent metabolizable energy (AME) and apparent metabolizable energy corrected to zero nitrogen balance (AMEn) values of feed in the initial rearing phase (10 to 13 days) were observed in birds fed pelleted feed or for feed prepared with 1.6% moisture. The highest ileal digestibility coefficients of amino acids were obtained with the consumption of pelleted feed prepared with a particle size of 650 microns and 1.6% moisture. CONCLUSION: Pelleted feed prepared with a milling particle size of 650 microns and 1.6% moisture provided increased ileal digestibility of amino acids and AMEn in the starter period. However, the expanded feed improved pellet quality and feed conversion of broilers at 42 days of age. We conclude that factors such as moisture, particle size and processing affect the pellet quality, and therefore should be considered when attempting to optimize broiler performance. PMID- 28920406 TI - Evaluation of high nutrient diets on litter performance of heat-stressed lactating sows. AB - OBJECTIVE: The present study investigated the litter performance of multiparous sows fed 3% and 6% densified diets at farrowing to weaning during summer with mean maximum room temperature of 30.5 degrees C. METHODS: A total of 60 crossbred multiparous sows were allotted to one of three treatments based on body weight according to a completely randomized design. Three different nutrient levels based on NRC were applied as standard diet (ST; metabolizable energy, 3,300 kcal/kg), high nutrient level 1 (HE1; ST+3% higher energy and 16.59% protein) and high nutrient level 2 (HE2; ST+6% higher energy and 17.04% protein). RESULTS: There was no variation in the body weight change. However, backfat thickness change tended to reduce in HE1 in comparison to ST treatment. Dietary treatments had no effects on feed intake, daily energy intake and weaning-to-estrus interval in lactating sows. Litter size, litter weight at weaning and average daily gain of piglets were significantly greater in sows in HE1 compared with ST, however, no difference was observed between HE2 and ST. Increasing the nutrient levels had no effects on the blood urea nitrogen, glucose, triglyceride, and creatinine at post-farrowing and weaning time. The concentration of follicle stimulating hormone, cortisol and insulin were not affected by dietary treatments either in post-farrowing or weaning time. The concentration of blood luteinizing hormone of sows in ST treatment was numerically less than sows in HE2 treatment at weaning. Milk and colostrum compositions such as protein, fat and lactose were not affected by the treatments. CONCLUSION: An energy level of 3,400 kcal/kg (14.23 MJ/kg) with 166 g/kg crude protein is suggested as the optimal level of dietary nutrients for heat stressed lactating sows with significant beneficial effects on litter size. PMID- 28920407 TI - Effect of mechanically deboned poultry meat content on technological properties and sensory characteristics of lamb and mutton sausages. AB - OBJECTIVE: This study aimed to develop a value-added product concerning technological and sensory characteristics changes of the use of mechanically deboned poultry meat (MDPM) as meat replacer in lamb and mutton emulsion-type sausages (mortadella). METHODS: Sausages were produced with lamb and mutton and with different contents of MDPM. Six treatments, using lamb or mutton and 0%, 30%, and 60% of MDPM in relation to the meat batter, were produced and analyzed for pH, proximal composition, calcium and residual nitrite content, water activity, 2-thiobarbituric acid reactive substances (TBARS), instrumental color and texture profile. The sensory profile of the mortadella's was also evaluated by acceptance test and check-all-that-applies (CATA) analysis. RESULTS: The MDPM addition increased (p<0.05) fat, residual nitrite and calcium content in the all sausage formulations, but mutton sausage had (p<0.05) higher fat and lower moisture content than lamb sausage. The pH, water activity, TBARS index and color was not affected by MDPM additions, while the mutton sausages were significantly redder (higher a*, C*, and lower h degrees ) and darker (lower L*) than lamb sausages. Adding up to 60% of MDPM reduced (p<0.05) sausages hardness and chewiness. Overall, the meat replacement by MDPM increased the sausages acceptance, but the mutton sausage with 30% of MDPM replacer were the most preferred. Consumers related that pink color, glossy appearance, poultry meat like taste, soft texture, juicy and greasy mouth feel to all sausages contain MDPM according to CATA analysis. CONCLUSION: Mutton from culled ewes can be utilized for mortadella production with 30% replacement of lean mutton and fat by MDPM. PMID- 28920408 TI - Characterization of gene expression and genetic variation of horse ERBB receptor feedback inhibitor 1 in Thoroughbreds. AB - OBJECTIVE: This study aimed to test the expression patterns of ERBB receptor feedback inhibitor 1 (ERRFI1) before and after exercise and the association of non-synonymous single-nucleotide polymorphisms (nsSNPs) of horse ERRFI1 with racing traits in Thoroughbreds. METHODS: We performed bioinformatics and gene expression analyses for horse ERRFI1. Transcription factor (TF) binding sites in the 5'-regulatory region of this gene were identified through a tool for prediction of TF-binding site (PROMO). A general linear model was used to detect the association between the nsSNP (LOC42830758 A to G) and race performance. RESULTS: Quantitative polymerase chain reaction analysis showed that expression level of ERRFI1 after exercise was 1.6 times higher than that before exercise. Ten transcription factors were predicted from the ERRFI1 regulatory region. A novel nsSNP (LOC42830758 A to G) was found in ERRFI1, which was associated with three racing traits including average prize money, average racing index, and 3 year-old starts percentile ranking. CONCLUSION: Our analysis will be helpful as a basis for studying genes and SNPs that affect race performance in racehorses. PMID- 28920409 TI - POU class 1 homeobox 1 gene polymorphisms associated with growth traits in Korean native chicken. AB - OBJECTIVE: POU class 1 homeobox 1 (POU1F1) mediates growth hormone expression and activity by altering transcription, eventually resulting in growth rate variations. Therefore, we aimed to identify chicken POU1F1 polymorphisms and evaluate the association between single nucleotide polymorphisms (SNPs) and growth-related traits, and logistic growth curve parameter traits (alpha, beta, and gamma). METHODS: Three SNPs (M_1 to M_3) were used to genotype 585 F1 and 88 F0 birds from five Korean native chicken lines using a polymerase chain reaction restriction fragment length polymorphism method. RESULTS: Single marker analyses and traits association analyses showed that M_2 was significantly associated with body weight at two weeks, weight gain from hatch to 2 weeks, and weight gain from 16 to 18 weeks (p<0.05). M_3 was significantly associated with weight gain from 14 to 16 weeks and from 16 to 18 weeks, and asymptotic body weight (alpha) (p<0.05). No traits were associated with M_1. The POU1F1 haplogroups were significantly associated with weight gain from 14 to 16 weeks (p = 0.020). Linkage disequilibrium test and Haploview analysis shown one main haploblock between M_2 and M_3 SNP. CONCLUSION: Thus, POU1F1 significantly affects the growth of Korean native chickens and their growth curve traits. PMID- 28920410 TI - Effect of seasonal changes on fertility parameters of Holstein dairy cows in subtropical climate of Taiwan. AB - OBJECTIVE: The purpose of this retrospective study was to investigate the relationship between temperature-humidity index (THI), season, and conception rate (CR) of Holstein cows in central Taiwan. METHODS: The mean performance and number of observations were statistically evaluated for various parameters, including age at first service, number of days open, gestation length, CR, and calving interval for different parities. RESULTS: The results indicate that the mean age at first service was 493.2 days; the gestation length was similar across all cows of different parities, ranging from 275.1 to 280.7 days. The overall CR of all inseminations was significantly lower in multiparous cows (47.26%+/-0.22%) than in heifers (57.14%+/-0.11%) (p<0.05). At THI>72 and during the hot season (from June to November), CRs for multiparous cows were significantly reduced compared to that for heifers, while the ratio remained unchanged among heifers for all seasons. CONCLUSION: To achieve a high CR, lactating cows should be bred in winter and spring (from December to May) from the start of the seasonal breeding program, whereas the heifer should be allowed to breed in summer and fall under the subtropical climate in Taiwan. PMID- 28920411 TI - Effect of inclusion level and adaptation duration on digestible energy and nutrient digestibility in palm kernel meal fed to growing-finishing pigs. AB - OBJECTIVE: An experiment was conducted to evaluate effects of inclusion level of palm kernel meal (PKM) and adaptation duration on the digestible energy (DE) and apparent total tract digestibility (ATTD) of chemical constituents in diets fed to growing-finishing pigs. METHODS: Thirty crossbred barrows (Duroc*Landrace*Large White) with an average initial body weight of 85.0+/-2.1 kg were fed 5 diets in a completely randomized design. The diets included a corn soybean meal basal diet and 4 additional diets in which corn and soybean meal were partly replaced by 10%, 20%, 30%, or 40% PKM. After 7 d of adaptation to the experimental diets, feces were collected from d 8 to 12, d 15 to 19, d 22 to 26, and d 29 to 33, respectively. RESULTS: The DE and ATTD of gross energy (GE), dry matter (DM), ash, organic matter (OM), neutral detergent fiber (NDF), acid detergent fiber (ADF), and crude protein (CP) in diets decreased linearly as the dietary PKM increased within each adaptation duration (p< 0.01). Diet containing 19.5% PKM had less DE value and ATTD of all detected items compared with other diets when fed to pigs for 14 days (p<0.05). The ATTD of CP in PKM calculated by 19.5% and 39.0% linearly increased as adaptation duration prolonged from 7 to 28 days (p<0 .01). CONCLUSION: Inclusion level of PKM and adaptation duration had an interactive effect on DE and the ATTD of GE, DM, OM, and CP (p<0.01 or 0.05) but ash, NDF, and ADF in diet (p> 0.05). Considering a stable determination, 21 days of adaptation to a diet containing 19.5% PKM is needed in pigs and a longer adaptation time is recommended as dietary PKM increases. PMID- 28920412 TI - Molecular cloning, purification, expression, and characterization of beta-1, 4 endoglucanase gene (Cel5A) from Eubacterium cellulosolvens sp. isolated from Holstein steers' rumen. AB - OBJECTIVE: This study was conducted to isolate the cellulolytic microorganism from the rumen of Holstein steers and characterize endoglucanase gene (Cel5A) from the isolated microorganism. METHODS: To isolate anaerobic microbes having endoglucanase, rumen fluid was obtained from Holstein steers fed roughage diet. The isolated anaerobic bacteria had 98% similarity with Eubacterium cellulosolvens (E. cellulosolvens) Ce2 (Accession number: AB163733). The Cel5A from isolated E. cellulolsovens sp. was cloned using the published genome sequence and expressed through the Escherichia coli BL21. RESULTS: The maximum activity of recombinant Cel5A (rCel5A) was observed at 50 degrees C and pH 4.0. The enzyme was constant at the temperature range of 20 degrees C to 40 degrees C but also, at the pH range of 3 to 9. The metal ions including Ca2+, K+, Ni2+, Mg2+, and Fe2+ increased the endoglucanase activity but the addition of Mn2+, Cu2+, and Zn2+ decreased. The Km and Vmax value of rCel5A were 14.05 mg/mL and 45.66 MUmol/min/mg. Turnover number, Kcat and catalytic efficiency, Kcat/Km values of rCel5A was 96.69 (s-1) and 6.88 (mL/mg/s), respectively. CONCLUSION: Our results indicated that rCel5A of E. cellulosolvens isolated from Holstein steers had a broad pH range with high stability under various conditions, which might be one of the beneficial characteristics of this enzyme for possible industrial application. PMID- 28920413 TI - Functional role of Forskolin and PD166285 in the development of denuded mouse oocytes. AB - OBJECTIVE: cAMP and mature promoting factor (MPF) play critical roles during the maturation of mammalian oocytes. The aim of this study was to produce the offspring from denuded oocytes (DOs) in mice by regulating cAMP and MPF. METHODS: In this study, we used DOs at the germinal vesicle (GV) stage in mice and regulated levels of cAMP and MPF in DOs by adding Forskolin and PD166285 during in vitro maturation without follicle stimulating hormone and luteinizing hormone, respectively. RESULTS: Combined use of 50 MUM Forskolin for 3 h and 2.5 MUM PD166285 for additional 21 h enhanced the developmental competence of DOs, maturation rate of DOs was 76.71%+/- 4.11%, blastocyst rate was 18.33%+/-4.44% after parthenogenetic activation (PA). The DOs could successfully be fertilized with sperm in vitro, cleavage rate was 17.02%+/-5.82% and blastocyst rate was 5.65%+/-3.10%. Besides, 2-cell in vitro fertilization embryos from DOs produced 4 normal live offspring (4/34). CONCLUSION: The results confirmed that the combination of Forskolin and PD166285 can induce DOs to complete meiosis process and produce normal offspring. PMID- 28920414 TI - Metagenomic analysis of bacterial community structure and diversity of lignocellulolytic bacteria in Vietnamese native goat rumen. AB - OBJECTIVE: In a previous study, analysis of Illumina sequenced metagenomic DNA data of bacteria in Vietnamese goats' rumen showed a high diversity of putative lignocellulolytic genes. In this study, taxonomy speculation of microbial community and lignocellulolytic bacteria population in the rumen was conducted to elucidate a role of bacterial structure for effective degradation of plant materials. METHODS: The metagenomic data had been subjected into Basic Local Alignment Search Tool (BLASTX) algorithm and the National Center for Biotechnology Information non-redundant sequence database. Here the BLASTX hits were further processed by the Metagenome Analyzer program to statistically analyze the abundance of taxa. RESULTS: Microbial community in the rumen is defined by dominance of Bacteroidetes compared to Firmicutes. The ratio of Firmicutes versus Bacteroidetes was 0.36:1. An abundance of Synergistetes was uniquely identified in the goat microbiome may be formed by host genotype. With regard to bacterial lignocellulose degraders, the ratio of lignocellulolytic genes affiliated with Firmicutes compared to the genes linked to Bacteroidetes was 0.11:1, in which the genes encoding putative hemicellulases, carbohydrate esterases, polysaccharide lyases originated from Bacteroidetes were 14 to 20 times higher than from Firmicutes. Firmicutes seem to possess more cellulose hydrolysis capacity showing a Firmicutes/Bacteroidetes ratio of 0.35:1. Analysis of lignocellulolytic potential degraders shows that four species belonged to Bacteroidetes phylum, while two species belonged to Firmicutes phylum harbouring at least 12 different catalytic domains for all lignocellulose pretreatment, cellulose, as well as hemicellulose saccharification. CONCLUSION: Based on these findings, we speculate that increasing the members of Bacteroidetes to keep a low ratio of Firmicutes versus Bacteroidetes in goat rumen has resulted most likely in an increased lignocellulose digestion. PMID- 28920415 TI - Comparative digestibility of nutrients and amino acids in high-fiber diets fed to crossbred barrows of Duroc boars crossed with Berkshire*Jiaxing and Landrace*Yorkshire. AB - OBJECTIVE: This experiment was conducted to determine the differences in the apparent ileal (AID) and total tract digestibility (ATTD) of nutrients and indispensable amino acids (IAA) in high-fiber diets with wheat middlings, rice bran or alfalfa meal fed to Duroc*(Landrace* Yorkshire) (DLY) and Duroc* (Berkshire*Jiaxing) (DBJ) growing barrows. METHODS: Eighteen DLY and 18 DBJ growing barrows were randomly allotted to a 2*3 factorial arrangement involving 2 crossbreeds and 3 high-fiber diets. The experiment lasted 15 d with 10 d for diets adaptation, 3 d for feces collection and 2 d for digesta collection. Three diets were based on corn and soybean meal with 25% wheat middlings, rice bran and alfalfa meal respectively. RESULTS: DBJ had a greater (p<0.05) AID of isoleucine, leucine, lysine, phenylalanine and valine and a lower (p<0.05) AID of methionine than DLY. The hindgut disappearance of acid detergent fiber for DBJ was greater (p<0.05) than DLY. The ATTD of gross energy, dry matter, organic matter, neutral detergent fiber and acid detergent fiber in wheat middlings diet were greater (p<0.05) than in rice bran and alfalfa meal diets. The hindgut disappearance of neutral detergent fiber and acid detergent fiber in wheat middlings diet or rice bran diet were the highest or lowest (p<0.05), and those of alfalfa meal diet were the middle. Barrows fed rice bran diet had a greater (p<0.05) hindgut disappearance of gross energy, dry matter and organic matter and lower hindgut disappearance of neutral detergent fiber and acid detergent fiber than barrows fed alfalfa meal diet. CONCLUSION: DBJ growing barrows showed a significant higher digestibility of fiber in the hindgut and most IAA in the small intestine compared with DLY barrows. The digestibilities of chemical constituents and IAA were affected by the diets formulated with different fiber sources. PMID- 28920416 TI - Effects of aflatoxin B1 combined with ochratoxin A and/or zearalenone on metabolism, immune function, and antioxidant status in lactating dairy goats. AB - OBJECTIVE: This experiment investigated the effects of aflatoxin B1 (AFB1) alone or mixed with ochratoxin A (OTA) and/or zearalenone (ZEA) on the metabolism, immune function, and antioxidant status of dairy goats. METHODS: Fifty lactating Laoshan dairy goats were randomly assigned to one of five treatment groups (n = 10) for 14 days. Goats were fed no additive (control) or administered with 50 MUg AFB1/kg dry matter (DM) (AFB1), 50 MUg AFB1/kg DM+100 MUg OTA/kg DM (AFB1+ OTA), 50 MUg AFB1/kg DM+500 MUg ZEA/kg DM (AFB1+ZEA), or 50 MUg AFB1/kg DM+100 MUg OTA/kg DM+500 MUg ZEA/kg DM (AFB1+OTA+ZEA). RESULTS: Dry matter intake and milk production were lower in goats fed AFB1+OTA+ZEA than in controls. Supplementation with AFB1, OTA, and ZEA significantly decreased red blood cell count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, and mean platelet volume, and significantly increased white blood cell count, when compared with the control group. Compared with control, the combination of AFB1, OTA, and ZEA significantly increased alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities, total bilirubin (TBIL), interleukin-6, and malondialdehyde (MDA), but significantly reduced immunoglobulin A concentration, the activities of superoxide dismutase (SOD) and glutathione peroxides (GSH-Px), and total antioxidant capacity (T-AOC) in serum. Administration of AFB1 combined with OTA led to higher ALP, ALT, TBIL, and MDA, as well as lower milk production, SOD and GSH-Px activities, and T-AOC, than administration of AFB1 combined with ZEA. CONCLUSION: The mixture of AFB1, OTA, and ZEA exerted the greatest adverse effects on dairy goats, meanwhile the deleterious damage of the other mycotoxin combinations were in varying degrees. The findings of this study could provide guidance for the prevention and treatment of the consequences of contamination of animal feeds with combinations of mycotoxin. PMID- 28920417 TI - Effects of deoxynivalenol- and zearalenone-contaminated feed on the gene expression profiles in the kidneys of piglets. AB - OBJECTIVE: Fusarium mycotoxins deoxynivalenol (DON) and zearalenone (ZEN), common contaminants in the feed of farm animals, cause immune function impairment and organ inflammation. Consequently, the main objective of this study was to elucidate DON and ZEN effects on the mRNA expression of pro-inflammatory cytokines and other immune related genes in the kidneys of piglets. METHODS: Fifteen 6-week-old piglets were randomly assigned to three dietary treatments for 4 weeks: control diet, and diets contaminated with either 8 mg DON/kg feed or 0.8 mg ZEN/kg feed. Kidney samples were collected after treatment, and RNA-seq was used to investigate the effects on immune-related genes and gene networks. RESULTS: A total of 186 differentially expressed genes (DEGs) were screened (120 upregulated and 66 downregulated). Gene ontology analysis revealed that the immune response, and cellular and metabolic processes were significantly controlled by these DEGs. The inflammatory stimulation might be an effect of the following enriched Kyoto encyclopedia of genes and genomes pathway analysis found related to immune and disease responses: cytokine-cytokine receptor interaction, chemokine signaling pathway, toll-like receptor signaling pathway, systemic lupus erythematosus (SLE), tuberculosis, Epstein-Barr virus infection, and chemical carcinogenesis. The effects of DON and ZEN on genome-wide expression were assessed, and it was found that the DEGs associated with inflammatory cytokines (interleukin 10 receptor, beta, chemokine [C-X-C motif] ligand 9, CXCL10, chemokine [C-C motif] ligand 4), proliferation (insulin like growth factor binding protein 4, IgG heavy chain, receptor-type tyrosine-protein phosphatase C, cytochrome P450 1A1, ATP-binding cassette sub-family 8), and other immune response networks (lysozyme, complement component 4 binding protein alpha, oligoadenylate synthetase 2, signaling lymphocytic activation molecule-9, alpha aminoadipic semialdehyde dehydrogenase, Ig lambda chain c region, pyruvate dehydrogenase kinase, isozyme 4, carboxylesterase 1), were suppressed by DON and ZEN. CONCLUSION: In summary, our results indicate that high concentrations of DON and ZEN suppress the inflammatory response in kidneys, leading to potential effects on immune homeostasis. PMID- 28920418 TI - Differential characterization of myogenic satellite cells with linolenic and retinoic acid in the presence of thiazolidinediones from prepubertal Korean black goats. AB - OBJECTIVE: Myogenic satellite cells were isolated from semitendinosus muscle of prepubertal Korean black goat to observe the differential effect of linolenic and retinoic acid in thepresence of thiazolidinediones (TZD) and also to observe the production insulin sensitive preadipocyte. METHODS: Cells were characterized for their stemness with cluster of differentiation 34 (CD34), CD13, CD106, CD44, Vimentin surface markers using flow cytometry. Cells characterized themselves as possessing significant (p<0.05) levels of CD13, CD34, CD106, Vimentin revealing their stemness potential. Goat myogenic satellite cells also exhibited CD44, indicating that they possessed a % of stemness factors of adipose lineage apart from their inherent stemness of paxillin factors 3/7. RESULTS: Cells during proliferation stayed absolutely and firmly within the myogenic fate without any external cues and continued to show a significant (p<0.05) fusion index % to express myogenic differentiation, myosin heavy chain, and smooth muscle actin in 2% horse serum. However, confluent myogenic satellite cells were the ones easily turning into adipogenic lineage. Intriguingly, upregulation in adipose specific genetic markers such as peroxisome proliferation-activated receptor gamma, adiponectin, lipoprotein lipase, and CCAAT/enhancer binding protein alpha were observed and confirmed in all given treatments. However, the amount of adipogenesis was found to be statistically significant (p<0.01) with linolenic acid as compared to retinoic acid in combination with TZD's. CONCLUSION: Retinoic acid was found to produce smaller preadipocytes which have been assumed to have insulin sensitization and hence retinoic acid could be used as a potential agent to sensitize tissues to insulin in combination with TZD's to treat diabetic conditions in humans and animals in future. PMID- 28920419 TI - Effects of dietary Spirulina on antioxidant status, lipid profile, immune response and performance characteristics of broiler chickens reared under high ambient temperature. AB - OBJECTIVE: Spirulina has been recognized formerly as a filamentous spiral-shaped blue-green algae but more recently as a genus of photosynthetic bacteria (Arthrospira). This microorganism is considered as a rich source of essential nutrients for human and animals. The present study was conducted to determine potential application of Spirulina for heat-exposed broilers. METHODS: Two hundred and fifty Cobb 500 chicks with male to female in equal ratio with average initial weight of 615.6 g at 17 days of age were divided into 5 treatments with 5 replicates of 10 chicks. Treatment groups were as follows: positive and negative controls with 0% Spirulina supplement and three Spirulina receiving groups with 5 g/kg (0.5%), 10 g/kg (1%), and 20 g/kg (2%) supplementation. Spirulina receiving groups as well as positive control were exposed to high ambient temperature at 36 degrees C for 6 h/d from 38 to 44 days of age. Biochemical variables were measured in serum samples at 35, 38, 42, and 45 days of broiler chickens age. RESULTS: The results showed that supplementation of the diet with Spirulina decreased concentration of stress hormone and some serum lipid parameters while enhanced humoral immunity response and elevated antioxidant status whereas it didn't meaningfully affect performance characteristics. Nevertheless, feed conversion ratio was improved numerically but not statistically in broilers fed with 1% Spirulina under high ambient temperature. CONCLUSION: Overall, the present study suggests that alleviation of adverse impacts due to high ambient temperature at biochemical level including impaired enzymatic antioxidant system, elevated stress hormone and lipid profile can be approached in broiler chickens through supplementation of the diet with Spirulina platensis. PMID- 28920421 TI - Endoscopic Retrograde Cholangiopancreatography in Nonagenarian Patients: Is It Really Safe? AB - BACKGROUND/AIMS: Literature on the safety of endoscopic retrograde cholangiopancreatography (ERCP) in elderly patients is divided. Based on this we decided to examine the safety of ERCP in nonagenarian patients. METHODS: A total of 1,389 patients, with a mean age of 63.94+/-19.62 years, underwent ERCP during the study period. There were 74 patients aged 90 years or older with a mean age of 92.07+/-1.8. Logistic regression showed that nonagenarian patients had a significantly increased odds of in-patient mortality (adjusted odds ratio [AOR]=9.6; 95% confidence interval [CI]=4, 23; p<=0.001). Charlson Comorbidity Index (CCI) >=2 was also an independent predictor of in-patient mortality (AOR=2.4; 95% CI=1.2, 5.2; p=0.021). Age >=90 was not associated with increased adverse events; however emergency procedures (AOR=2.4; 95% CI=1.5, 4; p<0.001) and CCI >=2 (AOR=2.6; 95% CI=1.7, 4.0; p<0.001) were more likely to have adverse events. CONCLUSIONS: Age >=90 and CCI >=2 are independently associated with increased odds of in-patient mortality in patients undergoing ERCP, whereas emergency procedures and CCI >=2 are associated with an increased adverse event rate. Caution must be exercised when considering ERCP in patients aged >=90 years and those with a CCI >=2. PMID- 28920422 TI - Dual-Activator Codoped Upconversion Nanoprobe with Core-Multishell Structure for in Vitro and in Vivo Detection of Hydroxyl Radical. AB - Monitoring the fluctuation of hydroxyl radical (.OH) in the body can serve as an effective tool for the prediction of relative diseases; however, it is highly challenging due to the radical's short lifetime, high reactivity, and extremely low concentration. Sandwich structured lanthanide-doped upconversion nanoparticles (UCNPs) exhibit unique luminescence properties and great prospects in bioimaging. Nonetheless, their rather low luminescence efficiency and intensity are serious limitations for their application. Herein, we report on dual-activator codoped UCNPs with a core-multishell structure that greatly improve the luminescence intensity and lifetime by 46-fold and 2.6-fold, respectively, compared to those of the monoactivator doped sandwich structured UCNPs. Moreover, emitting ions in the designed core-multishell (CMS)-UCNPs were confined in a homogeneous and thin shell layer (~2 nm); thus, the luminescence resonance energy transfer (LRET)-based CMS-UCNPs@azo dye nanoprobe exhibited a largely shortened energy transfer distance and a pronounced luminescence quenching yield (97%), affording the nearly zero background signal and achieving an ultrahigh sensitivity for the detection of .OH (with limit of quantitation (LOQ) of 0.10 fM). With good biocompatibility, low biotoxicity, and enhanced luminescence intensity and lifetime, the developed nanoprobe was competent in monitoring the subtle fluctuation of .OH concentration both in vitro and in vivo. PMID- 28920420 TI - Metachronous Gastric Cancer Following Curative Endoscopic Resection of Early Gastric Cancer. AB - This review article summarizes knowledge about metachronous gastric cancer (MGC) occurring after curative endoscopic resection (ER) of early gastric cancer (EGC), treatment outcomes of patients who developed MGC, and efficacy of Helicobacter pylori eradication to prevent MGC. The incidence of MGC following curative ER increases over time and is higher than in patients undergoing gastrectomy. Increasing age and multifocal EGC are independent risk factors for developing MGC. An MGC following curative ER is usually a small (<20 mm) and differentiated intramucosal cancer. Most MGC lesions are found at an early stage on semiannual or annual surveillance endoscopy and are successfully treated by further ER, with excellent long-term outcomes. Eradication of H. pylori may reduce the risk of MGC following ER of EGC, but further prospective studies with long-term outcomes are required. Surveillance endoscopy following gastric ER should be continued indefinitely, due to the risk of MGC even after successful H. pylori eradication. Risk stratification and tailored endoscopic surveillance schedules need to be developed. PMID- 28920423 TI - Self-Organization of Ions at the Interface between Graphene and Ionic Liquid DEME TFSI. AB - Electrochemical effects manifest as nonlinear responses to an applied electric field in electrochemical devices, and are linked intimately to the molecular orientation of ions in the electric double layer (EDL). Herein, we probe the origin of the electrochemical effect using a double-gate graphene field effect transistor (GFET) of ionic liquid N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium bis(trifluoromethylsulfonyl)imide (DEME-TFSI) top-gate, paired with a ferroelectric Pb0.92La0.08Zr0.52Ti0.48O3 (PLZT) back-gate of compatible gating efficiency. The orientation of the interfacial molecular ions can be extracted by measuring the GFET Dirac point shift, and their dynamic response to ultraviolet visible light and a gate electric field was quantified. We have observed that the strong electrochemical effect is due to the TFSI anions self-organizing on a treated GFET surface. Moreover, a reversible order-disorder transition of TFSI anions self-organized on the GFET surface can be triggered by illuminating the interface with ultraviolet-visible light, revealing that it is a useful method to control the surface ion configuration and the overall performance of the device. PMID- 28920424 TI - Nanotubular Iridium-Cobalt Mixed Oxide Crystalline Architectures Inherited from Cobalt Oxide for Highly Efficient Oxygen Evolution Reaction Catalysis. AB - Here, we report the unique transformation of one-dimensional tubular mixed oxide nanocomposites of iridium (Ir) and cobalt (Co) denoted as IrxCo1-xOy, where x is the relative Ir atomic content to the overall metal content. The formation of a variety of IrxCo1-xOy (0 <= x <= 1) crystalline tubular nanocomposites was readily achieved by electrospinning and subsequent calcination process. Structural characterization clearly confirmed that IrxCo1-xOy polycrystalline nanocomposites had a tubular morphology consisting of Ir/IrO2 and Co3O4, where Ir, Co, and O were homogeneously distributed throughout the entire nanostructures. The facile formation of IrxCo1-xOy nanotubes was mainly ascribed to the inclination of Co3O4 to form the nanotubes during the calcination process, which could play a critical role in providing a template of tubular structure and facilitating the formation of IrO2 by being incorporated with Ir precursors. Furthermore, the electroactivity of obtained IrxCo1-xOy nanotubes was characterized for oxygen evolution reaction (OER) with rotating disk electrode voltammetry in 1 M NaOH aqueous solution. Among diverse IrxCo1-xOy, Ir0.46Co0.54Oy nanotubes showed the best OER activity (the least-positive onset potential, greatest current density, and low Tafel slope), which was even better than that of commercial Ir/C. The Ir0.46Co0.54Oy nanotubes also exhibited a high stability in alkaline electrolyte. Expensive Ir mixed with cheap Co at an optimum ratio showed a greater OER catalytic activity than pure Ir oxide, one of the most efficient OER catalysts. PMID- 28920425 TI - A Far-Red-Emitting Fluorescence Probe for Sensitive and Selective Detection of Peroxynitrite in Live Cells and Tissues. AB - In this study, the far-red-emitting fluorescence probe 1, containing a rhodamine derivative and a hydrazide reactive group, was developed for peroxynitrite detection and imaging. This probe, which is cell permeable and shows high sensitivity and selectivity in fluorometric detection of peroxynitrite over other ROS/RNS, was successfully utilized to detect exogenous and endogenous peroxynitrite in HeLa and RAW 264.7 cells, respectively. More importantly, 1 can also be used to detect endogenous peroxynitrite generated in Pseudomonas aeruginosa (PAO1)-infected mouse bone marrow-derived neutrophils. We anticipate that the new probe will serve as a powerful molecular imaging tool in investigations of the role(s) played by peroxynitrite in a variety of physiological and pathological contexts. PMID- 28920426 TI - Methotrexate-Camptothecin Prodrug Nanoassemblies as a Versatile Nanoplatform for Biomodal Imaging-Guided Self-Active Targeted and Synergistic Chemotherapy. AB - "All-in-one" carrier-free-based nano-multi-drug self-delivery system could combine triple advantages of small molecules, nanoscale characteristics, and synergistic combination therapy together. Researches have showed that dual-acting small-molecular methotrexate (MTX) could target and kill the folate-receptor overexpressing cancer cells. Inspired by this mechanism, a novel collaborative early-phase tumor-selective targeting and late-phase synergistic anticancer approach was developed for the self-assembly of chemotherapeutic drug-drug conjugate, which showed various advantages of more simplicity, efficiency, and flexibility over the conventional approach based only on single or combination cancer chemotherapy. MTX and 10-hydroxyl camptothecin (CPT) were chosen to conjugate through ester linkage. Because of the amphiphilicity and ionicity, MTX CPT conjugates as molecular building blocks could self-assemble into MTX-CPT nanoparticles (MTX-CPT NPs) in aqueous solution, thus notably improving the aqueous solubility of CPT and the membrane permeability of MTX. The MTX-CPT NPs with a precise drug-to-drug ratio showed pH-/esterase-responsive drug release, sequential function "Targeting-Anticancer" switch, and real-time monitoring fluorescence "Off-On" switch. By doping with a lipophilic near-infrared (NIR) cyanine dye (e.g., 1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide, DiR), the prepared DiR-loaded MTX-CPT NPs acted as an effective probe for in vivo NIR fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging. Both in vitro and in vivo studies demonstrated that MTX-CPT NPs could specifically codeliver multidrug to different sites of action with distinct anticancer mechanisms to kill folate-receptor-overexpressing tumor cells in a synergistic way. This novel, simple, and highly convergent self-targeting nanomulti-drug codelivery system exhibited great potential in cancer therapy. PMID- 28920427 TI - Noncontinuously Responding Polymeric Actuators. AB - Reversible movements of current polymeric actuators stem from the continuous response to signals from a controlling unit, and subsequently cannot be interrupted without stopping or eliminating the input trigger. Here, we present actuators based on cross-linked blends of two crystallizable polymers capable of pausing their movements in a defined manner upon continuous cyclic heating and cooling. This noncontinuous actuation can be adjusted by varying the applied heating and cooling rates. The feasibility of these devices for technological applications was shown in a 140 cycle experiment of free-standing noncontinuous shape shifts, as well as by various demonstrators. PMID- 28920428 TI - Inhibition of Human Amylin Amyloidogenesis by Human Amylin-Fragment Peptides: Exploring the Effects of Serine Residues and Oligomerization upon Inhibitory Potency. AB - To date, fragments from within the amyloidogenic-patch region of human amylin (hAM) have been shown to aggregate independently of the full-length peptide. In this study, we show that under certain conditions, both oligomers of NFGAILSS and the monomeric form are capable of inhibiting the aggregation of the full-length hAM sequence. The inhibition, rather than aggregate seeding, observed with the soluble portion of aged NFGAILSS solutions was particularly striking occurring at far substoichiometric levels. Apparently, the oligomer form of this fragment is responsible for inhibiting the transition from random coil to beta-sheet or serves as a disaggregator of hAM beta-oligomers. Sequential deletion of the serine residues from NFGAILSS results in a decrease of inhibition, indicating that these residues are important to the activity of this fragment. We, like others, observed instances of alpha-helix-like CD spectra prior to beta-sheet formation as part of the amyloidogenesis pathway. The partially aggregated sample and the fragments studied display spectroscopic diagnostics, suggesting that they slow down the conversion of full-length hAM monomers to cytotoxic oligomers. PMID- 28920429 TI - Hybrid MoS2/h-BN Nanofillers As Synergic Heat Dissipation and Reinforcement Additives in Epoxy Nanocomposites. AB - Two-dimensional (2D) nanomaterials as molybdenum disulfide (MoS2), hexagonal boron nitride (h-BN), and their hybrid (MoS2/h-BN) were employed as fillers to improve the physical properties of epoxy composites. Nanocomposites were produced in different concentrations and studied in their microstructure, mechanical and thermal properties. The hybrid 2D mixture imparted efficient reinforcement to the epoxy leading to increases of up to 95% in tensile strength, 60% in ultimate strain, and 58% in Young's modulus. Moreover, an enhancement of 203% in thermal conductivity was achieved for the hybrid composite as compared to the pure polymer. The incorporation of MoS2/h-BN mixture nanofillers in epoxy resulted in nanocomposites with multifunctional characteristics for applications that require high mechanical and thermal performance. PMID- 28920430 TI - Click-Functionalized SERS Nanoprobes with Improved Labeling Efficiency and Capability for Cancer Cell Imaging. AB - Precise identification and detection of cancer cells using nanoparticle probes are critically important for early cancer diagnosis and subsequent therapy. We herein develop novel folate receptor (FR)-targeted surface-enhanced Raman scattering (SERS) nanoprobes for cancer cell imaging based on a click coupling strategy. A Raman-active derivative (5,5'-dithiobis(2-nitrobenzoic acid)-N3 (DNBA N3)) is designed with a disulfide bond for covalently anchoring to the surface of hollow gold nanoparticles (HAuNPs) and a terminal azide group for facilitating highly efficient conjugation with the bioligand. Modification of HAuNPs with DNBA N3 yields monolayer coverage of Raman labels absorbed on the nanoparticle surface (HAuNP-DNBA-N3) and strong SERS signals. HAuNP-DNBA-N3 can be simply and effectively conjugated with folate bicyclo[6.1.0]nonyne derivatives via a copper free click reaction. The synthesized nanoprobes (HAuNP-DNBA-folic acid (FA)) exhibit excellent targeted capacities to FR-positive cancer cells relative to FR negative cells through SERS mappings. The receptor-mediated delivery behaviors are confirmed by comparison with the uptake of HAuNP-DNBA-N3 and free FA competition experiments. In addition to its good stability and benign biocompatibility, the developed SERS nanoprobes have great potential for applications in targeted tumor imaging. PMID- 28920431 TI - Isolation and Characterization of a Novel, Highly Selective Astaxanthin-Producing Marine Bacterium. AB - A high-throughput screening approach for astaxanthin-producing bacteria led to the discovery of a novel, highly selective astaxanthin-producing marine bacterium (strain N-5). Phylogenetic analysis based on partial 16S rRNA gene and phenotypic metabolic testing indicated it belongs to the genus Brevundimonas. Therefore, it was designated as Brevundimonas sp. strain N-5. To identify and quantify carotenoids produced by strain N-5, HPLC-DAD and HPLC-MS methods were used. The culture conditions including media, shaking, and time had significant effects on cell growth and carotenoids production including astaxanthin. The total carotenoids were ~601.2 MUg g-1 dry cells including a remarkable amount (364.6 MUg g-1 dry cells) of optically pure astaxanthin (3S, 3'S) isomer, with high selectivity (~60.6%) under medium aeration conditions. Notably, increasing the culture aeration enhanced astaxanthin production up to 85% of total carotenoids. This is the first report that describes a natural, highly selective astaxanthin producing marine bacterium. PMID- 28920432 TI - PLK1-Targeted Fluorescent Tumor Imaging with High Signal-to-Background Ratio. AB - As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, and in vitro and in vivo imaging experiments all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregulated tumors with remarkable signal-to background ratios. These findings represent the first example of small-molecule based fluorescent imaging of tumors using PLK1 as a target, which could provide new avenues for tumor diagnosis and precision therapeutics. PMID- 28920434 TI - Ultralow-Temperature Solution-Processed Aluminum Oxide Dielectrics via Local Structure Control of Nanoclusters. AB - Oxide dielectric materials play a key role in a wide range of high-performance solid-state electronics from semiconductor devices to emerging wearable and soft bioelectronic devices. Although several previous advances are noteworthy, their typical processing temperature still far exceeds the thermal limitations of soft materials, impeding their wide utilization in these emerging fields. Here, we report an innovative route to form highly reliable aluminum oxide dielectric films using an ultralow-temperature (<60 degrees C) solution process with a class of oxide nanocluster precursors. The extremely low-temperature synthesis of oxide dielectric films was achieved by using low-impurity, bulky metal-oxo hydroxy nanoclusters combined with a spatially controllable and highly energetic light activation process. It was noteworthy that the room-temperature light activation process was highly effective in dissociating the metal-oxo-hydroxy clusters, enabling the formation of a dense atomic network at low temperature. The ultralow-temperature solution-processed oxide dielectrics demonstrated high breakdown field (>6 MV cm-1), low leakage (~1 * 10-8 A cm-2 at 2 MV cm-1), and excellent electrical stability comparable to those of vacuum-deposited and high temperature-processed dielectric films. For potential applications of the oxide dielectrics, transparent metal oxides and carbon nanotube active devices as well as integrated circuits were implemented directly on both ultrathin polymeric and highly stretchable substrates. PMID- 28920433 TI - Fluorotryptophan Incorporation Modulates the Structure and Stability of Transthyretin in a Site-Specific Manner. AB - Abnormal deposition of aggregated wild-type (WT) human transthyretin (TTR) and its pathogenic variants is responsible for cardiomyopathy and neuropathy related to TTR amyloidosis. The tryptophan (Trp) fluorescence measurements typically used to study structural changes of TTR do not yield site-specific information on the two Trp residues per TTR protomer. To obtain such information, tryptophan labeled with fluorine at the 5 and 6 positions (5FW and 6FW) was incorporated into TTR. Fluorescence of 5FW and 6FW-labeled WT-TTR (WT-5FW and WT-6FW) and a single-Trp mutant W41Y showed that the photophysics of incorporated fluoro-Trp is consistent with site-specific solvation of the indole ring of W41 and W79. 19F-NMR showed that solvent accessibility depends on both the location of the Trp and the position of the fluorine substituent in the indole ring. Unexpectedly, differences were observed in the rates of aggregation, with WT-6FW aggregating more rapidly than WT-5FW or WT-TTR. Real-time 19F-NMR urea unfolding experiments revealed that WT-5FW is kinetically more stable than WT-6FW, consistent with the aggregation assay. In addition, structural perturbations of residues distant from either Trp site are more extensive in WT-6FW. Notably, residues in the dimer interfaces are perturbed by 6FW at residue 79; pathogenic mutations in these regions are associated with reduced tetramer stability and amyloidogenesis. The differences in behavior that arise from the replacement of a fluorine at the 5 position of a tryptophan with one at the adjacent 6-position emphasize the delicate balance of stability in the TTR tetramer. PMID- 28920435 TI - Molecular Packing, Hydrogen Bonding, and Fast Dynamics in Lysozyme/Trehalose/Glycerol and Trehalose/Glycerol Glasses at Low Hydration. AB - Water and glycerol are well-known to facilitate the structural relaxation of amorphous protein matrices. However, several studies evidenced that they may also limit fast (~picosecond-nanosecond, ps-ns) and small-amplitude (~A) motions of proteins, which govern their stability in freeze-dried sugar mixtures. To determine how they interact with proteins and sugars in glassy matrices and, thereby, modulate their fast dynamics, we performed molecular dynamics (MD) simulations of lysozyme/trehalose/glycerol (LTG) and trehalose/glycerol (TG) mixtures at low glycerol and water concentrations. Upon addition of glycerol and/or water, the glass transition temperature, Tg, of LTG and TG mixtures decreases, the molecular packing of glasses is improved, and the mean-square displacements (MSDs) of lysozyme and trehalose either decrease or increase, depending on the time scale and on the temperature considered. A detailed analysis of the hydrogen bonds (HBs) formed between species reveals that water and glycerol may antiplasticize the fast dynamics of lysozyme and trehalose by increasing the total number and/or the strength of the HBs they form in glassy matrices. PMID- 28920436 TI - Rational Design of Solution-Processed Ti-Fe-O Ternary Oxides for Efficient Planar CH3NH3PbI3 Perovskite Solar Cells with Suppressed Hysteresis. AB - Electron-extraction layer (EEL) plays a critical role in determining the charge extraction and the power conversion efficiencies of the organometal-halide perovskite solar cells (PSCs). In this work, Ti-Fe-O ternary oxides were first developed to work as an efficient EEL in planar PSC. Compared with the widely used TiOx and the pure FeOx, the ternary composites show superior properties in multiple aspects including the excellent stability of the precursor solution, good coverage on the substrates, outstanding electrical properties, and suitable energy levels. By varying the Fe content from 0 to 100% in the Ti-Fe-O composites, the conductivity of the resultant compact layer was markedly improved, confirmed by consistent results from the conductive atomic force microscopy and the linear sweep voltammetry measurements. Meanwhile, the compositional engineering tunes the energy level alignment of the Ti-Fe-O EEL/CH3NH3PbI3 interface to a region that is favorable for obtaining excellent charge-extraction property. The combinational advantages of the Ti-Fe-O composites significantly improved the photovoltaic performance of the as-prepared solar cells. An increase of over 20% in the short-circuit current (JSC) density has been achieved due to a modified EEL conductivity and energy alignment with the perovskite layer. The reduction in the surface recombination and enhancement of the charge collection efficiency also result in about 15% increase in the fill factor. Notably, the device also showed remarkably alleviated hysteresis behavior, revealing a prominently inhibited surface recombination. PMID- 28920437 TI - Real-Time Metabolic Interactions between Two Bacterial Species Using a Carbon Based pH Microsensor as a Scanning Electrochemical Microscopy Probe. AB - We have developed a carbon-based, fast-response potentiometric pH microsensor for use as a scanning electrochemical microscopy (SECM) chemical probe to quantitatively map the microbial metabolic exchange between two bacterial species, commensal Streptococcus gordonii and pathogenic Streptococcus mutans. The 25 MUm diameter H+ ion-selective microelectrode or pH microprobe showed a Nernstian slope of 59 mV/pH and high selectivity against major ions such Na+, K+, Ca2+, and Mg2+. In addition, the unique conductive membrane composition aided us in performing an amperometric approach curve to position the probe and obtain a high-resolution pH map of the microenvironment produced by the lactate-producing S. mutans biofilm. The x-directional pH scan over S. mutans also showed the influence of the pH profile on the metabolic activity of another species, H2O2 producing S. gordonii. When these bacterial species were placed in close spatial proximity, we observed an initial increase in the local H2O2 concentration of approximately 12 +/- 5 MUM above S. gordonii, followed by a gradual decrease in H2O2 concentration (>30 min) to almost zero as lactate was produced, and a subsequent decrease in pH with a more pronounced metabolic output of S. mutans. These results were supported by gene expression and confocal fluorescence microscopic studies. Our findings illustrate that H2O2-producing S. gordonii is dominant while the buffering capacity of saliva is valid (~pH 6.0) but is gradually taken over by S. mutans as the latter species slowly starts decreasing the local pH to 5.0 or less by producing lactic acid. Our observations demonstrate the unique capability of our SECM chemical probes for studying real time metabolic interactions between two bacterial species, which would not otherwise be achievable in traditional assays. PMID- 28920438 TI - Conduction Mechanisms at Interface of AlN/SiN Dielectric Stacks with AlGaN/GaN Heterostructures for Normally-off High Electron Mobility Transistors: Correlating Device Behavior with Nanoscale Interfaces Properties. AB - In this work, the conduction mechanisms at the interface of AlN/SiN dielectric stacks with AlGaN/GaN heterostructures have been studied combining different macroscopic and nanoscale characterizations on bare materials and devices. The AlN/SiN stacks grown on the recessed region of AlGaN/GaN heterostructures have been used as gate dielectric of hybrid metal-insulator-semiconductor high electron mobility transistors (MISHEMTs), showing a normally-off behavior (Vth = +1.2 V), high channel mobility (204 cm2 V-1 s-1), and very good switching behavior (ION/IOFF current ratio of (5-6) * 108 and subthreshold swing of 90 mV/dec). However, the transistors were found to suffer from a positive shift of the threshold voltage during subsequent bias sweeps, which indicates electron trapping in the dielectric stack. To get a complete understanding of the conduction mechanisms and of the charge trapping phenomena in AlN/SiN films, nanoscale current and capacitance measurements by conductive atomic force microscopy (C-AFM) and scanning capacitance microscopy (SCM) have been compared with a macroscopic temperature-dependent characterization of gate current in MIS capacitors. The nanoscale electrical analyses showed the presence of a spatially uniform distribution of electrons trapping states in the insulator and the occurrence of a density of 7 * 108 cm-2 of local and isolated current spots at high bias values. These nanoscale conductive paths can be associated with electrically active defects responsible for the trap-assisted current transport mechanism through the dielectric, observed by the temperature-dependent characterization of the gate current. The results of this study can be relevant for future applications of AlN/SiN bilayers in GaN hybrid MISHEMT technology. PMID- 28920439 TI - Multimaterial 3D Printing of Graphene-Based Electrodes for Electrochemical Energy Storage Using Thermoresponsive Inks. AB - The current lifestyles, increasing population, and limited resources result in energy research being at the forefront of worldwide grand challenges, increasing the demand for sustainable and more efficient energy devices. In this context, additive manufacturing brings the possibility of making electrodes and electrical energy storage devices in any desired three-dimensional (3D) shape and dimensions, while preserving the multifunctional properties of the active materials in terms of surface area and conductivity. This paves the way to optimized and more efficient designs for energy devices. Here, we describe how three-dimensional (3D) printing will allow the fabrication of bespoke devices, with complex geometries, tailored to fit specific requirements and applications, by designing water-based thermoresponsive inks to 3D-print different materials in one step, for example, printing the active material precursor (reduced chemically modified graphene (rCMG)) and the current collector (copper) for supercapacitors or anodes for lithium-ion batteries. The formulation of thermoresponsive inks using Pluronic F127 provides an aqueous-based, robust, flexible, and easily upscalable approach. The devices are designed to provide low resistance interface, enhanced electrical properties, mechanical performance, packing of rCMG, and low active material density while facilitating the postprocessing of the multicomponent 3D-printed structures. The electrode materials are selected to match postprocessing conditions. The reduction of the active material (rCMG) and sintering of the current collector (Cu) take place simultaneously. The electrochemical performance of the rCMG-based self-standing binder-free electrode and the two materials coupled rCMG/Cu printed electrode prove the potential of multimaterial printing in energy applications. PMID- 28920440 TI - Unrestricted Mass Spectrometric Data Analysis for Identification, Localization, and Quantification of Oxidative Protein Modifications. AB - Oxidation generates multiple diverse post-translational modifications resulting in changes in protein structure and function associated with a wide range of diseases. Of these modifications, carbonylations have often been used as hallmarks of oxidative damage. However, accumulating evidence supports the hypothesis that other oxidation products may be quantitatively more important under physiological conditions. To address this issue, we have developed a holistic mass spectrometry-based approach for the simultaneous identification, localization, and quantification of a broad range of oxidative modifications based on so-called "dependent peptides". The strategy involves unrestricted database searches with rigorous filtering focusing on oxidative modifications. The approach was applied to bovine serum albumin and human serum proteins subjected to metal ion-catalyzed oxidation, resulting in the identification of a wide range of different oxidative modifications. The most common modification in the oxidized samples is hydroxylation, but carbonylation, decarboxylation, and dihydroxylation are also abundant, while carbonylation showed the largest increase in abundance relative to nonoxidized samples. Site-specific localization of modified residues reveals several "oxidation hotspots" showing high levels of modification occupancy, including specific histidine, tryptophan, methionine, glutamate, and aspartate residues. The majority of the modifications, however, occur at low occupancy levels on a diversity of side chains. PMID- 28920442 TI - Novelty of Dynamic Process in the Synthesis of Biocompatible Silica Nanotubes by Biomimetic Glycyldodecylamide as a Soft Template. AB - A dynamic process in the synthesis of silica nanotubes (SNTs) by utilizing glycyldodecylamide (GDA) as a soft template was thoroughly investigated. The morphological evolution from GDA to SNTs was deeply explored to elucidate the formation mechanism for optimizing the synthesis procedure. Various analytical tools, namely, XRD, FTIR, SEM, TEM, Z-potential, and N2 adsorption/desorption isotherms, were employed during the synthesis procedure. The interactive structure of GDA was also investigated using TEM-EDX as a function of aging time. These studies revealed the stepwise morphology of nanograin, nanofiber, curved plate, and nanotube in the ethanol/water solution when aged at room temperature. The supramolecular GDA molded the vesicle type nanostructure which was surrounded by silica and facilitated the formation of uniform SNTs. The stimulus for GDA to be curved into a vesicle was the intermolecular hydrogen bonding between adjacent amide groups of the template molecules. This was illustrated by FTIR spectra of GDA-silica intermediate by detecting the transition of amide I peak from 1678 to 1635 cm-1. The effect of hydrogen bonding became stronger when the sample was aged. PMID- 28920441 TI - New Insight of Common Regulatory Pathways in Human Trabecular Meshwork Cells in Response to Dexamethasone and Prednisolone Using an Integrated Quantitative Proteomics: SWATH and MRM-HR Mass Spectrometry. AB - The molecular pathophysiology of corticosteroid-induced ocular hypertension (CIH) is not well understood. To determine the biological mechanisms of CIH, this study investigated protein expression profiles of human trabecular meshwork (hTM) cells in response to dexamethasone and prednisolone treatment. Both discovery-based sequential windowed data independent acquisition of the total high-resolution mass spectra (SWATH-MS) and targeted based high resolution multiple reaction monitoring (MRM-HR) confirmation were applied using a hybrid quadrupole-time-of flight mass spectrometer. A comprehensive list of 1759 proteins (1% FDR) was generated from the hTM. Quantitative proteomics revealed 20 differentially expressed proteins (p-value <= 0.05 and fold-change >= 1.5 or <= 0.67) commonly induced by prednisolone and dexamethasone, both at 300 nM. These included connective tissue growth factor (CTGF) and thrombospondin-1 (THBS1), two proteins previously implicated in ocular hypertension, glaucoma, and the transforming growth factor-beta pathway. Their gene expressions in response to corticosteroids were further confirmed using reverse-transcription polymerase chain reaction. Together with other novel proteins identified in the data sets, additional pathways implicated by these regulated proteins were the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) signaling pathway, integrin cell surface interaction, extracellular matrix (ECM) proteoglycans, and ECM-receptor interaction. Our results indicated that an integrated platform of SWATH-MS and MRM-HR allows high throughput identification and confirmation of novel and known corticosteroid-regulated proteins in trabecular meshwork cells, demonstrating the power of this technique in extending the current understanding of the pathogenesis of CIH. PMID- 28920443 TI - Four Fallacies and an Oversight: Searching for Martian Life. AB - While it is anticipated that future human missions to Mars will increase the amount of biological and organic contamination that might be distributed on that planet, robotic missions continue to grow in capability and complexity, requiring precautions to be taken now to protect Mars, and particularly areas of Mars that might be Special Regions. Such precautionary cleanliness requirements for spacecraft have evolved over the course of the space age, as we have learned more about planetary environments, and are the subject of regular deliberations and decisions sponsored by the Committee on Space Research (COSPAR). COSPAR's planetary protection policy is maintained as an international consensus standard for spacecraft cleanliness that is recognized by the United Nations Committee on the Peaceful Uses of Outer Space. In response to the paper presented in this issue by Fairen et al. (2017), we examine both their concept of evidence for possible life on Mars and their logic in recommending that spacecraft cleanliness requirements be relaxed to access Special Regions "before it is too late." We find that there are shortcomings in their plans to look for evidence of life on Mars, that they do not support their contention that appropriate levels of spacecraft cleanliness are unaffordable, that there are major risks in assuming martian life could be identified by nucleic acid sequence comparison (especially if those sequences are obtained from a Special Region contaminated with Earth life), and that the authors do not justify their contention that exploration with dirty robots, now, is preferable to the possibility that later contamination will be spread by human exploration. We also note that the potential effects of contaminating resources and environments essential to future human occupants of Mars are both significant and not addressed by Fairen et al. (2017). Key Words: Mars-Special Region-Mission-Life detection-Planetary protection. Astrobiology 17, 971-974. PMID- 28920444 TI - MRI findings and demographics of elastofibroma dorsi: assessment of diffusion weighted imaging and contrast enhancement patterns. AB - Background Elastofibroma dorsi is a rare pseudotumoral lesion. Thus, there is no report of magnetic resonance imaging (MRI) findings that investigates multiple patients particularly with respect to diffusion-weighted imaging (DWI) findings and contrast enhancement patterns. Purpose To describe the imaging findings of elastofibroma on MRI, particularly DWI findings and contrast enhancement patterns, and to further investigate patient demographics. Material and Methods Forty-four patients with elastofibroma that underwent MRI were enrolled in this retrospective study. All images were evaluated by two radiologists to visually assess the signal intensity for each sequence. Enhanced elastofibromas were classified into four categories to assess the enhancement pattern. Differences in gender and laterality were also assessed statistically. Results An equal number of men and women were included (n = 22 each). There was no significant difference in laterality ( P = 0.783). All lesions (73 lesions) had low signal intensity on both T1-weighted (T1W) and T2-weighted (T2W) images: heterogeneous in 56, homogeneous in 17. None of the 41 lesions with DWI had true abnormal diffusion restriction. The average ADC value was 1.36 * 10-3 +/- 0.29 mm2/s. All 31 lesions that had contrast-enhanced MRI were classified according to enhancement pattern: homogeneous (three lesions, 9.7%); heterogeneous (15 lesions, 48.4%); streak-like (three lesions, 9.7%); and rim-like (ten lesions, 32.2%). Conclusion There were no statistically significant differences in gender or laterality. Elastofibroma showed homogeneous to heterogeneous low signal intensity on T1W and T2W images. No lesion showed abnormal diffusion restriction, and all lesions demonstrated enhancement on MRI. PMID- 28920445 TI - Recovery of bioactive molecules from chestnut (Castanea sativa Mill.) by-products through extraction by different solvents. AB - The underutilised forest and industrial biomass of Castanea sativa (Mill.) is generally discarded during post-harvest and food processing, with high impact on environmental quality. The searching on alternative sources of natural antioxidants from low-cost supplies, by methods involving environment-friendly techniques, has become a major goal of numerous researches in recent times. The aim of the present study was the set-up of a biomolecules extraction procedure from chestnut leaves, burs and shells and the assessing of their potential antioxidant activity. Boiling water was the best extraction solvent referring to polyphenols from chestnut shells and burs, whereas the most efficient for leaves resulted 60% ethanol at room temperature. Greatest polyphenol contents were 90.35, 60.01 and 17.68 mg gallic acid equivalents g-1 in leaves, burs and shells, respectively. Moreover, flavonoids, tannins and antioxidant activity were assessed on the best extract obtained from each chestnut by-product. PMID- 28920446 TI - Key considerations for LC-MS analysis of protein biotherapeutics in tissues. PMID- 28920447 TI - Synthesis and cytotoxic activity of 4-O-beta-D-galactopyranosyl derivatives of phenolic acids esters. AB - The glycosylation of naturally occurring phenolic acids has a significant impact on their solubility, stability and physiochemical properties. D-Galactose residue was found to form a part of glycoconjugates in several tissues and involved in a variety of physiological process. To the best of our knowledge, we have noticed a little information about the glycosylation of the phenolic acids with galactose residue. In this work, we describe the glycosylation of methyl vanillate and methyl ferulate with peracetylated-beta-D-galactopyranose in the presence of BF3.OEt2. The coupling reaction yielded efficiently and selectively only the acetylated beta-D-galactopyranosides 3 and 6. Removal of the acetyl groups using sodium methoxide afforded the corresponding beta-D-galactopyranosides 4 and 7 in good yields. Anticancer activity in vitro was evaluated against two human cancer cell lines (MCF-7 breast cancer cell lines and PC-3 prostate cancer cell lines). beta-D-galactopyranosides 4 and 7 demonstrated improved cytotoxic activity compared to the parental esters. PMID- 28920449 TI - The relationship between migraine and rosacea: Systematic review and meta analysis. AB - Objective To systematically review the association between migraine and rosacea. Background Migraine is a complex disorder with episodes of headache, nausea, photo- and phonophobia. Rosacea is an inflammatory skin condition with flushing, erythema, telangiectasia, papules, and pustules. Both are chronic disorders with exacerbations of symptoms almost exclusively in areas innervated by the trigeminal nerve. Previous studies found an association between these disorders. We review these findings, provide a meta-analysis, and discuss possible pathophysiological commonalities. Methods A search through PubMed and EMBASE was undertaken for studies investigating the association between all forms of migraine and rosacea published until November 2016, and meta-analysis of eligible studies. Results Nine studies on eight populations were identified. Studies differed in methodology and diagnostic process, but all investigated co occurrence of migraine and rosacea. Four studies were eligible for meta-analysis, resulting in a pooled odds ratio of 1.96 (95% confidence interval 1.41-2.72) for migraine in a rosacea population compared to a non-rosacea population. Conclusion Our meta-analysis confirmed an association in occurrence of migraine and rosacea. Future studies should specifically investigate possible shared pathophysiological mechanisms between the two disorders. PMID- 28920450 TI - Singlicate analysis in regulated bioanalysis using ligand-binding assays: where are we heading? PMID- 28920448 TI - Assessing the impact of headaches and the outcomes of treatment: A systematic review of patient-reported outcome measures (PROMs). AB - Aims To critically appraise, compare and synthesise the quality and acceptability of multi-item patient reported outcome measures for adults with chronic or episodic headache. Methods Systematic literature searches of major databases (1980-2016) to identify published evidence of PROM measurement and practical properties. Data on study quality (COSMIN), measurement and practical properties per measure were extracted and assessed against accepted standards to inform an evidence synthesis. Results From 10,903 reviewed abstracts, 103 articles were assessed in full; 46 provided evidence for 23 PROMs: Eleven specific to the health-related impact of migraine (n = 5) or headache (n = 6); six assessed migraine-specific treatment response/satisfaction; six were generic measures. Evidence for measurement validity and score interpretation was strongest for two measures of impact, Migraine-Specific Quality of Life Questionnaire (MSQ v2.1) and Headache Impact Test 6-item (HIT-6), and one of treatment response, the Patient Perception of Migraine Questionnaire (PPMQ-R). Evidence of reliability was limited, but acceptable for the HIT-6. Responsiveness was rarely evaluated. Evidence for the remaining measures was limited. Patient involvement was limited and poorly reported. Conclusion While evidence is limited, three measures have acceptable evidence of reliability and validity: HIT-6, MSQ v2.1 and PPMQ-R. Only the HIT-6 has acceptable evidence supporting its completion by all "headache" populations. PMID- 28920451 TI - Demonstrating biosimilar and originator antidrug antibody binding comparability in antidrug antibody assays: a practical approach. AB - Biosimilar drug development has brought new challenges to bioanalytical ligand binding assays used to determine drug concentration, antidrug antibodies and neutralizing antibodies. One particular challenge is how to demonstrate that the antidrug antibody assay can adequately detect antibodies against both biosimilar and originator. In this paper, we review the current guidelines and literature for practical recommendations and present a gap analysis. Case examples of antibody binding comparability testing are presented, and the challenges and implications are discussed. Based on the lessons learned from our biosimilar assay applications, we recommend a bioanalytical comparability testing approach that is outlined and discussed. PMID- 28920452 TI - Challenges and opportunities in bioanalytical support for gene therapy medicinal product development. AB - Gene and nucleic acid therapies have demonstrated patient benefits to address unmet medical needs. Beside considerations regarding the biological nature of the gene therapy, the quality of bioanalytical methods plays an important role in ensuring the success of these novel therapies. Inconsistent approaches among bioanalytical labs during preclinical and clinical phases have been observed. There are many underlying reasons for this inconsistency. Various platforms and reagents used in quantitative methods, lacking of detailed regulatory guidance on method validation and uncertainty of immunogenicity strategy in supporting gene therapy may all be influential. This review summarizes recent practices and considerations in bioanalytical support of pharmacokinetics/pharmacodynamics and immunogenicity evaluations in gene therapy development with insight into method design, development and validations. PMID- 28920455 TI - A new 4-arylflavan from the pericarps of Horsfieldia motleyi displaying dual inhibition against alpha-glucosidase and free radicals. AB - In search for effective antidiabetic agents that simultaneously inhibit alpha glucosidase and scavenge free radicals, Horsfieldia motleyi showed promising bioactivity according to the proposed criteria. Bioassay-guided isolation of pericarp extract yielded a new 4-arylflavan named myristinin G (6), whose gross structure and absolute configuration were verified by 2D NMR and electronic circular dichorism (ECD). Myristinin G (6) concomitantly inhibited alpha glucosidases (IC50 107.0 and 126.9 MUM) and free radicals (SC50 54.3 and 279.9 MUM). Of interest, 6 inhibited sucrase through an uncompetitive manner, which is rare in nature. PMID- 28920454 TI - Investigation of O-glycosylation heterogeneity of recombinant coagulation factor IX using LC-MS/MS. AB - AIM: Recombinant coagulation factor IX (rFIX) has extraordinarily multiple post translational modifications including N-glycosylation and O-glycosylation which have a drastic effect on biological functions and in vivo recovery. Unlike N glycosylation extensively characterized, there are a few studies on O glycosylation due to its intrinsic complexity. In-depth O-glycosylation analysis is necessary to better understand and assess pharmacological activity of rFIX. RESULTS: We determined unusual O-glycosylations including O-fucosylation and O glucosylation which were located at Serine 53 and 61, respectively in EGF domain. Other O-glycosylations bearing core 1 glycan moiety were found on activation peptide. CONCLUSION: This is the first comprehensive study to characterize O glycosylation of rFIX using MS-based glycomic and glycoproteomic approaches. Site specific profiling will be a powerful platform to determine bioequivalence of biosimilars. PMID- 28920456 TI - Child Sexual Abuse Prevention Opportunities: Parenting, Programs, and the Reduction of Risk. AB - To date, child sexual abuse (CSA) prevention has relied largely on child-focused education, teaching children how to identify, avoid, and disclose sexual abuse. The purpose of this article is to explore how prevention opportunities can include parents in new and innovative ways. We propose that parents can play a significant role as protectors of their children via two pathways: (i) directly, through the strong external barriers afforded by parent supervision, monitoring, and involvement; and (ii) indirectly, by promoting their children's self efficacy, competence, well-being, and self-esteem, which the balance of evidence suggests will help them become less likely targets for abuse and more able to respond appropriately and disclose abuse if it occurs. In this article, we first describe why teaching young children about CSA protective behaviors might not be sufficient for prevention. We then narratively review the existing research on parents and prevention and the parenting and family circumstances that may increase a child's risk of experiencing sexual abuse. Finally, we make a number of recommendations for future approaches to prevention that may better inform and involve parents and other adult protectors in preventing CSA. PMID- 28920453 TI - Sensitive and comprehensive analysis of O-glycosylation in biotherapeutics: a case study of novel erythropoiesis stimulating protein. AB - AIM: Glycosylation of recombinant human erythropoietins (rhEPOs) is significantly associated with drug's quality and potency. Thus, comprehensive characterization of glycosylation is vital to assess the biotherapeutic quality and establish the equivalency of biosimilar rhEPOs. However, current glycan analysis mainly focuses on the N-glycans due to the absence of analytical tools to liberate O-glycans with high sensitivity. We developed selective and sensitive method to profile native O-glycans on rhEPOs. RESULTS: O-glycosylation on rhEPO including O acetylation on a sialic acid was comprehensively characterized. Details such as O glycan structure and O-acetyl-modification site were obtained from tandem MS. CONCLUSION: This method may be applied to QC and batch analysis of not only rhEPOs but also other biotherapeutics bearing multiple O-glycosylations. PMID- 28920457 TI - Implementing a tiered approach to bioanalytical method validation for large molecule ligand-binding assay methods in pharmacokinetic assessments. AB - Bioanalytical methods must enable the delivery of data that meet sound, scientifically justified, fit-for-purpose criteria. At early phases of biotherapeutic drug development, suitable criteria of a ligand-binding assay could be met for pharmacokinetic (PK) in-study sample testing without a full validation defined by regulatory guidelines. To ensure fit-for-purpose methods support PK testing through all phases of biotherapeutic development, three tiers of method validation - regulatory, scientific and research validations - are proposed. The three-tiered framework for method validation outlines the differences in the parameters that should be assessed, the acceptance criteria that may be applied, and the documentation necessary at each level. The criteria for selecting the appropriate application of each of these PK method validation workflows are discussed. PMID- 28920458 TI - Nordic walking increases circulating VEGF more than traditional walking training in postmenopause. AB - OBJECTIVES: Nordic walking (NW) is widely practiced by postmenopausal women. Its effects are peculiar owing to the involvement of more muscle groups than in traditional walking training (WT). Since mechanical load promotes secretion of vascular endothelial growth factor (VEGF) from both skeletal muscle and muscle endothelium, the aim of the study was to compare the effect of NW and WT on VEGF levels. METHOD: Thirty postmenopausal women were randomly assigned to NW or WT. Both groups trained 40-50 min/day, three times per week, at a mean intensity of 12 on a 15-category scale of the ratings of perceived exertion. Since VEGF is also released from adipocytes, anthropometric parameters were assessed. RESULTS: NW increased circulating VEGF more than WT (p = 0.041). Furthermore, both study groups exhibited an average decrease in weight (p = 0.023), body mass index (p = 0.024), hip circumference (p = 0.001), and arm fat index, although WT participants had higher values for this index at baseline (p < 0.001) and thus exhibited a greater net decrease compared with the NW participants (p < 0.011). CONCLUSIONS: These data imply that NW increases the level of circulating VEGF more than does traditional walking when the intensity of training is equivalent. PMID- 28920459 TI - ALSUntangled 42: Elysium health's "basis". PMID- 28920460 TI - In situ biobutanol recovery from clostridial fermentations: a critical review. AB - Butanol is a precursor of many industrial chemicals, and a fuel that is more energetic, safer and easier to handle than ethanol. Fermentative biobutanol can be produced using renewable carbon sources such as agro-industrial residues and lignocellulosic biomass. Solventogenic clostridia are known as the most preeminent biobutanol producers. However, until now, solvent production through the fermentative routes is still not economically competitive compared to the petrochemical approaches, because the butanol is toxic to their own producer bacteria, and thus, the production capability is limited by the butanol tolerance of producing cells. In order to relieve butanol toxicity to the cells and improve the butanol production, many recovery strategies (either in situ or downstream of the fermentation) have been attempted by many researchers and varied success has been achieved. In this article, we summarize in situ recovery techniques that have been applied to butanol production through Clostridium fermentation, including liquid-liquid extraction, perstraction, reactive extraction, adsorption, pervaporation, vacuum fermentation, flash fermentation and gas stripping. We offer a prospective and an opinion about the past, present and the future of these techniques, such as the application of advanced membrane technology and use of recent extractants, including polymer solutions and ionic liquids, as well as the application of these techniques to assist the in situ synthesis of butanol derivatives. PMID- 28920461 TI - Discovery and development of tramadol for the treatment of pain. AB - INTRODUCTION: Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed. Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its 'mild effect' on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics. PMID- 28920463 TI - Evaluation of genotoxicity and subchronic toxicity of standardized rose hip extract. AB - Rose hip is the fruit of the rose plant, which is widely used in food, cosmetics and as a traditional medicine. Therefore, rose hip is considered safe and has a sufficient history of consumption as food. However, few studies have reported on the safety of rose hip extracts in toxicological analyses. Thus, to evaluate the safety of rosehip polyphenol MJ (RHPMJ), an aqueous ethanol extract standardized with the trans-tiliroside content, we performed genotoxicity and 90-day repeated oral dose toxicity studies in compliance with the Organisation for Economic Co operation and Development-Good Laboratory Practice. RHPMJ did not induce gene mutations in reverse mutation tests of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA strains and did not induce chromosomal aberrations in cultured Chinese hamster lung (CHL/IU) cells. Moreover, micronucleus tests using rat bone marrow showed RHPMJ had no micronucleus-inducing potential. Finally, 90-day repeated oral dose toxicity studies (100-1000 mg/kg) in male and female rats showed no treatment-related toxicity in rats. These data indicate that the RHPMJ had no genotoxicity and a no observed-adverse-effect level greater than 1000 mg/kg in rats. PMID- 28920462 TI - Involvement of atrial natriuretic peptide in abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart. AB - BACKGROUND: Nitric oxide (NO) is an effective mediator of ischemic preconditioning (IPC)-induced cardioprotection. Atrial natriuretic peptide (ANP) is downregulated after ovariectomy, which results in reduction in the level of NO. The present study deals with the investigation of the role of ANP in abrogated cardioprotective effect of IPC in the ovariectomized rat heart. METHODS: Heart was isolated from ovariectomized rat and mounted on Langendorff's apparatus, subjected to 30 min of ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Krebs Henseleit solution. The myocardial infract size was estimated employing triphenyltetrazolium chloride stain, and coronary effluent was analyzed for creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release to consider the degree of myocardial injury. The cardiac release of NO was estimated by measuring the level of nitrite in coronary effluent. RESULTS: IPC-mediated cardioprotection was significantly attenuated in ovariectomized rat as compared to normal rat, which was restored by perfusion with ANP. However, this observed cardioprotection was significantly attenuated by perfusion with L-NAME, an endothelial nitric oxide synthase inhibitor, and Glibenclamide, a KATP channel blocker, alone or in combination noted in terms of increase in myocardial infract size, release of CK-MB and LDH, and also decrease in release of NO. CONCLUSION: Thus, it is suggested that ANP restores the attenuated cardioprotective effect of IPC in the ovariectomized rat heart which may be due to increase in the availability of NO and consequent increase activation of mitochondrial KATP channels. PMID- 28920464 TI - Absorption sites of orally administered drugs in the small intestine. AB - INTRODUCTION: In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors. Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies. Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy. PMID- 28920465 TI - Fish-oil-derived eicosapentaenoic acid decreases survivin expression and induces wt-p53 accumulation with caspase-3 activation in acute lymphoblastic leukemia cells. AB - BACKGROUND: Defects in modulating wild-type (wt) p53 and survivin are associated with a resistant disease in acute lymphoblastic leukemia (ALL). Yet, no wt-p53 and survivin modulating drugs have been approved for clinical application in ALL. Here, we investigated if in vitro eicosapentaenoic acid (EPA) concentrations equal to human plasma levels are able to target wt-p53 and survivin. METHODS: Wt p53 Molt-4 cells (ALL cell line) were treated with 50, 100, 150, and 200 uM of EPA after which cell number, viability, proliferation rate, survivin expression, wt-p53 accumulation, caspase-3 activation, and apoptosis were evaluated. RESULTS: After 48- and 72-h treatments with EPA at concentrations ranging from 50 to 200 uM, cell proliferation rates were measured to be 71.5-32.6% and 68.2-13.7% and metabolic activities were measured to be 77-44% and 71-26%, respectively. Treatment with 50-200 uM of EPA for 48 h resulted in 14.1-74.6% and 69.5-45.5% decreases in survivin mRNA and protein levels, respectively. EPA induced 1.3-6 and 1.9-20-fold increases in caspase-3 activation and wt-p53 accumulation, respectively. Increase in wt-p53/survivin and caspase-3/survivin ratios from 1 in untreated cells to 20.3 and 5.8 was measured for 150 uM of EPA. Low necrotic rates ranging from 0.3% to 2.8% and an increase in the number of total apoptotic cells (early + late) ranging from 9.8% to 81% were also observed with increasing EPA concentrations. CONCLUSION: EPA induces strongly wt-p53 with a remarkable decrease in survivin expression, representing an attractive compound to modulate wt-p53 and survivin in ALL cells. PMID- 28920466 TI - Evaluation of the revised Schwartz creatinine-based glomerular filtration rate estimating equation in Black African children in KwaZulu-Natal, South Africa. AB - Background The use of serum creatinine equations for estimating glomerular filtration rate is well known in adults and children. We evaluated the revised Schwartz creatinine-based estimated glomerular filtration rate prediction equation in Black African children in KwaZulu-Natal, South Africa. Methods Review of medical records of all Black African patients aged 2-18 years old who have had glomerular filtration rate determined by intravenous Technetium-99 m-diethylene triamine-pentaacetate, for the period 1 January 2010 to 31 December 2014 at the Inkosi Albert Luthuli Central Hospital, Durban, South Africa was performed. Estimated glomerular filtration rate result obtained using the revised Schwartz equation was compared to Technetium-99 m-diethylene-triamine-pentaacetate plasma clearance measured glomerular filtration rate. Accuracy of the estimated glomerular filtration rate equations within 10% (P10) and 30% (P30) of the measured glomerular filtration rate, sensitivity and specificity for predicting glomerular filtration rate < 60 mL/min/1.73 m2 and < 30 mL/min/1.73 m2 was determined. Results Results from 148 African children between 2 and 18 years old were analysed. P10 and P30 values were 16 and 49%, respectively. Sensitivity of 92.9% (95% CI: 80.5-85), specificity of 95.3 (95% CI: 89.3-98.5) and AUC of 0.96 (95% CI 0.92-0.99) were obtained for measured estimated glomerular filtration rate < 60 mL/min/1.73 m2. Sensitivity of 88.2% (95% CI: 63.6-98.5), specificity of 90.8 (95% CI: 84.5-95.2) and area under the curve of 0.93 (95% CI 0.88-0.96) were obtained for measured estimated glomerular filtration rate < 30 mL/min/1.73 m2. Conclusions The revised Schwartz equation did not meet the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines of 90% of estimated glomerular filtration rate results within 30% of measured glomerular filtration rate. PMID- 28920467 TI - Association of subcutaneous and visceral fat with circulating microRNAs in a middle-aged Japanese population. AB - Purpose It has been demonstrated that circulating microRNA profiles are affected by physiological conditions. Several studies have demonstrated that microRNAs play important roles in the regulation of adiposity. However, few have investigated the relationship between circulating microRNAs and obesity, which has become a major public health problem worldwide. This study investigated the association between circulating microRNAs and obesity in a Japanese population. Methods Obesity parameters, such as subcutaneous and visceral fat adipose tissue, body fat percentage, and body mass index were assessed in a cross-sectional sample of 526 participants who attended health examinations in Yakumo, Japan. In addition, five circulating microRNAs (miR-20a, -21, -27a, -103a, and -320), which are involved in adipocyte proliferation and differentiation, were quantified using real-time polymerase chain reaction amplification. Results We compared the circulating microRNA concentrations in a percentile greater than 75th (high) with below the value (low) of subcutaneous adipose tissue, visceral fat adipose tissue, body mass index, and per cent body fat. For visceral fat adipose tissue, significant decrease in miR-320 expression was observed in high group. Also, for body mass index, significant change of miR-20a, -27a, 103a, and 320 expression level was observed in high group. Multiple linear regression analysis demonstrated that circulating levels of some microRNA such as miR-27a were significantly associated with subcutaneous adipose tissue, visceral fat adipose tissue, and body mass index. Conclusions Our findings support the need for further studies to determine whether such changes are consistent across different populations and whether the identified microRNAs may represent novel biomarkers to predict the susceptibility and progression of obesity-related disorders. PMID- 28920468 TI - Macrocomplexes and discordant high-sensitivity cardiac troponin concentrations. AB - Background Analytical comparisons between different high-sensitivity cardiac troponin (hs-cTn) assays are important for reassurance of results performed with different methodologies and to identify potential interferences or confounders to result interpretation. Our objective in the present study was to compare Beckman Coulter's latest hs-cTnI assay to Abbott's hs-cTnI assay and to assess agreement between results. Methods Two hundred ethylenediaminetetraacetic acid plasma samples that had clinically reported hs-cTnI results from the Abbott ARCHITECTi2000 that spanned the analytical range were stored (median = 4 h), re centrifuged and retested for hs-cTnI on the Abbott ARCHITECTi1000 and Beckman Coulter Access2 analysers. Passing-Bablok regression and fold-differences were evaluated, with differences approximately three-fold between results further subjected to Roche hs-cTnT testing and polyethylene glycol precipitation. Results The Beckman and Abbott hs-cTnI concentrations were correlated ( r = 0.95) with Beckman yielding proportionally lower concentrations (slope = 0.78; 95%CI: 0.74 0.85). There were 12 samples that yielded Abbott hs-TnI concentrations >=3-fold higher than the Beckman hs-cTnI concentrations; of which nine samples from seven different patients had sufficient quantity for additional testing. All seven patients had macrocomplexes as determined with polyethylene glycol precipitation that affected the Abbott hs-cTnI assay. One patient with Abbott hs-cTnI results >1300 ng/L had polyethylene glycol, heterophile antibodies and creatine kinase-MB testing performed which confirmed that a macrocomplex most likely affected the Abbott and Roche (hs-cTnT = 65 ng/L) assays but not the Beckman (hs-cTnI = 12 ng/L) assay. Conclusion The hs-cTnI concentrations obtained from ethylenediaminetetraacetic acid plasma between the Beckman and Abbott assays are highly correlated, with large differences in concentrations (>=3-fold) between Abbott and Beckman assays possible due to macrocomplexes. PMID- 28920471 TI - Unilateral Blepharitis With Fine Follicular Scaling. PMID- 28920470 TI - Silver Nitrate Staining of the Fingernails. PMID- 28920469 TI - The canonical way to make a heart: beta-catenin and plakoglobin in heart development and remodeling. AB - The main mediator of the canonical Wnt pathway, beta-catenin, is a major effector of embryonic development, postnatal tissue homeostasis, and adult tissue regeneration. The requirement for beta-catenin in cardiogenesis and embryogenesis has been well established. However, many questions regarding the molecular mechanisms by which beta-catenin and canonical Wnt signaling regulate these developmental processes remain unanswered. An interesting question that emerged from our studies concerns how beta-catenin signaling is modulated through interaction with other factors. Recent experimental data implicate new players in canonical Wnt signaling, particularly those which modulate beta-catenin function in many its biological processes, including cardiogenesis. One of the interesting candidates is plakoglobin, a little-studied member of the catenin family which shares several mechanistic and functional features with its close relative, beta catenin. Here we have focused on the function of beta-catenin in cardiogenesis. We also summarize findings on plakoglobin signaling function and discuss possible interplays between beta-catenin and plakoglobin in the regulation of embryonic heart development. Impact statement Heart development, function, and remodeling are complex processes orchestrated by multiple signaling networks. This review examines our current knowledge of the role of canonical Wnt signaling in cardiogenesis and heart remodeling, focusing primarily on the mechanistic action of its effector beta-catenin. We summarize the generally accepted understanding of the field based on experimental in vitro and in vivo data, and address unresolved questions in the field, specifically relating to the role of canonical Wnt signaling in heart maturation and regeneration. What are the modulators of canonical Wnt, and particularly what are the potential roles of plakoglobin, a close relative of beta-catenin, in regulating Wnt signaling?Answers to these questions will enhance our understanding of the mechanism by which the canonical Wnt signaling regulates development of the heart and its regeneration after damage. PMID- 28920473 TI - Who You Gonna Call? / Qui faut-il appeler? PMID- 28920472 TI - It May Look Similar to a Xanthogranuloma Under the Microscope but It Does Not Really Walk Like One Clinically . . . PMID- 28920474 TI - The State of Ethnic Dermatology in Canada. AB - Approximately 30% of Canadians will be members of a visible minority by 2031. When dermatology became an independent medical discipline in the late 18th and early 19th centuries, most residents of Canada and the United States were of Northern European descent. Morphology and descriptions of dermatoses are based on patients with light skin. Skin of colour dermatology refers to a unique field in dermatology dedicated to the diagnosis and management of disorders that are more prevalent in patients with moderately to richly pigmented skin. Important differences in the presentation of common dermatoses such as seborrheic dermatitis and acne exist in patients with darker skin types. The effect of traditional treatments for common and uncommon dermatoses is also an important consideration in managing patients with skin of colour. Such treatments may result in adverse effects such as postinflammatory hyperpigmentation or keloid scarring at a higher rate. Most respondents from a 2013 UK study of dermatology residents and consultants agreed that individuals with 'ethnic skin' had specific and unique dermatological problems. The Royal College of Physician and Surgeons of Canada's Objectives of Training in Dermatology states that residents must demonstrate the requisite knowledge, skills, and attitudes for effective patient centred care and service to a diverse population. Future steps include creating a national society of dermatologists interested in clinical and academic aspects of ethnic dermatology. As well, presentations on skin of colour dermatology could be encouraged at major Canadian dermatology meetings. PMID- 28920475 TI - Generalised Eruptive Keratoacanthomas of Grzybowski. PMID- 28920476 TI - Digital Anaesthesia and Relevant Digital Anatomy for the Dermatologist. AB - Cutaneous surgery requires a precise understanding of anatomy. This review describes the clinically relevant anatomy of the hand and relates it to the most common methods of digital anaesthesia. PMID- 28920477 TI - If It Looks Like a Xanthogranuloma and Walks Like a Xanthogranuloma . . . PMID- 28920478 TI - Pityriasis Folliculorum of the Back Thoracic Area: Pityrosporum, Keratin Plugs, or Demodex Involved? PMID- 28920479 TI - Reticular Erythema and Hyperpigmentation in a Woman. PMID- 28920480 TI - Merkel Cell Carcinoma. PMID- 28920481 TI - Two new lignans from the resin of Bursera microphylla A. gray and their cytotoxic activity. AB - Two new lignans, namely 7-O-podophyllotoxinyl butyrate (1) and dihydroclusin 9 acetate (2), were isolated from the dichloromethane fraction of a methanol extract of Bursera microphylla (Burseraceae), along with eight known lignans (3 10). Their structures were determined by means of comprehensive spectroscopic analysis. Lignans 2-6 were tested for their anti-proliferative activity on the cancer cell lines LS180, A549 and HeLa, and on a non-cancer cell line, ARPE-19. Only compounds 4 and 5 showed an interesting activity on HeLa cells. PMID- 28920483 TI - Hydroxycamptothecin liposomes based on thermal and magnetic dual-responsive system: preparation, in vitro and in vivo antitumor activity, microdialysis-based tumor pharmacokinetics. AB - Due to the absence of lactone form of hydroxycamptothecin, the commercially available hydroxycamptothecin injection exhibits inefficient therapeutic effects. In this study, we constructed a novel delivery system (thermosensitive magnetic liposomes) that protects lactone form of hydroxycamptothecin from blood or water. After hydroxycamptothecin was loaded into the thermosensitive magnetic liposome (HCPT/TML), its in vitro and in vivo antitumor activity and microdialysis-based tumour pharmacokinetics were determined. The results demonstrated that HCPT/TMLs possessed favourable physicochemical features and significant cytotoxicity against the Huh-7 cells in vitro. In the in vivo antitumor study and tumour pharmacokinetics, HCPT/TMLs displayed effective targeting delivery and antitumor effects, which corresponded to the determined hydroxycamptothecin concentration in tumour tissue. In conclusion, this thermal and magnetic dual-responsive system can efficiently deliver hydroxycamptothecin to tumour tissue and has great potential application in cancer treatment. PMID- 28920482 TI - Fowl aviadenovirus serotype 1 confirmed as the aetiological agent of gizzard erosions in replacement pullets and layer flocks in Great Britain by laboratory and in vivo studies. AB - An investigation into the aetiology and pathogenesis of adenoviral gizzard erosion has been conducted following three natural outbreaks affecting one flock of 6-week-old replacement pullets and two consecutive placements of free range layers at the age of 21 and 23 weeks. Affected flocks showed increased mortality (0.12-0.30% per week), and gizzard lesions were consistent with fowl aviadenovirus (FAdV) involvement. To substantiate the initial findings, a selection of archived formalin-fixed paraffin-embedded gizzard samples from another 12 pullet and layer flocks, for which macroscopic and histopathological diagnosis of the disease were recorded in Great Britain during the period 2009 2016, were also investigated. In situ hybridization (ISH), virology and/or PCR confirmed the presence of FAdV species-A, serotype-1 (FAdV-A, FAdV-1) DNA in gizzard samples of all 15 cases investigated. Co-infections with additional FAdV serotypes including FAdV-8a were detected by serology and/or virology in two of the pullet flocks. However, species-specific in situ hybridization revealed that pathological changes of affected gizzards were only associated with the detection of FAdV-A. A subsequent in vivo study infecting 21-day-old SPF pullets with FAdV 1 or FAdV-8a strains isolated from the 6-week-old replacement pullets revealed characteristic pathomorphological changes only in the gizzards from birds infected with FAdV-1. While infection with FAdV-8a was confirmed by virology and serology, infected SPF birds did not develop pathomorphological changes. Therefore, the aetiological involvement of the isolated FAdV-8a in the development of adenoviral gizzard erosion in commercial pullets has been ruled out. PMID- 28920485 TI - The Use of Soft Tissue Expanders Prior to Total Ankle Arthroplasty. AB - : Soft tissue coverage and tension-free closure can often be challenging in patients with ankle arthropathy being considered for total ankle arthroplasty. We present 2 patients with severe posttraumatic ankle arthropathy who underwent placement of a soft tissue expander to assist with soft tissue coverage prior to total ankle arthroplasty. LEVELS OF EVIDENCE: Level IV. PMID- 28920486 TI - Osteochondral Lesions of the Ankle. PMID- 28920487 TI - Unilateral Dislocation of the Posterior Tibialis Tendon (PTT) and Flexor Digitorum Longus Tendon With Contralateral PTT Subluxation in a Patient With Congenitally Shallow Flexor Groove. AB - INTRODUCTION: Flexor tendon dislocation from the flexor tendon groove posterior of the medial malleolus has been previously described, and may be difficult to diagnose initially, but is amendable to surgical treatment with good outcomes. We present a unique case of unilateral dislocation of the posterior tibialis and flexor digitorum longus tendons with contralateral flexor digitorum longus subluxation that was treated surgically with a good outcome. CASE PRESENTATION: A 37-year-old active duty male sustained a dislocation and subluxation of the flexor tendons bilaterally after a forced dorsiflexion injury. Bilateral ankle magnetic resonance imaging revealed the injuries that this patient sustained and aided in surgical planning. Surgical Treatment. Bilateral flexor tendon groove deepening with periosteal flap elevation and retinacular repair. DISCUSSION/CONCLUSION: This injury has not been previously described in the literature after a forced dorsiflexion mechanism. Advanced imaging is helpful as this injury may be initially misdiagnosed. This case shows that delayed bilateral reconstruction of the flexor tendon grooves and retinacula are reliable methods for pain relief to allow a patient to return to a physically demanding level of function. LEVELS OF EVIDENCE: Level V. PMID- 28920488 TI - Broomsticks, Tennis Balls and Locking Plates. PMID- 28920489 TI - Primer in Genetics and Genomics, Article 5-Further Defining the Concepts of Genotype and Phenotype and Exploring Genotype-Phenotype Associations. AB - As nurses begin to incorporate genetic and genomic sciences into clinical practice, education, and research, it is essential that they have a working knowledge of the terms foundational to the science. The first article in this primer series provided brief definitions of the basic terms (e.g., genetics and genomics) and introduced the concept of phenotype during the discussion of Mendelian inheritance. These terms, however, are inconsistently used in publications and conversations, and the linkage between genotype and phenotype requires clarification. The goal of this fifth article in the series is to elucidate these terms, provide an overview of the research methods used to determine genotype-phenotype associations, and discuss their significance to nursing through examples from the current nursing literature. PMID- 28920491 TI - Consumer satisfaction with antipsychotic medication-monitoring appointments: the role of consumer-prescriber communication patterns. AB - OBJECTIVE: The study was designed to explore patterns of prescriber communication behaviors as they relate to consumer satisfaction among a serious mental illness sample. METHODS: Recordings from 175 antipsychotic medication-monitoring appointments between veterans with psychiatric disorders and their prescribers were coded using the Roter Interaction Analysis System (RIAS) for communication behavioral patterns. RESULTS: The frequency of prescriber communication behaviors (i.e., facilitation, rapport, procedural, psychosocial, biomedical, and total utterances) did not reliably predict consumer satisfaction. The ratio of prescriber to consumer utterances did predict consumer satisfaction. CONCLUSIONS: Consistent with client-centered care theory, antipsychotic medication consumers were more satisfied with their encounters when their prescriber did not dominate the conversation. PRACTICE IMPLICATIONS: Therefore, one potential recommendation from these findings could be for medication prescribers to spend more of their time listening to, rather than speaking with, their SMI consumers. PMID- 28920492 TI - Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma. AB - INTRODUCTION: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice. PMID- 28920493 TI - Construction and evaluation in vitro and in vivo of tedizolid phosphate loaded cationic liposomes. AB - First, the SA-TDZA-Lips were prepared by reverse-phase evaporation method. Then, the drug release behaviour was evaluated by dynamic membrane dialysis in vitro and the preliminary safety was evaluated by haemolysis method. Finally, with tedizolid phosphate injection (TDZA-Inj) and tedizolid phosphate loaded liposomes (TDZA-Lips) as the control groups, the pharmacokinetic characteristic and tissues distribution of SA-TDZA-Lips were evaluated after intravenous injection. As a result, the stearylamine modified tedizolid phosphate liposomal delivery system was constructed successfully and the particle size was 194.9 +/- 2.93 nm. The encapsulation efficiency (EE) was 53.52 +/- 2.18%. The in vitro release of SA TDZA-Lips was in accordance with Weibull equation. And there was no haemolysis happened, which indicated good preliminary safety for injection. The results of pharmacokinetics showed that the t1/2beta increased by 0.74 times and 0.51 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The MRT of SA-TDZA-Lips was 1.30 and 1.09 times higher than that of TDZA-Inj group and TDZA Lips group, respectively. The AUC was 2.40 times and 0.23 times higher than that of TDZA-Inj group and TDZA-Lips group, respectively. The tissue distribution results showed that the relative uptake rate (Re) of TDZA in the lung was 1.527, which indicated the targeting. In conclusion, the SA-TDZA-Lips prepared in this study had several advantages like positive charge, strong cell affinity, prolonged circulation time in vivo, sustained release effect, and increased drug concentration in lungs. All advantages above provided significant clinical value of application for the treatment of bacterial pneumonia with tedizolid phosphate. PMID- 28920494 TI - Early postnatal weight gain as a predictor for the development of retinopathy of prematurity. AB - OBJECTIVE: The objective of this study is to validate the reliability of early postnatal weight gain as an accurate predictor of type 1 retinopathy of prematurity (ROP) requiring treatment in a large predominantly Hispanic US cohort with the use of an online tool called WINROP (weight, neonatal retinopathy of prematurity (IGF-1), neonatal retinopathy of prematurity). STUDY DESIGN: Retrospective cohort study consisted of preterm infants <32 weeks gestation and birth weight <1500 g. Weekly weights to 36 weeks post-menstrual age or discharge if earlier were entered into the WINROP tool. This tool generated alarm and risk indicator for developing ROP. The infants with type 1 ROP requiring treatment as well as all stages of ROP were compared with the alarms and risks generated by WINROP tool. RESULTS: A total of 492 infants were entered into the WINROP tool. The infants who developed type 1 ROP requiring treatment, the WINROP tool detected 80/89 (90%) at less than 32 weeks gestation. Nine infants developed type 1 ROP were classified as low risk and did not alarm. CONCLUSIONS: Postnatal weight gain alone, in predominantly Hispanic US population, predicted type 1 ROP requiring treatment before 32 weeks of gestation in infants with a sensitivity of 90%. The tool appeared to identify majority of affected infants much earlier than the scheduled screening. PMID- 28920495 TI - Twelve tips on how to compile a medical educator's portfolio. AB - Medical education is an expanding area of specialist interest for medical professionals. Whilst most doctors will be familiar with the compilation of clinical portfolios for scrutiny of their clinical practice and provision of public accountability, teaching portfolios used specifically to gather and demonstrate medical education activity remain uncommon in many non-academic settings. For aspiring and early career medical educators in particular, their value should not be underestimated. Such a medical educator's portfolio (MEP) is a unique compendium of evidence that is invaluable for appraisal, revalidation, and promotion. It can stimulate and provide direction for professional development, and is a rich source for personal reflection and learning. We recommend that all new and aspiring medical educators prepare an MEP, and suggest twelve tips on how to skillfully compile one. PMID- 28920496 TI - SPIN: rapid synthesis, purification, and concentration of small drug-loaded liposomes. AB - Liposomes are one of the most studied nano-delivery systems. However, only a handful of formulations have received FDA approval. Existing liposome synthesis techniques are complex and specialized, posing a major impediment in design, implementation, and mass production of liposome delivery systems as therapeutic agents. Here, we demonstrate a unique 'synthesis and purification of injectable nanocarriers' (SPIN) technology for rapid and efficient production of small drug loaded liposomes using common benchtop equipment. Unilamellar liposomes with mean diameter of 80 nm and polydispersity of 0.13 were synthesized without any secondary post-processing techniques. Encapsulation of dextrans (300-20,000 Da) representing small and large molecular drug formulations was demonstrated without affecting the liposome characteristics. 99.9% of the non-encapsulated molecules were removed using a novel filter centrifugation technique, largely eliminating the need for tedious ultracentrifugation protocols. Finally, the functional efficacy of loaded liposomes as drug delivery vehicles was validated by encapsulating a fluorescent cell tracker (CMFDA) and observing the liposomal release and subsequent uptake of dye by metastatic breast cancer cells (MDA-MB 231) in vitro. The proposed simplified technique addresses the existing challenges associated with liposome preparation in resource limited settings and offers significant potential for advances in translational pharmaceutical development. PMID- 28920497 TI - Reply letter to: "Can modern biology interpret the mystery of the birth of Christ?" PMID- 28920498 TI - An update on biomarker discovery and use in axial spondyloarthritis. AB - INTRODUCTION: Evaluation of diagnosis, disease activity, and risk for joint damage all represent important unmet clinical needs in the management of axial spondyloarthritis that have been explored using biomarkers. Areas covered: This review used the search terms biomarkers, ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, pathogenesis, genetics, diagnostic tools, prognosis, to explore advances in biomarker development relevant to unmet clinical needs. Expert commentary: Despite major advances in the identification of genetic risk markers, HLA-B*27 remains the only marker with clinical utility for diagnostic purposes. Serological antibody to class II-associated invariant chain peptide (CLIP) requires further validation. A substantial array of biomarkers related to inflammatory processes and cartilage and bone remodeling have been evaluated using established clinical tools as well as new MRI-based outcomes for disease activity. Beyond C-reactive protein (CRP), none have demonstrated substantial associations with these parameters to justify clinical use and high priority candidates for further validation have not been identified. Leading candidates for further validation studies of prognostic biomarkers are metalloproteinases (MMP), calprotectin, adipokines, MMP-degraded citrullinated fragments of connective tissue proteins such as vimentin, and factors that regulate MMP expression. New approaches have explored combinations of targeted biomarkers and metabolomics analyses to identify optimal profiles of biomarkers related to the clinical endpoint of interest. PMID- 28920499 TI - Tactile Radar: experimenting a computer game with visually disabled. AB - BACKGROUND: Visually disabled people increasingly use computers in everyday life, thanks to novel assistive technologies better tailored to their cognitive functioning. Like sighted people, many are interested in computer games - videogames and audio-games. Tactile-games are beginning to emerge. The Tactile Radar is a device through which a visually disabled person is able to detect distal obstacles. In this study, it is connected to a computer running a tactile game. The game consists in finding and collecting randomly arranged coins in a virtual room. METHODS: The study was conducted with nine congenital blind people including both sexes, aged 20-64 years old. Complementary methods of first and third person were used: the debriefing interview and the quasi-experimental design. RESULTS: The results indicate that the Tactile Radar is suitable for the creation of computer games specifically tailored for visually disabled people. CONCLUSIONS: Furthermore, the device seems capable of eliciting a powerful immersive experience. Methodologically speaking, this research contributes to the consolidation and development of first and third person complementary methods, particularly useful in disabled people research field, including the evaluation by users of the Tactile Radar effectiveness in a virtual reality context. Implications for rehabilitation Despite the growing interest in virtual games for visually disabled people, they still find barriers to access such games. Through the development of assistive technologies such as the Tactile Radar, applied in virtual games, we can create new opportunities for leisure, socialization and education for visually disabled people. The results of our study indicate that the Tactile Radar is adapted to the creation of video games for visually disabled people, providing a playful interaction with the players. PMID- 28920500 TI - Acute toxicity of the bowel after stereotactic robotic radiotherapy for abdominopelvic oligometastases. AB - AIM: To correlate dose-volume histogram (DVH) parameters with appearance of grade >=2 acute and late gastrointestinal toxicity of stereotactic body radiotherapy (SBRT) in patients with abdominopelvic solitary or oligometastatic disease outside the liver. MATERIAL AND METHODS: Acute and late bowel toxicity of 84 abdominopelvic oligometastatic patients was registered. A logistic regression was performed between different DVH parameters and presence of grade >=2 acute and late toxicity. A Normal Tissue Complication Probability (NTCP) model was built with significant parameters to determine complication probabilities (CP). RESULTS: Thirteen (15%) of 84 patients experienced of grade >=2 acute toxicity, while 8 (10%) reported late toxicity complications. A significant relationship was found for EQD2 (V30Gy, V40Gy, V50Gy and V65Gy) and grade >=2 acute toxicity. Dmax and D2 were not significant. Late grade >=2 toxicity was not significantly correlated with any DVH parameter. According to our NTCP model for V40Gy, an irradiated bowel volume of 10 cm3 of V40Gy resulted in CP of grade >=2 acute toxicity of less than 10%. Local control was 87% at 2 years and 82% at 5 years. Overall survival was 61% at 2 years and 32% at 5 years. CONCLUSIONS: After SBRT for abdominopelvic oligometastases, in general, the presence of acute and late toxicity was low. A significant relationship was found for V30Gy, V40Gy, V50Gy and V65Gy and grade >=2 acute toxicity. We estimated acute complication probabilities per volume of irradiated bowel by V40Gy and V50Gy. PMID- 28920501 TI - Kidney dosimetry during 177Lu-DOTATATE therapy in patients with neuroendocrine tumors: aspects on calculation and tolerance. AB - BACKGROUND: Fractionated therapy with 177Lu-DOTATATE has been reported to be an effective treatment for patients with metastasized neuroendocrine tumors. To optimize the treatment, absorbed doses to risk organs are calculated for the individual patient. For each organ, absorbed dose due to activity in the organ itself (self-dose) and that originating from other organs (cross-dose) are calculated from serial measurements to obtain the activity distribution following treatment. The main aim of the present work were to calculate the cross-dose contribution to the total absorbed kidney dose. METHODS: Five hundred patients with neuroendocrine tumors undergoing therapy with 177Lu-DOTATATE were included. Scintigraphic planar whole body images and single photon emission computed tomography/computed tomography (SPECT/CT) over the abdomen were acquired at 1, 4 and 7 days after treatment. Kidney self-dose was calculated based on radioactivity distribution obtained from SPECT/CT. Cross-dose to kidneys was estimated using organ-based analysis of planar whole body images and cross-fire dose factors from Olinda/EXM 1.1. RESULTS: Cross-dose to kidneys in the majority of patients were less than 2% and almost all cross-doses were less than 10%. Cross-dose exceeded 10% only in rare cases of patients with high tumor burden and low absorbed doses to kidneys. CONCLUSIONS: The absorbed dose from 177Lu octreotate to solid organs due to cross-fire is generally low and can usually be neglected. PMID- 28920502 TI - Clinical and metabolic characteristics of Turkish adolescents with polycystic ovary syndrome. AB - The aim of this study was to investigate the clinical, endocrine, metabolic features and prevalence of metabolic syndrome (MBS) in Turkish adolescents with polycystic ovary syndrome (PCOS) and the differences in metabolic parameters between adolescent PCOS with or without the presence of polycystic ovaries (PCO) on ultrasound. Subjects (n = 77) were classified into two groups: oligomenorrhea (O) and clinical and/or biochemical hyperandrogenism (HA) (n = 38), without PCO and O + HA with PCO (n = 39). The control group consisted of 33 age-matched adolescents. Adolescents with PCOS had a significantly higher body mass index (BMI), waist circumference and levels of LH, LH/FSH ratio, triglyceride, insulin, HOMA-IR, free androgen index and lower levels of SHBG and FSH. After adjustment for BMI, LH, LH: FSH ratio remained significantly higher. Adolescents with PCOS had a higher prevalence of MBS. No significant differences in lipid profiles, insulin levels and insulin sensitivity in both the PCOS groups were seen. HDL-C levels were lower in the O + HA + PCO group compared to the controls. BMI may be the major contributing factor in the development of metabolic abnormalities in adolescents with PCOS. Impact statement Many studies have investigated the effect of PCOS on metabolic and cardiovascular risks. It is thought that PCOS increases metabolic and cardiovascular risks. Increase in metabolic and cardiovascular risks associated with PCOS may be handled with early diagnosis and early intervention of PCOS in adolescents, although the diagnosis of PCOS in adolescents could be hard because of the features of PCOS overlapping normal pubertal physiological events. However, early identification of adolescent girls with PCOS may provide opportunities for prevention of well-known health risks associated with this syndrome and reduction of long-term health consequences of PCOS by reducing androgen levels and improving metabolic profile. Our results also support that BMI may be the major contributing factor in the development of metabolic abnormalities in adolescents with PCOS. PMID- 28920503 TI - Aplousobranchia ascidians in Andaman and Nicobar Islands: a combined morphological and molecular discrimination. AB - Aplousobranchia ascidians from two different families were integrated with morphological characteristics and molecular phylogenetic analysis for the first time. The present study employed morphological descriptions (colony structures, tunic, zooids, spicules stigmata and test) and a molecular approach, using a fragment of the mitochondrial cytochrome oxidase I (COI) gene of four Aplousobranchia colonial ascidians Aplidium conicum (98%), Aplidium elegans (98%), Didemnum fulgens (92%) and Trididemnum cyanophorum (94%) from Andaman and Nicobar Islands. Bar-coded sequences were extracted with BLAST format from NCBI and the heritable diversity of the submitted sequences were compared with associated ascidian species. Study revealed that the evolutionary relationship among the ascidian species exhibited the constant clades, which may help for rapid reassessment of morphological characters of the species distributed worldwide. PMID- 28920504 TI - Outpatient cervical ripening in a district general hospital: a five-year retrospective cohort study. AB - The number of women undergoing induction of labour has risen steadily in recent years. Outpatient induction is becoming more common in the UK in response to the required increase in resources, although evidence supporting its safety is lacking. We reviewed the notes of low-risk women presenting for outpatient cervical ripening using prostaglandins over a five-year period, and compared our neonatal and maternal outcomes to local and national data. Of the 502 eligible women, 400 underwent outpatient treatment. Most women returned early, in labour. There were no foetal, neonatal or maternal deaths, and our neonatal morbidity compared favourably with local rates. Mode of delivery and major maternal complication rates were comparable to national maternity indicators. We conclude that outpatient cervical ripening following careful case selection does not appear to increase neonatal or maternal mortality or morbidity. It offers patients an alternative to traditional inpatient induction and may improve allocation of hospital resources. Impact statement We present a retrospective cohort study of neonatal and maternal outcomes in 502 women selected for outpatient cervical ripening for postmaturity at Bedford Hospital over the five year period from 2010 to 2015. This study was conceived following a previous publication in this journal from Bedford Hospital in 2002 by Neale et al., which described the outcomes of 100 women who underwent outpatient cervical ripening. Our conclusions compare the results from the two studies. Out of our combined sample of 602 women, 491 were discharged home following administration of prostaglandins. This represents the largest sample size in the published literature on outpatient induction of labour, which was first undertaken in our unit in 1998 and is now widely practiced within the UK. Several publications, including the 2013 Cochrane review by Kelly et al. and a recent large survey of practice (Sharp et al. 2016 ) have highlighted the paucity of available data regarding the safety of this procedure as an outpatient. We therefore hope that the results of our study will be of interest to many maternity units who currently undertake or are considering to provide the facility for outpatient cervical ripening as a prelude to induction of labour. PMID- 28920505 TI - Learning to use a rear-mounted power assist for manual wheelchairs. AB - OBJECTIVES: 1) To investigate how much training manual wheelchair users perceive is required to learn to use a rear-mounted power assist safely and confidently. 2) To evaluate how the power assist affected wheelchair users' ability to negotiate a standardized obstacle course, wheelchair skills capacity and wheelchair mobility confidence. METHOD: This study used a pre- versus post-test intervention design. Outcome measures included a standardized obstacle course, and modified versions of the Wheelchair Skills Test 4.2 (WST) and the Wheelchair Confidence Measure. RESULTS: The 11 participants felt safe and confident using the power assist within one to two training sessions. However, some potential safety concerns were noted. Participants performed two obstacle course tasks significantly more quickly with the power assist. CONCLUSIONS: Participants felt safe using the device with limited training and the device facilitated some mobility task performance. Further research is needed to understand the outcomes of long-term, community use. Implications for Rehabilitation Most experienced wheelchair users wanted only one or two training sessions with a new rear mounted power assist device; however, some safety concerns were noted. The device did not appear to affect user's confidence. The device enabled users to perform some mobility tasks more quickly and allowed some users to perform some mobility tasks they were unable to perform in their regular MWC. PMID- 28920506 TI - Online professionalism - A student perspective. A response to Hemming et al. PMID- 28920507 TI - Navigating the structure-function-evolutionary relationship of CsaA chaperone in archaea. AB - CsaA is a protein involved in the post-translational translocation of proteins across the cytoplasmic membrane. It is considered to be a functional homolog of SecB which participates in the Sec-dependent translocation pathway in an analogous manner. CsaA has also been reported to act as a molecular chaperone, preventing aggregation of unfolded proteins. It is essentially a prokaryotic protein which is absent in eukaryotes, but found extensively in bacteria and earlier thought to be widely present in archaea. The study of phylogenetic distribution of CsaA among prokaryotes suggests that it is present only in few archaeal organisms, mainly species of Thermoplasmatales and Halobacteriales. Interestingly, the CsaA protein from these two archaeal orders cluster separately on the phylogenetic tree with CsaA from Gram-positive and Gram-negative bacteria. It, thus, appears that this protein might have been acquired in these archaeal organisms through independent horizontal gene transfer (HGT) events from different bacteria. In this review, we summarize the earlier biochemical, structural, and functional characterization studies of CsaA. We draw new insights into the evolutionary history of this protein through phylogenetic and structural comparison of bacterial CsaA with modelled archaeal CsaA from Picrophilus torridus and Natrialba magadii. PMID- 28920508 TI - Internal carotid artery dissection among younger and older patients with acute ischemic stroke. AB - : Purpose/Aim of the study: Carotid artery dissection (CAD) is a known causative factor in the etiology of acute ischemic stroke in young patients. However, the significance of CAD in older patients with acute ischemic stroke is unclear with only a few prior clinical studies. In order to isolate the influence of CAD as an independent factor, we performed multivariate analyses of common covariables in acute ischemic stroke patients in northern Israel. MATERIALS AND METHODS: Three hundred and forty-seven consecutive patients who suffered from acute ischemic stroke had initial CT angiography (CTA) ordered from the emergency room. We reviewed the CTAs for radiologic signs of CAD, and recorded patients' demographic and clinical data from the hospital's computerized information system. RESULTS: Eighteen of the 347 patients (5.19%) had CTA evidence of CAD, with no statistically significant differences based on age, gender or ethnicity. A statistically significant inverse association between hypertension and a lower rate of CAD was found before and after stepwise logistic regression, while hyperlipidemia showed a trend toward a similar inverse association that was borderline for statistical significance. CONCLUSIONS: Our study shows that CAD is an independent and significant causative factor for acute ischemic stroke. Therefore, diagnostic imaging is indicated to rule out CAD not only in young patients, but rather in all patients with acute ischemic stroke. The inverse correlation between common vascular risk factors (i.e. hypertension and hyperlipidemia) and CAD points to CAD as an independent nonatherosclerotic causative factor in the etiology of acute ischemic stroke. PMID- 28920509 TI - Diagnosis of hyponatremia and increased risk of a subsequent cancer diagnosis: results from a nationwide population-based cohort study. AB - BACKGROUND: Hyponatremia has recently been associated with subsequent cancer risk. This population-based nationwide study assessed whether the diagnosis of hyponatremia can predict a cancer diagnosis within most common cancers. MATERIAL AND METHODS: Using Danish medical registries, we identified 16,220 patients with a first-time diagnosis of hyponatremia, without a cancer diagnosis, from January 2006 through November 2013. We quantified the relative risk of a subsequent cancer diagnosis by standardized incidence ratios (SIRs), comparing observed cancer incidence among patients diagnosed with hyponatremia to that expected, based on national cancer incidence during that period. RESULTS: During 40,207 person-years of follow-up, we observed 1546 cancer diagnoses compared to 956 expected (SIR: 1.62; 95% confidence interval (CI), 1.54-1.70). The increase in risk of a cancer diagnosis following a hyponatremia diagnosis was most pronounced within 0-6 months of follow-up (SIR 4.16; 95% CI, 3.85-4.48) and in the younger age group; 0-29 years (SIR 8.71; 95% CI, 2.82-20.28), 30-49 years (SIR 3.16; 95% CI, 2.26-4.31), 50-69 years (SIR 2.29; 95% CI, 2.10-2.48) and 70 + years (SIR 1.35; 95% CI, 1.27-1.44). Within six months after a hyponatremia diagnosis, the SIRs increased 10-fold for cancers of the lung (SIR 17.14; 95% CI, 15.15-19.32), brain (SIR 13.52; 95% CI, 8.90-19.66) and liver (SIR 13.26; 95% CI, 7.57-21.53) and increased 5 to 10-fold for cancers of the pancreas (SIR 8.25; 95% CI, 5.72 11.53), esophagus (SIR 6.59; 95% CI, 3.15-12.12), kidney (SIR 6.36; 95% CI, 3.39 10.88), pharynx (SIR 6.15; 95% CI, 1.27-17.97) and non-Hodgkin lymphoma (SIR 6.10; 95% CI, 4.17-8.61). The rate increased across virtually all types of cancers, except melanoma and basal cell carcinomas. CONCLUSIONS: A diagnosis of hyponatremia may be a marker of occult neoplasms, especially cancers of the lung, brain, liver, pancreas, esophagus, kidney, pharynx and non-Hodgkin lymphoma. Hyponatremia may aid in early detection of cancer. PMID- 28920510 TI - The stakeholders' project in neuropsychological report writing: a survey of neuropsychologists' and referral sources' views of neuropsychological reports. AB - OBJECTIVE: Though some neuropsychological groups have proposed criteria and suggestions for clinical report writing there has never been professional consensus or accepted published guidelines on how to write reports. Given the paucity of guidelines and the evolving practice climate, we sought to survey neuropsychologists and referral source stakeholders to understand current report writing practices. METHOD: The data were collected in two SurveyMonkey surveys via professional list servs, email, and LinkedIn clinical interest groups. RESULTS: Results of the survey indicate many neuropsychologists spend multiple hours writing reports that they believe will not be read completely by stakeholders. A striking 73% of referral sources reported slow turnaround time of neuropsychological reports negatively affected their patient care. Referral sources reported they value the diagnosis/impression and recommendations sections the most; in contrast, they did not find the history, behavioral observations, emotional functioning, or descriptions of cognitive domains sections as useful. CONCLUSIONS: The survey findings highlight the disjuncture between what neuropsychologists typically do in their practice of report writing versus what they believe is useful for patients and referral sources. The survey also highlights differences between writing practices of neuropsychologists and what referral sources identify as the most valuable aspects of reports to assist them in caring for their patients. PMID- 28920511 TI - A feasibility study of working memory training for individuals with paediatric onset multiple sclerosis. AB - OBJECTIVE: To investigate the feasibility and experiences of paediatric-onset multiple sclerosis (MS) patients completing a working memory training programme. METHODS: Nine paediatric-onset MS patients (mean age 19.3 +/- 4.1 years) identified as having attention and/or working memory difficulties underwent a five-week (five days/week) internet-based working memory training programme (CogmedTM); weekly coaching was provided. Measures of adherence and tolerance were used to establish the feasibility of implementing computerised cognitive training. Qualitative experiences reported by the patients were analysed and factors that may modulate the effects of training were explored. RESULTS: Six of the nine enrolled patients completed the programme within the recommended time, and all individuals, with the exception of one, were considered to tolerate the training well. Eight of the nine participants acknowledged that training was helpful in one or more ways. All but one participant reported improvements in working memory, although evidence for improvement on objective neuropsychological testing was limited. Lower normalised brain volume emerged as a potentially important variable in predicting extent of improvement on the training programme. CONCLUSION: Selected paediatric-onset MS patients can tolerate and complete an intensive cognitive rehabilitation programme. Future investigation of moderators of training effects and the stability of the findings over time is needed. PMID- 28920512 TI - Rhythmic Three-Part Harmony: The Complex Interaction of Maternal, Placental and Fetal Circadian Systems. AB - From the perspective of circadian biology, mammalian pregnancy presents an unusual biological scenario in which an entire circadian system (i.e., that of the fetus) is embodied within another (i.e., that of the mother). Moreover, both systems are likely to be influenced at their interface by a third player, the placenta. Successful pregnancy requires major adaptations in maternal physiology, many of which involve circadian changes that support the high metabolic demands of the growing fetus. A functional role for maternal circadian adaptations is implied by the effects of circadian disruption, which result in pregnancy complications including higher risks for miscarriage, preterm labor, and low birth weight. Various aspects of fetal physiology lead to circadian variation, at least in late gestation, but it remains unclear what drives this rhythmicity. It likely involves contributions from the maternal environment and possibly from the placenta and the developing intrinsic molecular clocks within fetal tissues. The role of the placenta is of particular significance because it serves not only to relay signals about the external environment (via the mother) but may also exhibit its own circadian rhythmicity. This review considers how the fetus may be influenced by dynamic circadian signals from the mother and the placenta during gestation, and how, in the face of these changing influences, a new fetal circadian system emerges. Particular emphasis is placed on the role of endocrine signals, most notably melatonin and glucocorticoids, as mediators of maternal fetal circadian interactions, and on the expression of the clock gene in the 3 compartments. Further study is required to understand how the mother, placenta, and fetus interact across pregnancy to optimize circadian adaptations that support adequate growth and development of the fetus and its transition to postnatal life in a circadian environment. PMID- 28920513 TI - Corrigendum to Breast cancer in systemic lupus. PMID- 28920515 TI - Quality of life in women of reproductive age: a comparative study of infertile and fertile women in a Nigerian tertiary centre. AB - The study examined the quality of life in women of reproductive age and the aim was to evaluate and compare the quality of life (QoL) scores among fertile and infertile women. A cross-sectional study was carried out among women attending the Gynaecology and Postnatal Clinics of Ekiti State University Teaching Hospital comparing their QoL using the World Health Organisation Quality of Life-BREF (WHOQOL-BREF) questionnaire. The age of fertile women was significantly higher than the age of infertile women (p < .05), while a significantly higher proportion of the infertile and fertile women and their spouses were civil servants (p < .05). Infertile women obtained significantly higher scores than fertile women in the physical domain (QoL) and significantly lower scores than fertile women in the social domain (QoL), (p < .05). Among the infertile women, those with secondary infertility had significantly better overall QoL scores, (p < .05). Logistic regression showed that infertility and unemployment in women were associated with significantly lower QoL scores in psychological and social domains (p < .05). The quality of life is significantly lower among infertile women compared to fertile ones and this should be borne in mind when attending to these women. Impact statement What is already known on this subject: Infertility has been shown to be associated with poor quality of life. Most of these studies were conducted in developed countries. What the results of this study add: The findings of this study revealed that women who were infertile had low quality of life scores compared to the fertile ones in physical, social and psychological domains. What the implications are of these findings for clinical practice and/or further research: A community-based and multicultural study involving more participants may shed more light on this topic in future research. Counselling sessions should be incorporated as part of the holistic approach in the day-to day management of the infertile women. PMID- 28920516 TI - High glucose-mediated overexpression of ICAM-1 in human vaginal epithelial cells increases adhesion of Candida albicans. AB - To investigate the involvement of ICAM-1 in the adhesion of Candida to the genitourinary epithelial cells in high glucose, we examined the adhesion of Candida albicans or Candida glabrata to human vaginal epithelial cells (VK2/E6E7) or human vulvovaginal epidermal cells (A431). These cells were cultured in 100, 500 or 3000 mg/dL glucose for three days and inoculated with Candida for 60 minutes. Followed by, adhering of Candida to the cells, which were counted. While the adhesion of Candida albicans to VK2/E6E7 significantly increased in the high glucose, A431 did not. We next examined the expression of ICAM-1 as a ligand on the epithelial cells. ICAM-1 expression was increased in VK2/E6E7 cultured in the high glucose; however, the expression level in A431 was not high compared with VK2/E6E7. This data suggested that ICAM-1 functions as one of ligands in the adhesion of Candida albicans to the vaginal epithelial cells in a high glucose environment. Impact statement What is already known on the subject: Candida's complement receptor is involved in the adhesion to epithelial cells. The expression of this receptor has been reported to increase as glucose concentration increases. This is considered as a contributing factor to the high risk for vulvovaginal candidiasis (VVC) in diabetes. On the host side, diabetic patients have a factor that facilitates adhesion of Candida to epithelial cells. This factor has been unknown until recently. What the results of this study add: In this study, we used a vaginal epithelial cell line and showed that the adhesion of C. albicans to cells increased at higher glucose concentrations. At the same time, ICAM-1 expression of cells also increased. Thereby, it is suggested that the expression of ICAM-1 in vaginal epithelial cells is increased by glucose such as urinary sugar in diabetic patients and is a condition for facilitating adhesion of Candida. What the implications are of these findings for clinical practice and/or further research: We expect not only host immune dysfunction but also alteration in epithelial cells will be focussed on as a cause of VVC in diabetic patients. PMID- 28920517 TI - Bleeding Control in Palliative Care Patients With the Help of Tranexamic Acid. AB - BACKGROUND: Persistent bleeding is a common reason for admitting patients with advanced cancer to a palliative care unit. Several reports show a successful therapeutic use of the antifibrinolytic agent tranexamic acid in palliative care patients having hemorrhages. However, it is not administered routinely in severe bleeding situations in palliative care, and general dosing recommendations are unclear. CASE PRESENTATION: We report on 3 patients who were treated with tranexamic acid due to symptomatic hemorrhage complicating different malignant processes. Case Management and Outcome: A dosing regimen of 1000 mg intravenous tranexamic acid 3 times a day caused an arrest of bleeding in the reported patients within 2 to 3 days. Having controlled the acute bleeding, we continued with an oral administration of 3000 mg per day as maintenance dose. CONCLUSIONS: The described dosing regimen was effective in controlling the symptomatic bleeding of the reported patients. Further studies are needed to get evidence based information on the optimal dosing regimen of tranexamic acid and to emphasize its significance in palliative medicine. PMID- 28920518 TI - The 'indirect costs' of underfunding foreign partners in global health research: A case study. AB - : This study of a global health research partnership assesses how U.S. fiscal administrative policies impact capacity building at foreign partner institutions. We conducted a case study of a research collaboration between Mbarara University of Science and Technology (MUST) in Mbarara, Uganda, and originally the University of California San Francisco (UCSF), but now Massachusetts General Hospital (MGH). Our case study is based on three of the authors' experiences directing and working with this partnership from its inception in 2003 through 2015. The collaboration established an independent Ugandan non-profit to act as a local fiscal agent and grants administrator and to assure compliance with the Ugandan labour and tax law. This structure, combined with low indirect cost reimbursements from U.S. federal grants, failed to strengthen institutional capacity at MUST. In response to problems with this model, the collaboration established a contracts and grants office at MUST. This office has built administrative capacity at MUST but has also generated new risks and expenses for MGH. We argue that U.S. fiscal administrative practices may drain rather than build capacity at African universities by underfunding the administrative costs of global health research, circumventing host country institutions, and externalising legal and financial risks associated with international work. ABBREVIATIONS: MGH: Massachusetts General Hospital; MUST: Mbarara University of Science and Technology; NIH: National Institutes of Health; UCSF: University of California San Francisco; URI: Uganda Research Institute. PMID- 28920519 TI - Withdrawal of spatial overt attention following intentional forgetting: evidence from eye movements. AB - Eye movements were measured to examine whether item-method directed forgetting involved a spatial overt attention shift. Experiment 1 showed that participants' eyes were moved away from the study word following the forget and ignore cues, but not the remember cue. Experiment 2 revealed that the eyes were moved away from the area that covered by the study word even when the study word disappeared upon the presentation of the memory cue. Both the study word and memory cue were presented auditorily in Experiment 3. In all experiments, the to-be-remembered words were recalled better than both to-be-forgotten and to-be-ignored words. More importantly, mental effort, as indexed by the pupil size, increased following the remember, as compared with the forget and ignore cues. These findings are discussed in terms of controlling spatial overt attention after encoding to withdraw attention from irrelevant information and to allocate cognitive resources to relevant information for long-term retention. PMID- 28920514 TI - Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases. AB - Despite the potential obstacle represented by the blood-brain barrier for extravasating malignant cells, metastases are more frequent than primary tumors in the central nervous system. Not only tightly interconnected endothelial cells can hinder metastasis formation, other cells of the brain microenvironment (like astrocytes and microglia) can also be very hostile, destroying the large majority of metastatic cells. However, malignant cells that are able to overcome these harmful mechanisms may benefit from the shielding and even support provided by cerebral endothelial cells, astrocytes and microglia, rendering the brain a sanctuary site against anti-tumor strategies. Thus, cells of the neurovascular unit have a Janus-faced attitude towards brain metastatic cells, being both destructive and protective. In this review, we present the main mechanisms of brain metastasis formation, including those involved in extravasation through the brain vasculature and survival in the cerebral environment. PMID- 28920520 TI - Greek public's ambivalence toward refugee children education. PMID- 28920521 TI - Implementing evidence-based smoking cessation treatment in psychosocial care units (CAPS) in Brazil. AB - BACKGROUND: The prevalence of smoking among mental health and addiction (MHA) patients is 3 times higher than it is in the general population, yet this patient population has received little help to combat smoking. Considering this, psychosocial care centers (CAPS - Centros de Atencao Psicossocial) are strategic locations for integrating tobacco dependence treatment (TDT) into existing treatment activities. METHODS: Our team provided an 8-hour training package to the staff of CAPS that have not been providing specialized TDT for smokers. Our curriculum included the following topics focused on the implementation of treatment for MHA smokers: management, epidemiology, medications, psychotherapy, and smoking/mental health assessment instruments. RESULTS: Our team trained the staff of 17 CAPS units within 10 cities - which included more than 186 health professionals. There were many barriers encountered as we provided this training. A summary of problems we faced were as follows: resistance to incorporating TDT in addiction/mental health-care units, resistance to the implementation of cognitive-behavioral therapy (CBT) (psychodynamic therapy and harm reduction were preferred) and treatment for smoking is already implemented in primary care network; resistance to the use of medication in addiction treatment (a preference for psychotherapy and psychosocial approach). CONCLUSION: We learned a number of important lessons as we worked to improve the delivery of TDT to MHA patients in Brazil: provide clinicians an opportunity to explore how they feel/think about providing TDT to their clients at the very outset of the training, rather than focusing on a specific type of behavioral therapy for TDT (such as CBT), which some may find objectionable; use more generic descriptions of behavioral therapy such as 'supportive counseling'; include training professionals who are open to other forms of behavioral therapy in addition to psychoanalysis and discuss the important impact that MHA units can have in improving the quality of life for their patients who smoke. PMID- 28920522 TI - Constraint and multimodal approaches to therapy for chronic aphasia: A systematic review and meta-analysis. AB - Aphasia is a significant cause of disability and reduced quality of life. Two speech pathology treatment approaches appear efficacious: multimodal and constraint-induced aphasia therapies. In constraint-induced therapies, non-verbal actions (e.g., gesture, drawing) are believed to interfere with treatment and patients are therefore constrained to speech. In contrast, multimodal therapies employ non-verbal modalities to cue word retrieval. Given the clinical and theoretical implications, a comparison of these two divergent treatments was pursued. This systematic review investigated both approaches in chronic aphasia at the levels of impairment, participation and quality of life. After a systematic search, the level of evidence and methodological quality were rated. Meta-analysis was conducted on 14 single case experimental designs using Tau-U, while heterogeneity in the four group designs precluded meta-analysis. Results showed that high-quality research was limited; however, findings were broadly positive for both approaches with neither being judged as clearly superior. Most studies examined impairment-based outcomes without considering participation or quality of life. The application and definition of constraint varied significantly between studies. Both constraint and multimodal therapies are promising for chronic post-stroke aphasia, but there is a need for larger, more rigorously conducted studies. The interpretation of "constraint" also requires clearer reporting. PMID- 28920523 TI - The social consequences of stigma-related self-concealment after acquired brain injury. AB - Social relationships often decline after brain injury. Although much of this is due to psychosocial impairments caused by the injury, the reactions to the injury of others in the person's wider social network, along with the response of the person with the injury to those reactions, also need to be considered. Anxiety about stigmatising reactions from others may lead some to conceal information about their brain injury. This study investigated some of the social consequences of such concealment. Sixty-five participants with acquired brain injury completed the Anticipated Stigma and Concealment Questionnaire, the Social Avoidance and Distress Scale, the UCLA Loneliness Scale, the Rosenberg Self-Esteem Scale, the Social Integration subscale of the Community Integration Questionnaire, and the Enacted Social Support Questionnaire. As hypothesised, concealment was associated with social anxiety, social avoidance, loneliness and lower self-esteem; and anxiety mediated the impact that concealment had on avoidance, loneliness and reduced community activity. However, contrary to expectation, concealment was not associated with reduced use of social support. Concealment may have negative consequences, but inappropriate disclosure can also be harmful. Services should support individuals to make optimal decisions about disclosing information about the brain injury and also help them address psychological barriers to disclosure. PMID- 28920524 TI - Remotely supported prehospital ultrasound: A feasibility study of real-time image transmission and expert guidance to aid diagnosis in remote and rural communities. AB - Introduction Our aim is to expedite prehospital assessment of remote and rural patients using remotely-supported ultrasound and satellite/cellular communications. In this paradigm, paramedics are remotely-supported ultrasound operators, guided by hospital-based specialists, to record images before receiving diagnostic advice. Technology can support users in areas with little access to medical imaging and suboptimal communications coverage by connecting to multiple cellular networks and/or satellites to stream live ultrasound and audio video. Methods An ambulance-based demonstrator system captured standard trauma and novel transcranial ultrasound scans from 10 healthy volunteers at 16 locations across the Scottish Highlands. Volunteers underwent brief scanning training before receiving expert guidance via the communications link. Ultrasound images were streamed with an audio/video feed to reviewers for interpretation. Two sessions were transmitted via satellite and 21 used cellular networks. Reviewers rated image and communication quality, and their utility for diagnosis. Transmission latency and bandwidth were recorded, and effects of scanner and reviewer experience were assessed. Results Appropriate views were provided in 94% of the simulated trauma scans. The mean upload rate was 835/150 kbps and mean latency was 114/2072 ms for cellular and satellite networks, respectively. Scanning experience had a significant impact on time to achieve a diagnostic image, and review of offline scans required significantly less time than live streamed scans. Discussion This prehospital ultrasound system could facilitate early diagnosis and streamlining of treatment pathways for remote emergency patients, being particularly applicable in rural areas worldwide with poor communications infrastructure and extensive transport times. PMID- 28920525 TI - Can urologists accurately stage and grade urothelial bladder cancer by assessing endoscopic photographs? AB - Introduction Assessment of urothelial bladder cancer during cystoscopy or transurethral resection of bladder tumour has a significant impact on the urologist's decision-making: treatment with simple outpatient fulguration, required depth of resection, and need of immediate post-surgical intravesical therapy. These choices depend heavily on the urologist's ability to accurately assess pre-biopsy tumour stage and grade. The aim of the study was to determine whether evaluation of photographs taken during transurethral resection of bladder tumour can reliably characterize a tumour's stage and grade. Methods Smartphone photographs of 50 urothelial bladder cancer cases were taken at the beginning of transurethral resection of bladder tumour and individually presented to seven senior urologists. All urologists were blinded to the final pathological report and to any other urological evaluation. Each one was asked to rate the tumour as low vs high grade and noninvasive Ta vs noninvasive T1 or muscle invasive. Results were compared with final pathology. Individual appraisal and the majority's opinion were evaluated. Results Urologists have correctly predicted tumour stage and grade in 63.5% of cases (222 of 350, average of 32 out of 50 accurate assessments). The final majority assessment was correct in 40 of 50 cases (80%). Sensitivity and specificity of the final results for the diagnosis of T1 or higher were 80% and 88.6%, respectively. Sensitivity and specificity for Ta low grade were 83.3% and 80%, respectively. Conclusions To the best of our knowledge, this is the first documented attempt to evaluate urologists' ability to assess urothelial bladder cancer stage and grade using endoscopic photographs. Urologists can usually identify stage and grade of urothelial bladder cancer but accuracy increases when multiple senior urologists examine the same photographs and achieve majority consensus. Presenting photographs of urothelial bladder cancer to a team of urologists may lead to an excellent decision regarding type and extent of surgical treatment and substantiate appropriate post-surgical management. PMID- 28920526 TI - Iatrogenic injury to the motor branch of the median nerve during percutaneous needle fasciotomy. PMID- 28920527 TI - Submuscular transposition with musculofascial lengthening for persistent or recurrent cubital tunnel syndrome in 34 patients. AB - : The two main surgical options for patients with persistent or recurrent cubital tunnel syndrome are subcutaneous and submuscular transposition. We retrospectively analysed the results of 34 patients with recalcitrant cubital tunnel syndrome who underwent submuscular transposition with musculofascial lengthening at our institutions. Of the 34 patients, 21 improved clinically after submuscular transposition with musculofascial lengthening, of which 16 were still satisfied at a mean follow-up of four years. In addition, all articles published between 1974 and January 2015 on subcutaneous and/or submuscular transposition of the ulnar nerve for recalcitrant cubital tunnel syndrome were reviewed. We found that previously published studies on this subject are too heterogeneous to compare. No recommendation can thus be made regarding the surgical technique for persistent or recurrent cubital tunnel syndrome. Our series shows that the musculofascial lengthening technique for submuscular transposition is a good option. More research is needed to compare the different surgical treatments. LEVEL OF EVIDENCE: IV. PMID- 28920528 TI - The diagnostic accuracy of the Montreal Cognitive Assessment in inpatient stroke rehabilitation. AB - The Montreal Cognitive Assessment (MoCA) is a commonly used screening measure for cognitive impairment; however, the diagnostic accuracy and optimal cutoff points in inpatients with mild stroke severity is unknown. We examined the diagnostic accuracy of the MoCA in an acute inpatient stroke rehabilitation unit (N = 95). The criterion neuropsychological assessment was the 30-minute National Institute of Neurological Disorders and Stroke-Canadian Stroke Network battery, modified to include the Symbol-Digit Modalities Test and Trail Making Test A & B. The MoCA had moderately strong diagnostic accuracy in receiver operating curve analyses, with areas under the curve ranging from .80 to .89 depending on the threshold for defining cognitive impairment. Sensitivity ranged from .72 to .87, and was generally greater than specificity, which ranged from .60 to .81. The optimal cutoff on the MoCA for detecting mild or greater cognitive impairment was <25/30. The optimal cutoff using more conservative definitions of cognitive impairment ranged from <23-24/30. Exploratory analyses of MoCA subgroups ("normal," "mildly impaired," and "functionally impaired") differed in the frequency and magnitude of impairment on the criterion neuropsychological assessment. These findings inform the clinical use of the MoCA in individuals with mild stroke in an inpatient rehabilitation setting. PMID- 28920529 TI - Surgical Interventions for Organ and Limb Ischemia Associated With Primary and Secondary Antiphospholipid Antibody Syndrome With Arterial Involvement. AB - OBJECTIVE: The association of antiphospholipid antibody syndrome (APS) and hypercoagulability is well known. Arterial compromise leading to ischemia of organs and/or limbs in patients with APS is uncommon, frequently unrecognized, and rarely described. We evaluated our institutional experience. METHODS: Retrospective review was conducted. From August 2007 to September 2016, 807 patients with diagnosis of APS were managed in our Institution. Patients with primary and secondary APS who required interventions were examined. Demographics, comorbidities, manifestations, procedures, complications, and other factors affecting outcomes were recorded. RESULTS: Fourteen patients (mean age 35 years old, standard deviation +/-14) were evaluated and treated by our service. Six (43%) of them had primary APS and 8 (57%) had secondary APS; 11 (79%) were female. Two (14%) experienced distal aorta and iliac arteries involvement, 3 (21%) visceral vessels disease, 2 (14%) in upper and 7 (50%) in the lower extremity vasculatures. Thirteen (93%) patients underwent direct open revascularization and 1 with hand ischemia (Raynaud disease) underwent sympathectomy. During the mean follow-up period of 48 months, reinterventions included a revision of the proximal anastomosis of an aortobifemoral bypass graft, 1 (7%) abdominal exploration for bleeding, 1 (7%) graft thrombectomy, and 4 (29%) amputations (2 below the knee, 1 above the knee, and 1 transmetatarsal). One (7%) death occurred secondary to sepsis in a patient who had acute mesenteric ischemia. Significant differences in clinical manifestations and outcomes were not observed among patients with primary and secondary APS. All patients remained on systemic anticoagulation. CONCLUSION: APS is a prothrombotic disorder that may lead to arterial involvement with less frequency than the venous circulation but has significant morbidity and limb loss rate. Arterial reconstruction seems feasible in an attempt to salvage organs and limbs; however, research is necessary to establish the optimal anticoagulation regime and long-term management following surgical interventions. PMID- 28920530 TI - Chronic ileitis with transmural migration of ingested foreign body treated by laparoscopy. AB - BACKGROUND: Ingestion of foreign bodies such as fish bone or chicken bone is relatively common in adults; however, resultant transmural migration is extremely rare. METHODS: We present a case of a 79-year-old woman with chronic low-grade abdominal pain, worsening over the last 4 days. Computed tomography revealed segmental small bowel wall thickening with chronic inflammation suggestive of Crohn's ileitis and oral steroids were commenced; only later, ingestion of a foreign body was suspected. RESULTS AND CONCLUSION: At diagnostic laparoscopy, a linear foreign body resembling a wooden splinter was identified. It had partly migrated through the chronically inflamed bowel wall without causing perforation or abdominal contamination. It was removed laparoscopically without an enterotomy or bowel resection. Microscopy revealed non-viable bone, likely fish or chicken bone. The patient made an uneventful recovery and was discharged 3 days later. Herein we emphasise on the differential diagnosis and presentation of chronically ingested foreign bodies, as well as the feature of chronic ileitis with uncomplicated transmural migration of the ingested foreign body that was treated laparoscopically without an enterotomy. PMID- 28920532 TI - The Impact of Traumatic Brain Injury on Later Life: Effects on Normal Aging and Neurodegenerative Diseases. AB - The acute and chronic effects of traumatic brain injury (TBI) have been widely described; however, there is limited knowledge on how a TBI sustained during early adulthood or mid-adulthood will influence aging. Epidemiological studies have explored whether TBI poses a risk for dementia and other neurodegenerative diseases associated with aging. We will discuss the influence of TBI and resulting medical comorbidities such as endocrine, sleep, and inflammatory disturbances on age-related gray and white matter changes and cognitive decline. Post mortem studies examining amyloid, tau, and other proteins will be discussed within the context of neurodegenerative diseases and chronic traumatic encephalopathy. The data support the suggestion that pathological changes triggered by an earlier TBI will have an influence on normal aging processes and will interact with neurodegenerative disease processes rather than the development of a specific disease, such as Alzheimer's or Parkinson's. Chronic neurophysiologic change after TBI may have detrimental effects on neurodegenerative disease. PMID- 28920531 TI - Role of Kruppel-Like Factor 4 in the Maintenance of Chemoresistance of Anaplastic Thyroid Cancer. AB - BACKGROUND: Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Kruppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS: ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS: ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1 papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS: ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells. PMID- 28920533 TI - Refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians: detection of naturally occurring osteoarthritis in laboratory cats. AB - Objectives Feline osteoarthritis causes pain and disability. Detection and measurement is challenging, relying heavily on owner report. This study describes refinement of the Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians. Methods A video analysis of osteoarthritic (n = 6) and non osteoarthritic (n = 4) cats facilitated expansion of scale items. Three successive therapeutic trials (using gabapentin, tramadol and oral transmucosal meloxicam spray) in laboratory cats with and without natural osteoarthritis (n = 12-20) permitted construct validation (assessments of disease status sensitivity and therapeutic responsiveness) and further scale refinements based on performance. Results Scale osteoarthritic sensitivity improved from phase I to phase III; phase III scale total score ( P = 0.0001) and 4/5 subcategories - body posture ( P = 0.0006), gait ( P = 0.0031), jumping (0.0824) and global distance examination ( P = 0.0001) - detected osteoarthritic cats. Total score inter-rater (intra-class correlation coefficients [ICC] = 0.64-0.75), intra-rater (ICC = 0.90 0.91) and overall internal consistency (Cronbach's alpha = 0.85) reliability were good to excellent. von Frey anesthesiometer-induced paw withdrawal threshold increased with gabapentin in phase I, in osteoarthritic cats ( P <0.001) but not in non-osteoarthritic cats ( P = 0.075). Night-time activity increased during gabapentin treatment. Objective measures also detected tramadol and/or meloxicam treatment effects in osteoarthritic cats in phases II and III. There was some treatment responsiveness: in phase I, 3/10 subcategory scores improved ( P <0.09) in treated osteoarthritic cats; in phase II, 3/8 subcategories improved; and in phase III, 1/5 subcategories improved ( P <0.096). Conclusions and relevance The revised scale detected naturally occurring osteoarthritis, but not treatment effects, in laboratory cats, suggesting future potential for screening of at-risk cats. Further study is needed to confirm reliability, validity (disease sensitivity and treatment responsiveness) and clinical feasibility, as well as cut-off scores for osteoarthritic vs non-osteoarthritic status, in client-owned cats. PMID- 28920534 TI - Analgesic effects of gabapentin and buprenorphine in cats undergoing ovariohysterectomy using two pain-scoring systems: a randomized clinical trial. AB - Objectives The aim of the study was to evaluate the analgesic efficacy of gabapentin-buprenorphine in comparison with meloxicam-buprenorphine or buprenorphine alone, and the correlation between two pain-scoring systems in cats. Methods Fifty-two adult cats were included in a randomized, controlled, blinded study. Anesthetic protocol included acepromazine-buprenorphine-propofol isoflurane. The gabapentin-buprenorphine group (GBG, n = 19) received gabapentin capsules (50 mg PO) and buprenorphine (0.02 mg/kg IM). The meloxicam buprenorphine group (MBG, n = 15) received meloxicam (0.2 mg/kg SC), buprenorphine and placebo capsules (PO). The buprenorphine group (BG, n = 18) received buprenorphine and placebo capsules (PO). Gabapentin (GBG) and placebo (MBG and BG) capsules were administered 12 h and 1 h before surgery. Postoperative pain was evaluated up to 8 h after ovariohysterectomy using a multidimensional composite pain scale (MCPS) and the Glasgow pain scale (rCMPS F). A dynamic interactive visual analog scale (DIVAS) was used to evaluate sedation. Rescue analgesia included buprenorphine and/or meloxicam if the MCPS ?6. A repeated measures linear model was used for statistical analysis ( P <0.05). Spearman's rank correlation between the MCPS and rCMPS-F was evaluated. Results The prevalence of rescue analgesia with a MCPS was not different ( P = 0.08; GBG, n = 5 [26%]; MBG, n = 2 [13%]; BG, n = 9 [50%]), but it would have been significantly higher in the BG (n = 14 [78%]) than GBG ( P = 0.003; n = 5 [26%]) and MBG ( P = 0.005; n = 4 [27%]) if intervention was based on the rCMPS F. DIVAS and MCPS/rCMPS-F scores were not different among treatments. A strong correlation was observed between scoring systems ( P <0.0001). Conclusions and relevance Analgesia was not significantly different among treatments using an MCPS. Despite a strong correlation between scoring systems, GBG/MBG would have been superior to the BG with the rCMPS-F demonstrating a potential type II error with an MCPS due to small sample size. PMID- 28920535 TI - Evaluation of incubation time for Microsporum canis dermatophyte cultures. AB - Objectives The goal of this study was to determine how frequently Microsporum canis was isolated after 1, 2 and 3 weeks of incubation on dermatophyte culture medium either from untreated cats or cats during treatment. Methods This was an observational retrospective study. Toothbrush fungal culture results were examined from two data pools: untreated cats with suspect skin lesions and weekly fungal cultures from cats being treated for dermatophytosis. Results Results from 13,772 fungal cultures were reviewed and 2876 (20.9%) were positive for M canis. Of these, 2800 were confirmed as positive within 14 days of incubation and only 76 (2.6%) required >14 days for confirmation of M canis. In pretreatment specimens, 98.2% (1057/1076) of M canis isolates were recovered within 14 days of incubation in specimens from cats not known to have received prior antifungal treatment. For cats receiving treatment, 96.8% (1743/1800) of M canis isolates were recovered within 14 days of incubation. Of the 57 cultures that required >14 days for finalization, 21 required extra incubation time because cultures were grossly abnormal, 12 had concurrent contaminant growth delaying microscopic confirmation and 24 had no growth in the first 14 days. Of these 24, 19 had 1-2 colony-forming units (cfu)/plate and the remaining five plates had 5 to >10 cfu/plate, all with abnormal morphology. Conclusions and relevance The findings of this study show that it is not necessary to hold pretreatment or post treatment fungal cultures for 21 days before finalizing cultures for no growth. Growth requiring >14 days had grossly abnormal morphology. PMID- 28920536 TI - Pleural lymphocyte-rich transudates in cats. AB - Objectives Non-chylous lymphorrhagic pleural effusions are transudative effusions with a predominance of lymphocytes; however, they do not contain chylomicrons and therefore do not have the classical milky aspect of true chylous effusion. This type of effusion has been anecdotally associated with cardiac diseases in cats, but studies are lacking. The aim of this study was to investigate the association between this type of effusion and the primary disease. Methods In this study, feline non-chylous lymphorrhagic pleural effusions were retrospectively selected from the database of the authors' institutions over a 3 year period. All cases underwent thoracic imaging, including echocardiography. Effusions classified as transudates with a predominance of lymphocytes on cytology were included. Results Thirty-three cases fulfilled the inclusion criteria: 23 (69.7%) had a concurrent cardiac disease, eight (24.2%) cases were associated with the presence of a mediastinal lymphoma or carcinoma or a thoracic mass, one case (3.0%) was a thymoma and one case (3.0%) was a sequela of a pyothorax. Conclusions and relevance Since a clear lymphatic origin of the fluid could not be demonstrated, lymphocyte-rich transudate might be considered a better designation for these kinds of effusions rather than non-chylous lymphorrhagic effusions. Although the number of cases in this preliminary study is low, the presence of a pleural lymphocyte-rich transudate in a cat should prompt the search for cardiac disease or intrathoracic neoplasia. PMID- 28920537 TI - Magnetic resonance imaging and brain injury in the chronic phase after aneurysmal subarachnoid hemorrhage: A systematic review. AB - Background Case-fatality rates after aneurysmal subarachnoid hemorrhage have decreased over the past decades. However, many patients who survive an aneurysmal subarachnoid hemorrhage have long-term functional and cognitive impairments. Aims We sought to review all data on conventional brain MRI obtained in the chronic phase after aneurysmal subarachnoid hemorrhage to (1) analyze the proportion of patients with cerebral infarction or brain volume changes; (2) investigate baseline determinants predictive of MRI-detected damage; and (3) assess if brain damage is predictive of patient outcome. Summary of review All original data published between 1 January 2000 and 4 October 2017 was searched using the PUBMED, EMBASE, and Web of Science databases. Based on preset inclusion criteria, 15 from 5200 articles were included with a total of 996 aneurysmal subarachnoid hemorrhage patients. Quality assessment, risk of bias assessment, and level of evidence assessment were performed. The results according to aim, with levels of evidence, were: (1) 25 to 81% of aneurysmal subarachnoid hemorrhage patients show infarcts (strong); there is a higher ratio of cerebrospinal fluid-to-intracranial volume in patients compared to controls (strong); (2) there is a negative relation between age (moderate), DCI (low) and brain volume measurement outcomes; (3) lower brain parenchymal volume (strong) and the presence of infarcts or infarct volumes (moderate) are associated with a worse outcome. Conclusion Patients after aneurysmal subarachnoid hemorrhage may demonstrate brain infarcts and decreased brain parenchyma, which is related to worse outcome. Thereby, both brain infarcts and brain volume measurements could be used as outcome markers in pharmaceutical trials. Systematic Review Registration PROSPERO CRD42016040095. PMID- 28920538 TI - Fibrinolytic for treatment of intraventricular hemorrhage: A meta-analysis and systematic review. AB - Background Intraventricular hemorrhage is a significant cause of mortality and morbidity worldwide. Treating intraventricular hemorrhage with intraventricular fibrinolytic therapy via a catheter is becoming an increasingly utilized intervention. Aims This meta-analysis aimed to investigate the role of intraventricular fibrinolytic treatment in hypertensive intraventricular hemorrhage patients and evaluate the effect sizes for survival as well as level of function at differing time points. Summary of review PubMed, CNKI, VIP, and Wanfang were searched using the terms "IVH" and "IVH and ICH" for human studies with adult patients published between January 1950 and July 2016. Seventeen publications were selected. Data analysis showed lower rates of mortality in the treatment group at 30 days ( P < 0.001), 180 days ( P = 0.001), 365 days ( P = 0.40), and overall ( P < 0.001). Pooling modified Rankin Scale and Glasgow outcome scale data, the treatment group had more good functional outcomes at 30 days ( P = 0.38), 90 days ( P = 0.04), 180 days ( P = 0.31), 365 days ( P = 0.76), and overall ( P = 0.02). Good functional outcome was defined as modified Rankin Scale score of 0 to 3 or a Glasgow outcome scale score of 3 to 5. Conclusions Intraventricular fibrinolytic for treatment of hypertensive intraventricular hemorrhage reduces mortality and potentially leads to an increased number of good functional outcomes. Different functional outcome scales (modified Rankin Scale or Glasgow outcome scale) produce different effect sizes. Intraventricular fibrinolytic treatment may offer intraventricular hemorrhage patients a targeted therapy that produces meaningful mortality benefit and possible functional outcome benefits. PMID- 28920539 TI - The effects of stabilization splint treatment on the volume of masseter muscle in sleep bruxism patients. AB - OBJECTIVE: The aim of this study was to evaluate, quantitatively, the volumetric effects of stabilization splint therapy on the masseter muscle of sleep bruxism (SB) patients. METHODS: The magnetic resonance (MR) images of 16 SB patients diagnosed by polysomnography (PSG) who used stabilization splints for four months were obtained before and after the therapy. The masseter muscle volume was calculated using Cavalieri's principle on the MR images. RESULTS: After the splint therapy, the mean volume of the masseter muscle did not reduce significantly. The fat and/or water content of the muscles did not change either. DISCUSSION: The stabilization splint therapy had no effect on the volume, fat and/or water content of the masseter muscle; however the discomfort was reduced in the patients. Although the effect of splint therapy is not fully understood, the non-invasive and reversible stabilization splint can be used in SB patients because of its relaxation effect on muscles. PMID- 28920540 TI - The effect of conventional versus figure-of-eight module ligation on mandibular incisor alignment: a randomised controlled trial. AB - OBJECTIVE: To determine whether using figure-of-eight modules affects the rate of lower incisor alignment compared with conventionally tied modules. DESIGN: Prospective randomised controlled trial. SETTING: Orthodontic department at Queen's Hospital, Burton upon Trent, UK. METHODS: One hundred and twenty participants were randomly allocated to conventional module or figure-of-eight module groups, stratified for extraction or non-extraction lower arch treatment. Eligibility criteria included patients who were 12-15 years of age at the start of treatment, in the permanent dentition, and had mandibular incisor irregularity of 5-10 mm (clinical observation). The primary outcome was the rate of lower incisor alignment during the first 12 weeks of orthodontic treatment. The secondary outcome was bracket failure rate. Lower labial segment alignment was measured on study models using the Little's Irregularity Index at the start (T0) of treatment, at 6 weeks (T1) and 12 weeks (T2). Case records were analysed to assess the number of bracket failures. RESULTS: The four groups were well matched at baseline with respect to gender, age and irregularity. All patients completed the trial and data were analysed on an intention to treat basis. In both ligation groups, the lower teeth aligned significantly faster when the treatment involved extractions, for the time periods T0-T1 and T0-T2 (p < 0.05). There were no statistically significant differences between conventional module and figure-of eight module ligation on the rate of alignment (per month) for all three-time periods. The bracket failure rate was also similar in both test groups; 4.08% for conventional and 3.21% for figure-of-eight ligation. CONCLUSIONS: Ligation with figure-of-eight modules has no clinically significant effect on the rate of lower incisor alignment; it does not seem to hinder or quicken the alignment of teeth. There were no differences in the mean number of bracket failures per person. PMID- 28920541 TI - Recovery of brodifacoum in vomitus following induction of emesis in dogs that had ingested rodenticide bait. AB - AIM: To assess the benefit of inducing emesis in dogs that have ingested rodenticide bait containing brodifacoum (BDF), by determining the amount of BDF in bait recovered from the vomitus relative to the estimated amount consumed. METHODS: Between 2014 and 2015 samples of vomitus from seven dogs that ingested rodenticide baits containing BDF were submitted by veterinarians in New Zealand. All seven dogs had been given apomorphine by the veterinarian and vomited within 1 hour of ingesting the bait. Some or all of the bait particles were retrieved from each sample and were analysed for concentrations of BDF using HPLC. Based on estimations of the mass of bait consumed, the concentration of BDF stated on the product label, and the estimated mass of bait in the vomitus of each dog, the amount of BDF in the vomited bait was calculated as a percentage of the amount ingested. RESULTS: For five dogs an estimation of the mass of bait ingested was provided by the submitting veterinarian. For these dogs the estimated percentage of BDF in the bait retrieved from the vomitus was between 10-77%. All dogs were well after discharge but only one dog returned for further testing. This dog had a normal prothrombin time 3 days after ingestion. CONCLUSIONS AND CLINICAL RELEVANCE: The induction of emesis within 1 hour of ingestion can be a useful tool in reducing the exposure of dogs to a toxic dose of BDF. The BDF was not fully absorbed within 1 hour of ingestion suggesting that the early induction of emesis can remove bait containing BDF before it can be fully absorbed. PMID- 28920542 TI - Brief manual-based single-session Motivational Interviewing for reducing high risk sexual behaviour in women - an evaluation. AB - The objective of this study was to develop and evaluate brief Motivational Interviewing (MI) to facilitate behaviour change in women at high risk of contracting sexually transmitted infections (STIs). One hundred and seventy-three women (mean age 24.7) at high risk of contracting STIs were randomized to a brief risk-reducing MI counselling intervention (n = 74) or assigned to the control group (n = 99). MI skill was assessed using the Motivational Interviewing Treatment Integrity (MITI) Coding System. Seventeen of 74 (23%) women tested for Chlamydia trachomatis (CT) in the MI intervention group and 22 of 99 (22%) in the control group had a genital CT infection 0-24 months before baseline. All additional CT testing was monitored up to 24 months for all 173 women in the study. None of the 49 CT-retested women in the MI group was CT infected, as compared to 3 of 72 (4%) women in the control group. A generalized estimating equations model with sexual high-risk behaviour measured at baseline and at six month follow-up produced an adjusted estimated odds ratio of 0.38 (95% confidence interval = 0.158, 0.909), indicating efficacy. Brief manual-based single-session MI counselling seems to be effective in reducing high-risk sexual behaviour in women at high risk of acquiring STIs. PMID- 28920543 TI - Control of clinical paratuberculosis in New Zealand pastoral livestock. AB - This review summarises current control measures for clinical paratuberculosis (Johne's disease; JD) in New Zealand pastoral livestock. Most New Zealand sheep, deer, beef and dairy cattle herds and flocks are infected by Mycobacterium avium ssp. paratuberculosis (Map). Dairy cattle and deer are mostly infected with bovine (Type II), and sheep and beef cattle with ovine (Type I) strains. Control in all industries is voluntary. While control in sheep and beef cattle is ad hoc, the dairy and deer industries have developed resources to assist development of farm-specific programmes. The primary target for all livestock is reduction of the incidence rate of clinical disease rather than bacterial eradication per se. For dairy farms, a nationally instituted JD-specific programme provides guidelines for risk management, monitoring and testing clinically suspect animals. While there is no formal programme for sheep farms, for those with annual prevalences of clinical disease >2%, especially fine wool breeds, vaccination may be a cost effective control option. The deer industry proactively monitors infection by a national abattoir surveillance programme and farmers with an apparent high disease incidence are encouraged to engage with a national network of trained consultants for management and control advice. Evaluation of the biological and economic effectiveness of control in all industries remains to be undertaken. Nevertheless, opportunities exist for farmers, who perceive significant JD problems in their herds/flocks, to participate in systematic best practice activities that are likely to reduce the number of clinical infections with Map on their farms, and therefore the overall prevalence of JD in New Zealand's farming industries. PMID- 28920544 TI - Identification of the location of the A1 pulley combining palpation technique with palm landmarks and percutaneous release of A1 pulley with a 19-gauge needle: A cadaveric study. AB - The aims of this study were to identify the location of the A1 pulley combining palpation technique with superficial palm landmarks and to determine the efficacy and safety of A1 pulley percutaneous release with a 19-gauge needle. Fourteen fresh frozen cadaveric specimens were used: 56 fingers and 14 thumbs. The location of the A1 pulley was based on anatomical landmarks and was identified in all digits. Complete release of the A1 pulley occurred in 60 of the 70 digits (85.7%). The length of the A1 pulley in thumbs was 5.7 mm and in other fingers 4.5 mm. There were no signs of neurovascular bundle injuries. The mean distance between needle pathway and neurovascular bundle was 4.3 mm in the thumbs and 6.5 mm in the other fingers. There were no total flexor tendon injuries. The location of the A1 pulley can be predicted with success. Percutaneous release of the A1 pulley with a 19-gauge needle shows acceptable results in both safety and efficacy. PMID- 28920545 TI - Median nerve movement in the carpal tunnel before and after carpal tunnel release using transverse ultrasound. AB - PURPOSE: We aimed to compare the movement of the median nerve within the carpal tunnel during wrist and finger motions between before and after carpal tunnel release (CTR) using transverse ultrasound in carpal tunnel syndrome (CTS) patients and to evaluate the biomechanical efficacy of CTR for CTS. METHODS: Twenty-four patients with CTS were examined by transverse ultrasound. The location of the median nerve within the carpal tunnel was examined quantitatively as a coordinate at varied wrist positions with finger extension and flexion, respectively, before and after CTR. RESULTS: We found that the median nerve moved statistically significantly more palmarly after CTR than before at all wrist positions during finger motion. The average median nerve displacement toward the palmar side at the palmar flexion position in finger flexion was the greatest among all positions. Additionally, the displacement amounts of the median nerve during finger motion at all wrist positions were statistically significantly smaller after CTR than before. CONCLUSIONS: The current study demonstrated the movement patterns of the median nerve in the carpal tunnel during wrist and finger motions compared before and after CTR using transverse ultrasound in CTS patients. The findings suggested that as the median nerve shifted greatly palmarly away from the tendons after CTR, the nerve avoids compression or shearing stress from the tendons. This ultrasound information could offer further understanding of the pathomechanics of CTS and provide a more accurate diagnosis of CTS and better treatment by CTR. PMID- 28920546 TI - Blood supply and vascularity of the glenoid labrum: Its clinical implications. AB - BACKGROUND: Tears of the glenoid labrum are common after dislocation of the glenohumeral joint. The outcome for healing or surgical reconstruction of the glenoid labrum relies on the extent of its vascularization. This study aims to evaluate the glenoid labrum blood supply and to determine its regional vascularity. MATERIALS AND METHODS: A total of 140 shoulders (30 male and 40 female cadavers) were examined: mean age 81.5 years, range 53-101 years. All blood vessels around the glenohumeral joint were dissected and recorded. Ten specimens with the glenoid labrum and fibrous capsule attached were randomly selected and detached at the glenoid neck and subjected to decalcification. Sections (10-20 MUm) were cut through the whole thickness of each specimen from the centre of the glenoid fossa perpendicular to the glenoid labrum at 12 radii corresponding to a clock face superimposed on the glenoid. Sections were stained using haematoxylin and eosin and then examined. RESULTS: The blood supply to the glenoid labrum is by direct branches from the second part of the axillary artery, subscapular, circumflex scapular and anterior circumflex humeral and posterior circumflex humeral arteries, as well as branches of muscular arteries supplying the surrounding muscles. CONCLUSION: This study shows that the glenoid labrum has a rich blood supply suggesting that, regardless of the types of the glenoid labrum lesions or their management, an excellent outcome for glenoid labrum healing and joint stability is possible. The observations also suggest that the blood supply to the glenoid labrum is sufficient, enabling its reattachment. PMID- 28920547 TI - Decreased postoperative gluteus medius muscle cross-sectional area measured by computed tomography scan in patients with intertrochanteric fractures nailing. AB - BACKGROUND: In patients with femoral intertrochanteric fractures treated by cephalomedullary (CM) nailing, abduction force reportedly decreased by 25-30% during the postoperative follow-up period. The purpose of the current study is to evaluate the cross-sectional area (CSA) and adipose tissue ratio (ATR) of the gluteus medius muscle on the postoperative computed tomography (CT) view, expecting this graphic study will support clinical results. MATERIALS AND METHODS: A total of 27 patients with femoral intertrochanteric fractures treated by CM femoral nail implants completed the study. The mean age at osteosynthesis was 83 years (range: 72-94 years). The mean postoperative follow-up period was 23 months. The three CT axial slice views were defined as slices A, B, and C corresponding to proximal, midway, and distal part of gluteus medius, respectively. The CSA and ATR were assessed bilaterally. RESULTS: The mean and standard deviation of CSA values (mm2) between the nonoperated/ operated side were as follows: slice A: 2225.8 +/- 621.2/1984.5 +/- 425.8; slice B: 2145.1 +/- 538.3/1854.9 +/- 383.9; and slice C: 1711.0 +/- 459.0/1434.5 +/- 396.9 ( p < 0.01 in slices A, B, and C). The mean and standard deviation of ATR values (%) from the nonoperative/ operative side were as follows: slice A: 2.8 +/- 1.7/5.2 +/- 3.5; slice B: 2.7 +/- 1.9/4.6 +/- 3.2; and slice C: 3.6 +/- 3.0/4.8 +/- 3.2 ( p < 0.01 in slices A and B and p < 0.05 in slice C). CONCLUSION: Our image findings documented that gluteus medius is significantly changed in CSA and ATR. The damage possibly triggers decrease in muscular strength of hip abduction in the postoperative follow-up period. This measurement is objective, and needed no patient's endurance and cooperation. PMID- 28920548 TI - Target range of motion at 3 months after arthroscopic rotator cuff repair and its effect on the final outcome. AB - PURPOSE: The postoperative protocol after arthroscopic rotator cuff repair (ARCR) is still controversial. Some surgeons recommend slower rehabilitation in order to improve the integrity of the repair, while others prefer early range-of-motion (ROM) exercise to avoid postoperative stiffness. The purpose of this study was to determine target ROM (T-ROM) measurements at 3 months after ARCR that are predictive of eventual full recovery without structural failure. METHODS: The cases consisted of 374 shoulders in 360 patients who underwent primary ARCR and were followed up for at least 2 years. Forward flexion (FF) and side-lying external rotation (ER) were measured preoperatively at 3, 6, 9, 12, and 24 months after surgery, and the patients were divided into six subgroups according to the values for each type of ROM at 3 months (ROM-3M). In each subgroup, the final ROM at 24 months after surgery was compared to determine the T-ROM. The average ROMs with time and re-tear rate were then compared between the under-T-ROM and over-T ROM groups. RESULTS: The only significant difference in FF was between the 120 129 degrees and 110-119 degrees ROM-3M groups. Therefore, the T-ROM for FF was determined to be 120 degrees . Similarly, the T-ROM for ER was determined to be 20 degrees . Each ROM in the over-T-ROM group was significantly better than that in the under-T-ROM group at all assessments. There was no significant difference in the re-tear rate between the groups. CONCLUSION: To acquire sufficient ROM in 2 years without high re-tear rate, a target FF of 120 degrees and ER of 20 degrees should be achieved within 3 months after surgery. PMID- 28920549 TI - Rupture of a non-traumatic anterior communicating artery aneurysm: Does location of aneurysm associate with functional independence following post-acute in patient neurorehabilitation? AB - OBJECTIVE: Patients with non-traumatic rupture of an aneurysm located at the anterior communicating artery (ACoA) often experience cognitive disabilities. It is unknown whether location of aneurysm also affects the possibility for improvement in functional independence compared to patients with an aneurysmal subarachnoid hemorrhage (a-SAH) located elsewhere. The aim was to explore the association between location of aneurysm (ACoA versus other) and level of functional independence, measured by Functional Independence Measure (FIM), at discharge from rehabilitation. Additionally, age and FIM at admission were explored. METHOD: Historical cohort study among 107 patients with a-SAH based on data from a clinical database and a population-based register. Data were analyzed using multivariable logistic regression. RESULTS: Patients with ACoA were admitted with poorer cognitive FIM (median 6 (IQR 5-14) compared to patients with aneurysms located elsewhere (median 12 (IQR 6-23) (p = 0.0129); no difference at discharge. No association between aneurysm location and functional independence was observed. Higher age was associated with poorer outcome in bowel management OR 0.54 (95% CI 0.31-0.92), bladder management OR 0.59 (95% CI 0.35-0.98), comprehension OR 0.53 (95% CI 0.30-0.94), and memory OR 0.48 (95% CI 0.25-0.93). Overall, FIM at admission was associated with functional independence at discharge with the exception of stair walking and bladder management which did not reach statistical significance. CONCLUSION: ACoA was not associated with poorer level of functional independence compared to patients with a-SAH located elsewhere. Higher age was associated with poorer outcome in continence, comprehension, and memory, whereas higher FIM was associated with better functional independence across items at discharge. PMID- 28920550 TI - Sit to stand activity during stroke rehabilitation. AB - Objectives The sit to stand (STS) movement is key to independence and commonly affected by stroke. Repetitive practice is likely to improve STS ability during rehabilitation, however current practice levels are unknown. The objective of this study was simply to count the number of STS movements performed during the rehabilitation period of stroke patients using a physical activity monitor (PAM) and test whether being observed altered outcome. Methods Participants were medically stable patients referred for rehabilitation following stroke. Participants were randomly allocated to either wear or not wear the PAM for 14 days. STS ability and general mobility were recorded before and after. Results Sixty-one patients was recruited; aged 68.4 +/- 13.15 years, weight 77.12 +/- 22.73 Kg, Height 1.67 +/- 0.1 m, within 9 +/- 9 days of their stroke and an NIHSS score of 6.4 +/- 3.3. The monitored group (n = 38) performed 25.00 +/- 17.24 daily STS movements. Those requiring assistance achieved 14.29 +/- 16.10 per day while those independent in the movement achieved 34.10 +/- 12.44. There was an overall improvement in mobility (p = 0.002) but not STS performance (p = 0.053) neither outcome was affected by group allocation (p = 0.158). Cognition and mobility at baseline explained around 50% of daily STS variability. Discussion Low levels of STS activity were recorded during the rehabilitation period of stroke patient. The mean daily STS activity was lower than reports for frail older people receiving rehabilitation, and substantially below levels recorded by community living older adults. STS repetitions may represent general physical activity and these low levels support previous reports of sedentary behavior during rehabilitation. PMID- 28920551 TI - A comprehensive in silico analysis of huntingtin and its interactome. AB - A polyglutamine expansion of the N-terminal region of huntingtin (Htt) causes Huntington's disease, a severe neurodegenerative disorder. Htt huge multidomain structure, the presence of disordered regions, and the lack of sequence homologs of known structure, so far prevented structural studies of Htt, making the study of its structure-function relationships very difficult. In this work, the presence and location of five Htt ordered domains (named from Hunt1 to Hunt5) has been detected and the structure of these domains has been predicted for the first time using a combined threading/ab initio modeling approach. This work has led to the identification of a previously undetected HEAT repeats region in the Hunt3 domain. Furthermore, a putative function has been assigned to four out of the five domains. Hunt1 and Hunt5, displaying structural similarity with the regulatory subunit A of protein phosphatase 2A, are predicted to play a role in regulating the phosphorylation status of cellular proteins. Hunt2 and Hunt3 are predicted to be homologs of two yeast importins and to mediate vescicles transport and protein trafficking. Finally, a comprehensive analysis of the Htt interactome has been carried out and is discussed to provide a global picture of the Htt's structure-function relationships. PMID- 28920552 TI - Clinical correlation of the area of inferior vena cava, iliac and femoral veins for stent use. AB - Objective The purpose of the study is to evaluate normal anatomical areas of infrarenal inferior vena cava, common iliac, external iliac and common femoral veins by intravascular ultrasound with the goal of assisting the development of venous-specific stents in the treatment of iliac vein stenosis. Method From February 2012 to December 2013, 656 office-based venograms were performed in our facility. Among them, 576 were stented and 80 were not. The measurements of veins were done intraoperatively using an intravascular ultrasound catheter to record areas of the inferior vena cava, proximal, middle and distal segments of common iliac vein, external iliac vein and common femoral vein. The data were compared between non-diseased segments of patients who were stented and those not stented. The stented diseased segments were excluded. Results The mean patient age was 67.33 years (range 22-96, SD +/-13.99). Our data included 218 males, 438 females and 324 right lower extremities and 332 left lower extremities. The presenting symptoms of these patients based on CEAP were C1(0), C2 (185), C3(233), C4(107), C5(89) and C6(42). No correlation was found between area of veins and age, gender, laterality and CEAP score (P > .13). Comparison of the areas of non diseased iliac vein segments between patients not stented and patients who underwent stenting showed a significant difference, with larger areas in non stented patients in the distal common iliac vein (P = .039) and inferior vena cava (P = .012). Younger age (P = .03) and male gender (P < .0001) were associated with increased area of iliac vein segments. Conclusion Utilizing the intravascular ultrasound-guided technique, we were able to define normal anatomical areas of non-diseased inferior vena cava, iliac and femoral veins, which could be employed to guide the development of appropriate-sized stents and other tools needed for the treatment of venous insufficiency. There is specific variability in areas of normal vein segments with age and gender with/without stents. PMID- 28920553 TI - Where is the nurse in nutritional care? PMID- 28920555 TI - Presentations at the annual meeting of the Finnish Society for Rheumatology, Turku, 26-27 January 2017. PMID- 28920554 TI - A pulmonary embolism response team's initial 20 month experience treating 87 patients with submassive and massive pulmonary embolism. AB - Pulmonary Embolism Response Teams (PERTs) have emerged to provide rapid multidisciplinary assessment and treatment of PE patients. However, descriptive institutional experience and preliminary outcomes data from such teams are sparse. PERT activations were identified through a retrospective review. Only confirmed submassive or massive PEs were included in the data analysis. In addition to baseline variables, the therapeutic intervention, length of stay (LOS), in-hospital mortality, and bleeding rate/severity were recorded. A total of 124 PERT activations occurred over 20 months: 43 in the first 10 months and 81 in the next 10. A total of 87 submassive (90.8%) and massive (9.2%) PE patients were included. The median age was 65 (51-75 IQR) years. Catheter-directed thrombolysis (CDT) was administered to 25 patients, systemic thrombolysis (ST) to six, and anticoagulation alone (AC) to 54. The median ICU stay and overall LOS were 6 (3-10 IQR) and 7 (4-14 IQR) days, respectively, with no association with any variables except a brain natriuretic peptide (BNP) >100 pg/mL ( p=0.008 ICU LOS; p=0.047 overall LOS). Twelve patients (13.7%) died in the hospital, nine of whom had metastatic or brain cancer, with a median overall LOS of 13 (11-17 IQR) days. There were five major bleeds: one in the CDT group, one in the ST group, and three in the AC group. Overall, (1) PERT activations increased after the first 10 months; (2) BNP >100 pg/mL was associated with a longer LOS; (3) rates of mortality and bleeding did not correlate with treatment; and (4) the majority of in-hospital deaths occurred in patients with advanced cancer. PMID- 28920556 TI - The effects of limb dominance and a short term, high intensity exercise protocol on both landings of the vertical drop jump: implications for the vertical drop jump as a screening tool. AB - The effectiveness of vertical drop jumps (VDJs) to screen for non-contact ACL injuries is unclear. This may be contributed to by discrete point analysis, which does not evaluate patterns of movement. Also, limited research exists on the second landing of VDJs, potential lower limb performance asymmetries and the effect of fatigue. Statistical parametric mapping investigated the main effects of landing, limb dominance and a high intensity, intermittent exercise protocol (HIIP) on VDJ biomechanics. Twenty-two male athletes (21.9 +/- 1.1 years, 180.5 +/- 5.5 cm, 79.4 +/- 7.8 kg) performed VDJs pre- and post-HIIP. Repeated measures ANOVA identified pattern differences during the eccentric phases of the first and second landings bilaterally. The first landing displayed greater (internal) knee flexor (eta2 = 0.165), external rotator (eta2 = 0.113) and valgus (eta2 = 0.126) moments and greater hip (eta2 = 0.062) and knee (eta2 = 0.080) flexion. The dominant limb generated greater knee flexor (eta2 = 0.062), external rotator (eta2 = 0.110) and valgus (eta2 = 0.065) moments. The HIIP only had one effect, increased thoracic flexion relative to the pelvis (eta2 = 0.088). Finally, the dominant limb demonstrated greater knee extensor moments during the second landing (eta2 = 0.100). ACL injury risk factors were present in both landings of VDJs with the dominant limb at potentially greater injury risk. Therefore, VDJ screenings should analyse both landings bilaterally. PMID- 28920558 TI - I shouldn't talk of medicine only: Biomedical and religious frameworks for understanding antiretroviral therapies, their invention and their effects. AB - Medical pluralism offers a long-standing means of analysing the different ways in which health and illness can be interpreted and responded to. It is not unusual for multiple health systems and meanings to co-exist at any one moment in time, offering different ways of understanding and responding to illness and disease. In addition to biomedical frameworks, religious beliefs offer another important means of facilitating healing. Based on qualitative interviews with 36 people living with HIV on antiretroviral therapies (ART) in Papua New Guinea (PNG), this paper examines the ways in which people bring together and synthesise religious and biomedical therapeutic approaches to the treatment and management of HIV. For most, ART is viewed as a divine gift to complement a regime of spiritual salvation, and adherence to treatment carries with it strong religious undertones. At the same time, ART provides a sense of hope for those living with a virus that was previously associated only with death. Brought together, these narratives provide important insights into the meanings of ART and the role of religion, prayer and repentance for people in PNG. The study also provides new insight into how people with HIV actively synthesise different approaches to health and healing. PMID- 28920557 TI - Automated MicroSPECT/MicroCT Image Analysis of the Mouse Thyroid Gland. AB - BACKGROUND: The ability of thyroid follicular cells to take up iodine enables the use of radioactive iodine (RAI) for imaging and targeted killing of RAI-avid thyroid cancer following thyroidectomy. To facilitate identifying novel strategies to improve 131I therapeutic efficacy for patients with RAI refractory disease, it is desired to optimize image acquisition and analysis for preclinical mouse models of thyroid cancer. METHODS: A customized mouse cradle was designed and used for microSPECT/CT image acquisition at 1 hour (t1) and 24 hours (t24) post injection of 123I, which mainly reflect RAI influx/efflux equilibrium and RAI retention in the thyroid, respectively. FVB/N mice with normal thyroid glands and TgBRAFV600E mice with thyroid tumors were imaged. In-house CTViewer software was developed to streamline image analysis with new capabilities, along with display of 3D voxel-based 123I gamma photon intensity in MATLAB. RESULTS: The customized mouse cradle facilitates consistent tissue configuration among image acquisitions such that rigid body registration can be applied to align serial images of the same mouse via the in-house CTViewer software. CTViewer is designed specifically to streamline SPECT/CT image analysis with functions tailored to quantify thyroid radioiodine uptake. Automatic segmentation of thyroid volumes of interest (VOI) from adjacent salivary glands in t1 images is enabled by superimposing the thyroid VOI from the t24 image onto the corresponding aligned t1 image. The extent of heterogeneity in 123I accumulation within thyroid VOIs can be visualized by 3D display of voxel-based 123I gamma photon intensity. CONCLUSIONS: MicroSPECT/CT image acquisition and analysis for thyroidal RAI uptake is greatly improved by the cradle and the CTViewer software, respectively. Furthermore, the approach of superimposing thyroid VOIs from t24 images to select thyroid VOIs on corresponding aligned t1 images can be applied to studies in which the target tissue has differential radiotracer retention from surrounding tissues. PMID- 28920560 TI - Indirect evidence of pathogen-associated altered oocyte production in queens of the invasive yellow crazy ant, Anoplolepis gracilipes, in Arnhem Land, Australia. AB - Anoplolepis gracilipes is one of the six most widespread and pestiferous invasive ant species. Populations of this invader in Arnhem Land, Australia have been observed to decline, but the reasons behind these declines are not known. We investigated if there is evidence of a pathogen that could be responsible for killing ant queens or affecting their reproductive output. We measured queen number per nest, fecundity and fat content of queens from A. gracilipes populations in various stages of decline or expansion. We found no significant difference in any of these variables among populations. However, 23% of queens were found to have melanized nodules, a cellular immune response, in their ovaries and fat bodies. The melanized nodules found in dissected queens are highly likely to indicate the presence of pathogens or parasites capable of infecting A. gracilipes. Queens with nodules had significantly fewer oocytes in their ovaries, but nodule presence was not associated with low ant population abundances. Although the microorganism responsible for the nodules is as yet unidentified, this is the first evidence of the presence of a pathogenic microorganism in the invasive ant A. gracilipes that may be affecting reproduction. PMID- 28920561 TI - The Care of Older Adults Experiencing Cognitive Challenges: How Interprofessional Teams Collaborate. AB - We conducted a scoping study to examine how interprofessional health care teams improve the outcomes of older adults experiencing cognitive challenges. We searched Ovid, Medline 1946, and MEDLINE In-Process and other non-indexed citations, using the concepts multi or interdisciplinary care teams, confusion or cognitive impairment, and elderly adults. Of 4,554 articles the review yielded, 34 relevant to our inquiry, using Arksey and O'Malley's methodological framework. Twenty-nine per cent of authors reported on the processes interprofessional teams use to achieve positive outcomes for older adults. They highlighted the importance of communication, staff strategies, and education interventions in achieving outcomes with older adults and in supporting interprofessional collaboration. The review revealed knowledge gaps about the processes teams use to collaborate in caring for older adults experiencing cognitive challenges, and how to best incorporate older adults and their families' perspectives in team decisions. More research to understand processes interprofessional teams use is needed. PMID- 28920559 TI - Functional Mechanics of a Pectin-Based Pleural Sealant after Lung Injury. AB - Pleural injury and associated air leaks are a major influence on patient morbidity and healthcare costs after lung surgery. Pectin, a plant-derived heteropolysaccharide, has recently demonstrated potential as an adhesive binding to the glycocalyx of visceral mesothelium. Since bioadhesion is a process likely involving the interpenetration of the pectin-based polymer with the glycocalyx, we predicted that the pectin-based polymer may also be an effective sealant for pleural injury. To explore the potential role of an equal (weight%) mixture of high-methoxyl pectin and carboxymethylcellulose as a pleural sealant, we compared the yield strength of the pectin-based polymer to commonly available surgical products. The pectin-based polymer demonstrated significantly greater adhesion to the lung pleura than the comparison products (p < 0.001). In a 25 g needle induced lung injury model, pleural injury resulted in an air leak and a loss of airway pressures. After application of the pectin-based polymer, there was a restoration of airway pressure and no measurable air leak. Despite the application of large sheets (50 mm2) of the pectin-based polymer, multifrequency lung impedance studies demonstrated no significant increase in tissue damping (G) or hysteresivity (eta)(p > 0.05). In 7-day survival experiments, the application of the pectin-based polymer after pleural injury was associated with no observable toxicity, 100% survival (N = 5), and restored lung function. We conclude that this pectin-based polymer is a strong and nontoxic bioadhesive with the potential for clinical application in the treatment of pleural injuries. PMID- 28920562 TI - Comparison of General and Local Anesthesia for Deep Brain Stimulator Insertion: A Systematic Review. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) has become a standard treatment for many patients with Parkinson's disease (PD). The reported clinical outcome measures for procedures done under general anesthesia (GA) compared to traditional local anesthetic (LA) technique are quite heterogeneous and difficult to compare. The aim of this systematic review and metaanalysis was to determine whether the clinical outcome after STN-DBS insertion under GA is comparable to that under LA in patients with Parkinson's disease. METHODS: The databases of Medline Embase, Cochrane library and Pubmed were searched for eligible studies (human trials, English language, published between 1946 and January of 2016). The primary outcome of this study was to assess the postoperative improvement in the symptoms, evaluated using either Unified Parkinson's Disease Rating Scale (UPDRS) scores or levodopa equivalent dosage (LEDD) requirement. RESULTS: The literature searches yielded 395 citations and six retrospective cohort studies with a sample size of 455 (194 in GA and 261 in LA) were included in the analysis. Regarding the clinical outcomes, there were no significant differences in the postoperative Unified Parkinson's disease rating scale and levodopa equivalent drug dosage between the GA and the LA groups. Similarly, the adverse events and target accuracy were also comparable between the groups. CONCLUSIONS: This systematic review and meta-analysis shows that currently there is no good quality data to suggest equivalence of GA to LA during STN-DBS insertion in patients with PD, with some factors trending towards LA. There is a need for a prospective randomized control trial to validate our results. PMID- 28920563 TI - Bitemporal v. high-dose right unilateral electroconvulsive therapy for depression: a systematic review and meta-analysis of randomized controlled trials - CORRIGENDUM. PMID- 28920564 TI - Intentional overdose of the novel anti-epileptic drug eslicarbazepine presenting with recurrent seizures and ventricular dysrhythmias. AB - Eslicarbazepine is a novel anti-epileptic agent indicated for the treatment of partial-onset seizures. We present the case of an 18 year old female that presented to the Emergency Department four hours after a reported intentional ingestion of an estimated 5600 mg of eslicarbazepine. Although initially hemodynamically stable and neurologically normal, shortly after arrival she developed confusion, rigidity and clonus, followed by recurrent seizures, hypoxemia and cardiac arrest which responded to cardiopulmonary resuscitation and wide complex tachycardia requiring defibrillation. Treatment for refractory seizures included benzodiazepines and eventual intubation and sedation with propofol. Cardiac toxicity responded to sodium bicarbonate. In addition, empiric hemodialysis was performed. In this case report, we discuss the successful management of the first reported overdose of eslicarbazepine using supportive care and hemodialysis. PMID- 28920565 TI - Regulatory functions of trehalose-6-phosphate synthase in the chitin biosynthesis pathway in Tribolium castaneum (Coleoptera: Tenebrionidae) revealed by RNA interference. AB - RNA interference (RNAi) is a very effective technique for studying gene function and may be an efficient method for controlling pests. Trehalose-6-phosphate synthase (TPS), which plays a key role in the synthesis of trehalose and insect development, was cloned in Tribolium castaneum (Herbst) (TcTPS) and the putative functions were studied using RNAi via the injection of double-stranded RNA (dsRNA) corresponding to conserved TPS and trehalose-6-phosphate phosphatase domains. Expression analyses show that TcTPS is expressed higher in the fat body, while quantitative real-time polymerase chain reaction results show that the expression of four trehalase isoforms was significantly suppressed by dsTPS injection. Additionally, the expression of six chitin synthesis-related genes, such as hexokinase 2 and glutamine-fructose-6-phosphate aminotransferase, was suppressed at 48 and 72 h post-dsTPS-1 and dsTPS-2 RNA injection, which were two dsTPS fragments that had been designed for two different locations in TcTPS open reading frame, and that trehalose content and trehalase 1 activity decreased significantly at 72 h post-dsRNA injection. Furthermore, T. castaneum injected with dsTPS-1 and dsTPS-2 RNA displayed significantly lower levels of chitin and could not complete the molting process from larvae to pupae, revealing abnormal molting phenotypes. These results demonstrate that silencing TPS gene leads to molting deformities and high mortality rates via regulation of gene expression in the chitin biosynthetic pathway, and may be a promising approach for pest control in the future. PMID- 28920566 TI - Field-evolved resistance to lambda-cyhalothrin in the lady beetle Eriopis connexa. AB - Natural enemies are exposed to insecticide sprays for herbivorous species and may evolve field resistance to insecticides. Natural enemies selected for resistance in the field, however, are welcome for pest control. The susceptibility of 20 populations of Eriopis connexa from various crop ecosystems to lambda-cyhalothrin was tested. Three bioassays were conducted: (i) topical treatment with lethal dose (LD)50 previously determined for populations considered standard for susceptibility (LD50S) and for resistance (LD50R) to lambda-cyhalothrin at technical grade; (ii) dose-mortality assay to calculate the LD for populations exhibiting significant survival to the LD50R; and (iii) determination of survival when exposed to dried residues at field rates. Among the 20 tested populations, seven populations did not survive or survival rates were lower than 10% when treated with LD50R; three populations survived >20%, but lower than 50%; while ten populations exhibited equal or greater survival rates compared with the 50% expected survival for the LD50R. Thus, these ten populations were subjected to dose-mortality response, and the LD50 values varied from 0.046 to 5.44 ug a.i./insect with resistance ratio of 8.52- to 884.08-folds. Adults from these ten populations that were ranked as resistant according to the LD50R exhibited survival from 44.5 to 100% exposed to the lowest and from 38.8 to 100% exposed to the highest field rates of lambda-cyhalothrin, respectively. Otherwise, the remaining ten populations ranked as susceptible according to the LD50R showed survival from 3.3 to 56% exposed to the lowest and from 0 to 17.7% exposed to the highest field rates of lambda-cyhalothrin, respectively. Therefore, 50% of the tested E. connexa populations exhibited field-evolved resistance to lambda cyhalothrin and the use of a discriminatory LD50 for resistance matched the survival obtained when exposed to the insecticide field rates. PMID- 28920567 TI - ELECTRONIC DEVICES FOR COGNITIVE IMPAIRMENT SCREENING: A SYSTEMATIC LITERATURE REVIEW. AB - OBJECTIVES: The reduction in cognitive decline depends on timely diagnosis. The aim of this systematic review was to analyze the current available information and communication technologies-based instruments for cognitive decline early screening and detection in terms of usability, validity, and reliability. METHODS: Electronic searches identified 1,785 articles of which thirty-four met the inclusion criteria and were grouped according to their main purpose into test batteries, measures of isolated tasks, behavioral measures, and diagnostic tools. RESULTS: Thirty one instruments were analyzed. Fifty-two percent were personal computer based, 26 percent tablet, 13 percent laptop, and 1 was mobile phone based. The most common input method was touchscreen (48 percent). The instruments were validated with a total of 4,307 participants: 2,146 were healthy older adults (M = 73.59; SD = 5.12), 1,104 had dementia (M = 74.65; SD = 3.98) and 1,057 mild cognitive impairment (M = 74.84; SD = 4.46). Only 6 percent were administered at home, 19 percent reported outcomes about usability, and 22 percent about understandability. The methodological quality of the studies was good, the weakest methodological area being usability. Most of the instruments obtained acceptable values of specificity and sensitivity. CONCLUSIONS: It is necessary to create home delivered instruments and to include usability studies in their design. Involvement of people with cognitive decline in all phases of the development process is of great importance to obtain valuable and user friendly products. It would be advisable for researchers to make an effort to provide cutoff points for their instruments. PMID- 28920569 TI - High-functioning autism patients share similar but more severe impairments in verbal theory of mind than schizophrenia patients. AB - BACKGROUND: Evidence suggests that autism and schizophrenia share similarities in genetic, neuropsychological and behavioural aspects. Although both disorders are associated with theory of mind (ToM) impairments, a few studies have directly compared ToM between autism patients and schizophrenia patients. This study aimed to investigate to what extent high-functioning autism patients and schizophrenia patients share and differ in ToM performance. METHODS: Thirty high-functioning autism patients, 30 schizophrenia patients and 30 healthy individuals were recruited. Participants were matched in age, gender and estimated intelligence quotient. The verbal-based Faux Pas Task and the visual-based Yoni Task were utilised to examine first- and higher-order, affective and cognitive ToM. The task/item difficulty of two paradigms was examined using mixed model analyses of variance (ANOVAs). Multiple ANOVAs and mixed model ANOVAs were used to examine group differences in ToM. RESULTS: The Faux Pas Task was more difficult than the Yoni Task. High-functioning autism patients showed more severely impaired verbal based ToM in the Faux Pas Task, but shared similar visual-based ToM impairments in the Yoni Task with schizophrenia patients. CONCLUSIONS: The findings that individuals with high-functioning autism shared similar but more severe impairments in verbal ToM than individuals with schizophrenia support the autism schizophrenia continuum. The finding that verbal-based but not visual-based ToM was more impaired in high-functioning autism patients than schizophrenia patients could be attributable to the varied task/item difficulty between the two paradigms. PMID- 28920568 TI - Pregnant women of South Asian ethnicity in Canada have substantially lower vitamin B12 status compared with pregnant women of European ethnicity. AB - Maternal vitamin B12 (B12) status has been inversely associated with adverse pregnancy outcomes and positively with fetal growth and infant development. South Asians, Canada's largest ethnic minority, are prone to B12 deficiency. Yet, data are lacking on B12 status in South Asian pregnant women in North America. We sought to determine B12 status, using multiple biomarkers, in 1st and 2nd trimester pregnant women of South Asian and, for comparison, European ethnicity living in Vancouver, Canada. In this retrospective cohort study, total B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine concentrations were quantified in two routinely collected (mean gestational week: 11.5 (range 8.3-13.9) and 16.5 (range 14.9-20.9)), banked serum samples of 748 healthy pregnant South Asian (n 371) and European (n 377) women. South Asian pregnant women had significantly lower B12 status than European pregnant women at both time points, as indicated by lower serum total B12 and holoTC concentrations, and higher MMA concentrations (all P<=0.001). The largest difference, which was substantial (Cohen's d>=0.5), was observed in mean serum total B12 concentrations (1st trimester: 189 (95 % CI 180, 199) v. 246 (95 % CI 236, 257) pmol/l; 2nd trimester: 176 (95 % CI 168, 185) v. 226 (95 % CI 216, 236) pmol/l). Further, South Asian ethnicity was a significant negative predictor of B12 status during pregnancy. South Asian women living in Vancouver have substantially lower B12 status during early pregnancy. Future research identifying predictors and health consequences of this observed difference is needed to allow for targeted interventions. PMID- 28920570 TI - Brain-relevant antibodies in first-episode psychosis: a matched case-control study. AB - BACKGROUND: There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). METHODS: Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case-control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. RESULTS: VGKC complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. CONCLUSIONS: This case-control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context. PMID- 28920572 TI - Addendum for Euro Surveill. 2017;22(35). PMID- 28920571 TI - Recurrent seasonal outbreak of an emerging serotype of Shiga toxin-producing Escherichia coli (STEC O55:H7 Stx2a) in the south west of England, July 2014 to September 2015. AB - The first documented British outbreak of Shiga toxin-producing Escherichia coli (STEC) O55:H7 began in the county of Dorset, England, in July 2014. Since then, there have been a total of 31 cases of which 13 presented with haemolytic uraemic syndrome (HUS). The outbreak strain had Shiga toxin (Stx) subtype 2a associated with an elevated risk of HUS. This strain had not previously been isolated from humans or animals in England. The only epidemiological link was living in or having close links to two areas in Dorset. Extensive investigations included testing of animals and household pets. Control measures included extended screening, iterative interviewing and exclusion of cases and high risk contacts. Whole genome sequencing (WGS) confirmed that all the cases were infected with similar strains. A specific source could not be identified. The combination of epidemiological investigation and WGS indicated, however, that this outbreak was possibly caused by recurrent introductions from a local endemic zoonotic source, that a highly similar endemic reservoir appears to exist in the Republic of Ireland but has not been identified elsewhere, and that a subset of cases was associated with human-to-human transmission in a nursery. PMID- 28920573 TI - Preliminary findings indicate nosocomial transmission and Roma population as most affected group in ongoing measles B3 genotype outbreak in Bulgaria, March to August 2017. AB - From March to August 2017, 165 measles cases were reported from three regions in Bulgaria. The age range was 0-55 years and 66% of the cases were under 9 years. The Roma population was disproportionally affected (89% of cases), 41% cases were unvaccinated and in 24 cases there was nosocomial transmission mostly in paediatric departments. A child under 12 months of age died. Control measures have been taken and the investigation is still ongoing. PMID- 28920574 TI - Status, quality and specific needs of Zika virus (ZIKV) diagnostic capacity and capability in National Reference Laboratories for arboviruses in 30 EU/EEA countries, May 2016. AB - With international travel, Zika virus (ZIKV) is introduced to Europe regularly. A country's ability to robustly detect ZIKV introduction and local transmission is important to minimise the risk for a ZIKV outbreak. Therefore, sufficient expertise and diagnostic capacity and capability are required in European laboratories. To assess the capacity, quality, operational specifics (guidelines and algorithms), technical and interpretation issues and other possible difficulties that were related to ZIKV diagnostics in European countries, a questionnaire was conducted among national reference laboratories in 30 countries in the European Union/European Economic Area (EU/EEA) in May 2016. While the coverage and capacity of ZIKV diagnostics in the EU/EEA national reference laboratories were found to be adequate, the assessment of the quality and needs indicated several crucial points of improvement that will need support at national and EU/EEA level to improve ZIKV preparedness, response and EU/EEA ZIKV surveillance activities. PMID- 28920577 TI - Late Side Effects of Chemotherapy and Radiotherapy in Early Childhood on the Teeth: Two Case Reports. PMID- 28920575 TI - The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition. AB - The P2X7 receptor mediates extracellular ATP signaling implicated in the development of devastating diseases such as chronic pain and cancer. Activation of the P2X7 receptor leads to opening of the characteristic dye-permeable membrane pore for molecules up to ~900 Da. However, it remains controversial what constitutes this peculiar pore and how it opens. Here we show that the panda receptor, when purified and reconstituted into liposomes, forms an intrinsic dye permeable pore in the absence of other cellular components. Unexpectedly, we found that this pore opens independent of its unique C-terminal domain. We also found that P2X7 channel activity is facilitated by phosphatidylglycerol and sphingomyelin, but dominantly inhibited by cholesterol through direct interactions with the transmembrane domain. In combination with cell-based functional studies, our data suggest that the P2X7 receptor itself constitutes a lipid-composition dependent dye-permeable pore, whose opening is facilitated by palmitoylated cysteines near the pore-lining helix. PMID- 28920576 TI - The DREAM complex through its subunit Lin37 cooperates with Rb to initiate quiescence. AB - The retinoblastoma Rb protein is an important factor controlling the cell cycle. Yet, mammalian cells carrying Rb deletions are still able to arrest under growth limiting conditions. The Rb-related proteins p107 and p130, which are components of the DREAM complex, had been suggested to be responsible for a continued ability to arrest by inhibiting E2f activity and by recruiting chromatin modifying enzymes. Here, we show that p130 and p107 are not sufficient for DREAM dependent repression. We identify the MuvB protein Lin37 as an essential factor for DREAM function. Cells not expressing Lin37 proliferate normally, but DREAM completely loses its ability to repress genes in G0/G1 while all remaining subunits, including p130/p107, still bind to target gene promoters. Furthermore, cells lacking both Rb and Lin37 are incapable of exiting the cell cycle. Thus, Lin37 is an essential component of DREAM that cooperates with Rb to induce quiescence. PMID- 28920579 TI - Point-of-care companion diagnostic tests for personalizing psychiatric medications: fulfilling an unmet clinical need. AB - Over the last decade stable isotope-labeled substrates have been used as probes for rapid, point-of-care, non-invasive and user-friendly phenotype breath tests to evaluate activity of drug metabolizing enzymes. These diagnostic breath tests can potentially be used as companion diagnostics by physicians to personalize medications, especially psychiatric drugs with narrow therapeutic windows, to monitor the progress of disease severity, medication efficacy and to study in vivo the pharmacokinetics of xenobiotics. Several genotype tests have been approved by the FDA over the last 15 years for both cytochrome P450 2D6 and 2C19 enzymes, however they have not been cleared for use in personalizing medications since they fall woefully short in identifying all non-responders to drugs, especially for the CYP450 enzymes. CYP2D6 and CYP2C19 are among the most extensively studied drug metabolizing enzymes, involved in the metabolism of approximately 30% of FDA-approved drugs in clinical use, associated with large individual differences in medication efficacy or tolerability essentially due to phenoconversion. The development and commercialization via FDA approval of the non-invasive, rapid (<60 min), in vivo, phenotype diagnostic breath tests to evaluate polymorphic CYP2D6 and CYP2C19 enzyme activity by measuring exhaled 13CO2 as a biomarker in breath will effectively resolve the currently unmet clinical need for individualized psychiatric drug therapy. Clinicians could personalize treatment options for patients based on the CYP2D6 and CYP2C19 phenotype by selecting the optimal medication at the right initial and subsequent maintenance dose for the desired clinical outcome (i.e. greatest efficacy and minimal side effects). PMID- 28920578 TI - Participation in Physical and Sportive Activities among Adult Turkish People with Hemophilia: A Single-Center Experience. PMID- 28920580 TI - Sandwiched ZnO@Au@CdS nanorod arrays with enhanced visible-light-driven photocatalytical performance. AB - The development of high-performance photocatalysts is central to efforts focused on taking advantage of solar energy to overcome environmental and energy crises. Integrating different functional materials artfully into nanostructures can deliver more efficient photocatalytic activity. Here, sandwiched ZnO@Au@CdS nanorod films were synthesized via successive ZnO nanorod electrodeposition, Au sputtering and CdS electrodeposition. The as-synthesized composites were characterized by UV-vis spectrophotometer, x-ray diffractometer, scanning and transmission electron microscopy. Their photocatalytic activity was assessed by degrading Rhodamine B solution under visible light irradiation. ZnO@Au@CdS exhibited better photocatalytic performance than ZnO@CdS throughout the visible light region, and the corresponding enhancement factor of Au nanoparticles was measured as a function of CdS loading amount, and it could reach 190% with CdS deposition for 1 min. The normalized rate constant could reach 0.387 h-1 for ZnO@Au@CdS-1min, which was equivalent to or better than results in reference photocatalysts. The enhancement mechanism of Au nanoparticles was estimated by comparing the monochromatic photocatalytic action spectra with the absorption spectrum of ZnO@Au@CdS, and it was mainly determined by incident photon energy. With selective excitation of Au nanoparticles by incident photons, the excited hot electrons in Au NPs are transferred to the conduction band of ZnO to boost photocatalytic reaction. With selective excitation of CdS, the enhanced interband absorption of CdS and relay station effect of Au nanoparticles should be responsible for the enhanced photocatalytic performance. Our work not only opens the door to the design of efficient supported photocatalysts, but also helps to understand the enhancement mechanism of LSPR effect on the photoelectric conversion of semiconductors. PMID- 28920581 TI - Bottle-brush-shaped heterostructures of NiO-ZnO nanowires: growth study and sensing properties. AB - We present here heterostructured ZnO-NiO nanowires (NWs), constituted by a core of single crystalline ZnO NWs, covered by poly-crystalline NiO nanorods (NRs). The bottle-brush shape was investigated by scanning electron microscopy and transmission electron microscope, confirming that a columnar growth of NiO occurred over the ZnO core, with a preferred orientation of NiO over ZnO NWs. The heterostructured devices are proposed for gas sensing application. Bare ZnO NWs and heterostructured sensors with two different thicknesses of NiO poly crystalline NRs were analysed for acetone, ethanol, NO2 and H2 detection. All sensors maintained n-type sensing mechanism, with improved sensing performance for lower thickness of NiO, due to high catalytic activity of NiO. The sensing dynamic is also strongly modified by the presence of heterojunction of NiO/ZnO, with a reduction of response and recovery times towards ethanol and acetone at 400 degrees C. PMID- 28920582 TI - An age-specific biokinetic model for iodine. AB - This paper reviews age-specific biokinetic data for iodine in humans and extends to pre-adult ages the baseline parameter values of the author's previously published model for systemic iodine in adult humans. Compared with the ICRP's current age-specific model for iodine introduced in Publication 56 (1989, pp 45 48), the present model provides a more detailed description of the behaviour of iodine in the human body; predicts moderately higher doses to the thyroid for short-lived isotopes of iodine; predicts similar doses to the thyroid for isotopes with half-time greater than a few hours; and, for most iodine isotopes, predicts substantially higher doses to salivary glands, stomach wall, liver, and kidneys. PMID- 28920583 TI - Ebosin: a potential therapeutic agent for rheumatoid arthritis and autoinflammatory syndromes. PMID- 28920585 TI - Role of programmed cell death 4 in diseases: a double-edged sword. PMID- 28920584 TI - Liver-resident NK cells and their potential functions. AB - Natural killer (NK) cells represent a heterogeneous population of innate lymphocytes with phenotypically and functionally distinct subsets. In particular, recent studies have identified a unique subset of NK cells residing within the liver that are maintained as tissue-resident cells, confer antigen-specific memory responses and exhibit different phenotypical and developmental characteristics compared with conventional NK (cNK) cells. These findings have encouraged researchers to uncover tissue-resident NK cells at other sites, and detailed analyses have revealed that these tissue-resident NK cells share many similarities with liver-resident NK cells and tissue-resident memory T cells. Here, we present a brief historical perspective on the discovery of liver resident NK cells and discuss their relationship to cNK cells and other emerging NK cell subsets and their potential functions.Cellular &Molecular Immunology advance online publication, 18 September 2017; doi:10.1038/cmi.2017.72. PMID- 28920586 TI - Neutrophils: Interfering with intestinal inflammation. PMID- 28920589 TI - Neuroimmunology: JAK in the itch. PMID- 28920590 TI - Incubation of Accumbal Neuronal Reactivity to Cocaine Cues During Abstinence Predicts Individual Vulnerability to Relapse. AB - An important goal for the treatment of cocaine addiction is to identify neuromarkers that can predict individual vulnerability to relapse after abstinence. There is some evidence that individual reactivity to cue-induced craving may predict subsequent relapse after a period of abstinence. Here we sought to identify the neuronal correlates of this predictive relationship in rats. Rats were trained to self-administer cocaine (6 h) for 16 days to induce escalation of cocaine intake. Then rats underwent a 1-month period of forced abstinence after which they were re-exposed to cocaine self-administration (6 h) for 8 additional days to induce re-escalation of cocaine intake. We recorded nucleus accumbens (NAc) neuronal responses to drug conditioned stimuli (CS) 1 day before and after 1 month of abstinence from cocaine intake escalation. Rats were ranked according to their individual percentage of CS responsive neurons recorded during the last day of abstinence and split by the median into two groups. We found evidence for a robust, incubation-like increase in NAc reactivity to cocaine cues after abstinence only in a subset of individuals (High CS rats). Importantly, compared with other rats that did not present an incubation of NAc reactivity to cocaine cues (Low CS rats), High CS rats were faster to re-escalate their intake of cocaine after abstinence. In addition, after re-escalation, they worked harder and were less sensitive to risk of punishment than Low CS rats, indicating a strengthened motivation to seek and/or take the drug in that group of rats. Overall, these findings indicate that incubation of NAc neuronal reactivity to cocaine cues during abstinence may constitute a predictive neuromarker for individual vulnerability to relapse. PMID- 28920587 TI - Complement in cancer: untangling an intricate relationship. AB - In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment. PMID- 28920592 TI - In situ synthesis of Au-shelled Ag nanoparticles on PDMS for flexible, long-life, and broad spectrum-sensitive SERS substrates. AB - A simple and fast one-step fabrication method of silver nanoparticles (AgNPs) on a polydimethylsiloxane (PDMS) film and their improvement as highly sensitive surface enhanced Raman scattering (SERS) substrates via atomically thin Au coatings is demonstrated. The thin Au layer provides oxidation resistivity while maintaining the broad spectral range SERS sensitivity of Ag nanoparticles. PMID- 28920591 TI - Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Dorsal Tegmental Nucleus Regulates Energy Balance. AB - The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding. PMID- 28920593 TI - A RAFT/MADIX method finely regulating the copolymerization of ethylene and polar vinyl monomers under mild conditions. AB - A RAFT/MADIX method can not only copolymerize ethylene with a diverse range of functionally polar monomers, but can also easily tune the polar composition and the polar monomer distribution along the produced copolymer chains. This highly versatile RAFT/MADIX copolymerization platform provides access to a diverse range of polyethylene materials. PMID- 28920594 TI - Terminal tungsten pnictide complex formation through pnictaethynolate decarbonylation. AB - Tungsten(iv) tetrakis(2,6-diisopropylphenoxide) (1) has been demonstrated to be a competent platform for decarbonylative formation of anionic terminal pnictide complexes upon treatment with pnictaethynolate anions: cyanate, 2 phosphaethynolate, and 2-arsaethynolate. These transformations constitute the first examples of terminal phosphide and arsenide complex formation at a transition metal center from OCP- and OCAs-, respectively. The phosphide and arsenide complexes are also the first to be isolated in a tetragonal, all-oxygen ligand environment. The scalar NMR coupling constants between tungsten-183 and nitrogen-15 or phosphorus-31 have been measured and contextualized using natural bond orbital (NBO) methods in terms of s orbital character in the sigma bonding orbital and pnictide lone pair. PMID- 28920595 TI - A unique rectilinearly pi-extended rhodamine dye with large Stokes shift and near infrared fluorescence for bioimaging. AB - The synthesis of a novel rectilinearly pi-extended rhodamine dye (TJ730) has been described. It exhibits NIR fluorescence emission with a Stokes shift of >110 nm. TJ730 and its ester derivative are cell permeable, have low cytotoxicity, are biocompatible, and can be directly used as NIR tracers for lysosome staining. Using TJ730 as a precursor, two probes have been prepared for Cu2+. PMID- 28920588 TI - gammadelta T cells in homeostasis and host defence of epithelial barrier tissues. AB - Epithelial surfaces line the body and provide a crucial interface between the body and the external environment. Tissue-resident epithelial gammadelta T cells represent a major T cell population in the epithelial tissues and are ideally positioned to carry out barrier surveillance and aid in tissue homeostasis and repair. In this Review, we focus on the intraepithelial gammadelta T cell compartment of the two largest epithelial tissues in the body - namely, the epidermis and the intestine - and provide a comprehensive overview of the crucial contributions of intraepithelial gammadelta T cells to tissue integrity and repair, host homeostasis and protection in the context of the symbiotic relationship with the microbiome and during pathogen clearance. Finally, we describe epithelium-specific butyrophilin-like molecules and briefly review their emerging role in selectively shaping and regulating epidermal and intestinal gammadelta T cell repertoires. PMID- 28920596 TI - Optical and magnetic properties of antiaromatic porphyrinoids. AB - Magnetic and spectroscopic properties of a number of formally antiaromatic carbaporphyrins, carbathiaporphyrins and isophlorins with 4n pi electrons have been investigated at density functional theory and ab initio levels of theory. The calculations show that the paratropic contribution to the magnetically induced ring-current strength susceptibility and the magnetic dipole-transition moment between the ground and the lowest excited state are related. The vertical excitation energy (VEE) of the first excited state decreases with increasing ring current strength susceptibility, whereas the VEE of the studied higher-lying excited states are almost independent of the size of the ring-current strength susceptibility. Strong antiaromatic porphyrinoids, based on the magnitude of the paratropic ring-current strength susceptibility, have small energy gaps between the highest occupied and lowest unoccupied molecular orbitals and a small VEE of the first excited state. The calculations show that only the lowest S0 -> S1 transition contributes signficantly to the magnetically induced ring-current strength susceptibility of the antiaromatic porphyrinoids. The decreasing optical gap combined with a large angular momentum contribution to the magnetic transition moment from the first excited state explains why molecules III-VII are antiaromatic with very strong paratropic ring-current strength susceptibilities. The S0 -> S1 transition is a magnetic dipole-allowed electronic transition that is typical for antiaromatic porphyrinoids with 4n pi electrons. PMID- 28920597 TI - An assessment of the random-phase approximation functional and characteristics analysis for noncovalent cation-pi interactions. AB - The binding energy is of great importance in understanding the formation and stability of noncovalent interactions. However, the determination of the binding energy with high precision and efficiency in medium- and long-range noncovalent interactions is still challenging for quantum chemistry. Here, we assess the performance of random-phase approximation (RPA), a fully non-local fifth-rung of the Jacob ladder functional, in determining the binding energy of cation-pi systems (cation = Li+, Na+, Be2+, Mg2+, Al+, and NH4+; pi = C6H6), which, to the best of our knowledge, has not been investigated. Using experimental results as the benchmark, we systematically compared the RPA method to the other ab initio methods (DFT/B3LYP, MP2, CCSD(T), and QCISD(T)) both in calculation accuracy and efficiency. From the perspective of accuracy, RPA is the best among these approaches, followed by the CCSD(T) and QCISD(T) methods. DFT/B3LYP and MP2 provide the worst accuracy. In addition, the computational efficiency of RPA is much faster than that of CCSD(T) and QCISD(T). We believe that RPA is a robust method for the precise description of medium- and long-range noncovalent interactions and is capable of providing benchmarking data. The interaction strength and interaction nature of cation-pi systems are further analyzed by atoms in molecules (AIM) and the color-mapped reduced density gradient (RDG) isosurface, which are consistent with the characteristics of a typical cation-pi interaction. PMID- 28920598 TI - Interaction between H2O, N2, CO, NO, NO2 and N2O molecules and a defective WSe2 monolayer. AB - In this study, the interaction between gas molecules, including H2O, N2, CO, NO, NO2 and N2O, and a WSe2 monolayer containing an Se vacancy (denoted as VSe) has been theoretically studied. Theoretical results show that H2O and N2 molecules are highly prone to be physisorbed on the VSe surface. The presence of the Se vacancy can significantly enhance the sensing ability of the WSe2 monolayer toward H2O and N2 molecules. In contrast, CO and NO molecules highly prefer to be molecularly chemisorbed on the VSe surface with the non-oxygen atom occupying the Se vacancy site. Furthermore, the exposed O atoms of the molecularly chemisorbed CO or NO can react with additional CO or NO molecules, to produce C-doped or N doped WSe2 monolayers. The calculated energies suggest that the filling of the CO or NO molecule and the removal of the exposed O atom are both energetically and dynamically favorable. Electronic structure calculations show that the WSe2 monolayers are p-doped by the CO and NO molecules, as well as the C and N atoms. However, only the NO molecule and N atom doped WSe2 monolayers exhibit significantly improved electronic structures compared with VSe. The NO2 and N2O molecules will dissociate directly to form an O-doped WSe2 monolayer, for which the defect levels due to the Se vacancy can be completely removed. The calculated energies suggest that although the dissociation processes for NO2 and N2O molecules are highly exothermic, the N2O dissociation may need to operate at an elevated temperature compared with room temperature, due to its large energy barrier of ~1 eV. PMID- 28920599 TI - Magnetic nanoparticle-enhanced surface plasmon resonance biosensor for extracellular vesicle analysis. AB - The sensitive analysis of small lipid extracellular vesicles (EVs) by using a grating-coupled surface plasmon resonance (GC-SPR) biosensor has been reported. In order to enable the analysis of trace amounts of EVs present in complex liquid samples, the target analyte is pre-concentrated on the sensor surface by using magnetic nanoparticles and its affinity binding is probed by wavelength interrogation of SPR. The GC-SPR has been demonstrated to allow for the implementation of efficient pulling of EVs to the sensor surface by using magnetic nanoparticles and an external magnetic field gradient applied through the sensor chip. This approach overcomes slow diffusion-limited mass transfer and greatly enhances the measured sensor response. The specific detection of different EV populations secreted from mesenchymal stem cells is achieved with a SPR sensor chip modified with antibodies against the surface marker CD81 and magnetic nanoparticles binding the vesicles via annexin V and cholera toxin B chain. PMID- 28920600 TI - Quantum-state-selected integral cross sections for the charge transfer collision of O2+(a4Piu5/2,3/2,1/2,-1/2: v+ = 1-2; J+) [O2+(X2Pig3/2,1/2: v+ = 22-23; J+)] + Ar at center-of-mass collision energies of 0.05-10.00 eV. AB - By employing the sequential electric field pulsing scheme for vacuum ultraviolet (VUV) laser pulsed field ionization-photoion (PFI-PI) detection, we have successfully recorded the spin-orbit and rovibronic state resolved VUV-PFI-PI spectra for O2+(a4Piu5/2,3/2,1/2,-1/2: nu+ = 0-2; J+) and O2+(X2Pig3/2,1/2: nu+ = 21-23; J+), indicating that O2+(a4Piu) and O2+(X2Pig) ions in these spin-orbit and rovibronic states can be prepared for ion-molecule collision studies. The present experiment is concerned with the measurement of absolute integral cross sections (sigma's) of the charge transfer reactions, O2+(a4Piu5/2,3/2,1/2,-1/2: nu+ = 1, 2; J+) [O2+(X2Pig1/2,3/2: nu+ = 22, 23)] + Ar -> Ar+ + O2. The fact that the O2+(a4Piu5/2,3/2,1/2,-1/2: nu+ = 1) and O2+(X2Pig3/2,1/2: nu+ = 22) [O2+(a4Piu5/2,3/2,1/2,-1/2: nu+ = 2) and O2+(X2Pig3/2,1/2: nu+ = 23)] states are in close energy resonance, makes these reactions ideal model systems for investigating the energy resonance and Franck-Condon factor (FCF) effects on the charge transfer reactivity of O2+. The sigma(a4Piu5/2,3/2,1/2,-1/2: nu+ = 1, 2) values are found to be about ten-fold higher than the sigma(X2Pig3/2,1/2: nu+ = 22, 23) values at Ecm = 0.05-10.00 eV, indicating that the FCFs play a predominant role in promoting these charge transfer reactions. The present ion molecule reaction study also shows that sigma(a4Piu) depends strongly on the spin orbit as well as the vibrational states with the order: sigma(a4Piu: v+ = 2) > sigma(a4Piu: v+ = 1), and sigma(a4Piu5/2: v+) > sigma(a4Piu3/2: v+) > sigma(a4Piu1/2: v+) > sigma(a4Piu-1/2: v+), where v+ = 1 and 2. The high sigma(a4Piu5/2,3/2,1/2,-1/2: v+ = 1, 2) values, along with their decreasing trend with increasing Ecm, are consistent with those expected for a long range charge transfer mechanism. However, the low sigma(X2Pig3/2,1/2: nu+ = 22, 23) values and the lack of Ecm-dependence observed in the Ecm range of 0.05-10.00 eV point to the involvement of short-range collision dynamics. PMID- 28920601 TI - Dynamics of coherence, localization and excitation transfer in disordered nanorings. AB - Self-assembled supramolecular aggregates are excellent candidates for the design of efficient excitation transport devices. Both artificially prepared and natural photosynthetic aggregates in plants and bacteria present an important degree of disorder that is supposed to hinder excitation transport. Besides, molecular excitations couple to nuclear motion affecting excitation transport in a variety of ways. We present an exhaustive study of exciton dynamics in disordered nanorings with long-range interactions under the influence of a phonon bath taking the LH2 system of purple bacteria as a model. Nuclear motion is explicitly taken into account by employing the Davydov ansatz description of the polaron and quantum dynamics are obtained using a time-dependent variational method. We reveal an optimal exciton-phonon coupling that suppresses disorder-induced localization and facilitate excitation de-trapping. This excitation transfer enhancement, mediated by environmental phonons, is attributed to energy relaxation toward extended, low-energy excitons provided by the precise LH2 geometry with anti-parallel dipoles and long-range interactions. An analysis of localization and spectral statistics is followed by dynamic measures of coherence and localization, transfer efficiency and superradiance. Linear absorption, 2D photon-echo spectra and diffusion measures of the exciton are examined to monitor the diffusive behavior as a function of the strengths of disorder and exciton phonon coupling. PMID- 28920602 TI - Correction: A novel nanozyme assay utilising the catalytic activity of silver nanoparticles and SERRS. AB - Correction for 'A novel nanozyme assay utilising the catalytic activity of silver nanoparticles and SERRS' by Sian Sloan-Dennison et al., Analyst, 2017, 142, 2484 2490. PMID- 28920603 TI - Controlling cation segregation in perovskite-based electrodes for high electro catalytic activity and durability. AB - Solid oxide cell (SOC) based energy conversion systems have the potential to become the cleanest and most efficient systems for reversible conversion between electricity and chemical fuels due to their high efficiency, low emission, and excellent fuel flexibility. Broad implementation of this technology is however hindered by the lack of high-performance electrode materials. While many perovskite-based materials have shown remarkable promise as electrodes for SOCs, cation enrichment or segregation near the surface or interfaces is often observed, which greatly impacts not only electrode kinetics but also their durability and operational lifespan. Since the chemical and structural variations associated with surface enrichment or segregation are typically confined to the nanoscale, advanced experimental and computational tools are required to probe the detailed composition, structure, and nanostructure of these near-surface regions in real time with high spatial and temporal resolutions. In this review article, an overview of the recent progress made in this area is presented, highlighting the thermodynamic driving forces, kinetics, and various configurations of surface enrichment and segregation in several widely studied perovskite-based material systems. A profound understanding of the correlation between the surface nanostructure and the electro-catalytic activity and stability of the electrodes is then emphasized, which is vital to achieving the rational design of more efficient SOC electrode materials with excellent durability. Furthermore, the methodology and mechanistic understanding of the surface processes are applicable to other materials systems in a wide range of applications, including thermo-chemical photo-assisted splitting of H2O/CO2 and metal-air batteries. PMID- 28920604 TI - A ratiometric fluorescent pH probe based on keto-enol tautomerization for imaging of living cells in extreme acidity. AB - 6-(Diethylamino)-2,3-dihydro-1H-xanthene-4-carbaldehyde (DDXC), a reported synthetic intermediate for near-infrared fluorescent dyes, was developed into a fluorescent pH probe for extreme acidity. The unique sensing mechanism of DDXC for pH is based on the reversible protonation of the carbonyl oxygen followed by keto-enol tautomerization. The probe displays a linear ratiometric fluorescence response (I512/I580) to H+ over the extremely acidic range of pH 2.0-4.0 with a pKa of 3.11, and features high fluorescence quantum yield (Phi = 0.60) and excellent selectivity. More importantly, the probe can be applied to ratiometric fluorescence imaging of pH changes in living cells, making it a potential molecular tool for pH-related cell biology study. PMID- 28920605 TI - Caution in interpreting FTIR/ATR spectral intensity values. AB - We discuss and demonstrate why FTIR/ATR spectra can only be calibrated in wavelength, not intensity, for comparison with other data sets at present. This is because the intensity calibration must remove the instrument response function. To address this problem, we suggest a possible approach. PMID- 28920606 TI - Microbial separation from a complex matrix by a hand-held microfluidic device. AB - Through a simple chemical activation of biomolecules present in the outer structures of microbial cells, microorganisms can be rapidly isolated on gold coated surfaces in a microfluidic device with over 99% capture efficiency. Bacterial and fungal cells can be selectively captured, concentrated and retrieved for further analysis. PMID- 28920607 TI - Tuning the electronic environment of zinc ions with a ligand for dendrite-free zinc deposition in an ionic liquid. AB - In this work, we report on the influence of an organic ligand on the electrodeposition of Zn from an ionic liquid (IL) electrolyte. Zinc oxide was first dissolved in a protic IL. By introducing a 2-methylimidazole (2-MIm) ligand, the electronic environment of zinc ions, Zn(ii) complexes and the structure of the IL are considerably altered, as verified by both X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy. Due to the electron donation effect of the ligand, the zinc ions become less positively charged and exhibit a lower binding energy by -0.5 eV, compared to its absence. The atomic force microscopy (AFM) results show that a higher push-through force is required to rupture the interfacial layers in the presence of the ligand compared to its absence. The ligand can interact with both the cation and the anion of the IL via hydrogen bonds, forming compact layers on the surface, which also has a strong influence on the electrochemical performance. The cyclic voltammograms show reduction peaks at -1.4 V in all cases, but the current density decreases as the concentration of 2-MIm increases. Dendritic zinc deposits were obtained in 1.5 mol L-1 ZnO/[EIm]TfO, while dendrite-free zinc structures were obtained in the presence of 1.5 mol L-1 2-MIm. PMID- 28920609 TI - High performance capacitive deionization electrodes based on ultrathin nitrogen doped carbon/graphene nano-sandwiches. AB - Here, ultrathin nitrogen-doped carbon/graphene nano-sandwiches were synthesized by carbonization of graphene oxide-based nanosheets, which were fully covered with ultrasmall ZIF-8 nanocrystals. The novel sandwich structure possesses large accessible surface area, excellent electrical conductivity, and high nitrogen content, thus showing superior desalination performance. PMID- 28920610 TI - Correction: Multiplex in vitro detection using SERS. AB - Correction for 'Multiplex in vitro detection using SERS' by Stacey Laing et al., Chem. Soc. Rev., 2016, 45, 1901-1918. PMID- 28920611 TI - An efficient algorithm for extracting the magnitude of the measurement error for fractional dynamics. AB - Modern live-imaging fluorescent microscopy techniques following the stochastic motion of labeled tracer particles, i.e. single particle tracking (SPT) experiments, have uncovered significant deviations from the laws of Brownian motion in a variety of biological systems. Accurately characterizing the anomalous diffusion for SPT experiments has become a central issue in biophysics. However, measurement errors raise difficulty in the analysis of single trajectories. In this paper, we introduce a novel surface calibration method based on a fractionally integrated moving average (FIMA) process as an effective tool for extracting both the magnitude of the measurement error and the anomalous exponent for autocorrelated processes of various origins. This method is developed using a toy model - fractional Brownian motion disturbed by independent Gaussian white noise - and is illustrated on both simulated and experimental biological data. We also compare this new method with the mean-squared displacement (MSD) technique, extended to capture the measurement noise in the toy model, which shows inferior results. The introduced procedure is expected to allow for more accurate analysis of fractional anomalous diffusion trajectories with measurement errors across different experimental fields and without the need for any calibration measurements. PMID- 28920612 TI - Visible-light-mediated oxidative demethylation of N6-methyl adenines. AB - We report a simple protocol that affords oxidative demethylation of N6-methyl groups in N6-methyl adenines (m6A). The biologically compatible photocatalyst riboflavin prompts a highly selective C-H abstraction from N6-methyl in adenines under the irradiation of a visible blue LED light, affording a novel and highly selective biomimetic demethylation of m6A and related N-methyl adenine analogues. PMID- 28920613 TI - Sulfonato-imino copper(ii) complexes: fast and general Chan-Evans-Lam coupling of amines and anilines. AB - Sulfonato-imine copper complexes with either chloride or triflate counteranions were prepared in a one-step reaction followed by anion-exchange. They are highly active in Chan-Evans-Lam couplings under mild conditions with a variety of amines or anilines, in particular with sterically hindered substrates. No optimization of reaction conditions other than time and/or temperature is required. PMID- 28920614 TI - Molecular weight prediction in polystyrene blends. Unprecedented use of a genetic algorithm in pulse field gradient spin echo (PGSE) NMR. AB - A genetic algorithm that uses boxcar functions (diffGA) has been applied for the first time in PGSE NMR. It reconstructs accurate diffusion coefficients for all the components of the mixture, and therefore predicts correct weight-average molecular weights for all of them. The results reported herein complement those obtained with established methods such as ITAMeD, CONTIN and TRAIn algorithms, and provide a detailed solution picture. Its robustness and limits have been stretched in order to ascertain the minimum separation within diffusion coefficients or relative proportion between components. In addition, the new genetic algorithm has been also applied to a mixture of small molecules, providing excellent results at very low computational times. PMID- 28920615 TI - The phenolic profiles of Radix Tetrastigma after solid phase extraction (SPE) and their antitumor effects and antioxidant activities in H22 tumor-bearing mice. AB - Radix Tetrastigma (RT), a herbal medicine and functional food in China, showed strong antiproliferative activities in vitro. However, the effects and the underlying mechanism of phenolic-rich extract of RT in H22 tumor-bearing mice are still unknown. Thus, the phenolic profiles and antitumor/antioxidant activities of a solid phase extraction (SPE) semi-purified extract of RT were investigated by a combination of chemical assays, LC-QTOF-MS/LC-QqQ-MS techniques and a tumor bearing mice model. As a result, the total phenolic/flavonoid contents (TPC/TFC) and 24 individual phenolics were identified and quantified, which showed higher contents than that of crude extract. Results also indicated that RT extract could inhibit tumor growth and induce apoptosis by regulating the expression of Bcl-2 family proteins and activating the caspase family proteins as well as suppressing tumor angiogenesis by inhibiting vascular endothelial growth factor (VEGF) expression. Besides, the interleukin-2 (IL-2) levels, tumor necrosis factor-alpha (TNF-alpha) production, CD4+/CD8+ ratio, and NK cell levels were increased by RT administration, while RT significantly increased superoxide dismutase (SOD)/glutathione peroxidase (GSH-Px) activities and decreased malondialdehyde (MDA) content. Summarily, the findings clearly demonstrated that RT extract could inhibit tumor growth by inducing apoptosis and inhibiting angiogenesis as well as preventing cancer by improving the immune functions and antioxidant activities. PMID- 28920616 TI - Vitamin C protects piglet liver against zearalenone-induced oxidative stress by modulating expression of nuclear receptors PXR and CAR and their target genes. AB - Zearalenone (ZEN), one of the most common mycotoxins found in human food and animal feed, has been shown to be effectively detoxified by vitamin C (Vc). The aim of this study was to investigate how vitamin C protects the piglet liver against oxidative stress induced by ZEN. A total of thirty-two healthy female crossbred weaning piglets (Duroc * Landrace * Large white) with an initial weight of 12.27 +/- 0.30 kg were randomly divided into four treatment groups of eight piglets per group. The dietary treatments included two zearalenone levels (0 mg kg-1 and 1.0 mg kg-1) and two vitamin C levels (2 mg kg-1 and 150 mg kg-1) in a 2 * 2 factorial arrangement, and the trial period was twenty-eight days. The results showed that dietary zearalenone could significantly increase the liver coefficient (P < 0.05) and ZEN residues in the liver of weaning piglets (P < 0.05), and hepatocyte swelling and granular degeneration were obvious. Additionally, dietary zearalenone significantly increased the level of MDA (P < 0.05) and decreased the level of SOD, T-AOC and GSHPx in the liver of piglets (P < 0.05). However, the addition of 150 mg kg-1 vitamin C to dietary zearalenone decreased the effects of zearalenone on the liver coefficient, ZEN residues and oxidative stress, which decreased the level of MDA and increased the levels of SOD, T-AOC and GSHPx in the liver of piglets. Overall, there was a significant increase in the mRNA levels of nuclear receptor genes (PXR, CAR), phase I metabolic enzyme genes (CYP1A1, CYP1A2, CYP1A6) and phase II metabolic enzyme genes (UGT1A1, UGT1A3, UGT1A6). In conclusion, vitamin C can alleviate damage to the liver of weaning piglets by modulating the nuclear receptor signaling pathway. PMID- 28920617 TI - Thermal conductivity of a perovskite-type metal-organic framework crystal. AB - We report for the first time the investigation of thermal conductivity for a perovskite-type MOF crystal. In situ single crystal X-ray diffraction technology was employed to track the phase transition of a newly synthesized perovskite MOF. The perovskite MOF crystal exhibits a low thermal conductivity of 1.3 W (K m)-1 in comparison to most of the bulk crystal materials at room temperature. PMID- 28920619 TI - A novel method for identifying potential disease-related miRNAs via a disease miRNA-target heterogeneous network. AB - MicroRNAs (miRNAs), as a kind of important small endogenous single-stranded non coding RNA, play critical roles in a large number of human diseases. However, the currently known experimental verifications of the disease-miRNA associations are still rare and experimental identification is time-consuming and labor-intensive. Accordingly, identifying potential disease-related miRNAs to help people understand the pathogenesis of complex diseases has become a hot topic. In this study, we take advantage of known disease-miRNA associations combined with a large number of experimentally validated miRNA-target associations, and further develop a novel disease-miRNA-target heterogeneous network for identifying disease-related miRNAs. The leave-one-out cross validation experiment and several statistical measures demonstrate that our method can effectively identify potential disease-related miRNAs. Furthermore, the good predictive performance of 15 common diseases and the manually confirmed analyses of the top 30 candidates of hepatocellular carcinoma, ovarian neoplasms and breast neoplasms further provide convincing evidence of the practical ability of our method. The source code implemented by our method is freely available at: . PMID- 28920620 TI - Observation of chemically protected polydimethylsiloxane: towards crack-free PDMS. AB - The current modification of polydimethylsiloxane (PDMS) substrates via oxygen plasma treatment causes surface cracks. Here, we demonstrate a method to prevent crack formation by chemical treatment. Chemical modification renders the surface hydrophilic for several days and is effective in preserving the elasticity of the PDMS surface at the nanoscale level. PMID- 28920625 TI - Simultaneous modulation of surface composition, oxygen vacancies and assembly in hierarchical Co3O4 mesoporous nanostructures for lithium storage and electrocatalytic oxygen evolution. AB - We developed a facile solution reductive method to simultaneously tune the surface composition, oxygen vacancies and three dimensional assembly in Co3O4 hierarchical nanostructures. The controllable surface composition, oxygen vacancies together with hierarchical micro/nanoarchitectures resulted in superior electrochemical properties when used as the anode materials for lithium-ion batteries and as an electrocatalyst for the oxygen evolution reaction. The excellent electrochemical performance is attributed to the synergistic effects of novel hierarchical morphology, crystal structure of the active materials, the improvement of intrinsic conductivity and inner surface area induced by the oxygen vacancies. The present strategy not only provides a facile method to assemble novel hierarchical architectures, but also paves a way to control surface structures (chemical composition and crystal defects) in other transition metal compounds, and thus will hold great promise in the fields of energy storage and conversion. PMID- 28920624 TI - Directed nucleophilic addition of phenoxides to cyclopropenes. AB - The alkali metal-templated addition of aryloxides across the double bond of non conjugated cyclopropenes is described. High cis-selectivity is achieved through a directing effect of a strategically positioned carboxamide functionality. PMID- 28920626 TI - Mononuclear salen-gallium complexes for iso-selective ring-opening polymerization (ROP) of rac-lactide. AB - A series of mononuclear salen-supported gallium amido/alkoxide derivatives were prepared and structurally characterized and subsequently used as initiators in rac-lactide ring-opening polymerisation (ROP). The reaction of variously substituted salen ligands (1a-1f) with 0.5 equiv. of Ga2(NMe2)6 allowed the isolation of the corresponding (salen)Ga-NMe2 chelates (2b-2d, 2f) via an amine elimination route, as poorly soluble compounds in common solvents. The (salen)Ga OBn derivatives (3a-3e) may be readily accessed by an amine elimination/alcoholysis sequence and the molecular structures of 3a, 3d and 3e were confirmed through X-ray crystallography diffraction analysis. The present (salen)Ga-X species may effectively mediate the iso-selective ROP of rac-LA in a controlled manner (Pm up to 0.77 using a 1/1 2f/BnOH mixture as ROP initiator), with a ROP activity greatly dependent upon steric hindrance and geometrical constraints imposed by the variously substituted salen ligands. Based on the present study, salen ligands with limited steric hindrance and a certain degree of flexibility appear best suited for iso-selective ROP by (salen)Ga chelates. The salen-gallium complex 3a is also effective for the controlled ROP of epsilon caprolactone (CL) and the production of PCL-b-PLA copolymers. PMID- 28920627 TI - Site preferences in hetero-metallic [Fe9-xNix] clusters: a combined crystallographic, spectroscopic and theoretical analysis. AB - The reaction of mixtures of Fe(O2CMe)2.2H2O and Ni(O2CMe)2.4H2O of various compositions with di-2-pyridyl ketone (py2CO, dpk) in MeCN under an inert atmosphere afforded a family of hetero-metallic enneanuclear clusters with general formula [Fe9-xNix(MU4-OH)2(O2CMe)8(py2CO2)4] (2, x = 1.00; 3: x = 6.02; 4, x = 7.46; 5, x = 7.81). Clusters 2-5 are isomorphous to the homo-metallic [Fe9] cluster (1) previously reported by some of us, and also isostructural to the known homo-metallic [Ni9] cluster. All four clusters contain a central MII ion in an unusual 8-coordinate site and eight peripheral MII ions in distorted octahedral environments. The distribution of FeII and NiII ions over these two distinct coordination sites in 2-5 can be established through a combination of X ray fluorescence and Mossbauer spectroscopies, which show that FeII preferentially occupies the unique 8-coordinate metal site while NiII accumulates in the octahedral holes. Density functional theory indicates that the distribution of ions across the two sites arises not from any intrinsic preference of the FeII ions for the 8-coordinate sites, but rather because of the large ligand field stabilization energy available to NiII in octahedral coordination. PMID- 28920629 TI - In situ construction of a heterojunction over the surface of a sandwich structure semiconductor for highly efficient photocatalytic H2 evolution under visible light irradiation. AB - Developing a heterostructure on the surface of a "sandwich" structure semiconductor is essential for full utilization of its heterojunction function and hence for designing efficient solar energy conversion systems. Here, we show that 2D-2D MoS2/MnSb2S4 heterostructure composites are designed for the first time and successfully synthesized by a simple in situ calcination pathway. Under visible light irradiation, the ca. 3.3 wt% MoS2/MnSb2S4 samples exhibited the highest activity for H2 evolution, which was 7.7 times higher than that of the pristine MnSb2S4 monolayer. The outstanding photocatalytic performance was attributed to the MoS2 nanosheets intimately growing on the surface [SbS]+ layers of monolayer MnSb2S4 nanosheets with the [SbS]+-[MnS2]2--[SbS]+ sandwich substructure to form the 2D-2D MoS2/MnSb2S4 heterojunction structure. More importantly, we prove that this specific heterojunction structure can lead to more weakening of the constraint of the valence electrons in the composited photocatalysts, which can promote the transfer of photogenerated electrons from MnSb2S4 to MoS2. The present study provides a new design strategy for the construction of a heterostructure to improve the photocatalytic H2 production activity highly efficiently. PMID- 28920628 TI - Fluoroquinolones as imaging agents for bacterial infection. AB - Diagnosis of deep-seated bacterial infection is difficult, as neither standard anatomical imaging nor radiolabeled, autologous leukocytes distinguish sterile inflammation from infection. Two recent imaging efforts are receiving attention: (1) radioactive derivatives of sorbitol show good specificity with Gram-negative bacterial infections, and (2) success in combining anatomical and functional imaging for cancer diagnosis has rekindled interest in 99mTc-fluoroquinolone based imaging. With the latter, computed tomography (CT) would be combined with single-photon-emission-computed tomography (SPECT) to detect 99mTc fluoroquinolone-bacterial interactions. The present minireview provides a framework for advancing fluoroquinolone-based imaging by identifying gaps in our understanding of the process. One issue is the reliance of 99mTc labeling on the reduction of sodium pertechnetate, which can lead to colloid formation and loss of specificity. Specificity problems may be reduced by altering the quinolone structure (for example, switching from ciprofloxacin to sitafloxacin). Another issue is the uncharacterized nature of 99mTc-ciprofloxacin binding to, or sequestration in, bacteria: specific interactions with DNA gyrase, an intracellular fluoroquinolone target, are unlikely. Labeling with 68Ga rather than 99mTc enables detection by positron emission tomography, but with similar biological uncertainties. Replacing the C6-F of the fluoroquinolone with 18F provides an alternative to pertechnetate and gallium that may lead to imaging based on drug interactions with gyrase. Gyrase-based imaging requires knowledge of fluoroquinolone action, which we update. We conclude that quinolone-based probes show promise for the diagnosis of infection, but improvements in specificity and sensitivity are needed. These improvements include the optimization of the quinolone structure; such chemistry efforts can be accelerated by refining microbiological assays. PMID- 28920630 TI - Experimental and ab initio studies of Cd5(BO3)3Cl: the first cadmium borate chlorine NLO material with isolated BO3 groups. AB - A nonlinear optical crystal cadmium borate chlorine (Cd5(BO3)3Cl) has been successfully grown through a spontaneous crystallization method. Cd5(BO3)3Cl crystallizes in the noncentrosymmetric space group Cm with isolated BO3 and distorted CdOnClm (n = 4, 5, 7; m = 0, 1, 2) polyhedra. Powder second harmonic generation (SHG) measurements on polycrystalline Cd5(BO3)3Cl indicated that the title compound is phase-matchable in the visible region and exhibits a large SHG response of about 5 * KH2PO4 (KDP). Further optical characterization suggested that the compound has a wide transparent region ranging from UV to near IR with a UV cutoff edge at about 295 nm. In addition, first-principles electronic structure calculations revealed that the macroscopic SHG coefficients of Cd5(BO3)3Cl originate from the cooperative effects of the BO3 groups with asymmetric pi-delocalization, the d10 cation Cd2+ with the polar displacement and the Cl- anions. PMID- 28920631 TI - Pneumocystis jirovecii genotyping: experience in a tertiary-care hospital in Northern Italy. AB - Respiratory samples from Pneumocystis jirovecii pneumonia (PJP) cases collected at a tertiary-care university hospital in Modena were analyzed for the presence of specific polymorphisms in the mitochondrial large subunit ribosomal RNA (mtLSU rRNA). Retrospectively, 57 cases were selected in a six-year period and 34 out of the 57 processed BAL samples returned PCR positive results, thus allowing further molecular analysis. The following P.jirovecii genotype distribution was observed: genotype 3 (50%), genotype 2 (23%), genotype 1 (18%), genotypes 1 or 4 (9%). These data add novel insights on P.jirovecii epidemiology, investigating a previously unstudied area of Northern Italy. A peculiar local distribution is highlighted with respect to other areas within the national panorama, thus encouraging further in-depth studies in an attempt to better understand the overall situation concerning P.jirovecii genotype circulation. PMID- 28920632 TI - Acute cardiotoxicity induced by doxorubicin in right ventricle is associated with increase of oxidative stress and apoptosis in rats. AB - Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but its efficiency is seriously limited by the risk of developing cardiomyopathy. The most recognized cardiotoxic effect is left ventricular (LF) dysfunction, but MRI and echocardiography data demonstrated significant right ventricle (RV) function impairment. In order to clarify this aspect, the present study investigated the potential of DOX to induce acute RV cardiotoxicity at the same time as LV impairment. Rats were intraperitoneally (i.p.) injected with a single dose of 15 mg/kg DOX. DOX-treated rats were characterized by decreased body and heart weights, elevated levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) activities compared to controls. Biochemical analyses on RV tissue revealed that the level of malondialdehyde (MDA) was significant increased (p<0.05) and activities of catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPX) antioxidant enzymes were decreased by 13%, 27% and 18%, respectively, compared to control. Histopathogical and electron microscopic studies revealed DOX-induced damage in both ventricles and an increase of interstitial collagen fibers compared to controls (p<0.001), whereas immunohistochemical analysis showed weak and irregular desmin expression. Furthermore, mitochondrion-induced apoptotic pathways were also activated in both ventricles, as reflected by the up regulation of Bax/Bcl-2 mRNA expression ratio (p<0.001) and increase of Bax and caspase-3 protein expression, as well as by the significant elevation of TUNEL positive nuclei, compared to controls (p<0.001). The results showed that DOX exerted RV toxic effects at the same time as those reported in the LV, which might be mediated through the mitochondrial-dependent apoptosis. PMID- 28920633 TI - Noninvasive ventilation in difficult endotracheal intubation: systematic and review analysis. AB - Noninvasive ventilation has been widely used in the management of acute respiratory failure in appropriate clinical settings. In addition to known benefit of alleviating the need for invasive mechanical ventilation, recent literature suggested its beneficial use in the process of endotracheal intubation. Search of the PubMed database and manual review of selected articles investigating the methods and outcomes of endotracheal intubation in difficult airway due to hypoxemic respiratory failure and the role of noninvasive ventilation in this process. Large randomized controlled studies focused on alternative approaches to endotracheal intubation in severe hypoxemic respiratory failure are largely missing but there are several retrospective cohort analysis and reports describing the novel technique describing the application of noninvasive ventilation during endotracheal intubation. Noninvasive ventilation can be used as an adjunct intervention that may maintain oxygenation and ventilation, prevent significant hemodynamic instability and provide a pneumatic stent to maintain upper airway patency, thus reducing the risks of intubation related complications. PMID- 28920634 TI - Outcomes analysis of stent-graft repair for thoracic aorta emergencies. AB - BACKGROUND: This study aimed to identify patient, pathology and procedure-related factors affecting perioperative and mid-term mortality of thoracic aorta emergencies. METHODS: Between 2007 and 2014, patients treated emergently with thoracic stent-graft were retrospectively reviewed. Variables analyzed were: age, renal insufficiency, shock, cardiac arrest, transfer status, pathology, debranching procedures, operation duration, vascular access and European System for Cardiac Operative Risk Evaluation (EuroSCORE). Seventy-four patients (54.5+/ 22 years) were treated for traumatic rupture (N.=31), aneurysm (TAA) (N.=16), acute aortic syndrome (N.=18), aorto-esophageal fistula (N.=2), floating thrombus (N.=7). Thirty-four patients (46%) were in shock, including 3 suffering preoperative cardiac arrest. Proximal landing zones were: zone 0 (N.=4), zone 1 (N.=4), zone 2 (N.=37), zone 3 (N.=21) and zone 4 (N.=8). Debranching procedures were performed in 16 cases (22%). RESULTS: Perioperative all-cause- mortality was 18.9% (N.=14). Univariable analysis identified age, renal insufficiency, shock, transfer status, cardiac arrest, debranching procedures in zones 0 or 4 and EuroSCORE as predictors of death (P=0.002, P=0.001, P=0.002, P=0.05, P=0.006, P=0.028, P<0.001 respectively). Multivariable analysis pinpointed shock and renal insufficiency as independent risk factors. Over a mean 41 months follow-up, survival was 72% at both 1 and 3 years and was impacted by pathology and debranching procedures. Aortic re-intervention rate was 12% (N.=9), significantly higher in TAA group (P=0.004). CONCLUSIONS: Hemorrhagic shock remains highly lethal for endovascular repair. Hybrid procedures in zones 0 or 4 should be avoided to improve short and mid-term outcomes. TAA groups require close surveillance to detect late events. PMID- 28920635 TI - Recent developments in juxtarenal and aorto-iliac interventions. PMID- 28920637 TI - Bypassing a bypass: transcatheter aortic valve replacement and percutaneous closure of a regurgitant apical-aortic conduit. PMID- 28920636 TI - Politetrafluorene suture used as artificial mitral chord: mechanical properties and surgical implications. AB - BACKGROUND: Novel surgical approach to repair degenerative mitral regurgitation such as transapical chordae tendineae replacement and "loop in loop" in loop techniques, need of artificial chordae longer than that used in the older techniques of chordae tendineae replacement. This difference in length has been reported as potential critical point for durability of artificial chordae. In the present paper we have investigated the elastic behavior of different diameter and length politetrafluorene (PTFE) suture threads as substitute of native chordae, to identify their reliability to use as long artificial chordae. METHODS: PTFE suture threads with different diameters were investigated in their mechanical properties at different length from 2 to 14 cm, by a servo hydraulic testing machine, to test the elastic properties of the sample in their use as mitral chordae substitutes. RESULTS: Our study shows that the chordae length is an important parameter that can change the performance of chordae itself. The analysis of elastic/properties of suture threads specimen, reveals that long PTFE chords have an optimal mechanical behavior in which elongation is accompanied by a safe elastic properties that make them well resistance during multiple tractions. CONCLUSIONS: In conclusion the use of PTFE as an artificial chordae may represent a valid choice in case of insertion of artificial chordae with extra anatomic length. PMID- 28920638 TI - Aortic valve neo-cuspidizations for aortic stenosis with small aortic annulus. PMID- 28920639 TI - Protection of Human Subjects. AB - On January 19, 2017, the Federal departments and agencies that are subject to the Federal Policy for the Protection of Human Subjects (referred to as the Common Rule) published a final rule amending the Common Rule. The Consumer Product Safety Commission (CPSC or Commission) adopts the Common Rule. PMID- 28920640 TI - Looking forward - April 2017. PMID- 28920641 TI - Using global surgical indicators to improve trauma care in Latin America. PMID- 28920642 TI - UM Ryder Trauma Center/ Israel fellowship program provides a model for global trauma training. PMID- 28920643 TI - QPP in 2017: Navigating the transition year. PMID- 28920644 TI - The future of trauma care on Capitol Hill: Implementing military-civilian trauma care and establishing a national trauma system. PMID- 28920645 TI - 2016 ACS International Governors Survey: Membership benefits and challenges for International Fellows are revealed in first-time study. PMID- 28920646 TI - Statement on the use of general anesthetics and sedation drugs in children and pregnant women. PMID- 28920647 TI - Reporting global codes data in 2017. PMID- 28920648 TI - Hernia repair and complex abdominal wall reconstruction. PMID- 28920649 TI - Diamonds in the rough-a case for rural surgery rotations. PMID- 28920650 TI - Junior investigators: Get engaged in the Alliance for Clinical Trials in Oncology. AB - The success of the Alliance and the cooperative groups in the National Cancer Institute's National Clinical Trials Network is dependent on the cooperative group's ability to help recruit and train the next generation of clinical researchers. PMID- 28920651 TI - ACS Case Reviews in Surgery and AHRQ Safety Program for ERAS: New ACS programs enhance quality patient care. PMID- 28920652 TI - New resources for surgeons to obtain true informed consent. PMID- 28920653 TI - Make no bones about it. PMID- 28920654 TI - In memoriam: Denton A. Cooley, MD, FACS, a fierce competitor. PMID- 28920655 TI - Looking forward - March 2017. PMID- 28920656 TI - Evolving insights for preventing surgeon errors: Balancing professionalism and cognition with knowledge and skill. PMID- 28920657 TI - Patient-reported outcomes in surgery: Listening to patients improves quality of care. PMID- 28920658 TI - Value-based health care: How to succeed in a bundled care APM. PMID- 28920659 TI - Coding for nipple-sparing and skin-sparing mastectomies. PMID- 28920660 TI - Practice changes for reducing UTIs in colon and rectal surgery patients. PMID- 28920661 TI - In search of the philosopher's stone: The ALCHEMIST study for lung cancer. PMID- 28920663 TI - Honoring mentors: An ACS tradition. PMID- 28920662 TI - Celebrating the sesquicentennial of Lord Joseph Lister. PMID- 28920664 TI - The Joint Commission clarifies stance on secure text messaging of patient care orders. PMID- 28920665 TI - Kinetic and Thermodynamic Control of Structure Transformations in a Family of Cobalt(II)-Organic Frameworks. AB - Dynamic metal-organic frameworks (MOFs) that respond to external stimuli have recently attracted great attention. However, the subtle control of dynamic processes as well as the illustration of the underlying mechanism, which is crucial for the targeted construction and modulation purpose, is extremely challenging. Herein, we report the achievement of simultaneous kinetic and thermodynamic modulation of the structure transformation processes of a family of cobalt(II)-organic frameworks, through the rational combination of coligand replacement, solvent molecule substitution, and ligand-based solid solution strategies. On the basis of the systematic investigation of the structural transformation behaviors, the underlying response mechanism and principles for modulation were illustrated. It is expected that this work can provide valuable hints for the study and further development of dynamic materials. PMID- 28920666 TI - Softoxometalate [{K6.5Cu(OH)8.5(H2O)7.5}0.5@{K3PW12O40}]n (n = 1348-2024) as an Efficient Inorganic Material for CO2 Reduction with Concomitant Water Oxidation. AB - An immediate challenge for chemists is to devise different methods to trap chemical energy using light by reduction of carbon dioxide to a transportable fuel. To reach this goal the major obstacle lies in finding a suitable material that is abundant and possesses catalytic power to effect such reduction reaction and perform this reduction reaction without using any external photosensitizer. Here we report for the first time a softoxometalate based on a {[K6.5Cu(OH)8.5(H2O)7.5]0.5[K3PW12O40]} metal oxide framework which is stable in reaction conditions that effectively performs photochemical CO2 reduction reaction in water with a very high turnover number of 613 and TOF of 47.15 h-1. We observe that during this reaction water gets oxidized to oxygen, while the electrons released directly go to CO2 reducing it to formic acid. A detailed account of the characterization of the catalyst along with that of products of this reaction is reported. PMID- 28920667 TI - Warm-White-Light-Emitting Diode Based on a Dye-Loaded Metal-Organic Framework for Fast White-Light Communication. AB - A dye@metal-organic framework (MOF) hybrid was used as a fluorophore in a white light-emitting diode (WLED) for fast visible-light communication (VLC). The white light was generated from a combination of blue emission of the 9,10-dibenzoate anthracene (DBA) linkers and yellow emission of the encapsulated Rhodamine B molecules. The MOF structure not only prevents dye molecules from aggregation induced quenching but also efficiently transfers energy to the dye for dual emission. This light-emitting material shows emission lifetimes of 1.8 and 5.3 ns for the blue and yellow components, respectively, which are significantly shorter than the 200 ns lifetime of Y3Al5O12:Ce3+ in commercial WLEDs. The MOF-WLED device exhibited a modulating frequency of 3.6 MHz for VLC, six times that of commercial WLEDs. PMID- 28920668 TI - Electrochemical and Diffusional Investigation of Na2FeIIPO4F Fluorophosphate Sodium Insertion Material Obtained from FeIII Precursor. AB - Sodium iron fluorophosphate (Na2FeIIPO4F) was synthesized by economic solvothermal combustion technique using FeIII precursors, developing one-step carbon-coated homogeneous product. Synchrotron diffraction and Mossbauer spectroscopy revealed the formation of single-phase product assuming an orthorhombic structure (s.g. Pbcn) with FeII species. This FeIII precursor derived Na2FeIIPO4F exhibited reversible Na+ (de)intercalation with discharge capacity of 100 mAh/g at a rate of C/10 involving flat FeIII/FeII redox plateaus located at 2.92 and 3.05 V (vs Na/Na+). It delivered good cycling stability and rate kinetics at room temperature. The stability of Na2FePO4F cathode was further verified by electrochemical impedance spectroscopy at different stages of galvanostatic analysis. Bond valence site energy (BVSE) calculations revealed the existence of 2-dimensional Na+ percolation pathways in the a-c plane with a moderate migration barrier of 0.6 eV. Combustion synthesized Na2FeIIPO4F forms an economically viable sodium battery material. Although the capacity of this cathode is relatively low, this study continues systematic work, which attempts to broaden the scope of reversible sodium insertion materials. PMID- 28920669 TI - In Situ Studies of Solid Electrolyte Interphase (SEI) Formation on Crystalline Carbon Surfaces by Neutron Reflectometry and Atomic Force Microscopy. AB - The solid electrolyte interphase (SEI) is a complex and fragile passivation layer with crucial importance for the functionality of lithium-ion batteries. Due to its fragility and reactivity, the use of in situ techniques is preferable for the determination of the SEI's true structure and morphology during its formation. In this study, we use in situ neutron reflectometry (NR) and in situ atomic force microscopy (AFM) to investigate the SEI formation on a carbon surface. It was found that a lithium-rich adsorption layer is already present at the open circuit voltage on the carbon sample surface and that the first decomposition products start to deposit close to this potential. During the negative potential sweep, the growth of the SEI can be observed in detail by AFM and NR. This allows precise monitoring of the morphology evolution and the resulting heterogeneities of individual SEI features. NR measurements show a maximum SEI thickness of 192 A at the lower cutoff potential (0.02 V vs Li/Li+), which slightly decreases during the positive potential scan. The scattering length density (SLD) obtained by NR provides additional information on the SEI's chemical nature and structural evolution. PMID- 28920670 TI - Fabrication of Hierarchical Porous Carbon Nanoflakes for High-Performance Supercapacitors. AB - In the current work, the carbon nanoflakes (CNs-Fe/KOH) and porous carbon (PC Ni/KOH) have been produced by using Fe(NO3)3/KOH and Ni(NO3)2/KOH as the cographitization/activation catalysts to treat the natural plane tree fluff, respectively. The as-prepared carbon materials show different morphologies when treated with different metal ions. Compared with PC-Ni/KOH, the CNs-Fe/KOH have both high graphitization degree (IG/ID = 1.53) and large SBET (1416 m2/g). In a three-electrode setup, the CNs-Fe/KOH electrode shows a high specific capacitance of 253 F/g at 10 A/g, with a capacitance retention of 92.64% after 10000 cycles in 2 M H2SO4 aqueous solution, which is far better than the sample without Fe3+ addition. In 1 M LiPF6 in ethylene carbonate/diethyl carbonate organic solution, CNs-Fe/KOH-based symmetric supercapacitor also presents an excellent specific capacitance of 32.2 F/g at 1 A/g. In addition, an energy density of 39.98 W h/kg can be achieved at the power density of 1.49 kW/kg. Influence of metal ions on the morphology and structure as well as electrochemical performance of the carbon materials are further analyzed in detail. The current work provides a novel path for design and fabrication of supercapacitor electrode materials with promising electrochemical performances. PMID- 28920671 TI - Development of a Multifunctional Nanobiointerface Based on Self-Assembled Fusion Protein rSbpA/ZZ for Blood Cell Enrichment and Phenotyping. AB - We present a multifunctional nanobiointerface for blood cell capture and phenotyping applications that features both excellent antifouling properties and high antibody activity. Multifunctionality is accomplished by modifying polymeric materials using self-assembled S-layer fusion-protein rSbpA/ZZ to immobilize high density antibodies at the two protein A binding sites of the rSbpA/ZZ nanolattice structure. Controlled orientation and alignment of the antibodies reduced antibody consumption 100-fold and increased cell capture efficiency 4-fold over standard methodologies. Cell analysis in complex samples was made possible by the remarkable antifouling properties of the rSbpA domain, while at the same time reducing unspecific binding and forgoing tedious blocking procedures. An automated microfluidic in situ cell analysis platform for isolation and phenotyping of primary peripheral blood mononuclear cells was developed as practical application. Results obtained using our automated microfluidic cell analysis platform showed that the multifunctional nanobiointerface can discriminate among T helper and cytotoxic T cells, and thymocytes. Additionally, on-chip cell capture under flow conditions using a high affinity CD 3 selective nanobiointerface preferentially isolated cells with strong surface marker expression. This means that our dynamic microfluidic cell purification method allows the enrichment of 773 CD 8 positive cytotoxic T cells out of a total blood cell population of 7728 PBMCs, which is an increase in cell enrichment of 8-fold with a purity of 85%. PMID- 28920672 TI - Assembling Hollow Cobalt Sulfide Nanocages Array on Graphene-like Manganese Dioxide Nanosheets for Superior Electrochemical Capacitors. AB - Metal-organic framework (MOF)-derived hollow cobalt sulfides have attracted extensive attention due to their porous shell that provides rich redox reactions for energy storage. However, their ultradispersed structure and the large size of MOF precursors result in relatively low conductivity, stability, and tap density. Therefore, the construction of an array of continuous hollow cages and tailoring of the inner cavity of MOF-derived materials is very effective for enhancing the electrochemical performance. Herein, we in situ assembled small Co-based zeolitic imidazolate framework (ZIF-67) on the both sides of negatively charged MnO2 nanosheets to fabricate a hierarchical sandwich-type composite with hollow cobalt sulfide nanocages/graphene-like MnO2. The graphene-like MnO2 nanosheets acted not only as a structure-directing agent to grow a ZIF-67 array but also as a promising electroactive material of electrochemical capacitors to provide capacitance. As an electrode material of supercapacitors, the as-prepared composites exhibit high specific capacitance (1635 F g-1 at 1 A g-1), great rate performance (reaching 1160 F g-1 at 10 A g-1), and excellent cycling stability (80% retention after 5000 cycles). The outstanding electrochemical properties of our designed materials can be attributed to the unique nanostructure that improved electrical conductivity, created more reactive active sites, and increased the diffusion pathway for electrolyte ions. PMID- 28920673 TI - Work Function Control of Germanium through Carborane-Carboxylic Acid Surface Passivation. AB - Self-assembled monolayers (SAMs) of carborane isomers with different dipole moments passivate germanium to modulate surface work function while maintaining chemical environment and surface energy. To identify head groups capable of monolayer formation on germanium surfaces, we studied thiol-, hydroxyl-, and carboxyl-terminated carboranes. These films were successfully formed with carboxylic acid head groups instead of the archetypal thiol, suggesting that the carborane cluster significantly affects headgroup reactivity. Film characterization included X-ray and ultraviolet photoelectron spectroscopies as well as contact angle goniometry. Using these carboranes, the germanium surface work function was tailored over 0.4 eV without significant changes to wetting properties. PMID- 28920674 TI - Boosting Catalytic Performance of Metal-Organic Framework by Increasing the Defects via a Facile and Green Approach. AB - The control of defects in crystalline materials has long been of significance since the defects are correlated with the performances of the materials. Yet such control remains a challenge for metal-organic frameworks (MOFs), which are usually well-crystallized under hydro-/solvothermal conditions. In this contribution, we demonstrate for the first time how to increase the defects of MOF via a facile and green approach as exemplified in the context of solvent-free synthesis of UiO-66(Zr). Such increase of defects leads to drastic enhancement of catalysis performance when compared to UiO-66(Zr) prepared from conventional hydro-/solvothermal synthesis. Our work therefore not only opens a new door for boosting the catalytic activities of MOFs but also contributes a new approach to control the defects in crystalline materials for various applications. PMID- 28920675 TI - Mitigation of N2O Emission from Aquaponics by Optimizing the Nitrogen Transformation Process: Aeration Management and Exogenous Carbon (PLA) Addition. AB - N2O production in aquaponics is an inevitable concern when aquaponics is developed as a future production system. In the present study, two attempts were applied to mitigate N2O emission from aquaponics, i.e., aeration in hydroponic bed (HA) and addition of polylactic acid (PLA) into fillers (PA). Results showed that N2O emission from HA and PA was decreased by 47.1-58.1% and 43.2-74.9% respectively compared with that in control. Denitrification was proved to be the main emission pathway in all treatments, representing 62.4%, 86.4%, and 75.8% of the total N2O emission in HA, PA, and control, respectively. However, production of plants in HA was severely impaired, which was only 3.04 +/- 0.39 kg/m2, while in PA and control, plants yields were 4.87 +/- 0.56 kg/m2 and 4.33 +/- 0.58 kg/m2. Combining the environmental and economic benefits, adding PLA in aquaponics may have a better future when developing and applying aquaponics systems. PMID- 28920676 TI - Changes in Amino Acid Profile in Roots of Glyphosate Resistant and Susceptible Soybean (Glycine max) Induced by Foliar Glyphosate Application. AB - Amino acid profiles are useful to analyze the responses to glyphosate in susceptible and resistant soybean lines. Comparisons of profiles for 10 amino acids (Asp, Asn, Glu, Gln, Ser, His, Gly, Thr, Tyr, Leu) by HPLC in soybean roots were performed in two near isogenic pairs (four varieties). Foliar application of glyphosate was made to soybean plants after 5 weeks of seeding. Roots of four varieties were collected at 0 and 72 h after glyphosate application (AGA) for amino acid analysis by HPLC. Univariate analysis showed a significant increase of several amino acids in susceptible as well as resistant soybean lines; however, amino acids from the major pathways of carbon (C) and nitrogen (N) metabolism, such as Asp, Asn, Glu and Gln, and Ser, increased significantly in susceptible varieties at 72 h AGA. Multivariate analysis using principal component analysis (2D PCA and 3D PCA) allowed different groups to be identified and discriminated based on the soybean genetic origin, showing the amino acid responses on susceptible and resistant varieties. Based on the results, it is possible to infer that the increase of Asn, Asp, Glu, Gln, and Ser in susceptible varieties would be related to the deregulation of C and N metabolism, as well as changes in the growth mechanisms regulated by Ser. PMID- 28920677 TI - Group 10 Metal Benzene-1,2-dithiolate Derivatives in the Synthesis of Coordination Polymers Containing Potassium Countercations. AB - The use of theoretical calculations has allowed us to predict the coordination behavior of dithiolene [M(SC6H4S)2]2- (M = Ni, Pd, Pt) entities, giving rise to the first organometallic polymers {[K2(MU-H2O)2][Ni(SC6H4S)2]}n and {[K2(MU H2O)2(thf)]2[K2(MU-H2O)2(thf)2][Pd3(SC6H4S)6]}n by one-pot reactions of the corresponding d10 metal salts, 1,2-benzenedithiolene, and KOH. The polymers are based on sigma,pi interactions between potassium atoms and [M(SC6H4S)2]2- (M = Ni, Pd) entities. In contrast, only sigma interactions are observed when the analogous platinum derivative is used instead, yielding the coordination polymer {[K2(MU-thf)2][Pt(SC6H4S)2]}n. PMID- 28920678 TI - Facing Challenges in Real-Life Application of Surface-Enhanced Raman Scattering: Design and Nanofabrication of Surface-Enhanced Raman Scattering Substrates for Rapid Field Test of Food Contaminants. AB - Surface-enhanced Raman scattering (SERS) is capable of detecting a single molecule with high specificity and has become a promising technique for rapid chemical analysis of agricultural products and foods. With a deeper understanding of the SERS effect and advances in nanofabrication technology, SERS is now on the edge of going out of the laboratory and becoming a sophisticated analytical tool to fulfill various real-world tasks. This review focuses on the challenges that SERS has met in this progress, such as how to obtain a reliable SERS signal, improve the sensitivity and specificity in a complex sample matrix, develop simple and user-friendly practical sensing approach, reduce the running cost, etc. This review highlights the new thoughts on design and nanofabrication of SERS-active substrates for solving these challenges and introduces the recent advances of SERS applications in this area. We hope that our discussion will encourage more researches to address these challenges and eventually help to bring SERS technology out of the laboratory. PMID- 28920679 TI - Regioselective Synthesis of 2,4,5-Trisubstituted Oxazoles and Ketene Aminals via Hydroamidation and Iodo-Imidation of Ynamides. AB - A novel and straightforward protocol is demonstrated for the synthesis of highly substituted oxazoles from readily accessible ynamides in the presence of ytterbium(III) trifluoromethanesulfonate [Yb(OTf)3], N-iodosuccinimide (NIS), and acetonitrile. Multiple oxazole skeletons in the aryl periphery are constructed in a single operation for the first time. The hydroamidation and iodo-imidation of ynamides to trisubstituted and tetrasubstituted ketene aminals is exemplified. An isotope labeling experiment is used to identify the oxygen source in this transformation. The reactions are scalable to the gram scale, testifying the robustness of the transformations. PMID- 28920680 TI - A Restricted Open Configuration Interaction with Singles Method To Calculate Valence-to-Core Resonant X-ray Emission Spectra: A Case Study. AB - In this work, a new protocol for the calculation of valence-to-core resonant X ray emission (VtC RXES) spectra is introduced. The approach is based on the previously developed restricted open configuration interaction with singles (ROCIS) method and its parametrized version, based on a ground-state Kohn-Sham determinant (DFT/ROCIS) method. The ROCIS approach has the following features: (1) In the first step approximation, many-particle eigenstates are calculated in which the total spin is retained as a good quantum number. (2) The ground state with total spin S and excited states with spin S' = S, S +/- 1, are obtained. (3) These states have a qualitatively correct multiplet structure. (4) Quasi degenerate perturbation theory is used to treat the spin-orbit coupling operator variationally at the many-particle level. (5) Transition moments are obtained between the relativistic many-particle states. The method has shown great potential in the field of X-ray spectroscopy, in particular in the field of transition-metal L-edge, which cannot be described correctly with particle-hole theories. In this work, the method is extended to the calculation of resonant VtC RXES [alternatively referred to as 1s-VtC resonant inelastic X-ray scattering (RIXS)] spectra. The complete Kramers-Dirac-Heisenerg equation is taken into account. Thus, state interference effects are treated naturally within this protocol. As a first application of this protocol, a computational study on the previously reported VtC RXES plane on a molecular managanese(V) complex is performed. Starting from conventional X-ray absorption spectra (XAS), we present a systematic study that involves calculations and electronic structure analysis of both the XAS and non-resonant and resonant VtC XES spectra. The very good agreement between theory and experiment, observed in all cases, allows us to unravel the complicated intensity mechanism of these spectroscopic techniques as a synergic function of state polarization and interference effects. In general, intense features in the RIXS spectra originate from absorption and emission processes that involve nonorthogonal transition moments. We also present a graphical method to determine the sign of the interference contributions. PMID- 28920681 TI - Access to Cyano-Containing Isoxazolines via Copper-Catalyzed Domino Cyclization/Cyanation of Alkenyl Oximes. AB - A highly efficient copper-catalyzed cyclization/cyanation cascade of unactivated olefins bearing oximes is described. A variety of cyano-containing isoxazolines have been obtained in high yields with cheap Cu(NO3)2.3H2O as the catalyst and TMSCN as the non-metallic cyanide source. The present method provides a mild, simple, and practical access to cyano-substituted isoxazolines and is amenable to gram scale. The simultaneous construction of C(sp3)-CN and C-O bonds can be achieved in one step. PMID- 28920682 TI - Carboxylate-Assisted Formation of Aryl-Co(III) Masked-Carbenes in Cobalt Catalyzed C-H Functionalization with Diazo Esters. AB - Herein we describe the synthesis of a family of aryl-Co(III)-carboxylate complexes and their reactivity with ethyl diazoacetate. Crystallographic, full spectroscopic characterization, and theoretical evidence of unique C-metalated aryl-Co(III) enolate intermediates is provided, unraveling a carboxylate-assisted formation of aryl-Co(III) masked-carbenes. Moreover, additional evidence for an unprecedented Co(III)-mediated intramolecular SN2-type C-C bond formation in which the carboxylate moiety acts as a relay is disclosed. This novel strategy is key to tame the hot reactivity of a metastable Co(III)-carbene and elicit C-C coupling products in a productive manner. PMID- 28920683 TI - Fate of Flumioxazin in Aquatic Plants: Two Algae (Pseudokirchneriella subcapitata, Synechococcus sp.), Duckweed (Lemna sp.), and Water Milfoil (Myriophyllum elatinoides). AB - Flumioxazin separately 14C-labeled at 1,2-positions of the tetrahydrophthalimide moiety or uniformly labeled at the phenyl ring was exposed to two algae and duckweed via the water layer and water milfoil via the water layer or bottom sediment for 14 days to investigate uptake and metabolic profiles in these aquatic plants. While 14C-flumioxazin received immediate hydrolysis through maleimide ring opening and amide bond cleavage with its hydrolytic half-life of <1 day in both water and sediment, the 14C-plant uptake was <=4.7% of the applied radioactivity (%AR) with water exposure for all plants and 0.9%AR with sediment exposure for water milfoil. No 14C-translocation between shoot/leaves and roots occurred in water milfoil. The components of 14C residues in plants were common among the species, which were the above hydrolysates and their transformation products, that is, dicarboxylic acid derivative metabolized via hydroxylation at the double bond of the cyclohexene ring followed by sugar conjugation with its counterpart amine derivative via acid conjugations. PMID- 28920685 TI - Evaluation of the Intramolecular Charge-Transfer Properties in Solvatochromic and Electrochromic Zinc Octa(carbazolyl)phthalocyanines. AB - 2,3,9,10,16,17,23.24-Octakis-(9H-carbazol-9-yl) phthalocyaninato zinc(II) (3) and 2,3,9,10,16,17,23.24-octakis-(3,6-di-tert-butyl-9H-carbazole) phthalocyaninato zinc(II) (4) complexes were prepared and characterized by NMR and UV-vis spectroscopies, magnetic circular dichroism (MCD), matrix-assisted laser desorption ionization mass spectrometry, and X-ray crystallography. UV-vis and MCD data are indicative of the interligand charge-transfer nature of the broad band observed in 450-500 nm range for 3 and 4. The redox properties of 3 and 4 were probed by electrochemical and spectro-electrochemical methods, which are suggestive of phthalocyanine-centered first oxidation and reduction processes. Photophysics of 3 and 4 were investigated by steady-state fluorescence and time resolved transient absorption spectroscopy demonstrating the influence of the carbazole substituents on deactivation from the first excited state in 3 and 4. Protonation of the meso-nitrogen atoms in 3 results in much faster deactivation kinetics from the first excited state. Spectroscopic data were correlated with density functional theory (DFT) and time-dependent DFT calculations on 3 and 4. PMID- 28920684 TI - Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation. AB - Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR.ligand complexes. The ensuing structure function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization. PMID- 28920686 TI - High-Pressure Synthesis of the Cobalt Pyrochlore Oxide Pb2Co2O7 with Large Cation Mixed Occupancy. AB - The novel A2B2O7-type compound Pb2Co2O7 was synthesized at 8 GPa and 1673 K. Synchrotron X-ray diffraction shows a cubic pyrochlore structure with space group Fd3m. Rietveld structural analysis reveals a large cation mixed occupancy at both A and B sites by about 40%, the greatest value found in the pyrochlore family. In combination with the X-ray absorption spectroscopy results, the specific chemical composition and charge states are determined to be (Co0.6Pb0.4)3+2(Pb0.6Co0.4)4+2O7, in which both the A-site Co3+ and the B-site Co4+ are low-spin. Due to the tetrahedral geometric frustration effects as well as the random Co4+ and Pb4+ distribution at the B site, spin glassy behavior is well observed following the conventional critical slowing down feature in Pb2Co2O7. PMID- 28920688 TI - Enantioselective Construction of Cyclopenta[b]indole Scaffolds via the Catalytic Asymmetric [3 + 2] Cycloaddition of 2-Indolylmethanols with p-Hydroxystyrenes. AB - The catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols to p hydroxystyrenes was established in the presence of a chiral phosphoramide, and this reaction provided chiral cyclopenta[b]indole scaffolds in generally high yields and with good enantioselectivities (up to 98% yield, 99:1 er). The control experiments demonstrated that the dual hydrogen-bonding activation mode of the chiral catalyst toward the two substrates played an important role in the reaction. In addition, the large-scale reaction indicated that this catalytic asymmetric [3 + 2] cycloaddition could be scaled up for the synthesis of chiral cyclopenta[b]indole derivatives. PMID- 28920687 TI - Manipulating Protein-Protein Interactions in Nonribosomal Peptide Synthetase Type II Peptidyl Carrier Proteins. AB - In an effort to elucidate and engineer interactions in type II nonribosomal peptide synthetases, we analyzed biomolecular recognition between the essential peptidyl carrier proteins and adenylation domains using nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics, and mutational studies. Three peptidyl carrier proteins, PigG, PltL, and RedO, in addition to their cognate adenylation domains, PigI, PltF, and RedM, were investigated for their cross species activity. Of the three peptidyl carrier proteins, only PigG showed substantial cross-pathway activity. Characterization of the novel NMR solution structure of holo-PigG and molecular dynamics simulations of holo-PltL and holo PigG revealed differences in structures and dynamics of these carrier proteins. NMR titration experiments revealed perturbations of the chemical shifts of the loop 1 residues of these peptidyl carrier proteins upon their interaction with the adenylation domain. These experiments revealed a key region for the protein protein interaction. Mutational studies supported the role of loop 1 in molecular recognition, as mutations to this region of the peptidyl carrier proteins significantly modulated their activities. PMID- 28920689 TI - A 320 Year Ice-Core Record of Atmospheric Hg Pollution in the Altai, Central Asia. AB - Anthropogenic emissions of the toxic heavy metal mercury (Hg) have substantially increased atmospheric Hg levels during the 20th century compared to preindustrial times. However, on a regional scale, atmospheric Hg concentration or deposition trends vary to such an extent during the industrial period that the consequences of recent Asian emissions on atmospheric Hg levels are still unclear. Here we present a 320 year Hg deposition history for Central Asia, based on a continuous high-resolution ice-core Hg record from the Belukha glacier in the Siberian Altai, covering the time period 1680-2001. Hg concentrations and deposition fluxes start rising above background levels at the beginning of the 19th century due to emissions from gold/silver mining and Hg production. A steep increase occurs after the 1940s culminating during the 1970s, at the same time as the maximum Hg use in consumer products in Europe and North America. After a distinct decrease in the 1980s, Hg levels in the 1990s and beginning of the 2000s return to their maximum values, which we attribute to increased Hg emissions from Asia. Thus, rising Hg emissions from coal combustion and artisanal and small-scale gold mining (ASGM) in Asian countries determine recent atmospheric Hg levels in Central Asia, counteracting emission reductions due to control measures in Europe and North America. PMID- 28920690 TI - Regional Intestinal Permeability in Rats: A Comparison of Methods. AB - Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (Peff) and apparent (Papp) permeability in all three regions and at both pH levels. Metoprolol had high Peff in all regions and at both pHs and high Papp at both pHs and in all regions except the jejunum, where Papp was low. Atenolol had low Peff in all regions and at both pHs, but had high Papp at pH 6.5 and low Papp at pH 7.4. There were good correlations between these rat in situ Peff (SPIP) and human in vivo Peff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model. PMID- 28920691 TI - Pyruvate Enolate Arylation and Alkylation: OBO Ester Protected Pyruvates as Useful Reagents in Organic Synthesis. AB - A protected pyruvate equivalent is described that allows arylation and arylation/alkylation reactions to be performed at the methyl group. Utilization of the OBO derivative of the pyruvate ester allowed the application of palladium catalyzed arylation reactions together with subsequent alkylation, under basic conditions. Moreover, the OBO protecting group could be easily removed in one step to provide access to a wide range of substituted pyruvate derivatives. PMID- 28920692 TI - Roseochelin B, an Algaecidal Natural Product Synthesized by the Roseobacter Phaeobacter inhibens in Response to Algal Sinapic Acid. AB - The secondary metabolome of the representative Roseobacter, Phaeobacter inhibens, was examined in response to algal sinapic acid. In addition to roseobacticides, sinapic acid induced the production of two new natural products, roseochelin A and B, which were characterized by NMR and X-ray crystallography. Functional assays showed that roseochelin B binds iron and is algaecidal against the algal host Emiliania huxleyi. It appears to be produced by a rarely observed combination of nonenzymatic and enzymatic transformations. PMID- 28920693 TI - pH Tunable and Divalent Metal Ion Tolerant Polymer Lipid Nanodiscs. AB - The development and applications of detergent-free membrane mimetics have been the focus for the high-resolution structural and functional studies on membrane proteins. The introduction of lipid nanodiscs has attracted new attention toward the structural biology of membrane proteins and also enabled biomedical applications. Lipid nanodiscs provide a native lipid bilayer environment similar to the cell membrane surrounded by a belt made up of proteins or peptides. Recent studies have shown that the hydrolyzed form of styrene maleic anhydride copolymer (SMA) has the ability to form lipid nanodiscs and has several advantages over protein or peptide based nanodiscs. SMA polymer lipid nanodiscs have become very important for structural biology and nanobiotechnological applications. However, applications of the presently available polymer nanodiscs are limited by their instability toward divalent metal ions and acidic conditions. To overcome the limitations of SMA nanodiscs and to broaden the potential applications of polymer nanodiscs, the present study investigates the tunability of SMA polymer nanodiscs by systematically modifying the maleic acid functional group. The two newly developed polymers and subsequent lipid nanodiscs were characterized using solid state NMR, FT-IR, TEM, and DLS experiments. The pH dependence and metal ion stability of these nanodiscs were studied using static light scattering and FTIR. The reported polymer nanodiscs exhibit unique pH dependent stability based on the modified functional group and show a high tolerance toward divalent metal ions. We also show these tunable nanodiscs can be used to encapsulate and stabilize a polyphenolic natural product curcumin. PMID- 28920694 TI - Gold-Catalyzed Synthesis of 1-(Indol-3-yl)carbazoles: Selective 1,2-Alkyl vs 1,2 Vinyl Migration. AB - Gold(III)-catalyzed cycloisomerization of alpha-bis(indol-3-yl)methyl alkynols selectively affords 1-(indol-3-yl)carbazoles, in a transformation that takes place through a selective 1,2-alkyl vs 1,2-vinyl migration step in the vinyl-gold intermediate generated from the initial 5-endo-spirocyclization. The reaction proceeds well with either tertiary or secondary starting alkynols as well as with a wide variety of alkyne substituents. The key role of the other indol-3-yl substituent for the unexpected selectivity in the 1,2 rearrangement has also been supported by DFT calculations that reveal a low barrier, two-step mechanism in the alkyl migration path where the second indole significantly stabilizes a carbocationic intermediate. PMID- 28920695 TI - Organic Radicals Outperform LiF as Efficient Electron-Injection Materials for Organic Light-Emitting Diodes. AB - One of the key issues for organic light-emitting diodes (OLEDs) is to achieve high electroluminescence efficiency and high power efficiency, which requires extremely efficient electron injection and thus low driving voltage. Here, we design a series of precursors for reactive organic radicals according to theoretical calculations and achieve efficient electron injection by using a highly reducing radical on the surface of the electron injection layer to reduce the electron injection barrier through an interface charge-transfer process. In contrast to bulk charge transfer in electron-transporting material, interface charge transfer allows us to make efficient electron injection at contact without introducing any structural and electronic disorder to electron-transporting material. 2-(2,4,6-Trimethoxyphenyl)-1,3-dimethyl-1H-benzoimidazol-3-ium (R3), with the strongest electron-donating ability, could largely reduce the electron injection barrier and outperform the previously reported organic radical (2-(2 methoxyphenyl)-1,3-dimethyl-1H-benzoimidazol-3-ium, o-MeO-DMBI or R1) and the widely used electron injection material (LiF) to boost device performance. PMID- 28920696 TI - Regio- and Stereospecific Construction of 3a-(1H-Indol-3-yl)pyrrolidinoindolines and Application to the Formal Syntheses of Gliocladins B and C. AB - A one-pot regio- and stereospecific strategy for the construction of 3a-(3 indolyl)-hexahydropyrrolo[2,3-b]indoles based on the condensation of an indole and an in situ generated cyclopropylazetoindoline has been developed. This unified strategy works with a variety of substituted indoles to produce 3a-(3 indolyl)hexahydropyrrolo[2,3-b]indole products in high yields. The utility of this transformation was highlighted in the formal total syntheses of gliocladins B and C. PMID- 28920698 TI - Correlating Bridging Ligand with Properties of Ligand-Templated [MnII3X3]3+ Clusters (X = Br-, Cl-, H-, MeO-). AB - Polynuclear manganese compounds have garnered interest as mimics and models of the water oxidizing complex (WOC) in photosystem II and as single molecule magnets. Molecular systems in which composition can be correlated to physical phenomena, such as magnetic exchange interactions, remain few primarily because of synthetic limitations. Here, we report the synthesis of a family of trimanganese(II) complexes of the type Mn3X3L (X = Cl-, H-, and MeO-) where L3- is a tris(beta-diketiminate) cyclophane. The tri(chloride) complex (2) is structurally similar to the reported tri(bromide) complex (1) with the Mn3X3 core having a ladder-like arrangement of alternating M-X rungs, whereas the tri(MU hydride) (3) and tri(MU-methoxide) (4) complexes contain planar hexagonal cores. The hydride and methoxide complexes are synthesized in good yield (48% and 56%) starting with the bromide complex employing a metathesis-like strategy. Compounds 2-4 were characterized by combustion analysis, X-ray crystallography, X-band EPR spectroscopy, SQUID magnetometry, and infrared and UV-visible spectroscopy. Magnetic susceptibility measurements indicate that the Mn3 clusters in 2-4 are antiferromagnetically coupled, and the spin ground state of the compounds (S = 3/2 (1, 2) or S = 1/2 (3, 4)) is correlated to the identity of the bridging ligand and structural arrangement of the Mn3X3 core (X = Br, Cl, H, OCH3). Electrochemical experiments on isobutyronitrile solutions of 3 and 4 display broad irreversible oxidations centered at 0.30 V. PMID- 28920699 TI - Visible-Light-Mediated Anti-Regioselective Nitrone 1,3-Dipolar Cycloaddition Reaction and Synthesis of Bisindolylmethanes. AB - The development of photoredox reactions of 1,3-dipolar cycloaddition of nitrones with alkenes is reported. It offers an efficient synthetic method to obtain isoxazolidine derivatives under mild conditions in synthetically useful yields. The nitrones are cyclized with oxidizable styrenes and aliphatic alkenes via a polar radical crossover cycloaddition reaction through photocatalytic reaction without additives. In addition, bis(indole)methanes can also be prepared through this method. PMID- 28920697 TI - Nepsilon- and O-Acetylation in Mycobacterium tuberculosis Lineage 7 and Lineage 4 Strains: Proteins Involved in Bioenergetics, Virulence, and Antimicrobial Resistance Are Acetylated. AB - Increasing evidence demonstrates that lysine acetylation is involved in Mycobacterium tuberculosis (Mtb) virulence and pathogenesis. However, previous investigations in Mtb have only monitored acetylation at lysine residues using selected reference strains. We analyzed the global Nepsilon- and O-acetylation of three Mtb isolates: two lineage 7 clinical isolates and the lineage 4 H37Rv reference strain. Quantitative acetylome analysis resulted in identification of 2490 class-I acetylation sites, 2349 O-acetylation and 141 Nepsilon-acetylation sites, derived from 953 unique proteins. Mtb O-acetylation was thereby significantly more abundant than Nepsilon-acetylation. The acetylated proteins were found to be involved in central metabolism, translation, stress responses, and antimicrobial drug resistance. Notably, 261 acetylation sites on 165 proteins were differentially regulated between lineage 7 and lineage 4 strains. A total of 257 acetylation sites on 161 proteins were hypoacetylated in lineage 7 strains. These proteins are involved in Mtb growth, virulence, bioenergetics, host pathogen interactions, and stress responses. This study provides the first global analysis of O-acetylated proteins in Mtb. This quantitative acetylome data expand the current understanding regarding the nature and diversity of acetylated proteins in Mtb and open a new avenue of research for exploring the role of protein acetylation in Mtb physiology. PMID- 28920700 TI - Highly Selective Construction of Medium-Sized Lactams by Palladium-Catalyzed Intramolecular Hydroaminocarbonylation of Aminoalkynes. AB - A novel palladium-catalyzed intramolecular hydroaminocarbonylation of aminoalkynes has been developed. This direct and operationally simple protocol provides a rapid and reliable approach to a diverse array of valuable seven- and eight-membered lactams with high chemoselectivity and regioselectivity. The high selectivity might be attributed to rational tuning the electronic nature of the amine moiety and the palladium catalyst, which enabled this transformation to proceed in the absence of acidic or any other additives under fairly mild reaction conditions. This method paves the way for the synthesis of medium-sized lactams. PMID- 28920702 TI - Novel technologies applied for recovery and value addition of high value compounds from plant byproducts: A review. AB - Plant byproducts of food processing industry line are undervalued yet important resource. These byproducts contain large percentage of high value functional substances such as antioxidants, pectin, polyphenols and so on. Recently, many research studies concentrated on innovative technologies that promise to overcome such issues as time consuming, inefficiency, and low yield, among others, which exist in most conventional techniques. Consequently, to achieve the recovery of nutraceuticals from high added-value by-products, it is necessary to have more knowledge of these novel technologies and more importantly explore the possibility of application of these latest technologies to the recovery downstream processing. The present work will summarize state-of-the-art technological approaches concerning extraction, superfine and drying applied to plant food processing residues. Simultaneously, the application of the bioactive components originated from byproducts in food industry will also be reviewed. PMID- 28920701 TI - Absence of a Band Gap at the Interface of a Metal and Highly Doped Monolayer MoS2. AB - High quality electrical contact to semiconducting transition metal dichalcogenides (TMDCs) such as MoS2 is key to unlocking their unique electronic and optoelectronic properties for fundamental research and device applications. Despite extensive experimental and theoretical efforts reliable ohmic contact to doped TMDCs remains elusive and would benefit from a better understanding of the underlying physics of the metal-TMDC interface. Here we present measurements of the atomic-scale energy band diagram of junctions between various metals and heavily doped monolayer MoS2 using ultrahigh vacuum scanning tunneling microscopy (UHV-STM). Our measurements reveal that the electronic properties of these junctions are dominated by two-dimensional metal-induced gap states (MIGS). These MIGS are characterized by a spatially growing measured gap in the local density of states (L-DOS) of the MoS2 within 2 nm of the metal-semiconductor interface. Their decay lengths extend from a minimum of ~0.55 nm near midgap to as long as 2 nm near the band edges and are nearly identical for Au, Pd, and graphite contacts, indicating that it is a universal property of the monolayer semiconductor. Our findings indicate that even in heavily doped semiconductors, the presence of MIGS sets the ultimate limit for electrical contact. PMID- 28920703 TI - Prognostic usefulness of an age-adapted equation for renal function assessment in older patients with acute coronary syndrome. AB - BACKGROUND:: Renal dysfunction negatively impacts survival in acute coronary syndrome patients. The Berlin Initiative Study creatinine-based (BIScrea) equation has recently been proposed for renal function assessment in older persons. However, up to now it is unknown if the superiority of the new BIScrea equation, with respect to the most recommended chronic kidney disease epidemiology collaboration creatinine-based (CKD-EPIcrea) formula, would translate into better risk prediction of adverse events in older patients with acute coronary syndrome. OBJECTIVES:: To study the impact of using estimated glomerular filtration rate calculated according to the BIScrea and CKD-EPIcrea equations on mortality in acute coronary syndrome patients aged 70 years and over. METHODS:: Retrospectively, between 2011 and 2016, a total of 2008 patients with acute coronary syndrome (64% men; age 79+/-7 years) were studied. Follow-up was 18+/-10 months. Measures of performance were evaluated using continuous data and stratifying patients into three estimated glomerular filtration rate subgroups: >=60, 59.9-30 and <30 mL/min/1.73 m2. RESULTS:: The two formulas afforded independent prognostic information over follow-up. However, risk prediction was most accurate using the BIScrea formula as evaluated by Cox proportional hazards models (hazard ratio (for each 10 mL/min/1.73 m2 decrease) 1.47 vs. 1.27 with the CKD-EPI equation; P<0.001 for comparison), c-statistic values (0.69 vs. 0.65, respectively; P=0.04 for comparison) and Bayesian information criterion. Net reclassification improvement based on the estimated glomerular filtration rate categories significantly favoured BIScrea +9 (95% confidence interval 2-16%; P=0.02). CONCLUSIONS:: Our findings suggest that the BIScrea formula may improve death risk prediction more than the CKD-EPIcrea formula in older patients with acute coronary syndrome. PMID- 28920704 TI - Endothelial-to-Mesenchymal Transition: A Potential Mechanism for Atherosclerosis Plaque Progression and Destabilization. AB - Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. EndMT is associated with fibroproliferative diseases, such as cancer progression and metastasis and cardiac and kidney fibrosis, and this condition has been extensively investigated over the past decade. Recently, studies showed that EndMT contributes to the initiation and progression of atherosclerotic lesion and plaque destabilization. Unstable atherosclerotic plaque rupture and subsequent thrombosis are the main pathological causes of acute cardiovascular events. EndMT is plastic and reversible. Therefore, our enhanced understanding on the mechanisms controlling EndMT and its roles in the atherosclerosis plaque progression and instability may provide a basis for the development of novel therapeutic strategies to stabilize and reverse atherosclerotic plaques. PMID- 28920705 TI - Human Endothelial Progenitor Cell-Derived Exosomes Increase Proliferation and Angiogenesis in Cardiac Fibroblasts by Promoting the Mesenchymal-Endothelial Transition and Reducing High Mobility Group Box 1 Protein B1 Expression. AB - Myocardial fibrosis is a characteristic feature of cardiomyopathies. However, no effective strategies to attenuate cardiac fibrosis are currently available. Late stage endothelial progenitor cells (EPCs) are precursors of endothelial cells (ECs) that repair the heart through a paracrine mechanism. In the present study, we tested whether EPC-derived exosomes regulate the differentiation of fibroblasts into ECs. We isolated late-stage EPCs from human peripheral blood (PB) and used immunofluorescence and flow cytometry to confirm their identity. Next, we isolated exosomes from the EPCs and characterized their morphology using electron microscopy and confirmed the expression of exosome-specific marker proteins using Western blots. We then investigated the in vitro effects of exosomes on the proliferation and angiogenesis of cardiac fibroblasts (CFs) and on the expression of the mesenchymal-endothelial transition (MEndT)-related genes and the myocardial fibrosis-regulated protein, high mobility group box 1 protein B1 (HMGB1). We found that human PB-EPC-derived exosomes enhanced the proliferation and angiogenesis of CFs in vitro. Furthermore, CFs stimulated with these exosomes showed increased expression of the EC-specific markers, like cluster of differentiation 31 and vascular endothelial growth factor receptor 2, and decreased expression of proteins involved in fibrosis, like alpha-smooth muscle actin, vimentin, collagen I, transforming growth factor-beta, and tumor necrosis factor-alpha. In addition, CFs stimulated with human PB-EPC-derived exosomes, inhibited the expression of HMGB1. Taken together, our study demonstrated that EPC-derived exosomes promote the proliferation and angiogenesis of CFs by inhibiting MEndT and decreasing the expression of HMGB1. PMID- 28920706 TI - Do night and around-the-clock firefighters' shift schedules induce deviation in tau from 24 hours of systolic and diastolic blood pressure circadian rhythms? AB - Systolic (S) and diastolic (D) blood pressures (BP) [SBP and DBP] are circadian rhythmic with period (tau) in healthy persons assumed to be maintained at 24.0h. We tested this assumption in a sample of 30 healthy career (mean >12 yrs) 30-to 46 yr-old male Caucasian French firefighters (FFs) categorized into three groups according to work schedule and duties: Group A - 12 FFs working 12h day, 12h night, and occasionally 24h shifts and whose primary duties are firefighting plus paramedical and road rescue services; Group B - 9 FFs working mostly 12h day and 12h night shifts and whose duties are answering incoming emergency calls and coordinating service vehicle dispatch from fire stations with Group A personnel; Group C - 9 day shift (09:00-17:00h) FFs charged with administrative tasks. SBP and DBP, both in winter and in summer studies of the same FFs, were sampled by ambulatory BP monitoring every 1h between 06:00-23:00h and every 2h between 23:01 05:59h, respectively, their approximate off-duty wake and sleep spans, for 7 consecutive days. Activity (wrist actigraphy) was also sampled at 1-min intervals. Prominent tau of each variable was derived by a power spectrum program written for unequal-interval time series data, and between-group differences in incidence of tau?24h of FFs were assessed by chi square test. Circadian rhythm disruption (tau?24h) of either the SBP or DBP rhythm occurred almost exclusively in night and 24h shift FFs of Group A and B, but almost never in day shift FFs of Group C, and it was not associated with altered tau from 24.0h of the circadian activity rhythm. In summer, occurrence of tau?24 for FFs of Group A and B differed from that for FFs of Group C in SBP (p=0.042) and DBP (p=0.015); no such differences were found in winter (p>0.10). Overall, manifestation of prominent tau?24h of SBP or DBP time series was greater in summer than winter, 27.6% versus 16.7%, when workload of Group B FFs, i.e. number of incoming emergency telephone calls, and of Group A FFs, i.e. number of dispatches for provision of emergency services, was, respectively, two and fourfold greater and number of 12h night shifts worked by Group B FFs and number of 24h shifts worked by Group A FFs was, respectively, 92% and 25% greater. FFs of the three groups exhibited no winter summer difference in tau?24h of SBP or SDP; however, tau?24h of DBP in Group B FFs was more frequent in summer than winter (p=0.046). Sleep/wake cycle disruption, sleep deprivation, emotional and physical stress, artificial light-at night, and altered nutrient timings are hypothesized causes of tau?24h for BP rhythms of affected Groups A and B FFs, but with unknown future health effects. PMID- 28920707 TI - In vitro and in vivo studies of Allium sativum extract against deltamethrin induced oxidative stress in rats brain and kidney. AB - The present study investigated the in vitro and the in vivo antioxidant capacities of Allium sativum (garlic) extract against deltamethrin-induced oxidative damage in rat's brain and kidney. The in vitro result showed that highest extraction yield was achieved with methanol (20.08%). Among the tested extracts, the methanol extract exhibited the highest total phenolic, flavonoids contents and antioxidant activity. The in vivo results showed that deltamethrin treatment caused an increase of the acetylcholinesterase level (AChE) in brain and plasma, the brain and kidney conjugated dienes and lipid peroxidation (LPO) levels as compared to control group. The antioxidant enzymes results showed that deltamethrin treatment induced a significantly decrease (p < 0.01) in brain and kidney antioxidant enzymes as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) to control group. The co-administration of garlic extract reduced the toxic effects in brain and kidney tissues induced by deltamethrin. PMID- 28920708 TI - Perceived usefulness and perceived ease of use of electronic health records among nurses: Application of Technology Acceptance Model. AB - BACKGROUND: Electronic health records (EHRs) are increasingly being implemented in healthcare organizations but little attention has been paid to the degree to which nurses as end-users will accept these systems and subsequently use them. OBJECTIVES: To explore nurses' perceptions of usefulness and ease-of-use of EHRs. The relationship between these constructs was examined, and its predictors were studied. METHOD: A national exploratory study was conducted with 1539 nurses from 15 randomly selected hospitals, representative of different regions and healthcare sectors in Jordan. Data were collected using a self-administered questionnaire, which was based on the Technology Acceptance Model. Correlations and linear multiple regression were utilized to analyze the data. RESULTS: Jordanian nurses demonstrated a positive perception of the usefulness and ease-of use of EHRs, and subsequently accepted the technology. Significant positive correlations were found between these two constructs. The variables that predict usefulness were the gender, professional rank, EHR experience, and computer skills of the nurses. The perceived ease-of-use was affected by nursing and EHR experience, and computers skills. CONCLUSION: This study adds to the growing body of knowledge on issues related to the acceptance of technology in the health informatics field, focusing on nurses' acceptance of EHRs. PMID- 28920709 TI - Comparison of oxidative stress biomarkers in hypertensive patients with or without hyperhomocysteinemia. AB - Hyperhomocysteinemia is an independent risk factor for cardiovascular impairment in hypertension. Oxidative stress is important in the molecular mechanisms associated with hypertension, but there are few studies focusing on the comparison of oxidative stress biomarkers in hypertensive patients with or without hyperhomocysteinemia. The study included 50 newly diagnosed hypertensive patients with hyperhomocysteinemia, 50 newly diagnosed hypertensive patients without hyperhomocysteinemia, and 50 age-matched healthy controls. Serum levels of malondialdehyde, nitric oxide, 8-isoprostane-F2alpha, superoxide dismutase, catalase, and glutathione peroxides were compared. Levels of malondialdehyde and 8-isoprostane-F2alpha were higher in both hypertensive groups than in the control group (8.3 +/- 1.8 MUmol/L vs. 6.5 +/- 1.3 MUmol/L vs. 4.3 +/- 1.2 MUmol/L, P < 0.05; 23.5 +/- 12.1 pg/mL vs. 17.4 +/- 10.3 pg/mL vs. 13.9 +/- 7.5 pg/mL, P < 0.05), while levels of superoxide dismutase and catalase were lower in both hypertensive groups than in the control group (120.5 +/- 13.7 U/mL vs. 131.3 +/- 18.2 U/mL vs. 149.1 +/- 14.6 U/mL, P < 0.05; 23.8 +/- 7.4 U/mL vs. 24.6 +/- 9.2 U/mL vs. 33.5 +/- 8.2 U/mL, P < 0.05). In hypertensive subgroups, serum malondialdehyde levels were higher in the hyperhomocysteinemia group than the other group (8.3 +/- 1.8 MUmol/L vs. 6.5 +/- 1.3 MUmol/L; P < 0.05), and superoxide dismutase activities were lower in the hyperhomocysteinemia group than the other group (120.5 +/- 13.7 U/mL vs. 131.3 +/- 18.2 U/mL; P < 0.05). Moreover, in hypertensive patients, homocysteine levels were significantly correlated with malondialdehyde (r = 0.39, P < 0.01), 8-isoprostane-F2alpha (r = 0.47, P < 0.05), superoxide dismutase (r = -0.51, P < 0.01), and catalase (r = 0.51, P < 0.05), respectively. Our findings demonstrated oxidative stress was more severe in hypertensive patients with hyperhomocysteinemia than those hypertensive patients without it. Besides, there were strong relationships between homocysteine activities and oxidative/antioxidative parameters, which indicated that homocysteine might aggravate the oxidative stress in hypertension to produce contributory effects on cardiovascular impairment. PMID- 28920710 TI - Use of strong opioids for chronic pain in osteoarthritis: an insight into the Latin American reality. AB - INTRODUCTION: Osteoarthritis is the most common cause of arthritis and one of the main causes of chronic pain. Although opioids are frequently employed for chronic pain treatment, their usage for osteoarthritis pain remains controversial due to the associated adverse effects. Most guidelines reserve their use for refractory pain in patients with hip and knee osteoarthritis. The situation is even more complex in Latin America, where the prevalence of insufficient pain treatment is high because of the limited availability and use of strong opioids. Areas covered: In this article we review the epidemiology of osteoarthritis, its socioeconomic burden, its impact as a chronic pain cause and the pharmacological treatment options, giving emphasis to the role of strong opioids, their safety and efficacy, especially in Latin American countries, where restrictions regulate their usage. Expert commentary: Usage of strong opioids is safe and effective in the short-term management of osteoarthritis with moderate to severe pain, when other pharmacological treatments are inadequate and surgery is contraindicated, provided their use adheres to existing guidelines. Educational programs for patients and physicians and further research on treating chronic pain with opioids should be implemented to reduce adverse effects and improve care quality. PMID- 28920711 TI - Rivaroxaban Causes Missed Diagnosis of Protein S Deficiency but Not of Activated Protein C Resistance (Factor V Leiden). AB - CONTEXT: - Rivaroxaban causes a false increase in activated protein C resistance (APCR) ratios and protein S activity. OBJECTIVE: - To investigate whether this increase masks a diagnosis of factor V Leiden (FVL) or protein S deficiency in a "real-world" population of patients undergoing rivaroxaban treatment and hypercoagulation testing. DESIGN: - During a 2.5-year period, we compared 4 groups of patients (n = 60): FVL heterozygous (FVL-HET)/taking rivaroxaban, wild type/taking rivaroxaban, FVL-HET/no rivaroxaban, and normal APCR/no rivaroxaban. Patients taking rivaroxaban were tested for protein S functional activity and free antigen (n = 32). RESULTS: - The FVL-HET patients taking rivaroxaban had lower APCR ratios than wild-type patients ( P < .001). For FVL-HET patients taking rivaroxaban, mean APCR was 1.75 +/- 0.12, versus 1.64 +/- 0.3 in FVL-HET patients not taking rivaroxaban ( P = .005). Activated protein C resistance in FVL-HET patients fell more than 3 SDs below the cutoff of 2.2 at which the laboratory reflexes FVL DNA testing. No cases of FVL were missed despite rivaroxaban. In contrast, rivaroxaban falsely elevated functional protein S activity, regardless of the presence or absence of FVL ( P < .001). A total of 4 of 32 patients (12.5%) had low free protein S antigen (range, 58%-67%), whereas their functional protein S activity appeared normal (range 75%-130%). Rivaroxaban would have caused a missed diagnosis of all cases of protein S deficiency during the study if testing relied on the protein S activity assay alone. CONCLUSIONS: - Despite rivaroxaban treatment, APCR testing can distinguish FVL-HET from normal patients, rendering indiscriminate FVL DNA testing of all patients on rivaroxaban unnecessary. Free protein S should be tested in patients taking rivaroxaban to exclude hereditary protein S deficiency. PMID- 28920712 TI - Maximized nanodrug-loaded mesenchymal stem cells by a dual drug-loaded mode for the systemic treatment of metastatic lung cancer. AB - Mesenchymal stem cells (MSCs), exhibiting tumor-tropic and migratory potential, can serve as cellular carriers to improve the effectiveness of anticancer agents. However, several challenges, such as the safety issue, the limited drug loading, the conservation of stemness and migration of MSCs, still remain in the MSC-based delivery system. In the present study, a novel nano-engineered MSC delivery system was established by loading doxorubicin (DOX)-polymer conjugates for the systemic treatment of pulmonary metastasis of breast cancer. For the first time, a dual drug-loaded mode, endocytosis and membrane-bound, was adopted to achieve the maximum amount of DOX conjugates in MSCs. The in vitro studies revealed the loaded MSCs possessed multifunctional properties, including preservation of the stemness and migration of MSCs, excellent stability of drug loading, acid sensitive drug release and obvious cytotoxicity against 4T1 cells. The in vivo studies confirmed that the loaded MSCs mainly located and long stayed in the lung where the foci of metastatic tumor situated. Importantly, loaded MSCs can significantly inhibit the tumor growth and prolong the life span of tumor-bearing mice in contrast with DOX and DOX-conjugate. The present loaded MSCs system suggested a promising strategy to solve several issues existed in cell-based delivery systems. Especially for the problem of low drug loading, the strategy, simultaneously loading nanodrug in cells' internal and membrane, might be the most desirable method so far and could be developed as a generalizable manner for cell-mediated tumor-targeted therapy. PMID- 28920713 TI - Estradiol decreases blood pressure in association with redox regulation in preeclampsia. AB - In this study, we tested a hypothesis that a short-term estradiol therapy may reduce blood pressure in preeclampsia by modulating plasma oxidative stress. The intramuscular injections of 10 mg 17-beta-estradiol were prescribed to preeclamptic pregnant women during the 3-day therapy before a labor induction. The analyses of mean arterial pressure (MAP), serum estradiol concentrations, plasma superoxide anion (O2.), hydrogen peroxide (H2O2), nitrites (NO2-), and peroxynitrite (ONOO-) were conducted before and during the therapy. We found that the plasma concentrations of oxidative stress markers, such as O2- and H2O2, are higher in preeclampsia and positively correlated with the MAP value. Moreover, it was shown that the plasma concentration of NO2- as an indicator of NO levels is higher in preeclampsia. A short-term intramuscular application of estradiol decreases the MAP value and the plasma concentration of O.-, H2O2, NO2-, and ONOO in preeclampsia. A positive correlation between the decrease of MAP values and the decrease of plasma concentrations of O2-, H2O2, and ONOO- was found in preeclampsia during a short-term estradiol therapy. We conclude that the short term estradiol therapy decreases the MAP value in preeclampsia by modulating the plasma oxidative stress. We speculate that the estradiol metabolism in preeclampsia is an important mechanism that contributes to vascular dysfunction. PMID- 28920714 TI - Expansible thermal gelling foam aerosol for vaginal drug delivery. AB - Vaginal delivery of antimicrobial drugs is the most effective method for the local treatment of the vaginal infections. However, current vaginal drug delivery systems (VDDS), including gel, lotion, aerosol and cream, are suffering from low penetration in the deep vaginal rugae and easy elimination by self-cleaning of vaginal canal. To address these issues, a foam aerosol based on the thermal transformation was designed to improve penetration efficiency and achieve the extended retention. The expansible thermal gelling foam aerosol (ETGFA) consisting of thermal sensitive matrix, silver nanoparticle, adhesive agent and propellant, was optimized by evaluations of precursor viscosity, foam expansion, thermal gelation, gel adhesiveness, antimicrobial effects and tissue irritation. The ETGFA would penetrate to the deep vaginal rugae to cover the infectious sites by foam expansion. Drug leakage was intended to be avoided by the thermal gelation at physiological temperature before foam collapse. The gel could be retained in the vaginal canal for extended time due to its superior adhesiveness when compared to the commercial gel Asimi(r). The ETGFA provided extended drug release for over 4 h and maintained effective drug concentrations at the infectious sites. The ETGFA containing silver nanoparticles showed dose-dependent antimicrobial effects on the vaginal floras and irritation reduction to the vaginal tissues. The results demonstrated that the ETGFA could overcome the limitations of conventional dosage forms, including poor drug penetration, carrier retention and patient compliance and satisfied the requirements for vaginal drug delivery. PMID- 28920715 TI - The mixed message behind "Medication-Assisted Treatment" for substance use disorder. AB - The gap between treatment utilization and treatment need for substance use disorders (SUDs) remains a significant concern in our field. While the growing call to bridge this gap often takes the form of more treatment services and/or better integration of existing services, this perspective proposes that more effective labels for and transparent descriptions of existing services would also have a meaningful impact. Adopting the perspective of a consumer-based health care model (wherein treatments and services are products and patients are consumers) allows us to consider how labels like Addiction-focused Medical Management, Medication-Assisted Treatment, Medication-Assisted Therapy, and others may actually be contributing to the underutilization problem rather than alleviating it. In this perspective, "Medication-Assisted Therapy" for opioid-use disorder (OUD) is singled out and discussed as inherently confusing, providing the message that pharmacotherapy for this disorder is a secondary treatment to other services which are generally regarded, in practice, as ancillary. That this mixed message is occurring amidst a nationwide "opioid epidemic" is a potential cause for concern and may actually serve to reinforce the longstanding, documented stigma against OUD pharmacotherapy. We recommend that referring to pharmacotherapy for SUD as simply "medication," as we do for other chronic medical disorders, will bring both clarity and precision to this effective treatment approach. PMID- 28920716 TI - Transposons: Moving Forward from Preclinical Studies to Clinical Trials. AB - Transposons have emerged as promising vectors for gene therapy that can potentially overcome some of the limitations of commonly used viral vectors. Transposons stably integrate into the target cell genome, enabling persistent expression of therapeutic genes. Transposons have evolved from being used as basic tools in biomedical research to bona fide therapeutics. Currently, the most promising transposons for gene therapy applications are derived from Sleeping Beauty (SB) or piggyBac (PB). Stable transposition requires co-delivery of the transposon DNA with the corresponding transposase gene, mRNA, or protein. Stable transposition efficiency can be substantially increased by using "next generation" transposon systems that combine codon-usage optimization with hyper activating mutations in the SB or PB transposases. By virtue of their relatively large capacity, gene therapy applications with relatively large therapeutic transgenes, such as full-length dystrophin, can now be envisaged. The authors and others have shown that efficient and stable gene transfer can be achieved with these next-generation transposons in several clinically relevant primary cells, such as CD34+ hematopoietic stem/progenitor cells, T cells, and mesenchymal and myogenic stem/progenitor cells that are amenable for ex vivo transfection. Alternatively, in vivo transposon gene delivery has been explored using non-viral vectors or nanoparticles or in combination with viral vectors. The therapeutic potential of these SB- and PB-based transposons has been demonstrated in preclinical models that mimic the cognate human diseases. However, there are still challenges impeding clinical translation of transposons pertaining mainly to the typical limiting efficiencies of most non-viral transfection methods and the intrinsic DNA toxicity. Nevertheless, it is particularly encouraging that transposons have now been used in gene therapy clinical trials. In particular, transposon-engineered T cells expressing chimeric antigen receptors are starting to yield promising results in patients with hematological malignancies. PMID- 28920717 TI - [Targeted treatment of renal cell carcinoma, treatment caused side-effects and side-effect management]. AB - Until the past decade, therapeutic options for unresectable and/or metastatic renal cell carcinoma were limited. Renal cell carcinoma is generally resistant to conventional chemotherapy, and only a small percentage of patients with renal cell carcinoma benefit from cytokine treatment. Since 2005, the advances in target-based therapy and immunotherapy modalities have created a paradigm shift in the treatment of renal cell carcinoma. Herein, we review the most up-to-date practices and emerging therapies for the treatment of renal cell carcinoma and focus on the threrapy caused side-effects and side-effect management. Orv Hetil. 2017; 158(38): 1488-1502. PMID- 28920719 TI - [History of hand transplantation: advancement in the operative technics, medications and the survival of the transplanted hands. Review of literature]. AB - The author summarizes briefly the history of hand allograft transplantation, the basics of the operative technics, and the medicinal treatment of the immunosuppression. He establishes that this operation requires complicated team work: many specialists must be united in the interest of the successful final outcome. The biggest problem is not the technical challenge of the complicated operation, but the ineffectiveness of immunosuppression, its complications; even though significant development has happened in this field and experimental results are also encouraging. The author discusses these questions in this publication in the mirror of literature data. He states, that a successful hand transplantation, with its sensory and motoric functions can increase quality of life, in contrast with the ortheses. Orv Hetil. 2017; 158(38): 1483-1487. PMID- 28920720 TI - [The first coronary artery revascularization surgery was performed fifty years ago]. PMID- 28920721 TI - [Changes in carbohydrate metabolism after kidney transplantation and their effects on cardiovascular risk]. AB - INTRODUCTION: Cardiovascular disease is the major cause of deaths after transplantation, with diabetes mellitus being the main risk factor in development. AIM: The aim of our study was to assess the prevalence of new onset diabetes mellitus in connection with the cardiovascular risk predicted by the HEART Score. METHOD: 44 patients were involved in our study; after overview of baseline data, OGTT was performed, followed by patient classification into the following groups: normal, impaired fasting glucose/impaired glucose tolerance, and new onset diabetes mellitus. Insulin resistance and kidney function were also assessed. RESULTS: Concerning baseline data, cold ischemic time (p = 0.016), body weight (p = 0.035), BMI (p = 0.025), and HbA1C (p = 0.0024) proved to be significantly different between normal and diabetic patients. Significant difference was found based on HOMA IR between the two groups 1.69+/-0.51 vs 6.46+/-1.42; p = 0.0017). Based on the HEART Score, patients with new onset diabetes mellitus were put into Group 3, which also reflects the risk which diabetes carries for the development of cardiovascular diseases. CONCLUSION: Cardiovascular risk can be decreased with increased allograft survival by early diagnosis and management of diabetes. Orv Hetil. 2017; 158(38): 1512-1516. PMID- 28920723 TI - ? PMID- 28920722 TI - [Comparative evaluation of vertigo in patients after stapedotomy and stapedectomy]. AB - INTRODUCTION AND AIM: The reason of gradually developing conductive hearing loss in otosclerotic patients is the ossification of the stapes footplate to the surrounding bony structures and the therapy of stapes fixation is mainly surgical. In stapedotomy the footplate of the stapes is fenestrated with laser and microdrill in a diameter of 0.8 mm, whereas in stapedectomy there is complete removal of the footplate followed by the reconstruction of the ossicular chain. In the early postoperative period, temporary vertigo is frequently recorded which significantly influences the recovery. METHOD: In the Department of Otorhinolaryngology, University of Pecs both stapedectomy and stapedotomy were performed on a daily basis between 01.02.2010 and 15.03.2012. Our study focused on comparing the degree of postoperative vertigo after the two types of surgery. We hypothesized that the smaller fenestration of the stapes footplate during stapedotomy limits exposure to the inner ear reducing the severity of dizziness. Vertigo was evaluated subjectively with a retrospective questionnaire and objectively with static posturography. RESULTS: On the 1st postoperative day, significantly fewer patients reported vertigo in the stapedotomy group and with significantly lower intensity. Results of the questionnaire regarding the later postoperative period showed no significant differences between the groups. Based on the analysis of the posturography test results, no significant difference was detected between the postoperative stability of the two groups. Results of the questionnaire and the posturography showed no correlation. Posturography test results did not confirm the presence of subjective vertigo. CONCLUSION: Many factors may play a role in the development of vertigo after stapes surgery, but the type of intervention does not influence it. Orv Hetil. 2017; 158(38): 1503 1511. PMID- 28920724 TI - Canadian Military Nurse Deaths in the First World War. AB - This paper examines the lives of sixty-one Canadian Nursing Sisters who served during the First World War, and whose deaths were attributed, more or less equally, to three categories: general illness, Spanish Influenza, and killed in action. The response by Canadian Army Medical Corps (CAMC) physicians to the loss of these early female officers who were, in fact, Canada's first female war casualties, suggests a gendered construction of illness at work in the CAMC. While nurses tried to prove themselves good soldiers, military physicians were quick to attribute their illnesses and deaths to horrific war conditions deemed unsuitable for women. This gendered response is particularly evident in how CAMC physicians invoked a causal role for neurasthenia or shell shock for the nurses' poor health. The health profile of these women also suggests that some of these deaths might have occurred had these women stayed in Canada, and it encourages future comparative research into death rates among physicians and orderlies. PMID- 28920727 TI - ? PMID- 28920726 TI - The "Human Subject," "Vulnerable Populations," and Medical History: The Problem of Presentism and the Discourse of Bioethics. AB - This discussion considers recent historical works of eugenics and sterilization in Canada, but it is not an historiographic review essay or critique per se of this literature. Rather, by focussing on the topic of historic diagnostic categories such as "feeble-minded," "idiot," and "moron," methodological issues such as historical presentism and its possible interactions with the discourse of modern bioethics are examined. The conclusions derived are meant only to be cautionary, and are neither prescriptive nor proscriptive. Medical historians undertaking analyses of currently contentious topics that may directly involve or indirectly allude to "human subjects" or "vulnerable populations" perhaps ought to reflect on the degree, if any, they may be anachronistically writing contemporary bioethical categories into bygone eras. PMID- 28920729 TI - ? PMID- 28920730 TI - Accidents and Violent Death in Early Modern London, 1650-1750 by Craig Spence Accidents and Violent Death in Early Modern London, 1650-1750 Craig Spence Woodbridge : Boydell Press , 2016 , xii+ 273 p., $115.00. PMID- 28920731 TI - ? PMID- 28920732 TI - ? PMID- 28920734 TI - Editors' Note / Note de la redaction. PMID- 28920735 TI - War-Torn Exchanges: The Lives and Letters of Nursing Sisters Laura Holland and Mildred Forbes, edited by Andrea McKenzie War-Torn Exchanges: The Lives and Letters of Nursing Sisters Laura Holland and Mildred Forbes Andrea McKenzie (ed.) Vancouver : UBC Press , 2016 , viii+ 256 p., $32.95. PMID- 28920736 TI - ? PMID- 28920738 TI - ? PMID- 28920737 TI - Letter to the Editor. PMID- 28920739 TI - The Politics of Hospital Provision in Early Twentieth-Century Britain by Barry M. Doyle The Politics of Hospital Provision in Early Twentieth-Century Britain Barry M. Doyle London : Pickering & Chatto , 2014 , xi+ 297 p., $42.36. PMID- 28920740 TI - ? PMID- 28920742 TI - ? PMID- 28920744 TI - ? PMID- 28920745 TI - ? PMID- 28920746 TI - ? PMID- 28920748 TI - Investigation of the transport and absorption of Angelica sinensis polysaccharide through gastrointestinal tract both in vitro and in vivo. AB - To investigate the absorption and delivery of ASP in gastrointestinal (GI) tract, cASP was successfully synthesized by chemically modifying with succinic anhydride and then conjugating with a near infrared fluorescent dye Cy5.5. Then, the capacity of oral absorption of cASP was evaluated. The results demonstrated that cASP had low toxicity and no disruption on the integrity of cell membrane. The endocytosis of cASP into the epithelial cells was time- and energy-dependent, which was mediated by macropinocytosis pathway and clathrin- and caveolae (or lipid raft)-related routes. Otherwise, the actin filaments played a relatively weak role at the same time. The transport study illustrated that cASP could penetrate through the epithelial monolayer and mainly mediated by the same routes as that in the endocytosis experiment. Moreover, both in vitro Ussing chamber and in vivo ligated intestinal loops models indicated that cASP could be diffused through the mucus barriers and be absorbed in the whole small intestine. Finally, near-infrared fluorescence imaging presented that cASP could be absorbed and circulated into the blood, then distributed into various organs after oral administration. In conclusion, ASP could be absorbed after oral administration through endocytosis process mainly mediated by macropinocytosis pathway and clathrin- and caveolae (or lipid raft)-related routes, then be absorbed and circulated into blood. This study presents a comprehensive understanding of oral delivery of cASP, which will provide theoretical basis for the clinical application of ASP. PMID- 28920750 TI - LETTER TO THE EDITOR. PMID- 28920749 TI - AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE COMMENTARY: MANAGING THYROID TUMORS DIAGNOSED AS NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES. AB - : This commentary summarizes the history and reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclei (NIFTP). It reviews the salient histopathologic features that are based on immunohistochemical and molecular profiles and serve as inclusion and exclusion criteria. The authors also provide their own point of view regarding the practical issues and possible concerns that may be raised by both clinicians and patients based on the diagnosis of NIFTP. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists EFVPTC = encapsulated FVPTC FNA = fine-needle aspiration FVPTC = follicular variant of papillary thyroid carcinoma NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features PTC = papillary thyroid carcinoma. PMID- 28920751 TI - Distress Due to Prognostic Uncertainty in Palliative Care: Frequency, Distribution, and Outcomes among Hospitalized Patients with Advanced Cancer. AB - BACKGROUND: Prognostic uncertainty is common in advanced cancer and frequently addressed during palliative care consultation, yet we know little about its impact on quality of life (QOL). OBJECTIVE: We describe the prevalence and distribution of distress due to prognostic uncertainty among hospitalized patients with advanced cancer before palliative care consultation. We evaluate the association between this type of distress and overall QOL before and after palliative care consultation. DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Hospitalized patients with advanced cancer who receive a palliative care consultation at two geographically distant academic medical centers. MEASUREMENTS: At the time of enrollment, before palliative care consultation, we asked participants: "Over the past two days, how much have you been bothered by uncertainty about what to expect from the course of your illness?" (Not at all/Slightly/Moderately/Quite a Bit/Extremely). We defined responses of "Quite a bit" and "Extremely" to be indicative of substantial distress. RESULTS: Two hundred thirty-six participants completed the baseline assessment. Seventy-seven percent reported being at least moderately bothered by prognostic uncertainty and half reported substantial distress. Compared with others, those who were distressed by prognostic uncertainty (118/236) reported poorer overall QOL before palliative care consultation (mean QOL 3.8 out of 10 vs. 5.3 out of 10, p = < 0.001) and greater improvement in QOL following consultation (Adjusted difference in mean QOL change = 1.1; 95% confidence interval = 0.2, 2.0). CONCLUSIONS: Prognostic uncertainty is a prevalent source of distress among hospitalized patients with advanced cancer at the time of initial palliative care consultation. Distress from prognostic uncertainty is associated with lower levels of preconsultation QOL and with greater pre-post consultation improvement in the QOL. PMID- 28920752 TI - Treatment of synthetic refinery wastewater in anoxic-aerobic sequential moving bed reactors and sulphur recovery. AB - Objective of the present study was to simultaneously biodegrade synthetic petroleum refinery wastewater containing phenol (750 mg/L), sulphide (750 mg/L), hydrocarbon (as emulsified diesel of 300 mg/L), ammonia-nitrogen (350 mg/L) at pH >9 in anoxic-aerobic sequential moving bed reactors. The optimum mixing speed of anoxic reactor was observed at 20 rpm and beyond that, removal rate remained constant. In anoxic reactor the minimum hydraulic retention time was observed to be 2 days for complete removal of sulphide, 40-50% removal of phenol and total hydrocarbons and 52% of sulphur recovery. The optimum HRT of aerobic moving bed reactor was observed as 16 h (total HRT of 64 h for anoxic and aerobic reactors) for complete removals of phenol, total hydrocarbons, COD (chemical oxygen demand) and ammonia-nitrogen with nitrification. PMID- 28920753 TI - Can the NHS learn from the rise and fall of ancient empires? PMID- 28920754 TI - Can we fix the uber-complexities of healthcare? PMID- 28920755 TI - Personalised healthcare and population healthcare. PMID- 28920757 TI - A decision theoretical modeling for Phase III investments and drug licensing. AB - For a new candidate drug to become an approved medicine, several decision points have to be passed. In this article, we focus on two of them: First, based on Phase II data, the commercial sponsor decides to invest (or not) in Phase III. Second, based on the outcome of Phase III, the regulator determines whether the drug should be granted market access. Assuming a population of candidate drugs with a distribution of true efficacy, we optimize the two stakeholders' decisions and study the interdependence between them. The regulator is assumed to seek to optimize the total public health benefit resulting from the efficacy of the drug and a safety penalty. In optimizing the regulatory rules, in terms of minimal required sample size and the Type I error in Phase III, we have to consider how these rules will modify the commercial optimization made by the sponsor. The results indicate that different Type I errors should be used depending on the rarity of the disease. PMID- 28920756 TI - Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea. AB - OBJECTIVE: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea. METHODS: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12 months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17). RESULTS: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12 months. CONCLUSION: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance. PMID- 28920758 TI - Occurrence and source apportionment of polycyclic aromatic hydrocarbons in soils and sediment from Hanfeng Lake, Three Gorges, China. AB - This study was conducted to investigate the pollutant status and the retention mechanism of polycyclic aromatic hydrocarbons (PAHs) in soils and sediment from bank-water-level-fluctuating zone (WLFZ)-water systems in Hanfeng Lake, Three Gorges, China. The concentrations of the 16 PAHs ranged from 21.8 to 1324 ng g-1 dry wt for all 20 soil and sediment samples. These concentration levels were remarkably lower than those in soils and sediment collected domestically and worldwide. PAHs with two and three rings were found to be dominant in all the samples, with phenanthrene being most abundant. The spatial distribution of PAHs in bank soil, WLFZ soil, and sediment implied that the transfer and fate of PAHs in the bank soil-WLFZ soil-sediment systems were influenced by both water dynamic factors and physicochemical properties of PAHs. Diagnostic ratio analysis and principal component analysis suggested that the PAHs in the areas of Hanfeng Lake were primarily (>75%) derived from coal combustion and vehicle emissions . Use of natural gas, improving gasoline/diesel quality and phasing out old and nonstandard vehicles and ships are proposed to control PAH contamination and protect drinking water safety in the region. PMID- 28920759 TI - Spatial distribution of polycyclic aromatic hydrocarbon and polychlorinated biphenyl sources in the Nakdong River Estuary, South Korea. AB - Our research team investigated the elemental composition and the presence of various toxic organic compounds, such as polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), in estuary surface sediments to trace the spatial distribution of the sources of pollution deposited in Nakdong River, Busan, South Korea. The spatial patterns of elemental composition and toxic organic compounds were determined from the measurements of total organic carbon (TOC), total nitrogen, total sulfur, PAHs, and PCBs. The sediments had TOC contents of between 0.02 and 1.80 wt% (avg. 0.34 wt%), depending on the amount of clay-sized particles. The concentrations of PAHs and PCBs (10.8-167.7 ng g-1 dry wt and 197.0-754.0 pg g-1 dry wt, respectively) in surface sediments revealed different spatial patterns for these compounds, suggesting that they partially originated from the combustion of fossil fuels and from the use of commercial PCB products at adjacent industrial complexes. Although these concentrations were far below the Sediment Quality Guideline (SQG) of the National Oceanic and Atmospheric Administration (NOAA), the sediments at one site contained PCBs at concentrations close to the response level (754.0 pg g-1 dry wt), and were dominated by low-molecular-weight PAHs. The PAHs and PCBs in Nakdong River Estuary sediments were likely to have originated from the combustion of fossil fuels and biomass at the adjacent industrial complexes. The primarily analyzed results determined that PAHs originated from the combustion of fossil fuels and biomass, and overall concentrations were related to the contributions of individual PAHs in most sediment samples. Based on the SQG of the NOAA, our results indicate that the anthropogenic activity should be considered on the future-sustainable management of this estuary system. PMID- 28920760 TI - Influence Analysis for the Area Under the Receiver Operating Characteristic Curve. AB - Classification measures play essential roles in the assessment and construction of classifiers. Hence, determining how to prevent these measures from being affected by individual observations has become an important problem. In this paper, we propose several indexes based on the influence function and the concept of local influence to identify influential observations that affect the estimate of the area under the receiver operating characteristic curve (AUC), an important and commonly used measure. Cumulative lift charts are also used to equipoise the disagreements among the proposed indexes. Both the AUC indexes and the graphical tools only rely on the classification scores, and both are applicable to classifiers that can produce real-valued classification scores. A real data set is used for illustration. PMID- 28920761 TI - Can ultra-wide field retinal imaging replace colour digital stereoscopy for glaucoma detection? AB - PURPOSE: Ultra-wide field (UWF) retinal imaging (Optomap, Optos plc, Dunfermline, UK) is a novel technique to image the peripheral fundus. The goal of this study was to explore the potential use of UWF imaging to detect glaucoma, and specifically to evaluate the reproducibility of measures of vertical cup-to-disc ratio (VCDR) using ultra-wide field (UWF), and the agreement between UWF and standard colour digital stereoscopy (CDS). METHODS: An observational study. From a population-based epidemiological study we selected 100 eyes from 100 consecutive participants who were imaged using both standard CDS and UWF retinal imaging. Estimation of the VCDR using both modalities was made by a masked glaucoma specialist and two masked independent observers. Reliability and agreement between colour digital stereoscopy and the UWF imaging was assessed by Bland-Altman scatterplots. RESULTS: Intra-observer reproducibility of the UWF imaging in estimating VCDRs produced Limits of Agreement (LOA) ranging from -0.13 to 0.1 (mean 0.02) and -0.14 to 0.14 (mean 0.0004) for observer 1 and 2 respectively. Inter-observer reliability between observer 1 and the glaucoma specialist for VCDR measurements using CDS and UWF produced LOA ranging from 0.37 to 0.15 (mean -0.11) and -0.24 to 0.26 (mean 0.0005) respectively. Bland Altman plots produced LOA of -0.16 to 0.20 (mean 0.02) between the two imaging methods for assessing VCDR when carried out by a glaucoma specialist. CONCLUSION: Grading of UWF imaging has high reproducibility in evaluating VCDR and agreement with stereoscopic optic disc imaging and may be suitable for glaucoma diagnosis in situations where CDS is not available. PMID- 28920763 TI - Critique of the IARC 100F Working Group Evaluation of Occupational Benzene Exposure: Suggestions for the October 2017 Benzene-Only Working Group Meeting. AB - Health agencies and institutions utilize International Agency for Research on Cancer (IARC) monographs because they are said to represent authoritative cancer evaluations and scientific references. The United States National Cancer Institute has provided support for the IARC Monographs Program for more than three decades. The Volume 100F Monograph, which was published in 2012, reports the evaluations of benzene and more than two dozen other agents performed by the IARC Working Group (WG) that met in Lyon, France from 20 to 27 October 2009. All had already been judged to be human carcinogens. This commentary discusses errors in the occupational exposure section (1.1.3) of the 100F Benzene Monograph ("monograph"). Millions of workers in developed and developing countries have long been known to be routinely exposed to benzene. Since exposures may exceed occupational exposure limits, the hope is that this commentary will be considered by the IARC benzene-only WG at its meeting in October 2017. PMID- 28920762 TI - Measuring dynamics of eukaryotic transcription initiation: Challenges, insights and opportunities. AB - Transcription of protein-encoding genes in eukaryotic cells is a dynamically coordinated process. Many of the key transcription regulators contain functionally essential intrinsically disordered regions (IDRs), the dynamic nature of which creates extra challenges to traditional biochemical analyses. Recent advances in single-molecule fluorescence imaging technology have enabled direct visualization of these rapid, complex and dynamic molecular interactions in real time. PMID- 28920764 TI - Recurrence of disease activity during pregnancy after cessation of fingolimod in multiple sclerosis. AB - BACKGROUND: Fingolimod is an effective treatment for active relapsing-remitting multiple sclerosis (MS). Discontinuation of therapy may be followed by recurrence of disease activity. Thus, female MS patients may be at risk of relapse during pregnancy after stopping fingolimod. OBJECTIVES AND METHODS: To report the disease course during pregnancy of five women who interrupted therapy with fingolimod for pregnancy. RESULTS: All patients experienced relapses during pregnancy and/or postpartum after stopping fingolimod. CONCLUSION: The risk of recurrence of disease activity during pregnancy after stopping fingolimod may be substantial. This should be considered and discussed with MS patients who are planning to become pregnant. PMID- 28920765 TI - Medication usage and falls in people with multiple sclerosis. AB - There is a need to identify modifiable risk factors for falls in people with multiple sclerosis (MS) to enable the design of successful falls prevention interventions. There is conflicting evidence regarding the association between medication use and occurrence of falls in MS. A total of 101 people with MS had medications classified using the Anatomical Therapeutic Classification system and number of falls prospectively monitored for 3 months. No association was noted between number of medications and falls. The use of genitourinary and sex hormones (odds ratio (OR) = 5.154, 95% confidence interval (CI) = 1.427-18.609, p = 0.012) and centrally acting muscle relaxant (OR = 5.181, 95% CI = 1.546-17.364, p = 0.008) medications were associated with an increased odds of being a faller. PMID- 28920766 TI - Clinical profile of patients with paraneoplastic neuromyelitis optica spectrum disorder and aquaporin-4 antibodies. AB - BACKGROUND:: In a minority of patients with neuromyelitis optica spectrum disorder (NMOSD) and aquaporin-4 antibodies (AQP4-IgG), the disease has a paraneoplastic origin. It is unknown whether these patients have distinctive clinical features. OBJECTIVE:: To report the clinical features of a series of patients with paraneoplastic NMOSD and AQP4-IgG and to review previously reported cases. METHODS:: Retrospective analysis of clinical records of 156 patients with NMOSD and AQP4-IgG and review of previously reported patients with paraneoplastic NMOSD and AQP4-IgG. Paraneoplastic patients were defined as those with cancer identified within 2 years of the diagnosis of NMOSD. RESULTS:: Five (3.2%) of 156 patients had paraneoplastic NMOSD, and 12 previously reported patients were identified. The most common tumors were adenocarcinoma of the lung (five patients) and breast (five). Compared with the 151 non-paraneoplastic NMOSD patients, the 17 (5 current cases and 12 previously reported) were older at symptom onset (median age = 55 (range: 17-87) vs 40 (range: 10-77) years; p = 0.006), more frequently male (29.4% vs 6.6%; p = 0.009), and presented with severe nausea and vomiting (41.2% vs 6.6%; p < 0.001). The frequency of longitudinal extensive transverse myelitis (LETM) as heralding symptom was similar in both groups, but patients with paraneoplastic NMOSD were older than those with non-paraneoplastic NMOSD (median age: 63 (range: 48-73) vs 43 (range: 14-74) years; p = 0.001). CONCLUSION:: Patients, predominantly male, with NMOSD and AQP4-IgG should be investigated for an underlying cancer if they present with nausea and vomiting, or LETM after 45 years of age. PMID- 28920768 TI - Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy. AB - Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy Stephen Hull, MHS, Sean Kelley, MD, MSc, and Janice L. Clarke, RN, BBA Editorial: Sexually Transmitted Infections-A Fixable Problem: David B. Nash, MD, MBA S-3 Introduction S-3 Rising Prevalence of Sexually Transmitted Diseases (STIs) S-4 Current Screening Rates for Chlamydia and Gonorrhea S-4 The Human Toll and Economic Burden of STI-Related Illness S-5 Current Screening Guidelines for Chlamydia and Gonorrhea S-5 Factors Contributing to Inadequate Screening, Diagnosis, and Treatment for STIs S-6 Methods Used to Improve Screening Rates S-7 Benefits of Opt-Out Screening Strategies for STIs S-8 Cost-Effectiveness of Screening for STIs S-8 Discussion S-9 Conclusion S 10. PMID- 28920767 TI - Auricular vagal nerve stimulation in peripheral arterial disease patients. AB - BACKGROUND: Auricular nerve stimulation has been proven effective in different diseases. We investigated if a conservative therapeutic alternative for claudication in peripheral arterial occlusive disease (PAD) via electroacupuncture of the outer ear can be established. PATIENTS AND METHODS: In this prospective, double-blinded trial an ear acupuncture using an electroacupuncture device was carried out in 40 PAD patients in Fontaine stage IIb. Twenty patients were randomized to the verum group using a fully functional electroacupuncture device, the other 20 patients received a sham device (control group). Per patient, eight cycles (1 cycle = 1 week) of electroacupuncture were performed. The primary endpoint was defined as a significantly more frequent doubling of the absolute walking distance after eight cycles in the verum group compared to controls in a standardized treadmill testing. Secondary endpoints were a significant improvement of the total score of the Walking Impairment Questionnaire (WIQ) as well as improvements in health related quality of life using the Short Form 36 Health Survey (SF-36). RESULTS: There were no differences in baseline characteristics between the two groups. The initial walking distance significantly increased in both groups (verum group [means]: 182 [95 % CI 128 236] meters to 345 [95 % CI 227-463] meters [+ 90 %], p < 0.01; control group [means]: 159 [95 % CI 109-210] meters to 268 [95 % CI 182-366] meters [+ 69 %], p = 0.01). Twelve patients (60 %) in the verum group and five patients (25 %) in controls reached the primary endpoint of doubling walking distance (p = 0.05). The total score of WIQ significantly improved in the verum group (+ 22 %, p = 0.01) but not in controls (+ 8 %, p = 0.56). SF-36 showed significantly improvements in six out of eight categories in the verum group and only in one of eight in controls. CONCLUSIONS: Electroacupuncture of the outer ear seems to be an easy-to-use therapeutic option in an age of increasingly invasive and mechanically complex treatments for PAD patients. PMID- 28920769 TI - Modacrylic anion-exchange fibers for Cr(VI) removal from chromium-plating rinse water in batch and flow-through column experiments. AB - The aim of this study was to investigate Cr(VI) removal from chromium-plating rinse water using modacrylic anion-exchange fibers (KaracaronTM KC31). Batch experiments were performed with synthetic Cr(VI) solutions to characterize the KC31 fibers in Cr(VI) removal. Cr(VI) removal by the fibers was affected by solution pH; the Cr(VI) removal capacity was the highest at pH 2 and decreased gradually with a pH increase from 2 to 12. In regeneration and reuse experiments, the Cr(VI) removal capacity remained above 37.0 mg g-1 over five adsorption desorption cycles, demonstrating that the fibers could be successfully regenerated with NaCl solution and reused. The maximum Cr(VI) removal capacity was determined to be 250.3 mg g-1 from the Langmuir model. In Fourier-transform infrared spectra, a Cr = O peak newly appeared at 897 cm-1 after Cr(VI) removal, whereas a Cr-O peak was detected at 772 cm-1 due to the association of Cr(VI) ions with ion-exchange sites. X-ray photoelectron spectroscopy analyses demonstrated that Cr(VI) was partially reduced to Cr(III) after the ion exchange on the surfaces of the fibers. Batch experiments with chromium-plating rinse water (Cr(VI) concentration = 1178.8 mg L-1) showed that the fibers had a Cr(VI) removal capacity of 28.1-186.4 mg g-1 under the given conditions (fiber dose = 1 10 g L-1). Column experiments (column length = 10 cm, inner diameter = 2.5 cm) were conducted to examine Cr(VI) removal from chromium-plating rinse water by the fibers under flow-through column conditions. The Cr(VI) removal capacities for the fibers at flow rates of 0.5 and 1.0 mL min-1 were 214.8 and 171.5 mg g-1, respectively. This study demonstrates that KC31 fibers are effective in the removal of Cr(VI) ions from chromium-plating rinse water. PMID- 28920770 TI - Functional Classification: Is There a Better Solution? PMID- 28920771 TI - What you don't see can kill you. AB - Traumatic retroperitoneal hematoma is a potentially life-threatening condition associated with both blunt and penetrating injury mechanisms to the structures in that region. PMID- 28920772 TI - Endogenous attention to object features modulates the ERP C1 component. AB - Converging neuroimaging and electrophysiological evidence supports the notion that selective attention can modulate neural activity not only in V1 (BA17)-as early as 40-60 ms post-stimulus-but also at the subcortical level (thalamic lateral geniculate nucleus, LGN). V1 modulation has been documented both in space based and (especially) object-based selection conditions, most of all in endogenous orienting paradigms. It seems then that an attentional modulation of the ERP C1 response-reflecting V1 modulation-would not be especially favoured by exogenous cuing as far as object-based attention is concerned. PMID- 28920773 TI - Metronidazole removal in powder-activated carbon and concrete-containing graphene adsorption systems: Estimation of kinetic, equilibrium and thermodynamic parameters and optimization of adsorption by a central composite design. AB - Metronidazole (MNZ) removal by two adsorbents, i.e., concrete-containing graphene (CG) and powder-activated carbon (PAC), was investigated via batch-mode experiments and the outcomes were used to analyze the kinetics, equilibrium and thermodynamics of MNZ adsorption. MNZ sorption on CG and PAC has followed the pseudo-second-order kinetic model, and the thermodynamic parameters revealed that MNZ adsorption was spontaneous on PAC and non-spontaneous on CG. Subsequently, two-parameter isotherm models, i.e., Langmuir, Freundlich, Temkin, Dubinin Radushkevich and Elovich models, were applied to evaluate the MNZ adsorption capacity. The maximum MNZ adsorption capacities ([Formula: see text]) of PAC and CG were found to be between 25.5-32.8 mg/g and 0.41-0.002 mg/g, respectively. Subsequently, the effects of pH, temperature and adsorbent dosage on MNZ adsorption were evaluated by a central composite design (CCD) approach. The CCD experiments have pointed out the complete removal of MNZ at a much lower PAC dosage by increasing the system temperature (i.e., from 20 degrees C to 40 degrees C). On the other hand, a desorption experiment has shown 3.5% and 1.7% MNZ removal from the surface of PAC and CG, respectively, which was insignificant compared to the sorbed MNZ on the surface by adsorption. The overall findings indicate that PAC and CG with higher graphene content could be useful in MNZ removal from aqueous systems. PMID- 28920774 TI - Kinetics of diuron under aerobic condition and residue analysis in sugarcane under subtropical field conditions. AB - The phenylureas group includes persistent herbicides which are major pollutants to soil and water. Dissipation kinetics of diuron in different soils under sugarcane field conditions was investigated. Diuron was extracted with acetone and florisil solid phase extraction clean-up and characterized by high performance liquid chromatography-UV. Diuron persisted for more than 100 days and dissipation followed monophasic first-order kinetics. Persistence was more in sandy loam compared to silty clay loam soil. Half-life of diuron in silty clay loam soil was 22.57 and 32.37 days and in sandy loam was 28.35 and 43.93 days at 2 and 4 kg ha-1applications, respectively. Average recovery in soil, bagasse, leaf-straw and juice ranged from 75.95% to 84.20%, 80.15% to 89.35%, 77.46% to 86.19% and 81.88% to 92.68%, respectively. The quantitation limits for soil, bagasse, leaf-straw and juice were 0.01, 0.03, 0.04 MUg g-1 and 0.008 MUg mL-1, respectively. Application of diuron inhibited growth of soil microbes initially but they recovered later. At harvest, diuron residues were below maximum residue limits in all samples. The study revealed that under subtropical conditions, diuron is safe for use in weed management and would not pose any residual/environmental problem and that sugarcane crop could be used safe for human/animal consumption. PMID- 28920775 TI - LAPAROSCOPIC-ASSISTED INSERTION OF A VENTRICULOPERITONEAL SHUNT IN A RESCUED ASIATIC BLACK BEAR (URSUS THIBETANUS) IN LAOS. AB - A 3-yr-old Asiatic black bear (Ursus thibetanus), weighing 68 kg, underwent a laparoscopic-assisted placement of a ventriculoperitoneal shunt for hydrocephalus in the Lao People's Democratic Republic. Rescued as a young cub with a notably domed head, the bear's condition had deteriorated with age, but euthanasia was not a viable option because of cultural issues. Surgery was attempted as a palliative measure. The bear had ventrally orientated crossed eyes (abducens nerve palsy and dorsal midbrain syndrome), papilledema, severe rhinorrhea, depressed mentation, lethargy, a very poor appetite, and was stunted. Hydrocephalus was confirmed via intraoperative 2.0-5.0 MHz head ultrasound, as no magnetic resonance imaging was available in the country. Surgery was planned via 3D modeling of museum skulls and brain cavity, and ultrasound examination of formalin-preserved brains of other carnivores with hydrocephalus. The bear demonstrated a notable improvement in mentation, appetite, and behavior, maintained for 4 yr following surgery. PMID- 28920776 TI - ESTABLISHING NORMAL FECAL FLORA IN WILD AUSTRALIAN PASSERINE BIRDS BY USE OF THE FECAL GRAM STAIN. AB - The purpose of this study was to determine the normal fecal bacterial and fungal flora and parasite prevalence in wild passerine birds found at the Australian Botanic Garden (Mount Annan, New South Wales). Wild passerine birds (n = 186) from 28 species were captured with mist nets. Fecal Gram stains (n = 155) were made from 26 species and analyzed for bacterial density, Gram stain morphology, and the presence of yeast. Fecal wet preparations (n = 139) were made from 24 passerine species and were analyzed for parasites. Our results showed that 81.9% of passerines sampled had bacteria present in their feces. The bacteria found were entirely Gram positive and consisted predominantly of cocci. Individuals that were caught on multiple occasions were found to have stable bacterial populations, apart from the red-browed finch (Neochmia temporalis). Insectivores had higher bacterial densities and cocci proportions than nectarivores had. Yeasts were rare in most species, with the exception of the bell miner (Manorina melanophrys) and noisy miner (Manorina melanocephala). The yeast, Macrorhabdus ornithogaster, and parasites were not observed in any fecal samples. These results will help practitioners to assess the health of Australian passerine species submitted for care or housed in zoological collections. PMID- 28920777 TI - HEART RATE AND INDIRECT BLOOD PRESSURE RESPONSES TO FOUR DIFFERENT FIELD ANESTHETIC PROTOCOLS IN WILD-BORN CAPTIVE CHIMPANZEES (PAN TROGLODYTES). AB - Limited data are available on hemodynamic responses to anesthetic protocols in wild-born chimpanzees (Pan troglodytes). Accordingly, this study characterized the heart rate (HR) and blood pressure responses to four anesthetic protocols in 176 clinically healthy, wild-born chimpanzees undergoing routine health assessments. Animals were anesthetized with medetomidine-ketamine (MK) (n = 101), tiletamine-zolazepam (TZ) (n = 30), tiletamine-zolazepam-medetomidine (TZM) (n = 24), or medetomidine-ketamine (maintained with isoflurane) (MKI) (n = 21). During each procedure, HR, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were regularly recorded. Data were grouped according to anesthetic protocol, and mean HR, SBP, and DBP were calculated. Differences between mean HR, SBP, and DBP for each anesthetic protocol were assessed using the Kruskall-Wallis test and a Dunn multiple comparisons post hoc analysis. To assess the hemodynamic time course response to each anesthetic protocol, group mean data (+/-95% confidence interval [CI]) were plotted against time postanesthetic induction. Mean HR (beats/min [CI]) was significantly higher in TZ (86 [80-92]) compared to MKI (69 [61-78]) and MK (62 [60-64]) and in TZM (73 [68-78]) compared to MK. The average SBP and DBP values (mm Hg [CI]) were significantly higher in MK (130 [126 134] and 94 [91-97]) compared to TZ (104 [96-112] and 58 [53-93]) and MKI (113 [103-123] and 78 [69-87]) and in TZM (128 [120-135] and 88 [83-93]) compared to TZ. Time course data were markedly different between protocols, with MKI showing the greatest decline over time. Both the anesthetic protocol adopted and the timing of measurement after injection influence hemodynamic recordings in wild born chimpanzees and need to be considered when monitoring or assessing cardiovascular health. PMID- 28920778 TI - FIRST REPORT OF TRYPANOSOMA EVANSI INFECTION (SURRA) IN A PUMA (FELIS CONCOLOR) OF LAHORE ZOO, PAKISTAN. AB - The blood protozoan Trypanosoma evansi, which is transmitted by biting flies, is frequently neglected due to subclinical infections. This report describes a case of trypanosomiasis due to T. evansi in a 9-yr-old male puma (Felis concolor) housed at the Lahore Zoo in Pakistan. Early in January 2015, this male puma presented with chronic lethargy, weight loss, incoordination, hyperthermia, anorexia, sunken eyes, and unthriftiness. Microscopic examination of Giemsa stained blood smears showed numerous Trypanosoma parasites. The puma was treated with diminazene aceturate subcutaneously twice. A few days later, a blood smear examination showed absence of trypanosomes. Five months later the cat presented with acute epistaxis and died. Postmortem examination showed emaciation, pale liver and kidneys, and hemorrhages on the spleen. Examination of a blood smear taken at the time of death showed numerous Trypanosoma parasites. PCR testing confirmed the presence of Trypanosoma DNA. DNA sequencing of two amplicons confirmed the presence of Trypanosoma in the blood smears with a 98-99% identity with the previously identified GenBank sequences. A phylogenetic tree was then constructed. Further studies are needed to improve our knowledge about the epidemiology and pathogenesis of T. evansi infection in wild animal species. PMID- 28920779 TI - OCULAR FINDINGS AND SELECT OPHTHALMIC DIAGNOSTIC TESTS IN CAPTIVE AMERICAN WHITE PELICANS (PELECANUS ERYTHRORHYNCHOS). AB - The aim of this study was to establish normal ophthalmic parameters for select diagnostic tests in American white pelicans (Pelecanuserythrorhynchos). Twenty one zoo-housed American white pelicans were manually restrained for noninvasive ocular diagnostic testing and complete ophthalmic examination. Tear production quantification using the phenol red thread test (PRTT), fluorescein staining, and intraocular pressure (IOP) evaluation were performed. In addition, conjunctival aerobic bacterial culture and culture-independent 16S rRNA amplicon sequencing were performed on select eyes. Normal variations and ocular abnormalities detected during complete ophthalmic examination were documented and photographed. Direct pupillary light reflex, menace response, and palpebral reflex were present in all birds. The value (mean +/- SD) for PRRT and IOP was 14.9 +/- 7.84 mm/15 sec and 9.0 +/- 1.41 mm Hg oculus uterque, respectively. Conjunctival culture in nine birds revealed no growth for six birds and Staphylococcus aureus growth in three birds. A high relative abundance of Mycoplasma sp. was detected in all samples based on 16S rRNA sequencing. The normal pelican eye was found to have relative conjunctival hyperemia, absent filoplumes, iris color ranging from light blue to brown, and a subcircular vertically elongated pupil. Ophthalmic abnormalities were noted in 10 of 21 birds. Common findings included corneal fibrosis, cataracts, and asteroid hyalosis. The most common ophthalmic abnormality in this species was cataracts. PMID- 28920780 TI - USE OF COMPOSITE MATERIALS AS A COMPONENT OF TUSK FRACTURE MANAGEMENT IN AN ASIAN ELEPHANT (ELEPHAS MAXIMUS) AND AN AFRICAN ELEPHANT (LOXODONTA AFRICANA). AB - Tusk fractures in Asian (Elephas maximus) and African elephants (Loxodonta africana) can result in damage to the distal end or to longitudinal cracks, potentially progressing to pulpitis. With pulp exposure, endodontic therapy is the treatment of choice, but conservative therapy has sufficed for some elephants. This manuscript describes the use of composite materials as a component of tusk fracture management. A 7-yr-old male Asian elephant fractured the distal end of both tusks with pulp exposure in one. Capping of each tusk with a Kevlar/fiberglass composite prevented further damage, and a modification allowed care of the exposed pulp tissue. A 34-yr-old male African elephant with a longitudinal crack received a carbon fiber/fiberglass composite circumferential wrap to potentially stabilize the crack. Compression of the crack was achieved, but follow-up was truncated due to bacterial pulpitis. Both cases show that composite material allows for lightweight, durable management of tusk fractures with continued radiographic monitoring. PMID- 28920781 TI - REFRACTOMETRIC URINE SPECIFIC GRAVITY OF FREE-LIVING EGYPTIAN FRUIT BATS (ROUSETTUS AEGYPTIACUS). AB - In both human and veterinary medicine, urine specific gravity (USG) is commonly measured by refractometry to indirectly reflect the osmolality of urine to thereby evaluate the kidney's ability to concentrate or dilute urine according to physiologic need and certain disease conditions. However, for accurate interpretation of the significance of any value, knowledge of the expected USG for the healthy species in question is required. It is generally believed that fruit bats, and Egyptian fruit bats (Rousettus aegyptiacus) in particular, are unable to highly concentrate their urine. In this study, the USG was determined using a handheld urine refractometer in 43 free-living Egyptian fruit bats of both sexes. The calculated nonparametric 90% confidence interval for Egyptian fruit bats in this study was 1.006-1.050, with no association with capture site, sex, weight, or packed cell volume and total solids. Results suggest that free living Egyptian fruit bats are able to highly concentrate their urine. PMID- 28920782 TI - EVALUATION OF LEAD AND MERCURY PREVALENCE IN BALD EAGLES (HALIAEETUS LEUCOCEPHALUS) FROM THE MID-ATLANTIC UNITED STATES. AB - Heavy metal contamination of the environment remains a critical issue. Lead and mercury exposure, particularly, can affect avian health. Bald eagles (Haliaeetus leucocephalus) ingest these metals through their diets. Lead and mercury prevalence were examined in bald eagles from three mid-Atlantic US states between 2004 and 2013. Blood samples were analyzed using atomic absorption spectrometry. Wilcoxon score tests were used to detect differences in lead and mercury over time. Counties of origin for birds with clinically significant metal levels were identified. There were no temporal trends found in lead and mercury prevalence. Eagles with clinically significant lead levels (>0.6 ppm) originated from near Chesapeake and Delaware bays, but most birds with clinically significant mercury levels (>1 ppm) originated from near Delaware and Barnegat bays. These findings indicate that lead and mercury contamination persists in this region and that routine sampling of bald eagles is a useful monitoring tool. PMID- 28920783 TI - SUCCESSFUL REDUCTION OF FEATHER-DAMAGING BEHAVIOR BY SOCIAL RESTRUCTURING IN A GROUP OF GOLDEN CONURES (GUARUBA GUAROUBA). AB - A variety of infectious and noninfectious causes may contribute to feather damaging behavior (FDB) in birds. This paper describes an episode of FDB behavior related to an isosexual group composition in a group of 20 golden conures (Guaruba guarouba) kept in a collective aviary. After ruling out infectious causative agents and analyzing the social bird group composition over a period of 10 yr, the male to female ratio of the group was reduced from 1.7 to 1.0. This intervention resulted in a significant improvement of the feather condition and improved reproduction. Further analysis revealed that FDB was not correlated to age, gender, or origin. In addition, FDB was associated with stress, as reflected by an elevated heterophil : lymphocyte ratio that decreased significantly following social restructuring. This study stresses the importance of an appropriate male to female ratio when golden conures are kept in aviaries. PMID- 28920784 TI - TREATMENT SUCCESS IN THREE ANDEAN BEARS (TREMARCTOS ORNATUS) WITH ALOPECIA SYNDROME USING OCLACITINIB MALEATE (APOQUEL(r)). AB - Andean bear (Tremarctos ornatus) alopecia syndrome (ABAS) commonly affects captive bears, particularly sexually mature females. ABAS is characterized by bilaterally symmetrical predominantly flank alopecia with or without profound pruritus and secondary bacterial and Malassezia infections. There is no effective treatment and severely affected bears have been euthanized. This paper describes the successful management of ABAS in three female Andean bears. Skin biopsies and cytology revealed a mixed dermal inflammatory infiltrate, alopecia, hyperkeratosis, and Malassezia dermatitis. Allergen specific serology was positive for environmental allergens in one case. Hematology, serum biochemistry, and thyroid and adrenal function were normal in all cases. There was no consistent response to novel diet trials, antifungals, antihistamines, allergen specific immunotherapy, or topical antimicrobials. There was a partial response to ciclosporin (Atopica(r) cat, Novartis Animal Health; 5 mg/kg po, sid) in one case and oral glucocorticoids in all cases (dexamethasone sodium phosphate, [Colvasone 0.2%, Norbrook], 0.15 mg/kg po, sid or prednisolone [Deltacortene, Bruno Farmaceutici, and Megasolone 20, Coophavet], 0.3-1.2 mg/kg po, sid), but treatment was withdrawn following adverse effects. Treatment with oclacitinib maleate (Apoquel(r), Zoetis; 0.46-0.5 mg/kg po, bid) resulted in rapid and complete resolution of the pruritus with subsequent improvement in demeanor and fur regrowth. After 5 mo, the bears were almost fully furred and off all other medication. Treatment was tapered to the lowest dose that prevented relapse of the pruritus (0.23-0.4 mg/kg po, sid). No adverse effects have been noted. ABAS is usually an intractable condition, and, to our knowledge, oclacitinib is the first treatment shown to result in sustained clinical improvement. Further studies on the etiology of ABAS, and on efficacy and long-term safety of oclacitinib are needed. PMID- 28920785 TI - DETOMIDINE AND BUTORPHANOL FOR STANDING SEDATION IN A RANGE OF ZOO-KEPT UNGULATE SPECIES. AB - General anesthesia poses risks for larger zoo species, like cardiorespiratory depression, myopathy, and hyperthermia. In ruminants, ruminal bloat and regurgitation of rumen contents with potential aspiration pneumonia are added risks. Thus, the use of sedation to perform minor procedures is justified in zoo animals. A combination of detomidine and butorphanol has been routinely used in domestic animals. This drug combination, administered by remote intramuscular injection, can also be applied for standing sedation in a range of zoo animals, allowing a number of minor procedures. The combination was successfully administered in five species of nondomesticated equids (Przewalski horse [ Equus ferus przewalskii; n = 1], onager [ Equus hemionus onager; n = 4], kiang [ Equus kiang ; n = 3], Grevy's zebra [ Equus grevyi ; n = 4], and Somali wild ass [ Equus africanus somaliensis; n = 7]), with a mean dose range of 0.10-0.17 mg/kg detomidine and 0.07-0.13 mg/kg butorphanol; the white ( Ceratotherium simum simum; n = 12) and greater one-horned rhinoceros ( Rhinoceros unicornis ; n = 4), with a mean dose of 0.015 mg/kg of both detomidine and butorphanol; and Asiatic elephant bulls ( Elephas maximus ; n = 2), with a mean dose of 0.018 mg/kg of both detomidine and butorphanol. In addition, the combination was successfully used for standing sedation in six species of artiodactylids: giraffe ( Giraffa camelopardalis reticulata; n = 3), western bongo ( Tragelaphus eurycerus eurycerus; n = 2), wisent ( Bison bonasus ; n = 5), yak ( Bos grunniens ; n = 1), water buffalo ( Bubalus bubalis ; n = 4) and Bactrian camel ( Camelus bactrianus ; n = 5). The mean dose range for artiodactylid species except bongo was 0.04 0.06 mg/kg detomidine and 0.03-0.06 mg/kg butorphanol. The dose in bongo, 0.15 0.20 mg/kg detomidine and 0.13-0.15 mg/kg butorphanol, was considerably higher. Times to first effect, approach, and recovery after antidote were short. The use of detomidine and butorphanol has been demonstrated to be a reliable, safe alternative to general anesthesia for a number of large ungulate species. PMID- 28920786 TI - CRYPTOCOCCUS NEOFORMANS VAR. GRUBII-ASSOCIATED RENAL AMYLOIDOSIS CAUSING PROTEIN LOSING NEPHROPATHY IN A RED KANGAROO (MACROPUS RUFUS). AB - A 10-year-old male castrated red kangaroo (Macropus rufus) presented with mandibular swelling. Examination findings included pitting edema with no dental disease evident on examination or radiographs. The results of blood work were moderate azotemia, hypoalbuminemia, and severely elevated urine protein:creatinine ratio (9.9). Radiographs showed an interstitial pattern of the caudal right lung, and an abdominal ultrasound demonstrated scant effusion. Symptomatic and empirical therapy with antibiotics, anti-inflammatory drugs, and an angiotensin-converting enzyme (ACE) inhibitor did not resolve clinical signs. Due to poor prognosis and declining quality of life, euthanasia was elected. Necropsy revealed chronic granulomatous pneumonia of the caudal right lung lobe with intralesional Cryptococcus, identified as C. neoformans var. grubii by DNA sequencing. Severe bilateral glomerular and tubulointerstitial amyloidosis induced protein-losing nephropathy, leading to tri-cavitary effusion, subcutaneous edema, and cachexia. The authors speculate that renal amyloidosis was associated with chronic cryptococcal pneumonia in this red kangaroo. PMID- 28920789 TI - AAZV PUBLICATIONS AVAILABLE. PMID- 28920787 TI - CALCINOSIS CIRCUMSCRIPTA IN A COHORT OF RELATED JUVENILE AFRICAN LIONS (PANTHERA LEO). AB - Three juvenile, genetically related African lions (Panthera leo) were evaluated for discrete dome-shaped subcutaneous masses present over the proximal lateral metatarsal-tarsal area. The lesions measured 3-8 cm in diameter, were fluctuant to firm, nonulcerated, and attached to underlying structures. On radiographic evaluation, the lesions were characterized by well-circumscribed punctate mineralizations in the soft tissue surrounded by soft tissue swelling without evidence of adjacent bony involvement. On cut surface, the lesions were made of numerous loculi containing 2-5-mm round-to-ovoid, white-to-gray, firm structures interspersed with fibrous tissue and pockets of serosanguinous fluid. Hematology, serum biochemistry, serum thyroid screening (including total thyroxine, total triiodothyronine, free thyroxine, and free triiodothyronine), and serum vitamin D panels (including parathyroid hormone, ionized calcium, and 25-hydroxyvitamin D) were unremarkable. Histopathologic evaluation of the lesions was consistent with calcinosis circumscripta with fibroplasia, chronic inflammation, and seroma formation. An additional two genetically related lions were considered suspect for calcinosis circumscripta based on presentation, exam findings, and similarity to the confirmed cases. All masses self-regressed and were not associated with additional clinical signs other than initial lameness in two cases. PMID- 28920790 TI - PHARMACOKINETICS, EFFICACY, AND SAFETY OF VORICONAZOLE AND ITRACONAZOLE IN HEALTHY COTTONMOUTHS (AGKISTRODON PISCIVORUS) AND MASSASAUGA RATTLESNAKES (SISTRURUS CATENATUS) WITH SNAKE FUNGAL DISEASE. AB - Snake fungal disease (SFD; Ophidiomyces ophiodiicola) is posing a significant threat to several free-ranging populations of pitvipers. Triazole antifungals have been proposed for the treatment of mycoses in reptiles; however, data are lacking about their safety and efficacy in snakes with SFD. Study 1 investigated in vitro susceptibility, and identified that plasma concentrations >250 ng/ml (voriconazole) and >1,000 ng/ml (itraconazole) may be effective in vivo for SFD. In Study 2, the pharmacokinetics after a single subcutaneous voriconazole injection were assessed in apparently healthy free-ranging cottonmouths (Agkistrodon piscivorus). Based on pilot-study results, four snakes were administered a single injection of voriconazole (5 mg/kg). One pilot snake and three full-study snakes died within 12 hr of voriconazole administration. All surviving snakes maintained plasma concentrations >250 ng/ml for 12-24 hr. In Study 3, two Eastern massasaugas (Sistrurus catenatus) and a timber rattlesnake (Crotalus horridus horridus) diagnosed with SFD were treated with voriconazole delivered by subcutaneous osmotic pumps. The timber rattlesnake (12.1-17.5 mg/kg/hr) reached therapeutic concentrations, whereas the massasaugas (1.02-1.6 mg/kg/hr) did not. In Study 4, the pharmacokinetics of a single 10-mg/kg per cloaca dose of itraconazole (Sporanox(r)) was evaluated in seven apparently healthy free-ranging cottonmouths. Similarly, the plasma and tissue concentrations did not meet therapeutic concentrations based on in vitro data. The data presented in this report serve as an initial step toward understanding the pharmacokinetics, efficacy, and safety of triazole antifungals in pitviper species with SFD. Further study is needed to determine the appropriate dose and route of administration of triazole antifungals in pitviper species. PMID- 28920791 TI - FEMORAL HEAD RESECTION IN TWO LIVINGSTONE'S FRUIT BATS (PTEROPUS LIVINGSTONII). AB - Two Livingstone's fruit bats (Pteropus livingstonii) presented with a unilateral partial paresis of the hind limbs. Radiographs revealed luxation of the coxofemoral joint and degenerative joint disease in the right coxofemoral joint in one case. The second case presented with recurrent luxation of the coxofemoral joint with osteoarthrosis of the femoral head. Clinical findings in both cases led to a decision to perform a femoral head resection. The performed surgery led to the recovery of normal function of the limb without any complications in both cases. PMID- 28920792 TI - SQUAMOUS CELL CARCINOMA OF THE ROSTRAL MAXILLA IN AN ADULT CAPTIVE WHITESPOTTED BAMBOO SHARK (CHILOSCYLLIUM PLAGIOSUM). AB - An approximately 10-yr-old adult female whitespotted bamboo shark (Chiloscyllium plagiosum) presented with a smooth, white, irregular, ulcerated, and expansile lesion on the left lateral aspect of the maxillary rostrum. The lesion had short periods of abrupt and rapid proliferation and then remained static for several months. Cytology and culture were nonspecific and did not reveal any discernible etiologic agents or cellular atypia. The lesion was nonresponsive to parenteral antibiotics. One year after the initial onset of the lesion, the ulcer was 10 cm in diameter, a percentage increase in size of 455%. Due to a protracted clinical course and lack of response to medication and supportive care, coupled with an acute onset of neurologic signs and self-inflicted trauma, the shark was euthanized. Histopathology of the mass disclosed a locally invasive squamous cell carcinoma with no evidence of metastasis. PMID- 28920793 TI - MULTI-DRUG RESISTANCE PATTERNS OF ENTERIC BACTERIA IN TWO POPULATIONS OF FREE RANGING EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA). AB - Gram-negative isolates (n = 84) from 71% of free-ranging Eastern box turtles (Terrapene carolina carolina) in Illinois and Tennessee, United States, demonstrated resistance to at least one antibiotic while 30% of isolates demonstrated resistance to two or more antibiotics. Resistance was observed against cefoxitin, amoxicillin-clavulanic acid, cefazolin, ampicillin, ticarcillin, cefovecin, and ceftiofur. Gram-positive bacteria were isolated from 49 turtles, and all were observed to be resistant to two or more antibiotics. Gram-positive isolate resistance was observed to penicillin, cefoxitin, oxacillin, clindamycin, amikacin, enrofloxacin, cefovecin, ceftiofur, cefazolin, marbofloxacin, gentamicin, erythromycin, trimethoprim-sulfamethoxazole, and chloramphenicol. Health parameters including packed cell volume, total white blood cell count (WBC), total solids (TS), and weight were not significantly different based on antibiotic resistance patterns; however, decreasing WBC and TS were observed when the number of antibiotic-resistant detections in Gram-positive bacteria increased. PMID- 28920794 TI - INTRAOCULAR PRESSURE AND EXAMINATION FINDINGS IN THREE SPECIES OF CENTRAL AND SOUTH AMERICAN TREE FROGS (CRUZIOHYLA CRASPEDOPUS, CRUZIOHYLA CALCARIFER, AND ANOTHECA SPINOSA). AB - The purpose of this prospective study was to describe intraocular pressure (IOP) and examination findings in three tree frog species (Cruziohyla craspedopus [fringe leaf frog], Cruziohyla calcarifer [splendid leaf frog], and Anotheca spinosa [spiny-headed or coronated tree frog]). Thirty-one C. craspedopus, four C. calcarifer, and five A. spinosa were weighed, sexed based on phenotype where possible, and examined using slit-lamp biomicroscopy and indirect ophthalmoscopy. IOP was measured using the TonoVet and TonoLab rebound tonometers while the frogs were held two ways (unrestrained, then restrained). Statistical differences were determined using one-way analysis of variance (ANOVA) and t-tests. Mean +/- SD IOP (TonoVet and TonoLab, respectively) was 15.1 +/- 2.5 mmHg and 15.6 +/- 4.1 mmHg in C. craspedopus; 14.8 +/- 1.5 mmHg and 18.8 +/- 3.1 mmHg in C. calcarifer; and 9.1 +/- 2.1 mmHg and 10.8 +/- 1.4 mmHg in A. spinosa. There was no significant difference in IOP in C. craspedopus by eye (Right vs Left), tonometer, or restraint method. IOP in female C. craspedopus was 1-3 mm Hg higher than in males with both devices (P < 0.05). IOP was statistically significantly different between all species for the TonoLab and between Cruziohyla genus frogs and A. spinosa for the TonoVet (P < 0.05). There was no difference in IOP measurements between the TonoVet and TonoLab in C. craspedopus. IOP varied by gender in C. craspedopus and between species, but not by tonometer. Ocular abnormalities were minimal in this group of captive bred frogs. PMID- 28920795 TI - EVALUATION OF SYMMETRIC DIMETHYLARGININE AS AN EARLY BIOMARKER OF CHRONIC KIDNEY DISEASE IN CAPTIVE CHEETAHS (ACINONYX JUBATUS). AB - Symmetric dimethylarginine (SDMA) has been shown to be a valuable biomarker for early detection of chronic kidney disease (CKD) in canine and feline patients. Recognition of early (subclinical) kidney disease would be of value in cheetahs (Acinonyx jubatus) as prevalence of CKD is relatively high in this species in captivity. Fifty-eight banked serum and plasma samples from seven adult cheetahs that died of CKD were analyzed for creatinine, urea, and SDMA. A marked increase in SDMA was noted on five of the tested cheetahs earlier than the rise of serum creatinine and urea (estimated 8-35 mo; mean 21.4 mo; median 22 mo). SDMA appears as an early biomarker to evaluate renal function for the diagnosis of CKD in cheetahs regardless of the cause of this disease. PMID- 28920796 TI - SUCCESSFUL LAPAROSCOPIC OVIDUCTAL ARTIFICIAL INSEMINATION IN THE CLOUDED LEOPARD (NEOFELIS NEBULOSA) IN THAILAND. AB - Captive breeding of clouded leopards (Neofelis nebulosa) is challenging because of mating incompatibility, high incidence of teratospermia in males, and inconsistent ovulation patterns in females. Assisted reproductive techniques, therefore, are necessary to overcome these issues and maintain the genetic diversity in the captive population. The objective was to use laparoscopic oviductal artificial insemination (AI) to breed genetically valuable females (n = 4; aged 4.5-5 yr) that were unsuccessfully paired. Fecal hormone metabolites (estrogen and progesterone) were extracted and measured by enzyme immunoassay for monitoring of ovarian activity 45 days before and 65 days after laparoscopic AI. For timed insemination, females were injected with 200 IU equine chorionic gonadotropin and 1,000 IU porcine luteinizing hormone (pLH) at the 82-hr interval. Ovarian assessment was performed by laparoscopy 44 hr after pLH administration. One nulliparous female out of four presented two ovulation sites on each ovary. The single female that had ovulated was inseminated with chilled semen collected from two males (8 * 106 and 2.7 * 106 motile spermatozoa, respectively, in each oviduct). A significant increase in fecal progesterone concentrations was observed after AI with a concentration peak (500 MUg/g dry feces) detected on day 24 after pLH injection, which was then sustained for more than 45 days after the pLH injection. The delivery of two cubs occurred on day 92 after pLH. Microsatellite marker analysis determined that both cubs were sired by the same male. This is the first report of a successful oviductal AI in the clouded leopard. PMID- 28920797 TI - DESCRIPTION OF GASTRIC ULCERS AND OF THEIR SUSPECTED, ASSOCIATED RISK FACTORS IN DECEASED WILD EQUIDS AT THE RESERVE AFRICAINE DE SIGEAN, FRANCE (2010-2016). AB - Gastric ulcers are common in domestic horses and foals, affecting at least 90% of unmedicated racehorses in active training. Despite these high prevalences in domestic horses, literature about this condition in wild equids is almost nonexistent. The presence of gastric ulcers was evaluated at necropsy in six species of wild equids that died at the Reserve Africane de Sigean, a safari park in the south of France from 2010 to 2016. Among the 55 individuals that died during that period, a description of the gastric mucosa was available in 82% (45/55) of cases. Considering the cases for which a description of the gastric mucosa was available, the prevalence of gastric ulcers was 64% (29/45). The highest prevalences were noted in Grant's zebra (Equus quagga boehmi) and Hartmann's mountain zebra (Equus zebra hartmannae) at 83% and 100%, respectively. In contrast to what is reported in domestic foals, gastric ulcerations were only diagnosed in one foal (out of 11 foals necropsied). The higher prevalence was noted in young individuals (3-36 mo old) at 93% (14/15); the lesions observed consisted mainly of single to multiple, superficial lesions, of which, only the mucosa was missing; these superficial lesions are often considered not clinically significant. The prevalence was lower for adults (74%; 14/19), but lesions were deeper or with a hyperemic or inflammatory appearance. All the lesions observed were located in the gastric, nonglandular, stratified squamous mucosa, along the margo plicatus. No statistical correlation could be found between the development of gastric ulcers and an ongoing, chronic pathologic process or a digestive tract pathology. The detection of gastric ulcers was, therefore, significantly greater in wild equids isolated in smaller enclosures. Nevertheless, additional larger scale research is needed to point out predisposing factors in equids under human care. PMID- 28920798 TI - UROLITHIASIS IN A GROUP OF VISAYAN WARTY PIGS (SUS CEBIFRONS NEGRINUS). AB - Four cases of obstructive urolithiasis occurred in male Visayan warty pigs (Sus cebifrons negrinus) during a 12-mo period. One animal died, two were euthanized, and one was treated successfully with a tube cystotomy procedure and a subsequent urinary acidification diet. Uroliths from two cases of urethral obstruction were analyzed and confirmed as calcium carbonate. A fifth nonobstructive case was suspected in an adult female in which calcium carbonate crystalluria was diagnosed, and that case was resolved with medical management. Possible causes of these uroliths included reduced water intake, increased calcium in the diet through use of lucerne hay, and concurrent urinary tract infections. Changes to the diet and access to water were correlated with cessation of further cases, and no recurrence has been seen to date. To the authors' knowledge, this is the first report of calcium carbonate urolithiasis and the first use of a tube cystotomy in a nondomestic pig species. PMID- 28920799 TI - PRESUMPTIVE PIT VIPER ENVENOMATION IN PSITTACINES IN A BRAZILIAN ZOO. AB - Snake bites represent a serious public health risk in many regions of the globe, especially in tropical areas. Clinical signs and postmortem changes are well described in human and other mammalian species. However, detailed case reports about venomous snake attacks in avian species are limited. This report describes presumptive fatal envenomations in three psittacines caused by pit vipers in a Brazilian zoo. In one case, a Brazilian lancehead (Bothrops moojeni) was captured in the aviary. In all three cases the dermis around the suspected snake bite area exhibited hemorrhages and edema. Histologically, degeneration and necrosis of subcutaneous musculature were observed. Lung, heart, and kidneys displayed focal hemorrhages. The local changes are similar to those described for mammalian patients including humans. However, except for the parenchymatous hemorrhages, additional external and internal gross and histopathological lesions were missing. After ruling out other causes, such as aggression and dicoumarinic intoxication, the presumptive diagnosis of snake envenomation was made. The smaller size and variabilities of pathophysiological effects of the venom in parrots might explain the different lesion patterns observed, compared with mammals. Possibly, the birds may have reacted differently to envenomation by pit vipers and died before the venom could cause macroscopic and histological changes often observed in mammals. PMID- 28920800 TI - CUTANEOUS T-CELL LYMPHOMA WITH LYMPH NODE METASTASIS IN AN ADULT ADDAX (ADDAX NASOMACULATUS). AB - A 13-yr-old male addax (Addax nasomaculatus) presented with locally extensive alopecia, slight erythema, and skin thickening on the medial aspect of the left rear leg between the stifle and tarsus. Cutaneous T-cell lymphoma was diagnosed after histopathology and immunohistochemical staining of representative skin punch biopsies. No treatment was elected, and the addax was euthanized 3 yr later because of poor body condition, chronic dental disease, and confirmed spread of lymphoma to other cutaneous locations. Postmortem evaluation revealed spread to multiple lymph nodes but no further organ metastasis. Serologic testing on archived serum for bovine leukemia virus (BLV) revealed no evidence of exposure or infection. In cattle, cutaneous lymphoma is a sporadic form of lymphoma that is relatively rare, not typically associated with BLV infection, and occurs in young animals (<3 yr). This is the first report of cutaneous lymphoma in a nondomestic bovid. PMID- 28920801 TI - EVALUATION OF A COMMERCIAL COMPETITIVE ENZYME-LINKED IMMUNOSORBENT ASSAY FOR DETECTION OF AVIAN INFLUENZA VIRUS SUBTYPE H5 ANTIBODIES IN ZOO BIRDS. AB - The hemagglutination inhibition (HI) test is the current gold standard for detecting antibodies to avian influenza virus (AIV). Enzyme-linked immunosorbent assays (ELISAs) have been explored for use in poultry and certain wild bird species because of high efficiency and lower cost. This study compared a commercial ELISA for detection of AIV subtype H5 antibodies with HI test of 572 serum samples from zoo birds. There was no significant difference between the results of the two tests when statistically compared by a McNemar chi2 test (P = 0.86) and assessment of kappa (kappa = 0.87). With a specificity of 94.2% (95% confidence interval [CI], 0.92-0.97), a sensitivity of 93.9% (95% CI, 0.91-0.97), and an excellent correlation between the two tests, this ELISA can be recommended as an alternative to the HI test for preliminary screening of zoo bird sera for antibodies to AIV subtype H5. PMID- 28920802 TI - SUMMER AND WINTER VITAMIN D3 LEVELS IN SEVEN PLATYRRHINE SPECIES HOUSED AT A BRITISH ZOO, WITH REFERENCE TO NATURAL UVB LEVELS. AB - Serum samples were collected from 24 platyrrhines of seven diurnal species housed with outdoor access at Bristol Zoo Gardens (United Kingdom) to test 25 hydroxyvitamin D3 (25OHD3) levels as part of the veterinary department's preventative health care program. Samples were collected in August 2008 (summer) and January 2009 (winter) to examine the effect of season on 25OHD3 levels. Dietary levels of vitamin D3 remained the same throughout the study period and fell within the range of 2000-4000 IU/kg dry matter, in accordance with current primate guidelines. Statistical analysis showed that there was no significant difference between the platyrrhines' summer 25OHD3 values (range, <4.0->150.0 MUg/L) and winter 25OHD3 values (range, <4.0-80.1 MUg/L). However, ultraviolet B (UVB) measurements taken at the zoo during the study period confirmed that UVB levels were significantly higher in summer (mean reading for 1200-1300 hours GMT time period, 153.8 MUW/cm2) compared with winter (mean reading for 1200-1300 hours GMT time period, 19.4 MUW/cm2). The 25OHD3 levels measured were generally found to be low compared with previously published values from healthy captive and wild platyrrhines. PMID- 28920803 TI - ASSESSMENT OF A LANCET-AND-SWAB BLOOD SAMPLING TECHNIQUE FOR SURVEILLANCE OF ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS INFECTION. AB - Lancing a finger elicits minimal pain in humans and is applied routinely to obtain small volumes of blood for clinical diagnostics. A modified lancet bleeding method and several blood sampling matrices were evaluated in this study for the purpose of routine elephant endotheliotropic herpesvirus (EEHV) surveillance in Asian elephants (Elephas maximus). The procedure enabled weekly sampling from elephants as young as 9 mo of age. The blood sampling matrices were evaluated for their sensitivity measuring beta-actin, tumor necrosis factor alpha, and/or EEHV-1 by quantitative polymerase chain reaction assays. Foam and flocked swabs produced significantly (P < 0.05) lower quantitation cycles, ie, increased analytical sensitivity, than filter papers, Whatman(r) FTA cards, or conventional cotton-tipped swabs. The two swab types also demonstrated comparable analytical sensitivity to that of a similar volume of EDTA whole blood for the detection of EEHV-1 DNA. This lancet-and-swab technique proved satisfactory for the detection of EEHV-1 viremia in two Asian elephant calves, and in one instance viremia could be detected 5 days prior to the development of clinical signs. Low blood yield from the lancet application may reduce sensitivity and compromise early detection of viremia. Therefore, standard venipuncture remains the recommended blood sampling method, and training for consistent and regular vein access should continue to be the priority for collections holding elephants. However, if appropriate measures are taken to collect an optimum blood volume, this lancet-and-swab technique offers a suitable alternative for EEHV surveillance in situations where venipuncture may not be practical. PMID- 28920804 TI - TRICHINELLA INFECTIONS IN RED FOXES (VULPES VULPES) AND GOLDEN JACKALS (CANIS AUREUS) IN SIX DISTRICTS OF SERBIA. AB - Wild animals, including red foxes (Vulpes vulpes) and golden jackals (Canis aureus), are the most important reservoirs of Trichinella spp. Although the red fox is considered one of the main reservoirs of Trichinella spp. in Europe, only a few animals have been examined in Serbia. The present study assessed Trichinella spp. infection in red foxes and golden jackals from the six districts in Serbia. Thirty-seven carcasses of red foxes and 13 carcasses of golden jackals shot during the official hunting season were examined. Larvae of Trichinella spp. were detected in 13 (35%) of 37 red foxes and in 8 (61%) of 13 golden jackals. Trichinella spiralis and Trichinella britovi were the only two species identified after a multiplex polymerase chain reaction analysis. Trichinella britovi infection was detected in 85% of red foxes and in 38% of golden jackals, and T. spiralis was detected in 15% of red foxes and in 63% of golden jackals. The findings emphasize the need for an active surveillance program for Trichinella spp. infection in wildlife in Serbia and the whole of the Balkans, with special attention on the red fox because it is widespread and occurs in high densities. PMID- 28920805 TI - PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE). AB - To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 MUg/ml for the lower dosage, and at 0.83 hr at 8.77 MUg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species. PMID- 28920806 TI - ACCURACY OF NONINVASIVE ANESTHETIC MONITORING IN THE ANESTHETIZED GIRAFFE (GIRAFFA CAMELOPARDALIS). AB - This study evaluated the accuracy of pulse oximetry, capnography, and oscillometric blood pressure during general anesthesia in giraffes (Giraffa camelopardalis). Thirty-two giraffes anesthetized for physiologic experiments were instrumented with a pulse oximeter transmittance probe positioned on the tongue and a capnograph sampling line placed at the oral end of the endotracheal tube. A human size 10 blood pressure cuff was placed around the base of the tail, and an indwelling arterial catheter in the auricular artery continuously measured blood pressure. Giraffes were intermittently ventilated using a Hudson demand valve throughout the procedures. Arterial blood for blood gas analysis was collected at multiple time points. Relationships between oxygen saturation as determined by pulse oximetry and arterial oxygen saturation, between arterial carbon dioxide partial pressure and end-tidal carbon dioxide, and between oscillometric pressure and invasive arterial blood pressure were assessed, and the accuracy of pulse oximetry, capnography, and oscillometric blood pressure monitoring evaluated using Bland-Altman analysis. All three noninvasive methods provided relatively poor estimates of the reference values. Receiver operating characteristic curve fitting was used to determine cut-off values for hypoxia, hypocapnia, hypercapnia, and hypotension for dichotomous decision-making. Applying these cut-off values, there was reasonable sensitivity for detection of hypocapnia, hypercapnia, and hypotension, but not for hypoxemia. Noninvasive anesthetic monitoring should be interpreted with caution in giraffes and, ideally, invasive monitoring should be employed. PMID- 28920807 TI - USE OF ORAL FLUOXETINE FOR THE TREATMENT OF ABNORMAL AGGRESSION IN TWO RED-NECKED WALLABIES (MACROPUS RUFOGRISEUS). AB - : Abnormal inter- and intraspecies aggression, perceived to be anxiety related, was identified in two male red-necked wallabies (Macropus rufogriseus) housed within a zoo. Aggressive episodes were directed at conspecifics, other exhibit animals, and, in one case, human caretakers. The clinical use of oral fluoxetine (0.5 mg/kg po bid) for a period of approximately 4 mo was effective in eliminating aggression towards humans and other animals in these two individuals. There was no evidence of recrudescence of aggression in either case following discontinuation of therapy for up to 3 yr posttreatment. Other than a period of mild transient sedation in one animal, side effects were not noted with fluoxetine treatment in these cases. Additional studies on the pharmacokinetics and side effects of fluoxetine treatment for anxiety behaviors are warranted in wallabies. PMID- 28920808 TI - CHARACTERIZING THE 25-HYDROXYVITAMIN D STATUS OF TWO POPULATIONS OF FREE-RANGING EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA). AB - Ultraviolet B radiation is recommended for captive reptiles to stimulate production of adequate levels of vitamin D; however, little is known regarding the vitamin D status in many free-ranging populations. Current reference ranges for vitamin D in eastern box turtles have not yet been established. Sixty free ranging eastern box turtles (Terrapene carolina carolina) from two well-studied populations in Illinois (n = 24) and Tennessee (n = 36) were assayed for plasma vitamin D concentration in 2014. There were no significant differences in concentrations between individuals in Illinois (mean: 117.5 nM/L) and Tennessee (mean: 98.7 nM/L) (P = 0.129) populations. Similarly, there were no differences in concentrations based on age class (P = 0.533) or sex (P = 0.532). There was a significant correlation between UV at the time of capture and vitamin D concentrations (R = 0.301, P = 0.030). Vitamin D was not correlated with total calcium (R = 0.018, P = 0.89) or Ca : P ratio (R = 0.025, P = 0.85). Diseases in captive individuals, including secondary nutritional hyperparathyroidism, may commonly be associated with vitamin D deficiencies, and clinical intervention relies on reference data. Vitamin D supplementation may be recommended if animals are deemed to be deficient. Data obtained can be used to improve the care of captive and free-ranging turtles by providing reference ranges, as well as better characterize the health of wild populations. PMID- 28920809 TI - EVALUATION OF BONE MINERALIZATION BY COMPUTED TOMOGRAPHY IN WILD AND CAPTIVE EUROPEAN COMMON SPADEFOOTS (PELOBATES FUSCUS), IN RELATION TO EXPOSURE TO ULTRAVIOLET B RADIATION AND DIETARY SUPPLEMENTS. AB - Captive rearing programs have been initiated to save the European common spadefoot (Pelobates fuscus), a toad species in the family of Pelobatidae, from extinction in The Netherlands. Evaluating whether this species needs ultraviolet B (UVB) radiation and/or dietary supplementation for healthy bone development is crucial for its captive management and related conservation efforts. The bone mineralization in the femurs and the thickest part of the parietal bone of the skulls of European common spadefoots (n = 51) was measured in Hounsfield units (HUs) by computed tomography. One group, containing adults (n = 8) and juveniles (n = 13), was reared at ARTIS Amsterdam Royal Zoo without UVB exposure. During their terrestrial lifetime, these specimens received a vitamin-mineral supplement. Another group, containing adults (n = 8) and juveniles (n = 10), was reared and kept in an outdoor breeding facility in Munster, Germany, with permanent access to natural UVB light, without vitamin-mineral supplementation. The HUs in the ARTIS and Munster specimens were compared with those in wild specimens (n = 12). No significant difference was found between the HUs in the femurs of both ARTIS and Munster adults and wild adults (P = 0.537; P = 0.181). The HUs in the skulls of both captive-adult groups were significantly higher than in the skulls of wild specimens (P = 0.020; P = 0.005). The HUs in the femurs of the adult ARTIS animals were significantly higher than the HUs in the femurs of the adult Munster animals (P = 0.007). The absence of UVB radiation did not seem to have a negative effect on the bone development in the terrestrial stage. This suggests that this nocturnal, subterrestrial amphibian was able to extract sufficient vitamin D3 from its diet and did not rely heavily on photobiosynthesis through UVB exposure. PMID- 28920810 TI - NEWLY DESCRIBED TOXOPLASMA GONDII STRAIN CAUSES HIGH MORTALITY IN RED NECKED WALLABIES (MACROPUS RUFOGRISEUS) IN A ZOO. AB - This manuscript describes an outbreak of fatal toxoplasmosis in wallabies. Ten adult red necked wallabies (Macropus rufogriseus) were imported from New Zealand to the Virginia Zoo. Agglutination testing upon admission into quarantine showed all animals to be negative for antibodies to Toxoplasma gondii. Nine of these wallabies died from acute toxoplasmosis within 59-565 (average 224) days after being moved onto exhibit. Clinical signs included lethargy, diarrhea, tachypnea, and ataxia that progressed rapidly; death without premonitory signs occurred in one case. Histopathologic examination revealed interstitial pneumonia, encephalomyelitis, myositis, enteritis, and myocarditis. The diagnosis was confirmed through serologic, histopathologic, and polymerase chain reaction (PCR) testing. Multilocus PCR-RFLP (restriction fragment length polymorphism) genotyping revealed that the first six animals were infected by a previously undiscovered Toxoplasma gondii genotype, designated as ToxoDB PCR-RFLP genotype No. 263. These six cases survived for an average of 118 days on exhibit before succumbing to toxoplasmosis. The other three wallabies were infected with a Toxoplasma gondii strain of ToxoDB PCR-RFLP genotype No. 4, which is a common strain type circulating in wild animals in North America. These three cases survived for an average of 435 days on exhibit before succumbing to toxoplasmosis. The outbreaks of toxoplasmosis in these wallabies are likely from two different sources. Furthermore, the results highlight Toxoplasma gondii PCR RFLP genotyping in parasite diagnosis and understanding parasite transmission and potential mitigation procedures. PMID- 28920811 TI - SALT BATH AS A TREATMENT FOR IDIOPATHIC DERMATITIS IN CAPTIVE NILE HIPPOPOTAMUS (HIPPOPOTAMUS AMPHIBIUS). AB - Ulcerative skin lesions were observed in two captive adult female hippos (Hippopotamus amphibius) from a zoological collection. Lesions appeared as cracking, peeling, or vesicles of the skin affecting the lateral and ventral aspects of the neck, limbs, thorax, and abdomen, dorsum, toes, and perineal region. Some lesions drained blood, serum, or purulent material. Histologic evaluation of sloughed skin consisted of deep dermal collagen with bacterial cellulitis and vasculitis and superficial fungal colonization. No viral pathogens were isolated and no fungal or bacterial pathogen predominated. Minimal response to systemic antibiotics and topical treatment was observed. Commercial cattle food-grade salt was added to the exhibit pool at 2-3 g/L with complete healing of all skin lesions within a 4-mo treatment period. No complications were observed. Patient compliance with salt bath therapy was higher and results more effective compared to topical and oral treatments. PMID- 28920812 TI - OPHTHALMIC EXAMINATION IN COMMON KESTRELS (FALCO TINNUCULUS) FROM SOUTH KOREA. AB - The purpose of this study was to establish reference ophthalmic findings in the common kestrel (Falco tinnunculus). Twenty healthy adult kestrels were included in this study. Ophthalmic examinations included slit lamp biomicroscopy, fundus exam, Schirmer tear test, conjunctival bacterial culture and isolation, corneal touch threshold, tonometry, and corneal diameter measurement. Mean tear production was 7.4 +/- 3.27 mm/min, and mean intraocular pressure measured via applanation tonometry was 10.5 +/- 3.15 mm Hg. In addition, the mean corneal touch threshold was 29.8 +/- 20.1 mm, and the mean corneal diameter was 9.8 +/- 1.1 mm. Of the 25 conjunctival swabs, 23 (92%) yielded bacterial growth. Most of these bacteria were gram positive (69.6%); the most predominant genus was Staphylococcus. This study presents reference values for ophthalmic examinations in common kestrels. PMID- 28920813 TI - MYCOBACTERIOSIS IN CAPTIVE PSITTACINES: A BRIEF REVIEW AND CASE SERIES IN COMMON COMPANION SPECIES (ECLECTUS RORATUS, AMAZONA ORATRIX, AND PIONITES MELANOCEPHALA). AB - In 2015, three psittacines were presented within 30 days, each with differing clinical signs and patient histories. A 13-yr-old male eclectus parrot (Eclectus roratus) was presented for weakness, depression, and acute anorexia. On presentation it was determined to have a heart murmur, severely elevated white blood cell count (93.9 103/MUl) with a left shift (2.8 103/MUl bands), and anemia (30%). Severe hepatomegaly was noted on radiographs, ultrasonography, and computed tomography. A cytological sample of the liver obtained through a fine needle aspirate revealed intracellular acid-fast bacilli identified as Mycobacterium avium. A 20-yr-old female double yellow-headed Amazon parrot (Amazona oratrix) was presented for a 1-mo history of lethargy and weight loss despite a good appetite. The parrot's total white blood cell count was 16.8 103/MUl and the PCV was 35%. Following its death, a necropsy revealed a generalized granulomatous condition that involved the small intestines, lungs, liver, spleen, and medullary cavities of the long bones, with intracellular acid fast bacilli identified as Mycobacterium genavense. The third case, an 18-mo-old female black-headed caique (Pionites melanocephala), was presented with a 1-day history of lethargy and depression. On presentation, the caique had a heart murmur, distended coelom, palpable thickening of the coelomic organs, and increased lung sounds. Following the caique's death, a complete necropsy revealed mycobacteriosis of the liver, spleen, small intestines, pericardial fat, and bone marrow. The infection was identified as Mycobacterium genavense. The importance of advances in Mycobacterium spp. identification, continued presence of this organism in captive avian populations, difficulty in obtaining a definitive antemortem diagnosis, and conflicting recommendations regarding treatment are thought-provoking areas of focus in this case series. PMID- 28920814 TI - ACUTE-PHASE RESPONSES IN HEALTHY, MALNOURISHED, AND OTOSTRONGYLUS-INFECTED JUVENILE NORTHERN ELEPHANT SEALS (MIROUNGA ANGUSTIROSTRIS). AB - Acute-phase proteins (APPs) are utilized to detect early inflammation in many domestic and nondomestic species, but variability exists between species and inflammatory diseases as to which APPs are most useful. Stranded juvenile northern elephant seals (NESs; Mirounga angustirostris) undergoing rehabilitation at the Marine Mammal Center experience high mortality rates due to severe arteritis caused by the lungworm, Otostrongylus circumlitis (OC), and there are currently no effective antemortem diagnostic tools for this disease. To characterize patterns of the acute-phase response in the NES, two APPs-serum amyloid A (SAA) and C-reactive protein (CRP)-were measured, and serum protein electrophoresis was performed to measure albumin and globulin fractions in 81 serum samples from 58 NESs in four different health states: healthy, malnourished, preclinical for OC infection, or clinical for OC infection. Compared to healthy NESs (median, 11.2 mg/L), SAA concentrations were significantly increased in malnourished (33.9 mg/L), preclinical (247 mg/L), and clinical OC-infected NESs (328 mg/L) (P < 0.05). CRP concentrations were increased only in clinical OC-infected NESs (median, 53.9 mg/L) and were below detectable limits in the other three groups (<0.01 mg/L). These results show that SAA and CRP are positive APPs in NESs with OC infection, and that SAA may serve as the major APP for this species. Albumin : globulin ratios were significantly increased in malnourished NESs (median, 1.26) and decreased in clinical OC infected NESs (0.53). As a result, albumin is a negative APP in the NES, similar to other mammalian species. APP monitoring can be helpful in detecting and monitoring inflammation in rehabilitating juvenile NESs. PMID- 28920815 TI - PRELIMINARY CHARACTERIZATION OF DILATED CARDIOMYOPATHY IN A CAPTIVE POPULATION OF BANDED MONGOOSES (MUNGOS MUNGO). AB - Between 2006 and 2015, a high incidence of dilated cardiomyopathy (DCM) was diagnosed in a captive population of banded mongooses (Mungos mungo) at Chester Zoo, United Kingdom. The aim of this study was to characterize DCM in these mongooses in order to raise awareness of this condition and help inform management and clinical decisions. Prospective clinical assessments, including echocardiography, radiography, and cardiac biomarkers, were carried out in four mongooses remaining in the collection. Radiographs from 15 mature mongooses were reviewed and cardiac size and metrics assessed. Ten postmortem reports and the histologic sections from nine of these cases were reviewed for cardiac lesions. Echocardiographic findings were consistent with a diagnosis of preclinical DCM in one out of the four cases assessed, and it was considered equivocal in a second case. Taurine levels were within normal limits for domestic carnivores. Radiographs in seven mongooses showed right-sided or generalized cardiomegaly. The width of the heart in intercostal spaces and vertebral-tracheal angle on the lateral view were the most-discriminatory radiographic variables for diagnosis of cardiac disease. At necropsy, there was gross pathological evidence consistent with DCM in seven out of 10 mongooses examined. Histopathologically, mild multifocal fibrosis and rare intermyofiber edema were observed. This study provides preliminary evidence that DCM occurs in captive banded mongoose, but etiology and wider prevalence need to be determined. PMID- 28920816 TI - UROLITHIASIS IN FREE-RANGING AND CAPTIVE OTTERS (LUTRA LUTRA AND AONYX CINEREA) IN EUROPE. AB - Between 1996 and 1998, 477 dead otters from different Central European countries were examined for urolithiasis, including 449 free-ranging Eurasian otters (Lutra lutra) as well as 17 Eurasian otters and 11 Asian small-clawed otters (Aonyx cinerea) from captivity. In the free-ranging specimens, uroliths (sand or stones) were found in 105 animals (23.4%), with no significant difference (P = 0.77) between the sexes. Uroliths were not present in any juveniles (n = 26) and urolithiasis was not considered the main cause of death in any individual. In captive specimens, uroliths were found in 11 out of 17 Eurasian otters (64.7%; four males and seven females), and in 3 out of 11 Asian small-clawed otters (27.3%). Histology could not find any signs of inflammation in examined kidneys (n = 179) or urinary bladders (n = 66). Analyzed stones of free-ranging and captive Eurasian otters were composed mainly of ammonium acid urate. The stones of three captive Asian small-clawed otters consisted mainly of calcium oxalate. The difference in prevalence of uroliths between free-ranging and captive Eurasian otters was significant (P < 0.001). Nevertheless, the prevalence in free ranging specimens of this study is higher than reported before. Differences between various habitats, environmental changes, and genetic predisposition all represent potential hypothetical explanations for these findings. PMID- 28920817 TI - INTESTINAL HISTOPLASMOSIS IN A CAPTIVE REINDEER (RANGIFER TARANDUS), MISSOURI, USA. AB - An infection with Histoplasma capsulatum was diagnosed in a farmed reindeer in Missouri, an endemic area for histoplasmosis, localized in the intestine. The intrahistiocytic organisms were identified in tissue sections using histologic methods and confirmed by immunohistochemistry. This is the first report of histoplasmosis in a reindeer or in any deer species. PMID- 28920818 TI - BIOCHEMISTRY PANEL REFERENCE INTERVALS FOR JUVENILE GOLDFISH (CARASSIUS AURATUS). AB - Reference intervals for diagnostic tests are vitally important for clinical decision making. Despite the popularity of pet goldfish (Carassius auratus), reference intervals have not been generated for routine biochemistry panel analytes in this species. This study establishes de novo reference intervals for packed cell volume and total solids, using 47 apparently healthy immature goldfish, and for 11 common chemistry panel analytes (albumin, aspartate aminotransferase, calcium, creatine kinase, globulin, blood glucose, sodium, potassium, phosphorous, total protein, and uric acid) using 39 immature goldfish. Robust reference intervals were generated following recommendations of the American Society for Veterinary Clinical Pathology. Linear regression was used to demonstrate a statistically significant relationship between body weight and calcium, albumin, total protein, potassium, packed cell volume, and total solids. The results of this study serve as a useful baseline for future reference interval generation in goldfish. PMID- 28920819 TI - DISSEMINATED TOXOPLASMOSIS IN A CAPTIVE ADULT DROMEDARY CAMEL (CAMELUS DROMEDARIUS). AB - An 11-yr-old dromedary camel (Camelus dromedarius) at a zoo in south Florida presented with diarrhea while being treated with enrofloxacin and dexamethasone for a chronic skin condition. Three weeks after initiation of therapy with dexamethasone, the camel developed diarrhea, which worsened despite treatment with antibiotics. The animal became increasingly debilitated, developed hemorrhagic diarrhea, declined rapidly over the next 3 days, and died despite aggressive fluid therapy and supportive care. Histologic examination revealed intralesional protozoal tissue cysts consistent with Toxoplasma gondii in the intestines, lungs, and liver, as well as lymphoid depletion of the spleen suggesting immunosuppression. To the author's knowledge this is the first reported case of disseminated toxoplasmosis that clinically manifested as hemorrhagic enterocolitis in a camel. PMID- 28920820 TI - MORBIDITY AND MORTALITY OF WILD TURTLES AT A NORTH CAROLINA WILDLIFE CLINIC: A 10 YEAR RETROSPECTIVE. AB - The medical records from 1,847 wild turtle patients seen between 2005 and 2014 by the Turtle Rescue Team at the North Carolina State University College of Veterinary Medicine were analyzed. Eastern box turtles (Terrapene carolina carolina; n = 947), yellow-bellied sliders (Trachemys scripta scripta; n = 301), cooters ( Pseudemys spp.; n = 235), common snapping turtles (Chelydra serpentina; n = 165), and eastern painted turtles (Chrysemys picta; n = 93) made up 94.3% of all patients. Patient admissions peaked in May when 25.6% (473/1,847) of all turtles were admitted. Cooters were the most-likely species to be gravid, and the loss of gravid females may put this population at increased risk for decline. The majority of wild turtles presented for anthropogenic causes, primarily vehicular trauma (63.2%; 1,168/1,847), which also had the greatest mortality at 57.8% (675/1,168) of any presenting complaint. Coelomic breach was the presenting injury with greatest risk of dying, increasing the risk of dying by 4.8 times. Other factors that were associated with increased mortality included head injuries, myiasis, and cranial or caudal midline injuries. Of all turtle species, eastern box turtles most commonly presented for nontraumatic conditions including aural abscesses (8.2%; 78/947), upper respiratory infections (6.3%; 60/947), and both conditions concurrently (2.5%; 14/947). While many turtles presented with little to no chance for survival in the wild, 47.6% were eventually released and that number increased to 62.0% released for those that survived 24 hr or longer after presentation. This study adds to the knowledge about the treatment of injured and diseased wild turtles in order to potentially ameliorate the overall impact of humans, especially as a result of vehicular trauma. PMID- 28920821 TI - SERUM FERRITIN CONCENTRATION IS NOT A RELIABLE BIOMARKER OF IRON OVERLOAD DISORDER PROGRESSION OR HEMOCHROMATOSIS IN THE SUMATRAN RHINOCEROS (DICERORHINUS SUMATRENSIS). AB - The aim of this study was to determine if ferritin is a reliable biomarker of iron overload disorder (IOD) progression and hemochromatosis in the Sumatran rhinoceros (Dicerorhinus sumatrensis) by developing a species-specific ferritin assay and testing historically banked samples collected from rhinos that did and did not die of hemochromatosis. Ferritin extracted from Sumatran rhino liver tissue was used to generate antibodies for the Enzyme Immunoassay. Historically banked Sumatran rhino serum samples (n = 298) obtained from six rhinos in US zoos (n = 290); five rhinos at the Sumatran Rhino Conservation Centre in Sungai Dusun, Malaysia (n = 5); and two rhinos in Sabah, Malaysia (n = 3) were analyzed for ferritin concentrations. Across all US zoo samples, serum ferritin concentrations ranged from 348 to 7,071 ng/ml, with individual means ranging from 1,267 (n = 25) to 2,604 ng/ml (n = 36). The ferritin profiles were dynamic, and all rhinos exhibited spikes in ferritin above baseline during the sampling period. The rhino with the highest mean ferritin concentration did not die of hemochromatosis and exhibited only mild hemosiderosis postmortem. A reproductive female exhibited decreases and increases in serum ferritin concurrent with pregnant and nonpregnant states, respectively. Mean (+/-SD) serum ferritin concentration for Sumatran rhinos in Malaysia was high (4,904 +/- 4,828 ng/ml) compared to that for US zoo rhinos (1,835 +/- 495 ng/ml). However, those in Sabah had lower ferritin concentrations (1,025 +/- 52.7 ng/ml) compared to those in Sungai Dusun (6,456 +/ 4,941 ng/ml). In conclusion, Sumatran rhino serum ferritin concentrations are dynamic, and increases often are not associated with illness or hemochromatosis. Neither a specific pattern nor the individual's overall mean ferritin concentration can be used to accurately assess IOD progression or diagnose hemochromatosis in this rhino species. PMID- 28920822 TI - A RETROSPECTIVE COMPARISON OF CHEMICAL IMMOBILIZATION WITH THIAFENTANIL, THIAFENTANIL-AZAPERONE, OR ETORPHINE-ACEPROMAZINE IN CAPTIVE PERSIAN FALLOW DEER (DAMA DAMA MESOPOTAMICA). AB - Records of 56 Persian fallow deer (Dama dama mesopotamica) immobilized for translocation were reviewed. Twenty-three were administered 0.05 +/- 0.01 (mean +/- SD) mg/kg thiafentanil (THIA), 20 were administered 0.045 +/- 0.008 mg/kg thiafentanil combined with 0.19 +/- 0.03 mg/kg azaperone (THIA-AZP), and 13 were administered 0.032 +/- 0.04 mg/kg etorphine-acepromazine (ETOR-ACP) by intramuscular remote injection. Parameters recorded and compared between groups included induction and recovery times, heart rate, respiratory rate, rectal temperature, oxygen saturation, blood pressure, reflexes, quality of immobilization, and blood concentrations of lactate and glucose. Naltrexone (THIA groups) or diprenorphine (ETOR-ACP) were administered for reversal. Mean induction time was significantly shorter in the THIA group versus the ETOR-ACP group (2.0 +/- 1.3 and 4.8 +/- 2.8 min, respectively), but not significantly shorter than the THIA-AZP group (2.8 +/- 3.1 min). Respiratory rate was significantly higher in the THIA group in comparison to the two other groups. None of the protocols provided excellent immobilization quality, which was significantly poorer in the THIA group. Following antagonist administration, all deer from the THIA and ETOR-ACP groups recovered quickly, while there were five perianesthetic morbidity and mortality cases in the THIA-AZP group. Mean recovery time was significantly shorter in the THIA group versus the THIA-AZP and ETOR-ACP groups (0.5 +/- 0.3, 1.1 +/- 0.8, and 2.3 +/- 1.1 min, respectively). In conclusion, the use of THIA provided faster induction and recovery, with less respiratory depression, but poorer immobilization. The THIA-AZP combination should be used with caution in Persian fallow deer until further investigation. PMID- 28920823 TI - DIAGNOSIS AND TREATMENT OF A UNILATERAL RENAL CYSTADENOMA IN AN AFRICAN LION (PANTHERA LEO). AB - A renal tubular cystadenoma was diagnosed in a 14-yr-old male African lion (Panthera leo). During a routine health evaluation, a left renal mass was identified via physical examination, radiographs, and abdominal ultrasonography. The mass was 30 * 15 cm in size and had a thin capsule with central hypoechoic fluid, suggestive of a perirenal cyst. An exploratory celiotomy with partial nephrectomy was performed without complications. Histologically, the tumor was characterized by a thick fibrous capsule surrounding multiple, variable-sized cysts that markedly compressed the adjacent fibrotic and atrophied renal cortex. Immunohistochemical labeling for Aquaporin-1 and Tamm-Horsfall protein was consistent with a renal tubular cystadenoma of proximal tubule origin. Renal cystadenomas are an uncommon benign epithelial neoplasm. There are only two documented case reports in domestic cats. This report represents the first documentation, to the authors' knowledge, of a renal cystadenoma in a lion. PMID- 28920824 TI - BASELINE HEALTH AND NUTRITION EVALUATION OF TWO SYMPATRIC NOCTURNAL LEMUR SPECIES (AVAHI LANIGER AND LEPILEMUR MUSTELINUS) RESIDING NEAR AN ACTIVE MINE SITE AT AMBATOVY, MADAGASCAR. AB - Extractive industries can have significant impacts on ecosystems through loss of habitat, degradation of water quality, and direct impact on floral and faunal biodiversity. When operations are located in sensitive regions with high biodiversity containing endangered or threatened species, it is possible to minimize impact on the environment by developing programs to scientifically monitor the impact on resident flora and fauna species in the early phases of operation so that effects can be mitigated whenever possible. This report presents the baseline health, nutrition, and trace mineral evaluation for 33 Avahi laniger (Eastern wooly lemur) and 15 Lepilemur mustelinus (greater sportive lemur) captured and given complete health evaluations that included the measurement of fat-soluble vitamins and trace minerals in addition to routine complete blood counts, serum chemistries, and parasite evaluations. All lemurs appeared healthy on physical examination despite the presence of minor wounds consistent with interspecies aggression in some individuals. Serum chemistry values were within expected ranges for other lemur species; however, A. laniger erythrocytes were significantly smaller than those of L. mustelinus. Serum nickel values were markedly higher than expected in both species, and selenium, copper, and cobalt levels were higher in L. mustelinus compared with A. laniger at the study site, as well as values for I. indri or P. diadema reported from other locations. Endoparasites and ectoparasites were typical of those reported in other wild lemur species, but load and diversity varied between A. laniger and L. mustelinus despite inhabiting the same forest ecosystem. This baseline assessment provides the foundation for ongoing monitoring. PMID- 28920825 TI - CJEM Debate Series: #Burnout - Burnout is inevitable in clinical emergency medicine practice. PMID- 28920826 TI - Hydrogenophaga soli sp. nov., isolated from rice field soil. AB - A novel Gram-stain-negative bacterial strain, designated strain S10T, was isolated from soil collected in a rice field in Goyang, South Korea. Cells of strain S10T were strictly aerobic, motile and rod-shaped. Colonies were round, convex, smooth and white. The strain grew optimally at 37 degrees C, pH 7.0 and 0 % (w/v) NaCl. Phylogenetic analysis of the 16S rRNA gene sequence of strain S10T revealed that the bacterium belongs to the family Comamonadaceae and is related to members of the genus Hydrogenophaga, with Hydrogenophaga caeni EMB71T being its closest relative (97.9 % sequence similarity). The DNA G+C content of strain S10T was 68.2 mol%. Strain S10T contained phosphatidylethanolamine and diphosphatidylglycerol as the major polar lipids. The major fatty acids were C16 : 0 and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The predominant respiratory quinone was ubiquinone Q-8. DNA-DNA hybridization values of strain S10T with Hydrogenophaga caeni KCTC 12613T, Hydrogenophaga atypica DSM 15342T and Hydrogenophaga defluvii DSM 15341T were 16.1+/-4.8, 49.0+/-3.2 and 21.9+/-8.8 %, respectively. Based on phylogenetic distinctiveness, DNA-DNA hybridization and specific physiological and biochemical characteristics, strain S10T (=KCTC 52520T=JCM 31711T) is classified as a novel species of the genus Hydrogenophaga, for which the name Hydrogenophagasoli sp. nov. is proposed. PMID- 28920827 TI - Marmoricola endophyticus sp. nov., an endophytic actinobacterium isolated from Thespesia populnea. AB - A novel endophytic actinobacterium, designated strain 8BXZ-J1T, was isolated from surface-sterilized branches of Thespesia populnea collected from Beilun Estuary Mangrove Forest National Nature Reserve in Guangxi, China, and examined by a polyphasic approach to determine its taxonomic position. Cells of the isolate were Gram-stain-positive, aerobic, non-spore-forming, non-motile and short rod shaped. Phylogenetic analysis based on 16S rRNA gene sequences suggested that strain 8BXZ-J1T belonged to the genus Marmoricola, sharing highest similarity with Marmoricola solisilvae DSM 27140T (96.9 %). The isolate grew at 10-35 degrees C (optimum, 28-30 degrees C), at pH 6.0-8.0 (optimum, pH 7.0) and in the presence of 0-10 % (w/v) NaCl (optimum, 0-5.0 %). The organism contained ll-2,6 diaminopimelic acid as the diagnostic diamino acid of the peptidoglycan, MK-8(H4) as the major menaquinone, and a polar lipid profile including diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and two unknown lipids. The major fatty acids of strain 8BXZ J1T were C18 : 0 10-methyl, iso-C16 : 0 and C16 : 0. The G+C content of the genomic DNA was 68.7 mol%. These data demonstrate that strain 8BXZ-J1T is representative of a novel species of the genus Marmoricola, for which the name Marmoricola endophyticus sp. nov. is proposed. The type strain is 8BXZ-J1T (=KCTC 39789T=CGMCC 1.16067T). PMID- 28920828 TI - Paenibacillus arcticus sp. nov., isolated from Arctic soil. AB - A Gram-positive, endospore-forming, strictly aerobic and rod-shaped bacterium, designated strain MME2_R6T, was isolated from Arctic soil, and it was identified by using a polyphasic taxonomic approach. This strain was psychrotolerant, growing at 4-24 degrees C. 16S rRNA gene sequence analysis showed that strain MME2_R6T was closest to Paenibacillus swuensis DY6T, with 93.9 % similarity. However, in phylogenetic analysis based on the 16S rRNA gene sequence, strain MME2_R6T showed that it clustered with Paenibacillus contaminans CKOBP-6T and the sequencing similarity between the two species was 93.7 %. Its major cellular fatty acid was anteiso-C15 : 0, like other Paenibacillus species. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The predominant isoprenoid quinone was menaquinone-7. The diagnostic diamino acid in the cell wall was meso-diaminopimelic acid. The genomic DNA G+C content was 44.2 mol%. Based on the results of phenotypic, chemotaxonomic and phylogenetic analyses, a novel species, Paenibacillus arcticus sp. nov., is proposed. The type strain is MME2_R6T (=JCM 30981T=PAMC 28731T). PMID- 28920829 TI - Allobranchiibius huperziae gen. nov., sp. nov., a member of Dermacoccaceae isolated from the root of a medicinal plant Huperzia serrata (Thunb.). AB - A Gram-stain-positive, non-spore-forming actinobacterial strain, designated CPCC 204077T, was isolated from the surface-sterilized root of a medicinal plant Huperzia serrata (Thunb.) collected from Sichuan Province, south-west China. The peptidoglycan type of strain CPCC 204077T was detected as A4alpha with an l-Lys-l Ser-d-Asp interpeptide bridge. Galactose, glucose, rhamnose and ribose were the sugar compositions in the whole-cell hydrolysates. MK-8(H4) was the only menaquinone. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, one unidentified phospholipid and one unidentified glycolipid. The major fatty acid was iso-C16 : 0. The genomic DNA G+C content was 71.0 mol%. The phylogenetic tree based on 16S rRNA gene sequences showed that strain CPCC 204077T stood for a distinct lineage within the family Dermacoccaceaealongside the genera Branchiibius, Demetria and Barrientosiimonas, with the highest 16S rRNA gene sequence similarities to Branchiibius hedensis Mer 29717T (95.0 %), Calidifontibacter indicus PC IW02T (95.0 %), Barrientosiimonas humi 39T (94.9 %) and Demetria terragena HKI 0089T (94.7 %), and less than 94.7 % sequence similarities to all other species. Signature nucleotides in the 16S rRNA sequence showed that the strain contained the Dermacoccaceaefamily-specific 16S rRNA signature nucleotides and a genus-specific diagnostic nucleotide signature pattern. Combining the genotypic and phenotypic analyses, we propose that strain CPCC 204077T represents a novel species of a new genus in the family Dermacoccaceae with the name Allobranchiibius huperziae gen. nov., sp. nov. Strain CPCC 204077T (=NBRC 110719T=DSM 29531T) is the type strain of the type species. PMID- 28920831 TI - Algoriphagus marisflavi sp. nov., isolated from water of an estuary environment. AB - A Gram-stain-negative, non-motile, aerobic and rod-shaped or ovoid bacterial strain, designated KEM-106T, was isolated from water of an estuary environment on the Yellow Sea, South Korea, and subjected to a polyphasic taxonomic study. Strain KEM-106T grew optimally at 30 degrees C and pH 7.0-8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences revealed that strain KEM-106T belonged to the genus Algoriphagus, clustering with the type strains of Algoriphagus litorisediminis and Algoriphagus aquaemixtae. Strain KEM-106T exhibited 16S rRNA gene sequence similarities of 96.5, 96.2 and 96.0 % to the type strains of Algoriphagus boritolerans, A. litorisediminis and A. aquaemixtae, respectively, and of 92.5-95.8 % to the type strains of the other Algoriphagus species. Strain KEM-106T contained MK-7 as the predominant menaquinone and iso-C15 : 0 and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) as the major fatty acids. The major polar lipids were phosphatidylethanolamine and phosphatidylcholine. The DNA G+C content of strain KEM-106T was 42.7 mol%. Differential phenotypic properties, together with its phylogenetic distinctiveness, revealed that strain KEM-106T is separated from recognized species of the genus Algoriphagus. On the basis of the data presented, strain KEM-106T is considered to represent a novel species of the genus Algoriphagus, for which the name Algoriphagus marisflavi sp. nov. is proposed. The type strain is KEM-106T (=KCTC 52979T=NBRC 112904T). PMID- 28920830 TI - Reclassification of Thiomicrospira hydrogeniphila (Watsuji et al. 2016) to Thiomicrorhabdus hydrogeniphila comb. nov., with emended description of Thiomicrorhabdus (Boden et al., 2017). AB - The genus Thiomicrorhabdus (Tmr) in the Piskirickettsiaceae in the Thiotrichales of the Gammaproteobacteria contains four species of sulfur-oxidising obligate chemolithoautotroph with validly published names, all previously classified as Thiomicrospira (Tms) species. Here we demonstrate that Thiomicrospira hydrogeniphila, a recently published hydrogen-utilising chemolithoautotroph closely related to Thiomicrorhabdus frisia (type species of Thiomicrorhabdus) should be classified as a member of the genus Thiomicrorhabdus and not Thiomicrospira, as Thiomicrorhabdus hydrogeniphila comb. nov., on the basis of comparative physiology and morphology as well as 16S rRNA (rrs) gene identity of Tms. hydrogeniphila MAS2T being closer to that of Tmr. frisia JB-A2T (99.1 %) than to Tms. pelophila DSM 1534T (90.5 %) or Hydrogenovibrio marinus MH-110T (94.1 %), and on the basis of the topology of 16S rRNA gene maximum likelihood trees, which clearly place Tms. hydrogeniphila within the genus Thiomicrorhabdus. It was also noted that thiosulfate-grown Thiomicrorhabdus spp. can be distinguished from Thiomicrospira spp. or Hydrogenovibrio spp. on the basis of the 3 dominant fatty acids (C16 : 1, C18 : 1 and C16 : 0), and from other Thiomicrorhabdus spp. on the basis of the fourth dominant fatty acid, which varies between the species of this genus - which could provide a useful diagnostic method. We provide an emended description of Thiomicrorhabdus (Boden R, Scott KM, Williams J, Russel S, Antonen K et al.Int J Syst Evol Microbiol 2017;67:1140-1151) to take into account the properties of Thiomicrorhabdus hydrogeniphila comb. nov. PMID- 28920832 TI - Salinifilum gen. nov., with description of Salinifilum proteinilyticum sp. nov., an extremely halophilic actinomycete isolated from Meighan wetland, Iran, and reclassification of Saccharopolyspora aidingensis as Salinifilum aidingensis comb. nov. and Saccharopolyspora ghardaiensis as Salinifilum ghardaiensis comb. nov. AB - A Gram-positive, halophilic actinobacterial strain Miq-12T was isolated from Meighan wetland in Iran. Strain Miq-12T was strictly aerobic, catalase positive and oxidase negative. The isolate grew at 12-25 % NaCl, at 30-50 degrees C and pH 5.5-10.5. The optimum NaCl, temperature and pH for growth were 15-20 %, 40 degrees C and 7.0-8.0, respectively. The cell wall of strain Miq-12T contained meso-diaminopimelic acid as diagnostic diamino acid and arabinose as whole-cell sugar. The polar lipid pattern consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and phosphatidylinositol. It synthesized cellular fatty acids of anteiso and iso-branched types, anteiso-C17 : 0, iso-C17:0, iso-C15:0, iso-C16 : 0. The major respiratory quinone was MK-9(H4). The G+C content of its genomic DNA was 72.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequence comparison revealed that strain Miq-12T belongs to the family Pseudonocardiaceae, constituted a separate clade, and showed the closest phylogenetic similarity to Saccharopolyspora aidingensis TRM 46074T (96.99 %) and Saccharopolyspora ghardaiensis CCUG 63370T (96.92 %). On the basis of phylogenetic analysis, phenotypic and chemotaxonomic characteristics, a novel genus and species of the family Pseudonocardiaceae, Salinifilum proteinilyticum gen. nov., sp. nov., are proposed. The type strain is Miq-12T (=IBRCM 11033T=LMG 28390T). We also propose that S. aidingensis and S. ghardaiensis should be transferred to this new genus and be named Salinifilum aidingensis comb. nov. and Salinifilum ghardaiensis comb. nov., respectively. The type strain of Salinifilum aidingensis comb. nov. is TRM 46074T (=CCTCCAA 2012014T=JCM 30185T) and the type strain of Salinifilum ghardaiensis comb. nov. is CCUG 63370T (=DSM 45606T=CECT 8304T). PMID- 28920833 TI - Longispora urticae sp. nov., isolated from rhizosphere soil of Urtica urens L., and emended descriptions of the species Longisporaalbida and Longisporafulva. AB - Two Gram-stain-positive, aerobic actinomycete strains, designated NEAU-PCY-3T and NEAU-PCY-4, were isolated from rhizosphere soil of Urtica urens L. collected from Anshan, Liaoning Province, northeast PR China. The 16S rRNA gene sequence analysis showed that the two strains exhibited 99.9 % 16S rRNA gene sequence similarity with each other and that they were most closely to Longispora fulva DSM 45356T (98.7, 98.9 %) and Longispora albida JCM 11711T (97.1, 97.2 %). Phylogenetic analysis based on the 16S rRNA gene sequences indicated that the two strains were located in the same lineage and formed a cluster with the genus Longispora. Both strains were observed to contain MK-10(H4) and MK-10(H6) as the predominant menaquinones. The cell wall peptidoglycan was found to contain meso diaminopimelic acid, d-glutamic acid, glycine and l-alanine. Whole-cell hydrolysates mainly contained galactose, ribose and xylose. The phospholipid profile contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, several glycolipids and several unknown lipids. The major cellular fatty acids for strain NEAU-PCY-3T were iso-C16 : 0, iso-C17 : 0, anteiso-C17 : 0 and C18 : 1omega5c. The DNA-DNA hybridization value between strains NEAU-PCY-3T and NEAU-PCY-4 was 83.6+/-0.4 %, and the values between the two strains and their closest phylogenetic relatives, belonging to the genus Longispora, were well below 70 %, supporting that they represented a distinct genomic species. An array of phenotypic characteristics also differentiated the strains from their closely related species, the only two validly published Longispora species. On the basis of the genetic, chemotaxonomic and phenotypic properties, strains NEAU-PCY-3T and NEAU-PCY-4 were classified as representatives of a novel species of the genus Longispora, for which the name Longispora urticae sp. nov. is proposed. The type strain is NEAU-PCY-3T (=DSM 105119T=CCTCC AA 2017017T). PMID- 28920834 TI - Streptomyces xylanilyticus sp. nov., isolated from soil. AB - A novel actinomycete, strain SR2-123T, belonging to the genus Streptomyces, was isolated from a soil sample collected from the Sakaerat Environmental Research Station, Thailand Institute of Scientific and Technological Research, Nakhon Ratchasima Province, Thailand. The taxonomic position of the strain was characterized using a polyphasic study. Strain SR2-123T contained ll diaminopimelic acid, glucose, mannose and ribose in whole-cell hydrolysates. The N-acyl type of muramic acid was acetyl. Menaquinones were MK-9(H6), MK-9(H8) and MK-9(H4). The predominant cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and iso-C17 : 0. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, an unknown phospholipid, unknown glycolipids, an unknown aminophospholipid, unknown lipids and an unknown aminolipid. The DNA G+C content was 74.8 mol%. The strain was closely related to Streptomyces coeruleorubidus JCM 4359T (98.5 %), Streptomyces flavofungini JCM 4753T (98.5 %), Streptomyces coerulescens NBRC 12758T (98. 5 %) and Streptomyces alboflavus JCM 4615T (98.4 %), based on 16S rRNA gene sequence similarities. The novel strain exhibited low DNA-DNA relatedness values with the type strains (11.4-25.0 %) of closely related species. On the basis of phenotypic and genotypic characteristics, strain SR2 123T could be distinguished from closely related species of the genus Streptomyces and represents a novel species of the genus Streptomyces for which the name Streptomyces xylanilyticus sp. nov. is proposed. The type strain is SR2 123T (=TISTR 2493T=KCTC 39909T). PMID- 28920835 TI - Erythrobacter arachoides sp. nov., isolated from ice core. AB - A Gram-stain-negative, rod-shaped bacterial strain, designed RC4-10-4T, belonging to the genus Erythrobacter, was isolated from the East Rongbuk Glacier on the Tibetan Plateau. Strain RC4-10-4T grew optimally at pH 7.0, at 25 degrees C and in the presence of 2 % (w/v) NaCl. Summed feature 3 (C16 : 1 omega6c and/or iso C15 : 0 2-OH), summed feature 8 (C18 : 1 omega7c and/or C18 : 1 omega6c) and C16 : 0 were the major fatty acids. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, sphingoglycolipid and phosphatidylcholine. Carotenoid was detected in the cells. The DNA G+C content of the novel strain was 66.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain RC4-10-4T formed a distinct phylogenetic lineage within the cluster comprising Erythrobacter strains. Similarities between the 16S rRNA gene sequences of strain RC4-10-4T and the closely related strains Erythrobacter luteus KCTC 42179T, Erythrobacter gangjinensis KCTC 22330T, Erythrobacter odishensis KCTC 23981T and Erythrobacter atlanticuls KCTC 42697T were 98.0, 97.6, 97.5 and 97.2 %. The DNA-DNA hybridization values were 37.6, 15.4, 29.8 and 35.8 %, respectively. Based on the phenotypic and phylogenetic characteristics, strain RC4-10-4T represents a novel species of the genus Erythrobacter, for which the name Erythrobacter arachoides sp. nov. is proposed, with the type strain RC4-10-4T (=CGMCC 1.15507T=JCM 31277T). PMID- 28920836 TI - Mycobacterium aquiterrae sp. nov., a rapidly growing bacterium isolated from groundwater. AB - A strain representing a rapidly growing, Gram-stain-positive, aerobic, rod shaped, non-motile, non-sporulating and non-pigmented species of the genus Mycobacterium, designated strain S-I-6T, was isolated from groundwater at Daejeon in Korea. The strain grew at temperatures between 10 and 37 degrees C (optimal growth at 25 degrees C), between pH 4.0 and 9.0 (optimal growth at pH 7.0) and at salinities of 0-5 % (w/v) NaCl, growing optimally with 2 % (w/v) NaCl. Phylogenetic analyses based on multilocus sequence analysis of the 16S rRNAgene, hsp65, rpoB and the 16S-23S internal transcribed spacer indicated that strain S-I 6T belonged to the rapidly growing mycobacteria, being most closely related to Mycobacterium sphagni. On the basis of polyphasic taxonomic analysis, the bacterial strain was distinguished from its phylogenetic neighbours by chemotaxonomic properties and other biochemical characteristics. DNA-DNA relatedness among strain S-I-6T and the closest phylogenetic neighbour strongly support the proposal that this strain represents a novel species within the genus Mycobacterium, for which the name Mycobacterium aquiterrae sp. nov. is proposed. The type strain is S-I-6T (=KACC 17600T=NBRC 109805T=NCAIM B 02535T). PMID- 28920837 TI - Bacillus solisilvae sp. nov., isolated from forest soil. AB - A novel Gram-stain-positive, motile, endospore-forming, rod-shaped bacterial strain, NEAU-cbsb5T, was isolated from forest soil from Changbai Mountain, Heilongjiang Province, China. The isolate grew at 15-40 degrees C (optimum 30 degrees C), at pH 6.0-8.0 (optimum pH 7.0) and in the presence of up to 4 % (w/v) NaCl, although NaCl was not required for growth. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain NEAU-cbsb5T formed a distinct lineage within the genus Bacillus and was most closely related to Bacillus acidiceler DSM 18954T (99.1 % similarity) and Bacillus luciferensis JCM 12212T (99.0 %). 16S rRNA gene sequence similarity to sequences of the type strains of other Bacillus species was less than 96.0 %. Average nucleotide identity (ANI) values between NEAU-cbsb5T and its most closely related species were 78.72-84.75 % by ANIm, ANIb and OrthoANIu analysis. The in silico DNA-DNA hybridization values between strain NEAU-cbsb5T and its close relatives B. acidiceler DSM 18954T and B. luciferensis JCM 12212T were both 23.80 %, again indicating they belong to different taxa. The major cellular fatty acids of NEAU-cbsb5T were iso C15 : 0, anteiso-C15 : 0 and C16 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and an unknown aminophospholipid. The cell-wall peptidoglycan contained meso diaminopimelic acid and the predominant menaquinones were MK-7 and MK-6. The genomic DNA G+C content was 33.0 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic data, strain NEAU-cbsb5T was classified as a representative of a novel species in the genus Bacillus, for which the name Bacillus solisilvae sp. nov. is proposed. The type strain is NEAU-cbsb5T (=CGMCC 1.14993T=DSM 100485T). PMID- 28920838 TI - Edaphobaculum flavum gen. nov., sp. nov., a member of family Chitinophagaceae, isolated from grassland soil. AB - A yellow-coloured, Gram-stain-negative, non-motile, rod-shaped, strictly aerobic bacterium, designated 1-116T, was isolated from Erdos grassland soil of Inner Mongolia, PR China. Phylogenetic analysis based on 16S rRNA genes showed that strain 1-116T was a member of family Chitinophagaceae and exhibited the highest similarities to Taibaiella koreensis THG-DT86T (90.1 %) and Flavihumibacter solisivae 3-3T (90.0 %), while the similarities to the other Chitinophagaceae type strains were lower than 90.0 %. Strain 1-116T grew at 16-33 degrees C (optimum 28 degrees C), pH 6.0-9.0 (optimum 7.0-8.0) and 0-0.5 % NaCl (w/v; optimum without NaCl). A flexirubin-type pigment was present. The DNA G+C content was 43.2 mol% and the only quinone present was menaquinone-7. The only polyamine detected was sym-homospermidine [30.7 umol (g dry weight)-1] and the predominant fatty acids were iso-C15 : 0 (20.8 %), iso-C15 : 1 G (25.1 %), summed feature 4 (anteiso-C17 : 1 B and/or iso-C17 : 1 I; 13.8 %) and iso-C17 : 0 3-OH (13.2 %). The major polar lipids were phosphatidylethanolamine, three unidentified lipids, an unidentified aminophospholipid and an unidentified glycolipid. On the basis of the polyphasic analyses, strain 1-116T represents a novel genus and species in the family Chitinophagaceae, for which the name Edaphobaculum flavum gen. nov., sp. nov., is proposed. The type strain of Edaphobaculum flavum is 1-116T (=CCTCC AB 2017054=KCTC 52843). PMID- 28920839 TI - Natronotalea proteinilytica gen. nov., sp. nov. and Longimonas haloalkaliphila sp. nov., extremely haloalkaliphilic members of the phylum Rhodothermaeota from hypersaline alkaline lakes. AB - Two proteolytic bacterial strains, BSker2T and BSker3T, were enriched from sediments of hypersaline alkaline lakes in Kulunda Steppe (Altai, Russia) with chicken feathers as substrate, followed by pure culture isolation on hypersaline alkaline media with casein. The cells were non-motile, filamentous, flexible rods. The isolates were obligately aerobic heterotrophs utilizing proteins and peptides as growth substrates. Both were obligate alkaliphiles, but differed in their pH optimum for growth: pH 9.5-9.8 for Bsker2T and pH 8.5-8.8 for BSker3T. The salt range for growth of both isolates was between 2 and 4.5 M total Na+ with an optimum at 2.5-3 M. No organic osmolytes were detected in cells of BSker2T, but they accumulated high intracellular concentrations of K+. The polar lipid fatty acids were dominated by unsaturated C16 and C18 species. The 16S rRNA gene phylogeny indicated that both strains belong to the recently proposed phylum Rhodothermaeota. BSker2T forms a novel genus-level branch, while BSker3T represents a novel species-level member in the genus Longimonas. On the basis of distinct phenotypic and genotypic properties, strain BSker2T (=JCM 31342T=UNIQEM U1009T) is proposed to be classified as a representative of a novel genus and species, Natronotalea proteinilyticagen. nov., sp. nov., and strain BSker3T (=JCM 31343T=UNIQEM U1010T) as a representative of a novel species, Longimonas haloalkaliphila sp. nov. PMID- 28920840 TI - Flavobacterium dispersum sp. nov., isolated from a freshwater spring. AB - A novel bacterial strain MVW-23T was isolated from a freshwater spring in Taiwan. The strain was Gram-staining-negative, strictly aerobic, motile by gliding, rod shaped and formed translucent yellow colonies. Optimal growth occurred at 20-30 degrees C, pH 7.0, and in the presence of 0.5-1 % NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain MVW-23T belonged to the genus Flavobacterium and showed the highest levels of sequence similarity with respect to Flavobacterium denitrificans ED5T (97.3 %), Flavobacterium kyungheense THG 107T (97.2 %) and Flavobacterium defluvii EMB117T (97.0 %). Strain MVW-23T contained iso-C15 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) and iso-C17 : 0 3-OH as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, three uncharacterized aminophospholipids and one uncharacterized phospholipid. The major polyamine was homospermidine. The major isoprenoid quinone was MK-6. The DNA G+C content of the genomic DNA was 39.9 mol%. The DNA-DNA hybridization value for strain MVW-23T with F. denitrificans DSM 15936T, F. kyungheense LMG 26575T and F. defluvii DSM 17963T was less than 35 %. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain MVW-23T should be classified as a novel species of the genus Flavobacterium, for which the name Flavobacterium dispersum sp. nov. is presented. The type strain is MVW-23T (=BCRC 80978T=LMG 29558T=KCTC 52234T). PMID- 28920841 TI - Desertibacillus haloalkaliphilus gen. nov., sp. nov., isolated from a saline desert. AB - Two Gram-stain-positive, rod-shaped and endospore-forming bacteria that represent a single species, designated strains KJ1-10-99T and KJ1-10-93, were isolated from a saline desert of Little Rann of Kutch, Gujarat, India. Analysis of 16S rRNA gene sequences revealed that the isolates belonged to the family Bacillaceae and were closely related to each other with 16S rRNA gene sequence similarity of 99.9 %. However, these two isolates formed a novel phylogenetic branch within this family. Both strains were aerobic, catalase and oxidase positive, and could grow optimally at 37 degrees C and pH 9. Further, strains KJ1-10-99T and KJ1-10-93 grew optimally at a NaCl concentration of 7.5 and 15 % (w/v), respectively. Both strains shared highest sequence similarity with Fermentibacillus polygoni IEB3T (96.90 %) followed by Bacillus nanhaiisediminis NH3T (96.3 %) and Bacillus alkalinitrilicus ANL-iso4T (96.3 %). The major cellular fatty acids were anteiso C15 : 0, anteiso-C17:0, C16 : 0, and iso-C15 : 0. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol in both strains. The predominant isoprenoid quinone was MK-7 in both the strains. The peptidoglycan contained meso diaminopimelic acid (meso-DAP) as the diagnostic diamino acid. The DNA G+C content of strains KJ1-10-99T and KJ1-10-93 were 48.7 and 48.9 mol% respectively. Both strains could be distinguished from closest phylogenetic neighbours based on a number of phenotypic properties. On the basis of polyphasic taxonomic analysis and phylogenetic data, we conclude that the strains KJ1-10-99T (=LMG 29918T=KCTC 33878T) and KJ1-10-93 (=LMG 29919=KCTC 33877) represent a novel species of a new genus in the family Bacillaceae, order Bacillales, for which the name Desertibacillus haloalkaliphilus gen. nov., sp. nov. is proposed. PMID- 28920842 TI - Marivibrio halodurans gen. nov., sp. nov., a marine bacterium in the family Rhodospirillaceae isolated from underground rock salt. AB - Gram-negative, spiral or curved rod-shaped cells of a bacterial strain, designated ZC80T, were isolated from a rock salt sample collected at Yunnan salt mine, China. Analysis of the strain's 16S rRNA gene sequence revealed a clear affiliation of this novel strain within the family Rhodospirillaceae. Strain ZC80T formed a robust cluster with Pelagibius litoralis CL-UU02T at a 16S rRNA gene sequence similarity level of 88.1 %. Strain ZC80T shared no more than 91.0 % 16S rRNA gene sequence similarity with the type strains of other species in the family Rhodospirillaceae. Strain ZC80T was able to grow in the presence of 2-15 % (w/v) NaCl, and grew at 10-50 degrees C and pH 6.0-10.0. The major fatty acids were C19 : 0 cyclo omega8c (41.3 %). The major isoprenoid quinone was ubiquinone 10 (Q-10). The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol and an unidentified aminolipid. The DNA G+C content of strain ZC80T was 60.8 mol%. On the basis of phylogenetic analyses and chemotaxonomic and physiological data, strain ZC80T is considered to represent a novel species of a new genus in the family Rhodospirillaceae, for which the name Marivibrio halodurans gen. nov., sp. nov. is proposed. The type strain of Marivibrio halodurans is ZC80T (=CGMCC 1.15697T=NBRC 112461T). PMID- 28920843 TI - Rejection of reclassification of Lactobacillus kimchii and Lactobacillus bobalius as later subjective synonyms of Lactobacillus paralimentarius using comparative genomics. AB - Lactobacillus bobalius, Lactobacillus kimchii and Lactobacillus paralimentarius belong to the genus Lactobacillus and show close phylogenetic relationships. In a previous study, L. bobalius and L. kimchii were proposed to be reclassified as later heterotypic synonyms of L. paralimentarius using high 16S rRNA gene sequence similarities (>=99.5 %) and DNA-DNA hybridization values (>=82 %). We determined high quality whole genome assemblies of the type strains of L. bobalius and L. kimchii, which were then compared with that of L. paralimentarius. Average nucleotide identity values among three genomes ranged from 91.4 to 92.3 % which are clearly below 95~96 %, the generally recognized cutoff value for bacterial species boundaries. On the basis of comparative genomic evidence, L. bobalius, L. kimchii, and L. paralimentarius should stand as separate species in the genus Lactobacillus. We therefore suggest rejecting the previous proposal to combine these three species into a single species. PMID- 28920844 TI - Identification of genes involved in galactooligosaccharide utilization in Bifidobacterium breve strain YIT 4014T. AB - Galactooligosaccharides (GOS) are mixed oligosaccharides that are mainly composed of galactosyllactoses (GLs), which include 3'-GL, 4'-GL, and 6'-GL. Data from numerous in vitro and in vivo studies have shown that GOS selectively stimulate the growth of bifidobacteria. Previously, we identified the gene locus responsible for 4'-GL utilization, but the selective routes of uptake and catabolism of 3'- and 6'-GL remain to be elucidated. In this study, we used differential transcriptomics to identify the utilization pathways of these GLs within the Bifidobacterium breve YIT 4014T strain. We found that the BBBR_RS 2305 2320 gene locus, which includes a solute-binding protein (SBP) of an ATP-binding cassette (ABC) transporter and beta-galactosidase, were up-regulated during 3'- and 6'-GL utilization. The substrate specificities of these proteins were further investigated, revealing that beta-galactosidase hydrolyzed both 3'-GL and 6'-GL efficiently. Our surface plasmon resonance results indicated that the SBP bound strongly to 6'-GL, but bound less tightly to 3'-GL. Therefore, we looked for the other SBPs for 3'-GL and found that the BBBR_RS08090 SBP may participate in 3'-GL transportation. We also investigated the distribution of these genes in 17 bifidobacterial strains, including 9 B. breve strains, and found that the beta galactosidase genes were present in most bifidobacteria. Homologues of two ABC transporter SBP genes were found in all B. breve strains and in some bifidobacteria that are commonly present in the human gut microbiota. These results provide insights into the ability of human-resident bifidobacteria to utilize the main component of GOS in the gastrointestinal tract. PMID- 28920845 TI - Modified use of real-time PCR detection of group B Streptococcus in pregnancy. AB - The CDC recommends antenatal screening of vaginal/rectal samples for Streptococcus agalactiae at 35-37 weeks' gestation, with intra-partum antibiotic prophylaxis for positive cases. We tested a modified use of the Cepheid Xpert GBS real-time PCR kit on enrichment cultures from 554 vaginal/rectal swabs compared to the current subculturing gold standard method. Swabs were inoculated on polymyxin nalidixic acid agar plates, and Todd-Hewitt enrichment broth cultures were examined daily for growth. Todd-Hewitt broth culture was also used for Xpert GBS. There was 92.06 % agreement between the subculture and PCR methods. Sensitivity of Xpert GBS was 100 %, specificity was 89.40 %, positive predictive value was 75.96 % and negative predictive value was 100 %. Colonization incidence was higher with younger (<=24 years) or older (>=35 years) maternal age. Modified use of the Cepheid Xpert GBS would assist rapid diagnosis of S. agalactiae colonization and facilitate timely and appropriate assignment to intra-partum antibiotic prophylaxis. PMID- 28920846 TI - Detection of the IncX3 plasmid carrying blaKPC-3 in a Serratia marcescens strain isolated from a kidney-liver transplanted patient. AB - Dissemination of resistance to carbapenems among Enterobacteriaceae through plasmids is an increasingly important concern in health care worldwide. Here we report the first description of an IncX3 plasmid carrying the blaKPC-3 gene in a strain of Serratia marcescens isolated from a kidney-liver transplanted patient at the transplantation centre ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, Italy). To localize the transposable element containing the resistance-associated gene Next-Generation Sequencing of the bacterial DNA was performed. S. marcescens was positive for blaKPC-3 and blaSHV-11 genes. The molecular analysis demonstrated that the blaKPC-3 gene of this bacterial strain was located in one copy of the Tn-3-like element Tn4401-a carried in a plasmid that is 53 392 bp in size and showed the typical IncX3 scaffold. Our data demonstrated the presence of a new blaKPC-3 harbouring the IncX3 plasmid in S. marcescens. The possible dissemination among Enterobacteriaceae of this type of plasmid should be monitored and evaluated in terms of clinical risk. PMID- 28920847 TI - Spirosoma carri sp. nov., isolated from an automobile air conditioning system. AB - A Gram-stain-negative and yellow-pigmented bacterial strain, designated TX0406T, was isolated from an automobile evaporator core collected in Korea. The cells were non-motile, aerobic and rod-shaped. The strain grew at 15-37 degrees C (optimum, 25 degrees C), at pH 6.0-7.0 (optimum, 6.5) and in the presence of 0 1.5 % (w/v) NaCl. Phylogenetically, the strain was related to members of the genus Spirosoma(93.7-90.7 % 16S rRNA sequence similarities) and showed the highest sequence similarity of 93.7 % to Spirosomapulveris JSH5-14T. The major fatty acids of the strain were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 1omega5c and C16 : 0. The predominant menaquinone was MK-7. The polar lipid profile revealed the presence of phosphatidylethanolamine, an unidentified aminolipid, unidentified aminophospholipids and unidentified lipids. The DNA G+C content of the strain was 58.7 mol%. Based on phenotypic, genotypic and chemotaxonomic data, strain TX0406T represents a novel species in the genus Spirosoma, for which the name Spirosoma carri sp. nov. (=KACC 19013T=NBRC 112494T) is proposed. PMID- 28920848 TI - Dyella agri sp. nov., isolated from reclaimed grassland soil. AB - A novel strain, DKC-1T, was isolated from reclaimed grassland soil and was characterized taxonomically by a polyphasic approach. Strain DKC-1T was a Gram staining-negative, light-yellow-coloured and rod shaped bacterium, motile with polar flagellum. It was able to grow at 20-37 degrees C, at pH 4.5-9.0 and with 0-3 % (w/v) NaCl concentration. Based on the 16S rRNA gene sequence analysis, strain DKC-1T formed a clade within the members of the genus Dyella and showed highest sequence similarities to Dyella japonica XD53T (98.36 %), Rhodanobacter aciditrophus sjH1T (97.92 %), Rhodanobacter koreensis THG-DD7T (97.74 %), Dyella kyungheensis THG-B117T (97.65 %) and Rhodanobacter terrae GP18-1T (97.40 %). The only respiratory quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidyl-N-methylethanolamine. The predominant fatty acids of strain DKC-1T were iso-C16 : 0, iso-C15 : 0, summed feature 9 (iso-C17 : 1omega9c and/or C16 : 0 10-methyl), iso-C17 : 0, iso-C11 : 0 3-OH and iso-C11 : 0. The genomic DNA G+C content of this novel strain was 63.1 mol%. The DNA-DNA relatedness between strain DKC-1T and its reference strains (D. japonica XD53T, R. aciditrophus sjH1T, R. koreensis THG-DD7T, D. kyungheensis THG-B117T and R. terrae GP18-1T) was 52.3, 44.7, 38.7, 49.0 and 32.7 %, respectively, which falls below the threshold value of 70 % for the strain to be considered as novel. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain DKC-1T represents a novel species of the genus Dyella, for which the name Dyella agri sp. nov. is proposed. The type strain is DKC-1T (=KEMB 9005-571T=KACC 19176T=JCM 31925T). PMID- 28920849 TI - Flavimarina flava sp. nov., isolated from Salicornia herbacea. AB - A Gram-stain-negative, motile-by-gliding, aerobic, non-spore-forming, rod-shaped and yellow-pigmented bacterium was isolated from Salicornia herbacea in the Yellow Sea and designated as strain MBLN091T. It belonged to the family Flavobacteriaceae. The 16S rRNA gene sequence of this isolated strain was similar to that of Flavimarina pacifica IDSW-73T with 94.8 % similarity, and with 92.3 92.8 % similarities to those of other closely related species of the genus Leeuwenhoekiella. The similarities of the RNA polymerase subunit B gene between this strain and F. pacifica KCTC 32466T and Leeuwenhoekiella marinoflava DSM 3653T were 80.5 and 80.2 %, respectively. Growth of strain MBLN091T was observed in the presence of 0.5-15.0 % (w/v) NaCl at 4-35 degrees C and pH 6.0-8.0, with optimal growth in the presence of 2.5-5.0 % (w/v) NaCl at 20-25 degrees C and pH 7.0. This isolate was able to hydrolyse gelatin. The only respiratory quinone was MK-6. The major polar lipids were phosphatidylethanolamine, an unidentified aminolipid and two unidentified lipids. Major fatty acids of the isolate were iso C15 : 0, summed feature 3 (C16 : 1 omega7c and/or C16 : 1 omega6c), iso-C17 : 0 3 OH and iso-C15 : 1 G. The genomic DNA G+C content was 39.6 mol%. The physiological features were closely related to F. pacifica. Therefore, strain MBLN091T is considered to represent a novel species within the genus Flavimarina, for which the name Flavimarina flava sp. nov. is proposed. The type strain is MBLN091T (=KCTC 52527T=JCM 31731T). PMID- 28920850 TI - Ramlibacter alkalitolerans sp. nov., alkali-tolerant bacterium isolated from soil of ginseng. AB - A novel bacterial strain, designated CJ661T, was isolated from soil of ginseng in Anseong, South Korea. Cells of strain CJ661T were white-coloured, Gram-staining negative, non-motile, aerobic and rod-shaped. Strain CJ661T grew optimally at 30 degrees C and pH 7.0. The analysis of 16S rRNA gene sequence of strain CJ661T showed that it belongs to the genus Ramlibacter within the family Comamonadaceae and was most closely related to Ramlibacter ginsenosidimutans KCTC 22276T (98.1 %), followed by Ramlibacter henchirensis DSM 14656T (97.1 %). DNA-DNA relatedness levels of strain CJ661T were 40.6 % to R. ginsenosidimutans KCTC 22276T and 25.0 % to R. henchirensis DSM 14656T. The major isoprenoid quinone was ubiquinone (Q 8). The predominant polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The major cellular fatty acids of strain CJ661T were summed feature 3 (C16 : 1 omega6c and/or C16 : 1 omega7c), C16 : 0 and summed feature 8 (C18 : 1 omega7c and/or C18 : 1 omega6c). The G+C content of the genomic DNA was 65.4 mol%. On the basis polyphasic taxonomic data, strain CJ661T represents a novel species in the genus Ramlibacter, for which name Ramlibacter alkalitolerans sp. nov. is proposed; the type strain is CJ661T (=KACC 19305T=JCM 32081T). PMID- 28920851 TI - Loktanella acticola sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, non-motile and coccoid, ovoid or rod-shaped bacterial strain, designated OISW-6T, was isolated from seawater near Oido, a South Korean island, and subjected to a polyphasic taxonomic study. Strain OISW 6T grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. The phylogenetic trees based on 16S rRNA gene sequences showed that strain OISW-6T fell within the clade comprising the type strains of Loktanella species. Strain OISW-6T exhibited 16S rRNA gene sequence similarity values of 97.0-98.9 % to Loktanellamaricola, Loktanellatamlensis, Loktanellarosea, Loktanellamaritima, Loktanellasediminilitoris and Loktanellalitorea, and of 94.0 96.3 % to the type strains of the other Loktanella species. Strain OISW-6T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids detected in strain OISW-6T were phosphatidylcholine, phosphatidylglycerol and one unidentified aminolipid. The DNA G+C content of strain OISW-6T was 57.3 mol% and its DNA-DNA relatedness values with the type strains of the six phylogenetically closely related Loktanella species were 8-25 %. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain OISW-6T is separated from recognized species of the genus Loktanella. On the basis of the data presented, strain OISW-6T is considered to represent a novel species of the genus Loktanella, for which the name Loktanellaacticola sp. nov. is proposed. The type strain is OISW-6T (=KCTC 52837T=NBRC 112781T). PMID- 28920852 TI - Experimental transmission to a calf of an isolate of Spanish classical scrapie. AB - Multiple theories exist regarding the origin of bovine spongiform encephalopathy (BSE). An early and prominent theory proposed that BSE was the result of the adaptation of sheep scrapie to cattle. The reports to date indicate that the distribution of the pathological prion protein (PrPSc) in experimental bovine scrapie is largely restricted to the central nervous system (CNS). Here, we describe pathological findings in a calf intracerebrally inoculated with a Spanish classical scrapie isolate. While clinical disease was observed 30 months after inoculation and PrPSc was detected in the CNS, the corresponding phenotype differed from that of BSE. Immunohistochemistry and PMCA also revealed the presence of PrPSc in the peripheral nerves, lymphoid tissues, skeletal muscle and gastrointestinal tract, suggesting centrifugal spread of the scrapie agent from the brain. To the best of our knowledge, this is the first report describing the detection of PrPSc in tissues other than the CNS after experimental transmission of scrapie to cattle. PMID- 28920853 TI - Flavobacterium chuncheonense sp. nov. and Flavobacterium luteum sp. nov., isolated from a freshwater lake. AB - Two Gram-staining-negative, orange coloured, non-motile, rod-shaped bacterial strains, designated strains IMCC26013T and IMCC26026T, were isolated from a freshwater sample collected from Lake Soyang in Korea. The 16S rRNA gene-based phylogenetic analyses showed that both strains belonged to the genus Flavobacterium and that strains IMCC26013T and IMCC26026T were most closely related to Flavobacterium psychrophilum (96.5 %) and Flavobacterium myungsuense (97.7 %), respectively. DNA G+C contents of strains IMCC26013T and IMCC26026T were 37.8 and 33.7 mol%, respectively. DNA-DNA relatedness between strain IMCC26026T and F. myungsuense HMD1033T was 56.4 %, showing a novel species status of strain IMCC26026T. Major fatty acid constituents (>10 %) of strain IMCC26013T were iso-C15 : 1 G, C15 : 1 omega6c, C17 : 1 omega6c and summed feature 3 (C16 : 1 omega6c and/or C16 : 1 omega7c) and those of strain IMCC26026T were iso-C15 : 0, anteiso-C15 : 0 and summed feature 3. Respiratory quinone detected in the two strains was MK-6. Both strains contained phosphatidylethanolamine as a major polar lipid. On the basis of these results, strains IMCC26013T and IMCC26026T were considered to represent novel species in the genus Flavobacterium, for which the names Flavobacterium chuncheonense (type strain IMCC26013T=KCTC 52573T=NBRC 112526T), and Flavobacterium luteum (type strain IMCC26026T=KCTC 52572T=NBRC 112527T) are proposed, respectively. PMID- 28920854 TI - In vitro activity of tedizolid and comparator agents against Gram-positive pathogens responsible for bone and joint infections. AB - Tedizolid, a second-generation oxazolidinone that displays a potent activity against Gram-positive pathogens, could be an interesting option for the treatment of bone and joint infections (BJIs). The aim of the study was to determine minimal inhibitory concentration (MIC) of tedizolid against a collection of 359 clinical isolates involved in clinically-documented BJIs and to compare them to those of comparator agents used in Gram-positive infections. Of the 104 Staphylococcusaureus and 102 coagulase-negative staphylococci (CoNS) isolates, 99 and 92 % were categorized as susceptible to tedizolid, respectively (MIC25=0.12/0.25 ug ml-1 and MIC90=0.25/0.5 ug ml-1), regardless of their methicillin resistance. MIC50 and MIC90 for the 51 enterococci, the 50 Corynebacterium spp. and the 52 Propionibacterium spp. were either equal or inferior to 0.5 ug ml-1. Altogether, tedizolid possessed a potent in vitro activity against most of the BJI Gram-positive pathogens with 95 % of them exhibiting a MIC <=0.5 ug ml-1. PMID- 28920855 TI - PfmA, a novel quorum-quenching N-acylhomoserine lactone acylase from Pseudoalteromonas flavipulchra. AB - Many bacteria, such as Proteobacteria, Cyanobacteria and Bacteroidetes, use N acylhomoserine lactones (AHLs) as quorum-sensing (QS) signal molecules for communication. Enzymatic degradation of AHLs, such as AHL acylase and AHL lactonase, can degrade AHLs (quorum quenching, QQ) to attenuate or disarm the virulence of pathogens. QQ is confirmed to be common in marine bacterial communities. Many genes encoding AHL acylases are found in marine bacteria and metagenomic collections, but only a few of these have been characterized in detail. We have reported that the marine bacterium Pseudoalteromonas flavipulchra JG1 can degrade AHLs. In the present study, a novel AHL acylase PfmA, which can degrade AHLs with acyl chains longer than 10 carbons, was identified from strain JG1. Ultra-performance liquid chromatography (UPLC) and electrospray ionization mass spectrometry (ESI-MS) analysis demonstrated that PfmA functions as an AHL acylase, which hydrolysed the amide bond of AHL. The purified PfmA of P. flavipulchra JG1 showed optimum activity at 30 degrees C and pH 7.0. PfmA belongs to the N-terminal nucleophile (Ntn) hydrolase superfamily and showed homology to a member of penicillin amidases, but PfmA can degrade ampicillin but not penicillin G. The residue Ser256 in PfmA is the active site according to site directed mutagenesis. Furthermore, PfmA reduced AHL accumulation and the production of virulence factors in Vibrio anguillarum VIB72 and Pseudomonas aeruginosa PAO1, and attenuated the virulence of P. aeruginosa to increase Artemia survival, which suggested that PfmA can be considered as a therapeutic agent to control AHL-mediated pathogenicity. PMID- 28920857 TI - Department of error. PMID- 28920856 TI - Correction: Evidence that Mediator is essential for Pol II transcription, but is not a required component of the preinitiation complex in vivo. PMID- 28920858 TI - Department of error. PMID- 28920859 TI - Department of error. PMID- 28920860 TI - May 10-16, 2014. PMID- 28920861 TI - Pharmacotherapy of type 2 diabetes: An update. AB - Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal. PMID- 28920862 TI - Enhanced endothelium epithelial sodium channel signaling prompts left ventricular diastolic dysfunction in obese female mice. AB - OBJECTIVE: Enhanced activation of cell specific mineralocorticoid receptors (MRs) in obesity plays a key role in the development of cardiovascular disease including cardiac diastolic dysfunction as a critical prognosticator. Our previous investigations demonstrated that selective endothelium MR activation promotes a maladaptive inflammatory response and fibrosis in cardiovascular tissue in female mice fed a western diet (WD), and this was associated with expression and activation of the epithelial sodium channel on the surface of endothelial cells (EnNaC). However, the specific role of EnNaC signaling in the development of cardiac stiffness and diastolic dysfunction has not been examined. We hypothesized that targeted inhibition of EnNaC with low dose amiloride would prevent WD-induced diastolic dysfunction by suppressing abnormal endothelial permeability, inflammation and oxidative stress, and myocardial fibrosis. MATERIALS/METHODS: Four week-old female C57BL6/J mice were fed a WD with or without a low dose of amiloride (1mg/kg/day) for 16weeks. Left ventricular cardiac function was evaluated by magnetic resonance imaging. In addition, we examined coronary vessel and cardiac remodeling, fibrosis, macrophage infiltration using immunohistochemistry, western blot and real time PCR. RESULTS: Amiloride, an antagonist of EnNaC, attenuated WD-induced impairment of left ventricular initial filling rate and relaxation time. Cardiac diastolic dysfunction was associated with increases in coronary endothelium remodeling and permeability that paralleled WD-induced increases in F-actin and fibronectin, decreased expression of claudin-5 and occludin, and increased macrophage recruitment, M1 polarization, cardiac oxidative stress, fibrosis and maladaptive remodeling. CONCLUSION: Our data support the concept that EnNaC activation mediates endothelium permeability which, in turn, promotes macrophage infiltration, M1 polarization, and oxidative stress, resulting in cardiac fibrosis and diastolic dysfunction in females with diet induced obesity. PMID- 28920864 TI - Department of Error. PMID- 28920865 TI - Department of Error. PMID- 28920866 TI - Department of Error. PMID- 28920867 TI - Department of Error. PMID- 28920868 TI - Department of Error. PMID- 28920869 TI - November 22-28, 2014. PMID- 28920870 TI - Erratum. PMID- 28920871 TI - Cathy Stinear. PMID- 28920873 TI - Treating rare disorders: time to act on unfair prices. PMID- 28920863 TI - White matter microstructure and cognitive decline in metabolic syndrome: a review of diffusion tensor imaging. AB - Metabolic syndrome is a cluster of cardiovascular risk factors defined by the presence of abdominal obesity, glucose intolerance, hypertension and/or dyslipidemia. It is a major public health epidemic worldwide, and a known risk factor for the development of cognitive dysfunction and dementia. Several studies have demonstrated a positive association between the presence of metabolic syndrome and worse cognitive outcomes, however, evidence of brain structure pathology is limited. Diffusion tensor imaging has offered new opportunities to detect microstructural white matter changes in metabolic syndrome, and a possibility to detect associations between functional and structural abnormalities. This review analyzes the impact of metabolic syndrome on white matter microstructural integrity, brain structure abnormalities and their relationship to cognitive function. Each of the metabolic syndrome components exerts a specific signature of white matter microstructural abnormalities. Metabolic syndrome and its components exert both additive/synergistic, as well as, independent effects on brain microstructure thus accelerating brain aging and cognitive decline. PMID- 28920874 TI - Unravelling neurodegeneration in multiple sclerosis. PMID- 28920875 TI - Traumatic brain injury: an enduring challenge. PMID- 28920876 TI - A new era of multiple sclerosis rehabilitation: lessons from stroke. PMID- 28920877 TI - Corrections. PMID- 28920878 TI - Edaravone for treatment of early-stage ALS - Authors' reply. PMID- 28920879 TI - Obesity and the nervous system: more questions. PMID- 28920880 TI - Edaravone for treatment of early-stage ALS. PMID- 28920881 TI - Obesity and the nervous system: more questions. PMID- 28920882 TI - Obesity and the nervous system: more questions - Authors' reply. PMID- 28920883 TI - David Menon: the incredible, incurable, clinical rationalist. PMID- 28920884 TI - Ed Wild. PMID- 28920885 TI - Gian Lorenzo Bernini's 17th century white noise machine. PMID- 28920887 TI - The chronic and evolving neurological consequences of traumatic brain injury. AB - Traumatic brain injury (TBI) can have lifelong and dynamic effects on health and wellbeing. Research on the long-term consequences emphasises that, for many patients, TBI should be conceptualised as a chronic health condition. Evidence suggests that functional outcomes after TBI can show improvement or deterioration up to two decades after injury, and rates of all-cause mortality remain elevated for many years. Furthermore, TBI represents a risk factor for a variety of neurological illnesses, including epilepsy, stroke, and neurodegenerative disease. With respect to neurodegeneration after TBI, post-mortem studies on the long-term neuropathology after injury have identified complex persisting and evolving abnormalities best described as polypathology, which includes chronic traumatic encephalopathy. Despite growing awareness of the lifelong consequences of TBI, substantial gaps in research exist. Improvements are therefore needed in understanding chronic pathologies and their implications for survivors of TBI, which could inform long-term health management in this sizeable patient population. PMID- 28920888 TI - Prediction of motor recovery after stroke: advances in biomarkers. AB - Stroke remains a leading cause of adult disability, and the recovery of motor function after stroke is crucial for the patient to regain independence. However, making accurate predictions of a patient's motor recovery and outcome is difficult when based on clinical assessment alone. Clinical assessment of motor impairment within a few days of stroke can help to predict subsequent recovery, while neurophysiological and neuroimaging biomarkers of corticomotor structure and function can help to predict both motor recovery and motor outcome after stroke. The combination of biomarkers can provide clinically useful information when planning the personalised rehabilitation of a patient. These biomarkers can also be used for patient selection and stratification in trials investigating rehabilitation interventions that are initiated early after stroke. Ongoing multicentre trials that incorporate motor biomarkers could help to bring their use into routine clinical practice. PMID- 28920886 TI - Retinal layer segmentation in multiple sclerosis: a systematic review and meta analysis. AB - BACKGROUND: Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. METHODS: In this systematic review and meta-analysis, we searched for studies in which SD OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. FINDINGS: Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20.10 MUm, 95% CI -22.76 to 17.44; p<0.0001) and in MSNON eyes (-7.41 MUm, -8.98 to -5.83; p<0.0001). The macula showed RNFL thinning of -6.18 MUm (-8.07 to -4.28; p<0.0001) in MSON eyes and -2.15 MUm (-3.15 to -1.15; p<0.0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16.42 MUm (-19.23 to -13.60; p<0.0001) for MSON eyes and -6.31 MUm ( 7.75 to -4.87; p<0.0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0.77 MUm, 0.25 to 1.28; p=0.003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1.21 MUm, 0.24 to 2.19; p=0.01). INTERPRETATION: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. FUNDING: None. PMID- 28920890 TI - Exercise in patients with multiple sclerosis. AB - Exercise can be a beneficial rehabilitation strategy for people with multiple sclerosis to manage symptoms, restore function, optimise quality of life, promote wellness, and boost participation in activities of daily living. However, this population typically engages in low levels of health-promoting physical activity compared with adults from the general population, a fact which has not changed in the past 25 years despite growing evidence of the benefits of exercise. To overcome this challenge, the main limitations to promoting exercise through the patient-clinician interaction must be addressed. These limitations are the inadequate quality and scope of existing evidence, incomplete understanding of the mechanisms underlying the beneficial effects of exercise in people with multiple sclerosis, and the absence of a conceptual framework and toolkit for translating the evidence into practice. Future research to address those limitations will be essential to inform decisions about the inclusion of exercise in the clinical care of people with multiple sclerosis. PMID- 28920889 TI - Therapies targeting DNA and RNA in Huntington's disease. AB - No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies. PMID- 28920891 TI - Roger Y. Tsien (1952-2016). PMID- 28920892 TI - Computationally Efficient Algorithms for Sparse, Dynamic Solutions to the EEG Source Localization Problem. AB - OBJECTIVE: Electroencephalography (EEG) and magnetoencephalography noninvasively record scalp electromagnetic fields generated by cerebral currents, revealing millisecond-level brain dynamics useful for neuroscience and clinical applications. Estimating the currents that generate these fields, i.e., source localization, is an ill-conditioned inverse problem. Solutions to this problem have focused on spatial continuity constraints, dynamic modeling, or sparsity constraints. The combination of these key ideas could offer significant performance improvements, but substantial computational costs pose a challenge for practical application of such approaches. Here, we propose a new method for EEG source localization that combines: 1) covariance estimation for both source and measurement noises; 2) linear state-space dynamics; and 3) sparsity constraints, using 4) novel computationally efficient estimation algorithms. METHODS: For source covariance estimation, we use a locally smooth basis alongside sparsity enforcing priors. For EEG measurement noise covariance estimation, we use an inverse Wishart prior density. We estimate these model parameters using an expectation-maximization algorithm that employs steady-state filtering and smoothing to expedite computations. RESULTS: We characterized the performance of our method by analyzing simulated data and experimental recordings of eyes-closed alpha oscillations. Our sparsity enforcing priors significantly improved estimation of both the spatial distribution and time course of simulated data, while improving computational time by more than 12-fold over previous dynamic methods. CONCLUSION: We developed and demonstrated a novel method for improved EEG source localization employing spatial covariance estimation, dynamics, and sparsity. SIGNIFICANCE: Our approach provides substantial performance improvements over existing methods using computationally efficient algorithms that will facilitate practical applications in both neuroscience and medicine. PMID- 28920893 TI - A Functional-Genetic Scheme for Seizure Forecasting in Canine Epilepsy. AB - OBJECTIVE: The objective of this work is the development of an accurate seizure forecasting algorithm that considers brain's functional connectivity for electrode selection. METHODS: We start by proposing Kmeans-directed transfer function, an adaptive functional connectivity method intended for seizure onset zone localization in bilateral intracranial EEG recordings. Electrodes identified as seizure activity sources and sinks are then used to implement a seizure forecasting algorithm on long-term continuous recordings in dogs with naturally occurring epilepsy. A precision-recall genetic algorithm is proposed for feature selection in line with a probabilistic support vector machine classifier. RESULTS: Epileptic activity generators were focal in all dogs confirming the diagnosis of focal epilepsy in these animals while sinks spanned both hemispheres in 2 of 3 dogs. Seizure forecasting results show performance improvement compared to previous studies, achieving average sensitivity of 84.82% and time in warning of 0.1. CONCLUSION: Achieved performances highlight the feasibility of seizure forecasting in canine epilepsy. SIGNIFICANCE: The ability to improve seizure forecasting provides promise for the development of EEG-triggered closed-loop seizure intervention systems for ambulatory implantation in patients with refractory epilepsy. PMID- 28920894 TI - Electrothermal Equivalent Three-Dimensional Finite-Element Model of a Single Neuron. AB - OBJECTIVE: We propose a novel approach for modelling the interdependence of electrical and mechanical phenomena in nervous cells, by using electrothermal equivalences in finite element (FE) analysis so that existing thermomechanical tools can be applied. METHODS: First, the equivalence between electrical and thermal properties of the nerve materials is established, and results of a pure heat conduction analysis performed in Abaqus CAE Software 6.13-3 are validated with analytical solutions for a range of steady and transient conditions. This validation includes the definition of equivalent active membrane properties that enable prediction of the action potential. Then, as a step toward fully coupled models, electromechanical coupling is implemented through the definition of equivalent piezoelectric properties of the nerve membrane using the thermal expansion coefficient, enabling prediction of the mechanical response of the nerve to the action potential. RESULTS: Results of the coupled electromechanical model are validated with previously published experimental results of deformation for squid giant axon, crab nerve fibre, and garfish olfactory nerve fibre. CONCLUSION: A simplified coupled electromechanical modelling approach is established through an electrothermal equivalent FE model of a nervous cell for biomedical applications. SIGNIFICANCE: One of the key findings is the mechanical characterization of the neural activity in a coupled electromechanical domain, which provides insights into the electromechanical behaviour of nervous cells, such as thinning of the membrane. This is a first step toward modelling three dimensional electromechanical alteration induced by trauma at nerve bundle, tissue, and organ levels. PMID- 28920895 TI - Matched Filtering for Heart Rate Estimation on Compressive Sensing ECG Measurements. AB - OBJECTIVE: Compressive sensing (CS) has recently been applied as a low-complexity compression framework for long-term monitoring of electrocardiogram (ECG) signals using wireless body sensor networks. Long-term recording of ECG signals can be useful for diagnostic purposes and to monitor the evolution of several widespread diseases. In particular, beat-to-beat intervals provide important clinical information, and these can be derived from the ECG signal by computing the distance between QRS complexes (R-peaks). Numerous methods for R-peak detection are available for uncompressed ECG. However, in the case of compressed sensed data, signal reconstruction can be performed with relatively complex optimization algorithms, which may require significant energy consumption. This paper addresses the problem of heart rate estimation from CS ECG recordings, avoiding the reconstruction of the entire signal. METHODS: We consider a framework, where the ECG signals are represented under the form of CS linear measurements. The QRS locations are estimated in the compressed domain by computing the correlation of the compressed ECG and a known QRS template. RESULTS: Experiments on actual ECG signals show that our novel solution is competitive with methods applied to the reconstructed signals. CONCLUSION: Avoiding the reconstruction procedure, the proposed method proves to be very convenient for real-time low-power applications. PMID- 28920896 TI - Analysis and Optimization of Loss Functions for Multiclass, Top-k, and Multilabel Classification. AB - Top-k error is currently a popular performance measure on large scale image classification benchmarks such as ImageNet and Places. Despite its wide acceptance, our understanding of this metric is limited as most of the previous research is focused on its special case, the top-1 error. In this work, we explore two directions that shed more light on the top-k error. First, we provide an in-depth analysis of established and recently proposed single-label multiclass methods along with a detailed account of efficient optimization algorithms for them. Our results indicate that the softmax loss and the smooth multiclass SVM are surprisingly competitive in top-k error uniformly across all k, which can be explained by our analysis of multiclass top-k calibration. Further improvements for a specific k are possible with a number of proposed top-k loss functions. Second, we use the top-k methods to explore the transition from multiclass to multilabel learning. In particular, we find that it is possible to obtain effective multilabel classifiers on Pascal VOC using a single label per image for training, while the gap between multiclass and multilabel methods on MS COCO is more significant. Finally, our contribution of efficient algorithms for training with the considered top-k and multilabel loss functions is of independent interest. PMID- 28920897 TI - Automated Analysis of Unregistered Multi-View Mammograms With Deep Learning. AB - We describe an automated methodology for the analysis of unregistered cranio caudal (CC) and medio-lateral oblique (MLO) mammography views in order to estimate the patient's risk of developing breast cancer. The main innovation behind this methodology lies in the use of deep learning models for the problem of jointly classifying unregistered mammogram views and respective segmentation maps of breast lesions (i.e., masses and micro-calcifications). This is a holistic methodology that can classify a whole mammographic exam, containing the CC and MLO views and the segmentation maps, as opposed to the classification of individual lesions, which is the dominant approach in the field. We also demonstrate that the proposed system is capable of using the segmentation maps generated by automated mass and micro-calcification detection systems, and still producing accurate results. The semi-automated approach (using manually defined mass and micro-calcification segmentation maps) is tested on two publicly available data sets (INbreast and DDSM), and results show that the volume under ROC surface (VUS) for a 3-class problem (normal tissue, benign, and malignant) is over 0.9, the area under ROC curve (AUC) for the 2-class "benign versus malignant" problem is over 0.9, and for the 2-class breast screening problem (malignancy versus normal/benign) is also over 0.9. For the fully automated approach, the VUS results on INbreast is over 0.7, and the AUC for the 2-class "benign versus malignant" problem is over 0.78, and the AUC for the 2-class breast screening is 0.86. PMID- 28920898 TI - Hybrid Pre-Log and Post-Log Image Reconstruction for Computed Tomography. AB - Tomographic image reconstruction for low-dose computed tomography (CT) is increasingly challenging as dose continues to reduce in clinical applications. Pre-log domain methods and post-log domain methods have been proposed individually and each method has its own disadvantage. While having the potential to improve image quality for low-dose data by using an accurate imaging model, pre-log domain methods suffer slow convergence in practice due to the nonlinear transformation from the image to measurements. In contrast, post-log domain methods have fast convergence speed but the resulting image quality is suboptimal for low dose CT data because the log transformation is extremely unreliable for low-count measurements and undefined for negative values. This paper proposes a hybrid method that integrates the pre-log model and post-log model together to overcome the disadvantages of individual pre-log and post-log methods. We divide a set of CT data into high-count and low-count regions. The post-log weighted least squares model is used for measurements in the high-count region and the pre log shifted Poisson model for measurements in the low-count region. The hybrid likelihood function can be optimized using an existing iterative algorithm. Computer simulations and phantom experiments show that the proposed hybrid method can achieve faster early convergence than the pre-log shifted Poisson likelihood method and better signal-to-noise performance than the post-log weighted least squares method. PMID- 28920899 TI - AutoBD: Automated Bi-Level Description for Scalable Fine-Grained Visual Categorization. AB - Compared with traditional image classification, fine-grained visual categorization is a more challenging task, because it targets to classify objects belonging to the same species, e.g., classify hundreds of birds or cars. In the past several years, researchers have made many achievements on this topic. However, most of them are heavily dependent on the artificial annotations, e.g., bounding boxes, part annotations, and so on. The requirement of artificial annotations largely hinders the scalability and application. Motivated to release such dependence, this paper proposes a robust and discriminative visual description named Automated Bi-level Description (AutoBD). "Bi-level" denotes two complementary part-level and object-level visual descriptions, respectively. AutoBD is "automated," because it only requires the image-level labels of training images and does not need any annotations for testing images. Compared with the part annotations labeled by the human, the image-level labels can be easily acquired, which thus makes AutoBD suitable for large-scale visual categorization. Specifically, the part-level description is extracted by identifying the local region saliently representing the visual distinctiveness. The object-level description is extracted from object bounding boxes generated with a co-localization algorithm. Although only using the image-level labels, AutoBD outperforms the recent studies on two public benchmark, i.e., classification accuracy achieves 81.6% on CUB-200-2011 and 88.9% on Car-196, respectively. On the large-scale Birdsnap data set, AutoBD achieves the accuracy of 68%, which is currently the best performance to the best of our knowledge.Compared with traditional image classification, fine-grained visual categorization is a more challenging task, because it targets to classify objects belonging to the same species, e.g., classify hundreds of birds or cars. In the past several years, researchers have made many achievements on this topic. However, most of them are heavily dependent on the artificial annotations, e.g., bounding boxes, part annotations, and so on. The requirement of artificial annotations largely hinders the scalability and application. Motivated to release such dependence, this paper proposes a robust and discriminative visual description named Automated Bi-level Description (AutoBD). "Bi-level" denotes two complementary part-level and object-level visual descriptions, respectively. AutoBD is "automated," because it only requires the image-level labels of training images and does not need any annotations for testing images. Compared with the part annotations labeled by the human, the image-level labels can be easily acquired, which thus makes AutoBD suitable for large-scale visual categorization. Specifically, the part-level description is extracted by identifying the local region saliently representing the visual distinctiveness. The object-level description is extracted from object bounding boxes generated with a co-localization algorithm. Although only using the image-level labels, AutoBD outperforms the recent studies on two public benchmark, i.e., classification accuracy achieves 81.6% on CUB-200-2011 and 88.9% on Car-196, respectively. On the large-scale Birdsnap data set, AutoBD achieves the accuracy of 68%, which is currently the best performance to the best of our knowledge. PMID- 28920900 TI - Fundamental Principles on Learning New Features for Effective Dense Matching. AB - In dense matching (including stereo matching and optical flow), nearly all existing approaches are based on simple features, such as gray or RGB color, gradient or simple transformations like census, to calculate matching costs. These features do not perform well in complex scenes that may involve radiometric changes, noises, overexposure and/or textureless regions. Various problems may appear, such as wrong matching at the pixel or region level, flattening/breaking of edges and/or even entire structural collapse. In this paper, we propose two fundamental principles based on the consistency and the distinctiveness of features. We show that almost all existing problems in dense matching are caused by features that violate one or both of these principles. To systematically learn good features for dense matching, we develop a general multi-objective optimization based on these two principles and apply convolutional neural networks to find new features that lie on the Pareto frontier. By using two-frame optical flow and stereo matching as applications, our experimental results show that the features learned can significantly improve the performance of state-of the-art approaches. Based on the KITTI benchmarks, our method ranks first on the two stereo benchmarks and is the best among existing two-frame optical-flow algorithms on flow benchmarks. PMID- 28920901 TI - Joint Graph Layouts for Visualizing Collections of Segmented Meshes. AB - We present a novel and efficient approach for computing joint graph layouts and then use it to visualize collections of segmented meshes. Our joint graph layout algorithm takes as input the adjacency matrices for a set of graphs along with partial, possibly soft, correspondences between nodes of different graphs. We then use a two stage procedure, where in the first step, we extend spectral graph drawing to include a consistency term so that a collection of graphs can be handled jointly. Our second step extends metric multi-dimensional scaling with stress majorization to the joint layout setting, while using the output of the spectral approach as initialization. Further, we discuss a user interface for exploring a collection of graphs. Finally, we show multiple example visualizations of graphs stemming from collections of segmented meshes and we present qualitative and quantitative comparisons with previous work. PMID- 28920902 TI - A Visual Analytics Framework for Identifying Topic Drivers in Media Events. AB - Media data has been the subject of large scale analysis with applications of text mining being used to provide overviews of media themes and information flows. Such information extracted from media articles has also shown its contextual value of being integrated with other data, such as criminal records and stock market pricing. In this work, we explore linking textual media data with curated secondary textual data sources through user-guided semantic lexical matching for identifying relationships and data links. In this manner, critical information can be identified and used to annotate media timelines in order to provide a more detailed overview of events that may be driving media topics and frames. These linked events are further analyzed through an application of causality modeling to model temporal drivers between the data series. Such causal links are then annotated through automatic entity extraction which enables the analyst to explore persons, locations, and organizations that may be pertinent to the media topic of interest. To demonstrate the proposed framework, two media datasets and an armed conflict event dataset are explored. PMID- 28920903 TI - Brain Control of an External Device by Extracting the Highest Force-Related Contents of Local Field Potentials in Freely Moving Rats. AB - A local field potential (LFP) signal is an alternative source to neural action potentials for decoding kinematic and kinetic information from the brain. Here, we demonstrate that the better extraction of force-related features from multichannel LFPs improves the accuracy of force decoding. We propose that applying canonical correlation analysis (CCA) filter on the envelopes of separate frequency bands (band-specific CCA) separates non-task related information from the LFPs. The decoding accuracy of the continuous force signal based on the proposed method were compared with three feature reduction methods: 1) band specific principal component analysis (band-specific PCA) method that extract the components which leads to maximum variance from the envelopes of different frequency bands; 2) correlation coefficient-based (CC-based) feature reduction that selects the best features from the envelopes sorted based on the absolute correlation coefficient between each envelope and the target force signal; and 3) mutual information-based (MI-based) feature reduction that selects the best features from the envelopes sorted based on the mutual information between each envelope and output force signal. The band-specific CCA method outperformed band specific PCA with 11% improvement, CC-based feature reduction with 16% improvement, and MI-based feature reduction with 18% improvement. In the online brain control experiments, the real-time decoded force signal from the 16-channel LFPs based on the proposed method was used to move a mechanical arm. Two rats performed 88 trials in seven sessions to control the mechanical arm based on the 16-channel LFPs. PMID- 28920904 TI - Modeling the Nonlinear Cortical Response in EEG Evoked by Wrist Joint Manipulation. AB - Joint manipulation elicits a response from the sensors in the periphery which, via the spinal cord, arrives in the cortex. The average evoked cortical response recorded using electroencephalography was shown to be highly nonlinear; a linear model can only explain 10% of the variance of the evoked response, and over 80% of the response is generated by nonlinear behavior. The goal of this paper is to obtain a nonparametric nonlinear dynamic model, which can consistently explain the recorded cortical response requiring little a priori assumptions about model structure. Wrist joint manipulation was applied in ten healthy participants during which their cortical activity was recorded and modeled using a truncated Volterra series. The obtained models could explain 46% of the variance of the evoked cortical response, thereby demonstrating the relevance of nonlinear modeling. The high similarity of the obtained models across participants indicates that the models reveal common characteristics of the underlying system. The models show predominantly high-pass behavior, which suggests that velocity related information originating from the muscle spindles governs the cortical response. In conclusion, the nonlinear modeling approach using a truncated Volterra series with regularization, provides a quantitative way of investigating the sensorimotor system, offering insight into the underlying physiology. PMID- 28920905 TI - Electrochemical Impedance Spectroscopy on Interdigitated Gold Microelectrodes for Glycosylated Human Serum Albumin Characterization. AB - Glycosylated albumin is considered as a potentially accurate indicator of shorter term average glucose concentration compared with the current standard HbA1c and as such, it is attracting the interest of the scientific community as a possible diagnosis marker for diabetic patients. The purpose of this paper is to achieve a better understanding of the glycation effect of albumin on its electrochemical properties. That is done through the use of Interdigitated gold microelectrodes (IDGE) as support in a label free impedimetric immunosensor for the detection of human serum albumin detection in glycated (GA) and non-glycated (HSA) form. Anti human serum albumin, a monoclonal antibody, was physisorbed on the surface of IDGE and used as a HSA/GA bioreceptor. Electrochemical impedance spectroscopy, cyclic voltammetry, and surface plasmon resonance imaging (SPRi) were used for the characterization of the grafted layers onto the gold surface. A detection range from 1 to 401 ng/mL of non glycated HSA antigen in phosphate buffered saline buffer was obtained with the impedance spectroscopy technique. The experiment led to the observation of a significant impedance difference between the glycated and non-glycated antigen of HSA. SPRi measurements confirmed these findings and allowed us to suggest an increase of the dielectric permittivity for human serum albumin upon glycation. PMID- 28920907 TI - Energy Analysis of Decoders for Rakeness-Based Compressed Sensing of ECG Signals. AB - In recent years, compressed sensing (CS) has proved to be effective in lowering the power consumption of sensing nodes in biomedical signal processing devices. This is due to the fact the CS is capable of reducing the amount of data to be transmitted to ensure correct reconstruction of the acquired waveforms. Rakeness based CS has been introduced to further reduce the amount of transmitted data by exploiting the uneven distribution to the sensed signal energy. Yet, so far no thorough analysis exists on the impact of its adoption on CS decoder performance. The latter point is of great importance, since body-area sensor network architectures may include intermediate gateway nodes that receive and reconstruct signals to provide local services before relaying data to a remote server. In this paper, we fill this gap by showing that rakeness-based design also improves reconstruction performance. We quantify these findings in the case of ECG signals and when a variety of reconstruction algorithms are used either in a low-power microcontroller or a heterogeneous mobile computing platform. PMID- 28920908 TI - A CMOS Front-End With Integrated Magnetoresistive Sensors for Biomolecular Recognition Detection Applications. AB - The development of giant magnetoresistive (GMR) sensors has demonstrated significant advantages in nanomedicine, particularly for ultrasensitive point-of care diagnostics. To this end, the detection system is required to be compact, portable, and low power consuming at the same time that a maximum signal to noise ratio is maintained. This paper reports a CMOS front-end with integrated magnetoresistive sensors for biomolecular recognition detection applications. Based on the characterization of the GMR sensor's signal and noise, CMOS building blocks (i.e., current source, multiplexers, and preamplifier) were designed targeting a negligible noise when compared with the GMR sensor's noise and a low power consumption. The CMOS front-end was fabricated using AMS [Formula: see text] technology and the magnetoresistive sensors were post-fabricated on top of the CMOS chip with high yield ( [Formula: see text]). Due to its low circuit noise (16 [Formula: see text]) and overall equivalent magnetic noise ([Formula: see text]), the full system was able to detect 250 nm magnetic nanoparticles with a circuit imposed signal-to-noise ratio degradation of only -1.4 dB. Furthermore, the low power consumption (6.5 mW) and small dimensions ([Formula: see text] ) of the presented solution guarantees the portability of the detection system allowing its usage at the point-of-care. PMID- 28920906 TI - ClotChip: A Microfluidic Dielectric Sensor for Point-of-Care Assessment of Hemostasis. AB - This paper describes the design, fabrication, and testing of a microfluidic sensor for dielectric spectroscopy of human whole blood during coagulation. The sensor, termed ClotChip, employs a three-dimensional, parallel-plate, capacitive sensing structure with a floating electrode integrated into a microfluidic channel. Interfaced with an impedance analyzer, the ClotChip measures the complex relative dielectric permittivity, epsilonr , of human whole blood in the frequency range of 40 Hz to 100 MHz. The temporal variation in the real part of the blood dielectric permittivity at 1 MHz features a time to reach a permittivity peak, , as well as a maximum change in permittivity after the peak, , as two distinct parameters of ClotChip readout. The ClotChip performance was benchmarked against rotational thromboelastometry (ROTEM) to evaluate the clinical utility of its readout parameters in capturing the clotting dynamics arising from coagulation factors and platelet activity. exhibited a very strong positive correlation ( r = 0.99, p < 0.0001) with the ROTEM clotting time parameter, whereas exhibited a strong positive correlation (r = 0.85, p < 0.001) with the ROTEM maximum clot firmness parameter. This paper demonstrates the ClotChip potential as a point-of-care platform to assess the complete hemostatic process using <10 MUL of human whole blood. PMID- 28920909 TI - Credit Card Fraud Detection: A Realistic Modeling and a Novel Learning Strategy. AB - Detecting frauds in credit card transactions is perhaps one of the best testbeds for computational intelligence algorithms. In fact, this problem involves a number of relevant challenges, namely: concept drift (customers' habits evolve and fraudsters change their strategies over time), class imbalance (genuine transactions far outnumber frauds), and verification latency (only a small set of transactions are timely checked by investigators). However, the vast majority of learning algorithms that have been proposed for fraud detection rely on assumptions that hardly hold in a real-world fraud-detection system (FDS). This lack of realism concerns two main aspects: 1) the way and timing with which supervised information is provided and 2) the measures used to assess fraud detection performance. This paper has three major contributions. First, we propose, with the help of our industrial partner, a formalization of the fraud detection problem that realistically describes the operating conditions of FDSs that everyday analyze massive streams of credit card transactions. We also illustrate the most appropriate performance measures to be used for fraud detection purposes. Second, we design and assess a novel learning strategy that effectively addresses class imbalance, concept drift, and verification latency. Third, in our experiments, we demonstrate the impact of class unbalance and concept drift in a real-world data stream containing more than 75 million transactions, authorized over a time window of three years. PMID- 28920910 TI - Online Density Estimation of Nonstationary Sources Using Exponential Family of Distributions. AB - We investigate online probability density estimation (or learning) of nonstationary (and memoryless) sources using exponential family of distributions. To this end, we introduce a truly sequential algorithm that achieves Hannan consistent log-loss regret performance against true probability distribution without requiring any information about the observation sequence (e.g., the time horizon $T$ and the drift of the underlying distribution $C$ ) to optimize its parameters. Our results are guaranteed to hold in an individual sequence manner. Our log-loss performance with respect to the true probability density has regret bounds of $O(({CT})^{1/2})$ , where $C$ is the total change (drift) in the natural parameters of the underlying distribution. To achieve this, we design a variety of probability density estimators with exponentially quantized learning rates and merge them with a mixture-of-experts notion. Hence, we achieve this square-root regret with computational complexity only logarithmic in the time horizon. Thus, our algorithm can be efficiently used in big data applications. Apart from the regret bounds, through synthetic and real-life experiments, we demonstrate substantial performance gains with respect to the state-of-the-art probability density estimation algorithms in the literature. PMID- 28920911 TI - Efficient Online Learning Algorithms Based on LSTM Neural Networks. AB - We investigate online nonlinear regression and introduce novel regression structures based on the long short term memory (LSTM) networks. For the introduced structures, we also provide highly efficient and effective online training methods. To train these novel LSTM-based structures, we put the underlying architecture in a state space form and introduce highly efficient and effective particle filtering (PF)-based updates. We also provide stochastic gradient descent and extended Kalman filter-based updates. Our PF-based training method guarantees convergence to the optimal parameter estimation in the mean square error sense provided that we have a sufficient number of particles and satisfy certain technical conditions. More importantly, we achieve this performance with a computational complexity in the order of the first-order gradient-based methods by controlling the number of particles. Since our approach is generic, we also introduce a gated recurrent unit (GRU)-based approach by directly replacing the LSTM architecture with the GRU architecture, where we demonstrate the superiority of our LSTM-based approach in the sequential prediction task via different real life data sets. In addition, the experimental results illustrate significant performance improvements achieved by the introduced algorithms with respect to the conventional methods over several different benchmark real life data sets. PMID- 28920912 TI - Superpixel-Based Foreground Extraction With Fast Adaptive Trimaps. AB - Extracting the foreground from a given complex image is an important and challenging problem. Although there have been many methods to perform foreground extraction, most of them are time-consuming, and the trimaps used in the matting step are labeled manually. In this paper, we propose a fast interactive foreground extraction method based on the superpixel GrabCut and image matting. Specifically, we first extract superpixels from a given image and apply GrabCut on them to obtain a raw mask. Due to that the resulting mask border is hard and toothing, we further propose fast and adaptive trimaps (FATs), and construct an FATs-based shared matting for computing a refined mask. Finally, by interactive processing, we can obtain the final foreground. Experimental results on the BSDS500 and alphamatting datasets demonstrate that our proposed method is faster than five representative methods, and performs better than the interactive representative methods in terms of the three evaluation criteria: 1) mean square error; 2) sum of absolute difference; and 3) execution time. PMID- 28920913 TI - Adaptive Control via Neural Output Feedback for a Class of Nonlinear Discrete Time Systems in a Nested Interconnected Form. AB - In this paper, an adaptive output feedback control is framed for uncertain nonlinear discrete-time systems. The considered systems are a class of multi input multioutput nonaffine nonlinear systems, and they are in the nested lower triangular form. Furthermore, the unknown dead-zone inputs are nonlinearly embedded into the systems. These properties of the systems will make it very difficult and challenging to construct a stable controller. By introducing a new diffeomorphism coordinate transformation, the controlled system is first transformed into a state-output model. By introducing a group of new variables, an input-output model is finally obtained. Based on the transformed model, the implicit function theorem is used to determine the existence of the ideal controllers and the approximators are employed to approximate the ideal controllers. By using the mean value theorem, the nonaffine functions of systems can become an affine structure but nonaffine terms still exist. The adaptation auxiliary terms are skillfully designed to cancel the effect of the dead-zone input. Based on the Lyapunov difference theorem, the boundedness of all the signals in the closed-loop system can be ensured and the tracking errors are kept in a bounded compact set. The effectiveness of the proposed technique is checked by a simulation study. PMID- 28920914 TI - Robust Visual Tracking via Online Discriminative and Low-Rank Dictionary Learning. AB - In this paper, we propose a novel and robust tracking framework based on online discriminative and low-rank dictionary learning. The primary aim of this paper is to obtain compact and low-rank dictionaries that can provide good discriminative representations of both target and background. We accomplish this by exploiting the recovery ability of low-rank matrices. That is if we assume that the data from the same class are linearly correlated, then the corresponding basis vectors learned from the training set of each class shall render the dictionary to become approximately low-rank. The proposed dictionary learning technique incorporates a reconstruction error that improves the reliability of classification. Also, a multiconstraint objective function is designed to enable active learning of a discriminative and robust dictionary. Further, an optimal solution is obtained by iteratively computing the dictionary, coefficients, and by simultaneously learning the classifier parameters. Finally, a simple yet effective likelihood function is implemented to estimate the optimal state of the target during tracking. Moreover, to make the dictionary adaptive to the variations of the target and background during tracking, an online update criterion is employed while learning the new dictionary. Experimental results on a publicly available benchmark dataset have demonstrated that the proposed tracking algorithm performs better than other state-of-the-art trackers. PMID- 28920915 TI - Revisiting local structural changes in GeO2 glass at high pressure. AB - Despite the great importance in fundamental and industrial fields, understanding structural changes for pressure-induced polyamorphism in network-forming glasses remains a formidable challenge. Here, we revisited the local structural transformations in GeO2 glass up to 54 GPa using x-ray absorption fine structure (XAFS) spectroscopy via a combination diamond anvil cell and polycapillary half lens. Three polyamorphic transitions can be clearly identified by XAFS structure refinement. First, a progressive increase of the nearest Ge-O distance and bond disorder to a maximum at ~5-16 GPa, in the same pressure region of previously observed tetrahedral-octahedral transformation. Second, a markedly decrease of the nearest Ge-O distance at ~16-22.6 GPa but a slight increase at ~22.6-32.7 GPa, with a concomitant decrease of bond disorder. This stage can be related to a second-order-like transition from less dense to dense octahedral glass. Third, another decrease in the nearest Ge-O distance at ~32.7-41.4 GPa but a slight increase up to 54 GPa, synchronized with a gradual increase of bond disorder. This stage provides strong evidence for ultrahigh-pressure polyamorphism with coordination number >6. Furthermore, cooperative modification is observed in more distant shells. Those results provide a unified local structural picture for elucidating the polyamorphic transitions and densification process in GeO2 glass. PMID- 28920916 TI - Monovacancy paramagnetism in neutron-irradiated graphite probed by 13C NMR. AB - We report on the magnetic properties of monovacancy defects in neutron-irradiated graphite, probed by $^{13}$C nuclear magnetic resonance spectroscopy. The bulk paramagnetism of the defect moments is revealed by the temperature dependence of the NMR frequency shift and spectral linewidth, both of which follow a Curie behavior, in agreement with measurements of the macroscopic magnetization. Compared to pristine graphite, the fluctuating hyperfine fields generated by the defect moments lead to an enhancement of the $^{13}$C nuclear spin-lattice relaxation rate $1/T_{1}$ by about two orders of magnitude. With an applied magnetic field of 7.1 T, the temperature dependence of $1/T_{1}$ below about 10 K can well be described by a thermally activated form, $1/T_{1}?propto?exp( ?Delta/k_{B}T)$, yielding a singular Zeeman energy of ($0.41?pm0.01$) meV, in excellent agreement with the sole presence of polarized, non-interacting defect moments. PMID- 28920917 TI - Study on the regulation of focal adesions and cortical actin by matrix nanotopography in 3D environment. AB - Matrix nanotopography plays an important role in regulating cell behaviors by providing spatial as well as mechanical cues for cells to sense. It has been proposed that nanoscale topography is possible to modulate the tensions which direct the formation of cytoskeleton and the organization of the membrane receptor within the cell, which in turn regulate intracellular mechanical and biochemical signaling. With current studies on this topic being performed mainly in 2D platforms, the question on how nanotopography can influence cell bahaviors in 3D environments has yet to be addressed. In this paper, we explored this question by placing cells in 3D hollow spherical polydimethylsiloxane scaffolds. After culturing rat embryonic fibroblast cells in two kinds of scaffold, one with smooth surface and the other with numerous nano-spikes, we observed that cells in the smooth scaffold have more anchoring sites and more focal adhesions than in the etched scaffold. Moreover, we found the presence of correlation between cortical actin, the important component for supporting cell attachment, and local cell geometry. PMID- 28920918 TI - Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus. AB - Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER-associated degradation (ERAD) is responsible for the clearance of misfolded pro-arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus. The results of this study demonstrate a role for ERAD in neuroendocrine cells and serve as a clinical example of the effect of misfolded ER proteins retrotranslocated through the membrane into the cytosol, where they are polyubiquitinated, extracted from the ER membrane, and degraded by the proteasome. Moreover, proAVP misfolding in hereditary central diabetes insipidus likely shares common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of youth. PMID- 28920919 TI - Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. AB - Inadequate pancreatic beta cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human beta cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of beta cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human beta cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human beta cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet beta cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human beta cell proliferation, and identify elements that could be adapted for therapeutic expansion of human beta cells. PMID- 28920921 TI - Increased intracellular proteolysis reduces disease severity in an ER stress associated dwarfism. AB - The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress-associated dwarfism MCDS. PMID- 28920920 TI - ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. AB - Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP producing neurons. Mice with global or AVP neuron-specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide-bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation. PMID- 28920923 TI - All TIEd up: mechanisms of Schlemm's canal maintenance. AB - Glaucoma is a leading cause of blindness, with an estimated world-wide prevalence of 3.5% in members of the population older than 40 years of age. Elevated intraocular pressure as the result of abnormal resistance to aqueous humor drainage is a major contributing, and the only preventable, factor in glaucoma development. Schlemm's canal (SC), a lymphatic-like vessel encircling the anterior portion of the eye, plays a key role in promoting aqueous humor outflow and maintenance of normal intraocular pressure. The risk of developing glaucoma increases with age; therefore, understanding mechanisms of SC maintenance and how aging affects SC function are of special importance, both for prevention and novel treatment approaches to glaucoma. Using a compelling array of genetic models, Kim et al. report in this issue of the JCI that continuous angiopoietin/TIE2 signaling is required for maintaining SC identity and integrity during adulthood and show that its age-related changes can be rescued by a TIE2 agonistic antibody. PMID- 28920922 TI - Galpha13 ablation reprograms myofibers to oxidative phenotype and enhances whole body metabolism. AB - Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge signals from cell surface receptors to potentiate or blunt responses against environmental changes. Here, we show that muscle-specific ablation of Galpha13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, Galpha13 and its downstream effector RhoA suppressed nuclear factor of activated T cells 1 (NFATc1), a chief regulator of myofiber conversion, by increasing Rho-associated kinase 2-mediated (Rock2-mediated) phosphorylation at Ser243. Ser243 phosphorylation of NFATc1 was reduced after exercise, but was higher in obese animals. Consequently, Galpha13 ablation in muscles enhanced whole-body energy metabolism and increased insulin sensitivity, thus affording protection from diet induced obesity and hepatic steatosis. Our results define Galpha13 as a switch regulator of myofiber reprogramming, implying that modulations of Galpha13 and its downstream effectors in skeletal muscle are a potential therapeutic approach to treating metabolic diseases. PMID- 28920924 TI - Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma. AB - Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma. PMID- 28920926 TI - Particulate allergens potentiate allergic asthma in mice through sustained IgE mediated mast cell activation. PMID- 28920925 TI - Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells. AB - P-element-induced wimpy testes (Piwi) proteins are known for suppressing retrotransposon activation in the mammalian germline. However, whether Piwi protein or Piwi-dependent functions occur in the mammalian soma is unclear. Contrary to germline-restricted expression, we observed that Piwi-like Miwi2 mRNA is indeed expressed in epithelial cells of the lung in adult mice and that it is induced during pneumonia. Further investigation revealed that MIWI2 protein localized to the cytoplasm of a discrete population of multiciliated airway epithelial cells. Isolation and next-generation sequencing of MIWI2-positive multiciliated cells revealed that they are phenotypically distinct from neighboring MIWI2-negative multiciliated cells. Mice lacking MIWI2 exhibited an altered balance of airway epithelial cells, demonstrating fewer multiciliated cells and an increase in club cells. During pneumococcal pneumonia, Miwi2 deficient mice exhibited increased expression of inflammatory mediators and increased immune cell recruitment, leading to enhanced bacterial clearance. Taken together, our data delineate MIWI2-dependent functions outside of the germline and demonstrate the presence of distinct subsets of airway multiciliated cells that can be discriminated by MIWI2 expression. By demonstrating roles for MIWI2 in airway cell identity and pulmonary innate immunity, these studies elucidate unanticipated physiological functions for Piwi proteins in somatic tissues. PMID- 28920927 TI - No Impact of Preadmission Anti-Inflammatory Drug Use on Risk of Depression and Anxiety After Critical Illness. AB - OBJECTIVES: Risk of depression and anxiety is elevated after intensive care. Drugs with anti-inflammatory properties may have antidepressant and anxiolytic effects. The aim of this study was to investigate the association between preadmission use of drugs with anti-inflammatory effects and risk of new-onset depression and anxiety among adult patients admitted to an ICU. DESIGN: Propensity score-matched, population-based cohort study. SETTING: All ICUs in Denmark from 2005 to 2013. PATIENTS: Adults receiving mechanical ventilation in an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 48,207 ICU patients were included. Exposures were preadmission single-agent or combined use of statins, nonsteroidal anti-inflammatory drugs, or glucocorticoids. Outcomes were cumulative incidence (risk) and risk ratio of new-onset psychiatrist diagnosed depression or anxiety or prescriptions for antidepressants or anxiolytics. Propensity score matching yielded 6,088 statin user pairs, 2,886 nonsteroidal anti-inflammatory drug user pairs, 1,440 glucocorticoid user pairs, and 1,743 combination drug user pairs. The cumulative incidence of anxiety and depression during the 3 years following intensive care was 18.0% (95% CI, 17.0 19.0%) for statin users, 21.3% (95% CI, 19.8-22.9%) for nonsteroidal anti inflammatory drug users, 17.4% (95% CI, 15.4-19.5%) for glucocorticoid users, and 19.0% (95% CI, 16.3-20.2%) for combination users. The cumulative incidence was similar in nonusers compared with users in all drug groups. The risk ratio of depression and anxiety 3 years after admission to ICU was 1.04 (95% CI, 0.96 1.13) for statin users, 1.00 (95% CI, 0.90-1.11) for nonsteroidal anti inflammatory drug users, 0.97 (95% CI, 0.82-1.14) for glucocorticoid users, and 1.05 (95% CI, 0.90-1.21) for combination users, compared with nonusers. Results were consistent across subgroups (gender, age, preadmission diseases, type of admission) and sensitivity analyses (depression and anxiety separately). CONCLUSIONS: Preadmission use of statins, nonsteroidal anti-inflammatory drugs, glucocorticoids, or combinations did not alter the risk of depression and anxiety after critical illness. PMID- 28920928 TI - Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy. AB - Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target. PMID- 28920929 TI - Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7gamma. AB - Nucleophosmin (NPM1) is a multifunctional nucleolar protein implicated in ribogenesis, centrosome duplication, cell cycle control, regulation of DNA repair and apoptotic response to stress stimuli. The majority of these functions are played through the interactions with a variety of protein partners. NPM1 is frequently overexpressed in solid tumors of different histological origin. Furthermore NPM1 is the most frequently mutated protein in acute myeloid leukemia (AML) patients. Mutations map to the C-terminal domain and lead to the aberrant and stable localization of the protein in the cytoplasm of leukemic blasts. Among NPM1 protein partners, a pivotal role is played by the tumor suppressor Fbw7gamma, an E3-ubiquitin ligase that degrades oncoproteins like c-MYC, cyclin E, Notch and c-jun. In AML with NPM1 mutations, Fbw7gamma is degraded following its abnormal cytosolic delocalization by mutated NPM1. This mechanism also applies to other tumor suppressors and it has been suggested that it may play a key role in leukemogenesis. Here we analyse the interaction between NPM1 and Fbw7gamma, by identifying the protein surfaces implicated in recognition and key aminoacids involved. Based on the results of computational methods, we propose a structural model for the interaction, which is substantiated by experimental findings on several site-directed mutants. We also extend the analysis to two other NPM1 partners (HIV Tat and CENP-W) and conclude that NPM1 uses the same molecular surface as a platform for recognizing different protein partners. We suggest that this region of NPM1 may be targeted for cancer treatment. PMID- 28920930 TI - GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle. AB - The GATOR1 (SEACIT) complex consisting of Iml1-Npr2-Npr3 inhibits target of rapamycin complex 1 (TORC1) in response to amino acid insufficiency. In glucose medium, Saccharomyces cerevisiae mutants lacking the function of this complex grow poorly in the absence of amino acid supplementation, despite showing hallmarks of increased TORC1 signaling. Such mutants sense that they are amino acid replete and thus repress metabolic activities that are important for achieving this state. We found that npr2Delta mutants have defective mitochondrial tricarboxylic acid (TCA)-cycle activity and retrograde response. Supplementation with glutamine, and especially aspartate, which are nitrogen containing forms of TCA-cycle intermediates, rescues growth of npr2Delta mutants. These amino acids are then consumed in biosynthetic pathways that require nitrogen to support proliferative metabolism. Our findings revealed that negative regulators of TORC1, such as GATOR1 (SEACIT), regulate the cataplerotic synthesis of these amino acids from the TCA cycle, in tune with the amino acid and nitrogen status of cells. PMID- 28920931 TI - Single-molecule FRET reveals the energy landscape of the full-length SAM-I riboswitch. AB - S-adenosyl-L-methionine (SAM) ligand binding induces major structural changes in SAM-I riboswitches, through which gene expression is regulated via transcription termination. Little is known about the conformations and motions governing the function of the full-length Bacillus subtilis yitJ SAM-I riboswitch. Therefore, we have explored its conformational energy landscape as a function of Mg2+ and SAM ligand concentrations using single-molecule Forster resonance energy transfer (smFRET) microscopy and hidden Markov modeling analysis. We resolved four conformational states both in the presence and the absence of SAM and determined their Mg2+-dependent fractional populations and conformational dynamics, including state lifetimes, interconversion rate coefficients and equilibration timescales. Riboswitches with terminator and antiterminator folds coexist, and SAM binding only gradually shifts the populations toward terminator states. We observed a pronounced acceleration of conformational transitions upon SAM binding, which may be crucial for off-switching during the brief decision window before expression of the downstream gene. PMID- 28920932 TI - A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity. AB - The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain. PMID- 28920933 TI - Modular organization of the brainstem noradrenaline system coordinates opposing learning states. AB - Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility. PMID- 28920934 TI - Esr1+ cells in the ventromedial hypothalamus control female aggression. AB - As an essential means of resolving conflicts, aggression is expressed by both sexes but often at a higher level in males than in females. Recent studies suggest that cells in the ventrolateral part of the ventromedial hypothalamus (VMHvl) that express estrogen receptor-alpha (Esr1) and progesterone receptor are essential for male but not female mouse aggression. In contrast, here we show that VMHvlEsr1+ cells are indispensable for female aggression. This population was active when females attacked naturally. Inactivation of these cells reduced female aggression whereas their activation elicited attack. Additionally, we found that female VMHvl contains two anatomically distinguishable subdivisions that showed differential gene expression, projection and activation patterns after mating and fighting. These results support an essential role of the VMHvl in both male and female aggression and reveal the existence of two previously unappreciated subdivisions in the female VMHvl that are involved in distinct social behaviors. PMID- 28920935 TI - Spinal cord injury-induced immunodeficiency is mediated by a sympathetic neuroendocrine adrenal reflex. AB - Acute spinal cord injury (SCI) causes systemic immunosuppression and life threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections. PMID- 28920937 TI - Resolving ultrafast exciton migration in organic solids at the nanoscale. AB - Effectiveness of molecular-based light harvesting relies on transport of excitons to charge-transfer sites. Measuring exciton migration, however, has been challenging because of the mismatch between nanoscale migration lengths and the diffraction limit. Instead of using bulk substrate quenching methods, here we define quenching boundaries all-optically with sub-diffraction resolution, thus characterizing spatiotemporal exciton migration on its native nanometre and picosecond scales. By transforming stimulated emission depletion microscopy into a time-resolved ultrafast approach, we measure a 16-nm migration length in poly(2,5-di(hexyloxy)cyanoterephthalylidene) conjugated polymer films. Combined with Monte Carlo exciton hopping simulations, we show that migration in these films is essentially diffusive because intrinsic chromophore energetic disorder is comparable to chromophore inhomogeneous broadening. Our approach will enable previously unattainable correlation of local material structure to exciton migration character, applicable not only to photovoltaic or display-destined organic semiconductors but also to explaining the quintessential exciton migration exhibited in photosynthesis. PMID- 28920936 TI - Dopamine induces soluble alpha-synuclein oligomers and nigrostriatal degeneration. AB - Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated alpha-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in alpha-synuclein transgenic mice. To address this, we manipulated both dopamine levels and alpha-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant alpha-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic alpha-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of alpha-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and alpha-synuclein aggregation. PMID- 28920938 TI - Partial breaking of the Coulombic ordering of ionic liquids confined in carbon nanopores. AB - Ionic liquids are composed of equal quantities of positive and negative ions. In the bulk, electrical neutrality occurs in these liquids due to Coulombic ordering, in which ion shells of alternating charge form around a central ion. Their structure under confinement is far less well understood. This hinders the widespread application of ionic liquids in technological applications. Here we use scattering experiments to resolve the structure of a widely used ionic liquid (EMI-TFSI) when it is confined inside nanoporous carbons. We show that Coulombic ordering reduces when the pores can accommodate only a single layer of ions. Instead, equally charged ion pairs are formed due to the induction of an electric potential of opposite sign in the carbon pore walls. This non-Coulombic ordering is further enhanced in the presence of an applied external electric potential. This finding opens the door for the design of better materials for electrochemical applications. PMID- 28920939 TI - Imaging and tuning polarity at SrTiO3 domain walls. AB - Electrostatic fields tune the ground state of interfaces between complex oxide materials. Electronic properties, such as conductivity and superconductivity, can be tuned and then used to create and control circuit elements and gate-defined devices. Here we show that naturally occurring twin boundaries, with properties that are different from their surrounding bulk, can tune the LaAlO3/SrTiO3 interface 2DEG at the nanoscale. In particular, SrTiO3 domain boundaries have the unusual distinction of remaining highly mobile down to low temperatures, and were recently suggested to be polar. Here we apply localized pressure to an individual SrTiO3 twin boundary and detect a change in LaAlO3/SrTiO3 interface current distribution. Our data directly confirm the existence of polarity at the twin boundaries, and demonstrate that they can serve as effective tunable gates. As the location of SrTiO3 domain walls can be controlled using external field stimuli, our findings suggest a novel approach to manipulate SrTiO3-based devices on the nanoscale. PMID- 28920940 TI - Self-replication: Nanostructure evolution. PMID- 28920941 TI - Reversible magnesium and aluminium ions insertion in cation-deficient anatase TiO2. AB - In contrast to monovalent lithium or sodium ions, the reversible insertion of multivalent ions such as Mg2+ and Al3+ into electrode materials remains an elusive goal. Here, we demonstrate a new strategy to achieve reversible Mg2+ and Al3+ insertion in anatase TiO2, achieved through aliovalent doping, to introduce a large number of titanium vacancies that act as intercalation sites. We present a broad range of experimental and theoretical characterizations that show a preferential insertion of multivalent ions into titanium vacancies, allowing a much greater capacity to be obtained compared to pure TiO2. This result highlights the possibility to use the chemistry of defects to unlock the electrochemical activity of known materials, providing a new strategy for the chemical design of materials for practical multivalent batteries. PMID- 28920942 TI - Exponential growth and selection in self-replicating materials from DNA origami rafts. AB - Self-replication and evolution under selective pressure are inherent phenomena in life, and but few artificial systems exhibit these phenomena. We have designed a system of DNA origami rafts that exponentially replicates a seed pattern, doubling the copies in each diurnal-like cycle of temperature and ultraviolet illumination, producing more than 7 million copies in 24 cycles. We demonstrate environmental selection in growing populations by incorporating pH-sensitive binding in two subpopulations. In one species, pH-sensitive triplex DNA bonds enable parent-daughter templating, while in the second species, triplex binding inhibits the formation of duplex DNA templating. At pH 5.3, the replication rate of species I is ~1.3-1.4 times faster than that of species II. At pH 7.8, the replication rates are reversed. When mixed together in the same vial, the progeny of species I replicate preferentially at pH 7.8; similarly at pH 5.3, the progeny of species II take over the system. This addressable selectivity should be adaptable to the selection and evolution of multi-component self-replicating materials in the nanoscopic-to-microscopic size range. PMID- 28920945 TI - Neutrophils: a cornerstone of liver ischemia and reperfusion injury. AB - Ischemia-reperfusion injury (IRI) is the main cause of morbidity and mortality due to graft rejection after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. This hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion phase, and is characterized by a large neutrophil recruitment to the liver. Production of cytokines, chemokines, and danger signals results in activation of resident hepatocytes, leukocytes, and Kupffer cells. The role of neutrophils as the main amplifiers of liver injury in IRI has been recognized in many publications. Several studies have shown that elimination of excessive neutrophils or inhibition of their function leads to reduction of liver injury and inflammation. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. In addition, the molecules necessary for this type of migration are poorly defined, as the liver presents an atypical sinusoidal vasculature in which the classical leukocyte migration paradigm only partially applies. This review summarizes recent advances in neutrophil-mediated liver damage, and its application to liver IRI. Basic mechanisms of activation of neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of danger signals, adhesion molecules, chemokines, glycosaminoglycans (GAGs), and metalloproteinases is explored. The precise definition of the molecular events that govern the recruitment of neutrophils and their movement into inflamed tissue may offer new therapeutic alternatives for hepatic injury by IRI and other inflammatory diseases of the liver. PMID- 28920944 TI - The dosage-dependent effect exerted by the NM23-H1/H2 homolog NDK-1 on distal tip cell migration in C. elegans. AB - Abnormal regulation of cell migration and altered rearrangement of the cytoskeleton are fundamental properties of metastatic cells. The first identified metastasis suppressor NM23-H1, which displays nucleoside-diphosphate kinase (NDPK) activity is involved in these processes. NM23-H1 inhibits the migratory and invasive potential of some cancer cells. Correspondingly, numerous invasive cancer cell lines (eg, breast, colon, oral, hepatocellular carcinoma, and melanoma) display low endogenous NM23 levels. In this review, we summarize mechanisms, which are linked to the anti-metastatic activity of NM23. In human cancer cell lines NM23-H1 was shown to regulate cytoskeleton dynamics through inactivation of Rho/Rac-type GTPases. The Drosophila melanogaster NM23 homolog abnormal wing disc (AWD) controls tracheal and border cell migration. The molecular function of AWD is well characterized in both processes as a GTP supplier of Shi/Dynamin whereby AWD regulates the level of chemotactic receptors on the surface of migrating cells through receptor internalization, by its endocytic function. Our group studied the role of the sole group I NDPK, NDK-1 in distal tip cell (DTC) migration in Caenorhabditis elegans. In the absence of NDK 1 the migration of DTCs is incomplete. A half dosage of NDPK as present in ndk-1 (+/-) heterozygotes results in extra turns and overshoots of migrating gonad arms. Conversely, an elevated NDPK level also leads to incomplete gonadal migration owing to a premature stop of DTCs in the third phase of migration, where NDK-1 acts. We propose that NDK-1 exerts a dosage-dependent effect on the migration of DTCs. Our data derived from DTC migration in C. elegans is consistent with data on AWD's function in Drosophila. The combined data suggest that NDPK enzymes control the availability of surface receptors to regulate cell sensing cues during cell migration. The dosage of NDPKs may be a coupling factor in cell migration by modulating the efficiency of receptor recycling. PMID- 28920943 TI - Expression, function, and regulation of the embryonic transcription factor TBX1 in parathyroid tumors. AB - Transcription factors active in embryonic parathyroid cells can be maintained in adult parathyroids and be involved in tumorigenesis. TBX1, the candidate gene of 22q11.2-DiGeorge syndrome, which includes congenital hypoparathyroidism, is involved in parathyroid embryogenesis. The study aimed to investigate expression, function, and regulation of the parathyroid embryonic transcription factor TBX1 in human parathyroid adult normal and tumor tissues. TBX1 transcripts were detected in normal parathyroids and were deregulated in parathyroid tumors. Using immunohistochemistry, TBX1 protein was detected, mainly at the nuclear level, in a consistent proportion of cells in normal adult parathyroids, whereas TBX1 immunoreactivity was absent in fetal parathyroids. TBX1-expressing cells were markedly reduced in about a half of adenomas (PAds) and two-thirds of carcinomas and the proportion of TBX1-expressing cells negatively correlated with the serum albumin-corrected calcium levels in the analyzed tumors. Moreover, a subset of TBX1-expressing tumor cells coexpressed PTH. TBX1 silencing in HEK293 cells, expressing endogenous TBX1, increased the proportion of cells in the G0/G1 phase of cell cycle; concomitantly, CDKN1A/p21 and CDKN2A/p16 transcripts increased and ID1 mRNA levels decreased. TBX1 silencing exerted similar effects in PAd-derived cells, suggesting cell cycle arrest. Moreover, in PAd-derived cells GCM2 and PTH mRNA levels were unaffected by TBX1 deficiency, whereas it was associated with reduction of WNT5A, an antagonist of canonical WNT/beta-catenin pathway. WNT/beta catenin activation by lithium chloride inhibited TBX1 expression levels both in HEK293 and PAd-derived cells. In conclusion, TBX1 is expressed in adult parathyroid cells and deregulated in parathyroid tumors, where TBX1 deficiency may potentially contribute to the low proliferative nature of parathyroid tumors. PMID- 28920946 TI - Potential niche indications for blinatumomab as a bridge to hematopoietic cell transplantation. PMID- 28920947 TI - The capacity-building approach was successful in the start-up process of the first HSCT center in Iraqi Kurdistan. PMID- 28920948 TI - Rejection of paternal vs maternal fully matched bone marrow grafts in children with thalassemia. PMID- 28920950 TI - Impact of a dedicated post-transplant vaccination service at an Australian cancer centre. PMID- 28920949 TI - Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis. AB - Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (?60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11 41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI. PMID- 28920951 TI - Srebp-controlled glucose metabolism is essential for NK cell functional responses. AB - Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate-malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate-malate shuttle inhibited production of interferon-gamma and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function. PMID- 28920952 TI - MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. AB - TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders can, in certain conditions, be attributed to RIPK1 kinase-dependent cell death. Survival, however, is the default response of most cells to TNF stimulation, indicating that cell demise is normally actively repressed and that specific checkpoints must be turned off for cell death to proceed. We identified RIPK1 as a direct substrate of MK2 in the TNFR1 signalling pathway. Phosphorylation of RIPK1 by MK2 limits cytosolic activation of RIPK1 and the subsequent assembly of the death complex that drives RIPK1 kinase-dependent apoptosis and necroptosis. In line with these in vitro findings, MK2 inactivation greatly sensitizes mice to the cytotoxic effects of TNF in an acute model of sterile shock caused by RIPK1-dependent cell death. In conclusion, we identified MK2-mediated RIPK1 phosphorylation as an important molecular mechanism limiting the sensitivity of the cells to the cytotoxic effects of TNF. PMID- 28920953 TI - Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny. AB - Current dogma asserts that mammalian lifelong blood production is established by a small number of blood progenitors. However, this model is based on assays that require the disruption, transplantation and/or culture of embryonic tissues. Here, we used the sample-to-sample variance of a multicoloured lineage trace reporter to assess the frequency of emerging lifelong blood progenitors while avoiding the disruption, culture or transplantation of embryos. We find that approximately 719 Flk1+ mesodermal precursors, 633 VE-cadherin+ endothelial precursors and 545 Vav1+ nascent blood stem and progenitor cells emerge to establish the haematopoietic system at embryonic days (E)7-E8.5, E8.5-E11.5 and E11.5-E14.5, respectively. We also determined that the spatio-temporal recruitment of endothelial blood precursors begins at E8.5 and ends by E10.5, and that many c-Kit+ clusters of newly specified blood progenitors in the aorta are polyclonal in origin. Our work illuminates the dynamics of the developing mammalian blood system during homeostasis. PMID- 28920954 TI - p38MAPK/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. AB - Receptor-interacting protein kinase-1 (RIPK1), a master regulator of cell fate decisions, was identified as a direct substrate of MAPKAP kinase-2 (MK2) by phosphoproteomic screens using LPS-treated macrophages and stress-stimulated embryonic fibroblasts. p38MAPK/MK2 interact with RIPK1 in a cytoplasmic complex and MK2 phosphorylates mouse RIPK1 at Ser321/336 in response to pro-inflammatory stimuli, such as TNF and LPS, and infection with the pathogen Yersinia enterocolitica. MK2 phosphorylation inhibits RIPK1 autophosphorylation, curtails RIPK1 integration into cytoplasmic cytotoxic complexes, and suppresses RIPK1 dependent apoptosis and necroptosis. In Yersinia-infected macrophages, RIPK1 phosphorylation by MK2 protects against infection-induced apoptosis, a process targeted by Yersinia outer protein P (YopP). YopP suppresses p38MAPK/MK2 activation to increase Yersinia-driven apoptosis. Hence, MK2 phosphorylation of RIPK1 is a crucial checkpoint for cell fate in inflammation and infection that determines the outcome of bacteria-host cell interaction. PMID- 28920955 TI - miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. AB - The mechanisms by which hypoxic tumours evade immunological pressure and anti tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies. PMID- 28920956 TI - Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. AB - Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre inducible method for cell-type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knock-in mice carrying frequent RTT-associated mutations (encoding T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene-expression changes were largely specific to each RTT-associated mutation and cell type. Lowly expressed cell-type enriched genes were preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2-mutant neurons further revealed reductions in the nascent transcription of long genes and uncovered widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene-expression changes between neighboring wild-type and mutant neurons, providing contextual insights into RTT etiology that support personalized therapeutic interventions. PMID- 28920957 TI - KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. AB - A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis. PMID- 28920958 TI - The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. AB - N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia. PMID- 28920959 TI - Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. AB - Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell enriched (CD34+ and CD34+CD38-) and differentiated (CD34-) cells derived from individuals with CML, and we compared the signature of these cells with that of their normal counterparts. Through combination of stable isotope-assisted metabolomics with functional assays, we demonstrate that primitive CML cells rely on upregulated oxidative metabolism for their survival. We also show that combination treatment with imatinib and tigecycline, an antibiotic that inhibits mitochondrial protein translation, selectively eradicates CML LSCs both in vitro and in a xenotransplantation model of human CML. Our findings provide a strong rationale for investigation of the use of TKIs in combination with tigecycline to treat patients with CML with minimal residual disease. PMID- 28920960 TI - Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma. AB - Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs. PMID- 28920961 TI - Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control. AB - Covalent modifications of histones have an established role as chromatin effectors, as they control processes such as DNA replication and transcription, and repair or regulate nucleosomal structure. Loss of modifications on histone N tails, whether due to mutations in genes belonging to histone-modifying complexes or mutations directly affecting the histone tails, causes developmental disorders or has a role in tumorigenesis. More recently, modifications affecting the globular histone core have been uncovered as being crucial for DNA repair, pluripotency and oncogenesis. Here we report monoallelic missense mutations affecting lysine 91 in the histone H4 core (H4K91) in three individuals with a syndrome of growth delay, microcephaly and intellectual disability. Expression of the histone H4 mutants in zebrafish embryos recapitulates the developmental anomalies seen in the patients. We show that the histone H4 alterations cause genomic instability, resulting in increased apoptosis and cell cycle progression anomalies during early development. Mechanistically, our findings indicate an important role for the ubiquitination of H4K91 in genomic stability during embryonic development. PMID- 28920962 TI - Coplanar semiconductor-metal circuitry defined on few-layer MoTe2 via polymorphic heteroepitaxy. AB - Crystal polymorphism selectively stabilizes the electronic phase of atomically thin transition-metal dichalcogenides (TMDCs) as metallic or semiconducting, suggesting the potential to integrate these polymorphs as circuit components in two-dimensional electronic circuitry. Developing a selective and sequential growth strategy for such two-dimensional polymorphs in the vapour phase is a critical step in this endeavour. Here, we report on the polymorphic integration of distinct metallic (1T') and semiconducting (2H) MoTe2 crystals within the same atomic planes by heteroepitaxy. The realized polymorphic coplanar contact is atomically coherent, and its barrier potential is spatially tight-confined over a length of only a few nanometres, with a lowest contact barrier height of ~25 meV. We also demonstrate the generality of our synthetic integration approach for other TMDC polymorph films with large areas. PMID- 28920963 TI - Tuning a circular p-n junction in graphene from quantum confinement to optical guiding. AB - The photon-like propagation of the Dirac electrons in graphene, together with its record-high electronic mobility, can lead to applications based on ultrafast electronic response and low dissipation. However, the chiral nature of the charge carriers that is responsible for the high mobility also makes it difficult to control their motion and prevents electronic switching. Here, we show how to manipulate the charge carriers by using a circular p-n junction whose size can be continuously tuned from the nanometre to the micrometre scale. The junction size is controlled with a dual-gate device consisting of a planar back gate and a point-like top gate made by decorating a scanning tunnelling microscope tip with a gold nanowire. The nanometre-scale junction is defined by a deep potential well created by the tip-induced charge. It traps the Dirac electrons in quantum confined states, which are the graphene equivalent of the atomic collapse states (ACSs) predicted to occur at supercritically charged nuclei. As the junction size increases, the transition to the optical regime is signalled by the emergence of whispering-gallery modes, similar to those observed at the perimeter of acoustic or optical resonators, and by the appearance of a Fabry-Perot interference pattern for junctions close to a boundary. PMID- 28920964 TI - Directed emission of CdSe nanoplatelets originating from strongly anisotropic 2D electronic structure. AB - Intrinsically directional light emitters are potentially important for applications in photonics including lasing and energy-efficient display technology. Here, we propose a new route to overcome intrinsic efficiency limitations in light-emitting devices by studying a CdSe nanoplatelets monolayer that exhibits strongly anisotropic, directed photoluminescence. Analysis of the two-dimensional k-space distribution reveals the underlying internal transition dipole distribution. The observed directed emission is related to the anisotropy of the electronic Bloch states governing the exciton transition dipole moment and forming a bright plane. The strongly directed emission perpendicular to the platelet is further enhanced by the optical local density of states and local fields. In contrast to the emission directionality, the off-resonant absorption into the energetically higher 2D-continuum of states is isotropic. These contrasting optical properties make the oriented CdSe nanoplatelets, or superstructures of parallel-oriented platelets, an interesting and potentially useful class of semiconductor-based emitters. PMID- 28920965 TI - Conformation-based signal transfer and processing at the single-molecule level. AB - Building electronic components made of individual molecules is a promising strategy for the miniaturization and integration of electronic devices. However, the practical realization of molecular devices and circuits for signal transmission and processing at room temperature has proven challenging. Here, we present room-temperature intermolecular signal transfer and processing using SnCl2Pc molecules on a Cu(100) surface. The in-plane orientations of the molecules are effectively coupled via intermolecular interaction and serve as the information carrier. In the coupled molecular arrays, the signal can be transferred from one molecule to another in the in-plane direction along predesigned routes and processed to realize logical operations. These phenomena enable the use of molecules displaying intrinsic bistable states as complex molecular devices and circuits with novel functions. PMID- 28920966 TI - [Prevention of cardiovascular diseases - Prophylactic program in a selected enterprise]. AB - BACKGROUND: In Poland cardiovascular diseases (CVD), classified as work-related diseases, are responsible for 25% of disability and cause 50% of all deaths, including 26.9% of deaths in people aged under 65 years. The aim of the study was to analyze employee expectations regarding CVD- oriented prophylactic activities in the selected enterprise. MATERIAL AND METHODS: A questionnaire, developed for this study, consists of: socio-demographic data, job characteristics, occupational factors, and questions about the respondents' expectations concerning the prevention program. The study group comprised 407 multi-profile company employees aged (mean) 46.7 years (standard deviation (SD) = 9.1), including 330 men (81.1%), mean age = 46.9 (SD = 9.2) and 77 women (18.9%), mean age = 45.9 (SD = 8.2) The study was performed using the method of auditorium survey. RESULTS: Employees declared the need for actions related to physical activity: use of gym, swimming pool, tennis (56.5%), smoking habits - education sessions on quitting smoking (24.6%). A few people were interested in activities related to healthy diet. According to the majority of the study group, the scope of preventive examinations should be expanded. Based on our own findings and literature data CVD- -oriented preventive program, addressed to the analyzed enterprise was prepared. The program will be presented in another paper. CONCLUSIONS: The results showed significant quantitative and qualitative differences in the classic and occupational CVD risk factors between men and women, as well as in preferences for participation in prevention programs. Therefore, gender differences should be taken into account when planning prevention programs. Med Pr 2017;68(6):757-769. PMID- 28920967 TI - [Facial prosthetics: grounds and techniques]. AB - Surgical treatment of advanced facial tumours is often physically, functionally and emotionally debilitating. The resulting defects often give grounds for surgical reconstruction, prosthetic reconstruction or a combination of both. During the past two decades, huge advances have been achieved in the development of prostheses. This has led to improved rehabilitation of facial defects. In the clinic of the Netherlands Cancer Institute - Antoni van Leeuwenhoek, both adhesive- and implant-retained facial prostheses are used. In recent decades, implant-retained prostheses have been used increasingly often. Patient satisfaction rates are very high for both types of prostheses. PMID- 28920968 TI - [A solitary, defined radiolucency on a panoramic radiograph; cyst or no cyst?] AB - Sharply defined radiolucencies on a panoramic radiograph are often interpreted as cystic laesions. In some cases, however, it appears to be another condition, or an anatomical variation. In the present case, involving 2 healthy patients, 1 or more sharply defined lucencies were seen in the lateral parts of the mandible. After exploration, in both cases, an empty cavity was found without epithelial lining, which is pathognomonic for a simple bone cyst. Multiple occurrences are uncommon. PMID- 28920969 TI - [Disease burden of extreme treatment anxiety; quality of life for patients with and without extreme dental treatment anxiety]. AB - In this study, a comparison was made between disease-specific (oral health related) quality of life (OHQoL), measured with the OHIP-14 questionnaire, and generic (general health-related) quality of life (GHQoL), measured with the EQ5D 5L questionnaire, in patients with and without extreme dental treatment anxiety. A total of 76 patients who could not be treated due to extreme dental treatment anxiety were referred to a centre for special dentistry. These patients were matched, according to age, gender and socioeconomic status, with participants in an epidemiological study on oral health (n = 1125). Wilcoxon signed-rank tests were used on both groups to compare GHQoL and OHQoL. The total OHIP score was higher (representing a lower quality of life) in the patient group than in the control group. Anxiety patients scored higher on all 7 domains of the OHIP-14. With respect to general quality of life, patients with extreme treatment anxiety were found to report lower utility scores than the matched control group. With these results, a total disease burden of 74,000 disability-adjusted life years (DALYs) was calculated for extreme treatment anxiety in the Netherlands. The findings of this study reveal that having extreme dental treatment anxiety results in a significant disease burden in the Netherlands. PMID- 28920970 TI - [Mind your teeth - the relationship between mastication and cognition]. AB - Elderly persons, especially those suffering from dementia, are at great risk of suffering from oral health problems such as orofacial pain and loss of natural teeth. A possible explanation could be that the cognitive and motor impairments resulting from dementia cause a decrease in self-care and as such, a worsening of oral health. An alternative explanation is that cognition and oral health influence each other. Animal studies show that a decrease in masticatory activity, for example due to a soft diet or loss of teeth, causes memory loss and neuronal degeneration. The relationship between mastication and cognition has also been researched in human studies, but a cause-effect relationship is not yet evident. It is likely that multiple factors play a role in this relationship, such as self-care, nutrition, stress and pain. PMID- 28920971 TI - [Dental erosion and young adults: what do they know and how would they like to receive information?] AB - Dental erosion occurs often among adolescents and young adults in the Netherlands. This problem requires attention because its consequences are irreversible. In this study (part of the 'Dental Research and Practice in the North Netherlands' project) a questionnaire was distributed to 331 young adults (age 20 to 25) from 25 dental practices. The goal of the study was to find out how much young adults know about dental erosion and how they wish to receive dental information. The results show that much is still unknown about dental erosion among young adults and that the extent of knowledge depended of the level of education and on information on dental erosion that had already been received. Participants preferred to receive information in a conversation with an oral healthcare professional, with the support of printed matter. PMID- 28920975 TI - Correction: Visible-light-enhanced power generation in microbial fuel cells coupling with 3D nitrogen-doped graphene. AB - Correction for 'Visible-light-enhanced power generation in microbial fuel cells coupling with 3D nitrogen-doped graphene' by Dan Guo et al., Chem. Commun., 2017, DOI: . PMID- 28920972 TI - [A PhD completed. Prevention and treatment of peri-implant diseases: cleaning of titanium dental implant surfaces]. AB - The effect of various instruments on titanium dental implant surfaces was evaluated. Furthermore, a clinical guideline was developed regarding the diagnosis, prevention and treatment of peri-implant diseases. Air abrasive devices appear to be the most suitable meachnical instruments to remove biofilm from implant surfaces. From the available chemotherapeutica, (citric)acid and hydrogen peroxide seem to have the best potential. Regular controls and meticulous maintenance from both the patients and dental care professionals are mandatory to avoid problems. Baseline clinical and radiographic recordings are important to be able to follow implants over time and to differentiate between health and disease. The first time to assess probing pocket depths around implants should be preferably around 8 weeks after prosthetic installation. Changes in clinical and/or radiographic parameters can be an alarming sign. Patients should receive individually tailored instructions for optimal oral hygiene. Prevention and early diagnosis is the key for long-term success with dental implants. PMID- 28920976 TI - Rhodium-catalyzed odorless synthesis of diaryl sulfides from borylarenes and S aryl thiosulfonates. AB - Various diaryl sulfides, including heteroaryl- and nitrogen-containing sulfides, have been efficiently prepared by rhodium-catalyzed odorless deborylative arylthiolation of organoborons with S-aryl thiosulfonates. The ready availability of starting materials and further transformation of sulfides have rendered a diverse range of organosulfur compounds easily accessible. PMID- 28920977 TI - Axial substitution of a precursor resulted in two high-energy copper(ii) complexes with superior detonation performances. AB - The design and synthesis of explosives with high performance, good thermal stability, and low sensitivity is an important subject for the development of energetic materials. Energetic complexes have recently emerged as a promising energetic material form. As one of the representatives, [Cu(Htztr)2(H2O)2]n (H2tztr = 3-(1H-tetrazol-5-yl)-1H-triazole) was previously reported with good energetic performance, outstanding thermostability (Tdec = 345 degrees C) and low sensitivity to impact and friction stimuli. However, due to the existence of water molecules, its effective energy density is remarkably decreased, resulting in a diminished detonation performance. In order to further improve the detonation performance, using [Cu(Htztr)2(H2O)2]n as a precursor, {[Cu(Htztr)(H2O)]NO3}n (1) and [Cu(H2tztr)2(HCOO)2]n (2) were synthesized by the axial substitution reaction with NO3- and HCOO-. The structures of 1 and 2 were characterized by single crystal X-ray diffraction. Both of them exhibit high thermal stabilities and insensitivities to impact and friction. Moreover, the same DFT calculation methodology shows that the heat of detonation of 2 (3.5663 kcal g-1) is significantly higher than that of the precursor [Cu(Htztr)2(H2O)2]n (2.1281 kcal g-1). Meanwhile, the empirical Kamlet-Jacobs equations were used to theoretically predict the detonation properties of the title complexes, and the results show that 1 and 2 have excellent detonation velocity (D) and detonation pressure (P). PMID- 28920978 TI - A two-photon fluorescent probe for ratiometric imaging of endogenous hypochlorous acid in live cells and tissues. AB - A fluorescent probe that enables ratiometric imaging of endogenous hypochlorous acid (HOCl) in cells and tissues by two-photon microscopy is developed based on a red-emitting acetyl-benzocoumarin (AcBC) dye. An oxathiolane group in the probe reacts with HOCl to generate the AcBC dye, which involves a ratiometric fluorescence change only toward HOCl along with high sensitivity. PMID- 28920979 TI - Structure and thermal relaxation of network units and crystallization of lithium silicate based glasses doped with oxides of Al and B. AB - The current study reports on the relaxation behaviour of lithium silicate based glasses as probed by NMR spectroscopy. A total of four glass compositions were studied with the parent composition being 28Li2O-72SiO2, and added dopants of Al and B. All the compositions showed significant differences in the NMR spectra of both annealed and non-annealed glasses demonstrating the structural relaxation behaviour. We extended our binary statistical mechanical model to these complex compositions to study the relaxation behaviour. By the combined use of the extended statistical mechanical model and broken ergodicity, we shed light on the mechanism of structural relaxation as understood by NMR spectroscopy. We studied the crystallization behaviour of the glasses and reported on the variations of the residual glass composition changes in the crystallization fraction. PMID- 28920980 TI - Glaser-Hay hetero-coupling in a bimetallic regime: a Ni(ii)/Ag(i) assisted base, ligand and additive free route to selective unsymmetrical 1,3-diynes. AB - A Ni(OAc)2/Ag(OTf) catalysed coupling of aryl alkynes and propargylic alcohol/ether/ester gave the corresponding unsymmetrical 1,3-diynes in good to excellent yields. The reaction does not require bases, ligands or additives and shows excellent hetero-selectivity, thereby addressing the current challenges in the field of coupling of two different terminal alkynes. PMID- 28920981 TI - Oxygenation of RZn(N,O)-type complexes as an efficient route to zinc alkoxides not accessible via the classical alcoholysis path. AB - The controlled oxygenation of alkylzinc complexes supported by a 2-ester substituted pyrrolate ligand (L) leads to zinc alkoxides with an uncommon structural motif in the solid state: a trimer [(L)Zn(MU-OtBu)]3 with the central [Zn3(MU-OR)3] ring and a tetramer [(L)Zn(MU3-OEt)]4 with a heterocubane-type structure. Strikingly, these seemingly simple zinc alkoxides are not accessible via the classical alcoholysis route. PMID- 28920982 TI - Ruthenium-catalysed one-pot regio- and diastereoselective synthesis of pyrrolo[1,2-a]indoles via cascade C-H functionalization/annulation. AB - A cascade approach has been developed towards dual C-C bond formation via consecutive C-H functionalization/cyclization giving access to pyrrolo[1,2 a]indoles in a highly regio- and diastereoselective manner using catalytic [Ru(p cymene)Cl2]2. The methodology was further expanded to attain pentacyclic structures involving manifold C-C bond creation. PMID- 28920983 TI - Unified elucidation of the entropy-driven and -opposed hydrophobic effects. AB - The association of nonpolar solutes is generally believed to be entropy driven, which has been shown to be true for the contact of small molecules, ellipsoids, and plates. However, it has been reported with surprise that a model cavity ligand binding is entropy opposed. How can these apparently conflicting behaviors be elucidated? Here, we calculate the potential of mean force between hard-sphere solutes with various diameters in water and its entropic and enthalpic components using a statistical-mechanical theory for molecular liquids. It is shown that there is a very wide region where both of the two components are negative and large with the entropy-enthalpy compensation. Even for spheres, their contact is weakly entropy opposed when they are medium-sized. The entropic component (EC) is decomposed into physically insightful constituents with the aid of our morphometric approach. They provide us with useful information on the signs and magnitudes of contributions from the structural difference between the water near a single solute surface and that within the space confined between two solute surfaces and from the total volume available for the translational displacement of water molecules in the system. The decomposition enables us to identify the essential factors for discussing the EC: the hydrogen-bonding properties and density structure of the water within the confined space and the degree of water crowding in the bulk. These are largely dependent on the geometric characteristics of the solute pair such as solute shape, size, and intersolute distance. Both of the entropy-driven and -opposed hydrophobic effects can be explained within the same theoretical framework. PMID- 28920984 TI - Tailoring the morphology followed by the electrochemical performance of NiMn-LDH nanosheet arrays through controlled Co-doping for high-energy and power asymmetric supercapacitors. AB - Herein, we tailor the surface morphology of nickel-manganese-layered double hydroxide (NiMn-LDH) nanostructures on 3D nickel-foam via a step-wise cobalt (Co) doping hydrothermal chemical process. At the 10% optimum level of Co-doping, we noticed a thriving tuned morphological pattern of NiMn-LDH nanostructures (NiCoMn LDH (10%)) in terms of the porosity of the nanosheet (NS) arrays which not only improves the rate capability as well as cycling stability, but also demonstrates nearly two-fold specific capacitance enhancement compared to Co-free and other NiCoMn-LDH electrodes with a half-cell configuration in 3 M KOH, suggesting that Co-doping is indispensable for improving the electrochemical performance of NiMn LDH electrodes. Moreover, when this high performing NiCoMn-LDH (10%) electrode is employed as a cathode material to fabricate an asymmetric supercapacitor (ASC) device with reduced graphene oxide (rGO) as an anode material, excellent energy storage performance (57.4 Wh kg-1 at 749.9 W kg-1) and cycling stability (89.4% capacitive retention even after 2500 cycles) are corroborated. Additionally, we present a demonstration of illuminating a light emitting diode for 600 s with the NiCoMn-LDH (10%)//rGO ASC device, evidencing the potential of the NiCoMn-LDH (10%) electrode in fabricating energy storage devices. PMID- 28920985 TI - Enantioselective synthesis of sterically hindered alpha-allyl-alpha-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation. AB - The highly enantioselective synthesis of sterically hindered alpha-allyl-alpha aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3 position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of alpha-aryl-beta-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding alpha-allyl-alpha-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 alpha aryl-beta-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted alpha-allyl-alpha-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed. PMID- 28920986 TI - Stratification in binary colloidal polymer films: experiment and simulations. AB - : When films are deposited from mixtures of colloidal particles of two different sizes, a diverse range of functional structures can result. One structure of particular interest is a stratified film in which the top surface layer has a composition different than in the interior. Here, we explore the conditions under which a stratified layer of small particles develops spontaneously in a colloidal film that is cast from a binary mixture of small and large polymer particles that are suspended in water. A recent model, which considers the cross-interaction between the large and small particles (Zhou et al., Phys. Rev. Lett., 2017, 118, 108002), predicts that stratification will develop from dilute binary mixtures when the particle size ratio (alpha), initial volume fraction of small particles (phiS), and Peclet number are high. In experiments and Langevin dynamics simulations, we systematically vary alpha and phiS in both dilute and concentrated suspensions. We find that stratified films develop when phiS is increased, which is in agreement with the model. In dilute suspensions, there is reasonable agreement between the experiments and the Zhou et al. MODEL: In concentrated suspensions, stratification occurs in experiments only for the higher size ratio alpha = 7. Simulations using a high Peclet number, additionally find stratification with alpha = 2, when phiS is high enough. Our results provide a quantitative understanding of the conditions under which stratified colloidal films assemble. Our research has relevance for the design of coatings with targeted optical and mechanical properties at their surface. PMID- 28920987 TI - Mechanisms of distinct activated carbon and biochar amendment effects on petroleum vapour biofiltration in soil. AB - We studied the effects of two percent by weight activated carbon versus biochar amendments in 93 cm long sand columns on the biofiltration of petroleum vapours released by a non-aqueous phase liquid (NAPL) source. Activated carbon greatly enhanced, whereas biochar slightly reduced, the biofiltration of volatile petroleum hydrocarbons (VPHs) over 430 days. Sorbent amendment benefitted the VPH biofiltration by retarding breakthrough during the biodegradation lag phase. Subsequently, sorbent amendment briefly reduced the mineralization of petroleum hydrocarbons by limiting their bioavailability. During the last and longest study period, when conditions became less supportive of microbial growth, because of inorganic nutrient scarcity, the sorbents again improved the pollution attenuation by preventing the degrading microorganisms from being overloaded with VPHs. A 16S rRNA gene based analysis showed sorbent amendment effects on soil microbial communities. Nocardioidaceae benefitted the most from petroleum hydrocarbons in activated carbon amended soil, whereas Pseudomonadacea predominated in unamended soil. Whilst the degrading microorganisms were overloaded with VPHs in the unamended soil, the reduced mobility and bioavailability of VPHs in the activated carbon amended soil led to the emergence of communities with higher specific substrate affinity, which removed bioavailable VPHs effectively at low concentrations. A numerical pollutant fate model reproduced these experimental observations by considering sorption effects on the pollutant migration and bioavailability for growth of VPH degrading biomass, which is limited by a maximum soil biomass carrying capacity. Activated carbon was a much stronger sorbent for VPHs than biochar, which explained the diverging effects of the two sorbents in this study. PMID- 28920988 TI - Fluorogenic NIR-probes based on 1,2,4,5-tetrazine substituted BF2 azadipyrromethenes. AB - A series of 1,2,4,5-tetrazine integrated near infrared (NIR) fluorophores based on the BF2 azadipyrromethene (NIR-AZA) class has been synthesised and their ability to modulate emission from low to high in response to Diels-Alder cycloaditions has been assessed. Substituents on the tetrazine component of the probe (Cl, OMe, p-NO2C6H4O) were seen to strongly influence quantum yields, fluorescence enhancement factors, and rates of cycloadditions. Cycloadditions between tetrazine-NIR-AZA constructs and a strained alkyne substrate were seen to be highly efficient in organic or aqueous solutions and in gels with high fluorescence enhancements of up to 48-fold observed. Real-time demonstration of the cycloaddition mediated fluorogenic property was achieved by imaging the "turn on" reaction within a continous flow micro-reactor. Preliminary evidence indicates that excited state quenching involves a photoinduced electron transfer. PMID- 28920989 TI - Half sandwich Ru(ii)-acylthiourea complexes: DNA/HSA-binding, anti-migration and cell death in a human breast tumor cell line. AB - Organometallic ruthenium complexes as potential anticancer agents have been explored due to their suitable properties, such as stability in the solid state and in solution, water solubility and low toxicity. In this study, eight metal complexes of this class were synthesized, characterized and their important biological activities against a human breast tumor cell line (MDA-MB-231) were studied. Complexes 1-8 were obtained in good yields and have been characterized by satisfactory elemental analyses, IR, 1D and 2D 1H and 13C{1H} NMR, UV-Vis spectroscopy, cyclic voltammetry, ESI-MS and X-ray diffractometry (1, 2, 3 and 6). All complexes exhibit growth inhibition on human breast and lung tumor cell lines, with IC50 values ranging from 6.0 to 45.0 MUM in 48 h. Four compounds were selected to evaluate the changes in the morphology, clonogenic, migration, cell cycle arrest and cell death in MDA-MB-231 cells. The complexes are able to induce morphological changes and inhibit the size, number of colonies and cell migration, and induce cell cycle arrest in the sub-G1 phase and apoptosis cell death. The interaction of the complexes with DNA was determined by performing spectroscopic titration, a competitive assay with thiazole orange, circular dichroism, gel electrophoresis and interactions with guanosine or guanosine monophosphate by 1H NMR, indicating the non-covalent interaction. The HSA binding affinity measured by spectrophotometric titration, revealed the hydrophobic and spontaneous association with the human protein. Overall, the studies indicated that these metal complexes are potential agents against MDA-MB-231 cells, encouraging us to continue studies of these types of compounds. PMID- 28920990 TI - A ruthenium water oxidation catalyst containing a bipyridine glycoluril ligand. AB - A mononuclear ruthenium complex [Ru(tpy)(bpg)H2O]2+ bearing a bipyridine glycoluril where bpg = 4b,5,7,7a-tetrahydro-4b,7a-nepiminomethanoimino-6H imidazo[4,5-f][1,10]phenanthro-line-6,13-dione acts as a robust water oxidation catalyst (WOC) at pH = 1 using Ce(iv) as a sacrificial oxidant. The turn over number (TON) for water oxidation is found to be ~5 times higher than the parent complex [Ru(tpy)(bpy)H2O]2+ where tpy = 2,2':6',2''-terpyridine; bpy = 2,2' bipyridine. The presence of intermolecular H-bonding groups and the electronic effect of the functionalized bipyridine ligand may play a significant role in water oxidation. PMID- 28920991 TI - Single-ion magnetism in seven-coordinate YbIII complexes with distorted D5h coordination geometry. AB - Two seven-coordinate compounds with pentagonal bipyramidal YbIII centers, namely, [Yb(H3Bmshp)(DMF)2Cl2].DMF.1.5H2O (1) and [Yb(H3Bmshp)(DMF)2Cl2].H4Bmshp (2) (H4Bmshp = (2,6-bis[(3-methoxysalicylidene)hydrazinecarbonyl]-pyridine)) were synthesized by changing the molar ratio of reactants in DMF. The structures of compounds 1 and 2 are very similar, except for the existence of different lattice molecules: one DMF and one and a half water molecules in 1, and one neutral uncoordinated ligand in 2. The coordination geometries of both the pentagonal bipyramidal YbIII centers (YbCl2N1O4) in compounds 1 and 2 are also very similar with only slight differences. Magnetic data analyses revealed that the subtle structure variations result in remarkable different slow magnetic relaxation properties of compounds 1 and 2. To further understand their magnetic behaviors, ab initio calculations were performed for both compounds 1 and 2. The calculated results indicate that the magnetic anisotropies of compounds 1 and 2 are significantly different: easy-plane magnetic anisotropy for 1 and easy-axis magnetic anisotropy for 2. To the best of our knowledge, these compounds are the first YbIII-based SIMs of pentagonal bipyramidal geometry. PMID- 28920992 TI - Children's Surgery Verification program officially under way. PMID- 28920993 TI - Cobalt(ii) containing liquid metal salts for electrodeposition of cobalt and electrochemical nanoparticle formation. AB - Cobalt(ii)-containing liquid metal salts (LMS) with N-alkylimidazole ligands and bis(trifluoromethanesulfonyl)imide (bistriflimide, Tf2N-) or methanesulfonate (mesylate, OMs-) anions were synthesized and characterized. The chain length of the alkyl side chain on the imidazole ligand was varied. All compounds were characterized using CHN analysis, DSC and FTIR measurements. Single-crystal X-ray diffraction measurements were performed on six of the compounds for which single crystals of good quality could be obtained. All cobalt(ii) centers are six coordinate with the N-alkylimidazole ligands in an octahedral configuration and the anions are non-coordinating. The same coordination environment was observed by EXAFS measurements on cobalt(ii) liquid metal salts in the liquid state. The electrochemical properties of the compounds with the lowest melting temperatures were investigated using cyclic voltammetry. It was found that part of the current was consumed in the electrodeposition of cobalt, whereas the other part of the current was consumed in the electrochemical formation of cobalt(0) nanoparticles. PMID- 28920994 TI - A light-up endoplasmic reticulum probe based on a rational design of red-emissive fluorogens with aggregation-induced emission. AB - Fine-tuning electron acceptors through changing one cyano group to an amide generates a more stable and emissive fluorophore with the character of aggregation-induced emission. Conjugation between the new fluorophore and CFFKDEL generated an excellent ER targeting light-up probe with high specificity and good photostability. PMID- 28920995 TI - Stability and partitioning of beta-carotene in whey protein emulsions during storage. AB - Varying the beta-carotene (0.1-0.3 g kg-1) and whey protein isolate (WPI) (2-20 g kg-1) concentrations in an oil-in-water (O/W) emulsion influenced the partitioning and stability of beta-carotene upon 30 d storage at 25 and 40 degrees C. The total beta-carotene in the emulsion was extracted with a solvent and quantified using UV/visible spectroscopy. The beta-carotene in oil phase was obtained using in situ Raman micro-spectroscopy. The beta-carotene in the aqueous phase was obtained by difference. Increasing beta-carotene concentration resulted in increased partitioning of beta-carotene into the aqueous phase whereas increasing WPI concentration had the opposite effect. With all freshly made emulsions, there was a higher proportion of beta-carotene found in the oil phase. At the end of the storage period, the higher proportion and concentration of beta carotene was in the aqueous phase. This suggested that oxidation of beta-carotene occurred faster in the oil phase and that WPI in the aqueous phase protected beta carotene against oxidation. This work informs the formulation of protein-based emulsions for the delivery of beta-carotene. PMID- 28920997 TI - Rapid and highly sensitive detection of extracellular and intracellular H2S by an azide-functionalized Al(iii)-based metal-organic framework. AB - A new, azide-functionalized Al(iii)-based metal-organic framework (MOF) denoted as CAU-10-N3 (1, CAU = Christian-Albrechts-University) and consisting of the 5 azido-isophthalic acid (H2IPA-N3) ligand was employed as a reaction-based fluorescent turn-on probe for the detection of H2S. The activated compound (1') showed fast, selective and highly sensitive sensing properties for extracellular H2S in HEPES buffer (10 mM, pH = 7.4). The material retained its high selectivity even in the presence of possibly competing biological species. The limit of detection of 1' for H2S is 2.65 MUM, which is lower than the earlier reports on MOFs for H2S sensing. The material displayed a short response time (420 s) and a significant increase (20-fold and 26-fold after 1 and 7 min of addition of Na2S, respectively) in the fluorescence intensity towards H2S. Macrophage cells loaded with probe 1' exhibited blue fluorescence with a response time of 15 min after Na2S addition, indicating the suitability of the probe for intracellular H2S detection. Moreover, CAU-10-N3 featured excellent detection performance (quick response and 32-fold increment in fluorescence intensity after 7 min of Na2S addition) in water. Hence, it can be utilized to regulate the H2S level in aqueous samples collected from the environment. PMID- 28920998 TI - Quantitative evaluation of PPAR-gamma2 Pro12Ala polymorphism with hypertension. AB - BACKGROUND: The peroxisome proliferator-activated receptor gamma2 (PPARgamma2)Pro12Ala polymorphism has been reported to be associated with hypertension. However, relevant studies have shown inconsistent results. METHODS: To quantitatively evaluate the relationship between the PPARgamma2Pro12Ala polymorphism and hypertension risk, we conducted a meta-analysis based on all available studies selected from Scopus, Web of Science, PubMed, Chinese National Knowledge Infrastructure, and Wanfang databases. RESULTS: In all, 13 studies were finally included in this meta-analysis. In the allelic model (Ala vs. Pro), the Ala allele of PPARgamma2 Pro12Ala polymorphism was associated with hypertension (Odds Ratio [OR] = 0.723, 95% confidence interval [CI] = 0.607-0.861). Sensitivity analysis and exclusion of studies with poor quality scores or controls complicated by other diseases confirmed the validity of this association. Moreover, the PPARgamma2Pro12Ala polymorphism was associated with hypertension in the codominant (OR = 0.710, 95% CI = 0.626-0.806), recessive (OR = 0.561, 95% CI = 0.418-0.754), and dominant (OR = 0.693, 95% CI = 0.577-0.833) models. CONCLUSION: The Ala allele appears to have a protective effect against hypertension and a dominant function. PMID- 28920999 TI - [Difficult decisions in end-of-life situations : An important team task]. PMID- 28921000 TI - [Hemodynamic interplay between tricuspid valve and right ventricle]. AB - The tricuspid valve and the right ventricle are hemodynamically closely related. Pathological changes of the valve or of the ventricle itself and also various diseases beyond that can result in a downward spiral of mutual interference, which is of prognostic importance for the patient. The development of a functional tricuspid regurgitation is of great importance. Especially with the help of 3D-echocardiography, more and more changes and mechanisms have been identified that are crucial in this process. This article provides a review of the relationship between the tricuspid valve and the right ventricle emphasizing the current knowledge of the causes, the pathophysiological concepts, the underlying structural changes and the therapeutic approaches based on this. PMID- 28921001 TI - C3aR and C5aR1 act as key regulators of human and mouse beta-cell function. AB - AIMS: Complement components 3 and 5 (C3 and C5) play essential roles in the complement system, generating C3a and C5a peptides that are best known as chemotactic and inflammatory factors. In this study we characterised islet expression of C3 and C5 complement components, and the impact of C3aR and C5aR1 activation on islet function and viability. MATERIALS AND METHODS: Human and mouse islet mRNAs encoding key elements of the complement system were quantified by qPCR and distribution of C3 and C5 proteins was determined by immunohistochemistry. Activation of C3aR and C5aR1 was determined using DiscoverX beta-arrestin assays. Insulin secretion from human and mouse islets was measured by radioimmunoassay, and intracellular calcium ([Ca2+]i), ATP generation and apoptosis were assessed by standard techniques. RESULTS: C3 and C5 proteins and C3aR and C5aR1 were expressed by human and mouse islets, and C3 and C5 were mainly localised to beta- and alpha-cells. Conditioned media from islets exposed for 1 h to 5.5 and 20 mM glucose stimulated C3aR and C5aR1-driven beta-arrestin recruitment. Activation of C3aR and C5aR1 potentiated glucose-induced insulin secretion from human and mouse islets, increased [Ca2+]i and ATP generation, and protected islets against apoptosis induced by a pro-apoptotic cytokine cocktail or palmitate. CONCLUSIONS: Our observations demonstrate a functional link between activation of components of the innate immune system and improved beta-cell function, suggesting that low-level chronic inflammation may improve glucose homeostasis through direct effects on beta-cells. PMID- 28921002 TI - [DDA-certified course for tropical and travel dermatology and the International Conference for Tropical and Clinical Dermatology : Yogyakarta/Indonesia, 3-6 May 2017]. PMID- 28921003 TI - Mortality and cardiorespiratory complications in trochanteric femoral fractures: a ten year retrospective analysis. AB - PURPOSE: Despite intense research and innovations in peri-operative management, a high mortality rate and frequent systemic complications in trochanteric femoral fractures persist. The aim of the present study was to identify predictive factors for mortality and cardio-respiratory complications after different treatment methods in a ten year period at a level I trauma centre. METHODS: Retrospectively, all patients above 60 years of age with trochanteric femoral fracture between January 2000 and May 2011 were analyzed at a level I trauma centre. Demographic variables, comorbidities, and data regarding the surgical procedures, including required transfusions and post-operative complications, were evaluated, and the in-hospital mortality was recorded. The grade of osteoporosis was classified radiographically using the Singh index. RESULTS: The in-hospital mortality rate was 8.2% among 437 patients (male/female ratio = 110/327, mean age = 81 years) with extramedullary open (n = 144), intramedullary (n = 166), and extramedullary minimally invasive (n = 125) procedures. Significant influential factors on in-hospital mortality were identified with binary logistic regression analysis: an age of >=90 years (P = 0.011), male sex (P = 0.003), a high American Society of Anesthesiologists (ASA) grade (3-5, P = 0.042), and a high osteoporosis grade (Singh index 3-1, P = 0.011). A total of 21.5% of the study population suffered cardio-respiratory complications post operatively. The specific mortality was 28.7% (P < 0.001), which was influenced by a high ASA grade (3-5, P = 0.002) and a high transfusion rate (P = 0.004). Minimally invasive locked plating was associated with increased cardio respiratory complications (P = 0.031). CONCLUSIONS: This study identified high patient age, distinctive comorbidities, male sex, and high osteoporosis grade as significant risk factors for increased in-hospital mortality in the treatment of trochanteric femoral fractures. Furthermore, high ASA grade and a liberal transfusion regime led to an increased incidence of cardio-respiratory complications. Patient-specific characteristics, especially osteoporosis grade and pre-existing medical conditions, may assist in the identification of high risk patients and allow a patient-specific geriatric co-management plan. PMID- 28921004 TI - Using Paleoecology to Inform Land Management as Climates Change: An Example from an Oak Savanna Ecosystem. AB - Oak savanna, a transitional ecosystem between open prairie and dense oak forest, was once widespread in Minnesota. Upon European settlement much of the oak savanna was destroyed. Recently, efforts to restore this ecosystem have increased and often include the reintroduction of fire. Though fire is known to serve an important role within oak savannas, there are currently few studies which address fire regimes on timescales longer than the last century. This research presents a paleoecological history of Sherburne National Wildlife Refuge (SNWR) in MN, USA, spanning the last ~8000 years. The objectives of this study were to use charcoal, pollen, and magnetic susceptibility of lake sediments collected from Johnson Slough (JS) within the refuge to evaluate the natural range of variability and disturbance history of the oak savanna within the refuge, assess the success of current restoration strategies, and add to the regional paleoecological history. The mid/late Holocene period of the JS record shows a period of high fire activity from ca. 6500 to 2600 cal year BP, with a shift from prairie to oak savanna occurring over this same period. A (possibly agricultural) disturbance to JS sediments affected the period from ca. 2600 cal year BP to 1963 AD, which includes the time of Euro-American settlement. However, the destruction and subsequent restoration of the oak savanna is evident in a pollen ratio of Quercus:Poaceae, indicating that current restoration efforts have been successful at restoring the oak savanna to within the natural range of variability seen just prior to destruction. PMID- 28921005 TI - Barriers and Solutions to Conducting Large International, Interdisciplinary Research Projects. AB - Global environmental problems such as climate change are not bounded by national borders or scientific disciplines, and therefore require international, interdisciplinary teamwork to develop understandings of their causes and solutions. Interdisciplinary scientific work is difficult enough, but these challenges are often magnified when teams also work across national boundaries. The literature on the challenges of interdisciplinary research is extensive. However, research on international, interdisciplinary teams is nearly non existent. Our objective is to fill this gap by reporting on results from a study of a large interdisciplinary, international National Science Foundation Partnerships for International Research and Education (NSF-PIRE) research project across the Americas. We administered a structured questionnaire to team members about challenges they faced while working together across disciplines and outside of their home countries in Argentina, Brazil, and Mexico. Analysis of the responses indicated five major types of barriers to conducting interdisciplinary, international research: integration, language, fieldwork logistics, personnel and relationships, and time commitment. We discuss the causes and recommended solutions to the most common barriers. Our findings can help other interdisciplinary, international research teams anticipate challenges, and develop effective solutions to minimize the negative impacts of these barriers to their research. PMID- 28921006 TI - Computer aided planning of orthopaedic surgeries: the definition of generic planning steps for bone removal procedures. AB - PURPOSE: An increasing number of orthopaedic surgeons are using computer aided planning tools for bone removal applications. The aim of the study was to consolidate a set of generic functions to be used for a 3D computer assisted planning or simulation. METHODS: A limited subset of 30 surgical procedures was analyzed and verified in 243 surgical procedures of a surgical atlas. Fourteen generic functions to be used in 3D computer assisted planning and simulations were extracted. RESULTS: Our results showed that the average procedure comprises 14 +/- 10 (SD) steps with ten different generic planning steps and four generic bone removal steps. CONCLUSIONS: In conclusion, the study shows that with a limited number of 14 planning functions it is possible to perform 243 surgical procedures out of Campbell's Operative Orthopedics atlas. The results may be used as a basis for versatile generic intraoperative planning software. PMID- 28921007 TI - The only constant is change. PMID- 28921008 TI - Molecular characterization of very virulent infectious bursal disease virus strains circulating in Egypt from 2003 to 2014. AB - In the present study, four very virulent infectious bursal disease virus (vvIBDV) isolates from flocks of chickens with vaccination failure in Egypt in 2003, 2007, 2010 and 2014 were characterized. The four viruses, designated USC2003, USC2007, USC2010 and USC2014, were detected by reverse transcription PCR, subjected to sequencing of both genomic segments (A and B) and compared with geographically and phylogenetically diverse IBDV strains. Phylogenetic analysis of segment A (complete) and B (partial) revealed a close relationship between Egyptian and vvIBDV reference strains of European and Asian origin. The sequences of segments of A and B the current Egyptian isolates were 96.1-98.2% and 96.5-98.7% identical, respectively, to those of other known vvIBDV isolates. The deduced amino acid sequences of VP1, polyprotein (pVP2-VP4-VP3) and VP5 revealed the presence of putative virulence determinants of Egyptian isolates compared with vvIBDV and less virulent (classical and variant) strains. The Egyptian isolates also possess unique amino acids substitutions within the hypervariable region of VP2 that differ from those of other reference IBDV strains. Further studies may be necessary to determine the pathogenic significance of these amino acid substitutions to fully understand the molecular epidemiology and evolution of IBDV. PMID- 28921010 TI - A technique for intraoperative maxillomandibular fixation. PMID- 28921009 TI - Radiation overexposure from repeated CT scans in young adults with acute abdominal pain. AB - PURPOSE: The purpose of this study is to assess the dose of ionizing radiation caused by repeated CT scans performed to investigate non-traumatic acute abdominal conditions in young adults. METHODS: Over 26 months, we collected a cohort of patients aged 18 to 45 years who were subject to at least one urgent contrast-enhanced abdomen/pelvis CT. Patients affected with urolithiasis, HIV infection, tumors, and vascular and chronic inflammatory bowel diseases were excluded. All abdomen/pelvis CT scans carried out at our institution for over 6 years were retrospectively tallied, and the effective doses (EDs) were computed by multiplying the total dose-length product by the appropriate anatomic conversion factor. Examples of age- and gender-adjusted lifetime attributable cancer risks were estimated using the online calculator Radiation Risk Assessment Tool. RESULTS: Sixty-one patients (average age 34.2 years) received multiple CT scans (average 2.7 scans per patient). ED largely varied among single- and multi phase acquisitions. Cumulative ED ranged from 14.1 mSv to a maximum of 436.6 mSv (average 70.1 mSv per person). Twenty-five patients (40.9%) received more than 50 mSv, 84% of them within year; 12 (19.7%) and 4 (6.6%) patients received more than 100 and 200 mSv, respectively. CONCLUSION: Young adults are subject to repetitive CT imaging to monitor urogenital, intestinal, hepatobiliary, and pancreatic disorders during non-operative management to detect and follow up abdominal emergencies requiring surgical intervention and to assess post-surgical complications. In this population, the risk of accruing high cumulative radiation exposure should be considered. PMID- 28921012 TI - [Meeting of the working group on gastroenteropathology on 22nd June 2017 : 101st conference of the German Society of Pathology]. PMID- 28921013 TI - Spinal cord injury as a complication of thoracic endovascular aneurysm repair. AB - OBJECTIVE: Spinal cord ischemia (SCI) is a devastating complication of thoracic aortic aneurysm repair in the era of thoracic endovascular aneurysm repair (TEVAR). This review aims to clarify the causes of SCI during TEVAR and to propose ways that it may be prevented. METHODS AND RESULTS: We performed an extensive literature search of SCI during TEVAR. Based on the existing literature, we examined the anatomy of the anterior spinal cord artery, which supplies blood to the anterior aspect of the spinal cord, and discuss reported effective ways to prevent SCI during TEVAR, including augmentation of arterial blood pressure and drainage of cerebrospinal fluid. CONCLUSION: After reviewing the mechanism of SCI during TEVAR, we evaluated promising preventative measures. PMID- 28921014 TI - [Legal medicine specialists within the framework of acute care : Analysis of legal medicine consultations in relation to the victims' statistics of the state office of criminal investigation in Saxony-Anhalt]. AB - BACKGROUND: In acute medical care, there are patients who have been injured by the influence of others. The aim of this study was to analyze all cases which were presented to the Institute for Legal Medicine of the University Halle (Saale). The cases where analyzed in relation to the victims' statistics of the state office of criminal investigation in Saxony-Anhalt. MATERIALS AND METHODS: The consultations of the Institute for Legal Medicine Halle-Wittenberg for 2012 2015 were evaluated with regard to the age and gender distribution, the reasons for the consultation and time until the request for consultations. These cases were statistically compared to the victims' statistics of the state office of criminal investigation in Saxony-Anhalt 2014-2015. RESULTS: A total of 536 cases (55.6% male and 44.4% female patients) were evaluated. In all, 62.1% of patients were under 18 years of age; 43.5% of all consultations were requested by pediatric (surgery) clinics. The most common reasons for consultation were sexual child abuse or violence against children (50.7%). Compared to the victims' statistics, significantly more children were examined by legal medicine specialists than could have been expected (p < 0.001). In adult patients, the most common causes for consultation were acts of violence (20.4%) and domestic violence (10.1%). Among adults, significantly more women and fewer men were presented than expected (p = 0.001). CONCLUSION: There were only a small number of consultations of legal medicine specialists in relation to the victims' statistics. Most of them were children and women. The temporal latency between the act of violence and the consultations was one day and more. The latency and the renunciation of the consultation of the legal medicine specialists can lead to loss of evidence. PMID- 28921016 TI - Nephrotic-range proteinuria and brown urine in an 8-year-old girl: Questions. PMID- 28921017 TI - The German Arthroscopy Registry (DART). AB - In Germany, more than 400,000 arthroscopic procedures are performed each year. The DART registry is designed to study the outcome of arthroscopic procedures of the shoulder, hip, knee and ankle joint under everyday clinical circumstances using patient-reported outcome measures (PROMs). DART aims at identifying patient specific factors correlated with therapy-associated complications and treatment failure and will help study the influence of concurrent joint diseases and procedures. To achieve these tasks, a Web-based remote data entry system will be applied and adapted to the needs of DART. DART will consist of a physician's and a patient's form to enter data on the specific disease, surgical procedure, joint specific outcome, disability and quality of life measured by validated scores up to 5 years following surgery. The pool of data will be subjected to further clinical investigations and subgroup analysis. Individual results will be made accessible to the surgeon and the patient. Moreover, public reports will be generated to provide healthcare authorities and insurance companies with information on the effectiveness of arthroscopic surgery. The aim of this article is to present the methodology of the registry. Level of evidence V. PMID- 28921018 TI - Effects of four volatile anesthesics on postanesthetic ventilation: a comparison of halothane, enflurane, isoflurane, and sevoflurane. AB - To investigate the effects of four volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) on postanesthetic ventilation and levels of consciousness, we enrolled 24 patients undergoing tympanoplasty in this study. Anesthesia was maintained with 67% nitrous oxide and one of four volatile anesthetics. We measured end-tidal carbon dioxide concentration (CETco2), minute volume ([Formula: see text]) and respiratory rate (RR), and determined the volatile anesthetic concentration in whole arterial blood (CBAnesth) and arterial carbon dioxide tension (Paco2) at 20 min and 2h after tracheal extubation. We also observed the level of consciousness (awake, drowsy, and asleep) before the measurement. Ventilatory variables were similar among the four groups at 20 min, although the ratio of volatile anesthetic concentration in the alveoli to the minimum alveolar concentration (MAC) (CAAnesth/MAC ratio) calculated from CBAnesth in the halothane group was twice those in the other groups. In the halothane group, Paco2 was significantly higher, and[Formula: see text] and RR were significantly lower compared with the isoflurane and sevoflurane groups at 2h. Halothane tended to prolong the recovery of levels of consciousness. We conclude that isoflurane and sevoflurane provide clinical advantages over halothane on postanesthetic ventilation and recovery of levels of consciousness. PMID- 28921019 TI - Comparison of renal function under deliberate hypotension during epidural plus light-enflurane anesthesia and during enflurane anesthesia. AB - We compared the effects of deliberate hypotension induced with trimethaphan on renal function and renal tubular damage under combined epidural and light enflurane anesthesia (epidural group) and enflurane anesthesia alone (enflurane group). The mean arterial blood pressure was maintained at 50-55 mm Hg for 2.5 h in both groups using continuous infusion of trimethaphan. The urine volume and free water clearance were significantly greater in the epidural group than in the enflurane group [1.8+/-1.8 (SD)vs 0.4+/-0.3 ml.kg-1.h-1 and 0.81+/-1.30vs -0.15+/ 0.22 ml.min-1, respectively] (P<0.05). The creatinine clearance and fractional sodium excretion rate did not differ significantly between the two groups. Urinary excretion of norepinephrine was significantly less in the epidural group than in the enflurane group (P<0.05); however, epinephrine excretion did not differ. Urinary excretion ofN-acetyl-beta-D-glucosaminidase was significantly less in the epidural group than in the enflurane, group (4.2+/-2.5vs 12.2+/-4.6 U.g-1 CR) (P<0.01). The plasma antidiuretic hormone concentration was significantly lower in the epidural group compared to the enflurene group (13+/ 23vs 57+/-42 pg.ml-1) (P<0.05). No significant difference in plasma atrial natriuretic peptide concentration was found between the groups. We conclude that renal function during trimethaphan-induced hypotension is better maintained under epidural plus light-enflurane anesthesia than under enflurane anesthesia alone. PMID- 28921020 TI - Lipid peroxide and leukotriene B3 production in patients undergoing cardiopulmonary bypass. AB - Cardiac surgery with cardiopulmonary bypass (CPB) is frequently associated with a complex array of post-operative clinical abnormalities, including low-output syndrome and pulmonary dysfunction. It has been reported that oxygen free radicals are one of the important factors causing reperfusion injury. To determine whether oxygen free radicals are produced during cardiac surgery, we studied nine patients anesthetized with high doses of fentanyl. Lipid peroxide (LPO) and leukotriene B4 (LTB4) levels increased significantly from 60 min after aortic ligation to 180 min after reperfusion (aortic declamping), compared with the levels before surgery, while superoxide dismutase (SOD) was not affected markedly. Creatine kinase (CK), CK muscle-brain (CK-MB), and neutrophils increased from 60 min after aortic declamping. Correlations were not observed between LPO and CK nor between LPO and CK-MB. These results suggest that free radicals are generated during cardiac surgery with cardiopulmonary bypass (CPB), but it is unclear whether free radicals cause tissue injury after cardiac surgery with CPB. PMID- 28921021 TI - Glucose tolerance in elderly patients does not deteriorate during anesthesia and surgical stress. AB - This study evaluated the glucose tolerance of elderly subjects compared with that of younger subjects under surgical stress. During surgery, glucose 0.1 g.kg-1 was administrated i.v. to the elderly group, aged 66-83 years (n=11, mean 73.5+/-5.9) and the control group, aged 19-64 years (n=11, mean 50.9+/-15.1), all of whom were scheduled for lower abdominal surgery and had a normal range of fasting blood sugar and glycosylated hemoglobin (HbA1C). Between 3 and 90min after glucose loading, the blood glucose levels of the control group increased more than those in the elderly group, and at 10 and 15 min those in the control group showed a significantly greater increase than those in the elderly group (P<0.05). Serum insulin concentrations increased at 3 and 5 min, but no significant difference was observed between the two groups. Cortisol and catecholamines also showed no significant difference between groups. It was concluded that glucose tolerance in elderly subjects does not deteriorate during lower abdominal surgery. PMID- 28921022 TI - Effect of high-frequency jet ventilation on heart rate variability. AB - We investigated the effects of high-frequency jet ventilation (HFJV) on heart rate variability in nine patients during fentanyl (10MUg.kg-1) anesthesia using power spectral density analysis. ECG and arterial pressure were recorded during intermittent positive pressure ventilation (IPPV) (tidal volume 8 ml.kg-1, respiratory rate 0.25 Hz) and during HFJV [5 Hz, 2.5 kg.(cm2)-1]. The R-R interval time series obtained were analyzed by the autoregressive method, and low frequency (LF) (0.05-0.15 Hz) power and high-frequency (HF) (0.20-0.50 Hz) power from R-R interval spectra were used for statistical comparison. LF power did not change during IPPV and HFJV (108.8+/-41.6 ms2 vs 105.8+/-22.4 ms2, mean+/-SE). HF power was detected during IPPV (65.1+/-14.3 ms2); however, it was not detected during HFJV. Plasma levels of norepinephrine and epinephrine were significantly higher during HFJV than during IPPV. The mean R-R interval, arterial pressure, and arterial blood gas data did not differ between IPPV and HFJV. These data indicate that, during fentanyl anesthesia, HFJV influences mainly the respiratory frequency fluctuation of heart rate variability, and they suggest that alteration of breathing patterns caused by HFJV might be involved, as well as elevated sympathetic neural outflow to the heart. PMID- 28921023 TI - Inhalational induction with isoflurane: the influence of lidocaine pretreatment. AB - The effect of intravenous lidocaine in reducing the incidence of complicated induction during a single vital capacity breath technique using isoflurane was studied. Forty patients were randomized into two groups to receive either placebo (group A) or intravenous lidocaine 1.5 mg.kg-1 (group B) just prior to induction. Inhalational induction using 2% isoflurane and 66% nitrous oxide in oxygen was then carried out. Patients pretreated with lidocaine had significantly fewer complications during induction of anesthesia. Modest decreases in blood pressure and heart rate were observed in both groups but were clinically insignificant. Intravenous lidocaine pretreatment significantly reduced the incidence of complications during inhalational induction. PMID- 28921024 TI - Sevoflurane anesthesia maintains reflex tachycardia on position change from supine recumbent to head-up tilt. AB - This study evaluated the effects of inhalational anesthetics on hemodynamic changes in response to head-up tilt in humans. Twenty-four patients were randomly divided into three groups that received either halothane, isoflurane, or sevoflurane. Changes in heart rate, blood pressure, and plasma norepinephrine concentrations were determined before and during head-up tilt position in the awake and anesthetized state. Head-up tilt caused a significant increase in the heart rate, concomitantly with a decrease or no significant changes in systolic blood pressure in the awake state. However, under 2 minimum alveolar concentrations (MAC) of halothane and isoflurane anesthesia, the heart rate did not significantly change during head-up tilt in spite of significant decreases in systolic blood pressure. In contrast, under 2 MAC of sevoflurane anesthesia, the heart rate significantly increased during head-up tilt. Plasma norepinephrine did not significantly alter during head-up tilt in the awake as well as the anesthetized state. These results suggest that sevoflurane maintains an increase in heart rate in response to head-up tilt, whereas halothane and isoflurane attenuate the response. PMID- 28921025 TI - Velocity measurements with a new ultrasonic Doppler method independent of angle of incidence. AB - Blood flow velocity measured by Doppler ultrasound is the relative velocity dependent on the path of the ultrasound beam, which should be influenced by its angle of incidence against the blood flow in the vessel. The angle of incidence generates varying changes in flow velocities that can be measured by the Doppler device. The aim of our study was to develop a new ultrasonic Doppler catheter which could provide a true flow velocity independently of the angle of the ultrasound beam against the flow direction, and to assess the validity of the true flow velocity obtained by a new device using the electromagnetic flowmeter. The newly developed Doppler catheter has a pair of adjoining ultrasonic crystals located on one side of the catheter at right angles to each other. Each Doppler shift, which is detected by two transducers (Deltaf1, Deltaf2) that sample the flow velocity at two closely spaced points, is used to compute two velocity measurements (V1 and V2); these are the velocities detected by the transducers. The true velocity was calculated using the following equation: V=((V1)2+(V2)2)1/2, where V = true velocity. The velocities were calculated by newly developed phase differential techniques. Using a continuous flow model, we compared the flow velocity measured by the new Doppler catheter with that assessed by an electromagnetic flow probe placed into the circuit. At between 0.42 and 4.49 l.min-1, the flow velocity measured by the new Doppler catheter (Doppler velocity) at five sampling depths was compared with the mean velocity calculated from the volumetric flow rate measured by an electromagnetic flowmeter (EMF velocity). The Doppler velocity (y) strongly correlated with the EMF velocity (x) at five sampling depths (r 2=0.99, respectively). At the maximal velocity sampling depth, the regression equation was y=1.29x+2.47 (r 2=0.99,P<0.0001,n=41, SEE=0.015). The Doppler velocity also correlated with the volumetric flow rate measured by the electromagnetic flowmeter (r 2=0.99). The flow velocity measurements using the new Doppler catheter and device we have developed can provide more instantaneous and useful information on hemodynamics. PMID- 28921026 TI - Experimental study of efficacy and optimal dose of intraoperative glucose in rabbits under general anesthesia. AB - This experimental study was designed to investigate the efficacy of glucose loading during surgery. Rabbits, fasted overnight, received 20 ml.kg-1.h-1 fluid infusion containing glucose at various concentration (0,0.5, 1.0, 1.5, 2.0% w/v) for 3 h intraoperatively. Plasma glucose level increased after the beginning of operation, but the increase was slight in groups given 0.2 g.kg-1.h-1 or lower doses of glucose. Glucose at higher doses caused marked hyperglycemia. These higher doses also promoted urinary glucose excretion, and in the group given the maximum glucose dose (0.4 g.kg-1.h-1), this parameter was significantly elevated compared with findings in the 0.2 g.kg-1.h-1 group (P<0.05), whereas it showed no significant difference among groups given 0-0.2g.kg-1.h-1. The liver glycogen content in animals that received no glucose was significantly lower than that of the 0.2 g.kg-1.h-1 group (P <0.01). However, there was no correlation between glycogen level and glucose dose among groups receiving glucose. These results suggest that intraoperative glucose supplementation is effective in preventing glycogen depletion, and indicate that, to avoid glucose overloading, the optimal dose is 0.1-0.2 g.kg-1.h-1. PMID- 28921027 TI - Anesthetic problems in a child with Waardenburg's syndrome and Hirschsprung's disease. PMID- 28921028 TI - Paradoxical air embolism detected by transesophageal echocardiography during hepatic resection. PMID- 28921029 TI - Difficulty in the removal of both nasogastric and endotracheal tubes: report of a case. PMID- 28921031 TI - In reply. PMID- 28921030 TI - Unusual vaporizer design may encourage irregular practices. PMID- 28921033 TI - Risk factors for prolapse recurrence: systematic review and meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: Female pelvic organ prolapse (POP) is a common condition, with a lifetime risk for surgery of 10-20%. Prolapse procedures are known to have a high reoperation rate. It is assumed that etiological factors for POP may also be risk factors for POP recurrence after surgery. There are few reviews available evaluating risk factors for prolapse and recurrence or recently updated meta-analysis on this topic. Our aim was to perform a systematic review and quantitative meta-analysis to determine risk factors for prolapse recurrence after reconstructive surgery. METHODS: Four electronic databases (MEDLINE, PubMed, EMBASE, and Google Scholar) were searched between 1995 and 1 January 2017, with no language restrictions. RESULTS: Twenty-five studies met inclusion criteria for a total of 5082 patients with an average recurrence rate of 36%. Variables on which a meta-analysis could be performed were body mass index (BMI) (n = 12), age (n = 11), preoperative stage (n = 9), levator avulsion (n = 8), parity (n = 8), constipation/straining (n = 6), number of compartments involved (n = 4), prior hysterectomy (n = 4), familiy history (n = 3), and several other predictors evaluated in only three studies. The following meta- analyses identified significant predictors: levator avulsion [odds ratio (OR) 2.76, P < 0.01], preoperative stage 3-4 (OR 2.11, P < 0.001), family history (OR 1.84, P = 0.006), and hiatal area (OR 1.06/cm2, P = 0.003). CONCLUSIONS: Levator avulsion, prolapse stage, and family history are significant risk factors for prolapse recurrence. PMID- 28921034 TI - Does nasal congestion have a role in decreased resistance to regular CPAP usage? AB - Nasal obstruction is known to cause resistance to continuous positive airway pressure (CPAP) therapy in obstructive sleep apnea syndrome (OSAS). In this paper, short- and long-term nasal congestion in OSAS patients receiving CPAP treatment were evaluated with acoustic rhinometry (AR). A total of 36 patients with moderate-to-severe OSAS, diagnosed with polysomnography were included in the study. Ten healthy subjects without OSAS constituted the control group. Pre treatment nasal patency were measured with AR in all participants. 26 patients used the recommended CPAP treatment. Ten patients did not accept CPAP treatment. The AR test was repeated for all the subjects after 1 and 3 months except the 3rd month's measurements of the control group. There was no statistically significant difference between the initial minimum cross-sectional area (MCA) measurements of OSAS patients, using or not using CPAP, and the control group (P > 0.05). However, the first month MCA measurements of patients receiving CPAP were found to be significantly decreased compared with the initial values (P < 0.001). There was no significant change in the first and third months MCA values in the control group and patients who did not use CPAP (P > 0.05). No significant difference revealed in the 3rd month MCA measurements of the patients using CPAP compared with the initial values (P > 0.05). In this study, the increased nasal congestion, which is thought to be the cause of CPAP resistance, was objectively demonstrated in OSAS patients using CPAP. In addition, the nasal congestion developing at the first month was shown to disappear over time, supporting the opinion that patient compliance in CPAP treatment is expected to increase after regular device usage. PMID- 28921035 TI - [Midportion Achilles tendinopathy]. AB - Although the incidence of midportion Achilles tendinopathy is under 1% in the general population, it is quite a common disease in runners that is characterized by the symptom triad of pain, swelling and impaired physical performance. Pain and swelling are located in the area 2 to 7 cm proximal the tendon insertion onto the calcaneus.Diagnosis is made by adequate clinical symptoms and corresponding findings in sonography and/or magnetic resonance imaging scans. Histopathologically, mostly degenerative changes in the tendon structure are found, sometimes accompanied by intra- and paratendinous inflammation.Treatment options are conservative or surgical, but conservative ones should be tried first. The best evidence is available for eccentric exercise protocols, which represent the gold standard in conservative treatment options, followed by extracorporal shockwave (ECSW) therapy and corticoid injections.In about 25% of all cases, because of unsatisfactory nonoperative treatment results, surgery is recommended. Open, minimally invasive as well as tenoscopic methods exist, which show patients' satisfactory rates of about 80%. The return to sport or full physical performance is variable and may take up to 18 months for both treatment regimens. PMID- 28921036 TI - Long-term outcomes and predictors of failure after surgery for stage IV apical pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare outcomes after uterosacral ligament suspension (USLS) or sacrocolpopexy for symptomatic stage IV apical pelvic organ prolapse (POP) and evaluate predictors of prolapse recurrence. METHODS: The medical records of patients managed surgically for stage IV apical POP from January 2002 to June 2012 were reviewed. A follow-up survey was sent to these patients. The primary outcome, prolapse recurrence, was defined as recurrence of prolapse symptoms measured by validated questionnaire or surgical retreatment. Survival time free of prolapse recurrence was estimated using the Kaplan-Meier method, and Cox proportional hazards models evaluated factors for an association with recurrence. RESULTS: Of 2633 women treated for POP, 399 (15.2%) had stage IV apical prolapse and were managed with either USLS (n = 355) or sacrocolpopexy (n = 44). Those managed with USLS were significantly older (p < 0.001) and less likely to have a prior hysterectomy (39.7 vs 86.4%; p < 0.001) or prior apical prolapse repair (8.2 38.6%; p < 0.001). Median follow-up was 4.3 years [interquartile range (IQR) 1.1-7.7]. Survival free of recurrence was similar between USLS and sacrocolpopexy (p = 0.43), with 5-year rates of 88.7 and 97.6%, respectively. Younger age [adjusted hazard ratio (aHR) 1.55, 95% confidence interval (CI) 1.12-2.13; p = 0.008] and prior hysterectomy (aHR 2.8, 95% CI 1.39-5.64; p = 0.004) were associated with the risk of prolapse recurrence, whereas type of surgery approached statistical significance (aHR 2.76, 95% CI 0.80-9.60; p = 0.11). CONCLUSIONS: Younger age and history of prior hysterectomy were associated with an increased risk of recurrent prolapse symptoms. Notably, excellent survival free of prolapse recurrence were obtained with both surgical techniques. PMID- 28921037 TI - [The patient blood management concept : Joint recommendation of the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. AB - Patient blood management is a multimodal concept that aims to detect, prevent and treat anemia, optimize hemostasis, minimize iatrogenic blood loss, and support a patient-centered decision to provide optimal use of allogeneic blood products. Although the World Health Organization (WHO) has already recommended patient blood management as a new standard in 2010, many hospitals have not implemented it at all or only in part in clinical practice. The German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery therefore demand that i) all professionals involved in the treatment should implement important aspects of patient blood management considering local conditions, and ii) the structural, administrative and budgetary conditions should be created in the health care system to implement more intensively many of the measures in Germany. PMID- 28921039 TI - Comment on "Hysteropreservation versus hysterectomy in the surgical treatment of uterine prolapse: systematic review and meta-analysis". PMID- 28921038 TI - Efficacy and safety of tacrolimus for myasthenia gravis: a systematic review and meta-analysis. AB - To evaluate the efficacy and safety of tacrolimus in patients with myasthenia gravis (MG), a systematic review and meta-analysis was performed. We searched PubMed and Embase for randomized controlled trials and clinical controlled trials in English language. Demographic and clinical characteristics of the MG patients were extracted. Differences in the current glucocorticoids (GC) dose in each included study were the primary outcome measure. The adverse events reported in each included study were used as safety evaluation. There were 5 trials included involving 683 patients. In this systematic review, we identified treatment with tacrolimus did not exhibit a statistically significant difference in the GC dose reduction at 6 months and 12 months compared with placebo. The standard mean differences in the GC dose reduction were -1.95 [(-4.20 to 0.30); p = 0.09] at 6 months and -1.72 [(-4.21 to 0.77); p = 0.18] at 12 months. But GC dose reduction from baseline in the tacrolimus group exceeded that in the controlled group. The weighted mean differences were -1.34 [(-2.46 to 0.23); p = 0.02] in the quantitative myasthenia gravis score and -1.10 [(-1.84 to -0.36); p = 0.004] in the myasthenia gravis activities of daily living score at 6 months. Adverse events were recorded in 80 of 347 patients (23%) treated with tacrolimus and most of them were mild. This meta-analysis proves that tacrolimus therapy is beneficial to improve clinical symptoms in MG patients. Tacrolimus may be a worthy therapy to relieve MG symptoms. PMID- 28921041 TI - Stabilization of scaphoid type B2 fractures with one or two headless compression screws. AB - INTRODUCTION: Fractures of the scaphoid account for the most commonly injured carpal bone. Minimally displaced fractures of the waist will heal in 85-90% when using a below elbow cast. However, fractures with displacement have a higher risk for nonunion. Therefore, open reduction and fixation with headless compression screws (HCS) have become the preferred method of treatment. The aim of this study was to compare the radiological and clinical outcome of unstable scaphoid B2 type fractures, stabilized using one or two headless compression screws. PATIENTS AND METHODS: A total of 47 unstable scaphoid B2 type fractures were included in this retrospective follow-up study. Twelve patients were not accessable and three refused to attend follow-up checks. Therefore, a total of 32 patients were included in this study with a mean follow-up interval of 43 (12-81) months. Twenty-two patients were treated using one HCS and ten with two HCS. Clinical assessment included range of motion (ROM), pain according to the visual analogue scale (VAS), grip strength, Disability of the Arm, Shoulder and Hand Score, Patient-Rated Wrist Evaluation Score, Michigan Hand Outcomes Questionnaire and modified Green O'Brien Wrist Score. The follow-up study on each patient included a CT-Scan of the wrist which was analyzed for union, osteoarthritis, dorsiflexed intercalated segment instability and humpback deformity. RESULTS: Radiologically, 29/32 (91%) of the scaphoid B2 type fractures showed union, 10/10 (100%) in the two HCS group and 19/22 (86%) in the one HCS group (p < 0.05). No significant differences could be found in respect to ROM, grip strength, VAS and scores between the groups. Screw removal was necessary in two patients in the two HCS group and one in the one HCS group. CONCLUSION: The unstable B2 type fractures of the scaphoid, when using two HCS without bone grafting is a safe method, shows a significantly higher union rate and equal clinical outcome compared to stabilization using only one HCS. PMID- 28921040 TI - Euro-Esli: a European audit of real-world use of eslicarbazepine acetate as a treatment for partial-onset seizures. AB - The Euro-Esli study was an exploratory pooled analysis of data from 14 European clinical practice studies, which was conducted to audit the real-world effectiveness, safety, and tolerability of eslicarbazepine acetate (ESL) as an adjunctive treatment for partial-onset seizures. Retention and effectiveness were assessed after 3, 6, and 12 months of ESL treatment, and at the final visit. Safety and tolerability were assessed throughout ESL treatment by evaluating adverse events (AEs) and ESL discontinuation due to AEs. Data from 2058 patients (52.1% male; mean age 44.0 years) were included. All 2058 patients were assessed for safety and 1975 (96.0%) patients were assessed for effectiveness. After 12 months, retention, responder (>=50% seizure frequency reduction), and seizure freedom rates were 73.4, 75.6, and 41.3%, respectively. AEs were reported for 34.0% of patients and led to discontinuation in 13.6% of patients. The most frequently reported AEs were dizziness (6.7% of patients), fatigue (5.4%), and somnolence (5.1%). No unexpected safety signals emerged over a median duration of follow-up of >5 years. Subgroup analyses revealed that ESL was significantly more effective in patients aged >=65 versus <65 years, in patients who were not receiving treatment with other sodium channel blockers versus those who were receiving treatment with other sodium channel blockers, and in patients who were receiving <2 versus >=2 concomitant antiepileptic drugs at baseline. Euro-Esli is the largest ESL clinical practice study conducted to date. This study provides strong and reassuring evidence of ESL's safety profile, and complements the data from clinical trials. PMID- 28921042 TI - Symptomatic treatment of dyspnea in advanced cancer patients : A narrative review of the current literature. AB - BACKGROUND: Dyspnea is a common, very distressing symptom in advanced cancer patients that challenges them, their relatives, and healthcare professionals. This narrative review summarizes important literature dealing with the evidence for opioids, benzodiazepines, oxygen, and steroids for treating dyspnea in advanced cancer patients. METHODS: A selective literature search was undertaken in PubMed, Embase, and the Cochrane Library and extended with literature from the reference lists of included studies up to April 2016. Inclusion criteria were that patients were suffering from advanced cancer and were receiving either opioids, benzodiazepines, corticosteroids, or oxygen. The outcome of interest was the reduction of dyspnea measured via a visual analogue scale (VAS), a numerical rating scale (NRS), or a Borg scale. This narrative review describes in detail the findings of 13 studies. RESULTS: Nine studies deal with the effectiveness of opioids for reducing dyspnea in advanced cancer patients. Five of these found a significant benefit to the use of opioids compared to a placebo. Three found no significant improvements, and two favored combinations of opioids and benzodiazepines. Few high-quality studies were available that used benzodiazepines (n = 3, no difference, significant improvement with midazolam + morphine, significant difference for midazolam) or oxygen (n = 2, both without significant difference). Only one study examined treating dyspnea with steroids in patients with advanced cancer, and that study indicated a benefit of steroids compared to a placebo. CONCLUSIONS: Opioids are the drug of choice for treating refractory dyspnea in advanced cancer patients. Neither benzodiazepines nor oxygen showed significant benefit. In addition, there is insufficient literature available to draw a conclusion about the effectiveness of steroids for treating persistent dyspnea in advanced cancer patients. PMID- 28921043 TI - Slow wave activity and executive dysfunction in children with sleep disordered breathing. AB - PURPOSE: This study aimed to examine slow wave activity (SWA), a marker of homeostatic regulation, as a potential mechanism linking sleep disordered breathing (SDB) with executive dysfunction in children. METHODS: Executive function domains of working memory, spatial planning, information processing, and sustained attention were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in children (N = 40; 5-12 years) referred for clinical diagnosis of SDB. Polysomnography records of non-snoring, age-matched controls (N = 34) were retrospectively examined for comparison of SWA. Power spectral analysis of the delta wave determined SWA. Group differences in sleep, respiratory, and SWA outcomes were examined. Mean CANTAB scores were compared to standardized norms and correlated against SWA. RESULTS: Children with SDB showed increased SWA compared to non-snoring controls and scored < 25th percentile for planning accuracy, speed of mental processing, and task efficiency, when compared against population norms. Increasing severity of SDB was associated with an increased difficulty in solving complex tasks and time on task performance. SWA was associated with performance on tasks of early problem solving and efficiency during sustained attention. CONCLUSIONS: SWA, a subtle measure of sleep disruption and sleep regulation, is associated with deficits in problem solving and sustained attention in children with SDB. As current mechanistic theories do not account for deficits observed in children with mild forms of SDB, this study provides a promising alternative. PMID- 28921044 TI - [Superbrown beauty : The surface of tanorexia and tanning dependence]. AB - Brown skin symbolizes fitness, health, youthfulness and beauty, combined with leisure, activity, and joy of life in the Central European culture. Tanorexia is a tanning dependence that describes the morbid excessive desire for constant skin tanning. Particularly young women are affected. This article shows the underlying psychodermatological disorders. PMID- 28921045 TI - [What is beauty? : Manifest for an aesthetic character medicine]. AB - Aesthetic medicine has in recent decades attained a growing social significance and firm place in the medical profession image. In a short time, a variety of technical procedures and processes have been developed and applied by specialized physicians. A further leading medical discussion regarding the central question "What is beauty" is missing compared with the technologically innovative progress. Beauty is characterized by an individual and subjective pleasure. Social media and fashion trends exert a central influence on common beauty ideals and aesthetic medicine. In practice, the artificial intervention must accord to the individual personality. Therefore, the professional term Aesthetic Medicine is insufficient and should be replaced by "Aesthetic Character Medicine". The particular purpose is the aim of graceful aging and a sustained adequate result which outlasts the zeitgeist. This requires medical know how and clear aesthetic self-conception of the physician. "Aesthetic Character Medicine" can be realized in a discourse, with the 10-step plan presented in this article. PMID- 28921047 TI - Child dermoid cyst mimicking a craniopharyngioma: the benefit of MRI T2-weighted diffusion sequence. AB - BACKGROUND: Brain dermoid cysts are very rare lesions. Although benign, these cysts may be associated with devastating complications due to mass effect or meningitis. The discovery of completely asymptomatic dermoid cysts in the pediatric population is exceedingly rare. Despite the advances in imaging modalities, it sometimes remains difficult to exclude the differential diagnosis of craniopharyngioma. CASE REPORT: We describe a 12-year-old boy addressed for suspicion of craniopharyngioma diagnosed by decreased visual acuity, bitemporal hemianopia and a CT scan showing a large hypodense suprasellar lesion with intralesional calcifications. Despite the unusual localization and size of this lesion, the absence of dermal sinus commonly found, and before visualizing a hyperintense mass on MRI-diffusion, the diagnosis of craniopharyngioma was ruled out in favor of a dermoid cyst. Radical excision was performed. CONCLUSION: In the suprasellar area, craniopharyngioma and dermoid cyst may have very similar radiological aspects: low density masses on CT scan and a hyperintense signal on T1-weighted MRI sequences with a variable signal on T2-weighted sequences. Hitherto, only two cases in literature have described suprasellar dermoid cyst. Their initial diagnosis was facilitated by the presence of a dermal sinus. PMID- 28921046 TI - Competition for electrons between pyridine and quinoline during their simultaneous biodegradation. AB - Biodegradation of pyridine and quinoline is initiated with mono-oxygenation reactions that require an intracellular electron donor. Simultaneous biodegradation of both substrates should set up competition for the intracellular electron donor that may inhibit one or more of the mono-oxygenation steps. An internal circulation baffled biofilm reactor (ICBBR) was used to evaluate the impacts of competition during pyridine and quinoline biodegradation. Compared with independent biodegradation, pyridine and quinoline removal rates were slowed when biodegraded simultaneously, although the pyridine removal rate decreased more than for quinoline. The first mono-oxygenation of quinoline (to 2 hydroxyquinoline) always was faster than the first mono-oxygenation of pyridine (to 2-hydroxypyridine), and the difference was accentuated with pyridine and quinoline which were biodegraded simultaneously due to the competition for intracellular electron donor. Competition also existed between the second mono oxygenations, and the removal rate of 2-hydroxypyridine was faster than the rate for 2-hydroxyquinoline, even though the rate was faster for quinoline than pyridine. Adding an exogenous electron donor accelerated all mono-oxygenations in proportion to the amount of donor added, but the increments were greater for quinoline due to its higher affinity for intracellular electron donors than pyridine. When actual coking wastewater was used as the background matrix, removals of pyridine and quinoline exhibited the same competitive trends. PMID- 28921048 TI - Antibacterial and antitumor activity of Bogorol B-JX isolated from Brevibacillus laterosporus JX-5. AB - Antimicrobial peptides are promising anti-infective agent candidates because they have a broad antimicrobial spectrum and bioactivity and are unlikely to elicit antibiotic resistance. The bogorols represent a new cationic antibiotic peptide and possess great therapeutic potential because of their bioactivity and precise mode of action. Here, we report that Bogorol B-JX (BBJX), a peptide previously isolated from Brevibacillus laterosporus JX-5 by us, has significant antibacterial and antitumor activities in vitro. BBJX was found to inhibit methicillin-resistant Staphylococcus aureus (MRSA) at 2.5 ug/mL with distinct mechanisms of action from those against Bacillus bombyseptieus and Escherichia coli. It penetrates MRSA membrane with little visible destruction and binds to genomic DNA. BBJX could inhibit the proliferation of human histiocytic lymphoma cell line U-937 and ConA-activated spleen cells at 5 ug/mL, but was not cytotoxic to the Jurkat cells, resting spleen cells or differentiated macrophage-like U-937 immunocytes. Moreover, BBJX caused apoptosis of U-937 cells by opening the mitochondrial permeability transition pore and stimulating the production of reactive oxygen species. Taken together, these studies provided basis for future medical application of the bogorols. PMID- 28921049 TI - The association between exposure to psychosocial work factors and mental health in older employees, a 3-year follow-up study. AB - PURPOSE: Unfavourable exposure to psychosocial work factors threatens older employees' mental health, and their sustained employment. This study assesses whether an improved compared to stable unfavourable and stable favourable exposure to psychosocial work factors is associated with a change in mental health in older employees at 3-year follow-up. METHODS: The current study used data from the Study on Transitions in Employment, Ability and Motivation (STREAM), in workers aged 45-65 years (n = 5249). Two-year (2010-2012) exposure was assessed for psychological demands, autonomy, support, mental load, and distributive justice. Linear regression analyses were performed to compare improved exposure to unfavourable psychosocial work factors with stable unfavourable and stable favourable exposure and mental health at follow-up (2013), corrected for confounders. Analyses were stratified for age groups (45-54 and 55-65 years) and gender. RESULTS: In certain subgroups, stable unfavourable exposure to psychological demands, autonomy, support, and distributive justice was associated with a significantly lower mental health score than improved exposure. Stable favourable exposure to support was associated with a higher mental health score than improved support, whereas stable favourable exposure to autonomy was associated with a lower mental health score compared to improved exposure. CONCLUSIONS: There is a longitudinal association between changes in exposure to psychosocial work factors and mental health. Improvement in unfavourable exposure to psychosocial work factors was associated with improved mental health. This is important information for organisations that consider deploying measures to improve the psychosocial work environment of older workers. PMID- 28921050 TI - Characterization of CcSTOP1; a C2H2-type transcription factor regulates Al tolerance gene in pigeonpea. AB - MAIN CONCLUSION: Al-responsive citrate-transporting CcMATE1 function and its regulation by CcSTOP1 were analyzed using NtSTOP1 -KD tobacco- and pigeonpea hairy roots, respectively, CcSTOP1 binding sequence of CcMATE1 showed similarity with AtALMT1 promoter. The molecular mechanisms of Aluminum (Al) tolerance in pigeonpea (Cajanus cajan) were characterized to provide information for molecular breeding. Al-inducible citrate excretion was associated with the expression of MULTIDRUGS AND TOXIC COMPOUNDS EXCLUSION (CcMATE1), which encodes a citrate transporter. Ectopic expression of CcMATE1-conferred Al tolerance to hairy roots of transgenic tobacco with the STOP1 regulation system knocked down. This gain-of function approach clearly showed CcMATE1 was involved in Al detoxification. The expression of CcMATE1 and another Al-tolerance gene, ALUMINUM SENSITIVE 3 (CcALS3), was regulated by SENSITIVE TO PROTON RHIZOTOXICITY1 (CcSTOP1) according to loss-of-function analysis of pigeonpea hairy roots in which CcSTOP1 was suppressed. An in vitro binding assay showed that the Al-responsive CcMATE1 promoter contained the GGNVS consensus bound by CcSTOP1. Mutation of GGNVS inactivated the Al-inducible expression of CcMATE1 in pigeonpea hairy roots. This indicated that CcSTOP1 binding to the promoter is critical for CcMATE1 expression. The STOP1 binding sites of both the CcMATE1 and AtALMT1 promoters contained GGNVS and a flanking 3' sequence. The GGNVS region was identical in both CcMATE1 and AtALMT1. By contrast, the 3' flanking sequence with binding affinity to STOP1 did not show similarity. Putative STOP1 binding sites with similar structures were also found in Al-inducible MATE and ALMT1 promoters in other plant species. The characterized Al-responsive CcSTOP1 and CcMATE1 genes will help in pigeonpea breeding in acid soil tolerance. PMID- 28921051 TI - Fine particle matters induce DNA damage and G2/M cell cycle arrest in human bronchial epithelial BEAS-2B cells. AB - There is compelling evidence that exposure to particulate matter (PM) is linked to lung tumorigenesis. However, there is not enough experimental evidence to support the specific mechanisms of PM2.5-induced DNA damage and cell cycle arrest in lung tumorigenesis. In this study, we investigated the toxic effects and molecular mechanisms of PM2.5 on bronchial epithelial (BEAS-2B) cells. PM2.5 exposure reduced cell viability and enhanced LDH activity. The cell growth curves of BEAS-2B cells decreased gradually with the increase in PM2.5 dosage. A significant increase in MDA content and a decrease in GSH-Px activity were observed. The generation of ROS was enhanced obviously, while apoptosis increased in BEAS-2B cells exposed to PM2.5 for 24 h. DNA damage was found to be more severe in the exposed groups compared with the control. For in-depth study, we have demonstrated that PM2.5 stimulated the activation of HER2/ErbB2 while significantly upregulating the expression of Ras/GADPH, p-BRAF/BRAF, p-MEK/MEK, p ERK/ERK, and c-Myc/GADPH in a dose-dependent manner. In summary, we suggested that exposure to PM2.5 sustained the activation of HER2/ErbB2, which in turn promoted the activation of the Ras/Raf/MAPK pathway and the expression of the downstream target c-Myc. The overexpression of c-Myc may lead to G2/M arrest and aggravate the DNA damage and apoptosis in BEAS-2B after exposure to PM2.5. PMID- 28921052 TI - In vitro evaluation of flow patterns and turbulent kinetic energy in trans catheter aortic valve prostheses. AB - OBJECTIVES: The objective of the current work was to evaluate flow and turbulent kinetic energy in different transcatheter aortic valve implants using highly undersampled time-resolved multi-point 3-directional phase-contrast measurements (4D Flow MRI) in an in vitro setup. MATERIALS AND METHODS: A pulsatile flow setup was used with a compliant tubing mimicking a stiff left ventricular outflow tract and ascending aorta. Five different implants were measured using a highly undersampled multi-point 4D Flow MRI sequence. Velocities and turbulent kinetic energy values were analysed and compared. RESULTS: Strong variations of turbulent kinetic energy distributions between the valves were observed. Maximum turbulent kinetic energy values ranged from 100 to over 500 J/m3 while through-plane velocities were similar between all valves. CONCLUSION: Highly accelerated 4D Flow MRI for the measurement of velocities and turbulent kinetic energy values allowed for the assessment of hemodynamic parameters in five different implant models. The presented setup, measurement protocol and analysis methods provides an efficient approach to compare different valve implants and could aid future novel valve designs. PMID- 28921053 TI - Herbs Used for the Treatment of Hypertension and their Mechanism of Action. AB - There is great interest lately, in the use of herbs for the treatment of hypertension and cardiovascular disease (CVD). Herbs and plants contain many phytochemicals that have been effective in the treatment of CVD and hypertension. Accumulating scientific evidence provides a reason for the use of herbs by health practitioners for treating their patients. The rationale for this expanding use of herbs is the belief of patients in a "holistic medicine" and that herbs are natural, safe, and effective. However, there are reasons of concern with the use of herbs, because they are not regulated or supervised carefully and their use could lead to serious complications or interactions with their combination with traditional medicines. In addition, their use is associated with significant out of pocket expenses, because their use is not compensated by health insurance providers. In this review, we present the scientific evidence for the use of herbs. PMID- 28921054 TI - Association of mineralocorticoid receptor antagonist use and in-hospital outcomes in patients with acute heart failure. AB - Mineralocorticoid receptor antagonists (MRAs) constitute a beneficial therapy in chronic heart failure, but their use in the acute heart failure (AHF) setting remains rather unexplored. To assess the effect of MRAs administered during hospitalization on in-hospital outcomes of patients with AHF, we performed a post hoc analysis of the Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF). Patients of the original study cohort (n = 4953) were categorized according to in-hospital MRA treatment status as MRA-treated (n = 1439) and untreated (n = 3514) subjects. Nearest-neighbor propensity score with 1:1 matching yielded a subsample of pairs of MRA-treated and MRA-untreated patients (n = 1003 in each treatment group) that were balanced in an extensive list of baseline characteristics. In-hospital mortality between MRA-treated and untreated patients were assessed by Cox regression analysis before and after adjustment for known prognostic factors and other concomitantly administered intravenous and oral HF specific therapies. In the matched cohort, in-hospital mortality was 4.2 vs 10.8% in MRA-treated vs untreated patients. Treatment with MRAs was associated with a reduction of in-hospital mortality [HR 0.372 (95% CI, 0.261-0.532), p < 0.001]. This association remained significant after adjustment for known prognostic factors and co-administered intravenous and oral HF therapies [HR: 0.618 (95% CI, 0.383-0.995), p = 0.048]. In conclusion, MRA therapy administered during hospitalization for AHF was associated with reduced in-hospital mortality. The role of MRAs in AHF deserves further examination in adequately powered randomized controlled studies. PMID- 28921055 TI - Implantation meets intervention: reopening of a thrombotic ostial occlusion of coronary sinus by angioplasty achieved improvement of cardiac venous drainage and allowed transvenous CRT implantation. PMID- 28921056 TI - Oxidative Stress in Atherosclerosis. AB - PURPOSE OF REVIEW: Atherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis. RECENT FINDINGS: There is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development. Research over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis. PMID- 28921057 TI - DVT Prevention in Stroke. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the prevention of venous thromboembolism (VTE) in stroke patients. We discuss use of oral anticoagulation and other interventions for the prevention of VTE. A new class of medications, non-vitamin K antagonist oral anticoagulants (NOACs), have been successfully trialed for the prevention of VTE. We review the data and guidance statements for VTE prevention. RECENT FINDINGS: Warfarin and vitamin K antagonist drugs have been the mainstay of VTE prevention for decades. More recently, NOACs have become available for both stroke and systemic embolism prevention in nonvalvular atrial fibrillation and for VTE treatment or prevention. NOACs have been shown to be at least noninferior for VTE prevention and treatment when compared with warfarin, and have a good safety profile. Other approaches include use of graduated compression stockings, intermittent compression stockings, inferior vena cava filters, and heparins. Selection of the appropriate VTE prophylaxis in stroke patients is important to reduce associated morbidity and mortality. PMID- 28921058 TI - The Influence of task Demands, Verbal Ability and Executive Functions on Item and Source Memory in Autism Spectrum Disorder. AB - Autism Spectrum Disorder (ASD) is generally associated with difficulties in contextual source memory but not single item memory. There are surprising inconsistencies in the literature, however, that the current study seeks to address by examining item and source memory in age and ability matched groups of 22 ASD and 21 comparison adults. Results show that group differences in source memory are moderated by task demands but not by individual differences in verbal ability, executive function or item memory. By contrast, unexpected group differences in item memory could largely be explained by individual differences in source memory. These observations shed light on the factors underlying inconsistent findings in the memory literature in ASD, which has important implications for theory and practice. PMID- 28921059 TI - Very Early Systemic Sclerosis and Pre-systemic Sclerosis: Definition, Recognition, Clinical Relevance and Future Directions. AB - PURPOSE OF REVIEW: The approach to systemic sclerosis (SSc) has changed over the years with an increasing focus on the very early diagnosis of the disease. The terminology identifying patients in the early phase of SSc has been significantly confusing in the last three decades. The purpose of this article is to analyze how the concept of "very early SSc" has evolved over the years, which is the role of an early diagnosis and how early treat patients. RECENT FINDINGS: Several attempts have been made over time, to create more sensitive and specific classification criteria to include the largest number of SSc patients, also in the earliest phase. An algorythm for the very early diagnosis of SSc was identified, diagnostic preliminary criteria proposed, and new 2013 ACR/EULAR SSc classification criteria published, including new items and adding emphasis to the vasculopathic manifestations. True biomarkers that could predict the disease evolution are still missing. Treat or not to treat patients in the earliest phases still remain a dilemma. For the moment, the only feasible clinical strategy in very early SSc remains a tight follow up program to detect in "real time" the early internal organ involvement which may allow an aggressive therapeutic agenda. PMID- 28921061 TI - Titration of propofol infusion using processed electroencephalogram during combined general and spinal anesthesia. AB - PURPOSE: To determine the necessary mean infusion rate of propofol during combined nitrous oxide (N2O) and propofol spinal anesthesia by using the processed electroencephalogram (pEEG). METHODS: Twelve elective gynecological patients were monitored by a Drager pEEG monitor under N2O and propofol spinal anesthesia. To make it easier to detect an inadequate depth of anesthesia, muscle relaxants were not given and the patients breathed spontaneously through a laryngeal mask airway. Manual step-down infusion of propofol was employed to provide intraoperative hypnosis. Propofol infusion was titrated to maintain cardiorespiratory parameters within 20% of baseline and the 90th percentile of the spectral edge frequency (SEF 90) of the pEEG between 10 and 13.5 Hz. RESULTS: The mean (SD) induction dose of propofol was 2.9 (0.4) mg.kg-1. The mean (SD) maintenance infusion rate was 4.2 (0.5) mg.kg-1.h-1. The mean (SD) time from the end of propofol infusion to the opening of the patient's eyes was 5.4 (2.0) min. No gross movements or intraoperative awareness was recognized. The mean (SD) SEF 90 during the maintenance of anesthesia was 12.2 (1.5) Hz, which increased significantly to 16.2 (1.9) Hz at 1 min before the patients opened their eyes in reponse to verbal commands. CONCLUSION: Titration of propofol infusion using SEF during combined general and spinal anesthesia provided a rapid recovery without any clinical signs of inadequate anesthesia. PMID- 28921060 TI - Comparison of sensitivity of neuromuscular monitoring tests: twitch versus tetanic test. AB - PURPOSE: The study was planned to compare the sensitivity of a twitch neuromuscular monitoring test, the train-of-four (TOF), with a tetanic test, double-burst stimulation (DBS), during a subclinical dose of vecuronium. METHODS: Twenty consenting. ASA I patients (16 to 65 years of age) of both sexes were studied. The ulnar nerve was stimulated at the wrist through surface electrodes by Myotest-DBS, and the adductor pollicis response was recorded on Myograph-2000. After stabilization of the twitch tension at titrated supramaximal stimuli (1 Hz), patients were randomly allocated into groups. In group 1 (n=10), the TOF test was monitored; in group 2 (n=10), the DBS test was monitoral. All patients received a priming dose of vecuronium (0.015 mg.kg-1); parameters such asT 1 and TOF ratio (TOFr) (T 4/T 1) were noted in group 1, andD 1 and DBS ratio (DBSr) (D 2/D 1) were noted during the vecuronium effect. RESULTS: The DBS test showed a wider range of change (from control 1.00 to 0.62+/-0.19 forD 1 and to 0.37+/-0.14 for DBSr) at a faster rate (0.07+/-0.04 min-1 forD 1 and 0.08+/-0.02 min-1 for DBSr) during the block progression phase than the TOF test parameters (T 1 and TOFr). The tetanic fade or DBSr showed peak onset later than peak twitch suppression. The rate of recovery of the DBS test was also slower than that of the TOF test after the peak effect. CONCLUSIONS: DBS is a more sensitive test than TOF to quantify the subclinical dose effect of vecuronium, and among the studied parameters (T 1, TOFr,D 1 and DBSr), DBSr, measuring tetanic fade, was the most sensitive single parameter. PMID- 28921062 TI - Target controlled priming for rapid onset of intubation dose: A new approach. AB - PURPOSE: To determine the pattern of onset of the intubating dose when given at a monitored target priming block in either phase of the priming drug effect. METHODS: Sixty consenting ASA I and II patients were premedicated by intramuscular buprenorphine (5 MUg.kg-1) 1h before surgery. Neuromuscular junction monitoring was done by stimulating the ulnar nerve at the wrist using Myotest and recording the adductor pollicis response on Myograph-2000. After stabilization of the twitch tension at the titrated supramaximal stimulus (1 Hz), double-burst stimuli (DBS) were given to monitor the priming effect of vecuronium bromide (Vb) (0.015 mg.kg-1). The DBS ratio (DBSr=D 2/D 1) was calculated for the DBS response, repeated at 20s. Depending on the target priming block level (DBSr 0.8, 0.6, or 0.5) and the phase of the priming block to give an intubating dose of Vb (0.8 mg.kg-1) injection, all patients were randomly assigned to six study groups: group 1 (DBSr 0.8), group 3 (DBSr 0.6), and group 5 (DBSr 0.5) during the priming block progression phase (before peakD 1 suppression), and group 2 (DBSr 0.8), group 4 (DBSr 0.6), and group 6 (DBSr 0.5) during the priming block regression phase (after peakD 1 suppression). Anesthesia was induced by thiopental (5-7 mg.kg-1) just before the intubating dose. The effect of the intubating dose on twitch stimuli (1 Hz) was monitored. RESULTS: We observed that in spite of significantly variable priming intervals for identical DBSr in two different phases, the onset time of the intubating dose to 0 response was identical in similar DBSr group patients; i.e., at 0.8 DBSr, 65.0+/-5.2s (group 1)vs 66.0+/-8.0s (group 2); at DBSr 0.6, 55.2+/-3.7s (group 3)vs 55.2+/-4.9s (group 4); and at DBSr 0.5, 43.5+/-4.8s (group 5)vs 43.5+/-4.2s (group 6). At 0 twitch response, the intubating conditions were comparable in patients of the six groups. CONCLUSION: In conclusion, target controlled priming (DBSr) for administration of the intubating dose appears to be a useful double-vision sign to predict the onset of the effect of the intubating dose precisely. PMID- 28921063 TI - Epidural anesthesia during hysterectomy diminishes postoperative pain and urinary cortisol release. AB - PURPOSE: To examine the hypothesis that epidural anesthesia throughout lower abdominal surgery would depress both postoperative pain and cortisol release. METHODS: Forty adult patients undergoing abdominal total hysterectomy were studied. The patients were randomly assigned to two groups. Group G received general anesthesia alone (sevoflurane 1.5%-2.5%); group E received a combination of epidural anesthesia (1.5% mepivacaine) with a light plane of general anesthesia (sevoflurane<0.5%). Postoperative analgesia was obtained epidurally by patient-controlled analgesia. Postoperative pain at rest and during movement was assessed by a visual analogue scale (VAS) at 2, 24, and 48 h following surgery. The plasma concentration and urinary excretion of cortisol were measured during the perioperative period. RESULTS: VAS values were lower in group E than in group G during movement at 24h (4.6+/-0.5vs 6.1+/-0.4 cm). Urinary cortisol excretion on the first postoperative day was less in group E than in group G (192+/-34vs 480+/-120MUg). CONCLUSIONS: Epidural blockade prior to surgical stimuli and throughout lower abdominal surgery reduces the postoperative dynamic pain and stress response. PMID- 28921064 TI - Normothermic cardiopulmonary bypass and cardioplegia reduce inotropic requirements and creatine kinase-MB after coronary artery bypass graft surgery. AB - PURPOSE: To determine whether normothermic cardiopulmonary bypass (CPB) and cardioplegia preserve myocardial function, reduce inotropic requirements, and reduce markers of myocardial ischemia following coronary artery bypass graft surgery (CABG). METHODS: We retrospectively reviewed the charts of 171 consecutive patients undergoing elective CABG by a single surgeon from April 1994 to December 1995. Hypothermic CPB with intermittent cold cardioplegia was used in 83 patients and normothermic CPB with intermittent warm cardioplegia in 88 patients. Demographic, surgical, hemodynamic, and inotropic requirements and laboratory data were reviewed. RESULTS: The duration of CPB was significantly shorter in the normothermic group (113+/-27vs 90+/-21 min;P<0.0001). After CPB the cardiac index was similar between groups, but significantly larger doses of both dopamine and dobutamine were required (8vs 5MUg.kg-1.min-1,P<0.0001), and significantly more patients required norepinephrine administration in the hypothermic group (18%vs 6%;P=0.01). Postoperative peak values of creatine kinase MB fraction (CK-MB) were significantly lower in the normothermic group (80+/-60vs 55+/-54 IU.I-1;P<0.0001). CONCLUSION: Normothermic CPB and cardioplegia reduce inotropic requirements and CK-MB following CABG. PMID- 28921065 TI - Effect of fentanyl on heart rate variability during mechanical ventilation. AB - PURPOSE: This study was performed to investigate the effect of fentanyl alone on heart rate variability (HRV) during mechanical ventilation using power spectral analysis. Arterial baroreceptor reflex was also tested with pharmacological manipulation to assess the contribution of vagal baroreceptor reflex modulation of HRV during fentanyl anesthesia. METHOD: Ten patients participated in this study. Electrocardiograms and arterial pressure were recorded prior to and during fentanyl (10 MUg.kg-1) and vecuronium (0.2 mg.kg-1) anesthesia, with respiratory rate and tidal volume controlled ventilation. R-R intervals were analyzed by fast Fourier transformation, and changes in low-frequency (LF) and high-frequency (HF) power were compared. Arterial baroreceptor reflex regulation was also tested with administration of nitroglycerin (250 MUg) or phenylephrine (250 MUg). RESULTS: HF power was significantly reduced during anesthesia from 3.20+/-2.93 to 0.46+/-0.48 ms2.Hz-1.103 (mean+/-SD,P<0.05). However, LF power did not change despite increases in plasma catecholamine concentrations. The response to phenylephrine was reduced during fentanyl anesthesia from 16.6+/-5.7 to 9.5+/-5.4 ms.mmHg-1 (P<0.05), whereas the response to nitroglycerin was not affected. CONCLUSION: Our data indicate that fentanyl modulates the respiratory frequency fluctuation of HRV. This is partly caused by the effects of fentanyl on arterial baroreflex sensitivity. PMID- 28921066 TI - Effects of hemoglobin concentration and temperature on the in vitro release of cyanide from sodium nitroprusside. AB - PURPOSE: This in vitro study was performed to determine whether changes in hemoglobin (Hb) concentration and temperature influenced the amount of cyanide (CN-) released from sodium nitroprusside (SNP). METHODS: Canine whole blood with a Hb concentration of 8.5 to 18.9 g.dl (5.3 to 18.9 mM) was equilibrated with SNP at either 37 degrees C or 25 degrees C, and CN- levels in plasma and red blood cells (RBC) were measured using the microdiffusion method. RESULTS: Changes in Hb concentration and temperature did not have any statistically significant effect on the CN- released from SNP in plasma. On the other hand, CN- levels in RBC decreased with increasing Hb concentrations. CN- levels in RBC were significantly lower at 25 degrees C than at 37 degrees C. CONCLUSION: Though the Hb concentration and temperature changed the amount of CN- released from SNP in RBC, the change observed was not clinically significant. PMID- 28921067 TI - Effect of inhaled nitroglycerine and sodium nitroprusside aerosol on hemodynamics and oxygenation in dogs with pulmonary hypertension. AB - PURPOSE: To test the hypothesis that inhalation of aerosol of glyceryl trinitrate or sodium nitroprusside might produce selective pulmonary vasodilation, causing an improvement of oxygenation with minimal systemic hypotension as inhaled nitric oxide gas, we investigated the effect of inhaled nitroglycerine and sodium nitroprusside aerosol on hemodynamics and oxygenation in dogs with pulmonary hypertension. METHODS: Pulmonary hypertension was induced by a continuous infusion of 1.0 to 4.0MUg.kg-1.min-1 U-46619 in anesthetized and mechanically ventilated dogs. Aerosol preparations consisted of normal saline, 250, 500, 1000, and 2000 ppm solutions of either glyceryl trinitrate or sodium nitroprusside were administered sequentially via the breathing circuit. RESULTS: Inhaled nitroglycerine and sodium nitroprusside aerosol caused neither selective pulmonary vasodilation nor improved oxygenation in this pulmonary hypertension model, unlike inhaled nitric oxide gas. CONCLUSION: These findings suggest that inhaled nitroglycerine and sodium nitroprusside aerosol is not effective in improving hemodynamic derangement or oxygenation in pulmonary hypertension. However, the effect of the substances in higher dose ranges remains to be defined. PMID- 28921068 TI - Comparison of sprotte and Quincke needles with respect to spinal fluid leakage using artificial spinal cord. AB - PURPOSE: This research investigated whether the Sprotte needle causes less leakage of CSF than the Quincke needle in the artificial spinal cord. METHODS: The changes in intradural pressure, extradural pressure, and leaked volume of CSF were evaluated following puncture with Sprotte and Quincke needles in the artificial spinal cord. RESULTS: The decrease in intradural pressure was 9.7+/ 1.8 mm H2O with the Sprotte needle and 20.5+/-2.7 mm H2O with the Quincke needle (P<0.05). The volume of leakage of artificial CSF was 2.0+/-0.3 ml with the Sprotte needle and 3.3 +/-0.3 ml with the Quincke needle (P<0.01). The extradural pressure increase was 166.1+/-8.2 mm H2O with the Sprotte needle and 186.8+/-13.2 mm H2O with the Quincke needle (P<0.05). CONCLUSION: The Sprotte needle produces less CSF leakage than the Quincke needle. PMID- 28921070 TI - Psoas compartment block for the treatment of lower-limb spasticity caused by spinal cord injury: report of a case. PMID- 28921069 TI - Use of nerve block techniques for postoperative analgesia. PMID- 28921071 TI - Thromboelastogram showing an undesirable effect of platelet transfusion on blood coagulability and fibrinolysis in a patient with aplastic anemia. PMID- 28921072 TI - Anesthetic management of a patient with variegate porphyria. PMID- 28921073 TI - Beneficial effect of ketamine hydrochloride in phantom limb pain: report of a case. PMID- 28921075 TI - RE: Takaya et al. Optimum priming dose of vecuronium for tracheal intubation.J. Anesth (1996) 10:244-247. PMID- 28921074 TI - A preliminary assessment of the intubating laryngeal mask airway. PMID- 28921076 TI - Rapid opioid detoxification under general anesthesia. PMID- 28921077 TI - RE: Yuge O: Renal toxicity of compound A with sevoflurane anesthesia: the benefits of sevoflurane appear to outweight the risks (editorial).J. Anesth 11:1 2. PMID- 28921079 TI - Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc 1 Complex: Virtual Screening, Synthesis, and Biochemical Assay. AB - Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc 1 or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc 1 complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc 1 complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions. Subsequently, the application of rational filtering procedure over the target database resulted in the elucidation of a novel class of cyt bc 1 complex potent inhibitors with comparable binding energies and biological activities to those of the standard inhibitor, antimycin. PMID- 28921080 TI - Erratum to: Distribution of Viruses Inhabiting Heterobasidion annosum in a Pine Dominated Forest Plot in Southern Finland. PMID- 28921082 TI - Expression analysis of transporter genes for screening candidate monolignol transporters using Arabidopsis thaliana cell suspensions during tracheary element differentiation. AB - The mechanism of monolignol transportation from the cytosol to the apoplast is still unclear despite being an essential step of lignification. Recently, ATP binding cassette (ABC) transporters were suggested to be involved in monolignol transport. However, there are no reliable clues to the transporters of the major lignin monomers coniferyl and synapyl alcohol. In this study, the lignification progress of Arabidopsis cultured cells during tracheary element differentiation was monitored. The expression of selected transporter genes, as well as lignification and cell-wall formation related genes as references, in differentiating cultured cell samples harvested at 2-day intervals was analyzed by real-time PCR and the data were statistically processed. The cell wall formation transcription factor MYB46, programmed-cell death related gene XCP1 and lignin polymerization peroxidase AtPrx25 were classified into the same cluster. Furthermore, the cluster closest to the abovementioned cluster contained the lignin synthesis transcription factor MYB58 and the Arabidopsis ABC transporters ABCG11, ABCG22, ABCG36 and ABCG29. This result suggested that these four ABC transporters may be involved in lignification. In the expression analysis, unexpectedly, the lignification-related genes CAD5 and C4H were not included in the same cluster as MYB58 and AtPrx25. The expression data also suggested that the lignification of tracheary elements in the culture, where lignification ratio finally reached to around 40%, continued after cell death because lignification actively progressed after programmed cell death-related gene started to be expressed. PMID- 28921081 TI - Site-saturation mutagenesis of mutant L-asparaginase II signal peptide hydrophobic region for improved excretion of cyclodextrin glucanotransferase. AB - The excretion of cyclodextrin glucanotransferase (CGTase) into the culture medium offers significant advantages over cytoplasmic expression. However, the limitation of Escherichia coli is its inability to excrete high amount of CGTase outside the cells. In this study, modification of the hydrophobic region of the N1R3 signal peptide using site-saturation mutagenesis improved the excretion of CGTase. Signal peptide mutants designated M9F, V10L and A15Y enhanced the excretion of CGTase three-fold and demonstrated two-fold higher secretion rate than the wild type. However, high secretion rate of these mutants was non productive for recombinant protein production because it caused up to a seven fold increase in cell death compared to the wild type. Our results indicated that the excretion of CGTase is highly dependent on hydrophobicity, secondary conformation and the type and position of amino acids at the region boundary and core segment of the h-region. PMID- 28921083 TI - Intraoperative contrast transesophageal echocardiography using Albunex. AB - This study was designed to investigate the effect of administration of the contrast material Albunex on intraoperative contrast transesophageal echocardiography for patients with mitral valve disease or coronary artery disease. We studied nine patients scheduled for elective coronary artery bypass grafting (CABG group) and nine patients scheduled for elective mitral valve replacement (MVR group), and used a transesophageal echocardiography probe and an echocardiographic system. During the period of stable hemodynamics before the start of cardiopulmonary bypass, Albunex in doses of 0.1 ml.kg-1 was injected at a rate of about 1 ml.s-1 from either the peripheral venous line or the distal lumen of the pulmonary arterial catheter, and the effect on contrast was compared. This effect was semiquantitatively assessed by using a grading scale from 0 to 3, with 0 indicating an absence of opacification and 3, full opacification of the cavities examined. In the CABG group, contrast resulting from administration of Albunex from the pulmonary arterial catheter was significantly better than that from the peripheral venous line, whereas in the MVR group, no improvement was found. Furthermore, when it was administered into the pulmonary artery, the effect on contrast for the MVR group was significantly lower than that for the CABG group. The efficacy rate of intraoperative contrast transesophageal echocardiography using Albunex was relatively low, and appeared to be affected by pulmonary circulation or many other factors such as the method of administration, including the route and injection pressure. PMID- 28921084 TI - Complications in the use of intravenous catheters for major surgery: A clinical study. AB - Two groups of patients received one of two intravenous catheters, a 20-gauge (ga) Criticon (C group;n=96) or a 20-gauge (ga) Vitaflon Plus (V group;n=100). Each catheter was inserted under identical cannulation conditions. Fluids and drugs used pre- and postoperatively were comparable in both groups. All catheters remained in place for a minimum of 4 days. Variables related to the quality of cannula were more favorable with the V group catheter. The incidence of early complications (erythema, swelling, tissue hardness, pain) was comparable in both groups. The survival distribution curves for all complications and swelling >2 cm were significantly longer in the V group. The frequency of swelling correlated with difficulty during vein penetration, slow blood flashback, and damage to the catheter. The incidence of complications following cannulation was high in both groups. The period from catheter insertion to the clinical onset of phlebitis was prolonged in both groups if antiphlebitogenous fluids were used. The incidence of late complications (phlebitis, displacement of the cannulae, etc.) and damage to the catheters was more frequent in the C group. The authors discuss the clinical relevance of these findings. PMID- 28921085 TI - Optimum priming dose of vecuronium for tracheal intubation. AB - To determine the optimum priming dose of vecuronium, we divided 173 surgical patients into five groups according to priming dose (0, 2.5, 5.0, 7.5, and 10 MUg.kg-1). For endotracheal intubation, we administered a priming dose of vecuronium, and then after 4 min, the remainder was injected for a total dosage of 0.15 mg.kg-1. Onset time was determined by a 95% depression of twitch height as shown by electromyography (EMG) of the hypothenar muscles. This was measured by repeating the train-of-four (TOF) stimulation. An increased priming dose shortened the onset time; however, this shortening rate diminished when the dosage was above 7.5 MUg.kg-1. In the zero priming dose group there was a significant correlation between onset time and age, and between onset time and body mass index (BMI) in women (r=0.62 and -0.45, respectively); however, this correlation was not observed in men. A priming dose of 10 MUg.kg-1 showed a decrease of TOF ratio to 95% or less in 1 out of 25 cases. Although one-third of the patients in the 5 and 7.5 MUg.kg-1 groups complained of clinical symptoms such as ptosis, this was clinically allowable. We conclude that the optimum priming dose of vecuronium is 7.5 MUg.kg-1; however, in obese patients, a smaller dosage would be recommended. PMID- 28921086 TI - Hemodynamic effects of oral clonidine premedication in lumbar epidural anesthesia. AB - Clonidine, an alpha2-adrenergic agonist, has a potent sympatholytic effect and augments the pressor effect of ephedrine during general anesthesia. We evaluated whether oral clonidine premedication would alter the hemodynamic changes and enhance the pressor response to intravenous ephedrine during epidural anesthesia in 35 adult patients. They were randomly administered either premedication with clonidine approximately 5 MUg.kg-1 po (n=17) or no clonidine medication (n=18). After establishment of epidural anesthesia, the hemodynamic response to ephedrine iv was measured in the awake state at 1-min intervals for 10 min. Then, the same hemodynamic measurement was repeated in the asleep state induced with midazolam iv. There were no differences in blood pressure (BP) and heart rate values between groups during the onset of epidural anesthesia, except that BP before epidural anesthesia was lower in the clonidine group than the control group (P<0.05). The magnitude and duration of pressor responses to ephedrine were comparable between groups in awake and asleep states. In conclusion oral clonidine premedication 5 MUg.kg-1 alters neither the hemodynamic changes nor the pressor response to intravenous ephedrine during epidural anesthesia. PMID- 28921087 TI - Protamine relaxes vascular smooth muscle by directly reducing cytosolic free calcium concentrations in small resistance arteries. AB - Protamine has been suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration ([Ca2+]i). However, there has been no direct evidence that protamine reduces the [Ca2+]i of vascular smooth muscle. We therefore studied the effects of protamine on changes in [Ca2+]i and tension induced by norepinephrine (NE) and high K+ in endothelium-denuded strips from rabbit small mesenteric artery, using fura-2-fluorometry and isometric tension recording methods. Both NE (1 MUM) and high K+ (40 mM) produced a transient phasic increase, followed by a tonic increase in [Ca2+]i and tension. Protamine concentration (15-500 MUg.ml-1)-dependently inhibited (P<0.05) the phasic and tonic components of both NE- and high K+-induced contraction with IC50 values of ~50 MUg.ml-1. Protamine (50 MUg.ml-1) inhibited (P<0.05) the phasic and tonic increases in [Ca2+]i caused by both NE and high K+ by ~40%-60%. We conclude that the direct vasodilator action of protamine is due, at least in part, to reduction of [Ca2+]i in vascular smooth muscle; this reduction in [Ca2+]i may be due to inhibition of both Ca2+ influx and Ca2+ release from intracellular Ca2+ stores. PMID- 28921088 TI - Difficult laryngoscopy and cephalometric roentgenograms in obstructive sleep apnea syndrome patients undergoing uvulopalatopharyngoplasty. AB - We retrospectively studied the incidence of difficult laryngoscopy in 53 subjects with obstructive sleep apnea syndrome (OSAS) undergoing uvulopalatopharyngoplasty (UPPP) and 72 subjects with chronic otitis media undergoing tympanoplasty (control group). The incidence of difficult laryngoscopy in the UPPP group was significantly higher than in the control group (18.9%vs 4.2%,P<0.001). To analyze the anatomical findings of difficult laryngoscopy in UPPP patients, cephalometric roentgenograms were compared between patients in whom direct laryngoscopy was difficult (difficult patients,n=10) and patients in whom direct laryngoscopy was not difficult (nondifficult patients,n=43). Cephalometric atlanto-occipital distance (cAOD) was less than 4mm in 80% of the difficult patients, and there were significant differences between the difficult patients and the nondifficult patients (2.8+/-3.3 mmvs 6.7+/-3.0 mm, mean +/-SD,P<0.001). There were significant differences in cephalometric effective mandibular length/cephalometric posterior depth of mandible ratio (cEML/cPDM) between the difficult patients and the nondifficult patients (4.0+/-0.6vs 4.5 +/-0.8,P<0.01); however, the calculation of cEML/cPDM was more difficult than cAOD. We concluded that OSAS patients undergoing UPPP are at high risk for difficult laryngoscopy, and that cAOD calculated from cephalometric roentgenograms is an easy and sensitive predictive indicator for the estimation of difficult laryngoscopy. PMID- 28921089 TI - Transcutaneous CO2 tension measurement as an indicator of severity of hemorrhagic shock. AB - This study was undertaken to evaluate whether transcutaneous CO2 tension (PtcCO2) could be used as an indicator of the global systemic severity of hemorrhagic shock. PtcCO2 levels in ten anesthetized mongrel dogs were measured during hemorrhage and during volume restoration and were correlated with mixed venous CO2 tension ([Formula: see text]). After withdrawal of 30ml.kg-1 blood, both PtcCO2 and[Formula: see text] increased significantly (from 43+/-7 to 70+/-27 torr (P<0.05) and from 48+/-6 to 59+/-12 torr (P<0.05), respectively). Throughout the experiments, PtcCO2 levels changed almost in parallel to[Formula: see text] levels. However, changes in PtcCO2 exceeded those in[Formula: see text] from the end of hemorrhage, at which time cardiac output decreased to 35% of the baseline value, until the end of volume restoration, and the changes in PtcCO2 showed a close logarithmic relationship with[Formula: see text] (r=0.78,n=110). Additionally, arterio-transcutaneous CO2 tension gradients[Formula: see text] showed a close exponential correlation with cardiac output per body weight (CO/BW) during the shedding phase (r=0.85,n=60), although the correlation with CO/BW lessened during the retransfusion phase (r=0.55,n=60). PtcCO2 was roughly correlated with[Formula: see text] during hemorrhagic shock, and levels of PtcCO2 higher than[Formula: see text] reflected critical tissue perfusion. PMID- 28921090 TI - Amrinone improves postischemic myocardial metabolism in the rat heart-lung preparation. AB - Amrinone, a phosphodiesterase inhibitor, is a non-glycosidic noncatecholamine with both vasodilator and positive inotropic effects. We were interested in assessing the effect of amrinone on postischemic cardiac performance in the isolated heart-lung preparation. Twenty-four male Wistar-ST rats were used. They were randomly divided into three groups. Amrinone, 10 MUg.ml-1 or 100 MUg.ml-1 was administered 8 min after the start of perfusion except in the control group. Ten minutes after the start of perfusion, all hearts were made globally ischemic for 8 min. Subsequently, the preparations were reperfused for 10 min. At the end of the experimental period, the hearts were freeze-clamped, and then myocardial high-energy phosphates, lactate, pyruvate, and glycogen were measured. Hemodynamic parameters in all groups decreased significantly during ischemia. However, there were no significant differences among the groups. The myocardial ATP level in the 100 MUg.ml-1 group was significantly higher than that in the control group. Adenosine diphosphate (ADP) and adenosine monophosphate (AMP) levels in the 100 MUg.ml-1 group were significantly lower than those in the control group. Myocardial lactate, pyruvate, and glycogen levels were not significantly different among the groups. This result suggests that amrinone improves postischemic myocardial metabolism. Although we could not measure coronary flow, amrinone might increase coronary flow with direct coronary vasodilation which would have increased the myocardial ATP and energy charge levels. PMID- 28921091 TI - Solubility of volatile anesthetics in plasma substitutes, albumin, intravenous fat emulsions, perfluorochemical emulsion, and aqueous solutions. AB - Using the gas chromatographic headspace sampling technique, we determined the solubility of volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) in plasma substitutes, albumin solution, intravenous fat emulsions, perfluorochemical FC-43 emulsion, and aqueous solutions at 37 degrees C. The order of magnitude of lambda value (liquid/gas partition coefficients) was halothane >enflurane>isoflurane> sevoflurane in all the parenteral infusion fluids except the perfluorochemical emulsion (FC-43). The FC-43/gas partition coefficients of the volatile anesthetics were almost the same at 5.5. The partition coefficients were affected by the osmolarity of solutions, hydrophobicity, and the structure of solutes. Also, the blood/gas partition coefficients in intravenous fat emulsions and FC-43 were calculated. It is suggested that fluid therapy, especially with intravenous fat emulsions or FC-43, may influence the blood/gas partition coefficients of anesthetics, and affect the induction of anesthesia. PMID- 28921092 TI - Changes in respiratory system resistance and reactance following acute respiratory and metabolic alkalosis in dogs. AB - To differentiate between the effects of respiratory and metabolic alkalosis on respiratory mechanics, respiratory system resistance (Rrs) and reactance (Xrs) were examined in anesthetized, paralyzed, and mechanically hyperventilated dogs. Rrs and Xrs were measured by the forced oscillation method with a random noise input of 0-25 Hz. Restoration to normocapnia by CO2 inhalation significantly increased Rrs (+23.4+/-4.0%), particularly at high-frequency ranges without alterations in Xrs or resonant frequencies, whereas an increase in pH without changes in partial pressure of arterial carbon dioxide (PaCO 2) by an administration of bicarbonate-carbonate mixture resulted in no significant alteration in Rrs or Xrs. A significant decrease in Rrs (-16.3+/-2.5%) following vagotomy or atropine administration was no longer affected by CO2 inhalation. These results suggest that (1) the vagus nerve appears to play a role in maintaining the resting tension of airway smooth muscle, (2) systemic hypocapnia decreases Rrs presumably due to the central airway dilation, and (3) this response is associated with a change in systemic partial pressure of carbon dioxide (PCO 2) rather than that in pH. PMID- 28921093 TI - Brain oxygenation monitored by near-infared spectroscopy during recovery from hemorrhagic shock. PMID- 28921094 TI - Persistent radiculopathy diagnosed and treated with epidural endoscopy. PMID- 28921095 TI - Anesthetic management for surgical repair of postinfarction ventricular septal defect. PMID- 28921096 TI - Central venous oxygen saturation accurately reflects mixed venous oxygen saturation during laparotomy. PMID- 28921097 TI - Transient cardiac depression during suprapubic prostatectomy under subarachoid block. PMID- 28921098 TI - Report on the 17th introductory training seminar of the Japan Medical Team for Disaster Relief (JMTDR). PMID- 28921099 TI - Report on the computer software contest at the 43rd Congress of the Japan Society of Anesthesiology. PMID- 28921102 TI - Pancreatic acinar cell carcinoma with extensive tumor embolism at the trunk of portal vein and pancreatic intraductal infiltration. AB - A 59-year-old man was admitted to the hospital with acute pancreatitis. The cause was suggested to be a pancreatic tumor based on computed tomography (CT). The pancreatic tumor was 45 mm with an extensive tumor embolism at the trunk of the portal vein and intraductal infiltration of the main pancreatic duct (MPD). The pancreatic tumor was diagnosed as acinar cell carcinoma (ACC) by endoscopic ultrasound guided fine needle aspiration. Therefore, the cause of acute pancreatitis was diagnosed to be intraductal infiltration of ACC in the MPD. Chemotherapy was initially performed because it was difficult to perform surgery due to extensive tumor embolism at the trunk of the portal vein. Degeneration and reduction of ACC and tumor embolism of the portal vein was noted on CT after chemotherapy, and extended distal pancreatectomy with portal vein reconstruction was performed. There has been no relapse for 5 years postoperative follow-up. This is an interesting and rare case because ACC with intraductal infiltration of MPD is low in frequency; most ACCs are asymptomatic when they are found, and many cases tend to have poor prognosis in spite of surgical cases. PMID- 28921103 TI - Biofeedback-Based, Videogame Balance Training in Autism. AB - The present study examined the effects of a visual-based biofeedback training on improving balance challenges in autism spectrum disorder (ASD). Twenty-nine youth with ASD (7-17 years) completed an intensive 6-week biofeedback-based videogame balance training. Participants exhibited training-related balance improvements that significantly accounted for postural-sway improvements outside of training. Participants perceived the training as beneficial and enjoyable. Significant moderators of training included milder stereotyped and ritualistic behaviors and better starting balance. Neither IQ nor BMI moderated training. These results suggest that biofeedback-based balance training is associated with balance improvements in youth with ASD, most robustly in those with less severe repetitive behaviors and better starting balance. The training was perceived as motivating, further suggesting its efficacy and likelihood of use. PMID- 28921105 TI - Association Between Air Pollution Exposure, Cognitive and Adaptive Function, and ASD Severity Among Children with Autism Spectrum Disorder. AB - Prenatal exposure to air pollution has been associated with autism spectrum disorder (ASD) risk but no study has examined associations with ASD severity or functioning. Cognitive ability, adaptive functioning, and ASD severity were assessed in 327 children with ASD from the Childhood Autism Risks from Genetics and the Environment study using the Mullen Scales of Early Learning (MSEL), the Vineland Adaptive Behavior Scales (VABS), and the Autism Diagnostic Observation Schedule calibrated severity score. Estimates of nitrogen dioxide (NO2), particulate matter (PM2.5 and PM10), ozone, and near-roadway air pollution were assigned to each trimester of pregnancy and first year of life. Increasing prenatal and first year NO2 exposures were associated with decreased MSEL and VABS scores. Increasing PM10 exposure in the third trimester was paradoxically associated with improved performance on the VABS. ASD severity was not associated with air pollution exposure. PMID- 28921104 TI - Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems. AB - pH is a critical parameter for biological and technological systems directly related with electrical charges. It can give rise to peculiar electrostatic phenomena, which also makes them more challenging. Due to the quantum nature of the process, involving the forming and breaking of chemical bonds, quantum methods should ideally by employed. Nevertheless, due to the very large number of ionizable sites, different macromolecular conformations, salt conditions, and all other charged species, the CPU time cost simply becomes prohibitive for computer simulations, making this a quite complex problem. Simplified methods based on Monte Carlo sampling have been devised and will be reviewed here, highlighting the updated state-of-the-art of this field, advantages, and limitations of different theoretical protocols for biomolecular systems (proteins and nucleic acids). Following a historical perspective, the discussion will be associated with the applications to protein interactions with other proteins, polyelectrolytes, and nanoparticles. PMID- 28921107 TI - Airway troubles related to the double-lumen endobronchial tube in thoracic surgery. AB - PURPOSE: Several case reports indicate critical respiratory complications in relation to the double-lumen endobronchial tube (DLT). A prospective survey for the airway problems in using the DLT is presented. METHODS: One hundred adult patients undergoing thoracotomy for lung cancer were investigated. Tube malposition and airway obstruction were searched using a fiber-optic scope. The endobronchial cuff was positioned just below the trachcal carina while the trachea was intubated with a DLT (Rusch). The distances of displacement, from the tracheal carina to the bronchial cuff, were measured during anesthesia using an epidural catheter, which had marks every 5 mm. The distances for correcting the tube position were measured at both the bronchial cuff and the level of the teethPaO2,PaCO2 andSPO2 were also measured. RESULTS: Malposition (displacement over 5 mm from the correct position) was found in 42 patients, and 40 of them were in a withdrawal direction, occurring at the postural change and during one lung ventilation, especially during manipulation of the lung hilum. Correcting distances at the level of the teeth were 15.3-3-times longer than those at the bronchial cuff. Airway deformities and gradual withdrawal of the bronchial cuff were found in association with surgical manipulation. Obstruction occurred at the tips of the tracheal tube in four patients and the bronchial tube in six patients, and at the tip of both in two patients. Hypoxemia (PaO2<60 mmHg) occurred in four patients and hypercapnea (PaCO2>60 mm Hg) in two patients. CONCLUSION: Most of the DLT obstructions were associated with withdrawal malposition. Great attention to DLT displacement and airway deformity is advised. PMID- 28921106 TI - Kinetic stability of membrane proteins. AB - Although membrane proteins constitute an important class of biomolecules involved in key cellular processes, study of the thermodynamic and kinetic stability of their structures is far behind that of soluble proteins. It is known that many membrane proteins become unstable when removed by detergent extraction from the lipid environment. In addition, most of them undergo irreversible denaturation, even under mild experimental conditions. This process was found to be associated with partial unfolding of the polypeptide chain exposing hydrophobic regions to water, and it was proposed that the formation of kinetically trapped conformations could be involved. In this review, we will describe some of the efforts toward understanding the irreversible inactivation of membrane proteins. Furthermore, its modulation by phospholipids, ligands, and temperature will be herein discussed. PMID- 28921108 TI - Ventilatory effects of laparoscopic cholecystectomy under general anesthesia. AB - PURPOSE: To investigate the ventilatory effect of laparoscopic cholecystectomy in patients under general anesthesia with epidural block. METHODS: We measured arterial blood gas, pulmonary carbon dioxide elimination (0000126;ECO2), the dead space/tidal volume ratio (VD/VT), and the alveolar-arterial PO2 difference [(A a)DO2] just before and 5, 10, 20, 40, and 80 min after peritoneal insufflation in eight patients who underwent laparoscopic cholecystectomy under general anesthesia with epidural block. The effect of laparoscopic cholecystectomy on these values was evaluated. The patients were ventilated on the controlled mode by Servo 900C with a constant tidal volume (VT 10ml.kg-1) and frequency (respiratory rate 12 breaths.min-1) throughout the study. RESULTS: After starting peritoneal insufflation the PaCO2 showed a sudden increase during the initial 10 min of about 4 mmHg followed by a gradual increase thereafter. The increase in000123;ECO2 was about 30ml.min-1 (20%) on average during the initial 20 min, and a plateau was reached within 20-40 min after peritoneal insufflation. Neither VD/VT nor (A-a)DO2 showed significant changes during the study. CONCLUSION: These results suggest that (1) transperitoneal absorption of CO2 may be the main cause of hypercarbia, and the hypercarbia is not attributed to the increase in VD/VT; and (2) oxygenation is not impaired during pneumoperitoneum. PMID- 28921109 TI - Differential effects of ketamine and MK-801 on A-fiber and C-fiber responses of spinal wide dynamic range neurons in the cat. AB - PURPOSE: To clarify whether ketamine suppresses both A-fiber-and C-fiber-mediated pain and to compare the effects of ketamine with those of MK-801. METHODS: Experiments were performed on urethane/chloralose-anesthetized cats. Glass capillary microelectrodes were used to record extracellular single unit activities from wide dynamic range (WDR) neurons in the spinal dorsal horn. Responses evoked by electrical stimulation of the superficial peroneal (SP), posterior tibial (PT), or both nerves were analyzed. The responses to successive electrical stimuli were displayed on a personal computer using a raster-dot processing program. RESULTS: A subanesthetic dose of intravenous ketamine suppressed both A- and C-fiber responses of WDR neurons in a dose-dependent manner without affecting A-fiber response of low-threshold mechanoreceptive (LTM) neurons. The C-fiber response was more markedly suppressed than the A-fiber response. Intravenous administration of MK-801, a specificN-methyl-D-aspartate (NMDA) antagonist, selectively suppressed the C-fiber response of WDR neurons. CONCLUSION: Intravenous ketamine may suppress both A-and C-fiber-mediated pain at a subanesthetic dose. This finding could be a scientific basis for the usefulness of ketamine during clinical procedures such as dressing changes or debridement of the burned patient. PMID- 28921111 TI - Yohimbine and flumazenil: effect on nitrous oxide-induced suppression of dorsal horn neurons in cats. AB - PURPOSE: The purpose of this study was to determine the mechanisms of nitrous oxide (N2O) antinociception at the spinal level with yohimbine (an alpha2 adrenergic antagonist) and flumazenil (a specific benzodiazepine antagonist) using chemonociceptive stimuli in spinal dorsal horn neurons in the cat. METHODS: A lumbar laminectomy extending from L4 to L6 was performed to allow insertion of a extracellular recording device via a microelectrode. Additional laminectomy was performed at the T12 level to transect the spinal cord. As a noxious stimulus, bradykinin (BK) was injected via the cannula inserted into the femoral artery. Animals were divided into four treatment groups for subsequent experiments: N2O+flumazenil, N2O+yohimbine, flumazenil (alone), and yohimbine (alone). RESULTS: N2O suppressed BK-induced nociceptive responses in transected feline spinal cords. The BK-induced neuronal firing rates were significantly suppressed: to 69.2%, 61.8%, and 52.2% of the baseline firing rate at 10, 20, and 30 min, respectively, after N2O administration. The 47.8% suppression on BK-induced neuronal responses at 30 min after N2O administration was reversed 5 min after administration of yohimbine (25.2% suppression). Similarly, N2O suppression (42.5%) on chemically induced neuronal responses was reversed by flumazenil (24.9% suppression) at identical postadministration intervals. CONCLUSION: These data imply that N2O suppresses the nociceptive responses in part probably through its agonistic binding activity to the alpha2-adrenergic, gamma-aminobutyric acid (GABA)-benzodiazepine, or both receptor systems in dorsal born neurons of the feline spinal cord. PMID- 28921110 TI - Detection of acetazolamide-induced increase in organ blood flow in rabbits by laser flowmetry. AB - PURPOSE: We investigated the mechanism by which inhibition of carbonic anhydrase (CA) increases organ blood flow. METHODS: Regional blood flow (rBF) in white rabbits anesthetized with ketamine/urethane was measured in the kidney, liver, stomach wall, and abdominal muscle by means of laser blood flow probes. Data obtained from rabbits receiving acetazolamide (AZ) to inhibit CA were compared with those obtained from rabbits ventilated with air containing increased concentrations of CO2. RESULTS: Systolic blood pressure, body temperature, hemoglobin, and base excess were unaffected by either treatment. Inhalation of CO2 increased blood flow in all organs tested as well as the cardiac output and PCO2 but decreased pH. Inhibition of CA by AZ administration increased the rBF only in the liver and kidney and did not increase cardiac output or decrease pH. CONCLUSION: Administration of AZ increased rBF in the tissues and organs that contained large amounts of CA without increasing the cardiac output or decreasing the pH, which suggests a direct local effect. A differential sensitivity to the retention of CO2 is suggested as a possible mechanism of the selectivity of the increase in rBF. PMID- 28921112 TI - The effect of CGRP-induced hypotension on organ blood flow during halothane anesthesia in dogs: a comparison with trimetaphan. AB - PURPOSE: Calcitonin gene-related peptide (CGRP) is an endogenous 37-amino-acid peptide which is a powerful vasodilator of the splanchnic circulation. To elucidate the effects of CGRP-induced hypotension on the organ blood flow, we compared the renal, hepatic, and pancreatic organ flows of CGRP-induced hypotension with those of trimetaphan (TMP) in halothane-anesthetized dogs. METHODS: Systemic hemodynamics and organ blood flow were determined in 18 mongrel dogs allocated to one of two groups: CGRP group (n=10) and TMP group (n=8). CGRP of TMP was infused at a rate sufficient to decrease the mean arterial pressure (MAP) to near 60 mmHg from the baseline values for a 60 min-hypotensive period. Organ blood flow was measured using the hydrogen clearance technique. RESULTS: The decrease in MAP was approximately 50% of baseline values (P<0.01). The hypotension induced by either CGRP or TMP was associated with a reduction (P<0.01) in systemic vascular resistance in both groups. Cardiac index (CI) in the CGRP group did not change significantly throughout the experiment. On the other hand, CI decreased at 30 min (P<0.01) and 60 min (P<0.01) during the hypotensive period in the TMP group. No changes were observed in renal, hepatic, and pancreatic blood flows in the CGRP group. Renal blood flow in the TMP group did not change significantly throughout the experiment. In contrast, hepatic blood flow resulted in a significant decrease (P<0.01) during TMP-induced hypotension. Pancreatic blood flow decreased during the hypotensive period (P<0.01) and at 30 min (P<0.05) after termination of TMP. CONCLUSION: These findings show that CGRP does not adversely affect renal, hepatic, and pancreatic organ blood flows even in the presence of profound hypotension in halothane anesthetized dogs. The results of this study suggest that CGRP may preserve organ blood flow during induced hypotension. PMID- 28921113 TI - Effects of vagal nerves or vagosympathetic trunks stimulation on the hemodynamics during spinal anesthesia in cats. AB - PURPOSE: To clarify the sudden onset of profound bradycardia or hypotension during spinal anesthesia, we stimulated vagal nerves (VN) or vagosympathetic trunks (VST) to examine the effects on the autonomic nervous system during spinal anesthesia with different degrees of cardiac sympathetic nerve block. METHODS: Cats were anesthetized and mechanically ventilated. The left stellate ganglion was exposed to record cardiac sympathetic nerve activity (CSNA). Systolic and diastolic blood pressures (BP), heart rate (HR), and CSNA were measured before and after intrathecal injections of 0.2, 0.5 and 1.0 ml of 1% lidocaine. After each intrathecal injection of lidocaine, bilateral VST (n=5, group A) or VN (n=5, group B) were stimulated and measurements were repeated. ]RESULTS: After 1.0 ml intrathecal injection of 1% lidocaine, CSNA was blocked completely, and BP and HR were decreased. In group A, BP were unchanged following VST stimulation while in group B, BP decreased approximately 30% by VN stimulation from the pre stimulation levels after 0.2, 0.5, and 1.0 ml injection of 1% lidocaine, respectively. HR decreased further, approximately 35% in group A and 50% in group B, by each stimulation from the prestimulation levels after 0.2, 0.5, and 1.0 ml injection of 1% lidocaine. CONCLUSION: These results suggest that hypotension and bradycardia during a high level of spinal anesthesia are due to the block of CSNA, and vagal reflex may produce profound hypotension and bradycardia especially in high spinal anesthesia. PMID- 28921114 TI - Effects of sevoflurane and halothane anesthesia on liver circulation and oxygen metabolism in the dog during hepatolobectomy. AB - PURPOSE: Effects of sevoflurane and halothane anesthesia on liver circulation and oxygen metabolism during hepatolobectomy were investigated in the dog, with the aim of choosing a better anesthetic for hepatic resection. METHODS: Sixteen mongrel dogs were randomly divided into two groups with eight in each. Electromagnetic flowmeters were used to measure hepatic arterial and portal venous blood flows (1) before the inhalation of each anesthetic (base line); (2) 1 h after the start of inhalation of 1.5 minimum alveolar concentration (MAC) anesthetic; (3) 1 h after hepatolobectomy with the same MAC of anesthesia; and (4) 2 h after the discontinuation of anesthesia. Measurements of systemic hemodynamics, blood gas tensions, plasma enzyme leaks and arterial ketone body ratio were made at the same time. RESULTS: Sevoflurane maintained hepatic arterial blood flow better than halothane anesthesia, both before and after hepatolobectomy. Hepatic arterial vascular resistance increased in the halothane group but did not change in the sevoflurane group after hepatolobectomy. No significant difference was found in oxygen metabolism and arterial ketone body ratio between two groups. Serum enzyme leakage was less in the sevoflurane group. CONCLUSION: Sevoflurane has less adverse effects on liver circulation, especially hepatic arterial blood flow, and hepatic function than halothane in the case of hepatolobectomy. PMID- 28921115 TI - Atelectasis during anesthesia: Can it be prevented? PMID- 28921116 TI - Stellate ganglion block therapy for a patient with Tietze's syndrome. PMID- 28921117 TI - Cardiac arrest following induction of anesthesia in a patient with acute massive pulmonary thromboembolism. PMID- 28921118 TI - Repeated total intravenous anesthesia for a patient with a history of enflurane induced rhabdomyolysis. PMID- 28921119 TI - Airway crisis during anesthesia in a patient with Wegener's granulomatosis. PMID- 28921120 TI - Spinal epidural pressure as a less-invasive monitoring of intracranial pressure: report of two cases of encephalitis. PMID- 28921121 TI - Protein C activation during cardiopulmonary resuscitation following out-of hospital cardiac arrest. PMID- 28921122 TI - Intravenous midazolam passage into breast milk. PMID- 28921123 TI - The use of obtuse needles in aspirating drugs from ampules in the practice of anesthesia. PMID- 28921125 TI - Exogenous Cannabinoid Efficacy: Merely a Pharmacokinetic Interaction? AB - Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies. PMID- 28921124 TI - Droplet volume variability as a critical factor for accuracy of absolute quantification using droplet digital PCR. AB - Accurate and precise nucleic-acid quantification is crucial for clinical and diagnostic decisions, as overestimation or underestimation can lead to misguided treatment of a disease or incorrect labelling of the products. Digital PCR is one of the best tools for absolute nucleic-acid copy-number determination. However, digital PCR needs to be well characterised in terms of accuracy and sources of uncertainty. With droplet digital PCR, discrepancies between the droplet volume assigned by the manufacturer and measured by independent laboratories have already been shown in previous studies. In the present study, we report on the results of an inter-laboratory comparison of different methods for droplet volume determination that is based on optical microscopy imaging and is traceable to the International System of Units. This comparison was conducted on the same DNA material, with the examination of the influence of parameters such as droplet generators, supermixes, operators, inter-cartridge and intra-cartridge variability, and droplet measuring protocol. The mean droplet volume was measured using a QX200TM AutoDGTM Droplet DigitalTM PCR system and two QX100TM Droplet DigitalTM PCR systems. The data show significant volume differences between these two systems, as well as significant differences in volume when different supermixes are used. We also show that both of these droplet generator systems produce droplets with significantly lower droplet volumes (13.1%, 15.9%, respectively) than stated by the manufacturer and previously measured by other laboratories. This indicates that to ensure precise quantification, the droplet volumes should be assessed for each system. PMID- 28921126 TI - Intravenous iloprost to recruit the microcirculation in septic shock patients? PMID- 28921127 TI - Synergistic effect of baicalein, wogonin and oroxylin A mixture: multistep inhibition of the NF-kappaB signalling pathway contributes to an anti inflammatory effect of Scutellaria root flavonoids. AB - Scutellaria root, the root of Scutellaria baicalensis Georgi, is a crude drug used for inflammatory diseases. In our previous report, the combination of flavonoids contained in Scutellaria root have been found to inhibit PGE2 production more strongly than individual flavonoids. Here, to investigate the mechanism of the synergistic effect, we examined the effects of an equimolar mixture (F-mix) of baicalein (1), wogonin (2) and oroxylin A (3) on the production of PGE2 in LPS-treated J774.1 cells. Although 1 and 3 inhibited COX-2 activity, the F-mix showed no synergistic effect on COX-2 inhibition. Therefore, we investigated the steps leading to the activation of COX-2 protein. Compounds 1 3 and F-mix inhibited the expression of COX-2 protein. However, only 2 inhibited the expression of COX-2 mRNA among the flavonoids, and the F-mix showed no synergistic effect. Only 1 inhibited NF-kappaB translocation into the nucleus, and the F-mix showed no synergistic effect. Although 2 did not affect NF-kappaB translocation, it strongly inhibited NF-kappaB-dependent transcriptional activity, and the F-mix inhibited the activity slightly more than 2. Compounds 1 3 also inhibited NO production, and the F-mix showed a synergistic effect. However, the effects of each flavonoid on the expression of iNOS mRNA were not consistent with those on COX-2 mRNA. Because the flavonoids inhibit different steps in the production of PGE2 and NO, and their mixture did not show apparent synergistic effects in each step, we conclude that the synergistic effect of the flavonoid mixture reflects the total effect of the flavonoids inhibiting different steps in the NF-kappaB signalling pathway. PMID- 28921128 TI - Precision of bone density and micro-architectural properties at the distal radius and tibia in children: an HR-pQCT study. AB - : Precision errors need to be known when monitoring bone micro-architecture in children with HR-pQCT. Precision errors for trabecular bone micro-architecture ranged from 1 to 8% when using the standard evaluation at the radius and tibia. Precision errors for cortical bone micro-architecture ranged from 1 to 11% when using the advanced cortical evaluation. INTRODUCTION: Our objective was to define HR-pQCT precision errors (CV%RMS) and least significant changes (LSCs) at the distal radius and tibia in children using the standard evaluation and the advanced cortical evaluation. METHODS: We scanned the distal radius (7% of ulnar length) and tibia (8% of tibia length) of 32 children (age range 8-13; mean age 11.3; SD 1.6 years) twice (1 week apart) using HR-pQCT (XtremeCT1). We calculated root-mean-squared coefficients of variation (CV%RMS) to define precision errors and LSC to identify differences required to detect change. RESULTS: Precision errors ranged between 1-8 and 1-5% for trabecular bone outcomes (obtained with standard evaluation) and between 1.5-11 and 0.5-6% for cortical bone outcomes (obtained with advanced cortical evaluation) at the distal radius and tibia, respectively. Related LSCs ranged between 3-21 and 3-14% for trabecular bone outcomes and between 4-30 and 2-16% for cortical bone outcomes at the distal radius and tibia, respectively. CONCLUSIONS: HR-pQCT precision errors were between 1 and 8% (LSC 3-21%) for trabecular bone outcomes and 1 and 11% (LSC 2 30%) for cortical bone outcomes at the radius and tibia in children. Cortical bone outcomes obtained using the advanced cortical evaluation appeared to have lower precision errors than cortical outcomes derived using the standard evaluation. These findings, combined with better-defined cortical bone contours with advanced cortical evaluation, indicate that metrics from advanced cortical evaluation should be utilized when monitoring cortical bone properties in children. PMID- 28921129 TI - Effects of phenylephrine and ephedrine on pulmonary arterial pressure in patients with cervical or lumbar epidural anesthesia, or enflurane anesthesia. AB - The authors studied systemic and pulmonary hemodynamic changes with ephedrine (EP) or phenylephrine (PH) when used to normalize arterial hypotension resulting from acute sympathectomy due to cervical or lumbar epidural anesthesia, or enflurane anesthesia in 52 patients. Both EP (0.2+/-0.05 mg.kg-1) and PH (0.025+/ 0.008 mg.kg-1) produced a significant increase in pulmonary arterial pressure (PAP) with a concomitant increase in arterial pressure (AP). In the patients anesthetized with cervical epidural block and NO2-O2, systolic PAP increased from 22+/-5 to 28+/-8 mmHg with EP and from 23+/-6 to 32+/-10 mmHg with PH in response to approximately 30 mmHg increase of AP, and the ratio of the increment of systolic PAP to systolic AP (DeltaPAP/DeltaAP) was 0.15+/-0.08 with EP and 0.20+/ 0.13 with PH (P<0.05); these changes did not differ significantly from those observed in the patients having lumbar epidural or enflurane-N2O-O2 anesthesia. The influence on cardiac output (CO) differed significantly between EP and PH; EP increased CO in all three groups (P<0.05), while PH did not elicit any significant changes in CO. A significant relationship between PAP and AP was found in patients given EP; the regression equation was DeltaPAP=0.22*DeltaAP-2.9 (r=0.77). The relationship in patients given PH was less significant (r=0.38). The results indicated that EP and PH elicit pulmonary hypertensive effect similarly in the patients with a high level of epidural anesthesia and that although both drugs act differently (EP mainly due to increases in the blood flow and PH solely due to its pulmonary vasconstrictive action), the increases in PAP were predictable, to some extent, from the increase of AP in anesthetized humans without predominant cardiopulmonary disorders. PMID- 28921130 TI - Electroencephalograms in children during isoflurane anesthesia. AB - The electroencephalograms (EEG) of 55 children under isoflurane anesthesia were studied to elucidate any change in pattern with age. The children ranged from 1 month to 14 years of age were divided into six age groups. The standard minimum alveolar concentration (MAC) was determined in each group. Anesthesia was induced using the slow induction method, and EEG was recorded at isoflurane concentrations of 1.5 MAC in 100% oxygen, 1.0 MAC in 100% oxygen, and 1.0 MAC under administration of 66% nitrous oxide in oxygen. Ventilation was controlled mechanically (end-tidal CO2 35-40 mmHg).At 1.5 MAC, the incidences of burst suppression in the groups of 6 months to 6 years of age were significantly less than in groups older or younger than that age (P<0.05). Except for infants less than 6 months of age, the mean values of maximum amplitude at 1.0 MAC were two to three times of those in adults. Children 3-6 years of age showed the highest value of 427.0+/-83.5 MUV. PMID- 28921131 TI - Left ventricular diastolic filling during coronary artery bypass surgery in patients with diabetes mellitus and/or hypertension. AB - To evaluate left ventricular diastolic filling (DF) using transesophageal Doppler echocardiography in 40 patients with or without diabetes mellitus and/or hypertension, we measured DF after induction of anesthesia, before and after cardiopulmonary bypass (CPB), and at the end of coronary artery bypass surgery (CABS). In 13 patients with complete measurements, there was no significant change in DF but diastolic filling time became shorter and peak velocity during atrial contraction increased significantly following CPB. In the other patients, the assessment of DF could be performed accurately in CABS patients without diabetes and/or hypertension, but not in CABS patients with these disorders because of a high incidence of fusion of the E-A waves, which is an indicator of impaired DF. When heart rate (HR) was more than 75 beats.min-1 (RR interval of less than 800 ms), the incidence of fusion points was significantly higher in patients with diabetes and/or hypertension than without (13 of 29s 1 of 9,P<0.05). It is suggested that a slower HR (less than 75 beat.min-1) is desirable in CABS patients with these disorders to avoid impairment of DF due to either prolonged systolic time or isovolumic relaxation time. PMID- 28921132 TI - Differential effects of vecuronium on the thumb and the big toe muscles evaluated by acceleration measurement. AB - To clarify the differential effects of vecuronium on the thumb and on the big toe, train-of-four (TOF) stimuli were applied to the ulnar nerve at the wrist and the tibial nerve at the ankle in anesthetized patients using two acceleration transducers. Ten adult patients, aged 21-55 years, were studied. Anesthesia was induced by an intravenous injection of thiopental, and vecuronium 0.1 mg.kg-1 was used for paralysis. Anesthesia was maintained with nitrous oxide (66%)-oxygen sevoflurane (1 MAC). The duration of time to the maximal twitch depression on the thumb and the big toe was 136.5+/-32.5 s and 183.0+/-40.1 s (P<0.05), respectively. The time to 25% recovery of the twitch height on the thumb and the big toe was 48.1+/-17.3 min and 39.1+/-11.6 min, respectively; the time to 50% recovery of twitch height on the thumb and the big toe was 54.1+/-16.1 min and 40.0+/-9.2 min (P<0.05), respectively. When paralysis was reversed at 25% of TOF ratio on the thumb, the value of the TOF ratio on the big toe was 58.5+/-18.2% (P<0.01). PMID- 28921133 TI - Effects of double administration of nicardipine of the cardiovascular response to tracheal intubation in hypertensive patients. AB - The efficacy of intravenous nicardipine in attenuating the cardiovascular responses to laryngoscopy and tracheal intubation was studied in 20 hypertensive patients. Ten patients received intravenous 1 mg of nicardipine 1 min before induction (N1 group). The other ten received 1 mg of nicardipine 1 min before induction and an additional 1 mg just before laryngoscopy (N2 group). In the N1 group, arterial pressure and heart rate increased significantly after tracheal intubation. In the N2 group, arterial pressure did not increase but heart rate increased more than that in N1 group. There was no significant difference in rate pressure product between the two groups. PMID- 28921134 TI - Comparison of bupivacaine and fentanyl as an adjuvant of epidural morphine for postoperative analgesia. AB - We conducted a retrospective study to determine whether bupivacaine or fentanyl is a better adjuvant to epidural morphine for postoperative analgesia using 108 patients. Following epidural lidocaine anesthesia with or without light general anesthesia for major gynecological surgeries, 59 patients received epidural morphine (EPM) 2 mg (group M), 21 patients received morphine 2 mg plus 0.25% plain bupivacaine 6-10 ml epidurally (group B), and 28 patients received morphine 2 mg plus fentanyl 100 MUg epidurally (group F). The analgesic interval, defined as the duration from EPM injection to the first request of analgesics for incisional pain, was significantly longer in group F than in group M (29+/-11vs 19+/-17 h,P<0.05), but similar to group B (22+/-14 h). Group F patients required the least amount of analgesics for incisional pain of the three groups during the first 24 h postoperatively (P<0.01). The incidence of adverse effects was similar among all three groups. In conclusion, fentanyl appears to be a better adjuvant to epidural morphine than bupivacaine. PMID- 28921135 TI - Effects of prostaglandin E1 on renal hemodynamics. AB - The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and the ratio of mean arterial pressure (MAP) to RBF (MAP/RBF), reflecting renal vascular resistance (RVR) were determined to investigate the effects of intravenously administered prostaglandin E1 (PGE1) on renal hemodynamics in humans. PGE1 produced no significant changes in GFR, but did cause significant increases in RPF and RBF and significant decreases in FF and MAP/RBF. The relationships between MAP and GFR, MAP and RBF, and MAP and MAP/RBF were investigated. PGE1 suppressed the increase of MAP/RBF along with the increase of MAP, increased the RBF along with the increase of MAP, and kept the GFR constant, regardless of MAP. Also, the effects of PGE1 on renal pericapillary vessels were simulated. According to this simulation, PGE1 had a vasodilator action on both preglomerular and postglomerular capillaries. PMID- 28921136 TI - Epidural anesthesia affects pulse oximeter readings and response time. AB - We investigated the effects of epidural anesthesia on pulse oximeter readings (Spo2) and response time because this type of anesthesia causes significant changes in microcirculation at measurement sites. Twenty patients were divided into lumbar epidural (L-EPI;n=10) and the cervical epidural (C-EPI;n=10) groups. Spo2 and skin blood flow (SBF) were measured at the finger and toe simultaneously by pulse oximeter and laser Doppler flowmeter, respectively. Data were collected before and after epidural anesthesia for 1 min and the response time was calculated by the difference between the finger and toe using the breath-holding method. Epidural anesthesia increased SBF in the blocked area and decreased it in the nonblocked area in both groups (P<0.01, respectively). In the L-EPI group, Spo2 was increased at the finger (P<0.05) and decreased at the toe (P<0.05). In the C-EPI group, Spo2 at both the finger and toe was decreased by the anesthesia. DeltaSpo2 (Spo2 at the finger minus Spo2 at the toe) was increased in the L-EPI group (P<0.05) and decreased in the C-EPI group (P<0.01). The difference in the response time became larger in the C-EPI group and smaller or opposite in the L EPI group after anesthesia. The difference in response time and SBF were significantly correlated (r=0.71;P<0.05). These results indicated that epidural anesthesia lowerd Spo2 and shortened the response time through vasodilation in the blocked area and caused the opposite reactions in the nonblocked area through compensatory vasoconstriction. PMID- 28921137 TI - Effects of combined intravenous nicardipine and diltiazem administration on the circulatory response to laryngoscopy and tracheal intubation. AB - To evaluate the effect of combined intravenous administration of the calcium antagonists, nicardipine and diltiazem, on the circulatory responses to tracheal intubation, the mean arterial pressure (MAP) and rate pressure product (RPP) in response to laryngoscopy following tracheal intubation were compared in patients receiving saline placebo or nicardipine 10 MUg.kg-1 and diltiazem 0.1 mg.kg-1 60 s before the initiation of laryngoscopy. Each group was comprised of ten patients undergoing elective surgery. The patients receiving saline showed a significant increase in MAP and RPP associated with tracheal intubation. However, these increases were significantly attenuated (P<0.05) in the patients to whom nicardipine and diltiazem were administered concurrently. PMID- 28921138 TI - Effect of prostaglandin E1 on arterial ketone body ratio in hepatectomy. AB - We evaluated the effect of prostaglandin E1 (PGE1) administration during hepatectomy on arterial ketone body ratio (AKBR), which is an indicator of liver function, and on other liver functions in the postoperative period. Eighteen patients were divided into two groups: Continuous intravenous administration of PGE1 (0.02 MUg.kg-1.h-1) was started immediately before hepatic resection and ceased at the end of operation in nine patients (PGE1 group); the other nine did not receive PGE1 (control group). After hepatic resection, a significant increase in AKBR was observed in the PGE1 group. However, no change was observed in the control group. In the PGE1 group, total bilirubin and SGOT recovered more rapidly to the preoperative level than in the control group. These findings suggested that PGE1 might have a protective effect on the liver. PMID- 28921139 TI - An analysis of CO2 elimination curves during artificial ventilation. AB - We have developed some indices to evaluate the phase III slope in CO2 elimination curves. The indices were applied to 12 mechanically ventilated patients in ICU to determine their stability under various ventilator settings. Fco2-sl[30-90] and[Formula: see text] expressed the mean incline of phase III slope in Fco2 volume curves and[Formula: see text]-volume curves, respectively. Fco2-SR and[Formula: see text]-SR expressed the ratio of the slopes in the first and second halves of the phase III portion in both curves. The indices were also applied to 108 elective surgery patients to determine their usefulness in predicting ventilatory efficiency during general anesthesia. In the first study, Fco2-sl[30-90] and[Formula: see text][30-90] correlated with ETco2, Vd/Vt and the volume of CO2 expired, but Fco2-SR and[Formula: see text]-SR were independent of these parameters.[Formula: see text]-SR did not show any significant changes under various ventilator settings except for application of PEEP. In the second study, those with impaired preoperative respiratory function had significantly larger values for[Formula: see text].[Formula: see text] was as sensitive as parameters such as VD/VT, arterial to end-tidal CO2 tension difference (a ET.Dco2), and volume pressure index (VPI) in prediting poor respiratory functions. We concluded that[Formula: see text] is a useful index for evaluating the phase III slope in CO2 elimination curves. PMID- 28921140 TI - Single-breath induction of anesthesia: comparison of enflurane and sevoflurane. AB - In this study induction of anesthesia using the single-breath technique with either enflurane or sevoflurane in oxygen was compared. Each group consisted of 16 unpremedicated volunteers who breathed approximately 1.7 minimum alveolar concentration (MAC) equivalents of either vapor. There were no significant differences in the cardiovascular and respiratory variables monitored. The induction of anesthesia with enflurane (141+/-41 s) required significantly more time than with sevoflurane (118+/-25 s). The enflurane group was associated with significantly more problems during induction, and showed moderate or sometimes severe excitatory movements of the extremities and/or coughing. Subjects in the enflurane group described the induction of anesthesia as less pleasant than in the sevoflurane group. We concluded that enflurane was less suitable for single breath induction of anesthesia compared with sevoflurane. PMID- 28921141 TI - Estimation of cerebrospinal fluid pressure via lumbar epidural space by equilibration method. AB - By introducing water into the lumbar epidural space from a vertically held tube under gravity, we measured lumbar epidural pressure (EDP) when the water meniscus no longer declined. In principle, the pressure of either side of dura mater had become equal at this time which is referred to as the equilibrium point. EDP measured in this way was consistently 1-3 mmHg lower than lumbar cerebrospinal fluid pressure (CSFP) not only immediately after the equilibrium point, but also for 5 min after the equilibrium point had been reached. Both EDP and CSFP responded sensitively to the manipulations of CSFP during this period. We suggest that this method may provide a means to continuously monitor CSFP by EDP. PMID- 28921142 TI - Differential effects of isoflurane, halothane, and ketamine on the regional methionine-enkephalinlike immunoreactivity in the mouse brain. AB - The widely used measurement index for anesthetic potency, minimum alveolar concentration (MAC), is hypothesized to be the sum of the effects on multiple neural systems whose contribution to anesthesia differs depending on the agents used. The present study, which compared the effects of halothane, isoflurane, and ketamine, at equipotent level of anesthesia, on the methionine-enkephalinergic neurons in 9 brain regions, showed a significant difference in the methionine enkephalin-like immunoreactivity (Met-ENK-like IR) among the anesthetics in each region. The order of the Met-ENK-like IR was: halothane > ketamine > isoflurane in the caudatus putamen; halothane > isoflurane ?ketamine in the nucleus accumbens and the ventral pallidum; halothane ?isoflurane > ketamine in the globus pallidus, the nucleus dorsomedialis hypothalami, and the nucleus ventromedialis hypothalami; and halothane > isoflurane > ketamine in the arcuate nucleus, the periaqueductal gray, and the nucleus reticularis parvocellularis. These findings indicate that these three anesthetics affect the methionine enkephalinergic neurons in the motor and pain controlling pathways in different fashions. PMID- 28921143 TI - Administration of MgSO4 failed to improve the neurological recovery after complete global brain ischemia in dogs. AB - The cerebral protective effects of MgSO4 after complete global brain ischemia were evaluated with EEG, evoked potentials (EP) and the neurological recovery score (NRS) in the dog. Complete global brain ischemia for 15 min was achieved by occluding the ascending aorta and the caval veins. The MgSO4 group (N=7) were injected with a 10% MgSO4 solution and the control group (N=7) were administered a normal saline intravenously from the beginning of the resuscitation to 48 h after ischemia. The EEG grades (1=normal, 5=flat) in the control group and the MgSO4 group were 3.9+/-0.1 (mean +/-SEM) and 3.7+/-0.3, and the EEG-EP scores (6=normal, 0=serious deterioration) were 2.6+/-0.4 and 2.7+/-0.4 4h after ischemia, respectively. The 7-day survival rates for ischemia were equal in both groups (5/7:71%). The NRSs (0=death, 100=normal) in the control group and the MgSO4 group were 50+/-3 (n=7) and 43+/-9 (n=7) on the 3rd day after ischemia, and were 56+/-5 (n=5) and 42+/-12 (n=5) on the 7th day. The differences between the two groups were not significant. We conclude that MgSO4 administered after ischemia has no beneficial effects on the recovery of EEG, EP and the NRS after 15 min of complete global brain ischemia in the dog. PMID- 28921144 TI - Intrathecal phentolamine increases blood flow and skin temperature in the hind limbs of dogs. AB - Spinal anesthesia with local anesthetics increases blood flow and skin temperature in the lower extremities. Although the effect of alpha2 adrenoceptor agonists on the spinal cord has been confirmed, there has been no such report of the effects of alpha-adrenoceptor antagonists. We studied the effects of intrathecal administration of phentolamine on the blood flow in the femoral artery and skin temperature in the hind limbs of seven dogs. One ml of 3% lidocaine (L group) or 1 ml of 0.1% phentolamine (P group) was injected into the intrathecal space. Blood flow significantly increased at 3 min in both groups, and no significant difference was observed between the groups at any phase. Pad skin temperature in the hind limbs increased significantly at 5 min in the L group and at 3 min in the P group (P<0.05). The only significant difference was observed at 30 min. High pad skin temperature continued for 60 min in the L group and for 90 min in the P group. With phentolamine i.v. (1 mg), there were no changes in blood flow in the femoral artery or pad skin temperature; there was only a decrease in blood pressure. In conclusion, the intrathecal alpha adrenoceptor antagonist, phentolamine, increases blood flow in the femoral artery and pad skin temperature in hind limbs in dogs similar to lidocaine. PMID- 28921145 TI - Relationship between cardiac output and mixed venous-arterialPCO 2 gradient in sodium bicarbonate-treated dogs. AB - We examined the relationship between cardiac output (CO) and mixed venous arterialPCO 2 gradient ([Formula: see text]) along with the other variables derived from arterial and/or mixed venous blood gases in sodium bicarbonate treated dogs. Six dogs with low cardiac output following cardiopulmonary resuscitation were used. CO, blood gases, and hemoglobin measurements were repeated every 20-30 min after administration of sodium bicarbonate or normal saline. All measurements were performed after the confirmation of a steady state of CO2 elimination by end-tidal CO2 monitoring. Arteriovenous oxygen content difference ([Formula: see text]), mixed venous oxygen saturation ([Formula: see text]), and[Formula: see text] were highly correlated with CO. The correlation coefficients between[Formula: see text],[Formula: see text], and[Formula: see text] werer=-0.81 (P<0.001),r=0.70 (P<0.001), andr=-0.77 (P<0.001), respectively. The results suggest that, if[Formula: see text] is measured during the steady state, except for the period during the transient increase in CO2 elimination just after the administration of sodium bicarbonate,[Formula: see text] can be used as an index of systemic perfusion even after the administration of sodium bicarbonate. PMID- 28921146 TI - Effects of vasodilators on fibrin-induced pulmonary edema, so-called neurogenic pulmonary edema, in the rat. AB - The present study was undertaken to evaluate the effects of vasodilators on the development of neurogenic pulmonary edema. Pulmonary edema was induced by injecting fibrinogen and thrombin into the cisterna magna of vagotomized rats (fibrin-induced pulmonary edema). Before the intrathecal injections, rats were pretreated with intravenous injection of one of the following vasodilators: phentolamine, isoproterenol, nifedipine, diltiazem, isosorbide dinitrate, or substance P. Each vasodilator reduced the incidence of fibrin-induced pulmonary edema and lung-water ratio dose-dependently except nifedipine and diltiazem. There was a uniform relationship between the lung-water ratio and the prefibrin mean arterial pressure obtained under administration of different doses of the each drug. A similar relationship was obtained even if the drug used was different. Treatment with nifedipine or diltiazem, however, diminished the blood pressure but provided less protection against the development of pulmonary edema. The blood volume in edema-positive lungs was minimally different from that in edema-negative lungs. These results suggest that the neurogenic pulmonary edema may be effectively prevented by most vasodilators except Ca++-blockers. PMID- 28921147 TI - Effects of biogenic amines and intravenous anesthetics on the activity of rat locus coeruleus neurons in vitro. AB - To examine the effects of biogenic amines and clinically relevant concentrations of intravenous anesthetics on neuronal activities, the authors analyzed both spontaneous and evoked activities of neurons in the nucleus locus coeruleus (LC)in vitro using a single unit recording technique. Spontaneous firing was observed in 37% (14/38) of LC neurons, andN-methyl-D-aspartate (NMDA, 50 MUM), glutamate (250 MUM), and carbachol (1-2 mM) elicited firing in 100% (38/38), 63% (12/19), and 58% (7/12) of silent LC neurons respectively. Noradrenaline (50 MUM) and serotonin (5-HT) (1-5 MUM) suppressed spontaneous and drug-induced activities in 47% (15/32) and 23% (8/35) of LC neurons, respectively. Pentobarbital (100 MUM) inhibited 50% (5/10) of LC neurons. All neurons activated by NMDA (n=8) and glutamate (n-3) were suppressed by ketamine (40 MUM), but fentanyl (1 MUM) only suppressed 60% (3/5) of spontaneously active and 75% (3/4) of glutamate-activated neurons. Identical LC neurons were inhibited by various combinations of noradrenaline, 5-HT, pentobarbital, ketamine, and fentanyl. The results suggest that clinically relevant concentrations of anesthetics and opioids modulate the activity of LC neurons induced by biogenic amines, excitatory amino acids, and acetylcholine. PMID- 28921148 TI - Halothane enhances the negative chronotropic and dromotropic effects of calcium channel antagonists. PMID- 28921149 TI - Anesthesia for Down's syndrome with atlantoaxial instability using laryngeal mask airway. PMID- 28921150 TI - General anesthesia for Marinesco-Sjogren syndrome. PMID- 28921151 TI - Retrograde and antegrade intubation techniques under general anesthesia through the laryngeal mask airway. PMID- 28921152 TI - A new method of airway management with a long endotracheal-bronchial tube using a coaxial technique. PMID- 28921153 TI - Esophageal tracheal combitube overcomes difficult intubation: flexion deformity of the cervical spine due to rheumatoid arthritis. PMID- 28921154 TI - Severe hyponatremia induced with mannitol in a patient with Bartter's syndrome. PMID- 28921155 TI - Pneumomediastinum with subcutaneous emphysema during anesthesia for an infant. PMID- 28921156 TI - Effects of lumbar puncture position on arterial blood gases. AB - We observed the changes in partial pressure of arterial oxygen (PaO 2) and carbon dioxide (PaCO 2) before and during assumption of the lateral position prior to lumbar puncture in 81 patients to investigate whether lung volume decreased and ventilation was suppressed. PaO 2 significantly decreased while the patients were in the lateral position, while PaCO 2 remained unchanged. There was a negative correlation between the change in PaO 2 and age [change in PaO 2 (mmHg)=-0.13*age (years)+4.28,P<0.01]. The fact that closing volume increases with age implies that the decrease in functional residual capacity in the lateral position could have caused the decrease in PaO 2. It is therefore advisable to continuously monitor arterial oxygenation using a noninvasive monitor, such as a pulse oximeter, while performing spinal or epidural block, especially in elderly patients. PMID- 28921157 TI - Effect of the lithotomy position on spinal anesthesia with hyperbaric tetracaine. AB - This study was performed to determine the effects of lithotomy position on the spread of analgesia and hemodynamics following spinal anesthesia with 0.5% hyperbaric tetracaine. Thirty patients who underwent hysterectomy due to myoma uteri were studied. All patients received spinal anesthesia in the left lateral decubitus position and were turned supine immediately after intrathecal administration of the drug. Fifteen patients were then placed in the horizontal lithotomy position within 10 s, and the remaining 15 were kept in the horizontal supine position for 30 min. There were no significant differences between the groups in mean arterial pressure, heart rate, cardiac output, and in the cephalad spread of analgesia. The lithotomy position had no effect on the spread of analgesia or anesthetic course of spinal anesthesia with hyperbaric tetracaine. PMID- 28921158 TI - Textbook of anesthesia on electronic media: trial version as a free software. AB - The author has compiled a textbook of anesthesia on a floppy diskette and has made it available as free software. It is called "KSAP", which stands for "Knowledge Source for Anesthesia Practice". He aims to create a new form of textbook that is appropriate for current technology. This is proposal is intended as sample in trial form. The advantages of this format are easy storage and easy use on personal computers, excellent portability and search ability, facilitation of revisions, and easy distribution. The amount of information in this text is slightly more than one megabyte. The entire book consists of approximately 500 text files, all of which were written by this author. All that is required to use this textbook is an MS-DOS computer and software which reads ASCII text files. Individual files are all simple text files. PMID- 28921159 TI - Report on the Computer Software Contest at the 40th Congress of the Japan Society of Anesthesiology. PMID- 28921160 TI - GP2013: A Rituximab Biosimilar. AB - GP2013 is the second biosimilar of the reference monoclonal anti-CD20 antibody rituximab to be approved in the EU. It is approved for use in all indications for which reference rituximab is approved, including follicular lymphoma (FL), diffuse large B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis and microscopic polyangiitis. GP2013 has similar physicochemical and pharmacodynamic properties to those of reference rituximab, and the pharmacokinetic biosimilarity of the agents has been shown in patients with RA. GP2013 demonstrated clinical efficacy equivalent to that of reference rituximab in patients with FL, and was generally well tolerated in this population. The tolerability, immunogenicity and safety profiles of GP2013 were similar to those of reference rituximab. The role of reference rituximab in the management of cancers and autoimmune conditions is well established and GP2013 provides an effective biosimilar alternative for patients requiring rituximab therapy. PMID- 28921161 TI - Deep brain stimulation for refractory temporal lobe epilepsy: a systematic review and meta-analysis with an emphasis on alleviation of seizure frequency outcome. AB - OBJECTIVE: Conflicting conclusions have been reported regarding predictors of deep brain stimulation (DBS) outcome in patients with refractory temporal lobe epilepsy (TLE). The main goal of this meta-analysis study was to identify possible predictors of remarkable seizure reduction (RSR). METHODS: We conducted a comprehensive search of English-language literature published since 1990 and indexed in PubMed, Embase, and the Cochrane Library that addressed seizure outcomes in patients who underwent DBS for refractory TLE. A pooled RSR rate was determined for eight included studies. RSR rates were analyzed relative to potential prognostic variables. Random- or fixed-effects models were used depending on the presence or absence of heterogeneity. RESULTS: The pooled RSR rate among 61 DBS-treated patients with TLE from 8 studies was 59%. Higher likelihood of RSR was found to be associated with lateralization of stimulation, lateralized ictal EEG findings, and a longer follow-up period. Seizure semiology, MRI abnormalities, and patient sex were not predictive of RSR rate. The best electrode type for RSR was the Medtronic 3389. Hippocampal and anterior thalamic nuclei (ATN) sites of stimulation had similar odds of producing RSR. CONCLUSIONS: DBS is an effective therapeutic modality for intractable TLE, particularly in patients with lateralized EEG abnormalities and in patients treated on the ictal side. This meta-analysis provides evidence-based information for determining DBS suitability in presurgical counseling and for explaining seizure outcomes. PMID- 28921162 TI - A bionanohybrid ZnAl-NADS ecological pesticide as a treatment for soft rot disease in potato (Solanum tuberosum L.). AB - Pectobacterium carotovorum (Pc) is a phytopathogenic strain that causes soft rot disease in potato (Solanum tuberosum L.), resulting in postharvest losses. Chemical control is effective for managing this disease, but overdoses cause adverse effects. Because farmers insist on using chemical agents for crop protection, it is necessary to develop more effective pesticides in which the active compound released can be regulated. In this context, we proposed the synthesis of ZnAl-NADS, in which nalidixic acid sodium salt (NADS) is linked to a ZnAl-NO3 layered double hydroxide (LDH) host as a nanocarrier. XRD, FT-IR, and SEM analyses confirmed the successful intercalation of NADS into the interplanar LDH space. The drug release profile indicated that the maximum release was completed in 70 or 170 min for free NADS (alone) or for NADS released from ZnAl NADS, respectively. This slow release was attributed to strong electrostatic interactions between the drug and the anion exchanger. A modulated release is preferable to the action of the bulk NADS, showing increased effectiveness and minimizing the amount of the chemical available to pollute the soil and the water. The fitting data from modified Freundlich and parabolic diffusion models explain the release behavior of the NADS, suggesting that the drug released from ZnAl-NADS bionanohybrid was carried out from the interlamellar sites, according to the ion exchange diffusion process also involving intraparticle diffusion (coeffect). ZnAl-NADS was tested in vitro against Escherichia coli (Ec) and Pc and exhibited bacteriostatic and biocidal effects at 0.025 and 0.075 mg mL-1, respectively. ZnAl-NADS was also tested in vivo as an ecological pesticide for combating potato soft rot and was found to delay typical disease symptoms. In conclusion, ZnAl-NADS can potentially be used to control pests, infestation, and plant disease. PMID- 28921163 TI - Discriminative stimulus properties of the atypical antipsychotic amisulpride: comparison to its isomers and to other benzamide derivatives, antipsychotic, antidepressant, and antianxiety drugs in C57BL/6 mice. AB - RATIONALE: Racemic (RS)-amisulpride (Solian(r)) is an atypical antipsychotic drug used to treat schizophrenia and dysthymia. Blockade of dopamine D2/D3 and/or serotonin 5-HT7 receptors is implicated in its pharmacological effects. While the (S)-amisulpride isomer possesses a robust discriminative cue, discriminative stimulus properties of (RS)-amisulpride have not been evaluated. OBJECTIVES: The present study established (RS)-amisulpride as a discriminative stimulus and assessed amisulpride-like effects of amisulpride stereoisomers, other benzamide derivatives, and antipsychotic, antidepressant, and anxiolytic drugs. METHODS: Adult, male C57BL/6 mice were trained to discriminate 10 mg/kg (RS)-amisulpride from vehicle in a two-lever food-reinforced operant conditioning task. RESULTS: (RS)-Amisulpride's discriminative stimulus was dose-related, time-dependent, and stereoselective. (S)-Amisulpride (an effective dose of 50% (ED50) = 0.21 mg/kg) was three times more potent than (RS)-amisulpride (ED50 = 0.60 mg/kg) or (R) amisulpride (ED50 = 0.68 mg/kg). (RS)-Amisulpride generalized fully to the structurally related atypical antipsychotic/antidysthymia drug sulpiride (Sulpor(r); ED50 = 7.29 mg/kg) and its (S)-enantiomer (ED50 = 9.12 mg/kg); moderate to high partial generalization [60-75% drug lever responding (%DLR)] occurred to the benzamide analogs tiapride (Tiapridal(r)) and raclopride, but less than 60% DLR to metoclopramide (Reglan(r)), nemonapride (Emilace(r)), and zacopride. Antipsychotic, antidepressant, and antianxiety drugs from other chemical classes (chlorpromazine, quetiapine, risperidone, and mianserin) produced 35-55% amisulpride lever responding. Lastly, less than 35% DLR occurred for clozapine, olanzapine, aripiprazole imipramine, chlordiazepoxide, and bupropion. CONCLUSIONS: (RS)-Amisulpride generalized to some, but not all benzamide derivatives, and it failed to generalize to any other antipsychotic, antidepressant, or antianxiety drugs tested. Interestingly, the (R)-isomer shared very strong stimulus properties with (RS)-amisulpride. This finding was in contrast to findings from Donahue et al. (Eur J Pharmacol 734:15-22, 2014), which found that the (R)-isomer did not share very strong stimulus properties when the (S)-isomer was the training drug. PMID- 28921164 TI - Age estimation based on Willems method versus new country-specific method in South African black children. AB - AIM: The aims of our study were to develop new maturity scores for dental age estimation in South African black children according to the Willems method, which was developed based on Belgian Caucasian (BC) reference data (Willems et al. J Forensic Sci 46(4):893-895, 2001), and to compare age prediction performance of both methods. SUBJECTS AND METHODS: A total of 986 panoramic radiographs of healthy South African black (SAB) children (493 males and 493 females) in the age range of 4.14 to 14.99 years (mean age 10.06 years) were selected for obtaining developmental staging scores (according to Demirjian et al. Hum Biol 45(2):211 227, 1973). Willems BC methodology was applied to develop new country-specific maturity scores (Willems SAB). Age prediction performance of Willems BC and Willems SAB was compared. RESULTS: On average, Willems BC renders acceptable results with an overestimation of chronological age of 0.06 years (SD 0.88 years) in SAB children. Compared to Willems SAB, the overall mean absolute error was slightly higher with Willems BC (0.62 and 0.68 years, respectively), but this was not significant in males. Also, the root mean squared error was marginally higher in Willems BC. CONCLUSION: The new age prediction method developed in South African black children was found to be better compared to Willems BC, although the difference seems to be small and clinically not relevant, especially in males. PMID- 28921165 TI - Erratum to: Prediction of vulnerability to bipolar disorder using multivariate neurocognitive patterns: a pilot study. AB - In the original version of this article (Wu et al. 2017), published on 1 September 2017, the name of author 'Bo Cao' was wrongly displayed. In this Erratum the incorrect name and correct name are shown. The original publication of this article has been corrected. PMID- 28921166 TI - From the Atlantic Forest to the borders of Amazonia: species richness, distribution, and host association of ectoparasitic flies (Diptera: Nycteribiidae and Streblidae) in northeastern Brazil. AB - Better knowledge of the geographical distribution of parasites and their hosts can contribute to clarifying aspects of host specificity, as well as on the interactions among hosts, parasites, and the environment in which both exist. Ectoparasitic flies of the Nycteribiidae and Streblidae families are highly specialized hematophagous parasites of bats, whose distributional patterns, species richness, and associations with hosts remain underexplored and poorly known in Brazil. Here, we used information available in the literature and unpublished data to verify if the occurrence of bat hosts in a given environment influences the occurrence and distribution of nycteribiid and streblid flies in different ecoregions in the northeastern Brazil. We evaluate species richness and similarity between ecoregions and tested correlations between species richness and the number of studies in each ecoregion and federative unit. We recorded 50 species and 15 genera of bat ectoparasitic flies on 36 species and 27 genera of bat hosts. The Atlantic Forest had the highest fly species richness (n = 31; 62%), followed by Caatinga (n = 27; 54%). We detected the formation of distinct groups, with low species overlap between ecoregions for both flies and bats. Fly species richness was correlated with host species richness and with the number of studies in each federative unit, but not with the number of studies by ecoregion. Due to the formation of distinct groups with low species overlap for both groups, host availability is likely to be one of the factors that most influence the occurrence of highly specific flies. We also discuss host specificity for some species, produced an updated list of species and distribution for both nycteribiid and streblid flies with information on interaction networks, and conclude by presenting recommendations for more effective inventories of bat ectoparasites in the future. PMID- 28921167 TI - Brain structural concomitants of resting state heart rate variability in the young and old: evidence from two independent samples. AB - Previous research has shown associations between brain structure and resting state high-frequency heart rate variability (HF HRV). Age affects both brain structure and HF HRV. Therefore, we sought to examine the relationship between brain structure and HF HRV as a function of age. Data from two independent studies were used for the present analysis. Study 1 included 19 older adults (10 males, age range 62-78 years) and 19 younger adults (12 males, age range 19-37). Study 2 included 23 older adults (12 males; age range 55-75) and 27 younger adults (17 males; age range 18-34). The root-mean-square of successive R-R interval differences (RMSSD) from ECG recordings was used as time-domain measure of HF HRV. MRI scans were performed on a 3.0-T Siemens Magnetom Trio scanner. Cortical reconstruction and volumetric segmentation were performed with the Freesurfer image analysis suite, including 12 regions as regions of interests (ROI). Zero-order and partial correlations were used to assess the correlation of RMSSD with cortical thickness in selected ROIs. Lateral orbitofrontal cortex (OFC) cortical thickness was significantly associated with RMSSD. Further, both studies, in line with previous research, showed correlations between RMSSD and anterior cingulate cortex (ACC) cortical thickness. Meta-analysis on adjusted correlation coefficients from individual studies confirmed an association of RMSSD with the left rostral ACC and the left lateral OFC. Future longitudinal studies are necessary to trace individual trajectories in the association of HRV and brain structure across aging. PMID- 28921168 TI - Chromosomal Abnormalities Affect the Surgical Outcome in Infants with Hypoplastic Left Heart Syndrome: A Large Cohort Analysis. AB - Patients with hypoplastic left heart syndrome (HLHS) can have associated genetic abnormalities. This study evaluated the incidence of genetic abnormalities among infants with HLHS and the short-term outcomes of this population during the first hospitalization. This is a retrospective analysis of the multi-center Pediatric Heath Information System database of infants with HLHS who underwent Stage I Norwood, Hybrid, or heart transplant during their first hospitalization from 2004 through 2013. We compared clinical data between infants with and without genetic abnormality, among the three most common chromosomal abnormalities, and between survivors and non-survivors. Multivariable analysis was completed to evaluate predictors of mortality among patients with genetic abnormalities. A total of 5721 infants with HLHS were identified; 282 (5%) had associated genetic abnormalities. The three most common chromosomal abnormalities were Turner (25%), DiGeorge (22%), and Downs (12.7%) syndromes. Over the study period, the number of patients with genetic abnormalities undergoing cardiac operations increased without any significant increases in mortality. Infants with genetic abnormalities compared to those without abnormalities had longer hospital length of stay and higher morbidity and mortality. Variables associated with mortality were lower gestational age, longer duration of vasopressor therapy, need for dialysis, and cardiopulmonary resuscitation; and complicated clinical course as suggested by necrotizing enterocolitis, septicemia. Presence of any genetic abnormality in infants with HLHS undergoing cardiac surgery is associated with increased mortality and morbidity. Timely genetic testing, appropriate family counseling, and thorough preoperative case selection are suggested for these patients for any operative intervention. PMID- 28921169 TI - Effects of acute salt stress on modulation of gene expression in a Malaysian salt tolerant indigenous rice variety, Bajong. AB - The small genome size of rice relative to wheat and barley, together with its salt sensitivity, make it an ideal candidate for studies of salt stress response. Transcriptomics has emerged as a powerful technique to study salinity responses in many crop species. By identifying a large number of differentially expressed genes (DEGs) simultaneously after the stress induction, it can provide crucial insight into the immediate responses towards the stressor. In this study, a Malaysian salt-tolerant indigenous rice variety named Bajong and one commercial rice variety named MR219 were investigated for their performance in plant growth and ion accumulation properties after salt stress treatment. Bajong was further investigated for the changes in leaf's transcriptome after 6 h of stress treatment using 100 mM NaCl. Based on the results obtained, Bajong is found to be significantly more salt tolerant than MR219, showing better growth and a lower sodium ion accumulation after the stress treatment. Additionally, Bajong was analysed by transcriptomic sequencing, generating a total of 130 millions reads. The reads were assembled into de novo transcriptome and each transcript was annotated using several pre-existing databases. The transcriptomes of control and salt-stressed samples were then compared, leading to the discovery of 4096 DEGs. Based on the functional annotation results obtained, the enrichment factor of each functional group in DEGs was calculated in relation to the total reads obtained. It was found that the group with the highest gene modulation was involved in the secondary metabolite biosynthesis of plants, with approximately 2.5% increase in relation to the total reads obtained. This suggests an extensive transcriptional reprogramming of the secondary metabolic pathways after stress induction, which could be directly responsible for the salt tolerance capability of Bajong. PMID- 28921170 TI - Comparison of novel multi-level Otsu (MO-PET) and conventional PET segmentation methods for measuring FDG metabolic tumor volume in patients with soft tissue sarcoma. AB - BACKGROUND: We have previously developed a novel and highly consistent PET segmentation algorithm using a multi-level Otsu method (MO-PET). The aim of this study was to evaluate the reliability of MO-PET compared to conventional PET segmentation methods for measuring 18F-FDG (FDG) PET metabolic tumor volume (MTV) in patients with soft tissue sarcoma (STS). Clinical and imaging data were obtained from the Cancer Imaging Archive. Forty-eight STS patients with FDG PET/CT and MR prior to therapy were analyzed. MTV of the tumor using MO-PET was compared to other conventional methods (absolute SUV threshold values of 2.0, 2.5, or 3.0 and percentage of tumor SUVmax values of 30, 40, 50, or 60%) and gradient-based method (PET EdgeTM). The reference volume was defined as an MR based gross tumor volume (GTV). Spearman, intra-class correlation, and Bland Altman analysis were performed to evaluate the correlation and agreement of MTV to GTV. RESULTS: MTVs obtained using each conventional SUV parameter, PET EdgeTM, and MO-PET were highly correlated with the GTV in Spearman and intra-class correlation analysis (p < 0.05). MO-PET and PET EdgeTM showed high intra-class correlation coefficient of MTV to GTV (0.93 and 0.84, respectively). The Bland Altman bias results showed the highest agreement for MTV using MO-PET with GTV (26.0 +/- 489.6 cm3) compared to other methods (SUV 2.0 with - 69.3 +/- 765.8, 30% SUVmax with - 255.0 +/- 876.6, and PET EdgeTM with - 26.46 +/- 668.82 cm3). CONCLUSIONS: PET MTV segmented with MO-PET showed higher correlation and agreement with GTV in comparison to conventional percentage SUVmax and absolute SUV threshold-based PET segmentation methods. MO-PET is comparable to PET EdgeTM. MO-PET is a reliable and consistent method for measuring tumor MTV. PMID- 28921171 TI - High fibrin/fibrinogen degradation product to fibrinogen ratio is associated with 28-day mortality and massive transfusion in severe trauma. AB - PURPOSE: There is a lack of association between coagulation biomarkers and long term mortality in severe trauma. We aimed to investigate the association between coagulation biomarkers on admission and outcome of late stage of trauma. METHODS: This retrospective observational study included patients admitted with severe trauma between 2012 and 2015. We used the area under the receiver operating characteristic curve (AUROC) of coagulation biomarkers to determine 28-day mortality. Head Abbreviated Injury Scale scores greater than 3 were defined as traumatic brain injury (TBI). The primary outcome was 28-day mortality and the secondary outcome was massive transfusion. RESULTS: Of the 1266 patients included in the study, 28-day mortality rate was 19.7% (n = 249) and 7.9% (n = 100) of patients received massive transfusion. The AUROC of fibrin/fibrinogen degradation product (FDP) to fibrinogen ratio had a significantly higher prognostic performance than other markers. Multivariate analysis revealed that D-dimer level [odds ratio (OR) 1.033; 95% confidence interval (CI) 1.016-1.051] and FDP/fibrinogen ratio (OR 1.007; 95% CI 1.001-1.013) were independently associated with 28-day mortality. D-dimer (OR 1.028; 95% CI 1.003-1.055) and FDP/fibrinogen ratio (OR 1.035; 95% CI 1.012-1.058) were associated with 28-day mortality in the TBI group. In the non-TBI group, D-dimer was associated with 28-day mortality (OR 1.033; 95% CI 1.008-1.059), but the FDP/fibrinogen ratio was not. FDP/fibrinogen ratio, not D-dimer level, was an independent predictor for massive transfusion (OR 1.005; 95% CI 1.001-1.010). CONCLUSIONS: High FDP/fibrinogen ratio on arrival is a predictor of 28-day mortality and the requirement for massive transfusion in severe trauma. PMID- 28921172 TI - [European Network of Official Medicines Control Laboratories : International OMCL Working Group Combating Counterfeit and other Illegal Medicines]. AB - Official medicines control laboratories (OMCLs) have for a long time been involved in testing activities related to suspected counterfeit or other illegal medicines in a number of European countries in support of national enforcement authorities. With the secretarial support of the European Directorate for the Quality of Medicines & HealthCare (EDQM), from 2005 onwards, the General European OMCL Network (GEON) has gradually introduced for its members tailored tools, joint test programmes and information/discussion platforms in the field of falsified medicines testing. Since 2011 a dedicated OMCL working group (OMCL Counterfeit/Illegal Medicines Working Group) has taken the lead in coordinating the different activities, which range from training programmes, symposia and focus topics at annual meetings to the development and improvement of databases and the drafting of common documents. The overall goal of these activities is to share know-how, to establish and identify centres of expertise, to further develop competencies in the field of analysis of falsified medicines, to challenge the competency of OMCLs in the testing of unknown samples, to raise awareness of the network and to leverage synergies in particular with respect to this field of expertise. All these measures aim at strengthening the network in the combat against falsified medicines, enlarging the field of activities of the OMCLs in this area and improving the hit rate with respect to the identification of adulterations. PMID- 28921173 TI - Maximizing safe resections: the roles of 5-aminolevulinic acid and intraoperative MR imaging in glioma surgery-review of the literature. AB - Malignant glioma surgery involves the challenge of preserving the neurological status of patients harboring these lesions while pursuing a maximal tumor resection, which is correlated with overall and progression-free survival. Presently, several tools exist for assisting neurosurgeons in visualizing malignant tissue. Fluorescence-guided surgery (FGS) with 5-aminolevulinic acid (5 ALA) has increasingly been used during the last decade for identifying malignant glioma. Intraoperative magnetic resonance imaging (iMRI), first introduced in the mid-1990s, is being evaluated as a further tool to maximize the extent of resection. We aimed to evaluate the literature and discuss synergies and differences between FGS with 5-ALA and iMRI. We conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. After excluding non-relevant articles, 16 articles were evaluated and included in the qualitative analysis, comprising 2 (n = 2) reviews of the literatures, 1 (n = 1) book chapter, and 13 (n = 13) clinical articles. ALA-induced fluorescence goes beyond the borders of gadolinium contrast enhancement. Several studies stress the synergy between both tools, enabling increase in extent of resection. We point out advantages of combining both methods. iMRI, however, is not widely available, is expensive, and is not recommended as sole resection control tool in high-grade glioma. For these centers, FGS together with mapping and monitoring techniques, neuronavigation and, when needed, intraoperative ultrasound provides an excellent setting for achieving state-of-the-art gross total resection of high-grade gliomas. PMID- 28921174 TI - Bilateral segmentectomies using virtual-assisted lung mapping (VAL-MAP) for metastatic lung tumors. AB - BACKGROUND: Virtual-assisted lung mapping (VAL-MAP) has been used not only in wedge resection but also in segmentectomy for hardly palpable lung nodules. We herein report a case of bilateral segmentectomy using VAL-MAP with chronological change of pulmonary function test results. CASE PRESENTATION: A 50-year-old female was found to have a colorectal cancer with pulmonary nodules in both sides of the lungs considered as synchronous lung metastases. After sigmoidectomy for primary cancer and chemotherapy, treatments for small nodules in both sides of the lungs were planned. Most nodules were small and supposed to be impalpable. We performed thoracoscopic segmentectomy of right S8 with the aid of VAL-MAP and, after 2 months, combined subsegmentectomy of left S8a and 9a and wide wedge resection of left S8b with the aid of VAL-MAP. All nodules suspected of lung metastases were successfully resected with adequate margins, and the decrease in pulmonary function was minimal compared with predicted postoperative forced vital capacity (FVC) and forced expiratory volume (FEV) 1.0 calculated by the numbers of subsegments. CONCLUSIONS: Bilateral segmentectomies of small impalpable metastatic tumors were performed successfully with the aid of VAL-MAP. PMID- 28921176 TI - Effect of ONO-1101, a novel short-acting beta-blocker on hemodynamic responses to isoflurane inhalation and tracheal intubation. AB - PURPOSE: We investigated the effect of a new ultrashort-acting beta-blocker, ONO 1101, on hemodynamic responses to isoflurane inhalation and tracheal intubation. METHODS: Fifty-four ASA PS 1 or 2 patients were randomly allocated to receive either ONO-1101, 0.04 mg.kg-1.min-1, or saline prior to tracheal intubation. Anesthesia was induced with thiamylal, 4 mg.kg-1, and vecuronium, 0.15 mg.kg-1. Tracheal intubation was carried out after 3 min controlled mask ventilation with 66% N2O and 3% inspired isoflurane in oxygen. Heart rate and blood pressure were continuously recorded from the start of induction until 5 min after intubation. Plasma concentrations of catecholamines were measured before induction, 3 min after initiating inhalation of isoflurane, and 1 min after tracheal intubation. RESULTS: Significant increases in heart rate occurred in both groups in response to isoflurane inhalation and tracheal intubation, but the magnitude of the increase was significantly less in the ONO-1101 group. Blood pressure increased after tracheal intubation in the saline group but remained unchanged in the ONO 1101 group. Plasma concentrations of norepinephrine increased after induction and intubation in both groups, with no significant difference between the groups. CONCLUSION: ONO-1101 infusion is effective for the attenuation of hemodynamic responses to isoflurane inhalation and tracheal intubation. PMID- 28921175 TI - Routine gastric residual volume measurement and energy target achievement in the PICU: a comparison study. AB - : Critically ill children frequently fail to achieve adequate energy intake, and some care practices, such as the measurement of gastric residual volume (GRV), may contribute to this problem. We compared outcomes in two similar European Paediatric Intensive Care Units (PICUs): one which routinely measures GRV (PICU GRV) to one unit that does not (PICU-noGRV). An observational pilot comparison study was undertaken. Eighty-seven children were included in the study, 42 (PICU GRV) and 45 (PICU-noGRV). There were no significant differences in the percentage of energy targets achieved in the first 4 days of PICU admission although PICU noGRV showed more consistent delivery of median (and IQR) energy targets and less under and over feeding for PICU-GRV and PICU-noGRV: day 1 37 (14-72) vs 44 (0 100), day 2 97 (53-126) vs 100 (100-100), day 3 84 (45-112) vs 100 (100-100) and day 4 101 (63-124) vs 100 (100-100). The incidence of vomiting was higher in PICU GRV. No necrotising enterocolitis was confirmed in either unit, and ventilator acquired pneumonia rates were not significantly different (7.01 vs 12 5.31 per 1000 ventilator days; p = 0.70) between PICU-GRV and PICU-noGRV units. CONCLUSIONS: The practice of routine gastric residual measurement did not significantly impair energy targets in the first 4 days of PICU admission. However, not measuring GRV did not increase vomiting, ventilator-acquired pneumonia or necrotising enterocolitis, which is the main reason clinicians cite for measuring GRV. What is known: * The practice of routinely measuring gastric residual volume is widespread in critical care units * This practice is increasingly being questioned in critically ill patients, both as a practice that increases * The likelihood of delivering inadequate enteral nutrition amounts and as a tool to assess feeding tolerance What is new: * Not routinely measuring gastric residual volume did not increase adverse events of ventilator acquired pneumonia, necrotising enterocolitis or vomiting. * In the first 4 days of PICU stay, energy target achievement was not significantly different, but the rates of under and over feeding were higher in the routine GRV measurement unit. PMID- 28921177 TI - Reduction of cardiovascular response to endotracheal intubation in normotensive patients by urapidil. AB - PURPOSE: Urapidil is an antihypertensive drug with actions of alpha1-receptor blockade and 5-HT1A (5-hydroxytryptamine) receptor stimulation. Although many agents have been used to attenuate the cardiovascular response to endotracheal intubation, few of them are related to urapidil. This study was done to evaluate the effects of urapidil on reducing the cardiovascular response to intubation. METHODS: In this randomized, double-blind, placebo-controlled study, 30 ASA I-II adult surgical patients without cardiovascular disease were divided into two groups of 15 each, receiving either an i.v. bolus of 0.6 mg.kg-1 urapidil 5 min before intubation or an equivalent volume of saline as control. The heart rate and the systolic and diastolic blood pressure were determined intermittently for 5 min before and 10 min after intubation. The mean blood pressure, product of systolic blood pressure and heart rate, and coefficient of variation (CV) of these variables around intubation were calculated. RESULTS: Urapidil had no effects on the heart rate (P>0.05), could effectively attenuate the increases in the diastolic and mean arterial pressures (P<0.05) caused by intubation, but had a weak effect on the systolic pressure (P>0.05) and its product with heart rate. In addition, the CV of the diastolic pressure and mean arterial pressure was greater (P<0.05) in the urapidil group than in the control group, which meant that the induction procedure with urapidil was not more stable than that when saline was used as placebo. CONCLUSION: The effects of urapidil on reducing the cardiovascular response to intubation are mild when uradipil is used 5 min before intubation. As urapidil mainly decreases diastolic blood pressure, an important determinant of cardiac blood supply, and it makes systolic, diastolic, and mean blood pressure fluctuate strongly during induction, we should be alert about its latent detrimental effect on patients, especially those with ischemic heart disease. PMID- 28921178 TI - Open-heart surgery without homologous blood transfusion in infants and children under simple deep hypothermia. AB - PURPOSE: To investigate the hematological changes during the perioperative period of open-heart surgery without homologous blood transfusion under simple deep hypothermia in infants and small children, and to define the limits of body weight for open-heart surgery without homologous blood transfusion under simple deep hypothermia. METHODS: We performed open-heart surgery without homologous blood transfusion under simple deep hypothermia on eight children, four infants, and a neonate with diagnoses of atrial septal defect, ventricular septal defect, on total anomalous pulmonary venous return (TATVR). All patients except for one with TAPVR were surface-cooled with ice water under deep ether anesthesia. Hematological examinations were performed seven times during the perioperative period. RESULTS: The body weight of the patients ranged from 2.5 to 15.0 kg (mean+/-SD, 9.5+/-3.5 kg) and the blood loss from 0.7 to 7.1g.kg-1 (4.6+/-2.0g.kg 1) The lowest values of the hematological findings in each case after surgery were as follows: Hb ranged from 7.6 to 10.9g.dl-1 (8.8+/-1.0g.dl-1), blood platelet count from 158*103 to 337*103 cells.ul-1-agonist (271+/-88 *103 cells.ul 1-agonist, and total protein from 4.3 to 5.5 g.dl-1 (5.0+/-0.4g.dl-1) CONCLUSION: Severe anemia and hypoproteinemia were not detected in any case, and, in particular, the reduction of the platelet count was slight. No events occurred as a result of decreased Hb concentration, serum protein, or both. PMID- 28921179 TI - Measurement of whole blood factor Xa-activated clotting time during hemodialysis with low-molecular-weight heparin. AB - PURPOSE: To determine whole blood factor Xa-activated clotting time (XaACT), a test for monitoring low-molecular-weight heparins (LMWHs). METHODS: Blood was obtained from six healthy volunteers. Dalteparin, a LMWH, was mixed with the blood to concentrations of 0,05 and 1.0IU.ml-1. XaACT, activated clotting time (ACT), and activated partial thromboplastin time (APTT) were measured at each dalteparin concentration. XaACT of blood from the outflow and inflow sides of the blood circuit in seven hemodialysis patients was measured before and after bolus administration of 1000 IU of dalteparin, followed by continuous infusion at a rate of 500IU.h-1. RESULTS: XaACT, ACT, and APTT in dalteparin-containing blood from volunteers were correlated with dalteparin concentration (y=312.8x+86.4;r 2=0.88;P<0.001,y=41.8x +113.5;r 2=0.83;P<0.001, andy=59.5x+38.8;r 2=0.80;P<0.001, respectively). The regression slope of XaACT was steeper than those of ACT and APTT (P<0.001). In hemodialysis patients, dalteparin increased XaACT on the outflow and inflow sides of the circuit (P<0.001,P<0.05, respectively). CONCLUSION: The measurement of XaACT can be employed to monitor LMWHs in clinical settings. PMID- 28921180 TI - Effect of phenylephrine on histamine-induced bronchoconstriction in dogs. AB - PURPOSE: Although an alpha-adrenoceptor has been suggested to be involved in the mechanism of asthma, the effect of alpha1-agonist on the airway is still unclear. In this study we evaluated the effect of phenylephrine on the airway with a direct visualization method using a superfine fiberoptic bronchoscope (SFB). METHODS: Seven mongrel dogs were anesthetized with pentobarbital (30 mg.kg-1 IV) and paralyzed by pancuronium (0.2mg.kg-1.h-1). The trachea was intubated with an endotracheal tube (ID 7 mm) that has a second lumen for insertion of a SFB (OD 2.2 mm) to monitor the bronchial cross-sectional area (BCA) continuously. The tip of a SFB was placed at the level between the second and third bronchial bifurcation. To assess hemodynamics, the direct arterial blood pressure (ABP) and pulmonary arterial pressure (PAP) were monitored via a femoral arterial catheter and Swan-Granz catheter. Bronchoconstriction was elicited by histamine (10 MUg.kg 1+ 500 MUg.kg-1.h-1_. At 30 min after the histamine was started, saline or phenylephrine (1, 10, and 100MUg.kg-1) was given intravenously. The BCA and hemodynamic variables were assessed before (basal) and 30 min after the histamine was started and 5 min after saline and each phenylephrine dose. RESULTS: Histamine reduced BCA by 40.3+/-6.3%. Phenylephrine at 10 and 100 MUg.kg-1 significantly increased the ABP and PAP; and it significantly decreased the BCA, by 6.5+/-6.9% and 14.2+/-7.9%, respectively. Plasma epinephrine and norepinephrine were also significantly reduced following phenylephrine 100 MUg.kg 1 IV. CONCLUSION: The dose of phenylephrine that produced vasopressive actions worsened the histamine-induced bronchoconstriction slightly but significantly. Therefore, phenylephrine should be used with caution in asthmatic patients. PMID- 28921181 TI - 7-Nitroindazole, a selective inhibitor of neuronal nitric oxide synthase: effect on sevoflurane MAC and cerebellar cyclic GMP in mice. AB - PURPOSE: Considerable evidence suggests that nitric oxide (NO) plays a role in synaptic transmission in the central and peripheral nervous systems. However, whether inhibition of NO synthesis decreases minimum alveolar concentration (MAC) of inhalational anesthetics is controversial. We examined the effects of 7 nitroindazole (7-NI), a selective inhibitor of neuronal NOS (nNOS), on the MAC of sevoflurane and cerebellar cyclic guanosine monophosphate (cGMP) levels in mice. METHODS: Sevoflurane MAC and cerebellar cGMP levels were determined in mice after acute intraperitoneal or weeklong gavage feeding of 7-NI. Sevoflurane MAC and cerebellar cGMP levels after chronic treatment were measured on days 1, 4, and 7 and were repeated after an acute intraperitoneal dose of nitro g -L-arginine methylester (L-NAME). RESULTS: Acute and chronic treatment with 7-NI decreased the sevoflurane MAC by 20%-30%. Reduction of cerebellar cGMP levels was greater after intraperitoneal administration of NOS inhibitors than after gavage feeding of 7-NI. CONCLUSION: Acute or chronic selective inhibition of neuronal NOS decreases the sevoflurane MAC and cerebellar cGMP levels in mice. 7-NI permitted probing of the role of NO in perception of noxious stimuli. PMID- 28921183 TI - Anesthesia for pediatric ambulatory surgery. PMID- 28921182 TI - Philosophy and efficacy of multidisciplinary approach to chronic pain management. PMID- 28921184 TI - Anesthetic management of a patient with acute fatty liver of pregnancy. PMID- 28921185 TI - Preoperative acute hypervolemic hemodilution with hydroxyethylstarch in a Jehovah's Witness: effects on hemodynamics and coagulation systems. PMID- 28921186 TI - Cardiac arrest during hip arthroplasty with cement gun. PMID- 28921187 TI - Moderation of Genetic Influences on Alcohol Involvement by Rural Residency among Adolescents: Results from the 1962 National Merit Twin Study. AB - Adolescents in rural and urban areas may experience different levels of environmental restrictions on alcohol use, with those in rural areas experiencing greater monitoring and less access to alcohol. Such restrictions may limit expression of genetic vulnerability for alcohol use, resulting in a gene environment interaction (G * E). This phenomenon has previously been reported in Finnish and Minnesota adolescents. The current study used data from 839 same-sex twin pairs from the 1962 National Merit Scholarship Qualifying Test to determine whether the G * E interaction would be evident in this earlier time period. We also assessed whether the G * E interaction would be moderated by sex, and whether family socioeconomic status (SES; income and parental education) may mediate the G * E interaction. Findings showed the expected interaction among females, with a weaker contribution of genes (2 vs. 44%) and greater contribution of shared environment (62 vs. 29%) to variation in alcohol involvement among rural as compared to urban residents. The G * E interaction was not observed among males, and operated independently from differences in family SES among rural and urban adolescents. This study represents a partial replication in a novel setting of the moderation of the genetic contribution to alcohol use by rural/urban residency, and suggests that SES differences may not explain this effect. PMID- 28921188 TI - Anesthesia mortality and morbidity in Japan: A study of lawsuit cases. AB - To date, there have been no systematic studies on anesthetic accidents in Japan. This study was conducted to clarify the present status of anesthetic accidents by sending a questionnaire to a group of plaintiff's lawyers specializing in medical malpractice. At present, because of manpower shortages, anesthesia is provided by either anesthesia specialists (anesthesiologists) or non-anesthesiologist physicians in Japan. Among 112 lawsuits which involved the use of anesthesia, 64 were analyzed as to the person primarily responsible for administering the anesthesia, the types of anesthesia, the details of major mishaps, and intraoperative monitoring. Of particular note was a large number of deaths from cardiac arrest and hypotension in spinal anesthesia administered by non anesthesiologists. The results clearly showed that non-anesthesiologists had a substantial incidence of mortality cases among accidents compared with anesthesiologists. Human error was the most frequent cause, but a lack and/or a grave omission of intraoperative monitors was found in non-anesthesiologist related cases. PMID- 28921189 TI - Preoperative estimation of pulmonary extravascular thermal volume in patients undergoing pneumonectomy. AB - Pulmonary extravascular thermal volume (PETV) was measured during pulmonary artery occlusion in 18 patients preoperatively and 7 patients postoperatively who were undergoing pneumonectomy. We found that the PETV decreased from 6.6+/-2.3 ml.kg-1 before occlusion to 4.1+/-1.6 ml.kg-1 during occlusion. There was a significant correlation between the PETVs before and during occlusion multiplied by the fraction of pulmonary perfusion (r=0.77,P<0.001). Although the PETV increased in two patients and decreased in four within 48 h after pneumonectomy, it returned to the value during occlusion at 3 weeks after pneumonectomy in seven patients. There was a significant correlation between the PETV during occlusion and that at 3 weeks after pneumonectomy (r=0.66,P<0.05). In conclusion, PETV during pulmonary artery occlusion is a reliable baseline value in the assessment of postoperative pneumonectomy values. PMID- 28921190 TI - Subanesthetic sevoflurane does not affect sympathetic or parasympathetic function. AB - To evaluate the effects of subanesthetic enflurane and sevoflurane on the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS), the blood level of norepinephrine (NE) and fluctuations in the R-R intervals were measured on electrocardiogram in humans given either 0.5 MAC enflurane or sevoflurane. Enflurane suppressed circulating plasma NE and elevated coefficients of variation (CV) of R-R intervals after 20 and 30 min of inhalation. In contrast, 0.5 MAC of sevoflurane slightly stimulated cardiovascular function without any change in blood NE. Sevoflurane lowered the CV to 84% of control after 30 min of inhalation. These results indicate that subanesthetic concentrations of sevoflurane are unlikely to perturb sympathetic and parasympathetic activities in humans without surgical stimulation when compared with enflurane. PMID- 28921191 TI - Intravenous magnesium sulfate as a preanesthetic medication: A double-blind study on its effects on hemodynamic stabilization at the time of tracheal intubation. AB - The effects of magnesium sulfate (MgSO4) as a preanesthetic medication were studied with regard to whether it can sedate or relieve a patient who is scheduled to undergo surgery, and whether it can control the hemodynamic response to tracheal intubation. Twenty adult patients in ASA status 1-2 undergoing elective surgery were studied. Ten patients received 50 mg.g-1 MgSO4 intravenously by drip infusion from 30 min before the induction of anesthesia, and another ten patients received saline as a control. The changes in mean arterial pressure (MAP) and rate pressure product (RPP) after the intubation were significantly suppressed in magnesium-treated patients, but a sedative effect was not observed. Therefore, MgSO4 was useful as a preanesthetic medication in suppressing the hemodynamic response associated with tracheal intubation. PMID- 28921192 TI - Clonidine premedication for sevoflurane anesthesia in upper abdominal surgery. AB - The effects of clonidine as a preanesthetic medication were compared with diazepam on clinical courses of sevoflurane anesthesia in 22 patients undergoing upper abdominal surgery. The patients were divided into two groups of 11 patients each according to preanesthetic medication: atropine 0.5 mg i.m. plus clonidine 0.3 mg p.o., or atropine 0.5 mg i.m. plus diazepam 10 mg p.o. 60-90 min prior to induction of anesthesia. Anesthesia was induced with fentanyl and thiopental, and was maintained with sevoflurane, 0.5%-1.5%, nitrous oxide and oxygen, supplemented with fentanyl, 0.5 MUg.kg-1.hr-1. While only one patient needed a vasodilator in the clonidine group for treatment of hypertension, seven patients needed it in the diazepam group. Pain score after extubation was higher in the diazepam group than in the clonidine group. The time when patients responded to verbal command after discontinuation of anesthetics was similar in both groups. Therefore, clonidine pretreatment was useful for sevoflurane anesthesia in upper abdominal surgery. PMID- 28921193 TI - Effects of a forced-air system (Bair Hugger, OR-type) on intraoperative temperature in patients with open abdominal surgery. AB - Intraoperative hypothermia is difficult to avoid and may present a significant clinical risk during the early postoperative phase. We evaluated a forced-air system [Bair Hugger, OR-type (BH)] for warming intraoperative patients with open abdominal surgery. Twenty patients received BH warming [BH(+) group] and another 20 patients, who served as controls, did not [BH(-) group]. Patients in both groups also received circulating blanket warming. Tempertures were measured at 30 min intervals throughout the operation in the rectum and on the tip of the index finger opposite the nail bed. The average operation time was 168.8+/-16.2 min. Rectal and fingertip temperatures in the BH(+) group were significantly higher than those in the BH(-) group, and central-peripheral temperature gradients in the BH(+) group were significantly smaller than those in the BH(-) group during the study, except at 180 min. No shivering occurred in either group. Therefore, BH is an effective warming device during open abdominal surgery. PMID- 28921194 TI - The effects of low-dose midazolam for induction of high-dose fentanyl anesthesia for coronary artery bypass graft. AB - A small dose of midazolam 0.06 mg/kg or diazepam 0.15 mg/kg was used for induction of high-dose fentanyl (50 MUg/kg) anesthesia in patients undergoing coronary artery bypass grafting operation. Hemodynamic variables were measured 5 min after the injection of midazolam or diazepam, after the end of the fentanyl infusion, and following endotracheal intubation. Midazolam and diazepam caused a slight but significant decrease in mean arterial pressure (-9.8%) and -11.8%), respectively) and a further significant depression was observed in the diazepam group but not in the midazolam group after fentanyl. Although the cardiac index was maintained in patients who received madazolam, a significant decrease was observed in the diazepam group (-28.5%) after administration of fentanyl. Heart rate was decreased in the diazepam group but not in the midazolam group. Therefore, a small dose of midazolam may be a suitable induction agent for high dose fentanyl anesthesia in patients with coronary artery disease. PMID- 28921195 TI - Effects of continuous epidural block on motor nerve conduction velocity in patients with lower spine disorders. AB - Thirty-one patients with severe low back pain were treated by continuous epidural block for 18+/-3 (mean+/-SEM) days. Motor nerve conduction velocity (MCV) of the common peroneal nerve was measured before and after the treatment. After the treatment, the visual analogue scale score (VAS) and straight leg-raising (SLR) test were markedly reduced (P<0.01), and MCV was increased significantly (P<0.001). A significant correlation (P<0.01) between the SLR test and MCV was found before the treatment. A significant correlation (P<0.001) between VAS and MCV was demonstrated after treatment. However, in three patients who showed no reduction in VAS even after the treatment, MCV became significantly (P<0.05) slower in spite of nearly normal SLR test results. These results suggest that epidural block treatment improves not only pain but also MCV, and that two parameters, SLR test and pain intensity, are related closely to the MCV. PMID- 28921196 TI - Hypomagnesemia during pediatric orthotopic liver transplantation. AB - We evaluated the incidence and severity of serum magnesium (Mg) abnormality along with other electrolyte and acid-base disturbances before and during the course of orthotopic liver transplantation (OLT) in pediatric patients. Serum Mg, Na, K, ionized Ca, pH, and blood gas measurements were performed before and hourly during the course of OLT. Hypomagnesemia was frequently observed in children undergoing OLT. Of a total of 30 recipients, 27 (90%) had hypomagnesemia before surgery; the mean serum Mg value at this time was 0.77+/-0.15 mmol/L. In most of the recipients, the serum Mg value showed a gradual decrease during the course of OLT until magnesium sulfate supplements were administered. On the other hand, the serum Na, K, and ionized Ca levels and acid-base balance were normal before the beginning of surgery. However, hypernatremia, hypokalemia, a decrease in ionized Ca, and metabolic acidosis were commonly observed during the course of OLT. We conclude that electrolyte abnormalities, including hypomagnesemia and metabolic acidosis, commonly develop in children during the course of OLT. The frequent assessment of electrolytes, pH and blood gases is essential for the correction of these abnormalities during the course of OLT. PMID- 28921197 TI - Statistical analysis of visual prognosis following stellate ganglion block treatment on patients with retinal vessel obstruction. AB - The visual outcome in 308 patients treated for retinal vessel obstruction was examined retrospectively and the effectiveness of each treatment was evaluated using stepwise multiple linear regression analysis and the chi-square test. Visual acuity was used as the parameter for assessing treatment effectiveness and the variables investigated included treatment factors [stellate ganglion block (SGB), urokinase administration, and prostaglandin administration] and patient factors (age, duration of visual impairment before treatment, hypertension, and diabetes mellitus). SGB treatment, the duration of visual impairment, and the presence of diabetes mellitus were significantly correlated with the visual prognosis following treatment. These results support the current hypothesis that SGB is a viable treatment for patients with obstructive disease of the retinal vessels. PMID- 28921198 TI - Evaluation of twitch responses obtained from abductor hallucis muscle as a monitor of neuromuscular blockade: Comparison with the results from adductor pollicis muscle. AB - The twitch responses evoked from the abductor hallucis muscle (AHM) and the adductor pollicis muscle (APM) were examined simultaneously in 20 anesthetized patients following a single bolus intravenous administration of 0.04 mg.kg-1 of vecuronium bromide. The mean onset time of vecuronium-induced depression of AHM twitch responses was significantly slower than that of APM twitch responses (4.9+/-1.5 minvs 3.7+/-1.2 min, mean+/-SD,P<0.001), and when the clinical duration times of vecuronium were compared, AHM twitch responses recovered more quickly than APM twitch responses (15.3+/-4.1 minvs 19.6+/-6.7 min,P<0.01), although there was no statistically significant difference in the spontaneous recovery time between AHM and APM (9.8+/-2.9 minvs 10.0+/-3.6 min). It is concluded that the twitch responses of AHM may be a useful monitor of neuromuscular blockade in anesthetized patients in whom setting the blockade monitor on the patient's arms is difficult, although monitoring of twitch response of AHM is less sensitive than that of APM in case of vecuronium administration. PMID- 28921199 TI - Suppressive action of enflurane on dorsal horn neurons in rabbits. AB - The neurophysiologic mechanism of the suppressive action of enflurane on spinal nociceptive transmission was examined in rabbits with intact and with transected spinal cords. Enflurane suppressed nociceptive responses in both intact and transected spinal cord groups. The suppressive effects of enflurane were significantly greater in the intact group than in the transected group. The suppressive effects of enflurane were not reversed by the addition of 0.2 mg.kg-1 of naloxone. These results suggest that enflurane suppresses nociceptive responses by activating descending inhibitory systems and directly suppressing activity at the spinal level. This suppressive action of enflurane does not interact with the opioid receptor. PMID- 28921200 TI - Relief of intractable perineal pain by coccygeal nerve block in anterior sacrococcygeal ligament after surgery for rectal cancer. AB - Intractable perineal pain often appears in the anal region following abdominoperineal resection for the treatment of rectal cancer. In such cases, a subarachnoid block or transsacral block is generally used to control pain. However, these procedures sometimes cause complications such as dysuria or sensory paralysis of the pudendum. A new method of pain control is presented herein using absolute alcohol as a neurolytic agent to relieve localized perineal pain through a coccygeal nerve block in the anterior sacrococcygeal ligament. Five cadavers were necropsied to localize the coccygeal nerve. A loop consisting of S4, S5, and Co was found to exist in the space surrounded by the anterior surface of the coccygeal bone and the anterior sacrococcygeal ligament. Absolute alcohol was injected into this space. It is essential that the neurolytic agent remain localized in this space to avoid complications and to successfully block perineal pain. In all patients, we found that this method was extremely effective in blocking localized perineal pain without any complications. PMID- 28921201 TI - Sevoflurane reduced but isoflurane maintained hepatic blood flow during anesthesia in man. AB - The indocyanine green (ICG) clearance rate (K) and estimated total hepatic blood flow (THBF) were studied by the single injection technique. The THBF was estimated from the calculated circulating blood volume and the fixed extraction rate. The blood concentration of ICG was determined by the finger piece technique. Twenty-seven patients were randomly divided into three groups of nine and received 67% nitrous oxide, 33% oxygen, and the following volatile anesthetics: 0.8% halothane, 1.2% isoflurane, or 1.7% sevoflurane. ICG (0.5 mg.kg 1) was administered intravenously and K was determined three times following the injection. The K value in the halothane and sevoflurane groups decreased significantly 1 h after induction of anesthesia: from 0.188+/-0.048 to 0.142+/ 0.029 in the halothane group and from 0.178+/-0.027 to 0.155+/-0.021 in the sevoflurane group. There was no significant change in the K value in the isoflurane group throughout the study. PMID- 28921202 TI - Local cerebral blood flow measured by stable xenon CT during fentanyl-diazepam anesthesia. AB - We assessed the local cerebral blood flow (LCBF) in 40 patients under fentanyl diazepam anesthesia. The measurement of LCBF was made using 50%-70% stable xenon with 20 min of inhalation interval and a shuttle method for computed tomography imaging. All patients were anesthetized with 5.95+/-1.76 MUg.kg-1 fentanyl and 0.22+/-0.07 mg.kg-1 diazepam under mechanical ventilation during CBF measurement. The values and distribution of LCBF on non-affected hemisphere appeared to be unaltered by fentanyldiazepam anesthesia. We also assessed the cerebral carbon dioxide reactivity in 6 patients. The cerebral carbon dioxide reactivity, expressed as percentage change in LCBF per unit change in arterial carbon dioxide partial pressure, was 5.39+/-1.07, and there were no significant differences of reactivity among regions studied. In conclusion, we showed reference values of LCBF and carbon dioxide reactivity, measured by stable xenon-enhanced computed tomography, in patients under fentanyl-diazepam anesthesia. Carbon dioxide reactivity was preserved in all regions including gray matter, white matter, and basal ganglia. PMID- 28921203 TI - Does intraoperative analgesia modify the immune response in surgical patients? AB - The effect of epidural analgesia combined with inhalational anesthesia on the perioperative immune response was measured by using two-color analysis for the classification of functional lymphocyte subpopulations. Twenty-eight patients undergoing upper abdominal surgery were divided into four groups: group 1, isoflurane and with N2O group 2, sevoflurane with N2O; group 3, epidural analgesia plus isoflurane with N2O; and group 4, epidural analgesia and sevoflurane with N2O. Peripheral lymphocyte subpopulations were measured before, during, and after the operation by using anti-CD4 and anti-CD8 monoclonal antibodies. Moreover, two-color analysis was performed using two kinds of monoclonal antibodies: anti-CD4 and anti-CD29W, and anti-CD4 and anti-CD45R. A decrease in CD4+ cells and CD4+ CD29W+ cells (helper-inducer T lymphocytes) was observed after the operation in groups 1, 2, and 4. Additionally, stress hormones such as epinephrine (EP), norepinephrine (NE), and cortisol (CO) were measured. EP was increased during and after the operation in groups 1 and 2, and after the operation in group 4, but the level was maintained throughout the study in group 3. In conclusion, prevention of noxious stimuli originating from operative fields by epidural block could prevent the increase in EP and the reduction of helper inducer T cells in patients undergoing upper abdominal surgery. PMID- 28921204 TI - Changes of oxygen transport variables and serum lactate during open-chest cardiac massage in dogs. AB - The aim of this study was to investigate the influence of critically low cardiac output (CO) upon oxygen transport. We especially focused on the changes of mixed venous oxygen saturation (S-vO2) in the presence of oxygen consumption ([Formula: see text]) debts. Additionally, we examined the correlation between the cumulative oxygen deficit (Def[Formula: see text]) and serum lactate. Def[Formula: see text] was calculated as the integrated area under the tissue[Formula: see text]) deficit (baseline[Formula: see text]-acutal[Formula: see text]) and time curve. To produce severe low CO, we performed openchest cardiopulmonary resuscitation (CPR) in 11 anesthetized dogs for 1 h. We made the measurements before (baseline values) and during the CPR at 10-min intervals. Supplydependent[Formula: see text] was observed when CO decreased below 40 ml.min 1.kg-1. The mean value of S-vO2 in the range of supply-dependent[Formula: see text] was 13+/-2% and did not change significantly during 1 h of CPR. The changes of lactate from baseline values were linearly correlated with Def[Formula: see text] (r=0.62,P<0.01), but absolute values of serum lactate were not. PMID- 28921205 TI - Effects and interaction of nicardipine and volatile anesthetics in the rat heart lung preparation. AB - The effects of the calcium channel blocker nicardipine (N) and the volatile anesthetics halothane (H), enflurane (E), isoflurane (I), and sevoflurane (S) on myocardial metabolism after postischemic reperfusion were assessed in the isolated rat heart-lung preparation. Wistar-ST rats were randomly divided into six groups (each groupn=9) as follows: control (C) group, no drugs; N group, N (100 ng.ml-1); H group, 1% H and N; E group, 2.2% E and N; I group, 1.5% I and N; and the S group, 3.3% S and N. In the presence of the volatile anesthetics, the preparations were perfused for 10 min, made globally ischemic for 8 min, and then reperfused for 10 min. N 100 ng.ml-1 was administered 5 min before ischemia except in the C group. Three hearts in the C and H groups (eachn=9) and one heart in the E group (n=9) failed to recover from ischemia. The recovery times in the N, I and S groups were significantly shorter than controls. Although there was no significant difference in myocardial lactate concentrations among the groups, ATP content in the N, H, E, I and S groups was significantly higher than in controls. Glycogen content in the N, E, I and S groups was also significantly higher than in controls. These results suggest that N improves myocardial recovery from ischemia; however, in the presence of H or E it may cause significant myocardial depression. PMID- 28921206 TI - Decomposition of enflurane in soda lime. AB - The stability of enflurane in soda lime was examined. A product of enflurane decomposition was detected after the reaction of enflurane with soda lime, but not in the absence of soda lime. The production of this compound, identified as 1 chloro-1,2-difluorovinyl difluoromethyl ether by gas chromatography-mass spectrometry, increased with time and temperature. The same decomposition product was produced by the reaction of enflurane with potassium, sodium, or calcium hydroxides, and it was also detected in the gas phase at a maximum concentration of 1.29 ppm at 420 min after 5% enflurane circulated with 200 ml/min carbon dioxide gas in a closed anesthesia circle system with a soda lime canister and a model lung. We concluded that enflurane was decomposed to 1-chloro-1,2 difluorovinyl difluoromethyl ether by soda lime. PMID- 28921207 TI - Effects of saikosaponins on hepatic damage induced by halothane and hypoxia in phenobarbital-pretreated rats. AB - The effects of saikosaponins-a.-b1,-b2,-c, and-d on hepatic damage induced by halothane and hypoxia were investigated in the rat. Inhalation of halothane under a hypoxic condition significantly increased serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels in rats pretreated with phenobarbital compared with rats pretreated without phenobarbital. Pretreatment with saikosaponin (especially-a and-d) and with phenobarbital suppressed the increase in serum GOT and GPT levels in comparison with the rats treated with phenobarbital, halothane, and hypoxia. Histological observation also confirmed that pretreatment with saikosaponin had a protective effect against liver cell damage caused by halothane and hypoxia. Saikosaponins-a and-d, the most effective saikosaponins against hepatic damage, inhibited the increases in cytochrome P450 and NADPH-cytochromec reductase activity which are induced by phenobarbital treatment. Therefore, it is suggested that the cytoprotective effect of saikosaponin against halothane-induced hepatitis under hypoxia is caused by inhibition of phenobarbital stimulation of the enzyme system for hepatic drug metabolism. PMID- 28921208 TI - Electrophysiologic effects of volatile anesthetics, sevoflurane and halothane, in a canine myocardial infarction model. AB - The effects of sevoflurane and halothane on the effective refractory period (ERP) and ventricular activation were examined in a canine myocardial infarction model. Sevoflurane (1 MAC) reduced the heart rate and prolonged ERP in both normal and infarcted zones. A prolongation of ERP with sevoflurane was observed also during atrial pacing at a fixed rate, but the effect was less than during sinus rhythm. Sevoflurane either further delayed or blocked the delayed activation entirely in the infarcted zones with only slight effects on the activation of the normal zones. Halothane (1 MAC) prolonged ERP during sinus rhythm and atrial pacing, but to a lesser extent during the latter. Halothane also depressed ventricular activation in the infarcted zone during atrial pacing. In conclusion, sevoflurane as well as halothane selectively depresed the delayed activation and the prolongation of ERP in myocardial infarction, which may inhibit ventricular arrhythmias in myocardial infarction. PMID- 28921209 TI - Anesthetic management of a child with olmsted's syndrome. PMID- 28921210 TI - A schematic guideline of tracheal intubation in patients with extensive burns in the posthealing period. PMID- 28921211 TI - A case of Eisenmenger's syndrome treated with extracorporeal lung and heart assist in the postpartum period. PMID- 28921212 TI - Coronary artery spasm induced by respiratory alkalosis. PMID- 28921213 TI - Williams syndrome: Anesthetic management for balloon dilatation of supravalvular aortic stenosis. PMID- 28921214 TI - A successful second living renal transplant in a child with severe mitral stenosis. PMID- 28921215 TI - ST segment depression repeatedly induced by isoflurane inhalation. PMID- 28921216 TI - Anesthetic management for a patient with oculocerebrorenal (Lowe's) syndrome. PMID- 28921217 TI - Effect of lower and higher alcohol fuel synergies in biofuel blends and exhaust treatment system on emissions from CI engine. AB - The present study deals with performance, emission and combustion studies in a single cylinder CI engine with lower and higher alcohol fuel synergies with biofuel blends and exhaust treatment system. Karanja oil methyl ester (KOME), widely available biofuel in India, and orange oil (ORG), a low carbon biofuel, were taken for this study, and equal volume blend was prepared for testing. Methanol (M) and n-pentanol (P) was taken as lower and higher alcohol and blended 20% by volume with KOME-ORG blend. Activated carbon-based exhaust treatment indigenous system was designed and tested with KOME-ORG + M20 and KOME-ORG + P20 blend. The tests were carried out at various load conditions at a constant speed of 1500 rpm. The study revealed that considering performance, emission and combustion studies, KOME-ORG + M20 + activated carbon are found optimum in reducing NO, smoke and CO2 emission. Compared to KOME, for KOME-ORG + M20 + activated carbon, NO emission is reduced from 10.25 to 7.85 g/kWh, the smoke emission is reduced from 49.4 to 28.9%, and CO2 emission is reduced from 1098.84 to 580.68 g/kWh. However, with exhaust treatment system, an increase in HC and CO emissions and reduced thermal efficiency is observed due to backpressure effects. PMID- 28921218 TI - Effect of glucose concentration on the subarachnoid spread of tetracaine in the parturient. AB - We have studied the effect of glucose concentration on the spread of tetracaine spinal anesthesia in 40 parturient patients. Forty women undergoing cesarean section received a subarachnoid injection of tetracaine 8 mg dissolved in either 5% or 10% glucose solution. The maximum cephalad spread of analgesia [median (range)] was higher with 10% glucose [T3 (T4-C8)] than with 5% glucose [T4 (T5.5 T2)]. The time from the spinal injection to the maximum spread of analgesia (mean +/- SD) was significantly shorter with 10% glucose (15 +/- min) than with 5% glucose (28 +/- 16 min). The cumulative dose of ephedrine was higher with 10% glucose (19 +/- 10 mg) than with the 5% glucose (13+/- 8 mg). In tetracaine spinal anesthesia, the rate of onset of analgesia was faster and the maximum level of analgesia was higher in the 10% glucose solution than in the 5% glucose solution. PMID- 28921219 TI - Effects of total intravenous anesthesia with propofol on immuno-endocrine changes during surgical stress. AB - Endocrine factors and cytokines are crucial to host responses to stress and infection. Because surgery is a major stressful condition, it is necessary to understand the influence of specific anesthetic procedures on immune-endocrine responses. The purpose of this study was to compare total intravenous anesthesia with propofol with conventional inhalational anesthesia on circulating cortisol, adrenocorticotropic hormone (ACTH), prolactin, alpha-melanocyte-stimulating hormone (alphaMSH), and the cytokine, interleukin-6 (IL-6) in healthy patients undergoing tubal ligation. The results show that circulating cortisol was significantly suppressed ous propofol completely abolished the response of circulating cortisol to surgery. Because ACTH responses to surgery were similar in the two groups, the inhibition likely occurred directly on the adrenal glands. This study is the first to report the effects of anesthesia on circulating alphaMSH, which was decreased significantly after induction with both anesthetic techniques and was still depressed at 90 min in the propofol patients. Other aspects of immune-endocrine responses to surgery were similar irrespective of anesthetic type, which further suggests a specific suppression of adrenal function by propofol. PMID- 28921220 TI - Comparison of the placental transfer of halothane, enflurane, sevoflurane, and isoflurane during cesarean section. AB - The concentrations of placental transfer of halothane (H), enflurane (E), sevoflurane (S), and isoflurane (I) were measured in 46 patients during cesarean section. The mean inhalation times of H (0.5%), E (1%), S (0.8%), and I (0.6%) were 13 min 27 s, 13 min 49s, 13 min 20s, and 8 min 8s, respectively. The mean concentrations in the maternal artery (MA) were 5.2mg.dl-1 in H, 12.3 mg.dl-1 in E, 5.2mg.dl-1 in S, and 2.4mg.dl-1 in I. The concentration ratio between the MA and the fetal umbilical vein (UV) was 0.44 for H, 0.49 for E, and 0.38 for S, and these ratios were not significantly different for these anesthetics. Although the concentration ratio for I (0.27) was significantly lower than those of the other three anesthetics, the UV:MA ratio was calculated to be 0.4 for an inhalation time 13 min. Our result, therefore, suggests that if the inhalation times were equal, the ratios of placental transfer would not differ among these four inhalational anesthetics. The Apgar scores in these four groups were not different from that in the group given only 66% nitrous oxide in oxygen as anesthetic (N2O group). The cardiovascular changes induced by skin incision were bigger in the N2O group than in the other groups. The use of a low concentration of H, E, S, or I is, therefore, suggested to be a useful and acceptable anesthetic method for cesarean section. PMID- 28921221 TI - Endocrine responses to total intravenous anesthesia with droperidol, fentanyl, and ketamine in cardiac patients. AB - Ketamine-induced sympathetic stimulation can be inhibited by administration of sedatives such as benzodiazepines, droperidol, or opioids. We have developed total intravenous anesthesia with ketamine in combination with droperidol and fentanyl (DFK) and have used this anesthetic method in more than 4000 surgical cases. In this study, we compared DFK in cardiac surgery with isoflurane-fentanyl anesthesia (AOI-F). Fourteen patients undergoing aortocoronary artery bypass graft surgery were randomly assigned to the DFK or AOI-F groups. The endocrine responses of the patients were evaluated from the plasma, levels of cortisol, antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), and aldosterone. In both groups, anesthesia per se did not induced any significant changes in the hormones. Although cortisol and ADH increased during surgery, ANP and aldosterone did not change appreciably. All hormones were significantly elevated after the end of cardiopulmonary bypass. There were no significant differences in any of the hormones, blood pressure, and heart rate measured at different points in both groups. These results showed that DFK anesthesia as a total intravenous anesthesia deserves to be studied in more depth. PMID- 28921222 TI - Spontaneous respiration should be avoided in frequency domain analysis of heart rate variability. AB - To determine whether spontaneous respiration is suitable for frequency domain analysis of heart rate (R-R interval) variability, we studied 15 volunteers (5 men and 10 women, aged 22-34 years) and evaluated the reproducibility of the power spectrum. Electrocardiograms were recorded for 5 min each with spontaneous and rate-controlled respiration (15 breaths.min-1), repeating the same protocol 1 week later. Fast Fourier transformation was performed using the digitized data of the R-R intervals. Mean heart rate, arterial pressure, and plasma catecholamines remained constant during the measurements. In spontaneous respiration, however, the respiratory rate was significantly lower during the second measurement (9.4+/ 2.1 breaths.min-1) than during the first measurement (10.9+/-2.6 breaths.min-1), and the low-frequency power increased from 2.61+/-2.36 to 5.14+/-5.06 sec2.Hz 1.10-3. After deleting five data sets because the respiratory peak was inseparable from the low-frequency area, there was no correlation in power spectra in four out of ten subjects between the two measurements. Data were comparable for rate-controlled respiration. Since respiratory parameters strongly influenced the low- and the high-frequency R-R interval power spectra, spontaneous respiration should be avoided. A constant respiratory condition is required to interpret results of frequency domain analysis of R-R interval variability. PMID- 28921223 TI - Leukocytosis after fluid loading and induction of epidural anesthesia. AB - The present study shows that leukocytosis occurs from fluid loading and from the small amounts of adrenaline given epidurally. Five healthy volunteers received an intravenous infusion of 25 ml.kg-1 b.w. of Ringer's acetate solution over 15, 30, 45, and 80 min, and epidural anesthesia (EDA) was induced in 25 urology patients using mepivacaine 2% with or without adrenaline 1?200 000. In the volunteers, we found that the total leukocyte count increased by up to 33% within 1 h after rapid volume loading. This increase was accounted for by neutrophils and lymphocytes. In the patients, the leukocyte count increased by 32% during the onset of EDA when mepivacaine with adrenaline was used. This increase was accounted for by lymphocytes. Our results suggest that caution is needed when interpreting the importance of a raised leukocyte count in samples taken in association with fluid loading and also when EDA is induced by a local anesthestic solution that contains adrenaline. PMID- 28921224 TI - Does cyclosporine affect the duration of action of vecuronium in renal transplant recipients? AB - The duration of action of vecuronium was tested in 41 surgical patients to evaluate whether cyclosporine modulates the action of vecuronium. The patients were divided into three groups: 12 patients with normal renal function (group A); 14 renal transplant recipients who had received cyclosporine before surgery (group B); and 15 patients with chronic renal failure undergoing surgery other than renal transplantation and who did not receive cyclosporine (group C). The times to 10% and 20% recovery of the first twitch (REC 10 and REC 20) after intravenous administration of vecuronium 0.12 mg.kg-1 were measured using an electromyogram in each group. REC 10 and REC 20 were significantly prolonged in the patients of group B (REC 10: 93+/-18 min, REC 20: 110+/-14 min) and group C (REC 10: 80+/-10 min, REC 20: 89+/-12 min) than in the patients of group A (REC 10: 39+/-5 min, REC 20: 45+/-5 min) (P<0.01). There was no significant difference in the duration of action of vecuronium between the patients of groups B and C. In summary, cyclosporine did not prolong the duration of action of vecuronium in the renal transplant recipients when the same dose was administered compared with the patients with chronic renal failure who did not receive cyclosporine. PMID- 28921225 TI - N-methyl-D-aspartate receptor agonists and antagonists partially affect the duration of ketamine anesthesia in the rat. AB - The effects of intracerebroventricular injection of excitatory amino acids which act on the N-Methyl-D-aspartate (NMDA) receptor complex on the duration of loss of righting reflex (DLRR) induced by intravenous injection to ketamine (20 mg/kg) were investigated in rats. Ketamine-induced DLRR was 10.3 min, but NMDA receptor agonistsD-alanine (200 MUg) or NMDA (0.15 MUg) did not change DLRR. However,D alanine combined with NMDA significantly shortened DLRR (7.7 min). The NMDA receptor antagonist 7-chlorokynurenic acid (10 MUg) alone prolonged DLRR significantly (16.2 min), but not when combined withD-alanine. These data suggest that NMDA receptor blockade contributes at least partially to the mechanism of ketamine anesthesia. PMID- 28921226 TI - The effects of isoflurane and sevoflurane on the left ventricular end-systolic pressure-volume relation in dogs. AB - The influence of two inhalational anesthetics, isoflurane and sevoflurane, on the end-systolic pressure-volume relations (ESPVR) of the left ventricle (LV) in situ was investigated in open-chest dogs anesthetized with alpha-chloralose. The LV volume was measured by a conductance catheter while the LV pressure was measured by a tipmicromanometer. The end-systolic elastance (Ees) of the LV was calculated as the slope of ESPVR which was elicited when the inferior vena cava was transiently occluded. The dogs were randomly assigned to two groups, receiving either 1.3% and 2.6% isoflurane (n=6) or 2.3% and 4.6% sevoflurane (n=6), which are equivalent to 1 and 2 MAC of isoflurane or sevoflurane, respectively. Both isoflurane and sevoflurane produced dose-dependent decreases in the cardiac output to a similar degree. Isoflurane and sevoflurane caused equivalent decreases in Ees of 23% and 16% at 1 MAC, and 48% and 41% at 2 MAC, respectively. Dobutamine 3 MUg.kg-1.min-1 produced a simultaneous restoration of Ees and recovery of the cardiac output at 1 and 2 MAC of both isoflurane and sevoflurane. We thus conclude that the depressant effect of sevoflurane on cardiac contractility is almost identical to that of isoflurane in the dog, and they are both reversed by the use of a low dose of dobutamine. PMID- 28921227 TI - Pendelluft is not the major contributor to respiratory insufficiency in dogs with flail chest: a mathematical analysis. AB - "Pendelluft", or out-of-phase movement of the airway gas between the intact and flait-chest-side lungs has long been believed to be the major contributor to respiratory dysfunction in patients with flail chest. However, conflicting findings have also been reported mainly from animal studies. The aim of this study was to provide a mathematical projection on this classical problem. We measured respiratory impedance (ZRS) of dogs with flail chest using a pseudorandom forced oscillation method. A mathematical model implementing flail chest was fitted toZRS. The fitted results were used in simulating the mechanical behavior of a respiratory system with flail chest during spontaneous breathing. Our results suggest that the paradoxical movement of breathing between the flail segment and the intact chest wall does not create substantial pendelluft and that alveolar hypoventilation is created by the wasting movement of the flail segment which interferes with effective thoracic expansion. PMID- 28921229 TI - Effects of propofol on guinea pig respiratory smooth muscle. AB - The effects of propofol on the tone of guinea pig respiratory smooth muscle was studied both in vitro and in vivo. In vitro, the activity of propofol on tracheal smooth muscle was investigated using a force displacement transducer for isometric tension responses. Isoproterenol was used as the control. Concentration response curves to propofol and isoproterenol were obtained using a cumulative dose schedule. Propofol (0.32-10.24 MUg.ml-1) relaxed the tracheal smooth muscle in a concentration-dependent manner, but was less potent than isoproterenol (equipotent molar ratio 29 000?1). This effect of propofol was not affected by prior administration of atropine, propranolol, prazocin, or yohimbine, and it did not appear to be mediated via calcium antagonism. The solvent for propofol (10% intralipid) had no effect on the tracheal smooth muscle in vitro. The in vivo study measured the effect of propofol on lung pressure in deeply anesthetized guinea pigs using histamine induced bronchoconstriction. Propofol (1-4.5 mg.kg-1, i.v.) exhibited neither relaxant nor constrictor effects. It is possible that the effects of propofol observed in vitro are due to nonspecific action, while the finding of no effect in vivo could be due to different tissue sensitivity to propofol, i.e., tracheal smooth muscle may be more responsive than bronchial smooth muscle. Propofol does not seem to have any deleterious effects on airway smooth muscle. PMID- 28921228 TI - Halothane suppresses the increase in intracellular calcium concentration of isolated rat myocytes during hydrogen peroxide perfusion. AB - Ischemia-reperfusion injury is probably caused by the generation of oxygen free radicals. The final common pathway to cell injury may be mediated by intracellular calcium overloading induced by oxygen free radicals. Volatile anesthetics have been shown to improve myocardial function following reperfusion. To determine whether or not oxygen radicals are involved in the mechanism by which volatile anesthetics improve myocardial function following reperfusion, we investigated the effects of hydrogen peroxide (H2O2) on the intracellular calcium concentration ([Ca2+]i) in isolated rat ventricular cells. First, the effects of volatile anesthetics, halothane, isoflurane, or sevoflurane, on [Ca2+]i were studied in the absence of H2O2. Next, myocytes were perfused with volatile anesthetics in the presence of H2O2. [Ca2+]i was measured using fura-2, a Ca2+ sensitive fluorescent dye. None of the volatile anesthetics changed [Ca2+]i in the absence of H2O2. In the presence of H2O2, [Ca2+]i gradually increased during H2O2 perfusion. Halothane delayed the onset of the increase in [Ca2+]i induced by H2O2, whereas sevoflurane and isoflurane accelerated the onset. Furthermore, sevoflurane caused more pronounced accumulation of intracellular calcium than did halothane and isoflurane. Therefore, the reduction of excessive intracellular calcium accumulation caused by halothane may have beneficial effects on myocardial function following reperfusion. PMID- 28921230 TI - Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain. AB - To study the effects of repeated ketamine administration (0: saline, 12.5, 25, and 50 mg.kg-1 every 3 days for a total of five times, subcutaneously) on the central muscarinic acetylcholine receptors (mAchRs), receptor binding assays of mAchR were carried out in the forebrain of mice, using [3H]quinuclidinyl benzilate ([3H]QNB) as a ligand. We also examined whether repeated ketamine administration could modify the sensitivity to scopolamine (0.5 mg.kg-1) (a muscarinic antagonist). Repeated ketamine administration produced a significant increase in the receptor density values (Bmax) for [3H]QNB (1520+/-51 fmol.mg protein-1 for the control group, 1650+/-43 for the 12.5 mg.kg-1 group, 1966+/-70 for the 25 mg.kg-1 group and 2064+/-125 for the 50 mg.kg-1 group) (P<0.05, when the 25 mg.kg-1 and 50 mg.kg-1 groups were compared to the control group) without any change in apparent affinity. Repeated ketamine reduced scopolamine-induced hyperlocomotion at 50 mg.kg-1 (P<0.05). We conclude that repeated ketamine administration produces up-regulation of mAchRs, which is probably associated with the altered Ach transmission of the central nervous system. PMID- 28921231 TI - Effects of morphine on visceral nociception evoked by colorectal distension in rats: comparative examinations of electrophysiological and behavioral responses. AB - The purpose of this study was to compare the effects of intravenously administered morphine on electrophysiological and behavioral responses to colorectal distension (CRD) and to examine the influence of noxious stimuli applied to another part of the body (a laminectomy) on the visceromotor response to CRD. The effects of morphine (0.1-6.4 mg.kg-1) were examined in rate anesthetized with pentobarbital. Electrophysiological (n=16) and behavioral experiments (n=47) were done. Electrophysiological experiments were conducted to examine the effects of morphine on the responses of visceral dorsal horn neurons to CRD; behavioral studies were conducted to compare the effects of morphine with and without a laminectomy (intact group:n=24; laminectomy group:n=23). Morphine suppressed the evoked activities of the visceral dorsal horn neurons in a dose dependent manner. Similar suppression of the behavioral visceromotor response was observed. Visceromotor thresholds were significantly lower in the intact group than in the laminectomy group during the control study. When morphine was administered, the visceromotor thresholds in both groups increased to a similar level. Behavioral and neurophysiological responses to CRD were suppressed in a similar fashion by morphine. Although laminectomy affected the threshold values of CRD for visceromotor responses, the laminectomy per se plays an insignificant role when adequate morphine is administered. PMID- 28921232 TI - General anesthesia for progressive external ophthalmoplegia syndrome. PMID- 28921233 TI - Continuous positive airway pressure oxygenation during one-lung ventilation with 50% nitrous oxide and isoflurane in oxygen. PMID- 28921234 TI - Oral clonidine relieved postoperative pain after pheochromocytoma resection. PMID- 28921235 TI - Relationship between clamping of the unilateral internal carotid artery and transient slowing of electrical activity in the bilateral hemisphere. PMID- 28921236 TI - Pressure control ventilation in a patient with low respiratory compliance and high airway resistance. PMID- 28921237 TI - Prediction of the distance from the skin to the lumbar epidural space in ex premature infants. PMID- 28921238 TI - Tracheal intubation through the laryngeal mask. PMID- 28921239 TI - Anesthesia and Takayasu's arteritis. PMID- 28921240 TI - A Satellite Meeting of the 11th World Congress of Anaesthesiologists. PMID- 28921242 TI - Use of computer-assisted design and manufacturing to localize dural venous sinuses during reconstructive surgery for craniosynostosis. AB - OBJECTIVE: Cranial vault remodeling surgery for craniosynostosis carries the potential risk of dural venous sinus injury given the extensive bony exposure. Identification of the dural venous sinuses can be challenging in patients with craniosynostosis given the lack of accurate surface-localizing landmarks. Computer-aided design and manufacturing (CAD/CAM) has allowed surgeons to pre operatively plan these complex procedures in an effort to increase reconstructive efficiency. An added benefit of this technology is the ability to intraoperatively map the dural venous sinuses based on pre-operative imaging. We utilized CAD/CAM technology to intraoperatively map the dural venous sinuses for patients undergoing reconstructive surgery for craniosynostosis in an effort to prevent sinus injury, increase operative efficiency, and enhance patient safety. Here, we describe our experience utilizing this intraoperative technology in pediatric patients with craniosynostosis. METHODS: We retrospectively reviewed the charts of children undergoing reconstructive surgery for craniosynostosis using CAD/CAM surgical planning guides at our institution between 2012 and 2016. Data collected included the following: age, gender, type of craniosynostosis, estimated blood loss, sagittal sinus deviation from the sagittal suture, peri operative outcomes, and hospital length of stay. RESULTS: Thirty-two patients underwent reconstructive cranial surgery for craniosynostosis, with a median age of 11 months (range, 7-160). Types of synostosis included metopic (6), unicoronal (6), sagittal (15), lambdoid (1), and multiple suture (4). Sagittal sinus deviation from the sagittal suture was maximal in unicoronal synostosis patients (10.2 +/- 0.9 mm). All patients tolerated surgery well, and there were no occurrences of sagittal sinus, transverse sinus, or torcular injury. CONCLUSIONS: The use of CAD/CAM technology allows for accurate intraoperative dural venous sinus localization during reconstructive surgery for craniosynostosis and enhances operative efficiency and surgeon confidence while minimizing the risk of patient morbidity. PMID- 28921241 TI - Evaluating the efficacy of vaginal dehydroepiandosterone for vaginal symptoms in postmenopausal cancer survivors: NCCTG N10C1 (Alliance). AB - BACKGROUND: Women with estrogen deficiencies can suffer from vaginal symptoms that negatively impact sexual health. This study evaluated vaginal dehydroepiandrosterone (DHEA) for alleviation of vaginal symptoms. METHODS: This three-arm randomized, controlled trial evaluated DHEA 3.25 mg and DHEA 6.5 mg, each compared to a plain moisturizer (PM) over 12 weeks, to improve the severity of vaginal dryness or dyspareunia, measured with an ordinal scale, and overall sexual health using the Female Sexual Function Index (FSFI). Postmenopausal women with a history of breast or gynecologic cancer who had completed primary treatment, had no evidence of disease, and reported at least moderate vaginal symptoms were eligible. The mean change from baseline to week 12 in the severity of vaginal dryness or dyspareunia for each DHEA dose was compared to PM and analyzed by two independent t tests using a Bonferroni correction. RESULTS: Four hundred sixty-four women were randomized. All arms reported improvement in either dryness or dyspareunia. Neither DHEA dose was statistically significantly different from PM at 12 weeks (6.25 mg, p = .08; 3.25 mg, p = 0.48), although a significant difference at 8 weeks for 6.5 mg DHEA was observed (p = 0.005). Women on the 6.5 mg arm of DHEA reported significantly better sexual health on the FSFI (p < 0.001). There were no significant differences in provider-graded toxicities and few significant differences in self-reported side effects. CONCLUSION: PM and DHEA improved vaginal symptoms at 12 weeks. However, vaginal DHEA, 6.5 mg, significantly improved sexual health. Vaginal DHEA warrants further investigation in women with a history of cancer. PMID- 28921243 TI - Comparative evaluation of TIVA with propofol-fentanyl and thiopental-sevoflurane anesthesia using laryngeal mask airway for diagnostic bronchoscopy. AB - PURPOSE: Diagnostic bronchoscopy is performed under general anesthesia in our hospital. This study was designed to determine whether total intravenous anesthesia (TIVA) with propofol-fentanyl provides more stable hemodynamics using a laryngeal mask airway (LMA) for diagnostic bronchoscopy than thiopental sevoflurane anesthesia. METHODS: Sixty patients scheduled for diagnostic bronchoscopy were randomly assigned to two groups. TIVA with propofol-fentanyl was induced with intravenous fentanyl 2 MUg.kg-1 and propofol 2 mg.kg-1 and maintained with continuous infusion of propofol with fentanyl. Thiopental sevoflurane anesthesia was induced with thiopental 5 mg.kg-1 and maintained with N2O/O2/sevoflurane. Insertion of the LMA was facilitated with vecuronium 0.1 mg.kg-1 i.v. in both groups. Ventilation was controlled, and administration of propofol and sevoflurane was continued until the end of the procedure. The LMA was removed when the patient was able to open his or her mouth. RESULTS: During TIVA, the mean arterial pressure and rate pressure product decreased significantly from induction until 20 min after the start of the procedure, and they were maintained at around 70 mmHg and 7000, respectively, during the procedure. There were no significant differences in heart rate,[Formula: see text] and[Formula: see text]. In thiopental-sevoflurane anesthesia, the mean arterial pressure and rate pressure product decreased significantly after induction and increased significantly from insertion of the LMA until removal of the LMA. Heart rate increased significantly after insertion of the LMA, insertion of the bronchoscope, and removal of the LMA. There were no significant differences in[Formula: see text] and[Formula: see text]. CONCLUSION: TIVA with propofol-fentanyl in conjunction with an LMA performs better than thiopental sevoflurane anesthesia for diagnostic bronchoscopy because of its superior maintenance of cardiovascular stability. PMID- 28921244 TI - A comparison between sevoflurane and propofol when combined with continuous epidural blockade in adult patients. AB - PURPOSE: The effects of sevoflurane and propofol, in combination with continuous epidural blockade, on blood pressure control and time of recovery from anesthesia were compared. METHODS: Adult patients were allocated to either a sevoflurane (n=54) or a propofol (n=64) group. Anesthesia was induced with either inhalation of 5% sevoflurane or intravenous administration of 2 mg.kg-1 propofol. After an injection of vecuronium, the trachea was intubated and anesthesia was maintained with continuous epidural blockade, air/oxygen, and sevoflurane or propofol. The systolic arterial pressure was maintained within +/-30% of that obtained on the ward. RESULTS: The number of cases requiring a change in the dose of either anesthetics or vasoactive agents was not different between the groups. However, the arterial pressure and heart rate were more stable in the propofol group than in the sevoflurane group (P<0.05). The length of time before tracheal extubation was shorter in the sevoflurane group (10.4+/-5.2 min, mean+/-SD) than the propofol group (15.0+/-11.2 min,P<0.05). CONCLUSION: Propofol anesthesia, in combination with continuous epidural blockade, results in more stable intraoperative hemodynamics than sevoflurane anesthesia, but requries a longer recovery time and results in larger interindividual variability than sevoflurane anesthesia. PMID- 28921245 TI - Effect of anesthetics on the self-sustained oscillation in an artificial membrane induced by repetitive conformational change of DOPH molecules between hydrophilic and hydrophobic phases. AB - PURPOSE: The mechanism of anesthesia was approached from a study of an artificial excitable membrane that well reproduced the active electrical properties of the nerve membrane. METHODS: Self-sustained oscillations of the membrane potential in a model membrane in which dioleyl phosphate (DOPH) was infiltrated into the pores of a millipore filter were utilized to investigate the effect of volatile anesthetic agents on the repetitive conformational change of DOPH molecules between hydrophilic multibilayers and hydrophobic oil droplets, while this process was coupled with diffusion of K+ across the membrane placed between KCl aqueous solutions. RESULTS: The period of the self-sustained oscillations increased due to the addition of volatile anesthetics to the aqueous solutions, and there were critical values of concentrations of volatile anesthetics above which the self-sustained oscillations disappeared. CONCLUSION: The volatile anesthetic agents affected the hydrophobic oil droplets of the DOPH molecules and impeded their repetitive conformational change between the hydrophilic and hydrophobic phases, just as local anesthetics had been reported to do. PMID- 28921246 TI - Effects of KRN2391-induced hypotension on the endocrine system and carbohydrate metabolism in halothane-anesthetized dogs. AB - PURPOSE: The hemodynamic profiles of KRN2391-induced hypotension have been reported to be a hyperdynamic state. However, the endocrine effects of KRN2391 induced hypotension remain to be elucidated. We investigated the endocrine and metabolic effects of KRN2391-induced hypotension on the plasma concentrations of catecholamines, aldosterone, cortisol, glucose, and lactic acid and on plasma renin activity. METHODS: Eight dogs were anesthetized with 087% halothane in oxygen. After a baseline period, mean arterial pressure (MAP) was lowered to 60 mmHg for 60min by the infusion of KRN2391. RESULTS: KRN2391-induced hypotension resulted in a 50% decrease (P<0.01) in MAP due to a 80% reduction (P<0.01) in systemic vascular resistance associated with a 224% increase (P<0.01) in cardiac index. Plasma norepinephrine concentrations increased (P<0.01) after 60 min of hypotension. Plasma epinephrine concentrations and plasma renin activity both increased (P<0.05) during the hypotensive period. Plasma aldosterone concentrations remained unchanged during the hypotensive period, but then increased (P<0.05) after termination of KRN2391. Plasma cortisol concentrations remained unchanged throughout the observation period. Plasma glucose concentrations increased (P<0.01) during the hypotensive period. Plasma lactic acid concentrations increased (P<0.01) throughout the observation period. CONCLUSION: KRN2391-induced hypotension activates the sympathetic nervous system and consequently may modulate the renin-angiotensin-aldosterone axis and carbohydrate metabolism. PMID- 28921247 TI - Muscle lactate concentration during experimental hemorrhagic shock. AB - PURPOSE: Blood lactate concentration does not correspond well to oxygen transport variables during circulatory shock. Prolonged washout of lactate from tissues during shock has been reported. This study was designed to test the hypothesis that the discrepancy between serum lactate and oxygen metabolism is caused by the failure of lactate to wash out from the tissues and that tissue lactate may reflect the oxygen metabolism better. METHODS: Using a canine model of hemorrhagic shock, lactate concentration measured in a muscle biopsy specimen and in arterial blood was compared with the cumulative deficit in oxygen consumption. RESULT: The cumulative deficit in oxygen consumption correlated with the concentration of lactate in muscle (r= 0.67,P<0.01) but not with that in blood. During shock, all muscle lactate levels were greater than those in serum, and a linear relationship was demonstrated between arterial(X) and muscle(Y) lactate levels (Y=2.45X-2.72,r=0.82,P<0.001). The muscle/serum lactate concentration ratio increased from 1 to 2.5 as the blood volume decreased. CONCLUSION: In the setting of experimental hemorrhagic shock, only tissue lactate levels reflected the true deficit in oxygen metabolism. The difference between lactate levels in muscle and serum represented the severity of the shock. PMID- 28921248 TI - Attenuation of nitric oxide-stimulated soluble guanylyl cyclase from the rat brain by halogenated volatile anesthetics. AB - PURPOSE: The present study was undertaken to examine whether interaction between halogenated volatile anesthetics and nitric oxide (NO) at soluble guanylyl cyclase (sGC) would occur in rat brain. METHODS: A soluble brain fraction was prepared from extensively perfused Sprague-Dawley rat brains by centrifugation and used as the source of sGC. sGC was incubated with NO and halogenated volatile anesthetics, and cGMP production was determined by enzyme immunoassay in aliquots of the supernatant. RESULTS: Halothane and sevoflurane produced significant (P<0.01) and dose-dependent inhibition of NO-stimulated sGC activity over a range of NO concentrations (2*10-9 to 2*10-5 M). Among the anesthetics, halothane tended to have a large inhibitory effect on NO-stimulated sGC activity, which was, however, not significant. sGC activity was also inhibited by both anesthetics (P<0.05) in the absence of NO stimulation. GTP dose-dependently increased both NO-stimulated and-nonstimulated sGC activities. Halothane and sevoflurane decreased these activities (P<0.01), but the inhibition by these anesthetics was not significant at higher GTP concentrations. CONCLUSION: These results suggest that halogenated volatile anesthetics can attenuate the activity of NO-stimulated sGC by competing with NO for the NO binding site on the enzyme. PMID- 28921249 TI - Continuous measurement of hematocrit using an intravascular catheter equipped with a fiberoptic transmission cell. AB - PURPOSE: The purpose of this study was to measure intravascular hematocrit values continuously by using a fiberoptic probe based on near-infrared photometry. METHODS: We produced a catheter 1.5 mm in diameter that use a pair of plastic fibers. One of the fibers, the measuring fiber, was used to measure the optical density of blood, and the other, the reference fiber, was used to decrease the signal-to-noise ratio. We employed an 805-nm laser diode as the light source. Two photodiodes were used to measure the intensity of the light transmitted through the two fibers, and the output signals were amplified and sent to a personal computer through an analog-to-digital converter. RESULTS: The hematocrit values obtained by this fiberoptic continuous measurement agreed well with those obtained by microcentrifugation within physiological ranges. CONCLUSIONS: This method is effective for monitoring the rapid changes in hematocrit. PMID- 28921250 TI - Iontophoresis using a local anesthetic for the treatment of pediatric acute herpetic pain. PMID- 28921251 TI - A case of multiple aneurysms of the vein of Galen with heart failure due to persistent fetal circulation. PMID- 28921252 TI - Propofol in a patient at risk for malignant hyperthermia: report of a case. PMID- 28921254 TI - Functional closed-system anesthesia using a function-equipped anesthesia machine and time-cycled ventilator. PMID- 28921253 TI - Alteration of regional brain oxygen saturation (rSO2) in a patient with cerebral damage after aortic arch replacement: carbon dioxide reactivity monitored by near infrared spectroscopy suggested inverse steal phenomenon. PMID- 28921255 TI - Removal of dried tenacious mucus plug from the trachea of an asthmatic patient with bronchoscopic forceps. PMID- 28921256 TI - Relation Between Different Measures of Glycemic Exposure and Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes Mellitus: An Observational Cohort Study. AB - INTRODUCTION: This retrospective cohort study investigated the relation between different measures of glycemic exposure and micro- and macrovascular complications among patients with type 2 diabetes. METHODS: The analysis included patients receiving oral antihyperglycemic agents between 1 January 2006 and 31 December 2014 from the General Practitioner Database from the PHARMO Database Network. All recorded HbA1c levels during follow-up were used to express glycemic exposure in four ways: index HbA1c, time-dependent HbA1c, exponential moving average (EMA) and glycemic burden. Association between glycemic exposure and micro-/macrovascular complications was analyzed by estimating hazard ratios and 95% confidence intervals using an adjusted (time-dependent) Cox proportional hazards model. RESULTS: The analysis included 32,725 patients (median age, 65 years; 47% female). Median follow-up was 5.4 years; median number of HbA1c measurements per patient was 18.0. From all measures, HbA1c at index showed the weakest relation between all micro-/macrovascular complications, with coronary artery disease (CAD) having the highest HR (95% CI): 1.18 (1.04-1.34) for HbA1c >=64 mmol/mol (8%). The time-dependent HbA1c model showed a significant association only for microvascular complications, with retinopathy having the highest HR (95% CI): 1.55 (1.40-1.73) for HbA1c >=64 mmol/mol (8%). EMA-defined exposure showed similar findings, although the effect of retinopathy was more pronounced [HR (95% CI): 1.81 (1.63-2.02) for HbA1c >=64 mmol/mol (8%)] and was also predictive for CAD [HR (95% CI): 1.29 (1.10-1.50) for HbA1c >=64 mmol/mol (8%)]. A statistically significant relation with glycemic burden was found for all selected micro-/macrovascular complications, with retinopathy having the highest HR (95%): 2.60 (2.19-3.07) for glycemic burden years >3. CONCLUSION: This study shows that greater and more prolonged exposure to hyperglycemia increases the risk of micro- and macrovascular complications. FUNDING: Janssen Pharmaceutica NV. PMID- 28921257 TI - Energy recovery from wastewater treatment plants through sludge anaerobic digestion: effect of low-organic-content sludge. AB - During anaerobic digestion, low-organic-content sludge sometimes is used as feedstock, resulting in deteriorated digestion performance. The operational experience of conventional anaerobic digestion cannot be applied to this situation. To investigate the feature of low-organic-content sludge digestion and explain its intrinsic mechanism, batch experiments were conducted using designed feedstock having volatile solids (VS) contents that were 30-64% of total solids (TS). The results showed that the accumulative biogas yield declined proportionally from 173.7 to 64.8 ml/g VS added and organic removal rate decreased from 34.8 to 11.8% with decreasing VS/TS in the substrate. The oligotrophic environment resulting from low-organic-content substrates led to decreased microbial activity and a switch from butyric fermentation to propionic fermentation. A first-order model described the biogas production from the batch experiments very well, and the degradation coefficient decreased from 0.159 to 0.069 day-1, exhibiting a positive relation with organic content in substrate. The results observed here corroborated with data from published literature on anaerobic digestion of low-organic-content sludge and showed that it may not be feasible to recover energy from sludge with an organic content lower than 50% through mono digestion. PMID- 28921258 TI - Models of kleptoparasitism on networks: the effect of population structure on food stealing behaviour. AB - The behaviour of populations consisting of animals that interact with each other for their survival and reproduction is usually investigated assuming homogeneity amongst the animals. However, real populations are non-homogeneous. We focus on an established model of kleptoparasitism and investigate whether and how much population heterogeneities can affect the behaviour of kleptoparasitic populations. We consider a situation where animals can either discover food items by themselves or attempt to steal the food already discovered by other animals through aggressive interactions. Representing the likely interactions between animals by a network, we develop pairwise and individual-based models to describe heterogeneities in both the population structure and other individual characteristics, including searching and fighting abilities. For each of the models developed we derive analytic solutions at the steady state. The high accuracy of the solutions is shown in various examples of populations with different degrees of heterogeneity. We observe that highly heterogeneous structures can significantly affect the food intake rate and therefore the fitness of animals. In particular, the more highly connected animals engage in more conflicts, and have a reduced food consumption rate compared to poorly connected animals. Further, for equivalent average level of connectedness, the average consumption rate of a population with heterogeneous structure can be higher. PMID- 28921260 TI - Renal toxicity of compound A with sevoflurane anesthesia: The benefits of sevoflurane appear to outweigh the risks. PMID- 28921261 TI - Predictors of inotropic support during weaning from cardiopulmonary bypass in coronary artery bypass grafting surgery. AB - Early or prophylactic inotropic drug administration is occasionally required to facilitate separation from cardiopulmonary bypass (CPB) in cardiac surgery. However, it is not without untoward effects and should be conducted on the basis of rational criteria. The purpose of our study was to clarify variables associated with the requirement for inotropic support during separation from CPB and to testify whether pre-CPB left ventricular (LV) function, as evaluated by transesophageal echocardiography (TEE), is one of the significant variables. Clinical profile data and TEE findings were retrospectively analyzed for 91 patients who had received elective primary isolated coronary artery bypass grafting (CABG) surgery. Post-CPB inotropic drug administration initiated prior to aortic decannulation was considered inotropic support for terminating CPB. Stepwise multiple logistic regression analysis identified pre-CPB LV regional wall motion abnormalities (RWMA), NYHA class, age, and duration of CPB (in order of significance) as factors associated with inotropic support for discontinuing CPB. Pre-CPB LV enddiastolic area or fractional area change was not a significant variable in the multivariate model. Our result suggests that evaluation of pre CPB LV RWMA is useful in predicting the need of inotropic intervention during separation from CPB in patients undergoing CABG surgery. PMID- 28921259 TI - Epigenetic effects of the pregnancy Mediterranean diet adherence on the offspring metabolic syndrome markers. AB - Metabolic syndrome (MS) has a multifactorial and not yet fully clarified origin. Insulin resistance is a key element that connects all the accepted components of MS (obesity, dyslipemia, high blood pressure, and hyperglycemia). There is strong evidence that epigenetic changes during fetal development are key factors in the development of MS. These changes are induced by maternal nutrition, among different factors, affecting the intrauterine environment. The Mediterranean diet has been shown to be a healthy eating pattern that protects against the development of MS in adults. Similarly, the Mediterranean diet could have a similar action during pregnancy, protecting the fetus against the development of MS throughout life. This review assembles studies carried out, both in animals and humans, on the epigenetic modifications associated with the consumption, during pregnancy, of Mediterranean diet main components. The relationship between these modifications and the occurrence of factors involved in development of MS is also explained. In addition, the results of our group relating adherence to the Mediterranean diet with MS markers are discussed. The paper ends suggesting future actuation lines in order to increase knowledge on Mediterranean diet adherence as a prevention tool of MS development. PMID- 28921262 TI - Effects of fentanyl on cardiovascular response during rapid sequence induction in hypertensive patients. AB - This study was carried out to evaluate the effects of fentanyl on cardiovascular and catecholamine responses during rapid sequence induction (RSI) in hypertensive patients. Twenty-eight patients were allocated into one of 3 groups: group 1 (n=7) consisted of normotensive patients receiving no fentanyl, group 2 (n=10) consisted of normotensive patients receiving fentanyl, and group 3 (n=11) consisted of hypertensive patients receiving fentanyl. RSI was performed with thiamylal (4mg.kg-1) and succinylcholine (2mg.kg-1) for all groups. In groups 2 and 3, fentanyl (4 MUg.kg-1) was given prior to induction. Measurements including systolic arterial pressure (SAP) and heart rate (HR) were made at preinduction (T1), preintubation (T2), 1 min after intubation (T3), and 3 min after intubation (T4). Simultaneously, plasma concentrations of epinephrine (E) and norepinephrine (NE) were measured at T1 and T3. Group 1 showed significant increases in SAP, HR, and NE at T3 as compared to T1. Group 2 showed a significant increase in HR at T3 but not in SAP or catecholamines. Group 3 showed no increase in SAP, HR, or catecholamines throughout the time course. The results suggest that fentanyl is useful to suppress sympathoadrenal and cardiovascular responses to RSI in hypertensive patients as well as normotensive patients. PMID- 28921263 TI - Effects of estazolam as a premedication in mentally retarded patients. AB - In anesthesia for mentally retarded patients, adequate preoperative sedation is important. We have investigated the sedative effects of estazolam in 16 mentally retarded patients who were given 0.1 mg.kg-1 orally; its sedative effects were compared with those of hydroxyzine (50 mg intramuscularly, 6 patients). Estazolam was observed to be significantly more effective as a sedative than hydroxyzine throughout the period under study. Estazolam was clinically effective in 94% of patients, no patient needing either additional drugs for sedation or heavy restraint. The sedative effects of estazolam lasted on average 9h and patients were still well sedated after the operation. There was no serious complication due to estazolam. Thus, it was found to be an effective drug for premedication in mentally retarded patients. PMID- 28921264 TI - Effects of pretreatment with magnesium on muscle relaxation and cardiovascular responses in tracheal intubation using the priming principle for vecuronium. AB - In addition to its direct effects on blood vessels, the myocardium, and neuromuscular junctions, magnesium can act as an adrenergic antagonist and can inhibit the release of catecholamines both from adrenergic nerve terminals and from the adrenal medulla. This study was undertaken to evaluate these effects of magnesium on muscle relaxation and cardiovascular response during tracheal intubation. Forty ASA I or II patients undergoing elective surgery were allocated to a magnesium or a control group. Three minutes after priming with vecuronium 0.015 mg.kg-1, the magnesium group received vecuronium 0.085 mg.kg-1 and magnesium sulfate 40 mg.kg-1, while the control group received an equivalent volume of vecuronium and saline. The percent change from baseline in mean arterial pressure after tracheal intubation was significantly smaller (P<0.01) in the magnesium group than in the control group, but the percent change in heart rate was similar. There were no significant changes in plasma catecholamine concentrations after tracheal intubation in either group. The onset time of vecuronium was significantly shorter in the magnesium group than in the control group. The duration of action of vecuronium was significantly longer in the magnesium group than in the control group. Serum magnesium concentrations at 90 min after its administration were significantly higher than baseline. We concluded that vecuronium priming with magnesium pretreatment inhibits the hypertension associated with tracheal intubation and shortens the onset time of vecuronium, but prolongs it duration of action. PMID- 28921265 TI - Parasympathetic nervous activity after administration of atropine and neostigmine using heart rate spectral analysis. AB - Recently, heart rate spectral analysis has become recognized as a powerful tool for quantitatively evaluating autonomic nervous system activity. The purpose of this study was to analyze parasympathetic nervous activity by heart rate spectral analysis after administration of atropine and neostigmine for reversal of residual neuromuscular blockade. For our study, 36 female patients (26-37 years of age), ASA physical status (PS) I, who were scheduled for laparoscopic examination, were randomly allocated to one of the following four groups: In group A (1?1), 9 patients received 1.0mg atropine followed 4 min later by 1.0 mg neostigmine. In group B (1?2), 9 patients received 0.5 mg atropine followed 4 min later by 1.0 mg neostigmine. In group C (1?2.5), 9 patients received 1.0 mg atropine followed 4 min later by 2.5 mg neostigmine. In group D (1?2 mix), 9 patients received a mixed solution of atropine 0.5 mg and neostigmine 1.0mg. After finishing the laparoscopic examination, additional anesthesia was maintained with 70% nitrous oxide, 30% oxygen, and 0.5% isoflurane. The control data were obtained 10 min after finishing the laparoscopic examination. After that, the data on atropine were obtained between 2 and 4min after administration of atropine, and the data on neostigmine were obtained between 5 and 7 min after administration of neostigmine. We selected power spectral density of the high frequency component (HF-p) in heart rate spectral analysis as an index to assess parasympathetic activity. In groups A, B, and C, the HF-p decreased after administration of atropine. In groups B and C, the HF-p increased after administration of neostigmine as compared to the control. In group A, the HF-p increased after neostigmine but did not differ from the control. The difference between groups D and B was not statistically significant. From the results of this study, we concluded that the muscarinic effect of neostigmine could not be sufficiently blocked by atropine at 1/2 dosages of neostigmine, but could be sufficiently blocked by atropine at equivalent dosages of neostigmine, under light isoflurane anesthesia. PMID- 28921266 TI - Continuous measurement of oxygen consumption using the reversed fick method. AB - We developed a continuous oxygen consumption (Vo2) measurement system employed the reversed Fick method, in which Vo2 in computed from continuously measured sured arterial and mixed venous oxygen saturation assed by pulse oximetry and mixed venous oximetry, respectively, and cardiac output by the heat deprivation technique. This system was compared with the conventional intermittent reversed fick method in 7 patients during surgery and with indirect calorimetry in 4 intensive care unit (ICU) patients. The Vo2 measured by the continuous reversed Fick method showed a high correlation with those simultaneously measured by the intermittent Fick method (r=0.97,P<0.01) and by indirect calorimetry (r=0.74,P<0.01). The 95% confidence limits (bias+/-2 SD) of the continuous reversed Fick method were -0.6+/-45 ml.min-1 with the intermittent Fick method and -31+/-56 ml.min-1 with indirect calorimetry. The continuous Fick method is in satisfactory agreement with the conventional methods for the measured of Vo2 and potentially allows for convenient assessment of Vo2 in critically ill patients. PMID- 28921267 TI - Studies of the mechanism of nephrotoxicity of compound A in rats. AB - CO2 absorbents acting on sevoflurane produce compound A [CF2=C(CF3)OCH2F]. Rats breathing 25-50 ppm of compound A for 3-12 h demonstrate corticomedullary renal injury. Several halogenated alkenes also produce a well described corticomedullary lesion by conversion of glutathione conjugates of these alkenes to cysteine s-conjugates and subsequent metabolism by renal cysteine conjugate beta-lyase to nephrotoxic halothionoacetyl halides. We tested whether a similar mechanism explained the nephrotoxicity of compound A or whether an oxidative metabolism of compound A by cytochrome P-450 was required for the induction of nephrotoxicity. A closed rebreathing system was used and male Wistar rats were exposed for 1 h to: (1) oxygen alone; (2) 800 ppm compound A; (3) 800 ppm compound A after pretreatment with intraperitoneal aminooxyacetic acid (AOAA), 0.5 mmoles/kg, an inhibitor of renal cysteine conjugate beta-lyase; (4) 600 ppm compound A; (5) 600 ppm compound A after pretreatment with intraperitoneal AOAA, 0.50 mmoles/kg plus acivicin (AT-125), 0.25 mmoles/kg, an inhibitor of gamma glutamyl transpeptidase; (6) 600 ppm compound A after pretreatment with 1600 mg/kg piperonyl butoxide (PB) subcutaneously, and (7) 600 ppm compound A after pretreatment with 100 mg/kg 1-aminobenzotriazole (ABT) by intraperitoneal injection (both PB and ABT inhibit cytochrome P-450s). All rats were killed 24 h following exposure to compound A or oxygen, or to pretreatments without compound A, and the kidneys were collected for histological analysis. Pretreatments given without compound A did not cause renal injury. Necrosis was found in 20.9+/-16.7% (mean+/-SD) of corticomedullary tubule cells following exposure of Wistar rats to 600 ppm compound A. Pretreatment with AOAA plus AT-125 increased necrosis to 57.9+/-32.6%, (P<0.005). PB or ABT given prior to compound A increased corticomedullary injury to 39.0+/-31.4% (P<0.02) and 51.2+/-31.8% (P<0.025), respectively. In rats exposed to 800 ppm compound A, pretreatment with AOAA increased necrosis from 63.8+/-30.1% to 81.2+/-27.7% (P<0.1). Unlike many other halogenated alkenes, compound A does not appear to produce renal injury by conversion of a cysteine S-conjugate to a toxic thiol, nor does injury require metabolism mediaited by cytochrome P-450. Injury may result from direct toxicity of compound A or by an undetermined metabolic pathway. PMID- 28921268 TI - Effects of bupivacaine and lidocaine on cardiac function in awake and pentobarbital-anesthetized rats. AB - Using an implanted Doppler crystal, we evaluated emodynamic changes induced by subconvulsive doses of bupivacaine and lidocaine in awake and pentobarbitalanesthetized rats. Low doses of lidocaine (2.0 mg.kg-1) and bupivacaine (0.5 mg.kg-1) changed hemodynamics minimally. However, a high dose of lidocaine (8.0 mg.kg-1) reduced heart rate, cardiac output, and regional myocardial wall thickening for a short period with or without anesthesia. In contrast, a high dose of bupivacaine (2.0 mg.kg-1) increased mean arterial pressure and did not change heart rate or regional myocardial wall thickening in the awake state. Under pentobarbital anesthesia, a high dose of lidocaine reduced mean arterial pressure significantly shortly after the injection, but bupivacaine did not. Thus, it is unlikely that bupivacaine has more potent cardiotoxicity than lidocaine in subconvulsive doses. PMID- 28921269 TI - Comparative hemodynamic effects of hypotension induced by diadenosine tetraphosphate (AP4A) and ATP in dogs. AB - ATP and diadenosine tetraphosphate (AP4A) have been shown to produce vasodilation mediated by P1- and P2-purinoceptor, respectively. The differing mechanisms involved in this vasodilating activity may induce different systemic hemodynamic changes. We compared the hemodynamic effects of AP4A-induced hypotension with those induced by ATP. Fourteen mongrel dogs were anesthetized with 0.87% halothane in oxygen (1 MAC). After the baseline period, mean arterial pressure was reduced to 60 mmHg for 60 min by the infusion of AP4A or ATP. The ATP- and AP4A-induced hypotension resulted in a maximum reduction in systemic vascular resistance of 43% and 46%, respectively (P<0.01), associated with a significant increase in stroke volume index. With ATP, a 20% of maximum increase (P<0.05) in cardiac index (CI) was observed during the induced hypotension. In contrast, AP4A induced hypotension did not result in any changes in CI throughout the observation period. The varying results concerning CI during the ATP- and AP4A induced hypotension were probably due to differences in ventricular filling pressure, since AP4A-induced hypotension was associated with decreases (P<0.01) in both right atrial and pulmonary capillary wedge pressures, whereas neither of these variables significantly changed with ATP. The hypotension induced by either ATP or AP4A was associated with a significant decrease in heart rate (HR). However, both the magnitude and duration of decreases in HR due to ATP-induced hypotension were more pronounced than those seen with AP4A. In conclusion, while both drugs were equally capable of inducing hypotension, our results suggest that AP4A was more suitable for induced hypotension because of its potent vasodilatory action with venodilation and less negative chronotropic action. PMID- 28921270 TI - Is ventilator-induced lung injury a promoter of multiple organ failure in adult respiratory distress syndrome? The effect of permissive hypercapnia on oxygenation and outcome. PMID- 28921271 TI - Anesthetic management of pediatric patients following fontan operation. PMID- 28921272 TI - Pulmonary embolism after laparoscopy-assisted colectomy. PMID- 28921274 TI - Maxillary bone defect by infraorbital nerve block. PMID- 28921273 TI - Effects of propofol on gravid human uterine muscle. PMID- 28921275 TI - Accidental penetration of a vocal cord by a nasogastric tube. PMID- 28921276 TI - Air in the brachiocephalic vein after sternotomy. PMID- 28921277 TI - Pulmonary aspiration during induction of general anesthesia in a postesophagectomy patient. PMID- 28921278 TI - Effect of low-dose infusion of prostaglandin E1 on vecuronium-induced neuromuscular blockade. AB - The effect of low-dose (20 ng.kg-1.min-1) infusion of prostaglandin E1 (PGE1) on vecuronium-induced neuromuscular blockade was studied. The study population consisted of 24 elderly patients (65-75 years old) and 24 younger adult patients (25-56 years old). They were randomly assigned to the control and PGE1 groups. The steady-state dose requirement (SSDR) of vecuronium was derived from ondemand infusion of the drug which produced a stable twitch height of 20% of its baseline reading, and recovery time after steady-state infusion was defined as the time for recovery from twitch height from 25% to 75%. The patients in the PGE1 group received an infusion of PGE1 20 ng.kg-1.min-1, while those in the control group received an infusion of normal saline. The SSDR (23.2+/-9.1 and 34.2+/-5.9 MUg.kg 1. hr-1, respectively;P=0.02) was significantly less and the recovery time (35.0+/-9.5 and 19.9+/-4.2 min, respectively;P=0.01) was significantly longer in the elderly than in the younger patients. However, low-dose infusion of PGE1 significantly increased the SSDR (23.2+/-9.1 to 37.4+/-3.7 MUg. kg-1.hr-1;P=0.01) and shortened the recovery time (35.0+/-9.5 to 23.5+/-4.0 min;P=0.02) in elderly patients. We concluded that low-dose infusion of PGE1 is effective in preventing the prolonged action of vecuronium in elderly patients. PMID- 28921279 TI - Correlation between renal function and pharmacokinetic parameters of inorganic fluoride following sevoflurane anesthesia. AB - We studied the correlation between renal function and pharmacokinetic parameters of inorganic fluoride following sevoflurane anesthesia. In 30 neurosurgical patients aged 40-70 years, anesthesia was induced with midazolam and sevoflurane and maintained with sevoflurane and nitrous oxide in oxygen. Serum and urine inorganic fluoride (F-) levels and beta2-microglobulin (BMG), blood urea nitrogen (BUN), and serum creatinine (Cr) were measured during and after anesthesia. The decrease rate of serum F- level and the area under the curve (AUC) of serum F- were calculated. Correlations among sevoflurane dosage, duration of administration, peak serum F- level, AUC, the decrease rate of serum F- level, and the maximum values in BUN, Cr, and urine BMG during the study were investigated. Urine BMG increased significantly after surgery but returned to the preoperative level in a week. BUN, Cr, and serum BMG remained within normal ranges during the study. Sevoflurane dosage and duration of administration were significantly correlated with AUC and the maximum value of urine BMG, but not with the peak serum F- level or the decrease rate of serum F-. AUC was significantly correlated with the maximum value of urine BMG. In sevoflurane anesthesia, sevoflurane dosage, duration of administration, and AUC affected urine BMG level, but not peak serum F-. PMID- 28921280 TI - Comparison of postoperative liver dysfunction following halothane and sevoflurane anesthesia in women undergoing mastectomy for cancer. AB - The incidence of an abnormal increase in the serum levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) following anesthesia with halothane and 65% nitrous oxide in oxygen (halothane group) or with sevoflurane and 65% nitrous oxide in oxygen (sevoflurane group) was compared in women undergoing surgery for breast cancer. An abnormal increase in GOT and GPT, both defined as higher than 50 IU, occurred postoperatively in 2 of the 150 patients (1.7%) in the sevoflurane group, and in 37 of the 200 (18.5%) in the halothane group (P<0.001). The elevated levels of serum transaminases after sevoflurane ranged from 50 to 65 IU whereas those after halothane ranged from 50 to 1000 IU, except for a value greater than 5000 IU in 1 patient. In the halothane group, there was a significant association between postoperative increases in serum transaminases and previous exposure to inhalation anesthetics, postoperative mitomycin therapy, and radiation therapy (all P<0.001). The results of multivariate analysis, when data from all patients were taken together, showed that the type of anesthetic (halothane) was the highest factor related to postoperative increases in GOT and GPT (odds ratio 35.85; 95% confidence interval 5.92-217.37), followed next by prior exposure to inhalation anesthetics (8.65; 2.96-25.27), postoperative radiation therapy (4.37; 1.70-11.19), and postoperative mitomycin therapy (3.56; 1.23-10.35). These data suggest that sevoflurane is less likely to cause anesthesia-related liver dysfunction than halothane. PMID- 28921281 TI - Isotonic hyponatremia and cerebrospinal fluid sodium during and after transurethral resection of the prostate. AB - We examined the effects on the central nervous system of hyponatremia during transurethral resection of the prostate (TURP). Initially, a prospective study was done on 165 consecutively treated patients undergoing TURP, to evaluate symptoms related to the serum osmolality. There were ten patients with hyponatremia below 120 mEq.L-1, and in whom the serum sodium decreased to 111.9+/ 6.4 mEq.L-1 (mean+/-SD) postoperatively, the measured serum osmolality remained near normal. The calculated osmolality decreased to 237.4+/-11.9 mOsm.kg-1 and the estimated osmolar gap was 33.5+/-10.4 mOsm.kg-1 due to absorption of the irrigating sorbitol. Neurological symptoms were mild and complications such as seizures or loss of consciousness nerver occurred. There were five other patients with hyponatremia (serum sodium 118.0+/-6.7 mEq.L-1) from whom lumbar cerebrospinal fluid (CSF) was collected before and after TURP through a single puncture. CSF sodium did not decrease throughout 1.5 h after TURP, and there was a CSF-to-serum sodium gradient. Our study shows that in cases of acute dilution hyponatremia during and after TURP, symptoms are mild because the serum osmolality remains near normal and CSF sodium does not decrease despite severe postoperative hyponatremia. PMID- 28921282 TI - Pharmacokinetics of ketamine during hypothermic cardiopulmonary bypass in cardiac patients. AB - Cardiopulmonary bypass (CPB) makes prediction of any drug concentration diffcult because both hypothermia and hemodilution can alter the pharmacokinetics of the drug. Eleven patients undergoing cardiac surgery under CPB were anesthetized with continuous infusion of ketamine combined with intermittent administration of droperidol and fentanyl. The infusion rate of ketamine was 2 mg.kg-1.hr-1 following a bolus administration of 1.5 mg.kg-1 for the induction of anesthesia. Blood concentrations of ketamine and its main metabolite, norketamine, were measured at 0, 30, and 60 min after the start of and the end of CPB, and 0, 1, 2, and 24 h after the cessation of ketamine infusion. Hypothermia increased blood ketamine levels during CPB, but the norketamine levels did not change. Although acute hemodilution would decrease blood ketamine levels, their levels were already significantly increased at 30 min after CPB. Hypothermic factors have a more kinetically important role during CPB than hemodilution. Increases in blood norketamine levels following rewarming indicate that hypothermia could impair ketamine metabolism in the liver. Further increase in the plasma concentration of ketamine until 30 min after the end of CPB might be due to blood transfusion containing ketamine from the CPB reservoir. PMID- 28921283 TI - Responses of interleukin-6 and tumor necrosis factor during and after cardiac surgery undergoing cardiopulmonary bypass and pancreatoduodenectomy. AB - To evaluate the effect of cardiopulmonary bypass on immunological function, we measured interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 12 patients undergoing cardiac surgery during and after cardiopulmonary bypass, and in 10 patients with pancreatoduodenectomy. Plasma IL-6 levels were determined using the Human Interleukin 6 ELISA Kit, and TNF levels were determined using a highly sensitive sandwich enzyme immunoassay. In patients with cardiac surgery, plasma levels of IL-6 and TNF increased during cardiopulmonary bypass, and in patients with pancreatoduodenectomy, IL-6 and TNF levels significantly increased at the end of intraabdominal manipulation. These results suggest that endotoxin may have activated the immune system and stimulated cytokine production after pancreatoduodenectomy and during bypass. PMID- 28921284 TI - Measuring time-varying respiratory mechanics during anesthesia. AB - We introduce a simple measurement technique which can track sudden and/or transient changes in respiratory mechanics even in unsteady respiration. Respiratory signals are segmented into single-breath signals. Breaths contaminated with noise produced by unsteadiness are discarded manually. A linear single-compartment model is fit to the data of "noise-free" single breaths, estimating its model parameters. respiratory mechanics is interpreted on the basis of breath-to-breath changes in the parameter estimates. The technique was tested in anesthetized subjects with unstable respiratory conditions. It was shown that the technique was noise insensitive and that the estimated model parameters well reflected the dynamic changes in respiratory mechanics. Although our method provides limited information compared with more sophisticated measurements, it may be useful when respiration is unstable, as frequently seen during light anesthesia or respiratory care. PMID- 28921285 TI - Sore throat and hoarseness after fiberoptic nasotracheal intubation. AB - Fiberoptic nasotracheal intubation is frequently chosen for surgery involving the oral cavity. In such cases, the endotracheal tube passes through the vocal cords into the trachea blindly, which may cause laryngeal trauma. We, therefore, studied the incidence of sore throat and hoarseness after fiberoptic nasotracheal intubation (n=44) and compared the results with those after conventional oral intubation (n=35). The incidence of sore throat was lower in the fiberoptic nasotracheal intubation group than in the conventional oral intubation group but the difference was not statistically significant (25.0%s 42.8%). The incidence of hoarseness after fiberoptic nasotracheal intubation was significantly lower than that after conventional oral intubation (4.5%s 34.3%,P<0.05). This study confirms a low incidence of laryngeal trauma in fiberoptic nasotracheal intubation. PMID- 28921286 TI - The effect of airway narrowing and dead space on the shape of the capnogram. AB - We have investigated the effects of incomplete obstruction of the endotracheal tube and the amount of additional dead space between the endotracheal tube and the capnographic sampling adapter on the shape of the capnogram. A 9.0-mm endotracheal tube was connected to a 3-L reservoir bag filled from the bottom with 5% carbon dioxide and 95% oxygen. The narrowed adapter (internal diameter: 3.0, 4.0, 6.5, and 9.0 mm), the capnographic sampling adapter, and a semiclosed respiratory system were successively connected to this endotracheal tube. Additional dead space (0, 30, 62, 92, 124, or 154 ml) was inserted between the narrowed adapter and the capnographic sampling adapter. The reservoir bag was ventilated with the anesthesia ventilator (fresh gas flow, 6 L.min-1; tidal volume, 500 ml; respiratory rate, 10 min-1, and inspiratory-expiratory ratio, 1?2). The capnogram from each initial ventilation was recorded and the peak carbon dioxide tension (Ppeak CO2) was also measured. The T90% value was defined as the time it took for the capnograph output to respond from 0% to 90% of the Ppeak CO2. The T90% value seen in a 3.0-mm adapter did not change compared with the value in a 9.0-mm adapter, when no additional dead space was connected between the endotracheal tube and the capnographic sampling adapter. Further, the slanting upstroke of the capnogram occurred only when the endotracheal tube narrowing and a large amount of dead space between the endotracheal tube and the capnographic sampling adapter coexisted. Thus, it is unlikely that incomplete obstruction of the endotracheal tube can easily be detected by the slanting upstroke of the capnogram. PMID- 28921287 TI - Cervical sympathectomy affects gonadotropin-releasing hormone, luteinizing hormone and testosterone in male rats. AB - To examine the effects of bilateral cervical sympathectomy on the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and testosterone (TS), 24 male rats were divided into four groups: control (C), light (L), sympathectomy (S), and light-sympathectomy (LS) groups. The C and S groups were kept under a 12-h light-dark cycle and the L and LS groups were kept under continuous light for 2 weeks. After 2 weeks, blood was collected and the rats were perfused with a fixative. GnRH neurons in the hypothalamus were stained immunohistochemically, and serum LH and TS levels were measured by radioimmunoassay. Although the difference in the number of GnRH neurons between the C and S groups was not significant, the L group was significantly lower than the C or LS groups. The serum LH and TS levels in the L group were higher than in the other groups. The present results suggest that continuous light increases GnRH secretion in the hypothalamus, followed by increased secretions of LH in the pituitary and TS in the testes, and bilateral cervical sympathectomy under continuous light inhibits these hormonal changes. However, a normal circadian rhythm does not affect gonadotropin secretion. Therefore, long-term and repeated stellate ganglion block may inhibit the increases of GnRH, LH, and TS secretions induced by continuous light. PMID- 28921288 TI - Protective effects of cyclosporine and allopurinol on transient global cerebral ischemia in gerbils. AB - The effects of cyclosporine and allopurinol on neuronal death following global cerebral ischemia were evaluated in Mongolian gerbils. The animals were randomly divided into four groups of 12 each: (1) sham operation as control, (2) occlusion of the bilateral common carotid arteries for 12 min and treatment with physiological saline, (3) occlusion plus treatment with 5 mg/kg of cyclosporine, and (4) occlusion plus treatment with 100 mg/kg of allopurinol 30 min before cerebral ischemia and daily thereafter for 6 days. On the 7th day after ischemia or sham operation, the gerbils' brains were removed. The number of necrotic pyramidal cells in the cortex and hippocampal CA1 was evaluated and tissue chemiluminescence (reflecting the presence of superoxide radicals) and lipid peroxides were examined. The number of necrotic pyramidal cells in each field of view (*100) of the cortex was 115+/-79 after ischemia, which was significantly larger than 14+/-8 in the control group, and was 45+/-33 and 60+/-49 after treatment with cyclosporine and allopurinol, respectively. The number of surviving pyramidal cells per mm length after ischemia in CA1 was 37+/-14, which was significantly smaller than 174+/-30 in the control group, but 78+/-31 following treatment with was cyclosporine, and 108+/-53 with allopurinol. A reduced number of necrotic pyramidal cells was associated with lower tissue chemiluminescence and lipid peroxides. The results suggest that both cyclosporine and allopurinol can inhibit neuronal death after global cerebral ischemia, and that autoimmunization and superoxide radicals are partially responsible for neuronal death. PMID- 28921289 TI - Hemodynamic effects of KRN2391 (potassium channel opener) in halothane anesthetized dogs. AB - The cardiovascular responses to an infusion of KRN2391, a potassium channel opener, was studied in halothane-anesthetized dogs. Intravenous administration of KRN2391 at 1.0 and 5.0 MUg.kg-1.min-1 for 60 min produced dose-dependent decreases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) associated with dose-dependent increases in the cardiac index (CI) and stroke volume index (SVI) but was not accompanied by an increase in heart rate (HR). The maximum decrease in MAP during the infusion of KRN2391 at 1.0 and 5.0 MUg.kg 1.min-1 was -13+/-7% (P<0.01) and -37+/-10% (P<0.01), respectively. The maximum reduction in SVR after 1.0 and 5.0 MUg.kg-1.min-1 was -20+/-11% (P<0.01) and 60+/-16% (P<0.01), respectively. A KRN2391 infusion of 1.0 and 5.0 MUg.kg-1.min-1 increased Cl a maximum of 11+/-13% (P<0.05) and 65+/-33% (P<0.01), respectively. KRN2391 1.0 MUg.kg-1.min-1 showed a tendency to increase SVI but this change was not significant, KRN2391 5.0 MUg.kg-1.min-1, however, produced a significant increase in SVI. The present results demonstrate that the decrease in MAP and the increases in CI and SVI caused by KRN2391 are due to a reduction in the afterload. Therefore, we conclude that these cardiovascular profiles of KRN2391 may be benificial in perioperative uses including the control of systemic blood pressure and the treatment of hypertension during halothane anesthesia in clinical practice. PMID- 28921290 TI - Low reactive-level laser irradiation on the stellate ganglion in dogs. AB - The aim of this study was to determine what effects low reactive-level laser irradiation (LLLI) of the stellate ganglion might have on the sympathetic fibers of the stellate ganglion in dogs. Following general anesthesia, the right stellate ganglion was exposed by thoracotomy. After stabilization, the following baseline measurements were taken: mean arterial pressure, heart rate, and blood flow of the common carotid artery. The stellate ganglion was directly irradiated for 10 min with a low-power laser. Measurements were taken for 60 min after LLLI. Immediately after the final measurement, stellate ganglion blockade was performed with 0.5% mepivacaine 1.5 ml. Measurements were taken again 15 min after stellate ganglion blockade with a local anesthetic. The changes in each variable were not statistically significant after LLLI. On the other hand, all variables changed significantly after the stellate ganglion blockade, including increased blood flow of the common carotid artery. In conclusion, this study demonstrated that LLLI to the stellate ganglion does not cause sympathetic blockade. PMID- 28921291 TI - Unusual circulatory responses in a case of acute idiopathic pandysautonomia. PMID- 28921292 TI - Adenosine for the treatment of sustained sinus nodal reentrant tachycardia during general anesthesia. PMID- 28921293 TI - Bronchial asthma-like attack after celiac plexus alcohol block. PMID- 28921294 TI - Sevoflurane anesthesia for renal transplanted patient-comparison with normal renal function subjects. PMID- 28921295 TI - Bronchospasm induced with ergometrine during high spinal anesthesia. PMID- 28921296 TI - Refractory atrial fibrillation in an emergency surgical patient: a sign of untreated thyrotoxicosis. PMID- 28921297 TI - Effects of epidural buprenorphine on bowel movement following gynecological surgery. PMID- 28921298 TI - Hepatic oxygen delivery-consumption relationship during anesthesia and hypoxemia in dogs. PMID- 28921300 TI - Letters to the Editor. PMID- 28921299 TI - Letters to the Editor. PMID- 28921301 TI - Misplacement of an epidural catheter via intervertebral foramen is not rare. PMID- 28921302 TI - Comparative evolutionary genomics of Corynebacterium with special reference to codon and amino acid usage diversities. AB - The present study has been aimed to the comparative analysis of high GC composition containing Corynebacterium genomes and their evolutionary study by exploring codon and amino acid usage patterns. Phylogenetic study by MLSA approach, indel analysis and BLAST matrix differentiated Corynebacterium species in pathogenic and non-pathogenic clusters. Correspondence analysis on synonymous codon usage reveals that, gene length, optimal codon frequencies and tRNA abundance affect the gene expression of Corynebacterium. Most of the optimal codons as well as translationally optimal codons are C ending i.e. RNY (R-purine, N-any nucleotide base, and Y-pyrimidine) and reveal translational selection pressure on codon bias of Corynebacterium. Amino acid usage is affected by hydrophobicity, aromaticity, protein energy cost, etc. Highly expressed genes followed the cost minimization hypothesis and are less diverged at their synonymous positions of codons. Functional analysis of core genes shows significant difference in pathogenic and non-pathogenic Corynebacterium. The study reveals close relationship between non-pathogenic and opportunistic pathogenic Corynebaterium as well as between molecular evolution and survival niches of the organism. PMID- 28921303 TI - Registry study to assess hair loss prevention with the Penguin Cold Cap in breast cancer patients receiving chemotherapy. AB - PURPOSE: Chemotherapy-induced alopecia is a distressing side effect of cancer treatment. The aim of this registry study was to assess efficacy and tolerability of scalp hypothermia using Penguin Cold Caps (Penguin) in breast cancer patients. METHODS: Hair loss was assessed by patients using a 100-point Visual Analog Scale (VAS) and by physicians using the 5-point Dean Scale at baseline, every 3-4 weeks during chemotherapy, and at least 1 month after completion of chemotherapy. The primary efficacy endpoint for success was defined as <=50% hair loss by patient report (VAS) at follow-up (FUP). Tolerability and satisfaction were assessed by patient report. RESULTS: 103 patients enrolled between 7/2010 and 6/2015; 97 are evaluable for the primary endpoint. Chemotherapy included docetaxel/cyclophosphamide (TC; n = 50) for 4-6 cycles every 3 weeks, weekly paclitaxel for 12 weeks then doxorubicin/cyclophosphamide (P/AC; n = 23) for 4 cycles every 2-3 weeks, AC then paclitaxel (AC/P; n = 10), docetaxel/carboplatin +/- trastuzumab (TCH; n = 4) for 4-6 cycles every 3 weeks. Overall, 61% of patients successfully prevented CIA; impact was regimen specific: TCH 100%, TC * 4 84%, TC * 5-6 50%, P/AC 43%, AC/P 20%. The most common toxicity was headache, reported by 78.5% of patients with mean pain level 37/100. Satisfaction among those who completed scalp cooling (SC) and FUP ranged from 74 to 100%. All patients who completed SC/FUP recommended Penguin. CONCLUSIONS: Scalp hypothermia with Penguin is effective in reducing alopecia, particularly for non anthracycline-based shorter regimens. Penguin was well tolerated and viewed favorably by most patients. PMID- 28921304 TI - Expression and purification of an FGF9 fusion protein in E. coli, and the effects of the FGF9 subfamily on human hepatocellular carcinoma cell proliferation and migration. AB - Fibroblast growth factor (FGF) 9 has oncogenic activity and plays an important role in the development of ovarian, lung, prostate, and gastric cancers. In the present study, with the aim of reducing the cost of utilizing growth factors in cancer research, a simple and efficient method for the preparation of recombinant human (rh)FGF9 in Escherichia coli was established. The rhFGF9 fusion protein (6 * His-TEV-rhFGF9) and the native protein released by tobacco etch virus (TEV) protease were obtained using a Ni-NTA system, with > 95% purity. Both purified forms of rhFGF9, with and without fusion tags, significantly stimulated the proliferation of NIH3T3 cells. The FGF9 subfamily, including FGF9, FGF16, and FGF20, in addition to rhFGF16, rhFGF9, and rhFGF20, were shown to stimulate the proliferation and migration of HuH7 human hepatocellular carcinoma (HCC) cells. Mechanistic studies revealed that the stimulation of HuH7 cell proliferation and migration with rhFGF9 and rhFGF20 were associated with the activation of the extracellular signal-regulated kinase (ERK) and nuclear factor kappaB (NF-kappaB) pathways and matrix metalloproteinase-26 (MMP26). Inhibition of the ERK and NF kappaB pathways blocked cell migration, and NF-kappaB was demonstrated to be regulated by ERK. Therefore, the present study demonstrates a simple method for the preparation of biologically active rhFGF9 protein. Furthermore, the results indicate that exogenous rhFGF9- and rhFGF20-activated ERK/NF-kappaB signal transduction pathways play important roles in the regulation of HCC cell proliferation and migration, and this discovery helps to find the potential for new solutions of the treatment of liver cancer. PMID- 28921305 TI - Allocation of Metals and Trace Elements in Different Tissues of Piscivorous Species Phalacrocorax carbo. AB - Great cormorants (Phalacrocorax carbo) are piscivorous birds, and as apex predators they accumulate high levels of contaminants from the aquatic ecosystems. In the present study, we analyzed distribution of Al, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Sr, and Zn in ten tissues (muscle, liver, kidney, spleen, gizzard, heart, skin, lard, breast feathers, and remiges) of the Great cormorants in the Marin Sprud locality, the Danube River, Serbia. Concentrations of elements in tissues were assessed by using inductively coupled plasma optical spectrometry. Linear discriminant analysis indicates that breast feathers and remiges have a high bioaccumulation potential for heavy metals (Cr, Pb, Sr, and Zn). Those tissues had the highest concentrations of lead (Pb) (2.179 +/- 0.742; 0628 +/- 0.282). Maximum concentrations of mercury (Hg) were detected in liver (30.673 +/- 14.081), followed by kidney, for the same element (17.409 +/- 5.676), respectively. The overall maximum metal accumulation was observed in breast feathers and remiges, followed by liver and kidney, whereas the minimum values were observed in muscle, skin, and lard. The greatest concentrations of Cr, Ni, Pb, Sr, Zn, and Al were detected in feather tissues. Our study confirms that great cormorant is a good indicator species for monitoring of pollution of river and wetland ecosystems. PMID- 28921306 TI - Brief Report: Feasibility and Preliminary Efficacy of Individual Mindfulness Therapy for Adults with Autism Spectrum Disorder. AB - Intervention research on adults with autism spectrum disorder (ASD) is sparse. Many adults with ASD experience impaired emotion regulation (ER), which is thought to contribute to higher rates of psychiatric comorbidities among adults with ASD and indirect effects upon adaptive functioning, interpersonal relationships, and vocational status. The purpose of this study was to investigate feasibility and initial efficacy of an adapted mindfulness-based individual therapy targeting ER difficulties for adults with ASD. There is evidence for feasibility based on acceptable treatment fidelity and participant satisfaction ratings. Of nine participants, seven demonstrated improvement in at least one of the following domains; impulse control, access to ER strategies, and emotional acceptance. Further research is recommended, including additional timepoints and a clinical cutoff-derived sample. PMID- 28921307 TI - Cam morphology and inguinal pathologies: is there a possible connection? AB - BACKGROUND: To analyse the prevalences of the cam and pincer morphologies in a cohort of patients with groin pain syndrome caused by inguinal pathologies. MATERIALS AND METHODS: Forty-four patients (40 men and 4 women) who suffered from groin pain syndrome were enrolled in the study. All the patients were radiographically and clinically evaluated following a standardised protocol established by the First Groin Pain Syndrome Italian Consensus Conference on Terminology, Clinical Evaluation and Imaging Assessment in Groin Pain in Athlete. Subsequently, all of the subjects underwent a laparoscopic repair of the posterior inguinal wall. RESULTS: The study demonstrated an association between the cam morphology and inguinal pathologies in 88.6% of the cases (39 subjects). This relationship may be explained by noting that the cam morphology leads to biomechanical stress at the posterior inguinal wall level. CONCLUSIONS: Athletic subjects who present the cam morphology may be considered a population at risk of developing inguinal pathologies. LEVEL OF EVIDENCE: Level IV, Observational cross sectional study. PMID- 28921308 TI - Pregnancy and delivery in moyamoya vasculopathy: experience of a single European institution. AB - Moyamoya vasculopathy (MMV) is a stenoocclusive cerebrovascular disease frequently affecting adolescent females. Thus, the management of pregnancy is of major interest for physicians dealing with MMV patients. However, clinical data concerning pregnant MMV patients is lacking. Our aim was to analyze the course of pregnancy in our European MMV patient cohort. We retrospectively identified MMV patients with a history of pregnancy who were treated in our institution. We analyzed demographic data, clinical symptoms, treatment, and detailed history of pregnancies. We identified 31 MMV patients (81% moyamoya disease (MMD), 6% unilateral MMD, 13% quasi MMD) with a history of pregnancy resulting in a total of 60 pregnancies and 48 deliveries. Ninety-four percent of the patients became symptomatic by ischemic events and 6% by headache. Eighty-one and nineteen percent of the patients experienced their pregnancies prior to (first group) or after the diagnosis (second group), respectively. In the first group, the mean age at first delivery and bypass treatment were 24 +/- 4 and 42 +/- 10, respectively. Eight percent of these patients were diagnosed as MMV due to ischemic events during perinatal period. In the second group, the mean age at first delivery and bypass treatment were 26 +/- 7 and 23 +/- 6, respectively. No cerebral events were reported within perinatal period in this group. All previously operated patients continued their aspirin medication at least until the 3rd trimester. The majority of the pregnancies occurred prior to diagnosis in our European patient cohort. Our data indicates a protective effect of surgical treatment for avoiding cerebral events during pregnancy and delivery for already diagnosed patients. PMID- 28921311 TI - Respiratory and cardiovascular effects of fentanyl during propofol-induced sedation under spinal anesthesia. AB - PURPOSE: To determine whether fentanyl augments respiratory and cardiovascular problems during propofol-induced sedation, we investigated the effects of propofol and fentanyl on respiratory and hemodynamic profiles in 30 female patients under spinal anesthesia, administering oxygen via face mask. METHODS: After spinal anesthesia, 20 patients were sedated with propofol (0.5 mg.kg-1 bolus, 3 mg.kg-1.h-1), followed by administration of either 2 MUg.kg-1 fentanyl in group PF or normal saline in group P, whereas another 10 patients (group F) received 2 MUg.kg-1 fentanyl without propofol. We measured heart rate, mean arterial pressure, end-tidal carbon dioxide tension, and respiratory rate before and after treatment. We also evaluated apnea, arterial oxygen desaturation, and airway obstruction. RESULTS: Mean arterial pressure was significantly lower in group P and PF than in group F. However, there were comparable changes in heart rate in the three groups. The combination of fentanyl and propofol decreased respiratory rate and increased end-tidal carbon dioxide tension more than fentanyl or propofol alone. Although apnea occurred in groups F and PF, arterial oxygen desaturation did not occur in any of the groups. CONCLUSION: The combination of fentanyl and propofol augmented the risks of respiratory depression and apnea compared with the use of fentanyl or propofol alone. PMID- 28921310 TI - Effects of Vildagliptin Add-on Insulin Therapy on Nocturnal Glycemic Variations in Uncontrolled Type 2 Diabetes. AB - INTRODUCTION: To investigate whether vildagliptin add-on insulin therapy improves glycemic variations in patients with uncontrolled type 2 diabetes (T2D) compared to patients with placebo therapy. METHODS: This was a 24-week, single-center, double-blind, placebo-controlled trial. Inadequately controlled T2D patients treated with insulin therapy were recruited between June 2012 and April 2013. The trial included a 2-week screening period and a 24-week randomized period. Subjects were randomly assigned to a vildagliptin add-on insulin therapy group (n = 17) or a matched placebo group (n = 16). Scheduled visits occurred at weeks 4, 8, 12, 16, 20, and 24. Continuous glucose monitoring (CGM) was performed before and at the endpoint of the study. RESULTS: A total of 33 subjects were admitted, with 1 patient withdrawing from the placebo group. After 24 weeks of therapy, HbA1c values were significantly reduced at the endpoint in the vildagliptin add on group. CGM data showed that patients with vildagliptin add-on therapy had a significantly lower 24-h mean glucose concentration and mean amplitude of glycemic excursion (MAGE). At the endpoint of the study, patients in the vildagliptin add-on group had a significantly lower MAGE and standard deviation compared to the control patients during the nocturnal period (0000-0600). A severe hypoglycemic episode was not observed in either group. CONCLUSION: Vildagliptin add-on therapy to insulin has the ability to improve glycemic variations, especially during the nocturnal time period, in patients with uncontrolled T2D. PMID- 28921312 TI - Humidification during low-flow anesthesia in children. AB - PURPOSE: The aim of this study was to compare the effect of low-flow anesthesia with or without a heat and moisture exchanger with high-flow anesthesia on airway gas humidification in children. METHODS: One hundred twenty children were randomly assigned to one of three groups: low-flow anesthesia with 0.5l.min-1 of total gas flow (LFA,n=40), low-flow anesthesia with 0.5l.min-1 using a heat and moisture exchanger (HME,n=40), and high-flow anesthesia with 6l.min-1 (HFA,n=40). The temperature and relative humidity of the inspired gas were measured throughout anesthesia. RESULTS: The relative humidity of the inspired gas in the HME group was increased compared with that of the LFA and HFA groups 20 min after induction (p<0.05). The airway humidification in the LFA group was higher than that in the HFA group 10 min after induction (p<0.05). The temperature of the inspired gas in the HME group was increased compared with that in the LFA and HFA groups after 70 min (P<0.05). CONCLUSION: Low-flow anesthesia is less effective in providing adequate humidification of inspired gas than low-flow anesthesia with a heat and moisture exchanger, but significantly better than high-flow anesthesia in children. PMID- 28921313 TI - Nitric oxide inhalation increases oxygen delivery after cardiovascular surgery in adult patients whether or not they have pulmonary hypertension. AB - PURPOSE: The purpose of this study was to quantify the increase in oxygen delivery (DO2) produced by nitric oxide (NO) inhalation, and to clarify whether NO inhalation might be effective in adult patients after cardiovascular surgery whether or not they have pulmonary hypertension (PH). METHODS: The study was done on 26 adult patients after cardiovascular surgery. The indications for NO inhalation were postoperative hypoxic respiratory failure (POHRF) with or without PH. NO was administered via a premixing system or via a side-stream system. The dose was adjusted to between 1 and 10 (5.7+/-2.0) (mean+/-SD) ppm. Data were obtained just before and within 120 min after the initiation of NO inhalation. We initially analyzed the data from all the patients together and then compared data from two groups made up from just 22 of the 26 patients: 14 patients without PH whose PaO2/FiO2 before NO inhalation was less than 200 mmHg (simple POHRF group), and 8 patients who had both POHRF and PH (systolic pulmonary arterial pressure higher than 40 mmHg) (POHRF with PH group). RESULTS: In the original group of 26 patients, significant improvements were observed in PaO2, PaO2/FiO2, CI, SPAP, CaO2, DO2I, and SvO2 during NO inhalation. The increase in DO2I was 68 ml.min-1.m 2 (+19.5%). PaO2, PaO2/FiO2, CaO2, DO2I, and SvO2 increased significantly in both groups. The increase in DO2I was 60 ml.min-1.m-2 (+18.9%) in the simple POPHRF group and 79ml.min-1.m-2 (+18.0%) in the POHRF with PH group. CONCLUSION: NO inhalation increases DO2 by approximately 20% in adult patients after cardiovascular surgery, irrespective of whether or not they have pulmonary hypertension. PMID- 28921309 TI - Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options. AB - BACKGROUND: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies. CONCLUSIONS: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies. PMID- 28921314 TI - Comparison of respiratory sparing effect between pancuronium and three new nondepolarizing muscle relaxants in rats. AB - PURPOSE: There is a large difference in sensitivity between respiratory muscles and other limb muscles. This phenomenon, known as the respiratory sparing effect (RSE), is well established withd-tubocurarine, pancuronium, and succinylcholine. The purpose of this study is to evaluate the RSE of these new relaxants, vecuronium, pipecuronium, and ORG9426. METHODS: The study was done in vivo using rats. Mechanical twitch responses of tibialis anterior muscle and diaphragm stimulated with the sciatic nerve and phrenic nerve, respectively, were recorded simultaneously to monitor neuromuscular transmission. Changes of mechanical twitch responses from both muscles were compared following the injection of four kinds of muscle relaxants (pancuronium, picuronium, recuronium, and ORG9426). RESULTS: T, D (%) represents the maximum depression in tibialis anterior and diaphragm, respectively. T-D (%), which means the sensitivity difference between the two kinds of muscle, was calculated by subtracting D from T. The T-Ds of pancuronium, pipecuronium, vecuronium, and ORG9426 were 86.0+/-2.6%, 81.4+/-1.9%, 77.7+/-2.1%, and 74.6+/-2.7%, respectively. CONCLUSIONS: The results indicated that the blockade produced by each muscle relaxant was lower in the diaphragm than in the anterior tibialis muscle. T-D was significantly smaller with vecuronium or ORG9426 than with pancuronium. PMID- 28921315 TI - Objective assessment of CNS function within 6 hours of spinal cord ischemia in rabbits. AB - PURPOSE: To develop a neurologic scoring (NS) system to objectively assess CNS function shortly after spinal cord ischemia. METHODS: Spinal cord ischemia was induced by temporarily clamping the infrarenal aorta in 27 rabbits anesthetized with isoflurane/N2O/O2 without muscle relaxants. Animals were divided ito group I, normothermic ischemia [I-a, 11 min (n=8); I-b, 12 min (n=8)], and group II, 60 min hypothermic ischemia targeted to II-a, 29.5 degrees C (n=5), and II-i, 30.0 degrees C (n=6). Postischemic neurologic function was scored from 0 to 6. RESULTS: Seventy-five percent of each group I subgroup ended with paraplegia. Function in the I-b group tended to be worse than in I-a (NS=1.7vs 1.9P>0.05). Hypothermia of 29.9+/-0.1 degrees C protected partially (NS=2.8), whereas 29.4+/ 0.1 degrees C resulted in significantly higher NS, starting at 150 min (P<0.05vs IIi) with total recovery 5.5 hours (P<0.0001) post re-perfusion. CONCLUSIONS: Protection of the spinal cord from ischemia can be objectively quantitated by our system. Protection strategies can be compared within 6 h of the ischemia-insult. PMID- 28921317 TI - Simple deep hypothermia for repair of congenital tracheal stenosis: a case report. PMID- 28921316 TI - The clinical pharmacology of remifentanil: a brief review. AB - Because it is still in its clinical infancy, it is difficult to predict with confidence exactly what role remifentanil will ultimately play in the delivery of anesthesia (and in other settings). It is clear, however, that remifentanil is a new pharmacologic tool with exciting potential that was not possible with the longer-acting opioids. On the basis of its familiar, fentanyl-like pharmacodynamic behavior and its short-acting pharmacokinetic profile, remifentanil may well be advantageous in a variety of settings in which profound opioid effect with subsequent rapid return of spontaneous ventilation and consciousness is desirable. Ongoing research and wide-spread clinical use will be required before the theoretical advantages associated with a short-acting opioid can be fully explored and confirmed. PMID- 28921318 TI - A case of accidental hypercapnia caused by a malpositioned expiratory valve disc, and experimental models for its prevention. PMID- 28921319 TI - A method of radiographic guiding for maxillary nerve block (pterygopalatine fossa oblique view). PMID- 28921320 TI - Effect of intrathecal pretreatment with taurine on neurological outcome after transient spinal cord ischemia in the rat. PMID- 28921321 TI - Glass fragments in infusate and a rupture of the balloon of a continuous epidural infusion apparatus. PMID- 28921323 TI - Effects of reduction of carrier gas flow rate on sevoflurane and isoflurane consumption and costs. AB - PURPOSE: To evaluate whether sevoflurane and isoflurane consumption would be actually halved by halving the carrier gas flow rate, as predicted by a theoretical model, we measured the consumed volume of liquid sevoflurane and isoflurane and total costs of anesthetic gas at carrier gas flow rates of 3 and 61.min-1. METHODS: Eighty patients of ASA physical status I or II were randomly assigned to one of four groups: sevoflurane at 3 or 61.min-1 and isoflurane at 3 or 61.min-1. Anesthesia was induced with thiamylal and maintained with sevoflurane or isoflurane, as well as with nitrous oxide in oxygen. The consumption of sevoflurane and isoflurane was measured by weighing the bottle of liquid agent, which was greater in the groups receiving 61.min-1 gas than in those receiving 31.min-1. RESULTS: Halving the carrier gas flow rate reduced the consumption of sevoflurane by 41.8% and that of isoflurane by 52.6%. It also reduced the total cost by 44.3% for sevoflurane and 49.2% for isoflurane. CONCLUSION: Halving the carrier gas flow rates halved the consumption of isoflurane but not of sevoflurane, indicating that factors other than carrier gas flow rates are involved in determining consumption in the clinical setting. PMID- 28921324 TI - Thoracic epidural blockade preserves left ventricular early diastolic filling assessed by transesophageal echocardiography. AB - PURPOSE: The objective of this study was to examine the effect of thoracic epidural anesthesia (TEA) on left ventricular systolic and diastolic function assessed by transesophageal echocardiography under general anesthesia. METHODS: Sixteen patients were allocated to control (n=8) and TEA (n=8) groups. We administered 1% mepivacaine (8.9+/-1.2 ml) into the thoracic epidural space in the TEA group. RESULTS: The concomitant decline of the left vertricular systolic functional parameters, such as end-systolic diameter and fractional shortening, was observed, whereas preload, as measured by end-diastolic diameter, and afterload, as measured by end-systolic wall stress, were unchanged. No significant alteration was observed in early peak velocity or deceleration rate. The deceleration time was independent of heart rate and was unchanged. CONCLUSION: High TEA reduces fractional shortening without any changes in preload and afterload, indicating impairment of systolic function, but early peak velocity, deceleration rate, and deceleration time, which are the indices of diastolic function, are not changed during high TEA combined with general anesthesia. PMID- 28921325 TI - Combined spinal-epidural anesthesia for cesarean section; needle-through-needle approach. AB - PURPOSE: The Portex "Spinal/Epidural Set" is designed for combined spinal epidural (CSE) anesthesia by the needle-through-needle approach. We evaluated the technical and clinical usefulness of CSE with this needle set, and also isobaric tetracaine, for cesarean section. METHODS: Thirty patients for cesarean section were included. In the left decubitus position, a 16-gauge epidural needle was introduced by the loss-of-resistance method into the lumbar intervertebral space. A 26-gauge spinal needle was threaded through the epidural needle into the subarachnoid space. Tetracaine dissolved in saline was injected. A 17-gauge catheter was advanced into the epidural space. The analgesic level was checked by the pin-prick method. RESULTS: The insertion in the first attempt was successful in 21 cases (70%) of the patients, and difficulty in insertion was not experienced. Inadvertent dural puncture occurred in one case, but no accidental subarachnoid catheterization was observed. Spinal anesthesia with tetracaine (11.1+/-0.5 mg) reached the level of Th6 on average, with a relatively wide range. Five cases (13%) were supplemented by epidural anesthesia. No postspinal headache was noted. CONCLUSION: CSE technique by the needle-through-needle approach is easy to handle, and provides a speedy, reliable, and flexible analgesia as well as postoperative pain relief for patients undergoing cesarean section. PMID- 28921326 TI - Middle-ear pressure variations during total intravenous anesthesia with propofol, fentanyl, and ketamine. AB - PURPOSE: As the middle-ear cavity is one of the noncompliant gas-filled cavities, an increase in middle-ear pressure (MEP) instead of volume expansion is observed with inhalation of nitrous oxide (N2O). Changes in MEP cause many complications, such as ear pain, temporary hearing impairment, and postoperative emesis. Therefore, we investigated changes in MEP during total intravenous anesthesia (TIVA) with propofol, fentanyl, and ketamine (PFK) and inhalation of N2O. METHODS: Twelve patients were anesthetized with PFK until 60 min after the induction of anesthesia, and then N2O (60%) inhalation was started. MEP was measured by impedance audiometry (ranging from -300 daPa to +200 daPa) at 10-min intervals during PFK, and at 2-min intervals after the inhalation of N2O. RESULTS: MEP gradually but significantly increased from the preanesthetic value of 16+/-8 to 34+/-12 (SEM) daPa 50 min after the induction of PFK. However, MEP did not exceed the normal limit. The values of MEP in all patients were more than 200 daPa within 36 min after the start of inhalation of N2O in oxygen. CONCLUSION: PFK had a minimal effect on MEP, whereas addition of N2O to PFK increased MEP dramatically. Therefore, TIVA, or at least PFK, would be a better choice for patients with middle-ear or upper-airway diseases. PMID- 28921327 TI - Transvascular fluid distribution of hyperoncotic Dextran solution. AB - PURPOSE: The purpose of this study was to confirm the changes in extra-aand intravascular fluid distribution during an i.v. influsion of hyperoncotic Dextran solution. METHODS: Twenty-three mongrel dogs with normal capillary integrities were divided into four groups. The R1 and R2 groups received i.v. infusion of Ringer lactate (RL) with a rate of 10 and 30 ml.kg-1.h-1, the D group 6% Dextran 70 solution (DEX) of 10 ml.kg-1.h-1. and the RD group DEX of 10 plus RL of 20 ml.kg-1.h-1. The distribution of infused fluid was assessed with the changes in circulating blood volume (CBV), extravascular fluid volume (EVW), and thoracic duct lymph volume (QL). RESULTS: In the R1 and R2 groups, EVW increased by 63% and 51%, respectively, of total infusion volume (tInf), while CBV increased by only 10% and 13% of tnf. In the D and RD groups, CBV increased by 103% and 51% of tInf. However, EVW decreased by 21% and increased by 32% of tInf, respectively. In the latter groups, the plasma volume filtered out into the extravascular compartment was less than in the corresponding former group by 52% and 6% of tInf, respectively and the restoration ratio of EVW by lymph was about 3 to 1.8 times greater. CONCLUSION: One-fourth to one-third of the plasma expanding effect of 6% Dextran 70 solution was ascribed to direct fluid drawing from the extravascular space, and the rest was due to both the decrease in plasma filtration into extravascular space and the increase in lymphatic restoration of EVW. PMID- 28921328 TI - Differential vascular reactivity of canine mesenteric arteries and veins to sevoflurane. AB - PURPOSE: The aim of this study was to compare the vascular reactivities of canine mesenteric arteries and veins to sevoflurane and to elucidate the underlying mechanism that is responsible for sevoflurane-induced hypotension. METHODS: Vascular rings of canine mesenteric arteries and veins were suspended in organ baths, and the effect of 2.3% and 4.6% sevoflurane on the contractile responses to transmural electrical stimulation (ES) and to norepinephrine (NE) were determined by recording isometric tension changes. The rings were contracted to a stable tension by the addition of NE and then exposed to increasing concentrations of sevoflurane (0%-5.1%). RESULTS: Sevoflurane attenuated the contractile responses to transmural ES in veins but not in arteries. The concentration responses to NE were not affected by sevoflurane in arteries or in veins. At stable precontraction induced by NE, when sevoflurane was placed in the bathing medium, arteries with intact endothelium had significant contraction at 1.7% and 3.4% sevoflurane, followed by relaxation at 5.1%. On the contrary, sevoflurane produced dose-dependent relaxation in endothelium-denuded arteries and endothelium-intact veins CONCLUSION: It is suggested that the relaxation of the veins by sevoflurane may be due to the inhibition of NE release from sympathetic nerve endings and to the direct inhibition of the contractile mechanisms of vascular smooth muscle. In arteries, sevoflurane causes endothelium dependent vasocontraction, probably by inhibiting the release of basal endothelium-derived relaxing factor (EDRF). PMID- 28921329 TI - Repeated shock after suspected anaphylactic reaction to a pulmonary artery catheter. PMID- 28921330 TI - Intraoperative hemodynamic management for minimally invasive direct coronary artery bypass: two case reports. PMID- 28921331 TI - Solubility and preparation of volatile anesthetic solution. PMID- 28921332 TI - Nasal continuous positive airway pressure improves airway obstruction during midazolam-induced sedation under spinal or epidural anesthesia. PMID- 28921333 TI - Effect of severe cardiac valve regurgitation on the onset of the neuromuscular blocking action of pancuronium. PMID- 28921334 TI - Successful use of nerve-block therapy with 12% tetracaine for trigeminal neuralgia caused by arteriovenous malformation. PMID- 28921335 TI - Detachment of a venous cannula into a blood vessel. PMID- 28921336 TI - An unusual cannister defect detected by an airway gas monitor. PMID- 28921337 TI - 3rd Annual Meeting of the Japanese Society of Cardiovascular Anesthesiologists Yokohama, Japan, November 21-22, 1998. PMID- 28921338 TI - The effect of high-dose vitamin D3 supplementation on bone mineral density in subjects with prediabetes. AB - : The rationale of this study was to determine the effect of high-dose vitamin D3 supplementation on bone mineral density (BMD). Prediabetic males given vitamin D had significantly less reduction in BMD at the femoral neck compared to the controls. The clinical implications of our findings require further investigation. INTRODUCTION: Type 2 diabetes mellitus is associated with increased fracture risk, and recent studies show crosstalk between bone and glucose metabolism. Few studies have investigated the effect of vitamin D supplementation on the bone without additional calcium. In the present study, we aimed to determine whether a high dose of vitamin D3 could improve bone mass density (BMD) in prediabetic subjects. METHODS: The current study was conducted as a secondary research on a previously performed trial, in which 511 subjects with prediabetes were randomized to vitamin D3 (20,000 IU per week) versus placebo for 5 years. BMD was measured using dual-energy X-ray absorptiometry (DEXA). RESULTS: Two hundred and fifty-six subjects were randomized to vitamin D and 255 to placebo. Mean baseline serum 25-hydroxyvitamin D (25(OH)D) level was 60 nmol/L. Two hundred and two and 214 in the vitamin D and placebo groups, respectively, completed BMD measurements, whereas one in each group was excluded due to use of bisphosphonates. Males given vitamin D had significantly less reduction in BMD at the femoral neck measurement site compared to the controls (0.000 versus - 0.010 g/cm2, p = 0.008). No significant differences between intervention groups were seen at the total hip measurement site, regarding both males and females. CONCLUSIONS: Vitamin D3 supplementation alone may be beneficial in males with prediabetes, but confirmatory studies are needed. PMID- 28921339 TI - Biotechnological production of value-added compounds by ustilaginomycetous yeasts. AB - The use of yeasts in bioprocesses can be considered one of the most relevant strategies in industrial biotechnology, and their potential is recognized due to the ability of these microorganisms for production of diverse value-added compounds. Yeasts from Ustilaginaceae family have been highlighted in the last years as a promising source of industrial interesting compounds, including enzymes, sugars, lipids, organic acids, and biosurfactants. These compounds may exhibit various applications in pharmaceutical, cosmetic, food, medical, and environmental fields, increasing the scientific attention in the study of ustilaginomycetous for biotechnological purposes. In this mini-review, we provide a comprehensive overview about the biotechnological use of yeasts from Ustilaginaceae family to produce value-added compounds, focusing in recent trends, characteristics of processes currently developed, new opportunities, and potential applications. PMID- 28921340 TI - Nephrotic-range proteinuria and brown urine in an 8-year-old girl: Answers. PMID- 28921341 TI - Sedative and respiratory effects of intramuscular midazolam as a premedicant: Influence of gender. AB - We compared the sedative and respiratory effects of intramuscular midazolam in men and women in a randomized, single-blind trial. The patients (203 men and 195 women) received a single dose of midazolam (0.05, 0.075, 0.1, or 0.15 mg.kg-1) intramuscularly 45 min before arriving at the operating room. Assessments in the operating room included sedation level and respiratory status rated on an objective four-point scale. Men given 0.075, 0.1, or 0.15 mg.kg-1 of midazolam exhibited greater sedation than did women given comparable doses. Midazolam 0.15 mg.kg-1 depressed respiration more frequently in men than in women. Plasma concentrations of midazolam were determined in 10 men, and 10 women randomly selected from the patients who received 0.15 mg.kg-1 of midazolam. A higher plasma concentration of midazolam, associated with a higher degree of sedation and respiratory depression, was attained in men than in women. These findings suggest that the optimal dose per unit body weight of intramuscular midazolam as premedication should be lower in men than in women to prevent over-sedation and respiratory depression. PMID- 28921342 TI - Does sex difference influence the neuromuscular blocking potencies of vecuronium? AB - One hundred and fifty patients of ASA class I-II undergoing elective surgery were given vecuronium 0.1 mg.kg-1 under fentanyl- (NLA), halothane, enflurane, isoflurane, or sevoflurane anesthesia, and the spontaneous recovery was monitored to study the sex differences as to onset time, duration [(T1, train of four (TOF)], and recovery index (T1, TOF). The onset time was significantly shorter in women than in men under isoflurane and sevoflurane anesthesia. No significant differences were seen between the sexes in terms of duration and recovery index of both T1 and TOF. We suggest that the results regarding onset time were due to the differences in distribution volume and extracellular fluid volume influenced by the proportions of lean body mass, fat tissue, and the occasional menstruation in women. It remains unclear, however, whether or not the effects of volatile gases to the sensitivity of receptors may contribute to the observed sex difference. Similar durations and recovery indexes in any anesthetic method indicate that the drug's rate of elimination is similar between the sexes. In conclusion, female patients favor the rapid onset of vecuronium when used under isoflurane or sevoflurane, but the recovery from the paralysis seems to be the same between the sexes regardless of the type of general anesthesia used. PMID- 28921343 TI - Sore throat incidence with the laryngeal mask: A comparison with orotracheal intubation. AB - The incidence of sore throat was evaluated among 80 healthy (ASA 1 and 2) nonpremedicated adult patients undergoing general anesthesia for general, plastic, urologic, gynecologic, and orthopedic surgery. The patients were randomly allocated in two groups: group one (n=39) consisted of patients in whom the airway was maintained by a laryngeal mask, and in group 2 (n=40), orotracheal intubation was performed. Both groups were similar in age, gender, site of surgery, and time of airway cannulation. Intraperitoneal surgery of the upper abdomen, and insertion of a nasogastric tube were exclusion criteria. The severity of sore throat was graded by the patients themselves using a visual analogue 100 mm scale, varying from 0 (no sore throat) to 10 (extremely sore). The sore throat incidence, severity and duration were significantly lower in the laryngeal mask group in comparison with the endotracheal intubation group. PMID- 28921344 TI - Cardiorespiratory dynamics during successful and unsuccessful trials of weaning from mechanical ventilation following cardiac surgery. AB - The purpose of this study was to examine the effects of a weaning trial with pressure support ventilation (PSV) on the cardiorespiratory dynamics in 20 cardiac surgery patients. In the patients who failed a weaning trial (failure group,n=6), the mean duration of cardiopulmonary bypass was 270+/-83 min and the mean postoperative lung-thorax compliance was 38+/-5 ml.cmH2O-1, whereas in successfully weaned patients (success group,n=14) they were 145+/-30 min and 55+/ 10 ml.cm H2O-1 respectively (mean+/-SD). Significant differences were recognized in those values between the two groups. Preoperative cardiac function, intraoperative blood loss, and postoperative fluid balance were similar in both groups. Cardiac index (CI) increased similarly in both groups. Pao2/FIo2 and percentage intrapulmonary shunt were constant in the success group, and these variables worsened in the failure group. Oxygen consumption ([Formula: see text]) increased and mixed venous O2 tension ([Formula: see text]) decreased in the failure group, whereas[Formula: see text] remained constant and[Formula: see text] increased in the success group. These data suggest that prolonged cardiopulmonary bypass might have produced acute lung injury. Decreased lung compliance may be responsible for rapid shallow breathing and an increase in oxygen consumption during a weaning trial, and may lead to weaning failure from mechanical ventilation. PMID- 28921345 TI - Simultaneous monitoring of noninvasive hemodynamic profile and capnography for tissue perfusion evaluation. AB - To study the simultaneous variations of end-tidal CO2 pressure (PetCO2) and aortic blood flow (ABF) during modifications of tissue perfusion, continuous noninvasive hemodynamic monitoring and continuous recording of PetCO2 were performed on 30 patients under general anesthesia and artificial mechanical ventilation. The 30 patients underwent orthopedic surgery on one of the lower limbs using a hemostatic tourniquet. Deflation of the pneumatic tourniquet resulted in a rise of ABF up to 39% (P<0.001), a rise of PetCO2 up to 17% (P<0.001), and a drop of total vascular systemic resistance (TVSR) of 59% (P<0.001). In all cases, the gradient of Paco2-PetCO2 showed mean variations of 1.2+/-0.5 mmHg. According to these results, the observed variations can not be explained by an alteration of the Ventilation/Perfusion (Vo/Q) ratio alone. It may be suggested that tissue hypoperfusion produced by a tourniquet generates CO2 and other metabolic products accumulation in tissues, which are removed during reperfusion. This would be expected to produce parallel increases in ABF and PetCO2. If the results are confirmed with further studies, rapid variations of PetCO2 during anesthesia may provide a noninvasive means of assessing the quality of global tissue perfusion. PMID- 28921346 TI - The influence of additional nitrous oxide during rapid anesthetic induction with sevoflurane. AB - In this study, a vital capacity rapid inhalation induction technique was used, and 4.5% sevoflurane in 100% oxygen and with 66% nitrous oxide in oxygen were compared. Each anesthetic gas was used on a group of 17 unpre-medicated volunteers. The induction time of sevoflurane in nitrous oxide with oxygen and sevoflurane in oxygen were 55+/-10 s and 81+/-22 s (SD), respectively, (P<0.05). Notable cardiovascular instability was not observed in either group. Serious complications such as laryngospasm, breath holding, and excessive salivation were not observed in either group. In conclusion, the addition of nitrous oxide to sevoflurane in oxygen is a useful technique because there were no increases in complications during the accelerated rapidity of induction. PMID- 28921347 TI - Lumbar epidural buprenorphine for postoperative pain relief following hepatectomy. AB - The induction of postoperative pain relief with lumbar epidural or intramuscular buprenorphine was studied in 30 patients undergoing hepatectomy. When patients first complained of pain after surgery, 0.06 mg or 0.12 mg of buprenorphine in 10 ml or 20 ml of saline was administered through an epidural catheter inserted at the L3-4 interspace, or 0.12 mg was administered intramuscularly. Two of seven patients receiving epidural buprenorphine 0.12 mg in 10 ml saline were completely pain-free, and the other five patients in this group had only slight pain. Four of eight patients receiving epidural buprenorphine 0.12 mg in 20 ml saline were completely pain-free, and the other four patients in this group had only slight pain. Epidural buprenorphine 0.06 mg in 20 ml saline and intramuscular buprenorphine 0.12 mg each yielded only incomplete analgesia. The duration of analgesia of epidural buprenorphine 0.12 mg administered at the lumbar level was about 8 h. There were no significant changes over time in circulatory or respiratory variables induced by buprenorphine. No patient had serious adverse effects. Lumbar epidural administration of buprenorphine 0.12 mg diluted to 10 or 20 ml (20 ml might be preferable) with saline is recommended for induction of postoperative analgesia following hepatectomy. PMID- 28921348 TI - Depression of sighing in the first three postoperative days with epidural morphine analgesia. AB - We have studied the effect of spontaneous sighs on maintaining arterial oxygenation in patients receiving epidural morphine for analgesia after upper abdominal surgery. Sixteen patients scheduled for elective gastrectomy were monitored continuously with pulse oximetry and respiratory inductive plethysmography (RIP) during one night preoperatively and for 60 h postoperatively with repeate arterial blood gas analysis. An average of 3.1+/-1.2 (+/-SD) sighs were observed per hour preoperatively during sleep while postoperative sighs were significantly depressed to an average less than one per hour throughout the 60 h of the monitoring period (P<0.05). Although postoperative Pao2 values were significantly lower than preoperative values, there was no correlation between the decreases in Pao2 values and number of sighs. Thus, it is unlikely that the long-term absence of spontaneous sighs observed may serve as a contributing factor for the long-lasting hypoxemia in the postoperative period. PMID- 28921349 TI - Preoperative hypoxemia in conscious patients after subarachnoid hemorrhage. AB - We retrospectively examined partial arterial pressure of oxygen (Pao2) afer subarachnoid hemorrhage (SAH), adjusted for patient-related risk factors for hypoxemia in 51 adult patients with no disturbance of consciousness undergoing surgery for clipping of intracranial aneurysms. A control group of 174 patients undergoing other operations were used for comparison. Arterial blood gas analysis was performed while patients were spontaneously breathing room air in the supine position before induction of anesthesia. The Pao2 in the SAH patients was significantly lower (p<0.0001) than that in the control group after adjustment for age, obesity, and smoking status. In three patients in the SAH group, Pao2 was less than 60 mmHg. Close monitoring of arterial oxygenation with pulse oximetry is desirable, and supplemental oxygen should be considered during transfer from the patients' room to the operating suite, even for conscious patients of SAH without cardiopulmonary disease. PMID- 28921350 TI - Influence of tumor size on anesthetic management for pheochromocytoma resection. AB - The relationship between tumor size and the complexity of anesthetic management was studied using several values: plasma catecholamine concentrations, requirement of vasoactive agents, surgical time, blood loss, plasma glucose concentrations, and hemodynamic variables. Ten patients with clinical and laboratory diagnosis of pheochromocytoma were prospectively studied. Each anesthesia was maintained using inhalational anesthetic agents. Control of arterial blood pressure (ABP), heart rate (HR), and pulmonary artery blood pressure (PABP) was attempted with only titrating the inhalational anesthetics and adenosine triphosphate (ATP). If the titration of both the inhalational anesthetic and ATP failed to control ABP, HR, or PABP, then phentolamine, propranolol, trinitroglycerine, or norepinephrine was additionally used. Tumor weight was significantly correlated with amount of blood loss, surgical time, duration of ATP requirement, maximal dose of ATP infusion used, maximal plasma glucose concentration, and plasma total catecholamine concentration. However, the tumor weight was not correlated with hemodynamic variables. Patients who required propranolol generally had a significantly larger tumor than those who did not. In conclusion, surgical removal of large pheochromocytoma required more complicated anesthetic management than that of small pheochromocytoma. PMID- 28921351 TI - Effect of alkalimized mepivacaine for epidural anesthesia on the skin temperature and skin blood flow: A mathematical analysis by simulation model. AB - The changes in skin blood flow after barbiturate injection are predictable based upon changes in skin temperature, assuming that these changes are followed by ramp function of the first-order system composed of blood vessel-tissue-skin. We applied this simulation model to epidural anesthesia, and investigated the analogy between theoretical and measured values using 2% alkalinized and nonalkalinized mepivacaine. During epidural anesthesia, a Laser Doppler flowmeter and a skin temperature probe were used to simultaneously measure skin blood flow and skin temperature. The onset time of increases in skin temperature and blood flow in the alkalinized group was shortened by one-fourth of that of the nonalkalinized group. In the nonalkalinized group, the pattern of changes in skin blood flow could not be predicted using the mathematical model. In the alkalinized group, however, the skin blood flow change was in accord with the theoretical values calculated from the skin temperature. These results indicate that the precise prediction of measured values by the simulation model is dependent on the speed of the sympathetic blockade. Conversely, the response to sympathetic nerve and blood vessels in different conditions can be assessed using this simulation model. PMID- 28921352 TI - Density-modulated t's array, a new technique of processed electroencephalogram, for monitoring the effects of midazolam and nitrous oxide during spinal anesthesia. AB - We have investigated the utility of a new electroencephalogram (EEG) processing system, density-modulated t's array (DTA), which we have installed in a laptop personal computer together with density-modulated spectral array (DSA) for clinical monitoring. Ten patients scheduled for orthopedic operations on the lower extremities were anesthetized with 0.5% bupivacaine intrathecally, 50% nitrous oxide in oxygen by mask, and midazolam at a dose of 0.1 mg/kg intravenously. Immediately following the administration of the drugs, the power at the frequencies between 15 and 20 Hz increased. However, the power at these higher frequencies disappeared gradually and the power in the delta band and the smaller one in the alpha band became predominant. This pattern of dominant-band shift on the DSA and DTA was observed in all the patients. In three of the patients, the sedation level remained stable as judged by the absence of body movement, quiet, regular breathing and stable hemodynamics as well as steady EEG frequency distribution throughout the operations. They awoke from anesthesia rapidly on withdrawal of nitrous oxide, with return of the power at the higher frequencies. In the other seven patients, the power at the higher frequencies suddenly reappeared on the DSA and DTA during operation and slight movements of the head and upper limbs were observed with rises in blood pressure and heart rate. In three of these seven patients, the EEG change notably preceded the physiological activities by a few minutes. On the DTA, the occurrence of any significant clinical phenomenon was displayed in a color representing at value greater than +/-3. The DTA, testing power changes in the EEG at each 1-Hz interval for significant difference, permits the visual and quantitative assessment of EEG changes. PMID- 28921353 TI - Cutaneous distribution of sympathetic postganglionic fibers from stellate ganglion: A retrograde axonal tracing study using wheat germ agglutinin conjugated with horseradish peroxidase. AB - Sympathetic postganglionic cells of the stellate ganglion (SG) projecting to the skin in young dogs were labeled retrogradely with wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP). After application of WGA-HRP into the dermis and/or subcutaneous tissue of the upper extremity, numerous labeled cells were observed in the SG. The sympathetic postganglionic fibers from the SG were distributed in the skin area between the third cervical vertebra and the level of the thirteenth rib. These fibers decreased in number toward the rostral and caudal skin area with a peak on the upper extremity. Sympathetic postganglionic cells in the SG projecting to these skin areas were found ipsilaterally to the injection side. No labeled cells were observed in the SG after injecting WGA-HRP into the epidermis and/or subcutaneous tissue of the face, the level of the second cervical vertebra, and the lower extremity.Sympathetic postganglionic neurons of the SG which project in the cervical and thoracic sympathetic trunks were labeled retrogradely with unconjugated horseradish peroxidase (HRP) applied to the cut end of the sympathetic trunks proximal to the SG. The application was made in the cervical sympathetic trunk (CST) caudal to the superior cervical ganglion (SCG). In the thoracic sympathetic trunk (TST), the application was made between the fourth and fifth thoracic sympathetic ganglia (T4 and T5), and between T10 and T11. Labeled cell bodies were observed in SG bilaterally. PMID- 28921354 TI - Attenuation of ischemia reperfusion-induced lung edema by prostaglandin I2 analogue OP-2507 in the isolated perfused rat lung. AB - Using the physiological salt solution (PSS)/Ficollperfused rat lung, we studied the effect of prostaglandin I2 (PGI2) analogue, OP-2507, on ischemia-reperfusion lung injury. Ischemia was induced by stopping perfusion and ventilation. Reperfusion after 90 min of normothermic ischemia increased mean pulmonary artery perfusion pressure (Ppa) and produced significant lung edema. Pretreatment with OP-2507 (200 ng.ml-1 and 1000 ng.ml-1) equally attenuated the increase in Ppa and lung edema after reperfusion. Lactate dehydrogenase release from the OP-2507 treated lungs of both doses were significantly lower than the untreated lungs. Thus, OP-2507 seems to be a useful agent for preventing ischemia-reperfusion lung injury. PMID- 28921355 TI - Effects of halothane and enflurane on epithelium-dependent contraction and ion transport of canine tracheal epithelium. AB - To gain insight into the cellular mechanisms involved in bronchodilation induced by inhalation anesthetics, we investigated whether halothane and enflurane can modulate functions of airway epithelium, such as epithelium-mediated bronchodilation and transepithelial transport. To measure the isometric tension of airways, paired rings of canine bronchi (4-6 mm OD), with and without the epithelium were mounted in Krebs-Ringer solution, gassed with 95% O2 and 5% CO2, and isometric tension was continuously recorded. To determine transepithelial transport, the posterior membranous portion of the trachea was mounted in Ussing type chambers and the potential difference (PD), short-circuit current (SCC), and transepithelial resistance (R) were determined.Halothane and enflurane increased the contractile responses of the trachea to acetylcholine (ACh) in strips either with or without epithelium. However, this enhancement of the contractile responses by volatile agents was much larger with the epithelium than without. Furthermore, halothane tended to gradually increase and then decrease SCC of the trachea, but these changes were not statistically significant. These results indicate that halothane may modulate contractile response of the isolated trachea to ACh, but has no effect on ion transport by airway epithelium. The responsiveness of the trachea may be regulated independently of ion transport by airway epithelium. PMID- 28921356 TI - Capillary blood flow and arteriolovenular shunt in various organs in hypotensive states induced by nitroglycerine, nitroprusside, and nicardipine. AB - The capillary blood flow of 14 organs was measured in dogs using the microsphere (9MUm diameter) trapping method under hypotension induced by administration of either nitroglycerin (NTG), nitroprusside (SNP), or nicardipine (NIC). Simultaneously, blood flow through the arteriolovenular shunt in the brain, kidney, liver, mesenteric organs, skeletal muscles of the pelvic limb, and all organs in the body, except the lungs, were measured by collecting venous blood drained from the organs at 4.8 ml.min-1 for 2 min. Capillary blood flow remained unchanged in most organs under hypotension with either NTG or SNP, but in increased in most organs, together with an increase in cardiac output, under hypotension with NIC. Arteriolovenular shunt tended to increase in four organs, with the exception of the liver, and increased in the whole body under hypotension with NTG. However, arteriolovenular shunt remained unchanged under hypotension with SNP. Arteriolovenular shunt increased in the mesenteric organs under hypotension with NIC, but decreased in the skeletal muscles of the pelvic limb. These results indicated that none of these hypotensive drugs impairs the nutrient supply to organs; further, NIC protects it much more since it does not increase the shunt flow through major organs. PMID- 28921357 TI - Alteration of vascular capacitance and blood flow distribution during halothane anesthesia. AB - We examined the effect of halothane on systemic vascular capacitance as well as on systemic vascular resistance using cardiopulmonary bypass in dogs. Venous outflows from two different vascular beds, the splanchnic and extrasplanchnic beds, were also measured. Under constant perfusion flow and constant central venous pressure, a change in reservoir blood volume inversely represented a change in systemic blood volume and then in systemic vascular capacitance, and a change in mean arterial pressure directly reflected a change in systemic vascular resistance. Administration of 1% and 2% halothane produced the blood concentrations of 0.58+/-0.14 mM and 1.34+/-0.06 mM, respectively. Systemic vascular resistance decreased by 12+/-6% and 40+/-4% during 1% and 2% halothane, respecitively. Systemic blood volume increased by 7+/-2 ml.kg-1 and 15+/-4 ml.kg 1 during 1% and 2% halothane, respectively. Halothane did not cause significant blood flow redistribution between the splanchnic and extrasplanchnic vascular beds. These results suggest that halothane causes an increase in systemic vascular capacitance as well as a decrease in systemic vascular resistance. This increase in vascular capacitance may contribute in part to a decrease in cardiac output during halothane anesthesia. PMID- 28921358 TI - Two cases of status asthmaticus treated with isoflurane. PMID- 28921359 TI - Cardiac anesthesia in idiopathic hypereosinophilic syndrome. PMID- 28921360 TI - Verapamil reduced pulmonary hypertension in adult respiratory distress syndrome. PMID- 28921361 TI - Anesthetic management of a patient suspected of having Lambert-Eaton syndrome due to an unexpected prolongation of vecuronium. PMID- 28921362 TI - Aggravated sleep apnea after general anesthesia in a patient with Shy-Drager syndrome. PMID- 28921363 TI - Treatment of acute unilateral lung disease with differential lung intubation followed by asynchronous independent lung ventilation. PMID- 28921364 TI - Management of a patient with severe kyphoscoliosis and postoperative respiratory failure. PMID- 28921365 TI - Misplacement of an epidural catheter into the lumbar quardratus muscle. PMID- 28921366 TI - Diagnostic value of bronchoalveolar lavage in fat embolism syndrome: Report of a case. PMID- 28921367 TI - Recovery of consciousness after an 18-min global cerebral ischemia. PMID- 28921368 TI - Marked systemic hypotension accompanied by pulmonary hypertension following protamine reversal of heparin: Case report. PMID- 28921369 TI - Letter to the editor. PMID- 28921370 TI - Report on the computer software contest at the Forty-First Congress of the Japan Society of Anesthesiology. PMID- 28921371 TI - International standards for a safe practice of anesthesia: A step toward total quality assurance of anesthesia practice. PMID- 28921372 TI - A new post: Laureate of the history of anesthesia. PMID- 28921373 TI - Released fraction of polychlorinated biphenyls from soil-biosolid system using a leaching procedure and its comparison with bioavailable fraction determined by wheat plant uptake. AB - The bioavailability of polychlorinated biphenyls (PCBs) in soils amended with biosolids was estimated using an aqueous leaching process of the compounds combined with rotating disk sorptive extraction (RDSE), and compared with bioavailability determined through of PCB absorption in wheat plants growing in the same soil-biosolid matrix. The matrices consisted of soil amended with biosolids at doses of 30, 90, and 200 Mg/ha, which increase concomitantly the organic matter content of the matrix. Considering that PCBs were natively absent in both the biosolids and soil used, the compounds were spiked in the biosolids and aged for 10 days. For each biosolid dose, the aqueous leaching profile was studied and equilibrium time was calculated to be 33 h. The leaching fractions determined by RDSE, considering total PCBs studied, were 12, 7, and 6% and the bioavailable fractions absorbed by the wheat root were found to be 0.5, 0.3, and 0.2% for 30, 90, and 200 Mg/ha doses, respectively. Both fractions leachable and bioavailable decrease with both increasing hydrophobicity of the compound (Kow) and increasing in the biosolid dose. It was found that both fractions (leaching and bioavailable) correlated according to the bivariate least squares regression, represented by a coefficient of correlation of 0.86. Therefore, the application of the chemical method involving a leaching procedure is an alternative to estimate the bioavailable fraction of PCBs in wheat plants in a simpler and in a shorter time. PMID- 28921374 TI - Prostate cancer clinical presentation, incidence, mortality and survival in Guadeloupe over the period 2008-2013 from a population-based cancer registry. AB - PURPOSE: The Caribbean population of Guadeloupe has one of the highest incidence rates of prostate cancer worldwide. In 2008, a population-based cancer registry was set up for the monitoring of cancer incidence in the aftermath of the environmental pollution with chlordecone, a persistent organochlorine insecticide formerly used in banana plantations. We describe the clinical presentation, incidence, mortality and survival of prostate cancer for the period 2008-2013. METHODS: The Guadeloupe cancer registry has been routinely collecting all incident cases of cancer since 2008. We compared age-specific incidence rates between different populations, and calculated incidence and mortality rates standardized to the world population. Kaplan-Meier observed survival and estimated age-standardized net survival were calculated by category for age, PSA level, and Gleason score using the Pohar-Perme method. RESULTS: Overall, 3,295 cases of prostate cancer were recorded. World-standardized incidence and mortality were respectively 184.1 [177.8-190.4] and 23.9 [21.9-25.7] per 100,000 person-years. At diagnosis, the mean age of patients was 68 +/- 9.6 years old and 22% were aged over 75. Median PSA level was 8.9 [IQR: 6.0-16.0] and 13.6% of the patients had a Gleason >= 8. Five-year observed and net survivals were, respectively, 79.6% [77.9-81.2] and 90.7% [88.6-92.8]. CONCLUSION: The incidence of prostate cancer in Guadeloupe is among the highest in the world, along with those of the neighboring Caribbean countries and US African-Americans. We observed no decrease in incidence rates, and a decreasing but non-significant trend in mortality rates, which nonetheless remain higher than in high-income countries. Many Genome-Wide Association Studies are conducted to identify genetic markers involved in prostate cancer risk. In the Caribbean, complementary studies on both lifestyle and behavioral factors should highlight potential common risks among populations who share both genetic and environmental characteristics. PMID- 28921375 TI - Convex-PL: a novel knowledge-based potential for protein-ligand interactions deduced from structural databases using convex optimization. AB - We present a novel optimization approach to train a free-shape distance-dependent protein-ligand scoring function called Convex-PL. We do not impose any functional form of the scoring function. Instead, we decompose it into a polynomial basis and deduce the expansion coefficients from the structural knowledge base using a convex formulation of the optimization problem. Also, for the training set we do not generate false poses with molecular docking packages, but use constant RMSD rigid-body deformations of the ligands inside the binding pockets. This allows the obtained scoring function to be generally applicable to scoring of structural ensembles generated with different docking methods. We assess the Convex-PL scoring function using data from D3R Grand Challenge 2 submissions and the docking test of the CASF 2013 study. We demonstrate that our results outperform the other 20 methods previously assessed in CASF 2013. The method is available at http://team.inria.fr/nano-d/software/Convex-PL/ . PMID- 28921376 TI - Legal issues in governing genetic biobanks: the Italian framework as a case study for the implications for citizen's health through public-private initiatives. AB - This paper outlines some of the challenges faced by regulation of genetic biobanking, using case studies coming from the Italian legal system. The governance of genetic resources in the context of genetic biobanks in Italy is discussed, as an example of the stratification of different inputs and rules: EU law, national law, orders made by authorities and soft law, which need to be integrated with ethical principles, technological strategies and solutions. After providing an overview of the Italian legal regulation of genetic data processing, it considers the fate of genetic material and IP rights in the event of a biobank's insolvency. To this end, it analyses two case studies: a controversial bankruptcy case which occurred in Sardinia, one of the first examples of private and public partnership biobanks. Another case study considered is the Chris project: an example of partnership between a research institute in Bolzano and the South Tyrolean Health System. Both cases seem to point in the same direction, suggesting expediency of promoting and improving public-private partnerships to manage biological tissues and biotrust to conciliate patent law and public interest. PMID- 28921377 TI - Basophils activated via TLR signaling may contribute to pathophysiology of type 1 autoimmune pancreatitis. AB - BACKGROUND: Pathophysiology of type 1 autoimmune pancreatitis (AIP) is still unclear. We previously reported that M2 macrophages might play an important role in type 1 AIP. Recently, it has been reported that basophils regulate differentiation to M2 macrophages. In this study, we investigated basophils from the pancreatic tissue and peripheral blood of individuals with type 1 AIP. METHODS: By using immunohistochemistry, we investigated basophils in pancreatic tissue from 13 patients with type 1 AIP and examined expression of toll-like receptors (TLRs) by these cells. Additionally, we obtained peripheral blood samples from 27 healthy subjects, 40 patients with type 1 AIP, 8 patients with alcoholic chronic pancreatitis, 10 patients with bronchial asthma, and 10 patients with atopic dermatitis, and analyzed activation of basophils by stimulating them with ligands of TLR1-9. We also compared TLR expression in basophils from the tissue and blood samples. RESULTS: Basophils were detected in pancreatic tissues from 10 of 13 patients with type 1 AIP. Flow cytometric analysis revealed that the ratios of basophils activated by TLR4 stimulation in type 1 AIP (9.875 +/- 1.148%) and atopic dermatitis (11.768 +/- 1.899%) were significantly higher than those in healthy subjects (5.051 +/- 0.730%; P < 0.05). Levels of basophils activated by TLR2 stimulation were higher in seven type 1 AIP cases. Furthermore, stimulation of TLR2 and/or TLR4, which were expressed by basophils in pancreas, activated basophils in peripheral blood. CONCLUSIONS: Basophils activated via TLR signaling may play an important role in the pathophysiology of type 1 AIP. PMID- 28921378 TI - Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts. AB - Beta-N-methylamino-L-alanine (BMAA) has been demonstrated to contribute to the onset of the ALS/Parkinsonism-dementia complex (ALS/PDC) and is implicated in the progression of other neurodegenerative diseases. While the role of BMAA in these diseases is still debated, one of the suggested mechanisms involves the activation of excitatory glutamate receptors. In particular, the excitatory effects of BMAA are shown to be dependent on the presence of bicarbonate ions, which in turn forms carbamate adducts in physiological conditions. The formation of carbamate adducts from BMAA and bicarbonate is similar to the formation of carbamate adducts from non-proteinogenic amino acids. Structural, chemical, and biological information related to non-proteinogenic amino acids provide insight into the formation of and possible neurological action of BMAA. This article reviews the carbamate formation of BMAA in the presence of bicarbonate ions, with a particular focus on how the chemical equilibrium of BMAA carbamate adducts may affect the molecular mechanism of its function. Highlights of nuclear magnetic resonance (NMR)-based studies on the equilibrium process between free BMAA and its adducts are presented. The role of divalent metals on the equilibrium process is also explored. The formation and the equilibrium process of carbamate adducts of BMAA may answer questions on their neuroactive potency and provide strong motivation for further investigations into other toxic mechanisms. PMID- 28921379 TI - Time trends in utilization of G-CSF prophylaxis and risk of febrile neutropenia in a Medicare population receiving adjuvant chemotherapy for early-stage breast cancer. AB - PURPOSE: The purpose of this study is to assess temporal trends in the use of granulocyte colony-stimulating factor (G-CSF) prophylaxis and risk of febrile neutropenia (FN) among older women receiving adjuvant chemotherapy for early stage breast cancer. METHODS: Women aged >= 66 years with diagnosis of early stage breast cancer who initiated selected adjuvant chemotherapy regimens were identified using the SEER-Medicare data from 2002 to 2012. Adjusted, calendar year-specific proportions were estimated for use of G-CSF primary prophylaxis (PP) and secondary prophylaxis and FN risk in the first and the second/subsequent cycles during the first course of chemotherapy, using logistic regression models. calendar-year-specific mean probabilities were estimated with covariates set to modal values. RESULTS: Among 11,107 eligible patients (mean age 71.7 years), 74% received G-CSF in the first course of chemotherapy. Of all patients, 5819 (52%) received G-CSF PP, and among those not receiving G-CSF PP, only 5% received G-CSF secondary prophylaxis. The adjusted proportion using G-CSF PP increased from 6% in 2002 to 71% in 2012. During the same period, the adjusted risk of FN in the first cycle increased from 2% to 3%; the adjusted risk increased from 1.5% to 2.9% among those receiving G-CSF PP and from 2.3% to 3.5% among those not receiving G-CSF PP. CONCLUSION: The use of G-CSF PP increased substantially during the study period. Although channeling of higher-risk patients to treatment with G-CSF PP is expected, the adjusted risk of FN among patients treated with G CSF PP tended to be lower than among those not receiving G-CSF PP. PMID- 28921380 TI - Relationship between drug burden and physical and cognitive functions in a sample of nursing home patients with dementia. AB - PURPOSE: The Drug Burden Index (DBI) is a tool to quantify the anticholinergic and sedative load of drugs. Establishing functional correlates of the DBI could optimize drug prescribing in patients with dementia. In this cross-sectional study, we determined the relationship between DBI and cognitive and physical functions in a sample of patients with dementia. METHODS: Using performance-based tests, we measured physical and cognitive functions in 140 nursing home patients aged over 70 with all-cause dementia. We also determined anticholinergic DBI (AChDBI) and sedative DBI (SDBI) separately and in combination as total drug burden (TDB). RESULTS: Nearly one half of patients (48%) used at least one DBI contributing drug. In 33% of the patients, drug burden was moderate (0 < TDB < 1) whereas in 15%, drug burden was high (TDB >= 1). Multivariate models yielded no associations between TDB, AChDBI, and SDBI, and physical or cognitive function (all p > 0.05). CONCLUSIONS: A lack of association between drug burden and physical or cognitive function in this sample of patients with dementia could imply that drug prescribing is more optimal for patients with dementia compared with healthy older populations. However, such an interpretation of the data warrants scrutiny as several dementia-related factors may confound the results of the study. PMID- 28921381 TI - Pentachlorophenol molecule design with lower bioconcentration through 3D-QSAR associated with molecule docking. AB - A three-dimensional quantitative structure activity relationship (3D-QSAR) model is built by using a comparative molecular similarity indices analysis (CoMSIA) technique with an experimentally determined logarithm of bioconcentration factors (logBCFs) for 36 phenols in fish. Meanwhile, with the pentachlorophenol (PCP) molecule as target molecules, contributions of the molecular fields indicate that the electrostatic fields are the main influences on the bioconcentration of the PCP molecule. Based on the analytical results of CoMSIA contour map of PCP and PCP molecular docking with SOD protease (PDB ID: 4A7T), the R6 substituent positions of PCP were modified to give seven new modified PCP molecules with low bioconcentration in this paper. The energy barrier calculation of the new modified PCP molecular reaction pathways can infer the order of the substitution reaction s as -SCl > -CH2Cl > -COCl > -CCl3 > -CH=CH2 > -NO2 > -SH. These calculations, combined with anaerobic biodegradation, ecotoxic effect, and mobility of new modified PCP molecules, enable a new environmentally friendly compound when the Cl at the R6 position of PCP was replaced with -COCl substituent with low bioconcentration (reduced by 32.89%), ecotoxic effect basically unchanged (increased by 1.37%), anaerobic biodegradation increased (increased by 24.81%), and mobility basically unchanged (reduced by 0.94%) to be designed. PMID- 28921382 TI - The association between infantile postural asymmetry and unsettled behaviour in babies. AB - : Unsettled infant behaviour is a common problem of infancy without known aetiology or clearly effective management. Some manual therapists propose that musculoskeletal dysfunction contributes to unsettled infant behaviour, yet reported improvement following treatment is anecdotal. The infantile postural asymmetry measurement scale is a tool which measures infantile asymmetry, a form of musculoskeletal dysfunction. The first part of the study aimed to investigate its reliability and validity for measuring infantile postural asymmetry. This study also aimed to investigate whether there was an association between infantile postural asymmetry and unsettled infant behaviour and whether an association was mediated by, or confounded with, the demographic variables of age, sex, parity, birth weight and weight gain in 12- to 16-week-old infants. Fifty-eight infants were recruited and a quantitative cross-sectional observational design was used. An association between unsettled behaviour and infantile postural asymmetry was not found. A significant difference between high and low cervical rotation deficit groups for surgency was detected in female babies and needs further examination. CONCLUSION: Questions remain regarding the construct validity of the infantile postural asymmetry scale. No association between unsettled infant behaviour and infantile postural asymmetry was found in 12- to 16-week-old infants. The influence of sex on the interaction between infantile postural asymmetry and infant behaviour needs further examination. An association between unsettled infant behaviour and infantile postural asymmetry is still unproven. What is known: * Unsettled infant behaviour has a considerable impact on many family situations. * Identifying a definitive cause has been a source of much examination and research. Many different hypotheses have been suggested yet much is still unknown. What is new: * The association between unsettled infant behaviour and infantile postural asymmetry is still unproven. * The need to validate a reliable tool to measure infantile postural asymmetry, with particular focus on cervical spine rotation deficit, is indicated. PMID- 28921383 TI - LncRNA-CCAT1 Promotes Migration, Invasion, and EMT in Intrahepatic Cholangiocarcinoma Through Suppressing miR-152. AB - BACKGROUND: Increasing evidence has suggested that lncRNA CCAT1 is upregulated and functions as a potential tumor promoter in many cancers. However, the potential biological roles and regulatory mechanisms of CCAT1 in intrahepatic cholangiocarcinoma (ICC) remain unclear. METHODS: We used real-time PCR to measure CCAT1 expression in ICC tissues and the adjacent normal tissues. The statistical analyses were applied to evaluate the prognostic value and associations of CCAT1 expression with clinical parameters. The CCAT1 was silenced with siRNA in ICC cells. The migration and invasion of ICC cells were detected with Transwell assay. The expressions of epithelial-mesenchymal transition (EMT) related proteins were evaluated to discover whether the process of EMT was involved. RESULTS: We found that CCAT1 expression was elevated in ICC tissues compared to the adjacent normal tissues. We also found that high CCAT1 expression is closely correlated with tumor progression in ICC patients. Furthermore, our results show that knockdown of CCAT1 significantly suppressed the migration and invasion of ICC cells. Additionally, CCAT1 silencing remarkably reverses the EMT phenotype of ICC cells. Moreover, bioinformatics analysis and luciferase reporter assay revealed that CCAT1 directly bound to the miR-152, which has been reported to serve as a tumor suppressor in variety cancers. Further investigation demonstrated that CCAT1 led to the metastasis and EMT activation of ICC cells through inhibiting miR-152. CONCLUSIONS: Our results suggested that CCAT1 functions as an oncogenic lncRNA in ICC, which could serve as a potential diagnostic and therapeutic target for ICC patients. PMID- 28921384 TI - Can diffusion-weighted imaging distinguish between benign and malignant pediatric liver tumors? AB - BACKGROUND: There are limited data on utility of diffusion-weighted imaging (DWI) in the evaluation of pediatric liver lesions. OBJECTIVE: To determine whether qualitative and quantitative DWI can be used to differentiate benign and malignant pediatric liver lesions. MATERIALS AND METHODS: We retrospectively reviewed MRIs in children with focal liver lesions to qualitatively evaluate lesions noting diffusion restriction, T2 shine-through, increased diffusion, hypointensity on DWI and apparent diffusion coefficient (ADC) maps, and intermediate signal on both, and to measure ADC values. Pathology confirmation or a combination of clinical, laboratory and imaging features, and follow-up was used to determine final diagnosis. RESULTS: We included 112 focal hepatic lesions in 89 children (median age 11.5 years, 51 female), of which 92 lesions were benign and 20 malignant. Interobserver agreement was almost perfect for both qualitative (kappa 0.8735) and quantitative (intraclass correlation coefficient [ICC] 0.96) diffusion assessment. All malignant lesions showed diffusion restriction. Most benign lesions other than abscesses were not restricted. There was significant association of qualitative restriction with malignancy and non restriction with benignancy (Fisher exact test P<0.0001). Mean normalized ADC values of malignant lesions (1.23x10-3 mm2/s) were lower than benign lesions (1.62x10-3 mm2/s; Student's t-test, P<0.015). However, there was significant overlap of ADC between benign and malignant lesions, with wide range for each diagnosis. Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.63 for predicting malignancy using an ADC cut-off value of <=1.20x10-3 mm2/s, yielding a sensitivity of 78% and a specificity of 54% for differentiating malignant from benign lesions. CONCLUSION: Qualitative diffusion restriction in pediatric liver lesions is a good predictor of malignancy and can help to differentiate between benign and malignant lesions, in conjunction with conventional MR sequences. Even though malignant lesions demonstrated significantly lower ADC values than benign lesions, the use of quantitative diffusion remains limited in its utility for distinguishing them because of the significant overlap and wide ranges of ADC values. PMID- 28921385 TI - Acute impact of home parenteral nutrition in patients with late-stage cancer on family caregivers: preliminary data. AB - PURPOSE: Since there is no information regarding quality of life of caregivers assisting patients with advanced malignancy on home parenteral nutrition, herewith we report a preliminary series of 19 patients who received total parenteral nutrition at home under the strict supervision of their relatives. METHODS: The relatives of 19 incurable patients with cancer-related cachexia, discharged from the hospital with a home parenteral nutrition program, were prospectively studied. They filled out a validated questionnaire, the Family Strain Questionnaire Short Form, prior to patient discharge and after 2 weeks of home care. The questionnaire included 30 items, which explored different domains regarding the superimposed burden on caregivers in relation to the assistance given to their relatives. RESULTS: Our findings show that the basal level of strain was relatively high (about three quarters of positive answers) but did not increase after 2 weeks of home care. Similarly, there was no difference in the nutritional status and quality of life of the patients. Eight patients and their relatives could be also analyzed after 2 months and the results maintained unchanged. CONCLUSION: This preliminary investigation shows that home parenteral nutrition does not exacerbate the level of strain on caregivers involved in surveillance of such a supportive intervention. It is possible that the perception of an active contribution to the benefit of patients, who maintained unchanged their nutritional status and quality of life, could gratify caregivers despite the objective burden in the constant supervision of administering Parenteral Nutrition. PMID- 28921386 TI - Midterm outcomes of two-staged hybrid ablation of persistent and long-standing persistent atrial fibrillation using the versapolar epicardial surgical device and subsequent catheter ablation. AB - PURPOSE: Hybrid ablation of atrial fibrillation (AF) is a promising treatment strategy for patients with non-paroxysmal AF, although, data regarding mid-term outcomes are limited. METHODS: Patients with persistent or long-standing persistent AF were enrolled. Initially, a thoracoscopic, right-sided, epicardial ablation was performed, with a goal of creating a box lesion on the posterior wall of the left atrium; a novel versapolar radiofrequency (RF) catheter was used. In patients enrolled later, occlusion of the left atrial appendage was also performed. An endocardial procedure was performed 2-4 months later, with the goal of confirming/completing the box lesion and ablating the ganglionated plexi and cavotricuspid isthmus. Efficacy was assessed using multiple 24-h and 1-week Holter monitoring. Analysis was performed to search for variables associated with procedure's failure. RESULTS: Forty-one patients (14 persistent and 27 long standing persistent AF) were enrolled with a mean AF duration of 33.5 +/- 33.1 months. Mean follow-up was 507.2 +/- 201.1 days (180-731). At the last follow-up visit, 27(65%) patients were arrhythmia-free, without anti-arrhythmics or need for re-ablation. Additional 4 patients (9.8%) were in sinus rhythm (SR) following re-ablation of postprocedural peri-mitral flutter and 4 (9.8%) were in SR on anti arrhythmics. Longer periods of preoperative AF were independently associated with worse arrhythmia-free survival (p = 0.015). Serious postoperative complications occurred in 3 (7.3%) patients; only 1 (2.4%) patient had clinical consequences after 6 months. CONCLUSIONS: Hybrid ablation of non-paroxysmal AF using a novel, versapolar RF device yields promising mid-term results. Better arrhythmia-free survival rates were found in AF patients with shorter AF duration. PMID- 28921387 TI - Analysis of 24 genes reveals a monogenic cause in 11.1% of cases with steroid resistant nephrotic syndrome at a single center. AB - BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of end-stage renal disease (ESRD) among patients manifesting at under 25 years of age. We performed mutation analysis using a high-throughput PCR based microfluidic technology in 24 single-gene causes of SRNS in a cohort of 72 families, who presented with SRNS before the age of 25 years. METHODS: Within an 18-month interval, we obtained DNA samples, pedigree information, and clinical information from 77 consecutive children with SRNS from 72 different families seen at Boston Children's Hospital (BCH). Mutation analysis was completed by combining high-throughput multiplex PCR with next-generation sequencing. We analyzed the sequences of 18 recessive and 6 dominant genes of SRNS in all 72 families for disease-causing variants. RESULTS: We identified the disease-causing mutation in 8 out of 72 (11.1%) families. Mutations were detected in the six genes: NPHS1 (2 out of 72), WT1 (2 out of 72), NPHS2, MYO1E, TRPC6, and INF2. Median age at onset was 4.1 years in patients without a mutation (range 0.5 18.8), and 3.2 years in those in whom the causative mutation was detected (range 0.1-14.3). Mutations in dominant genes presented with a median onset of 4.5 years (range 3.2-14.3). Mutations in recessive genes presented with a median onset of 0.5 years (range 0.1-3.2). CONCLUSION: Our molecular genetic diagnostic study identified underlying monogenic causes of steroid-resistant nephrotic syndrome in ~11% of patients with SRNS using a cost-effective technique. We delineated some of the therapeutic, diagnostic, and prognostic implications. Our study confirms that genetic testing is indicated in pediatric patients with SRNS. PMID- 28921388 TI - Immunomodulatory potential of nanocurcumin-based formulation. AB - Vitamins, minerals, and nanocurcumin play a substantial role in various nutraceutical/pharmaceutical formulations that are widely used in therapeutics, cosmetics, and dietary supplements. The current study aimed to investigate the comparative in vitro immunomodulatory effect of a novel nanocurcumin-based formulation with curcumin in LPS-induced cytokine expression, NK cells' activity, and phagocytosis. The proinflammatory cytokines (TNF-alpha, IL-1beta, and MIP 1alpha) and NK cells' activity were measured in cell supernatants using ELISA assay; however, phagocytosis activity was performed using colorimetric analysis. The chemical characterization of novel nanocurcumin-based formulation using LC-MS (R t 19.02 min) and mass spectra analysis (m/z 369.04) confirmed the presence of the curcumin in highest peak concentration. MTT assay in three tested cell-lines showed that the formulation was found non-toxic at all the tested concentrations. The expression of TNF-alpha, IL-1beta, and MIP-1alpha in splenocytes was significantly (p <= 0.001) inhibited. Besides, the NK cells' activity and phagocytosis (macrophage) were increased significantly (p <= 0.001). Overall, the promising results of this study indicated the significant immunomodulatory effect of nanocurcumin-based formulation compared to the curcumin, which could be used against various inflammatory disorders such as allergy, asthma, autoimmune diseases, coeliac disease, inflammatory bowel disease, etc. PMID- 28921389 TI - Altered Structure and Intrinsic Functional Connectivity in Post-stroke Aphasia. AB - Previous studies have demonstrated that alterations of gray matter exist in post stroke aphasia (PSA) patients. However, so far, few studies combined structural alterations of gray matter volume (GMV) and intrinsic functional connectivity (iFC) imbalances of resting-state functional MRI to investigate the mechanism underlying PSA. The present study investigated specific regions with GMV abnormality in patients with PSA (n = 17) and age- and sex- matched healthy controls (HCs, n = 20) using voxel-based morphometry. In addition, we examined whether there is a link between abnormal gray matter and altered iFC. Furthermore, we explored the correlations between abnormal iFC and clinical scores in aphasic patients. We found significantly increased GMV in the right superior temporal gyrus, right inferior parietal lobule (IPL)/supramarginal gyrus (SMG), and left middle occipital gyrus. Decreased GMV was found in the right caudate gyrus, bilateral thalami in PSA patients. Patients showed increased remote interregional FC between the right IPL/SMG and right precuneus, right angular gyrus, right superior occipital gyrus; while reduced FC in the right caudate gyrus and supplementary motor area, dorsolateral superior frontal gyrus. Moreover, iFC strength between the left middle occipital gyrus and the left orbital middle frontal gyrus was positively correlated with the performance quotient. We suggest that GMV abnormality contributes to interregional FC in PSA. These results may provide useful information to understand the pathogenesis of post-stroke aphasia. PMID- 28921390 TI - The State of Men's Health Services in the Veterans Health Administration. AB - PURPOSE OF REVIEW: For many diseases that place a large burden on our health care system, men often have worse health outcomes than women. As the largest single provider of health care to men in the USA, the Veterans Health Administration (VA) has the potential to serve as leader in the delivery of improved men's health care to address these disparities. RECENT FINDINGS: The VA system has made recent strides in improving benefits for aspects of men's health that are traditionally poorly covered, such as treatment for male factor infertility. Despite this, review of Quality Enhancement Research Initiatives (QUERIs) within the VA system reveals few efforts to integrate disparate areas of care into a holistic men's health program. Policies to unify currently disparate aspects of men's health care will ensure that the VA remains a progressive model for other health care systems in the USA. PMID- 28921391 TI - Effects of web-based interventions on cancer patients' symptoms: review of randomized trials. AB - PURPOSE: Symptom management is of high priority in cancer care. Information and communication technology allows interventions to be provided through the internet to enhance the delivery of care. This study aimed to review the effects of web based interventions on cancer patients' symptoms. METHODS: MEDLINE, PSychINFO, PubMed, CINAHL, and Cochrane databases were systematically searched. Included were randomized controlled trials (RCTs), pilot RCTs, or quasi-experimental (QE) studies focusing on web-based interventions in adult cancer patients with at least one outcome primary or secondary, in terms of symptoms, treatment side effects, or distress. Data were analyzed study by study. RESULTS: Twenty studies were identified. All web interventions included information, 16 included self management support, 14 included self-monitoring, 13 included feedback/tailored information, 12 used communication with health-care professionals, and eight used communication with other patients. Overall, 13 studies reported positive symptom outcomes. Psychological distress was reported in eight studies with positive intervention effects in three. Symptoms of anxiety/depression were reported in ten studies with positive intervention effects in five. Somatic symptom severity was reported in ten studies with intervention effects found in six, and symptom distress was reported in six studies with intervention effects found in all. CONCLUSIONS: This review shows the promising potential of web-based interventions for cancer symptom management, although it was limited by considerable heterogeneity in the interventions tested and targeted outcomes. The multidimensional nature of symptoms was partly addressed; only one study was guided by a comprehensive theoretical model of cancer symptom management. It can only be speculated which web elements are important for effective symptom outcomes. Further testing is needed for web-based cancer symptom management. PMID- 28921392 TI - Resveratrol attenuates high glucose-induced endothelial cell apoptosis via mediation of store-operated calcium entry. AB - The aim of this study was to evaluate the influence of resveratrol on HG-induced calcium entry in islet microvascular (MS-1) endothelial cells. MS-1 cells were pretreated with resveratrol or 2-APB (an inhibitor of store-operated calcium entry) and then incubated with high glucose. Cell viability was determined using the cell counting kit-8 method. Reactive oxygen species, endothelial apoptosis, and NO production were detected by DHE probe, TUNEL detection, and nitrate reductase assay kit. Protein levels of SOCE were detected by western blotting. Pretreatment with resveratrol significantly attenuated HG-induced endothelial apoptosis and improved cell viability. However, pretreatment with resveratrol and 2-APB abolished this effect, suggesting that the attenuation of HG-induced apoptosis by resveratrol may be associated with SOCE. Subsequent analyses indicated that HG induced the SOCE-related proteins, including TRPC1, Orai1, and Stim1. These results suggest that resveratrol pretreatment is associated with relieved HG-induced endothelial apoptosis at least partly via inhibition of SOCE related proteins. PMID- 28921393 TI - Genome-wide compound heterozygote analysis highlights alleles associated with adult height in Europeans. AB - Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL. The analysis identified six regions (3q23, 5q35.1, 6p21.31, 6p21.33, 7q21.2, and 9p24.3), where multiple pairs of SNPs as CH showed genome wide significant association with height (P < 1.67 * 10-10). Of those, 9p24.3 represents a novel region influencing adult height, whereas the others have been highlighted in the previous GWAS on height based on analysis of individual SNPs. A replication analysis in 4080 Australians of European ancestry confirmed the significant CH-like association at 9p24.3 (P < 0.05). Together, the collapsed genotypes at these six loci explained 2.51% of the height variance (after adjusting for sex and age), compared with 3.23% explained by the 14 top associated SNPs at 14 loci identified by traditional GWAS in the same data set (P < 5 * 10-8). Overall, our study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its "missing heritability". Moreover, our findings raise promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations. PMID- 28921394 TI - Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat Induced Pulmonary Fibrosis. AB - Pirfenidone is known to slow the decline in vital capacity and increase survival in idiopathic pulmonary fibrosis (IPF). Besides, administration of glucocorticoids, e.g., prednisolone has been the conventional strategy to the treatment of patients with this disease, although their efficacy is under debate. Since multiple coactivated pathways are involved in the pathogenesis of IPF, combination therapy is a foundation strategy to cover many more synergetic mechanisms and increase response. The aim of the present study was to compare the therapeutic efficacy of prednisolone plus pirfenidone with pirfenidone alone in PQ-induced lung fibrosis. After development of PQ-induced lung fibrosis, pirfenidone, prednisolone, and their combination were administered for 14 consecutive days. Lung pathological lesions, along with increased hydroxyproline were determined in the paraquat group. Paraquat also caused oxidative stress and increasing the proinflammatory and profibrotic gene expression. Pirfenidone attenuated the PQ-induced pulmonary fibrosis from the analysis of antioxidant enzymes but prednisolone had no such effect. Co-treatment with pirfenidone and prednisolone suppressed lung hydroxyproline content, TGF-beta1, and TNF-alpha; however, prednisolone alone could not suppress pulmonary fibrosis which was significantly suppressed only by pirfenidone. Pirfenidone also suppressed the increase in MMP-2 and TIMP-1 induced by PQ. All of these effects were exaggerated when pirfenidone coadministered with prednisolone. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of hydroxyproline content, oxidative stress and proinflammatory and profibrotic gene expression during the development of PQ-induced pulmonary fibrosis in rats and combination therapy with prednisolone can represent more potent therapeutic effects. PMID- 28921395 TI - Analysis of integrated clinical trial protocols in early phases of medicinal product development. AB - PURPOSE: While in the past, most clinical trial applications (CTAs) following non integrated (standard) protocols were used to investigate one primary objective concerning a (new) drug, nowadays, the use of integrated protocols investigating multiple objectives within the same CTA becomes more and more popular. The aims of the present study were to investigate the usage and the impact of integrated protocols on regulatory activities and to find the motivation for their increasing use. METHODS: Two thousand nine hundred sixty-nine phase I and I/II CTAs submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) during the time period from August 1, 2004, until August 31, 2014, were analysed with regard to protocol and sponsor status, duration until initial authorisation and the number of substantial amendments and their respective approval times. Additionally, applicants who submitted integrated protocols to BfArM were interviewed with respect to their opinion on integrated protocols in an online survey. RESULTS: The percentage of integrated protocols has constantly increased by approximately 10% within the last 10 years from 17.9% in 2004 to 28.2% in 2014. It could be shown that authorisation procedures with single integrated protocols take significantly longer until initial authorisation (58 vs. 53 days) requires more substantial amendments (1.9 vs. 1.2 amendments per CTA) and the approval of the entirety of amendments takes longer to process as compared to standard protocols (22 vs. 14 days). Nevertheless, applicants prefer the use of integrated protocols due to higher time and cost economy for the entire phase I development process. CONCLUSION: Although clinical trials (CTs) following integrated protocols are partly more time-consuming and costly, still, time and/or money may be saved during drug development due to the fact that overall, fewer CTs are needed than with standard protocols. Hence, the main reason for the increasing use of integrated protocols is improved time and cost efficiencies when conducting CTs. PMID- 28921396 TI - Determination of dominant sources of nitrate contamination in transboundary (Russian Federation/Ukraine) catchment with heterogeneous land use. AB - Nitrate contamination of surface water and shallow groundwater was studied in transboundary (Russia/Ukraine) catchment with heterogeneous land use. Dominant sources of nitrate contamination were determined by applying a dual delta 15N-NO3 and delta 18O-NO3 isotope approach, multivariate statistics, and land use analysis. Nitrate concentration was highly variable from 0.25 to 22 mg L-1 in surface water and from 0.5 to 100 mg L-1 in groundwater. The applied method indicated that sewage to surface water and sewage and manure to groundwater were dominant sources of nitrate contamination. Nitrate/chloride molar ratio was added to support the dual isotope signature and indicated the contribution of fertilizers to the nitrate content in groundwater. Groundwater temperature was found to be an additional indicator of manure and sewerage leaks in the shallow aquifer which has limited protection and is vulnerable to groundwater pollution. PMID- 28921397 TI - A binding-block ion selective mechanism revealed by a Na/K selective channel. AB - Mechanosensitive (MS) channels are extensively studied membrane protein for maintaining intracellular homeostasis through translocating solutes and ions across the membrane, but its mechanisms of channel gating and ion selectivity are largely unknown. Here, we identified the YnaI channel as the Na+/K+ cation selective MS channel and solved its structure at 3.8 A by cryo-EM single-particle method. YnaI exhibits low conductance among the family of MS channels in E. coli, and shares a similar overall heptamer structure fold with previously studied MscS channels. By combining structural based mutagenesis, quantum mechanical and electrophysiological characterizations, we revealed that ion selective filter formed by seven hydrophobic methionine (YnaIMet158) in the transmembrane pore determined ion selectivity, and both ion selectivity and gating of YnaI channel were affected by accompanying anions in solution. Further quantum simulation and functional validation support that the distinct binding energies with various anions to YnaIMet158 facilitate Na+/K+ pass through, which was defined as binding block mechanism. Our structural and functional studies provided a new perspective for understanding the mechanism of how MS channels select ions driven by mechanical force. PMID- 28921398 TI - Preliminary analysis of numerical chromosome abnormalities in reciprocal and Robertsonian translocation preimplantation genetic diagnosis cases with 24 chromosomal analysis with an aCGH/SNP microarray. AB - PURPOSE: The aim of this study was to determine whether an interchromosomal effect (ICE) occurred in embryos obtained from reciprocal translocation (rcp) and Robertsonian translocation (RT) carriers who were following a preimplantation genetic diagnosis (PGD) with whole chromosome screening with an aCGH and SNP microarray. We also analyzed the chromosomal numerical abnormalities in embryos with aneuploidy in parental chromosomes that were not involved with a translocation and balanced in involved parental translocation chromosomes. METHODS: This retrospective study included 832 embryos obtained from rcp carriers and 382 embryos from RT carriers that were biopsied in 139 PGD cycles. The control group involved embryos obtained from age-matched patient karyotypes who were undergoing preimplantation genetic screening (PGS) with non-translocation, and 579 embryos were analyzed in the control group. A single blastomere at the cleavage stage or trophectoderm from a blastocyst was biopsied, and 24 chromosomal analysis with an aCGH/SNP microarray was conducted using the PGD/PGS protocols. Statistical analyses were implemented on the incidences of cumulative aneuploidy rates between the translocation carriers and the control group. RESULTS: Reliable results were obtained from 138 couples, among whom only one patient was a balanced rcp or RT translocation carrier, undergoing PGD testing in our center from January 2012 to June 2014. For day 3 embryos, the aneuploidy rates were 50.7% for rcp carriers and 49.1% for RT carriers, compared with the control group, with 44.8% at a maternal age < 36 years. When the maternal age was >= 36 years, the aneuploidy rates were increased to 61.1% for rcp carriers, 56.7% for RT carriers, and 60.3% for the control group. There were no significant differences. In day 5 embryos, the aneuploidy rates were 24.5% for rcp carriers and 34.9% for RT carriers, compared with the control group with 53.6% at a maternal age < 36 years. When the maternal age was >= 36 years, the aneuploidy rates were 10.7% for rcp carriers, 26.3% for RT carriers, and 57.1% for the control group. The cumulative aneuploidy rates of chromosome translocation carriers were significantly lower than the control group. No ICE was observed in cleavage and blastocyst stage embryos obtained from these carriers. Additionally, the risk of chromosomal numerical abnormalities was observed in each of the 23 pairs of autosomes or sex chromosomes from day 3 and day 5 embryos. CONCLUSION: There was not enough evidence to prove that ICE was present in embryos derived from both rcp and RT translocation carriers, regardless of the maternal age. However, chromosomal numerical abnormalities were noticed in 23 pairs of autosomes and sex chromosomes in parental structurally normal chromosomes. Thus, 24-chromosomal analysis with an aCGH/SNP microarray PGD protocol is required to decrease the risks of failure to diagnose aneuploidy in structurally normal chromosomes. PMID- 28921400 TI - Gut Microbiota and IL-17A: Physiological and Pathological Responses. AB - IL-17A is a cytokine which is produced by several immune and non-immune cells. The cytokine plays dual roles from protection from microbes and protection from pro-inflammatory based diseases to induction of the pro-inflammatory based diseases. The main mechanisms which lead to the controversial roles of IL-17A are yet to be clarified. Gut microbiota (GM) are the resident probiotic bacteria in the gastrointestinal tracts which have been introduced as a plausible regulator of IL-17A production and functions. This review article describes the recent information regarding the roles played by GM in determination of IL-17A functions outcome. PMID- 28921399 TI - Artesunate Inhibits Renal Ischemia Reperfusion-Stimulated Lung Inflammation in Rats by Activating HO-1 Pathway. AB - Artesunate (AS), a semi-synthetic derivative of Artemisia, has been shown to exert a wide range of pharmacological effects, such as anti-inflammatory and antioxidant functions. However, the protective functions of AS on renal ischemia reperfusion injury (RIR)-stimulated lung inflammation remain unclear. In this research, acute lung injury (ALI) was stimulated by renal ischemia reperfusion injury (RIR). AS (15 mg/kg) was intraperitoneal administrated to rat 1 h before RIR stimulation. Serum and pulmonary NO, MDA, IL-6, MIP-2, and PGE2 levels, arterial blood gas and biochemistry, lung wet/dry weight ratio and MPO activity, total cell number and protein concentration in BALF, tissue histology, and NF kappaB expression were determined. The results indicated that serum and pulmonary NO, MDA, IL-6, MIP-2, and PGE2 levels, lung wet/dry weight ratio and MPO activity, total cell number, and protein concentration in BALF enhanced after RIR stimulation. These alterations were mitigated by AS. AS attenuated lung wet/dry weight ratio and MPO activity, total cell number, and protein concentration in BALF. AS attenuated RIR-stimulated pulmonary NF-kappaB phosphorylation. In addition, these previously mentioned actions of AS were antagonized by suppressing HO-1 pathway. However, RIR-stimulated arterial blood gas and biochemistry and lung histopathology were also attenuated by AS. In summary, AS inhibited RIR-stimulated lung inflammation by activating HO-1 pathway. PMID- 28921401 TI - Experience with curative radiotherapy for cervix cancer in the Bahamas for 2006 2016. AB - BACKGROUND: Cervix cancer is a significant health problem. As access to quality care in Small Island Developing States improves, and cancer centers become established, providers of care can summarize local experience to benchmark system quality and look for ways to further improve value. METHODS: This is a retrospective study of all cases of cervix cancer managed 2006-2016 at The Cancer Centre Bahamas, in conjunction with Princess Margaret Hospital, Nassau, affiliated with The University of West Indies. Seventy-two women received curative radiotherapy or chemoradiotherapy. Herein are reported presenting characteristics, treatments, waiting and overall treatment times, plus outcomes of recurrence, survival, and adverse events. RESULTS: For 68 newly diagnosed cases, median waiting time (diagnosis to commencing treatment) was 110 days. It was 90 days for those 47 cases who had no prior surgery or neoadjuvant chemotherapy. Overall, 99% of intended external radiotherapy fractions, 74% of brachytherapy sessions, and 79% of concurrent weekly chemotherapy were administered. For all 72 cases, median overall treatment time was 63 days; and for the 47 case sub-group, it was 78 days during 2006-2010 and 65 days during 2011-2016 (p = 0.005), so improving over calendar time. Four cases experienced grade 3-4 toxicities. Twelve had urological complications from disease or treatment. Five cases experienced local failure; eight experienced distant failure. Newly diagnosed stage 2B (26/72) had a 2-year survival of 71%. CONCLUSION: This report demonstrates the impact of providing curative radiation based treatments for cervical cancer in a small state. It suggests ways to further improve operations and justifies additional research. PMID- 28921402 TI - An improved risk-explicit interval linear programming model for pollution load allocation for watershed management. AB - Although the risk-explicit interval linear programming (REILP) model has solved the problem of having interval solutions, it has an equity problem, which can lead to unbalanced allocation between different decision variables. Therefore, an improved REILP model is proposed. This model adds an equity objective function and three constraint conditions to overcome this equity problem. In this case, pollution reduction is in proportion to pollutant load, which supports balanced development between different regional economies. The model is used to solve the problem of pollution load allocation in a small transboundary watershed. Compared with the REILP original model result, our model achieves equity between the upstream and downstream pollutant loads; it also overcomes the problem of greatest pollution reduction, where sources are nearest to the control section. The model provides a better solution to the problem of pollution load allocation than previous versions. PMID- 28921403 TI - Biochar composites with nano zerovalent iron and eggshell powder for nitrate removal from aqueous solution with coexisting chloride ions. AB - Biochar (BC) was produced from date palm tree leaves and its composites were prepared with nano zerovalent iron (nZVI-BC) and hen eggshell powder (EP-BC). The produced BC and its composites were characterized by SEM, XRD, BET, and FTIR for surface structural, mineralogical, and chemical groups and tested for their efficiency for nitrate removal from aqueous solutions in the presence and absence of chloride ions. The incidence of graphene and nano zerovalent iron (Fe0) in the nZVI-BC composite was confirmed by XRD. The nZVI-BC composite possessed highest surface area (220.92 m2 g-1), carbon (80.55%), nitrogen (3.78%), and hydrogen (11.09%) contents compared to other materials. Nitrate sorption data was fitted well to the Langmuir (R 2 = 0.93-0.98) and Freundlich (R 2 = 0.90-0.99) isotherms. The sorption kinetics was adequately explained by the pseudo-second order, power function, and Elovich models. The nZVI-BC composite showed highest Langmuir predicted sorption capacity (148.10 mg g-1) followed by EP-BC composite (72.77 mg g-1). In addition to the high surface area, the higher nitrate removal capacity of nZVI-BC composite could be attributed to the combination of two processes, i.e., chemisorption (outer-sphere complexation) and reduction of nitrate to ammonia or nitrogen by Fe0. The appearance of Fe-O stretching and N-H bonds in post-sorption FTIR spectra of nZVI-BC composite suggested the occurrence of redox reaction and formation of Fe compound with N, such as ferric nitrate (Fe(NO3)3.9H2O). Coexistence of chloride ions negatively influenced the nitrate sorption. The decrease in nitrate sorption with increasing chloride ion concentration was observed, which could be due to the competition of free active sites on the sorbents between nitrate and chloride ions. The nZVI-BC composite exhibited higher nitrate removal efficiency compared to other materials even in the presence of highest concentration (100 mg L-1) of coexisting chloride ion. PMID- 28921405 TI - Cannabis-Associated Asthma and Allergies. AB - Inhalation of cannabis smoke is its most common use and the pulmonary complications of its use may be the single most common form of drug-induced pulmonary disease worldwide. However, the role of cannabis consumption in asthma patients and allergic clinical situations still remains controversial. To review the evidence of asthma and allergic diseases associated with the use of marijuana, we conducted a search of English, Spanish, and Portuguese medical using the search terms asthma, allergy, marijuana, marihuana, and cannabis. Entries made between January 1970 and March 2017 were retrieved. Several papers have shown the relationship between marijuana use and increase in asthma and other allergic diseases symptoms, as well as the increased frequency of medical visits. This narrative review emphasizes the importance to consider cannabis as a precipitating factor for acute asthma and allergic attacks in clinical practice. Although smoking of marijuana may cause respiratory symptoms, there is a need for more studies to elucidate many aspects in allergic asthma patients, especially considering the long-term use of the drug. These patients should avoid using marijuana and be oriented about individual health risks, possible dangers of second-hand smoke exposure, underage use, safe storage, and the over smoking of marijuana. PMID- 28921404 TI - Effectiveness of a New Lead-Shielding Device and Additional Filter for Reducing Staff and Patient Radiation Exposure During Videofluoroscopic Swallowing Study Using a Human Phantom. AB - Interventional radiology procedures often involve lengthy exposure to fluoroscopy derived radiation. We therefore devised a videofluoroscopic swallowing study (VFSS) procedure using a human phantom that proved to protect the patient and physician by reducing the radiation dose. We evaluated a new lead-shielding device and separately attached additional filters (1.0-, 2.0-, and 3.0-mm Al filters and a 0.5-mm Cu filter) during VFSS to reduce the patient's entrance skin dose (ESD). A monitor attached to the human phantom's neck measured the ESD. We also developed another lead shield (VFSS Shielding Box, 1.0-mm Pb equivalent) and tested its efficacy using the human phantom and an ionization chamber radiation survey meter with and without protection from scattered radiation at the physician's position on the phantom. We then measured the scattered radiation (at 90 and 150 cm above the floor) after combining the filters with the VFSS Shielding Box. With the additional filters, the ESD was reduced by 15.4-55.1%. With the VFSS Shielding Box alone, the scattered radiation was reduced by about 10% compared with the dose without additional shielding. With the VFSS Shielding Box and filters combined, the scattered radiation dose was reduced by a maximum of about 44% at the physician's position. Thus, the additional lead-shielding device effectively provided protection from scattered radiation during fluoroscopy. These results indicate that the combined VFSS Shielding Box and filters can effectively reduce the physician's and patient's radiation doses. PMID- 28921406 TI - Genome Annotation and Validation of Keratin-Hydrolyzing Proteolytic Enzymes from Serratia marcescens EGD-HP20. AB - Stabilization and utilization of poultry waste demand efficient biodegradation either by mixture of enzymes or by microbial system that can produce different types of protein-hydrolyzing enzymes. For utilization of this keratinous biomass, in the present study, genome was sequenced and annotated for a bacterium having multiple enzymatic options for hydrolysis of different soluble and insoluble protein fractions of poultry waste. Among the soluble protein substrates, optimum production of enzyme and soluble protein was observed in case of casein, whereas among the insoluble protein substrates, maximum production of enzyme was achieved when broken nails were used. Conditions for enhanced enzyme activity with concurrent degradation of keratin-rich poultry feather waste to protein-rich hydrolysate were optimized for different growth parameters. The bacterium grew well and highest protease production occurred in 144 h at mesophilic temperature (30 degrees C) and alkaline condition (pH 8-10) with enzyme activities of 134 and 168 U/mL, respectively. PMID- 28921407 TI - Combat exposure, emotional and physical role limitations, and substance use among male United States Army Reserve and National Guard soldiers. AB - PURPOSE: Combat-exposed soldiers are at an increased risk for health problems that diminish quality of life (QOL) and substance use. We explored the cross sectional associations between combat exposure and two measures of QOL, and the effect of substance use on those associations. METHODS: Data are from the baseline wave of Operation: SAFETY, an ongoing survey-based study of United States Army Reserve/National Guard (USAR/NG) soldiers and their partners. Our sample consisted of male USAR/NG soldiers with a history of deployment (N = 248). Limitations in usual activity due to physical and emotional problems were assessed using the 36-Item Short-Form Health Survey (SF-36). RESULTS: Greater combat exposure was independently associated with limitations in usual activity due to physical (regression coefficient = -0.35, 95% CI -0.55 to -0.16, R 2 = 0.09; p < 0.01) and emotional (regression coefficient = -0.32, 95% CI -0.56 to 0.09, R 2 = 0.09; p < 0.01) problems. Combat exposure had a significant interaction with frequent heavy drinking on physical role limitations (regression coefficient = -0.65, 95% CI -1.18 to -0.12, R 2 = 0.12; p < 0.05) and emotional role limitations (regression coefficient = -0.83, 95% CI -1.46 to -0.19, R 2 = 0.12; p < 0.05). Combat exposure also had a significant interaction with lifetime non-medical use of prescription drugs on physical role limitations (regression coefficient = 0.81, 95% CI 0.18-1.45, R 2 = 0.11; p < 0.05). CONCLUSION: Combat is an unmodifiable risk factor for poor QOL among soldiers; however, frequent heavy drinking and non-medical use of prescription drugs modifies the relationship between combat exposure and QOL. Therefore, substance use is a potential point of intervention to improve QOL among soldiers. PMID- 28921408 TI - Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis. AB - Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 +/- 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4-6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events. PMID- 28921409 TI - The Duality of Economic Issues With Medication Non-adherence in Patients With Inflammatory Arthritis. AB - PURPOSE OF REVIEW: In this review, we synthesize current data on non-adherence across inflammatory arthritides and explore (1) the effects of economic factors on non-adherence and (2) the impacts of non-adherence on economic outcomes. RECENT FINDINGS: Recent evidence demonstrates medication non-adherence rates as high as 74% in ankylosing spondylitis (AS), 90% in gout, 50% in psoriatic arthritis (PsA), 75% in systemic lupus erythematosus (SLE), and 82% in rheumatoid arthritis (RA). The effects of socioeconomic factors have been studied most in RA and SLE but with inconsistent findings. Nonetheless, the evidence points to having prescription coverage and costs of treatment as important factors in RA and education as an important factor in SLE. Limited data in AS and gout, and no studies of the effects of socioeconomic factors in PsA, show knowledge gaps for future research. Finally, there is a dearth of data with respect to the impacts of non-adherence on economic outcomes. PMID- 28921411 TI - Differences in the Severity, Distress, Interference, and Frequency on Cancer Related Symptoms Between Island Hispanic Puerto Ricans and Mainland Non-Hispanic Whites. AB - The knowledge base of cancer-related symptoms is increasing; yet, limited attention has been given to provide evidence on differences in the perception of cancer symptoms between ethnic groups, especially in the Hispanic Puerto Rican (PR) population. To examine whether there are significant differences in the severity, distress, interference, and frequency of cancer symptoms between island Hispanic PR and mainland non-Hispanic whites. In this secondary data analysis, data from 109 Hispanic PR was matched by age, gender and cancer diagnosis with data from non-Hispanic whites. Cancer symptoms were assessed using the Cancer Symptom Scale (CSS). Mann-Whitney statistical test was used to evaluate pairwise differences between Hispanic PR and non-Hispanic whites on symptoms from the CSS. There were significant differences on some symptoms including PR reporting: (a) more intense itching, swelling, taste change, difficulty sleeping, bloating, depression, sadness, worry, and nervousness; (b) significantly greater distress about taste change, appetite, anxiety, depression, worry, and feeling nervous; (c) rash, anxiety, depression, sadness, and nervousness interfered the most with their daily lives; and, (d) that the frequency of occurrence of the symptoms of pain, itching, dizziness, taste change, anxiety, sadness, and nervousness was higher compared to non-Hispanic whites. PR cancer patients are at increased risk for experiencing greater severity of cancer symptoms compared to non-Hispanic whites. But because the Hispanic oncology population does not always report symptoms, risking under-assessment and under-management, this suggests there may be a greater need for symptoms surveillance for this population. PMID- 28921410 TI - Vyacheslav (Slava) Klimov (1945-2017): A scientist par excellence, a great human being, a friend, and a Renaissance man. AB - Vyacheslav Vasilevich (V.V.) Klimov (or Slava, as most of us called him) was born on January 12, 1945 and passed away on May 9, 2017. He began his scientific career at the Bach Institute of Biochemistry of the USSR Academy of Sciences (Akademy Nauk (AN) SSSR), Moscow, Russia, and then, he was associated with the Institute of Photosynthesis, Pushchino, Moscow Region, for about 50 years. He worked in the field of biochemistry and biophysics of photosynthesis. He is known for his studies on the molecular organization of photosystem II (PSII). He was an eminent scientist in the field of photobiology, a well-respected professor, and, above all, an outstanding researcher. Further, he was one of the founding members of the Institute of Photosynthesis in Pushchino, Russia. To most, Slava Klimov was a great human being. He was one of the pioneers of research on the understanding of the mechanism of light energy conversion and of water oxidation in photosynthesis. Slava had many collaborations all over the world, and he is (and will be) very much missed by the scientific community and friends in Russia as well as around the World. We present here a brief biography and some comments on his research in photosynthesis. We remember him as a friendly and enthusiastic person who had an unflagging curiosity and energy to conduct outstanding research in many aspects of photosynthesis, especially that related to PSII. PMID- 28921412 TI - How close are we to therapies for Sanfilippo disease? AB - Sanfilippo disease is one of mucopolysaccharidoses (MPS), a group of lysosomal storage diseases characterized by accumulation of partially degraded glycosaminoglycans (GAGs). It is classified as MPS type III, though it is caused by four different genetic defects, determining subtypes A, B, C and D. In each subtype of MPS III, the primary storage GAG is heparan sulfate (HS), but mutations leading to A, B, C, and D subtypes are located in genes coding for heparan N-sulfatase (the SGSH gene), alpha-N-acetylglucosaminidase (the NAGLU gene), acetyl-CoA:alpha-glucosaminide acetyltransferase (the HGSNAT gene), and N acetylglucosamine-6-sulfatase (the GNS gene), respectively. Neurodegenerative changes in the central nervous system (CNS) are major problems in Sanfilippo disease. They cause severe cognitive disabilities and behavioral disturbances. This is the main reason of a current lack of therapeutic options for MPS III patients, while patients from some other MPS types (I, II, IVA, and VI) can be treated with enzyme replacement therapy or bone marrow or hematopoietic stem cell transplantations. Nevertheless, although no therapy is available for Sanfilippo disease now, recent years did bring important breakthroughs in this aspect, and clinical trials are being conducted with enzyme replacement therapy, gene therapy, and substrate reduction therapy. These recent achievements are summarized and discussed in this review. PMID- 28921413 TI - Honeycomb-like appearance on optical coherence tomography in right coronary artery. PMID- 28921414 TI - Multimedia education program and nutrition therapy improves HbA1c, weight, and lipid profile of patients with type 2 diabetes: a randomized clinical trial. AB - PURPOSE: To evaluate the effect of a multimedia education program and nutrition therapy on metabolic control in patients with type 2 diabetes. RESEARCH QUESTION: What is the effect of a multimedia education program and nutritional therapy on metabolic control in type 2 diabetes? PATIENTS AND METHODS: A randomized clinical trial was conducted in 351 patients randomly assigned to either an experimental group receiving a multimedia diabetes education program (MDE) and nutrition therapy (NT) (NT + MDE: n = 173), or to a control group who received nutrition therapy only (NT: n = 178). At baseline, 7, 14, and 21 months, the glycated hemoglobin (HbA1c), glucose, cholesterol, triglycerides, LDL-cholesterol, and HDL cholesterol were measured. Weight, body mass index (BMI), waist circumference (WC), fat percentage, fat and lean mass, systolic blood pressure (SBP), and diastolic (DBP) were also recorded. RESULTS: Glycated hemoglobin decreased in both groups, although the group with NT + MDE had a greater reduction, with a difference of -0.76% (95%CI -1.33 to -0.19) at 7 months and -0.73% (95%CI -1.37 to -0.09) at 21 months. Only in the NT + MDE did the glucose decrease at 7 (-41.2 mg/dL; 95%CI -52.0 to -30.5), 14 (-27.8 mg/dL; 95%CI -32.6 to -23.1), and 21 months (-36.6 mg/dL; 95%CI -46.6 to -26.6). Triglycerides and the atherogenic index decreased in both groups at 7 and 14 months; while only in the NT + MDE group did it decrease at 21 months. (p < 0.05). Weight decreased at 21 months in the NT + MDE group (-1.23, -2.29 at -0.16; p < 0.05). CONCLUSION: Nutrition therapy and a multimedia diabetes education program have a favorable impact on achieving metabolic control goals in type 2 diabetes. PMID- 28921415 TI - Comparing the Safety and Efficacy of Celecoxib for the Treatment of Osteoarthritis in Asian and non-Asian Populations: An Analysis of Data from Two Randomized, Double-blind, Placebo-controlled, Active-comparator Trials. AB - INTRODUCTION: Celecoxib is an effective treatment for pain associated with osteoarthritis. There are differences in patient demographics among ethnic groups, with Asian populations typically smaller in body size. As a consequence, there may be a perception that celecoxib is less effective, or has poorer tolerability in Asian patients. METHODS: This analysis compares data from two multicenter, randomized, double-blind, placebo-controlled, active-comparator trials of celecoxib for the treatment of osteoarthritis of the knee: one study in Asian patients and the other in a mixed population comprised mostly of non-Asian patients (from which Asian patients were excluded for this analysis). Each trial was of similar design, with patients randomized 2:2:1 to 6 weeks treatment with celecoxib 200 mg once daily, active comparator (naproxen 500 mg twice daily or ibuprofen 800 mg three times daily), or placebo. The primary efficacy endpoint in each trial was the change from baseline to week 6 in the Patient's Assessment of Arthritis Pain, as measured on a visual analog scale. RESULTS: In total, 329 patients were included in the efficacy analysis, 179 in the Asian study and 150 in the non-Asian study. The Asian population was significantly older and smaller in body size (P < 0.0001). There was no significant difference between the Asian and non-Asian populations in change in pain score (95% confidence interval) at study endpoint with celecoxib [-1.1 (-7.7, 5.5); P = 0.7400] or placebo [-5.2 ( 14.8, 4.4); P = 0.2870]. There were also no notable differences in safety outcomes between populations. CONCLUSIONS: Due to the smaller size of some Asian patients with OA, physicians may be tempted to decrease the dose of celecoxib below the therapeutic range recognized by regulatory authorities; these data suggest that dose changes are not necessary. FUNDING: Pfizer Inc. PMID- 28921416 TI - miR-17-5p Regulates Differential Expression of NCOA3 in Pig Intramuscular and Subcutaneous Adipose Tissue. AB - Fat distribution affects economic value in pork production. Intramuscular adipose tissue (IMAT) improves meat quality, whereas subcutaneous adipose tissue (SCAT) is usually regarded as waste. In the present study, we analyzed IMAT/SCAT (I/S) ratios in each pig. Individuals selected from a population of 1200 Suhuai pigs were divided into two cohorts; those with high I/S ratios and those with low I/S ratios, and correlations between nuclear Receptor Co-activator 3 (NCOA3), a critical gene involved in regulating fat accumulation, and fat distribution were investigated. The ratio of IMAT NCOA3 to SCAT NCOA3 expression levels (NCOA3I/NCOA3S) was higher in the high I/S group compared with the low I/S group. The NCOA3 expression level in fat tissue was positively correlated with fat deposition. miR-17-5p was identified as a putative regulator of NCOA3 based on bioinformatics prediction analysis followed by gene expression analysis. The miR 17-5pI/miR-17-5pS ratio was negatively correlated with the NCOA3I/NCOA3S ratio. The predicted relationship between miR-17-5p and NCOA3 was further verified by dual luciferase activity assays, qPCR, and western blots. Overexpression of miR 17-5p in intramuscular preadipocytes inhibited NCOA3 expression and reduced preadipocyte differentiation. FABP4 and PPARG expression were also significantly decreased, as was triglyceride content. Meanwhile, knockdown of miR-17-5p significantly increased NCOA3 expression and promoted intramuscular preadipocyte differentiation. Based on these results, we propose that differential expression of NCOA3 in pig intramuscular and subcutaneous adipose tissue is regulated by miR 17-5p. PMID- 28921417 TI - Bacteriocinogenic LAB Strains for Fermented Meat Preservation: Perspectives, Challenges, and Limitations. AB - Over the last decades, much research has focused on lactic acid bacteria (LAB) bacteriocins because of their potential as biopreservatives and their action against the growth of spoilage microbes. Meat and fermented meat products are prone to microbial contamination, causing health risks, as well as economic losses in the meat industry. The use of bacteriocin-producing LAB starter or protective cultures is suitable for fermented meats. However, although bacteriocins can be produced during meat processing, their levels are usually much lower than those achieved during in vitro fermentations under optimal environmental conditions. Thus, the direct addition of a bacteriocin food additive would be desirable. Moreover, safety and technological characteristics of the bacteriocinogenic LAB must be considered before their widespread applications. This review describes the perspectives and challenges toward the complete disclosure of new bacteriocins as effective preservatives in the production of safe and "healthy" fermented meat products. PMID- 28921419 TI - Sentinel Lymph Node Biopsy in Endometrial Cancer: a New Standard of Care? AB - OPINION STATEMENT: Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment in endometrial cancer (EMCA). Unfortunately, full lymphadenectomy bears significant surgical and postoperative risks. The majority of patients with clinical stage I disease will not have metastatic disease; thus, a full lymphadenectomy only increases morbidity in this population of patients. The use of the sentinel lymph node (SLN) biopsy has emerged as an alternative to complete lymphadenectomy in EMCA. By removing the highest yield lymph nodes, the SLN biopsy has the same diagnostic ability as lymphadenectomy while minimizing morbidity. The sensitivity of sentinel lymph node identification with robotic fluorescence imaging for detecting metastatic endometrial and cervical cancer (FIRES) trial published this year is the largest prospective, multi-institution trial investigating the accuracy of the SLN biopsy for endometrial and cervical cancer. Results of this trial found an excellent sensitivity (97.2%) and false negative rate (3%) with the technique. The conclusions from the FIRES trial and those of a recent meta analysis are that SLN biopsy has an acceptable diagnostic accuracy in detecting lymphatic metastases, and can replace lymphadenectomy for this diagnostic purpose. There remains controversy surrounding the SLN biopsy in high-risk disease and the use of adjuvant therapy in the setting of low volume disease detected with ultrastaging. Current data suggests that the technique is accurate in high-risk disease and that the increased detection of metastasis helps guide adjuvant therapy such that oncologic outcomes are likely not affected by forgoing a full lymphadenectomy. Further prospective study is needed to investigate the impact of low volume metastatic disease on oncologic outcomes and the need for adjuvant therapy in these patients. PMID- 28921418 TI - Coping with Phantom Limb Pain. AB - Phantom limb pain is a chronic neuropathic pain that develops in 45-85% of patients who undergo major amputations of the upper and lower extremities and appears predominantly during two time frames following an amputation: the first month and later about 1 year. Although in most patients the frequency and intensity of pain diminish over time, severe pain persists in about 5-10%. It has been proposed that factors in both the peripheral and central nervous systems play major roles in triggering the development and maintenance of pain associated with extremity amputations. Chronic pain is physically and mentally debilitating, affecting an individual's capacity for self-care, but also diminishing an individual's daily capacity for personal and economic independence. In addition, the pain may lead to depression and feelings of hopelessness. A National Center for Biotechnology Information study found that in the USA alone, the annual cost of dealing with neuropathic pain is more than $600 billion, with an estimated 20 million people in the USA suffering from this condition. Although the pain can be reduced by antiepileptic drugs and analgesics, they are frequently ineffective or their side effects preclude their use. The optimal approach for eliminating neuropathic pain and improving individuals' quality of life is the development of novel techniques that permanently prevent the development and maintenance of neuropathic pain, or that eliminate the pain once it has developed. What is still required is understanding when and where an effective novel technique must be applied, such as onto the nerve stump of the transected peripheral axons, dorsal root ganglion neurons, spinal cord, or cortex to induce the desired influences. This review, the second of two in this journal volume, examines the techniques that may be capable of reducing or eliminating chronic neuropathic pain once it has developed. Such an understanding will improve amputees' quality of life by blocking the mechanisms that trigger and/or maintain PLP and chronic neuropathic pain. PMID- 28921420 TI - Causes of an increased pressure gradient through the left ventricular outflow tract: a West Coast experience. AB - BACKGROUND: Left ventricular outflow tract obstruction (LVOTO) occurs from not only obstructive hypertrophic cardiomyopathy but also other conditions such as sigmoid septum or post mitral valve repair. However, the changes of the LVOT pressure gradient (LVOT PG) in LVOTO with various conditions remain unclear. METHODS: The clinical characteristics and echocardiographic parameters of 73 patients with LVOT PG >=50 mmHg at rest on Doppler ultrasound were retrospectively investigated. RESULTS: In these patients (age 69 +/- 15 years, 38% male), high prevalences of hypertension (66%) and anemia (43%) were observed. The most frequent clinical disease causing LVOTO was hypertrophic obstructive cardiomyopathy (HOCM) (74%). There were other conditions, including hypertensive left ventricular hypertrophy (9%), post-open heart surgery (7%), sigmoid septum (4%), hyperkinetic LV (3%), takotsubo cardiomyopathy (1.5%), and discrete subaortic membrane (1.5%). Significant improvement or reduction of LVOTO was observed in 93% of cases at follow-up (mean 44 months) echocardiography compared with the initial one with the use of medications and transcatheter procedures. CONCLUSIONS: The causes of LVOTO are diverse. However, the occurrence of LVOTO might depend on the coexistence of primary morphological LV characteristics and hemodynamic LV status. Specific factors causing LVOTO need to be investigated, and efforts for improvement of each individual status by the appropriate approach are required. PMID- 28921421 TI - Tissue Engineering of 3D Organotypic Microtissues by Acoustic Assembly. AB - There is a rapidly growing interest in generation of 3D organotypic microtissues with human physiologically relevant structure, function, and cell population in a wide range of applications including drug screening, in vitro physiological/pathological models, and regenerative medicine. Here, we provide a detailed procedure to generate structurally defined 3D organotypic microtissues from cells or cell spheroids using acoustic waves as a biocompatible and scaffold free tissue engineering tool. PMID- 28921424 TI - Platforms for Recombinant Therapeutic Glycoprotein Production. AB - The majority of FDA-approved biology-derived products are recombinant glycoproteins. These proteins have been used for the treatment of several diseases, with numerous products currently approved for clinical use. The choice of the expression system is a key step toward a successful functional protein production, since glycosylation influences yield, pharmacokinetics, biological activity, and immunogenicity. This chapter covers the general aspects of therapeutic recombinant glycoproteins and the platforms that are being employed for their production. PMID- 28921422 TI - High Incidence of Secondary Hyperparathyroidism in Bariatric Patients: Comparing Different Procedures. AB - BACKGROUND: Bariatric surgery is an effective therapy for morbid obesity but may reduce calcium absorption and significantly decrease the bone mineral density. This study examined the prevalence of secondary hyperparathyroidism (SHPT) in obese subjects during follow-up after different bariatric surgeries. We investigated predictors of SHPT. METHODS: We enrolled 1470 obese subjects undergoing bariatric/metabolic surgery with at least 1-year follow-up, including 322 patients undergoing Roux-en-Y gastric bypass (RYGB), 695 undergoing single anastomosis (mini-) gastric bypass (SAGB), 93 undergoing laparoscopic adjustable gastric banding (LAGB), and 360 undergoing sleeve gastrectomy (SG). Five years of data were available for 215 patients. Patients were instructed to supplement their diet according to the guideline. Calcium, parathyroid hormone (PTH), and vitamin D levels were measured before surgery and at 1 and 5 years after surgery. SHPT was defined as PTH > 69 pg/mL. RESULTS: The overall prevalence of SHPT was high, 21.0% before surgery and was not different between patients with different bariatric procedures. Pre-operative PTH correlated with age, BMI, and vitamin D levels. Multi-variate analysis confirmed that vitamin D level was the only independent predictor of SHPT before surgery. The prevalence of SHPT increased to 35.4% at 1 year after surgery and 63.3% at 5 years after surgery. SAGB had the highest prevalence of SHPT (50.6%) followed by RYGB (33.2%), LAGB (25.8%), and SG (17.8%) at 1 year after surgery. At 5 years after surgery, SAGB still had the highest prevalence of SHPT (73.6%), followed by RYGB (56.6%), LAGB (38.5%), and SG (41.7%). Serum PTH at 1 year after surgery correlated with decreased BMI and weight loss. Multi-variate analysis confirmed that age, sex, calcium level, and bypass procedure were independent predictor of SHPT after surgery. CONCLUSIONS: The prevalence of SHPT is high in morbidly obese patients before bariatric surgery which is related to vitamin D deficiency. The prevalence of SHPT increased continually along with the time after bariatric surgery, especially in patients receiving SAGB, followed by RYGB. The supplementation of vitamin D and calcium have to be higher in bypass procedure, especially in malabsorptive procedure. PMID- 28921425 TI - Uncovering Innovation Features and Emerging Technologies in Molecular Biology through Patent Analysis. AB - Scientific research at universities has a crucial role in leveraging a country's innovative potential. Sectors that require greater investments in technology for the development of their research, such as biotechnology, need to be aware of the frontier state-of-the-art technology and the knowledge incrusted within it. Although the information available in scientific articles is well explored in academic environment, the patent literature, where much of the technological information is present, is still poorly accessed. This chapter is intended to instruct students and researchers at universities to look at patent document analysis as a source of scientific and technological information and explore its applications. Within this chapter, we use the technological area regarding immunoglobulins inventions (monoclonal and polyclonal antibodies) as example to provide directions on how to develop a patent landscape to get an overview of the inventions in a certain field; how to map a collaborative network of inventors/assignees to help the pursuit and identification of future partnerships; and lastly we describe the steps of how to set up a network of patent citations with the aim of forecasting emerging technologies. We strongly believe that incorporate data from patents in planning phase of research projects at academia, as well as to establish partnerships and join R&D efforts to invest on promising technologies, is of great relevance to leverage the growth of the biotechnology sector. PMID- 28921426 TI - Production of Full-Length Antibody by Pichia pastoris. AB - The methylotrophic yeast Pichia pastoris has become an increasingly popular host for recombinant protein expression in recent times. MRL pioneered a glycoengineered humanized P. pastoris expression system that could produce glycoproteins with glycosylation profiles similar to mammalian systems. Therapeutic glycoproteins produced by the humanized P. pastoris platform have shown comparable folding, stability, and in vitro and in vivo efficacies in preclinical models to their counterparts produced from the CHO cells. P. pastoris offers a cost and time efficient alternative platform for therapeutic protein production. This chapter describes a protocol for using P. pastoris to produce full-length monoclonal antibodies. It covers a broad spectrum of antibody expression technologies in P. pastoris, including expression vector construction, yeast transformation, high-throughput strain selection, fermentation, and antibody purification. PMID- 28921427 TI - Human Cells as Platform to Produce Gamma-Carboxylated Proteins. AB - The gamma-carboxylated proteins belong to a family of proteins that depend on vitamin K for normal biosynthesis. The major representative gamma-carboxylated proteins are the coagulation system proteins, for example, factor VII, factor IX, factor X, prothrombin, and proteins C, S, and Z. These molecules have harbored posttranslational modifications, such as glycosylation and gamma-carboxylation, and for this reason they need to be produced in mammalian cell lines. Human cells lines have emerged as the most promising alternative to the production of gamma carboxylated proteins. In this chapter, the methods to generate human cells as a platform to produce gamma-carboxylated proteins, for example the coagulation factors VII and IX, are presented. From the cell line modification up to the vitamin K adaptation of the produced cells is described in the protocols presented in this chapter. PMID- 28921428 TI - Production of Recombinant Factor VIII in Human Cell Lines. AB - Human cell lines can produce recombinant proteins much more similar to their natural counterpart, compared to other mammalian cell lines, reducing potential immunogenic reactions. Recombinant proteins produced in nonhuman cells can have in its structure glycan epitopes, such as Galalpha1,3-Gal (alpha-Gal) and N glycolylneuraminic acid (Neu5Gc) residues, that are antigenic to humans and can potentially affect the efficacy of the recombinant product. Therefore, the production of recombinant factor VIII (rFVIII) in human cell lines is a new approach to avoid nonhuman glycosylation. Here, we describe a protocol to produce rFVIII in the human cell line SK-HEP, using a lentiviral vector to produce high quantities of the recombinant protein. PMID- 28921429 TI - Strategies to Suspension Serum-Free Adaptation of Mammalian Cell Lines for Recombinant Glycoprotein Production. AB - Serum-free suspension cultures are preferably required for recombinant protein production due to its readiness in upstream/downstream processing and scale-up, therefore increasing process productivity and competitiveness. This type of culture replaces traditional cell culturing as the presence of animal-derived components may introduce lot-a-lot variability and adventitious pathogens to the process. However, adapting cells to serum-free conditions is challenging, time consuming, and cell line and medium dependent. In this chapter, we present different approaches that can be used to adapt mammalian cell lines from an anchorage-dependent serum supplemented culture to a suspension serum-free culture. PMID- 28921430 TI - Production of Recombinant Rabies Virus Glycoprotein by Insect Cells in a Single Use Fixed-Bed Bioreactor. AB - A single-use fixed-bed bioreactor (iCELLis nano) can be used for cultivating non adherent insect cells, which can be then recovered for scaling up or for harvesting a membrane-associated viral glycoprotein with high quality in terms of preserved protein structure and biological function. Here, we describe the procedures for establishing genetically modified Drosophila melanogaster Schneider 2 (S2) cell cultures in the iCELLis nano bioreactor and for quantifying by ELISA the recombinant rabies virus glycoprotein (rRVGP) synthesized. By using the described protocol of production, the following performance can be regularly achieved: 1.7 +/- 0.6 * 1E10 total cells; 2.4 +/- 0.8 * 1E7 cells/mL and 1.2 +/- 0.9 MUg of rRVGP/1E7 cells; 1.5 +/- 0.8 mg of total rRVGP. PMID- 28921431 TI - Cell-Free Production of Protein Biologics Within 24 H. AB - Protein biologics have emerged as a safe and effective group of drug products that can be used in a variety of medical disorders and clinical settings, including treatment of orphan diseases, personalized medicine, and point-of-care applications. However, the full potential of protein biologics for such applications will not be realized until there are methods available for rapid and cost-effective production of small scale products for individual needs. Here, we describe a modular and scalable method for rapid and adaptable production of protein-based medical products at small doses. The method includes cell-free synthesis of the protein target in a reactor module followed by a fluidic process for protein purification. As a proof of concept, we describe the application of this method for expression and purification of a bioactive pharmaceutically relevant protein biologic, recombinant human erythropoietin, at a single dose within 24 h. This method can be applied toward the development of automated platforms for rapid and adaptive production of protein biologics at the point of care in response to specific medical needs. PMID- 28921432 TI - Demonstration-Scale High-Cell-Density Fermentation of Pichia pastoris. AB - Pichia pastoris has been one of the most successful heterologous overexpression systems in generating proteins for large-scale production through high-cell density fermentation. However, optimizing conditions of the large-scale high-cell density fermentation for biochemistry and industrialization is usually a laborious and time-consuming process. Furthermore, it is often difficult to produce authentic proteins in large quantities, which is a major obstacle for functional and structural features analysis and industrial application. For these reasons, we have developed a protocol for efficient demonstration-scale high-cell density fermentation of P. pastoris, which employs a new methanol-feeding strategy-biomass-stat strategy and a strategy of increased air pressure instead of pure oxygen supplement. The protocol included three typical stages of glycerol batch fermentation (initial culture phase), glycerol fed-batch fermentation (biomass accumulation phase), and methanol fed-batch fermentation (induction phase), which allows direct online-monitoring of fermentation conditions, including broth pH, temperature, DO, anti-foam generation, and feeding of glycerol and methanol. Using this protocol, production of the recombinant beta xylosidase of Lentinula edodes origin in 1000-L scale fermentation can be up to ~900 mg/L or 9.4 mg/g cells (dry cell weight, intracellular expression), with the specific production rate and average specific production of 0.1 mg/g/h and 0.081 mg/g/h, respectively. The methodology described in this protocol can be easily transferred to other systems, and eligible to scale up for a large number of proteins used in either the scientific studies or commercial purposes. PMID- 28921433 TI - Large-Scale Transient Transfection of Suspension Mammalian Cells for VLP Production. AB - Large-scale transient transfection of mammalian cell suspension cultures enables the production of biological products in sufficient quantity and under stringent quality attributes to perform accelerated in vitro evaluations and has the potential to support preclinical or even clinical studies. Here we describe the methodology to produce VLPs in a 3L bioreactor, using suspension HEK 293 cells and PEIPro as a transfection reagent. Cells are grown in the bioreactor to 1 * 106 cells/mL and transfected with a plasmid DNA-PEI complex at a ratio of 1:2. Dissolved oxygen and pH are controlled and are online monitored during the production phase and cell growth and viability can be measured off line taking samples from the bioreactor. If the product is labeled with a fluorescent marker, transfection efficiency can be also assessed using flow cytometry analysis. Typically, the production phase lasts between 48 and 96 h until the product is harvested. PMID- 28921434 TI - Bioreactor-Based Production of Glycoproteins in Plant Cell Suspension Cultures. AB - Recombinant glycoproteins such as monoclonal antibodies have a major impact on modern healthcare systems, e.g., as the active pharmaceutical ingredients in anticancer drugs. A specific glycan profile is often necessary to achieve certain desirable activities, such as the effector functions of an antibody, receptor binding or a sufficient serum half-life. However, many expression systems produce glycan profiles that differ substantially from the preferred form (usually the form found in humans) or produce a diverse array of glycans with a range of in vivo activities, thus necessitating laborious and costly separation and purification processes. In contrast, protein glycosylation in plant cells is much more homogeneous than other systems, with only one or two dominant forms. Additionally, these glycan profiles tend to remain stable when the process and cultivation conditions are changed, making plant cells an ideal expression system to produce recombinant glycoproteins with uniform glycan profiles in a consistent manner. This chapter describes a protocol that uses fermentations using plant cell cultures to produce glycosylated proteins using two different types of bioreactors, a classical autoclavable STR 3-L and a wave reactor. PMID- 28921435 TI - Fed-Batch CHO Cell Culture for Lab-Scale Antibody Production. AB - Fed-batch culture is the most commonly used upstream process in industry today for recombinant monoclonal antibody production using Chinese hamster ovary (CHO) cells. Developing and optimizing this process in the lab is crucial for establishing process knowledge, which enables rapid and predictable tech-transfer to manufacturing scale. In this chapter, we describe stepwise how to carry out fed-batch CHO cell culture for lab-scale antibody production. PMID- 28921436 TI - Strategies to Develop Therapeutic N- and O-Hyperglycosylated Proteins. AB - Glycoengineering by N- and/or O-hyperglycosylation represents a procedure to introduce potential sites for adding N- and/or O-glycosyl structures to proteins with the aim of producing biotherapeutics with improved pharmacodynamic and pharmacokinetic properties. In this chapter, a detailed description of the steps routinely performed to generate new proteins having high content of N- and/or O glycosyl moieties is carried out. The rational strategy involves the initial stage of designing N- and/or O-hyperglycosylated muteins to be expressed by mammalian cells and includes the upstream and downstream processing stages necessary to develop hyperglycosylated versions of the proteins of interest with the purpose of beginning the long road toward producing biobetters. PMID- 28921437 TI - Expression of Glycosylated Proteins in Bacterial System and Purification by Affinity Chromatography. AB - The bacterial expression of glycoproteins has experienced significant progress in recent years, particularly in regard to the production of conjugate vaccines against pathogens. In this case, a protein carrier conjugated with glycosides is used to produce intense stimulation of the immune system. Glycoconjugate vaccines account for 35% of the global vaccine market, and consequently, several biotechnological companies have developed products for the purification of glycosylated proteins to attain homogeneity. In this chapter we present a general process for glycoprotein production in Escherichia coli and a practice method for purification of glycosylated proteins, using affinity chromatography. PMID- 28921438 TI - Purification Methods for Recombinant Factor VIII Expressed in Human Liver SK-Hep Cells. AB - Coagulation factor VIII is one of the largest proteins attempted to be expressed in recombinant form. A very complex and labile protein which has a very short half-live and need a fast and efficient purification chain. Here, we describe a simple purification sequence using multimodal Capto MMC, affinity FVIII select and ion exchange SP-Fastflow chromatography steps without subjecting the target molecule to mechanical and temperature stress, separating impurities from rFVIII using net charge, hydrophobicity, and affinity of the molecules. PMID- 28921439 TI - Purification Method for Recombinant hG-CSF by Affinity Chromatography. AB - The human granulocytic colony-stimulating factor (hG-CSF) acts mainly by promoting the maturation of granulocytes and stimulating their phagocytic and chemotactic activity. It has been used in the treatment of many diseases, in particular in neutropenic conditions. Here, we describe the purification process of the recombinant protein hG-CSF expressed in Pichia pastoris. The protein purification proved to be efficient using the nickel affinity chromatography method described in this chapter. PMID- 28921440 TI - Microplate-Based Method for High-Throughput Screening (HTS) of Chromatographic Conditions Studies for Recombinant Protein Purification. AB - High-throughput screening (HTS) systems have emerged as important tools to provide fast and low cost evaluation of several conditions at once since it requires small quantities of material and sample volumes. These characteristics are extremely valuable for experiments with large number of variables enabling the application of design of experiments (DoE) strategies or simple experimental planning approaches. Once, the capacity of HTS systems to mimic chromatographic purification steps was established, several studies were performed successfully including scale down purification. Here, we propose a method for studying different purification conditions that can be used for any recombinant protein, including complex and glycosylated proteins, using low binding filter microplates. PMID- 28921441 TI - Purification and Autoactivation Method for Recombinant Coagulation Factor VII. AB - Recombinant coagulation factor VII is a very important and complex protein employed for treatment of hemophiliac patients (hemophilia A/B) who develop inhibitors antibodies to conventional treatments (FVIII and FIX). The rFVII is a glycosylated molecule and circulates in plasma as zymogen of 50 kDa. When activated the molecule is cleaved to 20-30 kDa and has a half-life of about 3 h, needing to be processed fast and efficiently until freeze-drying. Here, we describe a very simple and fast purification sequence for rFVII using affinity FVII Select resin and a dialysis system that can be easily scaled up. PMID- 28921442 TI - Preparation of Immunoliposomes by Direct Coupling of Antibodies Based on a Thioether Bond. AB - Drug delivery is of paramount importance, since the drug needs to be delivered to a specific site, in adequate concentration, avoiding degradation in order to provide therapeutic efficacy. Different nanocarriers have been used over the years for this purpose and liposomes are well-established systems due to the high biocompatibility and the possibility to vehiculate both hydrophilic and lipophilic drugs. In order to circumvent the rapid clearance by the reticuloendothelial system and to avoid the healthy cells exposure to the drug, long circulating liposomes containing polyethyleneglycol (PEG) and functionalized liposomes for targeted delivery have been developed. Immunoliposomes consist of liposomes containing antibodies or antibody fragments attached at the membrane surface. This attachment can be performed using PEG lipids, containing a reactive terminal group such as maleimide and thiolated antibodies. Additionaly, the use of PEG chains as spacers increases antibody-antigen affinity, since the antibody is not shielded by the steric hindrance of PEG and also due to the correct orientation of antibodies for interaction with receptors on cell surface. In this chapter, we describe and discuss in details the protocol to prepare anti epidermal growth factor receptor (anti-EGFR) and anti-human epidermal growth factor receptor 2 (anti-HER2) liposomes using cetuximab and trastuzumab as antibodies. We present the direct coupling method based on the maleimide thioether reaction for these immunoliposomes preparation and present some characterization steps and in vitro studies in cell culture which can be used for better understanding these nanocarriers. PMID- 28921443 TI - Polyester-Based Nanoparticles for the Encapsulation of Monoclonal Antibodies. AB - Aliphatic polyesters have been widely explored for biomedical applications (e.g., drug delivery systems, biomedical devices, and tissue engineering). Recently, polyesters have been used in nanoparticle formulations for the controlled release of monoclonal antibodies (mAbs) for the enhanced efficacy of antibody-based therapy. Polyester-based nanoparticles for mAb delivery provide decreased antibody dosage, increased antibody stability and protection and longer therapeutic action, ultimately translating to an increased therapeutic index. Additionally, nanoencapsulation holds the potential for the selective cellular recognition and internalization of mAbs, in the disease context when intracellular organelles and molecules (e.g., enzymes, transcription factors and oncogenic proteins) are the preferred target. We present here a detailed method to prepare mAb-loaded polyester-based nanoparticles and the various techniques to characterize the resulting nanoparticles and mAb structure. Finally, we highlight different biological approaches to assess the in vitro bioactivity of the antibody upon nanoparticle release. PMID- 28921444 TI - Polyester-Based Nanoparticles for Delivery of Therapeutic Proteins. AB - Therapeutic proteins are widely used to treat severe conditions, such as oncologic and metabolic diseases, and also for vaccination. They are recognized for its high biopotency, but their hydrophilicity and high molecular weight make its transport through membranes difficult to achieve. They may also suffer in vivo structural instability caused by a proteolytic cleavage, turning them biological inactive. Polyester-based nanoparticles are useful tools to overcome such problems, and deliver therapeutic proteins in a controlled and localized manner, decreasing the number of administrations needed and enhancing the therapeutic outcome. The biodegradable and biocompatible nature of such carriers makes them feasible to be administered by invasive and noninvasive routes. Since nanoparticles are produced in suspension form, they are usually lyophilized to increase its long-term storage stability. Therefore, the aim of this work is to propose an intuitive protocol for production and lyophilization of polyester based nanoparticles for therapeutic proteins delivery. The characterization techniques to evaluate the nanoparticle and lyophilisate features, as well as the structural stability of the loaded protein are also described. For these purposes, PLGA nanoparticles and human insulin are used as models. PMID- 28921445 TI - Quantification of Coagulation Factor VIII by Selective Reaction Monitoring. AB - Coagulation factor VIII (FVIII) is an important glycoprotein involved in the extrinsic coagulation cascade. Mutations in FVIII gene results in hemophilia A, a recessive coagulation disorder that is clinically managed by administration of purified FVIII from blood donors or recombinant FVIII. Because of its fundamental therapeutic application, biotechnological production of FVIII requires rigid quality control and monitoring in patients and clinical trials. Here, we describe a protocol for a mass spectrometry based approach termed selective reaction monitoring (SRM) as an important alternative tool for accurate and sensitive quantitation of purified or recombinant FVIII. PMID- 28921446 TI - Can a Novel ICU Data Display Positively Affect Patient Outcomes and Save Lives? AB - The aim of this study was to quantify the impact of ProCCESs AWARE, Ambient Clinical Analytics, Rochester, MN, a novel acute care electronic medical record interface, on a range of care process and patient health outcome metrics in intensive care units (ICUs). ProCCESs AWARE is a novel acute care EMR interface that contains built-in tools for error prevention, practice surveillance, decision support and reporting. We compared outcomes before and after AWARE implementation using a prospective cohort and a historical control. The study population included all critically ill adult patients (over 18 years old) admitted to four ICUs at Mayo Clinic, Rochester, MN, who stayed in hospital at least 24 h. The pre-AWARE cohort included 983 patients from 2010, and the post AWARE cohort included 856 patients from 2014. We analyzed patient health outcomes, care process quality, and hospital charges. After adjusting for patient acuity and baseline demographics, overall in-hospital and ICU mortality odds ratios associated with AWARE intervention were 0.45 (95% confidence interval 0.30 to 0.70) and 0.38 (0.22, 0.66). ICU length of stay decreased by about 50%, hospital length of stay by 37%, and total charges for hospital stay by 30% in post AWARE cohort (by $43,745 after adjusting for patient acuity and demographics). Better organization of information in the ICU with systems like AWARE has the potential to improve important patient outcomes, such as mortality and length of stay, resulting in reductions in costs of care. PMID- 28921447 TI - Structure, Pharmacology and Roles in Physiology of the P2Y12 Receptor. AB - P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The platelet ADP-receptor which has been denominated P2Y12 receptor is an important target in pharmacotherapy. The receptor couples to Galphai2 mediating an inhibition of cyclic AMP accumulation and additional downstream events including the activation of phosphatidylinositol-3-kinase and Rap1b proteins. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel block P2Y12 receptors and, thereby, inhibit ADP-induced platelet aggregation. These drugs are used for the prevention and therapy of cardiovascular events such as acute coronary syndromes or stroke. The recently published three-dimensional crystal structures of the human P2Y12 receptor in complex with agonists and antagonists will facilitate the development of novel therapeutic agents with reduced adverse effects. P2Y12 receptors are also expressed on vascular smooth muscle cells and may be involved in the pathophysiology of atherogenesis. P2Y12 receptors on microglial cells operate as sensors for adenine nucleotides released during brain injury. A recent study indicated the involvement of microglial P2Y12 receptors in the activity-dependent neuronal plasticity. Interestingly, there is evidence for changes in P2Y12 receptor expression in CNS pathologies including Alzheimer's diseases and multiple sclerosis. P2Y12 receptors may also be involved in systemic immune modulating responses and the susceptibility to develop bronchial asthma. PMID- 28921448 TI - Assessment of dose uniformity around high dose rate 192Ir and 60Co stepping sources. AB - This study aimed to evaluate dose uniformity for 192Ir and 60Co stepping sources. High dose rate 192Ir and 60Co stepping sources were simulated by the MCNPX Monte Carlo code. To investigate dose uniformity, treatment lengths of 30, 50, 100, and 150 mm with stepping distances of 3, 5, 7, and 10 mm were considered. Finally, dose uniformity for the 192Ir and 60Co stepping sources with increasing distances from the source were assessed at these treatment lengths and steps. The findings showed that the dose distribution was non-uniform for regions in close vicinity of the source, especially in the high source steps, but for most points at distances >10 mm from the center of the source, the dose distribution was uniform. For most points, the dose uniformity increased with reduction of the source steps and increments of the transverse distance from the source. The dose non-uniformity was similar for most of the corresponding points of 60Co and 192Ir sources with the same treatment lengths and source steps, except at the distance of 150 mm. When using stepping technique for the treatment of tumors, more attention should be focused on treatment planning, especially with higher stepping distances and lower transverse distances from the source. PMID- 28921449 TI - Overexpression of FZD1 and CAIX are Associated with Invasion, Metastasis, and Poor-Prognosis of the Pancreatic Ductal Adenocarcinoma. AB - Approximately 80% of patients with pancreatic ductal adenocarcinoma (PDAC) have metastatic disease with poor prognosis, but clinically available biomarkers have not yet been identified. This study was to investigate the clinical significance of FZD1 and CAIX in PDACs. FZD1 and CAIX protein expression was measured using EnVision immunohistochemistry. Positive FZD1 or CAIX expression was significantly higher in PDAC than that in precursor lesions (p < 0.01). Positive FZD1 or CAIX expression was significantly lower in cases with well-differentiated adenocarcinoma, no-metastasis of the lymph node, no-invasion of regional tissues, and TNM I/II stage disease than in cases with poorly-differentiated adenocarcinoma, metastasis and invasion, and TNM stage III+ IV stage disease (p < 0.05 or p < 0.01). The expression of FZD1 positively correlated with CAIX in PDAC (P = 0.000). Univariate Kaplan-Meier analysis showed that FZD1 and/or CAIX expression (p < 0.001) was significantly associated with shorter overall survival (p < 0.05). Cox multivariate analysis showed that differentiation, tumor mass, lymph node metastasis, invasion, TNM stage, FZD1 and CAIX levels negatively correlated with overall survival. Positive FZD1 and CAIX expressions are poor prognostic factors in PDAC patients. FZD1 and CAIX might be important biological markers for the carcinogenesis, metastasis, invasion, and prognosis of PDAC. PMID- 28921450 TI - Nutrients Other than Selenium Are Important for Promoting Children's Health in Kashin-Beck Disease Areas. AB - Overall nutritional status has been proved associated with people's health. The overall nutritional status of children in Kashin-Beck disease (KBD) areas has been overlooked for decades. Therefore, it is worth investigating in the current generation to gather evidence and make suggestions for improvement. A cross sectional study with three 24-h dietary recalls was conducted to collect raw data on the daily food intake of children. Recorded food was converted into daily nutrient intakes using CDGSS 3.0 software. WHO AnthroPlus software was used to analyse the BMI-for-age z-score (BAZ) for estimating the overall nutrition status of children. All the comparisons and regression analyses were conducted with SPSS 18.0 software. Multiple nutrient intakes among children from the Se-supplemented KBD-endemic were under the estimated average requirement. The protein-to carbohydrate ratio (P/C ratio) was significantly higher in children from the non Se-supplemented KBD-endemic area than the other areas (P < 0.001). The children's BAZ was negatively associated with age (B = -0.095, P < 0.001) and the number of KBD relatives (B = -0.277, P = 0.04), and it was positively associated with better housing conditions, receiving colostrum, and daily intakes of niacin and zinc by multivariate regression analysis (F = 10.337, R = 0.609, P < 0.001).Compared to non-Se-supplemented KBD-endemic area and non-endemic areas, children in Se-supplemented KBD-endemic areas have an insufficient intake of multiple nutrients. School breakfast and lunch programmes are recommended, and strict implementation is the key to ensuring a positive effect. PMID- 28921451 TI - Distribution of malignant lymphomas in the anterior mediastinum: a single institution study of 76 cases in Japan, 1997-2016. AB - We analyzed the distribution of tumors and lymphomas of the anterior mediastinum diagnosed between 1997 and 2016 at the National Cancer Center Hospital, Japan. The median age of 283 patients with anterior mediastinal tumors was 48 (range 6 84) years, and 143 (51%) were male. The incidence of tumors was as follows: thymoma, 34%; thymic carcinoma, 16%; primary mediastinal large B-cell lymphoma (PMBL), 13%; germ cell tumors, 10%; classical Hodgkin lymphoma (CHL), 9%; thymic cyst, 7%; metastatic tumors, 3%; T lymphoblastic leukemia/lymphoma (T-LBL), 2%; other lymphomas, 3%; and others, 3%. Of the newly diagnosed lymphomas in 60 patients, PMBL (46%) was the most frequent, followed by CHL (32%), T-LBL (12%), mucosa-associated lymphoid tissue lymphoma (3%), and other lymphomas (7%). These findings suggest a recent increase in PMBL in Japan. The frequency and subtype of lymphoma differ with age and sex. In female patients <=40 years old, 58% of the anterior mediastinal tumors were PMBL (39%) or CHL (19%). Germ cell tumors were the most frequent in male patients <=40 years old, followed by CHL (21%), PMBL (17%), and T-LBL (10%). This distribution may serve as a reference for routine histologic diagnosis of lymphomas in the anterior mediastinum in Japan. PMID- 28921452 TI - The spectrum of imaging appearances of mullerian duct anomalies: focus on MR imaging. AB - Mullerian duct anomalies (MDAs) are the result of incomplete development, vertical or lateral fusion, or absorption of the mullerian ducts. The range of anomalies includes uterovaginal agenesis or hypoplasia, unicornuate uterus, uterus didelphys, bicornuate uterus, septate uterus, and arcuate uterus. Correct diagnosis and classification of these anomalies are essential because pregnancy outcomes and treatment options vary between the types of anomaly. Furthermore, early identification of MDAs helps to avoid prolonged symptomatic periods and the complications that may subsequently arise, such as infertility, endometriosis, and neoplasm. Although many of these abnormalities are initially diagnosed by ultrasound or hysterosalpingography, MR imaging is the most accurate noninvasive modality available for classification of the various anomalies because of its better anatomic assessment compared with other diagnostic modalities. Familiarity with the wide variety of MDA presentations can help in the planning of appropriate treatment. PMID- 28921453 TI - Upper and lower limbs composition: a comparison between anthropometry and dual energy X-ray absorptiometry in healthy people. AB - : The detection of changes in lean mass (LM) distribution can help to prevent disability. This study assessed the degree of association between anthropometric measurements and dual-energy X-ray absorptiometry (DXA) body composition (BC) parameters of the upper and lower limbs in a healthy general population and collected DXA age- and sex-specific values of BC that can be useful to build a reference standard. PURPOSE: The primary aim of this study was to investigate the reliability of some widely available anthropometric measurements in the assessment of body composition (BC) at the limbs, especially in terms of muscle mass, in a large sample of healthy subjects of different age bands and sex, using fat mass (FM) and lean mass (LM) parameters derived by dual-energy X-ray absorptiometry (DXA) as the gold standard. The secondary aim was to collect DXA age- and sex-specific values of BC of left and right limbs (upper and lower) in a healthy Italian population to be used as reference standards. METHODS: Two hundred fifty healthy volunteers were enrolled. Arm circumference (AC) and thigh circumference (ThC) were measured, and total and regional BC parameters were obtained by a whole-body DXA scan (Lunar iDXA, Madison, WI, USA; enCORETM 2011 software version 13.6). RESULTS: FM/LM showed only fair correlation with AC and ThC in females (r = 0.649 and 0.532, respectively); in males and in the total population, the correlation was low (r = 0.360 or lower, and p non-statistically significant). AC and ThC were not well representative of arms LM in both genders (females r = 0.452, males r = 0.530) independently of age. In general, men of all age groups showed higher values of LM and lean mass index (LMI) in both total and segmental upper and lower limbs. In males, the maximum LM and LMI were achieved in the fifth decade in both upper and lower limbs and then started to decrease with aging. In females, no significant modification with aging was identified in LM and LMI. CONCLUSION: According to our results, anthropometry is not well representative of LM of arms in both genders, independently of age; therefore, a densitometric examination should be considered for a correct assessment of BC at limbs. PMID- 28921455 TI - Construction of an HRP-streptavidin bound antigen and its application in an ELISA for porcine circovirus 2 antibodies. AB - A fusion protein SBP-Cap?41, consisting of Cap?41 (without 41 amino acids at the N-terminus) protein of porcine circovirus 2 (PCV2) and a streptavidin binding peptide (SBP), was constructed. This fusion protein binds to HRP-labeled streptavidin (HRP-SA) through high affinity between SBP and SA, forming an HRP streptavidin bound antigen (Hsb-Ag) with both immunoreactivity and enzymatic activity, which can be used in a double-antigen sandwich ELISA for detection of PCV2 antibodies. Comparison of the characteristics of the HSb-Cap?41 and chemical conjugates of the recombinant Cap?41 protein showed that the HSb-Cap?41 based double-antigen sandwich ELISA (HBDS-ELISA) had higher specificity and sensitivity. Use of the HBDS-ELISA detected PCV2-IgG in 9 injected pigs as early as 10 days p.i., 3 days earlier than both a double-antigen sandwich ELISA (DS ELISA) based on a chemically conjugated antigen, and a commercial indirect ELISA kit. PMID- 28921456 TI - Blood-Brain Barrier in a Haemophilus influenzae Type a In Vitro Infection: Role of Adenosine Receptors A2A and A2B. AB - The blood-brain barrier (BBB) is mainly made up of tightly connected microvascular endothelial cells (BMECs), surrounded by pericytes (BMPCs) which regulate BBB tightness by providing soluble factors that control endothelial proliferation. Haemophilus influenzae type a (Hia) is able to reach the BBB, crossing it, thus causing meningitis. In this study, by using an in vitro model of BBB, performed with human BMECs and human BMPCs in co-culture, we demonstrated that, after Hia infection, the number of hBMPCs decreased whereas the number of hBMECs increased in comparison with non-infected cells. SEM and TEM images showed that Hia was able to enter hBMECs and reduce TEER and VE-cadherin expression. When the cells were infected in presence of SCH58261 and PSB603 but not DPCPX, an increase in TEER values was observed thus demonstrating that A2A and A2B adenosine receptors play a key role in BBB dysfunction. These results were confirmed by the use of adenosine receptor agonists CGS21680, CCPA, and NECA. In infected co-cultures cAMP and VEGF increased and TEER reduction was counter balanced by VEGF-R1 or VEGF-R2 antibodies. Moreover, the phosphorylated CREB and Rho-A significantly increased in infected hBMECs and hBMPCs and the presence of SCH58261 and PSB603 significantly abrogated the phosphorylation. In conclusion, this study demonstrated that the infection stimulated A2A and A2B adenosine receptors in hBMECs and hBMPCs thus inducing the pericytes to release large amounts of VEGF. The latter could be responsible for both, pericyte detachment and endothelial cell proliferation, thus provoking BBB impairment. PMID- 28921457 TI - Ode to Glia: A Tribute to Bruce Ransom. PMID- 28921458 TI - Pharmacogenetics and Pharmacogenomics in Moderate-to-Severe Psoriasis. AB - Pharmacogenetics is the study of variations in DNA sequence related to drug response. Moreover, the evolution of biotechnology and the sequencing of human DNA have allowed the creation of pharmacogenomics, a branch of genetics that analyzes human genes, the RNAs and proteins encoded by them, and the inter-and intra-individual variations in expression and function in relation to drug response. Pharmacogenetics and pharmacogenomics are being used to search for biomarkers that can predict response to systemic treatments, including those for moderate-to-severe psoriasis. Psoriasis is a chronic inflammatory disease with an autoimmune contribution. Although its etiology remains unknown, genetic, epigenetic, and environmental factors play a role in its development. Diverse systemic and biologic therapies are used to treat moderate-to-severe psoriasis. However, these treatments are not curative, and patients exhibit a wide range of responses to them. Moderate-to-severe psoriasis is usually treated with systemic immunomodulators such as acitretin, ciclosporin, and methotrexate. Anti-tumor necrosis factor (TNF) drugs (adalimumab, etanercept, or infliximab) are the first line treatment for patients resistant to conventional systemic therapies. Although these therapies are very efficient, around 30-50% of patients have inadequate response. Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 and is used for moderate-to-severe psoriasis. New drugs (apremilast, brodalumab, guselkumab, ixekizumab, and secukinumab) have recently been approved for psoriasis. However, response rates to systemic treatments for moderate-to-severe psoriasis range from 35 to 80%, so it is necessary to identify non-invasive biomarkers that could help predict treatment outcomes of these therapies and individualize care for patients with psoriasis. These biomarkers could improve patient quality of life and reduce health costs and potential side effects. Pharmacogenetic studies have identified potential biomarkers for response to biologic treatments for moderate-to-severe psoriasis. These biomarkers need to be validated in clinical trials involving large cohorts of patients before they can be translated to the clinic. We review pharmacogenetics and pharmacogenomics studies for the treatment of moderate-to severe plaque psoriasis. PMID- 28921459 TI - Chimeric Virus as a Source of the Potato Leafroll Virus Antigen. AB - Large quantities of potato leafroll virus (PLRV) antigen are difficult to obtain because this virus accumulates in plants at a low titer. To overcome this problem, we constructed a binary vector containing chimeric cDNA, in which the coat protein (CP) gene of the crucifer infecting tobacco mosaic virus (crTMV) was substituted for the coat protein gene of PLRV. The PLRV movement protein (MP) gene, which overlaps completely with the CP gene, was doubly mutated to eliminate priming of the PLRV MP translation from ATG codons with no changes to the amino acid sequence of the CP. The untranslated long intergenic region located upstream of the CP gene was removed from the construct. Transcribed powerful tobamovirus polymerase of the produced vector synthesized PLRV CP gene that was, in turn, translated into the protein. CP PLRV packed RNAs from the helical crTMV in spherical virions. Morphology, size and antigenic specificities of the wild-type and chimeric virus were similar. The yield of isolated chimera was about three orders higher than the yield of native PLRV. The genetic manipulations facilitated the generation of antibodies against the chimeric virus, which recognize the wild-type PLRV. PMID- 28921460 TI - NFBD1/MDC1 participates in the regulation of proliferation and apoptosis in human laryngeal squamous cell carcinoma. AB - PURPOSE: The objective of the study was to investigate the role of NFBD1 in the proliferation and apoptosis of laryngeal squamous cell carcinoma (LSCC) cells. METHODS: Immunohistochemistry (IHC) and qRT-PCR was employed to determine the expressions of NFBD1 protein and mRNA in LSCC tissues and adjacent noncancerous tissues. After the downregulation of NFBD1 expression, the colony formation assay, MTS assay and apoptosis assay were used to investigate the changes in the proliferation and apoptosis of Hep2 cells. The mechanisms by which silencing NFBD1 promote apoptosis of Hep2 cells were examined by western blotting. Furthermore, xenograft models were used to evaluate the proliferation of Hep2 cells in vivo. RESULTS: NFBD1 protein was upregulated in 55.6% of LSCC cancer tissues compared with adjacent normal tissues (26.7%). NFBD1 knockdown in Hep2 cells significantly impacted proliferation and apoptosis, and silencing NFBD1 might promote apoptosis of Hep2 cells by activating the mitochondrial apoptotic pathway. Xenograft models showed that silencing NFBD1 also significantly inhibited tumor growth. CONCLUSIONS: Our data highlight that NFBD1 participates in the regulation of proliferation and apoptosis in LSCC, and suggest that NFBD1 could be a promising therapy target. PMID- 28921461 TI - Prediction of neoadjuvant chemotherapy response using diffuse optical spectroscopy in breast cancer. AB - PURPOSE: Near-infrared diffuse optical spectroscopy (DOS) has been recently used to predict neoadjuvant chemotherapy response (NAC). In the present study, we explore the change in blood-oxygen content using DOS to predict NAC response against breast cancer. MATERIALS AND METHODS: A total of 20 patients were enrolled and underwent DOS scan with blood-oxygen detection before each treatment cycle. The first DOS scan was performed before NAC treatment (pretreatment), and subsequent scans were performed after each NAC treatment circle. Changes in blood content and oxygen content by DOS were evaluated and compared with tumor size, and their changes were analyzed in response versus nonresponse group. RESULTS: Thirteen patients were classified into response and seven patients into nonresponse group. The tumor blood content value (-1.06 +/- 0.43) and oxygen content value (0.48 +/- 0.17) of DOS at pretreatment was significantly different from presurgery in response group (P < 0.05), but not in nonresponse group. In response group, the percentage change in blood content (median 91.19%) was significantly larger than tumor size (median 48.89%) (P = 0.0035), while in oxygen content (median 47.11%) is not (P = 0.2815). Comparing each cycle, the percentage change in blood content could distinguish responder from non-responder as early as after the first treatment cycle (19.1 versus 6.6%, P = 0.0265). Blood content percentage sensitivity was 76.9% and specificity was 85.7% (AUC 0.912), while oxygen content percentage sensitivity was 76.9% and specificity was 71.4% (AUC 0.797). CONCLUSION: Both blood and oxygen content measured by DOS could be used to discriminate responder to the treatment versus non-responder. Among the two, percentage change of blood content was more precise and earlier than that of oxygen content to predicted breast tumor response. The percentage change in blood content could distinguish responder from non-responder after the first treatment cycle. PMID- 28921462 TI - Bifidobacterium pseudocatenulatum CECT 7765 Ameliorates Neuroendocrine Alterations Associated with an Exaggerated Stress Response and Anhedonia in Obese Mice. AB - Obesity, besides being a problem of metabolic dysfunction, constitutes a risk factor for psychological disorders. Experimental models of diet-induced obesity have revealed that obese animals are prone to anxious and depressive-like behaviors. The present study aimed to evaluate whether Bifidobacterium pseudocatenulatum CECT 7765 could reverse the neurobehavioral consequences of obesity in a high-fat diet (HFD) fed mouse model via regulation of the gut-brain axis. Adult male wild-type C57BL-6 mice were fed a standard diet or HFD, supplemented with either placebo or the bifidobacterial strain for 13 weeks. Behavioral tests were performed, and immune and neuroendocrine parameters were analyzed including leptin and corticosterone and their receptors, Toll-like receptor 2 (TLR2) and neurotransmitters. We found that obese mice showed anhedonia (p < 0.050) indicative of a depressive-like behavior and an exaggerated hypothalamic-pituitary axis (HPA)-mediated stress response to acute physical (p < 0.001) and social stress (p < 0.050), but these alterations were ameliorated by B. pseudocatenulatum CECT 7765 (p < 0.050). These behavioral effects were parallel to reductions of the obesity-associated hyperleptinemia (p < 0.001) and restoration of leptin signaling (p < 0.050), along with fat mass loss (p < 0.010). B. pseudocatenulatum CECT 7765 administration also led to restoration of the obesity-induced reductions in adrenaline in the hypothalamus (p < 0.010), involved in the hypothalamic control of energy balance. Furthermore, the bifidobacterial strain reduced the obesity-induced upregulation of TLR2 protein or gene expression in the intestine (p < 0.010) and the hippocampus (p < 0.050) and restored the alterations of 5-HT levels in the hippocampus (p < 0.050), which could contribute to attenuating the obesity-associated depressive-like behavior (p < 0.050). In summary, the results indicate that B. pseudocatenulatum CECT 7765 could play a role in depressive behavior comorbid with obesity via regulation of endocrine and immune mediators of the gut-brain axis. PMID- 28921463 TI - Activation of the Innate Immune Receptors: Guardians of the Micro Galaxy : Activation and Functions of the Innate Immune Receptors. AB - The families of innate immune receptors are the frontline responders to danger. These superheroes of the host immune systems populate innate immune cells, surveying the extracellular environment and the intracellular endolysosomal compartments and cytosol for exogenous and endogenous danger signals. As a collective the innate immune receptors recognise a wide array of stimuli, and in response they initiate specific signalling pathways leading to activation of transcriptional or proteolytic pathways and the production of inflammatory molecules to destroy foreign pathogens and/or resolve tissue injury. In this review, I will give an overview of the innate immune system and the activation and effector functions of the families of receptors it comprises. Current key concepts will be described throughout, including innate immune memory, formation of innate immune receptor signalosomes, inflammasome formation and pyroptosis, methods of extrinsic cell communication and examples of receptor cooperation. Finally, several open questions and future directions in the field of innate immunity will be presented and discussed. PMID- 28921464 TI - Posttranslational Modification Control of Inflammatory Signaling. AB - Inflammation is usually the defensive reaction of the immune system to the invasion of pathogen and the exogenous objects. The activation of inflammation helps our body to eliminate pathogenic microbe, virus, and parasite harming our health, while under many circumstances inflammation is the direct cause of the pathological damage in tissues and dysfunction of organs. The posttranslational modification (PTM) of the inflammatory pathways, such as TLR pathways, RLR pathways, NLR pathway, intracellular DNA sensors, intracellular RNA sensors, and inflammasomes, is crucial in the regulation of these signaling trails. Ubiquitination, phosphorylation, polyubiquitination, methylation, and acetylation are the main forms of the PTM, and they respectively play different roles in signaling regulation. The effects of the PTM range from the production of pro inflammatory factors and the interaction between adaptors and receptors to cell translocation in response to the infectious or other dangerous factors. In this chapter, we will have an overview of the different ways of the posttranslational modifications in different inflammatory signaling pathways and their essential roles in regulation of inflammation. PMID- 28921465 TI - Emerging Roles for Epigenetic Programming in the Control of Inflammatory Signaling Integration in Heath and Disease. AB - Macrophages and dendritic cells initiate the innate immune response to infection and injury and contribute to inflammatory signaling to maintain the homeostasis of various tissues, which includes resident macrophages for the elimination of invading microorganisms and tissue damage. Inappropriate inflammatory signaling can lead to persistent inflammation and further develop into autoimmune and inflammation-associated diseases. Inflammatory signaling pathways have been well characterized, but how these signaling pathways are converted into sustained and diverse patterns of expression of cytokines, chemokines, and other genes in response to environmental challenges is unclear. Emerging evidence suggests the important role of epigenetic mechanisms in finely tuning the outcome of the host innate immune response. An understanding of epigenetic regulation of innate immune cell identity and function will enable the identification of the mechanism between gene-specific host defenses and inflammatory disease and will also allow for exploration of the program of innate immune memory in health and disease. This information could be used to develop therapeutic agents to enhance the host response, preventing chronic inflammation through preserving tissues and signaling integrity. PMID- 28921466 TI - Roles of HDACs in the Responses of Innate Immune Cells and as Targets in Inflammatory Diseases. AB - Histone deacetylases (HDACs) are an emerging class of molecules involved in the epigenetic regulation of innate immune responses through Toll-like receptor (TLR) and interferon (IFN) signaling pathways. HDACs are also key drivers of inflammatory diseases via epigenetic regulation through chromatin DNA and histone modification by methylation and acetylation, among other mechanisms, which control innate immune cell gene expression. Importantly, these epigenetic changes are reversible, and HDACs may also be targeted by small-molecule HDAC inhibitors, which have been used in clinical settings for cancer therapy. Here, we highlight HDACs as strong therapeutic molecules and explore HDAC-induced mechanisms regulating innate immune responses and inflammatory cytokine control, with the goal of developing personalized medicine for the treatment of human diseases, including inflammatory diseases and immune disorders. Currently, this novel class of immunomodulatory therapeutics is being evaluated in the laboratory, in preclinical models, and in the clinic. PMID- 28921467 TI - miR-155 Dysregulation and Therapeutic Intervention in Multiple Sclerosis. AB - microRNAs play a fundamental role in the immune system. One particular microRNA, miR-155 plays a critical role in hematopoietic cell development and tightly regulates innate and adaptive immune responses in response to infection. However, its dysregulation, more specifically its overexpression, is closely associated with various inflammatory disorders. The purpose of this review is to consolidate how miR-155 underpins a variety of processes that contribute to the pathology of multiple sclerosis (MS). In particular, the impact of miR-155 is discussed with respect to human pathology and animal models. How miR-155 contributes to the activation of pathogenic immune cells, the permeability of the blood-brain barrier, and neurodegeneration in relation to MS is described. Many environmental risk factors associated with MS susceptibility can cause upregulation of miR-155, while many of the current disease-modifying treatments may work by inhibiting miR 155. From this review, it is clear that miR-155 is a realistic and feasible diagnostic, prognostic, and therapeutic target for the treatment of MS. PMID- 28921468 TI - Inflammasomes in the Gut Mucosal Homeostasis. AB - Inflammasomes are critical checkpoints in inflammation. The activation of inflammasome can cause a series of inflammatory responses including maturation of interleukin (IL)-1beta and IL-18 and a specialized form of cell death called pyroptosis. Since its identification in the early 2000s, inflammasomes have been implicated to play multifaceted roles in varied pathological and physiological conditions, especially in the mucosal compartments including the gut. Maintaining gut mucosal homeostasis has always been a remarkable challenge for the host due to both the vast mucosal surface that is exposed to the outside and the enormous amount of local microbiota. To accomplish this challenge, the host mounts a constant dynamic low-grade inflammatory response (physiological inflammation) in coping with insults of microbes in the intestine. This book chapter aims to summarize the current knowledge of how inflammasomes contribute to gut mucosal homeostasis. PMID- 28921469 TI - Microbial Factors in Inflammatory Diseases and Cancers. AB - The intestinal microbes form a symbiotic relationship with their human host to harvest energy for themselves and their host and to shape the immune system of their host. However, alteration of this relationship, which is named as a dysbiosis, has been associated with the development of different inflammatory diseases and cancers. It is found that metabolites, cellular components, and virulence factors derived from the gut microbiota interact with the host locally or systemically to modulate the dysbiosis and the development of these diseases. In this book chapter, we discuss the role of these microbial factors in regulating the host signaling pathways, the composition and load of the gut microbiota, the co-metabolism of the host and the microbiota, the host immune system, and physiology. In particular, we highlight how each microbial factor can contribute in the manifestation of many diseases such as cancers, Inflammatory Bowel Diseases, obesity, type-2 diabetes, non-alcoholic fatty liver diseases, nonalcoholic steatohepatitis, and cardiovascular diseases. PMID- 28921470 TI - cGAS-STING Activation in the Tumor Microenvironment and Its Role in Cancer Immunity. AB - Stimulator of interferon (IFN) genes (STING) is a key mediator in the immune response to cytoplasmic DNA sensed by cyclic GMP-AMP (cGAMP) synthase (cGAS). After synthesis by cGAS, cGAMP acts as a second messenger activating STING in the cell harboring cytoplasmic DNA but also in adjacent cells through gap junction transfer. While the role of the cGAS-STING pathway in pathogen detection is now well established, its importance in cancer immunity has only recently started to emerge. Nonetheless, STING appears to be an essential component in the recruitment of immune cells to the tumor microenvironment, which is paramount to immune clearance of the tumor. This review presents an overview of the growing literature around the role of the cGAS-STING pathway in the tumor microenvironment, with a specific focus on the role that cancer cells may play in the direct activation of this pathway, and its amplification through cell-cell transfer of cGAMP. PMID- 28921471 TI - TLR Agonists as Adjuvants for Cancer Vaccines. AB - Toll-like receptors (TLRs) are one of the best characterised families of pattern recognition receptors (PRRs) and play a critical role in the host defence to infection. Accumulating evidence indicates that TLRs also participate in maintaining tissue homeostasis by controlling inflammation and tissue repair, as well as promoting antitumour effects via activation and modulation of adaptive immune responses. TLR agonists have successfully been exploited to ameliorate the efficacy of various cancer therapies. In this chapter, we will discuss the rationales of using TLR agonists as adjuvants to cancer treatments and summarise the recent findings of preclinical and clinical studies of TLR agonist-based cancer therapies. PMID- 28921472 TI - Telomere Damage Response and Low-Grade Inflammation. AB - Telomeres at the ends of chromosomes safeguard genome integrity and stability in human nucleated cells. However, telomere repeats shed off during cell proliferation and other stress responses. Our recent studies show that telomere attrition induces not only epithelial stem cell senescence but also low-grade inflammation in the lungs. The senescence-associated low-grade inflammation (SALI) is characteristic of alveolar stem cell replicative senescence, increased proinflammatory and anti-inflammatory cytokines, infiltrated immune cells, and spillover effects. To date, the mechanisms underlying SALI remain unclear. Investigations demonstrate that senescent epithelial stem cells with telomere erosion are not the source of secreted cytokines, containing no significant increase in expression of the genes coding for increased cytokines, suggesting an alternative senescence-associated secretory phenotype (A-SASP). Given that telomere loss results in significant alterations in the genomes and accumulations of the cleaved telomeric DNA in the cells and milieu externe, we conclude that telomere position effects (TPEs) on gene expression and damage-associated molecular patterns (DAMPs) in antigen presentation are involved in A-SASP and SALI in response to telomere damage in mammals. PMID- 28921473 TI - The Development and Diversity of ILCs, NK Cells and Their Relevance in Health and Diseases. AB - Next to T and B cells, natural killer (NK) cells are the third largest lymphocyte population. They are recently re-categorized as innate lymphocytes (ILCs), which also include ILC1, ILC2, ILC3, and the lymphoid tissue inducer (LTi) cells. Both NK cells and ILC1 cells are designated as group 1 ILCs because they secrete interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF). However, in contrast to ILC1 and all other ILCs, NK cells possess potent cytolytic functions that resemble cytotoxic T lymphocytes (CTL). In addition, NK cells express, in a stochastic manner, an array of germ line-encoded activating and inhibitory receptors that recognize the polymorphic regions of major histocompatibility class I (MHC-I) molecules and self-proteins. Recognition of self renders NK cell tolerance to self-healthy tissues, but fail to recognize self ('missing-self') leads to activation to neoplastic transformation and infections of certain viruses. In this chapter, we will summarize the development of NK cells in the context of ILCs, describe the diversity of phenotype and function in blood and tissues, and discuss their involvement in health and diseases in humans. PMID- 28921474 TI - Origins of Phantom Limb Pain. AB - Phantom limb pain (PLP) is a chronic neuropathic pain occurring in 45-85% of patients who undergo major amputations of the upper and lower extremities. Chronic pain is physically and mentally debilitating, affecting an individual's potential for self-care and the performance of daily living activities essential for personal and economic independence. In addition, chronic pain may lead to depression and feelings of hopelessness. A National Center for Biotechnology Information study found that in the USA alone, the annual cost of dealing with neuropathic pain is more than $600 billion, with an estimated 20 million people in the USA suffering this condition. PLP manifest predominantly during two time frames post-amputation: during days to a month and again at around 1 year. In most patients, the frequency and intensity of the chronic neuropathic pain diminish over time, but severe pain persists in about 5-10% of patients. The development and maintenance of neuropathic pain is attributed to extremity amputations causing changes in peripheral axon properties and neuronal circuitry in both the peripheral and central nervous systems: peripheral axons, dorsal root ganglia, the spinal cord, and the cortex. However, it is not clear how the changes in neuronal properties in these different locations affect neuropathic pain. Is pain initiated by one set of post-amputation changes while the pain is maintained by another set of changes? If one set of amputation-induced changes, such as those of peripheral axons, are reverted to normal, is the chronic pain reduced or eliminated, while reversing another set of neuronal changes and neuronal circuits to normal do not reduce or eliminate the pain? Or, must all the amputation-induced changes be reverted to normal for pain to be eliminated? While this review examines the mechanisms underlying the induction or maintenance of PLP, it is beyond its scope to examine the mechanisms that may permanently reduce or eliminate neuropathic pain. This paper is the first of two reviews in this journal and deals with the causes of chronic PLP development and maintenance, while the second review examines potential mechanisms that may be responsible for promoting the capacity to coping with PLP by reducing or eliminating it. PMID- 28921475 TI - Legacy effects of continuous chloropicrin-fumigation for 3-years on soil microbial community composition and metabolic activity. AB - Chloropicrin is widely used to control ginger wilt in China, which have an enormous impact on soil microbial diversity. However, little is known on the possible legacy effects on soil microbial community composition with continuous fumigation over different years. In this report, we used high throughput Illumina sequencing and Biolog ECO microplates to determine the bacterial community and microbial metabolic activity in ginger harvest fields of non-fumigation (NF), chloropicrin-fumigation for 1 year (F_1) and continuous chloropicrin-fumigation for 3 years (F_3). The results showed that microbial richness and diversity in F_3 were the lowest, while the metabolic activity had no significant difference. With the increase of fumigation years, the incidence of bacterial wilt was decreased, the relative abundance of Actinobacteria and Saccharibacteria were gradually increased. Using LEfSe analyses, we found that Saccharibacteria was the most prominent biomarker in F_3. Eight genera associated with antibiotic production in F_3 were screened out, of which seven belonged to Actinobacteria, and one belonged to Bacteroidetes. The study indicated that with the increase of fumigation years, soil antibacterial capacity may be increased (possible reason for reduced the incidence of bacterial wilt), and Saccharibacteria played a potential role in evaluating the biological effects of continuous fumigation. PMID- 28921476 TI - Expression of Concern to: Role of physiotherapy in the mobilization of patients with spinal cord injury undergoing human embryonic stem cells transplantation. AB - The Editors-in-Chief of Clinical and Translational Medicine are issuing an editorial expression of concern to alert readers that concerns have been raised regarding the ethics of this study [1]. Appropriate editorial action will be taken once this has been fully investigated. Geeta Shroff disagrees with this notice. Dipin Thakur, Varun Dhingra, Deepak Singh Baroli, Deepanshu Khatri and Rahul Dev Gautam have not responded to our correspondence about this article. PMID- 28921477 TI - Out-of-pocket expenditure and catastrophic health spending on maternal care in public and private health centres in India: a comparative study of pre and post national health mission period. AB - BACKGROUND: The National Health Mission (NHM), one of the largest publicly funded maternal health programs worldwide was initiated in 2005 to reduce maternal, neo natal and infant mortality and out-of-pocket expenditure (OOPE) on maternal care in India. Though evidence suggests improvement in maternal and child health, little is known on the change in OOPE and catastrophic health spending (CHS) since the launch of NHM. AIM: The aim of this paper is to provide a comprehensive estimate of OOPE and CHS on maternal care by public and private health providers in pre and post NHM periods. DATA AND METHOD: The unit data from the 60th and 71st rounds of National Sample Survey (NSS) is used in the analyses. Descriptive statistics is used to understand the differentials in OOPE and CHS. The CHS is estimated based on capacity to pay, derived from household consumption expenditure, the subsistence expenditure (based on state specific poverty line) and household OOPE on maternal care. Data of both rounds are pooled to understand the impact of NHM on OOPE and CHS. The log-linear regression model and the logit regression models adjusted for state fixed effect, clustering and socio-economic and demographic correlates are used in the analyses. RESULTS: Women availing themselves of ante natal, natal and post natal care (all three maternal care services) from public health centres have increased from 11% in 2004 to 31% by 2014 while that from private health centres had increased from 12% to 20% during the same period. The mean OOPE on all three maternal care services from public health centres was US$60 in pre-NHM and US$86 in post-NHM periods while that from private health center was US$170 and US$300 during the same period. Controlling for socioeconomic and demographic correlates, the OOPE on delivery care from public health center had not shown any significant increase in post NHM period. The OOPE on delivery care in private health center had increased by 5.6 times compared to that from public health centers in pre NHM period. Economic well being of the households and educational attainment of women is positively and significantly associated with OOPE, linking OOPE and ability to pay. The extent of CHS on all three maternal care from public health centers had declined from 56% in pre NHM period to 29% in post NHM period while that from private health centres had declined from 56% to 47% during the same period. The odds of incurring CHS on institutional delivery in public health centers (OR .03, 95% CI 0.02, 06) and maternal care (OR 0.06, 95% CI 0.04, 0.07) suggest decline in CHS in the post NHM period. Women delivering in private health centres, residing in rural areas and poor households are more likely to face CHS on maternal care. CONCLUSION: NHM has been successful in increasing maternal care and reducing the catastrophic health spending in public health centers. Regulating private health centres and continuing cash incentive under NHM is recommended. PMID- 28921478 TI - Interstitial pneumonia with autoimmune features: an additional risk factor for ARDS? AB - BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF) identifies a recently recognized autoimmune syndrome characterized by interstitial lung disease and autoantibodies positivity, but absence of a specific connective tissue disease diagnosis or alternative etiology. We retrospectively reviewed the clinical presentation, diagnostic workup and management of seven critically ill patients who met diagnostic criteria for IPAF. We compared baseline characteristics and clinical outcome of IPAF patients with those of the population of ARDS patients admitted in the same period. RESULTS: Seven consecutive patients with IPAF admitted to intensive care unit for acute respiratory distress syndrome (ARDS) were compared with 78 patients with ARDS secondary to a known risk factor and with eight ARDS patients without recognized risk factors. Five IPAF patients (71%) survived and were discharged alive from ICU: Their survival rate was equal to that of patients with a known risk factor (71%), while the subgroup of patients without risk factors had a markedly lower survival (38%). According to the Berlin definition criteria, ARDS was severe in four IPAF patients and moderate in the remaining three. All had multiple organ dysfunction at presentation. The most frequent autoantibody detected was anti SSA/Ro52. All patients required prolonged mechanical ventilation (median duration 49 days, range 10-88); four received extracorporeal membrane oxygenation and one received low-flow extracorporeal CO2 removal. All patients received immunosuppressive therapy. CONCLUSIONS: This is the first description of a cohort of critical patients meeting the diagnostic criteria for IPAF presenting with ARDS. This diagnosis should be considered in any critically ill patient with interstitial lung disease of unknown origin. While management is challenging and level of support high, survival appears to be good and comparable to that of patients with ARDS associated with a known clinical insult. PMID- 28921479 TI - Erratum to: Development of a circulation direct sampling and monitoring system for O2 and CO2 concentrations in the gas-liquid phases of shake-flask systems during microbial cell culture. AB - Following publication of the original article (Takahashi et al. 2017), the authors reported that there was a mistake in the legend of Figure 2. PMID- 28921480 TI - The biodiversity of Lactobacillus spp. from Iranian raw milk Motal cheese and antibacterial evaluation based on bacteriocin-encoding genes. AB - Lactobacilli, as the largest group of lactic acid bacteria, produce large amounts of antimicrobial metabolites such as organic acids, fatty acids, ammonia, hydrogen peroxide, diacetyl and bacteriocin, which inhibit the growth of pathogenic bacteria and increase shelf life of food. The aim of this study was to identify the Lactobacillus spp. isolated from Iranian raw milk Motal cheese and to detect the presence of bacteriocin genes in the isolated Lactobacillus strains exhibiting antimicrobial activity. For this purpose, 6 Motal cheese samples from Dasht-e-Moghan region, Iran, were subjected to microbial characterization. Nineteen Lactobacillus spp. were isolated and subsequently identified based on biochemical and molecular methods. According to the sequencing of isolates, Lactobacillus spp. consisted primarily of Lactobacillus brevis, Lactobacillus plantarum, Lactobacillus casei and Lactobacillus buchneri. The identified isolates were then evaluated for antimicrobial activity against Escherichia coli ATCC 25922, Listeria innocua ATCC 33090 and Staphylococcus aureus ATCC 25923. The results of PCR analysis using specific primers of genes encoding Bacteriocin, revealed the presence of Plantaricin A and Plantaricin EF in all Lactobacillus plantarum isolates and Brevicin 174A in 5 of Lactobacillus brevis isolates, whereas the gene encoding Pediocin PA-1 was not observed in any of examined isolates. It is therefore concluded that bacteriocinogenic isolates could be recommended as suitable candidates to be used as starter, adjunct-starter or antimicrobial agents for production of fermented and non-fermented products. PMID- 28921481 TI - Negative magnetic resonance imaging in three cases of anterior tibial cortex stress fractures. AB - Anterior mid-tibial cortex stress fractures (ATCSF) are uncommon and notoriously challenging to treat. They are termed high risk due to their predilection to prolonged recovery, nonunion and complete fracture. Early diagnosis is essential to avoid progression and reduce fracture complications. Imaging plays a key role in confirming the diagnosis. Magnetic resonance imaging (MRI) is accepted as the gold standard modality due to its high accuracy and nonionizing properties. This report describes three cases of ATCSFs in recreational athletes who had positive radiographic findings with no significant MRI changes. Two athletes had multiple striations within their tibias. Despite the radiographic findings, their severity of symptoms were low with mild or no tenderness on examination. Clinicians should be mindful that the ATCSFs may not present with typical acute stress fracture symptoms. We recommend that plain radiographs should be used as the first line investigation when suspecting ATCSFs. Clinicians should be aware that despite MRI being considered the gold standard imaging modality, we report three cases where the MRI was unremarkable, whilst radiographs and computed tomography confirmed the diagnosis. We urge clinicians to continue to use radiographs as the first line imaging modality for ATCSFs and not to directly rely on MRI. Those who opt directly for MRI may be falsely reassured causing a delay in diagnosis. PMID- 28921483 TI - From Virus to vector to medicine: Foreword by guest editors. PMID- 28921482 TI - Analysis of gender-based differences among surgeons in Japan: results of a survey conducted by the Japan Surgical Society. Part. 2: personal life. AB - PURPOSE: To assess the true conditions and perceptions of the personal lives of men and women working as surgeons in Japan. METHODS: In 2014, all e-mail subscribed members of the Japan Surgical Society (JSS, n = 29,861) were invited to complete a web-based survey. The questions covered demographic information, work environment, and personal life (including marital status, childcare, and nursing care for adult family members). RESULTS: In total, 6211 surgeons (5586 men and 625 women) returned the questionnaires, representing a response rate of 20.8%. Based on the questionnaire responses, surgeons generally prioritize work and spend most of their time at work, although women with children prioritize their family over work; men spend significantly fewer hours on domestic work/childcare than do their female counterparts (men 0.76 h/day vs. women 2.93 h/day, p < 0.01); and both men and women surgeons, regardless of their age or whether they have children, place more importance on the role of women in the family. CONCLUSIONS: The personal lives of Japanese surgeons differed significantly according to gender and whether they have children. The conservative idea that women should bear primary responsibility for the family still pertains for both men and women working as surgeons in Japan. PMID- 28921484 TI - Reply to the Letter by S. Sorscher Regarding "Implications of BRAF Mutations in dMMR Colorectal Cancers". AB - ?. PMID- 28921486 TI - Expression of Concern to: Evaluation of patients with multiple sclerosis using reverse nutech functional score and expanded disability status scale after human embryonic stem cell therapy. AB - The Editors-in-Chief of Clinical and Translational Medicine are issuing an editorial expression of concern to alert readers that concerns have been raised regarding the ethics of this study [1]. Appropriate editorial action will be taken once this has been fully investigated. The author disagrees with this notice. PMID- 28921485 TI - The Neglected Cerebello-Limbic Pathways and Neuropsychological Features of the Cerebellum in Emotion. PMID- 28921487 TI - Family support and gains in school readiness: A longitudinal study. AB - BACKGROUND: Traditional measures of school readiness are labour-intensive and do not assess family support. AIMS: The current study used the newly developed Brief Early Skills and Support Index (BESSI: Hughes, Daly, Foley, White and Devine 2015) to examine 6-month longitudinal stability and change in teachers' ratings of young children's school readiness and investigate the role of family support as a predictor of school readiness. SAMPLE: Five hundred and seventy-eight children (270 boys; 74.2% White British) were included at Time 1 aged 2.58-5.84 years (Mage = 3.98 years, SD = 0.66). METHOD: Teachers and nursery workers completed BESSI questionnaires for each participant on two occasions separated by 6 months. RESULTS: The four latent factors of the BESSI (i.e., Behavioural Adjustment, Language and Cognition, Daily Living Skills and Family Support) exhibited longitudinal measurement invariance and individual differences in ratings on each factor showed strong stability over time. BESSI ratings were also sensitive to improvements over time. Auto-regressive models showed that family support and family income (as measured by eligibility for pupil premium support) at Time 1 each uniquely predicted child outcomes at Time 2. CONCLUSIONS: These findings highlight the importance of family contexts for children's school readiness. PMID- 28921488 TI - Report from the first European Dermato-Epidemiology Network forum. AB - The first European Dermato-Epidemiology Network (EDEN) forum was held on 30-31 March 2017 in Madrid, Spain. Dermatoepidemiology describes the study of causes, prevention, health services research and evaluation of interventions of skin diseases. EDEN aims to promote high-quality research, share expertise and facilitate collaboration. These aims were achieved during the EDEN forum by including a preconference course on skin cancer epidemiology; having excellent world-leading guest speakers on causality, quality of care, pharmacoepidemiology and missing data analysis; and including delegates who presented and discussed innovative research findings. The meeting brought together delegates from 11 different countries. We welcome everyone with an interest in clinical research and epidemiology related to skin disease to attend next year's meeting in March 2018 in Berlin. PMID- 28921489 TI - Effects of diesel exhaust particles on coagulation. PMID- 28921491 TI - Non-Hodgkin lymphoma and obesity. PMID- 28921492 TI - Response letter (Dr. Mion's Letter to the Editor). PMID- 28921493 TI - Vibration Ball Milling for the Synthesis of 5'-Thioadenosine 5'-Pyrophosphate (P' >5') Adenosine (dASppA). AB - Using vibration ball milling, 5'-chloro-5'-deoxyadenosine (CldA) reacts cleanly with 4-methoxybenzyl mercaptan (MobSH), under basic conditions, to the corresponding thioether (MobSdA), which is isolated following precipitation and trituration. Under acidic conditions, in a one-pot, two-step process, MobSdA is transformed into 5'-deoxy-5'-(5-nitropyridyl-2-disulfanyl)-adenosine (NPySSdA). Michaelis-Arbuzov (M-A) reaction of NPySSdA with tris(trimethylsilyl) phosphite proceeds to completion within 30 min as determined by 31 P NMR, and the persilylated M-A product thus formed can be stored in solution under anhydrous conditions at room temperature for several days (in contrast, the anionic phosphorothiolate monoester is labile to hydrolysis). Following evaporation, mechanochemical mixing of the crude M-A product with the nucleotide donor adenosine 5'-monophosphomorpholidate under acidic activation in the presence of additional water gives rapid hydrolytic desilylation and phosphate coupling, so that essentially complete reaction is observed after 90 min and dASppA isolated following C-18 reversed phase HPLC and desalting (>99% pure as determined by monitoring at 260 nm). (c) 2017 by John Wiley & Sons, Inc. PMID- 28921495 TI - Probing RNA Folding Pathways by RNA Fingerprinting. AB - This unit provides protocols for using native polyacrylamide gel electrophoresis to distinguish folding and unfolding conformers of RNA. It is useful for studying conformers that can exchange in a period of minutes or seconds, and that are thus difficult to study by solution-based methods. Conformers that have been separated and immobilized in the gel matrix can be used to study catalytic activity with or without being eluted from the gel. The method can be applied to a wide variety of catalytic RNAs and RNA-protein complexes. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921494 TI - Solid-Phase Synthesis of RNA Analogs Containing Phosphorodithioate Linkages. AB - The oligoribonucleotide phosphorodithioate (PS2-RNA) modification uses two sulfur atoms to replace two non-bridging oxygen atoms at an internucleotide phosphorodiester backbone linkage. Like a natural phosphodiester RNA backbone linkage, a PS2-modified backbone linkage is achiral at phosphorus. PS2-RNAs are highly stable to nucleases and several in vitro assays have demonstrated their biological activity. For example, PS2-RNAs silenced mRNA in vitro and bound to protein targets in the form of PS2-aptamers (thioaptamers). Thus, the interest in and promise of PS2-RNAs has drawn attention to synthesizing, isolating, and characterizing these compounds. RNA-thiophosphoramidite monomers are commercially available from AM Biotechnologies and this unit describes an effective methodology for solid-phase synthesis, deprotection, and purification of RNAs having PS2 internucleotide linkages. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921496 TI - Nucleoside-O-Methyl-(H)-Phosphinates: Novel Monomers for the Synthesis of Methylphosphonate Oligonucleotides Using H-Phosphonate Chemistry. AB - This unit comprises the straightforward synthesis of protected 2' deoxyribonucleoside-O-methyl-(H)-phosphinates in both 3'- and 5'-series. These compounds represent a new class of monomers compatible with the solid-phase synthesis of oligonucleotides using H-phosphonate chemistry and are suitable for the preparation of both 3'- and 5'-O-methylphosphonate oligonucleotides. The synthesis of 4-toluenesulfonyloxymethyl-(H)-phosphinic acid as a new reagent for the preparation of O-methyl-(H)-phosphinic acid derivatives is described. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921497 TI - Quantitative Analysis of Nucleic Acid Stability with Ligands Under High Pressure to Design Novel Drugs Targeting G-Quadruplexes. AB - Nucleic acids (DNA and RNA) can form various non-canonical structures. Because some serious diseases are caused by the conformational change of G-quadruplex DNA structures, the development of ligands that bind and stabilize G-quadruplex DNA is of interest to the field of nucleic acid chemistry. Volumetric changes (DeltaV) in the biomolecular reaction include the structural change of biomolecules and hydration behaviors, which provide information about the tertiary interaction between G-quadruplex DNA and ligands. Thus, it is valuable to investigate DeltaV values to understand the mechanism of interaction between non-canonical structures and their ligands. This unit describes methods that can be used to quantitatively analyze the interaction between G-quadruplex DNA and ligands by using high-pressure UV melting. The combination of thermodynamic parameters (DeltaG, DeltaH, DeltaS, and DeltaV) is a powerful tool to elucidate the mechanism of ligand binding to G-quadruplex without real structural analysis by NMR and X-ray spectroscopy, and gives useful information to design novel drugs. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921498 TI - Synthesis of 4'-Selenoribonucleosides, the Building Blocks of 4'-SelenoRNA, Using a Hypervalent Iodine. AB - Herein is described a detailed protocol for the synthesis of 4' selenoribonucleoside derivatives that involves the use of a hypervalent iodine species. These derivatives are versatile units for the preparation of 4' selenoRNA. Large-scale synthesis of a 4-selenosugar starting from D-ribose is achieved in eight steps, including a final chromatographic purification. The resulting 4-selenosugar is then subjected to the one-pot Pummerer-like reaction using hypervalent iodine in the presence of silylated nucleobases. The reaction with silylated uracil affords the desired 4'-selenouridine derivatives with excellent beta-selectivity and in good yield. Conversely, when purine nucleobases are used in the Pummerer-like reaction, N7 4'-selenoribonucleoside isomers are obtained alongside the desired N9 isomers. However, the undesired N7 isomers can be converted to the desired N9 ones under acidic conditions. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921499 TI - Synthesis of the Phosphoramidite Units for Benzene-Glycol Nucleic Acid. AB - Benzene-glycol nucleic acid-DNA chimeras form thermally and thermodynamically stable duplexes with complementary RNAs, and have base-discriminating abilities. This unit describes the synthesis of four nucleoside analogs, an adenine, cytosine, thymine, and guanine analogs with base-benzene-glycol structure. The synthesis starts with conversion of (S)-mandelic acid in arylboronic acid derivative, common intermediate. Nucleobase coupling of the intermediate and phosphitylation afford to phosphoroamidite units. (c) 2017 by John Wiley & Sons, Inc. PMID- 28921500 TI - Growth hormone therapy for people with thalassaemia. AB - BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Our database and trial registry searches are current to 10 August 2017 and 08 August 2017, respectively. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The quality of the evidence was assessed using GRADE criteria. MAIN RESULTS: One parallel trial conducted in Turkey was included. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The quality of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) 0.33 to 0.15 (moderate quality evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate quality evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period. AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate quality that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed. PMID- 28921501 TI - Immunological tolerance to LCMV antigens differently affects control of acute and chronic virus infection in mice. AB - Cytotoxic T lymphocytes (CTLs) play a key role in the control of lymphocytic choriomeningitis virus (LCMV) infection. In C57BL/6 mice (H-2b ), the CTL response is mainly directed against epitopes from the LCMV glycoprotein (GP) and the nucleoprotein (NP) which represent the two major viral proteins. The role of GP- versus NP-derived epitopes for viral clearance was examined using transgenic (tg) mice ubiquitously expressing LCMV GP and NP, respectively. These mice lack GP- or NP-specific CTLs and show decreased levels of GP- or NP-specific antibodies as a result of tolerance induction. During acute LCMV infection, CTLs specific for GP- and NP-derived epitopes are generated with similar frequencies. Nonetheless, we found that lack of GP- but not of NP-specific CTLs abolished control of acute LCMV infection. In contrast, after high-dose or chronic LCMV infection, virus elimination was delayed to a similar extent in GP- and NP-tg mice. Thus, immunological tolerance to LCMV antigens differently affects virus clearance in acute and chronic infection settings. In addition, our data reveal that immunodominance of H-2b -restricted LCMV-specific CTL epitopes and their antiviral activity do not strictly correlate. PMID- 28921502 TI - Delayed cord clamping and cord gas analysis at birth. AB - Delayed cord clamping for at least 60 s in both term and preterm babies is a major recent change in clinical care. Delayed cord clamping has several effects on other possible interventions. One of these is the effect of delayed cord clamping on umbilical artery gas analysis. When indicated, umbilical artery gas analysis can safely be done either with early cord clamping or, probably most of the times it is necessary, during delayed cord clamping with the cord still unclamped. Paired blood samples (one from the umbilical artery and one from the umbilical vein) can be taken from the pulsating and unclamped cord, immediately after birth, during delayed cord clamping, without any effect on either the accuracy of umbilical artery gas analysis or the transfusion of blood through delayed cord clamping. Umbilical artery gas analysis should instead not be done after delayed cord clamping, since delayed cord clamping alters several acid based parameters and lactate values. PMID- 28921503 TI - Time spent in the clinical environment is the most important aspect of medical education - we need to protect it. PMID- 28921504 TI - Galpha12 facilitates shortening in human airway smooth muscle by modulating phosphoinositide 3-kinase-mediated activation in a RhoA-dependent manner. AB - BACKGROUND AND PURPOSE: PI3K-dependent activation of Rho kinase (ROCK) is necessary for agonist-induced human airway smooth muscle cell (HASMC) contraction, and inhibition of PI3K promotes bronchodilation of human small airways. The mechanisms driving agonist-mediated PI3K/ROCK axis activation, however, remain unclear. Given that G12 family proteins activate ROCK pathways in other cell types, their role in M3 muscarinic acetylcholine receptor-stimulated PI3K/ROCK activation and contraction was examined. EXPERIMENTAL APPROACH: Galpha12 coupling was evaluated using co-immunoprecipitation and serum response element (SRE)-luciferase reporter assays. siRNA and pharmacological approaches, as well as overexpression of a regulator of G-protein signaling (RGS) proteins were applied in HASMCs. Phosphorylation levels of Akt, myosin phosphatase targeting subunit-1 (MYPT1), and myosin light chain-20 (MLC) were measured. Contraction and shortening were evaluated using magnetic twisting cytometry (MTC) and micro-pattern deformation, respectively. Human precision-cut lung slices (hPCLS) were utilized to evaluate bronchoconstriction. KEY RESULTS: Knockdown of M3 receptors or Galpha12 attenuated activation of Akt, MYPT1, and MLC phosphorylation. Galpha12 coimmunoprecipitated with M3 receptors, and p115RhoGEF RGS overexpression inhibited carbachol-mediated induction of SRE-luciferase reporter. p115RhoGEF-RGS overexpression inhibited carbachol-induced activation of Akt, HASMC contraction, and shortening. Moreover, inhibition of RhoA blunted activation of PI3K. Lastly, RhoA inhibitors induced dilation of hPCLS. CONCLUSIONS AND IMPLICATIONS: Galpha12 plays a crucial role in HASMC contraction via RhoA-dependent activation of the PI3K/ROCK axis. Inhibition of RhoA activation induces bronchodilation in hPCLS, and targeting Galpha12 signaling may elucidate novel therapeutic targets in asthma. These findings provide alternative approaches to the clinical management of airway obstruction in asthma. PMID- 28921505 TI - NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib. AB - B cell receptor (BCR) signaling is a key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. To detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2,192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL. Intriguingly, NFATC1 promoter DNA hypomethylation levels were significantly variant in clinical trial cohorts from different disease progression stages and furthermore correlated with Binet disease staging and thymidine kinase levels, strongly suggesting a central role of NFATC1 in CLL development. Functionally, DNA hypomethylation at NFATC1 promoter inversely correlated with RNA levels of NFATC1 and dysregulation correlated with expression of target genes BCL-2, CCND1 and CCR7. The inhibition of the NFAT regulator calcineurin with tacrolimus and cyclosporin A and the BCR signaling inhibitor ibrutinib significantly reduced NFAT activity in leukemic cell lines, and NFAT inhibition resulted in increased apoptosis of primary CLL cells. In summary, our results indicate that the aberrant activation of NFATC1 by DNA hypomethylation and BCR signaling plays a major role in the pathomechanism of CLL. PMID- 28921506 TI - Neurologic injury and patient displacement in gynecologic laparoscopic surgery using a beanbag and shoulder supports. AB - OBJECTIVE: To quantify the incidence of peripheral neuropathy in gynecologic laparoscopic surgery using a combination of beanbag, eggcrate foam, and shoulder supports; and to assess patient displacement during surgery in a steep Trendelenburg position and determine variables correlated with displacement. METHODS: A retrospective study included all gynecologic laparoscopic surgeries performed by one high-volume surgeon at a US center between September 15, 2007, and September 15, 2012. Data included neurologic deficits or extremity pain, any other complications, and-for the final study year-surgical time as well as patient and beanbag displacement. RESULTS: Among 967 patients, no long-term neuropathy was reported, 6 (0.6%) patients had transient shoulder pain beyond the first 24 hours (resolved by initial postoperative visit), and 7 (0.7%) were lost to follow-up. No neurologic complications were reported. Median beanbag and total patient displacement were 0 cm (interquartile range 0-0) and 0 cm (interquartile range 0-2), respectively. Patient displacement relative to the table was correlated with the total surgical time (P=0.025) and patient weight (P=0.023). The median displacement was greater in hysterectomy than non-hysterectomy procedures (P=0.003). CONCLUSION: Use of beanbags with shoulder supports and convoluted foam armboard pads was associated with minimal patient displacement and risk of arm and leg neurologic injury. PMID- 28921507 TI - Modulation of Wnt signaling is essential for the differentiation of ciliated epithelial cells in human airways. AB - Wnt signaling is essential for the differentiation of airway epithelial cells during development. Here, we examined the role of Wnt signaling during redifferentiation of ciliated airway epithelial cells in vitro at the air liquid interface as a model of airway epithelial repair. Phases of proliferation and differentiation were defined. Markers of squamous metaplasia and epithelial ciliation were followed while enhancing beta-catenin signaling by blocking glycogen synthase kinase 3beta with SB216763 and shRNA as well as inhibiting canonical WNT signaling with apical application of Dickkopf 1 (Dkk1). Our findings indicate that enhanced beta-catenin signaling decreases the number of ciliated cells and causes squamous changes in the epithelium, whereas treatment with DDk1 leads to an increased number of ciliated cells. PMID- 28921508 TI - Selection on skewed characters and the paradox of stasis. AB - Observed phenotypic responses to selection in the wild often differ from predictions based on measurements of selection and genetic variance. An overlooked hypothesis to explain this paradox of stasis is that a skewed phenotypic distribution affects natural selection and evolution. We show through mathematical modeling that, when a trait selected for an optimum phenotype has a skewed distribution, directional selection is detected even at evolutionary equilibrium, where it causes no change in the mean phenotype. When environmental effects are skewed, Lande and Arnold's (1983) directional gradient is in the direction opposite to the skew. In contrast, skewed breeding values can displace the mean phenotype from the optimum, causing directional selection in the direction of the skew. These effects can be partitioned out using alternative selection estimates based on average derivatives of individual relative fitness, or additive genetic covariances between relative fitness and trait (Robertson Price identity). We assess the validity of these predictions using simulations of selection estimation under moderate sample sizes. Ecologically relevant traits may commonly have skewed distributions, as we here exemplify with avian laying date - repeatedly described as more evolutionarily stable than expected - so this skewness should be accounted for when investigating evolutionary dynamics in the wild. PMID- 28921509 TI - BAFF augments IgA2 and IL-10 production by TLR7/8 stimulated total peripheral blood B cells. AB - Class-switching of B cells to IgA can be induced via both T-cell-dependent and T cell-independent mechanisms. IgA is most predominantly produced mucosally and is important for combating infections and allergies. In contrast to mice, humans have two forms of IgA; IgA1 and IgA2 with diverse tissue distribution. In early life, IgA levels might be sub-optimal especially during the fall season when bacterial and viral infections are more common. Therefore, we investigated using human B cells whether T-cell-independent factors -promoting cell survival, class switching and immunoglobulin secretion- BAFF, APRIL, IL-10 and retinoic acid can boost IgA production in the context of viral or bacterial infection. To this end total and naive peripheral blood B cells were stimulated with these factors for 6 days in the presence or absence of TLR7/8 agonist R848 (mimicking viral infection) or TLR9 agonist CpG-ODN (mimicking bacterial infection). We show that BAFF significantly augments IgA2 production in TLR7/8 stimulated mature, but not naive B cells. In addition, BAFF augments IL-10 production and viability in TLR7/8 and TLR9 stimulated mature B cells. These data warrant further investigation of its role in immune regulation both in the periphery and mucosal tissues in early life or during disease. PMID- 28921510 TI - Development of a formaldehyde biosensor with application to synthetic methylotrophy. AB - Formaldehyde is a prevalent environmental toxin and a key intermediate in single carbon metabolism. The ability to monitor formaldehyde concentration is, therefore, of interest for both environmental monitoring and for metabolic engineering of native and synthetic methylotrophs, but current methods suffer from low sensitivity, complex workflows, or require expensive analytical equipment. Here we develop a formaldehyde biosensor based on the FrmR repressor protein and cognate promoter of Escherichia coli. Optimization of the native repressor binding site and regulatory architecture enabled detection at levels as low as 1 uM. We then used the sensor to benchmark the in vivo activity of several NAD-dependent methanol dehydrogenase (Mdh) variants, the rate-limiting enzyme that catalyzes the first step of methanol assimilation. In order to use this biosensor to distinguish individuals in a mixed population of Mdh variants, we developed a strategy to prevent cross-talk by using glutathione as a formaldehyde sink to minimize intercellular formaldehyde diffusion. Finally, we applied this biosensor to balance expression of mdh and the formaldehyde assimilation enzymes hps and phi in an engineered E. coli strain to minimize formaldehyde build-up while also reducing the burden of heterologous expression. This biosensor offers a quick and simple method for sensitively detecting formaldehyde, and has the potential to be used as the basis for directed evolution of Mdh and dynamic formaldehyde control strategies for establishing synthetic methylotrophy. PMID- 28921511 TI - Bone marrow type 2 innate lymphoid cells: a local source of interleukin-5 in interleukin-33-driven eosinophilia. AB - T helper type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2s) and eosinophil progenitors have previously been described to produce interleukin-5 (IL-5) in the airways upon allergen provocation or by direct administration of IL-33. Eosinophilic airway inflammation is known to be associated with IL-5-dependent eosinophil development in the bone marrow, however, the source of IL-5 remains unclear. T helper cells, ILC2s and CD34+ progenitors have been proposed to be involved in this process, therefore, we investigated whether these cells are taking part in eosinophilopoiesis by producing IL-5 locally in the bone marrow in IL-33-driven inflammation. Airway exposure with IL-33 led to eosinophil infiltration in airways and elevated eotaxin-2/CCL24. Importantly, IL-5 production as well as expression of the IL-33 receptor increased in ILC2s in the bone marrow under this treatment. A small but significant induction of IL-5 was also found in CD34+ progenitors but not in T helper cells. Similar results were obtained by in vitro stimulation with IL-33 where ILC2s rapidly produced large amounts of IL-5, which coincided with the induction of eosinophil hematopoiesis. IL-33-mediated eosinophil production was indeed dependent on IL-5 as both airway and bone marrow eosinophils decreased in mice treated with anti-IL-5 in combination with IL-33. Interestingly, the responsiveness of ILC2s to IL-33 as well as IL-33-induced eotaxin-2/CCL24 were independent of the levels of IL-5. In summary, we demonstrate for the first time that IL-33 acts directly on bone marrow ILC2s, making them an early source of IL-5 and part of a process that is central in IL-33-driven eosinophilia. PMID- 28921512 TI - Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer. AB - Dacomitinib, an irreversible small-molecule pan-ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 uM dacomitinib and 10 uM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib-induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti-secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib-induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO-1 and occludin, and internalization of claudin-1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib-induced ileal damage. Crofelemer worsened dacomitinib-induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting. PMID- 28921514 TI - Erratum. PMID- 28921515 TI - Education and Healthcare System Effects on Tooth Loss and Dementia Incidence in Later Life. PMID- 28921513 TI - Use of a clinical-laboratory score to guide treatment of gestational diabetes. AB - OBJECTIVE: To assess the outcomes of implementing a clinical-laboratory score in the treatment of pregnant women with gestational diabetes. METHODS: A retrospective before-and-after implementation analysis was undertaken using data and neonatal outcomes for pregnant women with gestational diabetes treated before (January 2011-December 2012; control group) and after (January 2013-December 2014; score group) introduction of a newly developed score. To evaluate the effects of score adoption, odds ratios with 95% confidence intervals were calculated after adjustment for confounding factors. RESULTS: The control group included a greater proportion of women treated with diet alone (170/312 [54.5%]) than the study group did (122/391 [31.2%]; P<0.001). By contrast, more women in the study group received metformin (172 [44.0%] vs 77 [24.7%]; P<0.001). The neonatal outcomes, including low Apgar scores at 1 minute and at 5 minutes and neonatal intensive care unit admission, were similar in both groups. Multivariate logistic regression analysis showed that the adoption of the score did not significantly affect the choice of treatment or the birth weight rating. CONCLUSION: The score served well as an orientation tool in therapeutic decision making and had no negative effect on the treatment choice and perinatal outcomes. PMID- 28921517 TI - Courses and Conferences. PMID- 28921516 TI - Effect of Synthetic Cannabinoids in Older Adults. PMID- 28921518 TI - High birth rates despite easy access to contraception and abortion: a cross sectional study. AB - INTRODUCTION: The aim of this study was to describe and compare contraceptive use, fertility, birth, and abortion rates in the Nordic countries. MATERIAL AND METHODS: National data on births, abortions, fertility rate (1975-2013), redeemed prescriptions of hormonal contraceptives and sales figures of copper intrauterine devices (2008-2013) among women 15-49 years of age in the Nordic countries were collected and analyzed. RESULTS: Use of hormonal contraceptives and copper intrauterine devices varied between 31 and 44%. The highest use was in Denmark (39-44%) and Sweden (40-42%). Combined hormonal contraception followed by the levonorgestrel-releasing intrauterine system were the most common methods. During 1975-2013 abortion rates decreased in Denmark (from 27/1000 women to 15/1000 women aged 15-44/1000 women) and Finland (from 20 to 10/1000 women), remained stable in Norway (~16) and Sweden (~20) and increased in Iceland (from 6 to 15/1000 women). Birth rates remained stable around 60/1000 women aged 15-44 in all countries except for Iceland where the birth rate decreased from 95 to 65/1000 women. Abortion rates were highest in the age group 20-24 years. In the same age group, Sweden had a lower contraceptive use (51%) compared with Denmark (59%) and Norway (56%) and a higher abortion rate 33/1000 compared with Denmark (25/1000) and Norway (27/1000). CONCLUSIONS: In contrast to the declining average fertility and birth rates in Europe, rates in the Nordic countries remain high and stable despite high contraceptive use and liberal access to abortion on women's request. PMID- 28921519 TI - Impact of pork collagen superfine powder on rheological and texture properties of Harbin red sausage. AB - : It is a challenge for producers to looking for excellent filler to satisfy the required qualities of high grade meat products such as Harbin red sausage in China. Four collagen superfine powders (CSPs) from pig skin with different heating pretreatments, named as T0 (non-heating), T1 (at 60C for 20 min), T2 (at 80C for 20 min), T3 (at 120C for 10 min), respectively, at various concentrations (1, 3, 5 wt %) were added to the sausage and their impact on sausage properties was investigated. Rheological results showed that addition of CSPs especially T2 increased the elastic modulus (G') of sausage, indicating the enhanced stabilization of meat batter due to formation of a coherent protein network. Furthermore, as the content of CSPs increased, the values of hardness, springiness, cohesiveness, and chewiness of the CSP-added sausages increased from texture profile analysis. Meantime, it was observed that appropriate preheating (i.e., lower than 80C for 20 min) benefited the texture profile of the sausages. With adding these CSPs, the cooking loss decreased, the values of L* and a* decreased while b* value of the sausages increased. SEM images illustrated that the CSP-added sausage was more compact and homogenous compared to the control. Also, the organoleptic evaluation results showed that the sensory properties of Harbin red sausage added CSP were the same as the control group. In conclusion, CSPs provide the potential to be used as a filler and textural modifier available for Harbin red sausage. PRACTICAL APPLICATIONS: Pig skin has cheap price, and easy to get. Pig skin-derived CSPs provide the potential to be used as a good filler and textured modifier available for high quality meat products, including Harbin red sausage. PMID- 28921521 TI - A paradigm for evaluation and management of the maxillary sinus before dental implantation. AB - OBJECTIVES: To determine a paradigm for evaluating and managing maxillary sinus conditions before dental implantation via preoperative sinonasal assessment. STUDY DESIGN: Prospective cohort study. METHODS: Eighty-four patients who underwent dental implantation with or without sinus augmentation were included. Maxillary sinus conditions were classified into groups 1 to 6 according to cone beam computed tomography (CT) findings: 1) nonspecific findings, 2) solitary polyp or cyst, 3) mucosal thickening, 4) air-fluid level or fluid accumulation, 5) near-total opacification of the maxillary or other paranasal sinus, and 6) calcification spots in the maxillary sinus. Dental implantation with or without sinus augmentation was suggested with postoperative sinus observation (groups 1 3), after medication for acute sinusitis (group 4), and after comprehensive treatment of chronic or fungal sinusitis (groups 5-6). Intraoperative and postoperative sinus-related complications were recorded. RESULTS: Two patients (groups 1 and 3) developed acute rhinosinusitis after sinus augmentation; both recovered completely with medical treatment. Schneiderian membrane perforation occurred during sinus lift surgery in six patients (group 1): five recovered after conservative medical therapy and close observation, whereas one required endoscopic sinus surgery and recovered well. No chronic rhinosinusitis developed after dental implantation. CONCLUSION: Craniofacial CT is crucial for pre-dental implantation sinonasal evaluation. The risk of dental implant-related chronic rhinosinusitis is low for patients with cysts, polyps, or mucosal thickening in the maxillary sinus. However, preventive endoscopic sinus surgery is recommended for patients with incurable chronic rhinosinusitis, fungal sinusitis, and large polyps or cysts. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1261-1267, 2018. PMID- 28921522 TI - Extraluminal biodegradable splint to treat upper airway anterior malacia: A preclinical proof of principle. AB - OBJECTIVE: Upper airway malacia highly complicates the treatment of benign laryngotracheal stenosis, and no ideal option is available to date. We here explore the use of extraluminal biodegradable splints in an animal model of long segment anterior tracheomalacia (TM). We show the efficacy, as well as the tissue tolerance, of a custom-made biodegradable extraluminal device surgically inserted around the trachea. STUDY DESIGN: Preclinical animal study. METHODS: Anterior TM was induced in rabbits through an anterior neck approach by removing eight consecutive anterior tracheal rings without damaging the underlying mucosa. Malacia was corrected during the same surgery by pexy sutures, suspending the tracheal mucosa to an experimental biodegradable device. Symptoms, survival, and tissue reaction were compared to healthy and sham surgery controls. RESULTS: The model induced death by respiratory failure within minutes. Ten animals received the experimental treatment, and those who survived the perioperative period remained asymptomatic with a maximum follow-up of 221 days. Histological studies at programmed euthanasia showed complete degradation of the prosthesis, with significant remnant fibrosis around the trachea. However, the tracheal stiffness of test segments was comparatively less than that of control segments. CONCLUSION: Extraluminal biodegradable splints rescued animals with a condition otherwise incompatible with life. It was well tolerated, leaving peritracheal fibrosis that was not as stiff as normal trachea. The external tracheal stiffening was sufficient for the test animals to live through the phase of severe acute hypercollapsibility. This represents a valid option to help pediatric patients with laryngotracheal stenosis and associated cartilaginous airway malacia. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E53-E58, 2018. PMID- 28921520 TI - Anti-Mullerian hormone and risk of ovarian cancer in nine cohorts. AB - Animal and experimental data suggest that anti-Mullerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : >=0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : >=0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer. PMID- 28921523 TI - A single-session growth mindset intervention for adolescent anxiety and depression: 9-month outcomes of a randomized trial. AB - BACKGROUND: Single-session interventions (SSIs) show promise in the prevention and treatment of youth psychopathology, carrying potential to improve the scalability and accessibility of youth psychological services. However, existing SSIs have conferred greater benefits for youths with anxiety, compared to depression or comorbid problems, and their effects have generally waned over time - particularly for follow-ups exceeding 3 months. METHOD: To help address these discrepancies, we tested whether a novel SSI teaching growth mindset of personality (the belief that personality is malleable) could reduce depression and anxiety and strengthen perceived control in high-risk adolescents (N = 96, ages 12-15). At baseline, youths were randomized to receive a 30-min, computer guided growth mindset intervention or a supportive-therapy control. Youths and parents reported youth anxiety and depressive symptoms, and youths reported their levels of perceived control, at baseline and across a 9-month follow-up period. RESULTS: Compared to the control program, the mindset intervention led to significantly greater improvements in parent-reported youth depression (d = .60) and anxiety (d = .28), youth-reported youth depression (d = .32), and youth reported perceived behavioral control (d = .29) by 9-month follow-up. Intervention effects were nonsignificant for youth-reported anxiety, although 9 month effect sizes reached the small-to-medium range (d = .33). Intervention group youths also experienced more rapid improvements in parent-reported depression, youth-reported depression, and perceived behavioral control across the follow-up period, compared to control group youths. CONCLUSIONS: Findings suggest a promising, scalable SSI for reducing internalizing distress in high risk adolescents. CLINICAL TRIAL REGISTRATION NUMBER: NCT03132298. PMID- 28921524 TI - Karyotype variation of CHO host cell lines over time in culture characterized by chromosome counting and chromosome painting. AB - Genomic rearrangements are a common phenomenon in rapidly growing cell lines such as Chinese hamster ovary (CHO) cells, a feature that in the context of production of biologics may lead to cell line and product instability. Few methods exist to assess such genome wide instability. Here, we use the population distribution of chromosome numbers per cell as well as chromosome painting to quantify the karyotypic variation in several CHO host cell lines. CHO-S, CHO-K1 8 mM glutamine, and CHO-K1 cells adapted to grow in media containing no glutamine were analyzed over up to 6 months in culture. All three cell lines were clearly distinguishable by their chromosome number distribution and by the specific chromosome rearrangements that were present in each population. Chromosome Painting revealed a predominant karyotype for each cell line at the start of the experiment, completed by a large number of variants present in each population. Over time in culture, the predominant karyotype changed for CHO-S and CHO-K1, with the diversity increasing and new variants appearing, while CHO-K1 0 mM Gln preferred chromosome pattern increased in percent of the population over time. As control, Chinese hamster lung fibroblasts were shown to also contain an increasing number of variants over time in culture. PMID- 28921525 TI - Comorbid symptoms of inattention, autism, and executive cognition in youth with putative genetic risk. AB - BACKGROUND: Symptoms of autism spectrum disorder (ASD) and inattention (IA) are highly comorbid and associated with deficits in executive cognition. Cognitive deficits have been posited as candidate endophenotypes of psychiatric traits, but few studies have conceptualized cognitive deficits as psychiatric comorbidities. The latter model is consistent with a latent factor reflecting broader liability to neuropsychological dysfunction, and explains heterogeneity in the cognitive profile of individuals with ASD and IA. METHODS: We tested competing models of covariance among symptoms of ASD, IA, and cognition in a sample of 73 youth with a known genetic mutation. RESULTS: A common executive factor fit best as a cognitive comorbidity, rather than endophenotype, of the shared variance between measures of IA and ASD symptoms. Known genetic risk explained a third of the shared variance among psychiatric and cognitive measures. CONCLUSIONS: Comorbid symptoms of ASD, IA, and cognitive deficits are likely influenced by common neurogenetic factors. Known genetic risk in ASD may inform future investigation of putative genetic causes of IA. PMID- 28921526 TI - Parsing heterogeneity in attention-deficit hyperactivity disorder using EEG-based subgroups. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition for which multiple efforts to characterize brain state differences are underway. The objective of this study was to identify distinct subgroups of resting electroencephalography (EEG) profiles among children with and without ADHD and subsequently provide extensive clinical characterization of the subgroups. METHODS: Latent class analysis was used with resting state EEG recorded from a large sample of 781 children with and without ADHD (N = 620 ADHD, N = 161 Control), aged 6-18 years old. Behavioral and cognitive characteristics of the latent classes were derived from semistructured diagnostic interviews, parent completed behavior rating scales, and cognitive test performance. RESULTS: A five-class solution was the best fit for the data, of which four classes had a defining spectral power elevation. The distribution of ADHD and control subjects was similar across classes suggesting there is no one resting state EEG profile for children with or without ADHD. Specific latent classes demonstrated distinct behavioral and cognitive profiles. Those with elevated slow-wave activity (i.e. delta and theta band) had higher levels of externalizing behaviors and cognitive deficits. Latent subgroups with elevated alpha and beta power had higher levels of internalizing behaviors, emotion dysregulation, and intact cognitive functioning. CONCLUSIONS: There is population-level heterogeneity in resting state EEG subgroups, which are associated with distinct behavioral and cognitive profiles. EEG measures may be more useful biomarkers of ADHD outcome or treatment response rather than diagnosis. PMID- 28921527 TI - Bumping heart and sweaty palms: physiological hyperarousal as a risk factor for child social anxiety. AB - BACKGROUND: Physiological hyperarousal in social situations is a characteristic of individuals with social anxiety disorder (SAD), but so far it has been rarely studied as a biological risk for SAD. Here, we investigate whether children at high risk for SAD (because of their parents' SAD) display physiological hyperarousal while interacting with a stranger. Also, we examine whether early physiological hyperarousal is related to later child social anxiety. METHOD: One hundred and seventeen children took part in the stranger-approach task when they were 2.5 and 4.5 years old. Heart rate (HR), heart rate variability (HRV), and electrodermal activity (EDA) were measured before, during, and after the conversation with a stranger. Both parents' lifetime SAD status and SAD severity were assessed before the birth of the child. Both parents and children reported on children's social anxiety symptoms when children were 7.5. RESULTS: Children of parents with the lifetime SAD diagnosis did not differ in their physiological activity from children of parents without lifetime SAD. However, children of parents with more severe SAD displayed heightened EDA throughout the task procedure. Increased HR and reduced HRV during the stranger-approach and elevated EDA throughout the task phases were linked to later child social anxiety. CONCLUSIONS: Parents' severity of SAD is related to child physiological hyperarousal early in their childhood. In addition, physiological hyperarousal in early childhood predicts later child social anxiety. Together, these findings suggest that early physiological hyperarousal in social situations may pose a risk for later child social anxiety and that physiological hyperarousal, and EDA in particular, may be a biological mechanism in the intergenerational transmission of SAD. PMID- 28921528 TI - Practitioner Review: Treatment of chronic insomnia in children and adolescents with neurodevelopmental disabilities. AB - BACKGROUND: Sleep disturbances, in particular insomnia, represent a common problem in children with neurodevelopmental disabilities (NDDs). Currently, there are no approved medications for insomnia in children by the US Food and Drug Administration or European Medicines Agency and therefore they are prescribed off label. We critically reviewed pediatric literature on drugs as well as nonpharmacological (behavioral) interventions used for sleep disturbances in children with NDDs. METHODS: PubMed, Ovid (including PsycINFO, Ovid MEDLINE(r) , and Embase), and Web of Knowledge databases were searched through February 12, 2017, with no language restrictions. Two authors independently and blindly performed the screening. RESULTS: Good sleep practices and behavioral interventions, supported by moderate-to-low level evidence, are the first recommended treatments for pediatric insomnia but they are often challenging to implement. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice but evidence supporting their use is still limited. An increasing body of evidence supports melatonin as the safest choice for children with NDDs. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Only few studies have been carried out in children's and adolescents' zolpidem, zaleplon, and eszopiclone, with contrasting results. Limited evidence supports the use of alpha-agonists such as clonidine to improve sleep onset latency, especially in attention deficit/hyperactivity disorder subjects. Tricyclic antidepressants, used in adults with insomnia, are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies. CONCLUSIONS: Here, we provided a tentative guide for the use of drugs for insomnia in children with NDDs. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy, effectiveness, and safety of the currently prescribed pediatric sleep medicines in children with NDDs. PMID- 28921529 TI - Metastatic spine tumor surgery: does perioperative blood transfusion influence postoperative complications? AB - BACKGROUND: The question of independent association between allogeneic blood transfusion (ABT) and postoperative complications in cancer surgeries has been controversial and remains so. In metastatic spine tumor surgery (MSTS), previous studies investigated the influence of ABT on survival, but not on postoperative complications. We aimed to evaluate the influence of perioperative ABT on postoperative complications and infections in patients undergoing MSTS. STUDY DESIGN AND METHODS: This retrospective study included 247 patients who underwent MSTS at a single tertiary institution between 2005 and 2014. The outcome measures were postoperative complications and infections within 30 days after MSTS. Multivariate logistic regression analyses were performed to assess influence of blood transfusion on the outcomes after adjusting for potential confounders. RESULTS: Of 247 patients, 133 (54%) received ABT with overall median (range) of 2 (0-10) units. The adjusted odds of developing any postoperative complication was 2.27 times higher in patients with transfusion (95% confidence interval [CI], 1.17-4.38; p = 0.01) and 1.24 times higher odds per every unit increase in blood transfusion (95% CI, 1.05-1.46; p < 0.01). Exposure to blood transfusion also increased the odds of having overall postoperative infections (odds ratio, 3.58; 95% CI, 1.15-11.11; p = 0.02) and there were 1.24 times higher odds per every unit increase in transfusion (95% CI, 1.01-1.54; p = 0.04). CONCLUSIONS: This study adds evidence to the literature implicating ABT to be influential on postoperative complications and infections in patients undergoing MSTS. Appropriate blood management measures should, therefore, be given a crucial place in the care of these patients so as to reduce any putative effect of blood transfusion. PMID- 28921530 TI - Sympatric parallel diversification of major oak clades in the Americas and the origins of Mexican species diversity. AB - Oaks (Quercus, Fagaceae) are the dominant tree genus of North America in species number and biomass, and Mexico is a global center of oak diversity. Understanding the origins of oak diversity is key to understanding biodiversity of northern temperate forests. A phylogenetic study of biogeography, niche evolution and diversification patterns in Quercus was performed using 300 samples, 146 species. Next-generation sequencing data were generated using the restriction-site associated DNA (RAD-seq) method. A time-calibrated maximum likelihood phylogeny was inferred and analyzed with bioclimatic, soils, and leaf habit data to reconstruct the biogeographic and evolutionary history of the American oaks. Our highly resolved phylogeny demonstrates sympatric parallel diversification in climatic niche, leaf habit, and diversification rates. The two major American oak clades arose in what is now the boreal zone and radiated, in parallel, from eastern North America into Mexico and Central America. Oaks adapted rapidly to niche transitions. The Mexican oaks are particularly numerous, not because Mexico is a center of origin, but because of high rates of lineage diversification associated with high rates of evolution along moisture gradients and between the evergreen and deciduous leaf habits. Sympatric parallel diversification in the oaks has shaped the diversity of North American forests. PMID- 28921531 TI - A naive Bayes algorithm for tissue origin diagnosis (TOD-Bayes) of synchronous multifocal tumors in the hepatobiliary and pancreatic system. AB - Synchronous multifocal tumors are common in the hepatobiliary and pancreatic system but because of similarities in their histological features, oncologists have difficulty in identifying their precise tissue clonal origin through routine histopathological methods. To address this problem and assist in more precise diagnosis, we developed a computational approach for tissue origin diagnosis based on naive Bayes algorithm (TOD-Bayes) using ubiquitous RNA-Seq data. Massive tissue-specific RNA-Seq data sets were first obtained from The Cancer Genome Atlas (TCGA) and ~1,000 feature genes were used to train and validate the TOD Bayes algorithm. The accuracy of the model was >95% based on tenfold cross validation by the data from TCGA. A total of 18 clinical cancer samples (including six negative controls) with definitive tissue origin were subsequently used for external validation and 17 of the 18 samples were classified correctly in our study (94.4%). Furthermore, we included as cases studies seven tumor samples, taken from two individuals who suffered from synchronous multifocal tumors across tissues, where the efforts to make a definitive primary cancer diagnosis by traditional diagnostic methods had failed. Using our TOD-Bayes analysis, the two clinical test cases were successfully diagnosed as pancreatic cancer (PC) and cholangiocarcinoma (CC), respectively, in agreement with their clinical outcomes. Based on our findings, we believe that the TOD-Bayes algorithm is a powerful novel methodology to accurately identify the tissue origin of synchronous multifocal tumors of unknown primary cancers using RNA-Seq data and an important step toward more precision-based medicine in cancer diagnosis and treatment. PMID- 28921532 TI - The morphological characterization of orientation-biased displaced large-field ganglion cells in the central part of goldfish retina. AB - The vertebrate retina has about 30 subtypes of ganglion cells. Each ganglion cell receives synaptic inputs from specific types of bipolar and amacrine cells ramifying at the same depth of the inner plexiform layer (IPL), each of which is thought to process a specific aspect of visual information. Here, we identified one type of displaced ganglion cell in the goldfish retina which had a large and elongated dendritic field. As a population, all of these ganglion cells were oriented in the horizontal axis and perpendicular to the dorsal-ventral axis of the goldfish eye in the central part of retina. This ganglion cell has previously been classified as Type 1.2. However, the circuit elements which synapse with this ganglion cell are not yet characterized. We found that this displaced ganglion cell was directly tracer-coupled only with homologous ganglion cells at sites containing Cx35/36 puncta. We further illustrated that the processes of dopaminergic neurons often terminated next to intersections between processes of ganglion cells, close to where dopamine D1 receptors were localized. Finally, we showed that Mb1 ON bipolar cells had ribbon synapses in the axonal processes passing through the IPL and made ectopic synapses with this displaced ganglion cell that stratified into stratum 1 of the IPL. These results suggest that the displaced ganglion cell may synapse with both Mb1 cells using ectopic ribbon synapses and OFF cone bipolar cells with regular ribbon synapses in the IPL to function in both scotopic and photopic light conditions. PMID- 28921533 TI - Dental treatment in the era of new anti-thrombotic agents. AB - BACKGROUND: In recent years, there have been dramatic changes in anti-thrombotic treatment as a result of new anti-thrombotic agents, as well as changes in the indications for their use. As a consequence, dentists are encountering larger numbers of patients who are undergoing anti-thrombotic treatment and who have increased risk for bleeding. The current paper aims to review the literature regarding up-to-date anti-thrombotic treatment and provide information regarding their implications on dentistry. METHODS: An online search was performed of the literature published between 2000 and 2016. Articles dealing with evidence-based clinical guidelines for anti-thrombotic treatments, as well as literature reporting the use of anti-thrombotic medications were included. The manuscripts were screened according to their relevance to dentistry as well as their treatment protocol guidelines. RESULTS: In total, 5,539 publications were identified: 56 of 554 evidence-based clinical guidelines were found that dealt with treatment protocols with anti-thrombotic agents; and 132 of 5,539 articles describe direct anti-thrombotic medications. CLINICAL IMPLICATIONS: Dental treatment includes a risk for bleeding. As a result of the increasing number of patients taking new-generation anti-thrombotic drugs, dentists must be up to date regarding the implications of such drugs on dental treatment as well as the practical means to achieve haemostasis. PMID- 28921534 TI - Exploring cellular behavior under transient gene expression and its impact on mAb productivity and Fc-glycosylation. AB - Transient gene expression (TGE) is a methodology employed in bioprocessing for the fast provision of recombinant protein material. Mild hypothermia is often introduced to overcome the low yield typically achieved with TGE and improve specific protein productivity. It is therefore of interest to examine the impact of mild hypothermic temperatures on both the yield and quality of transiently expressed proteins and the relationship to changes in cellular processes and metabolism. In this study, we focus on the ability of a Chinese hamster ovary cell line to galactosylate a recombinant monoclonal antibody (mAb) product. Through experimentation and flux balance analysis, our results show that TGE in mild hypothermic conditions led to a 76% increase in qP compared to TGE at 36.5 degrees C in our system. This increase is accompanied by increased consumption of nutrients and amino acids, together with increased production of intracellular nucleotide sugar species, and higher rates of mAb galactosylation, despite a reduced rate of cell growth. The reduction in biomass accumulation allowed cells to redistribute their energy and resources toward mAb synthesis and Fc glycosylation. Interestingly, the higher capacity of cells to galactosylate the recombinant product in TGE at 32 degrees C appears not to have been assisted by the upregulation of galactosyltransferases (GalTs), but by the increased expression of N-acetylglucosaminyltransferase II (GnTII) in this cell line, which facilitated the production of bi-antennary glycan structures for further processing. PMID- 28921536 TI - Technical Note: A simulation study on the feasibility of radiotherapy dose enhancement with calcium tungstate and hafnium oxide nano- and microparticles. AB - PURPOSE: To assess the radiotherapy dose enhancement (RDE) potential of calcium tungstate (CaWO4 ) and hafnium oxide (HfO2 ) nano- and microparticles (NPs). A Monte Carlo simulation study was conducted to gauge their respective RDE potentials relative to that of the broadly studied gold (Au) NP. The study was warranted due to the promising clinical and preclinical studies involving both CaWO4 and HfO2 NPs as RDE agents in the treatment of various types of cancers. The study provides a baseline RDE to which future experimental RDE trends can be compared to. METHODS: All three materials were investigated in silico with the software Penetration and Energy Loss of Positrons and Electrons (PENELOPE 2014) developed by Francesc Salvat and distributed in the United States by the Radiation Safety Information Computational Center (RSICC) at Oak Ridge National Laboratory. The work utilizes the extensively studied Au NP as the "gold standard" for a baseline. The key metric used in the evaluation of the materials was the local dose enhancement factor (DEFloc ). An additional metric used, termed the relative enhancement ratio (RER), evaluates material performance at the same mass concentrations. RESULTS: The results of the study indicate that Au has the strongest RDE potential using the DEFloc metric. HfO2 and CaWO4 both underperformed relative to Au with lower DEFloc of 2-3 * and 4-100 *, respectively. CONCLUSIONS: The computational investigation predicts the RDE performance ranking to be: Au > HfO2 > CaWO4 . PMID- 28921537 TI - Nasotracheal intubation over a bougie vs. non-bougie intubation: a prospective randomised, controlled trial in older children and adults using videolaryngoscopy. AB - Conventionally, nasotracheal intubation has consisted of blind nasal passage and external manipulation of the tube through the glottis ('conventional technique'), a technique associated with a high incidence of nasal trauma. We evaluated a novel technique for routine asleep (i.e. post-induction) nasotracheal intubation using a bougie ('bougie technique'), which uses a nasopharyngeal airway to guide a paediatric bougie nasotracheally for use as a Seldinger tracheal intubation guide. Two hundred and fifty-seven older children (> 8 years) and adults were randomly assigned to videolaryngoscopy-assisted nasotracheal intubation using either the conventional or the bougie technique. The hypothesis was that the bougie technique would result in less nasopharyngeal trauma. The bougie technique was associated with significantly less nasopharyngeal bleeding than the conventional technique at both 60-90 s (55% vs. 68%; p = 0.033) and 5 min (51% vs. 70%; p = 0.002). The severity of bleeding was also significantly less with the bougie technique, with an OR for active bleeding of 0.42 (95%CI 0.20-0.87; p = 0.020) at 60-90 s and 0.15 (95%CI 0.06-0.37; p < 0.0001) at 5 min. Magill forceps were needed significantly less often with the bougie technique (9% vs. 28%, p = 0.0001) and there was no difference in first attempt and overall success rates between the two techniques (p = 0.133 and p = 0.750, respectively). Not only is nasal intubation over a bougie as successful as the conventional technique, it also significantly decreases both the incidence and severity of nasopharyngeal trauma, as well as the need for the use of Magill forceps. PMID- 28921535 TI - Genome-wide host RNA signatures of infectious diseases: discovery and clinical translation. AB - The use of whole blood gene expression to derive diagnostic biomarkers capable of distinguishing between phenotypically similar diseases holds great promise but remains a challenge. Differential gene expression analysis is used to identify the key genes that undergo changes in expression relative to healthy individuals, as well as to patients with other diseases. These key genes can act as diagnostic, prognostic and predictive markers of disease. Gene expression 'signatures' in the blood hold the potential to be used for the diagnosis of infectious diseases, where current diagnostics are unreliable, ineffective or of limited potential. For diagnostic tests based on RNA signatures to be useful clinically, the first step is to identify the minimum set of gene transcripts that accurately identify the disease in question. The second requirement is rapid and cost-effective detection of the gene expression levels. Signatures have been described for a number of infectious diseases, but 'clinic-ready' technologies for RNA detection from clinical samples are limited, though existing methods such as RT-PCR are likely to be superseded by a number of emerging technologies, which may form the basis of the translation of gene expression signatures into routine diagnostic tests for a range of disease states. PMID- 28921538 TI - A fast inverse treatment planning strategy facilitating optimized catheter selection in image-guided high-dose-rate interstitial gynecologic brachytherapy. AB - PURPOSE: Interstitial high-dose rate (HDR) brachytherapy is an important therapeutic strategy for the treatment of locally advanced gynecologic (GYN) cancers. The outcome of this therapy is determined by the quality of dose distribution achieved. This paper focuses on a novel yet simple heuristic for catheter selection for GYN HDR brachytherapy and their comparison against state of the art optimization strategies. The proposed technique is intended to act as a decision-supporting tool to select a favorable needle configuration. MATERIALS: The presented heuristic for catheter optimization is based on a shrinkage-type algorithm (SACO). It is compared against state of the art planning in a retrospective study of 20 patients who previously received image-guided interstitial HDR brachytherapy using a Syed Neblett template. From those plans, template orientation and position are estimated via a rigid registration of the template with the actual catheter trajectories. All potential straight trajectories intersecting the contoured clinical target volume (CTV) are considered for catheter optimization. Retrospectively generated plans and clinical plans are compared with respect to dosimetric performance and optimization time. RESULTS: All plans were generated with one single run of the optimizer lasting 0.6-97.4 s. Compared to manual optimization, SACO yields a statistically significant (P <= 0.05) improved target coverage while at the same time fulfilling all dosimetric constraints for organs at risk (OARs). Comparing inverse planning strategies, dosimetric evaluation for SACO and "hybrid inverse planning and optimization" (HIPO), as gold standard, shows no statistically significant difference (P > 0.05). However, SACO provides the potential to reduce the number of used catheters without compromising plan quality. CONCLUSION: The proposed heuristic for needle selection provides fast catheter selection with optimization times suited for intraoperative treatment planning. Compared to manual optimization, the proposed methodology results in fewer catheters without a clinically significant loss in plan quality. The proposed approach can be used as a decision support tool that guides the user to find the ideal number and configuration of catheters. PMID- 28921539 TI - Evolution of the endoscopic modified Lothrop procedure: A systematic review and meta-analysis. AB - OBJECTIVE: Since first described in the 1990s, the endoscopic modified Lothrop procedure (EMLP) has been the subject of a growing body of literature. We performed a review to compare indications and outcomes of EMLP in an early cohort of publications (1990-2008) versus a contemporary cohort (2009-2016) and compare outcomes associated with follow-up >=2 years versus <2 years. DATA SOURCES: PubMed, SCOPUS and Cochrane databases. REVIEW METHODS: An English-language search of the PubMed and Ovid databases was conducted to identify publications from 1990 to 2016 reporting clinical outcomes of EMLP. Meta-analysis was performed using Statistical Analysis System 9.4. RESULTS: A total of 1,205 patients were abstracted from 29 articles with a mean follow-up of 29.1 +/- 10.3 months. The overall rate of significant or complete symptom improvement was 86.5% (95% confidence interval [CI]: 84.2%-88.7%). The overall patency rate was 90.7% (95% CI: 89.1%-92.3%), with a revision rate of 12.6% (95% CI: 10.6%-14.3%). Compared to the early cohort, patients in the contemporary cohort underwent EMLP more often for tumors (P < .001), had higher rates of complete or significant symptom improvement (90.0% vs. 82.6 %, P < .001); and trended toward greater patency rates (92.1% vs. 88.6%, P = .052). Compared to the short-term follow-up cohort, the long-term cohort showed no differences in symptom improvement or patency, but the revision rate was higher (14.5% vs. 9.2%, P = .016). CONCLUSIONS: In the last decade, EMLP has been performed more frequently for tumors. Recent studies have demonstrated improved symptom outcomes and a trend toward improved patency rates. The revision rate increased significantly when follow-up exceeded 2 years. Laryngoscope, 128:317-326, 2018. PMID- 28921540 TI - Imaging stem cell distribution, growth, migration, and differentiation in 3-D scaffolds for bone tissue engineering using mesoscopic fluorescence tomography. AB - Regenerative medicine has emerged as an important discipline that aims to repair injury or replace damaged tissues or organs by introducing living cells or functioning tissues. Successful regenerative medicine strategies will likely depend upon a simultaneous optimization strategy for the design of biomaterials, cell-seeding methods, cell-biomaterial interactions, and molecular signaling within the engineered tissues. It remains a challenge to image three-dimensional (3-D) structures and functions of the cell-seeded scaffold in mesoscopic scale (>2 ~ 3 mm). In this study, we utilized angled fluorescence laminar optical tomography (aFLOT), which allows depth-resolved molecular characterization of engineered tissues in 3-D to investigate cell viability, migration, and bone mineralization within bone tissue engineering scaffolds in situ. PMID- 28921541 TI - Automatic labeling of MR brain images through extensible learning and atlas forests. AB - PURPOSE: Multiatlas-based method is extensively used in MR brain images segmentation because of its simplicity and robustness. This method provides excellent accuracy although it is time consuming and limited in terms of obtaining information about new atlases. In this study, an automatic labeling of MR brain images through extensible learning and atlas forest is presented to address these limitations. METHODS: We propose an extensible learning model which allows the multiatlas-based framework capable of managing the datasets with numerous atlases or dynamic atlas datasets and simultaneously ensure the accuracy of automatic labeling. Two new strategies are used to reduce the time and space complexity and improve the efficiency of the automatic labeling of brain MR images. First, atlases are encoded to atlas forests through random forest technology to reduce the time consumed for cross-registration between atlases and target image, and a scatter spatial vector is designed to eliminate errors caused by inaccurate registration. Second, an atlas selection method based on the extensible learning model is used to select atlases for target image without traversing the entire dataset and then obtain the accurate labeling. RESULTS: The labeling results of the proposed method were evaluated in three public datasets, namely, IBSR, LONI LPBA40, and ADNI. With the proposed method, the dice coefficient metric values on the three datasets were 84.17 +/- 4.61%, 83.25 +/- 4.29%, and 81.88 +/- 4.53% which were 5% higher than those of the conventional method, respectively. The efficiency of the extensible learning model was evaluated by state-of-the-art methods for labeling of MR brain images. Experimental results showed that the proposed method could achieve accurate labeling for MR brain images without traversing the entire datasets. CONCLUSION: In the proposed multiatlas-based method, extensible learning and atlas forests were applied to control the automatic labeling of brain anatomies on large atlas datasets or dynamic atlas datasets and obtain accurate results. PMID- 28921542 TI - Pathogen inactivation of Dengue virus in red blood cells using amustaline and glutathione. AB - BACKGROUND: Dengue virus (DENV) is an arbovirus primarily transmitted through mosquito bite; however, DENV transfusion-transmitted infections (TTIs) have been reported and asymptomatic DENV RNA-positive blood donors have been identified in endemic countries. DENV is considered a high-risk pathogen for blood safety. One of the mitigation strategies to prevent arbovirus TTIs is pathogen inactivation. In this study we demonstrate that the amustaline and glutathione (S-303/GSH) treatment previously found effective against Zika virus in red blood cells (RBCs) is also effective in inactivating DENV. STUDY DESIGN AND METHODS: Red blood cells were spiked with high levels of DENV. Viral RNA loads and infectious titers were measured in the untreated control and before and after pathogen inactivation treatment of RBC samples. DENV infectivity was also assessed over five successive cell culture passages to detect any potential residual replicative virus. RESULTS: The mean +/- SD DENV titer in RBCs before inactivation was 6.61 +/- 0.19 log 50% tissue culture infectious dose (TCID50 )/mL and the mean viral RNA load was 8.42 log genome equivalents/mL. No replicative DENV was detected either immediately after completion of treatment using S-303/GSH or after cell culture passages. CONCLUSION: Treatment using S-303/GSH inactivated high levels of DENV in RBCs to the limit of detection. In combination with previous studies showing the effective inactivation of DENV in plasma and platelets using the licensed amotosalen/UVA system, this study demonstrates that high levels of DENV can be inactivated in all blood components. PMID- 28921544 TI - Commentary: So was it worth it? A commentary on Fricke et al. and Hagen et al. (2017). AB - Fricke et al. and Hagen et al. (2017) each report on large-scale pragmatic randomised controlled trials delivered in schools or nurseries, investigating language interventions for vulnerable children and showing moderate positive effect sizes. Such research is part of a recent development of 'what works' research in England, and the number of 'what works' trials continues to increase, largely through funding from the Sutton Trust, who are concerned with disadvantaged children, to the Educational Endowment Foundation (EEF). 'What works' research is not firmly accepted by all educationalists, however, results of trials are now available quickly and presented in a manner intended to be accessible to practitioners. This development may facilitate principled decisions on the adoption of interventions by schools, as trials and their outcomes may be interrogated to support decisions on whether the anticipated impact is worth the cost of implementation. PMID- 28921543 TI - Language growth in children with heterogeneous language disorders: a population study. AB - BACKGROUND: Language development has been characterised by significant individual stability from school entry. However, the extent to which trajectories of language growth vary in children with language disorder as a function of co occurring developmental challenges is a question of theoretical import, with implications for service provision. METHODS: SCALES employed a population-based survey design with sample weighting procedures to estimate growth in core language skills over the first three years of school. A stratified sample (n = 529) received comprehensive assessment of language, nonverbal IQ, and social, emotional and behavioural difficulties at 5-6 years of age and 95% of the sample (n = 499) were assessed again at ages 7-8. Language growth was measured using both raw and standard scores in children with typical development, children with language disorder of unknown origin, and children with language disorders associated with a known clinical condition and/or intellectual disability. RESULTS: Overall, language was stable at the individual level (estimated ICC = 0.95) over the first three years of school. Linear mixed effects models highlighted steady growth in language raw scores across all three groups, including those with multiple developmental challenges. There was little evidence, however, that children with language disorders were narrowing the gap with peers (z-scores). Adjusted models indicated that while nonverbal ability, socioeconomic status and social, emotional and behavioural deficits predicted initial language score (intercept), none predicted language growth (slope). CONCLUSIONS: These findings corroborate previous studies suggesting stable language trajectories after ages 5-6 years, but add considerably to previous work by demonstrating similar developmental patterns in children with additional nonverbal cognitive deficits, social, emotional, and behavioural challenges, social disadvantage or clinical diagnoses. PMID- 28921545 TI - Editorial: New frontiers in the scientific study of developmental language disorders. AB - Developmental language disorders (DLD) are common and have far-reaching developmental consequences. Nevertheless, public awareness of DLD is poor, and one goal of this special issue is to showcase a set of papers that provide a clear and coherent message about the nature and impact of DLD, and the potential of intervention to mitigate these impacts. In this editorial, we highlight seminal papers JCPP has published on language disorders over the last 40 years. Many of the issues raised then are still relevant now; however, the papers that comprise this special issue exemplify how far the field has come in achieving consensus on terminology and diagnostic criteria, and producing highly consistent findings on the stability and impact of DLD, and the potential for language change in response to targeted interventions. The editorial concludes with a road map for future research and clinical priorities that includes the need for randomised controlled trials that specifically address the impact of co morbidities on response to treatment, impacts of intervention on broader developmental outcomes, and the experiences of adults with DLD. PMID- 28921547 TI - A clinical, randomized study on the influence of dental whitening on Streptococcus mutans population. AB - BACKGROUND: Dental whitening with peroxides has been popularized through the at home technique, which employs low concentrations of peroxide applied in individual trays. However, there are few clinical trials reporting the effects of its continuous use on oral microbiota. Thus, the purpose of the present clinical, randomized study was to evaluate the influence of at-home whitening treatment on Streptococcus mutans in saliva, buccal mucosa, and subgingival and supragingival plaque. METHODS: Thirty volunteers were randomly divided into two study groups (N = 15) according to the whitening therapy: G CP, whitening using 10% carbamide peroxide 4 h daily for 21 days; and G HP, whitening using 6% hydrogen peroxide 1.5 h daily for 21 days. Samples from the predetermined locations were collected at three evaluation periods: T1, before; T2, immediately after; and T3, 30 days after the beginning of the treatment. The microbiological evaluation was made using conventional and molecular methods. RESULTS: Student's t-test demonstrated a statistically significant decrease in S. mutans population in the subgingival and supragingival plaque for HP samples between T1 and T2 no difference was found between T1 and T3 regardless of the location and the whitening product used (alpha = 0.05). CONCLUSIONS: Although HP reduced S. mutans during treatment, the levels returned to baseline when assessed 30 days after the treatment. PMID- 28921548 TI - Smoking cessation and response to periodontal treatment. AB - Smoking has detrimental oral effects. The aim of this study was to review the literature related to the impact of smoking cessation on periodontal health, periodontal disease and periodontal treatment outcome as well as to review the smoking cessation strategies and the dentist's role in the smoking cessation effort. Smoking cessation seems to have a positive effect on the periodontium, to decrease the risk for incidence and progression of periodontitis and to lead to a non-significant trend for greater mean probing depth reductions after non surgical treatment over a 12-month period. Smoking cessation effect on the periodontium should be further investigated. Dentists should inform their patients on the harmful effect of smoking and the beneficial effect of smoking cessation on oral health. They should advise, motivate and support their patients to quit smoking. Smoking-control strategies should be incorporated in dental practise. The dentist's role in the smoking cessation effort is important. Guidelines on smoking-control strategies applied in the dental office are required. PMID- 28921546 TI - Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression. AB - Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA-Seq study of stage 4/M primary tumors, enriched BM-derived diagnostic and relapse DTCs, as well as the corresponding BM-derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors (q < 0.001, |log2 FC|>2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs (q < 8 * 10-75 log2 FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut-offs (q < 0.01, |log2 FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3/PUMA, STK11, CADM4 and GLTSCR2. This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. PMID- 28921549 TI - DeltaFlucs: Brighter Photinus pyralis firefly luciferases identified by surveying consecutive single amino acid deletion mutations in a thermostable variant. AB - The bright bioluminescence catalyzed by Photinus pyralis firefly luciferase (Fluc) enables a vast array of life science research such as bio imaging in live animals and sensitive in vitro diagnostics. The effectiveness of such applications is improved using engineered enzymes that to date have been constructed using amino acid substitutions. We describe DeltaFlucs: consecutive single amino acid deletion mutants within six loop structures of the bright and thermostable *11 Fluc. Deletion mutations are a promising avenue to explore new sequence and functional space and isolate novel mutant phenotypes. However, this method is often overlooked and to date there have been no surveys of the effects of consecutive single amino acid deletions in Fluc. We constructed a large semi rational DeltaFluc library and isolated significantly brighter enzymes after finding *11 Fluc activity was largely tolerant to deletions. Targeting an "omega loop" motif (T352-G360) significantly enhanced activity, altered kinetics, reduced Km for D-luciferin, altered emission colors, and altered substrate specificity for redshifted analog DL-infraluciferin. Experimental and in silico analyses suggested remodeling of the Omega-loop impacts on active site hydrophobicity to increase light yields. This work demonstrates the further potential of deletion mutations, which can generate useful Fluc mutants and broaden the palette of the biomedical and biotechnological bioluminescence enzyme toolbox. PMID- 28921550 TI - Sugars from woody tissue photosynthesis reduce xylem vulnerability to cavitation. AB - Reassimilation of internal CO2 via woody tissue photosynthesis has a substantial effect on tree carbon income and wood production. However, little is known about its role in xylem vulnerability to cavitation and its implications in drought driven tree mortality. Young trees of Populus nigra were subjected to light exclusion at the branch and stem levels. After 40 d, measurements of xylem water potential, diameter variation and acoustic emission (AE) were performed in detached branches to obtain acoustic vulnerability curves to cavitation following bench-top dehydration. Acoustic vulnerability curves and derived AE50 values (i.e. water potential at which 50% of cavitation-related acoustic emissions occur) differed significantly between light-excluded and control branches (AE50,light-excluded = -1.00 +/- 0.13 MPa; AE50,control = -1.45 +/- 0.09 MPa; P = 0.007) denoting higher vulnerability to cavitation in light-excluded trees. Woody tissue photosynthesis represents an alternative and immediate source of nonstructural carbohydrates (NSC) that confers lower xylem vulnerability to cavitation via sugar-mediated mechanisms. Embolism repair and xylem structural changes could not explain this observation as the amount of cumulative AE and basic wood density did not differ between treatments. We suggest that woody tissue assimilates might play a role in the synthesis of xylem surfactants for nanobubble stabilization under tension. PMID- 28921551 TI - Zika virus RNA detection in asymptomatic blood donors during an outbreak in the northeast region of Sao Paulo State, Brazil, 2016. AB - BACKGROUND: In 2015, there was a large Zika virus (ZIKV) outbreak in Brazil. The proportion of asymptomatic infections is very high, and it is possible for transfusion-transmitted ZIKV (TT-ZIKV) infection to occur. The prevalence of asymptomatic ZIKV infection among Brazilian blood donors during this epidemic outbreak is unknown. STUDY DESIGN AND METHODS: Plasma samples obtained between October 2015 and May 2016 from 1393 volunteer blood donors were tested for ZIKV RNA. The viral load was quantified using an in-house standard curve. Additionally, positive ZIKV RNA samples were tested for anti-ZIKV immunoglobulin (Ig)M and anti-ZIKV IgG. RESULTS: Of the 1393 blood samples, ZIKV RNA was detected in 37 (n = 37/1393; 2.7%). The median infection viral load detected was 7714 copies/mL (ranging from 135-124,220 copies/mL). The majority of the positive samples (70.3%) exhibited a viral load of approximately 103 copies/mL. Six samples that were positive for ZIKV RNA were also positive for anti-ZIKV IgM and IgG (n = 6/37; 13.5%). CONCLUSION: This is the first study evaluating the prevalence of ZIKV RNA among Brazilian blood donors, which was relatively high and might lead to TT-ZIKV infection. It is unclear whether the simultaneous presence of anti-ZIKV IgM and IgG in RNA-positive donations or the viral load influences transfusion transmission of the infection. This study also adds to the global understanding of ZIKV prevalence in blood donors during outbreaks and the transfusion impact of the infection. PMID- 28921552 TI - Immunomodulatory effect of cryopreserved platelets: altered BDCA3+ dendritic cell maturation and activation in vitro. AB - BACKGROUND: Cryopreservation of platelets (PLTs) is useful in remote areas to overcome logistic problems associated with supply and can extend the shelf life to 2 years. During cryopreservation, properties of PLTs are modified. Whether changes in the cryopreserved PLT (CPP) product are associated with modulation of recipients' immune function is unknown. We aimed to characterize the immune profile of myeloid dendritic cells (mDCs) and the specialized blood DC antigen (BDCA)3+ subset after exposure to CPPs. STUDY DESIGN AND METHODS: Using an in vitro whole blood model of transfusion, the effect of CPPs on mDC and BDCA3+ DC surface antigen expression and inflammatory mediator production was examined using flow cytometry. In parallel, polyinosinic:polycytidylic acid (poly(I:C)) or lipopolysaccharide (LPS) was utilized to model processes activated in viral or bacterial infection, respectively. RESULTS: Cryopreserved PLTs had minimal impact on mDC responses but significantly modulated BDCA3+ DC responses in vitro. Exposure to CPPs alone up regulated BDCA3+ DC CD86 expression and suppressed interleukin (IL)-8, tumor necrosis factor (TNF)-alpha, and interferon-gamma inducible protein (IP)-10 production. In both models of infection-related processes, exposure to CPPs down regulated BDCA3+ DC expression of CD40, CD80, and CD83 and suppressed BDCA3+ DC production of IL-8, IL-12, and TNF-alpha. CPPs suppressed CD86 expression in the presence of LPS and IP-10 and IL-6 production with poly(I:C). CONCLUSION: Cryopreserved PLTs may be immunosuppressive, and this effect is more evident when processes associated with infection are concurrently activated, especially for BDCA3+ DCs. This suggests that transfusion of CPPs in patients with infection may result in impaired BDCA3+ DC responses. PMID- 28921553 TI - Response of Caligus rogercresseyi (Boxshall & Bravo, 2000) to treatment with Hydrogen Peroxide: Recovery of parasites, fish infestation and egg viability under experimental conditions. AB - Hydrogen peroxide (HP) is used to remove C. rogercresseyi from fish but little is known about its effect on this species. This study determined EC50 and concentration immobilizing 100% of specimens, capacity of parasites exposed to HP to recover and infest fish, and effect on survival into the copepodid stage. EC50 and concentration immobilizing 100% of specimens were estimated by exposing parasites for 20 min to 11 concentrations and evaluating effect at 1 and 24 h post-exposure. Capacity to recover and infest fish, and survival into copepodid were evaluated by exposing parasites and eggs to HP for 20 min. Recovery and fish infestation were evaluated at 25 and 24 h post-exposure, respectively. Eggs were grown until control reached the copepodid stage and survival calculated. EC50 was 709.8 ppm.100% immobilization was obtained at 825 ppm. Male and female recover 0.5 and 1 h post-exposure, respectively. Percentage of parasites exposed and not exposed to HP that were recovered on fish was not significantly different. Survival to copepodid was lower in those exposed to HP. HP effect is greater on copepodids, but 100% of the mobile stages are immobilized under 825 ppm causing detachment from fish and potentially driven away, reducing infestation risk. PMID- 28921554 TI - DJ-1 deficiency impairs autophagy and reduces alpha-synuclein phagocytosis by microglia. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder, of which 1% of the hereditary cases are linked to mutations in DJ-1, an oxidative stress sensor. The pathological hallmark of PD is intercellular inclusions termed Lewy Bodies, composed mainly of alpha-Synuclein (alpha-Syn) protein. Recent findings have shown that alpha-Syn can be transmitted from cell to cell, suggesting an important role of microglia, as the main scavenger cells of the brain, in clearing alpha-Syn. We previously reported that the knock down (KD) of DJ-1 in microglia increased cells' neurotoxicity to dopaminergic neurons. Here, we discovered that alpha-Syn significantly induced elevated secretion of the proinflammatory cytokines IL-6 and IL-1beta and a significant dose-dependent elevation in the production of nitric oxide in DJ-1 KD microglia, compared to control microglia. We further investigated the ability of DJ-1 KD microglia to uptake and degrade soluble alpha-Syn, and discovered that DJ-1 KD reduces cell surface lipid raft expression in microglia and impairs their ability to uptake soluble alpha-Syn. Autophagy is an important mechanism for degradation of intracellular proteins and organelles. We discovered that DJ-1 KD microglia exhibit an impaired autophagy-dependent degradation of p62 and LC3 proteins, and that manipulation of autophagy had less effect on alpha-Syn uptake and clearance in DJ-1 KD microglia, compared to control microglia. Further studies of the link between DJ-1, alpha-Syn uptake and autophagy may provide useful insights into the role of microglia in the etiology of the PD. PMID- 28921555 TI - Improved performance of Pseudomonas putida in a bioelectrochemical system through overexpression of periplasmic glucose dehydrogenase. AB - It was recently demonstrated that a bioelectrochemical system (BES) with a redox mediator allowed Pseudomonas putida to perform anoxic metabolism, converting sugar to sugar acids with high yield. However, the low productivity currently limits the application of this technology. To improve productivity, the strain was optimized through improved expression of glucose dehydrogenase (GCD) and gluconate dehydrogenase (GAD). In addition, quantitative real-time RT-PCR analysis revealed the intrinsic self-regulation of GCD and GAD. Utilizing this self-regulation system, the single overexpression strain (GCD) gave an outstanding performance in the electron transfer rate and 2-ketogluconic acid (2KGA) productivity. The peak anodic current density, specific glucose uptake rate and 2KGA producing rate were 0.12 mA/cm2 , 0.27 +/- 0.02 mmol/gCDW /hr and 0.25 +/- 0.02 mmol/gCDW /hr, which were 327%, 477%, and 644% of the values of wild-type P. putida KT2440, respectively. This work demonstrates that expression of periplasmic dehydrogenases involved in electron transfer can significantly improve productivity in the BES. PMID- 28921556 TI - Dating and Sexual Violence Research in the Schools: Balancing Protection of Confidentiality with Supporting the Welfare of Survivors. AB - Rigorous research and program evaluation are needed to understand the experience of dating and sexual violence among youth and the impact of prevention and intervention efforts. Our dilemma in doing this work occurred when youth disclosed dating and sexual violence on a research survey. What responsibility do researchers have to protect survivors' confidentiality as a research participant versus taking steps to ensure the student has the opportunity to access help? In our evaluation of a pilot dating violence prevention program, our protocols employed widely used procedures for providing resources to participants upon their completion of the survey and de-identifying survey data. Upon reviewing preliminary survey results, we became concerned that these established procedures were not sufficient to support research participants who were adolescent survivors of dating and sexual violence. We followed a structured ethical decision-making process to examine legal and ethical considerations, consult with colleagues, consider impacts and alternative solutions, and ultimately find a solution. Through this process, we developed procedures that balance participant confidentiality and the desire to support the welfare of survivors, which other researchers may want to employ when conducting youth sexual and dating violence research in school and community settings. PMID- 28921557 TI - Accountability, Collaboration, and Social Change: Ethical Tensions in an Action Research Project to Address Untested Sexual Assault Kits (SAKs). AB - We conducted a collaborative action research project with stakeholders in Detroit, Michigan, to develop long-term policy strategies to resolve ~11,000 untested rape kits that were discovered in a police storage facility in August 2009. In our research, we uncovered overwhelming evidence of victim-blaming behaviors and fundamental disrespect of rape survivors by the police, which directly contributed to their decisions not to submit kits for forensic testing. We had an ethical responsibility to report these negative findings accurately and completely, and in doing so, we were concerned that police stakeholders might disengage from the action research project and hamper our other ethical responsibilities to promote general and public welfare. In this article, we examine the ethical challenges of balancing accountability, collaboration, and social change. PMID- 28921558 TI - Safety and efficacy of intravenous iron polymaltose, iron sucrose and ferric carboxymaltose in pregnancy: A systematic review. AB - BACKGROUND: Intravenous (IV) iron in pregnancy is useful where oral iron is not tolerated or a rapid replenishment of iron is required. AIMS: To review the literature on the efficacy and safety of different IV iron preparations in the management of antenatal iron-deficiency anaemia (IDA). MATERIALS AND METHODS: We searched MEDLINE, Embase and Scopus from inception to June 2016. Eligible studies were randomised controlled trials (RCTs) and observational studies, involving administration of IV iron (ferric carboxymaltose (FCM), iron polymaltose (IPM) or iron sucrose (IS)), regardless of comparator, to manage antenatal IDA. Two independent reviewers selected studies, extracted data and assessed quality. RESULTS: A total of 47 studies were eligible (21 RCTs and 26 observational studies), investigating IS (n = 2635; 41 studies), FCM (n = 276; four studies) and IPM (n = 164; three studies). All IV preparations resulted in significant improvements in haematological parameters, with a median increase of 21.8 g/L at 3-4 weeks and 30.1 g/L by delivery, but there was no evidence of any associated improvements in clinical outcomes. A greater median increase in Hb was observed with a high (25 g/L; range: 20-39.6 g/L) compared with low dose (20 g/L; range: 6.2-50.3 g/L). The median prevalence of adverse drug reactions for IPM (2.2%; range: 0-4.5%) was lower than FCM (5.0%; range: 0-20%) and IS (6.7%; range: 0 19.5%). CONCLUSION: While IV iron in pregnancy improves haematological parameters, there is an absence of evidence for improvements in important maternal or perinatal outcomes. No single preparation of IV iron appeared to be superior, with the current IV iron preparation of choice largely determined by cost and convenience around administration. PMID- 28921559 TI - Plant evolutionary developmental biology. Introduction to a special issue. PMID- 28921560 TI - On plant growth and form. PMID- 28921561 TI - The ribokinases of Arabidopsis thaliana and Saccharomyces cerevisiae are required for ribose recycling from nucleotide catabolism, which in plants is not essential to survive prolonged dark stress. AB - Nucleotide catabolism in Arabidopsis thaliana and Saccharomyces cerevisiae leads to the release of ribose, which requires phosphorylation to ribose-5-phosphate mediated by ribokinase (RBSK). We aimed to characterize RBSK in plants and yeast, to quantify the contribution of plant nucleotide catabolism to the ribose pool, and to investigate whether ribose carbon contributes to dark stress survival of plants. We performed a phylogenetic analysis and determined the kinetic constants of plant-expressed Arabidopsis and yeast RBSKs. Using mass spectrometry, several metabolites were quantified in AtRBSK mutants and double mutants with genes of nucleoside catabolism. Additionally, the dark stress performance of several nucleotide metabolism mutants and rbsk was compared. The plant PfkB family of sugar kinases forms nine major clades likely representing distinct biochemical functions, one of them RBSK. Nucleotide catabolism is the dominant ribose source in plant metabolism and is highly induced by dark stress. However, rbsk cannot be discerned from the wild type in dark stress. Interestingly, the accumulation of guanosine in a guanosine deaminase mutant strongly enhances dark stress symptoms. Although nucleotide catabolism contributes to carbon mobilization upon darkness and is the dominant source of ribose, the contribution appears to be of minor importance for dark stress survival. PMID- 28921563 TI - Advanced genomic testing may aid in counseling of isolated agenesis of the corpus callosum on prenatal ultrasound. AB - OBJECTIVE: Isolated agenesis of the corpus callosum on fetal ultrasound has a varied prognosis. Microarray and exome sequencing (ES) might aid in prenatal counseling. METHOD: This study includes 25 fetuses with apparently isolated complete corpus callosum (cACC) on ultrasound. All cases were offered single nucleotide polymorphism array. Complementary ES was offered postnatally in selected cases. Clinical physical and neurodevelopmental follow-up was collected. RESULTS: Eighteen cases opted for single nucleotide polymorphism array testing, which detected a causal anomaly in 2/18 (11.1%; 95% CI 2.0%-31%). Among ongoing pregnancies without a causal anomaly on microarray, 30% (95% CI 8.5%-60%) showed intellectual disability. Postnatal magnetic resonance imaging and physical examination often (64%; 95% CI 38%-85%, and 64%; 95% CI 38%-85%, respectively) revealed additional physical anomalies in cases without a causal anomaly on microarray. Two cases appeared truly isolated after birth. Postnatal sequencing in 4 of 16 cases without a causal anomaly on microarray but with intellectual disability and/or additional postnatal physical anomalies revealed 2 single-gene disorders. Therefore, the estimated diagnostic yield of ES in chromosomally normal cACC fetuses is between 2/4 (50%; 95% CI 11%-89%) and 2/16 (13.3%; 95% CI 2.4%-36%). CONCLUSION: In accordance with current guidelines, we conclude that microarray should be offered in case of isolated cACC on ultrasound. ES is likely to be informative for prenatal counseling and should be offered if microarray is normal. PMID- 28921562 TI - A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders. AB - OBJECTIVE: De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred. METHODS: We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction. RESULTS: In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk. CONCLUSIONS: Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis. PMID- 28921564 TI - Machine-specific quality assurance procedure for stereotactic treatments with dynamic couch rotations. AB - OBJECTIVE: We present a method in which the treatment couch's accuracy is measured using the electronic portal imaging device (EPID) and a phantom of our own construction. Using this phantom, we were able to quantify the treatment couch walkout, and the rotation angle accuracy for both static and dynamic couch treatments. These measurements were used to provide an accurate measure of the treatment couch isocenter as well as to verify the couch rotation angle recorded in the trajectory log. METHODS: The phantom was constructed using a polystyrene slab in which five ball bearings of 4 mm diameter are placed on the same plane at varying radii (0, 2.8, 4.4, 5.6, and 6.7 cm). The couch was rotated through its full extent (-90, 90 degrees) while MV images were acquired continuously. The couch rotational accuracy was calculated using a least squares minimization which fit the locations of the BBs to their expected locations relative to reference setup conditions. Using this approach, rotation angle and isocenter walkout was calculated in three dimensions. These measurements were used to quantify the accuracy of the couch as well as to validate the Varian TrueBeam trajectory logs. Additionally, a method for an EPID-based couch star-shot measurement was developed and compared with the traditional film-based method. RESULTS: The measured couch center of rotation consisted of a cloud of points clustered around the room isocenter within 0.7 mm distance. The trajectory log couch angle values agreed with those recorded in the DICOM header of the EPID images to the third significant digit and the couch rotation angles recorded in the trajectory log and DICOM header agreed with the calculated values to 0.08 degrees. Comparison of couch star-shot measurement developed in this study with film-based star-shot measurements gave an agreement to within 0.2 mm. CONCLUSION: We have developed a quality assurance method for the treatment couch which is simple, accurate, and enables the user to access a multitude of consistent data with a single measurement. Using this method, we have shown that the treatment couch is accurate for both static and dynamic stereotactic deliveries. PMID- 28921565 TI - The impact of P-glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors. AB - Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244), and pimasertib (AS703026): PD0325901 was the weakest substrate of P-gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2-/- mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, our study recommends further development of PD0325901 for the treatment of intracranial neoplasms. PMID- 28921566 TI - PEGylation of cationic liposomes encapsulating soluble Leishmania antigens reduces the adjuvant efficacy of liposomes in murine model. AB - Although there have been several attempts to develop a vaccine against leishmaniasis, no vaccine in human has been developed yet. Liposomes consisting of 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) encapsulating soluble Leishmania antigens (SLA) enhance protective immunity of SLA against Leishmania major infection in mice. However, they immobilized at the injection site because of their positive charge. To overcome the problem, shielding the surface charge with polyethylene glycol (PEGylation) was chosen in this study. Liposomal SLA consisting different concentrations of PEG (1.9%-15% mol) were prepared. BALB/c mice were immunized three times in 3 weeks intervals with different formulations. Lesion development and parasite burden in footpad and spleen were evaluated to specify the type of generated immune response and extent of protection. Th1/Th2 cytokine profiles and IgG isotypes were also analysed. The maximum protection was observed in mice immunized with Lip-SLA or pLip-SLA (1.9%) due to smaller footpad swelling, reduction in parasite load, an increase in IgG2a and IFN-gamma production. Our results showed that immunization of mice with a high level of PEG (>7.5%) did not improve protective immunity of liposomal SLA. The presence of PEG, particularly more than 3.75%, is not recommended for protection against leishmaniasis. PMID- 28921567 TI - Fragile Y Chromosomes (retrospective on DOI 10.1002/bies.201500040). PMID- 28921569 TI - Murine red blood cells from genetically distinct donors cross-regulate when stored together. AB - BACKGROUND: Donor variability of red blood cell (RBC) storage has been observed in both humans and animal models. We utilized a strain of mice with RBCs known to store well (B6) and a strain known to store poorly (FVB) to test the hypothesis that RBCs affected the storage of other RBCs. STUDY DESIGN AND METHODS: Five strains of mice were used: 1) transgenic B6 mice expressing green fluorescent protein (GFP) in their RBCs (GFP.B6), 2) wild-type B6 mice, 3) wild-type FVB mice, 4) F1 crosses between GFP.B6 and FVB mice (GFP.F1), and 5) the analogous wild-type (B6xFVB) F1 cross. GFP.B6 or GFP.F1 RBCs were mixed with wild-type (non GFP) RBCs from B6 or FVB strains before storage. Twenty-four-hour RBC recoveries were determined for stored RBCs by enumerating circulating GFP+ RBCs by flow cytometry. RESULTS: Twenty-four-hour recoveries of GFP.F1 RBCs was increased by co-storage with B6 RBCs but decreased by co-storage with FVB RBCs. This effect was dose dependent when tested with GFP.B6 RBCs; the more FVB blood added, the worse the 24-hour recoveries became. RBC cross-regulation did not occur when B6 and FVB RBCs were separated by a semipermeable membrane with a 0.4-um size cutoff. CONCLUSION: These findings demonstrate that RBCs affect the storage of other RBCs, in both positive and negative directions, indicating not only that RBC storage is intrinsic to the RBC but that RBC-RBC communication occurs. Additional studies will be required to determine the nature of this effect and if these findings translate into human RBC storage. PMID- 28921568 TI - Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma. AB - Unfolded protein response (UPR) has roles not only in resolving the accumulation of unfolded proteins owing to endoplasmic reticulum (ER) stress, but also in regulation of cellular physiological functions. ER stress transducers providing the branches of UPR signaling are known to localize in distal dendritic ER of neurons. These reports suggest that local activation of UPR branches may produce integrated outputs for distant communication, and allow regulation of local events in highly polarized neurons. Here, we demonstrated that synaptic activity- and brain-derived neurotrophic factor (BDNF)-dependent local activation of UPR signaling could be associated with dendritic functions through retrograde signal propagation by using murine neuroblastoma cell line, Neuro-2A and primary cultured hippocampal neurons derived from postnatal day 0 litter C57BL/6 mice. ER stress transducer, inositol-requiring kinase 1 (IRE1), was activated at postsynapses in response to excitatory synaptic activation. Activated dendritic IRE1 accelerated accumulation of the downstream transcription factor, x-box binding protein 1 (XBP1), in the nucleus. Interestingly, excitatory synaptic activation-dependent up-regulation of XBP1 directly facilitated transcriptional activation of BDNF. BDNF in turn drove its own expression via IRE1-XBP1 pathway in a protein kinase A-dependent manner. Exogenous treatment with BDNF promoted extension and branching of dendrites through the protein kinase A-IRE1-XBP1 cascade. Taken together, our findings indicate novel mechanisms for communication between soma and distal sites of polarized neurons that are coordinated by local activation of IRE1-XBP1 signaling. Synaptic activity- and BDNF-dependent distinct activation of dendritic IRE1-XBP1 cascade drives BDNF expression in cell soma and may be involved in dendritic extension. Cover Image for this issue: doi. 10.1111/jnc.14159. PMID- 28921570 TI - Behavioural responses of infective-stage copepodids of the salmon louse (Lepeophtheirus salmonis, Copepoda:Caligidae) to host-related sensory cues. AB - The salmon louse (Lepeophtheirus salmonis [Kroyer]) is an ectoparasitic copepod that causes disease in farmed Atlantic salmon (Salmo salar) and may play a role in the decline of some wild salmonid populations. Controlling lice infestations is a major cost for the salmon industry; this has stimulated the pursuit of alternative approaches to controlling them. One such approach involves determining, and then disrupting, the sensory cues used by the parasite to find its host. In this context, we examined the behavioural responses of lice copepodids to light flicker-simulating light reflecting from the sides of the salmon host and/or the shadows cast by fish passing overhead-and water-soluble chemicals released from the skin of the salmon. From these observations, we estimate that visual cues such as those presented here would operate at relatively long range (metres to tens of metres). A diffuse host-related olfactory cue stimulated swimming, however, it remains unclear whether olfactory cues provide directional information. The observations presented herein could be used to disrupt the link between the parasite and host fish, using a large number of traps deployed at a distance from a salmon farm, for example, thereby reducing sea lice infestation pressure. PMID- 28921571 TI - Comparing touch senses of naive and expert panels through treated hair swatches: which associated wordings correlate with hair physical properties? AB - OBJECTIVES: This study (i) compared the sense of touch between a naive and expert panels, under visual or blind conditions, using differently treated hair swatches and (ii) explored possible common wordings used by both panels and their possible links with some physical properties of hairs. METHODS: Two sets of 15 hair swatches of Caucasian and Chinese origins were differently treated (bleached, permed, brushed, etc.) or organized (root-tip vs. tip-root). These were evaluated by tactile assessments by two panels (105 naive consumers and 10 hair experts) under visual or blind conditions, in two geographical locations. A series of 17 defined antonym adjectives, as descriptors, allowed responses of each panel to being scored and their preference mappings to being defined on a like-dislike scale. Hair swatches were measured and assessed by various instrumental techniques (bending, diameter, cuticle cohesion, alignments of hair). RESULTS: Apart from a few overlaps, all 15 hair swatches were well differentiated by both panels which showed a global agreement, making experts reliable assessors. Only three descriptors among 17 correlated with some objective measurements. Tactile visual assessments differ from those performed tactile blind in both panels. Agreements between both panels appear, however, closer under tactile-blind conditions. CONCLUSION: Trained hair experts were confirmed as reliable representatives of a larger and naive cohort, viewed as consumers. Hair swatches were well differentiated by both panels, with comparable descriptor rankings. PMID- 28921572 TI - Production-level risk factors for syncytial hepatitis in farmed tilapia (Oreochromis niloticus L). AB - Syncytial hepatitis (SHT) is an emerging viral disease of tilapia characterized by significant morbidity and mortality. This study aimed to establish the production-level risk factors associated with presence and severity of SHT. Production factors were analysed during multiple outbreaks of SHT that occurred between 2011 and 2013 on a single tilapia farm in Ecuador and compared with the year 2010 before the SHT outbreaks. Relative risks, t tests, modified Poisson and forward stepwise linear regression analyses were performed using EPIINFOTM. Compared to other strains, Chitralada had an elevated risk of SHT [RR = 2.1 (95%CI 1.8-2.4)]. Excessive mortality associated with the presence (and severity) of SHT increased by 611 (365), 6,814 (5,768) and 388 (340) deaths per 100,000 fry when stocking density, dissolved oxygen and pond production cycles were raised by 1 fish/m2 , 1 mg/L and 1 cycle, respectively. Excessive mortality associated with the presence (and severity) of SHT decreased by 337 (258) and 1,354 (1,025) deaths per 100,000 when stocking weight and water temperature increased by 1 g and 1 degrees C, respectively. Time (season and stocking year) was not significantly associated with SHT. This study shows that some production factors increase the risk incidence and severity of SHTon a farm. PMID- 28921574 TI - Ideology and resistance in young people's experiences of health under the 'imperative of enjoyment'. AB - This article explores upper secondary school students' understandings and experiences of health in Denmark, where public health promotions appeal to pleasure. Health promotion thereby taps into capitalist society's 'imperative of enjoyment', which reproduces ideological fantasies about the fulfilment of desires through the consumption of health. Based on qualitative empirical material produced through participatory and visual methods during fieldwork conducted in 2012, the analysis shows that relations between healthiness and pleasure are conflated and paradoxical: the students try to fit into society not only by being healthy, but also by enjoying healthiness; but if they fail pleasure, they fail healthiness and experience a loss of individual social value. Although the 'enjoyment society' has the potential to produce individualisation and marginalisation, the students in this study actively attempt to subvert its double bind by insisting that collective experiences with peers constitutes the foundation of enjoyable healthiness. Nevertheless, public health promotions that reproduce enjoyment as an imperative, even in the pursuit of health, risk reinforcing young people's resistance towards health. PMID- 28921573 TI - Contralateral breast cancers: Independent cancers or metastases? AB - A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in three cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all three cases. In three additional cases, there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases. PMID- 28921577 TI - Time for training? PMID- 28921575 TI - Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women. AB - Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>1/2 MCL; 5 mg/L nitrate-nitrogen, 40 ug/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HRp95vs. Q1 = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HRQ4vs. Q1 = 0.70, 95% CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >1/2 MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HRp95vs. Q1 = 1.66, 95% CI 1.00-2.75;ptrend = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer. PMID- 28921576 TI - Rape Myth Acceptance in Sexually Assaulted Adolescents' School Contexts: Associations with Depressed Mood and Alcohol Use. AB - High school students exposed to sexual assault (SA) are at risk for negative outcomes like depressed mood and high-risk drinking. Although evidence suggests that both social contexts and internalized stigma can affect recovery from SA, no research to date has directly examined the presence of stigma in social contexts such as high schools as a correlate of adjustment after SA. In this study, the self-reported rape myth acceptance (RMA) of 3080 students from 97 grade cohorts in 25 high schools was used to calculate grade-mean and school-mean RMA, which was entered into multilevel models predicting depressed mood and alcohol use among N = 263 SA survivors within those schools. Two forms of RMA were assessed (i.e., rape denial and traditional gender expectations). Results indicate that higher grade-mean rape denial was associated with higher risk for depressed mood among high school boys and girls exposed to SA, and higher grade-mean traditional gender expectations were associated with higher risk for alcohol use among girls exposed to SA. Survivors' own RMA and school-level RMA were not significantly associated with their depressed mood or alcohol use. Although causality cannot be concluded, these findings suggest that interventions that reduce stigma in social contexts should be explored further as a strategy to improve well-being among high-school-aged survivors of SA. PMID- 28921578 TI - The "Darknet": The new street for street drugs. AB - WHAT IS KNOWN AND OBJECTIVE: The "Darknet" ("dark web") has emerged as a means by which illegal drug buys and deliveries can be arranged with apparent anonymity and impunity. Healthcare providers should be aware of this growing source of illicit drugs. COMMENT: The "Darknet" refers to networks isolated from the Internet that cannot be accessed via conventional search engines. They require special software that is protected by special encryption. The initial legitimate use of a "Darknet" to conceal personal information against misuse or political reprisal is being exploited to conceal the identity of buyers and sellers in illegal drug transactions. Instructions on how to obtain access to the "Darknet" are readily available on conventional Internet web pages. WHAT IS NEW AND CONCLUSION: The "Darknet" has changed the paradigm of illegal drug importation and distribution by providing a difficult-to-trace transaction, and delivery via legitimate couriers directly to the home. PMID- 28921579 TI - Material basis studies of anti-Influenza A active ingredients in Tanreqing Injection. AB - Tanreqing Injection (TRQ) has been used primarily in treating infections of the upper respiratory tract and serious influenza in China, as a classical compound herbal recipe. TRQ had been demonstrated to have effects of clearing heat, eliminating phlegm, detoxification, reducing inflammation and alleviating cough. The survival rate, histopathology of lungs and viral titers in mice were evaluated in this study to verify the curative effect of TRQ. However, there is not enough information about the components. In the present study, a high performance and practical LC/QTOF/MS method was developed for characterization and identification of the natural ingredients in TRQ. A total of 60 compounds, including 10 amino acids, 10 iridoid glucosides, 14 flavonoids, 13 other phenolic compounds, 10 steroid acids and three other compounds, were characterized and identified. We also confirmed the material basis of anti-Influenza A active ingredients in TRQ. Therefore, we have developed an accurate analytical method. LC/QTOF/MS could be applied for identification the complex components in traditional Chinese medicine. PMID- 28921580 TI - Integrating prior information into microwave tomography Part 1: Impact of detail on image quality. AB - PURPOSE: The authors investigate the impact that incremental increases in the level of detail of patient-specific prior information have on image quality and the convergence behavior of an inversion algorithm in the context of near-field microwave breast imaging. A methodology is presented that uses image quality measures to characterize the ability of the algorithm to reconstruct both internal structures and lesions embedded in fibroglandular tissue. The approach permits key aspects that impact the quality of reconstruction of these structures to be identified and quantified. This provides insight into opportunities to improve image reconstruction performance. METHODS: Patient-specific information is acquired using radar-based methods that form a regional map of the breast. This map is then incorporated into a microwave tomography algorithm. Previous investigations have demonstrated the effectiveness of this approach to improve image quality when applied to data generated with two-dimensional (2D) numerical models. The present study extends this work by generating prior information that is customized to vary the degree of structural detail to facilitate the investigation of the role of prior information in image formation. Numerical 2D breast models constructed from magnetic resonance (MR) scans, and reconstructions formed with a three-dimensional (3D) numerical breast model are used to assess if trends observed for the 2D results can be extended to 3D scenarios. RESULTS: For the blind reconstruction scenario (i.e., no prior information), the breast surface is not accurately identified and internal structures are not clearly resolved. A substantial improvement in image quality is achieved by incorporating the skin surface map and constraining the imaging domain to the breast. Internal features within the breast appear in the reconstructed image. However, it is challenging to discriminate between adipose and glandular regions and there are inaccuracies in both the structural properties of the glandular region and the dielectric properties reconstructed within this structure. Using a regional map with a skin layer only marginally improves this situation. Increasing the structural detail in the prior information to include internal features leads to reconstructions for which the interface that delineates the fat and gland regions can be inferred. Different features within the glandular region corresponding to tissues with varying relative permittivity values, such as a lesion embedded within glandular structure, emerge in the reconstructed images. CONCLUSION: Including knowledge of the breast surface and skin layer leads to a substantial improvement in image quality compared to the blind case, but the images have limited diagnostic utility for applications such as tumor response tracking. The diagnostic utility of the reconstruction technique is improved considerably when patient-specific structural information is used. This qualitative observation is supported quantitatively with image metrics. PMID- 28921581 TI - miR-122 promotes metastasis of clear-cell renal cell carcinoma by downregulating Dicer. AB - Although overall downregulation of microRNAs (miRNAs) is a general feature of clear-cell renal cell carcinoma (ccRCC), several miRNAs are consistently upregulated, among which miR-122 was markedly increased in ccRCC tissues. Our study aims to determine the functional importance and underlying mechanism of miR 122 in ccRCC metastasis. Here, we demonstrate that the expression of miR-122 increased in ccRCC tissues, and higher miR-122 expression was found in ccRCC tissues with metastatic disease than in those without metastasis. The increased miR-122 levels were associated with poor metastasis-free survival in ccRCC patients with localized disease. Dicer was validated as a direct functional target of miR-122. Overexpression of miR-122 promoted migration and invasion of ccRCC cells in vitro and metastatic behavior of ccRCC cells in vivo. Inhibition of miR-122 attenuated this metastatic phenotype in vitro. Importantly, miR-122 exerted its pro-metastatic properties in ccRCC cells by downregulating Dicer and its downstream effector, the miR-200 family, thereby inducing epithelial mesenchymal transition (EMT). Our results suggest an important role of the miR 122/Dicer/miR-200s/EMT pathway in ccRCC metastasis. Furthermore, miR-122 may serve as a biomarker for discriminating ccRCC with metastatic potential. PMID- 28921582 TI - Retribution as hierarchy regulation: Hierarchy preferences moderate the effect of offender socioeconomic status on support for retribution. AB - People punish others for various reasons, including deterring future crime, incapacitating the offender, and retribution, or payback. The current research focuses on retribution, testing whether support for retribution is motivated by the desire to maintain social hierarchies. If so, then the retributive tendencies of hierarchy enhancers or hierarchy attenuators should depend on whether offenders are relatively lower or higher in status, respectively. Three studies showed that hierarchy attenuators were more retributive against high-status offenders than for low-status offenders, that hierarchy enhancers showed a stronger orientation towards retributive justice, and that relationship was stronger for low-status, rather than high-status, criminal offenders. These findings clarify the purpose and function of retributive punishment. They also reveal how hierarchy-regulating motives underlie retribution, motives which, if allowed to influence judgements, may contribute to biased or ineffective justice systems. PMID- 28921583 TI - Associations of alcohol intake, smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage, anatomic site and tumor molecular subtype. AB - The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-1994) and wave 2 (2003-2007). We included participants diagnosed to 31 August 2015 with incident stages I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance. PMID- 28921584 TI - We didn't say that: Challenges in the Public Dissemination of a Research Finding with Controversial Implications. AB - In the March 2014 issue of American Journal of Community Psychology, we published an article that examined the tension between two core values in the field of community psychology: promoting contextual conditions that foster respect for diversity and promoting contextual conditions that foster sense of community. We concluded that processes of social network formation could help explain why diversity and sense of community are seemingly incompatible goals. The study's findings initially disseminated through the usual academic channels, and later through mainstream media outlets. However, they also eventually appeared on blogs and discussion forums devoted to white nationalism. The findings were viewed there as having demonstrated the evils of diversity, and thus having vindicated the white nationalist agenda. As a result, we were forced to consider whether and how to set the record straight. In this first-person narrative, we describe our study's journey from AJCP to white nationalist blogs, discussing how we ultimately responded to the situation, and concluding with some lessons learned. PMID- 28921586 TI - Down syndrome maternal serum markers in oocyte donation and other assisted reproductive technologies. AB - OBJECTIVE: Because maternal serum markers (pregnancy-associated plasma protein A, human chorionic gonadotropin free beta subunit, and alpha-fetoprotein) used for Down syndrome (DS) screening have been described as predictors of obstetrical complications and because assisted reproductive technology (ART) pregnancies are known to be at increased risk for obstetrical complications, it is unclear whether or not correction factors should be applied to the calculated risk of DS. The purpose of this study was to evaluate DS maternal serum markers in oocyte donation (OD) and ART pregnancies in comparison with natural pregnancies. METHOD: Multicenter retrospective 2010 to 2013 study in singleton pregnancies was used. First- and second-trimester DS screenings in 614 OD and 1921 ART pregnancies versus 7268 natural pregnancies are compared. RESULTS: There was a significant increase in hCGbeta in the OD group for both trimesters (first trimester: 1.28 MoM vs 1.02; P < .001 and second trimester: 1.32 MoM vs 1 MoM; P < .001). Pregnancy-associated plasma protein A was significantly lower in the ART group (0.92 and 1.02 MoM P < .001). CONCLUSION: Maternal serum markers for DS screening are significantly modified in ART and OD pregnancies. Because these markers are also markers for obstetrical complications, the rationale for applying correction factors is questionable. PMID- 28921587 TI - Dimethyl fumarate treatment after traumatic brain injury prevents depletion of antioxidative brain glutathione and confers neuroprotection. AB - Dimethyl fumarate (DMF) is an immunomodulatory compound to treat multiple sclerosis and psoriasis with neuroprotective potential. Its mechanism of action involves activation of the antioxidant pathway regulator Nuclear factor erythroid 2-related factor 2 thereby increasing synthesis of the cellular antioxidant glutathione (GSH). The objective of this study was to investigate whether post traumatic DMF treatment is beneficial after experimental traumatic brain injury (TBI). Adult C57Bl/6 mice were subjected to controlled cortical impact followed by oral administration of DMF (80 mg/kg body weight) or vehicle at 3, 24, 48, and 72 h after the inflicted TBI. At 4 days after lesion (dal), DMF-treated mice displayed less neurological deficits than vehicle-treated mice and reduced histopathological brain damage. At the same time, the TBI-evoked depletion of brain GSH was prevented by DMF treatment. However, nuclear factor erythroid 2 related factor 2 target gene mRNA expression involved in antioxidant and detoxifying pathways was increased in both treatment groups at 4 dal. Blood brain barrier leakage, as assessed by immunoglobulin G extravasation, inflammatory marker mRNA expression, and CD45+ leukocyte infiltration into the perilesional brain tissue was induced by TBI but not significantly altered by DMF treatment. Collectively, our data demonstrate that post-traumatic DMF treatment improves neurological outcome and reduces brain tissue loss in a clinically relevant model of TBI. Our findings suggest that DMF treatment confers neuroprotection after TBI via preservation of brain GSH levels rather than by modulating neuroinflammation. PMID- 28921585 TI - AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer. AB - While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines. PMID- 28921588 TI - Integrating prior information into microwave tomography part 2: Impact of errors in prior information on microwave tomography image quality. AB - PURPOSE: The authors have developed a method to combine a patient-specific map of tissue structure and average dielectric properties with microwave tomography. The patient-specific map is acquired with radar-based techniques and serves as prior information for microwave tomography. The impact that the degree of structural detail included in this prior information has on image quality was reported in a previous investigation. The aim of the present study is to extend this previous work by identifying and quantifying the impact that errors in the prior information have on image quality, including the reconstruction of internal structures and lesions embedded in fibroglandular tissue. This study also extends the work of others reported in literature by emulating a clinical setting with a set of experiments that incorporate heterogeneity into both the breast interior and glandular region, as well as prior information related to both fat and glandular structures. METHODS: Patient-specific structural information is acquired using radar-based methods that form a regional map of the breast. Errors are introduced to create a discrepancy in the geometry and electrical properties between the regional map and the model used to generate the data. This permits the impact that errors in the prior information have on image quality to be evaluated. Image quality is quantitatively assessed by measuring the ability of the algorithm to reconstruct both internal structures and lesions embedded in fibroglandular tissue. The study is conducted using both 2D and 3D numerical breast models constructed from MRI scans. RESULTS: The reconstruction results demonstrate robustness of the method relative to errors in the dielectric properties of the background regional map, and to misalignment errors. These errors do not significantly influence the reconstruction accuracy of the underlying structures, or the ability of the algorithm to reconstruct malignant tissue. Although misalignment errors do not significantly impact the quality of the reconstructed fat and glandular structures for the 3D scenarios, the dielectric properties are reconstructed less accurately within the glandular structure for these cases relative to the 2D cases. However, general agreement between the 2D and 3D results was found. CONCLUSION: A key contribution of this paper is the detailed analysis of the impact of prior information errors on the reconstruction accuracy and ability to detect tumors. The results support the utility of acquiring patient-specific information with radar-based techniques and incorporating this information into MWT. The method is robust to errors in the dielectric properties of the background regional map, and to misalignment errors. Completion of this analysis is an important step toward developing the method into a practical diagnostic tool. PMID- 28921589 TI - Susceptibility, behaviour, and retention of the parasitic salmon louse (Lepeophtheirus salmonis) differ with Atlantic salmon population origin. AB - Atlantic salmon populations across the world have diverse ecological and evolutionary histories, from wild anadromous or landlocked, to domestication and genetic modification. The natural host behaviours confer protection from infestation by ectoparasitic salmon lice Lepeophtheirus salmonis, yet whether genetic origin results in different behaviours and thus susceptibility to infestation is unknown. In common garden experiments, we tested antiparasite behaviours, susceptibility and retention of salmon lice in wild anadromous, wild landlocked, domesticated and genetically modified domesticated strains. Within domesticated strains, we tested two infestation histories (previously infested and naive) and a new phenotype (albino colouring). Farmed stocks initially acquired 24%-44% higher levels of parasite density than the wild and landlocked strains. Burst swimming and displacement behaviours were higher in the domesticated groups, and jumping was more prevalent in the domesticated strains. At 34 days post-infestation, domesticated strains and the wild anadromous strain did not differ significantly from each other; however, landlocked salmon had increased infestation levels considerably. Domesticated strains lost ~20% (+/ 9.9%-16.5%; 95% CI) of their initial parasite load, while parasite load increased by 5.5% (+/-30.1%) for wild salmon and 20.1% (+/-28.5%) in landlocked salmon. This study provides early evidence for diverged host-parasite interactions associated with domestication in this system. PMID- 28921590 TI - Developing a prediction model for cardiovascular risk after orthotopic liver transplantation. PMID- 28921591 TI - Treatment of a mobile intracardiac thrombus using ultra-slow low-dose tissue plasminogen activator in combination with heparin. AB - WHAT IS KNOWN AND OBJECTIVE: Free-floating thrombi in the right heart occur in a subset of patients with pulmonary embolism with high rates of mortality if untreated. Treatment of choice is controversial and likely patient specific as studies have failed to consistently show a significant difference in mortality between options. CASE SUMMARY: We present a case of a 45-year-old female with a mobile right heart thrombus treated with ultra-slow, low-dose t-PA infusion in combination with heparin. WHAT IS NEW AND CONCLUSION: Ultra-slow, low-dose infusion of t-PA may be an option for treatment of mobile intracardiac thrombi. PMID- 28921592 TI - Radiosensitization by inhibiting DNA repair: Turning the spotlight on homologous recombination. PMID- 28921593 TI - Reply. PMID- 28921594 TI - The international normalized ratio (INR): What reagent, what instrument? The assessment of the agreement between INR values according to different reagent/instrument combinations. AB - WHAT IS KNOWN AND OBJECTIVE: The international normalized ratio (INR) is widely used to monitor patients on vitamin K antagonists. This study aimed to assess the agreement of INR values obtained with different thromboplastin/instrument combinations. MATERIAL AND METHODS: International normalized ratio was determined on plasmas from 330 patients undergoing antivitamin K treatment (with acenocoumarol), using two calibration methods and four reagent/instrument combinations: Both Neoplastine CI and Neoplastine CI Plus on STA-R instrument from Diagnostica STAGO, Asnieres, France; and both Thromborel S and Innovin on SYSMEX 2100i instrument from Siemens Health Care Diagnostics, Marbung, Germany. The agreement analysis was done using the Bland-Altman plot and the Cohen Kappa coefficient. RESULTS: The mean of the differences between the INR values and the limits of agreement were -0.07 [-0.51 to 0.38] for the Neoplastine CI plus and Neoplastine CI reagents, -0.08 [-1.18 to 1.03] for the Thromborel S and Innovin reagents when the INR was calculated, -0.1 [-1.15 to 0.95] for the Thromborel S and Innovin reagents when the INR was directly calibrated and -0.1 [-0.7 to 0.5] for the Neoplastine CI plus and Thromborel S. Cohen's kappa coefficients were 0.94, 0.76, 0.85 and 0.82, respectively. NEW FINDINGS AND CONCLUSION: The agreement between the four reagent/instrument combinations was high enough to classify patients as inefficaciously or efficaciously anticoagulated. The data interpretation should always be related to the clinical purpose. PMID- 28921595 TI - The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. AB - : We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN gamma) 3' untranslated region (coined ARE-Del-/- ), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del-/- mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE-Del-/- Ifnar1-/- mice dramatically reduces liver pathology and abrogated sex bias. More importantly, female ARE-Del-/- mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE-Del-/- Ifnar1-/- mice corrects these GC abnormalities, including abnormal follicular structure. CONCLUSION: Our data implicate type I IFN signaling as a necessary component of the sex bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. (Hepatology 2018;67:1408-1419). PMID- 28921597 TI - Ultrastructure of spermatozoa of spider crabs, family Mithracidae (Crustacea, Decapoda, Brachyura): Integrative analyses based on morphological and molecular data. AB - Recent studies based on morphological and molecular data provide a new perspective concerning taxonomic aspects of the brachyuran family Mithracidae. These studies proposed a series of nominal changes and indicated that the family is actually represented by a different number and representatives of genera than previously thought. Here, we provide a comparative description of the ultrastructure of spermatozoa and spermatophores of some species of Mithracidae in a phylogenetic context. The ultrastructure of the spermatozoa and spermatophore was observed by scanning and transmission electron microscopy. The most informative morphological characters analysed were thickness of the operculum, shape of the perforatorial chamber and shape and thickness of the inner acrosomal zone. As a framework, we used a topology based on a phylogenetic analysis using mitochondrial data obtained here and from previous studies. Our results indicate that closely related species share a series of morphological characteristics of the spermatozoa. A thick operculum, for example, is a feature observed in species of the genera Amphithrax, Teleophrys, and Omalacantha in contrast to the slender operculum observed in Mithraculus and Mithrax. Amphithrax and Teleophrys have a rhomboid perforatorial chamber, while Mithraculus, Mithrax, and Omalacantha show a wider, deltoid morphology. Furthermore, our results are in agreement with recently proposed taxonomic changes including the separation of the genera Mithrax (previously Damithrax), Amphithrax (previously Mithrax) and Mithraculus, and the synonymy of Mithrax caribbaeus with Mithrax hispidus. Overall, the spermiotaxonomy of these species of Mithracidae represent a novel set of data that corroborates the most recent taxonomic revision of the family and can be used in future taxonomic and phylogenetic studies within this family. PMID- 28921596 TI - Single cocaine exposure does not alter striatal pre-synaptic dopamine function in mice: an [18 F]-FDOPA PET study. AB - Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre-synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre- and post synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre-synaptic dopamine function remain unclear. Non-invasive imaging techniques such as positron emission tomography have revealed impaired pre-synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre-synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15-20 min post treatment (p < 0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (KiCer: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l-amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre-treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre-synaptic dopaminergic neurons are not initiated following a single exposure to the drug. PMID- 28921599 TI - The Stories We Tell: Introduction to the Special Issue on Ethical Challenges in Community Psychology Research and Practice. AB - This Special Issue examines ethical challenges in community psychology research and practice. The literature on ethics in community psychology has remained largely abstract and aspirational, with few concrete examples and case studies, so the goal of this Special Issue was to expand our written discourse about ethical dilemmas in our field. In these articles, researchers and practitioners share stories of specific ethical challenges they faced and how they sought to resolve them. These first-person narratives examine how ethical challenges come about, how community psychology values inform ethical decision making, and how lessons learned from these experiences can inform an ethical framework for community psychology. PMID- 28921598 TI - Association of serum osteocalcin levels with major adverse cardiovascular events: A 4.4-year retrospective cohort study. AB - We investigated whether the serum osteocalcin levels at baseline were associated with the incidence of major adverse cardiovascular events (MACE) in a population based retrospective cohort study of Chinese subjects. Coronary angiography was used to diagnose coronary artery disease (CAD). Survival curves were analyzed by performing log-rank tests with Kaplan-Meier figures. Multivariable Cox proportional hazards regression was performed to identify the association of serum osteocalcin levels with the incidence of MACE. A total of 247 subjects with a mean age of 65.50 +/- 10.38 years were enrolled in the analysis. After a mean follow-up time of 4.4 +/- 2.6 years, MACE occurred in 175 cases. For men patients, those with serum osteocalcin levels higher than 17.22 ng/mL had significantly lower fasting plasma glucose (FPG) than those with serum osteocalcin levels lower than 17.22 ng/mL (P < .05). According to the multivariate Cox proportional hazards regression, the lower serum osteocalcin levels and the higher risk of future MACE occurred in men with CAD at baseline (hazard ratio = 0.970; 95% confidence interval 0.943-0.999, P = .04). However, this difference was not significant either in men without CAD or in women. In conclusion, relatively lower serum osteocalcin levels were associated with a higher risk of MACE in Chinese men with CAD. PMID- 28921600 TI - Injury Patterns Sustained in Fatal Motor Vehicle Collisions with Driver's Third Generation Airbag Deployment. AB - The Office of the Chief Coroner for Ontario database for 2011-2012 was used to compare fatal injury patterns in drivers whose third-generation airbags deployed compared to first- and second-generation airbag deployments and airbag nondeployments with and without seatbelt use. There were 110 frontal and offset frontal crashes analyzed. The small sample size meant that the odds of craniocerebral, cervical spinal, thoracic, and abdominal injuries were not statistically different for airbag generation, deployment status, and seatbelt use; however, the risk of fatal thoracic injuries in third- and second-generation cases was increased. Seatbelt usage in third- and second-generation deployment cases reduced the risk of all injuries except abdominal trauma. High severity impacts and occupant compartment intrusion were frequently observed. The analyses in this retrospective study were challenged by data that were not collated in a standardized way and were limited in details about scene, vehicle, and driver variables. PMID- 28921601 TI - Is 2-Hydroxypropyl-beta-cyclodextrin a Suitable Carrier for Central Administration of Delta9 -Tetrahydrocannabinol? Preclinical Evidence. AB - Preclinical Research Delta9 -Tetrahydrocannabinol (THC) is a hydrophobic compound that has a potent antinociceptive effect in animals after intrathecal (IT) or intracerebroventricular (ICV) administration. The lack of a suitable solvent precludes its IT administration in humans. 2-Hydroxypropyl-beta-cyclodextrin (HPbetaCD) increases the water solubility of hydrophobic drugs and is approved for IT administration in humans. To investigate whether HPbetaCD might be a suitable carrier for ICV administration of THC in rats, two formulations containing THC complexed with HPbetaCD (30 and 135 MUg of THC per animal) and vehicle were administered to Wistar rats. The antinociceptive effect (using the tail flick test), locomotor activity, and body temperature were evaluated. ICV injection of 135 MUg of THC/HPbetaCD complex increased tail flick latency, reduced locomotor activity, and had a dual effect on body temperature. The 30 MUg THC/HPbetaCD formulation only produced a hyperthermic effect. All animals appeared healthy, with no difference between the groups. These results were similar to those obtained in other preclinical studies in which THC was administered centrally using solvents that are unsuitable for IT administration in humans because of their toxicity. Our findings suggest that HPbetaCD may be a useful carrier for IT administration of THC in humans. Drug Dev Res 78 : 411-419, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921603 TI - Trace DNA Sampling Success from Evidence Items Commonly Encountered in Forensic Casework. AB - Trace DNA analysis is a significant part of a forensic laboratory's workload. Knowing optimal sampling strategies and item success rates for particular item types can assist in evidence selection and examination processes and shorten turnaround times. In this study, forensic short tandem repeat (STR) casework results were reviewed to determine how often STR profiles suitable for comparison were obtained from "handler" and "wearer" areas of 764 items commonly submitted for examination. One hundred and fifty-five (155) items obtained from volunteers were also sampled. Items were analyzed for best sampling location and strategy. For casework items, headwear and gloves provided the highest success rates. Experimentally, eyeglasses and earphones, T-shirts, fabric gloves and watches provided the highest success rates. Eyeglasses and latex gloves provided optimal results if the entire surfaces were swabbed. In general, at least 10%, and up to 88% of all trace DNA analyses resulted in suitable STR profiles for comparison. PMID- 28921602 TI - Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study. AB - : We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 * 10-8 ) in the genome-wide association study. Long term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. CONCLUSION: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2017). PMID- 28921604 TI - Stress-testing the affect misattribution procedure: Heterogeneous control of affect misattribution procedure effects under incentives. AB - The affect misattribution procedure (AMP) is widely used to measure sensitive attitudes towards classes of stimuli, by estimating the effect that affectively charged prime images have on subsequent judgements of neutral target images. We test its resistance to efforts to conceal one's attitudes, by replicating the standard AMP design while offering small incentives to conceal attitudes towards the prime images. We find that although the average AMP effect remains positive, it decreases significantly in magnitude. Moreover, this reduction in the mean AMP effect under incentives masks large heterogeneity: one subset of individuals continues to experience the 'full' AMP effect, while another reduces their effect to approximately zero. The AMP thus appears to be resistant to efforts to conceal one's attitudes for some individuals but is highly controllable for others. We further find that those individuals with high self-reported effort to avoid the influence of the prime are more often able to eliminate their AMP effect. We conclude by discussing possible mechanisms. PMID- 28921605 TI - Simple determination of betaine, l-carnitine and choline in human urine using self-packed column and column-switching ion chromatography with nonsuppressed conductivity detection. AB - A sequential online extraction, clean-up and separation system for the determination of betaine, l-carnitine and choline in human urine using column switching ion chromatography with nonsuppressed conductivity detection was developed in this work. A self-packed pretreatment column (50 * 4.6 mm, i.d.) was used for the extraction and clean-up of betaine, l-carnitine and choline. The separation was achieved using self-packed cationic exchange column (150 * 4.6 mm, i.d.), followed by nonsuppressed conductivity detection. Under optimized experimental conditions, the developed method presented good analytical performance, with excellent linearity in the range of 0.60-100 MUg mL-1 for betaine, 0.75-100 MUg mL-1 for l-carnitine and 0.50-100 MUg mL-1 for choline, with all correlation coefficients (R2 ) >0.99 in urine. The limits of detection were 0.15 MUg mL-1 for betaine, 0.20 MUg mL-1 for l-carnitine and 0.09 MUg mL-1 for choline. The intra- and inter-day accuracy and precision for all quality controls were within +/-10.32 and +/-9.05%, respectively. Satisfactory recovery was observed between 92.8 and 102.0%. The validated method was successfully applied to the detection of urinary samples from 10 healthy people. The values detected in human urine using the proposed method showed good agreement with the measurement reported previously. PMID- 28921607 TI - In labor or in limbo? The experiences of women undergoing induction of labor in hospital: Findings of a qualitative study. AB - BACKGROUND: Induction of labor currently accounts for around 25% of all births in high-resource countries, yet despite much research into medical aspects, little is known about how women experience this process. This study aimed to explore in depth the induction experience of primiparous women. METHODS: A qualitative study was undertaken, using a sample of 21 first-time mothers from a maternity unit in the south of England. Semi-structured interviews were conducted in women's homes between 3 and 6 weeks postnatally. Data were recorded, transcribed, and analyzed thematically. RESULTS: Women awaiting induction on the prenatal ward appeared to occupy a liminal state between pregnancy and labor. Differences were noted between women's and midwives' notions of what constituted "being in labor" and the ward lacked the flexibility to provide individualized care for women in early labor. Unexpected delays in the induction process were common and were a source of anxiety, as was separation from partners at night. Women were not always clear about their plan of care, which added to their anxiety. CONCLUSIONS: Conceptualizing induction as a liminal state may enhance understanding of women's feelings and promote a more woman-centered approach to care. Thorough preparation for induction, including an explanation of possible delays is fundamental to enabling women to form realistic expectations. Care providers need to consider whether women undergoing induction are receiving adequate support, analgesia, and comfort aids conducive to the promotion of physiological labor and the reduction of anxiety. PMID- 28921606 TI - Dynamic residual pattern of azoxystrobin in Swiss chard with contribution to safety evaluation. AB - This study aimed at quantifying the residual amount of azoxystrobin in Swiss chard samples grown under greenhouse conditions at two different locations (Gwangju and Naju, Republic of Korea). Samples were extracted with acetonitrile, separated by salting out, and subjected to purification by using solid-phase extraction. The analyte was identified using liquid chromatography-ultraviolet detection. The linearity of the calibration range was excellent with coefficient of determination 1.00. Recovery at three different spiking levels (0.1, 0.5, and 4 mg/kg) ranged between 82.89 and 109.46% with relative standard deviation <3. The limit of quantification, 0.01 mg/kg, was considerably much lower than the maximum residue limit (50 mg/kg) set by the Korean Ministry of Food and Drug Safety. The developed methodology was successfully used for field-treated leaves, which were collected randomly at 0-14 days following azoxystrobin application. The rate of disappearance in/on Swiss chard was ascribed to first-order kinetics with a half-life of 8 and 5 days, in leaves grown in Gwangju and Naju greenhouses, respectively. Risk assessments revealed that the acceptable daily intake percentage is substantially below the risk level of consumption at day 0 (in both areas), thus encouraging its safe consumption. PMID- 28921608 TI - Moral bioenhancement and agential risks: Good and bad outcomes. AB - In Unfit for the Future, Ingmar Persson and Julian Savulescu argue that our collective existetial predicment is unprecedentedly dangerous due to climate change and terrorism. Given these global risks to human prosperity and survival, Persson and Savulescu argue that we should explore the radical possibility of moral bioenhancement in addition to cognitive enhancement. In this article, I argue that moral bioenhancements could nontrivially exacerbate the threat posed by certain kinds of malicious agents, while reducing the threat of other kinds. This introduces a previously undiscussed complication to Persson and Savulescu's proposal. In the final section, I present a novel argument for why moral bioenhancement should either be compulsory or not be made available to the public at all. PMID- 28921609 TI - Biomarkers for equine joint injury and osteoarthritis. AB - We report the results of a symposium aimed at identifying validated biomarkers that can be used to complement clinical observations for diagnosis and prognosis of joint injury leading to equine osteoarthritis (OA). Biomarkers might also predict pre-fracture change that could lead to catastrophic bone failure in equine athletes. The workshop was attended by leading scientists in the fields of equine and human musculoskeletal biomarkers to enable cross-disciplinary exchange and improve knowledge in both. Detailed proceedings with strategic planning was written, added to, edited and referenced to develop this manuscript. The most recent information from work in equine and human osteoarthritic biomarkers was accumulated, including the use of personalized healthcare to stratify OA phenotypes, transcriptome analysis of anterior cruciate ligament (ACL) and meniscal injuries in the human knee. The spectrum of "wet" biomarker assays that are antibody based that have achieved usefulness in both humans and horses, imaging biomarkers and the role they can play in equine and human OA was discussed. Prediction of musculoskeletal injury in the horse remains a challenge, and the potential usefulness of spectroscopy, metabolomics, proteomics, and development of biobanks to classify biomarkers in different stages of equine and human OA were reviewed. The participants concluded that new information and studies in equine musculoskeletal biomarkers have potential translational value for humans and vice versa. OA is equally important in humans and horses, and the welfare issues associated with catastrophic musculoskeletal injury in horses add further emphasis to the need for good validated biomarkers in the horse. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:823-831, 2018. PMID- 28921610 TI - Validation and adaptation of the danger assessment-5: A brief intimate partner violence risk assessment. AB - AIMS: The aim of this study was to assess the predictive validity of the DA-5 with the addition of a strangulation item in evaluating the risk of an intimate partner violence (IPV) victim being nearly killed by an intimate partner. BACKGROUND: The DA-5 was developed as a short form of the Danger Assessment for use in healthcare settings, including emergency and urgent care settings. Analyzing data from a sample of IPV survivors who had called the police for domestic violence, the DA-5 was tested with and without an item on strangulation, a potentially fatal and medically damaging IPV tactic used commonly by dangerous abusers. DESIGN: Researchers interviewed a heterogeneous sample of 1,081 women recruited by police between 2009-2013 at the scene of a domestic violence call; 619 (57.3%) were contacted and re-interviewed after an average of 7 months. METHODS: The predictive validity of the DA-5 was assessed for the outcome of severe or near lethal IPV re-assault using sensitivity, specificity and ROC curve analysis techniques. RESULTS: The original DA-5 was found to be accurate (AUC = .68), equally accurate with the strangulation item from the original DA substituted (AUC = .68) and slightly more accurate (but not a statistically significant difference) if multiple strangulation is assessed. CONCLUSION: We recommend that the DA-5 with the strangulation item be used for a quick assessment of homicide or near homicide risk among IPV survivors. A protocol for immediate referral and examination for further injury from strangulation should be adopted for IPV survivors at high risk. PMID- 28921611 TI - Dendritic spines provide cognitive resilience against Alzheimer's disease. AB - OBJECTIVE: Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer's disease (AD) begin years prior to clinical dementia onset. However, some 30 to 50% of older individuals who harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology, structural changes in dendritic spines would distinguish individuals who had or did not have clinical dementia. METHODS: We compared dendritic spines within layer II and III pyramidal neuron dendrites in Brodmann area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from bright-field microscopy images that enabled accurate 3-dimensional digital reconstruction of dendritic structure for morphologic analyses. RESULTS: Spine density was similar among control and CAD cases but was reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging. INTERPRETATION: These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia. Ann Neurol 2017;82:602-614. PMID- 28921612 TI - Systematic review and meta-analysis of non-pharmacological interventions to reduce the symptoms of mild to moderate anxiety in pregnant women. AB - AIM: To assess the effectiveness of non-pharmacological interventions for pregnant women with symptoms of mild to moderate anxiety. BACKGROUND: Many pregnant women experience mild to moderate symptoms of anxiety and could benefit from additional support. Non-pharmacological interventions have been suggested for use during pregnancy. DESIGN: A systematic review of randomized controlled trials. DATA SOURCES: Randomized controlled trials published since 1990, identified from electronic databases: Medline; CINAHL; Maternity and Infant Care; PsycINFO; Cochrane Database of Systematic Reviews; CENTRAL; EMBASE; Centre for Reviews and Dissemination; Social Sciences Citation Index; ASSIA; HTA Library; Joanna Briggs Institute Evidence-Based Practice database; Allied and Complementary Medicine. REVIEW METHODS: Conducted according to the Centre for Reviews and Dissemination procedure. Papers were screened (N = 5,222), assessed for eligibility (N = 57) and selected for inclusion (N = 25). The Cochrane Collaboration's tool for assessing risk of bias was used. Papers were assessed for clinical and statistical heterogeneity and considered for meta-analysis. Descriptive analysis of the data was conducted. RESULTS: Psychological, mind body, educational and supportive interventions were delivered individually and to groups of pregnant women over single or multiple sessions. The State-Trait Anxiety Inventory was the most commonly used anxiety measure. In 60% of studies there were fewer than 40 participants. Meta-analysis of three studies indicated no observed beneficial effect in the reduction of anxiety. CONCLUSION: There was insufficient evidence from which to draw overall conclusions regarding the benefit of interventions. Results were predominantly based on small samples. Many papers provided an inadequate description of methods which prevented a full assessment of methodological quality. PMID- 28921613 TI - Voxel-based multimodel fitting method for modeling time activity curves in SPECT images. AB - PURPOSE: Estimating the biodistribution and the pharmacokinetics from time sequence SPECT images on a per-voxel basis is useful for studying activity nonuniformity or computing absorbed dose distributions by convolution of voxel kernels or Monte-Carlo radiation transport. Current approaches are either region based, thus assuming uniform activity within the region, or voxel-based but using the same fitting model for all voxels. METHODS: We propose a voxel-based multimodel fitting method (VoMM) that estimates a fitting function for each voxel by automatically selecting the most appropriate model among a predetermined set with Akaike criteria. This approach can be used to compute the time integrated activity (TIA) for all voxels in the image. To control fitting optimization that may fail due to excessive image noise, an approximated version based on trapezoid integration, named restricted method, is also studied. From this comparison, the number of failed fittings within images was estimated and analyzed. Numerical experiments were used to quantify uncertainties and feasibility was demonstrated with real patient data. RESULTS: Regarding numerical experiments, root mean square errors of TIA obtained with VoMM were similar to those obtained with bi exponential fitting functions, and were lower (< 5% vs. > 10%) than with single model approaches that consider the same fitting function for all voxels. Failure rates were lower with VoMM and restricted approaches than with single-model methods. On real clinical data, VoMM was able to fit 90% of the voxels and led to less failed fits than single-model approaches. On regions of interest (ROI) analysis, the difference between ROI-based and voxel-based TIA estimations was low, less than 4%. However, the computation of the mean residence time exhibited larger differences, up to 25%. CONCLUSIONS: The proposed voxel-based multimodel fitting method, VoMM, is feasible on patient data. VoMM leads organ-based TIA estimations similar to conventional ROI-based method. However, for pharmacokinetics analysis, studies of spatial heterogeneity or voxel-based absorbed dose assessment, VoMM could be used preferentially as it prevents model overfitting. PMID- 28921615 TI - Plasticizer di(2-ethylhexyl)phthalate interferes with osteoblastogenesis and adipogenesis in a mouse model. AB - Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis, and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2-ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose-dependently decreased by DEHP and MEHP (10-100 uM) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin (OCN), Wnt1, and beta-catenin were significantly decreased in DEHP- and MEHP-treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARgamma mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated beta-catenin/beta-catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARgamma inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP-treated mice, osteoblastogenesis and Runx2, Wnt1, and beta-catenin expression were decreased, but adipogenesis and PPARgamma expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/beta-catenin-regulated and thus triggering bone loss. PPARgamma signaling may play an important role in MEHP- and DEHP-induced suppression of osteogenesis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1124-1134, 2018. PMID- 28921614 TI - An optimized framework for quantitative magnetization transfer imaging of the cervical spinal cord in vivo. AB - PURPOSE: To develop a framework to fully characterize quantitative magnetization transfer indices in the human cervical cord in vivo within a clinically feasible time. METHODS: A dedicated spinal cord imaging protocol for quantitative magnetization transfer was developed using a reduced field-of-view approach with echo planar imaging (EPI) readout. Sequence parameters were optimized based in the Cramer-Rao-lower bound. Quantitative model parameters (i.e., bound pool fraction, free and bound pool transverse relaxation times [ T2F, T2B], and forward exchange rate [kFB ]) were estimated implementing a numerical model capable of dealing with the novelties of the sequence adopted. The framework was tested on five healthy subjects. RESULTS: Cramer-Rao-lower bound minimization produces optimal sampling schemes without requiring the establishment of a steady state MT effect. The proposed framework allows quantitative voxel-wise estimation of model parameters at the resolution typically used for spinal cord imaging (i.e. 0.75 * 0.75 * 5 mm3 ), with a protocol duration of ~35 min. Quantitative magnetization transfer parametric maps agree with literature values. Whole-cord mean values are: bound pool fraction = 0.11(+/-0.01), T2F = 46.5(+/-1.6) ms, T2B = 11.0(+/-0.2) us, and kFB = 1.95(+/-0.06) Hz. Protocol optimization has a beneficial effect on reproducibility, especially for T2B and kFB . CONCLUSION: The framework developed enables robust characterization of spinal cord microstructure in vivo using qMT. Magn Reson Med 79:2576-2588, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28921617 TI - Re: "TRASER: An innovative device for the treatment of nasal telangiectasias," lasers in surgery and medicine, 2017;49(6):625-631. PMID- 28921616 TI - Tangential migration of corridor guidepost neurons contributes to anxiety circuits. AB - In mammals, thalamic axons are guided internally toward their neocortical target by corridor (Co) neurons that act as axonal guideposts. The existence of Co-like neurons in non-mammalian species, in which thalamic axons do not grow internally, raised the possibility that Co cells might have an ancestral role. Here, we investigated the contribution of corridor (Co) cells to mature brain circuits using a combination of genetic fate-mapping and assays in mice. We unexpectedly found that Co neurons contribute to striatal-like projection neurons in the central extended amygdala. In particular, Co-like neurons participate in specific nuclei of the bed nucleus of the stria terminalis, which plays essential roles in anxiety circuits. Our study shows that Co neurons possess an evolutionary conserved role in anxiety circuits independently from an acquired guidepost function. It furthermore highlights that neurons can have multiple sequential functions during brain wiring and supports a general role of tangential migration in the building of subpallial circuits. PMID- 28921620 TI - Late hepatitis B reactivation following direct-acting antiviral-based treatment of recurrent hepatitis C in an anti-HBc-positive liver transplant recipient. AB - Direct-acting antivirals (DAAs) have changed the landscape of hepatitis C virus (HCV) treatment, but chronic hepatitis C (CHC) remains a leading indication for liver transplantation (LT). Hepatitis B virus (HBV) reactivation has been reported in HBV-HCV-coinfected patients treated with DAAs. We report on a case of late HBV reactivation after DAA-based treatment of recurrent hepatitis C in an antibody against hepatitis B core antigen (anti-HBc)-positive LT recipient. (Hepatology 2017). PMID- 28921621 TI - "But We Want to Work": The Movement of Child Workers in Peru and the Actions for Reducing Child Labor. AB - The program Educame Primero (Educate Me First) is an evidence-based practice for eradicating child labor that has been applied with positive results in Colombia, Peru, and several Central American countries. In this article, we describe the difficulties of implementing the program in two poor areas of Lima (Peru) between 2014 and 2016. Specifically, we discuss three ethical challenges faced during the implementation of the program: (a) the existence of a movement of working children that defends the right of children to work; (b) the polarization of some community-based associations and government institutions on how to deal with the problems of working children; and (c) the use of network indicators in the evaluation of the community's level of cohesion. Taking the Code of Ethics of the General Council of Associations of Psychologists in Spain as a guide, we adopted a consensus approach in planning and research design, combining different criteria of value with the participation of different stakeholders. The implementation of the program in Peru gave preference to developing skills in children over changing attitudes in relation to child protection, although the intervention openly declared its aims when engaging institutions and families. Finally, we address how social network research places special ethical demands on conventional ethical standards. Our experience with this project shows the importance of acting as a bridge between different stakeholders and assessing how all of them benefit from the intervention. PMID- 28921619 TI - Alcohol Reduces Arterial Remodeling by Inhibiting Sonic Hedgehog-Stimulated Stem Cell Antigen-1 Positive Progenitor Stem Cell Expansion. AB - BACKGROUND: Cell and molecular mechanisms mediating the cardiovascular effects of alcohol are not fully understood. Our aim was to determine the effect of moderate ethanol (EtOH) on sonic hedgehog (SHh) signaling in regulating possible stem cell antigen-1 positive (Sca1+ ) progenitor stem cell involvement during pathologic arterial remodeling. METHODS: Partial ligation or sham operation of the left carotid artery was performed in transgenic Sca1-enhanced green fluorescent protein (eGFP) mice gavaged with or without "daily moderate" EtOH. RESULTS: The EtOH group had reduced adventitial thickening and less neointimal formation, compared to ligated controls. There was expansion of eGFP-expressing (i.e., Sca1+ ) cells in remodeled vessels postligation (day 14), especially in the neo intima. EtOH treatment reduced the number of Sca1+ cells in ligated vessel cross-sections concomitant with diminished remodeling, compared to control ligated vessels. Moreover, EtOH attenuated SHh signaling in injured carotids as determined by immunohistochemical analysis of the target genes patched 1 and Gli2, and RT-PCR of whole-vessel Gli2 mRNA levels. Intraperitoneal injection of ligated Sca1-eGFP mice with the SHh signaling inhibitor cyclopamine diminished SHh target gene expression, reduced the number of Sca1+ cells, and ameliorated carotid remodeling. EtOH treatment of purified Sca1+ adventitial progenitor stem cells in vitro inhibited SHh signaling, and their rSHh-induced differentiation to vascular smooth muscle cells. CONCLUSIONS: EtOH reduces SHh-responsive Sca1+ progenitor cell myogenic differentiation/expansion in vitro and during arterial remodeling in response to ligation injury in vivo. Regulation of vascular Sca1+ progenitor cells in this way may be an important novel mechanism contributing to alcohol's cardiovascular protective effects. PMID- 28921622 TI - National survey on managing minor childhood traumatic head injuries in the Netherlands shows low guideline adherence and large interhospital variations. PMID- 28921623 TI - One-step synthesis of [18 F]cabozantinib for use in positron emission tomography imaging of c-Met. AB - Cabozantinib is an FDA-approved kinase inhibitor for the treatment of medullary thyroid cancer and advanced renal cell carcinoma, which exerts its therapeutic effect by inhibiting, among others, the tyrosine kinase c-Met. Noninvasive imaging techniques are becoming increasingly important clinically to ensure drug efficacy, staging, monitoring, and patient stratification. PET isotope labelled tyrosine kinase inhibitors have, for the same reason, potential as PET tracers for imaging of various cancers. On the basis of cabozantinib, we synthesized the novel boronic acid pinacol ester 4 as a labelling precursor, where the boronic ester moiety replaces the fluorine native to this kinase inhibitor. By this, we wanted to explore whether recently developed Cu-mediated fluorination methods are adaptable to more complex substrates and thereby provide easy access to [18 F]cabozantinib directly. Hydrolysis was implemented before preparative purification due to challenges with on-column hydrolysis of the precursor 4, and [18 F]cabozantinib was obtained in >=99% radiochemical purity and in 2.8 +/- 0.05% (n = 4) isolated decay corrected yield in a synthesis time of 90 minutes. The molar activity of representative batches was determined to be 17 +/- 8 GBq/MUmol. PMID- 28921625 TI - Solving doubts about L-ornithine L-aspartate for overt hepatic encephalopathy: Whom and how to treat. PMID- 28921624 TI - Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease. AB - BACKGROUND: Pivotal clinical trials found that ticagrelor reduced ischaemic complications to a greater extent than clopidogrel, and also that the benefit gradually increased with the reduction in creatinine clearance. However, the underlying mechanisms remains poorly explored. METHODS: This was a single-centre, prospective, randomized clinical trial involving 60 hospitalized Adenosine Diphosphate (ADP) P2Y12 receptor inhibitor-naive patients with chronic kidney disease (CKD) (estimated glomerular filtration rate <60 ml min-1 1.73 m-2 ) and non-ST-elevation acute coronary syndromes (NSTE-ACS). Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor (180 mg loading dose, then followed by 90 mg twice daily) or clopidogrel (600 mg loading dose, then followed by 75 mg once daily). The primary endpoint was the P2Y12 reactive unit (PRU) value assessed by VerifyNow at 30 days. The plasma concentrations of ticagrelor and clopidogrel and their active metabolites were measured in the first 10 patients in each group at baseline, and at 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the loading dose. RESULTS: Baseline characteristics were well matched between the two groups. Our results indicated a markedly lower PRU in patients treated with ticagrelor vs. clopidogrel at 30 days (32.6 +/- 11.29 vs. 203.7 +/- 17.92; P < 0.001) as well as at 2 h, 8 h and 24 h after the loading dose (P < 0.001). Ticagrelor and its active metabolite AR-C124910XX showed a similar time to reach maximum concentration (Cmax ) of 8 h, with the maximum concentration (Cmax ) of 355 (242.50-522.00) ng ml-1 and 63.20 (50.80-85.15) ng ml-1 , respectively. Both clopidogrel and its active metabolite approached the Cmax at 2 h, with a similar Cmax of 8.67 (6.64-27.75) ng ml-1 vs. 8.53 (6.94-15.93) ng ml-1 . CONCLUSION: Ticagrelor showed much more potent platelet inhibition in comparison with clopidogrel in patients with CKD and NSTE-ACS. PMID- 28921626 TI - Relationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus. AB - Previous studies investigating the relationship between sodium intake and blood pressure have mostly relied on dietary recall and clinic blood pressure measurement. In this cross-sectional study, we aimed to investigate the relationship between 24 hour urinary sodium and potassium excretion, and their ratio, with 24 hour ambulatory blood pressure parameters including nocturnal blood pressure dipping in patients with type 1 and 2 diabetes. We report that in 116 patients with diabetes, systolic blood pressure was significantly predicted by the time of day, age, the interaction between dipping status with time, and 24 hour urinary sodium-to-potassium ratio (R2 = 0.83) with a relative contribution of 53%, 21%, 20% and 6%, respectively. However, there was no interaction between urinary sodium-to-potassium ratio and dipping status. PMID- 28921627 TI - Preterm infants with necrotising enterocolitis demonstrate an unbalanced gut microbiota. AB - AIM: This Lebanese study tested the hypothesis that differences would exist in the gut microbiota of preterm infants with and without necrotising enterocolitis (NEC), as reported in Western countries. METHODS: This study compared 11 infants with NEC and 11 controls, all born at 27-35 weeks, in three neonatal intensive care units between January 2013 and March 2015. Faecal samples were collected at key time points, and microbiota was analysed by culture, quantitative PCR (qPCR) and temperature temporal gel electrophoresis (TTGE). RESULTS: The cultures revealed that all preterm infants were poorly colonised and harboured no more than seven species. Prior to NEC diagnosis, significant differences were observed by qPCR with a higher colonisation by staphylococci (p = 0.034) and lower colonisations by enterococci (p = 0.039) and lactobacilli (p = 0.048) in the NEC group compared to the healthy controls. Throughout the study, virtually all of the infants were colonised by Enterobacteriaceae at high levels. TTGE analysis revealed no particular clusterisation, showing high interindividual variability. CONCLUSION: The NEC infants were poorly colonised with no more than seven species, and the controls had a more diversified and balanced gut microbiota. Understanding NEC aetiology better could lead to more effective prophylactic interventions and a reduced incidence. PMID- 28921628 TI - Who wins in the weaning process? Juvenile feeding morphology of two freshwater mussel species. AB - The global decline of freshwater mussels can be partially attributed to their complex life cycle. Their survival from glochidium to adulthood is like a long obstacle race, with juvenile mortality as a key critical point. Mass mortality shortly after entering into a juvenile state has been reported in both wild and captive populations, thus weakening the effective bivalve population. A similar phenomenon occurs during metamorphosis in natural and hatchery populations of juvenile marine bivalves. Based on a morphological analysis using scanning electron microscopy of newly formed juveniles of the freshwater species Margaritifera margaritifera (L.) (Margaritiferidae) and Unio mancus Lamarck (Unionidae), we show that a second metamorphosis, consisting of drastic morphological changes, occurs that leads to suspension feeding in place of deposit feeding by the ciliated foot. We hypothesize that suspension feeding in these two species improves due to a gradual development of several morphological features including the contact between cilia of the inner gill posterior filaments, the inner gill reflection, the appearance of the ctenidial ventral groove and the formation of the pedal palps. Regardless of the presence of available food, a suspension feeding mode replaces deposit feeding, and juveniles unable to successfully transition morphologically or adapt to the feeding changes likely perish. PMID- 28921629 TI - Validation of prognostic scores to predict short-term mortality in patients with acute-on-chronic liver failure. AB - BACKGROUND AND AIM: The aim of this study was to validate the chronic liver failure-sequential organ failure assessment score (CLIF-SOFAs), CLIF consortium organ failure score (CLIF-C OFs), CLIF-C acute-on-chronic liver failure score (CLIF-C ACLFs), and CLIF-C acute decompensation score in Korean chronic liver disease patients with acute deterioration. METHODS: Acute-on-chronic liver failure was defined by either the Asian Pacific Association for the study of the Liver ACLF Research Consortium (AARC) or CLIF-C criteria. The diagnostic performances for short-term mortality were compared by the area under the receiver operating characteristic curve. RESULTS: Among a total of 1470 patients, 252 patients were diagnosed with ACLF according to the CLIF-C (197 patients) or AARC definition (95 patients). As the ACLF grades increased, the survival rates became significantly lower. The areas under the receiver operating characteristic of the CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs were significantly higher than those of the Child-Pugh, model for end-stage liver disease, and model for end stage liver disease-Na scores in ACLF patients according to the CLIF-C definition (all P < 0.05), but there were no significant differences in patients without ACLF or in patients with ACLF according to the AARC definition. The CLIF-SOFAs, CLIF-C OFs, and CLIF-C ACLFs had higher specificities with a fixed sensitivity than liver specific scores in ACLF patients according to the CLIF-C definition, but not in ACLF patients according to the AARC definition. CONCLUSIONS: The CLIF SOFAs, CLIF-C OFs, and CLIF-C ACLFs are useful scoring systems that provide accurate information on prognosis in patients with ACLF according to the CLIF-C definition, but not the AARC definition. PMID- 28921630 TI - Metabolic assessment of a migraine model using relaxation-enhanced 1 H spectroscopy at ultrahigh field. AB - PURPOSE: This study evaluates biochemical imbalances in a rat model that reflects dysfunctional pathways in migraine. The high sensitivity and spectral dispersion available to 1 H MRS at 21.1 T expands metabolic profiling in this migraine model to include lactate (Lac), taurine (Tau), aspartate, and Gly-a mixture of glycine, glutamine, and glutamate. METHODS: Sprague-Dawley male rats were administered in situ an intraperitoneal injection of nitroglycerin (NTG) to induce the migraine analogue or saline as a control. A selective relaxation-enhanced MR spectroscopy sequence was used to target upfield metabolites from a 4-mm3 voxel for 2.5 h after injection. RESULTS: Significant increases were evident for Lac as early as 10 min after NTG injection, peaking over 50% compared with baseline and control (normalized Lac/N-acetyl aspartate with NTG = 1.54 +/- 0.65 versus with saline = 0.99 +/- 0.08). Tau decreased progressively in controls over 2 h after injection, but remained elevated with NTG, peaking at 105 min after injection (normalized Tau/N-acetyl aspartate with NTG = 1.10 +/- 0.18 versus with saline = 0.85 +/- 0.14). Total creatine under NTG showed significant decreases with time and compared with saline; Gly demonstrated temporal increases for NTG. CONCLUSIONS: These changes indicate an altered metabolic profile in the migraine analogue consistent with early changes in neural activity and/or vasodilation consistent with progressively enhanced neuroprotection and osmoregulation. Magn Reson Med 79:1266-1275, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921631 TI - Validation of highly accelerated real-time cardiac cine MRI with radial k-space sampling and compressed sensing in patients at 1.5T and 3T. AB - PURPOSE: To validate an optimal 12-fold accelerated real-time cine MRI pulse sequence with radial k-space sampling and compressed sensing (CS) in patients at 1.5T and 3T. METHODS: We used two strategies to reduce image artifacts arising from gradient delays and eddy currents in radial k-space sampling with balanced steady-state free precession readout. We validated this pulse sequence against a standard breath-hold cine sequence in two patient cohorts: a myocardial infarction (n = 16) group at 1.5T and chronic kidney disease group (n = 18) at 3T. Two readers independently performed visual analysis of 68 cine sets in four categories (myocardial definition, temporal fidelity, artifact, noise) on a 5 point Likert scale (1 = nondiagnostic, 2 = poor, 3 = adequate or moderate, 4 = good, 5 = excellent). Another reader calculated left ventricular (LV) functional parameters, including ejection fraction. RESULTS: Compared with standard cine, real-time cine produced nonsignificantly different visually assessed scores, except for the following categories: 1) temporal fidelity scores were significantly lower (P = 0.013) for real-time cine at both field strengths, 2) artifacts scores were significantly higher (P = 0.013) for real-time cine at both field strengths, and 3) noise scores were significantly (P = 0.013) higher for real-time cine at 1.5T. Standard and real-time cine pulse sequences produced LV functional parameters that were in good agreement (e.g., absolute mean difference in ejection fraction <4%). CONCLUSION: This study demonstrates that an optimal 12 fold, accelerated, real-time cine MRI pulse sequence using radial k-space sampling and CS produces good to excellent visual scores and relatively accurate LV functional parameters in patients at 1.5T and 3T. Magn Reson Med 79:2745-2751, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921632 TI - Elevated solute transport at sites of diffuse matrix damage in cortical bone: Implications on bone repair. AB - : Diffuse matrix damage in rat cortical bone has been observed to self-repair efficiently in 2 weeks without activating bone remodeling, and unlike the case with linear cracks, the local osteocytes at the sites of diffuse damage remain healthy. However, the reason(s) for such high efficiency of matrix repair remains unclear. We hypothesized that transport of minerals and other compounds essential for damage repair is enhanced at the damaged sites and further increased by the application of tensile loading. To test our hypothesis, diffuse damage was introduced in notched bovine wafers under cyclic tensile loading and unloading. Using the Fluorescence Recovery After Photobleaching (FRAP) approach, we measured the transport of a small fluorescent tracer (sodium fluorescein, 376 Da) in damaged versus undamaged regions and under varying tensile load magnitudes (0.2 N, 10 N, 20 N, and 30 N), which corresponded to nominal strains of 12.5, 625, 1,250, and 1,875 microstrains, respectively. We found a 37% increase in transport of fluorescein in damaged regions relative to undamaged regions and a further ~18% increase in transport under 20 N and 30 N tension compared to the non-loaded condition, possibly due to the opening of the cracking surfaces. The elevated transport of minerals and other adhesive proteins may, at least partially, account for the highly effective repair of diffuse damage observed in vivo. CLINICAL SIGNIFICANCE: Diffuse damage adversely affects bone's fracture resistance and this study provided quantitative data on elevated transport, which may be involved in repairing diffuse damage in vivo. 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:692-698, 2018. PMID- 28921633 TI - Spontaneous mechanical and electrical activities of human calf musculature at rest assessed by repetitive single-shot diffusion-weighted MRI and simultaneous surface electromyography. AB - PURPOSE: Assessment of temporal and spatial relations between spontaneous mechanical activities in musculature (SMAM) at rest as revealed by diffusion weighted imaging (DWI) and electrical muscular activities in surface EMG (sEMG). Potential influences of static and radiofrequency magnetic fields on muscular activity on sEMG measurements at rest were examined systematically. METHODS: Series of diffusion-weighted stimulated echo planar imaging were recorded with concurrent sEMG measurements. Electrical activities in sEMG were analyzed by non parametric Friedman and two-sample Kolmogorov-Smirnov test. Direct correlation of both modalities was investigated by temporal mapping of electrical activity in sEMG to DWI repetition interval. RESULTS: Electrical activities in sEMG and number of visible SMAMs in DWI showed a strong correlation (rho = 0.9718). High accordance between sEMG activities and visible SMAMs in DWI in a near-surface region around sEMG electrodes was achieved. Characteristics of sEMG activities were almost similar under varying magnetic field conditions. CONCLUSION: Visible SMAMs in DWI have shown a close and direct relation to concurrent signals recorded by sEMG. MR-related magnetic fields had no significant effects on findings in sEMG. Hence, appearance of SMAMs in DWI should not be considered as imaging artifact or as effects originating from the special conditions of MR examinations. Spatial and temporal distributions of SMAMs indicate characteristics of spontaneous (microscopic) mechanical muscular action at rest. Therefore, DWI techniques should be considered as non-invasive tools for studying physiology and pathophysiology of spontaneous activities in resting muscle. Magn Reson Med 79:2784-2794, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921634 TI - The role of whole-brain diffusion MRI as a tool for studying human in vivo cortical segregation based on a measure of neurite density. AB - PURPOSE: To investigate whether diffusion MRI can be used to study cortical segregation based on a contrast related to neurite density, thus providing a complementary tool to myelin-based MRI techniques used for myeloarchitecture. METHODS: Several myelin-sensitive MRI methods (e.g., based on T1 , T2 , and T2*) have been proposed to parcellate cortical areas based on their myeloarchitecture. Recent improvements in hardware, acquisition, and analysis methods have opened the possibility of achieving a more robust characterization of cortical microstructure using diffusion MRI. High-quality diffusion MRI data from the Human Connectome Project was combined with recent advances in fiber orientation modeling. The orientational average of the fiber orientation distribution was used as a summary parameter, which was displayed as inflated brain surface views. RESULTS: Diffusion MRI identifies cortical patterns consistent with those previously seen by MRI methods used for studying myeloarchitecture, which have shown patterns of high myelination in the sensorimotor strip, visual cortex, and auditory areas and low myelination in frontal and anterior temporal areas. CONCLUSION: In vivo human diffusion MRI provides a useful complementary noninvasive approach to myelin-based methods used to study whole-brain cortical parcellation, by exploiting a contrast based on tissue microstructure related to neurite density, rather than myelin itself. Magn Reson Med 79:2738-2744, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921635 TI - Prediction of phosphorylation sites based on Krawtchouk image moments. AB - Protein phosphorylation is one of the most pervasive post-translational modifications and regulates diverse cellular processes in organisms. Under the catalysis of protein kinases, protein phosphorylation usually occurred in the residues serine (S), threonine (T), or tyrosine (Y). In this contribution, we proposed a novel scheme (named KMPhos) for the theoretical prediction of protein phosphorylation sites. First, the numerical matrix was obtained from a protein sequence fragment by replacing the characters of the residues with the chemical descriptors of amino acid molecules to approximately describe the chemical environment of the protein fragment, which was turned to the grayscale image. Then the Krawtchouk image moments were calculated and used to establish the support vector machine models. The accuracies of 10-fold cross validation for the obtained models on the training set are up to 89.7%, 88.6%, and 90.1% for the residues S, Y, and T, respectively. For the independent test set, the prediction accuracies are up to 90.7% (S), 87.8% (T), and 89.3% (Y). The results of ROC and other evaluations are also satisfactory. Compared with several specialized prediction tools, KMPhos provided the higher accuracy and reliability. An available KMPhos package is provided and can be used directly for phosphorylation sites prediction. PMID- 28921636 TI - Diagnostic challenge of non-specific visual symptoms: consideration of Heidenhain variant of Creutzfeldt-Jakob disease. PMID- 28921637 TI - To Serve or Not to Serve: Ethical and Policy Implications. AB - The Institute of Medicine (IOM) is one of the nation's more influential health related non-profit organizations. It plays a large role in shaping health policy by commissioning panels to develop "white papers" describing research and recommendations on a variety of health topics. These white paper publications are often used to help make policy decisions at the legislative and executive levels. Such a prominent institution might seem like a natural ally for policy-related collaborative efforts. As community psychologists, we strongly endorse efforts to positively influence public policy at the national level. However, while serving on influential panels and commissions like the IOM might seem to be very much part of the ethos of our discipline, there are occasions when such institutions are pursuing a mission that inadvertently has the potential to instigate divisive friction among community activists and organizations. A case study is presented whereby I describe my decision not to accept an invitation to serve on a controversial IOM panel. I explore the ethical challenges regarding maintaining my independence from this institution and its attempt to redefine chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), as well as the process of searching for alternative avenues for collaborating with community activists to influence policy related to these debilitating illnesses. PMID- 28921639 TI - Standing in the Shifting Sands of Molecular Targeting and Precision Medicine Is the Oasis of 21st-Century Oncology Therapeutics. PMID- 28921640 TI - The Role of Clinical Pharmacology in Oncology Dose Selection: Advances and Opportunities in Personalized Medicine. PMID- 28921638 TI - Graft-infiltrating PD-L1hi cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance. AB - : Although a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. We investigated the role of intragraft dendritic cells (DCs) and cross-dressing in mouse major histocompatibility complex (MHC) mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. Although donor interstitial DCs diminished rapidly after transplantation, they were replaced in the liver by host DCs that peaked on postoperative day (POD) 7 and persisted indefinitely. Approximately 60% of these recipient DCs displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0%-2%) of cross-dressed DCs (CD-DCs) was evident in the spleen. CD-DCs sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of interleukin-10 compared with non-CD-DCs (nCD-DCs) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)hi T cell immunoglobulin and mucin domain containing 3 (TIM-3)+ exhausted graft infiltrating CD8+ T cells were observed. Unlike nCD-DCs, the CD-DCs failed to stimulate proliferation of allogeneic T cells but markedly suppressed antidonor host T cell proliferation. CD-DCs were much less evident in allografts from DNAX activating protein of 12 kDa (DAP12)-/- donors that were rejected acutely. CONCLUSION: These findings suggest that graft-infiltrating PD-L1hi CD-DCs may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. (Hepatology 2018;67:1499-1515). PMID- 28921641 TI - Pharmacokinetic-Guided Dosing of New Oral Cancer Agents. AB - Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition. PMID- 28921642 TI - Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk-Benefit Approach. AB - Targeted therapies are now considered an integral component in the treatment armamentarium for many malignancies, and the approach to developing these drugs needs to be refined from the previous cytotoxic paradigm of toxicity-guided dose finding and identification of maximum tolerated dose to a paradigm driven by target activity. Moving away from the toxicity-driven dose finding and justification model requires an integrated approach in order to adequately characterize the risk-benefit of a drug. This approach starts with understanding the importance of collecting samples for pharmacokinetic and pharmacodynamic assessments in all phases of clinical development to fully characterize the pharmacokinetics and identify covariates and then correlating exposure to key markers of safety and efficacy in pharmacometric analyses to perform a robust risk-benefit assessment and establish the right dose. In addition, for oral agents, decisions on administering the drug with respect to food can impact dose among other clinical trial outcomes such as tolerability and patient compliance. Understanding the importance of model-based drug development as a decision-making tool to support drug development through incorporation of all relevant data allows for a robust risk-benefit assessment at key decision points. Utilization of clinical pharmacology tools and assessments throughout development will provide the key components of a successful oncology development program. PMID- 28921643 TI - Bridging Adult Experience to Pediatrics in Oncology Drug Development. AB - Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers. PMID- 28921644 TI - Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors. AB - Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen 4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. PMID- 28921645 TI - Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future. PMID- 28921646 TI - How Often Are Drugs Made Available Under the Food and Drug Administration's Expanded Access Process Approved? AB - In this review of individual patient expanded-access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded-access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded-access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drug's approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)'s expanded-access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients. PMID- 28921647 TI - Pharmacogenomics Implementation at the National Institutes of Health Clinical Center. AB - The National Institutes of Health Clinical Center (NIH CC) is the largest hospital in the United States devoted entirely to clinical research, with a highly diverse spectrum of patients. Patient safety and clinical quality are major goals of the hospital, and therapy is often complicated by multiple cotherapies and comorbidities. To this end, we implemented a pharmacogenomics program in 2 phases. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. The purpose of this review is to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC. PMID- 28921648 TI - RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions. AB - RNA-based therapeutic technologies represent a rapidly expanding class of therapeutic opportunities with the power to modulate cellular biology in ways never before possible. With RNA-targeted therapeutics, inhibitors of previously undruggable proteins, gene expression modulators, and even therapeutic proteins can be rationally designed based on sequence information alone, something that is not possible with other therapeutic modalities. The most advanced RNA therapeutic modalities are antisense oligonucleotides (ASOs) and small interfering RNAs. Particularly with ASOs, recent clinical data have demonstrated proof of mechanism and clinical benefit with these approaches across several nononcology disease areas by multiple routes of administration. In cancer, next-generation ASOs have recently demonstrated single-agent activity in patients with highly refractory cancers. Here we discuss advances in RNA therapeutics for the treatment of cancer and the challenges that remain to solidify these as mainstay therapeutic modalities to bridge the pharmacogenomic divide that remains in cancer drug discovery. PMID- 28921649 TI - Dose Finding Versus Speed in Seamless Immuno-Oncology Drug Development. PMID- 28921650 TI - Antibody-Drug Conjugates as Cancer Therapeutics: Past, Present, and Future. AB - Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion. PMID- 28921651 TI - Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice. AB - Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. PMID- 28921652 TI - Necessity of more sensitivity analyses and interpretations from public health perspectives. PMID- 28921653 TI - Visualization of temporal patterns in patient record data. AB - Visualization contributes to a variety of tasks, from reviewing individual patient records to helping researchers assess data quality, find patients of interest, review temporal patterns and anomalies, or understand differences between cohorts. We review some of visualization techniques developed at the University of Maryland. PMID- 28921654 TI - Influence of Cocaine-Related Images and Alcohol Administration on Inhibitory Control in Cocaine Users. AB - BACKGROUND: Alcohol use and impulsivity, including decreased inhibitory control, predict poor treatment outcomes for individuals with cocaine use disorders. This study sought to determine the effects of alcohol administration on inhibitory control following cocaine-related and neutral cues on the Attentional Bias Behavioral Activation (ABBA) task in cocaine users. We hypothesized that the proportion of inhibitory failures would increase following cocaine, compared to neutral, cues. We further hypothesized that there would be an interaction between alcohol administration and task version, such that alcohol would impair inhibitory control following cocaine, but not neutral cues. METHODS: Fifty current cocaine users completed this mixed-model, double-blind, placebo controlled, crossover study over 2 experimental sessions. The ABBA task was completed following alcohol administration (0.0 and 0.65 g/kg). Subject-rated drug effect and physiological measures were collected prior to and after alcohol administration. RESULTS: Proportion of inhibitory failures was increased following cocaine-related cues compared to neutral cues independent of alcohol dose. Alcohol administration also produced prototypical subject-rated drug effects. CONCLUSIONS: A better understanding of the relationship between alcohol consumption and inhibitory control in cocaine users could direct the development of interventions to decrease the risk of relapse in individuals who drink and display impaired inhibitory control. PMID- 28921655 TI - Fast dynamic ventilation MRI of hyperpolarized 129 Xe using spiral imaging. AB - PURPOSE: To develop and optimize a rapid dynamic hyperpolarized 129 Xe ventilation (DXeV) MRI protocol and investigate the feasibility of capturing pulmonary signal-time curves in human lungs. THEORY AND METHODS: Spiral k-space trajectories were designed with the number of interleaves Nint = 1, 2, 4, and 8 corresponding to voxel sizes of 8 mm, 5 mm, 4 mm, and 2.5 mm, respectively, for field of view = 15 cm. DXeV images were acquired from a gas-flow phantom to investigate the ability of Nint = 1, 2, 4, and 8 to capture signal-time curves. A finite element model was constructed to investigate gas-flow dynamics corroborating the experimental signal-time curves. DXeV images were also carried out in six subjects (three healthy and three chronic obstructive pulmonary disease subjects). RESULTS: DXeV images and numerical modelling of signal-time curves permitted the quantification of temporal and spatial resolutions for different numbers of spiral interleaves. The two-interleaved spiral (Nint = 2) was found to be the most time-efficient to obtain DXeV images and signal-time curves of whole lungs with a temporal resolution of 624 ms for 13 slices. Signal time curves were well matched in three healthy volunteers. The Spearman's correlations of chronic obstructive pulmonary disease subjects were statistically different from three healthy subjects (P < 0.05). CONCLUSION: The Nint = 2 spiral demonstrates the successful acquisition of DXeV images and signal-time curves in healthy subjects and chronic obstructive pulmonary disease patients. Magn Reson Med 79:2597-2606, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28921656 TI - Animal models for studying the etiology and treatment of low back pain. AB - Chronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain (LBP). This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of LBP can be divided into the following five categories: Discogenic LBP, radicular back pain, facet joint osteoarthritis back pain, muscle-induced LBP, and spontaneous occurring LBP models. These models are important not only for enhancing our knowledge of how LBP is generated, but also for the development of novel therapeutic regimens to treat LBP in patients. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1305-1312, 2018. PMID- 28921657 TI - Extremely prematurely born adolescents self-report of anxiety symptoms, and the mothers' reports on their offspring. AB - AIM: To compare anxiety symptoms in adolescents born extremely prematurely to term-born controls. METHODS: We had 96 preterm-born adolescents and 40 term-born controls from Denmark, and their mothers score the adolescents on the Revised Children Anxiety and Depression scale. We analysed group differences, cross informant correlations and relative risks for elevated anxiety symptoms. RESULTS: Self-reported anxiety symptoms did not significantly differ, although the upper confidence limit (95% CI: -3.3 to 5.1) supported an odds ratio of 2 for the preterm-born participants. Mothers of the preterm-born participants reported higher social anxiety symptoms than did mothers of controls (51.7 versus 46.8, p = 0.001). The relative risk for being above a threshold indicating distressing anxiety was small from self-reports (1.39; p = 0.60). From mother-reports, the relative risk was noticeable but not significant (4.58; p = 0.14). Cross informant scores correlated significant for total anxiety and social anxiety for the preterm-born (rtau = 0.2, p = 0.001; rtau = 0.3, p <= 0.001). CONCLUSIONS: Self-reports did not clearly indicate more anxiety in the preterm group, although confidence intervals supported a possible twofold increase. Mother- and self reports correlated only for the preterm group, which may indicate increased sensitivity for their children's symptoms. PMID- 28921658 TI - Evaluating instrument responsiveness in joint function: The HOOS JR, the KOOS JR, and the PROMIS PF CAT. AB - : 12345Responsiveness is the ability to detect change over time and is an important aspect of measures used to detect treatment effects. The purpose of this study was to assess the responsiveness of the HOOS JR, the KOOS JR, and the PROMIS Physical Function (PF) computerized adaptive test (CAT) in a joint reconstruction practice. 983 patients were evaluated for joint conditions between 2014 and 2017 in an orthopaedic clinic and completed the three instruments at baseline and 3 and/or 6-month follow-up visits. Average age was 61.03 years (SD = 12.33, Range = 18-90 years) and the majority of the patients were White (n = 875, 89.0%). Three-month responsiveness was calculated two ways, as between 80 and 100 days and as 90 days and beyond. Six-month responsiveness was calculated as 170 190 days and as 180 days and beyond. All changes from baseline scores were significant at the 3-, >3-, and >6-month follow-up (p < 0.05). All three measures showed large effect sizes, ranging from 0.80-1.20 at each time-point. The standardized response mean was large for each measure and at each time-point (Range = 1.06-1.53). This study demonstrated the responsiveness of the HOOS JR, KOOS JR, and the PROMIS PF in adult reconstruction patients. The PROMIS PF was consistently the most responsive instrument in this analysis. CLINICAL SIGNIFICANCE: The HOOS JR, KOOS JR, and PROMIS PF are useful clinical instruments for assessing treatment change and may be selected as relevant to the specific needs and conditions of the adult joint reconstruction patient population. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1178-1184, 2018. PMID- 28921660 TI - Rapid whole-brain gray matter imaging using single-slab three-dimensional dual echo fast spin echo: A feasibility study. AB - PURPOSE: To achieve rapid, high resolution whole-brain gray matter (GM) imaging by developing a novel, single-slab three-dimensional dual-echo fast-spin-echo pulse sequence and GM-selective reconstruction. METHODS: Unlike conventional GM imaging that uses time-consuming double-inversion-recovery preparation, the proposed pulse sequence was designed to have two split portions along the echo train, in which the first half was dedicated to yield short inversion recovery (IR)-induced white matter suppression and variable-flip-angle-induced two-step GM signal evolution while the second half cerebrospinal fluid-only signals. Multi step variable-flip-angle schedules and sampling reordering were optimized to yield high GM signals while balancing cerebrospinal fluid signals between ECHOes. GM-selective images were then reconstructed directly from the weighted subtraction between ECHOes by solving a sparse signal recovery problem. In vivo studies were performed to validate the effectiveness of the proposed method over conventional double-inversion-recovery. RESULTS: The proposed method, while achieving one millimeter isotropic, whole-brain GM imaging within 5.5 min, showed superior performance than conventional double-inversion-recovery in producing GM only images without apparent artifacts and noise. CONCLUSION: We successfully demonstrated the feasibility of the proposed method in achieving whole-brain GM imaging in a clinically acceptable imaging time. The proposed method is expected to be a promising alternative to conventional double-inversion-recovery in clinical applications. Magn Reson Med 78:1691-1699, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921659 TI - Ligature-induced peri-implantitis and periodontitis in mice. AB - AIM: Peri-implantitis (PI), inflammation around dental implants, shares characteristics with periodontitis (PD). However, PI is more difficult to control and treat, and detailed pathophysiology is unclear. We aimed to compare PI and PD progression utilizing a murine model. MATERIALS AND METHODS: Four-week-old male C57BL/6J mice had their left maxillary molars extracted. Implants were placed in healed extraction sockets and osseointegrated. Ligatures were tied around the implants and second molars. Controls did not receive ligatures. Mice were sacrificed 1 week, 1 and 3 months (n >= 5/group/time point) post-ligature placement. Bone loss analysis was performed. Histology was performed for: haematoxylin and eosin (H&E), tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-8 (MMP-8), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB), toluidine blue and calcein. RESULTS: PI showed statistically greater bone loss compared to PD at 1 and 3 months. At 3 months, 20% of implants in PI exfoliated; no natural teeth exfoliated in PD. H&E revealed that alveolar bone surrounding implants in PI appeared less dense compared to PD. PI presented with increased osteoclasts, MMP-8 and NF-kappaB, compared to PD. CONCLUSION: PI exhibited greater tissue and bone destruction compared to PD. Future studies will characterize the pathophysiological differences between the two conditions. PMID- 28921661 TI - Association of gout and depression: A systematic review and meta-analysis. AB - OBJECTIVE: Several studies have shown that gout is associated with depression symptoms. In this study, a systematic review and meta-analysis was performed to explore the relationship between gout and depression. METHODS: Published articles were identified through a comprehensive review of PUBMED and EMBASE. Data from studies reporting relative risks, odds ratios, or hazard ratios comparing the risk of depression among participants who had gout versus those without gout were analyzed. A random-effect model was used to calculate pooled odds ratios and 95% confident intervals (CI). RESULTS: Seven studies, which included 411 745 participants, aligned with our inclusion criteria and were included in the meta analysis. Pooled analysis showed an association between gout and depression, with an odds ratio of 1.19 (95%CI, 1.11, 1.29; I2 = 60.2%). Subgroup-analysis adjusted (or not) by study type or study quality showed a statistically significant association of gout and depression in all subgroups. Sensitivity analysis by 1-study removed analysis, excluding articles of self-reported gout assessment or male-only, confirmed the robustness of our results. CONCLUSION: Our meta-analysis demonstrates a positive association between gout and depression. Further large-scale prospective cohort studies are needed to investigate the causality between gout and depression. PMID- 28921662 TI - Atenolol treatment for severe Infantile Hemangiomas: a single-centre prospective study. PMID- 28921664 TI - A glimmer of light at the end of the tunnel? PMID- 28921663 TI - Insect Bite Hypersensitivity in Horses is Associated with Airway Hyperreactivity. AB - BACKGROUND: Genetic and epidemiologic evidence suggests that in horses, as in other species, different manifestations of hypersensitivity may occur together. HYPOTHESIS: Horses affected with insect bite hypersensitivity (IBH) show airway hyperreactivity (AH) to inhaled histamine, even in the absence of overt clinical signs of equine asthma (EA). ANIMALS: Twenty-two healthy controls (group C), 24 horses suffering from IBH alone (group IBH), and 23 horses suffering from IBH and EA (group IBH/EA). METHODS: The clinical histories were assessed using 2 standardized questionnaires, the Horse Owner Assessed Respiratory Signs Index (HOARSI), and IBH scoring. Horses were classified as EA-affected if their HOARSI was >1 and as IBH-affected if IBH score was >0. Confounding disorders were excluded by clinical examination. The arterial partial pressure of oxygen (PaO2 ) was measured and flowmetric plethysmography used to assess airway reactivity to increasing doses of inhaled histamine. RESULTS: The median histamine provocation concentration (PC) when ?flow values increased by 35% (PC35) was significantly higher in group C (5.94 [1.11-26.33] mg/mL) compared to group IBH (2.95 [0.23 10.13] mg/mL) and group IBH/EA (2.03 [0.43-10.94] mg/mL; P < 0.01). The PC50 and PC75 showed very similar differences between groups. Furthermore, PaO2 was significantly lower in group IBH (84 +/- 8 mmHg) and group IBH/EA (78 +/- 11 mmHg) compared to group C (89 +/- 6 mmHg; P < 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: IBH is associated with AH and decreased PaO2 , even in the absence of overt respiratory clinical signs. PMID- 28921665 TI - Effects of Oral Prednisone Administration on Serum Cystatin C in Dogs. AB - BACKGROUND: Oral administration of glucocorticoid alters serum cystatin C (sCysC) concentration in humans. OBJECTIVE: To determine if oral administration of prednisone alters sCysC in dogs without pre-existing renal disease. ANIMALS: Forty six dogs were included: 10 dogs diagnosed with steroid responsive meningitis arteritis (SRMA; group A), 20 dogs diagnosed of pituitary-dependent hyperadrenocorticism (PDH; group B), and 16 healthy control dogs (group C). METHODS: Retrospective observational study. SRMA diagnosed dogs were administered prednisone 4 mg/kg/24 h PO 7 days, reducing the dose to 2 mg/kg/24 h 7 days before medication withdrawal. In group A, sampling was performed at days 0, 7, 14 and a final control at day 21. Blood and urine samples were collected in the 3 groups, and in group A, sampling was performed at all time points (days 1, 7, 14, and 21). RESULTS: In group A, sCysC was significantly higher at day 7 compared to the control group (0.4 +/- 0.04 mg/L vs. 0.18 +/- 0.03 mg/L mean +/- SEM respectively P < 0.01); sCysC values decreased to basal at day 14 when the dose was decreased and after 1 week of withdrawal of prednisone (0.27 +/- 0.03 mg/L for group A at day 14 and 0.15 +/- 0.02 mg/L at day 21; P > 0.05). Dogs with PDH included in group B did not have significant differences in sCysC (0.22 +/- 0.03 mg/L) compared to control (P > 0.05). CONCLUSIONS AND CLINICAL IMPORTANCE: Oral administration of prednisone unlike altered endogenous glucocorticoid production, increases sCysC in dogs in a dose-dependent fashion. PMID- 28921666 TI - Comparison of laparoscopic gastropexy performed via intracorporeal suturing with knotless unidirectional barbed suture using a needle driver versus a roticulated endoscopic suturing device: 30 cases. AB - OBJECTIVE: To compare two suturing techniques for prophylactic laparoscopic gastropexy in healthy dogs. STUDY DESIGN: Retrospective case series. ANIMALS: Thirty healthy client-owned dogs from breeds predisposed to gastric dilation volvulus. METHODS: Medical records of dogs presented for prophylactic laparoscopic gastropexy performed with knotless unidirectional barbed suture were reviewed. Dogs were grouped based on the device used for suturing, consisting of an endoscopic needle driver (END) vs an endoscopic suturing device (ESD). Signalment, weight, surgery time, number of suture bites per side of gastropexy, and intraoperative complications were compared between groups. RESULTS: The END group consisted of 10 dogs, with a median age of 1.09 years (range 0.5-2.67), weight of 41.5 kg (range 25-66), surgical time of 49.5 minutes (range 35-77), and a median of 5 suture bites per side (range 4-6). The ESD group included 20 dogs, with a median age of 1.75 years (range 0.6-8.75, P = .0944), weight was 37.5 kg (range 20-62, P = .5823), surgical time of 55 minutes (range 30-76, P = .808), and a median of 6 suture bites for the first side (range 4-7, P = .072) and 7 for the second side (range 4-8, P = .003). No major complications and no conversion to open celiotomy occured in either group. Minor complications occurred in 3 dogs in the ESD group, all related to device dysfunction and suture breakage. CONCLUSION: Laparoscopic gastropexy may be performed effectively with either of these suturing techniques. PMID- 28921667 TI - Polysubstance Use Among Adolescents in a Low Income, Rural Community: Latent Classes for Middle- and High-School Students. AB - PURPOSE: Rural communities are currently being impacted by a nationwide epidemic of prescription opioid misuse. Rural adolescent substance users may be at substantial risk for later addiction to these and other drugs. METHODS: This study uses Latent Class Analysis to identify subtypes of polysubstance users among a sample of 7,074 rural adolescents. Separate models were estimated for middle- and high-school youth. Predictive validity was estimated using cumulative ordinal logistic regression of the classes on a set of youth and family characteristics. FINDINGS: We identified a 4-class solution for both middle- and high-school students marked by initiation of an increasing number of substances used at greater frequency. These classes included Substance Nonusers, Primarily Alcohol Users, Initiators-Low Frequency Users, and Initiators-Moderate-to-High Lifetime Frequency Users. About 6%-10% of youth reported using prescription drugs at least once, and in the moderate-to-high frequency class, middle-school youth were more likely to use prescription drugs and inhalants compared to high-school youth in the same class. The 4 classes were associated with race/ethnicity, and in high school with receiving free/reduced price lunch. CONCLUSION: In general, younger adolescents have lower overall use rates, but within certain classes identified by this analysis, the observed pattern suggests that younger cohorts are turning to prescription drugs and inhalants. These findings support the implementation of universal substance use prevention programs, targeted programs for youth experiencing risk factors associated with substance use, and improved rural substance abuse treatment options. PMID- 28921668 TI - Controlling Molecular Doping in Organic Semiconductors. AB - The field of organic electronics thrives on the hope of enabling low-cost, solution-processed electronic devices with mechanical, optoelectronic, and chemical properties not available from inorganic semiconductors. A key to the success of these aspirations is the ability to controllably dope organic semiconductors with high spatial resolution. Here, recent progress in molecular doping of organic semiconductors is summarized, with an emphasis on solution processed p-type doped polymeric semiconductors. Highlighted topics include how solution-processing techniques can control the distribution, diffusion, and density of dopants within the organic semiconductor, and, in turn, affect the electronic properties of the material. Research in these areas has recently intensified, thanks to advances in chemical synthesis, improved understanding of charged states in organic materials, and a focus on relating fabrication techniques to morphology. Significant disorder in these systems, along with complex interactions between doping and film morphology, is often responsible for charge trapping and low doping efficiency. However, the strong coupling between doping, solubility, and morphology can be harnessed to control crystallinity, create doping gradients, and pattern polymers. These breakthroughs suggest a role for molecular doping not only in device function but also in fabrication applications beyond those directly analogous to inorganic doping. PMID- 28921669 TI - Respiratory variation in left ventricular cardiac function with 3D double golden angle whole-heart cine imaging. AB - PURPOSE: To develop a 3-dimensional free-breathing cardiovascular MR technique for quantifying the variation in left ventricular end-diastolic volume (LVEDV) during the respiratory cycle. METHODS: A 3-dimensional radial trajectory with double golden-angle ordering was used for free-running data acquisition during free breathing in healthy volunteers (N = 8). A respiratory self-gating signal was extracted from the center of k-space, and data were retrospectively binned into eight respiratory phases in end-diastole. Three-dimensional image volumes with 2-mm isotropic spatial resolution were reconstructed with conjugate-gradient sensitivity encoding for acquisition durations of 4.5, 9, and 25 min. The LVEDV was manually segmented for each respiratory phase and acquisition duration. RESULTS: Respiratory-induced variation expressed as minimum LVEDV (during mid inspiration) relative to maximum LVEDV (during mid-expiration) was 5.9 +/- 0.3% for 4.5 min, 5.3 +/- 0.4% for 9 min (P = 0.64 versus 4.5 min), and 5.0 +/- 0.4% for 25 min (P = 0.25 versus 4.5 min, and P = 1.00 versus 9 min). CONCLUSIONS: The proposed technique enables high spatial-resolution quantification of the respiratory variation in LVEDV during free breathing in under 5 min, and was found to be 5 to 6% for healthy volunteers. Magn Reson Med 79:2693-2701, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28921670 TI - Circular-circular regression model with a spike at zero. AB - With reference to a real data on cataract surgery, we discuss the problem of zero inflated circular-circular regression when both covariate and response are circular random variables and a large proportion of the responses are zeros. The regression model is proposed, and the estimation procedure for the parameters is discussed. Some relevant test procedures are also suggested. Simulation studies and real data analysis are performed to illustrate the applicability of the model. PMID- 28921671 TI - Methyl Jasmonate Ameliorates Unpredictable Chronic Mild Stress-Induced Behavioral and Biochemical Alterations in Mouse Brain. AB - Preclinical Research The effects of methyl jasmonate (MJ; 5, 10, 20 mg/kg, i.p), a natural product widely used for the relief of stress, depression, and exhaustion on unpredictable chronic mild stress (UCMS)-induced depression-like behaviors in mice was assessed and compared to those of imipramine (IMP; 10 mg/kg, i.p). MJ and IMP were given 30 min before exposure to UCMS with the procedure repeated daily for 2 weeks; 24 h after the stress session, the tail suspension test (TST) and sucrose preference test were assessed. MJ decreased immobility time in the TST and reversed impaired intake of sucrose relative to the stressed control suggesting antidepressant-like activity. MJ also reduced UCMS-induced increases in corticosterone and MDA (malondialdehyde) levels and attenuated UCMS-induced decreases in GSH and TNF-alpha levels and SOD activity. These findings suggest that MJ attenuated UCMS-induced depressive-like behaviors through decreased levels of corticosterone and decreasing oxidative stress and neuroinflammation in mouse brain.Drug Dev Res 78 : 381-389, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921672 TI - A novel, in-frame KMT2B deletion in a patient with apparently isolated, generalized dystonia. PMID- 28921673 TI - Safety of Back-Transfer to Local Hospitals During an Acute Care Hospitalization. AB - PURPOSE: This paper investigates patient outcomes including length of stay (LOS), cost of hospitalization, bounce-back rates, transition to hospice care, and mortality, following back-transfer. METHODS: This study was an observational case control study of adults hospitalized in Iowa between 2005 and 2013 to identify back-transferred patients. Back-transfer was defined as the transfer of rural patients near the end of their acute hospitalization in a comprehensive medical center back to a local community hospital for the completion of their medical care. Demographic, geographic, rurality, procedural, and disease information was compared between case and control groups, then propensity score (PS) matching was performed to create comparable groups to perform analyses. FINDINGS: Over the 9 year period, 1,056,773 patients meeting inclusion criteria were admitted, of which 430 (0.04%) were back-transferred. After PS matching, LOS was 60% (95% CI: 0.50-0.71) higher and costs were 42% (95% CI: 0.33-0.50) higher in the back transferred group. Back-transferred cases had 8.34 (95% CI: 3.66-19.0) times the odds of hospice transition and 2.17 (95% CI: 1.37-3.46) the odds of mortality compared to controls. Four percent of back-transfers "failed" with the patient being returned to the larger hospital before discharge. CONCLUSIONS: Back transfer is a rare occurrence, and it is associated with longer LOS, higher hospitalization cost, higher mortality, more hospice transfers, and occasional bounce-backs to comprehensive medical centers. Future work should focus more on prospective indications for transfer, the role of end-of-life care, financial impact, and identifying patient populations for whom back-transfer is safest. PMID- 28921674 TI - Decline in effort capacity with age: Echocardiographic stress analysis in the elderly. AB - BACKGROUND: The present study was designed to assess the underlying mechanism of decline in effort capacity seen with aging. METHODS: We analyzed 250 healthy senior patients (>=65 years) with an ejection fraction >=60% who underwent a stress echocardiogram test. The seniors (aged 65-94) were divided into 3 equal age groups (groups 1, 2, and 3), and their echo characteristics at rest and peak exercise (measured and calculated) were compared. RESULTS: Diastolic function at rest declined significantly (E lateral, E septal, E/E', A) with age, while other rest parameters were similar. There was a significant reduction in peak cardiac output (CO) associated with age (time * age group interaction; P < .05), which was attributed to the combination an attenuated stroke volume (SV) and heart rate (HR) response. The decline in effort capacity with age was the product of the combined effect of cardiac (reduced LVEDV and HR response) and noncardiac (reduction in arteriovenous difference; P = .02 for interaction) causes. CONCLUSION: The cardiovascular system undergoes several age-related changes. Decline in effort capacity is an ongoing process of aging and consists of several changes in the cardiac and noncardiac systems, comprising a decline in CO and its components, specifically the peak exercise LVEDV, peak heart rate, and the ability of the muscles to extract enough oxygen for the necessary effort. PMID- 28921675 TI - Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. AB - Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor-dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain-of-function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions. PMID- 28921676 TI - Perioperative passport: empowering people with diabetes along their surgical journey. AB - AIM: To determine whether a handheld 'perioperative passport' could improve the experience of perioperative care for people with diabetes and overcome some of the communication issues commonly identified in inpatient extracts. METHODS: Individuals with diabetes undergoing elective surgery requiring at least an overnight stay were identified via a customized information technology system. Those allocated to the passport group were given the perioperative passport before their hospital admission. A 26-item questionnaire was completed after surgery by 50 participants in the passport group (mean age 69 years) and by 35 participants with diabetes who followed the usual surgical pathway (mean age 70 years). In addition, the former group had a structured interview about their experience of the passport. RESULTS: The prevalence of those who reported having received prior information about their expected diabetes care was 35% in the control group vs 92% in the passport group (P<0.001). The passport group found the information given significantly more helpful (P<0.001), including the advice on medication adjustment (P=0.008). Furthermore, those with the passport were more involved in planning their diabetes care (P <0.001), less anxious whilst in hospital (P<0.044) and better prepared to manage their diabetes on discharge (P<=0.001). The mean length of hospital stay was shorter in the passport group, although the difference did not reach significance (4.4 vs 6.5 days; P<0.058). Content analysis indicated that the passport was well liked and innovative. CONCLUSION: Our data indicate that the perioperative passport is effective in both informing and involving people in their diabetes care throughout the perioperative period. PMID- 28921677 TI - Clinical profile of hepatitis C virus infection in a developing country: India. AB - BACKGROUND AND AIM: The epidemiology and clinical profile of hepatitis C virus (HCV) varies worldwide, and data from developing countries are sparse. The aim of the present study was to assess the clinical profile of HCV infection in a developing country in South-East Asia (India). METHODS: This observational study assessed patient demographics, viral characteristics, risk factors for virus acquisition, and disease characteristics in HCV patients diagnosed between January 2004 and December 2015. RESULTS: Of 8035 patients who were diagnosed with HCV infection, a majority were men (68.3%), middle aged (52.2%), and from low (34%) to middle (46%) socioeconomic status and rural population (69.8%). Eighty two percent had identifiable risk factors, the most common being history of dental treatment (52%) and therapeutic injections with reusable syringes/needles (45%). Household contacts of index patients had high prevalence of HCV (15.3%). Common genotypes were genotype 3 (70.4%) and genotype 1 (19.3%). Although a majority of patients were either asymptomatic (54.8%) or had non-specific symptoms (6.7%) at presentation, a significant proportion (9.3%) had advanced liver disease. Presentation with cirrhosis (38.8%) was associated with male gender, higher age at time of virus detection, rural residence, alcohol or opium intake, and coinfections with hepatitis B virus or human immunodeficiency virus. CONCLUSIONS: Hepatitis C virus infection in northern India is seen more commonly in men, the middle aged and people from rural background and low to middle socioeconomic status. The common possible risk factors are dental treatment and exposure to reused syringes and needles. Although the most common presentation is incidental detection, a large number of patients present with advanced liver disease. PMID- 28921678 TI - Ipsilateral corticotectal projections from the primary, premotor and supplementary motor cortical areas in adult macaque monkeys: a quantitative anterograde tracing study. AB - The corticotectal projection from cortical motor areas is one of several descending pathways involved in the indirect control of spinal motoneurons. In non-human primates, previous studies reported that cortical projections to the superior colliculus (SC) originated from the premotor cortex (PM) and the primary motor cortex, whereas no projection originated from the supplementary motor area (SMA). The aim of the present study was to investigate and compare the properties of corticotectal projections originating from these three cortical motor areas in intact adult macaques (n = 9). The anterograde tracer biotinylated dextran amine was injected into one of these cortical areas in each animal. Individual axonal boutons, both en passant and terminaux, were charted and counted in the different layers of the ipsilateral SC. The data confirmed the presence of strong corticotectal projections from the PM. A new observation was that strong corticotectal projections were also found to originate from the SMA (its proper division). The corticotectal projection from the primary motor cortex was quantitatively less strong than that from either the premotor or SMAs. The corticotectal projection from each motor area was directed mainly to the deep layer of the SC, although its intermediate layer was also a consistent target of fairly dense terminations. The strong corticotectal projections from non-primary motor areas are in position to influence the preparation and planning of voluntary movements. PMID- 28921679 TI - Maternal immune activation leads to increased nNOS immunoreactivity in the brain of postnatal day 2 rat offspring. AB - Neuronal nitric oxide synthase (nNOS) is a key arginine metabolising enzyme in the brain, and nNOS-derived nitric oxide (NO) plays an important role in regulating glutamatergic neurotransmission. NO and its related molecules are involved in the pathogenesis of schizophrenia, and human genetic studies have identified schizophrenia risk genes encoding nNOS. This study systematically investigated how maternal immune activation (MIA; a risk factor for schizophrenia) induced by polyinosinic:polycytidylic acid affected nNOS immunoreactivity in the brain of the resulting male and female offspring at the age of postnatal day (PND) 2. Immunohistochemistry revealed a markedly increased intensity of nNOS-positive cells in the CA3 and dentate gyrus subregions of the hippocampus, the somatosensory cortex, and the striatum, but not the frontal cortex and hippocampal CA1 region, in the MIA offspring when compared to control group animals. There were no sex differences in the effect. Given the role of nNOS in glutamatergic neurotransmission and its functional relationship with glutamate NMDA receptors, increased nNOS immunoreactivity may indicate the up regulation of NMDA receptor function in MIA rat offspring at an early postnatal age. Future research is required to determine whether these changes contribute to the neuronal and behavioral dysfunction observed in both juvenile and adult MIA rat offspring. PMID- 28921680 TI - Measurement of urinary concentrations of the mycotoxins zearalenone and sterigmatocystin as biomarkers of exposure in mares. AB - Mycotoxins may affect animal health, including reproduction. Little is known about the clinical relevance of exposure of horses to contaminated feed. This study aimed at (i) monitoring the levels of the mycotoxins zearalenone (ZEN), with its metabolites alpha- and beta-zearalenol (alpha- and beta-ZOL), and sterigmatocystin (STC) in urine samples from thoroughbred mares in Japan and (ii) relating these findings to the potential effects on reproductive efficacy of breeding mares. Sixty-three urine samples of breeding mares from 59 breeding farms were used. Urine samples and reproductive records were collected from each mare when it was presented to the stallion station. Urinary concentrations of ZEN, alpha- and beta-ZOL, and STC were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). ZEN, alpha- and beta-ZOL were measurable in the urine of all examined mares, indicating the prevalence of ZEN in equine feeds. In seven of the 63 samples, STC was also detected at levels ranging from 1.3 to 18.0 pg/mg creatinine. No significant correlation between the concentrations of mycotoxins and pregnancy status was observed. In conclusion, measurement of mycotoxins in urine samples is a useful non-invasive method for monitoring the systemic exposure of mares to multiple mycotoxins. PMID- 28921682 TI - Construction of Condensed Polycyclic Aromatic Frameworks through Intramolecular Cycloaddition Reactions Involving Arynes Bearing an Internal Alkyne Moiety. AB - Facile synthetic methods for condensed polycyclic aromatic compounds via aryne intermediates are reported. The generation of arynes bearing a (3 arylpropargyl)oxy group from the corresponding o-iodoaryl triflate-type precursors efficiently afforded arene-fused oxaacenaphthene derivatives, which were formed through intramolecular [2+4] cycloaddition. Extending the method to the generation of arynes bearing a 1,3-diyne moiety led to a continuous generation of naphthalyne intermediate through the hexadehydro Diels-Alder reaction involving the aryne triple bond. This novel type of aryne-relay chemistry enabled the synthesis of a unique aminoarylated oxaacenaphthene derivative and highly ring-fused anthracene derivatives. PMID- 28921681 TI - Anti-Obesity Activity of Saringosterol Isolated from Sargassum muticum (Yendo) Fensholt Extract in 3T3-L1 Cells. AB - Saringosterol, a steroid isolated from Sargassum muticum, a brown edible alga widely distributed on the seashores of southern and eastern Korea, has been shown to exhibit anti-obesity effect. In this study, we investigated the anti-obesity activity of saringosterol through various experiments. The inhibitory effect of saringosterol on adipogenesis was evaluated via Oil Red O staining in 3T3-L1 preadipocytes. After confirming that saringosterol is not cytotoxic to these cells by using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, the effect of saringosterol on the expression of various adipogenesis related genes was analyzed via quantitative real-time polymerase chain reaction and western blotting. We demonstrated that saringosterol dose dependently inhibited adipocyte differentiation and expression of adipogenic marker genes such as adipocyte fatty acid-binding protein, adiponectin, resistin, and fatty acid synthase in 3T3-L1 cells. In addition, saringosterol significantly inhibited the mRNA and protein expression of peroxisome proliferator-activated receptor gamma and CCAAT enhancer-binding protein alpha in 3T3-L1 cells. Collectively, these findings indicate that saringosterol isolated from S. muticum exhibits anti obesity effect by inhibiting the expression of adipogenic transcription factors and marker genes and that it may be developed as a drug to suppress adipogenesis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28921683 TI - Corticospinal responses following strength training: a systematic review and meta analysis. AB - Strength training results in changes in skeletal muscle; however, changes in the central nervous system also occur. Over the last 15 years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation, have been used to study the neural adaptations to strength training. This review explored the hypothesis that the neural adaptations to strength training may be due to changes in corticospinal excitability and inhibition and, such changes, contribute to the gain in strength following strength training. A systematic review, according to PRISMA guidelines, identified studies by database searching, hand-searching and citation tracking between January 1990 and the first week of February 2017. Methodological quality of included studies was determined using the Downs and Black quality index. Data were synthesised and interpreted from meta-analysis. Nineteen studies investigating the corticospinal responses following strength training were included. Meta-analysis found that strength training increased strength [standardised mean difference (SMD) 0.84, 95% CI 0.55 to 1.13], decreased short-interval intracortical inhibition (SMD -1.00, 95% CI -1.84 to 0.17) and decreased the cortical silent period (SMD -0.66, 95% CI -1.00 to 0.32). Strength training had no effect on motor threshold (SMD -0.12, 95% CI 0.49 to 0.25), but a borderline effect for increased corticospinal excitability (SMD 0.27, 95% CI 0.00 to 0.54). In untrained healthy participants, the corticospinal response to strength training is characterised by reduced intracortical inhibition and cortical silent period duration, rather than changes in corticospinal excitability. These data demonstrate that strength training targets intracortical inhibitory networks within the primary motor cortex (M1) and corticospinal pathway, characterising an important neural adaptation to strength training. PMID- 28921684 TI - Generation of Stable Ruthenium(IV) Ketimido Complexes by Oxidative Addition of Oxime Esters to Ruthenium(II): Reactivity Studies Based on Electronic Properties of the Ru-N Bond. AB - The reaction of an oxime ester with [Ru(PPh3 )3 X2 ] proceeded smoothly at room temperature to afford a stable RuIV ketimido complex as oxidative adduct. The structure of the complex was unambiguously determined by X-ray crystallographic analysis, which showed an almost linear Ru-N-C array. The electronic properties of the nitrogen atom were estimated by DFT calculations, and the results suggested double-bond character of the Ru-N bond. Kinetic studies and consideration of the substituent effect on the oxime ester led to the proposal of a reaction mechanism involving oxidative addition, which could proceed by N,O chelating coordination to the Ru center prior to N-O bond cleavage. The obtained Ru ketimido complex could be transformed into a ruthenacycle by C-H activation by a concerted metalation-deprotonation mechanism in dichloromethane/methanol. Ru ketimido complexes with a tethered alkyne or alkene moiety underwent chloroamination of unsaturated C-C bonds followed by C-H activation, which resulted in the formation of a ruthenacycle. Considering the LUMO of an isolated Ru ketimido complex, the chloroamination should proceed by a synchronous 1,3 dipolar cycloaddition-type mechanism. Insight into the character and reactivity of Ru ketimido complexes will be helpful for developments in the catalytic transformation of oxime esters. PMID- 28921685 TI - Four-year incidence rate and predictors of root caries among community-dwelling south Brazilian older adults. AB - OBJECTIVE: This study aimed to assess the incidence density (ID) of new root caries lesions and restorations among community-living south Brazilian older adults and to assess its association with predictor variables. METHODS: We conducted a prospective cohort with a random sample of elders from the municipality of Carlos Barbosa, in south Brazil. Trained dentists performed interviews and oral examinations in 388 individuals at baseline, of which 273 were retained at follow-up 4 years later. Our outcome was root caries ID, with 100 root-years as its unit of measure. Demographic, biological and lifestyle predictors were tested with Poisson regression. RESULTS: The mean number of roots at baseline among participants was 7.0 (SD +/- 4.9) and the incidence rate per 100 root-year 4.9 (SD +/- 8.9). Incidence of root caries among these older Brazilians was of 47.3%. The associated factors with the incidence of root caries were age, geographic location of residence, frequency of tooth brushing and stimulated saliva flow rate. CONCLUSION: Age, external environment, personal practices and oral status were predictors of the incidence of root caries. Preventive strategies including the use of fluorides and instruction to improve the attitude and behaviour towards oral hygiene are needed. PMID- 28921686 TI - The effects of dynamical synapses on firing rate activity: a spiking neural network model. AB - Accumulating evidence relates the fine-tuning of synaptic maturation and regulation of neural network activity to several key factors, including GABAA signaling and a lateral spread length between neighboring neurons (i.e., local connectivity). Furthermore, a number of studies consider short-term synaptic plasticity (STP) as an essential element in the instant modification of synaptic efficacy in the neuronal network and in modulating responses to sustained ranges of external Poisson input frequency (IF). Nevertheless, evaluating the firing activity in response to the dynamical interaction between STP (triggered by ranges of IF) and these key parameters in vitro remains elusive. Therefore, we designed a spiking neural network (SNN) model in which we incorporated the following parameters: local density of arbor essences and a lateral spread length between neighboring neurons. We also created several network scenarios based on these key parameters. Then, we implemented two classes of STP: (1) short-term synaptic depression (STD) and (2) short-term synaptic facilitation (STF). Each class has two differential forms based on the parametric value of its synaptic time constant (either for depressing or facilitating synapses). Lastly, we compared the neural firing responses before and after the treatment with STP. We found that dynamical synapses (STP) have a critical differential role on evaluating and modulating the firing rate activity in each network scenario. Moreover, we investigated the impact of changing the balance between excitation (E) and inhibition (I) on stabilizing this firing activity. PMID- 28921687 TI - Multimodal treatment of a dog with disseminated cutaneous viral papillomatosis. AB - BACKGROUND: Canine papillomaviruses (CPVs) are associated with varied cutaneous manifestations. Spontaneous resolution typically occurs within one to 12 months. This case report describes multimodal treatment of a dog with severe disseminated papillomatosis. CLINICAL SUMMARY: An eight-month-old, female spayed, mixed breed dog was presented with a two month history of rapidly progressing papillomatosis and lack of response to oral azithromycin therapy. The dog was severely pruritic and malodorous; the weight and growth of lesions had progressed to affect the dog's gait and vision, and led to decreased quality of life. The dog was treated with substantial surgical debulking of lesions, followed by daily topical 5% imiquimod cream applied to nonexcisable lesions, and received five doses of an experimental recombinant CPV2 L1 vaccine every 14 days for 10 weeks. At the end of the 10 weeks, two lesions remained and were excised. No additional treatment was needed and 10 months post-treatment the dog was lesion free. CONCLUSION: New therapies need to be developed and assessed, in controlled treatment trials, to determine the efficacy of single modality therapeutic interventions for severe, persistent canine cutaneous papillomatosis. PMID- 28921688 TI - Outcomes of infants with a birthweight less than or equal to 500 g in Northern England: 15 years experience. AB - AIM: We aimed to evaluate mortality and short-term neonatal morbidity of babies born <=500 g cared for in the Northern Neonatal Network over a 15-year period. METHOD: Using regional databases, we identified all live-born babies >=22 weeks gestation and <=500 g, in North East England and North Cumbria from 1998 to 2012. We quantified major neonatal morbidities and survival to one year. RESULTS: We identified 104 live-born babies >=22 weeks gestation and <=500 g (birth prevalence 0.22/1000), of which 49 were admitted for intensive care. Overall one year survival was 11%, but survival for those receiving intensive care was 22%. There was significant short-term neonatal morbidity in survivors, in particular retinopathy of prematurity and chronic lung disease. CONCLUSION: Survival of babies born weighing <=500 g in this cohort remains poor despite advances in neonatal care, with considerable short-term neonatal morbidity in survivors. This could be due to a combination of attitudes and a rather conservative approach towards resuscitation and intensive care, and the intrinsic nature of these tiny babies. PMID- 28921689 TI - Associations between eating disorder related symptoms and participants' utilization of an individualized Internet-based prevention and early intervention program. AB - OBJECTIVE: Flexible, individualized interventions allow participants to adjust the intensity of support to their current needs. Between-persons, participants with greater needs can receive more intense support, within-persons, participants can adjust utilization to their current level of symptoms. The purpose of the present study was to analyze associations between ED-related symptoms and utilization of the individualized program ProYouth both between- and within persons, aiming to investigate whether participants adapt utilization intensity to their current needs. METHOD: Generalized estimated equations (GEEs) were used to analyze log data on program utilization (monthly page visits, monthly use of chats and forum) assessed via server logs and self-reported data on ED-related symptoms from N = 394 ProYouth participants who provided longitudinal data for at least two months. RESULTS: Between-persons, page visits per month were significantly associated with compensatory behavior, body dissatisfaction, and binge eating. Monthly use of the more intense modules with personal support chat and forum was associated with the frequency of compensatory behavior. Within persons, unbalanced nutrition and dieting showed the strongest associations with monthly page visits. Monthly use of chats and forum was significantly associated with compensatory behavior and unbalanced nutrition and dieting. DISCUSSION: Results indicate that program utilization is associated with ED-related symptoms between- as well as within-persons. The individualized, flexible approach of ProYouth thus seems to be a promising way for Internet-based provision of combined prevention and early intervention programs addressing ED. PMID- 28921690 TI - Tissue-specific and time-dependent clonal expansion of ENU-induced mutant cells in gpt delta mice. AB - DNA mutations play a crucial role in the origins of cancer, and the clonal expansion of mutant cells is one of the fundamental steps in multistage carcinogenesis. In this study, we correlated tumor incidence in B6C3F1 mice during the period after exposure to N-ethyl-N-nitrosourea (ENU) with the persistence of ENU-induced mutant clones in transgenic gpt delta B6C3F1 mice. The induced gpt mutations afforded no selective advantage in the mouse cells and could be distinguished by a mutational spectrum that is characteristic of ENU treatment. The gpt mutations were passengers of the mutant cell of origin and its daughter cells and thus could be used as neutral markers of clones that arose and persisted in the tissues. Female B6C3F1 mice exposed for 1 month to 200 ppm ENU in the drinking water developed early thymic lymphomas and late liver and lung tumors. To assay gpt mutations, we sampled the thymus, liver, lung, and small intestine of female gpt delta mice at 3 days, 4 weeks, and 8 weeks after the end of ENU exposure. Our results reveal that, in all four tissues, the ENU-induced gpt mutations persisted for weeks after the end of mutagen exposure. Clonal expansion of mutant cells was observed in the thymus and small intestine, with the thymus showing larger clone sizes. These results indicate that the clearance of mutant cells and the potential for clonal expansion during normal tissue growth depends on tissue type and that these factors may affect the sensitivity of different tissues to carcinogenesis. Environ. Mol. Mutagen. 58:592-606, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921691 TI - Quantitative determination and validation of octreotide acetate using 1 H-NMR spectroscopy with internal standard method. AB - Quantitative nuclear magnetic resonance (qNMR) is a well-established technique in quantitative analysis. We presented a validated 1 H-qNMR method for assay of octreotide acetate, a kind of cyclic octopeptide. Deuterium oxide was used to remove the undesired exchangeable peaks, which was referred to as proton exchange, in order to make the quantitative signals isolated in the crowded spectrum of the peptide and ensure precise quantitative analysis. Gemcitabine hydrochloride was chosen as the suitable internal standard. Experimental conditions, including relaxation delay time, the numbers of scans, and pulse angle, were optimized first. Then method validation was carried out in terms of selectivity, stability, linearity, precision, and robustness. The assay result was compared with that by means of high performance liquid chromatography, which is provided by Chinese Pharmacopoeia. The statistical F test, Student's t test, and nonparametric test at 95% confidence level indicate that there was no significant difference between these two methods. qNMR is a simple and accurate quantitative tool with no need for specific corresponding reference standards. It has the potential of the quantitative analysis of other peptide drugs and standardization of the corresponding reference standards. PMID- 28921692 TI - Mechanistic Studies on the Role of [CuII (CO3 )n ]2-2n as a Water Oxidation Catalyst: Carbonate as a Non-Innocent Ligand. AB - Recently it was reported that copper bicarbonate/carbonate complexes are good electro-catalysts for water oxidation. However, the results did not enable a decision whether the active oxidant is a CuIII or a CuIV complex. Kinetic analysis of pulse radiolysis measurements coupled with DFT calculations point out that CuIII (CO3 )n3-2n complexes are the active intermediates in the electrolysis of CuII (CO3 )n2-2n solution. The results enable the evaluation of E degrees [(CuIII/II (CO3 )n )aq ]~1.42 V versus NHE at pH 8.4. This redox potential is in accord with the electrochemical report. As opposed to literature suggestions for water oxidation, the present results rule out single-electron transfer from CuIII (CO3 )n3-2n to yield hydroxyl radicals. Significant charge transfer from the coordinated carbonate to CuIII results in the formation of C2 O62- by means of a second-order reaction of CuIII (CO3 )n3-2n . The results point out that carbonate stabilizes transition-metal cations at high oxidation states, not only as a good sigma donor, but also as a non-innocent ligand. PMID- 28921693 TI - Liquid-Cell Electron Microscopy of Adsorbed Polymers. AB - Individual macromolecules of polystyrene sulfonate and poly(ethylene oxide) are visualized with nanometer resolution using transmission electron microscopy (TEM) imaging of aqueous solutions with and without added salt, trapped in liquid pockets between creased graphene sheets. Successful imaging with 0.3 s per frame is enabled by the sluggish mobility of the adsorbed molecules. This study finds, validating others, that an advantage of this graphene liquid-cell approach is apparently to retard sample degradation from incident electrons, in addition to minimizing background scattering because graphene windows are atomically thin. Its new application here to polymers devoid of metal-ion labeling allows the projected sizes and conformational fluctuations of adsorbed molecules and adsorption-desorption events to be analyzed. Confirming the identification of the observed objects, this study reports statistical analysis of datasets of hundreds of images for times up to 100 s, with variation of the chemical makeup of the polymer, the molecular weight of the polymer, and the salt concentration. This observation of discrete polymer molecules in solution environment may be useful generally, as the findings are obtained using an ordinary TEM microscope, whose kind is available to many researchers routinely. PMID- 28921694 TI - Protease activated receptor 2 controls myelin development, resiliency and repair. AB - Oligodendrocytes are essential regulators of axonal energy homeostasis and electrical conduction and emerging target cells for restoration of neurological function. Here we investigate the role of protease activated receptor 2 (PAR2), a unique protease activated G protein-coupled receptor, in myelin development and repair using the spinal cord as a model. Results demonstrate that genetic deletion of PAR2 accelerates myelin production, including higher proteolipid protein (PLP) levels in the spinal cord at birth and higher levels of myelin basic protein and thickened myelin sheaths in adulthood. Enhancements in spinal cord myelin with PAR2 loss-of-function were accompanied by increased numbers of Olig2- and CC1-positive oligodendrocytes, as well as in levels of cyclic adenosine monophosphate (cAMP), and extracellular signal related kinase 1/2 (ERK1/2) signaling. Parallel promyelinating effects were observed after blocking PAR2 expression in purified oligodendrocyte cultures, whereas inhibiting adenylate cyclase reversed these effects. Conversely, PAR2 activation reduced PLP expression and this effect was prevented by brain derived neurotrophic factor (BDNF), a promyelinating growth factor that signals through cAMP. PAR2 knockout mice also showed improved myelin resiliency after traumatic spinal cord injury and an accelerated pattern of myelin regeneration after focal demyelination. These findings suggest that PAR2 is an important controller of myelin production and regeneration, both in the developing and adult spinal cord. PMID- 28921696 TI - Exome sequencing identifies a TCF4 mutation in a Chinese pedigree with symmetrical acral keratoderma. AB - BACKGROUND: Symmetrical acral keratoderma (SAK) is a rare skin disorder and its pathogenesis and inheritability are unknown. OBJECTIVES: To investigate the inheritance and pathogenesis of SAK. METHODS: Four SAK cases occurred in a four generation Chinese family. Exome sequencing identified SNPs with potential SAK related mutations, and a potentially responsible gene transcription factor 4 (TCF4) was identified. TCF4 was then sequenced in all 11 family members, and pedigree analysis was performed. Histopathology and immunohistochemistry evaluated TCF4 expression in skin lesions. The gene mutation was investigated in human keratinocytes for keratin-related protein expression. RESULTS: A novel heterozygous missense mutation, c.85C>A (p.Pro29Thr) was found in TCF4. The mutation showed autosomal dominant inheritance and perfectly cosegregated with the SAK phenotype in all family members. In skin lesions, TCF4 was present in the cytoplasm and membranes of the basal layer, the stratum spinosum and the stratum granulosum of the epidermis. The mutant TCF4 induced overexpression of differentiation markers including KRT1, KRT14, loricrin and involucrin. CONCLUSIONS: A SAK-related gene mutation in TCF4 may function through transcriptional regulation of keratin. PMID- 28921695 TI - Frequency-dependent regulation of intrinsic excitability by voltage-activated membrane conductances, computational modeling and dynamic clamp. AB - As one of the most unique properties of nerve cells, their intrinsic excitability allows them to transform synaptic inputs into action potentials. This process reflects a complex interplay between the synaptic inputs and the voltage dependent membrane currents of the postsynaptic neuron. While neurons in natural conditions mostly fire under the action of intense synaptic bombardment and receive fluctuating patterns of excitation and inhibition, conventional techniques to characterize intrinsic excitability mainly utilize static means of stimulation. Recently, we have shown that voltage-gated membrane currents regulate the firing responses under current step stimulation and under physiologically more realistic inputs in a differential manner. At the same time, a multitude of neuron types have been shown to exhibit some form of subthreshold resonance that potentially allows them to respond to synaptic inputs in a frequency-selective manner. In this study, we performed virtual experiments in computational models of neurons to examine how specific voltage-gated currents regulate their excitability under simulated frequency-modulated synaptic inputs. The model simulations and subsequent dynamic clamp experiments on mouse hippocampal pyramidal neurons revealed that the impact of voltage-gated currents in regulating the firing output is strongly frequency-dependent and mostly affecting the synaptic integration at theta frequencies. Notably, robust frequency-dependent regulation of intrinsic excitability was observed even when conventional analysis of membrane impedance suggested no such tendency. Consequently, plastic or homeostatic regulation of intrinsic membrane properties can tune the frequency selectivity of neuron populations in a way that is not readily expected from subthreshold impedance measurements. PMID- 28921697 TI - Cross-country skiing is associated with lower all-cause mortality: A population based follow-up study. AB - The prospective relationship between leisure-time cross-country skiing and any fatal events is uncertain. We aimed to assess the associations of leisure-time cross-country skiing habits with the risk of all-cause mortality in a general population. A 12-month physical activity questionnaire was used at baseline to assess the frequency, average duration, and intensity of cross-country skiing in a prospective population-based cohort of 2087 middle-aged men from eastern Finland. Hazard ratios (HRs; 95% confidence intervals) were calculated for all cause mortality. During a median (interquartile range) follow-up of 26.1 (18.7 28.0) years, 1028 all-cause mortality outcomes were recorded. In analyses adjusted for several established risk factors and other potential confounders, when compared to men who did not do any cross-country skiing, the HRs (95% CIs) of all-cause mortality were 0.84 (0.73-0.97) and 0.80 (0.67-0.96) for men who did 1-200 and >200 metabolic equivalent-hours per year of cross-country skiing, respectively. Similarly, compared to men who did not do any cross-country skiing, the corresponding adjusted HRs (95% CIs) for all-cause mortality were 0.84 (0.72 0.97) and 0.82 (0.69-0.97) for men who did 1-60 min/wk and >60 min/wk of cross country skiing, respectively. The associations were similar across several subgroups, except for evidence of effect modification by body mass index and history of diabetes. Total volume as well as duration of leisure-time cross country skiing is each inversely and independently associated with all-cause mortality in a middle-aged Caucasian male population. PMID- 28921698 TI - A Reduced Graphene Oxide/Disodium Terephthalate Hybrid as a High-Performance Anode for Sodium-Ion Batteries. AB - As a promising candidate for large-scale energy storage systems, sodium-ion batteries (SIBs) are experiencing a rapid development. Organic conjugated carboxylic acid anodes not only have tailorable electrochemical properties but also are easily accessible. However, the low stability and electrical conductivity hamper their practical applications. In this study, disodium terephthalate (Na2 TP), the most favorable organic conjugated carboxylic acid anode material for SIBs, was proposed to integrate with graphene oxide (GO) by an anti-solvent precipitation process, which ensures the uniform and tight coating of GO on the Na2 TP surface. GO is electrochemically reduced during the first several cycles of the electrochemical measurement, which buffers the volume change and improves the electrical conductivity of Na2 TP, resulting in a better cyclic and rate performance. The incorporation of only 5 wt % GO onto Na2 TP leads to a reversible capability of 235 mA h g-1 after 100 cycles at a current rate of 0.1 C, which is the best among the state of the art organic anodes for SIBs. The one-step synthesis together with the low costs of the raw materials show a promise for the scalable preparation of anode materials for practical SIBs. PMID- 28921699 TI - Morphological determinants of signal carrier frequency in katydids (Orthoptera): a comparative analysis using biophysical evidence of wing vibration. AB - Male katydids produce mating calls by stridulation using specialized structures on the forewings. The right wing (RW) bears a scraper connected to a drum-like cell known as the mirror and a left wing (LW) that overlaps the RW and bears a serrated vein on the ventral side, the stridulatory file. Sound is generated with the scraper sweeping across the file, producing vibrations that are amplified by the mirror. Using this sound generator, katydids exploit a range of song carrier frequencies (CF) unsurpassed by any other insect group, with species singing as low as 600 Hz and others as high as 150 kHz. Sound generator size has been shown to scale negatively with CF, but such observations derive from studies based on few species, without phylogenetic control, and/or using only the RW mirror length. We carried out a phylogenetic comparative analysis involving 94 species of katydids to study the relationship between LW and RW components of the sound generator and the CF of the male's mating call, while taking into account body size and phylogenetic relationships. The results showed that CF negatively scaled with all morphological measures, but was most strongly related to components of the sound generation system (file, LW and RW mirrors). Interestingly, the LW mirror (reduced and nonfunctional) predicted CF more accurately than the RW mirror, and body size is not a reliable CF predictor. Mathematical models were verified on known species for predicting CF in species for which sound is unknown (e.g. fossils or museum specimens). PMID- 28921700 TI - Low-dose fractionated irradiation promotes axonal regeneration beyond reactive gliosis and facilitates locomotor function recovery after spinal cord injury in beagle dogs. AB - Injury to the adult central nervous system (CNS) results in the formation of glial scar tissues. Glial scar-induced failure of regenerative axon pathfinding may limit axon regrowth beyond the lesion site and cause incorrect reinnervation and dystrophic appearance of stalled growth after CNS trauma. Glial scars also upregulate chondroitin sulphate proteoglycans (CSPGs) and expression of proinflammatory factor(s) that form a barrier to axonal regeneration. Therefore, interventions for glial scarring are an attractive strategy for augmenting axonal sprouting and regeneration and overcoming the physical and molecular barriers impeding functional repair. The glial reaction occurs shortly after spinal cord injury (SCI) and can persist for days or weeks with upregulation of cell cycle proteins. In this study, we utilised Beagle dogs to establish a preclinical SCI model and examine the efficacy of low-dose fractionated irradiation (LDI) treatment, which was performed once a day for 14 days (2 Gy per dose, 28 Gy in total). Low-dose fractionated irradiation is a stable method for suppressing cell activation and proliferation through interference in the cell cycle. Our results demonstrated that LDI could reduce astrocyte and microglia activation/proliferation and attenuate CSPGs and IL-1beta expression. Low-dose fractionated irradiation also promoted and provided a pathway for long-distance axon regeneration beyond the lesion site, induced reinnervation of axonal targets and restored locomotor function after SCI in Beagle dogs. Taken together, our findings suggest that LDI would be a promising therapeutic strategy for targeting glial scarring, promoting axon regeneration and facilitating reconstruction of functional circuits after SCI. PMID- 28921701 TI - An exception among diatoms: unique organization of genes involved in isoprenoid biosynthesis in Rhizosolenia setigera CCMP 1694. AB - The marine diatom Rhizosolenia setigera is unique among this group of microalgae given that it is only one of a handful of diatom species that can produce highly branched isoprenoid (HBI) hydrocarbons. In our efforts to determine distinguishing molecular characteristics in R. setigera CCMP 1694 that could help elucidate the underlying mechanisms for its ability to biosynthesize HBIs, we discovered the occurrence of independent genes encoding for two isopentenyl diphosphate isomerases (RsIDI1 and RsIDI2) and one squalene synthase (RsSQS), enzymes that catalyze non-consecutive steps in isoprenoid biosynthesis. These genes are peculiarly fused in all other genome-sequenced diatoms to date, making their organization in R. setigera CCMP 1694 a clear distinguishing molecular feature. Phylogenetic and sequence analysis of RsIDI1, RsIDI2, and RsSQS revealed that such an arrangement of individually transcribed genes involved in isoprenoid biosynthesis could have arisen through a secondary gene fission event. We further demonstrate that inhibition of squalene synthase (SQS) shifts the flux of exogenous isoprenoid precursors towards HBI biosynthesis suggesting the competition for isoprenoid substrates in the form of farnesyl diphosphate between the sterol and HBI biosynthetic pathways in this diatom. PMID- 28921702 TI - 3D analysis of mitosis distribution highlights the longitudinal zonation and diarch symmetry in proliferation activity of the Arabidopsis thaliana root meristem. AB - To date CYCB1;1 marker and cortex cell lengths have been conventionally used to determine the proliferation activity of the Arabidopsis root meristem. By creating a 3D map of mitosis distribution we showed that these markers overlooked that stele and endodermis save their potency to divide longer than the cortex and epidermis. Cessation of cell divisions is not a random process, so that mitotic activity within the endodermis and stele shows a diarch pattern. Mitotic activity of all root tissues peaked at the same distance from the quiescent center (QC); however, different tissues stopped dividing at different distances, with cells of the protophloem exiting the cell cycle first and the procambial cells being the last. The robust profile of mitotic activity in the root tip defines the longitudinal zonation in the meristem with the proliferation domain, where all cells are able to divide; and the transition domain, where the cell files cease to divide. 3D analysis of cytokinin deficient and cytokinin signaling mutants showed that their proliferation domain is similar to that of the wild type, but the transition domain is much longer. Our data suggest a strong inhibitory effect of cytokinin on anticlinal cell divisions in the stele. PMID- 28921704 TI - Editor's Picks. PMID- 28921703 TI - Poly(vinylidene fluoride-co-chlorotrifluoroethylene) Modification via Organocatalyzed Atom Transfer Radical Polymerization. AB - To address the challenge of metal contamination, a "graft from" approach via organocatalyzed atom transfer radical polymerization (O-ATRP) is developed to synthesize poly(vinylidene fluoride-co-chlorotrifluoroethylene) (P(VDF-co-CTFE)) graft copolymers. N-phenylphenothiazine is utilized as a model organic photoredox catalyst for catalyzing the (co)polymerization of methyl methacrylate (MMA), methacrylate (MA), and n-butyl acrylate (BA). By employing this technique, high temporal control of polymerization and graft content are achieved. A series of P(VDF-co-CTFE)-g-PMMA, P(VDF-co-CTFE)-g-PMA, and P(VDF-co-CTFE)-g-PBA is prepared under mild conditions. The resultant graft copolymer can be used as macroinitiator to re-initiate O-ATRP to synthesize P(VDF-co-CTFE)-g-(PMMA-b-PMA), which might exhibit the potential application as novel dielectric material. PMID- 28921705 TI - Green Tea Makes Polyphenol Nanoparticles with Radical-Scavenging Activities. AB - The constant demand for functional nanomaterials from natural biomass polymers usually requires new "green" synthetic strategies without using any foreign additives. Here, the green fabrication of a series of polyphenol nanoparticles (PNs) only from green tea extraction compounds is reported (i.e., tea polyphenols and theophylline). It is found that the nanoparticle formation process involves covalent copolymerization of monomers, as well as noncovalent self-assembly pathways. Additionally, the resulting PNs exhibit better free-radical scavenging activities compared with similar-sized, polydopamine-based synthetic melanin nanoparticles. This class of biomass-based functional nanoparticles is promising as green and effective antioxidant agents in general. PMID- 28921706 TI - Chronic endometritis: Really so relevant in repeated IVF failure? PMID- 28921707 TI - A visual approach of care pathways from the French nationwide SNDS database - from population to individual records: the ePEPS toolbox. AB - Secondary use of medical and administrative databases has become a powerful tool for epidemiological studies. In that respect, the recent access opening of French nationwide health record database or Systeme National des Donnees de Sante is a great opportunity to carry out comprehensive health studies at the country level. However, using this database is far from being straightforward for nonexpert data scientists; so, dedicated tools needed to be developed. Our contribution is focused on data management and visualization tools able to query and cope with the complexity of care pathways of patients. The scope of the toolbox presented below goes from interactive tools for building groups of patients to timeline representations of individual patient healthcare trajectories. PMID- 28921708 TI - Scopoletin Supplementation Ameliorates Steatosis and Inflammation in Diabetic Mice. AB - Scopoletin is a bioactive component in many edible plants and fruits. This study investigated the effects of scopoletin on hepatic steatosis and inflammation in a high-fat diet fed type 1 diabetic mice by comparison with metformin. Scopoletin (0.01%, w/w) or metformin (0.5%, w/w) was provided with a high-fat diet to streptozotocin-induced diabetic mice for 11 weeks. Both scopoletin and metformin lowered blood glucose and HbA1c , serum ALT, TNF-alpha and IL-6 levels, glucose intolerance, and hepatic lipid accumulation compared with the diabetic control group. Scopoletin or metformin down-regulated hepatic gene expression of triglyceride (Pparg, Plpp2, and Dgat2) and cholesterol (Hmgcr) synthesis as well as inflammation (Tlr4, Myd88, Nfkb1, Tnfa, and Il6), while it up-regulated Cyp7a1 gene. Hepatic PPARgamma and DGAT2 protein levels were also down-regulated in scopoletin or metformin group compared with the control group. Scopoletin or metformin also inhibited hepatic fatty acid synthase and phosphatidate phosphohydrolase activities. These results suggest that scopoletin protects against diabetes-induced steatosis and inflammation by inhibiting lipid biosynthesis and TLR4-MyD88 pathways. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28921709 TI - Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study. AB - We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein >=1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine <=1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure. PMID- 28921710 TI - Non-stick properties of thin-film coatings on dental-restorative instruments. AB - The non-stick properties of thin-film coatings on dental-restorative instruments were investigated by static contact-angle measurement using dental filler resin as well as by scanning electron microscopy of the amount of sticking dental restorative material. Furthermore, using a customized dipping measurement set-up, non-stick properties were evaluated by measuring force-by-time when the instrument was pulled out of restorative material. Minor improvements in non stick properties were obtained with commercial diamond-like carbon and commercial polytetrafluoroethylene-based coatings. Major improvements were obtained with an in-house fabricated superhydrophobic coating prepared by a multistep process consisting of surface microstructuring by etching in hydrogen fluoride (HF): hydrogen peroxide (H2 O2 ) (1:1; vol/vol), atomic layer deposition of a 7 nm coating of aluminium oxide and titanium oxide, and a self-assembled monolayer of fluorinated organosilicon. Superhydrophobic coatings provide a possible future solution to prevent unwanted adnerence of composite restorative material to dental instruments. PMID- 28921711 TI - FoxP expression identifies a Kenyon cell subtype in the honeybee mushroom bodies linking them to fruit fly alphabetac neurons. AB - The arthropod mushroom bodies (MB) are a higher order sensory integration centre. In insects, they play a central role in associative olfactory learning and memory. In Drosophila melanogaster (Dm), the highly ordered connectivity of heterogeneous MB neuron populations has been mapped using sophisticated molecular genetic and anatomical techniques. The MB-core subpopulation was recently shown to express the transcription factor FoxP with relevance for decision-making. Here, we report the development and adult distribution of a FoxP-expressing neuron population in the MB of honeybees (Apis mellifera, Am) using in situ hybridisation and a custom-made antiserum. We found the same expression pattern in adult bumblebees (Bombus terrestris, Bt). We also designed a new Dm transgenic line that reports FoxP transcriptional activity in the MB-core region, clarifying previously conflicting data of two other reporter lines. Considering developmental, anatomical and molecular similarities, our data are consistent with the concept of deep homology of FoxP expression in neuron populations coding reinforcement-based learning and habit formation. PMID- 28921712 TI - A review of NMR methods used in the study of the structure and dynamics of ionic liquids. AB - Recently, NMR spectroscopy has been emerging out as a powerful tool to study the structure and dynamics of ionic liquids (ILs) and ILs-Li+ salt mixtures. This mini-review primarily focuses on the applications of various NMR spectroscopic techniques such as self-diffusion measurements, NMR relaxometry, two-dimensional NMR, and other novel NMR approaches to study the structure and dynamics of ILs and its mixtures with lithium salts. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28921713 TI - Chebulinic Acid Isolated From the Fruits of Terminalia chebula Specifically Induces Apoptosis in Acute Myeloid Leukemia Cells. AB - Chebulinic acid, an ellagitannin found in the fruits of Terminalia chebula, has been extensively used in traditional Indian system of medicine. It has shown to have various biological activities including antitumor activity. The present study aims to investigate the cytotoxic potential of chebulinic acid in human myeloid leukemia cells. Interestingly, chebulinic acid caused apoptosis of acute promyelocytic leukemia HL-60 and NB4 cells but not K562 cells. In vitro antitumor effects of chebulinic acid were investigated by using various acute myeloid leukemia cell lines. Chebulinic acid treatment to HL-60 and NB4 cells induced caspase activation, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, chromatin condensation, and changes in the mitochondrial membrane permeability. Additionally, inhibition of caspase activation drastically reduced the chebulinic acid-induced apoptosis of acute promyelocytic leukemia cells. Our data also demonstrate that chebulinic acid-induced apoptosis in HL-60 and NB4 cells involves activation of extracellular signal-regulated kinases, which, when inhibited with ERK inhibitor PD98059, mitigates the chebulinic acid-induced apoptosis. Taken together, our findings exhibit the selective potentiation of chebulinic acid-induced apoptosis in acute promyelocytic leukemia cells. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28921714 TI - Fetal microchimerism in human brain tumors. AB - Sex differences in cancer incidence and survival, including central nervous system tumors, are well documented. Multiple mechanisms contribute to sex differences in health and disease. Recently, the presence of fetal-in-maternal microchimeric cells has been shown to have prognostic significance in breast and colorectal cancers. The frequency and potential role of these cells has not been investigated in brain tumors. We therefore selected two common primary adult brain tumors for this purpose: meningioma, which is sex hormone responsive and has a higher incidence in women, and glioblastoma, which is sex hormone independent and occurs more commonly in men. Quantitative PCR was used to detect the presence of male DNA in tumor samples from women with a positive history of male pregnancy and a diagnosis of either glioblastoma or meningioma. Fluorescence in situ hybridization for the X and Y chromosomes was used to verify the existence of intact male cells within tumor tissue. Fetal microchimerism was found in approximately 80% of glioblastoma cases and 50% of meningioma cases. No correlations were identified between the presence of microchimerism and commonly used clinical or molecular diagnostic features of disease. The impact of fetal microchimeric cells should be evaluated prospectively. PMID- 28921715 TI - A crisis in diabetes research funding. PMID- 28921716 TI - Corrigenda. PMID- 28921717 TI - Corrigenda. PMID- 28921718 TI - International Guest Scholar: Paving the way from reconstructive to regenerative surgery. PMID- 28921720 TI - Synthetic Metals. PMID- 28921721 TI - Effects of the availability of accurate proprioceptive information on older adults' postural sway and muscle co-contraction. AB - During conditions of increased postural instability, older adults exhibit greater lower limb muscle co-contraction. This response has been interpreted as a compensatory postural strategy, which may be used to increase proprioceptive information from muscle spindles or to stiffen the lower limb as a general response to minimise postural sway. The current study aimed to test these two hypotheses by investigating use of muscle co-contraction during sensory transitions that manipulated proprioceptive input. Surface EMG was recorded from the bilateral tibialis anterior and gastrocnemius medialis muscles, in young (aged 18-30) and older adults (aged 68-80) during blind-folded postural assessment. This commenced on a fixed platform (baseline: 2 min), followed by 3 min on a sway-referenced platform (adaptation) and a final 3 min on a fixed platform again (reintegration). Sensory reweighting was slower in older adults, as shown by a significantly larger and longer postural sway after-effect once a stable platform was restored. Muscle co-contraction showed similar after-effects, whereby older adults showed a larger increase in co-contraction once the stable platform had been restored, compared to young adults. This co-contraction after effect did not return to baseline until after 1 min. Our evidence for high muscle co-contraction during the reintroduction of veridical proprioceptive input suggests that increased co-contraction in older adults is not dependent on contemporaneous proprioceptive input. Rather, it is more likely that co contraction is a general postural strategy used to minimise postural sway, which is increased during this sensory transition. Future research should examine whether muscle co-contraction is typically a reactive or anticipatory response. PMID- 28921722 TI - Interactive effects of music tempi and intensities on grip strength and subjective affect. AB - Pretask music is widely used by athletes albeit there is scant empirical evidence to support its use. The present study extended a line of work into pretask music by examining the interactive effects of music tempo and intensity (volume) on the performance of a simple motor skill and subjective affect. A 2 * 2 within subjects factorial design was employed with an additional no-music control, the scores from which were used as a covariate. A sample of 52 male athletes (Mage = 26.1 +/- 4.8 years) was exposed to five conditions: fast/loud (126 bpm/80 dBA), fast/quiet (126 bpm/70 dBA), slow/loud (87 bpm/80 dBA), slow/quiet (87 bpm/70 dBA) music, and a no-music control. Dependent variables were grip strength, measured with a handgrip dynamometer, and subjective affect, assessed by use of the Affect Grid. The tempo and intensity components of music had interactive effects for grip strength but only main effects for subjective affect. Fast-tempo music played at a high intensity yielded the highest grip strength, while fast tempo music played at a low-intensity resulted in much lower grip strength (Mdiff. = -1.11 Force kg). For affective valence, there were main effects of tempo and intensity, with fast and loud music yielding the highest scores. For affective arousal, there was no difference between tempi although there was between intensities, with the high-intensity condition yielding higher scores. The present findings indicate the utility of fast/loud pretask music in enhancing affective valence and arousal in preparation for a simple or gross motor task. PMID- 28921723 TI - Effect of prophylactic cefalexin treatment on the development of bacterial infection in acute radiation-induced dermatitis in dogs: a blinded randomized controlled prospective clinical trial. AB - BACKGROUND: Acute radiation-induced dermatitis (ARID) is a common sequela of radiation therapy and carries the risk of secondary bacterial skin infection. No standard of care exists for managing canine ARID and evidence-based guidelines are lacking; however, prophylactic use of antibiotics is common. HYPOTHESIS/OBJECTIVES: To evaluate the impact of prophylactic cefalexin on the prevalence and severity of bacterial infection in canine ARID. ANIMALS: Seventeen dogs treated with definitive-intent radiotherapy. METHODS: All dogs were treated with definitive-intent radiation therapy (48-57.5 gray) targeted to the skin surface. Dogs were randomized to receive either prophylactic cefalexin (22 mg/kg twice daily) beginning halfway through the prescribed radiotherapy course (cohort A) or to serve as controls (cohort B). Aerobic skin cultures and surface cytological evaluation were performed at first onset of moist desquamation and one week following completion of radiation therapy. Skin toxicity grading and owner quality of life (QoL) questionnaires were performed weekly. The rate of infection, multidrug resistance status, toxicity severity and QoL between cohorts were compared. RESULTS: Staphylococcus schleiferi and S. pseudintermedius were the most frequent bacterial agents isolated in both cohorts. There was no significant difference in prevalence of bacterial infection or overall QoL between cohorts at either time point; however, multidrug-resistant infections were significantly increased in cohort A versus cohort B. Clinician- and client perceived severity of toxicity was significantly greater and median duration of moist desquamation was significantly longer in cohort A than cohort B. CONCLUSIONS AND CLINICAL IMPORTANCE: Prophylactic use of cefalexin for management of canine ARID is not recommended. PMID- 28921719 TI - Inflammation alters AMPA-stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons. AB - Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium-permeable versus impermeable AMPARs can result in disruptions of [Ca2+ ]i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca2+ ]i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, this study sought to determine whether a proinflammatory environment alters AMPA-stimulated [Ca2+ ]i through calcium-permeable AMPARs and/or L-type VGCCs in dopamine-2- and dopamine-1-expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA-stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist-induced [Ca2+ ]i was mediated by calcium-permeable AMPARs because the responses were completely blocked by a selective calcium-permeable AMPAR antagonist. We used isradipine, the highly selective L-type VGCC antagonist to determine the role of L-type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA-stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L-type VGCCs and calcium-permeable AMPARs are important mediators of this effect. PMID- 28921724 TI - "Discrete peaks" of excitability and map overlap reveal task-specific organization of primary motor cortex for control of human forearm muscles. AB - The primary motor cortex (M1) presents a somatotopic organization of body parts, but with overlap between muscle/movement representations. This distinct but overlapping M1 organization is believed to be important for individuated control and movement coordination, respectively. Discrete peaks of greater excitability observed within M1 might underpin organization of cortical motor control. This study aimed to examine interactions between M1 representations of synergist and antagonist forearm muscles, compare regions of greater excitability during different functional tasks, and compare characteristics of M1 representation recorded using surface and fine-wire (fw ) electrodes. Transcranial magnetic stimulation (TMS) was applied over M1 for mapping the representation of 4 forearm muscles (extensor carpi radialis brevis [ECRB], extensor digitorum communis, flexor carpi radialis, and flexor digitorum superficialis) during three tasks: rest, grip, and wrist extension in 14 participants. There are three main findings. First, discrete areas of peak excitability within the M1 representation of ECRBfw were identified during grip and wrist extension suggesting that different M1 areas are involved in different motor functions. Second, M1 representations of synergist muscles presented with greater overlap of M1 representations than muscles with mainly antagonist actions, which suggests a role in muscle coordination. Third, as larger normalized map volume and overlap were observed using surface than fine-wire electrodes, data suggest that cross talk from adjacent muscles compromised interpretation of recordings made with surface electrodes in response to TMS. These results provide a novel understanding of the spatial organization of M1 with evidence of "functional somatotopy." This has important implications for cortical control of movement. Hum Brain Mapp 38:6118-6132, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921726 TI - Chlamydia trachomatis regulates innate immune barrier integrity and mediates cytokine and antimicrobial responses in human uterine ECC-1 epithelial cells. AB - PROBLEM: Chlamydia trachomatis infection is the most common sexually transmitted bacterial infection worldwide and known to increase the risk for HIV acquisition. Few studies have investigated how infection of epithelial cells compromises barrier integrity and antimicrobial response. METHOD OF STUDY: ECC-1 cells, a human uterine epithelial cell line, were treated with live and heat-killed C. trachomatis. Epithelial barrier integrity measured as transepithelial resistance (TER), chemokines antimicrobial levels, and antimicrobial mRNA expression was measured by ELISA and Real-time RT-PCR. RESULTS: Epithelial barrier integrity was compromised when cells were infected with live, but not with heat-killed, C. trachomatis. IL-8 secretion by ECC-1 cells increased in response to live and heat killed C. trachomatis, while MCP-1, HBD2 and trappin2/elafin secretion decreased with live C. trachomatis. CONCLUSION: Live C. trachomatis suppresses ECC-1 innate immune responses by compromising the barrier integrity, inhibiting secretion of MCP-1, HBD2, and trappin-2/elafin. Differential responses between live and heat killed Chlamydia indicate which immune responses are dependent on ECC-1 infection rather than the extracellular presence of Chlamydia. PMID- 28921727 TI - Hot off the Press: Embedded Clinical Decision Support in Electronic Health Record Decreases Use of High-cost Imaging in the Emergency Department: EmbED Study. AB - This longitudinal before/after study of embedded clinical decision rules assessed the effects of clinical decision support on use of common imaging studies. Among high users, rates of computed tomograhy (CT) scan of the brain and CT of the cervical spine were reduced after implementation of embedded clinical decision instruments, while in low users, rates increased. This article summarizes the manuscript and the Skeptics Guide to Emergency Medicine podcast, as well as the ensuing social media/online discussion. PMID- 28921725 TI - Coenzyme Q10 Prevents the Interleukin-1 Beta Induced Inflammatory Response via Inhibition of MAPK Signaling Pathways in Rat Articular Chondrocytes. AB - Preclinical Research Osteoarthritis (OA) is a widely prevalent degenerative joint disease that severely impairs the health of the elderly population resulting in a heavy economic burden worldwide. Coenzyme Q10 (CoQ10) has shown anti-inflammatory effects in some diseases. The present study aimed to investigate if CoQ10 would suppress catabolic responses of interleukin (IL)-1beta-induced chondrocytes. Rat chondrocytes were cultured and pretreated with CoQ10, and then stimulated with or without IL-1beta (10 ng/ml). The expression and production of matrix metalloproteinase (MMP)-3, MMP-9, and MMP13 were determined using real-time PCR and Western blotting. CoQ10 suppressed MMP-3, MMP-9, and MMP13 production induced by IL-1beta, and markedly inhibited IL-1beta-induced MAPK pathways in rat chondrocytes. The present study provides insight into potential mechanisms by which CoQ10 protects against degeneration of cartilage in patients with OA, which may lead to new approaches for the treatment of OA.Drug Dev Res 78 : 403-410, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921728 TI - Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association? AB - Undifferentiated connective tissue diseases (UCTDs) are a heterogeneous group of disorders characterized by symptoms and signs suggestive of systemic autoimmune rheumatic disease (ARD), but which do not fulfill all the established criteria for definite diagnosis of a condition. Although a third of UCTDs can progress to a definite ARD within months or years, most UCTDs can remain stable for years with minimal disease activity. The annual incidence of UCTD in the general population ranges from 14 to 140 per 100 000 people. UCTDs are associated with the persistence of several circulating autoantibodies including antinuclear, antiphospholipid or antithyroid antibodies. Immunological evaluation of subjects with UCTDs suggests a proinflammatory state and dysregulation of the Th1/Th2 balance. Autoantibodies have well-known deleterious effects on placentation and have been associated with an increased risk of prematurity, fetal growth restriction (FGR), preeclampsia, and congenital atrioventricular heart block. Although epidemiological and biological data suggest a potential negative impact on reproductive outcomes, the relationship between UCTD and pregnancy outcomes has not been adequately studied. While awaiting definitive data from large studies, obstetricians should be aware that rheumatic disorders in their early, incomplete, or undifferentiated phases can adversely affect pregnancy outcomes, increasing the likelihood of pregnancy loss, FGR, preeclampsia, and prematurity. PMID- 28921729 TI - Long-range cortical dynamics: a perspective from the mouse sensorimotor whisker system. AB - In the mammalian neocortex, the capacity to dynamically route and coordinate the exchange of information between areas is a critical feature of cognitive function, enabling processes such as higher-level sensory processing and sensorimotor integration. Despite the importance attributed to long-range connections between cortical areas, their exact operations and role in cortical function remain an open question. In recent years, progress has been made in understanding long-range cortical circuits through work focused on the mouse sensorimotor whisker system. In this review, we examine recent studies dissecting long-range circuits involved in whisker sensorimotor processing as an entry point for understanding the rules that govern long-range cortical circuit function. PMID- 28921730 TI - Comparison of the percentages of CD4+ CD25high FOXP3+ , CD4+ CD25low FOXP3+ , and CD4+ FOXP3+ Tregs, in the umbilical cord blood of babies born to mothers with and without preeclampsia. AB - PROBLEM: Little is known about how preeclampsia affects regulatory T-cell count and functions in umbilical cord blood of babies born to preeclamptic mothers. Here, we analyze the percentage of CD4+ CD25high FOXP3+ , CD4+ CD25low FOXP3+ , and CD4+ FOXP3+ Tregs, in the umbilical cord blood of babies born to mothers with and without preeclampsia. METHOD OF STUDY: The percentage of umbilical cord blood CD4+ CD25high FOXP3+ , CD4+ CD25low FOXP3+ , and CD4+ FOXP3+ Tregs were analyzed by flow cytometry. RESULTS: CD4+ CD25high FOXP3+ Treg (%) and CD4+ FOXP3+ Treg (%) were significantly lower, while CD4+ CD25low (%) was significantly higher in umbilical cord blood of babies born to preeclamptic mothers. CONCLUSION: Preeclampsia is associated with immune dysregulation which leads to a deficiency in Treg (CD4+ CD25high FOXP3+ ) in the umbilical cord blood of babies born to preeclamptic mothers. PMID- 28921731 TI - Interobserver Agreement in Pediatric Cervical Spine Injury Assessment Between Prehospital and Emergency Department Providers. AB - BACKGROUND: Investigators have derived cervical spine injury (CSI) decision support tools from physician observations. There is a need to demonstrate that prehospital emergency medical services (EMS) providers can use these tools to appropriately determine the need for spinal motion restrictions and make field disposition decisions. OBJECTIVES: The objective was to determine the interobserver agreement between EMS and emergency department (ED) providers for CSI risk assessment variables and overall gestalt for CSI in children after blunt trauma. METHODS: This was a planned, substudy of a four-site, prospective cohort of children < 18 years transported by EMS to pediatric EDs for evaluation of CSI after blunt trauma. Inclusion criteria were trauma team activation and/or EMS initiated spinal motion restriction. Exclusion criteria were penetrating trauma, transfer to another facility for definitive care, state custody, or substantial language barrier. For each eligible child, the transporting EMS provider and treating ED provider independently recorded their clinical assessment for CSI. This included mechanism of injury and patient history and physical examination findings. We assessed each paired variable for interobserver agreement between EMS and ED provider using kappa (kappa) analysis. We considered variables with kappa lower confidence interval values >=0.4 to have moderate or better agreement. RESULTS: We obtained 1,372 paired observations for 29 variables. After finding prevalence and observer bias were adjusted for, all variables achieved moderate to better agreement including eight variables previously shown to be independently associated with CSI in children: diving mechanism, high-risk motor vehicle collision, altered mental status, focal neurologic findings, neck pain, torticollis, substantial torso injury, and predisposing medical condition. EMS and ED providers, however, showed less than moderate agreement for their overall gestalt for CSI in children. Of note, both EMS and ED providers did not assess for neck pain, inability to move the neck, and/or cervical spine tenderness in more than 10% of study patients. CONCLUSIONS: Emergency medical services and ED providers achieved at least moderate agreement in the assessment of CSI risk factors in children after blunt trauma. However, EMS and ED providers did not achieve moderate agreement on gestalt for CSI and some risk factors went unassessed by providers. These findings support the development of a pediatric CSI risk assessment tool for EMS and ED providers to reduce interventions for those children at very low risk for CSIs while still identifying all children with injury. PMID- 28921732 TI - From medico-administrative databases analysis to care trajectories analytics: an example with the French SNDS. AB - Medico-administrative data like SNDS (Systeme National de Donnees de Sante) are not collected initially for epidemiological purposes. Moreover, the data model and the tools proposed to SNDS users make their in-depth exploitation difficult. We propose a data model, called the ePEPS model, based on healthcare trajectories to provide a medical view of raw data. A data abstraction process enables the clinician to have an intuitive medical view of raw data and to design a study specific view. This view is based on a generic model of care trajectory, that is a sequence of time stamped medical events for a given patient. This model is combined with tools to manipulate care trajectories efficiently. PMID- 28921733 TI - Effects of individual and partner factors on anxiety and depression in Taiwanese prostate cancer patients: A longitudinal study. AB - Studies exploring the mediating and predictive factors of anxiety and depression for prostate cancer patients in Eastern countries are scant. Guided by the transactional model of stress and coping, this study determined the predictors and mediators of anxiety and depression in prostate cancer patients. The participants comprised 115 prostate cancer patients and 91 partners. The patients and partners completed questionnaires regarding physical symptoms, disease appraisals, coping behaviours, anxiety and depression in the period before confirmation of treatment decisions and 1, 3, 6 and 12 months after treatment. The results revealed that partner anxiety engendered a stressful situation and aggravated patient anxiety. Patients' threat appraisals and affective-oriented coping behaviours mediated the relationships between their anxiety levels and those of their partners. The patients' most recent prostate-specific antigen (PSA) levels and hormonal symptoms were key predictors of their anxiety and depression levels. The patients' harm appraisals mediated the relationships between their most recent PSA levels and hormonal symptoms and depression. Their threat appraisals and affective-oriented coping behaviours mediated the relationships between their hormonal symptoms and anxiety and depression. To manage those key factors, reframing, appraising disease and improving coping behaviours may reduce anxiety and depression levels in prostate cancer patients. PMID- 28921734 TI - The extracellular signal-regulated kinase 1/2 triggers angiogenesis in human ectopic endometrial implants by inducing angioblast differentiation and proliferation. AB - PROBLEM: The role of extracellular signal-regulated kinase (ERK)1/2-mediated angiogenesis during endometriotic nidation is unknown. We posit that ERK1/2 induced angioblast differentiation and proliferation promotes ectopic endometrial angiogenesis. METHODS OF STUDY: Human eutopic and ectopic endometria were immunostained for total- (T-) or phosphorylated- (P-) ERK1/2 or double immunostained for P-ERK1/2-CD34 and PCNA-CD34. Estradiol (E2 ), cytokines, normal peritoneal fluid (NPF) or endometriotic peritoneal fluid (EPF) +/-PD98059, an ERK1/2 inhibitor, treaded primary human endometrial endothelial cells (HEECs) were evaluated by T-/P-ERK1/2 immunoblotting, MTT viability and tube formation assays. RESULTS: HEECs exhibited higher endothelial P-ERK1/2 immunoreactivity in ectopic vs eutopic endometria. Double-immunostained ectopic endometria displayed abundant CD34-positive angioblasts exhibiting strong P-ERK1/2 and PCNA immunoreactivity. EPF and vascular growth factor (VEGF)-A significantly increased HEEC proliferation and P-ERK1/2 levels. PD98059 reduced basal, EPF, and VEGF induced HEEC proliferation and promoted vascular stabilization following tube formation. CONCLUSION: Enhanced ERK1/2 activity in angioblasts by such peritoneal factors as VEGF, E2 induces proliferation to trigger ectopic endometrial angiogenesis. PMID- 28921735 TI - Three shades of grey: detecting brain abnormalities in children with autism using source-, voxel- and surface-based morphometry. AB - Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interactions, communication and stereotyped behaviour. Recent evidence from neuroimaging supports the hypothesis that ASD deficits in adults may be related to abnormalities in a specific frontal-temporal network [Autism-specific Structural Network (ASN)]. To see whether these results extend to younger children and to better characterize these abnormalities, we applied three morphometric methods on brain grey matter (GM) of children with and without ASD. We selected 39 sMRI images of male children with ASD and 42 typically developing (TD) from the Autism Brain Imaging Data Exchange database. We used source-based morphometry (SoBM), a whole-brain multivariate approach to identify GM networks, voxel-based morphometry (VBM), a voxel-wise comparison of the local GM concentration and surface-based morphometry (SuBM) for the estimation of the cortical parameters. SoBM showed a bilateral frontal-parietal-temporal network different between groups, including the inferior-middle temporal gyrus, the inferior parietal lobule and the postcentral gyrus; VBM returned differences only in the right temporal lobe; SuBM returned a thinning in the right inferior temporal lobe thinner in ASD, a higher gyrification in the right superior parietal lobule in TD and in the middle frontal gyrus in ASD. For the first time, we investigated the brain abnormalities in children with ASD using three morphometric techniques. The results were relatively consistent between methods, stressing the role of an Autism-specific Structural Network in ASD individuals. We also make methodological speculations on the relevance of using multivariate and whole-brain neuroimaging analysis to capture ASD complexity. PMID- 28921737 TI - Partnering to Change the World for People with Haemophilia: 7th Haemophilia Global Summit, Madrid, Spain 22-24 September 2016. PMID- 28921736 TI - Graphene Oxide (GO) as Stabilizer for Preparing Chirally Helical Polyacetylene/GO Hybrid Microspheres via Suspension Polymerization. AB - Hybrid materials consisting of polymers and graphene are gathering ever-growing interest. This article reports a novel methodology for preparing chirally helical polyacetylene/graphene hybrid microspheres (MPs) via suspension polymerization in which graphene oxide (GO) or alkynylated GO (M?GO) serves as a sole stabilizer. Such polymerizations show remarkable advantages in circumventing the difficulties in usual suspension polymerizations and especially in directly providing clean hybrid MPs. Scanning electron microscopy (SEM), Raman spectra, and electron dispersive spectroscopy indicate that graphene sheets cover the MPs through physical interaction (GO) or covalent bonds (M?GO). The hybrid MPs are also characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy, and thermogravimetric analysis. Circular dichroism spectra demonstrate that the polymer chains constituting the MPs adopt predominantly one-handed helices, endowing the MPs with intriguing optical activity. The established strategy opens a new approach for preparing hybrid MPs constructed by acetylenic polymers and GO. PMID- 28921738 TI - Partnering to change the world for people with haemophilia: 7th Haemophilia Global Summit, Madrid, Spain 22-24 September 2016. AB - The 7th Haemophilia Global Summit was held in Madrid, Spain, in September 2016. With a programme designed, for the 6th consecutive year, by a Scientific Steering Committee of haemophilia experts, the aim of the summit was to share optimal management strategies for haemophilia at all life stages and to provide an opportunity for specialists from across the haemophilia multidisciplinary care team to engage in discussion and debate with leading international experts on current and future areas of research. Topics covered ranged from the optimisation of haemophilia management, emerging issues in clinical care, practical approaches and future perspectives, in addition to patient engagement and empowerment in modern haemophilia care. PMID- 28921739 TI - A rapid review of needs assessment tools for post-treatment cancer survivors. AB - Relevant, comprehensive and psychometrically rigorous needs assessment tools are needed to ensure appropriate care is delivered to cancer survivors who have completed treatment. The aim of this rapid review was to identify and describe needs assessment tools that are used in cancer survivors post-treatment, assess their psychometric properties and describe their use in clinical care. The electronic databases Medline, Cochrane Library, CINAHL and PsycINFO were searched. Six studies were identified that described five needs assessment tools used in cancer survivors post-treatment. None of these tools covered all domains of unmet need nor demonstrated adequate evidence of all recommended criteria of validity and reliability. Few had been evaluated for use in a clinical environment. Out of the five tools, the Survivor Unmet Needs Survey (SUNS) showed the strongest psychometric properties. There is little empirical evidence available to guide recommendations on the most appropriate process of conducting needs assessment with cancer survivors once they have completed treatment. PMID- 28921740 TI - 5-HTTLPR moderates the association between interdependence and brain responses to mortality threats. AB - While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5-HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self-report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5-HTTLPR were scanned using fMRI while they performed a one-back task on death-related, death-unrelated negative, and neutral words. Participants' interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death related words in emotion-related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5-HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death-related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157-6171, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921741 TI - Chalcogen-Atom-Annulated Perylene Diimide Trimers for Highly Efficient Nonfullerene Polymer Solar Cells. AB - This communication reports the synthesis of two novel chalcogen-atom-annulated perylene diimide (PDI) trimers with twisted structures, TriPDI-S and TriPDI-Se, for efficient nonfullerene polymer solar cells. TriPDI-Se exhibits more compact molecular arrangement due to the stronger intermolecular interactions induced by the selenium atom. This selenium annulation endows TriPDI-Se with improved absorption and crystallinity in its blend film. The resulting devices exhibit enhanced Jsc of 17.15 mA cm-2 and fill factor (FF) of 66.8%, which are much higher than those of TriPDI-S devices (Jsc = 16.71 mA cm-2 ; FF = 63.6%). Although TriPDI-Se exhibits lower-lying energy levels, TriPDI-Se devices still obtain a higher Voc of 0.77 V compared to TriPDI-S devices (Voc = 0.74 V), which is mainly originated from the reduced recombination in the related devices. Finally, the power conversion efficiency is significantly elevated from 7.86% for TriPDI-S devices to 8.82% for TriPDI-Se devices. PMID- 28921742 TI - Processing of temporally patterned sounds in the auditory cortex of Seba's short tailed bat,Carollia perspicillata. AB - This article presents a characterization of cortical responses to artificial and natural temporally patterned sounds in the bat species Carollia perspicillata, a species that produces vocalizations at rates above 50 Hz. Multi-unit activity was recorded in three different experiments. In the first experiment, amplitude modulated (AM) pure tones were used as stimuli to drive auditory cortex (AC) units. AC units of both ketamine-anesthetized and awake bats could lock their spikes to every cycle of the stimulus modulation envelope, but only if the modulation frequency was below 22 Hz. In the second experiment, two identical communication syllables were presented at variable intervals. Suppressed responses to the lagging syllable were observed, unless the second syllable followed the first one with a delay of at least 80 ms (i.e., 12.5 Hz repetition rate). In the third experiment, natural distress vocalization sequences were used as stimuli to drive AC units. Distress sequences produced by C. perspicillata contain bouts of syllables repeated at intervals of ~60 ms (16 Hz). Within each bout, syllables are repeated at intervals as short as 14 ms (~71 Hz). Cortical units could follow the slow temporal modulation flow produced by the occurrence of multisyllabic bouts, but not the fast acoustic flow created by rapid syllable repetition within the bouts. Taken together, our results indicate that even in fast vocalizing animals, such as bats, cortical neurons can only track the temporal structure of acoustic streams modulated at frequencies lower than 22 Hz. PMID- 28921743 TI - Exercise training dose differentially alters muscle and heart capillary density and metabolic functions in an obese rat with metabolic syndrome. AB - NEW FINDINGS: What is the central question of this study? Regular exercise is recommended as a non-pharmacological approach for the prevention and treatment of metabolic syndrome. However, the impact of different combinations of intensity, duration and frequency of exercise on metabolic syndrome and microvascular density has not been reported. What is the main finding and its importance? We provide evidence on the impact of aerobic exercise dose on metabolic and microvascular alterations in an experimental model of metabolic syndrome induced by high-fat diet. We found that the exercise frequency and duration were the main factors affecting anthropometric and metabolic parameters and microvascular density in the skeletal muscle. Exercise intensity was related only to microvascular density in the heart. We evaluated the effect of the frequency, duration and intensity of exercise training on metabolic parameters and structural capillary density in obese rats with metabolic syndrome. Wistar-Kyoto rats were fed either a standard commercial diet (CON) or a high-fat diet (HFD). Animals that received the HFD were randomly separated into either a sedentary (SED) group or eight different exercise groups that varied according to the frequency, duration and intensity of training. After 12 weeks of aerobic exercise training, the body composition, aerobic capacity, haemodynamic variables, metabolic parameters and capillary density in the heart and skeletal muscle were evaluated. All the exercise training groups showed reduced resting systolic blood pressure and heart rate and normalized fasting glucose. The minimal amount of exercise (90 min per week) produced little effect on metabolic syndrome parameters. A moderate amount of exercise (150 min per week) was required to reduce body weight and improve capillary density. However, only the high amount of exercise (300 min per week) significantly reduced the amount of body fat depots. The three-way ANOVA showed a main effect of exercise frequency and duration for the improvement of metabolic syndrome and capillary density in skeletal muscle. Exercise intensity was a main factor in reversing microvascular rarefaction in the heart. PMID- 28921744 TI - Cholinergic basal forebrain structures are not essential for mediation of the arousing action of glutamate. AB - The cholinergic basal forebrain contributes to cortical activation and receives rich innervations from the ascending activating system. It is involved in the mediation of the arousing actions of noradrenaline and histamine. Glutamatergic stimulation in the basal forebrain results in cortical acetylcholine release and suppression of sleep. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing action of glutamate. To clarify this question, we administered N-methyl D-aspartate (NMDA), a glutamate agonist, into the basal forebrain in intact rats and after destruction of the cholinergic cells in the basal forebrain with 192 immunoglobulin (Ig)G-saporin. In eight Han-Wistar rats with implanted electroencephalogram/electromyogram (EEG/EMG) electrodes and guide cannulas for microdialysis probes, 0.23 MUg 192 IgG-saporin was administered into the basal forebrain, while the eight control animals received artificial cerebrospinal fluid. Two weeks later, a microdialysis probe targeted into the basal forebrain was perfused with cerebrospinal fluid on the baseline day and for 3 h with 0.3 mmNMDA on the subsequent day. Sleep-wake activity was recorded for 24 h on both days. NMDA exhibited a robust arousing effect in both the intact and the lesioned rats. Wakefulness was increased and both non-REM and REM sleep were decreased significantly during the 3-h NMDA perfusion. Destruction of the basal forebrain cholinergic neurones did not abolish the wake-enhancing action of NMDA. Thus, the cholinergic basal forebrain structures are not essential for the mediation of the arousing action of glutamate. PMID- 28921745 TI - Transcription factor CCAAT/enhancer-binding protein-beta upregulates microRNA, let-7f-1 in human endocervical cells. AB - PROBLEM: In endocervical epithelial cells (End1/E6E7), miRNA let-7f plays an important role in the control of innate immunity. The underlying molecular mechanism for let-7f regulation in these cells remains largely unclear. METHODS OF STUDY: let-7f was knocked down in End1/E6E7 cells using siRNA, and differential gene expression was analyzed by microarray. Differentially expressed genes were validated by qPCR and Western blot. Expression of let-7f was studied by qPCR after inhibition of C/EBPbeta with betulinic acid (BA) and pCMVbeta plasmid and after overexpression of C/EBPbeta with pCMVbeta+ plasmid. ChIP assay was performed to confirm binding of C/EBPbeta to let-7f promoter. Levels of Lin28A/B were checked by qPCR after similar treatment. RESULTS: let-7f knockdown (KD) affects the expression of many transcription factors (eg, C/EBPbeta) which are important regulators of immune responses. We observed let-7f-1 promoter to contain 6 C/EBPbeta binding sites. KD of C/EBPbeta led to decreased let-7f expression while overexpression of C/EBPbeta increased its expression. Treatment of End1/E6E7 cells with TLR-3 ligand, poly(I:C) increased binding of C/EBPbeta at binding sites 3, 5, and 6. Expression of Lin28A/B also changed upon inhibition and overexpression of C/EBPbeta. Its expression is opposite to that of let-7f in End1/E6E7 cells. CONCLUSION: let-7f-1 is a direct target of transcription factor, C/EBPbeta in End1/E6E7 cells. PMID- 28921746 TI - Identification of occult active infection using PET-CT in a combined liver-kidney transplant candidate. AB - This case describes a patient being considered for combined liver-kidney transplantation for Caroli's disease with a failed renal transplant. A chronic septic focus could not be located with standard imaging techniques, such as ultrasonography and computed tomography. This case report highlights the observation that a retained non-functioning transplant can be the cause of fever of unknown origin and PET-CT can be useful in diagnosing these challenging cases. PMID- 28921747 TI - Pitfalls in accelerometer-based measurement of physical activity: The presence of reactivity in an adult population. AB - When a behavior is monitored, it is likely to change, even if no change may be intended. This phenomenon is known as measurement reactivity. We investigated systematic changes in accelerometer-based measures over the days of monitoring as an indicator of measurement reactivity in an adult population. One hundred seventy-one participants from the general population (65% women; mean age = 55 years, range: 42-65 years) wore accelerometers for 7 consecutive days to measure sedentary behavior and physical activity (PA). Latent growth models were used (a) to investigate changes in accelerometer wear time over the measurement days and (b) to identify measurement reactivity indicated by systematic changes in sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). Over the measurement days, participants reduced accelerometer wear time by trend (rate of change [b] = -4.7 min/d, P = .051, Cohen's d = .38), increased ST (b = 2.4 min/d, P = .018, d = .39), and reduced LPA (b = -2.4 min/d, P = .015, d = .38). Participants did not significantly reduce MVPA (P = .537). Our data indicated that accelerometry might generate reactivity. Small effects on ST and LPA were found. Thus, the validity of accelerometer-based data on ST and LPA may be compromised. Systematic changes observed in accelerometer wear time may further bias accelerometer-based measures. MVPA seems to be less altered due to the presence of an accelerometer. PMID- 28921748 TI - Increased risk organ transplantation in the pediatric population. AB - IRD organs are classified by the Public Health Service to be at above-average risk for harboring human immunodeficiency virus, hepatitis C, and hepatitis B. Traditionally underutilized, there exists even greater reluctance for their use in pediatric patients. We performed a retrospective analysis via the United Network for Organ Sharing database of all pediatric renal and hepatic transplants performed from 2004 to 2008 in the United States. Primary outcomes were patient and graft survival. Proportional hazards regression was performed to control for potentially confounding factors. Waitlist time, organ acceptance rates, and infectious transmissions were analyzed. There were 1830 SRD renal, 92 IRD renal, 1695 SRD hepatic, and 59 IRD hepatic transplants. There were no statistically significant differences in allograft or patient survival in either group. Acceptance rates of IRD organs were lower for kidney (1.5% IRD vs 4.82% SRD) and liver (1.99% IRD vs 4.51% SRD). One transmission of a bloodborne pathogen involving a pediatric recipient out of 7797 unique transplants was reported from 2008 to 2015. IRD organs appear to have equivalent outcomes. Increasing their utilization may improve access to transplant while decreasing wait times and circumventing waitlist morbidity and mortality. PMID- 28921749 TI - Functional specific-T-cell expansion after first cytomegalovirus reactivation predicts viremia control in allogeneic hematopoietic stem cell transplant recipients. AB - The use of preemptive antiviral therapy to prevent cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients might result in over-treatment, inducing drug-related toxicity and viral resistance. A search for predictive markers is needed to determine requirement for antiviral therapy. Clinical follow-up, in combination with the use of streptamers (STs) and cytokine-intracellular staining, could help to identify patients at high risk for CMV reactivations. To study the immune response and reactivation control by CMV-specific CD8+ T-cell (CMV-CTL) populations, we monitored 25 patients who have undergone allo-HSCT by using ST multimer and intracellular cytokine staining. Our study has revealed that the presence of functional CMV-specific T cells, determined by early interferon gamma production or by significant T-cell expansion after first CMV reactivation, correlated with short CMV viremia duration and low number of CMV reactivations. By contrast, the absence of functional CMV-CTLs does correlate with CMV recurrence. These results support that behavior of CMV-specific subpopulations after reactivation influences reactivations and can guide preemptive therapy. PMID- 28921750 TI - Successful treatment with intrauterine delivery of dexamethasone for repeated implantation failure. AB - PROBLEM: Effective therapy for endometrial receptivity of patients with repeated embryo implantation failure (RIF) is far undeveloped. Whether intrauterine perfusion of dexamethasone (DXM), local administration of drugs with less systematic side-effects, benefit for embryo implantation by suppressing uterine NK (uNK) cells to improve endometrial receptivity remains unknown. METHOD OF STUDY: Women with RIF were analyzed for the correlation between the percentage of uNK cells during implantation window and following clinical pregnancy rate to determine the appropriate range of uNK for embryo implantation. Women with RIF and extremely increased uNK cells were treated with transvaginal intrauterine perfusion of DXM. Quantification of uNK cells before and after this treatment was analyzed by immunohistochemistry staining for understanding potential underlying mechanism. Pregnancy outcome was evaluated for the efficiency and safety of this novel therapy. RESULTS: The clinical pregnancy rate was decreased if the percentage of uNK cells was higher than the 75th percentile (18.06%), which was considered as the cutoff value for increased uNK cells. All eight patients with increased uNK cells responded to DXM-induced decrease on uNK cells number, and seven got clinical pregnancy. Three delivered with a healthy baby at term without any pregnancy complication and three achieved an ongoing pregnancy, but one suffered from early miscarriage. CONCLUSION: We report for the first time the beneficial effect of intrauterine perfusion of DXM for patients with RIF characterized by high number of uNK cells. The potential mechanism is downregulation of the proportion of uNK cells, which may improve endometrial receptivity and enhance embryo implantation. PMID- 28921751 TI - Long-term complete remission in a patient with focal segmental glomerulosclerosis associated with Guillain-Barre syndrome. PMID- 28921752 TI - Bullous lesions in a haemodialysis patient. PMID- 28921754 TI - Corrigendum. PMID- 28921753 TI - Acute kidney injury in a renal transplant recipient due to concomitant use of vancomycin and foscarnet. PMID- 28921755 TI - Homozygous mutation in the NPHP3 gene causing foetal nephronophthisis. AB - We present a case of a foetal sonographic finding of hyper-echogenic kidneys, which led to a strategic series of genetic tests and identified a homozygous mutation (c.424C > T, p. R142*) in the NPHP3 gene. Our study provides a rare presentation of NPHP3-related ciliopathy and adds to the mutation spectrum of the gene, being the first one from Pakistani population. With a thorough literature review, it also advocates for molecular assessment of ciliopathies to improve risk estimate for future pregnancies, and identify predisposed asymptomatic carriers. PMID- 28921757 TI - The neurobiological bases of autism spectrum disorders: the R451C-neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum. AB - Autism spectrum disorders (ASDs) comprise a heterogeneous group of disorders with a complex genetic etiology. Current theories on the pathogenesis of ASDs suggest that they might arise from an aberrant synaptic transmission affecting specific brain circuits and synapses. The striatum, which is part of the basal ganglia circuit, is one of the brain regions involved in ASDs. Mouse models of ASDs have provided evidence for an imbalance between excitatory and inhibitory neurotransmission. Here, we investigated the expression of long-term synaptic plasticity at corticostriatal glutamatergic synapses in the dorsal striatum of the R451C-NL3 phenotypic mouse model of autism. This mouse model carries the human R451C mutation in the neuroligin 3 (NL3) gene that has been associated with highly penetrant autism in a Swedish family. The R451C-NL3 mouse has been shown to exhibit autistic-like behaviors and alterations of synaptic transmission in different brain areas. However, excitatory glutamatergic transmission and its long-term plasticity have not been investigated in the dorsal striatum so far. Our results indicate that the expression of long-term synaptic depression (LTD) at corticostriatal glutamatergic synapses in the dorsal striatum is impaired by the R451C-NL3 mutation. A partial rescue of LTD was obtained by exogenous activation of cannabinoid CB1 receptors or enhancement of the endocannabinoid tone, suggesting that an altered cannabinoid drive might underlie the deficit of synaptic plasticity in the dorsal striatum of R451C-NL3 mice. PMID- 28921756 TI - Temporal alignment of anticipatory motor cortical beta lateralisation in hidden visual-motor sequences. AB - Performance improves when participants respond to events that are structured in repeating sequences, suggesting that learning can lead to proactive anticipatory preparation. Whereas most sequence-learning studies have emphasised spatial structure, most sequences also contain a prominent temporal structure. We used MEG to investigate spatial and temporal anticipatory neural dynamics in a modified serial reaction time (SRT) task. Performance and brain activity were compared between blocks with learned spatial-temporal sequences and blocks with new sequences. After confirming a strong behavioural benefit of spatial-temporal predictability, we show lateralisation of beta oscillations in anticipation of the response associated with the upcoming target location and show that this also aligns to the expected timing of these forthcoming events. This effect was found both when comparing between repeated (learned) and new (unlearned) sequences, as well as when comparing targets that were expected after short vs. long intervals within the repeated (learned) sequence. Our findings suggest that learning of spatial-temporal structure leads to proactive and dynamic modulation of motor cortical excitability in anticipation of both the location and timing of events that are relevant to guide action. PMID- 28921758 TI - "The days when the anatomist commanded the respect and confidence of his medical colleagues solely on the basis of his knowledge of static morphology, are rapidly disappearing". PMID- 28921759 TI - A pedagogical framework for facilitating parents' learning in nurse-parent partnership. AB - Nursing work increasingly demands forms of expertise that complement specialist knowledge. In child and family nursing, this need arises when nurses work in partnership with parents of young children at risk. Partnership means working with parents in respectful, negotiated and empowering ways. Existing partnership literature emphasises communicative and relational skills, but this paper focuses on nurses' capacities to facilitate parents' learning. Referring to data from home visiting, day-stay and specialist toddler clinic services in Sydney, a pedagogical framework is presented. Analysis shows how nurses notice aspects of children, parents and parent-child interactions as a catalyst for building on parents' strengths, enhancing guided chance or challenging unhelpful constructs. Prior research shows the latter can be a sticking point in partnership, but this paper reveals diverse ways in which challenges are folded into learning process that position parents as agents of positive change. Noticing is dependent on embodied and communicative expertise, conceptualised in terms of sensory and reported channels. The framework offers a new view of partnership as mind expanding for the parent and specifies the nurse's role in facilitating this process. PMID- 28921761 TI - Risk factors leading to increased rehospitalization rates among adolescents admitted to an acute care child and adolescent psychiatric hospital. AB - PROBLEM: Suicide is the third leading cause of death in adolescents in the United States, with suicidal behavior peaking in adolescence. Suicidal and self-harming behavior is often chronic, with an estimated 15-30% of adolescents who attempt suicide having a second suicide attempt within a year. The focus of acute psychiatric hospitalization is on stabilization of these psychiatric symptoms resulting at times in premature discharge. Finding from studies based on high rehospitalization rates among adolescents admitted to an acute psychiatric hospital indicates that adolescents continue to experience crisis upon discharge from an acute psychiatric hospital, leading to the question of whether or not these adolescents are being discharged prematurely. METHODS: A chart review was performed on 98 adolescent clients admitted to an acute psychiatric hospital to identify risk factors that may increase rehospitalization among adolescents admitted to an acute psychiatric hospital. Clients admitted to the hospital within a 12-month time frame were compared to clients who were not readmitted during that 12-month period. RESULTS: History of self-harming behavior and length of stay greater than 5 days were found to be risk factors for rehospitalization. CONCLUSIONS: Adolescent clients who are admitted to an acute psychiatric hospital with a history of self-harming behavior and extended length of stay need to be identified and individualized treatment plans implemented for preventing repeat hospitalizations. PMID- 28921760 TI - Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences. AB - BACKGROUND AND AIMS: The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. DESIGN: Genome-wide association study (GWAS). SETTING: Multiple sites within Canada and the United States. PARTICIPANTS: AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n = 504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n = 450). MEASUREMENTS: Genome wide SNP genotyping, the NMR (phenotype) and population substructure and NMR covariates. FINDINGS: Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190 and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P = 1.47e-39; beta = 0.59 per C (versus T) allele, SE = 0.045), located ~9.5 kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in individuals of European descent. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n = 480). None of the hits were in UGT or OCT2 genes. CONCLUSIONS: Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours and tobacco-related disease risk. PMID- 28921763 TI - Implementation and Preliminary Clinical Outcomes of a Pharmacist-managed Venous Thromboembolism Clinic for Patients Treated With Rivaroxaban Post Emergency Department Discharge. AB - OBJECTIVE: The objective was to describe the implementation, work flow, and differences in outcomes between a pharmacist-managed clinic for the outpatient treatment of venous thromboembolism (VTE) using a non-vitamin K oral anticoagulant versus care by a primary care provider (PCP). METHODS: Patients in the studied health system that are diagnosed with low-risk VTE in the emergency department are often discharged without hospital admission. These patients are treated with a non-vitamin K oral anticoagulant and follow-up either in a pharmacist-managed VTE clinic or with their PCP. Pharmacists in the VTE clinic work independently under a collaborative practice agreement (CPA). An evaluation of 34 patients, 17 in each treatment arm, was conducted to compare the differences in treatment-related outcomes of rivaroxaban when managed by a pharmacist versus a PCP. RESULTS: The primary endpoint was a 6-month composite of anticoagulation treatment-related complications that included a diagnosis of major bleeding, recurrent thromboembolism, or fatality due to either major bleeding or recurrent thromboembolism. Secondary endpoints included number of hospitalizations, adverse events, and medication adherence. There was no difference in the primary endpoint between groups with one occurrence of the composite endpoint in each treatment arm (p = 1.000), both of which were recurrent thromboembolic events. Medication adherence assessment was formally performed in eight patients in the pharmacist group versus no patients in the control group. No differences were seen among other secondary endpoints. CONCLUSIONS: The pharmacist-managed clinic is a novel expansion of clinical pharmacy services that treats patients with low-risk VTEs with rivaroxaban in the outpatient setting. The evaluation of outcomes provides support that pharmacist managed care utilizing standardized protocols under a CPA may be as safe as care by a PCP. PMID- 28921764 TI - Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant. AB - Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC. PMID- 28921765 TI - Assessing fire impacts on the carbon stability of fire-tolerant forests. AB - The carbon stability of fire-tolerant forests is often assumed but less frequently assessed, limiting the potential to anticipate threats to forest carbon posed by predicted increases in forest fire activity. Assessing the carbon stability of fire-tolerant forests requires multi-indicator approaches that recognize the myriad ways that fires influence the carbon balance, including combustion, deposition of pyrogenic material, and tree death, post-fire decomposition, recruitment, and growth. Five years after a large-scale wildfire in southeastern Australia, we assessed the impacts of low- and high-severity wildfire, with and without prescribed fire (<=10 yr before), on carbon stocks in multiple pools, and on carbon stability indicators (carbon stock percentages in live trees and in small trees, and carbon stocks in char and fuels) in fire tolerant eucalypt forests. Relative to unburned forest, high-severity wildfire decreased short-term (five-year) carbon stability by significantly decreasing live tree carbon stocks and percentage stocks in live standing trees (reflecting elevated tree mortality), by increasing the percentage of live tree carbon in small trees (those vulnerable to the next fire), and by potentially increasing the probability of another fire through increased elevated fine fuel loads. In contrast, low-severity wildfire enhanced carbon stability by having negligible effects on aboveground stocks and indicators, and by significantly increasing carbon stocks in char and, in particular, soils, indicating pyrogenic carbon accumulation. Overall, recent preceding prescribed fire did not markedly influence wildfire effects on short-term carbon stability at stand scales. Despite wide confidence intervals around mean stock differences, indicating uncertainty about the magnitude of fire effects in these natural forests, our assessment highlights the need for active management of carbon assets in fire tolerant eucalypt forests under contemporary fire regimes. Decreased live tree carbon and increased reliance on younger cohorts for carbon recovery after high severity wildfire could increase vulnerabilities to imminent fires, leading to decisions about interventions to maintain the productivity of some stands. Our multi-indicator assessment also highlights the importance of considering all carbon pools, particularly pyrogenic reservoirs like soils, when evaluating the potential for prescribed fire regimes to mitigate the carbon costs of wildfires in fire-prone landscapes. PMID- 28921762 TI - Inhibition shapes the organization of hippocampal representations. AB - Hippocampal neurons become tuned to stimuli that predict behaviorally salient outcomes. This plasticity suggests that memory formation depends upon shifts in how different anatomical inputs can drive hippocampal activity. Here, I present evidence that inhibitory neurons can provide such a mechanism for learning related changes in the tuning of pyramidal cells. Inhibitory currents arriving on the dendrites of pyramidal cells determine whether an excitatory input can drive action potential output. Specificity and plasticity of this dendritic modulation allows for precise, modifiable changes in how afferent inputs are integrated, a process that defines a neuron's receptive field. In addition, feedback inhibition plays a fundamental role in biasing which excitatory neurons may be co-active. By defining the rules of synchrony and the rules of input integration, interneurons likely play an important role in the organization of memory representation within the hippocampus. PMID- 28921766 TI - Effects of zoochory on the spatial genetic structure of plant populations. AB - Spatial genetic structure (SGS) of plants results from the nonrandom distribution of related individuals. SGS provides information on gene flow and spatial patterns of genetic diversity within populations. Seed dispersal creates the spatial template for plant distribution. Thus, in zoochorous plants, dispersal mode and disperser behaviour might have a strong impact on SGS. However, many studies only report the taxonomic group of seed dispersers, without further details. The recent increase in studies on SGS provides the opportunity to review findings and test for the influence of dispersal mode, taxonomic affiliation of dispersers and their behaviour. We compared the proportions of studies with SGS among groups and tested for differences in strength of SGS using Sp statistics. The presence of SGS differed among taxonomic groups, with reduced presence in plants dispersed by birds. Strength of SGS was instead significantly influenced by the behaviour of seed dispersal vectors, with higher SGS in plant species dispersed by animals with behavioural traits that result in short seed dispersal distances. We observed high variance in the strength of SGS in plants dispersed by animals that actively or passively accumulate seeds. Additionally, we found SGS was also affected by pollination and marker type used. Our study highlights the importance of vector behaviour on SGS even in the presence of variance created by other factors. Thus, more detailed information on the behaviour of seed dispersers would contribute to better understand which factors shape the spatial scale of gene flow in animal-dispersed plant species. PMID- 28921768 TI - MicroRNA-326-3p ameliorates high glucose and ox-LDL-IC- induced fibrotic injury in renal mesangial cells by targeting FcgammaRIII. AB - AIM: The aim of the present study was to identify the regulatory relationship between miR-326-3p and FcgammaRIII, and to explore the involvement of miR-326 3p/FcgammaRIII/TGF-beta/Smad signalling pathway in fibrotic injury, which was induced by the high glucose (HG) and oxidized low density lipoprotein immune complex (ox-LDL-IC) in mouse glomerular mesangial cells (GMCs). METHODS: Dual luciferase reporter system and real time PCR (RT-PCR) were used to identify FcgammaRIII as a target gene of miR-326-3p. Lentiviral transduction was used to construct different expression of miR-326-3p in GMCs, which were divided into three groups: miR-326-3p mimics group (miR-326-3p group), miR-326-3p inhibitor group (miR-326-3p-inhibit group) and scramble control group (control group). Then, each group was stimulated by normal glucose (NG), HG, ox-LDL-IC and HG + ox LDL-IC, respectively. RT-PCR and western blot were used to measure the expressions of Col-I, CTGF, alpha-SMA, TGF-beta, Smad2/3 and pSmad2/3. RESULTS: FcgammaRIII was regulated negatively by miR-326-3p in GMCs under the condition of HG and ox-LDL-IC, which implied FcgammaRIII as a target gene of miR-326-3p. Furthermore, compared with normal glucose group, the expressions of Col-I, CTGF, alpha-SMA, TGF-beta and pSmad2/3 were higher under the condition of HG, ox-LDL-IC and HG + ox-LDL-IC (P < 0.05). In particular, miR-326-3p-inhibit groups exhibited the most significant increase (P < 0.05), while miR-326-3p could attenuate the increase (P < 0.05). CONCLUSION: FcgammaRIII was identified as a target gene of miR-326-3p. MiR-326-3p/FcgammaRIII/TGF-beta/Smad signaling pathway was investigated to be involved in the pathophysiology of renal fibrosis of DKD. PMID- 28921767 TI - Expansion of CD4 phenotype among CD160 receptor-expressing lymphocytes in murine pregnancy. AB - PROBLEM: CD160, a cell surface co-receptor, is capable of up- or downregulating cell proliferation, cytotoxicity or cytokine production on lymphocytes. Our aim was to investigate CD160+ lymphocytes in the periphery and at the maternal-foetal interface during murine pregnancy. METHOD OF STUDY: CD4+ , CD8+ and gamma/delta T cell phenotype, TIM3 co-expression and cytotoxic activity of CD160+ lymphocytes of pregnant BALB/c mice were analysed by flow cytometry. RESULTS: The percentage of CD160+ lymphocytes in the decidua was unchanged compared to non-pregnant endometrium; however, the ratio of CD4+ cells within the CD160 population was significantly increased. The co-expression of TIM3 co-inhibitory molecule and cytotoxicity of CD160+ cells were increased in the decidua. CONCLUSION: The expansion of CD4-expressing CD160+ decidual lymphocytes is a new observation suggesting a potential regulatory role of T-cell function during mouse pregnancy. The altered immunological character of CD160+ lymphocytes could play a role in the maintenance of murine pregnancy. PMID- 28921769 TI - Construction of Agropyron Gaertn. genetic linkage maps using a wheat 660K SNP array reveals a homoeologous relationship with the wheat genome. AB - Agropyron Gaertn. (P genome) is a wild relative of wheat that harbours many genetic variations that could be used to increase the genetic diversity of wheat. To agronomically transfer important genes from the P genome to a wheat chromosome by induced homoeologous pairing and recombination, it is necessary to determine the chromosomal relationships between Agropyron and wheat. Here, we report using the wheat 660K single nucleotide polymorphism (SNP) array to genotype a segregating Agropyron F1 population derived from an interspecific cross between two cross-pollinated diploid collections 'Z1842' [A. cristatum (L.) Beauv.] (male parent) and 'Z2098' [A. mongolicum Keng] (female parent) and 35 wheat-A. cristatum addition/substitution lines. Genetic linkage maps were constructed using 913 SNP markers distributed among seven linkage groups spanning 839.7 cM. The average distance between adjacent markers was 1.8 cM. The maps identified the homoeologous relationship between the P genome and wheat and revealed that the P and wheat genomes are collinear and relatively conserved. In addition, obvious rearrangements and introgression spread were observed throughout the P genome compared with the wheat genome. Combined with genotyping data, the complete set of wheat-A. cristatum addition/substitution lines was characterized according to their homoeologous relationships. In this study, the homoeologous relationship between the P genome and wheat was identified using genetic linkage maps, and the detection mean for wheat-A. cristatum introgressions might significantly accelerate the introgression of genetic variation from Agropyron into wheat for exploitation in wheat improvement programmes. PMID- 28921770 TI - Does an observer's empathy influence my pain? Effect of perceived empathetic or unempathetic support on a pain test. AB - The physiological and behavioural effects of empathy for other's pain have been widely investigated, while the opposite situation, i.e. the influence on one's pain of empathetic feedback from others, remains largely unexplored. Here, we assessed whether and how empathetic and unempathetic comments from observers modulate pain and associated vegetative reactions. In Study 1, conversations between observers of a pain study were recorded by professional actors. Comments were prepared to be perceived as empathetic, unempathetic or neutral, and were validated in 40 subjects. In a subsequent pain experiment (Study 2), changes in subjective pain and heart rate were investigated in 30 naive participants who could overhear the empathetic or unempathetic conversations pre-recorded in study 1. Subjective pain was significantly attenuated when hearing empathetic comments, as compared to both unempathetic and neutral conditions, while unempathetic comments failed to significantly modulate pain. Heart rate increased when hearing unempathetic remarks and when receiving pain stimuli, but heart acceleration to nociceptive stimulation was not correlated with pain ratings. These results suggest that empathetic feedback from observers has a positive influence on pain appraisal and that this effect may surpass the negative effect of unempathetic remarks. Negative remarks can either trigger feelings of guilt or induce irritation/anger, with antagonistic effects on pain that might explain inter individual variation. As in basal conditions heart rate and pain perception are positively correlated, their dissociation here suggests that changes in subjective pain were linked to a cognitive bias rather than changes in sensory input. PMID- 28921771 TI - Iron deficiency stress can induce MxNAS1 protein expression to facilitate iron redistribution in Malus xiaojinensis. AB - Iron (Fe) is a vital trace element in plants, and deficiency of this element in apple trees can reduce fruit quality. Nicotianamine (NA) is known to play an important role in Fe transport and endogenous hormone balance. In the present study, we investigated the role of a nicotianamine synthase 1 gene (MxNas1) in an apple species, Malus xiaojinensis, that has a more Fe-efficient genotype than other apple species and ecotypes. To characterise the response of M. xiaojinensis to Fe deficiency, we used quantitative Q-PCR to determine the level of expression of MxNas1 and Western blot to measure protein levels. Immunohistochemical staining and GFP fluorescence localisation of the MxNAS1 protein were also carried out. HPLC and polarised absorption spectrophotometry were performed to investigate the effects of overexpression of MxNas1 in order to elucidate the role of MxNAS1 in the cellular uptake of active Fe in tobacco suspension cells. We found that MxNas1 expression and protein levels were higher under Fe deficiency stress than under Fe sufficiency. Immunohistochemical staining showed that MxNAS1 was localised mainly in the epidermal and vascular tissues of the roots, vascular tissues of the stem and palisade cells of mature leaves, and in parenchyma cells of young leaves. MxNAS1 was mainly localised in the plasma membranes and vesicles of protoplasts. In addition, overexpression of MxNas1 in stable transgenic tobacco cells increased NA and active Fe content under Fe sufficiency. The results suggest that MxNas1 expression in M. xiaojinensis is induced in response to Fe deficiency stress, resulting in higher levels of the protein. MxNAS1 may be involved in the redistribution of Fe in M. xiaojinensis under Fe deficiency. PMID- 28921772 TI - Interplay of classic Exp and specific Vfm quorum sensing systems on the phenotypic features of Dickeya solani strains exhibiting different virulence levels. AB - Bacteria from the genus Dickeya cause severe symptoms on numerous economically important plants. Dickeya solani is the Dickeya species most frequently found on infected potato plants in Europe. D. solani strains from different countries show high genetic homogeneity, but significant differences in their virulence level. Dickeya species possess two quorum sensing (QS) mechanisms: the Exp system based on classic N-acyl-homoserine lactone (AHL) signals and a specific system depending on the production and perception of a molecule of unknown structure, Virulence Factor Modulating (VFM). To study the interplay between these two QS systems, five D. solani strains exhibiting different virulence levels were selected. Mutants were constructed by inactivating genes coding for each QS system. Double mutants were obtained by simultaneous inactivation of genes coding for both QS systems. Most of the D. solani mutants showed an attenuation of chicory maceration and a decreased production of plant cell wall-degrading enzymes (PCWDEs) and motility, but to different degrees depending on the strain. The VFM-QS system seems to regulate virulence in both D. solani and Dickeya dadantii, but the AHL-QS system has greater effects in D. solani than in D. dadantii. The inactivation of both QS systems in D. solani did not reveal any additive effect on the tested features. The inactivation of vfm genes generally has a more dominant effect relative to that of exp genes. Thus, VFM- and AHL-QS systems do not work in synergy to modulate the production of diverse virulence factors and the ability to macerate plant tissue. PMID- 28921773 TI - Performance of aneuploid backcross hybrids between the crop Brassica napus and its wild relative B. rapa. AB - Crossings between the diploid wild Brassica rapa (AA, 2n = 20) and the tetraploid cultivar B. napus (AACC, 2n = 38) can readily be made. Backcrosses to the wild B. rapa (BC1 ) produce aneuploids with variable chromosome numbers between 20 and 29. How does survival and performance relate to DNA content of plants? Growth of the BC1 plants was measured in the lab. One plant in the F1 self-pollinated spontaneously and produced abundant F2 seeds that were also examined. The number of C-chromosomes was estimated from DNA values obtained with flow cytometry. Average DNA value of the BC1 was similar to that of the parents, which shows that C-chromosomes do not reduce success of pollen or embryos. The average DNA value in the F2 was 13% higher than in the F1 , suggesting that extra C-chromosomes facilitated gamete success and/or embryo survival. Under both optimal and drought stress conditions growth and survival of BC1 hybrids was similar to that of B. rapa. No significant correlations existed between growth or survival and DNA value. Aneuploid plants were not inferior under the conditions of the growth room and may persist in nature. We discuss other factors, such as herbivory, that could prevent hybrid establishment in the field. PMID- 28921774 TI - Modulating vicarious tactile perception with transcranial electrical current stimulation. AB - Our capacity to share the experiences of others is a critical part of social behaviour. One process thought to be important for this is vicarious perception. Passively viewing touch activates some of the same network of brain regions as the direct experience of touch. This vicarious experience is usually implicit, but for some people, viewing touch evokes conscious tactile sensations (mirror touch synaesthesia). Recent work has attempted to induce conscious vicarious touch in those that do not normally experience these sensations, using transcranial direct current stimulation (tDCS). Anodal tDCS applied to primary somatosensory cortex (SI) was found to induce behavioural performance akin to mirror-touch synaesthesia on a visuotactile interference task. Here, we conducted two experiments that sought to replicate and extend these findings by examining: (i) the effects of tDCS and high-frequency transcranial random noise stimulation (tRNS) targeted at SI and temporo-parietal junction (TPJ) on vicarious tactile perception, (ii) the extent to which any stimulation effects were specific to viewing touch to humans vs. inanimate agents and (iii) the influence of visual perspective (viewing touch from one's own vs. another's perspective) on vicarious perception. In Experiment 1, tRNS targeted at SI did not modulate vicarious perception. In Experiment 2, tDCS targeted at SI, but not TPJ, resulted in some modulation of vicarious perception, but there were important caveats to this effect. Implications regarding mechanisms of vicarious perception are discussed. Collectively, the findings do not provide convincing evidence for the potential to modulate vicarious tactile perception with transcranial electrical current stimulation. PMID- 28921775 TI - What can Parents' Self-report of Reading Difficulties Tell Us about Their Children's Emergent Literacy at School Entry? AB - Research has linked family risk (FR) of reading difficulties (RD) with children's difficulties in emergent literacy development. This study is the first to apply parents' self-report of RD as a proxy for FR in a large sample (n = 1171) in order to test group differences in children's emergent literacy. Emergent literacy, the home literacy environment and children's interest in literacy and letters were compared across different groups of FR children around the school entry. The FR children performed lower in emergent literacy compared with not-FR children. Furthermore, when comparing FR children with one parent reporting RD and children with both parents reporting RD, moderate group differences were found in Emergent Literacy. Finally, parents' self-report of RD was a significant contributor of emergent literacy after controlling for the home literacy environment, children's gender, their interest in literacy and letters, months in kindergarten, vocabulary and parents' education. Our findings suggest that schools should monitor the reading development of children with parents self reporting RD closely - especially if both parents self-report RD. (c) 2017 The Authors. Dyslexia published by John Wiley & Sons Ltd. PMID- 28921776 TI - Transcriptional responses to short-term and long-term host plant experience and parasite load in an oligophagous beetle. AB - Oligophagous herbivores must adjust their enzymatic machinery to the different host plant species they consume. If different hosts are used from one generation to the next, adaptation may be highly plastic, while if a single host is used over several generations, there may be a longer-term response due to natural selection. Using an experimental evolutionary approach, we investigated effects of long-term experience vs. short-term responses to different host plants in the oligophagous mustard leaf beetle Phaedon cochleariae. After 26 generations of continuous feeding on either Brassica rapa, Nasturtium officinale or Sinapis alba, freshly hatched larvae were kept on these plants or moved to one of the other host plants for ten days. Global transcriptional patterns as shown by microarrays revealed that between 1% and 16.1% of all 25,227 putative genes were differentially expressed in these treatments in comparison with the control line constantly feeding on B. rapa. A shift back from S. alba to B. rapa caused the largest changes in gene transcription and may thus represent the harshest conditions. Infection rates with a gregarine parasite were intermediate in all lines that were constantly kept on one host, but much lower or higher when short term shifts to other host plants occurred. In conclusion, transcriptional plasticity in genes related to metabolism, digestion and general cellular processes plays a key role in long- and short-term responses of the beetle to changing host plant conditions, whereby the specific conditions also affect the interactions between the beetle host and its gregarine parasite. PMID- 28921777 TI - Doubly N-Confused [36]Octaphyrin(1.1.1.1.1.1.1.1): Isomerization, Bis-Metal Coordination, and Topological Chirality. AB - A novel [36]octaphyrin analogue embedding two N-confused pyrrole units demonstrated unique prototropy-coupled isomerization between the Figure-of-eight and dumbbell conformers. Upon bis-metal coordination, fixation of fully pi conjugated Figure-of-eight structures was achieved as referred from the X-ray crystal structure. Chirogenesis of the helical enantiomers was proved by intense circular dichroism (CD) response in the near infrared (NIR) region. PMID- 28921778 TI - Alcohol e-Help: study protocol for a web-based self-help program to reduce alcohol use in adults with drinking patterns considered harmful, hazardous or suggestive of dependence in middle-income countries. AB - BACKGROUND AND AIMS: Given the scarcity of alcohol prevention and alcohol use disorder treatments in many low and middle-income countries, the World Health Organization launched an e-health portal on alcohol and health that includes a Web-based self-help program. This paper presents the protocol for a multicentre randomized controlled trial (RCT) to test the efficacy of the internet-based self help intervention to reduce alcohol use. DESIGN: Two-arm randomized controlled trial (RCT) with follow-up 6 months after randomization. SETTING: Community samples in middle-income countries. PARTICIPANTS: People aged 18+, with Alcohol Use Disorders Identification Test (AUDIT) scores of 8+ indicating hazardous alcohol consumption. INTERVENTION AND COMPARATOR: Offer of an internet-based self help intervention, 'Alcohol e-Health', compared with a 'waiting list' control group. The intervention, adapted from a previous program with evidence of effectiveness in a high-income country, consists of modules to reduce or entirely stop drinking. MEASUREMENTS: The primary outcome measure is change in the Alcohol Use Disorders Identification Test (AUDIT) score assessed at 6-month follow-up. Secondary outcomes include self-reported the numbers of standard drinks and alcohol-free days in a typical week during the past 6 months, and cessation of harmful or hazardous drinking (AUDIT < 8). ANALYSIS: Data analysis will be by intention-to-treat, using analysis of covariance to test if program participants will experience a greater reduction in their AUDIT score than controls at follow up. Secondary outcomes will be analysed by (generalized) linear mixed models. Complier average causal effect and baseline observations carried forward will be used in sensitivity analyses. COMMENTS: If the Alcohol e-Health program is found to be effective, the potential public health impact of its expansion into countries with underdeveloped alcohol prevention and alcohol use disorder treatment systems world-wide is considerable. PMID- 28921779 TI - Local pre-adaptation to disturbance and inbreeding-environment interactions affect colonisation abilities of diploid and tetraploid Centaurea stoebe. AB - Primary colonisation in invasive ranges most commonly occurs in disturbed habitats, where anthropogenic disturbance may cause physical damage to plants. The tolerance to such damage may differ between cytotypes and among populations as a result of differing population histories (adaptive differentiation between ruderal verus natural habitats). Moreover, founder populations often experience inbreeding depression, the effects of which may increase through physical damage due to inbreeding-environment interactions. We aimed to understand how such colonisation processes differ between diploid and tetraploid Centaurea stoebe populations, with a view to understanding why only tetraploids are invasive. We conducted a clipping experiment (frequency: zero, once or twice in the growing season) on inbred versus outbred offspring originating from 37 C. stoebe populations of varying cytotype, range and habitat type (natural versus ruderal). Aboveground biomass was harvested at the end of the vegetation period, while re sprouting success was recorded in the following spring. Clipping reduced re sprouting success and biomass, which was significantly more pronounced in natural than in ruderal populations. Inbreeding depression was not detected under benign conditions, but became increasingly apparent in biomass when plants were clipped. The effects of clipping and inbreeding did not differ between cytotypes. Adaptive differentiation in disturbance tolerance was higher among populations than between cytotypes, which highlights the potential of pre-adaptation in ruderal populations during early colonisation on anthropogenically disturbed sites. While the consequences of inbreeding increased through clipping-mediated stress, they were comparable between cytotypes, and consequently do not contribute to understanding the cytotype shift in the invasive range. PMID- 28921780 TI - Factors associated with attrition in substance using patients enrolled in an intensive outpatient program. AB - BACKGROUND AND OBJECTIVES: Data suggest individuals with substance use disorders (SUD) have high rates of attrition from treatment and exhibit impairments on measures of executive functioning (EF). The primary aim of this pilot study was to investigate if EF is associated with attrition from a 1 month intensive outpatient program (IOP) for SUD, and examine the feasibility of implementing the project. METHODS: Baseline neurocognitive functioning was assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the self reported Behavior Rating Inventory of Executive Functioning (BRIEF-A) questionnaire. RESULTS: Thirty subjects enrolled in the pilot study: including 20 "completers" (age 39.5 +/- 13.1 years) and 10 "drop-outs" who discontinued the IOP prior to completion (age 32 +/- 11.1 years). IOP drop-out was associated with earlier age of substance use onset (all p-values <0.05) and male gender, as well as greater SUD, opiate use, and past week substance use. Overall a high level of executive dysfunction was found on the BRIEF-A and CANTAB assessments, and specific differences emerged between completers and drop outs. However, no statistically significant differences were found between these groups on measures of depression, anxiety, or ADHD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Overall, findings from this pilot study suggest high levels of self-reported executive dysfunction, but EF's predictive association with drop-out was limited. Measures of addiction severity were more strongly associated with attrition, suggesting potential utility of brief motivational interventions prior to commencing an IOP may improve retention. Further investigations with larger and more diverse samples are warranted. (Am J Addict 2017;26:780-787). PMID- 28921781 TI - Valganciclovir (VGCV) followed by cytomegalovirus (CMV) hyperimmune globulin compared to VGCV for 200 days in abdominal organ transplant recipients at high risk for CMV infection: A prospective, randomized pilot study. AB - BACKGROUND: With the advent of effective antivirals against cytomegalovirus (CMV), use of CMV hyperimmune globulin (HIG) has decreased. Although antiviral prophylaxis in patients at high risk for CMV is effective, many patients still have late infection, never developing antibodies sufficient to achieve immunity. Utilizing a combination of antiviral and CMV HIG may allow patients to achieve immunity and decrease late CMV infections. METHODS: This was a prospective randomized, open-label, pilot study comparing valganciclovir (VGCV) prophylaxis for 200 days vs VGCV for 100 days followed by CMV HIG in abdominal transplant recipients at high risk for CMV. The primary outcome was a comparison of late CMV disease. RESULTS: Forty patients were randomized to VGCV for 200 days (n = 20) or VGCV for 100 days followed by 3 doses of monthly CMV HIG (n = 20). Numerically, more overall CMV infections occurred in the CMV HIG group (45 vs 20%, P = .09). No differences in overall CMV infections or late CMV disease were seen between groups (20% vs 15%, P = 1.00 and 0 vs 0, P = 1.00). All CMV disease occurred within 200 days, with 63% occurring while patients were on VGCV. No differences were found in toxicities, graft function, or rejection between groups. Patients with CMV infection at any time had a higher body weight than those who did not have an infection (82 vs 95 kg, P = .049). CONCLUSION: Use of CMV HIG sequentially with prophylaxis may be an effective and affordable prophylactic regimen in abdominal transplant recipients at high risk for CMV, and warrants larger prospective study. Increased monitoring for patients with obesity may be warranted. PMID- 28921782 TI - Estimate your dose: RADDOSE-3D. AB - We present the current status of RADDOSE-3D, a software tool allowing the estimation of the dose absorbed in a macromolecular crystallography diffraction experiment. The code allows a temporal and spatial dose contour map to be calculated for a crystal of any geometry and size as it is rotated in an X-ray beam, and gives several summary dose values: among them diffraction weighted dose. This allows experimenters to plan data collections which will minimize radiation damage effects by spreading the absorbed dose more homogeneously, and thus to optimize the use of their crystals. It also allows quantitative comparisons between different radiation damage studies, giving a universal "x axis" against which to plot various metrics. PMID- 28921784 TI - The evolution of gonad expenditure and gonadosomatic index (GSI) in male and female broadcast-spawning invertebrates. AB - Sedentary broadcast-spawning marine invertebrates, which release both eggs and sperm into the water for fertilization, are of special interest for sexual selection studies. They provide unique insight into the early stages of the evolutionary succession leading to the often-intense operation of both pre- and post-mating sexual selection in mobile gonochorists. Since they are sessile or only weakly mobile, adults can interact only to a limited extent with other adults and with their own fertilized offspring. They are consequently subject mainly to selection on gamete production and gamete success, and so high gonad expenditure is expected in both sexes. We review literature on gonadosomatic index (GSI; the proportion of body tissue devoted to gamete production) of gonochoristic broadcast spawners, which we use as a proxy for gonad expenditure. We show that such taxa most often have a high GSI that is approximately equal in both sexes. When GSI is asymmetric, female GSI usually exceeds male GSI, at least in echinoderms (the majority of species recorded). Intriguingly, though, higher male GSI also occurs in some species and appears more common than female-biased GSI in certain orders of gastropod molluscs. Our limited data also suggest that higher male GSI may be the prevalent pattern in sperm casters (where only males release gametes). We explore how selection might have shaped these patterns using game theoretic models for gonad expenditure that consider possible trade-offs with (i) somatic maintenance or (ii) growth, while also considering sperm competition, sperm limitation, and polyspermy. Our models of the trade-off between somatic tissue (which increases survival) and gonad (which increases reproductive success) predict that GSI should be equal for the two sexes when sperm competition is intense, as is probably common in broadcast spawners due to synchronous spawning in aggregations. Higher female GSI occurs under low sperm competition. Sperm limitation appears unlikely to alter these conclusions qualitatively, but can also act as a force to keep male GSI high, and close to that of females. Polyspermy can act to reduce male GSI. Higher male than female GSI is predicted to be less common (as observed in the data), but can occur when ova/ovaries are sufficiently more resource-intensive to produce than sperm/testes, for which some evidence exists. We also show that sex-specific trade-offs between gonads and growth can generate different life-history strategies for males and females, with males beginning reproduction earlier. This could lead to apparently higher male GSI in empirical studies if immature females are included in calculations of mean GSI. The existence of higher male GSI nonetheless remains somewhat problematic and requires further investigation. When sperm limitation is low, we suggest that the natural logarithm of the male/female GSI ratio may be a suitable index for sperm competition level in broadcast spawners, and that this may also be considered as an index for internally fertilizing taxa. PMID- 28921783 TI - Barriers to listing for HIV-infected patients being evaluated for kidney transplantation. AB - Human immunodeficiency virus (HIV)-infected patients have excellent outcomes following kidney transplantation (KT) but still might face barriers in the evaluation and listing process. The aim of this study was to characterize the patient population, referral patterns, and outcomes of HIV-infected patients who present for KT evaluation. We performed a single-center retrospective cohort study of HIV-infected patients who were evaluated for KT. The primary outcome was time to determination of eligibility for KT. Between 2011 and 2015, 105 HIV infected patients were evaluated for KT. Of the 105 patients, 73 were listed for transplantation by the end of the study period. For those who were deemed ineligible, the most common reasons cited were active substance abuse (n = 7, 22%) and failure to complete the full transplant evaluation (n = 7, 22%). Our cohort demonstrated a higher proportion of HIV-infected patients eligible for KT than in previous studies, likely secondary to advances in HIV management. Among those who were denied access to transplantation, we identified that many were unable to complete the evaluation process, and that active substance abuse was common. Future prospective studies should examine reasons and potential interventions for the lack of follow-through and drug use we observed in this population. PMID- 28921786 TI - Lipid production and characterization by Mortierella (Umbelopsis) isabellina cultivated on lignocellulosic sugars. AB - AIMS: To study and characterize the lipids produced by Mortierella (Umbelopsis) isabellina, during its growth on mixtures of glucose and xylose. METHODS AND RESULTS: Glucose and xylose were utilized as carbon sources, solely or in blends, under nitrogen-limited conditions, in batch-flask trials (initial sugars at 80 g l-1 ). Significant lipid production (maximum lipid 17.8 g l-1 ; lipid in DCW 61.0% w/w; lipid on glucose consumed 0.23 g g-1 ) occurred on glucose employed solely, while xylose concentration in the growth medium was conversely correlated with lipid accumulation. With increasing xylose concentrations into the blend, lipid storage decreased while xylitol in significant concentrations (up to 24 g l 1 ) was produced. Irrespective of the sugar blend employed, significant quantities of endopolysaccharides were detected in the first growth steps (in the presence of nitrogen into the medium or barely after its disappearance) while lipids were stored thereafter. Neutral lipids, mainly composed of triacylglycerols, were the main microbial lipid fraction. Phospholipids were quantified both through fractionation and subsequent gravimetric determination and also through determination of phosphorus, and it seemed that the second method was more accurate. Phospholipids were mainly composed of phosphatidylcholine and another nonidentified compound presumably being phosphatidyldimethylethanolamine. CONCLUSIONS: Mortierella isabellina is suitable to convert lignocellulosic sugars into lipids. SIGNIFICANCE AND IMPACT OF THE STUDY: Differentiations between metabolism on xylose and glucose were reported. Moreover, this is one of the first reports indicating extensive analysis of microbial lipids produced by M. isabellina. PMID- 28921785 TI - Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy. AB - The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high-risk or very high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow-up time was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT. PMID- 28921787 TI - Myocardial bridging is associated with exercise-induced ventricular arrhythmia and increases in QT dispersion. AB - BACKGROUND: A myocardial bridge (MB) has been associated with ventricular arrhythmia and sudden death during exercise. QT dispersion (QTd) is a measure of abnormal repolarization and may predict ventricular arrhythmia. We investigated the frequency of ventricular arrhythmias during exercise and the QTd at rest and after exercise, in patients with an MB compared to a normal cohort. METHODS: We studied the rest and stress ECG tracings of patients with an MB suspected by focal septal buckling on exercise echocardiography (EE) (Echo-MB group, N = 510), those with an MB confirmed by another examination (MB group, N = 110), and healthy controls (Control group, N = 198). RESULTS: The frequency of exercise induced premature ventricular contractions (PVCs) was significantly higher in the Echo-MB and MB groups compared with the Control group (both p < .001). In all, 25 patients (4.9%) in the Echo-MB group, seven patients (6.4%) in the MB group and no patients in the Control group had exercise-induced non-sustained ventricular tachycardia (NSVT). There was no difference in the baseline QTd between the groups. In the Echo-MB and MB groups, QTd postexercise increased significantly when compared with baseline (both p < .001). Patients with NSVT had a higher frequency of male gender and an even greater increase in QTd with exercise compared with the non-NSVT group. DISCUSSION: There is an increased frequency of exercise-induced PVCs and NSVT in patients with MBs. Exercise significantly increases QTd in MB patients, with an even greater increase in QTd in MB patients with NSVT. Exercise in MB patients results in ventricular arrhythmias and abnormalities in repolarization. PMID- 28921788 TI - Characterization of Doubly Ionic Hydrogen Bonds in Protic Ionic Liquids by NMR Deuteron Quadrupole Coupling Constants: Differences to H-bonds in Amides, Peptides, and Proteins. AB - We present the first deuteron quadrupole coupling constants (DQCCs) for selected protic ionic liquids (PILs) measured by solid-state NMR spectroscopy. The experimental data are supported by dispersion-corrected density functional theory (DFT-D3) calculations and molecular dynamics (MD) simulations. The DQCCs of the N D bond in the triethylammonium cations are the lowest reported for deuterons in PILs, indicating strong hydrogen bonds between ions. The NMR coupling parameters are compared to those in amides, peptides, and proteins. The DQCCs show characteristic behavior with increasing interaction strength of the counterion and variation of the H-bond motifs. We report the similar presence of the quadrupolar splitting pattern and the narrow liquid line in the NMR spectra over large temperature ranges, indicating the heterogeneous nature of PILs. PMID- 28921789 TI - Re: Assessing cervical intraepithelial neoplasia as an indicator disease for HIV in a low endemic setting: a population-based register study. PMID- 28921790 TI - Authors' reply re: The fetal safety of clomiphene citrate: a population based retrospective cohort study. PMID- 28921791 TI - Pre-eclampsia is primarily a placental disorder: FOR: Pre-eclampsia is primarily a placental disorder. PMID- 28921792 TI - Re: A paradigm shift in the origin of ovarian cancer: the ovary is no longer to blame: Is the ovary to blame for tubal carcinoma? PMID- 28921793 TI - Authors' reply re: Painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey. PMID- 28921794 TI - Cerebral palsy; clinical safety of clomiphene citrate; BJOG's impact. PMID- 28921796 TI - Authors' reply re: Assessing cervical intraepithelial neoplasia as an indicator disease for HIV in a low endemic setting: a population-based register study. PMID- 28921795 TI - Re: Painful sex (dyspareunia) in women: prevalence and associated factors in a British population probability survey: Dyspareunia is a global public health problem! PMID- 28921798 TI - Pre-eclampsia is primarily a placental disorder: AGAINST: Pre-eclampsia: the heart matters. PMID- 28921799 TI - Re: The tale of Dr Steppenwolf and his great statistical machine - a modern parable. PMID- 28921801 TI - Complications, symptoms, quality of life and pregnancy in cholestatic liver disease. AB - Cholestatic liver diseases (CLDs) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end-stage liver disease. Many patients with CLD are diagnosed between the ages of 20-50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health-related quality of life (HRQOL) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prominent CLDs, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL. Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy. PMID- 28921800 TI - Initial testing (stage 1) of M6620 (formerly VX-970), a novel ATR inhibitor, alone and combined with cisplatin and melphalan, by the Pediatric Preclinical Testing Program. AB - BACKGROUND: M6620 is a novel inhibitor of the DNA damage repair enzyme ATR, and has potentiated the activity of cisplatin and irinotecan in non-small cell lung cancer and colon cancer xenografts, respectively. PROCEDURES: M6620 was tested in vitro at concentrations ranging from 1.0 nM to 10.0 MUM and at 75 nM in combination with cisplatin or melphalan. M6620 was tested against 24 solid tumor xenografts alone and in combination with cisplatin. Cisplatin was administered intraperitoneally on days 1 and 8 at a dose of 5 mg/kg. M6620 was administered intravenously on days 2 and 9 at 20 mg/m2 approximately 16 hr after cisplatin. RESULTS: The median relative IC50 (rIC50 ) value for M6620 was 0.19 MUM (range 0.03-1.38 MUM). M6620 reduced the mean IC50 of cisplatin and melphalan by 1.48- and 1.95-fold, respectively. M6620 as a single agent in vivo induced significant differences in event-free survival (EFS) distribution in 5 of 24 (21%) solid tumor xenografts, but induced no objective responses. Cisplatin as a single agent induced significant differences in EFS distribution compared to control in 18 of 24 (75%) solid tumor xenografts. Three objective responses to cisplatin were observed. The M6620 and cisplatin combination induced significant differences in EFS distribution compared to control in 21 of 24 (88%), with four objective responses. CONCLUSIONS: M6620 showed modest potentiation of cisplatin and melphalan activity for some cell lines. M6620 showed little single-agent activity and the addition of M6620 to cisplatin significantly prolonged time to event for a minority of tested xenografts across several histologies. PMID- 28921802 TI - Environmental DNA metabarcoding: Transforming how we survey animal and plant communities. AB - The genomic revolution has fundamentally changed how we survey biodiversity on earth. High-throughput sequencing ("HTS") platforms now enable the rapid sequencing of DNA from diverse kinds of environmental samples (termed "environmental DNA" or "eDNA"). Coupling HTS with our ability to associate sequences from eDNA with a taxonomic name is called "eDNA metabarcoding" and offers a powerful molecular tool capable of noninvasively surveying species richness from many ecosystems. Here, we review the use of eDNA metabarcoding for surveying animal and plant richness, and the challenges in using eDNA approaches to estimate relative abundance. We highlight eDNA applications in freshwater, marine and terrestrial environments, and in this broad context, we distill what is known about the ability of different eDNA sample types to approximate richness in space and across time. We provide guiding questions for study design and discuss the eDNA metabarcoding workflow with a focus on primers and library preparation methods. We additionally discuss important criteria for consideration of bioinformatic filtering of data sets, with recommendations for increasing transparency. Finally, looking to the future, we discuss emerging applications of eDNA metabarcoding in ecology, conservation, invasion biology, biomonitoring, and how eDNA metabarcoding can empower citizen science and biodiversity education. PMID- 28921803 TI - The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis. AB - Patients with cirrhosis and portal hypertension often develop complications from a variety of organ systems leading to a multiple organ failure. The combination of liver failure and portal hypertension results in a hyperdynamic circulatory state partly owing to simultaneous splanchnic and peripheral arterial vasodilatation. Increases in circulatory vasodilators are believed to be due to portosystemic shunting and bacterial translocation leading to redistribution of the blood volume with central hypovolemia. Portal hypertension per se and increased splanchnic blood flow are mainly responsible for the development and perpetuation of the hyperdynamic circulation and the associated changes in cardiovascular function with development of cirrhotic cardiomyopathy, autonomic dysfunction and renal dysfunction as part of a cardiorenal syndrome. Several of the cardiovascular changes are reversible after liver transplantation and point to the pathophysiological significance of portal hypertension. In this paper, we aimed to review current knowledge on the pathophysiology of arterial vasodilatation and the hyperdynamic circulation in cirrhosis. PMID- 28921804 TI - Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents. AB - BACKGROUND: Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. PROCEDURE: We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. RESULTS: The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR] = 4.870, P < 0.001), and BSI between day 0 and +30 prior to AGVHD (HR = 3.010, P = 0.001). CONCLUSIONS: These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal. PMID- 28921805 TI - Cytochrome P450 diversification and hostplant utilization patterns in specialist and generalist moths: Birth, death and adaptation. AB - Across insect genomes, the size of the cytochrome P450 monooxygenase (CYP) gene superfamily varies widely. CYPome size variation has been attributed to reciprocal adaptive radiations in insect detoxification genes in response to plant biosynthetic gene radiations driven by co-evolution between herbivores and their chemically defended hostplants. Alternatively, variation in CYPome size may be due to random "birth-and-death" processes, whereby exponential increase via gene duplications is limited by random decay via gene death or transition via divergence. We examined CYPome diversification in the genomes of seven Lepidoptera species varying in host breadth from monophagous (Bombyx mori) to highly polyphagous (Amyelois transitella). CYPome size largely reflects the size of Clan 3, the clan associated with xenobiotic detoxification, and to some extent phylogenetic age. Consistently across genomes, families CYP6, CYP9 and CYP321 are most diverse and CYP6AB, CYP6AE, CYP6B, CYP9A and CYP9G are most diverse among subfamilies. Higher gene number in subfamilies is due to duplications occurring primarily after speciation and specialization ("P450 blooms"), and the genes are arranged in clusters, indicative of active duplicating loci. In the parsnip webworm, Depressaria pastinacella, gene expression levels in large subfamilies are high relative to smaller subfamilies. Functional and phylogenetic data suggest a correlation between highly dynamic loci (reflective of extensive gene duplication, functionalization and in some cases loss) and the ability of enzymes encoded by these genes to metabolize hostplant defences, consistent with an adaptive, nonrandom process driven by ecological interactions. PMID- 28921806 TI - A large-area, spatially continuous assessment of land cover map error and its impact on downstream analyses. AB - Land cover maps increasingly underlie research into socioeconomic and environmental patterns and processes, including global change. It is known that map errors impact our understanding of these phenomena, but quantifying these impacts is difficult because many areas lack adequate reference data. We used a highly accurate, high-resolution map of South African cropland to assess (1) the magnitude of error in several current generation land cover maps, and (2) how these errors propagate in downstream studies. We first quantified pixel-wise errors in the cropland classes of four widely used land cover maps at resolutions ranging from 1 to 100 km, and then calculated errors in several representative "downstream" (map-based) analyses, including assessments of vegetative carbon stocks, evapotranspiration, crop production, and household food security. We also evaluated maps' spatial accuracy based on how precisely they could be used to locate specific landscape features. We found that cropland maps can have substantial biases and poor accuracy at all resolutions (e.g., at 1 km resolution, up to ~45% underestimates of cropland (bias) and nearly 50% mean absolute error (MAE, describing accuracy); at 100 km, up to 15% underestimates and nearly 20% MAE). National-scale maps derived from higher-resolution imagery were most accurate, followed by multi-map fusion products. Constraining mapped values to match survey statistics may be effective at minimizing bias (provided the statistics are accurate). Errors in downstream analyses could be substantially amplified or muted, depending on the values ascribed to cropland adjacent covers (e.g., with forest as adjacent cover, carbon map error was 200% 500% greater than in input cropland maps, but ~40% less for sparse cover types). The average locational error was 6 km (600%). These findings provide deeper insight into the causes and potential consequences of land cover map error, and suggest several recommendations for land cover map users. PMID- 28921808 TI - Long-term agricultural management does not alter the evolution of a soybean rhizobium mutualism. AB - Leguminous crops, like soybeans, often rely on biologically fixed nitrogen via their symbiosis with rhizobia rather than synthetic nitrogen inputs. However, agricultural management practices may influence the effectiveness of biological nitrogen fixation (BNF). While the ecological effects of agricultural management on rhizobia have received some attention, the evolutionary effects have been neglected in comparison. Resource mutualism theory predicts that evolutionary effects are likely, however. Both fertilization and tillage are predicted to cause the evolution of rhizobia that provide fewer growth benefits to plant hosts and fix less nitrogen. This study capitalized on a Long-Term Ecological Research experiment that manipulated agricultural management practices in a corn-soybean wheat row crop system for 24 yr to investigate whether four different management practices (conventional, no-till, low chemical input, and certified organic) cause rhizobia populations to evolve to become more or less cooperative. We found little evidence that 24 yr of varying management practices affect the net growth benefits rhizobia provide to soybeans, although soybean plants inoculated with soils collected from conventional treatments tended to have lower BNF rates than plants inoculated with soils from the no-till, low input, and organic management treatments. These findings suggest that rhizobia will continue to provide adequate growth benefits to leguminous crops in the future, even in intensively managed systems. PMID- 28921807 TI - The Italian compassionate use of sofosbuvir in HCV patients waitlisted for liver transplantation: A national real-life experience. AB - BACKGROUND & AIMS: This study aimed to assess the real-life clinical and virological outcomes of HCV waitlisted patients for liver transplantation (LT) who received sofosbuvir/ribavirin (SOF/R) within the Italian compassionate use program. METHODS: Clinical and virological data were collected in 224 patients with decompensated cirrhosis and/or hepatocellular carcinoma (HCC) receiving daily SOF/R until LT or up a maximum of 48 weeks. RESULTS: Of 100 transplanted patients, 51 were HCV-RNA negative for >4 weeks before LT (SVR12: 88%) and 49 negative for <4 weeks or still viraemic at transplant: 34 patients continued treatment after LT (bridging therapy) (SVR12: 88%), while 15 stopped treatment (SVR12: 53%). 98 patients completed SOF/R without LT (SVR12: 73%). In patients with advanced decompensated cirrhosis (basal MELD >=15 and/or C-P >=B8), a marked improvement of the scores occurred in about 50% of cases and almost 20% of decompensated patients without HCC reached a condition suitable for inactivation and delisting. CONCLUSIONS: These real-life data indicate that in waitlisted patients: (i) bridging antiviral therapy can be an option for patients still viraemic or negative <4 weeks at LT; and (ii) clinical improvement to a condition suitable for delisting can occur even in patients with advanced decompensated cirrhosis. PMID- 28921809 TI - Structures of the Heme Acquisition Protein HasA with Iron(III)-5,15 Diphenylporphyrin and Derivatives Thereof as an Artificial Prosthetic Group. AB - Iron(III)-5,15-diphenylporphyrin and several derivatives were accommodated by HasA, a heme acquisition protein secreted by Pseudomonas aeruginosa, despite possessing bulky substituents at the meso position of the porphyrin. Crystal structure analysis revealed that the two phenyl groups at the meso positions of porphyrin extend outside HasA. It was shown that the growth of P. aeruginosa was inhibited in the presence of HasA coordinating the synthetic porphyrins under iron-limiting conditions, and that the structure of the synthetic porphyrins greatly affects the inhibition efficiency. PMID- 28921810 TI - Bones Morphogenic Protein-4 and retinoic acid combined treatment comparative analysis for in vitro differentiation potential of murine mesenchymal stem cells derived from bone marrow and adipose tissue into germ cells. AB - Nowadays, infertility is no longer considered as an unsolvable disorder due to progresses in germ cells derived from stem lineage with diverse origins. Technical and ethical challenges push researchers to investigate various tissue sources to approach more efficient gametes. The purpose of the current study is to investigate the efficacy of a combined medium, retinoic acid (RA) together with Bone Morphogenic Protein-4 (BMP4), on differentiation of Bone Marrow Mesenchymal Stem Cells (BMMSCs) and adipose-derived mesenchymal stem cells (ADMSCs) into germ cells. Murine MSCs were obtained from both Bone Marrow (BM) and Adipose Tissue (AT) samples and were analyzed for surface markers to get further verification of their nature. BMMSCs and ADMSCs were induced into osteogenic and adipogenic lineage cells respectively, to examine their multipotency. They were finally differentiated into germ cells using media enriched with BMP4 for 4 days followed by addition of RA for 7 days (11 days in total). Analyzing of differentiation potential of BMMSCs- and ADMSCs were performed via Immunofluorescence, Flowcytometry and Real time-PCR techniques for germ cell-specific markers (Mvh, Dazl, Stra8 and Scp3). Mesenchymal surface markers (CD90 and CD44) were expressed on both BMMSCs and ADMSCs, while endothelial and hematopoietic cell markers (CD31 and CD45) had no expression. Finally, all germ-specific markers were expressed in both BM and AT. Although germ cells differentiated from ADMSCs showed faster growth and proliferation as well as easy collection, they significantly expressed germ-specific markers lower than BMMSCs. This suggests stronger differentiation potential of murine BMMSCs than ADMSCs. PMID- 28921811 TI - A role for the non-receptor tyrosine kinase ACK1 in TNF-alpha-mediated apoptosis and proliferation in human intestinal epithelial caco-2 cells. AB - The roles of tumor necrosis factor alpha (TNF-alpha) and its mediators in cellular processes related to intestinal diseases remain elusive. In this study, we aimed to determine the biological role of activated Cdc42-associated kinase 1 (ACK1) in TNF-alpha-mediated apoptosis and proliferation in Caco-2 cells. ACK1 expression was knocked down using ACK1-specific siRNAs, and ACK1 activity was disrupted using a small molecule ACK1 inhibitor. The Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) and the BrdU incorporation assays were used to measure apoptosis and cell proliferation, respectively. ACK1 specific siRNA and the pharmacological ACK1 inhibitor significantly abrogated the TNF-alpha-mediated anti-apoptotic effects and proliferation of Caco-2 cells. Interestingly, TNF-alpha activated ACK1 at tyrosine 284 (Tyr284), and the ErbB family of proteins was implicated in ACK1 activation in Caco-2 cells. ACK1-Tyr284 was required for protein kinase B (AKT) activation, and ACK1 signaling was mediated through recruiting and phosphorylating the down-stream adaptor protein AKT, which likely promoted cell proliferation in response to TNF-alpha. Moreover, ACK1 activated AKT and Src enhanced nuclear factor-kB (NF-kB) activity, suggesting a correlation between NF-kB signaling and TNF-alpha-mediated apoptosis in Caco-2 cells. Our results demonstrate that ACK1 plays an important role in modulating TNF-alpha-induced aberrant cell proliferation and apoptosis, mediated in part by ACK1 activation. ACK1 and its down-stream effectors may hold promise as therapeutic targets in the prevention and treatment of gastrointestinal cancers, in particular, those induced by chronic intestinal inflammation. PMID- 28921812 TI - Evaluation of air samplers and filter materials for collection and recovery of airborne norovirus. AB - AIMS: The aim of this study was to identify the most efficient sampling method for quantitative PCR-based detection of airborne human norovirus (NoV). METHODS AND RESULTS: A comparative experiment was conducted in an aerosol chamber using aerosolized murine norovirus (MNV) as a surrogate for NoV. Sampling was performed using a nylon (NY) filter in conjunction with four kinds of personal samplers: Gesamtstaubprobenahme sampler (GSP), Triplex-cyclone sampler (TC), 3-piece closed faced Millipore cassette (3P) and a 2-stage NIOSH cyclone sampler (NIO). In addition, sampling was performed using the GSP sampler with four different filter types: NY, polycarbonate (PC), polytetrafluoroethylene (PTFE) and gelatine (GEL). The sampling efficiency of MNV was significantly influenced by both sampler and filter type. The GSP sampler was found to give significantly (P < 0.05) higher recovery of aerosolized MNV than 3P and NIO. A higher recovery was also found for GSP compared with TC, albeit not significantly. Finally, recovery of aerosolized MNV was significantly (P < 0.05) higher using NY than PC, PTFE and GEL filters. CONCLUSIONS: The GSP sampler combined with a nylon filter was found to be the best method for personal filter-based sampling of airborne NoV. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification of a suitable NoV air sampler is an important step towards studying the association between exposure to airborne NoV and infection. PMID- 28921813 TI - What is the safest mode of birth for extremely preterm breech singleton infants who are actively resuscitated? A systematic review and meta-analyses. AB - BACKGROUND: The safest delivery mode of extremely preterm breech singletons is unknown. OBJECTIVES: To determine safest delivery mode of actively resuscitated extremely preterm breech singletons. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov from January 1994 to May 2017. SELECTION CRITERIA: We included studies comparing outcomes by delivery mode in actively resuscitated breech infants between 23+0 and 27+6 weeks. DATA COLLECTION AND ANALYSIS: We synthesised data using random effects, generated odds ratios, 95% confidence intervals and number-needed-to-treat (NNT). Our primary outcomes were death (neonatal, before discharge, or by 6 months) and severe intraventricular haemorrhage (grades III/IV), stratified by gestational age (23+0 -24+6 , 25+0 -26+6 , 27+0 -27+6 weeks). MAIN RESULTS: We included 15 studies with 12 335 infants. We found that caesarean section was associated with a 41% decrease in odds of death between 23+0 and 27+6 weeks [odds ratio (OR) 0.59, 95% CI 0.36-0.95, NNT 8], with the greatest decrease at 23+0 -24+6 weeks (OR 0.58, 95% CI 0.44-0.75, NNT 7). The OR at 25+0 -26+6 and 27+0 -27+6 weeks were 0.72 (95% CI 0.34-1.52) and 2.04 (95% CI 0.20-20.62), respectively. We found that caesarean section was associated with 49% decrease in odds of severe intraventricular haemorrhage between 23+0 and 27+6 weeks (OR 0.51, 95% CI 0.29 0.91, NNT 12), whereas the OR at 25+0 -26+6 and 27+0 -27+6 was 0.29 (95% CI 0.07 1.12) and 0.91 (95% CI 0.27-3.05), respectively. CONCLUSIONS: Caesarean section was associated with reductions in the odds of death by 41% and of severe intraventricular haemorrhage by 49% in actively resuscitated breech singletons < 28 weeks of gestation. The data are mostly observational, which may be inherently biased, and scarce on other morbidities, necessitating thorough discussion between parents and clinicians. TWEETABLE ABSTRACT: Caesarean section associated with lower odds of death and severe intraventricular haemorrhage in actively resuscitated breech singletons <28 weeks. PMID- 28921814 TI - Nabilone pharmacotherapy for cannabis dependence: A randomized, controlled pilot study. AB - BACKGROUND AND OBJECTIVES: We assessed the safety, tolerability, and preliminary efficacy of nabilone, a cannabinoid agonist, to treat cannabis dependence. METHODS: Eighteen adults with DSM-IV cannabis dependence were randomized to receive either 2 mg/day of nabilone (n = 10) or placebo (n = 8) for 10 weeks in addition to medication management. Twelve participants, six in each group, completed treatment. The safety and tolerability of nabilone was assessed at each visit. Any side effects from nabilone or the placebo were documented. Cannabis use outcomes were assessed via self-report of days of use and twice-weekly urine cannabinoid tests; secondary outcomes included cannabis craving and anxiety. RESULTS: We assessed safety and tolerability at each study visit. A total of eight adverse events, all mild or moderate, were reported in two participants in the nabilone group, and six events were reported in four participants in the placebo group during study treatment. A total of eight adverse events were reported in two participants in the nabilone group and six events were reported in four participants in the placebo group during study treatment. All reported adverse events were rated mild-to-moderate. There were no side effects deemed serious enough to be classified as an FDA-defined serious adverse event. In general, participants in both groups reported reduced cannabis use according to self-report over the course of the study, although these reductions were not statistically discernible. Moreover, there was no difference in cannabis use between the nabilone group and the placebo group as measured by self-report. DISCUSSION AND CONCLUSIONS: Nabilone pharmacotherapy was safe and well-tolerated in participants with cannabis dependence. Future studies might evaluate a higher dose of nabilone to determine its effects on cannabis use outcomes in participants with cannabis dependence. SCIENTIFIC SIGNIFICANCE: There remains a clear need for additional pharmacotherapy trials for cannabis dependence, and nabilone remains a candidate for such trials. (Am J Addict 2017;26:795-801). PMID- 28921815 TI - Low-gluten, nontransgenic wheat engineered with CRISPR/Cas9. AB - Coeliac disease is an autoimmune disorder triggered in genetically predisposed individuals by the ingestion of gluten proteins from wheat, barley and rye. The alpha-gliadin gene family of wheat contains four highly stimulatory peptides, of which the 33-mer is the main immunodominant peptide in patients with coeliac. We designed two sgRNAs to target a conserved region adjacent to the coding sequence for the 33-mer in the alpha-gliadin genes. Twenty-one mutant lines were generated, all showing strong reduction in alpha-gliadins. Up to 35 different genes were mutated in one of the lines of the 45 different genes identified in the wild type, while immunoreactivity was reduced by 85%. Transgene-free lines were identified, and no off-target mutations have been detected in any of the potential targets. The low-gluten, transgene-free wheat lines described here could be used to produce low-gluten foodstuff and serve as source material to introgress this trait into elite wheat varieties. PMID- 28921816 TI - Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement. AB - BACKGROUND: Donor cell leukemia (DCL) occurs after allogeneic hematopoietic stem cell transplantation. Several mechanisms, including occult leukemic/preleukemic subclones in the donor graft and germline predisposition to leukemia, are proposed to be associated with DCL's molecular pathogenesis. We report a comprehensive genetic analysis of a patient with KMT2A-rearranged DCL after allogeneic bone marrow transplantation for refractory cytopenia of childhood. PROCEDURE: We performed a whole-exome sequencing of the recipient's peripheral blood before transplant and the donor's peripheral blood and the recipient's bone marrow at the time of DCL diagnosis. RNA sequencing was also performed to detect fusion genes in DCL blasts. RESULTS: There were no germline mutations that were associated with a predisposition to leukemia in the recipient and donor. Furthermore, there were no detectable somatic alterations except KMT2A-MLLT10 and other related gene fusions in DCL. KMT2A-MLLT10 was not detectable in the donor's bone marrow. CONCLUSION: We propose a novel pattern of the molecular pathogenesis of DCL solely involving a genetic mutation acquired after transplant with no identifiable genetic factor related to the donor and recipient. PMID- 28921818 TI - Blinatumomab activity in a patient with Down syndrome B-precursor acute lymphoblastic leukemia. AB - Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B-precursor acute lymphoblastic leukemia (BP-ALL). Given the strong association of MRD and outcome in non-Down syndrome (non-DS) BP ALL, it is likely that MRD levels are also of prognostic significance in DS BP ALL. We report here the successful use of blinatumomab, a bispecific T-cell engager antibody construct, in a patient with DS BP-ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP-ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab. PMID- 28921817 TI - Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. AB - BACKGROUND AND PURPOSE: To establish and validate diagnostic criteria for adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. METHODS: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide 'probable' and 'possible' designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. RESULTS: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as 'probable' and 32 (39%) were diagnosed as 'possible,' leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled 'probable' or 'possible' to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. CONCLUSIONS: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP. PMID- 28921819 TI - Effectiveness of a new tool for self-evaluation of adherence to antimuscarinic drug treatment in older patients of both sexes with urge incontinence. AB - AIM: The present study was a comparison of the validity of the Medication Adherence Self-Report Inventory (MASRI) questionnaire with other methods of assessing adherence to antimuscarinic drugs treatment in older patients with urge incontinence. METHODS: The experiment involved 733 men and women aged >65 years who had noted no less than one urge incontinence episode per day. At the beginning of the experiment, and after 4, 8 and 12 weeks, their adherence to treatment was monitored using the MASRI. RESULTS: The construct validity of the tool was confirmed by data on the correlation of the percentage of non-adherent patients according to the MASRI and the percentage of patients having a belief barrier on the Brief Medication Questionnaire screen (r = 0.89, P <= 0.01; r = 0.91, P <= 0.01; and r = 0.91, P <= 0.05 at the 4th, 8th and 12th week of the follow up). The hypothesis of competitive validity was supported by comparing the percentage of non-adherent patients according to the MASRI and the number of missed doses on the Brief Medication Questionnaire screen (r = 0.94, P <= 0.01; r = 0.85, P <= 0.05; and r = 0.7, P <= 0.05), and according to a visual count of pills. The area under the curve at the 4th, 8th , and 12th week was 0.95 +/- 0.04, 0.92 +/- 0.03 and 0.94 +/- 0.04, respectively. CONCLUSION: The MASRI questionnaire has high validity, and is effective for evaluating adherence to treatment among older patients with urge incontinence taking antimuscarinic drugs. Using the MASRI would imply lower costs and greater availability of diagnostics, and it is the tool of choice in clinical practice. Geriatr Gerontol Int 2018; 18: 115-122. PMID- 28921820 TI - Systematic review and network meta-analysis on the relative efficacy of osteoporotic medications: men with prostate cancer on continuous androgen deprivation therapy to reduce risk of fragility fractures. AB - Androgen-deprivation therapy (ADT) is an effective treatment for men with advanced prostate cancer, but loss of bone mineral density (BMD) is a major risk factor for fractures. This review compared the efficacy of available treatments to provide prescribing guidance to healthcare professionals. This is the first review to compare the effectiveness of different osteoporotic treatments (bisphosphonates, denosumab, toremifene, and raloxifene) on BMD in patients with non-metastatic prostate cancer on ADT using network meta-analysis. Results suggest that all evaluated treatments are effective in improving BMD compared to placebo. Zoledronic acid (ZA) was found to have a greater improvement in BMD compared to other active treatments at all three studied sites, except for risedronate, which had better BMD improvement compared to ZA at the femoral neck site in one small study. Our study did not identify evidence that one drug is unequivocally more effective than another. All drugs appeared to be effective in reducing the rate of bone loss. Healthcare professionals should also consider patient preference, costs, and local availability as part of the decision process. PMID- 28921821 TI - Iridium-Catalyzed Direct C-H Amidation Polymerization: Step-Growth Polymerization by C-N Bond Formation via C-H Activation to Give Fluorescent Polysulfonamides. AB - We report a powerful strategy for activation of C-H bonds to produce polysulfonamides by an atom-economical and green method using iridium-catalyzed direct C-H amidation polymerization (DCAP). After screening various directing groups, additives, silver salts, concentrations, and temperatures to optimize DCAP, high-molecular-weight (up to 149 kDa) and defect-free polysulfonamides were synthesized from various bis-sulfonyl azides. Although these polymers do not have conventional fluorescent conjugated cores, they emit blue light with large Stokes shifts and high quantum yields upon photoexcitation owing to an excited-state intramolecular proton-transfer process. PMID- 28921822 TI - Construction of human induced pluripotent stem cell-derived oriented bone matrix microstructure by using in vitro engineered anisotropic culture model. AB - Bone tissue has anisotropic microstructure based on collagen/biological apatite orientation, which plays essential roles in the mechanical and biological functions of bone. However, obtaining an appropriate anisotropic microstructure during the bone regeneration process remains a great challenging. A powerful strategy for the control of both differentiation and structural development of newly-formed bone is required in bone tissue engineering, in order to realize functional bone tissue regeneration. In this study, we developed a novel anisotropic culture model by combining human induced pluripotent stem cells (hiPSCs) and artificially-controlled oriented collagen scaffold. The oriented collagen scaffold allowed hiPSCs-derived osteoblast alignment and further construction of anisotropic bone matrix which mimics the bone tissue microstructure. To the best of our knowledge, this is the first report showing the construction of bone mimetic anisotropic bone matrix microstructure from hiPSCs. Moreover, we demonstrated for the first time that the hiPSCs-derived osteoblasts possess a high level of intact functionality to regulate cell alignment. (c) 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 360-369, 2018. PMID- 28921823 TI - Encoding seasonal information in a two-oscillator model of the multi-oscillator circadian clock. AB - The suprachiasmatic nucleus (SCN) is a collection of about 10 000 neurons, each of which functions as a circadian clock with slightly different periods and phases, that work in concert with form and maintain the master circadian clock for the organism. The diversity among neurons confers on the SCN the ability to robustly encode both the 24-h light pattern as well as the seasonal time. Cluster synchronization brings the different neurons into line and reduces the large population to essentially two oscillators, coordinated by a macroscopic network motif of asymmetric repulsive-attractive coupling. We recount the steps leading to this simplification and rigorously examine the two-oscillator case by seeking an analytical solution. Through these steps, we identify physiologically relevant parameters that shape the behaviour of the SCN network and delineate its ability to store past details of seasonal variation in photoperiod. PMID- 28921824 TI - Characterization of lacquer films from the middle and late Chinese warring states period 476-221BC. AB - The famous lacquer wares excavated from the Jiuliandun Tombs of the middle and late Warring States period (476-221 BC) were analyzed using scanning electron microscopy/energy as well as dispersive X-ray spectrometry (SEM/EDS), Raman spectroscopy (RS), optical microscopy (OM), and X-ray diffraction (XRD). The results showed a multilayer structure in the lacquer film, including a Qihui layer (a layer made of lacquer and various plasters), undercoat layer (or finishing coat) and colored paint layer mixed with various inorganic particles, such as quartz (SiO2 ) and hydroxyapatite [Ca5 (PO4 )3 (OH)], as fillers in the Qihui layers or orpiment (As2 S3 ) and cinnabar (HgS), which were used as a yellow or red pigment, respectively. With the help of elemental mapping images, a double-layer structure of the lacquer plaster was observed, corresponding to a mixture of lacquer liquid and bone ash [Ca5 (PO4 )3 (OH)], with large-diameter particles in the ground lacquer layer near the wooden body and small quartz (SiO2 ) particles in upper lacquer layer. Specifically, quartz particles detected in the undercoat layer as fillers could be beneficial for improving the moshardness value, cost reduction and abrasive resistance of the lacquer film. In fact, the mixed method that used urushi and inorganic particles to form lacquer plaster was an important technological innovation and deeply influenced lacquering technologies worldwide. The results of this study will not only contribute to understanding the importance of lacquer skills in the Chinese Warring States but also provide information for cultural relic conservation as well as modern lacquer manufacturing for their protection and duplication. PMID- 28921825 TI - Robotic sigmoidectomy for chronic complicated diverticular disease - a video vignette. PMID- 28921826 TI - Growing evidence of the beneficial effects of a marine protein-based dietary supplement for treating hair loss. AB - BACKGROUND: Hair loss is a common condition among women with a range of causes including nutritional deficiencies. AIMS: To review the clinical data supporting the use of an oral marine supplement designed to promote hair growth. PATIENTS/METHODS: Adult women with temporary thinning hair. Following an initial pilot study, five randomized, double-blind studies assessed the effectiveness of the oral marine supplement for promoting hair growth. Each study was approved by one or more institutional review boards. RESULTS: Together, these studies demonstrated the ability of oral marine supplements to increase the growth of terminal and vellus hairs, increase the diameter of terminal and vellus hairs, and decrease hair loss. This product is beneficial for men as well as women. CONCLUSIONS: A dietary supplement containing a marine complex and other natural ingredients can safely and effectively promote hair growth and decrease hair shedding in women and men with thinning hair. PMID- 28921827 TI - miR-203 inhibits cell proliferation, invasion, and migration of non-small-cell lung cancer by downregulating RGS17. AB - Involvement of the RGS17 oncogene in the promotion of non-small-cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of miRNAs in Regulator of G Protein Signaling 17 (RGS17)-induced NSCLC, we showed that miR-203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined whether miR-203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR-203 on RGS17, we used lung cancer cell lines, A549 and Calu-1, and the constructed miR-203 and RGS17 overexpression vectors. The CCK8 kit was used to determine cell proliferation, and the Transwell(r) assay was used to measure cell invasion and migration. RT-PCR, western blots, and immunofluorescence were used to analyze expression of miR-203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR-203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. Expression of miR-203 inhibited proliferation, invasion, and migration of lung cancer cell lines A549 and Calu-1 by targeting RGS17. The regulatory effect of miR-203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR-203 downregulated RGS17 by direct integration into the 3'-UTR of RGS17 mRNA. In vivo studies showed that expression of miR-203 significantly inhibited growth of tumors. Taken together, the results suggested that expression of miR-203 inhibited tumor growth and metastasis by targeting RGS17. PMID- 28921828 TI - [HDL-C/apoA-I]: A multivessel cardiometabolic risk marker in women with T2DM. AB - AIMS: Although women have higher high-density lipoprotein cholesterol (HDL-C) than have men, their HDL particles are also prone to become small, dense, and dysfunctional in case of type 2 diabetes mellitus (T2DM). To assess the vascular risk related to HDLs of different sizes/densities without direct measurement, we adjusted HDL-C to its main apolipoprotein (apoA-I) as [HDL-C/apoA-I]. This ratio estimates HDL sizes and provides indices as to their number, cholesterol load, and density. METHODS: We stratified 280 Caucasian T2DM women according to [HDL C/apoA-I] quartiles (Q) to determine how they are segregated according to cardiometabolic risk, beta-cell function, glycaemic control, and vascular complications. Five parameters were derived from combined determination of HDL-C and apoA-I: HDL size, HDL number, cholesterol load per particle (pP), apoA-I pP, and HDL density. RESULTS: An adverse cardiometabolic profile characterized QI and QII patients whose HDLs were denser and depleted in apoA-I, whereas QIII patients had HDLs with characteristics closer to those of controls. QIV patients had HDLs of supernormal size/composition and a more favourable phenotype in terms of fat distribution; insulin sensitivity (64% vs 41%), metabolic syndrome, and beta-cell function (32% vs 23%); exogenous insulin (44 vs 89 U.d-1 ); and glycaemic control (glycated haemoglobin, 56 vs 61 mmol.mol-1 ), associated with lower prevalence of microvascular/macrovascular complications: all-cause microangiopathy 47% vs 61%; retinopathy 22% vs 34%; all-cause macroangiopathy 19% vs 31%; and coronary artery disease 6% vs 24% (P < .05). CONCLUSION: [HDL-C/apoA-I] can stratify T2DM women according to metabolic phenotype, macrovascular and coronary damage, beta-cell function, microangiopathic risk, and retinopathy. This ratio is a versatile and readily available marker of cardiometabolic status and vascular complications in T2DM women. PMID- 28921829 TI - Vegetation demographics in Earth System Models: A review of progress and priorities. AB - Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real-world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first-generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter-disciplinary communication. PMID- 28921830 TI - Trends, application and future prospectives of microbial carbonic anhydrase mediated carbonation process for CCUS. AB - Growing industrialization and the desire for a better economy in countries has accelerated the emission of greenhouse gases (GHGs), by more than the buffering capacity of the earth's atmosphere. Among the various GHGs, carbon dioxide occupies the first position in the anthroposphere and has detrimental effects on the ecosystem. For decarbonization, several non-biological methods of carbon capture, utilization and storage (CCUS) have been in use for the past few decades, but they are suffering from narrow applicability. Recently, CO2 emission and its disposal related problems have encouraged the implementation of bioprocessing to achieve a zero waste economy for a sustainable environment. Microbial carbonic anhydrase (CA) catalyses reversible CO2 hydration and forms metal carbonates that mimic the natural phenomenon of weathering/carbonation and is gaining merit for CCUS. Thus, the diversity and specificity of CAs from different micro-organisms could be explored for CCUS. In the literature, more than 50 different microbial CAs have been explored for mineral carbonation. Further, microbial CAs can be engineered for the mineral carbonation process to develop new technology. CA driven carbonation is encouraging due to its large storage capacity and favourable chemistry, allowing site-specific sequestration and reusable product formation for other industries. Moreover, carbonation based CCUS holds five-fold more sequestration capacity over the next 100 years. Thus, it is an eco-friendly, feasible, viable option and believed to be the impending technology for CCUS. Here, we attempt to examine the distribution of various types of microbial CAs with their potential applications and future direction for carbon capture. Although there are few key challenges in bio-based technology, they need to be addressed in order to commercialize the technology. PMID- 28921831 TI - Analysis of the spotted gar genome suggests absence of causative link between ancestral genome duplication and transposable element diversification in teleost fish. AB - Teleost fish have been shown to contain many superfamilies of transposable elements (TEs) that are absent from most tetrapod genomes. Since theories predict an increase in TE activity following polyploidization, such diversity might be linked to the 3R whole-genome duplication that occurred approximately 300 million years ago before the teleost radiation. To test this hypothesis, we have analyzed the genome of the spotted gar Lepisosteus oculatus, which diverged from the teleost lineage before the 3R duplication. Our results indicate that TE diversity and copy numbers are similar in gar and teleost genomes, suggesting that TE diversity was ancestral and not linked to the 3R whole-genome duplication. We propose that about 25 distinct superfamilies of TEs were present in the last ancestor of gars and teleost fish about 300 million years ago in the ray-finned fish lineage. PMID- 28921832 TI - Synthesis and bioactivity assessment of high silica content quaternary glasses with Ca: P ratios of 1.5 and 1.67, made by a rapid sol-gel process. AB - Sol-gel glasses in quaternary silica-sodium-calcium-phosphorous systems have been synthesized using a rotary evaporator for rapid drying without ageing. This novel fast drying method drastically decreases the total drying and ageing time from several weeks to only 1 hour, thus overcoming a serious drawback in sol-gel preparation procedures for bioglasses. This work investigates the bioactivity behavior of two glasses synthesized by this fast method, with Ca:P ratios of 1.5, and 1.67. X-ray diffraction (XRD), Inductive coupled plasma, Fourier-transform infrared, and Raman spectroscopy were used to confirm the bioactivity of the synthesized powders. MAS-NMR was also used to assess the degree of silica polymerization. The composition with a higher Ca:P = 1.67 ratio showed better bioactivity in comparison to the one with Ca:P = 1.5, which exhibited little bio response with up to 4 weeks of immersion in SBF (simulated body fluid). It was also found that an orbital agitation rate of 120 rpm favors the interfacial bio mineralization reactions, promoting the formation of a crystalline hydroxyapatite (HAp) layer at the surface of the (Ca:P = 1.67) composition after 2 weeks immersion in SBF. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 510-520, 2018. PMID- 28921833 TI - Guideline of guidelines: asymptomatic microscopic haematuria. AB - The aim of the present study was to review major organizational guidelines on the evaluation and management of asymptomatic microscopic haematuria (AMH). We reviewed the haematuria guidelines from: the American Urological Association; the consensus statement by the Canadian Urological Association, Canadian Urologic Oncology Group and Bladder Cancer Canada; the American College of Physicians; the Joint Consensus Statement of the Renal Association and British Association of Urological Surgeons; and the National Institute for Health and Care Excellence. All guidelines reviewed recommend evaluation for AMH in the absence of potential benign aetiologies, with the evaluation including cystoscopy and upper urinary tract imaging. Existing guidelines vary in their definition of AMH (role of urine dipstick vs urine microscopy), the age threshold for recommending evaluation, and the optimal imaging method (computed tomography vs ultrasonography). Of the reviewed guidelines, none recommended the use of urine cytology or urine markers during the initial AMH evaluation. Patients should have ongoing follow-up after a negative initial AMH evaluation. Significant variation exists among current guidelines for AMH with respect to who should be evaluated and in what manner. Given the patient and health system implications of balancing appropriately focused and effective diagnostic evaluation, AMH represents a valuable future research opportunity. PMID- 28921834 TI - The role of pre-morbid diabetes on developing amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: The literature on the association between diabetes and amyotrophic lateral sclerosis (ALS) consists of a limited number of studies. This cohort study was developed in order to assess the role of diabetes on the risk of developing ALS. METHODS: The study population was represented by all residents in Turin (Italy) at the beginning of 1996 who participated in the 1991 census, over 14 years of age (n = 727 977) and followed up for ALS occurrence from 1998 to 2014. Presence of diabetes at baseline or during follow-up was ascertained through two Piedmont regional sources: the Diabetes Registry and the Anatomical Therapeutic Chemical Drug Prescription Archive. The risk of ALS was estimated using the Piedmont and Valle d'Aosta ALS Registry (PARALS). The association of diabetes, treated as a time-dependent variable, with ALS onset was estimated through Cox proportional hazard regression models adjusted for age, gender, education and marital status. RESULTS: During follow-up, 397 subjects developed ALS, 24 of whom were already diabetic before ALS onset. Diabetes was associated with a significantly decreased risk of ALS [hazard ratio, 0.30 (95% confidence interval, 0.19-0.45)] without differences in risk by gender, age class or ALS phenotype. CONCLUSION: The results support the protective role of diabetes toward ALS. PMID- 28921835 TI - Reply to comment on: Insurance coverage decisions for pediatric proton therapy. PMID- 28921836 TI - Clinical assessment of coronary arteries in Kawasaki disease: Focus on echocardiographic assessment. AB - Echocardiography is an excellent noninvasive imaging modality for evaluation and follow-up of cardiac lesions, especially coronary artery changes occurring as a result of Kawasaki disease. The information obtained has prognostic implications and can be complemented with other modes of imaging for risk stratification and optimization of both medical and interventional therapy. The aim of this article is to describe the time line of echocardiographic follow-up of patients affected with Kawasaki disease. The classification of coronary artery changes and transthoracic echocardiographic views recommended for detailed evaluation of the coronary arteries are delineated in detail in this report. PMID- 28921837 TI - Coronary artery bypass grafting versus percutaneous coronary intervention in patients with noninsulin treated type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. AB - BACKGROUND: The outcomes and prognosis of revascularization by either coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) in patients with noninsulin-treated type 2 diabetes mellitus (NITDM) have not yet been well established. METHODS: Randomized controlled trials (RCTs) were identified by searching Pubmed, EMBASE, and Cochrane library from inception until May 2016. Heterogeneity was evaluated, and the pooled hazard ratio (HR) was calculated by using a fixed-effect model. A random-effect model was used when statistically significant heterogeneity was observed (I2 >= 50%). All data analyses were carried out by using RevMan 5.3 and STATA software 12.0. RESULTS: A total of 4 RCTs involving 5 studies, consisting of 2270 patients with noninsulin treated type 2 diabetes mellitus, were identified. Compared with CABG-treated patients, PCI-treated patients had significantly higher all-cause mortality (HR 1.39; 95% CI 1.01 to 1.91; P = .04), myocardial infarction (HR 2.14; 95% CI 1.40 to 3.27; P = .0004), repeated revascularization (HR 2.52; 95% CI 1.77 to 3.57; P < .00001), and major adverse cardiovascular and cerebrovascular events (HR 1.50; 95% CI 1.20-1.87; P = .0004). However, PCI was associated with lower incidence of stoke (HR 0.47; 95% CI 0.24 to 0.90; P = .02). CONCLUSIONS: In NITDM patients, our study suggests that CABG surgery is associated with reduced risk of mortality and morbidity, although with increased incidence of stroke compared with percutaneous coronary intervention. The decision if to have percutaneous coronary intervention or CABG surgery should factor the risk for stroke of the patients when considering CABG over percutaneous coronary intervention. Adequately powered RCTs are needed to confirm the results of this meta-analysis. PMID- 28921838 TI - Robot-assisted kidney transplantation: comparison of the first 40 cases of open vs robot-assisted transplantations by a single surgeon. AB - OBJECTIVE: To compare the outcomes of the first 40 patients to undergo robot assisted kidney transplantation (RAKT) with those of the first 40 patients who underwent open KT (OKT) by a single surgeon at the Dr Sadi Konuk Training Hospital. PATIENTS AND METHODS: We prospectively collected the data of the first 40 patients to undergo RAKT between January 2016 and February 2017 (RAKT group), and compared them with the first 40 patients to undergo OKT between November 2010 and April 2015 (OKT group). Comparisons were made using one-way analysis of variance or the Kruskal-Wallis test for continuous variables, and the chi-squared or Fisher's exact test for categorical variables. RESULTS: There were 40 patients in both the RAKT and OKT groups. In the RAKT group, the mean (SD) operative time was 265.375 (46.63) min, total ischaemia time was 96.7 (30.02) min, re-warming time was 54.70 (17.80) min, and estimated blood loss (EBL) was 182.25 (55.26) mL. Whilst in the OKT group the mean (SD) operative time was 250.25 (41) min (P = 0.129), total ischaemia time was 71.79 (8.55) min (P < 0.01), re-warming time was 37.30 (4.07) min (P < 0.001), and EBL was 210.75 (28.96) mL (P = 0.005). At 12-24 h postoperatively, linear visual analogue scale pain scores were significantly lower in the RAKT group (P < 0.001), and the RAKT group had a significantly shorter drain withdrawal time, at a mean (SD) of 3.45 (0.93) vs 7.67 (2.11) days in the OKT group (P < 0.001). CONCLUSION: Satisfactory functional outcomes can be achieved by either OKT or RAKT. However, the latter technique seems to have some advantages over the former in that it is less invasive, results in less pain postoperatively, has a shorter drain withdrawal time, and has the potential for fewer complications. PMID- 28921839 TI - Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group. AB - BACKGROUND: The purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols. METHODS: Seventy-nine patients, treated between 1994 and 2006, were analyzed after stratification into three age groups: <1 month, between 1 and 3 months, and between 3 and 6 months. All received preoperative chemotherapy. RESULTS: Clinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had alpha-fetoprotein <100 ng/ml, 68 were operated by partial hepatectomy, and 7 received liver transplant. Chemotherapy courses were delayed in 8.5%, 8.4%, and 11.8% of cycles in the three groups. Doses were calculated according to weight for children <5 and 5-10 kg, and further reduced in 18.1%, 6.8%, and 5.9% of cycles. Acute toxicity was manageable. Long-term hearing loss was the major problem at follow-up occurring in two-thirds of children. Ten patients experienced progression or relapse, and 5 of 10 died. After a median follow-up of 5.6 years, the 5-year overall survival (OS) and event-free survival (EFS) were 91% (95% confidence interval [CI]: 84-96%) and 87% (95% CI: 78-92%), respectively. CONCLUSIONS: The 5-year OS and EFS of children <6 months of age affected by HB seem to be similar to those documented in the elder children. Dose reduction does not seem to jeopardize the long-term outcome and may explain the lower toxicity profile. Ototoxicity though appears as high as in the whole population of SIOPEL 2 and 3. The treatment for these children should be further explored in international studies, particularly focusing on prevention of hearing loss. PMID- 28921840 TI - The role of cadherin genes in five major psychiatric disorders: A literature update. AB - Converging evidence from candidate gene, genome-wide linkage, and association studies support a role of cadherins in the pathophysiology of five major psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). These molecules are transmembrane proteins which act as cell adhesives by forming adherens junctions (AJs) to bind cells within tissues. Members of the cadherin superfamily are also involved in biological processes such as signal transduction and plasticity that have been implicated in the etiology of major psychiatric conditions. Although there are over 110 genes mapped to the cadherin superfamily, our literature survey showed that evidence of association with psychiatric disorders is strongest for CDH7, CHD11, and CDH13. Gene enrichment analysis showed that those cadherin genes implicated in psychiatric disorders were overrepresented in biological processes such as in cell-cell adhesion (GO:0007156 & GO:0098742) and adherens junction organization (GO:0034332). Further, cadherin genes were also mapped to processes that have been linked to the development of psychiatric disorders such as nervous system development (GO:0007399). To further understand the role of cadherin SNPs implicated in psychiatric disorders, we utilized an in silico computational pipeline to functionally annotate associated variants. This analysis yielded eight variants mapped to PCDH1-13, CDH7, CDH11, and CDH13 that are predicted to be biologically functional. Functional genomic evaluation is now required to understand the molecular mechanism by which these variants might confer susceptibility to psychiatric disorders. PMID- 28921841 TI - In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles. AB - Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age-associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans. PMID- 28921842 TI - AnchorQuery: Rapid online virtual screening for small-molecule protein-protein interaction inhibitors. AB - AnchorQuery (http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue. The inclusion of this anchor not only biases the compounds to interact with proteins, it also enables a rapid, sublinear time pharmacophore search algorithm. AnchorQuery provides all the tools necessary for users to perform online interactive virtual screens of millions of compounds, including pharmacophore elucidation and search, and enrichment analysis. Accessibility: AnchorQuery is freely accessible at http://anchorquery.csb.pitt.edu. PMID- 28921843 TI - Potential proton and photon dose degradation in advanced head and neck cancer patients by intratherapy changes. AB - PURPOSE: Evaluation of dose degradation by anatomic changes for head-and-neck cancer (HNC) intensity-modulated proton therapy (IMPT) relative to intensity modulated photon therapy (IMRT) and identification of potential indicators for IMPT treatment plan adaptation. METHODS: For 31 advanced HNC datasets, IMPT and IMRT plans were recalculated on a computed tomography scan (CT) taken after about 4 weeks of therapy. Dose parameter changes were determined for the organs at risk (OARs) spinal cord, brain stem, parotid glands, brachial plexus, and mandible, for the clinical target volume (CTV) and the healthy tissue outside planning target volume (PTV). Correlation of dose degradation with target volume changes and quality of rigid CT matching was investigated. RESULTS: Recalculated IMPT dose distributions showed stronger degradation than the IMRT doses. OAR analysis revealed significant changes in parotid median dose (IMPT) and near maximum dose (D1ml ) of spinal cord (IMPT, IMRT) and mandible (IMPT). OAR dose parameters remained lower in IMPT cases. CTV coverage (V95% ) and overdose (V107% ) deteriorated for IMPT plans to (93.4 +/- 5.4)% and (10.6 +/- 12.5)%, while those for IMRT plans remained acceptable. Recalculated plans showed similarly decreased PTV conformity, but considerable hotspots, also outside the PTV, emerged in IMPT cases. Lower CT matching quality was significantly correlated with loss of PTV conformity (IMPT, IMRT), CTV homogeneity and coverage (IMPT). Target shrinkage correlated with increased dose in brachial plexus (IMRT, IMPT), hotspot generation outside the PTV (IMPT) and lower PTV conformity (IMRT). CONCLUSIONS: The study underlines the necessity of precise positioning and monitoring of anatomy changes, especially in IMPT which might require adaptation more often. Since OAR doses remained typically below constraints, IMPT plan adaptation will be indicated by target dose degradations. PMID- 28921844 TI - Functional traits determine tree growth and ecosystem productivity of a tropical montane forest: Insights from a long-term nutrient manipulation experiment. AB - Trait-response effects are critical to forecast community structure and biomass production in highly diverse tropical forests. Ecological theory and few observation studies indicate that trees with acquisitive functional traits would respond more strongly to higher resource availability than those with conservative traits. We assessed how long-term tree growth in experimental nutrient addition plots (N, P, and N + P) varied as a function of morphological traits, tree size, and species identity. We also evaluated how trait-based responses affected stand scale biomass production considering the community structure. We found that tree growth depended on interactions between functional traits and the type or combination of nutrients added. Common species with acquisitive functional traits responded more strongly to nutrient addition, mainly to N + P. Phosphorous enhanced the growth rates of species with acquisitive and conservative traits, had mostly positive effects on common species and neutral or negative effects in rare species. Moreover, trees receiving N + P grew faster irrespective of their initial size relative to trees in control or to trees in other treatment plots. Finally, species responses were highly idiosyncratic suggesting that community processes including competition and niche dimensionality may be altered under increased resource availability. We found no statistically significant effects of nutrient additions on aboveground biomass productivity because acquisitive species had a limited potential to increase their biomass, possibly due to their generally lower wood density. In contrast, P addition increased the growth rates of species characterized by more conservative resource strategies (with higher wood density) that were poorly represented in the plant community. We provide the first long-term experimental evidence that trait-based responses, community structure, and community processes modulate the effects of increased nutrient availability on biomass productivity in a tropical forest. PMID- 28921845 TI - Detection and delineation of squamous neoplasia with hyperspectral imaging in a mouse model of tongue carcinogenesis. AB - Hyperspectral imaging (HSI) holds the potential for the noninvasive detection of cancers. Oral cancers are often diagnosed at a late stage when treatment is less effective and the mortality and morbidity rates are high. Early detection of oral cancer is, therefore, crucial in order to improve the clinical outcomes. To investigate the potential of HSI as a noninvasive diagnostic tool, an animal study was designed to acquire hyperspectral images of in vivo and ex vivo mouse tongues from a chemically induced tongue carcinogenesis model. A variety of machine-learning algorithms, including discriminant analysis, ensemble learning, and support vector machines, were evaluated for tongue neoplasia detection using HSI and were validated by the reconstructed pathological gold-standard maps. The diagnostic performance of HSI, autofluorescence imaging, and fluorescence imaging were compared in this study. Color-coded prediction maps were generated to display the predicted location and distribution of premalignant and malignant lesions. This study suggests that hyperspectral imaging combined with machine learning techniques can provide a noninvasive tool for the quantitative detection and delineation of squamous neoplasia. PMID- 28921846 TI - Improvement of polytrauma management-quality inspection of a newly introduced course concept. AB - RATIONALE, AIMS, AND OBJECTIVES: A systematic literature search for training course concepts for care of severely injured and severely ill patients respecting improvement of process and outcome yielded little data. For several years, the University Hospital of Bonn has hosted a shock-room management course which, on the one hand, communicates human factor aspects and, on the other hand, pursues interdisciplinary and interprofessional team training. The Bonn shock-room management course (BSM-course(r)) differs from other courses in both format and principles. The aim of this study was to evaluate the quality of the structure of the course based on course evaluations of participants and its impact on the quality of the process and results for polytrauma care. METHODS: Single-center retrospective evaluation study (2011 to 2014). It was based on data from simulator training and records from the German Trauma Registry (DGU)(r). RESULTS: Subjective evaluation of participants (n = 188) of the structure quality of Bonn's shock-room management course was overall positive. Objective measures of course participant performance also improved during simulation training (P = 0.012). An increasing number of trained employees also had a positive influence in reducing process time for shock-room care. Further, the course likewise had a positive impact on documentation quality (degree of completion), with regard to 4 relevant predictive parameters. Early mortality during the first 24 hours remained constant at 6.0-6.5% between 2011 and 2013, yet it decreased to 3.1% in 2014. CONCLUSION: The BSM-course(r) represents a symbiosis of horizontal team approach of trauma care and human factor training. The course format is able to ensure interdisciplinary and interprofessional team training with a high degree of efficiency. Furthermore, the presented work shows that a modern course concept can improve the quality of trauma care. PMID- 28921847 TI - N,N'-methylenebis(acrylamide)-crosslinked poly(acrylic acid) particles as doxorubicin carriers: A comparison between release behavior of physically loaded drug and conjugated drug via acid-labile hydrazone linkage. AB - N,N'-methylenebis(acrylamide) (MBA)-crosslinked poly(acrylic acid) (PAA) particles with low degree of cross-linking were synthesized using distillation precipitation polymerization. Size and size distribution of particles were obtained using dynamic light scattering and field emission scanning electron microscopy( and results showed that microspheres had a narrow size dispersity. Proton nuclear magnetic resonance results indicated that amount of cross-linker in structure of particles is a little more than the molar percentage of feeded MBA because of greater activity ratio of MBA than AA. pH-responsive behavior of samples was investigated using UV-vis. absorption at 480 nm where each sample showed a sudden deplete in UV absorbance at a peculiar pH. Synthesized particles were used as carriers of anti-cancer drug doxorubicin using two different approaches including physically loading of drug and drug conjugation via an acid labile hydrazone linkage. Release results showed that in the first case, amount of released drug has an inverse relationship with the amount of cross-linker in the structure and also, by adding an acid-labile linkage, the amount of burst release decreased drastically. Also, the amount of released drug for conjugated systems was much lesser than particles with physically loaded drug. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 342-348, 2018. PMID- 28921848 TI - Interconversion Rates between Conformational States as Rationale for the Membrane Permeability of Cyclosporines. AB - Cyclic peptides have regained interest as potential inhibitors of challenging targets but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone, it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA. The structure of CsE differs only in a backbone methylation, but its membrane permeability is one order of magnitude lower. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA. PMID- 28921849 TI - Effects of pre-surgical nasoalveolar moulding on maxillary arch and nasal form in unilateral cleft lip and palate before lip surgery. AB - OBJECTIVES: To investigate the effects of pre-surgical nasoalveolar moulding (PNAM) on the maxillary arch and nasal form in patients with unilateral cleft lip and palate (UCLP). SETTING AND SAMPLE POPULATION: This is a retrospective case series study. The subjects were infants with complete UCLP who were treated with PNAM (n = 18) at Kagoshima University Medical and Dental Hospital (Japan) between 2006 and 2013. MATERIAL AND METHODS: Maxillary dental casts and facial photographs were taken at the time of the first visit and immediately prior to lip surgery to evaluate the maxillary arch and nasal form changes. The dental casts were scanned with a laser scanner, and changes in the 3-Dimensional coordinates of anatomical landmarks and alveolar cleft width were analysed. Moreover, we investigated the correlation between the changes in the maxillary alveolar arch and nasal form. RESULTS: Regarding the maxillary alveolar arch form, the anterior points of the major segment had moved significantly to the cleft side just prior to the time of lip repair, and the alveolar cleft width was significantly decreased. For nasal form, the inclination and displacement of the columella were significantly improved. The improvement of columella inclination was moderately correlated with the posterior movement of the anterior points of the major segment. CONCLUSIONS: These findings indicate that PNAM for infants with UCLP enhanced symmetry in the maxillary alveolar arch and nasolabial form. In addition, the posterior movement of the anterior points of the maxillary alveolar arch was correlated with the improvement of columella deformation. PMID- 28921850 TI - Prospective comparison of transperineal magnetic resonance imaging/ultrasonography fusion biopsy and transrectal systematic biopsy in biopsy naive patients. AB - OBJECTIVES: To evaluate the value of multiparametric magnetic resonance imaging (mpMRI) in the detection of significant prostate cancer (PCa) and to compare transperineal MRI/ultrasonography fusion biopsy (fusPbx) with conventional transrectal systematic biopsy (sysPbx) in biopsy-naive patients. PATIENTS AND METHODS: This multicentre, prospective trial investigated biopsy-naive patients with suspicion of PCa undergoing transperineal fusPbx in combination with transrectal sysPbx (comPbx). The primary outcome was the detection of significant PCa, defined as Gleason pattern 4 or 5. We analysed the results after a study period of 2 years. RESULTS: The study included 214 patients. The median (range) number of targeted and systematic cores was 6 (2-15) and 12 (6-18), respectively. The overall PCa detection rate of comPbx was 52%. FusPbx detected more PCa than sysPbx (47% vs 43%; P = 0.15). The detection rate of significant PCa was 38% for fusPbx and 35% for sysPbx (P = 0.296). The rate of missed significant PCa was 14% in fusPbx and 21% in sysPbx. ComPbx detected significantly more significant PCa than fusPbx and sysPbx alone (44% vs 38% vs 35%; P < 0.005). In patients presenting with Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions there was a higher detection rate of significant PCa than in patients presenting with PI-RADS <=3 lesions in comPbx (61% vs 14%; P < 0.005). CONCLUSIONS: For biopsy-naive men with tumour-suspicious lesions in mpMRI, the combined approach outperformed both fusPbx and sysPbx in the detection of overall PCa and significant PCa. Thus, biopsy-naive patients may benefit from sysPbx in combination with mpMRI targeted fusPbx. PMID- 28921851 TI - New intellectual disability syndrome identified: WDR26 haploinsufficiency is rare but could provide explanations to some patients. PMID- 28921852 TI - Genome-wide cell free fetal DNA screening spots variations standard screening doesn't: Diagnostic testing data needed to validate results and prove accuracy. PMID- 28921853 TI - Cover Image, Volume 173A, Number 10, October 2017. AB - The cover image, by Rani A. Bashir et al., is based on the Original Article Lin Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders, DOI: 10.1002/ajmg.a.38355. PMID- 28921855 TI - Utility of the immature platelet fraction in pediatric immune thrombocytopenia: Differentiating from bone marrow failure and predicting bleeding risk. AB - BACKGROUND: Differentiating childhood immune thrombocytopenia (ITP) from other cause of thrombocytopenia remains a diagnosis of exclusion. Additionally factors that predict bleeding risk for those patients with ITP are currently not well understood. Previous small studies have suggested that immature platelet fraction (IPF) may differentiate ITP from other causes of thrombocytopenia and in combination with other factors may predict bleeding risk. METHODS: We performed a retrospective chart review of thrombocytopenic patients with an IPF measured between November 1, 2013 and July 1, 2015. Patients were between 2 months and 21 years of age with a platelet count <50 * 109 /l. Each patient chart was reviewed for final diagnosis and bleeding symptoms. A bleeding severity score was retrospectively assigned. RESULTS: Two hundred seventy two patients met inclusion criteria, 97 with ITP, 11 with bone marrow failure (BMF), 126 with malignancy, and 38 with other causes of thrombocytopenia. An IPF > 5.2% differentiated ITP from BMF with 93% sensitivity and 91% specificity. Absolute immature platelet number (AIPN) was significantly lower in ITP patients with severe to life threatening hemorrhage than those without, despite similar platelet counts. On multivariate analysis, an IPF < 10.4% was confirmed as an independent predictor of bleeding risk at platelet counts <10 * 109 /l in patients with ITP. CONCLUSIONS: IPF measurement alone has utility in both the diagnosis of ITP and identifying patients at increased risk of hemorrhage. Further study is required to understand the pathophysiological differences of ITP patients with lower IPF/AIPN. PMID- 28921857 TI - Opportunistic attachment assembles plant-pollinator networks. AB - Species and interactions are being lost at alarming rates and it is imperative to understand how communities assemble if we have to prevent their collapse and restore lost interactions. Using an 8-year dataset comprising nearly 20 000 pollinator visitation records, we explore the assembly of plant-pollinator communities at native plant restoration sites in an agricultural landscape. We find that species occupy highly dynamic network positions through time, causing the assembly process to be punctuated by major network reorganisations. The most persistent pollinator species are also the most variable in their network positions, contrary to what preferential attachment - the most widely studied theory of ecological network assembly - predicts. Instead, we suggest assembly occurs via an opportunistic attachment process. Our results contribute to our understanding of how communities assembly and how species interactions change through time while helping to inform efforts to reassemble robust communities. PMID- 28921858 TI - Rainfall variability and fine-scale life history tradeoffs help drive niche partitioning in a desert annual plant community. AB - Tradeoffs have long been an essential part of the canon explaining the maintenance of species diversity. Despite the intuitive appeal of the idea that no species can be a master of all trades, there has been a scarcity of linked demographic and physiological evidence to support the role of resource use tradeoffs in natural systems. Using five species of Chihuahuan desert summer annual plants, I show that demographic tradeoffs driven by short-term soil moisture variation act as a mechanism to allow multiple species to partition a limiting resource. Specifically, by achieving highest fitness in either rainfall pulse or interpulse periods, variability reduces fitness differences through time that could promote coexistence on a limiting resource. Differences in fitness are explained in part by the response of photosynthesis to changing soil moisture. My results suggest that increasing weather variability, as predicted under climate change, could increase the opportunity for coexistence in this community. PMID- 28921856 TI - Disruption of perineuronal nets increases the frequency of sharp wave ripple events. AB - Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells (PCs) and require initial excitation of CA1 PCs as well as participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of PCs thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1. As compared with vehicle, pre-treatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pre-treatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events. PMID- 28921859 TI - Trophic interaction modifications: an empirical and theoretical framework. AB - Consumer-resource interactions are often influenced by other species in the community. At present these 'trophic interaction modifications' are rarely included in ecological models despite demonstrations that they can drive system dynamics. Here, we advocate and extend an approach that has the potential to unite and represent this key group of non-trophic interactions by emphasising the change to trophic interactions induced by modifying species. We highlight the opportunities this approach brings in comparison to frameworks that coerce trophic interaction modifications into pairwise relationships. To establish common frames of reference and explore the value of the approach, we set out a range of metrics for the 'strength' of an interaction modification which incorporate increasing levels of contextual information about the system. Through demonstrations in three-species model systems, we establish that these metrics capture complimentary aspects of interaction modifications. We show how the approach can be used in a range of empirical contexts; we identify as specific gaps in current understanding experiments with multiple levels of modifier species and the distributions of modifications in networks. The trophic interaction modification approach we propose can motivate and unite empirical and theoretical studies of system dynamics, providing a route to confront ecological complexity. PMID- 28921860 TI - Shifts of community composition and population density substantially affect ecosystem function despite invariant richness. AB - There has been considerable focus on the impacts of environmental change on ecosystem function arising from changes in species richness. However, environmental change may affect ecosystem function without affecting richness, most notably by affecting population densities and community composition. Using a theoretical model, we find that, despite invariant richness, (1) small environmental effects may already lead to a collapse of function; (2) competitive strength may be a less important determinant of ecosystem function change than the selectivity of the environmental change driver and (3) effects on ecosystem function increase when effects on composition are larger. We also present a complementary statistical analysis of 13 data sets of phytoplankton and periphyton communities exposed to chemical stressors and show that effects on primary production under invariant richness ranged from -75% to +10%. We conclude that environmental protection goals relying on measures of richness could underestimate ecological impacts of environmental change. PMID- 28921861 TI - Soil microbial communities drive the resistance of ecosystem multifunctionality to global change in drylands across the globe. AB - The relationship between soil microbial communities and the resistance of multiple ecosystem functions linked to C, N and P cycling (multifunctionality resistance) to global change has never been assessed globally in natural ecosystems. We collected soils from 59 dryland ecosystems worldwide to investigate the importance of microbial communities as predictor of multifunctionality resistance to climate change and nitrogen fertilisation. Multifunctionality had a lower resistance to wetting-drying cycles than to warming or N deposition. Multifunctionality resistance was regulated by changes in microbial composition (relative abundance of phylotypes) but not by richness, total abundance of fungi and bacteria or the fungal: bacterial ratio. Our results suggest that positive effects of particular microbial taxa on multifunctionality resistance could potentially be controlled by altering soil pH. Together, our work demonstrates strong links between microbial community composition and multifunctionality resistance in dryland soils from six continents, and provides insights into the importance of microbial community composition for buffering effects of global change in drylands worldwide. PMID- 28921863 TI - Gender differences in brain networks during verbal Sternberg tasks: A simultaneous near-infrared spectroscopy and electro-encephalography study. AB - Gender differences in psychological processes have been of great interest in a variety of fields including verbal fluency, emotion processing and working memory. Previous studies suggested that women outperform men in verbal working memory (VWM). However, the inherent mechanisms are still unclear. To obtain a deeper insight into the gender differences in brain networks in VWM, this study used near-infrared spectroscopy (NIRS) and electro-encephalography (EEG) simultaneously to investigate gender-related brain networks during verbal Sternberg tasks. NIRS results confirmed that women surpass men in VWM from the perspective of both brain activation and connectivity. Results of EEG (effective connectivity and event-related spectral power) showed that men tend to use a more visuospatial strategy to encode memory. In addition, novel analysis methods of brain networks can provide useful information about the gender specifics of brain functions. Gender-related pseudo-color maps constructed from all channels of average HbO2 activity during low- and high-load tasks (from 0 to 6 seconds after beginning). PMID- 28921864 TI - Blisters, ulcers, crusts, and atrophic scars on the back of the hands and the extensor aspects of the forearms. PMID- 28921862 TI - Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. AB - AIMS: To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. MATERIALS AND METHODS: In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin >=1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] >=60 mL/min/1.73 m2 ) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. RESULTS: A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2 ). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were -0.7% (-7.5 mmol/mol) and -0.8% (-8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%-14.1%) vs placebo (0%-1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups. CONCLUSIONS: Ertugliflozin added to metformin and sitagliptin was well-tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks. PMID- 28921865 TI - Extramedullary hematopoiesis: a new feature of inherited thrombocytopenias? AB - : Essentials Extramedullary hematopoiesis (EMH) represents a pathologic finding in adult life. We report a mass-like EMH in the presacral space in a patient with ANKRD26-related thrombocytopenia. We found possible correlation between EMH and conditions causing lifelong thrombocytopenia. EMH can cause masses of unknown origin in patients with inherited thrombocytopenias. SUMMARY: Most commonly located in the liver and spleen, extramedullary hematopoiesis (EMH) is the presence of hematopoietic tissue outside the bone marrow. MYH9-related thrombocytopenia (MYH9-RD) and ANKRD26-related thrombocytopenia (ANKRD26-RT) are two of the most frequent forms of inherited thrombocytopenia (IT). Until recently, EMH has been associated with neoplastic and non-neoplastic hematologic conditions in which ITs were not included. We describe a case of mass-like EMH in the presacral space in a patient affected with ANKRD26-RT, comparing it with another case of paravertebral EMH we recently described in a subject with MYH9 RD. The surprisingly similitude of such a finding in the context of a group of rare disorders induces us to speculate about the possible pathogenic relationship between EMH and conditions causing lifelong thrombocytopenia, particularly the entity of ITs. Finally, we suggest that EMH has to be taken into consideration in the diagnostic work-up of masses of unknown origin in subjects affected with ITs. PMID- 28921866 TI - Autophagy and cancer - insights from mouse models. AB - (Macro-)autophagy is an evolutionary conserved 'self-digestion program' that serves to maintain cellular metabolism and is implicated in many pathological processes such as cancer. In recent years, an increasing number of studies in murine cancer models have provided a plethora of sometimes conflicting results about the role of autophagy in cancer biology. This review summarizes these studies and raises awareness that there are situations in which autophagy blockage might indeed reduce tumor growth, but that sometimes the exact opposite is the case. It is therefore vital to mimic patient conditions in preclinical mouse experiments as thoroughly as possible before commencing clinical trials. PMID- 28921867 TI - Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia. AB - A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4* better cell binding activity and 2* higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv-targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer-pirarubicin conjugate. PMID- 28921868 TI - Surface modification of ultrahigh molecular weight polyethylene by plasma-induced in-situ grafting with vinyl triethoxysilane. AB - Ultrahigh molecular weight polyethylene (UHMWPE) is an excellent material with high performance, but it is very difficult to covalently introduce functional groups on its surface owing to its inherently inert structure, which constrains its further application. In this study, vinyl triethoxysilane (VTEOS) containing hydrolysable alkoxyl groups was in situ grafted on UHMWPE by air plasma treatment. The plasma treatment conditions for VTEOS grafting were optimized. The structure of the modified UHMWPE was characterized with FTIR and XPS. The relatively high VTEOS content was obtained when the treating conditions were about 20 W, 125 Pa for 10 min. And FTIR results showed that the grafted structure on the surface was stable for long time duration in the ambient environment. After the treatment, the roughness of the surface increased and the water contact angle of the modified sample dropped to 47.5 degrees from 92.8 degrees of the unmodified one. TGA and XRD results indicated that plasma treatment would not change the bulk structure of UHMWPE greatly. Cell culture experiments showed that fibroblasts on the modified samples had notably high viability and proliferation rate with good adhesion shape. Hence, it might be an effective method to improve the surface properties of UHMWPE for biomedical applications by plasma-induced in situ grafting with VTEOS. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 321-332, 2018. PMID- 28921869 TI - Simplified and age-appropriate recommendations for added sugars in children. AB - Excess sugar intake increases risk for obesity and related comorbidities among children. The World Health Organization (WHO), American Heart Association (AHA) and the 2015 USDA dietary recommendations have proposed guidelines for added sugar intake to reduce risk for disease. WHO and USDA recommendations are presented as a percentage of daily calories from added sugar. This approach is not easily understood or translated to children, where energy needs increase with age. The AHA recommendation is based on a fixed value of 25 g of added sugar for all children 2-19 years of age. This approach does not take into account the different levels of intake across this wide age range. Due to these limitations, we adapted current recommendations for added sugars based on daily energy needs of children 2-19 years. We used those values to derive simple regression equations to predict grams or teaspoons of added sugars per day based on age that would be equivalent to 10% of daily energy needs. This proposed approach aligns with the changing nutritional needs of children and adolescents during growth. PMID- 28921870 TI - Detection and genetic characterization of Porcine circovirus type 3 in Italy. AB - Porcine circovirus type 3 (PCV3) was recently proposed as a new porcine circovirus. It has been described by researchers in the USA and China and associated with porcine dermatitis and nephropathy syndrome, reproductive failure and systemic inflammation disease. The study reports the occurrence of the new virus in Italy. PCV3 was detected in the tissues of foetuses and stillborn piglets coming from two farms located in the Po Valley. The genome sequences of the two Italian strains share 99.7% to 97.8% of nucleotide identity with those available in GenBank. Results strengthen the hypothesis of PCV3 as a new emerging porcine circovirus, widespread all over the world. It follows the urgency of investigating in depth epidemiology and pathogenicity associated with this new virus. PMID- 28921871 TI - Methylene blue-assisted submucosal dissection in transanal surgery - a video vignette. PMID- 28921872 TI - First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-centre, phase 2 study. AB - OBJECTIVE: To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. PATIENTS AND METHODS: In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (Tumour-Node-Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. RESULTS: From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median (interquartile range [IQR]) follow-up duration was 19.8 (6.3-25.7) months; 12-month progression-free survival was 26.2% (95% confidence interval [CI] 13.2-51.9); 12-month overall survival (OS) was 54.9% (95% CI 36.4-82.8). The median (IQR) OS of locally advanced patients was 20 (11.1-not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high-risk human papillomavirus-positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non-responders) and it was confirmed in all post-dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non-responders. CONCLUSION: Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies. PMID- 28921873 TI - Diagnostic specificity of the African swine fever virus antibody detection enzyme linked immunosorbent assay in feral and domestic pigs in the United States. AB - African swine fever (ASF) is a highly contagious haemorrhagic disease of pigs that has the potential to cause mortality nearing 100% in naive animals. While an outbreak of ASF in the United States' pig population (domestic and feral) has never been reported, an introduction of the disease has the potential to cause devastation to the pork industry and food security. During the recovery phase of an outbreak, an antibody detection diagnostic assay would be required to prove freedom of disease within the previously infected zone and eventually nationwide. Animals surviving an ASF infection would be considered carriers and could be identified through the persistence of ASF viral antibodies. These antibodies would demonstrate exposure to the disease and not vaccination, as there is no ASF vaccine available. A well-established commercial enzyme-linked immunosorbent assay (ELISA) detects antibodies against ASF virus (ASFV), but the diagnostic specificity of the assay had not been determined using serum samples from the pig population of the United States. This study describes an evaluation of the World Organization for Animal Health (OIE)-recommended Ingezim PPA COMPAC ELISA using a comprehensive cohort (n = 1791) of samples collected in the United States. The diagnostic specificity of the assay was determined to be 99.4% (95% confidence interval (CI): [98.9, 99.7]). The result of this study fills a gap in understanding the performance of the Ingezim PPA COMPAC ELISA in the ASF naive pig population of the United States. PMID- 28921874 TI - Polaronic Charge Carrier-Lattice Interactions in Lead Halide Perovskites. AB - Almost ten years after the renaissance of the popular perovskite-type semiconductors based on lead salts with the general formula AMX3 (A=organic or inorganic cation; M=divalent metal; X=halide), many facets of photophysics continue to puzzle researchers. In this Minireview, light is shed on the low mobilities of charge carriers in lead halide perovskites with special focus on the lattice properties at non-zero temperature. The polar and soft lattice leads to pronounced electron-phonon coupling, limiting carrier mobility and retarding recombination. We propose that the proper picture of excited charge carriers at temperature ranges that are relevant for device operations is that of a polaron, with Frohlich coupling constants between 1=30 mg/g or estimated glomerular filtration rate <60 mL/min/1.73 m2 . Over 8 years, 20.1% of participants without CKD and 30.5% with CKD developed aTRH. The multivariable-adjusted hazard ratio for aTRH comparing participants with CKD vs those without CKD was 1.45 (95% CI, 1.12-1.86). Participants with an albumin to creatinine ratio >=30 vs <30 mg/g (hazard ratio, 1.44; 95% CI, 1.04-2.00) and estimated glomerular filtration rate of 45 to 59 mL/min/1.73 m2 and <45 vs >=60mL/min/1.73 m2 (hazard ratio, 1.60 [95% CI, 1.16 2.20] and 2.05 [95% CI, 1.28-3.26], respectively) were more likely to develop aTRH. PMID- 28921876 TI - Validation of artificial neural networks as a methodology for donor-recipient matching for liver transplantation. AB - In 2014, we reported a model for donor-recipient (D-R) matching in liver transplantation (LT) based on artificial neural networks (ANNs) from a Spanish multicenter study (Model for Allocation of Donor and Recipient in Espana [MADR E]). The aim is to test the ANN-based methodology in a different European health care system in order to validate it. An ANN model was designed using a cohort of patients from King's College Hospital (KCH; n = 822). The ANN was trained and tested using KCH pairs for both 3- and 12-month survival models. End points were probability of graft survival (correct classification rate [CCR]) and nonsurvival (minimum sensitivity [MS]). The final model is a rule-based system for facilitating the decision about the most appropriate D-R matching. Models designed for KCH had excellent prediction capabilities for both 3 months (CCR area under the curve [AUC] = 0.94; MS-AUC = 0.94) and 12 months (CCR-AUC = 0.78; MS-AUC = 0.82), almost 15% higher than the best obtained by other known scores such as Model for End-Stage Liver Disease and balance of risk. Moreover, these results improve the previously reported ones in the multicentric MADR-E database. In conclusion, the use of ANN for D-R matching in LT in other health care systems achieved excellent prediction capabilities supporting the validation of these tools. It should be considered as the most advanced, objective, and useful tool to date for the management of waiting lists. Liver Transplantation 24 192-203 2018 AASLD. PMID- 28921877 TI - Analysis of infantile fibrosarcoma reveals extensive T-cell responses within tumors: Implications for immunotherapy. AB - BACKGROUND: Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors. PROCEDURE: IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells. Real-time PCR was applied to evaluate tumor expression of chemokines/cytokines and tumor antigens. RESULTS: Significant infiltration of both CD4+ and CD8+ T cells was found in seven of 10 IFS but rarely found in age- and sex-matched rhabdomyosarcoma tumors. The TILs from recurrent IFS tumors expressed high levels of costimulatory molecules such as CD28, 4-1BB, and OX40, but little or no coinhibitory molecules such as PD-1 and CTLA4, Tim3, Lag3, and CD39. Upon activation, large portions of TILs produced IFN gamma and TNF-alpha. Eighteen out of 40 T cell lines generated from surgically removed tumors could recognize autologous tumor cells. Moreover, we found that IFS tumors expressed high levels of T-cell chemokines such as CXCL10 and CXCL16, and also classic tumor antigens such as CTAG2, GAGE, and NY-ESO-1, whose expression could be further enhanced by treatment with epigenetic modulator decitabine. CONCLUSIONS: IFS tumors are highly immunogenic and expansion of TILs followed by adoptive cell transfer could be a potential immunotherapy for IFS patients undergoing tumor recurrence. PMID- 28921878 TI - Simplifying sampling for African swine fever surveillance: Assessment of antibody and pathogen detection from blood swabs. AB - African swine fever (ASF) is a notifiable disease with serious socio-economic consequences that has been present in wild boar in the Baltic States and Poland since 2014. An introduction of ASF is usually accompanied by increased mortality, making fallen wild boar and hunted animals with signs of disease the main target for early warning and passive surveillance. It is difficult, however, to encourage hunters and foresters to report and take samples from these cases. A pragmatic and easy sampling approach with quick-drying swabs could facilitate this. In this study, we further evaluated the use of dry blood swabs for the detection of ASFV antibody and genome with samples from animal trials and diagnostic submissions (blood, bone and organs) from Estonia. Compared to serum samples, dried blood swabs yielded 93.1% (95% confidence interval: [83.3, 98.1]) sensitivity and 100% [95.9, 100.0] specificity in a commercial ASFV antibody ELISA. Similarly, the swabs gave a sensitivity of 98.9% [93.4, 100.0] and a specificity of 98.1% [90.1, 100.0] for genome detection by a standard ASFV p72 qPCR when compared to EDTA blood. The same swabs were tested in a VP72-antibody lateral flow device, with a sensitivity of 94.7% [85.4, 98.9] and specificity of 96.1% [89.0, 99.2] compared to the serum ELISA. When GenoTube samples tested in ELISA and LFD were compared, the sensitivity was 96.3% [87.3, 99.5] and the specificity was 93.8% [86.0, 97.9]. This study demonstrates reliable detection of ASFV antibody and genome from swabs. A field test of the swabs with decomposed wild boar carcasses in an endemic area in Estonia also gave promising results. Thus, this technique is a practical approach for surveillance of ASF in both free and endemic areas. PMID- 28921879 TI - Natural and Artificial Mn4 Ca Cluster for the Water Splitting Reaction. AB - The oxygen-evolving center (OEC) in photosystem II (PSII) is a unique biological catalyst that splits water into electrons, protons, and O2 by using solar energy. Recent crystallographic studies have revealed that the structure of the OEC is an asymmetric Mn4 Ca cluster, which provides a blueprint to develop man-made water splitting catalysts for artificial photosynthesis. Although it is a great challenge to mimic the whole structure and function of the OEC in the laboratory, significant advances have recently been achieved. In this Minireview, recent progress on mimicking the natural OEC is discussed. New strategies are suggested to construct more stable and efficient new generation of catalytic materials for the water splitting reaction based on the artificial Mn4 Ca cluster in the future. PMID- 28921880 TI - Dwarfism in homozygous Agc1CreERT mice is associated with decreased expression of aggrecan. AB - Aggrecan (Acan), a large proteoglycan is abundantly expressed in cartilage tissue. Disruption of Acan gene causes dwarfism and perinatal lethality of homozygous mice. Because of sustained expression of Acan in the growth plate and articular cartilage, AgcCre model has been developed for the regulated ablation of target gene in chondrocytes. In this model, the IRES-CreERT-Neo-pgk transgene is knocked-in the 3'UTR of the Acan gene. We consistently noticed variable weight and size among the AgcCre littermates, prompting us to examine the cause of this phenotype. Wild-type, Cre-heterozygous (Agc+/Cre ), and Cre-homozygous (AgcCre/Cre ) littermates were indistinguishable at birth. However, by 1-month, AgcCre/Cre mice showed a significant reduction in body weight (18-27%) and body length (19-22%). Low body weight and dwarfism was sustained through adulthood and occurred in both genders. Compared with wild-type and Agc+/Cre littermates, long bones and vertebrae were shorter in AgcCre/Cre mice. Histological analysis of AgcCre/Cre mice revealed a significant reduction in the length of the growth plate and the thickness of articular cartilage. The amount of proteoglycan deposited in the cartilage of AgcCre/Cre mice was nearly half of the WT littermates. Analysis of gene expression indicates impaired differentiation of chondrocyte in hyaline cartilage of AgcCre/Cre mice. Notably, both Acan mRNA and protein was reduced by 50% in AgcCre/Cre mice. A strong correlation was noted between the level of Acan mRNA and the body length. Importantly, Agc+/Cre mice showed no overt skeletal phenotype. Thus to avoid misinterpretation of data, only the Agc+/Cre mice should be used for conditional deletion of a target gene in the cartilage tissue. PMID- 28921881 TI - Use of a radial projection to reduce the statistical uncertainty of spot lateral profiles generated by Monte Carlo simulation. AB - Monte Carlo (MC) simulation has been used to generate commissioning data for the beam modeling of treatment planning system (TPS). We have developed a method called radial projection (RP) for postprocessing of MC-simulation-generated data. We used the RP method to reduce the statistical uncertainty of the lateral profile of proton pencil beams with axial symmetry. The RP method takes advantage of the axial symmetry of dose distribution to use the mean value of multiple independent scores as the representative score. Using the mean as the representative value rather than any individual score results in substantial reduction in statistical uncertainty. Herein, we present the concept and step-by step implementation of the RP method, as well as show the advantage of the RP method over conventional measurement methods for generating lateral profile. Lateral profiles generated by both methods were compared to demonstrate the uncertainty reduction qualitatively, and standard error comparison was performed to demonstrate the reduction quantitatively. The comparisons showed that statistical uncertainty was reduced substantially by the RP method. Using the RP method to postprocess MC data, the corresponding MC simulation time was reduced by a factor of 10 without quality reduction in the generated result from the MC data. We concluded that the RP method is an effective technique to increase MC simulation efficiency for generating lateral profiles for axially symmetric pencil beams. PMID- 28921882 TI - Recommendations for obesity prevention among adolescents from disadvantaged backgrounds: a concept mapping study among scientific and professional experts. AB - The present study aimed to enrich the scientific evidence on obesity prevention programmes for adolescents from socio-economically disadvantaged backgrounds with practice-based experiences from both scientific and professional experts in the field of youth obesity prevention. We used the participatory method of concept mapping. Two concept mapping sessions were conducted: one with programme coordinators of national/regional obesity prevention programmes across Europe (n = 8) and one with scientists participating in European obesity prevention projects (n = 5). Five recommendations were extracted from both concept maps: (1) involve adolescents in the design and delivery of the programme, (2) invest in family/parental capacity building, (3) provide and support a healthy school food and physical activity environment, (4) regulate exposure to unhealthy messages/advertising and (5) facilitate safe and active travel. These recommendations can be used as a conceptual framework for programme development for preventing obesity in adolescents. PMID- 28921883 TI - Role of Co-Sensitizers in Dye-Sensitized Solar Cells. AB - Co-sensitization is a popular route towards improved efficiency and stability of dye-sensitized solar cells (DSSCs). In this context, the power conversion efficiency (PCE) values of DSSCs incorporating Ru- and porphyrin-based dyes can be improved from 8-11 % to 11-14 % after the addition of additives, co adsorbents, and co-sensitizers that reduce aggregation and charge recombination in the device. Among the three supporting material types, co-sensitizers play a major role to enhance the performance and stability of DSSCs, which is requried for commercialization. In this Minireview, we highlight the role co-sensitizers play in improving photovoltaic performance of devices containing Ru- and porphyrin-based sensitizers. PMID- 28921884 TI - Structural characterization and functional analysis of cystathionine beta synthase: an enzyme involved in the reverse transsulfuration pathway of Bacillus anthracis. AB - : The reverse transsulfuration pathway has been reported to produce cysteine from homocysteine in eukaryotes ranging from protozoans to mammals while bacteria and plants produce cysteine via a de novo pathway. Interestingly, the bacterium Bacillus anthracis includes enzymes of the reverse transsulfuration pathway viz. cystathionine beta-synthase [BaCBS, previously annotated to be an O-acetylserine sulfhydrylase (OASS)] and cystathionine gamma-lyase. Here, we report the structure of BaCBS at a resolution of 2.2 A. The enzyme was found to show CBS activity only with activated serine (O-acetylserine) and not with serine, and was also observed to display OASS activity but not serine sulfhydrylase activity. BaCBS was also found to produce hydrogen sulfide (H2 S) upon reaction of cysteine and homocysteine. A mutational study revealed Glu 220, conserved in CBS, to be necessary for generating H2 S. Structurally, BaCBS display a considerably more open active site than has been found for any other CBS or OASS, which was attributed to the presence of a helix at the junction of the C- and N-terminal domains. The root-mean-square deviation (RMSD) between the backbone Calpha carbon atoms of BaCBS and those of other CBSs and OASSs were calculated to be greater than 3.0 A. The pyridoxal 5'-phosphate at the active site was not traced, and appeared to be highly flexible due to the active site being wide open. Phylogenetic analysis revealed the presence of an O-acetylserine-dependent CBS in the bacterial domain and making separate clade from CBS and OASS indicating its evolution for specific function. DATABASE: Structural data are available in the PDB under the accession number 5XW3. PMID- 28921885 TI - Identification of a divergent genotype of equine arteritis virus from South American donkeys. AB - A novel equine arteritis virus (EAV) was isolated and sequenced from feral donkeys in Chile. Phylogenetic analysis indicates that the new virus and South African asinine strains diverged at least 100 years from equine EAV strains. The results indicate that asinine strains belonged to a different EAV genotype. PMID- 28921886 TI - Clinical practices and attitudes regarding the diagnosis and management of heart failure: findings from the CORE Needs Assessment Survey. AB - AIMS: CORE is a continuing medical education initiative designed to support the evidence-based management of heart failure (HF) in the primary and secondary care settings. The goal of the CORE Needs Assessment Survey is to describe current clinical practice patterns and attitudes among global stakeholders in HF care. METHODS AND RESULTS: The CORE Steering Committee guided the development of survey questions to assess clinical practice, confidence, and attitudes/perceptions among cardiologists, primary care physicians, and nurses involved in HF management. In total, 346 healthcare professionals from Australia (n = 59), Austria (n = 59), Canada (n = 60), Spain (n = 58), Sweden (n = 52), and the UK (n = 58) contributed survey data. Results revealed multiple gaps over the spectrum of HF care, including diagnosis (low recognition of the signs and symptoms of HF and limited use of diagnostic tests), treatment planning (underuse of recommended agents and subtherapeutic dosing), treatment monitoring and adjustment (lack of adherence to recommendations), and long-term management (low confidence in providing patient education). Although primary care and specialist physicians and nurses shared common unmet needs, healthcare professional-specific clinical gaps were also identified. CONCLUSIONS: The CORE Needs Assessment Survey provides timely data describing current clinical practices and attitudes among physicians and nurses regarding key aspects of HF care. These findings will be useful for guiding the development of interventions tailored to the specific educational needs of different provider types and designed to support the evidence-based care of patients with HF. PMID- 28921888 TI - Erratum. PMID- 28921887 TI - Chemical Components, Biological Activities, and Toxicological Evaluation of the Fruit (Aril) of Two Precious Plant Species from Genus Taxus. AB - The fruit (aril) of the endangered genus Taxus plants is an abandoned herbal resource. Traditionally, people enthusiastically focus on its bark, its renewable, tremendous arils fall into the soil with seeds after they are mature. The present research investigated the fruit of two species from the genus Taxus, Taxus chinensis var. mairei, and Taxus media, with regards to their antioxidant and antihyperglycaemic activities, safety, and bioactive constituents. Results showed that T. chinensis var. mairei and T. media both had certain biological activities with T. chinensis var. mairei better in antioxidant activity and T. media better in antihyperglycaemic activity. Correlation analysis revealed that the differences in bioactivities depended on content of their mainly chemical components. The mice acute oral toxicity test indicated that the methanol extracts of the two biotypes of Taxus were safe. And nineteen compounds were tentatively assigned from the two varieties, via tandem mass spectrometry using a LC-ESI-Q-TOF-MS instrument, which included phenols, flavonoids, and terpenes. These results indicate a possible application of Taxus fruit extracts in various fields like in food industry, however, this still needs further investigations. PMID- 28921889 TI - The reality of de novo malignancy: Sadly, not fake news. PMID- 28921892 TI - Viral reactivation imitates relapse of pemphigus vulgaris in an immunosuppressed patient. PMID- 28921891 TI - Enhanced formation of >C1 Products in Electroreduction of CO2 by Adding a CO2 Adsorption Component to a Gas-Diffusion Layer-Type Catalytic Electrode. AB - The addition of a CO2 -adsorption component (substituted imidazolate-based SIM-1 crystals) to a gas-diffusion layer-type catalytic electrode enhances the activity and especially the selectivity towards >C1 carbon chain products (ethanol, acetone, and isopropanol) of a Pt-based electrocatalyst that is not able to form products of CO2 reduction involving C-C bond formation under conventional (liquid phase) conditions. This indicates that the increase of the effective CO2 concentration at the electrode active surface is the factor controlling the formation of >C1 products rather than only the intrinsic properties of the electrocatalyst. PMID- 28921890 TI - Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. AB - : Essentials Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism. Children aged 1 to < 12 years were given dabigatran etexilate in an open-label, single-arm study. The pharmacokinetic pharmacodynamic relationship was similar to that seen in adult patients. There were no serious adverse events, bleeding events or recurrent venous thromboembolism. SUMMARY: Background The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. Objectives To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE. Patients/Methods Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age-adjusted and weight-adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics-related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)-pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs). Results Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady-state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single-dose group (screening period) and in one patient in the multiple-dose group (on-treatment period). Conclusion The current study supports the further evaluation of DE OLFs in pediatric patients with VTE. PMID- 28921893 TI - A case of ocular infection with Onchocerca lupi in a dog from Germany. AB - Onchocerca lupi is an emerging zoonotic parasite infecting the ocular connective tissue of dogs, cats and humans. The only known case of canine ocular onchocerciasis in Germany was documented in 2002 in a shelter dog. However, the species of Onchocerca causing the infection could not be identified. Here, we report a case of the ocular infection with O. lupi in a dog, confirmed by PCR and sequencing of the cox1 gene. Further investigations are required to assess the risk factors for transmission and spread of the parasite in Germany. PMID- 28921894 TI - Macrophage Area Content and Phenotype in Hepatic and Adipose Tissue in Patients with Obesity Undergoing Roux-en-Y Gastric Bypass. AB - OBJECTIVE: To investigate hepatic and adipose tissue macrophage content in subjects with obesity and the role of adipose tissue macrophages in weight loss induced improved insulin sensitivity (IS). METHODS: A cross-sectional and a longitudinal study were combined to investigate the role of macrophages in subcutaneous (SAT) and visceral (VAT) adipose tissue and the liver in obesity induced impaired IS and improvements with weight loss. Macrophage markers (CD68, CD163, and CD206) in SAT, VAT, and the liver from patients with obesity were investigated. The same macrophage markers were investigated in SAT from 18 patients with obesity before and ~18 months after a diet- and Roux-en-Y gastric bypass-induced weight loss. RESULTS: SAT macrophage markers did not decrease with weight loss, but macrophage concentration may have increased, concomitant with improved IS. Hepatic macrophage markers did not correlate to VAT mass or macrophage markers, but they were higher in patients with obesity compared with patients without obesity. Hepatic anti-inflammatory macrophage markers correlated positively with hepatic IS. VAT and SAT macrophage markers did not correlate. CONCLUSIONS: The results indicate that decreased SAT macrophage content is not a primary driver for weight loss-induced IS improvements, but a better hepatic CD163 and CD206 macrophage profile may contribute to improved glycemic control. SAT macrophage markers were not predictive for VAT macrophage markers. PMID- 28921895 TI - Genetic characterization of African swine fever virus isolates from soft ticks at the wildlife/domestic interface in Mozambique and identification of a novel genotype. AB - African swine fever virus (ASFV) is one of the most threatening infectious diseases of pigs. There are not sufficient data to indicate the importance of the sylvatic cycle in the spread and maintenance of the disease locally and potentially, globally. To assess the capacity to maintain ASF in the environment, we investigated the presence of soft tickreservoirs of ASFV in Gorongosa National Park (GNP) and its surrounding villages. A total of 1,658 soft ticks were recovered from warthog burrows and pig pens at the wildlife/livestock interface of the GNP and viral DNA was confirmed by nested PCR in 19% of Ornithodoros porcinus porcinus and 15% of O. p. domesticus. However, isolation of ASFV was only achieved in approximately 50% of the PCR-positive samples with nineteen haemadsorbing virus isolates recovered. These were genotyped using a combination of partial sequencing of the B646L gene (p72) and analysis of the central variable region (CVR) of the B602L gene. Eleven isolates were classified as belonging to genotype II and homologous to contemporary isolates from southern Africa, the Indian Ocean and eastern Europe. Three isolates grouped within genotype V and were similar to previous isolates from Mozambique and Malawi. The remaining five isolates constituted a new, previously unidentified genotype, designated genotype XXIV. This work confirms for the first time that the virus currently circulating in eastern Europe is likely to have a wildlife origin, and that the large diversity of ASFV maintained in wildlife areas can act as a permanent sources of different strains for the domestic pig value chain in Mozambique and beyond its boundaries. Their genetic similarity to ASFV strains currently spreading across Europe justifies the need to continue studying the sylvatic cycle in this African country and other parts of southern Africa in order to identify potential hot spots of ASF emergence and target surveillance and control efforts. PMID- 28921896 TI - Evaluating Potential Risks of Food Allergy and Toxicity of Soy Leghemoglobin Expressed in Pichia pastoris. AB - SCOPE: The Soybean (Glycine max) leghemoglobin c2 (LegHb) gene was introduced into Pichia pastoris yeast for sustainable production of a heme-carrying protein, for organoleptic use in plant-based meat. The potential allergenicity and toxicity of LegHb and 17 Pichia host-proteins each representing >=1% of total protein in production batches are evaluated by literature review, bioinformatics sequence comparisons to known allergens or toxins, and in vitro pepsin digestion. METHODS AND RESULTS: Literature searches found no evidence of allergenicity or toxicity for these proteins. There are no significant sequence matches of LegHb to known allergens or toxins. Eleven Pichia proteins have modest identity matches to minor environmental allergens and 13 Pichia proteins have significant matches to proteins from toxic sources. Yet the matched allergens and toxins have similar matches to proteins from the commonly consumed yeast Saccharomyces cerevisiae, without evidence of food allergy or toxicity. The demonstrated history of safe use indicates additional tests for allergenicity and toxicity are not needed. The LegHb and Pichia sp. proteins were rapidly digested by pepsin at pH 2. CONCLUSION: These results demonstrate that foods containing recombinant soy LegHb produced in Pichia sp. are unlikely to present an unacceptable risk of allergenicity or toxicity to consumers. PMID- 28921897 TI - A Combined Experimental and Theoretical Approach to Understand the Structure and Properties of N-Methylpyrrolidone-Based Protic Ionic Liquids. AB - Correlation of the structure and properties of ionic liquids (ILs) is essential for the development of optimized materials in the fields of gas capture and separation, battery electrolytes, and cellulose dissolution processes. In view of this, a detailed vibrational spectroscopic analysis and quantum-chemical calculations were performed to explore the interionic interactions in ILs based on the N-methylpyrrolidone cation and a carboxylate anion. FTIR and Raman spectroscopy were applied to identify the hydrogen-bonding interactions between ion pairs, in which redshifted vibrational modes were observed as a function of the anion chain length. This observation was verified by the bond lengthening and enhanced hydrogen-bonding energies, as manifested in the structure and natural bond orbital (NBO) calculations. Furthermore, conductivity was measured at different temperatures to envisage the effect of the alkyl chain on the mobility of ions in the ILs. Finally, rheological measurements were implemented to explain the flow behavior of these ILs, which revealed a decrease in shear viscosity with an increase in temperature, that is, a Newtonian trend over a range of shear rates. The observed trend in transport properties was supported by the ion-pair binding energy. Stronger interactions between the IL cations and anions led to a decrease in the number of free ions and lowered the conductivity. In these protic ILs, the intermolecular N-H???O and C-H???O interactions played an important role in governing their physicochemical properties. PMID- 28921898 TI - Maternal Chronic Folate Supplementation Ameliorates Behavior Disorders Induced by Prenatal High-Fat Diet Through Methylation Alteration of BDNF and Grin2b in Offspring Hippocampus. AB - SCOPE: Maternal consumption of a high-fat diet (HFD) during pregnancy increases the risk of behavioral problems. Folate plays an important role in neuroplasticity and the preservation of neuronal integrity. This study aims at determining the influence of diets supplemented with folate on offspring behavior, and the mechanisms involved. METHODS AND RESULTS: Female mice were fed a control diet, an HFD, control diet supplemented with folate, or an HFD supplemented with folate for 5 weeks before mating. Open field task and elevated plus maze are used to evaluate the offspring behaviors. Results showed that offspring cognitive performance and anxiety-related behaviors, including those related to open field exploration and elevated plus maze, were significantly improved when dams were treated with folate in pregnancy. Moreover, the maternal folate supplement decreased BDNF and Grin2b methylation and upregulated their expressions in the brain of offspring, which were associated with decreasing the expression of DNA methyltransferases compared with those dams were treated only HFD in pregnancy. CONCLUSION: Maternal folate supplementation ameliorates behavior disorders induced by prenatal high-fat diet. The beneficial effects were associated with methylation and expression alteration of BDNF and Grin2b genes. PMID- 28921899 TI - Stimulus-Induced Conformational Transformation of a Cyclic Peptide for Selective Cell-Targeting On-Off Gatekeeper for Mesoporous Nanocarriers. AB - alphav beta3 Integrin is upregulated on many cancer cells. We designed a dual functional cyclic peptide gatekeeper with a capability of stimuli-responsive conformational transformation which could serve as a selective cell-targeting on off gatekeeper for mesoporous nanocarriers. The advantage of employing the motif of stimuli-induced conformational transformation of cyclic peptides is that they could be utilized not only as an on-off gatekeeper for the triggered release of cargo drugs but also as a targeting ligand of the carriers to desired cells with their respective binding receptors. The peptide gatekeepers on the surface of nanocarriers exhibited on-off gatekeeping via conformational transformation triggered by intracellular glutathione levels of the cancer cells. The cyclic RGD sequence of the peptide gatekeepers enhanced the intracellular uptake into tumor cells (A549) and the therapeutic efficacy of the nanocarrier. PMID- 28921900 TI - Efficacy and safety of switching from basal insulin to once-daily insulin degludec/insulin aspart in Japanese patients with inadequately controlled type 2 diabetes: A 4-week, randomized, open-label, treat-to-target study. AB - AIMS/INTRODUCTION: A prospective, 4-week, single-center, randomized, open-label, parallel-group, treat-to-target study was carried out to develop an algorithm for safe and effective switching from basal insulin to once-daily insulin degludec/insulin aspart (IDegAsp) in patients with inadequately controlled type 2 diabetes. MATERIALS AND METHODS: Patients were randomly assigned to continue their current basal insulin therapy (n = 10) or to switch to IDegAsp on a 1:1 unit basis (n = 10). The insulin dose could be titrated once weekly, targeting a self-measured blood glucose of 80-100 mg/dL before breakfast. A mixed meal test was carried out at baseline and after 4 weeks. RESULTS: After 4 weeks, the mean daily dose of insulin was similarly increased by 60% in both groups, and there was a significant decrease of mean plasma glucose and glucose area under the glucose concentration vs time curve for 2 h in the meal test. The mean estimated treatment difference (IDegAsp group - basal insulin group) of the mean plasma glucose level was -28 mg/dL (95% confidence interval -47 to -8, P = 0.008) after 4 weeks and that of the area under the glucose concentration vs time curve for 2 h was -2,800 mg/min/dL (95% confidence interval -5,300 to -350, P = 0.028), confirming the superiority of IDegAsp to basal insulin. In the IDegAsp group, the 2-h postprandial plasma glucose level was significantly decreased to the fasting plasma glucose range. There were no confirmed hypoglycemic episodes in either group during the 4-week study period. CONCLUSIONS: After switching from basal insulin, the IDegAsp dose can be uptitrated by 60% based on fasting plasma glucose data. However, monitoring of postprandial glucose should be considered before further uptitration of IDegAsp. PMID- 28921901 TI - StructureSelector: A web-based software to select and visualize the optimal number of clusters using multiple methods. AB - Inferences of population genetic structure are of great importance to the fields of ecology and evolutionary biology. The program structure has been widely used to infer population genetic structure. However, previous studies demonstrated that uneven sampling often leads to wrong inferences on hierarchical structure. The most widely used DeltaK method tends to identify the uppermost hierarchy of population structure. Recently, four alternative statistics (medmedk, medmeak, maxmedk and maxmeak) were proposed, which appear to be more accurate than the previously used methods for both even and uneven sampling data. However, the lack of easy-to-use software limits the use of these appealing new estimators. Here, we developed a web-based user-friendly software structureselector to calculate the four appealing alternative statistics together with the commonly used Ln Pr(X|K) and DeltaK statistics. structureselector accepts the result files of structure, admixture or faststructure as input files. It reports the "best" K for each estimator, and the results are available as HTML or tab separated tables. The program can also generate graphical representations for specific K, which can be easily downloaded from the server. The software is freely available at http://lmme.qdio.ac.cn/StructureSelector/. PMID- 28921903 TI - Risk factors for postoperative ileus after colorectal cancer surgery. AB - AIM: To assess the rate and independent risk factors of postoperative ileus (POI) after colorectal cancer surgery. METHODS: Three hundred consecutive patients underwent colorectal surgery for cancer at the State Scientific Centre of coloproctology, Moscow, Russia, between November 2015 and August 2016. POI was diagnosed as an absence of intestinal function for 72 hours or more after operation and confirmed by plain radiography. Uni- and multivariate logistic regression of the tumour-, patient- and treatment-related factors was performed. All patients had epidural catheters with multimodal analgesia. RESULTS: Thirty nine patients (13%) had postoperative ileus. The variables associated with this condition in univariate analysis were age < 64 y.o. (p = 0.02), male gender (p = 0.02), BMI >= 25 kg/m2 (p = 0.02), moderate drinking (p = 0.02), heavier drinking (p < 0.0001), opioids (p = 0.02), history of abdominal operation (p = 0.003), firm, extensive adhesions as a result of previous surgery (p = 0.005), multivisceral resection (p = 0.009), blood loss >= 150 mL (p = 0.006), haemotransfusion (p = 0.01) and open approach (p = 0.006). In the multivariate logistic regression, BMI >= 26 kg/m2 (p = 0.008), opioids (p = 0.04) history of abdominal operation (p = 0.04) and adhesions (p = 0.03) were identified as independent risk factors. CONCLUSION: Postoperative ileus is a common complication in colorectal surgery. The results of our study suggest at least two surgeon-dependent risk factors, i.e., open approach and opioids in the postoperative period. This article is protected by copyright. All rights reserved. PMID- 28921902 TI - Mechanistic Parameters of Electrocatalytic Water Oxidation on LiMn2 O4 in Comparison to Natural Photosynthesis. AB - Targeted improvement of the low efficiency of water oxidation during the oxygen evolution reaction (OER) is severely hindered by insufficient knowledge of the electrocatalytic mechanism on heterogeneous surfaces. We chose LiMn2 O4 as a model system for mechanistic investigations as it shares the cubane structure with the active site of photosystem II and the valence of Mn3.5+ with the dark stable S1 state in the mechanism of natural photosynthesis. The investigated LiMn2 O4 nanoparticles are electrochemically stable in NaOH electrolytes and show respectable activity in any of the main metrics. At low overpotential, the key mechanistic parameters of Tafel slope, Nernst slope, and reaction order have constant values on the RHE scale of 62(1) mV dec-1 , 1(1) mV pH-1 , -0.04(2), respectively. These values are interpreted in the context of the well-studied mechanism of natural photosynthesis. The uncovered difference in the reaction sequence is important for the design of efficient bio-inspired electrocatalysts. PMID- 28921904 TI - Developing a DNA barcode library for perciform fishes in the South China Sea: Species identification, accuracy and cryptic diversity. AB - DNA barcodes were studied for 1,353 specimens representing 272 morphological species belonging to 149 genera and 55 families of Perciformes from the South China Sea (SCS). The average Kimura 2-parameter (K2P) distances within species, genera and families were 0.31%, 8.71% and 14.52%, respectively. A neighbour joining (NJ) tree, Bayesian inference (BI) and maximum-likelihood (ML) trees and Automatic Barcode Gap Discovery (ABGD) revealed 260, 253 and 259 single-species representing clusters, respectively. Barcoding gap analysis (BGA) demonstrated that barcode gaps were present for 178 of 187 species analysed with multiple specimens (95.2%), with the minimum interspecific distance to the nearest neighbour larger than the maximum intraspecific distance. A group of three Thunnus species (T. albacares, T. obesus and T. tonggol), a pair of Gerres species (G. oyena and G. japonicus), a pair of Istiblennius species (I. edentulous and I. lineatus) and a pair of Uranoscopus species (U. oligolepis and U. kaianus) were observed with low interspecific distances and overlaps between intra- and interspecific genetic distances. Three species (Apogon ellioti, Naucrates ductor and Psenopsis anomala) showed deep intraspecific divergences and generated two lineages each, suggesting the possibility of cryptic species. Our results demonstrated that DNA barcodes are highly reliable for delineating species of Perciformes in the SCS. The DNA barcode library established in this study will shed light on further research on the diversity of Perciformes in the SCS. PMID- 28921905 TI - Antibiotic resistant Escherichia coli in southeastern Australian pig herds and implications for surveillance. AB - To investigate public health implications of antibiotics to control post-weaning scours, we surveyed 22 commercial pig herds in southeastern Australia. Fifty faecal samples per herd were collected from pre- and post-weaned piglets. Presumptive Escherichia coli isolates were confirmed by MALDI-TOF MS. Isolates (n = 325) were screened for susceptibility to 19 veterinary antibiotics using MIC broth microdilution. All 325 E. coli isolates underwent further testing against 27 antibiotics used in human medicine and were screened for ETEC adhesin and enterotoxin genes (F4 (K88), F5 (K99), F6 (987P), F18, F41, STa, STb, Stx2e and LT) by multiplex PCR. Isolates identified as phenotypically resistant to third generation cephalosporin (3GC) and aminoglycoside antibiotics were screened by multiplex PCR/reverse line blot to detect common beta-lactam and aminoglycosides resistance genes, confirmed by sequencing. Twenty (6.1%) of the E. coli isolates were resistant to 3GC antibiotics and 24 (7.4%) to the aminoglycoside antibiotic gentamicin. Genetic analysis revealed six different extended spectrum beta lactamase (ESBL) genes (blaCTX-M-1, -14, -15, -27, blaSHV-12 and blaCMY-2-like genes), four of which have not been previously reported in Australian pigs. Critically, the prevalence of 3GC resistance was higher in non-pathogenic (non ETEC) isolates and those from clinically normal (non-diarrhoeal) samples. This highlights the importance of non-ETECE. coli as reservoirs of antimicrobial resistance genes in piglet pens. Antimicrobial resistance surveillance in pig production focused on diagnostic specimens from clinically-affected animals might be potentially misleading. We recommend that surveillance for emerging antimicrobial resistance such as to 3GC antibiotics should include clinically healthy pigs. PMID- 28921906 TI - Outcomes of severe uveitic glaucoma treated with Baerveldt implant: can blindness be prevented? AB - PURPOSE: To evaluate long-term outcomes on efficacy and safety of severe uveitic glaucoma treated with a Baerveldt glaucoma implant (BGI). METHODS: A retrospective study of 47 eyes of 47 patients with uveitic glaucoma treated by a BGI between September 2002 and September 2015. Main outcome measures were intraocular pressure (IOP), number of glaucoma medications, course of the uveitis, visual acuity (VA) and complications. RESULTS: Mean IOP dropped from 30.6 +/- 8.1 mmHg with 3.6 +/- 1.1 glaucoma medications at baseline to 10.6 +/- 4.3 mmHg with 1.0 +/- 1.3 glaucoma medications after a mean follow-up of 63.6 +/- 43.1 months. In the majority of cases, IOP remained stable during follow-up. However, especially in several patients with viral uveitis, episodes with IOP peaks were observed during a flare-up despite a functioning implant. These peaks remained below preoperative levels. During follow-up, 16 patients (34%) experienced a clinically significant VA loss, mainly because of late-stage glaucoma or hypotony maculopathy. Early postoperative complications were transient choroidal effusion (n = 5), shallow/flat anterior chamber (n = 4), hyphaema (n = 2) and suprachoroidal haemorrhage (n = 1). The most important late postoperative complication was hypotony maculopathy (n = 5), three of these in juvenile idiopathic arthritis (JIA) patients. CONCLUSION: The BGI is an effective and safe treatment for patients with refractive secondary glaucoma due to uveitis. In a majority of patients, VA remains stable and a low and stable IOP is maintained over time with an acceptable number of complications. In particular, patients with viral uveitis and glaucoma should be closely monitored for IOP peaks that may occur during episodes of a flare-up of uveitis, whereas at the other end of the spectrum, patients with JIA seem much more prone to hypotony maculopathy. PMID- 28921907 TI - Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma. AB - Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS-mutant and BRAFWT NRASWT metastatic melanoma. To target these pathways, NRAS mutant and BRAFWT NRASWT patients received oral trametinib at 1.5 mg daily and GSK2141795 at 50 mg daily in a two-cohort Simon two-stage design. Participants had adequate end-organ function and no more than two prior treatment regimens. Imaging assessments were performed at 8-week intervals. A total of 10 NRAS-mutant and 10 BRAFWT NRASWT patients were enrolled. No objective responses were noted in either cohort. The median PFS and OS were 2.3 and 4.0 months in the NRAS-mutant cohort and 2.8 and 3.5 months in the wild-type cohort. Grade 3 and grade 4 adverse events, primarily rash, were observed in 25% of patients. We conclude that the combination of trametinib and GSK2141795 does not have significant clinical activity in NRAS-mutant or BRAFWT NRASWT melanoma. PMID- 28921908 TI - Biphasic insulin aspart-30 reduces glycemic variability to a greater degree than insulin detemir: A randomized controlled trial of once-daily insulin regimens using continuous glucose monitoring. AB - INTRODUCTION: We compared the efficacy of insulin detemir and biphasic insulin aspart-30 given in the morning as an add-on to oral hypoglycemic agents in type 2 diabetes patients. MATERIALS AND METHODS: The present study enrolled 30 patients with poorly controlled type 2 diabetes (8% <= glycated hemoglobin < 11%) being treated with oral hypoglycemic agent mono- or combination therapy with biguanides, sulfonylureas or thiazolidinediones. The patients were randomly assigned to insulin detemir (group D) or insulin aspart-30 (group A) given in the morning as add-on to oral hypoglycemic agents. After adjusting their insulin doses, the patients that underwent continuous glucose monitoring during a 3-day hospitalization and with day 2 continuous glucose monitoring data were subjected to analysis. RESULTS: There was no significant difference in patient background, baseline glycated hemoglobin levels and insulin doses during continuous glucose monitoring between the two groups. The percent coefficient of variation of 24-h glucose levels was significantly lower in group A (20.4 +/- 7.6) than in group D (27.1 +/- 6.5; P = 0.015). Similarly, mean amplitude of glycemic excursions was significantly smaller in group A (80 +/- 32) than in group D (102 +/- 14; P = 0.021). Postprandial glucose excursions were significantly smaller after breakfast in group A (65 +/- 31 mg/dL) than in group D (106 +/- 32 mg/dL; P = 0.002). CONCLUSIONS: As once-daily insulin injection therapy given before breakfast in type 2 diabetes patients, the biphasic insulin analog might represent a better insulin option in significantly lowering the percent coefficient of variation and mean amplitude of glycemic excursions than the long acting insulin preparation. PMID- 28921909 TI - First Natural Endocranial Cast of a Fossil Snake (Cretaceous of Patagonia, Argentina). AB - In this study, we describe a natural endocranial cast included in a partially preserved medium-sized skull of the Upper Cretaceous South American snake Dinilysia patagonica. The endocast is composed of sedimentary filling of the cranial cavity in which the posterior brain, the vessels, the cranial nerves, and the inner ear surrounded by delicate semicircular canals, are represented. It is simple in form, with little differentiation between the three main areas (Forebrain, Midbrain, and Hindbrain), and without flexures. The nervous system is well preserved. The posterior brain surface is smooth, except for two small prominences that make up the cerebellum. A large inner ear is preserved on the right side; it consists of a voluminous central mass, the vestibule, which occupies most of the space defined by the three semicircular canals. In particular, the lateral semicircular canal is very close to the vestibule. This characteristic, in combination with the medium to large body size of Dinilysia, its large skull and dorsally exposed orbits, and vertebrae bearing a rather high neural spine on a depressed neural arch, suggests that this snake would have had a semifossorial lifestyle. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 301:9-20, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28921910 TI - 100 days with scans of the same Catphan phantom on the same CT scanner. AB - Quality control (QC) of CT scanners is important to evaluate image quality and radiation dose. Different QC phantoms for testing image quality parameters on CT are commercially available, and Catphan phantoms are widely used for this purpose. More data from measured image quality parameters on CT are necessary to assess test methods, tolerance levels, and test frequencies. The aim of this study was to evaluate the stability of essential image quality parameters for axial and helical scans on one CT scanner over time. A Catphan 600 phantom was scanned on a Philips Ingenuity CT scanner for 100 days over a period of 6 months. At each day of testing, one helical scan covering the entire phantom and four axial scans covering four different modules in the phantom were performed. All images were uploaded into Image Owl for automatic analysis of CT numbers, modular transfer function (MTF), low-contrast resolution, noise, and uniformity. In general, the different image quality parameters for both scan techniques were stable over time compared to given tolerance levels. Average measured CT numbers differed between axial and helical scans, while MTF was almost identical for helical and axial scans. Axial scans had better low-contrast resolution and less noise than helical scans. The uniformity was relatively similar for axial and helical scans. Most standard deviations of measured values were larger for helical scans compared to axial scans. Test results in this study were stable over time for both scan techniques, but further studies on different CT scanners are required to confirm that this also holds true for other systems. PMID- 28921911 TI - Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance. AB - The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy. In the case of prodrugs, the resistance phenomenon is often related to a mutation in the gene encoding for the activation enzymes, resulting thus in a default of these enzymes that are no more able to activate prodrugs. Consequently, identification of the prodrugs targets and a better understanding of their modes of action and also of their activation mechanisms are of crucial importance. Related to their molecular mechanism of activation, these prodrugs may thus be classified in four categories: activation via oxidation (catalase-peroxidase (KatG) or flavin monooxygenase (EthA) enzymes), condensation (FolP1 and FolC), hydrolysis (by the amidase PncA) and reduction (by the nitroreductase DnD) mechanisms. For each prodrug, these mechanisms are described in details, as well as the mechanism of action of its active metabolite. Finally, the reported resistance related to these mechanisms of activation/action are also addressed in a molecular perspective. PMID- 28921912 TI - Fate of Worn-Out Functional Teeth in the Upper Jaw Dentition of Sicyopterus japonicus (Gobioidei: Sicydiinae) During Tooth Replacement. AB - Mochizuki and Fukui (Jpn J Ichthyol 30 () 27-36) studied the development and replacement of the upper jaw teeth in a Japanese fish species, Sicyopterus japonicus (Gobioidei: Sicydiinae), and they reported that worn-out functional teeth in the upper jaw were not shed outside the skin but were taken into the soft tissue of the upper jaw and completely resorbed there. To date, however, this phenomenon appears poorly documented. Furthermore, the mechanism for the resorption of these teeth remains to be determined. In this study, we examined this phenomenon by using 3D microcomputed tomography (m-CT), scanning electron microscopy (SEM), and various techniques of light (LM) and electron (EM) microcopy. This study demonstrated that the upper jaw dentition of this fish was more or less simultaneously replaced with the replacement occurring during short time periods and that the lingual movement of the replacement teeth to the functional tooth position advanced simultaneously in a given row. Furthermore, our study also revealed that many worn-out functional teeth were engulfed by the oral epithelium, invaginated into the lingual shallow ditch of the premaxilla, and were resorbed/degraded completely by numerous foreign body giant cells rather than by odontoclasts during periods of at least three intervals of tooth replacement. The complete resorption/degradation of worn-out functional teeth in the soft tissue of the upper jaw suggests the possibility of the reuse of their components (minerals such as Ca and P, including Fe) for rapid and successional production of new replacement teeth in the upper jaw of adult S. japonicus. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 301:111-124, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28921913 TI - High-resolution imaging of muscle attachment structures in Caenorhabditis elegans. AB - We used structured illumination microscopy (SIM) to obtain super-resolution images of muscle attachment structures in Caenorhabditis elegans striated muscle. SIM imaging of M-line components revealed two patterns: PAT-3 (beta-integrin) and proteins that interact in a complex with the cytoplasmic tail of beta-integrin and localize to the basal muscle cell membrane [UNC-112 (kindlin), PAT-4 (ILK), UNC-97 (PINCH), PAT-6 (alpha-parvin), and UNC-95], are found in discrete, angled segments with gaps. In contrast, proteins localized throughout the depth of the M line (UNC-89 (obscurin) and UNC-98) are imaged as continuous lines. Systematic immunostaining of muscle cell boundaries revealed that dense body components close to the basal muscle cell membrane also localize at cell boundaries. SIM imaging of muscle cell boundaries reveal "zipper-like" structures. Electron micrographs reveal electron dense material similar in appearance to dense bodies located adjacent to the basolateral cell membranes of adjacent muscle cells separated by ECM. Moreover, by EM, there are a variety of features of the muscle cell boundaries that help explain the zipper-like pattern of muscle protein localization observed by SIM. Short dense bodies in atn-1 mutants that are null for alpha-actinin and lack the deeper extensions of dense bodies, showed "zipper like" structures by SIM similar to cell boundary structures, further indicating that the surface-proximal components of dense bodies form the "zipper-like" structures at cell boundaries. Moreover, mutants in thin and thick filament components do not have "dot-like" dense bodies, suggesting that myofilament tension is required for assembly or maintenance of proper dense body shape. PMID- 28921914 TI - Comparison of the relationship between multiple parameters of glycemic variability and coronary plaque vulnerability assessed by virtual histology intravascular ultrasound. AB - AIMS/INTRODUCTION: Increased glycemic variability is an important contributing factor to coronary artery disease. Although various parameters of glycemic variability can be derived by continuous glucose monitoring, the clinical relevance of individual parameters has remained unclear. We have now analyzed the relationship of such parameters to coronary plaque vulnerability. MATERIALS AND METHODS: The standard deviation of glucose levels (SD glucose), mean amplitude of glycemic excursions (MAGE), continuous overlapping net glycemic action calculated every 1 h (CONGA-1) and mean of daily differences (MODD) were calculated from continuous glucose monitoring data for 53 patients hospitalized for percutaneous coronary intervention. The relationship of these parameters to the percentage necrotic core of total plaque volume (%NC) as assessed by virtual histology intravascular ultrasound (a predictor of coronary plaque rupture) was evaluated. RESULTS: All parameters of glycemic variability were significantly correlated with %NC, with correlation coefficients of 0.593, 0.626, 0.318, and 0.388 for log(SD glucose), log(MAGE), CONGA-1 and log(MODD), respectively. Simple linear regression analysis showed that the coefficients of determination for %NC and either log(SD glucose; 0.352) or log(MAGE; 0.392) were greater than those for %NC and either CONGA-1 (0.101) or log(MODD; 0.151), whereas the residual sums of squares for the former relationships (1045.1 and 979.5, respectively) were smaller than those for the latter (1449.3 and 1369.6, respectively). CONCLUSIONS: The present data suggest that SD glucose and MAGE are more highly correlated with coronary plaque vulnerability than are CONGA-1 and MODD, and are thus likely better predictors of coronary artery disease. PMID- 28921915 TI - Weekly glucagon-like peptide-1 receptor agonist albiglutide as monotherapy improves glycemic parameters in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. AB - AIMS/INTRODUCTION: The present phase 3, randomized, double-blind 24-week study with extension to 1 year assessed the efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. MATERIALS AND METHODS: Patients received weekly albiglutide 30 mg (n = 160), albiglutide 50 mg (n = 150) or a placebo switched to albiglutide 30 mg after 24 weeks (n = 77). Open-label daily liraglutide 0.9 mg (n = 103) was included as a reference. Oral antidiabetic drug use was discontinued before baseline. The primary end-point was 24-week change from baseline in glycated hemoglobin (HbA1c). Secondary end-points included fasting plasma glucose, bodyweight and adverse events. RESULTS: At 24 weeks, mean HbA1c changes from baseline were 1.10, -1.30, and 0.25% for albiglutide 30, 50 mg and placebo, respectively (P vs placebo <0.0001 for both albiglutide doses), -1.19% for liraglutide. Decreases in HbA1c with albiglutide were sustained through the study. Mean fasting plasma glucose decreased by >=20 mg/dL, and the mean change in bodyweight was <=0.5 kg through 1 year across groups. Most commonly reported adverse events were nasopharyngitis, constipation and nausea. The incidence of adverse events was higher in active treatment groups than in the placebo group. Few hypoglycemia events were reported; no patient withdrew as a result of hypoglycemia. No new safety signals were detected. CONCLUSIONS: Albiglutide monotherapy achieved clinically significant decreases in HbA1c and fasting plasma glucose with good tolerability in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. PMID- 28921916 TI - Inversed Expression Patterns of S100A4 and E-Cadherin in Cervical Cancers: Implication in Epithelial-Mesenchymal Transition. AB - Cervical cancer/CC is the third commonest female malignancy worldwide. The aggressive growth and distal metastases are the leading causes of CC mortality, which is largely due to epithelial-mesenchymal transition/EMT. Fibroblast specific protein S100A4 promotes cancer metastasis and epithelial type cadherin/E cadherin play pivotal roles in cell-cell and cell-extracellular matrix interaction. Therefore, the expression patterns of S100A4 and E-cadherin reflect statuses of EMT of carcinoma cells. However, S100A4 expression and its relevance with E-cadherin and HPV16 infection in cervical cancers remain unknown. This study aims to address the above issues using cervical cancer specimens. Immunohistochemistry reveals that the levels of mesenchymal marker S100A4 is upregulated (>++) in cervical adenocarcinomas/CACs (12/16; 75%) and squamous cell carcinomas/CSCCs (23/28; 82%) than that in noncancerous glandular epithelia/GE (0/12; 0%) and squamous epithelia/SE (0/12; 0%). Epithelial marker membranous E cadherin is remarkably reduced on the surface of CAC and CSCC cells (P = 0.00; P = 0.00), especially those showing poorly differentiated phenotypes (P < 0.05) in comparison with their noncancerous counterparts. Correlative analyses revealed an inverse relationship between S100A4 and E-cadherin expression among the cervical cancer samples (P = 0.01, r = -0.38). S100A4 expression level in HPV16-infected group is higher than that in HPV16-free group (P = 0.02). These results suggest the close correlation of S100A4 upregulation with cervical cancer formation and HPV16 infection and E-cadherin reduction with the grades of CC dedifferentiation. The concurrent gain of S100A4 and loss of membrane E-cadherin suggest EMT tendency of CC cells and can be regarded as an unfavorable prognostic parameter of CC patients. Anat Rec, 300:2184-2191, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921917 TI - Changes on the Pancreas in Experimental Diabetes and the Effect of Lycopene on These Changes: Pdx-1, Ngn-3, and Nestin Expressions. AB - The aim of the present study was to investigate changes occurring in the number of beta cells, as well as the expressions of Ngn-3, nestin and Pdx-1 of pancreatic progenitor cells in the pancreas of experimentally-induced adult diabetic rats and to determine the effect of orally-administered lycopene on these changes. Following the administration of 50 mg/kg streptozotocin to rats, four groups of animals were established: control + corn oil, control + lycopene, diabetic + corn oil and diabetic + lycopene. The animals in the control + lycopene and diabetic + lycopene groups received 4 mg/kg lycopene for a period of four weeks. The expressions of insulin, Ngn-3, nestin, and Pdx-1 were determined through immunohistochemistry in sections taken from pancreas tissue samples at the end of the experiment. The number of insulin-positive cells was found to be significantly low in the diabetic groups compared to the control groups. In addition, the presence of Ngn-3 and nestin-positive cells within the exocrine pancreas surrounding the islands was noted in the diabetic groups. Lycopene, in general did not have any effect in any of the parameters analyzed in the present study. It is suggested that these cells would function as stem cells to replace the lost beta-cell population. It is also suggested that it is possible to demonstrate the antioxidant effects of lycopene in the pancreas of diabetic rats by increasing the dose and duration of lycopene administration. Anat Rec, 300:2200-2207, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921918 TI - Proteomic Response of Human Umbilical Vein Endothelial Cells to Histamine Stimulation. AB - The histamine receptors (HRs) represent a subclass of G protein-coupled receptors (GPCRs) and comprise four subtypes. Due to their numerous physiological and pathological effects, HRs are popular drug targets for the treatment of allergic reactions or the regulation of gastric acid secretion. Hence, an understanding of the functional selectivity of HR ligands has gained importance. These ligands can bind to specific GPCRs and selectively activate defined pathways. Supporting the activation of a therapeutically necessary pathway without the activation of other signaling cascades can result in drugs with more specific activity and fewer side effects. To evaluate the cellular consequences resulting from receptor binding, comprehensive analyses of cellular protein alterations upon incubation with ligands are required. For this purpose, endothelial cells are treated with histamine, as the endogenous ligand of HRs, to obtain a global overview of its cellular effects. Quantitative proteomics and pathway analyses of histamine treated and untreated cells reveal enrichment of the nuclear factor-kappaB and tumor necrosis factor signaling pathways, cytokine-cytokine receptor interactions, complement and coagulation cascades, and acute inflammatory processes upon histamine treatment. This strategy offers the opportunity to monitor HR-mediated signaling in a multidimensional manner. PMID- 28921919 TI - Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial. AB - AIMS/INTRODUCTION: Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia. MATERIALS AND METHODS: This was a post-hoc subgroup analysis of a multinational, parallel-group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5-12.0% were randomized to double-blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary end-point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries. RESULTS: After 24 weeks, the mean +/- standard error reduction from baseline in HbA1c (mean 10.0%) was -2.99 +/- 0.18% with linagliptin/metformin and -1.84 +/- 0.18% with linagliptin; a treatment difference of -1.15% (95% confidence interval -1.65 to -0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. The mean bodyweight change after 24 weeks was -0.45 +/- 0.41 kg and 1.33 +/- 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference -1.78 kg [95% confidence interval -2.99 to -0.57, P = 0.0043]). Drug related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations. CONCLUSIONS: In people from Asia with newly diagnosed type 2 diabetes mellitus and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy might be a viable treatment for such individuals. PMID- 28921922 TI - Assessing healthcare professional knowledge, attitudes, and practices on hypertension management. Announcing a new World Hypertension League resource. AB - To assist hypertension control programs and specifically the development of training and education programs on hypertension for healthcare professionals, the World Hypertension League has developed a resource to assess knowledge, attitudes, and practices on hypertension management. The resource assesses: (1) the importance of hypertension as a clinical and public health risk; (2) education in national or international hypertension recommendations; (3) lifestyle causes of hypertension; (4) measurement of blood pressure, screening, and diagnosis of hypertension; (5) lifestyle therapy counseling; (6) cardiovascular risk assessment; (7) antihypertensive drug therapy; and (8) adherence to therapy. In addition, the resource assesses the attitudes and practices of healthcare professionals for task sharing/shifting, use of care algorithms, and use of registries with performance reporting functions. The resource is designed to help support the Global Hearts Alliance to provide standardized and enhanced hypertension control globally. PMID- 28921923 TI - Glucose intolerance as the key risk factor for metabolic syndrome. PMID- 28921924 TI - Effects of Surgical Anatomical Correction of Pelvic Anterior Compartment Defect on Lower Urinary Tract Symptoms. AB - OBJECTIVE: To evaluate the effects of surgical anatomical correction on lower urinary tract symptoms (LUTS) in patients with a pelvic anterior compartment defect (PACD). METHODS: This prospective study was carried out on 30 women who had stage II-IV PACD. The women were questioned regarding LUTS symptoms such as urgency, urge incontinence, frequency, hesitancy, abnormal emptying, nocturia and dysuria pre and postoperatively. After a 7-month follow up, the comparison of LUTS symptoms with respect to their healing, existence or de novo appearance was performed using the McNemar and Bowner and Wilcoxon signed-rank tests. RESULTS: For the repair of ACD, 15, 8 and 7 women were operated on using site-specific surgery, transvaginal mesh placement and anterior colporrhaphy, respectively. Surgery has significantly improved the LUTS: urgency (100 vs 26.7%, urge incontinence (70 vs 16.7%), frequency (76.7 vs 13.3%), abnormal emptying (56.7 vs 10%), hesitancy (30 vs 6.7%), nocturia (83.3 vs 60%) and dysuria (30 vs 6.7%). The differences were statistically significant (P < 0.05). CONCLUSIONS: The correctional surgery on anterior compartment defects not only maintains the anatomy but also significantly heals the LUTS. PMID- 28921925 TI - Symmetrical hyperpigmentation of the forehead in a 37-year-old female patient from Guinea, West Africa. PMID- 28921926 TI - Inhibition of Vascular Endothelial Growth Factor Receptor Decreases Regenerative Angiogenesis in Axolotls. AB - Angiogenesis is crucial for tissue growth and repair in mammals, and is chiefly regulated by vascular endothelial growth factor (VEGF) signaling. We evaluated the effect of chemical inhibition of VEGF receptor signaling in animals with superior regenerative ability, axolotl salamanders, to determine the impact on vascularization and regenerative outgrowth. Following tail amputation, treated animals (100 nM PTK787) and controls were examined microscopically and measured over the month-long period of regeneration. Treatment with VEGFR inhibitor decreased regenerative angiogenesis; drug-treated animals had lower vascular densities in the regenerating tail than untreated animals. This decrease in neovascularization, however, was not associated with a decrease in regenerative outgrowth or with morphological abnormalities in the regrown tail. Avascular but otherwise anatomically normal regenerative outgrowth over 1 mm beyond the amputation plane was observed. The results suggest that in this highly regenerative species, significant early tissue regeneration is possible in the absence of a well-developed vasculature. This research sets the groundwork for establishing a system for the chemical manipulation of angiogenesis within the highly regenerative axolotl model, contributing to a better understanding of the role of the microvasculature within strongly proliferative yet well-regulated environments. Anat Rec, 300:2273-2280, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28921927 TI - Fast and cost-effective single nucleotide polymorphism (SNP) detection in the absence of a reference genome using semideep next-generation Random Amplicon Sequencing (RAMseq). AB - Biodiversity has suffered a dramatic global decline during the past decades, and monitoring tools are urgently needed providing data for the development and evaluation of conservation efforts both on a species and on a genetic level. However, in wild species, the assessment of genetic diversity is often hampered by the lack of suitable genetic markers. In this article, we present Random Amplicon Sequencing (RAMseq), a novel approach for fast and cost-effective detection of single nucleotide polymorphisms (SNPs) in nonmodel species by semideep sequencing of random amplicons. By applying RAMseq to the Eurasian otter (Lutra lutra), we identified 238 putative SNPs after quality filtering of all candidate loci and were able to validate 32 of 77 loci tested. In a second step, we evaluated the genotyping performance of these SNP loci in noninvasive samples, one of the most challenging genotyping applications, by comparing it with genotyping results of the same faecal samples at microsatellite markers. We compared (i) polymerase chain reaction (PCR) success rate, (ii) genotyping errors and (iii) Mendelian inheritance (population parameters). SNPs produced a significantly higher PCR success rate (75.5% vs. 65.1%) and lower mean allelic error rate (8.8% vs. 13.3%) than microsatellites, but showed a higher allelic dropout rate (29.7% vs. 19.8%). Genotyping results showed no deviations from Mendelian inheritance in any of the SNP loci. Hence, RAMseq appears to be a valuable tool for the detection of genetic markers in nonmodel species, which is a common challenge in conservation genetic studies. PMID- 28921929 TI - Tumor-suppressive miR-145 co-repressed by TCF4-beta-catenin and PRC2 complexes forms double-negative regulation loops with its negative regulators in colorectal cancer. AB - The frequently dysregulated Wnt/beta-catenin signaling in different malignancies, by activation of its own or orchestration with other co-factors, regulates various oncogenic or tumor-suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt-induced oncogenic miRNAs, the specific mechanism underlying the Wnt-repressed tumor-suppressive miRNAs is much less understood. In our study, firstly by analyzing a ChIP-seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor-suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA-mediated knock-down tests and protein and chromatin immunoprecipitations, we found the TCF4-beta-catenin complex can recruit the histone trimethylation complex PRC2 as a co-repressor while binding to the TCF4-binding element (TBE) in the promoter regions of miR 145, miR-132 and miR-212. Thus, upon Wnt signaling activation, the PRC2-mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor suppressive miR-145 co-repressed by Wnt signaling and histone trimethylation, forms double-negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR-145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/beta-catenin signaling and tumor-suppressive miRNAs reciprocally regulate each other in CRC cells. PMID- 28921928 TI - Inverted formins: A subfamily of atypical formins. AB - Formins are a family of regulators of actin and microtubule dynamics that are present in almost all eukaryotes. These proteins are involved in many cellular processes, including cytokinesis, stress fiber formation, and cell polarization. Here we review one subfamily of formins, the inverted formins. Inverted formins as a group break several formin stereotypes, having atypical biochemical properties and domain organization, and they have been linked to kidney disease and neuropathy in humans. In this review, we will explore recent research on members of the inverted formin sub-family in mammals, zebrafish, fruit flies, and worms. PMID- 28921930 TI - Big Five aspects of personality interact to predict depression. AB - OBJECTIVE: Research has shown that three personality traits-Neuroticism, Extraversion, and Conscientiousness-moderate one another in a three-way interaction that predicts depressive symptoms in healthy populations. We test the hypothesis that this effect is driven by three lower-order traits: withdrawal, industriousness, and enthusiasm. We then replicate this interaction within a clinical population for the first time. METHOD: Sample 1 included 376 healthy adults. Sample 2 included 354 patients diagnosed with current major depressive disorder. Personality and depressive tendencies were assessed via the Big Five Aspect Scales and Personality Inventory for DSM-5 in Sample 1, respectively, and by the NEO-PI-R and Beck Depression Inventory-II in Sample 2. RESULTS: Withdrawal, industriousness, and enthusiasm interacted to predict depressive tendencies in both samples. The pattern of the interaction supported a "best two out of three" principle, in which low risk scores on two trait dimensions protects against a high risk score on the third trait. Evidence was also present for a "worst two out of three" principle, in which high risk scores on two traits are associated with equivalent depressive severity as high risk scores on all three traits. CONCLUSIONS: These results highlight the importance of examining interactive effects of personality traits on psychopathology. PMID- 28921931 TI - Technical Note: A simple algorithm to convert EPID gray values into absorbed dose to water without prior knowledge. AB - PURPOSE: Full integration of EPID-based dosimetry in a global quality control workflow is still complicated. All the actual solutions are based on a relation between image gray-level signal and total linac-delivered dose. In this study, we propose a simple algorithm relying pixel gray-level of EPID image with average linac delivered dose per acquisition frame. METHODS: Calibration models are constructed for Varian and Elekta linacs including scattering conditions and EPID arm backscatter-specific corrections. Only simple homogeneous fields are required to establish the EPID dose conversion model for each x-ray beam. Then, the model was evaluated by comparing calculated and converted dose distributions for homogeneous and modulated beams using gamma maps. RESULTS: To fit average dose per frame (Dfnorm ) vs pixel gray value (Ngnorm ) of each EPID image, a logarithmic curve Dfnorm=A+B*lnNgnorm-C, has been chosen where A, B and C are constants depending on beam energy. Gamma comparison (2%, 2 mm, threshold 15%) between converted images and calculated dose distributions for linac control and pretreatment patient fields led to a gamma pass rate higher than 97% for all the analyzed fields. CONCLUSIONS: Without a prior irradiation settings knowledge except the incident energy beam, we use EPID as a reliable dose to water detector for both homogeneous and modulated beams. PMID- 28921933 TI - It's all in the genes... well almost. PMID- 28921932 TI - Fetal MRI compared with ultrasound for the diagnosis of obstructive genital malformations. AB - OBJECTIVE: To compare the accuracy of magnetic resonance imaging (MRI) and ultrasound (US) to diagnose and characterize congenital obstructive genital abnormalities. METHOD: Retrospective cohort of 20 fetuses who underwent a fetal MRI following a US diagnosis of obstructive urogenital malformation. We compared MRI and US findings and their correlation with the definitive diagnosis. RESULT: The correct diagnosis was obtained in 6/20 (30%) cases and 19/20 cases (95%) with US and MRI, respectively. MRI revealed additional information to US in 15/20 cases (75%) and modified the prenatal management in 14 fetuses (70%). The identification rates of the most important anatomical landmarks for the diagnosis, using US and MRI, were compared. Bladder: US 17/20 (85%) vs MRI 20/20 (100%) P = 0.23; vagina: US 6/19 (31.5%) vs MRI 19/19 (100%) P < 10-4 ; uterus: US 11/19 (57.8%) vs MRI 19/19 (100%) P = 0.003, kidneys: US: 40/40 (100%) MRI: 40/40 (100%) P = 1, ureters: US 14/40 (35%) vs MRI 30/40 (75%) P=0.001, rectum: US 6/20 (30%) MRI 20/20 (100%) P < 10-4 , and sacrum: US 20/20 (100%) vs MRI 17/20 (85%) P = 0.23. CONCLUSION: In fetuses with obstructive urogenital malformations, MRI facilitates assessment of major pelvic organs and provides significant information that may alter the prenatal management. PMID- 28921936 TI - Sprouty2 is involved in the control of osteoblast proliferation and differentiation through the FGF and BMP signaling pathways. AB - Fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) play essential roles in bone formation and osteoblast activity through the extracellular signal-regulated kinase 1/2 (ERK1/2) and Smad pathways. Sprouty family members are intracellular inhibitors of the FGF signaling pathway, and four orthologs of Sprouty have been identified in mammals. In vivo analyses have revealed that Sprouty2 is associated with bone formation. However, the mechanism by which the Sprouty family controls bone formation has not been clarified. In this study, we investigated the involvement of Sprouty2 in osteoblast proliferation and differentiation. We examined Sprouty2 expression in MC3T3-E1 cells, and found that high levels of Sprouty2 expression were induced by basic FGF stimulation. Overexpression of Sprouty2 in MC3T3-E1 cells resulted in suppressed proliferation compared with control cells. Sprouty2 negatively regulated the phosphorylation of ERK1/2 after basic FGF stimulation, and of Smad1/5/8 after BMP stimulation. Furthermore, Sprouty2 suppressed the expression of osterix, alkaline phosphatase, and osteocalcin mRNA, which are markers of osteoblast differentiation. Additionally, Sprouty2 inhibited osteoblast matrix mineralization. These results suggest that Sprouty2 is involved in the control of osteoblast proliferation and differentiation by downregulating the FGF-ERK1/2 and BMP-Smad pathways, and suppresses the induction of markers of osteoblast differentiation. PMID- 28921934 TI - Mirror trends of plasticity and stability indicators in primate prefrontal cortex. AB - Research on plasticity markers in the cerebral cortex has largely focused on their timing of expression and role in shaping circuits during critical and normal periods. By contrast, little attention has been focused on the spatial dimension of plasticity-stability across cortical areas. The rationale for this analysis is based on the systematic variation in cortical structure that parallels functional specialization and raises the possibility of varying levels of plasticity. Here, we investigated in adult rhesus monkeys the expression of markers related to synaptic plasticity or stability in prefrontal limbic and eulaminate areas that vary in laminar structure. Our findings revealed that limbic areas are impoverished in three markers of stability: intracortical myelin, the lectin Wisteria floribunda agglutinin, which labels perineuronal nets, and parvalbumin, which is expressed in a class of strong inhibitory neurons. By contrast, prefrontal limbic areas were enriched in the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII), known to enhance plasticity. Eulaminate areas have more elaborate laminar architecture than limbic areas and showed the opposite trend: they were enriched in markers of stability and had lower expression of the plasticity-related marker CaMKII. The expression of glial fibrillary acidic protein (GFAP), a marker of activated astrocytes, was also higher in limbic areas, suggesting that cellular stress correlates with the rate of circuit reshaping. Elevated markers of plasticity may endow limbic areas with flexibility necessary for learning and memory within an affective context, but may also render them vulnerable to abnormal structural changes, as seen in neurologic and psychiatric diseases. PMID- 28921935 TI - Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization. AB - BACKGROUND AND AIMS: Studying the consequences of addictive behaviours is challenging, with understanding causal relationships from observational data being particularly difficult. For example, people who smoke or drink excessively are often systematically different from those who do not, are less likely to participate in research and may misreport their behaviours when they do. Furthermore, the direction of causation between an addictive behaviour and outcome may be unclear. Mendelian randomization (MR) offers potential solutions to these problems. METHODS: We describe MR's principles and the criteria under which it is valid. We identify challenges and potential solutions in its application (illustrated using two applied examples) and describe methodological extensions in its application. RESULTS: MR is subject to certain assumptions, and requires the availability of appropriate genetic data, large sample sizes and careful design and conduct. However, it has already been applied successfully to the addiction literature. The relationship between alcohol consumption (proxied by a variant in the ADH1B gene) and cardiovascular risk has been investigated, finding that alcohol consumption increases risk, with no evidence of a cardioprotective effect at moderate consumption levels. In addition, heaviness of smoking (proxied by a variant in the CHRNA5-A3-B4 gene cluster) and risk of depression and schizophrenia have been investigated, with no evidence of a causal effect of smoking on depression but some evidence of a causal effect on schizophrenia. CONCLUSIONS: Mendelian randomization analyses are already producing robust evidence for addiction-related practice and policy. As genetic variants associated with addictive behaviours are identified, the potential for Mendelian randomization analyses will grow. Methodological developments are also increasing its applicability. PMID- 28921937 TI - Ventricular assist device use in single ventricle congenital heart disease. AB - As VAD have become an effective therapy for end-stage heart failure, their application in congenital heart disease has increased. Single ventricle congenital heart disease introduces unique physiologic challenges for VAD use. However, with regard to the mixed clinical results presented within this review, we suggest that patient selection, timing of implant, and center experience are all important contributors to outcome. This review focuses on the published experience of VAD use in single ventricle patients and details physiologic challenges and novel approaches in this growing pediatric and adult population. PMID- 28921938 TI - Prostate cancer treatment in renal transplant recipients: a systematic review. AB - The aim of this review was to summarize the current evidence and to highlight the main issues future research needs to address regarding prostate cancer (PCa) treatment in renal transpant recipients (RTRs). We conducted a search of AMED, Medline and Embase up to 17 November 2016 to investigate oncological and functional outcomes of PCa treatment in RTR. Type and use/protocols of immunosuppression and peri-operative antibiotic drugs were also assessed. The search was implemented manually. Exclusion criteria were absence of full text or absence of information that allowed us to differentiate oncological and/or functional outcomes of each therapeutic approach used. We included 241 patients from 27 retrospective studies published between 1991 and 2016; seven of the studies were case-control and 20 were case series. We also considered nine case reports published between 1999 and 2016. Follow-up ranged from 1 to 120 months. PCa was organ-confined, with Gleason score <=6 in 75.2% and 60.4% of patients. Surgery was the most frequent treatment used (n = 186), for which cancer-specific (CSS) and overall survival (OS) rates were both 96.8%. Functional outcomes, including continence and erectile function, and complications were less frequently reported and were generally similar to those reported for radical prostatectomy (RP) in non-RTRs. Other treatment methods in the patients included in the review were radiotherapy (RT) +/- androgen deprivation therapy (ADT; n = 34; OS 88.2%; CSS 88.2%), ADT alone (n = 14; OS 42.9%; CSS 64.3%), brachytherapy (BT; n = 11; OS and CSS 100%), watchful waiting (n = 4) and active surveillance (n = 1). Overall no treatment-related graft loss occurred. Immunosuppression and antibiotic schemes were poorly reported and inconsistent. Outcomes of PCa treatment in RTRs are encouraging and do not appear to be inferior to those of non-RTR. RP was the most commonly assessed approach, whilst RT, BT and ADT were less frequent. Immunosuppression and antibiotic use were poorly reported and highly variable. High-quality studies are needed because the current level of evidence is low, and our results should therefore be interpreted with caution. PMID- 28921939 TI - Extreme hepatic resections for the treatment of advanced hepatoblastoma: Are planned close margins an acceptable approach? AB - BACKGROUND: Orthotopic liver transplantation (OLT) is considered the standard for children with hepatoblastoma (HB) in whom complete surgical resection is not possible. However, OLT is not always available or feasible. OBJECTIVE: To describe the outcome of children with HB who were initially deemed unresectable and underwent complex hepatectomy with planned close margins, and ultimately avoided OLT. METHODS: Demographic data, surgical and pathologic details, and survival information were collected from children treated for HB between January 2010 to December 2015. RESULTS: Among six children (median age 12 months (3-41 months)), PRETEXT classification was III (n = 2), III/IV (n = 1), and IV (n = 3). Patients received a median of six cycles (range 4-7) of platinum-based induction chemotherapy; five received doxorubicin. Experienced pediatric surgeons performed extended right and left hepatectomy in five and one patients, respectively, with assistance of an experienced liver transplant surgeon (n = 4). Microscopic margins were positive (n = 2) and negative but close (n = 4; 2-5 mm). Two patients required vascular reconstruction of the vena cava. At median follow-up of 3.3 years (1.7-4.6 years), there was no evidence of local recurrence. One patient had recurrence of pulmonary disease 3 months after surgery. CONCLUSIONS: Patients with advanced HB treated with complex surgical resections with positive or close negative margins had good outcomes without OLT. We suggest that planned positive or close microscopic margins in highly selected HB patients may spare the morbidity of OLT and offer an alternative for those ineligible for OLT. Our experience illustrates the importance of a multidisciplinary team specialized in the management of liver tumors. PMID- 28921940 TI - Attribution of human infections with Shiga toxin-producing Escherichia coli (STEC) to livestock sources and identification of source-specific risk factors, The Netherlands (2010-2014). AB - Shiga toxin-producing Escherichia coli (STEC) is a zoonotic pathogen of public health concern whose sources and transmission routes are difficult to trace. Using a combined source attribution and case-control analysis, we determined the relative contributions of four putative livestock sources (cattle, small ruminants, pigs, poultry) to human STEC infections and their associated dietary, animal contact, temporal and socio-econo-demographic risk factors in the Netherlands in 2010/2011-2014. Dutch source data were supplemented with those from other European countries with similar STEC epidemiology. Human STEC infections were attributed to sources using both the modified Dutch model (mDM) and the modified Hald model (mHM) supplied with the same O-serotyping data. Cattle accounted for 48.6% (mDM) and 53.1% (mHM) of the 1,183 human cases attributed, followed by small ruminants (mDM: 23.5%; mHM: 25.4%), pigs (mDM: 12.5%; mHM: 5.7%) and poultry (mDM: 2.7%; mHM: 3.1%), whereas the sources of the remaining 12.8% of cases could not be attributed. Of the top five O-serotypes infecting humans, O157, O26, O91 and O103 were mainly attributed to cattle (61% 75%) and O146 to small ruminants (71%-77%). Significant risk factors for human STEC infection as a whole were the consumption of beef, raw/undercooked meat or cured meat/cold cuts. For cattle-attributed STEC infections, specific risk factors were consuming raw meat spreads and beef. Consuming raw/undercooked or minced meat were risk factors for STEC infections attributed to small ruminants. For STEC infections attributed to pigs, only consuming raw/undercooked meat was significant. Consuming minced meat, raw/undercooked meat or cured meat/cold cuts were associated with poultry-attributed STEC infections. Consuming raw vegetables was protective for all STEC infections. We concluded that domestic ruminants account for approximately three-quarters of reported human STEC infections, whereas pigs and poultry play a minor role and that risk factors for human STEC infection vary according to the attributed source. PMID- 28921943 TI - Self-Assembly of Mesoscale Artificial Clathrin Mimics. AB - Fluidic control and sampling in complex environments is an important process in biotechnology, materials synthesis, and microfluidics. An elegant solution to this problem has evolved in nature through cellular endocytosis, where the dynamic recruitment, self-assembly, and spherical budding of clathrin proteins allows cells to sample their external environment. Yet despite the importance and utility of endocytosis, artificial systems which can replicate this dynamic behavior have not been developed. Guided by clathrin's unusual structure, we created simplified metallic microparticles that capture the three-legged shape, particle curvature, and interfacial attachment characteristics of clathrin. These artificial clathrin mimics successfully recreate biomimetic analogues of clathrin's recruitment, assembly, and budding, ultimately forming extended networks at fluid interfaces and invaginating immiscible phases into spheres under external fields. Particle curvature was discovered to be a critical structural motif, greatly limiting irreversible aggregation and inducing the legs' selective tip-to-tip attraction. This architecture provides a template for a class of active self-assembly units to drive structural and dimensional transformations of liquid-liquid interfaces and microscale fluidic sampling. PMID- 28921941 TI - The Lactococcus lactis KF147 nonribosomal peptide synthetase/polyketide synthase system confers resistance to oxidative stress during growth on plant leaf tissue lysate. AB - Strains of Lactococcus lactis isolated from plant tissues possess adaptations that support their survival and growth in plant-associated microbial habitats. We previously demonstrated that genes coding for a hybrid nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) system involved in production of an uncharacterized secondary metabolite are specifically induced in L. lactis KF147 during growth on plant tissues. Notably, this NRPS/PKS has only been identified in plant-isolated strains of L. lactis. Here, we show that the L. lactis KF147 NRPS/PKS genes have homologs in certain Streptococcus mutans isolates and the genetic organization of the NRPS/PKS locus is conserved among L. lactis strains. Using an L. lactis KF147 mutant deficient in synthesis of NrpC, a 4' phosphopantetheinyl transferase, we found that the NRPS/PKS system improves L. lactis during growth under oxidative conditions in Arapidopsis thaliana leaf lysate. The NRPS/PKS system also improves tolerance of L. lactis to reactive oxygen species and specifically H2 O2 and superoxide radicals in culture medium. These findings indicate that this secondary metabolite provides a novel mechanism for reactive oxygen species detoxification not previously known for this species. PMID- 28921944 TI - Plasmonic Silicon Quantum Dots Enabled High-Sensitivity Ultrabroadband Photodetection of Graphene-Based Hybrid Phototransistors. AB - Highly sensitive photodetection even approaching the single-photon level is critical to many important applications. Graphene-based hybrid phototransistors are particularly promising for high-sensitivity photodetection because they have high photoconductive gain due to the high mobility of graphene. Given their remarkable optoelectronic properties and solution-based processing, colloidal quantum dots (QDs) have been preferentially used to fabricate graphene-based hybrid phototransistors. However, the resulting QD/graphene hybrid phototransistors face the challenge of extending the photodetection into the technologically important mid-infrared (MIR) region. Here, we demonstrate the highly sensitive MIR photodetection of QD/graphene hybrid phototransistors by using plasmonic silicon (Si) QDs doped with boron (B). The localized surface plasmon resonance (LSPR) of B-doped Si QDs enhances the MIR absorption of graphene. The electron-transition-based optical absorption of B-doped Si QDs in the ultraviolet (UV) to near-infrared (NIR) region additionally leads to photogating for graphene. The resulting UV-to-MIR ultrabroadband photodetection of our QD/graphene hybrid phototransistors features ultrahigh responsivity (up to ~109 A/W), gain (up to ~1012), and specific detectivity (up to ~1013 Jones). PMID- 28921945 TI - Multiwalled Carbon Nanotubes Dramatically Affect the Fruit Metabolome of Exposed Tomato Plants. AB - Here, we reported that multiwalled carbon nanotubes (MWCNT) added to hydroponics system can enhance fruit production of exposed tomato plants. We quantified the exact amount of MWCNT accumulated inside of fruits collected by MWCNT-exposed plants using an advanced microwave induced heating technique (MIH). We found that absorption of MWCNT by tomato fruits significantly affected total fruit metabolome as was confirmed by LC-MS. Our data highlight the importance of comprehensive toxicological risk assessment of plants contaminated with carbon nanomaterials. PMID- 28921946 TI - Biomimetic Magnetosomes as Versatile Artificial Antigen-Presenting Cells to Potentiate T-Cell-Based Anticancer Therapy. AB - Adoptive T-cell transfer for cancer therapy relies on both effective ex vivo T cell expansion and in vivo targeting performance. One promising but challenging method for accomplishing this purpose is to construct multifunctional artificial antigen-presenting cells (aAPCs). We herein developed biomimetic magnetosomes as versatile aAPCs, wherein magnetic nanoclusters were coated with azide-engineered leucocyte membranes and then decorated with T-cell stimuli through copper-free click chemistry. These nano aAPCs not only exhibited high performance for antigen specific cytotoxic T-cell (CTL) expansion and stimulation but also visually and effectively guided reinfused CTLs to tumor tissues through magnetic resonance imaging and magnetic control. The persisting T cells were able to delay tumor growth in a murine lymphoma model, while the systemic toxicity was not notable. These results together demonstrated the excellent potential of this "one-but-all" aAPC platform for T-cell-based anticancer immunotherapy. PMID- 28921947 TI - Large-Scale Fabrication of Silicon Nanowires for Solar Energy Applications. AB - The development of silicon (Si) materials during past decades has boosted up the prosperity of the modern semiconductor industry. In comparison with the bulk-Si materials, Si nanowires (SiNWs) possess superior structural, optical, and electrical properties and have attracted increasing attention in solar energy applications. To achieve the practical applications of SiNWs, both large-scale synthesis of SiNWs at low cost and rational design of energy conversion devices with high efficiency are the prerequisite. This review focuses on the recent progresses in large-scale production of SiNWs, as well as the construction of high-efficiency SiNW-based solar energy conversion devices, including photovoltaic devices and photo-electrochemical cells. Finally, the outlook and challenges in this emerging field are presented. PMID- 28921948 TI - BAF180: Its Roles in DNA Repair and Consequences in Cancer. AB - In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. BAF180 has now been linked to more than 30 types of cancers, including ccRCC, cholangiocarcinomas, esophageal squamous cell carcinoma, bladder cancer, and breast cancer. The mutations associated with BAF180 are most often truncations, which result in a loss of protein expression. This loss has been shown to adversely affect the expression of genes, likely because BAF180 is the chromatin recognition subunit of PBAF. In addition, BAF180 functions in numerous DNA repair mechanisms. Its roles in mediating DNA repair are likely the mechanism by which BAF180 acts a tumor suppressor protein. As research on this protein gains more interest, scientists will begin to piece together the complicated puzzle of the BAF180 protein and why its loss often results in cancer. PMID- 28921949 TI - Effects of High Temperature and Thermal Cycling on the Performance of Perovskite Solar Cells: Acceleration of Charge Recombination and Deterioration of Charge Extraction. AB - In this work, we investigated the effects of high operating temperature and thermal cycling on the photovoltaic (PV) performance of perovskite solar cells (PSCs) with a typical mesostructured (m)-TiO2-CH3NH3PbI3-xClx-spiro-OMeTAD architecture. After temperature-dependent grazing-incidence wide-angle X-ray scattering, in situ X-ray diffraction, and optical absorption experiments were carried out, the thermal durability of PSCs was tested by subjecting the devices to repetitive heating to 70 degrees C and cooling to room temperature (20 degrees C). An unexpected regenerative effect was observed after the first thermal cycle; the average power conversion efficiency (PCE) increased by approximately 10% in reference to the as-prepared device. This increase of PCE was attributed to the heating-induced improvement of the crystallinity and p doping in the hole transporter, spiro-OMeTAD, which promotes the efficient extraction of photogenerated carriers. However, further thermal cycles produced a detrimental effect on the PV performance of PSCs, with the short-circuit current and fill factor degrading faster than the open-circuit voltage. Similarly, the PV performance of PSCs degraded at high operation temperatures; both the short circuit current and open-circuit voltage decreased with increasing temperature, but the temperature-dependent trend of the fill factor was the opposite. Our impedance spectroscopy analysis revealed a monotonous increase of the charge transfer resistance and a concurrent decrease of the charge-recombination resistance with increasing temperature, indicating a high recombination of charge carriers. Our results revealed that both thermal cycling and high temperatures produce irreversible detrimental effects on the PSC performance because of the deteriorated interfacial photocarrier extraction. The present findings suggest that the development of robust charge transporters and proper interface engineering are critical for the deployment of perovskite PVs in harsh thermal environments. PMID- 28921950 TI - Highly Efficient and Rapid Neural Differentiation of Mouse Embryonic Stem Cells Based on Retinoic Acid Encapsulated Porous Nanoparticle. AB - An improved cell conversion strategy for neural differentiation of mouse embryonic stem (mES) cells is developed by incorporating functionalized mesoporous silica nanoparticle (MSN) as an efficient delivery carrier of retinoic acid (RA), which is a pleiotropic factor required for initiation of neural differentiation. Traditional RA-mediated neural differentiation methods required either preactivation of the cells to the differentiating state by embryoid body (EB) formation or repetitive treatment of the differentiation factor. Our modified cell conversion system involves only singular treatment of the RA/MSN complex, which simplified the whole process and accelerated neural induction to be finished within 6 days with high quality. With our new method, neural cells were successfully derived from mES cells with stable expression of neurite marker gene. PMID- 28921951 TI - A Spring in Performance: Silica Nanosprings Boost Enzyme Immobilization in Microfluidic Channels. AB - Enzyme microreactors are important tools of miniaturized analytics and have promising applications in continuous biomanufacturing. A fundamental problem of their design is that plain microchannels without extensive static internals, or packings, offer limited exposed surface area for immobilizing the enzyme. To boost the immobilization in a manner broadly applicable to enzymes, we coated borosilicate microchannels with silica nanosprings and attached the enzyme, sucrose phosphorylase, via a silica-binding module genetically fused to it. We showed with confocal fluorescence microscopy that the enzyme was able to penetrate the ~70 MUm-thick nanospring layer and became distributed uniformly in it. Compared with the plain surface, the activity of immobilized enzyme was enhanced 4.5-fold upon surface coating with nanosprings and further increased up to 10-fold by modifying the surface of the nanosprings with sulfonate groups. Operational stability during continuous-flow biocatalytic synthesis of alpha glucose 1-phosphate was improved by a factor of 11 when the microreactor coated with nanosprings was used. More than 85% of the initial conversion rate was retained after 840 reactor cycles performed with a single loading of enzyme. By varying the substrate flow rate, the microreactor performance was conveniently switched between steady states of quantitative product yield (50 mM) and optimum productivity (19 mM min-1) at a lower product yield of 40%. Surface coating with silica nanosprings thus extends the possibilities for enzyme immobilization in microchannels. It effectively boosts the biocatalytic function of a microstructured reactor limited otherwise by the solid surface available for immobilizing the enzyme. PMID- 28921952 TI - Nano Air Seeds Trapped in Mesoporous Janus Nanoparticles Facilitate Cavitation and Enhance Ultrasound Imaging. AB - The current contrast agents utilized in ultrasound (US) imaging are based on microbubbles which suffer from a short lifetime in systemic circulation. The present study introduces a new type of contrast agent for US imaging based on bioresorbable Janus nanoparticles (NPs) that are able to generate microbubbles in situ under US radiation for extended time. The Janus NPs are based on porous silicon (PSi) that was modified via a nanostopper technique. The technique was exploited to prepare PSi NPs which had hydrophobic pore walls (inner face), while the external surfaces of the NPs (outer face) were hydrophilic. As a consequence, when dispersed in an aqueous solution, the Janus NPs contained a substantial amount of air trapped in their nanopores. The specific experimental setup was developed to prove that these nano air seeds were indeed acting as nuclei for microbubble growth during US radiation. Using the setup, the cavitation thresholds of the Janus NPs were compared to their completely hydrophilic counterparts by detecting the subharmonic signals from the microbubbles. These experiments and the numerical simulations of the bubble dynamics demonstrated that the Janus NPs generated microbubbles with a radii of 1.1 MUm. Furthermore, the microbubbles generated by the NPs were detected with a conventional medical ultrasound imaging device. Long systemic circulation time was ensured by grafting the NPs with two different PEG polymers, which did not affect adversely the microbubble generation. The present findings represent an important landmark in the development of ultrasound contrast agents which possess the properties for both diagnostics and therapy. PMID- 28921953 TI - New Antimony Selenide/Nickel Oxide Photocathode Boosts the Efficiency of Graphene Quantum-Dot Co-Sensitized Solar Cells. AB - A novel assembly of a photocathode and a photoanode is investigated to explore their complementary effects in enhancing the photovoltaic performance of a quantum-dot solar cell (QDSC). While p-type nickel oxide (NiO) has been used previously, antimony selenide (Sb2Se3) has not been used in a QDSC, especially as a component of a counter electrode (CE) architecture that doubles as the photocathode. Here, near-infrared (NIR) light-absorbing Sb2Se3 nanoparticles (NPs) coated over electrodeposited NiO nanofibers on a carbon (C) fabric substrate was employed as the highly efficient photocathode. Quasi-spherical Sb2Se3 NPs, with a band gap of 1.13 eV, upon illumination, release photoexcited electrons in addition to other charge carriers at the CE to further enhance the reduction of the oxidized polysulfide. The p-type conducting behavior of Sb2Se3, coupled with a work function at 4.63 eV, also facilitates electron injection to polysulfide. The effect of graphene quantum dots (GQDs) as co-sensitizers as well as electron conduits is also investigated in which a TiO2/CdS/GQDs photoanode structure in combination with a C-fabric CE delivered a power-conversion efficiency (PCE) of 5.28%, which is a vast improvement over the 4.23% that is obtained by using a TiO2/CdS photoanode (without GQDs) with the same CE. GQDs, due to a superior conductance, impact efficiency more than Sb2Se3 NPs do. The best PCE of a TiO2/CdS/GQDs-nS2-/Sn2--Sb2Se3/NiO/C-fabric cell is 5.96% (0.11 cm2 area), which, when replicated on a smaller area of 0.06 cm2, is seen to increase dramatically to 7.19%. The cell is also tested for 6 h of continuous irradiance. The rationalization for the channelized photogenerated electron movement, which augments the cell performance, is furnished in detail in these studies. PMID- 28921955 TI - Characterization of Site-Specific Glycosylation in Influenza A Virus Hemagglutinin Produced by Spodoptera frugiperda Insect Cell Line. AB - Influenza hemagglutinin is a surface glycoprotein related to virus invasion and host immune system response. Understanding site specific glycosylation of hemagglutinin will increase our knowledge about virus evolution and can improve the design and quality of vaccines. In our study, we used glycoproteomic analysis based on multienzyme digestion followed by LC tandem MS analysis to determine the glycosylation of Influenza hemagglutinin (H1/A/California/04/2009) using the following steps: PNGaseF treatment combined with trypsin or pepsin digestion was used to determine the glycosites and glycan occupancy. Three enzymes, trypsin, AspN, and pepsin, were used separately to generate suitable glycopeptides for online LC tandem MS analysis. The glycan structure of a given glycopeptide was determined by collision-induced dissociation MS/MS fragmentation, and the peptide backbone information was provided by collision-induced dissociation (CID)-MS3 fragmentation. With this approach, 100% sequence coverage of the hemagglutinin sample was obtained. Six glycosylation sites fitting the sequon N-X-S/T were successfully confirmed, and the glycan heterogeneity as well as the ratios of glycoforms were determined at each site. PMID- 28921954 TI - Remote, Late-Stage Oxidation of Aliphatic C-H Bonds in Amide-Containing Molecules. AB - Amide-containing molecules are ubiquitous in natural products, pharmaceuticals, and materials science. Due to their intermediate electron-richness, they are not amenable to any of the previously developed N-protection strategies known to enable remote aliphatic C-H oxidations. Using information gleaned from a systematic study of the main features that makes remote oxidations of amides in peptide settings possible, we developed an imidate salt protecting strategy that employs methyl trifluoromethanesulfonate as a reversible alkylating agent. The imidate salt strategy enables, for the first time, remote, nondirected, site selective C(sp3)-H oxidation with Fe(PDP) and Fe(CF3PDP) catalysis in the presence of a broad scope of tertiary amides, anilide, 2-pyridone, and carbamate functionality. Secondary and primary amides can be masked as N-Ns amides to undergo remote oxidation. This novel imidate strategy facilitates late-stage oxidations in a broader scope of medicinally important molecules and may find use in other C-H oxidations and metal-mediated reactions that do not tolerate amide functionality. PMID- 28921956 TI - Recognition of DNA Supercoil Geometry by Mycobacterium tuberculosis Gyrase. AB - Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M. tuberculosis gyrase on positively supercoiled DNA were investigated. Results indicate that the enzyme acts rapidly on overwound DNA and removes positive supercoils much faster than it introduces negative supercoils into relaxed DNA. Canonical gyrase and topoisomerase IV distinguish supercoil handedness differently during the DNA cleavage reaction: while gyrase maintains lower levels of cleavage complexes on overwound DNA, topoisomerase IV maintains similar levels of cleavage complexes on both over- and underwound substrates. M. tuberculosis gyrase maintained lower levels of cleavage complexes on positively supercoiled DNA in the absence and presence of quinolone-based drugs. By retaining this important feature of canonical gyrase, the dual function M. tuberculosis type II enzyme remains a safe enzyme to act in front of replication forks and transcription complexes. Finally, the N-terminal gate region of the enzyme appears to be necessary to distinguish supercoil handedness during DNA cleavage, suggesting that the capture of the transport segment may influence how gyrase maintains cleavage complexes on substrates with different topological states. PMID- 28921958 TI - Electronic Structural Analysis of Copper(II)-TEMPO/ABNO Complexes Provides Evidence for Copper(I)-Oxoammonium Character. AB - Copper/aminoxyl species are proposed as key intermediates in aerobic alcohol oxidation. Several possible electronic structural descriptions of these species are possible, and the present study probes this issue by examining four crystallographically characterized Cu/aminoxyl halide complexes by Cu K-edge, Cu L2,3-edge, and Cl K-edge X-ray absorption spectroscopy. The mixing coefficients between Cu, aminoxyl, and halide orbitals are determined via these techniques with support from density functional theory. The emergent electronic structure picture reveals that Cu coordination confers appreciable oxoammonium character to the aminoxyl ligand. The computational methodology is extended to one of the putative intermediates invoked in catalytic Cu/aminoxyl-driven alcohol oxidation reactions, with similar findings. Collectively, the results have important implications for the mechanism of alcohol oxidation and the underlying basis for cooperativity in this co-catalyst system. PMID- 28921957 TI - Silver Nanowires for Reconfigurable Bloch Surface Waves. AB - The use of a single silver nanowire as a flexible coupler to transform a free space beam into a Bloch surface wave propagating on a dielectric multilayer is proposed. Based on Huygens' Principle, when a Gaussian beam is focused onto a straight silver nanowire, a Bloch surface wave is generated and propagates perpendicular to the nanowire. By curving the silver nanowire, the surface wave can be focused. Furthermore, the spatial phase of the incident laser beam can be actively controlled with the aid of a spatial light modulator, resulting in the reconfigurable or dynamically controlled Bloch surface waves. The low cost of the chemically synthesized silver nanowires and the high flexibility with regard to tuning the spatial phase of the incident light make this approach very promising for various applications including optical micromanipulation, fluorescence imaging, and sensing. PMID- 28921959 TI - Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors. AB - In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H2C?CH-Acc, 1) and styrenes (PhCH?CH-Acc, 2) with pyridinium ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloromethyl anion 5. Substitution of the 57 measured second-order rate constants (log k) and the previously reported nucleophile-specific parameters N and sN for 3-5 into the correlation log k = sN(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters sN, N, and E for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of 3-5 at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4 and 5), respectively. The electrophilicity parameters E thus determined can be used to calculate the rates of the reactions of Michael acceptors 1 and 2 with any nucleophile of known N and sN. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with the LUMO energies and with Parr's electrophilicity index omega, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities. PMID- 28921960 TI - Boron Difluoride Adducts of a Flexidentate Pyridine-Substituted Formazanate Ligand: Property Modulation via Protonation and Coordination Chemistry. AB - The synthesis and characterization of a flexidentate pyridine-substituted formazanate ligand and its boron difluoride adducts, formed via two different coordination modes of the title ligand, are described. The first adduct adopted a structure that was typical of other boron difluoride adducts of triarylformazanate ligands and contained a free pyridine subsituent, while the second was formed via the chelation of nitrogen atoms from the formazanate backbone and the pyridine substituent. Stepwise protonation of the pydridine functionalized adduct, which is essentially nonemissive, resulted in a significant increase in the fluorescence quantum yield up to a maximum of 18%, prompting the study of this adduct as a pH sensor. The coordination chemistry of each adduct was explored through reactions with nickel(II) bromide [NiBr2(CH3CN)2], triflate [Ni(OTf)2], and 1,1,1,4,4,4-hexafluoroacetylacetonate [Ni(hfac)2(H2O)2] salts. Coordination to nickel(II) ions altered the physical properties of the boron difluoride formazanate adducts, including red-shifted absorption maxima and less negative reduction potentials. Together, these studies have demonstrated that the physical and electronic properties of boron difluoride adducts of formazanate ligands can be readily modulated through protonation and coordination chemistry. PMID- 28921961 TI - Three-Dimensional Reconstruction of Nuclear Envelope Architecture Using Dual Color Metal-Induced Energy Transfer Imaging. AB - The nuclear envelope, comprising the inner and the outer nuclear membrane, separates the nucleus from the cytoplasm and plays a key role in cellular functions. Nuclear pore complexes (NPCs), which are embedded in the nuclear envelope, control transport of macromolecules between the two compartments. Here, using dual-color metal-induced energy transfer (MIET), we determine the axial distance between Lap2beta and Nup358 as markers for the inner nuclear membrane and the cytoplasmic side of the NPC, respectively. Using MIET imaging, we reconstruct the 3D profile of the nuclear envelope over the whole basal area, with an axial resolution of a few nanometers. This result demonstrates that optical microscopy can achieve nanometer axial resolution in biological samples and without recourse to complex interferometric approaches. PMID- 28921962 TI - Pentafluorosulfanyl Substituents in Polymerization Catalysis. AB - Highly electron-withdrawing pentafluorosulfanyl groups were probed as substituents in an organometallic catalyst. In Ni(II) salicylaldiminato complexes as an example case, these highly electron-withdrawing substituents allow for polymerization of ethylene to higher molecular weights with reduced branching due to significant reductions in beta-hydrogen elimination. Combined with the excellent functional group tolerance of neutral Ni(II) complexes, this suppression of beta-hydrogen elimination allows for the direct polymerization of ethylene in water to nanocrystal dispersions of disentangled, ultrahigh-molecular weight linear polyethylene. PMID- 28921964 TI - Versatile Synthetic Route for beta-Functionalized Chlorins and Porphyrins by Varying the Size of Michael Donors: Syntheses, Photophysical, and Electrochemical Redox Properties. AB - One-pot facile synthesis and characterization of novel beta-substituted meso tetraphenylporphyrins and/or chlorins were described. The high regioselective reactivity of active methylene compounds in Michael addition reaction was reported to access beta-substituted trans-chlorins. Size-dependent approach was applied for the fine-tuning of product formation from porphyrins to chlorins. Notably, we were able to isolate mono/trisubstituted porphyrin and/or di/tetra substituted chlorin from one-pot synthesis for the first time in porphyrin chemistry. Single-crystal X-ray diffraction analysis revealed the quasiplanar to moderate nonplanar conformation of chlorins due to trans orientation of beta substituents, whereas porphyrins exhibited higher mean plane deviation from 24 atom core (Delta24) as compared to chlorins. beta-Functionalized chlorins exhibited lower protonation constants and much higher deprotonation constants as compared to porphyrins revealing the combined effect of the conformation of macrocyclic core and the electronic nature of beta-substituents. Facile synthesis of porphyrins and/or chlorins based on the size of Michael donor employed and in turn resulted in tunable photophysical and electrochemical redox properties are the significant features of the present work. PMID- 28921963 TI - Direct Vapor Growth of Perovskite CsPbBr3 Nanoplate Electroluminescence Devices. AB - Metal halide perovskite nanostructures hold great promises as nanoscale light sources for integrated photonics due to their excellent optoelectronic properties. However, it remains a great challenge to fabricate halide perovskite nanodevices using traditional lithographic methods because the halide perovskites can be dissolved in polar solvents that are required in the traditional device fabrication process. Herein, we report single CsPbBr3 nanoplate electroluminescence (EL) devices fabricated by directly growing CsPbBr3 nanoplates on prepatterned indium tin oxide (ITO) electrodes via a vapor-phase deposition. Bright EL occurs in the region near the negatively biased contact, with a turn-on voltage of ~3 V, a narrow full width at half-maximum of 22 nm, and an external quantum efficiency of ~0.2%. Moreover, through scanning photocurrent microscopy and surface electrostatic potential measurements, we found that the formation of ITO/p-type CsPbBr3 Schottky barriers with highly efficient carrier injection is essential in realizing the EL. The formation of the ITO/p-type CsPbBr3 Schottky diode is also confirmed by the corresponding transistor characteristics. The achievement of EL nanodevices enabled by directly grown perovskite nanostructures could find applications in on-chip integrated photonics circuits and systems. PMID- 28921965 TI - Mycelium-Enhanced Bacterial Degradation of Organic Pollutants under Bioavailability Restrictions. AB - This work examines the role of mycelia in enhancing the degradation by attached bacteria of organic pollutants that have poor bioavailability. Two oomycetes, Pythium oligandrum and Pythium aphanidermatum, were selected as producers of mycelial networks, while Mycobacterium gilvum VM552 served as a model polycyclic aromatic hydrocarbon (PAH) degrading bacterium. The experiments consisted of bacterial cultures exposed to a nondisturbed nonaqueous phase liquid (NAPL) layer containing a heavy fuel spiked with 14C-labeled phenanthrene that were incubated in the presence or absence of the mycelia of the oomycetes in both shaking and static conditions. At the end of the incubation, the changes in the total alkane and PAH contents in the NAPL residue were quantified. The results revealed that with shaking and the absence of mycelia, the strain VM552 grew by utilizing the bulk of alkanes and PAHs in the fuel; however, biofilm formation was incipient and phenanthrene was mineralized following zero-order kinetics, due to bioavailability limitations. The addition of mycelia favored biofilm formation and dramatically enhanced the mineralization of phenanthrene, up to 30 times greater than the rate without mycelia, possibly by providing a physical support to bacterial colonization and by supplying nutrients at the NAPL/water interface. The results in the static condition were very different because the bacterial strain alone degraded phenanthrene with sigmoidal kinetics but could not degrade alkanes or the bulk of PAHs. We suggest that bacteria/oomycete interactions should be considered not only in the design of new inoculants in bioremediation but also in biodegradation assessments of chemicals present in natural environments. PMID- 28921966 TI - Tool for Rapid Analysis of Glycopeptide by Permethylation via One-Pot Site Mapping and Glycan Analysis. AB - To overcome the challenges in the analysis of protein glycosylation, we have developed a comprehensive and universal tool through permethylation of glycopeptides and their tandem mass spectrometric analysis. This method has the potential to simplify glycoprotein analysis by integrating glycan sequencing and glycopeptide analysis in a single experiment. Moreover, glycans with unique glycosidic linkages, particularly from prokaryotes, which are resistant to enzymatic or chemical release, could also be detected and analyzed by this methodology. Here we present a strategy for the permethylation of intact glycopeptides, obtained via controlled protease digest, and their characterization by using advanced mass spectrometry. We used bovine RNase B, human transferrin, and bovine fetuin as models to demonstrate the feasibility of the method. Remarkably, the glycan patterns, glycosylation site, and their occupancy by N-glycans are all detected and identified in a single experimental procedure. Acquisition on a high resolution tandem-MSn system with fragmentation methodologies such as high-energy collision dissociation (HCD) and collision induced dissociation (CID), provided the complete sequence of the glycan structures attached to the peptides. The behavior of 20 natural amino acids under the basic permethylation conditions was probed by permethylating a library of short synthetic peptides. Our studies indicate that the permethylation imparts simple, limited, and predictable chemical transformations on peptides and do not interfere with the interpretation of MS/MS data. In addition to this, permethylated O-glycans in unreduced form (released by beta elimination) were also detected, allowing us to profile O-linked glycan structures simultaneously. PMID- 28921967 TI - Quantifying Secondary Structure Changes in Calmodulin Using 2D-IR Spectroscopy. AB - Revealing the details of biomolecular processes in solution needs tools that can monitor structural dynamics over a range of time and length scales. We assess the ability of 2D-IR spectroscopy in combination with multivariate data analysis to quantify changes in secondary structure of the multifunctional calcium-binding messenger protein Calmodulin (CaM) as a function of temperature and Ca2+ concentration. Our approach produced quantitative agreement with circular dichroism (CD) spectroscopy in detecting the domain melting transitions of Ca2+ free (apo) CaM (reduction in alpha-helix structure by 13% (CD) and 15% (2D)). 2D IR also allows accurate differentiation between melting transitions and generic heating effects observed in the more thermally stable Ca2+-bound (holo) CaM. The functionally relevant random-coil-alpha-helix transition associated with Ca2+ uptake that involves just 7-8 out of a total of 148 amino acid residues was clearly detected. Temperature-dependent Molecular Dynamics (MD) simulations show that apo-CaM exists in dynamic equilibrium with holo-like conformations, while Ca2+ uptake reduces conformational flexibility. The ability to combine quantitative structural insight from 2D-IR with MD simulations thus offers a powerful approach for measuring subtle protein conformational changes in solution. PMID- 28921968 TI - Automated Solid-Phase Click Synthesis of Oligonucleotide Conjugates: From Small Molecules to Diverse N-Acetylgalactosamine Clusters. AB - We developed a novel technique for the efficient conjugation of oligonucleotides with various alkyl azides such as fluorescent dyes, biotin, cholesterol, N acetylgalactosamine (GalNAc), etc. using copper-catalysed alkyne-azide cycloaddition on the solid phase and CuI.P(OEt)3 as a catalyst. Conjugation is carried out in an oligonucleotide synthesizer in fully automated mode and is coupled to oligonucleotide synthesis and on-column deprotection. We also suggest a set of reagents for the construction of diverse conjugates. The sequential double-click procedure using a pentaerythritol-derived tetraazide followed by the addition of a GalNAc or Tris-GalNAc alkyne gives oligonucleotide-GalNAc dendrimer conjugates in good yields with minimal excess of sophisticated alkyne reagents. The approach is suitable for high-throughput synthesis of oligonucleotide conjugates ranging from fluorescent DNA probes to various multi-GalNAc derivatives of 2'-modified siRNA. PMID- 28921969 TI - Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. AB - Electrosynthesis has much to offer to the synthetic organic chemist. But in order to be widely accepted as a routine procedure in an organic synthesis laboratory, electrosynthesis needs to be presented in a much more user-friendly way. The literature is largely based on electrolysis in a glass beaker or H-cells that often give poor performance for synthesis with a very slow rate of conversion and, often, low selectivity and reproducibility. Flow cells can lead to much improved performance. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a number of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant solution through the cell. In addition, the needs of the synthetic organic chemist can often be met by flow cells operating with recycle of the reactant solution. These cells give a high rate of product formation while the reactant concentration is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported. PMID- 28921970 TI - Tris-heteroleptic Iridium Complexes Based on Cyclometalated Ligands with Different Cores. AB - A series of tris-heteroleptic iridium complexes of the form [Ir(C^N1)(C^N2)(acac)] combining 2-phenylpyridine (ppy), 2-(2,4 difluorophenyl)pyridine (dFppy), 1-phenylpyrazole (ppz), and 1-(2,4 difluorophenyl)pyrazole (dFppz) as the C^N ligands have been synthesized and fully characterized by NMR, X-ray crystallography, UV-vis absorption and emission spectroscopy, and electrochemical methods. It is shown that "static properties" (e.g., absorption and emission spectra and redox potentials) are primarily dictated by the overall architecture of the complex, while "dynamic properties" (e.g., excited-state lifetime and radiative and nonradiative rate constants) are, in addition, sensitive to the specific positioning of the substituents. As a result, the two complexes [Ir(dFppy)(ppz)(acac)] and [Ir(ppy)(dFppz)(acac)] have the same emission maxima and redox potentials, but their radiative and nonradiative rate constants differ significantly by a factor ~2. Then acetylacetonate (acac) was replaced by picolinate (pic), and two pairs of diastereoisomers were obtained. As expected, the use of pic as the ancillary ligand results in blue-shifted emission, stabilization of the oxidation potential, and improvement of the photoluminescence quantum yield, and only minor differences in the optoelectronic properties are found between the two diastereoisomers of each pair. PMID- 28921971 TI - Paper Sensor Coated with a Poly(carboxybetaine)-Multiple DOPA Conjugate via Dip Coating for Biosensing in Complex Media. AB - Cellulose paper is an ideal diagnostic platform for low-cost, easily disposable and lightweight implementation, but requires surface modification to achieve detection with high sensitivity and specificity in complex media. In this work, a polymer-catechol conjugate containing a superhydrophilic nonfouling poly(carboxylbetaine) (pCB) and four surface-binding l-3,4-dihydroxyphenylalanine (DOPA) groups, pCB-(DOPA)4, were applied onto a paper-based sensor surface via a simple "graft-to" immersion process to render the surface with both nonfouling and protein functionalizable properties. This dip-coating technique is effective, convenient and robust as compared to the "graft-from" techniques reported previously with similar nonfouling properties. The coated paper sensor showed both increased analyte diffusion rate and improved sensitivity of glucose detection in human blood serum. The capability of pCB-(DOPA)4-modified paper sensor for specific antigen-antibody detection was demonstrated via the covalent immobilization of bovine serum albumin antibody (anti-BSA) and fibrinogen antibody (anti-Fg) onto the pCB-coated surface via simple 1-ethyl-3-(3 (dimethylamino)propyl)-carbodiimide and N-hydroxysuccinimide (EDC/NHS) chemistry. PMID- 28921973 TI - Evans-Showell-Type Polyoxometalates Constructing High-Dimensional Inorganic Organic Hybrid Compounds with Copper-Organic Coordination Complexes: Synthesis and Oxidation Catalysis. AB - Four new hybrid architectures containing a [Co2Mo10H4O38]6- polyoxoanion, (en)[Cu3(ptz)4(H2O)4][Co2Mo10H4O38].24H2O (1), (Hbim)2[{Cu(bim)2(H2O)2}2{Co2Mo10H4O38}].5H2O (2), H2[Cu(dpdo)3(H2O)4][{Cu2(dpdo)3(H2O)4(CH3CN)}2{Co2Mo10H4O38}2].9H2O (3), and (H2bpp)4[{Cu(H2O)2}{NaCo2Mo10H4O38}2].10H2O (4), where ptz = 5-(4-pyridyl)-1H tetrazole, en = ethylenediamine, bim = benzimidazole, dpdo = 4,4'-bipyridine-N,N' dioxide, and bpp = 1,3-bis(4-pyridyl)propane, have been prepared and characterized through elemental analysis, thermogravimetric analysis, IR spectroscopy, and powder and single-crystal X-ray diffraction. Compound 1 shows a 3D host-guest framework composed of 3D Cu-ptz as the host and Evans-Showell-type polyoxoanion [Co2Mo10H4O38]6- as the guest. Compound 2 is constructed from [Co2Mo10H4O38]6- polyoxoanions and Cu-bim coordination complexes to form a 2D covalent layer. Compound 3 also exhibits a 2D hybrid network based on [Co2Mo10H4O38]6- polyoxoanions linked by Cu-dpdo coordination groups. Compound 4 is a 1D double-chain structure composed of [Co2Mo10H4O38]6- polyoxoanions joined together by Na+ and Cu2+ cations. As far as we know, compound 1 is the first host guest compound with an Evans-Showell-type polyoxometalate as the guest, and compounds 2 and 3 are the first 2D inorganic-organic hybrid architectures constructed from Evans-Showell-type polyoxometalates. Compounds 1-4 are redox catalysts that heterogeneously prompt sulfide and alcohol oxidation with excellent efficiency. PMID- 28921974 TI - The Hydrophobic Effect and the Role of Cosolvents. AB - Cosolvents modulate aqueous solubility, hydrophobic interactions, and the stability and function of most proteins in the living cell. Our molecular-level understanding of cosolvent effects is incomplete, not only at the level of complex systems such as proteins, but also at the level of very fundamental interactions that underlie the hydrophobic effect. This Feature Article discusses cosolvent effects on the aqueous solubility of nonpolar solutes, hydrophobic interactions, and hydrophobic self-assembly/collapse of aqueous polymers, recently studied with molecular dynamics simulations. It is shown that direct interactions of cosolvents with nonpolar solutes and aqueous polymers can strengthen hydrophobic interactions and can contribute to stabilizing collapsed globular structures. The molecular-level explanation of these observations requires a better understanding of the entropy associated with fluctuations of attractive solute-solvent interactions and of length-scale dependencies of this quantity. PMID- 28921972 TI - What Can Be Learned from Nuclear Resonance Vibrational Spectroscopy: Vibrational Dynamics and Hemes. AB - Nuclear resonance vibrational spectroscopy (NRVS; also known as nuclear inelastic scattering, NIS) is a synchrotron-based method that reveals the full spectrum of vibrational dynamics for Mossbauer nuclei. Another major advantage, in addition to its completeness (no arbitrary optical selection rules), is the unique selectivity of NRVS. The basics of this recently developed technique are first introduced with descriptions of the experimental requirements and data analysis including the details of mode assignments. We discuss the use of NRVS to probe 57Fe at the center of heme and heme protein derivatives yielding the vibrational density of states for the iron. The application to derivatives with diatomic ligands (O2, NO, CO, CN-) shows the strong capabilities of identifying mode character. The availability of the complete vibrational spectrum of iron allows the identification of modes not available by other techniques. This permits the correlation of frequency with other physical properties. A significant example is the correlation we find between the Fe-Im stretch in six-coordinate Fe(XO) hemes and the trans Fe-N(Im) bond distance, not possible previously. NRVS also provides uniquely quantitative insight into the dynamics of the iron. For example, it provides a model-independent means of characterizing the strength of iron coordination. Prediction of the temperature-dependent mean-squared displacement from NRVS measurements yields a vibrational "baseline" for Fe dynamics that can be compared with results from techniques that probe longer time scales to yield quantitative insights into additional dynamical processes. PMID- 28921975 TI - Intricacies of van der Waals Interactions in Systems with Elongated Bonds Revealed by Electron-Groups Embedding and High-Level Coupled-Cluster Approaches. AB - Noncovalent interactions between molecules with stretched intramonomer covalent bonds are a fascinating, yet little studied area. This shortage of information stems largely from the inability of most of the commonly used computational quantum chemistry methods to accurately describe weak long-range and strong nondynamic correlations at the same time. In this work, we propose a geminal based approach, abbreviated as EERPA-GVB, capable of describing such systems in a robust manner using relatively inexpensive computational steps. By examining a few van der Waals complexes, we demonstrate that the elongation of one or more intramolecular covalent bonds leads to an enhanced attraction between the monomers. We show that this increase in attraction occurs as the electron density characterizing intramolecular covalent bonds depletes and migrates toward the region between the monomers. As the covalent intramonomer bonds continue to stretch, the intermolecular interaction potential passes through a minimum and eventually goes up. The findings resulting from our EERPA-GVB calculations are supported and further elucidated by the symmetry-adapted perturbation theory and coupled-cluster (CC) computations using methods that are as sophisticated as the CC approach with a full treatment of singly, doubly, and triply excited clusters. PMID- 28921976 TI - Isolation, Synthesis, and Biological Activity of Chlorinated Alkylresorcinols from Dictyostelium Cellular Slime Molds. AB - Eight chlorinated alkylresorcinols, monochasiol A-H (1-8), were isolated from the fruiting bodies of Dictyostelium monochasioides. Compounds 1-8 were synthesized to confirm their structures and to obtain sufficient material for performing biological tests. Monochasiol A (1) selectively inhibited the concanavalin A induced interleukin-2 production in Jurkat cells, a human T lymphocyte cell line. Monochasiols were biogenetically synthesized by the combination of biosynthetic enzymes relating to the principal polyketides, MPBD and DIF-1, produced by Dictyostelium discoideum. PMID- 28921977 TI - Photoinduced Bimolecular Electron Transfer in Ionic Liquids. AB - The present work seeks to better understand the role of solute diffusion and solvation dynamics on bimolecular electron transfer in ionic liquids (ILs). Steady-state and time-resolved measurements of the reductive fluorescence quenching of five fluorophores ("F") by six quenchers ("Q"; electron donors) are reported in acetonitrile and two ionic liquids, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide and trihexyl(tetradecyl)phosphonium bis(trifluoromethylsulfonyl)amide. Data were collected on 66 different F-Q solvent systems, which span a 2.0 eV range in driving force and viscosities that vary 1000-fold, enabling stringent tests of bimolecular electron transfer models. A Stern-Volmer analysis yielded much larger diffusion-limited rates than simple kinetic theory predictions in the ILs and the absence of a Marcus turnover. Use of an approximate solution to the spherical diffusion-reaction equation enabled testing of several models for the reaction rate distance dependence. The Smoluchowski and Collins-Kimball models, which assume reaction at a single distance, are able to fit the data collected in acetonitrile solutions reasonably well, but not the data in the IL solvents. An extended sink model, incorporating a finite reaction zone, was able to fit all data satisfactorily with only three adjustable parameters. Diffusion coefficients extracted from these fits were much larger for the neutral versus anionic quenchers and close to predicted values. Molecular dynamics simulations and density-functional methods were then used to explore solvation structures and electronic couplings. The electronic coupling between contact F-Q pairs was found to vary strongly with the relative location and orientation of the reactants. Information from these simulations was used to constrain a model based on classical Marcus theory, which provided physically reasonable fits with only two adjustable parameters, but required systematic reduction of the driving forces in order to suppress a rate turnover at large driving force. The latter requirement indicates that reaction rates in ionic liquids are limited by some factor not properly accounted for in bimolecular electron transfer models based on a spherical diffusion-reaction approach. Small amplitude motions within contact F-Q pairs, which gate the electronic coupling, are suggested to be the limiting dynamics. PMID- 28921978 TI - Electrocatalytic CO2 Reduction by Imidazolium-Functionalized Molecular Catalysts. AB - We present the first examples of CO2 electro-reduction catalysts that feature charged imidazolium groups in the secondary coordination sphere. The functionalized Lehn-type catalysts display significant differences in their redox properties and improved catalytic activities as compared to the conventional reference catalyst. Our results suggest that the incorporated imidazolium moieties do not solely function as a charged tag but also alter mechanistic aspects of catalysis. PMID- 28921979 TI - Design, Syntheses, and in Vitro Evaluation of New Fluorine-18 Radiolabeled Tau Labeling Molecular Probes. AB - Deposition of aggregates of hyperphosphorylated tau protein is a hallmark of tauopathies like Alzheimer and many other neurodegenerative diseases. A sensitive and selective method of in vivo detection of tau-aggregate presence and distribution could provide the means of an early diagnosis of tau-associated diseases. Furthermore, the use of selective molecular probes that enable histochemical differentiation of protein aggregates post-mortem would be advantageous for the insight into the properties of tau protein aggregates. We chose to design new molecular probes based on the structure of 2-(1-(6-((2 [18F]fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile to investigate their likelihood of fitting into VQIVYK tau protein binding channel model. In a modular approach, using cross-coupling reactions, we synthesized a series of candidates, radiolabeled them with fluorine-18 radioisotope, and determined their physicochemical and in vitro binding properties. Herein we report the synthesis of a series of molecular probes capable of detection of tau protein deposits in vitro. PMID- 28921980 TI - Benchmark of Dynamic Electron Correlation Models for Seniority-Zero Wave Functions and Their Application to Thermochemistry. AB - Wave functions restricted to electron-pair states are promising models to describe static/nondynamic electron correlation effects encountered, for instance, in bond-dissociation processes and transition-metal and actinide chemistry. To reach spectroscopic accuracy, however, the missing dynamic electron correlation effects that cannot be described by electron-pair states need to be included a posteriori. In this Article, we extend the previously presented perturbation theory models with an Antisymmetric Product of 1-reference orbital Geminal (AP1roG) reference function that allows us to describe both static/nondynamic and dynamic electron correlation effects. Specifically, our perturbation theory models combine a diagonal and off-diagonal zero-order Hamiltonian, a single-reference and multireference dual state, and different excitation operators used to construct the projection manifold. We benchmark all proposed models as well as an a posteriori Linearized Coupled Cluster correction on top of AP1roG against CR-CC(2,3) reference data for reaction energies of several closed-shell molecules that are extrapolated to the basis set limit. Moreover, we test the performance of our new methods for multiple bond breaking processes in the homonuclear N2, C2, and F2 dimers as well as the heteronuclear BN, CO, and CN+ dimers against MRCI-SD, MRCI-SD+Q, and CR-CC(2,3) reference data. Our numerical results indicate that the best performance is obtained from a Linearized Coupled Cluster correction as well as second-order perturbation theory corrections employing a diagonal and off-diagonal zero-order Hamiltonian and a single-determinant dual state. These dynamic corrections on top of AP1roG provide substantial improvements for binding energies and spectroscopic properties obtained with the AP1roG approach, while allowing us to approach chemical accuracy for reaction energies involving closed-shell species. PMID- 28921981 TI - Use of (Cyclopentadienone)iron Tricarbonyl Complexes for C-N Bond Formation Reactions between Amines and Alcohols. AB - The application of a series of (cyclopentadienone)iron tricarbonyl complexes to "borrowing hydrogen" reactions between amines and alcohols was completed in order to assess their catalytic activity. The electronic variation of the aromatic groups flanking the C?O of the cyclopentadienone influenced the efficiency of the reactions; however, in other cases, the Knolker catalyst 1, containing trimethylsilyl groups flanking the cyclopentadienone ketone, gave the best results. In some cases, the change of the ratio of amine to alcohol improves the conversion significantly. The application of iron catalysts to the synthesis of a range of amines, including unsaturated amines, was investigated. PMID- 28921982 TI - Mortiamides A-D, Cyclic Heptapeptides from a Novel Mortierella sp. Obtained from Frobisher Bay. AB - Four new cyclic heptapeptides, mortiamides A-D (1-4), were obtained from a novel Mortierella sp. isolate obtained from marine sediment collected from the intertidal zone of Frobisher Bay, Nunavut, Canada. The structures of the compounds were elucidated by NMR spectroscopy and tandem mass spectrometry. The absolute configurations of the amino acids were determined using Marfey's method. Localization of l and d amino acids within each compound was ascertained by retention time comparison of the partial hydrosylate products of each compound to synthesized dipeptide standards using LC-HRMS. Compounds 1-4 did not exhibit any significant antimicrobial or cytotoxic activity. PMID- 28921983 TI - The First State in the Catalytic Cycle of the Water-Oxidizing Enzyme: Identification of a Water-Derived MU-Hydroxo Bridge. AB - Nature's water-splitting catalyst, an oxygen-bridged tetramanganese calcium (Mn4O5Ca) complex, sequentially activates two substrate water molecules generating molecular O2. Its reaction cycle is composed of five intermediate (Si) states, where the index i indicates the number of oxidizing equivalents stored by the cofactor. After formation of the S4 state, the product dioxygen is released and the cofactor returns to its lowest oxidation state, S0. Membrane-inlet mass spectrometry measurements suggest that at least one substrate is bound throughout the catalytic cycle, as the rate of 18O-labeled water incorporation into the product O2 is slow, on a millisecond to second time scale depending on the S state. Here, we demonstrate that the Mn4O5Ca complex poised in the S0 state contains an exchangeable hydroxo bridge. On the basis of a combination of magnetic multiresonance (EPR) spectroscopies, comparison to biochemical models and theoretical calculations we assign this bridge to O5, the same bridge identified in the S2 state as an exchangeable fully deprotonated oxo bridge [Perez Navarro, M.; et al. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 15561]. This oxygen species is the most probable candidate for the slowly exchanging substrate water in the S0 state. Additional measurements provide new information on the Mn ions that constitute the catalyst. A structural model for the S0 state is proposed that is consistent with available experimental data and explains the observed evolution of water exchange kinetics in the first three states of the catalytic cycle. PMID- 28921984 TI - Melting Behavior of a DNA Four-Way Junction Using Spectroscopic and Calorimetric Techniques. AB - Intramolecular four-way junctions are structures present during homologous recombination, repair of double stranded DNA breaks, and integron recombination. Because of the wide range of biological processes four-way junctions are involved in, understanding how and under what conditions these structures form is critical. In this work, we used a combination of spectroscopic and calorimetric techniques to present a complete thermodynamic description of the unfolding of a DNA four-way junction (FWJ) and its appropriate control stem-loop motifs (Dumbbell, GAAATT-Hp, CTATC-Hp, GTGC-Hp, and GCGC-Hp). The overall results show that the four-way junction increases the cooperative unfolding of its stems, although the reason for this is unclear, as the arms do not unfold as coaxial stacks, and thus its melting behavior cannot be accurately described by its control molecules. This is in contrast to what has been seen for two- and three way junctions. In addition, the lack of base stacking and the DeltaHvH/DeltaHcal ratio seen at low salt indicate the four-way junction exists as a mixture of conformations, one of which is most likely the open-X structure which has unpaired bases at the junction. This was confirmed by single value decomposition of CD and UV spectra. This indicates that at low salt there is a third spectroscopically distinct species, while at higher salt there are only two species, folded and unfolded. Based on the enthalpy, Deltanion, and DeltanW, the dominant folded structure at high salt is most likely the antiparallel stacked-X structure. PMID- 28921986 TI - Combining Density Functional Theory and Green's Function Theory: Range-Separated, Nonlocal, Dynamic, and Orbital-Dependent Hybrid Functional. AB - We present a rigorous framework which combines single-particle Green's function theory with density functional theory based on a separation of electron-electron interactions into short- and long-range components. Short-range contribution to the total energy and exchange-correlation potential is provided by a density functional approximation, while the long-range contribution is calculated using an explicit many-body Green's function method. Such a hybrid results in a nonlocal, dynamic, and orbital-dependent exchange-correlation functional of a single-particle Green's function. In particular, we present a range-separated hybrid functional called srSVWN5-lrGF2 which combines the local-density approximation and the second-order Green's function theory. We illustrate that similarly to density functional approximations, the new functional is weakly basis-set dependent. Furthermore, it offers an improved description of the short range dynamic correlation. The many-body contribution to the functional mitigates the many-electron self-interaction error present in many density functional approximations and provides a better description of molecular properties. Additionally, we illustrate that the new functional can be used to scale down the self-energy and, therefore, introduce an additional sparsity to the self-energy matrix that in the future can be exploited in calculations for large molecules or periodic systems. PMID- 28921985 TI - Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity. AB - The function of p53 protein, also known as "genome guardian", might be impaired by the overexpression of its primary cellular inhibitor, the murine double minute 2 protein (MDM2). However, the recent finding that MDM2-selective inhibitors induce high levels of its homologue MDM4, prompt us to identify, through a receptor-based virtual screening on an in house database, dual MDM2/MDM4 binders. Compound 1 turned out to possess an IC50 of 93.7 and of 4.6 nM on MDM2 and MDM4, respectively. A series of compounds were synthesized to optimize its activity on MDM2. As a result, compound 12 showed low nanomolar IC50 for both targets. NMR studies confirmed the pocket of binding of 12 as predicted by the Glide docking software. Notably, 12 was able to cause concentration-dependent inhibition of cell proliferation, yielding an IC50 value of 356 +/- 21 nM in neuroblastoma SHSY5Y cells and proved even to efficiently block cancer stem cell growth. PMID- 28921987 TI - A Novel Arylurea Fatty Acid That Targets the Mitochondrion and Depletes Cardiolipin To Promote Killing of Breast Cancer Cells. AB - Cancer cell mitochondria are promising anticancer drug targets because they control cell death and are structurally and functionally different from normal cell mitochondria. We synthesized arylurea fatty acids and found that the analogue 16-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (13b) decreased proliferation and activated apoptosis in MDA-MB-231 breast cancer cells in vitro and in vivo. In mechanistic studies 13b emerged as the prototype of a novel class of mitochondrion-targeted agents that deplete cardiolipin and promote cancer cell death. PMID- 28921988 TI - Interaction of Food Additives with Intestinal Efflux Transporters. AB - Breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2) and P-glycoprotein (P-gp) are ABC transporters that are expressed in the intestine, where they are involved in the efflux of many drugs from enterocytes back into the intestinal lumen. The inhibition of BCRP, MRP2, and P-gp can result in enhanced absorption and exposure of substrate drugs. Food additives are widely used by the food industry to improve the stability, flavor, and consistency of food products. Although they are considered safe for consumption, their interactions with intestinal transporters are poorly characterized. Therefore, in this study, selected food additives, including preservatives, colorants, and sweeteners, were studied in vitro for their inhibitory effects on intestinal ABC transporters. Among the studied compounds, several colorants were able to inhibit BCRP and MRP2, whereas P-gp was fairly insensitive to inhibition. Additionally, one sweetener was identified as a potent inhibitor of BCRP. Dose-response studies revealed that the IC50 values of the inhibitors were lower than the estimated intestinal concentrations after the consumption of beverages containing food colorants. This suggests that there is potential for previously unrecognized transporter-mediated food additive-drug interactions. PMID- 28921989 TI - Universal Calibration of Computationally Predicted N 1s Binding Energies for Interpretation of XPS Experimental Measurements. AB - Computationally predicted N 1s core level energies are commonly used to interpret the experimental measurements obtained with X-ray photoelectron spectroscopy. This work compares the application of Koopmans' theorem to core electrons using the B3LYP functional with two commonly used basis sets, analyzes the factors relevant to the comparison of the computational with experimental data, and presents several correlations that allow an accurate prediction of the N 1s binding energy. The first correlation is obtained with a series of known nitrogen containing functional groups on well-characterized organic monolayers. This approach can then be reliably extended to a number of nitrogen-containing chemical systems on silicon surfaces in which the nature of the chemical environment of nitrogen atoms had only been proposed based on a number of analytical techniques. In most of those cases, the XPS analysis is consistent with the proposed structures, but is not always sufficient for conclusive assignments. Third, it was attempted to also include N-containing systems on metals. Despite the admittedly oversimplified approach taken in this case (the metal surface is approximated by a single atom), the observed correlations are still experimentally useful, although in this case significant outliers are found. Finally, previously published correlations between experimental and theoretical C 1s data were reexamined, yielding a set of correlations that allow experimentalists to predict C 1s and N 1s XPS spectra with high accuracy. PMID- 28921990 TI - Disruption of Asymmetric Lipid Bilayer Models Mimicking the Outer Membrane of Gram-Negative Bacteria by an Active Plasticin. AB - The outer membrane (OM) of Gram-negative bacteria is a complex and asymmetric bilayer that antimicrobial peptides must disrupt in order to provoke the cell lysis. The inner and external leaflets of the OM are mainly composed of phospholipids (PL), and lipopolysaccharide (LPS), respectively. Supported lipid bilayers are interesting model systems to mimic the lipid asymmetric scaffold of the OM and determine the quantitative and mechanistic effect of antimicrobial agents, using complementary physicochemical techniques. We report the formation of asymmetric PL/LPS bilayers using the Langmuir-Blodgett/Langmuir-Schaefer technique on two different surfaces (sapphire and mica) with synthetic phospholipids constituting the inner leaflet and bacteria-extracted mutant LPS making up the outer one. The combination of neutron reflectometry and atomic force microscopy techniques allowed the examination of the asymmetric scaffold structure along the normal to the interface and its surface morphology in buffer conditions. Our results allow discrimination of two structurally related peptides, one neutral and inactive, and the other cationic and active. The active cationic plasticin PTCDA1-KF disrupts the asymmetric OM at relevant concentrations through a carpeting scenario characterized by a dramatic removal of lipid molecules from the surface. PMID- 28921991 TI - Direct Palladium-Catalyzed Carbonylative Transformation of Allylic Alcohols and Related Derivatives. AB - A direct, palladium-catalyzed, carbonylative transformation of allylic alcohols for the synthesis of beta,gamma-unsaturated carboxylic acids has been developed. With formic acid as the CO source, various allylic alcohols were conveniently transformed into the corresponding beta,gamma-unsaturated carboxylic acids with excellent linear and (E)-selectivity. The reaction was performed under mild conditions; toxic CO gas manipulation and high-pressure equipment were avoided in this procedure. PMID- 28921992 TI - Mechanistic Understanding of the Synergistic Potential of Azole Fungicides in the Aquatic Invertebrate Gammarus pulex. AB - Azole fungicides are known inhibitors of the important enzyme class cytochrome P450 monooxygenases (CYPs), thereby influencing the detoxification of co occurring substances via biotransformation. This synergism in mixtures containing an azole has mostly been studied by effect measurements, while the underlying mechanism has been less well investigated. In this study, six azole fungicides (cyproconazole, epoxiconazole, ketoconazole, prochloraz, propiconazole, and tebuconazole) were selected to investigate their synergistic potential and their CYP inhibition strength in the aquatic invertebrate Gammarus pulex. The strobilurin fungicide azoxystrobin was chosen as co-occurring substrate, and the synergistic potential was measured in terms of internal concentrations of azoxystrobin and associated biotransformation products (BTPs). Azoxystrobin is biotransformed by various reactions, and 18 BTPs were identified. By measuring internal concentrations of azoxystrobin and its BTPs with high-resolution tandem mass spectrometry in the presence and absence of azole fungicides followed by toxicokinetic modeling, we showed that the inhibition of CYP-catalyzed biotransformation reactions indeed played a role for the observed synergism. However, synergism was only observed for prochloraz at environmentally realistic concentrations. Increased uptake rate constants, an increase in the total internal concentration of azoxystrobin and its BTPs, in vivo assays for measuring CYP activities, and G. pulex video-tracking suggested that the 2-fold increase in bioaccumulation, and, thereby, the raised toxicity of azoxystrobin in the presence of prochloraz is not only caused by inhibited biotransformation but even more by increased azoxystrobin uptake induced by hyperactivity. PMID- 28921993 TI - Lactam-Stapled Cell-Penetrating Peptides: Cell Uptake and Membrane Binding Properties. AB - Stapling of side chains to stabilize an alpha-helical structure has been generally associated with an increased uptake of CPPs. Here, we compare four amphiphilic stapled peptides with their linear counterparts in terms of their membrane binding and conformational features in order to correlate these with uptake efficiency and toxicological effects. The impact of lactam stapling was found to vary strongly with regard to the different aspects of peptide-membrane interactions. Nearly all stapled peptides caused less membrane perturbation (vesicle leakage, hemolysis, bacterial lysis) than their linear counterparts. In one case (MAP-1) where stapling enhanced alpha-helicity in aqueous and lipid environments, leakage was eliminated while cell uptake in HEK293 and HeLa cells remained high, which improved the overall characteristics. The other systems (DRIM, WWSP, KFGF) did not improve, however. The data suggest that cell uptake of amphipathic CPPs correlates with their adopted alpha-helix content in membranes rather than their helicity in solution. PMID- 28921994 TI - Anisotropic Cracking of Nanocrystal Superlattices. AB - The synthesis colloidal nanocrystals in nonpolar organic solvents has led to exceptional size- and shape-control, enabling the formation of nanocrystal superlattices isostructural to atomic lattices built with nanocrystals rather than atoms. The long aliphatic ligands (e.g., oleic acid) used to achieve this control separate nanocrystals too far in the solid state for most charge transporting devices. Solid-state ligand exchange, which brings particles closer together and enhances conductivity, necessitates large changes in the total volume of the solid (compressive stress), which leads to film cracking. In this work, truncate octahedral lead selenide nanocrystals are shown to self-assemble into body-centered cubic superlattices in which the atomic axes of the individual nanocrystals are coaligned with the crystal axes of the superlattice. Due to this coalignment, upon ligand exchange of the superlattices, cracking is preferentially observed on ?011? superlattice directions. This observation is related to differences in the ligand binding to exposed {100} and {111} planes of the PbSe nanocrystal surfaces. This result has implications for binary and more complex structures in which differential reactivity of the constituent elements can lead to disruption of the desired structure. In addition, cracks in PbSe superlattices occur in a semiregular spacings inversely related to the superlattice domain size and strongly influenced by the presence of twin boundaries, which serve as both emission centers and propagation barriers for fractures. This work shows that defects, similar to behavior in nanotwinned metals, could be used to engineer enhanced mechanical strength and electrical conductivity in nanocrystal superlattices. PMID- 28921995 TI - The Angel and the Devil on your shoulder: Friends mitigate and exacerbate 21st birthday alcohol-related consequences. AB - Twenty-first birthdays are associated with heavier drinking and more negative consequences than any other high-risk drinking event. Friends are the strongest social influence on young adult drinking; however, previous research on college students' drinking has often only examined individuals' perceptions of "friends" generally. Unfortunately, this may obscure the positive influence of some friends and the negative influence of others. Using data drawn from a larger intervention study aimed at reducing 21st birthday drinking, this research examined how specific friends (N = 166) who were present at 21st birthday celebrations may have exacerbated or mitigated celebrants' (N = 166) experience of alcohol-related consequences, as well as how characteristics of that friendship moderate these effects. Controlling for sex, alcohol consumption, and friend prointoxication intentions for the celebrants' 21st birthday drinking, higher friend prosafety/support intentions predicted the celebrants experiencing fewer alcohol related consequences. Higher prosafety/support intentions also buffered participants from the negative influence of friend prointoxication intentions. Furthermore, the closeness of the friendship moderated this effect. At high levels of closeness, having a friend with lower prosafety/support intentions was associated with more alcohol-related consequences for the celebrant. Post hoc analyses revealed that this effect may have been driven by discrepancies between celebrants' and friends' reports of friendship closeness; celebrants' perception of closeness that was higher than the friends' perception was associated with the celebrant experiencing more alcohol-related consequences. Results demonstrate the ways that specific friends can both mitigate and exacerbate 21st birthday alcohol related consequences. The implications of the present findings for incorporating specific friends into drinking-related interventions are discussed. (PsycINFO Database Record PMID- 28921998 TI - Modeling Bivariate Change in Individual Differences: Prospective Associations Between Personality and Life Satisfaction. AB - A number of structural equation models have been developed to examine change in 1 variable or the longitudinal association between 2 variables. The most common of these are the latent growth model, the autoregressive cross-lagged model, the autoregressive latent trajectory model, and the latent change score model. The authors first overview each of these models through evaluating their different assumptions surrounding the nature of change and how these assumptions may result in different data interpretations. They then, to elucidate these issues in an empirical example, examine the longitudinal association between personality traits and life satisfaction. In a representative Dutch sample (N = 8,320), with participants providing data on both personality and life satisfaction measures every 2 years over an 8-year period, the authors reproduce findings from previous research. However, some of the structural equation models overviewed have not previously been applied to the personality-life satisfaction relation. The extended empirical examination suggests intraindividual changes in life satisfaction predict subsequent intraindividual changes in personality traits. The availability of data sets with 3 or more assessment waves allows the application of more advanced structural equation models such as the autoregressive latent trajectory or the extended latent change score model, which accounts for the complex dynamic nature of change processes and allows stronger inferences on the nature of the association between variables. However, the choice of model should be determined by theories of change processes in the variables being studied. (PsycINFO Database Record PMID- 28921997 TI - Simulating drinking in social networks to inform alcohol prevention and treatment efforts. AB - Adolescent drinking influences, and is influenced by, peer alcohol use. Several efficacious adolescent alcohol interventions include elements aimed at reducing susceptibility to peer influence. Modeling these interventions within dynamically changing social networks may improve our understanding of how such interventions work and for whom they work best. We used stochastic actor-based models to simulate longitudinal drinking and friendship formation within social networks using parameters obtained from a meta-analysis of real-world 10th grade adolescent social networks. Levels of social influence (i.e., friends affecting changes in one's drinking) and social selection (i.e., drinking affecting changes in one's friendships) were manipulated at several levels, which directly impacted the degree of clustering in friendships based on similarity in drinking behavior. Midway through each simulation, one randomly selected heavy-drinking actor from each network received an "intervention" that either (a) reduced their susceptibility to social influence, (b) reduced their susceptibility to social selection, (c) eliminated a friendship with a heavy drinker, or (d) initiated a friendship with a nondrinker. Only the intervention that eliminated targeted actors' susceptibility to social influence consistently reduced that actor's drinking. Moreover, this was only effective in networks with social influence and social selection that were at higher levels than what was found in the real-world reference study. Social influence and social selection are dynamic processes that can lead to complex systems that may moderate the effectiveness of network-based interventions. Interventions that reduce susceptibility to social influence may be most effective among adolescents with high susceptibility to social influence and heavier-drinking friends. (PsycINFO Database Record PMID- 28921999 TI - Predictive Validity and Adjustment of Ideal Partner Preferences Across the Transition Into Romantic Relationships. AB - Although empirical research has investigated what we ideally seek in a romantic partner for decades, the crucial question of whether ideal partner preferences actually guide our mating decisions in real life has remained largely unanswered. One reason for this is the lack of designs that assess individuals' ideal partner preferences before entering a relationship and then follow up on them over an extended period. In the Gottingen Mate Choice Study (GMCS), a preregistered, large-scale online study, we used such a naturalistic prospective design. We investigated partner preferences across 4 preference domains in a large sample of predominantly heterosexual singles (N = 763, aged 18-40 years) and tracked these individuals across a period of 5 months upon a possible transition into romantic relationships. Attesting to their predictive validity, partner preferences prospectively predicted the characteristics of later partners. This was equally true for both sexes, except for vitality-attractiveness where men's preferences were more predictive of their later partners' standing on this dimension than women's. Self-perceived mate value did not moderate the preference-partner characteristics relations. Preferences proved to be relatively stable across the 5 months interval, yet were less stable for those who entered a relationship. Subgroup analyses using a newly developed indicator of preference adjustment toward (vs. away from) partner characteristics revealed that participants adjusted their preferences downward when partners fell short of initial preferences, but showed no consistent adjustment when partners exceeded them. Results and implications are discussed against the background of ongoing controversies in mate choice and romantic relationship research. (PsycINFO Database Record PMID- 28921996 TI - Treatments for Internet gaming disorder and Internet addiction: A systematic review. AB - Problems related to excessive use of the Internet and video games have recently captured the interests of both researchers and clinicians. The goals of this review are to summarize the literature on treatment effectiveness for these problems and to determine whether any treatments meet the minimum requirement of an evidence-based treatment as defined by Chambless et al. (1998). Studies of treatments for Internet gaming disorder (IGD) and Internet addiction were examined separately, as past studies have linked IGD to more severe outcomes. The systematic review identified 26 studies meeting predefined criteria; 13 focused on treatments for IGD and 13 on Internet addiction. The results highlighted a paucity of well-designed treatment outcome studies and limited evidence for the effectiveness of any treatment modality. Studies were limited by methodological flaws, including small sample sizes, lack of control groups, and little information on treatment adherence, among other problems. In addition, the field is beset by a lack of consistent definitions of and established instruments to measure IGD and Internet addiction. The results of this review highlight the need for additional work in the area of treatment development and evaluation for IGD and Internet addiction. Attention to methodological concerns identified within this review should improve subsequent research related to treating these conditions, and ultimately outcomes of patients suffering from them. (PsycINFO Database Record PMID- 28922000 TI - Humblebragging: A distinct-and ineffective-self-presentation strategy. AB - Self-presentation is a fundamental aspect of social life, with myriad critical outcomes dependent on others' impressions. We identify and offer the first empirical investigation of a prevalent, yet understudied, self-presentation strategy: humblebragging. Across 9 studies, including a week-long diary study and a field experiment, we identify humblebragging-bragging masked by a complaint or humility-as a common, conceptually distinct, and ineffective form of self presentation. We first document the ubiquity of humblebragging across several domains, from everyday life to social media. We then show that both forms of humblebragging-complaint-based or humility-based-are less effective than straightforward bragging, as they reduce liking, perceived competence, compliance with requests, and financial generosity. Despite being more common, complaint based humblebrags are less effective than humility-based humblebrags, and are even less effective than simply complaining. We show that people choose to deploy humblebrags particularly when motivated to both elicit sympathy and impress others. Despite the belief that combining bragging with complaining or humility confers the benefits of each strategy, we find that humblebragging confers the benefits of neither, instead backfiring because it is seen as insincere. (PsycINFO Database Record PMID- 28922001 TI - Reasons probably won't change your mind: The role of reasons in revising moral decisions. AB - Although many philosophers argue that making and revising moral decisions ought to be a matter of deliberating over reasons, the extent to which the consideration of reasons informs people's moral decisions and prompts them to change their decisions remains unclear. Here, after making an initial decision in 2-option moral dilemmas, participants examined reasons for only the option initially chosen (affirming reasons), reasons for only the option not initially chosen (opposing reasons), or reasons for both options. Although participants were more likely to change their initial decisions when presented with only opposing reasons compared with only affirming reasons, these effect sizes were consistently small. After evaluating reasons, participants were significantly more likely not to change their initial decisions than to change them, regardless of the set of reasons they considered. The initial decision accounted for most of the variance in predicting the final decision, whereas the reasons evaluated accounted for a relatively small proportion of the variance in predicting the final decision. This resistance to changing moral decisions is at least partly attributable to a biased, motivated evaluation of the available reasons: participants rated the reasons supporting their initial decisions more favorably than the reasons opposing their initial decisions, regardless of the reported strategy used to make the initial decision. Overall, our results suggest that the consideration of reasons rarely induces people to change their initial decisions in moral dilemmas. (PsycINFO Database Record PMID- 28922002 TI - Behavioral activation strategies for major depression in transdiagnostic cognitive-behavioral therapy: An evidence-based case study. AB - Behavioral activation (BA) is a treatment approach that uses functional analysis and context-dependent strategies to enhance environmental positive reinforcement for adaptive, healthy behavior, and decrease behavioral avoidance. BA has gained considerable support for the treatment of depression and can be broadly applied across a wide range of settings and clinical populations. In this article, we provide a brief description of BA as a therapeutic behavioral strategy for depression and present a clinical case example illustrating the integration of BA with other components of a transdiagnostic cognitive-behavioral treatment for emotional disorders. Implications for clinical practice and avenues for future research will be discussed. (PsycINFO Database Record PMID- 28922003 TI - Behavioral activation strategies in cognitive-behavioral therapy for anxiety disorders. AB - Considerable work and attention has supported the use of behavioral activation (BA) strategies in the treatment of depressive disorders. Although not often recognized, BA, both implicitly and explicitly, appears to be conceptually and empirically relevant to the treatment of diverse problem areas, including the anxiety disorders. This article addresses the role of BA strategies in transdiagnostic cognitive-behavioral therapy (CBT) for anxiety and related disorders, including in cases without comorbid depression. Following a brief introduction to a transdiagnostic CBT model of anxiety and related disorders, this article will: (a) provide a rationale for the integration of BA strategies as a potentially potent facilitator of therapeutic change; (b) identify relevant treatment targets of BA in anxiety disorders; and (c) illustrate the implementation and impacts of these strategies using a clinical case example. Finally, suggestions for future research and implications for training and practice will be noted. (PsycINFO Database Record PMID- 28922004 TI - Behavioral activation in the treatment of metacognitive dysfunctions in inhibited type personality disorders. AB - Behavioral interventions are proposed as a critical treatment component in psychotherapy for personality disorders. The current study explores behavioral interventions as a mechanism of change in Metacognitive Interpersonal Therapy, an integrative psychotherapy for personality disorders. The goals and implementation of behavioral principles are illustrated through the single case study of Roger, a 57-year-old man diagnosed with avoidant personality disorder and depressive personality disorder. Transcripts of interviews and therapy sessions illustrate the role of behavioral interventions, including behavioral activation, in Roger's treatment. Roger demonstrated a reliable change from baseline to posttreatment across all measures. He also showed gains with regard to his occupational functioning, interpersonal relationships, and sense of fulfilment. Implications with regard to treatment planning for personality disorders are discussed. (PsycINFO Database Record PMID- 28922005 TI - Behavioral activation in TFP: The role of the treatment contract in transference focused psychotherapy. AB - Transference-focused psychotherapy (TFP) is a manualized evidence-based treatment for borderline and other severe personality disorders that is based on psychoanalytic object relations theory. Similar to other psychodynamic psychotherapies, TFP focuses on changing psychological structures, but also focuses on symptom and behavioral change, particularly the importance of being active (e.g., obtaining a job or involvement in similar activities). In TFP, the establishment of the treatment contract, also known as the treatment frame, is where goals such as work and other activities are agreed upon. The focus on such activities is particularly relevant to the concept of behavioral activation. We provide a clinical vignette to illustrate how TFP utilizes behavioral activation in facilitating treatment outcome both at the behavioral level and at the psychological level. (PsycINFO Database Record PMID- 28922006 TI - Process factors explaining psycho-social outcomes in adventure therapy. AB - The development and factor analysis of the Adventure Therapy Experience Scale (ATES) is the first attempt found in the literature to empirically and quantitatively identify therapeutic factors theorized to affect change in the adventure therapy experience (Russell & Gillis, 2017). This study utilizes the ATES to explore how its inherent factors may impact treatment outcome utilizing a routine outcome monitoring process to empirically test how these factors may contribute to treatment outcome over time. The sample of 168 males 21.5 years of age completed an average of 79.6 days in the 90-day adventure-based substance use disorder residential treatment program. In the model, adventure-based experiences are a primary treatment tool. For outcome monitoring, all clients were administered the Outcome Questionnaire (OQ-45.2) at intake, every 2 weeks, and at discharge. In addition, clients were administered the 18-item ATES every 2 weeks. The ATES contains 2 items measuring how helpful the adventure experience was as well as how mindful they were of their treatment process during the experience. Clients also answer 16 Likert items measuring responses on 4 subscales: group adventure, nature, challenge, and reflection. Results reveal that clients, on average, improved in their psycho-social functioning as measured by the OQ 45.2. Weeks with higher helpfulness, mindfulness, and group adventure scores than the client's average helpfulness, mindfulness, and group adventure score, had greater decreases in OQ scores than weeks with lower helpfulness, mindfulness, and group adventure scores. Clients with higher aggregate helpfulness and group adventure scores, across all treatment weeks, had greater decreases in OQ scores than clients with lower aggregate helpfulness and group adventure scores. Implications for practice and future research are also discussed. (PsycINFO Database Record PMID- 28922007 TI - Attachment-based family therapy and individual emotion-focused therapy for unresolved anger: Qualitative analysis of treatment outcomes and change processes. AB - Twenty-six clients who received 10 sessions of either attachment-based family therapy (ABFT) or individual emotion-focused therapy (EFT) for unresolved anger toward a parent were interviewed 6 months after completing treatment. Interviews were analyzed using the consensual qualitative research approach. Clients in both conditions reported improved relationships with parents, gaining a new perspective of their parent, increased compassion toward parent, less reactivity to anger, feeling cleaned-out, and acquiring new coping strategies. Whereas ABFT clients more often reported improved relationships with parents, EFT clients more often reported feeling cleaned-out. Clients in both groups attributed change to productive emotional processing. Also, clients in both groups attributed change to saying difficult things that had never been said before directly to parents, though more so in ABFT. Whereas ABFT clients noted the importance of their parents participating in treatment and mutual vulnerability, EFT clients noted the importance of remembering previously avoided memories and feelings, and getting their anger of their chest. While some EFT clients reported that therapy had a negative impact on their relationship with their parents and increased their anger, some ABFT clients reported that the positive impact of therapy during the active phase of treatment did not last, though there were no meaningful between-groups differences regarding these negative treatment outcomes and processes. Results are discussed in the context of previous quantitative findings from the same sample, and in the context of prior research on experiential and emotion-focused therapies. Implications for future research are noted. (PsycINFO Database Record PMID- 28922008 TI - Crying in psychotherapy: The perspective of therapists and clients. AB - Eighteen U.S.-based doctoral students in counseling or clinical psychology were interviewed by phone regarding experiences of crying in therapy. Specifically, they described crying as therapists with their clients, as clients with their therapists, and experiences when their therapists cried in the participants' therapy. Data were analyzed using consensual qualitative research. When crying with their clients, therapists expressed concern about the appropriateness/impact of crying, cried only briefly and because they felt an empathic connection with their clients, thought that the crying strengthened the relationship, discussed the event with their supervisor, and wished they had discussed the event more fully with clients. Crying as clients was triggered by discussing distressing personal events, was accompanied by a mixture of emotions regarding the tears, consisted of substantial crying to express pain or sadness, and led to multiple benefits (enhanced therapy relationship, deeper therapy, and insight). When their therapists cried, the crying was brief, was triggered by discussions of termination, arose from therapists' empathic connection with participants, and strengthened the therapy relationship. Implications for research, training, and practice are presented. (PsycINFO Database Record PMID- 28922009 TI - The development and initial validation of the Countertransference Management Scale. AB - Countertransference is an important aspect of the therapeutic relationship that exists in therapies of all theoretical orientations, and depending on how it is managed, it can either help or hinder treatment. Management of countertransference has been measured almost exclusively with the Countertransference Factors Inventory (Van Wagoner, Gelso, Hayes, & Diemer, 1991) and its variations, all of which focus on 5 therapist qualities theorized to facilitate management: self-insight, conceptualizing ability, empathy, self integration, and anxiety management. Existing versions of the Countertransference Factors Inventory, however, possess certain psychometric limitations that appear to constrain how well they assess actual management of countertransference during a therapy session. We thus sought to develop a new measure that addressed these limitations and that captured the 5 therapist qualities as constituents (rather than correlates) of countertransference management that manifest in the treatment hour. The development and initial validation of the resulting 22-item Countertransference Management Scale (CMS) is described here. Exploratory factor analysis of ratings of 286 therapy supervisors of current supervisees indicated that the 5 constituents of countertransference management could be grouped into 2 correlated factors: "Understanding Self and Client" and "Self-Integration and Regulation." Evidence of convergent and criterion-related validity was supported by CMS total and subscale scores correlating as expected with measures of theoretically relevant constructs, namely, therapist countertransference behavior, theoretical framework, self-esteem, observing ego, empathic understanding, and tolerance of anxiety. Results also supported the internal consistency of the CMS and its subscales. Research, clinical, and training implications are discussed. (PsycINFO Database Record PMID- 28922010 TI - Detecting memory performance validity with DETECTS: A computerized performance validity test. AB - Evaluating performance validity is essential in neuropsychological and forensic assessments. Nonetheless, most psychological assessment tests are unable to detect performance validity and other methods must be used for this purpose. A new Performance Validity Test (DETECTS - Memory Performance Validity Test) was developed with several characteristics that enhance test utility. Moreover, precise response time measurement was added to DETECTS. Two groups of participants (normative and simulator group) completed DETECTS and three memory tests from the Wechsler Memory Scale III. Simulators achieved considerably lower scores (hits) and higher response times in DETECTS compared with the normative group. All participants in the normative group were classified correctly and no simulator was classified as having legitimate memory deficits. Thus, DETECTS seems to be a valuable computerized Performance Validity Test with reduced application time and effective cut-off scores as well as high sensitivity, specificity, and positive and negative predictive power values. Lastly, response time may be a very useful measure for detecting memory malingering. PMID- 28922011 TI - South Asian immigrant women's suggestions for culturally-tailored HIV education and prevention programs. AB - Using a community-based, socialist feminist qualitative study, and an emergent research design, we explored the unique individual experiences of South Asian immigrant women living with HIV in the Greater Toronto Area (GTA) of Ontario, Canada. We assessed both the HIV risk context and the strategies for HIV education and prevention as expressed by study participants. Grounded in Connell's social theory of gender, a thematic analysis of semi-structured interviews with 12 women yielded six themes related to the power and impact of stigmatization, community's denial of HIV, infidelity, manifested in resistance to discussing sex and condom use, non-disclosure, and lack of HIV knowledge. This study validated the legitimacy of listening to the voices of South Asian immigrant women living with HIV, who communicated 20 recommendations for researchers, educators, community organizations, and service providers to culturally-tailor HIV education programs. PMID- 28922012 TI - Neuropsychological outcome of a case of Susac syndrome: A two-year follow-up study. AB - Susac syndrome is a rare condition characterised by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. Of the few published cases, there is variability with regard to cognitive outcome. We describe the clinical course and neuropsychological performance of a 21-year-old male patient presenting with severe encephalopathy and later developing the full triad fulfilling the diagnosis of Susac syndrome. PMID- 28922013 TI - Identification of a practical and reliable method for the evaluation of litter moisture in turkey production. AB - 1. An experiment was conducted to compare 5 different methods for the evaluation of litter moisture. 2. For litter collection and assessment, 55 farms were selected, one shed from each farm was inspected and 9 points were identified within each shed. 3. For each device, used for the evaluation of litter moisture, mean and standard deviation of wetness measures per collection point were assessed. 4. The reliability and overall consistency between the 5 instruments used to measure wetness were high (alpha = 0.72). 5. Measurement of three out of the 9 collection points were sufficient to provide a reliable assessment of litter moisture throughout the shed. 6. Based on the direct correlation between litter moisture and footpad lesions, litter moisture measurement can be used as a resource based on-farm animal welfare indicator. 7. Among the 5 methods analysed, visual scoring is the most simple and practical, and therefore the best candidate to be used on-farm for animal welfare assessment. PMID- 28922014 TI - World Federation of Athletic Training and Therapy World Congress 2017 Faculty of Health, Camilo Jose Cela University September 29-October 1, 2017 Madrid, Spain. PMID- 28922015 TI - Over-the-top ACL Reconstruction Plus Extra-articular Lateral Tenodesis With Hamstring Tendon Grafts: Prospective Evaluation With 20-Year Minimum Follow-up. AB - BACKGROUND: There are few published studies with very long-term follow-up of combined intra- and extra-articular anterior cruciate ligament (ACL) reconstruction. PURPOSE: To analyze clinical and radiographic outcomes of over the-top ACL reconstruction plus extra-articular lateral tenodesis with autologous hamstrings at minimum 20-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Of 60 originally eligible patients who underwent over-the top ACL reconstruction with double-stranded hamstring tendon (leaving intact graft tibial insertions) and extra-articular lateral plasty (performed with the remnant part of tendons), 52 were prospectively evaluated at a minimum 20-year follow-up (mean follow-up, 24 years; 41 men, 11 women; mean age at time of surgery, 25.5 +/- 7.6 years). Twenty-nine patients were available for prospective evaluations: clinical (Lysholm, Tegner, and objective International Knee Documentation Committee [IKDC]), instrumented (KT-2000), and radiographic (standard, long-standing, and Merchant views). Subjective KOOS (Knee injury and Osteoarthritis Outcome Score) and objective inertial sensor pivot-shift analysis (KiRA) were carried out at final follow-up. Twenty-three patients were investigated by phone interview for subjective Tegner score and documented complications, rerupture, or revision surgery. RESULTS: At final follow-up, mean Lysholm score was 85.7 +/- 14.6; median Tegner score, 4 (range, 3-5); sport activity resumption, 86.2%; and objective IKDC score, good or excellent in 86% of patients (31%, A; 55%, B). Only 3 of 26 patients (12%) had >5-mm manual maximum KT-2000 side-to-side difference. KiRA system documented positive pivot-shift (>0.9-m/s2 tibial acceleration side-to-side difference) in these 3 of 26 patients (12%). Statistically significant changes were as follows: decrease in Tegner score from 7 (range, 6-8) at 5-year follow-up to 4 (range, 3-5) at 10 years ( P < .0001) and decrease in Lysholm score from 96.1 +/- 7.3 at 10-year follow-up to 85.7 +/- 14.6 at 20 years ( P = .0003). Radiographic evaluation demonstrated significant difference of medial joint space between injured and healthy knees in patients with concomitant medial meniscectomy (n = 8, 3.2 +/- 0.6 vs 5.0 +/- 1.8 mm, P = .0114). No significant differences were reported regarding lateral or patellofemoral joint space. One patient (2%) experienced rerupture, with 3 of 52 (5.8%) having a contralateral ACL injury (excluded from KT-2000 and radiographic evaluations). Overall, 4 of 29 clinical failures (objective IKDC, KT-2000) and 1 rerupture among 52 patients were registered at final follow-up. CONCLUSION: Studied surgical technique demonstrated good results in laxity control at 20-year minimum follow-up. The lateral extra-articular plasty associated with ACL reconstruction did not generate lateral knee or patellofemoral osteoarthritis. The factor increasing osteoarthritis was meniscectomy. PMID- 28922016 TI - High Degree of Variability in Reporting of Clinical and Patient-Reported Outcomes After Hip Arthroscopy. AB - BACKGROUND: Hip arthroscopy for the treatment of intra-articular pathology is a rapidly expanding field. Outcome measures should be reported to document the efficacy of arthroscopic procedures; however, the most effective outcome measures are not established. PURPOSE: To evaluate the variability in outcomes reported after hip arthroscopy and to compare the responsiveness of patient-reported outcome (PRO) instruments. STUDY DESIGN: Systematic review. METHODS: We reviewed primary hip arthroscopy literature between January 2011 and September 2016 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Patient and study characteristics were recorded. Pre- and postoperative means and SDs of PROs were recorded from articles that used 2 or more PROs with a 1-year minimum follow-up. From this subset of articles, we compared the responsiveness between PRO instruments using the effect size, standard response mean, and relative efficiency. RESULTS: We identified 130 studies that met our inclusion/exclusion criteria, which totaled 16,970 patients (17,511 hips, mean age = 37.0 years, mean body mass index = 25.9 kg/m2). Radiographic measures were reported in 100 studies. The alpha angle and center edge angle were the most common measures. Range of motion was reported in 81 of 130 articles. PROs were reported in 129 of 130 articles, and 21 different PRO instruments were identified. The mean number of PROs per article was 3.2, and 78% used 2 or more PROs. The most commonly used PRO was the modified Harris Hip Score, followed by the Hip Outcome Score (HOS)-Activities of Daily Living, HOS Sport, visual analog scale, and Nonarthritic Hip Score (NAHS). The 2 most responsive PRO tools were the International Hip Outcome Tool (iHOT)-12 and the NAHS. CONCLUSION: Outcomes reporting is highly variable in the hip arthroscopy literature. More than 20 different PRO instruments have been used, which makes comparison across studies difficult. A uniform set of outcome measures would allow for clearer interpretation of the hip arthroscopy literature and offer potential conclusions from pooled data. On the basis of our comparative responsiveness results and previously reported psychometric properties of the different PRO instruments, we recommend more widespread adoption of the iHOT PROs instruments to assess hip arthroscopy outcomes. PMID- 28922017 TI - Effects of Chronic and Intermittent Calorie Restriction on Adropin Levels in Breast Cancer. AB - Adropin is a peptide hormone that has been implicated in insulin resistance and as a potential regulator of growth. The aim of this study is to determine the effect of calorie restriction on circulating levels of adropin in the MMTV TGFalpha breast cancer mouse model and investigate the effects of adropin peptide on the viability of MCF-7 and MDA-231 breast cancer cells in culture. Ten-week old mice were assigned to either ad libitum-fed (AL), chronic calorie-restricted, or intermittent calorie-restricted groups. Concentrations of serum adropin were measured using an enzyme-linked immunosorbent assay. Results showed an inverse correlation between serum adropin levels and mouse age that was attenuated by calorie restriction. In the AL group the level of adropin was significantly lower at week 50 compared to levels at week 10. However, among the calorie-restricted groups, serum levels of adropin remained high at week 50. The cell-line-specific effects were observed after treatment of cancer cell lines with a series of adropin concentrations (5, 10, 25, 50 ng/mL). Flow cytometry analysis showed that MCF-7 cells entered the early phase of apoptosis after treatment with 50 ng/mL for 24 h. Adropin may be involved in the protective effects that calorie restriction has on breast cancer risk. PMID- 28922019 TI - Sleep problems and daytime sleepiness in children with ADHD: Associations with social, emotional, and behavioral functioning at school, a cross-sectional study. AB - BACKGROUND: Sleep problems and daytime sleepiness are common in children with attention-deficit hyperactivity disorder (ADHD) and are associated with poor parent-reported functional outcomes. However, the potential impact of sleep problems or daytime sleepiness on the school functioning of children with ADHD remains unknown. We aimed to determine if sleep problems and daytime sleepiness were associated with the social, emotional, and behavioral school-based functioning of children with ADHD and comorbid sleep problems. METHODS: Children aged 5-13 years with ADHD and a moderate-severe sleep problem (confirmed using American Academy of Sleep Medicine diagnostic criteria) were recruited from 43 pediatric practices across Victoria and Queensland, Australia (N = 257). Parent rated sleep problems were assessed using the Children's Sleep Habits Questionnaire (CSHQ) and teacher-rated daytime sleepiness using the Teacher's Daytime Sleepiness Questionnaire. Teacher-rated social, emotional, and behavioral school functioning was assessed using three scales (peer problems, emotional problems, and conduct problems) from the Strength and Difficulties Questionnaire. Data was analyzed using Pearson correlations and linear regression models. RESULTS: Teacher-rated daytime sleepiness was associated with higher levels of emotional (beta = 0.39; 95% CI = 0.25-0.52) and behavioral problems (beta = 0.47; CI = 0.36-0.58) in adjusted models. While total sleep duration and parent-rated sleep problems were not associated with daytime sleepiness or school functioning, the CSHQ subscale night wakings was correlated with teacher-rated daytime sleepiness (r = 0.21; p < 0.01). CONCLUSIONS: Daytime sleepiness (possibly as an indicator of sleep quality) may be a better predictor of school functioning in children with ADHD who have concomitant sleep problems than total sleep duration or parent-rated sleep problems. PMID- 28922018 TI - Tacrolimus Ointment for Refractory Posterior Blepharitis. AB - PURPOSE: This prospective, randomized, double-blind interventional case series was designed to evaluate the short-term efficacy of 0.03% tacrolimus ointment as a new therapeutic approach for refractory cases of posterior blepharitis. METHODS: Forty eyes (20 patients) with posterior blepharitis refractory to previous treatment were randomized. Eighteen eyes (9 patients) were treated with 0.03% tacrolimus ointment and 20 eyes (10 patients) with placebo ointment twice daily. Patients were evaluated with a questionnaire and slit-lamp examination 14 days and 28 days after treatment, and symptoms and signs of blepharitis were compared to those observed at baseline. RESULTS: We could observe statistical difference in the outcome measurements of meibomian gland secretion, conjunctival hyperemia, telangiectasia of inferior lid, Rose Bengal, and fluorescein scoring for the study group. As for the symptoms score, we observed statistical difference in the symptoms scoring for pruritus and dry eye sensation in the tacrolimus group. CONCLUSION: This study suggests that topical administration of 0.03% tacrolimus ointment can improve some symptoms and some ocular surface status in patients with refractory posterior blepharitis. PMID- 28922020 TI - Seasonal and weather variation of sleep and physical activity in 12-14-year-old children. AB - BACKGROUND: Understanding variation in physical activity (PA) and sleep is necessary to develop novel intervention strategies targeting adolescents' health behaviors. We examined the extent to which PA and sleep vary by aspects of the physical environment. PARTICIPANTS: We performed a cross-sectional analysis of 669 adolescents in the Project Viva cohort. METHODS: We estimated total PA, sleep duration, sleep efficiency, and sleep midpoint timing from wrist accelerometers. We used multivariable linear regression models and generalized estimated equations to assess associations of PA and sleep with season and daily weather conditions obtained from the National Oceanic and Atmospheric Administration archive. RESULTS: Mean age was 12.9 (SD 0.6) years; 51% were female and 68% were white. Mean sleep duration was 466 (SD 42) min per night and total PA was 1,652 (SD 431) counts per min per day. Sleep midpoint time was 41 (95% CI: 27 to 54) min later in summer, 28 (95% CI: -41 to -14) min earlier in spring, and 29 (95% CI: -43 to -15) min earlier in autumn compared to winter. Higher temperature and longer day length both were associated with small reductions of nightly sleep duration. Adolescents were less physically active during winter and on rainy and short sunlight days. There was an inverse U-shaped relationship between PA and mean temperature. CONCLUSIONS: Season was associated with large changes in sleep timing, and smaller changes in other sleep and PA measurements. Given the importance of sleep and circadian alignment, future health behavioral interventions may benefit by targeting "season-specific" interventions. PMID- 28922021 TI - Pharmacokinetic drug evaluation of ezetimibe + simvastatin for the treatment of hypercholesterolemia. AB - INTRODUCTION: Cholesterol lowering treatment is mainly based on statins eventually associated to adjunctive drugs of different class such as ezetimibe. In the present review, we analysed the pharmacokinetics, efficacy and safety of ezetimibe + simvastatin drug association. Areas covered: The bio-equivalence of ezetimibe and simvastatin when co-administrated in separate tablets or combined in a single pill is well documented. Ezetimibe is absorbed in small intestine, reaching peak plasma concentrations in 4-12 h, with a plasma half-life of 22 h. Simvastatin, ingested as a prodrug, is hydrolyzed in liver to its active beta hydroxyacid metabolite, reaching peak plasma concentrations in 2-4 h, with a plasma half-life of approximately 5 h. The available evidence support the clinical efficacy of this drug combination, both in term of LDL-cholesterol reduction and cardiovascular risk decrease. Expert opinion: The synergistic action of these two drugs and the efficacy and safety extensively demonstrated of their association (in particular in the large IMProved Reduction of Outcomes: Vytorin Efficacy International Trial -IMPROVE-IT-) promote its clinical use, especially in subjects with high cardiovascular risk who need to optimize their LDL-Cholesterolemia, but also in patients who cannot tolerate high-dose of more powerful statins. PMID- 28922022 TI - Implementing a collaborative coaching intervention for professionals providing care to children and their families: An exploratory study. AB - The growing complexity of healthcare requires family and interprofessional partnerships to deliver effective care. Interprofessional coaching can enhance family-centred practice and collaboration. The purpose of this study was to explore the acceptability and feasibility of collaborative coaching training to improve family centredness within acute paediatric rehabilitation. Using a participatory action design, service providers (SPs; n = 36) underwent a 6-month coaching programme involving coaching workshops, learning triads, and tailored sessions with a licensed coach. The feasibility and acceptability of coaching on SPs' family interactions and care was explored. Measure of Processes of Care (MPOC) and MPOC-SP, a coaching skills questionnaire, and focus groups were used to evaluate the acceptability of coaching training. We found that structured coaching training was feasible and SPs reported significant improvements in their coaching skills; however, MPOC and MPOC-SP scores did not reveal significant differences. Qualitative themes indicated that clinicians are developing coaching competencies and applying these skills in clinical practice. Participants perceived that the coaching approach strengthened relationships amongst colleagues, and they valued the opportunity for interprofessional learning. Findings suggest that coaching offers promise as an approach to facilitate successful patient outcomes and improve processes of care. Preliminary findings indicate that interprofessional coaching training is acceptable, feasible, and can significantly improve SP coaching skills and improve team cohesion. Further research to study the effects of coaching on interprofessional care using validated outcome measures and to assess the impact on service delivery is recommended. PMID- 28922023 TI - Fatty acid synthase (FASN) as a therapeutic target in breast cancer. AB - INTRODUCTION: Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to explain how FASN is intertwined with various signaling networks to cell-autonomously regulate breast cancer initiation and progression, FASN has received considerable attention as a therapeutic target. However, despite the ever-growing evidence demonstrating the involvement of FASN as part of the cancer-associated metabolic reprogramming, translation of the basic science-discovery aspects of FASN blockade to the clinical arena remains a challenge. Areas covered: Ten years later, we herein review the preclinical lessons learned from the pharmaceutical liabilities of the first generation of FASN inhibitors. We provide an updated view of the current development and clinical testing of next generation FASN-targeted drugs. We also discuss new clinico-molecular approaches that should help us to convert roadblocks into roadways that will propel forward our therapeutic understanding of FASN. Expert opinion: With the recent demonstration of target engagement and early signs of clinical activity with the first orally available, selective, potent and reversible FASN inhibitor, we can expect Big pharma to revitalize their interest in lipogenic enzymes as well-credentialed targets for oncology drug development in breast cancer. PMID- 28922024 TI - The implementation of multiple interprofessional integrated modules by health sciences faculty in Chile. AB - Multiple interprofessional integrated modules (MIIM) 1 and 2 are two required, cross-curricular courses developed by a team of health professions faculty, as well as experts in education, within the Faculty of Medicine of the University of Chile. MIIM 1 focused on virtual cases requiring team decision-making in real time. MIIM 2 focused on a team-based community project. The evaluation of MIIM included student, teacher, and coordinator perspectives. To explore the perceptions of this interprofessional experience quantitative data in the form of standardised course evaluations regarding teaching methodology, interpersonal relations and the course organisation and logistics were gathered. In addition, qualitative perceptions were collected from student focus groups and meetings with tutors and coordinators. Between 2010 and 2014, 881 students enrolled in MIIM. Their evaluation scores rated interpersonal relations most highly, followed by organisation and logistics, and then teaching methodology. A key result was the learning related to interprofessional team work by the teaching coordinators, as well as the participating faculty. The strengths of this experience included student integration and construction of new knowledge, skill development in making decisions, and collective self-learning. Challenges included additional time management and tutors' role. This work requires valuation of an alternative way of learning, which is critical for the performance of future health professionals. PMID- 28922025 TI - Prevalence of Staphylococcal Enterotoxins in Ready-to-Eat Foods Sold in Istanbul. AB - The aim of this study was to investigate the prevalence of staphylococcal enterotoxins (SEs) in ready-to-eat (RTE) foods sold in Istanbul, Turkey. A total of 5,241 samples were randomly collected from various caterers, hotels, and restaurants from 2014 to 2016. The samples were classified into four groups: (i) various cooked RTE meat and vegetable meals, (ii) various RTE salads, charcuterie, and cold appetizers, (iii) various cooked RTE bakery products (pasta, pastries, pizza, pita, ravioli, etc.), and (iv) any cooked RTE sweets and desserts (pudding, custard, cream, ashura, etc.). The samples were examined for the presence of SEs by 3M Tecra Staph Enterotoxin Visual Immunoassay method, which is a manual enzyme-linked immunosorbent assay method. Among all samples, only 1 (0.019%) RTE meal (vegetable meal with meat) was found to be contaminated with SEs, a good result in terms of staphylococcal food poisoning risk and public health. PMID- 28922026 TI - Characterization of Quinolone Resistance in Salmonella enterica from Farm Animals in China. AB - This study was focused on the prevalence and antimicrobial susceptibilities of Salmonella directly isolated at animal clinics in Guangdong, People's Republic of China. The isolation rates from chickens, ducks, and pigs were 11.3% (11 of 97 samples), 15.4% (53 of 344 samples), and 3.0% (13 of 434 samples), respectively. Among the 77 Salmonella enterica isolates, the most predominant serovar was Typhimurium (81.8%, 63 isolates), followed by serovars Meleagridis (2.6%, 2 isolates) and Abaetetuba (1.3%, 1 isolate). Salmonella isolates were resistant to ciprofloxacin (16.9% of isolates) and nalidixic acid (66.2% of isolates), and 68 isolates (88.3%) were multidrug resistant, displaying resistance to three or more classes of antimicrobial agents. Eighteen isolates (23.4%) had at least one plasmid-mediated quinolone resistance gene, which was identified using PCR and DNA sequencing. The most prevalent plasmid-mediated quinolone resistance gene was aac(6')-Ib-cr, found in 14 isolates (18.2%), followed by oqxAB (9.1%) and qnrS (7.8%). Alterations in the gyrA gene were detected in 24 (57.1%) of 42 strains with a ciprofloxacin MIC of >=0.25 MUg/mL; the same level of susceptibility was found for enrofloxacin. Six types of mutations were found in the quinolone resistance determining regions of gyrA, and the predominant one (S83Y) was found singly in 15 (62.5%) of 24 isolates. We also found 22 different pulsed-field gel electrophoresis types among the Salmonella isolates. The Salmonella serovars and MICs of ciprofloxacin were similar within clusters, although individual differences were noted. This finding suggests that resistance plasmids were horizontally transmitted but also clonally spread. PMID- 28922027 TI - Further Evidence of How Unbuffered Starvation at 4 degrees C Influences Listeria monocytogenes EGD-e, HCC23, F2365, and Scott A. AB - The soilborne pathogen Listeria monocytogenes frequently contaminates food products and food processing environments and is able to survive desiccation, high osmotic pressures, and starvation. However, little is known about how this pathogen survives starvation at 4 degrees C. This study provides evidence that L. monocytogenes is able to survive total nutrient starvation for 4 weeks. L. monocytogenes strains EGD-e, Scott A, F2365, and HCC23 were starved individually in sterile water. Colony counts declined over 4 weeks, with Scott A declining the most rapidly. Transmission electron microscopy images revealed degradation of starving cell membranes and altered cytosols. Starving cells were subjected to the metabolic inhibitors fluoride, arsenite, 2,4-dinitrophenol, iodoacetate, and cyanide individually. Iodoacetate, which inhibits glyceraldehyde-3-phosphate dehydrogenase, completely reduced cultivable counts below the level of detection compared with the control starving cells; 2,4-dinitrophenol, which dissipates proton motive force, almost completely reduced cultivable counts. These results suggest that L. monocytogenes strains EGD-e, Scott A, F2365, and HCC23 are actively using part of the glycolysis pathway while starving. These results suggest that starving L. monocytogenes cells retain aspects of active metabolism. PMID- 28922028 TI - Analysis of Aflatoxin M1 in Breast Milk and Its Association with Nutritional and Socioeconomic Status of Lactating Mothers in Lebanon. AB - Aflatoxin B1 (AFB1) is the most potent of the dietary aflatoxins, and its major metabolite, aflatoxin M1 (AFM1), is frequently found in the breast milk of lactating mothers. The aim of this study was to assess the occurrence and factors associated with AFM1 contamination of breast milk collected from lactating mothers in Lebanon. A total of 111 breast milk samples were collected according to the guidelines set by the World Health Organization. Samples were analyzed with a competitive enzyme-linked immunosorbent assay between December 2015 and November 2016. A survey was used to determine the demographic and anthropometric characteristics of participating lactating mothers. Dietary habits were assessed using a semiquantitative food frequency questionnaire. Mean (+/-standard deviation) concentration of AFM1 in the breast milk samples was 4.31 +/- 1.8 ng/L, and 93.8% of samples contained AFM1 at 0.2 to 7.9 ng/L. The mean concentration of AFM1 was significantly lower (P < 0.05) in fall and winter (4.1 +/- 1.9 ng/L) than in spring and summer (5.0 +/- 1.7 ng/L). None of the samples exceeded the European Commission regulation limit (25 ng/L) for infant milk replacement formula. AFM1 contamination was significantly associated (P < 0.05) with the daily consumption of white cheeses but not with the consumption of meat or cereal products. No significant association (P > 0.05) was observed between AFM1 concentrations in breast milk and anthropometric sociodemographic factors (age and level of education) or the governorate of residence of the nursing mothers. The mean AFM1 estimated daily intake was found to be 0.69 ng/day/kg of body weight. Although the incidence of AFM1 contamination was low, our first-of its-kind study highlights the importance of conducting investigations on mycotoxin contamination in breast milk and of developing protection strategies to tackle the exposure of infants to this potent chemical hazard. PMID- 28922029 TI - Exploratory Study into the Microbiological Quality of Spinach and Cabbage Purchased from Street Vendors and Retailers in Johannesburg, South Africa. AB - Knowledge of the microbiological quality and prevalence of antibiotic resistance and virulence genes in bacterial isolates from leafy green vegetables supplied by formal suppliers (retailers) and informal suppliers (street vendors) in South Africa is limited. Because leafy vegetables have been implicated in foodborne disease outbreaks worldwide, 180 cabbage and spinach samples were collected from three major retailers and nine street vendors in Johannesburg, South Africa. Escherichia coli and coliforms were enumerated using Petrifilm plates. The prevalence of Listeria monocytogenes, Salmonella, and Shigella was determined using real-time PCR analysis. Identities of presumptive E. coli isolates from the fresh produce were confirmed using matrix-assisted laser desorption-ionization time of flight mass spectroscopy. Isolates were characterized using phenotypic (antibiotic resistance) and genotypic (phylogenetic and virulence gene) analysis. Hygiene indicator bacteria levels on spinach from formal and informal retailers exceeded the maximum level specified by the Department of Health guidelines for fresh fruit and vegetables. E. coli counts for street vendor spinach were higher (P < 0.0789) than those for retailer spinach. E. coli was present in only two cabbage samples, at 0.0035 CFU/g. L. monocytogenes and Salmonella were detected in 7.2 and 5% of the 180 samples, respectively, based on real-time PCR analysis; Shigella was not detected. Of the 29 spinach E. coli isolates, 37.9% were multidrug resistant. Virulence genes eae and stx1 were present in 14 and 3% of the spinach E. coli isolates, respectively; the stx2 gene was not detected. Eighty-six percent of these isolates belonged to phylogroup A, 3% belonged to group C, 7% belonged to group E, and 3% belonged to clade 1. The results from the current exploratory study on the microbiological quality of spinach bought from selected retailers highlight the need for continued surveillance on a larger scale, especially in the informal sector, to characterize the potential health risks to the consumer. PMID- 28922030 TI - Rapid Detection and Classification of Salmonella enterica Shedding in Feedlot Cattle Utilizing the Roka Bioscience Atlas Salmonella Detection Assay for the Analysis of Rectoanal Mucosal Swabs. AB - With an increasing focus on preharvest food safety, rapid methods are required for the detection and quantification of foodborne pathogens such as Salmonella enterica in beef cattle. We validated the Atlas Salmonella Detection Assay (SEN), a nucleic acid amplification technology that targets Salmonella rRNA, for the qualitative detection of S. enterica with sample enrichment using immunomagnetic separation as a reference test, and we further evaluated its accuracy to predict pathogen load using SEN signal-to-cutoff (SCO) values from unenriched samples to classify animals as high or nonhigh shedders. Rectoanal mucosal swabs (RAMS) were collected from 238 beef cattle from five cohorts located in the Midwest or southern High Plains of the United States between July 2015 and April 2016. Unenriched RAMS samples were used for the enumeration and SEN SCO analyses. Enriched samples were tested using SEN and immunomagnetic separation methods for the detection of Salmonella. The SEN method was 100% sensitive and specific for the detection of Salmonella from the enriched RAMS samples. A SEN SCO value of 8, with a sensitivity of 93.5% and specificity of 94.3%, was found to be an optimum cutoff value for classifying animals as high or nonhigh shedders from the unenriched RAMS samples. The SEN assay is a rapid and reliable method for the qualitative detection and categorization of the shedding load of Salmonella from RAMS in feedlot cattle. PMID- 28922033 TI - Controlling You Watching Me: Measuring Perception Control on Social Media. AB - Online self-presentation assumes that individuals intentionally control how others perceive them based on their online behaviors. Existing tools are limited in their ability to measure this notion of perception control and there is little understanding around factors which may affect the desire for perception control. This article reports on the development of a perception control scale and comparisons of perception control across age and between genders. A total of 222 participants completed an online survey with items measuring perception control and participant demographics. A principal component analysis revealed a one factor, 12-item scale explaining 41.14% of the variance. Perception control was found to increase with age and did not differ between genders. Results are consistent with existing impression management research suggesting that while participants of both genders desire to control how others perceive them, as a person's sense of self stabilizes over time, they are less motivated to change their behaviors to control others' impressions of them. PMID- 28922034 TI - Personality Traits and Social Media Use in 20 Countries: How Personality Relates to Frequency of Social Media Use, Social Media News Use, and Social Media Use for Social Interaction. AB - This study examines the relationship between peoples' personality traits and social media uses with data from 20 societies (N = 21,314). A measure of the "Big Five" personality traits is tested on key social media dimensions: frequency of use, social interaction, and news consumption. Across diverse societies, findings suggest that while extraversion, agreeableness, and conscientiousness are all positive predictors of different types of social media use, emotional stability and openness are negatively related to them. PMID- 28922035 TI - Robotic Technology Remains a Necessary Part of Healthcare's Future Editorial. PMID- 28922031 TI - Optic Nerve Head Characteristics in Chronic Angle Closure Glaucoma Detected by Swept-Source OCT. AB - PURPOSE: To compare structural features in prelaminar and laminar tissues of the optic nerve head (ONH) in chronic angle closure glaucoma (CACG), primary open angle glaucoma (POAG), and control subjects. MATERIALS AND METHODS: ONH imaging was performed using swept-source optical coherence tomography (SS-OCT) for measurements of minimum rim width at Bruch's membrane opening (BMO-MRW), horizontal, and vertical lamina cribrosa depth (LCD). Prelaminar defects, categorized as hole and wedge, and lamina cribrosa (LC) defects were identified. Enhanced depth imaging spectral domain OCT (EDI-OCT) customized to perform high resolution volume scans was used in conjunction to further characterize prelaminar holes. One eye per subject was analyzed. RESULTS: Eighty subjects (20 CACG, 40 POAG, and 20 controls) were included in the study. CACG and POAG groups had similar mean deviation on Humphrey visual field testing (-6.9 +/- 5.1 vs. 6.3 +/- 6.0 dB, p > 0.05) and IOP on the day of imaging (14.0 +/- 3.1 vs. 13.8 +/ 2.7 mmHg, p > 0.05). Thinnest and global BMO-MRW in CACG (120.3 +/- 44.8, 225.5 +/- 53.9 MUm) and POAG (109.7 +/- 56.3, 213.8 +/- 59.7 MUm) groups were lower than controls (200.1 +/- 40.8, 308.3 +/- 70.8 MUm; p < 0.001 for both). Prelaminar holes were most frequent in CACG (65.0%) than POAG (25.0%, p=0.008) or control groups (20.0%, p=0.01). After adjusting for demographic and ophthalmic covariates, CACG was associated with increased odds of having prelaminar holes compared to POAG (odds ratio, 9.79; 95% CI, 2.12-45.19; p=0.003). Hole volume was similar between CACG and POAG (p > 0.05), but the CACG group had more holes per scan than POAG (maximum 2.5 +/- 1.9 vs. 1.2 +/- 0.4, p=0.02). Prelaminar wedge defects were less common in the CACG than the POAG group (5.0% vs. 37.5%, p=0.02). The CACG group did not differ from controls in laminar characteristics, such as LCD and LC defects. CONCLUSIONS: SS-OCT evaluation of the ONH revealed more frequent prelaminar holes in CACG compared to POAG and control patients. PMID- 28922036 TI - Location and Modality Effects in Online Dating: Rich Modality Profile and Location-Based Information Cues Increase Social Presence, While Moderating the Impact of Uncertainty Reduction Strategy. AB - This study investigates how different interface modality features of online dating sites, such as location awareness cues and modality of profiles, affect the sense of social presence of a prospective date. We also examined how various user behaviors aimed at reducing uncertainty about online interactions affect social presence perceptions and are affected by the user interface features. Male users felt a greater sense of social presence when exposed to both location and accessibility cues (geographical proximity) and a richer medium (video profiles). Viewing a richer medium significantly increased the sense of social presence among female participants whereas location-based information sharing features did not directly affect their social presence perception. Augmented social presence, as a mediator, contributed to users' greater intention to meet potential dating partners in a face-to-face setting and to buy paid memberships on online dating sites. PMID- 28922038 TI - A mixed methods study of emotional exhaustion: Energizing and depleting work within an innovative healthcare team. AB - This mixed methods study documents emotional exhaustion experiences among care team members during the development of an innovative team approach for caring for adults with serious illness. A mixed methods study design was employed to examine depleting work experiences that may produce emotional exhaustion, and energizing aspects of the work that may increase meaningfulness of work, thus reducing emotional exhaustion. The population studied included team members involved in care for adults with serious illness (n = 18). Team members were surveyed quarterly over an 18-month period using the Maslach Burnout Inventory (MBI). The MBI measures burnout, defined as the inability to continue work because of the interactional toll of the work. Analyses of MBI data show that although overall levels of burnout are low, 89% of team members reported moderate/high levels of emotional exhaustion during at least one survey period. In order to understand the kinds of work experiences that may produce or ameliorate emotional exhaustion, qualitative interviews were also conducted with team members at the end of the 18-month period. Major qualitative findings indicate that disputes within the team, environmental pressures, and standardisation of meaningful work leave team members feeling depleted. Having authentic relationships with patients, working as a team, believing in the care model, and practicing autonomy and creativity help team members to restore their emotional energy. Supports for team members' well-being are critical for continued innovation. We conclude with recommendations for improving team members' well-being. PMID- 28922039 TI - Teaching and learning activities to educate nursing students for interprofessional collaboration: A scoping review. AB - To prepare new graduates with the knowledge, skills, and attitudes to engage in effective interprofessional collaboration (IPC) in practice, healthcare professional programmes need to ensure their curriculum provides opportunities for interprofessional education (IPE) and IPC. To strengthen IPE within an undergraduate curriculum and meet the professional requirements set out by regulatory bodies to prepare new graduate nurses to achieve IPC competencies, a curriculum initiative was developed to expand IPE across the four years of the Baccalaureate of Science in Nursing (BSN) programme. The purpose of this scoping review was to identify published teaching-learning activities in undergraduate nursing programmes to inform the development and integration of IPE curricula. The literature included was identified by searching the following electronic databases: EMBASE and EBSCO (CINAHL, Medline, Education Research Complete, ERIC). The search was limited to articles with abstracts published between 2008 and 2016 in the English language. All ten studies that met inclusion criteria reported students' perceived interprofessional education as valuable in facilitating their achievement of IPC competencies. Interprofessional education is an approach for preparing nursing students with knowledge, skills, and attitudes to achieve IPC competencies and therefore, urgently needs to become more prevalent in nursing curricula. Educators can use a variety of IPE teaching-learning activities to support students' achievement of IPC competencies in order to prepare new practitioners to engage in effective IPC in a variety of healthcare milieus. Nurse educators are encouraged to intentionally integrate learning opportunities into current and future undergraduate nursing education to prepare collaborative ready graduate nurses. PMID- 28922040 TI - Professional, generational, and gender differences in perception of organisational values among Israeli physicians and nurses: Implications for retention. AB - The global health workforce today is more age diverse than ever before and spans three generations: baby boomers, X and Y generations. Each generation has a distinct set of characteristics, values, and beliefs. This diversity can lead to increased creativity and a greater richness of values and skills, but at the same time it can also lead to value clashes, disrespect, and conflicts. This study aimed to examine professional, generational, and gender differences in the perception of the importance of organisational values among nurses and physicians working in both hospitals and outpatient clinics in Israel. Data were collected from a large sample of nurses and physicians (N = 603) from 11 hospitals and community services across Israel. The participants completed a self-administered questionnaire rating the perceived importance of 20 organisational values, such as leadership, risk-taking, competition, power, and collaboration. The five values ranked most important were performance quality, cooperation, commitment, effectiveness, and efficiency. The five values ranked least important were competition, marketing, power, risk-taking, and assertiveness. Significant value differences were found by profession, generation, and gender. Nurses scored efficiency, assertiveness, risk-taking, power, and marketing higher than physicians did. The Y generation scored power higher and marketing lower than the two older generations. Women ranked the values of cooperation, commitment, innovativeness, vision, and marketing significantly higher than men did. Understanding differences between professions, generations, and gender is a useful first step in improving employees' job satisfaction, productivity, and retention. PMID- 28922041 TI - Garment Therapy does not Improve Function in Children with Cerebral Palsy: A Systematic Review. AB - AIMS: To conduct a systematic review asking, does garment therapy improve motor function in children with cerebral palsy? METHODS: A systematic review with meta analysis was conducted to review the literature. Inclusion criteria involved the wearing of therapy suits/garments in children with cerebral palsy. The primary outcome of interest was movement related function and secondary outcomes included impairment, participation, parental satisfaction and adverse outcomes of garment wear. RESULTS: 14 studies with 234 participants were included, of which 5 studies were included for meta-analysis. Garment therapy showed a nonsignificant effect on post-intervention function as measured by the Gross Motor Function Measure when compared to controls (MD = -1.9; 95% CI = -6.84, 3.05). Nonsignificant improvements in function were seen long-term (MD = -3.13; 95% CI = -7.57, 1.31). Garment therapy showed a significant improvement in proximal kinematics (MD = 5.02; 95% CI = -7.28, -2.76), however significant improvements were not demonstrated in distal kinematics (MD = -0.79; 95% CI = -3.08, 1.49). CONCLUSIONS: This review suggests garment therapy does not improve function in children with cerebral palsy. While garment therapy was shown to improve proximal stability, this benefit must be considered functionally and consider difficulties associated with garment use. PMID- 28922042 TI - Reliability and criterion validity of measurements using a smart phone-based measurement tool for the transverse rotation angle of the pelvis during single leg lifting. AB - OBJECTIVE: The purposes of this study were to determine the intra-rater test retest reliability of a smart phone-based measurement tool (SBMT) and a three dimensional (3D) motion analysis system for measuring the transverse rotation angle of the pelvis during single-leg lifting (SLL) and the criterion validity of the transverse rotation angle of the pelvis measurement using SBMT compared with a 3D motion analysis system (3DMAS). METHOD: Seventeen healthy volunteers performed SLL with their dominant leg without bending the knee until they reached a target placed 20 cm above the table. This study used a 3DMAS, considered the gold standard, to measure the transverse rotation angle of the pelvis to assess the criterion validity of the SBMT measurement. Intra-rater test-retest reliability was determined using the SBMT and 3DMAS using intra-class correlation coefficient (ICC) [3,1] values. The criterion validity of the SBMT was assessed with ICC [3,1] values. RESULT: Both the 3DMAS (ICC = 0.77) and SBMT (ICC = 0.83) showed excellent intra-rater test-retest reliability in the measurement of the transverse rotation angle of the pelvis during SLL in a supine position. Moreover, the SBMT showed an excellent correlation with the 3DMAS (ICC = 0.99). CONCLUSION: Measurement of the transverse rotation angle of the pelvis using the SBMT showed excellent reliability and criterion validity compared with the 3DMAS. PMID- 28922043 TI - Association between triglyceride/high-density lipoprotein ratio and hearing impairment in a Korean population. AB - OBJECTIVE: The aim of the present study was to evaluate the clinical association between triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio and hearing impairment in a Korean population. PATIENTS AND METHODS: This was a cross sectional study (n = 18,004). Participants were divided into 4 quartiles based on their TG/HDL-C ratio: first quartile (1Q), second quartile (2Q), third quartile (3Q), and fourth quartile (4Q). The threshold values at 0.5, 1, and 2 kHz were averaged to obtain the low- or mid-frequency pure-tone average (Low/Mid-Freq), and the values at 3, 4, and 6 kHz were averaged to obtain the high-frequency pure tone average (High-Freq). The average hearing threshold (AHT) was calculated as the pure-tone average of the thresholds at 0.5, 1, 2, and 3 kHz. Hearing loss (HL) was defined as an AHT of >40 dB. RESULTS: The Low/Mid-Freq, High-Freq, and AHT values were the highest among participants in 4Q than among those in the other quartiles. Compared with those in 1Q, 2Q, or 3Q, participants in 4Q exhibited a 1.32, 1.27, and 1.16-fold higher odds for HL, respectively. Partial correlation coefficients for TG/HDL-C ratio were 0.065 for Low/Mid-Freq, 0.041 for High-Freq, and 0.060 for AHT (P < 0.001 for all). Linear regression analyses showed that beta +/- SE for TG/HDL-C ratio was 0.293 +/- 0.038 on multivariate analysis. In addition, all subgroup analyses except diabetes participants showed statistically significant association between TG/HDL-C ratio and HL. CONCLUSION: High TG/HDL-C ratio was associated with hearing impairment in a Korean population. PMID- 28922044 TI - Evaluation of the Reliability of the Challenge when used to Measure Advanced Motor Skills of Children with Cerebral Palsy. AB - AIMS: The Challenge was designed as an extension to the GMFM-66 to assess advanced motor skills of children with cerebral palsy (CP) who walk/run independently. This study evaluated the Challenge's inter-rater and test-retest reliability. METHODS: Thirty children with CP (GMFCS level I [n = 24] and II [n = 6]) completed the Challenge, with re-testing one to two weeks later. Seven physiotherapist assessors passed the Challenge criterion test pre-administration. A single assessor administered and scored test and retest sessions (test-retest reliability). A second assessor independently scored one of these sessions (inter rater reliability). RESULTS: Inter-rater reliability was excellent (ICC = 0.97, 95%CI 0.94-0.99, CoV < 10%), with no bias (Bland-Altman plot). Test-retest ICC was excellent (ICC = 0.94, 95% CI 0.88-0.97. CoV < 10%, and Minimum Detectable Change (MDC90) was 4.47 points. Many participants indicated practising at home pre-retest session. CONCLUSIONS: There was strong rating consistency between assessors. While test-retest ICC estimates were also high, Challenge scores were higher at retest. The MDC90 was still in a range (>4.5 points) that seems clinically viable for change detection. Test-retest reliability could be reassessed with children instructed not to practice between assessments to determine the extent to which between-session practice influenced scores. PMID- 28922045 TI - Monomeric M2e antigen in VesiVax(r) liposomes stimulates protection against type a strains of influenza comparable to liposomes with multimeric forms of M2e. AB - Given the interest in the ectodomain of the matrix 2 (M2e) channel protein as a target for development of a universal influenza vaccine, we examined the role of the antigen configuration of M2e in generating a protective immune response. A series of M2e mutations and a truncated M2e segment were prepared as a means of controlling the formation of monomer, dimer, and higher order multimeric forms of M2e. Each of these M2e peptides was incorporated into a liposome-based vaccine technology platform previously shown to stimulate a protective response to influenza A infection using M2e as a mixture of monomers, dimers and multimers (L M2e1-HD/MPL). Our results using these modified forms of M2e produced 90-100% survival following lethal challenge with H1N1 (A/PR/8/34) in both inbred BALB/c and outbred Swiss Webster mice vaccinated with a truncated monomeric form of the M2 protein, M2e1-15 in liposomes. These observations show that a tetrameric configuration is not required to elicit significant protection when the M2e antigen is formulated in immunogenic liposomes and further, that the first 15 amino acids of M2e likely play a primary role in providing the protective immune response. PMID- 28922046 TI - Supraorbital electrical stimulation in management of chronic type tension headache: A randomized controlled study. AB - BACKGROUND AND PURPOSE: Headache disorders are considered one of the ten most disabling conditions, for both males and females, according to the World Health Organization. Chronic type tension headache (CTTH) has a prevalence of 2-3% within the general population. The purpose of this research was to investigate the effect of stimulating noninvasively the trigeminal nerve in the supraorbital area (SOES) for treatment of CTTH. METHODS: In an 8-week period of intervention, 45 patients were divided equally into three groups. Both group A "study" and group B received conventional physical therapy program three times a week. Group A received additional SOES for 20 minutes daily. Group C was on prescribed medications only. Assessments occurred pre and post intervention using Headache Impact Test (HIT), headache frequency, and visual analogue scale (VAS) for pain. RESULTS: In between groups, comparison showed statistically significant differences between all groups (p < 0.000). Within-group comparisons showed that both groups A and B showed a significant improvement in all measured data. Improvement percent of group A was HIT = 18.4% and VAS = 63.0%, p <= 0.0001, and group B was HIT = 12.5% and VAS = 28.2%, p <= 0.0002, while group C showed no significant improvement with improvement percent HIIT = 1.2% and VAS = 8.6%, p <= 0.5. Patients in groups A and B reported less headache frequencies than group C. CONCLUSION: SOES had positive therapeutic results for treatment of CTTH. PMID- 28922047 TI - Long term average speech spectra of Turkish. AB - Long-term average speech spectra (LTASS) are a voice analysis method that is recommended to be used in various areas, such as hearing aid fittings, automatic speaker recognition and voice disorders. Evaluations of LTASS in different languages have been published; however, this analysis has not been conducted for the Turkish. Therefore, the first aim of this study was to conduct this analysis, generate normative values and compare the obtained LTASS curve for the Turkish with those obtained for other languages reported in the literature. To achieve this objective, 40 adults with healthy hearing and speech characteristics were evaluated. Long-term spectral shape is presented in a graphical form, with visual comparisons to other research findings. Spectral differences by gender were analyzed, with statistically significant differences observed between gender groups and overall LTASS. The LTASS curve for the Turkish is similar to those reported for other languages, but there are also observable differences. Use of generated speech signals in hearing aid fitting procedures is recommended. PMID- 28922048 TI - Effect of dry needling on myofascial pain syndrome of the quadratus femoris: A case report. AB - This case report describes a 40-year-old male who presented with posterior thigh pain managed unsuccessfully with massage therapy, chiropractic adjustments, and physical therapy. The diagnosis of myofascial pain syndrome (MPS) involving the quadratus femoris (QF) was purely clinical, based on palpatory findings and ruling out other conditions through deductive reasoning. This is potentially a first time report, describing the successful management of MPS of the QF with dry needling (DN) using a recently published DN grading system. Immediate improvements were noted in all the outcome measures after the first treatment, with complete pain-resolution maintained at a 4-month follow-up. PMID- 28922049 TI - Magnitudes of muscle activation of spine stabilizers in healthy adults during prone on elbow planking exercises with and without a fitness ball. AB - Prone planking exercises have been used by rehabilitation professionals to activate torso muscles in healthy persons and those with low back pain. The aim of this study was to compare the magnitude of electromyographic (EMG) muscle activation from 10 right-sided muscles as demonstrated by the percentage of maximum voluntary isometric contraction (%MVIC) during four planking procedures. Surface EMG activity was acquired from the following muscles: (1) iliocostalis lumborum (IL), (2) longissimus thoracis (LT), (3) lumbar multifidus (LM), (4) rectus abdominis (RA), (5) external oblique (EO), (6) internal oblique (IO), (7) serratus anterior (SA), (8) latissimus dorsi (LD), (9) hamstrings (HS), and (10) gluteus maximus (GM). Thirteen male and 13 females performed prone plank on floor (PPOF), prone plank on ball (PPOB), stir-the-pot on ball (STP), and prone plank on ball with hip extension (PPHE). Previous investigators have not studied the STP and PPHE. During STP, three muscles (RA, EO, and IO) demonstrated very high (>61% MVIC) EMG activation and one muscle (SA) demonstrated high (41-60% MVIC) EMG activation. During PPHE, five muscles (GM, HS, EO, IO, and LM) demonstrated very high EMG activation and two muscles (RA and SA) demonstrated high EMG activation. Clinically, we concluded that STP and PPHE exercises were effective ways to activate RA, EO, IO, and SA at levels conducive to strengthening (> 50% MVIC), with PPHE able to additionally activate GM, HS, and LM at a strengthening level. PMID- 28922051 TI - Effect of hospital simulation tutorials on nursing and pharmacy student perception of interprofessional collaboration: Findings from a pilot study. AB - Interprofessional learning (IPL) during formal training enables interprofessional collaboration (IPC) in the workforce; however, on-campus IPL opportunities are seldom incorporated into curricula. We describe the development and implementation of two hospital simulation tutorials between nursing and pharmacy students. Students were required to provide "usual care" to a simulated patient at admission and discharge. A pre-post survey design was used to evaluate changes in Interdisciplinary Education Perception Scale (IEPS) score and student perceived educational value of the tutorials. The tutorials had a positive effect on IEPS scores (p < 0.001), whereas gender and profession did not appear to influence scores (p = 0.082 and p = 0.923, respectively). Tutorials were rated either good or very good by 89.9% of students and 79.6% of students reporting new insights into the other profession This tutorial format could be easily adapted by other institutions as an engaging and rewarding strategy to better prepare students for IPC the workforce. PMID- 28922050 TI - How to interpret high levels of distress when using the Distress Thermometer in the long-term follow-up clinic? A study with Acute Lymphoblastic Leukemia survivors. AB - OBJECTIVES: Recent guidelines recommend to assess emotional distress in pediatric oncology during treatment and in after care. One tool used to do this is the distress thermometer (DT), a simple tool which has almost exclusively been studied in its screening abilities. Given its increased used as a measure of distress per se, it is necessary to document its concurrent validity. The goal of this study was to identify clinical domains (eg, depression, anxiety) and individual symptoms associated with pediatric cancer survivors' rating on the DT. PARTICIPANTS: To do so we used data collected from 84 young (<=18 years old), and 120 older (>18 years old) survivors who were treated for pediatric leukemia. METHODS: Participants responded to self-report questionnaires as part of a research visit. RESULTS: Results from stepwise regressions show that in the younger group, high scores on the thermometer were associated with higher negative affectivity only. In adults, high scores were associated with higher anxiety, higher negative affectivity, and lower positive affectivity. When exploring associations with individual items, we found that the main emotional tone reflected by the thermometer score was anxiety. CONCLUSIONS: Interpreting ratings on the thermometer should probably focus on anxiety in childhood cancer survivors. This widely used tool also does not measure the same domains in young versus older survivors, so that age groups should be considered separately in future work. PMID- 28922052 TI - Applications of emerging transmission electron microscopy technology in PCD research and diagnosis. AB - Primary Ciliary Dyskinesia (PCD) is a heterogeneous genetic condition characterized by dysfunction of motile cilia. Patients suffer from chronic infection and inflammation of the upper and lower respiratory tract. Diagnosis of PCD is confirmed by identification of a hallmark defect of ciliary ultrastructure or by identification of biallelic pathogenic mutations in a known PCD gene. Since the first description of PCD in 1976, assessment of ciliary ultrastructure by transmission electron microscopy (TEM) has been central to diagnosis and research. Electron tomography is a technique whereby a series of transmission electron micrographs are collected at different angles and reconstructed into a single 3D model of a specimen. Electron tomography provides improved spatial information and resolution compared to a single micrograph. Research by electron tomography has revealed new insight into ciliary ultrastructure and consequently ciliary function at a molecular and cellular level. Gene discovery studies in PCD have utilized electron tomography to define the structural consequences of variants in cilia genes. Modern transmission electron microscopes capable of electron tomography are increasingly being installed in clinical laboratories. This presents the possibility for the use of tomography technique in a diagnostic setting. This review describes the electron tomography technique, the contribution tomography has made to the understanding of basic cilia structure and function and finally the potential of the technique for use in PCD diagnosis. PMID- 28922054 TI - Economic burden of pneumococcal infections in children under 5 years of age. AB - The present study aimed to determine the cost of childhood pneumococcal infections under 5 years of age and to provide further data for future health economy studies. Electronic medical records of children diagnosed with meningitis caused by S. pneumoniae and all-cause pneumonia, and acute otitis media (AOM) between January 2013-April 2014 were retrospectively evaluated. Direct costs for the treatments of hospitalized patients (pneumonia and pneumococcal meningitis) including costs of healthcare services consisted of costs of hospital bed, examination, laboratory analyses, scanning methods, consultation, vascular access procedures, and infusion and intravenous treatments. Direct costs for patients (AOM) treated in outpatient setting included constant price paid for the examination and cost of prescribed antibiotics. Indirect costs included cost of work loss of parents and their transportation expenses. Data of 130 children with pneumococcal meningitis (n = 10), pneumonia (n = 53), and AOM (n = 67) were analyzed. The total median cost was ?4,060.38 (direct cost: ?3,346.38 and indirect cost: ?829.18) for meningitis, ?835.91 (direct cost: ?480.66 and indirect cost: ?330.09) for pneumonia, and ?117.32 (direct cost: ?17.59 and indirect cost: ?99.73) for AOM. The medication cost (p = 0.047), indirect cost (p = 0.032), and total cost (p = 0.011) were significantly higher in pneumonia patients aged >=36 months than those aged <36 months; however, direct cost of AOM were significantly higher in the patients aged <36 months (p = 0.049). Results of the present study revealed that the treatment cost was significantly enhanced for hospitalization and for advanced disease. Thus, preventive actions, mainly vaccination, should be conducted regularly. PMID- 28922056 TI - Secondary defects detected by transmission electron microscopy in primary ciliary dyskinesia diagnostics. AB - Primary ciliary dyskinesia (PCD) is predominantly an autosomal recessively inherited condition that affects ~1 in 15,000 people. Diagnosis of PCD can be complex and is ordinarily based on the results of multiple investigations. These investigations include nasal nitric oxide, high-speed video microscopy, genotyping, and electron microscopy analysis of ciliary ultrastructure. A diagnosis is ultimately confirmed by the presence of a hallmark defect identified by transmission electron microscopy or biallelic variants in a known PCD gene. Secondary ciliary defects are commonly seen in samples submitted for diagnosis of PCD. Acquired secondary ciliary ultrastructural abnormalities, which are not caused by a variant in a ciliary gene, are usually transient and reversible however failure to separate primary versus secondary defects can lead to misdiagnosis. In this review, we describe causes of secondary ciliary defects, identify the ultrastructural appearances associated with secondary ciliary dyskinesia and finally suggest methods to avoid misdiagnosis of PCD due to these acquired ciliary defects. PMID- 28922055 TI - Nance-Horan syndrome in females due to a balanced X;1 translocation that disrupts the NHS gene: Familial case report and review of the literature. AB - The Nance-Horan syndrome is an X-linked disorder characterized by congenital cataract, facial features, microcornea, microphthalmia, and dental anomalies; most of the cases are due to NHS gene mutations on Xp22.13. Heterozygous carrier females generally present less severe features, and up to 30% of the affected males have intellectual disability. We describe two patients, mother and daughter, manifesting Nance-Horan syndrome. The cytogenetic and molecular analyses demonstrated a 46,X,t(X;1)(p22.13;q22) karyotype in each of them. No copy-number genomic imbalances were detected by high-density microarray analysis. The mother had a preferential inactivation of the normal X chromosome; expression analysis did not detect any mRNA isoform of NHS. This is the first report of Nance-Horan syndrome due to a skewed X chromosome inactivation resulting from a balanced translocation t(X;1) that disrupts the NHS gene expression, with important implications for clinical presentation and genetic counseling. PMID- 28922053 TI - Distribution and function of voltage-gated sodium channels in the nervous system. AB - Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail. PMID- 28922057 TI - The Dietary Food Components Capric Acid and Caprylic Acid Inhibit Virulence Factors in Candida albicans Through Multitargeting. AB - Capric acid and caprylic acid are the dietary food components. They are found to inhibit the virulence factors like morphogenesis, adhesion, and biofilm formation in the human pathogenic yeast Candida albicans. Our study demonstrated that yeast to-hyphal signal transduction pathways were affected by capric acid and caprylic acid. The expression profile of genes associated with serum-induced morphogenesis showed reduced expressions of Cdc35, Hwp1, Hst7, and Cph1 by the treatment with both the fatty acids. Cell elongation gene, Ece1, was surprisingly downregulated by 5208-fold by the treatment of caprylic acid. Nrg1 and Tup1, negative regulators of hyphal formation, were overexpressed in presence of capric or caprylic acid. Cell cycle studies revealed that capric and caprylic acids arrested cell cycle at G2/M and S phase. Targeting the virulence factors like yeast-to-hyphal transition is efficacious for treatment of opportunistic fungal infections. This research suggests that both capric and caprylic acid may be effective interventions for treating C. albicans yeast infections. PMID- 28922058 TI - Evolution of Regions Containing Antibiotic Resistance Genes in FII-2-FIB-1 ColV Colla Virulence Plasmids. AB - Three ColV virulence plasmids carrying antibiotic resistance genes were assembled from draft genome sequences of commensal ST95, ST131, and ST2705 Escherichia coli isolates from healthy Australians. Plasmids pCERC4, pCERC5, and pCERC9 include almost identical backbones containing FII-2 and FIB-1 replicons and the conserved ColV virulence region with an additional ColIa determinant. Only pCERC5 includes a complete, uninterrupted F-like transfer region and was able to conjugate. pCERC5 and pCERC9 contain Tn1721, carrying the tet(A) tetracycline resistance determinant in the same location, with Tn2 (blaTEM; ampicillin resistance) interrupting the Tn1721 in pCERC5. pCERC4 has a Tn1721/Tn21 hybrid transposon carrying dfrA5 (trimethoprim resistance) and sul1 (sulfamethoxazole resistance) in a class 1 integron. Four FII-2:FIB-1 ColV-ColIa plasmids in the GenBank nucleotide database have a related transposon in the same position, but an IS26 has reshaped the resistance gene region, deleting 2,069 bp of the integron 3'-CS, including sul1, and serving as a target for IS26 translocatable units containing blaTEM, sul2 and strAB (streptomycin resistance), or aphA1 (kanamycin/neomycin resistance). Another ColV-ColIa plasmid containing a related resistance gene region has lost the FII replicon and acquired a unique transfer region via recombination within the resistance region and at oriT. Eighteen further complete ColV plasmid sequences in GenBank contained FIB-1, but the FII replicons were of three types, FII-24, FII-18, and a variant of FII-36. PMID- 28922059 TI - The Currency of Science. PMID- 28922060 TI - Risk Factors for Nasal Colonization by Methicillin-Resistant Staphylococci in Healthy Humans in Professional Daily Contact with Companion Animals in Portugal. AB - Methicillin-resistant staphylococci (MRS), namely Staphylococcus aureus (MRSA) and Staphylococcus pseudintermedius (MRSP), are opportunistic agents of great importance in human and veterinary medicine. The aims of this study were to investigate the frequency, persistence, and risk factors associated with nasal colonization by MRS in people in daily contact with animals in Portugal. Seventy nine out of 129 (61.2%) participants were found to be colonized by, at least, one methicillin-resistant (MR) staphylococci species (MR Staphylococcus epidermidis [n = 68], MRSA [n = 19], MR Staphylococcus haemolyticus [n = 7], MRSP [n = 2], and other coagulase-negative staphylococci [n = 4]). Three lineages were identified among the MRSA isolates (n = 7): the major human healthcare clone in Portugal (ST22-t032-IV, n = 3), the livestock-associated MRSA (ST398-t108-V, n = 3), and the New York-/Japan-related clone (ST105-t002-II, n = 1). MRSP isolates belonged to the European clone ST71-II-III. We identified two risk factors for nasal colonization by MRS in healthy humans: (i) being a veterinary professional (veterinarian and veterinary nurse) (p < 0.0001, odds ratio [OR] = 6.369, 95% confidence interval [CI, 2.683-15.122]) and (ii) have contacted with one MRSA- or MRSP-positive animal (p = 0.0361, OR = 2.742, 95% CI [1.067-7.045]). The follow up study revealed that the majority (85%) remain colonized. This study shows that MRS in veterinary clinical practice is a professional hazard and highlights the need to implement preventive measures to minimize spread. PMID- 28922061 TI - Alanine Aminotransferase and Total Bilirubin Are Synergistically Associated with Metabolic Syndrome Among Middle-Aged and Elderly Japanese Women. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. Alanine aminotransferase (ALT) at high levels and total bilirubin (T-BiL) at low levels were oxidative potentials, but it was uncertain whether ALT and T-BiL had an additive interaction for the risk of MetS. METHODS: From a single community, we recruited 864 women (70 +/- 8 years) during their annual health examination. We cross-sectionally investigated whether ALT and T-BiL are associated with MetS and its components based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report. RESULTS: Of these subjects, 415 women (48.0%) had MetS. Participants with MetS had a higher ALT and lower T-BiL level than those without MetS. The adjusted-odds ratios (OR) (95% confidence interval [CI]) for MetS across tertiles of ALT and T-BiL were 1.00, 1.19 (0.78-1.81), and 1.86 (1.24 2.80) and 1.00, 0.96 (0.65-1.43), and 0.54 (0.36-0.81), respectively. When ALT and T-BiL were categorized into three binary characteristics by tertiles of ALT and T-BiL, high T-BiL was associated with decreased risk for MetS in a multivariable model (OR: 0.55, 95% CI: 0.37-0.82), especially among those with 1st tertile ALT. Similarly, high ALT was also associated with increased risk for MetS in a multivariate model (OR: 1.81, 95% CI: 1.20-2.71), especially among those with 2nd & 3rd tertiles of T-BiL. In the formal testing of addictive interaction between ALT and T-BiL for MetS, presence of T-BiL <0.72 mg/dL (1st and 2nd tertile) alone was not associated with increased risk of MetS in a multivariate analysis, and presence of ALT >=16 IU/L (2nd and 3rd tertile) alone was not associated with increased risk of MetS. CONCLUSIONS: These results suggested that higher ALT and lower T-BiL levels were synergistically associated with MetS, independent of other confounding factors among Japanese women. PMID- 28922062 TI - Online Educational Tool to Promote Bone Health in Cancer Survivors. AB - Osteoporosis burden is significant in cancer survivors. Websites providing health information abound, but their development, quality, and source of information remain unclear. Our aim was to use a systematic and transparent approach to create an educational website on bone health, and to evaluate its potential to improve knowledge, self-management, and awareness in prostate cancer (PCa) and breast cancer (BCa) survivors. Guided by the Health Belief Model, we created a website using international standards and evaluated it in 10 PCa and 10 BCa survivors with self-administered questionnaire before, after, and 1 month after navigating the website. The mean scores on the knowledge questionnaire at baseline, postintervention and 1 month were, respectively, 5.1 (+/-2.0), 6.9 (+/ 2.5), and 6.7 (+/-2.4), p < .008, in PCa and 3.4 (+/-2.7), 7.6 (+/-3.0), and 6.5 (+/-3.8), p = .016, in BCa survivors. Acceptability ratings ranged from 60% to 100%. Participants found the website useful, helpful, and able to raise bone health awareness. Our website improved bone health knowledge in both PCa and BCa survivors. A systematic and transparent approach to the development of online educational websites could result in a tool capable of meeting the educational needs of targeted consumers. Cancer survivors could benefit from proven online educational tools. PMID- 28922063 TI - Individual calibration of accelerometers in children and their health-related implications. AB - This study compared children's physical activity (PA) levels, the prevalence of children meeting current guidelines of >=60 minutes of daily moderate to vigorous PA (MVPA), and PA-health associations using individually calibrated (IC) and empirical accelerometer cutpoints. Data from 75 (n = 32 boys) 10-12 year old children were included in this study. Clustered cardiometabolic (CM) risk, directly measured cardiorespiratory fitness (CRF), anthropometric and 7 day accelerometer data were included within analysis. PA data were classified using Froude anchored IC, Evenson et al. (Evenson, K. R., Catellier, D. J., Gill, K., Ondrak, K. S., & McMurray, R. G. (2008). Calibration of two objective measures of physical activity for children. Journal of Sports Sciences, 26(14), 1557-1565. doi:10.1080/02640410802334196) (Ev) and Mackintosh et al. (Mackintosh, K. A., Fairclough, S. J., Stratton, G., & Ridgers, N. D. (2012). A calibration protocol for population-specific accelerometer cutpoints in children. PLoS One, 7(5), e36919. doi:10.1371/journal.pone.0036919) (Mack) cutpoints. The proportion of the cohort meeting >=60mins MVPA/day ranged from 37%-56% depending on the cutpoints used. Reported PA differed significantly across the cutpoint sets. IC LPA and MPA were predictors of CRF (LPA: standardised beta = 0.32, p = 0.002, MPA: standardised beta = 0.27 p = 0.013). IC MPA also predicted BMI Z-score (standardised beta = -0.35, p = 0.004). Ev VPA was a predictor of BMI Z-score (standardised beta = -0.33, p = 0.012). Cutpoint choice has a substantial impact on reported PA levels though no significant associations with CM risk were observed. Froude IC cutpoints represent a promising approach towards classifying children's PA data. PMID- 28922064 TI - Erbium:Yttrium Aluminum Garnet Laser-Activated Sodium Hypochlorite Irrigation: A Promising Procedure for Minimally Invasive Endodontics. AB - OBJECTIVE: This study was to evaluate the potential of Erbium:Yttrium Aluminum Garnet laser-activated sodium hypochlorite irrigation (Er:YAG + NaOCl) for minimally invasive endodontics (MIE). BACKGROUND DATA: Er:YAG laser irradiation can dramatically enhance the penetration of NaOCl, which may be a promising protocol for MIE. METHODS: Extracted human teeth were contaminated with Enterococcus faecalis for 4 weeks. The infected canals were then shaped to different apical terminal working widths (ATWW, 15#/0.04, 20#/0.04, 25#/0.04, 30#/0.04, and 40#/0.04) and treated with either Er:YAG + NaOCl (0.3 W, 20 sec) or NaOCl alone. Then, the ATWW were fixed at 15#/0.04, and the canals were treated with Er:YAG + NaOCl at 0.3 W for 40 and 60 sec, or at 0.5 and 1.0 W for 20 sec. Finally, bacterial reductions were evaluated using the cell count method. RESULTS: Er:YAG + NaOCl showed a higher disinfection efficacy at each ATWW compared with NaOCl alone (p < 0.001). The maximum bacterial reduction was 99.9% for the 40#/Er:YAG + NaOCl group and 93.6% for the 40#/NaOCl group. To achieve similar disinfection efficacy, the Er:YAG + NaOCl group needed a smaller ATWW than the NaOCl group. At a fixed ATWW, increasing the output power of the Er:YAG laser was more effective than increasing the radiation time to improve the disinfection efficacy of Er:YAG + NaOCl. The 15#/Er:YAG + NaOCl group reached the maximum bacterial reduction of 99.2% when the Er:YAG laser was activated at 1.0 W for 20 sec. CONCLUSIONS: The 15#/Er:YAG + NaOCl with the Er:YAG laser irradiation at 1.0 W for 20 sec may be considered a promising procedure for MIE. PMID- 28922065 TI - A Study Examining the Effect of a Short Bout of Postprandial Walking on the Glycemic Effect of a Meal: Type 1 Diabetes. AB - OBJECTIVE: The purpose of this pilot study was to determine whether 15 minutes of postprandial walking has an effect on the glycemic response to a breakfast beverage in individuals with type 1 diabetes (T1DM). METHODS: Seven participants, aged 22.3 +/- 4.3 years, with T1DM using intensive insulin therapy completed 2 days of data collection. On day 1, participants measured baseline fasting blood glucose (BG) with a glucometer, consumed an 8-ounce Boost(r) beverage (41 grams carbohydrate), administered a bolus of insulin according to the carbohydrate load and fasting BG, and sat quietly, repeating BG measurements 15, 30, 60, 90, and 120 minutes after consumption. On day 2, participants repeated the protocol, but walked 15 minutes at 50% to 60% maximum heart rate immediately after beverage consumption. RESULTS: The difference between peak and baseline (peak - baseline) BG and incremental glucose area under the curve (iAUC) were lower in all but one participant on the walking compared to the sedentary day. Mean peak - baseline BG was significantly lower on the walking day compared to the sedentary day (6.4 +/- 1.2 vs 14.4 +/- 3.4 mmol/L, respectively, p = 0.016) as was the iAUC, (241.1 +/- 155.8 vs 468.6 +/- 94.5 mmol/L/120 min, respectively, p = 0.031). CONCLUSIONS: Fifteen minutes of postprandial walking can blunt the spike in BG and overall glycemic response to a breakfast beverage in young adults with T1DM and may be an effective and realistic component in the management of T1DM. PMID- 28922066 TI - The Effect of Lysozyme on Reducing Biofilms by Staphylococcus aureus, Pseudomonas aeruginosa, and Gardnerella vaginalis: An In Vitro Examination. AB - Two basic questions about lysozyme activities on the selected microorganisms were investigated, namely whether lysozyme inhibits biofilm production and which concentrations of the enzyme have the ability to change the natural biofilm producing capacity of different strains of Staphylococcus aureus (methicillin sensitive and resistant), Streptococcus pyogenes, Pseudomonas aeruginosa, and Gardnerella vaginalis. The effect of lysozyme on biofilm formation capacities of 16 strains of selected microorganisms was investigated, whereby four testing replicates have been performed in vitro using the Test Tube method, and the potential of lysozyme to change biofilm forming capacities depending on its concentration, species, and strains of microorganisms is demonstrated. A lysozyme concentration of 30 MUg/ml indicated to have the highest inhibiting effect on all tested microorganisms. Furthermore, G. vaginalis was the most sensitive of them all, as its biofilm formation was inhibited in the presence of as low as 2.5 MUg/ml of lysozyme. At enzyme concentrations of 7.5-50 MUg/ml (with the exception of 30 MUg/ml) the biofilm forming capacities of P. aeruginosa were enhanced. Depending on the strain of P. aeruginosa, the total biofilm quantity was either reduced or unaffected at lysozyme concentrations of 2.5, 5, 7.5, and 30 MUg/ml. In contrast, lysozyme concentrations below 15 or 20 MUg/ml did not affect or increase the volume of biofilm formation, while higher concentrations (15, 20, 25 MUg/ml) reduced biofilm formation by 50% (3/6) and 30 MUg/ml of biofilm reduced biofilm forming capacity of S. aureus by 100% (6/6). The results of this study are a strong foundation for further research on lysozyme as a modulator of the biofilm forming capacity of different species with the potential to aid in the development of new drugs for the treatment of oral and vaginal infections. PMID- 28922067 TI - Conceptual elaboration versus direct lexical access in WAIS-similarities: differential effects of white-matter lesions and gray matter volumes. AB - Wechsler Adult Intelligence Scale (WAIS) subscale Similarities have been classified as a test of either verbal comprehension or of inductive reasoning. The reason may be that items divide into two categories. We tested the hypothesis of heterogeneity of items in WAIS-Similarities. Consecutive patients at a memory clinic and healthy controls participated in the study. White-matter hyperintensities (WMHs) and normalized temporal lobe volumes were measured based on Magnetic resonance Imaging (MRI), and tests of verbal memory and attention were used in addition to WAIS-Similarities to collect behavioural data. Factor analysis supported the hypothesis that two factors are involved in the performance of WAIS-similarities: (1) semiautomatic lexical access and (2) conceptual elaboration. These factors were highly correlated but provided discriminative diagnostic information: In logistic regression analyses, scores of the lexical access factor and of the conceptual elaboration factor discriminated patients with mild cognitive impairment from Alzheimer's disease patients and from healthy controls, respectively. High scores of WMH, indicating periventricular white-matter lesions, predicted factor scores of direct lexical access but not those of conceptual elaboration, which were predicted only by medial and lateral temporal lobe volumes. PMID- 28922068 TI - Influence of Flaxseed Lignan Supplementation to Older Adults on Biochemical and Functional Outcome Measures of Inflammation. AB - Evidence from the literature suggests that dietary flaxseed lignans have the ability to modulate inflammation, which is recognized as the underlying basis of multiple chronic human diseases in older adults. Our objective was to determine the effects of oral lignan supplementation on biochemical and functional indicators of inflammation as well as safety and tolerability in older healthy adults. We designed a randomized, double-blind, placebo-controlled clinical trial in older healthy adults (60-80 years) to assess flaxseed lignan-enriched complex (~38% secoisolariciresinol diglucoside [SDG]; 600 mg SDG dose) oral supplementation effects on biochemical and functional indicators of inflammation and safety and tolerability in older healthy adults after 6 months of once-daily oral administration. The clinical trial confirmed that plasma concentration of total flaxseed lignans (free and conjugated forms) secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (ENL) were significantly associated with daily oral supplementation of flaxseed lignan-enriched complex (p < 0.05). A significant decrease in systolic blood pressure (SBP; from a mean of 155 +/- 13 mm Hg at baseline to 140 +/- 11 mm Hg at 24 weeks) was observed in lignan supplemented participants stratified into an SBP >=140 mm Hg subcategory (p = 0.04). No differences were found between treatment or placebo groups in terms of cognition, pain, activity, physical measurements (calf, waist, and upper arm circumstances), and grip strength. With respect to blood inflammatory markers, lipid profiles, and biochemical parameters, no significant differences were found between treatment and placebo groups at the end of the 6-month supplementation. No adverse effects were reported during supplementation. These data further support the safety and tolerability of long-term flaxseed lignan-enriched complex supplementation in older adults and identify an ability to favorably modulate SBP, an important risk factor in cardiovascular disease. PMID- 28922069 TI - Glutamatergic Agents in the Treatment of Compulsivity and Impulsivity in Child and Adolescent Psychiatry: a Systematic Review of the Literature. AB - OBJECTIVE: Research has implicated glutamatergic projections between the various frontal subregions in the pathogenesis of compulsivity and impulsivity. Reducing striatal glutamate release, or antagonising the action of glutamate at its receptors, may therefore represent viable treatment strategies. Several glutamatergic agents with regulatory approval for other indications are available and may be of potential benefit in the treatment of compulsivity/impulsivity in psychiatric disorders in paediatric patients. METHOD: This review was performed according to PRISMA guidelines and evaluates available scientific literature concerning the use of glutamatergic agents in these patients, in order to determine their reported effectiveness/efficacy and tolerability/safety. RESULTS: Out of a total of 1,426 publications, 21 trials examining six glutamatergic substances in patients with obsessive-compulsive disorder, autism spectrum disorders, and attention deficit/hyperactivity disorder were included. CONCLUSIONS: Trial designs as well as results were heterogeneous and thus comparability was limited. Available data support the hypothesis that glutamatergic agents are of potential value in the treatment of compulsivity/impulsivity in children and adolescents. Based on the data reviewed, memantine and N-acetylcysteine suggest the best risk-benefit profile for future trials. Riluzole should primarily be further investigated in adults. Clinical research of this nature is a key element of the TACTICS Consortium project funded by the European Union (FP7). PMID- 28922070 TI - Defective calcineurin/NFAT signaling in myeloid cells and susceptibility to aspergillosis in post-transplant patients. PMID- 28922072 TI - Body mass index and psychosocial job quality: An analysis of working Australians from the Household, Income and Labour Dynamics in Australia survey. AB - The study investigated the association between psychosocial job quality and body mass index (BMI) by sex. Regression models examining potential differences in the job stressor-BMI relationship between men and women were conducted using longitudinal data from working Australians and a psychosocial job stressor index. There was strong evidence of an association between psychosocial job stressors and BMI for females but not males. Compared with no psychosocial job stressors, 1 adversity was associated with 0.13 kg/m2 (95% CI: -0.42-0.67); 2 adversities were associated with 0.53 kg/m2 (-0.00-1.07); and 3 or more adversities were associated with 0.87 kg/m2 (0.30-1.45) increase in mean BMI for females. Females were found to have on average 0.32 kg/m2 (0.16-0.49) increase in BMI per increase in psychosocial job stressor. Psychosocial job stressors appear to have an adverse effect on women's weight. PMID- 28922071 TI - Implementing electronic data capture at a well-established health and demographic surveillance site in rural northern Malawi. AB - This article aims to assess multiple issues of resources, staffing, local opinion, data quality, cost, and security while transitioning to electronic data collection (EDC) at a long-running community research site in northern Malawi. Levels of missing and error fields, delay from data collection to availability, and average number of interviews per day were compared between EDC and paper in a complex, repeated annual household survey. Three focus groups with field and data staff with experience using both methods, and in-depth interviews with participants were carried out. Cost for each method were estimated and compared. Missing data was more common on paper questionnaires than on EDC, and a similar number were carried out per day. Fieldworkers generally preferred EDC, but data staff feared for their employment. Most respondents had no strong preference for a method. The cost of the paper system was estimated to be higher than using EDC. The existing infrastructure and technical expertise could be adapted to using EDC, but changes have an impact on data processing jobs as fewer, and better qualified staff are required. EDC is cost-effective, and, for a long-running site, may offer further savings, as devices can be used in multiple studies and perform several other functions. EDC is accepted by fieldworkers and respondents, has good levels of quality and timeliness, and security can be maintained. EDC is well-suited for use in a well-established research site using and developing existing infrastructure and expertise. PMID- 28922073 TI - The effects of individual- and network-level factors on discussion of cancer experiences: Survivors of childhood cancer in Korea. AB - This study aimed to identify young adult Korean cancer survivors' individual- (psychological distress, stigma, sociodemographic variables, and cancer-related variables) and network-level factors (relationship type, social support type) that influence discussion of their cancer experiences. Sixty-eight survivors of childhood cancer who were recruited using snowball sampling nominated 245 individuals from their networks, including family and intimate partners (40%) and friends and acquaintances (60%), as people with whom they most frequently interacted. Results of multilevel modeling analysis indicated that higher levels of internalized shame were a prominent individual-level factor associated with a lack of discussion of cancer experiences. Relationship type and support type at the network-level were also significant correlates of discussion of cancer experiences. Programs for reducing the survivors' shame, improving illness identity, and providing professional training for building social relationships that are intimate and in which they could exchange reciprocal support may help Korean childhood cancer survivors to openly share their cancer experiences with others in their social network and to be successful in the journey of cancer survivorship. PMID- 28922074 TI - Breast cancer survivors' perceptions of participating in a supervised exercise intervention: An exploratory review of the literature. AB - BACKGROUND: Despite the reported beneficial effects of physical activity (PA) during and after cancer diagnosis, current research data suggest that the percentages of breast cancer survivors who adhere to PA recommendations are low. The objective of the present systematic, critical review was to identify, analyze, and provide a summary of qualitative literature findings, which have explored breast cancer survivors' experiences of participating in an exercise/PA intervention after cancer treatment. METHODS: A systematic search was conducted using CINAHL, PsychINFO, PubMed, and Scopus electronic databases to search for qualitative literature published during 2000-2016. A total of six studies that met the inclusion criteria were reviewed. Thematic synthesis, following Thomas and Harden's methods, were used to analyze the data. FINDINGS: Seven descriptive themes were developed: control, focus, transitioning phase, regaining a sense of confidence, enhanced spirits, social support, and safe environment. The findings suggested that participation in supervised exercise interventions enhanced the self-confidence and mood of breast cancer survivors. It allowed them to regain control and provide a focus, thereby allowing them to move forward in their lives. CONCLUSION: The results of this systematic critical review indicated that the supervised exercise was a positive experience for breast cancer survivors. PMID- 28922075 TI - Factors associated with optimal antenatal care use in Northern region, Ghana. AB - The objective of this study was to investigate the factors associated with the optimal use of antenatal care (ANC) during pregnancy. A facility-based cross sectional survey was conducted between February and August 2014 among nursing mothers (n = 578) attending postnatal and child welfare clinics in three districts in Northern Ghana, representing urban, peri-urban, and rural zones. The developed questionnaire aided the collection of information on maternal demographic characteristics, health status, household assets, and ANC attendance. Binary logistic regression was modeled to estimate the association between optimal ANC use and mothers' characteristics. Approximately 81% of the respondents had >=4 ANC visits during pregnancy, and coverage was over 99%. Mothers who had any formal education (adjusted odds ratio [AOR] = 1.7, 95% confidence interval [CI] = 1.0-2.8, P = 0.040) lived in middle class socioeconomic households (AOR = 2.6, 95%CI = 1.4-4.8, P = 0.003) and resided in urban areas (AOR = 2.0, 95%CI = 1.2-3.3, P = 0.006) were significantly more likely to report the optimal ANC use. Mothers' education, socioeconomic status, and proximity to a health facility were positively associated with the optimal ANC use. Education of females and policy initiatives aimed at improving the rural urban divide are essential to optimize the use of ANC. PMID- 28922077 TI - Corrigendum. PMID- 28922076 TI - CRISPR-Cas Technology in Viral Therapeutics. PMID- 28922078 TI - The tipping point of change in Anorexia Nervosa (AN): Qualitative findings from an online study. AB - OBJECTIVE: The aim of this study was to understand factors related to treatment and/or recovery from self-reported Anorexia Nervosa (AN), including 'the tipping point of change'. METHOD: An online questionnaire was developed and administered from December 2014 to December 2015 to individuals >=18 years of age with AN in the past or currently who were recruited through eating disorder organizations in Australia and the United Kingdom. Responses to a specific qualitative question on 'the tipping point of change' were analyzed using conventional content analysis (CCA). RESULTS: One hundred sixty-one participants completed some or all of the questionnaire; only 67 women (41.61%) answered Question six on 'the tipping point of change', and analyses were restricted to data from these women. The themes identified were: 1) realizing the loss of something valuable, 2) the risk of losing something valuable, and 3) something to live for/stay well for. CONCLUSION: These results are important for health-care providers as they work with patients to identify life experiences, including 'loss/potential loss' and 'the need for preservation', that have personal significance. Some patients may realize that 'enough is enough'; something needs to change. These intrinsic motivating factors may also be the impetus for eventual recovery for some individuals. PMID- 28922079 TI - Continuing Education-"The Action Level"(r). AB - Access "The Action Level"(r) Questions online at: http://www.acgih.org/products/joeh/alquestions.htm Access "The Action Level"(r) Answers online at: http://www.acgih.org/products/joeh/alanswers.htm Access "The Action Level"(r) Registration Form online at: https://www.acgih.org/products/joeh/alregfrm.htm "The Action Level,"(r) a self study, continuing education program, provides a convenient and interesting opportunity for individuals to expand their knowledge in relevant areas of industrial hygiene, as well as occupational and environmental safety and health. The program is approved by both the American Board of Industrial Hygiene and the Board of Certified Safety Professionals, which award Certification Maintenance (CM) points and Continuance of Certification (COC) points, respectively, for successful participation. Participants must read each issue of the Journal, answer "The Action Level"(r) questions, and return the completed answer sheet at the end of that issue's "The Action Level"(r) column. To earn the designated CM or COC credit, a score of 70 percent or better is required within a 12-month period. Certified Industrial Hygienists and Certified Associate Industrial Hygienists may earn 2 points per year. Certified Safety Professionals may earn 1.2 points per year. Enrollment is possible each month, but points are awarded only four times each year - in March, June, September, and December - to participants who score an average of 70 percent or better within each three-month period. If you register in August 2014, you will receive 0.5 CM points and/or 0.3 COC points after you have completed answers sheets for August and September 2014, and scored a 70 percent or better average on them (only in your first quarter of enrollment, if enrolling in the middle of the quarter, will you be permitted to submit answer sheets for two months and receive full credit; three answer sheets are required for all other quarters). In the next quarter, you'll receive 0.5 CM points and/or 0.3 COC points after satisfactorily completing answer sheets for the October, November and December, 2014 issues, and so on. To enroll, complete the registration form and the answer sheet at the end of this "The Action Level"(r) column. The cost is $219 (ACGIH(r)/AIHA members)/$249 (nonmembers) for one year. Nonmembers are encouraged to become members to take advantage of the member discount. For more information regarding ACGIH(r) membership, call 513-742 2020, or apply online at http://www.acgih.org/members/memberform.htm . Checks must be in U.S. currency, drawn on a U.S. bank, and payable to ACGIH(r). We also accept AmEx, MasterCard, Discover and Visa. This continuing education program fee is separate from the Journal subscription cost. The fee covers administration costs and is nonrefundable. Submissions must be received by the date listed on each answer sheet. PMID- 28922080 TI - Factors associated with residential mobility during pregnancy. AB - Our objective was to determine the factors associated with residential moving during pregnancy, as it may increase stress during pregnancy and affect birth outcomes. Data were obtained from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Participants were recruited from December 2006 to June 2011 and included 1,448 pregnant women. The average gestational age at enrollment was 23 weeks. The primary outcome of residential mobility was defined as any change in address during pregnancy. Multivariate regression was used to assess the adjusted associations of factors with residential mobility. Out of 1,448 participants, approximately 9 percent moved between baseline (enrollment) and delivery. After adjusting for covariates, mothers with lower educational attainment [less than high school (adjusted odds ratio [aOR] = 3.74, 95% confidence interval [CI] = 1.78, 7.85) and high school/technical school (aOR = 3.57, 95% CI = 2.01, 6.32) compared to college degree or higher], and shorter length of residence in neighborhood were more likely to have moved compared to other mothers. Length of residence was protective of mobility (aOR = 0.91, 95% CI = 0.86, 0.96 per year). Increased understanding of residential mobility during pregnancy may help improve the health of mothers and their children. PMID- 28922081 TI - Clinical outcomes following conservative management of chronic traumatic cervical myelopathy: A case report. AB - BACKGROUND AND PURPOSE: There is limited evidence supporting the conservative management of patients with cervical myelopathy. The purpose of this report is to describe the intervention and outcomes of conservative physical therapy interventions for one patient with chronic cervical myelopathy. CASE DESCRIPTION: This case was a 50-year-old male who sustained a neck injury following a rear-end collision 4 years prior to this therapeutic episode. The patient presented with decreased range of motion in the cervical spine and right upper extremity, strength deficits, altered sensation, poor posture, and reported chronic cervical region pain and difficulty sleeping. INTERVENTION: The patient completed 10 weeks of conservative physical therapy. The patient completed the Neck Disability Index (NDI), Medical Outcome Survey Sleep Scale (MSS), short-form McGill Pain Questionnaire (SFMPQ), Patient-Specific Functional Scale (PSFS), and baseline clinical measurements of flexibility and strength were obtained. OUTCOMES: After the 10-week episode of care, the following changes were noted from baseline: 18% improvement on the NDI, 26% improvement on the MSS, 25% decrease in pain on the SFMPQ, and a 39% improvement on the total score of the PSFS. Cervical range of motion measurements increased between 25% and 100%. Grip strength demonstrated a 465% increase on the right upper extremity and a 25% increase on the left upper extremity. DISCUSSION: This case report suggests that conservative management of chronic traumatic cervical myelopathy was effective in helping to improve pain, sleep, and function in this patient with a traumatic mechanism of injury. PMID- 28922082 TI - Combinatorial peptide-based epitope mapping from Ebola virus DNA vaccines and infections reveals residue-level determinants of antibody binding. AB - Ebola virus (EBOV) infection is highly lethal and results in severe febrile bleeding disorders that affect humans and non-human primates. One of the therapeutic approaches for treating EBOV infection focus largely on cocktails of monoclonal antibodies (mAbs) that bind to specific regions of the EBOV glycoprotein (GP) and neutralize the virus. Recent structural studies using cryo electron microscopy have identified key epitopes for several EBOV mAbs. While such information has yielded deep insights into antibody binding, limitations on resolution of these structures often preclude a residue-level analysis of EBOV epitopes. In this study, we performed combinatorial peptide-based epitope mapping of EBOV GP against a broad panel of mAbs and polyclonal sera derived from several animal species vaccinated with EBOV DNA and replicon vaccines and/or exposed to EBOV infection to identify residue-level determinants of antibody binding. The peptide-based epitope mapping obtained from a wide range of serum and mAb samples, combined with available cryo-EM structure reconstructions revealed fine details of antibody-virus interactions, allowing for a more precise and comprehensive mapping of antibody epitopes on EBOV GP. We show how these residue level epitope definitions can be used to characterize antigenic variation across different filoviruses, and provide a theoretical basis for predicting immunity and cross-neutralization in potential future outbreaks. PMID- 28922084 TI - Abstracts from the NIH Office of Research on Women's Health 2017 Annual BIRCWH Meeting - Building Interdisciplinary Research Careers in Women's Health October 25, 20172017 Annual Meeting of the Building Interdisciplinary Research Careers in Women's Health Program Lisa Begg, Dr.P.H, R.N. PMID- 28922083 TI - Strategies in recommending influenza vaccination in Europe and US. AB - There is potential for influenza vaccine programmes to make a substantial impact on the disease burden. The World Health Organization (WHO) has identified young children, pregnant women, persons with chronic medical conditions, and the elderly as being at risk for severe influenza disease and therefore important groups to be considered for influenza vaccination. Applying the methodology of scoping review of grey and scientific literature we described the European and the US approach to influenza vaccine prevention. Although vaccination remains the most effective means of reducing the incidence and severity of influenza, vaccine uptake in many European countries remains suboptimal (i.e. 45.5% in the elderly, 24% in health care workers, from 49.8% in patients with chronic medical conditions, median 23.6% in pregnant women) and vaccine strategies are not harmonized in particular with regard to vaccinating healthy children. Whereas in the US the vaccine strategies are more standardized across states and vaccine coverage are higher than those reported in EU on average. The integration of different strategies is crucial in order to increase influenza vaccine coverage: public health authorities should encourage healthcare workers to vaccinate themselves, as target category, and to recommend seasonal influenza vaccination to people in the target groups; there should also be structured communication campaigns on influenza and influenza vaccines, directed specifically at these target groups, and an adequate and sustainable funding is also an important factor to achieve higher vaccination coverage rates. PMID- 28922086 TI - Assessment of Ah receptor transcriptional activity mediated by halogenated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) in human and mouse cell systems. AB - Polybrominated and mixed bromo/chloro dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) are emerging environmental contaminants of concern. Thus far, an understanding of the toxicological behavior of these chemical species and their impact upon human health is incomplete. Here we utilized human and mouse hepatocellular carcinoma cell lines to examine the ability of differentially halogenated PXDD/F congeners to induce aryl hydrocarbon receptor (AHR)-mediated transcriptional activity. Dose-response experiments in reporter cell lines identified varied potencies among differentially halogenated PXDD/F isomers by comparison of EC50 values relative to the prototypical AHR agonist, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). Brominated PXDD/F species displayed reduced capacity to activate the mouse AHR, compared to TCDD. Only BrCl3 dibenzo-p-dioxin was found to have a greater relative potency than TCDD to induce human AHR transcriptional activity. Human cells required ~10-29-fold higher ligand concentrations to induce analogous AHR activity, relative to mouse cells. Decreased sensitivity of the human AHR to brominated dibenzofuran congeners directly corresponded to the number of bromine functional groups. Mixtures of these compounds exhibited an additive effect on AHR activation. The data also support the inclusion of mixed halogenated dibenzo-p-dioxins and dibenzofurans into routine environmental screening procedures as well as more thorough toxicological characterization of PXDD/Fs. PMID- 28922087 TI - Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors. AB - Purpose The use of anthracycline chemotherapy is associated with heart failure (HF) among survivors of non-Hodgkin lymphoma (NHL). We aimed to understand the contribution of preexisting cardiovascular risk factors to HF risk among NHL survivors. Methods Using Danish registries, we identified adults diagnosed with aggressive NHL from 2000 to 2010 and sex- and age-matched general-population controls. We assessed HF from 9 months after diagnosis through 2012. We used Cox regression analysis to assess differences in risk for HF between survivors and general population controls. Among survivors only, preexisting cardiovascular factors (hypertension, dyslipidemia, and diabetes) and preexisting cardiovascular disease were ascertained. We used multivariable Cox regression to model the association of preexisting cardiovascular conditions on subsequent HF. Results Among 2,508 survivors of NHL and 7,399 controls, there was a 42% increased risk of HF among survivors compared with general population controls (hazard ratio [HR], 1.42; 95% CI, 1.07 to 1.88). Among survivors (median age at diagnosis, 62 years; 56% male), 115 were diagnosed with HF during follow-up (median years of follow-up, 2.5). Before NHL diagnosis, 39% had >= 1 cardiovascular risk factor; 92% of survivors were treated with anthracycline-containing regimens. In multivariable analysis, intrinsic heart disease diagnosed before lymphoma was associated with increased risk of HF (HR, 2.71; 95% CI, 1.15 to 6.36), whereas preexisting vascular disease had no association with HF ( P > .05). Survivors with cardiovascular risk factors had an increased risk of HF compared with those with none (for 1 v 0 cardiovascular risk factors: HR, 1.63; 95% CI, 1.07 to 2.47; for >= 2 v 0 cardiovascular risk factors: HR, 2.86; 95% CI, 1.56 to 5.23; joint P < .01). Conclusion In a large, population-based cohort of NHL survivors, preexisting cardiovascular conditions were associated with increased risk of HF. Preventive approaches should take baseline cardiovascular health into account. PMID- 28922089 TI - The "Jolly Fat" Effect in Middle-Aged Korean Women. AB - BACKGROUND: It has been hypothesized that depression and obesity are bi directionally associated, and when overweight people appear to show a lower risk of depression, this supports the "Jolly Fat" hypothesis. The aim of this study was to examine the "Jolly Fat" hypothesis in middle-aged women in Korea, by different perceived stress levels. METHODS: We performed a cross-sectional study of 44 to 56 aged Korean women (n = 2201) who underwent a health check-up program at the healthcare centers of Kangbuk Samsung Hospital (Seoul and Suwon centers) in Korea. General and abdominal obesity were defined as body mass index >=25 kg/m2 and waist circumference >=85 cm, respectively. Depressive symptoms were measured by a Korean version of the Center for Epidemiologic Studies-Depression scale. The association between obesity and depressive symptoms was investigated by using multiple logistic regression analyses by different levels of perceived stress, with adjustment for potential confounding factors. RESULTS: The prevalence of general and abdominal obesity and depressive symptoms were 23.7%, 21.4%, and 16.5%, respectively. Women with general obesity were less likely to have depressive symptoms (odds ratio [OR]: 0.50; 95% confidence interval [CI]: 0.25-1.00; p-value: 0.049) in the low-stress group. We also found that women with abdominal obesity had a 60% decrease in the odds of having depressive symptoms (OR: 0.40; 95% CI: 0.18-0.87; p-value: 0.02) in the low-stress group. No significant association was found in the high-stress group. CONCLUSIONS: These findings indicate that the relationship between obesity and depressive symptoms in the Korean middle-aged women supports the "Jolly Fat" hypothesis. Further, our results underscore the role of stress as an important potential mediator exerting effects on the association between obesity and depressive symptoms. PMID- 28922088 TI - Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease Due to Meibomian Gland Disease. AB - PURPOSE: Meibomian gland disease is generally accepted as the leading cause for evaporative dry eye disease (DED). In a previous study, perfluorohexyloctane, a semifluorinated alkane, has been demonstrated to significantly increase tear film breakup time and to reduce corneal fluorescein staining in patients with evaporative DED, thereby vastly reducing dry eye-related symptoms. This study was set up to evaluate perfluorohexyloctane in a larger population of patients with Meibomian gland dysfunction. METHODS: Seventy-two patients with Meibomian gland disease and associated dry eye received 1 drop of perfluorohexyloctane 4 times daily during an observational, prospective, multicenter, 6-8-week study. Clinical assessment included best-corrected visual acuity, intraocular pressure, Schirmer test I, tear film breakup time, anterior and posterior blepharitis assessment, number of expressible Meibomian glands, meibum quality and quantity, ocular surface fluorescein staining, lid margin and symptom assessment, and Ocular Surface Disease Index (OSDI(c)). RESULTS: From the 72 patients recruited, 61 completed the trial per protocol. Nine patients did not apply the medication as recommended and 2 patients were lost to follow-up. Tear film breakup time, corneal and conjunctival fluorescein staining, number of expressible Meibomian glands, and severity of anterior and posterior blepharitis significantly improved after 6-8 weeks of perfluorohexyloctane application. In addition, symptoms improved as demonstrated by a significant decrease of OSDI-values from 37 (+/-13) to 26 (+/-16). CONCLUSIONS: In concordance with previous findings, 6-8 weeks of topical application of perfluorohexyloctane significantly improves clinical signs of Meibomian gland disease and associated mild to moderate DED. PMID- 28922090 TI - Microsaccades and interest areas during free-viewing sport task. AB - Microsaccades are important fixation eye movements for visual scene perception. Compared to novices, athletes make fewer fixations of longer duration toward limited interest areas crucial for action prediction. Thus, our aim was to study the microsaccade features during those fixations. Gaze behaviour of expert and novice table tennis players was recorder during a task in which subjects were instructed to predict the direction of the ball after the opponent's throw. Three interest areas from the opponent's body and one from the ball trajectory were identified. We analysed correctness of predictions, fixations, microsaccades and saccades to estimate the relationship between eye movements toward interest areas and success in the task. Compared to novices, experts fixated more on hand-racket during forehand and on trunk during backhand drive technique. Longer fixations on hand-racket and trunk were associated with higher microsaccade rate with a narrower directional distribution of them. It probably means that athletes focused their gaze on these small areas, suggesting enhanced attention mainly to them, and fewer consideration for the surrounding regions. We can assume that microsaccade rate and average direction could be related to the salience of interest areas during performance. PMID- 28922092 TI - From risky behaviour to sexy adventures: reconceptualising young people's online sexual activities. AB - Western discourses about young people and sexuality centre around the concept of risk. Anxieties have been fuelled by the increasing popularity of social media and practices such as 'sexting' and watching 'sexually explicit' materials online. Research has shown however that such risk discourses mainly serve to moralise about, pathologise and police particular behaviours and children. In order to counter such paternalism, researchers advocated a reconceptualisation of youth not as passive victims, but as active agents who actively negotiate sexual experiences and discourses. In this paper, which is based on ethnographic fieldwork among young people in The Netherlands, I argue that we need a reconceptualisation not only of youth, but also of their sexual practices, especially their online sexual practices. Mobilising an interdisciplinary interaction between critical socio-cultural studies of risk, feminist theory and adventure studies, I propose to reconceptualise these practices as 'adventures' rather than 'risky behaviour'. This opens up possibilities for a more reasoned analysis that acknowledges: (1) the distinction between risks and outcomes of an activity; (2) the constructive potential of risk; and (3) the subjective, dynamic character of risk and pleasure. PMID- 28922093 TI - Safer sexual practices among African American women: intersectional socialisation and sexual assertiveness. AB - Scholars have posited that childhood socialisation experiences may play a key role in influencing behaviours and attitudes that contribute to the acquisition of HIV. This study examined the links between past ethnic-racial and gender socialisation, sexual assertiveness and the safe sexual practices of African American college women utilising a cluster analytic approach. After identifying separate racial-gender and ethnic-gender socialisation profiles, results indicated that ethnic-gender socialisation cluster profiles were directly associated with sexual assertiveness and safer sex behaviour. Greater levels of ethnic socialisation and low traditional gender role socialisation were found to be associated with greater sexual assertiveness and safer sex behaviour. Further analysis showed that sexual assertiveness mediated the links between the identified ethnic-gender socialisation profiles and safer sex behaviour. Implications for policy and programme development are discussed. PMID- 28922091 TI - How Cancer Patients Use and Benefit from an Interactive Cancer Communication System. AB - Despite the mounting evidence of efficacy of eHealth interventions, their mechanisms of action remain unknown. The current study analyzed patient log data as each patient engaged in an eHealth system called the Comprehensive Health Enhancement Support System (CHESS) and reports on how patients engage with different combinations of eHealth services over time. Newly diagnosed breast cancer patients (N = 443) were given access for 6 months to one of four different configurations of CHESS: (1) Information, (2) Information and Support, (3) Information, Support, and Coaching (Full CHESS), and (4) Full CHESS and Mentor. Besides a baseline survey, three follow-up posttests were administered. Action log data on how patients engaged with the CHESS were also collected and merged with surveys to examine how patients benefit during the cancer experience. The findings suggest that usage patterns were not competitive, implying that cancer patients' access to more complex tools generates more use with their time spreading out over the diverse services. Despite overall decline in usage rates, it was less severe in Full CHESS and Mentor condition, suggesting that communication functions drive long-term engagement with the system. Notably, the strongest relation between use and cancer information competence appeared late in the follow-up period. PMID- 28922094 TI - Remembering - but not knowing - disturbs the relational bindings newly established in short-term/working memory: an age-group comparison. AB - The aim of this study was to highlight that episodic memory and working memory compete for the same resource, which would be diminished in aging. Using the remember/know paradigm, we compared the interference related to the retrieval of words on the parallel processing of preestablished relational bindings (Shifting condition) or newly established relational bindings (Updating condition). Within each age-group, participants had comparable performances in remembering across recognition conditions. However, the results showed that only updating activity was impaired after a remember response was given in the younger group. This specific interaction between updating and remembering - but not knowing - tends to indicate that both working memory and episodic memory rely on the ability to establish contextualized representations. In the older group, the performance in updating activity was impaired regardless of the kind of the competing retrieval. Limitations in terms of interference hypothesis and limited resource hypothesis are discussed. PMID- 28922095 TI - End-of-Volume Editorial Board. PMID- 28922096 TI - The Effects of Ramadan Fasting on Body Composition, Blood Pressure, Glucose Metabolism, and Markers of Inflammation in NAFLD Patients: An Observational Trial. AB - BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and is a serious global health problem. Regarding the increasing prevalence of NAFLD, finding various strategies to prevent and manage the disease is of great importance. The aim of this study was to determine the effects of caloric restriction during Ramadan fasting on anthropometric indices, fasting glucose, plasma insulin, insulin resistance, and inflammatory cytokines (C reactive protein and interleukin 6) in patients with NAFLD. METHODS: We conducted this study with 83 patients with NAFLD, 42 of whom decided to fast and 41 controls who decided not to fast for Ramadan, between June 18 and July 17, 2015. Anthropometric parameters were measured and a sample of venous blood was obtained for biochemical assays before and after Ramadan. RESULTS: There was a significant decrease in all anthropometric parameters as well as fasting glucose, plasma insulin, and insulin resistance. Relative to the nonfasting group, fasting significantly reduced circulating inflammatory, but changes in blood pressure after Ramadan were not significant. CONCLUSIONS: This study shows significant effects on parameters during Ramadan fasting such as anthropometric indices, fasting glucose, plasma insulin, and inflammatory cytokines in patients with NAFLD. The results of this study suggest that Ramadan fasting may be useful to improve NAFLD, so further studies are needed in this area. PMID- 28922097 TI - Gender differences in variables associated with sleep quality in chronic tension type headache. AB - We aimed to evaluate gender differences in the relationships between headache features, sleep quality, anxiety, depressive symptoms, and burden of headache in 193 patients (73 percent women) with chronic tension type headache (CTTH). Sleep quality was assessed with the Pittsburgh Sleep Quality Index. Headache features were collected with a four-week diary. The Hospital Anxiety and Depression Scale was used to assess anxiety/depressive symptoms. Headache Disability Inventory was used to evaluate the burden of headache. In men with CTTH, sleep quality was positive correlated with headache frequency (r = 0.310; p = .018), emotional (r = 0.518; p < .001) and physical (r = 0.468; p < .001) burden of headache, and depressive symptoms (r = 0.564; p < .001). In women, positive correlations were observed between sleep quality and headache intensity (r = 0.282; p < .001), headache frequency (r = 0.195; p = .021), emotional burden (r = 0.249; p = .004), and depressive symptoms (r = 0.382; p < .001). The results of stepwise regression analyses revealed that depressive symptoms and emotional burden of headache explained 37.2 percent of the variance in sleep quality in men (p < .001), whereas depressive symptoms and headache intensity explained 17.4 percent of the variance in sleep quality in women (p < .001) with CTTH. Gender differences associated with poor sleep should be considered for proper management of individuals with CTTH. PMID- 28922098 TI - The effects of familial acculturative stress and hopelessness on suicidal ideation by immigration status among college students. AB - OBJECTIVES: Based on acculturative family distancing theory, we examined whether familial acculturative stress interacted with hopelessness to predict suicidal ideation differentially among emerging adult immigrant versus nonimmigrant college students. PARTICIPANTS: We recruited 152 generationally and racially/ethnically diverse college students (42 immigrants) from 2012 to 2013. METHODS: Participants completed measures of hopelessness, depressive symptoms, ethnic identity, familial acculturative stress, and suicidal ideation. RESULTS: Immigrant status interacted with hopelessness and familial acculturative stress. Hopelessness was associated with less suicidal ideation among immigrants than among nonimmigrants at a familial acculturative stress score below the 11th percentile, but greater suicidal ideation among immigrants than among nonimmigrants at a familial acculturative stress score above the 72nd percentile. CONCLUSIONS: Familial acculturative stress may exacerbate the effect of hopelessness on suicidal ideation among immigrant college students, and should be monitored during suicide risk assessment and treatment. PMID- 28922099 TI - The Effects of Probiotic Supplementation on Gene Expression Related to Inflammation, Insulin, and Lipids in Patients With Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Limited data are available assessing the effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis (MS). OBJECTIVES: The current study was conducted to assess the effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with MS. METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed among 40 patients with MS. Participants were randomly assigned into two groups to receive either a probiotic capsule containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 * 109 colony-forming units/g each; n = 20) or placebo (n = 20) for 12 weeks. Gene expression related to inflammation, insulin, and lipids was quantified in blood samples of patients with MS with the reverse transcription polymerase chain reaction (RT-PCR) method. RESULTS: We found that compared with placebo, probiotic supplementation down-regulated gene expression of interleukin-8 (IL-8; p < 0.001) and tumor necrosis factor-alpha (TNF-alpha) mRNA (p < .001) in peripheral blood mononuclear cells of patients with MS. We did not observe any significant effect of probiotic supplementation on gene expression of interleukin-1 (IL-1), peroxisome proliferator-activated receptor gamma (PPAR-gamma), or oxidized low density lipoprotein receptor (LDLR) in peripheral blood mononuclear cells of patients with MS. CONCLUSIONS: Overall, probiotic supplementation for 12 weeks in patients with MS significantly improved gene expression of IL-8 and TNF-alpha but did not influence IL-1, PPAR-gamma, or LDLR. PMID- 28922101 TI - This is who we are: building community for HIV prevention with young gay and bisexual men in Beirut, Lebanon. AB - Young gay men in Beirut are at significantly elevated risk of HIV infection compared with the general Lebanese population. Despite nascent HIV prevention efforts in the region, there is a need for effective community-level HIV prevention interventions tailored for young gay men. This qualitative study examined internal dynamics within Beirut's gay community as a basis for developing community-level interventions. Peer ethnographers were trained to collect field notes on conversations between young gay men in public spaces in Beirut, and conducted follow-up focus groups with young gay men. Analyses revealed three major themes: (1) the need for safe spaces in which to socialise, (2) the importance of being able to locate and connect with other young gay men, and (3) ambivalence regarding a gay community that was supportive in some ways but also fragmented and often judgemental. Study findings also confirm the existence of external threats to community such as stigma, cultural and familial norms regarding heterosexuality and criminalisation of refugee status. Understanding such community dynamics and the environmental context is central to designing effective community-based HIV prevention programmes. PMID- 28922102 TI - Sleep Duration and Quality Among Women Aged 40-59, by Menopausal Status. AB - Data from the National Health Interview Survey, 2015. Among those aged 40-59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period. Postmenopausal women aged 40-59 were more likely than premenopausal women aged 40-59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week. Postmenopausal women aged 40-59 (55.1%) were more likely than premenopausal women aged 40-59 (47.0%) to not wake up feeling well rested 4 days or more in the past week. PMID- 28922100 TI - Frequency and Antibiotic Resistance of Bacteria Implicated in Community Urinary Tract Infections in North Aveiro Between 2011 and 2014. AB - AIMS: The present study aims to evaluate the predominance of uropathogens responsible for urinary tract infection (UTI) and determine their resistance patterns, to assess if the recommended empirical treatment is appropriate for the studied population. Samples were collected in Aveiro (Portugal) from an ambulatory service between June 2011 and June 2014. RESULTS: From the 4,270 positive urine samples for UTI, 3,561 (83%) were from women and only 709 (17%) were from men. The bacterium Escherichia coli was the most frequent uropathogen, followed by Klebsiella sp., Enterococcus sp., and Proteus mirabilis. E. coli was also the uropathogen presenting less resistance to antibiotics, including those recommended as first and second line UTI treatment. In general, bacteria isolated from men were more resistant to antimicrobials than bacteria isolated from women. CONCLUSIONS: The results of this study emphasized the relevance to consider sex as a differentiating factor in the choice of UTI empirical treatment, mainly due to differences in antimicrobial resistance. From the first line drugs recommended by the European Association of Urology (EAU) to empirical treatment of uncomplicated UTI, nitrofurantoin is the most appropriate drug for both sexes. Ciprofloxacin, although appropriate for treatment in women, is not appropriate to treat UTIs in men. From the second line drugs, both trimethoprim-sulfamethoxazole (TMP-SMX) and amoxicillin-clavulanic acid (AMX-CA) are appropriate drugs for treatment of uncomplicated UTI in women, but not as effective for men. PMID- 28922103 TI - Budd-Chiari Syndrome. AB - Budd-Chiari syndrome (BCS) is a rare disease with an incidence of 0.1 to 10 per million inhabitants a year caused by impaired venous outflow from the liver mostly at the level of hepatic veins and inferior vena cava. Etiological factors include hypercoagulable conditions, myeloprolipherative diseases, anatomical variability of the inferior vena cava, and environmental conditions. Survival rates in treated patients range from 42 to 100% depending on the etiology and the presence of risk factors including parameters of Child-Pugh score, sodium and creatinine plasma levels, and the choice of treatment. Without treatment, 90% of patients die within 3 years, mostly due to complications of liver cirrhosis. BCS can be classified according to etiology (primary, secondary), clinical course (acute, chronic, acute or chronic lesion), and morphology (truncal, radicular, and venooclusive type). The diagnosis is established by demonstrating obstruction of the venous outflow and structural changes of the liver, portal venous system, or a secondary pathology by ultrasound, computed tomography, or magnetic resonance. Laboratory and hematological tests are an integral part of the comprehensive workup and are invaluable in recognizing hematological and coagulation disorders that may be identified in up to 75% of patients with BCS. The recommended therapeutic approach to BCS is based on a stepwise algorithm beginning with medical treatment (a consensus of expert opinion recommends anticoagulation in all patients), endovascular treatment to restore vessel patency (angioplasty, stenting, and local thrombolysis), placement of transjugular portosystemic shunt (TIPS), and orthotopic liver transplantation as a last resort rescue treatment. PMID- 28922104 TI - Interleukin-2, Interferon-gamma Gene Polymorphisms in Recurrent Aphthous Stomatitis. AB - Recurrent aphthous stomatitis (RAS) is the most common oral ulcerative inflammatory disease with unknown etiology. IL-2 and IFN-gamma are secreted by Th1 cells and the elevated levels of them have been reported in RAS. Single nucleotide polymorphisms (SNPs) of IL-2 and IFN-gamma genes could alter the cytokine production. The aim of this study was to investigate frequencies of IL-2 and IFN-gamma alleles and genotypes in a group of patients with minor-RAS (MiRAS). PCR-SSP method used to type genomic DNA of 64 Iranian patients with MiRAS for IL-2 gene (G -330 T) and (G +166 T) and IFN-gamma gene at position UTR5644 (A/T). Frequency of each allele and genotype was compared with control group. IL-2 +166 G allele was significantly lower among patients which was reflected in significantly decreased of GG genotype at this position, while IL-2 +166 T allele was significantly higher among patients, IL-2 GT genotype was also significantly higher in RAS patients. No significant differences were found regarding IL-2 -330 G/T allele frequencies, while IL-2 GT genotype at this position was significantly higher among patients and IL-2 -330 TT genotype was significantly lower among RAS patients. Although no significant differences were found in IFN-gamma allele frequencies at UTR5644 (A/T), AT genotype at this position was significantly overrepresented among patients compared with controls. Results of this study suggest that certain SNPs of IL-2 and IFN-gamma genes have association with predisposition of individuals to RAS. More studies in different ethnic groups are needed to confirm results of this study. PMID- 28922105 TI - Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families. AB - Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations in EXT1 and EXT2 genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA in EXT1 and EXT2 genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2-10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, different EXT1 gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found in EXT2 gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurred de novo in probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities. PMID- 28922106 TI - IgG4-related Disease - A Patient with Multiple Organ Involvement. AB - IgG4-related diseases represent a heterogeneous group of conditions characterised by elevated serum IgG4 levels and fibrotic or sclerosing changes in the affected organs or systems accompanied by IgG4-positive plasma cells. A disease associated with IgG4 may affect virtually any organ - salivary glands, periorbital tissue, kidneys, lungs, meninges, aorta, prostate, pericardium or skin. Histopathological findings are uniform, characterised by a major lymphoplasmocytic infiltrate and the presence of IgG4-producing plasma cells, irrespective of the affected site. It can be difficult to establish a correct diagnosis due to the lack of clinical symptoms. Treatment with immunosuppressive drugs provides good results and requires interdisciplinary cooperation. PMID- 28922107 TI - Colonic Perforation: A Medical Complication. AB - Hypothyroidism is a common comorbidity that on acute presentation is often overlooked. It can be an easily managed condition; however non-compliance can have severe consequences. In the presented case it was requirement for emergency surgery that resulted in stoma formation. This case is a first example of the need to include patient's decision making process with regards to medication adherence in the setting of chronic disease. PMID- 28922108 TI - Meropenem-induced Valproic Acid Elimination: A Case Report of Clinically Relevant Drug Interaction. AB - We present two case reports of drug interaction between valproic acid and meropenem. In comparison with expected population-kinetic based serum levels, we observed 90.8 and 93.5% decrease in valproic acid serum levels during concomitant administration with meropenem. If carbapenems need to be administered to valproic acid treated patient, other anticonvulsant addition seems to be the appropriate as most probably the valproic acid dose escalation would not be sufficient to achieve therapeutic serum concentration. PMID- 28922110 TI - An Automated System for the Detection and Classification of Retinal Changes Due to Red Lesions in Longitudinal Fundus Images. AB - People with diabetes mellitus need annual screening to check for the development of diabetic retinopathy (DR). Tracking small retinal changes due to early diabetic retinopathy lesions in longitudinal fundus image sets is challenging due to intra- and intervisit variability in illumination and image quality, the required high registration accuracy, and the subtle appearance of retinal lesions compared to other retinal features. This paper presents a robust and flexible approach for automated detection of longitudinal retinal changes due to small red lesions by exploiting normalized fundus images that significantly reduce illumination variations and improve the contrast of small retinal features. To detect spatio-temporal retinal changes, the absolute difference between the extremes of the multiscale blobness responses of fundus images from two time points is proposed as a simple and effective blobness measure. DR related changes are then identified based on several intensity and shape features by a support vector machine classifier. The proposed approach was evaluated in the context of a regular diabetic retinopathy screening program involving subjects ranging from healthy (no retinal lesion) to moderate (with clinically relevant retinal lesions) DR levels. Evaluation shows that the system is able to detect retinal changes due to small red lesions with a sensitivity of at an average false positive rate of 1 and 2.5 lesions per eye on small and large fields-of-view of the retina, respectively. PMID- 28922109 TI - Protein-mediated RNA folding governs sequence-specific interactions between rotavirus genome segments. AB - Segmented RNA viruses are ubiquitous pathogens, which include influenza viruses and rotaviruses. A major challenge in understanding their assembly is the combinatorial problem of a non-random selection of a full genomic set of distinct RNAs. This process involves complex RNA-RNA and protein-RNA interactions, which are often obscured by non-specific binding at concentrations approaching in vivo assembly conditions. Here, we present direct experimental evidence of sequence specific inter-segment interactions between rotavirus RNAs, taking place in a complex RNA- and protein-rich milieu. We show that binding of the rotavirus encoded non-structural protein NSP2 to viral ssRNAs results in the remodeling of RNA, which is conducive to formation of stable inter-segment contacts. To identify the sites of these interactions, we have developed an RNA-RNA SELEX approach for mapping the sequences involved in inter-segment base-pairing. Our findings elucidate the molecular basis underlying inter-segment interactions in rotaviruses, paving the way for delineating similar RNA-RNA interactions that govern assembly of other segmented RNA viruses. PMID- 28922111 TI - Optimization of the Working Conditions for Magnetic Nanoparticle-Enhanced Microwave Diagnostics of Breast Cancer. AB - Magnetic nanoparticle-aided microwave imaging is recently gaining an increasing interest as a potential tool for breast cancer diagnostics. This is due to the peculiar features of magnetic nanoparticles, which are biocompatible, can be selectively targeted to the tumor, and may change their microwave magnetic response when modulated by a polarizing magnetic field. This latter aspect is particularly appealing, as it enables the physical separation of the microwave signal due the malignancy, targeted by the nanoparticles, from that due to healthy tissue. This increases the specificity of the diagnostic tool, in principle allowing a diagnosis based solely on the detection of the signal due to the nanoparticles response. In this respect, a proper choice of the polarizing field modulation can remarkably increase the detection performances. This paper deals with this issue, by providing the mathematical framework for such an optimization and a procedure for estimating the required quantities from a set of proper measurements. The procedure is then experimentally demonstrated by applying it to a recently developed ultrawideband radar system for the magnetic nanoparticle-aided detection of breast cancer. For such a system, the optimal magnetic field modulation is determined. PMID- 28922112 TI - Effects of Flexible Dry Electrode Design on Electrodermal Activity Stimulus Response Detection. AB - OBJECTIVE: The focus of this research is to evaluate the effects of design parameters including surface area, distance between and geometry of dry flexible electrodes on electrodermal activity (EDA) stimulus response detection. METHODS: EDA is a result of the autonomic nervous system being stimulated, which causes sweat and changes the electrical characteristics of the skin. Standard silver/silver chloride (Ag/AgCl) EDA electrodes are rigid and lack conformability in contact with skin. In this study, flexible dry Ag/AgCl EDA electrodes were fabricated on a compliant substrate, used to monitor EDA stimulus responses and compared to results simultaneously collected by rigid dry Ag/AgCl electrodes. RESULTS: A repeatable fabrication process for flexible Ag/AgCl electrodes has been established. Surface area, distance between and geometry of electrodes are shown to affect the detectability of the EDA response and the minimum number of sweat glands to be covered by the electrodes has been estimated at 140, or more, in order to maintain functionality. The optimal flexible EDA electrode is a serpentine design with a 0.15 cm2 surface area and a 0.20 cm distance with an average Pearson correlation coefficient of . CONCLUSION: Fabrication of flexible electrodes is described and an understanding of the effects of electrode designs on the EDA stimulus response detection has been established and is potentially related to the coverage of sweat glands. SIGNIFICANCE: This work presents a novel systematic approach to understand the effects of electrode designs on monitoring EDA which is of importance for the design of wearable EDA monitoring devices. PMID- 28922113 TI - Force-Based Representation for Non-Rigid Shape and Elastic Model Estimation. AB - This paper addresses the problem of simultaneously recovering 3D shape, pose and the elastic model of a deformable object from only 2D point tracks in a monocular video. This is a severely under-constrained problem that has been typically addressed by enforcing the shape or the point trajectories to lie on low-rank dimensional spaces. We show that formulating the problem in terms of a low-rank force space that induces the deformation and introducing the elastic model as an additional unknown, allows for a better physical interpretation of the resulting priors and a more accurate representation of the actual object's behavior. In order to simultaneously estimate force, pose, and the elastic model of the object we use an expectation maximization strategy, where each of these parameters are successively learned by partial M-steps. Once the elastic model is learned, it can be transfered to similar objects to code its 3D deformation. Moreover, our approach can robustly deal with missing data, and encode both rigid and non-rigid points under the same formalism. We thoroughly validate the approach on Mocap and real sequences, showing more accurate 3D reconstructions than state-of-the-art, and additionally providing an estimate of the full elastic model with no a priori information. PMID- 28922114 TI - Cross-Modal Scene Networks. AB - People can recognize scenes across many different modalities beyond natural images. In this paper, we investigate how to learn cross-modal scene representations that transfer across modalities. To study this problem, we introduce a new cross-modal scene dataset. While convolutional neural networks can categorize scenes well, they also learn an intermediate representation not aligned across modalities, which is undesirable for cross-modal transfer applications. We present methods to regularize cross-modal convolutional neural networks so that they have a shared representation that is agnostic of the modality. Our experiments suggest that our scene representation can help transfer representations across modalities for retrieval. Moreover, our visualizations suggest that units emerge in the shared representation that tend to activate on consistent concepts independently of the modality. PMID- 28922115 TI - Colour Constancy Beyond the Classical Receptive Field. AB - The problem of removing illuminant variations to preserve the colours of objects (colour constancy) has already been solved by the human brain using mechanisms that rely largely on centre-surround computations of local contrast. In this paper we adopt some of these biological solutions described by long known physiological findings into a simple, fully automatic, functional model (termed Adaptive Surround Modulation or ASM). In ASM, the size of a visual neuron's receptive field (RF) as well as the relationship with its surround varies according to the local contrast within the stimulus, which in turn determines the nature of the centre-surround normalisation of cortical neurons higher up in the processing chain. We modelled colour constancy by means of two overlapping asymmetric Gaussian kernels whose sizes are adapted based on the contrast of the surround pixels, resembling the change of RF size. We simulated the contrast dependent surround modulation by weighting the contribution of each Gaussian according to the centre-surround contrast. In the end, we obtained an estimation of the illuminant from the set of the most activated RFs' outputs. Our results on three single-illuminant and one multi-illuminant benchmark datasets show that ASM is highly competitive against the state-of-the-art and it even outperforms learning-based algorithms in one case. Moreover, the robustness of our model is more tangible if we consider that our results were obtained using the same parameters for all datasets, that is, mimicking how the human visual system operates. These results suggest a dynamical adaptation mechanisms contribute to achieving higher accuracy in computational colour constancy. PMID- 28922116 TI - Iterative Low-Dose CT Reconstruction With Priors Trained by Artificial Neural Network. AB - Dose reduction in computed tomography (CT) is essential for decreasing radiation risk in clinical applications. Iterative reconstruction algorithms are one of the most promising way to compensate for the increased noise due to reduction of photon flux. Most iterative reconstruction algorithms incorporate manually designed prior functions of the reconstructed image to suppress noises while maintaining structures of the image. These priors basically rely on smoothness constraints and cannot exploit more complex features of the image. The recent development of artificial neural networks and machine learning enabled learning of more complex features of image, which has the potential to improve reconstruction quality. In this letter, K-sparse auto encoder was used for unsupervised feature learning. A manifold was learned from normal-dose images and the distance between the reconstructed image and the manifold was minimized along with data fidelity during reconstruction. Experiments on 2016 Low-dose CT Grand Challenge were used for the method verification, and results demonstrated the noise reduction and detail preservation abilities of the proposed method. PMID- 28922118 TI - A Fast Gradient Method for Nonnegative Sparse Regression With Self-Dictionary. AB - A nonnegative matrix factorization (NMF) can be computed efficiently under the separability assumption, which asserts that all the columns of the given input data matrix belong to the cone generated by a (small) subset of them. The provably most robust methods to identify these conic basis columns are based on nonnegative sparse regression and self-dictionaries, and require the solution of large-scale convex optimization problems. In this paper, we study a particular nonnegative sparse regression model with self-dictionary. As opposed to previously proposed models, this model yields a smooth optimization problem, where the sparsity is enforced through linear constraints. We show that the Euclidean projection on the polyhedron defined by these constraints can be computed efficiently, and propose a fast gradient method to solve our model. We compare our algorithm with several state-of-the-art methods on synthetic data sets and real-world hyperspectral images.A nonnegative matrix factorization (NMF) can be computed efficiently under the separability assumption, which asserts that all the columns of the given input data matrix belong to the cone generated by a (small) subset of them. The provably most robust methods to identify these conic basis columns are based on nonnegative sparse regression and self-dictionaries, and require the solution of large-scale convex optimization problems. In this paper, we study a particular nonnegative sparse regression model with self dictionary. As opposed to previously proposed models, this model yields a smooth optimization problem, where the sparsity is enforced through linear constraints. We show that the Euclidean projection on the polyhedron defined by these constraints can be computed efficiently, and propose a fast gradient method to solve our model. We compare our algorithm with several state-of-the-art methods on synthetic data sets and real-world hyperspectral images. PMID- 28922119 TI - PURE-LET Image Deconvolution. AB - We propose a non-iterative image deconvolution algorithm for data corrupted by Poisson or mixed Poisson-Gaussian noise. Many applications involve such a problem, ranging from astronomical to biological imaging. We parameterize the deconvolution process as a linear combination of elementary functions, termed as linear expansion of thresholds. This parameterization is then optimized by minimizing a robust estimate of the true mean squared error, the Poisson unbiased risk estimate. Each elementary function consists of a Wiener filtering followed by a pointwise thresholding of undecimated Haar wavelet coefficients. In contrast to existing approaches, the proposed algorithm merely amounts to solving a linear system of equations, which has a fast and exact solution. Simulation experiments over different types of convolution kernels and various noise levels indicate that the proposed method outperforms the state-of-the-art techniques, in terms of both restoration quality and computational complexity. Finally, we present some results on real confocal fluorescence microscopy images and demonstrate the potential applicability of the proposed method for improving the quality of these images.We propose a non-iterative image deconvolution algorithm for data corrupted by Poisson or mixed Poisson-Gaussian noise. Many applications involve such a problem, ranging from astronomical to biological imaging. We parameterize the deconvolution process as a linear combination of elementary functions, termed as linear expansion of thresholds. This parameterization is then optimized by minimizing a robust estimate of the true mean squared error, the Poisson unbiased risk estimate. Each elementary function consists of a Wiener filtering followed by a pointwise thresholding of undecimated Haar wavelet coefficients. In contrast to existing approaches, the proposed algorithm merely amounts to solving a linear system of equations, which has a fast and exact solution. Simulation experiments over different types of convolution kernels and various noise levels indicate that the proposed method outperforms the state-of-the-art techniques, in terms of both restoration quality and computational complexity. Finally, we present some results on real confocal fluorescence microscopy images and demonstrate the potential applicability of the proposed method for improving the quality of these images. PMID- 28922120 TI - Motion Estimation in Echocardiography Using Sparse Representation and Dictionary Learning. AB - This paper introduces a new method for cardiac motion estimation in 2-D ultrasound images. The motion estimation problem is formulated as an energy minimization, whose data fidelity term is built using the assumption that the images are corrupted by multiplicative Rayleigh noise. In addition to a classical spatial smoothness constraint, the proposed method exploits the sparse properties of the cardiac motion to regularize the solution via an appropriate dictionary learning step. The proposed method is evaluated on one data set with available ground-truth, including four sequences of highly realistic simulations. The approach is also validated on both healthy and pathological sequences of in vivo data. We evaluate the method in terms of motion estimation accuracy and strain errors and compare the performance with state-of-the-art algorithms. The results show that the proposed method gives competitive results for the considered data. Furthermore, the in vivo strain analysis demonstrates that meaningful clinical interpretation can be obtained from the estimated motion vectors.This paper introduces a new method for cardiac motion estimation in 2-D ultrasound images. The motion estimation problem is formulated as an energy minimization, whose data fidelity term is built using the assumption that the images are corrupted by multiplicative Rayleigh noise. In addition to a classical spatial smoothness constraint, the proposed method exploits the sparse properties of the cardiac motion to regularize the solution via an appropriate dictionary learning step. The proposed method is evaluated on one data set with available ground-truth, including four sequences of highly realistic simulations. The approach is also validated on both healthy and pathological sequences of in vivo data. We evaluate the method in terms of motion estimation accuracy and strain errors and compare the performance with state-of-the-art algorithms. The results show that the proposed method gives competitive results for the considered data. Furthermore, the in vivo strain analysis demonstrates that meaningful clinical interpretation can be obtained from the estimated motion vectors. PMID- 28922117 TI - Magnetic Resonance Mediated Radiofrequency Ablation. AB - To introduce magnetic resonance mediated radiofrequency ablation (MR-RFA), in which the MRI scanner uniquely serves both diagnostic and therapeutic roles. In MR-RFA scanner-induced RF heating is channeled to the ablation site via a Larmor frequency RF pickup device and needle system, and controlled via the pulse sequence. MR-RFA was evaluated with simulation of electric and magnetic fields to predict the increase in local specific-absorption-rate (SAR). Temperature-time profiles were measured for different configurations of the device in agar phantoms and ex vivo bovine liver in a 1.5 T scanner. Temperature rise in MR-RFA was imaged using the proton resonance frequency method validated with fiber-optic thermometry. MR-RFA was performed on the livers of two healthy live pigs. Simulations indicated a near tenfold increase in SAR at the RFA needle tip. Temperature-time profiles depended significantly on the physical parameters of the device although both configurations tested yielded temperature increases sufficient for ablation. Resected livers from live ablations exhibited clear thermal lesions. MR-RFA holds potential for integrating RF ablation tumor therapy with MRI scanning. MR-RFA may add value to MRI with the addition of a potentially disposable ablation device, while retaining MRI's ability to provide real time procedure guidance and measurement of tissue temperature, perfusion, and coagulation. PMID- 28922121 TI - Motion Blur Kernel Estimation via Deep Learning. AB - The success of the state-of-the-art deblurring methods mainly depends on the restoration of sharp edges in a coarse-to-fine kernel estimation process. In this paper, we propose to learn a deep convolutional neural network for extracting sharp edges from blurred images. Motivated by the success of the existing filtering-based deblurring methods, the proposed model consists of two stages: suppressing extraneous details and enhancing sharp edges. We show that the two stage model simplifies the learning process and effectively restores sharp edges. Facilitated by the learned sharp edges, the proposed deblurring algorithm does not require any coarse-to-fine strategy or edge selection, thereby significantly simplifying kernel estimation and reducing computation load. Extensive experimental results on challenging blurry images demonstrate that the proposed algorithm performs favorably against the state-of-the-art methods on both synthetic and real-world images in terms of visual quality and run-time. PMID- 28922122 TI - Semi-Automatic Generation of Stream Surfaces via Sketching. AB - We present a semi-automatic approach for stream surface generation. Our approach is based on the conjecture that good seeding curves can be inferred from a set of streamlines. Given a set of densely traced streamlines over the flow field, we design a sketch-based interface that allows users to describe their perceived flow patterns through drawing simple strokes directly on top of the streamline visualization results. Based on the 2D stroke, we identify a 3D seeding curve and generate a stream surface that captures the flow pattern of streamlines at the outermost layer. Then, we remove the streamlines whose patterns are covered by the stream surface. Repeating this process, users can peel the flow by replacing the streamlines with customized surfaces layer by layer. Furthermore, we propose an optimization scheme to identify the optimal seeding curve in the neighborhood of an original seeding curve based on surface quality measures. To support interactive optimization, we design a parallel surface quality estimation strategy that estimates the quality of a seeding curve without generating the surface. Our sketch-based interface leverages an intuitive painting metaphor which most users are familiar with. We present results using multiple data sets to show the effectiveness of our approach. PMID- 28922123 TI - A Data-Driven Approach for Furniture and Indoor Scene Colorization. AB - We present a data-driven approach that colorizes 3D furniture models and indoor scenes by leveraging indoor images on the internet. Our approach is able to colorize the furniture automatically according to an example image. The core is to learn image-guided mesh segmentation to segment the model into different parts according to the image object. Given an indoor scene, the system supports colorization-by-example, and has the ability to recommend the colorization scheme that is consistent with a user-desired color theme. The latter is realized by formulating the problem as a Markov random field model that imposes user input as an additional constraint. Our system is able to imitate the colorization results for those scenes containing the same type of objects, but with spatially varied patterns. We contribute to the community a hierarchically organized image-model database with correspondences between each image and the corresponding model at the part-level. Our experiments and a user study show that our system produces perceptually convincing results comparable to those generated by interior designers. PMID- 28922124 TI - Improving the Capacity of Molecular Communication Using Enzymatic Reaction Cycles. AB - This paper considers the capacity of a diffusion-based molecular communication link assuming the receiver uses chemical reactions. The key contribution is we show that enzymatic reaction cycles, which is a class of chemical reactions commonly found in cells consisting of a forward and a backward enzymatic reaction, can improve the capacity of the communication link. The technical difficulty in analyzing enzymatic reaction cycles is that their reaction rates are nonlinear. We deal with this by assuming that the amount of certain chemicals in the enzymatic reaction cycle is large. In order to simplify the problem further, we use singular perturbation to study a particular operating regime of the enzymatic reaction cycles. This allows us to derive a closed-form expression of the channel gain. This expression suggests that we can improve the channel gain by increasing the total amount of substrate in the enzymatic reaction cycle. By using numerical calculations, we show that the effect of the enzymatic reaction cycle is to increase the channel gain and to reduce the noise, which results in a better signal-to-noise ratio and in turn a higher communication capacity. Furthermore, we show that we can increase the capacity by increasing the total amount of substrate in the enzymatic reaction cycle. PMID- 28922125 TI - Efficiency Enhancement for an Inductive Wireless Power Transfer System by Optimizing the Impedance Matching Networks. AB - Inductive wireless power transfer (IWPT) is a promising power technology for implantable biomedical devices, where the power consumption is low and the efficiency is the most important consideration. In this paper, we propose an optimization method of impedance matching networks (IMN) to maximize the IWPT efficiency. The IMN at the load side is designed to achieve the optimal load, and the IMN at the source side is designed to deliver the required amount of power (no-more-no-less) from the power source to the load. The theoretical analyses and design procedure are given. An IWPT system for an implantable glaucoma therapeutic prototype is designed as an example. Compared with the efficiency of the resonant IWPT system, the efficiency of our optimized system increases with a factor of 1.73. Besides, the efficiency of our optimized IWPT system is 1.97 times higher than that of the IWPT system optimized by the traditional maximum power transfer method. All the discussions indicate that the optimization method proposed in this paper could achieve a high efficiency and long working time when the system is powered by a battery. PMID- 28922126 TI - Functional Contour-following via Haptic Perception and Reinforcement Learning. AB - Many tasks involve the fine manipulation of objects despite limited visual feedback. In such scenarios, tactile and proprioceptive feedback can be leveraged for task completion. We present an approach for real-time haptic perception and decision-making for a haptics-driven, functional contour-following task: the closure of a ziplock bag. This task is challenging for robots because the bag is deformable, transparent, and visually occluded by artificial fingertip sensors that are also compliant. A deep neural net classifier was trained to estimate the state of a zipper within a robot's pinch grasp. A Contextual Multi-Armed Bandit (C-MAB) reinforcement learning algorithm was implemented to maximize cumulative rewards by balancing exploration versus exploitation of the state-action space. The C-MAB learner outperformed a benchmark Q-learner by more efficiently exploring the state-action space while learning a hard-to-code task. The learned C-MAB policy was tested with novel ziplock bag scenarios and contours (wire, rope). Importantly, this work contributes to the development of reinforcement learning approaches that account for limited resources such as hardware life and researcher time. As robots are used to perform complex, physically interactive tasks in unstructured or unmodeled environments, it becomes important to develop methods that enable efficient and effective learning with physical testbeds. PMID- 28922127 TI - Jointly Learning Structured Analysis Discriminative Dictionary and Analysis Multiclass Classifier. AB - In this paper, we propose an analysis mechanism-based structured analysis discriminative dictionary learning analysis discriminative dictionary learning, framework. The ADDL seamlessly integrates ADDL, analysis representation, and analysis classifier training into a unified model. The applied analysis mechanism can make sure that the learned dictionaries, representations, and linear classifiers over different classes are independent and discriminating as much as possible. The dictionary is obtained by minimizing a reconstruction error and an analytical incoherence promoting term that encourages the subdictionaries associated with different classes to be independent. To obtain the representation coefficients, ADDL imposes a sparse -norm constraint on the coding coefficients instead of using or norm, since the - or -norm constraint applied in most existing DL criteria makes the training phase time consuming. The code-extraction projection that bridges data with the sparse codes by extracting special features from the given samples is calculated via minimizing a sparse code approximation term. Then we compute a linear classifier based on the approximated sparse codes by an analysis mechanism to simultaneously consider the classification and representation powers. Thus, the classification approach of our model is very efficient, because it can avoid the extra time-consuming sparse reconstruction process with trained dictionary for each new test data as most existing DL algorithms. Simulations on real image databases demonstrate that our ADDL model can obtain superior performance over other state of the arts. PMID- 28922128 TI - Deep Manifold Learning Combined With Convolutional Neural Networks for Action Recognition. AB - Learning deep representations have been applied in action recognition widely. However, there have been a few investigations on how to utilize the structural manifold information among different action videos to enhance the recognition accuracy and efficiency. In this paper, we propose to incorporate the manifold of training samples into deep learning, which is defined as deep manifold learning (DML). The proposed DML framework can be adapted to most existing deep networks to learn more discriminative features for action recognition. When applied to a convolutional neural network, DML embeds the previous convolutional layer's manifold into the next convolutional layer; thus, the discriminative capacity of the next layer can be promoted. We also apply the DML on a restricted Boltzmann machine, which can alleviate the overfitting problem. Experimental results on four standard action databases (i.e., UCF101, HMDB51, KTH, and UCF sports) show that the proposed method outperforms the state-of-the-art methods. PMID- 28922129 TI - Dissipativity and Synchronization of Generalized BAM Neural Networks With Multivariate Discontinuous Activations. AB - This paper is concerned with the dissipativity and synchronization problems of a class of delayed bidirectional associative memory (BAM) neural networks in which neuron activations are modeled by discontinuous bivariate functions. First, the concept of the Filippov solution is extended to functional differential equations with discontinuous right-hand sides and mixed delays via functional differential inclusions. The global dissipativity of the Filippov solution to the considered BAM neural networks is proven using generalized Halanay inequalities and matrix measure approaches. Second, to realize global exponential complete synchronization of BAM neural networks with multivariate discontinuous activations, discontinuous state feedback controllers are designed using functional differential inclusions theory and nonsmooth analysis theory with generalized Lyapunov functional method. Finally, several numerical examples are provided to demonstrate the applicability and effectiveness of our proposed results. PMID- 28922130 TI - Haze Removal Using Radial Basis Function Networks for Visibility Restoration Applications. AB - Restoration of visibility in hazy images is the first relevant step of information analysis in many outdoor computer vision applications. To this aim, the restored image must feature clear visibility with sufficient brightness and visible edges, while avoiding the production of noticeable artifacts. In this paper, we propose a haze removal approach based on the radial basis function (RBF) through artificial neural networks dedicated to effectively removing haze formation while retaining not only the visible edges but also the brightness of restored images. Unlike traditional haze-removal methods that consist of single atmospheric veils, the multiatmospheric veil is generated and then dynamically learned by the neurons of the proposed RBF networks according to the scene complexity. Through this process, more visible edges are retained in the restored images. Subsequently, the activation function during the testing process is employed to represent the brightness of the restored image. We compare the proposed method with the other state-of-the-art haze-removal methods and report experimental results in terms of qualitative and quantitative evaluations for benchmark color images captured in typical hazy weather conditions. The experimental results demonstrate that the proposed method is able to produce brighter and more vivid haze-free images with more visible edges than can the other state-of-the-art methods. PMID- 28922131 TI - Riemann Liouvelle Fractional Integral Based Empirical Mode Decomposition for ECG Denoising. AB - Electrocardiograph (ECG) denoising is the most important step in diagnosis of heart-related diseases, as the diagnosis gets influenced with noises. In this paper, a new method for ECG denoising is proposed, which incorporates empirical mode decomposition algorithm with Riegmann Liouvelle (RL) fractional integral filtering and Savitzky-Golay (SG) filtering. In the proposed method, noisy ECG signal is decomposed into its intrinsic mode functions (IMFs), from which noisy IMFs, corrupted with high-frequency (HF) and low-frequency (LF) noises, are identified by proposed noisy-IMFs identification methodologies. To denoise the signal, RL fractional integral filtering and SG filtering are applied on noisy IMFs corrupted with HF and LF noises, respectively; ECG signal is reconstructed with denoised IMFs and remaining signal dominant IMFs to obtain noise-free ECG signal. Proposed methodology is tested with MIT-BIH arrhythmia database. Its performance, in terms of signal-to-noise ratio and mean square error, is compared with other related ECG denoising methods based on fractional integral, empirical mode decomposition, and ensemble empirical mode decomposition. The obtained results by proposed method prove that the proposed method gives efficient noise removal performance. PMID- 28922132 TI - Design of Secure and Lightweight Authentication Protocol for Wearable Devices Environment. AB - Wearable devices are used in various applications to collect information including step information, sleeping cycles, workout statistics, and health related information. Due to the nature and richness of the data collected by such devices, it is important to ensure the security of the collected data. This paper presents a new lightweight authentication scheme suitable for wearable device deployment. The scheme allows a user to mutually authenticate his/her wearable device(s) and the mobile terminal (e.g., Android and iOS device) and establish a session key among these devices (worn and carried by the same user) for secure communication between the wearable device and the mobile terminal. The security of the proposed scheme is then demonstrated through the broadly accepted real-or random model, as well as using the popular formal security verification tool, known as the Automated validation of Internet security protocols and applications. Finally, we present a comparative summary of the proposed scheme in terms of the overheads such as computation and communication costs, security and functionality features of the proposed scheme and related schemes, and also the evaluation findings from the NS2 simulation. PMID- 28922133 TI - Aligning Event Logs to Task-Time Matrix Clinical Pathways in BPMN for Variance Analysis. AB - Clinical pathways (CPs) are popular healthcare management tools to standardize care and ensure quality. Analyzing CP compliance levels and variances is known to be useful for training and CP redesign purposes. Flexible semantics of the business process model and notation (BPMN) language has been shown to be useful for the modeling and analysis of complex protocols. However, in practical cases one may want to exploit that CPs often have the form of task-time matrices. This paper presents a new method parsing complex BPMN models and aligning traces to the models heuristically. A case study on variance analysis is undertaken, where a CP from the practice and two large sets of patients data from an electronic medical record (EMR) database are used. The results demonstrate that automated variance analysis between BPMN task-time models and real-life EMR data are feasible, whereas that was not the case for the existing analysis techniques. We also provide meaningful insights for further improvement. PMID- 28922134 TI - Training-Based Gradient LBP Feature Models for Multiresolution Texture Classification. AB - Local binary pattern (LBP) is a simple, yet efficient coding model for extracting texture features. To improve texture classification, this paper designs a median sampling regulation, defines a group of gradient LBP (gLBP) descriptors, proposes a training-based feature model mapping method, and then develops a texture classification frame using the multiresolution feature fusion of four gLBP descriptors. Cooperated by median sampling, four descriptors encode a pixel respectively by central gradient, radial gradient, magnitude gradient and tangent gradient to generate initial gLBP patterns. The feature mapping models of gLBP descriptors are constructed by the maximal relative-variation rate (mr2) of rotation-invariant patterns, and then prestored as mapping lookup files. By mapping, initial patterns can be transformed into low-dimensional ones. And then it generates multiresolution texture features via the joint and concatenation of gLBP descriptors on different sampling parameters. A trained nearest neighbor classifier with chi-square distance is applied to classify textures by feature histograms. The experimental results of simulation on five public texture databases show that the proposed method is reliable and efficient in texture classification. In comparison with nine other similar approaches, including two state-of-the-art ones, the proposed method runs faster than most of them and also outperforms all of them in terms of classification accuracy and noise robustness. It achieves higher accuracy and has also better robustness to the Salt&Pepper and Gaussian noise added artificially into texture images. PMID- 28922135 TI - Learning From Short Text Streams With Topic Drifts. AB - Short text streams such as search snippets and micro blogs have been popular on the Web with the emergence of social media. Unlike traditional normal text streams, these data present the characteristics of short length, weak signal, high volume, high velocity, topic drift, etc. Short text stream classification is hence a very challenging and significant task. However, this challenge has received little attention from the research community. Therefore, a new feature extension approach is proposed for short text stream classification with the help of a large-scale semantic network obtained from a Web corpus. It is built on an incremental ensemble classification model for efficiency. First, more semantic contexts based on the senses of terms in short texts are introduced to make up of the data sparsity using the open semantic network, in which all terms are disambiguated by their semantics to reduce the noise impact. Second, a concept cluster-based topic drifting detection method is proposed to effectively track hidden topic drifts. Finally, extensive studies demonstrate that as compared to several well-known concept drifting detection methods in data stream, our approach can detect topic drifts effectively, and it enables handling short text streams effectively while maintaining the efficiency as compared to several state of-the-art short text classification approaches. PMID- 28922136 TI - Reaching Non-Negative Edge Consensus of Networked Dynamical Systems. AB - In this paper, the problem of non-negative edge consensus of undirected networked linear time-invariant systems is addressed by associating each edge of the network with a state variable, for which a distributed algorithm is constructed. Sufficient conditions referring only to the number of edges are derived for non negative edge consensus of the networked systems. Subsequently, the linear programming method and a low-gain feedback technique are introduced to simplify the design of the feedback gain matrix for achieving the non-negative edge consensus. It is found that the low-gain feedback technique has a good effect on the non-negative edge consensus of the networked systems subject to input saturation. Numerical simulations are presented to verify the effectiveness of the theoretical results. PMID- 28922137 TI - Finite-Time Synchronization of Networks via Quantized Intermittent Pinning Control. AB - This technical correspondence considers finite-time synchronization of dynamical networks by designing aperiodically intermittent pinning controllers with logarithmic quantization. The control scheme can greatly reduce control cost and save both communication channels and bandwidth. By using multiple Lyapunov functions and convex combination techniques, sufficient conditions formulated by a set of linear matrix inequalities are derived to guarantee that all the node systems are synchronized with an isolated trajectory in a finite settling time. Compared with existing results, the main characteristics of this paper are twofold: 1) quantized controller is used for finite-time synchronization and 2) the designed multiple Lyapunov functions are strictly decreasing. An optimal algorithm is proposed for the estimation of settling time. Numerical simulations are provided to demonstrate the effectiveness of the theoretical analysis. PMID- 28922138 TI - Finite-Time Adaptive Control for a Class of Nonlinear Systems With Nonstrict Feedback Structure. AB - This paper focuses on finite-time adaptive neural tracking control for nonlinear systems in nonstrict feedback form. A semiglobal finite-time practical stability criterion is first proposed. Correspondingly, the finite-time adaptive neural control strategy is given by using this criterion. Unlike the existing results on adaptive neural/fuzzy control, the proposed adaptive neural controller guarantees that the tracking error converges to a sufficiently small domain around the origin in finite time, and other closed-loop signals are bounded. At last, two examples are used to test the validity of our results. PMID- 28922139 TI - 3D printed multiplexed electrospinning sources for large-scale production of aligned nanofiber mats with small diameter spread. AB - We report the design, fabrication, and characterization of novel, low-cost, and modular miniaturized nanofiber electrospinning sources for the scalable production of non-woven aligned nanofiber mats with low diameter variation. The devices are monolithic arrays of electrospinning emitters made via stereolithography; the emitters are arranged so each element has an independent line of sight to a rotating collector surface. Linear and zigzag emitter packing were evaluated using a PEO solution with the aim of maximizing the throughput of nanofibers with the smallest diameter and narrowest distribution. Current versus flowrate characterization of the devices showed that for a given flowrate a zigzag array produces more current per emitter than a linear array of the same emitter pitch and array size. In addition, the data demonstrate that larger and denser arrays have a net gain in flow rate per unit of active length. Visual inspection of the devices suggests uniform operation in devices with as many as 17 emitters with 300 MUm inner diameter and 1.5 mm emitter gap. Well-aligned nanofiber mats were collected on a rotating drum and characterized; the 17 emitter device produced the same narrow nanofiber distribution (~81 nm average diameter, ~17 nm standard deviation) for all tested flow rates, which is strikingly different to the performance shown by 1-emitter sources where the average fiber diameter significantly increased and the statistics notably widened when the flowrate increases. Therefore, the data demonstrate that massively multiplexing the emitters is a viable approach to greatly increase the throughput of non-woven aligned nanofiber mats without sacrificing the statistics of the nanofibers generated. The production of dry nanofibers by the 17-emitter array is estimated at 33.0 mg min-1 (1.38 mg min-1 per mm of active length), which compares favorably with the reported multiplexed electrospinning arrays with emitters distributed along a line. PMID- 28922140 TI - A point kernel algorithm for microbeam radiation therapy. AB - Microbeam radiation therapy (MRT) is a treatment approach in radiation therapy where the treatment field is spatially fractionated into arrays of a few tens of micrometre wide planar beams of unusually high peak doses separated by low dose regions of several hundred micrometre width. In preclinical studies, this treatment approach has proven to spare normal tissue more effectively than conventional radiation therapy, while being equally efficient in tumour control. So far dose calculations in MRT, a prerequisite for future clinical applications are based on Monte Carlo simulations. However, they are computationally expensive, since scoring volumes have to be small. In this article a kernel based dose calculation algorithm is presented that splits the calculation into photon and electron mediated energy transport, and performs the calculation of peak and valley doses in typical MRT treatment fields within a few minutes. Kernels are analytically calculated depending on the energy spectrum and material composition. In various homogeneous materials peak, valley doses and microbeam profiles are calculated and compared to Monte Carlo simulations. For a microbeam exposure of an anthropomorphic head phantom calculated dose values are compared to measurements and Monte Carlo calculations. Except for regions close to material interfaces calculated peak dose values match Monte Carlo results within 4% and valley dose values within 8% deviation. No significant differences are observed between profiles calculated by the kernel algorithm and Monte Carlo simulations. Measurements in the head phantom agree within 4% in the peak and within 10% in the valley region. The presented algorithm is attached to the treatment planning platform VIRTUOS. It was and is used for dose calculations in preclinical and pet-clinical trials at the biomedical beamline ID17 of the European synchrotron radiation facility in Grenoble, France. PMID- 28922142 TI - Reduced amputation rate with isovolemic hemodilution in critical limb ischemia patients. AB - AIMS: Critical limb ischemia (CLI) patients are characterized by intractable pain in spite of medication, non-healing ulcers, and gangrene. The objective of this study was to investigate whether or not isovolemic hemodilution treatment can reduce the rate of major amputations in CLI. METHODS: 28 patients were studied who had tissue loss on Rutherford Grade III, Category 5 or 6. The subjects were divided into two arms: standard-of-care, conventional therapy (CT) (n = 15) as a control group and hemodilution therapy (HT) (n = 13) as a study group. For the HT group, weekly isovolemic hemodilution was performed over 4 consecutive weeks, removing 250 ml of whole blood with the infusion of hydroxyl-ethyl starch solution. Blood viscosity, hematocrit, hemoglobin, ankle-brachial index, VA pain scale, time-to-amputation from admission, and survival time were measured. RESULTS: The mean Hct gradually decreased from 36.6 to 35.1, whereas the WBV at a shear rate of 1 s-1 significantly decreased from 18.2 to 10.5 during the same period. Subsequently, tissue oxygen delivery index, defined as the ratio of Hct to WBV at a shear rate of 1 s-1, increased from 24.4 to 37.0 by 51.7%, suggesting improvements in oxygen delivery in the patients. The average rate of lower limb major amputation in the control group was 93% (14/15), whereas that in the study group was 31% (4/13) (p = 0.001). Amputation-free median survival time and amputation-free 5-year survival rate in the control group were 1.2 months and 7%, while those in the study group were 30.2 months and 44% (p = 0.001). There were no adverse effects from repetitive hemodilution in the study group. CONCLUSIONS: Isovolemic hemodilution treatment of CLI patients was found to be well-tolerated and reduced the rate of major amputation resulting from the deterioration of CLI. PMID- 28922143 TI - Leukocyte-reduced platelet-rich plasma stimulates the in vitro proliferation of adipose-tissue derived mesenchymal stem cells depending on PDGF signaling. AB - BACKGROUND: Platelet-rich Plasma (PRP) is suggested as xenoprotein-free cell culture medium replacement for animal-derived supplements. OBJECTIVE: The aim of this study was to investigate PRP-triggered signaling in adipose derived mesenchymal stem cells (ASCs). METHODS: PRP was obtained from 4 male patients. We incubated ASCs in alpha-MEM with different Platelet derived growth factor (PDGF) subtypes or 10% or 20% pooled PRP or 20% fetal calf serum (FCS) prior to determination of the S-phase fraction (SPF). To investigate the influence of PDGF signaling on ASCs, PDGF receptor beta inhibitor was added, and protein expression of ASCs was measured. RESULTS: ASCs exposed to 20% PRP, PDGF-AB and - BB demonstrated significant higher SPF in comparison to PDGF-AA and 20% FCS after 48 hours (all P < 0.05). PDGF receptor beta inhibition diminished the PRP-induced SPF increase of ASCs significantly after 48 hours (P < 0.01). ASCs with PDGF receptor beta inhibition showed significant higher PDGF receptor beta and significant lower c-MYC expression compared to untreated cells in presence of 20% PRP after 48 hours (both P < 0.05). CONCLUSIONS: The proliferation promoting effect of PRP on ASCs is mediated by PDGF signaling and is associated with c-MYC overexpression. PMID- 28922145 TI - New developments in clinical microcirculation imaging. PMID- 28922144 TI - Short-term hypoxia and vasa recta function in kidney slices. AB - BACKGROUND: Descending vasa recta (DVR) supply the inner part of outer renal medulla an area at risk for hypoxic damages. OBJECTIVE: We hypothesize increased vasoreactivity after hypoxia/re-oxygenation (H/R) in DVR, which might contribute to the reduced medullary perfusion after an ischemic event. METHODS: Live kidney slices (200MUm) from SD rats were used for functional experiments. TUNEL assay and H&E staining were used to estimate slice viability. Kidney slices were treated with carbogen or hypoxia (1% O2) for 60 or 90 min and vasoreactivity to Ang II (10-7 M) was recorded by DIC microscopy after re-oxygenation with carbogen. Expression of NOS and NADPH enzymes mRNA were determined in iron perfusion isolated VR. RESULTS: Percentage of apoptotic cells increased in control and H/R after 90 min in the medulla. Ang II- induced constriction of DVR was reduced after 90 min in control (compared to 60 min), but not after H/R. NOS enzymes mRNA expression levels decreased over 90 min hypoxia. CONCLUSIONS: Increased reactivity of DVR to Ang II after H/R compared to control (90 min) suggest a role of DVR in renal ischemia/reperfusion injury. PMID- 28922146 TI - Preliminary clinical evaluation of automated analysis of the sublingual microcirculation in the assessment of patients with septic shock: Comparison of automated versus semi-automated software. AB - INTRODUCTION: The outcome of patients in septic shock has been shown to be related to changes within the microcirculation. Modern imaging technologies are available to generate high resolution video recordings of the microcirculation in humans. However, evaluation of the microcirculation is not yet implemented in the routine clinical monitoring of critically ill patients. This is mainly due to large amount of time and user interaction required by the current video analysis software. The aim of this study was to validate a newly developed automated method (CCTools(r)) for microcirculatory analysis of sublingual capillary perfusion in septic patients in comparison to standard semi-automated software (AVA3(r)). METHODS: 204 videos from 47 patients were recorded using incident dark field (IDF) imaging. Total vessel density (TVD), proportion of perfused vessels (PPV), perfused vessel density (PVD), microvascular flow index (MFI) and heterogeneity index (HI) were measured using AVA3(r) and CCTools(r). RESULTS: Significant differences between the numeric results obtained by the two different software packages were observed. The values for TVD, PVD and MFI were statistically related though. CONCLUSION: The automated software technique successes to show septic shock induced microcirculation alterations in near real time. However, we found wide degrees of agreement between AVA3(r) and CCTools(r) values due to several technical factors that should be considered in the future studies. PMID- 28922147 TI - Microcirculation research in community hospitals - challenges and chances. AB - Community hospitals provide ideal conditions for large clinical studies because of the high volume of unselected patients admitted every year. With regard to microcirculatory studies, there are still some feasibility problems which are not solved yet. First of all, the lack of reliable automated software to analyze microcirculatory images represents the most important issue. Secondly, hardware aspects still need improvements regarding portability and miniaturization. Finally, to conduct studies of the microcirculation in a community hospital is also always a funding issue. The cost of the measurement device is hereby only one factor. Main cost factor is the personnel. PMID- 28922148 TI - Glycocalyx in vivo measurement. AB - The endothelial glycocalyx (EG) lining the endoluminal surface of the capillaries has been proposed as a key component of the microcirculation and a major player in microvascular pathology. Recent advances in the understanding of its physiological role and clinical significance have been made upon the development of methods allowing EG assessment in clinical medicine. Laboratory methods can assess the amount of EG damage by measuring levels of its degradation products (e.g. syndecan-1, heparan sulphate and hyaluronan sulphate), mostly in the plasma, however, their physiological turnover disqualifies them from being the reliable index of EG damage. At the bedside, in vivo video microscopy tools technologies (e.g. Side-stream Dark Field imaging technology) allow indirect assessment of EG thickness in sublingual microcirculation by measuring the penetration extent (called Perfused Boundary Region) of flowing red blood cells into the EG. PMID- 28922149 TI - The Relationships Between Components of Metabolic Syndrome and Mild Cognitive Impairment Subtypes: A Cross-Sectional Study of Japanese Older Adults. AB - BACKGROUND: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear. OBJECTIVE: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults. METHODS: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components and MCI subtypes were analyzed using multiple logistic regression. RESULTS: MetS prevalence was greater in participants with naMCI (men: p = 0.030; women: p = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13-5.32; women: OR: 1.94, 95% CI: 1.12-3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19-2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25-3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03-1.94) and raised glucose (OR: 1.32, 95% CI: 1.02-1.71) were associated with naMCI. CONCLUSION: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components. PMID- 28922150 TI - Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications. AB - Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/MUmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain. PMID- 28922151 TI - Dickkopf 3 (Dkk3) Improves Amyloid-beta Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer's Disease. AB - Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid beta, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3beta, a central negative regulator in canonical Wnt signaling, and upregulated PKCbeta1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3beta and the inhibition of PKCbeta1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD. PMID- 28922152 TI - Brain Biomarkers in Familial Alzheimer's Disease Mouse Models. AB - Alzheimer's disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer's disease (FAD). These deficits are readily detected in young adults, at 2-3 months of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1H-MRS) signal at 1.28 ppm. Here we examined the use of 1H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice. PMID- 28922154 TI - Atrial Fibrillation is Independently Associated with Cognitive Impairment after Ischemic Stroke. AB - BACKGROUND: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer's disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear. OBJECTIVE: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease. METHODS: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3-6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends. RESULTS: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12-4.75; p = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function. CONCLUSION: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI. PMID- 28922153 TI - Sex-Dependent Associations of Serum Uric Acid with Brain Function During Aging. AB - Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer's disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (beta= 0.006; p = 0.03) and visuospatial abilities (beta= 0.007; p = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women. PMID- 28922155 TI - Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model. AB - The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-beta (Abeta) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Abeta aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Abeta pathology. PMID- 28922156 TI - Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload. AB - An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid beta peptide (Abeta42), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ ions induced by Abeta42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Abeta42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD. PMID- 28922157 TI - Longer-Term Investigation of the Value of 18F-FDG-PET and Magnetic Resonance Imaging for Predicting the Conversion of Mild Cognitive Impairment to Alzheimer's Disease: A Multicenter Study. AB - BACKGROUND: The value of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and magnetic resonance imaging (MRI) for predicting conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD) in longer-term is unclear. OBJECTIVE: To evaluate longer-term prediction of MCI to AD conversion using 18F-FDG-PET and MRI in a multicenter study. METHODS: One hundred and fourteen patients with MCI were followed for 5 years. They underwent clinical and neuropsychological examinations, 18F-FDG-PET, and MRI at baseline. PET images were visually classified into predefined dementia patterns. PET scores were calculated as a semi quantitative index. For structural MRI, z-scores in medial temporal area were calculated by automated volume-based morphometry (VBM). RESULTS: Overall, 72% patients with amnestic MCI progressed to AD during the 5 year follow-up. The diagnostic accuracy of PET scores over 5 years was 60% with 53% sensitivity and 84% specificity. Visual interpretation of PET images predicted conversion to AD with an overall 82% diagnostic accuracy, 94% sensitivity, and 53% specificity. The accuracy of VBM analysis presented little fluctuation through 5 years and it was highest (73%) at the 5-year follow-up, with 79% sensitivity and 63% specificity. The best performance (87.9% diagnostic accuracy, 89.8% sensitivity, and 82.4% specificity) was with a combination identified using multivariate logistic regression analysis that included PET visual interpretation, educational level, and neuropsychological tests as predictors. CONCLUSION: 18F-FDG-PET visual assessment showed high performance for predicting conversion to AD from MCI, particularly in combination with neuropsychological tests. PET scores showed high diagnostic specificity. Structural MRI focused on the medial temporal area showed stable predictive value throughout the 5-year course. PMID- 28922158 TI - Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial. AB - BACKGROUND: Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved. OBJECTIVE: To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals' profile is superior to generic training. METHODS: Older adults with MCI (n = 9), MrNPS (n = 11), or both (MCI+, n = 25) were randomized into a home based individually-tailored and adaptive CCT (n = 21) or an active control condition (AC; n = 23) in a double-blind design. Interventions lasted 8-12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up. RESULTS: Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition. CONCLUSIONS: Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed. PMID- 28922159 TI - Can Musical or Painting Interventions Improve Chronic Pain, Mood, Quality of Life, and Cognition in Patients with Mild Alzheimer's Disease? Evidence from a Randomized Controlled Trial. AB - BACKGROUND: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer's disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. OBJECTIVE: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. METHODS: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n = 31) or painting group (PG; n = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a 'per protocol' approach. RESULTS: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p = 0.01), reduced anxiety (Time effect: F = 10.74; p < 0.0001), improved Quality of Life (Time effect: F = 6.79; p = 0.002), improved digit span (F = 12.93; p = 0.001), and inhibitory processes (Time effect: F = 4.93; p = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p = 0.004). CONCLUSION: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance. PMID- 28922160 TI - Memantine for Alzheimer's Disease: An Updated Systematic Review and Meta analysis. AB - BACKGROUND: The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. OBJECTIVE: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. METHODS: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. RESULTS: Thirty studies (n = 7,567; memantine versus placebo: N = 11, n = 3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: N = 17, n = 4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD) = -0.24, 95% confidence intervals (95% CIs) = -0.34, -0.15, p < 0.00001, I2 = 35% ] and BD (SMD = -0.16, 95% CIs = 0.29, -0.04, p = 0.01, I2 = 52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMD = -0.20, 95% CIs = -0.34, -0.07, p = 0.003, I2 = 36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMD = -0.20, 95% CIs = -0.36, -0.03, p = 0.02, I2 = 77%) and a trend of CF improvement (SMD = -0.11, 95% CIs = -0.22, 0.01, p = 0.06, I2 = 56%). However, in the sensitivity analysis of double-blind, placebo controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMD = -0.11, 95% CIs = -0.21, 0.01, p = 0.04, I2 = 40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMD = -0.18, 95% CIs = -0.31, -0.05, p = 0.006, I2 = 49%). No differences were detected in all-cause discontinuation between the groups. CONCLUSIONS: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs. PMID- 28922162 TI - Sphingolipids in Alzheimer's Disease and Related Disorders. PMID- 28922161 TI - Comorbidity Analysis between Alzheimer's Disease and Type 2 Diabetes Mellitus (T2DM) Based on Shared Pathways and the Role of T2DM Drugs. AB - BACKGROUND: Various studies suggest a comorbid association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. OBJECTIVE: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. METHOD: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources. RESULTS: Using comparative analysis, we have identified several putative "shared pathways". We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD. CONCLUSION: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD. PMID- 28922163 TI - Bilingualism and Cognitive Decline: A Story of Pride and Prejudice. AB - In a recent review, Mukadam, Sommerlad, and Livingston (2017) argue that bilingualism offers no protection against cognitive decline. The authors examined the results of 13 studies (five prospective, eight retrospective) in which monolinguals and bilinguals were compared for cognitive decline and onset of dementia symptoms. Analysis of four of the five prospective studies resulted in the conclusion that there was no difference between monolinguals and bilinguals, whereas seven of the eight retrospective studies actually showed bilingualism to result in a four-to-five year delay of symptom onset. The authors decided to ignore the results from the retrospective studies in favor of those from the prospective studies, reasoning that the former may be confounded by participants' cultural background and education levels. In this commentary, we argue that most of these studies actually controlled for these two variables and still found a positive effect of bilingualism. Furthermore, we argue that the meta-analysis of the prospective studies is not complete, lacking the results of two crucial reports. We conclude that the literature offers substantial evidence for a bilingual effect on the development of cognitive decline and dementia. PMID- 28922164 TI - Analysis of Participant Withdrawal in Huntington Disease Clinical Trials. PMID- 28922165 TI - The gastrointestinal-brain axis in humans as an evolutionary advance of the root leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin. AB - Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with biophotons and use them for proper brain function. Further, as auxin drives the "arborescence" of roots within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastrointestinal tract. This auxin/serotonin parallel suggests the root-branch axis in plants may be an evolutionary precursor to the gastrointestinal-brain axis in humans. Finally, it is hypothesized that light might be an important factor, both in gastrointestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness. PMID- 28922166 TI - Clinical Tremor Severity Estimation Using an Instrumented Eating Utensil. AB - We demonstrate the feasibility of estimating clinical tremor scores using an eating utensil with motion-sensing and tremor-cancellation technology in thirteen patients with tremor. Three experts scored hand tremor using the modified Fahn- Tolosa-Marin (FTM) scale. A linear model was trained to estimate tremor severity using the recorded motion signals. The average neurologist FTM score was 1.6+/ 0.7 for PD and 2.6+/-0.7 for ET patients. The average model score was 1.6+/-0.7 for PD and 2.6+/-0.6 for ET. Correlation coefficient between the clinical and model tremor scores was 0.91 (p < 0.001). Motion data from an instrumented eating utensil accurately derived tremor ratings enabling practical, objective daily monitoring. PMID- 28922168 TI - Evaluation of RNA Blood Biomarkers in Individuals at Risk of Parkinson's Disease. AB - BACKGROUND: Substantial progress has been made in the discovery of blood biomarkers for Parkinson's disease (PD), a progressive neurodegenerative disease that affects more than 4 million worldwide. Olfactory dysfunction and dopamine deficits usually precede motor symptoms years before the onset of PD. A readily accessible biomarker useful for identifying patients at risk of PD is expected to accelerate clinical trials. OBJECTIVE: To evaluate previously identified PD blood RNA biomarkers in a cohort of asymptomatic individuals at risk of PD. METHODS: Here we tested 16 previously identified PD RNA biomarkers using quantitative PCR assays in a total of 269 blood samples at baseline from hyposmic and normosmic participants enrolled in the Parkinson's Associated Risk Syndrome study. RESULTS: Expression levels of four biomarkers, SOD2, PKM2, ZNF134, and ZNF160 were negatively correlated with the total Unified Parkinson's Disease Rating Scale, thus suggesting these biomarkers may be useful to stratify patients prior to the onset of motor symptoms. Levels of SOD2 were upregulated in hyposmic males compared to females, whereas levels of PKM2 were upregulated in hyposmic males compared to normosmic males and hyposmic females. Further, levels of SOD2 were upregulated in males with abnormal dopamine transporter (DAT) scans compared to females with abnormal DAT scans. CONCLUSIONS: These results suggest that some of these biomarkers may be useful for stratification of individuals at risk for PD and that there may be sex differences in the expression of some biomarkers. Future studies in larger longitudinal studies will be key to assessing the validity of these findings. PMID- 28922167 TI - Statins and Cognition in Parkinson's Disease. AB - BACKGROUND: The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. OBJECTIVES: Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. METHODS: Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. RESULTS: At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU. PMID- 28922169 TI - App-Based Bradykinesia Tasks for Clinic and Home Assessment in Parkinson's Disease: Reliability and Responsiveness. AB - BACKGROUND: Clinical rating of bradykinesia in Parkinson disease (PD) is challenging as it must combine several movement features into a single score. Additionally, in-clinic assessment cannot capture fluctuations throughout the day. OBJECTIVE: To evaluate the reliability and responsiveness of a motion sensor based tablet app for objective bradykinesia assessment in clinic and at home as compared to clinical ratings. METHODS: Thirty-two PD patients treated with subthalamic deep brain stimulation (DBS) were outfitted with a motion sensor on the index finger of the more affected hand to perform two repetitions of finger tapping, hand opening-closing, and arm pronation-supination tasks with DBS on and 10, 20, and 30 minutes after turning DBS off. Tasks were videotaped for blinded clinician rating using the Modified Bradykinesia Rating Scale (MBRS). Participants were then sent home with an app-based system to perform two repetitions of the same tasks six times per day spaced two hours apart, three days per week, for two weeks. Intraclass correlation (ICC) and minimal detectable change (MDC) were calculated. RESULTS: As the effects of DBS wore off, motion sensors detected worsening of amplitude sooner than did clinician-rated MBRS for all three tasks. ICCs were significantly higher and MDCs were significantly lower for motion sensors in the clinic and at home than for clinician ratings (p < 0.01). CONCLUSIONS: The tablet-based app demonstrated higher reliability and responsiveness in capturing bradykinesia-related tasks in the clinic and at home than did clinician ratings. This tool may enhance the assessment of novel therapies. PMID- 28922170 TI - A Critical Assessment of Exosomes in the Pathogenesis and Stratification of Parkinson's Disease. AB - Extracellular vesicles including exosomes are released by a variety of cell types including neurons and exhibit molecular profiles that reflect normal and disease states. As their content represents a snapshot of the intracellular milieu, they could be exploited as biomarkers of the otherwise inaccessible brain microenvironment. In addition they may contribute to the progression of neurodegenerative disorders by facilitating the spread of misfolded proteins at distant sites or activating immune cells. This review summarizes recent advances in the study of exosomes in Parkinson's disease pathophysiology and their potential as disease biomarkers. PMID- 28922173 TI - Accommodating individuals with traumatic brain injury: An analysis of employer initiated cases handled by the Job Accommodation Network. AB - BACKGROUND: The Job Accommodation Network (JAN) has provided customized accommodation information to employers, individuals with disabilities, and their representatives (e.g., family, rehabilitation counselors, union representatives) since 1983. For each inquiry where such information is sought, detailed records are maintained regarding the type of inquiries made and the information provided. OBJECTIVE: The objective of the current study is to present a descriptive analysis of the employer-initiated cases related to Traumatic Brain Injury (TBI) handled by the accommodation specialists at JAN during the five years from 2012 through 2016. METHODS: Records related to instances of TBI as recorded by the JAN accommodation specialists were reviewed. Information pertaining to the type of business, occupational category, limitations being experienced by the individual, and issues discussed with the accommodation specialist are presented. RESULTS: The type of businesses and the occupational categories indicated by the employer were broad ranging, although there was a preponderance of cases in the area of Public Administration. Limitations related to cognition were the most frequent for which employers sought accommodation information. The largest category for the type of issues discussed was related to the Americans with Disabilities Act and other disability-pertinent legislation. CONCLUSIONS: The incidence of employers seeking accommodation information for individuals who have incurred a TBI is very low (0.5%). Findings support those of other authors such as Ponsford and Spitz (2015), in that accommodation information was most frequently requested for individuals in professional (i.e., office-type jobs), rather than for laborer positions. PMID- 28922171 TI - Pancreatic Polypeptide in Parkinson's Disease: A Potential Marker of Parasympathetic Denervation. AB - BACKGROUND AND OBJECTIVES: Parkinson's disease (PD) patients experience several non-motor symptoms from the gastrointestinal tract that may partly be caused by parasympathetic deficiency. The pancreas is densely innervated by the vagus nerve, which mediates early meal-induced secretion of pancreatic polypeptide (PP). Early secretion after sham feeding has been validated as a marker of vagal integrity. Thus, the aim was to evaluate the ratio of increased PP plasma levels after sham feeding in PD and correlate findings with gastrointestinal transit time (GITT). METHODS: Twenty-five PD patients and 17 controls were included. PP, insulin, and blood glucose levels were measured before, during, and after sham feeding with white bread and chocolate spread. GITT was measured using radiopaque markers. Furthermore, faeces samples were analyzed for pancreatic elastase enzyme as a marker of exocrine pancreatic function. RESULTS: PD patients showed significantly lower PP ratio levels after sham feeding, which was most pronounced at 10 minutes. No significant association was seen between attenuated PP response and GITT in PD patients. No between-group differences were seen in glucose or insulin levels over time, but PD patients showed generally lower insulin levels compared to controls. No difference was found in faeces pancreatic elastase. CONCLUSIONS: Early-to-moderate stage PD patients demonstrated significantly decreased PP response after sham feeding suggestive of vagal denervation. PMID- 28922174 TI - Evaluating the effectiveness of Facebook to impact the knowledge of evidence based employment practices by individuals with traumatic brain injury: A knowledge translation random control study. AB - BACKGROUND: Individuals with traumatic brain injury (TBI) experience difficulty with obtaining and maintaining employment post-injury. Although vocational rehabilitation (VR) can be one option to provide individuals with TBI support and services to lead to successful employment outcomes, information about these services can be difficult and confusing to navigate. Providing information on evidence-based employment practices to individuals with TBI through social media could be an effective approach. OBJECTIVE: The objective of this study was to compare the effect of a knowledge translation (KT) strategy and the use of a secret Facebook group, on the knowledge of evidence-based employment research by individuals with traumatic brain injury (TBI). METHODS: The study used a randomized pretest-posttest control group design. Sixty individuals with TBI were recruited through clubhouse programs in the state where the authors resided as well as through support groups nationally for individuals with TBI, and were randomly assigned to one of two groups. Both groups received information on evidence-based employment practices for individuals with traumatic brain injury (TBI) over a three month period. One group received the information via participation in a secret Facebook group while the comparison group received information as an "e-news" email blast. Participants were assessed pre- and post intervention with a Likert-scale instrument designed to measure knowledge of evidenced-based employment information for TBI. RESULTS: Both groups gained a significant amount of knowledge between baseline and post-intervention. However, there were no significant differences between groups in knowledge gained at post intervention. CONCLUSION: While the study did not identify the most effective means of delivering information to individuals with TBI, it does provide some guidance for future KT research. PMID- 28922175 TI - Project Career: Perceived benefits of iPad apps among college students with Traumatic Brain Injury (TBI). AB - BACKGROUND: Project Career is an interprofessional five-year development project designed to improve academic and employment success of undergraduate students with a traumatic brain injury (TBI) at two- and four-year colleges and universities. Students receive technology in the form of iPad applications ("apps") to support them in and out of the classroom. OBJECTIVE: To assess participants' perspectives on technology at baseline and perceived benefit of apps after 6 and 12 months of use. METHODS: This article address a component of a larger study. Participants included 50 college-aged students with traumatic brain injuries. Statistical analysis included data from two Matching Person and Technology (MPT) assessment forms, including the Survey of Technology Use at baseline and the Assistive Technology Use Follow-Up Survey: Apps Currently Using, administered at 6- and 12-months re-evaluation. Analyses included frequencies and descriptives. RESULTS: Average scores at baseline indicated positive perspectives on technology. At 6 months, quality of life (67%) and academics (76%) improved moderately or more from the use of iPad apps. At 12 months, quality of life (65%) and academics (82%) improved moderately or more from the use of iPad apps. CONCLUSION: Students with a TBI have positive perspectives on technology use. The results on perceived benefit of apps indicated that students with a TBI (including civilians and veterans) report that the apps help them perform in daily life and academic settings. PMID- 28922176 TI - Cognition and return to work after mild/moderate traumatic brain injury: A systematic review. AB - BACKGROUND: Approximately two percent of the United States population are traumatic brain injury (TBI) survivors. The unemployment rate among them is substantial. Cognitive skills are essential to perform any job. OBJECTIVE: We analyzed the literature on cognitive rehabilitation (CR) related to mild/moderate TBI to learn the influence of cognition on return to work (RTW) post TBI. METHODS: We conducted a systematic review of the studies on CR related to RTW post TBI that were published between 2000 and 2015. RESULTS: We critically reviewed 30 studies that met the inclusion criteria. Ten studies highlighted cognition as a predictor variable, seven studies demonstrated support for cognitive testing in RTW assessments, and 13 studies showed the efficacy of CR in facilitating RTW post TBI. CONCLUSION: Cognition plays a significant role in predicting and facilitating RTW in patients with TBI. PMID- 28922177 TI - Project Career: An individualized postsecondary approach to promoting independence, functioning, and employment success among students with traumatic brain injuries. AB - BACKGROUND: Project Career is a five-year interdisciplinary demonstration project funded by NIDILRR. It provides technology-driven supports, merging Cognitive Support Technology (CST) evidence-based practices and rehabilitation counseling, to improve postsecondary and employment outcomes for veteran and civilian undergraduate students with traumatic brain injury (TBI). GOAL: Provide a technology-driven individualized support program to improve career and employment outcomes for students with TBI. OBJECTIVES: Project staff provide assessments of students' needs relative to assistive technology, academic achievement, and career preparation; provide CST training to 150 students; match students with mentors; provide vocational case management; deliver job development and placement assistance; and maintain an electronic portal regarding accommodation and career resources. METHODS: Participating students receive cognitive support technology training, academic enrichment, and career preparatory assistance from trained professionals at three implementation sites. Staff address cognitive challenges using the 'Matching Person with Technology' assessment to accommodate CST use (iPad and selected applications (apps)). JBS International (JBS) provides the project's evaluation. RESULTS: To date, 117 students participate with 63% report improved life quality and 75% report improved academic performance. CONCLUSION: Project Career provides a national model based on best practices for enabling postsecondary students with TBI to attain academic, employment, and career goals. PMID- 28922179 TI - Using a telehealth service delivery approach to working with an undergraduate student with a traumatic brain injury: A case study. AB - BACKGROUND: Project Career is a five year NIDILRR-funded interprofessional demonstration project aimed to improve the academic and career success of undergraduate students who have a traumatic brain injury (TBI). The information for this case study was collected and synthesized by an occupational therapy graduate student intern for one of the Project Career sites in collaboration with the Technology and Employment Coordinator for the site, the co-PI for Project Career, and the student participant. OBJECTIVE: A case study is presented to provide an understanding of one of the Project Career participant's experience using a telehealth service delivery approach to working with Project Career for academic and career support. METHODS: The participant's case notes, direct communication with the intern, and outcome assessments were used to perform a qualitative analysis. RESULTS: The participant reported that he believed Project Career was an effective support service for him. However, the participant's initial and 6-month outcome assessment scores are inconclusive regarding improvements in his academic abilities and satisfaction with academic and career attainment. CONCLUSION: Further research on the effectiveness of using a telehealth service delivery approach to working with undergraduate students with a TBI is needed. PMID- 28922180 TI - Qualitative case studies of professional-level workers with traumatic brain injuries: A contextual approach to job accommodation and retention. AB - BACKGROUND: Traumatic brain injury (TBI) is a multi-systemic disability that causes a wide range of difficulties with personal and social functioning. METHODS: Four individuals with TBI participated in an evaluation of barriers to their continued employment following graduation from college. A trained interviewer completed the Work Experience Survey (WES) in teleconsultation sessions with each participant. RESULTS: Researchers applied a qualitative case study research design. Participants reported a wide range of difficulties in performing essential functions of their jobs (3 to 24) that have the potential to significantly affect their productivity. Career mastery problems reflected outcomes associated with TBI such as 'believing that others think I do a good job' and 'having the resources (e.g., knowledge, tools, supplies, and equipment) needed to do the job.' Indicative of their wish to continue their current employment, participants reported high levels of job satisfaction. CONCLUSIONS: The WES is a cost-effective needs assessment tool to aid health and rehabilitation professionals in providing on-the-job supports to workers with TBI. PMID- 28922182 TI - The use of the Model of Occupational Self Efficacy in improving the cognitive functioning of individuals with brain injury: A pre- and post-intervention study. AB - BACKGROUND: Individuals diagnosed with a Traumatic Brain Injury (TBI) often experience major limitations in returning to work despite participating in rehabilitation programmes. OBJECTIVE: The aim of the study was to determine whether individuals who sustained a traumatic brain injury experienced improved cognitive functioning after participating in an intervention programme that utilizes the Model of Occupational Self-Efficacy (MOOSE). PARTICIPANTS: Ten (10) individuals who were diagnosed with a mild to moderate brain injury participated in the study. METHOD: The research study was positioned within the quantitative paradigm specifically utilizing a pre and post intervention research design. In order to gather data from the participants, the Montreal Cognitive Assessment (MOCA) was used to determine whether the individual with brain injury's cognitive functioning improved after participating in a vocational rehabilitation model called the Model of Occupational Self Efficacy (MOOSE). RESULTS: All the participants in this study presented with an improvement in MOCA test scores. The results of the study revealed a statistically significant effect of the intervention (i.e. MOOSE) on cognitive functioning measured using the Montreal Cognitive Assessment, F(4, 6) = 15.95, p = 0.002. CONCLUSION: The findings of this study indicated that MOOSE is a useful model to facilitate the return of individuals living with a TBI back to work. It is also suggested that cognitive rehabilitative activities be included as part of the vocational rehabilitation programme. PMID- 28922183 TI - Parental awareness of schoolbag carriage: A comparative study of Irish and United States parents. AB - BACKGROUND: Given the global nature of schoolbag carriage, there has been extensive research on schoolbag weight and use with resultant guidance on many aspects of carrying a schoolbag. However, there is limited evidence of knowledge translation or parents' awareness of schoolbag carriage. OBJECTIVE: This study investigated parental awareness of factors related to schoolbag carriage. METHOD: A cross-sectional survey using an anonymous 30-item questionnaire and purposive sampling was used. Questionnaires were distributed to parents of primary school children through the schools. Descriptive statistics of frequencies and percentages were used and associations were tested using Chi-square analysis in SPSS v23. RESULTS: A total of 700 parents in Ireland (Ire) and the United States (US) participated in the study (n = 444 [Ire] and n = 256 [US]). Generally, parents had satisfactory awareness of appropriate schoolbag type and carriage. The majority of children owned a backpack (89.9% [Ire] vs. 93.7% [US]), although fewer parents considered this to be the most suitable bag for their child (69.6% [Ire] vs. 88.2% [US]). More Irish parents (29.2%) favoured a wheeled schoolbag compared to US parents (6.2%) (p < 0.001). The majority (70.8% [Ire] vs. 55.7% [US]) wanted more information. The preferred platforms for receiving information were a handout (78.1% [Ire] vs. 71.6% [US]) and on-line (44.6% [Ire] vs. 53.9% [US]). CONCLUSIONS: Despite gaps identified, parents had good awareness of factors relating to schoolbag carriage, but this study shows that they would like more information. The preferred platform for knowledge translation was a handout. Parents are the best advocates for safety promotion and represent the group most likely to improve schoolbag carriage among children. PMID- 28922184 TI - Subjective measures of work-related fatigue in automobile factory employees. AB - BACKGROUND: Work-related fatigue is common among automobile factory employees. OBJECTIVES: The purpose of this study was to assess fatigue of employees at a Chinese automobile factory. METHODS: 238 employees (119 engineers and 119 workers) participated in this study. The following questionnaires were completed: demographic survey questionnaire, working condition questionnaire (WCQ), functional assessment of chronic illness therapy-fatigue (FACIT-F), subscales of multidimensional fatigue inventory (MFI), and Pittsburgh sleep quality index (PSQI). RESULTS: Both engineers and workers experienced fatigue. The workers (35.6 years old, SD = 6.7) generally felt more fatigue than engineers (42.6 years old, SD = 6.4). The engineers claimed to be more satisfied with the working conditions than workers. The WCQ showed good properties for assessing work related factors, which were significantly correlated with fatigue (r = 0.568 for engineers and r = 0.639 for workers). For engineers, general fatigue was observed regularly and frequently, and for workers, physical fatigue usually had a long duration. CONCLUSIONS: The fatigue was significantly correlated with work-related factors, especially working environment and monotony. For workers, the duration of the work day also affected their fatigue. Some improvements to the working condition in this automobile factory should be considered. PMID- 28922185 TI - A pilot study to precisely quantify forces applied by sonographers while scanning: A step toward reducing ergonomic injury. AB - BACKGROUND: There is a significantly high rate of work-related musculsokeletal injuries in sonography professionals. To date, assessment of risk factors for work- related injuries in sonographers has been based primarily on surveys, subjective reports, and observational methods. There is a need to develop quantitative techniques to better understand risk factors and develop preventive interventions. OBJECTIVE: We pilot tested a high-resolution force-measuring probe capable of precisely measuring forces applied through the transducer by sonographers and used this novel direct measurement technique to evaluate forces during abdominal imaging. METHODS: Twelve sonographers with varied experience, ranging from 1-33 years, performed routine abdominal scans on 10 healthy volunteers who had varied body mass indices (BMI). Imaging was conducted using the force-measuring probe, which provided real-time measurement of forces, and angles. Data were compared by sonographer years of experience and subject BMI. RESULTS: In total, 47 abdominal examinations were performed as part of this study, and all images met standards for clinical diagnostic quality. The mean contact force applied across all exams was 8.2+/-4.3 Newtons (N) (range: 1.2-36.5 N). For subjects in the high BMI group (BMI>25, n = 4) the mean force was 10.5 N (range: 8.9-13.2 N) compared to 7.9 N (range: 5.9-10.9 N) for subjects with normal BMI (BMI = 18.5-25, n = 6). Similarly, the mean maximum force applied for subjects with high BMI (25.3 N) was significantly higher than force applied for subjects with normal BMI (17.4 N). No significant difference was noted in the amount of force applied by sonographers with more than 5 years of experience (n = 6) at 8.2 N (Range: 5.1-10.0 N) compared to less experienced sonographers (n = 6), whose forces averaged 8.1 N (Range: 5.8-10.0 N). CONCLUSIONS: It is feasible to directly measure forces applied by sonographers using a high-resolution force measurement system. Forces applied during abdominal imaging vary widely, are significantly higher when scanning subjects with high BMI, and are not related to sonographer years of experience. This force measurement system has the potential to provide an additional quantitative data point to explore the impact of applied forces on sonographer related musculoskeletal injury, particularly in conjunction with various body positions, exam types and force durations. PMID- 28922187 TI - Novel Histologic Finding: Adipose Tissue Is Prevalent Within Penile Tunica Albuginea and Corpora Cavernosa: An Anatomic Study of 63 Specimens and Considerations for Cancer Invasion. AB - Adipose tissue, along with arteries, veins, and peripheral nerves, is a normal constituent of mesenchymal tissues encasing the corpora cavernosa at the level of the penile shaft, variously designated as penile fascia or Bucks fascia. To our knowledge, the presence of fat has not been previously reported within the corpora cavernosa. One or 2 transversal histologic sections at the level of the surgical margin at the shaft of 63 consecutive partial penectomy specimens for squamous cell carcinoma were evaluated. From outer to inner tissues, 3 anatomic levels were identified: (1) outer fascia composed of a loose fibrovascular mesenchyme containing some nerve branches. Adipose tissue was present in the majority of the cases. (2) The tunica albuginea, a thick and dense fibroelastic band of tissue separating the outer fascia from the erectile tissues of the corpora cavernosa. Adipose tissue within the albuginea was present in 21 specimens (19%). (3) Erectile tissues of corpora cavernosa. Besides the typical erectile tissues, adipose tissue was present in 33 cases (52%). The fatty tissue was focal or multifocal and scant and peripherally located at the junction of the tunica albuginea with the corpora. In some cases, it was associated with small amounts of fibrous tissue, small vessels, and nerves. We are reporting the presence of adipose tissue in the tunica albuginea and the corpora cavernosa. It is possible that adipose tissue, along with small nutritional vessels and nerves perforates from the fascia, in which fat is usually present, through the tunica albuginea to reach the corpora. In a previous examination of the local routes of cancer spread, we found this pathway to be one of the mechanisms of cancer invading the penile corpora from the penile fascia. PMID- 28922188 TI - New insights into the role of glycosylation in lipoprotein metabolism. AB - PURPOSE OF REVIEW: Human genetics has provided new insights into the role of protein glycosylation in regulating lipoprotein metabolism. Here we review these new developments and discuss the biological insights they provide. RECENT FINDINGS: Case descriptions of patients with congenital defects in N glycosylation (CDG-I) frequently describe a distinct hypocholesterolemia in these rare multisystem clinical syndromes. Two novel CDGs with disturbed Golgi homeostasis and trafficking defects result in mixed glycosylation disorders, hepatic steatosis and hypercholesterolemia. In addition, the presence of particular N-glycans is essential for physiological membrane expression of scavenger receptor B1 and for adequate lipolytic activity of endothelial lipase. GalNAc-T2, a specific O-glycosyl transferase, was found to be a direct modulator of HDL metabolism across mammals, validating its relationship with HDL-c found in genome-wide association studies. Furthermore, genetic variation in ASGR1, the major subunit of the asialoglycoprotein receptor (ASGPR), was found to be associated with a reduction in LDL-c and risk of coronary artery disease. SUMMARY: Protein glycosylation plays an important regulatory role in lipoprotein metabolism. Greater insight into how protein glycosylation regulates lipoprotein metabolism could provide novel approaches for the treatment of dyslipidemia. PMID- 28922189 TI - ACR-ACNM Practice Parameter for the Performance of Dopamine Transporter (DaT) Single Photon Emission Computed Tomography (SPECT) Imaging for Movement Disorders. AB - This American College of Radiology and American College of Nuclear Medicine joint clinical practice parameter is for performance of dopamine transporter single photon emission computed tomography (SPECT) imaging, for patients with movement disorders. Parkinsonian syndrome (PS) consists of a group of neurodegenerative diseases including Parkinson disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). Accurate diagnosis of PS is critical for clinical management. An important diagnostic dilemma is the differentiation of PS and non neurodegenerative disorders, such as essential tremor (ET) or drug-induced tremor, due to the overlap of clinical symptoms. The management approach to these conditions is distinctly different. An abnormal iodine-123 ioflupane SPECT scan suggests a decreased amount of dopamine transporter in the striatum, that is, a diagnosis of nigrostriatal neurodegenerative PS, whereas a normal scan suggests ET or other nondegenerative parkinsonism (drug-induced, vascular, or psychogenic). PMID- 28922190 TI - Spinal Metastasis Characterized on FDG PET/CT in Head and Neck Squamous Cell Carcinoma. AB - Spinal metastases are rare in head and neck cancer. We present a rare case of vocal cord squamous cell cancer that metastasized to the spinal cord and cauda equina. A 63-year-old man presented with acute back pain and bilateral leg weakness 5 months after having a surgical treatment for moderately differentiated vocal cord squamous cell cancer (T2 N0 M0). Restaging F-FDG PET examination demonstrated a soft tissue mass with intense hypermetabolism in the distal spinal cord and a hypermetabolic leptomeningeal metastatic deposit at the L3 level. The findings were confirmed on MRI prior to treatment. PMID- 28922191 TI - ACR-SPR-STR Practice Parameter for the Performance of Cardiac Positron Emission Tomography - Computed Tomography (PET/CT) Imaging. AB - This clinical practice parameter has been developed collaboratively by the American College of Radiology (ACR), the Society for Pediatric Radiology (SPR), and the Society of Thoracic Radiology (STR). This document is intended to act as a guide for physicians performing and interpreting positron emission tomography computed tomography (PET/CT) of cardiac diseases in adults and children. The primary value of cardiac PET/CT imaging include evaluation of perfusion, function, viability, inflammation, anatomy, and risk stratification for cardiac related events such as myocardial infarction and death. Optimum utility of cardiac PET/CT is achieved when images are interpreted in conjunction with clinical information and laboratory data. Measurement of myocardial blood flow, coronary flow reserve and detection of balanced ischemia are significant advantages of cardiac PET perfusion studies. Increasingly cardiac PET/CT is used in diagnosis and treatment response assessment for cardiac sarcoidosis. PMID- 28922192 TI - Differentiation of Malignant Thrombus From Bland Thrombus of the Portal Vein in Patient With Hepatocellular Carcinoma on 18F-FDG PET CT. AB - Hepatocellular carcinoma carries a high risk of invasion of the portal vein. Neoplastic and bland portal vein thrombi discrimination is of great clinical significance for determining the therapeutic approach, predicting survival, and assessing candidates for liver transplantation. F-FDG PET/CT may be helpful in discriminating between malignant and portal vein thrombi. We present the case of a 61-year old man who presented with hepatocellular carcinoma with portal vein involvement. F-FDG PET/CT has a role in differentiating malignant from benign portal vein thrombosis. PMID- 28922193 TI - Update on second trimester medical abortion. AB - PURPOSE OF REVIEW: To review recent literature on second trimester abortion with medical methods. RECENT FINDINGS: Across studies published in the recent past, it is apparent that women prefer shorter procedures and procedure times. Several randomized controlled trials have confirmed adding mifepristone to the second trimester medication abortion regimen results in shorter abortion intervals from first misoprostol administration to complete fetal expulsion. A study of simultaneous administration of mifepristone and misoprostol yielded shorter mean 'total' abortion times, presenting several logistical advantages. Recent studies on the continuous dosing of misoprostol have produced critical evidence to support continued dosing until expulsion. These studies had a more practical design compared with previous protocols that capped the number of misoprostol doses. SUMMARY: Second trimester surgical abortion is well tolerated and increasingly expeditious. Further research is needed to refine second trimester medical abortion methods, specific to the mifepristone, misoprostol dosing interval. A 12-hour mifepristone to misoprostol interval may be the optimal interval balancing patient preferences and logistical considerations. Pragmatic dosing, including continuous dosing of misoprostol, could yield results that better inform clinical guidelines and reduce burden on patient, provider, and health facility. PMID- 28922194 TI - Benign Neonatal Sleep Myoclonus Evokes Somatosensory Responses. AB - PURPOSE: Benign neonatal sleep myoclonus is a common nonepileptic condition occurring in neurologically normal full-term newborns. During jerks, EEG has always been described as normal. The aim of this study was to describe EEG changes associated with the myoclonic jerks. METHODS: Polygraphic video-EEG recordings of four full-term neonates presenting benign neonatal sleep myoclonus were studied. Myoclonic jerks were analyzed regarding their topography, frequency, propagation pattern, and reflex component. EEG averaging time-locked to myoclonic jerks and to somatosensory stimuli (realized by tapping on palms and feet) was performed to study eventual EEG correlates of myoclonus and to asses somatosensory evoked responses-for the latter, two control newborns were added. RESULTS: Visual analysis of the EEG disclosed theta band slow waves on central and vertex electrodes concomitant to myoclonic jerks and jerk-locked back averaging disclosed a sequence of deflections, not preceding, but following the myoclonus. This response predominated on the vertex electrode (CZ) and consisted of five components (N1, P1, N2, P2, and N3), with only the three later components being constantly present (at 110, 200, and 350-500 ms, respectively). Back averaging locked to the tactile stimuli in four subjects and two control newborns showed similar components and were comparable to those described in the literature as late somatosensory evoked responses in full-term newborns. CONCLUSIONS: Myoclonic jerks in benign neonatal sleep myoclonus can evoke visually identifiable EEG potentials on vertex electrodes corresponding to somatosensory responses. This EEG aspect may be misleading and could give rise to an anti-seizure treatment that mostly worsens the condition. PMID- 28922195 TI - Dispositional Mindful Attention in Relation to Negative Affect, Tobacco Withdrawal, and Expired Carbon Monoxide On and After Quit Day. AB - BACKGROUND: Mindfulness (or "Mindful Attention") has been described as the presence or absence of attention to, and awareness of, what is occurring in the present moment. Among smokers, greater mindfulness is associated with greater effect stability and reduced cue-induced craving. While studies have shown that mindfulness is associated with other smoking-related factors such as reduced withdrawal symptoms using cross-sectional data, relatively little is known about the associations between baseline mindful attention and future abstinence-related effect/withdrawal. The current study sought to examine whether levels of mindful attention before cessation predicts negative affect, withdrawal, and level of expired carbon monoxide (CO) on quit day, and also 3 and 7 days after quitting, during a self-quit attempt. METHODS: Data from 58 adults (mean age = 34.9; 65.5% male) participating in a self-quit study were available for analysis. Self-report measures of mindful attention, negative affect, and withdrawal symptoms were collected. Biochemical measurement of expired CO was also collected. Dependent variables were assessed on quit day, and also 3 and 7 days after quitting. Covariates included age, race, sex, self-reported level of cigarette dependence, and smoking status through 7 days. Multivariate regression was used to evaluate the association of baseline mindful attention in relation to the studied outcomes. RESULTS: Greater mindful attention predicted lower negative affect and reduced withdrawal at all 3 time-points. Mindful attention did not predict levels of expired CO. CONCLUSIONS: The findings suggest that mindful attention before or during smoking-cessation treatment may help to reduce negative affect and withdrawal, which serve as barriers to cessation for many smokers. PMID- 28922197 TI - THE COMMENTARIES: A SUMMARY. PMID- 28922196 TI - Editorial. PMID- 28922198 TI - REPLY. PMID- 28922199 TI - LETTER TO THE EDITOR. PMID- 28922200 TI - Editorial. PMID- 28922202 TI - THE COMMENTARIES: A SUMMARY. PMID- 28922201 TI - Loosening the Gordian Knot1 of Governance in Integrated Health Care Delivery Systems. AB - A new organizational species is emerging-the integrated health care delivery system. Aligned with both the anticipated provisions of federal and state health care reform initiatives and emerging purchaser demands, integrated delivery systems could dominate many health care markets by the end of this decade. Integration is both the defining feature and key imperative of such systems. Because of the unique position of boards, governance is potentially the ultimate integrator. Yet little attention had been focused on integrated delivery system governance. Accordingly, this article will address the governance of integrated delivery systems through three questions: (1) What are the distinguishing characteristics of integrated health care delivery systems? (2) What are the distinctive issues and challenges associated with governing integrated delivery systems? and (3) What different forms of governance can be employed by these systems and what factors influence the effectiveness of these forms? PMID- 28922203 TI - Addressing Social and Economic Responsibilities through Governance. PMID- 28922204 TI - REPLY. PMID- 28922205 TI - Impact of Advanced Age on Survival in Patients Undergoing Resection of Hepatocellular Carcinoma: Report of a Japanese Nationwide Survey. AB - OBJECTIVE: The impact of age on survival after hepatic resection for hepatocellular carcinoma (HCC) has not been thoroughly examined. We reviewed the data of a nationwide follow-up survey to determine the outcomes of hepatectomy for HCC in elderly patients. BACKGROUND: Management of malignant diseases in elderly patients has become a global clinical issue because of the increased life expectancy worldwide. Advancements in surgical techniques and perioperative management have reduced age-related contraindications for liver surgery. METHODS: In all, 12,587 patients with HCC who underwent curative hepatic resection were included in this cohort study and classified according to age group [40-59 years (n = 2991), 60-74 years (n = 7576,), and >=75 years (n = 2020)]. Clinicopathological features, long-term survival, and cumulative incidences of death after hepatic resection were compared among the groups. The cause-specific subdistribution hazard ratios for 3 types of death depending on age were also estimated. RESULTS: Preoperative liver function tests showed that the prothrombin activity and platelet count were higher in the >=75-year age group than in the other age groups. The overall survival was significantly lower in the elderly than younger patients. However, recurrence-free survival was almost identical among the 3 groups. The cumulative incidence of HCC-related or liver-related death was almost identical among the 3 groups; however, the cumulative incidence of other causes of death was significantly different. The 60-year subdistribution hazard ratio for other causes of death increased remarkably with increasing age. CONCLUSIONS: Elderly patients in this nationwide survey had significantly worse overall survival after hepatectomy than middle-aged and young patients. The cumulative incidence of other causes of death in elderly patients was significantly different from that of HCC-related or liver-related death among the 3 groups. PMID- 28922206 TI - Hidden Costs of Hospitalization After Firearm Injury: National Analysis of Different Hospital Readmission. AB - OBJECTIVE: To compare the risk factors and costs associated with readmission after firearm injury nationally, including different hospitals. BACKGROUND: No national studies capture readmission to different hospitals after firearm injury. METHODS: The 2013 to 2014 Nationwide Readmissions Database was queried for patients admitted after firearm injury. Logistic regression identified risk factors for 30-day same and different hospital readmission. Cost was calculated. Survey weights were used for national estimates. RESULTS: There were 45,462 patients admitted for firearm injury during the study period. The readmission rate was 7.6%, and among those, 16.8% were readmitted to a different hospital. Admission cost was $1.45 billion and 1-year readmission cost was $131 million. Sixty-four per cent of those injured by firearms were publicly insured or uninsured. Readmission predictors included: length of stay >7 days [odds ratio (OR) 1.43, P < 0.01], Injury Severity Score >15 (OR 1.41, P < 0.01), and requiring an operation (OR 1.40, P < 0.01). Private insurance was a predictor against readmission (OR 0.81, P < 0.01). Predictors of readmission to a different hospital were unique and included: initial admission to a for-profit hospital (OR 1.52, P < 0.01) and median household income >=$64,000 (OR 1.48, P < 0.01). CONCLUSIONS: A significant proportion of the national burden of firearm readmissions is missed by not tracking different hospital readmission and its unique set of risk factors. Firearm injury-related hospitalization costs $791 million yearly, with the largest fraction paid by the public. This has implications for policy, benchmarking, quality, and resource allocation. PMID- 28922207 TI - Sweet Sixteen: The Prospective Clinical Trials of John L. Cameron, MD-The Clinician-Scientist: From Alternate-allocation to Randomized Controlled Trials. AB - : The era of randomized controlled trials was ushered in by the British epidemiologist-statistician Austin Bradford Hill, with his work on the use of streptomycin in patients with tuberculosis. John L. Cameron, can be linked to 16 prospective clinical trials over his career thus far, starting with alternate allocation trials and transitioning to prospective, randomized, placebo controlled trials. These trials studied various topics in surgery-from pancreatitis to surgical site infections, to drain trials, a trial in Crohn disease and multiple trials in pancreatic surgery and cancer. Herein are described the "sweet sixteen" prospective clinical trials of Dr Cameron. PMID- 28922208 TI - Patient-Centered Outcome Spectrum: An Evidence-based Framework to Aid in Shared Decision-making. AB - OBJECTIVE: Our objective was to develop an alternate construct for reporting anticipated outcomes after emergency general surgery (EGS) that presents risk in terms of a composite measure. BACKGROUND: Currently available prediction tools generate risk outputs for discrete as opposed to composite measures of postoperative outcomes. A construct to synthesize multiple discrete estimates into a global understanding of a patient's likely postoperative health status is lacking and could augment shared decision-making conversations. METHODS: Using the 2012 to 2014 American College of Surgeons National Surgical Quality Improvement Program Participant Use File, we developed the Patient-Centered Outcomes Spectrum (PCOS) for patients >=65 years old who underwent an EGS operation. The PCOS defines 3 exclusive types of global outcomes (good, intermediate, and bad outcomes) and allows patients to be prospectively stratified by both their EGS diagnosis and preoperative surgical risk profile. RESULTS: Of the patients in our study population, 13,330 (46.4%) experienced a 30 day postoperative course considered a good outcome. Conversely, 3791 (13.2%) of study patients experienced a bad outcome. The remainder of patients (11,617; 40.4%) were classified as experiencing an intermediate outcome. The incidence of good, intermediate, and bad outcomes was 69.7%, 28.2%, and 2.1% for low-risk patients, and 22.0%, 48.9%, and 29.1% for high-risk patients. Diagnosis-specific PCOS constructs are also provided. CONCLUSIONS: Consistent with the goals of shared decision-making, the PCOS provides an evidence-based construct based upon a composite outcome measure for patients and providers as they weigh the risks of undergoing EGS. PMID- 28922209 TI - How Can Best Practices in Recruitment and Selection Improve Diversity in Surgery? PMID- 28922210 TI - Screening for DSM-5 Somatic Symptom Disorder: Diagnostic Accuracy of Self-Report Measures Within a Population Sample. AB - OBJECTIVE: The new DSM-5 somatic symptom disorder was introduced to improve the diagnosis of persons experiencing what used to be called somatoform disorders. So far, it is unclear whether existing self-report measures are useful to detect the new somatic symptom disorder. This study investigates the diagnostic accuracy of three self-report questionnaires that measure somatic complaints (15 item Patient Health Questionnaire [PHQ-15]) and psychological features (7-item Whiteley Index [WI-7]; Scale for Assessing Illness Behavior [SAIB]), in detecting somatic symptom disorder. METHODS: A nationally representative general population survey was performed resulting in 250 participants (minimum age = 14 years. 12.8% participation rate). Assessment took place at baseline and 12-month follow-up. Individual and combined diagnostic accuracy of the PHQ-15, WI-7, and SAIB in detecting somatic symptom disorder was evaluated using the area under the curve (AUC) of a receiver operating characteristic. RESULTS: Diagnostic accuracy was adequate to good for each individual questionnaire (PHQ-15: AUC = 0.79, p < .001, 95% confidence interval [CI] = 0.73-0.85; WI-7: AUC = 0.76, p < .001, 95% CI = 0.69-0.83; SAIB: AUC = 0.77, p < .001, 95% CI = 0.71-0.83). Combining the PHQ-15 and the WI-7 slightly improved diagnostic accuracy (AUC = 0.82, p < .001, 95% CI = 0.77-0.88), as did the combination of all three questionnaires (AUC = 0.85, p < .001, 95% CI = 0.79-0.90). CONCLUSIONS: The PHQ-15, WI-7, and SAIB are useful screening instruments to detect persons at risk for somatic symptom disorder, and a combination of these three instruments slightly improves diagnostic accuracy. Their use in routine care will lead to improved detection rates. PMID- 28922211 TI - Acute Effects of Ammonia Inhalants on Strength and Power Performance in Trained Men. AB - Bartolomei, S, Nigro, F, Luca, G, Gabriele, S, Ciacci, S, Hoffman, JR, and Merni, F. Acute effects of ammonia inhalants on strength and power performance in trained men. J Strength Cond Res 32(1): 244-247, 2018-The aim of the present study was to investigate the influence of ammonia inhalants on lower body power and maximal isometric strength in trained men. Twenty experienced resistance trained men (age = 26.7 +/- 3.7 years; body weight = 80.59 +/- 9.0 kg; body height = 179.5 +/- 5.7 cm) were tested for counter movement jump power (CMJP), maximal force, and peak rate of force development (pRFD20) expressed during an isometric midthigh pull (IMTP). Assessments were performed using either an ammonia inhalant (AI), a placebo (PL), or no inhalants (N). One-way analysis of variance (ANOVA) with repeated measures was used to compare strength and power performance between the different trials. A significant (p < 0.01) increase in pRFD20 was detected following the use of AI. No significant effects of trial were noted for CMJP and IMTP maximal force (p = 0.251 and p = 0.075, respectively). Results of the present study showed a potential ergogenic effect of AI on rate of force development (i.e., explosive force output), with a trend toward an improvement in maximal force production. The mechanism of action may be related to the stimulatory action of AI often reported by athletes as a "psyching-up" effect. The positive effect of AI on the rate of force development may represent an advantage in sports requiring high rates of force production. PMID- 28922212 TI - Equity of Physical Characteristics Between Adolescent Males and Females Participating in Single- or Mixed-Sex Sport. AB - Krause, LM, Naughton, GA, Benson, AC, and Tibbert, S. Equity of physical characteristics between adolescent males and females participating in single- or mixed-sex sport. J Strength Cond Res 32(5): 1415-1421, 2018-Policies on single- or mixed-sex junior sports participation continue to be challenged publically and legally. Often challenges relate to perceptions of size and performance variability between adolescent males and females, yet the evidence base behind these challenges lacks recent review and rigor. Physical performance was compared between males and females from 2 groups of younger (<13 years, n = 109, 67% females, 33% males) and older (>=13 years, n = 108, 43% females, 57% males) adolescents. Using a cross-sectional design, adolescents were tested for speed, strength, power, and endurance. No sex differences were found for most of the physical test results in the <13 years age group, although males showed greater endurance (p = 0.020) and upper-body strength (p = 0.010) than females. However, among adolescents aged >=13 years, males scored better than females in all physical tests, without exception (p > 0.05). Further explorations comparing how many females in the same age grouping shared test results equal to or greater than the top third of males were fewer in the older than younger age group. Equality of participation in mixed-sex sport becomes more difficult to guarantee for older adolescents when results from generic sport-related physical test performances are considered. PMID- 28922214 TI - A Home for Surgical Pain Management: The Perioperative Pain Service. PMID- 28922213 TI - Elastic Resistance Effectiveness on Increasing Strength of Shoulders and Hips. AB - Elastic resistance is a common training method used to gain strength. Currently, progression with elastic resistance is based on the perceived exertion of the exercise or completion of targeted repetitions; exact resistance is typically unknown. This study's objective is to determine if knowledge of load during elastic resistance exercise will increase strength gains during exercises. Participants were randomized into two strength training groups, elastic resistance only and elastic resistance using a load cell (LC) that displays force during exercise. The LC group used a Smart Handle (Patterson Medical Supply, Chicago, IL) to complete all exercises. Each participant completed the same exercises three times weekly for 8 weeks. The LC group was provided with a set load for exercises whereas the elastic resistance only group was not. Participant's strength was tested at baseline and program completion, measuring isometric strength for shoulder abduction (SAb), shoulder external rotation (SER), hip abduction (HAb), and hip extension (HEx). Independent t-tests were used to compare the normalized torques between groups. No significant differences were found between groups. Shoulder strength gains did not differ between groups (SAb p>0.05; SER p>0.05). Hip strength gains did not differ between groups (HAb p>0.05; HEx p>0.05). Both groups increased strength due to individual supervision, constantly evaluating degree of difficulty associated with exercise and providing feedback while using elastic resistance. Using a LC is as effective as supervised training and could provide value in a clinic setting when patients are working unsupervised. PMID- 28922215 TI - A Risky Proposition: Blood Transfusion and the Risk of Surgical Site Infections. PMID- 28922216 TI - Opioid-Free Analgesia in the Era of Enhanced Recovery After Surgery and the Surgical Home: Implications for Postoperative Outcomes and Population Health. PMID- 28922217 TI - Do Allogeneic Blood Transfusions Cause Infection? PMID- 28922218 TI - Not If, but How? Using Technology and Task-Sharing to Strengthen the Global Anesthesia Workforce. PMID- 28922219 TI - Trial Registration and Outcome Reporting: A Bait and Switch? PMID- 28922220 TI - Safe Driving on the Pharmacokinetic Highway. PMID- 28922221 TI - Prognostic Significance of Post-CABG Enzyme Elevations. PMID- 28922222 TI - In Response. PMID- 28922224 TI - THE COMMENTARIES: A SUMMARY. PMID- 28922223 TI - Editorial. PMID- 28922225 TI - REPLY. PMID- 28922226 TI - Effect of High Inspiratory Oxygen Fraction on Endothelial Function in Healthy Volunteers: A Randomized Controlled Crossover Pilot Study. AB - It has been suggested that high inspiratory oxygen concentrations during anesthesia may be associated with higher postoperative mortality due to endothelial dysfunction. A randomized controlled crossover study was conducted with 25 healthy male volunteers. They inhaled an oxygen concentration of 30% and 80%. The endothelial function was assessed using noninvasive digital pulse amplitude tonometry (EndoPAT) supported by endothelial biomarkers. The difference in endothelial function between the 2 treatments was 0.05 (95% confidence interval, -0.36 to 0.27; P = .77). Endothelial biomarkers were unaffected. Inhalation of a high oxygen fraction in healthy volunteers did not result in a significant reduction of endothelial function. PMID- 28922227 TI - Incidence and Risk Factors of Coagulation Profile Derangement After Liver Surgery: Implications for the Use of Epidural Analgesia-A Retrospective Cohort Study. AB - BACKGROUND: Hepatic surgery is a major abdominal surgery. Epidural analgesia may decrease the incidence of postoperative morbidities. Hemostatic disorders frequently occur after hepatic resection. Insertion or withdrawal (whether accidental or not) of an epidural catheter during coagulopathic state may cause an epidural hematoma. The aim of the study is to determine the incidence of coagulopathy after hepatectomy, interfering with epidural catheter removal, and to identify the risk factors related to coagulopathy. METHODS: We performed a retrospective review of a prospective, multicenter, observational database including patients over 18 years old with a history of liver resection. Main collected data were the following: age, preexisting cirrhosis, Child-Pugh class, preoperative and postoperative coagulation profiles, extent of liver resection, blood loss, blood products transfused during surgery. International normalized ratio (INR) >=1.5 and/or platelet count <80,000/mm defined coagulopathy according to the neuraxial anesthesia guidelines. A logistic regression analysis was performed to assess the association between selected factors and a coagulopathic state after hepatic resection. RESULTS: One thousand three hundred seventy-one patients were assessed. Seven hundred fifty-nine patients had data available about postoperative coagulopathy, which was observed in 53.5% [95% confidence interval, 50.0-57.1]. Maximum derangement in INR occurred on the first postoperative day, and platelet count reached a trough peak on postoperative days 2 and 3. In the multivariable analysis, preexisting hepatic cirrhosis (odds ratio [OR] = 2.49 [1.38-4.51]; P = .003), preoperative INR >=1.3 (OR = 2.39 [1.10 5.17]; P = .027), preoperative platelet count <150 G/L (OR = 3.03 [1.77-5.20]; P = .004), major hepatectomy (OR = 2.96 [2.07-4.23]; P < .001), and estimated intraoperative blood loss >=1000 mL (OR = 1.85 [1.08-3.18]; P = .025) were associated with postoperative coagulopathy. CONCLUSIONS: Coagulopathy is frequent (53.5% [95% confidence interval, 50.0-57.1]) after liver resection. Epidural analgesia seems safe in patients undergoing minor hepatic resection without preexisting hepatic cirrhosis, showing a normal preoperative INR and platelet count. PMID- 28922228 TI - Anesthesia Capacity in Ghana: A Teaching Hospital's Resources, and the National Workforce and Education. AB - BACKGROUND: Quality anesthetic care is lacking in low- and middle-income countries (LMICs). Global health leaders call for perioperative capacity reports in limited-resource settings to guide improved health care initiatives. We describe a teaching hospital's resources and the national workforce and education in this LMIC capacity report. METHODS: A prospective observational study was conducted at Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana, during 4 weeks in August 2016. Teaching hospital data were generated from observations of hospital facilities and patient care, review of archival records, and interviews with KATH personnel. National data were obtained from interviews with KATH personnel, correspondence with Ghana's anesthesia society, and review of public records. RESULTS: The practice of anesthesia at KATH incorporated preanesthesia clinics, intraoperative management, and critical care. However, there were not enough physicians to consistently supervise care, especially in postanesthesia care units (PACUs) and the critical care unit (CCU). Clean water and electricity were usually reliable in all 16 operating rooms (ORs) and throughout the hospital. Equipment and drugs were inventoried in detail. While much basic infrastructure, equipment, and medications were present in ORs, patient safety was hindered by hospital-wide oxygen supply failures and shortage of vital signs monitors and working ventilators in PACUs and the CCU. In 2015, there were 10,319 anesthetics administered, with obstetric and gynecologic, general, and orthopedic procedures comprising 62% of surgeries. From 2011 to 2015, all-cause perioperative mortality rate in ORs and PACUs was 0.65% or 1 death per 154 anesthetics, with 99% of deaths occurring in PACUs. Workforce and education data at KATH revealed 10 anesthesia attending physicians, 61 nurse anesthetists (NAs), and 7 anesthesia resident physicians in training. At the national level, 70 anesthesia attending physicians and 565 NAs cared for Ghana's population of 27 million. Providers were heavily concentrated in urban areas, and NAs frequently practiced independently. Two teaching hospitals provided accredited postgraduate training modeled after European curricula to 22 anesthesia resident physicians. CONCLUSIONS: While important limitations to capacity exist in Ghana, the overall situation is good compared to other LMICs. Many of the challenges encountered resulted from insufficient PACU and CCU provisions and few providers. Inadequate outcomes reporting made analysis and resolution of problem areas difficult. While many shortcomings stemmed from limited funding, strengthening physician commitment to overseeing care, ensuring oxygen supplies are uninterrupted, keeping ventilators in working order, and making vital signs monitors ubiquitously available are feasible ways to increase patient safety with the tools currently in place. PMID- 28922229 TI - MicroRNAs as Clinical Biomarkers and Therapeutic Tools in Perioperative Medicine. AB - Over the past decade, evolutionarily conserved, noncoding small RNAs-so-called microRNAs (miRNAs)-have emerged as important regulators of virtually all cellular processes. miRNAs influence gene expression by binding to the 3'-untranslated region of protein-coding RNA, leading to its degradation and translational repression. In medicine, miRNAs have been revealed as novel, highly promising biomarkers and as attractive tools and targets for novel therapeutic approaches. miRNAs are currently entering the field of perioperative medicine, and they may open up new perspectives in anesthesia, critical care, and pain medicine. In this review, we provide an overview of the biology of miRNAs and their potential role in human disease. We highlight current paradigms of miRNA-mediated effects in perioperative medicine and provide a survey of miRNA biomarkers in the field known so far. Finally, we provide a perspective on miRNA-based therapeutic opportunities and perspectives. PMID- 28922230 TI - Optimal Dose of Perineural Dexamethasone to Prolong Analgesia After Brachial Plexus Blockade: A Systematic Review and Meta-analysis. AB - BACKGROUND: Perineural dexamethasone has gained popularity in regional anesthesia to prolong analgesia duration. However, uncertainty remains regarding the optimal perineural dose. Clarification of this characteristic is of significant importance as the administration of dexamethasone may lead to dose-dependent complications. The objective of this meta-analysis was to define the optimal perineural dexamethasone dose to prolong analgesia after brachial plexus blockade for adult patients undergoing upper limb surgery. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and searched databases including MEDLINE, PubMed, and EMBASE until January 2017, without language restriction. Only trials comparing perineural dexamethasone and local anesthetics with local anesthetics alone for brachial plexus blocks were included in the present meta-analysis. The Cochrane Collaboration's Risk of Bias Tool was used to assess the methodological quality of each trial and meta-analyses were performed following a random effects model. The primary outcome was duration of analgesia for each type of local anesthetic (short-/intermediate-acting and long-acting local anesthetics). A meta-regression followed by a subgroup analysis were performed to assess the impact of different perineural dexamethasone doses on duration of analgesia; for the latter analysis, trials were grouped in low (1-4 mg) and moderate (5-10 mg) dexamethasone doses. Secondary outcomes included the rate of neurologic complication and resting pain scores and morphine consumption within the first 24 hours. RESULTS: Thirty-three controlled trials, including 2138 patients, were identified. The meta-regression revealed a ceiling effect with a perineural dexamethasone dose of 4 mg when combined with short-/intermediate-acting (8 trials; 366 participants) or long acting local anesthetics (23 trials; 1869 participants). This finding was confirmed by subgroup analyses comparing low and moderate dexamethasone doses. With short-/intermediate-acting local anesthetics, the mean difference (95% confidence interval) of analgesia duration with low and moderate doses was 277 (234-322) minutes and 229 (161-297) minutes, respectively. With long-acting local anesthetics, the mean differences with low and moderate doses were 505 (342-669) minutes and 509 (443-575) minutes. Perineural dexamethasone did not increase the rate of neurologic complications (risk ratio [95% confidence interval], 1.40 [0.54-3.63]). The Grades of Recommendation, Assessment, Development, and Evaluation quality of evidence for the primary and secondary outcomes were very low, due mainly to limitations, inconsistency, indirectness, and publication bias. CONCLUSIONS: There is currently very low quality evidence that 4 mg of perineural dexamethasone represents a ceiling dose that prolongs analgesia duration by a mean period of 6 and 8 hours when combined with short-/intermediate or long-acting local anesthetics, respectively. Additional data are needed to explore the threshold for this effect, particularly with doses below 4 mg. The risk of neurologic complications is probably not increased (very low evidence). PMID- 28922231 TI - Use of Regional Anesthesia for Outpatient Surgery Within the United States: A Prevalence Study Using a Nationwide Database. AB - BACKGROUND: Regional anesthesia is of benefit for outpatient surgery given its demonstrated improvement in analgesia and decrease in complications, resulting in shorter average recovery room times and lower hospital readmission rates. Unfortunately, there are few epidemiological studies outlining the overall utilization of peripheral nerve blocks (PNBs) in this setting. Therefore, the primary objective of this study was to report the overall utilization of several types of PNBs among all candidate cases in the outpatient setting within the United States. METHODS: We identified all cases from the National Anesthesia Clinical Outcomes Registry that were performed as an outpatient surgery. We reported the frequency of various types of PNBs among all candidate cases, defined as cases that potentially could have received a PNB. Changes in prevalence of PNB utilization from 2010 to 2015 were analyzed by using logistic regression. RESULTS: Of the 12,911,056 outpatient surgeries in the National Anesthesia Clinical Outcomes Registry, 3,297,372 (25.5%) were amenable to a PNB. However, the overall PNB frequency was only 3.3% of the possible cases. The overall utilization for PNB of the brachial plexus, sciatic nerve, and femoral nerve were 6.1%, 1.5%, and 1.9%, respectively. The surgical procedures generating the highest volume of PNBs were shoulder arthroscopies and anterior cruciate ligament reconstruction, in which 41% and 32% received a PNB, respectively. During this time period, there was a significant increase in overall PNB utilization for both single-injection and continuous PNB (P < .0001). However, the proportion of continuous PNB to single-injection PNB did not increase significantly. CONCLUSIONS: While the overall frequency of PNB is relatively low, there was a significant increase in its prevalence during the study period. Regional anesthesia offers significant positive impact for perioperative outcomes and hospital efficiency metrics; however, it is not clear what is limiting its widespread use. Future studies are necessary to identify barriers and disparities in care to implement methods to increase regional anesthesia volume nationwide where beneficial and appropriate. PMID- 28922232 TI - The "Ear-Sternal Notch" Line-How Should You Lie? PMID- 28922234 TI - Consensus Statement by the Congenital Cardiac Anesthesia Society: Milestones for the Pediatric Cardiac Anesthesia Fellowship. AB - Pediatric cardiac anesthesiology has evolved as a subspecialty of both pediatric and cardiac anesthesiology and is devoted to caring for individuals with congenital heart disease ranging in age from neonates to adults. Training in pediatric cardiac anesthesia is a second-year fellowship with variability in both training duration and content and is not accredited by the Accreditation Council on Graduate Medical Education. Consequently, in this article and based on the Accreditation Council on Graduate Medical Education Milestones Model, an expert panel of the Congenital Cardiac Anesthesia Society, a section of the Society of Pediatric Anesthesiology, defines 18 milestones as competency-based developmental outcomes for training in the pediatric cardiac anesthesia fellowship. PMID- 28922233 TI - Endoscopic Versus Open Repair for Craniosynostosis in Infants Using Propensity Score Matching to Compare Outcomes: A Multicenter Study from the Pediatric Craniofacial Collaborative Group. AB - BACKGROUND: The North American Pediatric Craniofacial Collaborative Group (PCCG) established the Pediatric Craniofacial Surgery Perioperative Registry to evaluate outcomes in infants and children undergoing craniosynostosis repair. The goal of this multicenter study was to utilize this registry to assess differences in blood utilization, intensive care unit (ICU) utilization, duration of hospitalization, and perioperative complications between endoscopic-assisted (ESC) and open repair in infants with craniosynostosis. We hypothesized that advantages of ESC from single-center studies would be validated based on combined data from a large multicenter registry. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. We analyzed 1382 infants younger than 12 months undergoing open (anterior and/or posterior cranial vault reconstruction, modified-Pi procedure, or strip craniectomy) or endoscopic craniectomy. The primary outcomes included transfusion data, ICU utilization, hospital length of stay, and perioperative complications; secondary outcomes included anesthesia and surgical duration. Comparison of unmatched groups (ESC: N = 311, open repair: N = 1071) and propensity score 2:1 matched groups (ESC: N = 311, open repair: N = 622) were performed by conditional logistic regression analysis. RESULTS: Imbalances in baseline age and weight are inherent due to surgical selection criteria for ESC. Quality of propensity score matching in balancing age and weight between ESC and open groups was assessed by quintiles of the propensity scores. Analysis of matched groups confirmed significantly reduced utilization of blood (26% vs 81%, P < .001) and coagulation (3% vs 16%, P < .001) products in the ESC group compared to the open group. Median blood donor exposure (0 vs 1), anesthesia (168 vs 248 minutes) and surgical duration (70 vs 130 minutes), days in ICU (0 vs 2), and hospital length of stay (2 vs 4) were all significantly lower in the ESC group (all P < .001). Median volume of red blood cell administered was significantly lower in ESC (19.6 vs 26.9 mL/kg, P = .035), with a difference of approximately 7 mL/kg less for the ESC (95% confidence interval for the difference, 3-12 mL/kg), whereas the median volume of coagulation products was not significantly different between the 2 groups (21.2 vs 24.6 mL/kg, P = .73). Incidence of complications including hypotension requiring treatment with vasoactive agents (3% vs 4%), venous air embolism (1%), and hypothermia, defined as <35 degrees C (22% vs 26%), was similar between the 2 groups, whereas postoperative intubation was significantly higher in the open group (2% vs 10%, P < .001). CONCLUSIONS: This multicenter study of ESC versus open craniosynostosis repair represents the largest comparison to date. It demonstrates striking advantages of ESC for young infants that may result in improved clinical outcomes, as well as increased safety. PMID- 28922235 TI - Perioperative Inflammation and Its Modulation by Anesthetics. AB - Surgery and other invasive procedures, which are routinely performed during general anesthesia, may induce an inflammatory response in the patient. This inflammatory response is an inherent answer of the body to the intervention and can be both beneficial and potentially harmful. The immune system represents a unique evolutionary achievement equipping higher organisms with an effective defense mechanism against exogenous pathogens. However, not only bacteria might evoke an immune response but also other noninfectious stimuli like the surgical trauma or mechanical ventilation may induce an inflammatory response of varying degree. In these cases, the immune system activation is not always beneficial for the patients and might carry the risk of concomitant, harmful effects on host cells, tissues, or even whole organ systems. Research over the past decades has contributed substantial information in which ways surgical patients may be affected by inflammatory reactions. Modulations of the patient's immune system may be evoked by the use of anesthetic agents, the nature of surgical trauma and the use of any supportive therapy during the perioperative period. The effects on the patient may be manifold, including various proinflammatory effects. This review focuses on the causes and effects of inflammation in the perioperative period. In addition, we also highlight possible approaches by which inflammation in the perioperative may be modulated in the future. PMID- 28922236 TI - Efficacy Outcome Measures for Pediatric Procedural Sedation Clinical Trials: An ACTTION Systematic Review. AB - Objective evaluations comparing different techniques and approaches to pediatric procedural sedation studies have been limited by a lack of consistency among the outcome measures used in assessment. This study reviewed those existing measures, which have undergone psychometric analysis in a pediatric procedural sedation setting, to determine to what extent and in what circumstances their use is justified across the spectrum of procedures, age groups, and techniques. The results of our study suggest that a wide range of measures has been used to assess the efficacy and effectiveness of pediatric procedural sedation. Most lack the evidence of validity and reliability that is necessary to facilitate rigorous clinical trial design, as well as the evaluation of new drugs and devices. A set of core pediatric sedation outcome domains and outcome measures can be developed on the basis of our findings. We believe that consensus among all stakeholders regarding appropriate domains and measures to evaluate pediatric procedural sedation is possible and that widespread implementation of such recommendations should be pursued. PMID- 28922237 TI - Minimizing the Harm of Accidental Awareness Under General Anesthesia: New Perspectives From Patients Misdiagnosed as Being in a Vegetative State. PMID- 28922238 TI - Primary central nervous system lymphoma: time for diagnostic biomarkers and biotherapies? AB - PURPOSE OF REVIEW: Primary central nervous system lymphoma (PCNSL) is a rare cancer with a somber prognosis in older patients, which it affects predominantly. Only in recent years have molecular alterations characterizing PCNSL been thoroughly described. This opens possibilities for the use of targeted therapies. Developments in imaging and biomarkers have also great potential to help clinicians faced with diagnostic and prognostic uncertainties. RECENT FINDINGS: Several biomarkers for PCNSL, such as different microRNAs, which could be tested in cerebrospinal fluid and vitreous fluid, and IL-10, which has been shown to have excellent sensitivity and specificity in the cerebrospinal fluid, have emerged in the last years. Methotrexate-based regimens remain the gold standard first-line treatment, with recent studies looking at the best adjunctive molecules to methotrexate, including rituximab, and at the role of autologous stem cell transplantation. As mutations leading to the activation of nuclear factor-kappa-B signaling are found in most PCNSLs, with mutations of MYD88 and CD79B particularly, ibrutinib is studied as molecule of great interest and encouraging results have been found in pilot studies. There is also great interest in the immunomodulatory drugs (lenalidomide) and immunotherapy (anti programmed cell death 1/programmed cell death 1 ligand 1). SUMMARY: Identification of molecular genetic and cytokine changes in tumor and liquid biopsies will have an increasing role in the diagnostic and follow-up of PCNSL but also in the treatment and management of the disease. PMID- 28922239 TI - Cleft Lip and Palate: An Experience of a Developing Center in Egypt. AB - BACKGROUND: Cleft lip and palate is the most common congenital anomaly in the head and neck region. These clefts are not just a distortion of the normal appearance, but they may impose a major influence on the whole patient's life, both functionally and psychologically. Clefts affect feeding, teething, hearing, speech, and social communication. The incidence of cleft lip and palate is variable in different countries and different communities. The surgical correction of cleft lip and palate went through many evolutions, but still there is no single universal protocol of repair; however, many European countries have adopted national protocols and have established cleft centers for the management and follow up of affected population. PATIENT AND METHODS: In this study, the problem of cleft lip and palate in the area of upper Egypt was presented through the records of patients admitted to the Department of Plastic Surgery at the Sohag University Hospital in a 15-year period (2001-2015). RESULTS: A total number of 1318 patients, who were admitted and had been operated upon in our department, were included in this study. The majority of patients presented to the department with a primary disease, yet 14.7% (194 patients) of them were first presented for a secondary interference after being operated upon elsewhere. A total number of 1923 surgical procedures were performed. PMID- 28922240 TI - An Efficient Method for Hair Containment During Head and Neck Surgery. AB - The authors present a simple technique for operations around hair-bearing areas such as during a rhytidectomy. Hair surrounding the surgical field is twisted into bundles and clipped with duckbill clips. The authors repeat the procedure for each strand of hair. Between 5 and 7 duckbill clips may be required per surgery.The clippers are faster, easily applicable, and well performing. They can be used with different hair lengths, and they do not require any additional trimming or shaving; clips also keep the hair firmly in place, and they do not loosen up in the process.This technical note explains a very simple, economical, and less time-consuming method to control hair located around the surgical site. It may be applied to all procedures within the field of the hair-bearing scalp, including craniofacial and maxillofacial surgery. PMID- 28922241 TI - A Shift in the Orbit: Immediate Endoscopic Reconstruction After Transnasal Orbital Tumors Resection. AB - Endoscopic endonasal resection of orbital lesions is a safe and common approach. Nevertheless, medial orbital wall defects following the procedure are not routinely addressed, potentially leading to diplopia and enophthalmos. In this article, the authors propose a new technique for purely endoscopic endonasal reconstruction of orbital wall defects following endoscopic endonasal resection of orbital lesions.The patient, a 43-year-old male, suffering from right exophthalmos and diplopia due to a venous malformation of the right orbit underwent endoscopic endonasal resection of the mass. Excision was followed by immediate transnasal endoscopic reconstruction with a commercially available porous polyethylene mesh (Medpor).The postoperative course was uneventful. The patient did not report any residual orbital asymmetry or diplopia. No recurrence of the venous malformation, mesh infection, or reconstruction instability was reported during the follow-up.The authors believe that this new technique could spur head and neck surgeons in strategically rethinking their approach to orbital tumors, proposing reconstruction to patients on a routine basis, and developing even more reliable and manageable solutions. PMID- 28922242 TI - Long-Term Follow-Up of Osseointegrated Orbital Prosthetic Reconstruction. AB - BACKGROUND: Osseointegrated implants have been used for craniofacial prosthetic reconstruction since 1979. The authors sought to review long-term outcomes of osseointegrated orbital reconstruction at the Institute for Reconstructive Sciences in Medicine (iRSM). METHODS: Twenty-six patients have undergone osseointegrated orbital prosthetic (OOP) reconstruction at iRSM since 1991. A retrospective chart review was performed and patient satisfaction assessed through a questionnaire used in previous osseointegration studies. Multivariate binary logistic regression analysis was performed to assess the relationship between smoking, age, sex, and previous radiation treatment with the occurrence of skin reactions and implant failures. A chi test was used to assess the relationship between implant position within the orbit and development of a skin reaction or implant failure. RESULTS: Patients received an average of 5.8 implants during the course of treatment. Follow-up ranged from 6 months to 24 years (mean = 10.6 years). A statistically significant correlation was found between skin reaction and age (P = 0.022), with younger patients more likely to develop a reaction. No variables in our model were significant for predicting implant failure. Overall, there were 39 failures of 155 osseointegrated implants, for a success rate of 74.8%. There was no relationship between skin reaction and implant failure compared to implant position within the orbit. Survey responses were received from 11 of 19 patients (58% response rate). Ninety-one percent of patients were overall satisfied with their prosthesis. CONCLUSIONS: There are minimal contraindications for consideration of OOP reconstruction. Patients find their prosthesis comfortable, report increased self-confidence, and are happy to have undergone reconstruction. PMID- 28922243 TI - Evaluation of the Changes in the Quality of Life in Patients Undergoing Orthognathic Surgery: A Multicenter Study. AB - Orthognathic surgery can affect patients' quality of life. The aim of the present study was to assess changes in quality of life during combined orthodontics surgery treatment and effect of orthodontist-surgeon teamwork on final patient's satisfaction. Twenty-six orthognathic patients who were referred to oral and maxillofacial department of 3 hospitals in Tehran were included in the study. Orthognathic quality of life questionnaire (OQLQ) was given to patients 1 week before, 4 weeks and 4 months after surgery. Two self-designed forms were used for evaluating mood and comfort of patients 1 week before surgery and 4 days after surgery. Self-designed forms were given to the orthodontists and the maxillofacial surgeons to assess quality of teamwork and difficulty of the procedure. Twenty-four patients (15 females and 9 males) with the mean age of 22.62 +/- 3.57 completed the study. Quality of life increased from 1 week before surgery to 4 months after surgery (P < 0.013) and the difference was statistically significant between OQLQ score at 1 week before surgery and that of 4 months postoperative. Esthetic and social domain showed significant changes during the studied period. Orthognathic quality of life questionnaire at 4 months postoperative was correlated with surgery difficulty and duration. It can be concluded that orthognathic surgery can improve quality of life, especially in esthetic and social aspects. PMID- 28922244 TI - Fibular Graft-Effective Panorama for Prosthetic Rehabilitation of Resected Mandible. AB - Surgical management of extensive tumors in the mandibular region leads to massive disfigurement of the face. Also the prosthetic outcome of such patients rehabilitated with free soft tissue flaps is very poor. Reconstruction of extensive defects to overcome the disfigurement is a challenging procedure and can be achieved with free fibula flap. Free fibula graft provides sufficient length of bone for the reconstruction of the postsurgical defects. Excellent vascularity of fibula flap allows for easy uptake of the graft and osseointegration of the dental implants. The addition of a skin island allows for absolute tension-free intraoral closure that enhances tongue mobility. Fibula graft allows proper tissue support after mandibular reconstruction. After rehabilitation with free fibula graft we can plan for prosthodontic rehabilitation with implant retained prosthesis leading to improved masticatory function. It also helps to improve speech outcome as a stable prosthesis can be delivered with the help of implants retained in the fibula graft. It is essential to assess the outcome of surgical reconstruction with fibula graft followed by prosthetic rehabilitation with implant retained prosthesis for their recognition as a treatment of preference. This article details the clinical report along with various clinical parameters for implant retained prosthetic rehabilitation of the patient who had undergone mandibular resection and reconstruction with free fibula graft. PMID- 28922245 TI - A Craniometric Analysis of Cranial Base and Cranial Vault Differences in Patients With Metopic Craniosynostosis. AB - PURPOSE: The effect of synostosis is not confined to the immediate vicinity of the suture. The authors hypothesized metopic craniosynostosis results in migration of lateral structures from midline, and differences in segmental volume of the cranial fossa. METHODS: A retrospective case-controlled cohort analysis of patients with nonsyndromic metopic craniosynostosis was performed. Craniometric angles, distances to landmarks from midline, cephalic index, and segmented volume ratios were calculated. A comparison group consisted of patients without cranial pathology or with mild positional plagiocephaly. RESULTS: Twenty patients with metopic craniosynostosis and 19 controls were identified. The bifrontal angle was significantly more acute in metopic patients. Distance from midline to the medial carotid, the foramen ovale, and the hypoglossal canal were all significantly longer in metopic patients. Ratio of anterior third to total cranial vault volume was significantly smaller in metopic patients; however, ratio of middle third to total cranial vault volume was significantly larger. As the bifrontal angle decreased by 1 degrees , the volume of the anterior third of the cranial vault was observed to decrease by 0.17% (P < 0.001). CONCLUSIONS: Patients with metopic craniosynostosis show a distinct and significant transverse lateralization of structures of the anterior skull base relative to midline, significant restriction of the anterior third of the cranial vault, and compensatory expansion of the middle third. There is a linear relationship between the bifrontal angle and the subsequent change in anterior third cranial vault volume. LEVEL OF EVIDENCE: IV; Therapeutic. PMID- 28922246 TI - Immediate Dental Implant Placement After Removal of Complex Odontoma. AB - The aim of the authors was to report a clinical case about immediate implant placement after the removal of complex odontoma. A 35-year-old female patient presented to private service complaining about absence of lower right first premolar. The computed tomographic showed radiopaque attenuation, surrounded by a narrow radiolucency in the area of dental absence, suggesting a mineralized lesion. The surgical removal of lesion was performed by intraoral access with general anesthesia and the implant of 3.75 * 10 mm (Neodent) was placed with the aid of a surgical guide, following the drill sequence established by the manufacturer. No complications were observed after 1 year with the prosthetic rehabilitation. PMID- 28922248 TI - Maxillary Corticotomies With Bone-to-Bone Retraction and Mandibular Segmental Osteotomy for Correcting an Anterior Double Protrusion. AB - BACKGROUNDS: This article presents maxillary corticotomies with bone-to-bone retraction and anterior segmental osteotomy (ASO) as an alternative to 2-jaw orthognathics in the bimaxilary protrusion patient with partially anchylosed maxillary anterior tooth. METHODS: The 18-year-old male, complaining of anterior protrusion, with a trauma history to the maxillary central incisor, and requesting rapid treatment, was treated with maxillary corticotomies in 2 stages and ASO in the mandible. The mandibular ASO and palatal corticotomy were done under local anesthesia and 2 weeks later, labial corticotomy followed. The anterior segment was retracted bodily using buccal C-tubes and a combination of the C-lingual retractor and palatal C-plate. RESULTS: Due to a concern about ankylosis of the maxillary right central incisor, retraction of the anterior bone/tooth segment was chosen over any attempt to move teeth through the bone. After bone-to-bone retraction, the remaining extraction space was closed by protraction of posteriors. The total treatment period was 18 months. There was good retraction of the anterior segment and retrusion of the lips. CONCLUSIONS: A combination of maxillary corticotomies with skeletal anchorage for bone-to-bone retraction and a mandibular ASO under local anesthesia might be an alternative treatment option for excellent profile change in a short treatment period. PMID- 28922249 TI - Impact of Septoplasty on Eustachian Tube Functions. AB - OBJECTIVE: To evaluate the impact of nasal septum deviation (NSD) and septoplasty on eustachian tube (ET) functions. MATERIAL AND METHODS: The study was designed as a prospective controlled study and conducted in a tertiary referral center. A study group of 25 patients who were scheduled for septoplasty for NSD; and a control group of 25 healthy individuals having no ear or nose symptoms were formed. Tympanometric analysis of ET function, subjective and objective analysis of nasal functions with acoustic rhinometry and rhinomanometry were performed. Patients in study group underwent nasal surgery and tests were repeated at postoperative 1st and 3rd months. RESULTS: Eustachian tube functions of study group were significantly worse than the control group (P = 0.032). ET functions were found to be poorer as the nasal airway resistances increase which was found to be close to significance (P = 0.056). One and 3 months after corrective surgery, both nasal airway functions and ET functions improved significantly reaching to the level of control group. CONCLUSIONS: Nasal septum deviation was associated with higher rates of ET dysfunction, which could be improved by the nasal surgery. However, in some patients, nasal surgery itself caused ET dysfunction in the early postoperative period. PMID- 28922250 TI - Use of Pedicled Buccal Fat Pad for Midface Augmentation. AB - The pedicled buccal fat pad has occasionally been used for the closure of oroantral and oronasal fistulae. However, this versatile and convenient technique has not been used widely in the field of esthetic surgery. The main cosmetic interest in the buccal fat pads was to surgically extract them to reduce cheek prominence. Here, the authors introduce a novel operative technique using the pedicled buccal fat pad for midface augmentation in patients with deficient soft tissue volume, particularly in the anterior malar or paranasal region. This rather simple surgical method can be performed either individually or concomitantly with reduction malarplasty. The surgical outcomes include a natural appearance with reliable long-term stability. PMID- 28922252 TI - Clinical Predictors and Natural History of Disease Extension in Patients with Ulcerative Proctitis. AB - BACKGROUND: A proportion of patients with initial presentation of ulcerative proctitis (UP) progress to more extensive colitis. We sought to characterize the natural history and identify clinical predictors of extension in UP. METHODS: We performed a retrospective cohort study of participants with a new diagnosis of UP from January 2000 to December 2015. We used Cox proportional hazard modeling to identify predictors of disease extension. RESULTS: We identified 169 new cases of UP with a median age of diagnosis of 40 years (range: 16-91 yr) and a median follow-up of 4.3 years (range: 3.3-15.1 yr). Fifty-three (31%) patients developed extension over the follow-up time. Compared with nonextenders, the need for immunosuppressive or biologic therapy was significantly higher among extenders (34% versus 2.6%, P < 0.001). In multivariable analyses, compared with UP cases with body mass index <25, the adjusted hazard ratios of extension were 1.75 (95% confidence interval [CI], 0.95-3.23) and 2.77 (95% CI, 1.07-7.14) among overweight and obese patients, respectively (Ptrend = 0.03). Similarly, patients with a history of appendectomy or endoscopic finding of moderate to severe disease had a higher risk of extension (adjusted hazard ratio = 2.74, 95% CI, 1.07-7.01 and 1.96, 95% CI, 1.05-3.67, respectively). CONCLUSIONS: In a retrospective cohort study, we show that appendectomy, body mass index, and endoscopic activity at the time of diagnosis of proctitis are associated with an increased risk of extension. In addition, our data suggest that extenders are more likely to require immunosuppressive or biologic therapy. PMID- 28922253 TI - Long-term Efficacy, Safety, and Immunogenicity of Biosimilar Infliximab After One Year in a Prospective Nationwide Cohort. AB - BACKGROUND: It has been previously shown that biosimilar infliximab CT-P13 is effective and safe in inducing remission in inflammatory bowel diseases. We report here the 1-year outcomes from a prospective nationwide inflammatory bowel disease cohort. METHODS: A prospective, nationwide, multicenter, observational cohort was designed to examine the efficacy and safety of CT-P13 in the induction and maintenance treatment of Crohn's disease (CD) and ulcerative colitis (UC). Demographic data were collected and a harmonized monitoring strategy was applied. Clinical remission, response, and biochemical response were evaluated at weeks 14, 30, and 54, respectively. Safety data were registered. RESULTS: Three hundred fifty-three consecutive inflammatory bowel disease (209 CD and 144 UC) patients were included, of which 229 patients reached the week 54 endpoint at final evaluation. Age at disease onset: 24/28 years (median, interquartile range: 19 34/22-39) in patients with CD/UC. Forty-nine, 53, 48% and 86, 81 and 65% of patients with CD reached clinical remission and response by weeks 14, 30, and 54, respectively. Clinical remission and response rates were 56, 41, 43% and 74, 66, 50% in patients with UC. Clinical efficacy was influenced by previous anti-tumor necrosis factor (TNF) exposure in patients with a drug holiday beyond 1 year. The mean C-reactive protein level decreased significantly in both CD and UC by week 14 and was maintained throughout the 1-year follow-up (both UC/CD: P < 0.001). Thirty-one (8.8%) patients had infusion reactions and 32 (9%) patients had infections. Antidrug antibody positivity rates were significantly higher throughout patients with previous anti-TNF exposure; concomitant azathioprine prevented antidrug antibody formation in anti-TNF-naive patients with CD. CONCLUSIONS: Results from this prospective nationwide cohort confirm that CT-P13 is effective and safe in inducing and maintaining long-term remission in both CD and UC. Efficacy was influenced by previous anti-TNF exposure; no new safety signals were detected. PMID- 28922257 TI - Endoscopic and Histological Assessment of Paediatric Inflammatory Bowel Disease Over a 3-Year Follow-up Period. AB - OBJECTIVES: Discrepancies between inflammatory bowel disease (IBD) endoscopic/histological extent are documented at diagnosis. It is unclear whether these differences persist through disease course, with potential impact on categorization and management. We aimed to analyze the progression of disease over a 3-year period. METHODS: Patients younger than 17 years, diagnosed between 2010 and 2013 at Southampton Children's Hospital and followed-up for 3 years were eligible. Primary outcome was disease extent at diagnosis and follow-up. Data are presented as percentage of patients undergoing endoscopy. Paris classification (PC) and PC using histological, rather than endoscopic disease, were determined. RESULTS: One hundred and twenty-five patients were included, 66 boys; Crohn's disease (CD) 74, ulcerative colitis (UC) 40, IBD unclassified (IBDU) 11. All had endoscopy at diagnosis. One hundred and two patients underwent >=1 repeat endoscopies.Disease extent reduced from diagnosis to first follow-up endoscopy for both endoscopic and histological disease extent (CD/UC/IBDU, all P < 0.00006). Histological extent remained greater than endoscopic in CD with significant differences in stomach, ileum, and large bowel at all follow-up points (P = < 0.045). Endoscopic matched histological extent in UC/IBDU. Applying a modified PC resulted in significant changes for CD (L3 27.4%-53.2%, P = 0.006, L3 + L4A 21%-50%, P = 0.001, and upper gastrointestinal disease 50% 80.6%, P = 0.0006) but not UC. CD height (-0.37 to -0.25) and weight (-1.09 to 0.19) standard deviation scores increased from diagnosis to follow-up. CONCLUSIONS: Histological disease is greater than endoscopic extent at diagnosis and during follow-up in CD, although not in UC/IBDU. Classification of disease extent in CD should be based on both endoscopic and histological criteria. PMID- 28922254 TI - Obese Patients Undergoing Ileal Pouch-Anal Anastomosis: Short-and Long-term Surgical Outcomes. AB - BACKGROUND: Ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients with chronic ulcerative colitis. Little is known about the impact of obesity on operative characteristics, short-term postoperative complications and long-term functional outcomes after IPAA. METHODS: A retrospective review of all patients undergoing IPAA for chronic ulcerative colitis at a single tertiary referral center between January 2002 and August 2013 was performed. Thirty-day postoperative complications and long-term functional outcomes were analyzed according to body mass index. RESULTS: Nine hundred nine IPAAs (154 obese [body mass index >= 30] and 755 not obese [body mass index < 30]) were performed during the study period. For 2-stage IPAA, obese patients were less likely to undergo laparoscopic IPAA (P < 0.0001), had greater estimated blood loss (P = 0.005), and longer operative times (P = 0.02). For 3-stage IPAA, obese patients were less likely to undergo a laparoscopic procedure (P = 0.03), had greater estimated blood loss (P < 0.0001), and longer operative times (P = 0.0002). Postoperatively, obese patients had a longer length of stay after a 2 stage procedure (P = 0.009), an increased rate of superficial surgical site infections (P = 0.003), and an increased rate of urinary tract infections (P = 0.03). Of the 61% (n = 546) of patients with IPAA with long-term (median 5.0 years) follow-up, there were no significant differences in functional outcomes including incontinence, frequency of bowel movements, pad usage, and pouchitis between the groups. CONCLUSIONS: Obesity impacts intraoperative complexity and 30 day postoperative outcomes. Long-term functional outcomes are not affected. These findings underscore the need to counsel patients on preoperative weight loss before undergoing elective IPAA. PMID- 28922258 TI - Dietary Fiber Intake in Children With Inflammatory Bowel Disease. AB - OBJECTIVES: The aim of the study was to estimate intake of total dietary fiber, and its soluble and insoluble fractions, by children with inflammatory bowel disease (IBD) in comparison with healthy controls. METHODS: This was a prospective controlled study on children with IBD. Food consumption data were collected by using the 3-day diet record. For intake of soluble and insoluble fibers author's questionnaire was used. RESULTS: The study included 50 children with IBD (80% in clinical remission) and 50 healthy controls. There were no statistically significant differences in age, weight, height, and BMI percentiles between both groups. The mean disease duration was 3.5 +/- 2.5 years. The daily median dietary fiber intake in patients was 15.3 +/- 4.2 g, whereas controls consumed about 14.1 +/- 3.6 g/day; differences were not statistically significant. The median intake of soluble fiber in the study group was 5.0 g/day and in controls 4.7 g/day, whereas the intake of insoluble fractions was 10.2 versus 9.7 g/day, respectively. The total fiber intake significantly increased with age and it was higher among boys in each age group. The boys better achieved adequate intake recommendations (P = 0.003). Both, children with IBD and healthy controls, did not meet the adequate intake recommendations. CONCLUSIONS: Intake of fiber in patients with IBD and healthy controls was comparable; however, in both groups, it was lower than recommended. PMID- 28922259 TI - Gastrointestinal Symptoms of Food Challenge-proven Non-IgE Cow's Milk Allergy Are Dissipated by Early School Age. AB - OBJECTIVES: The aim of this study was to evaluate the current well-being and dietary restrictions in children 6 years after food challenge-confirmed diagnosis of non-IgE cow's milk protein allergy, compared to peers with gastrointestinal symptoms but negative food challenge. This study aimed to evaluate the diagnostic process retrospectively. METHODS: This is an Internet-based survey for mothers whose children underwent 6 years ago the double-blind, placebo-controlled food challenge for cow's milk (CM) because of gastrointestinal symptoms causing suspicion of non-IgE CM protein allergy. Concurrent dietary restrictions, overall well-being, medical history, and retrospective views on the food challenge were queried using a study-specific questionnaire, the Quality of life using PedsQL general score and parental stress with the Parenting Stress Index questionnaire. RESULT: Mothers of 42 children (23 girls), median age of 6.7 years (range 5.7 8.6), participated in the survey, the response rate was 70%. All children now consumed cow's milk protein. The only food restrictions reported were empirical lactose-free diets in 7 children (17%). One-third of the children in both groups were presently reported to have eating-related issues such as picky eating. Quality of life was good and present parenting stress was average in both groups. The majority of the mothers (87%) felt positive or neutral about the food challenge performed in infancy. CONCLUSIONS: The non-IgE CM allergy with gastrointestinal symptoms diagnosed in infancy was a transient condition with good outcome. At an early school age, nearly all children have a good quality of life and a regular diet. The use of the double-blind, placebo-controlled food challenge was well-endorsed. PMID- 28922260 TI - Increased Risk of Inflammatory Bowel Disease in a Population-based Cohort Study of Patients With Hirschsprung Disease. AB - OBJECTIVES: Hirschsprung disease (HSCR) has previously been associated with inflammatory bowel disease (IBD). There are no data to show how common this association is. The aim of the present study was to assess the risk of IBD in individuals with HSCR in a population-based cohort. METHODS: This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was IBD. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and 10 age- and sex-matched controls per patient, randomly selected from the Swedish Population Register. Individuals with IBD were identified in the Swedish National Patient Register. Data were validated by checking for relevant surgical procedures, and, or prescription of drugs for IBD registered in the Swedish Drug Registry. RESULTS: The cohort comprised 739 individuals with HSCR (565 boys) and 7390 controls (5650 boys). The median age at diagnosis of IBD was not different between the groups; 19 years (5-34) versus 21 years (7-37), P = 0.21. Twenty of the 739 individuals with HSCR and 41 of the 7390 controls had IBD, odds ratio 4.99, and 95% confidence interval 2.85 to 8.45. In the exposed group, 15 individuals had Crohn disease and 5 ulcerative colitis at their latest admission compared to 18 individuals with Crohn disease and 23 with ulcerative colitis in the unexposed group, P = 0.030. CONCLUSION: There is an increased risk of IBD in patients with HSCR, which should be considered in clinical practice. PMID- 28922261 TI - The Effect of Gluten-free Diet on Clinical Symptoms and the Intestinal Mucosa of Patients With Potential Celiac Disease. AB - In this prospective study, we evaluated the effect of gluten-free diet (GFD) in a cohort of 65 children with potential celiac disease. Patients received GFD for signs/symptoms (N = 47) or parents' choice (N = 18). Most frequent signs/symptoms were low body mass index (36%), recurrent abdominal pain (34%), and diarrhea (19%). Of the 35/47 patients followed-up on GFD, only 54% (19/35) showed a complete clinical response. In 9 of 65 patients an intestinal biopsy was also performed after at least 1 year of GFD. No significant differences were observed in terms of Marsh grade (P = 0.33), lamina propria CD25+ cells (P = 0.80), CD3+ (P = 0.9), and gammadelta+ (P = 0.59) intraepithelial lymphocytes density and intestinal anti-TG2 deposits (P = 0.60). In conclusion, caution is necessary before attributing all symptoms to gluten in this condition. PMID- 28922262 TI - Sugar in Infants, Children and Adolescents: A Position Paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. AB - The consumption of sugars, particularly sugar-sweetened beverages (SSBs; beverages or drinks that contain added caloric sweeteners (ie, sucrose, high fructose corn syrup, fruit juice concentrates), in European children and adolescents exceeds current recommendations. This is of concern because there is no nutritional requirement for free sugars, and infants have an innate preference for sweet taste, which may be modified and reinforced by pre- and postnatal exposures. Sugar-containing beverages/free sugars increase the risk for overweight/obesity and dental caries, can result in poor nutrient supply and reduced dietary diversity, and may be associated with increased risk of type 2 diabetes mellitus, cardiovascular risk, and other health effects. The term "free sugars," includes all monosaccharides/disaccharides added to foods/beverages by the manufacturer/cook/consumer, plus sugars naturally present in honey/syrups/unsweetened fruit juices and fruit juice concentrates. Sugar naturally present in intact fruits and lactose in amounts naturally present in human milk or infant formula, cow/goat milk, and unsweetened milk products is not free sugar. Intake of free sugars should be reduced and minimised with a desirable goal of <5% energy intake in children and adolescents aged >=2 to 18 years. Intake should probably be even lower in infants and toddlers <2 years. Healthy approaches to beverage and dietary consumption should be established in infancy, with the aim of preventing negative health effects in later childhood and adulthood. Sugar should preferably be consumed as part of a main meal and in a natural form as human milk, milk, unsweetened dairy products, and fresh fruits, rather than as SSBs, fruit juices, smoothies, and/or sweetened milk products. Free sugars in liquid form should be replaced by water or unsweetened milk drinks. National Authorities should adopt policies aimed at reducing the intake of free sugars in infants, children and adolescents. This may include education, improved labelling, restriction of advertising, introducing standards for kindergarten and school meals, and fiscal measures, depending on local circumstances. PMID- 28922263 TI - Prospective Side by Side Comparison of Outcomes and Complications With a Simple Versus Intensive Anticoagulation Monitoring Strategy in Pediatric Extracorporeal Life Support Patients. AB - OBJECTIVES: A continuous infusion of unfractionated heparin is the most common anticoagulant used for pediatric patients on extracorporeal life support. The objective of this study was to compare extracorporeal life support complications and outcomes between two large-volume pediatric extracorporeal life support centers that use different anticoagulation strategies. DESIGN: Prospective, observational cohort study. SETTING: The University of Michigan used simple anticoagulation monitoring, whereas the University of Alberta used an intensive anticoagulation monitoring strategy. PATIENTS: Pediatric patients on extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was major bleeding per extracorporeal life support run defined as bleeding that was retroperitoneal, pulmonary, or involved the CNS; bleeding greater than 20 mL/kg over 24 hours; or bleeding that required surgical intervention. Secondary outcomes measured were patient thrombosis per run, circuit thrombosis per run, and survival to hospital discharge per patient. Eighty-eight patients (95 runs) less than 18 years old were enrolled at the two centers over 2 years. The two centers enrolled different extracorporeal life support populations; University of Alberta enrolled more postcardiac surgical patients (74% vs 47%; p = 0.005). The indication for extracorporeal life support support also varied by center (p = 0.04). The two centers used similar proportions of VA extracorporeal life support (p = 0.3). Median (interquartile range) unfractionated heparin doses were similar between University of Michigan and University of Alberta, 30 (21-34) U/kg/hr and 26 (22-31) U/kg/hr, p value equals to 0.3, respectively. Median (interquartile range) antifactor Xa was lower in the University of Michigan cohort (0.23 [0.19-0.28] vs 0.41 [0.36-0.46] U/mL; p < 0.001). There was no significant difference in major bleeding (15% University of Michigan vs 21% University of Alberta; p = 0.6) or in patient thromboses (18% University of Michigan vs 13% University of Alberta; p = 0.5). There was no significant difference in survival to hospital discharge (University of Michigan 63% vs University of Alberta 73%; p = 0.1). CONCLUSIONS: Although this prospective cohort study compared different pediatric extracorporeal life support populations, the results did not identify a significant difference in outcomes between simple and intensive anticoagulation monitoring strategies. PMID- 28922264 TI - Validation of a Portable Coagulometer for Routine In-Hospital Use for Newborns. AB - OBJECTIVES: To verify the reliability and clinical benefits of the coagulation tests made by a point of care device in newborn admitted to a neonatal unit. DESIGN: We made a statistical comparison between results obtained by the point of care device versus conventional laboratory analysis. SETTING: Level 3 neonatal unit. PATIENTS: Thirty-one infants admitted to the neonatal unit at the San Cecilio University Hospital (Granada, Spain) were recruited to this study. INTERVENTIONS: All underwent a double analytical determination: a small drop of blood was taken for analysis with a portable coagulometer (qLabs Electrometer Plus) and the rest of the blood sample was analyzed with conventional hospital laboratory equipment. MEASUREMENTS AND MAIN RESULTS: According to the linearity test performed, the measuring methods presented a good linear regression fit. Lin's concordance coefficient showed a "good" agreement for activated partial prothrombin time and international normalized ratio (>0.61) and a moderate one for prothrombin time (0.41-0.6) for the sample of newborns. CONCLUSIONS: The portable coagulometer qLabs Electrometer Plus device has the potential to be an alternative to standard hospital coagulation autoanalyzers in a subset of patients where the amount of blood drawn can have significant risks. Our study is the first of its kind to analyze the use of this device with severely ill newborns. PMID- 28922265 TI - "Stuck in the ICU": Caring for Children With Chronic Critical Illness. AB - OBJECTIVE: Neonatal ICUs and PICUs increasingly admit patients with chronic critical illness: children whose medical complexity leads to recurrent and prolonged ICU hospitalizations. We interviewed participants who routinely care for children with chronic critical illness to describe their experiences with ICU care for pediatric chronic critical illness. DESIGN: Semi-structured interviews. Interviews were transcribed and analyzed for themes. SETTING: Stakeholders came from five regions (Seattle, WA; Houston, TX; Jackson, MS; Baltimore, MD; and Philadelphia, PA). SUBJECTS: Fifty-one stakeholders including: 1) interdisciplinary providers (inpatient, outpatient, home care, foster care) with extensive chronic critical illness experience; or 2) parents of children with chronic critical illness. INTERVENTIONS: Telephone or in-person interviews. MEASUREMENTS AND MAIN RESULTS: Stakeholders identified several key issues and several themes emerged after qualitative analysis. Issues around chronic critical illness patient factors noted that patients are often relocated to the ICU because of their medical needs. During extended ICU stays, these children require longitudinal relationships and developmental stimulation that outstrip ICU capabilities. Family factors can affect care as prolonged ICU experience leads some to disengage from decision-making. Clinician factors noted that parents of children with chronic critical illness are often experts about their child's disease, shifting the typical ICU clinician-parent relationship. Comprehensive care for children with chronic critical illness can become secondary to needs of acutely ill patients. Lastly, with regard to system factors, stakeholders agreed that achieving consistent ICU care goals is difficult for chronic critical illness patients. CONCLUSIONS: ICU care is poorly adapted to pediatric chronic critical illness. Patient, family, clinician, and system factors highlight opportunities for targeted interventions toward improvement in care. PMID- 28922266 TI - Time to Asthma-Related Readmission in Children Admitted to the ICU for Asthma. AB - OBJECTIVES: To compare the time to asthma-related readmissions between children with a previous ICU hospitalization for asthma and those with a non-ICU hospitalization and to explore predictors of time to readmission in children admitted to the ICU. DESIGN: Retrospective cohort study using a pan-Canadian administrative inpatient database from April 1, 2008, to March 31, 2014. SETTING: All adult and pediatric Canadian hospitals. SUBJECTS: Children 2-17 years old with a hospitalization for asthma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 26,168 children were hospitalized 33,304 times during the study period. The time to readmission was shorter in the ICU group compared with the non-ICU group (median time to readmission 27 mo in ICU vs 35 mo in non-ICU group). Preschool-aged children (hazard ratio, 1.48; 95% CI, 1.02-2.14) and increased length of stay (hazard ratio, 1.63; 95% CI, 1.17-2.27) were associated with a shorter time to readmission. CONCLUSIONS: Children previously admitted to the ICU for asthma had a shorter time to asthma-related readmission, compared with children who did not require intensive care, underlining the importance of targeted long-term postdischarge follow-up of these children. Children of preschool age and who have a lengthier hospital stay are particularly at risk for future morbidity. PMID- 28922267 TI - The 1-Year Follow-Up Clinic for Neonates and Children After Respiratory Extracorporeal Membrane Oxygenation Support: A 10-Year Single Institution Experience. AB - OBJECTIVES: To establish the effectiveness of a "1-year extracorporeal membrane oxygenation follow-up clinic" and to characterize any neurodevelopmental concerns identified. DESIGN: Single-center retrospective cohort of respiratory extracorporeal membrane oxygenation survivors over 10 years. SETTING: Nationally commissioned center for neonatal and pediatric (> 28 d of life) respiratory extracorporeal membrane oxygenation. PATIENTS: Children attending the follow-up clinic 1 year after receiving respiratory extracorporeal membrane oxygenation between 2003 and 2013. INTERVENTIONS: Standardized follow-up 1 year after extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: In 10 years, 290 children received extracorporeal membrane oxygenation, 194 (67%) survived; all were offered 1-year follow-up, and 98 (51%) attended the clinic. Among these, 51 of 98 (52%) had meconium aspiration syndrome, and 74 of 98 (75%) were on veno arterial extracorporeal membrane oxygenation with a median (interquartile range) duration of 6 days (4-8 d). Neurodevelopmental problems were identified in 30 of 98 (30%). The specific abnormalities noted included neurologic (seizures, motor, or vision abnormalities) (n = 8), hearing with/without language delay (n = 8), and behavioral problems (as reported by parents) (n = 6), with eight of 30 (27%) having difficulties spanning these domains. An acute neurologic event on extracorporeal membrane oxygenation was found to be the only risk factor for neurodevelopmental concerns (p = 0.006 with odds ratio 5.4 [95% CI, 1.63-17.92]). Despite having neither a cardiac arrest nor an acute neurologic event documented, 18 of 74 (24.3%), 95% CI (15.1-35.7), had neurodevelopmental concerns at 1-year follow-up. Among the nonattenders, 30 (15%) had local follow-up, and 66 (34%) were lost to follow-up. CONCLUSIONS: All extracorporeal membrane oxygenation survivors need follow-up either at the extracorporeal membrane oxygenation center or in their community, as evidenced by the 1-year follow-up data. Our 1-year extracorporeal membrane oxygenation follow-up clinic provides an opportunity to engage with families, identify neurodevelopmental concerns, and signpost to appropriate services. Of concern, one third of survivors are lost to follow-up, some with an acute neurologic event on extracorporeal membrane oxygenation, a significant risk factor. A consensus-based standardized national follow-up program is vital. PMID- 28922268 TI - Early Exercise in Critically Ill Youth and Children, a Preliminary Evaluation: The wEECYCLE Pilot Trial. AB - OBJECTIVES: To determine the feasibility of conducting a full trial evaluating the efficacy of early mobilization using in-bed cycling as an adjunct to physiotherapy, on functional outcomes in critically ill children. DESIGN: Single center, pilot, randomized controlled trial. SETTING: Twelve-bed tertiary care, medical-surgical PICU at McMaster Children's Hospital, Hamilton, ON, Canada. PATIENTS: Children 3-17 years old who were limited to bed-rest with an expected PICU stay of at least 48 hours. Patients were excluded if they were at their baseline level of function, already mobilizing out of bed or expected to do so within 24 hours. INTERVENTIONS: Patients were randomized in a 2:1 ratio to early mobilization using in-bed cycling in addition to usual care physiotherapy (cycling arm) or to usual care physiotherapy alone (control). Usual care was according to institutional practice guidelines. The primary outcome was feasibility and safety. MEASUREMENTS AND MAIN RESULTS: Thirty patients were enrolled (20 to the cycling and 10 to control) over a 12-month period, at a 93.7% consent rate. The median (interquartile range) time from PICU admission to mobilization was 1.5 days (1-3) in the cycling arm and 2.5 days (2-7) in the control arm. Total duration of mobilization therapy in PICU was 210 (152-380) and 136 minutes (42-314 min) in cycling and control arms, respectively. Total number of PICU days mobilized was 5.0 (3-6) with cycling and 2.5 (2-4.8) with usual care. No adverse events occurred in either arm. The main threat to feasibility of mobilization was the availability of physiotherapists or research personnel. CONCLUSIONS: Early mobilization is safe and feasible in the PICU. In-bed cycling may facilitate greater duration and intensity of mobilization, in critically ill children. A full-scale randomized controlled trial is warranted to evaluate the efficacy of this intervention on PICU-acquired morbidities and functional outcomes in this population. PMID- 28922269 TI - Extubation Failure Is Associated With Increased Mortality Following First Stage Single Ventricle Reconstruction Operation. AB - OBJECTIVES: To identify the prevalence, causes, risk factors, and outcomes associated with extubation failure following first stage single ventricle reconstruction surgery. DESIGN: Retrospective cohort analysis of neonates who underwent a first stage single ventricle reconstruction operation. Extubation failure was defined as endotracheal reintubation within 48 hours of first extubation attempt. SETTING: The Royal Children's Hospital, Melbourne. PATIENTS: Data were collected for all infants who underwent a Norwood or Damus-Kaye-Stansel procedure between 2005 and 2014 at our institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extubation failure occurred in 23 of 137 neonates (16.8%; 95% CI, 11.0-24.1%) who underwent a trial of extubation. Overall, 42 patients (30.7%) were extubated to room air, 88 (64.2%) to nasal continuous positive airway pressure, and seven (5.1%) to high-flow nasal cannulae, though there was no major difference in extubation failure rates between these three groups (p = 0.37). The median time to reintubation was 16.7 hours (interquartile range, 3.2-35.2), and male infants failed extubation more frequently (63.2% vs 87.0%; p = 0.02), although age, gestation, weight, cardiac diagnosis (hypoplastic left heart syndrome vs other single ventricle conditions), shunt type (modified Blalock-Taussig vs right ventricle-pulmonary artery shunt), intraoperative perfusion times, preextubation mechanical ventilation duration, preextubation acid-base status, and postoperative fluid balance were not related to extubation outcome. Infants who failed extubation had a higher intensive care mortality (19.4% vs 3.5%; p = 0.03) and in-hospital mortality (30.4% vs 6.1%; p < 0.001). CONCLUSIONS: There is a high prevalence of extubation failure following first stage single ventricle reconstruction, and this is associated with considerably worse patient outcomes. The high prevalence and also the wide variation in rates of extubation failure in reported literature provide with an opportunity for implementation of quality assurance activities to minimize this complication and improve outcomes. PMID- 28922270 TI - Decision-Making in Pediatric Transport Team Dispatch Using Script Concordance Testing. AB - OBJECTIVES: Our objective was to compare decision-making in dispatching pediatric transport teams by Medical Directors of pediatric transport teams (serving as experts) to that of Pediatric Intensivists and Critical Care fellows who often serve as Medical Control physicians. Understanding decision-making around team composition and dispatch could impact clinical management, cost effectiveness, and educational needs. DESIGN: Survey was developed using Script Concordance Testing guidelines. The survey contained 15 transport case vignettes covering 20 scenarios (45 questions). Eleven scenarios assessed impact of intrinsic patient factors (e.g., procedural needs), whereas nine assessed extrinsic factors (e.g., weather). SETTING: Pediatric Critical Care programs accredited by the Accreditation Council for Graduate Medical Education (the United States). SUBJECTS: Pediatric Intensivists and senior Critical Care fellows at Pediatric Critical Care programs were the target population with Transport Medical Directors serving as the expert panel. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survey results were scored per Script Concordance Testing guidelines. Concordance within groups was assessed using simple percentage agreement. There was little concordance in decision-making by Transport Medical Directors (median Script Concordance Testing percentage score [interquartile range] of 33.9 [30.4 37.3]). In addition, there was no statistically significant difference between the median Script Concordance Testing scores among the senior fellows and Pediatric Intensivists (31.1 [29.6-33.2] vs 29.7 [28.3-32.3], respectively; p = 0.12). Transport Medical Directors were more concordant on reasoning involving intrinsic patient factors rather than extrinsic factors (10/21 vs 4/24). CONCLUSIONS: Our study demonstrates pediatric transport team dispatch decision making discordance by pediatric critical care physicians of varying levels of expertise and experience. Script Concordance Testing at a local level may better elucidate standards in medical decision-making within pediatric critical care physicians. The development of a curriculum, which provides education and trains our workforce on the logistics of pediatric transport team dispatch, would help standardize practice and evaluate outcomes based on decision-making. PMID- 28922272 TI - Editorial. PMID- 28922271 TI - The Impact of Telemedicine on Pediatric Critical Care Triage. AB - OBJECTIVE: To examine the relationship between pediatric critical care telemedicine consultation to rural emergency departments and triage decisions. We compare the triage location and provider rating of the accuracy of remote assessment for a cohort of patients who receive critical care telemedicine consultations and a similar group of patients receiving telephone consultations. DESIGN: Retrospective evaluation of consultations occurring between April 2012 and March 2016. SETTING: Pediatric critical care telemedicine and telephone consultations in 52 rural healthcare settings in South Carolina. PATIENTS: Pediatric patients receiving critical care telemedicine or telephone consultations. INTERVENTION: Telemedicine consultations. MEASUREMENTS AND MAIN RESULTS: Data were collected from the consulting provider for 484 total consultations by telephone or telemedicine. We examined the providers' self reported assessments about the consultation, decision-making, and triage outcomes. We estimate a logit model to predict triage location as a function of telemedicine consult age and sex. For telemedicine patients, the odds of triage to a non-ICU level of care are 2.55 times larger than the odds for patients receiving telephone consultations (p = 0.0005). Providers rated the accuracy of their assessments higher when consultations were provided via telemedicine. When patients were transferred to a non-ICU location following a telemedicine consultation, providers indicated that the use of telemedicine influenced the triage decision in 95.7% of cases (p < 0.001). For patients transferred to a non ICU location, an increase in transfers to a higher level of care within 24 hours was not observed. CONCLUSION: Pediatric critical care telemedicine consultation to community hospitals is feasible and results in a reduction in PICU admissions. This study demonstrates an improvement in provider-reported accuracy of patient assessment via telemedicine compared with telephone, which may produce a higher comfort level with transporting patients to a lower level of care. Pediatric critical care telemedicine consultations represent a promising means of improving care and reducing costs for critically ill children in rural areas. PMID- 28922273 TI - Response from the Feature Authors. PMID- 28922274 TI - Letter to the Editor. PMID- 28922275 TI - Indications for CT-Angiography of the Vertebral Arteries After Trauma. AB - STUDY DESIGN: Retrospective. OBJECTIVE: The purpose of this project is to identify factors that predict vertebral artery injury (VAI) in an effort to assess risks and benefits of computed tomography angiography (CT-A) of the neck in the trauma setting. We seek to develop guidelines for practitioners to stratify patients at medium/high risk of VAI from those who are at low risk. SUMMARY OF BACKGROUND DATA: VAI and blunt carotid injury (BCI) together comprise blunt cerebrovascular injury (BCVI). More is known about risk factors for BCI than for VAI, but the neurovascular complications associated with VAI are similarly disastrous. With increasing frequency, trauma providers are using CT-A to screen for BCVI; this test carries risks that include radiation exposure and nephrotoxicity, in addition to higher cost of treatment and longer hospital stay. METHODS: Trauma patients seen over 4 months at an urban, level 1 trauma were analyzed. BCVI screening was conducted in 144/1854 (7.77%) patients. Presence of VAI and several clinical characteristics were recorded. Univariate analysis and binomial logistic regression analysis were conducted at a 95% significance level. RESULTS: VAI was diagnosed in 0.49% of the study population. Univariate analysis determined six factors associated with positive VAI screening. Regression analysis showed four factors that independently predicted VAI: female sex, decreased Glasgow Coma Scale, cervical spine (c-spine) fracture, and concurrent BCI. A positive c-spine physical examination trended toward predicting VAI without achieving significance. CONCLUSION: Several independent predictors of VAI were identified. This study highlights the importance of identifying patients at a higher risk for VAI and indicating CT-A of the neck versus those who are at low risk and can be evaluated without undergoing advanced imaging, as CT-A appears unnecessary for most trauma patients. LEVEL OF EVIDENCE: 3. PMID- 28922276 TI - Risk Factors for Surgical Site Infection After Posterior Lumbar Spinal Surgery. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The purpose of this study was to identify the independent risk factors for postoperative surgical site infection (SSI) after posterior lumbar spinal surgery based on the perioperative factors analysis. SUMMARY OF BACKGROUND DATA: SSI is one of the most common complications after spinal surgery. Previous studies have identified different risk factors for postoperative SSI after lumbar spinal surgery. However, most of the studies were focused on the patient and procedure-related factors. Few studies reported the correlation between laboratory tests and postoperative SSI. METHODS: A retrospective study was carried out in a single institution. Patients who underwent posterior lumbar spinal surgery between January 2010 and August 2016 were included in this study. All patients' medical records were reviewed and patients with postoperative SSI were identified. Perioperative variables were included to determine the risk factors for SSI by univariate and multivariate regression analysis. RESULTS: A total of 2715 patients undergoing posterior lumbar spinal surgery were included in this study. Of these patients, 64 (2.4%) were detected with postoperative SSI, including 46 men and 18 women. Diabetes mellitus (P = 0.026), low preoperative serum level of calcium (P = 0.009), low preoperative and postoperative albumin (P = 0.025 and 0.035), high preoperative serum glucose (P = 0.029), multiple fusion segments (P < 0.001), increased surgical time and estimated blood loss (P = 0.023 and 0.005), decreased postoperative hemoglobin (P = 0.008), and prolonged drainage duration (P = 0.016) were found to be the independent risk factors for SSI. Multilevel fusion and a history of diabetes mellitus were the two strongest risk factors (odds ratio = 2.329 and 2.227) for SSI. CONCLUSION: Based on a large population analysis, previous reported risk factors for SSI were confirmed in this study while some new independent risk factors were identified significantly associated with SSI following lumbar spinal surgery, including preoperative low serum level of calcium, decreased preoperative and postoperative albumin, and decreased postoperative hemoglobin. LEVEL OF EVIDENCE: 4. PMID- 28922277 TI - Percutaneous Posterior Transarticular Atlantoaxial Fixation for the Treatment of Odontoid Fractures in the Elderly: A Prospective Study. AB - STUDY DESIGN: A prospective study of 20 multimorbid patients older than 65 years undergoing minimally invasive surgical treatment for odontoid fracture. OBJECTIVE: To analyze the results of percutaneous transarticular atlantoaxial screw fixation as a new minimally invasive treatment modality in this high risk group of patients. SUMMARY OF BACKGROUND DATA: Odontoid fractures are a common injury pattern in the elderly. These fractures typically present significant challenges as geriatric patients often have multiple comorbidities that may adversely affect fracture management. Despite numerous publications on this subject, with a trend toward primary operative stabilization, the appropriate treatment for this frequent and potentially life threatening injury remains controversial. METHODS: Between January 2013 and December 2015, 20 consecutive patients underwent posterior percutaneous transarticular atlantoaxial screw fixation for odontoid fracture type II. The two main inclusion criteria were age 65 years or older and ASA score of III or IV. The screws were inserted percutaneously with the help of two fluoroscopy devices. Clinical and radiological examinations were regularly performed for a minimum of 18 months postoperatively. RESULTS: The mean age was 81 years, all of them with multiple comorbidities. Reduction of the fracture and screw insertion was possible in all cases. The mean operative time was 51.75 minutes and mean blood loss was 41.7 mL. Three patients died in the first 3 months after surgery. Healing of the fracture occurred in 15 patients (88.2%). Revision surgery was not necessary in any of the patients. Mean visual analogue scale (VAS) at the final follow-up was 2.4, and mean patient satisfaction score was 7.1. CONCLUSION: Percutaneous transarticular atlantoaxial fixation in elderly patients offers a good minimally invasive operative treatment in this multimorbid group of patients. This new technique with short operative time is well tolerated by the geriatric patients leading to a healing rate up to 88%. LEVEL OF EVIDENCE: 4. PMID- 28922278 TI - Defining the "Critical Elements" for the Most Common Procedures in Spine Surgery: A Consensus of Orthopedic and Neurosurgical Surgeons. AB - STUDY DESIGN: Survey. OBJECTIVE: To define the critical elements of common spine surgeries. SUMMARY OF BACKGROUND DATA: Despite significant relevance to the field of spine surgery, the term "critical element" of surgery has not been clearly defined. Every surgical procedure involves numerous steps, each with its own potential for complications and harm to the patient. Despite its crucial role in surgical training, billing, and the ethicality of concurrent surgery, the term "critical element" of surgery has not been defined. METHODS: A survey was administered to surgeons associated with AO Spine North America and the Society for Minimally Invasive Spine Surgery to determine the critical elements for four common spine procedures: open lumbar laminectomy and fusion, microdiscectomy, anterior cervical discectomy and fusion (ACDF), and posterior cervical laminectomy and fusion. Respondents were asked which steps necessitated their direct supervision. Surgical subspecialty, level of experience, and practice demographics were also recorded. RESULTS: For all applicable procedures, decompression, instrumentation, and fusion were designated as critical elements. Patient positioning and fascial closure were not. Radiographic localization was considered critical for all procedures, except posterior cervical laminectomy and fusion. Exposure was not considered critical for any procedures, except ACDF. Certain substeps of decompression in ACDF and open lumbar laminectomy and fusion were not considered critical. Orthopaedic surgeons considered exposure and fusion in ACDF procedures to be critical whereas neurosurgeons did not. Surgeons operating in private practice considered every step of these common procedures to be critical elements. CONCLUSION: Decompression, instrumentation, and fusion were considered critical elements of common spine surgeries. There were significant differences in responses according to surgical specialty and practice setting. Future research is necessary to determine the implications of these findings and guide the definition of the "critical portions" of surgery. LEVEL OF EVIDENCE: 1. PMID- 28922279 TI - Translation, Cross-cultural Adaptation and Validation of the Farsi Version of NIH Task Force's Recommended Multidimensional Minimal Dataset for Research on Chronic Low Back Pain. AB - STUDY DESIGN: Translation and cultural adaptation of the National Institutes of Health (NIH) Task Force's minimal dataset. OBJECTIVE: The purpose of this study was to evaluate validity and reliability of the Farsi version of NIH Task Force's recommended multidimensional minimal dataset for research on chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Considering the high treatment cost of CLBP and its increasing prevalence, NIH Pain Consortium developed research standards (including recommendations for definitions, a minimum dataset, and outcomes' report) for studies regarding CLBP. Application of these recommendations could standardize research and improve comparability of different studies in CLBP. METHODS: This study has three phases: translation of dataset into Farsi and its cultural adaptation, assessment of pre-final version of dataset's comprehensibility via a pilot study, and investigation of the reliability and validity of final version of translated dataset. Subjects were 250 patients with CLBP. Test-retest reliability, content validity, and convergent validity (correlations among different dimensions of dataset and Farsi versions of Oswestry Disability Index, Roland Morris Disability Questionnaire, Fear Avoidance Belief Questionnaire, and Beck Depression Inventory-II) were assessed. RESULTS: The Farsi version demonstrated good/excellent convergent validity (the correlation coefficient between impact dimension and ODI was r = 0.75 [P < 0.001], between impact dimension and Roland-Morris Disability Questionnaire was r = 0.80 [P < 0.001], and between psychological dimension and BDI was r = 0.62 [P < 0.001]). The test-retest reliability was also strong (intraclass correlation coefficient value ranged between 0.70 and 0.95) and the internal consistency was good/excellent (Chronbach's alpha coefficients' value for two main dimensions including impact dimension and psychological dimension were 0.91 and 0.82 [P < 0.001], respectively). In addition, its face validity and content validity were acceptable. CONCLUSION: The Farsi version of minimal dataset for research on CLBP is a reliable and valid instrument for data gathering in patients with CLBP. This minimum dataset can be a step toward standardization of research regarding CLBP. LEVEL OF EVIDENCE: 3. PMID- 28922280 TI - Time Demand and Radiation Dose in 3D-Fluoroscopy-based Navigation-assisted 3D Fluoroscopy-controlled Pedicle Screw Instrumentations. AB - STUDY DESIGN: Prospective single-center cohort study to record additional time requirements and radiation dose in navigation-assisted O-arm-controlled pedicle screw (PS) instrumentations. OBJECTIVE: The aim of this study was to evaluate amount of extra-time and radiation dose for navigation-assisted PS instrumentations of the thoracolumbosacral spine using O-arm 3D-real-time navigation (O3DN) compared to non-navigated spinal procedures (NNSPs) with a single C-arm and postoperative computed tomography (CT) scan for controlling PS positions. SUMMARY OF BACKGROUND DATA: 3D-navigation is reported to enhance PS insertion accuracy. But time-consuming navigational steps and considerable additional radiation doses seem to limit this modern technique's attraction. A detailed analysis of additional time demand and extra-radiation dose in 3D navigated spine surgery is not provided in literature, yet. METHODS: From February 2011 through July 2015, 306 consecutive posterior instrumentations were performed in vertebral levels T10-S1 using O3DN for PS insertion. The duration of procedure-specific navigational steps of the overall collective (I) and the last cohort of 50 consecutive O3DN-surgeries (II) was compared to the average duration of analogous surgical steps in 100 consecutive NNSP using a single C-arm. 3D radiation dose (dose-length-product, DLP) of navigational and postinstrumentation O-arm scans in group I and II was compared to the average DLP of 100 diagnostic lumbar CT scans. RESULTS: The average presurgical time from patient positioning on the operating table to skin incision was 46.2 +/- 10.1 minutes (O3DN, I) and 40.6 +/- 9.8 minutes (O3DN, II) versus 30.6 +/- 8.3 minutes (NNSP) (P < 0.001, each). Intraoperative interruptions for scanning and data processing took 3.0 +/- 0.6 minutes. DLPs averaged 865.1 +/- 360.8 mGycm (O3DN, I) and 562.1 +/- 352.6 mGycm (O3DN, II) compared to 575.5 +/- 316.5 mGycm in diagnostic lumbar CT scans (P < 0.001 (I), P ~ 0.81 [II]). CONCLUSION: After procedural experience, navigated surgeries can be performed with an additional time demand of 13.0 minutes compared to NNSP, and with a total DLP below that of a diagnostic lumbar CT scan (P ~ 0.81). LEVEL OF EVIDENCE: 4. PMID- 28922281 TI - Systematic Changes in the National Surgical Quality Improvement Program Database Over the Years Can Affect Comorbidity Indices Such as the Modified Frailty Index and Modified Charlson Comorbidity Index for Lumbar Fusion Studies. AB - STUDY DESIGN: Retrospective cohort study of prospectively collected data. OBJECTIVE: The aim of this study was to investigate the influence of changes in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database over the years on the calculation of the modified Frailty Index (mFI) and the modified Charlson Comorbidity Index (mCCI) for posterior lumbar fusion studies. SUMMARY OF BACKGROUND DATA: Multiple studies have utilized the mFI and/or mCCI and showed them to be predictors of adverse postoperative outcomes. However, changes in the NSQIP database have resulted in definition changes and/or missing data for many of the variables included in these indices. No studies have assessed the influence of different methods of treating missing values when calculating these indices on such studies. METHODS: Elective posterior lumbar fusions were identified in NSQIP from 2005 to 2014. The mFI was calculated for each patient using three methods: treating conditions for which data was missing as not present, dropping patients with missing values, and normalizing by dividing the raw score by the number of variables collected. The mCCI was calculated by the first two of these methods. Mean American Society of Anesthesiologists (ASA) scores used for comparison. RESULTS: In total, 19,755 patients were identified. Mean ASA score increased between 2005 and 2014 from 2.27 to 2.50 (+10.1%). For each of the methods of data handling noted above, mean mFI over the years studied increased by 33.3%, could not be calculated, and increased by 183.3%, respectively. Mean mCCI increased by 31.2% and could not be calculated respectively. CONCLUSION: Systematic changes in the NSQIP database have resulted in missing data for many of the variables included in the mFI and the mCCI and may affect studies utilizing these indices. These changes can be understood in the context of ASA trends, and raise questions regarding the use of these indices with data available in later NSQIP years. LEVEL OF EVIDENCE: 3. PMID- 28922282 TI - The GRIND Project: Get Ready to Initiate a Nursing Degree. AB - Numbers of students who declare a prenursing major and who enter a nursing program are vastly different. The GRIND (Get Ready to Initiate a Nursing Degree) research project, which operated for 3-week sessions from 2011 to 2015, exposed students to the nursing career through hospital tours and human simulation while instructing in study skills, dosage calculation, and standardized test preparation. Participants' understanding of nursing improved, and most felt at least somewhat to extremely prepared for nursing after participation. Student success in nursing is predicated on the tools learners acquire; investment in prenursing programs adds to student success. PMID- 28922283 TI - The Use of Phenomenology in Nursing Education: An Integrative Review. AB - AIM: The purpose of this integrative review was to synthesize research to address two questions about phenomenology in nursing education: How has Husserlian phenomenology been used in nursing education? What is the importance of Husserlian phenomenology in nursing education? BACKGROUND: Phenomenology is utilized in nursing education to explore the experiences of faculty and students. METHOD: Whittemore and Knafl's integrative method guided the analysis of the research. Nine articles meeting inclusion criteria were reviewed. Studies addressed faculty student experiences. RESULTS: The reviewed research revealed that phenomenology is used in nursing education to understand, identify, describe, and explore various phenomena. CONCLUSION: New knowledge gained from this integrative review about phenomenology is beneficial to nursing education. PMID- 28922284 TI - Improving Program NCLEX Pass Rates: Strategies from One State Board of Nursing. AB - AIM: This article describes the response of the Illinois Board of Nursing to an escalating number of prelicensure nursing programs with low National Council Licensure Examination (NCLEX) pass rates. The response aligns with stipulations of the Illinois Nurse Practice Act and best practices. BACKGROUND: NCLEX success is crucial to launching the careers of nursing graduates and to maintaining approval status of prelicensure programs by state regulatory bodies. Boards strive to guide programs with low pass rates fairly and consistently. METHOD: The Illinois Board of Nursing created a tool and process addressing curriculum and resources, faculty, students, and administrative support in a programmatic approach to improving pass rates. RESULTS: Initial outcomes were positive. Anecdotal evidence of programs in good standing also confirmed the tool's value as a resource to promoting graduate success. CONCLUSION: A programmatic approach can provide guidance for boards of nursing to address low NCLEX pass rates in a consistent evidence-based manner. PMID- 28922285 TI - What, where and why: exploring fluorodeoxyglucose-PET's ability to localise and differentiate infection from cancer. AB - PURPOSE OF REVIEW: To review the utility of FDG-PET imaging in detecting the cause of fever and infection in patients with cancer. RECENT FINDINGS: FDG-PET has been shown to have high sensitivity and accuracy for causes of neutropenic fever, leading to higher diagnostic certainty in this group. Recent advances in pathogen-specific labelling in PET to identify Aspergillus spp. and Yersinia spp. infections in mice, as well as differentiating between Gram-positive, Gram negative and mycobacterial infections are promising. SUMMARY: Patients with cancer are vulnerable to infection and fever, and the causes of these are frequently unclear using conventional diagnostic methods leading to high morbidity and mortality, length of stay and costs of care. FDG-PET/CT, with its unique complementary functional and anatomical information as well as its whole body imaging capability, has demonstrated use in detecting occult infection in immunocompromised patients, including invasive fungal and occult bacterial infections, as well as defining extent of infection. By demonstrating disease resolution following treatment and allowing earlier cessation of therapy, FDG-PET acts as a key tool for antimicrobial and antifungal stewardship. Limitations include at times poor differentiation between infection, malignancy and sterile inflammation, however, exciting new technologies specific to infectious pathogens may help alleviate that issue. Further prospective randomised research is needed to explore these benefits in a nonbiased fashion. PMID- 28922286 TI - Nocardia infections in solid organ and hematopoietic stem cell transplant recipients. AB - PURPOSE OF REVIEW: Nocardia spp. is a gram-positive bacteria that may cause infections in humans. Nocardiosis has been described since the early years of transplantation. This review aims to provide an overview of present knowledge regarding posttransplant nocardiosis, with a focus on recent findings. RECENT FINDINGS: Nocardiosis is not rare among transplant recipients, especially after thoracic transplantation and/or in case of intense immunosuppressive regimen or use of tacrolimus. Low-dose cotrimoxazole is not effective to prevent nocardiosis. Although lung is the most common site of infection, more than 40% of organ transplant patients have a disseminated infection. As central nervous system involvement is frequent (about 1/3 of the patients) and possibly asymptomatic, brain imaging is mandatory. Diagnosis relies on direct examination and culture; molecular species identification is useful to guide treatment. Although cotrimoxazole is the drug for which we have the strongest clinical experience, other antibiotics such as linezolid, parenteral cephalosporins, carbapenems, and amikacin can be used to treat nocardiosis. Although treatment duration has historically been set to at least 6 months, shorter durations (<120 days) seem associated with a good outcome in selected patients. SUMMARY: Physicians in charge of transplant patients should be aware of nocardiosis. Diagnosis and management of transplant recipients with nocardiosis require a multidisciplinary approach. PMID- 28922287 TI - Pregabalin Toxicity Manifesting as Reversible Encephalopathy With Continuous Triphasic Waves in Electroencephalogram. AB - A 74-year-old man with peripheral neuropathy due to diabetes presented with deliberate ingestion of 450 mg of pregabalin (PBG) over a period of 8 hours followed by altered mental status. A bedside electroencephalogram was performed to rule out nonconvulsive status epilepticus, which showed continuous triphasic waves (TWs) with slow background activity. He recovered after 48 hours of stopping PBG, and his repeat electroencephalogram after 72 hours did not show any TWs. We present a rare case of PBG-induced TWs thereby highlighting the extent of the etiologic spectrum of TWs and discussing the literature related to this association. PMID- 28922288 TI - Addition of Filgrastim (Neupogen) for Clozapine Rechallenge in the Case of Parkinson Disease Patient. PMID- 28922289 TI - Letter to the Editor About "Efficacy of Treatments for Infantile Spasms: A Systematic Review". PMID- 28922290 TI - Effectiveness of Low-Dose Aripiprazole Monotherapy in the Treatment for an Adolescent With Obsessive-Compulsive Disorder. PMID- 28922291 TI - Population-based models of planning for palliative care in older people. AB - PURPOSE OF REVIEW: Health service planning requires demographic, clinical, and health systems data and is unique to each health system. Planning for palliative care in older people must include patients and their carers. This review explores literature from the last 24 months. RECENT FINDINGS: The proportion of people living in skilled nursing facilities is increasing and many residents require quality palliative care. Simultaneously, the complexity of care for older people is also increasing. Systematic approaches to improving palliative care in these facilities have shown benefits that are cost-effective.Although advance care planning is widely promoted, a randomized controlled trial failed to show the benefits seen in nonrandomized trials. This requires a reconceptualization of current programs that seek to increase uptake.Caregivers take on complex decision making which can be stressful. By contrast, patients are often very confident that the people who are close to them will make good decisions on their behalf.Specific subgroups considered in this review include carers (and the challenges they face), the 'oldest old' and people with dementia. SUMMARY: Excellent research is being done to improve the care of older people with palliative care needs. Ultimately, how can key findings be incorporated into clinical care? PMID- 28922292 TI - Advances in delivery of ambulatory autologous stem cell transplantation for multiple myeloma. AB - PURPOSE OF REVIEW: Autologous stem cell transplantation (ASCT) is generally performed in the inpatient setting in its entirety. Several centers have demonstrated the feasibility of performing ASCT for myeloma in the ambulatory setting. We review the safety, cost-effectiveness, complications and outcomes of outpatient ASCT for myeloma. RECENT FINDINGS: Published studies are heterogeneous but suggest that outpatient ASCT for myeloma is cost-effective and associated with a shorter or no initial hospitalization, albeit there is a high rate of readmission for complications. The transplant-related mortality rate is less than 1%. Stringent patient selection criteria that include emphasis on functional status, caregiving support and psychosocial aspects for each patient are critical for identifying patients most appropriate for ASCT in the ambulatory setting. There exists considerable variability in outpatient transplant models and supportive care guidelines and data do not support preference for one delivery model over another. Survival and other transplant-related outcomes have not been reported widely and whether patients fare better with outpatient transplantation remains to be explored. SUMMARY: Outpatient ASCT for multiple myeloma is feasible and well tolerated in selected patients. Several care models for outpatient ASCT exist and can be implemented based on transplant resources and preference. PMID- 28922293 TI - The role of vitamin D in cancer cachexia. AB - PURPOSE OF REVIEW: The possibility to use vitamin D supplementation to improve muscle wasting, with particular focus on cancer cachexia, is discussed. RECENT FINDINGS: Vitamin D exerts biological actions on myogenic precursor proliferation and differentiation, impinging on muscle regeneration. However, the effects of VitD supplementation in diseases associated with muscle atrophy, such as cancer cachexia, are poorly investigated. Data obtained in experimental models of cancer cachexia show that the administration of vitamin D to tumor-bearing animals is not able to prevent or delay both muscle wasting and adipose tissue depletion, despite increased expression of muscle vitamin D receptor. Not just vitamin D supplementation impairs muscle damage-induced regeneration, suggesting that upregulation of vitamin D receptor signaling could contribute to muscle wasting. SUMMARY: Vitamin D supplementation is likely beneficial to reduce or delay aging related sarcopenia and osteoporosis, although the available data still put in evidence significant discrepancies. By contrast, VitD supplementation to tumor bearing animals or to rats with arthritis was shown to be totally ineffective. In this regard, the adoption of VitD treatment in patients with cancer cachexia or other chronic diseases should be carefully evaluated, in particular whenever a regenerative process might be involved. PMID- 28922294 TI - Health professionals' quality of life in relation to end of life care. AB - PURPOSE OF REVIEW: Palliative care professionals are frequently exposed to stressful and demanding situations in the assistance of patients and their families, therefore research related to their quality of life is a relevant topic to provide evidence on interventions oriented to professional self-care. RECENT FINDINGS: Research about professionals' quality of life is having a profuse development with core concepts being under review. SUMMARY: Currently, burnout syndrome and compassion fatigue are considered relevant determinants of professionals' quality of life. Self-awareness-based interventions could bring positive influence on the context of a multidimensional approach to professionals' self-care. Self-care topics should be considered to be included in professional training programmes. PMID- 28922295 TI - Spiritual needs of patients with cancer in palliative care: an integrative review. AB - PURPOSE OF REVIEW: The experience of a life crisis, such as the experience of end of-life terminality whenever facing cancer can make the spiritual needs of patients clear. The goal of this revision was to synthesize the existing evidence regarding the spiritual needs of patients with cancer in palliative care. RECENT FINDINGS: An integrated revision of the literature was conducted regarding the database sources from PubMed, CINAHL, EMBASE, LILACS and Scopus, without publishing year restrictions. There were 16 primary studies included. A total of 1469 patients have been evaluated, whereas eight groups of spiritual needs have been identified: finding the meaning and purpose of life; finding the meaning in experiencing the disease; being connected to other people, God and nature; having access to religious/spiritual practices; physical, psychological, social and spiritual wellbeing; talking about death and the experience of dying; making the best out of their time; being independent and being treated like a normal person. SUMMARY: It is essential to pay attention to patients' spiritual dimensions regarding palliative care. Therefore, patients' spiritual needs must be identified and remedied or mitigated. It is necessary to develop studies that find specific strategies and interventions for the treatment of these needs. PMID- 28922296 TI - Trajectories of Glycemic Change in a National Cohort of Adults With Previously Controlled Type 2 Diabetes. AB - BACKGROUND: Individualized diabetes management would benefit from prospectively identifying well-controlled patients at risk of losing glycemic control. OBJECTIVES: To identify patterns of hemoglobin A1c (HbA1c) change among patients with stable controlled diabetes. RESEARCH DESIGN: Cohort study using OptumLabs Data Warehouse, 2001-2013. We develop and apply a machine learning framework that uses a Bayesian estimation of the mixture of generalized linear mixed effect models to discover glycemic trajectories, and a random forest feature contribution method to identify patient characteristics predictive of their future glycemic trajectories. SUBJECTS: The study cohort consisted of 27,005 US adults with type 2 diabetes, age 18 years and older, and stable index HbA1c <7.0%. MEASURES: HbA1c values during 24 months of observation. RESULTS: We compared models with k=1, 2, 3, 4, 5 trajectories and baseline variables including patient age, sex, race/ethnicity, comorbidities, medications, and HbA1c. The k=3 model had the best fit, reflecting 3 distinct trajectories of glycemic change: (T1) rapidly deteriorating HbA1c among 302 (1.1%) youngest (mean, 55.2 y) patients with lowest mean baseline HbA1c, 6.05%; (T2) gradually deteriorating HbA1c among 902 (3.3%) patients (mean, 56.5 y) with highest mean baseline HbA1c, 6.53%; and (T3) stable glycemic control among 25,800 (95.5%) oldest (mean, 58.5 y) patients with mean baseline HbA1c 6.21%. After 24 months, HbA1c rose to 8.75% in T1 and 8.40% in T2, but remained stable at 6.56% in T3. CONCLUSIONS: Patients with controlled type 2 diabetes follow 3 distinct trajectories of glycemic control. This novel application of advanced analytic methods can facilitate individualized and population diabetes care by proactively identifying high risk patients. PMID- 28922298 TI - The Impact of Nondifferential Exposure Misclassification on the Performance of Propensity Scores for Continuous and Binary Outcomes: A Simulation Study. AB - PURPOSE: To investigate the ability of the propensity score (PS) to reduce confounding bias in the presence of nondifferential misclassification of treatment, using simulations. METHODS: Using an example from the pregnancy medication safety literature, we carried out simulations to quantify the effect of nondifferential misclassification of treatment under varying scenarios of sensitivity and specificity, exposure prevalence (10%, 50%), outcome type (continuous and binary), true outcome (null and increased risk), confounding direction, and different PS applications (matching, stratification, weighting, regression), and obtained measures of bias and 95% confidence interval coverage. RESULTS: All methods were subject to substantial bias toward the null due to nondifferential exposure misclassification (range: 0%-47% for 50% exposure prevalence and 0%-80% for 10% exposure prevalence), particularly if specificity was low (<97%). PS stratification produced the least biased effect estimates. We observed that the impact of sensitivity and specificity on the bias and coverage for each adjustment method is strongly related to prevalence of exposure: as exposure prevalence decreases and/or outcomes are continuous rather than categorical, the effect of misclassification is magnified, producing larger biases and loss of coverage of 95% confidence intervals. PS matching resulted in unpredictably biased effect estimates. CONCLUSIONS: The results of this study underline the importance of assessing exposure misclassification in observational studies in the context of PS methods. Although PS methods reduce confounding bias, bias owing to nondifferential misclassification is of potentially greater concern. PMID- 28922300 TI - Recent advances in the field of warm ex-vivo liver perfusion. AB - PURPOSE OF REVIEW: Organ shortage remains a major obstacle for liver transplantation, resulting in an increased mortality on the liver transplant waiting list. The usage of extended criteria donors (ECD) is a strategy to increase the number of available donor organs, however, with the risk of a higher rate of posttransplant graft dysfunction. Novel preservation strategies, such as warm ex-vivo liver perfusion, could improve the outcome of liver transplantation with ECD grafts. The present review summarizes the advances in the field of warm ex-vivo liver perfusion over the last 12 months. RECENT FINDINGS: The feasibility and safety of warm ex-vivo liver perfusion has been determined in several single center clinical trials. Furthermore, a large phase III multicenter trial demonstrated decreased liver injury and improved graft function in warm perfused versus cold stored grafts. New strategies for graft assessment and modification during machine perfusion have been evaluated with promising results. SUMMARY: Warm ex-vivo liver perfusion has been successfully translated into the clinical setting. Recent research is focusing on graft assessment and graft modification during machine perfusion. PMID- 28922301 TI - Hypothermic liver perfusion. AB - PURPOSE OF REVIEW: The review describes recent developments in hypothermic machine liver perfusion with a special focus on underlying protective mechanisms, and the role of this perfusion technique in high-risk donor-recipient combinations. RECENT FINDINGS: To maximize the number of transplantable donor livers, several centres are exploring new machine preservation techniques. In this context, hypothermic machine perfusion has been recently introduced into the clinical setting of human liver transplantation, and the effect of endischemic cold liver perfusion on posttransplant complications is currently under investigation in two multicentre, randomized controlled trials. In addition, current case series demonstrated promising results regarding the protection from intrahepatic biliary complications, particularly when livers from extended criteria donors including donation after circulatory death grafts were used. Hypothermic machine perfusion may, therefore, help to push the boundaries of acceptance criteria for high-risk donor livers. SUMMARY: In this review, we, first, describe the concept of hypothermic machine liver perfusion and present results from current clinical studies. Next, we provide details of our perfusion approach step-by-step and highlight novel pathways of reperfusion injury and protection. Third, we discuss the impact of this perfusion approach in different clinical scenarios. Finally, we report on recent clinical implementations and future aspects. PMID- 28922302 TI - Resident Knowledge, Surgical Skill, and Confidence in Transobturator Vaginal Tape Placement: The Value of a Cadaver Laboratory. AB - OBJECTIVES: The objective of this study is to examine the effect of additional cadaver laboratory use in training obstetrics and gynecology (OBGYN) residents on transobturator vaginal tape (TOT) insertion. METHODS: Thirty-four OBGYN residents were randomized into 2 groups (group 1, control; group 2, intervention; 17 in each group). Before and after the interventions, written knowledge and confidence levels were assessed. Both groups received didactic lectures using a bony pelvis and an instructional video on TOT insertion; group 2 participated in a half day cadaver laboratory. Surgical skills were assessed by placing 1 arm of the TOT trocar on a custom-designed pelvic model simulator while being graded by an Female Pelvic Medicine and Reconstructive Surgery (FPMRS) board-certified proctor. RESULTS: Demographics were comparable. Baseline knowledge and confidence level before interventions were similar. After interventions, knowledge scores improved for both groups (8.8% for group 1; 14.1% for group 2); TOT insertion scores were significantly higher in group 2 (6.76/15 +/- 2.54 group 1; 10.24/15 +/- 2.73 group 2, P < 0.01); confidence scores improved in both groups. The pelvic model simulator was rated as the most useful method to learn TOT placement by group 1. Group 2 rated TOT simulation (47%) and cadaver laboratory (41%). All trainees reported that the pelvic model was highly realistic. CONCLUSIONS: Cadaver laboratory exposure, along with other educational interventions (lectures and video), improves OBGYN residents' confidence, knowledge, and surgical skills regarding TOT placement. The custom-designed pelvic model allows for a realistic simulation of TOT placement: it can be used to assess resident surgical skills and also aid the training of OBGYN residents. PMID- 28922303 TI - Perioperative Outcomes, Complications, and Efficacy of Robotic-Assisted Prolapse Repair: A Single Institution Study of 196 Patients. AB - : Abdominal pelvic organ prolapse repair is efficacious for uterovaginal and apical prolapse. We describe the safety and efficacy of robotic prolapse repair in a large teaching institution. METHODS: Consecutive robotic-assisted prolapse repairs at a single institution between 2006 and 2014 were retrospectively reviewed for patient characteristics, operative information, and outcomes. RESULTS: A total of 196 women (mean age, 61 +/- 9 years) underwent robotic prolapse repair (189 sacrocolpopexy, 6 sacrohysteropexy, 1 enterocele repair). Concomitant procedures included hysterectomy (88), midurethral sling (84), and/or Burch colposuspension (7). Mean odds ratio time was 242 +/- 69.9 minutes, and median length of stay was 1 day. Intraoperative complications were as follows: cystotomy (4), vaginotomy (4), conversion to open (2), bowel injury/aborted (1), adhesions/aborted (1), and ureteral injury (1). Women with complications had greater blood loss than those without complications (P = 0.0015). Immediate (<30 days) postoperative complications were rare: port-site hernia (2), discitis (1), ileus (1), and ulnar neuropraxia (3). At median follow-up of 9 months (range, 0 85 months), 14 women had recurrent grade 3 prolapse, and 4 had grade 2 apical prolapse. Nine of 14 women had additional prolapse repair at a mean of 9.5 +/- 6.3 months. Vaginal mesh exposure was detected in 12 (6.3%) of 192 women. There were 6 procedures for mesh exposure and 2 procedures for exposed sutures. One mesh erosion into the bladder required open excision. CONCLUSIONS: In this large series of robotic prolapse repair, complications are infrequent. Short-term apical outcomes are excellent. Few women required additional compartment repairs within 1 year with 6% rate of mesh exposure. PMID- 28922304 TI - Estimated Blood Loss During Vaginal Hysterectomy and Adnexal Surgery Described With an Intraoperative Pictographic Tool. AB - OBJECTIVE: We describe a novel way to calculate estimated blood loss (EBL) using an intraoperative pictographic tool in gynecologic surgery. METHODS: A pictographic tool to estimate sponge saturation was developed to calculate EBL during surgery. A prospective cohort of women 18 years or older undergoing benign vaginal hysterectomy with planned adnexal surgery at Mayo Clinic were consented for use of the pictographic tool. Demographic, preoperative, intraoperative, and postoperative data were abstracted. Estimated blood loss was compared among surgeons, anesthesia providers, and the pictographic tool and then correlated with change in hemoglobin. RESULTS: Eighty-one patients met inclusion with mean age of 45.3 +/- 8.7 years. Successful vaginal hysterectomy was achieved in all patients with successful completion of planned adnexectomy in 69 (85.2%). Mean EBL among surgeons, anesthesia providers, and pictographic estimates, respectively, was as follows: 199.4 +/- 81.9 mL, 195.5 +/- 152.2 mL, and 288.5 +/ 186.6 mL, with concordance correlation coefficients for surgeons and anesthesia providers versus pictographic tool of 0.40 (95% confidence interval, 0.29-0.51) and 0.68 (95% confidence interval, 0.57-0.79), respectively. The mean postoperative change in hemoglobin was -1.8 g/dL; there were no postoperative transfusions. Change in hemoglobin was more correlated with blood loss estimates from surgeons (r = -0.31, P = 0.008) and anesthesia providers (r = -0.37, P = 0.003) than the pictographic tool (r = -0.19, P = 0.11). CONCLUSIONS: Use of a pictographic tool to objectively estimate blood loss demonstrated significant overestimations compared with both anesthesia providers' and surgeons' estimates because the pictographic tool was less correlated with postoperative change in hemoglobin than anesthesia provider and surgeon estimates. PMID- 28922305 TI - Mayer-Rokitansky-Kuster-Hauser Syndrome With Bilateral Ovarian Sertoli Cell Tumors: Review of the Literature and Report of a Rare Case. AB - BACKGROUND: Patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome are infertile secondary to hypoplasia or complete agenesis of the uterus, yet they remain at risk of primary neoplasms of the ovaries because embryologically the uterus and ovaries develop via separate mechanisms. CASE: A 72-year-old nulliparous woman with a history of primary amenorrhea underwent an exploratory laparotomy for a suspected uterine fibroid. In addition to the pelvic mass, the patient was found to have findings consistent with MRKH syndrome. Postoperative pathological examination demonstrated bilateral ovarian Sertoli cell tumors. CONCLUSIONS: The case presented is unique in that 2 rare pathologies, bilateral Sertoli cell tumors of the ovary and MRKH syndrome, developed concomitantly in the same patient. PMID- 28922306 TI - Do the Surgical Outcomes of Rectovaginal Fistula Repairs Differ for Obstetric and Nonobstetric Fistulas? A Retrospective Cohort Study. AB - OBJECTIVES: Rectovaginal fistulas can occur from both obstetric and nonobstetric (eg, inflammatory bowel disease, iatrogenic, or traumatic) etiologies. Current data on factors contributing to rectovaginal repair success or failure are limited, making adequate patient counseling difficult. Our objective was to compare outcomes of transperineal rectovaginal fistula repair performed in a single referral center on women with obstetric and nonobstetric causes. METHODS: We performed a retrospective cohort study of women who had a transperineal rectovaginal fistula repair performed by a urogynecologist at the University of Michigan from 2005 to 2015. Data were obtained by chart review and included demographics, medical comorbidities, fistula etiology, history of a prior fistula repair, failure of current repair, time to failure, and operative details. Repair failure was defined as fistula symptoms with presence of recurrent fistula on exam or imaging in the postoperative follow-up period. Comparisons between the obstetric and nonobstetric cohorts were performed using chi, Fisher exact, and Wilcoxon rank sum tests. Relative risks were calculated to identify predictors of failure. RESULTS: Eighty-eight women were included-53 obstetric and 35 nonobstetric fistulas. The overall fistula repair failure rate was 22.7% (n = 20). Median follow-up was 157.0 days (range, 47.5-402.0). Of all the factors, only nonobstetric etiology was significantly associated with an increased risk of repair failure (relative risk, 3.53 [range, 1.50-8.32]; P = 0.004. CONCLUSIONS: Nonobstetric rectovaginal fistulas have a nearly 4-fold increased risk of repair failure compared with obstetric fistulas. Our results will help surgeons adequately counsel patients on potential outcomes of surgical repair of obstetric versus nonobstetric rectovaginal fistulas. PMID- 28922307 TI - Safe summers: Adapting evidence-based injury prevention into a summer curriculum. AB - BACKGROUND: Unintentional injury is the leading cause of death for those aged 0 years to 19 years. St. Louis Children's Hospital created Safety Land, a comprehensive injury prevention intervention which is provided during summer months. This program uses a life-size board game to teach safety education to children in ages 5 years to 11 years. The purpose of this study was to evaluate the effect of Safety Land on safety knowledge in children that participated in the intervention. METHODS: St. Louis Children's Hospital identified ZIP codes with the highest use of the emergency room for injury. Daycares and summer camps within these ZIP codes were targeted for the Safety Land intervention. A multiple choice pretest and posttest survey was designed to measure knowledge change within program participants. Students were selected for testing based on site availably. Within these sites, a convenience sample of children was selected for pretesting and posttesting. Safety Land staff conducted the pretest a week before the intervention, and the posttest was administered the week after the intervention. A total knowledge score was calculated to determine overall knowledge change. Descriptive statistics and independent-samples t tests were conducted to determine statistical significance of change in knowledge (p < 0.05) for each question. RESULTS: Between May 2014 and August 2016, 3,866 children participated in Safety Land. A total of 310 children completed the pretest and 274 completed the posttest. Mean test scores increased from 66.7% to 85.1% and independent-samples t test of the total knowledge score was significant (p < 0.05) between pretest and posttest values. CONCLUSION: Findings suggest that this intervention is effective in increasing the knowledge of safety behaviors for children receiving the curriculum during the summer months. Further research should focus on long-term behavior changes in these youth. PMID- 28922308 TI - LARGE RETINAL PIGMENT EPITHELIAL RIP ASSOCIATED WITH BULLOUS RETINAL AND CHOROIDAL DETACHMENT. AB - PURPOSE: To report a giant retinal pigment epithelium rip in a patient with a bullous retinal and choroidal detachment. METHODS: Case report with widefield imaging, fundus autofluorescence, and optical coherence tomography of the retina. RESULTS: This 62-year-old patient had a history of advanced glaucoma, trabeculectomy, blebitis, and endophthalmitis. He had cataract surgery 6 weeks before presentation. He was found to have a large bullous retinal and choroidal detachment with a large retinal pigment epithelium tear at the limit of the choroidal detachment. After vitrectomy for retinal detachment repair, the tear was observed to extend inferiorly at the margins of the choroidal detachment. CONCLUSION: This case report demonstrates that large retinal pigment epithelium rips can be found associated with large bullous choroidal and retinal detachments. These tears seem similar to tears that have been observed after trabeculectomy. PMID- 28922309 TI - Quantifying the Physiological Stress Response to Simulated Maritime Pilotage Tasks: The Influence of Task Complexity and Pilot Experience. AB - OBJECTIVE: The aim of this study was to quantify the stress associated with performing maritime pilotage tasks in a high-fidelity simulator. METHODS: Eight trainee and 13 maritime pilots completed two simulated pilotage tasks of varying complexity. Salivary cortisol samples were collected pre- and post-simulation for both trials. Heart rate was measured continuously throughout the study. RESULTS: Significant changes in salivary cortisol (P = 0.000, eta = 0.139), average (P = 0.006, eta = 0.087), and peak heart rate (P = 0.013, eta = 0.077) from pre- to postsimulation were found. Varying task complexity did partially influence stress response; average (P = 0.016, eta = 0.026) and peak heart rate (P = 0.034, eta = 0.020) were higher in the experimental condition. Trainees also recorded higher average (P = 0.000, eta = 0.054) and peak heart rates (P = 0.027, eta = 0.022). CONCLUSION: Performing simulated pilotage tasks evoked a measurable stress response in both trainee and expert maritime pilots. PMID- 28922310 TI - The Astounding Reciprocity of Movement-Related Interactions. PMID- 28922311 TI - Motor Imagery Training After Stroke: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND AND PURPOSE: A number of studies have suggested that imagery training (motor imagery [MI]) has value for improving motor function in persons with neurologic conditions. We performed a systematic review and meta-analysis to assess the available literature related to efficacy of MI in the recovery of individuals after stroke. METHODS: We searched the following databases: PubMed, Web of Knowledge, Scopus, Cochrane, and PEDro. Two reviewers independently selected clinical trials that investigated the effect of MI on outcomes commonly investigated in studies of stroke recovery. Quality and risk of bias of each study were assessed. RESULTS: Of the 1156 articles found, 32 articles were included. There was a high heterogeneity of protocols among studies. Most studies showed benefits of MI, albeit with a large proportion of low-quality studies. The meta-analysis of all studies, regardless of quality, revealed significant differences on overall analysis for outcomes related to balance, lower limb/gait, and upper limb. However, when only high-quality studies were included, no significant difference was found. On subgroup analyses, MI was associated with balance gains on the Functional Reach Test and improved performance on the Timed Up and Go, gait speed, Action Research Arm Test, and the Fugl-Meyer Upper Limb subscale. DISCUSSION AND CONCLUSIONS: Our review reported a high heterogeneity in methodological quality of the studies and conflicting results. More high-quality studies and greater standardization of interventions are needed to determine the value of MI for persons with stroke.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A188). PMID- 28922312 TI - Maximum Step Length Test Performance in People With Parkinson Disease: A Cross sectional Study. AB - BACKGROUND AND PURPOSE: The Maximum Step Length Test (MSLT), a measure of one's capacity to produce a large step, has been studied in older adults, but not in people with Parkinson disease (PD). We characterized performance and construct validity of the MSLT in PD. METHODS: Forty participants (mean age: 65.12 +/- 8.20 years; 45% female) with idiopathic PD completed the MSLT while "OFF" and "ON" anti-PD medication. Construct validity was investigated by examining relationships between MSLT and measures of motor performance. The following measures were collected: Mini-Balance Evaluation Systems Test (Mini-BESTest), Activities-specific Balance Confidence (ABC) scale, gait velocity, 6-minute walk test (6MWT), Movement Disorder Society-Unified Parkinson Disease Rating Scale subsection III (MDS-UPDRS III), and Timed Up and Go (TUG) test. A repeated measures analysis of variance tested for main effects of medication and stepping direction and the interaction between the 2. Pearson or Spearman correlations were used to assess the relationships between MSLT and motor performance measures (alpha = 0.05). RESULTS: Regardless of medication status, participants stepped further in the forward direction compared with the backward and lateral directions (P < 0.001). Participants increased MSLT performance when ON medication compared with OFF-medication (P = 0.004). Regardless of medication status, MSLT was moderately to strongly related to Mini-BESTest, TUG, and 6MWT. DISCUSSION AND CONCLUSIONS: People with PD stepped furthest in the forward direction when performing the MSLT. Increased MSLT performance was observed in the ON-medication state compared with OFF-medication; however, the small increase may not be clinically meaningful. Given the relationships between the MSLT and the Mini-BESTest, 6MWT, and TUG, MSLT performance appears to be associated with balance and gait hypokinesia in people with PD.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A186). PMID- 28922313 TI - Lateral Perturbation-Induced Stepping: Strategies and Predictors in Persons Poststroke. AB - BACKGROUND AND PURPOSE: Falls commonly occur as weight is transferred laterally, and impaired reactive stepping responses are associated with falls after stroke. The purpose of this study was to examine differences in and the determinants of mediolateral (M-L) protective stepping strategies when pulled off balance toward the paretic and nonparetic sides. METHODS: Eighteen individuals more than 6 months poststroke were pulled in the M-L direction by a lateral waist-pull perturbation system. Step type (crossover, medial, and lateral) and count were recorded, along with first-step initiation time, length, and clearance. Sensorimotor variables including hip adductor/abductor and ankle plantar flexor/dorsiflexor peak isokinetic torques, paretic foot plantar cutaneous sensation, and motor recovery were used to predict step type by discriminant function analyses (DFAs). RESULTS: Regardless of pull direction, nearly 70% of trials required 2 or more recovery steps, with more frequent nonparetic leg first steps, 63.5%. The step type was significantly different for pull direction (P = 0.005), with a greater percentage of lateral steps when pulled toward the nonparetic side (45.1%) compared with the paretic side (17.5%). The M-L step length of the lateral step was increased (P < 0.001), with a reduced step clearance (P = 0.05), when pulled toward the paretic side compared with a pull toward the nonparetic side. DFAs revealed that nonparetic and paretic-side pulls could respectively classify step type 64% and 60% of the time, with foot cutaneous sensation discriminating for pull direction. DISCUSSION AND CONCLUSIONS: Balance recovery initiated with the nonparetic leg occurred more frequently in response to M-L perturbations, and paretic foot cutaneous sensation was an important predictor of the stepping response regardless of the pull direction.Video Abstract available for more insights from the authors (see Video, Supplementary Digital Content 1, http://links.lww.com/JNPT/A190). PMID- 28922314 TI - Temporal Indices of Ankle Clonus and Relationship to Electrophysiologic and Clinical Measures in Persons With Spinal Cord Injury. AB - BACKGROUND AND PURPOSE: Clonus arising from plantar flexor hyperreflexia is a phenomenon that is commonly observed in persons with spastic hypertonia. We assessed the temporal components of a biomechanical measure to quantify ankle clonus, and validated these in persons with spasticity due to spinal cord injury. METHODS: In 40 individuals with chronic (>1 year) spinal cord injury, we elicited ankle clonus using a standardized mechanical perturbation (drop test). We examined reliability and construct validity of 2 components of the drop test: clonus duration (timed with a stopwatch) and number of oscillations in the first 10-second interval (measured via optical motion capture). We compared these measures to the Spinal Cord Assessment Tool for Spastic reflexes (SCATS) clonus score and H-reflex/M-wave (H/M) ratio, a clinical and electrophysiologic measure, respectively. RESULTS: Intra- and interrater reliability of clonus duration measurement was good [intraclass correlation coefficient, ICC (2, 1) = 1.00]; test-retest reliability was good both at 1 hour [ICC (2, 2) = 0.99] and at 1 week [ICC (2, 2) = 0.99]. Clonus duration was moderately correlated with SCATS clonus score (r = 0.58). Number of oscillations had good within-session test-retest reliability [ICC (2, 1) > 0.90] and strong correlations with SCATS clonus score (r = 0.86) and soleus H/M ratio (r = 0.77). DISCUSSION AND CONCLUSIONS: Clonus duration and number of oscillations as measured with a standardized test are reliable and valid measures of plantar flexor hyperreflexia that are accessible for clinical use. Tools for objective measurement of ankle clonus are valuable for assessing effectiveness of interventions directed at normalizing reflex activity associated with spasticity.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A179). PMID- 28922315 TI - Validation of Fear of Falling and Balance Confidence Assessment Scales in Persons With Dystonia. AB - BACKGROUND AND PURPOSE: Falls are problematic for people living with neurological disorders and a fear of falling can impact on actual falls. Fear of falling is commonly assessed using the Falls Self-Efficacy Scale International (FES-I) or the Activities-specific Balance Confidence (ABC) Scale. These scales can predict risk of falling. We aimed to validate the FES-I and the ABC in persons with dystonia. METHODS: We conducted an online survey of people with dystonia, collecting information on demographics, 6-month falls history, dystonia disability, and the FES-I and ABC scales. Scales were validated for structural validity and internal consistency. We also examined goodness-of-fit, convergent validity, and predictive validity, and determined cutoff scores for predicting falls risk. RESULTS: Survey responses (n = 122) showed that both FES-I and ABC scales have high internal validity and convergent validity with the Functional Disability Questionnaire in persons with dystonia. Each scale examines a single factor, fear of falling (FES-I) and balance confidence (ABC). At least one fall was reported by 39% of participants; the cutoff value for falls risk was found to be 29.5 and 71.3 for the FES-I and the ABC respectively. DISCUSSION AND CONCLUSIONS: The FES-I and the ABC scales are valid scales to examine fear of falling and balance confidence in persons with dystonia. Fear of falling is high and balance confidence is low and both are worse in those with dystonia who have previously fallen.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A182). PMID- 28922316 TI - Barnes and Leahy Promotion of Doctoral Studies (PODS) 2017 Awards. PMID- 28922317 TI - Medical genetic services in a developing country: lesson from Thailand. AB - PURPOSE OF REVIEW: The aim of the review was to give an example of how advances in medical genetics impact a developing country and how Thailand struggles to improve medical genetic services. RECENT FINDINGS: Thailand is an example of a developing country with limited resources and low geneticist-to-population ratio. The country formally followed decentralized healthcare system (even though practically centralized) and is a nation with growing public interest in medical genetic technology. Nonetheless, efforts have been and are still being made in expanding clinical genetics services, improving access to laboratory diagnosis, increasing rare disease medication in national formulary, and the training of medical genetics personnel. For an endemic genetic disorder such as thalassemia, a universal prevention and control program is available and has had some success. SUMMARY: Lesson learned in country like Thailand may be a useful model for other developing nations. Several strategies can be attempted to integrate the advances in medical genetics into medical practices in developing countries with relatively low income per capita and geographic discrepancy in healthcare distribution. PMID- 28922318 TI - Vaccination during pregnancy: first line of defense for expecting mothers and vulnerable young infants. AB - PURPOSE OF REVIEW: Maternal vaccination is a well-tolerated and effective way to protect mothers, their developing fetuses, and their young infants from infectious diseases. Although influenza vaccine and diphtheria, tetanus, and acellular pertussis (Tdap) vaccine are recommended for all pregnant women, uptake rates in the United States remain low. This review will focus on the rationale, scientific evidence, and perceptions of vaccination during pregnancy. RECENT FINDINGS: Recent studies show that administration of influenza and Tdap vaccines during pregnancy is well tolerated and provides protection to the pregnant woman, her fetus, and young infant. Studies have shown that many pregnant women look to their obstetricians to guide their prenatal care. A strong provider recommendation remains the greatest impetus to increase vaccine uptake. Both healthcare providers and expectant mothers should continue to be educated on the importance and safety of the influenza and Tdap vaccines during pregnancy. SUMMARY: Providers play a central role in advising patients and their families about the importance of maternal vaccination. The strong recommendation of providers and the availability of maternal vaccines in OB/GYN offices are keys to improve vaccine uptake. Attention must be paid to further development of intervention techniques that address unique barriers such as vaccine cost, storage concerns, and misinformation about vaccine safety. PMID- 28922319 TI - Disparities in access to care in marginalized populations. AB - PURPOSE OF REVIEW: The current article reviews recent literature related to three groups whose health is affected by barriers to the healthcare system: refugee and immigrant populations; youth who are lesbian, gay, bisexual, transgender, queer, or questioning; and those with mental health problems. RECENT FINDINGS: Refugee and immigrant populations are increasing worldwide, and recent work has focused on improving their access to mental, dental, and preventive care. Lesbian, gay, bisexual, transgender, queer, or questioning youth have unique healthcare needs but frequently lack a support system and may not be forthcoming about their sexuality or sex identity. A rising number of children are being diagnosed with mental health disorders, but due to multiple factors, youth are not receiving the care they need. SUMMARY: Pediatric healthcare providers should be aware of the unique challenges faced by youth displaced from their country of origin, who are lesbian, gay, bisexual, or transgender or are questioning their sexuality or sex identity, and who struggle with mental health disorders. Toolkits, other educational resources, and novel technological advances can assist pediatricians in ensuring optimal health care of these at-risk groups. PMID- 28922320 TI - Autologous Fat Injection versus Lundborg Resection Arthroplasty for the Treatment of Trapeziometacarpal Joint Osteoarthritis. AB - BACKGROUND: Various operative approaches exist for treatment of trapeziometacarpal joint osteoarthritis. The aim of this study was to compare the results of Lundborg resection arthroplasty with solely autologous fat injection. METHODS: Twenty-one patients with symptomatic osteoarthritis of the trapeziometacarpal joint (Eaton-Littler classification stages III/IV) underwent either a Lundborg resection arthroplasty (n = 12) or autologous fat injection into the trapeziometacarpal joint (n = 9). Both groups were comparable regarding demographic and clinical data. Patient records were evaluated retrospectively regarding operative time; Disabilities of the Arm, Shoulder, and Hand questionnaire score; postoperative time until resolution of symptoms; pain level; grip and pinch force; and satisfaction with the treatment. RESULTS: Both groups had similar length of follow-up of at least 12 months. The duration of the operation was significantly shorter in the fat group (13 +/- 5 minutes) compared with the resection group (31 +/- 5 minutes) (p < 0.05). The Disabilities of the Arm, Shoulder, and Hand questionnaire score (resection group, 21.9 +/- 6.2; fat group, 24.0 +/- 5.0) and the pain level at follow-up (resection group, 1.0 +/- 0.7; fat group, 2.9 +/- 0.8) were comparable (p > 0.05). The time until complete resolution of symptoms was significantly shorter in the fat group (1.7 +/- 2.1 months) compared with the resection group (5.7 +/- 3.1 months) (p < 0.05). Grip and pinch strength and overall satisfaction with the treatment were comparable (p > 0.05). CONCLUSION: Both autologous fat grafting and Lundborg resection arthroplasty resulted in improved function of the operative hand and a clear reduction of symptoms, whereas autologous fat injection seems to have advantages attributable to a shorter time until resolution of symptoms and shorter operative times. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28922321 TI - Patient-Reported Outcomes following Breast Conservation Therapy and Barriers to Referral for Partial Breast Reconstruction. AB - BACKGROUND: The purpose of this study was to evaluate the self-reported aesthetic outcome of breast conservation therapy in a generalized sample of patients, and to describe potential barriers to referral for partial breast reconstruction. METHODS: Consecutive breast conservation therapy patients completing radiotherapy over a 1-year period at a regional cancer center were identified. Eligible patients were contacted by means of mail/e-mail and invited to participate. Participants completed the BREAST-Q breast conservation therapy module along with a questionnaire examining feelings about breast reconstruction. Multiple regression analysis was performed using the satisfaction with breasts scale as the dependent variable. RESULTS: Surveys were completed by 185 of 592 eligible participants (response rate, 31.3 percent; mean age, 61 years) an average of 38 months after lumpectomy. The mean score for the BREAST-Q satisfaction with breasts scale was 59 of 100. Younger age (p = 0.038), lumpectomy reexcision (p = 0.018), and lumpectomy at a nonacademic center (p = 0.026) were significantly associated with lower satisfaction. Bra size, months from lumpectomy, and tumor quadrant/size were not significantly associated with satisfaction (p > 0.05). The most common statements regarding reconstruction were "I don't feel the need for it" (60.0 percent), "I don't like the thought of having breast implants" (22.7 percent), and "I don't want any more surgeon/doctor visits" (22.2 percent). Before lumpectomy, only 1.6 percent had a consultation for reconstruction, and only 22.7 percent were aware of this option. If offered, 33.1 percent of patients would have attended this consultation. CONCLUSION: There is an unmet demand for partial breast reconstruction, with an opportunity to advocate and increase awareness on behalf of patients undergoing breast conservation therapy. PMID- 28922322 TI - Vectra 3D Imaging for Quantitative Volumetric Analysis of the Upper Limb: A Feasibility Study for Tracking Outcomes of Lymphedema Treatment. AB - BACKGROUND: Secondary lymphedema of the upper limb is a common sequela following lymphadenectomy during oncologic surgery. The gold standard for evaluating treatment outcomes in upper limb lymphedema is limb volume measurement. However, current techniques lack sensitivity to localized changes. In this study, the Vectra 3D imaging system was used to accurately and precisely obtain volume measurements of the upper limb in patients with lymphedema. METHODS: A feasibility study was performed in 11 patients with lymphedema and 22 upper extremities; 24 arms were evaluated in total. Three-dimensional images were taken of the upper extremities, and Vectra 3D software was used to calculate the volume of the hand, forearm, and upper arm. These measurements were compared to traditional circumference (tape) and water displacement measurements. RESULTS: The 24 arm volumes ranged from 1517 to 4050 cc. The Vectra 3D provided precise and accurate volume measurements (average SD +/- 1.0 percent of total volume). Measurements of the forearm and upper arm correlated with circumference measurements (R = 0.991) and were in good agreement, with the mean difference between measurement techniques being 2.8 +/- 2.0 percent. Three-dimensional measurements of hand, forearm, and upper arm correlated with water measurements (R = 0.990) and had a mean difference between measurement techniques of 2.6 +/- 2.1 percent. CONCLUSIONS: The Vectra 3D system provides precise and accurate data comparable to those of the most commonly used technique to estimate limb volume (tape measurement) and gold-standard water volume measurement. Three-dimensional imaging also offers several advantages, including time efficiency and obtaining localized measurements with high spatial resolution. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 28922323 TI - Face Graft Scaffold Production in a Rat Model. AB - BACKGROUND: As a route toward face bioengineering, the authors previously reported the production of a complete scaffold by perfusion-decellularization of a porcine ear subunit graft and partial recellularization. To extend the scaffold to the whole face and to down-scale it, they applied their findings to a rodent hemifacial graft model. METHODS: After the animals were killed, seven full thickness rat hemiface grafts were harvested with the common carotid artery and the external jugular vein as a pedicle, and cannulated. Grafts were decellularized by a detergent-based protocol: either by perfusion through the common carotid artery, or by mechanical agitation. After decellularization, samples were analyzed for DNA quantification and histology by hematoxylin and eosin, Masson trichrome, Sirius red, or Safranin O staining. Vascular tree patency was assessed by microangiographic computed tomography after contrast injection. Cell-friendly extracellular matrix was assessed by seeding of human adipose-derived stem cells and vital staining after 7 days of culture. RESULTS: Decellularization was effective in both groups, with a cell clearance at all levels, with the exception of cartilage areas in the agitation-treated groups. Microscopic assessment found a well-preserved extracellular matrix in both groups. Vascular contrast was found in all regions of the scaffolds. After the animals were killed, seeded cells were found viable and well distributed on all scaffolds. CONCLUSIONS: The authors successfully decellularized face grafts in a rodent model, with a preserved vascular tree. Perfusion-decellularization led to better and faster results compared with mechanical agitation but is not mandatory in this model. The rat face is an interesting scaffold model for further recellularization studies, in the final goal of human face bioengineering. PMID- 28922324 TI - Biological Properties and Therapeutic Value of Cryopreserved Fat Tissue. AB - BACKGROUND: Fat grafting frequently requires multiple treatments and thus repeated liposuction to achieve treatment goals. The purpose of this study was to evaluate whether cryopreservation of adipose tissue may facilitate future fat grafting. METHODS: Lipoaspirates were harvested from six women and preserved using two cryopreservation methods: (1) simple cooling to -80 degrees C (cryo-1); or (2) programmed cooling to -196 degrees C (cryo-2). Fresh fat, cryo-1 fat, and cryo-2 fat were analyzed both in vitro and in vivo. RESULTS: Immunohistochemistry of both types of cryopreserved adipose tissue revealed that most adipocytes were necrotic. The cell number and viability of stromal vascular fraction cells were significantly decreased in cryo-1 fat (1.7 * 10 cells, 42.6 percent viable) and cryo-2 fat (2.0 * 10 cells, 55.4 percent viable), compared with fresh fat (3.9 * 10 cells, 90.6 percent viable). Although adipose-derived stem cells were cultured successfully from all fats, functional adipose-derived stem cells from cryopreserved fats were much fewer, with comparable multilineage differentiating capacity. In vivo studies using human fat grafted into immunocompromised mice revealed that, 3 months after transplantation, all of the cryopreserved fats maintained their volume to some extent; however, the cryopreserved fats were mostly filled with dead tissue and produced significantly lower engraftment scores than fresh fat. CONCLUSIONS: Most adipocytes were killed in the process of cryopreservation and thawing. Adipose-derived stem cells were isolated from cryopreserved fat, but the number of functional adipose-derived stem cells was very limited in both cryopreservation methods. After grafting, cryopreserved fat was retained as dead and fibrous tissue, suggesting a risk of clinical complications such as oil cysts. PMID- 28922325 TI - Metacarpal-Like Hand: Classification and Treatment Guidelines for Microsurgical Reconstruction with Toe Transplantation. AB - The metacarpal-like hand is a severe hand injury, never addressed before. It describes a hand that has lost a significant degree of prehension through a wide array of amputations, involving all digits proximal to the functional length except in one finger or in two digits, including the thumb. The thumb condition can be used to differentiate between two types. In type I, the thumb is intact or amputated at or distal to the interphalangeal joint (functional length); therefore, the reconstruction is focused mainly on fingers. In type II, the thumb is amputated proximal to the interphalangeal joint; therefore, the reconstruction is focused on both the thumb and fingers. Thumb amputation level, integrity of the first basal joint, and functionality of the thenar muscles can be used to subdivide type II. Functional reconstruction should consider the patient's desire and vocational needs. The finger left with adequate functional length is assessed for its location, level of amputation, and joint motion, especially the proximal interphalangeal joint. The goal is to use the reliable techniques of toe-to-hand surgery to reconstruct more opposable units, at least two fingers, whether adjacent to each other or not, and the thumb, when needed, to achieve a functionally and aesthetically better hand instead of a functionally adequate hand, with a more acceptable to ideally natural hand cascade. Strategic, individualized toe transfer(s) is the key element in fulfilling the goals of this operation whether single or multiple toes are transplanted. PMID- 28922326 TI - The Smile Index: Part 1. A Large-Scale Study of Phenotypic Norms for Preoperative and Postoperative Unilateral Cleft Lip. AB - BACKGROUND: Unilateral cleft lip has a spectrum of disease morphology, but severity classifications are difficult given the absence of accessible, objective assessment tools or reference data. The authors characterize the spectrum of cleft morphology before and after surgical repair for a large, multi-ethnic population using easily identifiable facial landmarks collected through a novel smart phone-based application. METHODS: Anthropometric measurements and standardized photographs were prospectively collected in Morocco, Bolivia, Vietnam, and Madagascar during medical missions in 2015 using an application designed specifically for the study. After data collection, two experienced cleft surgeons and two laypersons subjectively ranked photographs based on the degree of deformity/aesthetics. RESULTS: One hundred forty-seven patients were analyzed. Mean preoperative cleft width ratio was 0.4 +/- 0.12. Nasolabial symmetry improved significantly from preoperatively to postoperatively for the following measurements: columellar angle (65 +/- 17 degrees to 87 +/- 8 degrees), nostril width ratio (1.7 +/- 0.68 to 1.0 +/- 0.22), philtral height ratio (0.8 +/- 0.14 to 1.0 +/- 0.14), and lip length ratio (0.9 +/- 0.26 to 1.0 +/- 0.11) (p < 0.001). Surgeon and layperson rankings showed high inter-rater reliability (r = 0.64, p < 0.001). Preoperatively, multivariate regression showed that cleft width ratio, nostril width ratio, and philtral height ratio were predictive of rank (p < 0.01). Postoperatively, philtral height ratio was most predictive of rank (p = 0.0097). Most cleft characteristics were not significantly different between countries. CONCLUSIONS: The authors present simpler, more straightforward measures to quantify preoperative and postoperative morphology/aesthetics and introduce a novel technology to streamline and standardize measurements to make data collection more accessible. PMID- 28922327 TI - Releasable Single Suture for Primary Pterygium Excision With a Conjunctival Autograft. AB - PURPOSE: To evaluate the efficacy of a releasable single suture for pterygium excision with a conjunctival autograft (CAG). METHODS: Retrospective case series at a tertiary eye care center in central India was conducted. Medical records of 150 patients, who underwent primary pterygium excision with a CAG secured by a single releasable 10-0 nylon suture in the last year were reviewed. The surgical duration was noted. The suture was released on the first postoperative day under topical anesthesia. Patients were followed up until 1 year. At each visit, factors studied were patient comfort [pain grading on a visual analog scale], graft apposition, complications, and recurrence. RESULTS: Mean age of patients was 39 +/- 11 years. Most patients in our study were female (58.7%). Sixty percent of pterygia were of Tan grade 2. The mean duration of surgery was 4.8 +/- 1.3 minutes. The maximum size of the CAG was 6 mm (3-6 mm). The graft retraction rate was 5.3% (1 mm retraction in the CAG more than 5.5 mm) with no event of graft loss. Four percent of patients had grade 1 recurrence. CONCLUSIONS: Releasable single suture may offer a good and simple alternative, which uses the gold standard technique of the CAG with exclusion of suture-related complications. PMID- 28922328 TI - Minor Salivary Gland Transplantation for Severe Dry Eyes. AB - Dry eye is a multifactorial disease comprising a wide spectrum of ocular surface alterations and symptoms of discomfort. In most patients with aqueous-deficient dry eye, pharmaceutical tear substitutes are used to control symptoms and prevent ocular surface damage. However, in severe dry eye conditions caused by cicatricial disorders, such as Stevens-Johnson syndrome and ocular cicatricial mucous membrane pemphigoid, noninvasive treatments are insufficient, and patients are at risk of developing complications that can lead to blindness. The use of salivary glands as a source of lubrication to treat severe cases of dry eye has been proposed by different authors. The first reports proposed parotid or submandibular gland duct transplantation into the conjunctival fornix. However, complications limited the functional outcomes. Minor salivary gland autotransplantation together with labial mucosa has been used as a complex graft to the conjunctival fornix in severe dry eye with a good outcome. Our group demonstrated significant improvements in best-corrected visual acuity, Schirmer I test score, corneal transparency, and neovascularization after using this technique. A symptoms questionnaire applied to these patients revealed improvements in foreign body sensation, photophobia, and pain. Similar to tears, saliva has a complex final composition comprising electrolytes, immunoglobulins, proteins, enzymes, and mucins. We demonstrated the viability of minor salivary glands transplanted into the fornix of patients with dry eye by performing immunohistochemistry on graft biopsies with antibodies against lactoferrin, lysozyme, MUC1, and MUC16. The findings revealed the presence of functional salivary gland units, indicating local production of proteins, enzymes, and mucins. PMID- 28922329 TI - Conventional Corneal Collagen Cross-Linking Versus Transepithelial Diluted Alcohol and Iontophoresis-Assisted Corneal Cross-Linking in Progressive Keratoconus. AB - PURPOSE: To compare clinical outcomes of conventional corneal cross-linking (C CXL) and diluted alcohol and iontophoresis-assisted corneal cross-linking (DAI CXL) for the treatment of progressive keratoconus (KC). METHODS: Ninety-three eyes of 80 patients with KC were treated by C-CXL (n = 47) or DAI-CXL (n = 46). Visual acuity, keratometry, KC indexes, pachymetry, and aberrations were recorded before treatment and 1, 3, 6, and 12 months after treatment. The demarcation line was assessed 1 month after treatment. RESULTS: A significant improvement in visual acuity was observed at month 3 and month 6 after DAI-CXL and C-CXL, respectively. A significant decrease in maximum keratometry was observed in both groups at month 6. The front symmetry index significantly improved in both groups after 6 months, whereas the Baiocchi Calossi Versaci index significantly improved only after DAI-CXL at month 12 (P = 0.01). Average keratometry and other KC indexes were stable during 12 months of follow-up. Central corneal thickness decreased by 28.6 and 40.2 MUm after DAI-CXL and C-CXL at month 1, respectively (P < 0.01), and it reached baseline at the 12th month (P = 0.14) only in the DAI CXL group. Higher-order aberrations, coma, and spherical aberration significantly worsened at month 1 (P < 0.01) only after C-CXL; however, they improved significantly at month 12 compared with baseline (P < 0.05) in both groups. The demarcation line was visible in all cases at month 1 at a mean depth of 302 +/- 56 MUm and 311 +/- 57 MUm after DAI-CXL and C-CXL, respectively (P = 0.7). CONCLUSIONS: The DAI-CXL protocol seems as effective as the C-CXL protocol in halting KC progression after 1 year of follow-up. PMID- 28922330 TI - Lamina Cribrosa Thickness in Patients With Keratoconus. AB - PURPOSE: To evaluate the thickness and depth of lamina cribrosa (LC) in the optic nerve head region of the eyes in patients with nonglaucomatous keratoconus and to compare the thickness and depth with those of age-matched controls. METHODS: This was a cross-sectional, observational study comprising 45 patients with keratoconus and 56 healthy subjects. Analysis of LC imaging was performed using spectral domain optical coherence tomography. Data collected included spherical equivalent, central corneal thickness, axial length, intraocular pressure, and keratometry. RESULTS: Eyes with keratoconus had significantly thinner LC (174.9 +/- 11.4 vs. 249.1 +/- 4.9 MUm, P < 0.001) compared with control group eyes. There was no statistically significant difference in the depth of LC between the keratoconus and control groups (P = 0.3). Multivariable analysis, controlled for age and sex, showed that the thickness of LC significantly correlated with central corneal thickness (P < 0.001). This association persisted (P < 0.001) after controlling for intraocular pressure in addition to age and sex. There was no significant correlation with other factors, including the spherical equivalent (P = 0.93) and keratometry (P = 0.46). CONCLUSIONS: The results of this study showed that optical coherence tomography measurement of LC revealed thinner LC for patients with keratoconus compared with healthy controls. The structural properties of the cornea may be related to the optic nerve. PMID- 28922331 TI - Descemet Membrane Thickening as a Sign for the Diagnosis of Corneal Graft Rejection: An Ex Vivo Study. AB - PURPOSE: To disclose, using an ex vivo study, the histopathological mechanism behind in vivo thickening of the endothelium/Descemet membrane complex (En/DM) observed in rejected corneal grafts (RCGs). METHODS: Descemet membrane (DM), endothelium, and retrocorneal membranes make up the total En/DM thickness. These layers are not differentiable by high-definition optical coherence tomography; therefore, the source of thickening is unclear from an in vivo perspective. A retrospective ex vivo study (from September 2015 to December 2015) was conducted to measure the thicknesses of DM, endothelium, and retrocorneal membrane in 54 corneal specimens (31 RCGs and 23 controls) using light microscopy. Controls were globes with posterior melanoma without corneal involvement. RESULTS: There were 54 corneas examined ex vivo with mean age 58.1 +/- 12.2 in controls and 51.7 +/- 27.9 years in RCGs. The ex vivo study uncovered the histopathological mechanism of En/DM thickening to be secondary to significant thickening (P < 0.001) of DM (6.5 +/- 2.4 MUm) in RCGs compared with controls (3.9 +/- 1.5 MUm). CONCLUSIONS: Our ex vivo study shows that DM is responsible for thickening of the En/DM in RCGs observed in vivo by high-definition optical coherence tomography and not the endothelium or retrocorneal membrane. PMID- 28922332 TI - Evaluation of Corneal Neovascularization Using Optical Coherence Tomography Angiography in Patients With Limbal Stem Cell Deficiency. AB - PURPOSE: Detection of the exact area of corneal neovascularization using slit lamp photography is often difficult. Thus, we evaluated corneal neovascularization in patients with limbal stem cell deficiency using optical coherence tomography angiography (OCTA). METHODS: Five patients with 5 eyes showing partial or total limbal stem cell deficiency were enrolled. Three eyes had severe corneal scarring. Five 6- * 6-mm images (frontal, upper, lower, nasal, and temporal) were obtained by OCTA. Slit-lamp photography was performed for all patients on the same day. RESULTS: OCTA has 2 advantages over slit-lamp photography for clear demonstration of corneal neovascularization. First, OCTA can show neovascularization in cases with severe corneal opacification. Second, OCTA can detect not only large vessels but also small vessels that cannot be seen by slit-lamp photography. CONCLUSIONS: OCTA is a powerful tool for objective evaluation of vascularization in the anterior and posterior segments of the eye. We have demonstrated that OCTA can visualize corneal neovascularization in patients with corneal diseases more clearly than slit-lamp photography. PMID- 28922333 TI - ROCK Inhibitor (Ripasudil) as Coadjuvant After Descemetorhexis Without an Endothelial Graft. PMID- 28922334 TI - Common malignant brain tumors: can 18F-FDG PET/CT aid in differentiation? AB - OBJECTIVES: The objectives of this study were to evalute the metabolic characteristics of common malignant space-occupying lesions (SOL) of the brain and to determine the utility of fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT in differentiating between the common types of malignant brain SOL. PATIENTS AND METHODS: All patients with brain SOL who were referred for an F-FDG PET/CT scan by a multidisciplinary team were included in this retrospective study. The metabolic characteristics of the brain lesions in the form of maximum standardized uptake value (SUVmax) along with tumor-to-background activity ratios were determined and differences were compared using nonparametric statistical tests. Histopathological confirmation was used as the gold standard in all patients. Receiver operating characteristic curve analysis was used to find the optimal SUVmax cutoff to differentiate the tumor types. RESULTS: Glioblastoma multiforme (GBM; n=30), lymphoma (n=25), and metastases (n=46) accounted for most malignant tumors (95.2%). Lymphomas showed a significantly high metabolic uptake (median SUVmax=20.3, range: 8.1-46.3) compared with GBM ( median SUVmax=10.3, range: 2.6-21.7) and metastases (median SUVmax=11.5, range: 2.9-19.6) (P=0.00). The tumor-to-background activity ratios for lymphomas were also significantly higher. There was an overlap in the metabolic uptake of GBM and metastases, with no significant difference between their SUVmax values (P=0.245). A SUVmax more than 15.5 showed an 84% sensitivity and an 80% specificity to diagnose lymphomas (area under the curve=0.876, P=0.00). Four patients with brain lymphoma had extracranial disease on F-FDG PET. Lung cancer was the most common primary malignancy in patients with brain metastases. CONCLUSION: Central nervous system lymphomas can be differentiated from GBM and metastases by their higher metabolic activity. In addition, F-FDG PET/CT can potentially impact therapeutic decisions by detecting primary malignancy in patients with metastatic brain lesions and extracranial disease sites in patients with brain lymphoma. PMID- 28922335 TI - The role of 68Ga-PSMA-I&T PET/CT in the pretreatment staging of primary prostate cancer. AB - OBJECTIVES: This retrospective study aimed to evaluate the role of Ga-PSMA-I&T PET/CT in the primary staging of newly diagnosed prostate cancer (PCa), with a focus on the detection of metastatic nodal disease. Correlation of the rate of detection of metastatic disease by Ga-PSMA-I&T PET/CT with the Gleason score (GS) and serum prostate-specific antigen (PSA) was performed to determine the GS and PSA criteria defining patients who would benefit from Ga-PSMA-I&T PET/CT imaging for staging, risk stratification and therapy optimization. PATIENTS AND METHODS: Patient data and images from 70 patients with a recent diagnosis of prostate cancer who had undergone Ga-PSMA-I&T PET/CT were analysed retrospectively. Data and images were analysed for the rate of detection of primary and metastatic PCa, and correlation with PSA and GS. RESULTS: The rate of detection of primary tumour by Ga-PSMA-I&T for patients with serum PSA less than 5 ng/ml was 73%. The corresponding rate was 90% for patients with PSA 5-10 ng/ml and 97% for patients with PSA more than 10 ng/ml. Metastatic PCa and/or infiltrative disease was detected in 24/70 study patients in total: 1/11 patients with PSA less than 5 ng/ml and 23/59 patients with serum PSA at least 5 ng/ml. The rate of detection of metastatic PCa was greater in patients with GS 9 or more (48%) relative to those with GS 8 (32%) or GS <=7 (18%). CONCLUSION: A role for Ga-PSMA-I&T PET/CT in primary PCa staging of high-grade disease (GS 8 or more and PSA >10 ng/ml) has been shown. There was a low rate of detection of PSMA-avid metastases in low grade disease (GS 7 or less and PSA <5 ng/ml), suggesting that there is a limited role for this modality in such cases. PMID- 28922336 TI - Improving women's health in low-income and middle-income countries. Part I: challenges and priorities. PMID- 28922338 TI - Does the beta-receptor antagonist esmolol have analgesic effects?: A randomised placebo-controlled cross-over study on healthy volunteers undergoing the cold pressor test. AB - BACKGROUND: Esmolol may attenuate the sympathetic response to pain and reduce postoperative opioid consumption. It is not clear whether esmolol has an analgesic effect per se. OBJECTIVES: The aim of this study was to evaluate the analgesic effect of esmolol in the absence of anaesthetics and opioids. We tested the hypothesis that esmolol would reduce the maximum pain intensity perceived during the cold pressor test (CPT) by 2 points on a 0 to 10 numeric pain rating scale (NRS) compared to placebo. DESIGN: Randomised, placebo-controlled cross over study. SETTING: Postoperative recovery area, Orebro University Hospital. Study period, November 2013 to February 2014. PARTICIPANTS: Fourteen healthy volunteers. Exclusion criteria included ongoing medication, pregnancy and breastfeeding and participation in other medical trials. INTERVENTIONS: At separate study sessions, participants received interventions: esmolol (0.7 mg kg bolus over 1 min followed by infusion at 10 MUg kg min); 0.9% normal saline bolus then remifentanil infusion at 0.2 MUg kg min and 0.9% normal saline bolus and infusion according to a random sequence. All infusions were administered over 30 min. MAIN OUTCOME MEASURES: Perceived maximum pain intensity score, pain tolerance and haemodynamic changes during CPT, and occurrence of side-effects to interventions compared to placebo, respectively. RESULTS: Esmolol did not reduce perceived pain intensity or pain tolerance during the CPT. The NRS-max score was similar for esmolol, 8.5 (+/-1.4) and placebo, 8.4 (+/-1.3). The mean difference was 0.1 [95% confidence interval (-1.2 to 1.4)], P value equal to 0.83. Remifentanil significantly reduced NRS-max scores, 5.4 (+/-2.1) compared to placebo, [mean difference -3.1 (95% confidence interval (-4.4 to -1.8)), P < 0.001]. Side-effects were seen with remifentanil but not with esmolol. CONCLUSION: No direct analgesic effect of esmolol could be demonstrated in the present study. The postoperative opioid-sparing effect demonstrated in previous studies, could therefore be secondary to other factors such as avoidance of opioid-induced hyperalgesia, synergy with coadministered opioids or altered pharmacokinetics of those drugs. TRIAL REGISTRATION: European clinical trials database, https://eudract.ema.europa.eu/, EudraCT no. 2011-005780-24. PMID- 28922337 TI - Role of the internet as an information resource before anaesthesia consultation: A French prospective multicentre survey. AB - BACKGROUND: Use of the internet as an information search tool has increased dramatically. Our study assessed preoperative use of the internet by patients to search for information regarding anaesthesia, surgery, pain or outcomes. OBJECTIVE(S): The aim of this study was to test whether patients used the internet prior to surgery and what kinds of information they looked for (anaesthetic technique, pain, adverse events, outcomes and surgery). Correlation between patient age and information sought about surgery from the internet was also explored. DESIGN: A prospective multicentre observational study. SETTING: In total, 14 French private and public institutions from May 2015 to January 2016. PATIENTS: In total, 3161 adult patients scheduled for elective surgery under regional or general anaesthesia. INTERVENTION(S): An anonymous questionnaire was presented to adult patients scheduled for elective surgery under regional or general anaesthesia for completion before the first meeting with the anaesthesiologist. The investigator at each centre completed specific items that the patient could not complete. MAIN OUTCOME MEASURES: We defined the primary endpoint as the number of patients who searched for information about their anaesthesia or surgery on the internet by the time of the their preanaesthetic consultation. RESULTS: Of the 3234 questionnaires distributed, responses were received from 3161 patients. Within this respondent sample, 1304 (45%) were professionally active and 1664 (59%) used the internet at least once per day. Among 3098 (98%) patients who answered the question concerning the primary endpoint, 1506 (48%) had searched the internet for information about their health. In total, 784 (25%) used the internet to find information about their surgery and 113 (3.5%) looked for specific information about anaesthesia. Of the 3161, 52% reported difficulty searching for appropriate information about anaesthesia on the internet. 'Daily use of the web' [odds ratio (OR) 2.0; (95% CI: 1.65 to 2.55) P < 0.001], 'use of the web on mobile devices' [OR 1.24; (95% CI: 1.02 to 1.50) P = 0.02] and 'asking general practitioner or surgeon about information' [OR 1.35; (95% CI: 1.11 to 1.64) P = 0.002] were significantly associated with the primary endpoint. CONCLUSION: The internet was not widely used by patients scheduled for elective surgery to search for information about anaesthesia and surgery in our French multicentre study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02442609. PMID- 28922339 TI - Incidence and risk factors of anaesthesia-related perioperative cardiac arrest: A 6-year observational study from a tertiary care university hospital. AB - BACKGROUND: In recent decades, the incidences of anaesthesia-related perioperative mortality and adverse outcomes have decreased drastically. However, to date, data on perioperative cardiac arrest and risk factors of perioperative cardiac arrest from European countries are scarce. OBJECTIVES: To determine the incidences of perioperative cardiac arrest and rates of anaesthesia-related and anaesthesia-contributory cardiac arrest. Identification of pre-existing risk factors leading to perioperative cardiac arrest. DESIGN: Retrospective cohort study. SETTING: Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Germany. INTERVENTIONS: Perioperative critical incident reports between 2007 and 2012 were screened, and reports on cardiac arrest within 24 h postoperatively were identified. Cardiac arrests were classified as 'anaesthesia-related', 'anaesthesia-contributory' or 'anaesthesia unrelated' by two reviewers independently. Univariate and multi-variate logistic regression analysis was used to identify risk factors associated with perioperative cardiac arrest. RESULTS: Analysis of 318 critical incidents from 169 500 anaesthetics revealed 99 perioperative cardiac arrests. This is an overall incidence of perioperative cardiac arrest of 5.8/10 000 anaesthetics [95% confidence interval (CI), 4.7 to 7.0]. The rate of anaesthesia-related cardiac arrest was 0.7/10 000 (95% CI, 0.3 to 1.1), and the rate of anaesthesia contributory cardiac arrest was 1.7/10 000 (95% CI, 1.1 to 2.3). Most cardiac arrests related to anaesthesia were due to respiratory events. From the multi variate analysis, American Society of Anesthesiologists physical status grade at least 3 [P = 0.007, odds ratio (OR) 2.59 (95% CI, 1.29 to 5.19)], emergency surgery [P < 0.001, OR 4.00 (95% CI, 2.15 to 7.54)] and pre-existing cardiomyopathy [P < 0.001, OR 17.48 (95% CI, 6.18 to 51.51)] emerged as predictors of cardiac arrest. CONCLUSION: These first available European data on perioperative cardiac arrest from a large unselected cohort indicate that the overall perioperative incidence of cardiac arrest at our institution was slightly lower than published in the literature, whereas rates of anaesthesia-related and anaesthesia-contributory cardiac arrest were comparable. Most cardiac arrests related to anaesthesia were due to respiratory events. American Society of Anesthesiologists physical status grade at least 3, emergency surgery and pre existing cardiomyopathy appear to be relevant risk factors for cardiac arrest. PMID- 28922340 TI - The impact of continuous non-invasive arterial blood pressure monitoring on blood pressure stability during general anaesthesia in orthopaedic patients: A randomised trial. AB - BACKGROUND: In patients undergoing general anaesthesia, intraoperative hypotension occurs frequently and is associated with adverse outcomes such as postoperative acute kidney failure, myocardial infarction or stroke. A history of chronic hypertension renders patients more susceptible to a decrease in blood pressure (BP) after induction of general anaesthesia. As a patient's BP is generally monitored intermittently via an upper arm cuff, there may be a delay in the detection of hypotension by the anaesthetist. OBJECTIVE: The current study investigates whether the presence of continuous BP monitoring leads to improved BP stability. DESIGN: Randomised, controlled and single-centre study. PATIENTS: A total of 160 orthopaedic patients undergoing general anaesthesia with a history of chronic hypertension. INTERVENTION: The patients were randomised to either a study group (n = 77) that received continuous non-invasive BP monitoring in addition to oscillometric intermittent monitoring, or a control group (n = 83) whose BP was monitored intermittently only. The interval for oscillometric measurements in both groups was set to 3 min. After induction of general anaesthesia, oscillometric BP values of the two groups were compared for the first hour of the procedure. Anaesthetists were blinded to the purpose of the study. MAIN OUTCOME MEASURE: BP stability and hypotensive events. RESULTS: There was no difference in baseline BP between the groups. After adjustment for multiple testing, mean arterial BP in the study group was significantly higher than in the control group at 12 and 15 min. Mean +/- SD for study and control group, respectively were: 12 min, 102 +/- 24 vs. 90 +/- 26 mmHg (P = 0.039) and 15 min, 102 +/- 21 vs. 90 +/- 23 mmHg (P = 0.023). Hypotensive readings below a mean pressure of 55 mmHg occurred more often in the control group (25 vs. 7, P = 0.047). CONCLUSION: Continuous monitoring contributes to BP stability in the studied population. TRIAL REGISTRATION: NCT02519101. PMID- 28922341 TI - 'Working toward understanding oligo and polymetastatic prostate cancer'. PMID- 28922342 TI - Drugs for cognitive loss and dementia. PMID- 28922343 TI - Tocilizumab (Actemra) for giant cell arteritis. PMID- 28922344 TI - Comparison table: drugs for Alzheimer's disease. PMID- 28922345 TI - Tilianin Post-Conditioning Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondrial Protection and Inhibition of Apoptosis. AB - BACKGROUND The aim of this study was to investigate the role of tilianin in modulating mitochondrial functions and mitochondria-mediated apoptosis during cardio-protection. MATERIAL AND METHODS Myocardial ischemia/reperfusion (I/R) injury was induced by 30 minutes coronary occlusion followed by two hours reperfusion in Sprague-Dawley rats. To investigate the cardio-protective effects of tilianin, apoptosis was evaluated by TUNEL. Mitochondrial ultrastructure and function were assessed by transmission electron microscopy, dynamics of mitochondrial permeability transition pore (mPTP) opening and ATP production in the myocardium; Ca2+ content and reactive oxygen species (ROS) were measured to evaluated the level of damage factors in the mitochondria. The related apoptotic proteins were analyzed through immunoblot. RESULTS Pretreatment with tilianin significantly reduced apoptosis after I/R injury in rats (p<0.05). In addition, tilianin could alleviate mitochondrial damage, markedly inhibited mPTP opening and improved ATP production (p<0.05). There was also a significant reduction for content of Ca2+ and ROS in the mitochondria (p<0.01). Apoptosis protein analysis found that treatment with tilianin led to the downregulation of apoptosis inducing factor (AIF) (p<0.01), and suppressed the leakage of cytochrome c and activation of caspase-3 (p<0.05). CONCLUSIONS This study showed that tilianin can alleviate apoptosis of cardiomyocytes and protect myocardium, possibly via the protection of mitochondria and repression of mitochondrial apoptotic pathways. Mechanistically, inhibition of Ca2+ overload, mPTP opening, and ROS production in mitochondria may explain the observed tilianin-mediated treatment effects. PMID- 28922346 TI - GRID-seq reveals the global RNA-chromatin interactome. AB - Higher eukaryotic genomes are bound by a large number of coding and non-coding RNAs, but approaches to comprehensively map the identity and binding sites of these RNAs are lacking. Here we report a method to capture in situ global RNA interactions with DNA by deep sequencing (GRID-seq), which enables the comprehensive identification of the entire repertoire of chromatin-interacting RNAs and their respective binding sites. In human, mouse, and Drosophila cells, we detected a large set of tissue-specific coding and non-coding RNAs that are bound to active promoters and enhancers, especially super-enhancers. Assuming that most mRNA-chromatin interactions indicate the physical proximity of a promoter and an enhancer, we constructed a three-dimensional global connectivity map of promoters and enhancers, revealing transcription-activity-linked genomic interactions in the nucleus. PMID- 28922348 TI - Stem cell biology and regenerative medicine for neonatal lung diseases. AB - Lung diseases remain one of the main causes of morbidity and mortality in neonates. Cell therapy and regenerative medicine have the potential to revolutionize the management of life-threatening and debilitating lung diseases that currently lack effective treatments. Over the past decade, the repair capabilities of stem/progenitor cells have been harnessed to prevent/rescue lung damage in experimental neonatal lung diseases. Mesenchymal stromal cells and amnion epithelial cells exert pleiotropic effects and represent ideal therapeutic cells for bronchopulmonary dysplasia, a multifactorial disease. Endothelial progenitor cells are optimally suited to promote lung vascular growth and attenuate pulmonary hypertension in infants with congenital diaphragmatic hernia or a vascular bronchopulmonary dysplasia phenotype. Induced pluripotent stem cells (iPSCs) are one of the most exciting breakthroughs of the past decade. Patient-specific iPSCs can be derived from somatic cells and differentiated into any cell type. iPSCs can be capitalized upon to develop personalized regenerative cell products for surfactant protein deficiencies-lethal lung disorders without treatment-that affect a single gene in a single cell type and thus lend themselves to phenotype-specific cell replacement. While the clinical translation has begun, more needs to be learned about the biology of these repair cells to make this translation successful. PMID- 28922349 TI - Cytochrome P450 and flavin-containing monooxygenase families: age-dependent differences in expression and functional activity. AB - BackgroundAge-dependent differences in pharmacokinetics exist for metabolically cleared medications. Differential contributions in the cytochrome P450 3A (CYP3A), CYP2C, and flavin-containing monooxygenases (FMOs) families have an important role in the metabolic clearance of a large number of drugs administered to children.MethodsUnlike previous semiquantitative characterization of age dependent changes in the expression of genes and proteins (western blot analysis), this study quantifies both gene and absolute protein expression in the same fetal, pediatric, and adult hepatic tissue. Expression was then correlated with the corresponding functional activities in the same samples.ResultsCYP3A and FMO families showed a distinct switch from fetal (CYP3A7 and FMO1) to adult isoforms (CYP3A4 and FMO3) at birth, whereas CYP2C9 showed a linear maturation from birth into adulthood. In contrast, analysis of CYP2C19 revealed higher expression and catalytic efficiency in pediatric samples compared with that in fetal and adult samples. Further, CYP3A and FMO enzymes exhibited an unexpectedly higher functional activity in fetal samples not entirely explained by protein expression.ConclusionThese surprising findings suggest that CYP and FMO enzymes may encounter development-related differences in their microenvironments that can influence the enzyme activity in addition to protein expression levels. PMID- 28922347 TI - Pearl millet genome sequence provides a resource to improve agronomic traits in arid environments. AB - Pearl millet [Cenchrus americanus (L.) Morrone] is a staple food for more than 90 million farmers in arid and semi-arid regions of sub-Saharan Africa, India and South Asia. We report the ~1.79 Gb draft whole genome sequence of reference genotype Tift 23D2B1-P1-P5, which contains an estimated 38,579 genes. We highlight the substantial enrichment for wax biosynthesis genes, which may contribute to heat and drought tolerance in this crop. We resequenced and analyzed 994 pearl millet lines, enabling insights into population structure, genetic diversity and domestication. We use these resequencing data to establish marker trait associations for genomic selection, to define heterotic pools, and to predict hybrid performance. We believe that these resources should empower researchers and breeders to improve this important staple crop. PMID- 28922352 TI - 60 years ago, Francis Crick changed the logic of biology. AB - In September 1957, Francis Crick gave a lecture in which he outlined key ideas about gene function, in particular what he called the central dogma. These ideas still frame how we understand life. This essay explores the concepts he developed in this influential lecture, including his prediction that we would study evolution by comparing sequences. PMID- 28922351 TI - Estimation of the mechanical properties of the eye through the study of its vibrational modes. AB - Measuring the eye's mechanical properties in vivo and with minimally invasive techniques can be the key for individualized solutions to a number of eye pathologies. The development of such techniques largely relies on a computational modelling of the eyeball and, it optimally requires the synergic interplay between experimentation and numerical simulation. In Astrophysics and Geophysics the remote measurement of structural properties of the systems of their realm is performed on the basis of (helio-)seismic techniques. As a biomechanical system, the eyeball possesses normal vibrational modes encompassing rich information about its structure and mechanical properties. However, the integral analysis of the eyeball vibrational modes has not been performed yet. Here we develop a new finite difference method to compute both the spheroidal and, specially, the toroidal eigenfrequencies of the human eye. Using this numerical model, we show that the vibrational eigenfrequencies of the human eye fall in the interval 100 Hz-10 MHz. We find that compressible vibrational modes may release a trace on high frequency changes of the intraocular pressure, while incompressible normal modes could be registered analyzing the scattering pattern that the motions of the vitreous humour leave on the retina. Existing contact lenses with embebed devices operating at high sampling frequency could be used to register the microfluctuations of the eyeball shape we obtain. We advance that an inverse problem to obtain the mechanical properties of a given eye (e.g., Young's modulus, Poisson ratio) measuring its normal frequencies is doable. These measurements can be done using non-invasive techniques, opening very interesting perspectives to estimate the mechanical properties of eyes in vivo. Future research might relate various ocular pathologies with anomalies in measured vibrational frequencies of the eye. PMID- 28922350 TI - Stem cells and cell-based therapies for cerebral palsy: a call for rigor. AB - Cell-based therapies hold significant promise for infants at risk for cerebral palsy (CP) from perinatal brain injury (PBI). PBI leading to CP results from multifaceted damage to neural cells. Complex developing neural networks are injured by neural cell damage plus unique perturbations in cell signaling. Given that cell-based therapies can simultaneously repair multiple injured neural components during critical neurodevelopmental windows, these interventions potentially offer efficacy for patients with CP. Currently, the use of cell-based interventions in infants at risk for CP is limited by critical gaps in knowledge. In this review, we will highlight key questions facing the field, including: Who are optimal candidates for treatment? What are the goals of therapeutic interventions? What are the best strategies for agent delivery, including timing, dosage, location, and type? And, how are short- and long-term efficacy reliably tracked? Challenges unique to treating PBI with cell-based therapies, and lessons learned from cell-based therapies in closely related neurological disorders in the mature central nervous system, will be reviewed. Our goal is to update pediatric specialists who may be counseling families about the current state of the field. Finally, we will evaluate how rigor can be increased in the field to ensure the safety and best interests of this vulnerable patient population. PMID- 28922353 TI - Synthesizing developmental trajectories. AB - Dynamical processes in biology are studied using an ever-increasing number of techniques, each of which brings out unique features of the system. One of the current challenges is to develop systematic approaches for fusing heterogeneous datasets into an integrated view of multivariable dynamics. We demonstrate that heterogeneous data fusion can be successfully implemented within a semi supervised learning framework that exploits the intrinsic geometry of high dimensional datasets. We illustrate our approach using a dataset from studies of pattern formation in Drosophila. The result is a continuous trajectory that reveals the joint dynamics of gene expression, subcellular protein localization, protein phosphorylation, and tissue morphogenesis. Our approach can be readily adapted to other imaging modalities and forms a starting point for further steps of data analytics and modeling of biological dynamics. PMID- 28922354 TI - Reconstructing promoter activity from Lux bioluminescent reporters. AB - The bacterial Lux system is used as a gene expression reporter. It is fast, sensitive and non-destructive, enabling high frequency measurements. Originally developed for bacterial cells, it has also been adapted for eukaryotic cells, and can be used for whole cell biosensors, or in real time with live animals without the need for euthanasia. However, correct interpretation of bioluminescent data is limited: the bioluminescence is different from gene expression because of nonlinear molecular and enzyme dynamics of the Lux system. We have developed a computational approach that, for the first time, allows users of Lux assays to infer gene transcription levels from the light output. This approach is based upon a new mathematical model for Lux activity, that includes the actions of LuxAB, LuxEC and Fre, with improved mechanisms for all reactions, as well as synthesis and turn-over of Lux proteins. The model is calibrated with new experimental data for the LuxAB and Fre reactions from Photorhabdus luminescens the source of modern Lux reporters-while literature data has been used for LuxEC. Importantly, the data show clear evidence for previously unreported product inhibition for the LuxAB reaction. Model simulations show that predicted bioluminescent profiles can be very different from changes in gene expression, with transient peaks of light output, very similar to light output seen in some experimental data sets. By incorporating the calibrated model into a Bayesian inference scheme, we can reverse engineer promoter activity from the bioluminescence. We show examples where a decrease in bioluminescence would be better interpreted as a switching off of the promoter, or where an increase in bioluminescence would be better interpreted as a longer period of gene expression. This approach could benefit all users of Lux technology. PMID- 28922356 TI - Mathematical modeling and quantitative analysis of HIV-1 Gag trafficking and polymerization. AB - Gag, as the major structural protein of HIV-1, is necessary for the assembly of the HIV-1 sphere shell. An in-depth understanding of its trafficking and polymerization is important for gaining further insights into the mechanisms of HIV-1 replication and the design of antiviral drugs. We developed a mathematical model to simulate two biophysical processes, specifically Gag monomer and dimer transport in the cytoplasm and the polymerization of monomers to form a hexamer underneath the plasma membrane. Using experimental data, an optimization approach was utilized to identify the model parameters, and the identifiability and sensitivity of these parameters were then analyzed. Using our model, we analyzed the weight of the pathways involved in the polymerization reactions and concluded that the predominant pathways for the formation of a hexamer might be the polymerization of two monomers to form a dimer, the polymerization of a dimer and a monomer to form a trimer, and the polymerization of two trimers to form a hexamer. We then deduced that the dimer and trimer intermediates might be crucial in hexamer formation. We also explored four theoretical combined methods for Gag suppression, and hypothesized that the N-terminal glycine residue of the MA domain of Gag might be a promising drug target. This work serves as a guide for future theoretical and experimental efforts aiming to understand HIV-1 Gag trafficking and polymerization, and might help accelerate the efficiency of anti AIDS drug design. PMID- 28922355 TI - Image identification from brain activity using the population receptive field model. AB - A goal of computational models is not only to explain experimental data but also to make new predictions. A current focus of computational neuroimaging is to predict features of the presented stimulus from measured brain signals. These computational neuroimaging approaches may be agnostic about the underlying neural processes or may be biologically inspired. Here, we use the biologically inspired population receptive field (pRF) approach to identify presented images from fMRI recordings of the visual cortex, using an explicit model of the underlying neural response selectivity. The advantage of the pRF-model is its simplicity: it is defined by a handful of parameters, which can be estimated from fMRI data that was collected within half an hour. Using 7T MRI, we measured responses elicited by different visual stimuli: (i) conventional pRF mapping stimuli, (ii) semi random synthetic images and (iii) natural images. The pRF mapping stimuli were used to estimate the pRF-properties of each cortical location in early visual cortex. Next, we used these pRFs to identify which synthetic or natural images was presented to the subject from the fMRI responses. We show that image identification using V1 responses is far above chance, both for the synthetic and natural images. Thus, we can identify visual images, including natural images, using the most fundamental low-parameter pRF model estimated from conventional pRF mapping stimuli. This allows broader application of image identification. PMID- 28922357 TI - Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations. AB - The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition. PMID- 28922359 TI - A first linkage map and downy mildew resistance QTL discovery for sweet basil (Ocimum basilicum) facilitated by double digestion restriction site associated DNA sequencing (ddRADseq). AB - Limited understanding of sweet basil (Ocimum basilicum L.) genetics and genome structure has reduced efficiency of breeding strategies. This is evidenced by the rapid, worldwide dissemination of basil downy mildew (Peronospora belbahrii) in the absence of resistant cultivars. In an effort to improve available genetic resources, expressed sequence tag simple sequence repeat (EST-SSR) and single nucleotide polymorphism (SNP) markers were developed and used to genotype the MRI x SB22 F2 mapping population, which segregates for response to downy mildew. SNP markers were generated from genomic sequences derived from double digestion restriction site associated DNA sequencing (ddRADseq). Disomic segregation was observed in both SNP and EST-SSR markers providing evidence of an O. basilicum allotetraploid genome structure and allowing for subsequent analysis of the mapping population as a diploid intercross. A dense linkage map was constructed using 42 EST-SSR and 1,847 SNP markers spanning 3,030.9 cM. Multiple quantitative trait loci (QTL) model (MQM) analysis identified three QTL that explained 37-55% of phenotypic variance associated with downy mildew response across three environments. A single major QTL, dm11.1 explained 21-28% of phenotypic variance and demonstrated dominant gene action. Two minor QTL dm9.1 and dm14.1 explained 5 16% and 4-18% of phenotypic variance, respectively. Evidence is provided for an additive effect between the two minor QTL and the major QTL dm11.1 increasing downy mildew susceptibility. Results indicate that ddRADseq-facilitated SNP and SSR marker genotyping is an effective approach for mapping the sweet basil genome. PMID- 28922358 TI - Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy. AB - Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option. However, insight is needed into the phenomenon of normalization and in which conditions it can realize its promise. In order to explore the effect of microenvironmental conditions and drug scheduling on normalization benefit, we build a mathematical model that incorporates tumor growth, angiogenesis and IFP. We administer various theoretical combinations of antiangiogenic agents and cytotoxic nanoparticles through heterogeneous vasculature that displays a similar morphology to tumor vasculature. We observe differences in drug extravasation that depend on the scheduling of combined therapy; for concurrent therapy, total drug extravasation is increased but in adjuvant therapy, drugs can penetrate into deeper regions of tumor. PMID- 28922360 TI - Comparison of background EEG activity of different groups of patients with idiopathic epilepsy using Shannon spectral entropy and cluster-based permutation statistical testing. AB - Idiopathic epilepsy is characterized by generalized seizures with no apparent cause. One of its main problems is the lack of biomarkers to monitor the evolution of patients. The only tools they can use are limited to inspecting the amount of seizures during previous periods of time and assessing the existence of interictal discharges. As a result, there is a need for improving the tools to assist the diagnosis and follow up of these patients. The goal of the present study is to compare and find a way to differentiate between two groups of patients suffering from idiopathic epilepsy, one group that could be followed-up by means of specific electroencephalographic (EEG) signatures (intercritical activity present), and another one that could not due to the absence of these markers. To do that, we analyzed the background EEG activity of each in the absence of seizures and epileptic intercritical activity. We used the Shannon spectral entropy (SSE) as a metric to discriminate between the two groups and performed permutation-based statistical tests to detect the set of frequencies that show significant differences. By constraining the spectral entropy estimation to the [6.25-12.89) Hz range, we detect statistical differences (at below 0.05 alpha-level) between both types of epileptic patients at all available recording channels. Interestingly, entropy values follow a trend that is inversely related to the elapsed time from the last seizure. Indeed, this trend shows asymptotical convergence to the SSE values measured in a group of healthy subjects, which present SSE values lower than any of the two groups of patients. All these results suggest that the SSE, measured in a specific range of frequencies, could serve to follow up the evolution of patients suffering from idiopathic epilepsy. Future studies remain to be conducted in order to assess the predictive value of this approach for the anticipation of seizures. PMID- 28922361 TI - Impact of four different recumbencies on the distribution of ventilation in conscious or anaesthetized spontaneously breathing beagle dogs: An electrical impedance tomography study. AB - The aim was to examine the effects of recumbency and anaesthesia on distribution of ventilation in beagle dogs using Electrical Impedance Tomography (EIT). Nine healthy beagle dogs, aging 3.7+/-1.7 (mean+/-SD) years and weighing 16.3+/-1.6 kg, received a series of treatments in a fixed order on a single occasion. Conscious dogs were positioned in right lateral recumbency (RLR) and equipped with 32 EIT electrodes around the thorax. Following five minutes of equilibration, two minutes of EIT recordings were made in each recumbency in the following order: RLR, dorsal (DR), left (LLR) and sternal (SR). The dogs were then positioned in RLR, premedicated (medetomidine 0.01, midazolam 0.1, butorphanol 0.1 mg kg-1 iv) and pre-oxygenated. Fifteen minutes later anaesthesia was induced with 1 mg kg-1 propofol iv and maintained with propofol infusion (0.1 0.2 mg kg-1 minute-1 iv). After induction, the animals were intubated and allowed to breathe spontaneously (FIO2 = 1). Recordings of EIT were performed again in four recumbencies similarly to conscious state. Centre of ventilation (COV) and global inhomogeneity (GI) index were calculated from the functional EIT images. Repeated-measures ANOVA and Bonferroni tests were used for statistical analysis (p < 0.05). None of the variables changed in the conscious state. During anaesthesia left-to-right COV increased from 46.8+/-2.8% in DR to 49.8+/-2.9% in SR indicating a right shift, and ventral-to-dorsal COV increased from 49.8+/-1.7% in DR to 51.8+/-1.1% in LLR indicating a dorsal shift in distribution of ventilation. Recumbency affected distribution of ventilation in anaesthetized but not in conscious dogs. This can be related to loss of respiratory muscle tone (e.g. diaphragm) and changes in thoracic shape. Changing position of thoraco abdominal organs under the EIT belt should be considered as alternative explanation of these findings. PMID- 28922362 TI - Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer. AB - BACKGROUND: Survival from gastric cancer remains poor, particularly in Western populations. Previous pre-clinical and subgroup analyses of clinical trials have suggested differing benefits from fluoropyrimidine-based chemotherapeutics for diffuse and intestinal gastric cancer. This analysis examines patterns of relapse with and without adjuvant chemotherapy after curative resection for gastric cancer in these subtypes to explore the Lauren classification as a predictive marker of benefit for fluoropyrimidine-based adjuvant chemotherapy. PATIENTS AND METHODS: Gastric cancer patients enrolled in an ongoing tissue banking study were analysed, 164 patients who would currently be considered for adjuvant therapy after curative resection were included in the analysis. Patients who did and did not receive adjuvant chemotherapy were compared. The primary end point was relapse free survival. RESULTS: Approximately 50% of patients received adjuvant chemotherapy, the majority receiving a fluoropyrimidine-based regimen. The comparison of Kaplan-Meier curves for patients who did and did not receive adjuvant chemotherapy are different between patients with intestinal and diffuse gastric cancer, and suggest that there may be a benefit in intestinal gastric cancer. The hazard ratio for adjuvant chemotherapy for intestinal gastric cancer was 0.56, (95% CI 0.27-1.17), suggesting a trend towards benefit that was lacking in diffuse gastric cancer patients (1.26, 95% CI 0.70-2.38). The patterns of relapse after adjuvant chemotherapy also differed between diffuse and intestinal gastric cancer. More than 50% of diffuse gastric cancer patients who received adjuvant chemotherapy relapsed within 12 months of surgery despite similar surgical parameters. CONCLUSIONS: Lauren classification is prognostic in gastric cancer. This analysis adds further evidence that it may also be predictive of benefit for fluoropyrimidine-based chemotherapeutics, with lower chemosensitivity seen in diffuse gastric cancer. Treating diffuse and intestinal gastric cancer as separate entities, with identification of efficacious treatments for diffuse gastric cancer will help in improving outcomes from gastric cancer. PMID- 28922363 TI - Predictors of post-thrombolysis symptomatic intracranial hemorrhage in Chinese patients with acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Predictors of symptomatic intracranial hemorrhage (sICH) in Chinese patients with acute ischemic stroke treated with recombinant tissue plasminogen activator remain unclear. METHODS: Data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) study were assessed to explore risk factors for symptomatic intracranial hemorrhage after intravenous thrombolysis. Three candidate sICH definitions were analyzed. RESULTS: Among 1128 patients with acute ischemic stroke treated with intravenous rtPA within 4.5 hours of symptom onset, 23 (2.0%), 44(3.9%) and 61 (5.4%) experienced modified mSITS-MOST, ECASS II, and NINDS defined sICH, respectively. Multivariate logistic regression revealed independent risk factors for sICH were age?70 years-old(sICH per NINDS, adjusted OR = 1.73[95%CI1.02-2.95],p = 0.04),diabetes(sICH per SITS-MOST, adjusted OR = 3.50 [95%CI1.34-9.16], p = 0.01), serum glucose on admission >9.0mmol/L(sICH per ECASS II, adjusted OR = 2.84[95%CI1.48-5.46], p = 0.002),NIHSS on admission>20(sICH per SITS-MOST, adjusted OR = 5.06[95%CI1.68-15.20], p = 0.004 or sICH per NINDS, adjusted OR 2.81[95%CI1.42-5.57], p = 0.003) and cardioembolism(sICH per SITS-MOST, adjusted OR = 7.09[95%CI2.41-20.87], p<0.001 or sICH per ECASS II, adjusted OR = 4.99[95%CI2.53-9.84], p<0.001)or sICH per NINDS, adjusted OR = 2.47[95%CI1.39 4.39], p = 0.002). CONCLUSION: Cardioembolism, NIHSS on admission higher than 20, serum glucose on admission higher than 9.0 mmol/L and age ?70 years were independent risk factors for symptomatic intracranial hemorrhage in Chinese patients with acute ischemic stroke treated with recombinant tissue plasminogen activator. PMID- 28922364 TI - Association of epicardial adipose tissue with serum level of cystatin C in type 2 diabetes. AB - OBJECTIVE: Accumulation of epicardial adipose tissue (EAT) is considered to be a cardiovascular risk factor independent from visceral adiposity, obesity, hypertension and diabetes. We explored the parameters related to EAT accumulation, aiming to clarify the novel pathophysiological roles of EAT in subjects with type 2 diabetes (T2DM). METHODS: We examined the laboratory values, including cystatinC, and surrogate markers used for evaluating atherosclerosis. EAT was measured as the sum of the adipose tissue area, obtained by plain computed tomography scans in 208 subjects with T2DM but no history of coronary artery disease. RESULTS: EAT correlated positively with age, body mass index (BMI), visceral fat area, leptin, cystatin C and C-peptide, while correlating negatively with adiponectin, estimated glomerular filteration rate (eGFR) and the liver-to-spleen ratio. Multiple linear regression analysis revealed serum cystatin C (beta = 0.175), leptin (beta = 0.536), BMI (beta = 0.393) and age (beta = 0.269) to be the only parameters showing independent statistically significant associations with EAT. When cystatin C was replaced with eGFR, eGFR showed no significant correlation with EAT. In reverse analysis, serum cystatin C was significantly associated with EAT after adjustment in multivariate analysis. DISCUSSION: EAT accumulation and elevated cystatin C have been independently regarded as risk factors influencing atherosclerosis. The strong association between EAT and cystatin C demonstrated herein indicates that EAT accumulation may play an important role in Cystatin C secretion, possibly contributing to cardiometabolic risk in T2DM patients. PMID- 28922366 TI - Optimizing information processing in neuronal networks beyond critical states. AB - Critical dynamics have been postulated as an ideal regime for neuronal networks in the brain, considering optimal dynamic range and information processing. Herein, we focused on how information entropy encoded in spatiotemporal activity patterns may vary in critical networks. We employed branching process based models to investigate how entropy can be embedded in spatiotemporal patterns. We determined that the information capacity of critical networks may vary depending on the manipulation of microscopic parameters. Specifically, the mean number of connections governed the number of spatiotemporal patterns in the networks. These findings are compatible with those of the real neuronal networks observed in specific brain circuitries, where critical behavior is necessary for the optimal dynamic range response but the uncertainty provided by high entropy as coded by spatiotemporal patterns is not required. With this, we were able to reveal that information processing can be optimized in neuronal networks beyond critical states. PMID- 28922365 TI - Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice. AB - Moringa (Moringa oleifera Lam.) seed extract (MSE) has anti-inflammatory and antioxidant activities. We investigated the effects of MSE enriched in moringa isothiocyanate-1 (MIC-1), its putative bioactive, on ulcerative colitis (UC) and its anti-inflammatory/antioxidant mechanism likely mediated through Nrf2 signaling pathway. Dextran sulfate sodium (DSS)-induced acute (n = 8/group; 3% DSS for 5 d) and chronic (n = 6/group; cyclic rotations of 2.5% DSS/water for 30 d) UC was induced in mice that were assigned to 4 experimental groups: healthy control (water/vehicle), disease control (DSS/vehicle), MSE treatment (DSS/MSE), or 5-aminosalicyic acid (5-ASA) treatment (positive control; DSS/5-ASA). Following UC induction, water (vehicle), 150 mg/kg MSE, or 50 mg/kg 5-ASA were orally administered for 1 or 2 wks. Disease activity index (DAI), spleen/colon sizes, and colonic histopathology were measured. From colon and/or fecal samples, pro-inflammatory biomarkers, tight-junction proteins, and Nrf2-mediated enzymes were analyzed at protein and/or gene expression levels. Compared to disease control, MSE decreased DAI scores, and showed an increase in colon lengths and decrease in colon weight/length ratios in both UC models. MSE also reduced colonic inflammation/damage and histopathological scores (modestly) in acute UC. MSE decreased colonic secretions of pro-inflammatory keratinocyte-derived cytokine (KC), tumor necrosis factor (TNF)-alpha, nitric oxide (NO), and myeloperoxidase (MPO) in acute and chronic UC; reduced fecal lipocalin-2 in acute UC; downregulated gene expression of pro-inflammatory interleukin (IL)-1, IL-6, TNF-alpha, and inducible nitric oxide synthase (iNOS) in acute UC; upregulated expression of claudin-1 and ZO-1 in acute and chronic UC; and upregulated GSTP1, an Nrf2-mediated phase II detoxifying enzyme, in chronic UC. MSE was effective in mitigating UC symptoms and reducing UC-induced colonic pathologies, likely by suppressing pro-inflammatory biomarkers and increasing tight-junction proteins. This effect is consistent with Nrf2-mediated anti-inflammatory/antioxidant signaling pathway documented for other isothiocyanates similar to MIC-1. Therefore, MSE, enriched with MIC-1, may be useful in prevention and treatment of UC. PMID- 28922367 TI - Perihematomal diffusion restriction as a common finding in large intracerebral hemorrhages in the hyperacute phase. AB - PURPOSE: There is growing evidence that a perihematomal area of restricted diffusion (PDR) exists in intraparenchymal hemorrhages (IPH) within 1 week of symptom onset (SO). Here, we study characteristics and the clinical impact of the PDR in patients with hyperacute (<= 6 hours from SO) IPH by means of apparent diffusion coefficient (ADC). METHODS: This monocentric, retrospective study includes 83 patients with first-ever primary IPH from 09/2002-10/2015. 3D volumetric segmentation was performed for the IPH, PDR, and perihematomal edema (PHE) on fluid-attenuated inversion recovery, T2*/susceptibility weighted images, and ADC images. RESULTS: A PDR was seen in 56/83 patients (67.5%) presenting with hyperacute IPH. Multivariate logistic regression analysis revealed every 10-year increase of age (HR 1.929, 95% CI 1.047-3.552, P = .035) and male gender (HR 5.672, 95% CI 1.038-30.992, P = .045) as significant predictors of the presence of a PDR, but not IPH size, IPH location, nor National Institutes of Health Stroke Scale Score (NIHSS) at admission. We found no difference in NIHSS at discharge, hematoma removal, or mortality rate in PDR-positive patients. ADC values of the PDR show a step-wise normalization with increasing time from SO. CONCLUSIONS: Occurrence of a PDR is a common finding in supratentorial hyperacute IPH, but shows no adverse short-term clinical impact. It may represent transient oligemic and metabolic changes. PMID- 28922369 TI - Crimean-Congo hemorrhagic fever virus nucleocapsid protein has dual RNA binding modes. AB - Crimean Congo hemorrhagic fever, a zoonotic viral disease, has high mortality rate in humans. There is currently no vaccine for Crimean Congo hemorrhagic fever virus (CCHFV) and chemical interventions are limited. The three negative sense genomic RNA segments of CCHFV are specifically encapsidated by the nucleocapsid protein into three ribonucleocapsids, which serve as templates for the viral RNA dependent RNA polymerase. Here we demonstrate that CCHFV nucleocapsid protein has two distinct binding modes for double and single strand RNA. In the double strand RNA binding mode, the nucleocapsid protein preferentially binds to the vRNA panhandle formed by the base pairing of complementary nucleotides at the 5' and 3' termini of viral genome. The CCHFV nucleocapsid protein does not have RNA helix unwinding activity and hence does not melt the duplex vRNA panhandle after binding. In the single strand RNA binding mode, the nucleocapsid protein does not discriminate between viral and non-viral RNA molecules. Binding of both vRNA panhandle and single strand RNA induce a conformational change in the nucleocapsid protein. Nucleocapsid protein remains in a unique conformational state due to simultaneously binding of structurally distinct vRNA panhandle and single strand RNA substrates. Although the role of dual RNA binding modes in the virus replication cycle is unknown, their involvement in the packaging of viral genome and regulation of CCHFV replication in conjunction with RdRp and host derived RNA regulators is highly likely. PMID- 28922368 TI - A tree of life based on ninety-eight expressed genes conserved across diverse eukaryotic species. AB - Rapid advances in DNA sequencing technologies have resulted in the accumulation of large data sets in the public domain, facilitating comparative studies to provide novel insights into the evolution of life. Phylogenetic studies across the eukaryotic taxa have been reported but on the basis of a limited number of genes. Here we present a genome-wide analysis across different plant, fungal, protist, and animal species, with reference to the 36,002 expressed genes of the rice genome. Our analysis revealed 9831 genes unique to rice and 98 genes conserved across all 49 eukaryotic species analysed. The 98 genes conserved across diverse eukaryotes mostly exhibited binding and catalytic activities and shared common sequence motifs; and hence appeared to have a common origin. The 98 conserved genes belonged to 22 functional gene families including 26S protease, actin, ADP-ribosylation factor, ATP synthase, casein kinase, DEAD-box protein, DnaK, elongation factor 2, glyceraldehyde 3-phosphate, phosphatase 2A, ras related protein, Ser/Thr protein phosphatase family protein, tubulin, ubiquitin and others. The consensus Bayesian eukaryotic tree of life developed in this study demonstrated widely separated clades of plants, fungi, and animals. Musa acuminata provided an evolutionary link between monocotyledons and dicotyledons, and Salpingoeca rosetta provided an evolutionary link between fungi and animals, which indicating that protozoan species are close relatives of fungi and animals. The divergence times for 1176 species pairs were estimated accurately by integrating fossil information with synonymous substitution rates in the comprehensive set of 98 genes. The present study provides valuable insight into the evolution of eukaryotes. PMID- 28922370 TI - Ileocolic resection is associated with increased susceptibility to injury in a murine model of colitis. AB - Ileocolic resection (ICR) is the most common intestinal resection performed for Crohn's disease, with recurrences commonly occurring at the site of the anastomosis. This study used an animal model of ICR in wild-type mice to examine immunologic changes that developed around the surgical anastomosis and how these changes impacted gut responses to minor acute injury. ICR was performed in adult 129S1/SvlmJ mice and results compared with mice receiving sham or no surgery. Dextran sodium sulfate was given either on post-operative day 9 or day 24 to evaluate immune responses in the intestine both immediately following surgery and after a period of healing. Fecal occult blood measurements and animal weights were taken daily. Cytokine levels were measured in ileal and colonic tissue. Bacterial load in the neo-terminal ileum was measured using qPCR. Immune cell populations in the intestinal tissue, mesenteric lymph nodes, and spleen were assessed using flow cytometry. Cytokine secretion in response to microbial products was measured in isolated mesenteric lymph nodes and spleen cells. ICR resulted in an initial elevation of inflammatory markers in the terminal ileum and colon followed by enhanced levels of bacterial growth in the neo-terminal ileum. Intestinal surgical resection resulted in the recruitment of innate immune cells into the colon that exhibited a non-responsiveness to microbial stimuli. DSS colitis phenotype was more severe in the ileocolic resection groups and this was associated with local and systemic immunosuppression as evidenced by a reduced cytokine responses to microbial stimuli. This study reveals the development of an immune non-responsiveness to microbial products following ileocolic resection that is associated with enhanced levels of bacterial growth in the neo-terminal ileum. These surgical-induced altered immune-microbial interactions in the intestine may contribute to disease recurrence at the surgical anastomosis site following ileocolic resections in patients with Crohn's disease. PMID- 28922371 TI - The association between cigarette smoking and inflammation: The Genetic Epidemiology Network of Arteriopathy (GENOA) study. AB - To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 +/-10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p<0.003). High sensitivity C-reactive protein was the most elevated biomarker among current smokers when compared to never smokers [GM ratio = 1.39 (95% CI: 1.23, 1.57); p <0.001]. Among former smokers, each pack-year of cigarettes smoked was associated with a 0.4% higher serum level of hsCRP [GM ratio = 1.004 (95% CI: 1.001, 1.006); p = 0.002] and each 5-year lapsed since quitting was associated with a 4% lower serum level of hsCRP [GM ratio = 0.96 (95% CI: 0.93, 0.99); p = 0.006]. However, we found no significant association of smoking intensity or burden with biomarkers of inflammation among current smokers. HsCRP appears to be the most sensitive biomarker of inflammation associated with cigarette smoking of those investigated, and could be a useful biomarker of smoking-related injury for the study and regulation of emerging tobacco products. PMID- 28922372 TI - Reduction of organelle motility by removal of potassium and other solutes. AB - There are surprisingly few studies that describe how the composition of cell culture medium may affect the trafficking of organelles. Here we utilize time lapse multi-channel fluorescent imaging to show that short term exposure of Huh-7 cells to medium lacking potassium, sodium, or chloride strongly reduces but does not eliminate the characteristic back and forth and cell-traversing movement of fluorescent EGF (FL-EGF) containing organelles. We focused on potassium because of its relatively low abundance in media and serum and its energy requiring accumulation into cells. Upon exposure to potassium free medium, organelle motility declined steadily through 90 min and then persisted at a low level. Reduced motility was confirmed in 5 independent cell lines and for organelles of the endocytic pathway (FL-EGF and Lysotracker), autophagosomes (LC3-GFP), and mitochondria (TMRE). As has been previously established, potassium free medium also inhibited endocytosis. We expected that diminished cellular metabolism would precede loss of organelle motility. However, extracellular flux analysis showed near normal mitochondrial oxygen consumption and only a small decrease in extracellular acidification, the latter suggesting decreased glycolysis or proton efflux. Other energy dependent activities such as the accumulation of Lysotracker, TMRE, DiBAC4(3), and the exclusion of propidium iodide remained intact, as did the microtubule cytoskeleton. We took advantage of cell free in vitro motility assays and found that removal of potassium or sodium from the reconstituted cytosolic medium decreased the movement of endosomes on purified microtubules. The results indicate that although changes in proton homeostasis and cell energetics under solute depletion are not fully understood, potassium as well as sodium appear to be directly required by the motile machinery of organelles for optimal trafficking. PMID- 28922373 TI - Dynein light chain regulates adaptive and innate B cell development by distinctive genetic mechanisms. AB - Mechanistic differences in the development and function of adaptive, high affinity antibody-producing B-2 cells and innate-like, "natural" antibody producing B-1a cells remain poorly understood. Here we show that the multi functional dynein light chain (DYNLL1/LC8) plays important roles in the establishment of B-1a cells in the peritoneal cavity and in the ongoing development of B-2 lymphoid cells in the bone marrow of mice. Epistasis analyses indicate that Dynll1 regulates B-1a and early B-2 cell development in a single, linear pathway with its direct transcriptional activator ASCIZ (ATMIN/ZNF822), and that the two genes also have complementary functions during late B-2 cell development. The B-2 cell defects caused by loss of DYNLL1 were associated with lower levels of the anti-apoptotic protein BCL-2, and could be supressed by deletion of pro-apoptotic BIM which is negatively regulated by both DYNLL1 and BCL-2. Defects in B cell development caused by loss of DYNLL1 could also be partially suppressed by a pre-arranged SWHEL Igm-B cell receptor transgene. In contrast to the rescue of B-2 cell numbers, the B-1a cell deficiency in Dynll1 deleted mice could not be suppressed by the loss of Bim, and was further compounded by the SWHEL transgene. Conversely, oncogenic MYC expression, which is synthetic lethal with Dynll1 deletion in B-2 cells, did not further reduce B-1a cell numbers in Dynll1-defcient mice. Finally, we found that the ASCIZ-DYNLL1 axis was also required for the early-juvenile development of aggressive MYC driven and p53-deficient B cell lymphomas. These results identify ASCIZ and DYNLL1 as the core of a transcriptional circuit that differentially regulates the development of the B-1a and B-2 B lymphoid cell lineages and plays a critical role in lymphomagenesis. PMID- 28922374 TI - Fractional laser exposure induces neutrophil infiltration (N1 phenotype) into the tumor and stimulates systemic anti-tumor immune response. AB - BACKGROUND: Ablative fractional photothermolysis (aFP) using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP. METHODOLOGY/PRINCIPAL FINDINGS: We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25), which expressed a tumor antigen, beta-galactosidase (beta-gal). aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg), which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP. CONCLUSION: We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed. PMID- 28922375 TI - Elevated IgG4 serum levels in patients with cystic fibrosis. AB - OBJECTIVE: Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients. METHODS: In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL. RESULTS: One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (<= 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations. CONCLUSION: An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated. PMID- 28922376 TI - News trends and web search query of HIV/AIDS in Hong Kong. AB - BACKGROUND: The HIV epidemic in Hong Kong has worsened in recent years, with major contributions from high-risk subgroup of men who have sex with men (MSM). Internet use is prevalent among the majority of the local population, where they sought health information online. This study examines the impacts of HIV/AIDS and MSM news coverage on web search query in Hong Kong. METHODS: Relevant news coverage about HIV/AIDS and MSM from January 1st, 2004 to December 31st, 2014 was obtained from the WiseNews databse. News trends were created by computing the number of relevant articles by type, topic, place of origin and sub-populations. We then obtained relevant search volumes from Google and analysed causality between news trends and Google Trends using Granger Causality test and orthogonal impulse function. RESULTS: We found that editorial news has an impact on "HIV" Google searches on HIV, with the search term popularity peaking at an average of two weeks after the news are published. Similarly, editorial news has an impact on the frequency of "AIDS" searches two weeks after. MSM-related news trends have a more fluctuating impact on "MSM" Google searches, although the time lag varies anywhere from one week later to ten weeks later. CONCLUSIONS: This infodemiological study shows that there is a positive impact of news trends on the online search behavior of HIV/AIDS or MSM-related issues for up to ten weeks after. Health promotional professionals could make use of this brief time window to tailor the timing of HIV awareness campaigns and public health interventions to maximise its reach and effectiveness. PMID- 28922378 TI - Relationships of orientation discrimination threshold and visual acuity with macular lesions in age-related macular degeneration. AB - PURPOSE: To measure visual acuity and metamorphopsia in patients with age-related macular degeneration (AMD) and to explore their relationship with macular lesions. METHODS: In this cross-sectional study, a total of 32 normal subjects (32 eyes) and 35 AMD patients (35 eyes) were recruited. They were categorized into 4 groups: normal, dry AMD, non-active wet AMD, and active wet AMD. Best corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study protocol. Metamorphopsia was quantified with the orientation discrimination threshold (ODT). Macular lesions, including drusen, sub-retinal fluid (SRF), intra-retinal fluid (IRF), pigmented epithelium detachment (PED), and scarring, were identified with spectral-domain optical coherence tomography (SD-OCT). A linear regression model was established to identify the relationships between the functional and structural changes. RESULTS: BCVA progressively worsened across the normal, dry AMD, non-active wet AMD, and active wet AMD groups (P < 0.001), and ODT increased across the groups (P < 0.001). The correlation between BCVA and ODT varied among the groups. The partial correlation between BCVA and ODT was -0.61 (P < 0.001). Linear regression showed that ODT significantly depended on IRF (beta = 0.61, P < 0.001), SRF (beta = 0.34, P = 0.003), and scarring (beta = 0.26, P = 0.050), while BCVA significantly depended only on scarring (beta = -0.52, P < 0.001), and IRF (beta = -0.36, P = 0.016). CONCLUSIONS: From dry AMD to active wet AMD, BCVA gradually worsened while ODT increased. The correlation between BCVA and ODT varied among these groups, indicating that AMD lesions affect them differently. ODT and BCVA should be used concurrently for better monitoring of the disease. PMID- 28922377 TI - C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis. AB - Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits. PMID- 28922379 TI - Elevating serotonin pre-partum alters the Holstein dairy cow hepatic adaptation to lactation. AB - Serotonin is known to regulate energy and calcium homeostasis in several mammalian species. The objective of this study was to determine if pre-partum infusions of 5-hydroxytryptophan (5-HTP), the immediate precursor to serotonin synthesis, could modulate energy homeostasis at the level of the hepatocyte in post-partum Holstein and Jersey dairy cows. Twelve multiparous Holstein cows and twelve multiparous Jersey cows were intravenously infused daily for approximately 7 d pre-partum with either saline or 1 mg/kg bodyweight of 5-HTP. Blood was collected for 14 d post-partum and on d30 post-partum. Liver biopsies were taken on d1 and d7 post-partum. There were no changes in the circulating concentrations of glucose, insulin, glucagon, non-esterified fatty acids, or urea nitrogen in response to treatment, although there were decreased beta-hydroxybutyrate concentrations with 5-HTP treatment around d6 to d10 post-partum, particularly in Jersey cows. Cows infused with 5-HTP had increased hepatic serotonin content and increased mRNA expression of the serotonin 2B receptor on d1 and d7 post-partum. Minimal changes were seen in the hepatic mRNA expression of various gluconeogenic enzymes. There were no changes in the mRNA expression profile of cell-cycle progression marker cyclin-dependent kinase 4 or apoptotic marker caspase 3, although proliferating cell nuclear antigen expression tended to be increased in Holstein cows infused with 5-HTP on d1 post-partum. Immunofluorescence assays showed an increased number of CASP3- and Ki67-positive cells in Holstein cows infused with 5-HTP on d1 post-partum. Given the elevated hepatic serotonin content and increased mRNA abundance of 5HTR2B, 5-HTP infusions may be stimulating an autocrine-paracrine adaptation to lactation in the Holstein cow liver. PMID- 28922380 TI - The Warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand. AB - To maintain optimal fitness, a cell must balance the risk of inadequate energy reserve for response to a potentially fatal perturbation against the long-term cost of maintaining high concentrations of ATP to meet occasional spikes in demand. Here we apply a game theoretic approach to address the dynamics of energy production and expenditure in eukaryotic cells. Conventionally, glucose metabolism is viewed as a function of oxygen concentrations in which the more efficient oxidation of glucose to CO2 and H2O produces all or nearly all ATP except under hypoxic conditions when less efficient (2 ATP/ glucose vs. about 36ATP/glucose) anaerobic metabolism of glucose to lactic acid provides an emergency backup. We propose an alternative in which energy production is governed by the complex temporal and spatial dynamics of intracellular ATP demand. In the short term, a cell must provide energy for constant baseline needs but also maintain capacity to rapidly respond to fluxes in demand particularly due to external perturbations on the cell membrane. Similarly, longer-term dynamics require a trade-off between the cost of maintaining high metabolic capacity to meet uncommon spikes in demand versus the risk of unsuccessfully responding to threats or opportunities. Here we develop a model and computationally explore the cell's optimal mix of glycolytic and oxidative capacity. We find the Warburg effect, high glycolytic metabolism even under normoxic conditions, is represents a metabolic strategy that allow cancer cells to optimally meet energy demands posed by stochastic or fluctuating tumor environments. PMID- 28922381 TI - The operation of a Research and Development (R&D) program and its significance for practice change in community pharmacy. AB - BACKGROUND: Community pharmacy practice in Australia is changing and Research and Development (R&D) in community pharmacy plays an important role in contributing to the changes. A range of Cognitive Pharmacy Services (CPS) were developed from R&D programs, yet their implementation has been minimal indicating slow practice change within community pharmacy. Given the vital role of R&D, little is known about the operation and the extent to which it has been effective in supporting practice change in community pharmacy. METHODS: In depth, semi-structured interviews were conducted with 27 key stakeholders in the pharmacy and healthcare system in Australia. All interviews were audio-recorded, transcribed ad verbatim and analysed using an inductive approach. RESULTS: Participants perceived that the R&D program has played an important role in the advent of CPS. Furthermore, they considered that evidence generated by the R&D projects is a critical influence on policy formulation, funding and implementation of CPS into practice. However, policy decisions and subsequent implementation are also influenced by other factors associated with context and facilitation which in turn foster or inhibit effective Knowledge Translation (KT) in the community pharmacy sector. CONCLUSION: While R&D programs have been viewed as essential for supporting changes in community pharmacy practice through development and funding of CPS, the overall impact has been small, as contemporary practice continues to be predominantly a dispensing model. Given the complexity and dynamic nature of the community pharmacy system, stakeholders must take into account the inter relationship between context, evidence and facilitation for successful KT in community pharmacy practice. PMID- 28922382 TI - Formal comment to Soler et al.: Great spotted cuckoo nestlings have no antipredatory effect on magpie or carrion crow host nests in southern Spain. PMID- 28922383 TI - Timing and adequate attendance of antenatal care visits among women in Ethiopia. AB - INTRODUCTION: Although ANC services are increasingly available to women in low and middle-income countries, their inadequate use persists. This suggests a misalignment between aims of the services and maternal beliefs and circumstances. Owing to the dearth of studies examining the timing and adequacy of content of care, this current study aims to investigate the timing and frequency of ANC visits in Ethiopia. METHODS: Data was obtained from the nationally representative 2011 Ethiopian Demographic and Health Survey (EDHS) which used a two-stage cluster sampling design to provide estimates for the health and demographic variables of interest for the country. Our study focused on a sample of 10,896 women with history of at least one childbirth event. Percentages of timing and adequacy of ANC visits were conducted across the levels of selected factors. Variables which were associated at 5% significance level were examined in the multivariable logistic regression model for association between timing and frequency of ANC visits and the explanatory variables while controlling for covariates. Furthermore, we presented the approach to estimate marginal effects involving covariate-adjusted logistic regression with corresponding 95%CI of delayed initiation of ANC visits and inadequate ANC attendance. The method used involved predicted probabilities added up to a weighted average showing the covariate distribution in the population. RESULTS: Results indicate that 66.3% of women did not use ANC at first trimester and 22.3% had ANC less than 4 visits. The results of this study were unique in that the association between delayed ANC visits and adequacy of ANC visits were examined using multivariable logistic model and the marginal effects using predicted probabilities. Results revealed that older age interval has higher odds of inadequate ANC visits. More so, type of place of residence was associated with delayed initiation of ANC visits, with rural women having the higher odds of delayed initiation of ANC visits (OR = 1.65; 95%CI: 1.26-2.18). However, rural women had 44% reduction in the odds of having inadequate ANC visits. In addition, multi-parity showed higher odds of delayed initiation of ANC visit when compared to the primigravida (OR = 2.20; 95%CI: 1.07-2.69). On the contrary, there was 36% reduction in the odds of multigravida having inadequate ANC visits when compared to the women who were primigravida. There were higher odds of inadequacy in ANC visits among women who engaged in sales/business, agriculture, skilled manual and other jobs when compared to women who currently do not work, after adjusting for covariates. From the predictive margins, assuming the distribution of all covariates remained the same among respondents, but everyone was aged 15-19 years, we would expect 71.8% delayed initiation of ANC visit. If everyone was aged 20-24years, 73.4%; 25 29years, 66.5%; 30-34years, 64.8%; 35-39years, 65.6%; 40-44years, 59.6% and 45 49years, we would expect 70.1% delayed initiation of ANC visit. If instead the distribution of age was as observed and for other covariates remained the same among respondents, but no respondent lived in the rural, we would expect about 61.4% delayed initiation of ANC visit; if however, everyone lived in the rural, and we would expect 71.6% delayed initiation in ANC visit. Model III revealed the predictive margins of all factors examined for delayed initiation for ANC visits, while Model IV presented the predictive marginal effects of the determinants of adequacy of ANC visits. CONCLUSION: The precise mechanism by which these factors affect ANC visits remain blurred at best. There may be factors on the demand side like the women's empowerment, financial support of the husband, knowledge of ANC visits in the context of timing, frequency and the expectations of ANC visits might be mediating the effects through the factors found associated in this study. Supply side factors like the quality of ANC services, skilled staff, and geographic location of the health centers also mediate their effects through the highlighted factors. Irrespective of the knowledge about the precise mechanism of action, policy makers could focus on improving women's empowerment, improving women's education, reducing wealth inequity and facilitating improved utilization of ANC through modifications on the supply side factors such as geographic location and focus on hard to reach women. PMID- 28922384 TI - Effects of salinity and drought on growth, ionic relations, compatible solutes and activation of antioxidant systems in oleander (Nerium oleander L.). AB - Nerium oleander is an ornamental species of high aesthetic value, grown in arid and semi-arid regions because of its drought tolerance, which is also considered as relatively resistant to salt; yet the biochemical and molecular mechanisms underlying oleander's stress tolerance remain largely unknown. To investigate these mechanisms, one-year-old oleander seedlings were exposed to 15 and 30 days of treatment with increasing salt concentrations, up to 800 mM NaCl, and to complete withholding of irrigation; growth parameters and biochemical markers characteristic of conserved stress-response pathways were then determined in stressed and control plants. Strong water deficit and salt stress both caused inhibition of growth, degradation of photosynthetic pigments, a slight (but statistically significant) increase in the leaf levels of specific osmolytes, and induction of oxidative stress-as indicated by the accumulation of malondialdehyde (MDA), a reliable oxidative stress marker-accompanied by increases in the levels of total phenolic compounds and antioxidant flavonoids and in the specific activities of ascorbate peroxidase (APX) and glutathione reductase (GR). High salinity, in addition, induced accumulation of Na+ and Cl- in roots and leaves and the activation of superoxide dismutase (SOD) and catalase (CAT) activities. Apart from anatomical adaptations that protect oleander from leaf dehydration at moderate levels of stress, our results indicate that tolerance of this species to salinity and water deficit is based on the constitutive accumulation in leaves of high concentrations of soluble carbohydrates and, to a lesser extent, of glycine betaine, and in the activation of the aforementioned antioxidant systems. Moreover, regarding specifically salt stress, mechanisms efficiently blocking transport of toxic ions from the roots to the aerial parts of the plant appear to contribute to a large extent to tolerance in Nerium oleander. PMID- 28922385 TI - Metabolomics analyses identify platelet activating factors and heme breakdown products as Lassa fever biomarkers. AB - Lassa fever afflicts tens of thousands of people in West Africa annually. The rapid progression of patients from febrile illness to fulminant syndrome and death provides incentive for development of clinical prognostic markers that can guide case management. The small molecule profile of serum from febrile patients triaged to the Viral Hemorrhagic Fever Ward at Kenema Government Hospital in Sierra Leone was assessed using untargeted Ultra High Performance Liquid Chromatography Mass Spectrometry. Physiological dysregulation resulting from Lassa virus (LASV) infection occurs at the small molecule level. Effects of LASV infection on pathways mediating blood coagulation, and lipid, amino acid, nucleic acid metabolism are manifest in changes in the levels of numerous metabolites in the circulation. Several compounds, including platelet activating factor (PAF), PAF-like molecules and products of heme breakdown emerged as candidates that may prove useful in diagnostic assays to inform better care of Lassa fever patients. PMID- 28922386 TI - New carboxamide derivatives bearing benzenesulphonamide as a selective COX-II inhibitor: Design, synthesis and structure-activity relationship. AB - Sixteen new carboxamide derivatives bearing substituted benzenesulphonamide moiety (7a-p) were synthesized by boric acid mediated amidation of appropriate benzenesulphonamide with 2-amino-4-picoline and tested for anti-inflammatory activity. One compound 7c showed more potent anti-inflammatory activity than celecoxib at 3 h in carrageenan-induced rat paw edema bioassay. Compounds 7g and 7k also showed good anti-inflammatory activity comparable to celecoxib. Compound 7c appeared selectivity index (COX-2/COX-1) better than celecoxib. Compound 7k appeared selectivity index (COX-2/COX-1) a little higher than the half of celecoxib while compound 7g is non-selective for COX-2. The LD50 of compounds 7c, 7g and 7k were comparable to celecoxib. PMID- 28922387 TI - Epistemic beliefs' role in promoting misperceptions and conspiracist ideation. AB - Widespread misperceptions undermine citizens' decision-making ability. Conclusions based on falsehoods and conspiracy theories are by definition flawed. This article demonstrates that individuals' epistemic beliefs-beliefs about the nature of knowledge and how one comes to know-have important implications for perception accuracy. The present study uses a series of large, nationally representative surveys of the U.S. population to produce valid and reliable measures of three aspects of epistemic beliefs: reliance on intuition for factual beliefs (Faith in Intuition for facts), importance of consistency between empirical evidence and beliefs (Need for evidence), and conviction that "facts" are politically constructed (Truth is political). Analyses confirm that these factors complement established predictors of misperception, substantively increasing our ability to explain both individuals' propensity to engage in conspiracist ideation, and their willingness to embrace falsehoods about high profile scientific and political issues. Individuals who view reality as a political construct are significantly more likely to embrace falsehoods, whereas those who believe that their conclusions must hew to available evidence tend to hold more accurate beliefs. Confidence in the ability to intuitively recognize truth is a uniquely important predictor of conspiracist ideation. Results suggest that efforts to counter misperceptions may be helped by promoting epistemic beliefs emphasizing the importance of evidence, cautious use of feelings, and trust that rigorous assessment by knowledgeable specialists is an effective guard against political manipulation. PMID- 28922388 TI - Expression and prognosis analyses of the Tob/BTG antiproliferative (APRO) protein family in human cancers. AB - BACKGROUND: Despite advances in early diagnosis and treatment, cancer remains the major cause of mortality in the world. The Tob/BTG antiproliferative (APRO) protein family is reported to participate in diverse human diseases. However, there's little known about their expression and prognostic values in most human cancers. METHODS: We performed a detailed cancer vs. normal analysis. The mRNA expression levels of APRO family in various cancers were analyzed via the Oncomine database. Moreover, the Kaplan-Meier Plotter and PrognScan databases were used to evaluate the prognostic values. RESULTS: We observed that the mRNA expression levels of TOB1-2 and BTG2 were decreased in most cancers compared with normal tissues, while BTG3 was upregulated in most cancers. In survival analyses based on Kaplan-Meier Plotter, TOB1, BTG1 and BTG4 showed significant associations with survival outcome of different subtypes of breast cancer. Decreased BTG2 was related with poor relapse free survival (RFS) in all subtypes of breast cancer. Especially, besides RFS, reduced BTG2 also indicated worse overall survival and distant metastasis free survival in breast cancer patients who were classified as luminal A. Significant prognostic effects of the whole APRO family were also found in lung adenocarcinoma, but not in squamous cell lung carcinoma. In addition, potential correlations between some APRO family members and survival outcomes were also observed in ovarian, colorectal and brain cancer. CONCLUSIONS: Some members of APRO family showed significant expression differences between cancer and normal tissues, and could be prognostic biomarkers for defined cancer types. PMID- 28922389 TI - Comprehensive metabolic characterization of serum osteocalcin action in a large non-diabetic sample. AB - Recent research suggested a metabolic implication of osteocalcin (OCN) in e.g. insulin sensitivity or steroid production. We used an untargeted metabolomics approach by analyzing plasma and urine samples of 931 participants using mass spectrometry to reveal further metabolic actions of OCN. Several detected relations between OCN and metabolites were strongly linked to renal function, however, a number of associations remained significant after adjustment for renal function. Intermediates of proline catabolism were associated with OCN reflecting the implication in bone metabolism. The association to kynurenine points towards a pro-inflammatory state with increasing OCN. Inverse relations with intermediates of branch-chained amino acid metabolism suggest a link to energy metabolism. Finally, urinary surrogate markers of smoking highlight its adverse effect on OCN metabolism. In conclusion, the present study provides a read-out of metabolic actions of OCN. However, most of the associations were weak arguing for a limited role of OCN in whole-body metabolism. PMID- 28922390 TI - Identifying novel transcription factors involved in the inflammatory response by using binding site motif scanning in genomic regions defined by histone acetylation. AB - The innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes. Because of that, a key challenge to delineating the regulators that control the temporal inflammatory response is that an innate immune regulator that may confer a selective advantage in the wild may be dispensable in the lab setting. In order to better understand the complete transcriptional response of primary macrophages to the bacterial endotoxin lipopolysaccharide (LPS), we designed a method that integrates temporally resolved gene expression and chromatin-accessibility measurements from mouse macrophages. By correlating changes in transcription factor binding site motif enrichment scores, calculated within regions of accessible chromatin, with the average temporal expression profile of a gene cluster, we screened for transcriptional factors that regulate the cluster. We have validated our predictions of LPS-stimulated transcriptional regulators using ChIP-seq data for three transcription factors with experimentally confirmed functions in innate immunity. In addition, we predict a role in the macrophage LPS response for several novel transcription factors that have not previously been implicated in immune responses. This method is applicable to any experimental situation where temporal gene expression and chromatin-accessibility data are available. PMID- 28922391 TI - Impedance biosensor for real-time monitoring and prediction of thrombotic individual profile in flowing blood. AB - A new biosensor for the real-time analysis of thrombus formation is reported. The fast and accurate monitoring of the individual thrombotic risk represents a challenge in cardiovascular diagnostics and in treatment of hemostatic diseases. Thrombus volume, as representative index of the related thrombotic status, is usually estimated with confocal microscope at the end of each in vitro experiment, without providing a useful behavioral information of the biological sample such as platelets adhesion and aggregation in flowing blood. Our device has been developed to work either independently or integrated with the microscopy system; thus, images of the fluorescently labeled platelets are acquired in real time during the whole blood perfusion, while the global electrical impedance of the blood sample is simultaneously monitored between a pair of specifically designed gold microelectrodes. Fusing optical and electrical data with a novel technique, the dynamic of thrombus formation events in flowing blood can be reconstructed in real-time, allowing an accurate extrapolation of the three dimensional shape and the spatial distribution of platelet thrombi forming and growing within artificial capillaries. This biosensor is accurate and it has been used to discriminate different hemostatic conditions and to identify weakening and detaching platelet aggregates. The results obtained appear compatible with those quantified with the traditional optical method. With advantages in terms of small size, user-friendliness and promptness of response, it is a promising device for the fast and automatic individual health monitoring at the Point of Care (POC). PMID- 28922392 TI - Facial thermal variations: A new marker of emotional arousal. AB - Functional infrared thermal imaging (fITI) is considered a promising method to measure emotional autonomic responses through facial cutaneous thermal variations. However, the facial thermal response to emotions still needs to be investigated within the framework of the dimensional approach to emotions. The main aim of this study was to assess how the facial thermal variations index the emotional arousal and valence dimensions of visual stimuli. Twenty-four participants were presented with three groups of standardized emotional pictures (unpleasant, neutral and pleasant) from the International Affective Picture System. Facial temperature was recorded at the nose tip, an important region of interest for facial thermal variations, and compared to electrodermal responses, a robust index of emotional arousal. Both types of responses were also compared to subjective ratings of pictures. An emotional arousal effect was found on the amplitude and latency of thermal responses and on the amplitude and frequency of electrodermal responses. The participants showed greater thermal and dermal responses to emotional than to neutral pictures with no difference between pleasant and unpleasant ones. Thermal responses correlated and the dermal ones tended to correlate with subjective ratings. Finally, in the emotional conditions compared to the neutral one, the frequency of simultaneous thermal and dermal responses increased while both thermal or dermal isolated responses decreased. Overall, this study brings convergent arguments to consider fITI as a promising method reflecting the arousal dimension of emotional stimulation and, consequently, as a credible alternative to the classical recording of electrodermal activity. The present research provides an original way to unveil autonomic implication in emotional processes and opens new perspectives to measure them in touchless conditions. PMID- 28922393 TI - A set of nutrient limitations trigger yeast cell death in a nitrogen-dependent manner during wine alcoholic fermentation. AB - Yeast cell death can occur during wine alcoholic fermentation. It is generally considered to result from ethanol stress that impacts membrane integrity. This cell death mainly occurs when grape musts processing reduces lipid availability, resulting in weaker membrane resistance to ethanol. However the mechanisms underlying cell death in these conditions remain unclear. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a given nutrient limitation and thus survive starvation. We show here that a set of micronutrients (oleic acid, ergosterol, pantothenic acid and nicotinic acid) in low, growth-restricting concentrations trigger cell death in alcoholic fermentation when nitrogen level is high. We provide evidence that nitrogen signaling is involved in cell death and that either SCH9 deletion or Tor inhibition prevent cell death in several types of micronutrient limitation. Under such limitations, yeast cells fail to acquire any stress resistance and are unable to store glycogen. Unexpectedly, transcriptome analyses did not reveal any major changes in stress genes expression, suggesting that post-transcriptional events critical for stress response were not triggered by micronutrient starvation. Our data point to the fact that yeast cell death results from yeast inability to trigger an appropriate stress response under some conditions of nutrient limitations most likely not encountered by yeast in the wild. Our conclusions provide a novel frame for considering both cell death and the management of nutrients during alcoholic fermentation. PMID- 28922394 TI - Sequence features of viral and human Internal Ribosome Entry Sites predictive of their activity. AB - Translation of mRNAs through Internal Ribosome Entry Sites (IRESs) has emerged as a prominent mechanism of cellular and viral initiation. It supports cap independent translation of select cellular genes under normal conditions, and in conditions when cap-dependent translation is inhibited. IRES structure and sequence are believed to be involved in this process. However due to the small number of IRESs known, there have been no systematic investigations of the determinants of IRES activity. With the recent discovery of thousands of novel IRESs in human and viruses, the next challenge is to decipher the sequence determinants of IRES activity. We present the first in-depth computational analysis of a large body of IRESs, exploring RNA sequence features predictive of IRES activity. We identified predictive k-mer features resembling IRES trans acting factor (ITAF) binding motifs across human and viral IRESs, and found that their effect on expression depends on their sequence, number and position. Our results also suggest that the architecture of retroviral IRESs differs from that of other viruses, presumably due to their exposure to the nuclear environment. Finally, we measured IRES activity of synthetically designed sequences to confirm our prediction of increasing activity as a function of the number of short IRES elements. PMID- 28922395 TI - An analysis of equine round pen training videos posted online: Differences between amateur and professional trainers. AB - Natural Horsemanship is popular among many amateur and professional trainers and as such, has been the subject of recent scientific enquiry. One method commonly adopted by Natural Horsemanship (NH) trainers is that of round pen training (RPT). RPT sessions are usually split into a series of bouts; each including two phases: chasing/flight and chasing offset/flight offset. However, NH training styles are heterogeneous. This study investigated online videos of RPT to explore the characteristics of RPT sessions and test for differences in techniques and outcomes between amateurs and professionals (the latter being defined as those with accompanying online materials that promote clinics, merchandise or a service to the public). From more than 300 candidate videos, we selected sample files for individual amateur (n = 24) and professional (n = 21) trainers. Inclusion criteria were: training at liberty in a Round Pen; more than one bout and good quality video. Sessions or portions of sessions were excluded if the trainer attached equipment, such as a lunge line, directly to the horse or the horse was saddled, mounted or ridden. The number of bouts and duration of each chasing and non-chasing phase were recorded, and the duration of each RPT session was calculated. General weighted regression analysis revealed that, when compared with amateurs, professionals showed fewer arm movements per bout (p<0.05). Poisson regression analysis showed that professionals spent more time looking up at their horses, when transitioning between gaits, than amateurs did (p<0.05). The probability of horses following the trainer was not significantly associated with amount of chasing, regardless of category. Given that, according to some practitioners, the following response is a goal of RPT, this result may prompt caution in those inclined to give chase. The horses handled by professionals showed fewer conflict behaviours (e.g. kicking, biting, stomping, head-tossing, defecating, bucking and attempting to escape), and fewer oral and head movements (e.g. head-lowering, licking and chewing) than those horses handled by amateurs Overall, these findings highlight the need for selectivity when using the internet as an educational source and the importance of trainer skill and excellent timing when using negative reinforcement in horse training. PMID- 28922397 TI - Acute exposure to blue wavelength light during memory consolidation improves verbal memory performance. AB - Acute exposure to light within the blue wavelengths has been shown to enhance alertness and vigilance, and lead to improved speed on reaction time tasks, possibly due to activation of the noradrenergic system. It remains unclear, however, whether the effects of blue light extend beyond simple alertness processes to also enhance other aspects of cognition, such as memory performance. The aim of this study was to investigate the effects of a thirty minute pulse of blue light versus placebo (amber light) exposure in healthy normally rested individuals in the morning during verbal memory consolidation (i.e., 1.5 hours after memory acquisition) using an abbreviated version of the California Verbal Learning Test (CVLT-II). At delayed recall, individuals who received blue light (n = 12) during the consolidation period showed significantly better long-delay verbal recall than individuals who received amber light exposure (n = 18), while controlling for the effects of general intelligence, depressive symptoms and habitual wake time. These findings extend previous work demonstrating the effect of blue light on brain activation and alertness to further demonstrate its effectiveness at facilitating better memory consolidation and subsequent retention of verbal material. Although preliminary, these findings point to a potential application of blue wavelength light to optimize memory performance in healthy populations. It remains to be determined whether blue light exposure may also enhance performance in clinical populations with memory deficits. PMID- 28922396 TI - Biochemical and immunological characterization of a novel monoclonal antibody against mouse leukotriene B4 receptor 1. AB - Leukotriene B4 (LTB4) receptor 1 (BLT1) is a G protein-coupled receptor expressed in various leukocyte subsets; however, the precise expression of mouse BLT1 (mBLT1) has not been reported because a mBLT1 monoclonal antibody (mAb) has not been available. In this study, we present the successful establishment of a hybridoma cell line (clone 7A8) that produces a high-affinity mAb for mBLT1 by direct immunization of BLT1-deficient mice with mBLT1-overexpressing cells. The specificity of clone 7A8 was confirmed using mBLT1-overexpressing cells and mouse peripheral blood leukocytes that endogenously express BLT1. Clone 7A8 did not cross-react with human BLT1 or other G protein-coupled receptors, including human chemokine (C-X-C motif) receptor 4. The 7A8 mAb binds to the second extracellular loop of mBLT1 and did not affect LTB4 binding or intracellular calcium mobilization by LTB4. The 7A8 mAb positively stained Gr-1-positive granulocytes, CD11b-positive granulocytes/monocytes, F4/80-positive monocytes, CCR2-high and CCR2-low monocyte subsets in the peripheral blood and a CD4-positive T cell subset, Th1 cells differentiated in vitro from naive CD4-positive T cells. This mAb was able to detect Gr-1-positive granulocytes and monocytes in the spleens of naive mice by immunohistochemistry. Finally, intraperitoneal administration of 7A8 mAb depleted granulocytes and monocytes in the peripheral blood. We have therefore succeeded in generating a high-affinity anti-mBLT1 mAb that is useful for analyzing mBLT1 expression in vitro and in vivo. PMID- 28922398 TI - Role of the P2 residue of human alpha 1-antitrypsin in determining target protease specificity. AB - Alpha 1-antitrypsin (A1AT) is a serine protease inhibitor that mainly inhibits neutrophil elastase in the lungs. A variant of A1AT at the P1 position with methionine 358 to arginine (A1AT-Pittsburgh) is a rapid inhibitor of thrombin with greatly diminished anti-elastase activity. The P2 residue (position 357) of A1AT-Pittsburgh has been shown to play an important role in interactions with thrombin and kallikrein, but the role of P2 residue in wild-type A1AT has largely been unraveled. Here, we investigated the effects of P2 proline substitutions in wild-type A1AT on interactions with porcine pancreatic elastase (PPE) and human neutrophil elastase (HNE). The mutant A1AT proteins (P357A, P357D, P357K, P357L, P357N, P357S, and P357W) were less efficient than the wild-type A1AT at inhibiting PPE and HNE. Among the mutants, P357D did not form a complex with PPE, whereas P357L, P357N, and P357W showed significantly reduced complex formation with PPE. Surprisingly, mass spectrometry analysis revealed that P357D had two cleavage sites after the P9 alanine and the P3 isoleucine residues. Our results indicate that the size and negative charge of the R group of the P2 residue influence the interaction with elastases. Specifically, the negative charge at the P2 residue is disfavored and the resulting conformational changes in the reactive center loop upon interaction with PPE lead to cleavage at new sites. Overall, the results of this study demonstrate a previously unknown role for P2 residue in determining inhibitory specificity of A1AT. PMID- 28922399 TI - Probing eukaryotic cell mechanics via mesoscopic simulations. AB - Cell mechanics has proven to be important in many biological processes. Although there is a number of experimental techniques which allow us to study mechanical properties of cell, there is still a lack of understanding of the role each sub cellular component plays during cell deformations. We present a new mesoscopic particle-based eukaryotic cell model which explicitly describes cell membrane, nucleus and cytoskeleton. We employ Dissipative Particle Dynamics (DPD) method that provides us with the unified framework for modeling of a cell and its interactions in the flow. Data from micropipette aspiration experiments were used to define model parameters. The model was validated using data from microfluidic experiments. The validated model was then applied to study the impact of the sub cellular components on the cell viscoelastic response in micropipette aspiration and microfluidic experiments. PMID- 28922401 TI - Rab11 family expression in the human placenta: Localization at the maternal-fetal interface. AB - Rab proteins are a family of small GTPases involved in a variety of cellular processes. The Rab11 subfamily in particular directs key steps of intracellular functions involving vesicle trafficking of the endosomal recycling pathway. This Rab subfamily works through a series of effector proteins including the Rab11 FIPs (Rab11 Family-Interacting Proteins). While the Rab11 subfamily has been well characterized at the cellular level, its function within human organ systems is still being explored. In an effort to further study these proteins, we conducted a preliminary investigation of a subgroup of endosomal Rab proteins in a range of human cell lines by Western blotting. The results from this analysis indicated that Rab11a, Rab11c(Rab25) and Rab14 were expressed in a wide range of cell lines, including the human placental trophoblastic BeWo cell line. These findings encouraged us to further analyse the localization of these Rabs and their common effector protein, the Rab Coupling Protein (RCP), by immunofluorescence microscopy and to extend this work to normal human placental tissue. The placenta is a highly active exchange interface, facilitating transfer between mother and fetus during pregnancy. As Rab11 proteins are closely involved in transcytosis we hypothesized that the placenta would be an interesting human tissue model system for Rab investigation. By immunofluorescence microscopy, Rab11a, Rab11c(Rab25), Rab14 as well as their common FIP effector RCP showed prominent expression in the placental cell lines. We also identified the expression of these proteins in human placental lysates by Western blot analysis. Further, via fluorescent immunohistochemistry, we noted abundant localization of these proteins within key functional areas of primary human placental tissues, namely the outer syncytial layer of placental villous tissue and the endothelia of fetal blood vessels. Overall these findings highlight the expression of the Rab11 family within the human placenta, with novel localization at the maternal-fetal interface. PMID- 28922403 TI - The declining interest in an academic career. AB - There is increasing evidence that science & engineering PhD students lose interest in an academic career over the course of graduate training. It is not clear, however, whether this decline reflects students being discouraged from pursuing an academic career by the challenges of obtaining a faculty job or whether it reflects more fundamental changes in students' career goals for reasons other than the academic labor market. We examine this question using a longitudinal survey that follows a cohort of PhD students from 39 U.S. research universities over the course of graduate training to document changes in career preferences and to explore potential drivers of such changes. We report two main results. First, although the vast majority of students start the PhD interested in an academic research career, over time 55% of all students remain interested while 25% lose interest entirely. In addition, 15% of all students were never interested in an academic career during their PhD program, while 5% become more interested. Thus, the declining interest in an academic career is not a general phenomenon across all PhD students, but rather reflects a divergence between those students who remain highly interested in an academic career and other students who are no longer interested in one. Second, we show that the decline we observe is not driven by expectations of academic job availability, nor by related factors such as postdoctoral requirements or the availability of research funding. Instead, the decline appears partly due to the misalignment between students' changing preferences for specific job attributes on the one hand, and the nature of the academic research career itself on the other. Changes in students' perceptions of their own research ability also play a role, while publications do not. We discuss implications for scientific labor markets, PhD career development programs, and science policy. PMID- 28922402 TI - New insights into the metastatic behavior after breast cancer surgery, according to well-established clinicopathological variables and molecular subtypes. AB - Despite advances in treatment, up to 30% of patients with early breast cancer (BC) experience distant disease relapse. However, a comprehensive understanding of tumor spread and site-specific recurrence patterns remains lacking. This retrospective case-control study included 103 consecutive patients with metastatic BC admitted to our institution (2000-2013). Cases were matched according to age, tumor biology, and clinicopathological features to 221 patients with non-metastatic BC (control group). The median follow-up period among the 324 eligible patients was 7.3 years. While relatively low values for sensitivity (71%) and specificity (56%) were found for axillary lymph node (ALN) involvement as an indicator of risk and pattern of distant relapse, nodal status remained the most powerful predictor of metastases (OR: 3.294; CL: 1.9-5.5). Rates of dissemination and metastatic efficiency differed according to molecular subtype. HER2-positive subtypes showed a stronger association with systemic spread (OR: 2.127; CL: 1.2-3.8) than other subgroups. Classification as Luminal or Non Luminal showed an increased risk of lung and distant nodal recurrence, and a decreased risk in bone metastases in the Non-Luminal group (OR: 2.9, 3.345, and 0.2, respectively). Tumors with HER2 overexpression had a significantly high risk for distant relapse (OR: 2.127) compared with HER2-negative tumors and also showed higher central nervous system (CNS) and lung metastatic potential (OR: 5.6 and 2.65, respectively) and low risk of bone disease progression (OR: 0.294). Furthermore, we found significant associations between biological profiles and sites of recurrence. A new process of clinical/diagnostic staging, including molecular subtypes, could better predict the likelihood of distant relapses and their anatomical location. Recognition and appreciation of clinically distinct molecular subtypes may assist in evaluation of the probability of distant relapses and their sites. Our analysis provides new insights into management of metastatic disease behavior, to lead to an optimal disease-tailored approach and appropriate follow-up. PMID- 28922405 TI - Assessment on induced genetic variability and divergence in the mutagenized lentil populations of microsperma and macrosperma cultivars developed using physical and chemical mutagenesis. AB - Induced mutagenesis was employed to create genetic variation in the lentil cultivars for yield improvement. The assessments were made on genetic variability, character association, and genetic divergence among the twelve mutagenized populations and one parent population of each of the two lentil cultivars, developed by single and combination treatments with gamma rays and hydrazine hydrates. Analysis of variance revealed significant inter-population differences for the observed quantitative phenotypic traits. The sample mean of six treatment populations in each of the cultivar exhibited highly superior quantitative phenotypic traits compared to their parent cultivars. The higher values of heritability and genetic advance with a high genotypic coefficient of variation for most of the yield attributing traits confirmed the possibilities of lentil yield improvement through phenotypic selection. The number of pods and seeds per plant appeared to be priority traits in selection for higher yield due to their strong direct association with yield. The cluster analysis divided the total populations into three divergent groups in each lentil cultivar with parent genotypes in an independent group showing the high efficacy of the mutagens. Considering the highest contribution of yield trait to the genetic divergence among the clustered population, it was confirmed that the mutagenic treatments created a wide heritable variation for the trait in the mutant populations. The selection of high yielding mutants from the mutant populations of DPL 62 (100 Gy) and Pant L 406 (100Gy + 0.1% HZ) in the subsequent generation is expected to give elite lentil cultivars. Also, hybridization between members of the divergent group would produce diverse segregants for crop improvement. Apart from this, the induced mutations at loci controlling economically important traits in the selected high yielding mutants have successfully contributed in diversifying the accessible lentil genetic base and will definitely be of immense value to the future lentil breeding programmes in India. PMID- 28922404 TI - Eco-epidemiological analysis of rickettsial seropositivity in rural areas of Colombia: A multilevel approach. AB - Rickettsiosis is a re-emergent infectious disease without epidemiological surveillance in Colombia. This disease is generally undiagnosed and several deadly outbreaks have been reported in the country in the last decade. The aim of this study is to analyze the eco-epidemiological aspects of rickettsial seropositivity in rural areas of Colombia where outbreaks of the disease were previously reported. A cross-sectional study, which included 597 people living in 246 households from nine hamlets in two municipalities of Colombia, was conducted from November 2015 to January 2016. The survey was conducted to collect sociodemographic and household characteristics (exposure) data. Blood samples were collected to determine the rickettsial seropositivity in humans, horses and dogs (IFA, cut-off = 1/128). In addition, infections by rickettsiae were detected in ticks from humans and animals by real-time PCR targeting gltA and ompA genes. Data was analyzed by weighted multilevel clog-log regression model using three levels (person, household and hamlets) and rickettsial seropositivity in humans was the main outcome. Overall prevalence of rickettsial seropositivity in humans was 25.62% (95%CI 22.11-29.12). Age in years (PR = 1.01 95%CI 1.01-1.02) and male sex (PR = 1.65 95%CI 1.43-1.90) were risk markers for rickettsial seropositivity. Working outdoors (PR = 1.20 95%CI 1.02-1.41), deforestation and forest fragmentation for agriculture use (PR = 1.75 95%CI 1.51-2.02), opossum in peridomiciliary area (PR = 1.56 95%CI 1.37-1.79) and a high proportion of seropositive domestic animals in the home (PR20-40% vs <20% = 2.28 95%CI 1.59 3.23 and PR>40% vs <20% = 3.14 95%CI 2.43-4.04) were associated with rickettsial seropositivity in humans. This study showed the presence of Rickettsia antibodies in human populations and domestic animals. In addition, different species of rickettsiae were detected in ticks collected from humans and animals. Our results highlighted the role of domestic animals as sentinels of rickettsial infection to identify areas at risk of transmission, and the importance of preventive measures aimed at curtailing deforestation and the fragmentation of forests as a way of reducing the risk of transmission of emergent and re-emergent pathogens. PMID- 28922400 TI - Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions. AB - Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-alpha-helical fold in one environment, assemble into all-beta sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Calpha atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer's amyloid beta and tau, Parkinson's alpha-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Abeta, tau, alphaS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions. PMID- 28922406 TI - Loss of liver-specific and sexually dimorphic gene expression by aryl hydrocarbon receptor activation in C57BL/6 mice. AB - The aryl hydrocarbon receptor (AhR) is a highly conserved transcription factor that mediates a broad spectrum of species-, strain-, sex-, age-, tissue-, and cell-specific responses elicited by structurally diverse ligands including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dose-dependent effects on liver specific and sexually dimorphic gene expression were examined in male and female mice gavaged with TCDD every 4 days for 28 or 92 days. RNA-seq data revealed the coordinated repression of 181 genes predominately expressed in the liver including albumin (3.7-fold), alpha-fibrinogen (14.5-fold), and beta-fibrinogen (17.4-fold) in males with corresponding AhR enrichment at 2 hr. Liver-specific genes exhibiting sexually dimorphic expression also demonstrated diminished divergence between sexes. For example, male-biased Gstp1 was repressed 3.0-fold in males and induced 4.5-fold in females, which were confirmed at the protein level. Disrupted regulation is consistent with impaired GHR-JAK2-STAT5 signaling and inhibition of female specific CUX2-mediated transcription as well as the repression of other key transcriptional regulators including Ghr, Stat5b, Bcl6, Hnf4a, Hnf6, Foxa1/2/3, and Zhx2. Attenuated liver-specific and sexually dimorphic gene expression was concurrent with the induction of fetal genes such as alpha-fetoprotein. The results suggest AhR activation causes the loss of liver specific and sexually dimorphic gene expression producing a functionally "de differentiated" hepatic phenotype. PMID- 28922407 TI - Segmental arterial stiffness in relation to B-type natriuretic peptide with preserved systolic heart function. AB - BACKGROUND: Central arterial stiffness has been shown to play a key role in cardiovascular disease. However, evidence regarding such arterial stiffness from various arterial segments in relation to B-type natriuretic peptide (BNP) remains elusive. METHODS: A total of 1255 participants (47.8% men; mean age: 62.6 +/- 12.3 [SD] years) with preserved left ventricular function (ejection fraction >=50%) and >=1 risk factors were consecutively studied. Arterial pulse wave velocity (PWV) by automatic device (VP-2000; Omron Healthcare) for heart-femoral (hf-PWV), brachial-ankle (ba-PWV), and heart-carotid (hc-PWV) segments were obtained and related to BNP concentrations (Abbott Diagnostics, Abbott Park, IL, USA). RESULTS: Subjects in the highest hf-PWV quartile were older and had worse renal function and higher blood pressure (all P < 0.05). Elevated PWV (m/s) was correlated with elevated BNP (pg/ml) (beta coefficient = 19.3, 12.4, 5.9 for hf PWV, ba-PWV, hc-PWV respectively, all p < 0.05). After accounting for clinical co variates and left ventricle mass index (LVMI), both hf-PWV and ba-PWV were correlated with higher BNP (beta coefficient = 8.3, 6.4 respectively, P < 0.01 for each). Adding both hf-PWV and ba-PWV to LVMI significantly expanded ROC in predicting abnormal BNP>100 pg/ml (both P < 0.01), but only hf-PWV presented significant integrated discrimination improvement to predict risk for BNP concentrations (0.7%, P = 0.029). CONCLUSION: A significant segmental PWV associated with biomarker BNP concentrations suggests that arterial stiffness is associated with myocardial damage. PMID- 28922408 TI - The role of the PI3K-Akt signaling pathway in the developmental competence of bovine oocytes. AB - The ovarian follicle encloses oocytes in a microenvironment throughout their growth and acquisition of competence. Evidence suggests a dynamic interplay among follicular cells and oocytes, since they are constantly exchanging "messages". We dissected bovine ovarian follicles and recovered follicular cells (FCs-granulosa and cumulus cells) and cumulus-oocyte complexes (COCs) to investigate whether the PI3K-Akt signaling pathway impacted oocyte quality. Following follicle rupture, COCs were individually selected for in vitro cultures to track the follicular cells based on oocyte competence to reach the blastocyst stage after parthenogenetic activation. Levels of PI3K-Akt signaling pathway components in FCs correlated with oocyte competence. This pathway is upregulated in FCs from follicles with high-quality oocytes that are able to reach the blastocyst stage, as indicated by decreased levels of PTEN and increased levels of the PTEN regulators bta-miR-494 and bta-miR-20a. Using PI3K-Akt responsive genes, we showed decreased FOXO3a levels and BAX levels in lower quality groups, indicating changes in cell cycle progression, oxidative response and apoptosis. Based on these results, the measurement of levels of PI3K-Akt pathway components in FCs from ovarian follicles carrying oocytes with distinct developmental competences is a useful tool to identify putative molecular pathways involved in the acquisition of oocyte competence. PMID- 28922409 TI - Purification and characterisation of the yeast plasma membrane ATP binding cassette transporter Pdr11p. AB - The ATP binding cassette (ABC) transporters Pdr11p and its paralog Aus1p are expressed under anaerobic growth conditions at the plasma membrane of the yeast Saccharomyces cerevisiae and are required for sterol uptake. However, the precise mechanism by which these ABC transporters facilitate sterol movement is unknown. In this study, an overexpression and purification procedure was developed with the aim to characterise the Pdr11p transporter. Engineering of Pdr11p variants fused at the C terminus with green fluorescent protein (Pdr11p-GFP) and containing a FLAG tag at the N terminus facilitated expression analysis and one step purification, respectively. The detergent-solubilised and purified protein displayed a stable ATPase activity with a broad pH optimum near 7.4. Mutagenesis of the conserved lysine to methionine (K788M) in the Walker A motif abolished ATP hydrolysis. Remarkably, and in contrast to Aus1p, ATPase activity of Pdr11p was insensitive to orthovanadate and not specifically stimulated by phosphatidylserine upon reconstitution into liposomes. Our results highlight distinct differences between Pdr11p and Aus1p and create an experimental basis for further biochemical studies of both ABC transporters to elucidate their function. PMID- 28922410 TI - Cesarean section without medical indication and risk of childhood asthma, and attenuation by breastfeeding. AB - BACKGROUND: Previous studies suggest that caesarean section (CS) may increase the risk of asthma in children, but none of them could preclude potential confounding effects of underlying medical indications for CS. We aim to assess the association between CS itself (without medical indications) and risk of childhood asthma. METHODS: We conducted a hospital-based case-control study on childhood asthma with 573 cases and 812 controls in Shanghai. Unconditional logistic regression models in SAS were employed to control for potential confounders. RESULTS: Our study found that CS without medical indication was significantly associated with elevated asthma risk (adjusted OR = 1.58 [95% CI 1.17-2.13]). However, this risk was attenuated in children fed by exclusive breastfeeding in the first six months after birth (adjusted OR = 1.39 [95% CI 0.92-2.10]). In contrast, the risk was more prominent in children with non-exclusive breastfeeding or bottle feeding (adjusted OR = 1.91 [95% CI 1.22-2.99]). CONCLUSIONS: CS without medical indication was associated with an increased risk of childhood asthma. Exclusive breastfeeding in infancy may attenuate this risk. PMID- 28922411 TI - Cytokine-induced killer cell delivery enhances the antitumor activity of oncolytic reovirus. AB - Oncolytic viruses (OV) have recently emerged as a promising therapeutic modality in cancer treatment. OV selectively infect and kill tumor cells, while sparing untransformed cells. The direct cytotoxic effects combined with the capacity to trigger an immune response make OV an appealing combination partner in the burgeoning field of cancer immunotherapy. One of the leading OV therapeutic candidates is the double-stranded RNA virus reovirus. In order to improve the oncolytic activity of reovirus and allow for systemic administration despite the prevalence of neutralizing antibodies, cytokine-induced killer (CIK) cells were explored as cell carriers for reovirus delivery. In this study, CIK cells were successfully loaded with reovirus ex vivo, and viral replication was limited in CIK cells. Confocal microscopy and flow cytometry demonstrated that CIK cells retained reovirus on the surface. Moreover, CIK cells could promote reovirus infection of tumor cells in the presence of neutralizing antibodies; meanwhile, cytotoxicity of CIK cells was increased after loading with reovirus. These findings support further investigation of reovirus and CIK combination for antitumor therapy. PMID- 28922412 TI - Walker occupancy has an impact on changing airborne bacterial communities in an underground pedestrian space, as small-dust particles increased with raising both temperature and humidity. AB - Although human occupancy is a source of airborne bacteria, the role of walkers on bacterial communities in built environments is poorly understood. Therefore, we visualized the impact of walker occupancy combined with other factors (temperature, humidity, atmospheric pressure, dust particles) on airborne bacterial features in the Sapporo underground pedestrian space in Sapporo, Japan. Air samples (n = 18; 4,800L/each sample) were collected at 8:00 h to 20:00 h on 3 days (regular sampling) and at early morning / late night (5:50 h to 7:50 h / 22:15 h to 24:45 h) on a day (baseline sampling), and the number of CFUs (colony forming units) OTUs (operational taxonomic units) and other factors were determined. The results revealed that temperature, humidity, and atmospheric pressure changed with weather. The number of walkers increased greatly in the morning and evening on each regular sampling day, although total walker numbers did not differ significantly among regular sampling days. A slight increase in small dust particles (0.3-0.5MUm) was observed on the days with higher temperature regardless of regular or baseline sampling. At the period on regular sampling, CFU levels varied irregularly among days, and the OTUs of 22-phylum types were observed, with the majority being from Firmicutes or Proteobacteria (gamma-), including Staphylococcus sp. derived from human individuals. The data obtained from regular samplings reveled that although no direct interaction of walker occupancy and airborne CFU and OTU features was observed upon Pearson's correlation analysis, cluster analysis indicated an obvious lineage consisting of walker occupancy, CFU numbers, OTU types, small dust particles, and seasonal factors (including temperature and humidity). Meanwhile, at the period on baseline sampling both walker and CFU numbers were similarly minimal. Taken together, the results revealed a positive correlation of walker occupancy with airborne bacteria that increased with increases in temperature and humidity in the presence of airborne small particles. Moreover, the results indicated that small dust particles at high temperature and humidity may be a crucial factor responsible for stabilizing the bacteria released from walkers in built environments. The findings presented herein advance our knowledge and understanding of the relationship between humans and bacterial communities in built environments, and will help improve public health in urban communities. PMID- 28922413 TI - Exploitation of stable nanostructures based on the mouse polyomavirus for development of a recombinant vaccine against porcine circovirus 2. AB - The aim of this study was to develop a suitable vaccine antigen against porcine circovirus 2 (PCV2), the causative agent of post-weaning multi-systemic wasting syndrome, which causes significant economic losses in swine breeding. Chimeric antigens containing PCV2b Cap protein sequences based on the mouse polyomavirus (MPyV) nanostructures were developed. First, universal vectors for baculovirus directed production of chimeric MPyV VLPs or pentamers of the major capsid protein, VP1, were designed for their exploitation as vaccines against other pathogens. Various strategies were employed based on: A) exposure of selected immunogenic epitopes on the surface of MPyV VLPs by insertion into a surface loop of the VP1 protein, B) insertion of foreign protein molecules inside the VLPs, or C) fusion of a foreign protein or its part with the C-terminus of VP1 protein, to form giant pentamers of a chimeric protein. We evaluated these strategies by developing a recombinant vaccine against porcine circovirus 2. All candidate vaccines induced the production of antibodies against the capsid protein of porcine circovirus after immunization of mice. The candidate vaccine, Var C, based on fusion of mouse polyomavirus and porcine circovirus capsid proteins, could induce the production of antibodies with the highest PCV2 neutralizing capacity. Its ability to induce the production of neutralization antibodies was verified after immunization of pigs. The advantage of this vaccine, apart from its efficient production in insect cells and easy purification, is that it represents a DIVA (differentiating infected from vaccinated animals) vaccine, which also induces an immune response against the mouse polyoma VP1 protein and is thus able to distinguish between vaccinated and naturally infected animals. PMID- 28922415 TI - Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis. AB - Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases. PMID- 28922416 TI - Multi-level computational methods for interdisciplinary research in the HathiTrust Digital Library. AB - We show how faceted search using a combination of traditional classification systems and mixed-membership topic models can go beyond keyword search to inform resource discovery, hypothesis formulation, and argument extraction for interdisciplinary research. Our test domain is the history and philosophy of scientific work on animal mind and cognition. The methods can be generalized to other research areas and ultimately support a system for semi-automatic identification of argument structures. We provide a case study for the application of the methods to the problem of identifying and extracting arguments about anthropomorphism during a critical period in the development of comparative psychology. We show how a combination of classification systems and mixed membership models trained over large digital libraries can inform resource discovery in this domain. Through a novel approach of "drill-down" topic modeling simultaneously reducing both the size of the corpus and the unit of analysis-we are able to reduce a large collection of fulltext volumes to a much smaller set of pages within six focal volumes containing arguments of interest to historians and philosophers of comparative psychology. The volumes identified in this way did not appear among the first ten results of the keyword search in the HathiTrust digital library and the pages bear the kind of "close reading" needed to generate original interpretations that is the heart of scholarly work in the humanities. Zooming back out, we provide a way to place the books onto a map of science originally constructed from very different data and for different purposes. The multilevel approach advances understanding of the intellectual and societal contexts in which writings are interpreted. PMID- 28922414 TI - A nonrandomized trial of vitamin D supplementation for Barrett's esophagus. AB - BACKGROUND: Vitamin D deficiency may increase esophageal cancer risk. Vitamin D affects genes regulating proliferation, apoptosis, and differentiation and induces the tumor suppressor 15-hydroxyprostaglandin dehydrogenase (PGDH) in other cancers. This nonrandomized interventional study assessed effects of vitamin D supplementation in Barrett's esophagus (BE). We hypothesized that vitamin D supplementation may have beneficial effects on gene expression including 15-PGDH in BE. METHODS: BE subjects with low grade or no dysplasia received vitamin D3 (cholecalciferol) 50,000 international units weekly plus a proton pump inhibitor for 12 weeks. Esophageal biopsies from normal plus metaplastic BE epithelium and blood samples were obtained before and after vitamin D supplementation. Serum 25-hydroxyvitamin D was measured to characterize vitamin D status. Esophageal gene expression was assessed using microarrays. RESULTS: 18 study subjects were evaluated. The baseline mean serum 25 hydroxyvitamin D level was 27 ng/mL (normal >=30 ng/mL). After vitamin D supplementation, 25-hydroxyvitamin D levels rose significantly (median increase of 31.6 ng/mL, p<0.001). There were no significant changes in gene expression from esophageal squamous or Barrett's epithelium including 15-PGDH after supplementation. CONCLUSION: BE subjects were vitamin D insufficient. Despite improved vitamin D status with supplementation, no significant alterations in gene expression profiles were noted. If vitamin D supplementation benefits BE, a longer duration or higher dose of supplementation may be needed. PMID- 28922417 TI - Lingering single-strand breaks trigger Rad51-independent homology-directed repair of collapsed replication forks in the polynucleotide kinase/phosphatase mutant of fission yeast. AB - The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Delta) cells of Schizosaccharomyces pombe. Here, we report that pnk1Delta cells have enhanced requirements for Rad3 (ATR/Mec1) and Chk1 checkpoint kinases, and the multi-BRCT domain protein Brc1 that binds phospho-histone H2A (gammaH2A) at damaged replication forks. The viability of pnk1Delta cells depends on Mre11 and Ctp1 (CtIP/Sae2) double-strand break (DSB) resection proteins, Rad52 DNA strand annealing protein, Mus81-Eme1 Holliday junction resolvase, and Rqh1 (BLM/WRN/Sgs1) DNA helicase. Coupled with increased sister chromatid recombination and Rad52 repair foci in pnk1Delta cells, these findings indicate that lingering SSBs in pnk1Delta cells trigger Rad51-independent homology directed repair of collapsed replication forks. From these data, we propose models for HDR-mediated tolerance of persistent SSBs with 3' phosphate in pnk1Delta cells. PMID- 28922418 TI - Detecting and confirming residual hotspots of lymphatic filariasis transmission in American Samoa 8 years after stopping mass drug administration. AB - The Global Programme to Eliminate Lymphatic Filariasis (LF) aims to eliminate the disease as a public health problem by 2020 by conducting mass drug administration (MDA) and controlling morbidity. Once elimination targets have been reached, surveillance is critical for ensuring that programmatic gains are sustained, and challenges include timely identification of residual areas of transmission. WHO guidelines encourage cost-efficient surveillance, such as integration with other population-based surveys. In American Samoa, where LF is caused by Wuchereria bancrofti, and Aedes polynesiensis is the main vector, the LF elimination program has made significant progress. Seven rounds of MDA (albendazole and diethycarbamazine) were completed from 2000 to 2006, and Transmission Assessment Surveys were passed in 2010/2011 and 2015. However, a seroprevalence study using an adult serum bank collected in 2010 detected two potential residual foci of transmission, with Og4C3 antigen (Ag) prevalence of 30.8% and 15.6%. We conducted a follow up study in 2014 to verify if transmission was truly occurring by comparing seroprevalence between residents of suspected hotspots and residents of other villages. In adults from non-hotspot villages (N = 602), seroprevalence of Ag (ICT or Og4C3), Bm14 antibody (Ab) and Wb123 Ab were 1.2% (95% CI 0.6-2.6%), 9.6% (95% CI 7.5%-12.3%), and 10.5% (95% CI 7.6-14.3%), respectively. Comparatively, adult residents of Fagali'i (N = 38) had significantly higher seroprevalence of Ag (26.9%, 95% CI 17.3-39.4%), Bm14 Ab (43.4%, 95% CI 32.4 55.0%), and Wb123 Ab 55.2% (95% CI 39.6-69.8%). Adult residents of Ili'ili/Vaitogi/Futiga (N = 113) also had higher prevalence of Ag and Ab, but differences were not statistically significant. The presence of transmission was demonstrated by 1.1% Ag prevalence (95% CI 0.2% to 3.1%) in 283 children aged 7 13 years who lived in one of the suspected hotspots; and microfilaraemia in four individuals, all of whom lived in the suspected hotspots, including a 9 year old child. Our results provide field evidence that integrating LF surveillance with other surveys is effective and feasible for identifying potential hotspots, and conducting surveillance at worksites provides an efficient method of sampling large populations of adults. PMID- 28922419 TI - Global services and support for children with developmental delays and disabilities: Bridging research and policy gaps. AB - Pamela Collins and colleagues explain the research and policy approaches needed globally to ensure children with developmental delays and disabilities are fully included in health and education services. PMID- 28922420 TI - Stable C and N isotope analysis of hair suggest undernourishment as a factor in the death of a mummified girl from late 19th century San Francisco, CA. AB - The chance discovery of a 1.5-3.5 years old mummified girl presents a unique opportunity to further our understanding of health and disease among children in 19th Century San Francisco. This study focuses on carbon and nitrogen stable isotope signatures in serial samples of hair that cover the last 14 months of her life. Results suggest an initial omnivorous diet with little input from marine resources or C4 plants. Around six months before death delta15N starts a steady increase, with a noticeable acceleration just two months before she died. The magnitude of delta15N change, +1.50/00 in total, is consistent with severe undernourishment or starvation. Cemetery records from this time period in San Francisco indicate high rates of infant and child mortality, mainly due to bacterial-borne infectious diseases, about two orders of magnitude higher than today. Taken together, we hypothesize that the girl died after a prolonged battle with such an illness. Results highlight the tremendous impacts that modern sanitation and medicine have had since the 1800s on human health and lifespan in the United States. PMID- 28922422 TI - Psychological effects of the intensified follow-up of the CEAwatch trial after treatment for colorectal cancer. AB - BACKGROUND: The aim of the study was to evaluate psychological effects of the state-of-art intensified follow-up protocol for colorectal cancer patients in the CEAwatch trial. METHOD: At two time points during the CEAwatch trial questionnaires regarding patients' attitude towards follow-up, patients' psychological functioning and patients' experiences and expectations were sent to participants by post. Linear mixed models were fitted to assess the influences and secular trends of the intensified follow-up on patients' attitude towards follow-up and psychological functioning. As secondary outcome, odds ratios were calculated using ordinal logistic mixed model to compare patients' experiences to their expectations, as well as their experiences at two different time points. RESULTS: No statistical significant effects of the intensified follow-up were found on patients' attitude towards the follow-up and psychological functioning variables. Patients had high expectations of the intensified follow-up and their experiences at the second time point were more positive compared to the scores at the first time point. CONCLUSION: The intensified follow-up protocol posed no adverse effects on patients' attitude towards follow-up and psychological functioning. In general, patients were more nervous and anxious at the start of the new follow-up protocol, had high expectations of the new follow-up protocol and were troubled by the nuisances of the blood sample testing. As they spent more time in the follow-up and became more adapted to it, the nervousness and anxiety decreased and the preference for the frequent blood test became high in replacement of conversations with the doctors. PMID- 28922421 TI - Effects of acute administration of donepezil or memantine on sleep-deprivation induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus). AB - The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions. PMID- 28922423 TI - Proprioception in patients with posterior cruciate ligament tears: A meta analysis comparison of reconstructed and contralateral normal knees. AB - Posterior cruciate ligament (PCL) reconstruction for patients with PCL insufficiency has been associated with postoperative improvements in proprioceptive function due to mechanoreceptor regeneration. However, it is unclear whether reconstructed PCL or contralateral normal knees have better proprioceptive function outcomes. This meta-analysis was designed to compare the proprioceptive function of reconstructed PCL or contralateral normal knees in patients with PCL insufficiency. All studies that compared proprioceptive function, as assessed with threshold to detect passive movement (TTDPM) or joint position sense (JPS) in PCL reconstructed or contralateral normal knees were included. JPS was calculated by reproducing passive positioning (RPP). Five studies met the inclusion/exclusion criteria for the meta-analysis. The proprioceptive function, defined as TTDPM (95% CI: 0.25 to 0.51 degrees ; P<0.00001) and RPP (95% CI: 0.19 to 0.45 degrees ; P<0.00001), was significantly different between the reconstructed PCL and contralateral normal knees. The mean difference in angle of error between the reconstructed PCL and contralateral normal knees was 0.06 degrees greater in TTDPM than by RPP. In addition, results from subgroup analyses, based on the starting angles and the moving directions of the knee, that evaluated TTDPM at 15 degrees flexion to 45 degrees extension, TTDPM at 45 degrees flexion to 110 degrees flexion, RPP in flexion, and RPP in extension demonstrated that mean angles of error were significantly greater, by 0.38 degrees (P = 0.0001), 0.36 degrees (P = 0.02), 0.36 degrees (P<0.00001), and 0.23 degrees (P = 0.04), respectively, in reconstructed PCL than in contralateral normal knees. The proprioceptive function of PCL reconstructed knees was decreased, compared with contralateral normal knees, as determined by both TTDPM and RPP. In addition, the amount of loss of proprioception was greater in TTDPM than in RPP, even with minute differences. Results from subgroup analysis, that evaluated the mean angles of error in moving directions through RPP, suggested that the moving direction of flexion has a significantly greater mean for angles of error than the moving direction of extension. Although the level of differences between various parameters were statistically significant, further studies are needed to determine whether the small differences (>1 degrees ) of the loss of proprioception are clinically relevant. PMID- 28922427 TI - Knowledge evolution in physics research: An analysis of bibliographic coupling networks. AB - Even as we advance the frontiers of physics knowledge, our understanding of how this knowledge evolves remains at the descriptive levels of Popper and Kuhn. Using the American Physical Society (APS) publications data sets, we ask in this paper how new knowledge is built upon old knowledge. We do so by constructing year-to-year bibliographic coupling networks, and identify in them validated communities that represent different research fields. We then visualize their evolutionary relationships in the form of alluvial diagrams, and show how they remain intact through APS journal splits. Quantitatively, we see that most fields undergo weak Popperian mixing, and it is rare for a field to remain isolated/undergo strong mixing. The sizes of fields obey a simple linear growth with recombination. We can also reliably predict the merging between two fields, but not for the considerably more complex splitting. Finally, we report a case study of two fields that underwent repeated merging and splitting around 1995, and how these Kuhnian events are correlated with breakthroughs on Bose-Einstein condensation (BEC), quantum teleportation, and slow light. This impact showed up quantitatively in the citations of the BEC field as a larger proportion of references from during and shortly after these events. PMID- 28922424 TI - Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites. AB - Proteases have been implicated in a variety of developmental processes during the malaria parasite lifecycle. In particular, invasion and egress of the parasite from the infected hepatocyte and erythrocyte, critically depend on protease activity. Although falcipain-1 was the first cysteine protease to be characterized in P. falciparum, its role in the lifecycle of the parasite has been the subject of some controversy. While an inhibitor of falcipain-1 blocked erythrocyte invasion by merozoites, two independent studies showed that falcipain 1 disruption did not affect growth of blood stage parasites. To shed light on the role of this protease over the entire Plasmodium lifecycle, we disrupted berghepain-1, its ortholog in the rodent parasite P. berghei. We found that this mutant parasite displays a pronounced delay in blood stage infection after inoculation of sporozoites. Experiments designed to pinpoint the defect of berghepain-1 knockout parasites found that it was not due to alterations in gliding motility, hepatocyte invasion or liver stage development and that injection of berghepain-1 knockout merosomes replicated the phenotype of delayed blood stage growth after sporozoite inoculation. We identified an additional role for berghepain-1 in preparing blood stage merozoites for infection of erythrocytes and observed that berghepain-1 knockout parasites exhibit a reticulocyte restriction, suggesting that berghepain-1 activity broadens the erythrocyte repertoire of the parasite. The lack of berghepain-1 expression resulted in a greater reduction in erythrocyte infectivity in hepatocyte-derived merozoites than it did in erythrocyte-derived merozoites. These observations indicate a role for berghepain-1 in processing ligands important for merozoite infectivity and provide evidence supporting the notion that hepatic and erythrocytic merozoites, though structurally similar, are not identical. PMID- 28922425 TI - Hypoxia-inducible factor-1 alpha as a therapeutic target for primary effusion lymphoma. AB - Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma with poor prognosis caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Previous studies have revealed that HIF-1alpha, which mediates much of the cellular response to hypoxia, plays an important role in life cycle of KSHV. KSHV infection promotes HIF-1alpha activity, and several KSHV genes are in turn activated by HIF-1alpha. In this study, we investigated the effects of knocking down HIF-1alpha in PELs. We observed that HIF-1alpha knockdown in each of two PEL lines leads to a reduction in both aerobic and anaerobic glycolysis as well as lipid biogenesis, indicating that HIF-1alpha is necessary for maintaining a metabolic state optimal for growth of PEL. We also found that HIF-1alpha suppression leads to a substantial reduction in activation of lytic KSHV genes, not only in hypoxia but also in normoxia. Moreover, HIF-1alpha knockdown led to a decrease in the expression of various KSHV latent genes, including LANA, vCyclin, kaposin, and miRNAs, under both normoxic and hypoxic conditions. These observations provide evidence that HIF-1alpha plays an important role in PEL even in normoxia. Consistent with these findings, we observed a significant inhibition of growth of PEL in normoxia upon HIF-1alpha suppression achieved by either HIF 1alpha knockdown or treatment with PX-478, a small molecule inhibitor of HIF 1alpha. These results offer further evidence that HIF-1alpha plays a critical role in the pathogenesis of PEL, and that inhibition of HIF-1alpha can be a potential therapeutic strategy in this disease. PMID- 28922426 TI - A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7-10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV. PMID- 28922428 TI - Diminished neutrophil extracellular trap (NET) formation is a novel innate immune deficiency induced by acute ethanol exposure in polymicrobial sepsis, which can be rescued by CXCL1. AB - Polymicrobial sepsis is the result of an exaggerated host immune response to bacterial pathogens. Animal models and human studies demonstrate that alcohol intoxication is a key risk factor for sepsis-induced mortality. Multiple chemokines, such as CXCL1, CXCL2 and CXCL5 are critical for neutrophil recruitment and proper function of neutrophils. However, it is not quite clear the mechanisms by which acute alcohol suppresses immune responses and whether alcohol-induced immunosuppression can be rescued by chemokines. Thus, we assessed whether acute ethanol challenge via gavage diminishes antibacterial host defense in a sepsis model using cecal ligation and puncture (CLP) and whether this immunosuppression can be rescued by exogenous CXCL1. We found acute alcohol intoxication augments mortality and enhances bacterial growth in mice following CLP. Ethanol exposure impairs critical antibacterial functions of mouse and human neutrophils including reactive oxygen species production, neutrophil extracellular trap (NET) formation, and NET-mediated killing in response to both Gram-negative (E. coli) and Gram-positive (Staphylococcus aureus) pathogens. As compared with WT (C57Bl/6) mice, CXCL1 knockout mice display early mortality following acute alcohol exposure followed by CLP. Recombinant CXCL1 (rCXCL1) in acute alcohol challenged CLP mice increases survival, enhances bacterial clearance, improves neutrophil recruitment, and enhances NET formation (NETosis). Recombinant CXCL1 (rCXCL1) administration also augments bacterial killing by alcohol-treated and E. coli- and S. aureus-infected neutrophils. Taken together, our data unveils novel mechanisms underlying acute alcohol-induced dysregulation of the immune responses in polymicrobial sepsis, and CXCL1 is a critical mediator to rescue alcohol-induced immune dysregulation in polymicrobial sepsis.